The experimental study of learning and plasticity has always been driven by an implicit question: how can physiological changes be adaptive and improve performance? For example, in Hebbian plasticity only synapses from presynaptic neurons that were active are changed, avoiding useless changes. Similarly, in dopamine-gated learning synapse changes depend on reward or lack thereof and do not change when everything is predictable. Within machine learning we can make the question of which changes are adaptive concrete: performance improves when changes correlate with the gradient of an objective function quantifying performance. This result is general for any system that improves through small changes. As such, physiology has always implicitly been seeking mechanisms that allow the brain to approximate gradients. Coming from this perspective we review the existing literature on plasticity-related mechanisms, and we show how these mechanisms relate to gradient estimation. We argue that gradients are a unifying idea to explain the many facets of neuronal plasticity. Abstract figure legend. This article is protected by copyright. All rights reserved.

In cognitive science, there is a tacit norm that phenomena such as cultural variation or synaesthesia are worthy examples of cognitive diversity that contribute to a better understanding of cognition, but that other forms of cognitive diversity (e.g., autism, attention deficit hyperactivity disorder/ADHD, and dyslexia) are primarily interesting only as examples of deficit, dysfunction, or impairment. This status quo is dehumanizing and holds back much-needed research. In contrast, the neurodiversity paradigm argues that such experiences are not necessarily deficits but rather are natural reflections of biodiversity. Here, we propose that neurodiversity is an important topic for future research in cognitive science. We discuss why cognitive science has thus far failed to engage with neurodiversity, why this gap presents both ethical and scientific challenges for the field, and, crucially, why cognitive science will produce better theories of human cognition if the field engages with neurodiversity in the same way that it values other forms of cognitive diversity. Doing so will not only empower marginalized researchers but will also present an opportunity for cognitive science to benefit from the unique contributions of neurodivergent researchers and communities.

From Puzzle to Progress: How Engaging With Neurodiversity Can Improve Cognitive Science

Neuroscientists rely on distributed spatio-temporal patterns of neural activity to understand how neural units contribute to cognitive functions and behavior. However, the extent to which neural activity reliably indicates a unit’s causal contribution to the behavior is not well understood. To address this issue, we provide a systematic multi-site perturbation framework that captures time-varying causal contributions of elements to a collectively produced outcome. Applying our framework to intuitive toy examples and artificial neuronal networks revealed that recorded activity patterns of neural elements may not be generally informative of their causal contribution due to activity transformations within a network. Overall, our findings emphasize the limitations of inferring causal mechanisms from neural activities and offer a rigorous lesioning framework for elucidating causal neural contributions.

When a neuron is driven beyond its threshold, it spikes. The fact that it does not communicate its continuous membrane potential is usually seen as a computational liability. Here we show that this spiking mechanism allows neurons to produce an unbiased estimate of their causal influence, and a way of approximating gradient descent-based learning. Importantly, neither activity of upstream neurons, which act as confounders, nor downstream non-linearities bias the results. We show how spiking enables neurons to solve causal estimation problems and that local plasticity can approximate gradient descent using spike discontinuity learning.

Deep neural networks implement a sequence of layer-by-layer operations that are each relatively easy to understand, but the resulting overall computation is generally difﬁcult to understand. We develop a simple idea for interpreting the layer-by-layer construction of useful representations: the role of each layer is to reformat information to reduce the “distance” to the target outputs. We formalize this intuitive idea of “distance” by leveraging recent work on metric representational similarity, and show how it leads to a rich space of geometric concepts. With this framework, the layer-wise computation implemented by a deep neural network can be viewed as a path in a high-dimensional representation space. We develop tools to characterize the geometry of these in terms of distances, angles, and geodesics. We then ask three sets of questions of residual networks trained on CIFAR-10: (1) how straight are paths, and how does each layer contribute towards the target? (2) how do these properties emerge over training? and (3) how similar are the paths taken by wider versus deeper networks? We conclude by sketching additional ways that this kind of representational geometry can be used to understand and interpret network training, or to prescriptively improve network architectures to suit a task.

Research on both natural intelligence (NI) and artificial intelligence (AI) generally assumes that the future resembles the past: intelligent agents or systems (what we call 'intelligence') observe and act on the world, then use this experience to act on future experiences of the same kind. We call this 'retrospective learning'. For example, an intelligence may see a set of pictures of objects, along with their names, and learn to name them. A retrospective learning intelligence would merely be able to name more pictures of the same objects. We argue that this is not what true intelligence is about. In many real world problems, both NIs and AIs will have to learn for an uncertain future. Both must update their internal models to be useful for future tasks, such as naming fundamentally new objects and using these objects effectively in a new context or to achieve previously unencountered goals. This ability to learn for the future we call 'prospective learning'. We articulate four relevant factors that jointly define prospective learning. Continual learning enables intelligences to remember those aspects of the past which it believes will be most useful in the future. Prospective constraints (including biases and priors) facilitate the intelligence finding general solutions that will be applicable to future problems. Curiosity motivates taking actions that inform future decision making, including in previously unmet situations. Causal estimation enables learning the structure of relations that guide choosing actions for specific outcomes, even when the specific action-outcome contingencies have never been observed before. We argue that a paradigm shift from retrospective to prospective learning will enable the communities that study intelligence to unite and overcome existing bottlenecks to more effectively explain, augment, and engineer intelligences.

Causal discovery (CD) from time-varying data is important in neuroscience, medicine, and machine learning. Techniques for CD include randomized experiments which are generally unbiased but expensive. It also includes algorithms like regression, matching, and Granger causality, which are only correct under strong assumptions made by human designers. How-ever, as we found in other areas of machine learning, humans are usually not quite right and human expertise is usually outperformed by data-driven approaches. Here we test if we can improve causal discovery in a data-driven way. We take a perturbable system with a large number of causal components (transistors), the MOS 6502 processor, acquire the causal ground truth, and learn the causal discovery procedure represented as a neural network. We ﬁnd that this procedure far outperforms human-designed causal discovery procedures, such as Mutual Information, LiNGAM, and Granger Causality both on MOS 6502 processor and the NetSim dataset which simulates functional magnetic resonance imaging (fMRI) results. We argue that the causality ﬁeld should consider, where possible, a supervised approach, where CD procedures are learned from large datasets with known causal relations instead of being designed by a human specialist. Our ﬁndings promise a new approach toward improving CD in neural and medical data and for the broader machine learning community.

Auditory perception requires categorizing sound sequences, such as speech, into classes, such as syllables. Auditory categorization depends not only on the sequences’ acoustic waveform, but also on the listener’s sensory uncertainty, any individual sound’s relevance to the task, and learning the temporal statistics of the acoustic environment. However, whether and how these factors interact to shape categorization is unknown. Here, we measured human participants’ performance on a multi-tone categorization task. Task-relevant tones contributed more to category choice than task-irrelevant tones, confirming that participants combined information about sensory features with task relevance. Conversely, poor estimates of tones’ task relevance or high sensory uncertainty adversely impacted category choice. Learning temporal statistics of sound category also affected decisions. The magnitude of this effect correlated inversely with participants’ relevance estimates. These results demonstrate that humans differentially weigh sensory uncertainty, task relevance and learning, providing a novel understanding of sensory decision-making under real-life behavioral demands.

The interplay of uncertainty, relevance and learning influences auditory categorization

As an organism develops, a zygote becomes the body through repeated cell division. This process produces the mitotic family tree, and cells specialize into their ultimate phenotype through interaction with other cells but also through the history of divisions. Biologists often cluster cells in the body into “cell types,” using e.g. their morphologies and molecular makeup. While morphomolecular cell type carries information about phenotype and function, there may be unknown, missing information available in this family tree. Emerging methods are making these lineage trees progressively observable. Here, using the complete mitotic family tree and connectome of the nematode C. elegans we ask about the role of cell-types and their family tree. We can thus evaluate how well we can predict synaptic connection with only cell-type information versus with the family tree lineage. We show that neglecting lineage can produce misleading insights into the mechanisms underlying neural wiring: underlying lineage can confound the effect of cell type. These results suggest that the concept of cell-type needs to be re-thought in the context of this emerging knowledge about cell lineage.

Causal discovery (CD) from time-varying data is important in neuroscience, medicine, and machine learning. Techniques for CD include randomized experiments which are generally unbiased but expensive. It also includes algorithms like regression, matching, and Granger causality, which are only correct under strong assumptions made by human designers. How-ever, as we found in other areas of machine learning, humans are usually not quite right and are usually outperformed by data-driven approaches. Here we test if we can improve causal discovery in a data-driven way. We take a system with a large number of causal components (transistors), the MOS 6502 processor, and meta-learn the causal discovery procedure rep-resented as a neural network. We ﬁnd that this procedure far outperforms human-designed causal discovery procedures, such as Mutual Information and Granger Causality. We argue that the causality ﬁeld should consider, where possible, a supervised approach, where CD procedures are learned from large datasets with known causal relations instead of being designed by a human specialist. Our ﬁndings promise a new approach toward CD in neural and medical data and for the broader machine learning community.

It has been hypothesized that some form of"modular"structure in artificial neural networks should be useful for learning, compositionality, and generalization. However, defining and quantifying modularity remains an open problem. We cast the problem of detecting functional modules into the problem of detecting clusters of similar-functioning units. This begs the question of what makes two units functionally similar. For this, we consider two broad families of methods: those that define similarity based on how units respond to structured variations in inputs ("upstream"), and those based on how variations in hidden unit activations affect outputs ("downstream"). We conduct an empirical study quantifying modularity of hidden layer representations of simple feedforward, fully connected networks, across a range of hyperparameters. For each model, we quantify pairwise associations between hidden units in each layer using a variety of both upstream and downstream measures, then cluster them by maximizing their"modularity score"using established tools from network science. We find two surprising results: first, dropout dramatically increased modularity, while other forms of weight regularization had more modest effects. Second, although we observe that there is usually good agreement about clusters within both upstream methods and downstream methods, there is little agreement about the cluster assignments across these two families of methods. This has important implications for representation-learning, as it suggests that finding modular representations that reflect structure in inputs (e.g. disentanglement) may be a distinct goal from learning modular representations that reflect structure in outputs (e.g. compositionality).

Clustering units in neural networks: upstream vs downstream information

Efficient neural codes naturally emerge through gradient descent learning

Object-based attention is a key component of the visual system, relevant for perception, learning, and memory. Neurons tuned to features of attended objects tend to be more active than those associated with non-attended objects. There is a rich set of models of this phenomenon in computational neuroscience. However, there is currently a divide between models that successfully match physiological data but can only deal with extremely simple problems and models of attention used in computer vision. For example, attention in the brain is known to depend on top-down processing, whereas self-attention in deep learning does not. Here, we propose an artificial neural network model of object-based attention that captures the way in which attention is both top-down and recurrent. Our attention model works well both on simple test stimuli, such as those using images of handwritten digits, and on more complex stimuli, such as natural images drawn from the COCO dataset. We find that our model replicates a range of findings from neuroscience, including attention-invariant tuning, inhibition of return, and attention-mediated scaling of activity. Understanding object based attention is both computationally interesting and a key problem for computational neuroscience.

Neuromatch Academy (https://neuromatch.io/academy) was designed as an online summer school to cover the basics of computational neuroscience in three weeks. The materials cover dominant and emerging computational neuroscience tools, how they complement one another, and specifically focus on how they can help us to better understand how the brain functions. An original component of the materials is its focus on modeling choices, i.e. how do we choose the right approach, how do we build models, and how can we evaluate models to determine if they provide real (meaningful) insight. This meta-modeling component of the instructional materials asks what questions can be answered by different techniques, and how to apply them meaningfully to get insight about brain function.

Neuromatch Academy: a 3-week, online summer school in computational neuroscience

Despite rapid advances in machine learning tools, the majority of neural decoding approaches still use traditional methods. Modern machine learning tools, which are versatile and easy to use, have the potential to significantly improve decoding performance. This tutorial describes how to effectively apply these algorithms for typical decoding problems. We provide descriptions, best practices, and code for applying common machine learning methods, including neural networks and gradient boosting. We also provide detailed comparisons of the performance of various methods at the task of decoding spiking activity in motor cortex, somatosensory cortex, and hippocampus. Modern methods, particularly neural networks and ensembles, significantly outperform traditional approaches, such as Wiener and Kalman filters. Improving the performance of neural decoding algorithms allows neuroscientists to better understand the information contained in a neural population and can help to advance engineering applications such as brain – machine interfaces. Our code package is available at github.com/kordinglab/neural_decoding.

A three-dimensional thalamocortical dataset for characterizing brain heterogeneity

A popular theory of perceptual processing holds that the brain learns both a generative model of the world and a paired recognition model using variational Bayesian inference. Most hypotheses of how the brain might learn these models assume that neurons in a population are conditionally independent given their common inputs. This simplification is likely not compatible with the type of local recurrence observed in the brain. Seeking an alternative that is compatible with complex interdependencies yet consistent with known biology, we argue here that the cortex may learn with an adversarial algorithm. Many observable symptoms of this approach would resemble known neural phenomena, including wake/sleep cycles and oscillations that vary in magnitude with surprise, and we describe how further predictions could be tested. We illustrate the idea on recurrent neural networks trained to model image and video datasets. This framework for learning brings variational inference closer to neuroscience and yields multiple testable hypotheses.

Population coding of conditional probability distributions in dorsal premotor cortex

Single reach plans in dorsal premotor cortex during a two-target task

The idea that lateral intraparietal cortex (LIP) integrates information for and against a decision, is one of the most popular models in neuroscience. However, a recent statistical analysis has suggested that LIP does not integrate information but that individual neurons’ activities jump. The result was based on a model comparison, which is often hard to interpret. There are two wor-ries that can render comparisons problematic. (1) Important as-pects of variance are contained in neither model. (2) The analysis is complicated, making it hard to verify. We thus followed up with a simple approach for model comparison: crossvalidation. We ﬁnd evidence that baseline ﬂuctuations describe much of the variance, which are properly modeled by neither the original paper’s drift-diﬀusion model, nor simple ramp or step models. Moreover, we ﬁnd that our straightforward analysis strategy prefers ramping models, both with and without trial-by-trial baseline ﬂuctuations. Our analysis, implementable in a few lines of code, suggests the importance of simple analyses.

Rate ﬂuctuations not steps dominate LIP activity during decision-making

Outsiders often perceive computational neuroscience as a coherent field that strives towards progressively better models of the brain. However, informal interactions with modelers often reveal wildly divergent goals. Here we explicitly address the diversity of goals that motivate and ultimately influence modeling efforts. We argue that a wide range of goals can be meaningfully taken to be of highest importance. A simple informal survey conducted on the Internet confirmed the diversity of goals in the community. We propose that many disagreements in evaluating the merit of computational research stem from differences in goals and not from the mechanics of constructing, describing, and validating models. We suggest that authors should state explicitly their goals when proposing models so that others can judge the quality of the research with respect to its goals.

Abbreviated title: Nonlinear M1 relation to motor output 3 4 Stephanie Naufel 1,2* , Joshua I. Glaser 3,4* , Konrad P. Kording 1,2,4-6 , Eric J. Perreault 1,3,4,5 Lee E. 5 Miller 1-5 6 7 1. Department of Biomedical Engineering, Northwestern University, Evanston, IL, 60208, USA 8 2. Department of Physiology, Northwestern University, Chicago, IL, 60611 USA 9 3. Interdepartmental Neuroscience Program, Northwestern University, Chicago, IL, 60611, 10 USA 11 4. Shirley Ryan AbilityLab (Formerly the Rehabilitation Institute of Chicago), Chicago, IL, 12 60611, USA 13 5. Department of Physical Medicine and Rehabilitation, Northwestern University, 14 Chicago, IL, 60611, USA 15 6. Department of Applied Mathematics, Northwestern University, Evanston, IL, 60208, USA 16 17 * These authors contributed equally to this work. 18 19 The authors declare no competing financial interests. 20 21 Acknowledgements: 22 The work was supported by NINDS grant R01NS053603 to LEM, a NSF Graduate Research 23 Fellowship under grant DGE-1324585 to SNN, and NEI grant F31 EY025532 to JIG. We would 24 like to thank CJ Heckman and Sara Solla for their valuable input. We also thank Chad Purnell 25 and Michael Gart for surgical assistance. 26 27 The current affiliations of Konrad P. Kording are as follows: 28 Department of Neuroscience, University of Pennsylvania, Philadelphia, IL, USA 29 Department of Biomedical Engineering, University of Pennsylvania, Philadelphia, IL, USA 30 31 Correspondence should be addressed to Dr. Lee E. Miller, Department of Physiology, Feinberg 32 School of Medicine, Northwestern University, 303 East Chicago Ave., Chicago, IL, 60611. E33 Mail: lm@northwestern.edu 34 35

1 A MUSCLE-ACTIVITY-DEPENDENT GAIN BETWEEN MOTOR CORTEX AND EMG 1 2 Abbreviated title : Nonlinear M 1 relation to motor output 3 4

Quasi-experimental causality in neuroscience and behavioural research

Current multielectrode techniques enable the simultaneous recording of spikes from hundreds of neurons. To study neural plasticity and network structure it is desirable to infer the underlying functional connectivity between the recorded neurons. Functional connectivity is defined by a large number of parameters, which characterize how each neuron influences the other neurons. A Bayesian approach that combines information from the recorded spikes (likelihood) with prior beliefs about functional connectivity (prior) can improve inference of these parameters and reduce overfitting. Recent studies have used likelihood functions based on the statistics of point-processes and a prior that captures the sparseness of neural connections. Here we include a prior that captures the empirical finding that interactions tend to vary smoothly in time. We show that this method can successfully infer connectivity patterns in simulated data and apply the algorithm to spike data recorded from primary motor (M1) and premotor (PMd) cortices of a monkey. Finally, we present a new approach to studying structure in inferred connections based on a Bayesian clustering algorithm. Groups of neurons in M1 and PMd show common patterns of input and output that may correspond to functional assemblies.

IEEE Transactions on Neural Systems and Rehabilitation Engineering

Bayesian Inference of Functional Connectivity and Network Structure From Spikes

When we see a friend talk we perceive the voice as coming from the mouth, but this percept can be fooled: a good puppeteer makes us perceive his voice as coming out of a puppet's mouth. In both cases, we infer a common cause to explain the correlation between the movement of the mouth and the sound of the voice. Numerous psychophysical studies have investigated how two cues are integrated into a common estimate of the position of the source. These position estimates are often consistent with an optimal Bayesian strategy. However, the brain must solve a harder problem than these models do: we are often surrounded by several sources of sensory stimulation. For example a car alarm may go off while someone is speaking. Given any two signals from different modalities, such as vision and audition, how does the brain decide whether they have a common cause or two independent causes -and hence whether they should be integrated or processed separately?

It is largely unknown how the properties of the auditory system relate to the properties of natural sounds. Here, we analyze representations of simulated neurons that have optimally sparse activity in response to spectro-temporal speech data. These representations share important properties with the auditory neurons determined in electrophysiological experiments.

Proceedings of the 2002 International Joint Conference on Neural Networks. IJCNN'02 (Cat. No.02CH37290)

Electrophysiological research on the properties of the apical dendrites of cortical deep layer pyramidal cells suggests that it acts, in addition to the soma, as a second site of synaptic integration. Each site integrates input from a subset of synapses and is able to generate regenerative potentials. The sites exchange information in stereotyped ways: Signals from the soma are transmitted to the apical dendrite via actively back-propagating dendritic action potentials. Slow regenerative calcium spikes transmit information from the apical dendrite to the soma. These calcium spikes lead to a strong and prolonged depolarization of the cell generating a burst of action potentials. This paper analyzes how the system learns if these calcium spikes trigger hebbian learning at active synapses. A cell is now described by two main variables the mean activity and the mean potential at the apical dendrite with the first variable defining the input to cells downstream and the latter what the cell learns. A system results where neurons learn to respond to those features that are correlated with activity on the higher layer, this property is similar to maximizing the mutual information between input and higher areas. Furthermore it learns invariances exploiting a spatial smoothness criterion.

Proceedings of the IEEE-INNS-ENNS International Joint Conference on Neural Networks. IJCNN 2000. Neural Computing: New Challenges and Perspectives for the New Millennium

Short-term synaptic plasticity and sensory adaptation as Bayesian inference

Catalyzing next-generation Artificial Intelligence through NeuroAI

Deep Learning (DL) is a surprisingly successful branch of machine learning. The success of DL is usually explained by focusing analysis on a particular recent algorithm and its traits. Instead, we propose that an explanation of the success of DL must look at the population of all algorithms in the field and how they have evolved over time. We argue that cultural evolution is a useful framework to explain the success of DL. In analogy to biology, we use `development' to mean the process converting the pseudocode or text description of an algorithm into a fully trained model. This includes writing the programming code, compiling and running the program, and training the model. If all parts of the process don't align well then the resultant model will be useless (if the code runs at all!). This is a constraint. A core component of evolutionary developmental biology is the concept of deconstraints -- these are modification to the developmental process that avoid complete failure by automatically accommodating changes in other components. We suggest that many important innovations in DL, from neural networks themselves to hyperparameter optimization and AutoGrad, can be seen as developmental deconstraints. These deconstraints can be very helpful to both the particular algorithm in how it handles challenges in implementation and the overall field of DL in how easy it is for new ideas to be generated. We highlight how our perspective can both advance DL and lead to new insights for evolutionary biology.

Nothing makes sense in deep learning, except in the light of evolution

Healthy young adults have a most preferred walking speed, step length, and step width that are close to energetically optimal. However, people can choose to walk with a multitude of different step lengths and widths, which can vary in both energy expenditure and preference. Here, we further investigate step length-width preferences and their relationship to energy expenditure. In line with a growing body of research, we hypothesized that people's preferred stepping patterns would not be fully explained by metabolic energy expenditure. To test this hypothesis, we used a two-alternative forced-choice paradigm. Fifteen participants walked on an oversized treadmill. Each trial, participants performed two prescribed stepping patterns and then chose the pattern they preferred. Over time, we adapted the choices such that there was 50% chance of choosing one pattern over another (equally preferred). If people's preferences are based solely on metabolic energy expenditure, then these equally preferred stepping patterns should have equal energy expenditure. In contrast, we found that energy expenditure differed across equally preferred step length-width patterns (p<0.001). On average, longer steps with higher energy expenditures were preferred over shorter and wider steps with lower energy expenditures (p<0.001). We also asked participants to rank a set of shorter, wider, and longer steps from most preferred to least preferred, and from most energy expended to least energy expended. Only 7/15 participants had the same rankings for their preferences and perceived energy expenditure. Our results suggest that energy expenditure is not the only factor influencing a person's conscious gait choices.

Energy expenditure does not solely explain step length-width choices during walking.

Peer review is an important part of science, aimed at providing expert and objective assessment of a manuscript. Because of many factors, including time constraints, unique expertise needs, and deference, many journals ask authors to suggest peer reviewers for their own manuscript. Previous researchers have found differing effects about this practice that might be inconclusive due to sample sizes. In this article, we analyze the association between author-suggested reviewers and review invitation, review scores, acceptance rates, and subjective review quality using a large dataset of close to 8K manuscripts from 46K authors and 21K reviewers from the journal PLOS ONE’s Neuroscience section. We found that all-author-suggested review panels increase the chances of acceptance by 20 percent points vs all-editor-suggested panels while agreeing to review less often. While PLOS ONE has since ended the practice of asking for suggested reviewers, many others still use them and perhaps should consider the results presented here.

Author-suggested reviewers rate manuscripts much more favorably: A cross-sectional analysis of the neuroscience section of PLOS ONE

Pitchers in baseball throw the ball with such high velocity and varying movement that batters only have a few hundred milliseconds to estimate whether to swing and how high to swing–contacting the ball too high or too low may produce hit balls that easily result in an out. Even before the pitcher releases the ball, the batter has some belief, or estimated distribution (a ‘prior’), of where the ball may land in the zone. Batters will update this prior belief with information from observing the pitch (the ‘likelihood’) to calculate their final estimate (the ‘posterior’). These models of behavior, called Bayesian models within movement science, predict that when players have better prior information, e.g. because they know the upcoming pitch due to ‘tipping’, that they will rely more on prior information; by contrast if their prior is less informative, e.g. because the pitch is very random as in the case of a knuckleball, they will instead rely more on the observation. Here we test these models using information from more than a million pitches from professional baseball. We find that batters integrate prior information with noisy observations to manage pitch uncertainty. Moreover, as predicted by a Bayesian model, a batter’s estimate of where to swing is biased towards the prior when the pitch is tipped and biased towards the likelihood in the case of pitches with high uncertainty. These results demonstrate that Bayesian ideas are relevant well beyond laboratory experiments and matter in the world of sports.

Bayesball: Bayesian Integration in Professional Baseball Batters

Many questions in neuroscience involve understanding of the responses of large populations of neurons. However, when dealing with large-scale neural activity, interpretation becomes difﬁcult, and comparisons between two animals, or across different time points becomes challenging. One major challenge that we face in modern neuroscience is that of correspondence e.g. we do not record the exact same neurons at the exact same times. Without some way to link two or more datasets, comparing different collections of neural activity patterns becomes impossible. Here, we describe approaches for leveraging shared latent structure across neural recordings to tackle this correspondence challenge. We review algorithms that map two datasets into a shared space where they can be directly compared, and argue that alignment is key for comparing high-dimensional neural activities across times, subsets of neurons, and individuals.

Comparing high-dimensional neural recordings by aligning their low-dimensional latent representations

Healthy young adults have a most preferred walking speed, step length, and step width that are close to energetically optimal. However, people can choose to walk with a multitude of different step lengths and widths, which can vary in both energy expenditure and preference. Here we further investigate step length-width preferences and their relationship to energy expenditure. In line with a growing body of research, we hypothesized that people’s preferred stepping patterns would not be fully explained by metabolic energy expenditure. To test this hypothesis we used a two-alternative forced-choice paradigm. Fifteen participants walked on an oversized treadmill. Each trial participants experienced two stepping patterns and then chose the pattern they preferred. Over time, we adapted the choices such that there was 50% chance of choosing one pattern over another (equally preferred). If people’s preferences are based solely on metabolic energy expenditure, then these equally preferred stepping patterns should have equal energy expenditure. We found that energy expenditure differed across equally preferred step length-width patterns (p < 0.001). On average, longer steps with higher energy expenditures were preferred over shorter and wider steps with lower energy expenditures (p < 0.001). We also asked participants to rank a set of shorter, wider, and longer steps from most preferred to least preferred, and from most energy expended to least energy expended. Only 7/15 participants had the same rankings for their preferences and perceived energy expenditure. Our results suggest that energy expenditure is not the only factor influencing a person’s conscious gait choices.

Energy expenditure does not explain step length-width choices during walking

Combining transcranial magnetic stimulation (TMS) with functional magnetic resonance imaging offers an unprecedented tool for studying how brain networks interact in vivo and how repetitive trains of TMS modulate those networks among patients diagnosed with affective disorders. TMS compliments neuroimaging by allowing the interrogation of causal control among brain circuits. Together with TMS, neuroimaging can provide valuable insight into the mechanisms underlying treatment effects and downstream circuit communication. Here we provide a background of the method, review relevant study designs, consider methodological and equipment options, and provide statistical recommendations. We conclude by describing emerging approaches that will extend these tools into exciting new applications. This article is categorized under: Psychology > Emotion and Motivation Psychology > Theory and Methods Neuroscience > Clinical Neuroscience.

Combining transcranial magnetic stimulation with functional magnetic resonance imaging for probing and modulating neural circuits relevant to affective disorders.

Abstract Neural networks are versatile tools for computation, having the ability to approximate a broad range of functions. An important problem in the theory of deep neural networks is expressivity; that is, we want to understand the functions that are computable by a given network. We study real, infinitely differentiable (smooth) hierarchical functions implemented by feedforward neural networks via composing simpler functions in two cases: (1) each constituent function of the composition has fewer inputs than the resulting function and (2) constituent functions are in the more specific yet prevalent form of a nonlinear univariate function (e.g., tanh) applied to a linear multivariate function. We establish that in each of these regimes, there exist nontrivial algebraic partial differential equations (PDEs) that are satisfied by the computed functions. These PDEs are purely in terms of the partial derivatives and are dependent only on the topology of the network. Conversely, we conjecture that such PDE constraints, once accompanied by appropriate nonsingularity conditions and perhaps certain inequalities involving partial derivatives, guarantee that the smooth function under consideration can be represented by the network. The conjecture is verified in numerous examples, including the case of tree architectures, which are of neuroscientific interest. Our approach is a step toward formulating an algebraic description of functional spaces associated with specific neural networks, and may provide useful new tools for constructing neural networks.

On PDE Characterization of Smooth Hierarchical Functions Computed by Neural Networks

Machine Learning and Surgical Outcomes Prediction: A Systematic Review.

For many psychiatric disorders, neuroimaging offers a potential for revolutionizing diagnosis, and potentially treatment, by providing access to preverbal mental processes. In their study"Machine learning of neural representations of suicide and emotion concepts identifies suicidal youth."1, Just and colleagues report that a Naive Bayes classifier, trained on voxelwise fMRI responses in human participants during the presentation of words and concepts related to mortality, can predict whether an individual had reported having suicidal ideations with a classification accuracy of 91%. Here we report a reappraisal of the methods employed by the authors, including re-analysis of the same data set, that calls into question the accuracy of the authors findings. The analysis is a case study in the dangers of overfitting in machine learning.

A critical reappraisal of predicting suicidal ideation using fMRI

Background The assessment of behaviors related to mental health typically relies on self-report data. Networked sensors embedded in smartphones can measure some behaviors objectively and continuously, with no ongoing effort. Objective This study aims to evaluate whether changes in phone sensor–derived behavioral features were associated with subsequent changes in mental health symptoms. Methods This longitudinal cohort study examined continuously collected phone sensor data and symptom severity data, collected every 3 weeks, over 16 weeks. The participants were recruited through national research registries. Primary outcomes included depression (8-item Patient Health Questionnaire), generalized anxiety (Generalized Anxiety Disorder 7-item scale), and social anxiety (Social Phobia Inventory) severity. Participants were adults who owned Android smartphones. Participants clustered into 4 groups: multiple comorbidities, depression and generalized anxiety, depression and social anxiety, and minimal symptoms. Results A total of 282 participants were aged 19-69 years (mean 38.9, SD 11.9 years), and the majority were female (223/282, 79.1%) and White participants (226/282, 80.1%). Among the multiple comorbidities group, depression changes were preceded by changes in GPS features (Time: r=−0.23, P=.02; Locations: r=−0.36, P<.001), exercise duration (r=0.39; P=.03) and use of active apps (r=−0.31; P<.001). Among the depression and anxiety groups, changes in depression were preceded by changes in GPS features for Locations (r=−0.20; P=.03) and Transitions (r=−0.21; P=.03). Depression changes were not related to subsequent sensor-derived features. The minimal symptoms group showed no significant relationships. There were no associations between sensor-based features and anxiety and minimal associations between sensor-based features and social anxiety. Conclusions Changes in sensor-derived behavioral features are associated with subsequent depression changes, but not vice versa, suggesting a directional relationship in which changes in sensed behaviors are associated with subsequent changes in symptoms.

Evaluation of Changes in Depression, Anxiety, and Social Anxiety Using Smartphone Sensor Features: Longitudinal Cohort Study

Typical systems neuroscience experiments correlate the activity of recorded neurons with controlled variations in stimuli or behavior. Such experiments are commonly taken to reveal that the neural activity is a ​representation of the stimulus or behavior. But what does this statement mean? Representation is a philosophical concept with a rich history going back at least to Aristotle. A careful reading of contemporary philosophy suggests four criteria of representation as they relate to neuroscience. First, a representation needs to correlate with the object in reality that it represents. Second, a representation needs to have some causal impact on behavior. Third, a representation should have its causal role exclusively -the absence of the representation should block the behavior it enables. Fourth, a representation should have teleological justification that specifies the cases in which it is a misrepresentation. We argue that not taking all four criteria seriously leads to statements that are neither neuroscientifically nor philosophically satisfying. We discuss how neuroscience can move towards a deeper notion of representation.

A Philosophical Understanding of Representation for Neuroscience

Physiological experiments have highlighted how the dendrites of biological neurons can nonlinearly process distributed synaptic inputs. However, it is unclear how aspects of a dendritic tree, such as its branched morphology or its repetition of presynaptic inputs, determine neural computation beyond this apparent nonlinearity. Here we use a simple model where the dendrite is implemented as a sequence of thresholded linear units. We manipulate the architecture of this model to investigate the impacts of binary branching constraints and repetition of synaptic inputs on neural computation. We find that models with such manipulations can perform well on machine learning tasks, such as Fashion MNIST or Extended MNIST. We find that model performance on these tasks is limited by binary tree branching and dendritic asymmetry and is improved by the repetition of synaptic inputs to different dendritic branches. These computational experiments further neuroscience theory on how different dendritic properties might determine neural computation of clearly defined tasks.

Might a Single Neuron Solve Interesting Machine Learning Problems Through Successive Computations on Its Dendritic Tree?

Employing DNA as a high-density data storage medium has paved the way for next-generation digital storage and biosensing technologies. However, the multipart architecture of current DNA-based recording techniques renders them inherently slow and incapable of recording fluctuating signals with sub-hour frequencies. To address this limitation, we developed a simplified system employing a single enzyme, terminal deoxynucleotidyl transferase (TdT), to transduce environmental signals into DNA. TdT adds nucleotides to the 3’ ends of single-stranded DNA (ssDNA) in a template-independent manner, selecting bases according to inherent preferences and environmental conditions. By characterizing TdT nucleotide selectivity under different conditions, we show that TdT can encode various physiologically relevant signals like Co2+, Ca2+, Zn2+ concentrations and temperature changes in vitro. Further, by considering the average rate of nucleotide incorporation, we show that the resulting ssDNA functions as a molecular ticker tape. With this method we accurately encode a temporal record of fluctuations in Co2+ concentration to within 1 minute over a 60-minute period. Finally, we engineer TdT to allosterically turn off in the presence of physiologically relevant concentration of calcium. We use this engineered TdT in concert with a reference TdT to develop a two-polymerase system capable of recording a single step change in Ca2+ signal to within 1 minute over a 60-minute period. This work expands the repertoire of DNA-based recording techniques by developing a novel DNA synthesis-based system that can record temporal environmental signals into DNA with minutes resolution.

Recording Temporal Signals with Minutes Resolution Using Enzymatic DNA Synthesis

The relationship between text message sentiment and self-reported depression.

A smartphone-based online system for fall detection with alert notifications and contextual information of real-life falls

Towards Democratizing and Automating Online Conferences: Lessons from the Neuromatch Conferences

Physiological experiments have highlighted how the dendrites of biological neurons can nonlinearly process distributed synaptic inputs. This is in stark contrast to units in artificial neural networks that are generally linear apart from an output nonlinearity. If dendritic trees can be nonlinear, biological neurons may have far more computational power than their artificial counterparts. Here we use a simple model where the dendrite is implemented as a sequence of thresholded linear units. We find that such dendrites can readily solve machine learning problems, such as MNIST or CIFAR-10, and that they benefit from having the same input onto several branches of the dendritic tree. This dendrite model is a special case of sparse network. This work suggests that popular neuron models may severely underestimate the computational power enabled by the biological fact of nonlinear dendrites and multiple synapses per pair of neurons. The next generation of artificial neural networks may significantly benefit from these biologically inspired dendritic architectures.

Can Single Neurons Solve MNIST? The Computational Power of Biological Dendritic Trees

Liquid biopsy (LB) technologies continue to improve in sensitivity, specificity, and multiplexing and can measure an ever growing library of disease biomarkers. However, clinical interpretation of the increasingly large sets of data these technologies generate remains a challenge. Machine learning is a popular approach to discover and detect signatures of disease. However, limited machine learning expertise in the LB field has kept the discipline from fully leveraging these tools and risks improper analyses and irreproducible results. In this paper, we develop a web-based automated machine learning tool tailored specifically for LB, where machine learning models can be built without the user's input. We also incorporate a differential privacy algorithm, designed to limit the effects of overfitting that can arise from users iteratively developing a panel with feedback from our platform. We validate our approach by performing a meta-analysis on 11 published LB datasets, and found that we had similar or better performance compared to those reported in the literature. Moreover, we show that our platform's performance improved when incorporating information from prior LB datasets, suggesting that this approach can continue to improve with increased access to LB data. Finally, we show that by using our platform the results achieved in the literature can be matched using 40% of the number of subjects in the training set, potentially reducing study cost and time. This self-improving and overfitting-resistant automatic machine learning platform provides a new standard that can be used to validate machine learning works in the LB field.

A web-based automated machine learning platform to analyze liquid biopsy data.

 BACKGROUND
 The assessment of behaviors related to mental health typically relies on self-report data. Networked sensors embedded in smartphones can measure some behaviors objectively and continuously, with no ongoing effort.
 
 OBJECTIVE
 This study aims to evaluate whether changes in phone sensor–derived behavioral features were associated with subsequent changes in mental health symptoms.
 
 METHODS
 This longitudinal cohort study examined continuously collected phone sensor data and symptom severity data, collected every 3 weeks, over 16 weeks. The participants were recruited through national research registries. Primary outcomes included depression (8-item Patient Health Questionnaire), generalized anxiety (Generalized Anxiety Disorder 7-item scale), and social anxiety (Social Phobia Inventory) severity. Participants were adults who owned Android smartphones. Participants clustered into 4 groups: multiple comorbidities, depression and generalized anxiety, depression and social anxiety, and minimal symptoms.
 
 RESULTS
 A total of 282 participants were aged 19-69 years (mean 38.9, SD 11.9 years), and the majority were female (223/282, 79.1%) and White participants (226/282, 80.1%). Among the multiple comorbidities group, depression changes were preceded by changes in GPS features (Time: r=−0.23, P=.02; Locations: r=−0.36, P<.001), exercise duration (r=0.39; P=.03) and use of active apps (r=−0.31; P<.001). Among the depression and anxiety groups, changes in depression were preceded by changes in GPS features for Locations (r=−0.20; P=.03) and Transitions (r=−0.21; P=.03). Depression changes were not related to subsequent sensor-derived features. The minimal symptoms group showed no significant relationships. There were no associations between sensor-based features and anxiety and minimal associations between sensor-based features and social anxiety.
 
 CONCLUSIONS
 Changes in sensor-derived behavioral features are associated with subsequent depression changes, but not vice versa, suggesting a directional relationship in which changes in sensed behaviors are associated with subsequent changes in symptoms.
 
 CLINICALTRIAL
 
Evaluation of Changes in Depression, Anxiety, and Social Anxiety Using Smartphone Sensor Features: Longitudinal Cohort Study (Preprint)

The COVID-19 outbreak has clear clinical and economic impacts, but also affects behaviors e.g. through social distancing, and may increase stress and anxiety. However, while case numbers are tracked daily, we know little about the psychological effects of the outbreak on individuals in the moment. Here we examine the psychological and behavioral shifts over the initial stages of the outbreak in the United States in an observational longitudinal study. Through GPS phone data we find that homestay is increasing, while being at work dropped precipitously. Using regular real-time experiential surveys we observe an overall increase in stress and mood levels which is similar in size to the weekend vs. weekday differences. As there is a significant difference between weekday and weekend mood and stress levels, this is an important decrease in wellbeing. For some, especially those affected by job loss, the mental health impact is severe.

Different scaling of linear models and deep learning in UKBiobank brain images versus machine-learning datasets

The number of biomedical publications is increasing exponentially every year. If we had the ability to access, manipulate, and link this information, we could extract knowledge that is perhaps hidden within the figures, text, and citations. In particular, the repositories made available by the PubMed and MEDLINE databases enable these kinds of applications at an unprecedented level. Examples of applications that can be built from this dataset range from predicting novel drug-drug interactions, classifying biomedical text data, searching specific oncological profiles, disambiguating author names, or automatically learning a biomedical ontology. Here, we describe Pubmed Parser (pubmed_parser), a software to mine Pubmed and MEDLINE efficiently. Pubmed Parser is built on top of Python and can therefore be integrated into a myriad of tools for machine learning such as scikit-learn and deep learning such as tensorflow and pytorch.

Pubmed Parser: A Python Parser for PubMed Open-Access XML Subset and MEDLINE XML Dataset XML Dataset

As neuroscientists we want to understand how causal interactions or mechanisms within the brain give rise to perception, cognition, and behavior. It is typical to estimate interaction effects from measured activity using statistical techniques such as functional connectivity, Granger Causality, or information flow, whose outcomes are often falsely treated as revealing mechanistic insight. Since these statistical techniques fit models to low-dimensional measurements from brains, they ignore the fact that brain activity is high-dimensional. Here we focus on the obvious confound of common inputs: the countless unobserved variables likely have more influence than the few observed ones. Any given observed correlation can be explained by an infinite set of causal models that take into account the unobserved variables. Therefore, correlations within massively undersampled measurements tell us little about mechanisms. We argue that these mis-inferences of causality from correlation are augmented by an implicit redefinition of words that suggest mechanisms, such as connectivity, causality, and flow.

The lure of misleading causal statements in functional connectivity research.

Abstract Within neuroscience, models have many roles, including driving hypotheses, making assumptions explicit, synthesizing knowledge, making experimental predictions, and facilitating applications to medicine. While specific modeling techniques are often taught, the process of constructing models for a given phenomenon or question is generally left opaque. Here, informed by guiding many students through modeling exercises at our summer school in CoSMo (Computational Sensory-Motor Neuroscience), we provide a practical 10-step breakdown of the modeling process. This approach makes choices and criteria more explicit and replicable. Experiment design has long been taught in neuroscience; the modeling process should receive the same attention.

Within computational neuroscience, informal interactions with modelers often reveal wildly divergent goals. In this opinion piece, we explicitly address the diversity of goals that motivate and ultimately influence modeling efforts. We argue that a wide range of goals can be meaningfully taken to be of highest importance. A simple informal survey conducted on the Internet confirmed the diversity of goals in the community. However, different priorities or preferences of individual researchers can lead to divergent model evaluation criteria. We propose that many disagreements in evaluating the merit of computational research stem from differences in goals and not from the mechanics of constructing, describing, and validating models. We suggest that authors state explicitly their goals when proposing models so that others can judge the quality of the research with respect to its stated goals.

Appreciating the variety of goals in computational neuroscience.

Randomized Controlled Trials (RCTs) are considered the gold standard for measuring the efficacy of medical interventions. However, RCTs are expensive, and use a limited population. Techniques to estimate the effects of stroke interventions from observational data that minimize confounding would be useful. We used regression discontinuity design (RDD), a technique well-established in economics, on the Get With The Guidelines-Stroke (GWTG-Stroke) data set. RDD, based on regression, measures the occurrence of a discontinuity in an outcome (e.g., odds of home discharge) as a function of an intervention (e.g., alteplase) that becomes significantly more likely when crossing the threshold of a continuous variable that determines that intervention (e.g., time from symptom onset, since alteplase is only given if symptom onset is less than e.g., 3 h). The technique assumes that patients near either side of a threshold (e.g., 2.99 and 3.01 h from symptom onset) are indistinguishable other than the use of the treatment. We compared outcomes of patients whose estimated onset to treatment time fell on either side of the treatment threshold for three cohorts of patients in the GWTG-Stroke data set. This data set spanned three different treatment thresholds for alteplase (3 h, 2003–2007, N = 1,869; 3 h, 2009–2016, N = 13,086, and 4.5 h, 2009–2016, N = 6,550). Patient demographic characteristics were overall similar across the treatment thresholds. We did not find evidence of a discontinuity in clinical outcome at any treatment threshold attributable to alteplase. Potential reasons for failing to find an effect include violation of some RDD assumptions in clinical care, large sample sizes required, or already-well-chosen treatment threshold.

Probing the Effective Treatment Thresholds for Alteplase in Acute Ischemic Stroke With Regression Discontinuity Designs

Neural microarchitecture is heterogeneous, varying both across and within brain regions. The consistent identification of regions of interest is one of the most critical aspects in examining neurocircuitry, as these structures serve as the vital landmarks with which to map brain pathways. Access to continuous, three-dimensional volumes that span multiple brain areas not only provides richer context for identifying such landmarks, but also enables a deeper probing of the microstructures within. Here, we describe a three-dimensional X-ray microtomography imaging dataset of a well-known and validated thalamocortical sample, encompassing a range of cortical and subcortical structures from the mouse brain . In doing so, we provide the field with access to a micron-scale anatomical imaging dataset ideal for studying heterogeneity of neural structure. Measurement(s) brain measurement Technology Type(s) micro-computed tomography Factor Type(s) brain region Sample Characteristic - Organism Mus musculus Machine-accessible metadata file describing the reported data: https://doi.org/10.6084/m9.figshare.13005527

Neural networks are versatile tools for computation, having the ability to approximate a broad range of functions. An important problem in the theory of deep neural networks is expressivity; that is, we want to understand the functions that are computable by a given network. We study real infinitely differentiable (smooth) hierarchical functions implemented by feedforward neural networks via composing simpler functions in two cases: 
1) each constituent function of the composition has fewer inputs than the resulting function; 
2) constituent functions are in the more specific yet prevalent form of a non-linear univariate function (e.g. tanh) applied to a linear multivariate function. 
We establish that in each of these regimes there exist non-trivial algebraic partial differential equations (PDEs), which are satisfied by the computed functions. These PDEs are purely in terms of the partial derivatives and are dependent only on the topology of the network. For compositions of polynomial functions, the algebraic PDEs yield non-trivial equations (of degrees dependent only on the architecture) in the ambient polynomial space that are satisfied on the associated functional varieties. Conversely, we conjecture that such PDE constraints, once accompanied by appropriate non-singularity conditions and perhaps certain inequalities involving partial derivatives, guarantee that the smooth function under consideration can be represented by the network. The conjecture is verified in numerous examples including the case of tree architectures which are of neuroscientific interest. Our approach is a step toward formulating an algebraic description of functional spaces associated with specific neural networks, and may provide new, useful tools for constructing neural networks.

PDE constraints on smooth hierarchical functions computed by neural networks

Large high-quality datasets of human body shape and kinematics lay the foundation for modelling and simulation approaches in computer vision, computer graphics, and biomechanics. Creating datasets that combine naturalistic recordings with high-accuracy data about ground truth body shape and pose is challenging because different motion recording systems are either optimized for one or the other. We address this issue in our dataset by using different hardware systems to record partially overlapping information and synchronized data that lend themselves to transfer learning. This multimodal dataset contains 9 hours of optical motion capture data, 17 hours of video data from 4 different points of view recorded by stationary and hand-held cameras, and 6.6 hours of inertial measurement units data recorded from 60 female and 30 male actors performing a collection of 21 everyday actions and sports movements. The processed motion capture data is also available as realistic 3D human meshes. We anticipate use of this dataset for research on human pose estimation, action recognition, motion modelling, gait analysis, and body shape reconstruction.

Neuromatch Academy: Teaching Computational Neuroscience with Global Accessibility

1 Massachusetts General Hospital 2 Harvard Medical School 3 University of Pennsylvania 4 Loyola University 5 University of Syracuse 6 Northwestern University 7 Sonat Consulting 8 Princeton University 9 NTT DATA Mathematical Systems Inc 10 605 11 Rockets of Awesome 12 Epoch Capital 13 University of Washington 14 IDLab-AIRO – Ghent University – imec 15 Clean Power Research 16 University of Trento 17 Columbia University 18 Georgia Tech 19 System1 Biosciences Inc 20 Research Institute for Agriculture, Fisheries and Food DOI: 10.21105/joss.01959

Pyglmnet: Python implementation of elastic-net regularized generalized linear models

Sensory learning in the mammalian cortex has long been hypothesized to involve the objective of variational inference (VI). Likely the most well-known algorithm for cortical VI is the Wake-Sleep algorithm (Hinton et al. 1995). However Wake-Sleep problematically assumes that neural activities are independent given lower-layers during generation. Here, we construct a VI system that is both compatible with neurobiology and avoids this assumption. The core of the system is a wake-sleep discriminator that classifies network states as inferred or self-generated. Inference connections learn by opposing this discriminator. This adversarial dynamic solves a core problem within VI, which is to match the distribution of stimulus-evoked (inference) activity to that of self-generated activity. Meanwhile, generative connections learn to predict lower-level activity as in standard VI. We implement this algorithm and show that it can successfully train the approximate inference network for generative models. Our proposed algorithm makes several biological predictions that can be tested. Most importantly, it predicts a teaching signal that is remarkably similar to known properties of the cholinergic system.

An adversarial algorithm for variational inference with a new role for acetylcholine

Scientific conferences and meetings have an important role in research, but they also suffer from a number of disadvantages: in particular, they can have a massive carbon footprint, they are time-consuming, and the high costs involved in attending can exclude many potential participants. The COVID-19 pandemic has led to the cancellation of many conferences, forcing the scientific community to explore online alternatives. Here, we report on our experiences of organizing an online neuroscience conference, neuromatch, that attracted some 3000 participants and featured two days of talks, debates, panel discussions, and one-on-one meetings facilitated by a matching algorithm. By offering most of the benefits of traditional conferences, several clear advantages, and with fewer of the downsides, we feel that online conferences have the potential to replace many legacy conferences.

The World Health Organization estimates that 15 million infants are born preterm every year [1]. This is of concern because these infants have a significant chance of having neuromotor or cognitive developmental delays due to cerebral palsy or other developmental issues [2]. Our long-term goal is to determine the roles emotion and movement play in the diagnosis of atypical infants. In this paper, we examine how automated emotion assessment may have potential to classify typically and atypically developing infants. We compare a custom supervised machine learning algorithm that utilizes individual and grouped facial features for infant emotion classification with a state-of-the-art neural network. Our results show that only three concavity features are needed for the concavity algorithm, and the custom algorithm performed with relatively similar performance to the neural network. Automatic sentiment labels used in tandem with infant movement kinematics would be further investigated to determine if emotion and movement are interdependent and predictive of an infant’s neurodevelopmental delay in disorders such as cerebral palsy.

2020 8th IEEE RAS/EMBS International Conference for Biomedical Robotics and Biomechatronics (BioRob)

Towards Automated Emotion Classification of Atypically and Typically Developing Infants

We can define a neural network that can learn to recognize objects in less than 100 lines of code. However, after training, it is characterized by millions of weights that contain the knowledge about many object types across visual scenes. Such networks are thus dramatically easier to understand in terms of the code that makes them than the resulting properties, such as tuning or connections. In analogy, we conjecture that rules for development and learning in brains may be far easier to understand than their resulting properties. The analogy suggests that neuroscience would benefit from a focus on learning and development.

The output of a neural network depends on its parameters in a highly nonlinear way, and it is widely assumed that a network's parameters cannot be identified from its outputs. Here, we show that in many cases it is possible to reconstruct the architecture, weights, and biases of a deep ReLU network given the ability to query the network. ReLU networks are piecewise linear and the boundaries between pieces correspond to inputs for which one of the ReLUs switches between inactive and active states. Thus, first-layer ReLUs can be identified (up to sign and scaling) based on the orientation of their associated hyperplanes. Later-layer ReLU boundaries bend when they cross earlier-layer boundaries and the extent of bending reveals the weights between them. Our algorithm uses this to identify the units in the network and weights connecting them (up to isomorphism). The fact that considerable parts of deep networks can be identified from their outputs has implications for security, neuroscience, and our understanding of neural networks.

Neurons are often probed by presenting a set of stimuli that vary along one dimension (e.g. color) and quantifying how this stimulus property affect neural activity. An open question, in particular where higher-level areas are involved, is how much tuning measured with one stimulus set reveals about tuning to a new set. Here we ask this question by estimating tuning to hue in macaque V4 from a set of natural scenes and a set of simple color stimuli. We found that hue tuning was strong in each dataset but was not correlated across the datasets, a finding expected if neurons have strong mixed selectivity. We also show how such mixed selectivity may be useful for transmitting information about multiple dimensions of the world. Our finding suggest that tuning in higher visual areas measured with simple stimuli may thus not generalize to naturalistic stimuli. New & Noteworthy Visual cortex is often investigated by mapping neural tuning to variables selected by the researcher such as color. How much does this approach tell us a neuron’s general ‘role’ in vision? Here we show that for strongly hue-tuned neurons in V4, estimating hue tuning from artificial stimuli does not reveal the hue tuning in the context of natural scenes. We show how models of optimal information processing suggest that such mixed selectivity maximizes information transmission.

Abstract Many systems neuroscientists want to understand neurons in terms of mediation; we want to understand how neurons are involved in the causal chain from stimulus to behavior. Unfortunately, most tools are inappropriate for that while our language takes mediation for granted. Here we discuss the contrast between our conceptual drive toward mediation and the difficulty of obtaining meaningful evidence.

Quantifying the role of neurons for behavior is a mediation question

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association

Automating Ischemic Stroke Subtype Classification Using Machine Learning and Natural Language Processing.

Limiting motor skill knowledge via incidental training protects against choking under pressure

Modern computer vision (CV) is often based on convolutional neural networks (CNNs) that excel at hierarchical feature extraction. The previous generation of CV approaches was often based on conditional random fields (CRFs) that excel at modeling flexible higher order interactions. As their benefits are complementary they are often combined. However, these approaches generally use mean-field approximations and thus, arguably, did not directly optimize the real problem. Here we revisit dual-decomposition-based approaches to CRF optimization, an alternative to the mean-field approximation. These algorithms can efficiently and exactly solve sub-problems and directly optimize a convex upper bound of the real problem, providing optimality certificates on the way. Our approach uses a novel fixed-point iteration algorithm which enjoys dual-monotonicity, dual-differentiability and high parallelism. The whole system, CRF and CNN can thus be efficiently trained using back-propagation. We demonstrate the effectiveness of our system on semantic image segmentation, showing consistent improvement over baseline models.

End-to-end Training of CNN-CRF via Differentiable Dual-Decomposition

In artificial neural networks trained with gradient descent, the weights used for processing stimuli are also used during backward passes to calculate gradients. For the real brain to approximate gradients, gradient information would have to be propagated separately, such that one set of synaptic weights is used for processing and another set is used for backward passes. This produces the so-called "weight transport problem" for biological models of learning, where the backward weights used to calculate gradients need to mirror the forward weights used to process stimuli. This weight transport problem has been considered so hard that popular proposals for biological learning assume that the backward weights are simply random, as in the feedback alignment algorithm. However, such random weights do not appear to work well for large networks. Here we show how the discontinuity introduced in a spiking system can lead to a solution to this problem. The resulting algorithm is a special case of an estimator used for causal inference in econometrics, regression discontinuity design. We show empirically that this algorithm rapidly makes the backward weights approximate the forward weights. As the backward weights become correct, this improves learning performance over feedback alignment on tasks such as Fashion-MNIST, SVHN, CIFAR-10 and VOC. Our results demonstrate that a simple learning rule in a spiking network can allow neurons to produce the right backward connections and thus solve the weight transport problem.

Intensive summer schools often provide strong students with career-changing impact, teaching them the art of the trade, letting them understand the logical underbelly of a field, and connecting them with an elite circle of peers and field leaders. Indeed, many professors attribute considerable aspects of their growth as a scientist to such schools. Such summer schools are an essential service to the community. A well-run summer school combines many of the aspects that jointly define students overall success. Eight years of organizing the annual two-week Computational Sensory-Motor Neuroscience (CoSMo, http://www.compneurosci.com/CoSMo) summer school has allowed us to experiment with different approaches and evaluate teaching outcomes, and we have seen rather clear patterns. Many new schools are started each year, only some move on to ongoing success, and the vast majority take a while until they reach very good ratings (our ratings are still increasing but approaching 10/10). Focusing on the student experience, we present a set of 10 simple rules to help you organize better summer schools that are more useful to students.

Ten Simple Rules for Organizing and Running a Successful Intensive Two-Week Course

Treatments often come with thresholds, e.g. we are given statins if our cholesterol is above a certain threshold. But which statin administration threshold maximizes our quality of life adjusted years? More generally, which threshold would optimize the average expected outcome? Regression discontinuity approaches are used to measure the local average treatment effect (LATE) and more recently also the Marginal Threshold Treatment Effect (MTTE), which shows how marginal changes in the threshold can affect the LATE. We extend this idea to define the problem of optimizing a policy threshold, i.e. selecting a threshold that optimizes the cumulative effect of the treatment on the treated. We present an estimator of the optimal threshold based on a constrained optimization framework. We show how to use machine learning (Gaussian process regression) for non-linear estimation. We also extend the estimation to a conservative threshold that is unlikely to produce harm, and we show how to include policy cost constraints. We apply these results to estimate an optimal tip-maximizing threshold for tip suggestions in taxi cabs Haggag (2014).

Formal models play a crucial role in advancing knowledge about brain function. However, there are many incoherencies and questions typically asked in the field: what are good model goals? Which modeling tools are appropriate for a given question? When can we compare models? How can we know if model choices are appropriate and justified? This highlights some of the complexity of the modeling enterprise and suggests that modeling should be regarded as a high-dimensional decision process. Unfortunately, there is currently a lack of structure, principles and guidelines regarding this decision process. Here, we propose an organization of the problem, model and outcome spaces by describing modeling as a decision process that links model space to model utility via a crucial action space, i.e. model selection. We then provide decision heuristics and guidelines for best practices to help the modeler in the decision process. We hope this will help both modelers and reader better appreciate different models as an exercise of fruitful complementarity rather than a battle over what’s the “right” model.

Emerging neuroimaging datasets (collected through modalities such as Electron Microscopy, Calcium Imaging, or X-ray Microtomography) describe the location and properties of neurons and their connections at unprecedented scale, promising new ways of understanding the brain. These modern imaging techniques used to interrogate the brain can quickly accumulate gigabytes to petabytes of structural brain imaging data. Unfortunately, many neuroscience laboratories lack the computational expertise or resources to work with datasets of this size: computer vision tools are often not portable or scalable, and there is considerable difficulty in reproducing results or extending methods. We developed an ecosystem of neuroimaging data analysis pipelines that utilize open source algorithms to create standardized modules and end-to-end optimized approaches. As exemplars we apply our tools to estimate synapse-level connectomes from electron microscopy data and cell distributions from X-ray microtomography data. To facilitate scientific discovery, we propose a generalized processing framework, that connects and extends existing open-source projects to provide large-scale data storage, reproducible algorithms, and workflow execution engines. Our accessible methods and pipelines demonstrate that approaches across multiple neuroimaging experiments can be standardized and applied to diverse datasets. The techniques developed are demonstrated on neuroimaging datasets, but may be applied to similar problems in other domains.

Toward A Reproducible, Scalable Framework for Processing Large Neuroimaging Datasets

Outlook A B Data : Brain : Potential Principles : Architecture : Learning Rules : Machine Learning Anatomy : Plasticity Rules : Systems

Keith EJ Tyo, Northwestern University, Evanston, USA k-tyo@northwestern.edu Namita J Bhan, Northwestern University, Evanston, USA Jon Strutz, Northwestern University, Evanston, USA Reza Kalhor, Harvard Medical School, Boston, MA, USA Joshua Glaser, University of Pennsylvania, Philadelphia, USA Edward Boyden, MIT, Cambridge, USA Konrad Kording, University of Pennsylvania, Philadelphia, USA George Church, Harvard Medical School, Boston, MA, USA

In recent years, deep learning has unlocked unprecedented success in various domains, especially in image, text, and speech processing. These breakthroughs may hold promise for neuroscience and especially for brain-imaging investigators who start to analyze thousands of participants. However, deep learning is only beneficial if the data have nonlinear relationships and if they are exploitable at currently available sample sizes. We systematically profiled the performance of deep models, kernel models, and linear models as a function of sample size on UK Biobank brain images against established machine learning references. On MNIST and Zalando Fashion, prediction accuracy consistently improved when escalating from linear models to shallow-nonlinear models, and further improved when switching to deep-nonlinear models. The more observations were available for model training, the greater the performance gain we saw. In contrast, using structural or functional brain scans, simple linear models performed on par with more complex, highly parameterized models in age/sex prediction across increasing sample sizes. In fact, linear models kept improving as the sample size approached ∼10,000 participants. Our results indicate that the increase in performance of linear models with additional data does not saturate at the limit of current feasibility. Yet, nonlinearities of common brain scans remain largely inaccessible to both kernel and deep learning methods at any examined scale.

Deep learning for brains?: Different linear and nonlinear scaling in UK Biobank brain images vs. machine-learning datasets

Marker-less video-based pose estimation promises to allow us to do movement science on existing video databases. We revisited the old question of how people synchronize their walking using real world data. We thus applied pose estimation to 348 video segments extracted from YouTube videos of people walking in cities. As in previous, more constrained, research, we find a tendency for pairs of people to walk in phase or in anti-phase with each other. Large video databases, along with pose-estimation algorithms, promise answers to many movement questions without experimentally acquiring new data.

Pose estimates from online videos show that side-by-side walkers synchronize movement under naturalistic conditions

Recording biological signals can be difficult in three-dimensional matrices, such as tissue. We present a DNA polymerase-based strategy that records temporal biosignals locally onto DNA to be read out later, which could obviate the need to extract information from tissue on the fly. We use a template-independent DNA polymerase, terminal deoxynucleotidyl transferase (TdT) that probabilistically adds dNTPs to single-stranded DNA (ssDNA) substrates without a template. We show that in vitro, the dNTP-incorporation preference of TdT changes with the presence of Co2+, Ca2+, Zn2+ and temperature. Extracting the signal profile over time is possible by examining the dNTP incorporation preference along the length of synthesized ssDNA strands like a molecular ticker tape. We call this TdT-based untemplated recording of temporal local environmental signals (TURTLES). We show that we can determine the time of Co2+ addition to within two minutes over a 60-minute period. Further, TURTLES has the capability to record multiple fluctuations. We can estimate the rise and fall of an input Co2+ pulse to within three minutes. TURTLES has at least 200-fold better temporal resolution than all previous DNA-based recording techniques.

The brain performs unsupervised learning and (perhaps) simultaneous supervised learning. This raises the question as to whether a hybrid of supervised and unsupervised methods will produce better learning. Inspired by the rich space of Hebbian learning rules, we set out to directly learn the unsupervised learning rule on local information that best augments a supervised signal. We present the Hebbian-augmented training algorithm (HAT) for combining gradient-based learning with an unsupervised rule on pre-synpatic activity, post-synaptic activities, and current weights. We test HAT’s effect on a simple problem (Fashion-MNIST) and find consistently higher performance than supervised learning alone. This finding provides empirical evidence that unsupervised learning on synaptic activities provides a strong signal that can be used to augment gradient-based methods. We further find that the meta-learned update rule is a time-varying function; thus, it is difficult to pinpoint an interpretable Hebbian update rule that aids in training. We do find that the meta-learner eventually degenerates into a non-Hebbian rule that preserves important weights so as not to disturb the learner’s convergence. 1 Prior Work and the Local Meta-Learning Setting Backpropagation achieves great performance in neural net optimization, but might not be biologically plausible because most problems are not explicitly phrased as classification with true labels, because neurons only know local signals (e.g. synaptic density, ACh levels, current), and because backpropagation uses the computational graph, a separate data structure with no known biological basis. Although some supervised training schemes are more biologically plausible (e.g. contrastive Hebbian learning[9] and equilibrium propagation[8]), it’s currently unknown whether the behavior of all neurons is accurately encapsulated by these models. We speculate that some local, unsupervised learning occurs in the brain and demonstrate that the addition of local, unsupervised rules to standard backpropagation actually improves the speed and robustness of learning. ∗Please find my most recent contact information at http://jeffreyscheng.com/. 33rd Conference on Neural Information Processing Systems (NeurIPS 2019), Vancouver, Canada.

Augmenting Supervised Learning by Meta-learning Unsupervised Local Rules

Whether one is delicately placing a contact lens on the surface of the eye or lifting a heavy weight from the floor, the motor system must produce a wide range of forces under different dynamical loads. How does the motor cortex, with neurons that have a limited activity range, function effectively under these widely varying conditions? In this study, we explored the interaction of activity in primary motor cortex (M1) and muscles (electromyograms, EMGs) of two male rhesus monkeys for wrist movements made during three tasks requiring different dynamical loads and forces. Despite traditionally providing adequate predictions in single tasks, in our experiments, a single linear model failed to account for the relation between M1 activity and EMG across conditions. However, a model with a gain parameter that increased with the target force remained accurate across forces and dynamical loads. Surprisingly, this model showed that a greater proportion of EMG changes were explained by the nonlinear gain than the linear mapping from M1. In addition to its theoretical implications, the strength of this nonlinearity has important implications for brain-computer interfaces (BCIs). If BCI decoders are to be used to control movement dynamics (including interaction forces) directly, they will need to be nonlinear and include training data from broad data sets to function effectively across tasks. Our study reinforces the need to investigate neural control of movement across a wide range of conditions to understand its basic characteristics as well as translational implications. NEW & NOTEWORTHY We explored the motor cortex-to-electromyogram (EMG) mapping across a wide range of forces and loading conditions, which we found to be highly nonlinear. A greater proportion of EMG was explained by a nonlinear gain than a linear mapping. This nonlinearity allows motor cortex to control the wide range of forces encountered in the real world. These results unify earlier observations and inform the next-generation brain-computer interfaces that will control movement dynamics and interaction forces.

Estimating the category and quality of interpersonal relationships from ubiquitous phone sensor data matters for studying mental well-being and social support. Prior work focused on using communication volume to estimate broad relationship categories, often with small samples. Here we contextualize communications by combining phone logs with demographic and location data to predict interpersonal relationship roles on a varied sample population using automated machine learning methods, producing better performance (F1 = 0.68) than using communication features alone (F1 = 0.62). We also explore the effect of age variation in the underlying training sample on interpersonal relationship prediction and find that models trained on younger subgroups, which is popular in the field via student participation and recruitment, generalize poorly to the wider population. Our results not only illustrate the value of using data across demographics, communication patterns and semantic locations for relationship prediction, but also underscore the importance of considering population heterogeneity in phone-based personal sensing studies.

Proceedings of the ACM on Interactive, Mobile, Wearable and Ubiquitous Technologies

During sensorimotor tasks, subjects use sensory feedback but also prior information. It is often assumed that the sensorimotor prior is just given by the experiment and that the details for acquiring this prior, e.g., the effector, are irrelevant. However, recent research has suggested that the construction of priors is nontrivial. To test if the sensorimotor details matter for the construction of a prior, we design two tasks which differ only in the effectors that subjects use to indicate their estimate. Both for a typical reaching setting and for an atypical wrist rotation setting, prior and feedback uncertainty matter as quantitatively predicted by Bayesian statistics. However, in violation of simple Bayesian models, the importance of the prior differs across effectors. Subjects overly rely on their prior in the typical reaching case compared to the wrist case. The brain is not naively Bayesian with a single and veridical prior.

It has been widely assumed that a neural network cannot be recovered from its outputs, as the network depends on its parameters in a highly nonlinear way. Here, we prove that in fact it is often possible to identify the architecture, weights, and biases of an unknown deep ReLU network by observing only its output. Every ReLU network defines a piecewise linear function, where the boundaries between linear regions correspond to inputs for which some neuron in the network switches between inactive and active ReLU states. By dissecting the set of region boundaries into components associated with particular neurons, we show both theoretically and empirically that it is possible to recover the weights of neurons and their arrangement within the network, up to isomorphism.

An infant’s risk of developing neuromotor impairment is primarily assessed through visual examination by specialized clinicians. Therefore, many infants at risk for impairment go undetected, particularly in under-resourced environments. There is thus a need to develop automated, clinical assessments based on quantitative measures from widely-available sources, such as video cameras. Here, we automatically extract body poses and movement kinematics from the videos of at-risk infants (N=19). For each infant, we calculate how much they deviate from a group of healthy infants (N=85 online videos) using Naïve Gaussian Bayesian Surprise. After pre-registering our Bayesian Surprise calculations, we find that infants that are at higher risk for impairments deviate considerably from the healthy group. Our simple method, provided as an open source toolkit, thus shows promise as the basis for an automated and low-cost assessment of risk based on video recordings.

The process through which neurons are labeled is a key methodological choice in measuring neuron morphology. However, little is known about how this choice may bias measurements. To quantify this bias we compare the extracted morphology of neurons collected from the same rodent species, experimental condition, gender distribution, age distribution, brain region and putative cell type, but obtained with 19 distinct staining methods. We found strong biases on measured features of morphology. These were largest in features related to the coverage of the dendritic tree (e.g., the total dendritic tree length). Understanding measurement biases is crucial for interpreting morphological data.

Quantifying How Staining Methods Bias Measurements of Neuron Morphologies

Climate change is one of the greatest challenges facing humanity, and we, as machine learning (ML) experts, may wonder how we can help. Here we describe how ML can be a powerful tool in reducing greenhouse gas emissions and helping society adapt to a changing climate. From smart grids to disaster management, we identify high impact problems where existing gaps can be filled by ML, in collaboration with other fields. Our recommendations encompass exciting research questions as well as promising business opportunities. We call on the ML community to join the global effort against climate change.

Background Sleep disturbances play an important role in everyday affect and vice versa. However, the causal day-to-day interaction between sleep and mood has not been thoroughly explored, partly because of the lack of daily assessment data. Mobile phones enable us to collect ecological momentary assessment data on a daily basis in a noninvasive manner. Objective This study aimed to investigate the relationship between self-reported daily mood and sleep quality. Methods A total of 208 adult participants were recruited to report mood and sleep patterns daily via their mobile phones for 6 consecutive weeks. Participants were recruited in 4 roughly equal groups: depressed and anxious, depressed only, anxious only, and controls. The effect of daily mood on sleep quality and vice versa were assessed using mixed effects models and propensity score matching. Results All methods showed a significant effect of sleep quality on mood and vice versa. However, within individuals, the effect of sleep quality on next-day mood was much larger than the effect of previous-day mood on sleep quality. We did not find these effects to be confounded by the participants’ past mood and sleep quality or other variables such as stress, physical activity, and weather conditions. Conclusions We found that daily sleep quality and mood are related, with the effect of sleep quality on mood being significantly larger than the reverse. Correcting for participant fixed effects dramatically affected results. Causal analysis suggests that environmental factors included in the study and sleep and mood history do not mediate the relationship.

Relationship Between Sleep Quality and Mood: Ecological Momentary Assessment Study

Prior knowledge about our environment influences our actions. How does this knowledge evolve into a final action plan and how does the brain represent this? Here, we investigated this question in the monkey oculomotor system during self-guided search of natural scenes. In the frontal eye field (FEF), we found a subset of neurons, “early neurons,” that contain information about the upcoming saccade long before it is executed, often before the previous saccade had even ended. Crucially, much of this early information did not relate to the actual saccade that would eventually be selected. Rather, it related to prior information about the probabilities of possible upcoming saccades based on the pre-saccade fixation location. Nearer to the time of saccade onset, a greater proportion of these neurons’ activities related to the saccade selection, although prior information continued to influence activity throughout. A separate subset of FEF neurons, “late neurons”, only represented the final action plan near saccade onset and not prior information. Our results demonstrate how, across the population of FEF neurons, prior information evolves into definitive saccade plans.

From prior information to saccade selection: evolution of frontal eye field activity during natural scene search

Any function can be constructed using a hierarchy of simpler functions through compositions. Such a hierarchy can be characterized by a binary rooted tree. Each node of this tree is associated with a function that takes as inputs two numbers from its children and produces one output. Since thinking about functions in terms of computation graphs is becoming popular, we may want to know which functions can be implemented on a given tree. Here, we describe a set of necessary constraints in the form of a system of nonlinear partial differential equations that must be satisfied. Moreover, we prove that these conditions are sufficient in contexts of analytic and bit-valued functions. In the latter case, we explicitly enumerate discrete functions and observe that there are relatively few. Our point of view allows us to compare different neural network architectures in regard to their function spaces. Our work connects the structure of computation graphs with the functions they can implement and has potential applications to neuroscience and computer science.

Excessively changing policies in many real world scenarios is difficult, unethical, or expensive. After all, doctor guidelines, tax codes, and price lists can only be reprinted so often. We may thus want to only change a policy when it is probable that the change is beneficial. In cases that a policy is a threshold on contextual variables we can estimate treatment effects for populations lying at the threshold. This allows for a schedule of incremental policy updates that let us optimize a policy while making few detrimental changes. Using this idea, and the theory of linear contextual bandits, we present a conservative policy updating procedure which updates a deterministic policy only when justified. We extend the theory of linear bandits to this rarely-switching case, proving that such procedures share the same regret, up to constant scaling, as the common LinUCB algorithm. However the algorithm makes far fewer changes to its policy and, of those changes, fewer are detrimental. We provide simulations and an analysis of an infant health well-being causal inference dataset, showing the algorithm efficiently learns a good policy with few changes. Our approach allows efficiently solving problems where changes are to be avoided, with potential applications in medicine, economics and beyond.

Rarely-switching linear bandits: optimization of causal effects for the real world

Backpropagation is driving today's artificial neural networks (ANNs). However, despite extensive research, it remains unclear if the brain implements this algorithm. Among neuroscientists, reinforcement learning (RL) algorithms are often seen as a realistic alternative: neurons can randomly introduce change, and use unspecific feedback signals to observe their effect on the cost and thus approximate their gradient. However, the convergence rate of such learning scales poorly with the number of involved neurons. Here we propose a hybrid learning approach. Each neuron uses an RL-type strategy to learn how to approximate the gradients that backpropagation would provide. We provide proof that our approach converges to the true gradient for certain classes of networks. In both feedforward and convolutional networks, we empirically show that our approach learns to approximate the gradient, and can match or the performance of exact gradient-based learning. Learning feedback weights provides a biologically plausible mechanism of achieving good performance, without the need for precise, pre-specified learning rules.

Over the last decade, computer science has made progress towards extracting body pose from single camera photographs or videos. This promises to enable movement science to detect disease, quantify movement performance, and take the science out of the lab into the real world. However, current pose tracking algorithms fall short of the needs of movement science; the types of movement data that matter are poorly estimated. For instance, the metrics currently used for evaluating pose tracking algorithms use noisy hand-labeled ground truth data and do not prioritize precision of relevant variables like three-dimensional position, velocity, acceleration, and forces which are crucial for movement science. Here, we introduce the scientific disciplines that use movement data, the types of data they need, and discuss the changes needed to make pose tracking truly transformative for movement science.

Abstract Background and Objectives Clinicians commonly prescribe assistive devices such as walkers or canes to reduce older adults’ fall risk. However, older adults may not consistently use their assistive device, and measuring adherence can be challenging due to self-report bias or cognitive deficits. Because walking patterns can change while using an assistive device, we hypothesized that smartphones and smartwatches, combined with machine-learning algorithms, could detect whether an older adult was walking with an assistive device. Research Design and Methods Older adults at an Adult Day Center (n = 14) wore an Android smartphone and Actigraph smartwatch while completing the six-minute walk, 10-meter walk, and Timed Up and Go tests with and without their assistive device on five separate days. We used accelerometer data from the devices to build machine-learning algorithms to detect whether the participant was walking with or without their assistive device. We tested our algorithms using cross-validation. Results Smartwatch classifiers could accurately detect assistive device use, but smartphone classifiers performed poorly. Customized smartwatch classifiers, which were created specifically for one participant, had greater than 95% classification accuracy for all participants. Noncustomized smartwatch classifiers (ie, an “off-the-shelf” system) had greater than 90% accuracy for 10 of the 14 participants. A noncustomized system performed better for walker users than cane users. Discussion and Implications Our approach can leverage data from existing commercial devices to provide a deeper understanding of walker or cane use. This work can inform scalable public health monitoring tools to quantify assistive device adherence and enable proactive fall interventions.

Task-oriented therapy consists of three stages: demonstration, observation and assistance. While demonstration using robots has been extensively studied, the other two stages rarely involve robots. This paper focuses on the transition between observation and assistance. More specifically, we tackle the robot’s decision making problem of whether to assist a patient or not based on the observation. The proposed method is to train a discrete tunnel shape 3-D decision boundary through correct demonstration to classify motions. Additional conditions such as slow progress, self correction and overshot motions are taken into account of the decision making. Preliminary experiments have been performed on BAXTER robot for a cup reaching task. The BAXTER robot is programmed to react according to the decision boundary. It assists the patient when the patient’s hand position is determined by the proposed algorithm to be unacceptable. Multiple cases including correct motion, continuous assistance, overshot, misaim and slow progress are tested. Results have confirmed the feasibility of the proposed method, which can reduce the current shortage of physical rehabilitation therapists.

2019 IEEE 16th International Conference on Rehabilitation Robotics (ICORR)

Towards Data-Driven Autonomous Robot-Assisted Physical Rehabilitation Therapy

Any information processing system should allocate resources where it matters: it should process frequent variable values with higher accuracy than less frequent ones. While this strategy minimizes average error, it also introduces an estimation bias. For example, human subjects perceive local visual orientation with a bias away from the orientations that occur most frequently in the natural world. Here, using an information theoretic measure, we show that pretrained neural networks, like humans, have internal representations that overrepresent frequent variable values at the expense of certainty for less common values. Furthermore, we demonstrate that optimized readouts of local visual orientation from these networks’ internal representations show similar orientation biases and geometric illusions as human subjects. This surprising similarity illustrates that when performing the same perceptual task, similar characteristic illusions and biases emerge for any optimal information processing system that is resource limited.

Shared visual illusions between humans and artificial neural networks

Claims are a fundamental unit of scientific discourse. The exponential growth in the number of scientific publications makes automatic claim extraction an important problem for researchers who are overwhelmed by this information overload. Such an automated claim extraction system is useful for both manual and programmatic exploration of scientific knowledge. In this paper, we introduce a new dataset of 1,500 scientific abstracts from the biomedical domain with expert annotations for each sentence indicating whether the sentence presents a scientific claim. We introduce a new model for claim extraction and compare it to several baseline models including rule-based and deep learning techniques. Moreover, we show that using a transfer learning approach with a fine-tuning step allows us to improve performance from a large discourse-annotated dataset. Our final model increases F1-score by over 14 percent points compared to a baseline model without transfer learning. We release a publicly accessible tool for discourse and claims prediction along with an annotation tool. We discuss further applications beyond biomedical literature.

Claim Extraction in Biomedical Publications using Deep Discourse Model and Transfer Learning

Machine Learning for Phone-Based Relationship Estimation: The Need to Consider Population Heterogeneity

Abstract When a neuron is driven beyond its threshold it spikes, and the fact that it does not communicate its continuous membrane potential is usually seen as a computational liability. Here we show that this spiking mechanism allows neurons to produce an unbiased estimate of their causal influence, and a way of approximating gradient descent learning. Importantly, neither activity of upstream neurons, which act as confounders, nor downstream non-linearities bias the results. By introducing a local discontinuity with respect to their input drive, we show how spiking enables neurons to solve causal estimation and learning problems.

Cognitive Computational Neuroscience: A New Conference for an Emerging Discipline

Prior to selecting an action, we often consider other possibilities. How does the brain represent these preliminary plans prior to action selection? Here, we investigated this question in the oculomotor system during self-guided search of natural scenes. We found two classes of neurons in the frontal eye field (FEF): 1) "late selection neurons" that represented the selected action plan not long before the upcoming saccade, and 2) "early selection neurons" that became predictive of the upcoming saccade much earlier, often before the previous saccade had even ended. Crucially, these early selection neurons did not only predict the upcoming saccade direction; they also reflected the probabilities of possible upcoming saccades, even when they did not end up being selected. Our results demonstrate that during naturalistic eye movements, separate populations of neurons code for preliminary and definitive plans.

From preliminary to definitive plans: two classes of neurons in frontal eye field

The idea that lateral intraparietal cortex (LIP) integrates information for and against a decision, is one of the most popular models in neuroscience. However, a recent statistical analysis has suggested that LIP does not integrate information but that individual neurons’ activities jump. The result was based on a model comparison, which is often hard to interpret. There are two worries that can render comparisons problematic. (1) Important aspects of variance are contained in neither model. (2) The analysis is complicated, making it hard to verify. We thus followed up with a simple approach for model comparison: crossvalidation. We find evidence that baseline fluctuations describe much of the variance, which are properly modeled by neither the original paper’s drift-diffusion model, nor simple ramp or step models. Moreover, we find that our straightforward analysis strategy prefers ramping models, both with and without trial-by-trial baseline fluctuations. Our analysis, implementable in a few lines of code, suggests the importance of simple analyses.

Rate fluctuations not steps dominate LIP activity during decision-making

 Sleep disturbances play an important role in everyday affect and vice versa. However, the causal day-to-day interaction between sleep and mood has not been thoroughly explored, partly because of the lack of daily assessment data. Mobile phones enable us to collect ecological momentary assessment data on a daily basis in a noninvasive manner.
 
 OBJECTIVE
 This study aimed to investigate the relationship between self-reported daily mood and sleep quality.
 
 METHODS
 A total of 208 adult participants were recruited to report mood and sleep patterns daily via their mobile phones for 6 consecutive weeks. Participants were recruited in 4 roughly equal groups: depressed and anxious, depressed only, anxious only, and controls. The effect of daily mood on sleep quality and vice versa were assessed using mixed effects models and propensity score matching.
 
 RESULTS
 All methods showed a significant effect of sleep quality on mood and vice versa. However, within individuals, the effect of sleep quality on next-day mood was much larger than the effect of previous-day mood on sleep quality. We did not find these effects to be confounded by the participants’ past mood and sleep quality or other variables such as stress, physical activity, and weather conditions.
 
 We found that daily sleep quality and mood are related, with the effect of sleep quality on mood being significantly larger than the reverse. Correcting for participant fixed effects dramatically affected results. Causal analysis suggests that environmental factors included in the study and sleep and mood history do not mediate the relationship.

Relationship Between Sleep Quality and Mood: Ecological Momentary Assessment Study (Preprint)

Neuroscience has long focused on finding encoding models that effectively ask “what predicts neural spiking?” and generalized linear models (GLMs) are a typical approach. It is often unknown how much of explainable neural activity is captured, or missed, when fitting a model. Here we compared the predictive performance of simple models to three leading machine learning methods: feedforward neural networks, gradient boosted trees (using XGBoost), and stacked ensembles that combine the predictions of several methods. We predicted spike counts in macaque motor (M1) and somatosensory (S1) cortices from standard representations of reaching kinematics, and in rat hippocampal cells from open field location and orientation. Of these methods, XGBoost and the ensemble consistently produced more accurate spike rate predictions and were less sensitive to the preprocessing of features. These methods can thus be applied quickly to detect if feature sets relate to neural activity in a manner not captured by simpler methods. Encoding models built with a machine learning approach accurately predict spike rates and can offer meaningful benchmarks for simpler models.

Modern Machine Learning as a Benchmark for Fitting Neural Responses

Much of neuroscience aims at reverse engineering the brain, but we only record a small number of neurons at a time. We do not currently know if reverse engineering the brain requires us to simultaneously record most neurons or if multiple recordings from smaller subsets suffice. This is made even more important by the development of novel techniques that allow recording from selected subsets of neurons, e.g. using optical techniques. To get at this question, we analyze a neural network, trained on the MNIST dataset, using only partial recordings and characterize the dependency of the quality of our reverse engineering on the number of simultaneously recorded "neurons". We find that reverse engineering of the nonlinear neural network is meaningfully possible if a sufficiently large number of neurons is simultaneously recorded but that this number can be considerably smaller than the number of neurons. Moreover, recording many times from small random subsets of neurons yields surprisingly good performance. Application in neuroscience suggests to approximate the I/O function of an actual neural system, we need to record from a much larger number of neurons. The kind of scaling analysis we perform here can, and arguably should be used to calibrate approaches that can dramatically scale up the size of recorded data sets in neuroscience.

Reverse engineering neural networks from many partial recordings

PLOS Computational Biology 2017 Reviewer and Editorial Board Thank You

New technologies that measure sparse molecular biomarkers from easily accessible bodily fluids (e.g. blood, urine, and saliva) are revolutionizing disease diagnostics and precision medicine. Microchip devices can measure more disease biomarkers with better sensitivity and specificity each year, but clinical interpretation of these biomarkers remains a challenge. Single biomarkers in 'liquid biopsy' often cannot accurately predict the state of a disease due to heterogeneity in phenotype and disease expression across individuals. To address this challenge, investigators are combining multiplexed measurements of different biomarkers that together define robust signatures for specific disease states. Machine learning is a useful tool to automatically discover and detect these signatures, especially as new technologies output increasing quantities of molecular data. In this paper, we review the state of the field of machine learning applied to molecular diagnostics and provide practical guidance to use this tool effectively and to avoid common pitfalls.

Machine learning to detect signatures of disease in liquid biopsies - a user's guide.

Improving the Accuracy of Scores to Predict Gastrostomy after Intracerebral Hemorrhage with Machine Learning.

The sociology of scientific validity: How professional networks shape judgement in peer review

Beyond the Catwalk: A how-to-model guide for Neuroscience that dispels the mysteries

Dynamic remapping in Monkey Frontal Eye Field preserves a retinotopic representation during visual search, then compresses space toward the search target.

Accelerating Dynamic Programs via Nested Benders Decomposition with Application to Multi-Person Pose Estimation

Corrigendum: Scaling of Optogenetically Evoked Signaling in a Higher-Order Corticocortical Pathway in the Anesthetized Mouse

1. Chemistry of Life Processes Institute, Northwestern University, Evanston, IL USA 2. Argonne Leadership Computing Facility, Argonne National Lab, Lemont, IL USA 3. Dept. Materials Science, Northwestern University, Evanston, IL USA 4. Advanced Photon Source, Argonne National Lab, Lemont, IL USA 5. Dept. Physics & Astronomy, Northwestern University, Evanston, IL USA 6. Dept. Bioengineering and Neuroscience, University of Pennsylvania, Philadelphia, USA 7. Dept. Electrical Engineering and Computer Sci., Northwestern University, Evanston, IL USA 8. Dept. Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA USA * Corresponding author, evadyer@gatech.edu

A Pipeline for Distributed Segmentation of Teravoxel Tomography Datasets

Quantitative analysis of corticocortical signaling is needed to understand and model information processing in cerebral networks. However, higher-order pathways, hodologically remote from sensory input, are not amenable to spatiotemporally precise activation by sensory stimuli. Here, we combined parametric channelrhodopsin-2 (ChR2) photostimulation with multi-unit electrophysiology to study corticocortical driving in a parietofrontal pathway from retrosplenial cortex (RSC) to posterior secondary motor cortex (M2) in mice in vivo. Ketamine anesthesia was used both to eliminate complex activity associated with the awake state and to enable stable recordings of responses over a wide range of stimulus parameters. Photostimulation of ChR2-expressing neurons in RSC, the upstream area, produced local activity that decayed quickly. This activity in turn drove downstream activity in M2 that arrived rapidly (5–10 ms latencies), and scaled in amplitude across a wide range of stimulus parameters as an approximately constant fraction (~0.1) of the upstream activity. A model-based analysis could explain the corticocortically driven activity with exponentially decaying kernels (~20 ms time constant) and small delay. Reverse (antidromic) driving was similarly robust. The results show that corticocortical signaling in this pathway drives downstream activity rapidly and scalably, in a mostly linear manner. These properties, identified in anesthetized mice and represented in a simple model, suggest a robust basis for supporting complex non-linear dynamic activity in corticocortical circuits in the awake state.

Scaling of Optogenetically Evoked Signaling in a Higher-Order Corticocortical Pathway in the Anesthetized Mouse

Marker-less video-based tracking promises to allow us to do movement science on existing video databases. We revisited the old question of how people synchronize their walking using real world data. We thus applied pose estimation to 348 video segments extracted from YouTube videos of people walking in cities. As in previous, more constrained, research, we find a tendency for pairs of people to walk in phase or in anti-phase with each other. Large video databases, along with pose-tracking algorithms, promise answers to many movement questions without experimentally acquiring new data.

Rahnev and Denison argue that human behavior is often described as ‘optimal’, despite many previous findings of suboptimality. We address how the literature handles these concepts and discuss our own findings on suboptimality. While we agree that the field should embrace the ‘systematic weirdness of human behavior’, this does not detract from the value of the Bayesian approach.

While optimal models are useful, optimality claims are not that common.

As neuroscientists we want to understand how causal interactions or mechanisms within the brain give rise to perception, cognition, and behavior. It is typical to estimate interaction effects from measured activity using statistical techniques such as functional connectivity, Granger Causality,or information flow, whose outcomes are often falsely treated as revealing mechanistic insight. Since these statistical techniques fit models to low-dimensional measurements from brains, they ignore the fact that brain activity is high-dimensional. Here we focus on the obvious confound of common inputs: the countless unobserved variables likely have more influence than the few observed ones. Any given observed correlation can be explained by an infinite set of causal models that take into account the unobserved variables. Therefore, correlations within massively undersampled measurements tell us little about mechanisms. We argue that these mis-inferences of causality from correlation are augmented by an implicit redefinition of words that suggest mechanisms, such as connectivity, causality, and flow.

The lure of causal statements: Rampant mis-inference of causality in estimated connectivity

Abstract Rahnev & Denison (R&D) argue that human behavior is often described as “optimal,” despite many previous findings of suboptimality. We address how the literature handles these concepts and discuss our own findings on suboptimality. Although we agree that the field should embrace the “systematic weirdness of human behavior” (sect. 6, para. 1), this does not detract from the value of the Bayesian approach.

Although optimal models are useful, optimality claims are not that common

The roles of supervised machine learning in systems neuroscience

The intricate morphology of neurons has fascinated since the dawn of neuroscience, and yet, it is hard to synthesize them. Current algorithms typically define a growth process with parameters that allow matching aspects of the morphologies. However, such algorithmic growth processes are far simpler than the biological ones. What is needed is an algorithm that, given a database of morphologies, produces more of those. Here, we introduce a generator for neuron morphologies that is based on a statistical sampling process. Our Reversible Jump Markov chain Monte Carlo (RJMCMC) method starts with a trivial neuron and iteratively perturbs the morphology bringing the features close to those of the database. By quantifying the statistics of the generated neurons, we find that it outperforms growth-based models for many features. Good generative models for neuron morphologies promise to be important both for neural simulations and for morphology reconstructions from imaging data.

To study how the brain works mechanistically, neuroscientists want to quantify causal interactions between neurons, typically requiring perturbations. When using optogenetic interventions, multiple neurons are usually perturbed which produces a confound – any of the stimulated neurons can have affected the postsynaptic neuron making it challenging to discern which of the neurons produced the causal effect. Here we show how such confounds produce large biases, and we explain how they can be reduced by combining instrumental variable (IV) and difference in differences (DiD) techniques from econometrics. The interaction between stimulation and the absolute refractory period of the neuron produces a weak, approximately random signal which can be exploited to estimate causal transmission probability. On simulated neural networks, we find that estimates using ideas from IV and DiD outperform naïve techniques suggesting that methods from causal inference can be useful when studying neural interactions.

Inferring causal connectivity from pairwise recordings and optogenetics

Improving generalization by regularizing in $L^2$ function space

Scientists reuse figure elements sometimes appropriately, e.g. when comparing methods, and sometimes inappropriately, e.g. when presenting an old experiment as a new control. To understand such reuse, automatically detecting it would be important. Here we present an analysis of figure element reuse on a large dataset comprising 760 thousand open access articles and 2 million figures. Our algorithm detects figure region reuse, while being robust to rotation, cropping, resizing, and contrast changes, and estimates which of the reuses have biological meaning. Then a three-person panel analyzes how problematic these biological reuses are using contextual information such as captions and full texts. Based on the panel reviews, we estimate that 9% of the biological reuses would be unanimously perceived as at least suspicious. We further estimate that 0.6% of all articles would be unanimously perceived as fraudulent, with inappropriate reuses occurring 43% across articles, 28% within article, and 29% within a figure. Our tool rapidly detects image reuse at scale, promising to be useful to a broad range of people that campaign for scientific integrity. We suggest that a great deal of scientific fraud will be, sooner or later, detectable by automatic methods.

The process through which neurons are probed and labeled for imaging is a key methodological choice in quantifying neuron morphology. However, little is known about how this choice may create biases in morphometrics. Here, we compare a large number of morphological features amongst samples collected from the same species, brain region, and cell-type. This allows us to identify differences in morphologies that can only be attributed to differences in experimental methods. In particular, we select four popular staining methods and compare each pair of them across different regions of the adult mouse brain. We find that all methods disagree in some respects when we look at the morphometry of the neurons. We propose that one explanation for this difference is the bias toward some cell types of neurons when one particular staining methods is being used. Our result indicates the importance of the choice of staining methods for studying neuronal morphology, and suggests that more experimental detail is needed to allow analysis across large datasets of neuron morphology.

Quantifying the effect of staining methods on extracted neuron morphology

To optimize a neural network one often thinks of optimizing its parameters, but it is ultimately a matter of optimizing the function that maps inputs to outputs. Since a change in the parameters might serve as a poor proxy for the change in the function, it is of some concern that primacy is given to parameters but that the correspondence has not been tested. Here, we show that it is simple and computationally feasible to calculate distances between functions in a $L^2$ Hilbert space. We examine how typical networks behave in this space, and compare how parameter $\ell^2$ distances compare to function $L^2$ distances between various points of an optimization trajectory. We find that the two distances are nontrivially related. In particular, the $L^2/\ell^2$ ratio decreases throughout optimization, reaching a steady value around when test error plateaus. We then investigate how the $L^2$ distance could be applied directly to optimization. We first propose that in multitask learning, one can avoid catastrophic forgetting by directly limiting how much the input/output function changes between tasks. Secondly, we propose a new learning rule that constrains the distance a network can travel through $L^2$-space in any one update. This allows new examples to be learned in a way that minimally interferes with what has previously been learned. These applications demonstrate how one can measure and regularize function distances directly, without relying on parameters or local approximations like loss curvature.

Objective: The TOAST classification for ischemic stroke (IS) is critical to determining management and predicting outcome. The adjudication process is done manually by highly trained stroke clinici...

Abstract WMP71: Using Machine Learning to Classify Ischemic Stroke Subtype From Electronic Heath Records

Abstract DNA polymerase fidelity is affected by both intrinsic properties and environmental conditions. Current strategies for measuring DNA polymerase error rate in vitro are constrained by low error subtype sensitivity, poor scalability, and lack of flexibility in types of sequence contexts that can be tested. We have developed the Magnification via Nucleotide Imbalance Fidelity (MagNIFi) assay, a scalable next-generation sequencing assay that uses a biased deoxynucleotide pool to quantitatively shift error rates into a range where errors are frequent and hence measurement is robust, while still allowing for accurate mapping to error rates under typical conditions. This assay is compatible with a wide range of fidelity-modulating conditions, and enables high-throughput analysis of sequence context effects on base substitution and single nucleotide deletion fidelity using a built-in template library. We validate this assay by comparing to previously established fidelity metrics, and use it to investigate neighboring sequence-mediated effects on fidelity for several DNA polymerases. Through these demonstrations, we establish the MagNIFi assay for robust, high-throughput analysis of DNA polymerase fidelity.

High-resolution mapping of DNA polymerase fidelity using nucleotide imbalances and next-generation sequencing

Neural plasticity can be seen as ultimately aiming at the maximization of reward. However, the world is complicated and nonlinear and so are neurons’ firing properties. A neuron learning to make changes that lead to the maximization of reward is an estimation problem: would there be more reward if the neural activity had been different? Statistically, this is a causal inference problem. Here we show how the spiking discontinuity of neurons can be a tool to estimate the causal influence of a neuron’s activity on reward. We show how it can be used to derive a novel learning rule that can operate in the presence of non-linearities and the confounding influence of other neurons. We establish a link between simple learning rules and an existing causal inference method from econometrics, yielding proofs of both the correctness of the approach as well as its asymptotic behavior.

Multi-person pose estimation (MPPE) in natural images is key to the meaningful use of visual data in many fields including movement science, security, and rehabilitation. In this paper we tackle MPPE with a bottom-up approach, starting with candidate detections of body parts from a convolutional neural network (CNN) and grouping them into people. We formulate the grouping of body part detections into people as a minimum-weight set packing (MWSP) problem where the set of potential people is the power set of body part detections. We model the quality of a hypothesis of a person which is a set in the MWSP by an augmented tree-structured Markov random field where variables correspond to body-parts and their state-spaces correspond to the power set of the detections for that part. 
We describe a novel algorithm that combines efficiency with provable bounds on this MWSP problem. We employ an implicit column generation strategy where the pricing problem is formulated as a dynamic program. To efficiently solve this dynamic program we exploit the problem structure utilizing a nested Bender's decomposition (NBD) exact inference strategy which we speed up by recycling Bender's rows between calls to the pricing problem. 
We test our approach on the MPII-Multiperson dataset, showing that our approach obtains comparable results with the state-of-the-art algorithm for joint node labeling and grouping problems, and that NBD achieves considerable speed-ups relative to a naive dynamic programming approach. Typical algorithms that solve joint node labeling and grouping problems use heuristics and thus can not obtain proofs of optimality. Our approach, in contrast, proves that for over 99 percent of problem instances we find the globally optimal solution and otherwise provide upper/lower bounds.

Background Sleep is a critical aspect of people’s well-being and as such assessing sleep is an important indicator of a person’s health. Traditional methods of sleep assessment are either time- and resource-intensive or suffer from self-reporting biases. Recently, researchers have started to use mobile phones to passively assess sleep in individuals’ daily lives. However, this work remains in its early stages, having only examined relatively small and homogeneous populations in carefully controlled contexts. Thus, it remains an open question as to how well mobile device-based sleep monitoring generalizes to larger populations in typical use cases. Objective The aim of this study was to assess the ability of machine learning algorithms to detect the sleep start and end times for the main sleep period in a 24-h cycle using mobile devices in a diverse sample. Methods We collected mobile phone sensor data as well as daily self-reported sleep start and end times from 208 individuals (171 females; 37 males), diverse in age (18−66 years; mean 39.3), education, and employment status, across the United States over 6 weeks. Sensor data consisted of geographic location, motion, light, sound, and in-phone activities. No specific instructions were given to the participants regarding phone placement. We used random forest classifiers to develop both personalized and global predictors of sleep state from the phone sensor data. Results Using all available sensor features, the average accuracy of classifying whether a 10-min segment was reported as sleep was 88.8%. This is somewhat better than using the time of day alone, which gives an average accuracy of 86.9%. The accuracy of the model considerably varied across the participants, ranging from 65.1% to 97.3%. We found that low accuracy in some participants was due to two main factors: missing sensor data and misreports. After correcting for these, the average accuracy increased to 91.8%, corresponding to an average median absolute deviation (MAD) of 38 min for sleep start time detection and 36 min for sleep end time. These numbers are close to the range reported by previous research in more controlled situations. Conclusions We find that mobile phones provide adequate sleep monitoring in typical use cases, and that our methods generalize well to a broader population than has previously been studied. However, we also observe several types of data artifacts when collecting data in uncontrolled settings. Some of these can be resolved through corrections, but others likely impose a ceiling on the accuracy of sleep prediction for certain subjects. Future research will need to focus more on the understanding of people’s behavior in their natural settings in order to develop sleep monitoring tools that work reliably in all cases for all people.

Scalable Passive Sleep Monitoring Using Mobile Phones: Opportunities and Obstacles

Using a DNA polymerase to record intracellular calcium levels has been proposed as a novel neural recording technique, promising massive-scale, single-cell resolution monitoring of large portions of the brain. This technique relies on local storage of neural activity in strands of DNA, followed by offline analysis of that DNA. In simple implementations of this scheme, the time when each nucleotide was written cannot be determined directly by post-hoc DNA sequencing; the timing data must be estimated instead. Here, we use a Dynamic Time Warping-based algorithm to perform this estimation, exploiting correlations between neural activity and observed experimental variables to translate DNA-based signals to an estimate of neural activity over time. This algorithm improves the parallelizability of traditional Dynamic Time Warping, allowing several-fold increases in computation speed. The algorithm also provides a solution to several critical problems with the molecular recording paradigm: determining recording start times and coping with DNA polymerase pausing. The algorithm can generally locate DNA-based records to within <10% of a recording window, allowing for the estimation of unobserved incorporation times and latent neural tunings. We apply our technique to an in silico motor control neuroscience experiment, using the algorithm to estimate both timings of DNA-based data and the directional tuning of motor cortical cells during a center-out reaching task. We also use this algorithm to explore the impact of polymerase characteristics on system performance, determining the precision of a molecular recorder as a function of its kinetic and error-generating properties. We find useful ranges of properties for DNA polymerase-based recorders, providing guidance for future protein engineering attempts. This work demonstrates a useful general extension to dynamic alignment algorithms, as well as direct applications of that extension toward the development of molecular recorders, providing a necessary stepping stone for future biological work.

Background Smartphones contain sensors that measure movement-related data, making them promising tools for monitoring physical activity after a stroke. Activity recognition (AR) systems are typically trained on movement data from healthy individuals collected in a laboratory setting. However, movement patterns change after a stroke (eg, gait impairment), and activities may be performed differently at home than in a lab. Thus, it is important to validate AR for gait-impaired stroke patients in a home setting for accurate clinical predictions. Objective In this study, we sought to evaluate AR performance in a home setting for individuals who had suffered a stroke, by using different sets of training activities. Specifically, we compared AR performance for persons with stroke while varying the origin of training data, based on either population (healthy persons or persons with stoke) or environment (laboratory or home setting). Methods Thirty individuals with stroke and fifteen healthy subjects performed a series of mobility-related activities, either in a laboratory or at home, while wearing a smartphone. A custom-built app collected signals from the phone’s accelerometer, gyroscope, and barometer sensors, and subjects self-labeled the mobility activities. We trained a random forest AR model using either healthy or stroke activity data. Primary measures of AR performance were (1) the mean recall of activities and (2) the misclassification of stationary and ambulatory activities. Results A classifier trained on stroke activity data performed better than one trained on healthy activity data, improving average recall from 53% to 75%. The healthy-trained classifier performance declined with gait impairment severity, more often misclassifying ambulatory activities as stationary ones. The classifier trained on in-lab activities had a lower average recall for at-home activities (56%) than for in-lab activities collected on a different day (77%). Conclusions Stroke-based training data is needed for high quality AR among gait-impaired individuals with stroke. Additionally, AR systems for home and community monitoring would likely benefit from including at-home activities in the training data.

Activity Recognition for Persons With Stroke Using Mobile Phone Technology: Toward Improved Performance in a Home Setting

Neuroscience has long focused on finding encoding models that effectively ask “what predicts neural spiking?” and generalized linear models (GLMs) are a typical approach. It is often unknown how much of explainable neural activity is captured, or missed, when fitting a GLM. Here we compared the predictive performance of GLMs to three leading machine learning methods: feedforward neural networks, gradient boosted trees (using XGBoost), and stacked ensembles that combine the predictions of several methods. We predicted spike counts in macaque motor (M1) and somatosensory (S1) cortices from standard representations of reaching kinematics, and in rat hippocampal cells from open field location and orientation. In general, the modern methods (particularly XGBoost and the ensemble) produced more accurate spike predictions and were less sensitive to the preprocessing of features. This discrepancy in performance suggests that standard feature sets may often relate to neural activity in a nonlinear manner not captured by GLMs. Encoding models built with machine learning techniques, which can be largely automated, more accurately predict spikes and can offer meaningful benchmarks for simpler models.

An Active Learning Module to Introduce Students to the Importance of Flowcharts and Technical Documentation

If the brain abstractly represents probability distributions as knowledge, then the modality of a decision, e.g. movement vs perception, should not matter. If on the other hand, learned representations are policies, they may be specific to the task where learning takes place. Here, we test this by asking if a learned spatial prior generalizes from a sensorimotor estimation task to a two-alternative-forced choice (2-Afc) perceptual comparison task. A model and simulation-based analysis revealed that while subjects learn the experimentally-imposed prior distribution in the sensorimotor estimation task, measured priors are consistently broader than expected in the 2-Afc task. That the prior does not fully generalize suggests that sensorimotor priors strongly resemble policies. In disagreement with standard Bayesian thought, the modality of the decision has a strong influence on the implied prior distributions.

Policies or Knowledge: Priors differ between perceptual and sensorimotor tasks

Credit assignment between body and object probed by an object transportation task

Dopaminergic Medication Increases Reliance on Current Information in Parkinson’s Disease

How effectively does activity in an upstream cortical area drive activity in a downstream area? To address this, we combined optogenetic photostimulation with multi-unit electrophysiology to study a parietofrontal corticocortical pathway from retrosplenial cortex to posterior secondary motor cortex in mice. Photostimulation in the upstream area produced local activity that decayed quickly. This activity in turn drove downstream activity that arrived rapidly (5-10 ms latencies), and scaled in amplitude across a wide range of stimulus parameters as an approximately constant fraction (~0.2) of the upstream activity. A model-based analysis could explain the corticocortically driven activity with exponentially decaying kernels (~20 ms time constant) and small delay. Reverse (antidromic) driving was similarly robust. The results show that corticocortical signaling in this pathway drives downstream activity in a mostly linear manner. The regular and predictable responses further suggest that precise stimulation driven control of cortical population activity should be possible.

Corticocortical signaling drives activity in a downstream area rapidly and scalably

Background It is important to understand the motor deficits of children with Cerebral Palsy (CP). Our understanding of this motor disorder can be enriched by computational models of motor control. One crucial stage in generating movement involves combining uncertain information from different sources, and deficits in this process could contribute to reduced motor function in children with CP. Healthy adults can integrate previously-learned information (prior) with incoming sensory information (likelihood) in a close-to-optimal way when estimating object location, consistent with the use of Bayesian statistics. However, there are few studies investigating how children with CP perform sensorimotor integration. We compare sensorimotor estimation in children with CP and age-matched controls using a model-based analysis to understand the process. Methods and findings We examined Bayesian sensorimotor integration in children with CP, aged between 5 and 12 years old, with Gross Motor Function Classification System (GMFCS) levels 1–3 and compared their estimation behavior with age-matched typically-developing (TD) children. We used a simple sensorimotor estimation task which requires participants to combine probabilistic information from different sources: a likelihood distribution (current sensory information) with a prior distribution (learned target information). In order to examine sensorimotor integration, we quantified how participants weighed statistical information from the two sources (prior and likelihood) and compared this to the statistical optimal weighting. We found that the weighing of statistical information in children with CP was as statistically efficient as that of TD children. Conclusions We conclude that Bayesian sensorimotor integration is not impaired in children with CP and therefore, does not contribute to their motor deficits. Future research has the potential to enrich our understanding of motor disorders by investigating the stages of motor processing set out by computational models. Therapeutic interventions should exploit the ability of children with CP to use statistical information.

The integration of probabilistic information during sensorimotor estimation is unimpaired in children with Cerebral Palsy

Background Wearable sensors gather data that machine-learning models can convert into an identification of physical activities, a clinically relevant outcome measure. However, when individuals with disabilities upgrade to a new walking assistive device, their gait patterns can change, which could affect the accuracy of activity recognition. Objective The objective of this study was to assess whether we need to train an activity recognition model with labeled data from activities performed with the new assistive device, rather than data from the original device or from healthy individuals. Methods Data were collected from 11 healthy controls as well as from 11 age-matched individuals with disabilities who used a standard stance control knee-ankle-foot orthosis (KAFO), and then a computer-controlled adaptive KAFO (Ottobock C-Brace). All subjects performed a structured set of functional activities while wearing an accelerometer on their waist, and random forest classifiers were used as activity classification models. We examined both global models, which are trained on other subjects (healthy or disabled individuals), and personal models, which are trained and tested on the same subject. Results Median accuracies of global and personal models trained with data from the new KAFO were significantly higher (61% and 76%, respectively) than those of models that use data from the original KAFO (55% and 66%, respectively) (Wilcoxon signed-rank test, P=.006 and P=.01). These models also massively outperformed a global model trained on healthy subjects, which only achieved a median accuracy of 53%. Device-specific models conferred a major advantage for activity recognition. Conclusions Our results suggest that when patients use a new assistive device, labeled data from activities performed with the specific device are needed for maximal precision activity recognition. Personal device-specific models yield the highest accuracy in such scenarios, whereas models trained on healthy individuals perform poorly and should not be used in patient populations.

Activity Recognition in Individuals Walking With Assistive Devices: The Benefits of Device-Specific Models

Authorship Correction: Scalable Passive Sleep Monitoring Using Mobile Phones: Opportunities and Obstacles

Perception is seen as a process that utilises partial and noisy information to construct a coherent understanding of the world. Here we argue that the experience of pain is no different; it is based on incomplete, multimodal information, which is used to estimate potential bodily threat. We outline a Bayesian inference model, incorporating the key components of cue combination, causal inference, and temporal integration, which highlights the statistical problems in everyday perception. It is from this platform that we are able to review the pain literature, providing evidence from experimental, acute, and persistent phenomena to demonstrate the advantages of adopting a statistical account in pain. Our probabilistic conceptualisation suggests a principles-based view of pain, explaining a broad range of experimental and clinical findings and making testable predictions.

Abstract The availability of smartphone and wearable sensor technology is leading to a rapid accumulation of human subject data, and machine learning is emerging as a technique to map those data into clinical predictions. As machine learning algorithms are increasingly used to support clinical decision making, it is vital to reliably quantify their prediction accuracy. Cross-validation (CV) is the standard approach where the accuracy of such algorithms is evaluated on part of the data the algorithm has not seen during training. However, for this procedure to be meaningful, the relationship between the training and the validation set should mimic the relationship between the training set and the dataset expected for the clinical use. Here we compared two popular CV methods: record-wise and subject-wise. While the subject-wise method mirrors the clinically relevant use-case scenario of diagnosis in newly recruited subjects, the record-wise strategy has no such interpretation. Using both a publicly available dataset and a simulation, we found that record-wise CV often massively overestimates the prediction accuracy of the algorithms. We also conducted a systematic review of the relevant literature, and found that this overly optimistic method was used by almost half of the retrieved studies that used accelerometers, wearable sensors, or smartphones to predict clinical outcomes. As we move towards an era of machine learning-based diagnosis and treatment, using proper methods to evaluate their accuracy is crucial, as inaccurate results can mislead both clinicians and data scientists.

The need to approximate the use-case in clinical machine learning

There are three prominent factors that can predict human visual-search behavior in natural scenes: the distinctiveness of a location (salience), similarity to the target (relevance), and features of the environment that predict where the object might be (context). We do not currently know how well these factors are able to predict macaque visual search, which matters because it is arguably the most popular model for asking how the brain controls eye movements. Here we trained monkeys to perform the pedestrian search task previously used for human subjects. Salience, relevance, and context models were all predictive of monkey eye fixations and jointly about as precise as for humans. We attempted to disrupt the influence of scene context on search by testing the monkeys with an inverted set of the same images. Surprisingly, the monkeys were able to locate the pedestrian at a rate similar to that for upright images. The best predictions of monkey fixations in searching inverted images were obtained by rotating the results of the model predictions for the original image. The fact that the same models can predict human and monkey search behavior suggests that the monkey can be used as a good model for understanding how the human brain enables natural-scene search.

Predicting rhesus monkey eye movements during natural-image search

Many annotation problems in computer vision can be phrased as integer linear programs (ILPs). The use of standard industrial solvers does not to exploit the underlying structure of such problems eg, the skeleton in pose estimation. The leveraging of the underlying structure in conjunction with industrial solvers promises increases in both speed and accuracy. Such structure can be exploited using Bender's decomposition, a technique from operations research, that solves complex ILPs or mixed integer linear programs by decomposing them into sub-problems that communicate via a master problem. The intuition is that conditioned on a small subset of the variables the solution to the remaining variables can be computed easily by taking advantage of properties of the ILP constraint matrix such as block structure. In this paper we apply Benders decomposition to a typical problem in computer vision where we have many sub-ILPs (eg, partitioning of detections, body-parts) coupled to a master ILP (eg, constructing skeletons). Dividing inference problems into a master problem and sub-problems motivates the development of a plethora of novel models, and inference approaches for the field of computer vision.

Exploiting skeletal structure in computer vision annotation with Benders decomposition

Background Automatically detecting falls with mobile phones provides an opportunity for rapid response to injuries and better knowledge of what precipitated the fall and its consequences. This is beneficial for populations that are prone to falling, such as people with lower limb amputations. Prior studies have focused on fall detection in able-bodied individuals using data from a laboratory setting. Such approaches may provide a limited ability to detect falls in amputees and in real-world scenarios. Objective The aim was to develop a classifier that uses data from able-bodied individuals to detect falls in individuals with a lower limb amputation, while they freely carry the mobile phone in different locations and during free-living. Methods We obtained 861 simulated indoor and outdoor falls from 10 young control (non-amputee) individuals and 6 individuals with a lower limb amputation. In addition, we recorded a broad database of activities of daily living, including data from three participants’ free-living routines. Sensor readings (accelerometer and gyroscope) from a mobile phone were recorded as participants freely carried it in three common locations—on the waist, in a pocket, and in the hand. A set of 40 features were computed from the sensors data and four classifiers were trained and combined through stacking to detect falls. We compared the performance of two population-specific models, trained and tested on either able-bodied or amputee participants, with that of a model trained on able-bodied participants and tested on amputees. A simple threshold-based classifier was used to benchmark our machine-learning classifier. Results The accuracy of fall detection in amputees for a model trained on control individuals (sensitivity: mean 0.989, 1.96*standard error of the mean [SEM] 0.017; specificity: mean 0.968, SEM 0.025) was not statistically different (P=.69) from that of a model trained on the amputee population (sensitivity: mean 0.984, SEM 0.016; specificity: mean 0.965, SEM 0.022). Detection of falls in control individuals yielded similar results (sensitivity: mean 0.979, SEM 0.022; specificity: mean 0.991, SEM 0.012). A mean 2.2 (SD 1.7) false alarms per day were obtained when evaluating the model (vs mean 122.1, SD 166.1 based on thresholds) on data recorded as participants carried the phone during their daily routine for two or more days. Machine-learning classifiers outperformed the threshold-based one (P<.001). Conclusions A mobile phone-based fall detection model can use data from non-amputee individuals to detect falls in individuals walking with a prosthesis. We successfully detected falls when the mobile phone was carried across multiple locations and without a predetermined orientation. Furthermore, the number of false alarms yielded by the model over a longer period of time was reasonably low. This moves the application of mobile phone-based fall detection systems closer to a real-world use case scenario.

Fall Detection in Individuals With Lower Limb Amputations Using Mobile Phones: Machine Learning Enhances Robustness for Real-World Applications

Abstract This three-part review takes a detailed look at the complexities of cross-validation, fostered by the peer review of Saeb et al.’s paper entitled “The need to approximate the use-case in clinical machine learning.” It contains perspectives by reviewers and by the original authors that touch upon cross-validation: the suitability of different strategies and their interpretation.

Using and understanding cross-validation strategies. Perspectives on Saeb et al.

Mixed reality (MR) has promise for learning, design, and entertainment, and for use during everyday life. However, when interacting with objects in mixed reality, will moving objects make us fall or perturb our postural stability? To address this question, we recruited participants, instructed them to stand quietly, and measured how much virtual objects presented in mixed reality (Microsoft HoloLens) affected their stance. We analyzed the effects of solid object and text, in both a static and a dynamic setting. Mixed reality events induced some movements, but the effect, while significant, was exceptionally small (< 1mm & < 0.5° perturbations in terms of mean distance and angle rotations). We conclude that induced movement in “real reality” should not be too much of a concern when designing mixed reality applications.

In this paper we asked the question: if we artificially raise the variability of torque control signals to match that of EMG, do subjects make similar errors and have similar uncertainty about their movements? We answered this question using two experiments in which subjects used three different control signals: torque, torque+noise, and EMG. First, we measured error on a simple target-hitting task in which subjects received visual feedback only at the end of their movements. We found that even when the signal-to-noise ratio was equal across EMG and torque+noise control signals, EMG resulted in larger errors. Second, we quantified uncertainty by measuring the just-noticeable difference of a visual perturbation. We found that for equal errors, EMG resulted in higher movement uncertainty than both torque and torque+noise. The differences suggest that performance and confidence are influenced by more than just the noisiness of the control signal, and suggest that other factors, such as the user’s ability to incorporate feedback and develop accurate internal models, also have significant impacts on the performance and confidence of a person’s actions. We theorize that users have difficulty distinguishing between random and systematic errors for EMG control, and future work should examine in more detail the types of errors made with EMG control.

EMG Versus Torque Control of Human–Machine Systems: Equalizing Control Signal Variability Does not Equalize Error or Uncertainty

Background Is someone at home, at their friend’s place, at a restaurant, or enjoying the outdoors? Knowing the semantic location of an individual matters for delivering medical interventions, recommendations, and other context-aware services. This knowledge is particularly useful in mental health care for monitoring relevant behavioral indicators to improve treatment delivery. Local search-and-discovery services such as Foursquare can be used to detect semantic locations based on the global positioning system (GPS) coordinates, but GPS alone is often inaccurate. Mobile phones can also sense other signals (such as movement, light, and sound), and the use of these signals promises to lead to a better estimation of an individual’s semantic location. Objective We aimed to examine the ability of mobile phone sensors to estimate semantic locations, and to evaluate the relationship between semantic location visit patterns and depression and anxiety. Methods A total of 208 participants across the United States were asked to log the type of locations they visited daily, using their mobile phones for a period of 6 weeks, while their phone sensor data was recorded. Using the sensor data and Foursquare queries based on GPS coordinates, we trained models to predict these logged locations, and evaluated their prediction accuracy on participants that models had not seen during training. We also evaluated the relationship between the amount of time spent in each semantic location and depression and anxiety assessed at baseline, in the middle, and at the end of the study. Results While Foursquare queries detected true semantic locations with an average area under the curve (AUC) of 0.62, using phone sensor data alone increased the AUC to 0.84. When we used Foursquare and sensor data together, the AUC further increased to 0.88. We found some significant relationships between the time spent in certain locations and depression and anxiety, although these relationships were not consistent. Conclusions The accuracy of location services such as Foursquare can significantly benefit from using phone sensor data. However, our results suggest that the nature of the places people visit explains only a small part of the variation in their anxiety and depression symptoms.

Mobile Phone Detection of Semantic Location and Its Relationship to Depression and Anxiety

Each of our movements is selected from any number of alternative movements. Some studies have shown evidence that the central nervous system (CNS) chooses to make the specific movements that are least affected by motor noise. Previous results showing that the CNS has a natural tendency to minimize the effects of noise make the direct prediction that if the relationship between movements and noise were to change, the specific movements people learn to make would also change in a predictable manner. Indeed, this has been shown for well-practiced movements such as reaching. Here, we artificially manipulated the relationship between movements and visuomotor noise by adding noise to a motor task in a novel redundant geometry such that there arose a single control policy that minimized the noise. This allowed us to see whether, for a novel motor task, people could learn the specific control policy that minimized noise or would need to employ other compensation strategies to overcome the added noise. As predicted, subjects were able to learn movements that were biased toward the specific ones that minimized the noise, suggesting not only that the CNS can learn to minimize the effects of noise in a novel motor task but also that artificial visuomotor noise can be a useful tool for teaching people to make specific movements. Using noise as a teaching signal promises to be useful for rehabilitative therapies and movement training with human-machine interfaces.

NEW & NOTEWORTHY
Many theories argue that we choose to make the specific movements that minimize motor noise. Here, by changing the relationship between movements and noise, we show that people actively learn to make movements that minimize noise. This not only provides direct evidence for the theories of noise minimization but presents a way to use noise to teach specific movements to improve rehabilitative therapies and human-machine interface control.

Abstract Despite rapid advances in machine learning tools, the majority of neural decoding approaches still use traditional methods. Modern machine learning tools, which are versatile and easy to use, have the potential to significantly improve decoding performance. This tutorial describes how to effectively apply these algorithms for typical decoding problems. We provide descriptions, best practices, and code for applying common machine learning methods, including neural networks and gradient boosting. We also provide detailed comparisons of the performance of various methods at the task of decoding spiking activity in motor cortex, somatosensory cortex, and hippocampus. Modern methods, particularly neural networks and ensembles, significantly outperform traditional approaches, such as Wiener and Kalman filters. Improving the performance of neural decoding algorithms allows neuroscientists to better understand the information contained in a neural population and can help to advance engineering applications such as brain–machine interfaces. Our code package is available at github.com/kordinglab/neural_decoding.

The objective of this study was to understand how people adapt to errors when using a myoelectric control interface. We compared adaptation across 1) non-amputee subjects using joint angle, joint torque, and myoelectric control interfaces, and 2) amputee subjects using myoelectric control interfaces with residual and intact limbs (five total control interface conditions). We measured trial-by-trial adaptation to self-generated errors and random perturbations during a virtual, single degree-of-freedom task with two levels of feedback uncertainty, and evaluated adaptation by fitting a hierarchical Kalman filter model. We have two main results. First, adaptation to random perturbations was similar across all control interfaces, whereas adaptation to self-generated errors differed. These patterns matched predictions of our model, which was fit to each control interface by changing the process noise parameter that represented system variability. Second, in amputee subjects, we found similar adaptation rates and error levels between residual and intact limbs. These results link prosthesis control to broader areas of motor learning and adaptation and provide a useful model of adaptation with myoelectric control. The model of adaptation will help us understand and solve prosthesis control challenges, such as providing additional sensory feedback.

Adaptation to random and systematic errors: Comparison of amputee and non-amputee control interfaces with varying levels of process noise

Abstract Lake et al. suggest that current AI systems lack the inductive biases that enable human learning. However, Lake et al.'s proposed biases may not directly map onto mechanisms in the developing brain. A convergence of fields may soon create a correspondence between biological neural circuits and optimization in structured architectures, allowing us to systematically dissect how brains learn.

Addendum of: Fall Detection in Individuals With Lower Limb Amputations Using Mobile Phones: Machine Learning Enhances Robustness for Real-World Applications

DNA binding strength increases the processivity and activity of a Y-Family DNA polymerase

Objective The objective of rehabilitation after spinal cord injury is to enable successful function in everyday life and independence at home. Clinical tests can assess whether patients are able to execute functional movements but are limited in assessing such information at home. A prototype system is developed that detects stand-to-reach activities, a movement with important functional implications, at multiple locations within a mock kitchen. Design Ten individuals with incomplete spinal cord injuries performed a sequence of standing and reaching tasks. The system monitored their movements by combining two sources of information: a triaxial accelerometer, placed on the subject's thigh, detected sitting or standing, and a network of radio frequency tags, wirelessly connected to a wrist-worn device, detected reaching at three locations. A threshold-based algorithm detected execution of the combined tasks and accuracy was measured by the number of correctly identified events. Results The system was shown to have an average accuracy of 98% for inferring when individuals performed stand-to-reach activities at each tag location within the same room. Conclusions The combination of accelerometry and tags yielded accurate assessments of functional stand-to-reach activities within a home environment. Optimization of this technology could simplify patient compliance and allow clinicians to assess functional home activities.

Sensor Fusion to Infer Locations of Standing and Reaching Within the Home in Incomplete Spinal Cord Injury

If the brain is inherently Bayesian, then behavior should show the signatures of Bayesian computation from an early stage in life without the need for learning. Children should integrate probabilistic information from prior and likelihood distributions to reach decisions and should be as statistically efficient as adults. To test this idea, we examined the integration of prior and likelihood information in a simple position estimation task comparing children aged 6-11 years and adults. During development, estimation performance became closer to the statistical optimum. Children use likelihood information as well as adults but are limited in their use of priors. This finding suggests that Bayesian behavior is not inherent but learnt over the course of development.

The development of Bayesian integration in sensorimotor estimation

Humans perform saccadic eye movements two to three times per second. When doing so, the nervous system strongly suppresses sensory feedback for extended periods of time in comparison with the movement time. Why does the brain discard so much visual information? Here we suggest that perceptual suppression may arise from efficient sensorimotor computations, assuming that perception and control are fundamentally linked. More precisely, we show that a Bayesian estimator should reduce the weight of sensory information around the time of saccades, as a result of signal dependent noise and of sensorimotor delays. Such reduction parallels the behavioral suppression occurring prior to and during saccades, and the reduction in neural responses to visual stimuli observed across the visual hierarchy. We suggest that saccadic suppression originates from efficient sensorimotor processing, indicating that the brain shares neural resources for perception and control.

Saccadic suppression as a perceptual consequence of efficient sensorimotor estimation

A new trend in medicine is the use of algorithms to analyze big datasets, e.g. using everything your phone measures about you for diagnostics or monitoring. However, these algorithms are commonly compared against weak baselines, which may contribute to excessive optimism. To assess how well an algorithm works, scientists typically ask how well its output correlates with medically assigned scores. Here we perform a meta-analysis to quantify how the literature evaluates their algorithms for monitoring mental wellbeing. We find that the bulk of the literature (∼77%) uses meaningless comparisons that ignore patient baseline state. For example, having an algorithm that uses phone data to diagnose mood disorders would be useful. However, it is possible to explain over 80% of the variance of some mood measures in the population by simply guessing that each patient has their own average mood—the patient-specific baseline. Thus, an algorithm that just predicts that our mood is like it usually is can explain the majority of variance, but is, obviously, entirely useless. Comparing to the wrong (population) baseline has a massive effect on the perceived quality of algorithms and produces baseless optimism in the field. To solve this problem we propose “user lift” that reduces these systematic errors in the evaluation of personalized medical monitoring.

Meaningless comparisons lead to false optimism in medical machine learning

Finding efficient and provable methods to solve non-convex o ptimization problems is an outstanding challenge in machine learning. A popular approach used to tackle non-c onvex problems is to use convex relaxation techniques to find a convex surrogate for the problem. Unfortunately, co nvex relaxations typically must be found on a problemby-problem basis. Thus, providing a general-purpose strat egy o estimate a convex relaxation would have a wide reaching impact. Here, we introduce Convex Relaxation Regression (CoRR), an approach for learning the convex relaxation of a wide class of smooth functions. The main idea behind our approach is to estimate the convex envelope of a functionf by evaluatingf at random points and then fitting a convex function to these fu nction evaluations. We prove that, as the number T of function evaluations grows, the solution of our algorith m converges to the global minimum off with a polynomial rate inT . Also our result scales polynomially with the dimension. Ou r approach enables the use of convex optimization tools to solve a broad class of non-convex optimization problems.

F eb 2 01 6 Convex Relaxation Regression : Efficient Optimization of Smooth Functions by Learning Their Convex Envelopes

Accelerometry-enabled measurement of walking performance with a robotic exoskeleton: a pilot study

Neuroscience has focused on the detailed implementation of computation, studying neural codes, dynamics and circuits. In machine learning, however, artificial neural networks tend to eschew precisely designed codes, dynamics or circuits in favor of brute force optimization of a cost function, often using simple and relatively uniform initial architectures. Two recent developments have emerged within machine learning that create an opportunity to connect these seemingly divergent perspectives. First, structured architectures are used, including dedicated systems for attention, recursion and various forms of short- and long-term memory storage. Second, cost functions and training procedures have become more complex and are varied across layers and over time. Here we think about the brain in terms of these ideas. We hypothesize that (1) the brain optimizes cost functions, (2) the cost functions are diverse and differ across brain locations and over development, and (3) optimization operates within a pre-structured architecture matched to the computational problems posed by behavior. In support of these hypotheses, we argue that a range of implementations of credit assignment through multiple layers of neurons are compatible with our current knowledge of neural circuitry, and that the brain’s specialized systems can be interpreted as enabling efficient optimization for specific problem classes. Such a heterogeneously optimized system, enabled by a series of interacting cost functions, serves to make learning data-efficient and precisely targeted to the needs of the organism. We suggest directions by which neuroscience could seek to refine and test these hypotheses.

Finding efficient and provable methods to solve non-convex optimization problems is an outstanding challenge in machine learning and optimization theory. A popular approach used to tackle non-convex problems is to use convex relaxation techniques to find a convex surrogate for the problem. Unfortunately, convex relaxations typically must be found on a problem-by-problem basis. Thus, providing a general-purpose strategy to estimate a convex relaxation would have a wide reaching impact. Here, we introduce Convex Relaxation Regression (CoRR), an approach for learning convex relaxations for a class of smooth functions. The main idea behind our approach is to estimate the convex envelope of a function $f$ by evaluating $f$ at a set of $T$ random points and then fitting a convex function to these function evaluations. We prove that with probability greater than $1-\delta$, the solution of our algorithm converges to the global optimizer of $f$ with error $\mathcal{O} \Big( \big(\frac{\log(1/\delta) }{T} \big)^{\alpha} \Big)$ for some $\alpha> 0$. Our approach enables the use of convex optimization tools to solve a class of non-convex optimization problems.

Convex Relaxation Regression: Black-Box Optimization of Smooth Functions by Learning Their Convex Envelopes

Neuroscience has focused on the detailed implementation of computation, studying neural codes, dynamics and circuits. In machine learning, however, artificial neural networks tend to eschew precisely designed codes, dynamics or circuits in favor of brute force optimization of a cost function, often using simple and relatively uniform initial architectures. Two recent developments have emerged within machine learning that create an opportunity to connect these seemingly divergent perspectives. First, structured architectures are used, including dedicated systems for attention, recursion and various forms of short- and long-term memory storage. Second, cost functions and training procedures have become more complex and are varied across layers and over time. Here we think about the brain in terms of these ideas. We hypothesize that (1) the brain optimizes cost functions, (2) the cost functions are diverse and differ across brain locations and over development, and (3) optimization operates within a pre-structured architecture matched to the computational problems posed by behavior. In support of these hypotheses, we argue that a range of implementations of credit assignment through multiple layers of neurons are compatible with our current knowledge of neural circuitry, and that the brain's specialized systems can be interpreted as enabling efficient optimization for specific problem classes. Such a heterogeneously optimized system, enabled by a series of interacting cost functions, serves to make learning data-efficient and precisely targeted to the needs of the organism. We suggest directions by which neuroscience could seek to refine and test these hypotheses.

In the Kappa effect, two visual stimuli are given, and their spatial distance affects their perceived temporal interval. The classical model assumes constant speed while a competing Bayesian model assumes a slow speed prior. The two models are based on different assumptions about the statistical structure of the environment. Here we introduce a new visual experiment to distinguish between these models. When fit to the data, both the two models replicated human response, but the slowness model makes better behavioral predictions than the speed constancy model, and the estimated constant speed is close to the absolute threshold of speed. Our findings suggest that the Kappa effect appears to be due to slow speeds, and also modulated by spatial variance.

Visual Abstract Methods for resolving the three-dimensional (3D) microstructure of the brain typically start by thinly slicing and staining the brain, followed by imaging numerous individual sections with visible light photons or electrons. In contrast, X-rays can be used to image thick samples, providing a rapid approach for producing large 3D brain maps without sectioning. Here we demonstrate the use of synchrotron X-ray microtomography (µCT) for producing mesoscale (∼1 µm 3 resolution) brain maps from millimeter-scale volumes of mouse brain. We introduce a pipeline for µCT-based brain mapping that develops and integrates methods for sample preparation, imaging, and automated segmentation of cells, blood vessels, and myelinated axons, in addition to statistical analyses of these brain structures. Our results demonstrate that X-ray tomography achieves rapid quantification of large brain volumes, complementing other brain mapping and connectomics efforts.

Machine learning allows detecting specific physical activities using data from wearable sensors. Such a quantification of patient mobility over time promises to accurately inform clinical decisions for physical rehabilitation. There are two strategies of setting up the machine learning problem: detect one patient's activities using data from the same patient (personal model) or detect their activities using data from other patients (global model), and we currently do not know if personal models are necessary. Here we consider the problem of detecting physical activities from a waist-worn accelerometer in patients who use a knee-ankle-foot orthosis (KAFO) to walk. We show that while a model based on healthy subjects has low accuracy, the global model performs as well as the personal model. This is encouraging because it suggests that condition-specific activity recognition algorithms are sufficient and that no data from individual patients is necessary.

2016 38th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC)

Activity recognition in patients with lower limb impairments: Do we need training data from each patient?

There is a strong emphasis on developing novel neuroscience technologies, in particular on recording from more neurons. There has thus been increasing discussion about how to analyze the resulting big datasets. What has received less attention is that over the last 30 years, papers in neuroscience have progressively integrated more approaches, such as electrophysiology, anatomy, and genetics. As such, there has been little discussion on how to combine and analyze this multimodal data. Here, we describe the growth of multimodal approaches, and discuss the needed analysis advancements to make sense of this data.

It has recently been suggested that movement variability directly increases the speed of motor learning. Here we use computational modeling of motor adaptation to show that variability can have a broad range of effects on learning, both negative and positive. Experimentally, we also find contributing and decelerating effects. Lastly, through a meta-analysis of published papers, we verify that across a wide range of experiments, movement variability has no statistical relation with learning rate. While motor learning is a complex process that can be modeled, further research is needed to understand the relative importance of the involved factors.

Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference

Activity recognition in patients with lower limb impairments: do we need training data from each patient?

High-Throughput Polymerase Fidelity Evolution in Microfluidic Droplets

Background: We control the movements of our body and limbs through our muscles. However, the forces produced by our muscles depend unpredictably on the commands sent to them. This uncertainty has two sources: irreducible noise in the motor system's processes (i.e., motor noise) and variability in the relationship between muscle commands and muscle outputs (i.e., model uncertainty). Any controller, neural or artificial, benefits from estimating these uncertainties when choosing commands. Methods: To examine these benefits, we used an experimental preparation of the rat hindlimb to electrically stimulate muscles and measure the resulting isometric forces. We compare a functional electric stimulation (FES) controller that represents and compensates for uncertainty in muscle forces with a standard FES controller that neglects uncertainty. Results: Accounting for uncertainty substantially increased the precision of force control. Conclusion: Our study demonstrates the theoretical and practical benefits of representing muscle uncertainty when computing muscle commands. Significance: The findings are relevant beyond FES as they highlight the benefits of estimating statistical properties of muscles for both artificial controllers and the nervous system.

A Probabilistic Analysis of Muscle Force Uncertainty for Control

Finding relevant publications is important for scientists who have to cope with exponentially increasing numbers of scholarly material. Algorithms can help with this task as they help for music, movie, and product recommendations. However, we know little about the performance of these algorithms with scholarly material. Here, we develop an algorithm, and an accompanying Python library, that implements a recommendation system based on the content of articles. Design principles are to adapt to new content, provide near-real time suggestions, and be open source. We tested the library on 15K posters from the Society of Neuroscience Conference 2015. Human curated topics are used to cross validate parameters in the algorithm and produce a similarity metric that maximally correlates with human judgments. We show that our algorithm significantly outperformed suggestions based on keywords. The work presented here promises to make the exploration of scholarly material faster and more accurate.

Science Concierge: A Fast Content-Based Recommendation System for Scientific Publications

Every movement we make represents one of many possible actions. In reaching tasks with multiple targets, dorsal premotor cortex (PMd) appears to represent all possible actions simultaneously. However, in many situations we are not presented with explicit choices. Instead, we must estimate the best action based on noisy information and execute it while still uncertain of our choice. Here we asked how both primary motor cortex (M1) and PMd represented reach direction during a task in which a monkey made reaches based on noisy, uncertain target information. We found that with increased uncertainty, neurons in PMd actually enhanced their representation of unlikely movements throughout both planning and execution. The magnitude of this effect was highly variable across sessions, and was correlated with a measure of the monkeys’ behavioral uncertainty. These effects were not present in M1. Our findings suggest that PMd represents and maintains a full distribution of potentially correct actions. DOI: http://dx.doi.org/10.7554/eLife.14316.001

Uncertainty leads to persistent effects on reach representations in dorsal premotor cortex

The next grand challenges for society and science are in the brain sciences. A collection of 60+ scientists from around the world, together with 10+ observers from national, private, and foundations, spent two days together discussing the top challenges that we could solve as a global community in the next decade. We eventually settled on three challenges, spanning anatomy, physiology, and medicine. Addressing all three challenges requires novel computational infrastructure. The group proposed the advent of The International Brain Station (TIBS), to address these challenges, and launch brain sciences to the next level of understanding.

To the Cloud! A Grassroots Proposal to Accelerate Brain Science Discovery

When we search for visual objects, the features of those objects bias our attention across the visual landscape (feature-based attention). The brain uses these top-down cues to select eye movement targets (spatial selection). The frontal eye field (FEF) is a prefrontal brain region implicated in selecting eye movements and is thought to reflect feature-based attention and spatial selection. Here, we study how FEF facilitates attention and selection in complex natural scenes. We ask whether FEF neurons facilitate feature-based attention by representing search-relevant visual features or whether they are primarily involved in selecting eye movement targets in space. We show that search-relevant visual features are weakly predictive of gaze in natural scenes and additionally have no significant influence on FEF activity. Instead, FEF activity appears to primarily correlate with the direction of the upcoming eye movement. Our result demonstrates a concrete need for better models of natural scene search and suggests that FEF activity during natural scene search is explained primarily by spatial selection.

Feature-based attention and spatial selection in frontal eye fields during natural scene search.

Author response: Uncertainty leads to persistent effects on reach representations in dorsal premotor cortex

Background Smartphones offer the hope that depression can be detected using passively collected data from the phone sensors. The aim of this study was to replicate and extend previous work using geographic location (GPS) sensors to identify depressive symptom severity. Methods We used a dataset collected from 48 college students over a 10-week period, which included GPS phone sensor data and the Patient Health Questionnaire 9-item (PHQ-9) to evaluate depressive symptom severity at baseline and end-of-study. GPS features were calculated over the entire study, for weekdays and weekends, and in 2-week blocks. Results The results of this study replicated our previous findings that a number of GPS features, including location variance, entropy, and circadian movement, were significantly correlated with PHQ-9 scores (r’s ranging from −0.43 to −0.46, p-values < .05). We also found that these relationships were stronger when GPS features were calculated from weekend, compared to weekday, data. Although the correlation between baseline PHQ-9 scores with 2-week GPS features diminished as we moved further from baseline, correlations with the end-of-study scores remained significant regardless of the time point used to calculate the features. Discussion Our findings were consistent with past research demonstrating that GPS features may be an important and reliable predictor of depressive symptom severity. The varying strength of these relationships on weekends and weekdays suggests the role of weekend/weekday as a moderating variable. The finding that GPS features predict depressive symptom severity up to 10 weeks prior to assessment suggests that GPS features may have the potential as early warning signals of depression.

The relationship between mobile phone location sensor data and depressive symptom severity

Imaging methods used in modern neuroscience experiments are quickly producing large amounts of data capable of providing increasing amounts of knowledge about neuroanatomy and function. A great deal of information in these datasets is relatively unexplored and untapped. One of the bottlenecks in knowledge extraction is that often there is no feedback loop between the knowledge produced (e.g., graph, density estimate, or other statistic) and the earlier stages of the pipeline (e.g., acquisition). We thus advocate for the development of sample-to-knowledge discovery pipelines that one can use to optimize acquisition and processing steps with a particular end goal (i.e., piece of knowledge) in mind. We therefore propose that optimization takes place not just within each processing stage but also between adjacent (and non-adjacent) steps of the pipeline. Furthermore, we explore the existing categories of knowledge representation and models to motivate the types of experiments and analysis needed to achieve the ultimate goal. To illustrate this approach, we provide an experimental paradigm to answer questions about large-scale synaptic distributions through a multimodal approach combining X-ray microtomography and electron microscopy.

From sample to knowledge: Towards an integrated approach for neuroscience discovery

When a saccade is expected to result in a reward, both neural activity in oculomotor areas and the saccade itself (e.g., its vigor and latency) are altered (compared with when no reward is expected). As such, it is unclear whether the correlations of neural activity with reward indicate a representation of reward beyond a movement representation; the modulated neural activity may simply represent the differences in motor output due to expected reward. Here, to distinguish between these possibilities, we trained monkeys to perform a natural scene search task while we recorded from the frontal eye field (FEF). Indeed, when reward was expected (i.e., saccades to the target), FEF neurons showed enhanced responses. Moreover, when monkeys accidentally made eye movements to the target, firing rates were lower than when they purposively moved to the target. Thus, neurons were modulated by expected reward rather than simply the presence of the target. We then fit a model that simultaneously included components related to expected reward and saccade parameters. While expected reward led to shorter latency and higher velocity saccades, these behavioral changes could not fully explain the increased FEF firing rates. Thus, FEF neurons appear to encode motivational factors such as reward expectation, above and beyond the kinematic and behavioral consequences of imminent reward.

Role of expected reward in frontal eye field during natural scene search.

The availability of smartphone and wearable sensor technology is leading to a rapid accumulation of human subject data, and machine learning is emerging as a technique to map that data into clinical predictions. As machine learning algorithms are increasingly used to support clinical decision making, it is important to reliably quantify their prediction accuracy. Cross-validation is the standard approach for evaluating the accuracy of such algorithms; however, several cross-validations methods exist and only some of them are statistically meaningful. Here we compared two popular cross-validation methods: record-wise and subject-wise. Using both a publicly available dataset and a simulation, we found that record-wise cross-validation often massively overestimates the prediction accuracy of the algorithms. We also found that this erroneous method is used by almost half of the retrieved studies that used accelerometers, wearable sensors, or smartphones to predict clinical outcomes. As we move towards an era of machine learning based diagnosis and treatment, using proper methods to evaluate their accuracy is crucial, as erroneous results can mislead both clinicians and data scientists.

There is a popular belief in neuroscience that we are primarily data limited, and that producing large, multimodal, and complex datasets will, with the help of advanced data analysis algorithms, lead to fundamental insights into the way the brain processes information. These datasets do not yet exist, and if they did we would have no way of evaluating whether or not the algorithmically-generated insights were sufficient or even correct. To address this, here we take a classical microprocessor as a model organism, and use our ability to perform arbitrary experiments on it to see if popular data analysis methods from neuroscience can elucidate the way it processes information. Microprocessors are among those artificial information processing systems that are both complex and that we understand at all levels, from the overall logical flow, via logical gates, to the dynamics of transistors. We show that the approaches reveal interesting structure in the data but do not meaningfully describe the hierarchy of information processing in the microprocessor. This suggests current analytic approaches in neuroscience may fall short of producing meaningful understanding of neural systems, regardless of the amount of data. Additionally, we argue for scientists using complex non-linear dynamical systems with known ground truth, such as the microprocessor as a validation platform for time-series and structure discovery methods. Author Summary Neuroscience is held back by the fact that it is hard to evaluate if a conclusion is correct; the complexity of the systems under study and their experimental inaccessability make the assessment of algorithmic and data analytic technqiues challenging at best. We thus argue for testing approaches using known artifacts, where the correct interpretation is known. Here we present a microprocessor platform as one such test case. We find that many approaches in neuroscience, when used na•vely, fall short of producing a meaningful understanding.

Good scientific writing is essential to career development and to the progress of science. A well-structured manuscript allows readers and reviewers to get excited about the subject matter, to understand and verify the paper’s contributions, and to integrate these contributions into a broader context. However, many scientists struggle with producing high-quality manuscripts and typically get little training in paper writing. Focusing on how readers consume information, we present a set of 10 simple rules to help you get across the main idea of your paper. These rules are designed to make your paper more influential and the process of writing more efficient and pleasurable.

Rewards associated with actions are critical for motivation and learning about the consequences of one’s actions on the world. The motor cortices are involved in planning and executing movements, but it is unclear whether they encode reward over and above limb kinematics and dynamics. Here, we report a categorical reward signal in dorsal premotor (PMd) and primary motor (M1) neurons that corresponds to an increase in firing rates when a trial was not rewarded regardless of whether or not a reward was expected. We show that this signal is unrelated to error magnitude, reward prediction error, or other task confounds such as reward consumption, return reach plan, or kinematic differences across rewarded and unrewarded trials. The availability of reward information in motor cortex is crucial for theories of reward-based learning and motivational influences on actions.

Background Depression is a common, burdensome, often recurring mental health disorder that frequently goes undetected and untreated. Mobile phones are ubiquitous and have an increasingly large complement of sensors that can potentially be useful in monitoring behavioral patterns that might be indicative of depressive symptoms. Objective The objective of this study was to explore the detection of daily-life behavioral markers using mobile phone global positioning systems (GPS) and usage sensors, and their use in identifying depressive symptom severity. Methods A total of 40 adult participants were recruited from the general community to carry a mobile phone with a sensor data acquisition app (Purple Robot) for 2 weeks. Of these participants, 28 had sufficient sensor data received to conduct analysis. At the beginning of the 2-week period, participants completed a self-reported depression survey (PHQ-9). Behavioral features were developed and extracted from GPS location and phone usage data. Results A number of features from GPS data were related to depressive symptom severity, including circadian movement (regularity in 24-hour rhythm; r=-.63, P=.005), normalized entropy (mobility between favorite locations; r=-.58, P=.012), and location variance (GPS mobility independent of location; r=-.58, P=.012). Phone usage features, usage duration, and usage frequency were also correlated (r=.54, P=.011, and r=.52, P=.015, respectively). Using the normalized entropy feature and a classifier that distinguished participants with depressive symptoms (PHQ-9 score ≥5) from those without (PHQ-9 score <5), we achieved an accuracy of 86.5%. Furthermore, a regression model that used the same feature to estimate the participants’ PHQ-9 scores obtained an average error of 23.5%. Conclusions Features extracted from mobile phone sensor data, including GPS and phone usage, provided behavioral markers that were strongly related to depressive symptom severity. While these findings must be replicated in a larger study among participants with confirmed clinical symptoms, they suggest that phone sensors offer numerous clinical opportunities, including continuous monitoring of at-risk populations with little patient burden and interventions that can provide just-in-time outreach.

Mobile Phone Sensor Correlates of Depressive Symptom Severity in Daily-Life Behavior: An Exploratory Study

Web-Based Assessment of Outcomes After Subarachnoid and Intracerebral Hemorrhage: A New Patient Centered Option for Outcomes Assessment

The motor system generates time-varying commands to move our limbs and body. Conventional descriptions of motor control and learning rely on dynamical representations of our body's state (forward and inverse models), and control policies that must be integrated forward to generate feedforward time-varying commands; thus these are representations across space, but not time. Here we examine a new approach that directly represents both time-varying commands and the resulting state trajectories with a function; a representation across space and time. Since the output of this function includes time, it necessarily requires more parameters than a typical dynamical model. To avoid the problems of local minima these extra parameters introduce, we exploit recent advances in machine learning to build our function using a stacked autoencoder, or deep network. With initial and target states as inputs, this deep network can be trained to output an accurate temporal profile of the optimal command and state trajectory for a point-to-point reach of a non-linear limb model, even when influenced by varying force fields. In a manner that mirrors motor babble, the network can also teach itself to learn through trial and error. Lastly, we demonstrate how this network can learn to optimize a cost objective. This functional approach to motor control is a sharp departure from the standard dynamical approach, and may offer new insights into the neural implementation of motor control.

Dominant and Nondominant Arm Reaching Differences in Control of Limb Dynamics During

Like humans, monkeys make saccades nearly three times a second. To understand the factors guiding this frequent decision, computational models of vision attempt to predict fixation locations using bottom-up visual features and top-down goals. How do the relative influences of these factors evolve over multiple time scales? Here we analyzed visual features at fixations using a retinal transform that provides realistic visual acuity by suitably degrading visual information in the periphery. In a task in which monkeys searched for a Gabor target in natural scenes, we characterized the relative importance of bottom-up and task-relevant influences by decoding fixated from nonfixated image patches based on visual features. At fast time scales, we found that search strategies can vary over the course of a single trial, with locations of higher saliency, target-similarity, edge–energy, and orientedness looked at later on in the trial. At slow time scales, we found that search strategies can be refined over several weeks of practice, and the influence of target orientation was significant only in the latter of two search tasks. Critically, these results were not observed without applying the retinal transform. Our results suggest that saccade-guidance strategies become apparent only when models take into account degraded visual representation in the periphery.

Modeling peripheral visual acuity enables discovery of gaze strategies at multiple time scales during natural scene search.

Author response: Automatic discovery of cell types and microcircuitry from neural connectomics

The two-alternative forced-choice (2AFC) task is the workhorse of psychophysics and is used to measure the just-noticeable difference, generally assumed to accurately quantify sensory precision. However, this assumption is not true for all mechanisms of decision making. Here we derive the behavioral predictions for two popular mechanisms, sampling and maximum a posteriori, and examine how they affect the outcome of the 2AFC task. These predictions are used in a combined visual 2AFC and estimation experiment. Our results strongly suggest that subjects use a maximum a posteriori mechanism. Further, our derivations and experimental paradigm establish the already standard 2AFC task as a behavioral tool for measuring how humans make decisions under uncertainty.

Which is my body and how do I distinguish it from the bodies of others, or from objects in the surrounding environment? The perception of our own body and more particularly our sense of body ownership is taken for granted. Nevertheless, experimental findings from body ownership illusions (BOIs), show that under specific multisensory conditions, we can experience artificial body parts or fake bodies as our own body parts or body, respectively. The aim of the present paper is to discuss how and why BOIs are induced. We review several experimental findings concerning the spatial, temporal, and semantic principles of crossmodal stimuli that have been applied to induce BOIs. On the basis of these principles, we discuss theoretical approaches concerning the underlying mechanism of BOIs. We propose a conceptualization based on Bayesian causal inference for addressing how our nervous system could infer whether an object belongs to our own body, using multisensory, sensorimotor, and semantic information, and we discuss how this can account for several experimental findings. Finally, we point to neural network models as an implementational framework within which the computational problem behind BOIs could be addressed in the future.

Over my fake body: body ownership illusions for studying the multisensory basis of own-body perception

Data-aware methods for dimensionality reduction and matrix decomposition aim to find low-dimensional structure in a collection of data. Classical approaches discover such structure by learning a basis that can efficiently express the collection. Recently, "self expression", the idea of using a small subset of data vectors to represent the full collection, has been developed as an alternative to learning. Here, we introduce a scalable method for computing sparse SElf-Expressive Decompositions (SEED). SEED is a greedy method that constructs a basis by sequentially selecting incoherent vectors from the dataset. After forming a basis from a subset of vectors in the dataset, SEED then computes a sparse representation of the dataset with respect to this basis. We develop sufficient conditions under which SEED exactly represents low rank matrices and vectors sampled from a unions of independent subspaces. We show how SEED can be used in applications ranging from matrix approximation and denoising to clustering, and apply it to numerous real-world datasets. Our results demonstrate that SEED is an attractive low-complexity alternative to other sparse matrix factorization approaches such as sparse PCA and self-expressive methods for clustering.

Self-Expressive Decompositions for Matrix Approximation and Clustering

Smartphone sensor correlates of depressive symptom severity in daily-life behavior

Healthcare services increasingly use the activity recognition technology to track the daily activities of individuals. In some cases, this is used to provide incentives. For example, some health insurance companies offer discount to customers who are physically active, based on the data collected from their activity tracking devices. Therefore, there is an increasing motivation for individuals to cheat, by making activity trackers detect activities that increase their benefits rather than the ones they actually do. In this study, we used a novel method to make activity recognition robust against deceptive behavior. We asked 14 subjects to attempt to trick our smartphone-based activity classifier by making it detect an activity other than the one they actually performed, for example by shaking the phone while seated to make the classifier detect walking. If they succeeded, we used their motion data to retrain the classifier, and asked them to try to trick it again. The experiment ended when subjects could no longer cheat. We found that some subjects were not able to trick the classifier at all, while others required five rounds of retraining. While classifiers trained on normal activity data predicted true activity with ~38% accuracy, training on the data gathered during the deceptive behavior increased their accuracy to ~84%. We conclude that learning the deceptive behavior of one individual helps to detect the deceptive behavior of others. Thus, we can make current activity recognition robust to deception by including deceptive activity data from a few individuals.

Current high-resolution imaging techniques require an intact sample that preserves spatial relationships. We here present a novel approach, “puzzle imaging,” that allows imaging a spatially scrambled sample. This technique takes many spatially disordered samples, and then pieces them back together using local properties embedded within the sample. We show that puzzle imaging can efficiently produce high-resolution images using dimensionality reduction algorithms. We demonstrate the theoretical capabilities of puzzle imaging in three biological scenarios, showing that (1) relatively precise 3-dimensional brain imaging is possible; (2) the physical structure of a neural network can often be recovered based only on the neural connectivity matrix; and (3) a chemical map could be reproduced using bacteria with chemosensitive DNA and conjugative transfer. The ability to reconstruct scrambled images promises to enable imaging based on DNA sequencing of homogenized tissue samples.

Puzzle Imaging: Using Large-Scale Dimensionality Reduction Algorithms for Localization

Trajectories and Final Positions in Reaching Different Learned Coordinate Frames for Planning

Introduction Current research suggests that the neuropathology of dementia—including brain changes leading to memory impairment and cognitive decline—is evident years before the onset of this disease. Older adults with cognitive decline have reduced functional independence and quality of life, and are at greater risk for developing dementia. Therefore, identifying biomarkers that can be easily assessed within the clinical setting and predict cognitive decline is important. Early recognition of cognitive decline could promote timely implementation of preventive strategies. Methods We included 89 community-dwelling adults aged 70 years and older in our study, and collected 32 measures of physical function, health status and cognitive function at baseline. We utilized an L1–L2 regularized regression model (elastic net) to identify which of the 32 baseline measures were strongly predictive of cognitive function after one year. We built three linear regression models: 1) based on baseline cognitive function, 2) based on variables consistently selected in every cross-validation loop, and 3) a full model based on all the 32 variables. Each of these models was carefully tested with nested cross-validation. Results Our model with the six variables consistently selected in every cross-validation loop had a mean squared prediction error of 7.47. This number was smaller than that of the full model (115.33) and the model with baseline cognitive function (7.98). Our model explained 47% of the variance in cognitive function after one year. Discussion We built a parsimonious model based on a selected set of six physical function and health status measures strongly predictive of cognitive function after one year. In addition to reducing the complexity of the model without changing the model significantly, our model with the top variables improved the mean prediction error and R-squared. These six physical function and health status measures can be easily implemented in a clinical setting.

Predicting Cognitive Function from Clinical Measures of Physical Function and Health Status in Older Adults

Statistics of Natural Stimuli? How Are Complex Cell Properties Adapted to the

In the discrete Tempotron learning problem a neuron receives time varying inputs and for a set of such input sequences ($\mathcal S_-$ set) the neuron must be sub-threshold for all times while for some other sequences ($\mathcal S_+$ set) the neuron must be super threshold for at least one time. Here we present a graphical treatment of a slight reformulation of the tempotron problem. We show that the problem's general form is equivalent to the question if a polytope, specified by a set of inequalities, is contained in the union of a set of equally defined polytopes. Using recent results from computational geometry, we show that the problem is W[1]-hard. This phrasing gives some new insights into the nature of gradient based learning algorithms. A sampling based approach can, under certain circumstances provide an approximation in polynomial time. Other problems, related to hierarchical neural networks may share some topological structure.

The clinical assessment of severity of depressive symptoms is commonly performed with standardized self-report questionnaires, most notably the patient health questionnaire (PHQ-9), which are usually administered in a clinic. These questionnaires evaluate symptoms that are stable over time. Ecological momentary assessment (EMA) methods, on the other hand, acquire patient ratings of symptoms in the context of their lives. Today's smartphones allow us to also obtain objective contextual information, such as the GPS location, that may also be related to depression. Considering clinical PHQ-9 scores as ground truth, an interesting question is to what extent the EMA ratings and contextual sensor data can be used as potential predictors of depression. To answer this question, we obtained PHQ-9 scores from 18 participants with a variety of depressive symptoms in our lab, and then collected their EMA and GPS sensor data using their smartphones over a period of two weeks. We analyzed the relationship between GPS sensor features, EMA ratings, and the PHQ-9 scores. While we found a strong correlation between a number of sensor features extracted from the two-week period and the PHQ-9 scores, the other relationships remained non-significant. Our results suggest that depression is better evaluated using long-term sensor-based measurements than the momentary ratings of mental state or short-term sensor information.

2015 9th International Conference on Pervasive Computing Technologies for Healthcare (PervasiveHealth)

The relationship between clinical, momentary, and sensor-based assessment of depression

EMG control of powered upper limb prostheses is difficult and imprecise. One approach for improving control is to help amputees develop more accurate internal models of their prosthetic device. This may be facilitated by an intuitive mapping of neural signals to device movement, a way of providing sensory feedback, or training methods. A first step, arguably, is to understand how an amputation affects adaptation. Here we studied trial-by-trial adaptation in a simple target-directed task with transhumeral amputees and healthy controls. We found that adaptation behavior was indistinguishable between amputees using the residual limb, amputees using the intact limb, and able-bodied subjects. Transhumeral amputees completed the task with larger errors than able-bodied subjects, but there was, perhaps surprisingly, no difference between the residual and intact limb.

2015 7th International IEEE/EMBS Conference on Neural Engineering (NER)

Similar trial-by-trial adaptation behavior across transhumeral amputees and able-bodied subjects

After Long-Term Practice Skill Representation in the Primary Motor Cortex

When reaching to grasp, we coordinate how we preshape the hand with how we move it. To ask how motor cortical neurons participate in this coordination, we examined the interactions between reach- and grasp-related neuronal ensembles while monkeys reached to grasp a variety of different objects in different locations. By describing the dynamics of these two ensembles as trajectories in a low-dimensional state space, we examined their coupling in time. We found evidence for temporal compensation across many different reach-to-grasp conditions such that if one neural trajectory led in time the other tended to catch up, reducing the asynchrony between the trajectories. Granger causality revealed bidirectional interactions between reach and grasp neural trajectories beyond that which could be attributed to the joint kinematics that were consistently stronger in the grasp-to-reach direction. Characterizing cortical coordination dynamics provides a new framework for understanding the functional interactions between neural populations.

Sequence production tasks are a standard tool to analyze motor learning, consolidation, and habituation. As sequences are learned, movements are typically grouped into subsets or chunks. For example, most Americans memorize telephone numbers in two chunks of three digits, and one chunk of four. Studies generally use response times or error rates to estimate how subjects chunk, and these estimates are often related to physiological data. Here we show that chunking is simultaneously reflected in reaction times, errors, and their correlations. This multimodal structure enables us to propose a Bayesian algorithm that better estimates chunks while avoiding overfitting. Our algorithm reveals previously unknown behavioral structure, such as an increased error correlations with training, and promises a useful tool for the characterization of many forms of sequential motor behavior.

Powered prostheses are controlled using electromyographic (EMG) signals, which may introduce high levels of uncertainty even for simple tasks. According to Bayesian theories, higher uncertainty should influence how the brain adapts motor commands in response to perceived errors. Such adaptation may critically influence how patients interact with their prosthetic devices; however, we do not yet understand adaptation behavior with EMG control. Models of adaptation can offer insights on movement planning and feedback correction, but we first need to establish their validity for EMG control interfaces. Here we created a simplified comparison of prosthesis and able-bodied control by studying adaptation with three control interfaces: joint angle, joint torque, and EMG. Subjects used each of the control interfaces to perform a target-directed task with random visual perturbations. We investigated how control interface and visual uncertainty affected trial-by-trial adaptation. As predicted by Bayesian models, increased errors and decreased visual uncertainty led to faster adaptation. The control interface had no significant effect beyond influencing error sizes. This result suggests that Bayesian models are useful for describing prosthesis control and could facilitate further investigation to characterize the uncertainty faced by prosthesis users. A better understanding of factors affecting movement uncertainty will guide sensory feedback strategies for powered prostheses and clarify what feedback information best improves control.

learning to novel contexts Natural error patterns enable transfer of motor

Much of human knowledge sits in large databases of unstructured text. Leveraging this knowledge requires algorithms that extract and record metadata on unstructured text documents. Assigning topics to documents will enable intelligent search, statistical characterization, and meaningful classification. Latent Dirichlet allocation (LDA) is the state-of-the-art in topic classification. Here, we perform a systematic theoretical and numerical analysis that demonstrates that current optimization techniques for LDA often yield results which are not accurate in inferring the most suitable model parameters. Adapting approaches for community detection in networks, we propose a new algorithm which displays high-reproducibility and high-accuracy, and also has high computational efficiency. We apply it to a large set of documents in the English Wikipedia and reveal its hierarchical structure. Our algorithm promises to make "big data" text analysis systems more reliable.

A high-reproducibility and high-accuracy method for automated topic classification

Hand, belt, pocket or bag: Practical activity tracking with mobile phones

To generate new movements, we have to generalize what we have learned from previously practiced movements. An important question, therefore, is how the breadth of training affects generalization: does practicing a broad or narrow range of movements lead to better generalization? We address this question with a force field learning experiment. One group adapted while making many reaches in a small region (narrow group), and another group adapted while making reaches in a large region (broad group). Subsequently, both groups were tested for their ability to generalize without visual feedback. Not surprisingly, the narrow group exhibited smaller adaptation errors, yet they did not generalize any better than the broad group. Path errors during generalization were indistinguishable across the two groups, whereas the broad group exhibited reduced terminal errors. These findings indicate that overall, practicing a variety of movements is advantageous for performance during generalization; movement paths are not hindered, and terminal errors are superior. Moreover, the evidence suggests a dissociation between the ability to generalize information about a novel dynamic disturbance, which generalizes narrowly, and the ability to locate the limb accurately in space, which generalizes broadly.

Our brain often needs to estimate unknown variables from imperfect information. Our knowledge about the statistical distributions of quantities in our environment (called priors) and currently available information from sensory inputs (called likelihood) are the basis of all Bayesian models of perception and action. While we know that priors are learned, most studies of prior-likelihood integration simply assume that subjects know about the likelihood. However, as the quality of sensory inputs change over time, we also need to learn about new likelihoods. Here, we show that human subjects readily learn the distribution of visual cues (likelihood function) in a way that can be predicted by models of statistically optimal learning. Using a likelihood that depended on color context, we found that a learned likelihood generalized to new priors. Thus, we conclude that subjects learn about likelihood.

Cancer and healthy cells have distinct distributions of molecular properties and thus respond differently to drugs. Cancer drugs ideally kill cancer cells while limiting harm to healthy cells. However, the inherent variance among cells in both cancer and healthy cell populations increases the difficulty of selective drug action. Here we formalize a classification framework based on the idea that an ideal cancer drug should maximally discriminate between cancer and healthy cells. More specifically, this discrimination should be performed on the basis of measurable cell markers. We divide the problem into three parts which we explore with examples. First, molecular markers should discriminate cancer cells from healthy cells at the single-cell level. Second, the effects of drugs should be statistically predicted by these molecular markers. Third, drugs should be optimized for classification performance. We find that expression levels of a handful of genes suffice to discriminate well between individual cells in cancer and healthy tissue. We also find that gene expression predicts the efficacy of some cancer drugs, suggesting that these cancer drugs act as suboptimal classifiers using gene profiles. Finally, we formulate a framework that defines an optimal drug, and predicts drug cocktails that may target cancer more accurately than the individual drugs alone. Conceptualizing cancer drugs as solving a discrimination problem in the high-dimensional space of molecular markers promises to inform the design of new cancer drugs and drug cocktails.

Faculty Opinions recommendation of Chronic, wireless recordings of large-scale brain activity in freely moving rhesus monkeys.

Neural connectomics has begun producing massive amounts of data, necessitating new analysis methods to discover the biological and computational structure. It has long been assumed that discovering neuron types and their relation to microcircuitry is crucial to understanding neural function. Here we developed a non-parametric Bayesian technique that identifies neuron types and microcircuitry patterns in connectomics data. It combines the information traditionally used by biologists in a principled and probabilistically coherent manner, including connectivity, cell body location, and the spatial distribution of synapses. We show that the approach recovers known neuron types in the retina and enables predictions of connectivity, better than simpler algorithms. It also can reveal interesting structure in the nervous system of Caenorhabditis elegans and an old man-made microprocessor. Our approach extracts structural meaning from connectomics, enabling new approaches of automatically deriving anatomical insights from these emerging datasets. DOI: http://dx.doi.org/10.7554/eLife.04250.001

Automatic discovery of cell types and microcircuitry from neural connectomics

Department of Physical Medicine and Rehabilitation,Rehabilitation Institute of Chicago, Northwestern University,Chicago, IL 60611, USASummaryOver the past few decades, one of the most salient lifestylechanges for us has been the use of computers. For manyof us, manual interaction with a computer occupies a largeportion of our working time. Through neural plasticity, thisextensivemovementtrainingshouldchangeourrepresenta-tion of movements (e.g., [1–3]), just like search enginesaffect memory [4]. However, how computer use affectsmotor learning is largely understudied. Additionally, asvirtually all participants in studies of perception and actionsare computer users, a legitimate question is whether in-sights from these studies bear the signature of computer-use experience. We compared non-computer users withage- and education-matched computer users in standardmotor learning experiments. We found that people learnedequallyfastbutthatnon-computerusersgeneralizedsigniﬁ-cantly less across space, a difference negated by two weeksof intensive computer training. Our ﬁndings suggest thatcomputer-use experience shaped our basic sensorimotorbehaviors, and this inﬂuence should be considered when-ever computer users are recruited as study participants.Results and DiscussionThe average computer user produces 7,400 mouse clicks perweek [5]. Computer use often involves globally linear transfor-mationsbetweenthebodymovementanditsscreenrepresen-tation, e.g., the mapping from hand movement to mousecursor position. Hence, with long-term interaction with mice,computer users probably develop an expectation that visuo-motor transformation between hand movement and its screenrepresentation should remain consistent across work space.Hence,inlinewithrecentﬁndingsthatpriorexperienceaffectsmotor control [6–9], and motor generalization in particular[10, 11], our working hypothesis is that people without com-puter experience will generalize more locally in visuomotorlearning and that this difference should be negated withcomputer-use training.To assess how such movement behaviors are affected bycomputer use, we recruited 18 Chinese migrant workers,nine of them being regular computer users (control group,age 41.9 6 8.9 years) and nine of them never having used acomputer before (non-computer-user group, age 38.2 6 10.1years). We also assembled a control group made up of ninecollege students (student group, age 21.9 6 2.4 years). All ofthese naive subjects were tested with a standard visuomotorgain adaptation experiment [12, 13] in which subjects learnedto move a cursor while their hand was hidden from view (Fig-ure 1A). The gain between the hand displacement and thecursor displacement was modiﬁed in the training direction(Figure 1B). Subjects adapted to this visuomotor gain changeand were subsequently tested in other directions to assesstheir directional generalization.So how does computer use affect movement behavior?It affected neither the speed of learning [F(8,18) = 0.91, p =0.53, one-way ANOVA] nor the degree of learning [F(8,18) =0.77, p = 0.64; Figure 2A]. However, the computer users,compared to the non-computer-user group, generalize muchmore into other directions [interaction effect F(8, 96) = 6.9,p < 0.0001; main effect on groups F(2, 24) = 12.5, p < 0.0001,two-way ANOVA; Figure 2B]. Interestingly, non-computerusers still have a broad generalization as their generalizationissigniﬁcantlylargerthanzeroevenatthelargestangularsep-aration of 180 (30.0% 6 6.9%; p < 0.001, one-sample t test).There is no difference between the computer group and thestudent group, suggesting that subjects of different agesbehave similarly as long as they are computer users.To establish the causal relationship, we recruited anothergroup of ten non-computer users and examined their general-ization before and after intensive computer-use training. Werealized that our movement interaction with computer ismostly via a computer mouse; this interaction involves a map-ping between a movement space and a visual space, rathersimilar to experimental setting in our and others’ studies. Wethus chose to give subjects intensive training on using com-puter mouse. Before training, their generalization was againquite narrow and their generalization was not signiﬁcant fromthat of the non-computer-user group in experiment 1 [Fig-ure 3A; two-way mixed-design ANOVA, main effect on groupsF(1,17)=0.24,p=0.63andinteractioneffectF(4,68)=0.25,p=0.92]. In the following 2 weeks, participants were instructed toplaycomputergames(e.g.,Pong)thatrequireintensivemouseusefor2hreachday.Wealsotestedtheirmouse-useabilitybyasking them to track a moving cursor with mouse cursor (Fig-ure 3B, inset). This tracking task was performed before andafter training on each day. The overall tracking error wasreduced across days (Figure 3B). More importantly, partici-pants exhibited signiﬁcantly larger generalization when theywere tested again after 14-day training (Figure 3A). Two-wayrepeated-measures ANOVA revealed signiﬁcant main effecton timing [before versus after training, F(1,9) = 13.08, p <0.01] and signiﬁcant interaction effect [F(4,36) = 9.48, p <0.0001]. The generalization was signiﬁcantly higher at all butthe 0 angular separations (p < 0.01 or p < 0.005 for simplemain effect tests). Two weeks of computer training convertedthe generalization patterns into those of computer users.Insummary,computeruseleaveslearningspeedunaffectedbutleadstoenhancedgeneralizationintountraineddirections.A possible reason for this change is that the gain mappingbetweenmousemovementsandcursormovementsisuniformacross different directions. Thus, long-term exposure to thissensorimotor mapping leads to our prior expectation ofconsistenttransformationbetweenmanualactionsandscreenrepresentations across directions. This prior expectation, in

Predicting eye movements of rhesus monkeys searching for pedestrians in natural images

Cervical spinal cord injury (SCI) paralyzes muscles of the hand and arm, making it difficult to perform activities of daily living. Restoring the ability to reach can dramatically improve quality of life for people with cervical SCI. Any reaching system requires a user interface to decode parameters of an intended reach, such as trajectory and target. A challenge in developing such decoders is that often few physiological signals related to the intended reach remain under voluntary control, especially in patients with high cervical injuries. Furthermore, the decoding problem changes when the user is controlling the motion of their limb, as opposed to an external device. The purpose of this study was to investigate the benefits of combining disparate signal sources to control reach in people with a range of impairments, and to consider the effect of two feedback approaches. Subjects with cervical SCI performed robot-assisted reaching, controlling trajectories with either shoulder electromyograms (EMGs) or EMGs combined with gaze. We then evaluated how reaching performance was influenced by task-related sensory feedback, testing the EMG-only decoder in two conditions. The first involved moving the arm with the robot, providing congruent sensory feedback through their remaining sense of proprioception. In the second, the subjects moved the robot without the arm attached, as in applications that control external devices. We found that the multimodal-decoding algorithm worked well for all subjects, enabling them to perform straight, accurate reaches. The inclusion of gaze information, used to estimate target location, was especially important for the most impaired subjects. In the absence of gaze information, congruent sensory feedback improved performance. These results highlight the importance of proprioceptive feedback, and suggest that multi-modal decoders are likely to be most beneficial for highly impaired subjects and in tasks where such feedback is unavailable.

Multimodal decoding and congruent sensory information enhance reaching performance in subjects with cervical spinal cord injury

Sequence production tasks are a standard tool to analyze motor learning, consolidation, and habituation. As sequences are learned, movements are typically grouped into subsets or chunks. For example, most Americans memorize telephone numbers in two chunks of 3 digits, and one chunk of 4. Studies generally use response times or error rates to estimate how subjects chunk, and these estimates are often related to physiological data. Here we show that chunking is simultaneously reflected in reaction times, errors, and their correlations. This multimodal structure enables us to propose a Bayesian algorithm that better estimate chunks while avoiding over-fitting. Our algorithm reveals previously unknown behavioral structure, such as an increased error correlations with training, and promises a useful tool for the characterization of many forms of sequential motor behavior. Multi-faceted aspects of chunking enable robust algorithms 3 Multi-faceted aspects of chunking enable robust algorithms Introduction One of the central questions in neuroscience, and cognitive and behavioral psychology is how the brain allows movement performance to improve with practice (Thorndike, 1898; Pavlov, 1927; Crossman, 1959; A. Newell & Rosenbloom, 1981; Skinner, 1938). When learning to produce sequences of actions, animals organize information into groups or “chunks” (Miller & George, 1956; K. M. Newell, 1991) and studying such chunks is a popular way of studying learning and memory. One common experimental paradigm to study movement chunking is the discrete sequence production task (DSP), where subjects learn, through many repetitions, to rapidly generate a fixed sequence of finger movements (Adams, 1984; Gentner, 1987; Verwey, 1996; Verwey & Dronkert, 1996; Logan & Bundesen, 2003). Understanding how practice leads to improved performance in this task promises to unveil how the central nervous system organizes temporal information in a way that enables fast, habitual processing (e.g., see Clerget et al., 2012). Indeed, evidence suggests that chunking is what allows efficient behavior. Performance gains in the DSP task correlate with motor chunking (Verwey, 1994, 1996; Verwey & Dronkert, 1996). This may be because long sequences cannot be stored in short term motor memory, or the optimal control problem for long sequences is generally infeasible (Todorov et al., 2005; Parr, 1998). Understanding motor chunking is crucial to understanding the organization of motor memory and movement efficiency. Motor chunks are known to leave characteristic traces on observed response times. One of the prominent features is a change in response times and errors at the beginning of chunks. There is a longer-than-usual pause during chunk concatenation (Verwey & Dronkert, 1996; Verwey, 1996). These differences in response times are frequently described and used in algorithms that reveal chunking behavior. It seems natural to think of each chunk as controlled by a single neural representation. And each representation should be able to produce these movements at the right speed, leading to additional predictions of features of chunking. When a new chunk is started, the transition should slow response times, and errors in the transition should lead to errors in the execution. However, we should also expect that each chunk is produced at a relatively fixed speed (Abrahamse et al., 2013). Reaction times and errors within a chunk should therefore be correlated, forming a novel hypothesis to test. There exists a range of methods for inferring chunking structure. The most common is to look at the mean response times during a set of trials and detect significant increases in certain elements of the sequence (Abrahamse et al., 2013; Verwey, 1996; Verwey & Dronkert, 1996; Verwey, 1994). These points of significant increase are marked as the start of a new chunk. This Multi-faceted aspects of chunking enable robust algorithms 4 simple method limits the analysis by requiring the experimenter to choose which ranges of trials to analyze. A recent approach based on community detection in networks (Wymbs et al., 2012) removes this limitation by modeling time explicitly and providing time varying evolution of chunk structures. These methods, however, cannot readily incoporate multiple signals (reponse times and errors) or deal with correlations of these signals within trials. In this article, we analyze data from seventeen subjects who participated in a DSP task over an average of 30 days of practice. We do find that the features reaction time, error, and their respective correlations are associated with chunking structure. Combining information across features and time allows us to construct a Bayesian algorithm that is consistently more precise than algorithms using only one feature. To verify the general applicability of our algorithm, we also analyze two datasets from non-human primates producing and learning sequences over months or even years. The resulting algorithm that combines the multimodal features of behavior and across time allows precise estimates of underlying chunking structure. Methods Experimental data We analyze data where humans or monkeys participate in a discrete sequence production (DSP) task. Subjects observe a cue that signals the next element of a sequence of elements to be executed. Each element of the sequence is signaled to the subject one at a time and after inputing the right element, the system advances to the next element, and so on until the end of the sequence (Figure 2A), which allows subjects to speed up the task by predicting the next element. Human data. We reanalyze data from a published study (Bassett et al., 2013). In short, twenty five subjects completed a training regimen involving the simultaneous acquisition of 6 different 10-element motor sequences using a discrete sequence production (DSP) task. Subjects were asked to input the elements as fast and accurate as possible. Over the course of a 6 week training regimen, subjects trained on the sequences both at home using their laptop computer as well as inside an MRI scanner. Training alternated between scanner and home locations, such that following each training session in the scanner, subjects performed a minimum of 10 sessions (1 session/day) at home over the next 2 weeks. This pattern of training repeated 3 times, so that subjects completed on average 30 home training sessions and 4 scan sessions. We only analyze the home training sessions. Sequence familiarity was manipulated during home training at three exposure levels. Each home training session consisted of 150 trials presented using a random schedule, so that two sequences trained extensively (around 2000 trials), two sequences trained moderately, and two sequences trained minimally. All subjects trained on the same sequence set and each at the same exposure level, which were maintained over the course of training. Only the highly trained sequences were analyzed in the present study. Sequence one is 2, 1, 3, 5, 4, 1, 3, 4, Multi-faceted aspects of chunking enable robust algorithms 5 2, and 5, and sequence two is 4, 2, 1, 3, 5, 2, 3, 1, 4, and 5. Fingers are sequentially numbered from (1) the thumb to (5) the pinky. We excluded 8 subjects because either lower participation rate, increase response times or error rates with practice. Monkey data. We reanalyze data from a published study (Matsuzaka et al., 2007, dataset D1): In short, two rhesus macaques participated in a 12-element 5-target discrete sequence production task. We analyze data from one monkey. Targets for the reaching movements were on a touch screen, chosen by touching the screen with the hand, and visually cued 300 ms after the previous target contact. However, the task allowed the monkeys to contact the next target in the sequence during the 300 ms delay before it was shown. When the monkeys made correct anticipatory responses, the task was incremented to the next element of the sequence without display of the touched target. As a result, the monkeys learned to perform the sequence in a predictive fashion without requiring visual cues. We reanalyze a second dataset from a previous study (Desmurget & Turner, 2010, dataset D2): In this task, two rhesus macaques participated in a 5-element 8-target discrete sequence production task (see also Desmurget & Turner, 2008, 2010). Targets for the movements were displayed on a monitor, chosen by steering a cursor through a target area with a joystick, and visually cued 230 ms after the previous target acquisition. The task required the animal to move the cursor in five consecutive out and back movements between the central start position and a series of five peripheral targets. As in dataset D1, with training, the monkey performed the task in a predictive fashion without relying on visual cues. Preprocessing The aim of this study is to understand the evolution of chunking structure over time. For this purpose, it is necessary to control for the effect of practice on overall movement speed that is unrelated to the within-sequence variability introduced by chunking. For example, by computing the mean response time as a function of trials, we can clearly see a trend that comes from practicing (Figure 2B). In our analysis, we remove this unrelated effect by performing a detrending of the response time data using an exponential model (Logan & Bundesen, 2003). There are alternative models for detrending practice curves, such as the power law, and depending on the cirscumstance different curves might be used (Heathcote et al., 2000). We assume that the practice component of response time depends on trials across days and the interaction between elements and trial RTt,i = a0 + a1 · exp(−b1 · t −b2 · t · i) } {{ } Practice effect + RRTt,i } {{ } Chunking + noise , (1) where t is the trial, i is the element. We control for the interaction of trial and element because Multi-faceted aspects of chunking enable robust algorithms 

Multi-faceted aspects of chunking enable robust algorithms 1 Running head : ALGORITHM FOR CHUNKING INFERENCE Multi-faceted aspects of chunking enable robust algorithms

A central issue in neural recording is that of distinguishing the activities of many neurons. Here, we develop a framework, based on Fisher information, to quantify how separable a neuron’s activity is from the activities of nearby neurons. We (1) apply this framework to model information flow and spatial distinguishability for several electrical and optical neural recording methods, (2) provide analytic expressions for information content, and (3) demonstrate potential applications of the approach. This method generalizes to many recording devices that resolve objects in space and thus may be useful in the design of next-generation scalable neural recording systems.

We propose a neural connectomics strategy called Fluorescent In-Situ Sequencing of Barcoded Individual Neuronal Connections (FISSEQ-BOINC), leveraging fluorescent in situ nucleic acid sequencing in fixed tissue (FISSEQ). FISSEQ-BOINC exhibits different properties from BOINC, which relies on bulk nucleic acid sequencing. FISSEQ-BOINC could become a scalable approach for mapping whole-mammalian-brain connectomes with rich molecular annotations.

Rosetta Brains: A Strategy for Molecularly-Annotated Connectomics

A fundamental challenge for the nervous system is to encode signals spanning many orders of magnitude with neurons of limited bandwidth. To meet this challenge, perceptual systems use gain control. However, whether the motor system uses an analogous mechanism is essentially unknown. Neuromodulators, such as serotonin, are prime candidates for gain control signals during force production. Serotonergic neurons project diffusely to motor pools, and, therefore, force production by one muscle should change the gain of others. Here we present behavioral and pharmaceutical evidence that serotonin modulates the input–output gain of motoneurons in humans. By selectively changing the efficacy of serotonin with drugs, we systematically modulated the amplitude of spinal reflexes. More importantly, force production in different limbs interacts systematically, as predicted by a spinal gain control mechanism. Psychophysics and pharmacology suggest that the motor system adopts gain control mechanisms, and serotonin is a primary driver for their implementation in force production.

The frontal eye field (FEF) plays a central role in saccade selection and execution. Using artificial stimuli, many studies have shown that the activity of neurons in the FEF is affected by both visually salient stimuli in a neuron's receptive field and upcoming saccades in a certain direction. However, the extent to which visual and motor information is represented in the FEF in the context of the cluttered natural scenes we encounter during everyday life has not been explored. Here, we model the activities of neurons in the FEF, recorded while monkeys were searching natural scenes, using both visual and saccade information. We compare the contribution of bottom-up visual saliency (based on low-level features such as brightness, orientation, and color) and saccade direction. We find that, while saliency is correlated with the activities of some neurons, this relationship is ultimately driven by activities related to movement. Although bottom-up visual saliency contributes to the choice of saccade targets, it does not appear that FEF neurons actively encode the kind of saliency posited by popular saliency map theories. Instead, our results emphasize the FEF's role in the stages of saccade planning directly related to movement generation.

Saliency and saccade encoding in the frontal eye field during natural scene search.

In the Tempotron learning problem a neuron receives time varying inputs and for a set of such input sequences (S set) the neuron must be sub-threshold for all times while for some other sequences (S+ set) the neuron must be super threshold for at least one time. Here we present a graphical treatment of a slight reformulation of the tempotron problem. We show that the problem’s general form is equivalent to the question if a polytope, specified by a set of inequalities, is contained in the union of a set of equally defined polytopes. Using recent results from computational geometry, we show that the problem is W[1]-hard. This phrasing gives some new insights into the nature of gradient based learning algorithms. A sampling based approach can, under certain circumstances provide an approximation in polynomial time. Other problems, related to hierarchical neural networks may share some topological structure.

Prosthetic devices need to be controlled by their users, typically using physiological signals. People tend to look at objects before reaching for them and we have shown that combining eye movements with other continuous physiological signal sources enhances control. This approach suffers when subjects also look at non-targets, a problem we addressed with a probabilistic mixture over targets where subject gaze information is used to identify target candidates. However, this approach would be ineffective if a user wanted to move towards targets that have not been foveated. Here we evaluated how the accuracy of prior target information influenced decoding accuracy, as the availability of neural control signals was varied. We also considered a mixture model where we assumed that the target may be foveated or, alternatively, that the target may not be foveated. We tested the accuracy of the models at decoding natural reaching data, and also in a closed-loop robot-assisted reaching task. The mixture model worked well in the face of high target uncertainty. Furthermore, errors due to inaccurate target information were reduced by including a generic model that relied on neural signals only.

We analyze the scaling and cost-performance characteristics of current and projected connectomics approaches, with reference to the potential implications of recent advances in diverse contributing ﬁelds. Three generalized strategies for dense connectivity mapping at the scale of whole mammalian brains are considered: electron microscopic axon tracing, optical imaging of combinatorial molecular markers at synapses, and bulk DNA sequencing of trans-synaptically exchanged nucleic acid barcode pairs. Due to advances in parallel-beam instrumentation, whole mouse brain electron microscopic image acquisition could cost less than $100 million, with total costs presently limited by image analysis to trace axons through large image stacks. It is difﬁcult to estimate the overall cost-performance of electron microscopic approaches because image analysis costs could fall dramatically with algorithmic improvements or large-scale crowd-sourcing. Optical microscopy at 50–100nm isotropic resolution could potentially read combinatorially multiplexed molecular information from individual synapses, which could indicate the identiﬁes of the pre-synaptic and post-synaptic cells without relying on axon tracing. An optical approach to whole mouse brain connectomics may therefore be achievable for less than $10 million and could be enabled by emerging technologies to sequence nucleic acids in-situ in ﬁxed tissue via ﬂuorescent microscopy. Strategies relying on bulk DNA sequencing, which would extract the connectome without direct imaging of the tissue, could produce a whole mouse brain connectome for $100k – $1 million or a mouse cortical connectome for $10k – $100k. Anticipated further reductions in the cost of DNA sequencing could lead to a $1000 mouse cortical connectome. Schalek, personal communication). In this case, imaging time and imaging cost decrease by a factor of 4. Furthermore, ATUM-based imaging has demonstrated the ability to perform multi-scale resolution (e.g., large axon tracts can be imaged at one pixel size and dwell time, while neuropil can be imaged at a smaller pixel size and dwell time); this further decreases the imaging time and cost.

Conneconomics: The Economics of Dense, Large-Scale, High-Resolution Neural Connectomics

Powered prostheses have the potential to restore abilities lost to amputation; however, many users report dissatisfaction with the control of their devices. The high variability of the EMG signals used to control powered devices likely burdens amputees with high movement uncertainty. In able-bodied subjects uncertainty affects adaptation, control, and feedback processing, which are often modeled using Bayesian statistics. Understanding the role of uncertainty for amputees might thus be important for the design and control of prosthetic devices. Here we quantified the role of uncertainty using a visual trial-by-trial adaptation approach. We compared adaptation behavior with two control interfaces meant to mimic able-bodied and prosthesis control: torque control and EMG control. In both control interfaces, adaptation rate decreased with high feedback uncertainty and increased with high mean error. However, we did observe different patterns of learning as the experiment progressed. For torque control, subjects improved and consequently adapted slower as the experiment progressed, while no such improvements were made for EMG control. Thus, EMG control resulted in overall adaptation behavior that supports Bayesian models, but with altered learning patterns and higher errors. These findings encourage further studies of adaptation with powered prostheses. A better understanding of the factors that alter learning patterns and errors will help design prosthesis control systems that optimize learning and performance for the prosthesis user.

2014 36th Annual International Conference of the IEEE Engineering in Medicine and Biology Society

The effect of powered prosthesis control signals on trial-by-trial adaptation to visual perturbations

Bayesian statistics defines how new information, given by a likelihood, should be combined with previously acquired information, given by a prior distribution. Many experiments have shown that humans make use of such priors in cognitive, perceptual, and motor tasks, but where do priors come from? As people never experience the same situation twice, they can only construct priors by generalizing from similar past experiences. Here we examine the generalization of priors over stochastic visuomotor perturbations in reaching experiments. In particular, we look into how the first two moments of the prior—the mean and variance (uncertainty)—generalize. We find that uncertainty appears to generalize differently from the mean of the prior, and an interesting asymmetry arises when the mean and the uncertainty are manipulated simultaneously.

Injuries of the cervical spinal cord can interrupt the neural pathways controlling the muscles of the arm, resulting in complete or partial paralysis. For individuals unable to reach due to high-level injuries, neuroprostheses can restore some of the lost function. Natural, multidimensional control of neuroprosthetic devices for reaching remains a challenge. Electromyograms (EMGs) from muscles that remain under voluntary control can be used to communicate intended reach trajectories, but when the number of available muscles is limited control can be difficult and unintuitive. We combined shoulder EMGs with target estimates obtained from gaze. Natural gaze data were integrated with EMG during closed-loop robotic control of the arm, using a probabilistic mixture model. We tested the approach with two different sets of EMGs, as might be available to subjects with C4and C5-level spinal cord injuries. Incorporating gaze greatly improved control of reaching, particularly when there were few EMG signals. We found that subjects naturally adapted their eye-movement precision as we varied the set of available EMGs, attaining accurate performance in both tested conditions. The system performs a near-optimal combination of both physiological signals, making control more intuitive and allowing a natural trajectory that reduces the burden on the user.

Real-Time Evaluation of a Noninvasive Neuroprosthetic Interface for Control of Reach

Most approaches to understanding human motor control assume that people maximize their rewards while minimizing their motor efforts. This tradeoff between potential rewards and a sense of effort is quantified with a cost function. While the rewards can change across tasks, our sense of effort is assumed to remain constant and characterize how the nervous system organizes motor control. As such, when a proposed cost function compares well with data it is argued to be the underlying cause of a motor behavior, and not simply a fit to the data. Implicit in this proposition is the assumption that this cost function can then predict new motor behaviors. Here we examined this idea and asked whether an inferred cost function in one setting could explain subject’s behavior in settings that differed dynamically but had identical rewards. We found that the pattern of behavior observed across settings was similar to our predictions of optimal behavior. However, we could not conclude that this behavior was consistent with a conserved sense of effort. These results suggest that the standard forms for quantifying cost may not be sufficient to accurately examine whether or not human motor behavior abides by optimality principles.

Target relevance modulates primate gaze behavior during natural scene search

Simultaneously measuring the activities of all neurons in a mammalian brain at millisecond resolution is a challenge beyond the limits of existing techniques in neuroscience. Entirely new approaches may be required, motivating an analysis of the fundamental physical constraints on the problem. We outline the physical principles governing brain activity mapping using optical, electrical, magnetic resonance, and molecular modalities of neural recording. Focusing on the mouse brain, we analyze the scalability of each method, concentrating on the limitations imposed by spatiotemporal resolution, energy dissipation, and volume displacement. Based on this analysis, all existing approaches require orders of magnitude improvement in key parameters. Electrical recording is limited by the low multiplexing capacity of electrodes and their lack of intrinsic spatial resolution, optical methods are constrained by the scattering of visible light in brain tissue, magnetic resonance is hindered by the diffusion and relaxation timescales of water protons, and the implementation of molecular recording is complicated by the stochastic kinetics of enzymes. Understanding the physical limits of brain activity mapping may provide insight into opportunities for novel solutions. For example, unconventional methods for delivering electrodes may enable unprecedented numbers of recording sites, embedded optical devices could allow optical detectors to be placed within a few scattering lengths of the measured neurons, and new classes of molecularly engineered sensors might obviate cumbersome hardware architectures. We also study the physics of powering and communicating with microscale devices embedded in brain tissue and find that, while radio-frequency electromagnetic data transmission suffers from a severe power–bandwidth tradeoff, communication via infrared light or ultrasound may allow high data rates due to the possibility of spatial multiplexing. The use of embedded local recording and wireless data transmission would only be viable, however, given major improvements to the power efficiency of microelectronic devices.

We often need to learn how to move based on a single performance measure that reflects the overall success of our movements. However, movements have many properties, such as their trajectories, speeds and timing of end-points, thus the brain needs to decide which properties of movements should be improved; it needs to solve the credit assignment problem. Currently, little is known about how humans solve credit assignment problems in the context of reinforcement learning. Here we tested how human participants solve such problems during a trajectory-learning task. Without an explicitly-defined target movement, participants made hand reaches and received monetary rewards as feedback on a trial-by-trial basis. The curvature and direction of the attempted reach trajectories determined the monetary rewards received in a manner that can be manipulated experimentally. Based on the history of action-reward pairs, participants quickly solved the credit assignment problem and learned the implicit payoff function. A Bayesian credit-assignment model with built-in forgetting accurately predicts their trial-by-trial learning.

Predicting cognitive function from clinical measures of mobility and health status: A L1-L2 regularized regression approach

Motor learning of novel dynamics is not represented in a single global coordinate system: evaluation of 1 mixed coordinate representations and local learning 2 3 Max Berniker , David W. Franklin , J. Randall Flanagan , Daniel M. Wolpert , Konrad Kording 1‡ 4 5 1 Rehabilitation Institute of Chicago, Northwestern University, Chicago, IL 60611, USA 6 2 Computational and Biological Learning Lab, Department of Engineering, University of Cambridge, 7 Cambridge, CB2 1PZ, United Kingdom 8 3 Departments of Psychology and Centre for Neuroscience Studies, Queen’s University, Kingston, Ontario, 9 Canada 10 11 † ‡ equal contributions 12 13 Abbreviated title: Evidence for mixed coordinate representations and local learning 14 15 Correspondence: 16 Max Berniker 17 Rehabilitation Institute of Chicago, 18 Northwestern University, Chicago, IL 60611, USA 19 mbernike@northwestern.edu 20 21 Articles in PresS. J Neurophysiol (December 18, 2013). doi:10.1152/jn.00493.2013

Motor Learning of Novel Dynamics Is Not Represented in a Single Global Coordinate System: Evaluation of 1 Mixed Coordinate Representations and Local Learning 2 3 Abbreviated Title: Evidence for Mixed Coordinate Representations and Local Learning 14

hand-weight changes Generalization of unconstrained reaching with

Wii Fit Balance Board Playing Improves Balance and Gait in Parkinson Disease

Reaching is one of the central experimental paradigms in the field of motor control, and many computational models of reaching have been published. While most of these models try to explain subject data (such as movement kinematics, reaching performance, forces, etc.) from only a single experiment, distinct experiments often share experimental conditions and record similar kinematics. This suggests that reaching models could be applied to (and falsified by) multiple experiments. However, using multiple datasets is difficult because experimental data formats vary widely. Standardizing data formats promises to enable scientists to test model predictions against many experiments and to compare experimental results across labs. Here we report on the development of a new resource available to scientists: a database of reaching called the Database for Reaching Experiments And Models (DREAM). DREAM collects both experimental datasets and models and facilitates their comparison by standardizing formats. The DREAM project promises to be useful for experimentalists who want to understand how their data relates to models, for modelers who want to test their theories, and for educators who want to help students better understand reaching experiments, models, and data analysis.

Motion games improve balance control in stroke survivors: A preliminary study based on the principle of constraint-induced movement therapy

We analyze the scaling and cost-performance characteristics of current and projected connectomics approaches, with reference to the potential implications of recent advances in diverse contributing fields. This analysis suggests potential cost-effective strategies for dense connectivity mapping at the scale of whole mammalian brains.

Spinal cord injury (SCI) paralyzes approximately 12,000 people each year in the United States. Individuals with an injury at and above the sixth cervical vertebra (C6) lose function in the upper and lower limbs. To provide greater independence to this population, the restoration of reaching and grasping movements is critically important. Functional electrical stimulation (FES) is currently the only clinical approach for reanimating paralyzed muscles. While it has been used with great success in this population, especially for the restoration of hand grasp, the user interfaces currently available are not suffi cient to control high-dimensional, dexterous movements of the hand and arm. Some neuroprostheses use purely

Advanced User Interfaces for Upper Limb Functional Electrical Stimulation

To be effective, a prescribed prosthetic device must match the functional requirements and capabilities of each patient. These capabilities are usually assessed by a clinician and reported by the Medicare K-level designation of mobility. However, it is not clear how the K-level designation objectively relates to the use of prostheses outside of a clinical environment. Here, we quantify participant activity using mobile phones and relate activity measured during real world activity to the assigned K-levels. We observe a correlation between K-level and the proportion of moderate to high activity over the course of a week. This relationship suggests that accelerometry-based technologies such as mobile phones can be used to evaluate real world activity for mobility assessment. Quantifying everyday activity promises to improve assessment of real world prosthesis use, leading to a better matching of prostheses to individuals and enabling better evaluations of future prosthetic devices.

Monitoring Functional Capability of Individuals with Lower Limb Amputations Using Mobile Phones

Successful motor performance requires the ability to adapt motor commands to task dynamics. A central question in movement neuroscience is how these dynamics are represented. Although it is widely assumed that dynamics (e.g., force fields) are represented in intrinsic, joint-based coordinates (Shadmehr R, Mussa-Ivaldi FA. J Neurosci 14: 3208–3224, 1994), recent evidence has questioned this proposal. Here we reexamine the representation of dynamics in two experiments. By testing generalization following changes in shoulder, elbow, or wrist configurations, the first experiment tested for extrinsic, intrinsic, or object-centered representations. No single coordinate frame accounted for the pattern of generalization. Rather, generalization patterns were better accounted for by a mixture of representations or by models that assumed local learning and graded, decaying generalization. A second experiment, in which we replicated the design of an influential study that had suggested encoding in intrinsic coordinates (Shadmehr and Mussa-Ivaldi 1994), yielded similar results. That is, we could not find evidence that dynamics are represented in a single coordinate system. Taken together, our experiments suggest that internal models do not employ a single coordinate system when generalizing and may well be represented as a mixture of coordinate systems, as a single system with local learning, or both.

Motor learning of novel dynamics is not represented in a single global coordinate system: evaluation of mixed coordinate representations and local learning

A molecular device that records time-varying signals would enable new approaches in neuroscience. We have recently proposed such a device, termed a “molecular ticker tape”, in which an engineered DNA polymerase (DNAP) writes time-varying signals into DNA in the form of nucleotide misincorporation patterns. Here, we define a theoretical framework quantifying the expected capabilities of molecular ticker tapes as a function of experimental parameters. We present a decoding algorithm for estimating time-dependent input signals, and DNAP kinetic parameters, directly from misincorporation rates as determined by sequencing. We explore the requirements for accurate signal decoding, particularly the constraints on (1) the polymerase biochemical parameters, and (2) the amplitude, temporal resolution, and duration of the time-varying input signals. Our results suggest that molecular recording devices with kinetic properties similar to natural polymerases could be used to perform experiments in which neural activity is compared across several experimental conditions, and that devices engineered by combining favorable biochemical properties from multiple known polymerases could potentially measure faster phenomena such as slow synchronization of neuronal oscillations. Sophisticated engineering of DNAPs is likely required to achieve molecular recording of neuronal activity with single-spike temporal resolution over experimentally relevant timescales.

Studies of motor generalization usually perturb hand reaches by distorting visual feedback with virtual reality or by applying forces with a robotic manipulandum. Whereas such perturbations are useful for studying how the central nervous system adapts and generalizes to novel dynamics, they are rarely encountered in daily life. The most common perturbations that we experience are changes in the weights of objects that we hold. Here, we use a center-out, free-reaching task, in which we can manipulate the weight of a participant's hand to examine adaptation and generalization following naturalistic perturbations. In both trial-by-trial paradigms and block-based paradigms, we find that learning converges rapidly (on a timescale of approximately two trials), and this learning generalizes mostly to movements in nearby directions with a unimodal pattern. However, contrary to studies using more artificial perturbations, we find that the generalization has a strong global component. Furthermore, the generalization is enhanced with repeated exposure of the same perturbation. These results suggest that the familiarity of a perturbation is a major factor in movement generalization and that several theories of the neural control of movement, based on perturbations applied by robots or in virtual reality, may need to be extended by incorporating prior influence that is characterized by the familiarity of the perturbation.

Generalization of unconstrained reaching with hand-weight changes.

Cancer and healthy cells have distinct distributions of molecular properties and thus respond differently to drugs. Cancer drugs ideally kill cancer cells while limiting harm to healthy cells. However, the inherent variance among cells in both cancer and healthy cell populations increases the difficulty of selective drug action. Here we propose a classification framework based on the idea that an ideal cancer drug should maximally discriminate between cancer and healthy cells. We first explore how molecular markers can be used to discriminate cancer cells from healthy cells on a single cell basis, and then how the effects of drugs are statistically predicted by these molecular markers. We then combine these two ideas to show how to optimally match drugs to tumor cells. We find that expression levels of a handful of genes suffice to discriminate well between individual cells in cancer and healthy tissue. We also find that gene expression predicts the efficacy of cancer drugs, suggesting that the cancer drugs act as classifiers using gene profiles. In agreement with our first finding, a small number of genes predict drug efficacy well. Finally, we formulate a framework that defines an optimal drug, and predicts drug cocktails that may target cancer more accurately than the individual drugs alone. Conceptualizing cancer drugs as solving a discrimination problem in the high-dimensional space of molecular markers promises to inform the design of new cancer drugs and drug cocktails.

Faculty Opinions recommendation of Testing Bayesian models of human coincidence timing.

Neuroprosthetic devices promise to allow paralyzed patients to perform the necessary functions of everyday life. However, to allow patients to use such tools it is necessary to decode their intent from neural signals such as electromyograms (EMGs). Because these signals are noisy, state of the art decoders integrate information over time. One systematic way of doing this is by taking into account the natural evolution of the state of the body-–by using a so-called trajectory model. Here we use two insights about movements to enhance our trajectory model: (1) at any given time, there is a small set of likely movement targets, potentially identified by gaze; (2) reaches are produced at varying speeds. We decoded natural reaching movements using EMGs of muscles that might be available from an individual with spinal cord injury. Target estimates found from tracking eye movements were incorporated into the trajectory model, while a mixture model accounted for the inherent uncertainty in these estimates. Warping the trajectory model in time using a continuous estimate of the reach speed enabled accurate decoding of faster reaches. We found that the choice of richer trajectory models, such as those incorporating target or speed, improves decoding particularly when there is a small number of EMGs available.

Decoding with limited neural data: a mixture of time-warped trajectory models for directional reaches

Fall prevention is a critical component of health care; falls are a common source of injury in the elderly and are associated with significant levels of mortality and morbidity. Automatically detecting falls can allow rapid response to potential emergencies; in addition, knowing the cause or manner of a fall can be beneficial for prevention studies or a more tailored emergency response. The purpose of this study is to demonstrate techniques to not only reliably detect a fall but also to automatically classify the type. We asked 15 subjects to simulate four different types of falls–left and right lateral, forward trips, and backward slips–while wearing mobile phones and previously validated, dedicated accelerometers. Nine subjects also wore the devices for ten days, to provide data for comparison with the simulated falls. We applied five machine learning classifiers to a large time-series feature set to detect falls. Support vector machines and regularized logistic regression were able to identify a fall with 98% accuracy and classify the type of fall with 99% accuracy. This work demonstrates how current machine learning approaches can simplify data collection for prevention in fall-related research as well as improve rapid response to potential injuries due to falls.

Because it looks funny and is pretty useless, we do not frequently touch our shoulder with our ear. It turns out that this insight has led to an exciting discovery in the field of cue combination. To interpret our senses, we rely on other senses. For example, to know how the image on our retina relates to the outside world, we need to know the alignment of our eyeball with respect to the outside world. To know this alignment, in turn, we need to know the orientation of our head relative to the outside world. Similar problems occur in other sensory and motor contexts. For example, the perceived direction of sound depends on the orientation of our head and movements of our body rely on the alignment of our body relative to the outside world. One way of formalizing these problems uses the idea of a coordinate system: every sensor provides information in a particular coordinates (e.g., retinal coordinates for visual input or joint angle coordinates for proprioceptive information). 
 
The fact that sensory information arrives in many different coordinate systems produces a challenge for the brain: how to combine information that is encoded in different coordinate systems for successful movements. Both behavioral (Soechting and Flanders, 1989; van Beers et al., 1999; Sober and Sabes, 2003) and neural recording (Wallace et al., 1998; Fetsch et al., 2007) studies have explored how the brain “transforms” information across coordinate systems. It is generally understood that information degrades as it is transformed across coordinate systems. 
 
Another important fact about information integration is that the brain must make all of its decisions based on unreliable and sometimes conflicting sensory data. Crucially, sensory uncertainty can be reduced by combining information from multiple sensors. Any combination needs to assign weights to different inputs. Should each sensor have the same importance or are some sensors more important than others? Based on studies showing that the brain often weights sensory inputs in a near-optimal fashion (Yuille and Kersten, 2006; Trommershauser et al., 2010), it is generally understood that the brain is exquisitely sensitive to statistical issues that occur when combining information. 
 
That coordinate transforms are costly and sensory information is uncertain sets the stage for a remarkably interesting problem. Tasks require precision in the relevant coordinate system. Imprecise sensory information arrives from multiple sources. How should the brain combine information from multiple sources to move successfully? One intuition is that information that requires less coordinate transformation should be trusted more than information that requires more transformation – it should get more weight. The current study by Blohm and Burns (2010) tests a crucial prediction of this intuition: if one sensor is made more difficult to transform into the required coordinate system then it should be assigned a lower weight. 
 
The authors begin with an established cue-conflict paradigm that allows the experimenter to measure the weight subjects put on vision versus proprioception (Sober and Sabes, 2003, 2005). Then, in a variant of the experiment, the subjects performed the task while holding their heads at a 30° angle. The rationale was that in this very unusual posture, we should have more uncertainty about the alignment of the head-centric and the body-centric coordinate systems. If this increases the difficulty of coordinate transformations then subjects should show less reliance on signals that must be transformed across coordinate systems. 
 
The authors beautifully show that changing the difficulty of the transformation affects weights. For example, in the experiment, proprioceptive information about the hand relative to the body should be independent of head tilt. Visual information about the same variable, on the other hand, should be affected by the tilt as it requires converting information from retinal to joint coordinates. Indeed, the authors find that head tilt leads to smaller visual weights (see Figure 8A, light blue line). However, at some level the paper raises as many questions as it answers, since there seem to be two completely independent (but not mutually exclusive) interpretations of the results. 
 
One interpretation, provided by the authors, is that the precision of our sense of head rotation is probably good when the head is held normally and less good when the head is rotated. This should be true due to the Weber-law properties of many sensors, which can result from the signal-dependent noise that has been characterized in the relevant orientation sensors. In this case, it is uncertainty about the relative orientation of the head to the body that gives rise on uncertainty about the alignment of the coordinate systems (Kording and Tenenbaum, 2006). In this interpretation transformed signals are given less weight during head rotation simply because our position sense from the eyes is made less reliable because of uncertainty about the head position. 
 
Another interpretation is that the precision of computations in the nervous system should be better for coordinate transformations that happen more often. As the head is usually roughly at a 90° angle relative to the shoulders, the nervous system has more experience and might devotes more neural resources to the associated coordinate transformation, independent of any signal-dependent noise arising from peripheral sensors. In this interpretation transformed signals are given less weight because the brain avoids the neural noise associated with performing a less-familiar version of the transformation. 
 
The paper thus opens up a new set of questions that should also be asked about previous studies (Sober and Sabes, 2003, 2005). How much of cross-modal weighting is determined by neural noise in coordinate transfers and how much is due to uncertainty about the coordinate system alignments? Future variants of the experiment could give additional cues about the relative alignment of the head or remove such cues. Such a manipulation should have no effect if neural noise dominates and should have a strong effect if alignment uncertainty dominates.

Due to multiple factors such as fatigue, muscle strengthening, and neural plasticity, the responsiveness of the motor apparatus to neural commands changes over time. To enable precise movements the nervous system must adapt to compensate for these changes. Recent models of motor adaptation derive from assumptions about the way the motor apparatus changes. Characterizing these changes is difficult because motor adaptation happens at the same time, masking most of the effects of ongoing changes. Here, we analyze eye movements of monkeys with lesions to the posterior cerebellar vermis that impair adaptation. Their fluctuations better reveal the underlying changes of the motor system over time. When these measured, unadapted changes are used to derive optimal motor adaptation rules the prediction precision significantly improves. Among three models that similarly fit single-day adaptation results, the model that also matches the temporal correlations of the non-adapting saccades most accurately predicts multiple day adaptation. Saccadic gain adaptation is well matched to the natural statistics of fluctuations of the oculomotor plant.

Saccadic gain adaptation is predicted by the statistics of natural fluctuations in oculomotor function

For rehabilitative devices to restore functional movement to paralyzed individuals, user intent must be determined from signals that remain under voluntary control. Tracking eye movements is a natural way to learn about an intended reach target and, when combined with just a small set of electromyograms (EMGs) in a probabilistic mixture model, can reliably generate accurate trajectories even when the target information is uncertain. To experimentally assess the effectiveness of our algorithm in closed-loop control, we developed a robotic system to simulate a reaching neuroprosthetic. Incorporating target information by tracking subjects' gaze greatly improved performance when the set of EMGs was most limited. In addition we found that online performance was better than predicted by the offline accuracy of the training data. By enhancing the trajectory model with target information the decoder relied less on neural control signals, reducing the burden on the user.

2012 Annual International Conference of the IEEE Engineering in Medicine and Biology Society

The two-alternative-forced-choice (2AFC) paradigm is the workhorse of psychophysics, used widely in fields ranging from neuroscience to economics. The data obtained from the 2AFC task is used to compute the just-noticeable-difference (JND), which is generally assumed to quantify sensory precision, independent of a subject’s beliefs (their prior) and how they represent uncertainty. However, this interpretation is only true for some specific theories of how humans make decisions under uncertainty. Yet, there are a host of alternative decision-making theories that make different predictions for how people behave in the 2AFC task and how to interpret the resulting data.

An investigation of how prior beliefs influence decision-making under uncertainty in a 2 AFC task

Mobile phones with built-in accelerometers promise a convenient, objective way to quantify everyday movements and classify those movements into activities. Using accelerometer data we estimate the following activities of 18 healthy subjects and eight patients with Parkinson’s disease: walking, standing, sitting, holding, or not wearing the phone. We use standard machine learning classifiers (support vector machines, regularized logistic regression) to automatically select, weigh, and combine a large set of standard features for time series analysis. Using cross validation across all samples we are able to correctly identify 96.1% of the activities of healthy subjects and 92.2% of the activities of Parkinson’s patients. However, when applying the classification parameters derived from the set of healthy subjects to Parkinson’s patients, the percent correct lowers to 60.3%, due to different characteristics of movement. For a fairer comparison across populations we also applied subject-wise cross validation, identifying healthy subject activities with 86.0% accuracy and 75.1% accuracy for patients. We discuss the key differences between these populations, and why algorithms designed for and trained with healthy subject data are not reliable for activity recognition in populations with motor disabilities.

Using Mobile Phones for Activity Recognition in Parkinson’s Patients

Generalization studies examine the influence of perturbations imposed on one movement onto other movements. The strength of generalization is traditionally interpreted as a reflection of the similarity of the underlying neural representations. Uncertainty fundamentally affects both sensory integration and learning and is at the heart of many theories of neural representation. However, little is known about how uncertainty, resulting from variability in the environment, affects generalization curves. Here we extend standard movement generalization experiments to ask how uncertainty affects the generalization of visuomotor rotations. We find that although uncertainty affects how fast subjects learn, the perturbation generalizes independently of uncertainty.

In the Turing test a computer model is deemed to “think intelligently” if it can generate answers that are indistinguishable from those of a human. We developed an analogous Turing-like handshake test to determine if a machine can produce similarly indistinguishable movements. The test is administered through a telerobotic system in which an interrogator holds a robotic stylus and interacts with another party - artificial or human with varying levels of noise. The interrogator is asked which party seems to be more human. Here, we compare the human-likeness levels of three different models for handshake: (1) Tit-for-Tat model, (2) λ model, and (3) Machine Learning model. The Tit-for-Tat and the Machine Learning models generated handshakes that were perceived as the most human-like among the three models that were tested. Combining the best aspects of each of the three models into a single robotic handshake algorithm might allow us to advance our understanding of the way the nervous system controls sensorimotor interactions and further improve the human-likeness of robotic handshakes.

Toward Perceiving Robots as Humans: Three Handshake Models Face the Turing-Like Handshake Test

Temporal Integration of Olfactory Perceptual Evidence in Human Orbitofrontal Cortex

How interactions between neurons relate to tuned neural responses is a longstanding question in systems neuroscience. Here we use statistical modeling and simultaneous multi-electrode recordings to explore the relationship between these interactions and tuning curves in six different brain areas. We find that, in most cases, functional interactions between neurons provide an explanation of spiking that complements and, in some cases, surpasses the influence of canonical tuning curves. Modeling functional interactions improves both encoding and decoding accuracy by accounting for noise correlations and features of the external world that tuning curves fail to capture. In cortex, modeling coupling alone allows spikes to be predicted more accurately than tuning curve models based on external variables. These results suggest that statistical models of functional interactions between even relatively small numbers of neurons may provide a useful framework for examining neural coding.

Functional Connectivity and Tuning Curves in Populations of Simultaneously Recorded Neurons

Differential Representations of Prior and Likelihood Uncertainty in the Human Brain

High-throughput recording of signals embedded within inaccessible micro-environments is a technological challenge. The ideal recording device would be a nanoscale machine capable of quantitatively transducing a wide range of variables into a molecular recording medium suitable for long-term storage and facile readout in the form of digital data. We have recently proposed such a device, in which cation concentrations modulate the misincorporation rate of a DNA polymerase (DNAP) on a known template, allowing DNA sequences to encode information about the local cation concentration. In this work we quantify the cation sensitivity of DNAP misincorporation rates, making possible the indirect readout of cation concentration by DNA sequencing. Using multiplexed deep sequencing, we quantify the misincorporation properties of two DNA polymerases – Dpo4 and Klenow exo− – obtaining the probability and base selectivity of misincorporation at all positions within the template. We find that Dpo4 acts as a DNA recording device for Mn2+ with a misincorporation rate gain of ∼2%/mM. This modulation of misincorporation rate is selective to the template base: the probability of misincorporation on template T by Dpo4 increases >50-fold over the range tested, while the other template bases are affected less strongly. Furthermore, cation concentrations act as scaling factors for misincorporation: on a given template base, Mn2+ and Mg2+ change the overall misincorporation rate but do not alter the relative frequencies of incoming misincorporated nucleotides. Characterization of the ion dependence of DNAP misincorporation serves as the first step towards repurposing it as a molecular recording device.

Measuring Cation Dependent DNA Polymerase Fidelity Landscapes by Deep Sequencing

Machine learning methods for interfacing humans with machines is an emerging area. Here we propose a novel algorithm for interfacing humans with powered lower limb prostheses for restoring control of naturalistic gait following amputation. Unlike most previous neural machine interfaces, our approach fuses control information from the user with sensor information from the prosthesis to approximate the closed loop behavior of the unimpaired sensorimotor system. We present a Bayesian framework to control an artificial knee by probabilistically mixing of process state estimates from different Kalman filters, each addressing separate regimes of locomotion such as level ground walking, walking up a ramp, and walking down a ramp. We show its utility as a mode classifier that is tolerant to temporary sensor faults which are frequently experienced in practical applications.

2011 Annual International Conference of the IEEE Engineering in Medicine and Biology Society

Sensor-fault tolerant control of a powered lower limb prosthesis by mixing mode-specific adaptive Kalman filters

Preface I. Theory and Fundamentals 1. Ideal-Observer Models of Cue Integration Landy, Banks, & Knill 2. Causal Inference in Sensorimotor Learning and Control Wei & Kording 3. The Role of Generative Knowledge in Object Perception Battaglia, Kersten, & Schrater 4. Generative Probabilistic Modeling: Understanding Causal Sensorimotor Integration Vijayakumar, Hospedales, & Haith 5. Modeling Cue Integration in Clutter Sahani & Whiteley 6. Recruitment of New Visual Cues for Perceptual Appearance Backus 7. Combining image signals before 3D reconstruction: The Intrinsic Constraint Model of Cue Integration Domini & Caudek 8. Cue Combination: Beyond So-Called "Optimality" Rosas & Wichmann II. Behavioral Studies 9. Priors and Learning in Cue Integration Seydell, Knill, & Trommershauser 10. Combining Vision With Audition and Touch, In Adults and In Children Burr, Binda, & Gori 11. The Statistical Relationship

Experiments on humans and other animals have shown that uncertainty due to unreliable or incomplete information affects behavior. Recent studies have formalized uncertainty and asked which behaviors would minimize its effect. This formalization results in a wide range of Bayesian models that derive from assumptions about the world, and it often seems unclear how these models relate to one another. In this review, we use the concept of graphical models to analyze differences and commonalities across Bayesian approaches to the modeling of behavioral and neural data. We review behavioral and neural data associated with each type of Bayesian model and explain how these models can be related. We finish with an overview of different theories that propose possible ways in which the brain can represent uncertainty.

Bayesian models: the structure of the world, uncertainty, behavior, and the brain

Experiments in systems neuroscience can be seen as consisting of three steps: (1) selecting the signals we are interested in, (2) probing the system with carefully chosen stimuli, and (3) getting data out of the brain. Here I discuss how emerging techniques in molecular biology are starting to improve these three steps. To estimate its future impact on experimental neuroscience, I will stress the analogy of ongoing progress with that of microprocessor production techniques. These techniques have allowed computers to simplify countless problems; because they are easier to use than mechanical timers, they are even built into toasters. Molecular biology may advance even faster than computer speeds and has made immense progress in understanding and designing molecules. These advancements may in turn produce impressive improvements to each of the three steps, ultimately shifting the bottleneck from obtaining data to interpreting it. This is an ‘‘Editors’ Outlook’’ article for PLoS Computational Biology Moore’s law has characterized progress in microprocessor techniques (see Figure 1, dashed). In very good approximation, computers have doubled in speed every 2 years. At the same time, computing has progressively gotten cheaper, and we can now successfully solve many computing problems that once seemed hard, such as speech recognition. We are also solving entirely new computational problems, such as searching billions of web pages for information on neuroscience or molecular biology. Such exponential growth makes solutions to seemingly insurmountable problems seem trivial given a bit of time. Meanwhile, simple computers have gotten cheaper over time. This decrease in costs was so dramatic that many of today’s toasters contain microprocessors for time-keeping, switching on or off heat, light feedback of heating state, and the handling of key presses. This makes building toasters simpler and ultimately cheaper. When computers were invented, toasters were certainly not an expected application of computing. Importantly, the speed of computers has increased dramatically faster than the number of neurons that can be simultaneously recorded [1] (Figure 1, dotted). Still, the increase of the number of simultaneously recorded neurons has allowed the development of advanced algorithms that take advantage of this growing number. Indeed, the field that analyzes multivariate neural data is large now and can analyze complicated interactions between large numbers of neurons [2–4], electroencephalography (EEG) or magnetoencephalography (MEG) recordings, optical recordings, or functional magnetic resonance imaging (fMRI) voxels [5,6]. However, as the amount of data increases, so does the complexity of the questions. For example, many current studies of neural data analysis ask how neurons interact, but as the number of neurons grows, the number of potential connections grows quadratically as each neuron may interact with each other neuron. This, in turn, leads to models with many free parameters, which requires new statistical methods of fitting these parameters. Molecular biology has seen accelerating progress over the last decades. One readily quantifiable cost in molecular biology is that of sequencing DNA. The development of a host of different methods has allowed the cost of sequencing each base pair to dramatically decrease over time (Figure 1, solid). The rate of improvement is much faster than that of neuron recording techniques or even Moore’s law. This development allowed sequencing the entire human genome at a price of billions of dollars in the year 2003, and sequencing the same genome at higher quality now costs less than $2,000. The current push is to sequence an entire genome for less than $1,000 [7]. This development allows solving many problems of obvious importance, such as the search for gene-related markers of disease [8]. From a computational perspective, a central objective of neuroscience is to understand how neurons convert their inputs into outputs and collectively produce action based on stimuli and internal processes, such as memory and attention. This leads to what I would call the three central steps of experimental approaches in systems neuroscience. (1) Select the signals that are important for a given neuroscience question. As long as we cannot approach understanding the entire brain at the same time, it is highly useful to select what to stimulate and what to measure. (2) Get stimuli into the brain. To understand what neurons do, inputs need to be defined or known. (3) Get data out of the brain. Only large amounts of data allow meaningful statistical inferences. Virtually all experimental approaches to systems neuroscience can be phrased in these terms. It is interesting to ponder a few well-known examples. In a typical single-cell visual cortex experiment [9] that studies how the visual cortex encodes visual stimuli, we would put an electrode into primary visual cortex (1), show various visual stimuli on a monitor in front of the animal (2), and record neural activity from the electrode (3). In a typical fMRI experiment about visual cortex [10], we would choose a contrast that tells us about changes in blood flow in the brain (which is a proxy for average firing rate) (1), stimulate subjects by using a set of fixed visual stimuli (2), and read Citation: Kording KP (2011) Of Toasters and Molecular Ticker Tapes. PLoS Comput Biol 7(12): e1002291. doi:10.1371/journal.pcbi.1002291 Editor: Karl J. Friston, University College London, United Kingdom Published December 29, 2011 Copyright: 2011 Konrad P. Kording. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Research was funded by the NIH grants 1R01NS063399 and 2P01NS044393. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. * E-mail: kk@northwestern.edu Competing Interests: The author has declared that no competing interests exist. PLoS Computational Biology | www.ploscompbiol.org 1 December 2011 | Volume 7 | Issue 12 | e1002291 out data using resonance signals (3). In a typical slice work experiment [11], we might identify a specific cell type under the microscope (1), activate other cells using glutamate uncaging (2), and then record signals from the intracellular electrode to find out how the other cells affect the recorded cell (3). In all these cases, selection, stimulation, and reading the data (‘‘data out’’) are crucial aspects of the work. Each of these steps has its own criteria for being maximally useful. For the selection step (1), we would like to select all the relevant signals and nothing else. For the stimulation step (2), we Figure 1. Comparison of the scaling laws between neuroscience (exponential fit from [1]), computer science (exponential fit of years 2000–2007 from [29]), and DNA sequencing, see [30]. Remarkably, the steepness of the curves is worth comparing while the offset on the y-axis is arbitrary. doi:10.1371/journal.pcbi.1002291.g001 Figure 2. The three central steps that define experiments in systems neuroscience. The question mark denotes areas where the author expects exciting developments. (A) Methods for selecting where neural signals come from. (B) Methods for stimulating neurons. (C) Methods for reading out the data. See text for detail. doi:10.1371/journal.pcbi.1002291.g002 PLoS Computational Biology | www.ploscompbiol.org 2 December 2011 | Volume 7 | Issue 12 | e1002291 want to be able to get in large amounts of well defined data with high information bandwidth and low noise [12]. Lastly, for the ‘‘data out’’ step (3), we want to get a lot of data out with low noise and high bandwidth. Lastly, given limited budgets, we want the techniques to be cheap. Certainly, as we scale up the analysis towards understanding larger systems, the price per unit of information must be limited. Each of the currently used approaches has limitations along the three steps. For example, fMRI has a huge number of channels, and can select essentially any brain area. Yet, it seems unlikely that it could be used to record only from certain cell types, such as interneurons [13], noise levels are high, and spatiotemporal resolution is low. Single-cell slice physiology is good at selecting neurons based on observable features like brain region and cell morphology, and it is low noise, but data out bandwidth is quite low and there may be biases in the selection of the recorded cells. Similarly, other current techniques are all rather limited on at least one of the three axes. Molecular biology is starting to offer powerful solutions to overcome limitations of the three steps [14], and I want to start by reviewing past progress. (1) The selection step. There are many different levels of selection. We might want to select individuals that have certain diseases for which there are genetic markers. In this case, we can select these individuals through genetic tests [15]. We might want to select neurons but not other cells (Figure 2A, upper), and this is possible through a set of well-established genetic methods that enable or disable gene expression using tissue-specific promoters [16,17]. We might want to select only a subset of all the cells (Figure 2A, middle) [18]. Lastly, we might only want to only select certain neurons that have defined physiological properties (Figure 2A, lower). Interestingly, it is even possible to select each cell individually and assign it a random color that is visible under the microscope [19]. Importantly, genetically selecting neurons enables certain ways of stimulating just those neurons and reading out only from those neurons (see below). Figure 3. Molecular ticker tapes. Neural activity affects an intracellular concentration. DNA polymerase copies a 

Optimal control theory is a powerful analytical tool useful for many diverse fields, including biological motor control, where the theory is used to predict characteristics of motor control problems under optimal conditions. However, finding solutions to these control problems can be very dif ficult when examining biological systems, where nonlinearity and stochasticity are typical. In an effort to overcome this dilemma and analyze more realistic problems, we present an algorithm that approximates the solution to the discrete time Hamilton-Jacobi-Bellman equations. As with similar local dynamic programming algorithms, the algorithm approximates a local solution around a nominal trajectory and progressively improves the trajectory and the value function's local esti mate. Using this algorithm, we obtain optimal solutions for a single joint musculo-skeletal system. In particular, we take advantage of this new algorithm to examine solutions with fast and discontinuous dynamics and non-Gaussian noise. These solutions are examined for some of the stereotypical responses of biological systems, such as the tri-phasic muscle activations and bell-shaped velocity profiles. The results are also compared with their deterministic counterparts, emphasizing the need for stochastic solutions.

Experiments in systems neuroscience can be seen as consisting of three steps: (1) selecting the signals we are interested in, (2) probing the system with carefully chosen stimuli, and (3) getting data out of the brain. Here I discuss how emerging techniques in molecular biology are starting to improve these three steps. To estimate its future impact on experimental neuroscience, I will stress the analogy of ongoing progress with that of microprocessor production techniques. These techniques have allowed computers to simplify countless problems; because they are easier to use than mechanical timers, they are even built into toasters. Molecular biology may advance even faster than computer speeds and has made immense progress in understanding and designing molecules. These advancements may in turn produce impressive improvements to each of the three steps, ultimately shifting the bottleneck from obtaining data to interpreting it.

Recent studies suggest that motor adaptation is the result of multiple, perhaps linear processes each with distinct time scales. While these models are consistent with some motor phenomena, they can neither explain the relatively fast re-adaptation after a long washout period, nor savings on a subsequent day. Here we examined if these effects can be explained if we assume that the CNS stores and retrieves movement parameters based on their possible relevance. We formalize this idea with a model that infers not only the sources of potential motor errors, but also their relevance to the current motor circumstances. In our model adaptation is the process of re-estimating parameters that represent the body and the world. The likelihood of a world parameter being relevant is then based on the mismatch between an observed movement and that predicted when not compensating for the estimated world disturbance. As such, adapting to large motor errors in a laboratory setting should alert subjects that disturbances are being imposed on them, even after motor performance has returned to baseline. Estimates of this external disturbance should be relevant both now and in future laboratory settings. Estimated properties of our bodies on the other hand should always be relevant. Our model demonstrates savings, interference, spontaneous rebound and differences between adaptation to sudden and gradual disturbances. We suggest that many issues concerning savings and interference can be understood when adaptation is conditioned on the relevance of parameters.

Estimating the Relevance of World Disturbances to Explain Savings, Interference and Long-Term Motor Adaptation Effects

The processing of sensory information is fundamental to the basic operation of the nervous system. Our nervous system uses this sensory information to gain knowledge of our bodies and the world around us. This knowledge is of great importance as it provides the coherent and accurate information necessary for successful motor control. Yet, all this knowledge is of an uncertain nature because we obtain information only through our noisy sensors. We are thus faced with the problem of integrating many uncertain pieces of information into estimates of the properties of our bodies and the surrounding world. Bayesian approaches to estimation formalize the problem of how this uncertain information should be integrated. Utilizing this approach, many studies make predictions that faithfully predict human sensorimotor behavior. WIREs Cogni Sci 2011 2 419-428 DOI: 10.1002/wcs.125 For further resources related to this article, please visit the WIREs website.

We live in an uncertain world, and each decision may have many possible outcomes; choosing the best decision is thus complicated. This chapter describes recent research in Bayesian decision theory, which formalises the problem of decision making in the presence of uncertainty and often provides compact models that predict observed behaviour. With its elegant formalisation of the problems faced by the nervous system, it promises to become a major inspiration for studies in neuroscience.

Poster 268 Wii Video Game Balance‐board Training: Does It Improve Balance and Gait in Adults With Parkinson Disease?

Recent studies in motor control have shown that visuomotor rotations for reaching have narrow generalization functions: what we learn during movements in one direction only affects subsequent movements into close directions. Here we wanted to measure the generalization functions for wrist movement. To do so we had 7 subjects performing an experiment holding a mobile phone in their dominant hand. The mobile phone's built in acceleration sensor provided a convenient way to measure wrist movements and to run the behavioral protocol. Subjects moved a cursor on the screen by tilting the phone. Movements on the screen toward the training target were rotated and we then measured how learning of the rotation in the training direction affected subsequent movements in other directions. We find that generalization is local and similar to generalization patterns of visuomotor rotation for reaching.

Measuring Generalization of Visuomotor Perturbations in Wrist Movements Using Mobile Phones

In systems neuroscience, neural activity that represents movements or sensory stimuli is often characterized by spatial tuning curves that may change in response to training, attention, altered mechanics, or the passage of time. A vital step in determining whether tuning curves change is accounting for estimation uncertainty due to measurement noise. In this study, we address the issue of tuning curve stability using methods that take uncertainty directly into account. We analyze data recorded from neurons in primary motor cortex using chronically implanted, multielectrode arrays in four monkeys performing center-out reaching. With the use of simulations, we demonstrate that under typical experimental conditions, the effect of neuronal noise on estimated preferred direction can be quite large and is affected by both the amount of data and the modulation depth of the neurons. In experimental data, we find that after taking uncertainty into account using bootstrapping techniques, the majority of neurons appears to be very stable on a timescale of minutes to hours. Lastly, we introduce adaptive filtering methods to explicitly model dynamic tuning curves. In contrast to several previous findings suggesting that tuning curves may be in constant flux, we conclude that the neural representation of limb movement is, on average, quite stable and that impressions to the contrary may be largely the result of measurement noise.

Statistical assessment of the stability of neural movement representations.

We tend to look at targets prior to moving our hand towards them. This means that our eye movements contain information about the movements we are planning to make. This information has been shown to be useful in the context of decoding of movement intent from neural signals. However, this is complicated by the fact that occasionally, subjects may want to move towards targets that have not been foveated, or may be distracted and temporarily look away from the intended target. We have previously accounted for this uncertainty using a probabilistic mixture over targets, where the gaze information is used to identify target candidates. Here we evaluate how the accuracy of prior target information influences decoding accuracy. We also consider a mixture model where we assume that the target may be foveated or, alternatively, that the target may not be foveated. We found that errors due to inaccurate target information were reduced by including a generic model representing movements to all targets into the mixture.

Dealing with noisy gaze information for a target-dependent neural decoder

[PDF]  [Full Text]  [Abstract] , July 22, 2008; 105 (29): 10233-10237. PNAS John Haitas, A. B. Bonds and Jon H. Kaas Jamie L. Reed, Pierre Pouget, Hui-Xin Qi, Zhiyi Zhou, Melanie R. Bernard, Mark J. Burish, Widespread spatial integration in primary somatosensory cortex [PDF]  [Full Text]  [Abstract] 2009; 101 (3): 1126-1140. J Neurophysiol Sonja Grün Data-Driven Significance Estimation for Precise Spike Correlation [PDF]  [Full Text]  [Abstract] , December 16, 2009; 29 (50): 15780-15795. J. Neurosci. Jason M. Samonds, Brian R. Potetz and Tai Sing Lee Primary Visual Cortex Cooperative and Competitive Interactions Facilitate Stereo Computations in Macaque [PDF]  [Full Text]  [Abstract] , January , 2010; 103 (1): 591-602. J Neurophysiol Beau Cronin, Ian H. Stevenson, Mriganka Sur and Konrad P. Körding Tuning-Curve Analysis Hierarchical Bayesian Modeling and Markov Chain Monte Carlo Sampling for [PDF]  [Full Text]  [Abstract] , December , 2010; 104 (6): 3276-3292. J Neurophysiol Hiroyuki Ito, Pedro E. Maldonado and Charles M. Gray Nucleus Dynamics of Stimulus-Evoked Spike Timing Correlations in the Cat Lateral Geniculate

Between Two Neurons Statistical Assessment of Time-Varying Dependency

Trust and reciprocity facilitate cooperation and are relevant to virtually all human interactions. They are typically studied using trust games: one subject gives (entrusts) money to another subject, which may return some of the proceeds (reciprocate). Currently, however, it is unclear whether trust and reciprocity in monetary transactions are similar in other settings, such as physical effort. Trust and reciprocity of physical effort are important as many everyday decisions imply an exchange of physical effort, and such exchange is central to labor relations. Here we studied a trust game based on physical effort and compared the results with those of a computationally equivalent monetary trust game. We found no significant difference between effort and money conditions in both the amount trusted and the quantity reciprocated. Moreover, there is a high positive correlation in subjects' behavior across conditions. This suggests that trust and reciprocity may be character traits: subjects that are trustful/trustworthy in monetary settings behave similarly during exchanges of physical effort. Our results validate the use of trust games to study exchanges in physical effort and to characterize inter-subject differences in trust and reciprocity, and also suggest a new behavioral paradigm to study these differences.

Visual-haptic cue integration with spatial and temporal disparity during pointing movements

Faculty Opinions recommendation of Stimulus onset quenches neural variability: a widespread cortical phenomenon.

Synaptic plasticity underlies learning and is thus central for development, memory, and recovery from injury. However, it is often difficult to detect changes in synaptic strength in vivo, since intracellular recordings are experimentally challenging. Here we present two methods aimed at inferring changes in the coupling between pairs of neurons from extracellularly recorded spike trains. First, using a generalized bilinear model with Poisson output we estimate time-varying coupling assuming that all changes are spike-timing-dependent. This approach allows model-based estimation of STDP modification functions from pairs of spike trains. Then, using recursive point-process adaptive filtering methods we estimate more general variation in coupling strength over time. Using simulations of neurons undergoing spike-timing dependent modification, we show that the true modification function can be recovered. Using multi-electrode data from motor cortex we then illustrate the use of this technique on in vivo data.

Inferring spike-timing-dependent plasticity from spike train data

Our nervous system continuously combines new information from our senses with information it has acquired throughout life. Numerous studies have found that human subjects manage this by integrating their observations with their previous experience (priors) in a way that is close to the statistical optimum. However, little is known about the way the nervous system acquires or learns priors. Here we present results from experiments where the underlying distribution of target locations in an estimation task was switched, manipulating the prior subjects should use. Our experimental design allowed us to measure a subject's evolving prior while they learned. We confirm that through extensive practice subjects learn the correct prior for the task. We found that subjects can rapidly learn the mean of a new prior while the variance is learned more slowly and with a variable learning rate. In addition, we found that a Bayesian inference model could predict the time course of the observed learning while offering an intuitive explanation for the findings. The evidence suggests the nervous system continuously updates its priors to enable efficient behavior.

When we stand upright, we integrate cues from multiple senses, such as vision and proprioception, to maintain and regulate our vertical posture. How these cues are combined has been the focus of a range of studies. These studies generally measured how subjects deviate from standing upright when confronted with a moving visual stimulus displayed in a virtual environment. Previous research had shown that uncertainty is central in such cue combination problems. Here we wanted to understand, quantitatively, how visual flow fields and uncertainty about them affect human posture. To do so, we combined experimental methods from perceptual psychophysics with methods from motor control studies. We used a two-alternative forced-choice paradigm to measure uncertainty as a function of the magnitude of a random-dot flow field and stimulus coherence. We subsequently measured movement amplitude as a function of visual stimulus parameters. In line with previous research, we find that sensorimotor behavior depends nonlinearly on the stimulus amplitude and, importantly, is affected by uncertainty. We find that this nonlinearity and uncertainty dependence is accurately predicted by standard Bayesian cue combination. Importantly, a Weber's law where visual uncertainty depends on stimulus amplitude is enough to explain the nonlinear behavior.

The uncertainty associated with visual flow fields and their influence on postural sway: Weber's law suffices to explain the nonlinearity of vection.

A central theme of systems neuroscience is to characterize the tuning of neural responses to sensory stimuli or the production of movement. Statistically, we often want to estimate the parameters of the tuning curve, such as preferred direction, as well as the associated degree of uncertainty, characterized by error bars. Here we present a new sampling-based, Bayesian method that allows the estimation of tuning-curve parameters, the estimation of error bars, and hypothesis testing. This method also provides a useful way of visualizing which tuning curves are compatible with the recorded data. We demonstrate the utility of this approach using recordings of orientation and direction tuning in primary visual cortex, direction of motion tuning in primary motor cortex, and simulated data.

Hierarchical Bayesian modeling and Markov chain Monte Carlo sampling for tuning-curve analysis.

Applications of Brain-Machine-Interfaces typically estimate user intent based on biological signals that are under voluntary control. For example, we might want to estimate how a patient with a paralyzed arm wants to move based on residual muscle activity. To solve such problems it is necessary to integrate obtained information over time. To do so, state of the art approaches typically use a probabilistic model of how the state, e.g. position and velocity of the arm, evolves over time - a so-called trajectory model. We wanted to further develop this approach using two intuitive insights: (1) At any given point of time there may be a small set of likely movement targets, potentially identified by the location of objects in the workspace or by gaze information from the user. (2) The user may want to produce movements at varying speeds. We thus use a generative model with a trajectory model incorporating these insights. Approximate inference on that generative model is implemented using a mixture of extended Kalman filters. We find that the resulting algorithm allows us to decode arm movements dramatically better than when we use a trajectory model with linear dynamics.

To stabilize our position in space we use visual information as well as non-visual physical motion cues. However, visual cues can be ambiguous: visually perceived motion may be caused by self-movement, movement of the environment, or both. The nervous system must combine the ambiguous visual cues with noisy physical motion cues to resolve this ambiguity and control our body posture. Here we have developed a Bayesian model that formalizes how the nervous system could solve this problem. In this model, the nervous system combines the sensory cues to estimate the movement of the body. We analytically demonstrate that, as long as visual stimulation is fast in comparison to the uncertainty in our perception of body movement, the optimal strategy is to weight visually perceived movement velocities proportional to a power law. We find that this model accounts for the nonlinear influence of experimentally induced visual motion on human postural behavior both in our data and in previously published results.

Department of Psychology, Peking University, Beijing, China 5 Departments of Physiology, Physical Medicine and Rehabilitation, and Applied Mathematics, 6 Northwestern University and Rehabilitation Institute of Chicago 7 Biomedical Engineering, LeTourneau University 8 9 Tel: 3122381768 10 Fax: 3122387605 11 corresponding author e-mail: k-wei@northwestern.edu 12 13 Articles in PresS. J Neurophysiol (September 22, 2010). doi:10.1152/jn.01025.2009

The nervous system uses nonspecific motor learning in response to 1 uncertain perturbations 2

The nervous system needs to control movement of a complex body in a complex world subject to uncertainty due to sensory and motor noise. In this issue, Mark Latash argues in favor of a framework that addresses these problems – the Hierarchical Equilibrium Point Hypothesis (as we call it here, HEPH). According to this hypothesis, movement is created by having a central controller specify a shift in the reference body configuration. This time-varying reference body configuration is passed on to lower level (e.g., limb) controllers, and finally to the lowest level controllers which set the thresholds of the tonic stretch reflex of individual muscles as assumed in the lambda model. 
 
In the context of this paper we find it useful to discuss other approaches, in particular approaches that focus on estimation (e.g. Internal models, IMs) and approaches that focus on control given estimations (e.g. Optimal control, OC)1. Specific proposals have been put forward of how the nervous system may implement estimation (neural IM) and proposals of how the nervous system may implement control (neural Control, nC). The EPH is a version of nC which suggests that the motor system simplifies the control problem by centrally adjusting parameters of the spinal proprioceptive feedback. The idea of distributed hierarchical control seems to have emerged in many communities to solve the problem of control complexity. We will briefly review the differences across approaches and highlight possible synergies.

Looking for synergies between the equilibrium point hypothesis and internal models.

Plasticity is a crucial component of normal brain function and a critical mechanism for recovery from injury. In vitro, associative pairing of presynaptic spiking and stimulus-induced postsynaptic depolarization causes changes in the synaptic efficacy of the presynaptic neuron, when activated by extrinsic stimulation. In vivo, such paradigms can alter the responses of whole groups of neurons to stimulation. Here, we used in vivo spike-triggered stimulation to drive plastic changes in rat forelimb sensorimotor cortex, which we monitored using a statistical measure of functional connectivity inferred from the spiking statistics of the neurons during normal, spontaneous behavior. These induced plastic changes in inferred functional connectivity depended on the latency between trigger spike and stimulation, and appear to reflect a robust reorganization of the network. Such targeted connectivity changes might provide a tool for rerouting the flow of information through a network, with implications for both rehabilitation and brain–machine interface applications.

We constantly make small errors during movement and use them to adapt our future movements. Movement experiments often probe this error-driven learning by perturbing movements and analyzing the after-effects. Past studies have applied perturbations of varying nature such as visual disturbances, position- or velocity-dependent forces and modified inertia properties of the limb. However, little is known about how the specific nature of a perturbation influences subsequent movements. For a single perturbation trial, the nature of a perturbation may be highly uncertain to the nervous system, given that it receives only noisy information. One hypothesis is that the nervous system can use this rough estimate to partially correct for the perturbation on the next trial. Alternatively, the nervous system could ignore uncertain information about the nature of the perturbation and resort to a nonspecific adaptation. To study how the brain estimates and responds to incomplete sensory information, we test these two hypotheses using a trial-by-trial adaptation experiment. On each trial, the nature of the perturbation was chosen from six distinct types, including a visuomotor rotation and different force fields. We observed that corrective forces aiming to oppose the perturbation in the following trial were independent of the nature of the perturbation. Our results suggest that the nervous system uses a nonspecific strategy when it has high uncertainty about the nature of perturbations during trial-by-trial learning.

The nervous system uses nonspecific motor learning in response to random perturbations of varying nature.

ABSTRACT The authors argue that “true” models that aim at faithfully mimicking or reproducing every property of the sensorimotor system cannot be compact as they need many free parameters. Consequently, most scientists in motor control use what are called “false” models—models that derive from well-defined approximations. The authors conceptualize these models as a priori limited in scope and approximate. As such, they argue that a quantitative characterization of the deviations between the system and the model, more than the mere act of falsifying, allows scientists to make progress in understanding the sensorimotor system. Ultimately, this process should result in models that explain as much data variance as possible. The authors conclude by arguing that progress in that direction could strongly benefit from databases of experimental results and collections of models.

Neurons in the sensory system exhibit changes in excitability that unfold over many time scales. These fluctuations produce noise and could potentially lead to perceptual errors. However, to prevent such errors, postsynaptic neurons and synapses can adapt and counteract changes in the excitability of presynaptic neurons. Here we ask how neurons could optimally adapt to minimize the influence of changing presynaptic neural properties on their outputs. The resulting model, based on Bayesian inference, explains a range of physiological results from experiments which have measured the overall properties and detailed time-course of sensory tuning curve adaptation in the early visual cortex. We show how several experimentally measured short term plasticity phenomena can be understood as near-optimal solutions to this adaptation problem. This framework provides a link between high level computational problems, the properties of cortical neurons, and synaptic physiology.

Sensory Adaptation and Short Term Plasticity as Bayesian Correction for a Changing Brain

publishes original articles on the function of the nervous system. It is published 12 times a year Journal of Neurophysiology

Nature in Response to Random Perturbations of Varying The Nervous System Uses Nonspecific Motor Learning

A central objective in neuroscience is to understand how neurons interact. Such functional interactions have been estimated using signals recorded with different techniques and, consequently, different temporal resolutions. For example, spike data often have sub-millisecond resolution while some imaging techniques may have a resolution of many seconds. Here we use multi-electrode spike recordings to ask how similar functional connectivity inferred from slower timescale signals is to the one inferred from fast timescale signals. We find that functional connectivity is relatively robust to low-pass filtering—dropping by about 10% when low pass filtering at 10 hz and about 50% when low pass filtering down to about 1 Hz—and that estimates are robust to high levels of additive noise. Moreover, there is a weak correlation for physiological filters such as hemodynamic or Ca2+ impulse responses and filters based on local field potentials. We address the origin of these correlations using simulation techniques and find evidence that the similarity between functional connectivity estimated across timescales is due to processes that do not depend on fast pair-wise interactions alone. Rather, it appears that connectivity on multiple timescales or common-input related to stimuli or movement drives the observed correlations. Despite this qualification, our results suggest that techniques with intermediate temporal resolution may yield good estimates of the functional connections between individual neurons.

On the Similarity of Functional Connectivity between Neurons Estimated across Timescales

In many domains, humans appear to combine perceptual cues in a near-optimal, probabilistic fashion: two noisy pieces of information tend to be combined linearly with weights proportional to the precision of each cue. Here we present a case where structural information plays an important role. The presence of a background cue gives rise to the possibility of occlusion, and places a soft constraint on the location of a target - in effect propelling it forward. We present an ideal observer model of depth estimation for this situation where structural or ordinal information is important and then fit the model to human data from a stereo-matching task. To test whether subjects are truly using ordinal cues in a probabilistic manner we then vary the uncertainty of the task. We find that the model accurately predicts shifts in subject's behavior. Our results indicate that the nervous system estimates depth ordering in a probabilistic fashion and estimates the structure of the visual scene during depth perception.

Structural inference affects depth perception in the context of potential occlusion

1 2 Running head: Statistics of Natural Movements 3 4 Ian S. Howard 5 Computational and Biological Learning Laboratory, 6 Department of Engineering, 7 University of Cambridge, 8 Trumpington Street, 9 Cambridge CB2 1PZ, UK 10 Email: ish22@cam.ac.uk 11 12 James N. Ingram 13 Computational and Biological Learning Laboratory, 14 Department of Engineering, 15 University of Cambridge, 16 Trumpington Street, 17 Cambridge CB2 1PZ, UK 18 Email: jni20@cam.ac.uk 19 20 Konrad P. Körding 21 Physiology and PM and R, 22 Rehabilitation Institute of Chicago, 23 Northwestern University, 24 345 E Superior Street, 25 60611 Chicago, IL, USA 26 Email: kk@northwestern.edu 27 28 Daniel M. Wolpert. 29 Computational and Biological Learning Laboratory, 30 Department of Engineering, 31 University of Cambridge, 32 Trumpington Street, 33 Cambridge CB2 1PZ, UK 34 Email: wolpert@eng.cam.ac.uk 35 36 37

Title: the Statistics of Natural Movements Are Reflected in Motor Errors 1 2 Running Head: Statistics of Natural Movements 3 4 27 28 the Statistics of Natural Movements Are Reflected in Motor Errors 41

Humans use their arms to engage in a wide variety of motor tasks during everyday life. However, little is known about the statistics of these natural arm movements. Studies of the sensory system have shown that the statistics of sensory inputs are key to determining sensory processing. We hypothesized that the statistics of natural everyday movements may, in a similar way, influence motor performance as measured in laboratory-based tasks. We developed a portable motion-tracking system that could be worn by subjects as they went about their daily routine outside of a laboratory setting. We found that the well-documented symmetry bias is reflected in the relative incidence of movements made during everyday tasks. Specifically, symmetric and antisymmetric movements are predominant at low frequencies, whereas only symmetric movements are predominant at high frequencies. Moreover, the statistics of natural movements, that is, their relative incidence, correlated with subjects' performance on a laboratory-based phase-tracking task. These results provide a link between natural movement statistics and motor performance and confirm that the symmetry bias documented in laboratory studies is a natural feature of human movement.

During motor adaptation the nervous system constantly uses error information to improve future movements. Today's mainstream models simply assume that the nervous system adapts linearly and proportionally to errors. However, not all movement errors are relevant to our own action. The environment may transiently disturb the movement production-for example, a gust of wind blows the tennis ball away from its intended trajectory. Apparently the nervous system should not adapt its motor plan in the subsequent tennis strokes based on this irrelevant movement error. We hypothesize that the nervous system estimates the relevance of each observed error and adapts strongly only to relevant errors. Here we present a Bayesian treatment of this problem. The model calculates how likely an error is relevant to the motor plant and derives an ideal adaptation strategy that leads to the most precise movements. This model predicts that adaptation should be a nonlinear function of the size of an error. In reaching experiments we found strong evidence for the predicted nonlinear strategy. The model also explains published data on saccadic gain adaptation, adaptation to visuomotor rotations, and force perturbations. Our study suggests that the nervous system constantly and effortlessly estimates the relevance of observed movement errors for successful motor adaptation.

A large number of experiments have asked to what degree human reaching movements can be understood as being close to optimal in a statistical sense. However, little is known about whether these principles are relevant for other classes of movements. Here we analyzed movement in a task that is similar to surfing or snowboarding. Human subjects stand on a force plate that measures their center of pressure. This center of pressure affects the acceleration of a cursor that is displayed in a noisy fashion (as a cloud of dots) on a projection screen while the subject is incentivized to keep the cursor close to a fixed position. We find that salient aspects of observed behavior are well-described by optimal control models where a Bayesian estimation model (Kalman filter) is combined with an optimal controller (either a Linear-Quadratic-Regulator or Bang-bang controller). We find evidence that subjects integrate information over time taking into account uncertainty. However, behavior in this continuous steering task appears to be a highly non-linear function of the visual feedback. While the nervous system appears to implement Bayes-like mechanisms for a full-body, dynamic task, it may additionally take into account the specific costs and constraints of the task.

Bayesian Integration and Non-Linear Feedback Control in a Full-Body Motor Task

When we learn how to throw darts we adjust how we throw based on where the darts stick. Much of skill learning is computationally similar in that we learn using feedback obtained after the completion of individual actions. We can formalize such tasks as a search problem; among the set of all possible actions, find the action that leads to the highest reward. In such cases our actions have two objectives: we want to best utilize what we already know (exploitation), but we also want to learn to be more successful in the future (exploration). Here we tested how participants learn movement trajectories where feedback is provided as a monetary reward that depends on the chosen trajectory. We mathematically derived the optimal search policy for our experiment using decision theory. The search behavior of participants is well predicted by an ideal searcher model that optimally combines exploration and exploitation.

Humans can adapt their motor behaviors to deal with ongoing changes. To achieve this, the nervous system needs to estimate central variables for our movement based on past knowledge and new feedback, both of which are uncertain. In the Bayesian framework, rates of adaptation characterize how noisy feedback is in comparison to the uncertainty of the state estimate. The predictions of Bayesian models are intuitive: the nervous system should adapt slower when sensory feedback is more noisy and faster when its state estimate is more uncertain. Here we want to quantitatively understand how uncertainty in these two factors affects motor adaptation. In a hand reaching experiment we measured trial-by-trial adaptation to a randomly changing visual perturbation to characterize the way the nervous system handles uncertainty in state estimation and feedback. We found both qualitative predictions of Bayesian models confirmed. Our study provides evidence that the nervous system represents and uses uncertainty in state estimate and feedback during motor adaptation.

Uncertainty of Feedback and State Estimation Determines the Speed of Motor Adaptation

In order to determine the points at which meeting discourse changes from one topic to another, probabilistic models were used to approximate the process through which meeting transcripts were produced. Gibbs sampling was used to estimate the values of random variables in the models, including the locations of topic boundaries. This paper shows how discourse features were integrated into the Bayesian model and reports empirical evaluations of the benefit obtained through the inclusion of each feature and of the suitability of alternative models of the placement of topic boundaries. It demonstrates how multiple cues to segmentation can be combined in a principled way, and empirical tests show a clear improvement over previous work.

A Probabilistic Model of Meetings That Combines Words and Discourse Features

Uncertainty constitutes a fundamental constraint on human sensorimotor control. Our sensors are noisy and do not provide perfect information about all the properties of the world. Moreover, our muscles generate noisy outputs and many tasks we perform vary in an unpredictable way. Here we review the computations that the CNS uses in the face of such sensory, motor and task uncertainty. We show that the CNS reduces the uncertainty in estimates about the state of the world by using a Bayesian combination of prior knowledge and sensory feedback. It is shown that these mechanisms generalize to state estimation of ones own body during movement. We review how the CNS optimizes decisions based on these estimates, examining the error criterion that people optimize when performing targeted movements. Finally, we describe how signal-dependent noise on the motor output places constraints on performance. Goal-directed movement arises from a model in which the statistics of our actions are optimized. Together these studies provide a probabilistic framework for sensorimotor control.

Estimating the sources of motor errors for adaptation and generalization

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Perceptual events derive their significance to an animal from their meaning about the world, that is from the information they carry about their causes. The brain should thus be able to efficiently infer the causes underlying our sensory events. Here we use multisensory cue combination to study causal inference in perception. We formulate an ideal-observer model that infers whether two sensory cues originate from the same location and that also estimates their location(s). This model accurately predicts the nonlinear integration of cues by human subjects in two auditory-visual localization tasks. The results show that indeed humans can efficiently infer the causal structure as well as the location of causes. By combining insights from the study of causal inference with the ideal-observer approach to sensory cue combination, we show that the capacity to infer causal structure is not limited to conscious, high-level cognition; it is also performed continually and effortlessly in perception.

The dynamics of memory as a consequence of optimal adaptation to a changing body

The purpose of our nervous system is to allow us to successfully interact with our environment. This normative idea is formalized by decision theory that defines which choices would be most beneficial. We live in an uncertain world, and each decision may have many possible outcomes; choosing the best decision is thus complicated. Bayesian decision theory formalizes these problems in the presence of uncertainty and often provides compact models that predict observed behavior. With its elegant formalization of the problems faced by the nervous system, it promises to become a major inspiration for studies in neuroscience.

Bayesian models of multisensory perception traditionally address the problem of estimating an underlying variable that is assumed to be the cause of the two sensory signals. The brain, however, has to solve a more general problem: it also has to establish which signals come from the same source and should be integrated, and which ones do not and should be segregated. In the last couple of years, a few models have been proposed to solve this problem in a Bayesian fashion. One of these has the strength that it formalizes the causal structure of sensory signals. We first compare these models on a formal level. Furthermore, we conduct a psychophysics experiment to test human performance in an auditory-visual spatial localization task in which integration is not mandatory. We find that the causal Bayesian inference model accounts for the data better than other models.

Comparing Bayesian models for multisensory cue combination without mandatory integration

Many recent studies analyze how data from different modalities can be combined. Often this is modeled as a system that optimally combines several sources of information about the same variable. However, it has long been realized that this information combining depends on the interpretation of the data. Two cues that are perceived by different modalities can have different causal relationships: (1) They can both have the same cause, in this case we should fully integrate both cues into a joint estimate. (2) They can have distinct causes, in which case information should be processed independently. In many cases we will not know if there is one joint cause or two independent causes that are responsible for the cues. Here we model this situation as a Bayesian estimation problem. We are thus able to explain some experiments on visual auditory cue combination as well as some experiments on visual proprioceptive cue integration. Our analysis shows that the problem solved by people when they combine cues to produce a movement is much more complicated than is usually assumed, because they need to infer the causal structure that is underlying their sensory experience.

Bayesian Statistics and Utility Functions in Sensorimotor Control

Action selection is a fundamental decision process for us, and depends on the state of both our body and the environment. Because signals in our sensory and motor systems are corrupted by variability or noise, the nervous system needs to estimate these states. To select an optimal action these state estimates need to be combined with knowledge of the potential costs or rewards of different action outcomes. We review recent studies that have investigated the mechanisms used by the nervous system to solve such estimation and decision problems, which show that human behaviour is close to that predicted by Bayesian Decision Theory. This theory defines optimal behaviour in a world characterized by uncertainty, and provides a coherent way of describing sensorimotor processes.

Probabilistic models of cognition Bayesian decision theory in sensorimotor control

Our motor system changes due to causes that span multiple timescales. For example, muscle response can change because of fatigue, a condition where the disturbance has a fast timescale or because of disease where the disturbance is much slower. Here we hypothesize that the nervous system adapts in a way that reflects the temporal properties of such potential disturbances. According to a Bayesian formulation of this idea, movement error results in a credit assignment problem: what timescale is responsible for this disturbance? The adaptation schedule influences the behavior of the optimal learner, changing estimates at different timescales as well as the uncertainty. A system that adapts in this way predicts many properties observed in saccadic gain adaptation. It well predicts the timecourses of motor adaptation in cases of partial sensory deprivation and reversals of the adaptation direction.

We present a method for unsupervised topic modelling which adapts methods used in document classification (Blei et al., 2003; Griffiths and Steyvers, 2004) to unsegmented multi-party discourse transcripts. We show how Bayesian inference in this generative model can be used to simultaneously address the problems of topic segmentation and topic identification: automatically segmenting multi-party meetings into topically coherent segments with performance which compares well with previous unsupervised segmentation-only methods (Galley et al., 2003) while simultaneously extracting topics which rate highly when assessed for coherence by human judges. We also show that this method appears robust in the face of off-topic dialogue and speech recognition errors.

Many streams of real-world data, such as conversations or bo dy movements, consist of relatively coherent segments, each chara terized by particular topics or controllers. Making sense of these data re qui s simultaneously segmenting the sequences and inferring the struc ture of the segments. We present a hierarchical Bayesian model that can be used to break a sequence of utterances or movements into segments with different distributions over topics or controllers. We apply t his model to a database of meetings, showing that its unsupervised segme ntation is competitive with other approaches, and a database of human h and movements, revealing some of the controllers for motions of the h and.

Many studies address how neurons in the barrel cortex of rats react to stimula- tion of the rat's whiskers. In this study we analyse how the statistical properties of whisker deflections from typical surfaces relate to the properties of neurons in the somatosensory system. We built an artificial whisker system to record realistic natural tactile data. An artificial whisker is moved about a set of surfaces of everyday objects. We analyse how simulated neurons can represent such stimuli in an optimally sparse fashion. These representations predict a number of interesting properties of neurons in the somatosensory system that have yet to be measured.

Predicting Properties of the Rat Somatosensory System by Sparse Coding

Sensory areas should be adapted to the properties of their natural stimuli. What are the underlying rules that match the properties of complex cells in primary visual cortex to their natural stimuli? To address this issue, we sampled movies from a camera carried by a freely moving cat, capturing the dynamics of image motion as the animal explores an outdoor environment. We use these movie sequences as input to simulated neurons. Following the intuition that many meaningful high-level variables, e.g., identities of visible objects, do not change rapidly in natural visual stimuli, we adapt the neurons to exhibit firing rates that are stable over time. We find that simulated neurons, which have optimally stable activity, display many properties that are observed for cortical complex cells. Their response is invariant with respect to stimulus translation and reversal of contrast polarity. Furthermore, spatial frequency selectivity and the aspect ratio of the receptive field quantitatively match the experimentally observed characteristics of complex cells. Hence, the population of complex cells in the primary visual cortex can be described as forming an optimally stable representation of natural stimuli.

How are complex cell properties adapted to the statistics of natural stimuli?

Making choices is a fundamental aspect of human life. For over a century experimental economists have characterized the decisions people make based on the concept of a utility function. This function increases with increasing desirability of the outcome, and people are assumed to make decisions so as to maximize utility. When utility depends on several variables, indifference curves arise that represent outcomes with identical utility that are therefore equally desirable. Whereas in economics utility is studied in terms of goods and services, the sensorimotor system may also have utility functions defining the desirability of various outcomes. Here, we investigate the indifference curves when subjects experience forces of varying magnitude and duration. Using a two-alternative forced-choice paradigm, in which subjects chose between different magnitude–duration profiles, we inferred the indifference curves and the utility function. Such a utility function defines, for example, whether subjects prefer to lift a 4-kg weight for 30 s or a 1-kg weight for a minute. The measured utility function depends nonlinearly on the force magnitude and duration and was remarkably conserved across subjects. This suggests that the utility function, a central concept in economics, may be applicable to the study of sensorimotor control.

A Neuroeconomics Approach to Inferring Utility Functions in Sensorimotor Control

Motivation The sensors of humans are plagued by noise, and likewise our muscles produce noisy outputs. Even if we had perfect sensors they would only tell us about the part of the world that we can currently sense. Uncertainty that stems from noise or the lack of complete knowledge places estimation of attributes of the worlds and control of our actuators firmly within a statistics framework. Bayesian statistics is the principled way of dealing with such problems. Much research in the field of machine learning addresses how artificial systems can optimally solve such problems . Bayesian learning and inference are thriving fields and the developed algorithms now allow efficient handling of complicated real world data. Recently many counterintuitive finding, such as visual illusions, in neuroscience can be understood by considering the brain is performing Bayesian estimation. At the same time studies start to appear where the neural correlate of such statistical processing is analyzed. Therefore the Bayesian approach may provide a framework to understand and macroscopic and microscopic attributes of neural function. In the studies described in this paper it was analyzed how human performance can be understood in terms of statistically optimal processing. These studies address how the human nervous system can use information to perform optimally in a world full of uncertainties.

Addressing Bayesian statistics and Utility functions in psychophysical experiments ( with particular focus on the motor system )

Motor learning can be defined as changing performance so as to optimize some function of the task, such as accuracy. The measure of accuracy that is optimized is called a loss function and specifies how the CNS rates the relative success or cost of a particular movement outcome. Models of pointing in sensorimotor control and learning usually assume a quadratic loss function in which the mean squared error is minimized. Here we develop a technique for measuring the loss associated with errors. Subjects were required to perform a task while we experimentally controlled the skewness of the distribution of errors they experienced. Based on the change in the subjects' average performance, we infer the loss function. We show that people use a loss function in which the cost increases approximately quadratically with error for small errors and significantly less than quadratically for large errors. The system is thus robust to outliers. This suggests that models of sensorimotor control and learning that have assumed minimizing squared error are a good approximation but tend to penalize large errors excessively.

Proceedings of the National Academy of Sciences of the United States of America

Processing of complex stimuli and natural scenes in the visual cortex

When we interact with objects in the world, the forces we exert are finely tuned to the dynamics of the situation. As our sensors do not provide perfect knowledge about the environment, a key problem is how to estimate the appropriate forces. Two sources of information can be used to generate such an estimate: sensory inputs about the object and knowledge about previously experienced objects, termed prior information. Bayesian integration defines the way in which these two sources of information should be combined to produce an optimal estimate. To investigate whether subjects use such a strategy in force estimation, we designed a novel sensorimotor estimation task. We controlled the distribution of forces experienced over the course of an experiment thereby defining the prior. We show that subjects integrate sensory information with their prior experience to generate an estimate. Moreover, subjects could learn different prior distributions. These results suggest that the CNS uses Bayesian models when estimating force requirements.

Integrating Top-Down and Bottom-Up Sensory Processing by Somato-Dendritic Interactions

Recent studies of biological auditory processing have revealed that sophisticated spectrotemporal analyses are performed by central auditory systems of various animals. The analysis is typically well matched with the statistics of relevant natural sounds, suggesting that it produces an optimal representation of the animal's acoustic biotope. We address this topic using simulated neurons that learn an optimal representation of a speech corpus. As input, the neurons receive a spectrographic representation of sound produced by a peripheral auditory model. The output representation is deemed optimal when the responses of the neurons are maximally sparse. Following optimization, the simulated neurons are similar to real neurons in many respects. Most notably, a given neuron only analyzes the input over a localized region of time and frequency. In addition, multiple subregions either excite or inhibit the neuron, together producing selectivity to spectral and temporal modulation patterns. This suggests that the brain's solution is particularly well suited for coding natural sound; therefore, it may prove useful in the design of new computational methods for processing speech.

An emerging paradigm analyses in what respect the properties of the nervous system reflect properties of natural scenes. It is hypothesized that neurons form sparse representations of natural stimuli: each neuron should respond strongly to some stimuli while being inactive upon presentation of most others. For a given network, sparse representations need fewest spikes, and thus the nervous system can consume the least energy. To obtain optimally sparse responses the receptive fields of simulated neurons are optimized. Algorithmically this is identical to searching for basis functions that allow coding for the stimuli with sparse coefficients. The problem is identical to maximizing the log likelihood of a generative model with prior knowledge of natural images. It is found that the resulting simulated neurons share most properties of simple cells found in primary visual cortex. Thus, forming optimally sparse representations is a very compact approach to describing simple cell properties. Many ways of defining sparse responses exist and it is widely believed that the particular choice of the sparse prior of the generative model does not significantly influence the estimated basis functions. Here we examine this assumption more closely. We include the constraint of unit variance of neuronal activity, used in most studies, into the objective functions. We then analyze learning on a database of natural (cat-cam) visual stimuli. We show that the effective objective functions are largely dominated by the constraint, and are therefore very similar. The resulting receptive fields show some similarities but also qualitative differences. Even for coefficient values for which the objective functions are dissimilar, the distributions of coefficients are similar and do not match the priors of the assumed generative model. In conclusion, the specific choice of the sparse prior is relevant, as is the choice of additional constraints, such as normalization of variance.

When we learn a new motor skill, we have to contend with both the variability inherent in our sensors and the task. The sensory uncertainty can be reduced by using information about the distribution of previously experienced tasks. Here we impose a distribution on a novel sensorimotor task and manipulate the variability of the sensory feedback. We show that subjects internally represent both the distribution of the task as well as their sensory uncertainty. Moreover, they combine these two sources of information in a way that is qualitatively predicted by optimal Bayesian processing. We further analyze if the subjects can represent multimodal distributions such as mixtures of Gaussians. The results show that the CNS employs probabilistic models during sensorimotor learning even when the priors are multimodal.

Learning in neural networks is usually applied to parameters related to linear kernels and keeps the nonlinearity of the model fixed. Thus, for successful models, properties and parameters of the nonlinearity have to be specified using a priori knowledge, which often is missing. Here, we investigate adapting the nonlinearity simultaneously with the linear kernel. We use natural visual stimuli for training a simple model of the visual system. Many of the neurons converge to an energy detector matching existing models of complex cells. The overall distribution of the parameter describing the nonlinearity well matches recent physiological results. Controls with randomly shuffled natural stimuli and pink noise demonstrate that the match of simulation and experimental results depends on the higher-order statistical properties of natural stimuli.

Learning the Nonlinearity of Neurons from Natural Visual Stimuli

The world from a cat’s perspective – statistics of natural videos

Many biological and artificial neural networks require the parallel extraction of multiple features, and meet this requirement with distinct populations of neurons that are selective to one property of the stimulus while being non-selective to another property. In this way, several populations can resolve a set of features independently of each other, and thus achieve a parallel mode of processing. This raises the question how an initially homogeneous population of neurons segregates into groups with distinct and complementary response properties. Using a colour image sequence recorded from a camera mounted on the head of a freely behaving cat, we train a network of neurons to achieve optimally stable responses, that is, responses that change minimally over time. This objective leads to the development of colour-selective neurons. Adding a second objective, decorrelating activity within the network, a subpopulation of neurons develops with achromatic response properties. Colour selective neurons tend to be non-oriented while achromatic neurons are orientation-tuned. The proposed objective thus successfully leads to the segregation of neurons into complementary populations that are either selective for colour or orientation.

Learning Distinct and Complementary Feature Selectivities from Natural Colour Videos

Neurons in primary visual cortex are typically classified as either simple or complex. Whereas simple cells respond strongly to grating and bar stimuli displayed at a certain phase and visual field location, complex cell responses are insensitive to small translations of the stimulus within the receptive field [ Hubel & Wiesel (1962)J. Physiol. (Lond.), 160, 106–154; Kjaer et al. (1997)J. Neurophysiol., 78, 3187–3197]. This constancy in the response to variations of the stimuli is commonly called invariance. Hubel and Wiesel's classical model of the primary visual cortex proposes a connectivity scheme which successfully describes simple and complex cell response properties. However, the question as to how this connectivity arises during normal development is left open. Based on their work and inspired by recent physiological findings we suggest a network model capable of learning from natural stimuli and developing receptive field properties which match those of cortical simple and complex cells. Stimuli are drawn from videos obtained by a camera mounted to a cat's head, so they should approximate the natural input to the cat's visual system. The network uses a competitive scheme to learn simple and complex cell response properties. Employing delayed signals to learn connections between simple and complex cells enables the model to utilize temporal properties of the input. We show that the temporal structure of the input gives rise to the emergence and refinement of complex cell receptive fields, whereas removing temporal continuity prevents this processes. This model lends a physiologically based explanation of the development of complex cell invariance response properties.

Learning the invariance properties of complex cells from their responses to natural stimuli

Learning Multiple Feature Representations from Natural Image Sequences

Neurons in mammalian cerebral cortex combine specific responses with respect to some stimulus features with invariant responses to other stimulus features. For example, in primary visual cortex, complex cells code for orientation of a contour but ignore its position to a certain degree. In higher areas, such as the inferotemporal cortex, translation-invariant, rotation-invariant, and even view point-invariant responses can be observed. Such properties are of obvious interest to artificial systems performing tasks like pattern recognition. It remains to be resolved how such response properties develop in biological systems. Here we present an unsupervised learning rule that addresses this problem. It is based on a neuron model with two sites of synaptic integration, allowing qualitatively different effects of input to basal and apical dendritic trees, respectively. Without supervision, the system learns to extract invariance properties using temporal or spatial continuity of stimuli. Furthermore, top-down information can be smoothly integrated in the same framework. Thus, this model lends a physiological implementation to approaches of unsupervised learning of invariant-response properties.

Neurons with Two Sites of Synaptic Integration Learn Invariant Representations

Extracting Slow Subspaces from Natural Videos Leads to Complex Cells

Optimization and learning - from microscopic cell properties to natural videos

The time course of natural stimuli leads to the emergence of complex cells

Supervised and Unsupervised Learning with Two Sites of Synaptic Integration

Many learning rules for neural networks derive from abstract objective functions. The weights in those networks are typically optimized utilizing gradient ascent on the objective function. In those networks each neuron needs to store two variables. One variable, called activity, contains the bottom-up sensory-fugal information involved in the core signal processing. The other variable typically describes the derivative of the objective function with respect to the cell's activity and is exclusively used for learning. This variable allows the objective function's derivative to be calculated with respect to each weight and thus the weight update. Although this approach is widely used, the mapping of such two variables onto physiology is unclear, and these learning algorithms are often considered biologically unrealistic. However, recent research on the properties of cortical pyramidal neurons shows that these cells have at least two sites of synaptic integration, the basal and the apical dendrite, and are thus appropriately described by at least two variables. Here we discuss whether these results could constitute a physiological basis for the described abstract learning rules. As examples we demonstrate an implementation of the backpropagation of error algorithm and a specific self-supervised learning algorithm using these principles. Thus, compared to standard, one-integration-site neurons, it is possible to incorporate interesting properties in neural networks that are inspired by physiology with a modest increase of complexity.

Supervised and self-supervised learning with two sites of synaptic integration?

Neural networks : the official journal of the International Neural Network Society

Since the classical work of D O Hebb 1949 The Organization of Behaviour (New York: Wiley) it is assumed that synaptic plasticity solely depends on the activity of the pre- and the post-synaptic cells. Synapses influence the plasticity of other synapses exclusively via the post-synaptic activity. This confounds effects on synaptic plasticity and neuronal activation and, thus, makes it difficult to implement networks which optimize global measures of performance. Exploring solutions to this problem, inspired by recent research on the properties of apical dendrites, we examine a network of neurons with two sites of synaptic integration. These communicate in such a way that one set of synapses mainly influences the neurons' activity; the other set gates synaptic plasticity. Analysing the system with a constant set of parameters reveals: (1) the afferents that gate plasticity act as supervisors, individual to every cell. (2) While the neurons acquire specific receptive fields the net activity remains constant for different stimuli. This ensures that all stimuli are represented and, thus, contributes to information maximization. (3) Mechanisms for maximization of coherent information can easily be implemented. Neurons with non-overlapping receptive fields learn to fire correlated and preferentially transmit information that is correlated over space. (4) We demonstrate how a new measure of performance can be implemented: cells learn to represent only the part of the input that is relevant to the processing at higher stages. This criterion is termed ‘relevant infomax’.

For biological realism, models of learning in neuronal networks often assume that synaptic plasticity solely depends on locally available signals, in particular on only the activity of the preand post-synaptic cells. As a consequence, synapses influence the plasticity of other synapses exclusively via the post-synaptic activity. Inspired by recent research on the properties of apical dendrites it has been suggested, that a second integration site in the apical dendrite may mediate specific global information. Here we explore this issue considering the example of learning invariant responses by examining a network of spiking neurones with two sites of synaptic integration. We demonstrate that results obtained in networks of units with continuous outputs transfer to the more realistic neuronal model. This allows a number of more specific experimental predictions, and is a necessary step to unified description of learning rules exploiting timing of action potentials. © 2000 Elsevier Science Ltd. Published by Éditions scientifiques et médicales Elsevier SAS

Attention : This is only the text proof , for the real paper please see the publishers site

A spike based learning rule for generation of invariant representations

Fund Established to Support Studies of Early Origins of Crohn ’ s Disease and Schizophrenia

Abstract Background Emerging neuroimaging datasets (collected with imaging techniques such as electron microscopy, optical microscopy, or X-ray microtomography) describe the location and properties of neurons and their connections at unprecedented scale, promising new ways of understanding the brain. These modern imaging techniques used to interrogate the brain can quickly accumulate gigabytes to petabytes of structural brain imaging data. Unfortunately, many neuroscience laboratories lack the computational resources to work with datasets of this size: computer vision tools are often not portable or scalable, and there is considerable difficulty in reproducing results or extending methods. Results We developed an ecosystem of neuroimaging data analysis pipelines that use open-source algorithms to create standardized modules and end-to-end optimized approaches. As exemplars we apply our tools to estimate synapse-level connectomes from electron microscopy data and cell distributions from X-ray microtomography data. To facilitate scientific discovery, we propose a generalized processing framework, which connects and extends existing open-source projects to provide large-scale data storage, reproducible algorithms, and workflow execution engines. Conclusions Our accessible methods and pipelines demonstrate that approaches across multiple neuroimaging experiments can be standardized and applied to diverse datasets. The techniques developed are demonstrated on neuroimaging datasets but may be applied to similar problems in other domains.

Toward a scalable framework for reproducible processing of volumetric, nanoscale neuroimaging datasets

A monomer having the general formula: wherein R R R X and Y are each independently CR

An optionally substituted fluorene derivative compound having the general formula:wherein R1and R2are any substitution, for example alkyl; R1and R2may be linked to form a saturated or unsaturated ring; L represents a reactive leaving group; X and Y each independently represent CR2, O, BR, NR, SiR2, S, S=O, SO2, PR or P=O(R) wherein R in each occurrence is independently selected from H or a substituent; Z represents a single bond or a divalent atom or group, and X-Z-Y forms an unconjugated ring or chain, with the proviso that at least one of R1and R2is an aryl or heteroaryl group if Z is a single bond. Particularly preferred compounds feature an X-Y-Z group that is (CH2)2-6. Polymers comprising these fluorene derivatives are also outlined and may be useful as semi-conducting polymers for use in organic light emitting diodes (OLEDs), photo-voltaic devices or field effect transistors.

Polymers comprising fluorene derivative repeat units and their preparation

Latent linear dynamical systems with Bernoulli observations provide a powerful modeling framework for identifying the temporal dynamics underlying binary time series data, which arise in a variety of contexts such as binary decision-making and discrete stochastic processes such as binned neural spike trains. Here, we develop a spectral learning method for fast, efficient fitting of Bernoulli latent linear dynamical system (LDS) models. Our approach extends traditional subspace identification methods to the Bernoulli setting via a transformation of the first and second sample moments. This results in a robust, fixed-cost estimator that avoids the hazards of local optima and the long computation time of iterative fitting procedures like the expectation-maximization (EM) algorithm. In regimes where data is limited or assumptions about the statistical structure of the data are not met, we demonstrate that the spectral estimate provides a good initialization for Laplace-EM fitting. Finally, we show that the estimator provides substantial benefits to real world settings by analyzing data from mice performing a sensory decision-making task.

Spectral learning of Bernoulli linear dynamical systems models for decision-making

Active learning seeks to reduce the amount of data required to fit the parameters of a model, thus forming an important class of techniques in modern machine learning. However, past work on active learning has largely overlooked latent variable models, which play a vital role in neuroscience, psychology, and a variety of other engineering and scientific disciplines. Here we address this gap by proposing a novel framework for maximum-mutual-information input selection for discrete latent variable regression models. We first apply our method to a class of models known as"mixtures of linear regressions"(MLR). While it is well known that active learning confers no advantage for linear-Gaussian regression models, we use Fisher information to show analytically that active learning can nevertheless achieve large gains for mixtures of such models, and we validate this improvement using both simulations and real-world data. We then consider a powerful class of temporally structured latent variable models given by a Hidden Markov Model (HMM) with generalized linear model (GLM) observations, which has recently been used to identify discrete states from animal decision-making data. We show that our method substantially reduces the amount of data needed to fit GLM-HMM, and outperforms a variety of approximate methods based on variational and amortized inference. Infomax learning for latent variable models thus offers a powerful for characterizing temporally structured latent states, with a wide variety of applications in neuroscience and beyond.

Understanding how multiple brain regions interact to produce behavior is a major challenge in systems neuroscience, with many regions causally implicated in common tasks such as sensory processing and decision making. However, a precise description of interactions between regions remains an open problem. Moreover, neural dynamics are nonlinear, non-stationary, and can vary dramatically across sessions, days, and animals. Here, we propose multi-region, switching dynamical systems (MR-SDS), a probabilistic model of multiple latent interacting systems that evolve with switching nonlinear dynamics and communication between regions. MR-SDS includes directed interactions between brain regions, allowing for estimation of state-dependent communication signals, and accounts for sensory inputs effects, history effects, and heterogeneity across days and animals. We show that our model accurately recovers latent trajectories, vector fields underlying switching nonlinear dynamics, and cross-region communication profiles in two simulations. We then apply our method to two large-scale, multi-region neural datasets involving mouse decision making. The first includes hundreds of neurons per region, recorded simultaneously at single-cell-resolution across 3 distant cortical regions. The second is a mesoscale widefield dataset of 8 adjacent cortical regions imaged across both hemispheres. On these multi-region datasets, our model outperforms existing piece-wise linear multi-region models and reveals multiple distinct dynamical states and a rich set of cross-region communication profiles.

Modeling communication and switching nonlinear dynamics in multi-region neural activity

An important problem in systems neuroscience is to characterize how a neuron integrates sensory inputs across space and time. The linear receptive field provides a mathematical characterization of this weighting function, and is commonly used to quantify neural response properties and classify cell types. However, estimating receptive fields is difficult in settings with limited data and correlated or high-dimensional stimuli. To overcome these difficulties, we propose a hierarchical model designed to flexibly parameterize low-rank receptive fields. The model includes Gaussian process priors over spatial and temporal components of the receptive field, encouraging smoothness in space and time. We also propose a new temporal prior called temporal relevance determination (TRD), which imposes a variable degree of smoothness as a function of time lag. We derive a scalable algorithm for variational Bayesian inference for both spatial and temporal receptive field components and hyperparameters. The resulting estimator scales to high-dimensional settings in which full-rank maximum likelihood or a posteriori estimates are intractable. We evaluate our approach on neural data from rat retina and primate cortex, and show that it substantially out-performs a variety of existing estimators. Our modeling approach will have useful extensions to a variety of other high-dimensional inference problems with smooth or low-rank structure.

Scalable variational inference for low-rank spatio-temporal receptive fields

Abstract A large body of work has suggested that neural populations exhibit low-dimensional dynamics during behavior. However, there are a variety of different approaches for modeling low-dimensional neural population activity. One approach involves latent linear dynamical system (LDS) models, in which population activity is described by a projection of low-dimensional latent variables with linear dynamics. A second approach involves low-rank recurrent neural networks (RNNs), in which population activity arises directly from a low-dimensional projection of past activity. Although these two modeling approaches have strong similarities, they arise in different contexts and tend to have different domains of application. Here we examine the precise relationship between latent LDS models and linear low-rank RNNs. When can one model class be converted to the other, and vice versa? We show that latent LDS models can only be converted to RNNs in specific limit cases, due to the non-Markovian property of latent LDS models. Conversely, we show that linear RNNs can be mapped onto LDS models, with latent dimensionality at most twice the rank of the RNN. A surprising consequence of our results is that a partially observed RNN is better represented by an LDS model than by an RNN consisting of only observed units.

Probing the Relationship Between Latent Linear Dynamical Systems and Low-Rank Recurrent Neural Network Models

Imaging neural activity in a behaving animal presents unique challenges in part because motion from an animal’s movement creates artifacts in fluorescence intensity time-series that are difficult to distinguish from neural signals of interest. One approach to mitigating these artifacts is to image two channels simultaneously: one that captures an activity-dependent fluorophore, such as GCaMP, and another that captures an activity-independent fluorophore such as RFP. Because the activity-independent channel contains the same motion artifacts as the activity-dependent channel, but no neural signals, the two together can be used to identify and remove the artifacts. However, existing approaches for this correction, such as taking the ratio of the two channels, do not account for channel-independent noise in the measured fluorescence. Here, we present Two-channel Motion Artifact Correction (TMAC), a method which seeks to remove artifacts by specifying a generative model of the two channel fluorescence that incorporates motion artifact, neural activity, and noise. We use Bayesian inference to infer latent neural activity under this model, thus reducing the motion artifact present in the measured fluorescence traces. We further present a novel method for evaluating ground-truth performance of motion correction algorithms by comparing the decodability of behavior from two types of neural recordings; a recording that had both an activity-dependent fluorophore and an activity-independent fluorophore (GCaMP and RFP) and a recording where both fluorophores were activity-independent (GFP and RFP). A successful motion correction method should decode behavior from the first type of recording, but not the second. We use this metric to systematically compare five models for removing motion artifacts from fluorescent time traces. We decode locomotion from a GCaMP expressing animal 20x more accurately on average than from control when using TMAC inferred activity and outperforms all other methods of motion correction tested, the best of which were ~8x more accurate than control.

Correcting motion induced fluorescence artifacts in two-channel neural imaging

Understanding decision-making is a core objective in both neuroscience and psychology, and computational models have often been helpful in the pursuit of this goal. While many models have been developed for characterizing behavior in binary decision-making and bandit tasks, comparatively little work has focused on animal decision-making in more complex tasks, such as navigation through a maze. Inverse reinforcement learning (IRL) is a promising approach for understanding such behavior, as it aims to infer the unknown reward function of an agent from its observed trajectories through state space. However, IRL has yet to be widely applied in neuroscience. One potential reason for this is that existing IRL frameworks assume that an agent’s reward function is fixed over time. To address this shortcoming, we introduce dynamic inverse reinforcement learning (DIRL), a novel IRL framework that allows for time-varying intrinsic rewards. Our method parametrizes the unknown reward function as a time-varying linear combination of spatial reward maps (which we refer to as “goal maps”). We develop an efficient inference method for recovering this dynamic reward function from behavioral data. We demonstrate DIRL in simulated experiments and then apply it to a dataset of mice exploring a labyrinth. Our method returns interpretable reward functions for two separate cohorts of mice, and provides a novel characterization of exploratory behavior. We expect DIRL to have broad applicability in neuroscience, and to facilitate the design of biologically-inspired reward functions for training artificial agents.

Dynamic Inverse Reinforcement Learning for Characterizing Animal Behavior

An influential framework within systems neuroscience posits that neural computations can be understood in terms of low-dimensional dynamics in recurrent circuits. A number of methods have thus been developed to extract latent dynamical systems from neural recordings, but inferring models that are both predictive and interpretable remains a difficult challenge. Here we propose a new method called Low-rank Inference from Neural Trajectories (LINT), based on a class of low-rank recurrent neural networks (lrRNNs) for which a link between connectivity and dynamics has been previously demonstrated. By fitting such networks to trajectories of neural activity, LINT yields a mechanistic model of latent dynamics, as well as a set of axes for dimensionality reduction and verifiable predictions for inactivations of specific populations of neurons. Here, we first demonstrate the consistency of our method and then apply it to two use cases: (i) we reverse-engineer “black-box” vanilla RNNs trained to perform cognitive tasks, and (ii) we infer latent dynamics and neural contributions from electrophysiological recordings of nonhuman primates performing a similar task.

Extracting computational mechanisms from neural data using low-rank RNNs

The rich variety of behaviors observed in animals arises through the complex interplay between sensory processing and motor control [1, 2, 3, 4, 5]. To understand these sensorimotor transformations, it is useful to build models that predict not only neural responses to sensory input [6, 7, 8, 9, 10] but also how each neuron causally contributes to behavior [11, 12]. Here we demonstrate a novel modeling approach to identify a one-to-one mapping between internal units in a deep neural network and real neurons by predicting the behavioral changes arising from systematic perturbations of more than a dozen neuron types. A key ingredient we introduce is “knockout training”, which involves perturbing the network during training to match the perturbations of the real neurons during behavioral experiments. We apply this approach to model the sensorimotor transformation of Drosophila melanogaster males during a complex, visually-guided social behavior [13, 14, 15, 16]. Contrary to prevailing views [17, 18, 19], our model suggests that visual projection neurons at the interface between the eye and brain form a distributed population code that collectively sculpts social behavior. Overall, our framework consolidates behavioral effects elicited from various neural perturbations into a single, unified model, providing a detailed map from stimulus to neuron to behavior.

One-to-one mapping between deep network units and real neurons uncovers a visual population code for social behavior

Opponent control of behavior by dorsomedial striatal pathways depends on task demands and internal state

Reduced neural activity but improved coding in rodent higher-order visual cortex during locomotion

Abstract A central question in neuroscience is how sensory inputs are transformed into percepts. At this point, it is clear that this process is strongly influenced by prior knowledge of the sensory environment. Bayesian ideal observer models provide a useful link between data and theory that can help researchers evaluate how prior knowledge is represented and integrated with incoming sensory information. However, the statistical prior employed by a Bayesian observer cannot be measured directly, and must instead be inferred from behavioral measurements. Here, we review the general problem of inferring priors from psychophysical data, and the simple solution that follows from assuming a prior that is a Gaussian probability distribution. As our understanding of sensory processing advances, however, there is an increasing need for methods to flexibly recover the shape of Bayesian priors that are not well approximated by elementary functions. To address this issue, we describe a novel approach that applies to arbitrary prior shapes, which we parameterize using mixtures of Gaussian distributions. After incorporating a simple approximation, this method produces an analytical solution for psychophysical quantities that can be numerically optimized to recover the shapes of Bayesian priors. This approach offers advantages in flexibility, while still providing an analytical framework for many scenarios. We provide a MATLAB toolbox implementing key computations described herein.

A General Framework for Inferring Bayesian Ideal Observer Models from Psychophysical Data

Approximate Bayesian inference methods provide a powerful suite of tools for finding approximations to intractable posterior distributions. However, machine learning applications typically involve selecting actions, which—in a Bayesian setting—depend on the posterior distribution only via its contribution to expected utility. A growing body of work on “loss-calibrated approximate inference” methods has therefore sought to develop posterior approximations sensitive to the influence of the utility function. Here we introduce loss-calibrated expectation propagation (Loss-EP), a loss-calibrated variant of expectation propagation. This method resembles standard EP with an additional factor that “tilts” the posterior towards higher-utility decisions. We show applications to Gaussian process classification under binary utility functions with asymmetric penalties on False Negative and False Positive errors, and show how this asymmetry can have dramatic consequences on what information is “useful” to capture in an approximation.

Loss-calibrated expectation propagation for approximate Bayesian decision-making

Making informed decisions in noisy environments requires integrating sensory information over time. However, recent work has suggested that it may be difficult to determine whether an animal’s decision-making strategy relies on evidence integration or not. In particular, strategies based on extrema-detection or random snapshots of the evidence stream may be difficult or even impossible to distinguish from classic evidence integration. Moreover, such non-integration strategies might be surprisingly common in experiments that aimed to study decisions based on integration. To determine whether temporal integration is central to perceptual decision making, we developed a new model-based approach for comparing temporal integration against alternative “non-integration” strategies for tasks in which the sensory signal is composed of discrete stimulus samples. We applied these methods to behavioral data from monkeys, rats, and humans performing a variety of sensory decision-making tasks. In all species and tasks, we found converging evidence in favor of temporal integration. First, in all observers across studies, the integration model better accounted for standard behavioral statistics such as psychometric curves and psychophysical kernels. Second, we found that sensory samples with large evidence do not contribute disproportionately to subject choices, as predicted by an extrema-detection strategy. Finally, we provide a direct confirmation of temporal integration by showing that the sum of both early and late evidence contributed to observer decisions. Overall, our results provide experimental evidence suggesting that temporal integration is an ubiquitous feature in mammalian perceptual decision-making. Our study also highlights the benefits of using experimental paradigms where the temporal stream of sensory evidence is controlled explicitly by the experimenter, and known precisely by the analyst, to characterize the temporal properties of the decision process.

Temporal integration is a robust feature of perceptual decisions

The ability to flexibly select and accumulate relevant information to form decisions, while ignoring irrelevant information, is a fundamental component of higher cognition. Yet its neural mechanisms remain unclear. Here we demonstrate that, under assumptions supported by both monkey and rat data, the space of possible network mechanisms to implement this ability is spanned by the combination of three different components, each with specific behavioral and anatomical implications. We further show that existing electrophysiological and modeling data are compatible with the full variety of possible combinations of these components, suggesting that different individuals could use different component combinations. To study variations across subjects, we developed a rat task requiring context-dependent evidence accumulation, and trained many subjects on it. Our task delivers sensory evidence through pulses that have random but precisely known timing, providing high statistical power to characterize each individual’s neural and behavioral responses. Consistent with theoretical predictions, neural and behavioral analysis revealed remarkable heterogeneity across rats, despite uniformly good task performance. The theory further predicts a specific link between behavioral and neural signatures, which was robustly supported in the data. Our results provide a new experimentally-supported theoretical framework to analyze biological and artificial systems performing flexible decision-making tasks, and open the door to the study of individual variability in neural computations underlying higher cognition.

A new theoretical framework jointly explains behavioral and neural variability across subjects performing flexible decision-making

Extracting the dynamics of behavior in sensory decision-making experiments

Accumulating evidence to make decisions is a core cognitive function. Previous studies have tended to estimate accumulation using either neural or behavioral data alone. Here we develop a unified framework for modeling stimulus-driven behavior and multi-neuron activity simultaneously. We applied our method to choices and neural recordings from three rat brain regions — the posterior parietal cortex (PPC), the frontal orienting fields (FOF), and the anterior-dorsal striatum (ADS) — while subjects performed a pulse-based accumulation task. Each region was best described by a distinct accumulation model, which all differed from the model that best described the animal’s choices. FOF activity was consistent with an accumulator where early evidence was favored while the ADS reflected near perfect accumulation. Neural responses within an accumulation framework unveiled a distinct association between each brain region and choice. Choices were better predicted from all regions using a comprehensive, accumulation-based framework and different brain regions were found to differentially reflect choice-related accumulation signals: FOF and ADS both reflected choice but ADS showed more instances of decision vacillation. Previous studies relating neural data to behaviorally-inferred accumulation dynamics have implicitly assumed that individual brain regions reflect the whole-animal level accumulator. Our results suggest that different brain regions represent accumulated evidence in dramatically different ways and that accumulation at the whole-animal level may be constructed from a variety of neural-level accumulators.

Neural population dynamics underlying evidence accumulation in multiple rat brain regions

A large body of work has suggested that neural populations exhibit low-dimensional dynamics during behavior. However, there are a variety of different approaches for modeling low-dimensional neural population activity. One approach involves latent linear dynamical system (LDS) models, in which population activity is described by a projection of low-dimensional latent variables with linear dynamics. A second approach involves low-rank recurrent neural networks (RNNs), in which population activity arises directly from a low-dimensional projection of past activity. Although these two modeling approaches have strong similarities, they arise in different contexts and tend to have different domains of application. Here we examine the precise relationship between latent LDS models and linear low-rank RNNs. When can one model class be converted to the other, and vice versa? We show that latent LDS models can only be converted to RNNs in specific limit cases, due to the nonMarkovian property of latent LDS models. Conversely, we show that linear RNNs can be mapped onto LDS models, with latent dimensionality at most twice the rank of the RNN. 1 ar X iv :2 11 0. 09 80 4v 1 [ qbi o. N C ] 1 9 O ct 2 02 1

Probing the relationship between linear dynamical systems and low-rank recurrent neural network models

Advances in neural recording present increasing opportunities to study neural activity in unprecedented detail. Latent variable models (LVMs) are promising tools for analyzing this rich activity across diverse neural systems and behaviors, as LVMs do not depend on known relationships between the activity and external experimental variables. However, progress in latent variable modeling is currently impeded by a lack of standardization, resulting in methods being developed and compared in an ad hoc manner. To coordinate these modeling efforts, we introduce a benchmark suite for latent variable modeling of neural population activity. We curate four datasets of neural spiking activity from cognitive, sensory, and motor areas to promote models that apply to the wide variety of activity seen across these areas. We identify unsupervised evaluation as a common framework for evaluating models across datasets, and apply several baselines that demonstrate benchmark diversity. We release this benchmark through EvalAI. http://neurallatents.github.io

Neural Latents Benchmark '21: Evaluating latent variable models of neural population activity

A classic view of the striatum holds that activity in direct and indirect pathways oppositely modulates motor output. Whether this involves direct control of movement, or reflects a cognitive process underlying movement, has remained unresolved. Here we find that strong, opponent control of behavior by the two pathways of the dorsomedial striatum (DMS) depends on a task’s cognitive demands. Furthermore, a latent state model (a hidden markov model with generalized linear model observations) reveals that—even within a single task—the contribution of the two pathways to behavior is state-dependent. Specifically, the two pathways have large contributions in one of two states associated with a strategy of evidence accumulation, compared to a state associated with a strategy of repeating previous choices. Thus, both the cognitive demands imposed by a task, as well as the strategy that mice pursue within a task, determine whether DMS pathways provide strong and opponent control of behavior.

Strong and opponent contributions of dorsomedial striatal pathways to behavior depends on cognitive demands and task strategy

Sufficient dimension reduction (SDR) methods are a family of supervised methods for dimensionality reduction that seek to reduce dimensionality while preserving information about a target variable of interest. However, existing SDR methods typically require more observations than the number of dimensions (N > p). To overcome this limitation, we propose Class-conditional Factor Analytic Dimensions (CFAD), a model-based dimensionality reduction method for high-dimensional, small-sample data. We show that CFAD substantially outperforms existing SDR methods in the small-sample regime, and can be extended to incorporate prior information such as smoothness in the projection axes. We demonstrate the effectiveness of CFAD with an application to functional magnetic resonance imaging (fMRI) measurements during visual object recognition and working memory tasks, where it outperforms existing SDR and a variety of other dimensionalityreduction methods.

Factor-analytic inverse regression for high-dimension, small-sample dimensionality reduction

An important problem in systems neuroscience is to identify the latent dynamics underlying neural population activity. Here we address this problem by introducing a low-dimensional nonlinear model for latent neural population dynamics using neural ordinary differential equations (neural ODEs), with noisy sensory inputs and Poisson spike train outputs. We refer to this as the Poisson Latent Neural Differential Equations (PLNDE) model. We apply the PLNDE framework to a variety of synthetic datasets, and show that it accurately infers the phase portraits and fixed points of nonlinear systems augmented to produce spike train data, including the FitzHugh-Nagumo oscillator, a 3-dimensional nonlinear spiral, and a nonlinear sensory decision-making model with attractor dynamics. Our model significantly outperforms existing methods at inferring single-trial neural firing rates and the corresponding latent trajectories that generated them, especially in the regime where the spike counts and number of trials are low. We then apply our model to multi-region neural population recordings from medial frontal cortex of rats performing an auditory decision-making task. Our model provides a general, interpretable framework for investigating the neural mechanisms of decision-making and other cognitive computations through the lens of dynamical systems.

Inferring Latent Dynamics Underlying Neural Population Activity via Neural Differential Equations

Neural decoding methods provide a powerful tool for quantifying the information content of neural population codes and the limits imposed by correlations in neural activity. However, standard decoding methods are prone to overfitting and scale poorly to high-dimensional settings. Here, we introduce a novel decoding method to overcome these limitations. Our approach, the Gaussian process multi-class decoder (GPMD), is well-suited to decoding a continuous low-dimensional variable from high-dimensional population activity, and provides a platform for assessing the importance of correlations in neural population codes. The GPMD is a multinomial logistic regression model with a Gaussian process prior over the decoding weights. The prior includes hyperparameters that govern the smoothness of each neuron’s decoding weights, allowing automatic pruning of uninformative neurons during inference. We provide a variational inference method for fitting the GPMD to data, which scales to hundreds or thousands of neurons and performs well even in datasets with more neurons than trials. We apply the GPMD to recordings from primary visual cortex in three different species: monkey, ferret, and mouse. Our decoder achieves state-of-the-art accuracy on all three datasets, and substantially outperforms independent Bayesian decoding, showing that knowledge of the correlation structure is essential for optimal decoding in all three species.

Efficient decoding of large-scale neural population responses with Gaussian-process multiclass regression

An open question in systems and computational neuroscience is how neural circuits accumulate evidence towards a decision. Fitting models of decision-making theory to neural activity helps answer this question, but current approaches limit the number of these models that we can fit to neural data. Here we propose a unifying framework for modeling neural activity during decision-making tasks. The framework includes the canonical drift-diffusion model and enables extensions such as multi-dimensional accumulators, variable and collapsing boundaries, and discrete jumps. Our framework is based on constraining the parameters of recurrent state-space models, for which we introduce a scalable variational Laplace-EM inference algorithm. We applied the modeling approach to spiking responses recorded from monkey parietal cortex during two decision-making tasks. We found that a two-dimensional accumulator better captured the trial-averaged responses of a set of parietal neurons than a single accumulator model. Next, we identified a variable lower boundary in the responses of an LIP neuron during a random dot motion task.

Unifying and generalizing models of neural dynamics during decision-making

Supplementary Material: A general recurrent state space framework for modeling neural dynamics during decision-making

Understanding how animals update their decision-making behavior over time is an important problem in neuroscience. Decision-making strategies evolve over the course of learning, and continue to vary even in well-trained animals. However, the standard suite of behavioral analysis tools is ill-equipped to capture the dynamics of these strategies. Here, we present a flexible method for characterizing time-varying behavior during decision-making experiments. We show that it successfully captures trial-to-trial changes in an animal’s sensitivity to not only task-relevant stimuli, but also task-irrelevant covariates such as choice, reward, and stimulus history. We use this method to derive insights from training data collected in mice, rats, and human subjects performing auditory discrimination and visual detection tasks. With this approach, we uncover the detailed evolution of an animal’s strategy during learning, including adaptation to time-varying task statistics, suppression of sub-optimal strategies, and shared behavioral dynamics between subjects within an experimental population.

Extracting the Dynamics of Behavior in Decision-Making Experiments

An open question in systems and computational neuroscience is how neural circuits accumulate evidence towards a decision. Fitting models of decision-making theory to neural activity helps answer this question, but current approaches limit the number of these models that we can fit to neural data. Here we propose a general framework for modeling neural activity during decisionmaking. The framework includes the canonical drift-diffusion model and enables extensions such as multi-dimensional accumulators, variable and collapsing boundaries, and discrete jumps. Our framework is based on constraining the parameters of recurrent state space models, for which we introduce a scalable variational Laplace EM inference algorithm. We applied the modeling approach to spiking responses recorded from monkey parietal cortex during two decision-making tasks. We found that a two-dimensional accumulator better captured the responses of a set of parietal neurons than a single accumulator model, and we identified a variable lower boundary in the responses of a parietal neuron during a random dot motion task. We expect this framework will be useful for modeling neural dynamics in a variety of decision-making settings.

A general recurrent state space framework for modeling neural dynamics during decision-making

Modeling statistical dependencies in multi-region spike train data

Prefrontal cortex exhibits multidimensional dynamic encoding during decision-making

A key challenge in understanding the sensory transformations of the visual system is to obtain a highly predictive model of responses from visual cortical neurons. Deep neural networks (DNNs) provide a promising candidate for such a model. However, DNNs require orders of magnitude more training data than neuroscientists can collect from real neurons because experimental recording time is severely limited. This motivates us to find images that train highly-predictive DNNs with as little training data as possible. We propose gaudy images---high-contrast binarized versions of natural images---to efficiently train DNNs. In extensive simulation experiments, we find that training DNNs with gaudy images substantially reduces the number of training images needed to accurately predict the simulated responses of visual cortical neurons. We also find that gaudy images, chosen before training, outperform images chosen during training by active learning algorithms. Thus, gaudy images overemphasize features of natural images, especially edges, that are the most important for efficiently training DNNs. We believe gaudy images will aid in the modeling of visual cortical neurons, potentially opening new scientific questions about visual processing, as well as aid general practitioners that seek ways to improve the training of DNNs.

High-contrast "gaudy" images improve the training of deep neural network models of visual cortex

A key problem in systems neuroscience is to understand how neural populations integrate relevant sensory inputs during decision-making. Here, we address this problem by training a structured recurrent neural network to reproduce both psychophysical behavior and neural responses recorded from monkey prefrontal cortex during a context-dependent per-ceptual decision-making task. Our approach yields a one-to-one mapping of model neurons to recorded neurons, and explicitly incorporates sensory noise governing the animal’s performance as a function of stimulus strength. We then analyze the dynamics of the resulting model in order to understand how the network computes context-dependent decisions. We find that network dynamics preserve both relevant and irrelevant stimulus information, and exhibit a grid of fixed points for different stimulus conditions as opposed to a one-dimensional line attractor. Our work provides new insights into context-dependent decision-making and offers a powerful framework for linking cognitive function with neural activity within an artificial model.

Recurrent dynamics of prefrontal cortex during context-dependent decision-making

How do animals learn? This remains an elusive question in neuroscience. Whereas reinforcement learning often focuses on the design of algorithms that enable artificial agents to efficiently learn new tasks, here we develop a modeling framework to directly infer the empirical learning rules that animals use to acquire new behaviors. Our method efficiently infers the trial-to-trial changes in an animal's policy, and decomposes those changes into a learning component and a noise component. Specifically, this allows us to: (i) compare different learning rules and objective functions that an animal may be using to update its policy; (ii) estimate distinct learning rates for different parameters of an animal's policy; (iii) identify variations in learning across cohorts of animals; and (iv) uncover trial-to-trial changes that are not captured by normative learning rules. After validating our framework on simulated choice data, we applied our model to data from rats and mice learning perceptual decision-making tasks. We found that certain learning rules were far more capable of explaining trial-to-trial changes in an animal's policy. Whereas the average contribution of the conventional REINFORCE learning rule to the policy update for mice learning the International Brain Laboratory's task was just 30%, we found that adding baseline parameters allowed the learning rule to explain 92% of the animals' policy updates under our model. Intriguingly, the best-fitting learning rates and baseline values indicate that an animal's policy update, at each trial, does not occur in the direction that maximizes expected reward. Understanding how an animal transitions from chance-level to high-accuracy performance when learning a new task not only provides neuroscientists with insight into their animals, but also provides concrete examples of biological learning algorithms to the machine learning community.

Mice alternate between discrete strategies during perceptual decision-making

Neural datasets often contain measurements of neural activity across multiple trials of a repeated stimulus or behavior. An important problem in the analysis of such datasets is to characterize systematic aspects of neural activity that carry information about the repeated stimulus or behavior of interest, which can be considered “signal”, and to separate them from the trial-to-trial fluctuations in activity that are not time-locked to the stimulus, which for purposes of such analyses can be considered “noise”. Gaussian Process factor models provide a powerful tool for identifying shared structure in high-dimensional neural data. However, they have not yet been adapted to the problem of characterizing signal and noise in multi-trial datasets. Here we address this shortcoming by proposing “signal-noise” Poisson-spiking Gaussian Process Factor Analysis (SNP-GPFA), a flexible latent variable model that resolves signal and noise latent structure in neural population spiking activity. To learn the parameters of our model, we introduce a Fourier-domain black box variational inference method that quickly identifies smooth latent structure. The resulting model reliably uncovers latent signal and trial-to-trial noise-related fluctuations in large-scale recordings. We use this model to show that predominantly, noise fluctuations perturb neural activity within a subspace orthogonal to signal activity, suggesting that trial-by-trial noise does not interfere with signal representations. Finally, we extend the model to capture statistical dependencies across brain regions in multi-region data. We show that in mouse visual cortex, models with shared noise across brain regions out-perform models with independent per-region noise.

Identifying signal and noise structure in neural population activity with Gaussian process factor models

Author Correction: Unsupervised identification of the internal states that shape natural behavior

An important problem in computational neuroscience is to understand how networks of spiking neurons can carry out various computations underlying behavior. Balanced spiking networks (BSNs) provide a powerful framework for implementing arbitrary linear dynamical systems in networks of integrate-and-fire neurons (Boerlin et al. [1]). However, the classic BSN model requires near-instantaneous transmission of spikes between neurons, which is biologically implausible. Introducing realistic synaptic delays leads to an pathological regime known as “ping-ponging”, in which different populations spike maximally in alternating time bins, causing network output to overshoot the target solution. Here we document this phenomenon and provide a novel solution: we show that a network can have realistic synaptic delays while maintaining accuracy and stability if neurons are endowed with conditionally Poisson firing. Formally, we propose two alternate formulations of Poisson balanced spiking networks: (1) a “local” framework, which replaces the hard integrate-and-fire spiking rule within each neuron by a “soft” threshold function, such that firing probability grows as a smooth nonlinear function of membrane potential; and (2) a “population” framework, which reformulates the BSN objective function in terms of expected spike counts over the entire population. We show that both approaches offer improved robustness, allowing for accurate implementation of network dynamics with realistic synaptic delays between neurons. Moreover, both models produce positive correlations between similarly tuned neurons, a feature of real neural populations that is not found in the original BSN. This work unifies balanced spiking networks with Poisson generalized linear models and suggests several promising avenues for future research.

Motion discrimination is a well-established model system for investigating how sensory signals are used to form perceptual decisions. Classic studies relating single-neuron activity in the middle temporal (MT) area to perceptual decisions have suggested that a simple linear readout could underlie motion discrimination behavior. A theoretically-optimal readout, in contrast, would take into account the correlations between neurons, and the sensitivity of individual neurons at each time point. However, it remains unknown how sophisticated the readout needs to be to support psychophysical motion discrimination or to approach optimal performance. Here, we compare the performance of various neurally-plausible decoders, trained to discriminate motion direction from small ensembles of simultaneously recorded MT neurons, with reference to the psychophysical performance of the animal. We found that decoding the stimulus without knowledge of the inter-neuronal correlations was sufficient to match an optimal (correlation-aware) decoder. Additionally, a decoder could match the psychophysical performance of the animals with at integration of up to half the stimulus and inherited temporal dynamics from the time-varying MT responses. These results demonstrate that simple, linear decoders operating upon small ensembles of neurons can match psychophysical (and optimal) sensitivity without taking correlations into account, and that such simple readout mechanisms can exhibit complex temporal properties inherited from the sensory dynamics themselves.

A simple linear readout of MT supports motion direction-discrimination performance.

Unsupervised identification of the internal states that shape natural behavior

Recent work has suggested that the prefrontal cortex (PFC) plays a key role in context-dependent perceptual decision-making. In this study, we addressed that role using a new method for identifying task-relevant dimensions of neural population activity. Specifically, we show that the PFC has a multidimensional code for context, decisions and both relevant and irrelevant sensory information. Moreover, these representations evolve in time, with an early linear accumulation phase followed by a phase with rotational dynamics. We identify the dimensions of neural activity associated with these phases and show that they do not arise from distinct populations but from a single population with broad tuning characteristics. Finally, we use model-based decoding to show that the transition from linear to rotational dynamics coincides with a plateau in decoding accuracy, revealing that rotational dynamics in the PFC preserve sensory choice information for the duration of the stimulus integration period. Aoi et al. used a new dimensionality-reduction method to disentangle the contributions of different task variables to neural population activity, which revealed rotational dynamics in monkey PFC during context-dependent decision-making.

Prefrontal cortex exhibits multi-dimensional dynamic encoding during decision-making

The shared response model provides a simple but effective framework to analyse fMRI data of subjects exposed to naturalistic stimuli. However when the number of subjects or runs is large, fitting the model requires a large amount of memory and computational power, which limits its use in practice. In this work, we introduce the FastSRM algorithm that relies on an intermediate atlas-based representation. It provides considerable speed-up in time and memory usage, hence it allows easy and fast large-scale analysis of naturalistic-stimulus fMRI data. Using four different datasets, we show that our method matches the performance of the original SRM algorithm while being about 5x faster and 20x to 40x more memory efficient. Based on this contribution, we use FastSRM to predict age from movie watching data on the CamCAN sample. Besides delivering accurate predictions (mean absolute error of 7.5 years), FastSRM extracts topographic patterns that are predictive of age, demonstrating that brain activity during free perception reflects age.

Correction: The Equivalence of Information-Theoretic and Likelihood-Based Methods for Neural Dimensionality Reduction

Gaussian Process Factor Analysis (GPFA) has been broadly applied to the problem of identifying smooth, low-dimensional temporal structure underlying large-scale neural recordings. However, spike trains are non-Gaussian, which motivates combining GPFA with discrete observation models for binned spike count data. The drawback to this approach is that GPFA priors are not conjugate to count model likelihoods, which makes inference challenging. Here we address this obstacle by introducing a fast, approximate inference method for non-conjugate GPFA models. Our approach uses orthogonal second-order polynomials to approximate the nonlinear terms in the non-conjugate log-likelihood, resulting in a method we refer to as \textit{polynomial approximate log-likelihood} (PAL) estimators. This approximation allows for accurate closed-form evaluation of marginal likelihoods and fast numerical optimization for parameters and hyperparameters. We derive PAL estimators for GPFA models with binomial, Poisson, and negative binomial observations and find the PAL estimation is highly accurate, and achieves faster convergence times compared to existing state-of-the-art inference methods. We also find that PAL hyperparameters can provide sensible initialization for black box variational inference (BBVI), which improves BBVI accuracy. We demonstrate that PAL estimators achieve fast and accurate extraction of latent structure from multi-neuron spike train data.

Efficient non-conjugate Gaussian process factor models for spike count data using polynomial approximations

The past decade has seen a multitude of new in vivo functional imaging methodologies. However, the lack of ground-truth comparisons or evaluation metrics makes large-scale, systematic validation impossible. Here we provide a new framework for evaluating TPM methods via in silico Neural Anatomy and Optical Microscopy (NAOMi) simulation. Our computationally efficient model generates large anatomical volumes of mouse cortex, simulates neural activity, and incorporates optical propagation and scanning to create realistic calcium imaging datasets. We verify NAOMi simulations against in vivo two-photon recordings from mouse cortex. We leverage this access to in silico ground truth to perform direct comparisons between different segmentation algorithms and optical designs. We find modern segmentation algorithms extract strong neural time-courses comparable to estimation using oracle spatial information, but with an increase in the false positive rate. Comparison between optical setups demonstrate improved resilience to motion artifacts in sparsely labeled samples using Bessel beams, increased signal-to-noise ratio and cell-count using low numerical aperture Gaussian beams and nuclear GCaMP, and more uniform spatial sampling with temporal focusing versus multi-plane imaging. Overall, by leveraging the rich accumulated knowledge of neural anatomy and optical physics, we provide a powerful new tool to assess and develop important methods in neural imaging.

Neural anatomy and optical microscopy (NAOMi) simulation for evaluating calcium imaging methods

Editorial overview: Machine learning, big data, and neuroscience

The activity of neural populations in the brains of humans and animals can exhibit vastly different spatial patterns when faced with different tasks or environmental stimuli. The degree of similarity between these neural activity patterns in response to different events is used to characterize the representational structure of cognitive states in a neural population. The dominant methods of investigating this similarity structure first estimate neural activity patterns from noisy neural imaging data using linear regression, and then examine the similarity between the estimated patterns. Here, we show that this approach introduces spurious bias structure in the resulting similarity matrix, in particular when applied to fMRI data. This problem is especially severe when the signal-to-noise ratio is low and in cases where experimental conditions cannot be fully randomized in a task. We propose Bayesian Representational Similarity Analysis (BRSA), an alternative method for computing representational similarity, in which we treat the covariance structure of neural activity patterns as a hyper-parameter in a generative model of the neural data. By marginalizing over the unknown activity patterns, we can directly estimate this covariance structure from imaging data. This method offers significant reductions in bias and allows estimation of neural representational similarity with previously unattained levels of precision at low signal-to-noise ratio. The probabilistic framework allows for jointly analyzing data from a group of participants. The method can also simultaneously estimate a signal-to-noise ratio map that shows where the learned representational structure is supported more strongly. Both this map and the learned covariance matrix can be used as a structured prior for maximum a posteriori estimation of neural activity patterns, which can be further used for fMRI decoding. We make our tool freely available in Brain Imaging Analysis Kit (BrainIAK). Author summary We show the severity of the bias introduced when performing representational similarity analysis (RSA) based on neural activity pattern estimated within imaging runs. Our Bayesian RSA method significantly reduces the bias and can learn a shared representational structure across multiple participants. We also demonstrate its extension as a new multi-class decoding tool.

Representational structure or task structure? Bias in neural representational similarity analysis and a Bayesian method for reducing bias

Accurate estimation of neural spike-rates is challenging due to fact that both stimulus-dependent spikerates and trial-by-trial noise are continuously timevarying and that neural spiking is well known to exhibit superor sub-Poisson behavior. In particular, the time-varying nature of the noise makes spikecount statistics sensitive to choices in temporal binsize selection (Cohen & Kohn, 2011). While methods have been proposed for both binless rate estimation and non-Poisson activity (R. Goris, Movshon, & Simoncelli, 2014; Charles, Park, Weller, Horwitz, & Pillow, 2018), no current over-dispersion model can perform arbitrary continuous-time rate estimation. We present here such a model, where we model the stimulus-based rate as a Gaussian Process (GP), and the rate driving the observed spiking is an additive combination of the stimulus GP and a noise process (also modeled as a GP), passed through a rectifying nonlinearity. Our model significantly generalizes previous over-dispersion models by both removing the bin-size dependence, as well as allowing estimation of the latent continuous-time spike-rates. Our model also explains the difference in statistics across bin sizes by accounting for temporal correlations. Given the noise parameters, we can estimate the stimulus GP via a maximum a-posteriori optimization, using a Laplace approximation to marginalize over the noise instantiations. We demonstrate out model both on simulated data as well as macaque V1 activity.

Additive Continuous-time Joint Partitioning of Neural Variability

Recent advances in recording technologies have allowed neuroscientists to record simultaneous spiking activity from hundreds to thousands of neurons in multiple brain regions. Such large-scale recordings pose a major challenge to existing statistical methods for neural data analysis. Here we develop highly scalable approximate inference methods for Poisson generalized linear models (GLMs) that require only a single pass over the data. Our approach relies on a recently proposed method for obtaining approximate sufficient statistics for GLMs using polynomial approximations [7], which we adapt to the Poisson GLM setting. We focus on inference using quadratic approximations to nonlinear terms in the Poisson GLM log-likelihood with Gaussian priors, for which we derive closed-form solutions to the approximate maximum likelihood and MAP estimates, posterior distribution, and marginal likelihood. We introduce an adaptive procedure to select the polynomial approximation interval and show that the resulting method allows for efficient and accurate inference and regularization of high-dimensional parameters. We use the quadratic estimator to fit a fully-coupled Poisson GLM to spike train data recorded from 831 neurons across five regions of the mouse brain for a duration of 41 minutes, binned at 1 ms resolution. Across all neurons, this model is fit to over 2 billion spike count bins and identifies fine-timescale statistical dependencies between neurons within and across cortical and subcortical areas.

Scaling the Poisson GLM to massive neural datasets through polynomial approximations

Recent work in theoretical neuroscience has shown that information-theoretic "efficient" neural codes, which allocate neural resources to maximize the mutual information between stimuli and neural responses, give rise to a lawful relationship between perceptual bias and discriminability that is observed across a wide variety of psychophysical tasks in human observers (Wei & Stocker 2017). Here we generalize these results to show that the same law arises under a much larger family of optimal neural codes, introducing a unifying framework that we call power-law efficient coding. Specifically, we show that the same lawful relationship between bias and discriminability arises whenever Fisher information is allocated proportional to any power of the prior distribution. This family includes neural codes that are optimal for minimizing Lp error for any p, indicating that the lawful relationship observed in human psychophysical data does not require information-theoretically optimal neural codes. Furthermore, we derive the exact constant of proportionality governing the relationship between bias and discriminability for different power laws (which includes information-theoretically optimal codes, where the power is 2, and so-called discrimax codes, where power is 1/2), and different choices of optimal decoder. As a bonus, our framework provides new insights into "anti-Bayesian" perceptual biases, in which percepts are biased away from the center of mass of the prior. We derive an explicit formula that clarifies precisely which combinations of neural encoder and decoder can give rise to such biases.

Power-law efficient neural codes provide general link between perceptual bias and discriminability

Summarizing high-dimensional data using a small number of parameters is a ubiquitous first step in the analysis of neuronal population activity. Recently developed methods use "targeted" approaches that work by identifying multiple, distinct low-dimensional subspaces of activity that capture the population response to individual experimental task variables, such as the value of a presented stimulus or the behavior of the animal. These methods have gained attention because they decompose total neural activity into what are ostensibly different parts of a neuronal computation. However, existing targeted methods have been developed outside of the confines of probabilistic modeling, making some aspects of the procedures ad hoc, or limited in flexibility or interpretability. Here we propose a new model-based method for targeted dimensionality reduction based on a probabilistic generative model of the population response data. The low-dimensional structure of our model is expressed as a low-rank factorization of a linear regression model. We perform efficient inference using a combination of expectation maximization and direct maximization of the marginal likelihood. We also develop an efficient method for estimating the dimensionality of each subspace. We show that our approach outperforms alternative methods in both mean squared error of the parameter estimates, and in identifying the correct dimensionality of encoding using simulated data. We also show that our method provides more accurate inference of low-dimensional subspaces of activity than a competing algorithm, demixed PCA.

Model-based targeted dimensionality reduction for neuronal population data

A major difficulty in studying the neural mechanisms underlying olfactory perception is the lack of obvious structure in the relationship between odorants and the neural activity patterns they elicit. Here we use odor-evoked responses in piriform cortex to identify a latent manifold specifying latent distance relationships between olfactory stimuli. Our approach is based on the Gaussian process latent variable model, and seeks to map odorants to points in a low-dimensional embedding space, where distances between points in the embedding space relate to the similarity of population responses they elicit. The model is specified by an explicit continuous mapping from a latent embedding space to the space of high-dimensional neural population firing rates via nonlinear tuning curves, each parametrized by a Gaussian process. Population responses are then generated by the addition of correlated, odor-dependent Gaussian noise. We fit this model to large-scale calcium fluorescence imaging measurements of population activity in layers 2 and 3 of mouse piriform cortex following the presentation of a diverse set of odorants. The model identifies a low-dimensional embedding of each odor, and a smooth tuning curve over the latent embedding space that accurately captures each neuron's response to different odorants. The model captures both signal and noise correlations across more than 500 neurons. We validate the model using a cross-validation analysis known as co-smoothing to show that the model can accurately predict the responses of a population of held-out neurons to test odorants.

Learning a latent manifold of odor representations from neural responses in piriform cortex

A popular approach to the study of information processing in the nervous system is to char-acterize neural responses in terms of a cascade of linear and nonlinear stages: a linear filter to describe the neuron’s stimulus integration properties, followed by a rectifying nonlinearity to convert filter output to spike rate. However, real neurons integrate stimuli via the modula-tion of nonlinear excitatory and inhibitory synaptic conductances. Here we introduce a bio-physically inspired point process model with conductance-based inputs. The model provides a novel interpretation of the popular Poisson generalized linear model (GLM) as a special kind of conductance-based model, where excitatory and inhibitory conductances are modulated in a “push-pull” manner so that total conductance remains constant. We relax this constraint to obtain a more general and flexible “conductance-based encoding model” (CBEM), which can exhibit stimulus-dependent fluctuations in gain and dynamics. We fit the model to spike trains of macaque retinal ganglion cells and show that, remarkably, we can accurately infer underlying inhibitory and excitatory conductances, using comparisons to intracellularly measured conductances. Using extracellular data, we corroborate the intracellular finding that synaptic excitation temporally precedes inhibition in retina. We show that the CBEM outperforms the classic GLM at predicting retinal ganglion cell responses to full-field stimuli, generalizes better across contrast levels, and captures inhibition-dependent response properties to spatially structured stimuli. The CBEM provides a powerful tool for gaining insights into the intracellular variables governing spiking, and forges an important link between extracellular characterization methods and biophysically detailed response models.

Inferring synaptic inputs from spikes with a conductance-based neural encoding model

Discrete Stepping and Nonlinear Ramping Dynamics Underlie Spiking Responses of LIP Neurons during Decision-Making

An Efficient and Naturalistic Experimental Paradigm for Spatiotemporal Assessment of Visual Behavior and Neurophysiology

Significance We characterize spatiotemporal integration of naturalistic, continuous visual motion of three primate species (humans, macaques, and marmosets). All three species volitionally, but naturally, track the center of expansion of a dynamic optic flow field. Detailed analysis of this flow-tracking behavior reveals lawful and repeatable dependencies of the behavior on nuances in the stimulus, revealing that even unconstrained and continuous behavior can exhibit the sort of precise dependencies typically studied only in artificial and constrained tasks. Much study of the visual system has focused on how humans and monkeys integrate moving stimuli over space and time. Such assessments of spatiotemporal integration provide fundamental grounding for the interpretation of neurophysiological data, as well as how the resulting neural signals support perceptual decisions and behavior. However, the insights supported by classical characterizations of integration performed in humans and rhesus monkeys are potentially limited with respect to both generality and detail: Standard tasks require extensive amounts of training, involve abstract stimulus–response mappings, and depend on combining data across many trials and/or sessions. It is thus of concern that the integration observed in classical tasks involves the recruitment of brain circuits that might not normally subsume natural behaviors, and that quantitative analyses have limited power for characterizing single-trial or single-session processes. Here we bridge these gaps by showing that three primate species (humans, macaques, and marmosets) track the focus of expansion of an optic flow field continuously and without substantial training. This flow-tracking behavior was volitional and reflected substantial temporal integration. Most strikingly, gaze patterns exhibited lawful and nuanced dependencies on random perturbations in the stimulus, such that repetitions of identical flow movies elicited remarkably similar eye movements over long and continuous time periods. These results demonstrate the generality of spatiotemporal integration in natural vision, and offer a means for studying integration outside of artificial tasks while maintaining lawful and highly reliable behavior.

Lawful tracking of visual motion in humans, macaques, and marmosets in a naturalistic, continuous, and untrained behavioral context

A large body of work on neural encoding has focused on “cascade” type models such as the linear-nonlinear-Poisson (LNP) model. This approach seeks to describe the encoding process in terms of a series of stages: (1) projection of the stimulus onto a bank of linear filters; (2) a nonlinear function combining these filter outputs; and (3) a noisy spike generation process. Here we explore the relationship of the LNP modeling framework to more recent approaches arising from the deep learning literature. Specifically, we show that deep neural network (DNN) and convolutional neural network (CNN) models of neural activity sit firmly within the LNP framework, and correspond to particular parametrizations of the nonlinear stage of the LNP model. Using data from primate retina and primary visual cortex, we compare the performance of LNP models fit with deep learning methods to LNP models fit with traditional estimators, including spike-triggered covariance (STC), information-theoretic spike-triggered averaging and covariance (iSTAC), and maximum likelihood estimators also known as “maximally informative dimensions” (MID). We show that models with nonlinearities parametrized by deep networks achieve higher accuracy for a fixed number of filters, and can extract a larger number of informative filters than traditional models. Finally, we perform a dimensionality analysis of LNP models trained with deep learning methods, revealing that a large number of filters are needed to accurately describe the neural responses of many cells even early in the visual pathway. This result overturns one of the central tenets of the LNP modeling framework: that neural computations are low-dimensional, or depend on the stimulus only via its projection onto a small number of linear filters. We discuss the implications of these findings for both the fitting and interpretation of LNP encoding models.

A comparison of deep learning and linear-nonlinear cascade approaches to neural encoding

Different neural networks trained on the same dataset often learn similar input-output mappings with very different weights. Is there some correspondence between these neural network solutions? For linear networks, it has been shown that different instances of the same network architecture encode the same representational similarity matrix, and their neural activity patterns are connected by orthogonal transformations. However, it is unclear if this holds for non-linear networks. Using a shared response model, we show that different neural networks encode the same input examples as different orthogonal transformations of an underlying shared representation. We test this claim using both standard convolutional neural networks and residual networks on CIFAR10 and CIFAR100.

Psychometric functions (PFs) quantify how external stimuli affect behavior and play an important role in building models of sensory and cognitive processes. Adaptive stimulus selection methods seek to select stimuli that are maximally informative about the PF given data observed so far in an experiment and thereby reduce the number of trials required to estimate the PF. Here we develop new adaptive stimulus selection methods for flexible PF models in tasks with two or more alternatives. We model the PF with a multinomial logistic regression mixture model that incorporates realistic aspects of psychophysical behavior, including lapses and multiple alternatives for the response. We propose an information-theoretic criterion for stimulus selection and develop computationally efficient methods for inference and stimulus selection based on semi-adaptive Markov Chain Monte Carlo (MCMC) sampling. We apply these methods to data from macaque monkeys performing a multi-alternative motion discrimination task, and show in simulated experiments that our method can achieve a substantial speed-up over random designs. These advances will reduce the data needed to build accurate models of multi-alternative PFs and can be extended to high-dimensional PFs that would be infeasible to characterize with standard methods.

Adaptive stimulus selection for multi-alternative psychometric functions with lapses

The sparse coding model posits that the visual system has evolved to efficiently code natural stimuli using a sparse set of features from an overcomplete dictionary. The classic sparse coding model suffers from two key limitations, however: (1) computing the neural response to an image patch requires minimizing a nonlinear objective function, which was initially not easily mapped onto a neurally plausible feedforward mechanism and (2) fitting the model to data relied on an approximate inference method that ignores uncertainty. Here we address these two shortcomings by formulating a variational inference method for the sparse coding model inspired by the variational auto-encoder (VAE) framework. The sparse-coding variational auto-encoder (SVAE) augments the classic sparse coding model with a probabilistic recognition model, parametrized by a deep neural network. This recognition model provides a neurally plausible implementation for the mapping from image patches to neural activities, and enables a principled method for fitting the sparse coding model to data via maximization of the evidence lower bound (ELBO). The SVAE differs from the traditional VAE in three important ways: the generative model is the sparse coding model instead of a deep network; the latent representation is overcomplete, with more latent dimensions than image pixels; and the prior over latent variables is a sparse or heavy-tailed instead of Gaussian. We fit the SVAE to natural image data under different assumed prior distributions, and show that it obtains higher test performance than previous fitting methods. Finally, we examine the response properties of the recognition network and show that it captures important nonlinear properties of neurons in the early visual pathway.

The process of learning new behaviors over time is a problem of great interest in both neuroscience and artificial intelligence. However, most standard analyses of animal training data either treat behavior as fixed or track only coarse performance statistics (e.g., accuracy, bias), providing limited insight into the evolution of the policies governing behavior. To overcome these limitations, we propose a dynamic psychophysical model that efficiently tracks trial-to-trial changes in behavior over the course of training. Our model consists of a dynamic logistic regression model, parametrized by a set of time-varying weights that express dependence on sensory stimuli as well as task-irrelevant covariates, such as stimulus, choice, and answer history. Our implementation scales to large behavioral datasets, allowing us to infer 500K parameters (e.g., 10 weights over 50K trials) in minutes on a desktop computer. We optimize hyperparameters governing how rapidly each weight evolves over time using the decoupled Laplace approximation, an efficient method for maximizing marginal likelihood in non-conjugate models. To illustrate performance, we apply our method to psychophysical data from both rats and human subjects learning a delayed sensory discrimination task. The model successfully tracks the psychophysical weights of rats over the course of training, capturing day-to-day and trial-to-trial fluctuations that underlie changes in performance, choice bias, and dependencies on task history. Finally, we investigate why rats frequently make mistakes on easy trials, and suggest that apparent lapses can be explained by sub-optimal weighting of known task covariates.

Convolutional neural networks, optimized for image classification, are state-of-the-art computational models for visual neural representation. Moreover, performance optimization often leads to better models of neural representation (Yamins et al., 2014). In this study, we investigate whether performance optimization always increases the similarity between the neural network and the brain, in terms of their representations. We compared AlexNet and a residual network on a recent human image-viewing fMRI dataset (Horikawa & Kamitani, 2017). The original study found a remarkable similarity between AlexNet and the brain (Horikawa & Kamitani, 2017). Although residual networks achieved better image classification performance, we found that the hidden representation of the residual network is much less similar to human brain representation, compared to AlexNet. This result suggests that performance optimization can eventually lead to systematic deviation from human brain representation. We conclude that additional neuroscience-inspired design is critical for building a better representation model of the brain.

Performance Optimization is Insufficient for Building Accurate Models for Neural Representation

An International Laboratory for Systems and Computational Neuroscience

Neurons in many brain areas exhibit high trial-to-trial variability, with spike counts that are over-dispersed relative to a Poisson distribution. Recent work (Goris et al., 2014) has proposed to explain this variability in terms of a multiplicative interaction between a stochastic gain variable and a stimulus-dependent Poisson firing rate, which produces quadratic relationships between spike count mean and variance. Here we examine this quadratic assumption and propose a more flexible family of models that can account for a more diverse set of mean-variance relationships. Our model contains additive Gaussian noise that is transformed nonlinearly to produce a Poisson spike rate. Different choices of the nonlinear function can give rise to qualitatively different mean-variance relationships, ranging from sub-linear to linear to multiplicative. Intriguingly, a rectified squaring nonlinearity produces a linear mean-variance function, corresponding to responses with constant Fano factor. We describe a computationally efficient method for fitting this model to data, and demonstrate that a majority of neurons in a V1 population are better described by a model with non-quadratic relationship between mean and variance. Lastly, we develop an application to Bayesian adaptive stimulus selection in closed-loop neurophysiology experiments, which shows that accounting for overdispersion can lead to dramatic improvements in adaptive tuning curve estimation.

Dethroning the Fano Factor: a flexible, model-based approach to partitioning neural variability

We examine the problem of rapidly and efficiently estimating a neuron’s linear receptive field (RF) from responses to high-dimensional stimuli. This problem poses important statistical and computational challenges. Statistical challenges arise from the need for strong regularization when using correlated stimuli in high-dimensional parameter spaces, while computational challenges arise from extensive time and memory costs associated with evidence-optimization and inference in high-dimensional settings. Here we focus on novel methods for scaling up automatic smoothness determination (ASD), an empirical Bayesian method for RF estimation, to high-dimensional settings. First, we show that using a zero-padded Fourier domain representation and a “coarse-to-fine” evidence optimization strategy gives substantial improvements in speed and memory, while maintaining exact numerical accuracy. We then introduce a suite of scalable approximate methods that exploit Kronecker and Toeplitz structure in the stimulus autocovariance, which can be related to the method of expected log-likelihoods [1]. When applied together, these methods reduce the cost of estimating an RF with tensor order D and d coefficients per tensor dimension from O(d3D) time and O(d2D) space for standard ASD to O(Dd log d) time and O(Dd) space. We show that evidence optimization for a linear RF with 160K coefficients using 5K samples of data can be carried out on a laptop in < 2s.

Scalable Bayesian inference for high-dimensional neural receptive fields

People make surprising but reliable perceptual errors. Here, we provide a unified explanation for errors in the perception of three-dimensional (3D) motion. To do so, we characterized the retinal motion signals produced by objects moving with arbitrary trajectories through arbitrary locations in 3D. Next, we developed a Bayesian model, treating 3D motion perception as optimal inference given sensory noise and the geometry of 3D viewing. The model predicts a wide array of systematic perceptual errors, that depend on stimulus distance, contrast, and eccentricity. We then used a virtual reality (VR) headset as well as a standard 3D display to test these predictions in both traditional psychophysical and more naturalistic settings. We found evidence that people make many of the predicted errors, including a lateral bias in the perception of motion trajectories, a dependency of this bias on stimulus contrast, viewing distance, and eccentricity, and a surprising tendency to misreport approaching motion as receding and vice versa. In sum, we developed a quantitative model that provides a parsimonious account for a range of systematic misperceptions of motion in naturalistic environments.

Systematic misperceptions of 3-D motion explained by Bayesian inference

While performing challenging perceptual tasks such as detecting a barely visible target, our perceptual reports vary across presentations of identical stimuli. This perceptual variability is presumably caused by neural variability in our brains. How much of the neural variability that correlates with the perceptual variability is present in the primary visual cortex (V1), the first cortical processing stage of visual information? To address this question, we recorded neural population responses from V1 using voltage-sensitive dye imaging while monkeys performed a challenging reaction-time visual detection task. We found that V1 population responses in the period leading to the decision correspond more closely to the monkey’s report than to the visual stimulus. These results, together with a simple computational model that allows one to quantify the captured choice-related variability, suggest that most of this variability is present in V1 as additive noise, and that areas downstream to V1 contain relatively little independent choice-related variability.

Majority of choice-related variability in perceptual decisions is present in early sensory cortex

The efficient coding hypothesis, which proposes that neurons are optimized to maximize information about the environment, has provided a guiding theoretical framework for sensory and systems neuroscience. More recently, a theory known as the Bayesian Brain hypothesis has focused on the brain’s ability to integrate sensory and prior sources of information in order to perform Bayesian inference. However, there is as yet no comprehensive theory connecting these two theoretical frameworks. We bridge this gap by formalizing a Bayesian theory of efficient coding. We define Bayesian efficient codes in terms of four basic ingredients: (1) a stimulus prior distribution; (2) an encoding model; (3) a capacity constraint, specifying a neural resource limit; and (4) a loss function, quantifying the desirability or undesirability of various posterior distributions. Classic efficient codes can be seen as a special case in which the loss function is the posterior entropy, leading to a code that maximizes mutual information, but alternate loss functions give solutions that differ dramatically from information-maximizing codes. In particular, we show that decorrelation of sensory inputs, which is optimal under classic efficient codes in low-noise settings, can be disadvantageous for loss functions that penalize large errors. Bayesian efficient coding therefore enlarges the family of normatively optimal codes and provides a more general framework for understanding the design principles of sensory systems. We examine Bayesian efficient codes for linear receptive fields and nonlinear input-output functions, and show that our theory invites reinterpretation of Laughlin’s seminal analysis of efficient coding in the blowfly visual system. One of the primary goals of theoretical neuroscience is to understand the functional organization of neurons in the early sensory pathways and the principles governing them. Why do sensory neurons amplify some signals and filter out others? What can explain the particular configurations and types of neurons found in early sensory system? What general principles can explain the solutions evolution has selected for extracting signals from the sensory environment? Two of the most influential theories for addressing these questions are the “efficient coding” hypothesis and the “Bayesian brain” hypothesis. The efficient coding hypothesis, introduced by Attneave and Barlow more than fifty years ago, uses the ideas from Shannon’s information theory to formulate a theory normatively optimal neural coding [1, 2]. The Bayesian brain hypothesis, on the other hand, focuses on the brain’s ability to perform Bayesian inference, and can be traced back to ideas from Helmholtz about optimal perceptual inference [3–7]. A substantial literature has sought to alter or expand the original efficient coding hypothesis [5, 8–18], and a large number of papers have considered optimal codes in the context of Bayesian inference [19–26], However, the two theories have never been formally connected within a single, comprehensive theoretical framework. Here we propose to fill this gap by formulating a general Bayesian theory of efficient coding that unites the two hypotheses. We begin by reviewing the key elements of each theory and then describe a framework for unifying them. Our approach involves combining a prior and model-based likelihood function with a neural resource constraint and a loss functional that quantifies what makes for a “good” posterior distribution. We show that classic efficient codes arise when we use information-theoretic quantities for these ingredients, but that a much larger family of Bayesian efficient codes can be constructed by allowing these ingredients to vary. We explore Bayesian efficient codes for several important cases of interest, namely linear receptive fields and nonlinear response functions. The latter case was examined in an influential paper by Laughlin that examined contrast coding in the blowfly large monopolar cells (LMCs) [27]; we reanalyze data from this paper and argue that LMC responses are in fact better described as minimizing the average square-root error than as maximizing mutual information.

Social interactions are crucial to the survival and well-being of all mammals, including humans. Although the prelimbic cortex (PL, part of medial prefrontal cortex) has been implicated in social behavior, it is not clear which neurons are relevant, nor how they contribute. We found that the PL contains anatomically and molecularly distinct subpopulations of neurons that target 3 downstream regions that have been implicated in social behavior: the nucleus accumbens (NAc), the amygdala, and the ventral tegmental area. Activation of NAc-projecting PL neurons (PL-NAc), but not the other subpopulations, decreased preference for a social target, suggesting an unique contribution of this population to social behavior. To determine what information PL-NAc neurons convey, we recorded selectively from them, and found that individual neurons were active during social investigation, but only in specific spatial locations. Spatially-specific inhibition of these neurons prevented the formation of a social-spatial association at the inhibited location. In contrast, spatially nonspecific inhibition did not affect social behavior. Thus, the unexpected combination of social and spatial information within the PL-NAc population appears to support socially motivated behavior by enabling the formation of social-spatial associations.

Combined Social and Spatial Coding in a Descending Projection from the Prefrontal Cortex

Decoding from populations of MT neurons during motion-discrimination

In many problem settings, parameter vectors are not merely sparse but dependent in such a way that non-zero coefficients tend to cluster together. We refer to this form of dependency as "region sparsity." Classical sparse regression methods, such as the lasso and automatic relevance determination (ARD), which model parameters as independent a priori, and therefore do not exploit such dependencies. Here we introduce a hierarchical model for smooth, region-sparse weight vectors and tensors in a linear regression setting. Our approach represents a hierarchical extension of the relevance determination framework, where we add a transformed Gaussian process to model the dependencies between the prior variances of regression weights. We combine this with a structured model of the prior variances of Fourier coefficients, which eliminates unnecessary high frequencies. The resulting prior encourages weights to be region-sparse in two different bases simultaneously. We develop Laplace approximation and Monte Carlo Markov Chain (MCMC) sampling to provide efficient inference for the posterior. Furthermore, a two-stage convex relaxation of the Laplace approximation approach is also provided to relax the inevitable non-convexity during the optimization. We finally show substantial improvements over comparable methods for both simulated and real datasets from brain imaging.

Dependent relevance determination for smooth and structured sparse regression

An exciting branch of machine learning research focuses on methods for learning, optimizing, and integrating unknown functions that are difficult or costly to evaluate. A popular Bayesian approach to this problem uses a Gaussian process (GP) to construct a posterior distribution over the function of interest given a set of observed measurements, and selects new points to evaluate using the statistics of this posterior. Here we extend these methods to exploit derivative information from the unknown function. We describe methods for Bayesian optimization (BO) and Bayesian quadrature (BQ) in settings where first and second derivatives may be evaluated along with the function itself. We perform sampling-based inference in order to incorporate uncertainty over hyperparameters, and show that both hyperparameter and function uncertainty decrease much more rapidly when using derivative information. Moreover, we introduce techniques for overcoming ill-conditioning issues that have plagued earlier methods for gradient-enhanced Gaussian processes and kriging. We illustrate the efficacy of these methods using applications to real and simulated Bayesian optimization and quadrature problems, and show that exploting derivatives can provide substantial gains over standard methods.

Exploiting gradients and Hessians in Bayesian optimization and Bayesian quadrature.

Running profoundly alters stimulus-response properties in mouse primary visual cortex (V1), but its effects in higher-order visual cortex remain unknown. Here we systematically investigated how locomotion modulates visual responses across six visual areas and three cortical layers using a massive dataset from the Allen Brain Institute. Although running has been shown to increase firing in V1, we found that it suppressed firing in higher-order visual areas. Despite this reduction in gain, visual responses during running could be decoded more accurately than visual responses during stationary periods. We show that this effect was not attributable to changes in noise correlations, and propose that it instead arises from increased reliability of single neuron responses during running.

Running reduces firing but improves coding in rodent higher-order visual cortex

In neuroscience, the similarity matrix of neural activity patterns in response to different sensory stimuli or under different cognitive states reflects the structure of neural representational space. Existing methods derive point estimations of neural activity patterns from noisy neural imaging data, and the similarity is calculated from these point estimations. We show that this approach translates structured noise from estimated patterns into spurious bias structure in the resulting similarity matrix, which is especially severe when signal-to-noise ratio is low and experimental conditions cannot be fully randomized in a cognitive task. We propose an alternative Bayesian framework for computing representational similarity in which we treat the covariance structure of neural activity patterns as a hyperparameter in a generative model of the neural data, and directly estimate this covariance structure from imaging data while marginalizing over the unknown activity patterns. Converting the estimated covariance structure into a correlation matrix offers a much less biased estimate of neural representational similarity. Our method can also simultaneously estimate a signal-to-noise map that informs where the learned representational structure is supported more strongly, and the learned covariance matrix can be used as a structured prior to constrain Bayesian estimation of neural activity patterns. Our code is freely available in Brain Imaging Analysis Kit (Brainiak) (https://github.com/IntelPNI/brainiak). 1 Neural pattern similarity as a way to understand neural representations Understanding how patterns of neural activity relate to internal representations of the environment is one of the central themes of both system neuroscience and human neural imaging [20, 5, 7, 15]. One can record neural responses (e.g. by functional magnetic resonance imaging; fMRI) while participants observe sensory stimuli, and in parallel, build different computational models to mimic the brain’s encoding of these stimuli. Neural activity pattern corresponding to each feature of an encoding model can then be estimated from the imaging data. Such activity patterns can be used to decode the perceived content with respect to the encoding features from new imaging data. The degree to which stimuli can be decoded from one brain area based on different encoding models informs us of the type of information represented in that area. For example, an encoding model based on motion energy in visual stimuli captured activity fluctuations from visual cortical areas V1 to V3, 30th Conference on Neural Information Processing Systems (NIPS 2016), Barcelona, Spain. and was used to successfully decode natural movie watched during an fMRI scan [14]. In contrast, encoding models based on semantic categories can more successfully decode information from higher level visual cortex [7]. While the decoding performance of different encoding models informs us of the type of information represented in a brain region, it does not directly reveal the structure of the representational space in that area. Such structure is indexed by how distinctively different contents are represented in that region [21, 4]. Therefore, one way to directly quantify the structure of the representational space in the neural population activity is to estimate the neural activity pattern elicited by each sensory stimulus, and calculate the similarity between the patterns corresponding to each pair of stimuli. This analysis of pair-wise similarity between neural activity patterns to different stimuli was named Representational Similarity Analysis (RSA) [11]. In fact, one of the earliest demonstrations of decoding from fMRI data was based on pattern similarity [7]. RSA revealed that the representational structures in the inferotemporal (IT) cortex of natural objects are highly similar between human and monkey [12] and a continuum in the abstract representation of biological classes exist in human ventral object visual cortex [2]. Because the similarity structure can be estimated from imaging data even without building an encoding model, RSA allows not only for model testing (by comparing the similarity matrix of neural data with the similarity matrix of the feature vectors when stimuli are represented with an encoding model) but also for exploratory study (e.g., by projecting the similarity structure to a low-dimensional space to visualize its structure, [11]). Therefore, originally as a tool for studying visual representations [2, 16, 10], RSA has recently attracted neuroscientists to explore the neural representational structure in many higher level cognitive areas [23, 18]. 2 Structured noise in pattern estimation translates into bias in RSA Although RSA is gaining popularity, a few recent studies revealed that in certain circumstances the similarity structure estimated by standard RSA might include a significant bias. For example, the estimated similarity between fMRI patterns of two stimuli is much higher when the stimuli are displayed closer in time [8]. This dependence of pattern similarity on inter-stimulus interval was hypothesized to reflect "temporal drift of pattern"[1], but we believe it may also be due to temporal autocorrelation in fMRI noise. Furthermore, we applied RSA to a dataset from a structured cognitive task (Fig 1A) [19] and found that the highly structured representational similarity matrix obtained from the neural data (Fig 1B,C) is very similar to the matrix obtained when RSA is applied to pure white noise (Fig 1D). Since no task-related similarity structure should exist in white noise while the result in Fig 1D is replicable from noise, this shows that the standard RSA approach can introduce similarity structure not present in the data. We now provide an analytical derivation to explain the source of both types of bias (patterns closer in time are more similar and spurious similarity emerges from analyzing pure noise). It is notable that almost all applications of RSA explicitly or implicitly assume that fMRI responses are related to task-related events through a general linear model (GLM):

Should you trust your RSA result? A Bayesian method for reducing bias in neural representational similarity analysis.

We recently presented a statistical comparison between two models of latent dynamics in macaque lateral intraparietal (LIP) area spike trains—a continuous ‘ramping’ (diffusion-to-bound) model, and a discrete ‘stepping’ model—and found that a substantial fraction of neurons (recorded in two different studies) were better supported by the stepping model (Latimer et al., 2015). Here, we respond to a recent challenge to the validity of these findings that focuses primarily on the possibility of a lower bound on LIP firing rates (Zylberberg & Shadlen, 2016). The paper in question proposed alternate formulations of the ramping model, and argued (via indirect analyses) that half the neurons in the population were better explained by the new model; if correct, this would lead to an even split in the number of neurons better explained by each model. These analyses, while interesting, do not alter the conclusions of our original paper. Here, we review the criticisms raised by Zylberberg & Shadlen and report several new analyses using models with lower bounds. First, we show that the stepping model continued to provide a better description of LIP spike trains when fit using only an early period of each trial. Second, we performed a direct model comparison between our stepping model and a ramping-with-baseline model proposed by Zylberberg & Shadlen; we found that (in a pleasing moment of agreement) roughly half the neurons were better explained by each model. Interestingly, inspection of the cells that switched classifications revealed that many did not strictly exhibit the classical ramping PSTHs that motivated these analyses in the first place. We also examined two other issues raised in recent discussions of LIP: (1) We show that a non-integrating model is consistent with some core aspects of behavioral data previously offered as evidence for continuous integration; and (2) We examine analyses based on the response covariance (“CorCE”), and show that it does not reliably distinguish ramping and stepping dynamics for our dataset. Taken together, these discussions highlight the value of data-driven characterizations of both neural and behavioral dynamics with appropriate statistical tools.

No cause for pause: new analyses of ramping and stepping dynamics in LIP (Rebuttal to Response to Reply to Comment on Latimer et al 2015)

A large body of recent work focuses on methods for extracting low-dimensional latent structure from multi-neuron spike train data. Most such methods employ either linear latent dynamics or linear mappings from latent space to log spike rates. Here we propose a doubly nonlinear latent variable model that can identify low-dimensional structure underlying apparently high-dimensional spike train data. We introduce the Poisson Gaussian-Process Latent Variable Model (P-GPLVM), which consists of Poisson spiking observations and two underlying Gaussian processes-one governing a temporal latent variable and another governing a set of nonlinear tuning curves. The use of nonlinear tuning curves enables discovery of low-dimensional latent structure even when spike responses exhibit high linear dimensionality (e.g., as found in hippocampal place cell codes). To learn the model from data, we introduce the decoupled Laplace approximation, a fast approximate inference method that allows us to efficiently optimize the latent path while marginalizing over tuning curves. We show that this method outperforms previous Laplace-approximation-based inference methods in both the speed of convergence and accuracy. We apply the model to spike trains recorded from hippocampal place cells and show that it compares favorably to a variety of previous methods for latent structure discovery, including variational auto-encoder (VAE) based methods that parametrize the nonlinear mapping from latent space to spike rates with a deep neural network.

Gaussian process based nonlinear latent structure discovery in multivariate spike train data

Neuroscience experiments often require training animals to perform tasks designed to elicit various sensory, cognitive, and motor behaviors. Training typically involves a series of gradual adjustments of stimulus conditions and rewards in order to bring about learning. However, training protocols are usually hand-designed, relying on a combination of intuition, guesswork, and trial-and-error, and often require weeks or months to achieve a desired level of task performance. Here we combine ideas from reinforcement learning and adaptive optimal experimental design to formulate methods for adaptive optimal training of animal behavior. Our work addresses two intriguing problems at once: first, it seeks to infer the learning rules underlying an animal's behavioral changes during training; second, it seeks to exploit these rules to select stimuli that will maximize the rate of learning toward a desired objective. We develop and test these methods using data collected from rats during training on a two-interval sensory discrimination task. We show that we can accurately infer the parameters of a policy-gradient-based learning algorithm that describes how the animal's internal model of the task evolves over the course of training. We then formulate a theory for optimal training, which involves selecting sequences of stimuli that will drive the animal's internal policy toward a desired location in the parameter space. Simulations show that our method can in theory provide a substantial speedup over standard training methods. We feel these results will hold considerable theoretical and practical implications both for researchers in reinforcement learning and for experimentalists seeking to train animals.

Two-photon (TP) calcium imaging is an important imaging modality in neuroscience, allowing for large-scale recording of neural activity in awake, behaving animals at behavior-relevant timescales. Interpretation of TP data requires the accurate extraction of temporal neural activity traces, which can be accomplished via manual or automated methods. In this work we seek to improve the accuracy of both manual and automated TP microscopy demixing methods by introducing a denoising algorithm based on a statistical model of TP data which includes spatial contiguity, sparse activity and Poisson observations. Our method leverages recent developments in stochastic filtering of structured signals based on Laplacian-scale mixture models (LSMs) to model the neural activity in TP data as a set of spatially correlated sparse variables. We apply our method on TP images taken from the visual cortex of an awake, behaving mouse, and demonstrate improved neural activity demixing over current pre-processing techniques.

2017 IEEE International Conference on Acoustics, Speech and Signal Processing (ICASSP)

Functional dissection of signal and noise in MT and LIP during decision-making

Dissociated functional significance of decision-related activity in the primate dorsal stream

Volumetric Two-photon Imaging of Neurons Using Stereoscopy (vTwINS)

Neural circuits contain heterogeneous groups of neurons that differ in type, location, connectivity, and basic response properties. However, traditional methods for dimensionality reduction and clustering are ill-suited to recovering the structure underlying the organization of neural circuits. In particular, they do not take advantage of the rich temporal dependencies in multi-neuron recordings and fail to account for the noise in neural spike trains. Here we describe new tools for inferring latent structure from simultaneously recorded spike train data using a hierarchical extension of a multi-neuron point process model commonly known as the generalized linear model (GLM). Our approach combines the GLM with flexible graph-theoretic priors governing the relationship between latent features and neural connectivity patterns. Fully Bayesian inference via P\'olya-gamma augmentation of the resulting model allows us to classify neurons and infer latent dimensions of circuit organization from correlated spike trains. We demonstrate the effectiveness of our method with applications to synthetic data and multi-neuron recordings in primate retina, revealing latent patterns of neural types and locations from spike trains alone.

Bayesian latent structure discovery from multi-neuron recordings

Discovering Event Structure in Continuous Narrative Perception and Memory

Shadlen et al.’s Comment focuses on extrapolations of our results that were not implied or asserted in our Report. They discuss alternate analyses of average firing rates in other tasks, the relationship between neural activity and behavior, and possible extensions of the standard models we examined. Although interesting to contemplate, these points are not germane to the findings of our Report: that stepping dynamics provided a better statistical description of lateral intraparietal area spike trains than diffusion-to-bound dynamics for a majority of neurons.

Response to Comment on “Single-trial spike trains in parietal cortex reveal discrete steps during decision-making”

A key problem in computational neuroscience is to find simple, tractable models that are nevertheless flexible enough to capture the response properties of real neurons. Here we examine the capabilities of recurrent point process models known as Poisson generalized linear models (GLMs). These models are defined by a set of linear filters and a point nonlinearity and are conditionally Poisson spiking. They have desirable statistical properties for fitting and have been widely used to analyze spike trains from electrophysiological recordings. However, the dynamical repertoire of GLMs has not been systematically compared to that of real neurons. Here we show that GLMs can reproduce a comprehensive suite of canonical neural response behaviors, including tonic and phasic spiking, bursting, spike rate adaptation, type I and type II excitation, and two forms of bistability. GLMs can also capture stimulus-dependent changes in spike timing precision and reliability that mimic those observed in real neurons, and can exhibit varying degrees of stochasticity, from virtually deterministic responses to greater-than-Poisson variability. These results show that Poisson GLMs can exhibit a wide range of dynamic spiking behaviors found in real neurons, making them well suited for qualitative dynamical as well as quantitative statistical studies of single-neuron and population response properties.

Capturing the Dynamical Repertoire of Single Neurons with Generalized Linear Models

1In neuroscience, the similarity matrix of neural activity patterns in response to different sensory stimuli or under different cognitive states reflects the structure of neural representational space. Existing methods derive point estimations of neural activity patterns from noisy neural imaging data, and the similarity is calculated from these point estimations. We show that this approach translates structured noise from estimated patterns into spurious bias structure in the resulting similarity matrix, which is especially severe when signal-to-noise ratio is low and experimental conditions cannot be fully randomized in a cognitive task. We propose an alternative Bayesian framework for computing representational similarity in which we treat the covariance structure of neural activity patterns as a hyper-parameter in a generative model of the neural data, and directly estimate this covariance structure from imaging data while marginalizing over the unknown activity patterns. Converting the estimated covariance structure into a correlation matrix offers an unbiased estimate of neural representational similarity. Our method can also simultaneously estimate a signal-to-noise map that informs where the learned representational structure is supported more strongly, and the learned covariance matrix can be used as a structured prior to constrain Bayesian estimation of neural activity patterns.

A Bayesian method for reducing bias in neural representational similarity analysis

A better way to explain neuronal activity A brain region called the lateral intraparietal (LIP) area is involved in primate decision-making. The dominant model to explain neuronal firing in LIP assumes that neurons slowly accumulate sensory evidence in favor of one choice or another. Latimer et al. hypothesized that neurons instead exhibit rapid steps or jumps in their firing rate, reflecting discrete changes in the animal's decision state. They recorded from LIP neurons in macaque monkeys performing a motion-discrimination task. LIP spike trains in most cells involved discrete stepping dynamics rather than slow evidence integration dynamics. Science, this issue p. 184 Macaque cortical neurons exhibit rapid “jumps” in spike rate, reflecting discrete changes in the animal’s decision state. Neurons in the macaque lateral intraparietal (LIP) area exhibit firing rates that appear to ramp upward or downward during decision-making. These ramps are commonly assumed to reflect the gradual accumulation of evidence toward a decision threshold. However, the ramping in trial-averaged responses could instead arise from instantaneous jumps at different times on different trials. We examined single-trial responses in LIP using statistical methods for fitting and comparing latent dynamical spike-train models. We compared models with latent spike rates governed by either continuous diffusion-to-bound dynamics or discrete “stepping” dynamics. Roughly three-quarters of the choice-selective neurons we recorded were better described by the stepping model. Moreover, the inferred steps carried more information about the animal’s choice than spike counts.

Single-trial spike trains in parietal cortex reveal discrete steps during decision-making

Bayesian inference for latent stepping and ramping models of spike train data

Subunit models provide a powerful yet parsimonious description of neural responses to complex stimuli. They are defined by a cascade of two linear-nonlinear (LN) stages, with the first stage defined by a linear convolution with one or more filters and common point nonlinearity, and the second by pooling weights and an output nonlinearity. Recent interest in such models has surged due to their biological plausibility and accuracy for characterizing early sensory responses. However, fitting poses a difficult computational challenge due to the expense of evaluating the log-likelihood and the ubiquity of local optima. Here we address this problem by providing a theoretical connection between spike-triggered covariance analysis and nonlinear subunit models. Specifically, we show that a "convolutional" decomposition of a spike-triggered average (STA) and covariance (STC) matrix provides an asymptotically efficient estimator for class of quadratic subunit models. We establish theoretical conditions for identifiability of the subunit and pooling weights, and show that our estimator performs well even in cases of model mismatch. Finally, we analyze neural data from macaque primary visual cortex and show that our moment-based estimator outperforms a highly regularized generalized quadratic model (GQM), and achieves nearly the same prediction performance as the full maximum-likelihood estimator, yet at substantially lower cost.

Convolutional spike-triggered covariance analysis for neural subunit models

We introduce a novel framework for estimating visual sensitivity using a continuous target-tracking task in concert with a dynamic internal model of human visual performance. Observers used a mouse cursor to track the center of a two-dimensional Gaussian luminance blob as it moved in a random walk in a field of dynamic additive Gaussian luminance noise. To estimate visual sensitivity, we fit a Kalman filter model to the human tracking data under the assumption that humans behave as Bayesian ideal observers. Such observers optimally combine prior information with noisy observations to produce an estimate of target position at each time step. We found that estimates of human sensory noise obtained from the Kalman filter fit were highly correlated with traditional psychophysical measures of human sensitivity (R2 > 97%). Because each frame of the tracking task is effectively a "minitrial," this technique reduces the amount of time required to assess sensitivity compared with traditional psychophysics. Furthermore, because the task is fast, easy, and fun, it could be used to assess children, certain clinical patients, and other populations that may get impatient with traditional psychophysics. Importantly, the modeling framework provides estimates of decision variable variance that are directly comparable with those obtained from traditional psychophysics. Further, we show that easily computed summary statistics of the tracking data can also accurately predict relative sensitivity (i.e., traditional sensitivity to within a scale factor).

Continuous psychophysics: Target-tracking to measure visual sensitivity.

Neural responses in visual cortex are influenced by visual stimuli and by ongoing spiking activity in local circuits. An important challenge in computational neuroscience is to develop models that can account for both of these features in large multi-neuron recordings and to reveal how stimulus representations interact with and depend on cortical dynamics. Here we introduce a statistical model of neural population activity that integrates a nonlinear receptive field model with a latent dynamical model of ongoing cortical activity. This model captures temporal dynamics and correlations due to shared stimulus drive as well as common noise. Moreover, because the nonlinear stimulus inputs are mixed by the ongoing dynamics, the model can account for a multiple idiosyncratic receptive field shapes with a small number of nonlinear inputs to a low-dimensional dynamical model. We introduce a fast estimation method using online expectation maximization with Laplace approximations, for which inference scales linearly in both population size and recording duration. We test this model to multi-channel recordings from primary visual cortex and show that it accounts for neural tuning properties as well as cross-neural correlations.

Low-dimensional models of neural population activity in sensory cortical circuits

A firing rate map, also known as a tuning curve, describes the nonlinear relationship between a neuron's spike rate and a low-dimensional stimulus (e.g., orientation, head direction, contrast, color). Here we investigate Bayesian active learning methods for estimating firing rate maps in closed-loop neurophysiology experiments. These methods can accelerate the characterization of such maps through the intelligent, adaptive selection of stimuli. Specifically, we explore the manner in which the prior and utility function used in Bayesian active learning affect stimulus selection and performance. Our approach relies on a flexible model that involves a nonlinearly transformed gaussian process (GP) prior over maps and conditionally Poisson spiking. We show that infomax learning, which selects stimuli to maximize the information gain about the firing rate map, exhibits strong dependence on the seemingly innocuous choice of nonlinear transformation function. We derive an alternate utility function that selects stimuli to minimize the average posterior variance of the firing rate map and analyze the surprising relationship between prior parameterization, stimulus selection, and active learning performance in GP-Poisson models. We apply these methods to color tuning measurements of neurons in macaque primary visual cortex.

Bayesian Active Learning of Neural Firing Rate Maps with Transformed Gaussian Process Priors

Encoding and decoding in parietal cortex during sensorimotor decision-making

Low-dimensional models of neural population recordings with complex stimulus selectivity

In many problem settings, parameter vectors are not merely sparse, but dependent in such a way that non-zero coefficients tend to cluster together. We refer to this form of dependency as "region sparsity". Classical sparse regression methods, such as the lasso and automatic relevance determination (ARD), model parameters as independent a priori, and therefore do not exploit such dependencies. Here we introduce a hierarchical model for smooth, region-sparse weight vectors and tensors in a linear regression setting. Our approach represents a hierarchical extension of the relevance determination framework, where we add a transformed Gaussian process to model the dependencies between the prior variances of regression weights. We combine this with a structured model of the prior variances of Fourier coefficients, which eliminates unnecessary high frequencies. The resulting prior encourages weights to be region-sparse in two different bases simultaneously. We develop efficient approximate inference methods and show substantial improvements over comparable methods (e.g., group lasso and smooth RVM) for both simulated and real datasets from brain imaging.

Sparse Bayesian structure learning with dependent relevance determination priors

Low-dimensional dynamical neural population models with shared stimulus drive

Probabilistic models of binary spike patterns provide a powerful tool for understanding statistical dependencies in large-scale neural recordings. Maximum entropy (or “maxent”) models, which seek to explain dependencies in terms of low-order interactions between neurons, have enjoyed remarkable success in modeling such patterns, particularly for small groups of neurons. However, these models are not computationally tractable for large populations, and low-order maxent models have been shown to be inadequate for some datasets. To overcome these limitations, we propose a family of “universal” models for binary spike patterns, where universality refers to the model’s ability to describe arbitrary distributions over all 2 binary patterns. Universal binary models consist of a well-behaved parametric base distribution and a flexible nonparametric component. Universal models automatically trade off between parametric and nonparametric behavior in a data-dependent manner in order to reap the benefits of both model classes. We derive computationally efficient inference methods using the cascaded logistic base distribution [1,2], which permits tractable scaling to large populations. The cascaded logistic model assumes the dependencies among neurons take a simple cascaded form, equivalent to a series of logistic regressions, with each neuron depending only upon those that came before. We prove a condition for the equivalence between the cascaded logistic and the 2nd-order maxent (or “Ising”) model, making cascade-logistic a reasonable choice for base distribution in a universal model. Specifically, any Ising model with pentadiagonal interactions is also a cascaded logistic model. We evaluate the performance of these models with neural data, and will compare to the “Reliable Interaction Model”, a recently proposed framework for building flexible models of binary spike patterns within the maximum entropy formalism [3].

A popular approach to neural characterization describes neural responses in terms of a cascade of linear and nonlinear stages: a linear filter to describe stimulus integration, followed by a nonlinear function to convert the filter output to spike rate. However, real neurons respond to stimuli in a manner that depends on the nonlinear integration of excitatory and inhibitory synaptic inputs. Here we introduce a biophysically inspired point process model that explicitly incorporates stimulus-induced changes in synaptic conductance in a dynamical model of neuronal membrane potential. Our work makes two important contributions. First, on a theoretical level, it offers a novel interpretation of the popular generalized linear model (GLM) for neural spike trains. We show that the classic GLM is a special case of our conductance-based model in which the stimulus linearly modulates excitatory and inhibitory conductances in an equal and opposite "push-pull" fashion. Our model can therefore be viewed as a direct extension of the GLM in which we relax these constraints; the resulting model can exhibit shunting as well as hyper-polarizing inhibition, and time-varying changes in both gain and membrane time constant. Second, on a practical level, we show that our model provides a tractable model of spike responses in early sensory neurons that is both more accurate and more interpretable than the GLM. Most importantly, we show that we can accurately infer intracellular synaptic conductances from extracellularly recorded spike trains. We validate these estimates using direct intracellular measurements of excitatory and inhibitory conductances in parasol retinal ganglion cells. The stimulus-dependence of both excitatory and inhibitory conductances can be well described by a linear-nonlinear cascade, with the filter driving inhibition exhibiting opposite sign and a slight delay relative to the filter driving excitation. We show that the model fit to extracellular spike trains can predict excitatory and inhibitory conductances elicited by novel stimuli with nearly the same accuracy as a model trained directly with intracellular conductances.

Inferring synaptic conductances from spike trains with a biophysically inspired point process model

Low Dimensional Dynamical Models of Neural Populations with Common Input

The brain uses population codes to form distributed, noise-tolerant representations of sensory and motor variables. Recent work has examined the theoretical optimality of such codes in order to gain insight into the principles governing population codes found in the brain. However, the majority of the population coding literature considers either conditionally independent neurons or neurons with noise governed by a stimulus-independent covariance matrix. Here we analyze population coding under a simple alternative model in which latent "input noise" corrupts the stimulus before it is encoded by the population. This provides a convenient and tractable description for irreducible uncertainty that cannot be overcome by adding neurons, and induces stimulus-dependent correlations that mimic certain aspects of the correlations observed in real populations. We examine prior-dependent, Bayesian optimal coding in such populations using exact analyses of cases in which the posterior is approximately Gaussian. These analyses extend previous results on independent Poisson population codes and yield an analytic expression for squared loss and a tight upper bound for mutual information. We show that, for homogeneous populations that tile the input domain, optimal tuning curve width depends on the prior, the loss function, the resource constraint, and the amount of input noise. This framework provides a practical testbed for examining issues of optimality, noise, correlation, and coding fidelity in realistic neural populations.

Optimal prior-dependent neural population codes under shared input noise

Many signals, such as spike trains recorded in multi-channel electrophysiological recordings, may be represented as the sparse sum of translated and scaled copies of waveforms whose timing and amplitudes are of interest. From the aggregate signal, one may seek to estimate the identities, amplitudes, and translations of the waveforms that compose the signal. Here we present a fast method for recovering these identities, amplitudes, and translations. The method involves greedily selecting component waveforms and then refining estimates of their amplitudes and translations, moving iteratively between these steps in a process analogous to the well-known Orthogonal Matching Pursuit (OMP) algorithm [11]. Our approach for modeling translations borrows from Continuous Basis Pursuit (CBP) [4], which we extend in several ways: by selecting a subspace that optimally captures translated copies of the waveforms, replacing the convex optimization problem with a greedy approach, and moving to the Fourier domain to more precisely estimate time shifts. We test the resulting method, which we call Continuous Orthogonal Matching Pursuit (COMP), on simulated and neural data, where it shows gains over CBP in both speed and accuracy.

Inferring sparse representations of continuous signals with continuous orthogonal matching pursuit

Predictive modeling of functional neuroimaging data has become an important tool for analyzing cognitive structures in the brain. Brain images are high-dimensional and exhibit large correlations, and imaging experiments provide a limited number of samples. Therefore, capturing the inherent statistical properties of the imaging data is critical for robust inference. Previous methods tackle this problem by exploiting either spatial sparsity or smoothness, which does not fully exploit the structure in the data. Here we develop a exible, hierarchical model designed to simultaneously capture spatial block sparsity and smoothness in neuroimaging data. We exploit a function domain representation for the high-dimensional small-sample data and develop ecient inference, parameter estimation, and prediction procedures. Empirical results with simulated and real neuroimaging data suggest that simultaneously capturing the block sparsity and smoothness properties can signicantly improve structure recovery and predictive modeling performance.

Probabilistic models for binary spike patterns provide a powerful tool for understanding the statistical dependencies in large-scale neural recordings. Maximum entropy (or "maxent") models, which seek to explain dependencies in terms of low-order interactions between neurons, have enjoyed remarkable success in modeling such patterns, particularly for small groups of neurons. However, these models are computationally intractable for large populations, and low-order max-ent models have been shown to be inadequate for some datasets. To overcome these limitations, we propose a family of "universal" models for binary spike patterns, where universality refers to the ability to model arbitrary distributions over all 2m binary patterns. We construct universal models using a Dirichlet process centered on a well-behaved parametric base measure, which naturally combines the flexibility of a histogram and the parsimony of a parametric model. We derive computationally efficient inference methods using Bernoulli and cascaded logistic base measures, which scale tractably to large populations. We also establish a condition for equivalence between the cascaded logistic and the 2nd-order maxent or "Ising" model, making cascaded logistic a reasonable choice for base measure in a universal model. We illustrate the performance of these models using neural data.

Universal models for binary spike patterns using centered Dirichlet processes

Mutual information (MI) quantifies the statistical dependency between a pair of random variables, and plays a central role in the analysis of engineering and biological systems. Estimation of MI is difficult due to its dependence on an entire joint distribution, which is difficult to estimate from samples. Here we discuss several regularized estimators for MI that employ priors based on the Dirichlet distribution. First, we discuss three "quasi-Bayesian" estimators that result from linear combinations of Bayesian estimates for conditional and marginal entropies. We show that these estimators are not in fact Bayesian, and do not arise from a well-defined posterior distribution and may in fact be negative. Second, we show that a fully Bayesian MI estimator proposed by Hutter (2002), which relies on a fixed Dirichlet prior, exhibits strong prior dependence and has large bias for small datasets. Third, we formulate a novel Bayesian estimator using a mixture-of-Dirichlets prior, with mixing weights designed to produce an approximately flat prior over MI. We examine the performance of these estimators with a variety of simulated datasets and show that, surprisingly, quasi-Bayesian estimators generally outperform our Bayesian estimator. We discuss outstanding challenges for MI estimation and suggest promising avenues for future research.

Bayesian and Quasi-Bayesian Estimators for Mutual Information from Discrete Data

We consider the problem of estimating Shannon's entropy H from discrete data, in cases where the number of possible symbols is unknown or even countably infinite. The Pitman-Yor process, a generalization of Dirichlet process, provides a tractable prior distribution over the space of countably infinite discrete distributions, and has found major applications in Bayesian non-parametric statistics and machine learning. Here we show that it provides a natural family of priors for Bayesian entropy estimation, due to the fact that moments of the induced posterior distribution over H can be computed analytically. We derive formulas for the posterior mean (Bayes' least squares estimate) and variance under Dirichlet and Pitman-Yor process priors. Moreover, we show that a fixed Dirichlet or Pitman-Yor process prior implies a narrow prior distribution over H, meaning the prior strongly determines the entropy estimate in the under-sampled regime. We derive a family of continuous measures for mixing Pitman-Yor processes to produce an approximately flat prior over H. We show that the resulting "Pitman-Yor Mixture" (PYM) entropy estimator is consistent for a large class of distributions. Finally, we explore the theoretical properties of the resulting estimator, and show that it performs well both in simulation and in application to real data.

Bayesian entropy estimation for countable discrete distributions

number of unobserved words), and show that the posterior mean can be efficiently computed via a simple numerical integral. The second estimator incorporates the prior knowledge about the spike trains. We use a simple Bernoulli process as a parametric model of the spike trains, and use a Dirichlet process to allow arbitrary deviation from the Bernoulli process. Under this model, very sparse spike trains are a priori orders of magnitude more likely than those with many spikes. Both estimators are computationally efficient, and statistically consistent. We applied those estimators to spike trains from early visual system to quantify neural coding characteristics.

We describe a set of fast, tractable methods for characterizing neural responses to high-dimensional sensory stimuli using a model we refer to as the generalized quadratic model (GQM). The GQM consists of a low-rank quadratic function followed by a point nonlinearity and exponential-family noise. The quadratic function characterizes the neuron's stimulus selectivity in terms of a set linear receptive fields followed by a quadratic combination rule, and the invertible nonlinearity maps this output to the desired response range. Special cases of the GQM include the 2nd-order Volterra model [1, 2] and the elliptical Linear-Nonlinear-Poisson model [3]. Here we show that for "canonical form" GQMs, spectral decomposition of the first two response-weighted moments yields approximate maximum-likelihood estimators via a quantity called the expected log-likelihood. The resulting theory generalizes moment-based estimators such as the spike-triggered co-variance, and, in the Gaussian noise case, provides closed-form estimators under a large class of non-Gaussian stimulus distributions. We show that these estimators are fast and provide highly accurate estimates with far lower computational cost than full maximum likelihood. Moreover, the GQM provides a natural framework for combining multi-dimensional stimulus sensitivity and spike-history dependencies within a single model. We show applications to both analog and spiking data using intracellular recordings of V1 membrane potential and extracellular recordings of retinal spike trains.

Spectral methods for neural characterization using generalized quadratic models

The receptive field (RF) of a sensory neuron describes how the neuron integrates sensory stimuli over time and space. In typical experiments with naturalistic or flickering spatiotemporal stimuli, RFs are very high-dimensional, due to the large number of coefficients needed to specify an integration profile across time and space. Estimating these coefficients from small amounts of data poses a variety of challenging statistical and computational problems. Here we address these challenges by developing Bayesian reduced rank regression methods for RF estimation. This corresponds to modeling the RF as a sum of space-time separable (i.e., rank-1) filters. This approach substantially reduces the number of parameters needed to specify the RF, from 1K-10K down to mere 100s in the examples we consider, and confers substantial benefits in statistical power and computational efficiency. We introduce a novel prior over low-rank RFs using the restriction of a matrix normal prior to the manifold of low-rank matrices, and use "localized" row and column covariances to obtain sparse, smooth, localized estimates of the spatial and temporal RF components. We develop two methods for inference in the resulting hierarchical model: (1) a fully Bayesian method using blocked-Gibbs sampling; and (2) a fast, approximate method that employs alternating ascent of conditional marginal likelihoods. We develop these methods for Gaussian and Poisson noise models, and show that low-rank estimates substantially outperform full rank estimates using neural data from retina and V1.

Bayesian inference for low rank spatiotemporal neural receptive fields

Shannon's entropy is a basic quantity in information theory, and a fundamental building block for the analysis of neural codes. Estimating the entropy of a discrete distribution from samples is an important and difficult problem that has received considerable attention in statistics and theoretical neuroscience. However, neural responses have characteristic statistical structure that generic entropy estimators fail to exploit. For example, existing Bayesian entropy estimators make the naive assumption that all spike words are equally likely a priori, which makes for an inefficient allocation of prior probability mass in cases where spikes are sparse. Here we develop Bayesian estimators for the entropy of binary spike trains using priors designed to flexibly exploit the statistical structure of simultaneously-recorded spike responses. We define two prior distributions over spike words using mixtures of Dirichlet distributions centered on simple parametric models. The parametric model captures high-level statistical features of the data, such as the average spike count in a spike word, which allows the posterior over entropy to concentrate more rapidly than with standard estimators (e.g., in cases where the probability of spiking differs strongly from 0.5). Conversely, the Dirichlet distributions assign prior mass to distributions far from the parametric model, ensuring consistent estimates for arbitrary distributions. We devise a compact representation of the data and prior that allow for computationally efficient implementations of Bayesian least squares and empirical Bayes entropy estimators with large numbers of neurons. We apply these estimators to simulated and real neural data and show that they substantially outperform traditional methods.

Bayesian entropy estimation for binary spike train data using parametric prior knowledge

Stimulus dimensionality-reduction methods in neuroscience seek to identify a low-dimensional space of stimulus features that affect a neuron’s probability of spiking. One popular method, known as maximally informative dimensions (MID), uses an information-theoretic quantity known as “single-spike information” to identify this space. Here we examine MID from a model-based perspective. We show that MID is a maximum-likelihood estimator for the parameters of a linear-nonlinear-Poisson (LNP) model, and that the empirical single-spike information corresponds to the normalized log-likelihood under a Poisson model. This equivalence implies that MID does not necessarily find maximally informative stimulus dimensions when spiking is not well described as Poisson. We provide several examples to illustrate this shortcoming, and derive a lower bound on the information lost when spiking is Bernoulli in discrete time bins. To overcome this limitation, we introduce model-based dimensionality reduction methods for neurons with non-Poisson firing statistics, and show that they can be framed equivalently in likelihood-based or information-theoretic terms. Finally, we show how to overcome practical limitations on the number of stimulus dimensions that MID can estimate by constraining the form of the non-parametric nonlinearity in an LNP model. We illustrate these methods with simulations and data from primate visual cortex.

The Equivalence of Information-Theoretic and Likelihood-Based Methods for Neural Dimensionality Reduction

Equating information-theoretic and likelihood-based methods for neural dimensionality reduction

We examine the problem of estimating the spike trains of multiple neurons from voltage traces recorded on one or more extracellular electrodes. Traditional spike-sorting methods rely on thresholding or clustering of recorded signals to identify spikes. While these methods can detect a large fraction of the spikes from a recording, they generally fail to identify synchronous or near-synchronous spikes: cases in which multiple spikes overlap. Here we investigate the geometry of failures in traditional sorting algorithms, and document the prevalence of such errors in multi-electrode recordings from primate retina. We then develop a method for multi-neuron spike sorting using a model that explicitly accounts for the superposition of spike waveforms. We model the recorded voltage traces as a linear combination of spike waveforms plus a stochastic background component of correlated Gaussian noise. Combining this measurement model with a Bernoulli prior over binary spike trains yields a posterior distribution for spikes given the recorded data. We introduce a greedy algorithm to maximize this posterior that we call “binary pursuit”. The algorithm allows modest variability in spike waveforms and recovers spike times with higher precision than the voltage sampling rate. This method substantially corrects cross-correlation artifacts that arise with conventional methods, and substantially outperforms clustering methods on both real and simulated data. Finally, we develop diagnostic tools that can be used to assess errors in spike sorting in the absence of ground truth.

A Model-Based Spike Sorting Algorithm for Removing Correlation Artifacts in Multi-Neuron Recordings

Entropy rate quantifies the amount of disorder in a stochastic process. For spiking neurons, the entropy rate places an upper bound on the rate at which the spike train can convey stimulus information, and a large literature has focused on the problem of estimating entropy rate from spike train data. Here we present Bayes least squares and empirical Bayesian entropy rate estimators for binary spike trains using hierarchical Dirichlet process (HDP) priors. Our estimator leverages the fact that the entropy rate of an ergodic Markov Chain with known transition probabilities can be calculated analytically, and many stochastic processes that are non-Markovian can still be well approximated by Markov processes of sufficient depth. Choosing an appropriate depth of Markov model presents challenges due to possibly long time dependencies and short data sequences: a deeper model can better account for long time dependencies, but is more difficult to infer from limited data. Our approach mitigates this difficulty by using a hierarchical prior to share statistical power across Markov chains of different depths. We present both a fully Bayesian and empirical Bayes entropy rate estimator based on this model, and demonstrate their performance on simulated and real neural spike train data.

Spike train entropy-rate estimation using hierarchical Dirichlet process priors

We consider the problem of estimating Shannon's entropy H in the under-sampled regime, where the number of possible symbols may be unknown or countably infinite. Dirichlet and Pitman-Yor processes provide tractable prior distributions over the space of countably infinite discrete distributions, and have found major applications in Bayesian non-parametric statistics and machine learning. Here we show that they provide natural priors for Bayesian entropy estimation, due to the analytic tractability of the moments of the induced posterior distribution over entropy H. We derive formulas for the posterior mean and variance of H given data. However, we show that a fixed Dirichlet or Pitman-Yor process prior implies a narrow prior on H, meaning the prior strongly determines the estimate in the under-sampled regime. We therefore define a family of continuous mixing measures such that the resulting mixture of Dirichlet or Pitman-Yor processes produces an approximately flat prior over H. We explore the theoretical properties of the resulting estimators and show that they perform well on data sampled from both exponential and power-law tailed distributions.

Bayesian estimation of discrete entropy with mixtures of stick-breaking priors

Il Memming Park, Evan Archer, Nicholas Priebe, and Jonathan Pillow A popular approach for investigating the neural code is via dimensionality reduction (DR): identifying a low-dimensional subspace of stimuli that modulate a neuron’s response. The two most popular DR methods for spike train response involve first and second moments of the spike-triggered stimulus distribution: the spike-triggered average (STA) and the eigenvectors of the spike-triggered covariance (STC). In many cases, these methods provide a set of filters which span the space to which a neuron is sensitive. However, their efficacy depends upon the choice of the stimulus distribution. It is well known that for radially symmetric stimuli, STA is a consistent estimator of the filter in the LNP model. Recently, Park and Pillow proposed an analogous model-based interpretation of both STA and STC analysis based on a quantity called the expected log-likelihood (ELL). Here, building upon the previous work, we present a novel model class—the generalized quadratic model (GQM)—which bridges a conceptual and methodological gap between moment-based dimensionality reduction on one hand and likelihood-based generative models on the other. The resulting theory generalizes spiketriggered covariance analysis to both analog and binary response data, and provides a framework enabling us to derive asymptotically-optimal moment-based estimators for a variety of non-Gaussian stimulus distributions. This extends prior work on the conditions of validity for moment-based estimators and associated dimensionality reduction techniques. The GQM is also a probabilistic model of neural responses, and as such generalizes several widely-used models including the LNP, the GLM, and the 2nd-order Volterra series. Finally, the GQM extends generalized linear models (GLMs) to allow multi-dimensional dependence on spike history. We apply these methods to simulated and real neural data from retina (spiking) and V1 (membrane potential).

Got a moment or two ? Neural models and linear dimensionality reduction

Active learning methods can dramatically improve the yield of neurophysiology experiments by adaptively selecting stimuli to probe a neuron's receptive field (RF). Bayesian active learning methods specify a posterior distribution over the RF given the data collected so far in the experiment, and select a stimulus on each time step that maximally reduces posterior uncertainty. However, existing methods tend to employ simple Gaussian priors over the RF and do not exploit uncertainty at the level of hyperparameters. Incorporating this uncertainty can substantially speed up active learning, particularly when RFs are smooth, sparse, or local in space and time. Here we describe a novel framework for active learning under hierarchical, conditionally Gaussian priors. Our algorithm uses sequential Markov Chain Monte Carlo sampling ("particle filtering" with MCMC) to construct a mixture-of-Gaussians representation of the RF posterior, and selects optimal stimuli using an approximate infomax criterion. The core elements of this algorithm are parallelizable, making it computationally efficient for real-time experiments. We apply our algorithm to simulated and real neural data, and show that it can provide highly accurate receptive field estimates from very limited data, even with a small number of hyperparameter samples.

Bayesian active learning with localized priors for fast receptive field characterization

Characterizing the information carried by neural populations in the brain requires accurate statistical models of neural spike responses. The negative-binomial distribution provides a convenient model for over-dispersed spike counts, that is, responses with greater-than-Poisson variability. Here we describe a powerful data-augmentation framework for fully Bayesian inference in neural models with negative-binomial spiking. Our approach relies on a recently described latent-variable representation of the negative-binomial distribution, which equates it to a Polya-gamma mixture of normals. This framework provides a tractable, conditionally Gaussian representation of the posterior that can be used to design efficient EM and Gibbs sampling based algorithms for inference in regression and dynamic factor models. We apply the model to neural data from primate retina and show that it substantially outperforms Poisson regression on held-out data, and reveals latent structure underlying spike count correlations in simultaneously recorded spike trains.

Fully Bayesian inference for neural models with negative-binomial spiking

Modeling the impact of common noise inputs on the network activity of retinal ganglion cells

A sizeable literature has focused on the problem of estimating a low-dimensional feature space for a neuron's stimulus sensitivity. However, comparatively little work has addressed the problem of estimating the nonlinear function from feature space to spike rate. Here, we use a Gaussian process (GP) prior over the infinite-dimensional space of nonlinear functions to obtain Bayesian estimates of the "non-linearity" in the linear-nonlinear-Poisson (LNP) encoding model. This approach offers increased flexibility, robustness, and computational tractability compared to traditional methods (e.g., parametric forms, histograms, cubic splines). We then develop a framework for optimal experimental design under the GP-Poisson model using uncertainty sampling. This involves adaptively selecting stimuli according to an information-theoretic criterion, with the goal of characterizing the nonlinearity with as little experimental data as possible. Our framework relies on a method for rapidly updating hyperparameters under a Gaussian approximation to the posterior. We apply these methods to neural data from a color-tuned simple cell in macaque V1, characterizing its nonlinear response function in the 3D space of cone contrasts. We find that it combines cone inputs in a highly nonlinear manner. With simulated experiments, we show that optimal design substantially reduces the amount of data required to estimate these nonlinear combination rules.

Active learning of neural response functions with Gaussian processes

The linear receptive field describes a mapping from sensory stimuli to a one-dimensional variable governing a neuron's spike response. However, traditional receptive field estimators such as the spike-triggered average converge slowly and often require large amounts of data. Bayesian methods seek to overcome this problem by biasing estimates towards solutions that are more likely a priori, typically those with small, smooth, or sparse coefficients. Here we introduce a novel Bayesian receptive field estimator designed to incorporate locality, a powerful form of prior information about receptive field structure. The key to our approach is a hierarchical receptive field model that flexibly adapts to localized structure in both spacetime and spatiotemporal frequency, using an inference method known as empirical Bayes. We refer to our method as automatic locality determination (ALD), and show that it can accurately recover various types of smooth, sparse, and localized receptive fields. We apply ALD to neural data from retinal ganglion cells and V1 simple cells, and find it achieves error rates several times lower than standard estimators. Thus, estimates of comparable accuracy can be achieved with substantially less data. Finally, we introduce a computationally efficient Markov Chain Monte Carlo (MCMC) algorithm for fully Bayesian inference under the ALD prior, yielding accurate Bayesian confidence intervals for small or noisy datasets.

One of the central problems in systems neuroscience is to understand how neural spike trains convey sensory information. Decoding methods, which provide an explicit means for reading out the information contained in neural spike responses, offer a powerful set of tools for studying the neural coding problem. Here we develop several decoding methods based on point-process neural encoding models, or forward models that predict spike responses to stimuli. These models have concave log-likelihood functions, which allow efficient maximum-likelihood model fitting and stimulus decoding. We present several applications of the encoding model framework to the problem of decoding stimulus information from population spike responses: (1) a tractable algorithm for computing the maximum a posteriori (MAP) estimate of the stimulus, the most probable stimulus to have generated an observed single- or multiple-neuron spike train response, given some prior distribution over the stimulus; (2) a gaussian approximation to the posterior stimulus distribution that can be used to quantify the fidelity with which various stimulus features are encoded; (3) an efficient method for estimating the mutual information between the stimulus and the spike trains emitted by a neural population; and (4) a framework for the detection of change-point times (the time at which the stimulus undergoes a change in mean or variance) by marginalizing over the posterior stimulus distribution. We provide several examples illustrating the performance of these estimators with simulated and real neural data.

Model-Based Decoding, Information Estimation, and Change-Point Detection Techniques for Multineuron Spike Trains

Neurons typically respond to a restricted number of stimulus features within the high-dimensional space of natural stimuli. Here we describe an explicit model-based interpretation of traditional estimators for a neuron's multi-dimensional feature space, which allows for several important generalizations and extensions. First, we show that traditional estimators based on the spike-triggered average (STA) and spike-triggered covariance (STC) can be formalized in terms of the "expected log-likelihood" of a Linear-Nonlinear-Poisson (LNP) model with Gaussian stimuli. This model-based formulation allows us to define maximum-likelihood and Bayesian estimators that are statistically consistent and efficient in a wider variety of settings, such as with naturalistic (non-Gaussian) stimuli. It also allows us to employ Bayesian methods for regularization, smoothing, sparsification, and model comparison, and provides Bayesian confidence intervals on model parameters. We describe an empirical Bayes method for selecting the number of features, and extend the model to accommodate an arbitrary elliptical nonlinear response function, which results in a more powerful and more flexible model for feature space inference. We validate these methods using neural data recorded extracellularly from macaque primary visual cortex.

Stimulus reconstruction or decoding methods provide an important tool for understanding how sensory and motor information is represented in neural activity. We discuss Bayesian decoding methods based on an encoding generalized linear model (GLM) that accurately describes how stimuli are transformed into the spike trains of a group of neurons. The form of the GLM likelihood ensures that the posterior distribution over the stimuli that caused an observed set of spike trains is log concave so long as the prior is. This allows the maximum a posteriori (MAP) stimulus estimate to be obtained using efficient optimization algorithms. Unfortunately, the MAP estimate can have a relatively large average error when the posterior is highly nongaussian. Here we compare several Markov chain Monte Carlo (MCMC) algorithms that allow for the calculation of general Bayesian estimators involving posterior expectations (conditional on model parameters). An efficient version of the hybrid Monte Carlo (HMC) algorithm was significantly superior to other MCMC methods for gaussian priors. When the prior distribution has sharp edges and corners, on the other hand, the hit-and-run algorithm performed better than other MCMC methods. Using these algorithms, we show that for this latter class of priors, the posterior mean estimate can have a considerably lower average error than MAP, whereas for gaussian priors, the two estimators have roughly equal efficiency. We also address the application of MCMC methods for extracting nonmarginal properties of the posterior distribution. For example, by using MCMC to calculate the mutual information between the stimulus and response, we verify the validity of a computationally efficient Laplace approximation to this quantity for gaussian priors in a wide range of model parameters; this makes direct model-based computation of the mutual information tractable even in the case of large observed neural populations, where methods based on binning the spike train fail. Finally, we consider the effect of uncertainty in the GLM parameters on the posterior estimators.

Efficient Markov Chain Monte Carlo Methods for Decoding Neural Spike Trains

The 8th annual computational and systems neuroscience (Cosyne) meeting

To make efficient use of their limited signaling capacity, sensory systems often use predictive coding. Predictive coding works by exploiting the statistical regularities of the environment--specifically, by filtering the sensory input to remove its predictable elements, thus enabling the neural signal to focus on what cannot be guessed. To do this, the neural filters must remove the environmental correlations. If predictive coding is to work well in multiple environments, sensory systems must adapt their filtering properties to fit each environment's statistics. Using the visual system as a model, we determine whether this happens. We compare retinal ganglion cell dynamics in two very different environments: white noise and natural. Because natural environments have more power than that of white noise at low temporal frequencies, predictive coding is expected to produce a suppression of low frequencies and an enhancement of high frequencies, compared with the behavior in a white-noise environment. We find that this holds, but only in part. First, predictive coding behavior is not uniform: most on cells manifest it, whereas off cells, on average, do not. Overlaid on this nonuniformity between cell classes is further nonuniformity within both cell classes. These findings indicate that functional considerations beyond predictive coding play an important role in shaping the dynamics of sensory adaptation. Moreover, the differences in behavior between on and off cell classes add to the growing evidence that these classes are not merely homogeneous mirror images of each other and suggest that their roles in visual processing are more complex than expected from the classic view.

Heterogeneous response dynamics in retinal ganglion cells: the interplay of predictive coding and adaptation.

Toward characterizion of the complete visual signal in a patch of retina

Recent work on the statistical modeling of neural responses has focused on modulated renewal processes in which the spike rate is a function of the stimulus and recent spiking history. Typically, these models incorporate spike-history dependencies via either: (A) a conditionally-Poisson process with rate dependent on a linear projection of the spike train history (e.g., generalized linear model); or (B) a modulated non-Poisson renewal process (e.g., inhomogeneous gamma process). Here we show that the two approaches can be combined, resulting in a conditional renewal (CR) model for neural spike trains. This model captures both real-time and rescaled-time history effects, and can be fit by maximum likelihood using a simple application of the time-rescaling theorem [1]. We show that for any modulated renewal process model, the log-likelihood is concave in the linear filter parameters only under certain restrictive conditions on the renewal density (ruling out many popular choices, e.g. gamma with shape k ≠ 1), suggesting that real-time history effects are easier to estimate than non-Poisson renewal properties. Moreover, we show that goodness-of-fit tests based on the time-rescaling theorem [1] quantify relative-time effects, but do not reliably assess accuracy in spike prediction or stimulus-response modeling. We illustrate the CR model with applications to both real and simulated neural data.

Time-rescaling methods for the estimation and assessment of non-Poisson neural encoding models

. This paper analyzes the generalization error of two-layer neural networks for computing the ground state of the Schrödinger operator on a 𝑑 -dimensional hypercube with Neumann boundary condition. We prove that the convergence rate of the generalization error is independent of dimension 𝑑 , under the a priori assumption that the ground state lies in a spectral Barron space. We verify such assumption by proving a new regularity estimate for the ground state in the spectral Barron space. The latter is achieved by a fixed point argument based on the Krein-Rutman theorem.

Statistical dependencies in the responses of sensory neurons govern both the amount of stimulus information conveyed and the means by which downstream neurons can extract it. Although a variety of measurements indicate the existence of such dependencies 1–3 , their origin and importance for neural coding arepoorlyunderstood.Hereweanalysethefunctionalsignificance of correlated firing in a complete population of macaque parasol retinal ganglion cells using a model of multi-neuron spike responses 4,5 . The model, with parameters fit directly to physiological data, simultaneously captures both the stimulus dependence and detailed spatio-temporal correlations in population responses, and provides two insights into the structure of the neural code. First, neuralencoding atthepopulation levelislessnoisy thanone would expect from the variability of individual neurons: spike timesaremoreprecise,andcanbepredictedmoreaccuratelywhen the spiking of neighbouring neurons is taken into account. Second, correlations provide additional sensory information: optimal, model-based decoding that exploits the response correlation structure extracts 20% more information about the visual scene than decoding under the assumption of independence, and preserves40%morevisualinformationthanoptimallineardecoding 6 . This model-based approach reveals the role of correlated activity in the retinal coding of visual stimuli, and provides a general framework for understanding the importance of correlated activity in populations of neurons. How does the spiking activity of a neural population represent the sensory environment? The answer depends critically on the structure of neuronal correlations, or the tendency of groups of neurons to fire temporally coordinated spike patterns. The statistics of suchpatterns have been studied in a variety of brain areas, and their significance in the processing and representation of sensory information has been

Spatio-temporalcorrelationsandvisualsignallingina complete neuronal population

Spatio-temporal correlations and visual signalling in a complete neuronal population

The coding of information by neural populations depends critically on the statistical dependencies between neuronal responses. However, there is no simple model that can simultaneously account for (1) marginal distributions over single-neuron spike counts that are discrete and non-negative; and (2) joint distributions over the responses of multiple neurons that are often strongly dependent. Here, we show that both marginal and joint properties of neural responses can be captured using copula models. Copulas are joint distributions that allow random variables with arbitrary marginals to be combined while incorporating arbitrary dependencies between them. Different copulas capture different kinds of dependencies, allowing for a richer and more detailed description of dependencies than traditional summary statistics, such as correlation coefficients. We explore a variety of copula models for joint neural response distributions, and derive an efficient maximum likelihood procedure for estimating them. We apply these models to neuronal data collected in macaque pre-motor cortex, and quantify the improvement in coding accuracy afforded by incorporating the dependency structure between pairs of neurons. We find that more than one third of neuron pairs shows dependency concentrated in the lower or upper tails for their firing rate distribution.

Point process encoding models provide powerful statistical methods for understanding the responses of neurons to sensory stimuli. Although these models have been successfully applied to neurons in the early sensory pathway, they have fared less well capturing the response properties of neurons in deeper brain areas, owing in part to the fact that they do not take into account multiple stages of processing. Here we introduce a new twist on the point-process modeling approach: we include unobserved as well as observed spiking neurons in a joint encoding model. The resulting model exhibits richer dynamics and more highly nonlinear response properties, making it more powerful and more flexible for fitting neural data. More importantly, it allows us to estimate connectivity patterns among neurons (both observed and unobserved), and may provide insight into how networks process sensory input. We formulate the estimation procedure using variational EM and the wake-sleep algorithm, and illustrate the model's performance using a simulated example network consisting of two coupled neurons.

Neural characterization in partially observed populations of spiking neurons

A central question in computational neuroscience concerns how the response properties of neural populations depend on the activity of neurons both within and outside the population. Various models contain different types and combinations of feedforward and recurrent connections. Each model can be characterized by the particular set of assumptions about what information underlies the population response, and these in turn are reflected in the model’s behavior. We propose that the population response is designed to preserve full information about the relevant dimension in the stimulus, which could be a single unambiguous value, a single ambiguous value, or more than one value. We design an objective based on preserving this information, and use it in training the weights in a model. Our results demonstrate that a combination of feedforward and recurrent connections can generate broadly information-preserving population responses in a network.

One of the central problems in systems neuroscience is that of characterizing the functional relationship between sensory stimuli and neural spike responses. Investigators call this the neural coding problem, because the spike trains of neurons can be considered a code by which the brain represents information about the state of the external world. One approach to understanding this code is to build mathematical models of the mapping between stimuli and spike responses; the code can then be interpreted by using the model to predict the neural response to a stimulus, or to decode the stimulus that gave rise to a particular response. In this chapter, we will examine likelihood-based approaches, which use the explicit probability of response to a given stimulus for both fitting the model and assessing its validity. We will show how the likelihood can be derived for several types of neural models, and discuss theoretical considerations underlying the formulation and estimation of such models. Finally, we will discuss several ideas for evaluating model performance, including time-rescaling of spike trains and optimal decoding using Bayesian inversion of the likelihood function.

Point process encoding models provide powerful statistical methods for understanding the responses of neurons to sensory stimuli. Although these models have been successfully applied to neurons in the early sensory pathway, they have fared less well in deeper brain areas, where responses are more highly nonlinear and more heavily influenced by feedback and recurrent processing. Here we propose an extension to the point-process modeling framework by introducing a population of hidden (or “latent”) neurons whose activity can influence the responses of observed neurons, resulting in a more general and more flexible model of population responses.

Estimating multi-neuronal point-process spiking models with partially observed data

Statistical models for neural encoding, decoding, and optimal stimulus design.

Response properties of sensory neurons are commonly described using receptive fields. This description may be formalized in a model that operates with a small set of linear filters whose outputs are nonlinearly combined to determine the instantaneous firing rate. Spike-triggered average and covariance analyses can be used to estimate the filters and nonlinear combination rule from extracellular experimental data. We describe this methodology, demonstrating it with simulated model neuron examples that emphasize practical issues that arise in experimental situations.

The neural decoding problem is of fundamental importance in computational and systems neuroscience: given the observed spike trains of a population of cells whose responses are related to a behaviorally-relevant signal~x, how can we estimate, or “decode,” ~x? Solving this problem experimentally is of basic importance both for our understanding of neural coding and for the design of neural prosthetic devices.

Model-based decoding, information estimation, and change- point detection in multi-neuron spike trains

We describe an information-theoretic framework for fitting neural spike responses with a Linear-Nonlinear-Poisson cascade model. This framework unifies the spike-triggered average (STA) and spike-triggered covariance (STC) approaches to neural characterization and recovers a set of linear filters that maximize mean and variance-dependent information between stimuli and spike responses. The resulting approach has several useful properties, namely, (1) it recovers a set of linear filters sorted according to their informativeness about the neural response; (2) it is both computationally efficient and robust, allowing recovery of multiple linear filters from a data set of relatively modest size; (3) it provides an explicit "default" model of the nonlinear stage mapping the filter responses to spike rate, in the form of a ratio of Gaussians; (4) it is equivalent to maximum likelihood estimation of this default model but also converges to the correct filter estimates whenever the conditions for the consistency of STA or STC analysis are met; and (5) it can be augmented with additional constraints on the filters, such as space-time separability. We demonstrate the effectiveness of the method by applying it to simulated responses of a Hodgkin-Huxley neuron and the recorded extracellular responses of macaque retinal ganglion cells and V1 cells.

Dimensionality reduction in neural models: an information-theoretic generalization of spike-triggered average and covariance analysis.

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Computing likelihoods in the stochastic integrate-and-fire model: numerical methods

Improved numberical methods for computing likelihoods in the stochastic integrate-and-fire model

Sensory encoding in spiking neurons depends on both the integration of sensory inputs and the intrinsic dynamics and variability of spike generation. We show that the stimulus selectivity, reliability, and timing precision of primate retinal ganglion cell (RGC) light responses can be reproduced accurately with a simple model consisting of a leaky integrate-and-fire spike generator driven by a linearly filtered stimulus, a postspike current, and a Gaussian noise current. We fit model parameters for individual RGCs by maximizing the likelihood of observed spike responses to a stochastic visual stimulus. Although compact, the fitted model predicts the detailed time structure of responses to novel stimuli, accurately capturing the interaction between the spiking history and sensory stimulus selectivity. The model also accounts for the variability in responses to repeated stimuli, even when fit to data from a single (nonrepeating) stimulus sequence. Finally, the model can be used to derive an explicit, maximum-likelihood decoding rule for neural spike trains, thus providing a tool for assessing the limitations that spiking variability imposes on sensory performance.

Prediction and Decoding of Retinal Ganglion Cell Responses with a Probabilistic Spiking Model

Comparing integrate-and-fire models estimated using intracellular and extracellular data

We examine a cascade encoding model for neural response in which a linear filtering stage is followed by a noisy, leaky, integrate-and-fire spike generation mechanism. This model provides a biophysically more realistic alternative to models based on Poisson (memoryless) spike generation, and can effectively reproduce a variety of spiking behaviors seen in vivo. We describe the maximum likelihood estimator for the model parameters, given only extracellular spike train responses (not intracellular voltage data). Specifically, we prove that the log-likelihood function is concave and thus has an essentially unique global maximum that can be found using gradient ascent techniques. We develop an efficient algorithm for computing the maximum likelihood solution, demonstrate the effectiveness of the resulting estimator with numerical simulations, and discuss a method of testing the model's validity using time-rescaling and density evolution techniques.

Maximum Likelihood Estimation of a Stochastic Integrate-and-Fire Neural Encoding Model

A fundamental goal of sensory systems neuroscience is the characterization of the functional relationship between environmental stimuli and neural response. The purpose of such a characterization is to elucidate the computation being performed by the system. Qualitatively, this notion is exemplified by the concept of the “receptive field”, a quasi-linear description of a neuron’s response properties that has dominated sensory neuroscience for the past 50 years. Receptive field properties are typically determined by measuring responses to a highly restricted set of stimuli, parameterized by one or a few parameters. These stimuli are typically chosen both because they are known to produce strong responses, and because they are easy to generate using available technology.

A high speed, low vibration bread bagger in which the top and bottom bag scoops move smoothly and solely horizontally by means of swinging pivot means that is suspended by hanger arms from the frame of the apparatus. Pneumatic means coupled to the pivotable top scoop support arm causes the top scoop to exert substantially the same force against the open mouth of a bag that is pulled over a loaf of bread, regardless of the diameter of the bags used.

Biases in white noise analysis due to non-Poisson spike generation

Recent work has examined the estimation of models of stimulus-driven neural activity in which some linear filtering process is followed by a nonlinear, probabilistic spiking stage. We analyze the estimation of one such model for which this nonlinear step is implemented by a noisy, leaky, integrate-and-fire mechanism with a spike-dependent aftercurrent. This model is a biophysically plausible alternative to models with Poisson (memory-less) spiking, and has been shown to effectively reproduce various spiking statistics of neurons in vivo. However, the problem of estimating the model from extracellular spike train data has not been examined in depth. We formulate the problem in terms of maximum likelihood estimation, and show that the computational problem of maximizing the likelihood is tractable. Our main contribution is an algorithm and a proof that this algorithm is guaranteed to find the global optimum with reasonable speed. We demonstrate the effectiveness of our estimator with numerical simulations.

Maximum Likelihood Estimation of a Stochastic Integrate-and-Fire Neural Model

Perceptual Completion across the Vertical Meridian and the Role of Early Visual Cortex

MORPHOLOGIE AMÉLIORÉE DE COUCHE POLYMÈRE POUR UNE ÉNERGIE ACCRUE ET UNE DISTRIBUTION DE COURANT À PARTIR D'UN HYBRIDE BATTERIE-SUPERCONDENSATEUR

L'invention concerne une composition contenant un materiau semi-conducteur organique et un materiau accepteur de triplets de formule (I) avec un niveau d'energie de triplet inferieur au niveau d'energie de triplet du materiau semi-conducteur organique. Dans la formule (I), chaque Ar represente un groupe aryle ou heteroaryle eventuellement substitue, n vaut 1-3, m vaut 1-5, q vaut 0 ou 1, chaque R 3 represente H ou un substituant, et chaque R 4 represente H ou un substituant. Quand R 4 ne represente pas H, les groupes R 4 et (Ar) m attaches au meme atome de carbone peuvent etre lies par une liaison directe ou un groupe divalent. Quand n ou m vaut au moins 2, les groupes Ar adjacents peuvent etre lies par un groupe divalent. Quand q vaut 0, R 3 ne represente pas H et est lie a (Ar) n par une liaison directe ou un groupe divalent.

Matériau organique émetteur de lumière, dispositif et procédé associés

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Composition électroluminescente organique, dispositif, et procédé

L'invention porte sur une composition, qui peut etre utile dans une diode electroluminescente organique, laquelle composition a un polymere electroluminescent fluorescent comportant des unites de repetition electroluminescentes, et une unite d'acceptation de triplets liee au polymere electroluminescent.

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○ Nordel MG est un elastomere EPDM qui consacre l'alliance de deux technologies: la polymerisation en phase gazeuse et la catalyse metallocene.

Description d'un nouvel elastomere chlore, son developpement, ses essais en laboratoire et finalement sa mise a l'epreuve dans l'application a laquelle il etait destine. Il s'agit de courroies de distribution synchrone qui sont a present largement utilisees dans l'industrie automobile

Une nouvelle génération d'élastomères chlorés : pour applications dynamiques aux températures élevées

We introduce a novel framework for estimating visual sensitivity using a continuous target-tracking task in concert with a dynamic internal model of human visual performance. In our main experiment, observers used a mouse cursor to track the center of a 2D Gaussian luminance target as it moved in a Brownian walk in a field of dynamic Gaussian luminance noise. To estimate visual sensitivity, we fit a Kalman filter to the tracking data assuming that humans behave roughly as Bayesian ideal observers. Such observers optimally combine prior information with noisy observations to produce an estimate of target location at each point in time. We found that estimates of human sensory noise obtained from the Kalman filter model were highly correlated with traditional psychophysical measures of human sensitivity (R2 > 0.97). Because data can be collected at the display frame rate, the amount of time required to measure sensitivity is greatly reduced relative to traditional psychophysics. While our modeling framework provides principled estimates of sensitivity that are directly comparable with those from traditional psychophysics, easily-computed summary statistics based on cross-correlograms of the tracking data also accurately predict relative sensitivity, and are thus good empirical substitutes for the more computationally-intensive Kalman filter fitting. As a second example, we show contrast sensitivity functions quickly determined using target tracking. Finally, we show that psychophysical reverse-correlation can also be quickly done via tracking. We conclude that dynamic target tracking is a viable and faster alternative to traditional psychophysical methods in many situations. Meeting abstract presented at VSS 2015.

Continuous Psychophysics: measuring visual sensitivity by dynamic target tracking.

Bayesian methods for intracellular recordings: electrode artifact compensation and noise removal

A nearly optimal correlation-independent readout of population activity

We analyzed pairwise dependencies in 36 neurons simultaneously recorded using a 100-electrode silicon arrays from the arm area of area M1 in a monkey. Neural activity and hand kinematics were recorded for several minutes during a tracking task (Serruya et al., 2002), and collected in 70 ms bins. Two third of the data (3531 bins, approx. 247 sec) was used for training, and the remaining third was kept for cross validation. Neurons in M1 show a variety of neural dependency

An electroluminescent device (20) having a first layer comprising a fluorinated first organic compound having one or more fluorine radicals and is soluble in a fluorinated solvent, wherein the first layer is adjacent to a second layer comprising a second organic compound in is insoluble a fluorinated solvent, and methods and materials for producing this device.

Composition which can be useful in an organic light emitting diode, wherein the composition has a fluorescent light emitting polymer, light-emitting repeat units and a triplet-accepting, which is bonded to the light-emitting polymer.

The light-emitting polymer with more than 5 mol% of a light-emitting, optionally substituted moiety having the general formula 1: or condensed derivatives thereof.

Increasing the efficiency of solution‐processable red emitters should allow the performance of OLED displays to be greatly improved. This paper discusses our progress with red‐emitting phosphorescent dendrimers, which offer excellent opportunities for achieving high efficiencies and are increasingly becoming an important technology for the next generation of OLED displays.

High molecular weight EPDM via metallocene catalyst and gas phase process

A new EPDM Nordel rubber is to the market, representing the fusion of the two latest technologies, gas phase polymerisation with metallocene catalysis. In this paper we look at the character of the polymer and its method of manufacture, in order to understand how it can form a complementary product range to the existing solution polymer, Nordel IP, made also with metallocene catalyst. The introductory product range of 5 polymers is described, with two of them selected to show comparisons of critical compound and vulcanisate properties against comparable solution polymerised grades. The first, MG NDR 47085, is a traditional high viscosity semicrystalline type which has been optimised to meet modern test specifications. The second, MG NDR 47130 is the first of a new class of very high viscosity polymers designed to give similar physical properties when containing even higher levels of extension of filler and oil, than traditional polymers.

We have synthesised a new family of dendrimers with stilbene dendrons attached to a porphyrin core via a stilbene unit and compared their properties with a family of dendrimers with the same core and dendrons but with the dendrons attached via a phenyl unit. The oxidation and reduction half potentials of the two dendrimer families were found to be the same and independent of generation indicating that the dendrons were not creating a micro-environment for the core. However, the rate of heterogeneous electron transfer was found to be strongly dependent on link type and generation. The photoluminescence quantum yield (PLQY) of the dendrimers was also found to be strongly dependent on the method of attachment of the core. In solution the dendrimers with the stilbene link between core and dendrons had PLQYs 1.5 times higher than their phenyl counterparts but in the solid state the trend was reversed with the phenyl linked dendrimers generally having a higher PLQY. The difference in properties has been assigned to the comparative openness of the dendrimer architectures and the effect of the dendrons on the shape of the porphyrin core.

The effect of intermolecular interactions on the electro-optical properties of porphyrin dendrimers with conjugated dendrons

Nordel MG EPDM represents the fusion of the two latest technologies, gas phase polymerisation and metallocene catalysis. J G Pillow and C Daniel of DuPont Dow Elastomers' European Technical Centre in Geneva look at the character of the polymer and its method of manufacture. The introductory product range of five polymers is described, with two of them selected to show comparisons of compound and vulcanisate properties against comparable solution polymerised grades. The first, NDR 47085, is a traditional high viscosity semicrystalline type which has been optimised to meet modern test specifications. The second, NDR 47130 is the first of a new class of very high viscosity polymers designed to give similar physical properties when containing even higher levels of extension of filler and oil than traditional polymers.

New EPDM combines metallocene catalysts with gas phase production

An efficient strategy has been developed for the preparation of four generations of electroluminescent dendrimers that contain tris(distyrylbenzenyl)amine cores, stilbene dendrons, and tert-butyl surface groups. The synthesis involved coupling of benzylphosphonate focused dendrons with tris(4'-formylstilbenyl)amine to give the dendrimers in yields ranging from 63 to 86%. The dendrimers were found to be monodisperse by gel-permeation chromatography. The zeroeth generation dendrimer underwent two chemically reversible oxidations while for the higher generations only one chemically reversible oxidation was observed. On reduction, the dendrimers were found to aggregate with the level of aggregation dependent on the switching potential. The four dendrimer generations were investigated by means of optical spectroscopy. Time-resolved luminescence of the dendrimers in solution showed that the excited state of each of the generations had a monoexponential decay with a lifetime of 1.8 ns. The photoluminescence quantum yield (PLQY) of the dendrimers in solution was independent of generation and was found to be in the region of 0.62. This suggests that the origin of the luminescence is the same for all dendrimer generations. In thin films, time-resolved luminescence of the zeroeth dendrimer generation revealed a long-lived luminescence component in the red part of the spectrum with a lifetime of 7.5 ns. This emission component could not be found in the first, second, and third generation dendrimers, where the long-lived luminescence had a lifetime of 1.5-3 ns at all detection wavelengths. Furthermore, the PLQY of the dendrimer films was found to be dependent on generation and significantly lower than the solution PLQYs. The dendrimer film PLQY increased with generation from 5% for the zereoth generation to 12% for the third generation. The differences observed in the time-resolved luminescence and PLQY of the dendrimers in the solid state arise from the fact that intermolecular interactions between the emissive cores of the dendrimers are considerably stronger in the zeroeth generation than in higher generations. The intermolecular interactions result in an aggregate, which we ascribe to an excited-state species, such as an excimer.

Synthesis and excited state spectroscopy of tris(distyrylbenzenyl)amine-cored electroluminescent dendrimers

Materials Science and Engineering B-advanced Functional Solid-state Materials

A simple two-step convergent iterative procedure has been developed for the preparation of stilbene dendrons containing an aldehyde at the center which can be coupled in a single step to give dendrimers that contain luminescent chromophores. The stilbene units in the dendrons are linked in a meta arrangement at the branching phenyl units allowing them to be treated, to a first approximation, as isolated chromophores. All the dendrimers are luminescent with emission observed from the core. The cores prepared were distyrylbenzene, distyrylanthracene, and meso-tetraphenylporphyrin which photoluminesce blue, yellow-green, and red, respectively. We found that all the dendrimers, independent of generation or core, could be spin-coated from solution to form good quality thin films, which shows that the processing conditions have been disengaged from the electronic properties in this series of materials.

A Facile Iterative Procedure for the Preparation of Dendrimers Containing Luminescent Cores and Stilbene Dendrons

We have compared the optical and electronic properties of a series of porphyrin centered dendrimers containing stilbene dendrons. The first and second generation dendrimers could be spin-coated from solution to form good quality thin films. Incorporation into single layer light-emitting diodes gave red-light emission with maximum external quantum efficiencies of 0.02% and 0.04% for the first and second generation dendrimers respectively. We have determined by photoluminescence studies that energy can be transferred efficiently from the stilbene dendrons to the porphyrin core and that PL emission is from the core. Cyclic voltammetry studies on the dendrimers show that the reductions are porphyrin centered with the dendrons only affecting the rate of heterogeneous electron transfer between the electrode and the dendrimers. This suggests that charge mobility within a dendrimer film in an LED will be affected by the porphyrin edge to porphyrin edge distance. We have studied the hydrodynamic radii of the dendrimers by gel permeation chromatography and found as expected that the average porphyrin edge to dendron edge distance increases with generation. This is consistent with the slowing of heterogeneous electron transfer observed in the cyclic voltammetry on increasing the generation number and suggests that the dendrons are interleaved in the solid state to facilitate charge transport.

Effect of generation on the electronic properties of light-emitting dendrimers

Control of colour and charge injection in conjugated dendrimer/polypyridine bilayer leds

CONJUGATED DENDRIMERS FOR LIGHT-EMITTING DIODES : EFFECT OF GENERATION

Constrained geometry catalyst technology (CGCT), the use of a specific form of metallocene catalyst in an improved solution process is now being used for the commercial production of two families of ethylene elastomer. This paper looks at these two families of elastomer, first to see why an established polymer would benefit from the change of manufacturing technology, and secondly to see how these two ethylene polymer types made with this same technology compare as a consequence of their different molecular structures.

Ethylene elastomers made using constrained geometry catalyst technology

We report a novel molecular engineering approach to organic materials for LEDs based on dendrimers. The molecules consist of a conjugated core, conjugated linkers, and surface groups, as illustrated schematically in figure 1. The conjugated core and linkers control the electronic properties, whilst the surface groups control the processing properties. This is a very attractive feature as it should enable electronic and processing properties to be optimised independently, in contrast to linear polymers where substitution can affect both.

Conjugated Dendrimers for Colour Control in Light-Emitting Diodes

In most psychological experiments, observers respond to multiple trials that are presented in a sequence. In perceptual psychology, it is common to assume that these responses are independent of responses on previous trials, as well as of stimuli presented on previous trials. There are, however, multiple reasons to question the ubiquitous assumption of “independent trials”– for example, responses in cognitive experiments depend on previous stimuli and responses, and it is unclear why perceptual tasks should be unaffected by such serial dependencies. This observation raises two central questions: First, how strong are trial by trial dependencies in psychophysical experiments? Second, what are statistical methods that would allow us to detect these dependencies, and to deal with them appropriately? Here, we present a model that allows for quantification of such trial by trial dependencies and apply it to psychophysical data-sets from perceptual decision tasks. Using multiple data-sets from one auditory and two visual experiments as well as simulated data, we show that our model successfully detects trial by trial dependencies if they are present and allows for a statistical assessment of the significance of these dependencies. Although the strength and direction of trial by trial dependencies varied considerably between observers, significant trial by trial dependencies were observed in 6 out of 7 observers. For those observers, model fits improved considerably if trial by trial history was incorporated into the model. The trial by trial dependencies we observed could be well captured by linear superposition of effects form multiple previous responses and stimuli. We conclude that previous trials and responses influence responses in perceptual tasks, too.

W. Senn1;2, M. Jakob2, K. Wyler2, J. Kleinle2, H.-R. L uscher3, H. Mey2, L. M uller2 Abstract | Methods of fuzzy logic are commonly used to model a complex system by a set of rules provided by experts. But fuzzy methods can also be applied to the reverse problem: given the inputoutput behavior of a system, what are the rules which are governing that behavior. We introduce this reengineering method to neuronal modeling and, as an example, we analyze a biological neuron of the Hodgkin-Huxley type. Starting from measured data of the membrane potential and the sodiumand potassium-current through the membrane, we extract fuzzy rules which determine the time course of the membrane potential in terms of the actual values of the membrane current. These fuzzy rules allow not only to rebuild the behavior but also to understand the underlying membrane mechanisms. The approach o ers a new representation of neuronal mechanisms in terms of linguistic rules.

Fuzzy methods are commonly used to produce a desired output of a complex system which can be steered by known expert rules. But fuzzy methods can also be applied to the reversed problem: if the input-output behavior of a system is given one wishes to nd the rules by which this behavior is evoked. We introduce this reversed method to neuronal modeling and, as an example, apply it to a biological neuron of the HodgkinHuxley type. Going out from measured data of the membran potential, the sodiumand potassium-current, we rebuild the membran behavior by fuzzy rules and show how these rules can lead to a better understanding of the underlying mechanisms. The appeal of the approach is that once the system variables are identi ed, the analysis runs comletely automatically. De ning in advance the width of the membership functions the number and speci ty of the outcoming rules can be tuned.

Neural posterior estimation methods based on discrete normalizing flows have become established tools for simulation-based inference (SBI), but scaling them to high-dimensional problems can be challenging. Building on recent advances in generative modeling, we here present flow matching posterior estimation (FMPE), a technique for SBI using continuous normalizing flows. Like diffusion models, and in contrast to discrete flows, flow matching allows for unconstrained architectures, providing enhanced flexibility for complex data modalities. Flow matching, therefore, enables exact density evaluation, fast training, and seamless scalability to large architectures--making it ideal for SBI. We show that FMPE achieves competitive performance on an established SBI benchmark, and then demonstrate its improved scalability on a challenging scientific problem: for gravitational-wave inference, FMPE outperforms methods based on comparable discrete flows, reducing training time by 30% with substantially improved accuracy. Our work underscores the potential of FMPE to enhance performance in challenging inference scenarios, thereby paving the way for more advanced applications to scientific problems.

Many scientific models are composed of multiple discrete components, and scien tists often make heuristic decisions about which components to include. Bayesian inference provides a mathematical framework for systematically selecting model components, but defining prior distributions over model components and developing associated inference schemes has been challenging. We approach this problem in an amortized simulation-based inference framework: We define implicit model priors over a fixed set of candidate components and train neural networks to infer joint probability distributions over both, model components and associated parameters from simulations. To represent distributions over model components, we introduce a conditional mixture of multivariate binary distributions in the Grassmann formalism. Our approach can be applied to any compositional stochastic simulator without requiring access to likelihood evaluations. We first illustrate our method on a simple time series model with redundant components and show that it can retrieve joint posterior distribution over a set of symbolic expressions and their parameters while accurately capturing redundancy with strongly correlated posteriors. We then apply our approach to drift-diffusion models, a commonly used model class in cognitive neuroscience. After validating the method on synthetic data, we show that our approach explains experimental data as well as previous methods, but that our fully probabilistic approach can help to discover multiple data-consistent model configurations, as well as reveal non-identifiable model components and parameters. Our method provides a powerful tool for data-driven scientific inquiry which will allow scientists to systematically identify essential model components and make uncertainty-informed modelling decisions.

Simultaneous identification of models and parameters of scientific simulators

Neural oscillations are ubiquitously observed in many brain areas. One proposed functional role of these oscillations is that they serve as an internal clock, or ‘frame of reference’. Information can be encoded by the timing of neural activity relative to the phase of such oscillations. In line with this hypothesis, there have been multiple empirical observations of such phase codes in the brain. Here we ask: What kind of neural dynamics support phase coding of information with neural oscillations? We tackled this question by analyzing recurrent neural networks (RNNs) that were trained on a working memory task. The networks were given access to an external reference oscillation and tasked to produce an oscillation, such that the phase difference between the reference and output oscillation maintains the identity of transient stimuli. We found that networks converged to stable oscillatory dynamics. Reverse engineering these networks revealed that each phase-coded memory corresponds to a separate limit cycle attractor. We characterized how the stability of the attractor dynamics depends on both reference oscillation amplitude and frequency, properties that can be experimentally observed. To understand the connectivity structures that underlie these dynamics, we showed that trained networks can be described as two phase-coupled oscillators. Using this insight, we condensed our trained networks to a reduced model consisting of two functional modules: One that generates an oscillation and one that implements a coupling function between the internal oscillation and external reference. In summary, by reverse engineering the dynamics and connectivity of trained RNNs, we propose a mechanism by which neural networks can harness reference oscillations for working memory. Specifically, we propose that a phase-coding network generates autonomous oscillations which it couples to an external reference oscillation in a multi-stable fashion. Author summary Many of our actions are rhythmic—walking, breathing, digesting and more. It is not surprising that neural activity can have a strong oscillatory component. Indeed, such brain waves are common, and can even be measured using EEG from the scalp. Perhaps less obvious is the presence of such oscillations during non-rhythmic behavior—such as memory maintenance and other cognitive functions. Reports of these cognitive oscillations have accumulated over the years, and various theories were raised regarding their origin and utilization. In particular, oscillations have been proposed to serve as a clock signal that can be used for temporal-, or phase-coding of information in working memory. Here, we studied the dynamical systems underlying this kind of coding, by using trained artificial neural networks as hypothesis generators. We trained recurrent neural networks to perform a working memory task, while giving them access to a reference oscillation. We were then able to reverse engineer the learned dynamics of the networks. Our analysis revealed that phase coded memories correspond to stable attractors in the dynamical landscape of the model. These attractors arose from the coupling of the external reference oscillation with oscillations generated internally by the network.

Trained recurrent neural networks develop phase-locked limit cycles in a working memory task

Recent advances in connectomics research enable the acquisition of increasing amounts of data about the connectivity patterns of neurons. How can we use this wealth of data to efficiently derive and test hypotheses about the principles underlying these patterns? A common approach is to simulate neural networks using a hypothesized wiring rule in a generative model and to compare the resulting synthetic data with empirical data. However, most wiring rules have at least some free parameters, and identifying parameters that reproduce empirical data can be challenging as it often requires manual parameter tuning. Here, we propose to use simulation-based Bayesian inference (SBI) to address this challenge. Rather than optimizing a single rule to fit the empirical data, SBI considers many parametrizations of a wiring rule and performs Bayesian inference to identify the parameters that are compatible with the data. It uses simulated data from multiple candidate wiring rules and relies on machine learning methods to estimate a probability distribution (the ‘posterior distribution over rule parameters conditioned on the data’) that characterizes all data-compatible rules. We demonstrate how to apply SBI in connectomics by inferring the parameters of wiring rules in an in silico model of the rat barrel cortex, given in vivo connectivity measurements. SBI identifies a wide range of wiring rule parameters that reproduce the measurements. We show how access to the posterior distribution over all data-compatible parameters allows us to analyze their relationship, revealing biologically plausible parameter interactions and enabling experimentally testable predictions. We further show how SBI can be applied to wiring rules at different spatial scales to quantitatively rule out invalid wiring hypotheses. Our approach is applicable to a wide range of generative models used in connectomics, providing a quantitative and efficient way to constrain model parameters with empirical connectivity data. Author summary The brain is composed of an intricately connected network of cells—what are the factors that contribute to constructing these patterns of connectivity, and how? To answer these questions, amassing connectivity data alone is not enough. We must also be able to efficiently develop and test our ideas about the underlying connectivity principles. For example, we could simulate a hypothetical wiring rule like “neurons near each other are more likely to form connections” in a computational model and generate corresponding synthetic data. If the synthetic, simulated data resembles the real, measured data, then we have some confidence that our hypotheses might be correct. The challenge, however, lies in finding all the potential wiring rules, or equivalently, all the parameters of the computational model that can reproduce the observed data, as this process is often idiosyncratic and labor-intensive. To tackle this challenge, we introduce an approach that combines computational modeling in connectomics, deep learning, and Bayesian statistical inference in order to automatically infer a probability distribution over the model parameters likely to explain the data. We demonstrate our approach by inferring wiring rules in a detailed model of the rat barrel cortex and find that the inferred distribution identifies multiple data-compatible model parameters, reveals biologically plausible parameter interactions, and allows us to make experimentally testable predictions.

Simulation-based inference for efficient identification of generative models in computational connectomics

Bayesian inference usually requires running potentially costly inference procedures separately for every new observation. In contrast, the idea of amortized Bayesian inference is to initially invest computational cost in training an inference network on simulated data, which can subsequently be used to rapidly perform inference (i.e., to return estimates of posterior distributions) for new observations. This approach has been applied to many real-world models in the sciences and engineering, but it is unclear how robust the approach is to adversarial perturbations in the observed data. Here, we study the adversarial robustness of amortized Bayesian inference, focusing on simulation-based estimation of multi-dimensional posterior distributions. We show that almost unrecognizable, targeted perturbations of the observations can lead to drastic changes in the predicted posterior and highly unrealistic posterior predictive samples, across several benchmark tasks and a real-world example from neuroscience. We propose a computationally efficient regularization scheme based on penalizing the Fisher information of the conditional density estimator, and show how it improves the adversarial robustness of amortized Bayesian inference.

Neonatal apneas and hypopneas present a serious risk for healthy infant development. Treating these adverse events requires frequent manual stimulation by skilled personnel, which can lead to alert fatigue. Automatically predicting these adverse events before they occur would enable the use of methods for automatic intervention. In this work, we propose a neural additive model to predict individual events of neonatal apnea and hypopnea and apply it to a physiological dataset from infants with Robin sequence at risk of upper airway obstruction. The dataset will be made publicly available together with this study. Our model achieved an average area under the receiver operating characteristic curve of 0.80 by additively combining information from different modalities of the respiratory polygraphy recording. This permits the prediction of individual apneas and hypopneas up to 15 seconds before they occur. Its additive nature makes the model inherently interpretable, which allowed insights into how important a given signal modality is for prediction and which patterns in the signal are discriminative. For our problem of predicting apneas and hyponeas in infants with Robin sequence, prior irregularities in breathing-related modalities as well as decreases in SpO2 levels were especially discriminative.

Neonatal apnea and hypopnea prediction in infants with Robin sequence with neural additive models for time series

Simulation-based inference (SBI) enables amortized Bayesian inference for simulators with implicit likelihoods. But when we are primarily interested in the quality of predictive simulations, or when the model cannot exactly reproduce the observed data (i.e., is misspecified), targeting the Bayesian posterior may be overly restrictive. Generalized Bayesian Inference (GBI) aims to robustify inference for (misspecified) simulator models, replacing the likelihood-function with a cost function that evaluates the goodness of parameters relative to data. However, GBI methods generally require running multiple simulations to estimate the cost function at each parameter value during inference, making the approach computationally infeasible for even moderately complex simulators. Here, we propose amortized cost estimation (ACE) for GBI to address this challenge: We train a neural network to approximate the cost function, which we define as the expected distance between simulations produced by a parameter and observed data. The trained network can then be used with MCMC to infer GBI posteriors for any observation without running additional simulations. We show that, on several benchmark tasks, ACE accurately predicts cost and provides predictive simulations that are closer to synthetic observations than other SBI methods, especially for misspecified simulators. Finally, we apply ACE to infer parameters of the Hodgkin-Huxley model given real intracellular recordings from the Allen Cell Types Database. ACE identifies better data-matching parameters while being an order of magnitude more simulation-efficient than a standard SBI method. In summary, ACE combines the strengths of SBI methods and GBI to perform robust and simulation-amortized inference for scientific simulators.

Generalized Bayesian Inference for Scientific Simulators via Amortized Cost Estimation

Neural cell types have classically been characterized by their anatomy and electrophysiology. More recently, single-cell transcriptomics has enabled an increasingly finer genetically defined taxonomy of cortical cell types but the link between the gene expression of individual cell types and their physiological and anatomical properties remains poorly understood. Here, we develop a hybrid modeling approach to bridge this gap. Our approach combines statistical and mechanistic models to predict cells’ electrophysiological activity from their gene expression pattern. To this end, we fit biophysical Hodgkin-Huxley models for a wide variety of cortical cell types using simulation-based inference, while overcoming the challenge posed by the model mismatch between the mathematical model and the data. Using multimodal Patch-seq data, we link the estimated model parameters to gene expression using an interpretable sparse linear regression model. Our approach recovers specific ion channel gene expressions as predictive of Hodgkin-Huxley ion channel densities, directly implicating their mechanistic role in determining neural firing.

Combined statistical-mechanistic modeling links ion channel genes to physiology of cortical neuron types

We can now measure the connectivity of every neuron in a neural circuit, but we are still blind to other biological details, including the dynamical characteristics of each neuron. The degree to which connectivity measurements alone can inform understanding of neural computation is an open question. Here we show that with only measurements of the connectivity of a biological neural network, we can predict the neural activity underlying neural computation. We constructed a model neural network with the experimentally determined connectivity for 64 cell types in the motion pathways of the fruit fly optic lobe but with unknown parameters for the single neuron and single synapse properties. We then optimized the values of these unknown parameters using techniques from deep learning, to allow the model network to detect visual motion. Our mechanistic model makes detailed experimentally testable predictions for each neuron in the connectome. We found that model predictions agreed with experimental measurements of neural activity across 24 studies. Our work demonstrates a strategy for generating detailed hypotheses about the mechanisms of neural circuit function from connectivity measurements. We show that this strategy is more likely to be successful when neurons are sparsely connected—a universally observed feature of biological neural networks across species and brain regions.

Connectome-constrained deep mechanistic networks predict neural responses across the fly visual system at single-neuron resolution

Generative modeling of 3D brain MRIs presents difﬁculties in achieving high visual ﬁdelity while ensuring sufﬁcient coverage of the data distribution. In this work, we propose to address this challenge with composable, multiscale morphological transformations in a variational autoencoder (VAE) framework. These transformations are applied to a chosen reference brain image to generate MRI volumes, equipping the model with strong anatomical inductive biases. We show substantial performance improvements in FID while retaining comparable, or superior, reconstruction quality compared to prior work based on VAEs and generative adversarial networks (GANs).

We present Sequential Neural Variational Inference (SNVI), an approach to perform Bayesian inference in models with intractable likelihoods. SNVI combines likelihood-estimation (or likelihood-ratio-estimation) with variational inference to achieve a scalable simulation-based inference approach. SNVI maintains the ﬂex-ibility of likelihood(-ratio) estimation to allow arbitrary proposals for simulations, while simultaneously providing a functional estimate of the posterior distribution without requiring MCMC sampling. We present several variants of SNVI and demonstrate that they are substantially more computationally efﬁcient than previous algorithms, without loss of accuracy on benchmark tasks. We apply SNVI to a neuroscience model of the pyloric network in the crab and demonstrate that it can infer the posterior distribution with one order of magnitude fewer simulations than previously reported. SNVI vastly reduces the computational cost of simulation-based inference while maintaining accuracy and ﬂexibility, making it possible to tackle problems that were previously inaccessible.

We combine amortized neural posterior estimation with importance sampling for fast and accurate gravitational-wave inference. We first generate a rapid proposal for the Bayesian posterior using neural networks, and then attach importance weights based on the underlying likelihood and prior. This provides (1) a corrected posterior free from network inaccuracies, (2) a performance diagnostic (the sample efficiency) for assessing the proposal and identifying failure cases, and (3) an unbiased estimate of the Bayesian evidence. By establishing this independent verification and correction mechanism we address some of the most frequent criticisms against deep learning for scientific inference. We carry out a large study analyzing 42 binary black hole mergers observed by LIGO and Virgo with the SEOBNRv4PHM and IMRPhenomXPHM waveform models. This shows a median sample efficiency of ≈10% (2 orders of magnitude better than standard samplers) as well as a tenfold reduction in the statistical uncertainty in the log evidence. Given these advantages, we expect a significant impact on gravitational-wave inference, and for this approach to serve as a paradigm for harnessing deep learning methods in scientific applications.

Neural Importance Sampling for Rapid and Reliable Gravitational-Wave Inference

Neural circuits can produce similar activity patterns from vastly different combinations of channel and synaptic conductances. These conductances are tuned for specific activity patterns but might also reflect additional constraints, such as metabolic cost or robustness to perturbations. How do such constraints influence the range of permissible conductances? Here, we investigate how metabolic cost affects the parameters of neural circuits with similar activity in a model of the pyloric network of the crab Cancer borealis. We use a novel machine learning method to identify a range of network models that can generate activity patterns matching experimental data, and find that neural circuits can consume largely different amounts of energy despite similar circuit activity. Furthermore, a reduced but still significant range of circuit parameters gives rise to energy-efficient circuits. We then examine the space of parameters of energy-efficient circuits and identify potential tuning strategies for low metabolic cost. Finally, we investigate the interaction between metabolic cost and temperature robustness. We show that metabolic cost can vary across temperatures, but that robustness to temperature changes does not necessarily incur an increased metabolic cost. Our analyses show that, despite metabolic efficiency and temperature robustness constraining circuit parameters, neural systems can generate functional, efficient, and robust network activity with widely disparate sets of conductances.

Energy-efficient network activity from disparate circuit parameters

Deep learning techniques for gravitational-wave parameter estimation have emerged as a fast alternative to standard samplers $\unicode{x2013}$ producing results of comparable accuracy. These approaches (e.g., DINGO) enable amortized inference by training a normalizing flow to represent the Bayesian posterior conditional on observed data. By conditioning also on the noise power spectral density (PSD) they can even account for changing detector characteristics. However, training such networks requires knowing in advance the distribution of PSDs expected to be observed, and therefore can only take place once all data to be analyzed have been gathered. Here, we develop a probabilistic model to forecast future PSDs, greatly increasing the temporal scope of DINGO networks. Using PSDs from the second LIGO-Virgo observing run (O2) $\unicode{x2013}$ plus just a single PSD from the beginning of the third (O3) $\unicode{x2013}$ we show that we can train a DINGO network to perform accurate inference throughout O3 (on 37 real events). We therefore expect this approach to be a key component to enable the use of deep learning techniques for low-latency analyses of gravitational waves.

Adapting to noise distribution shifts in flow-based gravitational-wave inference

Inferring parameters of computational models that capture experimental data is a 9 central task in cognitive neuroscience. Bayesian statistical inference methods usually require the 10 ability to evaluate the likelihood of the model—however, for many models of interest in cognitive 11 neuroscience, the associated likelihoods cannot be computed eﬃciently. Simulation-based 12 inference (SBI) oﬀers a solution to this problem by only requiring access to simulations produced 13 by the model. Previously, Fengler et al. introduced Likelihood Approximation Networks (LAN, 14 Fengler et al., 2021) which make it possible to apply SBI to models of decision-making, but require 15 billions of simulations for training. Here, we provide a new SBI method that is substantially more 16 simulation-eﬃcient. Our approach, Mixed Neural Likelihood Estimation (MNLE), trains neural 17 density estimators on model simulations to emulate the simulator, and is designed to capture 18 both the continuous (e.g., reaction times) and discrete (choices) data of decision-making models. 19 The likelihoods of the emulator can then be used to perform Bayesian parameter inference on 20 experimental data using standard approximate inference methods like Markov Chain Monte 21 Carlo sampling. We demonstrate MNLE on two variants of the drift-diﬀusion model (DDM) and 22 show that it is substantially more eﬃcient than LANs: MNLE achieves similar likelihood accuracy 23 with six orders of magnitude fewer training simulations, and is signiﬁcantly more accurate than 24 LANs when both are trained with the same budget. This enables researchers to perform SBI on 25 custom-tailored models of decision-making, leading to fast iteration of model design for scientiﬁc 26 discovery.

Flexible and eﬃcient 1 simulation-based inference for 2 models of decision-making 3

Simulation-based inference (SBI) refers to statistical inference on stochastic models for which we can generate samples, but not compute likelihoods. Like SBI algorithms, generative adversarial networks (GANs) do not require explicit likelihoods. We study the relationship between SBI and GANs, and introduce GATSBI, an adversarial approach to SBI. GATSBI reformulates the variational objective in an adversarial setting to learn implicit posterior distributions. Inference with GATSBI is amortised across observations, works in high-dimensional posterior spaces and supports implicit priors. We evaluate GATSBI on two SBI benchmark problems and on two high-dimensional simulators. On a model for wave propagation on the surface of a shallow water body, we show that GATSBI can return well-calibrated posterior estimates even in high dimensions. On a model of camera optics, it infers a high-dimensional posterior given an implicit prior, and performs better than a state-of-the-art SBI approach. We also show how GATSBI can be extended to perform sequential posterior estimation to focus on individual observations. Overall, GATSBI opens up opportunities for leveraging advances in GANs to perform Bayesian inference on high-dimensional simulation-based models.

GATSBI: Generative Adversarial Training for Simulation-Based Inference

Simulation-based inference (SBI) solves statistical inverse problems by repeatedly running a stochastic simulator and inferring posterior distributions from model-simulations. To improve simulation efficiency, several inference methods take a sequential approach and iteratively adapt the proposal distributions from which model simulations are generated. However, many of these sequential methods are difficult to use in practice, both because the resulting optimisation problems can be challenging and efficient diagnostic tools are lacking. To overcome these issues, we present Truncated Sequential Neural Posterior Estimation (TSNPE). TSNPE performs sequential inference with truncated proposals, sidestepping the optimisation issues of alternative approaches. In addition, TSNPE allows to efficiently perform coverage tests that can scale to complex models with many parameters. We demonstrate that TSNPE performs on par with previous methods on established benchmark tasks. We then apply TSNPE to two challenging problems from neuroscience and show that TSNPE can successfully obtain the posterior distributions, whereas previous methods fail. Overall, our results demonstrate that TSNPE is an efficient, accurate, and robust inference method that can scale to challenging scientific models.

Truncated proposals for scalable and hassle-free simulation-based inference

Personalized neurorehabilitative precision medicine: from data to therapies (MWKNeuroReha) – a multi-centre prospective observational clinical trial to predict long-term outcome of patients with acute motor stroke

A prominent theory proposes that the temporal order of a sequence of items held in memory is reflected in ordered firing of neurons at different phases of theta oscillations 1. We probe this theory by directly measuring single neuron activity (1420 neurons) and local field potentials (LFP, 921 channels) in the medial temporal lobe of 16 epilepsy patients performing a working memory task for temporal order. We observe theta oscillations and preferential firing of single neurons at theta phase during memory maintenance. We find that - depending on memory performance - phase of firing is related to item position within a sequence. However, in contrast to the theory, phase order did not match item order. To investigate underlying mechanisms, we subsequently trained recurrent neural networks (RNNs) to perform an analogous task. Similar to recorded neural activity, we show that RNNs generate theta oscillations during memory maintenance. Importantly, model neurons exhibit theta phase-dependent firing related to item position, where phase of firing again did not match item order. Instead, we observed a mechanistic link between phase order, stimulus timing and oscillation frequency - a relationship we subsequently confirmed in our neural recordings. Taken together, in both biological and artificial neural networks we provide validating evidence for the role of phase-of-firing in memory processing while at the same time challenging a long-held theory about the functional role of spiking and oscillations in sequence memory.

Phase of firing does not reflect temporal order in sequence memory of humans and recurrent neural networks

Simulation-based Bayesian inference (SBI) can be used to estimate the parameters of complex mechanistic models given observed model outputs without requiring access to explicit likelihood evaluations. A prime example for the application of SBI in neuroscience involves estimating the parameters governing the response dynamics of Hodgkin-Huxley (HH) models from electrophysiological measurements, by inferring a posterior over the parameters that is consistent with a set of observations. To this end, many SBI methods employ a set of summary statistics or scientifically interpretable features to estimate a surrogate likelihood or posterior. However, currently, there is no way to identify how much each summary statistic or feature contributes to reducing posterior uncertainty. To address this challenge, one could simply compare the posteriors with and without a given feature included in the inference process. However, for large or nested feature sets, this would necessitate repeatedly estimating the posterior, which is computationally expensive or even prohibitive. Here, we provide a more efficient approach based on the SBI method neural likelihood estimation (NLE): We show that one can marginalize the trained surrogate likelihood post-hoc before inferring the posterior to assess the contribution of a feature. We demonstrate the usefulness of our method by identifying the most important features for inferring parameters of an example HH neuron model. Beyond neuroscience, our method is generally applicable to SBI workflows that rely on data features for inference used in other scientific fields.

Efficient identification of informative features in simulation-based inference

Single-unit recordings in the brain of behaving human subjects provide a unique opportunity to advance our understanding of neural mechanisms of cognition. These recordings are exclusively performed in medical centers during diagnostic or therapeutic procedures. The presence of medical instruments along with other aspects of the hospital environment limit the control of electrical noise compared to animal laboratory environments. Here, we highlight the problem of an increased occurrence of simultaneous spike events on different recording channels in human single-unit recordings. Most of these simultaneous events were detected in clusters previously labeled as artifacts and showed similar waveforms. These events may result from common external noise sources or from different micro-electrodes recording activity from the same neuron. To address the problem of duplicate recorded events, we introduce an open-source algorithm to identify these artificial spike events based on their synchronicity and waveform similarity. Applying our method to a comprehensive dataset of human single-unit recordings, we demonstrate that our algorithm can substantially increase the data quality of these recordings. Given our findings, we argue that future studies of single-unit activity recorded under noisy conditions should employ algorithms of this kind to improve data quality.

Duplicate Detection of Spike Events: A Relevant Problem in Human Single-Unit Recordings

The hippocampal dentate gyrus is an important relay conveying sensory information from the entorhinal cortex to the hippocampus proper. During exploration, the dentate gyrus has been proposed to act as a pattern separator. However, the dentate gyrus also shows structured activity during immobility and sleep. The properties of these activity patterns at cellular resolution, and their role in hippocampal-dependent memory processes have remained unclear. Using dual-color in vivo two-photon Ca2+ imaging, we show that in immobile mice dentate granule cells generate sparse, synchronized activity patterns associated with entorhinal cortex activation. These population events are structured and modified by changes in the environment; and they incorporate place- and speed cells. Importantly, they are more similar than expected by chance to population patterns evoked during self-motion. Using optogenetic inhibition, we show that granule cell activity is not only required during exploration, but also during immobility in order to form dentate gyrus-dependent spatial memories.

Synchronous activity patterns in the dentate gyrus during immobility

We demonstrate unprecedented accuracy for rapid gravitational wave parameter estimation with deep learning. Using neural networks as surrogates for Bayesian posterior distributions, we analyze eight gravitational wave events from the first LIGO-Virgo Gravitational-Wave Transient Catalog and find very close quantitative agreement with standard inference codes, but with inference times reduced from O(day) to 20 s per event. Our networks are trained using simulated data, including an estimate of the detector noise characteristics near the event. This encodes the signal and noise models within millions of neural-network parameters and enables inference for any observed data consistent with the training distribution, accounting for noise nonstationarity from event to event. Our algorithm-called "DINGO"-sets a new standard in fast and accurate inference of physical parameters of detected gravitational wave events, which should enable real-time data analysis without sacrificing accuracy.

Real-time gravitational-wave science with neural posterior estimation

The original"Seven Motifs"set forth a roadmap of essential methods for the field of scientific computing, where a motif is an algorithmic method that captures a pattern of computation and data movement. We present the"Nine Motifs of Simulation Intelligence", a roadmap for the development and integration of the essential algorithms necessary for a merger of scientific computing, scientific simulation, and artificial intelligence. We call this merger simulation intelligence (SI), for short. We argue the motifs of simulation intelligence are interconnected and interdependent, much like the components within the layers of an operating system. Using this metaphor, we explore the nature of each layer of the simulation intelligence operating system stack (SI-stack) and the motifs therein: (1) Multi-physics and multi-scale modeling; (2) Surrogate modeling and emulation; (3) Simulation-based inference; (4) Causal modeling and inference; (5) Agent-based modeling; (6) Probabilistic programming; (7) Differentiable programming; (8) Open-ended optimization; (9) Machine programming. We believe coordinated efforts between motifs offers immense opportunity to accelerate scientific discovery, from solving inverse problems in synthetic biology and climate science, to directing nuclear energy experiments and predicting emergent behavior in socioeconomic settings. We elaborate on each layer of the SI-stack, detailing the state-of-art methods, presenting examples to highlight challenges and opportunities, and advocating for specific ways to advance the motifs and the synergies from their combinations. Advancing and integrating these technologies can enable a robust and efficient hypothesis-simulation-analysis type of scientific method, which we introduce with several use-cases for human-machine teaming and automated science.

Simulation Intelligence: Towards a New Generation of Scientific Methods

Publisher Correction: Deep learning enables fast and dense single-molecule localization with high accuracy

Inferring parameters of computational models that capture experimental data is a central task in cognitive neuroscience. Bayesian statistical inference methods usually require the ability to evaluate the likelihood of the model—however, for many models of interest in cognitive neuroscience, the associated likelihoods cannot be computed effciently. Simulation-based inference (SBI) offers a solution to this problem by only requiring access to simulations produced by the model. Here, we provide an effcient SBI method for models of decision-making. Our approach, Mixed Neural Likelihood Estimation (MNLE), trains neural density estimators on model simulations to emulate the simulator, and is designed to capture both the continuous (e.g., reaction times) and discrete (choices) data of decision-making models. The likelihoods of the emulator can then be used to perform Bayesian parameter inference on experimental data using standard approximate inference methods like Markov Chain Monte Carlo sampling. We demonstrate MNLE on two variants of the drift-diffusion model (DDM) and compare its performance to a recently proposed method for SBI on DDMs, called Likelihood Approximation Networks (LANs, Fengler et al. 2021). We show that MNLE is substantially more effcient than LANs: it achieves similar likelihood accuracy with six orders of magnitude fewer training simulations, and is substantially more accurate than LANs when both are trained with the same budget. This enables researchers to train MNLE on custom-tailored models of decision-making, leading to fast iteration of model design for scientific discovery.

Flexible and efficient simulation-based inference for models of decision-making

Forming a complete picture of the relationship between neural activity and body kinetics requires quantification of skeletal joint biomechanics during behavior. However, without detailed knowledge of the underlying skeletal motion, inferring joint kinetics from surface tracking approaches is difficult, especially for animals where the relationship between surface anatomy and skeleton changes during motion. Here we developed a videography-based method enabling detailed three-dimensional kinetic quantification of an anatomically defined skeleton in untethered freely-behaving animals. This skeleton-based model has been constrained by anatomical principles and joint motion limits and provided skeletal pose estimates for a range of rodent sizes, even when limbs were occluded. Model-inferred joint kinetics for both gait and gap-crossing behaviors were verified by direct measurement of limb placement, showing that complex decision-making behaviors can be accurately reconstructed at the level of skeletal kinetics using our anatomically constrained model.

Anatomically-based skeleton kinetics and pose estimation in freely-moving rodents

Author response: Synchronous activity patterns in the dentate gyrus during immobility

Recent advances in probabilistic modelling have led to a large number of simulation-based inference algorithms which do not require numerical evaluation of likelihoods. However, a public benchmark with appropriate performance metrics for such 'likelihood-free' algorithms has been lacking. This has made it difficult to compare algorithms and identify their strengths and weaknesses. We set out to fill this gap: We provide a benchmark with inference tasks and suitable performance metrics, with an initial selection of algorithms including recent approaches employing neural networks and classical Approximate Bayesian Computation methods. We found that the choice of performance metric is critical, that even state-of-the-art algorithms have substantial room for improvement, and that sequential estimation improves sample efficiency. Neural network-based approaches generally exhibit better performance, but there is no uniformly best algorithm. We provide practical advice and highlight the potential of the benchmark to diagnose problems and improve algorithms. The results can be explored interactively on a companion website. All code is open source, making it possible to contribute further benchmark tasks and inference algorithms.

Objective. Most neuroprosthetic implants employ pulsatile square-wave electrical stimuli, which are significantly different from physiological inter-neuronal communication. In case of retinal neuroprosthetics, which use a certain type of pulsatile stimuli, reliable object and contrast discrimination by implanted blind patients remained challenging. Here we investigated to what extent simple objects can be discriminated from the output of retinal ganglion cells (RGCs) upon sinusoidal stimulation. Approach. Spatially confined objects were formed by different combinations of 1024 stimulating microelectrodes. The RGC activity in the ex vivo retina of photoreceptor-degenerated mouse, of healthy mouse or of primate was recorded simultaneously using an interleaved recording microelectrode array implemented in a CMOS-based chip. Main results. We report that application of sinusoidal electrical stimuli (40 Hz) in epiretinal configuration instantaneously and reliably modulates the RGC activity in spatially confined areas at low stimulation threshold charge densities (40 nC mm−2). Classification of overlapping but spatially displaced objects (1° separation) was achieved by distinct spiking activity of selected RGCs. A classifier (regularized logistic regression) discriminated spatially displaced objects (size: 5.5° or 3.5°) with high accuracy (90% or 62%). Stimulation with low artificial contrast (10%) encoded by different stimulus amplitudes generated RGC activity, which was classified with an accuracy of 80% for large objects (5.5°). Significance. We conclude that time-continuous smooth-wave stimulation provides robust, localized neuronal activation in photoreceptor-degenerated retina, which may enable future artificial vision at high temporal, spatial and contrast resolution.

Discrimination of simple objects decoded from the output of retinal ganglion cells upon sinusoidal electrical stimulation

Simulation-based inference with conditional neural density estimators is a powerful approach to solving inverse problems in science. However, these methods typically treat the underlying forward model as a black box, with no way to exploit geometric properties such as equivariances. Equivariances are common in scientific models, however integrating them directly into expressive inference networks (such as normalizing flows) is not straightforward. We here describe an alternative method to incorporate equivariances under joint transformations of parameters and data. Our method -- called group equivariant neural posterior estimation (GNPE) -- is based on self-consistently standardizing the"pose"of the data while estimating the posterior over parameters. It is architecture-independent, and applies both to exact and approximate equivariances. As a real-world application, we use GNPE for amortized inference of astrophysical binary black hole systems from gravitational-wave observations. We show that GNPE achieves state-of-the-art accuracy while reducing inference times by three orders of magnitude.

Neural circuits can produce similar activity patterns from vastly different combinations of channel and synaptic conductances. These conductances are tuned for specific activity patterns but might also reflect additional constraints, such as metabolic cost or robustness to perturbations. How do such constraints influence the range of permissible conductances? Here, we investigate how metabolic cost affects the parameters of neural circuits with similar activity in a model of the pyloric network of the crab Cancer borealis. We use a novel machine learning method to identify a range of network models that can generate activity patterns matching experimental data. We find that neural circuits can consume largely different amounts of energy despite similar circuit activity. We then study how circuit parameters get constrained by minimizing energy consumption and identify circuit parameters that might be subject to metabolic tuning. Finally, we investigate the interaction between metabolic cost and temperature robustness. We show that metabolic cost can vary across temperatures, but that robustness to temperature changes does not necessarily incur an increased metabolic cost. Our analyses show that, despite metabolic efficiency and temperature robustness constraining circuit parameters, neural systems can generate functional, efficient, and robust network activity with widely disparate sets of conductances.

The ability to preferentially stimulate different retinal pathways is an important area of research for improving visual prosthetics. Recent work has shown that different classes of retinal ganglion cells (RGCs) have distinct linear electrical input filters for low-amplitude white noise stimulation. The aim of this study is to provide a statistical framework for characterizing how RGCs respond to white-noise electrical stimulation. We used a nested family of Generalized Linear Models (GLMs) to partition neural responses into different components—progressively adding covariates to the GLM which captured non-stationarity in neural activity, a linear dependence on the stimulus, and any remaining non-linear interactions. We found that each of these components resulted in increased model performance, but that even the non-linear model left a substantial fraction of neural variability unexplained. The broad goal of this paper is to provide a much-needed theoretical framework to objectively quantify stimulus paradigms in terms of the types of neural responses that they elicit (linear vs. non-linear vs. stimulus-independent variability). In turn, this aids the prosthetic community in the search for optimal stimulus parameters that avoid indiscriminate retinal activation and adaptation caused by excessively large stimulus pulses, and avoid low fidelity responses (low signal-to-noise ratio) caused by excessively weak stimulus pulses.

Characterizing Retinal Ganglion Cell Responses to Electrical Stimulation Using Generalized Linear Models

The hippocampal dentate gyrus is an important relay conveying sensory information from the entorhinal cortex to the hippocampus proper. During exploration, the dentate gyrus has been proposed to act as a pattern separator. However, the dentate gyrus also shows structured activity during immobility and sleep. The properties of these activity patterns at cellular resolution, and their role in hippocampal-dependent memory processes have remained unclear. Using dual-color in-vivo two-photon Ca2+ imaging, we show that in immobile mice dentate granule cells generate sparse, synchronized activity patterns associated with entorhinal cortex activation. These population events are structured and modified by changes in the environment; and they incorporate place- and speed cells. Importantly, they recapitulate population patterns evoked during self-motion. Using optogenetic inhibition during immobility, we show that granule cell activity during immobility is required to form dentate gyrus-dependent spatial memories. These data suggest that memory formation is supported by dentate gyrus replay of population codes of the current environment.

Dentate gyrus population activity during immobility supports formation of precise memories

Deep learning enables fast and dense single-molecule localization with high accuracy

Developmental programs that guide neurons and their neurites into specific subvolumes of the mammalian neocortex give rise to lifelong constraints for the formation of synaptic connections. To what degree do these constraints affect cortical wiring diagrams? Here we introduce an inverse modeling approach to show how cortical networks would appear if they were solely due to the spatial distributions of neurons and neurites. We find that neurite packing density and morphological diversity will inevitably translate into non-random pairwise and higher-order connectivity statistics. More importantly, we show that these non-random wiring properties are not arbitrary, but instead reflect the specific structural organization of the underlying neuropil. Our predictions are consistent with the empirically observed wiring specificity from subcellular to network scales. Thus, independent from learning and genetically encoded wiring rules, many of the properties that define the neocortex' characteristic network architecture may emerge as a result of neuron and neurite development.

The impact of neuron morphology on cortical network architecture

Bayesian inference for synaptic connectivity rules in anatomically realistic cortical connectomes

Understanding how rich dynamics emerge in neural populations requires models exhibiting a wide range of behaviors while remaining interpretable in terms of connectivity and single-neuron dynamics. However, it has been challenging to fit such mechanistic spiking networks at the single-neuron scale to empirical population data. To close this gap, we propose to fit such data at a mesoscale, using a mechanistic but low-dimensional and, hence, statistically tractable model. The mesoscopic representation is obtained by approximating a population of neurons as multiple homogeneous pools of neurons and modeling the dynamics of the aggregate population activity within each pool. We derive the likelihood of both single-neuron and connectivity parameters given this activity, which can then be used to optimize parameters by gradient ascent on the log likelihood or perform Bayesian inference using Markov chain Monte Carlo (MCMC) sampling. We illustrate this approach using a model of generalized integrate-and-fire neurons for which mesoscopic dynamics have been previously derived and show that both single-neuron and connectivity parameters can be recovered from simulated data. In particular, our inference method extracts posterior correlations between model parameters, which define parameter subsets able to reproduce the data. We compute the Bayesian posterior for combinations of parameters using MCMC sampling and investigate how the approximations inherent in a mesoscopic population model affect the accuracy of the inferred single-neuron parameters.

Inference of a Mesoscopic Population Model from Population Spike Trains

A common problem in computational neuroscience is the comparison of competing models in the light of observed data. Bayesian model comparison provides a statistically sound framework for this comparison based on the evidence each model provides for the data. In practice, however, models are often defined through complex simulators so that methods relying on likelihood functions are not applicable. Previous approaches in the field of Approximate Bayesian Computation (ABC) rely on rejection sampling to circumvent the likelihood, but are typically computationally inefficient. We propose an efficient method to perform Bayesian model comparison for simulation-based models. Using recent advances in posterior density estimation, we train a mixture-density network to map features of the observed data to the parameters of the posterior over models. We show that the method performs accurately on two tractable example problems, and present an application to a use case scenario from computational neuroscience – the comparison of ion channel models.

Neural population responses to sensory stimuli can exhibit both nonlinear stimulusdependence and richly structured shared variability. Here, we show how adversarial training can be used to optimize neural encoding models to capture both the deterministic and stochastic components of neural population data. To account for the discrete nature of neural spike trains, we use and compare gradient estimators for adversarial optimization of neural encoding models. We illustrate our approach on population recordings from primary visual cortex. We show that adding latent noise-sources to a convolutional neural network yields a model which captures both the stimulus-dependence and noise correlations of the population activity.

Adversarial Training of Neural Encoding Models on Population Spike Trains

Single-molecule localization microscopy constructs super-resolution images by the sequential imaging and computational localization of sparsely activated fluorophores. Accurate and efficient fluorophore localization algorithms are key to the success of this computational microscopy method. We present a novel localization algorithm based on deep learning which significantly improves upon the state of the art. Our contributions are a novel network architecture for simultaneous detection and localization, and a new training algorithm which enables this deep network to solve the Bayesian inverse problem of detecting and localizing single molecules. Our network architecture uses temporal context from multiple sequentially imaged frames to detect and localize molecules. Our training algorithm combines simulation-based supervised learning with autoencoder-based unsupervised learning to make it more robust against mismatch in the generative model. We demonstrate the performance of our method on datasets imaged using a variety of point spread functions and fluorophore densities. While existing localization algorithms can achieve optimal localization accuracy in data with low fluorophore density, they are confounded by high densities. Our method significantly outperforms the state of the art at high densities and thus, enables faster imaging than previous approaches. Our work also more generally shows how to train deep networks to solve challenging Bayesian inverse problems in biology and physics.

Teaching deep neural networks to localize sources in super-resolution microscopy by combining simulation-based learning and unsupervised learning

Deep neural networks progressively transform their inputs across multiple processing layers. What are the geometrical properties of the representations learned by these networks? Here we study the intrinsic dimensionality (ID) of data-representations, i.e. the minimal number of parameters needed to describe a representation. We find that, in a trained network, the ID is orders of magnitude smaller than the number of units in each layer. Across layers, the ID first increases and then progressively decreases in the final layers. Remarkably, the ID of the last hidden layer predicts classification accuracy on the test set. These results can neither be found by linear dimensionality estimates (e.g., with principal component analysis), nor in representations that had been artificially linearized. They are neither found in untrained networks, nor in networks that are trained on randomized labels. This suggests that neural networks that can generalize are those that transform the data into low-dimensional, but not necessarily flat manifolds.

Intrinsic dimension of data representations in deep neural networks

12 78 4 v 1 [ cs . L G ] 2 9 M ay 2 01 9 Intrinsic dimension of data representations in deep neural networks

How can one perform Bayesian inference on stochastic simulators with intractable likelihoods? A recent approach is to learn the posterior from adaptively proposed simulations using neural network-based conditional density estimators. However, existing methods are limited to a narrow range of proposal distributions or require importance weighting that can limit performance in practice. Here we present automatic posterior transformation (APT), a new sequential neural posterior estimation method for simulation-based inference. APT can modify the posterior estimate using arbitrary, dynamically updated proposals, and is compatible with powerful flow-based density estimators. It is more flexible, scalable and efficient than previous simulation-based inference techniques. APT can operate directly on high-dimensional time series and image data, opening up new applications for likelihood-free inference.

Automatic Posterior Transformation for Likelihood-Free Inference

Choice (-history) correlations in sensory cortex: cause or consequence?

Single-molecule localization fluorescence microscopy constructs super-resolution images by sequential imaging and computational localization of sparsely activated fluorophores. Accurate and efficient fluorophore localization algorithms are key to the success of this computational microscopy method. We present a novel localization algorithm based on deep learning which significantly improves upon the state of the art. Our contributions are a novel network architecture for simultaneous detection and localization, and new loss function which phrases detection and localization as a Bayesian inference problem, and thus allows the network to provide uncertainty-estimates. In contrast to standard methods which independently process imaging frames, our network architecture uses temporal context from multiple sequentially imaged frames to detect and localize molecules. We demonstrate the power of our method across a variety of datasets, imaging modalities, signal to noise ratios, and fluorophore densities. While existing localization algorithms can achieve optimal localization accuracy at low fluorophore densities, they are confounded by high densities. Our method is the first deep-learning based approach which achieves state-of-the-art on the SMLM2016 challenge. It achieves the best scores on 12 out of 12 data-sets when comparing both detection accuracy and precision, and excels at high densities. Finally, we investigate how unsupervised learning can be used to make the network robust against mismatch between simulated and real data. The lessons learned here are more generally relevant for the training of deep networks to solve challenging Bayesian inverse problems on spatially extended domains in biology and physics.

Teaching deep neural networks to localize single molecules for super-resolution microscopy

Mechanistic modeling in neuroscience aims to explain neural or behavioral phenomena in terms of underlying causes. A central challenge in building mechanistic models is to identify which models and parameters can achieve an agreement between the model and experimental data. The complexity of models and data characterizing neural systems makes it infeasible to solve model equations analytically or tune parameters manually. To overcome this limitation, we present a machine learning tool that uses density estimators based on deep neural networks— trained using model simulations—to infer data-compatible parameters for a wide range of mechanistic models. Our tool identifies all parameters consistent with data, is scalable both in the number of parameters and data features, and does not require writing new code when the underlying model is changed. It can be used to analyze new data rapidly after training, and can be applied to either raw data or selected data features. We demonstrate our approach for parameter inference on ion channels, receptive fields, and Hodgkin–Huxley models. Finally, we use it to explore the space of circuit configurations which give rise to rhythmic activity in a network model of the crustacean stomatogastric ganglion, and to provide hypotheses for compensation mechanisms. The approach presented here will help close the gap between data-driven and theory-driven models of neural dynamics.

Training deep neural density estimators to identify mechanistic models of neural dynamics

Inferring the parameters of neural simulations from high-dimensional observations

Accuracy of Rats in Discriminating Visual Objects Is Explained by the Complexity of Their Perceptual Strategy

In recent years, two-photon calcium imaging has become a standard tool to probe the function of neural circuits and to study computations in neuronal populations. However, the acquired signal is only an indirect measurement of neural activity due to the comparatively slow dynamics of fluorescent calcium indicators. Different algorithms for estimating spike rates from noisy calcium measurements have been proposed in the past, but it is an open question how far performance can be improved. Here, we report the results of the spikefinder challenge, launched to catalyze the development of new spike rate inference algorithms through crowd-sourcing. We present ten of the submitted algorithms which show improved performance compared to previously evaluated methods. Interestingly, the top-performing algorithms are based on a wide range of principles from deep neural networks to generative models, yet provide highly correlated estimates of the neural activity. The competition shows that benchmark challenges can drive algorithmic developments in neuroscience.

Community-based benchmarking improves spike rate inference from two-photon calcium imaging data

Approximate Bayesian Computation (ABC) provides methods for Bayesian inference in simulation-based stochastic models which do not permit tractable likelihoods. We present a new ABC method which uses probabilistic neural emulator networks to learn synthetic likelihoods on simulated data -- both local emulators which approximate the likelihood for specific observed data, as well as global ones which are applicable to a range of data. Simulations are chosen adaptively using an acquisition function which takes into account uncertainty about either the posterior distribution of interest, or the parameters of the emulator. Our approach does not rely on user-defined rejection thresholds or distance functions. We illustrate inference with emulator networks on synthetic examples and on a biophysical neuron model, and show that emulators allow accurate and efficient inference even on high-dimensional problems which are challenging for conventional ABC approaches.

s (Alphabetical by First Author) Towards a Computational Model of Child Gesture-Speech Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Olga Abramov, Stefan Kopp, Ulrich Mertens, Anne Németh, Katharina Rohlfing and Friederike Kern Explaining Quantitative Judgments with a Mixture Model Combining Exemplar Retrieval and Cue-abstraction. . . . . . . 2 Rebecca Albrecht, Janina A. Hoffmann, Timothy J. Pleskac, Jörg Rieskamp and Bettina von Helversen The cognitive utility of flawed metaphors in mathematical problem-solving . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Analyzing biological and artificial neural networks: challenges with opportunities for synergy?

Accuracy of Rats in Discri minating Visual Objects Is Explained by the Complexity of Their Perceptual Strategy Graphical

Transfer learning for adaptation to new tasks is usually performed by either finetuning all model parameters or parameters in the final layers. We show that good target performance can also be achieved on typical domain adaptation tasks by adapting only the normalization statistics and affine transformations of layers throughout the network. We apply this adaptation scheme to supervised domain adaptation on common digit datasets and study robustness properties under perturbation by noise. Our results indicate that (1) adaptation to noise exceeds the difficulty of widely used digit benchmarks in domain adaptation, (2) the similarity of the optimal adaptation parameters for different domains is strongly predictive of generalization performance, and (3) generalization performance is highest with training on a rich environment or high noise levels.

Multi-Task Generalization and Adaptation between Noisy Digit Datasets: An Empirical Study

We introduce salad, an open source toolbox that provides a unified implementation of state-of-the-art methods for transfer learning, semi-supervised learning and domain adaptation. In the first release, we provide a framework for reproducing, extending and combining research results of the past years, including model architectures, loss functions and training algorithms. The toolbox along with first benchmark results and further resources is accessible at domainadaptation.org.

Salad: A Toolbox for Semi-supervised Adaptive Learning Across Domains

Adaptively learned calibration kernels for stable importance sampling in regression ABC

During perceptual decisions the activity of sensory neurons covaries with choice, a covariation often quantified as “choice-probability”. Moreover, choices are influenced by a subject's previous choice (serial dependence) and neuronal activity often shows temporal correlations on long (seconds) timescales. Here, we test whether these findings are linked. Using generalized linear models, we analyze simultaneous measurements of behavior and V2 neural activity in macaques performing a visual discrimination task. Both, decisions and spiking activity show substantial temporal correlations and cross-correlations but seem to reflect two mostly separate processes. Indeed, removing history effects using semipartial correlation analysis leaves choice probabilities largely unchanged. The serial dependencies in choices and neural activity therefore cannot explain the observed choice probability. Rather, serial dependencies in choices and spiking activity reflect two predominantly separate but parallel processes, which are coupled on each trial by covariations between choices and activity. These findings provide important constraints for computational models of perceptual decision-making that include feedback signals. SIGNIFICANCE STATEMENT Correlations, unexplained by the sensory input, between the activity of sensory neurons and an animal's perceptual choice (“choice probabilities”) have received attention from both a systems and computational neuroscience perspective. Conversely, whereas temporal correlations for both spiking activity (“non-stationarities”) and for a subject's choices in perceptual tasks (“serial dependencies”) have long been established, they have typically been ignored when measuring choice probabilities. Some accounts of choice probabilities incorporating feedback predict that these observations are linked. Here, we explore the extent to which this is the case. We find that, contrasting with these predictions, choice probabilities are largely independent of serial dependencies, which adds new constraints to accounts of choice probabilities that include feedback.

Can Serial Dependencies in Choices and Neural Activity Explain Choice Probabilities?

Using Bayesian inference to estimate receptive fields from a small number of spikes

26th Annual Computational Neuroscience Meeting (CNS*2017): Part 1

In recent years, two-photon calcium imaging has become a standard tool to probe the function of neural circuits and to study computations in neuronal populations1, 2. However, the acquired signal is only an indirect measurement of neural activity due to the comparatively slow dynamics of fluorescent calcium indicators3. Different algorithms for estimating spike trains from noisy calcium measurements have been proposed in the past4‒8, but it is an open question how far performance can be improved. Here, we report the results of the spikefinder challenge, launched to catalyze the development of new spike inference algorithms through crowd-sourcing. We present ten of the submitted algorithms which show improved performance compared to previously evaluated methods. Interestingly, the top-performing algorithms are based on a wide range of principles from deep neural networks to generative models, yet provide highly correlated estimates of the neural activity. The competition shows that benchmark challenges can drive algorithmic developments in neuroscience.

Community-based benchmarking improves spike inference from two-photon calcium imaging data

Flexible Bayesian inference for mechanistic models of neural dynamics

A powerful approach for understanding neural population dynamics is to extract low-dimensional trajectories from population recordings using dimensionality reduction methods. Current approaches for dimensionality reduction on neural data are limited to single population recordings, and can not identify dynamics embedded across multiple measurements. We propose an approach for extracting low-dimensional dynamics from multiple, sequential recordings. Our algorithm scales to data comprising millions of observed dimensions, making it possible to access dynamics distributed across large populations or multiple brain areas. Building on subspace-identification approaches for dynamical systems, we perform parameter estimation by minimizing a moment-matching objective using a scalable stochastic gradient descent algorithm: The model is optimized to predict temporal covariations across neurons and across time. We show how this approach naturally handles missing data and multiple partial recordings, and can identify dynamics and predict correlations even in the presence of severe subsampling and small overlap between recordings. We demonstrate the effectiveness of the approach both on simulated data and a whole-brain larval zebrafish imaging dataset.

Extracting low-dimensional dynamics from multiple large-scale neural population recordings by learning to predict correlations

The rise of large-scale recordings of neuronal activity has fueled the hope to gain new insights into the collective activity of neural ensembles. How can one link the statistics of neural population activity to underlying principles and theories? One attempt to interpret such data builds upon analogies to the behaviour of collective systems in statistical physics. Divergence of the specific heat—a measure of population statistics derived from thermodynamics—has been used to suggest that neural populations are optimized to operate at a “critical point”. However, these findings have been challenged by theoretical studies which have shown that common inputs can lead to diverging specific heat. Here, we connect “signatures of criticality”, and in particular the divergence of specific heat, back to statistics of neural population activity commonly studied in neural coding: firing rates and pairwise correlations. We show that the specific heat diverges whenever the average correlation strength does not depend on population size. This is necessarily true when data with correlations is randomly subsampled during the analysis process, irrespective of the detailed structure or origin of correlations. We also show how the characteristic shape of specific heat capacity curves depends on firing rates and correlations, using both analytically tractable models and numerical simulations of a canonical feed-forward population model. To analyze these simulations, we develop efficient methods for characterizing large-scale neural population activity with maximum entropy models. We find that, consistent with experimental findings, increases in firing rates and correlation directly lead to more pronounced signatures. Thus, previous reports of thermodynamical criticality in neural populations based on the analysis of specific heat can be explained by average firing rates and correlations, and are not indicative of an optimized coding strategy. We conclude that a reliable interpretation of statistical tests for theories of neural coding is possible only in reference to relevant ground-truth models.

Signatures of criticality arise from random subsampling in simple population models

Amortized inference for fast spike prediction from calcium imaging data

Calcium imaging permits optical measurement of neural activity. Since intracellular calcium concentration is an indirect measurement of neural activity, computational tools are necessary to infer the true underlying spiking activity from fluorescence measurements. Bayesian model inversion can be used to solve this problem, but typically requires either computationally expensive MCMC sampling, or faster but approximate maximum-a-posteriori optimization. Here, we introduce a flexible algorithmic framework for fast, efficient and accurate extraction of neural spikes from imaging data. Using the framework of variational autoencoders, we propose to amortize inference by training a deep neural network to perform model inversion efficiently. The recognition network is trained to produce samples from the posterior distribution over spike trains. Once trained, performing inference amounts to a fast single forward pass through the network, without the need for iterative optimization or sampling. We show that amortization can be applied flexibly to a wide range of nonlinear generative models and significantly improves upon the state of the art in computation time, while achieving competitive accuracy. Our framework is also able to represent posterior distributions over spike-trains. We demonstrate the generality of our method by proposing the first probabilistic approach for separating backpropagating action potentials from putative synaptic inputs in calcium imaging of dendritic spines.

Fast amortized inference of neural activity from calcium imaging data with variational autoencoders

Flexible Bayesian inference for complex models of single neurons

Mechanistic models of single-neuron dynamics have been extensively studied in computational neuroscience. However, identifying which models can quantitatively reproduce empirically measured data has been challenging. We propose to overcome this limitation by using likelihood-free inference approaches (also known as Approximate Bayesian Computation, ABC) to perform full Bayesian inference on single-neuron models. Our approach builds on recent advances in ABC by learning a neural network which maps features of the observed data to the posterior distribution over parameters. We learn a Bayesian mixture-density network approximating the posterior over multiple rounds of adaptively chosen simulations. Furthermore, we propose an efficient approach for handling missing features and parameter settings for which the simulator fails, as well as a strategy for automatically learning relevant features using recurrent neural networks. On synthetic data, our approach efficiently estimates posterior distributions and recovers ground-truth parameters. On in-vitro recordings of membrane voltages, we recover multivariate posteriors over biophysical parameters, which yield model-predicted voltage traces that accurately match empirical data. Our approach will enable neuroscientists to perform Bayesian inference on complex neuron models without having to design model-specific algorithms, closing the gap between mechanistic and statistical approaches to single-neuron modelling.

Flexible statistical inference for mechanistic models of neural dynamics

Large-scale recordings of neuronal activity make it possible to gain insights into the collective activity of neural ensembles. It has been hypothesized that neural populations might be optimized to operate at a ‘thermodynamic critical point’, and that this property has implications for information processing. Support for this notion has come from a series of studies which identified statistical signatures of criticality in the ensemble activity of retinal ganglion cells. What are the underlying mechanisms that give rise to these observations? Here we show that signatures of criticality arise even in simple feed-forward models of retinal population activity. In particular, they occur whenever neural population data exhibits correlations, and is randomly sub-sampled during data analysis. These results show that signatures of criticality are not necessarily indicative of an optimized coding strategy, and challenge the utility of analysis approaches based on equilibrium thermodynamics for understanding partially observed biological systems.

Signatures of criticality arise in simple neural population models with correlations

Painfree and accurate Bayesian estimation of psychometric functions for (potentially) overdispersed data

Full Bayesian inference for model-based receptive field estimation, with application to primary visual cortex

Stitching neural activity in space and time: theory and practice

Psychometric functions are frequently used in vision science to model task performance. These sigmoid functions can be fit to data using likelihood maximization, but this ignores the reliability or variance of the point estimates. In contrast Bayesian methods automatically calculate this reliability. However, using Bayesian methods in practice usually requires expert knowledge, user interaction and computation time. Also most methods---including Bayesian ones---are vulnerable to non-stationary observers (whose performance is not constant). For such observers all methods, which assume a stationary binomial observer are overconfident in the estimates. We present Psignifit 4, a new method for fitting psychometric functions, which provides an efficient Bayesian analysis based on numerical integration, which requires little user-interaction and runs in seconds on a common office computer. Additionally it fits a beta-binomial model increasing the stability against non-stationarity and contains standard settings including a heuristic to set the prior based on the interval of stimulus levels in the experimental data. Obviously all properties of the analysis can be adjusted. To test our method it was run on extensive simulated datasets. First we tested the numerical accuracy of our method with different settings and found settings which calculate a good estimate fast and reliably. Testing the statistical properties, we find that our method calculates correct or slightly conservative confidence intervals in all tested conditions, including different sampling schemes, beta-binomial observers, other non-stationary observers and adaptive methods. When enough data was collected to overcome the small sample bias caused by the prior, the point estimates are also essentially unbiased. In summary we present a user-friendly, fast, correct and comprehensively tested Bayesian method to fit psychometric functions, which handles non-stationary observers well and is freely available as an MATLAB implementation online. Meeting abstract presented at VSS 2015.

Psignifit 4: Pain-free Bayesian Inference for Psychometric Functions.

Neural population activity often exhibits rich variability and temporal structure. This variability is thought to arise from single-neuron stochasticity, neural dynamics on short time-scales, as well as from modulations of neural firing properties on long time-scales, often referred to as "non-stationarity". To better understand the nature of co-variability in neural circuits and their impact on cortical information processing, we need statistical models that are able to capture multiple sources of variability on different time-scales. Here, we introduce a hierarchical statistical model of neural population activity which models both neural population dynamics as well as inter-trial modulations in firing rates. In addition, we extend the model to allow us to capture non-stationarities in the population dynamics itself (i.e., correlations across neurons). 
We develop variational inference methods for learning model parameters, and demonstrate that the method can recover non-stationarities in both average firing rates and correlation structure. Applied to neural population recordings from anesthetized macaque primary visual cortex, our models provide a better account of the structure of neural firing than stationary dynamics models.

Hierarchical models for neural population dynamics in the presence of non-stationarity

Neural population coding: combining insights from microscopic and mass signals

A statistical characterization of neural population responses in V1

Two-photon imaging of neuronal populations in the primary visual cortex representation of the overhead visual field

Correlations and signatures of criticality in neural population models

Neural population activity often exhibits rich variability. This variability is thought to arise from single-neuron stochasticity, neural dynamics on short time-scales, as well as from modulations of neural firing properties on long time-scales, often referred to as non-stationarity. To better understand the nature of co-variability in neural circuits and their impact on cortical information processing, we introduce a hierarchical dynamics model that is able to capture inter-trial modulations in firing rates, as well as neural population dynamics. We derive an algorithm for Bayesian Laplace propagation for fast posterior inference, and demonstrate that our model provides a better account of the structure of neural firing than existing stationary dynamics models, when applied to neural population recordings from primary visual cortex.

Unlocking neural population non-stationarities using hierarchical dynamics models

Neural computations at all scales of evolutionary and behavioural complexity are carried out by recurrently connected networks of neurons that communicate with each other, with neurons elsewhere in the brain, and with muscles through the firing of action potentials or “spikes”. To understand how nervous tissue computes, it is therefore necessary to understand how the spiking of neurons is shaped both by inputs to the network and by the recurrent action of existing network activity. Whereas most historical spike data were collected one neuron at a time, new techniques including silicon multi-electrode array recording and scanning 2-photon, light-sheet or light-field fluorescence calcium imaging increasingly make it possible to record spikes from dozens, hundreds and potentially thousands of individual neurons simultaneously. These new data offer unprecedented empirical access to network computation, promising breakthroughs both in our understanding of neural coding and computation (Stevenson & Kording 2011), and our ability to build prosthetic neural interfaces (Santhanam, Ryu, Yu, Afshar & Shenoy 2006). Fulfilment of this promise will require powerful methods for data modelling and analysis, able to capture

Estimating state and Parameters in state space Models of Spike trains

Anatomical basis of spiking correlation in upper layers of somatosensory cortex

Neural population activity often exhibits rich variability. This variability can arise from single-neuron stochasticity, neural dynamics on short time-scales, as well as from modulations of neural firing properties on long time-scales, often referred to as neural non-stationarity. To better understand the nature of co-variability in neural circuits and their impact on cortical information processing, we introduce a hierarchical dynamics model that is able to capture both slow inter-trial modulations in firing rates as well as neural population dynamics. We derive a Bayesian Laplace propagation algorithm for joint inference of parameters and population states. On neural population recordings from primary visual cortex, we demonstrate that our model provides a better account of the structure of neural firing than stationary dynamics models.

Unlocking neural population non-stationarity using a hierarchical dynamics model

Dissecting choice-probabilities in V2 neurons using serial dependence

Statistical methods for characterizing cortical population activity

Crowdsourced analysis of clinical trial data to predict amyotrophic lateral sclerosis progression

Using sequential dependencies in neural activity and behavior to dissect choice related activity in V2

Bayesian Inference on psychometric functions. The method is fast and convenient to use. Furthermore, we provide suitable defaults for all common settings. By fitting a beta-binomial model our method exhibits increased robustness against nonstationary behaviour caused, e.g., by fluctuations in attention or learning. We performed extensive simulations to validate our method and software implementation. Finally we provide generic methods to compare several psychometric functions statistically. All methods are freely available:  https://github.com/wichmann-lab/psignifit

Predicting noise correlations for non-simultaneously measured neuron pairs

This manuscripts contains additional material for the manuscript “A model of neural population activity in the presence of common input explains higher-order correlations and entropy”. It contains very detailed step-by-step derivations and proofs for all the formulas used in the paper. We aimed to present derivations in a self-contained manner, rather than in a brief and elegant one. We also included some additional explanations, additional figures and enlarged versions of some figures, as well as additional references.

Supplementary details and explanations for paper “ A model of neural population activity in the presence of common input explains higher-order correlations and entropy ”

In the perceptual sciences, experimenters study the causal mechanisms of perceptual systems by probing observers with carefully constructed stimuli. It has long been known, however, that perceptual decisions are not only determined by the stimulus, but also by internal factors. Internal factors could lead to a statistical influence of previous stimuli and responses on the current trial, resulting in serial dependencies, which complicate the causal inference between stimulus and response. However, the majority of studies do not take serial dependencies into account, and it has been unclear how strongly they influence perceptual decisions. We hypothesize that one reason for this neglect is that there has been no reliable tool to quantify them and to correct for their effects. Here we develop a statistical method to detect, estimate, and correct for serial dependencies in behavioral data. We show that even trained psychophysical observers suffer from strong history dependence. A substantial fraction of the decision variance on difficult stimuli was independent of the stimulus but dependent on experimental history.We discuss the strong dependence of perceptual decisions on internal factors and its implications for correct data interpretation.

Quantifying the effect of intertrial dependence on perceptual decisions.

Neural population activity in cortical circuits is not solely driven by external inputs, but is also modulated by endogenous states which vary on multiple time-scales. To understand information processing in cortical circuits, we need to understand the statistical structure of internal states and their interaction with sensory inputs. Here, we present a statistical model for extracting hierarchically organised neural population states from multi-channel recordings of neural spiking activity. Population states are modelled using a hidden Markov decision tree with state-dependent tuning parameters and a generalised linear observation model. We present a variational Bayesian inference algorithm for estimating the posterior distribution over parameters from neural population recordings. On simulated data, we show that we can identify the underlying sequence of population states and reconstruct the ground truth parameters. Using population recordings from visual cortex, we find that a model with two levels of population states outperforms both a one-state and a two-state generalised linear model. Finally, we find that modelling of state-dependence also improves the accuracy with which sensory stimuli can be decoded from the population response.

A Bayesian model for identifying hierarchically organised states in neural population activity

As mentioned in the introduction, most researchers in the perceptual sciences are aware of the potential contamination of behavioural data by internal factors, at least during informal discussions. In stark contrast, we felt that rather few published papers actually discussed or corrected for internal factors. To confirm—or disconfirm—our impression, we attempted to obtain a rough estimate of the prevalence of serial dependency discussions in the relevant literature. To this end we searched the 2011 volume of a high-impact neuroscience journal (Nature Neuroscience) as well as in an established specialist journal for visual psychophysics (Journal of Vision).

Appendix to ‘ Quantifying the effect of inter-trial dependence on perceptual decisions ’

Temporal Jitter of the BOLD Signal Reveals a Reliable Initial Dip and Improved Spatial Resolution

Inferring interactions between cell types from multiple calcium imaging snapshots of the same neural circuit

Inferring neural population dynamics from multiple partial measurements of the same circuit

Simultaneous recordings of the activity of large neural populations are extremely valuable as they can be used to infer the dynamics and interactions of neurons in a local circuit, shedding light on the computations performed. It is now possible to measure the activity of hundreds of neurons using 2-photon calcium imaging. However, many computations are thought to involve circuits consisting of thousands of neurons, such as cortical barrels in rodent somatosensory cortex. Here we contribute a statistical method for "stitching" together sequentially imaged sets of neurons into one model by phrasing the problem as fitting a latent dynamical system with missing observations. This method allows us to substantially expand the population-sizes for which population dynamics can be characterized—beyond the number of simultaneously imaged neurons. In particular, we demonstrate using recordings in mouse somatosensory cortex that this method makes it possible to predict noise correlations between non-simultaneously recorded neuron pairs.

Inferring neural population dynamics from multiple partial recordings of the same neural circuit

Inferring decoding strategies from choice probabilities in the presence of correlated variability

Maximum entropy models have become popular statistical models in neuroscience and other areas in biology and can be useful tools for obtaining estimates of mutual information in biological systems. However, maximum entropy models fit to small data sets can be subject to sampling bias; i.e., the true entropy of the data can be severely underestimated. Here, we study the sampling properties of estimates of the entropy obtained from maximum entropy models. We focus on pairwise binary models, which are used extensively to model neural population activity. We show that if the data is well described by a pairwise model, the bias is equal to the number of parameters divided by twice the number of observations. If, however, the higher order correlations in the data deviate from those predicted by the model, the bias can be larger. Using a phenomenological model of neural population recordings, we find that this additional bias is highest for small firing probabilities, strong correlations and large population sizes—for the parameters we tested, a factor of about four higher. We derive guidelines for how long a neurophysiological experiment needs to be in order to ensure that the bias is less than a specified criterion. Finally, we show how a modified plug-in estimate of the entropy can be used for bias correction.

How biased are maximum entropy models of neural population activity

Ongoing advances in experimental technique are making commonplace simultaneous recordings of the activity of tens to hundreds of cortical neurons at high temporal resolution. Latent population models, including Gaussian-process factor analysis and hidden linear dynamical system (LDS) models, have proven effective at capturing the statistical structure of such data sets. They can be estimated efficiently, yield useful visualisations of population activity, and are also integral building-blocks of decoding algorithms for brain-machine interfaces (BMI). One practical challenge, particularly to LDS models, is that when parameters are learned using realistic volumes of data the resulting models often fail to reflect the true temporal continuity of the dynamics; and indeed may describe a biologically-implausible unstable population dynamic that is, it may predict neural activity that grows without bound. We propose a method for learning LDS models based on expectation maximisation that constrains parameters to yield stable systems and at the same time promotes capture of temporal structure by appropriate regularisation. We show that when only little training data is available our method yields LDS parameter estimates which provide a substantially better statistical description of the data than alternatives, whilst guaranteeing stable dynamics. We demonstrate our methods using both synthetic data and extracellular multi-electrode recordings from motor cortex.

Learning stable, regularised latent models of neural population dynamics

Inferring decoding strategy from choice probabilities in the presence of noise correlations

We explored the manner in which spatial information is encoded by retinal ganglion cell populations. We flashed a set of 36 shape stimuli onto the tiger salamander retina and used different decoding algorithms to read out information from a population of 162 ganglion cells. We compared the discrimination performance of linear decoders, which ignore correlation induced by common stimulation, with nonlinear decoders, which can accurately model these correlations. Similar to previous studies, decoders that ignored correlation suffered only a modest drop in discrimination performance for groups of up to ∼30 cells. However, for more realistic groups of 100+ cells, we found order-of-magnitude differences in the error rate. We also compared decoders that used only the presence of a single spike from each cell with more complex decoders that included information from multiple spike counts and multiple time bins. More complex decoders substantially outperformed simpler decoders, showing the importance of spike timing information. Particularly effective was the first spike latency representation, which allowed zero discrimination errors for the majority of shape stimuli. Furthermore, the performance of nonlinear decoders showed even greater enhancement compared with linear decoders for these complex representations. Finally, decoders that approximated the correlation structure in the population by matching all pairwise correlations with a maximum entropy model fit to all 162 neurons were quite successful, especially for the spike latency representation. Together, these results suggest a picture in which linear decoders allow a coarse categorization of shape stimuli, whereas nonlinear decoders, which take advantage of both correlation and spike timing, are needed to achieve high-fidelity discrimination.

Latent linear dynamical systems with generalised-linear observation models arise in a variety of applications, for instance when modelling the spiking activity of populations of neurons. Here, we show how spectral learning methods (usually called subspace identification in this context) for linear systems with linear-Gaussian observations can be extended to estimate the parameters of a generalised-linear dynamical system model despite a non-linear and non-Gaussian observation process. We use this approach to obtain estimates of parameters for a dynamical model of neural population data, where the observed spike-counts are Poisson-distributed with log-rates determined by the latent dynamical process, possibly driven by external inputs. We show that the extended subspace identification algorithm is consistent and accurately recovers the correct parameters on large simulated data sets with a single calculation, avoiding the costly iterative computation of approximate expectation-maximisation (EM). Even on smaller data sets, it provides an effective initialisation for EM, avoiding local optima and speeding convergence. These benefits are shown to extend to real neural data.

Spectral learning of linear dynamics from generalised-linear observations with application to neural population data

Maximum entropy models have become popular statistical models in neuroscience and other areas in biology, and can be useful tools for obtaining estimates of mutual information in biological systems. However, maximum entropy models fit to small data sets can be subject to sampling bias; i.e. the true entropy of the data can be severely underestimated. Here we study the sampling properties of estimates of the entropy obtained from maximum entropy models. We show that if the data is generated by a distribution that lies in the model class, the bias is equal to the number of parameters divided by twice the number of observations. However, in practice, the true distribution is usually outside the model class, and we show here that this misspecification can lead to much larger bias. We provide a perturbative approximation of the maximally expected bias when the true model is out of model class, and we illustrate our results using numerical simulations of an Ising model; i.e. the second-order maximum entropy distribution on binary data.

Relationship between decoding strategy, choice probabilities and neural correlations in perceptual decision-making task

Neurons in the neocortex code and compute as part of a locally interconnected population. Large-scale multi-electrode recording makes it possible to access these population processes empirically by fitting statistical models to unaveraged data. What statistical structure best describes the concurrent spiking of cells within a local network? We argue that in the cortex, where firing exhibits extensive correlations in both time and space and where a typical sample of neurons still reflects only a very small fraction of the local population, the most appropriate model captures shared variability by a low-dimensional latent process evolving with smooth dynamics, rather than by putative direct coupling. We test this claim by comparing a latent dynamical model with realistic spiking observations to coupled generalised linear spike-response models (GLMs) using cortical recordings. We find that the latent dynamical approach outperforms the GLM in terms of goodness-of-fit, and reproduces the temporal correlations in the data more accurately. We also compare models whose observations models are either derived from a Gaussian or point-process models, finding that the non-Gaussian model provides slightly better goodness-of-fit and more realistic population spike counts.

The effect of common input on higher-order correlations and entropy in neural populations

Simultaneously recorded neurons exhibit correlations whose underlying causes are not known. Here, we use a population of threshold neurons receiving correlated inputs to model neural population recordings. We show analytically that small changes in second-order correlations can lead to large changes in higher-order redundancies, and that the resulting interactions have a strong impact on the entropy, sparsity, and statistical heat capacity of the population. Our findings for this simple model may explain some surprising effects recently observed in neural population recordings.

Common input explains higher-order correlations and entropy in a simple model of neural population activity.

Modern recording techniques such as multi-electrode arrays and two-photon imaging methods are capable of simultaneously monitoring the activity of large neuronal ensembles at single cell resolution. These methods finally give us the means to address some of the most crucial questions in systems neuroscience: what are the dynamics of neural population activity? How do populations of neurons perform computations? What is the functional organization of neural ensembles? 
 
While the wealth of new experimental data generated by these techniques provides exciting opportunities to test ideas about how neural ensembles operate, it also provides major challenges: multi-cell recordings necessarily yield data which is high-dimensional in nature. Understanding this kind of data requires powerful statistical techniques for capturing the structure of the neural population responses, as well as their relationship with external stimuli or behavioral observations. Furthermore, linking recorded neural population activity to the predictions of theoretical models of population coding has turned out not to be straightforward. 
 
These challenges motivated us to organize a workshop at the 2009 Computational Neuroscience Meeting in Berlin to discuss these issues. In order to collect some of the recent progress in this field, and to foster discussion on the most important directions and most pressing questions, we issued a call for papers for this Research Topic. We asked authors to address the following four questions: 
 
What classes of statistical methods are most useful for modeling population activity? 
 
What are the main limitations of current approaches, and what can be done to overcome them? 
 
How can statistical methods be used to empirically test existing models of (probabilistic) population coding? 
 
What role can statistical methods play in formulating novel hypotheses about the principles of information processing in neural populations? 
 
A total of 15 papers addressing questions related to these themes are now collected in this Research Topic. Three of these articles have resulted in “Focused reviews” in Frontiers in Neuroscience (Crumiller et al., 2011; Rosenbaum et al., 2011; Tchumatchenko et al., 2011), illustrating the great interest in the topic. Many of the articles are devoted to a better understanding of how correlations arise in neural circuits, and how they can be detected, modeled, and interpreted. For example, by modeling how pairwise correlations are transformed by spiking non-linearities in simple neural circuits, Tchumatchenko et al. (2010) show that pairwise correlation coefficients have to be interpreted with care, since their magnitude can depend strongly on the temporal statistics of their input-correlations. In a similar spirit, Rosenbaum et al. (2010) study how correlations can arise and accumulate in feed-forward circuits as a result of pooling of correlated inputs. 
 
Lyamzin et al. (2010) and Krumin et al. (2010) present methods for simulating correlated population activity and extend previous work to more general settings. The method of Lyamzin et al. (2010) allows one to generate synthetic spike trains which match commonly reported statistical properties, such as time varying firing rates as well signal and noise correlations. The Hawkes framework presented by Krumin et al. (2010) allows one to fit models of recurrent population activity to the correlation-structure of experimental data. Louis et al. (2010) present a novel method for generating surrogate spike trains which can be useful when trying to assess the significance and time-scale of correlations in neural spike trains. Finally, Pipa and Munk (2011) study spike synchronization in prefrontal cortex during working memory. 
 
A number of studies are also devoted to advancing our methodological toolkit for analyzing various aspects of population activity (Gerwinn et al., 2010; Machens, 2010; Staude et al., 2010; Yu et al., 2010). For example, Gerwinn et al. (2010) explain how full probabilistic inference can be performed in the popular model class of generalized linear models (GLMs), and study the effect of using prior distributions on the parameters of the stimulus and coupling filters. Staude et al. (2010) extend a method for detecting higher-order correlations between neurons via population spike counts to non-stationary settings. Yu et al. (2010) describe a new technique for estimating the information rate of a population of neurons using frequency-domain methods. Machens (2010) introduces a novel extension of principal component analysis for separating the variability of a neural response into different sources. 
 
Focusing less on the spike responses of neural populations but on aggregate signals of population activity, Boatman-Reich et al. (2010) and Hoerzer et al. (2010) describe methods for a quantitative analysis of field potential recordings. While Boatman-Reich et al. (2010) discuss a number of existing techniques in a unified framework and highlight the potential pitfalls associated with such approaches, Hoerzer et al. (2010) demonstrate how multivariate autoregressive models and the concept of Granger causality can be used to infer local functional connectivity in area V4 of behaving macaques. 
 
A final group of studies is devoted to understanding experimental data in light of computational models (Galan et al., 2010; Pandarinath et al., 2010; Shteingart et al., 2010). Pandarinath et al. (2010) present a novel mechanism that may explain how neural networks in the retina switch from one state to another by a change in gap junction coupling, and conjecture that this mechanism might also be found in other neural circuits. Galan et al. (2010) present a model of how hypoxia may change the network structure in the respiratory networks in the brainstem, and analyze neural correlations in multi-electrode recordings in light of this model. Finally, Shteingart et al. (2010) show that the spontaneous activation sequences they find in cultured networks cannot be explained by Zipf's law, but rather require a wrestling model. 
 
The papers of this Research Topic thus span a wide range of topics in the statistical modeling of multi-cell recordings. Together with other recent advances, they provide us with a useful toolkit to tackle the challenges presented by the vast amount of data collected with modern recording techniques. The impact of novel statistical methods on the field and their potential to generate scientific progress, however, depends critically on how readily they can be adopted and applied by laboratories and researchers working with experimental data. An important step toward this goal is to also publish computer code along with the articles (Barnes, 2010) as a successful implementation of advanced methods also relies on many details which are hard to communicate in the article itself. In this way it becomes much more likely that other researchers can actually use the methods, and unnecessary re-implementations can be avoided. Some of the papers in this Research Topic already follow this goal (Gerwinn et al., 2010; Louis et al., 2010; Lyamzin et al., 2010). We hope that this practice becomes more and more common in the future and encourage authors and editors of Research Topics to make as much code available as possible, ideally in a format that can be easily integrated with existing software sharing initiatives (Herz et al., 2008; Goldberg et al., 2009).

Statistical Analysis of Multi-Cell Recordings: Linking Population Coding Models to Experimental Data

Simultaneously recorded neurons exhibit correlations whose underlying causes are not known. Here, we use a population of threshold neurons receiving correlated inputs to model neural population recordings. We show analytically that small changes in second-order correlations can lead to large changes in higher correlations, and that these higher-order correlations have a strong impact on the entropy, sparsity and statistical heat capacity of the population. Remarkably, our findings for this simple model may explain a couple of surprising effects recently observed in neural population recordings.

An analytically tractable model of neural population activity in the presence of common input explains higher-order correlations and entropy

One major challenge in the sensory sciences is to identify the stimulus features on which sensory systems base their computations, and which are predictive of a behavioral decision: they are a prerequisite for computational models of perception. We describe a technique (decision images) for extracting predictive stimulus features using logistic regression. A decision image not only defines a region of interest within a stimulus but is a quantitative template which defines a direction in stimulus space. Decision images thus enable the development of predictive models, as well as the generation of optimized stimuli for subsequent psychophysical investigations. Here we describe our method and apply it to data from a human face classification experiment. We show that decision images are able to predict human responses not only in terms of overall percent correct but also in terms of the probabilities with which individual faces are (mis-) classified by individual observers. We show that the most predictive dimension for gender categorization is neither aligned with the axis defined by the two class-means, nor with the first principal component of all faces-two hypotheses frequently entertained in the literature. Our method can be applied to a wide range of binary classification tasks in vision or other psychophysical contexts.

Estimating predictive stimulus features from psychophysical data: The decision image technique applied to human faces.

Toolbox for inference in generalized linear models of spiking neurons

Reconstructing stimuli from the spike trains of neurons is an important approach for understanding the neural code. One of the difficulties associated with this task is that signals which are varying continuously in time are encoded into sequences of discrete events or spikes. An important problem is to determine how much information about the continuously varying stimulus can be extracted from the time-points at which spikes were observed, especially if these time-points are subject to some sort of randomness. For the special case of spike trains generated by leaky integrate and fire neurons, noise can be introduced by allowing variations in the threshold every time a spike is released. A simple decoding algorithm previously derived for the noiseless case can be extended to the stochastic case, but turns out to be biased. Here, we review a solution to this problem, by presenting a simple yet efficient algorithm which greatly reduces the bias, and therefore leads to better decoding performance in the stochastic case.

Reconstructing Stimuli from the Spike Times of Leaky Integrate and Fire Neurons

As multi-electrode and imaging technology begin to provide us with simultaneous recordings of large neuronal populations, new methods for modeling such data must also be developed. Here, we present a model for the type of data commonly recorded in early sensory pathways: responses to repeated trials of a sensory stimulus in which each neuron has it own time-varying spike rate (as described by its PSTH) and the dependencies between cells are characterized by both signal and noise correlations. This model is an extension of previous attempts to model population spike trains designed to control only the total correlation between cells. In our model, the response of each cell is represented as a binary vector given by the dichotomized sum of a deterministic “signal” that is repeated on each trial and a Gaussian random “noise” that is different on each trial. This model allows the simulation of population spike trains with PSTHs, trial-to-trial variability, and pairwise correlations that match those measured experimentally. Furthermore, the model also allows the noise correlations in the spike trains to be manipulated independently of the signal correlations and single-cell properties. To demonstrate the utility of the model, we use it to simulate and manipulate experimental responses from the mammalian auditory and visual systems. We also present a general form of the model in which both the signal and noise are Gaussian random processes, allowing the mean spike rate, trial-to-trial variability, and pairwise signal and noise correlations to be specified independently. Together, these methods for modeling spike trains comprise a potentially powerful set of tools for both theorists and experimentalists studying population responses in sensory systems.

Modeling Population Spike Trains with Specified Time-Varying Spike Rates, Trial-to-Trial Variability, and Pairwise Signal and Noise Correlations

Generalized Linear Models (GLMs) are commonly used statistical methods for modelling the relationship between neural population activity and presented stimuli. When the dimension of the parameter space is large, strong regularization has to be used in order to fit GLMs to datasets of realistic size without overfitting. By imposing properly chosen priors over parameters, Bayesian inference provides an effective and principled approach for achieving regularization. Here we show how the posterior distribution over model parameters of GLMs can be approximated by a Gaussian using the Expectation Propagation algorithm. In this way, we obtain an estimate of the posterior mean and posterior covariance, allowing us to calculate Bayesian confidence intervals that characterize the uncertainty about the optimal solution. From the posterior we also obtain a different point estimate, namely the posterior mean as opposed to the commonly used maximum a posteriori estimate. We systematically compare the different inference techniques on simulated as well as on multi-electrode recordings of retinal ganglion cells, and explore the effects of the chosen prior and the performance measure used. We find that good performance can be achieved by choosing an Laplace prior together with the posterior mean estimate.

Bayesian Inference for Generalized Linear Models for Spiking Neurons

Predicting psychophysical responses from stimulus features: A statistical evaluation of human gender categorization models

Sensory input statistics and network mechanisms in primate primary visual cortex

Simultaneously recorded neurons often exhibit correlations in their spiking activity. These correlations shape the statistical structure of the population activity, and can lead to substantial redundancy across neurons. Here, we study the effect of pairwise correlations on the population spike count statistics and redundancy in populations of threshold-neurons in which response-correlations arise from correlated Gaussian inputs. We investigate the scaling of the redundancy as the population size is increased, and compare the asymptotic redundancy in our models to the corresponding maximumand minimum entropy models.

The effect of pairwise neural correlations on global population statistics

Spike trains recorded from populations of neurons can exhibit substantial pairwise correlations between neurons and rich temporal structure. Thus, for the realistic simulation and analysis of neural systems, it is essential to have efficient methods for generating artificial spike trains with specified correlation structure. Here we show how correlated binary spike trains can be simulated by means of a latent multivariate gaussian model. Sampling from the model is computationally very efficient and, in particular, feasible even for large populations of neurons. The entropy of the model is close to the theoretical maximum for a wide range of parameters. In addition, this framework naturally extends to correlations over time and offers an elegant way to model correlated neural spike counts with arbitrary marginal distributions.

Imaging techniques such as optical imaging of intrinsic signals, 2-photon calcium imaging and voltage sensitive dye imaging can be used to measure the functional organization of visual cortex across different spatial and temporal scales. Here, we present Bayesian methods based on Gaussian processes for extracting topographic maps from functional imaging data. In particular, we focus on the estimation of orientation preference maps (OPMs) from intrinsic signal imaging data. We model the underlying map as a bivariate Gaussian process, with a prior covariance function that reflects known properties of OPMs, and a noise covariance adjusted to the data. The posterior mean can be interpreted as an optimally smoothed estimate of the map, and can be used for model based interpolations of the map from sparse measurements. By sampling from the posterior distribution, we can get error bars on statistical properties such as preferred orientations, pinwheel locations or pinwheel counts. Finally, the use of an explicit probabilistic model facilitates interpretation of parameters and quantitative model comparisons. We demonstrate our model both on simulated data and on intrinsic signaling data from ferret visual cortex.

The timing of action potentials in spiking neurons depends on the temporal dynamics of their inputs and contains information about temporal fluctuations in the stimulus. Leaky integrate-and-fire neurons constitute a popular class of encoding models, in which spike times depend directly on the temporal structure of the inputs. However, optimal decoding rules for these models have only been studied explicitly in the noiseless case. Here, we study decoding rules for probabilistic inference of a continuous stimulus from the spike times of a population of leaky integrate-and-fire neurons with threshold noise. We derive three algorithms for approximating the posterior distribution over stimuli as a function of the observed spike trains. In addition to a reconstruction of the stimulus we thus obtain an estimate of the uncertainty as well. Furthermore, we derive a ‘spike-by-spike’ online decoding scheme that recursively updates the posterior with the arrival of each new spike. We use these decoding rules to reconstruct time-varying stimuli represented by a Gaussian process from spike trains of single neurons as well as neural populations.

Pairwise Correlations and Multineuronal Firing Patterns in the Primary Visual Cortex of the Awake, Behaving Macaque

Modeling populations of spiking neurons with the Dichotomized Gaussian distribution

All information about the visual world passes through the optic nerve, so with access to the spike trains of a large number of retinal ganglion cells, one should be able to construct a decoding algorithm to discriminate different visual stimuli. Despite the inherent noise in the response of the ganglion cell population, everyday visual experience is highly deterministic. We have designed an experiment to study the nature of the population code of the retina in the “low error” regime.

The role of stimulus correlations for population decoding in the retina

Contour-propagation algorithms for semi-automated reconstruction of neural processes

How pairwise correlations aect the redundancy in large populations of neurons

Analysis of Pattern Recognition Methods in Classifying Bold Signals in Monkeys at 7-Tesla

Comparison of pattern recognition methods in classifying high-resolution BOLD signals obtained at high magnetic field in monkeys.

Stimulus selectivity of sensory neurons is often characterized by estimating their receptive field properties such as orientation selectivity. Receptive fields are usually derived from the mean (or covariance) of the spike-triggered stimulus ensemble. This approach treats each spike as an independent message but does not take into account that information might be conveyed through patterns of neural activity that are distributed across space or time. Can we find a concise description for the processing of a whole population of neurons analogous to the receptive field for single neurons? Here, we present a generalization of the linear receptive field which is not bound to be triggered on individual spikes but can be meaningfully linked to distributed response patterns. More precisely, we seek to identify those stimulus features and the corresponding patterns of neural activity that are most reliably coupled. We use an extension of reverse-correlation methods based on canonical correlation analysis. The resulting population receptive fields span the subspace of stimuli that is most informative about the population response. We evaluate our approach using both neuronal models and multi-electrode recordings from rabbit retinal ganglion cells. We show how the model can be extended to capture nonlinear stimulus-response relationships using kernel canonical correlation analysis, which makes it possible to test different coding mechanisms. Our technique can also be used to calculate receptive fields from multi-dimensional neural measurements such as those obtained from dynamic imaging methods.

Right from the first synapse in the retina, visual information gets distributed across several parallel channels with different temporal filtering properties. Yet, commonly used system identification tools for characterizing neural responses, such as the spike-triggered average, only allow one to investigate the individual neural responses independently of each other. Conversely, many population coding models of neurons and correlations between neurons concentrate on the encoding of a single-variate stimulus.

There are two aspects to unsupervised learning of invariant representations of images: First, we can reduce the dimensionality of the representation by finding an optimal trade-off between temporal stability and informativeness. We show that the answer to this optimization problem is generally not unique so that there is still considerable freedom in choosing a suitable basis. Which of the many optimal representations should be selected? Here, we focus on this second aspect, and seek to find representations that are invariant under geometrical transformations occuring in sequences of natural images. We utilize ideas of 'steerability' and Lie groups, which have been developed in the context of filter design. In particular, we show how an anti-symmetric version of canonical correlation analysis can be used to learn a full-rank image basis which is steerable with respect to rotations. We provide a geometric interpretation of this algorithm by showing that it finds the two-dimensional eigensubspaces of the average bivector. For data which exhibits a variety of transformations, we develop a bivector clustering algorithm, which we use to learn a basis of generalized quadrature pairs (i.e. 'complex cells') from sequences of natural images.

Unsupervised learning of a steerable basis for invariant image representations

Generalized linear models are the most commonly used tools to describe the stimulus selectivity of sensory neurons. Here we present a Bayesian treatment of such models. Using the expectation propagation algorithm, we are able to approximate the full posterior distribution over all weights. In addition, we use a Laplacian prior to favor sparse solutions. Therefore, stimulus features that do not critically influence neural activity will be assigned zero weights and thus be effectively excluded by the model. This feature selection mechanism facilitates both the interpretation of the neuron model as well as its predictive abilities. The posterior distribution can be used to obtain confidence intervals which makes it possible to assess the statistical significance of the solution. In neural data analysis, the available amount of experimental measurements is often limited whereas the parameter space is large. In such a situation, both regularization by a sparsity prior and uncertainty estimates for the model parameters are essential. We apply our method to multi-electrode recordings of retinal ganglion cells and use our uncertainty estimate to test the statistical significance of functional couplings between neurons. Furthermore we used the sparsity of the Laplace prior to select those filters from a spike-triggered covariance analysis that are most informative about the neural response.

Bayesian Inference for Spiking Neuron Models with a Sparsity Prior

Identification of stimulus-response functions is a central problem in systems neuroscience and related areas. Prominent examples are the estimation of receptive fields and classification images [1]. In most cases, the relationship between a high-dimensional input and the system output is modeled by a linear (first-order) or quadratic (second-order) model. Models with third or higher order dependencies are seldom used, since both parameter estimation and model interpretation can become very difficult.

Nonlinear Receptive Field Analysis: Making Kernel Methods Interpretable

Right from the first synapse in the retina, the visual information gets distributed across several parallel channels with different temporal filtering properties (Wässle, 2004). Yet, the prevalent system identification tool for characterizing neural responses, the spike-triggered average, only allows one to investigate the individual neural responses independently of each other. Here, we present a novel data analysis tool for the identification of temporal population codes based on canonical correlation analysis (Hotelling, 1936). Canonical correlation analysis allows one to find ‘population receptive fields’ (PRF) which are maximally correlated with the temporal response of the entire neural population. The method is a convex optimization technique which essentially solves an eigenvalue problem and is not prone to local minima.

Identifying temporal population codes in the retina using canonical correlation analysis

Decision-Images: A tool for identifying critical stimulus features

Attempting to model human categorization and similarity judgements is both a very interesting but also an exceedingly difficult challenge. Some of the difficulty arises because of conflicting evidence whether human categorization and similarity judgements should or should not be modelled as to operate on a mental representation that is essentially metric. Intuitively, this has a strong appeal as it would allow (dis)similarity to be represented geometrically as distance in some internal space. Here we show how a single stimulus, carefully constructed in a psychophysical experiment, introduces l2 violations in what used to be an internal similarity space that could be adequately modelled as Euclidean. We term this one influential data point a conflictual judgement. We present an algorithm of how to analyse such data and how to identify the crucial point. Thus there may not be a strict dichotomy between either a metric or a non-metric internal space but rather degrees to which potentially large subsets of stimuli are represented metrically with a small subset causing a global violation of metricity.

Implications of correlated neuronal noise in decision making circuits for physiology and behavior

In patients suffering from retinal degenerative diseases such as retinitis pigmentosa, 
the photoreceptor cells in the retina deteriorate. However, the neurons in the diseased 
retina (retinal ganglion cells { RGCs) remain intact and are able to respond 
to stimuli. These neurons may be stimulated electrically to potentially restore rudimentary 
vision to those suffering from retinal degenerative diseases. However, the 
viability of such an approach would be limited by how reliably RGCs respond to 
electrical stimuli. Hence, the aim of this project was to develop computational approaches 
to quantify how variable RGC responses are to electrical stimulation. We 
used generalized linear models (GLMs) for this analysis. These models were used to 
assess the degree of nonstationarity, linear stimulus dependence and nonlinear stimulus 
dependence in the responses of different types of retinal ganglion cells. We show 
that while most RGCs are highly nonlinear in their responses, a marked fraction of 
the responses can be explained by assuming a linear dependence on the stimulus. 
We also found that, contrary to expectation, there were no significant differences in 
the non-stationarity, linearity or non-linearity between different RGC types.

Characterizing Retinal Ganglion Cell Responses toElectrical Stimulation

The classification of psychiatry to date is governed firstly by psychopathological symptoms and syndromes in addition to factors of personal and family history. It succeeded for the first time after discovering the serotonin-shortage syndrome, to correlate the different psychopathological conditions with a biochemical disturbance, as the result of which a new indication orientation based on a functional target syndrom could come about in psychiatry.

[Progress toward functional diagnosis in psychiatry. The serotonin deficiency syndrome].

Scientists and engineers employ stochastic numerical simulators to model empirically observed phenomena. In contrast to purely statistical models, simulators express scientific principles that provide powerful inductive biases, improve generalization to new data or scenarios and allow for fewer, more interpretable and domain-relevant parameters. Despite these advantages, tuning a simulator's parameters so that its outputs match data is challenging. Simulation-based inference (SBI) seeks to identify parameter sets that a) are compatible with prior knowledge and b) match empirical observations. Importantly, SBI does not seek to recover a single 'best' data-compatible parameter set, but rather to identify all high probability regions of parameter space that explain observed data, and thereby to quantify parameter uncertainty. In Bayesian terminology, SBI aims to retrieve the posterior distribution over the parameters of interest. In contrast to conventional Bayesian inference, SBI is also applicable when one can run model simulations, but no formula or algorithm exists for evaluating the probability of data given parameters, i.e. the likelihood. We present $\texttt{sbi}$, a PyTorch-based package that implements SBI algorithms based on neural networks. $\texttt{sbi}$ facilitates inference on black-box simulators for practising scientists and engineers by providing a unified interface to state-of-the-art algorithms together with documentation and tutorials.

Neural mechanisms of perceptual decision making have been extensively studied in experimental settings that mimic stable environments with repeating stimuli, fixed rules, and payoffs. In contrast, we live in an ever-changing environment and have varying goals and behavioral demands. To accommodate variability, our brain flexibly adjusts decision-making processes depending on context. Here, we review a growing body of research that explores the neural mechanisms underlying this flexibility. We highlight diverse forms of context dependency in decision making implemented through a variety of neural computations. Context-dependent neural activity is observed in a distributed network of brain structures, including posterior parietal, sensory, motor, and subcortical regions, as well as the prefrontal areas classically implicated in cognitive control. We propose that investigating the distributed network underlying flexible decisions is key to advancing our understanding and discuss a path forward for experimental and theoretical investigations. Expected final online publication date for the Annual Review of Physiology, Volume 85 is February 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Anomalous sensitivity enhancement of nano-graphitic electrochemical micro-sensors with reducing the operating voltage.

What do distinct parietal neural responses for face and motion discrimination tasks reveal about the mechanisms of the decision-making process?

While networks of neurons, glia and vascular systems enable and support brain functions, to date, mathematical tools to decode network dynamics and structure from very scarce and partially observed neuronal spiking behavior remain underdeveloped. Large neuronal networks contribute to the intrinsic neuron transfer function and observed neuronal spike trains encoding complex causal information processing, yet how this emerging causal fractal memory in the spike trains relates to the network topology is not fully understood. Towards this end, we propose a novel statistical physics inspired neuron particle model that captures the causal information flow and processing features of neuronal spiking activity. Relying on synthetic comprehensive simulations and real-world neuronal spiking activity analysis, the proposed fractional order operators governing the neuronal spiking dynamics provide insights into the memory and scale of the spike trains as well as information about the topological properties of the underlying neuronal networks. Lastly, the proposed model exhibits superior predictions of animal behavior during multiple cognitive tasks.

Neuron particles capture network topology and behavior from single units

Lateral intraparietal (LIP) neurons represent formation of perceptual decisions involving eye movements. In circuit models for these decisions, neural ensembles that encode actions compete to form decisions. Consequently, decision variables (DVs) are represented as partially potentiated action plans, where ensembles increase their average responses for stronger evidence supporting their preferred actions. As another consequence, DV representation and readout are implemented similarly for decisions with identical competing actions, irrespective of input and task context differences. Here, we challenge those core principles using a novel face-discrimination task, where LIP firing rates decrease with supporting evidence, contrary to conventional motion-discrimination tasks. These opposite response patterns arise from similar mechanisms in which decisions form along curved population-response manifolds misaligned with action representations. These manifolds rotate in state space based on task context, necessitating distinct readouts. We show similar manifolds in lateral and medial prefrontal cortices, suggesting a ubiquitous representational geometry across decision-making circuits.

The geometry of the representation of decision variable and stimulus difficulty in the parietal cortex

Technical advances in artificial manipulation of neural activity have precipitated a surge in studying the causal contribution of brain circuits to cognition and behavior. However, complexities of neural circuits challenge interpretation of experimental results, necessitating theoretical frameworks for system-atic explorations. Here, we take a step in this direction, using, as a testbed, recurrent neural networks trained to perform a perceptual decision. We show that understanding the computations implemented by network dynamics enables predicting the magnitude of perturbation effects based on changes in the network’s phase plane. Inactivation effects are weaker for distributed network architectures, are more easily discovered with non-discrete behavioral readouts (e.g., reaction times), and vary considerably across multiple tasks implemented by the same circuit. Finally, networks that can “learn” during inactivation recover function quickly, often much faster than the original training time. Our framework explains past empirical observations by clarifying how complex circuits compensate and adapt to perturbations.

Recurrent neural circuits overcome partial inactivation by compensation and re-learning

Representational geometry of perceptual decisions in the monkey parietal cortex

Visual object recognition relies on elaborate sensory processes that transform retinal inputs to object representations, but it also requires decision-making processes that read out object representations and function over prolonged time scales. The computational properties of these decision-making processes remain underexplored for object recognition. Here, we study these computations by developing a stochastic multifeature face categorization task. Using quantitative models and tight control of spatiotemporal visual information, we demonstrate that human subjects (five males, eight females) categorize faces through an integration process that first linearly adds the evidence conferred by task-relevant features over space to create aggregated momentary evidence and then linearly integrates it over time with minimum information loss. Discrimination of stimuli along different category boundaries (e.g., identity or expression of a face) is implemented by adjusting feature weights of spatial integration. This linear but flexible integration process over space and time bridges past studies on simple perceptual decisions to complex object recognition behavior. SIGNIFICANCE STATEMENT Although simple perceptual decision-making such as discrimination of random dot motion has been successfully explained as accumulation of sensory evidence, we lack rigorous experimental paradigms to study the mechanisms underlying complex perceptual decision-making such as discrimination of naturalistic faces. We develop a stochastic multifeature face categorization task as a systematic approach to quantify the properties and potential limitations of the decision-making processes during object recognition. We show that human face categorization could be modeled as a linear integration of sensory evidence over space and time. Our framework to study object recognition as a spatiotemporal integration process is broadly applicable to other object categories and bridges past studies of object recognition and perceptual decision-making.

Linear Integration of Sensory Evidence over Space and Time Underlies Face Categorization

Nano-engineering the material structure of preferentially oriented nano-graphitic carbon for making high-performance electrochemical micro-sensors

Seeing With a Few Photons: Bridging Cellular and Circuit Mechanisms With Perception

Goal-directed behavior requires integrating sensory information with prior knowledge about the environment. Behavioral biases that arise from these priors could increase positive outcomes when the priors match the true structure of the environment, but mismatches also happen frequently and could cause unfavorable outcomes. Biases that reduce gains and fail to vanish with training indicate fundamental suboptimalities arising from ingrained heuristics of the brain. Here, we report systematic, gain-reducing choice biases in highly-trained monkeys performing a motion direction discrimination task where only the current stimulus is behaviorally relevant. The monkey’s bias fluctuated at two distinct time scales: slow, spanning tens to hundreds of trials, and fast, arising from choices and outcomes of the most recent trials. Our finding enabled single trial prediction of biases, which influenced the choice especially on trials with weak stimuli. The pre-stimulus activity of neuronal ensembles in the monkey prearcuate gyrus represented these biases as an offset along the decision axis in the state space. This offset persisted throughout the stimulus viewing period, when sensory information was integrated, leading to a biased choice. The pre-stimulus representation of history-dependent bias was functionally indistinguishable from the neural representation of upcoming choice before stimulus onset, validating our model of single-trial biases and suggesting that pre-stimulus representation of choice could be fully defined by biases inferred from behavioral history. Our results indicate that the prearcuate gyrus reflects intrinsic heuristics that compute bias signals, as well as the mechanisms that integrate them into the oculomotor decision-making process.

Prefrontal cortex represents heuristics that shape choice bias and its integration into future behavior

A crucial challenge in targeted manipulation of neural activity is to identify perturbation sites whose stimulation exerts significant effects downstream (high efficacy), a procedure currently achieved by labor-intensive trial-and-error. Targeted perturbations will be greatly facilitated by understanding causal interactions within neural ensembles and predicting the efficacy of perturbation sites before intervention. Here, we address this issue by developing a computational framework to predict how single-site micorstimulation alters the ensemble spiking activity in an alert monkey’s prefrontal cortex. Our framework uses delay embedding techniques to infer the ensemble’s functional causal flow (FCF) based on the functional interactions inferred at rest. We validate FCF using ground truth data from models of cortical circuits, showing that FCF is robust to noise and can be inferred from brief recordings of even a small fraction of neurons in the circuit. A detailed comparison of FCF with several alternative methods, including Granger causality and transfer entropy, highlighted the advantages of FCF in predicting perturbation effects on empirical data. Our results provide the foundation for using targeted circuit manipulations to develop targeted interventions suitable for brain-machine interfaces and ameliorating cognitive dysfunctions in the human brain.

Predicting perturbation effects from resting activity using functional causal flow

Significance We present a theory of neural circuits’ design and function, inspired by the random connectivity of real neural circuits and the mathematical power of random projections. Specifically, we introduce a family of statistical models for large neural population codes, a straightforward neural circuit architecture that would implement these models, and a biologically plausible learning rule for such circuits. The resulting neural architecture suggests a design principle for neural circuit—namely, that they learn to compute the mathematical surprise of their inputs, given past inputs, without an explicit teaching signal. We applied these models to recordings from large neural populations in monkeys’ visual and prefrontal cortices and show them to be highly accurate, efficient, and scalable. The brain represents and reasons probabilistically about complex stimuli and motor actions using a noisy, spike-based neural code. A key building block for such neural computations, as well as the basis for supervised and unsupervised learning, is the ability to estimate the surprise or likelihood of incoming high-dimensional neural activity patterns. Despite progress in statistical modeling of neural responses and deep learning, current approaches either do not scale to large neural populations or cannot be implemented using biologically realistic mechanisms. Inspired by the sparse and random connectivity of real neuronal circuits, we present a model for neural codes that accurately estimates the likelihood of individual spiking patterns and has a straightforward, scalable, efficient, learnable, and realistic neural implementation. This model’s performance on simultaneously recorded spiking activity of >100 neurons in the monkey visual and prefrontal cortices is comparable with or better than that of state-of-the-art models. Importantly, the model can be learned using a small number of samples and using a local learning rule that utilizes noise intrinsic to neural circuits. Slower, structural changes in random connectivity, consistent with rewiring and pruning processes, further improve the efficiency and sparseness of the resulting neural representations. Our results merge insights from neuroanatomy, machine learning, and theoretical neuroscience to suggest random sparse connectivity as a key design principle for neuronal computation.

Learning probabilistic neural representations with randomly connected circuits

Bayesian inference with incomplete knowledge explains perceptual confidence and its deviations from accuracy

The subthalamic nucleus (STN) is theorized to globally suppress movement through connections with downstream basal ganglia structures. Current theories are supported by increased STN activity when subjects withhold an uninitiated action plan, but a critical test of these theories requires studying STN responses when an ongoing action is replaced with an alternative. Here, we perform this test using an extended reaching task with instructions to switch movement trajectory mid-action. We show that STN activity decreases during action switches, contrary to prevalent theories. Further, beta oscillations in the local field potential in STN, which are associated with movement inhibition do not show increased power or entraining of neuronal firing during switches. We report an inhomogeneous population neural code in STN, with one sub-population encoding movement kinematics and direction and another encoding unexpected action switches. We suggest an elaborate neural code in STN that contributes to planning actions and changing the plans.

Distinct population code for movement kinematics and changes of ongoing movements in human subthalamic nucleus

An integral feature of human memory is the ability to recall past events. What distinguishes such episodic memory from associative and semantic memories is the joint encoding and retrieval of “what,” “where,” and “when” (WWW) of events. Here, we investigated whether the WWW components of episodes are retrieved with equal fidelity. Using a novel task where human participants were probed on the WWW components of a recently-viewed synthetic movie, we found fundamental differences in mnemonic accuracy between these components. The memory of “when” had the lowest accuracy and was most severely influenced by primacy and recency. Further, the memory of “when” and “where” were most susceptible to interference due to changes in memory load. These findings suggest that episodes are not stored and retrieved as a coherent whole. Rather, memory components preserve a degree of independence, suggesting that remembering coherent episodes is an active reconstruction process.

Differences in memory for what, where, and when components of recently-formed episodes

: Targeted manipulation of neural activity will be greatly facilitated by understanding causal interactions within neural ensembles. Here, we introduce a novel statistical method to infer a network’s “functional causal ﬂow” (FCF) from ensemble neural recordings. Using ground truth data from models of cortical circuits, we show that FCF captures functional hierarchies in the ensemble and reliably predicts the eﬀects of perturbing individual neurons or neural clusters. Critically, FCF is robust to noise and can be inferred from the activity of even a small fraction of neurons in the circuit. It thereby permits accurate prediction of circuit perturbation eﬀects with existing recording technologies for the primate brain. We conﬁrm this prediction by recording changes in the prefrontal ensemble spiking activity of alert monkeys in response to single-electrode microstimulation. Our results provide a foundation for using targeted circuit manipulations to develop new brain-machine interfaces or ameliorate cognitive dysfunctions in the human brain.

Predicting perturbation eﬀects from resting state activity using functional causal ﬂow

Designing and Interpreting Psychophysical Investigations of Cognition

We studied the fine temporal structure of spiking patterns of groups of up to 100 simultaneously recorded units in the prefrontal cortex of monkeys performing a visual discrimination task. We characterized the vocabulary of population activity patterns using 10 ms time bins and found that different sets of population activity patterns (codebooks) are used in different task epochs and that spiking correlations between units play a large role in defining those codebooks. Models that ignore those correlations fail to capture the population codebooks in all task epochs. Further, we show that temporal sequences of population activity patterns have strong history-dependence and are governed by different transition probabilities between patterns and different correlation time scales, in the different task epochs, suggesting different computational dynamics governing each epoch. Together, the large impact of spatial and temporal correlations on the dynamics of the population code makes the observed sequences of activity patterns many orders of magnitude more likely to appear than predicted by models that ignore these correlations and rely only on the population rates. Surprisingly, however, models that ignore these correlations perform quite well for decoding behavior from population responses. The difference of encoding and decoding complexity of the neural codebook suggests that one of the goals of the complex encoding scheme in the prefrontal cortex is to accommodate simple decoders that do not have to learn correlations.

Strongly correlated spatiotemporal encoding and simple decoding in the prefrontal cortex

Graphene Electrodes: Quantitative Principles for Precise Engineering of Sensitivity in Graphene Electrochemical Sensors (Adv. Mater. 6/2019)

Perceptual systems adapt to their inputs. As a result, prolonged exposure to particular stimuli alters judgments about subsequent stimuli. This phenomenon is commonly assumed to be sensory in origin. Changes in the decision-making process, however, may also be a component of adaptation. Here, we quantify sensory and decision-making contributions to adaptation in a facial expression paradigm. As expected, exposure to happy or sad expressions shifts the psychometric function toward the adaptor. More surprisingly, response times show both an overall decline and an asymmetry, with faster responses opposite the adapting category, implicating a substantial change in the decision-making process. Specifically, we infer that sensory changes from adaptation are accompanied by changes in how much sensory information is accumulated for the two choices. We speculate that adaptation influences implicit expectations about the stimuli one will encounter, causing modifications in the decision-making process as part of a normative response to a change in context.

Sensory and decision-making processes underlying perceptual adaptation

A major practical barrier for implementing carbon-based electrode arrays with high device-packing density is to ensure large, predictable, and homogeneous sensitivities across the array. Overcoming this barrier depends on quantitative models to predict electrode sensitivity from its material structure. However, such models are currently lacking. Here, we show that the sensitivity of multilayer graphene electrodes increases linearly with the average point defect density, whereas it is unaffected by line defects or oxygen-containing groups. These quantitative relationships persist until the electrode material transitions to a fully disordered sp carbon, where sensitivity declines sharply. We show that our results generalize to a variety of graphene production methods and use them to derive a predictive model that guides nano-engineering graphene structure for optimum sensitivity. Our approach achieves reproducible fabrication of miniaturized sensors with extraordinarily higher sensitivity than conventional material. These results lay the foundation for new integrated electrochemical sensor arrays based on nano-engineered graphene.

Quantitative principles for precise engineering of sensitivity in carbon-based electrochemical sensors

A major difficulty in implementing carbon‐based electrode arrays with high device‐packing density is to ensure homogeneous and high sensitivities across the array. Overcoming this obstacle requires quantitative microscopic models that can accurately predict electrode sensitivity from its material structure. Such models are currently lacking. Here, it is shown that the sensitivity of graphene electrodes to dopamine and serotonin neurochemicals in fast‐scan cyclic voltammetry measurements is strongly linked to point defects, whereas it is unaffected by line defects. Using the physics of point defects in graphene, a microscopic model is introduced that explains how point defects determine sensitivity. The predictions of this model match the empirical observation that sensitivity linearly increases with the density of point defects. This model is used to guide the nanoengineering of graphene structures for optimum sensitivity. This approach achieves reproducible fabrication of miniaturized sensors with extraordinarily higher sensitivity than conventional materials. These results lay the foundation for new integrated electrochemical sensor arrays based on nanoengineered graphene.

Quantitative Principles for Precise Engineering of Sensitivity in Graphene Electrochemical Sensors

The brain represents and reasons probabilistically about complex stimuli and motor actions using a noisy, spike-based neural code. A key building block for such neural computations, as well as the basis for supervised and unsupervised learning, is the ability to estimate the surprise or likelihood of incoming high-dimensional neural activity patterns. Despite progress in statistical modeling of neural responses and deep learning, current approaches either do not scale to large neural populations or cannot be implemented using biologically realistic mechanisms. Inspired by the sparse and random connectivity of real neuronal circuits, we present a new model for neural codes that accurately estimates the likelihood of individual spiking patterns and has a straightforward, scalable, efficiently learnable, and realistic neural implementation. This model’s performance on simultaneously recorded spiking activity of >100 neurons in the monkey visual and prefrontal cortices is comparable or better than that of current models. Importantly, the model can be learned using a small number of samples, and using a local learning rule that utilizes noise intrinsic to neural circuits. Slower, structural changes in random connectivity, consistent with rewiring and pruning processes, further improve the efficiency and sparseness of the resulting neural representations. Our results merge insights from neuroanatomy, machine learning, and theoretical neuroscience to suggest random sparse connectivity as a key design principle for neuronal computation.

Learning probabilistic representations with randomly connected neural circuits

Studies in multiple species have revealed the existence of neural signals that lawfully co-vary with different aspects of the decision-making process, including choice, sensory evidence that supports the choice, and reaction time. These signals, often interpreted as the representation of a decision variable (DV), have been identified in several motor preparation circuits and provide insight about mechanisms underlying the decision-making process. However, single-trial dynamics of this process or its representation at the neural population level remain poorly understood. Here, we examine the representation of the DV in simultaneously recorded neural populations of dorsal premotor (PMd) and primary motor (M1) cortices of monkeys performing a random dots direction discrimination task with arm movements as the behavioral report. We show that single-trial DVs covary with stimulus difficulty in both areas but are stronger and appear earlier in PMd compared to M1 when the stimulus duration is fixed and predictable. When temporal uncertainty is introduced by making the stimulus duration variable, single-trial DV dynamics are accelerated across the board and the two areas become largely indistinguishable throughout the entire trial. These effects are not trivially explained by the faster emergence of motor kinematic signals in PMd and M1. All key aspects of the data were replicated by a computational model that relies on progressive recruitment of units with stable choice-related modulation of neural population activity. In contrast with several recent results in rodents, decision signals in PMd and M1 are not carried by short sequences of activity in non-overlapping groups of neurons but are instead distributed across many neurons, which once recruited, represent the decision stably during individual behavioral epochs of the trial.

Population dynamics of choice representation in dorsal premotor and primary motor cortex

When multiple pieces of information bear on a decision, the best approach is to combine the evidence provided by each one. Evidence integration models formalize the computations underlying this process [1–3], explain human perceptual discrimination behavior [4–11], and correspond to neuronal responses elicited by discrimination tasks [12–17]. These findings indicate that evidence integration is key to understanding the neural basis of decision-making [18–21]. Evidence integration has most often been studied with simple tasks that limit the timescale of deliberation to hundreds of milliseconds, but many natural decisions unfold over much longer durations. Because neural network models imply acute limitations on the timescale of evidence integration [22–26], it is unknown whether current computational insights can generalize beyond rapid judgments. Here, we introduce a new psychophysical task and report model-based analyses of human behavior that demonstrate evidence integration at long timescales. Our task requires probabilistic inference using brief samples of visual evidence that are separated in time by long and unpredictable gaps. We show through several quantitative assays how decision-making can approximate a normative integration process that extends over tens of seconds without accruing significant memory leak or noise. These results support the generalization of evidence integration models to a broader class of behaviors while posing new challenges for models of how these computations are implemented in biological networks.

Decision-making through integration of sensory evidence at prolonged timescales

When multiple pieces of information bear on a decision, the best approach is to integrate the evidence provided by each one. Signatures of evidence integration have been identified in neuronal responses during decision formation, leading many investigations of how the brain produces complex behavior to focus on these computations. Yet, because evidence integration has most often been studied in simple tasks with short timescales of deliberation, it is unknown whether these models can provide a general account of decision-making. Here, we introduce a novel psychophysical paradigm with a long and discontinuous timescale of evidence availability. We show that choice behavior in this task reflects an evidence integration process that can extend over tens of seconds without loss of information due to memory leak or noise. Our results reveal that temporally-extended decisions approximate the normative computations used for rapid sensory discrimination, validating the generality of the evidence integration framework for modeling human cognition.

Psychophysical reverse correlation reflects both sensory and decision-making processes

Decision Making through Integration of Sensory Evidence at Prolonged Timescales

When the visual system analyses distributed patterns of sensory inputs, what features of those distributions does it use? It has been previously demonstrated that higher-order statistical moments of luminance distributions influence perception of static surfaces and textures. Here, we tested whether the brain also represents higher-order moments of dynamic stimuli. We constructed random dot kinematograms where dots moved according to probability distributions that selectively differed in terms of their mean, variance, skewness, or kurtosis. When viewing these stimuli, human observers were sensitive to the mean direction of coherent motion and to the variance of the individual dot displacement angles, but they were insensitive to skewness and kurtosis. Observer behavior accorded with a model of directional motion energy, suggesting that information about higher-order moments is discarded early in the visual processing hierarchy. These results demonstrate that use of higher-order moments is not a general property of visual perception.

Perceptual insensitivity to higher-order statistical moments of coherent random dot motion

(Invited) A Hybrid CMOS-Graphene Integrated Sensing Platform for Subsecond Dopamine Detection

Understanding dopamine (DA) signaling in the brain is essential for advancing our knowledge of pathological disorders such as drug addiction, Parkinson's disease, and schizophrenia. Currently, fast-scan cyclic voltammetry (FSCV) with carbon microfiber (CMF) electrodes is the method of choice in neuroscience labs for monitoring the concentration of phasic (transient) DA release. This method offers sub-second temporal resolution and high specificity because the signal of interest occurs at a known potential. However, existing CMF electrodes are bulky, limiting the spatial resolution to single-site measurements. Further, they are produced through manual processes (e.g. cutting CMFs under optical microscope), thus introducing significant device variability [1]. Lastly, when long probes (3-to-5cm) are used to monitor DA release in deep brain structures of large animals, environmental noise severely diminishes the detection limit [1]. To address these problems, we combine advances in nanofabrication with silicon chip manufacturing to create a heterogeneous integrated CMOS-graphene sensor for accurate measurement of DA with high spatiotemporal resolution (Fig. 15.7.1).

15.7 Heterogeneous integrated CMOS-graphene sensor array for dopamine detection

We introduce a hybrid CMOS-graphene sensor array for subsecond measurement of dopamine via fast-scan cyclic voltammetry (FSCV). The prototype chip has four independent CMOS readout channels, fabricated in a 65-nm process. Using planar multilayer graphene as biologically compatible sensing material enables integration of miniaturized sensing electrodes directly above the readout channels. Taking advantage of the chemical specificity of FSCV, we introduce a region of interest technique, which subtracts a large portion of the background current using a programmable low-noise constant current at about the redox potentials. We demonstrate the utility of this feature for enhancing the sensitivity by measuring the sensor response to a known dopamine concentration in vitro at three different scan rates. This strategy further allows us to significantly reduce the dynamic range requirements of the analog-to-digital converter (ADC) without compromising the measurement accuracy. We show that an integrating dual-slope ADC is adequate for digitizing the background-subtracted current. The ADC operates at a sampling frequency of 5–10 kHz and has an effective resolution of about 60 pA, which corresponds to a theoretical dopamine detection limit of about 6 nM. Our hybrid sensing platform offers an effective solution for implementing next-generation FSCV devices that can enable precise recording of dopamine signaling in vivo on a large scale.

Hybrid CMOS-Graphene Sensor Array for Subsecond Dopamine Detection

Neural Mechanisms of Post-error Adjustments of Decision Policy in Parietal Cortex

17 Object categories are recognized at multiple levels of hierarchical abstractions. 18 Psychophysical studies have shown a more rapid perceptual access to the mid-level 19 category information (e.g. human faces) than the higher (superordinate; e.g. animal) or 20 the lower (subordinate; e.g. face identity) levels. Mid-level category members share many 21 features while few features are shared between members of different mid-level 22 categories. To better understand the neural basis of expedited access to mid-level 23 category information we examined neural responses of the inferior temporal (IT) cortex 24 of macaque monkeys viewing a large number of object images. We found an earlier 25 representation of mid-level categories in the IT population and single unit responses 26 compared to superordinate and subordinate level categories. The short latency 27 representation of mid-level category information shows that visual cortex first divides the 28 category shape space at its sharpest boundaries defined by high/low within/between 29 group similarity. This short latency mid-level category boundary map may be prerequisite 30 for representation of other categories at more global and finer scales. 31 32

Title : Temporal dynamics of visual category representation in the macaque inferior temporal 2 cortex 3 Author names :

Editorial overview: Neurobiology of cognitive behavior: Complexity of neural computation and cognition

Consciousness encompasses a variety of functions and properties, such as awakening, awareness, and subjective aspects of both perception and volition (e.g., qualia and authorship, respectively). It remains to be seen whether these diverse functions are related to one another through common neural mechanisms, and if so how. Here, we advance the thesis that the neural mechanisms that give rise to conscious states share features with neural mechanisms that underlie simpler forms of decisions. The neurobiology of decision-making provides detailed insight into how the brain deliberates and reasons from evidence to make choices. The underlying mechanisms, mainly studied in animals, could support a variety of complex cognitive functions that probably operate independently of many aspects of consciousness. For example, many complex decisions in humans rely upon wakefulness but not upon awareness or authorship. In animal studies, decisions are typically embodied: they can be described as selection among possible actions. By substituting “circuits” for “actions” in the preceding phrase, we generalize from “deciding to do” to “deciding to consider” or, more generally, “deciding to decide to. . ..” This is an appealing notion from the perspective of brain evolution, because it allows us to recognize ideation as an elaboration of a simpler sensory-motor design. We propose that many of the functions of consciousness are simply ways of engaging the environment. Thus consciousness might be mediated by (nonconscious) decisions to engage, as in awakening, or to engage in a certain way, as when attaching narrative to action. Although the neural mechanisms underlying “decisions to engage” are unknown, they are likely to involve intralaminar (and matrix) thalamus and processes that “decide” to turn other circuits on. This idea invites an analogy between the functions of brain regions that project to M.N. Shadlen (*) HHMI and Department of Physiology and Biophysics, University of Washington, Seattle, WA 98115, USA e-mail: shadlen@u.washington.edu S. Dehaene and Y. Christen (eds.), Characterizing Consciousness: From Cognition to the Clinic? Research and Perspectives in Neurosciences, DOI 10.1007/978-3-642-18015-6_2, # Springer-Verlag Berlin Heidelberg 2011 27 matrix thalamus, including the “default system”, and the role of parietal cortex in perceptual decisions. While highly speculative, we think “decision to engage” provides a biologically plausible and computationally coherent hypothesis about the neural correlates of consciousness.

Characterizing Consciousness: From Cognition to the Clinic?-ReadingSample

Confidence Is the Bridge b etween Multi-stage Decisions Graphical

Latimer et al. (Reports, 10 July 2015, p. 184) claim that during perceptual decision formation, parietal neurons undergo one-time, discrete steps in firing rate instead of gradual changes that represent the accumulation of evidence. However, that conclusion rests on unsubstantiated assumptions about the time window of evidence accumulation, and their stepping model cannot explain existing data as effectively as evidence-accumulation models.

Comment on “Single-trial spike trains in parietal cortex reveal discrete steps during decision-making”

Three challenges for connecting model to mechanism in decision-making

Significance Decisions are guided by available information and strategies that link information to action. Following a bad outcome, two potential sources of error—flawed strategy and poor information—must be distinguished to improve future performance. In a direction discrimination task where subjects decide by accumulating sensory evidence to a bound, we show that humans disambiguate sources of error by integrating expected accuracy and outcome over multiple choices. The strategy switches when the integral reaches a threshold. A hierarchy of decision processes in which lower levels integrate sensory evidence over short timescales, and higher levels interact with lower levels over longer timescales, quantitatively explains the behavior. Expected accuracy links these two levels and enables adaptive changes of decision strategy. Decision-making in a natural environment depends on a hierarchy of interacting decision processes. A high-level strategy guides ongoing choices, and the outcomes of those choices determine whether or not the strategy should change. When the right decision strategy is uncertain, as in most natural settings, feedback becomes ambiguous because negative outcomes may be due to limited information or bad strategy. Disambiguating the cause of feedback requires active inference and is key to updating the strategy. We hypothesize that the expected accuracy of a choice plays a crucial rule in this inference, and setting the strategy depends on integration of outcome and expectations across choices. We test this hypothesis with a task in which subjects report the net direction of random dot kinematograms with varying difficulty while the correct stimulus−response association undergoes invisible and unpredictable switches every few trials. We show that subjects treat negative feedback as evidence for a switch but weigh it with their expected accuracy. Subjects accumulate switch evidence (in units of log-likelihood ratio) across trials and update their response strategy when accumulated evidence reaches a bound. A computational framework based on these principles quantitatively explains all aspects of the behavior, providing a plausible neural mechanism for the implementation of hierarchical multiscale decision processes. We suggest that a similar neural computation—bounded accumulation of evidence—underlies both the choice and switches in the strategy that govern the choice, and that expected accuracy of a choice represents a key link between the levels of the decision-making hierarchy.

Hierarchical decision processes that operate over distinct timescales underlie choice and changes in strategy

Object categories are recognized at multiple levels of hierarchical abstractions. Psychophysical studies have shown a more rapid perceptual access to the mid-level category information (e.g., human faces) than the higher (superordinate; e.g., animal) or the lower (subordinate; e.g., face identity) level. Mid-level category members share many features, whereas few features are shared among members of different mid-level categories. To understand better the neural basis of expedited access to mid-level category information, we examined neural responses of the inferior temporal (IT) cortex of macaque monkeys viewing a large number of object images. We found an earlier representation of mid-level categories in the IT population and single-unit responses compared with superordinate- and subordinate-level categories. The short-latency representation of mid-level category information shows that visual cortex first divides the category shape space at its sharpest boundaries, defined by high/low within/between-group similarity. This short-latency, mid-level category boundary map may be a prerequisite for representation of other categories at more global and finer scales.

Temporal dynamics of visual category representation in the macaque inferior temporal cortex.

Decisions are accompanied by a degree of confidence that a selected option is correct. A sequential sampling framework explains the speed and accuracy of decisions and extends naturally to the confidence that the decision rendered is likely to be correct. However, discrepancies between confidence and accuracy suggest that confidence might be supported by mechanisms dissociated from the decision process. Here we show that this discrepancy can arise naturally because of simple processing delays. When participants were asked to report choice and confidence simultaneously, their confidence, reaction time and a perceptual decision about motion were explained by bounded evidence accumulation. However, we also observed revisions of the initial choice and/or confidence. These changes of mind were explained by a continuation of the mechanism that led to the initial choice. Our findings extend the sequential sampling framework to vacillation about confidence and invites caution in interpreting dissociations between confidence and accuracy. DOI: http://dx.doi.org/10.7554/eLife.12192.001

A common mechanism underlies changes of mind about decisions and confidence

Natural Grouping of Neural Responses Reveals Spatially Segregated Clusters in Prearcuate Cortex

Effects of Cortical Microstimulation on Confidence in a Perceptual Decision

Dynamics of Neural Population Responses in Prefrontal Cortex Indicate Changes of Mind on Single Trials

Errata to Effects of cortical microstimulation on confidence in a perceptual decision [Neuron 83, (2014) 797-804]

The quantitative study of decision-making has traditionally rested on three key behavioral measures: accuracy, response time, and confidence. Of these, confidence--defined as the degree of belief, prior to feedback, that a decision is correct-is least well understood at the level of neural mechanism, although recent years have seen a surge in interest in the topic among theoretical and systems neuroscientists. Here we review some of these developments and highlight a particular candidate mechanism for assigning confidence in a perceptual decision. The mechanism is appealing because it is rooted in the same decision-making framework--bounded accumulation of evidence--that successfully explains accuracy and reaction time in many tasks, and it is validated by neurophysiology and microstimulation experiments.

Predicting the Accuracy of a Decision: A Neural Mechanism of Confidence.

Decision making often involves a tradeoff between speed and accuracy. Previous studies indicate that neural activity in the lateral intraparietal area (LIP) represents the gradual accumulation of evidence toward a threshold level, or evidence bound, which terminates the decision process. The level of this bound is hypothesized to mediate the speed-accuracy tradeoff. To test this, we recorded from LIP while monkeys performed a motion discrimination task in two speed-accuracy regimes. Surprisingly, the terminating threshold levels of neural activity were similar in both regimes. However, neurons recorded in the faster regime exhibited stronger evidence-independent activation from the beginning of decision formation, effectively reducing the evidence-dependent neural modulation needed for choice commitment. Our results suggest that control of speed vs accuracy may be exerted through changes in decision-related neural activity itself rather than through changes in the threshold applied to such neural activity to terminate a decision. DOI: http://dx.doi.org/10.7554/eLife.02260.001

A neural mechanism of speed-accuracy tradeoff in macaque area LIP

We have calculated the intrinsic dimensionality of visual object representations in anterior inferotemporal (AIT) cortex, based on responses of a large sample of cells stimulated with photographs of diverse objects. Because dimensionality was dependent on data set size, we determined asymptotic dimensionality as both the number of neurons and number of stimulus image approached infinity. Our final dimensionality estimate was 93 (SD: 11), indicating that there is basis set of approximately 100 independent features that characterize the dimensions of neural object space. We believe this is the first estimate of the dimensionality of neural visual representations based on single-cell neurophysiological data. The dimensionality of AIT object representations was much lower than the dimensionality of the stimuli. We suggest that there may be a gradual reduction in the dimensionality of object representations in neural populations going from retina to inferotemporal cortex as receptive fields become increasingly complex.

Dimensionality of Object Representations in Monkey Inferotemporal Cortex

Author response: A neural mechanism of speed-accuracy tradeoff in macaque area LIP

Episodic recollection entails the conscious remembrance of event details associated with previously encountered stimuli. Recollection depends on both the establishment of cortical representations of event features during stimulus encoding and the cortical reinstatement of these representations at retrieval. Here, we used multivoxel pattern analyses of functional magnetic resonance imaging data to examine how cortical and hippocampal activity at encoding and retrieval drive recollective memory decisions. During encoding, words were associated with face or scene source contexts. At retrieval, subjects were cued to recollect the source associate of each presented word. Neurally derived estimates of encoding strength and pattern reinstatement in occipitotemporal cortex were computed for each encoding and retrieval trial, respectively. Analyses demonstrated that (1) cortical encoding strength predicted subsequent memory accuracy and reaction time, (2) encoding strength predicted encoding-phase hippocampal activity, and (3) encoding strength and retrieval-phase hippocampal activity predicted the magnitude of cortical reinstatement. Path analyses further indicated that cortical reinstatement partially mediated both the effect of cortical encoding strength and the effect of retrieval-phase hippocampal activity on subsequent source memory performance. Taken together, these results indicate that memory-guided decisions are driven in part by a pathway leading from hippocampally linked cortical encoding of event attributes to hippocampally linked cortical reinstatement at retrieval.

Cortical reinstatement mediates the relationship between content-specific encoding activity and subsequent recollection decisions.

Behavioral The Behavioral Effects of Adaptation to Facial Expressions are Explained by Changes in the Decision-Making Process

Many decisions involve integration of evidence conferred by discrete cues over time. However, the neural mechanism of this integration is poorly understood. Several decision-making models suggest that integration of evidence is implemented by a dynamic system whose state evolves toward a stable point representing the decision outcome. The internal dynamics of such point attractor models render them sensitive to the temporal gaps between cues because their internal forces push the state forward once it is dislodged from the initial stable point. We asked whether human subjects are as sensitive to such temporal gaps. Subjects reported the net direction of stochastic random dot motion, which was presented in one or two brief observation windows (pulses). Pulse strength and interpulse interval varied randomly from trial to trial. We found that subjects' performance was largely invariant to the interpulse intervals up to at least 1 s. The findings question the implementation of the integration process via mechanisms that rely on autonomous changes of network state. The mechanism should be capable of freezing the state of the network at a variety of firing rate levels during temporal gaps between the cues, compatible with a line of stable attractor states.

Integration of Direction Cues Is Invariant to the Temporal Gap between Them

Keiji Tanaka cortex to object stimuli Statistics of visual responses in primate inferotemporal

As we shift our gaze to explore the visual world, information enters cortex in a sequence of successive snapshots, interrupted by phases of blur. Our experience, in contrast, appears like a movie of a continuous stream of objects embedded in a stable world. This perception of stability across eye movements has been linked to changes in spatial sensitivity of visual neurons anticipating the upcoming saccade, often referred to as shifting receptive fields (Duhamel et al., 1992; Walker et al., 1995; Umeno and Goldberg, 1997; Nakamura and Colby, 2002). How exactly these receptive field dynamics contribute to perceptual stability is currently not clear. Anticipatory receptive field shifts toward the future, postsaccadic position may bridge the transient perisaccadic epoch (Sommer and Wurtz, 2006; Wurtz, 2008; Melcher and Colby, 2008). Alternatively, a presaccadic shift of receptive fields toward the saccade target area (Tolias et al., 2001) may serve to focus visual resources onto the most relevant objects in the postsaccadic scene (Hamker et al., 2008). In this view, shifts of feature detectors serve to facilitate the processing of the peripheral visual content before it is foveated. While this conception is consistent with previous observations on receptive field dynamics and on perisaccadic compression (Ross et al., 1997; Morrone et al., 1997; Kaiser and Lappe, 2004), it predicts that receptive fields beyond the saccade target shift toward the saccade target rather than in the direction of the saccade. We have tested this prediction in human observers via the presaccadic transfer of the tilt-aftereffect (Melcher, 2007).

Anticipatory Saccade Target Processing and the Presaccadic Transfer of Visual Features

We have characterized selectivity and sparseness in anterior inferotemporal cortex, using a large data set. Responses were collected from 674 monkey inferotemporal cells, each stimulated by 806 object photographs. This 806 × 674 matrix was examined in two ways: columnwise, looking at responses of a single neuron to all images (single-neuron selectivity), and rowwise, looking at the responses of all neurons caused by a single image (population sparseness). Selectivity and sparseness were measured as kurtosis of probability distributions. Population sparseness exceeded single-neuron selectivity, with specific values dependent on the size of the data sample. This difference was principally caused by inclusion, within the population, of neurons with a variety of dynamic ranges (standard deviations of responses over all images). Statistics of large responses were examined by quantifying how quickly the upper tail of the probability distribution decreased (tail heaviness). This analysis demonstrated that population responses had heavier tails than single-neuron responses, consistent with the difference between sparseness and selectivity measurements. Population responses with spontaneous activity subtracted had the heaviest tails, following a power law. The very light tails of single-neuron responses indicate that the critical feature for each neuron is simple enough to have a high probability of occurring within a limited stimulus set. Heavy tails of population responses indicate that there are a large number of different critical features to which different neurons are tuned. These results are inconsistent with some structural models of object recognition that posit that objects are decomposed into a small number of standard features.

Statistics of visual responses in primate inferotemporal cortex to object stimuli.

Variance as a Signature of Neural Computations during Decision Making

Decisions are often based on a combination of new evidence with prior knowledge of the probable best choice. Optimal combination requires knowledge about the reliability of evidence, but in many realistic situations, this is unknown. Here we propose and test a novel theory: the brain exploits elapsed time during decision formation to combine sensory evidence with prior probability. Elapsed time is useful because (1) decisions that linger tend to arise from less reliable evidence, and (2) the expected accuracy at a given decision time depends on the reliability of the evidence gathered up to that point. These regularities allow the brain to combine prior information with sensory evidence by weighting the latter in accordance with reliability. To test this theory, we manipulated the prior probability of the rewarded choice while subjects performed a reaction-time discrimination of motion direction using a range of stimulus reliabilities that varied from trial to trial. The theory explains the effect of prior probability on choice and reaction time over a wide range of stimulus strengths. We found that prior probability was incorporated into the decision process as a dynamic bias signal that increases as a function of decision time. This bias signal depends on the speed–accuracy setting of human subjects, and it is reflected in the firing rates of neurons in the lateral intraparietal area (LIP) of rhesus monkeys performing this task.

Elapsed Decision Time Affects the Weighting of Prior Probability in a Perceptual Decision Task

3 Abstract Consciousness encompasses a variety of functions and properties, such 4 as awakening, awareness, and subjective aspects of both perception and volition 5 (e.g., qualia and authorship, respectively). It remains to be seen whether these 6 diverse functions are related to one another through common neural mechanisms, 7 and if so how. Here, we advance the thesis that the neural mechanisms that give rise 8 to conscious states share features with neural mechanisms that underlie simpler 9 forms of decisions. The neurobiology of decision-making provides detailed insight 10 into how the brain deliberates and reasons from evidence to make choices. The 11 underlying mechanisms, mainly studied in animals, could support a variety of 12 complex cognitive functions that probably operate independently of many aspects 13 of consciousness. For example, many complex decisions in humans rely upon 14 wakefulness but not upon awareness or authorship. In animal studies, decisions 15 are typically embodied: they can be described as selection among possible actions. 16 By substituting “circuits” for “actions” in the preceding phrase, we generalize from 17 “deciding to do” to “deciding to consider” or, more generally, “deciding to decide 18 to. . ..” This is an appealing notion from the perspective of brain evolution, because 19 it allows us to recognize ideation as an elaboration of a simpler sensory-motor 20 design. We propose that many of the functions of consciousness are simply ways 21 of engaging the environment. Thus consciousness might be mediated by (non22 conscious) decisions to engage, as in awakening, or to engage in a certain way, as 23 when attaching narrative to action. Although the neural mechanisms underlying 24 “decisions to engage” are unknown, they are likely to involve intralaminar (and 25 matrix) thalamus and processes that “decide” to turn other circuits on. This 26 idea invites an analogy between the functions of brain regions that project to

Exploring visual object representations with similarity-matrix analysis

Bounded accumulation of evidence in parietal cortex: A flexible neural mechanism for making decisions and estimating certainty

Decisive Monkeys Decision-making is a central theme in current research in cognitive neuroscience. Behavioral protocols have provided an entry into explorations of the neural processes that underlie decision-making. Empirical studies have provided support for a diffusion model in which information accumulates over time until a threshold is reached, with noisiness in the inputs related to decision errors. Kiani and Shadlen (p. 759) developed a behavioral task to study choice certainty and identified the corresponding neuronal representations in monkeys. The monkeys were allowed to choose to opt out of an uncertain, higher reward choice in favor of a certain, lower payoff. The same neurons that encoded the information used to make a choice also encoded the extent of certainty, which in humans would be described as the degree of confidence in one's decision. Neurons in the primate parietal cortex encode information required to make a decision and also the certainty of that choice. The degree of confidence in a decision provides a graded and probabilistic assessment of expected outcome. Although neural mechanisms of perceptual decisions have been studied extensively in primates, little is known about the mechanisms underlying choice certainty. We have shown that the same neurons that represent formation of a decision encode certainty about the decision. Rhesus monkeys made decisions about the direction of moving random dots, spanning a range of difficulties. They were rewarded for correct decisions. On some trials, after viewing the stimulus, the monkeys could opt out of the direction decision for a small but certain reward. Monkeys exercised this option in a manner that revealed their degree of certainty. Neurons in parietal cortex represented formation of the direction decision and the degree of certainty underlying the decision to opt out.

Representation of Confidence Associated with a Decision by Neurons in the Parietal Cortex

Decision by Neurons in the Parietal Cortex Representation of Confidence Associated with a

Decisions about sensory stimuli are often based on an accumulation of evidence in time. When subjects control stimulus duration, the decision terminates when the accumulated evidence reaches a criterion level. Under many natural circumstances and in many laboratory settings, the environment, rather than the subject, controls the stimulus duration. In these settings, it is generally assumed that subjects commit to a choice at the end of the stimulus stream. Indeed, failure to benefit from the full stream of information is interpreted as a sign of imperfect accumulation or memory leak. Contrary to these assumptions, we show that monkeys performing a direction discrimination task commit to a choice when the accumulated evidence reaches a threshold level (or bound), sometimes long before the end of stimulus. This bounded accumulation of evidence is reflected in the activity of neurons in the lateral intraparietal cortex. Thus, the readout of visual cortex embraces a termination rule to limit processing even when potentially useful information is available.

Bounded Integration in Parietal Cortex Underlies Decisions Even When Viewing Duration Is Dictated by the Environment

Erratum: Corrigendum: Decision-making with multiple alternatives

The aim of statistical decision theories is to understand how evidence, prior knowledge, and values lead an organism to commit to one of a number of alternatives. Two main statistical decision theories, signal detection theory and sequential analysis, assert that decision makers obtain evidence—often from the senses—that is corrupted by noise and weigh this evidence alongside bias and value to select the best choice. Signal detection theory has been the dominant conceptual framework for perceptual decisions near threshold. Sequential analysis extends this framework by incorporating time and introducing a rule for terminating the decision process. This extension allows the trade-off between decision speed and accuracy to be studied, and invites us to consider decision rules as policies on a stream of evidence acquired in time. In light of these theories, simple perceptual decisions, which can be studied in the neurophysiology laboratory, allow principles that apply to more complex decisions to be exposed. The goal of this chapter is to “go beyond the data” to postulate a number of unifying principles of complex decisions based on our fi ndings with simple decisions. We make speculative points and argue positions that should be viewed as controversial and provocative. In many places, a viewpoint will merely be sketched without going into much detail and without ample consideration of alternatives, except by way of contrast when necessary to make a point. The aim is not to convince but to pique interest. The chapter is divided into two main sections. The fi rst suggests that an intentionbased framework for decision making extends beyond simple perceptual decisions to a broad variety of more complex situations. The second, which is a logical extension of the fi rst, poses a challenge to Bayesian inference as the dominant mathematical foundation of decision making. 04Shadlen10Dec07.pdf 72 M. N. Shadlen et al.

Inferior Temporal Cortex Object Category Structure in Response Patterns of Neuronal Population in Monkey

Matching Categorical Object Representations in Inferior Temporal Cortex of Man and Monkey

This chapter considers the neural basis of visual decisions and simple binary decisions made upon the sequential analysis of evidence, and also explains the accuracy and speed of perceptual decisions as a function of difficulty. It also presents evidence of possible neural implementation of the computational principles in the parietal cortex of a monkey.

The Speed and Accuracy of a Simple Perceptual Decision: A Mathematical Primer.

Our mental representation of object categories is hierarchically organized, and our rapid and seemingly effortless categorization ability is crucial for our daily behavior. Here, we examine responses of a large number (>600) of neurons in monkey inferior temporal (IT) cortex with a large number (>1,000) of natural and artificial object images. During the recordings, the monkeys performed a passive fixation task. We found that the categorical structure of objects is represented by the pattern of activity distributed over the cell population. Animate and inanimate objects created distinguishable clusters in the population code. The global category of animate objects was divided into bodies, hands, and faces. Faces were divided into primate and nonprimate faces, and the primate-face group was divided into human and monkey faces. Bodies of human, birds, and four-limb animals clustered together, whereas lower animals such as fish, reptile, and insects made another cluster. Thus the cluster analysis showed that IT population responses reconstruct a large part of our intuitive category structure, including the global division into animate and inanimate objects, and further hierarchical subdivisions of animate objects. The representation of categories was distributed in several respects, e.g., the similarity of response patterns to stimuli within a category was maintained by both the cells that maximally responded to the category and the cells that responded weakly to the category. These results advance our understanding of the nature of the IT neural code, suggesting an inherently categorical representation that comprises a range of categories including the amply investigated face category.

Object category structure in response patterns of neuronal population in monkey inferior temporal cortex.

Microstimulation of inferotemporal cortex influences face categorization

Erratum: Microstimulation of inferotemporal cortex influences face categorization (Nature (2006) 442 (692-695))

Effects of neonatal C-fiber depletion on the integration of paired-whisker inputs in rat barrel cortex

Neurons in the visual system respond to different visual stimuli with different onset latencies. However, it has remained unknown which stimulus features, aside from stimulus contrast, determine the onset latencies of responses. To examine the possibility that response onset latencies carry information about complex object images, we recorded single-cell responses in the inferior temporal cortex of alert monkeys, while they viewed >1,000 object stimuli. Many cells responded to human and non-primate animal faces with comparable magnitudes but responded significantly more quickly to human faces than to non-primate animal faces. Differences in onset latency may be used to increase the coding capacity or enhance or suppress information about particular object groups by time-dependent modulation.

Differences in onset latency of macaque inferotemporal neural responses to primate and non-primate faces.

Effects of GABAA receptor inhibition on response properties of barrel cortical neurons in C-Fiber-depleted rats

Subjects were asked to report the number of items in a display as the items moved along a circular path around the fixation point. As the rotation speed increased, the apparent number of items also increased. This motion-induced overestimation (MIO) effect was investigated in three experiments. In the first experiment, the effect of rotation speed and set size was explored with an enumeration task. The overestimation error increased with an increase in speed or number of items in the display. In the second experiment, we used an adjustment paradigm to measure the speed threshold of MIO effect onset. Temporal rate of the display, which was defined as product of rotation speed and the number of rotating items, was the determining factor of MIO onset. In the third experiment, moving items were marked with different colours. Surprisingly, the number of perceived items was still overestimated even though the number of perceived colours was not.

Motion-Induced Overestimation of the Number of Items in a Display

Effects of neonatal C-fiber depletion on discrimination of principal and adjacent whisker stimulation within rat individual cortical barrels

This paper presents a new approach to the sensorless speed control of six-phase induction machine (6PIM). The new technique uses an Adaptive Neural Fuzzy Inference Systems (ANFIS) as a rotor speed estimator to avoid using mechanical sensor. This makes the reference model free of pure integration and less sensitive to stator resistance variations. The ANFIS has been trained offline to estimate the rotor speed in wide range of operation and has been implemented online to perform field-oriented control of 6PIM. The data for training the ANFIS are obtained from experimental measurements based on the current model, avoiding voltage and flux sensors and has the advantage of considering all drive nonlinearities. Control loops of rotor speed and stator currents employ Fuzzy-PI (FPI) controller. The input-output scale factors of all FPI systems are tuned using Genetic Algorithms (GA) to achieve better results. Experimental results prove that the proposed method has high precision and good dynamic quality in speed estimation and control of 6PIM.

IECON 2011 - 37th Annual Conference of the IEEE Industrial Electronics Society

Intelligent sensorless speed control of six-phase induction machine

This paper presents a new approach to the sensorless position control of six-phase induction machine (6PIM). A fuzzy-PI (FPI) system has been employed to estimate the rotor position and avoid using mechanical sensor. Also, high-accuracy positioning of a 6PIM rotor can be obtained using such FPI system in model control loops. The input-output scale factors of all FPI systems are tuned using genetic algorithms to achieve better results. The proposed scheme is validated through experimental results, and it is demonstrated that an FPI configuration is attainable to implement rotor position estimation and control in 6PIM drives.

Sensorless position control of six-phase induction machine using fuzzy-PI system

The lives of minoritized migrant youth are marked—although distinctly—by histories and contemporary practices of exclusion. As subjects who are refused (or refuse) recognition as members of settler-colonial or postcolonial states, these youth often contend with disaffection within the spaces where their lives unfold. Informed by a research collaboration with migrant newcomer youth in France, this article engages autobiographical histories and Indigenous theoretical frames to explore how critical youth-directed research may enable new relationalities and youth political subjectivities. The consonant experiences and histories of migration that emerged in this research—in discussions of displacement, surveillance, reorientation, and movements through school spaces—raise questions of what approaches to research on youth political subjectivities are needed when disaffection and displacement are shared conditions. Exploring these questions with migrant newcomer youth yields insights on how research can constitute a terrain for imagining new relationalities and possibilities of belonging.

Working with Youth Counternarratives: Enjoining Transnational Youth Displacements, Sociopolitical Belonging, and Indigenous Scholarship

Contributing to a growing body of research on acknowledging U.S. imperialism within teacher education, this article explores how knowledge production on Iran—and U.S.-Iran relations more broadly—in secondary education represents a site of what Britzman has called difficult knowledge. Here, the difficulty of classroom engagements with the theme of U.S. imperialism is highlighted in several epistemic stumbling blocks, notably notions of White epistemic authority, neoliberal multiculturalism, and imperial feeling. Drawing upon data collected during a 9-month ethnographic study, the analysis presents classroom scenes from a high school world literature unit on Marjane Satrapi’s Persepolis, selected by the teacher to explore themes of colonialism, imperialism, and revolution. Despite these intentions, classroom engagements with the text often reproduced Orientalist understandings. These findings inform the concluding argument that mobilizes contrapuntal reading as a generative technique for teacher education research and practice to identify and confront the epistemic bases that normalize systems of oppression.

“Why Do We Need to Know About This?”: U.S. Imperialism, Persepolis, and Knowledge Production on Iran in the Classroom

ABSTRACT Across the world, Muslims in non-Muslim majority countries are seen as alien humans, relegated to the margins of citizenship, permitted tenuous forms of belonging as long as they follow the “Good Muslim” script assigned to them by the majority. In the U.S., youth from Muslim American immigrant communities have awakened to, and are rejecting, this conditional citizenship. Drawing on a nation-wide qualitative study with youth from diverse Muslim immigrant communities, we argue that, since 9/11, there have been significant changes in young Muslim Americans’ self-perceptions and attitudes toward their rights, citizenship, and feelings of belonging. These youth recognize themselves as people of colour and are more likely than their parents’ generations to link their struggles with those of other racially minoritized communities, thus suggesting a more radical politics of belonging in the United States.

“Muslims are Finally waking up”: post-9/11 American immigrant youth challenge conditional citizenship

Abstract Berlant’s notion of cruel optimism refers to investments in material structures, social norms, and ideological claims of being that work against individual and collective flourishing. Drawing on ethnographic and interview data spanning 2007–2016, this longitudinal study utilizes cruel optimism to explore material and affective investments of middle class Jordanian men into becoming educated, despite their acknowledgement that education delivers limited social mobility. Analyses of school-to-work transitions suggest Jordanian youth is confronting longer periods of transition, rather than indefinitely living in times of compromised possibility. However, a focus on ameliorating transitions and ‘mismatches’ in youth skills and expectations, does not adequately consider how shared understandings of the promise of education change over time, nor how uncertainties of transition become normalized as everyday life. Through participants’ life trajectories, this article examines youth modes of improvisation when ‘transitions’ persist indeterminately, and sanctioned means of future-building fail to deliver normative ideals of the present.

Being late, going with the flow, always doing more: the cruel optimism of higher education in Jordan

ABSTRACT In this article, we explore how locally situated educational practices and policies aimed at inclusion and integration may contribute to racialised exclusion for students. Our analysis brings together two ethnographic studies of how minoritised Muslim youth navigate secondary schooling in Denmark and the US. Our cases illustrate how assumptions held by school staff toward the youth in our studies were rooted in both Islamophobic tropes and deeply held nationalist beliefs about the benevolence of the US and Denmark. Cindi Katz's notion of ‘countertopography’ is critical to our argument that Islamophobia is productive of similar practices of surveillance and exclusion across disparate educational settings. As an analytical framework, countertopography opens important possibilities for critical and comparative qualitative inquiry, with specific promise for highlighting how seemingly dissimilarly educational spaces may be imbued with similar social meanings, and how these meanings are constituted by recurring unequal social relations between individuals and groups therein.

Conditional hospitality and coercive concern: countertopographies of Islamophobia in American and Danish schools

Though "emergency" is a key concept in the field of education in emergencies, scholars and practitioners have long been ambivalent about this term and what conditions it can refer to. In this article, drawing from the work of anthropologist Janet Roitman, I critically revisit the concepts of emergency and crisis, and propose that understanding emergency primarily as a moment of shock or the unexpected event obscures how seemingly normal conditions may produce their own impasses. Rather than being characterized by a consensus of meaning, crises entail narrative constructions that create new temporalities and frame certain questions and responses as possible, others as not. In this article, I juxtapose two narrative constructions of crisis in popular culture to explore how narrative constructions of the war on drugs can produce jarringly different accounts of the crises they are said to represent. I suggest that explicitly attending to the underlying politics of crisis narration—though possibly complicating emergency response—is vital to naming and resolving possible ethical blind spots and impasses in the field of education in emergencies.

When Emergency Becomes Everyday Life: Revisiting a Central EiE Concept in the Context of the War on Drugs

Drawing upon ethnographic and case study research conducted across two educational settings in the United States, this article examines emergent spaces and practices of education that result from, or are affected by, the presence of minoritized diasporic communities. In light of ongoing currents of xenophobia in the United States and practices of racialization in everyday experiences of schooling, I argue that these diasporic educational spaces work as counterspaces of epistemic possibility, in which conceptions of identity and belonging—ones that are often foreclosed in the mainstream and predominantly white educational spaces—become viable. Examining the cultural production within these spaces troubles the idea that diasporic educational spaces primarily maintain or privilege transnational ties to “home.” I conclude that these educational spaces highlight two related points: first, diasporic educational sites engender creative possibilities for reworking exclusionary discourses; second, they point to the need for a further decentering and decolonization of pedagogy and curriculum in public secondary schools.

“Somewhere We Can Breathe”: Diasporic Counterspaces of Education as Sites of Epistemological Possibility

Abstract This paper is based on an ethnographic study of a progressive high school programme that privileges critical thinking amongst its students. Drawing upon feminist poststructuralist educational research, we propose an analysis of classroom discourse in order to highlight the diverse legitimation processes that enable gendered subjectivities in one high school setting. Our findings indicate that pedagogic styles alter the pattern of legitimation for gendered subject positions in the three classroom settings studied, and create different possibilities for the interrogation of normative gender scripts in the classroom. While appeals to teacher authority are the basis for the legitimation of alternative gendered subject positions in all three classrooms, agential student-led interactions are more apparent in challenging normative gender scripts. Our study demonstrates the need to consider the diverse sources of discursive authority for gendered claims in schools and seeks nuance in understanding pedagogical authority and gendered knowledge construction.

Legitimate subjects: diverse pedagogical practices and gendered subjectivities in high school classrooms

Decentering Americanness: Transnational Youth Experiences of Recognition and Belonging in Two U.S. High Schools

Purpose
The purpose of this paper is to examine how the exercise of administrative authority to suspend the Muslim Student Association (MSA), an affinity group at a suburban Midwestern high school, was experienced and perceived by affected students. Notably, it traces the mobilization of the MSA students to challenge the principal’s authority through formal channels within the district to reopen the affinity group. In doing so, the students’ activism represents an example of dissensus, or mode of political engagement that challenges top-down models of fostering equity and diversity in schools.

Design/methodology/approach
The data are drawn from a nine-month ethnographic case study at an inner-ring suburban school in a large Midwestern metropolitan area. Data include participant observation of classrooms and affinity group meetings, semi-structured individual and group interviews, informal conversation and analytical memos synthesizing ethnographic fieldnotes.

Findings
Though the school and district have made different investments in strengthening equity and diversity at the school, transnational and minoritized Muslim students report a school climate that is characterized by exclusion and racialized surveillance. The principal’s decision to suspend the MSA was characterized by a narrow understanding of the purpose of the group and the identities of the student members. The decision to suspend the MSA, however, produced conditions centering the agentive potential of marginalized and minoritized students.

Originality/value
This paper opens up the tensions challenges of incorporating student voice into educational decision making. Notably, it highlights important possibilities for political action students when their voices cannot or will not be heard by those who make decisions on their behalf.

ABSTRACT This article utilizes the idea of hospitality to explore how educative practices contribute to the making of citizens at Light Falls High School (LHS), a suburban American secondary school that professes a strong commitment to racial equity and global awareness. The data are derived from an ethnographic case study which took place in 2013–2014. I primarily draw upon the classroom experiences and narratives of transnational youth – those with social lives, cultural practices, and notions of self that are not bounded by one nation – and several educators to tell the story of hospitality at LHS. Three techniques emerged by which conditional hospitality shaped the possibilities of welcome and recognition of transnational students – questioning attachment, conditioning speech, and conditioning space – and these in turn constitute normative thresholds that fix these students in difference, delimit their belonging, and constrain their possibilities of membership. The gift of welcome meant to make non-normative students feel welcome often comes with caveats that uphold narratives of benevolence and superiority of the United States as an exceptional nation, affirm the notion of White indigeneity, and allow for mitigation in acknowledging structural racism.

Between hosts and guests: Conditional hospitality and citizenship in an American suburban school

This article offers three meditations on the 2016 election of Donald Trump for consideration by the readers of Anthropology & Education Quarterly: first, to query what is “new” about this political era; second, to draw attention to the performance of political opposition and violences of solidarity; third, to document my own navigations of the political present as a researcher and educator with thoughts for others who work with or are marked as “targeted populations.”

How Much of This Is New? Thoughts on How We Got Here, Solidarity, and Research in the Current Moment

ABSTRACT The intent of this series is to generate a space for critical reflection and inquiry on a burgeoning form of sociopolitical labor of schooling, that of educating against “extremism.” In the United States’ ongoing “War on Terror” being waged across the Middle East, North and East Africa, and South Asia, formal and informal schooling have long been conscripted into efforts to mitigate extremism among “vulnerable” youth populations. More recently, the rise of strident anti-immigrant and anti-refugee sentiments across North America and Europe has contributed to the normalization of xenophobic-and particularly Islamophobic-political discourse. In this climate, state surveillance and policing of immigrant and Muslim communities are proliferating (as are racially/religiously motivated attacks against them). Regardless of their citizenship status, youth from these communities (or who are imagined to be from these communities) are often construed as vulnerable/threatening Others. This has implications for education research, and suggests global movement and production of discourse around education as a means of security and countering extremism, which warrants closer and comparative inquiry. In response to these developments, we ask: what does it mean to educate against extremism? Who has the power to name bodies, ideas, and acts as extremists? What is the utility of this terminology at this particular historical moment? We have invited different scholars to think with these questions and to contribute original perspectives on the interplay of security, education, migration, and xenophobia.

When Schooling Becomes a Tactic of Security: Educating to Counter “Extremism”

In the year since the editors atDiaspora, Indigenous, andMinority Education first discussed the possibility of this series, the intersections of schooling with race, religion, citizenship, and security have only assumed greater significance in public debate, electoral politics, and political discourse across North America and Europe. The final two articles in the invited series, “Critical Engagements with the Politics of ‘Extremism’ and Schooling,” contributed by Arshad I. Ali and David Lundie, consider the educational, political, and social effects of the encroachment of counter-terrorism initiatives in theUnited States andUnitedKingdom upon Muslim youth and communities. Arshad I. Ali’s article addresses contemporary elisions of liberalism and the viability of Muslim cultural citizenship in theUnited States in particular. Given the historical constructions of Islam as a foil forWestern civilization, Ali asks the reader to consider whether a Muslim can be a citizen in the United States, when anti-Muslim sentiment is normalized and state counter-terrorist programs are predicated on a belief that community networks are the conduit through which Muslim youth are radicalized. Drawing upon Black struggles for civil and political rights in the United States, he argues that the recognition of nonnormative bodies as citizens has historically entailed relinquishing internationalist solidarities and anti-imperial critique of the state. At a time when White nationalist thought is enjoying a resurgence in mainstream American politics, Ali asks his reader whether excising global connections and infiltration by the security apparatus intoMuslim communities would still be insufficient as a condition of sociopolitical membership. Relatedly, David Lundie’s article argues the growing conflation of race and religion in the UK has spurred a focus away from multiculturalist-pluralist conceptions of communities toward a more assimilatory project of protecting “British values.” Using the example of the “Trojan Horse” moral panic in Birmingham in the United Kingdom, Lundie argues that community education—a longstanding aspect of local control of British schooling—has become increasingly implicated in counter-terrorism and security apparatuses. Lundie’s essay traces different policy shifts to point to a tension in maintaining a tradition of community oversight of schooling and state security imperatives wherein the “local” is seen as a suspect population. Notably, he highlights how the participation of certain communities (meaning “Muslim”) in community education seemingly portends a broader social fragmentation and political threat—paving the way for new educational policies, monitoring regimes, and compliance requirements. Though contextually and theoretically distinct, both essays draw attention to the growing conflation of race and religion in security policies that operate within educational settings and across different Muslim communities. These two articles also point to the retrenchment of the terms of belonging, and the hierarchies and contradictions of political membership in liberal multicultural states experiencing surges in nativist fear and anger. Together, they raise trenchant questions about how schooling is implicated in reflecting and producing the polity (and its suspect Others) in a time when securitization is a proliferating logic of governance, and contribute important points of departure for future inquiry in a still-emergent field of inquiry.

Concluding Our Invited Essay Series: “Critical Engagements with the Politics of ‘Extremism’ and Schooling”

ABSTRACT This issue of Diaspora, Indigenous, and Minority Education features two essays responding to Adeela Arshad-Ayaz and M. Ayaz Naseem'’s lead article for this series, “Creating “Invited” Spaces for Counter-Radicalization and Counter-Extremism Education.” Drawing upon metaphor and empirical research, these essays impart important theoretical tools for scholars who work on questions of migration, social justice, belonging, and security in education.

Our Invited Essay Series: “Critical Engagements with the Politics of ‘Extremism’ and Schooling”

Syriana directed by Stephen Gaghan. Warner Brothers, 2005. 128 min.

In Jordan, gender equality is often depicted as an important social concern in policy texts, national media, and reports by international development institutions. In these reports, ‘gender' is often synonymous with ‘women’, and efforts are directed to improving parity in social and economic outcomes. This article argues that males are often overlooked or invisible in such accounts, and are more readily visible as obstacles to gender equality or embodiments of masculine crisis. Drawing upon ethnographic work in two government high schools for boys, I analyse everyday practices and social experiences of male students and teachers in schools to argue that they constitute an overlooked site to analyse the construction of gendered subjectivities. Mainstream accounts fail to account for how schooling is constitutive of gender struggle for boys, and how this struggle is connected to the changing nature of social membership in Jordan spurred in part by social and economic pressures.

‘These boys are wild': constructions and contests of masculinities at two Jordanian high schools

This paper explores the possibilities of engaging in cross-disciplinary research to generate social studies curricula that disrupt singular historical constructions about the Middle East and North Africa (MENA), specifically for US high school teachers and students. As part of a larger multi-sited study that investigated and analyzed the common categories used to describe and teach MENA in US World History textbooks, the team engaged in multidisciplinary scholarship on the region to (1) review and analyze the five most widely adopted high school World History textbooks in the US; (2) share analyses with researchers and experts in the fields of MENA studies, history, and religion; (3) synthesize and integrate innovative scholarship on the region for potential curricula; and (4) generate robust alternative curricula for Grades 9-12 teachers. The authors, consequently, consider how educational research spurs innovative and culturally relevant curricular interventions for high school teachers. We argue thorough analysis of existing textbooks, informed by deep understandings of contested versions of historical events, should undergird social studies curriculum development. We suggest multidisciplinary and transnational collaboration can inform curricula in order to respond critically to singular narrations of peoples, cultures, and histories of a region.

New Curricular Approaches to Teaching About the Middle East and North Africa

From a human capital perspective, schooling has long represented an engine of economic growth, individual advancement, and competitiveness in the global market. In recent years, this theorization of schooling has become linked with articulations of national security in both the Global North and South, as policymakers, private sector actors, and international donor agencies frequently describe economic growth and opportunities for individual advancement as requisites to social and political stability. Lost amid the current US foreign policy discourses about the Middle East is an analysis of how neo-liberal educational reforms in both regions are similarly reconfiguring relationships between the nation-state and its young citizens. In critically interrogating how the sociopolitical work of schooling is articulated in Jordanian and American education policy texts, this article argues that neo-liberal discourses of ‘choice’, ‘accountability’ and ‘participation’ in current regimes of education reform seemingly produce new formations of citizenship locally (national security) and globally (global citizenship). Yet, this reordering of civic relationships serves to reify the (economic) interests of the nation-state and maintain a specific global hegemonic order. However, the article also highlights ways in which peoples' movements in the United States of America (USA) and Jordan are challenging the notions that these policies are merely tacitly accepted by most.

Securing the State through the Production of ‘Global’ Citizens: Analyzing Neo-Liberal Educational Reforms in Jordan and the USA

This article highlights how a community-organized language school that teaches Persian serves as a site of diasporic cultural production. Specifically, I examine how the school serves as a site to teach the Persian language, delimit cultural meanings, and facilitate a sense of belonging and community membership among a diverse group of parents and children. This study also endeavors to situate the views of parents, teachers, and students in this exploratory case study within a larger history of diasporic Iranian experience in the United States. In doing so, the analysis shows that community education efforts remain vital to the understanding and exploration of notions of identity and culture that may be socially contested and produced within diasporic communities.

The Pedagogy of Visibility: Constructs and Contests of Iranianness in a Community-Organized School in a Large Southern U.S. City

This article analyzes the ways in which Iran and Iranians are represented in Western news media sources. Through detailed textual analysis of articles in Time and Newsweek between 1998 and 2009, it demonstrates that journalistic representations of Iran and Iranians are not simply efforts aimed at describing the real Iran, but rather form the basis of what Said refers to as a powerful “community of interpretation” that often reflects and reproduces certain xenophobic stereotypes of non-Western foreign subjects. While some shifts in Western media representations of Iranians have occurred in the thirty years since the revolution, the underlying ontological assumptions of these representations have remained remarkably durable. That is to say, the dominant representational discourse found in these newsmagazines depicts the political behavior of Iranians on the basis of essentialized notions of Persian and/or Islamic civilization, while very often emphasizing the taken for granted superiority of the West. Earlier Orientalist discourses focus on the difference of non-Western foreign subjects by denigrating them as fundamentally anti-modern and incapable of political, cultural and economic development without Western intervention. This article presents an unmistakable discursive pattern in American journalism whereby certain Iranians are incorporated into Western civilization by virtue of their embrace of a Western modernity.

Good Iranian, Bad Iranian: Representations of Iran and Iranians in Time and Newsweek (1998–2009)

Persian bilingual and community education among Iranian-Americans in New York City

Through educational campaigns and partnerships with the international community, the Jordanian government has indicated a desire to create a more loyal, democratic, and self-enterprising citizenry. While the participation of girls in public life is encouraged by the Jordanian regime and valorised by the international community, little effort is made to ensure and understand the participation of boys in such spaces, and what this participation produces. By highlighting the experiences and narratives of boys, including those of Palestinian origin, in two government secondary schools in Amman, this article examines how top-down efforts to produce a particular national identity have engendered a performative kind of citizenship in schools, in which students interrogate official accounts of Jordanian-ness through various practices of signification. This use of performativity, adapted from Judith Butler's work on gender, raises two important points: first, the learning of citizenship and national identity is a contingent and self-reflexive process; second, practices of citizenship cannot be understood outside the sociopolitical norms that regulate them.

Performing the ‘Knights of Change’: male youth narratives and practices of citizenship in Jordanian schools

By juxtaposing male secondary student and teacher classroom practices with a postcolonial analysis of the structural and discursive forces that characterize education reform in Jordan, this study draws attention to the ways that authoritarian regimes may coopt peace education language and concepts, such as ‘dialogue’ and ‘empowerment’, to create a democratic veneer for neoliberal educational projects. Jordanian (along with other Arab and Muslim) male youth are often discursively positioned in transnational accounts as objects of educational intervention requiring assistance to become democratic and empowered citizens rather than subjects of self-empowerment. Employing a postcolonial framework of centering ‘marginalized’ voices, then, challenges prevalent cultural representations of Jordanian youth as ‘vulnerable’ and allows scholars and practitioners to see how students enact agency and contest sociopolitical norms in everyday practices of schooling. Using ethnographic data collected in two government secondary schools in Jordan, the author highlights satirical practices in different venues as a means by which male secondary students subvert such structural constraints and exercise transformative agency in schools. These findings are then related back to the need for critical educators to engage with local knowledge and meanings to become more effective practitioners and scholars in the field across diverse sociopolitical and economic contexts.

When projects of ‘empowerment’ don’t liberate: Locating agency in a ‘postcolonial’ peace education

THE EFFECTIVENESS OF STRESS INOCULATION GROUP TRAINING ON SOMATIZATION AND ANXIETY OF THE CORONARY HEART DISEASE PATIENTS

Molding the knights of change: National identity, schooling, and masculinity in two Jordanian high schools for boys

Just as we succeeded in imbuing Japan and Germany with liberalism and democracy after we had defeated them decisively on the battlefield, so the defeat of terrorism, which in practice means the defeat of the various regimes that sponsor terror and of the Islamist movement, may open the way to new thinking in the Middle East. Although it is unlikely that we will occupy any countries as long or as thoroughly as we did at the end of World War II, our

Islamic Education in Afghanistan: Revisiting the United States’ Role

This paper explores the plausibility of a hypothesis that puts forth perceived educational opportunity as a significant pull factor influencing Iranians' decisions to immigrate to the United States. Drawing on various literatures, including research on educational policy in Iran, government policy papers, and figures from recent studies and census data, the authors establish a case for investigating the correlation between perceived educational opportunity (or lack thereof) and immigration. Empirical findings presented here from a preliminary survey of 101 Iranian-born individuals living in the U.S. suggest that such a correlation may indeed exist, thus providing compelling grounds for further research in this area. The paper expands on existing literature by extending prevailing accounts of unfavorable conditions in Iran as push factors for emigration, to include the draw of perceived educational opportunity, as a coexisting and influential pull factor for immigration to the U.S.

Education and Emigration: The case of the Iranian-American community

When mice run, activity in their primary visual cortex (V1) is strongly modulated. This observation has altered conception of a brain region assumed to be a passive image processor. Extensive work has followed to dissect the circuits and functions of running-correlated modulation. However, it remains unclear whether visual processing in primates might similarly change during locomotion. We measured V1 activity in marmosets while they viewed stimuli on a treadmill. In contrast to mouse V1, marmoset V1 was slightly but reliably suppressed during running. Population-level analyses revealed trial-to-trial fluctuations of shared gain across V1 in both species, but these gain modulations were smaller and more often negatively correlated with running in marmosets. Thus, population-scale gain fluctuations of V1 reflect a common feature of mammalian visual cortical function, but important quantitative differences yield distinct consequences for the relation between vision and action in primates versus rodents.

Organisms process sensory information in the context of their own moving bodies, an idea referred to as embodiment. This idea is important for developmental neuroscience, and increasingly plays a role in robotics and systems neuroscience. The mechanisms that support such embodiment are unknown, but a manifestation could be the observation in mice of brain-wide neuromodulation, including in the primary visual cortex, driven by task-irrelevant spontaneous body movements. Here we tested this hypothesis in macaque monkeys, a primate model for human vision, by simultaneously recording visual cortex activity and facial and body movements. Activity in the visual cortex (V1, V2, V3/V3A) was associated with the animals’ own movements, but this modulation was largely explained by the impact of the movements on the retinal image. These results suggest that embodiment in primate vision may be realized by input provided by the eyes themselves.

Activity in primate visual cortex is minimally driven by spontaneous movements

Determining how color and form are integrated within macaque V1 neurons through combined neurophysiology and computational modeling

Detailed characterization of neural selectivity in free viewing primates

Decision-related feedback in visual cortex lacks spatial selectivity

To understand the complexity of stimulus selectivity in primary visual cortex (V1), models constructed to match observed responses to complex time-varying stimuli, instead of to explain responses to simple parametric stimuli, are increasingly used. While such models often can more accurately reflect the computations performed by V1 neurons in more natural visual environments, they do not by themselves provide insight into established measures of V1 neural selectivity such as receptive field size, spatial frequency tuning and phase invariance. Here, we suggest a series of analyses that can be directly applied to encoding models to link complex encoding models to more interpretable aspects of stimulus selectivity, applied to nonlinear models of V1 neurons recorded in awake macaque in response to random bar stimuli. In linking model properties to more classical measurements, we demonstrate several novel aspects of V1 selectivity not available to simpler experimental measurements. For example, we find that individual spatiotemporal elements of the V1 models often have a smaller spatial scale than the overall neuron sensitivity, and that this results in non-trivial tuning to spatial frequencies. Additionally, our proposed measures of nonlinear integration suggest that more classical classifications of V1 neurons into simple versus complex cells are spatial-frequency dependent. In total, rather than obfuscate classical characterizations of V1 neurons, model-based characterizations offer a means to more fully understand their selectivity, and provide a means to link their classical tuning properties to their roles in more complex, natural, visual processing. Significance statement Visual neurons are increasingly being studied with more complex, natural visual stimuli, with increasingly complex models necessary to characterize their response properties. Here, we describe a battery of analyses that relate these more complex models to classical characterizations. Using such model-based characterizations of V1 neurons furthermore yields several new insights into V1 processing not possible to capture in more classical means to measure their visual selectivity.

Model-based characterization of the selectivity of neurons in primary visual cortex

A potential role for binocular integration without binocular disparity information in primary visual cortex

Amplification of feature selectivity by spatial convolution in primary visual cortex

Beyond fixation: foveal receptive field estimation in freely viewing primates

Decoding is a powerful approach for measuring the information contained in the activity of neural populations. As a result, decoding analyses are now used across a wide range of model organisms and experimental paradigms. However, typical analyses employ general purpose decoding algorithms that do not explicitly take advantage of the structure of neural variability, which is often low-dimensional and can thus be effectively characterized using latent variables. Here we propose a new decoding framework that exploits the low-dimensional structure of neural population variability by removing correlated variability that is unrelated to the decoded variable, then decoding the resulting denoised activity. We demonstrate the efficacy of this framework using simulated data, where the true upper bounds for decoding performance are known. A linear version of our decoder provides an estimator for the decoded variable that can be more efficient than other commonly used linear estimators such as linear discriminant analysis. In addition, our proposed decoding framework admits a simple extension to nonlinear decoding that compares favorably to standard feed-forward neural networks. By explicitly modeling shared population variability, the success of the resulting linear and nonlinear decoders also offers a new perspective on the relationship between shared variability and information contained in large neural populations.

A latent variable approach to decoding neural population activity

Functional characterization of retinal ganglion cells using tailored nonlinear modeling

Parallel Processing of Sound Dynamics across Mouse Auditory Cortex via Spatially Patterned Thalamic Inputs and Distinct Areal Intracortical Circuits.

With modern neurophysiological methods able to record neural activity throughout the visual pathway in the context of arbitrarily complex visual stimulation, our understanding of visual system function is becoming limited by the available models of visual neurons that can be directly related to such data. Different forms of statistical models are now being used to probe the cellular and circuit mechanisms shaping neural activity, understand how neural selectivity to complex visual features is computed, and derive the ways in which neurons contribute to systems-level visual processing. However, models that are able to more accurately reproduce observed neural activity often defy simple interpretations. As a result, rather than being used solely to connect with existing theories of visual processing, statistical modeling will increasingly drive the evolution of more sophisticated theories. Expected final online publication date for the Annual Review of Vision Science, Volume 5 is September 16, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The quest for interpretable models of neural population activity

Characterizing neural processing in foveal primary visual cortex

Visual motion is a ubiquitous component of animals’ sensory experience and its encoding is critical for navigation and movement. Yet its impact on behavior and neural coding is not well understood. Combining pupillometry with cellular calcium imaging measurements of thalamocortical axons in awake behaving mice, we examined the impact of arousal and behavioral state on encoding of visual motion in the visual thalamus. We discovered that back-to-front visual motions elicits a robust behavioral response that shapes tunings of visual thalamic responses. Consistent with an arousal mechanism, the effects were pronounced during stillness and weak or absent during locomotor activity and under anesthesia. The impact on neuronal tuning was specific, biasing population response patterns in favor of back-to-front motion. The potent influence of visual motion on behavioral state dynamically affect sensory coding at early visual processing stages. Further research is required to reveal the circuitry and function of this novel mechanism.

Behavioral response to visual motion impacts population coding in the mouse visual thalamus

A long-standing observation about primary visual cortex (V1) is that the stimulus selectivity of neurons can be well explained with a cascade of linear computations followed by a nonlinear rectification stage. This framework remains highly influential in systems neuroscience and has also inspired recent efforts in artificial intelligence. The success of these models include describing the disparity-selectivity of binocular neurons in V1. Some aspects of real neuronal disparity responses are hard to explain with simple linear-nonlinear models, notably the attenuated response of real cells to “anticorrelated” stimuli which violate natural binocular image statistics. General linear-nonlinear models can account for this attenuation, but no one has yet tested whether they quantitatively match the response of real neurons. Here, we exhaustively test this framework using recently developed optimisation techniques. We show that many cells are very poorly characterised by even general linear-nonlinear models. Strikingly, the models can account for neuronal responses to unnatural anticorrelated stimuli as well as to most natural, correlated stimuli. However, the models fail to capture the particularly strong response to binocularly correlated stimuli at the preferred disparity of the cell. Thus, V1 neurons perform an amplification of responses to correlated stimuli which cannot be accounted for by a linear-nonlinear cascade. The implication is that even simple stimulus selectivity in V1 requires more complex computations than previously envisaged. Significance statement A long-standing question in sensory systems neuroscience is whether the computations performed by neurons in primary visual cortex can be described by repeated elements of linear-nonlinear units (a linear filtering/pooling stage followed by a subsequent output nonlinearity, such as a squaring). This question goes back to the Nobel-prize winning work by Hubel & Wiesel who argued that orientation selectivity in V1 can qualitatively be explained in this way. In this paper, we show that V1 neurons have an amplification of their response to stimuli which are contrast matched in the two eyes, and that the recovered models cannot describe this property. We argue that this likely represents more sophisticated computations than can be compactly described by the linear-nonlinear cascade framework.

Current models cannot account for V1’s specialisation for binocular natural image statistics

Sensory neurons often have variable responses to repeated presentations of the same stimulus, which can significantly degrade the information contained in those responses. Such variability is often shared across many neurons, which in principle can allow a decoder to mitigate the effects of such noise, depending on the structure of the shared variability and its relationship to sensory encoding at the population level. Latent variable models offer an approach for characterizing the structure of this shared variability in neural population recordings, although they have thus far typically been used under restrictive mathematical assumptions, such as assuming linear transformations between the latent variables and neural activity. Here we leverage recent advances in machine learning to introduce two nonlinear latent variable models for analyzing large-scale neural recordings. We first present a general nonlinear latent variable model that is agnostic to the stimulus tuning properties of the individual neurons, and is hence well suited for exploring neural populations whose tuning properties are not well characterized. This motivates a second class of model, the Generalized Affine Model, which simultaneously determines each neuron’s stimulus selectivity and a set of latent variables that modulate these stimulus responses both additively and multiplicatively. While these approaches can detect general nonlinear relationships in shared neural variability, we find that neural activity recorded in anesthetized primary visual cortex (V1) is best described by a single additive and single multiplicative latent variable, i.e., an “affine model”. In contrast, application of the same models to recordings in awake macaque prefrontal cortex discover more general nonlinearities to compactly describe the population response variability. These results thus demonstrate how nonlinear latent variable models can be used to describe population variability, and suggest that a range of methods is necessary to study different brain regions under different experimental conditions.

Characterizing the nonlinear structure of shared variability in cortical neuron populations using latent variable models

The ability of sensory networks to transiently store information on the scale of seconds can confer many advantages in processing time-varying stimuli. How a network could store information on such intermediate time scales, between typical neurophysiological time scales and those of long-term memory, is typically attributed to persistent neural activity. An alternative mechanism which might allow for such information storage is through temporary modifications to the neural connectivity which decay on the same second-long time scale as the underlying memories. Earlier work that has explored this method has done so by emphasizing one attractor from a limited, pre-defined set. Here, we describe an alternative, a Transient Attractor network, which can learn any pattern presented to it, store several simultaneously, and robustly recall them on demand using targeted probes in a manner reminiscent of Hopfield networks. We hypothesize that such functionality could be usefully embedded within sensory cortex, and allow for a flexibly-gated short-term memory, as well as conferring the ability of the network to perform automatic de-noising, and separation of input signals into distinct perceptual objects. We demonstrate that the stored information can be refreshed to extend storage time, is not sensitive to noise in the system, and can be turned on or off by simple neuromodulation. The diverse capabilities of transient attractors, as well as their resemblance to many features observed in sensory cortex, suggest the possibility that their actions might underlie neural processing in many sensory areas.

Sound stimuli are characterized by their rich spectral and temporal dynamic properties. Individual neurons in auditory cortex (ACX) encode both spectral and temporal aspects of sounds e.g. sound onset and/or offset. While the different fields of the ACX show gradients of frequency selectivity the large-scale organization of sound dynamics is unknown. We used widefield imaging of GCaMP6s in awake mouse ACX combined with a novel unsupervised image segmentation technique to investigate the spatiotemporal representation of sound onset and offset. Using this technique, we identified known auditory fields but also detected novel ACX areas. Furthermore, we found that ACX areas differed in their responses to tone onset and offset. Multiple areas were preferentially activated by tone offset, and on-response areas were more spatially localized than off-response areas. We also found tonotopy in off-responses. Together our results demonstrate a different spatial distribution of neurons across ACX for processing sound onsets versus offsets.

Spatial organization of the mouse auditory cortex to sound dynamics revealed using automated image segmentation

Simplified detection of ON/OFF receptive fields using a nonlinear input model

Isolating the circuit components behind contrast adaptation within the Rod-Bipolar pathway

Visual processing depends on specific computations implemented by complex neural circuits. Here, we present a circuit-inspired model of retinal ganglion cell computation, targeted to explain their temporal dynamics and adaptation to contrast. To localize the sources of such processing, we used recordings at the levels of synaptic input and spiking output in the in vitro mouse retina. We found that an ON-Alpha ganglion cell’s excitatory synaptic inputs were described by a divisive interaction between excitation and delayed suppression, which explained nonlinear processing already present in ganglion cell inputs. Ganglion cell output was further shaped by spike generation mechanisms. The full model accurately predicted spike responses with unprecedented millisecond precision, and accurately described contrast adaption of the spike train. These results demonstrate how circuit and cell-intrinsic mechanisms interact for ganglion cell function and, more generally, illustrate the power of circuit-inspired modeling of sensory processing.

Divisive suppression explains high-precision firing and contrast adaptation in retinal ganglion cells

Computations performed by the visual pathway are constructed by neural circuits distributed over multiple stages of processing, and thus it is challenging to determine how different stages contribute on the basis of recordings from single areas. In the current article, we address this problem in the lateral geniculate nucleus (LGN), using experiments combined with nonlinear modeling capable of isolating various circuit contributions. We recorded cat LGN neurons presented with temporally modulated spots of various sizes, which drove temporally precise LGN responses. We utilized simultaneously recorded S-potentials, corresponding to the primary retinal ganglion cell (RGC) input to each LGN cell, to distinguish the computations underlying temporal precision in the retina from those in the LGN. Nonlinear models with excitatory and delayed suppressive terms were sufficient to explain temporal precision in the LGN, and we found that models of the S-potentials were nearly identical, although with a lower threshold. To determine whether additional influences shaped the response at the level of the LGN, we extended this model to use the S-potential input in combination with stimulus-driven terms to predict the LGN response. We found that the S-potential input "explained away" the major excitatory and delayed suppressive terms responsible for temporal patterning of LGN spike trains but revealed additional contributions, largely PULL suppression, to the LGN response. Using this novel combination of recordings and modeling, we were thus able to dissect multiple circuit contributions to LGN temporal responses across retina and LGN, and set the foundation for targeted study of each stage.

Nonlinear computations shaping temporal processing of precortical vision.

Author response: Divisive suppression explains high-precision firing and contrast adaptation in retinal ganglion cells

The activity of sensory cortical neurons is not only driven by external stimuli, but is also shaped by other sources of input to the cortex. Unlike external stimuli these other sources of input are challenging to experimentally control or even observe, and as a result contribute to variability of neuronal responses to sensory stimuli. However, such sources of input are likely not “noise”, and likely play an integral role in sensory cortex function. Here, we introduce the rectified latent variable model (RLVM) in order to identify these sources of input using simultaneously recorded cortical neuron populations. The RLVM is novel in that it employs non-negative (rectified) latent variables, and is able to be much less restrictive in the mathematical constraints on solutions due to the use an autoencoder neural network to initialize model parameters. We show the RLVM outperforms principal component analysis, factor analysis and independent component analysis across a variety of measures using simulated data. We then apply this model to the 2-photon imaging of hundreds of simultaneously recorded neurons in mouse primary somatosensory cortex during a tactile discrimination task. Across many experiments, the RLVM identifies latent variables related to both the tactile stimulation as well as non-stimulus aspects of the behavioral task, with a majority of activity explained by the latter. These results suggest that properly identifying such latent variables is necessary for a full understanding of sensory cortical function, and demonstrates novel methods for leveraging large population recordings to this end.

Revealing unobserved factors underlying cortical activity using a rectified latent variable model applied to neural population recordings

Robust extraction of the diversity of ganglion cell computation via spatially correlated stimuli and nonlinear modeling

The responses of sensory neurons can be quite different to repeated presentations of the same stimulus. Here, we demonstrate a direct link between the trial-to-trial variability of cortical neuron responses and network activity that is reflected in local field potentials (LFPs). Spikes and LFPs were recorded with a multielectrode array from the middle temporal (MT) area of the visual cortex of macaques during the presentation of continuous optic flow stimuli. A maximum likelihood-based modeling framework was used to predict single-neuron spiking responses using the stimulus, the LFPs, and the activity of other recorded neurons. MT neuron responses were strongly linked to gamma oscillations (maximum at 40 Hz) as well as to lower-frequency delta oscillations (1–4 Hz), with consistent phase preferences across neurons. The predicted modulation associated with the LFP was largely complementary to that driven by visual stimulation, as well as the activity of other neurons, and accounted for nearly half of the trial-to-trial variability in the spiking responses. Moreover, the LFP model predictions accurately captured the temporal structure of noise correlations between pairs of simultaneously recorded neurons, and explained the variation in correlation magnitudes observed across the population. These results therefore identify signatures of network activity related to the variability of cortical neuron responses, and suggest their central role in sensory cortical function. SIGNIFICANCE STATEMENT The function of sensory neurons is nearly always cast in terms of representing sensory stimuli. However, recordings from visual cortex in awake animals show that a large fraction of neural activity is not predictable from the stimulus. We show that this variability is predictable given the simultaneously recorded measures of network activity, local field potentials. A model that combines elements of these signals with the stimulus processing of the neuron can predict neural responses dramatically better than current models, and can predict the structure of correlations across the cortical population. In identifying ways to understand stimulus processing in the context of ongoing network activity, this work thus provides a foundation to understand the role of sensory cortex in combining sensory and cognitive variables.

The ability to distinguish between elements of a sensory neuron's activity that are stimulus independent versus driven by the stimulus is critical for addressing many questions in systems neuroscience. This is typically accomplished by measuring neural responses to repeated presentations of identical stimuli and identifying the trial-variable components of the response as noise. In awake primates, however, small “fixational” eye movements (FEMs) introduce uncontrolled trial-to-trial differences in the visual stimulus itself, potentially confounding this distinction. Here, we describe novel analytical methods that directly quantify the stimulus-driven and stimulus-independent components of visual neuron responses in the presence of FEMs. We apply this approach, combined with precise model-based eye tracking, to recordings from primary visual cortex (V1), finding that standard approaches that ignore FEMs typically miss more than half of the stimulus-driven neural response variance, creating substantial biases in measures of response reliability. We show that these effects are likely not isolated to the particular experimental conditions used here, such as the choice of visual stimulus or spike measurement time window, and thus will be a more general problem for V1 recordings in awake primates. We also demonstrate that measurements of the stimulus-driven and stimulus-independent correlations among pairs of V1 neurons can be greatly biased by FEMs. These results thus illustrate the potentially dramatic impact of FEMs on measures of signal and noise in visual neuron activity and also demonstrate a novel approach for controlling for these eye-movement-induced effects. SIGNIFICANCE STATEMENT Distinguishing between the signal and noise in a sensory neuron's activity is typically accomplished by measuring neural responses to repeated presentations of an identical stimulus. For recordings from the visual cortex of awake animals, small “fixational” eye movements (FEMs) inevitably introduce trial-to-trial variability in the visual stimulus, potentially confounding such measures. Here, we show that FEMs often have a dramatic impact on several important measures of response variability for neurons in primary visual cortex. We also present an analytical approach for quantifying signal and noise in visual neuron activity in the presence of FEMs. These results thus highlight the importance of controlling for FEMs in studies of visual neuron function, and demonstrate novel methods for doing so.

Variability and Correlations in Primary Visual Cortical Neurons Driven by Fixational Eye Movements

Cat Lateral Geniculate Nucleus Variability and Information in a Neural Code of the

An accurate circuit-based description of retinal ganglion cell computation

Saccadic modulation of stimulus processing in primary visual cortex

Angularis of the Barn Owl Computational Diversity in the Cochlear Nucleus

Forebrain Gaze Fields of the Barn Owl Frequency-Specific, Adaptive Plasticity in the Early Auditory Experience Induces

Owl's Inferior Colliculus Sounds by the Discharge Patterns of Neurons in the Representation of Temporal Features of Complex

Physiological Characterization of Retinal Ganglion Cell Types in Tilapia mariae

for Population Coding With Disparity-Vergence Eye Movements: Evidence Single-Unit Activity in Cortical Area MST Associated

Sweeps, and Sinusoidal Amplitude Modulations Auditory Midbrain: Responses to Noise, Frequency Processing of Modulated Sounds in the Zebra Finch

Reliable representation of the spectrotemporal features of an acoustic stimulus is critical for sound recognition. However, if all neurons respond with identical firing to the same stimulus, redundancy in the activity patterns would reduce the information capacity of the population. We thus investigated spike reliability and temporal fluctuation coding in an ensemble of neurons recorded in vitro from the avian auditory brain stem. Sequential patch-clamp recordings were made from neurons of the cochlear nucleus angularis while injecting identical filtered Gaussian white noise currents, simulating synaptic drive. The spiking activity in neurons receiving these identically fluctuating stimuli was highly correlated, measured pairwise across neurons and as a pseudo-population. Two distinct uncorrelated noise stimuli could be discriminated using the temporal patterning, but not firing rate, of the spike trains in the neural ensemble, with best discrimination using information at time scales of 5-20 ms. Despite high cross-correlation values, the spike patterns observed in individual neurons were idiosyncratic, with notable heterogeneity across neurons. To investigate how temporal information is being encoded, we used optimal linear reconstruction to produce an estimate of the original current stimulus from the spike trains. Ensembles of trains sampled across the neural population could be used to predict >50% of the stimulus variation using optimal linear decoding, compared with ∼20% using the same number of spike trains recorded from single neurons. We conclude that heterogeneity in the intrinsic biophysical properties of cochlear nucleus neurons reduces firing pattern redundancy while enhancing representation of temporal information.

Heterogeneity of intrinsic biophysical properties among cochlear nucleus neurons improves the population coding of temporal information.

oscillations in the rd1 mouse retina Intrinsic bursting of AII amacrine cells underlies

In many forms of retinal degeneration, photoreceptors die but inner retinal circuits remain intact. In the rd1 mouse, an established model for blinding retinal diseases, spontaneous activity in the coupled network of AII amacrine and ON cone bipolar cells leads to rhythmic bursting of ganglion cells. Since such activity could impair retinal and/or cortical responses to restored photoreceptor function, understanding its nature is important for developing treatments of retinal pathologies. Here we analyzed a compartmental model of the wild-type mouse AII amacrine cell to predict that the cell's intrinsic membrane properties, specifically, interacting fast Na and slow, M-type K conductances, would allow its membrane potential to oscillate when light-evoked excitatory synaptic inputs were withdrawn following photoreceptor degeneration. We tested and confirmed this hypothesis experimentally by recording from AIIs in a slice preparation of rd1 retina. Additionally, recordings from ganglion cells in a whole mount preparation of rd1 retina demonstrated that activity in AIIs was propagated unchanged to elicit bursts of action potentials in ganglion cells. We conclude that oscillations are not an emergent property of a degenerated retinal network. Rather, they arise largely from the intrinsic properties of a single retinal interneuron, the AII amacrine cell.

Intrinsic bursting of AII amacrine cells underlies oscillations in the rd1 mouse retina.

Neuronal selectivity results from both excitatory and suppressive inputs to a given neuron. Suppressive influences can often significantly modulate neuronal responses and impart novel selectivity in the context of behaviorally relevant stimuli. In this work, we use a naturalistic optic flow stimulus to explore the responses of neurons in the middle temporal area (MT) of the alert macaque monkey; these responses are interpreted using a hierarchical model that incorporates relevant nonlinear properties of upstream processing in the primary visual cortex (V1). In this stimulus context, MT neuron responses can be predicted from distinct excitatory and suppressive components. Excitation is spatially localized and matches the measured preferred direction of each neuron. Suppression is typically composed of two distinct components: (1) a directionally untuned component, which appears to play the role of surround suppression and normalization; and (2) a direction-selective component, with comparable tuning width as excitation and a distinct spatial footprint that is usually partially overlapping with excitation. The direction preference of this direction-tuned suppression varies widely across MT neurons: approximately one-third have overlapping suppression in the opposite direction as excitation, and many other neurons have suppression with similar direction preferences to excitation. There is also a population of MT neurons with orthogonally oriented suppression. We demonstrate that direction-selective suppression can impart selectivity of MT neurons to more complex velocity fields and that it can be used for improved estimation of the three-dimensional velocity of moving objects. Thus, considering MT neurons in a complex stimulus context reveals a diverse set of computations likely relevant for visual processing in natural visual contexts.

Diverse Suppressive Influences in Area MT and Selectivity to Complex Motion Features

The computation represented by a sensory neuron's response to stimuli is constructed from an array of physiological processes both belonging to that neuron and inherited from its inputs. Although many of these physiological processes are known to be nonlinear, linear approximations are commonly used to describe the stimulus selectivity of sensory neurons (i.e., linear receptive fields). Here we present an approach for modeling sensory processing, termed the Nonlinear Input Model (NIM), which is based on the hypothesis that the dominant nonlinearities imposed by physiological mechanisms arise from rectification of a neuron's inputs. Incorporating such ‘upstream nonlinearities’ within the standard linear-nonlinear (LN) cascade modeling structure implicitly allows for the identification of multiple stimulus features driving a neuron's response, which become directly interpretable as either excitatory or inhibitory. Because its form is analogous to an integrate-and-fire neuron receiving excitatory and inhibitory inputs, model fitting can be guided by prior knowledge about the inputs to a given neuron, and elements of the resulting model can often result in specific physiological predictions. Furthermore, by providing an explicit probabilistic model with a relatively simple nonlinear structure, its parameters can be efficiently optimized and appropriately regularized. Parameter estimation is robust and efficient even with large numbers of model components and in the context of high-dimensional stimuli with complex statistical structure (e.g. natural stimuli). We describe detailed methods for estimating the model parameters, and illustrate the advantages of the NIM using a range of example sensory neurons in the visual and auditory systems. We thus present a modeling framework that can capture a broad range of nonlinear response functions while providing physiologically interpretable descriptions of neural computation.

Inferring Nonlinear Neuronal Computation Based on Physiologically Plausible Inputs

Despite detailed knowledge about the anatomy and physiology of neurons in primary visual cortex (V1), the large numbers of inputs onto a given V1 neuron make it difficult to relate them to the neuron’s functional properties. For example, models of direction selectivity (DS), such as the Energy Model, can successfully describe the computation of phase-invariant DS at a conceptual level, while leaving it unclear how such computations are implemented by cortical circuits. Here, we use statistical modeling to derive a description of DS computation for both simple and complex cells, based on physiologically plausible operations on their inputs. We present a new method that infers the selectivity of a neuron’s inputs using extracellular recordings in macaque in the context of random bar stimuli and natural movies in cat. Our results suggest that DS is initially constructed in V1 simple cells through summation and thresholding of non-DS inputs with appropriate spatiotemporal relationships. However, this de novo construction of DS is rare, and a majority of DS simple cells, and all complex cells, appear to receive both excitatory and suppressive inputs that are already DS. For complex cells, these numerous DS inputs typically span a fraction of their overall receptive fields and have similar spatiotemporal tuning but different phase and spatial positions, suggesting an elaboration to the Energy Model that incorporates spatially localized computation. Furthermore, we demonstrate how these computations might be constructed from biologically realizable components, and describe a statistical model consistent with the feed-forward framework suggested by Hubel and Wiesel.

Construction of Direction Selectivity through Local Energy Computations in Primary Visual Cortex

Intracellular studies have revealed the importance of cotuned excitatory and inhibitory inputs to neurons in auditory cortex, but typical spectrotemporal receptive field models of neuronal processing cannot account for this overlapping tuning. Here, we apply a new nonlinear modeling framework to extracellular data recorded from primary auditory cortex (A1) that enables us to explore how the interplay of excitation and inhibition contributes to the processing of complex natural sounds. The resulting description produces more accurate predictions of observed spike trains than the linear spectrotemporal model, and the properties of excitation and inhibition inferred by the model are furthermore consistent with previous intracellular observations. It can also describe several nonlinear properties of A1 that are not captured by linear models, including intensity tuning and selectivity to sound onsets and offsets. These results thus offer a broader picture of the computational role of excitation and inhibition in A1 and support the hypothesis that their interactions play an important role in the processing of natural auditory stimuli.

Inferring the role of inhibition in auditory processing of complex natural stimuli.

Neurons in the medial superior temporal (MST) area of the primate visual cortex respond selectively to complex motion patterns defined by expansion, rotation, and deformation. Consequently they are often hypothesized to be involved in important behavioral functions, such as encoding the velocities of moving objects and surfaces relative to the observer. However, the computations underlying such selectivity are unknown. In this work we have developed a unique, naturalistic motion stimulus and used it to probe the complex selectivity of MST neurons. The resulting data were then used to estimate the properties of the feed-forward inputs to each neuron. This analysis yielded models that successfully accounted for much of the observed stimulus selectivity, provided that the inputs were combined via a nonlinear integration mechanism that approximates a multiplicative interaction among MST inputs. In simulations we found that this type of integration has the functional role of improving estimates of the 3D velocity of moving objects. As this computation is of general utility for detecting complex stimulus features, we suggest that it may represent a fundamental aspect of hierarchical sensory processing.

Hierarchical processing of complex motion along the primate dorsal visual pathway

Simple cells found in primary visual cortex are orientation selective. It has been experimentally found that they acquire this property with time i.e. learning of orientation selectivity takes place. Many computational models have been proposed for the development of orientation selectivity. Most of the models proposed so far are either abstract in nature or are very simplified version of actual learning mechanism. In this work we propose a model for development of orientation selectivity based on spike timing dependent plasticity (STDP), which till now is considered to be the actual learning mechanism adopted by neural circuits. We could obtain elongated segregated receptive field structure thus giving simple cells the property of orientation selectivity. We also observe that input activity plays a major role in the development of orientation selectivity, too much or too less a correlation between the inputs activities do not result in the formation of segregated ON and OFF regions in the RF structure [1]. There is also a need of normalization for the development of orientation selectivity.

Development of Receptive Field Structure of Simple Cell using Spike Timing Dependent Plasticity (STDP)

An Instructive Role for Patterned Spontaneous Retinal Activity in Mouse Visual Map Development

Visual neurons can respond with extremely precise temporal patterning to visual stimuli that change on much slower time scales. Here, we investigate how the precise timing of cat thalamic spike trains—which can have timing as precise as 1 ms—is related to the stimulus, in the context of both artificial noise and natural visual stimuli. Using a nonlinear modeling framework applied to extracellular data, we demonstrate that the precise timing of thalamic spike trains can be explained by the interplay between an excitatory input and a delayed suppressive input that resembles inhibition, such that neuronal responses only occur in brief windows where excitation exceeds suppression. The resulting description of thalamic computation resembles earlier models of contrast adaptation, suggesting a more general role for mechanisms of contrast adaptation in visual processing. Thus, we describe a more complex computation underlying thalamic responses to artificial and natural stimuli that has implications for understanding how visual information is represented in the early stages of visual processing.

Temporal Precision in the Visual Pathway through the Interplay of Excitation and Stimulus-Driven Suppression

Midbrain Auditory Single Neurons and Groups of Neurons in the Discrimination of Communication Vocalizations by

Construction of direction selectivity in V1: from simple to complex cells

A third GNM model of the LGN neuron that explicitly includes a filtered version of the RGC input (left) can determine if there are other inputs in addition to the RGC that influence the LGN spike train. (as in [9])There were no same-sign inhibitory filters detected, consistent with its retinal origin (#5 above).

The role of inhibition in formatting visual information in the retina and LGN

32 33 An understanding of the neural code in a given visual area is often confounded by the immense 34 complexity of visual stimuli combined with the number of possible meaningful patterns that 35 comprise the response spike train. In the Lateral Geniculate Nucleus (LGN), visual stimulation 36 generates spike trains comprised of short spiking episodes (‘events’) separated by relatively long 37 intervals of silence, which establishes a basis for in-depth analysis of the neural code. By studying 38 this event structure in both artificial and natural visual stimulus contexts and at different contrasts, 39 we are able to describe the dependence of event structure on stimulus class and discern which 40 aspects generalize. We find that the event structure on coarse time scales is robust across stimulus 41 and contrast, and can be explained by receptive field processing. However, the relationship between 42 the stimulus and fine-time-scale features of events is less straightforward, partially due to a 43 significant amount of trial-to-trial variability. A new measure called “label information” identifies 44 structural elements of events that can contain up to 30% more information in the context of natural 45 movies, compared with what is available from the overall event timing. The first interspike interval 46 of an event most robustly conveys additional information about the stimulus, and is somewhat more 47 informative than the event spike count, and much more informative than the presence of bursts. 48 Nearly every event is preserved across contrast despite changes in their fine-time-scale features, 49 suggesting that – at least on a coarse level – the stimulus selectivity of LGN neurons is contrast 50 invariant. Event-based analysis thus casts previously studied elements of LGN coding such as 51 contrast adaptation and receptive field processing in a new light, and leads to broad conclusions 52 about the composition of the LGN neuronal code. 53 54

Journal of Neurophysiology Title Page Title: the Episodic Nature of Spike Trains in the Early Visual Pathway Authors: Episodic Coding in the Lgn Contact Information

Spike time dependent plasticity (STDP) has been observed in both developing and adult animals. Theoretical studies suggest that it implicitly leads to both competition and homeostasis in addition to correlation-based plasticity, making it a good candidate to explain developmental refinement and plasticity in a number of systems. However, it has only been observed to play a clear role in development in a small number of cases. Because the fast time scales necessary to elicit STDP, it would likely be inefficient in governing synaptic modifications in the absence of fast correlations in neural activity. In contrast, later stages of development often depend on sensory inputs that can drive activity on much faster time scales, suggesting a role in STDP in many sensory systems after opening of the eyes and ear canals. Correlations on fast time scales can be also be present earlier in developing microcircuits, such as those produced by specific transient “teacher” circuits in the cerebral cortex. By reviewing examples of each case, we suggest that STDP is not a universal rule, but rather might be masked or phased in, depending on the information available to instruct refinement in different developing circuits. Thus, this review describes selected cases where STDP has been studied in developmental contexts, and uses these examples to suggest a more general framework for understanding where it could be playing a role in development.

The Applicability of Spike Time Dependent Plasticity to Development

An understanding of the neural code in a given visual area is often confounded by the immense complexity of visual stimuli combined with the number of possible meaningful patterns that comprise the response spike train. In the lateral geniculate nucleus (LGN), visual stimulation generates spike trains comprised of short spiking episodes ("events") separated by relatively long intervals of silence, which establishes a basis for in-depth analysis of the neural code. By studying this event structure in both artificial and natural visual stimulus contexts and at different contrasts, we are able to describe the dependence of event structure on stimulus class and discern which aspects generalize. We find that the event structure on coarse time scales is robust across stimulus and contrast and can be explained by receptive field processing. However, the relationship between the stimulus and fine-time-scale features of events is less straightforward, partially due to a significant amount of trial-to-trial variability. A new measure called "label information" identifies structural elements of events that can contain ≤30% more information in the context of natural movies compared with what is available from the overall event timing. The first interspike interval of an event most robustly conveys additional information about the stimulus and is somewhat more informative than the event spike count and much more informative than the presence of bursts. Nearly every event is preserved across contrast despite changes in their fine-time-scale features, suggesting that--at least on a coarse level--the stimulus selectivity of LGN neurons is contrast invariant. Event-based analysis thus casts previously studied elements of LGN coding such as contrast adaptation and receptive field processing in a new light and leads to broad conclusions about the composition of the LGN neuronal code.

The episodic nature of spike trains in the early visual pathway.

How is stimulus processing of the lateral geniculate nucleus derived from its input(s)?

It is well-known that adaptation to stimulus properties has important effects on the activity of neurons in sensory systems. Previous single-cell studies found that t he spikes from individual retinal, LGN, and V1 cells show more temporal variability across repeats of suboptimal stimuli, such as low-contrast stimuli [1,2,3]. However, it is not known how adaptation affects spi ke-timing precision in a population of cells.

Adaptation effects on spike-timing precision within and across LGN cells

Patterned spontaneous activity in the developing retina is necessary to drive synaptic refinement in the lateral geniculate nucleus (LGN). Using perforated patch recordings from neurons in LGN slices during the period of eye segregation, we examine how such burst-based activity can instruct this refinement. Retinogeniculate synapses have a novel learning rule that depends on the latencies between pre- and postsynaptic bursts on the order of one second: coincident bursts produce long-lasting synaptic enhancement, whereas non-overlapping bursts produce mild synaptic weakening. It is consistent with “Hebbian” development thought to exist at this synapse, and we demonstrate computationally that such a rule can robustly use retinal waves to drive eye segregation and retinotopic refinement. Thus, by measuring plasticity induced by natural activity patterns, synaptic learning rules can be linked directly to their larger role in instructing the patterning of neural connectivity.

A Burst-Based “Hebbian” Learning Rule at Retinogeniculate Synapses Links Retinal Waves to Activity-Dependent Refinement

Adaptation to Stimulus Contrast and Correlations during Natural Visual Stimulation

Temporal precision in the neural code and the timescales of natural vision

Until recently, neurons in the healthy brain were considered immune-privileged because they did not appear to express MHC class I (MHCI). However, MHCI mRNA was found to be regulated by neural activity in the developing visual system and has been detected in other regions of the uninjured brain. Here we show that MHCI regulates aspects of synaptic function in response to activity. MHCI protein is colocalized postsynaptically with PSD-95 in dendrites of hippocampal neurons. In vitro, whole-cell recordings of hippocampal neurons from β2m/TAP1 knockout (KO) mice, which have reduced MHCI surface levels, indicate a 40% increase in mini-EPSC (mEPSC) frequency. mEPSC frequency is also increased 100% in layer 4 cortical neurons. Similarly, in KO hippocampal cultures, there is a modest increase in the size of presynaptic boutons relative to WT, whereas postsynaptic parameters (PSD-95 puncta size and mEPSC amplitude) are normal. In EM of intact hippocampus, KO synapses show a corresponding increase in vesicles number. Finally, KO neurons in vitro fail to respond normally to TTX treatment by scaling up synaptic parameters. Together, these results suggest that postsynaptically localized MHCl acts in homeostatic regulation of synaptic function and morphology during development and in response to activity blockade. The results also imply that MHCI acts retrogradely across the synapse to translate activity into lasting change in structure.

Tuning curves are widely used to characterize the responses of sensory neurons to external stimuli, but there is an ongoing debate as to their role in sensory processing. Commonly, it is assumed that a neuron's role is to encode the stimulus at the tuning curve peak, because high firing rates are the neuron's most distinct responses. In contrast, many theoretical and empirical studies have noted that nearby stimuli are most easily discriminated in high-slope regions of the tuning curve. Here, we demonstrate that both intuitions are correct, but that their relative importance depends on the experimental context and the level of variability in the neuronal response. Using three different information-based measures of encoding applied to experimentally measured sensory neurons, we show how the best-encoded stimulus can transition from high-slope to high-firing-rate regions of the tuning curve with increasing noise level. We further show that our results are consistent with recent experimental findings that correlate neuronal sensitivities with perception and behavior. This study illustrates the importance of the noise level in determining the encoding properties of sensory neurons and provides a unified framework for interpreting how the tuning curve and neuronal variability relate to the overall role of the neuron in sensory encoding.

The Relationship between Tornado Reports and Cloud-to-Ground Lightning Polarity in the Southeastern United States during the Cool Season from 1989 to 2002

Sensory neurons, especially at the early stages of the pathway, are often characterized by their selectivity to particular features of the stimulus. Nevertheless, it is often a challenge to relate this feature sensitivity to the encoding of naturalistic stimuli. In the rat vibrissa pathway, thalamocortical neurons selectively respond to velocity transients. However, impinging suppressive influences on thalamocortical neurons further complicate this selectivity by causing a highly nonlinear dependence of single-cell responses on stimulus history. The high capacity of the vibrissa pathway for encoding textural information indicates that feature selectivity is an important property of this tactile sensory system. The main goal of this study was therefore to quantify the feature-selectivity of S1 neurons in the vibrissa pathway. We found that these neurons encode higher velocities with greater spike counts, higher temporal precision, and shorter response latencies. Furthermore, high-velocity stimuli were shown to evoke stronger poststimulus response suppression, but also recovered from a given amount of suppression more quickly. We hypothesize that a model based on responses to paired deflections at various velocities can accurately predict single-cell responses to more complex, naturalistic stimuli. We are subsequently developing a dimensionality-reduction transformation that maps continuous vibrissa deflections into simplified pulse sequences such that both stimuli evoke very similar single-cell responses. Used with naturalistic stimuli obtained via high-speed videography of behaving animals, this transformation provides insight into the computations carried out by single neurons in the layer 4 of the vibrissa cortex. It also provides a basis on which studies of population coding can further develop our understanding of the coding of tactile textures by this brain area.

Cortical maps are remarkably precise, with organized arrays of thalamocortical afferents (TCAs) that project into distinct neuronal modules. Here, we present evidence for the involvement of efficient neurotransmitter release in mouse cortical barrel map development using barrelless mice, a loss-of-function mutant of calcium/calmodulin-activated adenylyl cyclase I (AC1), and mice with a mutation in Rab3-interacting molecule 1α (RIM1α), an active zone protein that regulates neurotransmitter release. We demonstrate that release efficacy is substantially decreased in barrelless TCAs. We identify RIMs as important phosphorylation targets for AC1 in the presynaptic terminal. We further show that RIM1α mutant mice have reduced TCA neurotransmitter release efficacy and barrel map deficits, although not as severe as those found in barrelless mice. This supports the role of RIM proteins in mediating, in part, AC1 signaling in barrel map development. Finally, we present a model to show how inadequacies in presynaptic function can interfere with activity-dependent processes in neuronal circuit formation. These results demonstrate how efficient synaptic transmission mediated by AC1 function contributes to the development of cortical barrel maps.

Role of Efficient Neurotransmitter Release in Barrel Map Development

Some of the greatest advances in neural coding have occurred in the visual system, where the relationship between visual stimuli and the observed neuronal activity is relatively straightforward. However, experiments that probe this relationship in more “natural” contexts have revealed many higher order aspects of visual neuron responses, such as their precise timing down to milliseconds, adaptation to contrast, and non-linear summation of multiple stimuli. Here, we describe a new modeling framework applied to LGN neuron data recorded in the context of both artificial noise stimuli and “natural” movies. The basis of this model is the familiar “LN” (linear-non-linear) cascade model based on a linear spatiotemporal receptive field (STRF), but adds a second “suppressive” STRF with different tuning properties. Extending the maximum-likelihood estimation framework proposed by [1], we simultaneously fit both spatiotemporal receptive fields using a modest amount of recording time in the context of both artificial “noise” stimuli and natural movies.

Direct measurement of “suppression” in the LGN in the context of natural stimuli and its implications for visual coding

In studying how visual neurons encode stimuli, there is currently a large divide between information theoretic approaches and more traditional receptive field-based analyses. While receptive fields (RFs) are straightforward to measure and are a standard part of almost every visual physiology experiment, traditional RF-based models of neurons are unable to explain the timing precision and the reliability of neural responses. At the same time, mutual information rates – which demonstrate the importance of reliability and precise timing in representing visual stimuli – are both difficult to measure experimentally and, on their own, do little to elucidate how the neuron actually encodes visual stimuli. Using a combination of experimental data and realistic simulations, we directly relate easily measurable elements of neuron encoding to the mutual information between the stimulus and response. We thus demonstrate how differences in visual encoding either across neurons or in the same neuron in different adaptation states relate to the role of the neuron in conveying visual information. We first develop an RF-based model of encoding that can reproduce the information rate of the neuron. Typical RF-based models of encoding use the receptive field to produce a linear prediction of the neural response, and then a non-linear function (the “non-linearity”) to map the linear prediction to a firing rate. In this way, this LN (linear non-linear) model conceptually separates how the neuron processes stimuli (L) from the details of how its response is generated (N). We show that the nonlinearity – which intuitively corresponds to the neuron’s reliability – is underestimated for real neurons because of their refractory period, and present a robust way to account for the refractory period and recover an accurate estimate of the neuron’s reliability. In doing so, we identify other easily measurable aspects of the neural response (such as the spike-time “jitter”) that are important in determining its information rate. Measuring these elements allows for a “model-based information calculation” (MBIC) that matches the single-spike information rate calculated through conventional approaches. This MBIC can be performed over single experimental trials, and applied to a vast array of conventional visual physiology experiments. Finally, we describe the dependence of the information rate on each encoding element. We analyze a library of LGN neurons recorded during spatiotemporal white noise experiments, and show how their information rates vary as a function of differences in their measurable properties. For example, an increased time scale of the refractory period corresponds to a decrease in both the information rate and firing rate, such that the amount of information per spike is higher. Similarly, a higher threshold (i.e., how selectively a neuron responds to stimuli) implies lower information and firing rates, but a higher information per spike. On the other hand, neurons with higher gain (i.e., stronger responses to the same stimuli) have a larger information rate but proportionally larger firing rate, such that there is negligible effect on the information per spike. In this way, we can relate the differences in information rates across the population of LGN neurons to different properties of their encoding. Thus, in developing a model-based information calculation, we describe which features of neuronal encoding are important to the role of visual neurons in representing the visual world. These features are the (1) receptive field, which describes the spatiotemporal integration of the neuron; (2) the non-linearity, which accounts for the reliability of firing; and (3) the recovery function and timing jitter, which account for the neuron’s temporal precision. In addition to providing an intuitive understanding of a neuron’s information rate, these encoding properties can be measured in any visual experiment that maps receptive fields, making an information theoretic approach accessible in a wide variety of experimental contexts.

The important aspects of visual encoding : relating receptive fields to mutual information rates in visual neurons

Although the Shannon mutual information can be used to reveal general features of the neural code, it cannot directly address which symbols of the code are significant. Further insight can be gained by using information measures that are specific to particular stimuli or responses. The specific information is a previously proposed measure of the amount of information associated with a particular response; however, as I show, it does not properly characterize the amount of information associated with particular stimuli. Instead, I propose a new measure: the stimulus-specific information (SSI), defined to be the average specific information of responses given the presence of a particular stimulus. Like other information theoretic measures, the SSI does not rely on assumptions about the neural code, and is robust to non-linearities of the system. To demonstrate its applicability, the SSI is applied to data from simulated visual neurons, and identifies stimuli consistent with the neuron's linear kernel. While the SSI reveals the essential linearity of the visual neurons, it also successfully identifies the well-encoded stimuli in a modified example where linear analysis techniques fail. Thus, I demonstrate that the SSI is an appropriate measure of the information associated with particular stimuli, and provides a new unbiased method of analysing the significant stimuli of a neural code.

Neural activity is often required for the final stages of synaptic refinement during brain development. It is thought that learning rulesacting at the individual synapse level, which specify how pre and postsynaptic activity lead to changes in synaptic efficacy, underlie such activity-dependent development. How such rules might function in vivo can be addressed in the retinogeniculate system because the input activity from the retina and its importance in development are both known. In fact, detailed studies of retinal waves have revealed their complex spatiotemporal properties, providing insights into the mechanisms that use such activity to guide development. First of all, the information useful for development is contained in the retinal waves and can be quantified, placing constraints on synaptic learning rules that use this information. Furthermore, knowing the distribution of activity over the entire set of inputs makes it possible to address a necessary component of developmental refinement: rules governing competition between synaptic inputs. In this way, the detailed knowledge of retinal input and lateral geniculate nucleus development provides a unique opportunity to relate the rules of synaptic plasticity directly to their role in development.

Retinal Waves: Implications for Synaptic Learning Rules during Development

Information theory provides tools to analyze neural ensembles that do not depend on assumptions of linearity or correlations in the stimulus ensemble. Here, we use a newly derived information theoretic measure, the stimulus-specific information (SSI), to analyze the important stimuli to simulated visual neurons. Using full-frame flicker stimuli as input to a simulated LGN neuron, we find that the SSI returns the linear kernel of the neuron. For correlated input, linear reconstruction is confounded by correlations in the stimulus. However, we show that the SSI reliably finds the linear kernel of the neuron independent of stimulus correlations. Thus, the SSI is a general tool to discern the important stimuli of neurons, independent of stimulus correlations. It should also be useful for neurons with non-linear response properties.

Information Theoretic Measure of Stimulus Significance is Not Confounded by Stimulus Correlations or Non-Linearities

Spontaneous neural activity that is present in the mammalian retina before the onset of vision is required for the refinement of retinotopy in the lateral geniculate nucleus and superior colliculus. This paper explores the information content of this retinal activity, with the goal of determining constraints on the nature of the developmental mechanisms that use it. Through information-theoretic analysis of multielectrode and calcium-imaging experiments, we show that the spontaneous retinal activity present early in development provides information about the relative positions of retinal ganglion cells and can, in principle, be used at retinogeniculate and retinocollicular synapses to refine retinotopy. Remarkably, we find that most retinotopic information provided by retinal waves exists on relatively coarse time scales, suggesting that developmental mechanisms must be sensitive to timing differences from 100 msec up to 2 sec to make optimal use of it. In fact, a simple Hebbian-type learning rule with a correlation window on the order of seconds is able to extract the bulk of the available information. These findings are consistent with bursts of action potentials (rather than single spikes) being the unit of information used during development and suggest new experimental approaches for studying developmental plasticity of the retinogeniculate and retinocollicular synapses. More generally, these results demonstrate how the properties of neuronal systems can be inferred from the statistics of their input.

Propagating neural activity in the developing mammalian retina is required for the normal patterning of retinothalamic connections. This activity exhibits a complex spatiotemporal pattern of initiation, propagation, and termination. Here, we discuss the behavior of a model of the developing retina using a combination of simulation and analytic calculation. Our model produces spatially and temporally restricted waves without requiring inhibition, consistent with the early depolarizing action of neurotransmitters in the retina. We find that highly correlated, temporally regular, and spatially restricted activity occurs over a range of network parameters; this ensures that such spatiotemporal patterns can be produced robustly by immature neural networks in which synaptic transmission by individual neurons may be unreliable. Wider variation of these parameters, however, results in several different regimes of wave behavior. We also present evidence that wave properties are locally determined by a single variable, the fraction of recruitable (i.e., nonrefractory) cells within the dendritic field of a retinal neuron. From this perspective, a given local area’s ability to support waves with a wide range of propagation velocities—as observed in experiment—reflects the variability in the local state of excitability of that area. This prediction is supported by whole-cell voltage-clamp recordings, which measure significant wave-to-wave variability in the amount of synaptic input a cell receives when it participates in a wave. This approach to describing the developing retina provides unique insight into how the organization of a neural circuit can lead to the generation of complex correlated activity patterns.

A two-layer model describes the spatiotemporal properties of spontaneous retinal waves

Dynamic Processes Shape Spatiotemporal Properties of Retinal Waves

We study the properties of a spin-polarized Fermi gas in a harmonic trap, using the semiclassical (Thomas-Fermi) approximation. Universal forms for the spatial and momentum distributions are calculated, and the results compared with the corresponding properties of a dilute Bose gas.

Case summary A 2-year-old female neutered domestic shorthair cat presented with an 18-month history of intermittent lameness on all four limbs. The cat was markedly lame on all four limbs. There was alternation between toe-walking on the forelimbs with a hunched posture and using the dorsal aspect of the carpi to walk on. The cat would hiss repeatedly when walking and would lie down tentatively, appearing happier and less painful when lying. When not lying, the cat preferred to sit back on the hindlimbs and non-weightbear on the forelimbs (the so-called kangaroo stance). Physical examination detected pain on palpation of the calcaneus bone and Achilles tendon bilaterally, and general resentment to handling. Investigations revealed an elevated creatine kinase, a positive Toxoplasma gondii IgG titre, toxic neutrophilic inflammation within the Achilles tendon bursae, electromyography and nerve conduction velocity studies consistent with a diffuse muscular disease, and histopathology of the muscle consistent with a chronic and diffuse myopathy. Arthrocentesis samples and an antinuclear antibodies titre were normal. Prior treatment with meloxicam had been ineffective. A 6-week course of clindamycin was prescribed; an improvement was seen within 3 days and clinical resolution at 3 months. The cat remained clinically normal after 20 months. Relevance and novel information To our knowledge, there have been no previously published reports of histopathologically confirmed myopathy as a result of T gondii in cats. This report suggests toxoplasmosis should be considered as a differential diagnosis in cats with myopathies or lameness in the absence of other causes.

Lameness, generalised myopathy and myalgia in an adult cat with toxoplasmosis

Does hoof deformation differ between horses with collapsed heels and horses with non-collapsed heels?

Group IVB and VB transition metal carbides, nitrides, borides and oxides are attractive for extreme environment applications. While stoichiometric phases tend to exhibit the highest temperature capability, highest hardness and superior chemical inertness, mixtures of binary stoichiometric phases and non-stoichiometric phases have demonstrated tailorable mechanical properties. Ternary systems have also exhibited unique mechanical properties in addition to superior oxidation behavior. Efforts at Plasma Processes, using vacuum plasma spray (VPS) fabrication, have focused on advancing the technology readiness level (TRL) and manufacturing readiness level (MRL) of various ultra-high temperature ceramics in the form of coatings and structural components. Studies have included fabrication and characterization of VPS deposits comprised of the following chemistries: Ta-C, Ta-Hf-C, Hf-N, Hf-Ta-N, Zr-C, Zr-O, Zr-C-Hf-O. This presentation will provide an overview of select chemistries and discuss the following:  Temperature-dependent physical and mechanical properties  Processing-microstructure-property relationship  Progression from coupon to sub-scale to full-scale fabrication

Ultra-high temperature ceramic coatings and structures formed by vacuum plasma spray

Suzy Q's is a retail business located in the southeastern United States. It offers hand-knitted scarves; handmade hair accessories; handcrafted beaded jewelry such as necklaces, bracelets, and earrings; small handmade children's toys; and stock and custom-printed T-shirts. It began operations in early 2014. The owners established an online store and developed plans to sell items at local craft fairs and farmers’ markets in the southeastern United States. During its initial launch, the business generated limited orders for its products. In the beginning there was a limited amount of advertising using social media, which consisted of establishing a Facebook page, posting notifications on the business's Facebook page, and posting notifications about the business to the owners’ personal contacts on Facebook. Despite establishing a web presence and utilizing social media in its first year of operations, Suzy Q's did not generate a significant number of orders and received very little revenue. The owners of Suzy Q's, our client, established a goal to generate at least $700 per month in revenue for the calendar year 2015. Our analysis of the business revealed that the managers and employees had the skills needed to perform the work, but the lack of orders presented an obstacle to achieving their business goals. After completing a performance analysis, we recommended that Suzy Q's establish a single online presence, implement a marketing effort, establish a local presence, create a dedicated studio space, and create a formal business plan. It was our belief that Suzy Q's had the potential to reach its goals set for 2015 and beyond if these solutions were implemented.

A series of (HfN)_1− x (TaN)_x, ceramics with x representing the starting powder blend compositions of 0.0, 18.8, 28.1, and 46.7 at.%, have been fabricated by vacuum plasma spraying. During the plasma spraying, the mixture lost approximately 25 at.% nitrogen facilitating the precipitation of metallic and metal-rich nitride phases. These specimens underwent static air oxidation exposure up to 1700 °C. In general, it was found that the addition of tantalum nitrides to the hafnium nitrides resulted in poorer oxidation behavior. However, the 18.8 at.% specimen deviated from this trend and had the lowest observed mass change. This specimen formed a dark-colored oxide scale, indexed as Hf_6Ta_2O_17, which acted as a passivation layer. Within the scale, hafnium oxynitride phases were observed. A transformation pathway in forming these rhombohedral oxynitride phases is proposed by the filling in of oxygen in the light element interstitial locations of the rhombohedral ε-Hf_3N_2 and ζ-Hf_4N_3 structures.

Oxidation behavior of vacuum plasma-sprayed hafnium–tantalum nitrides

A wide variety of microstructures have been obtained by vacuum plasma spraying (VPS) 39Ta:61C atomic percent feedstock powders. During processing, the powder feed was fed through a high energy VPS plasma plume, where altering nozzle angle changed the overall retained carbon concentration in the deposited material. The samples were subsequently sintered and hot isostatic pressed to homogenize and consolidate the microstructure. The microstructures consisted of grains that were either equiaxed or acicular. In the samples with less carbon loss, the equiaxed grains were either the TaC phase or a TaC matrix that encased fine laths of Ta4C3. In the sample with the most carbon loss, acicular grains were found containing layered and parallel TaC, Ta2C, and Ta4C3 laths along the major-axis of the grains. The phases of the compounds have been determined by using complimentary X-ray diffraction and electron diffraction techniques. Focused ion beam serial sectioning and transmission electron microscopy tilt series tomography were performed to generate three-dimensional reconstructions of the microstructure morphologies. This article addresses how tantalum carbide microstructures are controlled by the overall concentration and phase fraction content in each of these samples.

Variations in Tantalum Carbide Microstructures with Changing Carbon Content

Influence of hafnium carbide on vacuum plasma spray processed tantalum carbide microstructures

The oxide inclusion and porosity defect structures in a tantalum carbide specimen fabricated from vacuum plasma spraying with postspraying sintering and hot-isostatic pressing has been characterized. The tantalum carbide powders were obtained using a carbothermal reduction process of tantalum oxide precursors. During its fabrication, oxide-based inclusions formed from intrinsic impurities in the powder. Using serial sectioning and three-dimensional reconstruction techniques, interconnected globular oxide inclusions were revealed to be within the matrix phase and in the grain boundaries. The oxide phase was identified to be z-Ta2O5 through selected area electron diffraction. The two- and three-dimensional porosity size distribution was compared and accounted for ~2% of the volume.

Quantification of Oxide Inclusions and Porosity Structure in a Tantalum Carbide Microstructure Fabricated From Carbothermal Reduced Tantalum Oxide Precursor Powders

The -TaC phase has a melting temperature near 4000 o C and is one of the highest melting temperatures known [1]. The precipitation of substoichiometric Ta-rich phases, such as -Ta 2 C and -Ta 4 C 3 , with similar high melting points, provides ample opportunities to tailor the microstructure for improved thermo-mechanical behavior. Vacuum plasma spraying (VPS) was used to fabricate a multi-phase structure of tantalum carbides as a function of chemistry and solidification route. During the VPS process, TaC powder was melted under a plasma arc and rapidly solidified onto a graphite mandrel. The loss of carbon was controlled by the resonance time the powder spent in the plasma. These samples were then hot isostatically pressed to homogenize the composition and densify the material. The solidification route with the subsequent precipitation of different Ta-rich substoichiometric phases can be used to modify the microstructure in the thermodynamic two-phase regime, figure 1. This work has explored how the precipitation of the multiple phases developed and controlled the resulting microstructure. Post processing, the specimens were characterized by X-ray and electron diffraction for phase identification. The specimens were then mounted and a 10 isolated pillar was cut out of the edge of the specimen for serial sectioning. A protective platinum cap, ~5 was deposited onto the surface of the pillar. This pillar was then focus ion beam (FIB) milled at 1 nA in a FEI Quanta 3D dual beam FIB at steps sizes of 100

Influence of Precipitation Sequence on the 3D TaC + Ta2C/Ta4C3 Microstructure Processed by Vacuum Plasma Spraying

Plasma Processing of Lunar Regolith Simulant for Oxygen and Glass Production

Abstract An investigation of microstructural development and structure–property relationships of transient liquid phase (TLP) bonded current generation γ-TiAl alloy, known as Gamma Met PX, is presented. This joining technique employed a composite interlayer consisting of a non-melting constituent (TiAl alloy) and a liquid forming constituent (copper). The microstructures of the bonds, identified using light microscopy and scanning electron microscopy, are correlated with room temperature mechanical performance. These studies suggested that joints can retain properties similar (i.e. >90%) to that of the bulk material when employing a suitable composite interlayer, bonding conditions and post-bond heat treatment. Additionally, comparisons are drawn between wide gap TLP bonding of an earlier generation γ-TiAl alloy, Ti–48Al–2Cr–2Nb (at.-%), and wide gap TLP bonding of Gamma Met PX.

Transient liquid phase bonding of Gamma Met PX: microstructure and mechanical properties

The wettability of various polycrystalline and single crystal nickel-base superalloys by a composite interlayer has been examined dynamically, using hot-stage light microscopy on sessile drop specimens (supplemented by post-spreading characterization), in order to explore the origins of differences in wettability. In this paper, the roles of both substrate-oxide composition and substrate microstructure in wettability are discussed.

Hot-Stage Light Microscopy Studies of the Wettability of Nickel-Base Superalloys during Transient Liquid Phase Bonding

Transient liquid phase bonding of a third generation gamma-titanium aluminum alloy: Gamma Met PX

Abstract A review of the transient liquid phase (TLP) bonding process is presented in this paper. This review concentrates on the mechanisms of the TLP process, including both microstructural development and wettability aspects. However, design related issues and engineering applications are also considered. The paper explains how the TLP bonding process offers the potential for producing joints with microstructures and hence mechanical properties that are similar to those of the parent materials. The process of isothermal solidification is discussed at some length. The paper considers the ways in which specific microstructural features of the substrate material–interlayer material combination influence microstructural development. A distinction is drawn between cases where the progression of isothermal solidification dominates the final microstructure and those where events occurring after the completion of isothermal solidification are paramount. The paper describes the practical limitations on the production of parent-metal-like microstructures and the complexity of microstructural development in real materials, especially where dissimilar substrates are involved. Modification of the TLP bonding process to accommodate cases of limited solid solubility and/or low diffusion coefficients is discussed.

The microstructures developed in dissimilar superalloy transient liquid phase (TLP) bonds are more complex than those between similar materials. This paper investigates the microstructure and mechanical properties of single crystal to polycrystalline nickel-base superalloy TLP bonds in an attempt to understand phenomena governing microstructural development and structure property relationships.

Microstructural development and relationship to mechanical properties in polycrystalline to single crystal nickel-base superalloy transient liquid phase (TLP) bonds

Microstructure and mechanical properties of titanium aluminide wide-gap, transient liquid-phase bonds prepared using a slurry-deposited composite interlayer

Transient liquid phase (TLP) bonding [1] is widely used in the aerospace industry for both initial fabrication and preand post-service repairs. TLP bonding is derived from high-temperature brazing [2]. However, unlike conventional brazing, extensive diffusion of bond-line and/or substrate constituents is allowed to occur during bonding. This induces compositional changes at the bond-line, which in turn raise the melting temperature of the interlayer used to form the bond. Thus, TLP bonds undergo isothermal re-solidification at the bonding temperature. If a suitable post-isothermal-solidification homogenization treatment is applied, the remelt-temperature, microstructure and hence properties of TLP bonded components can match those of the parent materials. Given that TLP bonding is conducted under isothermal conditions, well below the melting temperature of the substrates and can reproduce parent-metal microstructures, this process is well suited to the joining of damage-sensitive materials, with carefully tailored microstructures, such as structural intermetallic compounds.

Transient Liquid Phase Bonding of Titanium Aluminide Alloys – A Microstructural Investigation

The crystallization behavior of the West Valley reference borosilicate glass. Progress report, October 1, 1986--September 30, 1987

Identification of excitation and inhibition in the auditory cortex using nonlinear modeling

Re-testing the energy model: identifying features and nonlinearities of complex cells.

Laboratory investigation; a journal of technical methods and pathology

Targeted Quantitative Mass Spectrometry Analysis of Protein Biomarkers From Previously Stained Single Formalin-Fixed Paraffin-Embedded Tissue Sections.

2558 Background: An ongoing multicenter, open-label, phase 1 study of the anti–CTLA-4 antibody MK-1308 in combination with pembro in advanced solid tumors (NCT03179436) revealed a manageable safety profile and promising efficacy in pts with first-line (1L) advanced NSCLC. Data from a larger sample size and longer follow-up are presented. Methods: In dose escalation (DE), pts with advanced solid tumors received MK-1308 by IV administration at 25, 75, or 200 mg Q3W ×1 cycle then in combination with pembro 200 mg Q3W ×4 cycles followed by pembro monotherapy (up to 35 cycles). In dose confirmation (DC), pts with 1L advanced NSCLC received MK-1308 at 25 or 75 mg—Q3W or Q6W—plus pembro 200 mg Q3W (up to 35 cycles). Safety (all treated pts), efficacy (subset of 1L NSCLC pts), pharmacokinetics (PK, all treated pts), and PD-L1 tumor expression (subset of 1L NSCLC pts) were analyzed. Results: 213 pts were treated (DE, n=39; DC, n=174). All pts were included in the safety analyses (median follow-up, 8 months); 113 pts from DC were included in the efficacy analyses (median follow-up, 8 months). PK showed a dose-dependent increase in MK-1308 exposure. Neither target dose-limiting toxicity (≥10%) nor maximum tolerated dose were reached for MK-1308 plus pembro; however, toxicity increased with increasing MK-1308 dose and shorter dosing intervals. Treatment-related adverse events grade ≥3 occurred at the lowest rates at 25 mg Q3W in DE (0%) and 25 mg Q6W in DC (25%) and at the highest rates at 200 mg Q3W in DE (75%) and 75 mg Q3W in DC (50%). Efficacy was observed at all MK-1308 dose levels and intervals: confirmed ORR per RECIST 1.1 by central review in 1L advanced NSCLC was 39% at 25 mg Q3W, 33% at 25 mg Q6W, 22% at 75 mg Q6W, and 25% at 75 mg Q3W; 6-month PFS and OS rates are 67% and 89% for the 25 mg Q6W arm. There was a 25% ORR in PD-L1–negative 1L advanced NSCLC pts. Conclusions: MK-1308 plus pembro was generally well tolerated with no unexpected toxicity and conferred encouraging antitumor activity in 1L advanced NSCLC pts. Efficacy, safety, and PK data suggest that 25 mg given Q6W is the recommended phase 2 dose for MK-1308 in combination with pembro. Clinical trial information: NCT03179436.

Antitumor activity and safety of MK-1308 (anti-CTLA-4) plus pembrolizumab (pembro) in patients (pts) with non-small cell lung cancer (NSCLC): Updated interim results from a phase I study.

Annals of oncology : official journal of the European Society for Medical Oncology

Phase I study of the CTLA-4 inhibitor MK-1308 in combination with pembrolizumab in patients with advanced solid tumors.

Inhibition of O-GlcNAcase leads to elevation of O-GlcNAc tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice

Generation and characterization of antibodies specific for caspase-cleaved neo-epitopes: a novel approach

Programmed cell death occurs physiologically via distinct morphological and biochemical features, namely apoptosis, necroptosis, or programmed necrosis. In all these processes, caspases play a crucial role. These cysteinyl aspartate-specific proteases (hence the name caspases) include a dozen of distinct enzymes that are involved in inflammation, activation, or execution of the apoptotic biochemical events. Here, we briefly outline the biochemical events involving capspases in cell death, with its clinical implication. The involvement in several oncological, infective and neurological diseases, as well as the development of low molecular compounds provide interesting therapeutic perspective in this growing area of research.

Maturation-dependent sensitivity of oligodendrocyte lineage cells to apoptosis: implications for normal development and disease

The genome of ε15, a serotype-converting, Group E1 Salmonella enterica-specific bacteriophage

The genome sequence of the Salmonella enterica serovar Anatum-specific, serotype-converting bacteriophage epsilon15 has been completed. The nonredundant genome contains 39,671 bp and 51 putative genes. It most closely resembles the genome of phiV10, an Escherichia coli O157:H7-specific temperate phage, with which it shares 36 related genes. More distant relatives include the Burkholderia cepacia-specific phage, BcepC6B (8 similar genes), the Bordetella bronchiseptica-specific phage, BPP-1 (8 similar genes) and the Photobacterium profundum prophage, P Pphipr1 (6 similar genes). epsilon15 gene identifications based on homologies with known gene families include the terminase small and large subunits, integrase, endolysin, two holins, two DNA methylase enzymes (one adenine-specific and one cytosine-specific) and a RecT-like enzyme. Genes identified experimentally include those coding for the serotype conversion proteins, the tail fiber, the major capsid protein and the major repressor. epsilon15's attP site and the Salmonella attB site with which it interacts during lysogenization have also been determined.

The genome of epsilon15, a serotype-converting, Group E1 Salmonella enterica-specific bacteriophage.

The permeability transition pore triggers Bax translocation to mitochondria during neuronal apoptosis

Primary cerebellar granule neurons (CGNs) require depolarizing extracellular potassium for their survival. Removal of depolarizing potassium triggers CGN apoptosis that requires induction of Bim, a BH3‐only Bcl‐2 family member. Bim is classically thought to promote apoptosis by neutralizing pro‐survival Bcl‐2 proteins. To determine if this is the principal function of Bim in CGNs, we contrasted Bim‐mediated apoptosis to neuronal death induced by HA14‐1, a BH3‐domain mimetic that antagonizes Bcl‐2 and Bcl‐x(L). HA14‐1 elicited CGN apoptosis characterized by caspase 3 and 9 activation, cytochrome c release, conformational activation of Bax, and mitochondrial depolarization. HA14‐1 provoked CGN apoptosis in the absence of Bim induction and negative regulators of Bim transcription did not prevent HA14‐1‐induced cell death. However, the antioxidant glutathione and its precursor, N‐acetyl‐l‐cysteine, suppressed HA14‐1‐induced apoptosis. Similarly, apoptosis induced by either a structurally distinct Bcl‐2/Bcl‐x(L) inhibitor (compound 6) or Bcl‐2 antisense oligonucleotides was diminished by glutathione. In contrast, antioxidants had no effect on CGN apoptosis provoked by either removal of depolarizing potassium or overexpression of a GFP–Bim fusion protein, two models of Bim‐dependent death. These data show that antagonism of Bcl‐2/Bcl‐x(L) function elicits oxidative stress‐dependent CGN apoptosis that is mechanistically distinct from Bim‐mediated cell death. These results further indicate that, although Bcl‐2/Bcl‐x(L) antagonism is sufficient to induce neuronal apoptosis, Bim likely promotes neuronal death by interacting with additional proteins besides Bcl‐2/Bcl‐x(L).

Distinct mechanisms of neuronal apoptosis are triggered by antagonism of Bcl‐2/Bcl‐x(L) versus induction of the BH3‐only protein Bim

Proteasome inhibition elicits a biphasic effect on neuronal apoptosis via differential regulation of pro-survival and pro-apoptotic transcription factors

Peroxisome proliferator activated receptors are nuclear hormone receptors that regulate the expression of genes containing a peroxisome proliferator activated receptor response element. We report here that the human bcl-2 gene contains a functional peroxisome proliferator activated receptor response element in the 3' untranslated region. Peroxisome proliferator activated receptor gamma bound the human bcl-2 peroxisome proliferator activated receptor response element in gel shift assays and co-transfection of this receptor led to increased luciferase activity from a reporter plasmid containing the human bcl-2 peroxisome proliferator activated receptor response element. Examination of peroxisome proliferator activated receptor gamma-transfected cells demonstrated an increased amount of bcl-2 message compared to empty vector-transfected cells. Confocal analyses confirmed that more Bcl-2 protein was present in peroxisome proliferator activated receptor gamma-transfected cells compared to control-transfected cells. The functionality of the increased Bcl-2 protein was examined using resistance to bile salt-induced apoptosis as the endpoint. Peroxisome proliferator activated receptor gamma-transfected cells were almost twice as resistant as control-transfected cells. These data show that PPARgamma can mediate transcription of bcl-2, resulting in an increase in Bcl-2 protein and protection from apoptosis. We discuss these findings with regards to their potential implications for colon carcinogenesis.

Identification of a functional peroxisome proliferator activated receptor response element in the 3' untranslated region of the human bcl-2 gene.

Glycogen synthase kinase-3β (GSK-3β) is a critical activator of neuronal apoptosis induced by a diverse array of neurotoxic insults. However, the downstream substrates of GSK-3β that ultimately induce neuronal death are unknown. Here, we show that GSK-3β phosphorylates and regulates the activity of Bax, a pro-apoptotic Bcl-2 family member that stimulates the intrinsic (mitochondrial) death pathway by eliciting cytochrome c release from mitochondria. In cerebellar granule neurons undergoing apoptosis, inhibition of GSK-3β suppressed both the mitochondrial translocation of an expressed green fluorescent protein (GFP)-Baxα fusion protein and the conformational activation of endogenous Bax. GSK-3β directly phosphorylated Baxα on Ser163, a residue found within a species-conserved, putative GSK-3β phosphorylation motif. Coexpression of GFP-Baxα with a constitutively active mutant of GSK-3β, GSK-3β(Ser9Ala), enhanced the in vivo phosphorylation of wild-type Baxα, but not a Ser163Ala mutant of Baxα, in transfected human embryonic kidney 293 (HEK293) cells. Moreover, cotransfection with constitutively active GSK-3β promoted the localization of Baxα to mitochondria and induced apoptosis in both transfected HEK293 cells and cerebellar granule neurons. In contrast, neither a Ser163Ala point mutant of Baxα nor a naturally occurring splice variant that lacks 13 amino acids encompassing Ser163 (Baxσ) were driven to mitochondria in HEK293 cells coexpressing constitutively active GSK-3β. In a similar manner, either mutation or deletion of the identified GSK-3β phosphorylation motif prevented the localization of Bax to mitochondria in cerebellar granule neurons undergoing apoptosis. Our results indicate that GSK-3β exerts some of its pro-apoptotic effects in neurons by regulating the mitochondrial localization of Bax, a key component of the intrinsic apoptotic cascade.

Glycogen Synthase Kinase-3β Phosphorylates Bax and Promotes Its Mitochondrial Localization during Neuronal Apoptosis

Resistance to apoptosis may be a critical phenotype that cells must acquire during skin carcinogenesis. The Akt kinase is a known upstream regulator of apoptosis in many cell types and has been shown to be activated by increased reactive oxygen species (ROS). We have previously demonstrated that two malignant variants (6M90 and 6R90) of the mouse keratinocyte 308 cell line have elevated ROS because of loss of catalase activity, and that this elevated ROS confers a growth advantage. We report here that in addition to a growth advantage, chronically increased ROS in the variants resulted in an increase in resistance to ultraviolet (UV) B–induced apoptosis. This resistance was due to basal increases of Akt phosphorylation in the malignant variants compared to the 308 cells. Modulation of ROS in 6M90 and 6R90 cells by catalase overexpression or antioxidant treatment resulted in decreased levels of Akt phosphorylation and subsequent loss of resistance to UVB‐induced apoptosis. Conversely, treatment of 308 cells with hydrogen peroxide caused increases in Akt phosphorylation and increased apoptosis resistance. These results indicate that the chronically elevated ROS often observed in tumors may contribute to a malignant phenotype by keeping Akt in a phosphorylated state, resulting in increased apoptosis resistance. © 2003 Wiley‐Liss, Inc.

Elevated basal reactive oxygen species and phospho‐Akt in murine keratinocytes resistant to ultraviolet B–induced apoptosis

Cultured rat cerebellar granule neurons (CGNs) require depolarization-mediated calcium influx for survival. Calcium regulates the activity of the pro-survival transcription factor, myocyte enhancer factor 2D (MEF2D). MEF2D is hyperphosphorylated and degraded in CGNs undergoing apoptosis induced by lowering the extracellular potassium concentration from 25 mM to 5 mM. Since insulin-like growth factor-I (IGF-I) is known to protect CGNs from apoptotic cell death, we investigated the effects of IGF-I on MEF2D processing during apoptosis. IGF-I administered during the apoptotic insult did not prevent the hyperphosphorylation of MEF2D and consequential loss of DNA binding. However, IGF-I significantly blocked the degradation of MEF2D. Furthermore, IGF-I had no effect on the initial loss of MEF2 transcriptional activity following hyperphosphorylation, but the recovery of MEF2 activity following restoration of intracellular calcium was significantly increased by IGF-I. We conclude that IGF-I blocks the degradation of MEF2D and enhances recovery of MEF2 activity by protecting MEF2D from caspase-dependent cleavage during apoptosis. These results suggest that IGF-I can prolong the time of commitment to irreversible cell death and enhance the recovery of neurons subjected to an acute apoptotic stimulus by preserving the activity of the pro-survival factor MEF2D.

Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme

Insulin-like growth factor-I suppresses degradation of the pro-survival transcription factor myocyte enhancer factor 2D (MEF2D) during neuronal apoptosis.

Many cancer cells develop resistance to apoptosis. It is important to understand how this phenotype develops, so that these cancers can be effectively treated. The results presented in this dissertation describe two molecular mechanisms of apoptosis resistance. A mouse keratinocyte model system consisting of the benign 308 parental cell line and two malignantly progressed variants (6M90 and 6R90 cells) were used to explore the relationship between reactive oxygen species (ROS) and apoptosis resistance. Previous work showed elevated basal levels of ROS in 6M90 and 6R90 cells. The results shown here demonstrate increased resistance to UV-induced apoptosis of the variants compared to the parental line. Pharmacological and genetic approaches were used to decrease the steady-state levels of ROS in the two malignant cell lines. This increased their sensitivity to apoptosis. ROS are implicated in the activation of the anti-apoptotic Akt kinase. 6M90 and 6R90 cells had higher levels of activated Akt. Modulation of ROS levels in the 6M90 and 6R90 cells decreased the levels of activated Akt. These studies provide a molecular mechanism to explain the chronically elevated ROS and apoptosis resistance seen in many tumors. Another mechanism by which tumor cells resist apoptosis is to upregulate the anti-apoptotic protein Bcl-2. A putative response element (PPRE) for the peroxisome proliferator activated nuclear receptor (PPAR) was found in the 3' UTR of bd-2. Further experiments indicated that the y subtype of PPAR bound the putative PPRE and could activate transcription. In cells transfected with PPARy, increased levels of bd-2 mRNA

Attenuation of catalase activity in the malignant phenotype plays a functional role in an in vitro model for tumor progression.

Evidence from a number of studies suggests that the mechanism by which tumor necrosis factor (TNF) kills transformed cells involves oxidative stress. NAD(P)H:(quinone acceptor) oxidoreductase (NQO1) is an antioxidant enzyme with particular relevance to cancer. The MCF-7 breast cancer cell line was stably transfected with rat NQO1 cDNA to determine whether increased NQO1 activity alters sensitivity to TNF-induced apoptosis. Five clones, with a range of NQO1 enzyme activities from 5- to 50-fold greater than the MCF-7 line, and two control transfectants were examined. Northern blot hybridization analyses and reverse transcription-PCR demonstrated that the increase in NQO1 activity in the transfectants was attributable to expression from the transfected rat sequence. Based on sulforhodamine B assays for the number of viable cells, the NQO1 clones showed increased sensitivity to EO9, an indoloquinone that undergoes bioactive reduction by NQO1. Viability studies also demonstrated that the NQO1 transfectants were significantly more sensitive to TNF than the control transfectants or MCF-7 parent. This increased sensitivity could not be explained by changes in superoxide dismutase or catalase activity or to increased sensitivity to oxidative stress in general, as assessed by response to hydrogen peroxide and paraquat treatment. Using dichlorodihydrofluorescein diacetate as a probe, we found that the NQO1 transfectants had no difference in baseline level of oxidative stress compared to the control cells but did exhibit greater intracellular oxidative stress after TNF treatment. We conclude that NQO1 can affect the TNF-mediated pathway to apoptosis.

Increased tumor necrosis factor-alpha sensitivity of MCF-7 cells transfected with NAD(P)H:quinone reductase.

Adipocytes disrupt the translational programme of acute lymphoblastic leukaemia to favour tumour survival and persistence

Background: Anterior shoulder instability can result in bone loss of both the anterior glenoid and the posterior humerus. Bone loss has been shown to lead to increased failure postoperatively and may necessitate more complex surgical procedures, resulting in worse clinical outcomes and posttraumatic arthritis. Hypothesis/Purpose: The purpose of this study was to investigate predictors of glenoid and humeral head bone loss in patients undergoing surgery for anterior shoulder instability. It was hypothesized that male sex, contact sport participation, traumatic dislocation, and higher number of instability events would be associated with greater bone loss. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 892 patients with anterior shoulder instability were prospectively enrolled in the Multicenter Orthopaedic Outcomes Network (MOON) Shoulder Instability cohort. The presence and amount of anterior glenoid bone loss and accompanying Hill-Sachs lesions were quantified. Descriptive information and injury history were used to construct proportional odds models for the presence of any bone defect, for defects >10% of the anterior glenoid or humeral head, and for combined bony defects. Results: Anterior glenoid bone loss and Hill-Sachs lesions were present in 185 (20.7%) and 470 (52.7%) patients, respectively. Having an increased number of dislocations was associated with bone loss in all models. Increasing age, male sex, and non-White race were associated with anterior glenoid bone defects and Hill-Sachs lesions. Contact sport participation was associated with anterior glenoid bone loss, and Shoulder Actitvity Scale with glenoid bone loss >10%. A positive apprehension test was associated with Hill-Sachs lesions. Combined lesions were present in 19.4% of patients, and for every additional shoulder dislocation, the odds of having a combined lesion was 95% higher. Conclusion: An increasing number of preoperative shoulder dislocations is the factor most strongly associated with glenoid bone loss, Hill-Sachs lesions, and combined lesions. Early surgical stabilization before recurrence of instability may be the most effective method for preventing progression to clinically significant bone loss. Patients should be made aware of the expected course of shoulder instability, especially in athletes at high risk for recurrence and osseous defects, which may complicate care and worsen outcomes. Registration: NCT02075775 (ClinicalTrials.gov identifier).

Background: Meniscal and chondral damage is common in the patient undergoing revision anterior cruciate ligament (ACL) reconstruction. Purpose: To determine if meniscal and/or articular cartilage pathology at the time of revision ACL surgery significantly influences a patient’s outcome at 6-year follow-up. Study Design: Cohort study; Level of evidence, 3. Methods: Patients undergoing revision ACL reconstruction were prospectively enrolled between 2006 and 2011. Data collection included baseline demographics, surgical technique, pathology, treatment, and scores from 4 validated patient-reported outcome instruments: International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Marx Activity Rating Scale. Patients were followed up at 6 years and asked to complete the identical set of outcome instruments. Regression analysis assessed the meniscal and articular cartilage pathology risk factors for clinical outcomes 6 years after revision ACL reconstruction. Results: An overall 1234 patients were enrolled (716 males, 58%; median age, 26 years). Surgeons reported the pathology at the time of revision surgery in the medial meniscus (45%), lateral meniscus (36%), medial femoral condyle (43%), lateral femoral condyle (29%), medial tibial plateau (11%), lateral tibial plateau (17%), patella (30%), and trochlea (21%). Six-year follow-up was obtained on 79% of the sample (980/1234). Meniscal pathology and articular cartilage pathology (medial femoral condyle, lateral femoral condyle, lateral tibial plateau, trochlea, and patella) were significant drivers of poorer patient-reported outcomes at 6 years (IKDC, KOOS, WOMAC, and Marx). The most consistent factors driving outcomes were having a medial meniscal excision (either before or at the time of revision surgery) and patellofemoral articular cartilage pathology. Six-year Marx activity levels were negatively affected by having either a repair/excision of the medial meniscus (odds ratio range, 1.45-1.72; P≤ .04) or grade 3-4 patellar chondrosis (odds ratio, 1.72; P = .04). Meniscal pathology occurring before the index revision surgery negatively affected scores on all KOOS subscales except for sports/recreation (P < .05). Articular cartilage pathology significantly impaired all KOOS subscale scores (P < .05). Lower baseline outcome scores, higher body mass index, being a smoker, and incurring subsequent surgery all significantly increased the odds of reporting poorer clinical outcomes at 6 years. Conclusion: Meniscal and chondral pathology at the time of revision ACL reconstruction has continued significant detrimental effects on patient-reported outcomes at 6 years after revision surgery.

Meniscal and Articular Cartilage Predictors of Outcome After Revision ACL Reconstruction: A 6-Year Follow-up Cohort Study

What are the Indications for Medial Ulnar Collateral Ligament Surgery in Baseball Players? An MRI Case-based Study.

Background: Characteristics regarding mechanism of injury, management, and return-to-play (RTP) rate and timing are important when treating and counseling athletes with rectus femoris tears. Purpose: To systematically review the literature to better understand the prevalence, sporting activity, injury mechanisms, and treatment of patients with rectus femoris injury and to provide prognostic information regarding the rate and timing of RTP. Study Design: Systematic review; Level of evidence, 4. Methods: Following the 2020 PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we queried PubMed/MEDLINE, Cochrane, OVID, EMBASE, and Google Scholar in March 2022 for studies reporting on athletes sustaining isolated, full-thickness tearing, or bony avulsion injuries to the proximal rectus femoris during sporting activity. Excluded were studies without evidence of full-thickness tearing or avulsion, with athletes sustaining concomitant injuries, or with injuries occurring from nonsporting activities. The percentage of athletes sustaining injuries was calculated based on sport, injury mechanism, and management (nonoperative versus operative). Results: Of 132 studies initially identified, 18 were included, comprising 132 athletes (mean age, 24.0 ± 5.4 years; range, 12-43 years). The most common sporting activities were soccer (70.5%) and rugby (15.2%). The most reported mechanisms of injury were kicking (47.6%) and excessive knee flexion/forced hip extension (42.9%). Avulsion injuries were reported in 86% (n = 114) of athletes. Nonoperative management was reported in 19.7% of athletes, with operative management performed in 80.3%. The mean follow-up time was 21.4 ± 11.4 months (range, 1.5-48 months). The RTP rate was 93.3% (n = 14) in nonoperatively treated and 100% (n = 106) in operatively treated athletes, and the mean RTP time was 11.7 weeks (range, 5.5-15.2 weeks) in nonoperatively treated and 22.1 weeks (range, 14.0-37.6 weeks) in operatively treated athletes. Complications were reported in 7.7% (2/26) of nonoperatively treated and 18% (n = 19/106) of operatively treated athletes. Conclusion: Full-thickness proximal rectus femoris injuries occurred most frequently in athletes participating in soccer and rugby secondary to explosive, eccentric contractions involved in kicking and sprinting. Operative management was performed in the majority of cases. Athletes who underwent operative repair had a 100% RTP rate versus 93.3% in athletes treated nonoperatively.

Isolated, Full-Thickness Proximal Rectus Femoris Injury in Competitive Athletes: A Systematic Review of Injury Characteristics and Return to Play

Background: Medial ulnar collateral ligament (mUCL) reconstructions are becoming increasingly prevalent among the overhand throwing population. Suture tape augmentation has the potential to provide biomechanical advantages over standard docking reconstruction. However, the optimal tensioning of the suture augmentation technique has not yet been evaluated. Purpose: To compare the subfailure biomechanical performance and graft strain of a standard docking mUCL reconstruction to an mUCL reconstruction using suture tape augmentation tensioned with 1 mm or 3 mm of laxity. Study Design: Controlled laboratory study. Methods: A total of 18 cadaveric elbows were dissected to the mUCL anterior band and biomechanically assessed via a valgus torque protocol to failure. Elbows were randomly assigned to be reconstructed via (1) a standard docking technique, (2) a suture-augmented reconstruction with 1-mm laxity, or (3) a suture-augmented reconstruction with 3-mm laxity. Reconstructed elbows were then subjected to the same loading protocol. Subfailure mechanical properties, failure mode, and mUCL/palmaris strain were assessed. Results: All reconstruction groups had decreased rotational stiffness, torque at 5° of angular rotation, and resilience compared with matched native controls. There were no differences in transition torque between groups. The failure mode of suture-augmented specimens was most often due to bone tunnel failure or reaching the maximum allowable angular displacement. In native controls or docking reconstructions, the primary failure mechanism was in the ligament or graft midsubstance. There were no significant differences in strain on the reconstructed or suture-augmented groups at any laxity compared with native controls. Conclusion: Suture augmentation results in similar subfailure joint biomechanical properties as the standard docking reconstruction procedure at both laxity levels in a cadaveric model. There are improvements in the failure mode of suture-augmented specimens compared with standard docking. Graft strain may be modestly reduced in the 1-mm laxity group compared with other reconstruction groups. Clinical Relevance: Suture augmentation at both 1-mm and 3-mm laxity appears to offer similar advantages in subfailure biomechanics to standard docking reconstruction of the mUCL, with some improvements associated with failure mode. Strain data suggest a potential avoidance of graft stress shielding when tensioning the suture augmentation to 3-mm laxity, which is not as apparent with 1-mm laxity.

Biomechanical Effect of Differential Tensioning on Suture-Augmented Ulnar Collateral Ligament Reconstruction of the Elbow

Return to Play Following Non-Surgical Management of Superior Labrum Anterior-Posterior Tears: A Systematic Review.

Background: The purpose of this study was to utilize the American Board of Orthopaedic Surgery (ABOS) Part-II Case List database to (1) define the practice patterns of sports medicine-trained ABOS Part- II Oral Examination Candidates and (2) describe the frequency and practice patterns of individuals who are dual fellowship-trained sports medicine candidates. Methods: The ABOS Part-II Case List database was utilized to define all cases submitted by 3,298 applicants indicating completion of a sports medicine fellowship between January 1, 2003, and January 1, 2020. Cases were classified by subspecialty category and case type. The frequency and practice patterns of candidates pursuing additional fellowship training (i.e., “dual fellowship-trained”) were recorded. Descriptive statistical methods were used to describe the annual and overall procedure volume and candidate case mix. Trends in the relative frequency of cases performed and fellowship training patterns were determined using linear regression analysis. Results: On average, sports medicine-trained candidates submitted 100.6 cases for review during the 6-month case collection period: 59.0 (58.6%) sports medicine/arthroscopy cases, 29.3 (29.1%) trauma/general cases, 4.5 (4.5%) adult reconstruction cases, and 7.8 (7.8%) “other” cases per candidate. Although candidates performed fewer total (r2 = 0.84, p < 0.001) and sports medicine/arthroscopy (r2 = 0.85, p < 0.001) cases over the study period, the proportion of sports medicine/arthroscopy cases did not change over the study period (p = 0.18). Dual fellowship training was indicated by 333 individuals (10.1%). The number of dual fellowship-trained candidates pursuing additional fellowship training in pediatrics and adult reconstruction increased over the study period, and the number of dual fellowship-trained candidates pursuing additional fellowship training in trauma decreased over the study period. Conclusions: Early-career sports medicine candidates are likely to perform >40% of cases outside of the sports medicine subspecialty. Sports medicine trainees are increasingly likely to pursue a second fellowship in pediatrics or adult reconstruction. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Early-Career Sports Medicine Surgeons Perform a Large Volume of Non-Sports Medicine Procedures

Background: Patients undergoing shoulder stabilization surgery have been shown to have elevated activity levels. Factors associated with shoulder activity in this patient population at baseline and after surgery are unknown. Hypothesis: Patient-specific variables are associated with shoulder activity level at baseline and at 2-year follow-up in a cohort of patients undergoing shoulder stabilization surgery. Study Design: Cohort study; Level of evidence, 2. Methods: Patients undergoing shoulder stabilization surgery were prospectively enrolled. As part of the data collection process, patients completed a previously validated Shoulder Activity Scale. A regression analysis was performed to assess the association of patient characteristics with baseline and 2-year follow-up shoulder activity levels. Results: A total of 764 (n = 612 men, n = 152 women) out of 957 patients (80%) undergoing shoulder stabilization surgery with a median age of 25 years had baseline and 2-year follow-up data and were included in the current analysis. The baseline shoulder activity level was associated with race ( P < .0001) and preoperative duration of instability (P < .0001). At 2 years, 52% of the cohort had returned to the same or higher activity level after surgery. Predictors of higher shoulder activity level at 2-year follow-up included higher baseline activity level (P < .0001), male sex (P < .0001), younger age (P = .004), higher body mass index (BMI) (P = .03), more dislocations (P = .03), nonsmokers (P = .04), and race (P = .04). Conclusion: A longer duration of preoperative symptoms was associated with a lower baseline activity in this cohort. High baseline preoperative shoulder activity, younger age, male sex, higher BMI, number of dislocations, and nonsmoking status predicted higher shoulder activity 2 years after shoulder stabilization surgery. Registration: NCT02075775 (ClinicalTrials.gov identifier).

Factors Associated With Shoulder Activity Level at Time of Surgery and at 2-Year Follow-up in Patients Undergoing Shoulder Stabilization Surgery

Objectives: Previous studies have demonstrated altered brain activation patterns on functional MRI for those with shoulder instability suggesting a potential link between recurrent instability, depression, and emotional wellbeing. It is unknown whether this potential link would differ between those with traumatic vs. atraumatic instability. The purpose of this study was to determine whether psychosocial factors and/or comorbid depression play a greater role in preoperative symptoms for patients with atraumatic or traumatic mechanisms of shoulder instability. We hypothesized that when controlling age, sex, and direction of instability, psychosocial factors and comorbid depression would be more predictive of shoulder-related pain and symptoms for patients with atraumatic instability than patients with traumatic instability. Methods: As part of the IRB-approved Multicenter Orthopaedic Outcomes Network (MOON) Shoulder Instability cohort, 1553 patients provided informed consent and completed pre- and intraoperative data collection. Patients were categorized based on self-reports of whether the mechanism of shoulder instability was traumatic (n=1267) or atraumatic (n=286). Multivariable linear regressions were performed to determine whether psychological factors (VR12, Mental Component Score (MCS), Depression Diagnosis, PAS-22) were predictive of preop ASES and WOSI score in the atraumatic group, controlling for age, sex, and the direction of instability. The same model was repeated for the traumatic instability group, and the model fit was compared between groups using the methods described by Cohen, Cohen, and West with p < 0.05 considered statistically significant. Results: Sex and Mental Component Scores (MCS) were significantly predictive of preop ASES and WOSI scores for the group with atraumatic instability (ASES r2=0.15, p<0.001; WOSI r2=0.17 p<0.001). The same model performed significantly worse for both ASES and WOSI scores in the group with traumatic instability (ASES r2=0.06, WOSI r2=0.07, p<0.05 for both ASES and WOSI). Conclusions: Preoperative psychosocial factors were found to be more predictive of shoulder-related pain and symptoms for patients with atraumatic instability. Across multiple orthopedic conditions, depression and emotional wellbeing have been associated with worse preoperative symptoms and inferior postoperative patient-reported outcomes. As opposed to medically optimizing patients prior to surgery, the current findings identify a subset of shoulder instability patients that may need to be psychologically optimized either prior to surgery or early in the postoperative period to potentially improve postoperative outcomes.

Poster 165: Psychosocial Factors Play a Greater Role in Preoperative Symptoms for Patients with Atraumatic Shoulder Instability: Data from the Moon-Shoulder Instability Group

Objective The objective of this study was to determine whether there are significant differences in terms of indications, techniques, patient variables, and objective and subjective outcome scores as a function of the geographic locale of published studies of knee articular cartilage surgery. Methods An electronic database search was performed of clinical studies evaluating knee articular cartilage procedures from 2000 to 2021. Studies were separated into global regions (Europe, Asia, North America, and South America) based on the study country. All cartilage-based treatments in each region were recorded. Patient age and sex, mechanism of injury, cartilage lesion size and location, follow-up time, failure rate, and knee outcome scores utilized were summarized and compared by region. Results A total of 2,923 studies were analyzed. Eighty level 1 and 2 studies met the inclusion criteria. The majority were from Europe (n = 60), followed by Asia (n = 11), North America (n = 7), and South America (n = 2). The majority of procedures in European and North American studies were cell-based and marrow-stimulation procedures. In Asian studies, the most common procedures were marrow-stimulation, experimental, and biologic procedures as defined by the authors. Asian countries had a higher proportion of females (P < 0.001) and an overall older patient population (P < 0.001). Regional variation was also seen in terms of lesion location, mechanism of injury, and failure rate. Conclusion Most high-level evidence for articular cartilage-based procedures of the knee comes from European countries. These studies vary by patient age and sex, anatomic location, and mechanism of injury. Global variation should be taken into consideration when interpreting and applying studies of knee articular cartilage surgery.

Global Variation in Studies of Articular Cartilage Procedures of the Knee: A Systematic Review

Obesity and Sex Influence Fatty Infiltration of the Rotator Cuff: The ROW and MOON Cohorts.

Stress Radiography Is a Reliable Method to Quantify Posterior Cruciate Ligament Insufficiency: A Systematic Review

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Posterior humeral avulsions of the inferior glenohumeral ligament represent an increasingly recognized but likely underdiagnosed source of posterior shoulder instability and pain.

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Injuries are commonly reported in athletic individuals who have sustained injury by either traumatic or atraumatic mechanisms; the ligament is most susceptible to injury with the shoulder in flexion, adduction, and internal rotation.

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Posterior humeral avulsions of the glenohumeral ligament often occur in the setting of concurrent injuries to the posterior or inferior labrum.

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Diagnosis is often challenging due to nonspecific symptoms and physical examination findings; a magnetic resonance arthrogram generally is utilized to identify avulsion from the humeral attachment; however, a definitive diagnosis is often made at the time of arthroscopic evaluation.

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In patients with persistent discomfort and limitations following nonoperative management, operative fixation, primarily utilizing arthroscopic techniques, can be performed to restore motion and glenohumeral stability.

Posterior Humeral Avulsion of the Glenohumeral Ligament: A Critical Analysis Review.

Global variation in isolated posterior cruciate ligament reconstruction

Background: Patients with anterior cruciate ligament (ACL) revision report lower outcome scores on validated knee questionnaires postoperatively compared to cohorts with primary ACL reconstruction. In a previously active population, it is unclear if patient-reported outcomes (PROs) are associated with a return to activity (RTA) or vary by sports participation level (higher level vs. recreational athletes). Hypotheses: Individual RTA would be associated with improved outcomes (ie, decreased knee symptoms, pain, function) as measured using validated PROs. Recreational participants would report lower PROs compared with higher level athletes and be less likely to RTA. Study Design: Cohort study; Level of evidence, 2. Methods: There were 862 patients who underwent a revision ACL reconstruction (rACLR) and self-reported physical activity at any level preoperatively. Those who did not RTA reported no activity 2 years after revision. Baseline data included patient characteristics, surgical history and characteristics, and PROs: International Knee Documentation Committee questionnaire, Marx Activity Rating Scale, Knee injury and Osteoarthritis Outcome Score, and the Western Ontario and McMaster Universities Osteoarthritis Index. A binary indicator was used to identify patients with same/better PROs versus worse outcomes compared with baseline, quantifying the magnitude of change in each direction, respectively. Multivariable regression models were used to evaluate risk factors for not returning to activity, the association of 2-year PROs after rACLR surgery by RTA status, and whether each PRO and RTA status differed by participation level. Results: At 2 years postoperatively, approximately 15% did not RTA, with current smokers (adjusted odds ratio [aOR] = 3.3; P = .001), female patients (aOR = 2.9; P < .001), recreational participants (aOR = 2.0; P = .016), and those with a previous medial meniscal excision (aOR = 1.9; P = .013) having higher odds of not returning. In multivariate models, not returning to activity was significantly associated with having worse PROs at 2 years; however, no clinically meaningful differences in PROs at 2 years were seen between participation levels. Conclusion: Recreational-level participants were twice as likely to not RTA compared with those participating at higher levels. Within a previously active cohort, no RTA was a significant predictor of lower PROs after rACLR. However, among patients who did RTA after rACLR, approximately 20% reported lower outcome scores. Most patients with rACLR who were active at baseline improved over time; however, patients who reported worse outcomes at 2 years had a clinically meaningful decline across all PROs.

Returning to Activity After Anterior Cruciate Ligament Revision Surgery: An Analysis of the Multicenter Anterior Cruciate Ligament Revision Study (MARS) Cohort at 2 Years Postoperative

Magnetic Resonance Imaging Assessment of Cartilage Appearance Following Marrow Stimulation of Osteochondritis Dissecans of the Humeral Capitellum.

Background: The anterior cruciate ligament (ACL) is crucial for knee proprioception and postural stability. While ACL reconstruction (ACLR) and rehabilitation improve postural stability, the timing in improvement of dynamic postural stability after ACLR remains relatively unknown. Purpose: To evaluate changes in dynamic postural stability after ACLR out to 24 months postoperatively. Study Design: Case series; Level of evidence, 4. Methods: Patients undergoing ACLR were prospectively enrolled, and dynamic postural stability was assessed within 2 days before surgery, at 3-month intervals postoperatively to 18 months, then at 24 months. Measurements were made on a multidirectional platform tracking the patient’s center of mass based on pelvic motion. The amount of time the patient was able to stay on the platform was recorded, and a dynamic motion analysis score, reflecting the patient’s ability to maintain one’s center of mass, was generated overall and in 6 independent planes of motion. Results: A total of 44 patients with a mean age of 19.7 ± 6.2 years completed the study protocol. Overall mean dynamic postural stability improved significantly at 3, 6, 9, and 12 months after surgery, with continued improvement out to 24 months. Notable improvements occurred in medial/lateral and anterior/posterior stability from baseline to 6 months postoperatively, while internal/external rotation and flexion/extension stability declined initially after surgery from baseline to 3 months postoperatively before stabilizing to the end of the study period. Conclusion: Overall dynamic postural stability significantly improved up to 12 months after ACLR. Improvement in postural stability occurred primarily in the medial/lateral and anterior/posterior planes of motion, with initial decreases in the flexion/extension and internal/external rotational planes of motion.

Changes in Dynamic Postural Stability After ACL Reconstruction: Results Over 2 Years of Follow-up

Background: Lytic or malpositioned tunnels may require bone grafting during revision anterior cruciate ligament reconstruction (rACLR) surgery. Patient characteristics and effects of grafting on outcomes after rACLR are not well described. Purpose: To describe preoperative characteristics, intraoperative findings, and 2-year outcomes for patients with rACLR undergoing bone grafting procedures compared with patients with rACLR without grafting. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 1234 patients who underwent rACLR were prospectively enrolled between 2006 and 2011. Baseline revision and 2-year characteristics, surgical technique, pathology, treatment, and patient-reported outcome instruments (International Knee Documentation Committee [IKDC], Knee injury and Osteoarthritis Outcome Score [KOOS], Western Ontario and McMaster Universities Osteoarthritis Index, and Marx Activity Rating Scale [Marx]) were collected, as well as subsequent surgery information, if applicable. The chi-square and analysis of variance tests were used to compare group characteristics. Results: A total of 159 patients (13%) underwent tunnel grafting—64 (5%) patients underwent 1-stage and 95 (8%) underwent 2-stage grafting. Grafting was isolated to the femur in 31 (2.5%) patients, the tibia in 40 (3%) patients, and combined in 88 patients (7%). Baseline KOOS Quality of Life (QoL) and Marx activity scores were significantly lower in the 2-stage group compared with the no bone grafting group (P≤ .001). Patients who required 2-stage grafting had more previous ACLRs (P < .001) and were less likely to have received a bone–patellar tendon–bone or a soft tissue autograft at primary ACLR procedure (P≤ .021) compared with the no bone grafting group. For current rACLR, patients undergoing either 1-stage or 2-stage bone grafting were more likely to receive a bone–patellar tendon–bone allograft (P≤ .008) and less likely to receive a soft tissue autograft (P≤ .003) compared with the no bone grafting group. At 2-year follow-up of 1052 (85%) patients, we found inferior outcomes in the 2-stage bone grafting group (IKDC score = 68; KOOS QoL score = 44; KOOS Sport/Recreation score = 65; and Marx activity score = 3) compared with the no bone grafting group (IKDC score = 77; KOOS QoL score = 63; KOOS Sport/Recreation score = 75; and Marx activity score = 7) (P≤ .01). The 1-stage bone graft group did not significantly differ compared with the no bone grafting group. Conclusion: Tunnel bone grafting was performed in 13% of our rACLR cohort, with 8% undergoing 2-stage surgery. Patients treated with 2-stage grafting had inferior baseline and 2-year patient-reported outcomes and activity levels compared with patients not undergoing bone grafting. Patients treated with 1-stage grafting had similar baseline and 2-year patient-reported outcomes and activity levels compared with patients not undergoing bone grafting.

Descriptive Characteristics and Outcomes of Patients Undergoing Revision Anterior Cruciate Ligament Reconstruction With and Without Tunnel Bone Grafting

Connective tissues, such as tendons, ligaments, and capsules, play a large role in locomotion and joint stability and are often subjected to traumatic injuries and degeneration. The purpose of this study was to evaluate if the mechanical and microstructural properties of connective tissues correlate with the age and sex of the human donor. Dissected samples were prepared for mechanical testing, consisting of 10 cycles of preconditioning, a stress‐relaxation ramp and hold, and a quasi‐static ramp to failure. During the testing protocol, the microstructural organization of tissues was analyzed using quantitative polarized light imaging. A linear mixed model was used to assess whether tissue type, donor age, or donor sex were significantly associated with mechanical and microstructural tissue properties. Tissue type had a significant effect on all parameters, while donor age and sex did not. Groupings by tissue type (i.e., tendon vs. ligament vs. capsule) were evident for microstructural data, with tendons having a tighter grouping and ligaments having a larger spread of values. The interaction of tissue type and age yielded a significant effect for linear modulus only (p = 0.007), with the palmaris tendon appearing to have the largest contribution to this effect. There were no significant interaction effects between sex and tissue type or donor age. Donor age appears to affect linear modulus in some, but not all, tissue types. Otherwise, age and sex do not have significant effects on the mechanical and microstructural properties of the range of connective tissues that were analyzed in this study.

Donor age and sex have limited effects on the mechanical and microstructural properties of human connective tissues

Injuries to the medial meniscus meniscocapsular junction, also known as ramp lesions, are common in the setting of anterior cruciate ligament injuries with a prevalence of 9% to 42%. Anatomically, ramp lesions involve disruption of the posterior meniscocapsular junction and meniscotibial ligaments. Biomechanically, ramp lesions are associated with an increase in anterior tibial translation and internal and external tibial rotation in anterior cruciate ligament-deficient cadaveric knees. Magnetic resonance imaging is useful in evaluating the meniscocapsular junction. Irregularity or increased signal near the posterior meniscocapsular junction and/or signal change indicative of posterior medial tibial plateau edema can suggest these injuries are present before surgical intervention. The current benchmark for diagnosis is arthroscopic visualization of the posterior medial meniscocapsular junction viewed through the intercondylar notch. Once a ramp lesion is identified, stability should be assessed by arthroscopic probing to determine the degree of anterior displacement. Optimal treatment has been debated in the literature, especially for stable ramp lesions, although good outcomes have been shown with and without repair. Repair is warranted for those lesions that are unstable to probing. Unfortunately, only limited literature available to guide clinicians on the optimal rehabilitation for ramp lesions.

Meniscal Ramp Lesions: Anatomy, Epidemiology, Diagnosis, and Treatment.

Background: Although graft choice may be limited in the revision setting based on previously used grafts, most surgeons believe that graft choice for anterior cruciate ligament (ACL) reconstruction is an important factor related to outcome. Hypothesis: In the ACL revision setting, there would be no difference between autograft and allograft in rerupture rate and patient-reported outcomes (PROs) at 6-year follow-up. Study Design: Cohort study; Level of evidence, 2. Methods: Patients who had revision surgery were identified and prospectively enrolled in this cohort study by 83 surgeons over 52 sites. Data collected included baseline characteristics, surgical technique and pathology, and a series of validated PRO measures. Patients were followed up at 6 years and asked to complete the identical set of PRO instruments. Incidence of additional surgery and reoperation because of graft failure were also recorded. Multivariable regression models were used to determine the predictors (risk factors) of PROs, graft rerupture, and reoperation at 6 years after revision surgery. Results: A total of 1234 patients including 716 (58%) men were enrolled. A total of 325 (26%) underwent revision using a bone-patellar tendon-bone (BTB) autograft; 251 (20%), soft tissue autograft; 289 (23%), BTB allograft; 302 (25%), soft tissue allograft; and 67 (5%), other graft. Questionnaires and telephone follow-up for subsequent surgery information were obtained for 809 (66%) patients, while telephone follow-up was only obtained for an additional 128 patients for the total follow-up on 949 (77%) patients. Graft choice was a significant predictor of 6-year Marx Activity Rating Scale scores (P = .024). Specifically, patients who received a BTB autograft for revision reconstruction had higher activity levels than did patients who received a BTB allograft (odds ratio [OR], 1.92; 95% CI, 1.25-2.94). Graft rerupture was reported in 5.8% (55/949) of patients by their 6-year follow-up: 3.5% (16/455) of patients with autografts and 8.4% (37/441) of patients with allografts. Use of a BTB autograft for revision resulted in patients being 4.2 times less likely to sustain a subsequent graft rupture than if a BTB allograft were utilized (P = .011; 95% CI, 1.56-11.27). No significant differences were found in graft rerupture rates between BTB autograft and soft tissue autografts (P = .87) or between BTB autografts and soft tissue allografts (P = .36). Use of an autograft was found to be a significant predictor of having fewer reoperations within 6 years compared with using an allograft (P = .010; OR, 0.56; 95% CI, 0.36-0.87). Conclusion: BTB and soft tissue autografts had a decreased risk in graft rerupture compared with BTB allografts. BTB autografts were associated with higher activity level than were BTB allografts at 6 years after revision reconstruction. Surgeons and patients should consider this information when choosing a graft for revision ACL reconstruction.

Association Between Graft Choice and 6-Year Outcomes of Revision Anterior Cruciate Ligament Reconstruction in the MARS Cohort

Background: A primary goal of anterior cruciate ligament reconstruction (ACLR) is to reduce pathologically increased anterior and rotational laxity of the knee, but the effects of residual laxity on patient-reported outcomes (PROs) after ACLR remain unclear. Hypothesis: Increased residual laxity at 2 years postoperatively is predictive of a higher risk of subsequent ipsilateral knee surgery and decreases in PRO scores from 2 to 6 years after surgery. Study Design: Cohort study; Level of evidence, 2. Methods: From a prospective multicenter cohort, 433 patients aged <36 years were identified at a minimum 2 years after primary ACLR. These patients underwent a KT-1000 arthrometer assessment and pivot-shift test and completed PRO assessments with the Knee injury and Osteoarthritis Outcome Score and International Knee Documentation Committee (IKDC) scores. Patients completed the same PROs at 6 years postoperatively, and any subsequent ipsilateral knee procedures during this period were recorded. Subsequent surgery risk and change in PROs from 2 to 6 years postoperatively were compared based on residual side-to-side KT-1000 arthrometer differences (<−1 mm, −1 to 2 mm, 2 to 6 mm, and >6 mm) in laxity at 2 years postoperatively. Multiple linear regression models were built to determine the relationship between 2-year postoperative knee laxity and 2- to 6-year change in PROs while controlling for age, sex, body mass index, smoking status, meniscal and cartilage status, and graft type. Results: A total of 381 patients (87.9%) were available for follow-up 6 years postoperatively. There were no significant differences in risk of subsequent knee surgery based on residual knee laxity. Patients with a difference >6 mm in side-to-side anterior laxity at 2 years postoperatively were noted to have a larger decrease in PROs from 2 to 6 years postoperatively (P < .05). No significant differences in any PROs were noted among patients with a difference <6 mm in side-to-side anterior laxity or those with pivot glide (IKDC B) versus no pivot shift (IKDC A). Conclusion: The presence of a residual side-to-side KT-1000 arthrometer difference <6 mm or pivot glide at 2 years after ACLR is not associated with an increased risk of subsequent ipsilateral knee surgery or decreased PROs up to 6 years after ACLR. Conversely, patients exhibiting a difference >6 mm in side-to-side anterior laxity were noted to have significantly decreased PROs at 6 years after ACLR.

Neither Residual Anterior Knee Laxity Up to 6 mm nor a Pivot Glide Predict Patient-Reported Outcome Scores or Subsequent Knee Surgery Between 2 and 6 Years After ACL Reconstruction

Early Improvement in Patient-Reported Outcome Scores After Operative Treatment of Osteochondritis Dissecans of the Humeral Capitellum.

Magnetic Resonance Imaging in Osteochondritis Dissecans of the Humeral Capitellum: Preoperative Assessment of Lesion Size and Lateral Wall Integrity.

Background: Arthroscopic shoulder capsulolabral repair using glenoid-based suture anchor fixation provides consistently favorable outcomes for patients with anterior glenohumeral instability. To optimize outcomes, inferior anchor position, especially at the 6-o’clock position, has been emphasized. Proponents of both the beach-chair (BC) and lateral decubitus (LD) positions advocate that this anchor location can be consistently achieved in both positions. Hypothesis: Patient positioning would be associated with the surgeon-reported labral tear length, total number of anchors used, number of anchors in the inferior glenoid, and placement of an anchor at the 6-o’clock position. Study Design: Cross-sectional study; Level of evidence, 3. Methods: This study was a cross-sectional analysis of a prospective multicenter cohort of patients undergoing primary arthroscopic anterior capsulolabral repair. Patient positioning in the BC versus LD position was determined by the operating surgeon and was not randomized. At the time of operative intervention, surgeon-reported labral tear length, total anchor number, anchor number in the inferior glenoid, and anchor placement at the 6-o’clock position were evaluated between BC and LD cohorts. Descriptive statistics and between-group differences (continuous: t test [normal distributions], Wilcoxon rank sum test [nonnormal distributions], and chi-square test [categorical]) were assessed. Results: In total, 714 patients underwent arthroscopic anterior capsulolabral repair (BC vs LD, 406 [56.9%] vs 308 [43.1%]). The surgeon-reported labral tear length was greater for patients having surgery in the LD position (BC vs LD [mean ± SD], 123.5°± 49° vs 132.3°± 44°; P = .012). The LD position was associated with more anchors placed in the inferior glenoid and more frequent placement of anchors at the 6-o’clock (BC vs LD, 22.4% vs 51.6%; P < .001). The LD position was more frequently associated with utilization of ≥4 total anchors (BC vs LD, 33.5% vs 46.1%; P < .001). Conclusion: Surgeons utilizing the LD position for arthroscopic capsulolabral repair in patients with anterior shoulder instability more frequently placed anchors in the inferior glenoid and at the 6-o’clock position. Additionally, surgeon-reported labral tear length was longer when utilizing the LD position. These results suggest that patient positioning may influence the total number of anchors used, the number of anchors used in the inferior glenoid, and the frequency of anchor placement at the 6 o’clock position during arthroscopic capsulolabral repair for anterior shoulder instability. How these findings affect clinical outcomes warrants further study. Registration: NCT02075775 (ClinicalTrials.gov identifier)

Beach Chair Versus Lateral Decubitus Position: Differences in Suture Anchor Position and Number During Arthroscopic Anterior Shoulder Stabilization

Performance of PROMIS Scores Compared to Legacy Metrics in Evaluating Outcomes after Surgical Treatment for Osteochondritis Dissecans of the Humeral Capitellum.

Ulnar collateral ligament (UCL) injuries are becoming increasingly common. The palmaris longus (PL) and gracilis (GR) tendons are the most common grafts used in UCL reconstructions. While clinical studies have demonstrated relatively similar outcomes for either graft, there is little quantitative data describing these grafts from a material perspective, specifically the mechanical and microstructural properties of these tissues and how they respond under dynamic loading. The purpose of this descriptive laboratory study was to quantify and compare the mechanical and microstructural properties of PL and GR tendons. A total of 13 PL and 11 GR cadaveric human tendons were obtained. Each specimen was divided into three subregions and subjected to preconditioning, ramp‐and‐hold stress‐relaxation and ramp‐to‐failure testing. Mechanical parameters were computed for each sample, and a polarized light imaging technique was used to simultaneously evaluate dynamic microstructural properties during testing. The PL had larger toe‐ and linear‐region modulus values than the GR. Within the GR, the distal subregion had stronger collagen alignment than the proximal subregion at the zero, transition and linear portions of the stress‐strain curve. The PL and GR, have similar mechanical properties and similar microstructural alignment under load. The PL graft has similar properties throughout its length whereas the GR properties exhibited slight differences in strength of alignment along its length. The PL and GR exhibit larger moduli values and more strongly/uniformly aligned collagenous microstructure when qualitatively compared to data previously published on the native UCL.

Mechanical properties and microstructural organization of common ulnar collateral ligament grafts: Palmaris longus and gracilis tendons

Background: The operative treatment of Achilles tendon ruptures has been associated with lower rerupture rates and better function but also a risk of surgery-related complications compared with nonoperative treatment, which may provide improved outcomes with accelerated rehabilitation protocols. However, economic decision analyses integrating the updated costs of both treatment options are limited in the literature. Purpose: To compare the cost-effectiveness of operative and nonoperative treatment of acute Achilles tendon tears. Study Design: Economic and decision analysis; Level of evidence, 2. Methods: An economic decision model was built to assess the cost-utility ratio (CUR) of open primary repair versus nonoperative treatment for acute Achilles tendon ruptures, based on direct costs from the practices of sports medicine and foot and ankle surgeons at a single tertiary academic center, with published outcome probabilities and patient utility data. Multiway sensitivity analyses were performed to reflect the range of data. Results: Nonoperative treatment was more cost-effective in the average scenario (nonoperative CUR, US$520; operative CUR, US$1995), but crossover occurred during the sensitivity analysis (nonoperative CUR range, US$224-US$2079; operative CUR range, US$789-US$8380). Operative treatment cost an extra average marginal CUR of US$1475 compared with nonoperative treatment, assuming uneventful healing in both treatment arms. The sensitivity analysis demonstrated a decreased marginal CUR of operative treatment when the outcome utility was maximized, and rerupture rates were minimized compared with nonoperative treatment. Conclusion: Nonoperative treatment was more cost-effective in average scenarios. Crossover indicated that open primary repair would be favorable for maximized outcome utility, such as that for young athletes or heavy laborers. The treatment decision for acute Achilles tendon ruptures should be individualized. These pilot results provide inferences for further longitudinal analyses incorporating future clinical evidence.

Operative Versus Nonoperative Treatment of Acute Achilles Tendon Ruptures: A Pilot Economic Decision Analysis

Background: Understanding predictors of pain is critical, as recent literature shows that comorbid back pain is an independent risk factor for worse functional and patient-reported outcomes (PROs) as well as increased opioid dependence after total joint arthroplasty. Purpose/Hypothesis: The purpose of this study was to evaluate whether comorbid back pain would be predictive of pain or self-reported instability symptoms at the time of stabilization surgery. We hypothesized that comorbid back pain will correlate with increased pain at the time of surgery as well as with worse scores on shoulder-related PRO measures. Study Design: Cross-sectional study; Level of evidence, 3. Methods: As part of the Multicenter Orthopaedic Outcomes Network (MOON) Shoulder Instability cohort, patients consented to participate in pre- and intraoperative data collection. Demographic characteristics, injury history, preoperative PRO scores, and radiologic and intraoperative findings were recorded for patients undergoing surgical shoulder stabilization. Patients were also asked, whether they had any back pain. Results: The study cohort consisted of 1001 patients (81% male; mean age, 24.1 years). Patients with comorbid back pain (158 patients; 15.8%) were significantly older (28.1 vs 23.4 years; P < .001) and were more likely to be female (25.3% vs 17.4%; P = .02) but did not differ in terms of either preoperative imaging or intraoperative findings. Patients with self-reported back pain had significantly worse preoperative pain and shoulder-related PRO scores (American Shoulder and Elbow Surgeons score, Western Ontario Shoulder Instability Index) (P < .001), more frequent depression (22.2% vs 8.3%; P < .001), poorer mental health status (worse scores for the RAND 36-Item Health Survey Mental Component Score, Iowa Quick Screen, and Personality Assessment Screener) (P < .01), and worse preoperative expectations (P < .01). Conclusion: Despite having similar physical findings, patients with comorbid back pain had more severe preoperative pain and self-reported symptoms of instability as well as more frequent depression and lower mental health scores. The combination of disproportionate shoulder pain, comorbid back pain and mental health conditions, and inferior preoperative expectations may affect not only the patient’s preoperative state but also postoperative pain control and/or postoperative outcomes.

The Prevalence and Clinical Implications of Comorbid Back Pain in Shoulder Instability: A Multicenter Orthopaedic Outcomes Network (MOON) Shoulder Instability Cohort Study

The present study was undertaken to evaluate changes in knee magnetic resonance imaging (MRI) findings over the course of 18 months in subjects with osteoarthritic change and meniscal tear treated with arthroscopic partial meniscectomy (APM) or nonoperatively with physical therapy (PT).

Early Magnetic Resonance Imaging–Based Changes in Patients With Meniscal Tear and Osteoarthritis: Eighteen‐Month Data From a Randomized Controlled Trial of Arthroscopic Partial Meniscectomy Versus Physical Therapy

Estimation of Location and Extent of Labral Tear Based on Preoperative Range of Motion in Patients Undergoing Arthroscopic Stabilization for Anterior Shoulder Instability

Are there Racial Differences between Patients Undergoing Surgery for Shoulder Instability? Data from the Multicenter Orthopaedic Outcomes Network (MOON) Shoulder Instability Group.

CONTEXT
Patients with anterior cruciate ligament (ACL) tears are likely to have deficient dynamic postural stability compared with healthy sex- and age-matched controls.

OBJECTIVES
To test the hypothesis that patients undergoing ACL reconstruction have decreased dynamic postural stability compared with matched healthy controls.

DESIGN
Prospective case-control study.

SETTING
Orthopedic sports medicine and physical therapy clinics.

PATIENTS OR OTHER PARTICIPANTS
Patients aged 20 years and younger with an ACL tear scheduled for reconstruction were enrolled prospectively. Controls were recruited from local high schools and colleges via flyers.

INTERVENTIONS
Patients underwent double-stance dynamic postural stability testing prior to surgery, recording time to failure and dynamic motion analysis (DMA) scores. Patients were then matched with healthy controls.

MAIN OUTCOME MEASURES
Demographics, time to failure, and DMA scores were compared between groups.

RESULTS
A total of 19 females and 12 males with ACL tears were matched with controls. Individuals with ACL tears were more active (Marx activity score: 15.7 [1.0] vs 10.8 [4.9], P < .001); had shorter times until test failure (84.4 [15.8] vs 99.5 [14.5] s, P < .001); and had higher (worse) DMA scores (627 [147] vs 481 [132], P < .001), indicating less dynamic postural stability. Six patients with ACL deficiency (1 male and 5 females) demonstrated lower (better) DMA scores than their controls, and another 7 (4 males and 3 females) were within 20% of controls.

CONCLUSIONS
Patients undergoing ACL reconstruction had worse global dynamic postural stability compared with well-matched controls. This may represent the effect of the ACL injury or preexisting deficits that contributed to the injury itself. These differences should be studied further to evaluate their relevance to ACL injury risk, rehabilitation, and return to play.

Decreased Postural Control in Patients Undergoing Anterior Cruciate Ligament Reconstruction Compared to Healthy Controls.

The last two decades have seen a drastic rise in the incidence of ulnar collateral ligament (UCL) injuries and their surgical treatment. There continues to be a better understanding of the related anatomy and biomechanics, as research continues to be active on the topic of the UCL of the elbow. The growing body of knowledge regarding UCL anatomy and biomechanics continue to inform surgeons on approaches for treatment, which continue to evolve.

Ulnar collateral ligament injury in the elbow: current trends for treatment

Background: Meniscal preservation has been demonstrated to contribute to long-term knee health. This has been a successful intervention in patients with isolated tears and tears associated with anterior cruciate ligament (ACL) reconstruction. However, the results of meniscal repair in the setting of revision ACL reconstruction have not been documented. Purpose: To examine the prevalence and 2-year operative success rate of meniscal repairs in the revision ACL setting. Study Design: Case-control study; Level of evidence, 3. Methods: All cases of revision ACL reconstruction with concomitant meniscal repair from a multicenter group between 2006 and 2011 were selected. Two-year follow-up was obtained by phone and email to determine whether any subsequent surgery had occurred to either knee since the initial revision ACL reconstruction. If so, operative reports were obtained, whenever possible, to verify the pathologic condition and subsequent treatment. Results: In total, 218 patients (18%) from 1205 revision ACL reconstructions underwent concurrent meniscal repairs. There were 235 repairs performed: 153 medial, 48 lateral, and 17 medial and lateral. The majority of these repairs (n = 178; 76%) were performed with all-inside techniques. Two-year surgical follow-up was obtained on 90% (197/218) of the cohort. Overall, the meniscal repair failure rate was 8.6% (17/197) at 2 years. Of the 17 failures, 15 were medial (13 all-inside, 2 inside-out) and 2 were lateral (both all-inside). Four medial failures were treated in conjunction with a subsequent repeat revision ACL reconstruction. Conclusion: Meniscal repair in the revision ACL reconstruction setting does not have a high failure rate at 2-year follow-up. Failure rates for medial and lateral repairs were both <10% and consistent with success rates of primary ACL reconstruction meniscal repair. Medial tears underwent reoperation for failure at a significantly higher rate than lateral tears.

Meniscal Repair in the Setting of Revision Anterior Cruciate Ligament Reconstruction: Results From the MARS Cohort

Surgical outcomes in the Frequency, Etiology, Direction, and Severity (FEDS) classification system for shoulder instability.

Background: Patients with posterior shoulder instability may have bone and cartilage lesions (BCLs) in addition to capsulolabral injuries, although the risk factors for these intra-articular lesions are unclear. Hypothesis: We hypothesized that patients with posterior instability who had a greater number of instability events would have a higher rate of BCLs compared with patients who had fewer instability episodes. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Data from the Multicenter Orthopaedic Outcomes Network (MOON) Shoulder Group instability patient cohort were analyzed. Patients aged 12 to 99 years undergoing primary surgical treatment for shoulder instability were included. The glenohumeral joint was evaluated by the treating surgeon at the time of surgery, and patients were classified as having a BCL if they had any grade 3 or 4 glenoid or humeral cartilage lesion, reverse Hill-Sachs lesion, bony Bankart lesion, or glenoid bone loss. The effects of the number of instability events on the presence of BCLs was investigated by use of Fisher exact tests. Logistic regression modeling was performed to investigate the independent contributions of demographic variables and injury-specific variables to the likelihood of having a BCL. Significance was defined as P < .05. Results: We identified 271 patients (223 male) for analysis. Bone and cartilage lesions were identified in 54 patients (19.9%) at the time of surgical treatment. A glenoid cartilage injury was most common and was identified in 28 patients (10.3%). A significant difference was noted between the number of instability events and the presence of BCLs (P = .025), with the highest rate observed in patients with 2 to 5 instability events (32.3%). Multivariate logistic regression modeling indicated that increasing age (P = .019) and 2 to 5 reported instability events (P = .001) were significant independent predictors of the presence of BCLs. For bone lesions alone, the number of instability events was the only significant independent predictor; increased risk of bone lesion was present for patients with 1 instability event (OR, 6.1; P = .012), patients with 2 to 5 instability events (OR, 4.2; P = .033), and patients with more than 5 instability events (OR, 6.0; P = .011). Conclusion: Bone and cartilage lesions are seen significantly more frequently with increasing patient age and in patients with 2 to 5 instability events. Early surgical stabilization for posterior instability may be considered to potentially limit the extent of associated intra-articular injury. The group of patients with more than 5 instability events may represent a different pathological condition, as this group showed a decrease in the likelihood of cartilage injury, although not bony injury.

Risk Factors for Intra-articular Bone and Cartilage Lesions in Patients Undergoing Surgical Treatment for Posterior Instability

Infection is a rare occurrence after revision anterior cruciate ligament reconstruction (rACLR). Because of the low rates of infection, it has been difficult to identify risk factors for infection in this patient population. The purpose of this study was to report the rate of infection following rACLR and assess whether infection is associated with patient‐ and surgeon‐dependent risk factors. We reviewed two large prospective cohorts to identify patients with postoperative infections following rACLR. Age, sex, body mass index (BMI), smoking status, history of diabetes, and graft choice were recorded for each patient. The association of these factors with postoperative infection following rACLR was assessed. There were 1423 rACLR cases in the combined cohort, with 9 (0.6%) reporting postoperative infections. Allografts had a higher risk of infection than autografts (odds ratio, 6.8; 95% CI, 0.9–54.5; p = .045). Diabetes (odds ratio, 28.6; 95% CI, 5.5–149.9; p = .004) was a risk factor for infection. Patient age, sex, BMI, and smoking status were not associated with risk of infection after rACLR.

Rate of infection following revision anterior cruciate ligament reconstruction and associated patient‐ and surgeon‐dependent risk factors: Retrospective results from MOON and MARS data collected from 2002 to 2011

Background: Anterior cruciate ligament (ACL) revision cohorts continually report lower outcome scores on validated knee questionnaires than primary ACL cohorts at similar time points after surgery. It is unclear how these outcomes are associated with physical activity after physician clearance for return to recreational or competitive sports after ACL revision surgery. Hypotheses: Participants who return to either multiple sports or a singular sport after revision ACL surgery will report decreased knee symptoms, increased activity level, and improved knee function as measured by validated patient-reported outcome measures (PROMs) and compared with no sports participation. Multisport participation as compared with singular sport participation will result in similar increased PROMs and activity level. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 1205 patients who underwent revision ACL reconstruction were enrolled by 83 surgeons at 52 clinical sites. At the time of revision, baseline data collected included the following: demographics, surgical characteristics, previous knee treatment and PROMs, the International Knee Documentation Committee (IKDC) questionnaire, Marx activity score, Knee injury and Osteoarthritis Outcome Score (KOOS), and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). A series of multivariate regression models were used to evaluate the association of IKDC, KOOS, WOMAC, and Marx Activity Rating Scale scores at 2 years after revision surgery by sports participation category, controlling for known significant covariates. Results: Two-year follow-up was obtained on 82% (986 of 1205) of the original cohort. Patients who reported not participating in sports after revision surgery had lower median PROMs both at baseline and at 2 years as compared with patients who participated in either a single sport or multiple sports. Significant differences were found in the change of scores among groups on the IKDC (P < .0001), KOOS-Symptoms (P = .01), KOOS–Sports and Recreation (P = .04), and KOOS–Quality of Life (P < .0001). Patients with no sports participation were 2.0 to 5.7 times more likely than multiple-sport participants to report significantly lower PROMs, depending on the specific outcome measure assessed, and 1.8 to 3.8 times more likely than single-sport participants (except for WOMAC-Stiffness, P = .18), after controlling for known covariates. Conclusion: Participation in either a single sport or multiple sports in the 2 years after ACL revision surgery was found to be significantly associated with higher PROMs across multiple validated self-reported assessment tools. During follow-up appointments, surgeons should continue to expect that patients who report returning to physical activity after surgery will self-report better functional outcomes, regardless of baseline activity levels.

Relationship Between Sports Participation After Revision Anterior Cruciate Ligament Reconstruction and 2-Year Patient-Reported Outcome Measures

Background: Traumatic anterior shoulder instability is a common condition affecting sports participation among young athletes. Clinical outcomes after surgical management may vary according to patient activity level and sport involvement. Overhead athletes may experience a higher rate of recurrent instability and difficulty returning to sport postoperatively with limited previous literature to guide treatment. Purpose: To report the clinical outcomes of patients undergoing primary arthroscopic anterior shoulder stabilization within the Multicenter Orthopaedic Outcomes Network (MOON) Shoulder Instability Consortium and to identify prognostic factors associated with successful return to sport at 2 years postoperatively. Study Design: Case series; Level of evidence, 4. Methods: Overhead athletes undergoing primary arthroscopic anterior shoulder stabilization as part of the MOON Shoulder Instability Consortium were identified for analysis. Primary outcomes included the rate of recurrent instability, defined as any patient reporting recurrent dislocation or reoperation attributed to persistent instability, and return to sport at 2 years postoperatively. Secondary outcomes included the Western Ontario Shoulder Instability Index and Kerlan-Jobe Orthopaedic Clinic Shoulder and Elbow questionnaire score. Univariate regression analysis was performed to identify patient and surgical factors predictive of return to sport at short-term follow-up. Results: A total of 49 athletes were identified for inclusion. At 2-year follow-up, 31 (63%) athletes reported returning to sport. Of those returning to sport, 22 athletes (45% of the study population) were able to return to their previous levels of competition (nonrefereed, refereed, or professional) in at least 1 overhead sport. Two patients (4.1%) underwent revision stabilization, although 14 (28.6%) reported subjective apprehension or looseness. Age (P = .87), sex (P = .82), and baseline level of competition (P = .37) were not predictive of return to sport. No difference in range of motion in all planes (P > .05) and Western Ontario Shoulder Instability Index scores (78.0 vs 80.1, P = .73) was noted between those who reported returning to sport and those who did not. Conclusion: Primary arthroscopic anterior shoulder stabilization in overhead athletes is associated with a low rate of recurrent stabilization surgery. Return to overhead athletics at short-term follow-up is lower than that previously reported for the general athletic population.

Clinical Outcomes After Anterior Shoulder Stabilization in Overhead Athletes: An Analysis of the MOON Shoulder Instability Consortium

Background: While a primary goal of anterior cruciate ligament (ACL) reconstruction is to reduce pathologically increased anterior and rotational knee laxity, the relationship between knee laxity after ACL reconstruction and patient-reported knee function remains unclear. Hypothesis: There would be no significant correlation between the degree of residual anterior and rotational knee laxity and patient-reported outcomes (PROs) 2 years after primary ACL reconstruction. Study Design: Cross-sectional study; Level of evidence, 3. Methods: From a prospective multicenter nested cohort of patients, 433 patients younger than 36 years of age injured in sports with no history of concomitant ligament surgery, revision ACL surgery, or surgery of the contralateral knee were identified and evaluated at a minimum 2 years after primary ACL reconstruction. Each patient underwent Lachman and pivot-shift evaluation as well as a KT-1000 arthrometer assessment along with Knee injury and Osteoarthritis Outcome Score and subjective International Knee Documentation Committee (IKDC) scores. A proportional odds logistic regression model was used to predict each 2-year PRO score, controlling for preoperative score, age, sex, body mass index, smoking, Marx activity score, education, subsequent surgery, meniscal and cartilage status, graft type, and range of motion asymmetry. Measures of knee laxity were independently added to each model to determine correlation with PROs. Results: Side-to-side manual Lachman differences were IKDC A in 246 (57%) patients, IKDC B in 183 (42%) patients, and IKDC C in 4 (<1%) patients. Pivot-shift was classified as IKDC A in 209 (48%) patients, IKDC B in 183 (42%) patients, and IKDC C in 11 (2.5%) patients. The mean side-to-side KT-1000 difference was 2.0 ± 2.6 mm. No significant correlations were noted between pivot-shift or anterior tibial translation as assessed by Lachman or KT-1000 and any PRO. All predicted differences in PROs based on IKDC A versus B pivot-shift and anterior tibial translation were less than 4 points. Conclusion: Neither the presence of IKDC A versus B pivot-shift nor increased anterior tibial translation of up to 6 mm is associated with clinically relevant decreases in PROs 2 years after ACL reconstruction.

Anterior and Rotational Knee Laxity Does Not Affect Patient-Reported Knee Function 2 Years After Anterior Cruciate Ligament Reconstruction

A detailed physical examination of the shoulder is crucial in creating a diagnosis in patients who present with shoulder pain. Tests of the cervical spine, scapula, and rotator cuff muscles have already been evaluated in a previous article. This article assesses provocative and instability examination tests of the shoulder. Descriptions on how the tests are performed and their diagnostic accuracy are presented.

Comprehensive Review of Provocative and Instability Physical Examination Tests of the Shoulder.

Biomechanical comparison of docking ulnar collateral ligament reconstruction with and without an internal brace.

Background: Multiple studies have shown that patients are susceptible to posttraumatic osteoarthritis (PTOA) after an anterior cruciate ligament (ACL) injury, even with ACL reconstruction (ACLR). Prospective studies using multivariable analysis to identify risk factors for PTOA are lacking. Purpose/Hypothesis: This study aimed to identify baseline predictors of radiographic PTOA after ACLR at an early time point. We hypothesized that meniscal injuries and cartilage lesions would be associated with worse radiographic PTOA using the Osteoarthritis Research Society International (OARSI) atlas criteria. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 421 patients who underwent ACLR returned on-site for standardized posteroanterior semiflexed knee radiography at a minimum of 2 years after surgery. The mean age was 19.8 years, with 51.3% female patients. At baseline, data on demographics, graft type, meniscal status/treatment, and cartilage status were collected. OARSI atlas criteria were used to grade all knee radiographs. Multivariable ordinal regression models identified baseline predictors of radiographic OARSI grades at follow-up. Results: Older age (odds ratio [OR], 1.06) and higher body mass index (OR, 1.05) were statistically significantly associated with a higher OARSI grade in the medial compartment. Patients who underwent meniscal repair and partial meniscectomy had statistically significantly higher OARSI grades in the medial compartment (meniscal repair OR, 1.92; meniscectomy OR, 2.11) and in the lateral compartment (meniscal repair OR, 1.96; meniscectomy OR, 2.97). Graft type, cartilage lesions, sex, and Marx activity rating scale score had no significant association with the OARSI grade. Conclusion: Older patients with a higher body mass index who have an ACL tear with a concurrent meniscal tear requiring partial meniscectomy or meniscal repair should be advised of their increased risk of developing radiographic PTOA. Alternatively, patients with an ACL tear with an articular cartilage lesion can be reassured that they are not at an increased risk of developing early radiographic knee PTOA at 2 to 3 years after ACLR.

Predictors of Radiographic Osteoarthritis 2 to 3 Years After Anterior Cruciate Ligament Reconstruction: Data From the MOON On-site Nested Cohort

Objectives: Multiple studies have shown patients are susceptible to post-traumatic osteoarthritis (PTOA) after anterior cruciate ligament (ACL) injury even with ACL reconstruction (ACLR). Prospective studies using multivariate analysis to identify risk factors for PTOA are lacking. This study aims to identify baseline predictors of radiographic PT OA after ACLR at an early time point and hypothesizes that meniscal injury and cartilage lesions will be associated with worse radiographic OA using the Osteoarthritis Research Society International (OARSI) atlas criteria. Methods: 421 patients who underwent ACLR returned onsite for standardized posteroanterior metatarsophalangeal radiographs a minimum of 2 years after surgery. At baseline, demographics, graft type, meniscal status/treatment, and cartilage status were collected. OARSI atlas criteria were used to grade all knee radiographs. Multivariable ordinal regression models identified baseline predictors of radiographic OARSI grades at follow-up. Results: The mean age was 19.8 years with 51.3% females. Higher age (odds ratio (OR) 1.06) and BMI (OR 1.05) were statistically significantly associated with higher OARSI grade in the medial compartment. Patients with a meniscal repair and a partial meniscectomy had statistically significantly higher OARSI grades in the medial compartment (meniscal repair OR 1.92 and meniscectomy OR 2.11) and in the lateral compartment (meniscal repair OR 1.96 and meniscectomy OR 2.97). Graft type, cartilage lesion, sex, and Marx activity scales had no significant association with OARSI grade. Conclusion: Older patients with a higher BMI who have an ACL tear with concurrent meniscal tear requiring partial meniscectomy or meniscal repair should be advised of their increased risk of developing radiographic OA. Alternatively, patients with an ACL tear with an articular cartilage lesion can be reassured that they are not at increased risk of developing radiographic knee OA at 2-3 years following ACLR.

Predictors of Radiographic Osteoarthritis 2-3 Years after ACL Reconstruction: Data from MOON Onsite Nested Cohort

Nonoperative treatment of atrauamtic, symptomatic, full thickness rotator cuff tears- five year follow-up of the moon shoulder group cohort

Background: The perioperative withdrawal of aspirin increases the risk of cardiac, neurologic, and vascular thromboembolic events. The safety of continuing aspirin in patients undergoing knee arthroscopy is unknown. Hypothesis: Perioperative continuation of aspirin does not increase surgical complications or worsen outcomes in patients 50 years of age and older undergoing knee arthroscopy. Study Design: Cohort study; Level of evidence, 3. Methods: This is a single-center, institutional review board–approved, prospective matched dual-cohort study comparing the surgical complication rates and postoperative outcomes of patients taking daily aspirin with those of unmedicated controls. Ninety patients who were 50 years of age or older and taking 81 mg or 325 mg daily aspirin were matched to 90 controls. Patients were matched on age, surgery type, and the use of a tourniquet. A complication was defined as bleeding, wound dehiscence, or wound infection requiring reoperation. Postoperative outcome measures including hematoma formation, extent of ecchymosis (mm), visual analog scale (VAS) scores for pain and swelling, and the Knee Injury and Osteoarthritis Outcome Score (KOOS) were collected preoperatively and postoperatively (10-14 days and 4-6 weeks). Results: There were no complications (0%) in either cohort. There was no difference in hematoma formation (aspirin, 1.8%; controls, 2.4%; P = .79), incidence of ecchymosis (aspirin, 17%; controls, 21%; P = .70), or the average extent of ecchymosis (aspirin, 124.6 mm; controls, 80.3 mm; P = .36) between patients taking aspirin and controls. There was no significant difference in pre- or postoperative knee range of motion between controls and patients taking aspirin. The KOOS subscores and VAS pain scores were similar between patients taking aspirin and controls at baseline and at follow-up. Conclusion: The perioperative continuation of daily aspirin in patients 50 years of age and older undergoing arthroscopic procedures of the knee is safe and does not result in an increased rate of bleeding or wound complications requiring reoperation. Continued aspirin use in patients 50 years of age and older had no significant effect on postoperative physical examination measures or patient-rated outcome scores.

The Perioperative Continuation of Aspirin in Patients Undergoing Arthroscopic Surgery of the Knee

DS_10.1177_0363546519856348 – Supplemental material for Relationship Between Sports Participation After Revision Anterior Cruciate Ligament Reconstruction and 2-Year Patient-Reported Outcome Measures

A thorough physical examination of the shoulder and cervical spine is critical in establishing a focused differential diagnosis of the pathology in and around the shoulder joint. Numerous tests have been described in the literature to help improve the diagnostic accuracy of specific shoulder or cervical spine pathology. A comprehensive approach for the physical examination of the cervical spine, scapula, and rotator cuff is presented and descriptions on how the tests are performed and the evidence behind why specific tests are used in enabling improved diagnosis of shoulder pathology are discussed.

A Comprehensive Review of Physical Examination Tests of the Cervical Spine, Scapula, and Rotator Cuff.

Background: In the setting of anterior shoulder instability, it is important to assess the reliability of orthopaedic surgeons to diagnose pathologic characteristics on the 2 most common imaging modalities used in clinical practice: standard plain radiographs and magnetic resonance imaging (MRI). Purpose: To assess the intra- and interrater reliability of diagnosing pathologic characteristics associated with anterior shoulder instability using standard plain radiographs and MRI. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: Patient charts at a single academic institution were reviewed for anterior shoulder instability injuries. The study included 40 sets of images (20 radiograph sets, 20 MRI series). The images, along with standardized evaluation forms, were distributed to 22 shoulder/sports medicine fellowship–trained orthopaedic surgeons over 2 points in time. Kappa values for inter- and intrarater reliability were calculated. Results: The overall response rate was 91%. For shoulder radiographs, interrater agreement was fair to moderate for the presence of glenoid lesions (κ = 0.49), estimate of glenoid lesion surface area (κ = 0.59), presence of a Hill-Sachs lesion (κ = 0.35), and estimate of Hill-Sachs surface area (κ = 0.50). Intrarater agreement was moderate for radiographs (κ = 0.48-0.57). For shoulder MRI, interrater agreement was fair to moderate for the presence of glenoid lesions (κ = 0.44), glenoid lesion surface area (κ = 0.35), Hill-Sachs lesion (κ = 0.33), Hill-Sachs surface area (κ = 0.28), humeral head edema (κ = 0.41), and presence of a capsulolabral injury (κ = 0.36). Fair agreement was found for specific type of capsulolabral injury (κ = 0.21). Intrarater agreement for shoulder MRI was moderate for the presence of glenoid lesion (κ = 0.59), presence of a Hill-Sachs lesion (κ = 0.52), estimate of Hill-Sachs surface area (κ = 0.50), humeral head edema (κ = 0.51), and presence of a capsulolabral injury (κ = 0.53), and agreement was substantial for glenoid lesion surface area (κ = 0.63). Intrarater agreement was fair for determining the specific type of capsulolabral injury (κ = 0.38). Conclusion: Fair to moderate agreement by surgeons was found when evaluating imaging studies for anterior shoulder instability. Agreement was similar for identifying pathologic characteristics on radiographs and MRI. There was a trend toward better agreement for the presence of glenoid-sided injury. The lowest agreement was observed for specific capsulolabral injuries.

Surgeon Agreement on the Presence of Pathologic Anterior Instability on Shoulder Imaging Studies

Predictors of radiographic osteoarthritis 2-3 years after acl reconstruction: data from the multicenter orthopaedic outcomes network onsite (MOON) nested cohort

Background: Patient-reported outcomes (PROs) are a valid measure of results after revision anterior cruciate ligament (ACL) reconstruction. Revision ACL reconstruction has been documented to have worse outcomes when compared with primary ACL reconstruction. Understanding positive and negative predictors of PROs will allow surgeons to modify and potentially improve outcome for patients. Purpose/Hypothesis: The purpose was to describe PROs after revision ACL reconstruction and test the hypothesis that patient- and technique-specific variables are associated with these outcomes. Study Design: Cohort study; Level of evidence, 2. Methods: Patients undergoing revision ACL reconstruction were identified and prospectively enrolled by 83 surgeons over 52 sites. Data included baseline demographics, surgical technique and pathology, and a series of validated PRO instruments: International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index, and Marx Activity Rating Scale. Patients were followed up at 2 years and asked to complete the identical set of outcome instruments. Multivariate regression models were used to control for a variety of demographic and surgical factors to determine the positive and negative predictors of PRO scores at 2 years after revision surgery. Results: A total of 1205 patients met the inclusion criteria and were successfully enrolled: 697 (58%) were male, with a median cohort age of 26 years. The median time since their most recent previous ACL reconstruction was 3.4 years. Two-year questionnaire follow-up was obtained from 989 patients (82%). The most significant positive predictors of 2-year IKDC scores were a high baseline IKDC score, high baseline Marx activity level, male sex, and having a longer time since the most recent previous ACL reconstruction, while negative predictors included having a lateral meniscectomy before the revision ACL reconstruction or having grade 3/4 chondrosis in either the trochlear groove or the medial tibial plateau at the time of the revision surgery. For KOOS, having a high baseline score and having a longer time between the most recent previous ACL reconstruction and revision surgery were significant positive predictors for having a better (ie, higher) 2-year KOOS, while having a lateral meniscectomy before the revision ACL reconstruction was a consistent predictor for having a significantly worse (ie, lower) 2-year KOOS. Statistically significant positive predictors for 2-year Marx activity levels included higher baseline Marx activity levels, younger age, male sex, and being a nonsmoker. Negative 2-year activity level predictors included having an allograft or a biologic enhancement at the time of revision surgery. Conclusion: PROs after revision ACL reconstruction are associated with a variety of patient- and surgeon-related variables. Understanding positive and negative predictors of PROs will allow surgeons to guide patient expectations as well as potentially improve outcomes.

Predictors of Patient-Reported Outcomes at 2 Years After Revision Anterior Cruciate Ligament Reconstruction

Objectives: Increased tibial slope (TS) may be associated with non-contact ACL injuries although potential confounding effects from various patient characteristics and radiographic quantification methods have not been rigorously studied. The association of TS with recurrent non-contact ACL injury after primary reconstruction is less defined. The purpose of this study was: 1) to assess the reliability and variability of TS values among different examiners, and 2) to compare TS between patients undergoing primary ACL reconstruction, re-injured patients undergoing revision ACL reconstruction, and an ACL-intact cohort. Methods: A total of 206 patients were prospectively enrolled in this single center, IRB-approved study that consisted of 3 groups: 1) ACL intact controls (CTRL, n=83), 2) first-time ACL injured patients from a non-contact mechanism (PRIM, n=77), and 3) patients with repeated non-contact ACL injury after primary ACL reconstruction (REV, n=46). Patients with prior knee surgery, radiographic signs of arthritis, chondral lesions ≥ grade 2, or insufficient radiographs were excluded. Repeated measurements of anterior and posterior TS were performed by 3 fellowship-trained sports medicine surgeons based on the previously described Utzschneider method that has a strong correlation to CT and MRI measurements. The anterior tibial slope (ATS) and posterior tibial slope (PTS) were measured to calculate an approximate mean medial tibial slope (MTS) based on the anatomic tibial axis. (Fig. 1). The intra- and inter-observer reliability were assessed by intra-class correlation coefficients (ICC). The MTS, ATS, PTS, age, BMI and sex distribution were compared among the three groups using one-way ANOVA with Tukey’s post hoc test and Chi-square test, respectively. The independent association of TS with ACL-intact controls (CTRL) vs. positive ACL injury (PRIM + REV) was assessed by multivariable logistic regression for MTS, ATS, and PTS, respectively. An a priori power analysis determined that 45 patients per group were needed to achieve a statistical power > 80% to detect a 1° difference (SD=3°) with α=0.05. Results: The ICC for intra- and inter-observer reliability in the calculation of TS ranged from 0.73-0.89 indicating substantial agreement. There was no significant difference in values for MTS, ATS, and PTS between the CTRL, PRIM and REV groups (p=0.42, 0.12, and 0.42, respectively). Patient age was highest in the CTRL group, followed by the REV, then PRIM groups (p<0.001) (Table 1). None of the TS values were independently associated with ACL injury based on multivariable logistic regression adjusted for age and sex. The mean ATS for all 206 subjects was 5° and 10° greater than that of the MTS and PTS, respectively (p < 0.001). ATS correlated only moderately to PTS (R2=0.49, p < 0.001). Conclusion: There is substantial intra- and inter-observer reliability in the radiographic assessment of medial tibial slope. Medial tibial slope was not associated with first time non-contact ACL tears or recurrent ACL graft tears undergoing reconstruction. Table 1. Patient characteristics and tibial slope quantified for three study groups. CTRL (n=83) PRIM (n=77 REV (n-46) p value Age (y.o) 37.1 +/-12.3 18.9 +/- 4.6 25.0 +/- 8.2 Sex (female, %) 56.6% 53.3% 39.1% 0.15 BMI (kg/m2) 26.6 +/- 5.9 24.7 +/- 4.5 26.5 +/- 4.4 0.83 ATS (degrees) 14.7 +/- 3.4 13.8 +/- 2.8 13.8 +/- 3.0 0.12 MTS (degrees) 10.2 +/- 3.1 9.6 +/- 2.7 10.0 +/- 2.7 0.42 PTS (degrees) 5.6 +/- 3.3 5.4 +/- 3.0 6.1 +/- 2.9 0.12

Is Medial Tibial Slope Associated With Non-contact ACL Tears? An Analysis Of Primary And Revision Acl Reconstruction Patients

Abstract Increased tibial slope may be associated with anterior cruciate ligament (ACL) injuries, although potential confounding effects from various patient characteristics and radiographic quantification methods have not been rigorously studied. The association of the slope of the lateral plateau with recurrent ACL injury after primary ACL reconstruction has recently been reported, but the role of medial slope is less well defined. The purpose of this study was to (1) assess medial tibial slope measurement reliability among examiners, (2) compare medial tibial slope values between patients undergoing primary ACL reconstruction, reinjured patients undergoing revision ACL reconstruction, and a control cohort with an intact ACL, (3) analyze if the medial tibial slope is an independent risk factor for noncontact ACL injury, and (4) assess how different anatomical references affect medial tibial slope values. A total of 206 patients were enrolled into one of three groups: (1) ACL-intact controls (CONTROL, n = 83), (2) first-time ACL-injured patients (PRIMARY, n = 77), and (3) patients undergoing revision ACL reconstruction (REVISION, n = 46). Three fellowship-trained sports medicine surgeons performed repeated measurements of plain lateral radiographs. The medial tibial slope was determined by three anatomical references: anterior tibial cortex (anterior tibial slope [ATS]), posterior tibial cortex (posterior tibial slope [PTS]), and the anatomical long axis of the tibia (composite tibial slope [CTS]). Substantial intra- and interobserver reliabilities were established by the intraclass correlation coefficient of 0.73 to 0.89. There was no difference in CTS, ATS, or PTS comparing the CONTROL, PRIMARY, and REVISION groups upon univariate analyses. Multivariable logistic regression model showed that none of the slope values was independently associated with ACL injury. The mean ATS for all 206 subjects was 4 and 8 degrees greater than the mean CTS and PTS, respectively. ATS correlated only moderately to PTS. We concluded that medial tibial slope measured on radiographs is not associated with primary or recurrent ACL injury, and has substantial variation and suboptimal correlation when using different anatomical references despite good inter- and intraobserver reliabilities.

Medial Tibial Slope Determined by Plain Radiography Is Not Associated with Primary or Recurrent Anterior Cruciate Ligament Tears

Background: Shoulder instability is a common diagnosis among patients undergoing shoulder surgery. Purpose: To perform a descriptive analysis of patients undergoing surgery for shoulder instability through a large multicenter consortium. Study Design: Case series; Level of evidence, 4. Methods: All patients undergoing surgery for shoulder instability who were enrolled in the MOON Shoulder Instability Study were included. Baseline demographics included age, sex, body mass index, and race. Baseline patient-reported outcomes (PROs) included the American Shoulder and Elbow Surgeons (ASES) score, Shoulder Activity Score, Western Ontario Shoulder Instability Index (WOSI), 36-Item Health Survey (RAND-36), and Single Assessment Numeric Evaluation (SANE). The preoperative physician examination included active range of motion (ROM) and strength testing. Preoperative imaging assessments with plain radiography, magnetic resonance imaging (MRI), and computed tomography were also included and analyzed. Results: Twenty-six surgeons had enrolled 863 patients (709 male, 154 female) across 10 clinical sites. The mean age for the cohort was 24 years (range, 12-63 years). Male patients represented 82% of the cohort. The primary direction of instability was anterior for both male (74%) and female (73%) patients. Football (24%) and basketball (13%) were the most common sports in which the primary shoulder injury occurred. No clinically significant differences were found in preoperative ROM between the affected and unaffected sides for any measurement taken. Preoperative MRI scans were obtained in 798 patients (92%). An anterior labral tear was the most common injury found on preoperative MRI, seen in 66% of patients, followed by a Hill-Sachs lesion in 41%. Poor PRO scores were recorded preoperatively (mean: ASES, 72.4; WOSI, 43.3; SANE, 46.6). Conclusion: The MOON Shoulder Instability Study has enrolled the largest cohort of patients undergoing shoulder stabilization to date. Anterior instability is most common among shoulder instability patients, and most patients undergoing shoulder stabilization are in their early 20s or younger. The results of this study provide important epidemiological information for patients undergoing shoulder stabilization surgery.

Descriptive Epidemiology of the MOON Shoulder Instability Cohort

Physical examination of the elbow is a critical component in formulating an accurate diagnosis. Various special physical examinations have been described to improve the clinician's ability to establish an accurate diagnosis. A comprehensive approach to the physical examination of the elbow, including special tests, may facilitate improved diagnosis of elbow pathology.

Background: The glenohumeral joint combines large range of motion and insufficient bony stabilization, making it susceptible to instability and dislocations. Arthroscopic surgery is routinely used as a diagnostic tool and has been considered the gold standard for the diagnosis of shoulder lesions. However, several studies have demonstrated variability in intraobserver and interobserver agreement. Purpose: To evaluate interobserver and intraobserver agreement in the assessment of intra-articular lesions associated with shoulder instability among fellowship-trained shoulder surgeons. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: A total of 24 arthroscopic videos from patients treated for recurrent shoulder instability were shown to a group of 10 fellowship-trained shoulder surgeons who are members of the Multicenter Orthopaedic Outcomes Network (MOON) Shoulder Group. They were presented to the surgeons on 2 different occasions at least 2 months apart. They were asked to classify labral tears by their position, type, extension, other intra-articular abnormality, and preferred treatment. No patient history or physical examination data were provided. The primary outcome was the median overall percentage of agreement for the surgeons performing a video review, measured for each variable evaluated. Intraclass correlation coefficients were used to evaluate continuous variables, and kappa values were used for categorical items. Results: Interobserver agreement was good for anterior labral lesions; good for Hill-Sachs lesions; and moderate for lesions of the superior labrum, posterior labrum, anterior sublabral foramen, and position and extension of the tear. Intraobserver agreement was either good or very good for all variables evaluated, except for being poor for inferior labral lesions and moderate for lesions of the meniscoid superior labrum. Conclusion: Interobserver and intraobserver reliability for the arthroscopic assessment of labral tears in patients with recurrent shoulder instability were good to moderate for the majority of anatomic structures assessed. There was relatively good agreement between shoulder instability surgeons on assessing and documenting shoulder instability–associated abnormalities. These findings are important when interpreting collaborative clinical cohort studies with numerous surgeons involved in the research.

Shoulder Instability: Interobserver and Intraobserver Agreement in the Assessment of Labral Tears

Abstract Revision anterior cruciate ligament (ACL) reconstruction typically has worse outcomes than primary reconstructions. Minimal long-term data exist regarding 5-year results. We chose to perform a systematic review to evaluate midterm (5-year) revision ACL reconstruction outcomes (patient-reported outcomes, reoperation, stability, arthritis) in comparison to primary ACL reconstructions at similar time points. Embase, Cochrane, and PubMed databases were queried, and four studies met the inclusion criteria. Two authors reviewed and performed data extraction. All were level 4 studies. Review of the studies demonstrated that results at 5 years are consistently worse than those noted in primary reconstructions for objective and patient-reported outcomes. Revision ACL reconstruction outcomes remain worse than primary reconstructions at midterm 5-year follow-up. The level of evidence is 4.

Revision Anterior Cruciate Ligament Reconstruction Outcomes at a Minimum of 5-Year Follow-Up: A Systematic Review

Background: The occurrence of physiologic knee hyperextension (HE) in the revision anterior cruciate ligament reconstruction (ACLR) population and its effect on outcomes have yet to be reported. Hypothesis/Purpose: The prevalence of knee HE in revision ACLR and its effect on 2-year outcome were studied with the hypothesis that preoperative physiologic knee HE ≥5° is a risk factor for anterior cruciate ligament (ACL) graft rupture. Study Design: Cohort study; Level of evidence, 2. Methods: Patients undergoing revision ACLR were identified and prospectively enrolled between 2006 and 2011. Study inclusion criteria were patients undergoing single-bundle graft reconstructions. Patients were followed up at 2 years and asked to complete an identical set of outcome instruments (International Knee Documentation Committee, Knee injury and Osteoarthritis Outcome Score, WOMAC, and Marx Activity Rating Scale) as well as provide information regarding revision ACL graft failure. A regression model with graft failure as the dependent variable included age, sex, graft type at the time of the revision ACL surgery, and physiologic preoperative passive HE ≥5° (yes/no) to assess these as potential risk factors for clinical outcomes 2 years after revision ACLR. Results: Analyses included 1145 patients, for whom 2-year follow-up was attained for 91%. The median age was 26 years, with age being a continuous variable. Those below the median were grouped as “younger” and those above as “older” (age: interquartile range = 20, 35 years), and 42% of patients were female. There were 50% autografts, 48% allografts, and 2% that had a combination of autograft plus allograft. Passive knee HE ≥5° was present in 374 (33%) patients in the revision cohort, with 52% being female. Graft rupture at 2-year follow-up occurred in 34 cases in the entire cohort, of which 12 were in the HE ≥5° group (3.2% failure rate) and 22 in the non-HE group (2.9% failure rate). The median age of patients who failed was 19 years, as opposed to 26 years for those with intact grafts. Three variables in the regression model were significant predictors of graft failure: younger age (odds ratio [OR] = 3.6; 95% CI, 1.6-7.9; P = .002), use of allograft (OR = 3.3; 95% CI, 1.5-7.4; P = .003), and HE ≥5° (OR = 2.12; 95% CI, 1.1-4.7; P = .03). Conclusion: This study revealed that preoperative physiologic passive knee HE ≥5° is present in one-third of patients who undergo revision ACLR. HE ≥5° was an independent significant predictor of graft failure after revision ACLR with a >2-fold OR of subsequent graft rupture in revision ACL surgery. Registration: NCT00625885 (ClinicalTrials.gov identifier).

Physiologic Preoperative Knee Hyperextension Is a Predictor of Failure in an Anterior Cruciate Ligament Revision Cohort: A Report From the MARS Group

PROMIS Scores Are Responsive to Early Changes in Patient Outcomes Following Arthroscopic Partial Meniscectomy

Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association

Patient Reported Outcomes Measurement Information System Scores Are Responsive to Early Changes in Patient Outcomes Following Arthroscopic Partial Meniscectomy.

Background: Anterior cruciate ligament (ACL) reconstruction can effectively return athletes to the playing field, but they are still at risk of developing posttraumatic osteoarthritis (PTOA). No studies have used multivariable analysis to evaluate the predictors of radiographic PTOA in the lateral compartment of the knee at short-term follow-up after ACL reconstruction. Purpose: To determine the predictors of radiographic joint space narrowing in the lateral compartment 2 to 3 years after ACL reconstruction in a young, active cohort. Study Design: Cohort study; Level of evidence, 2. Methods: A nested cohort of 358 patients from the Multicenter Orthopaedic Outcomes Network (MOON) prospective cohort who were aged ≤33 years, were injured playing a sport, and had never undergone surgery on the contralateral knee were followed up 2 years after ACL reconstruction with questionnaires and with weightbearing knee radiographs using the metatarsophalangeal (MTP) joint technique. The joint space width in the lateral compartment was measured using a semiautomatic computerized method, and multivariable predictive modeling was used to evaluate the relationship between meniscus treatment, cartilage injury, graft type, and joint space while adjusting for age, sex, body mass index, and Marx activity score. Results: The mean lateral joint space width was 0.11 mm narrower on the ACL-reconstructed knee compared with the contralateral healthy knee (7.69 mm vs 7.80 mm, respectively; P < .01). Statistically significant predictors of a narrower joint space width on the ACL-reconstructed knee included lateral meniscectomy (P < .001) and a Marx activity score less than 16 points (P < .001). Conclusion: This study identifies lateral meniscectomy and a lower baseline Marx activity score to be predictors of radiographic joint space narrowing in the lateral compartment 2 to 3 years after ACL reconstruction in young, active patients without a prior knee injury.

Differences in the Lateral Compartment Joint Space Width After Anterior Cruciate Ligament Reconstruction: Data From the MOON Onsite Cohort

Background: High-grade acromioclavicular (AC) joint separations are relatively rare injuries that are often treated surgically, yet more information is needed about the risks of various surgical procedures in terms of considering and counseling patients regarding operative versus nonoperative treatment. Purpose: To calculate whether the volume of surgical treatment of AC joint separations increased over a recent 12-year period; to examine the nature and frequency of complications, reoperations, and readmissions associated with these procedures; and to assess whether patient- and surgeon-specific factors or surgical technique affected these rates. Study Design: Cross-sectional study; Level of evidence, 3. Methods: The American Board of Orthopaedic Surgery (ABOS) database for orthopaedic surgeons taking the Part II examination was reviewed from 2005 to 2016 to identify surgical treatment of AC joint separations. The authors calculated the percentage of all surgical cases in the ABOS database and rates of complications, reoperations, and readmissions. Association of these sequelae with patient- and surgeon-specific factors and surgical techniques was assessed. Results: There was no difference in the number or percentage of cases per year over the study period. There was an overall complication rate of 24.5%, a reoperation rate of 7.3%, and a readmission rate of 1.9%. Patients ≥40 years of age had significantly higher complication, reoperation, and readmission rates as compared with patients <40 years of age. There were significant differences in complication, reoperation, readmission, and displacement rates dependent on the type of surgical procedure performed. The highest complication rates were seen with open suspensory fixation, screw fixation, open reduction internal fixation, and arthroscopic coracoclavicular ligament repair or reconstruction. The highest reoperation rates were seen with screw fixation, open reduction internal fixation, and open suspensory fixation. Conclusion: The volume of surgical treatment for AC joint separations did not change significantly over the study period. Complication, reoperation, and readmission rates were dependent on the type of surgical procedure performed and patient age. This information should assist surgeons in discussing risks when considering and counseling patients regarding operative versus nonoperative treatment.

Surgical Volume and Postoperative Complications of Acromioclavicular Joint Separations: Analysis of the ABOS Part II Examination

Background: Patient preference information has become increasingly more important in clinical decision making. Purpose: To assess patient preferences when making treatment decisions in the shoulder to determine which features are more important according to patient age, race, activity level, and sex. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Study participants aged ≥18 years were surveyed as to their preferences regarding surgical treatment for shoulder and proximal biceps abnormalities. Survey features included time to return to unrestricted activities, time to return to work, size and appearance of scars, the potential for persistent pain in the upper arm or shoulder, fatigue in the biceps with repetitive lifting, potential for muscle cramping, and deformity in the proximal biceps. Participants also completed a validated shoulder activity scale, and demographic data regarding age, race, and sex were collected. Results: A total of 349 participants (166 female, 183 male) with a mean age of 45 years (range, 18-81 years) completed the survey. Overall, time to return to unrestricted activities and residual pain were considered very important to the majority of the respondents, while the size and appearance of surgical scars were of little importance. Prior shoulder pain (ρ = –0.17; P = .01) and prior shoulder surgery (ρ = –0.16; P = .03) correlated to concern about time to return to unrestricted activities. Younger age (ρ = –0.11; P = .04) and a higher level of education (ρ = 0.14; P = .03) correlated with greater concern for time to return to work. Women and African Americans were more concerned about the size and appearance of surgical scars (ρ = –0.28; P < .0001 and ρ = –0.20; P = .0002, respectively) and biceps deformity. Respondents with a higher activity level (ρ = 0.20; P = .0002) and men (ρ = 0.11; P = .04) were more concerned about fatigue. Conclusion: Concerns about residual pain, time to return to unrestricted activities, and time away from work are important to patients when considering the treatment for shoulder lesions. Patient preferences are associated with age, sex, race, and shoulder activity level. These features should be considered when discussing treatment options for shoulder and proximal biceps tendon disorders.

Patient Preferences for the Treatment of Shoulder and Proximal Biceps Disorders Are Associated With Patient Age, Race, Sex, and Activity Level

Background: The opioid epidemic in the United States has placed increased pressure on physicians to engage in responsible opioid prescribing practices. However, surgeons currently have little information to guide their postoperative prescription decision-making. The purpose of this study was to assess opioid consumption after knee arthroscopy and identify preoperative factors that may predict higher opioid usage. Methods: A prospective observational study of 221 patients was conducted in patients undergoing outpatient knee arthroscopy for meniscal repair, partial meniscectomy, debridement, chondroplasty, or loose body removal. Participants recorded their daily opioid consumption in a postoperative pain diary. Total opioid consumption was calculated from counts of remaining pills at the 2-week and 6-week postoperative office visits. Variables, including age, sex, body mass index, smoking status, alcohol consumption, preoperative pain severity and duration, preoperative opioid usage, Patient-Reported Outcomes Measurement Information System (PROMIS) scores, and the Connor-Davidson Resilience Scale, were evaluated for an association with opioid consumption. Results: Total opioid consumption ranged from 0 to 188 pills, with a median of 7 pills (hydrocodone 5-mg equivalents). Forty-six percent of patients took ⩽5 pills, 59% took ⩽10 pills, and 81% took ⩽20 pills. Fifty-six percent of patients had discontinued opioid usage by the third postoperative day. Eighty-eight percent of patients had surplus opioid medication at the time of the final follow-up. Patients undergoing meniscal repair, smokers, and those taking preoperative opioids were significantly more likely to take ≥20 pills (p < 0.05). Conclusions: The median number of pills taken after knee arthroscopy is 7, with the majority of patients consuming ⩽20 pills. Meniscal repair, smoking, and preoperative opioid usage were associated with higher postoperative opioid consumption. Level of Evidence: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Background: The ulnar collateral ligament (UCL) microstructural organization and collagen fiber realignment in response to load are unknown. Purpose/Hypothesis: The purpose was to describe the real-time microstructural collagen changes in the anterior bundle (AB) and posterior bundle (PB) of the UCL with tensile load. It was hypothesized that the UCL AB is stronger and stiffer with more highly aligned collagen during loading when compared with the UCL PB. Study Design: Descriptive laboratory study. Methods: The AB and PB from 34 fresh cadaveric specimens were longitudinally sectioned to allow uniform light passage for quantitative polarized light imaging. Specimens were secured to a tensile test machine and underwent cyclic preconditioning, a ramp-and-hold stress-relaxation test, and a quasi-static ramp to failure. A division-of-focal-plane polarization camera captured real-time pixelwise microstructural data of each sample during stress-relaxation and at the zero, transition, and linear points of the stress-strain curve. The SD of the angle of polarization determined the deviation of the average direction of collagen fibers in the tissue, while the average degree of linear polarization evaluated the strength of collagen alignment in those directions. Since the data were nonnormally distributed, the median ± interquartile range are presented. Results: The AB has larger elastic moduli than the PB (P < .0001) in the toe region (median, 2.73 MPa [interquartile range, 1.1-5.6 MPa] vs 0.65 MPa [0.44-1.5 MPa]) and the linear region (13.77 MPa [4.8-40.7 MPa] vs 1.96 MPa [0.58-9.3 MPa]). The AB demonstrated larger stress values, stronger collagen alignment, and more uniform collagen organization during stress-relaxation. PB collagen fibers were more disorganized than the AB during the zero (P = .046), transitional (P = .011), and linear (P = .007) regions of the stress-strain curve. Both UCL bundles exhibited very small changes in collagen alignment (SD of the angle of polarization) with load. Conclusion: The AB of the UCL is stiffer and stronger, with more strongly aligned and more uniformly oriented collagen fibers, than the PB. The small changes in collagen alignment indicate that the UCL response to load is due more to its static collagen organization than to dynamic changes in collagen alignment. Clinical Relevance: The UCL collagen organization may explain its susceptibility to injury with repetitive valgus loads.

Mechanical Properties and Microstructural Collagen Alignment of the Ulnar Collateral Ligament During Dynamic Loading

Background: Articular cartilage health is an important issue following anterior cruciate ligament (ACL) injury and primary ACL reconstruction. Factors present at the time of primary ACL reconstruction may influence the subsequent progression of articular cartilage damage. Hypothesis: Larger meniscus resection at primary ACL reconstruction, increased patient age, and increased body mass index (BMI) are associated with increased odds of worsened articular cartilage damage at the time of revision ACL reconstruction. Study Design: Case-control study; Level of evidence, 3. Methods: Subjects who had primary and revision data in the databases of the Multicenter Orthopaedics Outcomes Network (MOON) and Multicenter ACL Revision Study (MARS) were included. Reviewed data included chondral surface status at the time of primary and revision surgery, meniscus status at the time of primary reconstruction, primary reconstruction graft type, time from primary to revision ACL surgery, as well as demographics and Marx activity score at the time of revision. Significant progression of articular cartilage damage was defined in each compartment according to progression on the modified Outerbridge scale (increase ≥1 grade) or >25% enlargement in any area of damage. Logistic regression identified predictors of significant chondral surface change in each compartment from primary to revision surgery. Results: A total of 134 patients were included, with a median age of 19.5 years at revision surgery. Progression of articular cartilage damage was noted in 34 patients (25.4%) in the lateral compartment, 32 (23.9%) in the medial compartment, and 31 (23.1%) in the patellofemoral compartment. For the lateral compartment, patients who had >33% of the lateral meniscus excised at primary reconstruction had 16.9-times greater odds of progression of articular cartilage injury than those with an intact lateral meniscus (P < .001). For the medial compartment, patients who had <33% of the medial meniscus excised at the time of the primary reconstruction had 4.8-times greater odds of progression of articular cartilage injury than those with an intact medial meniscus (P = .02). Odds of significant chondral surface change increased by 5% in the lateral compartment and 6% in the medial compartment for each increased year of age (P ≤ .02). For the patellofemoral compartment, the use of allograft in primary reconstruction was associated with a 15-fold increased odds of progression of articular cartilage damage relative to a patellar tendon autograft (P < .001). Each 1-unit increase in BMI at the time of revision surgery was associated with a 10% increase in the odds of progression of articular cartilage damage (P = .046) in the patellofemoral compartment. Conclusion: Excision of the medial and lateral meniscus at primary ACL reconstruction increases the odds of articular cartilage damage in the corresponding compartment at the time of revision ACL reconstruction. Increased age is a risk factor for deterioration of articular cartilage in both tibiofemoral compartments, while increased BMI and the use of allograft for primary ACL reconstruction are associated with an increased risk of progression in the patellofemoral compartment.

Risk Factors and Predictors of Significant Chondral Surface Change From Primary to Revision Anterior Cruciate Ligament Reconstruction: A MOON and MARS Cohort Study

Background: Revision anterior cruciate ligament (ACL) reconstruction has been documented to have worse outcomes compared with primary ACL reconstruction. Hypothesis: Certain factors under the control of the surgeon at the time of revision surgery can both negatively and positively affect outcomes. Study Design: Case-control study; Level of evidence, 3. Methods: Patients undergoing revision ACL reconstruction were identified and prospectively enrolled between 2006 and 2011. Data collected included baseline demographics, intraoperative surgical technique and joint disorders, and a series of validated patient-reported outcome instruments (International Knee Documentation Committee [IKDC] subjective form, Knee Injury and Osteoarthritis Outcome Score [KOOS], Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC], and Marx activity rating scale) completed before surgery. Patients were followed up for 2 years and asked to complete an identical set of outcome instruments. Regression analysis was used to control for age, sex, body mass index (BMI), activity level, baseline outcome scores, revision number, time since last ACL reconstruction, and a variety of previous and current surgical variables to assess the surgical risk factors for clinical outcomes 2 years after revision ACL reconstruction. Results: A total of 1205 patients (697 male [58%]) met the inclusion criteria and were successfully enrolled. The median age was 26 years, and the median time since their last ACL reconstruction was 3.4 years. Two-year follow-up was obtained on 82% (989/1205). Both previous and current surgical factors were found to be significant contributors toward poorer clinical outcomes at 2 years. Having undergone previous arthrotomy (nonarthroscopic open approach) for ACL reconstruction compared with the 1-incision technique resulted in significantly poorer outcomes for the 2-year IKDC (P = .037; odds ratio [OR], 2.43; 95% CI, 1.05-5.88) and KOOS pain, sports/recreation, and quality of life (QOL) subscales (P ≤ .05; OR range, 2.38-4.35; 95% CI, 1.03-10.00). The use of a metal interference screw for current femoral fixation resulted in significantly better outcomes for the 2-year KOOS symptoms, pain, and QOL subscales (P ≤ .05; OR range, 1.70-1.96; 95% CI, 1.00-3.33) as well as WOMAC stiffness subscale (P = .041; OR, 1.75; 95% CI, 1.02-3.03). Not performing notchplasty at revision significantly improved 2-year outcomes for the IKDC (P = .013; OR, 1.47; 95% CI, 1.08-1.99), KOOS activities of daily living (ADL) and QOL subscales (P ≤ .04; OR range, 1.40-1.41; 95% CI, 1.03-1.93), and WOMAC stiffness and ADL subscales (P ≤ .04; OR range, 1.41-1.49; 95% CI, 1.03-2.05). Factors before revision ACL reconstruction that increased the risk of poorer clinical outcomes at 2 years included lower baseline outcome scores, a lower Marx activity score at the time of revision, a higher BMI, female sex, and a shorter time since the patient’s last ACL reconstruction. Prior femoral fixation, prior femoral tunnel aperture position, and knee flexion angle at the time of revision graft fixation were not found to affect 2-year outcomes in this revision cohort. Conclusion: There are certain surgical variables that the physician can control at the time of revision ACL reconstruction that can modify clinical outcomes at 2 years. Whenever possible, opting for an anteromedial portal or transtibial surgical exposure, choosing a metal interference screw for femoral fixation, and not performing notchplasty are associated with significantly better 2-year clinical outcomes.

Surgical Predictors of Clinical Outcomes After Revision Anterior Cruciate Ligament Reconstruction

Background: The windmill pitching motion has been associated with risk for shoulder injury. Because there are no pitching limits on youth fast-pitch softball pitchers, these athletes often pitch multiple games across consecutive days. Strength changes, fatigue levels, and shoulder pain that develop among female fast-pitch pitchers over the course of consecutive days of pitching have not been investigated. Hypothesis: Over the course of 2- and 3-day fast-pitch softball tournaments, pitchers will develop progressive objective weakness and increased subjective shoulder fatigue and pain without complete recovery between days. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Fourteen female fast-pitch softball pitchers between the ages of 14 and 18 years were evaluated for strength and fatigue changes across 2- and 3-day tournaments. At the beginning and end of each day of tournament play, pitchers were asked to quantify shoulder fatigue and shoulder pain levels of their dominant throwing arm using a 10-point visual analog scale (VAS). Shoulder abduction, flexion, external rotation, internal rotation, elbow flexion, and elbow extension strength measurements were gathered using a handheld dynamometer. Results: Over the course of an average single day of tournament participation, pitchers developed significant increases in VAS scores for shoulder fatigue (median, 2.0; 95% CI, 1.3-3.0) and pain (median, 1.3; 95% CI, 0.5-2.3) and significant strength loss in all tested motions. Pitchers also developed significant increases in VAS shoulder fatigue (median, 3.5; 95% CI, 1.5-5.5), VAS shoulder pain (median, 2.5; 95% CI, 1.0-4.5), and strength loss in all tested motions over the entire tournament. Shoulder pain, fatigue, and strength do not fully recover between days. The accumulation of subjective shoulder pain and fatigue over the course of tournament play were closely correlated. Conclusion: Among youth female fast-pitch softball pitchers, there is a progressive increase in shoulder fatigue, pain, and weakness over the course of 2- and 3-day tournaments without full recovery between consecutive days of pitching.

Effect of Pitching Consecutive Days in Youth Fast-Pitch Softball Tournaments on Objective Shoulder Strength and Subjective Shoulder Symptoms

Background: In ice hockey players, serious bone injuries in the foot and ankle, especially those attributed to impact from the moving puck, may be radiographically occult and underrecognized. Purpose/Hypothesis: The purpose of this research was to study foot and ankle bone injuries detected with magnetic resonance imaging (MRI) that occurred in elite hockey players. The hypothesis was that these injuries predominate medially, especially when caused by the impact from the puck, and are associated with prolonged lost playing time. Study Design: Case series; Level of evidence, 4. Methods: Three independent observers, blinded to the mechanism of injury, retrospectively reviewed foot and ankle MRI examinations acquired after 31 acute injuries that occurred in 27 elite ice hockey players who had no radiographically visible fractures. Bone abnormalities were classified as fractures or varying degrees of contusion based on predetermined definitions. Interobserver agreement was analyzed with kappa statistics. The association between the injury mechanism and the bones involved was examined with the Fisher exact test. A t test was applied to determine if MRI evidence of a severe bone injury (defined as either a fracture or a high-grade bone contusion) was associated with longer recovery times, when return-to-play information was available. Results: The observers identified at least 1 bone injury in 27 of the 31 MRI examinations, including 10 with radiographically occult fractures. Agreement among the 3 observers for injury categorization was substantial (κ = 0.76). Seventeen injuries were caused by a direct blow (15 from a moving puck, 2 from an uncertain source), resulting in 6 fractures and 6 high-grade bone contusions, with 14 of the 17 involving a medial bone (medial malleolus, navicular, or first metatarsal base). Compared with other mechanisms, direct impaction was statistically more likely to result in a severe bone injury and to involve the medial foot and ankle. In 20 injuries where return-to-play information was available, players with severe bone injuries missed a mean of 10.6 games compared with 2.4 games for other players (P = .05). Conclusion: MRI can show severe bone injuries that are not visible radiographically in ice hockey players. Most fractures and high-grade contusions involve the medial ankle and midfoot bones, can be caused by direct blows from the puck, and are associated with prolonged recovery times.

Subradiographic Foot and Ankle Fractures and Bone Contusions Detected by MRI in Elite Ice Hockey Players

Shoulder Activity Level is Associated With Type of Employment and Income in the Normative Population Without Shoulder Disorders

Background: While revision anterior cruciate ligament reconstruction (ACLR) can be performed to restore knee stability and improve patient activity levels, outcomes after this surgery are reported to be inferior to those after primary ACLR. Further reoperations after revision ACLR can have an even more profound effect on patient satisfaction and outcomes. However, there is a current lack of information regarding the rate and risk factors for subsequent surgery after revision ACLR. Purpose: To report the rate of reoperations, procedures performed, and risk factors for a reoperation 2 years after revision ACLR. Study Design: Case-control study; Level of evidence, 3. Methods: A total of 1205 patients who underwent revision ACLR were enrolled in the Multicenter ACL Revision Study (MARS) between 2006 and 2011, composing the prospective cohort. Two-year questionnaire follow-up was obtained for 989 patients (82%), while telephone follow-up was obtained for 1112 patients (92%). If a patient reported having undergone subsequent surgery, operative reports detailing the subsequent procedure(s) were obtained and categorized. Multivariate regression analysis was performed to determine independent risk factors for a reoperation. Results: Of the 1112 patients included in the analysis, 122 patients (11%) underwent a total of 172 subsequent procedures on the ipsilateral knee at 2-year follow-up. Of the reoperations, 27% were meniscal procedures (69% meniscectomy, 26% repair), 19% were subsequent revision ACLR, 17% were cartilage procedures (61% chondroplasty, 17% microfracture, 13% mosaicplasty), 11% were hardware removal, and 9% were procedures for arthrofibrosis. Multivariate analysis revealed that patients aged <20 years had twice the odds of patients aged 20 to 29 years to undergo a reoperation. The use of an allograft at the time of revision ACLR (odds ratio [OR], 1.79; P = .007) was a significant predictor for reoperations at 2 years, while staged revision (bone grafting of tunnels before revision ACLR) (OR, 1.93; P = .052) did not reach significance. Patients with grade 4 cartilage damage seen during revision ACLR were 78% less likely to undergo subsequent operations within 2 years. Sex, body mass index, smoking history, Marx activity score, technique for femoral tunnel placement, and meniscal tearing or meniscal treatment at the time of revision ACLR showed no significant effect on the reoperation rate. Conclusion: There was a significant reoperation rate after revision ACLR at 2 years (11%), with meniscal procedures most commonly involved. Independent risk factors for subsequent surgery on the ipsilateral knee included age <20 years and the use of allograft tissue at the time of revision ACLR.

Subsequent Surgery After Revision Anterior Cruciate Ligament Reconstruction: Rates and Risk Factors From a Multicenter Cohort

Background: Revision anterior cruciate ligament (ACL) reconstruction has been documented to have worse outcomes compared with primary ACL reconstructions. Purpose/Hypothesis: The purpose of this study was to determine if the prevalence, location, and/or degree of meniscal and chondral damage noted at the time of revision ACL reconstruction predicts activity level, sports function, and osteoarthritis symptoms at 2-year follow-up. The hypothesis was that meniscal loss and high-grade chondral damage noted at the time of revision ACL reconstruction will result in lower activity levels, decreased sports participation, more pain, more stiffness, and more functional limitation at 2 years after revision surgery. Study Design: Cohort study; Level of evidence, 2. Methods: Between 2006 and 2011, a total of 1205 patients who underwent revision ACL reconstruction by 83 surgeons at 52 hospitals were accumulated for study of the relationship of meniscal and articular cartilage damage to outcome. Baseline demographic and intraoperative data, including the International Knee Documentation Committee (IKDC) subjective knee evaluation, Knee injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Marx activity score, were collected initially and at 2-year follow-up to test the hypothesis. Regression analysis was used to control for age, sex, body mass index, smoking status, activity level, baseline outcome scores, revision number, time since last ACL reconstruction, incidence of having a previous ACL reconstruction on the contralateral knee, previous and current meniscal and articular cartilage injury, graft choice, and surgeon years of experience to assess the meniscal and articular cartilage risk factors for clinical outcomes 2 years after revision ACL reconstruction. Results: At 2-year follow-up, 82% (989/1205) of the patients returned their questionnaires. It was found that previous meniscal injury and current articular cartilage damage were associated with the poorest outcomes, with prior lateral meniscectomy and current grade 3 to 4 trochlear articular cartilage changes having the worst outcome scores. Activity levels at 2 years were not affected by meniscal or articular cartilage pathologic changes. Conclusion: Prior lateral meniscectomy and current grade 3 to 4 changes of the trochlea were associated with worse outcomes in terms of decreased sports participation, more pain, more stiffness, and more functional limitation at 2 years after revision surgery, but they had no effect on activity levels. Registration: NCT00625885

Meniscal and Articular Cartilage Predictors of Clinical Outcome After Revision Anterior Cruciate Ligament Reconstruction

2013 Neer Award: predictors of failure of nonoperative treatment of chronic, symptomatic, full-thickness rotator cuff tears.

Prevention of Labral and Rotator Cuff Injuries in the Overhead Athlete

Background: Football puts athletes at risk for knee injuries such meniscus and anterior cruciate ligament (ACL) tears, which are associated with the development of osteoarthritis (OA). Previous knee surgery, player position, and body mass index (BMI) may be associated with knee OA. Hypothesis: In elite football players undergoing knee magnetic resonance imaging at the National Football League’s Invitational Combine, the prevalence of knee OA is associated with previous knee surgery and BMI. Study Design: Retrospective cohort. Level of Evidence: Level 4. Methods: A retrospective review was performed of all participants of the National Football League Combine from 2005 to 2009 who underwent magnetic resonance imaging of the knee because of prior knee injury, surgery, or knee-related symptoms or concerning examination findings. Imaging studies were reviewed for evidence of OA. History of previous knee surgery—including ACL reconstruction, meniscal procedures, and articular cartilage surgery—and position were recorded for each athlete. BMI was calculated based on height and weight. Results: There was a higher prevalence of OA in knees with a history of previous knee surgery (23% vs 4.0%, P < 0.001). The prevalence of knee OA was 4.0% in those without previous knee surgery, 11% in those with a history of meniscus repair, 24% of those with a history of ACL reconstruction, and 27% of those with a history of partial meniscectomy. Among knees with a previous ACL reconstruction, the rate of OA doubled in tibiofemoral compartments in which meniscal surgery was performed. BMI >30 kg/m2 was also associated with a higher risk of OA (P = 0.007) but player position was not associated with knee OA. Conclusions: Previous knee surgery, particularly ACL reconstruction and partial meniscectomy, and elevated BMI are associated with knee OA in elite football players. Future research should investigate ways to minimize the risk of OA after knee surgery in these athletes. Clinical Relevance: Treatment of knee injuries in football athletes should consider chondroprotection, including meniscal preservation and cartilage repair, when possible.

Knee Osteoarthritis Is Associated With Previous Meniscus and Anterior Cruciate Ligament Surgery Among Elite College American Football Athletes

Fast-Pitch Softball Pitchers Experience a Significant Increase in Pain and Fatigue During a Single High School Season

Introduction: The use of MRI is increasing when evaluating patients with knee pain because it is highly sensitive for detecting intra-articular pathology. However, such changes can be associated with degenerative joint disease, which may be demonstrated with weight-bearing radiographs. The purpose of this study was to determine how often MRI was obtained before orthopaedic referral in patients aged ≥40 years with knee pain, how often weight-bearing radiographs were obtained before MRI, and whether such imaging influenced treatment recommendations.Methods: In a study of 599 new patients, participating physicians documented the presence of a prereferral MRI and/or plain radiographic studies, the results of weight-bearing radiographs, treatment recommendations, and the impact of any prereferral imaging.Results: Prereferral use of MRI occurred in 130 patients (22%). Of these patients, plain radiographic studies were obtained for 58% before MRI and 13% had weight-bearing radiographs. Ultimately, 17% had weight-bearing radiographs that demonstrated >50% loss of joint space. Forty-eight percent of prereferral MRIs did not contribute to treatment recommendations. In patients with >50% loss of joint space, MRI was considered unnecessary in 95% of the cases.Discussion: Many prereferral MRIs do not contribute to clinical decision making. Weight-bearing radiographs can help identify those patients in whom MRI is unlikely to be helpful.Level of Evidence: Level III

The Use of MRI in Evaluating Knee Pain in Patients Aged 40 Years and Older

Warren R. Dunn, MD, MPH, John E. Kuhn, MD, MS*, Rosemary Sanders, BA, Qi An, MS, Keith M. Baumgarten, MD, Julie Y. Bishop, MD, Robert H. Brophy, MD, James L. Carey, MD, MPH, Frank Harrell, PhD, Brian G. Holloway, MD, Grant L. Jones, MD, C. Benjamin Ma, MD, Robert G. Marx, MD, MS, Eric C. McCarty, MD, Sourav K. Poddar, MD, Matthew V. Smith, MD, Edwin E. Spencer, MD, Armando F. Vidal, MD, Brian R. Wolf, MD, MS, Rick W. Wright, MD, for the MOON Shoulder Group

Neer Award : predictors of failure of nonoperative treatment of chronic , symptomatic , full-thickness rotator cuff tears

Background: There is a scarcity of literature evaluating injuries in youth fast-pitch softball players. Purpose: To perform a descriptive analysis of player-reported injuries in youth fast-pitch softball position players and pitchers during a single select-level season. Study Design: Prospective observation cohort study. Level of Evidence: Level 3. Methods: Ninety-eight athletes (48 pitchers, 50 position players) were followed for a single select fast-pitch softball season. Study participants completed web-based surveys every 3 weeks reporting injuries related to participation in fast-pitch softball. Injury was defined as pain causing cessation of participation in the current game or practice that prevents the player’s return to that session or any pain that causes cessation of a player’s customary participation on the day after the day of onset. Results: The median age of the study participants was 14 years (range, 9-18 years). There were 49 reported injuries in 98 athletes. The average age was 13 years for those not injured and 14 years for those who were injured (P < 0.02). There were 31 injuries that were not related to pitching: 19 occurred in position players and 12 occurred in pitchers; 70% of these injuries were to the lower extremity. The proportion of injuries not related to pitching was significantly greater than the proportion of injuries related to pitching (P < 0.02). Eighteen injuries among the 48 pitchers (38%) were directly attributed to pitching. Among the 18 pitching injuries, 11 (61%) involved the shoulder. The majority (78%) of injuries related to pitching occurred in the first 6 weeks of the season. Conclusion: There was a high incidence of injury in this prospective cohort of youth select-level fast-pitch softball players. Better off-season and preseason conditioning may be a key factor for reducing pitching injuries. Clinical Relevance: Recognition of injury patterns in fast-pitch softball players is critical to developing strategies to keep these athletes competing safely.

Prospective Player-Reported Injuries in Female Youth Fast-Pitch Softball Players

Context: Anterior cruciate ligament (ACL) reconstruction rehabilitation has evolved over the past 20 years. This evolution has been driven by a variety of level 1 and level 2 studies. Evidence Acquisition: The MOON Group is a collection of orthopaedic surgeons who have developed a prospective longitudinal cohort of the ACL reconstruction patients. To standardize the management of these patients, we developed, in conjunction with our physical therapy committee, an evidence-based rehabilitation guideline. Study Design: Clinical review. Level of Evidence: Level 2. Results: This review was based on 2 systematic reviews of level 1 and level 2 studies. Recently, the guideline was updated by a new review. Continuous passive motion did not improve ultimate motion. Early weightbearing decreases patellofemoral pain. Postoperative rehabilitative bracing did not improve swelling, pain range of motion, or safety. Open chain quadriceps activity can begin at 6 weeks. Conclusion: High-level evidence exists to determine appropriate ACL rehabilitation guidelines. Utilizing this protocol follows the best available evidence.

Understanding of Meniscus Injury and Expectations of Meniscus Surgery in Patients Presenting for Orthopaedic Care.

Recent advances in our understanding of the function of the hip capsule have clarified its importance to normal hip function and kinematics. The iliofemoral ligament is the primary stabilizing structure for controlling anterior translation and external rotation of the hip, and is violated by the arthroscopic interportal capsulotomy. Microinstability of the hip occurring after surgical trauma remains a poorly defined clinical entity. In certain at-risk populations, capsular repair should be considered as part of an arthroscopic hip procedure to achieve optimal outcomes and avoid iatrogenic instability (dislocation or microinstability). Despite a lack of conclusive evidence-based indications, we recommend capsular repair in the settings of borderline hip dysplasia (or dysplastic variants such as increased femoral anteversion), hip hypermobility, connective tissue disorders, and traumatic or atraumatic instability. With careful attention to arthroscopic capsular management, adequate exposure can be achieved and reproducibly allow for an effective capsular repair when indicated.

Biomechanics of the Hip Capsule and Capsule Management Strategies in Hip Arthroscopy

Background: Multiple techniques have been suggested for the treatment of isolated knee articular cartilage injuries. For smaller lesions (<2-5 cm2), microfracture and osteochondral autograft transplantation (OAT) are commonly used options. With an increasing focus on health care efficiency, analyzing the cost-effectiveness of treatment modalities has become increasingly important. Purpose/Hypothesis: The purpose of this study was to analyze the costs and outcomes of microfracture and OAT to compare their cost-effectiveness. The hypothesis was that microfracture would be more cost-effective. Study Design: Economic and decision analysis; Level of evidence, 2. Methods: A literature search was performed to identify studies comparing microfracture and OAT for the treatment of articular cartilage lesions of the distal femur in an adult population. Data from these studies including surgical time, failure rates, revision surgeries, outcome scores, and return to athletics were then incorporated into a constructed cost model using standard accounting methodology. The model was based on actual 2013 cost figures (in US dollars) for all procedure, operating room, and instrumentation costs. Results: Three studies, with a mean follow-up of 8.7 years, met the inclusion criteria of having evidence level 1 or 2 comparing microfracture and OAT. There was a cumulative 28.6% reoperation rate among patients undergoing microfracture compared with 12.5% among patients undergoing OAT. While both groups demonstrated significant improvements compared with preoperative levels, the only significant differences in any outcome score reported between the 2 procedures were the International Cartilage Repair Society (ICRS) score and patient-reported return to their previous sports activity level. While microfracture had a lower initial cost ($3100), these savings lessened over 1 year ($1843) and 10 years ($996). Microfracture was more cost-effective when comparing Lysholm and Hospital for Special Surgery scores, whereas OAT was more cost-effective when comparing Tegner and ICRS scores. There was a significantly lower cost for return to play in athletes after OAT versus microfracture at 1 year ($11,428 vs $16,953, respectively), 3 years ($12,856 vs $38,000, respectively), and 10 years ($32,141 vs $60,799, respectively). Conclusion: Published level 1 and 2 clinical studies with a 10-year follow-up demonstrated that the net cost and cost-effectiveness of microfracture and OAT are comparable for the treatment of isolated articular cartilage lesions of the distal femur. Clinical Relevance: Given similar clinical outcomes, microfracture and OAT are both viable, cost-effective first-line treatment options for these injuries.

Microfracture and Osteochondral Autograft Transplantation Are Cost-effective Treatments for Articular Cartilage Lesions of the Distal Femur

http://ajs.sagepub.com/content/early/2015/07/09/0363546515591261 The online version of this article can be found at: DOI: 10.1177/0363546515591261 published online July 9, 2015 Am J Sports Med D. Josh Miller, Matthew V. Smith, Matthew J. Matava, Rick W. Wright and Robert H. Brophy Articular Cartilage Lesions of the Distal Femur Microfracture and Osteochondral Autograft Transplantation Are Cost-effective Treatments for

Articular Cartilage Lesions of the Distal Femur Microfracture and Osteochondral Autograft Transplantation Are Cost-effective Treatments for

A biomechanical analysis of the soft tissue and osseous constraints of the hip joint

BACKGROUND
For many orthopaedic disorders, symptoms correlate with disease severity. The objective of this study was to determine if pain level is related to the severity of rotator cuff disorders.

METHODS
A cohort of 393 subjects with an atraumatic symptomatic full-thickness rotator-cuff tear treated with physical therapy was studied. Baseline pretreatment data were used to examine the relationship between the severity of rotator cuff disease and pain. Disease severity was determined by evaluating tear size, retraction, superior humeral head migration, and rotator cuff muscle atrophy. Pain was measured on the 10-point visual analog scale (VAS) in the patient-reported American Shoulder and Elbow Surgeons (ASES) score. A linear multiple regression model was constructed with use of the continuous VAS score as the dependent variable and measures of rotator cuff tear severity and other nonanatomic patient factors as the independent variables. Forty-eight percent of the patients were female, and the median age was sixty-one years. The dominant shoulder was involved in 69% of the patients. The duration of symptoms was less than one month for 8% of the patients, one to three months for 22%, four to six months for 20%, seven to twelve months for 15%, and more than a year for 36%. The tear involved only the supraspinatus in 72% of the patients; the supraspinatus and infraspinatus, with or without the teres minor, in 21%; and only the subscapularis in 7%. Humeral head migration was noted in 16%. Tendon retraction was minimal in 48%, midhumeral in 34%, glenohumeral in 13%, and to the glenoid in 5%. The median baseline VAS pain score was 4.4.

RESULTS
Multivariable modeling, controlling for other baseline factors, identified increased comorbidities (p = 0.002), lower education level (p = 0.004), and race (p = 0.041) as the only significant factors associated with pain on presentation. No measure of rotator cuff tear severity correlated with pain (p > 0.25).

Anatomic features defining the severity of atraumatic rotator cuff tears are not associated with the pain level. Factors associated with pain are comorbidities, lower education level, and race.

LEVEL OF EVIDENCE
Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Symptoms of pain do not correlate with rotator cuff tear severity: a cross-sectional study of 393 patients with a symptomatic atraumatic full-thickness rotator cuff tear.

An increase in cranial acetabular version with age: implications for femoroacetabular impingement.

Gender and racial differences in focal and global acetabular version.

The duration of symptoms does not correlate with rotator cuff tear severity or other patient-related features: a cross-sectional study of patients with atraumatic, full-thickness rotator cuff tears.

Background: Labral tears often occur in the same quadrant of the acetabulum at a small depression previously referred to as the psoas valley. Understanding the anatomic variations of this depression could help us understand the etiology of labral tears. Purpose: To describe the location and dimensions of the depression located in the anterosuperior acetabular rim. The hypothesis was that the location of this depression would be consistent with the common location of acetabular labral tears described in the literature. Study Design: Controlled laboratory study. Methods: A total of 240 pelvic specimens were divided into 2 groups (n = 120 for each) according to age (younger age group: 21.36 ± 3.12 years [range, 14-24 years]; older age group: 42.30 ± 10.27 years, [range, 25-60 years]).Specimens were also categorized based on sex (mean age: 31.93 ± 12.31 years [male]; 32.08 ± 13.66 years [female]) and race (mean age: 31.45 ± 13.16 years [black]; 32.57 ± 12.82 years [white]). The depth and width of the acetabular depression were measured using a digital caliper, and the location was measured using a goniometer. Results: The psoas valley was observed in every specimen and was located in the anterosuperior quadrant of the acetabulum. Its depth was significantly greater (P < .001) in males (5.35 ± 1.60 mm) than in females (3.95 ± 1.31 mm). The width of the psoas valley was also greater (P < .001) in males (29.39 ± 3.98 mm) than in females (24.49 ± 4.80 mm). There were no differences in size or location of the depression between races or age groups. The psoas valley was located between 3.92 ± 0.42 o’clock anteriorly and 2.12 ± 0.77 o’clock posteriorly. Conclusion: The differences observed in the study data are believed to be a result of the different anatomic morphologies of the pelvis in males and females. This loss of bony support, caused by the depression, could be the underlying cause of weakening of the acetabular labrum as people age. Clinical Relevance: The loss of bony support in the anterosuperior acetabular depression could contribute to the labral tears that commonly occur in this area. Understanding the normal anatomy of this area could be important in determining the risk of labral tears as well as treatment options.

Characterization of Human Anterosuperior Acetabular Depression in Correlation With Labral Tears

Context: Sideline management of sports-related joint dislocations often places the treating medical professional in a challenging position. These injuries frequently require prompt evaluation, diagnosis, reduction, and postreduction management before they can be evaluated at a medical facility. Our objective is to review the mechanism, evaluation, reduction, and postreduction management of sports-related dislocations to the shoulder, elbow, finger, knee, patella, and ankle joints. Evidence Acquisition: A literature review was performed using the PubMed database to evaluate previous and current publications focused on joint dislocations. This review focused on articles published between 1980 and 2013. Study Design: Clinical review. Level of Evidence: Level 4. Results: The clinician should weigh the benefits and risks of on-field reduction based on their knowledge of the injury and the presence of associated injuries. Conclusion: When properly evaluated and diagnosed, most sports-related dislocations can be reduced and initially managed at the game.

Background: Most surgeons believe that graft choice for anterior cruciate ligament (ACL) reconstruction is an important factor related to outcome; however, graft choice for revision may be limited due to previously used grafts. Hypotheses: Autograft use would result in increased sports function, increased activity level, and decreased osteoarthritis symptoms (as measured by validated patient-reported outcome instruments). Autograft use would result in decreased graft failure and reoperation rate 2 years after revision ACL reconstruction. Study Design: Cohort study; Level of evidence, 2. Methods: Patients undergoing revision ACL reconstruction were identified and prospectively enrolled by 83 surgeons at 52 sites. Data collected included baseline demographics, surgical technique, pathologic abnormalities, and the results of a series of validated, patient-reported outcome instruments (International Knee Documentation Committee [IKDC], Knee injury and Osteoarthritis Outcome Score [KOOS], Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC], and Marx activity rating score). Patients were followed up at 2 years and asked to complete the identical set of outcome instruments. Incidences of additional surgery and reoperation due to graft failure were also recorded. Multivariate regression models were used to determine the predictors (risk factors) of IKDC, KOOS, WOMAC, Marx scores, graft rerupture, and reoperation rate at 2 years after revision surgery. Results: A total of 1205 patients (697 [58%] males) were enrolled. The median age was 26 years. In 88% of patients, this was their first revision, and 341 patients (28%) were undergoing revision by the surgeon who had performed the previous reconstruction. The median time since last ACL reconstruction was 3.4 years. Revision using an autograft was performed in 583 patients (48%), allograft was used in 590 (49%), and both types were used in 32 (3%). Questionnaire follow-up was obtained for 989 subjects (82%), while telephone follow-up was obtained for 1112 (92%). The IKDC, KOOS, and WOMAC scores (with the exception of the WOMAC stiffness subscale) all significantly improved at 2-year follow-up (P < .001). In contrast, the 2-year Marx activity score demonstrated a significant decrease from the initial score at enrollment (P < .001). Graft choice proved to be a significant predictor of 2-year IKDC scores (P = .017). Specifically, the use of an autograft for revision reconstruction predicted improved score on the IKDC (P = .045; odds ratio [OR] = 1.31; 95% CI, 1.01-1.70). The use of an autograft predicted an improved score on the KOOS sports and recreation subscale (P = .037; OR = 1.33; 95% CI, 1.02-1.73). Use of an autograft also predicted improved scores on the KOOS quality of life subscale (P = .031; OR = 1.33; 95% CI, 1.03-1.73). For the KOOS symptoms and KOOS activities of daily living subscales, graft choice did not predict outcome score. Graft choice was a significant predictor of 2-year Marx activity level scores (P = .012). Graft rerupture was reported in 37 of 1112 patients (3.3%) by their 2-year follow-up: 24 allografts, 12 autografts, and 1 allograft and autograft. Use of an autograft for revision resulted in patients being 2.78 times less likely to sustain a subsequent graft rupture compared with allograft (P = .047; 95% CI, 1.01-7.69). Conclusion: Improved sports function and patient-reported outcome measures are obtained when an autograft is used. Additionally, use of an autograft shows a decreased risk in graft rerupture at 2-year follow-up. No differences were noted in rerupture or patient-reported outcomes between soft tissue and bone–patellar tendon–bone grafts. Surgeon education regarding the findings of this study has the potential to improve the results of revision ACL reconstruction.

Effect of Graft Choice on the Outcome of Revision Anterior Cruciate Ligament Reconstruction in the Multicenter ACL Revision Study (MARS) Cohort

A patient’s activity level is increasingly recognized as an important factor that can influence orthopaedic outcomes. Validated, reliable activity measurement tools now exist for the shoulder, hip, knee, and ankle. These tools can be directly applied as outcome measures that determine whether interventions restored function. It is now evident that activity level is a powerful prognostic factor for outcomes in orthopaedic procedures such as anterior cruciate ligament reconstruction, articular cartilage repair, and total joint arthroplasty. Yet despite the recent increase in studies that have made use of quantitative, joint-specific activity scales, much room remains for further understanding of the exact role of activity level in the progression, treatment, and patient perception of musculoskeletal disorders, particularly in the shoulder and ankle, as well as in pediatric patients.

The Role of Activity Level in Orthopaedics: An Important Prognostic and Outcome Variable

Correlation between magnetic resonance imaging and clinical outcomes after knee cartilage repair: author's response.

Since its original description by Jobe et al. in 19861, ulnar collateral ligament reconstruction has become the standard treatment for ulnar collateral ligament deficiency in throwing athletes. There have been several modifications of the original procedure that aimed to maintain the integrity of the flexor pronator mass insertion on the medial humeral epicondyle and to improve the biomechanical strength of graft fixation2,3. Regardless of surgical technique, reported clinical outcomes have shown a rate of return to competition of 80% to 90% for throwing athletes4,5. One common thread in studies evaluating outcomes of ulnar collateral ligament reconstruction is the use of autograft for the reconstruction.

Until now, there have been no reports of outcomes using allograft for ulnar collateral ligament reconstruction. In this issue of The Journal of Bone and Joint Surgery, Savoie et al. report the first case series, to my knowledge, on the use of allograft for ulnar collateral ligament reconstruction. In their study, …

Ulnar collateral ligament reconstruction with allograft: is it a home run?

Background: Magnetic resonance imaging (MRI) is often used to assess cartilage after surgical repair. The correlation between MRI and clinical outcomes is not well understood. Hypothesis: Postoperative MRI findings correlate with clinical outcome measures in patients after articular cartilage surgery of the knee. Study Design: Meta-analysis. Methods: A systematic review of the literature was performed to identify studies in which MRI and clinical outcomes were correlated after autologous chondrocyte implantation (ACI), osteochondral autograft transfer system (OATS), or microfracture. Studies that reported correlation coefficients (r) for different MRI parameters were then included in a meta-analysis. Results: A total of 26 studies were identified for inclusion in this systematic review, 15 of which were included in the meta-analysis. Most of the studies (n = 19) involved ACI, although studies were available for OATS (n = 5) and microfracture (n = 4). The strongest MRI correlates with clinical outcomes after ACI were graft hypertrophy (r = 0.72) and repair tissue signal (r = 0.71). After microfracture, the strongest MRI correlates were the Henderson score (r = 0.97), subchondral edema (r = 0.77), and repair tissue signal (r = 0.76). Correlations after OATS were not as strong, with defect fill (r = 0.53) and repair tissue structure (r = 0.51) being the strongest. Conclusion: The MRI findings do correlate with clinical outcomes after cartilage repair surgery in the knee, although the specific parameters that correlate best vary by the type of procedure performed. No current MRI classification system has been shown to correlate with clinical outcomes after all types of cartilage repair surgery.

Correlation Between Magnetic Resonance Imaging and Clinical Outcomes After Cartilage Repair Surgery in the Knee

Objectives: While the windmill pitch used in fast-pitch softball is considered by many to be safe compared to the overhead baseball pitch, there is little information that exists regarding the effects of the fatigue on fast-pitch softball pitchers. Recent biomechanical evidence suggests that the stress on the shoulder from the windmill pitch rivals that seen in baseball pitchers. We aim to characterize the effects of windmill pitching on pain, fatigue, range of motion (ROM) and strength in high school fast-pitch softball pitchers during a single season. Methods: We evaluated shoulder and elbow strength (dynamometer), ROM (goniometer), pain (visual analog scale (VAS)) and fatigue (VAS-fatigue and Borg questionnaire) in 21 (ages 15-18) high school fast-pitch softball pitchers before and after a single game during the first week of the high school softball season. Of the 21 pitchers, 17 were re-evaluated before and after a single game during the last week of the high school softball season with the aforementioned measurements. A study-team member recorded the number of pitches thrown by each pitcher for the games being evaluated. We recorded the number of games pitched by each pitcher during the high school season based on the pitchers’ report. Results: Of the 21 players, two players were injured mid-season and could not complete follow up. Two players were lost to follow-up. The average number of pitches thrown per player per game was 89±25 (range 30-161). The average games pitched was 12±5.7 (range 5-24). Supraspinatus (p<0.001), biceps (p<0.001), and external rotation strength in abduction and in neutral (p<0.001) decreased significantly post-game compared to pre-game regardless of the time of the season. Pain and fatigue were significantly higher post-game than pre-game (p<0.018) regardless of the time of the season. Pre-game VAS pain and fatigue at the end of the season correlated with the number games pitched during the season (r=0.66-0.73, p<0.006). There was an inverse linear relationship between games pitched and pre-game biceps, supraspinatus, and external rotation strength at the end of the season compared to beginning of season (r=-0.66-0.88, p<0.006). At the end of season compared to the beginning of season, there was a significant difference in pre-game pain, fatigue, biceps, supraspinatus, and external rotation strength between players who pitched more than 10 games versus players who pitched less than 10 games (p<0.033). Conclusion: Biceps and rotator cuff strength decrease significantly throughout the course of a game. Pitching more games during a season significantly increases pain and fatigue while significantly decreasing pre-game biceps and rotator cuff strength. Softball pitchers may be at increased risk of injury from fatigue during the course of a single game and over the entire season. Targeted strengthening as well as adequate rest intervals should be evaluated in these athletes.

Analysis of Subjective and Objective Fatigue In Fast-pitch Softball Pitchers during A Single Season

Effectiveness of physical therapy in treating atraumatic full-thickness rotator cuff tears: a multicenter prospective cohort study.

Correlation between magnetic resonance imaging and clinical outcomes after knee cartilage repair: letter to the editor.

Recovery of Postural Stability After Anterior Cruciate Ligament Reconstruction

Shoulder arthroscopy is currently one of the more common orthopaedic procedures, with an estimated 1.4 million procedures performed per year worldwide1. Many of these procedures are being performed on an outpatient basis and present substantial postoperative pain control challenges to the surgeon and anesthesiologist. An integral component of successful ambulatory surgical treatment is achieving and maintaining adequate pain management during the early postoperative course.

The pain during the first twenty-four to forty-eight hours after arthroscopic shoulder surgery is often equivalent to that after open surgery, with 30% of patients reporting severe pain on the first postoperative day2. In a study of more than 15,000 outpatient surgical procedures from nine different surgical specialties, pain was responsible for 12% of the unplanned postoperative hospital admissions3. A retrospective review of 222 shoulder arthroscopy cases revealed a 2% rate of unplanned overnight admission because of pain symptoms4. Additionally, postoperative pain may instigate endocrine and metabolic responses, autonomic reflexes, nausea, and constipation that potentially lead to delayed postoperative rehabilitation, adhesive capsulitis, hospital admission, and loss of work days5-7. As a result, many different modalities have been described in both the orthopaedic and anesthesiology literature to minimize postoperative pain following ambulatory surgery8.

Traditionally, these surgical procedures were performed under general anesthesia with infiltration of local anesthetic and parenteral administration of opioids to achieve early postoperative pain relief. Over forty years ago, Winnie reported the results of an interscalene brachial plexus block involving a single anesthetic injection for pain control following shoulder surgery9. Nearly two decades later, Tuominen et al. described an interscalene block technique involving the placement of an indwelling catheter to provide continuous infusion of anesthetic for two to three days of pain relief10. A third modality …

Interscalene brachial plexus block for arthroscopic shoulder surgery: a systematic review.

Whether arthroscopic partial meniscectomy for symptomatic patients with a meniscal tear and knee osteoarthritis results in better functional outcomes than nonoperative therapy is uncertain.

METHODS
We conducted a multicenter, randomized, controlled trial involving symptomatic patients 45 years of age or older with a meniscal tear and evidence of mild-to-moderate osteoarthritis on imaging. We randomly assigned 351 patients to surgery and postoperative physical therapy or to a standardized physical-therapy regimen (with the option to cross over to surgery at the discretion of the patient and surgeon). The patients were evaluated at 6 and 12 months. The primary outcome was the difference between the groups with respect to the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical-function score (ranging from 0 to 100, with higher scores indicating more severe symptoms) 6 months after randomization.

RESULTS
In the intention-to-treat analysis, the mean improvement in the WOMAC score after 6 months was 20.9 points (95% confidence interval [CI], 17.9 to 23.9) in the surgical group and 18.5 (95% CI, 15.6 to 21.5) in the physical-therapy group (mean difference, 2.4 points; 95% CI, -1.8 to 6.5). At 6 months, 51 active participants in the study who were assigned to physical therapy alone (30%) had undergone surgery, and 9 patients assigned to surgery (6%) had not undergone surgery. The results at 12 months were similar to those at 6 months. The frequency of adverse events did not differ significantly between the groups.

In the intention-to-treat analysis, we did not find significant differences between the study groups in functional improvement 6 months after randomization; however, 30% of the patients who were assigned to physical therapy alone underwent surgery within 6 months. (Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases; METEOR ClinicalTrials.gov number, NCT00597012.).

Surgery versus physical therapy for a meniscal tear and osteoarthritis.

Katz JN, Brophy RH, Chaisson CE, de Chaves L, Cole BJ, Dahm DL, Donnell-Fink LA, Guermazi A, Haas AK, Jones MH, Levy BA, Mandl LA, Martin SD, Marx RG, Miniaci A, Matava MJ, Palmisano J, Reinke EK, Richardson BE, Rome BN, Safran-Norton CE, Skoniecki DJ, Solomon DH, Smith MV, Spindler KP, Stuart MJ, Wright J, Wright RW, Losina E. Surgery Versus Physical Therapy for a Meniscal Tear and Osteoarthritis. N Engl J Med. 2013 May 2;368(18):1675-84.

Arthroscopic partial meniscectomy was not more effective than physical therapy for meniscal tear and knee osteoarthritis.

Background: The shoulder activity score is a valid and reliable shoulder-specific questionnaire that measures a patient’s shoulder activity level over the previous year. No age- and sex-based normative data exist for the shoulder activity score. Hypothesis: The hypothesis was that age is inversely related to the shoulder activity score in patients with no history of shoulder symptoms or treatment for a shoulder condition. The authors also tested the hypothesis that in the same population of patients, men are more active with their shoulders than women. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Participants in 8 age/sex groups, composed of adults aged 18 years and older in the United States, were surveyed via the Internet by a marketing research firm. Participants completed the shoulder activity score and reported their age, sex, and any history of shoulder symptoms or treatment. The survey was sent to 2773 people, with 2403 people completing the entire survey. Participants with a history of shoulder symptoms or treatment were excluded from this analysis, leaving 1625 patients as healthy controls. Results: The mean shoulder activity score of healthy controls was 8 ± 5 (range, 0-20). Men scored higher on the shoulder activity score than women of the same age group (9 vs 7, respectively; P < .0001). Shoulder activity scores decreased with age in both men and women (P < .0001). Men were more likely to participate in contact (15% vs 7.4%, respectively; P < .001) and overhead-throwing sports (19% vs 10%, respectively; P < .001) than women. Participation in contact and overhead-throwing sports also decreased with age. Conclusion: In healthy controls, the shoulder activity score decreased with age and was lower in women than in men. Participation in contact and overhead-throwing sports decreased in women and older patients. These normative data are an important baseline for comparing untreated and treated shoulder cohorts to better understand the variance in shoulder activity level and how it may relate to clinical outcomes.

Outcome measures may consist of simple questions or they may be more complex instruments that evaluate multiple interrelated domains that influence patient function. Outcome measures should be relevant to patients, easy to use, reliable, valid, and responsive to clinical changes. The Disabilities of the Arm, Shoulder and Hand score can be used to measure disability for any region of the upper limb. Joint and disease-specific outcome measures have been developed for the shoulder, the elbow, and the wrist and hand. Many of these measures would benefit from further research into their validity, reliability, and optimal applicability.

Upper extremity-specific measures of disability and outcomes in orthopaedic surgery.

78 1 PREVALENCE OF ROTATOR CUFF INJURY IN SENIOR 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 ATHLETES AND ITS ASSOCIATION WITH PAIN AND SHOULDER FUNCTION Patrick J. McMahon, MD, Amit Prasad, MD, Kimberly A. Francis, MS, James J. Irrgang, PhD, McMahon Orthopaedics and University of Pittsburgh, Pittsburgh, Pennsylvania, USA Background: Cadaveric and imaging studies have found full thickness rotator cuff tears in about 25% of Americans over 60 years of age. Older individuals with rotator cuff injuries may complain of difficulties not only with activities of daily living but also with athletics. Treating these senior athletes requires knowledge of the prevalence of asymptomatic rotator cuff injuries. Hypothesis/Purpose: We hypothesized that rotator cuff tears would be less common in elite senior athletes than reported prior in similar aged individuals of the general population, as many of those with tears would fail to make it to the Senior Olympics. We also hypothesized that pain and shoulder function would correlate with severity of rotator cuff injury.Methods:Weassessed pain with the visual analog scale (VAS), and shoulder function with the ASES and DASH outcome measures in 141 volunteers at the Senior Olympics. All were greater than 60 years of age with no history of fracture, osteoarthritis or shoulder surgery. Ultrasound evaluation was performed by an experienced musculoskeletal radiologist. We compared the prevalence of pain between those with rotator cuffs classified as 1) normal, 2) tendinosis, 3) partial-thickness tear or 4) full-thickness tear. We also compared ASES and DASH scores between the painless and painful shoulders. Statistical analysis was performed with t-tests and c tests as appropriate, with 0.05 set as the level of significance. Results: There were 20 shoulders with a normal cuff and 5% were painful, 23 with tendinosis and 35% painful, 68 with a partial and 32% painful, and 30 with a full-thickness rotator cuff tear and 25% painful. There was a greater proportion of individuals with pain that had a rotator cuff injury (p1⁄40.016). But pain was not an indicator of severity of injury as the prevalence of pain was similar in those with tendinosis, partial-thickness cuff tears and full-thickness cuff tears (p>0.05). Painful shoulders had an ASES score of 69612 and a DASH score of 17613, worse than those with painless shoulders, ASES of 9567 and DASH of 666, respectively (p<0.0001 for each). Neither the ASES nor the DASH were significantly different in comparison of those with tendinosis, partial-thickness cuff tears or full-thickness cuff tears (p>0.05). Conclusions: The prevalence of full thickness rotator cuff tears is similar in senior athletes to same-aged individuals of the general population. Tendinosis and partial-thickness tears are even more common than full thickness rotator cuff tears. Pain was a good predictor of rotator cuff injury but was a poor predictor of its severity. Athletes with pain had poorer shoulder function but the ASES and DASH were poor predictors of the severity of rotator cuff injury. Clinical Significance: Rotator cuff tears in older individuals do not need to be repaired for successful participation in athletics as some have no symptoms and others are able to cope with their rotator cuff injury. 130 131 132 133 134 135 136 137 138 2 RELATIONSHIP BETWEENDURATIONOF ROTATOR CUFF TEAR SYMPTOMS AND PATIENT PRESENTATION FEATURES Kenneth P. Unruh, MD, Warren R. Dunn, MD, MPH, John E. (Jed) Kuhn, MD, Rosemary Sanders, BA, Angel Qi An, MS, Keith M. Baumgarten, MD, Julie Y. Bishop, MD, Robert H. Brophy, MD, James L. Carey, MD, MPH, G. Brian Holloway, MD, Grant L. Jones,MD,C. BenjaminMa,MD, Robert G.Marx,MD,MPH, Eric

Context: Osteochondritis dissecans (OCD) of the capitellum is most often seen in adolescents who participate in sports that involve repetitive loading of the elbow. Unstable defects typically require surgical intervention that involves fragment fixation, debridement, or reconstruction with an osteochondral autograft transfer. Optimum surgical management of unstable defects remains controversial. Type of Study: Clinical review. Evidence Acquisition: Relevant articles published after 1992 were identified using MEDLINE, the EMBASE database, and the Cochrane Library. Results: Both debridement and osteochondral autograft transfer for treatment of capitellar OCD lesions result in good short- and midterm outcomes with a high rate of return to sports. Larger defects involving more than 50% of the articular surface or involving the lateral margin of the capitellum may have worse outcomes after debridement and may be better treated with fragment fixation or osteochondral autograft transfer. Conclusions: High-level evidence is lacking to determine the superiority of debridement or osteochondral autograft transfer for the treatment of capitellar OCD lesions. A prospective longitudinal multicenter study, using validated outcome measures, that enrolls a large number of patients is needed to establish optimal treatment for unstable capitellar OCD lesions.

Surgical Treatment for Osteochondritis Dissecans of the Capitellum

Background: The results of surgical treatment for femoroacetabular impingement have been increasingly reported, and more advanced intra-articular disease has been identified as an important predictive factor of outcome. Yet, the reliability of arthroscopic hip disease classification has not been well defined. Purpose/Hypothesis: To determine the intraobserver and interobserver reliability of the Beck classification of labral and articular cartilage disease (anterior-superior acetabular rim) encountered in hip arthroscopy. Secondly, we identified the sources of poor reliability that may be improved with future disease classification schemes. Our hypothesis was that the Beck classification of labral and chondral lesions would demonstrate substantial reliability, while the differentiation of early forms of disease would be a common source of disagreement. Study Design: Cohort study; Level of evidence, 3. Methods: Four experienced hip arthroscopists reviewed standardized arthroscopic videos of 40 cases. Arthroscopic findings at the anterior-superior acetabular rim were classified using the Beck classification of labral and articular cartilage disease. Repeat classification of videos was performed at least 2 weeks later. The reliability of arthroscopic classification was defined using the average weighted Cohen κ values and agreement rates. Results: Arthroscopic classification of labral disease using the Beck classification demonstrated moderate to substantial interobserver reliability (average κ = .62; range, .48-.78) and an overall agreement rate of 81.7%. Intraobserver reliability showed a similar level of reliability (average κ = .65; agreement rate, 80.6%). The differentiation between labral degeneration and labral detachment was a common source of disagreement. Similarly, the Beck classification of articular cartilage disease had moderate to substantial interobserver reliability (average κ = .65; range, .49-.78) and overall agreement rate of 57.5%. Intraobserver reliability showed a slightly better level of reliability (average κ = .80; agreement rate, 77.5%). The differentiation between articular cartilage malacia and debonding was a common source of disagreement. Conclusion: The arthroscopic classification of acetabular rim disease with the Beck classification has substantial interobserver reliability. This level of reliability is similar to previously reported arthroscopic disease classifications in the knee and shoulder and seems appropriate for future outcome reporting. Future classifications that eliminate common sources of disagreement may further improve the reliability.

The Reliability of Arthroscopic Classification of Acetabular Rim Labrochondral Disease

Outcome measures may be simple questions or complex measures that assess multiple interrelated domains affecting treatment outcomes. Outcome measures should be relevant to patients, easy to use, reliable, valid, and responsive to clinical changes. Joint and disease-specific outcome measures have been developed for the hip, knee, and foot and ankle. Many of these measures would benefit from further research into their validity, reliability, and optimal applicability. General health measures and activity level scores should be included in outcome assessments after treatment for orthopaedic conditions.

Lower extremity-specific measures of disability and outcomes in orthopaedic surgery.

An increasing emphasis has been placed across health care on evidence‐based medicine with higher level studies, such as randomized trials and prospective cohort studies. Historically, clinical research in orthopaedic surgery has been dominated by studies with low patient numbers from a limited number of surgeons. The purpose of this study was to test our hypothesis that orthopaedics has fewer multi‐center collaborative studies as compared to other medical disciplines. We chose three leading journals from general medicine, a leading journal from the surgical subspecialties of obstetrics and gynecology, ophthalmology and otolaryngology, and three leading journals from orthopaedic surgery based on highest impact factor. We compared the percentage of collaborative studies and the number of contributing institutions and authors in original research manuscripts published in 2009 between general medical, surgical subspecialty and orthopaedic surgery journals. A significantly higher percentage of manuscripts resulted from multicenter collaborative efforts in the general medical literature (p < 0.000001) and the other surgical subspecialty literature (p < 0.000001) compared to the orthopaedic surgery literature. Manuscripts published in the general medical journals came from more institutions (p < 0.0001) and had significantly more authors (p < 0.000001) than those published in the orthopaedic surgery journals. There is an opportunity to stimulate greater multicenter collaborative research, which correlates with increased patient numbers, a higher level of evidence and more generalizable findings, in the orthopaedic surgery community. These efforts can be supported through increased funding, surgeon participation, and appropriate expansion of authorship for multicenter studies in orthopaedic journals. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1523–1528, 2012

Multi‐investigator collaboration in orthopaedic surgery research compared to other medical fields

http://ajs.sagepub.com/content/40/8/1722 The online version of this article can be found at: DOI: 10.1177/0363546512449424 2012 40: 1722 originally published online June 15, 2012 Am J Sports Med Jones, Bruce Miller, Matthew Smith and Rick W. Wright Michael Khazzam, John E. Kuhn, Ed Mulligan, Joseph A. Abboud, Keith M. Baumgarten, Robert H. Brophy, Grant L. Intraobserver Agreement Magnetic Resonance Imaging Identification of Rotator Cuff Retears After Repair : Interobserver and

Agreement Magnetic Resonance Imaging Identification of Rotator Cuff Retears After Repair : Interobserver and

Revision anterior cruciate ligament (ACL) reconstruction is believed to have an inferior outcome compared with primary ACL reconstruction. The available literature on the outcome of revision ACL reconstruction is sparse compared with that for primary reconstruction. The purpose of this systematic review was to test the hypothesis that the outcome of revision ACL reconstruction compares unfavorably with the historical outcome of primary ACL reconstruction.

METHODS
A systematic review of studies evaluating the outcome of revision ACL reconstructions with a minimum of two years of follow-up was performed. Pooled data were collected when appropriate and a mixed-effect-model meta-analysis was performed for important outcome measures that were reported in several studies (objective graft failure, Lysholm score, International Knee Documentation Committee [IKDC] subjective score, and IKDC objective score). Objective failure was defined as repeat revision, a side-to-side difference of >5 mm measured with use of a KT1000 arthrometer, or a pivot-shift grade of 2+ or 3+.

RESULTS
Twenty-one studies were included, and 863 of the 1004 patients in these studies had a minimum of two years of follow-up and were analyzed. The pooled mean age of the patients at the time of the revision procedure was 30.6 years, and 66% were male. Objective failure occurred in 13.7% ± 2.7% of the patients (95% confidence interval, 8.0% to 19.4%). The mean Lysholm score in 491 patients was 82.1 ± 3.3 (95% confidence interval, 74.6 to 89.5) according to a mixed-model meta-analysis. The mean IKDC subjective score in 202 patients was 74.8 ± 4.4 (95% confidence interval, 62.5 to 87.0).

Revision ACL reconstruction resulted in a worse outcome compared with primary ACL reconstruction. Patient-reported outcome scores were inferior to previously published results of primary ACL reconstruction, but these differences may not be clinically important. A dramatically elevated failure rate was noted after revision ACL reconstruction; this rate was nearly three to four times the failure rate in prospective series of primary ACL reconstructions.

Outcome of revision anterior cruciate ligament reconstruction: a systematic review.

Background: Magnetic resonance imaging (MRI) is the most commonly used imaging modality to assess the rotator cuff. Currently, there are a limited number of studies assessing the interobserver and intraobserver reliability of MRI after rotator cuff repair. Hypothesis: Fellowship-trained orthopaedic shoulder surgeons will have good inter- and intraobserver agreement with regard to features of the repaired rotator cuff (repair integrity, fat content, muscle volume, number of tendons involved, tear size, and retract) on MRI. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: Seven fellowship-trained orthopaedic shoulder surgeons reviewed 31 MRI scans from 31 shoulders from patients who had previous rotator cuff repair. The scans were evaluated for the following characteristics: rotator cuff repair status (full-thickness retear vs intact repair), tear location, tendon thickness, fatty infiltration, atrophy, number of tendons involved in retear, tendon retraction, status of the long head of the biceps tendon, and bone marrow edema in the humeral head. Surgeons were asked to review images at 2 separate time points approximately 9 months apart and complete an evaluation form for each scan at each time point. Multirater kappa (κ) statistics were used to assess inter- and intraobserver reliability. Results: The interobserver agreement was highest (80%, κ = 0.60) for identifying full-thickness retears, tendon retear retraction (64%, κ = 0.45), and cysts in the greater tuberosity (72%, κ = 0.43). All other variables were found to have fair to poor agreement. The worst interobserver agreement was associated with identifying rotator cuff footprint coverage (47%, κ = −0.21) and tendon signal intensity (29%, κ = −0.01). The mean intraobserver reproducibility was also highest (77%-90%, κ = 0.71) for full-thickness retears, quality of the supraspinatus (47%-83%, κ = 0.52), tears of the long head of the biceps tendon (58%-94%, κ = 0.49), presence of bone marrow edema in the humeral head (63%-87%, κ = 0.48), cysts in the greater tuberosity (70%-83%, κ = 0.47), signal in the long head of the biceps tendon (60%-80%, κ = 0.43), and quality of the infraspinatus (37-90%, κ = 0.43). The worst intraobserver reproducibility was found in identification of the location of bone marrow edema (22%-83%, κ = −0.03). Conclusion: The results of this study indicate that there is substantial variability when evaluating MRI scans after rotator cuff repair. Intact rotator cuff repairs or full-thickness retears can be identified with moderate reliability. These findings indicate that additional imaging modalities may be needed for accurate assessment of the repaired rotator cuff.

Magnetic Resonance Imaging Identification of Rotator Cuff Retears After Repair

Purpose: To compare arthroscopic access to the acetabulum for loose body removal using a standard rigid straight grasper and a flexible grasper. Methods: Using a standard hip arthroscopy teaching model, the acetabulum was divided into 6 zones. Small pieces of rubber, used to simulate loose bodies, were evenly distributed throughout each zone and secured to the acetabulum using adhesive. Anterolateral and anterior portals were created for viewing and working. Using a standardized amount of femoral distraction, the rigid straight grasper and the flexible grasper were used to retrieve loose bodies from each portal in separate trials. Twenty loose bodies were available for retrieval from each zone, through each portal, and for each instrument. A total of 480 loose bodies were available for retrieval across all variables. Results: Both the rigid and the flexible graspers were effective in retrieving loose bodies from zone 3 through the anterior and anterolateral portals. The rigid grasper and the flexible grasper were equally effective in removing loose bodies from zone 4 through the anterior portal but not the anterolateral portal. The rigid straight grasper was not effective in reaching anterior and inferior zones of the acetabulum from either portal. Overall, the rigid grasper was able to retrieve 42% of the loose bodies (48% from the anterior portal and 36% from the lateral portal). The flexible grasper was able to retrieve 100% of the loose bodies from both working portals. Conclusions: Through standard arthroscopy portals, the rigid straight grasper can be effective for accessing some portions of the acetabulum with better access obtained from the anterior portal. The flexible grasper allows greater arthroscopic access to the acetabulum. Clinical Relevance: Use of flexible instrumentation in hip arthroscopy may improve our ability to treat pathologic conditions in all areas of the hip joint.

Loose Body Removal in Hip Arthroscopy: Rigid Versus Flexible Instrumentation

Treating mulitligament knee dislocations can be difficult. Initial treatment should consist of immediate reduction and care for limb-threatening injuries. Physical examination, x-rays, and magnetic resonance imaging are often necessary to clearly define the injury pattern. Occasionally, a computed tomography scan is beneficial to better characterize fractures. Timing for definitive treatment of the multiligament knee injury depends on associated injuries at the time of injury, the integrity of the soft tissues, the vascular status of the limb, and the condition of the knee at presentation. In general, early surgery is indicated in patients with associated fractures, vascular compromise, and patellar or quadriceps tendon ruptures. We also tend to favor acute repair of lateral-sided injuries with or without graft augmentation. Medial collateral ligament (MCL) injuries can be treated with immobilization unless the MCL is displaced or if there is associated meniscal extrusion. The condition of the knee largely determines whether the cruciate ligaments should be acutely reconstructed or reconstructed in a staged procedure. We treat complete posterior cruciate ligament injuries with a double-bundle arthroscopic inlay technique. The decision to use allograft or autograft depends on the severity of the knee injury, the demands that will be placed on the knee, and patient wishes. The return to a high level of sports participation after this injury is challenging and usually takes at least 9 to 12 months.

Background Acetabular labrum tears are now commonly diagnosed in young and active patients. Because the role of the acetabular labrum is incompletely understood, it is critical to determine how these tears affect native hip biomechanics. Hypothesis Radial and circumferential labral tears significantly decrease hip stability and significantly alter strain patterns in the anterior and anterior-superior acetabular labrum. Study Design Controlled laboratory study. Methods Twenty-two human cadaveric hips without evidence of degeneration or dysplasia were assigned to a circumferential tear (n = 11) and a radial tear (n = 11) group. The hips were tested in a neutral position with an average compressive force of 25 N. In the circumferential tear group, the labral states were intact; 1-, 2-, and 3-cm circumferential tears; a 3-cm partial labrectomy; and a full labrectomy. In the radial tear group, the labral states were intact; a radial tear; a 1-, 2-, and 3-cm partial labrectomy; and a full labrectomy. The effect of labral injury on the stability ratio (peak dislocation force/compressive loads) and labral strain in the anterior and anterior-superior labrum was analyzed using repeated-measures analysis of variance. Results There was no significant difference in stability ratio after circumferential tears 3 cm or less in size compared with the intact labral state. Strain in the anterior and anterior-superior labrum was either unchanged or increased after circumferential labral tear. There was no significant difference in stability ratio after a radial tear or a 1-cm partial labrectomy compared with the intact labral state. A 2-cm partial labrectomy significantly decreased the stability ratio. Anterior and anterior-superior labral strain significantly decreased after a radial tear. Conclusion Under the influence of joint compression in a neutral hip position, the acetabular labrum continues to resist femoral head dislocation despite detachment from the acetabular rim. A radial tear in the acetabular labrum decreases adjacent labral strain, but removal of 2 cm or more of the acetabular labrum is needed before hip stability decreases. Clinical Relevance The findings suggest that the acetabular labrum continues to function to resist femoral head translation despite chondral-labral separation and that labral preservation, particularly with larger tears, may be important for maintaining hip stability. Further studies are needed to determine the effect of partial labral excision on the stability ratio with the hip in provocative positions such as extension, external rotation, and abduction.

Effect of Acetabular Labrum Tears on Hip Stability and Labral Strain in a Joint Compression Model

Sport-specific outcomes after anterior cruciate ligament reconstruction.

Hip instability is becoming a more commonly recognized source of pain and disability in patients. Traumatic causes of hip instability are often clear. Appropriate treatment includes immediate reduction, early surgery for acetabular rim fractures greater than 25% or incarcerated fragments in the joint, and close follow-up to monitor for avascular necrosis. Late surgical intervention may be necessary for residual symptomatic hip instability. Atraumatic causes of hip instability include repetitive external rotation with axial loading, generalized ligamentous laxity, and collagen disorders like Ehlers-Danlos. Symptoms caused by atraumatic hip instability often have an insidious onset. Patients may have a wide array of hip symptoms while demonstrating only subtle findings suggestive of capsular laxity. Traction views of the affected hip can be helpful in diagnosing hip instability. Open and arthroscopic techniques can be used to treat capsular laxity. We describe an arthroscopic anterior hip capsular plication using a suture technique.

Background: Only one case of simultaneous avulsion fractures of the anterior superior and anterior inferior iliac spines has been previously reported. This was associated with a hip dislocation. Methods: A 16-year-old male adolescent sustained ipsilateral avulsion fractures of his superior and inferior iliac spines from a hyperextension injury of his right hip in a skiing accident. He healed satisfactorily after nonoperative treatment with protected weight bearing and limited active hip range of motion. Results: The patient healed in 12 weeks and returned to full activities, including sports, without complications. Conclusions: Conservative treatment of simultaneous ipsilateral avulsion fractures of the anterior superior and anterior inferior iliac spines can lead to a good outcome. Level of Evidence: Level V.

Simultaneous Ipsilateral Avulsion of the Anterior Superior and Anterior Inferior Iliac Spines in an Adolescent

Background: The purpose of this study was to utilize the American Board of Orthopaedic Surgery (ABOS) Part-II Case List database to (1) de ﬁ ne the practice patterns of sports medicine-trained ABOS Part- II Oral Examination Candidates and (2) describe the frequency and practice patterns of individuals who are dual fellowship-trained sports medicine candidates. Methods: The ABOS Part-II Case List database was utilized to de ﬁ ne all cases submitted by 3,298 applicants indicating completion of a sports medicine fellowship between January 1, 2003, and January 1, 2020. Cases were classi ﬁ ed by subspecialty category and case type. The frequency and practice patterns of candidates pursuing additional fellowship training (i.e., “ dual fellowship-trained ” ) were recorded. Descriptive statistical methods were used to describe the annual and overall procedure volume and candidate case mix. Trends in the relative frequency of cases performed and fellowship training patterns were determined using linear regression analysis. Results: On average, sports medicine-trained candidates submitted 100.6 cases for review during the 6-month case collection period: 59.0 (58.6%) sports medicine/arthroscopy cases, 29.3 (29.1%) trauma/general cases, 4.5 (4.5%) adult reconstruction cases, and 7.8 (7.8%) “ other ” cases per candidate. Although candidates performed fewer total (r 2 = 0.84, p < 0.001) and sports medicine/arthroscopy (r 2 = 0.85, p < 0.001) cases over the study period, the proportion of sports medicine/arthroscopy cases did not change over the study period (p = 0.18). Dual fellowship training was indicated by 333 individuals (10.1%).

the Orthopaedic forum Early-Career Sports Medicine Surgeons Perform a Large Volume of Non-Sports Medicine Procedures Regarding Orthopaedic Surgeons Specializing in Sports Medicine

Spin orbital–coupled exciton-polaritons and spin-polarized condensates are found in lead halide perovskites.

Spin-orbit–coupled exciton-polariton condensates in lead halide perovskites

Visualization of dynamic polaronic strain fields in hybrid lead halide perovskites

Stabilization of a black CsPbI 3 Perovskite phase via octahedral tilting control with pressure

Yb3+-doped inorganic metal-halide perovskites (Yb3+:CsPbX3, X = Cl, Br) have recently been discovered to display highly efficient quantum cutting, in which the energy from individual blue or UV photons absorbed by the material is re-emitted in the form of pairs of near-infrared photons by Yb3+ dopants. Experimental photoluminescence quantum yields approaching 200{%} have been reported. As the first quantum-cutting materials that combine such high photoluminescence quantum yields with strong, broadband absorption in the visible, these materials offer unique opportunities for enhancing the efficiencies of solar technologies. Little is known about the fundamental origins of this quantum cutting, however. Here, we describe variable-temperature and time-resolved photoluminescence studies of Yb3+:CsPbCl3 in two disparate forms - colloidal nanocrystals and macroscopic single crystals. Both forms show very similar spectroscopic properties, demonstrating that quantum cutting is an intrinsic property of the Yb3+:CsPbX3 composition itself. Diverse Yb3+ speciation is observed in both forms by low-temperature photoluminescence spectroscopy, but remarkably, quantum cutting is dominated by the same specific Yb3+ species in both cases. Time-resolved photoluminescence measurements provide direct evidence of the previously hypothesized intermediate state in the quantum-cutting mechanism. This intermediate state mediates relaxation from the photogenerated excited state of the perovskite to the emissive excited state of Yb3+, and hence is of critical mechanistic importance. At room temperature, this intermediate state is populated within a few picoseconds and has a decay time of only ~ 7 ns in both nanocrystalline and single-crystal Yb3+:CsPbCl3. The mechanistic implications of these observations are discussed.

Yb3+
 speciation and energy-transfer dynamics in quantum-cutting 
Yb3+
-doped 
CsPbCl3
 perovskite nanocrystals and single crystals

Both all inorganic and hybrid halide perovskites recently demonstrated undeniably remarkable characteristics for a wide range of optoelectronic applications. The perovskite fever began with 3D halide perovskites of chemical formula AMX3 with A a small organic or an inorganic cation, M a metal (Pb2+, Sn2+, Ge2+), and X a halogen (I-, Br-, Cl-), which opened a route toward low-cost manufacture of solar cells, offering currently certified conversion efficiencies over 25%.[1] Since the initial breakthrough mid-2012,[2] halide perovskites attracted worldwide efforts from the scientific community[3] leading to an extensive exploration of their structural versatility and an ever-growing diversity of structures.[3] Prior to the perovskite fever, especially in the 90's, most experimental efforts on halide perovskites focused on chemistry and optical characterizations of monolayered halide perovskites of chemical formula A'MX4, with A' a larger organic cation.[4] 
Currently, many different perovskite as well as non-perovskite metal-halide networks are synthesized and their optoelectronic properties deserve to be unraveled (Figure). Among others, new compositions such as A'2An-1MnX3n+1 afford layered structures with a controlled number (n) of octahedra in the perovskite layer and thus offer an ideal platform for fundamental understanding.3,5 Here, through a couple of recent examples,[5,6] we will discuss their optoelectronic properties based on theoretical modeling. Impact of composition and structural pattern on properties will be inspected, with particular emphasis on the effect of quantum and dielectric confinements on charge carriers and excitons. 
[1] https://www.nrel.gov/pv/cell-efficiency.html. [2] M. M. Lee & al. JACS 134, 17396 (2012); H.-S Kim & al. Sci. Rep. 2, 591(2012). [2] Special issue, Chem. Rev. 119, 3033 (2019). [3] C. Katan & al. Chem. Rev. 119, 3140 (2019). [4] G. C. Papavassiliou Prog. Solid State Chem. 25, 125 (1997); D. B. Mitzi Prog. Inorg. Chem. John Wiley & Sons (1999). [5] L. Mao & al. Chem, in press (2019). [6] M. Smith & al. Chem. Sci. 8, 1960 (2017); J.-C. Blancon & al. Science 355, 1288 (2017); B. Traore & al. ACS Nano 12, 3321 (2018); J.-C. Blancon & al. Nat. Com. 9, 2254 (2018); M. Kepenekian & al. Nano Lett. 18, 5603 (2018); J. Leveillee & al. PRMater. 2, 105406 (2018) and submitted. X. Li & al. Chem. Mater. 31, 3582 and JACS 141, 12880 (2019).

Theoretical insight on quantum and dielectric confinement in metal-halide perovskites

Metal-halide semiconductors exhibit attractive properties for a host of applications including photovoltaics, solid-state lighting, and photodetection. Among the remarkable recent developments is the discovery of extraordinarily high photoluminescence quantum yields in Yb3+-doped inorganic lead-halide perovskites. Although all previous research and development of such quantum-cutting materials has involved solution-phase preparation, particularly as colloidal nanocrystals, such methods can introduce both processing and technical challenges that limit the scope of accessible compositions, morphologies, and scaled-up applications. Here, we demonstrate a scalable single-source vapor deposition (SSVD) method for depositing high-quality conformal thin films of complex metal-halide perovskites, including doped perovskites, over large areas at high deposition rates. Focusing on quantum-cutting Yb3+:CsPb(Cl1–xBrx)3, we demonstrate large-area deposition of films with photoluminescence quantum yields as high as 183...

Single-Source Vapor Deposition of Quantum-Cutting Yb3+:CsPb(Cl1–xBrx)3 and Other Complex Metal-Halide Perovskites

Layered halide perovskites offer a versatile platform for manipulating light through synthetic design. Although most layered perovskites absorb strongly in the ultraviolet (UV) or near-UV region, their emission can range from the UV to the infrared region of the electromagnetic spectrum. This emission can be very narrow, displaying high color purity, or it can be extremely broad, spanning the entire visible spectrum and providing high color rendition (or accurately reproducing illuminated colors). The origin of the photoluminescence can vary enormously. Strongly correlated electron-hole pairs, permanent lattice defects, transient light-induced defects, and ligand-field transitions in the inorganic layers and molecular chromophores in the organic layers can be involved in the emission mechanism. In this review, we highlight the different types of photoluminescence that may be attained from layered halide perovskites, with an emphasis on how the emission may be systematically tuned through changes to the bulk crystalline lattice: changes in composition, structure, and dimensionality.

With nearly 20% of global electricity consumed by lighting, more efficient illumination sources can enable massive energy savings. However, effectively creating the high-quality white light required for indoor illumination remains a challenge. To accurately represent color, the illumination source must provide photons with all the energies visible to our eye. Such a broad emission is difficult to achieve from a single material. In commercial white-light sources, one or more light-emitting diodes, coated by one or more phosphors, yield a combined emission that appears white. However, combining emitters leads to changes in the emission color over time due to the unequal degradation rates of the emitters and efficiency losses due to overlapping absorption and emission energies of the different components. A single material that emits broadband white light (a continuous emission spanning 400-700 nm) would obviate these problems. In 2014, we described broadband white-light emission upon near-UV excitation from three new layered perovskites. To date, nine white-light-emitting perovskites have been reported by us and others, making this a burgeoning field of study. This Account outlines our work on understanding how a bulk material, with no obvious emissive sites, can emit every color of the visible spectrum. Although the initial discoveries were fortuitous, our understanding of the emission mechanism and identification of structural parameters that correlate with the broad emission have now positioned us to design white-light emitters. Layered hybrid halide perovskites feature anionic layers of corner-sharing metal-halide octahedra partitioned by organic cations. The narrow, room-temperature photoluminescence of lead-halide perovskites has been studied for several decades, and attributed to the radiative recombination of free excitons (excited electron-hole pairs). We proposed that the broad white emission we observed primarily stems from exciton self-trapping. Here, the exciton couples strongly to the lattice, creating transient elastic lattice distortions that can be viewed as "excited-state defects". These deformations stabilize the exciton affording a broad emission with a large Stokes shift. Although material defects very likely contribute to the emission width, our mechanistic studies suggest that the emission mostly arises from the bulk material. Ultrafast spectroscopic measurements support self-trapping, with new, transient, electronic states appearing upon photoexcitation. Importantly, the broad emission appears common to layered Pb-Br and Pb-Cl perovskites, albeit with a strong temperature dependence. Although the emission is attributed to light-induced defects, it still reflects changes in the crystal structure. We find that greater out-of-plane octahedral tilting increases the propensity for the broad emission, enabling synthetic control over the broad emission. Many of these perovskites have color rendering abilities that exceed commercial requirements and mixing halides affords both "warm" and "cold" white light. The most efficient white-light-emitting perovskite has a quantum efficiency of 9%. Improving this value will make these phosphors attractive for solid-state lighting, particularly as large-area coatings that can be deposited inexpensively. The emission mechanism can also be extended to other low-dimensional systems. We hope this Account aids in expanding the phase space of white-light emitters and controlling their exciton dynamics by the synthetic, spectroscopic, theoretical, and engineering communities.

Unusual photophysical properties of organic–inorganic hybrid perovskites have not only enabled exceptional performance in optoelectronic devices, but also led to debates on the nature of charge carriers in these materials. This study makes the first observation of intense terahertz (THz) emission from the hybrid perovskite methylammonium lead iodide (CH3NH3PbI3) following photoexcitation, enabling an ultrafast probe of charge separation, hot‐carrier transport, and carrier–lattice coupling under 1‐sun‐equivalent illumination conditions. Using this approach, the initial charge separation/transport in the hybrid perovskites is shown to be driven by diffusion and not by surface fields or intrinsic ferroelectricity. Diffusivities of the hot and band‐edge carriers along the surface normal direction are calculated by analyzing the emitted THz transients, with direct implications for hot‐carrier device applications. Furthermore, photogenerated carriers are found to drive coherent terahertz‐frequency lattice distortions, associated with reorganizations of the lead‐iodide octahedra as well as coupled vibrations of the organic and inorganic sublattices. This strong and coherent carrier–lattice coupling is resolved on femtosecond timescales and found to be important both for resonant and far‐above‐gap photoexcitation. This study indicates that ultrafast lattice distortions play a key role in the initial processes associated with charge transport.

Terahertz Emission from Hybrid Perovskites Driven by Ultrafast Charge Separation and Strong Electron–Phonon Coupling

Terahertz Emission: Terahertz Emission from Hybrid Perovskites Driven by Ultrafast Charge Separation and Strong Electron–Phonon Coupling (Adv. Mater. 11/2018)

We investigate the consequences of dimensional confinement on halide double perovskites by synthesizing two-dimensional analogues of the recently reported three-dimensional double perovskite Cs2AgBiBr6. The layered perovskites (BA)4AgBiBr8 (1) and (BA)2CsAgBiBr7 (2) (BA = CH3(CH2)3NH3+) feature metal-halide sheets of mono and bilayer thickness, respectively, where the ordered double-perovskite lattice is partitioned by organic cations. Electronic structure calculations indicate that the indirect bandgap of Cs2AgBiBr6 becomes direct when the infinitely thick inorganic lattice is reduced to monolayer thickness. Calculations on model systems allow us to separate the effects of dimensional reduction from those of the accompanying structural distortions in the inorganic sublattice. Detailed optical characterization shows that the photophysical properties of 1 and 2 are markedly different than those of their well-studied lead-halide analogs. Hybrid layered derivatives of double perovskites substantially expand on the substitutional flexibility of halide perovskites to encompass greater compositional and electronic diversity.

Layered Halide Double Perovskites: Dimensional Reduction of Cs2AgBiBr6.

The two-dimensional congeners of the well-known three-dimensional perovskites display new properties enabled by their reduced dimensionality. Here, organic molecules separate inorganic sheets, affording the properties of both discrete molecules and extended solids in single, well-defined materials. The choice of organic and inorganic components engenders a large range of structural motifs, which yield diverse properties such as electroluminescence, white-light emission, photoconductivity, porosity, and reactivity. Layered halide perovskites have been known for decades. Their recent resurgence compels us to understand the fundamental studies that set the stage for their current technological relevance. We are not providing a comprehensive review of this vast and rapidly growing field. Instead, we highlight some of the discoveries that have directed current research in this field. We hope to introduce new researchers to layered halide perovskites to bring fresh perspectives to study this venerable family of materials that continue to surprise us today.

The structural and electronic adaptability ranges of a [VO(SeO3)(HSeO3)] framework found in organically templated vanadium selenites were determined using a three step approach, informed by cheminformatics descriptors, involving (i) the extraction of the most important reaction parameters from historical reaction data, (ii) a fractional factorial design on those parameters to better explore chemical space and (iii) decision tree construction on organic molecular properties to determine the factors governing framework formation. This process enabled the elucidation of both the structural and electronic adaptability ranges and provided the context to extract chemical understanding from the structural features that give rise to these respective ranges. This work resulted in the synthesis and structural determination of five new compounds.

Understanding structural adaptability: a reactant informatics approach to experiment design

Conversion of lanthanide glutarate chlorides with interstitial THF into lanthanide glutarates with unprecedented topologies

Hybrid perovskites combine the optical and electronic versatility of ionic inorganic solids with the synthetic diversity and tunability of covalent organic molecules. Their multicomponent, crystalline architectures, incorporating a wide array of metals, ligands, and organic molecules, can be synthetically fine-tuned to accommodate diverse target technologies. In this Perspective, we highlight how the utility of hybrid perovskites can be further extended through chemical and physical postsynthetic transformations, with an emphasis on the design of functional solids. We describe strategies that we and other researchers have developed for using the parent perovskite to direct the structure or morphology of the product. We further show how the perovskite structure provides a unique reaction vessel for performing chemical transformations that cannot be accessed through conventional methods. We hope this Perspective motivates both organic and inorganic chemists to further expand the versatility of these technol...

Between the Sheets: Postsynthetic Transformations in Hybrid Perovskites

Similar to organoammonium cations that template the well-studied layered perovskites, organosulfonium cations template the layered Pb–Br hybrid (tms)4Pb3Br10 (1; tms = (CH3)3S+). Upon ultraviolet excitation, this colorless, organic-inorganic hybrid exhibits broad red/near-infrared photoluminescence (PL) with a massive Stokes shift of ca. 1.7 eV. A suite of PL measurements suggests that the broad emission is an intrinsic property of the material. We ascribe this emission to radiative recombination of self-trapped excitons in the inorganic sublattice, which features both face- and corner-sharing Pb–Br octahedra. We further demonstrate that complex sulfonium-based cations can expand this family of lead-halide hybrids while maintaining the broad, Stokes-shifted PL. The use of more exotic main-group cations affords an exciting opportunity for synthetic chemists to expand the phase-space of semiconducting hybrids with unusual properties for potential applications in optoelectronics.

Broadband Emission with a Massive Stokes Shift from Sulfonium Pb–Br Hybrids

We show that post-synthetic small-molecule intercalation can significantly reduce the electronic confinement of 2D hybrid perovskites. Using a combined experimental and theoretical approach, we explain structural, optical, and electronic effects of intercalating highly polarizable molecules in layered perovskites designed to stabilize the intercalants. Polarizable molecules in the organic layers substantially alter the optical and electronic properties of the inorganic layers. By calculating the spatially resolved dielectric profiles of the organic and inorganic layers within the hybrid structure, we show that the intercalants afford organic layers that are more polarizable than the inorganic layers. This strategy reduces the confinement of excitons generated in the inorganic layers and affords the lowest exciton binding energy for an n 1⁄4 1 perovskite of which we are aware. We also demonstrate a method for computationally evaluating the exciton's binding energy by solving the Bethe–Salpeter equation for the exciton, which includes an ab initio determination of the material's dielectric profile across organic and inorganic layers. This new semi-empirical method goes beyond the imprecise phenomenological approximation of abrupt dielectric-constant changes at the organic–inorganic interfaces. This work shows that incorporation of polarizable molecules in the organic layers, through intercalation or covalent attachment, is a viable strategy for tuning 2D perovskites towards mimicking the reduced electronic confinement and isotropic light absorption of 3D perovskites while maintaining the greater synthetic tunability of the layered architecture.

lectronic con fi nement in layered perovskites through intercalation †

Absorption of light in hybrid perovskite solar cells leads to ultrafast large-amplitude deformations of the inorganic sublattice. Femtosecond resolution electron scattering techniques are applied to resolve the first atomic-scale steps following absorption of a photon in the prototypical hybrid perovskite methylammonium lead iodide. Following above-gap photoexcitation, we directly resolve the transfer of energy from hot carriers to the lattice by recording changes in the mean square atomic displacements on 10-ps time scales. Measurements of the time-dependent pair distribution function show an unexpected broadening of the iodine-iodine correlation function while preserving the Pb–I distance. This indicates the formation of a rotationally disordered halide octahedral structure developing on picosecond time scales. This work shows the important role of light-induced structural deformations within the inorganic sublattice in elucidating the unique optoelectronic functionality exhibited by hybrid perovskites and provides new understanding of hot carrier—lattice interactions, which fundamentally determine solar cell efficiencies.

Light-induced picosecond rotational disordering of the inorganic sublattice in hybrid perovskites

The juxtaposition of fused cyclobutadienoid (CBD) with benzenoid creates intriguing alternating antiaromatic and aromatic conjugation. Synthetic accessibility of such molecules, however, has been challenging and limited in scope. We report a modular and streamlined synthetic strategy to access a large variety of polycyclic conjugated hydrocarbons with fused CBD. Synthesis was achieved through efficient palladium-catalyzed C-H activated annulation between abundant aryl bromides and oxanorbornenes, followed by aromatization under acidic conditions. The influence of four-membered ring was examined using spectroscopy, crystallography, and computation. This strategy will facilitate exploration on the chemical, structural, and electronic properties of such conjugated systems containing CBD.

Streamlined Synthesis of Polycyclic Conjugated Hydrocarbons Containing Cyclobutadienoids via C-H Activated Annulation and Aromatization.

Towards Clean Water Combining Multiple Filtration and Disinfection Techniques

The recently discovered phenomenon of broadband white-light emission at room temperature in the (110) two-dimensional organic-inorganic perovskite (N-MEDA)[PbBr4] (N-MEDA = N(1)-methylethane-1,2-diammonium) is promising for applications in solid-state lighting. However, the spectral broadening mechanism and, in particular, the processes and dynamics associated with the emissive species are still unclear. Herein, we apply a suite of ultrafast spectroscopic probes to measure the primary events directly following photoexcitation, which allows us to resolve the evolution of light-induced emissive states associated with white-light emission at femtosecond resolution. Terahertz spectra show fast free carrier trapping and transient absorption spectra show the formation of self-trapped excitons on femtosecond time-scales. Emission-wavelength-dependent dynamics of the self-trapped exciton luminescence are observed, indicative of an energy distribution of photogenerated emissive states in the perovskite. Our results are consistent with photogenerated carriers self-trapped in a deformable lattice due to strong electron-phonon coupling, where permanent lattice defects and correlated self-trapped states lend further inhomogeneity to the excited-state potential energy surface.

Mechanism for Broadband White-Light Emission from Two-Dimensional (110) Hybrid Perovskites.

The role of non-covalent interactions on vanadium tellurite chain connectivities

Structural differences in [V2Te2O10]n(2n-) chain metrics are directly ascribed to variations in noncovalent interactions in a series of organically templated vanadium tellurites, including [C6H17N3][V2Te2O10]·H2O, [C5H16N2][V2Te2O10], and [C4H14N2][V2Te2O10]. The noncovalent interaction (NCI) method was used to locate, quantify, and visualize intermolecular interactions in [C4H14N2][V2Te2O10] and [C5H16N2][V2Te2O10]. Variations in the van der Waals attractions between [1,4-diaminobutaneH2](2+) and [1,5-diaminopentaneH2](2+) result in divergent packing motifs for these cations, which causes a reorganization of N-H···O hydrogen bonding and variances in the [V2Te2O10]n(2n-) chain metrics. The application of the NCI method to this type of solid-state structure provides a direct method to elucidate the structural effects of weak noncovalent interactions.

Role of noncovalent interactions in vanadium tellurite chain connectivities.

The extended charge equilibration (EQeq) scheme computes atomic partial charges using the experimentally measured ionization potentials and electron affinities of atoms. However, EQeq erroneously predicts constant (environment independent) charges for high-oxidation-state transition metals in amine-templated metal oxide (ATMO) compounds, contrary to the variation observed in iterative Hirshfeld (Hirshfeld-I) charges, bond-valence sum calculations, and formal oxidation state calculations. To fix this problem, we present a simple, noniterative empirical pairwise correction based on the Pauling bond-order/distance relationship, which we denote EQeq+C. We parametrized the corrections to reproduce the Hirshfeld-I charges of ATMO compounds and REPEAT charges of metal organic framework (MOF) compounds. The EQeq+C correction fixes the metal charge problem and significantly improves the partial atomic charges compared to EQeq. We demonstrate the transferability of the parametrization by applying it to a set of unrelated dipeptides. After an initial parametrization, the EQeq+C correction requires minimal computational overhead, making it suitable for treating large unit cell solids and performing large-scale computational materials screening.

EQeq+C: An Empirical Bond-Order-Corrected Extended Charge Equilibration Method.

A series of organically templated vanadium selenites has been prepared under mild hydrothermal conditions. Single crystals of [C5H14N2][(VO)3(SeO3)2(HSeO3)4], [C5H14N2][VO(SeO3)2], [(R)-C5H14N2][(VO)3(SeO3)2(HSeO3)4], and [(S)-C5H14N2][(VO)3(SeO3)2(HSeO3)4] were grown from VOSO4, SeO2, and 2-methylpiperazine. Controlling the initial pH of the reaction mixture allows for one to select between the compounds found in the VOSO4/SeO2/2-methylpiperazine system, as the solution pH directly affects the relative ratio of the HSeO3(-) and SeO3(2-) concentrations. Moreover, partial resolution of racemic 2-methylpiperazine is observed in [C5H14N2][(VO)3(SeO3)2(HSeO3)4], which is understood through the use of a one-dimensional Ising model. The use of enantiomerically pure 2-methylpiperazine results in fully ordered and fully resolved structures.

Formation principles for vanadium selenites: the role of pH on product composition.

A series of organically templated vanadium tellurites has been prepared under mild hydrothermal conditions. Single crystals were grown from mixtures of NaVO3, Na2TeO3, and either 1,4-diaminobutane, 1,6-diaminohexane, or N,N,N′,N′-tetramethylethylenediamine in H2O. Each compound contains similar [V2Te2O10]n2n– layers. The layer metrics of [1,4-diaminobutaneH2][V2Te2O10], [1,6-diaminohexaneH2][V2Te2O10], [N,N,N′,N′-tetramethylethylenediamineH2][V2Te2O10], and [piperazineH2][V2Te2O10] reflect the steric bulk of the respective amines. Topotactic conversions between compounds through amine exchange are possible in reactions in which an increase in the strength of the amine–[V2Te2O10]n2n– hydrogen-bonding network is observed.

A set of formation principles governing organically templated vanadium selenite oxalates are described in the context of nine new compounds. The compositions of the reaction mixture dictate the form of the secondary building units from which [(VO)2(C2O4)(SeO3)2]n2n– layers are constructed. The strength of hydrogen-bonding interactions is maximized in these compounds, directly affecting the orientations of the organic ammonium cations and enabling amine packing efficiency to affect layer tessellation. The orientations of selenite stereoactive lone pairs are driven by the minimization of internal void space. Compound symmetry can be directed to chiral space groups through the use of chiral components, with the use of either (R)-2-methylpiperazine or (S)-2-methylpiperazine, resulting in noncentrosymmetric, polar, chiral structures that crystallize in the space group P21 (No. 4).

Interface engineering of graphene for universal applications as both anode and cathode in organic photovoltaics

The title compound, {(C6H21N4)[V3O9]·H2O}n, crystallizes as a salt with [trenH3]3+ cations [tren is tris(2-aminoethyl)amine], and one-dimensional anionic {[VVO3]−}n (metavanadate) chains along the c-axis direction. Three crystallographically distinct VV sites and one occluded water molecule are present for every [trenH3]3+ cation in the unit cell. The {[VVO3]−}n chains are composed of vertex-sharing [VO4] tetrahedra and have a repeat unit of six tetrahedra. Each tetrahedron in the chain contains two terminal and two μ2-bridging oxide ligands. The [trenH3]3+ cations, {[VVO3]−}n anions and occluded water molecules participate in an extensive three-dimensonal hydrogen-bonding network. The three terminal ammonium sites of the [trenH3]3+ cations each form strong N—H⋯O hydrogen bonds to terminal oxide ligands on the {[VVO3]−}n chain. Each occluded water molecule also donates two O—H⋯O hydrogen bonds to the terminal oxide ligands.

Inducing polarity in [VO3]nn- chain compounds using asymmetric hydrogen-bonding networks

Differences in the [V2Te2O10]n2n– layer topologies in [C6H16N2][V2Te2O10] and [C5H14N2][V2Te2O10] are the result of deviations in the C–H···O hydrogen-bonding networks. Stronger influences, such as reagent concentrations and charge density matching, were minimized through the use of both nearly identical reaction gels and 2,5-dimethylpiperazine and 2-methylpiperaine, which have very similar charge densities. Reactant concentration and charge density matching effects were quantified using composition space analyses, molecular and geometric decomposition surface areas, and Iterative Hirshfeld partial atomic charges.

Beyond Charge Density Matching: The Role of C–H···O Interactions in the Formation of Templated Vanadium Tellurites

Synthesis and Crystal Structure of MnII(OAc)2[15-MCMnIII(N)shi-5](Im)3(EtOH)3 (shi3− = salicylhydroximate, −OAc = acetate, Im = imidazole, and EtOH = ethanol)

Microprobe X-ray Absorption Spectroscopy of Chalcogen Doped Silicon

Large‐scale prostate cancer (PCa) database reviews have found a consistent discrepancy in the mortality rate in Black patients compared to their White counterparts. Furthermore, differences in PCa treatment and outcomes among Black men of different ethnic origins have also been identified. Due to the heterogeneity of PCa‐impacted communities and the unclear impact of patient immigration status on treatment outcomes, we sought to determine the demographic factors associated with treatment choice for definitive treatment of PCa in our single institution's patient population of Black immigrants.

Definitive treatment choice among Black immigrants with prostate cancer: Analysis of patient surveys distributed at a single safety‐net institution

Bladder cancer care has been increasingly concentrated in high‐volume metropolitan medical centres (ie, “regionalisation” of care). We aimed to assess the potential role of geographic factors, including facility region and distance to treatment centre, as determinants of neoadjuvant chemotherapy (NAC) delivery in patients with non‐metastatic urothelial muscle‐invasive bladder cancer (MIBC) using nationally representative data from the United States.

Determinants of neoadjuvant chemotherapy for urothelial muscle‐invasive bladder cancer: Does location matter?

NCCN Risk Reclassification in Black men with low and intermediate risk Prostate Cancer after genomic testing.

Background and Objectives: The National Cancer Database (NCDB) captures nearly 70% of all new cancer diagnoses in the United States, but there exists significant variation in this capture rate based on primary tumor location and other patient demographic factors. Prostate cancer has the lowest coverage rate of all major cancers, and other genitourinary malignancies likewise fall below the average NCDB case coverage rate. We aimed to explore NCDB coverage rates for patients with genitourinary cancers as a function of race. Materials and Methods: We compared the incidence of cancer cases in the NCDB with contemporary United States Cancer Statistics data. Results: Across all malignancies, American Indian/Alaskan Natives subjects demonstrated the lowest capture rates, and Asian/Pacific Islander subjects exhibited the second-lowest capture rates. Between White and Black subjects, capture rates were significantly higher for White subjects overall and for prostate cancer and kidney cancer in White males, but significantly higher for bladder cancer in Black versus White females. No significant differences were observed in coverage rates for kidney cancer in females, bladder cancer in males, penile cancer, or testicular cancer in White versus Black patients. Conclusions: Differential access to Commission on Cancer-accredited treatment facilities for racial minorities with genitourinary cancer constitutes a unique avenue for health equity research.

Racial Differences in Incident Genitourinary Cancer Cases Captured in the National Cancer Database

MANAGEMENT OF VESICOURETERAL REFLUX IN A PATIENT WITH RECURRENT FEBRILE URINARY TRACT INFECTIONS, NEUROGENIC BLADDER, AND URETERAL TRIPLICATION.

The rapid spread of COVID‐19 has placed tremendous strain on the American healthcare system. Few prior studies have evaluated the well‐being of or changes to training for American resident physicians during the COVID‐19 pandemic. We aim to study predictors of trainee well‐being and changes to clinical practice using an anonymous survey of American urology residents.

Well‐being and education of urology residents during the COVID‐19 pandemic: Results of an American National Survey

Determinants of adequate lymph node dissection following neoadjuvant chemotherapy in patients with urothelial muscle-invasive bladder cancer: results from the National Cancer Database

Pathologic upstaging in renal cell carcinoma (RCC) is common and confers a significant risk of poor surgical and survival outcomes. Preoperative predictors of upstaging are of great clinical relevance but empirical evidence specific to racial minorities remains scarce.

Assessing the role of race in pathological upstaging of renal cell carcinoma: Results from the National Cancer Database

Inguinal hernia of the distal ureter causing hydronephrosis: A rare case

Penile Preservation With Subcutaneous Transposition During Fournier's Gangrene

A 54-year-old man presented to the office with gross painless hematuria, dysuria, and urinary frequency. He was diagnosed with renal cell carcinoma of the kidney and transitional cell carcinoma of the bladder. The article reviews the presentation, radiology, pathology, and intervention of an uncommon case of synchronous primary carcinomas, and aims to show the importance of continued clinical suspicion for multiple genitourinary primary neoplasms.

Key Points Postchemotherapy, of 100 CRMRD+ patients, 42% remained progression free at 1 year (spontaneous CRMRD− or low-level NPM1mut persistence). Relapse is associated with FLT3-ITD and poor NPM1mut MRD response after chemotherapy. MRD-directed preemptive therapy may prolong remission.

Clinical impact of NPM1-mutant molecular persistence after chemotherapy for acute myeloid leukemia

 Background
 Outcomes for patients with blast-phase chronic myeloid leukaemia (BP-CML) are extremely poor, and allogeneic stem cell transplantation (alloSCT) represents the only opportunity for cure. Crucially, long-term survival post-transplant depends on first attaining a return to chronic phase though salvage treatment. Novel strategies that improve response and can optimise transplant outcomes are therefore required. In the era of tyrosine kinase inhibitors (TKIs), BP-CML has become an orphan disease. Consequently, the prospective trials needed to guide clinical practice are rarely attempted. We now report the final results of the prospective MATCHPOINT trial which uses an innovative EffTox design to investigate the activity and tolerability of the TKI ponatinib in combination with high-dose chemotherapy, to improve remission status and transplant outcomes in BP-CML.
 Methods and patients
 Between March 2015 and April 2018, 17 patients were recruited through the UK Trials Acceleration Programme to this dose-finding, seamless phase I/II trial of daily ponatinib combined with fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin (PON-FLAG-IDA) salvage therapy. We employed EffTox, an advanced Bayesian method to simultaneously consider response to treatment (efficacy) and dose-limiting toxicity (DLT) in all treated patients, providing a single measure of clinical utility, which then informed the subsequent dose level recommendation. The primary objective was to determine the optimal dose of ponatinib, in combination with chemotherapy, as determined by the EffTox model. The primary outcomes were attainment of a second chronic phase and occurrence of a DLT. Secondary outcomes investigated the toxicity of combination therapy, alloSCT outcomes, and survival. The median follow-up of trial patients is 41 months.
 Results
 Nine patients completed one cycle of PON-FLAG-IDA, a further eight patients completed both planned cycles. Using an EffTox analysis, the optimal dose of ponatinib was determined as 30mg once daily. Eleven patients achieved a return to chronic phase and four experienced a DLT, fulfilling the pre-specified criteria for clinically relevant efficacy and toxicity. After PON-FLAG-IDA salvage, eight patients attained complete cytogenetic response and five major molecular response (MMR). The most common grade 3-4 non-hematologic toxicities were febrile neutropenia (29% of patients), lung infection (24%), fever (18%) and hypocalcaemia (18%). Three patients experienced treatment-related mortality. Twelve patients proceeded to alloSCT, of whom seven are alive after median 36 months post-transplant follow-up. Only one of the five patients achieving MMR relapsed post-alloSCT, neither of the other relapsing patients achieved a second chronic phase pre-transplant. Median overall survival (OS) of the whole cohort was 12 months (95% confidence interval 6 months to non-calculable), median OS of patients undergoing alloSCT has not been reached.
 Conclusions
 Ponatinib has shown that it can be safely combined with high-dose chemotherapy to achieve a return to chronic phase in patients with BP-CML, and represents an effective novel treatment strategy in this high-risk population. Responding patients subsequently undergoing alloSCT can benefit from long-term disease-free survival. The EffTox method enabled very efficient data usage from this high-risk patient population, and is a model for investigating novel therapies in other ultra-orphan cancers.
 Figure: Overall survival of the MATCHPOINT cohort
 Figure 1 Figure 1.
 
 Copland: Incyte: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Jazz: Honoraria, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; Cyclacel Ltd: Research Funding. Byrne: Incyte: Honoraria. Rothwell: Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Honoraria. Brock: Eli Lily: Honoraria; Invex Therapeutics: Honoraria; Merck: Honoraria; Roche: Honoraria; AstraZeneca: Current holder of individual stocks in a privately-held company; GSK: Current holder of individual stocks in a privately-held company. De Lavallade: Pfizer, Novartis.: Honoraria; Bristol Myers Squibb, Incyte: Honoraria, Research Funding. Craddock: Novartis Pharmaceuticals: Other: Advisory Board ; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Clark: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria. Smith: Daiichi Sankyo: Speakers Bureau; Pfizer: Speakers Bureau; ARIAD: Honoraria. Milojkovic: Novartis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau. Yap: Faron Pharmaceuticals: Honoraria; Celgene: Honoraria.
 
 Ponatinib for the treatment of blast-phase CML

Ponatinib in Combination with FLAG-IDA Chemotherapy for Blast-Phase Chronic Myeloid Leukemia: Final Results of the Seamless Phase I/II Dose-Finding UK Trials Acceleration Programme (TAP) Matchpoint Trial

Nonmyeloablative Allogeneic Transplantation With Post-Transplant Cyclophosphamide for Acute Myeloid Leukemia With IDH Mutations: A Single Center Experience.

Ponatinib with fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor chemotherapy for patients with blast-phase chronic myeloid leukaemia (MATCHPOINT): a single-arm, multicentre, phase 1/2 trial.

 Background: Gemtuzumab (GO) is an antibody drug conjugate that links a CD33 antibody to calicheamicin, a potent DNA-damaging agent. GO has been studied in combination with standard chemotherapy in multiple randomized clinical trials, though the doses and schedules of GO in these studies varied significantly. In a meta-analysis, 1 the addition of GO was found to improve relapse-free (RFS) and overall survival (OS), particularly in patients with favorable cytogenetics. It is now approved for use in combination with 7+3 in newly diagnosed CD33-positive AML. The studies that supported its approval were heterogenous and, in clinical practice, the uptake and utilization patterns for GO have been wide-ranging. At Johns Hopkins Sidney Kimmel Cancer Center, a single dose of GO at a dose of 3 mg/m2 has been incorporated into standard 7+3 induction for patients with core binding factor (CBF) AML since . Herein, we report the impact of this practice change on clinical outcomes for patients with CBF AML.
 Methods: 72 patients with newly-diagnosed, previously untreated CBF AML from 2008-2020 were identified. Electronic medical records were reviewed for initial CBF AML presentation, management, and outcomes. Patient, disease, and transplant characteristics were summarized by treatment groups using descriptive statistics. Group differences were tested via Wilcoxon rank-sum test, chi-square test of independence, and Fisher's exact disease. Kaplan-Meier estimates were reported for OS and RFS. Group differences were tested via log-rank test. All analyses were carried out with R version 4.0.2 using the "survival" and "cmprsk" packages (R Foundation for Statistical Computing, Vienna, Austria).
 Results: There were 28 (40%) patients who received GO and 43 (60%) who did not (non-GO) (Table 1). The percentage of patients in the GO group who had favorable ELN risk was similar to the non-GO group (p>0.9). The proportion of patients with inv(16) was lower in the GO group (p=0.018) while the proportion of patients with t(8;21) was greater in the GO group (p=0.018). At presentation, the GO group had a significantly lower mean WBC compared to the non-GO group (p = .007). The rates of complete response (CR) after induction were similar between the GO and non-GO groups (p = 0.6). The GO group took longer to achieve neutrophil count (0.5 K/cu mm) recovery (p=0.13) whereas the non-GO group took longer to achieve a platelet count of 100K/cu mm (p=0.005). The rates of post-induction measurable residual disease (MRD) by flow cytometry were similar between the GO and non-GO groups (p=0.6). 7 (24%) patients in the GO group and 13 (30%) of patients in the non-GO group underwent allogeneic bone marrow transplant in first remission. The only non-hematologic adverse effects noted in the GO group were rapid weight gain in 2 patients (7%) and grade I/II elevated liver enzymes in 5 patients (18%). No grade III-IV liver enzyme abnormalities. There were no therapy-related deaths in the GO group and no episodes of vaso-occlusive disease in those who went on to transplant. There was a trend towards improved RFS (p=0.05, Figure C-D) and significantly improved OS (p=0.04, Figure B) favoring patients who received a one-time dose of GO.
 Conclusions: Patients who received GO had a trend towards improved RFS and significantly improved OS compared to patients who did not. This real-world study suggests that there may be a benefit, with little detriment, to the addition of a single dose of GO. The study, however, is limited by differences between the two groups including WBC at presentation, distribution of inv(16) vs. t(8;21), the eras in which patients were diagnosed and treated, and shorter median follow-up time for the GO group. Our study was further limited by missing data for a significant proportion of patients with regards to C-KIT and rates of post-induction MRD by PCR. It is important to note that this study compared GO and any regimen (not limited to 7+3) to any regimen without GO. Treatment protocols evolved during GO utilization and these changes in practice patterns could have impacted clinical outcomes. Lastly, this study highlights the fact that patients with CBF AML can expect to have favorable outcomes.
 References:
 1. Hills RK, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: A meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol. 2014;15(9):986-996.
 
 DeZern: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Incorporating Gemtuzumab into the Treatment of Core Binding Factor Acute Myeloid Leukemia: A Single Center Experience

 Early data suggest that patients undergoing salvage chemotherapy for relapsed or refractory (R/R) acute myeloid leukaemia (AML) have poor outcomes if infected with SARS-CoV-2, and nosocomial transmission has been a major problem worldwide. Gilteritinib is effective in R/R FLT3 mutated AML, is significantly less immunosuppressive and does not require hospital admission, however at the start of the pandemic this was not yet approved for routine use in all countries. In the United Kingdom, the National Health Service (NHS) made gilteritinib available as an emergency measure from late April 2020 to patients aged >16y with R/R FLT3 mutated AML, with the aim of reducing both mortality and healthcare resource use. We report a health-system-wide real world data collection for toxicity and patient outcomes across 27 NHS Hospitals.
 Methods
 Each patient was registered on a central NHS database, with clinicians certifying that their patient met the above criteria. Anonymised data were retrospectively collected by treating physicians. Gilteritinib dose, duration and toxicity information was requested for the first 4 cycles of therapy. Response definitions were as per European Leukaemia Network (ELN) guidelines. A total of 81 patients have been registered on the scheme, with outcomes reported here for those with follow-up information at a data cut on 1st August 2021.
 Results
 Fifty patients were included with a median age of 59y (range 19 - 77) and 50% male. The majority (83%) had an ECOG performance status of 0-1. AML was secondary to a previous haematological disorder in 12%, therapy-related in 4% and de novo in the remaining 84%. The disease was refractory to the last therapy in 38%. Most patients had previously received 1 (65%) or 2 (33%) lines of therapy, including intensive chemotherapy in a majority (86%). A FLT3 inhibitor had previously been administered to 45% and 35% were post allogeneic transplant. The FLT3 mutation was an internal tandem duplication (ITD) in 80% and tyrosine kinase domain (TKD) mutation in 22%. NPM1 mutations were detected in 34%. Next-generation sequencing results were available for 94% of patients, with mutations in IDH1 or IDH2 in 12.5%, ASXL1 in 2%, RUNX1 in 21% and no TP53 mutations.
 Patients spent a median 3.5 days in hospital in cycle 1, 0 days in cycles 2 and 3 and 1 day in cycle 4. In cycles 1, 2, 3 and 4, the median number of days of grade 4 neutropenia was 18, 7, 7.5, and 6.5 respectively, and the grade 4 thrombocytopenia was 2, 7, 0.5 and 0.5. The composite complete remission (CR) / CR with incomplete haematological recovery (CRi) rate was 27%. MRD data is being collected. The best response was morphological leukaemia free state (MLFS) in 4%, partial remission (PR) in 25% and refractory disease in 38%. The rate of combined CR/CRi did not differ in those with previous exposure to FLT3 inhibitors (23% vs 32%, p=0.6) or with past allogeneic transplant (29% vs 27%, p=0.3). There were no CR/CRi in patients with adverse cytogenetic risk.
 Median follow-up was 10.5 months (95%CI 7.3 - 12.3) with median overall survival (OS) 6.7 months (95%CI 4.5 - not reached). Mortality at day 30 was 0% and day 60 was 14%. 12-month overall survival was 38%. Patients who achieved a CR/CRi had a 12-month OS of 83%, and for PR this was 35%. Survival did not differ in those with previous FLT3 inhibitor exposure (HR 1.0, p>0.9) or allogeneic transplant (HR 0.63, p=0.3). Seven patients (14%) so far have been bridged with gilteritinib to allogeneic transplant.
 Conclusion
 Our data demonstrate that gilteritinib is well tolerated and clinically active in adults with relapsed FLT3 mutated AML. Importantly, during the COVID-19 pandemic, its availability has permitted the great majority of treatment to be delivered as an outpatient with significant resource saving at a time of critically constrained inpatient resources. Patients who achieve CR/CRi have good short-term outcomes and are able to proceed to a potentially curative allogeneic stem cell transplant.
 
 Figure 1
 
 Disclosures
 
 Belsham: 
 Celgene: Other: meeting attendance; Abbvie: Other: meeting attendance. Byrne: 
 Incyte: Honoraria. Khan: 
 Abbvie: Honoraria; Astellas: Honoraria; Takeda: Honoraria; Jazz: Honoraria; Gilead: Honoraria; Novartis: Honoraria. Khwaja: 
 Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Latif: 
 Kite: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Speakers Bureau; Takeda UK: Speakers Bureau. Loke: 
 Amgen: Honoraria; Daichi Sankyo: Other: Travel Support; Janssen: Honoraria; Novartis: Other: Travel Support; Pfizer: Honoraria. Munisamy: 
 Jazz Pharmaceuticals: Speakers Bureau; Roche: Speakers Bureau. Murthy: 
 Abbvie: Other: support to attend educational conferences.. Smith: 
 Daiichi Sankyo: Speakers Bureau; Pfizer: Speakers Bureau; ARIAD: Honoraria. Craddock: 
 Novartis Pharmaceuticals: Other: Advisory Board ; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dillon: 
 Amgen: Other: Research support (paid to institution); Astellas: Consultancy, Other: Educational Events , Speakers Bureau; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Session chair (paid to institution), Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: educational events; Jazz: Other: Education events; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research Support, Educational Events.

Gilteritinib for Relapsed Acute Myeloid Leukaemia with FLT3 Mutation during the COVID-19 Pandemic: Real World Experience from the UK National Health Service

 Based on early evidence of a high rate of coronavirus mortality in patients with acute myeloid leukaemia (AML) undergoing intensive chemotherapy (IC), the national health service (NHS) in the United Kingdom temporarily made venetoclax available as an alternative therapy, with the aim of reducing both mortality and healthcare resource use. From late April 2020, venetoclax was available to patients aged >16y with NPM1 mutation without FLT3 internal tandem duplication (ITD), patients aged >50y with NPM1, IDH1 or IDH2 mutations (regardless of FLT3 status) and patients aged >60y without favourable-risk cytogenetics. Venetoclax could be given with either azacitidine or low-dose cytarabine (LDAC), with the latter recommended mainly for patients with NPM1 mutation. We report a health-system-wide real world data collection for toxicity and patient outcomes across 65 NHS Hospitals.
 Methods
 Each patient was registered on a central NHS database. Clinicians certified that their patient met the above criteria, had not received previous AML treatment, and was fit for induction chemotherapy. Anonymised data were retrospectively collected by treating physicians. Venetoclax dose, duration and toxicity information was requested for the first 4 cycles of therapy. Response definitions were as per European Leukaemia Network (ELN) guidelines. A total of 870 patients have been registered on the scheme, with outcomes reported here for those with follow-up information at a data cut on 1st August 2021.
 Results
 There were 301 patients, median age 72y (range 34 - 90) with 62% male. The majority (81%) had an ECOG performance status of 0-1. AML was secondary to a previous haematological disorder in 33%, therapy-related in 10% and de novo in the remaining 57%. MRC cytogenetic risk was intermediate in 70% and adverse in 27%. NPM1 mutations were detected in 28% and FLT3-ITD in 12%. Next-generation sequencing results were available in 86% of patients, which detected mutations in IDH1 or IDH2 in 28%, ASXL1 in 20%, RUNX1 in 17% and TP53 in 12%. The ELN risk was favourable for 23%, intermediate for 30% and adverse for 44%.
 A majority received venetoclax in combination with azacitidine (85%), with the remaining 15% receiving LDAC. The LDAC cohort was enriched for de novo AML (76% vs 54%) and NPM1-mutated disease (56% vs 23%). Most patients (81%) followed the recommended initial schedule of venetoclax 100mg daily for 28 days in combination with posaconazole or voriconazole. Patients spent a median 14 days in hospital in cycle 1, then a median of 0 days for cycles 2-4. In cycles 1, 2, 3 and 4, the median number of days for recovery of neutrophils to >0.5x10 9/L was 33, 25, 24 and 14 respectively, and the median number of days to recovery of platelets to >50x10 9/L was 22, 3, 0 (no drop below 50) and 0.
 The composite complete remission (CR) / CR with incomplete haematological recovery (CRi) rate was 70%. MRD data is being collected. The best response was morphological leukaemia free state (MLFS) in 2%, partial remission in 7% and refractory disease in 11%. CR/CRi was higher in de novo (78%) compared to secondary AML (57%, p=0.02); NPM1 mutated (78% vs 67%, p=0.02) and IDH1/IDH2 mutated disease (85% vs 62%, p=0.02). ELN favourable risk patients had the highest CR/CRi rate (85%, intermediate 71%, adverse 60%, p=0.01).
 Median follow-up was 8.2 months (95%CI 7.8 - 9.0) with median overall survival (OS) 12.8 months (95%CI 10.9 - not reached). Mortality at day 30 was 5.7% and day 60 was 8.4%. 12-month overall survival was 51%, increasing to 71% in those who achieved CR/CRi. Survival was poorer in secondary (HR 1.9, p <0.01) and therapy-related AML (HR 2.1, p=0.02), better in NPM1 mutated (HR 0.6, p=0.02) and IDH mutated (HR 0.5, p=0.02) disease and poorer with TP53 mutation (HR 2.0, p=0.01). Overall survival did not differ for patients treated with LDAC compared to azacitidine (HR 1.1, p=0.7).
 This large real-world study demonstrates CR/CRi and survival rates comparable to those reported in prospective clinical trials. Importantly, during the COVID-19 pandemic, the adoption of venetoclax regimens permitted the great majority of treatment to be delivered as an outpatient with significant resource saving at a time of critically constrained inpatient resources. The data support prospective comparisons of venetoclax-based regimens to IC in fit adults with AML particularly in older patients with de novo AML, NPM1-mutated and IDH-mutated disease.
 
 Figure 1
 
 Belsham: 
 Celgene: Other: meeting attendance; Abbvie: Other: meeting attendance. Khan: 
 Pfizer: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Novartis: Other: Travel; Daichi Sankyo: Other: Travel. Murthy: 
 ARIAD: Honoraria; Pfizer: Speakers Bureau; Daiichi Sankyo: Speakers Bureau. Whitmill: 
 Daiichi-sankyo: Other: travel fees; EHA in stockholm: Other: conference support. Craddock: 
 Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Jazz: Other: Education events; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: educational events; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Session chair (paid to institution), Speakers Bureau; Menarini: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Other: Educational Events , Speakers Bureau; Amgen: Other: Research support (paid to institution); Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research Support, Educational Events.

Venetoclax with Azacitidine or Low Dose Cytarabine As an Alternative to Intensive Chemotherapy in Fit Adults during the COVID19 Pandemic: Real World Data from the UK National Health Service

Introduction
 Molecular MRD assays targeting NPM1 mutant (mut) transcripts have an established role for monitoring treatment efficacy in patients with NPM1mut AML. Approximately 25% of NPM1mut patients show persistent MRD level in the bone marrow (BM) at the end of treatment (EOT), which is associated with a higher risk of relapse (Ivey, NEJM 2016; Kronke, JCO 2011). Molecular persistence at low copy number (MP-LCN) is defined by the European LeukemiaNet (ELN) as MRD positivity in patients in morphological complete remission (CR) with <1000-2000 transcripts per 105ABL and a relative increase of <1 log between any two positive samples collected after EOT (Schuurhuis, Blood 2018). The UK NCRI working group recently reported the impact of NPM1mut MRD burden and FLT3-ITD status on risk of relapse after allogeneic stem cell transplantation (Dillon, Blood 2020), however the clinical relevance of NPM1mut MP-LCN in patients who are not transplanted is unknown. We aimed to characterize the natural history of persistent NPM1mut MRD after chemotherapy and to identify factors associated with subsequent disease progression.
 Methods
 Consecutive patients with newly diagnosed NPM1mut AML receiving at least 2 cycles of intensive chemotherapy were included if MRD remained detectable at EOT. UK patients were all enrolled in the NCRI AML17 and AML19 studies. Australian patients were retrospectively identified. BM samples were analyzed by either RT-qPCR (n=75) (Ivey, NEJM 2016) or ultra-deep next-generation sequencing (UD-NGS, n=5, excluded from Cox model). We applied the ELN definitions for molecular progression or relapse (considered together as molecular failure [MF]), MP-LCN and complete molecular remission (CRMRD-). Kaplan Meier survival estimates were calculated from EOT to death (OS), and/or morphologic relapse (RFS), and/or MF (EFS). The optimal NPM1mut expression threshold was pre-determined by recursive partitioning. Variables with p<0.1 from univariate analysis were included in the final multivariate Cox model and confirmed by backward selection method. Copy numbers are expressed per 105ABL copies (for RT-qPCR) or as percentage of total reads (for UD-NGS).
 Results
 A total of 80 patients had NPM1mut detectable at a median of 37 days (range 19-90; 12 [15%] were >60 days) from last course of chemotherapy; characteristics summarized in Table 1. The majority of patients (89%) had received 3-4 cycles of chemotherapy. At EOT, the median NPM1mut transcript level by RT-qPCR was 11 copies (range 0.3-8699; 3 were >2000) and median reduction from baseline was 4.7 log (range 2.1-6.0). A total of 34 patients (45%; 4 not monitored) fulfilled the criteria for MP-LCN.
 With a median follow-up time of 24 mo (range 8-77), 27 (34%) spontaneously achieved a sustained CRMRD- for >6 months, 31 (39%) had MF and 13 (16%) had morphologic relapse without preceding MF (due to rapid relapse [n=8], lack of monitoring [n=3], extramedullary or NPM1 wild-type relapse [n=1 each]) (Figure 1). Nine patients (11%) had persisting MP-LCN (included transient MRD negativity): median interval between EOT to the last known positive sample was 12 mo (range 3-32), and all patients currently remain alive and without morphologic relapse by the data cut-off date July 13, 2020.
 Next, we examined the variables associated with MF and/or morphologic relapse. In univariate analysis, factors associated (p<0.1) with disease progression were white cell count, FLT3-ITD, <4 cycles of chemotherapy received, EOT NPM1mut ≥15 copies, and <4 log reduction from baseline (Table 2). In multivariate analysis (and confirmed by backward selection), only baseline FLT3-ITD (HR 2.5, 95% CI 1.3-4.6) and EOT NPM1mut MRD <4 log reduction from baseline (HR 3.2, 95% CI 1.7-6.2) retained significance. Patients with none, either, or both of these features had a median EFS of not reached, 5.8 and 1.4 mo, respectively (Figure 2). The corresponding 2-year RFS was 73%, 54% and 0% (median 3.5 mo).
 We describe the natural history of patients with NPM1 mutated AML who remain MRD positive after completing intensive chemotherapy. Almost half either spontaneously achieve MRD-negativity or have stable low-level expression without relapse with minimum follow up of 8 mo. Patients with both FLT3-ITD and <4 log reduction in transcript levels at the end of therapy are at very high risk of disease progression and warrant consideration of pre-emptive treatment.
 
 Tiong: Pfizer: Consultancy; Servier: Consultancy; Amgen: Consultancy, Honoraria. Dillon:Abbvie: Honoraria, Research Funding; Novartis: Honoraria; Menarini: Honoraria; Astellas: Honoraria; Pfizer: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria, Research Funding. Bajel:Abbvie: Honoraria; Pfizer: Honoraria; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria; Astellas: Honoraria. Russell:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Jazz: Research Funding, Speakers Bureau. Wei:MacroGenics: Consultancy, Honoraria; Pfizer: Honoraria; Servier: Consultancy, Honoraria, Research Funding; Walter and Eliza Hall Institute: Other: former employee and receives a fraction of its royalty stream related to venetoclax; Celgene: Consultancy, Honoraria, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Research Funding; Genentech: Honoraria; Astra Zeneca: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

The Natural History of NPM1MUT Measurable Residual Disease (MRD) Positivity after Completion of Chemotherapy in Acute Myeloid Leukemia (AML)

Background: Mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes are found in approximately 20% of patients with acute myeloid leukemia (AML). Although independent prognostic data are lacking, our program often moves patients with IDH-mutated AML (mIDH) towards allogeneic bone marrow transplant (BMT). Reports on the impact of mIDH on BMT outcomes are conflicting. One study (Quek L, et al. Blood Adv. 2016; 1(3):19320) found improved rates of relapse (RR), relapse free survival (RFS) and overall survival (OS) for patients with mIDH1, whereas another study (Salhotra A, et al. Clin Lymphoma, Myeloma Leuk. 2019 Jul 1;19(7):e400-5) reported higher RR, but no differences in RFS or OS for patients with mIDH1/2. In light of the approved IDH1/2 inhibitors, the role of early BMT for such patients requires additional study. We examined the BMT outcomes of patients with mIDH AML compared to wildtype (wt)-IDH AML.
 Patients and methods: Patients with AML who underwent a first allo-BMT at Johns Hopkins between 2014 and 2020 and had molecular testing for IDH mutation status were included. Patients were grouped according to IDH mutation status (mIDH versus wt-IDH). Patient demographics, molecular genetics, initial treatment response, and BMT characteristics were compared. Post-BMT RR, RFS and OS were then compared between groups. Multivariate models were used to assess the prognostic significance of mIDH after controlling for co-variates. We also examined the relationship between peri-BMT IDH inhibitor use and IDH mutation status at the time of post-BMT relapse.
 Results: We identified 109 patients with mIDH AML, 70 (64%) of whom underwent BMT. 210 BMT patients with wt-IDH AML were used as a comparison. Outcomes between patients with mIDH1 and mIDH2 AML were similar and they were combined for all further analyses. Patients with mIDH were generally older (mean age at diagnosis 61 (range 28-75) vs. 54 (range 19-76), p < .001), less likely to have poor-risk cytogenetics, more likely to have a haploidentical donor, and more likely to receive non-myeloablative conditioning (Table 1). mIDH AML was associated with co-mutations in SRSF2 and DNMT3A mutations and less likely to have TET2 and KRAS co-mutations.
 Patients with mIDH had significantly improved post-BMT RR, RFS and OS compared to patients with wt-IDH (log rank p = 0.04, .01, and .01 respectively, Figure 1). In a multivariate model controlling for ELN risk classification, mIDH was associated with improved OS with a trend towards significance (HR 0.51, 95% CI 0.24 - 1.10, p = 0.085). Recognizing that significant heterogeneity exists within ELN risk groups, we examined the specific components of poor ELN risk classification in each group and found that poor risk in the wt-IDH group was primarily driven by complex karyotypes and TP53 mutations, whereas the ELN poor risk was driven by RUNX1 or ASXL1 co-mutation in the mIDH group. In a model controlling for specific genetic abnormalities (complex karyotype, TP53 mutation, and KRAS mutation) IDH mutation status was not an independent prognostic factor (HR 0.66, 0.34 - 1.28, p = 0.2, Table 2). We also assessed whether improved outcomes might be associated with use of IDH inhibitors in the pre or post-BMT setting. 22 (31%) of the 70 patients with mIDH AML received pre-BMT IDH inhibitors and an additional 4 patients received post-BMT maintenance. Of the 15 patients with mIDH who relapsed post-BMT, 13 had mIDH at the time of relapse. 11 of the 11 patients who had never received an IDH inhibitor had mIDH at relapse compared to 2 of 4 (50%) patients who had received IDH inhibitors (p = .057).
 Conclusion: In our cohort, patients with mIDH AML had significantly better OS, RFS, and RR following BMT compared to patients with wt-IDH. However, our analyses suggest that IDH mutations are associated with favorable genetic abnormalities and that the differences in BMT outcome are likely attributable to these differing genetic profiles as opposed to the presence of the mIDH. Differences in outcome were specifically driven by a lower prevalence of complex cytogenetics, TP53 mutations, and KRAS mutations amongst mIDH AML and were incompletely captured by ELN risk classification. In addition, the frequency with which post-BMT relapsed AML bears the IDH-mutant clone suggests that incorporation of IDH inhibitors into the peri-BMT setting, as is currently being studied in large randomized trials (NCT03564821, NCT03515512), may further improve outcomes.
 
 DeZern: Celgene: Consultancy, Honoraria; Astex: Research Funding; Abbvie: Consultancy; MEI: Consultancy. Levis:Astellas: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; FujiFilm: Honoraria, Research Funding; Amgen: Honoraria; Menarini: Honoraria. Smith:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Transplant Outcomes for IDH-Mutated AML: Good Outcomes Thanks to Keeping Good Company

Since being identified in China in December 2019, coronavirus disease 2019 (Covid-19) has rapidly evolved into a global pandemic with over 4 million cases and more than 270,000 deaths.(1) Following the first reported cases in the United Kingdom (UK) in late January 2020, numbers have continued to rise with 223,060 cases and 32,065 deaths reported as of 11th May 2020.(2) Initial reports from China have indicated that Covid-19 has an overall mortality rate of 1.4%. However, the prognosis varies widely between groups, with age over 60 years and underlying conditions including hypertension, diabetes, cardiovascular disease and cancer identified as risk factors for severe disease and death.(3) The initial reports from China show that patients with cancer are over-represented among individuals who develop severe Covid-19 after contracting the virus.(4) Patients with haematological malignancies are expected to be at increased risk of adverse outcomes from this viral infection, due being immunosuppressed as a consequence of the underlying cancer, and from the effects of therapy.

Clinical outcome of coronavirus disease 2019 in haemato‐oncology patients

Relapse remains the most common cause of treatment failure for patients with acute myeloid leukaemia (AML) who undergo allogeneic stem cell transplantation (alloSCT) and carries a grave prognosis. Multiple studies have identified the presence of measurable residual disease (MRD) assessed by flow cytometry (FCM) prior to alloSCT as a strong predictor of relapse, but it is not clear how these findings apply to patients who test positive in molecular MRD assays which have far greater sensitivity. We analysed pre-transplant blood and bone marrow samples by reverse-transcription polymerase chain reaction (RT-qPCR) in 107 patients with NPM1 mutant AML enrolled in the UK National Cancer Research Institute (NCRI) AML17 study. After a median follow-up of 4.9 years, patients with negative, low (<200 copies / 105 ABL in the PB and <1000 copies in the BM) and high levels of MRD had an estimated 2y overall survival (OS) of 83%, 63% and 13% respectively (p<0.0001). Focussing on patients with low level MRD prior to alloSCT, those with FLT3 ITD had significantly poorer outcome (hazard ratio, HR, 6.14, p=0.01). Combining these variables was highly prognostic, dividing patients into two groups with 2y OS of 17% and 82% (HR 13.2, p<0.0001). T-depletion was associated with significantly reduced survival both in the entire cohort (2y OS 56% vs 96%, HR 3.24, p=0.0005) and in MRD positive patients (2y OS 34% vs 100%, HR 3.78, p=0.003) but there was no significant effect of either conditioning regimen or donor source on outcome. Registered at ISRCTN (http://www.isrctn.com/ISRCTN55675535).

Molecular MRD status and outcome after transplantation in NPM1 mutated AML: results from the UK NCRI AML17 study.

Background: The outcome of patients with blast phase chronic myeloid leukaemia (CML) remains extremely poor despite the advent of tyrosine kinase inhibitors (TKIs), and the majority of blast phase patients have already failed the currently licensed TKIs during the chronic phase. Currently there is no standard therapy for patients with blast phase CML, but most will receive 2 or 3 courses of chemotherapy or a TKI, followed by stem cell transplantation (alloSCT). In the PACE clinical trial of ponatinib, 23% of patients with blast phase CML achieved major cytogenetic response, with overall survival of 20% at 12 months. To date, there has been no prospective evaluation of salvage chemotherapy in combination with ponatinib.
 Methods: MATCHPOINT is a seamless Phase I/II trial to determine the optimal dose of ponatinib in combination with conventional chemotherapy (fludarabine, cytarabine, idarubicin and G-CSF; FLAG-IDA) for the treatment of CML in blast phase. An efficient Bayesian design, EffTox, which utilises both efficacy and toxicity to select desirable doses for subsequent patient cohorts, was used. Given the observed patient outcomes and the investigators' prior beliefs, the next cohort's dose is chosen adaptively to optimize the risk-benefit trade-off between efficacy and toxicity. The initial ponatinib dose was 30mg daily, commenced on day 1 of FLAG-IDA chemotherapy. Where possible, ponatinib was given continuously during the remission-induction phase, but ponatinib therapy was interrupted from day 28 of each cycle if haematologic recovery had not occurred. Patients received one or two cycles of FLAG-IDA chemotherapy plus ponatinib at the allocated dose level, and then proceeded to alloSCT followed by ponatinib maintenance. The co-primary outcome measured toxicity (dose-limiting toxicity; DLT) during the first therapy cycle and efficacy (clinical response; haematologic or cytogenetic) after the first cycle.
 Results: A total of 17 patients were recruited between March 2015 and May 2018. Eight presented with de-novo blast phase CML and 9 had progressed on TKI. Eight patients had additional cytogenetic abnormalities and 3 had BCR-ABL kinase domain mutations (E255K x2 and T315I x1) at study entry. Nine and 8 patients commenced 1 or 2 cycles of FLAG-IDA + ponatinib, respectively. Of these, 16 patients were evaluable for the primary analysis. Treatment-related mortality (TRM) occurred in 3 patients during remission-induction (cardiomyopathy x1, pulmonary haemorrhage x1 and marrow aplasia x1). During cycle 1, 4/16 patients experienced a DLT (raised ALT x1, fulminant cardiomyopathy x1, cerebral sinus vein thrombosis x1, elevated amylase x1). Eleven of 16 (69%) patients achieved a clinical response, defined as either complete haematologic (3 patients) or cytogenetic response (1 minor and 9 major [2 partial and 7 complete]). Five patients achieved major molecular remission after cycle 1. All patients were recommended to be dosed at the 30mg dose, which was defined as the optimal dose for ponatinib with FLAG-IDA. Nine patients proceeded to alloSCT (7 myeloablative and 2 reduced intensity). Four patients developed acute GvHD (grades 2-4) and 3 had CMV reactivation. Four patients re-started ponatinib maintenance post alloSCT, and de-escalated to 15mg if major molecular remission was maintained. Overall 1-year survival was 45.8% (95% CI 26.9-77.7%), estimated using Kaplan Meier.
 Summary/Conclusion: We report the first prospective trial of ponatinib and conventional chemotherapy for blast phase CML. The EffTox model combined Phase I and II, and delivered efficiency in determining the trial's optimal dose. This innovative statistical model has the potential to be applied in other rare malignancies. We confirm that FLAG-IDA + ponatinib 30mg, is a tolerable combination in blast phase CML, with promising response and survival. Post-transplant ponatinib was well tolerated and no excess toxicity was observed when ponatinib was used both pre- and post alloSCT. The combination of ponatinib and FLAG-IDA represents a potentially important advance in the treatment of blast phase CML, a rare complication which currently has a very poor outcome.
 
 Copland: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; Cyclacel: Research Funding. Byrne:Ariad/Incyte: Honoraria, Speakers Bureau. Brock:Astrazeneca: Equity Ownership, Honoraria. De Lavallade:Incyte biosciences: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Clark:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ariad/Incyte: Honoraria; Jazz Pharmaceuticals: Honoraria; AbbVie: Honoraria. Milojkovic:Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Yap:Celgene: Honoraria; Faron Pharmaceuticals: Other: Consultancy.
 
 Ponatinib is a tyrosine kinase inhibitor (TKI). It is licensed to treat: - chronic myeloid leukaemia where the leukaemic cells have gene change (mutation) called T315I - acute lymphoblastic leukaemia that has an abnormal chromosome called the Philadelphia chromosome, or has the T315I mutation

FLAG-IDA and Ponatinib in Patients with Blast Phase Chronic Myeloid Leukaemia: Results from the Phase I/II UK Trials Acceleration Programme Matchpoint Trial

GATA2 monoallelic expression underlies reduced penetrance in inherited GATA2-mutated MDS/AML

Allogeneic haematopoietic stem‐cell transplantation remains the only curative treatment for relapsed/refractory acute myeloid leukaemia (AML) and high‐risk myelodysplasia but has previously been limited to patients who achieve remission before transplant. New sequential approaches employing T‐cell depleted transplantation directly after chemotherapy show promise but are burdened by viral infection and require donor lymphocyte infusions (DLI) to augment donor chimerism and graft‐versus‐leukaemia effects. T‐replete transplantation in sequential approaches could reduce both viral infection and DLI usage. We therefore performed a single‐arm prospective Phase II clinical trial of sequential chemotherapy and T‐replete transplantation using reduced‐intensity conditioning without planned DLI. The primary endpoint was overall survival. Forty‐seven patients with relapsed/refractory AML or high‐risk myelodysplasia were enrolled; 43 proceeded to transplantation. High levels of donor chimerism were achieved spontaneously with no DLI. Overall survival of transplanted patients was 45% and 33% at 1 and 3 years. Only one patient developed cytomegalovirus disease. Cumulative incidences of treatment‐related mortality and relapse were 35% and 20% at 1 year. Patients with relapsed AML and myelodysplasia had the most favourable outcomes. Late‐onset graft‐versus‐host disease protected against relapse. In conclusion, a T‐replete sequential transplantation using reduced‐intensity conditioning is feasible for relapsed/refractory AML and myelodysplasia and can deliver graft‐versus‐leukaemia effects without DLI.

Durable graft‐versus‐leukaemia effects without donor lymphocyte infusions – results of a phase II study of sequential T‐replete allogeneic transplantation for high‐risk acute myeloid leukaemia and myelodysplasia

Background : While myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are considered sporadic hematopoietic stem cell clonal disorders, there are rare occurrences of familial cases (<5%) where two or more individuals within the same family are affected. These high-risk examples are characterised by wide variations in the age of onset, disease latency and outcome between and within families, making their investigation, follow-up and treatment all the more challenging.To date, germline mutations in 11 disease genes have been described, with mutations in the myeloid transcription factor GATA2 representing one of the best-characterised genetic loci predisposing to inherited hematological malignancies. We have noted that within GATA2 families, particularly those segregating a germline p.Thr354Met mutation, there is striking evidence of reduced penetrance. In our example, two first-degree cousins (III.1 and III.3) developed high-risk MDS with monosomy 7 with a third cousin (III.7) presenting with significant leukopenia (monocytopenia [0.1x109/L] and neutropenia [0.8x109/L]). This contrasts with the parental generation (II.1, II.3 and II.5) who all remain hematologically normal and symptom free into their mid-late 60s ( Figure 1 ). We therefore set out to understand these differences in clinical presentation between mutation carriers.

Aims: To investigate the molecular mechanisms underlying the variable penetrance and clinical heterogeneity observed in a GATA2 -mutated family.

Results: Targeted deep-sequencing of 33 genes frequently mutated in MDS/AML revealed a low overall burden of acquired mutations in the symptomatic carriers with no mutations detected in asymptomatic family members. It was noteworthy that an acquired ASXL1 mutation (p.Gly646TrpfsTer12) was identical in all affected individuals (III.1, III.3 and III.7) ( Figure 1 ) although the variant allele frequency was lower (12%) in III.7 and remained stable (range 12-6%) over a 4 year monitoring period. GATA2 expression was lower in III.7 as assessed by quantitative RT-PCR and strikingly this was associated with monoallelic expression of the mutated GATA2 allele with complete loss of the wild-type (WT) allele expression. Temporal analysis of III.7 at yearly intervals demonstrated reactivation of the WT allele 2 years later, coinciding with a marked improvement in hematological parameters (normal monocyte count, neutrophils >1x109/L). These changes in GATA2 expression were not linked to gross changes in methylation, as assessed by methylation specific PCR and bisulphite sequencing, nor acquisition of additional mutations in the WT promoter. Instead, we believe that allele-specific fluctuations in expression are accompanied by changes in chromatin structure at the promoter. Using a SNP (rs1806462 [C/A]) located in the 5'UTR of GATA2 , we assessed allele-specific enrichment of H3K4me3 and H3K27me3 chromatin marks by chromatin immunoprecipitation. Sanger sequencing revealed a significant enhancement in the deposition of H3K4me3 activating chromatin mark on the mutated allele compared to the WT allele at diagnosis and this was reversed at later follow-up, correlating with reactivation of the WT allele expression. There were no discernible allele-specific differences in the H3K27me3 mark across the phenotypes at different time-points.

Conclusion: Variable penetrance amongst germline mutation carriers is a feature of many families with inherited forms of MDS/AML and this may be related to the nature of secondary genetic events acquired in at-risk individuals. In this study, however, we show that changes in the WT:mutant allele expression ratio as a result of local and allele-specific changes in chromatin deposition may also influence the penetrance of the inherited mutation.

![Figure 1][1] 

Figure 1 

Disclosures Cavenagh: Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau.

 [1]: pending:yes

Variable Penetrance Is Linked with Monoallelic Gene Expression in Inherited GATA2-Mutated MDS/AML

Introduction: VTD is an effective regimen for patients with multiple myeloma and forms a backbone for the addition of novel agents. The MUK-six trial aimed to improve the efficacy by adding Panobinostat, a now FDA approved pan-histone deacetylase inhibitor that demonstrated synergy with proteasome inhibition and immunomodulatory agents in pre-clinical models. We have previously reported the phase 1 dose finding part which determined the MTD of panobinostat with VTD to be 20mg. Here we present the efficacy results from the recommended dose (RD) expansion phase (primary end point) and safety, tolerability data for all patients during the induction phase of the study. Methods: MUK-six was a multi-centre UK Phase I/IIa trial for patients with relapsed and relapsed/ refractory myeloma who had received between 1 and 4 prior lines of therapy. Subjects received VTD-P (bortezomib 1.3mg/2sc days 1 and 8, thalidomide 100mg daily (50mg if pre-existing neuropathy), dexamethasone 20mg days 1, 2, 8, 9 and panobinostat 20mg days 1, 3, 5, 8, 10, 12) every 3 weeks for up to 16 cycles (induction) followed by 1 year of panobinostat maintenance. Those planned for autologous stem cell transplantation (ASCT) received a minimum of 6 cycles of VTD-P. All patients treated with VTD-P received venous thrombosis prophylaxis as per institutional practice. Responses were assessed using modified IWG uniform response criteria and toxicity graded by CTCAE V4.0. Results: 46 patients were treated at the RD and were of a median age of 60 years (41-76). 80.4% had received one prior line of therapy (range 1-4), 71.7% had prior bortezomib and 39.2% prior thalidomide. Most patients were ISS 1 (60.9%), 45.7% had adverse FISH lesions at baseline, 8.7% had 17p deletion. 6 patients remain on treatment at the time of this abstract. 51.3% of patients came off study to proceed to ASCT. The overall response rate (≥PR) for patients receiving at least one dose of panobinostat was 91.3%, ≥VGPR 45.7% (CR 6.5%, VGPR 39.1%, PR 45.7%). The ≥VGPR rate for those with standard FISH was 52.1% vs 42.9% for adverse FISH. Those treated at first relapse had higher overall responses to those treated later in their disease course (≥PR 94.6% vs 77.8%). Responses were independent of prior bortezomib exposure (≥PR 90.9%, ≥VGPR 45.5% vs PR≥92.3%, ≥VGPR 46.2%). Treatment was generally well tolerated, with a mean panobinostat dose of 17.4mg (86.8% of the RD) delivered across all cycles. 32.1% of those starting at 50mg thalidomide stopped the drug due to toxicity, and 52.6% of those starting at 100mg required dose reductions/stopping. 46 serious adverse events were reported in 27 patients which were mainly infections (17/46, 37.0%). The commonest grade 3-4 toxicities reported for all 57 patients were: neutropenia (14, 24.6%), hypophosphatemia (11, 19.3%), thrombocytopenia (8, 14.1%) and diarrhoea (6, 10.5%). Of note there were no reports of ≥ grade 3 neuropathy. The most frequent grade 1-2 toxicities were fatigue (50, 87.7%), neuropathy (43, 75.5%), constipation (35, 61.4%), diarrhoea (35, 61.4%), bone pain (33, 57.9%), and nausea (27, 47.4%). 2 patients withdrew consent due to toxicity. Conclusions: This study demonstrated that panobinostat can be safely given in combination with VTD and appears highly effective with a response rate of 91.3%, ≥VGPR 45.6% despite 72% having previous bortezomib. This regimen was well tolerated, in particular the incidence of diarrhoea, neuropathy and asthenia/fatigue appeared lower than that observed in the PANORAMA 2 trial (San Miguel et al., 2014). It is possible that the incorporation of a low intensity subcutaneous bortezomib schedule (2 doses every 3 weeks) contributed to the lesser toxicity. Acknowledgements: This trial was part of the Myeloma UK Clinical Trial Network, ISRCTN: 59395590. Disclosures Popat:Janssen: Honoraria. Off Label Use: Panobinostat: use outside of FDA licence, not yet EU approved. Kishore:Celgene: Other: Conference Sponsorship; Jazz pharma: Other: Conference Sponsorship. Oakervee:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Yong:Janssen: Honoraria; Autolous: Consultancy; Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Novartis: Consultancy. Cook:Sanofi: Consultancy, Honoraria, Speakers Bureau; Jazz Pharma: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Chugai: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cavenagh:Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau.

Bortezomib (Velcade), Thalidomide, Dexamethasone and Panobinostat (VTD-P) Is a Safe, Well Tolerated and Efficacious Regimen for Patients with Relapsed Multiple Myeloma: Preliminary Results of the Muk-Six Trial

There is limited published data on the mode of relapse presentation in acute myeloid leukaemia (AML) and the efficacy of routine outpatient monitoring in detecting relapse. In diffuse large B cell lymphoma, studies looking at postremission surveillance imaging found that the majority of relapses were detected at patient self-presentation;1 however, there is no similar data available for AML. Such information would be of relevance to all patients in occupations requiring medical checks for public safety reasons, such as pilots and public transport drivers, where the risk of acute incapacitation must be assessed prior to employment health clearance.

A retrospective analysis was conducted of 101 cases meeting criteria for relapsed AML that were treated in our centre from September 2007 to February 2014, focusing on the mode of presentation and the severity of symptoms at the time of relapse. Patient characteristics are shown in table 1. The median age was 51 years (range 18–76 years) and 24 patients had received a T-replete reduced intensity allogeneic haematopoietic stem cell transplant (HSCT) as consolidation therapy in first remission (CR1). Our current surveillance practice, based on international guidelines for patients with AML who have completed therapy involves a full blood count (FBC) every 1–3 months for the first 2 years, then every 3–6 months up to 5 years and annually thereafter.2 During this period, minimal residual …

Clinical and laboratory characteristics of acute myeloid leukaemia (AML) at relapse and the risk of acute incapacitation

In-depth molecular investigation of familial leukemia has been limited by the rarity of recognized cases. This study examines the genetic events initiating leukemia and details the clinical progression of disease across multiple families harboring germ-line CEBPA mutations. Clinical data were collected from 10 CEBPA-mutated families, representing 24 members with acute myeloid leukemia (AML). Whole-exome (WES) and deep sequencing were performed to genetically profile tumors and define patterns of clonal evolution. Germline CEBPA mutations clustered within the N-terminal and were highly penetrant, with AML presenting at a median age of 24.5 years (range, 1.75-46 years). In all diagnostic tumors tested (n = 18), double CEBPA mutations (CEBPAdm) were detected, with acquired (somatic) mutations preferentially targeting the C-terminal. Somatic CEBPA mutations were unstable throughout the disease course, with different mutations identified at recurrence. Deep sequencing of diagnostic and relapse paired samples confirmed that relapse-associated CEBPA mutations were absent at diagnosis, suggesting recurrence was triggered by novel, independent clones. Integrated WES and deep sequencing subsequently revealed an entirely new complement of mutations at relapse, verifying the presentation of a de novo leukemic episode. The cumulative incidence of relapse in familial AML was 56% at 10 years (n = 11), and 3 patients experienced ≥3 disease episodes over a period of 17 to 20 years. Durable responses to secondary therapies were observed, with prolonged median survival after relapse (8 years) and long-term overall survival (10-year overall survival, 67%). Our data reveal that familial CEBPA-mutated AML exhibits a unique model of disease progression, associated with favorable long-term outcomes.

Disease evolution and outcomes in familial AML with germline CEBPA mutations.

Elacytarabine in relapsed/refractory acute myeloid leukaemia: an evaluation of clinical efficacy, pharmacokinetics, cardiac safety and effects on lipid profile.

Acute myeloid leukaemia (AML) is a type of cancer of the part of the bone marrow that normally makes ‘myeloid’ cells. These include red cells (transport oxygen), platelets (control bleeding), and n...

Problems of sexual function and fertility in long‐term survivors (≥5 years) of haematological malignancy are often neglected in clinic. Our centre carried out a questionnaire study in this population addressing patient‐perceived fertility and sexual function. 718 patients responded (56% of those invited; 39% Hodgkin, 45% non‐Hodgkin lymphoma, 16% acute leukaemia). Respondent women were more likely to remain childless than a normal control population. Self‐reported infertility was more likely in men than women [odds ratio (OR) 1·77, P = 0·001]. Myeloablative therapy increased the likelihood of childlessness (OR 2·48, P = 0·004). Few attended fertility support services (12%). 24% of men banked sperm and 29% of these used the sample, of which 46% resulted in successful pregnancy. Fertility clinic attendance and sperm storage was more likely post‐1990 (OR 4·05, P < 0·001; OR 5·05, P < 0·001 respectively). Reporting a negative impact of cancer on sexual function was more common in women than men (OR 2·20, P < 0·001), and increased with current age and age at diagnosis (by 3–4% per year, P ≤ 0·001) but decreased with longer follow‐up (by 2%/year, P = 0·005). Patients on anti‐depressants and those reporting cancer‐related body change/appearance concerns more frequently reported a negative impact (P < 0·04 and P < 0·03 respectively). These self‐reported outcomes confirm literature findings, suggest improvement over time, but highlight a need for involvement of support services.

Fertility and sexual function in long‐term survivors of haematological malignancy: using patient‐reported outcome measures to assess a neglected area of need in the late effects clinic

A recently published population-based study showed an improvement in 5-year relative survival of patients with acute myeloid leukaemia (AML) presenting between 1971 and 2006 (Shah et al, 2013). In the light of that analysis, results for 285 younger adults with AML treated during that time period are presented, with a current minimum follow-up of 14 years, highlighting the role of intensive consolidation. A strategy of using myeloablative therapy comprising intermediate-dose cytosine arabinoside (ara-C) and total body irradiation (TBI), subsequently termed high-dose treatment (HDT), with autologous haematopoietic stem cell support as consolidation of first complete remission (CR) was followed at six European hospitals. Ara-C was chosen because of its efficacy in AML and the lack of need for the immunosuppressive effect of cyclophosphamide in the autologous setting. Two hundred and eighty-five consecutive, newly-diagnosed patients with AML aged <60 years (excluding those with AML-M3) commenced treatment between 1988 and 1996 (Table SI). There were two groups: the first 144 patients, aged <50 years, received: doxorubicin, 25 mg/m daily for 3 d, with ara-C iv and 6-thioguanine orally, each at a dose of 100 mg/m bd for 7 d as initial therapy. HDT was supported by autologous bone marrow transplantation (Rohatiner et al, 2000). Subsequently, 141 patients aged <60 years (84 aged <50 years and concurrently, 57 aged 50–60 years) received idarubicin, 10 mg/m iv for 3 d with ara-C iv, 100 mg/m, bd for 7 d and etoposide iv: 100 mg/m/d for 5 d, followed by HDT with peripheral blood progenitor cell (PBPC) support. Patients were included irrespective of karyotype or evidence of preceding myelodysplasia. All analyses were by ‘intention to treat’. Karyotypic analysis was successful in 219/285 patients (77%), and ‘risk group’ was allocated according to Medical Research Council criteria (Grimwade, 2001). FLT3 status was evaluable in 135/285 patients (47%) from whom leukaemic blast cells had been cryopreserved at the time of diagnosis. Clinical characteristics at the time of diagnosis are shown in Table I. On achievement of CR with one or two cycles of remission induction therapy, two further cycles of the same regimen were followed by collection and cryopreservation of autologous bone marrow or PBPC. The latter were mobilised using granulocyte colony-stimulating factor, 5 lg/kg/d until the neutrophil count was >2 0 9 10/l. The collection of mononuclear cells >1 0 9 10/kg, with CD34 +ve cells >1 0 9 10/kg were considered ‘sufficient’ to proceed to HDT. The latter comprised ara-C: 1 mg/m by iv infusion, bd for 6 d followed by TBI: 200 cGy, bd for 3 d. Complete remission was achieved in 215/285 (75%) patients overall (106/144 [74%] and 109/141[77%] in the two groups respectively) (Table SII). CR rates reflected cytogenetic ‘risk group’; ‘favourable’: 29/31 (94%), ‘intermediate’: 135/172 (78%), and ‘poor’: 8/16 (50%), (P = 0 02). FLT3-internal tandem duplication (ITD) status did not significantly influence achievement of CR. Only 121/215 patients eligible to receive HDT did so. The most frequent reasons for not proceeding to HDT (for the two groups combined) were: early recurrence – 37 patients, patient considered ‘not fit enough’ following chemotherapy – 24, elective allograft – 23, insufficient numbers of PBPC – 11 and patient choice – 10 (Table SIII). Time to haematological recovery, and hence duration of hospital stay, were significantly shorter for the PBPC group (P = 0 04) (Table SIV). With the current minimum follow-up of 14 years, 34% of patients (96/285) are alive. Recurrence occurred in 113/215 patients (53%) in whom CR was achieved, between 1 month and 12 6 years. On multivariate analysis, only age and cytogenetic risk group were significantly associated with achievement of CR (P = 0 002 and 0 006 respectively) and with overall survival (P = 0 004 and 0 002) (Table SV). Considering only patients aged <50 years (for comparability), there was no significant difference in overall or relapse-free survival according to FLT3-ITD status or treatment. The profound prognostic significance of karyotype ‘translated’ into a clear difference in survival according to ‘risk group’ as shown in Fig 1. This analysis confirms the long-term efficacy of very intensive consolidation therapy. With now very long follow-up, 38% of patients in whom CR was achieved remain recurrence-free. Whilst this is gratifying, there were two critical failings: first, the CR rate of 75%, essential to proceed to HDT, meant that the strategy failed for 25% of patients in the first instance. Furthermore, changing to a potentially more effective remission induction regimen did not help. Second, the ‘attrition rate’, due predominantly to induction therapy-related morbidity or early recurrence, precluded large numbers of patients from receiving the planned therapy. This has been a problem in virtually every study of HDT in

Myeloblative therapy with autologous haematopoietic stem cell support as consolidation of first remission in acute myeloid leukaemia – very long follow‐up

The toxicity burden and long‐term anti‐leukaemic effect of non‐myeloablative (NMA) allogeneic haematopoietic stem‐cell transplantation (AHSCT) for acute myeloid leukaemia (AML) and myelodysplasia (MDS) remains undefined. We report the outcome of 56 patients with AML/MDS transplanted from human leucocyte antigen‐matched donors using NMA conditioning without T‐cell depletion. With a median follow‐up of 5 years, treatment‐related mortality was 9% and current disease‐free survival (CDFS) was 45% (overall) and 55% (patients transplanted in remission). Development of graft‐versus‐host disease upon withdrawal of post‐transplant immunosuppression was associated with less relapse and better CDFS. These data confirm that NMA AHSCT without T‐cell depletion is safe and can result in sustained remissions of AML/MDS.

Long‐term survival with low toxicity after allogeneic transplantation for acute myeloid leukaemia and myelodysplasia using non‐myeloablative conditioning without T cell depletion

Acute myeloid leukemia (AML) induces bone marrow (BM) failure in patients, predisposing them to life-threatening infections and bleeding. The mechanism by which AML mediates this complication is unknown but one widely accepted explanation is that AML depletes the BM of hematopoietic stem cells (HSCs) through displacement. We sought to investigate how AML affects hematopoiesis by quantifying residual normal hematopoietic subpopulations in the BM of immunodeficient mice transplanted with human AML cells with a range of genetic lesions. The numbers of normal mouse HSCs were preserved whereas normal progenitors and other downstream hematopoietic cells were reduced following transplantation of primary AMLs, findings consistent with a differentiation block at the HSC–progenitor transition, rather than displacement. Once removed from the leukemic environment, residual normal hematopoietic cells differentiated normally and outcompeted steady-state hematopoietic cells, indicating that this effect is reversible. We confirmed the clinical significance of this by ex vivo analysis of normal hematopoietic subpopulations from BM of 16 patients with AML. This analysis demonstrated that the numbers of normal CD34+CD38− stem-progenitor cells were similar in the BM of AML patients and controls, whereas normal CD34+CD38+ progenitors were reduced. Residual normal CD34+ cells from patients with AML were enriched in long-term culture, initiating cells and repopulating cells compared with controls. In conclusion the data do not support the idea that BM failure in AML is due to HSC depletion. Rather, AML inhibits production of downstream hematopoietic cells by impeding differentiation at the HSC–progenitor transition.

Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation

Background Germline mutations in the N-terminal of CCAAT/enhancer binding protein α ( CEBPA ) are a feature of autosomal dominant AML. Despite the strong penetrance of these mutations, the age of disease onset varies considerably and is usually precipitated by acquiring a C-terminal mutation. Although biallelic CEBPA -mutations in sporadic AML are associated with favorable clinical outcomes, little is known about long-term survival or the secondary molecular events linked with familial cases.

Aims We sought to establish the long term clinical outcomes in familial CEBPA- mutated AML and to examine the patterns of secondary mutations associated with leukemic transformation.

Methods and Results Disease specific and follow up information was collected in 16 affected patients, from 7 pedigrees, published between 2004 and 2011. In 94% of patients (n=15), at least 3 years follow up was achieved. All pedigrees had a germline N-terminal CEBPA mutation and 17 of 18 documented disease episodes had an acquired C-terminal mutation.

The age at AML diagnosis varied from 2-39 years (median 24.5 yrs) with a single asymptomatic carrier detected (now 23 yrs). With the exception of 1 patient diagnosed in 1963, all cases received combination chemotherapy at diagnosis. Additional consolidation comprised autologous stem cell transplantation (SCT, n=3) and allogeneic SCT in 1 patient failing to achieve CR post induction therapy. Ten patients had at least 1 further disease episode, the first recurrence presenting after a median of 2.1 years (range 0.5-14 yrs), 5 continued in CR and 1 patient was lost to follow up. In 3 out of 4 patients, where CEBPA was screened at recurrence, the acquired C-terminal mutations differed from diagnosis, signifying new episodes of AML. The median overall survival (OS) for the entire cohort was 20 years (1.1-46 yrs, n=16) and 17.3 years for patients with multiple disease episodes, reflecting durable responses to second line therapies.

To identify potential co-operating mutations in CEBPA pedigrees, whole exome sequencing (WES) was performed in 7 tumor samples from 5 patients across 3 pedigrees, all with the germline mutation p.P23fs ([Figure 1][1]). All tumor DNA samples were sequenced with matched remission or skin DNA as a germline control. The number of acquired mutations in familial tumors was similar to sporadic disease, with 10-22 (median=14) non-synonymous tier 1 mutations per sample. In addition to the acquired C-terminal CEBPA mutation, these included established AML loci such as EZH2, TET2 , WT1 , GATA2 , NRAS, CSF3R and the recently identified cohesin complex gene, SMC3 . Of note, FLT3-ITD , NPM1 and DNMT3A mutations were absent in all tumors. A minimum of 2 established mutations were identified in each tumor and, at present, we can only speculate on which additional mutations are ‘driver' or ‘passenger' events.

![Figure][2] 

Reflecting findings in sporadic AML, biallelic CEBPA and GATA2 mutations co-occurred in both siblings from Pedigree 1 and were subsequently identified by Sanger sequencing in the child III.2 ([Figure 1][1]). All 3 patients continue in long term remission following chemotherapy. We were able to trace the clonal evolution in patient I.2 (Pedigree 3) by WES of 3 consecutive tumor samples which arose over a 17 year period. At diagnosis (Dx) the patient received induction and consolidation chemotherapy and remained disease free for 14 years. The second disease episode (R1) was treated with chemotherapy followed by autologous SCT and the third presentation (R2) was chemo-refractory. Tumor DNA from R2 was clonally related to Dx, sharing 7 identical mutations, including the original C-terminal CEBPA deletion. In contrast, R1 appeared molecularly distinct from Dx and R2, most likely representing a new clone which was subsequently eradicated with treatment.

Conclusion This is the first report of long term clinical outcomes in familial CEBPA -mutated AML. Although many patients experienced disease recurrence, our extended follow up showed that OS remained favorable despite multiple episodes of disease. Assessment of C-terminal CEBPA mutations provided a unique insight into the recurrence of AML, with some patients appearing to develop completely new leukemic episodes. Although the penetrance of germline mutations is high, healthy carriers and late onset disease are noted, emphasizing the need for clinical vigilance and screening of all related potential SCT donors.

Disclosures: No relevant conflicts of interest to declare.

 [1]: #F1
 [2]: pending:yes

Familial AML With Germline CEBPA Mutations: Extended Clinical Outcomes and Analysis Of Secondary Mutations Using Whole Exome Sequencing

Abstract 3174 Background: As survival rates continue to improve for patients with haematological malignancy, there is an increasing emphasis on quality of life (QOL) as an important treatment outcome. Long-term survivors can experience a variety of adverse physical late effects of cancer therapy. However, psychological, e.g. depression and anxiety, and social problems can also have profoundly adverse effects on patients9 QOL that may not be adequately addressed in the management of long-term survivors. In this retrospective cohort study of late effects in 718 British survivors of lymphoma and leukaemia (5–40 years since diagnosis), treated at a single centre, participants completed a series of questionnaires including the Hospital Anxiety and Depression Scale (HADS) and the Impact of Cancer (IOCv2) scale, which is a QOL instrument specifically designed to measure both positive and negative impacts of cancer in long-term survivors. Objective: To examine the association between depression and anxiety (HADS) and QOL (IOCv2). Patients and Methods: Ethical approval obtained from the National Research Ethics Service Ref: 11/NE/0095 All patients, aged ≥18 years at time of entry into study, with a confirmed diagnosis of haematological malignancy and alive ≥5 years since initial diagnosis, and who had received treatment at St. Bartholomew9s Hospital, London (n=1,288) were sent a questionnaire comprising socio-demographic details and a series of medical and psychosocial measures, including IOCv2 and HADS. Responses were received from 718 (response rate = 56%) patients (280 Hodgkin9s Lymphoma (HL), 326 Non-Hodgkin9s lymphoma (NHL) [109 Diffuse Large B- Lymphoma (DLBCL), 128 Follicular Lymphoma (FL), 89 other NHL (ONHL)], and 112 Acute Leukaemia (AL)). Statistical Analysis: Spearman rank correlation between HADS scores and positive and negative scales of IOCv2 were examined, and, where significant, mean scores for each scale/domain were compared between groups scoring >15 on HADS (indicating a high possibility of clinical depressive or anxiety disorder) and ≤15, using multivariable linear regression analysis and adjusting for age, years since diagnosis, gender, relationship status and ethnicity in HL, DLBCL, FL/ONHL and AL respectively. Bonferroni corrections were used for multiple testing. Results: Fifteen percent (HL 14%; DLBCL 15%, FL/ONHL 18%; AL 16%) of participants had HADS scores >15 indicative of a clinical mood or anxiety disorder. There was no statistically significant difference between HADS scores across the diagnostic groups ( P =0.65). There was a significant correlation between HADS scores and IOC negative impact scale scores (r=0.68, P P P 15 in all diagnostic groups after adjusting for current age, years since diagnosis, gender, relationship status and ethnicity (total 2.87 vs. 3.83; HL 3.24 vs. 3.90; DLBCL 3.28 vs. 4.40; FL/ONHL 2.81 vs. 3.90; AL 2.03 vs. 3.24). Similar significant results ( P ≤0.02) were also observed at the negative domain level. In the adjusted analyses, those who were in a relationship had significantly lower IOC negative impact scores than those who were not in a relationship in HL ( P =0.01) and DLBCL, ( P P Conclusions: Levels of depression and anxiety symptoms are higher in long-term cancer survivors than in the general population and strongly correlated with negative impact of cancer in all types of haematological malignancy, regardless of prognosis. Other factors, such as age, years since diagnosis and degree of social support, are also contributory and a greater understanding of how these interact is needed to improve quality of life and other healthcare needs of long-term survivors. Disclosures: Gribben: Celgene: Honoraria; Roche: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Pharmacyclics: Honoraria.

The Relationship of Depression and Anxiety and Impact of Cancer in Long-Term Survivors of Haematological Malignancy.

expected, these patients had more advanced disease and more frequent extranodal localization at presentation. In this study, we demonstrated that the addition of rituximab to CHOP was associated with a reduction in the incidence of secondary CNS involvement. Moreover, compared to the pre-rituximab era, progression during systemic treatment is less frequent, CNS relapses tend to be isolated and, most strikingly, leptomeningeal involvement is uncommon. These findings are similar to the Vancouver group’s study (Villa et al, 2010). The reduced incidence of secondary CNS involvement was also demonstrated by Boehme et al, 2009; and Shimazu et al, 2009;. However, a greater proportion of leptomeningeal relapses in R-CHOP-treated patients was observed in the former study. Conversely, the addition of rituximab did not change the incidence of secondary CNS involvement in the other three studies (Feugier et al, 2004; : Yamamoto et al, 2010; Tai et al, 2011). In contrast to previous studies, our R-CHOP-treated patients with secondary CNS involvement were younger and, probably for that reason, half of them were successfully salvaged with second-line treatment. Zdravko Mitrovic Martin Bast Philip J. Bierman Robert G. Bociek Julie M. Vose Wing C. Chan James O. Armitage Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA, School of Medicine, University of Zagreb, Zagreb, Croatia, and Department of Internal Medicine, Division of Hematology/Oncology, University of Nebraska Medical Center, Omaha, NE, USA. E-mail: joarmita@unmc.edu

Bile acid malabsorption in patients with graft‐versus‐host disease of the gastrointestinal tract

While most myelodysplastic syndrome/acute myeloid leukemia cases are sporadic, rare familial cases occur and provide some insight into leukemogenesis. The most clearly defined familial cases result from inherited mutations in RUNX1 or CEBPA. Recently, novel germline mutations in GATA2 have been reported. We, therefore, investigated individuals from families with one or more first-degree relatives with myelodysplastic syndrome/acute myeloid leukemia with wild-type RUNX1 and CEBPA, for GATA2 mutations. Screening for other recurrent mutations was also performed. A GATA2 p.Thr354Met mutation was observed in a pedigree in which 2 first-degree cousins developed high-risk myelodys-plastic syndrome with monosomy 7. They were also observed to have acquired identical somatic ASXL1 mutations and both died despite stem cell transplantation. These findings confirm that germline GATA2 mutations predispose to familial myelodysplastic syndrome/acute myeloid leukemia, and that monosomy 7 and ASXL1 mutations may be recurrent secondary genetic abnormalities triggering overt malignancy in these families.

Germ-line GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival

Abstract 3480 Background: Outcomes for patients with refractory or relapsed acute myeloid leukaemia (AML) are extremely poor and allogeneic haemopoietic stem cell transplantation (HSCT) provides the best hope for prolonged disease free survival. Ablative HSCT combines high dose, anti-leukaemic chemoradiotherapy and the graft versus leukaemia (GVL) effect, but is associated with significant toxicity and mortality and these risks rise exponentially with advancing age. Several factors mitigate against an attempt to transplant patients after relapsed disease, including a low probability of achieving second remission, high re-induction mortality, prolonged cytopenias and opportunistic infections and prolonged hospitalization. Based on promising results [1], we undertook a phase II study of sequential chemotherapy immediately followed by reduced intensity conditioning (RIC)-Allo with the aim of increasing the safety and applicability of AlloHSCT, while maintaining its antileukaemic efficacy. Patients/Methods: All eligible patients received treatment with Daunorubicin 45mg/m2 OD IV D-15 to D-13 and AraC 1.5g/m2 BD IV D-15 to D-10, a three day rest period, and conditioning with Fludarabine 25mg/m2 D-6 to D-2 and Cyclophosphamide 1g/m2 D-3 and -2 before receiving HSCT. Graft versus Host Disease (GVHD) prophylaxis was with Cyclosporine and Methotrexate. To date 33 patients were enrolled (table 1), of whom 31 patients underwent transplant. Results: 28/31 (90.3%) patients engrafted (neutrophils ≥0.5 and platelets ≥ 20) at a median of 33.5 days (15-49), while 3 died between d21-51 due to sepsis. The median d30, d60 and d100 whole blood chimerism was 96% (range 4–100), 80% (range 5–100), and 76% (range 0–100) respectively. 6/31 (19.4%) developed acute GVHD; 5 grade 1–2, 1 grade 4. Chronic GVHD was documented in 8 patients, extensive GVHD in 4/8. 7 patients had CMV re-activation (no CMV disease) and 1 non-specified pneumonitis. Median time of hospitalization was 37 days (30-61). No patient has required DLI to date. 18 pts (56.25%) achieved complete remission (CR) as assessed by day 30 bone marrow (BM). 2 had Conclusions: Sequential treatment with cytoreductive therapy and immediate RIC Allo is associated with good engraftment rates with a TRM acceptable for this high risk group. Our preliminary data indicate a favourable survival outcome for these patients with a particularly poor prognosis. 1. Schmid C, Scheuning M, Schwerdtfeger et al. Long-term survival in refractory acute myeloid leukemia afetr sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood. 2006;108:1092-1099. Disclosures: Gribben: Roche: Consultancy; Celgene: Consultancy; GSK: Honoraria; Napp: Honoraria.

A Phase II Trial of Sequential Treatment with Cytoreductive Therapy and Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation for Relapsed/Refractory Acute Myeloid Leukaemia, High-Risk MDS and Other High Risk Myeoid Malignancies: An Interim Report.

A novel K509I mutation of KIT identified in familial mastocytosis-in vitro and in vivo responsiveness to imatinib therapy.

The persistence of minimal residual disease (MRD) posttreatment may provide an early indicator of impending relapse in acute myeloid leukaemia (AML) (Raanani & Ben-Bassat, 2004). The absence of an appropriate molecular signature in 40–60% of AML patients who have normal cytogenetics associated with intermediate risk has limited the analysis in this group. Through advances in mutation analysis a list of recurring gene mutations as potential MRD targets are now being compiled. Many AML cells have more than one recurring mutation, indicating that there is a multistep pathogenesis of disease. Mutation events in AML have been detected by analysis of the blast cells; therefore, chronology of mutational events within the stem cell and/or early progenitor populations has not been established. Many of these mutations result in the insertion or deletion of a small number of additional nucleotides that should allow for the design of a specific primer against the unique sequence generated by the mutation (Pabst et al, 2001). Found in approximately 20% of normal karyotype AML, the presence of CEBPA mutation segregates with favourable risk among this otherwise intermediate risk group. The CEBPA gene encodes the granulocytic differentiation factor CCAAT Enhancer Binding Protein-alpha and plays a crucial role in granulocytic differentiation of haematopoietic stem cells and has antiproliferative activity in various cell types. Mutation in CEBPA was investigated as a potential MRD marker because of its prevalence in normal karyotype AML, the frequency of insertion and deletion mutations enabling a straightforward design of mutation-specific primers and concordance between presentation and relapse (Tiesmeier et al, 2003). Four patients with normal karyotype AML FAB type M1 were selected for study based on the availability of diagnostic (patients 1, 3 and 4) or relapse (patient 2) bone marrow (BM) and on the presence of CEBPA mutations identified during previous screening (Snaddon et al, 2003). Samples were collected and analysed in accordance with the requirements of the local ethics committee. Five real-time quantitative polymerase chain reaction (RQ-PCR) assays were developed that selectively amplified mutated CEBPA DNA from four patients. Figure 1A and B demonstrates the RQ-PCR strategy used in this study. Three patients (1, 2 and 3) had an insertion mutation in the region of the gene that codes for the C-terminal DNA-binding/basic leucine zipper domain of the protein, the fourth contained mutations corresponding to both the Nand C-terminal regions of the C/EBP-a protein (4a and 4b respectively). Mutations in 1, 2, 4a, and 4b were all tandem duplications ranging from 3 to 57 base pairs (bp) in length while patient 3 had a 3-bp insertion. Mutation-specific forward primers were designed by making use of the unique sequences generated by the insertion mutations along with the introduction of single nucleotide changes in the primers to prevent annealing to the wild-type (WT) sequence. Patient-specific primer sequences are given in Fig 1C. Real-time PCR analysis was performed on 25 ll reaction mixture in duplicate using Taqman chemistry on the ABI PRISM 7700 Sequence Detector (Applied Biosystems, Warrington, UK) with default settings. b-2-Microglobulin was used as the endogenous reference gene to assess total cell number per well. The specificity of each RQ-PCR assay was tested by amplifying 750 ng (equivalent to 125 000 cells) of each patient’s diagnostic BM DNA, wt DNA, patient diagnostic BM DNA serially diluted in wt DNA and no template controls, in duplicate. An assay was deemed to be specific if no amplification was observed with wt DNA. To test the sensitivity of each assay a standard curve was generated by five serial dilutions of diagnostic DNA in water (ranging from 125 000 to 4 cells per well). In all amplification plots the same threshold was maintained to allow comparison between experiments. The correlation coefficient of the standard curves was at least 0Æ95, indicating that the assays had a high probability of precise quantification. The mean Ct for DNA equivalent to 125 000 cells was 24Æ6 (range 24–27). The mean slope of the dilution curves was )3Æ2 (range )3Æ5 to )2Æ8), indicating good amplification efficiencies (the perfect theoretical slope is )3Æ3). As shown in Fig 1C, the maximum reproducible sensitivity (defined as the dilution for which duplicates were both positive) for all the patient mutation assays was 10 (8Æ0 · 10; 10 in 125 000) and therefore were of the required order of sensitivity, >10, for an MRD monitoring assay. Insufficient material was available for retrospective MRD monitoring in these patients. Instead we have taken advantage of the assay’s ability to quantify mutated cells for the determination of presence or absence of mutation within the leukaemic stem cell (LSC) population. The LSC generally accounts for approximately 1% of leukaemic cells (Hope et al, 2004). As with the normal haematopoietic stem cell (HSC) compartment, LSCs are not functionally homogeneous and correspondence

Development of a quantitative real‐time polymerase chain reaction method for monitoring CEBPA mutations in normal karyotype acute myeloid leukaemia

Our group has previously shown an association between acquired uniparental disomy 11p and homozygous gene mutation of Wilm’s tumour 1 (WT1) in a patient with normal karyotype acute myeloid leukemia (AML). Based on this observation the incidence of WT1 mutation was investigated in a cohort of normal karyotype AMLs. Mutation screening was performed on 70 patients (median age 55 years, range 19–78 years) by a PCR-direct sequencing approach using intronic primers flanking exons 2–10 of WT1. Mutation status was inferred from the resultant traces and confirmed by use of TOPO TA cloning and sequence analysis of the corresponding mutated clones. Mutations were detected in 7/70 (10%) patients; these typically resulted in insertion of 1–16 bp that led to the disruption of the DNA binding domain of the protein. The mutation profile of FLT3-ITD, NPM and CEBPA was also examined in this cohort of patients to compare the additional mutational events present in WT1 mutated and non-mutated cases. A significant positive association was observed between WT1 and FLT3-ITD mutation with 6/7 WT1 mutated cases having a FLT3-ITD compared to 20/63 non mutated cases (p=0.01). There was no association between mutations in WT1 and either of the good prognostic mutational markers, CEBPA and NPM. All 6 patients with both WT1 and FLT3 mutations were refractory to intensive induction chemotherapy with WT1 mutation showing a trend towards a worse overall survival when compared with the non-mutated group (p=0.07). We can conclude therefore that WT1 is mutated in 10% of normal karyotype AML, is positively associated with FLT3-ITD status and identifies a putative subgroup of normal karyotype AML who fail to achieve remission with conventional cytotoxic therapy and have a poor overall survival. Validation of this data in larger series would support the inclusion of WT1 in the current molecular risk stratification of normal karyotype AML based on CEBPA, NPM and FLT3-ITD status.

Wilm’s Tumour 1 (WT1) Mutations Are Associated with FLT3-ITD Mutation and Poor Prognosis in Normal Karyotype AML.

Genome-wide single nucleotide polymorphism analysis has revealed large-scale cryptic regions of acquired homozygosity in the form of segmental uniparental disomy in approximately 20% of acute myeloid leukemias. We have investigated whether such regions, which are the consequence of mitotic recombination, contain homozygous mutations in genes known to be mutational targets in leukemia. In 7 of 13 cases with uniparental disomy, we identified concurrent homozygous mutations at four distinct loci (WT1, FLT3, CEBPA, and RUNX1). This implies that mutation precedes mitotic recombination which acts as a "second hit" responsible for removal of the remaining wild-type allele, as has recently been shown for the JAK2 gene in myeloproliferative disorders.

Association between acquired uniparental disomy and homozygous gene mutation in acute myeloid leukemias.

A study was undertaken to develop an acute myeloid leukaemia (AML) screening panel to uncover novel recurring gene mutations. Analysis was performed on six genes known to be mutated in AML (RUNX1, FLT3, KIT, CEBPA, PTPN11 and NRAS) and an additional two candidate genes (CCND3 and FES) in a panel of 175 primary human AML samples that included all French–American–British types except M3, and all cytogenetic risk groups. One hundred and fifteen mutations were identified in 97 (55%) patients comprising 81 patients (46%) with one mutation, 14 patients (8%) with two mutations and two patients (1%) with three mutations. Fifty‐five of 88 (63%) patients with normal karyotype AML had at least one mutation. Correlation was observed between KIT mutation and ‘favourable risk’ cytogenetics (P < 0·001), CEBPA mutation and ‘intermediate risk’ cytogenetics (P = 0·045), and PTPN11 mutation and ‘poor risk’ disease (P < 0·001). The frequency of individual gene mutation was in accordance with previously published studies. Three novel mutations of FLT3 were detected (Y589D, D839G, Y842H) that would have been overlooked by conventional gel electrophoresis. A 51‐bp deletion was detected in CCND3 in a patient with normal karyotype AML. This validated panel now provides an important tool to evaluate other candidate genes in the genesis of myeloid malignancy.

Development of a human acute myeloid leukaemia screening panel and consequent identification of novel gene mutation in FLT3 and CCND3

Mutation studies in Acute Myeloid Leukaemia (AML) are complicated by the existence of distinct morphological and cytogenetic subtypes; consequently although mutations in any one gene may occur in only 5% of AML, the frequency of mutation may differ both between the different FAB-types and cytogenetic risk groups studied. It is important therefore not only to validate the screening methodology used but also the suitability of the patient panel tested. A screening panel was developed allowing detection of novel recurring gene mutations within samples derived from patients with AML. Mutation analysis of 6 previously described genes ( RUNX1 , FLT3 , KIT , CEBPA , PTPN11 , NRAS ) and 2 candidate genes ( CCND3 , FES ) were carried out in a cohort of 175 AML samples representing all FAB types (except M3) and cytogenetic risk groups using a combination of SSCP, DHPLC and sequence analysis. One hundred and fifteen mutations were identified in 97 (55%) patients comprising 81 patients (46%) with one mutation, 14 patients (8%) with 2 mutations, and 2 patients (1%) with 3 mutations. Fifty-five out of 88 (63%) patients with normal karyotype AML had at least one mutation. There was was a weak negative association between FLT3 ITD and loop mutation (p = 0.095), a positive association between KIT mutation and favourable risk cytogenetics (p = 0.001), CEBPA mutation and intermediate risk/normal cytogenetics (p = 0.045) and PTPN11 mutation and poor risk disease (p = 0.001). The frequency of individual gene mutation was in accordance with previously published studies. Three novel mutations of FLT3 (Y589D, D839G, Y842H) were detected in 4 patients that would have been overlooked by conventional gel electrophoresis techniques. A single in frame 51bp deletion of nucleotide 939 – 990, resulting in a deletion of 17 amino acids at the carboxyl-terminus of the cyclin D3 protein was identified in a single patient. Overall, both the pattern and mutation frequencies reported in this cohort are similar to those in the literature supporting its further use as an investigational tool in the evaluation of candidate genes in the genesis of myeloid malignancy.

Development of a Human Acute Myeloid Leukaemia Screening Panel and Identification of Novel Gene Mutations.

High level expression of FLT3 in acute myeloid (AML) and lymphoid (ALL) leukaemias has been demonstrated by PCR techniques. This suggests that FLT3 and its ligand may play a significant role in the proliferation of leukaemic blast cells. Mutations of FLT3 are the most common genetic lesion in AML, occurring in 20–30% of cases, and confer an adverse prognosis. Flow cytometry was used as an alternative method to investigate FLT3 expression in acute leukaemia. Surface expression of FLT3 was measured in 111 bone marrow or peripheral blood samples of patients with AML or ALL using a phycoerythrin-labelled monoclonal IgG1 antibody (Coulter-Immunotech). Exons 14 – 15 and 20 were amplified from DNA extracted from mononuclear cells of 38 of the 111 samples. Internal tandem duplication (ITD) and mutation of the D835 position of the activation loop of FLT3 were identified by SSCP and direct sequencing. 82% (47/57) of AML and 81% (34/42) of B-lineage ALL samples showed ≥ 20% (range, 20 – 97%) positivity for FLT3 using flow cytometry. The Mean Fluorescence Intensity (MFI) was similar between the two groups and no significant difference was found between adult (82%) and paediatric (80%) samples. However, FLT3 expression in all 9 T-ALL samples (pro, intermediate and late subtypes) was negative with markedly reduced MFIs. Of the 25 AML cases tested for ITD/D835Y, 5 (20%) were positive (4 ITDs, 1 D835Y). Surface FLT3 expression in these 5 cases (% and MFI) was the same as in those with wild-type FLT3. No mutations of FLT3 were found in the ALL cases tested (9 B-ALL, 4 T-ALL). Of three biphenotypic leukaemias, one case with myeloid/B lineage positivity was FLT3+ by flow cytometry, while another with myeloid/T lineage markers, was FLT3−. A diagnostic conundrum was a patient with AML morphologically (cytogenetics failed): CD33+, MPO−, CD13− CD117−; T-lineage markers CD2+, CD5+, CD7+, as well as TdT+. The T-lineage specific marker cytoplasmic CD3 was negative. Only FLT3 positivity allowed a definitive diagnosis of AML to be made. In conclusion, surface FLT3 expression was present in > 80% of AML and B-lineage ALL, but in 0% (0/9) of T-ALL cases. Detection of this antigen should be included in the diagnostic immunophenotyping of acute leukaemias and is important where T-ALL needs to be excluded. Flow cytometric FLT3 expression cannot differentiate cases with or without ITD or point mutations of FLT3.

Flow Cytometric FLT3 Expression in Acute Leukaemias Is of Diagnostic Value but Does Not Correlate with ITD / D835Y Mutation Status.

We describe a family in whom three members affected by acute myeloid leukemia (AML) had an identical, 212delC mutation in CEBPA, the gene encoding the granulocytic differentiation factor C/EBPalpha. Unaffected family members did not have this mutation. Latent periods of 10, 18, and 30 years elapsed before the onset of overt leukemia in the three patients. One of them had a second CEBPA mutation, but only at the time of diagnosis. All three patients are currently well, with no abnormalities in the bone marrow. CEBPA mutation is apparently the primary event in the development of AML in this family.

Two siblings (III-1 and III-5) were referred to St Bartholomew’s Hospital for treatment for Acute Myeloid Leukaemia (AML) within the space of 2 weeks. There was a family history of AML (see figure) occurring in their father (II-3). All other family members were alive and well. Patient II-3 was diagnosed with AML in September 1963, aged 10, patient III-1 presented in February 2003, aged 30 and his sister Patient III-5, aged 18 the following week. A diagnosis of AML FAB type M2Eo was made for both III-1 and III-5 and cytogenetic evaluation was normal. Following the diagnosis, patients III-1 and III-5 received 4 courses of combination chemotherapy. Both achieved a complete remission after the first course of therapy and both presented soon after discharge following their final course of therapy with arthralgias, fever and malaise. At that time both patients had raised white counts (28.2 x 10 9 /l and 20.4 x 10 9 /l respectively) in the absence of overt sepsis and off G-CSF. The abnormalities in both patients resolved without medical intervention. At the time of writing, both patients are well with normal blood counts over 17 months from diagnosis. Patient III-1 was shown to have a del (C) mutation in CEBPA at nucleotide 212 in DNA extracted from a peripheral blood sample taken at diagnosis. The corresponding protein, S21fsX158, is predicted to terminate prematurely at codon 158. III-5 was also noted to have an identical del (C) mutation in her diagnostic sample. DNA extracted from their remission peripheral blood samples and germline DNA from buccal swabs, from all 3 affected individuals, further demonstrated the presence of the del(C) 212 mutation. In this family the CEBPA mutation appears to be fully penetrant: AML developed in all carriers of the 212 del(C) mutation, identified. The long latency period (10 years - II-3, 18 years - III-5 and 30 years - III-1) suggests that one or more additional mutations is necessary for the development of overt acute leukaemia. Mutation analysis was extended to include several other genes implicated in the development of AML ( KRAS , NRAS , KIT , PTPN11 , FLT3 and RUNX1 ), but no mutations were identified other than a second CEBPA mutation (duplication of nucleotides 1050 to 1085) on the other allele in patient III-1. Direct sequencing of CEBPA from DNA extracted from peripheral blood mononuclear cells from seven healthy family members (including II-1, II-2, III-2 and III-3) confirmed the presence of wild-type sequence in each case. In summary this study describes a family with familial CEBPA mutation associated with AML and having a putative regeneration syndrome following completion of therapy. All 3 affected individuals had been previously well with no prior medical history and no obvious dysmorphism. CEBPA mutation did not therefore appear to be part of a syndrome, such as FPD/AML seen with RUNX1 mutation. However, the resultant leukaemias did appear to be similar with myeloblastic morphology, normal cytogenetics, aberrant CD7 expression and the presence of Auer rods. This observation may enable other kindreds with similar phenotype to be selectably screened for CEBPA mutation.

The Wiskott-Aldrich-Syndrome family member 1 (WASF1) gene on 6q21 is down-regulated in specific AML cytogenetic subtypes.

CEBPA encodes the transcription factor C/EBPα and is specifically up‐regulated during granulocytic differentiation. The gene is mutated in approximately 20% of patients with acute myeloid leukemia (AML) FAB type M2 and occurs in the absence of the t(8;21). In much the same way as specific translocations are associated with a particular AML FAB type, the identification of non‐random associations of gene mutation with karyotype or FAB type may be helpful in elucidating the molecular basis of certain forms of leukemia. To confirm these initial findings, 99 patients with AML FAB type M1 or M2 were screened for CEBPA mutations by use of a PCR–single‐strand conformational polymorphism and sequencing approach. Nine CEBPA mutations were identified in eight patients. The mutations were clustered toward the COOH terminal of the protein and occurred exclusively in the intermediate cytogenetic risk group (8/64, 12.5%). Two patients with biallelic mutation, one homozygous for 1137Ins (57 bp) and another with two CEBPA mutations, 1096Ins (27 bp) and 363Ins (GGCC), were observed. There was no evidence for deletion of this region in the other six mutated samples analyzed by fluorescence in situ hybridization with a BAC clone spanning the CEBPA locus. CEBPA mutation status was not demonstrated to be of prognostic importance in this patient group, although this may reflect the selection and size of the AML population studied. In conclusion, mutation of CEBPA is a recurrent finding in AML and appears specific to the intermediate cytogenetic risk group patients. © 2003 Wiley‐Liss, Inc.

Mutations of CEBPA in acute myeloid leukemia FAB types M1 and M2

Mutations in the runt homology domain of CBFalpha2 in myeloid malignancies with acquired trisomy 21.

understandings of the agreements through which reliance systems come to be, and are sustained and developed, are insufficient. All well and geographical, but whenever so much comes to rest on grounded deliberation and agreement (of some form, however contested), reservations unhelpfully nag away; power, co-option, capture, misrecognition, bland consensus, exhaustion. All the more so when the spatial contract is described as a ‘nested and constantly evolving series of collective settlements’ (p. 40), fine conceptually, but practically deeply involved; and six principles for a ‘healthy social contract’ are outlined, all hard to disagree with, but suggesting a policing of what grounded deliberation may deem constitutes ‘an agreement’. First and foremost though an intellectual and analytical framework is proposed, assertively laying down a normative proposition and an approach to analysing reliance systems, starting from how they already are, in order to ‘build healthier systems’ from the bottom up. Some may well find their explicit rejection of political ideology and dramatic change problematic. But ‘retrofitting is the only revolution that doesn’t threaten people’s capacities to lead their lives’ (p. 79) is a rather nicely expressed endorsement of the materiality of reformism, which I found hard to refute. On the other hand with so much in the mix, fractures open up. Seeing like a system (chapter 2) I found hard to reconcile with seeing like a settlement (chapter 3) and begs questions about what spatial contracts would then be oriented to. Positioning, in the final chapter, the universal basic income as one of two examples of the ‘spatial contract in practice’ also for me undermined some key propositions made earlier, in particular in relation to the essential materiality of reliance systems as tangible things in the built environment, and the grounding of the spatial contract in place. But there is a compelling and accessible narrative here, with a political relevance that readily resonates, for example, with the substance of the climate emergency and to inequalities in experiences of Covid-19. Gordon Walker Lancaster University, UK IV Reliance Systems and the Contingencies of Human Freedom: Author Response The kind words and insightful criticisms the symposium authors offered for The Spatial Contract are both generous and generative. They give us hope that future readers will find the book to rate highly on what Gordon Walker refers to as their ‘useful-ometer’. The Spatial Contract is above anything else a framework, and frameworks are designed to be useful. 6 Progress in Human Geography XX(X Book review symposium 1737 institutional form, a push-back against currents of individualism in both their neoliberal and frugal self-reliance forms. Arguments are strongly made. That reliance systems are the primary purpose of politics, in our recent experience exploitative, destructive, unsustainable, but also transformative and progressive, something crucial to argue for and argue over. And there are some nice distinctions between the material and functional components of reliance systems, and their dynamics are stressed rather than their inertia, echoing conceptualizations of relations between infrastructure and practice. So, I could imagine working with the idea of reliance systems, even if it’s not a language to capture the political imagination. The core idea of the spatial contract was, in the end, a bit less persuasive, early on described as a ‘politics of provisioning for human agency’ (a rather circular phrase) and not helped by the deficiencies and dangers of Hobbes’ social version. But I swung again from cool to mildly warm as it emerged as a sort of grounded version of the social contract, retaining the notion of formal and informal agreement (from the ground up), but emphasizing the specificities of history and geography that mean that general, abstract understandings of the agreementsunderstandings of the agreements through which reliance systems come to be, and are sustained and developed, are insufficient. All well and geographical, but whenever so much comes to rest on grounded deliberation and agreement (of some form, however contested), reservations unhelpfully nag away; power, co-option, capture, misrecognition, bland consensus, exhaustion. All the more so when the spatial contract is described as a ‘nested and constantly evolving series of collective settlements’ (p. 40), fine conceptually, but practically deeply involved; and six principles for a ‘healthy social contract’ are outlined, all hard to disagree with, but suggesting a policing of what grounded deliberation may deem constitutes ‘an agreement’. First and foremost though an intellectual and analytical framework is proposed, assertively laying down a normative proposition and an approach to analysing reliance systems, starting from how they already are, in order to ‘build healthier systems’ from the bottom up. Some may well find their explicit rejection of political ideology and dramatic change problematic. But ‘retrofitting is the only revolution that doesn’t threaten people’s capacities to lead their lives’ (p. 79) is a rather nicely expressed endorsement of the materiality of reformism, which I found hard to refute. On the other hand with so much in the mix, fractures open up. Seeing like a system (chapter 2) I found hard to reconcile with seeing like a settlement (chapter 3) and begs questions about what spatial contracts would then be oriented to. Positioning, in the final chapter, the universal basic income as one of two examples of the ‘spatial contract in practice’ also for me undermined some key propositions made earlier, in particular in relation to the essential materiality of reliance systems as tangible things in the built environment, and the grounding of the spatial contract in place. But there is a compelling and accessible narrative here, with a political relevance that readily resonates, for example, with the substance of the climate emergency and to inequalities in experiences of Covid-19. Gordon Walker Lancaster University, UK IV Reliance Systems and the Contingencies of Human Freedom: Author Response The kind words and insightful criticisms the symposium authors offered for The Spatial Contract are both generous and generative. They give us hope that future readers will find the book to rate highly on what Gordon Walker refers to as their ‘useful-ometer’. The Spatial Contract is above anything else a framework, and frameworks are designed to be useful. 6 Progress in Human Geography XX(X) The book was released in March 2020, and within 2 months the coronavirus pandemic and the murder of George Floyd altered our lives and our perspectives. These terrible events, which were compounded by the looming climate disaster, have sadly only made a core claim of the book more relevant: we must start seeing our politics in terms of the reliance systems that realize our basic freedoms and essential life functions. This means understanding, for example, the right to health in terms of personal protective equipment (PPE) supply chains or understanding the right to safety in terms of policing systems instead of only police officers. ‘Seeing like a system’ helps us appreciate where injustices emerge, and how we might address them. Understanding these systems in relation to settlements – ‘seeing like a settlement’ – reveals starkly how systems like healthcare and policing touch down in places in radically different ways. While it may seem obvious that reforming policing in Minneapolis is not the same as reforming policing in Oakland, and that fixing one city’s policing system isn’t the same as reducing gross differences in Covid death, we hope that the book provides useful tools to analyse systems and settlements, and to understand both better. Systemic racism may be part of inequality in most settlements and most systems, but they are ultimately systems of different racisms we need to unpack if we are to make real change. As multiple authors point out, this sort of language often is too abstract. We agree. A core challenge to demonstrating the value of the Spatial Contract is to develop more detailed applications of the model to a heterogeneous range of concrete cases. To rectify this would require several lengthy studies. In this short space, we offer a sketch of one application to a capacity the recent pandemic has shown to be very important – the capacity to test for SARSCoV-2 infection. From a spatial contract perspective, this capacity is realized in a complex reliance system. It is not centred on any one person or any one tool. For example, in the case of reverse transcription-polymerase chain reaction (RT-PCR) tests, there is, from our point of view, no such thing as a test, full stop. This may seem paradoxical. But it’s not. Rather there are swabs, the collection kits, technicians who assist in collecting and others who process the sample, machines that do the processing, the labs housing those machines, those labs’ heating, ventilation, and air conditioning (HVAC) and biocontainment systems, the data collection equipment and so on. All of these, conceived diachronically and not synchronically, must operate in a complex dance in order for someone to have the effective capacity to administer a single RT-PCR test. Even this sketchy analysis drives us away from an idealized, abstract conception of a SARS-CoV-2 test to a materially and socially realized conception of the capacity to test for infection. The book argues that using this model avoids the mistake of conceiving of phenomena as distinct as mass transit and healthcare as somehow discrete abstracta, and instead facilitates conceiving of them as geographically, historically and socially contextualized systems that evolve in time. The book also argues that this approach reveals the complex ways in which retrofitting existing systems can expand certain rights, such as, for examp

Agency, capabilities and geographical politics: A book review symposium

The spatial contract: A new politics of provision for an urbanized planet

This chapter argues that a constitutive feature of authority over oneself is intentions functioning as content-independent reasons not to reopen deliberations and as content-independent reasons to do as intended. It first argues that deliberations and intentions have certain functional roles, namely, completed deliberations function as reasons to intend, intentions function as reasons not to reopen deliberations about whether to act as intended, and intentions also function as reasons to act as intended. Second, it argues that if any form of authority is possible at all, it must be an agent’s authority over herself. We are, in short, authorities over ourselves and we exercise this authority by commanding ourselves to act. These commands are intentions. The chapter concludes that either sound deliberations and the intentions they produce are reasons or there is no such thing as agential authority.

Reliance Structures: How Urban Public Policy Shapes Human Agency

Intentions have been a central subject of research since contemporary philosophy of action emerged in the middle of the twentieth century. For almost that entire period, the approach has been to treat the study of intentions as separate from the study of morality. This essay offers a brief overview of that history and then suggests some ways forward, as exemplified by the essays collected in this volume.

While the Fair Work Act makes it difficult to have costs awarded against a party in general protection matters, it certainly won't help if you're guilty of the same 'sins'.

Workplace law: Parties in glass houses ... Costs in general protection matters

Changes in the prosecution policies of government entities are possible following a recent Supreme Court of Queensland decision.

Workplace law: Employee privacy: Take care when dealing with records

Most sectors of the Australian economy, including the legal sector, are in a period of significant business uncertainty.

Workplace law: The redundancy strategy: Employer obligations and employee entitlements

This thesis concerns epistemic and practical rationality. That is, it is about what to believe and what to do. In Chapter 1, 1 argue that theories of practical rationality should be understood as evaluating decisions as opposed to ordinary sorts of non-mental actions. In Chapter 2, I use the machinery developed in Chapter 1 to rebut 'Money Pump' or 'Diachronic Dutch Book' arguments, which draw conclusions about rational beliefs and preferences from premises about how rational agents will behave over time. In Chapter 3, I develop a new objection to the Synchronic Dutch Book Argument, which concludes that rational agents must have probabilistic degrees of belief in order to avoid predictable exploitation in betting scenarios. Thesis Supervisor: Caspar Hare Title: Associate Professor of Philosophy

Despite a national skills shortage, the Federal Government has announced reform of subclass 457 visas in a tightening of laws for employment of international workers. Matthew Smith explains what this could mean for your clients.

Workplace law: 457 unlucky for some?: Visa reforms may threaten business viability

I t is common to talk about options, where an option is a course of action an agent can take. A course of action, in turn, is that which can be the object of intention. For example, the infinitives in the following three cases pick out courses of action: I intend to have a beer; I intend to get a job at the mill; I intend to join the union. Talk of options occurs in the context of discussions of agency, judgments about what rationality requires, assessments of what we have most reason to do, accounts of what morality requires, and so it is found throughout philosophy of action, theories of practical reason, moral theories, etc. It has not often been noticed in this literature (in fact, as far as I can tell it has never been noticed) that there are two ways to understand what makes something an option: first, an option just is some course of action physically open (or, to be maximally liberal, logically open) to an agent; second, an option just is some course of action that the agent either in fact deliberates about taking or is psychologically capable of deliberating about taking.1 Let us, for the moment, dub the first kind of option an external option and the second kind of option an internal option. At any given time, there are far more external options open to an agent than the agent is psychologically capable of deliberating about taking or actually does deliberate about taking. Even if we fixed an otherwise normal agent’s ends and fixed his attitudes towards his ends such that the ends stood in transitive preference relations to one another, and even if that agent was a maximally consistent and coherent practical reasoner, there would still remain many more means to achieving all the agent’s ends than the (otherwise normal) agent in

Consider norms of war that do not follow from independent moral standards. For example, an independent moral standard might be that killing an innocent person is impermissible, but a norm of war might be that killing a noncombatant is impermissible. A further norm of war would stipulate the conditions that must be met for someone to be a noncombatant. And so on.

This paper has a two-pronged thesis. First, laws should be understood as making factual claims about the moral order. Second, the truth or falsity of these claims depends as much on the content of the law as on whether the lawmaker has political authority. In particular, laws produced by legitimate authorities are successful as laws when they guide subjects' behavior by giving subjects authoritative reasons for action. This paper argues that laws produced by legitimate authorities accomplish this task (i) by being on their own sufficient to change the moral state of affairs, which (ii) thereby generates for people new moral reasons to act that they can read right off of the legislation.

WHAT is the moral significance of terrorism? To answer this question, I begin with the following assumptions, for which I offer no argument: all acts of terrorism are morally objectionable and there is at least one (non-moral) feature that makes all acts of terrorism morally objectionable (that is, all acts of terrorism are morally objectionable in at least one and the same way). This does not rule out the possibility that some acts of terrorism may be morally permissible or even morally required. Permissible and obligatory acts may nonetheless fail to be morally “pure.” They may have some morally objectionable features. In this way, a terrorist act is like all acts to which “thick” predicates are applicable. For example, all brutal acts are morally objectionable. But there might be cases in which a brutal act is nonetheless excusable or even morally required. A rude comment is always objectionable (although perhaps not morally so), but there might be some cases in which it is excusable to be rude. In such instances, we might say that it is regrettable that such actions had to be taken and we might condemn those who put us in the position to have to resort to such objectionable measures even if they are the same people who are the objects of our morally objectionable act (and we therefore end up in a sense blaming the victim). We might say, with only modest inaccuracy, that good people are being forced to do bad (which is to say, morally objectionable) things. Let us call the ineliminable moral objectionableness of all terrorist acts the special objectionableness of terrorism. So we can put the question addressed in this paper in the following way: What accounts for the special objectionableness

Capturing the Lessons of What Works: An Evaluation and Development Perspective on Neighbourhood Working and Devolution Birmingham

I challenge the following positions in this article. First, I challenge what I take to be the standard philosophical view of revolution, which is (i) that revolution is justifiable only in obvious circumstances not worth theorizing about; and (ii) that a legal right to revolution is, in some sense, incoherent. Second, I challenge what I take to be the dominant philosophical understanding of sovereignty, which is (i) that there cannot be two sovereigns simultaneously governing a single territory; and (ii) that sovereignty is paradigmatically realized in centralized and hierarchical authority structures governing well-defined geographical territories.

A central tenet of positivism is that social practices are at the foundations of law. This has been cashed out in a variety of ways. For example, Austin argues that, among other practices, a habit of obedience to a sovereign is at the foundations of law, and Hart argues that at the foundations of law is the converging attitudes and behaviors of a class of relevant officials. Since Hart, some prominent positivists have employed either David Lewis's analysis of conventions or Michael Bratman's theory of shared cooperative activities to develop new accounts of the social practices that are at the foundations of law, whatever those foundations might be. In this paper, I identify five features characteristic of the Lewisean and Bratmanian models of social facts—models of what I call hypercommittal social practices. I then show that models of social facts that have these features ought not to be used to explain the way in which a social practice is at the foundations the law. I conclude that hypercommittal social practices such as Lewisean conventions or Bratmanian shared activities are not at the foundations of law.

THE LAW AS A SOCIAL PRACTICE: Are Shared Activities at the Foundations of Law?

This technical note is part of a series collaboratively produced by the US Army Corps of Engineers (USACE)–Institute for Water Resources (IWR) and the US Army Engineer Research and Development Center (ERDC). It describes the funding and financing process for the South Bay Salt Pond Restoration Project in San Francisco Bay, California and, like the other technical notes in this series, documents successful examples of funding natural infrastructure projects. The research effort is a collaboration between the Engineering With Nature® (EWN®) and Systems Approach to Geomorphic Engineering (SAGE) programs of USACE. A key need for greater application of natural infrastructure approaches is information about obtaining funds to scope, design, construct, monitor, and adaptively manage these projects. As natural infrastructure techniques vary widely by location, purpose, and scale, there is no standard process for securing funds. The goal of this series is to share lessons learned about a variety of funding and financing methods to increase the implementation of natural infrastructure projects.

Financing natural infrastructure : South Bay Salt Pond Restoration Project, California

ABSTRACT Day, F.P.; Adams, E.C.; Gibala-Smith, L.A.; Graziani, D.J.; McMillan, B.; Sedghi, N.; Shafer, J., and Smith, M., 2018. Determining change in coastal barrier island dune vegetation following a decade of nitrogen fertilization. Nitrogen deposition from agricultural and industrial sources is a threat to terrestrial biodiversity, and impacts are likely to be greatest in nitrogen-deficient systems. The results of a 10 year fertilization treatment on nitrogen-deficient coastal barrier island dunes and the decade following cessation of fertilizer application are reported here. The study objective was to determine the resilience of the dune plant communities. Would these communities return to their former state in terms of density, species composition, and species diversity after nitrogen additions ended, and if so, how rapid was their recovery? Plant density by species and species diversity were determined over a 20 year period from permanent plots established on three different-aged dunes on a Virginia barrier island. Two dominant species responded differently to nitrogen additions. Ammophila breviligulata abundance was enhanced by the additions, and, in most cases, Spartina patens abundance was repressed. On the older Hog Island dunes, the addition of nitrogen over a 10 year period had a dramatic and rapid negative effect on diversity. However, recovery to diversity values observed in the control plots was rapid, beginning almost immediately after nitrogen additions were stopped. The dune vegetation on a Virginia barrier island appears to be quite resilient, as it rapidly recovered from diversity loss after 10 years of nitrogen additions.

Determining Change in Coastal Barrier Island Dune Vegetation Following a Decade of Nitrogen Fertilization

Groundwater Thresholds for Root Decomposition and the Relation to Barrier Island Plant Communities

GROUNDWATER THRESHOLDS FOR ROOT DECOMPOSITION, AND THE RELATION TO BARRIER ISLAND ECOLOGICAL STATE CHANGES Matthew L. Smith Old Dominion University, 2015 Director: Dr. Frank P. Day Barrier islands off the eastern shore of Virginia exhibit distinct habitats that abruptly transition between periodically brackish/freshwater marshes, wooded swales, and sparsely vegetated dunes. There is strong evidence that the plant communities and ecosystem processes occurring in each habitat are primarily influenced by nutrient availability and the distance between two of the three free surfaces: land and freshwater. At the Virginia Coast Reserve-Long Term Ecological Research Site in Virginia, USA, thresholds to belowground decomposition rates were identified by measuring decay of native roots and rhizomes at 32 elevations in relation to mean annual groundwater levels (-0.356 – 1.937 m). Negative exponential decay rates (k = 0.310 –0.915 yr-1) varied according to average distance to the freshwater free surface, with lowest decay occurring in low elevation/anoxic conditions (marsh, and bottom soils of a wooded swale), and the highest decay occurring at mid to high elevations (upper soils in wooded swales and all dune sites). The majority of variance in decay rates can be explained by mean annual depth to the freshwater free surface (r2 = 0.78). Locations with mean annual groundwater depths greater than 1 m appear substantially less affected by fluctuations in groundwater levels (r2 = 0.09) than locations nearer to groundwater (r2 = 0.83). Belowground decay was more rapid from 0-20 cm compared to 20-40 cm (p < 0.05) and was divided into 3 groups (low, moderate, and high decay) that correspond to the three interior barrier island ecological states. Results from this study indicate a strong relationship between decay rate dependence on groundwater levels and state changes on a barrier island.

Groundwater thresholds for root decomposition and the relation to barrier island ecological state changes

Abstract Murphy MH, Gandino CJ, Ringler NH, Kirby L, Johnson S, Smith M, Schroeder S. 2015. Assessment of the Onondaga Lake, New York, fish community following reductions of nutrient inputs from a wastewater treatment plant. Lake Reserv Manage. 31:347–358. Fish surveys have been periodically conducted on Onondaga Lake since 1927; more intensive surveys began in 1989 by the State University of New York, College of Environmental Science and Forestry, and have continued annually. Recent efforts (2000–2012) by the Onondaga County Department of Water Environment Protection documented the fish community prior to and following (post-2005) major reductions in nutrient loading to Onondaga Lake from the wastewater treatment facility in Syracuse, New York. These upgrades have had dramatic effects on the lake fish community; adult species richness has increased from 13 species recorded in 1946 to more than 40 species documented annually since 2008 and more than 50 species documented since 2000. Adult species diversity has varied since 2000, with increasing dominance by largemouth bass, yellow perch, and brown bullhead. Adult fish diversity was significantly higher following wastewater treatment plant upgrades in 2004 and 2005 (F1,18 = 5.26, P = 0.03). Dramatic increases in macrophyte coverage and dreissenid mussel densities also have been documented. Rarefaction analysis was conducted to standardize survey results by computing expected species richness values from 2000 to 2012 as well as relative to 1946. Expected species richness was not statistically significant following upgrades compared to prior (F1,23 = 3.81; P = 0.075). Linear regression of expected species richness showed a significant increasing trend for the 2002–2012 gillnet data (ES52 = 0.391*YEAR + 67.66, r2 = 0.59, P < 0.006) and the 1946–2012 trap net data (ES164 = 0.203*YEAR + 4.44, r2 = 0.81, P < 0.005). The Onondaga Lake fish community is still adapting to the various water quality changes, and continued monitoring is necessary to understand the trophic structure of the lake and how this may affect sportfishing opportunities in the future.

Assessment of the Onondaga Lake, New York, fish community following reductions of nutrient inputs from a wastewater treatment plant

Remapping Persian Literary History, 1700–1900. Kevin L. Schwartz (Edinburgh: Edinburgh University Press, 2020). Pp. 233. $100.00 hardcover. ISBN 9781474450843

In the winter of 1778, an earthquake shattered the city of Kashan. Three poets, Āẕar, Hātef, and Sabāhi, responded to the disaster in verse. Although all three are commonly associated with the Bāzgasht-e adabi (Literary Return) school that championed the style of an earlier era, their poems display an affinity with more contemporary Safavid poetry, particularly that of Mohtasham Kāshāni. In their responses to the earthquake, the poets acted as agents of social order, helping their audience to cope with their loss by putting the calamity into more familiar religious and cultural contexts (such as comparisons to the death of Emām Hoseyn at Karbalāʾ) and enabling them to move forward into the future.

Betrayed by Earth and Sky: Poetry of Disaster and Restoration in Eighteenth-Century Iran

PEDAGOGICAL EFFICACY AND STUDENT SPATIAL ABILITY CONCERNING THE AR SANDBOX: A STUDY DESIGN

APPLYING COGNITIVE SCIENCE FINDINGS TO THE REDESIGN OF A PALEONTOLOGY COURSE FOR NON-MAJORS

Moving toward the Modern: The Nationalist Imagery of Malik al‑Shu‘arā Bahār

INCREASING CLIMATE CHANGE LITERACY IN NON-GEOLOGY UNDERGRADUATE MAJORS AT THE UNIVERSITY OF KANSAS

The bāzgasht-e adabi (literary return) school is generally portrayed in modern historical studies as a reaction to the so-called sabk-e Hendi (Indian style) of poetry, which is said to have dominated Persian letters during the reign of the Safavids. Much of the terminology we use to discuss this movement— sabk, for instance—as well as the qualitative arguments are taken directly from scholars of the early twentieth century, and from Malek al-Sho'arā' Mohammad Taqi Bahār (d. 1951), who coined the phrase bāzgasht-e adabi, in particular. Despite the pivotal role with which the bāzgasht poets are credited, their work is little studied and the influence of twentieth century nationalism on our conception of these poets and their place in literary history is not clearly understood. By exploring the complex social ties among the earliest representatives of the school, we gain a deeper understanding of the motivations and methods of transmission among the poets beyond the framework which a nationalistic approach provides.

Literary Connections: Bahar's Sabkshenasi and the Bazgasht-e Adabi

Literary courage : language, land and the nation in the works of Malik al-Shuʿār ā Bahar

It is a sad fact, or perhaps a happy one, that many geoscientists in academia will find themselves in front of a classroom of 100–300 undergraduate nonscience majors, lecturing to them for three hours per week. Whether it is ‘Rocks for Jocks’ or ‘Waves for Babes,’ students often are under the impression that geoscience classes will be the least painful way to fulfill their science credit requirements. The sense of personal anonymity that can accompany large-enrollment classes often results in a different level of student engagement compared with smaller classes. Thus, if students are physically present at all, instructors often have only their much-divided attention. How can professors keep 300 students, even the ones in the back of the classroom who are barely visible, awake and engaged?

856: Assessing Satisfaction and Side Effects With NSAIDs vs. Opioids in Postoperative Pediatric Patients

1279: Iatrogenic Heart Failure Secondary to Cardiac Catheterization-Induced Arteriovenous Fistula

INTRODUCTION: We report a novel attempt to relieve venous cannula outflow obstruction utilizing temporary dialysis catheters connected to a continuous renal replacement therapy (CRRT) circuit to provide alternative venous return METHODS: A 57-year-old male with a history of type 2 diabetes was diagnosed with SARS-COV-2 at an outside hospital He required intubation and mechanical ventilation He continued to have declining respiratory function and was transferred for veno-venous ECMO support The inflow cannula was placed in the left femoral vein and the outflow cannula in the right femoral vein On ECMO day 2 the patient was noted to have edema of the left lower extremity (LLE) concerning for thrombosis and/or venous outflow obstruction from the ECMO cannula This continued to worsen, and by ECLS day 5 the patient's LLE began to show signs of phlegmasia cerulea dolens As such, we were forced with the decision to either attempt to relieve the obstruction or decannulate the patient The vascular surgery team was consulted to assist In our institution, we prefer to extubate or perform tracheostomy while still on ECMO Therefore, we attempted to relieve the obstruction first The vascular surgeons elected to place two temporary dialysis catheters: one in the left lesser saphenous vein and one in the right internal jugular vein The catheters were then connected using a CRRT circuit The goal was to provide additional venous drainage for the LLE using the CRRT circuit to pump and filter before returning the blood to the right atrium Unfortunately, we were not able to generate the blood flows necessary for the CRRT circuit to function We then attempted to make a direct connection between the two catheters with standard intravenous tubing hoping that the pressure in the venous system in the LLE would be high enough to let blood flow through the tubing without the assistance of a pump This worked initially, but the IV tubing eventually clotted Ultimately, the decision was made to decannulate the patient and transition to more aggressive ventilator strategies RESULTS: We may attempt this again in the future to relieve outflow obstruction However, only if it is possible to use a larger vein for the outflow catheter to generate the requisite flows

1023: Attempt to Relieve Venous Outflow Obstruction During VV ECMO With a CRRT Circuit

Paradoxical hypotension is an unrecognized risk of push-dose epinephrine overdose.

This research focused on the metabolic costs associated with squatting to failure and squatting to failure with blood flow restriction cuffs. Each individual training program lasted a total of three weeks; consisting of two training days per week. Two groups were used for this study; proximal occlusion of legs and non-occluded legs. The occlusion group left the cuffs on until their final set was complete and pressure was maintained at 140 mmHg. The final session was monitored by a metabolic cart which recorded oxygen consumption levels throughout the workout. Oxygen consumption levels can be used to estimate aerobic costs, which can be combined with anaerobic cost estimates to produce a total metabolic cost profile for this squatting to failure program.

Metabolic Costs of Blood Flow Restriction Training Under Moderate Load to Failure

Matthew Smith of Nantwich Veterinary Group invites Companion readers to consider a lethargic English Springer Spaniel.

Adult supraglottitis is a serious and potentially life-threatening condition, characterised by inflammation of the supraglottic structures of the larynx, namely the arytenoids, the false vocal cords, the laryngeal ventricles, the aryepiglottic folds and the epiglottis. This condition presents a diagnostic challenge owing to the non-specific nature of the clinical presentation. Patients with supraglottitis can rapidly develop airway compromise due to swelling of the supraglottic structures, potentially leading to respiratory arrest. In infective cases of supraglottitis, the infection can spread to adjacent structures, resulting in parapharyngeal abscess, epiglottic abscess or Lemierre Syndrome (thrombosis of the internal jugular vein).

Although the incidence of supraglottitis has decreased in children since the introduction of the Haemophilus influenza type B (HiB) vaccine, most epidemiological studies suggest the incidence in adults has stayed the same1 or increased,2 with figures for the annual incidence varying from 1.1 to 4.7 per …

The British journal of general practice : the journal of the Royal College of General Practitioners

Adult supraglottitis: a potential airway emergency that can present in primary care.

A 41 year old professional bodybuilder presented with worsening dysphagia and regurgitation. Neck examination and flexible nasolaryngoscopy were unremarkable, but …

Response to Angoulvant et al.: Acute purulent pericarditis in childhood: don’t forget β-haemolytic group-A Streptococcus

1st-3rd Year Division.Runner Up.Faculty Mentor: Robert Beckstead.Librarian Mentor: Jacquie Houston

Determination of virulence factors associated with histomas melagridis in blackhead disease in gallinaceous birds

Regional importance of Alnus pollen as an aeroallergen: a comparative clinical and aeropalynological study of Worcester (UK) and Poznan (Poland) regions

Untargeted lipidomics has previously been applied to the study of daphnids and the discovery of biomarkers that are indicative of toxicity. Typically, liquid chromatography—mass spectrometry is used to measure the changes in lipid abundance in whole-body homogenates of daphnids, each only ca. 3 mm in length which limits any biochemical interpretation of site-specific toxicity. Here, we applied mass spectrometry imaging of Daphnia magna to combine untargeted lipidomics with spatial resolution to map the molecular perturbations to defined anatomical regions. A desorption electrospray ionization—mass spectrometry (DESI-MS) method was optimized and applied to tissue sections of daphnids exposed to bisphenol-A (BPA) compared to unexposed controls, generating an untargeted mass spectrum at each pixel (35 µm2/pixel) within each section. First, unique lipid profiles from distinct tissue types were identified in whole-body daphnids using principal component analysis, specifically distinguishing appendages, eggs, eye, and gut. Second, changes in the lipidome were mapped over four stages of normal egg development and then the effect of BPA exposure on the egg lipidome was characterized. The primary perturbations to the lipidome were annotated as triacylglycerides and phosphatidylcholine, and the distributions of the individual lipid species within these classes were visualized in whole-body D. magna sections as ion images. Using an optimized DESI-MS workflow, the first ion images of D. magna tissue sections were generated, mapping both their baseline and BPA-perturbed lipidomes.

Spatially Mapping the Baseline and Bisphenol-A Exposed Daphnia magna Lipidome Using Desorption Electrospray Ionization—Mass Spectrometry

Abstract Poly- and perfluoroalkyl substances (PFAS) are chemically and thermally stable, hydrophobic, lipophobic compounds used in stain repellants and water and oil surfactants, and associated with immunosuppression and peroxisome proliferator activity. Perfluoro-n-decanoic acid (PFDA, (CF3(CF2)8COOH), a fluorinated straight chain fatty acid compound, is reported to induce thymic atrophy and reversible bone marrow hypocellularity in rodent models. The objective of this study was to assess potential immunotoxicity of PFDA, due to its structural similarity to other immunosuppressive PFASs. Female Harlan Sprague–Dawley rats were exposed to 0–2.0 mg PFDA/kg by oral gavage daily for 28 d. Female B6C3F1/N mice were exposed once/week to 0–5.0 mg PFDA/kg by gavage for 4 weeks. Animals were evaluated for effects on immune cell populations in spleen and bone marrow, and innate, humoral-, and cell-mediated immunity. Mice were also evaluated for resistance to Influenza virus. Treatment-related hepatocyte necrosis and hepatomegaly were observed in rats treated with 0.5 mg PFDA/kg/d. In mice, hepatomegaly (26–89%) was observed following exposure to ≥0.625 mg PFDA/kg/week, while splenic atrophy (20%) was observed at 5.0 mg PFDA/kg/week. At 5.0 mg PFDA/kg/week, total spleen cells, and Ig + and NK + cells were decreased (17.6–27%). At ≥ 1.25 mg PFDA/kg/week the numbers of splenic CD3+, CD4+, CD8+, and Mac3+ cells were decreased (10.5–39%). No changes were observed in leukocyte subpopulations in PFDA-exposed rats. Phagocytosis by fixed-tissue macrophages was decreased in liver (specific activity, 24–39%) at ≥0.25 mg PFDA/kg/d in rats. PFDA-induced effects on humoral- and cell-mediated immunity, host resistance, and bone marrow progenitor cells were limited. These data suggest that exposure to PFDA may induce adverse effects in rat liver in a manner consistent with the PFAS class, and may also alter the balance of immune cell populations in lymphoid tissues in mice.

Immunotoxic and hepatotoxic effects of perfluoro-n-decanoic acid (PFDA) on female Harlan Sprague–Dawley rats and B6C3F1/N mice when administered by oral gavage for 28 days

Abstract Sodium dichromate dihydrate (SDD), an inorganic compound containing hexavalent chromium (Cr(VI)), is a common environmental contaminant of groundwater sources due to widespread industrial use. There are indications in the literature that Cr(VI) may induce immunotoxic effects following dermal exposure, including acting as both an irritant and a sensitizer; however, the potential immunomodulatory effects of Cr(VI) following oral exposure are relatively unknown. Following the detection of Cr(VI) in drinking water sources, the National Toxicology Program (NTP) conducted extensive evaluations of the toxicity and carcinogenicity of SDD following drinking water exposure, including studies to assess the potential for Cr(VI) to modulate immune function. For the immunotoxicity assessments, female Fischer 344/N (F344/N) and Sprague Dawley (SD) rats and female B6C3F1 mice were exposed to SDD in drinking water for 28 consecutive days and evaluated for alterations in cellular and humoral immune function as well as innate immunity. Rats were exposed to concentrations of 0, 14.3, 57.3, 172, or 516 ppm SDD while mice were exposed to concentrations of 0, 15.6, 31.3, 62.5, 125, or 250 ppm SDD. Final mean body weight and body weight gain were decreased relative to controls in 250 ppm B6C3F1 mice and 516 ppm SD rats. Water consumption was significantly decreased in F344/N and SD rats exposed to 172 and 516 ppm SDD; this was attributed to poor palatability of the SDD drinking water solutions. Several red blood cell-specific parameters were significantly (5–7%) decreased in 250 ppm mice; however, these parameters were unaffected in rats. Sporadic increases in the spleen IgM antibody response to sheep red blood cells (SRBC) were observed, however, these increases were not dose-dependent and were not reproducible. No significant effects were observed in the other immunological parameters evaluated. Overall, exposure to Cr(VI) in drinking water had limited effects on the immune system in both rats and mice.

Assessment of immunotoxicity in female Fischer 344/N and Sprague Dawley rats and female B6C3F1 mice exposed to hexavalent chromium via the drinking water

Abstract C60 fullerene (C60), or buckminsterfullerene, is a spherical arrangement of 60 carbon atoms, having a diameter of approximately 1 nm, and is produced naturally as a by-product of combustion. Due to its small size, C60 has attracted much attention for use in a variety of applications; however, insufficient information is available regarding its toxicological effects. The effects on respiratory toxicity and immunotoxicity of C60 aggregates (50 nm [nano-C60] and 1 μm [micro-C60] diameter) were examined in B6C3F1/N mice and Wistar Han rats after nose-only inhalation for 13 weeks. Exposure concentrations were selected to allow for data evaluations using both mass-based and particle surface area-based exposure metrics. Nano-C60 exposure levels selected were 0.5 and 2 mg/m3 (0.033 and 0.112 m2/m3), while micro-C60 exposures were 2, 15 and 30 mg/m3 (0.011, 0.084 and 0.167 m2/m3). There were no systemic effects on innate, cell-mediated, or humoral immune function. Pulmonary inflammatory responses (histiocytic infiltration, macrophage pigmentation, chronic inflammation) were concentration-dependent and corresponded to increases in monocyte chemoattractant protein (MCP)-1 (rats) and macrophage inflammatory protein (MIP)-1α (mice) in bronchoalveolar lavage (BAL) fluid. Lung overload may have contributed to the pulmonary inflammatory responses observed following nano-C60 exposure at 2 mg/m3 and micro-C60 exposure at 30 mg/m3. Phenotype shifts in cells recovered from the BAL were also observed in all C60-exposed rats, regardless of the level of exposure. Overall, more severe pulmonary effects were observed for nano-C60 than for micro-C60 for mass-based exposure comparisons. However, for surface-area-based exposures, more severe pulmonary effects were observed for micro-C60 than for nano-C60, highlighting the importance of dosimetry when evaluating toxicity between nano- and microparticles.

Respiratory toxicity and immunotoxicity evaluations of microparticle and nanoparticle C60 fullerene aggregates in mice and rats following nose-only inhalation for 13 weeks

Abstract Tungsten is a naturally occurring, high-tensile strength element that has been used in a number of consumer products. Tungsten has been detected in soil, waterways, groundwater, and human tissue and body fluids. Elevated levels of tungsten in urine were reported for populations exposed to tungstate in drinking water in areas where natural tungsten formations were prevalent. Published reports indicated that sodium tungstate may modulate hematopoiesis, immune cell populations, and immune responses in rodent models. The objective of this study was to assess potential immunotoxicity of sodium tungstate dihydrate (STD), a drinking water contaminant. Female B6C3F1/N mice received 0–2000 mg STD/L in their drinking water for 28 d, and were evaluated for effects on immune cell populations in spleen and bone marrow, and humoral-mediated, cell-mediated, and innate immunity. Three different parameters of cell-mediated immunity were similarly affected at 1000 mg STD/L. T-cell proliferative responses against allogeneic leukocytes and anti-CD3 were decreased 32%, and 21%, respectively. Cytotoxic T-lymphocyte activity was decreased at all effector:target cell ratios examined. At 2000 mg STD/L, the absolute numbers of CD3+ T-cell progenitor cells in bone marrow were increased 86%, but the alterations in B-lymphocyte and other progenitor cells were not significant. There were no effects on bone marrow DNA synthesis or colony forming capabilities. STD-induced effects on humoral-mediated immunity, innate immunity, and splenocyte sub-populations were limited. Enhanced histopathology did not detect treatment-related lesions in any of the immune tissues. These data suggest exposure to STD in drinking water may adversely affect cell-mediated immunity.

Immunotoxic effects of sodium tungstate dihydrate on female B6C3F1/N mice when administered in drinking water

The objective of this study was to determine the effects of the phytoestrogen genistein (GEN) on the time of onset and/or the incidence of type 1 diabetes (T1D) in female nonobese diabetic (NOD) mice, when administered GEN by gavage once every day for up to 180 days. Five groups of mice (approximately 24 animals/group; 6–7 weeks of age) were included: naive control, vehicle control (25 mM Na2CO3 in water), and 3 GEN treatment groups (2 mg/kg, 6 mg/kg, and 20 mg/kg). Mice were maintained on a soy- and alfalfa-free diet (5K96) during the study and were monitored for blood glucose changes every week. When compared to the vehicle control, exposure to 2-mg/kg GEN produced significant decreases ranging from 55 to 79% in the total incidences of diabetes (blood glucose ≥ 250 mg/dl) and severe diabetes (blood glucose ≥ 400 mg/dl) starting at week 14 of the study. However, during the later stages of the study (i.e., after week 23), the 2-mg/kg dose had no effect on disease incidence. In animals treated with 6-mg/kg and 20-mg/kg GEN, significant decreases in the total incidence of diabetes were observed starting at week 16, while the incidence of severe diabetes was significantly decreased with the changes being observed initially at weeks 18 and 17 for the 6-mg/kg and 20-mg/kg GEN treatment groups, respectively. Several lines of evidence, including histopathological analysis, suggested that GEN protected the pancreas from autoimmune destruction. However, this protective effect of GEN was absent when female NOD mice were maintained on NTP-2000 rodent diet, which contained 5% soybean meal and 7.5% alfalfa meal (the total concentrations of phytoestrogens ranged between 95 and 134 mg/kg). In summary, oral dosing of GEN reduced the incidence and increased the time to onset of T1D in female NOD mice but only when fed a soy- and alfalfa-free diet.

Genistein Protects Female Nonobese Diabetic Mice from Developing Type 1 Diabetes When Fed a Soy- and Alfalfa-free Diet

The potential for human exposure to the diverse and ever-changing world of nanoscale materials has raised concerns about their influence on health and disease. The novel physical and chemical properties of these materials, which are associated with their small size, complicate toxicological evaluations. Further, these properties may make engineered nanomaterials (ENMs) a prime target for interaction with the immune system following uptake by phagocytes. Undesired effects on antigen-presenting cells and other phagocytic cells are of concern due to the high likelihood of ENM uptake by these cells. In addition, ENM interactions with lymphocytes and other cell types can contribute to a varied spectrum of possible effects, including inflammation, hypersensitivity, and immunomodulation. Furthermore, the mast cell (a type of immune cell traditionally associated with allergy) appears to contribute to certain inflammatory and toxic effects associated with some ENMs. Although incidental exposure may be undesirable, nanomedicines engineered for various clinical applications provide opportunities to develop therapies that may or may not intentionally target the immune system. The interaction between ENMs and the immune system and the resulting pharmacokinetic and phenotypic responses are critical factors that dictate the balance between toxicity and clinical efficacy of nanotherapeutics.

Toxicological sciences : an official journal of the Society of Toxicology

From immunotoxicity to nanotherapy: the effects of nanomaterials on the immune system.

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association

Immunomodulatory activity of orphan drug Elmiron® in female B6C3F1/N mice.

The use of brominated flame retardants and incineration of bromine-containing materials has lead to an increase in polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs) in the environment. Measurable amounts of PBDD/Fs have been detected in soil, seafood, and human breast milk and serum. Studies indicate that the relative potencies of some PBDD/Fs based on enzyme induction are equivalent to those of some polychlorinated dibenzo-p-dioxins and dibenzofurans. To assess the humoral immunity relative potencies of PBDD/Fs and compare them to their chlorinated analogs, female B6C3F1/N mice received a single oral exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrabromodibenzofuran (TBDF), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentabromodibenzofuran (1PeBDF), 1,2,3,7,8-pentachlorodibenzofuran (1PeCDF), 2,3,4,7,8-pentabromodibenzofuran (4PeBDF), 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF), 2,3-dibromo-7,8-dichlorodibenzo-p-dioxin (DBDCDD), or 2,3,7-tribromodibenzo-p-dioxin (TriBDD). Inhibition of the immunoglobulin M (IgM) antibody forming cell response was measured 4 days following immunization with sheep red blood cells. The data were fit to a Hill model to estimate the ED50 for inhibition. Expression of xenobiotic metabolizing enzyme (XME) and thyroxine transport protein (Ttr) genes in liver was measured by PCR to assess aryl hydrocarbon-mediated responses. TCDD, TBDF, TCDF, 1PeBDF, 4PeBDF, 4PeCDF, and DBDCDD suppressed the IgM antibody response and Ttr gene expression, and upregulated phase I XME genes. 1PeCDF suppressed the IgM antibody response but only upregulated phase I XME genes; TriBDD had no effect on antibody response. The rank order of potency (ED50) for these chemicals was TCDD>TBDF>4PeBDF>TCDF/4PeCDF/1PeBDF>1PeCDF. Whereas TCDD was the most potent compound tested, the brominated analogs were more potent than their chlorinated analogs, suggesting that these compounds should be considered in toxic equivalency factor evaluation and risk assessment.

Relative potency for altered humoral immunity induced by polybrominated and polychlorinated dioxins/furans in female B6C3F1/N mice.

Abstract Nanoparticle titanium dioxide (nano-TiO2) is a white pigment widely used in foods, sunscreens, and other cosmetic products. However, it remains unclear whether exposure to nano-TiO2 results in immunosuppressive effects or induces a contact hypersensitivity response. To address these data gaps, studies were conducted with the hypothesis that nano-TiO2 exposure could alter immune responses. After 28 days of oral gavage, nano-TiO2 (1.25–250 mg/kg in 0.5% methylcellulose) produced no significant effects on innate, humoral, or cell-mediated immune functions in female B6C3F1 mice. Furthermore, there were no effects on the weights of selected organs (spleen, thymus, liver, lung, and kidneys with adrenals). Following dermal exposure on the ears for 3 days, nano-TiO2 (2.5–10% w/v in 4:1 acetone:olive oil) did not affect auricular lymph node cell proliferation, although an irritancy response was observed following treatment with 5% and 10% nano-TiO2. Dermal sensitization (2.5–10%) on the back and subsequent challenge (10%) on the right ear with nano-TiO2 produced no significant effects on percentage ear swelling in the Mouse Ear Swelling Test (MEST). However, when nano-TiO2 was injected subcutaneously along the mid-line on top of the head at 125–250 mg/kg (in 0.5% methylcellulose), significant increases in auricular lymph node cell proliferation resulted. These results demonstrate that immune effects of nano-TiO2 exposure are route-of-exposure dependent, and they suggest that irritancy and/or potential hypersensitivity responses may occur following parenteral exposure or dermal administration of nano-TiO2 to compromised skin.

Route-dependent systemic and local immune effects following exposure to solutions prepared from titanium dioxide nanoparticles

Abstract Recently, there has been a renewed interest in the use of the minipig as an alternative to dogs and non-human primates for conducting toxicological assessments in non-rodent species. Since the T-dependent antibody response (TDAR) is one of the most widely-accepted assays used in the assessment of immunocompetence, the present study was undertaken to characterize the primary and secondary TDAR to keyhole limpet hemocyanin (KLH) in the Göttingen Minipig®. Following primary immunization with either 2 or 10 mg KLH, anti-swine IgM and IgG ELISAs were optimized and individual animal responses were evaluated over time. Immunization with 10 mg KLH on Day 0 promoted primary IgM responses that peaked 6–9 days after antigen administration, while primary IgG levels peaked on Day 13 or 14. Secondary IgG antibody levels (following secondary injection with 2 mg KLH on Day 14) plateaued on Days 20–22. Anti-KLH antibody levels were decreased in minipigs treated with cyclophosphamide (CPS), a known immunosuppressant, at doses ranging from 12.5–50 mg/kg/day, while antibody levels in animals treated with 2.5 mg CPS/kg/day were similar to levels in saline-treated swine. These results demonstrate that the Göttingen Minipig® can be a useful alternative non-rodent species to the dog and the non-human primate for evaluating the TDAR to KLH in regulatory assessments of immunotoxicity.

Characterization of the T-dependent antibody response (TDAR) to keyhole limpet hemocyanin (KLH) in the Göttingen minipig

Immunomodulatory effects of black cohosh (Actaea racemosa) extract in female B6C3F1/N mice.

Evaluating the Adverse Effects of Nanomaterials on the Immune System with Animal Models

Previous reports indicated that inhalation of JP-8 aviation turbine fuel is immunosuppressive. However, in some of those studies, the exposure concentrations were underestimated, and percent of test article as vapor or aerosol was not determined. Furthermore, it is unknown whether the observed effects are attributable to the base hydrocarbon fuel (jet fuel kerosene) or to the various fuel additives in jet fuels. The present studies were conducted, in compliance with Good Laboratory Practice (GLP) regulations, to evaluate the effects of jet fuel kerosene on the immune system, in conjunction with an accurate, quantitative characterization of the aerosol and vapor exposure concentrations. Two female rodent species (B6C3F1 mice and Crl:CD rats) were exposed by nose-only inhalation to jet fuel kerosene at targeted concentrations of 0, 500, 1000, or 2000 mg/m3 for 6 h daily for 28 d. Humoral, cell-mediated, and innate immune functions were subsequently evaluated. No marked effects were observed in either species on body weights, spleen or thymus weights, the T-dependent antibody-forming cell response (plaque assay), or the delayed-type hypersensitivity (DTH) response. With a few exceptions, spleen cell numbers and phenotypes were also unaffected. Natural killer (NK) cell activity in mice was unaffected, while the NK assessment in rats was not usable due to an unusually low response in all groups. These studies demonstrate that inhalation of jet fuel kerosene for 28 d at levels up to 2000 mg/m3 did not adversely affect the functional immune responses of female mice and rats.

Jet Fuel Kerosene is not Immunosuppressive in Mice or Rats Following Inhalation for 28 Days

Although numerous models are used to evaluate the immunotoxic effects of xenobiotics on cell-mediated immunity (CMI), no holistic model for evaluating such effects on the delayed-type hypersensitivity (DTH) response has gained widespread acceptance. Due to a lack of interference from antigen-specific antibody production, the Candida albicans DTH model has recently been demonstrated to be a more appropriate model for assessing effects on CMI than other DTH models that utilize different sensitizing antigens, such as sheep erythrocytes (SRBC) or keyhole limpet hemocyanin (KLH). The present studies were conducted to validate the C. albicans DTH model for its ability to detect suppression (or the lack thereof) of CMI following exposure for 28 days to well-characterized immunosuppressive drugs, each having a different mechanism of action. The compounds evaluated included azathioprine (AZA), cyclophosphamide (CPS), cyclosporin A (CSA), dexamethasone (DEX), and the non-immunotoxic compound, benzo[e]pyrene (B[e]P). Exposure to each of the four known immunotoxicants resulted in statistically significant decreases in the DTH response to C. albicans. Footpad swelling was decreased following exposure to AZA at ≥ 20 mg/kg but not at 10 mg/kg, CPS at ≥ 10 mg/kg but not at 5 mg/kg, CSA at ≥ 3 mg/kg but not at 1 mg/kg, or DEX at ≥ 0.3 mg/kg (intermittently at 0.1 mg/kg) but not at 0.03 mg/kg. As expected, exposure to B[e]P for 28 days at doses up to 40 mg/kg had no effect on the DTH response. These results demonstrated that the C. albicans DTH assay in the B6C3F1 mouse was capable of appropriately classifying each test article as to its immunotoxic effects on CMI. Furthermore, comparisons of these results with previous reports of effects on ex vivo CMI end points suggest that this DTH assay may be more sensitive than standard ex vivo assays at detecting immunosuppressive effects.

Validation of the Candida albicans delayed-type hypersensitivity (DTH) model in the female B6C3F1 mouse for use in immunotoxicological investigations

Electrospun polycaprolactone (EPCL) is currently being investigated for use in tissue engineering applications such as vascular grafts. However, the effects of electrospun polymers on systemic immune responses following in vivo exposure have not previously been examined. The work presented evaluates whether EPCL in either a microfibrous or nanofibrous form affects innate, humoral and/or cell-mediated immunity using a standard immunotoxicological testing battery. Holistic in vivo endpoints examined include the antibody-forming cell assay (AFC or plaque assay) and the delayed-type hypersensitivity response to Candida albicans. In addition, natural killer cell cytotoxic activity was assessed using an ex vivo assay and splenic cell population phenotypes were analyzed by flow cytometry for material exposure-related changes. Results indicated that 28 day subcutaneous implantation of EPCL, either in microfibrous or nanofibrous form, did not affect the systemic functions of the immune system in 12–16 week old female B6C3F1 mice.

Evaluation of innate, humoral and cell-mediated immunity in mice following in vivo implantation of electrospun polycaprolactone

Monochloramine has been used to provide a disinfecting residual in water distribution systems where it is difficult to maintain an adequate free-chlorine residual or where disinfection by-product formation is of concern. The goal of this study was to characterize the immunotoxic effects of chloramine in female B6C3F1 mice when administered via the drinking water. Mice were exposed to chloramine-containing deionized tap water at 2, 10, 20, 100, or 200 ppm for 28 days. No statistically significant differences in drinking water consumption, body weight, body weight gain, organ weights, or hematological parameters between the exposed and control animals were noted during the experimental period. There were no changes in the percentages and numbers of total B-lymphocytes, T-lymphocytes, CD4+ and CD8+ T-lymphocytes, natural killer (NK) cells, and macrophages in the spleen. Exposure to chloramine did not affect the IgM antibody-forming cell response to sheep red blood cells (SRBC) or anti-SRBC IgM antibody production. Minimal effects, judged to be biologically insignificant, were observed in the mixed-leukocyte response and NK activity. In conclusion, chloramine produced no toxicological and immunotoxic effects in female B6C3F1 mice when administered for 28 days in the drinking water at concentrations ranging from 2–200 ppm.

Immunotoxicological profile of chloramine in female B6C3F1 mice when administered in the drinking water for 28 days

Contact sensitizing potential of annatto extract and its two primary color components, cis-bixin and norbixin, in female BALB/c mice.

Dibromoacetic acid (DBA) is a disinfection by-product commonly found in drinking water as a result of chlorination/ ozonation processes. The Environmental Protection Agency estimates that more than 200 million people consume disinfected water in the United States. This study was conducted to evaluate the potential immunotoxicological effects of DBA exposure when administered for 28 days via drinking water to B6C3F1 mice, at concentrations of 125, 500, and 1000 mg/L. Multiple endpoints were evaluated to assess innate, humoral, and cell-mediated immune components, as well as host resistance. Standard toxicological parameters were unaffected, with the exception of a dose–responsive increase in liver weight and a decrease in thymus weight at the two highest exposure levels. Splenocyte differentials were affected, although the effects were not dose–responsive. Exposure to DBA did not significantly affect humoral immunity (immunoglobulin M [IgM] plaque assay and serum IgM anti-sheep erythrocyte titers) or cell-mediated immunity (mixed-leukocyte response). No effects were observed on innate immune function in either interferon-γ-induced in vitro macrophage cytotoxic activity or basal natural killer (NK)-cell activity. Augmented NK-cell activity (following exposure to polyinosinic-polycytidylic acid) was decreased at the low dose, however the effect was not dose–responsive. Finally, DBA exposure had no effect on resistance to infection with either Streptococcus pneumoniae or Plasmodium yoelii, or challenge with B16F10 melanoma cells. With the exception of changes in thymus weight, these results indicate that DBA exposure resulted in no immunotoxic effects at concentrations much larger than those considered acceptable in human drinking water.

Immunotoxicity of dibromoacetic acid administered via drinking water to female B6C3F1 mice

In light of cell sourcing issues and the lack of a bioreactor comparable to the body, many in the field of tissue engineering have focused their efforts on designing biomaterials capable of in situ regeneration. The theory is that, by using the body as both the bioreactor and the source for cell infiltration, scaffolds composed of bioresorbable materials can be remodeled into native tissue. Thus, research into the effects of such materials on the host immune response is increasingly important. This study applies an immunotoxicological approach to evaluate the effects of electrospun blends of polydioxanone (PDO) and collagen type I on murine innate and acquired immune responses. Results indicated that these materials had few effects on innate immune responses, yet they produced significant immunomodulatory effects in multiple endpoints evaluating both branches of acquired immunity (i.e., cell-mediated and humoral immunity). Specifically, collagen content appeared to be responsible for suppression of cell-mediated immunity, while blends of PDO and collagen appeared to be more suppressive of antibody-forming cell responses than either PDO or collagen alone. These results demonstrate the importance of completing evaluations into the immunotoxicological effects of biomaterials, and they suggest that such testing should become a primary focus when evaluating a material's potential foruse in tissue engineering applications.

Modulation of murine innate and acquired immune responses following in vitro exposure to electrospun blends of collagen and polydioxanone.

1,2:5,6-Dibenzanthracene (DBA) is ubiquitous in our environment as a contaminant produced by incomplete combustion of organics from sources such as forest fires, cigarette smoke, and asphalt paving, and it is more immunosuppressive of the T-dependent antibody-forming cell (AFC) response than the well-studied polycyclic aromatic hydrocarbon, benzo(a)pyrene. The systemic immunosuppressive effects of DBA were investigated following a single pharyngeal aspiration (pa) in female B6C3F1 mice. The immunotoxic effects of DBA were evaluated using numerous assays of varying complexity to evaluate innate (natural killer [NK] cell activity), cell-mediated (T-lymphocyte proliferation, mixed leukocyte response [MLR], cytotoxic T-lymphocyte [CTL] activity, delayed-type hypersensitivity [DTH]), and humoral immunity (B-lymphocyte proliferation, T-dependent antibody responses). A single pa of DBA at doses up to 30 mg/kg had no effect on NK cell activity, anti-CD3 antibody-mediated T-lymphocyte proliferation, the MLR, or B-lymphocyte proliferation. DBA at 30 mg/kg suppressed Concanavalin A (ConA)-stimulated T-lymphocyte proliferation and the CTL response. DBA exposure reduced cytokine production in spleen cell culture supernatants after in vitro stimulation with ConA or lipopolysaccharide (LPS). Immunosuppression was observed at lower doses in the holistic assays. The DTH response to Candida albicans was significantly decreased at 3.0 mg/ kg DBA, while the AFC response was intermittently suppressed at 1.0 mg/kg, with no effect observed at 0.3 mg/kg. These results demonstrate that a single pa of DBA produces systemic immunotoxicity, and of the assays utilized, the holistic assays (i.e., DTH, AFC) appear to be most sensitive to the immunosuppressive effects of DBA.

Systemic immunosuppression following a single pharyngeal aspiration of 1,2:5,6-dibenzanthracene in female B6C3F1 mice

The objective of these studies was to establish and compare delayed-type hypersensitivity (DTH) models, using keyhole limpet hemocyanin (KLH), sheep red blood cells (SRBC), and Candida albicans as sensitizing antigens, for their capability to assess a DTH response (utilizing footpad swelling as the endpoint) with minimal confounding factors resulting from antigen-specific antibody (Ab) production. The key elements of the DTH are the sensitization dose, time interval between sensitization and challenge [i.e. the challenge interval (CI)], and the challenge dose. Models were established by first determining the challenge dose, or the amount of antigen that produced no greater footpad swelling 24-h post-injection than the trauma induced by injection of physiological saline. Time-course studies determined the CI that produced a peak response for each antigen. Dose-response sensitization studies were conducted to determine the optimum sensitization concentration (i.e. maximum footpad swelling with minimal impact by antigen-specific Ab production). Footpad swelling decreased dose-responsively with increasing KLH sensitization concentration and corresponded to a dose-responsive increase in KLH-specific Ab levels. In the SRBC model, footpad swelling decreased at the high dose (1 × 109 SRBC/mouse), and a corresponding increase in SRBC-specific Ab was observed at this dose level. A dose-responsive increase in footpad swelling was observed in the C. albicans model up to 3 × 107 organisms/mouse, while antigen-specific antibody levels were not different from background (unsensitized) levels following sensitization with any concentration of C. albicans (up to 1.2 × 108 organisms/mouse, the highest concentration tested). Finally, each model was evaluated for its ability to detect immunosuppression following exposure to benzo[a]pyrene (B[a]P), with the C. albicans model demonstrating greater sensitivity than the other models. These results indicate that, of the three models examined here, the C. albicans DTH model may be the most appropriate model for evaluating effects on cell-mediated immunity when conducting immunotoxicological investigations.

Establishment and comparison of delayed-type hypersensitivity models in the B6C3F1 mouse

In vitro evaluations of innate and acquired immune responses to electrospun polydioxanone-elastin blends.

The identification of radiative and nonradiative channels and, how these are affected by aggregation, help rationalise emissive properties and aid in the design of yet more efficient ESIPT fluorophores in the condensed phase.

Molecular and crystalline requirements for solid state fluorescence exploiting excited state intramolecular proton transfer

A new nanoparticle sizing and characterization technique is described allowing nanoparticles in a suspension to be individually but simultaneously detected and analysed in real time using a laser-based microscope system. The technique uniquely allows the user a simple and direct qualitative view of the sample under analysis and from which an independent quantitative estimation of sample size, size distribution and concentration can be immediately obtained. Nanoparticles of all types and in any solvent can be detected, sized and counted through video-based tracking of their Brownian motion when illuminated by a specially configured laser beam. Examples of analyses of a wide range of sample types will be shown including nano-emulsions from pharmaceutical and clinical applications and metal oxides and nanoceramics from the chemical, pigments and coatings industries. Novel advances in the technique will be described which allow each particle to be simultaneously analysed not just in terms of its size but also light scattering power (mass/refractive index) and fluorescence from which 3D plots of size v. light scatter or fluorescence can be produced.

Simultaneous, Real-time, Mutli-parameter Analysis of Nanoparticles in Liquids

DOE and FreedomCAR technical targets of 6.0 and 9.0 wt.% are set forth capacities to realize a “holy grail” for hydrogen storage systems for 2010 and 2015 respectively. Alkali metal complex hydrides with high theoretical hydrogen capacity, for example: LiBH4 (18 wt.%), are being investigated for their properties to store large quantities of hydrogen. The catalytic doping of SiO2, seems to enhance the performance of LiBH4. However, the poor cyclic reversibility due to thermodynamic barrier limits their wide usage. Recently, a destabilization mechanism was adopted in order to improve the cycling capacity of LiBH4 by the addition of MgH2. We have successfully synthesized the complex hydride mixtures LiBH4 + 1⁄2MgH2 + Xmol% ZnCl2 catalyst (X=2, 4, 6, 8 and 10) by an inexpensive mechano-chemical process. The structural characterization by X-ray powder diffraction profiles exhibit the presence of LiCl, MgH2 and LiBH4 as majority and minority phases. Besides, the LiCl peaks relative intensity increases with increase of ZnCl2 concentration. The thermal decomposition (gravimetric weight loss) and heat flow measurements have been performed by simultaneous DSC and TGA techniques. An earlier decomposition temperature of 270° C has been observed for the 10mol% ZnCl2 doped LiBH4/MgH2 in comparison to the pristine LiBH4 compound. The pressure-composition-temperature isotherms of the destabilized LiBH4 show an extended plateau pressure around 4-5 bars at 350° C with a good cyclic stability.

Mechanochemical Synthesis, Structural Characterization and Visible Light Photocatalysis of TiO 2 /ZnFe 2 O 4 Nnanocomposites

Synthesis and Characterization of Nanoscale Transition Metal Complex for Hydrogen Storage

ABSTRACT Porous 6H-SiC and 4H-SiC wafers formed by anodization have been characterized in this study prior to and following the CVD deposition of SiC epitaxial layers, using a combination of synchrotron white beam x-ray topography (SWBXT), SEM, TEM and optical microscopy. Under the high temperatures employed during epitaxial growth, a significant change in pore morphology occurs. While no evidence of reduced screw dislocation density in the epilayers is obtained, a small tilt of the epilayers with respect to the porous substrate observed on x-ray topographs could play a role in limiting penetration of defects from the substrate. INTRODUCTION Currently, the application of SiC towards fabricating high temperature, high frequency and high power electronic devices is limited by the quality of SiC epilayers grown on SiC bulk substrates. Recently, a novel growth technique has been discovered to reduce defect density in and improve the quality of SiC epilayers involving their growth on porous SiC (PSC) buffer layers [1,2]. PSC substrates formed by anodization in an electrochemical cell [3] have already been developed for other applications such as power device passivation [4] and room temperature visible luminescence [5]. In SiC epitaxial growth, the porous layer acts as a buffer for defects that are likely to penetrate into the epilayer from the substrate. To better understand the role of porous layers in SiC epitaxial growth, pore structures in PSC substrates (4H & 6H) have been studied before and after epitaxial growth using a number of characterization techniques including SWBXT, SEM and TEM. Preliminary results and analysis are presented here.

Characterization of Porous SiC Substrates and of the Epilayer Structures Grown on Them

This work presents a novel approach to fine-tuning the size, shape, and interparticle spacing of nanoparticles fabricated by nanosphere lithography (NSL). This approach, termed angle-resolved nanosphere lithography (AR NSL), is a variant of NSL that yields vastly different, and increasingly flexible, nanostructures. This is accomplished by controlling the angle, θ, between the surface normal of the sample assembly and the propagation vector of the material deposition beam. Comparison of experimental results to simulated nanoparticle array geometries generated using an analytical model show excellent qualitative agreement. Using AR NSL, we have demonstrated that it is possible to reduce in-plane nanoparticle dimensions by a factor of 4. This important result shows that it will be possible to achieve fabrication of nanoparticles with precision control of their dimensions in a size regime comparable with the industry standard electron beam lithography. AR NSL provides a massively parallel, rather than serial...

Angle-Resolved Nanosphere Lithography: Manipulation of Nanoparticle Size, Shape, and Interparticle Spacing

Nanosphere lithography (NSL) is an inexpensive, inherently parallel, high-throughput, and materials-general nanofabrication technique capable of producing well-ordered 2D periodic particle arrays of nanoparticles. This paper focuses on the synthesis of size-tunable silver nanoparticle arrays by nanosphere lithography and their structural characterization by atomic force microscopy (AFM). The in-plane diameter, a, of Ag nanoparticles was tuned from 21 to 126 nm by systematic variation of the nanosphere diameter, D. Similarly, the out-of-plane height, b, was tuned from 4 to 47 nm by varying the mass thickness, dm, of the Ag overlayer. Experimental measurements of a, b, and interparticle spacing dip of many individual nanoparticles as a function of D and dm were carried out using AFM. These studies show (i) b = dm, (ii) dip accurately corresponds to predictions based on the nanosphere mask geometry, (iii) a, after correction for AFM tip convolution, is governed only by the mask geometry and the standard devi...

Nanosphere Lithography: Size-Tunable Silver Nanoparticle and Surface Cluster Arrays

To see if there has been a decrease in patient delay, professional delay, diagnostic delay, and treatment delay in laryngeal cancer.

To determine the added cost of care and analyze risk factors in patients who suffered vocal fold paralysis (VFP) after thyroid surgery.

To evaluate the indications for observation versus surgery in the management of cotton swab‐induced tympanic membrane perforations (TMP).

Otologic complications of cotton swab use: One institution's experience

The Use of External Retropulsion to Remove a Wedged Metallic Drawer Knob From the Cervical Esophagus in an Autistic Patient

Otologic Complications of Q‐Tip Use: One Institution's Experience

The term “catastrophe” has a complex history that has become deeply embedded in Western, and increasingly global, cultures. So it is natural enough, when confronted by a phenomenon as harrowing as climate change, to employ the concept and its attendant connotations. But the lens of catastrophe often distorts more than it reveals.

Abstract:The term “catastrophe” has a complex history that has become deeply embedded in Western, and increasingly global, cultures. So it is natural enough, when confronted by a phenomenon as harrowing as climate change, to employ the concept and its attendant connotations. But the lens of catastrophe often distorts more than it reveals.

Tragedy, Catastrophe, Ecology: Introduction to “Performing Against the Catastrophe”

Microdramas: Crucibles for Theater and Time by John H. Muse (review)

Proteins, pathologies and politics : dietary innovation and disease from the nineteenth century

My thesis project Splitting Water with Wood is an installation consisting of a handmade boat and projected video of a durational performance that engaged the boat in unconventional ways. Throughout the project and paper, I employ conceptions of faith as a crucial lens to begin to understand my current body of work; a handcrafted boat as an exploratory apparatus, the labor surrounding it as an act of devotion, and a resulting performance that experiments with ideas about baptism. By challenging presupposed notions of how a boat traditionally functions, I rely on the lively materiality of the object and its environment to capture and extract previously unforeseen possibilities. It considers the do-ityourself lineage in my family and how that history of fabricating, constructing, and repairing informs me as an artist. Splitting Water with Wood draws on personal stories of my past and reimagines them as new narratives to explore the many facets of my Midwestern roots and provides insight to myself as a maker.

The Nervous Stage: Nineteenth-century Neuroscience and the Birth of Modern Theatre

Dubbed ‘hysterical' by its alleged editor, this anonymous collection of entries cataloging peculiar sensations of the (principally Western European) nineteenth- century hovers between glossary and glossolalia, raising the question not only of whether it is genuine, but whether it is an article at all.

The Georg Buchner Prize is the highest literary honor for German language writers, and the full extent of Buchner's influence-from Gerhart Hauptmann to Christa Wolf, Max Reinhardt to Robert Wilson, Alban Berg to Tom Waits-defies cataloging. When Georg Buchner died in 1837 at the age of twenty-three, he left behind a small and heterogenous body of work, most of it unpublished: three plays, a novella, a political pamphlet, a dissertation, medical lectures, and letters. Matthew Wilson Smith has newly translated Buchner's introduction to On Cranial Nerves. Each text is accompanied by explanatory annotations. The editor's introduction examines the complexities of Buchner's short life and how they informed his writing. The volume also contains ten illustrations. "Contexts" includes Buchner's correspondence with the people who knew him best, impressions of Buchner from a fellow medical student, excerpts from Buchner's diary, the wanted poster calling for Buchner's arrest for political conspiracy as well as the real-life inspirations his novella, Lenz, and his best-known play, Woyzeck. For ease of reference, "Criticism" is topically arranged by work and includes assessments by, among others, Laura Ginters, Victor Brombert, Bertolt Brecht, Henry Schmidt, Andrew Webber, Rainer Maria Rilke, and George Steiner. Three accounts of important productions of Danton's Death are reprinted, including John Houseman's remarks on Orson Welles's staging. Finally, the speeches of four winners of the Georg Buchner Prize-Paul Celan, Christa Wolf, Heiner Muller, and Durs Grunbein-are reprinted in their entirety. A Chronology of Buchner's life and work and a Selected Bibliography are also included.

A central crisis of representation in the Victorian period was this: how might one represent an ill that is not villainous but systemic? This article traces the ways in which several Victorians struggled to address that quandary during a brief period of paradigm shift: the middle years of the 1860s. The article’s first half explores ways in which the railway accident interrupted central conventions of melodrama. This section surveys editorial cartoonists, writers for Dickens’s journals Household Words and All the Year Round, volume one of Karl Marx’s Capital (1867), and Augustin Daly’s sensation drama Under the Gaslight (1867). The second half focuses on Dickens’s ghost story “No. 1 Branch Line. The Signal-Man.” Written a year after the Staplehurst disaster, the story gropes toward a new language for a traumatic condition, a language haunted by melodrama even as it moves beyond it.

The American Dream to Me, Myself, & I (2010), and Albee in Performance offers an important account of Albee’s own double act as playwright/director. While the work of Albee as director may never outshine the brilliant work of Albee as playwright, Solomon has done a service to both by showing the deep relationship between these twins; and in getting to know the former, one can better understand and appreciate the latter.

The Theatre of the Bauhaus: The Modern and Postmodern Stage of Oskar Schlemmer (review)

You find yourself in a room, with rice-paper walls and bamboo mats, a Japanese house standing on stilts in middle of the sea. Wooden stairs lead down to the surface of the water, and on the water floats a boat. You descend the staircase and you are in the boat and you sail into the sea in this boat drawn by seahorses, as golden icons float upwards overhead like self-similar fractals, products of some iterated function system, or air bubbles from some invisible leviathan. You are Mariko Horo, Mariko the Wanderer, or you are seeing the world through her eyes, and the time is some point, or many points, between the twelfth and twentysecond centuries. You sail westward to a land that alternately appears as Paradise, Purgatory, Limbo, and Inferno; you reverse Marco Polo’s travels, discovering and dreaming Venice as an exotic Occident. Ghosts of Palladio and Dante haunt these islands, as do darker specters of a more recent past, of Vietnam and Abu Ghraib, of the Virgin Mary as Guan Yin, of Byzantine frescos and Tibetan tankas swirling in a fiery Court of Final Judgment. 1 Like her creation Mariko Horo, the digital artist Tamiko Thiel is a border-crosser and an explorer of virtual space. She recalls: growing up mixed race in the U.S.A. at a time when the media did not admit of non-white Americans. Although born in the U.S., my first memories are from Japan (where I lived from ages two–five . . .), and my first impressions of the U.S. were of a strange, empty land filled with tall, pale people. As a child, growing up outside the Japanese American community in a white, working-class neighborhood in Seattle, since I could not “see” myself in the images of America, I maintained that I was Japanese—until I turned fourteen, that Age of Enlightenment, and realized that I was not socially Japanese, would not fit into Japanese society and would not want to do so. 2

troupe based on their replicating her idealized appearance. In chapter five, Garelick briefly traces the more familiar connections between Fuller and theatre practitioners such as Craig and Appia, before addressing questions of Fuller’s multiple identities and the differences between her performance of self and the reality. These are examined in relation to the developments in modern drama associated with artists such as Ibsen, Strindberg, and Pirandello. In Garelick’s persuasive telling, Fuller shares their concerns with interiority and their play with character and the fourth wall. As well as examining Fuller’s artistic development within modernist performance, Garelick also places her work within a broader historical context, noting, for instance, her engagement with Orientalism and Imperialism during the 1900 World Fair in Paris. Finally, in extending as well as drawing upon recent theoretical writing on Fuller, Garelick ensures that Fuller does not disappear into one of her own magical illusions. In a brief ‘‘Afterword,’’ Garelick suggests that there are current performance strands that sustain a physical link with Fuller’s work, such as the work of dancer Jody Sperling, who ‘‘uses Fuller’s dances as a springboard for her own postmodern fantasies,’’ and ‘‘an underground party entertainment known as ‘flagging,’ which is uncannily reminiscent of Fuller’s work’’ (18). This wellillustrated and probing book is an important contribution to the scholarship on Loie Fuller and, with its contemporary resonances, should prove of interest to practitioners and academics in the fields of live-art and sitespecific performance as well as dance.

Focusing on the period from 1910 to 1915, this article argues that Richard Wagner's work was crucial to the development of American cinema. Critics and artists not only advocated Wagner's composition techniques for film accompaniment, but also turned Wagner into an emblem for far broader reforms. These reforms included a greater integration of music and film, a conception of film as a high art, and a conception of film as a medium for national purification and bourgeoisification. These reforms, and their connection to Wagner, helped set the stage for the use of "The Ride of the Valkyries" in D. W. Griffith's The Birth of a Nation (1915).

American Valkyries: Richard Wagner, D. W. Griffith, and the Birth of Classical Cinema

Matthew Wilson Smith discusses Wagner's “Parsifal” in relation to emerging discourses of psychology and aesthetics, and suggests that the work becomes in the process a proto-modern opera that dramatizes the increasingly problematic nature of both the self and representation.

German Studies across the Disciplines Bennett, Benjamin. All Theater Is Revolutionary Theater. Ithaca: Cornell University Press, 2005.241 pp. $39.95 hardcover. Benjamin Bennett, the author of several important studies of modern European (chiefly German) literature, has long combined great erudition with a willingness to overturn the applecart. To the good fortune of theater scholars in particular, one of the central questions of his career has been the relationship between literature and drama. In All Theater Is Revolutionary Theater, which serves as something of a sequel to his earlier Theater As Problem, Bennett offers further reflections on this troubled and troubling relationship. The argument of this provocative book rests on two fundamental assertions, each of which Bennett elaborates and defends. The first is that Western drama has always been regarded as a discrete literary or poetic type, and the second is that drama has always been distinguished from other types of writing in ways that trouble the whole system of literary classification. From Aristotle onwards, theorists and practitioners have attempted to incorporate drama into a larger system of the written word (whether under the sign of "poetry" or "literature"), and yet drama has consistently resisted such incorporation even as it has attracted it. The reason for the confusion is simple: drama both is and is not a literary type. Strongly inspired by Artaud and Brecht, Bennett develops a performance theory that makes drama the incurably rebellious child of the written word. Bennett's book derives much of its substance and subtlety from his close readings of a wide variety of sources. Beginning with Aristotle's Poetics (the shadow of which hangs over the entirety of this book), Bennett shows how Aristotle attempts to incorporate physical performance into his larger definition of drama as a poetic genre. It is an impossible project, marking the Poetics as the first of a long line of noble failures of Western dramatic theory. Leaping ahead to the modern stage, Bennett brings together Brecht and Artaud, emphasizing the commonality of their work (especially their challenges to the written word) against their more obvious differences. Further chapters offer readings of a host of theater artists: Buchner, Wedekind, Shaw, Eliot, Beckett, and Robert Wilson, among others. Bennett's close readings of individual works are at least as valuable as his broader theoretical arguments. His discussion otLeben des Galilei, which elucidates the ways in which Brecht's text grapples with long-standing problems of the relation of writing to performance, is a significant contribution to critical understanding of that play. …

While it has never proved very successful in America — its first New York production in 1963 was a complete flop — Max Frisch’s Andorra has had no shortage of European admirers. The London premiere was a critical triumph, with Kenneth Tynan embracing it as “a near masterpiece,” and the Times dubbing it “one of the great plays of post-war theatre.” After initial storms of controversy in the German-speaking world, it moved from theaters into classrooms, where it now occupies a stature roughly equivalent to Death of a Salesman in the American canon. In light of the fact that a professional production of Andorra has not been attempted in New York for nearly four decades, the play would seem ripe for renewal. Theatre for a New Audience assembled an impressive production team to do just that. The work was staged at the Lucille Lortel Theatre by Liviu Ciulei, working from a new translation of the play by Village Voice critic Michael Feingold, who previously translated Frisch’s The Firebugs. The cast includes notable Broadway hands Bill Buell (the Innkeeper), Laurie Kennedy (the Mother), and Nicholas Kepros (the Priest). Such a pool of talent, however, could not make up for the fact that Frisch’s best-known play is also his creakiest and preachiest. If the work seemed heavy-handed to its first New York audiences, it has improved little with age. The setting is Andorra, a small, mountainous state that, Frisch writes, “has nothing to do with the real small state of that name, nor does it stand for another real small state.” The latter part of Frisch’s disavowal is more difficult to swallow than the former, for the playwright’s native Switzerland is clearly a referent here. Andorra, we learn, is a proud, peaceful nation threatened with invasion by the neighboring “Blacks” (Blackshirts, in Feingold’s translation), and the shadow of war has raised tensions within the Andorran town. The town’s citizens are broad caricatures of Swiss Bürgers and their families, well-meaning, conservative souls whose volk-iness is equal parts patriotic nostalgia and anti-Semitic bigotry. Standing somewhat outside the community is Andri, an adopted youth whom the citizens believe to be Jewish and who becomes the central target of their subtle and not-so-subtle anti-Semitism. productions

This journal entry of Ibsen's, written in early 1883, presents the reader with 'certain difficulties. To begin with, it departs from Ibsen's typical journal style; almost without exception, the notes that precede and follow it are explicit indictments of society: "Patriotism and such things are but passing phases"; "Marriage [...] has ruined the human race, set the brand of slavery on everybody"; "[L]et doctors experiment on journalists and politicians." But this entry is different, trickier to interpret. Is it yet another indictment, an accolade, or merely a neutral observation? Are we to mourn the fact that "adults have lost the ability to play with dolls," or celebrate the fact that "powers of logical thought are developed" with age? Or are we simply meant to note these characteristics impassively?

KCG, responsible Agency of maritime SAR operation has been known to address the marine casualties well, however, it was criticized because KCG failed to take prompt and effective response to the recent Ferry disaster at the very early stage. In this regards, the authors analyze the characteristics of marine incident with historical data, and also review and examine the national SAR system focusing on SAR coordination and human resources to make recommendation and suggestion in order to minimize the loss of lives to future marine incidents. As a result, KCG shall augment its capabilities, inter alia, fast libeboats and rescue helicopters for prompt response to marine incidents at the coastal waters, and KCG shall re-adjust the establishment of Rescue Coordination Center to improve operational problems of current system in accordance with IMO guidance, KCG is required to introduce mandatory training, qualification and certificate system to enhance the professionalism of SAR personnel.

A Study on the Improvement of Search and Rescue Coordination for Effective Response to Marine Casualties

This paper compared the consistency of the Environment Stress(ES) model and the Potential Risk Assessment Model (PARK model, which was developed based on a Korean mariner risk perception) for the Busan adjacent waterway. Evaluation of accuracy and comparison of these two models have been made by Vessel Traffic Service (VTS) officers in the Busan VTS Centre. The assessment results of Busan waterway show that the PARK model is more consistent than the ES model as follows. (1) The difference between assessment results applying ES model and PARK model with risk degree of VTSOs were 34% and 5% respectively in six typical traffic situations. (2) The assessment using PARK model is more suitable and identical with the VTSOs opinion in his or her duty time.

A Comparison of ES and PARK Maritime Traffic Risk Assessment Models in a Korean Waterway

Korea has a systemic problem with lack of engine maintenance, especially among the Commercial Fishing Vessel fleet. This results in a inordinate percent of SAR call-outs for vessels with engine failure. These SAR call-outs lead to a free tow to shore by KCG or by one of its volunteer associates. Although these tows are not a terrible economic burden on KCG, it is a burden in terms of time and resources mis-allocated. This paper proposes a Commercial Fishing Vessel Examination (CFVE) program modeled after the program run by USCG. It is expected that adopting the CFVE program, KCG may be able to create a culture of safety among fishermen; thus, replicating the USCG's success rates.

A Plan for Reducing SAR Call-outs for Fishing Vessels in Korean Waters

This paper proposes that the Marine Search & Rescue and Salvage Association of Korea (MARSA) can provide KCG a very positive return on investment; that is, MARSA will save lives and property well over the budget needed from KCG to operate MARSA. To perform this Cost-Benefit Analysis, actual performance data and other figures are taken from the USCG Auxiliary, and these figures are used to project expected possible MARSA results. In this paper, MARSA is projected to provide a 1,493 % return on investment.

On the Improvement of SAR Coordination for Effective Response to Marine Casualties

The Asymmetry Within: A Renewed Look at Cupid’s Bow in Unilateral Cleft Lip

Scarlett, before the war, life was beautiful. There was a glamor to it, a perfection and a completeness and a symmetry to it like Grecian art. Maybe it wasn’t so to everyone. I know that now . . . Now, I know that in the old days it was a shadow show I watched. I avoided everything which was not shadowy, people and situations which were too real, too vital. I resented their intrusion. I tried to avoid you too, Scarlett. You were too full of living and too real and I was cowardly enough to prefer shadows and dreams. (Margaret Mitchell, Gone With the Wind–Ch. XXXI)

“Ridiculous Extremes”: Historical Accuracy, Gone With the Wind, and the Role of Beauty in Plantation Tourism

Date of Award 5-2017 Degree Type Dissertation Degree Name Doctor of Philosophy Major English Major Professor Bill Hardwig Committee Members Mary Papke, Martin Griffin, Thomas Haddox, Derek Alderman Abstract In the aftermath of the American Civil War, national periodicals such as Harper's, The Century, and The Atlantic Monthly eagerly solicited and published literature depicting small, often isolated regional communities within the United States – literature collectively referred to as local color. This project examines a tension that exists between two conflicting impulses that drove local color writing – one that sought to participate in an ethnographic project rooted in literary realism, the other that reveled in representing local spaces as sites of ambiguity, uncertainty, illegibility, and impenetrability. "Translating Chopin's Parrot" argues that literary historicists, drawn to the ethnographic elements of local color, often elide or fail to account for the tension that exists between these elements and those that, in accentuating indeterminacy and mystery, contest and complicate ethnography's empirical presuppositions. Unsurprisingly, this tension has led to interpretive conflicts over the most fruitful approach to reading local color literature. This project divides these conflicts into four categories – conflicts over definitions, translations, mappings, and misreadings of genre. It takes as a case study literature written about Creole and Cajun Louisiana during the heyday of local color (1865-1914) and articulates what a historicist framework can and cannot illuminate about texts by George Washington Cable, Charles Gayarré, Lafcadio Hearn, Kate Chopin, and Alice Dunbar-Nelson. In doing so, it makes the larger argument that, rather than occupying a quaint and idiosyncratic niche within nineteenth-century American literature, local color grapples with significant epistemological, aesthetic, and hermeneutic questions. Recommended Citation Smith, Matthew Paul, "Translating Chopin's Parrot: Local Color Louisiana and the Limits of Literary Interpretation, 1865-1914. " PhD diss., University of Tennessee, 2017. https://trace.tennessee.edu/utk_graddiss/4425  Download

Translating Chopin's Parrot: Local Color Louisiana and the Limits of Literary Interpretation, 1865-1914

Contents: Preface Acknowledgements Chronology Chapter 1: Student Years 1905-10 and the Fauvist Work 1910-20 Chapter 2: Smith's Experience of War and its Effect on his Cornish Landscapes of 1920 Chapter 3: Towards Maturity: The Nude and Figure Paintings of the 1920s Chapter 4: Creative Profusion: Flower Paintings, Landscapes, Still Lifes and the Portraits 1930-55 A User's Guide to the Catalogue Catalogue Raisonne of the Oil Paintings Appendix I: A Note on Smith's Technique Appendix II: Addendum of Further Works Solo Exhibitions Group Exhibitions Bibliography Picture Credits.

Catalogue raisonné of the oil paintings of Matthew Smith : with a critical introduction to his work

Regan Dunn, John Day Fossil Beds National Monument, 32651 Highway 19, Kimberly, OR 97848; regan_dunn@nps.gov Theodore Fremd, John Day Fossil Beds National Monument, 32651 Highway 19, Kimberly, OR 97848; ted_fremd@nps.gov James Hammett, John Day Fossil Beds National Monument, 32651 Highway 19, Kimberly, OR 97848; jim_hammett@nps.gov Matthew Smith, John Day Fossil Beds National Monument, 32651 Highway 19, Kimberly, OR 97848; matt_smith@nps.gov

"La batalla de Chile y the Panama Deception". Presentación cinematográfica de dos eventos históricos

Landscapes: the journal of the international centre for landscape and language

Matthew Smith from USA on a WILD (Writing in Landscapes Downunder) in July 2003

We calibrate and test a division-of-focal-plane red-green-blue (RGB) full-Stokes imaging polarimeter in a variety of indoor and outdoor environments. The polarimeter, acting as a polarization camera, utilizes a low dispersion microretarder array on top of a sensor with Bayer filters and wire-grid linear polarizers. We also present the design and fabrication of the microretarder array and the assembly of the camera and validate the performance of the camera by taking multiple RGB full-Stokes images and videos. Our camera has a small form factor due to its single-sensor design and the unique capability to measure the intensity, color, and polarization of an optical field in a single shot.

Division of focal plane red-green-blue full-Stokes imaging polarimeter.

An imaging Mueller matrix polarimeter, named the red-green-blue (RGB)950, takes images of medium-sized (tens of centimeters) objects by using a very bright source, large polarization state generator, and high-quality camera. Its broadband extended light source switches between red, green, blue, and near-infrared light to allow taking polarimetric images for comparison with RGB camera images. The large diffuse source makes shadow transitions gradual and spreads out the specular reflected spot into a larger less conspicuous area.

during controlled hemorrhage and resuscitation Retinal venous oxygen saturation and cardiac output

Abstract— Test equipment for reflective LCD devices must use a calibration target to mimic a known state of the intended display devices under test (DUTs). This target must also mimic the polarization effects of the DUTs. Traditionally, a mirror and quarter‐wave plate (MQWP) assembly is used for this function. By accounting for the reflectivity of the mirror and the transmission of the QWP, a reference target can be generated. The effects of the use of a QWP in this role will be examined and additional effects for which compensation must be performed in order to achieve accurate test results will be discussed.

Performance limitations with mirror/QWP reference targets for reflective LCD measurements

Measured Mueller matrices of optical elements can be used to mathematically predict end-to-end performance of polarization-critical optical systems. Techniques for properly handling depolarization effects, near-perfect polarizers, and reflective elements are presented.

Capabilities and Limitations of Using Measured Mueller Matrices to Predict Complex Optical System Performance

Measuring, Modeling and Tolerancing Polarization-Critical Optical Systems

Test equipment for reflective LC display devices must use a calibration target to mimic a known state of the intended display devices under test (DUTs). This target must also mimic the polarization effects of the DUTs. Traditionally, a mirror and quarter wave plate (MQWP) assembly is used for this function. By accounting for the reflectivity of the mirror and the transmission of the QWP, a reference target can be generated. This paper examines effects of use of a QWP in this role and discusses additional effects for which compensation must be performed in order to get accurate test results.

37.2: Performance Limitations with Mirror/QWP Reference Targets for Reflective Liquid Crystal Display Measurements

The objective was to test calibration of an eye oximeter (EOX) in a vitiligo swine eye and correlate retinal venous oxygen saturation (Srv(O(2))), mixed venous oxygen saturation (Sv(O(2))), and cardiac output (CO) during robust changes in blood volume. Ten anesthetized adult Sinclair swine with retinal vitiligo were placed on stepwise decreasing amounts of oxygen. At each oxygen level, femoral artery oxygen saturation (Sa(O(2))) and retinal artery oxygen saturation (Sra(O(2))) were obtained. After equilibration on 100% O(2), subjects were bled at 1.4 ml. kg(-1). min(-1) for 20 min. Subsequently, anticoagulated shed blood was reinfused at the same rate. During graded hypoxia, exsanguination, and reinfusion, Sra(O(2)) and Srv(O(2)) were measured by using the EOX, and CO and Sv(O(2)) were measured by using a pulmonary artery catheter. During graded hypoxia, Sra(O(2)) correlated with Sa(O(2)) (r = 0.92). Srv(O(2)) correlated with Sv(O(2)) (r = 0.89) during exsanguination and reinfusion. Sv(O(2)) and Srv(O(2)) correlated with CO during blood removal and resuscitation (r = 0.92). Use of vitiligo retinas improved the calibration of EOX measurements. In this robust hemorrhage model, Srv(O(2)) correlates with CO and Sv(O(2)) across the range of exsanguination and resuscitation.

Retinal venous oxygen saturation and cardiac output during controlled hemorrhage and resuscitation.

An optimization of a dual-rotating-retarder Mueller matrix polarimeter is performed by minimizing the condition number of the system data reduction matrix. The optimum retardance for the rotating retarders is found to be 127 degrees. If exactly 16 intensity measurements are used for the calculation, we observe a complex relationship between the condition number and the size of the angular increments of the two retarders. If many intensity measurements are made, thus over-specifying the calculation, we find broad optimal ranges of angular increments of the two retarders that yield essentially equal performance.

The dual-rotating-retarder configuration is one of the most common forms of the Mueller matrix polarimeter. I perform an optimization of this polarimeter configuration by minimizing the condition number of the system data reduction matrix. I find the optimum retardance for the rotating retarders to be 127 degrees. If exactly 16 intensity measurements are used for a Mueller matrix calculation, a complex relationship exists between the condition number and the sizes of the angular increments of the two retarders. If many intensity measurements are made, thus overspecifying the calculation, I find broad optimal ranges of angular increments of the two retarders that yield essentially equal performance. Experimental results are given.

Optimization of a dual-rotating-retarder Mueller matrix polarimeter.

The extinction of light passing through a blood vessel comprises both absorbed and scattered components, the latter of which includes relatively strong forwardly transmitted and directly reflected components. The effect of such vessels on incident light beams of arbitrary polarization is most thoroughly described by the vessel's transmission and reflection Mueller matrices. The Mueller matrices of illuminated mock blood vessels (diameter 102-278 micrometers ) in these two important directions have been measured at a wavelength of 633 nm using a Mueller matrix imaging polarimeter. The measured Mueller matrices are presented, decomposed, and analyzed to determine the sample's retardance and depolarization as a function of vessel diameter. It is expected that characterization of these matrices should broaden light-vessel modeling techniques by permitting calculation of the transmitted and reflected properties of arbitrary input polarization states.

Measurement of the transmission and reflection Mueller matrices of a thin blood column

The goal of making calibrated oxygen saturation measurements of blood in retinal arteries and veins via a noninvasive spectroscopic technique has nearly been realized. Semi-continuous advancement in the field of retinal vessel oximetry over the last three decades has resulted in several technologies that seem poised for commercialization. In this paper, we present our instrumentation and technique for making well-calibrated saturation measurements of the blood in retinal vessels. The Eye Oximeter (EOX) is a confocal scanning laser ophthalmoscope capable of acquiring multi-spectral images. Analysis of these spectral vessel images allows spectroscopic determination of the oxygen saturation of blood within each vessel. The primary emphasis of this paper is to illustrate the effect of fundus pigmentation on these oximetric measurements. We show that decreasing fundus reflectivity is mathematically similar to decreasing the vessel thickness. The apparent decreased vessel thickness is a direct consequence of scattering by red blood cells. We present in vitro and in vivo measurements that demonstrate an instrument calibration that is nearly independent of vessel diameter and fundus reflectivity.

Minimizing the influence of fundus pigmentation on retinal vessel oximetry measurements

A system for characterizing polarization controllers and other fiber components with Mueller matrices is presented. Most polarization controllers, such as lithium niobate modulators or PLZT electro-optical modulators, exhibit a wide range of polarization behaviors at constant drive voltage including elliptical retardance, polarization dependant loss (PDL), and depolarization. Specifying the half wave voltage for such devices describes their desired characteristic, an electrically addressable retardance, but not the undesired characteristics. Devices with complex polarization behaviors require a similarly comprehensive description of their polarization effects. We present example measurements that demonstrate how the Mueller matrix as a function of voltage provides a complete description of the desired retardance and the undesired PDL. Such polarization controller Mueller matrices can be multiplied with Mueller matrices for other photonic components to quantify how component polarizations interact.

Characterizing polarization controllers with Mueller matrix polarimetry

In recent years, several investigators have begun to explore polarized light imagery as a potential diagnostic tool. For example, polarimetric images have shown promise in identifying a variety of dermatological conditions. Because tissues tend to depolarize a large fraction (~85%) of incident light, the Mueller calculus lends itself well to these applications. A particular property of the Mueller matrix, the Depolarization Index, has demonstrated promise in discriminating between cancerous and benign moles. In this paper, we discuss the depolarizing aspects of tissues, however we primarily attempt to analyze the small fraction of light that has retained a polarization state. Analyzing the residual polarizing properties of a sample is challenging, and it requires a polar decomposition of the measured Mueller matrix into the basic properties of diattenuation, retardance, and depolarization. The diattenuation and retardance images contain information about the complex refractive index of the tissue, including any spatial variations in the index. We present measurements of the diattenuation and retardance of laser light reflected from skin as a function if incident angle and scattered angle.

Previous infrared polarization imaging research has shown manmade objects to be sources of emitted and reflected polarized radiation while natural backgrounds are predominantly unpolarized. The prior work underscored the dramatic improvements in signal to clutter ratio that could be achieved in a typical target acquisition scenario using polarization sensing techniques. Initial investigations into the polarization signatures of surface scattered mines have also shown polarization techniques are able to provide strong cues to mine presence. The US Army Night Vision and Electronics Sensors Directorate has developed complete Stokes imaging polarimeters in the midwave infrared (MWIR, 3-5 µm)1,2, the short wave infrared (SWIR, 1-2 µm) and the visible wavebands in order to investigate polarization phenomenology and to quantify expected improvements to target acquisition and mine detection. This paper will review the designs of the polarization cameras and will summarize efforts to calibrate them. An example phenomenology study of MWIR polarization from surface scattered landmines will be presented.

Several techniques for measuring the oxygen saturation of blood in retinal vessels have been reported. One interesting application of retinal vessel oximetry is the identification of occult blood loss in trauma victims. However, all the devices described to date are too bulky and cumbersome to be used in a trauma bay or in the field. We present a design for a handheld instrument that performs four-wavelength retinal vessel oximetry. This device is comparable in size and weight to a commercially available camcorder, and is suitable for use in the trauma bay. The compact size of this device could also extend its applications beyond traditional clinical settings, as it could be used by primary care physicians and home health care workers for the screening and monitoring of ophthalmic diseases. Principles of operation and preliminary data from the device will be described.

Recent studies have indicated that polarized light may be useful in the discrimination between benign and malignant moles. In fact, imaging polarimetry could provide noninvasive diagnosis of a range of dermatological disease states. However, in order to design an efficacious sensor for clinical use, the complete polarization-altering properties of a particular disease must be well understood. We present Mueller matrix imaging polarimetry as a technique for characterizing various dermatological diseases. Preliminary Mueller matrix imagery at 633 nm suggests that both malignant moles and lupus lesions may be identified through polarimetric measurements. Malignant moles are found to be less depolarizing than the surrounding tissue, and lupus lesions are found to have rapidly varying retardance orientation.

Accurately measuring the oxygen saturation of blood within retinal arteries and veins has proven to be a deceptively difficult task. Despite the excellent optical accessibility of the vessels and a wide range of reported instrumentation, we are unaware of any measurement technique that has proven to be calibrated across wide ranges of vessel diameter and fundus pigmentation. We present an overview of our retinal oximetry technique, present the results of an in vitro calibration experiment, and present preliminary human data.

Accurately calibrating an infrared polarimeter presents several challenges. Some of these challenges include characterization of the polarization elements within the polarimeter, overcoming the effects of thermal emissions within the polarimeter, and developing a test setup and procedure for conclusively verifying the instrument calibration. We describe our efforts to absolutely calibrate our imaging Stokes polarimeter that operates in the mid-wave infrared band (3 to 5 microns). We have developed a generator that provides well-controlled polarization states for calibrating the polarimeter. This generator overcomes problems associated with thermal emissions, stray reflections, and narcissus effects. While the polarization state emitted by the generator is not known with extreme accuracy, we are able to rotate the generated state without affecting its degree of polarization or ellipticity. We show that we can create a complete set of input states to allow a full calibration of the polarimeter, and we describe a technique for optimizing the calibration based on a variance-minimization. Results of our calibration are presented, indicating that our polarimeter precision is better than 0.1%. This technique is not limited to infrared polarimeters and should therefore have broad applicability.

Scanning laser microscopy is a widely used technique in ophthalmoscopy for providing high-resolution real time images of the retina. We describe a scanning laser ophthalmoscope that acquires retinal images at four wavelengths for the purpose of measuring the oxygen saturation of blood in retinal arteries and veins. Images at all four wavelengths are obtained across a single video frame using a temporal interlacing technique. An extraction procedure then permits analysis of four monochromatic images. A technique for calculating oxygen saturation from a multi-spectral image set is presented, along with preliminary measurements. The choice of wavelengths dramatically affects the oxygen saturation calculation accuracy and we present an optimized wavelength set and the calculated oxygen saturation results. The potential applications for this technology range from the diagnosis of various ophthalmic diseases to the detection of blood loss in trauma victims.

Multispectral confocal scanning laser ophthalmoscope for retinal vessel oximetry

The scattering of He-Ne laser light incident on a flowing column of whole human blood has been measured and analyzed. An automated scatterometer whose sample chamber simulates a small caliber blood vessel was used to perform the measurements and is described. Angular scattered light distributions due to flowing blood columns for two independently varied parameters, blood oxygenation and hemoglobin concentration, are presented. It is found that the dependence of the scattering distribution on blood oxygenation is minimal while the dependence on hemoglobin concentration is strong. A nominally transparent sample of human plasma has also been investigated to quantify its scattering characteristics. The whole blood scattering results are compared to theoretical predictions obtained using a Monte Carlo simulation employing the Mie single particle phase function and macroscopic transport coefficients obtained from published literature. The best correlation was found when the largest published scattering coefficient was employed in the simulation. However, a strong correlation between the measured and predicted scattering distributions was only obtained when unphysically high values of the scattering coefficient were used in the simulation.

Retinal vessel oxygen saturation has been suggested as a parameter for monitoring a wide range of conditions including occult blood los and a variety of ophthalmic diseases. We have developed an Eye Oximeter (EOX), that noninvasively measures the oxygen saturation of the blood in individual large retinal vessels using scanning lasers. 1D vessel extinction profiles are obtained at four wavelengths (629, 678, 821 and 899 nm), and the vessel transmittances computed. The oxygen saturation of blood within the vessel is then calculated from the transmittance data. We have performed an in vitro experiment on human blood which demonstrates the calibration of the EOX measurements and validates our oximetry equations. Retinal vessel oxygen saturation was measured in a human subject and found to be 65%O2Sat and 101 - 102%O2Sat in the veins and arteries on the optic disk. Irregularities in the background measured away from the optic disk resulted in a large variance in the calculated saturation when compared to measurements made on the disk.

Instrument for the measurement of retinal vessel oxygen saturation

Most organic materials are quite opaque to IR radiation, making it nearly impossible to measure the polarization properties at these wavelengths. By placing the highly absorbing organic material on a high index of refraction prism and making use of the evanescent field present at the interface for angles exceeding the critical angle, it is possible to measure the organic material's polarization characteristics. Attenuated Total Reflection (ATR) devices have been constructed in-house for use in our IR polarimeter operating over the spectral range of 3-14 microns. Single bounce internal reflection ZnSe prisms are used in our devices to measure the polarization characteristics of highly absorbing materials. Using attenuated total reflection along with a dual rotating retarder polarimeter, it is possible to determine the full Mueller Matrix, and thus determine the linear and circular diattenuation and retardance. With this information we can determine the complex index of refraction, dichroic ratio, and isotropic ratio of materials which are opaque in the IR region. With this knowledge of the material polarization properties, it may be possible to determine the orientation of the molecules in films made of long helical organic molecules and determine the enantiomeric purity of stereo-isomers. The theoretical performance of these devices with a focus on the organic chemical applications has been determined and compared with experiments. In this paper we present a summary of the theoretical basis for the measurements and make comparisons with our measurements.

To make accurate imagin polarimetry measurements, it is imperative that the individual polarization images comprising a data set are spatially well registered. Both the Stokes Imaging Polarimeter at the University of Alabama in Huntsville and the Multispectral IR Stokes Imagining Polarimeter at Night Vision Laboratories use a rotating quarter-wave linear retarder followed by a fixed linear polarizer to measure Stokes vector images. The rotating retarder cause small amounts of image wander at the detector array. In this paper, we quantify the effects of this image wander on the calculated polarization parameters, and present data indicating the maximum acceptable image wander for typical scenes.

We describe the design and development of an imaging polarimeter that will simultaneously measure Stokes vector images in the mid-wave IR and long-wave IR wavebands. We present an analysis of the expected errors that arise due to spectral variations in the polarization elements of the instrument across each waveband. FInally, instrument calibration and polarization images acquired in the MWIR waveband are presented.

Mueller matrix imaging polarimetry represents a novel means of characterizing the polarization effects of optoelectronic devices. The Mueller matrix contains the complete polarization properties of a sample, and can therefore be used to calculate properties such as phase retardance, polarization dependant losses and polarization crosstalk. The complete polarization properties of a series of GaAs/AlGaAs self-imaging waveguide beamsplitters were measured with an imaging Mueller matrix polarimeter. Polarization properties were mapped across high resolution images of the devices' outcoupling faces, and the uniformity of the polarization properties was measured. Properties investigated include magnitude and orientation of linear retardance, polarization dependant losses, and crosstalk between TE and TM modes.

Polarization characterization of self-imaging GaAs/AlGaAs waveguide beamsplitters using Mueller matrix imaging polarimetry

The polarization and depolarization properties of two types of targets have been derived from the experimental determination of their Mueller matrix image. Each polarization signature is deduced from the polar decomposition of the Mueller matrix into images of retardance, diattenuation, polarizance, and depolarization. Different correlations between the polarization parameters and synthesized angle of incidence and angle of scatter images have been developed to determine an approximation of the angle of incidence from the polarization signatures.

Polarization signatures of spherical and conical targets measured by Mueller matrix imaging polarimetry

Imaging polarimetry is a novel method of characterizing the polarization effects of optoelectronic devices. From the Mueller matrix image, any polarization property of a device can be determined. High resolution polarization images of the outcoupling faces of several self-imaging GaAs/AlGaAs waveguide beamsplitters were made in the Mueller matrix imaging polarimeter at the University of Alabama in Huntsville. Interesting polarization states of the device modes (TE and TM), the magnitude of linear retardance varied significantly across a device. Polarization losses were also observed to vary across the faces of the devices. These effects could not have been observed by simply measuring the crosstalk between the TE and TM modes. The results of this study could lead to the detection of defect mechanisms in optoelectronic devices through Mueller matrix measurements.

Mueller matrix imaging of GaAs/AlGaAs self-imaging beamsplitting waveguides

Abstract : A previous study presented interesting data indicating the ability of the Polarization Diversity Active Imaging techniques (PDAI) to measure polarization signatures of objects of simple shape (conical and spherical objects). Polarimetric signatures of such objects are obtained by applying a powerful decomposition technique, previously developed under earlier AFOSR contract. A complete description of the object in then obtained. Such decomposition can be used for detection, discrimination and classification of targets. This second phase has extended the study of the dynamic behavior of one of the previous targets (cone used as a re-entry vehicle mode.) By then rotating that sample target to make polarization movie, the evolution of the decomposed polarization signature can then the fully examined. The analysis performed for each position finally provides the dynamic behaviors of the target depending on either its orientation or the position of the detection system. The second goal of this phase was the development of a method for estimating the refractive index of a target from its Mueller matrix image. Our investigations show that the refractive index can be estimated either by using data resulting from the polar decomposition method or from the Mueller matrix image of the object after different steps of data processing. Such parameter is essential in order to progress in the understanding of these polarized high/material interactions.

Polarization Diversity Active Imaging: Mueller Matrix Imaging Polarimetry of Spheres and Cones Estimation of the Refractive Index from the Polarization Signatures

We describe a noninvasive technique and instrumentation for measuring the oxygen saturation of blood in retinal arteries and veins. A white-light image of a subject's retina is presented to an operator. The operator targets a particular retinal artery or vein and initiates the measurement procedure. The measurements are made by scanning low-power lasers into the eye and across the retinal vessel. The light reflected and scattered back out of the eye is collected and measured. The oxygen saturation of blood within the vessel is spectroscopically determined by analyzing the vessel absorption profiles at two or more wavelengths. A complete saturation measurement can be made in less than one second, allowing real-time measurement during physiological changes. The sensitivity of this measurement technique to changes in retinal saturation has been demonstrated through a series of pilot studies in anesthetized swine. We present data indicating that retinal venous oxygen saturation decreases predictably during ongoing blood loss, indicating a potential application of an eye oximeter to nonivasively monitor blood loss. Current invasive techniques for monitoring bleeding, such as fiber optic pulmonary catheters, are not suited for use early in trauma situations. A portable eye oximeter may therefore provide a new technique for reducing mortality in the emergency department setting.

Technique for noninvasive monitoring of blood loss via oxygen saturation measurements in the eye

Oxygen saturation measurements of retinal arteries and veins during physiologic changes

Abstract This article will explore the characteristics of various broadband instruments that are available to measure microwave (MW) and radio-frequency (RF) electromagnetic fields. Instrument selection depends on both the design of the instrument and the characteristics of the field to be measured, including its frequency, modulation, and pulse width. Of the instrumentation currently available, accurate near-field and far-field measurements can be made if the inherent design strengths and limitations of the various types of instruments are known in advance. All broadband instrumentation consists of three basic components—an antenna, a detector, and a transmission line—although their responses to a particular RF or MW field may be dramatically different. The important characteristics of these instruments include their out-of-band response, isotropy, zero stability, linearity, RF potential sensitivity, and nonsinusoidal response. Calibration of instruments, the various methods of calibration available, and...

Characteristics of Broadband Instrumentation Used to Measure Microwave and Radiofrequency Electromagnetic Radiation in Occupational Settings

Fractals have been used successfully in generating missing information in scene reconstruction. If this information is processed using coherent optical techniques, then it is important to understand the properties of the Fourier transforms of fractals. Since fractals with square or rectangular bases are representative of pixel structures found on most electrically adressed spatial light modulators, a square-based fractal has been generated and its far field diffraction pattern calculated. The properties of the resulting Fourier spectrum are discussed.

A new vector magnetograph is being developed at NASA's Marshall Space Flight Center (MSFC) to measure polarization from active regions on the Sun. This paper will describe the polarization characteristics of the elements that make up the MSFC EXperimental Vector Magnetograph (EXVM) polarimeter. Based on those characteristics, the systematic errors associated with this polarimeter will be modeled and the polarization resolution that could be achieved in a space-based (or balloon-based) instrument will be discussed.

Polarization characteristics of the Marshall Space Flight Ctr. (MSFC) experimental vector magnetograph

Although zero-order quartz waveplates are widely used in instrumentation that needs good temperature and field-of-view characteristics, the residual errors associated with these devices can be very important in high resolution polarimetry measurements. This paper will discuss how the field-of-view characteristics are affected by retardation errors and the misalignment of optic axes in a double crystal waveplate. The paper will then describe the retardation measurements that were made on zero-order quartz and single-order `achromatic' waveplates and how the misalignment errors affect those measurements.

The MSFC's Experimental Vector Magnetograph (EXVM) is an instrument that observes a 4.4 x 8.8 arcmin field of the sun. The transverse and longitudinal components of the surface magnetic field and the line-of-sight velocities of the photospheric gases can be determined from polarimetric and spectral analysis of the 525.02 nm absorption line of Fe 1. The EXVM has been breadboarded and tested in the laboratory. The optics of the EXVM were tested with a point-diffraction (Smartt) interferometer. The 12 inch Cassegrain telescope was found to have 0.20 waves RMS (at 525.02 nm) of aberration. The post-telescope relay optics were nearly diffraction limited on-axis and had about one wave of primary coma as the predominant aberration at full-field. From theoretical modulation transfer function (MTF) curves of known aberrations, it was concluded that the EXVM should attain a maximum spatial resolution of about 0.5 arcseconds. A resolution test target indicated maximum angular resolutions better than 0.6 arcsec on-axis and 0.7 arcsec at full-field-of-view. A 2D inch heliostat (sun-tracking mirror) was used to direct sunlight into the lab and into the EXVM. Solar images obtained were limited by atmospheric seeing effects. During brief moments of good seeing, angular resolutions of about 1 arcsecond were realized with the EXVM.

Alpha Centauri is a triple star system with two Sun-like stars, α Cen A (V = 0.01) and B (V = 1.33), and a third fainter red dwarf star, Proxima Centauri. Most current transit missions cannot produce precision photometry of α Cen A and B as their detectors saturate for these very bright stars. The Arcsecond Space Telescope Enabling Research in Astrophysics (ASTERIA) was a technology demonstration mission that successfully demonstrated two key technologies necessary for precision photometry achieving line-of-sight fine-pointing stability of 0.5″ rms and focal plane temperature control of ±0.01 K over a period of 20 minutes. The payload consisted of a 6.7 cm aperture diameter refractive camera and used a scientific complementary metal-oxide semiconductor detector that enabled monitoring of the brightest stars without saturating. We obtained spatially unresolved (blended) observations of α Cen A and B during opportunistic science campaigns as part of ASTERIA’s extended mission. The resulting 1σ photometric precision for the blended α Cen A and B data is 250 ppm (parts per million) per 9 s exposure. We do not find evidence of transits in the blended data. We establish limits for transiting exoplanets around both α Cen A and B using transit signal injection and recovery tests. We find that ASTERIA is sensitive to planets with radii as small as 3.0 R ⊕ around α Cen A and 3.7 R ⊕ around α Cen B, corresponding to signals of ∼500 ppm (signal-to-noise ratio = 5.0) in the blended data, with periods ranging from 0.5 to 6 days.

Transit Search for Exoplanets around Alpha Centauri A and B with ASTERIA

Over the past two years, JPL has used the ASTERIA (Arcsecond Space Telescope Enabling Research In Astrophysics) CubeSat as an in-flight test platform during extended missions. ASTERIA successfully completed its prime mission in early 2018, and continued to operate in low Earth orbit (LEO) for an additional twenty months. This paper describes demonstrations that were performed on the spacecraft and on the ground-based testbed during the extended mission. These demonstrations fall into three categories: Autonomy technology maturation, hardware characterization, and science discovery. Autonomy technology maturation supported three development efforts. The first shifted the spacecraft commanding paradigm from time-based sequences to Task Networks (tasknets), which allow simpler commanding and more robust onboard execution. The second demonstrated onboard orbit determination in Low Earth Orbit (LEO) without GPS. This activity used a fully-independent means of spacecraft orbit determination for Earth orbiters using only passive imaging. The third technology provided in situ hardware health state estimation using a model-based reasoning technique. These three technologies were demonstrated either in flight or on the testbed individually, and then were combined to demonstrate the capability to perform autonomous navigation on board without ground intervention, even in the presence of anomalies. Hardware characterization involved both onboard and ground-based activities. On board, nonstandard attitude control modes were commanded to characterize the spacecraft pointing jitter as a function of target brightness, reaction wheel speed, controller gain, and the number of guide stars. The results provide insights into the contribution of jitter to the ASTERIA photometry and inform the feasibility of future astrophysics small satellite missions for which jitter control is an enabling technology. On the ground, the ASTERIA Operations Team coordinated with Amazon Web Services (AWS) to configure their new ground stations to communicate with ASTERIA to prove out their viability. ASTERIA used AWS ground stations for nominal operations for the last four months of the mission. Finally, ASTERIA continued to perform exoplanet science as the spacecraft was well-suited to execute long-term monitoring of stars such as alpha Centauri to search for small transiting planets. The science team also imaged a number of interesting objects including a comet, an asteroid, cities at night, and the moon, and coordinated with other projects on Targets of Opportunity for follow-up confirmations and co-observations. Throughout the prime and the extended missions, the ASTERIA spacecraft proved to be a mighty platform that “will go into history as an innovative milestone.” [1]

HD 219134 is a K3V dwarf star with six reported radial-velocity discovered planets. The two innermost planets b and c show transits, raising the possibility of this system to be the nearest (6.53 pc), brightest (V = 5.57) example of a star with a compact multiple transiting planet system. Ground-based searches for transits of planets beyond b and c are not feasible because of the infrequent transits, long transit duration (∼5 hr), shallow transit depths (<1%), and large transit time uncertainty (∼half a day). We use the space-based telescopes the Arcsecond Space Telescope Enabling Research in Astrophysics (ASTERIA) and the Transiting Exoplanet Survey Satellite (TESS) to search for transits of planets f (P = 22.717 days and ) and d (P = 46.859 days and ). ASTERIA was a technology demonstration CubeSat with an opportunity for science in an extended program. ASTERIA observations of HD 219134 were designed to cover the 3σ transit windows for planets f and d via repeated visits over many months. While TESS has much higher sensitivity and more continuous time coverage than ASTERIA, only the HD 219134 f transit window fell within the TESS survey’s observations. Our TESS photometric results definitively rule out planetary transits for HD 219134 f. We do not detect the Neptune-mass HD 219134 d transits and our ASTERIA data are sensitive to planets as small as 3.6 R⊕. We provide TESS updated transit times and periods for HD 219134 b and c, which are designated TOI 1469.01 and 1469.02 respectively.

HD 219134 Revisited: Planet d Transit Upper Limit and Planet f Transit Nondetection with ASTERIA and TESS

The process of aligning an instrument focal plane to precursor optics such as a telescope can be a difficult and time-consuming process. The final alignment must achieve sufficient performance at multiple locations across the field of view. In the case of instruments with infinite conjugates, such as a space telescope, there are practical challenges in illuminating the system at multiple off-axis field points simultaneously. Iteration during the alignment process can cause a lengthy search for local minima within the performance cost function. This paper presents a focal plane alignment methodology that avoids the above difficulties and obtains the desired level of optical performance in an efficient manner. The approach is based on systematically measuring spot size across a set of field points and defocus positions, and then using a least squares fit to determine the optimal location for the focal plane. This approach has the additional benefit of revealing the amount of field curvature present in the instrument. It also provides the analyst with a direct calculation of the shims needed to place the focal plane at the computed best-fit location. This approach was successfully applied to the Arcsecond Space Telescope Enabling Research In Astrophysics (ASTERIA) payload. ASTERIA is a cubesat mission that was deployed into low-Earth orbit in November 2017 and operated until December 2019. In addition to presenting the theoretical basis for the methodology, this paper will present laboratory measurements obtained during the payload alignment campaign. This approach is applicable to future space-borne optical instruments that require an efficient methodology for focal plane alignment with limited cost or schedule resources.

An Efficient Focal Plane Alignment Methodology with Application to the ASTERIA Nanosatellite Space Telescope

Arcsecond Space Telescope Enabling Research In Astrophysics (ASTERIA) is a 6U CubeSat space telescope (10 cm × 20 cm × 30 cm, 10 kg). ASTERIA’s primary mission objective was demonstrating two key technologies for reducing systematic noise in photometric observations: high-precision pointing control and high-stability thermal control. ASTERIA demonstrated 0.″5 rms pointing stability and ±10 mK thermal control of its camera payload during its primary mission, a significant improvement in pointing and thermal performance compared to other spacecraft in ASTERIA’s size and mass class. ASTERIA launched in 2017 August and deployed from the International Space Station in 2017 November. During the prime mission (2017 November–2018 February) and the first extended mission that followed (2018 March–2018 May), ASTERIA conducted opportunistic science observations, which included the collection of photometric data on 55 Cancri, a nearby exoplanetary system with a super-Earth transiting planet. The 55 Cancri data were reduced using a custom pipeline to correct complementary metal-oxide semiconductor (CMOS) detector column-dependent gain variations. A Markov Chain Monte Carlo approach was used to simultaneously detrend the photometry using a simple baseline model and fit a transit model. ASTERIA made a marginal detection of the known transiting exoplanet 55 Cancri e (∼2 ), measuring a transit depth of 374 ± 170 ppm. This is the first detection of an exoplanet transit by a CubeSat. The successful detection of super-Earth 55 Cancri e demonstrates that small, inexpensive spacecraft can deliver high-precision photometric measurements.

Demonstrating High-precision Photometry with a CubeSat: ASTERIA Observations of 55 Cancri e

Accurate, long-term solar spectral irradiance (SSI) measurements are vital for interpreting how solar variability impacts Earth’s climate and for validating climate model sensitivities to spectrally varying solar forcing. The Compact Spectral Irradiance Monitor (CSIM) 6U CubeSat successfully launched on Dec. 3rd, 2018 as part of the SpaceX SSO-A: SmallSat Express Mission ultimately achieving a sun-synchronous 575 km orbit. CSIM brings new, emerging technology advancements to maturation by demonstrating the unique capabilities of a complete SSI mission with inherent low mass and compact design. The instrument is a compact, two-channel prism spectral radiometer incorporating Si, InGaAs, and extended InGaAs focal plane photodiodes to record the solar spectrum daily across a continuous wavelength region spanning 200 – 2800 nm (>97% of the total solar irradiance). A new, novel electrical substitution radiometer (ESR) using vertically aligned carbon-nanotube (VACNT) bolometers serves as an absolute detector for periodic on-orbit spectral calibration corrections. Pre-launch component level performance characterizations and final instrument end-to-end absolute calibration achieved low combined standard uncertainty (uc<0.5%) in irradiance. These calibrations were performed in the LASP Spectral Radiometer Facility (SRF), a comprehensive spectral irradiance calibration facility utilizing a tunable laser system tied to an SI-traceable cryogenic radiometer. On-orbit, optical degradation corrections to better than 0.05% / year uncertainty are achieved by comparing periodic, simultaneous solar measurements of the two CSIM channels operating with significantly different solar exposure duty cycles. Operational overlap of CSIM with existing SSI measurements validate concepts for maintaining critical long-term solar data records.

Compact spectral irradiance monitor flight demonstration mission

ASTERIA (Arcsecond Space Telescope Enabling Research In Astrophysics) is a CubeSat space telescope currently operating in low-Earth orbit. It is expected to remain in orbit at least through October 2019. Developed as a technology demonstration mission under the Jet Propulsion Laboratory Phaeton Program for training early-career engineers, ASTERIA has achieved sub-arcsecond pointing stability and milliKelvin thermal stability over 20-minute observations. These capabilities-unprecedented in a CubeSat platform-have enabled photometric precision better than 1000 parts per million per minute (0.1%/min) while observing nearby bright stars (apparent visual magnitude magv < 6). Following the second extended mission, we are now using the spacecraft in its third extension as a platform to demonstrate additional capabilities as well as continue science observations. This project will perform the following four well-focused activities that will raise the technology readiness of key spacecraft technologies. 1. Shift the paradigm to operate spacecraft from open-loop commanding to closed-loop command execution: We will introduce “task networks” (tasknets)which allow simpler commanding and more robust onboard execution. 2. Demonstrate onboard orbit determination in Low Earth Orbit (LEO) using autonomous navigation (Autonav)without the Global Positioning System (GPS): This activity will demonstrate a fully independent means of spacecraft orbit determination for Earth orbiters using only passive imaging. 3. Collect data on ASTERIA that will feed into future missions by characterizing the spacecraft pointing jitter as a function of target brightness, reaction wheel speed, controller gain, and number of guide stars. 4. Perform ASTERIA extended mission science: ASTERIA has demonstrated unprecedented photometric precision for a CubeSat mission. The spacecraft is uniquely suited to perform long-term monitoring of stars such as alpha Centauri for small transiting planets. The discovery of a transiting Earth-sized planet around alpha Cen A and/or B would be of the highest scientific value as such a planet would be our closest exoplanetary neighbor orbiting a Sunlike star. These demonstrations will provide in-flight testing of new autonomy technologies, maximize the scientific potential of this operational spacecraft, and provide additional characterization of hardware for future small satellite missions using similar subsystems.

Extended Mission Technology Demonstrations Using the ASTERIA Spacecraft

The Arcsecond Space Telescope Enabling Research in Astrophysics (ASTERIA) is a 10-kg, 6U CubeSat in low-Earth orbit that was able to achieve subarcsecond pointing stability and repeatability. To date, this is the best pointing on a spacecraft of its size. This paper will analyze various aspects of the performance of its key piece of hardware-the payload. First, a model of the optics and imager, which is used to simulate stellar images, will be presented. The imager parameters used in this model were derived from simple ground measurements. Next, a centroiding algorithm is provided and used on the simulated images to predict centroiding performance. These results will be shown to match on-orbit telemetry of centroiding performance, validating the modeling approach. This paper will then describe an approach for and results of a geometric camera calibration algorithm to estimate the focal length, distortion, and alignment parameters. The modeling, analyses, and results presented in this paper provide key information that can be used in a time-domain pointing simulation or a frequency-domain pointing error analysis.

Camera Modeling, Centroiding Performance, and Geometric Camera Calibration on ASTERIA

The Arcsecond Space Telescope Enabling Research in Astrophysics (ASTERIA) was deployed from the International Space Station (ISS) on 20 November 2017, beginning a technology demonstration and opportunistic science mission to advance the state of the art in nanosatellite performance for astrophysical observations. The goal of ASTERIA is to achieve arcsecond-level line-of-sight pointing error and highly stable focal plane temperature control. These capabilities enable precision photometry—i.e. the careful measurement of stellar brightness over time—which in turn allows investigation of astrophysical phenomena such as transiting exoplanets. By the end of the 90-day prime mission, ASTERIA had achieved line-of-sight pointing stability of approximately 0.5 arcseconds root mean square (RMS) over 20-minute observations, pointing repeatability of 1 milliarcsecond RMS from one observation to the next, and focal plane temperature stability better than ±0.01 K over 20-minute observations. This paper presents an overview of the ASTERIA flight and ground system, summarizes the pre-delivery test campaign, and discusses the on-orbit performance obtained by the pointing and thermal control subsystems. We also describe the process for planning opportunistic science observations and present lessons learned from development and operations. Having successfully operated for over 200 days as of this writing, ASTERIA is currently in an extended mission to observe nearby bright stars for transiting exoplanets.

On-Orbit Results and Lessons Learned from the ASTERIA Space Telescope Mission

ASTERIA Operations Demonstrates the Value of Combining the Mission Assurance and Fault Protection Roles on CubeSats

ASTERIA: Arcsecond Space Telescope Enabling Research in Astrophysics

REgolith X-Ray Imaging Spectrometer (REXIS) Aboard NASA’s OSIRIS-REx Mission

Instrument systems such as imagers, radars, spectrometers, and radiometers are important to users in the astronomy, Earth science, defense, and intelligence communities. Relatively early in the development cycle, performance requirements are defined at the top level and allocated to various subsystems or components. This is a critical step, as poor requirement definition and resulting requirement instability has historically led to increased cost and, in some cases, program cancelation. Defining requirements for instrument systems is uniquely challenging in part due to the divide between system users (e.g. scientists) and system designers (e.g. engineers). The two groups frequently differ in terms of background, objectives, and priorities, and this disconnect often leads to difficulty in evaluating and resolving requirement trade-offs. The objective of this thesis is to develop a model-based approach to requirement definition that addresses the above challenges. The goal of the methodology is to map science objectives to a set of top-level engineering requirements in a manner that enables traceability in the requirement hierarchy and facilitates informed trades across the science/engineering interface. This is accomplished by casting the requirement definition process as an optimization problem. First, an executable instrument model is created to capture the forward mapping between engineering decisions and science capability. The model is then exercised to find an inverse mapping that produces multiple sets of top-level engineering requirements that all meet the performance objectives. A new heuristic optimization algorithm is developed to carry out this task efficiently and exhaustively. Termed the Level Set Genetic Algorithm (LSGA), this procedure identifies contours of equal performance in the design space using an elitepreserving selection operator to ensure convergence, together with a global diversity metric to ensure thorough exploration. LSGA is derivative-free, parallelizable, and compatible with mixed integer problems, making it applicable to a wide variety of modeling and simulation scenarios. As a case study, the model-based requirement definition methodology is applied to the Regolith X-ray Imaging Spectrometer (REXIS), an instrument currently in development at MIT and scheduled to launch on NASA’s OSIRIS-REx asteroid sample

The OSIRIS-REx Mission was selected under the NASA New Frontiers program and is scheduled for launch in September of 2016 for a rendezvous with, and collection of a sample from the surface of asteroid Bennu in 2019. 101955 Bennu (previously 1999 RQ36) is an Apollo (near-Earth) asteroid originally discovered by the LINEAR project in 1999 which has since been classified as a potentially hazardous near-Earth object. The REgolith X-Ray Imaging Spectrometer (REXIS) was proposed jointly by MIT and Harvard and was subsequently accepted as a student led instrument for the determination of the elemental composition of the asteroid's surface as well as the surface distribution of select elements through solar induced X-ray fluorescence. REXIS consists of a detector plane that contains 4 X-ray CCDs integrated into a wide field coded aperture telescope with a focal length of 20 em for the detection of regions with enhanced abundance in key elements at 50 m scales. Elemental surface distributions of approximately 50-200 m scales can be detected using the instrument as a simple collimator. An overview of the observation strategy of the REXIS instrument and expected performance are presented here.

The REgolith X-Ray Imaging Spectrometer (REXIS) for OSIRIS-REx: identifying regional elemental enrichment on asteroids

ExoplanetSat is a proposed 10×10×34-cm space telescope designed to detect down to Earth-sized exoplanets in an orbit out to the habitable zone of bright, Sun-like stars via the transit method. Achieving this science objective requires one-arcsecond line-of-sight pointing control for the science CCD detector, an unprecedented requirement for CubeSats. A two-stage control architecture that coordinates coarse rigid-body attitude control with fine line-of-sight pointing control will be employed to meet this challenging pointing requirement. Detailed testing of the reaction wheels and CMOS detectors has been performed to extract key performance parameters used in simulations. The results of these simulations indicate that a 1.4 arcsecond pointing precision (3σ) is achievable. To meet the 1.0-arcsecond pointing requirement, several options are analyzed. In particular, a new technique to estimate reaction wheel vibrations for feedforward cancellation of reaction wheel vibrations is presented. This estimator adaptively estimates disturbances from noisy sensor measurements and effectively stores disturbance amplitude and phase in memory as a function of wheel speed. In addition to these simulation results, testing results from a hardware-in-the-loop (HWIL) testbed demonstrate the capability of the fine pointing control loop. Future plans for complete HWIL testing of the coarse and fine control loops are presented.

One-arcsecond line-of-sight pointing control on exoplanetsat, a three-unit CubeSat

We present a CubeSat mission for the discovery of exoplanets down to 1 Earth radius around the nearest and brightest Sun-like stars. The spacecraft prototype―termed ExoplanetSat―is a 3U space telescope designed to monitor a single target from low Earth orbit. The optical payload will precisely measure stellar brightness, seeking the characteristic dip in intensity that indicates a transiting exoplanet. Once ExoplanetSat identifies a candidate exoplanet, larger assets can be used to conduct follow-up observations to characterize the atmospheric constituents. The prototype will serve as the basis of an eventual fleet of nanosatellites, each independently monitoring a single bright, nearby star. Given the spacecraft’s low mass and sub-pixel sensitivity variations in the science detector, image jitter and its resultant photometric noise is a primary concern. The attitude determination and control subsystem (ADCS) mitigates this using a two-stage pointing control architecture that combines 3-axis reaction wheels for arcminute-level coarse pointing with a piezoelectric translation stage at the focal plane for fine image stabilization to the arcsecond level. The ExoplanetSat optical design combines star camera and science functions into a single device that fits into the 3U form factor. This paper presents the ExoplanetSat science case, mission overview, concept of operations, and spacecraft configuration.

The ExoplanetSat Mission to Detect Transiting Exoplanets with a CubeSat Space Telescope

CubeSats are a class of nanosatellites that conform to a standardized 10 cm x 10 cm x 10 cm, 1 kg form factor. This miniaturization, along with a standardized deployment device for launch vehicles, allows CubeSats to be launched at low cost by sharing the trip to orbit with other spacecraft. Part of the original motivation for the CubeSat platform was also to allow university students to participate more easily in space technology development and to gain hands-on experience with flight hardware. The Department of Aeronautics and Astronautics along with the Department of Earth, Atmospheric, and Planetary Studies (EAPS) at the Massachusetts Institute of Technology (MIT) recently completed a three semester-long course that uses the development of a CubeSat-based science mission as its core teaching method. Serving as the capstone academic experience for undergraduates, the goal of this class is to design and build a CubeSat spacecraft that serves a relevant science function, such as the detection of exoplanets transiting nearby stars. This project-based approach gives students essential first hand insights into the challenges of balancing science requirements and engineering design. Students are organized into subsystem-specific teams that refine and negotiate requirements, explore the design trade space, perform modeling and simulation, manage interfaces, test subsystems, and finally integrate prototypes and flight hardware. In this work we outline the heritage of capstone design/build classes at MIT, describe the class format in greater detail, and give results on the ability to meet learning objectives using this pedagogical approach.

Enhancing undergraduate education in aerospace engineering and planetary sciences at MIT through the development of a CubeSat mission

The trend in future space telescopes points toward increased primary mirror diameter, which improves resolution and sensitivity. However, given the constraints on mass and volume deliverable to orbit by current launch vehicles, creative design solutions are needed to enable increased mirror size while keeping mass and volume within acceptable limits. Lightweight, segmented, rib-stiffened, actively controlled primary mirrors have emerged as a potential solution. Embedded surface-parallel actuators can be used to change the mirror prescription onorbit, lowering mirror mass overall by enabling lighter substrate materials such as silicon carbide (SiC) and relaxing manufacturing constraints. However, the discrete nature of the actuators causes high spatial frequency residual errors when commanding low-order prescription changes. A parameterized finite element model is used to simulate actuator-induced residual error and investigate design solutions that mitigate this error source. Judicious specification of mirror substrate geometry and actuator length is shown to reduce actuator-induced residual while keeping areal density constant. Specifically, a sinusoidally-varying rib shaping function is found to increase actuator influence functions and decrease residual. Likewise, longer actuators are found to offer reduced residual. Other options for geometric shaping are discussed, such as rib-to-facesheet blending and the use of two dimensional patch actuators.

Minimizing actuator-induced errors in active space telescope mirrors

Abstract : Heritage space telescope mirror technology-i.e. large, monolithic glass primary mirrors-has reached an upper limit on allowable aperture diameter given launch vehicle volume and mass constraints. The next generation of space telescopes will feature lightweight, actively controlled, segmented primary mirrors in order to achieve the advances in angular resolution and sensitivity that larger aperture diameters permit. Active control via embedded surface-parallel electrostrictive actuators provides the capability to change a mirror segment's optical prescription on orbit, to correct either quasi-static disturbances or manufacturing errors. Commanding low-order prescription changes (e.g. radius of curvature) using discretely-placed actuators, however induces high spatial frequency residual error in the mirror surface figure, resulting in wavefront error (WFE) that degrades optical performance. A key challenge is reducing this actuator-induced high frequency WFE to below acceptable levels while simultaneously commanding a particular change in global shape. This thesis considers a new set of geometric design variables that affect high-spatial frequency residual error in an effort to mitigate actuator-induced WFE. Specifically less conventional variations in rib height, actuator geometry, and rib-to-facesheet intersection geometry are exploited to achieve improved performance in silicon carbide (SiC) mirrors. A parametric finite element model is used to explore the trade space among these new parameters and to predict performance improvements. Simulation results show that these additional geometric considerations reduce actuator-induced WFE while keeping mirror mass and complexity constant.

Minimizing Actuator-Induced Residual Error in Active Space Telescope Primary Mirrors

ExoplanetSat is a proposed three-unit CubeSat designed to detect down to Earth-sized exoplanets in an orbit out to the habitable zone of Sun-like stars via the transit method. To achieve the required photometric precision to make these measurements, the target star must remain within the same fraction of a pixel, which is equivalent to controlling the pointing of the satellite to the arcsecond level. The satellite will use a two-stage control system: coarse control will be performed by a set of reaction wheels, desaturated by magnetic torque coils, and fine control will be performed by a piezoelectric translation stage. Since no satellite of this size has previously demonstrated this high level of pointing precision, a simulation has been developed to prove the feasibility of realizing such a system. The current baseline simulation has demonstrated the ability to hold the target star to within 0.05 pixels or 1.8 arcseconds (with an 85 mm lens and 15 μm pixels), in the presence of large reaction wheel disturbances as well as external environmental disturbances. This meets the current requirement of holding the target star to 0.14 pixels or 5.0 arcseconds. Other high-risk aspects of the design have been analyzed such as the effect of changing the guide star centroiding error, changing the CMOS sampling frequency, and reaction wheel selection on the slew performance of the satellite. While these results are promising as an initial feasibility analysis, further model improvements and hardware-in-the-loop tests are currently underway.

Achieving high-precision pointing on ExoplanetSat: initial feasibility analysis

Nanosatellites, i.e. spacecraft that weigh between 1 and 10 kg, are drawing increasing interest as platforms for conducting on-orbit science. This trend is primarily driven by the ability to piggyback nanosatellites on the launch of large spacecraft and hence achieve orbit at greatly reduced cost. The CubeSat platform is a standardized nanosatellite configuration, consisting of one, two, or three 10 cm x 10 cm x 10 cm units (1, 2, or 3 "U"s) arranged in a row. We present a CubeSat-based concept for the discovery of transiting exoplanets around the nearest and brightest Sun-like stars. The spacecraft prototype - termed ExoplanetSat - is a 3U space telescope capable of monitoring a single target star from low Earth orbit. Given the volume limitations of the CubeSat form factor, designing a capable spacecraft requires overcoming significant challenges. This work presents the initial satellite configuration along with several subsystem-specific solutions to the aforementioned constraints. An optical design based on a modified commercial off-the-shelf camera lens is given. We also describe a novel two-stage attitude control architecture that combines 3-axis reaction wheels for coarse pointing with a piezoelectric translation stage at the focal plane for fine pointing. Modeling and simulation results are used to demonstrate feasibility by quantifying ExoplanetSat pointing precision, signal-to-noise ratio, guide star magnitude, and additional design parameters which determine system performance.

ExoplanetSat: detecting transiting exoplanets using a low-cost CubeSat platform

The trend in future space telescopes is towards larger apertures, which provide increased sensitivity and improved angular resolution. Lightweight, segmented, rib-stiffened, actively controlled primary mirrors are an enabling technology, permitting large aperture telescopes to meet the mass and volume restrictions imposed by launch vehicles. Such mirrors, however, are limited in the extent to which their discrete surface-parallel electrostrictive actuators can command global prescription changes. Inevitably some amount of high spatial frequency residual error is added to the wavefront due to the discrete nature of the actuators. A parameterized finite element mirror model is used to simulate this phenomenon and determine designs that mitigate high spatial frequency residual errors in the mirror surface figure. Two predominant residual components are considered: dimpling induced by embedded actuators and print-through induced by facesheet polishing. A gradient descent algorithm is combined with the parameterized mirror model to allow rapid trade space navigation and optimization of the mirror design, yielding advanced design heuristics formulated in terms of minimum machinable rib thickness. These relationships produce mirrors that satisfy manufacturing constraints and minimize uncorrectable high spatial frequency error.

Minimizing high spatial frequency residual error in active space telescope mirrors

Natural disasters and military conflicts have demonstrated the ongoing need for high resolution imagery with nearly continuous coverage on short notice. Current satellite systems do not meet this need because they suffer from low resolution (high altitude orbits and/or small optics) or intermittent coverage (low orbits). The Continuous Responsive Imaging System in Space (CRISIS) optimizes the trade between resolution and coverage by utilizing a constellation of small, inexpensive, rapidly deployable Earth observation satellites. Initial mission analysis has demonstrated that a constellation of eight satellites at 600 km altitude evenly distributed throughout two perpendicular planes can satisfy resolution and responsiveness requirements simultaneously. Total development cost for the entire system is comparable to that of a single traditional commercial Earth-observing satellite and the individual CRISIS spacecraft are within the mass and volume limits of low-cost launch vehicles such as the Pegasus XL or Falcon 1e. This configuration was selected from a trade space of 1350 different architectures using a parameterized model implemented in Matlab and Satellite Toolkit.

Spacecraft and Constellation Design for a Continuous Responsive Imaging System in Space

A simulation of a GPS-INS guided artillery shell was used to analyze the sensitivity of miss distance to unmodeled errors in aerodynamic and environmental parameters. Based on the sensitivity analysis, a Kalman filter was designed to estimate errors in coefficient of drag, coefficient of pitching moment, initial velocity and the horizontal wind component. A covariance analysis showed that the filter improved knowledge of these quantities. These unmodeled errors, which are countered by active guidance in the presence of a GPS signal, could be ameliorated earlier in the flight if they were known, thereby reducing the impact of GPS-jamming in the final portions of flight. Thesis Supervisor: George Schmidt Title: Lecturer, Department of Aeronautics and Astronautics Director, Guidance Technology Center Charles Stark Draper Laboratory Technical Supervisor: Tom Thorvaldsen Title: Principle Member, Technical Staff, Charles Stark Draper Laboratory Acknowledgments May 13, 1998 This thesis is dedicated to my parents, to whom I owe everything. The assistance of my technical advisor, Tom Thorvaldsen, was not only indispensible to the completion of this work, but was unflagging and went well beyond the call of a thesis advisor. Without him this thesis would not have been possible. I owe a great deal to my academic advisor, Dr. George Schmidt, for his support throughout the thesis process. Brent Appleby, Don Gustavson, Edward Lanzilotta and Marc McConley each provided assistance, often when it was far from convenient, for which I am sincerely grateful. The staff and administration of Draper Laboratory was a bottomless source of advice and support-technical and otherwise--during the production of this thesis. I am greatly indebted to them for their assistance. This thesis was prepared at the Charles Stark Draper Laboratory under Draper Laboratory Corporate Sponsored Research, CSR-13256. Publication of this thesis does not constitute approval by the Draper Laboratory or the sponsoring agency of the findings or conclusions contained herein. It is published for the exchange and stimulation of ideas. Permission is hereby granted by the author to the Massachusetts Institute of Technology to reproduce any or all of this thesis.

In-flight estimation of environmental and aerodynamic modeling errors for a GPS-INS guided artillery shell in a GPS-jamming environment

Molecular testing of lung adenocarcinomas for epidermal growth factor (EGFR) mutations and an anaplastic lymphoma kinase (ALK) translocation is important to guide directed therapy with tyrosine kinase inhibitors. The goal of this study was to determine whether transthoracic computed tomography-guided core needle biopsy (CNB) and fine-needle aspiration (FNA) biopsy specimens were equally suitable for molecular testing.

METHODS
We determined the percentage of 52 CNB and 120 FNA specimens that contained sufficient paraffin-embedded tumor tissue for EGFR, KRAS, and ALK testing over a period of 2 years. We correlated sample sufficiency with the sampling method, tumor size, biopsy operator, pathologist assessing the adequacy of the sample, and the number of FNA passes performed.

RESULTS
Univariate analysis showed that CNB specimens provided a significantly higher number of samples sufficient for molecular testing than did FNA specimens (67% vs 46%; P = .007) and that one operator achieved a significantly higher percentage of sufficient FNA specimens. Binomial logistic regression found sufficiency of FNA samples to correlate with tumor size (P = .015) but not operator.

When paraffin-embedded tissue is used for molecular testing of lung cancer, CNB specimens are more likely than FNA specimens to provide adequate tissue for molecular testing. Obtaining a sufficient FNA specimen depends on the tumor size and the individual performing the biopsy.

Adequacy of core needle biopsy specimens and fine-needle aspirates for molecular testing of lung adenocarcinomas.

Objective: The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) provides a reporting scheme for thyroid fine needle aspiration (FNA) and includes three indeterminate categories with different management strategies. This study analyzes indeterminate thyroid FNAs in children, and correlates these findings with the histological features. Methods: A total of 179 thyroid FNA specimens were retrieved from children. Cases were categorized by TBSRTC. Only cases diagnosed as atypia (AUS)/follicular lesion of undetermined significance (FLUS), suspicious for follicular or oncocytic neoplasm (SFON), or suspicious for malignancy (SM) were selected and correlated with the nodule size and histological follow-up. Results: Sixty-eight cases were identified, including 43 (63%) AUS/FLUS diagnoses, 19 (28%) SFON, and 6 (9%) SM. On follow-up, 48% were malignant, including 28% AUS/FLUS cases, 58% SFON, and 100% SM. The average size of the malignant lesions diagnosed preoperatively as AUS/FLUS was 1.5 cm (range 0.7-4.5), compared to 3.3 cm (range 1.2-6.6) in SFON and 2.8 cm (range 0.7-3.8) in SM. Malignancies included 92% papillary thyroid carcinoma (PTC), 77% of which were the follicular variant of PTC (FVPTC) and 8% follicular carcinomas. The AUS/FLUS cases were largely due to compromised specimens (49%) and the highest malignancy rate occurred in those with cytological atypia (50%). Conclusions: This study shows an incremental risk of malignancy within the indeterminate categories using TBSRTC in children. Malignant nodules with a preoperative AUS/FLUS diagnosis tended to be smaller than those with a SFON or SM diagnosis, and the vast majority of malignancies were PTC, with a high proportion being FVPTC.

Indeterminate Pediatric Thyroid Fine Needle Aspirations: A Study of 68 Cases

Cytological-Histological Correlation in Indeterminate Pediatric Thyroid Fine Needle Aspirations: A Study of 68 cases

Primary bladder adenocarcinoma versus metastatic colorectal adenocarcinoma: a persisting diagnostic challenge

All hospitals deal with patient deaths. Multiple departments and personnel must be coordinated to ensure that decedents are safely managed. Prior to 2004, at the University of Pittsburgh Medical Center (UPMC), when a patient passed away, the process of alerting involved personnel, transporting the decedent, and tracking the completion of clinical documents was cumbersome and inefficient. In order to address these concerns, UPMC Remains Tracker, a web-based application, was developed to improve the efficiency and simplify the logistics related to the management of patient deaths. The UPMC Information Services division developed UPMC Remains Tracker, an application that tracks decedents′ locations, documentation status, and autopsy status within UPMC hospitals. We assessed qualitative improvement in decedent remains tracking, decedent paperwork management, and staff satisfaction and compliance. UPMC Remains Tracker improved the process of tracking decedents′ locations, identifying involved personnel, monitoring autopsy requests, and determining the availability for funeral home transportation. Resident satisfaction with UPMC Remains Tracker was generally positive and scored as "Improved efficiency" and makes identifying and tracking decedents "Much easier". Additionally, the nursing staff reacted favorably to the application. A retrospective review of the use of the application in the management of 100 decedents demonstrated a 93% compliance rate. Among the cases requiring an autopsy, there was a 90% compliance rate. The process of tracking decedents, their paperwork, involved staff, and decedent autopsy status is often inefficient. This assessment suggests that incorporating new technologies such as UPMC Remains Tracker into the management of hospital deaths provides accurate tracking of remains, streamlines the administrative tasks associated with deaths, and increases nursing and resident satisfaction and compliance.

University of Pittsburgh Medical Center Remains Tracker: A novel application for tracking decedents and improving the autopsy workflow

Tissue repositories maintained by pathology departments represent an abundant resource of clinically annotated human specimens. The storage expenses associated with pathology archives are known to administrators of most pathology departments. However, such basic repository characteristics as the quality of stored materials, ease of access, and search and retrieval rates are often unclear. The aims of our work were to design a framework to assess the quality of a historic pathology archive, to propose the definition of "archive integrity," and to provide benchmarks for tissue block retrieval rates and DNA integrity. We share our experience with scanning approximately 120,000 pathology reports from 1956 to 1979 into an electronically searchable archive, with a $9,000 budget, completed in 6 weeks. Several ethical and legal considerations that shaped the technical side of this project are discussed.

Pathology archive: evaluation of integrity, regulatory compliance, and construction of searchable database from print reports.

Large-scale battery energy storage systems (BESS) are drawing the attention of researchers as numbers installed globally is rising rapidly. Like single cells, the battery states, most importantly state of charge (SOC) and state of health (SOH) of BESSs are essential for their operation. However, for large-scale battery systems, the data granularity, accuracy and quality are limited compared with the cell-level. To achieve accurate state estimation of battery systems the selection of data used for processing is essential. In this paper, it is shown that how to evaluate and select system-level data for SOC and SOH estimation. These methods are expected to be used for other BESSs.

IECON 2021 – 47th Annual Conference of the IEEE Industrial Electronics Society

Data-selection for state estimation of large-scale battery systems

Practical state estimation using Kalman filter methods for large-scale battery systems

This paper investigates a delay compensation control for coordinating aggregated energy storage systems (ESSs) of dissimilar characteristics to provide fast frequency regulation, particularly the UK National Grid enhanced frequency response (EFR) service. The dynamic model of a generic micro-grid system comprising synchronous generator, load, and EFR-providing ESS is established. Theoretical analyses of the compensation effects are conducted using describing function techniques to model the EFR nonlinearities. The theoretical study indicates the compensation control’s beneficial effects through an increase in the micro-grid system’s equivalent regulating energy (the inverse of the frequency droop coefficient). The analytical results are validated by RTDS simulations of a representative micro-grid system, which is based on the measured characteristics of a real aggregated ESS fleet, including a 180kWh/240kW commercial battery ESS asset and a 1MWh/2MW battery asset located 100 miles apart. Simulations show that the frequency deviation of the micro-grid system in response to a 10% sinusoidal power imbalance at the network’s natural angular frequency could be reduced by 74% through the inclusion of two BESSs providing EFR with a total capacity of 10% of the micro-grid; a further reduction of 42% can be obtained through the implementation of the proposed delay compensation method.

2020 IEEE 9th International Power Electronics and Motion Control Conference (IPEMC2020-ECCE Asia)

Delay Compensation Amongst Aggregated Storage Assets Providing Fast Frequency Regulation

In many parts of the developing world, portable, rechargeable lithium-ion battery packs are being used to provide energy in areas where traditional solutions, such as micro-grids are not viable. This study provides a comparison of the effects of three charging regimes, designed to maximise either stored energy, cycle life or charge speed, on the performance of a batch of lithium-ion cells, when cycled at elevated temperature. The results show that by reducing the voltage stresses on the cell, cycle degradation can be reduced by two-thirds, thus resulting in much increased cell lifetime; this may be achieved whilst only reducing energy storage capability by around 15%. Further, it is demonstrated that significant increases in charge speed are possible without any appreciable loss in stored energy and only a modest increase in degradation over the lifetime of the cell.

2019 IEEE International Conference on Industrial Technology (ICIT)

A Comparison of the Effects of Charging Strategies on Lithium-ion Cell Performance in High Temperature Environments

Dynamic Charge Acceptance (DCA) is an important consideration for battery performance, particularly when batteries are used as power buffers within larger systems. This paper presents an experimental analysis of the effects of cycle-related degradation on the DCA performance of lead-acid cells. The results show that capacity loss due to degradation does not provide a reliable indication of the cells DCA performance, in fact for the typical lifetime of the cell DCA performance remains broadly constant, independent of degradation. Only at very severe levels of degradation is DCA performance seen to appreciably reduce. The results show that the more rapid degradation of lead cells need not be such a concern in applications where DCA performance is key. The results also have implications for second-life uses of cells in similar applications.

2018 IEEE 27th International Symposium on Industrial Electronics (ISIE)

An Experimental Analysis of the Effect of Cell Degradation on Dynamic Charge Acceptance in Lead-Acid Cells

Batteries are increasingly important in modern technologies. This is particularly true in the automotive sector, with hybrid vehicles using batteries to augment the traction power traditionally provided by the internal combustion engine. In such applications, one of the most important factors is the Dynamic Charge Acceptance (DCA) performance of the battery. 
 
This study investigates the standard method for establishing DCA performance and determines how the individual parameters of the test procedure and external factors influence the performance of lead-acid cells. This work identifies shortcomings of the standard test, which result in the true DCA performance being better than the standard test suggests. A series of modifications are proposed, which are shown to produce a more representative result. 
 
An investigation is performed to determine the effect of cell degradation on charge acceptance. This shows that the DCA test itself is not well suited to assessing the effects of degradation on DCA, and causes the results to appear worse than reality. The work also demonstrates that the usual methods of characterising degradation do not correlate well with DCA performance, and there is very little reduction in charge acceptance over the operational life of the cell. 
 
Investigations are undertaken into methods by which DCA performance may be improved. This shows that the application of ac ripple currents to batteries causes a significant increase in charge acceptance, and demonstrates how the frequency of the ripple is important in achieving the best results. This study also shows that the ripple currents have no detrimental effects on the health of the battery. 
 
Finally, the work is extended to cover lithium cells. This shows that whilst the DCA performance of lithium is more consistent, maximum charge acceptance is less than lead. It is shown that, by reducing maximum charge voltage, cycle life of cells can be extended without significant loss of stored energy.

Improvements in testing and performance of batteries for automotive applications

During a successful 2 year technology demonstration of the tunable diode laser spectroscopy (TDLS) based Multi-Gas Monitor (MGM) on the International Space Station (ISS), we began discussing with the US Navy the possibility of conducting a sea trial of an MGM on a submarine. The sea trial would also include a gas chromatography/differential mobility spectrometer based Air Quality Monitor (AQM), which is used operationally on ISS for select volatile organic compounds. AQM results will be the subject of a separate paper. The Navys interest in testing NASA equipment is in a planned update to the environmental monitoring equipment used aboard submarines. NASAs goal is studying submarines as closed environment analogs to spacecraft. MGMs core technology was developed by Vista Photonics Inc using Small Business Innovation Research (SBIR) grants and expanded for various applications using NASA program funding. The MGM measures oxygen, carbon dioxide, ammonia and water vapor in ambient air, displays concentrations with temperature and pressure, and stores 30 second moving averages. The sea trial involves colocating the instrument with the Central Air Monitor (CAM) and connecting it to rack power prior to departure, and letting it run during the entire sea trial of a few months duration. All data stored is inside MGM, with no connection to the vessel data bus. Crew intervention is limited to checking MGM periodically to see that it is working and power cycling if the display is OFF. After the trial is over, the unit with its data will be retrieved. Post sea trial calibration check and data analysis are planned and results will be compared with both CAM data and results from MGMs ISS technology demonstration.

This paper presents the results of a series of tests to determine the influence of high-frequency injected ripple currents on the Dynamic Charge Acceptance (DCA) performance of lead-acid batteries. A wide-bandwidth battery model is described, this being a hybrid of the standard Randles model and a high-frequency model previously described in literature. A bespoke test procedure is described, based on the existing DCA Short Test profile. The results demonstrate that the injection of ripple currents can significantly improve charge acceptance.

IECON 2017 - 43rd Annual Conference of the IEEE Industrial Electronics Society

Experimental analysis of the influence of high-frequency ripple currents on dynamic charge acceptance in lead-acid batteries

For the past 4 years, the Air Quality Monitor (AQM) has been the operational instrument for measuring trace volatile organic compounds on the International Space Station (ISS). The key components of the AQM are the inlet preconcentrator, the gas chromatograph (GC), and the differential mobility spectrometer. Onboard the ISS are two AQMs with different GC columns that detect and quantify 22 compounds. The AQM data contributes valuable information to the assessment of air quality aboard ISS for each crew increment. The US Navy is looking to update its submarine air monitoring suite of instruments and the success of the AQM on ISS has led to a jointly planned submarine sea trial of a NASA AQM. In addition to the AQM, the Navy is also interested in the Multi-Gas Monitor (MGM), which measures major constituent gases (oxygen, carbon dioxide, water vapor, and ammonia). A separate paper will present the MGM sea trial preparation and the analysis of most recent ISS data. A prototype AQM, which is virtually identical to the operational AQM, has been readied for the sea trial. Only 1 AQM will be deployed during the sea trial, but this is sufficient for NASA purposes and to detect the compounds of interest to the US Navy for this trial. The data from the sea trial will be compared to data from archival samples collected before, during, and after the trial period. This paper will start with a brief history of past collaborations between NASA and the U.S. and U.K. navies for trials of air monitoring equipment. An overview of the AQM technology and protocols for the submarine trial will be presented. The majority of the presentation will focus on the AQM preparation and a summary of available data from the trial.

Preparation of the NASA Air Quality Monitor for a U.S. Navy Submarine Sea Trial

Accurate radiation-induced event-rate predictions are critical in establishing expected electronic equipment performance in natural space and terrestrial avionic environments. Some sources of uncertainty, like environmental software models, cannot easily be improved. However, the statistical certainty of collected data, facility rental expense, and engineering man-power can be optimized through high fidelity automated test. The investment in automated test development results in a lower overall cost of a test campaign, while simultaneously maximizing statistical certainty of the collected data. This is achieved by tailoring the automated test to expedite the event data capture per unit of real time at atmospheric neutron test facilities.

Automating atmospheric neutron testing: Minimizing cost and improving statistical certainty

This paper presents the results of a series of tests to determine the Dynamic Charge Acceptance (DCA) performance of small form-factor 2 V, 6 Ah, carbon-enhanced VRLA cells designed for Hybrid Electric Vehicle (HEV) applications. A test procedure has been written for a battery test system, based on a modified DCA Short Test profile. Results have been obtained for a batch of cells, tested at various temperatures, rest periods and states of charge. These conditions have been chosen to mimic a range of real-life scenarios which could potentially be encountered during HEV operation. The resulting analysis demonstrates clear variations and trends in DCA performance which may be used to inform conditions for future testing regimes. The same test procedure is then applied to standard lead-acid cells and the results compared.

IECON 2016 - 42nd Annual Conference of the IEEE Industrial Electronics Society

Experimental analysis of dynamic charge acceptance test conditions for lead-acid cells

Design and Implementation of Aircraft System Health Management (ASHM) Utilizing Existing Data Feeds

Aircraft System Health Management (ASHM) is a web application used for Boeing 787® and Airbus A320® and A380® aircraft system monitoring by airlines and field engineers worldwide which also serves all existing Aircraft Condition Monitoring Function (ACMF) reports, Flight Deck Effects (FDE) records and aircraft metadata to UTC engineering teams to aid in efficient aftermarket support. This enables creation, testing and fielding of off-board diagnostics and prognostics modules of varying levels of sophistication, that convert this abundance of existing data into actionable and timely knowledge about a/c fleet health. ASHM encourages and promotes cross functional collaboration allowing those with the most subject matter expertise within the enterprise to access the field data they need to observe operational performance and to create, test and field modules that can actively diagnose and warn field service professionals of problems when and potentially before they arise. A practical case study related to monitoring of the novel Boeing 787® electromechanically driven distributed aircraft environmental systems is presented. This use case motivates a discussion of pragmatic lessons learned in the fielding of diagnostic and prognostics solutions.

Lessons Learned in Implementing a Practical Aircraft System Health Management ( ASHM ) System

Although typical Health and Usage Monitoring Systems (HUMS) intend to support a transition from scheduled part replacements to performing maintenance upon evidence of need, they generally exhibit a limited ability to diagnose component faults early and accurately in complex systems such as a helicopter drive train. Consequently, the traditional approach to implementing Condition Based Maintenance (CBM) programs is slow, requires substantial amounts of human supervision, and ultimately lacks prognostics. A team of developers from Impact Technologies, the U.S. Army Research Laboratory and the Georgia Institute of Technology, with support from the U.S. Army, have been working over the past 3 years to develop a methodology to improve the performance of U.S. Army helicopter CBM systems, and facilitate transition from scheduled maintenance to implementation of prognostics. This paper presents an integrated diagnostic enhancement and prognostic architecture and the corresponding software suite, and discusses how a hybrid and systematic approach to sensing, data processing, fault feature extraction, fault diagnosis, and parallel health-based and usage-based failure prognosis can be used to improve the performance of HUMS and CBM activities. The paper also provides an application example, and discusses validation steps for the new approach to diagnostic enhancement and prognostics.

Integrated Software Platform for Diagnostics and Prognostics with Air Vehicle HUMS

In this study, the authors conducted a model-based, engine system analysis of Electro-Mechanical Actuators (EMAs). This effort employed an existing, NASA developed, aircraft engine model. A critical engine actuator within the model was replaced by a dynamic, physics based EMA model that includes: controller, motor, drivetrain and feedback sensor sub-models. The actuator model includes simulation of the electrical, mechanical and thermal response of the system. The resulting platform was used to simulate a range of critical actuator fault conditions including: feedback resolver fault, ball-screw degradation, motor winding short, and LVDT non-linearity. Since the available experimental data from propulsion system EMAs is very limited, this platform provides an ideal opportunity to evaluate and enhance prognostic capability for critical engine applications. The model fault tests were used to demonstrate a prototype prognostics and health management (PHM) system for engine EMAs. First, the system response was used to develop an appropriate mode detection algorithm to identify the ideal system conditions for collection of diagnostic evidence. Then, using the acquired transient and steady-state system response, diagnostic data features were derived from EMA related sensors and engine performance parameters. Using these features as a starting point, a system level reasoner was created using multiple classification techniques including LDA, QDA and SVM. Using model generated data with simulated system variance, it was demonstrated that the reasoner provides excellent fault detection, isolation and severity assessment capability for all considered fault modes. Finally, a suitable actuator life model was developed and a probabilistic prognostic approach was used to determine the remaining useful life of the system. The demonstrated PHM system will significantly enhance the ability to safely operate aircraft, schedule maintenance activities, optimize operational life cycles, and reduce support costs.© 2011 ASME

Prognostics and Health Management of Aircraft Engine EMA Systems

Although typical Health and Usage Monitoring Systems (HUMS) intend to support a transition from scheduled part replacements to performing maintenance upon evidence of need, they generally exhibit a limited ability to diagnose component faults early and accurately in complex systems such as a helicopter drive train. Consequently, the traditional approach to implementing Condition Based Maintenance (CBM) programs is slow, requires substantial amounts of human supervision (including case-by-case data analysis and results verification), and ultimately shuns prognostic activities. Causes of these limitations, which ultimately lead to an underrepresentation of prognostics in fielded CBM systems, include: (i) the sensitivity of sensors and condition indicators to signal noise and operating modes; (ii) use of empirical condition indicators not fully understood at the fleet-wide level; (iii) uncertainty in damage progression tracking; (iv) the inherent risk of condition prognosis; and (v) the lack diagnostic and prognostic validation with known fault cases. To improve the performance of CBM systems and facilitate transition from scheduled maintenance to reliable implementation of diagnostics and prognostics, a team of developers from Impact Technologies, the U.S. Army Research Laboratory and the Georgia Institute of Technology, with support from the U.S. Army have been working over the past 2½ years to develop a methodology that is capable of addressing the challenges listed. This work has been a part of the Air Vehicle Diagnostics and Prognostics Improvement Program (AVDPIP), a collaborative agreement to develop, test and evaluate modular software components that provide enhancements to diagnostic systems already in service, as well as add failure prognosis capabilities for critical Army aircraft components. This paper presents the integrated diagnostic enhancement and prognostic architecture, as well as the software suite developed under the collaborative program, and discusses how a hybrid and systematic approach to sensing, data processing, fault feature extraction, fault diagnosis, and parallel health- based and usage-based failure prognosis can be used to improve the performance of a wide variety of HUMS and CBM activities in support of implementing prognostics. The software architecture contains generic components and algorithms building on model based and data driven methodologies that are applicable to a variety of critical components in complex systems such as those found in a helicopter drive train. *

Integrated Software Platform for Fleet Data Analysis, Enhanced Diagnostics, and Safe Transition to Prognostics for Helicopter Component CBM

A major objective of Health and Usage Monitoring Systems (HUMS) is to transition from time based part replacement to performing maintenance actions based on evidence of need. While existing HUMS capability has demonstrated progress, the ability to diagnose component faults in their early stages is limited. This is due in part to sensitivity to signal noise, variations in environmental and operating conditions, and underutilization of prognostic techniques. Using the representative example of the fan support bearing in the oil cooler of the UH-60 helicopter, this paper discusses key areas to improve fault detection methods for health monitoring of a damaged helicopter transmission component. These include: (1) sensing and data processing tools, (2) selection and extraction of optimum condition indicators/features, (3) fusion of data at the sensor and feature levels, and (4) incipient fault detection using a Bayesian estimation framework. Results illustrating the effectiveness of these techniques are presented for fielded UH-60 bearing vibration data and laboratory test results.

Diagnostic enhancements for air vehicle HUMS to increase prognostic system effectiveness

Expanded deployment of Electro-Mechanical Actuators (EMAs) in critical applications has created much interest in EMA Prognostic Health Management (PHM), a key enabling technology of Condition Based Maintenance (CBM). As such, Impact Technologies, LLC is collaborating with the NASA Ames Research Center to perform a number of research efforts in support of NASA's Integrated Vehicle Health Management (IVHM) initiatives. These efforts have combined experimental test stand development, laboratory seeded fault testing, and physical model-based health monitoring in a comprehensive PHM system development strategy. This paper discusses two closely related EMA research programs being conducted by Impact and NASA Ames. The first of these efforts resulted in the creation of an electro-mechanical actuator test stand for the Prognostics Center of Excellence at the NASA Ames Research Center. The second effort is ongoing and is utilizing physics-based modeling techniques to develop an algorithm and software package toolset for PHM of aircraft EMA systems using a hybrid (virtual sensor) approach.

Experimental and analytical development of health management for Electro-Mechanical Actuators

In 2000 a corehole at the National Aeronautics and Space Administration (NASA) Langley Research Center, Hampton, Va., was continuously cored through the entire coastal plain section into crystalline basement rock by the U.S. Geological Survey (USGS) and its cooperators; a high-resolution seismic-reflection and seismic-refraction survey across the York-James Peninsula was simultaneously conducted. The core and land-based seismic data were needed to interpret the Chesapeake Bay impact crater's effects on the geological and hydrogeological framework of the lower York-James Peninsula. This kind of information is required to determine the location of the crater's buried outer margin escarpment. The USGS-NASA Langley corehole reached a total depth of 635.1 meters (m; 2,083.8 feet (ft)); the hole penetrated 235.65 m (773.12 ft) of postimpact sediments overlying 390.63 m (1,281.6 ft) of synimpact debris and 8.9 m (29.1 ft) of crystalline basement rock. The synimpact and postimpact stratigraphic units of the new corehole correlate well with units interpreted by Powars and Bruce (1999, USGS Professional Paper 1612) from geophysical logs and descriptions of cuttings from a preexisting test well that was located about 520 m (1,700 ft) east of the new corehole. The postimpact deposits recovered in the USGS-NASA Langley core include, in ascending order, the following units: the very clayey, calcareous Chickahominy Formation (upper Eocene); the glauconitic, phosphatic, and partly shelly lithologies of both the Drummonds Corner beds (a newly recognized upper lower Oligocene stratigraphic unit) and the Old Church Formation (upper Oligocene); the shelly and sandy beds of the Calvert Formation (lower Miocene); the primarily siliciclastic, fine-grained part of the Calvert Formation (middle Miocene), the St. Marys Formation (upper Miocene), and the lower part of the Eastover Formation (upper Miocene); the siliciclastic, locally glauconitic, fine- to coarse-grained, fossiliferous upper part of the Eastover (upper Miocene) and the Yorktown Formation (lower and upper Pliocene); and the fluvial to estuarine Tabb Formation (upper Pleistocene). The land-based seismic-reflection survey was run adjacent to the Langley corehole to correlate velocities and reflectors with the lithology of the core. The seismic profile also shows that most of the synimpact crater debris consists of highly fractured and fault-bounded, blocky material with distinctive anisotropy and reflection patterns. The overlying postimpact deposits show disruption zones suggesting fracturing and faulting; the scale of deformation in the postimpact deposits is orders of magnitude less than the scale of deformation within the synimpact deposits. Recovery of several angled fractures with slickensides and a fault filled with gouge within the postimpact section provides supportive evidence for their signature on the seismic images. These postimpact fractures and faults may be related to continued compaction and megablock movement. The existence of a preimpact James River structural zone along the southern and southwestern margin of the crater has an apparent additive effect to synimpact and postimpact structural adjustments of the region.

Physical stratigraphy of the upper eocene to quaternary postimpact section in the USGS-NASA langley core, Hampton, Virginia

The Oil-Free Turbomachinery Program at the NASA Glenn Research center is committed to, revolutionary improvements in performance, efficiency and reliability of turbomachinery propulsion systems. One of the key breakthroughs by which this goal is being achieved is the maturation of air lubricated foil bearing technology. Through experimental testing, foil bearings have demonstrated a variety of exceptional qualities that show them to have an important role in the future of rotordynamic lubrication. Most of the work done with foil bearings thus far has considered ambient air at atmospheric pressure as the working fluid or lubricating fluid in the bearing. However, special applications of oil-free technology require the use of air at non- standard ambient conditions or completely different working fluids altogether. The NASA Jupiter Icy Moon Orbiter program presents power generation needs far beyond that of any previous space exploration effort. The proposed spacecraft will require significant power generation to provide the propulsion necessary to reach the moons of Jupiter and navigate between them. Once there, extensive scientific research will be conducted that will also present significant power requirements. Such extreme needs require exploring a new method for power generation in space. A proposed solution involves a Brayton cycle nuclear fission reactor. The nature of this application requires reliable performance of all reactor components for many years of operation under demanding conditions. This includes the bearings which will be operating with an alternative working fluid that is a combination of Helium and Xenon gases commonly known as HeXe. This fluid has transport and thermal properties that vary significantly from that of air and the effect of these property differences on bearing performance must be considered. One of the most promising applications of oil-free technology is in aircraft turbine engines. Eliminating the oil supply systems from aircraft engines will lead to significant weight and maintenance reduction. In such applications, the lubricating fluid will be high altitude air. This air will be at much lower pressure than that at sea level. Again this property change will result in a change in bearing performance, and analysis is required to quantify this effect. The study of these alternate working fluid properties will be conducted in two ways: analytically and experimentally. Analytical research will include the use of a mathematical code that can predict film thickness profiles for various ambient conditions. Estimations of load capacity can be made based upon the film thickness trends. These values will then be compared to those obtained from classical rigid bearing analysis. Experimental Research will include testing a foil bearing at a variety of ambient air pressures. The analytical and experimental data will be compared to draw conclusions on bearing performance under alternate working fluid properties.

Consideration of Alternate Working Fluid Properties in Gas Lubricated Foil Journal Bearings

Preliminary report on the USGS-NASA Langley Corehole -- the Chesapeake Bay Impact Crater Project: A. Operational summary for the USGS -- NASA Langley Corehole, Hampton, Virginia. B. Preliminary geologic summary for the USGS -- NASA Langley Corehol, Hampton, Virginia

This technical note is part of a series collaboratively produced by the US Army Corps of Engineers (USACE)–Institute for Water Resources (IWR) and the US Army Engineer Research and Development Center (ERDC). It describes the funding process for Exploration Green, a largescale community initiative that transformed a former golf course into a multipurpose green space with flood detention, habitat, and recreation benefits. It is one in a series of technical notes that document successful examples of funding natural infrastructure projects. The research effort is a collaboration between the Engineering With Nature® (EWN®) and Systems Approach to Geomorphic Engineering (SAGE) programs of USACE. A key need for greater application of natural infrastructure approaches is information about obtaining funds to scope, design, construct, monitor, and adaptively manage these projects. As natural infrastructure techniques vary widely by location, purpose, and scale, there is no standard process for securing funds. The goal of this series is to share lessons learned about a variety of funding and financing methods to increase the implementation of natural infrastructure projects.

Regional, national and societal pressures are increasing with a view towards reducing the use of mains water for the irrigation of urban green infrastructure. The research aimed to separately evaluate the effects upon urban green infrastructure of irrigation using untreated or raw greywater (RGW), irrigation using a mains water comparison and importantly, irrigation using greywater treated using an industrial grade treatment system (TGW). The treatment system is in use in buildings in the City of London and elsewhere. Different mixes of soil and growing media were also included in the methodology. 
 
Some authors have previously investigated, regarding food production and agriculture, the advantages and disadvantages of irrigation using raw greywater. Some results have included evidence showing that applying RGW to the irrigation of soils has led to a detrimental effect upon Soil Water Holding Capacity (SWHC). In the current research, the operational system providing up to 1m3 of treated greywater per day made possible comparisons of effects upon SWHC produced by the three types of irrigation water. The effects of the three irrigation streams on different soil compositions (50:50, 80:20 and 20:80, as ratios of growing medium to compost) were measured. 
 
The differences between the irrigation systems in their effects upon growing media and composts were found to be small; an adverse impact upon SWHC also arose from mains water irrigation. The results will assist in the forthcoming design of drainage and SUDS systems to support the wider use of lightly loaded greywater for the irrigation of urban green infrastructure.

Evidence concerning the irrigation of urban green infrastructure using lightly loaded greywater

Separating greywater before it combines with sewage and laundry effluents can be used to sustain urban environments and their green infrastructure by irrigating using treated greywater. An analytical approach to the quality and reuse opportunities for greywater leads to the determination of water reuse and irrigation potential, feasibility, and water stewardship. The evidence from various studies shows that lightly loaded greywaters can probably be used with confidence for watering certain types of green infrastructure. This is an important potential means for sustaining vegetation during times of water stress or drought. 
 For larger volume discharges, affordable system configurations for achieving licensable discharges to support plants need to be identified and approved. For smaller, domestic-scale discharges, it appears that there is often little legislative barrier to direct irrigation using treated greywater. 
 Rationalisation of the technology configuration, and thus the potential costs to be incurred, will provide an opportunity to carefully design and implement landscaping specifically to work in conjunction with irrigation systems. This will reduce levels of pollutants entering the urban environment while establishing and developing the opportunity for more greywater sources to be utilised in a sustainable manner.

Fragility fractures: A complex interaction of the health care system- the patient and the bone: Can we do better?

Greywater of both treated (TGW) and untreated (GW) types are significant alternatives to mains water (MW) for sustaining the growth and expansion of green infrastructure. The aims of this thesis were first to evaluate GW and TGW as alternatives to MW for the purpose of irrigation of green walls and green roofs. Second, to determine whether irrigation water that has percolated through a green walls soil matrix can be further recycled and reused. GW was treated by a membrane bioreactor (MBR) and produced a high quality TGW, which met British Standards GW reuse requirements. A number of significant water quality improvements were achieved including the complete removal of bacterial species. Notably, GW turbidity was reduced from S.B±4.7 NTU to 0.6±0.2 NTU. Reduction in sodium (Na) concentrations were negligible or below limits of detection with inflow GW having 19.74±S.33 mg/l and outflow TGW 19.67±4.93 mg/1. Sodium was a constituent of particular interest since it is a key constituent of bathroom products as well as causing detrimental effects on soil and plant health in significant concentrations. Green wall irrigation trials showed that when comparing soils irrigated with synthetic GW and MW that no elevation ofsodium concentrations in the filtrate and soil samples was observed. The nutrient content and microbiological quality of green wall filtrate were influenced to a greater extent by its interaction with the soil matrix than the irrigation water type (synthetic GW, MW and TGW). Literary research has shown that GW irrigation ofsoils significantly reduced the SWHC (soil water holding capacity). The green walls irrigation trial results showed that the SWHC decreased by 24%, 23% and 20% when irrigated with synthetic GW, MWand TGW respectively. This demonstrates that the MW irrigation caused a SWHC decrease and that the additional decrease due to GW irrigation was only 1 %. Lightly loaded GW irrigation would not only allow for the replacement of MW but also provide filtered water, which can be collected and utilised. This project highlights a sustainable irrigation alternative to further integrated green walls into the urban environment. Results show that there was minimal effect of GW irrigation on soil, filtrate and leaf tissue in comparison to MW and TGW irrigation.

The function of a green wall system when integrated with greywater treatment, recycling, and irrigation : exploration of water quality, water resources and planting media

Individuals of the annual sedge, Fimbristylis autumnalis (L.) Roem. & Schult., were discovered on August 28, 2016 on a sandy western shore of Loon Lake, Kejimkujik National Park and National Historic Site, Nova Scotia. This is the first record for this taxon in Nova Scotia and for the Maritime Provinces of Canada; a voucher specimen (ECS043741) is deposited in the E.C. Smith Herbarium (ACAD), Wolfville, Nova Scotia. This wide-ranging sedge of the Americas has a North America distribution suggestive of an Atlantic Coastal Plain affinity (NatureServe 2017) although its distribution extends into Central and South America (IUCN 2017). It is imperilled in Maine and Quebec but elsewhere, it seems typical of coastal plain marshes (Kost et al. 2007), pond shores (McAvoy and Bowman 2002), vernal pools (Cutko and Rawinski 2008) and reservoirs (DeBerry and Perry 2005). In Nova Scotia, this diminutive annual was growing in sand on the lower shore of a large watershed area lake where it occupied a vertical shoreline band from 1.4 to 1.6m below the winter high water mark (Figure 1). This new record is similar to the find of the equally diminutive sedge annual, Cyperus diandrus Torr. on the drawn down shore at the outflow of Third Lake, Nova Scotia (Hill 2001). Both of these small sedges occupy an exceedingly narrow niche, the lowest exposed shorelines of large watershed area lakes. The shoreline profile for slender fimbry (F. autumnalis) in Nova Scotia was dominated by tall shrubbery [Gaylussacia baccata (Wangenh.) K. Koch] at the top of the shoreline, tall C4 graminoid (Panicum virgatum L.) in midshore, followed successively down the shore by Cladium mariscoides (Muhl.) Torr., Fimbristylis autumnalis, Eriocaulon aquaticum (Hill) Druce,

First Record in Maritime Canada of the Coastal Plain Annual, Slender Fimbry, Fimbristylis autumnalis (Cyperaceae), on a Lake Shore in a Low Rainfall Year

Aims: To evaluate the potential for substituting green roof mains water irrigation by irrigation using lightly loaded synthetic greywater. 
Study Design: The planted green roof system was designed to be operated and tested within a glasshouse. 
Place and Duration of Study: Schools of Engineering, and Plant Sciences, The University of Reading, for 28 days commencing 28th of May 2012. 
Methodology: A trial was conducted for comparing two planting schemes using Sedum and Stachys Byzantina and a third unplanted control. The three sets of growing boxes were subdivided between substrate depths of 10cm and 20cm. By further subdivision, half of each set were watered using mains water, and half using a synthetic greywater. The soil composition and water quality of the drainage (filtrate) water were monitored. Statistical analysis of the results was conducted. 
Results: Consistency was observed in influent pH and EC, in both mains and greywater samples. Influent Na concentrations were higher in the greywater samples due to detergent content. The Na mass balance calculations for all boxes showed that some Na mass was unaccounted for when comparing aggregated concentrations in influent, plant tissue and soil with the aggregated Na mass in filtrate, plant tissue and soil water. It was concluded that this was likely to be due to retained/ponded irrigation water in the boxes, difficulties in attaining homogenous box flushing and the underestimation of soil Na. The variation in substrate depth affected all results. The plants themselves seemed to have little significant influence on the measured parameters, with the exception of the accumulation of Na mass in plants irrigated with greywater. 
Conclusion: No improvement was observed in the quality of the greywater following filtration through the soil matrix. For longer term watering using greywater, a choice of Na resistant species should be considered, although the Sedum species used in this trial showed no recorded adverse growth effects due to Na accumulation.

Monitoring drainage water quality during green roof irrigation trials using synthetic greywater

A manufactured aeration and nanofiltration MBR greywater system was tested during continuous operation at the University of Reading, to demonstrate reliability in delivery of high quality treated greywater. Its treatment performance was evaluated against British Standard criteria [BSI (Greywater Systems—Part 1 Code of Practice: BS8525-1:2010. BS Press, 2010); (Greywater Systems—Part 2 Domestic Greywater Treatment, Requirements and Methods: BS 8525-2:2011. BS Press, 2011)]. The low carbon greywater recycling technology produced excellent analytical results as well as consistency in performance. User acceptance of such reliably treated greywater was then evaluated through user perception studies. The results inform the potential supply of treated greywater to student accommodation. Out of 135 questionnaire replies, 95% demonstrated a lack of aversion in one or more attributes, to using treated, recycled greywater.

Developments in the quality of treated greywater supplies for buildings, and associated user perception and acceptance

Two separate research questions on greywater were presented; firstly, whether the operation of a commercial greywater system at the University of Reading could provide a continuous supply of suitably treated greywater for potential domestic reuse at the halls of residence; secondly, on the basis that such a suitably treated supply of greywater could be made available to the halls of residence, what user expectations regarding the use of the domestic greywater supplies might be expected.The first research question concerned the quality of greywater that could be produced by commercially available aeration and ultra-filtration greywater units. A greywater treatment process was installed at the School of Construction Management and Engineering, at the University of Reading. The quality of treated greywater produced by the treatment plant was demonstrated to meet the British Standard chemical and microbiological quality standards. Therefore, the greywater supply is expected to be of a suitable quality to be capable of meeting user expectations in the halls of residence.The second research question concerned the characteristics of user expectations.135 replies were received in response to a greywater questionnaire survey amongst students and researchers living in the University halls of residence. Of these, 95% of respondents fell into four groups; 1) those in support of greywater for all uses, 2) those in suport of greywater for most uses, 3) those in support of greywater for non-drinking uses only; 4) those in support of it "if it is safe to use". The respondent population of 135 people demonstrated a number of remarkable features, including a general lack of distaste for a domestic greywater supply. This may suggest that environmental awareness has developed since the earliest surveys of the 1970s and the observations of Po et al [11]. Then applying the observations of Kaercher [8],would suggest that the findings of the current study should next be tested in a student population that has daily access to the use of domestic greywater supplies. That might then confirm whether or not any lack of preconceived aversion to greywater could be demonstrated in the daily domestic greywater consumption. Future research will be directed to this question.

Attribites of greywater reuse: well-controlled greywater treatment and user perception

Geophysical detection of on-site wastewater plumes in the North Carolina Coastal Plain, USA

GEOPHYSICAL AND WATER QUALITY CHARACTERIZATION OF ON-SITE WASTEWATER TREATMENT SYSTEM EFFLUENT PLUMES AT TWO SCHOOLS IN THE NORTH CAROLINA COASTAL PLAIN

Working in the grave : the development of a health and safety system on the Witwatersrand gold mines, 1900-1939

Mining disaster in instalments: the completion of the foundations for the modern health and safety system on the Witwatersrand gold mines 1930 -1939

Shape features of working memory-related deep-brain regions differentiate high and low community functioning in schizophrenia

Clinical insight and cognitive functioning as mediators in the relationships between symptoms of psychosis, depression, and suicide ideation in first-episode psychosis.

Early-onset schizophrenia (EOS) shares many biological and clinical features with adult-onset schizophrenia (AOS), but may represent a unique subgroup with greater susceptibility for disease onset and worsened symptomatology and progression, which could potentially derive from exaggerated neurodevelopmental abnormalities. Neurobiological explanations of schizophrenia have emphasized the involvement of deep-brain structures, particularly alterations of the thalamus, which have been linked to core features of the disorder. The aim of this study was to compare thalamic shape abnormalities between EOS and AOS subjects and determine whether unique behavioral profiles related to these differences. It was hypothesized abnormal thalamic shape would be observed in anterior, mediodorsal and pulvinar regions in both schizophrenia groups relative to control subjects, but exacerbated in EOS. Magnetic resonance T1-weighted images were collected from adult individuals with EOS (n = 28), AOS (n = 33), and healthy control subjects (n = 60), as well as collection of clinical and cognitive measures. Large deformation high-dimensional brain mapping was used to obtain three-dimensional surfaces of the thalamus. General linear models were used to compare groups on surface shape features, and Pearson correlations were used to examine relationships between thalamic shape and behavioral measures. Results revealed both EOS and AOS groups demonstrated significant abnormal shape of anterior, lateral and pulvinar thalamic regions relative to CON (all p < 0.007). Relative to AOS, EOS exhibited exacerbated abnormalities in posterior lateral, mediodorsal and lateral geniculate thalamic regions (p = 0.003). Thalamic abnormalities related to worse episodic memory in EOS (p = 0.03) and worse working memory (p = 0.047) and executive functioning (p = 0003) in AOS. Overall, findings suggest thalamic abnormalities are a prominent feature in both early- and late-onset schizophrenia, but exaggerated in EOS and have different brain-behavior profiles for each. The persistence of these abnormalities in adult EOS patients suggests they may represent markers of disrupted neurodevelopment that uniquely relate to the clinical and cognitive aspects of the illness.

Thalamic Shape Abnormalities Differentially Relate to Cognitive Performance in Early-Onset and Adult-Onset Schizophrenia

Distinct Thalamic Abnormalities Differentially Relate to Cognition in Early-Onset Relative to Adult-Onset Schizophrenia

Objective: Deficits in cognitive empathy are well-documented in individuals with schizophrenia and are related to reduced community functioning. The temporoparietal junction (TPJ) is closely linked to cognitive empathy. We compared the relationship between baseline cognitive empathy and changes in TPJ thickness over 24 months between individuals with schizophrenia and healthy controls. Methods: Individuals with schizophrenia (n = 29) and healthy controls (n = 26) completed a cognitive empathy task and underwent structural neuroimaging at baseline and approximately 24 months later. Symmetrized percent change scores were calculated for right and left TPJ, as well as whole-brain volume, and compared between groups. Task accuracy was examined as a predictor of percent change in TPJ thickness and whole-brain volume in each group. Results: Individuals with schizophrenia demonstrated poorer accuracy on the cognitive empathy task (p < 0.001) and thinner TPJ cortex relative to controls at both time points (p = 0.01). In schizophrenia, greater task accuracy was uniquely related to less thinning of the TPJ over time (p = 0.02); task accuracy did not explain changes in left TPJ or whole-brain volume. Among controls, task accuracy did not explain changes in right or left TPJ, or whole-brain volume. Conclusions: Our findings suggest that greater cognitive empathy may explain sustained integrity of the right TPJ in individuals with schizophrenia, suggesting a contributory substrate for the long-term maintenance of this process in psychosis. Cognitive empathy was not related to changes in whole-brain volume, demonstrating the unique role of the TPJ in cognitive empathy.

Cognitive Empathy and Longitudinal Changes in Temporo-Parietal Junction Thickness in Schizophrenia

Basal ganglia shape features differentiate schizoaffective disorder from schizophrenia

Mental health interventions do not yet offer complete, client-defined functional recovery, and novel directions in treatment research are needed to improve the efficacy of available interventions. One promising direction is the integration of social work and cognitive neuroscience methods, which provides new opportunities for clinical intervention research that will guide development of more effective mental health treatments that holistically attend to the biological, social, and environmental contributors to disability and recovery. This article reviews emerging trends in cognitive neuroscience and provides examples of how these advances can be used by social workers and allied professions to improve mental health treatment. We discuss neuroplasticity, which is the dynamic and malleable nature of the brain. We also review the use of risk and resiliency biomarkers and novel treatment targets based on neuroimaging findings to prevent disability, personalize treatment, and make interventions more targeted and effective. The potential of treatment research to contribute to neuroscience discoveries regarding brain change is considered from the experimental-medicine approach adopted by the National Institute of Mental Health. Finally, we provide resources and recommendations to facilitate the integration of cognitive neuroscience into mental health research in social work.

Using Cognitive Neuroscience to Improve Mental Health Treatment: A Comprehensive Review

OBJECTIVE
Research typically characterizes cannabis use by self-report of cannabis intake frequency. In an effort to better understand relationships between measures of cannabis use, we evaluated if Δ-9-tetrahydrocannabinol (THC) and metabolite concentrations (biometrics) were associated with a calibrated timeline followback (TLFB) assessment of cannabis use.

METHOD
Participants were 35 young adult male cannabis users who completed a calibrated TLFB measure of cannabis use over the past 30 days, including time of last use. The calibration required participants handling four plastic bags of a cannabis substitute (0.25, 0.5, 1.0, and 3.5 grams) to quantify cannabis consumed. Participants provided blood and urine samples for analysis of THC and metabolites, at two independent laboratories. Participants abstained from cannabis use on the day of sample collection. We tested Pearson correlations between the calibrated TLFB measures and cannabis biometrics.

RESULTS
Strong correlations were seen between urine and blood biometrics (all r > .73, all p < .001). TLFB measures of times of use and grams of cannabis consumed were significantly related to each biometric, including urine 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH) and blood THC, 11-hydroxy-THC (11-OH-THC), THCCOOH, THCCOOH-glucuronide (times of use: r > .48-.61, all p < .05; grams: r > .40-.49, all p < .05).

This study extends prior work to show TLFB methods significantly relate to an extended array of cannabis biometrics. The calibration of cannabis intake in grams was associated with each biometric, although the simple TLFB measure of times of use produced the strongest relationships with all five biometrics. These findings suggest that combined self-report and biometric data together convey the complexity of cannabis use, but allow that either the use of calibrated TLFB measures or biometrics may be sufficient for assessment of cannabis use in research.

Recent Self-Reported Cannabis Use Is Associated With the Biometrics of Delta-9-Tetrahydrocannabinol.

Progressive deterioration of thalamic nuclei relates to cortical network decline in schizophrenia

Alcohol-dependent liver transplantation (LT) patients who resume alcohol consumption are at risk for a number of alcohol-related problems including liver injury and liver failure. Post-LT patients are strongly advised to remain abstinent. However, we do not know how well this population complies due to a lack of valid methods (self-report and/or biomarkers) to identify alcohol use. Studies suggest as many as 50% resume alcohol use within 5 years. Phosphatidylethanol (PEth) is a new cell-membrane phospholipid biomarker to identify alcohol use in the past 28 days. This prospective study followed 213 LT recipients at 2 U.S. liver transplant centers.

METHODS
Sample included 213 LT subjects; 70.9% (n = 151/213) had a history of alcohol dependence prior to transplantation and 29.1% (n = 62/213) served as non-alcohol-dependent controls. Subjects participated in face-to-face interviews to assess alcohol use using a 30-day calendar. The protocol called for collecting blood samples at baseline, 6-, and 12-month follow-up.

RESULTS
Seventy percent (149/213) who reported no alcohol use had consistently negative PEth levels (<8 ng/ml). A total of 26.4% (57/213), 44 alcohol-dependent patients and 13 controls, had a positive PEth test of >8 ng/ml either at baseline and/or during the follow-up period. Alcohol-dependent subjects (23.8%; n = 36/151) and 16.1% (n = 10/62) controls reported no alcohol use but had at least 1 positive PEth test. Of the 11.2% (24/213) post-LT subjects who reported recent alcohol use, over half (11/24) had a positive PEth. The 13 self-reported alcohol users with a negative PEth level reported insufficient drinking to trigger PEth formation.

Adoption of PEth as part of routine posttransplant care of LT recipients will enable early identification of patients at risk of alcohol use and facilitate abstinence in patients with a history of alcohol dependence and alcohol-related liver damage.

Phosphatidylethanol Detects Moderate‐to‐Heavy Alcohol Use in Liver Transplant Recipients

Individuals with schizophrenia display notable deficits in social functioning. Research indicates that neural connectivity within the default mode network (DMN) is related to social cognition and social functioning in healthy and clinical populations. However, the association between DMN connectivity, social cognition, and social functioning has not been studied in schizophrenia. For the present study, the authors used resting-state neuroimaging data to evaluate connectivity between the main DMN hubs (i.e., the medial prefrontal cortex [mPFC] and the posterior cingulate cortex-anterior precuneus [PPC]) in individuals with schizophrenia (n = 28) and controls (n = 32). The authors also examined whether DMN connectivity was associated with social functioning via social attainment (measured by the Specific Levels of Functioning Scale) and social competence (measured by the Social Skills Performance Assessment), and if social cognition mediates the association between DMN connectivity and these measures of social functioning. Results revealed that DMN connectivity did not differ between individuals with schizophrenia and controls. However, connectivity between the mPFC and PCC hubs was significantly associated with social competence and social attainment in individuals with schizophrenia but not in controls as reflected by a significant group-by-connectivity interaction. Social cognition did not mediate the association between DMN connectivity and social functioning in individuals with schizophrenia. The findings suggest that fronto-parietal DMN connectivity in particular may be differentially associated with social functioning in schizophrenia and controls. As a result, DMN connectivity may be used as a neuroimaging marker to monitor treatment response or as a potential target for interventions that aim to enhance social functioning in schizophrenia.

Default Mode Functional Connectivity Is Associated With Social Functioning in Schizophrenia

Cortical thickness of neural substrates supporting cognitive empathy in individuals with schizophrenia

Impaired cognitive empathy is a core social cognitive deficit in schizophrenia associated with negative symptoms and social functioning. Cognitive empathy and negative symptoms have also been linked to medial prefrontal and temporal brain networks. While shared behavioral and neural underpinnings are suspected for cognitive empathy and negative symptoms, research is needed to test these hypotheses. In two studies, we evaluated whether resting‐state functional connectivity between data‐driven networks, or components (referred to as, inter‐component connectivity), predicted cognitive empathy and experiential and expressive negative symptoms in schizophrenia subjects. Study 1: We examined associations between cognitive empathy and medial prefrontal and temporal inter‐component connectivity at rest using a group‐matched schizophrenia and control sample. We then assessed whether inter‐component connectivity metrics associated with cognitive empathy were also related to negative symptoms. Study 2: We sought to replicate the connectivity‐symptom associations observed in Study 1 using an independent schizophrenia sample. Study 1 results revealed that while the groups did not differ in average inter‐component connectivity, a medial‐fronto‐temporal metric and an orbito‐fronto‐temporal metric were related to cognitive empathy. Moreover, the medial‐fronto‐temporal metric was associated with experiential negative symptoms in both schizophrenia samples. These findings support recent models that link social cognition and negative symptoms in schizophrenia. Hum Brain Mapp 38:1111–1124, 2017. © 2016 Wiley Periodicals, Inc.

Fronto‐temporal connectivity predicts cognitive empathy deficits and experiential negative symptoms in schizophrenia

The nicotine metabolite ratio (NMR) has been shown to predict response to the transdermal nicotine patch, such that faster nicotine metabolism is associated with a lower abstinence rate. Menthol cigarette use, versus nonmenthol cigarette use, slows nicotine metabolism and therefore may attenuate the effect of NMR on smoking abstinence. In this study, we evaluated whether cigarette type (menthol vs. nonmenthol) modified the association between NMR and short-term abstinence. This was a secondary analysis examining treatment in the first 8 weeks of 21 mg/day nicotine patch therapy in a completed clinical trial (n = 474). Menthol cigarette use was based on self-report. NMR was defined dichotomously (0 = fast, 1 = slow) to distinguish between fast (≥0.47) versus slow NMR. Using logistic regression analysis, we tested whether cigarette type moderated the association between NMR and bioverified 7-day point prevalence abstinence at Week 8. Covariates include nicotine dependence, age, race, and gender. Three hundred two participants reported smoking menthol cigarettes, of which 234 (77%) were classified as slow NMR. Among the 172 nonmenthol smokers, 136 were classified as slow NMR (79%). Contrary to our expectations, the NMR ×Cigarette Type interaction effect on abstinence was not significant (odds ratio [OR] = 0.91, p = .86). Excluding the interaction variable, fast NMR was associated with decreased likelihood of abstinence (OR = 0.55, p = .03), but menthol cigarette use was not (OR = 1.15, p = .56). Further exploration of risk factors among menthol cigarette smokers, especially among racially diverse and light smokers, could clarify the association between menthol cigarette use and poorer smoking outcomes.

Does Menthol Cigarette Use Moderate the Effect of Nicotine Metabolism on Short-Term Smoking Cessation?

Individuals with schizophrenia are burdened with impairments in functional outcome, despite existing interventions. The lack of understanding of the neurobiological correlates supporting adaptive function in the disorder is a significant barrier to developing more effective treatments. This research conducted a systematic and meta-analytic review of all peer-reviewed studies examining brain-functional outcome relationships in schizophrenia. A total of 53 (37 structural and 16 functional) brain imaging studies examining the neural correlates of functional outcome across 1631 individuals with schizophrenia were identified from literature searches in relevant databases occurring between January, 1968 and December, 2016. Study characteristics and results representing brain-functional outcome relationships were systematically extracted, reviewed, and meta-analyzed. Results indicated that better functional outcome was associated with greater fronto-limbic and whole brain volumes, smaller ventricles, and greater activation, especially during social cognitive processing. Thematic observations revealed that the dorsolateral prefrontal cortex, anterior cingulate, posterior cingulate, parahippocampal gyrus, superior temporal sulcus, and cerebellum may have role in functioning. The neural basis of functional outcome and disability is infrequently studied in schizophrenia. While existing evidence is limited and heterogeneous, these findings suggest that the structural and functional integrity of fronto-limbic brain regions is consistently related to functional outcome in individuals with schizophrenia. Further research is needed to understand the mechanisms and directionality of these relationships, and the potential for identifying neural targets to support functional improvement.

A Systematic and Meta-analytic Review of Neural Correlates of Functional Outcome in Schizophrenia

Neural correlates of preserved facial affect perception in high functioning schizophrenia

High functioning individuals with schizophrenia have preserved social perception but not mentalizing abilities

Research suggests siblings of individuals with schizophrenia are at a heightened risk for depressive symptomatology. Research has not yet examined whether the strains of growing up with a brother or sister with schizophrenia contribute to this risk. This study examined whether early life course burdens associated with an emerging mental illness, and current objective and subjective caregiver burden predicted depressive symptoms in siblings of individuals with schizophrenia.

METHOD
Forty-one siblings of individuals with schizophrenia were recruited from a large study of schizophrenia neurobiology to complete a self-administered questionnaire and a neuropsychological test battery.

RESULTS
Early life course burdens and current objective and subjective burdens explained incremental variance in depressive symptoms of siblings of individuals with schizophrenia after accounting for gender and global neurocognitive function. Higher levels of depressive symptoms among siblings were associated with perceptions of being stigmatized by the community (β=.37, p<.01), and perceiving that the brother or sister's emerging illness negatively impacted the sibling's social life during childhood and adolescence (β=.39, p<.01). Taking on adult responsibilities while the sibling was growing up was found to be protective against depressive symptoms in adulthood (β= -.36, p<.01).

Early life course burdens associated with having a sibling with schizophrenia and current subjective burden provide insight into psychosocial factors that may contribute to the risk for depression in this sibling group. Mental health service providers and psychoeducation programs would benefit by considering these factors when developing family-based interventions.

Life Course Challenges Faced by Siblings of Individuals with Schizophrenia May Increase Risk for Depressive Symptoms.

Impaired cognitive empathy (ie, understanding the emotional experiences of others) is associated with poor social functioning in schizophrenia. However, it is unclear whether the neural activity underlying cognitive empathy relates to social functioning. This study examined the neural activation supporting cognitive empathy performance and whether empathy-related activation during correctly performed trials was associated with self-reported cognitive empathy and measures of social functioning. Thirty schizophrenia outpatients and 24 controls completed a cognitive empathy paradigm during functional magnetic resonance imaging. Neural activity corresponding to correct judgments about the expected emotional expression in a social interaction was compared in schizophrenia subjects relative to control subjects. Participants also completed a self-report measure of empathy and 2 social functioning measures (social competence and social attainment). Schizophrenia subjects demonstrated significantly lower accuracy in task performance and were characterized by hypoactivation in empathy-related frontal, temporal, and parietal regions as well as hyperactivation in occipital regions compared with control subjects during accurate cognitive empathy trials. A cluster with peak activation in the supplementary motor area (SMA) extending to the anterior midcingulate cortex (aMCC) correlated with social competence and social attainment in schizophrenia subjects but not controls. These results suggest that neural correlates of cognitive empathy may be promising targets for interventions aiming to improve social functioning and that brain activation in the SMA/aMCC region could be used as a biomarker for monitoring treatment response.

Alterations in brain activation during cognitive empathy are related to social functioning in schizophrenia.

Cannabis use has been associated with episodic memory (EM) impairments and abnormal hippocampus morphology among both healthy individuals and schizophrenia subjects. Considering the hippocampus' role in EM, research is needed to evaluate the relationship between cannabis‐related hippocampal morphology and EM among healthy and clinical groups. We examined differences in hippocampus morphology between control and schizophrenia subjects with and without a past (not current) cannabis use disorder (CUD). Subjects group‐matched on demographics included 44 healthy controls (CON), 10 subjects with a CUD history (CON‐CUD), 28 schizophrenia subjects with no history of substance use disorders (SCZ), and 15 schizophrenia subjects with a CUD history (SCZ‐CUD). Large‐deformation, high‐dimensional brain mapping with MRI produced surface‐based representations of the hippocampus that were compared across all four groups and correlated with EM and CUD history. Surface maps of the hippocampus were generated to visualize morphological differences. CON‐CUD and SCZ‐CUD were characterized by distinct cannabis‐related hippocampal shape differences and parametric deficits in EM performance. Shape differences observed in CON‐CUD were associated with poorer EM performance, while shape differences observed in SCZ‐CUD were associated with a longer duration of CUD and shorter duration of CUD remission. A past history of CUD may be associated with notable differences in hippocampal morphology and EM impairments among adults with and without schizophrenia. Although the results may be compatible with a causal hypothesis, we must consider that the observed cannabis‐related shape differences in the hippocampus could also be explained as biomarkers of a neurobiological susceptibility to poor memory or the effects of cannabis. © 2015 Wiley Periodicals, Inc.

Cannabis‐related episodic memory deficits and hippocampal morphological differences in healthy individuals and schizophrenia subjects

Brief Report: Vocational Outcomes for Young Adults with Autism Spectrum Disorders at Six Months After Virtual Reality Job Interview Training

Cluster analysis differentiates high and low community functioning in schizophrenia: Subgroups differ on working memory but not other neurocognitive domains

Cognitive empathy contributes to poor social functioning in schizophrenia: Evidence from a new self-report measure of cognitive and affective empathy

Cognitive empathy impairments have been linked to poor social functioning in schizophrenia. However, prior studies primarily used self-reported empathy measures developed decades ago that are not well-aligned with contemporary models of empathy. We evaluated empathy and its relationship to social functioning in schizophrenia using the recently developed Questionnaire of Cognitive and Affective Empathy (QCAE). Schizophrenia (n=52) and healthy comparison (n=37) subjects completed the QCAE, Interpersonal Reactivity Index (IRI), and measures of neurocognition, symptoms, and social functioning. Between-group differences on the QCAE, and relationships between QCAE and IRI subscales, neurocognition, symptoms, and social functioning were examined. The schizophrenia group reported significantly lower cognitive empathy than comparison subjects, which was driven by low online simulation scores. Cognitive empathy explained significant variance in social functioning after accounting for neurocognition and symptoms. Group differences for affective empathy were variable; the schizophrenia group reported similar proximal responsivity, but elevated emotion contagion relative to comparison subjects. These findings bolster support for the presence and functional significance of impaired cognitive empathy in schizophrenia using a contemporary measure of empathy. Emerging evidence that some aspects of affective empathy may be unimpaired or hyper-responsive in schizophrenia and implications for the assessment and treatment of empathy in schizophrenia are discussed.

Cognitive empathy contributes to poor social functioning in schizophrenia: Evidence from a new self-report measure of cognitive and affective empathy.

Empathy, depressive symptoms, and social functioning among individuals with schizophrenia

Empathic deficits have been linked to poor functioning in schizophrenia, but this work is mostly limited to self-report data. This study examined whether performance-based empathy measures account for incremental variance in social competence and social attainment above and beyond self-reported empathy, neurocognition, and clinical symptoms. Given the importance of working memory in theoretical models of empathy and in the prediction of functioning in schizophrenia, we also examined whether empathy mediates the relationship between working memory and functioning. Sixty outpatients and 45 healthy controls were compared on performance-based measures of 3 key components of empathic responding, including facial affect perception, emotional empathy (affective responsiveness), and cognitive empathy (emotional perspective-taking). Participants also completed measures of self-reported empathy, neurocognition, clinical symptoms, and social competence and attainment. Patients demonstrated lower accuracy than controls across the 3 performance-based empathy measures. Among patients, these measures showed minimal relations to self-reported empathy but significantly correlated with working memory and other neurocognitive functions as well as symptom levels. Furthermore, cognitive empathy explained significant incremental variance in social competence (∆R (2) = .07, P < .05) and was found to mediate the relation between working memory and social competence. Performance-based measures of empathy were sensitive to functionally relevant disturbances in schizophrenia. Working memory deficits appear to have an important effect on these disruptions in empathy. Empathy is emerging as a promising new area for social cognitive research and for novel recovery-oriented treatment development.

Performance-based empathy mediates the influence of working memory on social competence in schizophrenia.

Cannabis use is associated with working memory (WM) impairments; however, the relationship between cannabis use and WM neural circuitry is unclear. We examined whether a cannabis use disorder (CUD) was associated with differences in brain morphology between control subjects with and without a CUD and between schizophrenia subjects with and without a CUD, and whether these differences related to WM and CUD history. Subjects group-matched on demographics included 44 healthy controls, 10 subjects with a CUD history, 28 schizophrenia subjects with no history of substance use disorders, and 15 schizophrenia subjects with a CUD history. Large-deformation high-dimensional brain mapping with magnetic resonance imaging was used to obtain surface-based representations of the striatum, globus pallidus, and thalamus, compared across groups, and correlated with WM and CUD history. Surface maps were generated to visualize morphological differences. There were significant cannabis-related parametric decreases in WM across groups. Similar cannabis-related shape differences were observed in the striatum, globus pallidus, and thalamus in controls and schizophrenia subjects. Cannabis-related striatal and thalamic shape differences correlated with poorer WM and younger age of CUD onset in both groups. Schizophrenia subjects demonstrated cannabis-related neuroanatomical differences that were consistent and exaggerated compared with cannabis-related differences found in controls. The cross-sectional results suggest that both CUD groups were characterized by WM deficits and subcortical neuroanatomical differences. Future longitudinal studies could help determine whether cannabis use contributes to these observed shape differences or whether they are biomarkers of a vulnerability to the effects of cannabis that predate its misuse.

Cannabis-related working memory deficits and associated subcortical morphological differences in healthy individuals and schizophrenia subjects.

Cannabis-Related Working Memory Deficits and Associated Subcortical Morphology

Basal ganglia and thalamic morphology in schizophrenia and bipolar disorder

Accurate perception of negative emotions predicts functional capacity in schizophrenia

Innovative Treatment of Geriatric Depression: A Feasibility Study

Longitudinal progression of frontal and temporal lobe changes in schizophrenia

Self-reported empathy deficits are uniquely associated with poor functioning in schizophrenia

Evidence suggests that there are elevated rates of alcohol-use disorders (AUDs) at each stage of schizophrenia. Although the literature examining the clinical implications of alcohol at the early stages of schizophrenia are rather sparse, findings from numerous studies suggest that comorbid AUDs in individuals with schizophrenia exacerbate psychopathology, undermine medication compliance, add to cognitive dysfunction, impaired community functioning and physical health. Although there are several clinical implications of AUDs, their inter-relationships are not well known and must be further studied to present a clearer clinical picture. Gaps in the literature and areas for future research will be discussed.

Poster #233 EMPATHY DEFICITS ARE UNIQUELY ASSOCIATED WITH POOR FUNCTIONING IN SCHIZOPHRENIA

Alcohol use disorders contribute to hippocampal and subcortical shape differences in schizophrenia

Thalamic morphology in schizophrenia and schizoaffective disorder.

Thought, feeling, and action in real time--monitoring of drug use in schizophrenia.

Epidemiologic and genetic studies suggest that bipolar disorder (BP) and schizophrenia (SCZ) may share common susceptibility genes (1). Volumetric neuroanatomical studies, however, do not indicate similarities between these two disorders. The hippocampus appears to be central to the pathophysiology of SCZ (2), and loss of gray matter in the hippocampus is often reported (3, 4). In contrast, there appears to be little change in hippocampal volume in BP. Rather, structural studies suggest that global measures of total cerebral and gray and white matter volumes in BP are largely normal (5). However, volumes of the amygdala are sometimes abnormal, compared to controls (CON) or SCZ patients (4, 5). Studying surface shape patterns can identify more subtle structural abnormalities not evident by volumetric studies. Surface shape abnormalities of the hippocampus have been reported in SCZ (6, 7), but no such studies have been conducted in BP. We used magnetic resonance imaging and a FreeSurfer-initiated fully automated brain segmentation method involving Large Deformation Diffeomorphic Metric Matching (8) to compare the volume and surface shape of the hippocampus and amygdala in SCZ and BP. We hypothesized that SCZ and BP would show similar shape patterns in the hippocampus and amygdala. Further, if SCZ and BP differed in the degree, but not the pattern, of structural irregularity, there would be an ordered relationship in surface shape among the SCZ, BP, and CON groups. Participants included individuals with bipolar I disorder (n = 12) and SCZ (n= 11), both based on DSM-IV criteria, as well as CON participants (n = 12). Participants were matched for age, gender, race, and handedness. Exclusion criteria included recent (within three months) substance dependence, mental retardation, and history of severe head injury. Principal component (PC) analysis was used to reduce the high dimensionality of structure surfaces, yielding an orthonormal set of PCs representing shape variation. Group differences in structure shapes were assessed using MANOVA with the weights from the first 10 PCs (> 82% shape variance) used as dependent variables. To test for an ordered variation in surface shape across the groups, we performed a canonical analysis using a general linear model with the PC scores as dependent variables and group as the predictor variable. The canonical analysis was designed to score BP subjects along a dimension of surface shape variation for each structure that maximized the difference between SCZ and CON (9). There was a trend-level significant effect for hippocampal volume [F(2,34) = 2.9, p = 0.07]. Post-hoc analysis of hippocampal volumes showed significant group difference on the left [F(2,34) = 3.5, p = 0.04] but not the right [F(2,34) = 2.0, p = 0.15]. Further analysis of the left hippocampus showed smaller volumes [mm (SD)] in SCZ [2,164 (370)] compared to BP [2,453 (174)] (p = 0.019) and CON [2,395 (252)] (p = 0.052). There was a significant hemisphere effect for hippocampal volume [right > left: F(1,34) = 91.7, p < 0.0001], but no hemisphere · diagnosis interaction. Covarying for cerebral volume eliminated the hemisphere · diagnosis interaction for the hippocampus. There were no group effects for amygdala volume [F(2,34) = 0.81, p = 0.45]. Significant hemispheric effects for amygdala volume were observed [right > left: F(1,34) = 16.5, p = 0.003], but no hemisphere · diagnosis interaction. MANOVA applied to the PC scores summarizing hippocampal surface variation, with hemisphere as a repeated factor, indicated a significant effect of group status (Wilks = 0.04, p = 0.004). Group comparisons based on the canonical shape score of the hippocampus did not show significant differences between BP and CON, while there were significant differences between BP and SCZ (p < 0.05). A visual representation of hippocampal shape in SCZ and BP compared to CON is shown in Figure 1. MANOVA applied to the PC scores Bipolar Disorders 2010: 12: 341–343 a 2010 The Authors Journal compilation a 2010 Blackwell Munksgaard

Morphometry of the hippocampus and amygdala in bipolar disorder and schizophrenia.

Bridging the gap between schizophrenia and psychotic mood disorders: Relating neurocognitive deficits to psychopathology

Prevalence of psychotic symptoms in substance users: a comparison across substances.

Article history: Received 9 April 2008 Received in revised form 21 July 2008 Accepted 28 July 2008 Available online xxxx Background: The neurobiological relationship between schizophrenia and psychotic mood disorders is not well understood. Neurocognitive deficits have been described in both types of disorders and have been proposed to reflect underlying neurobiological dysfunction. Examining the relationship between neurocognitive function and psychopathology could help illuminate the neurobiological relationship between schizophrenia and psychotic mood disorders. Methods: Participants included 72 individuals with DSM-IV schizophrenia, 25 individuals with schizoaffective disorder or bipolar disorder with psychotic features, and 72 community controls. Standardized scores and correlations between four domains of neurocognition and psychopathology were examined. Results: Individuals with schizophrenia and psychotic mood disorders scored similarly on several dimensions of neurocognitive function and psychopathology. The relationships between neurocognitive function and psychopathology were similar in the two groups. Conclusions: Individuals with schizophrenia and psychotic mood disorders were similar in terms of both the level of impairment in neurocognitive function and psychopathology, as well as in the relationship between the two dimensions of illness. These results suggest that schizophrenia and psychotic mood disorders such as schizoaffective disorder and bipolar disorder with psychotic features are on a neurobiological continuum. © 2008 Elsevier B.V. All rights reserved.

Bridging the gap between schizophrenia and psychotic mood disorders : Relating neurocognitive de fi cits to psychopathology

Subclinical expression of schizophrenia-like symptoms in non-psychotic siblings of individuals with schizophrenia

Temperament and character as schizophrenia-related endophenotypes in non-psychotic siblings

Elevated rates of substance use disorders in non-psychotic siblings of individuals with schizophrenia

Objectives: Research suggests that the quality of sibling relationships has a significant impact on the lives of adults with schizophrenia. A life course perspective was used to guide an investigation of the predictors of the quality of the relationship between adults with schizophrenia and their siblings. Methods: The data come from a longitudinal study of families of adults with schizophrenia. This study is based on a survey of 136 siblings of adults with schizophrenia. Multiple regression was used to estimate the predictors of sibling relationship quality. Results: Siblings reported a better relationship when they grew up in a more cohesive family environment (beta=.16, p<.05) and when they experienced more personal gains from coping with the challenges of a brother’s or sister’s mental illness (beta=.37, p<.001). Siblings reported a worse relationship when they perceived their brother or sister with schizophrenia as having control over his or her symptoms (beta=–.18, p<.05), expressed greater fear of their brother’s or sister’s behavior (beta=–.17, p<.05), and indicated that their brother or sister had struck or threatened them at some point in their lives (beta=–.18, p<.05). Conclusions: The quality of the sibling relationship is a major contributor to sibling involvement in the future and to the quality of life of adults with schizophrenia. By identifying the factors associated with positive sibling relationships, mental health providers will be better prepared to engage siblings in the treatment process and help promote stronger bonds of affection between adults with schizophrenia and their siblings. (Psychiatric Services 59:57–62, 2008)

Factors Contributing to the Quality of Sibling Relationships for Adults With Schizophrenia

Research suggests that the quality of sibling relationships has a significant impact on the lives of adults with schizophrenia. A life course perspective was used to guide an investigation of the predictors of the quality of the relationship between adults with schizophrenia and their siblings.

METHODS
The data come from a longitudinal study of families of adults with schizophrenia. This study is based on a survey of 136 siblings of adults with schizophrenia. Multiple regression was used to estimate the predictors of sibling relationship quality.

RESULTS
Siblings reported a better relationship when they grew up in a more cohesive family environment (beta=.16, p<.05) and when they experienced more personal gains from coping with the challenges of a brother's or sister's mental illness (beta=.37, p<.001). Siblings reported a worse relationship when they perceived their brother or sister with schizophrenia as having control over his or her symptoms (beta=-.18, p<.05), expressed greater fear of their brother's or sister's behavior (beta=-.17, p<.05), and indicated that their brother or sister had struck or threatened them at some point in their lives (beta=-.18, p<.05).

The quality of the sibling relationship is a major contributor to sibling involvement in the future and to the quality of life of adults with schizophrenia. By identifying the factors associated with positive sibling relationships, mental health providers will be better prepared to engage siblings in the treatment process and help promote stronger bonds of affection between adults with schizophrenia and their siblings.

Factors contributing to the quality of sibling relationships for adults with schizophrenia.

Sibling expectations to provide future instrumental or emotional support for a brother or sister with schizophrenia when parents became disabled or died were examined. Data came from a sample of 137 siblings participating in a longitudinal study of aging families of adults with schizophrenia. Early socialization experiences, the quality of the sibling relationship, and personal caregiver gains propel siblings toward a future caregiving role, whereas geographic distance and beliefs about the controllability of psychiatric symptoms reduce expectations of future involvement.

Siblings of adults with schizophrenia: expectations about future caregiving roles.

OBJECTIVE
This study examined the importance of the quality of the sibling relationship to the life satisfaction of adults with schizophrenia.

METHODS
Data were drawn from a longitudinal survey of aging families of adults with schizophrenia. Ninety-three dyads of adults with schizophrenia and their siblings participated. Participants independently completed a self-administered mail questionnaire. Data on the quality of the sibling relationship were taken from the siblings' scores on the Positive Affect Index, and data on life satisfaction of the adult with schizophrenia were measured by the self and present life subscale of the Satisfaction With Life Scale.

RESULTS
Adults with schizophrenia had higher levels of life satisfaction when their siblings reported having a closer and more supportive relationship with their sibling with schizophrenia.

Our findings provide evidence of the saliency of the sibling relationship to quality of life of adults with schizophrenia in midlife.

The effect of the quality of sibling relationships on the life satisfaction of adults with schizophrenia.

DOCUMENTATION OF LANDSLIDE ACTIVITY ALONG THE COLD RIVER, ACWORTH, NH USING DENDROCHRONOLOGY

Paddling With the Ghost of the Giver: An Expedition by Canoe Down the Mekong Delta

Shifts in the hydrologic regime of Florida’s Apalachicola River have been attributed to anthropogenic changes throughout its watershed, including local dam construction. To assess impacts of those shifts on floodplain forests, we reconstructed tree growth using dendrochronology and compared these trends with hydrological and climatic variables. Comparisons of stream-gage data before and after dam construction on the Apalachicola River revealed statistically significant mean declines in annual average stage. Mean minimum annual stages, rise rates, and fall rates also decreased, while hydrograph reversals increased. Growth in four tree species correlated strongly with site-specific inundation parameters. A wetter climate in the two decades following dam construction and fine-scale fluctuation of the hydrograph may have set the stage for positive growth releases. Logging and hurricane wind throw events may have also contributed. However, drier conditions in the last two decades are now exacerbated by stage-discharge declines that had been masked previously. Tree growth rates and recruitment have decreased and, in the absence of a major disturbance, the forest canopy is composed of an older cohort of individuals. Our findings highlight how hydrograph variability, climate change, and vegetation disturbance are all relevant for gaging and anticipating the range of impacts of river modification on floodplain forests.

Hydrological shifts and tree growth responses to river modification along the Apalachicola River, Florida

USAGE Permission is granted to copy this article for use in teaching and research. Republication, systematic reproduction, or collective redistribution of any portion of this article by photocopy machine, reposting, or other means is permitted only with the approval of The Oceanography Society. Send all correspondence to: info@tos.org or The Oceanography Society, PO Box 1931, Rockville, MD 20849-1931, USA. Oceanography THE OFFICIAL MAGAzINE OF THE OCEANOGRAPHY SOCIETY

Lava geochemistry as a probe into crustal formation at the East Pacific Rise

Temporal and Spatial Variability in the Geochemistry of Axial and CoAxial Segment Lavas and their Mantle Sources

Rapid cooling rates at an active mid-ocean ridge from zircon thermochronology

Delineation of a produced water plume in Pointe Coupee Parish, Louisiana

Long-Term Change in Hydrology, Tree Growth, and Forest Composition along the Apalachicola River

Over 60% of the Earth’s magma flux, > 21 km 3 /yr, takes place at mid-ocean ridges (MOR). These divergent plate boundaries are the loci of volcanism and plutonism that form the oceanic crust, which covers over 70% of Earth’s surface. Mid-ocean ridge magmas typically undergo less modification and differentiation from their original primary melt composition than magmas erupted in continental settings or at oceanic islands. With a less complicated history, these MOR lavas provide a clearer window into mantle melting and magma chamber processes. Much insight into many different magmatic rock suites can be gained by understanding the magmatic processes involved in the formation of mid-ocean ridge lavas and determining their petrogenetic histories. The major rock type recovered at MOR is basalt. In fact, because it is so common, basalt found at spreading ridges are called MORB, or mid-ocean ridge basalts. Other terms that have commonly been used to describe MORB include ocean ridge basalts (ORB), abyssal tholeiites, ocean ridge tholeiites and low-K olivine tholeiites, implying certain compositional characteristics. In this investigation you will examine the petrography and geochemistry of 6 samples of mid-ocean ridge basalt and related differentiated lavas recovered from the Cleft segment of southern Juan de Fuca Ridge (JdFR), a medium spreading-rate MOR in the northeast Pacific Ocean (Figure 1). The goals of this investigation are to: 1. Investigate magmatism in a mid-ocean ridge environment

The petrology and geochemistry of a xenolith, a fragment of a melt‐bearing cumulate, within a recently erupted mid‐ocean ridge (MOR) lava flow provide information on petrogenetic processes occurring within the newly forming oceanic crust beneath the northern East Pacific Rise (NEPR). The xenolith reveals important petrologic information about MOR magmatic systems concerning (1) melt distribution in a crystal‐dominated mush; (2) melt‐crystal reactions within the mush; (3) the chemistry of melts that have contributed to the cumulate lithology; and (4) the chemistry of axial melts that enter the axial magma system. The xenolith was enclosed within a moderately primitive, normal mid‐ocean ridge basalt (NMORB) erupted in 1991 within the neovolcanic zone of the NEPR, at approximately 9°50′N. The sample is a matrix‐dominated, cumulate olivine anorthosite, composed of anorthite (An94‐90) and bytownite (An89‐70), intergranular olivine (Fo86±0.3), minor sulfide and spinel, and intergranular glass. Marginal corrosion of plagioclase, and possibly olivine, and internal remelting of plagioclase indicate syntexis. It is surmised that the pore volume was eviscerated several times with moderately primitive basaltic melts and reduced by intergranular crystallization of forsteritic olivine. The presence of anorthite as a cumulate phase in the xenolith and the observation of anorthite xenocrysts in NMORB lavas, and as a cumulate phase in ophiolite gabbros, indicate that Ca‐rich melts that are not a part of the NMORB lineage play an important role in the construction of the oceanic crust.

Magmatic processes in developing oceanic crust revealed in a cumulate xenolith collected at the East Pacific Rise, 9°50′N

The δ13C of slash pine foliage dark‐respired CO2 (δ13CF) was measured at temperatures ranging from 6.6° to 30°C. The δ13CF was 13C‐enriched initially after dark by as much as 9‰ and declined toward an asymptotic value after a few hours in the dark. Maximum enrichment in δ13CF occurred at the lowest temperatures and the decline in δ13CF toward the asymptotic value took longer at lower temperatures. The effect of this temporal variation in foliage enriched CO2 on determination of the δ13CO2 of ecosystem respiration (δ13CR) was investigated using two approaches by measuring the nighttime CO2 concentration and δ13CO2 ratio in a 30‐m‐tall pine forest in Florida, United States. The first approach (time series) consisted of making measurements at a single height at midcanopy from 1 hour after sunset until 0200 local time. The second approach (profile) consisted of making measurements at multiple heights from ground level to the top of the canopy synoptically prior to dawn. For each method a Keeling plot was used to estimate the δ13CR. The δ13CR values determined with the time series were 13C‐enriched relative to those determined from profiles on average by 1.0‰ and by as much as 3.1‰. A mass balance was used to determine the impact of the nonconstancy of δCF on the overall Keeling plot intercepts. For the months examined, results indicate that (1) the enrichment in the Keeling intercepts determined from time series compared to those determined from profiles was consistent with the addition of nighttime foliage respired 13C‐enriched CO2 and (2) Keeling plots determined from midcanopy heights appear linear despite the addition of temporally variable source δ13CO2 (range: 4‰). A common approach that specifies the time (predawn) and spatial distribution (multiple heights) for CO2 collection is suggested to improve intercomparisons of δ13CR from different ecosystems.

Influence of 13C‐enriched foliage respired CO2 on δ13C of ecosystem‐respired CO2

Mush Zone Xenolith Reveals Complex Magmatic Processes in the Crust Beneath the East Pacific Rise Axis

Geochemical heterogeneity within mid-ocean ridge lava flows: insights into eruption, emplacement and global variations in magma generation

Geophysical and petrological boundaries on mid‐ocean ridges provide ideal locations to study the relationships between magmatic, tectonic, and hydrothermal processes. Alvin‐based observational data and geochemical data for basalts and hydrothermal fluids are used to investigate these relationships at an axial discontinuity on the East Pacific Rise (EPR) crest between ∼9°36′N and 9°38′N. This ridge‐crest discontinuity is morphologically expressed by the overlap of an eastern and western axial summit collapse trough (ASCT) that delimits the primary volcanic and hydrothermal loci along the ridge crest in this area. The ASCTs overlap by ∼3 km and are offset in a right‐lateral sense by 0.45 km. Near‐bottom imaging of this area in 1989 and 1991 shows changes in volcanic morphology and increases in hydrothermal and biological activity consistent with the occurrence of a magmatic event during that time interval. When combined with the inferred age and structure of the seafloor, basalt geochemistry, and hydrothermal fluid chemistry, these temporal changes suggest active southward propagation of the eastern ASCT and show that the western ASCT was unaffected by the recent magmatic event. Numerous extinct hydrothermal vents and older‐looking lava flow surfaces suggest waning of magmatic activity in the western ASCT.Young‐looking lava flows within or proximal to the eastern ASCT have anomalously high Mg numbers relative to the regional trend and are chemically similar to lava erupted in 1991 along the 9°46′–52′N EPR region. We propose that the young‐looking lava flows in the eastern ASCT are related to the 1991 eruption. Data show that the 9°37′N axial discontinuity marks a magmatic and hydrothermal boundary along the EPR ridge‐crest, and we argue that it be classified as a third‐order discontinuity. This result is consistent with geophysical evidence suggesting fundamental differences in the crust and upper mantle north and south of the 9°37′N discontinuity.

Magmatic processes and segmentation at a fast spreading mid‐ocean ridge: Detailed investigation of an axial discontinuity on the East Pacific Rise crest at 9°37′N

Volcanic Morphology of the East Pacific Rise Crest 9°49′–52′: Implications for volcanic emplacement processes at fast-spreading mid-ocean ridges

Downtown Boise, Idaho is a vibrant, safe, and pedestrian friendly city to work, shop, live and play. However, Boise has not always enjoyed its current state of well being. For many years downtown Boise was a desolate wasteland. Very few people frequented downtown, and nearly no one resided downtown. From the late 1960s to the mid 1970s nearly eight city blocks of Boise's Central Business District were demolished with money from Federal Urban Renewal Grants. Thereafter, the redevelopment of downtown Boise was stopped for 15 years due to the supposedly imminent arrival of a downtown, enclosed, retail mall. Thanks to the vision of a few politicians and the actions of a couple of agencies Downtown Boise recovered. This thesis analyzes the mistakes and wisdom of Boise's urban renewal efforts as well as the actions of politicians and agencies in making downtown Boise into a successful mixed-use downtown. In particular, this thesis focuses on what went wrong during Boise's first downtown urban renewal attempt and the actions and practices put into place to ensure the same mistakes did not occur during the second renewal period. I will conclude by highlighting the lessons learned through the process of rejuvenating downtown Boise. This thesis is intended to aid cities that find themselves in the desolate situation Downtown Boise found itself 15 years ago. By understanding both the process by which downtown Boise was changed and the lessons learned throughout the first and second urban renewal endeavors, it is my hope that cities will gain ideas to assist them in the rebuilding and improving of their own downtowns. Thesis Supervisor: William Wheaton, Professor of Economics

The rebirth of downtown Boise : how it was accomplished and lessons learned

Geochronology and geochemistry of lavas from the 1996 North Gorda Ridge eruption

Data from a suite of closely spaced lava flows recovered within the axial summit caldera and on the crestal plateau of the East Pacific Rise around lat 9°31′N indicate that eruptions on this fast-spreading part of the mid-ocean ridge occur throughout the crestal region and are not restricted to the axis. These eruptions contribute to a complex distribution of basalts of various ages and a significant thickening of seismic layer 2A away from the axis in our study area. Small-scale (<600 m) diversity and nonsystematic distribution of lava types may reflect rapid changes in magma chemistry that occur during crystallization and replenishment in small magma lenses, coupled with the effects of frequent low-volume eruptions both within and outside of the axial summit caldera.

Small-scale spatial and temporal variations in mid-ocean ridge crest magmatic processes

Three morphologically distinct regions within the neovolcanic zone of the Cleft segment of the southern Juan de Fuca Ridge were investigated and sampled in detail using the DSRV Alvin. Additional along-strike and off-axis samples were recovered by dredge. The southernmost region, the Southern Cleft site, is characterized by a 3-km-wide axial valley floored by ponded sheet flows and bisected by a 30- to 50-m-wide cleft. Farther north at the “Young Sheet Flow” site, the ridge axis is characterized by a distinct 500-m-wide inner graben that is largely covered by distinctly younger looking sheet flows. The northernmost of the three regions is defined by a linear series of discontinuous constructional pillow mounds that extend the trend of the Cleft segment well into the zone of overlap with the neighboring Vance segment. The pillowed lavas at the “Young Pillow Mound” site represent the most recent episode of volcanism along the Cleft segment. Strong correlations exist between degrees of fractionation, relative ages of lavas, and latitude; lavas are progressively younger looking and more mafic to the north. The compositional range of mid-ocean ridge basalts from the neovolcanic zone can generally be accounted for by 35–40% low-pressure fractional crystallization of relatively primitive, but not primary, depleted (N-type) melts. Scatter of the geochemical data about calculated liquid lines of descent is probably the result of mixing of magmas with slightly different parental compositions, generated from small-scale mantle heterogeneities. Furthermore, the chemical variability may be the result of mixing of very depleted and more enriched sources or melts that are present beneath the southern Juan de Fuca Ridge. The more primitive nature of the young pillow mound basalts and their slightly different chemical characteristics indicates they cannot be simply related to the older southernmost lavas by along-axis flow in a continuous axial magma chamber or conduit. Rather, the data suggest lavas were derived from discrete magma chambers or lenses, each in a different stage of evolution. The youngest events may be associated with a new influx of magma into the northern part of the segment and subsequent northward diking and propagation to form the new pillow mounds. The oldest stage (∼40% additional crystallization of the most mafic composition) is associated with focused hydrothermal activity and tectonic extension, whereas the youngest events are characterized by ridge inflation, diking, and dispersed hydrothermal activity. Geochemical and tectonomagmatic features observed along the Cleft segment are similar to those recently documented along the East Pacific Rise from 9°30′N–10°N suggesting the scales, processes, and stages of magmagenesis are similar along medium to fast spreading ridge segments.

Petrology and geochemistry of basalts from the southern Juan de Fuca Ridge: Controls on the spatial and temporal evolution of mid‐ocean ridge basalt

Volcanic eruption of the mid-ocean ridge along the East Pacific Rise crest at 9°45-52'N: direct submersible observations of seafloor phenomena associated with an eruption event in April, 1991

Investigators involved in the ADVENTURE program, an Alvin dive program on the East Pacific Rise crest at 9°–10°N, have reported evidence suggesting very recent and possibly ongoing eruptive activity along this portion of the mid-ocean ridge. Preliminary age dating of basalt samples from the new flows (Figure 1) suggest that the eruption did, in fact, occur during the March–April 1991 dive program. 
 
The East Pacific Rise (EPR) between 9° and 10°N has been the site of much marine geological and geophysical research over the past decade. Research in this region has included a host of interdisciplinary field programs such as numerous high-resolution multibeam and side-looking sonar surveys, multichannel seismic and high-resolution tomographic surveys, a near-bottom refraction survey, ARGO optical/acoustical nearbottom mapping, and closely spaced rock sampling along the crest and upper flanks of the EPR in this area.

The Ceramics from Ras Hafun in Somalia: Notes on a Classical Maritime Site

Mass Cytometry reveals unique phenotypic patterns associated with subclonal diversity and outcomes in multiple myeloma

 Background: Cyclin dependent kinase (CDK) 4/6 inhibitors (CDK 4/6i) can improve outcomes in ER-positive/HER2-negative (ER+/HER2-) breast cancer. The choice of CDK 4/6i selection and dose depends on clinical context and/or potential side effect of profile of each unique CDK 4/6i. The objective of this study was to evaluate practice patterns in patients initiated on CDK 4/6i and assess adherence to recommended laboratory monitoring in breast cancer patients in both an institutional and national dataset. Methods: The institutional cohort (IC) involved a retrospective chart review of patients newly initiated on palbociclib between May 8, 2018 - June 4, 2019 at Mayo Clinic, Rochester. The national cohort (NC) reviewed medical and pharmacy claims data from the OptumLabs Data Warehouse (OLDW) and included patients who were initiated on palbociclib (P), ribociclib (R) or abemaciclib (A) between February 6, 2015 - September 30, 2019. NC patients were required to have a minimum of 6 months baseline coverage, 6 months coverage after first prescription and Day 1 labs drawn. For both cohorts, patients were ≥18 years old with metastatic ER+/HER2- breast cancer. Data was collected for up to 6 cycles of treatment and included cycle start dates, doses, dates of lab draws and dose changes. Laboratory adherence was defined as a complete blood count being drawn +/- 3 days of the defined timepoint for the IC and +/- 5 days for the NC with a l4-day window for Cycle 1, Day 1 labs. Results: The IC included 81 patients and the NC 2600. In the NC, the most prescribed CDK 4/6i was P (90%), followed by A (6%) and R (4%). Prescription breakdown by geographic region was Midwest (26%), Northeast (14%), South (47%), West (13%). Ethnic breakdown of the group was White (68%), Black (15%), Hispanic (8%), Asian (3%) and unknown (6%). P practice pattern data were available for both the IC and NC, but R and A data in the NC only. In the IC, the initial P dose was 125 mg (95%), 100 mg (1%) and 75 mg (4%). In the NC, P (n=2329) dose was 125 mg (81%), 100 mg (15%) and 75 mg (4%). Dose reductions were common with 25% and 28% of patients requiring one dose reduction and 16% and 9% of patients requiring two dose reductions in the IC and NC, respectively. In NC patients initially treated with P, 5% were subsequently treated with A and 2% with R. In the NC, A (n=163) was initiated at 200 mg (7%), 150 mg (79%), 100 mg (10%) and 50 mg (4%). One dose reduction was required in 25% of patients and 6% required two dose reductions. Of those initially treated with A, 16% were subsequently treated with P and 1% with R. In the NC, R (n=108) was initiated at 600 mg (81%), 400 mg (8%) and 200 mg (11%). One dose reduction was required in 17% of patients and 2% required two dose reductions. Of those initially treated with R, 7% each were subsequently treated with P and 10% with A. Laboratory adherence was assessed for P only. For the IC, a total of 81 patients were included (mean age 61±13 years, 98% female and 95% White). The NC included 2329 patients (mean age 66±12 years, 99% female and 69% White). Laboratory adherence is listed in the table below:
 Conclusions: P was the most commonly prescribed CDK 4/6i. Dose reductions were less common with R. Adherence to laboratory monitoring was higher in our institutional cohort than in a national administrative claims database. Initiatives to ensure that labs are drawn at recommended timepoints during P therapy will be important for safety.
 ICNCC1D193%100%C1D1589%61%C2D191%71%C2D1558%55%C3D199%62%C4D190%55%C5D184%53%C6D178%50%C = cycle, D = day.
 Citation Format: Jodi Taraba, Kavya Swarna, Allison Golbach, Lindsey Sangaralingham, Kathryn Ruddy, Kristin Mara, Matthew Smith, Tufia Haddad, Karthik Giridhar. Evaluation of CDK 4/6 inhibitor practice patterns and institutional versus national adherence to palbociclib laboratory monitoring in breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-23-05.

Abstract P3-23-05: Evaluation of CDK 4/6 inhibitor practice patterns and institutional versus national adherence to palbociclib laboratory monitoring in breast cancer patients

Impact of CD138 Magnetic Bead-based Positive Selection on Bone Marrow Plasma Cell Surface Markers.

To study the impact of dose modification and temporary interruption of ibrutinib in routine clinical practice, we conducted a retrospective study of consecutive CLL patients treated with ibrutinib outside the context of a clinical trial at Mayo Clinic, (Rochester, MN) from 11/2013 to 12/2017. Of 209 patients, 131 (74%) had unmutated IGHV, 38 (20%) had TP53 disruption, and 47 (22%) were previously untreated. A total of 87/209 (42%) patients started reduced dose ibrutinib (<420 mg daily; n = 43, physician preference; n = 33, concomitant medications; and n = 11, other). During 281 person‐years of treatment, 91/209 patients had temporary dose interruption (54%, nonhematologic toxicity; 29%, surgical procedures; 10%, hematologic toxicity; and 7%, other). After a median follow‐up of 24 months, the estimated median event‐free survival (EFS) was 36 months, and median overall survival (OS) was not reached. On multivariable analyses, temporary ibrutinib interruption (hazard ratio [HR]: 2.37, P = .006) and TP53 disruption at ibrutinib initiation (HR: 1.81, P = .048) were associated with shorter EFS, whereas only TP53 disruption (HR: 2.38, P = .015) was associated with shorter OS. Initial ibrutinib dose and dose modification during therapy did not appear to impact EFS or OS. These findings illustrate the challenges associated with continuous oral therapy with ibrutinib in patients with CLL.

The impact of dose modification and temporary interruption of ibrutinib on outcomes of chronic lymphocytic leukemia patients in routine clinical practice

Background: Multiple myeloma (MM) remains an incurable plasma cell (PC) malignancy. Despite improvements in clinical outcomes, variability in treatment response exists. Some patients experience innate resistance, while others develop resistance over the course of treatment. Identifying signatures of treatment response and resistance is essential to predicting effective treatment strategies. Given the phenotypic clonal heterogeneity observed in MM, we hypothesize that resistant and sensitive subpopulations have unique phenotypic signatures. We used mass cytometry (CyTOF) to characterize primary MM samples and correlated their phenotypic signatures with treatment response.
 Methods: We characterized 102 primary MM samples by CyTOF using 37 antibodies (see figure). Frozen whole BM specimens were thawed, stained with antibodies, barcoded, and analyzed on a Helios mass cytometer. Data was processed using Cytobank or Pathsetter and analyzed using t-distributed stochastic neighbor embedding (t-SNE) algorithm. T-SNE plots for CD45+ cells were created using lineage defining markers. T-SNE plots of neoplastic PCs (CD138+,CD3-,CD16-,CD19-,cytoplasmic kappa or lambda+) were created using all remaining markers. A differential analysis of each sample's clusters was performed against all other events. Z-score values, representing marker changes from the differential analysis, for each cluster were used to group similar clusters across all samples, allowing us to compare sub populations of PCs between patients (see figure). From these groups of clusters with similar changes in markers, we calculated the proportion of cells with increases or decreases in markers for each sample. Results were compared to IMWG 90-day response criteria using a random forest model.
 Results: We performed mass cytometry on 102 samples from 68 unique MM patients. Median age was 66 years (range 34-95) with a 1.5:1 male:female ratio. 37 (36%) had NDMM, 55 (54%) had RRMM, 2 (2%) had SMM and 8 cases (8%) had unknown status. FISH studies revealed 47 (46%) had hyperdiploidy without a recurrent primary IgH rearrangement, 31 (30%) had t(11;14), 13 (13%) had t(4;14), 5 (5%) had 14;16 or 14;20, 3 (3%) had hyperhaploidy and 3 (3%) had an undefined primary. 54 (53%) had 1q gain/amp, 22 (22%) had TP53 deletion, 22 (22%) had a MYC rearrangement and 71% had high mSMART risk. Nearly all patients received an immunomodulatory compound, a proteasome inhibitor and dexamethasone. 2 (2%) had complete response (CR), 10 (9.8%) very good partial response (VGPR), 36 (35%) had partial response (PR), 14 (14%) had minimal response (MR), 13 (13%) had stable disease (SD) and 17 (17%) had progressive disease (PD).
 Characterization of CD45+ cells identified a relatively conserved and reproducible map from each patient. Notable differences included an ~2-fold reduction in the percentage of total B cells (CD45+,CD3-,CD19+)/total CD45+ cells in cases with high risk mSMART, RRMM and TP53 deletion compared to cases with standard risk, NDMM or normal TP53 status. Similar B-cell reductions were found in RRMM vs. NDMM samples from matched-patients. In contrast to the conserved t-SNE structure of the CD45+ population, the neoplastic PC population displayed dramatically reduced t-SNE structural consistency. Heterogeneity between patient samples and between the same patient samples over time was observed. We focused our analysis on 22 patients with serial samples. The proportion of each t-SNE group present in each patient sample was calculated and then correlated to the 90-day response metric. We identified a phenotypic group whose proportion increased in relation to disease progression (R2=0.85). This group had elevated BCL-2, pSTAT3, CD56 levels and reduced CD45 and CD81 levels. Evaluating individual markers, we found an increase in the proportion of cells with elevated BCL-2, pS6, Ki67, and IKZF1 levels in relation to disease progression. We also observed an increase in the proportion of cells with reduced pCREB levels and a reduction in the proportion of cells with reduced CD147 levels in relation to disease progression.
 Conclusions: We have utilized CyTOF to characterize phenotypic and functional markers in MM cells on a single cell level and can identify unique subgroups that change in relation to disease progression. Future analysis will correlate phenotypic signatures with ISS stage, mSMART risk, cytogenetic abnormality and type of treatment.
 Figure 1
 
 Kumar: Kite Pharma: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Sanofi: Research Funding; MedImmune: Research Funding; Karyopharm: Consultancy; Merck: Consultancy, Research Funding; Carsgen: Other, Research Funding; Cellectar: Other; Novartis: Research Funding; Adaptive Biotechnologies: Consultancy; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genecentrix: Consultancy; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Tenebio: Other, Research Funding; BMS: Consultancy, Research Funding; Dr. Reddy's Laboratories: Honoraria.

Phenotypic and Functional Characterization of Multiple Myeloma By Single Cell Mass Cytometry (CyTOF)

 Background: Chronic myelogenous leukemia (CML) is a BCR-ABL1 driven myeloid neoplasm, with excellent response rates to tyrosine kinase inhibitors (TKI). TKI such as imatinib (IM), dasatinib (DAS), nilotinib (NIL), bosutinib (BOS), and ponatinib (PON) currently US FDA approved, have dramatically changed survival outcomes. That being said, two main challenges exist; suboptimal responses and TKI intolerance. The reason why some patients tolerate/respond to TKI better than others is unknown, but is potentially explainable based on drug metabolism. The field of pharmacogenomics (PGX) is rapidly evolving, with commercial panel's rapidly assessing metabolic pathways such as cytochrome P450 (CYP), UGTA1A, p-glycoprotein/ABCB1. We carried out this study using a 22 gene-PGX panel to assess potential causes of TKI related intolerance and suboptimal responses in compliant patients.
 Methods: Twenty-nine Mayo Clinic patients with CML were prospectively recruited after informed consent. Buccal swabs were utilized for PGX testing to assess variations/polymorphisms involving CYP3A4/5, 1A2, 2C9, UGT1A1, amongst others (www.Oneome.com). Three groups of patients were recruited, those with i) TKI intolerance, ii) suboptimal responses by ELN criteria, iii) and newly diagnosed cases, to assess if PGX testing could explain TKI intolerance or resistance, or alter choice of therapy in newly diagnosed cases. A pharmacology review was obtained to interpret reports in all cases.
 Results:
 29 patients with CML were prospectively enrolled, median age 64 years, 15 (52%) male. At last follow up (median 21 months), 3 (10%) deaths and no disease progressions were documented. 82% received first line IM, whereas 18% received first line DAS. Major metabolic pathways assessed for IM included, CYP3A4 and 5, while minor pathways included 2C19, 2C9 and 2D6. Majority (83%) of IM patients had normal major pathways with 17% being intermediate-normal. With regards to the minor pathways, 25% were rapid metabolizers for 2C19, whereas 29% were intermediate and 4% poor metabolizers for 2C9 and 50% and 16% were intermediate and poor metabolizers for 2D6. In all IM treated patients PGX testing did not completely explain intolerance or resistance and did not change clinical decision making. Front line DAS was used in 18% and the major pathway assessed was CYP 3A4, with 80% being normal and 20% being intermediate metabolizers. Once again PGX testing did not completely explain intolerance/resistance and no therapeutic changes were based on PGX analysis.
 Seventeen (59%) patients received second line TKI therapy (50% each for intolerance and resistance), with DAS (58%) and NIL (29%), being the two most common. Once again for DAS, 90% had normal 3A4 metabolism while 10% were intermediate and for NIL 80% were normal and 20% intermediate. Only one of 2 NIL treated patients with UGTA1A polymorphisms developed indirect hyperbilirubinemia (grade 1). In the second line setting, PGX testing did not completely explain or alter treatment decisions. BOS was used as a third line agent in 3 (>10%) patients, 2 who remained refractory and one with intolerance, and all three were normal CYP3A4 metabolizers. None of these patients developed diarrhea a common side effect of BOS. PON was used in one patient with intermediate CYP3A4 metabolism as a 5th line agent and the patient continues to have refractory disease with no thrombotic events. In all cases, no changes were made to concomitant medications based on PGX testing.
 Conclusion: In conclusion, while PGX testing has rapidly evolved and become commercially available, in the context of TKI therapy for CML, while it offers useful insights on minor metabolic derangements and side effects like NIL induced hyperbilirubinemia, in our study, currently limited by a small sample size, it did not completely explain TKI intolerance or resistance. Recruitment of additional patients (n=100) and correlations with plasma drug levels are currently ongoing.
 Table. Table.
 
 Al-Kali: Novartis: Research Funding. Stewart:Amgen Inc., Celgene, Roche, Seattle Genetics: Research Funding; Amgen Inc., BMS, Celgene, Takeda, Roche, Seattle Genetics, Janssen, Ono: Consultancy.

The Clinical Utility of Pharmacogenomics Testing in Assessing Tyrosine Kinase Inhibitor Therapy, Intolerance and Responses in Patients with Chronic Myelogenous Leukemia

Abstract Due to Cytochrome P450 3A (CYP3A) metabolism, clinical trials of ibrutinib-treated chronic lymphocytic leukemia (CLL) patients prohibited concurrent medications metabolized by CYP3A. We evaluated concomitant medication use in 118 ibrutinib-treated CLL patients outside the context of clinical trials. Seventy-five (64%) patients were on medications that could increase ibrutinib toxicity and 4 (3%) were on drugs that could decrease ibrutinib efficacy. Nineteen (16%) patients were on concomitant CYP3A inhibitors (11 moderate, 8 strong), and 4 (3%) were on CYP3A inducers (two patients were on both CYP3A inhibitors and inducers). Although the ibrutinib starting dose was changed in 18 patients on CYP3A interacting medications, no difference in 18-month progression-free survival or rate of ibrutinib discontinuation was observed in patients who were not. In routine clinical practice, 2 of 3 CLL patients commencing ibrutinib are on a concomitant medication with potential to influence ibrutinib metabolism. Formal medication review by a pharmacist should be considered in all patients initiating ibrutinib.

Pharmacovigilance during ibrutinib therapy for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in routine clinical practice

Introduction: Ibrutinib has shown remarkable safety and efficacy in CLL. Due to CYP3A4 (3A4) metabolism, the concurrent use of 3A4 inhibitors/inducers with ibrutinib should be avoided. Ibrutinib is also associated with bleeding complications, in part due to effects on collagen-mediated platelet aggregation, thus caution is advised with the simultaneous use of anticoagulant (AC) and antiplatelet agents. It is unknown what proportion of CLL patients starting ibrutinib therapy in routine practice are on these medications. We conducted a retrospective study to evaluate these aspects in a large cohort of CLL pts treated with ibrutinib outside the context of clinical trials.

Methods: Following IRB approval, consecutive CLL pts who initiated ibrutinib off-protocol at Mayo Clinic, Rochester, MN from November 2013 through July 2015 were evaluated. A medication review for drug-drug interactions was performed by a pharmacist on all pts. Baseline characteristics, concomitant medications, and toxicity were recorded. Time to toxicity and ibrutinib discontinuation were analyzed by Kaplan Meier and cumulative incidence methods accounting for competing risk of death, respectively.

Results: Ninety-six CLL pts started ibrutinib. Median age was 66 years and 64 (67%) were male. Ibrutinib indications included: relapsed/refractory CLL (n=84), treatment-naive CLL with del17p (n=8), and CLL with Richter's transformation (n=4). Approximately 80% had unmutated IGHV and 45% had del17p or del11q on FISH. Upon initial pharmacy consult prior to ibrutinib, the median number of concomitant medications was 9 (range, 1-31). Sixty (63%) pts were taking concurrent medications increasing their risk of ibrutinib toxicity and 4 (4%) pts were on drugs potentially reducing ibrutinib efficacy.

At ibrutinib initiation, 16 (17%) pts were on concomitant 3A4 inhibitors . This included 9 (9%) on moderate 3A4 inhibitors (fluconazole, diltiazem, imatinib, cyclosporine) and 7 (7%) on strong 3A4 inhibitors (voriconazole, posaconazole, clarithromycin, itraconazole). In 4 pts, the 3A4 inhibitor was switched to another agent or discontinued to allow standard 420 mg daily dosing. Ibrutinib was initiated at 140 mg daily in 7 pts on moderate 3A4 inhibitors and at 140 mg every 48 hours in 5 pts on strong 3A4 inhibitors.

Four (4%) pts were on strong 3A4 inducers (carbamazepine, rifampin, rifabutin) at the initiation of ibrutinib. The 3A4 inducer was discontinued prior to ibrutinib start in 3 pts, while the initial ibrutinib dose was decreased to 140 mg every 48 hours in the remaining patient (also on 2 strong 3A4 inhibitors).

During the course of ibrutinib, an additional 8 (8%) pts were started on 3A4 inhibitors/inducers which necessitated dose modifications.

Upon commencing ibrutinib, 9 (9%) pts were on concomitant AC (6 warfarin, 3 enoxaparin). Due to significant bleeding risk, warfarin was switched to enoxaparin in 2 pts, to aspirin (ASA) in 1 and warfarin was discontinued in 1. In 2 pts, an alternative AC could not be used so ibrutinib was begun at 140 mg daily and titrated upward.

Twenty-nine (30%) pts were on ASA (3 [3%] also on clopidogrel) at ibrutinib initiation. Nineteen (20%) pts were on selective serotonin release inhibitors (SSRIs), and 9 (9%) were on NSAIDs. Thirteen (13%) pts were on fish oil and 24 (25%) were on herbal medications; all of which were discontinued prior to starting ibrutinib.

Ten (10%) pts had clinically significant bleeding on ibrutinib including 4 (4%) requiring hospitalization (1 subdural hematoma). Of these 4 pts, 1 was on enoxaparin, 2 were on a SSRI and 1 a NSAID. Six pts had minor bleeding necessitating a dose reduction of ibrutinib to 140-280 mg daily. After 16 months follow-up, the risk of bleeding was 21% (95% CI: 1-37%, Figure).

After a median follow-up of 7.6 months, 73 (76%) pts remain on ibrutinib. There was no difference in rates of discontinuation of ibrutinib between patients who were on 3A4 inhibitors/inducers versus those who were not.

Conclusion: In the "real-world" setting, 2 out of 3 CLL patients commencing ibrutinib therapy is on a concomitant medication with a potentially clinically significant drug-drug interaction with ibrutinib. These findings have implications for the practicing hematologist who must maintain a high degree of vigilance when prescribing ibrutinib to CLL pts. We highly recommend a formal medication review by a clinical pharmacist in all patients initiating ibrutinib.

![Figure 1.][1] 

Figure 1. 

Disclosures Ding: Merck: Research Funding. Kay: Hospira: Research Funding; Tolero Pharma: Research Funding; Genentech: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding. Shanafelt: Glaxo-Smith_Kline: Research Funding; Pharmactckucs: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Cephalon: Research Funding; Janssen: Research Funding; Hospira: Research Funding; Polyphenon E Int'l: Research Funding.

The Importance of Pharmacovigilance during Ibrutinib Therapy for Chronic Lymphocytic Leukemia (CLL) in Routine Clinical Practice

Background: Animal pollination supports agricultural production for many healthy foods, such as fruits, vegetables, nuts, and legumes, that provide key nutrients and protect against noncommunicable disease. Today, most crops receive suboptimal pollination because of limited abundance and diversity of pollinating insects. Animal pollinators are currently suffering owing to a host of direct and indirect anthropogenic pressures: land-use change, intensive farming techniques, harmful pesticides, nutritional stress, and climate change, among others. Objectives: We aimed to model the impacts on current global human health from insufficient pollination via diet. Methods: We used a climate zonation approach to estimate current yield gaps for animal-pollinated foods and estimated the proportion of the gap attributable to insufficient pollinators based on existing research. We then simulated closing the “pollinator yield gaps” by eliminating the portion of total yield gaps attributable to insufficient pollination. Next, we used an agriculture–economic model to estimate the impacts of closing the pollinator yield gap on food production, interregional trade, and consumption. Finally, we used a comparative risk assessment to estimate the related changes in dietary risks and mortality by country and globally. In addition, we estimated the lost economic value of crop production for three diverse case-study countries: Honduras, Nepal, and Nigeria. Results: Globally, we calculated that 3%–5% of fruit, vegetable, and nut production is lost due to inadequate pollination, leading to an estimated 427,000 (95% uncertainty interval: 86,000, 691,000) excess deaths annually from lost healthy food consumption and associated diseases. Modeled impacts were unevenly distributed: Lost food production was concentrated in lower-income countries, whereas impacts on food consumption and mortality attributable to insufficient pollination were greater in middle- and high-income countries with higher rates of noncommunicable disease. Furthermore, in our three case-study countries, we calculated the economic value of crop production to be 12%–31% lower than if pollinators were abundant (due to crop production losses of 3%–19%), mainly due to lost fruit and vegetable production. Discussion: According to our analysis, insufficient populations of pollinators were responsible for large present-day burdens of disease through lost healthy food consumption. In addition, we calculated that low-income countries lost significant income and crop yields from pollinator deficits. These results underscore the urgent need to promote pollinator-friendly practices for both human health and agricultural livelihoods. https://doi.org/10.1289/EHP10947

Pollinator Deficits, Food Consumption, and Consequences for Human Health: A Modeling Study

Despite recent advances in understanding the role of biodiversity in ecosystem-service provision, the links between the health of ecosystem-service providers and human health remain more uncertain. During the past decade, an increasing number of studies have argued for the positive impacts of healthy pollinator communities (defined as functionally and genetically diverse species assemblages that are sustained over time) on human health. Here, we begin with a systematic review of these impacts, finding only two studies that concomitantly quantified aspects of pollinator health and human health. Next, we identify relevant research relating to four pathways linking pollinator health and human health: nutrition, medicine provisioning, mental health and environmental quality. These benefits are obtained through improved pollination of nutritious crops and an estimated approximately 28 000 animal-pollinated medicinal plants; the provisioning of pollinator-derived products such as honey; the maintenance of green spaces and biocultural landscapes that improve mental health; and cleaner air, water and food resulting from pollinator-centred initiatives to reduce agrochemical use. We suggest that pollinator diversity could be a proxy for the benefits that landscapes provide to human health. This article is part of the theme issue ‘Natural processes influencing pollinator health: from chemistry to landscapes’.

Exploring connections between pollinator health and human health

Projections of future food security require careful interpretation because they are often based on models that include only a subset of biophysical variables and have inherent uncertainties, caution Samuel Myers and colleagues

Current guidance underestimates risk of global environmental change to food security

The lost opportunity from insufficient pollinators for global food supplies and human health.

1. McGinnis JM, Foege WH. Actual causes of death in the United States. JAMA. 1993;270(18):2207-2212. 2. GBD 2017 Diet Collaborators. Health effects of dietary risks in 195 countries, 1990-2017: a systematic analysis for the global burden of disease study 2017. Lancet. 2019;393(10184): 1958-1972. doi:10.1016/S0140-6736(19)30041-8 3. Myers S, Frumkin H, eds. Planetary Health:Protecting Nature to Protect Ourselves. Island Press; 2020. 4. The EAT-Lancet Commission on Food, Planet, Health. https:// eatforum.org/eat-lancet-commission/ accessed 2/17/22 5. Fadnes LT, Økland JM, Haaland ØA, Johansson KA. Estimating impact of food choices on life expectancy: a modeling study. PLoS Med. 2022;19(2):e1003889. 6. Gardner CD, Hartle JC, Garrett RD, Offringa LC, Wasserman AS. Maximizing the intersection of human health and the health of the environment with regard to the amount and type of protein produced and consumed in the United States. Nutr Rev. 2019; 77(4):197-215. 7. Marinova D, Raphaeli T.Meat is a complex health issue but a simple climate one: the world needs to eat less of it. The Conversation. 7/5/ 14. https://theconversation.com/meat-is-a-complex-health-issue-buta-simple-climate-one-the-world-needs-to-eat-less-of-it-44006.

The Environmental Cost of Red Meat: Striking the Right Balance Between Nutrition and Nature

Most global dietary forecasts predict a reduction in nutritional deficiencies over the next several decades driven by significant increases in environmentally unsustainable livestock and animal source food consumption. Here, we explore a more environmentally sensitive alternative to improve global nutrition, consuming insects. Our study focuses on Africa and Asia, two continents with a history of eating insects and high rates of nutritional deficiency. We model the impact of adding modest amounts (2.5, 5 and 10 g per day, dry weight) of regionally appropriate and farmable species on total nutrient intake and population-wide risk of deficiency for specific nutrients of concern: protein, zinc, folate, and vitamin B12. We also estimate the total potential change in dietary iron. Five grams per day of insect consumption could alleviate a considerable amount of risk of nutritional deficiency: 67 million (95% uncertainty interval: 49–84 million) fewer people at risk of protein deficiency, 166 million (120–220 million) fewer people at risk of zinc deficiency, 237 million (120–439 million) fewer people at risk of folate deficiency, and 251 million (28–2271) fewer people at risk for vitamin B12 deficiency. For iron, per capita supplies could increase by 3% (0.8%–6.0%) with insects, and even more so for vulnerable groups in countries currently suffering severe rates of anemia: 4.2% (0.5%–8.8%) for women of childbearing age and 4.1% (0.4%–10.0%) for children under 5. Doubling or halving insect intake per capita causes the benefits for nutritional deficiency risk to roughly double or halve accordingly. Effects are most pronounced in South and Central Asia, though sub-Saharan Africa, East Asia, and Southeast Asia also see considerable reduction in nutritional risk. These results demonstrate the potential for insects to fill a crucial role in providing nutrition for these populous and rapidly developing regions while safeguarding the global environment.

Nutritional and environmental benefits of increasing insect consumption in Africa and Asia

The impacts of climate change are not equally distributed globally. We examined the global distribution of CO2 emissions and the ensuing distribution of increases in the risk of zinc and protein deficiency resulting from elevated atmospheric CO2 concentrations. We estimated cumulative per capita (2011–2050) CO2 emissions for 146 countries using existing measurement data and by apportioning regional emissions projections. We tested the relationship between cumulative per capita CO2 emissions and the risk of additional zinc and protein deficiency at the population-level and country-level. At the population-level (i.e., population-weighted), we observed a significant inverse association between CO2 emissions and the percentage of the population placed at additional risk of zinc (p-value: <0.001) and protein (p-value: <0.01) deficiencies. Country-level (i.e., unweighted) analyses produced significant but less strong associations. Populations with lower per capita CO2 emissions between 2011 and 2050 will experience a disproportionately high nutritional burden, highlighting socioeconomic, geospatial, and intergenerational injustices.

The Mismatch between Anthropogenic CO2 Emissions and Their Consequences for Human Zinc and Protein Sufficiency Highlights Important Environmental Justice Issues

Dams provide energy and irrigation water, but also alter natural water flows that support fisheries. This tradeoff presents a risk for human nutrition in regions dependent on aquatic foods, including the Lower Mekong Basin (LMB), where over 100 dams are planned or in construction. Previous models estimate significant reductions in fishery production resulting from these dams. This study estimates the number of new nutritionally insecure people (i.e., those at risk for nutritional deficiencies) associated with Mekong damming. We calculated population-level nutritional needs based on the Estimated Average Requirements (EARs) for Cambodia and the entire LMB. We then estimated fish-derived nutrient supplies by integrating data on annual fishery production and fish nutrient content for a wide range of species. Finally, we synthesized available literature and modeling results on the impacts of damming on fisheries production, and estimated the consequent impact on inadequate intakes of protein, zinc, niacin, thiamin, riboflavin, and calcium, as well as potential vulnerability to losses of dietary iron. Hydropower development could restrict access to subsistence fish from the Mekong River Basin and lead to increased risk of nutritional deficiencies in Cambodia and the LMB. Our median estimates suggest that by 2030, relative to 2010, inadequate intakes could lead to an increased population at risk of nutritional deficiencies in the LMB by 0.21 to 2.23 million people for protein, 0.12 to 1.17 million people for zinc, 0.41 to 1.58 million people for niacin, 0.47 to 0.87 million people for thiamin, 0.70 to 2.31 million people for riboflavin, and approximately 10,000 people for calcium. This increased population at risk is additional to those currently malnourished. We then calculated that the average iron intake of many age-sex groups (constituting 58% of the population) will be below 150% of their EAR in 2030, indicating a potential risk of increased inadequate iron intake. Fish is the main source of animal source foods and critical micronutrients in the LMB. In the absence of mitigation efforts, any reductions in fishery production could increase already high levels of nutrient deficiency, creating a widespread risk of nutrition insecurity.

Impacts of Mainstream Hydropower Development on Fisheries and Human Nutrition in the Lower Mekong

Background: India has made important strides in reducing nutritional deficiencies over the past several decades. However, for micronutrients such as zinc, previous studies have suggested a worsening situation, contrary to most other dietary indicators. Adding to this burden, higher carbon dioxide (CO2) levels of 550 ppm, projected to potentially occur within decades, could reduce the zinc content of many staple crops. Objective: To assess the historical prevalence of inadequate zinc intake, as well as to estimate the future prevalence attributable to rising CO2. Methods: Seven household food consumption surveys between 1983 and 2012 were used to calculate total dietary zinc, phytate, and absorbable zinc intakes and to assess the prevalence of historic inadequacy in zinc intake. The added nutritional effect of elevated CO2 on zinc intake is then modeled. Results: Prevalence of inadequate absorbable zinc intake has increased from 17.1% (15.3%-19.0%) in 1983 to 24.6% (22.3%-27.1%) in 2011-12, corresponding to an additional 82 million people consuming inadequate zinc than would have otherwise if 1983 rates had persisted. These increases in inadequacy have been driven by a relatively constant zinc intake being increasingly insufficient to meet a 5% growth in zinc requirements due to the aging of the population. Reaching 550 ppm CO2 by 2050 could potentially increase the prevalence of inadequate zinc intake by another 3.9 percentage points (2.1-5.8), corresponding to 65 million additional people having inadequate zinc intake. Conclusions: The persistently worsening trend for zinc—opposite most other measures of human nutrition—shows that it may pose an ongoing risk unless addressed.

Combining the effects of increased atmospheric carbon dioxide on protein, iron, and zinc availability and projected climate change on global diets: a modelling study

Carbon dioxide levels are rising globally. The increasing CO2 levels reduce the concentration of nutrients in many of the crops that are consumed worldwide (wheat, rice, barley, maize, legumes, and potatoes). The larger effects for human health are concentrated in regions that heavily rely on these crops for their nutrition such as South and Southeast Asia, North Africa, and the Middle East. Because these effects are likely to be hidden, we should better monitor the nutritional status of populations as well as crop nutrient content over the coming decades.

Rising carbon dioxide is decreasing nutrition in crops and endangering health among the less wealthy

Predicting nutrient content of ray-finned fishes using phylogenetic information

www.feedthefuture.gov Carbon dioxide (CO2) levels are rising globally at a rapid pace, on track to surpass 550 parts per million (ppm) by midcentury. Studies have found that, when grown under elevated CO2 concentrations of 546–586 ppm, many food crops—including wheat, rice, barley, and soybeans—have lowered concentrations of nutrients, including many that are important for overall health, such as iron, zinc, and protein. Elevated CO2 also affects both the quantity and quality of forage, thereby affecting animal performance and production and, consequently, the availability of nutrients from animal-source foods, such as meat, milk, and eggs. This loss of dietary nutrients in foods could translate to increased nutritional deficiency for hundreds of millions of people already on the brink of deficiency—mainly developing countries in Asia, the Middle East, and North Africa based on dietary preferences for the commodities most affected. This policy note examines the link between rising CO2 levels and declining nutritional content for a number of major crops, as well as forage. The discussion includes a comparison of the varying effects by crop, and strategies to address this challenge in the context of climate change.

The Crucial Role of Nutrients for Health , and the Impact of Rising Carbon Dioxide Levels

Background: Production of rice and wheat increased dramatically in India over the past decades, with reduced proportion of coarse cereals in the food supply. Objective: We assess impacts of changes in cereal consumption in India on intake of iron and other micronutrients and whether increased consumption of coarse cereals could help alleviate anemia prevalence. Methods: With consumption data from over 800 000 households, we calculate intake of iron and other micronutrients from 84 food items from 1983 to 2011. We use mixed-effect models to relate state-level anemia prevalence in women and children to micronutrient consumption and household characteristics. Results: Coarse cereals reduced from 23% to 6% of calories from cereals in rural households (10% to 3% in urban households) between 1983 and 2011, with wide variations across states. Loss of iron from coarse cereals was only partially compensated by increased iron from other cereals and food groups, with a 21% (rural) and 11% (urban) net loss of total iron intake. Models indicate negative association between iron from cereals and anemia prevalence in women. The benefit from increased iron from coarse cereals is partially offset by the adverse effects from antinutrients. For children, anemia was negatively associated with heme–iron consumption but not with iron from cereals. Conclusions: Loss of coarse cereals in the Indian diet has substantially reduced iron intake without compensation from other food groups, particularly in states where rice rather than wheat replaced coarse cereals. Increased consumption of coarse cereals could reduce anemia prevalence in Indian women along with other interventions.

Impact of Historical Changes in Coarse Cereals Consumption in India on Micronutrient Intake and Anemia Prevalence

Great progress has been made in addressing global undernutrition over the past several decades, in part because of large increases in food production from agricultural expansion and intensification. Food systems, however, face continued increases in demand and growing environmental pressures. Most prominently, human-caused climate change will influence the quality and quantity of food we produce and our ability to distribute it equitably. Our capacity to ensure food security and nutritional adequacy in the face of rapidly changing biophysical conditions will be a major determinant of the next century's global burden of disease. In this article, we review the main pathways by which climate change may affect our food production systems-agriculture, fisheries, and livestock-as well as the socioeconomic forces that may influence equitable distribution.

Climate Change and Global Food Systems: Potential Impacts on Food Security and Undernutrition.

Measuring the effects of anthropogenic CO2 emissions on global nutrient intakes: a modelling analysis

Aquaculture now supplies half of the fish consumed directly by humans. We evaluate whether aquaculture, given current patterns of production and distribution, supports the needs of poor and food-insecure populations throughout the world. We begin by identifying 41 seafood-reliant nutritionally vulnerable nations (NVNs), and ask whether aquaculture meets human nutritional demand directly via domestic production or trade, or indirectly via purchase of nutritionally rich dietary substitutes. We find that a limited number of NVNs have domestically farmed seafood, and of those, only specific aquaculture approaches (e.g. freshwater) in some locations have the potential to benefit nutritionally vulnerable populations. While assessment of aquaculture’s direct contribution via trade is constrained by data limitations, we find that it is unlikely to contribute substantially to human nutrition in vulnerable groups, as most exported aquaculture consists of high-value species for international markets. We also determine that subpopulations who benefit from aquaculture profits are likely not the same subpopulations who are nutritionally vulnerable, and more research is needed to understand the impacts of aquaculture income gains. Finally, we discuss the relationship of aquaculture to existing trends in capture fisheries in NVNs, and suggest strategies to create lasting solutions to nutritional security, without exacerbating existing challenges in access to food and land resources.

Does Aquaculture Support the Needs of Nutritionally Vulnerable Nations?

Understanding dietary patterns is vital to reducing the number of people experiencing hunger (about 795 million), micronutrient deficiencies (2 billion), and overweight or obesity (2.1 billion). We characterize global trends in dietary quality by estimating micronutrient density of the food supply, prevalence of inadequate intake of 14 micronutrients, and average prevalence of inadequate intake of these micronutrients for all countries between 1961 and 2011. Over this 50-year period, the estimated prevalence of inadequate intakes of micronutrients has declined in all regions due to increased total production of food and/or micronutrient density. This decline has been particularly strong in East and Southeast Asia and weaker in South Asia and sub-Saharan Africa. Sub-Saharan Africa is the only region where dietary micronutrient density has declined over this 50-year period. At the global level, micronutrients with the lowest levels of adequate estimated intake are calcium, iron, vitamin A, and zinc, but there are strong differences between countries and regions. Fortification has reduced the estimated prevalence of inadequate micronutrient intakes in all low-income regions, except South Asia. The food supply in many countries is still far below energy requirements, which suggests a need to increase the availability and accessibility of nutritious foods. Countries where the food energy supply is adequate show a very large variation in dietary quality, and in many of these countries people would benefit from more diverse diets with a greater proportion of micronutrient-dense foods. Dietary quality can be improved through fortification, biofortification, and agricultural diversification, as well as efforts to improve access to and use of micronutrient-dense foods and nutritional knowledge. Reducing poverty and increasing education, especially of women, are integral to sustainably addressing malnutrition.

Global trends in dietary micronutrient supplies and estimated prevalence of inadequate intakes

Insufficient data exist for accurate estimation of global nutrient supplies. Commonly used global datasets contain key weaknesses: 1) data with global coverage, such as the FAO food balance sheets, lack specific information about many individual foods and no information on micronutrient supplies nor heterogeneity among subnational populations, while 2) household surveys provide a closer approximation of consumption, but are often not nationally representative, do not commonly capture many foods consumed outside of the home, and only provide adequate information for a few select populations. Here, we attempt to improve upon these datasets by constructing a new model—the Global Expanded Nutrient Supply (GENuS) model—to estimate nutrient availabilities for 23 individual nutrients across 225 food categories for thirty-four age-sex groups in nearly all countries. Furthermore, the model provides historical trends in dietary nutritional supplies at the national level using data from 1961–2011. We determine supplies of edible food by expanding the food balance sheet data using FAO production and trade data to increase food supply estimates from 98 to 221 food groups, and then estimate the proportion of major cereals being processed to flours to increase to 225. Next, we estimate intake among twenty-six demographic groups (ages 20+, both sexes) in each country by using data taken from the Global Dietary Database, which uses nationally representative surveys to relate national averages of food consumption to individual age and sex-groups; for children and adolescents where GDD data does not yet exist, average calorie-adjusted amounts are assumed. Finally, we match food supplies with nutrient densities from regional food composition tables to estimate nutrient supplies, running Monte Carlo simulations to find the range of potential nutrient supplies provided by the diet. To validate our new method, we compare the GENuS estimates of nutrient supplies against independent estimates by the USDA for historical US nutrition and find very good agreement for 21 of 23 nutrients, though sodium and dietary fiber will require further improvement.

Global Expanded Nutrient Supply (GENuS) Model: A New Method for Estimating the Global Dietary Supply of Nutrients

Background: Accurate data on dietary habits are crucial for understanding impacts on disease and informing policy priorities. Nation-specific food balance sheets from the United Nations FAO provided the only available global dietary estimates but with uncertain validity. Objectives: We investigated how FAO estimates compared with nationally representative, individual-based dietary surveys from the Global Dietary Database (GDD) and developed calibration equations to improve the validity of FAO data to estimate dietary intakes. Design: FAO estimates were matched to GDD data for 113 countries across the following 9 major dietary metrics for 30 y of data (1980–2009): fruit, vegetables, beans and legumes, nuts and seeds, whole grains, red and processed meats, fish and seafood, milk, and total energy. Both absolute and percentage differences in FAO and GDD mean estimates were evaluated. Linear regression was used to evaluate whether FAO estimates predicted GDD dietary intakes and whether this prediction varied according to age, sex, region, and time. Calibration equations were developed to adjust FAO estimates to approximate national dietary surveys validated by using randomly split data sets. Results: For most food groups, FAO estimates substantially overestimated individual-based dietary intakes by 74.5% (vegetables) and 270% (whole grains) while underestimating beans and legumes (−50%) and nuts and seeds (−29%) (P < 0.05 for each). In multivariate regressions, these overestimations and underestimations for each dietary factor further varied by age, sex, region, and time (P < 0.001 for each). Split–data set calibration models, which accounted for country-level covariates and other sources of heterogeneity, effectively adjusted FAO estimates to approximate estimates from national survey data (r = 0.47–0.80) with small SEs of prediction (generally 1–5 g/d). Conclusions: For all food groups and total energy, FAO estimates substantially exceeded or underestimated individual-based national surveys of individual intakes with significant variation depending on age, sex, region, and time. Calibration models effectively adjusted the comprehensive, widely accessible FAO data to facilitate a more-accurate estimation of individual-level dietary intakes nationally and by age and sex.

Assessing global dietary habits: a comparison of national estimates from the FAO and the Global Dietary Database1234

Effects of decreases of animal pollinators on human nutrition and global health: a modelling analysis

Abstract: Tularemia is an infectious zoonotic disease caused by one of several subspecies of Francisella tularensis bacteria. Infections by F. tularensis are common throughout the northern hemisphere and have been detected in more than 250 wildlife species. In Alaska, US, where the pathogen was first identified in 1938, studies have identified F. tularensis antibodies in a diverse suite of taxa, including insects, birds, and mammals. However, few such investigations have been conducted recently and knowledge about the current distribution and disease ecology of F. tularensis is limited, particularly in Arctic Alaska, an area undergoing rapid environmental changes from climate warming. To help address these information gaps and provide insights about patterns of exposure among wildlife, we assessed the seroprevalence of F. tularensis antibodies in mammals and tundra-nesting geese from the Arctic Coastal Plain of Alaska, 2014–17. With a commercially available slide agglutination test, we detected antibodies in 14.7% of all individuals sampled (n=722), with titers ranging from 1:20 to 1:320. We detected significant differences in seroprevalence between family groups, with Canidae (foxes, Vulpes spp.) and Sciuridae (Arctic ground squirrel, Spermophilus parryii) having the highest seroprevalence at 21.5% and 33.3%, respectively. Mean seroprevalence for Ursidae (polar bears, Ursus maritimus) was 13.3%, whereas Cervidae (caribou, Rangifer tarandus) had comparatively low seroprevalence at 6.5%. Antibodies were detected in all Anatidae species sampled, with Black Brant (Branta bernicla nigricans) having the highest seroprevalence at 13.6%. The detection of F. tularensis antibodies across multiple taxa from the Arctic Coastal Plain and its nearshore marine region provides evidence of exposure to this pathogen throughout the region and highlights the need for renewed surveillance in Alaska.

A SEROLOGIC SURVEY OF FRANCISELLA TULARENSIS EXPOSURE IN WILDLIFE ON THE ARCTIC COASTAL PLAIN OF ALASKA, USA

Paralytic shellfish toxins associated with Arctic Tern mortalities in Alaska

Abstract: Between 2014 and 2017, widespread seabird mortality events were documented annually in the Bering and Chukchi seas, concurrent with dramatic reductions of sea ice, warmer than average ocean temperatures, and rapid shifts in marine ecosystems. Among other changes in the marine environment, harmful algal blooms (HABs) that produce the neurotoxins saxitoxin (STX) and domoic acid (DA) have been identified as a growing concern in this region. Although STX and DA have been documented in Alaska (US) for decades, current projections suggest that the incidence of HABs is likely to increase with climate warming and may pose a threat to marine birds and other wildlife. In 2017, a multispecies die-off consisting of primarily Northern Fulmars (Fulmarus glacialis) and Short-tailed Shearwaters (Ardenna tenuirostris) occurred in the Bering and Chukchi seas. To evaluate whether algal toxins may have contributed to bird mortality, we tested carcasses collected from multiple locations in western and northern Alaska for STX and DA. We did not detect DA in any samples, but STX was present in 60% of all individuals tested and in 88% of Northern Fulmars. Toxin concentrations in Northern Fulmars were within the range of those reported from other STX-induced bird die-offs, suggesting that STX may have contributed to mortalities. However, direct neurotoxic action by STX could not be confirmed and starvation appeared to be the proximate cause of death among birds examined in this study.

Investigation of Algal Toxins in a Multispecies Seabird Die-Off in the Bering and Chukchi Seas

Acute oral toxicity and tissue residues of saxitoxin in the mallard (Anas platyrhynchos).

Algal toxins in Alaskan seabirds: Evaluating the role of saxitoxin and domoic acid in a large-scale die-off of Common Murres.

ABSTRACT: Mosquito vectors play a crucial role in the distribution of avian Plasmodium parasites worldwide. At northern latitudes, where climate warming is most pronounced, there are questions about possible changes in the abundance and distribution of Plasmodium parasites, their vectors, and their impacts to avian hosts. To better understand the transmission of Plasmodium among local birds and to gather baseline data on potential vectors, we sampled a total of 3,909 mosquitoes from three locations in south-central Alaska during the summer of 2016. We screened mosquitoes for the presence of Plasmodium parasites using molecular techniques and estimated Plasmodium infection rates per 1,000 mosquitoes using maximum likelihood methods. We found low estimated infection rates across all mosquitoes (1.28 per 1,000), with significantly higher rates in Culiseta mosquitoes (7.91 per 1,000) than in Aedes mosquitoes (0.57 per 1,000). We detected Plasmodium in a single head/thorax sample of Culiseta, indicating potential for transmission of these parasites by mosquitoes of this genus. Plasmodium parasite DNA isolated from mosquitoes showed a 100% identity match to the BT7 Plasmodium lineage that has been detected in numerous avian species worldwide. Additionally, microscopic analysis of blood smears collected from black-capped chickadees (Poecile atricapillus) at the same locations revealed infection by parasites preliminarily identified as Plasmodium circumflexum. Results from our study provide the first information on Plasmodium infection rates in Alaskan mosquitoes and evidence that Culiseta species may play a role in the transmission and maintenance of Plasmodium parasites in this region.

Evidence of Culiseta Mosquitoes as Vectors for Plasmodium Parasites in Alaska

Prevalence and diversity of avian blood parasites in a resident northern passerine

Abstract Aim To investigate the structure and rate of gene flow among populations of habitat‐specialized species to understand the ecological and evolutionary processes underpinning their population dynamics and historical demography, including speciation and extinction. Location Peruvian and Argentine Andes. Taxon Two subspecies of torrent duck (Merganetta armata). Methods We sampled 156 individuals in Peru (M. a. leucogenis; Chillón River, n = 57 and Pachachaca River, n = 49) and Argentina (M. a. armata; Arroyo Grande River, n = 33 and Malargüe River, n = 17), and sequenced the mitochondrial DNA (mtDNA) control region to conduct coarse and fine‐scale demographic analyses of population structure. Additionally, to test for differences between subspecies, and across genetic markers with distinct inheritance patterns, a subset of individuals (Peru, n = 10 and Argentina, n = 9) was subjected to partial genome resequencing, obtaining 4,027 autosomal and 189 Z‐linked double‐digest restriction‐associated DNA sequences. Results Haplotype and nucleotide diversities were higher in Peru than Argentina across all markers. Peruvian and Argentine subspecies showed concordant species‐level differences (ΦST mtDNA = 0.82; ΦST autosomal = 0.30; ΦST Z chromosome = 0.45), including no shared mtDNA haplotypes. Demographic parameters estimated for mtDNA using IM and IMa2 analyses, and for autosomal markers using ∂a∂i (isolation‐with‐migration model), supported an old divergence (mtDNA = 600,000 years before present (ybp), 95% HPD range = 1.2 Mya to 200,000 ybp; and autosomal ∂a∂i = 782,490 ybp), between the two subspecies, characteristic of deeply diverged lineages. The populations were well‐differentiated in Argentina but moderately differentiated in Peru, with low unidirectional gene flow in each country. Main conclusions We suggest that the South American Arid Diagonal was preexisting and remains a current phylogeographic barrier between the ranges of the two torrent duck subspecies, and the adult territoriality and breeding site fidelity to the rivers define their population structure.

Old divergence and restricted gene flow between torrent duck (Merganetta armata) subspecies in the Central and Southern Andes

Abstract We assessed hematozoa infection in Spectacled Eiders (Somateria fischeri) at two areas in Alaska, US. No Haemoproteus or Plasmodium species were detected. Leucocytozoon prevalence was 6.5% for adults across sites and 41.9% for juveniles sampled in the Arctic, providing evidence for local transmission. All Leucocytozoon haplotypes were previously detected in waterfowl.

Evidence for Haemosporidian Parasite Infections in Spectacled Eiders (Somateria fischeri) Sampled in Alaska, USA during the Breeding Season

The decline of top carnivores has released large herbivore populations around the world, incurring socioeconomic costs such as increased animal–vehicle collisions. Attempts to control overabundant deer in the Eastern United States have largely failed, and deer–vehicle collisions (DVCs) continue to rise at alarming rates. We present the first valuation of an ecosystem service provided by large carnivore recolonization, using DVC reduction by cougars as a case study. Our coupled deer population models and socioeconomic valuations revealed that cougars could reduce deer densities and DVCs by 22% in the Eastern United States, preventing 21,400 human injuries, 155 fatalities, and $2.13 billion in avoided costs within 30 years of establishment. Recently established cougars in South Dakota prevent $1.1 million in collision costs annually. Large carnivore restoration could provide valuable ecosystem services through such socio‐ecological cascades, and these benefits could offset the societal costs of coexistence.

Socioeconomic Benefits of Large Carnivore Recolonization Through Reduced Wildlife‐Vehicle Collisions

Haemosporidian parasite infections in grouse and ptarmigan: Prevalence and genetic diversity of blood parasites in resident Alaskan birds

Detection, prevalence, and transmission of avian hematozoa in waterfowl at the Arctic/sub-Arctic interface: co-infections, viral interactions, and sources of variation

Prevalence and genetic diversity of haematozoa in South American waterfowl and evidence for intercontinental redistribution of parasites by migratory birds

A fundamental question in evolutionary genetics concerns the extent to which adaptive phenotypic convergence is attributable to convergent or parallel changes at the molecular sequence level. Here we report a comparative analysis of hemoglobin (Hb) function in eight phylogenetically replicated pairs of high- and low-altitude waterfowl taxa to test for convergence in the oxygenation properties of Hb, and to assess the extent to which convergence in biochemical phenotype is attributable to repeated amino acid replacements. Functional experiments on native Hb variants and protein engineering experiments based on site-directed mutagenesis revealed the phenotypic effects of specific amino acid replacements that were responsible for convergent increases in Hb-O2 affinity in multiple high-altitude taxa. In six of the eight taxon pairs, high-altitude taxa evolved derived increases in Hb-O2 affinity that were caused by a combination of unique replacements, parallel replacements (involving identical-by-state variants with independent mutational origins in different lineages), and collateral replacements (involving shared, identical-by-descent variants derived via introgressive hybridization). In genome scans of nucleotide differentiation involving high- and low-altitude populations of three separate species, function-altering amino acid polymorphisms in the globin genes emerged as highly significant outliers, providing independent evidence for adaptive divergence in Hb function. The experimental results demonstrate that convergent changes in protein function can occur through multiple historical paths, and can involve multiple possible mutations. Most cases of convergence in Hb function did not involve parallel substitutions and most parallel substitutions did not affect Hb-O2 affinity, indicating that the repeatability of phenotypic evolution does not require parallelism at the molecular level.

Convergent Evolution of Hemoglobin Function in High-Altitude Andean Waterfowl Involves Limited Parallelism at the Molecular Sequence Level

Convergent Evolution of HemoglobinFunction in High-Altitude Andean WaterfowlInvolves Limited Parallelism at the MolecularSequence Level

A real-time, quantitative PCR protocol for assessing the relative parasitemia of Leucocytozoon in waterfowl.

NASA Arctic-Boreal Vulnerability Experiment ( ABoVE) pre-solictation information. The ABoVE Concise Experiment (ACEP) plan refines the science questions and rationale for ABoVE, poses a next tier of science questions, and lays out a top-level study design. The study design defines the ABoVE study domain and research areas, identifies the types of studies and observations needed to address the ABoVE science questions, and provides guidance for study implementation.

Infection rates, parasitemia levels, and genetic diversity of hematozoa in New World waterfowl

Parasitismo y incubación conjunta del nido de Cauquén Común (Chloephaga picta) por Pato Maicero (Anas georgica). Nest parasitism is a relatively uncommon but well-studied reproductive strategy in birds. About 1% of bird species are known to deposit their eggs in the nests of other species (Payne 1977). Intraspecific parasitism, which can be difficult to detect, is even more taxo-Laying eggs in the nests of other birds and exploiting the parental care of other individuals can offer advantages to the parasite, such as enhanced fecundity and the avoidance of predation and energetic costs associated with incubation and brood care, or eliminate constraints associated with building a nest (Sorenson 1992, 1997). Parasitism can also serve as 'best-of-a-bad-job', alternative reproductive strategy when an individual's ability to nest in a typical manner is limited or curtailed by poor environmental conditions (Sorenson 1991, 1993). Additionally, the host may benefit if the cost of raising parasitic young is not great, as is the case in precocial species (Rohwer & Freeman 1989) and the presence of parasitic young in amalgamated broods dilutes preda-tion on the host offspring (Munro & Bedard 1977, Lank et al. 1989, 1991, Eadie & Lumd-sen 1985, Eadie et al. 1988). Nest parasitism has thus been shown to be a regular and flexible feature of the nesting biology of many different species, having evolved in different ecological contexts with various proximate and historical factors (Eadie et al. Here we report the first record of nest parasitism by the Yellow-billed Pintail (Anas georgica), a dabbling duck species endemic to South America. Nest parasitism is common in yet due to a scarcity of studies in the region few records of this type of behavior have been reported for South American waterfowl (Eadie et al. 1988, Yom-Tov 2001; but see Gibson 1920). Our finding also is noteworthy because what initially appeared as a parasitic egg-laying event to the observers was likely a case of joint incubation and competition for the nest site, resulting in the expulsion of partially incubated eggs and cracked eggs within the next bowl. On 1 November 2011, we observed a Yellow billed Pintail and Upland Goose (Chloe-phaga picta) sitting on the same nest bowl (Fig. 1A) in a flooded pasture at Estancia Bella Vista, near Sarmiento, Chubut, Argentina (45.60°S, 68.99°W). Upon approaching the nest, the Yellow-billed Pintail and Upland Goose flushed together for a short period of flight (Fig. 1B). The nest contained …

Parasitism and joint incubation of upland goose (Chloephaga picta) nest by yellow-billed pintail (Anas georgica)

Interpretation of Dihydrorhodamine-1,2,3 Flow Cytometry in Chronic Granulomatous Disease: an Atypical Exemplar

Functional Confirmation of DNA Repair Defect in Ataxia Telangiectasia (AT) Infants Identified by Newborn Screening for Severe Combined Immunodeficiency (NBS SCID).

Application of DNA- and RNA-based sequencing techniques to tumour tissue samples in the clinical laboratory

NAPDH Oxidase-Specific Flow Cytometry Allows for Rapid Genetic Triage and Classification of Novel Variants in Chronic Granulomatous Disease

Utility of DNA, RNA, Protein, and Functional Approaches to Solve Cryptic Immunodeficiencies

DNA ligase 4 deficiency (LIG4-SCID) causes lymphopenia (T-B-NK+) and a radiosensitive SCID (RS-SCID) phenotype. We demonstrate, for the first time, flow cytometric-based kinetic analysis of phosphorylated H2AX (γH2AX) in lymphocyte subsets, especially NK cells, for the assessment of LIG4-SCID. Measurement of phosphorylated (p) ATM, SMC1, and H2AX (γH2AX) was performed by flow cytometry to assess DNA repair defects in a 3-year-old girl. Functional assessment (phosphorylation) was measured in T and NK cells (B cells were absent) before irradiation (background control) or after low-dose (2Gy) irradiation (1 and 24 hours). We observed maximal γH2AX at 1 hour postirradiation, with dephosphorylation at 24 hours postirradiation in healthy control patients. The patient showed normal frequencies (percentage) of T cells and NK cells for γH2AX, but increased levels of γH2AX compared with control patients at 1 hour postirradiation. At 24 hours postirradiation, there was a lack of dephosphorylation in a substantial proportion of lymphocytes (with differences observed between T and NK cells) compared with healthy control patients. Although there was dephosphorylation of γH2AX at 24 hours in patient lymphocytes compared with 1 hour, the amount remained elevated at 24 hours compared with in control patients. The data from pATM and pSMC1 were uninformative. Flow-based kinetic analysis of γH2AX is a useful marker for the diagnosis of LIG4-SCID.

Application of a radiosensitivity flow assay in a patient with DNA ligase 4 deficiency.

WILD syndrome is GATA2 deficiency: A novel deletion in the GATA2 gene.

Context: P450 oxidoreductase deficiency (PORD) is a unique congenital adrenal hyperplasia variant that manifests with glucocorticoid deficiency, disordered sex development (DSD), and skeletal malformations. No comprehensive data on genotype-phenotype correlations in Caucasian patients are available. Objective: The objective of the study was to establish genotype-phenotype correlations in a large PORD cohort. Design: The design of the study was the clinical, biochemical, and genetic assessment including multiplex ligation-dependent probe amplification (MLPA) in 30 PORD patients from 11 countries. Results: We identified 23 P450 oxidoreductase (POR) mutations (14 novel) including an exonic deletion and a partial duplication detected by MLPA. Only 22% of unrelated patients carried homozygous POR mutations. p.A287P was the most common mutation (43% of unrelated alleles); no other hot spot was identified. Urinary steroid profiling showed characteristic PORD metabolomes with variable impairment of 17α-hydroxylase and 21-hydroxylase. Short cosyntropin testing revealed adrenal insufficiency in 89%. DSD was present in 15 of 18 46,XX and seven of 12 46,XY individuals. Homozygosity for p.A287P was invariably associated with 46,XX DSD but normal genitalia in 46,XY individuals. The majority of patients with mild to moderate skeletal malformations, assessed by a novel scoring system, were compound heterozygous for missense mutations, whereas nearly all patients with severe malformations carried a major loss-of-function defect on one of the affected alleles. Conclusions: We report clinical, biochemical, and genetic findings in a large PORD cohort and show that MLPA is a useful addition to POR mutation analysis. Homozygosity for the most frequent mutation in Caucasians, p.A287P, allows for prediction of genital phenotype and moderate malformations. Adrenal insufficiency is frequent, easily overlooked, but readily detected by cosyntropin testing.

Genotype-Phenotype Analysis in Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency

The molecular genetic diagnosis of inherited metabolic disorders is challenging. The diseases are rare, and most show locus heterogeneity. Hence, testing of the genes associated with IMDs is time consuming and often not easily available. We report a resequencing array that allows the simultaneous resequencing of up to 92 genes associated with IMDs. To validate the array, DNA samples from 51 patients with 52 different known variants (including point variants, small insertion, and deletions [indels]) in seven genes (C14ORF133, GAA, NPC1, NPC2, VPS33B, WFS1, and SLC19A2) were amplified by PCR and hybridized to the array. A further patient cohort with 48 different mutations in NPC1 were analyzed blind. Out of 76 point variants, 73 were identified using automated software analysis followed by manual review. Ten insertion and deletion variants were detected in the extra tiling using mutation specific probes, with 11 heterozygous deletions and 3 heterozygous insertions. In summary, we identified 96% (95% confidence interval [CI] 89–99%) of point variants added to the array, but the pickup rate reduced to 83% (95% CI 75–89%) when insertions/deletions were included. Although the methodology has strengths and weaknesses, application of this technique could expedite diagnosis in most patients with multilocus IMDs. Hum Mutat 31:1–8, 2010. © 2010 Wiley‐Liss, Inc.

Design and validation of a metabolic disorder resequencing microarray (BRUM1)

Multiplex ligation-dependent probe amplification (MLPA) analysis is an effective tool for the detection of novel intragenic PLA2G6 mutations: implications for molecular diagnosis.

Complex Morphological Analysis of Cerebral Aneurysms Through the Novel Use of Fractal Dimension as a Predictor of Rupture Status.

Percutaneous transluminal angioplasty and/or stenting for the treatment of basilar artery stenosis: a systematic review and meta-analysis

INTRODUCTION: Basilar artery stenosis (BAS) carries high morbidity and mortality, with variable outcomes reported after endovascular treatments. METHODS: PubMed, EMBASE, Web-of-Science, Scopus, and Cochrane were searched upon the PRISMA guidelines to include studies describing PTAS for BAS. Pooled rates of intervention-related complications and outcomes were analyzed with random-effect model meta-analyses. RESULTS: We included 25 studies comprising 1016 patients. Patients were mostly male (79.5%), with hypertension (81.1%) and/or dyslipidemia (56.4%), and presenting with transient ischemic attack (54.4%) or stroke (45.6%). BAS frequently involved the middle basilar artery (51.4%), and were mostly classified as Mori-B (57.4%). PTAS for BAS was indicated in patients with severe (≥50%-70%) symptomatic BAS refractory to dual antiplatelet therapy. Patients underwent angioplasty (95.5%) and/or stenting (92.2%), preferably using Wingspan or Apollo stents. Median baseline BAS was 81% (range, 53%-99%), while median post-intervention BAS was 13% (0%-75%). Actuarial rates of successful intervention and “good” final outcome were 100% (95% CI: 100%-100%) and 89% (95% CI: 85%-93%). Intervention-related recurrent ischemic stroke occurred in 85 patients (8.3%) with actuarial rates of 5% (95% CI: 4%-7%), and was differentiated into perforator (5.4%), in-stent (2.6%), and embolic (0.4%). Actuarial rates of intervention-related dissection, restenosis, and death were 0% (95% CI: 0%-0%), 1% (95%CI: 0%-1%), and 0% (95% CI: 0%-2%). CONCLUSIONS: Elective PTAS is safe and effective in selected patients with medically-refractory, severe, symptomatic, and non-acute BAS. Different stent types and angioplasty-assisted procedures should be considered based on specific clinico-radiological characteristics of the lesions.

388 Percutaneous Transluminal Angioplasty and/or Stenting for the Treatment of Basilar Artery Stenosis: A Systematic Review and Meta-Analysis

OBJECTIVE
Although the role of inflammation in the development of aneurysms is established, less is known about the development of intracranial aneurysms in the setting of underlying autoimmune disease. The underlying systemic inflammatory characteristics of disorders such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren's syndrome may influence the development of intracranial aneurysms through common inflammatory pathways. The authors hypothesized that there is an association between underlying autoimmune disease and aneurysm growth and rupture.

METHODS
Medical records of patients who underwent cerebral angiography between August 2018 and August 2021 were manually reviewed. Autoimmune diseases as defined for this study are those known to have systemic inflammatory effects on the central nervous system or multiple other organ systems. Statistical analysis, including construction of multivariable linear and logistic regression models, was performed using R version 4.1.0.

RESULTS
Chart review identified 190 patients with 469 ruptured and unruptured saccular intracranial aneurysms. There were 31 patients with 44 aneurysms identified as having an autoimmune disease. The mean size of a ruptured aneurysm was significantly smaller among patients with autoimmune disease compared with patients without autoimmune disease (4.14 mm vs 5.34 mm, p = 0.03). The multivariate logistic regression model did not identify any significant association between rupture and autoimmune disease when controlling for other variables (p = 0.49). In the multivariate linear regression model, autoimmune disease was still significantly associated with a smaller size at rupture (p = 0.04), and smoking was associated with a larger size at rupture (p = 0.03) when controlling for other variables. A second multivariate logistic regression model found autoimmune disease to be independently associated with rupture at a size smaller than 7 mm (p = 0.02), while smoking was independently associated with rupture at a size larger than 7 mm (p = 0.01).

Autoimmune disease is associated with a smaller aneurysm size at rupture, although it is not associated with rupture itself. This association may be due to inflammatory pathways that are common to autoimmune diseases as well as aneurysm wall development. Although the authors were unable to identify any association between rupture status and the presence of autoimmune disease, the association between smaller size at rupture and autoimmune disease warrants further studies, as autoimmune disease may influence the trajectory of aneurysm development and the decision to treat.

Association between underlying autoimmune disease and small aneurysm size at rupture.

Differences in Automated Perfusion Software: Do They Matter Clinically?

 Introduction:
 Treatment of acute ischemic stroke in the late window changed with the positive results of DAWN and DEFUSE III. Both trials required the use of automated perfusion software for inclusion. Because differences in the predicted core or penumbra between software can lead to differences in eligibility for endovascular thrombectomy (EVT), we sought to compare whether these potential differences would have changed eligibility for EVT by DAWN or DEFUSE III criteria.
 
 Methods:
 Patients presenting or transferred to the University of Cincinnati Medical Center between April 23
 rd
 2019 and July 22
 nd
 2019 with acute ischemic stroke secondary to large vessel occlusions within the anterior circulation in the extended time window (>6-24 hours) who underwent CT perfusion (CTP) imaging were prospectively tracked. CTP findings, clinical course, age and initial NIHSS were retrospectively reviewed. The primary outcome was EVT eligibility using DAWN or DEFUSE criteria. Secondary outcomes were penumbra (Tmax>6s) and core (CBF<30%) volumes. McNemar test and kappa coefficients were used to assess the agreement in the primary outcome. Intra-class correlation coefficients were used to evaluate the agreement between the software for secondary outcomes.
 
 Results:
 Of 46 included patients, the Viz CTP and RAPID software provided discordant EVT eligibility in 5 cases (4 by DEFUSE criteria and 1 by DAWN). By DAWN criteria, agreement was almost perfect between the software packages (kappa 0.96, 95% CI 0.87-1.00, p<0.0001). By DEFUSE III criteria, the two software demonstrated excellent agreement (kappa 0.82, 95% CI 0.65-0.99, p<0.0001).
 
 Discussion:
 We observed no difference in eligibility for EVT using either software when both DEFUSE and DAWN criteria were considered. If using only one trial’s criteria, 10.6% of patients would have had differing eligibility for EVT depending on the package used, although this difference did not demonstrate statistical significance.
 
Abstract WP107: Differences In Automated Perfusion Softwares: Do They Matter Clinically?

BACKGROUND Inferior petrosal sinus sampling (IPSS) is a useful technique in the diagnosis of Cushing’s disease (CD) when the imaging finding is negative or equivocal. Different authors have reported considerable variability in the ability to determine tumor laterality with IPSS. Here the authors present a retrospective case series of 7 patients who underwent IPSS using a systematic algorithm to improve lateralization accuracy by identifying optimal sampling sites on the basis of individual cavernous sinus drainage patterns in each patient. OBSERVATIONS Of the 7 patients identified, 6 were determined to have CD and subsequently underwent surgery. IPSS was accurate in all patients from whom laterality was predicted. Arterial and venous angiography were used to define cavernous sinus drainage patterns and determine optimal sampling sites. All patients who underwent surgery achieved hormonal cure. LESSONS All IPSS predictions of lateralization were correct when available, and all patients who underwent surgery achieved hormonal cure. Advances in angiographic techniques for identification of the site of primary drainage from the cavernous sinus and subsequent optimization of microcatheter placement may improve the ability to predict tumor laterality.

An algorithm to improve lateralization accuracy of inferior petrosal sinus sampling: procedural nuances for complex patterns of venous drainage. Patient series

Carotid artery stenosis is implicated in up to 40% of all ischemic strokes. Accordingly, symptomatic, high-grade carotid artery stenosis portends an especially high risk of future stroke. Intervention via open or endovascular approaches drastically reduces this risk. Under the appropriate conditions, carotid artery stenting serves as a safe and effective alternative to carotid endarterectomy. We present the case of a 57-yr-old male with symptomatic, high-grade stenosis of his right internal carotid artery, for whom a history of radiation to the head and neck represented a relative contraindication to carotid endarterectomy, and thus endovascular treatment with angioplasty and stenting was performed. Informed consent was obtained prior to the procedure. Intraprocedurally, stent delivery past the area of stenosis proved somewhat challenging. However, by employing several nuanced maneuvers, we utilized our guiding catheter in a nonconventional manner in order to successfully perform the procedure. As the field of neuroendovascular surgery evolves, each case provides us unique lessons, which in turn expands our interventional capabilities and adds to the armamentarium of neuroendovascular techniques. We present this surgical video both as a means to provide a general overview of carotid artery stenting, and to share a lesson learned through the implementation of an interesting technical nuance.

Stenting in High-Grade Internal Carotid Artery Stenosis: 2-Dimensional Operative Video.

As of this writing, the growing coronavirus disease 2019 (COVID-19) pandemic has suspended international travel, has injected instability in global financial markets, and has led to widespread school and business closures. There are increased calls for social distancing, avoidance of unnecessary physical contacts/interactions, and even mandatory isolation in some countries. These restrictions are leading hospitals and healthcare systems to suspend elective procedures and limit staff interactions with patients to essential personnel only. The currently reported overall case fatality rate of COVID19 is 2.3% in the general population, and is higher (14.8%) in patients >80 years of age. Further, patients with COVID-19 requiring hospitalization suffer a number of cardiovascular complications including arrhythmias (16.7% of patients) and heart failure (23% of patients), raising the risk for acute ischemic stroke (AIS). Indeed, cerebrovascular complications have been reported in 5% to 6% of patients with severe COVID-19. In this context, emergent delivery of endovascular therapy (EVT) requires careful planning and deliberation with special attention to patient selection, resource utilization, and the safety of healthcare providers. With the goal of minimizing the negative impact of COVID-19 on acute stroke patients and healthcare providers, we assembled a multidisciplinary working group to develop consensus-based recommendations and an algorithm for evaluation and treatment of acute stroke patients eligible for EVT during the COVID-19 pandemic. The role of intravenous thrombolysis is not addressed here because EVT presents unique challenges compared with intravenous drug administration. Three populations of potential thrombectomy patients are highlighted: (1) emergency department (ED) patients with stroke and suspected COVID-19, (2) admitted patients with COVID-19 who develop stroke, and (3) patients with stroke who present to a hospital with constrained resources due to COVID-19. Recommendations are discussed and a clinical algorithm is proposed with anticipated decision points of care. This algorithm takes into account the American Heart Association/American Stroke Association (AHA/ASA) EVT guidelines, the safety of patients and staff, the predictors of mortality in patients with COVID-19, and the appropriate utilization of scarce resources. Our working group concluded that diagnosis with COVID-19 is not necessarily a contraindication to EVT for stroke. However, particular care must be taken when preparing patients with COVID-19 for EVT to ensure staff safety. In addition, it may be reasonable during these times of extreme resource limitation to modify current EVT protocols including patient selection and post-EVT care, and to avoid EVT in unstable, severely critically ill patients with COVID-19.

Endovascular Therapy for Patients With Acute Ischemic Stroke During the COVID-19 Pandemic: A Proposed Algorithm

We read with interest Chen et al.’s recent article, ‘‘Malignant cerebellar edema in three-year-old girl following accidental opioid ingestion and fentanyl administration.’’ We found the imaging and clinical characteristics to be strikingly similar to our recent case series describing adult patients with a similar pattern of cerebellar edema, as well as acute injury to the hippocampi and scattered in the basal ganglia, which we termed ‘‘CHANTER syndrome.’’ As described by Chen et al., there are similar cases in the pediatric literature focusing on cerebellar edema. There are additionally cases in the adult literature describing hippocampal injury in the setting of opiate exposure, with Barash and Kofke suggesting this may be a direct fentanyl-associated toxidrome. In our case series, the heterogeneity of exposures may suggest this is a variant of anoxic injury, perhaps somehow mediated or otherwise influenced by opiates or other exposures. Supratentorial findings appear to differ between pediatric and adult cases, with Chen et al. reporting a pattern of leukoencephalopathy, and our cases involving hippocampal and basal ganglia injury, with the white matter relatively spared. Nonetheless, there is a striking commonality in the described cerebellar edema, not in a vascular territory, ultimately causing obstructive hydrocephalus in a manner that is distinct from typical anoxic injury. We agree with the authors that this is a subject that warrants further evaluation in both the adult and pediatric realms. References

Response to “Malignant cerebella edema in three-year-old girl following accidental opioid ingestion and fentanyl administration”

Wall shear stress, the frictional force of blood flow tangential to an artery lumen, has been demonstrated in multiple studies to influence aneurysm formation and risk of rupture. In this article, the authors review the ways in which shear stress may influence aneurysm growth and rupture through changes in the vessel wall endothelial cells, smooth-muscle cells, and surrounding adventitia, and they discuss shear stress-induced pathways through which these changes occur.

Cerebellar Hippocampal and Basal Nuclei Transient Edema with Restricted diffusion (CHANTER) Syndrome

This study evaluated the effect of two biocontaminant surrogates on the activity and performance of activated sludge. In the presence of bacteriophage MS2 at 3.2 × 108 PFU/ml, the peak respiration rates varied between 9.1 and 10.5 mg O2/gVSS/hr, generally similar to the rates observed in negative controls. MS2 did not alter the molar CO2‐produced‐to‐O2 consumed stoichiometry observed during respiration. Similar results were observed for Bacillus globigii (BG). Ethanol, a potential co‐contaminant associated with biocontamination incidents, can inhibit initial oxygen uptake. MS2 and BG both adsorbed to activated sludge; post‐exposure viability was confirmed for BG but not for MS2. This study is the first to evaluate the effects of BG and MS2 on activated sludge, and it presents a protocol that can be used in operational situations.

Functional resilience of activated sludge exposed to Bacillus globigii and bacteriophage MS2

Plotting a Line: Liminality and Border as Concept and Device in Walter Scott’s Rob Roy (1817)

The Effect of Bacillus Globigii Spores on the Activity and Performance of Activated Sludge

A TRACE METALS DATABASE OF CAVE SEDIMENTS OF THE MIDCONTINENT U.S.A.

The midcontinent of the United States has thousands of documented caves. These caves contain cave sediments, which are the accumulation of biological, geological, and anthropological debris. At this time there is no known database for trace metals of cave sediments of the midcontinent United States. Considering that caves host a wide variety of life, it is important to create a database to examine potential effects of trace metals on cave systems. In order to develop this baseline, 14 caves were sampled from across the midcontinent. Caves were selected based on geologic and hydrologic attributes. The sediments were analyzed for the following suite of metals: Al, As, B, Ba, Ca, Cd, Co, Cr, Cu, Fe, La, Mg, Mn, Ni, P, Pb, S, Sr, V, and Zn. As documented in this study, metal variation among caves is dictated by land use history, surficial watersheds, and geology. The preliminary results indicated that mineralization and anthropogenic impacts amplified trace metal concentrations in two caves, which were omitted to further evaluate the remaining 12 caves based on geologic and hydrologic factors. When geologic factors were examined, the geochemical variation between evaporites and carbonates resulted in B, Mg, S, and Sr concentrations being clearly associated with evaporites, while the differences between limestone and dolostone are primarily related to the mineralogy. When hydrologic attributes were analyzed, urban areas were more enriched with Cd, Cu, La, Mn, and Zn because of the multitude of potential sources available in urban areas over rural areas.

A Trace Metal Content Database Of Cave Sediments Of Midcontinent U.S.A.

Analysis and reactions of aqueous selenide and other reduced inorganic selenium compounds under anoxic conditions

This paper presents a critical analysis of the First Bosporus Bridge. The bridge crosses the Bosporus Straits, uniting the two banks of Istanbul with a road crossing for the first time. The bridge was completed in 1973 and has a main span of 1074 m. This paper considers aspects of aesthetics, loading, strength, construction and future requirements.

CRITICAL ANALYSIS OF THE FIRST BOSPORUS BRIDGE, ISTANBUL, TURKEY

This paper is a detailed assessment and analysis of Charles Bridge which crosses the river Vlatva in the heart of Prague. The paper explores the history, aesthetics, design and construction of the bridge as well as the success of the bridge in terms of fulfilling its functions. The report also provides a basic structural analysis of the bridge with simplified calculations before offering possible bridge improvements based on a critical analysis.

Abstract This paper provides a detailed review of Alessandro Roncaglia’s book, The Age of Fragmentation: A History of Contemporary Thought, published in 2019. It is shown by Roncaglia in this book that since early in the twentieth century economic thought has fragmented into many different research fields, and into many different theoretical approaches, and yet the mainstream of contemporary economics has become progressively dominated by the marginalist approach. The review accounts for the main themes in Roncaglia’s interpretation of the development of contemporary economic thought in its many different fields and theoretical perspectives and his evaluation of their scientific contribution. A central argument of Roncaglia is that because of the fragmented nature of economics and the cultural-political factors shaping research funding of it, the history of economic thought has never been more important for communication and mutual comprehension across the discipline to ensure its intellectual health and ethical standing.

Economics: A Fragmented and Troubled Scientific Discipline? A Review of Alessandro Roncaglia’s The Age of Fragmentation: A History of Contemporary Economic Thought (2019)

We study the coevolution of the fall in the US corporate-sector labor share and the rise of business activity in tax-preferred pass-throughs. We find that reallocating activity to the form it would have taken prior to the Tax Reform Act of 1986 accounts for one-third of the decline in the corporate-sector labor share between 1978 and 2017. Our adjustments are concentrated among mid-market firms in services, magnifying the role of the manufacturing sector and superstar firms in driving the remaining decline in the labor share. Our findings highlight the importance of tax policy when measuring factor shares. (JEL D22, E25, H25, K34, L60, L80)

 This paper is concerned with the role of effective demand in Malthus’s theory of accumulation expounded in his Principles of Political Economy. As is well known, Keynes praised Malthus for being a forerunner in identifying a lack of effective demand as a cause of depression in economic activity and a constraint on growth. There have since been many interpretations in the literature of Malthus’s position by reference to his arguments against Say’s Law in contending the possibility of “general gluts” and to his theory of capital accumulation. We begin by examining Malthus’s conception of the supply-side factors that determine what we call, “potential accumulation”, being accumulation that is not constrained by demand. The paper then considers the role of effective demand in Malthus’s well known contention of the possibility of “general gluts” and, connectedly, in his theory of demand-constrained capital accumulation. On this basis, we then appraise whether Malthus’s theory anticipates Keynes’s principle of effective demand by reference to the debate on this question in the literature, showing that while Malthus lacked a meaningful saving-investment analysis, he does provide insights important to the modern demand-led approach to growth.

A Reconsideration of the Role of Demand in Malthus’s Theory of Accumulation*

This paper uses administrative tax data to estimate top wealth in the United States. We assemble new data that links people to their sources of capital income and develop new methods to estimate the degree of return heterogeneity within asset classes. Disaggregated fixed income data reveal that rich individuals earn much more of their interest income in higher-yielding forms, and have much greater exposure to credit risk. Consequently, in recent years, the interest rate on fixed income at the top is approximately three times higher than the average. Using firm-level characteristics to value firms, we find that twenty percent of total pass-through business wealth accrues to those with losses. We combine this new data on fixed income and pass-through business returns with refined estimates of C-corporation equity, housing, and pension wealth to deliver new capitalized wealth estimates. Our approach---which builds on Saez and Zucman (2016) and Bricker, Henriques, and Hansen (2018)---reduces bias because wealth and rates of return are correlated. From 1989 to 2016, the top 1%, 0.1%, and 0.01% wealth shares increased by 7.6, 5.1, and 3.0 percentage points, respectively, to 31.5%, 15.0%, and 7.0%. While these changes are less dramatic than some prior estimates, wealth is very concentrated: the top 1% holds nearly as much wealth as either the bottom 90% or the "P90-99" class. We discuss implications for income inequality measures, capital tax policy, and savings behavior.

Top Wealth in America: New Estimates and Implications for Taxing the Rich

How important is human capital at the top of the U.S. income distribution? A primary source of top income is private “pass-through” business profit, which can include entrepreneurial labor income for tax reasons. This article asks whether top pass-through profit mostly reflects human capital, defined as all inalienable factors embodied in business owners, rather than financial capital. Tax data linking 11 million firms to their owners show that top pass-through profit accrues to working-age owners of closely held mid-market firms in skill-intensive industries. Pass-through profit falls by three-quarters after owner retirement or premature death. Classifying three-quarters of pass-through profit as human capital income, we find that the typical top earner derives most of her income from human capital, not financial capital. Growth in pass-through profit is explained by both rising productivity and a rising share of value added accruing to owners.

Ghislain Deleplace, Ricardo on Money: A Reappraisal. (Abingdon, UK: Routledge, 2017), pp. xvi + 417, $140 (hardcover). ISBN: 9780415661584.

The main purpose of this paper is to show that the Keynesian-Kaleckian demand-led theory of growth proposed within the classical framework of prices and distribution as articulated by Sraffa (1960), is superior to the neoclassical supply-driven theory in explaining economic growth. After showing the fundamental theoretical problem with the neoclassical supply-driven approach to growth, we expound a demand-led model of growth that abandons ‘steady-state’ and, instead, adopts an ‘historical approach’ in which the data is specified for historical periods of time. The model incorporates the contribution of technical progress to demand-led growth and, thereby, provides the basis to identify the most important political, social, and institutional developments that historically explain growth and economic development since the advent of capitalism. Our historical analysis shows how demand-led growth theory can provide the foundation for a new and more coherent interpretation of the history of economic development.

Demand-Led Growth Theory in a Classical Framework: Its Superiority, Its Limitations, and Its Explanatory Power

We provide novel insights into firm behavior by investigating their response to the corporate income tax. First, we expand the set of firms typically studied to include the full distribution of firms by using administrative tax data on the population of nearly 2 million corporations filing an IRS Form 1120. Second, we develop an empirical strategy that produces estimates with less bias, smaller variance, and less sensitivity to model parameters than previous methods. We find that the corporate income tax distorts firms’ behavior, causing them to report 8 percent less taxable income, implying an elasticity of corporate taxable income of 0.5. We also find that firms reduce their income primarily by making adjustments to reported revenues and costs, rather than making real changes to hiring or investment. Finally, we find that optimizing frictions caused by accounting rules substantially reduce the magnitude of the response of firms to the corporate income tax.

At a Loss: The Real and Reporting Elasticity of Corporate Taxable Income

CAPITA – Treasury’s microsimulation model of personal income tax and transfers

Abstract David Ricardo and Thomas Tooke were contemporaries in the ‘golden era’ of English classical economics. Whereas Ricardo can be characterised as the supreme deductive thinker among the classical economists of the time, Tooke can be characterised as the supreme inductive and empirical thinker. Ricardo’s substantive contributions were to the core theory of value and distribution. Tooke’s substantive contributions were to the empirical analysis of prices and to monetary theory and policy. The relationship between these two classical economists with their very different approaches to economics is explored and their substantive contributions to the development of classical economics are compared. Tooke’s banking school monetary theory is shown to represent an outright rejection of Ricardo’s well-established monetary theory. It is argued that Tooke’s monetary theory provides a more valuable and lasting contribution than Ricardo’s quantity theory of money to the development of classical economics after Sraffa. In a brief conclusion, the different substantive contributions of these two economists to modern classical economics are reconciled.

Ricardo the ‘Logician’ versus Tooke the ‘Empiricist’: On Their Different Substantive Contributions to Classical Economics

This paper is concerned with the reception and influence of Ricardo's Principles in the non-English-speaking world. It mainly focuses on those writers who have appreciated and elaborated on Ricardo's core theory of value and distribution in contributing toward the advancement of classical economics. The paper shows that with the exception of Marx and a few notable scholars, Ricardo's contribution was generally not well received nor well understood in the European Continent in the first half of the nineteenth century. It then shows that with the rise of Marx and the spread of Marxism there was a renewed interest in Ricardo's core theory in Europe and Japan in the late nineteenth and early twentieth century that led to some important though neglected contributions toward the scientific advancement of classical economics.

SOME NOTES ON THE RECEPTION OF RICARDO'S PRINCIPLES IN THE NON-ENGLISH-SPEAKING WORLD

We study rising business income among top income households using a large sample of U.S. firms linked to their owners and workers from 1999-2015. We establish four findings. First, business income growth accounts for nearly all of the rise in top income inequality in the 21st century. Second, business income growth is broad-based across sectors and not concentrated among a few top firms. Third, top-owned firms earn higher profit margins than other firms, which is primarily due to diverging firm performance rather than reallocation of top ownership, risk, or disguised labor payments for tax minimization. Fourth, profits have increased most in firms that rely on high-skilled human capital, especially when deployed at the top of the organization. Our findings suggest that market-based forces play a leading role in generating not only labor income inequality, but also capital income inequality. These findings have implications for central issues in economics: the measurement and determinants of income inequality and the labor share, the dispersion in firm productivity, the returns to schooling, and taxation of top labor and capital income.

With the strong post-war economic recovery of the developed nations and the birth of many new nations formerly under colonial rule there was in the 1950s and 1960s considerable interest in policy-making to promote economic growth and development internationally. Through the newly created institutions of the World Bank, International Monetary Fund, International Bank for Reconstruction and Development and the United Nations, the United States, no doubt motivated by the Cold War with the Communist bloc, made a concerted effort in international economic development. It was in this context that development economics flourished and, connectedly, so did economic history. Indeed, development economists of this era such as Rosenstein-Rodan, Ragnar Nurkse, Simon Kuznets, Arthur Lewis and Walter Rostow were concerned with the ‘big picture’ questions in explaining growth and development and were in varying degrees also economic historians. The history of economic development naturally provided an empirical basis to identify the main social, political and economic elements they considered to be conducive to promoting growth. In addition, after a long period of neglect, there was an advancement in the theory of economic growth during this period, largely in the footsteps of Harrod (1939; 1948) and Domar (1946; 1947): on the one hand, along ‘Keynes-Kaleckian’ lines by Kaldor (1957; 1962; 1965) and Robinson (1956) at Cambridge University; and, on the other hand, along traditional neo-classical lines, by Solow (1956) and Swan (1956), and which became the dominant theory. Interestingly, much of the development economics of this era consisted of an attempt to apply theory to an interpretation of economic history and to employ economic history in the development of a ‘model’ to explain the growth necessary for modernisation and the policies to promote it.

On Rostow ’ s ‘ Stages ’ Thesis and Explanation of ‘ Take-Off ’ Growth

aftermath of the 2008 market crash. He does not appear in the index at all, and, as near as I can tell, his name appears exactly once in the entire book, as part of a list of seven fi gures who supposedly showed that Keynes’s economics is incompatible with Walrasian general equilibrium, near the beginning of the essay by Mirowski. The other six are Robert Clower, Frank Hahn, John Hicks, Alan Kirman, Franklin Fisher, and Paul Davidson, but there is no further discussion of this group, Minsky in particular, who came at the end of the list. Perhaps it is viewed that Minsky was too far outside the triangle, not even worth the mention that Leijonhufvud gets, or perhaps too much a member of one of the offi cially established heterodox schools so carefully ignored, the Post Keynesians, although Friedrich Hayek and Ludwig von Mises received many mentions, even if there was not a full discussion of the Austrian school. I confess to being mystifi ed by this curious lacuna involving Minsky. I conclude by noting in Duarte’s essay that one of the most prescient of established commentators he briefl y mentions is the completely conventional Frederick Mishkin, author of the most widely used money and banking textbook in the US, who, in 2007, prior to the crash and while serving on the US Federal Reserve Board of Governors, offered the following list for improving monetary policymaking (p. 215): “(1) enrich estimated DSGE models so as to make them more realistic to the eyes of central bankers; (2) improve or extend the way nominal rigidities are usually incorporated in such models; (3) move from models with representative agents to ones with heterogeneity of agents; (4) incorporate (and better understand the role of) fi nancial frictions; (5) go beyond rational expectations and embed behavioral economics into macroeconomics; (6) introduce learning into macro models; (7) keep a scent of art in monetary policymaking because economists ‘can never be sure what is the right model of the economy.’” Needless to say, all this is easier to suggest than to do, and the not-so-subtle implication of many of the authors in this book is that to do these things may well require moving beyond the DSGE models as microfounded as they have been up until this time, even though they fail to offer a clear path as to how that should be done. Nevertheless, their efforts are deeply informative and most worthy of serious attention and consideration in this well-edited and -written book.

Millmow Alex J.,The Power of Economic Ideas: The Origins of Keynesian Macroeconomic Management in Interwar Australia 1929–1939 (Canberra:Australian National University Press,2010), pp.310, $A28.00. ISBN978-1-921-66626-1

Blair, the Treasury and the Single Currency: Behind Closed Doors

1. Introduction 2. Whitehall, the Treasury and Policy-making 3. The Callaghan Government and the ERM 4. The Thatcher Government and the ERM 5. The Thatcher Government and the ERM con/d 6. The Major Government and EMU at Maastricht 7. The Major Government and EMU at Maastricht con/d 8. The Blair Government and the Single Currency 9. The Blair Government and the Single Currency con/d 10. Conclusions

Policy-Making in the Treasury: Explaining Britain’s Chosen Path on European Economic and Monetary Union.

In 1823, William Blake (1774-1852) published the pamphlet Observations of the Effects Produced by the Expenditure of Government during the Restriction of Cash Payments, which made a significant contribution to debate about the economic effects of government fiscal policy during the French wars (1793-1815) and the postwar period of economic stagnation in Britain. This article is concerned with critically examining Blake’s arguments on the effect of British government war expenditure and taxes on economic activity and price inflation during the wars and then on the role of the subsequent retrenchment of government expenditure in explaining postwar economic stagnation. The essay shows that Blake was an ardent critic of Say’s law and argued that the postwar British economic depression characterized by a persistent general glut of commodities was the result of a lack of demand, which was mainly brought about by a policy of fiscal austerity. In this connection it is shown that Blake believed capital accumulation to be demand constrained, with many of his insights into the accumulation process essentially “Keynesian” (or “Kaleckian”) in spirit.

William Blake on the Effects of Government Fiscal Policy on Activity and Prices

In developing economies, managers often choose to hide their firms' activities, and their profits, beyond the reach of government officials. For instance, recent surveys conducted by the World Bank suggest that it is quite common for firms to underreport sales in an effort to evade taxes. In this study, I develop a novel methodology to estimate the extent of sales underreporting using readily available firm financial data. The model builds on the observation that, holding total output constant, there is a one-for-one relationship between output that is sold and output that is used to restock inventory. Deviations from unity in this relationship (e.g. only one unit is reported as sold for every two units that leave inventory), are interpreted as evidence of unreported sales. Applying this model to a sample of Indian manufacturing firms over the period from 1998 to 2007, I examine how sales underreporting is influenced by the business cycle and by the institutional environment, including the regulatory burden, corruption and tax enforcement. For robustness, I benchmark my estimates against the World Bank Enterprise Survey dataset for India, which includes alternative estimates of sales underreporting based on the perceptions of local managers. Comparison with the survey data provides broad support for the model.

Microeconomics: Welfare Economics & Collective Decision-Making eJournal

Doing It Under the Table: Unreported Sales in India's Manufacturing Sector

Ricardo versus Tooke: on the enduring value of their respective monetary theories to classical economics

This paper builds upon the Keynesian theory of demand-led growth in order to provide an analytical framework for explaining economic growth and development in concrete terms, consistent with the fundamental idea that growth in output and employment is determined by the growth in aggregate demand. The framework employs a historical approach to identify the main factors and their role in explaining demand-led growth and the accumulation process. The theoretical model developed abandons steady-state conditions by proposing that capacity utilisation varies in the long run as well as in the short run to ensure output has the elasticity to accommodate levels of autonomous demand free of any capacity saving constraint. On the basis of our analytical framework, the paper considers the main factors that explain the growth in aggregate demand: first, by examining the variables that determine the ‘super-multiplier’ and what social, institutional and technical conditions can cause its value to change over time; second, by identifying the components of autonomous demand and the main forces explaining their growth; and third, by considering the manner in which technical progress promotes demand-led growth.

D.P. O’Brien and J. Creedy, eds., Darwin’s Clever Neighbour, George Warde Norman and his Circle (Cheltenham, UK: Edward Elgar, 2010), pp. lvi, 444, $165. ISBN 978-1-84844-557-4.

This book’s main objective is to analyse the role of innovation in the growth process by reference to the transformative effect on the US economy of the information and communications technology (ICT) revolution that occurred in the 1990s. Gualerzi’s study is valuable because it is one of the few examinations of the role of innovation in the growth process from the standpoint that growth is demand driven, an approach grounded in the Keynesian theory of effective demand. In the dominant Swan-Solow growth theory based on the aggregate production function, innovation is treated as exogenous and its role in the growth process is simplistic. Even in endogenous growth models, which treat innovation as endogenous to a supply-driven growth process, the role attributed to innovation remains naively uncomplicated by any possibility of a demand constraint. By contrast, from the standpoint of demand-led growth theory the process by which innovation contributes to growth is recognised to be highly complex, with causation running both ways between demand growth and technological innovation which, while interdependent, are also shaped by exogenous forces. Gualerzi endeavours to navigate this complex terrain by identifying the more systematic causal linkages in a case study of the 1990s ICT revolution. The book is divided into three parts. The first sketches out a conceptual framework for systematically analysing how innovation is generated and contributes to demand-led growth through structural change. The main focus is on innovation of consumer products, which alters the composition of consumption. The argument draws upon the Schumpeterian notion that a technologically induced growth spurt is associated with the emergence of new markets, new products and new patterns of consumption. But in Gualerzi’s framework the crucial variable is the investment that generates the innovation and creates and markets new consumer products, and which, in line with demand-led growth theory, he treats as autonomous from income. This sort of investment is distinct from capacity adjusting induced-investment generated according to the ‘accelerator principle’. For Gualerzi this autonomous (‘innovation’) investment in the creation of new products, which alters the composition of demand and brings about structural change, is the main dynamic by which innovation drives growth. A key role of this innovative investment is to expand the variety of the composition of demand through ‘need development’ (i.e. creating a socio-economic and cultural Review of Political Economy, Volume 24, Number 4, 663–676, October 2012

The Coming of Age of Information Technologies and the Path of Transformational Growth

1. Introduction 2. Tooke's Contributions 3. Tooke's Approach to Value and Distribution 4. An Explanation of Agricultural Price Movements 5. An Explanation of General Price Movements 6. The Monetary Thought of the Pre-Banking School Tooke, 1819-1838 7. The Monetary Thought of the Banking School Tooke, 1840-1857 8. Tooke's Legacy

On almost every point Tooke takes the opposite view to Ricardo. “Abstract arguments”, as Tooke is pleased to call Ricardo‟s reasoning, find no place in his book [i.e. History of Prices]. His conclusions are always preceded by a detailed description and analysis of facts, and are so superior to and so much more comprehensive than the Ricardian simplifications as to make the latter seem unrecognisable. History and theory go hand in hand.‟ (1840: 180)

The results of Vancouver’s 2008 municipal election led to critiques that South Asian candidates, and possibly all visible minority candidates, face reduced electability under Vancouver’s at-large electoral system than they would under a different municipal electoral system. This thesis employs numerous quantitative research methods to assess whether visible minority candidates do face reduced electability under the at-large system compared to a ward system proposed for Vancouver in 2004. The extent that Vancouver’s 2008 election results fulfil three U.S. Supreme Court conditions for establishing minority vote dilution is also assessed as part of this thesis research.

Desperately Seeking Representation: An Investigation into Visible Minority Electability under Vancouver’s At-large Electoral System

Among those commentators who have closely studied Thomas Tooke‟s (1774-1858) political economy there is general agreement that there was a transformation in his monetary thought after 1838, from an „orthodox‟ quantity theory position to an antiquantity theory position embodied within his novel banking school theory. 1 For this reason Tooke‟s monetary thought is considered to consist of two main phases in its evolution. The first is the pre-banking school phase, covering Tooke‟s writings and parliamentary evidence from 1819 to 1838 when, broadly speaking, his monetary thought remained within the bounds of the quantity theory approach orthodox among most classical economists of the early nineteenth century. The second phase comprises Tooke‟s writings and parliamentary evidence from 1840 to 1857 when he developed his banking school theory as an alternative to the classical‟s quantity theory approach. The only accounts in the secondary literature of this transformation are provided by T.E. Gregory in his one-hundred-and-twenty page „Introduction‟ to the 1928 reprint of Tooke‟s History of Prices and by Arnon in his book, Thomas Tooke: Pioneer of Monetary Theory (1991). In our view neither of these authors provides a satisfactory explanation for Tooke‟s transformation, mainly because their accounts of his monetary thought, both of his pre-banking school position and banking school theory, is incomplete. After all, the essential question here is what did Tooke transform from and to what did he transform into? The question therefore resolves around both an interpretation of Tooke‟s pre-banking school monetary thought as well as his banking school thought. A staunch quantity theorist, Gregory (1928) provides a fairly sketchy and unsympathetic account of

This article examines Thomas Tooke's (1773–1858) position on the English Corn Laws from 1815 until their repeal in 1846. It shows that like most classical economists, Tooke was a strong supporter of free trade who vehemently opposed the Corn Laws, believing that they generally contributed toward greater instability in the price of corn without effectively protecting domestic farming and securing for Britain a ready supply of corn. The article also explores Tooke's view on the distributional impact of the Corn Laws, showing that distinct from Ricardo's position, he believed they tended to redistribute income in favor of landlords at the expense of workers rather than capitalists. Indeed, it is shown that above all Tooke opposed the Corn Laws because they tended to lower the living standards of working people and, at times of unproductive harvests, contributed to acute shortages of foodstuffs that imposed much hardship onto the “lowest classes” of society.

The Spanish colonial labour regime in Latin America was known as the mita, and provided the Indian workers needed for numerous Spanish enterprises. The best known of the mita institutions was the Potosi mita, which lasted from 1573 to 1825. It drafted male Indians from the Viceroyalty of Peru to work in the huge Spanish silver mines at Potosi. The mita placed a heavy burden on the backs of Indian peasants, and adversely affected village life, since many Indians migrated to escape the harsh conditions of the mines. Yet while the Indians suffered as a result of Spanish colonial oppression, it would be a mistake to see them simply as passive victims; in fact, they exercised personal agency in a number of significant ways. One of these hots was by choosing whether to go to the mines or to migrate. Another way was by deciding either to leave Potosi after serving their time of forced labour or to stay on as voluntary workers, which had considerable economic benefits; and indeed, many of them elected to stay. Ironically, in giving the Indians this latter choice, the coercion of the Potosi mita ended up creating the voluntary long-term labour force that the Spanish had hoped for from the start.

Labouring to Choose, Choosing to Labour: Coercion and Choice in the Potosi Mita

Tourism economic impacts: The case of equine camping in southern Illinois

Abstract This paper examines the position of Thomas Tooke (1774–1858) on the issues at the centre of the Bullionist controversies, which occurred during the restriction of cash payments by the Bank of England in the period 1797–1821. It shows that Tooke was a strong supporter of resumption and the gold standard, but that from the beginning, his monetary thought significantly differed from that of the Bullionists. The paper shows that Tooke's explanation of price inflation and the depreciation of the paper currency as well as his assessment of the Bank of England largely supported the position of the anti-Bullionists against the Bullionists.

The leading theorist of the banking school, the main author of the monumental six-volume History of Prices (1838–1857) and the author of the brilliant pamphlet, An Inquiry into the Currency Principle (1844), Thomas Tooke (1774–1858) can be rightfully counted among the most prominent figures in English nineteenth-century monetary thought. Aside from an impressive number of writings, Tooke gave evidence to ten parliamentary committees concerned with various economic policy issues between 1819 and 1848. But despite Tooke’s considerable contribution, the literature is bereft of a comprehensive survey of his life and work. This paper endeavours partially to fill this void in the literature, by providing a biographical sketch of Tooke together with a chronological survey of all his contributions to political economy. In particular, the paper shows how most of Tooke’s writings were motivated by debates over economic policy issues.

This paper argues that Thomas Tooke's (1773--1858) most important legacy to economics is not his conception of "endogenous money", however important, but is instead his original proposition that the long-run "average" rate of interest entered into the normal cost of production and, therefore, the normal prices of commodities, reflecting the notion that the interest rate systematically governs the normal rate of profit. The paper shows that this conception of an "autonomous" rate of interest advanced by Tooke contributes to overcoming the long-run neutrality of monetary forces which has traditionally characterized economic theory within the framework of "modern" classical analysis. Copyright 2006, Oxford University Press.

On Interest and Profit: Thomas Tooke's Major Legacy to Economics

Growth, poverty reduction, and social peace are all undermined when public expenditure management and taxation are weak and when the fiscal deficit and public debt are not managed successfully. And large-scale aid and debt relief cannot work without a good fiscal system. The macroeconomic frameworks of many poor countries are improving, but fiscal policy's full potential will not be realized until good and accountable expenditure and taxation systems are built. Good fiscal policy can raise economic growth through well-chosen public investments provided that the spending is large enough. Growth itself increases the tax base generating the potential for higher public spending on poverty reduction. Fiscal reform can be a tool for peace when an unfair distribution of spending and taxation generates grievances that turn violent. Overall, fiscal policy reveals more about the political priorities underpinning a country's development strategy than any other area of policymaking.

The main opponent to the Bank Charter Act of 1844 in the Currency-Banking School debates of the 1840s and 1850s was undoubtedly Thomas Tooke (1774–1858). As is well known, the 1844 Bank Act embodied the Currency School's plan for the institutional separation of the Bank's “public” function of issuing banknotes in exchange for coin (bullion) from its “private” business of banking, consisting of receiving deposits, buying and selling securities in the open market, and discounting bills brought to its door. The objective of this plan was to compel the Bank of England to issue its banknotes pari pasu with changes in its bullion reserves. The Bank Charter Act of 1844 was perhaps the first attempt to introduce central banking “rules.” Tooke's grounds for criticizing the Act are, therefore, of interest to contemporary monetary economists. From 1840 until his last publication in 1857, Tooke engaged in a relentless campaign against the institutional separation of Bank of England functions under the 1844 Act. Before the Act's inception Tooke criticized the Currency School's plan on theoretical, as well as policy grounds. After its inception Tooke mainly criticized the 1844 Bank Act for actually contributing to monetary instability. These criticisms stemmed from Tooke's long-established position on banking policy together with the Banking School theory he largely developed in the early 1840s.

On Central Banking “Rules”: Tooke's Critique of the Bank Charter Act of 1844

This paper examines the method of analysis and theoretical approach Thomas Tooke (1774–1858) employed in his empirical study of English prices. It is shown that Tooke adopted the “long period method” formulated by Adam Smith to analyse a capitalist society. It is shown that like most nineteenth-century classical economists, Tooke adopted a modified version of Adam Smith's “adding-up” approach to normal prices and distribution which incoporated Ricardo's theory of rent. The paper shows that based on this approach, Tooke explained short-run fluctuations in prices be reference to factors that disrupted the adjustment of supply to the “effectual” demand for commodities.

Staff Papers Series STAFF PAPER P 83-22 SEPTEMBER 1983 INSTTIWTIONAL CONSIDERATIONS IN TARGETING SOIL CONSERVATION

In the 1840s Thomas Tooke (1774–1858) developed novel monetary principles which formed the basis of the Banking School position. This article provides a systematic account of Tooke’s banking school theory, central to which was his conception of ‘endogenous money’ and the causal relationship between the rate of interest, spending, and the price level. It is shown that in the context of 19th-century classical economics Tooke’s banking school theory is much more coherent than has so far been appreciated in the literature. Indeed, it can be, and is, argued that Tooke’s theory was a constructive alternative to the classicals’ quantity theory of money.

Endogenous money, interest and prices: Tooke's monetary thought revisited

A monetary explanation of distribution consists of the conception that the distribution of income between wages and profits is primarily determined by the money rate of interest on the basis as an institutionally determined policy variable, it systematically governs the rate of profit, which, for a given technique of production, determines the real wage as a residual of net income. This paper shows that consistent with a Sraffa model in which the real wage is not determined by the 'subsistence' of workers, a monetary explanation of distribution is as historically plausible in a gold money economy of , ‘old' nineteenth century capitalism as it is in a fiat money economy of 'modern' twentieth century capitalism. It is shown that such a explanation is logically different in a gold money economy to that which is proposed in a fiat money economy mainly because of the different manner in which the real wage (or price-wage ratio) is residually determined. The paper then examines the implications of this fundamental difference for the relationship between the interest rate, money wage bargaining and the price level in the two different kinds of monetary systems.

A Monetary Explanation of Distribution in a 'Gold Money Economy.'

The leading theorist of the Banking School and author of the monumental six volume History of Prices(1838-1857) and the brilliant pamphlet, An Inquiry into the Currency Principle (1844), Thomas Tooke (1774-1858) is one of the most prominent figures in nineteenth century monetary thought. This paper aims to expound the central features of Tooke's monetary analysis. The paper first examines his early pre-banking school views on monetary questions which led him to reject the classical quantity theory. It then examines Tooke's banking school principles on the relation between money, interest and the price level. By way of conclusion, the logical consistency of Tooke's monetary thought within the theoretical framework of classical economics is examined critically in order to evaluate its relevance to contemporary monetary economics.

This report describes an approach for developing conditional projections of the U.S. farm structure. The traditional approach to projecting the distribution of farms by size uses a Markov model with stationary (constant) transition probabilities. Although a useful tool for extrapolation of current trends, the stationary Markov approach cannot model the impacts on farm structure of varying economic and social causal forces. Data are now available for developing Markov models with nonstationary transition probabilities. In this document, a simple nonstationary Markov model of U.S. farm structure is described and estimated and its performance in predicting actual changes in farm numbers and sizes through 1986 is assessed. The nonstationary Markov model makes fuller use of the information available and generates a path of structural change that seems closer to what actually occurred after 1978. (Author/KC) *********************************************************************** * Reproductions supplied by EDRS are the best that can be made * * from the original document. * *********************************************************************** United States Department of Agriculture Economic Research Service Agriculture and Rural Economy Division A Conditional Approach to Projecting Farm Structure

MF01/PCO2 Plus Postage. Adults; Agricultural Production; *Agriculture; *Differences; *Economics; *Farmers; Farm Management; Farm Occupations; Government Role; *Policy Formation; Public Policy; *Regional Characteristics Farms and the people who live on them differ dramatically from one part of the United States to another. These differences are prominent both from one region to the next as well as between farms and people in the same region. The varying characteristics of agriculture and the farm population have helped r;hape regional experiences in the 1980s. In the Midwest and Northern Plains, heavy reliance on income from sales of government-supported crops, large numbers of financially vulnerabl.: midsized farms, and fewer alternative sources of income have led to the most widespread farm financial distress and the most persistent calls for agricultural policy remedies. In other parts of the country, income problems among farm households are as often linked to low earnings in manufacturing as in agriculture. Still other parts of the farm population are rather affluent and unaffected by federal farm policies. The varying circumstances in which the farm population lives and works affect the likely impacts of agricultural and rural development policies, In some regions, farm policy remains highly significant to farm households and rural communities as a component of income and economic development. In others, farm people themselves are likely to be affected much more by policies directed to all residents than by policies specifically targeting the agricultural sector. (Author/KC) *********************************************************************** Reproductions supplied by EDRS are the best that can be made from the original document. *********************************************************************** United States Department of Agriculture Economic Research Service Agriculture and Rural Economy Division Regional Characteristics of U.S. Farms and Farmers in the 1980's Matthew G. Smith Fred Hines U S DEPARTMENT OF EDUCATIDN Off e of EducahonaI Research and Improvement E CATIONAL RESOURCES INFORMATION CENTER (MCI Thi5 document has been reproduced as received from the person or orgarmzahon ongInatIng a r f qmor changes have been made to improve reproduction quality Romts of view or opirvons stated fn this do u ment do not necessaniy represent of hc,at OERI posMon , policy

Regional Characteristics of U.S. Farms and Farmers in the 1980's. ERS Staff Report No. AGES880128.

Net entries of young farm operators on commercial-sized farms declined by about 40 percent between 1974 and 1982 Fewer entries of young farmers and the continued aging and retirement of older farmers caused the number of commercial farms to drop between 1978 and 1982 The 1982 age distribution and the 1978-82 entry and exit rates suggest a continuing decline in commercial farm numbers and a redistribution of farm assets The article uses a modified version of age cohort analysis to estimate rates of net entries and exits of farm operators in 1974-78 and 1978-82

Entry, Exit, and the Age Distribution of Farm Operators, 1974-82

Farm numbers and average farm size in the United States have held about constant since the 1974 Census. but the proportion of mid-sized farms has decreased This pattern follows four decades of a strong trend toward fewer and larger farms Markov analysis IS a standard procedure for projecting changes In the number and distribution of firms In an Industry based on observations of recent changes Previous applications to the US farm sector have met With difficulty because of a lack of appropriate data This article applies Markov analysis to a recently available longitudinal data set for 1974-78 from the Census of Agriculture The model predicts reasonably well the actual changes during 1978-82 and indicates that the future distribution of farms by acres per farm will be more like the present than the present is like the past

This paper will outline an approach to targeting soil conservation efforts that rests upon an analysis of physical, economic, and institutional parameters. Within this context, the literature on the relationship between soil erosion and some common arrangements of land ownership and control will be examined to provide insights useful in the formulation of public policy and to suggest further opportunities for research.

INSTITUTIONAL CONSIDERATIONS IN TARGETING SOIL CONSERVATION EFFORTS

THE MINNESOTA RURAL REAL ESTATE MARKET IN 1982... INCLUDING SPECIAL STUDIES OF: THE USE OF CONTRACTS FOR DEED, THE RED RIVER VALLEY, THE TWIN CITIES METROPOLITAN AREA , VALUES OF FARMS OF DIFFERENT QUALITY, 1963-1982

The Minnesota Rural Real Estate Market In 1981... Including Special Studies Of: The Red River Valley, Southwestern Minnesota , A Contour Map Of Minnesota Land Value, A Comparison With The U.S. Census Of Agriculture

41 Carbapenem resistance in Enterobacterales is a public health threat. Klebsiella 42 pneumoniae carbapenemase (encoded by alleles of the bla KPC family) is one of the 43 commonest transmissible carbapenem resistance mechanisms worldwide. The 44 dissemination of bla KPC has historically been associated with distinct K. pneumoniae 45 lineages (clonal group 258 [CG258]), a particular plasmid family (pKpQIL), and a 46 composite transposon (Tn 4401) . In the UK, bla KPC has represented a large-scale, 47 persistent, management challenge for some hospitals, particularly in North-West 48 England. The dissemination of bla KPC has evolved to be polyclonal and poly-species, 49 but the genetic mechanisms underpinning this evolution have not been elucidated in 50 detail; this study used short-read whole genome sequencing of 604 bla KPC -positive 51 isolates (Illumina) and long-read assembly (PacBio)/polishing (Illumina) of 21 52 isolates for characterisation. We observed the dissemination of bla KPC (predominantly 53 bla KPC-2 ; 573/604 [95%] isolates) across eight species and more than 100 known 54 sequence types. Although there was some variation at the transposon level (mostly 55 Tn 4401 a, 584/604 (97%) isolates; predominantly with ATTGA-ATTGA target site 56 duplications, 465/604 [77%] isolates), bla KPC spread appears to have been supported 57 by highly fluid, modular exchange of larger genetic segments amongst plasmid 58 populations dominated by IncFIB (580/604 isolates), IncFII (545/604 isolates) and 59 IncR replicons (252/604 isolates). The subset of reconstructed plasmid sequences (21 60 isolates, 77 plasmids) also highlighted modular exchange amongst non- bla KPC and 61 bla KPC plasmids, and the common presence of multiple replicons within bla KPC 62 plasmid structures (>60%).

Genomic epidemiology of complex, multi-species, plasmid-borne bla KPC 1 carbapenemase in Enterobacterales in the UK, 2009-2014

Carbapenem resistance in Enterobacterales is a public health threat. Klebsiella pneumoniae carbapenemase (encoded by alleles of the blaKPC family) is one of the most common transmissible carbapenem resistance mechanisms worldwide. The dissemination of blaKPC historically has been associated with distinct K. pneumoniae lineages (clonal group 258 [CG258]), a particular plasmid family (pKpQIL), and a composite transposon (Tn4401). ABSTRACT Carbapenem resistance in Enterobacterales is a public health threat. Klebsiella pneumoniae carbapenemase (encoded by alleles of the blaKPC family) is one of the most common transmissible carbapenem resistance mechanisms worldwide. The dissemination of blaKPC historically has been associated with distinct K. pneumoniae lineages (clonal group 258 [CG258]), a particular plasmid family (pKpQIL), and a composite transposon (Tn4401). In the United Kingdom, blaKPC has represented a large-scale, persistent management challenge for some hospitals, particularly in North West England. The dissemination of blaKPC has evolved to be polyclonal and polyspecies, but the genetic mechanisms underpinning this evolution have not been elucidated in detail; this study used short-read whole-genome sequencing of 604 blaKPC-positive isolates (Illumina) and long-read assembly (PacBio)/polishing (Illumina) of 21 isolates for characterization. We observed the dissemination of blaKPC (predominantly blaKPC-2; 573/604 [95%] isolates) across eight species and more than 100 known sequence types. Although there was some variation at the transposon level (mostly Tn4401a, 584/604 [97%] isolates; predominantly with ATTGA-ATTGA target site duplications, 465/604 [77%] isolates), blaKPC spread appears to have been supported by highly fluid, modular exchange of larger genetic segments among plasmid populations dominated by IncFIB (580/604 isolates), IncFII (545/604 isolates), and IncR (252/604 isolates) replicons. The subset of reconstructed plasmid sequences (21 isolates, 77 plasmids) also highlighted modular exchange among non-blaKPC and blaKPC plasmids and the common presence of multiple replicons within blaKPC plasmid structures (>60%). The substantial genomic plasticity observed has important implications for our understanding of the epidemiology of transmissible carbapenem resistance in Enterobacterales for the implementation of adequate surveillance approaches and for control.

Genomic Epidemiology of Complex, Multispecies, Plasmid-Borne blaKPC Carbapenemase in Enterobacterales in the United Kingdom from 2009 to 2014

Carbapenem resistance in Enterobacterales is a public health threat. Klebsiella pneumoniae carbapenemase (encoded by alleles of the blaKPC family) is one of the commonest transmissible carbapenem resistance mechanisms worldwide. The dissemination of blaKPC has historically been associated with distinct K. pneumoniae lineages (clonal group 258 [CG258]), a particular plasmid family (pKpQIL), and a composite transposon (Tn4401). In the UK, blaKPC has caused a large-scale, persistent outbreak focused on hospitals in North-West England. This outbreak has evolved to be polyclonal and poly-species, but the genetic mechanisms underpinning this evolution have not been elucidated in detail; this study used short-read whole genome sequencing of 604 blaKPC-positive isolates (Illumina) and long-read assembly (PacBio)/polishing (Illumina) of 21 isolates for characterisation. We observed the dissemination of blaKPC (predominantly blaKPC-2; 573/604 [95%] isolates) across eight species and more than 100 known sequence types. Although there was some variation at the transposon level (mostly Tn4401a, 584/604 (97%) isolates; predominantly with ATTGA-ATTGA target site duplications, 465/604 [77%] isolates), blaKPC spread appears to have been supported by highly fluid, modular exchange of larger genetic segments amongst plasmid populations dominated by IncFIB (580/604 isolates), IncFII (545/604 isolates) and IncR replicons (252/604 isolates). The subset of reconstructed plasmid sequences also highlighted modular exchange amongst non-blaKPC and blaKPC plasmids, and the common presence of multiple replicons within blaKPC plasmid structures (>60%). The substantial genomic plasticity observed has important implications for our understanding of the epidemiology of transmissible carbapenem resistance in Enterobacterales, for the implementation of adequate surveillance approaches, and for control. IMPORTANCE Antimicrobial resistance is a major threat to the management of infections, and resistance to carbapenems, one of the “last line” antibiotics available for managing drug-resistant infections, is a significant problem. This study used large-scale whole genome sequencing over a five-year period in the UK to highlight the complexity of genetic structures facilitating the spread of an important carbapenem resistance gene (blaKPC) amongst a number of bacterial species that cause disease in humans. In contrast to a recent pan-European study from 2012-2013(1), which demonstrated the major role of spread of clonal blaKPC-Klebsiella pneumoniae lineages in continental Europe, our study highlights the substantial plasticity in genetic mechanisms underpinning the dissemination of blaKPC. This genetic flux has important implications for: the surveillance of drug resistance (i.e. making surveillance more difficult); detection of outbreaks and tracking hospital transmission; generalizability of surveillance findings over time and for different regions; and for the implementation and evaluation of control interventions.

Genomic epidemiology of a complex, multi-species plasmid-borne blaKPC carbapenemase outbreak in Enterobacterales in the UK, 2009-2014

Dynamics of extended-spectrum cephalosporin resistance in pathogenic Escherichia coli isolated from diseased pigs in Quebec, Canada.

The phenotypic and genotypic antimicrobial resistance of enterotoxigenic Escherichia coli and commensal Escherichia coli obtained from healthy and diseased swine in Australia, Canada and Vietnam

Phylogenetic and molecular insights into the evolution of multidrug-resistant porcine enterotoxigenic Escherichia coli in Australia.

Investigating gene-cassettes within Class 1 integrons in multi-drug resistant enterotoxigenic Escherichia coli isolated from pigs

Background Over the past 10 years, job interview training has emerged as an area of study among adults with schizophrenia and other serious mental illnesses who face significant challenges when navigating job interviews. The field of mental health services research has limited access to assessments of job interview skills with rigorously evaluated psychometric properties. Objective We sought to evaluate the initial psychometric properties of a measure assessing job interview skills via role-play performance. Methods As part of a randomized controlled trial, 90 adults with schizophrenia or other serious mental illnesses completed a job interview role-play assessment with eight items (and scored using anchors) called the mock interview rating scale (MIRS). A classical test theory analysis was conducted including confirmatory factor analyses, Rasch model analysis and calibration, and differential item functioning; along with inter-rater, internal consistency, and test-retest reliabilities. Pearson correlations were used to evaluate construct, convergent, divergent, criterion, and predictive validity by correlating the MIRS with demographic, clinical, cognitive, work history measures, and employment outcomes. Results Our analyses resulted in the removal of a single item (sounding honest) and yielded a unidimensional total score measurement with support for its inter-rater reliability, internal consistency, and test-retest reliability. There was initial support for the construct, convergent, criterion, and predictive validities of the MIRS, as it correlated with measures of social competence, neurocognition, valuing job interview training, and employment outcomes. Meanwhile, the lack of correlations with race, physical health, and substance abuse lent support for divergent validity. Conclusion This study presents initial evidence that the seven-item version of the MIRS has acceptable psychometric properties supporting its use to assess job interview skills reliably and validly among adults with schizophrenia and other serious mental illnesses. Clinical Trial Registration NCT03049813.

Psychometric properties of the mock interview rating scale for schizophrenia and other serious mental illnesses

BACKGROUND: The study of job interview training is an emerging area among transition-age autistic youth who face significant challenges when navigating job interviews. The autism field has limited measures that have undergone rigorous psychometric evaluation. OBJECTIVE: We sought to evaluate the psychometric properties of adapted self-report measures assessing job interview skills and job interview anxiety. METHODS: As part of two parent randomized controlled trials, eighty-five transition-age autistic youth completed measures related to the strength of their job interview skills and their level of job interview anxiety. We conducted classical test theory analyses, exploratory and confirmatory factor analyses, and Rasch model analytic and calibration analyses. Pearson correlations were used to establish concurrent, divergent, and criterion validity by correlating these scales with measures of social challenges, depressive symptoms, behaviors, neuropsychological functioning, and work history. RESULTS: Our analyses yielded two brief and reliable scales: Measure of Job Interview Skills (MOJO-iSkills) and Measure of Job Interview Anxiety (MOJO-iAnxiety), which demonstrated initial concurrent, divergent, and criterion validities when correlated with measures of depressive symptoms, social challenges, internalizing and externalizing behavior, and work history. CONCLUSION: This study presents initial evidence that MOJO-iSkills and MOJO-iAnxiety have acceptable psychometric properties supporting they can be used to reliably and validly assess job interview skills and interview anxiety.

Development and psychometric properties of self-reported job interview skills and job interview anxiety for autistic transition-age youth

Virtual Reality Job Interview Training (VR-JIT) and Virtual Interview Training for Transition Age Youth (VIT-TAY) demonstrated initial effectiveness at increasing employment among transition-age youth with disabilities engaged in pre-employment transition services. We characterized activities and estimated the labor and non-labor costs required to prepare schools to implement VR-JIT or VIT-TAY. Implementation preparation and support teams reported labor hours throughout the implementation preparation process. Implementation preparation labor hours at 43 schools cost approximately $1,427 per school, while non-labor costs were $100 per trainee (student). We estimated the replication of implementation preparation labor activities would cost $1,024 per school (range: $841-$1,208). Most costs were spent in delivery planning and teacher training. Given that implementation preparation costs can be barriers to intervention adoption, our results provide critical information for contemplating future implementation of VR-JIT or VIT-TAY.

Implementation Preparation Costs of Virtual Interview Training in Pre-Employment Transition Services: A Budget Impact Analysis

Virtual Interview Training Among BIPOC Autistic Transition-Age Youth: A Secondary Analysis of an Initial Effectiveness RCT.

Virtual Interview Training for Transition- Age Youth and Virtual Reality Job Interview Training are job interview simulators with demonstrated effectiveness in randomized controlled trials. We evaluated their dose responses via secondary data analysis of 558 transition-age youth with disabilities in 47 schools where the simulators were implemented in quasi-experimental studies. Cut-point analyses determined dosing efficiency and efficacy to optimize competitive employment. The most efficient dose when accounting for the balance between dose and employment was completing nine virtual interviews. The most efficacious dose to maximize the likelihood of successful employment was 38, but varied across race, IQ, IDEA categories,and employment history. This study provides a novel approach to inform implementation guidelines for virtual interview training in pre-employment transition services. Limitations and implications for research and practice are discussed.

Virtual Job Interview Training: A Dose Response to Improve Employment for Transition-Age Youth With Disabilities

Purpose: Mental health providers are well-positioned to engage in suicide prevention efforts, yet implementation depends on skill acquisition and providers often report feeling underprepared. This pilot study explored the acceptability, feasibility, and preliminary effectiveness of three suicide prevention-focused simulations with virtual clients. Method: Students ( n = 22) were recruited from a Master of Social Work program, completed pre- and post-test surveys, and engaged with three simulated trainings: (1) suicide risk assessment, (2) safety planning, and (3) motivating a client to treatment. Results: Simulations were reported to be acceptable and feasible, with strong student desire and need for greater suicide prevention training. We observed significant improvements over time in clinical skills via simulated training scores and perceptions of clinical preparedness. Discussion: Preliminary findings indicate simulated training with virtual clients is promising and suggest the three suicide prevention simulations may be useful, scalable, and effective in social work training programs and beyond.

Computerized Suicide Prevention Clinical Training Simulations: A Pilot Study

Despite many autistic adults expressing a desire to work, nearly 85% of adults on the autism spectrum are unemployed. The autism community has identified that the job interview is a significant obstacle to obtaining employment. A growing field of research has focused on evaluating innovative training tools to improve interview skills. Our previous work shows that a virtual reality job interview training (VR-JIT) tool improves certain job interview skills (such as sounding professional, establishing rapport), but does not improve the ability to speak about personal strengths and abilities. Thus, the current study combined VR-JIT with a new training tool: Kessler Foundation Strength Identification and Expression (KF-STRIDE), an intervention which uses principles of positive psychology. KF-STRIDE targets identification of personal character strengths and expressing those strengths to employers in a socially appropriate way. The current study evaluated effectiveness and acceptability of the combined intervention in 20 autistic youth, randomized to an experimental group (n=10) and a services-as-usual (SAU) control group (n=10). Those in the experimental group participated in a 12 session intervention (9 sessions using VR-JIT and 3 sessions in KF-STRIDE). Each session was roughly one hour. Job interview performance was assessed by video-recorded mock job interviews rated by blinded assessors pre- and post- the intervention. Paired samples t-tests were conducted to examine differences in job interview skills from baseline to follow up in both groups. The intervention group showed a significant improvement from baseline to follow-up in job interview skills in general (p = .004), and specifically sharing strengths about themselves to a future employer (p = .004). No significant differences were seen from baseline to follow-up in the SAU group. Feedback from those who participated in the intervention indicated high acceptability. The autism population is significantly underemployed leaving these individuals disadvantaged in living independent lives. Two innovative tools: VR-JIT and KF-STRIDE successfully improved job interview skills, including the ability to identify and express character strengths. These findings indicate that these combined tools may help to improve employment skills for individuals on the autism spectrum. During the first year of life, typically developing infants can discriminate fast, successive changes in auditory sounds, occurring in the tens of milliseconds range. This rapid auditory processing (RAP) skill is essential to decoding ongoing speech and to the establishment of phonetic maps. Compromised language abilities are ubiquitous in individuals with autism spectrum disorder (ASD), a highly heritable developmental condition. Language delays are already present at 12 months of age in infant siblings of children with ASD, suggesting that prelinguistic processing abilities are compromised. However, the neural mechanisms sub-serving language acquisition in ASD are poorly understood. This EEG-based study investigated oscillatory mechanisms underlying RAP in infants with a family history of ASD (FHA) and matched controls (CT). At 4- months, infants were presented with an auditory oddball paradigm while dense-array EEG was recorded. Infants passively listen to tone pairs separated by a short inter-stimulus interval. Source localization of event-related generators and time-frequency analysis of event-related oscillations at the source level were conducted. A two-dipole model identified sources of activation in the left (LAC) and right (RAC) auditory cortices. We present here preliminary results from a small sample of 6 infants (4 males and 2 females) in each group. Significant oscillatory differences in spectral power and phase synchrony were found between the groups. Specifically, the FHA group exhibited less spectral power for the standard representation in low-gamma in LAC and RAC, mid-gamma in RAC, and high-gamma in LAC compared to the CT group. During deviant discrimination, FHA group showed less power than CTs in theta, gamma, and high gamma in both LAC and RAC sources. The FHA displayed less phase synchrony in the theta range for the standard in RAC and the deviant in both LAC and RAC sources than in CT group. Our preliminary results indicate that RAP is already altered at 4 months in FHA infants and suggest that some of the linguistic differences observed in ASD may arise from variations in oscillatory patterns subserving pre-linguistic processing abilities. Detecting the earliest signs of deviation may be critical for implementing targeted interventions oriented to improving atypical developmental trajectories. Early Intervention Programs (EIP) are federally-mandated services for children ages 0-36 months with various developmental delays/disabilities, including Autism Spectrum Disorder (ASD). EIP provide opportunities to learn and practice social interactions and skills prior to entry into the school system. Preschool enrollment qualifies these children for the continuation of services in school under the Preschool Disability (PSD) classification. Despite the benefits of PSD classification, usage among children with ASD is limited. To evaluate how involvement in EIP was associated with participation in PSD, five consecutive cycles (2006-2016) of surveillance by the New Jersey Autism Study were analyzed using the CDC Autism and Developmental Disabilities Monitoring Network methodology. Information on 4050 8-year-old children with ASD from Essex, Hudson, Ocean, and Union counties was analyzed. Demographic covariates, including sex, race, and socioeconomic status, along with the clinical covariates, intellectual disability and degree of impairment, were considered. Pearson Chi-square tests, standard logistic regression models, adjusted odds ratios (AOR) with 95% confidence intervals (CI) were used to analyze data. Among ASD children who received EIP, 88.0% continued to receive PSD services, compared to 46.5% of those who did not participate in EIP (p<0.001). No sex-based differences were observed. Non-Hispanic white children had the lowest PSD usage (63.9%) and non-Hispanic black children had the highest (68.5%) rates of use. Children residing in high-income areas were more likely to participate in PSD compared to children in low-income regions (p<0.01). Children with co-occurring intellectual disability and those with greater severity of impairment had greater odds of PSD classification compared to peers (p<0.001). In adjusted models, children who participated in EIP were 8-9 times more likely to receive PSD services. While differences in birth year and race remained, income was not a significant predictor. Interestingly, county of residence was a significant increase dendritic spine density when it is acutely deleted in adult mouse cortical neurons, suggesting a novel role in circuit maintenance. Taken together, our results provide novel insights into Nrp2’s diverse roles in distinct temporal and cell-type specific signaling in excitatory and inhibitory neurons’ development required for the proper establishment and maintenance of E/I balance in mammalian brain circuits and behavior output. for that may put their safety at risk or cause injury. content and safety education typically Study Design: To better understand safety and safety education issues and to develop recommendations for ASD/disability-related safety education and training, we facilitated eleven nationwide Inclusion in Innovation Summit brainstorming sessions. The summit was one component of “Living Safely with Disabilities and Special Health Needs,” an initiative funded in part by an Inclusive Healthy Communities Grant from the Division of Disability Services, New Jersey Department of Human Services. Methods: Each summit session, co-led by a disabled advocate and subject matter expert, discussed a previously-identified high impact safety topic: law enforcement interactions, fire safety, elopement/being lost, and recognizing/communicating personal violence and abuse. Invitees nationwide included disabled advocates, emergency responders, researchers, caregivers, educators, and others. Results: 165 participated. Main points included the need for greater involvement of disabled people in design, implementation, and evaluation of safety education/training; dearth of outcome data on effectiveness of safety education/training; and the promise of Augmented Reality/Virtual Reality (AR/VR) as a training modality. Benefits of AR/VR for people with various disabilities, caregivers, emergency responders, educators, and other safety stakeholders its immersive nature safe participation and practice of safety skills including in high risk included customization across situations, disability and diverse the to models that aim to reproduce maternal immune activation (MIA) using bacterial and viral mimetics during gestation have shown long lasting behavioral changes in the offspring reminiscent of human neurodevelopmental disorders, including communication, cognitive and social deficits. Animal and epidemiological studies also have implicated inflammatory cytokines as key pathogenic agents. We have shown previously that administering IL-6 to mouse pups on postnatal days 3-6 affects the balance of neural stem cells and neural progenitors in secondary germinal matrices, resulting in fewer neurons, astrocytes and oligodendrocytes being produced in late developing brain structures relevant to the behavioral deficits seen in MIA models. We hypothesized that these cellular deficits may affect synaptogenesis in brain circuits responsible for social behaviors and communication. Using field potential recordings from the Schaffer collateral-CA1 synapses in acute dorsal hippocampal slices from young adults, we found that male mice injected perinatally with IL-6 had strong trends towards both enhanced LTP and LTD, suggesting that IL-6 treatment is potentia

Rutgers University Center for Autism Research, Education, and Services (RUCARES)

Virtual-Reality Job Interview Training in Pre-Employment Transition Services: A Dose Effect Analysis

As the certified peer support specialist (CPSS) workforce matures, their roles evolve, leading to gaps in knowledge about their activities. This study aimed to address these gaps through a survey on CPSS activities, self-rated skills, job satisfaction, and financial well-being. The project team recruited a community advisory board of CPSSs to lead survey development. A survey link was e-mailed to all known CPSSs in the state of Michigan (N=1,128), yielding 394 respondents (35% response rate), of whom 319 were included in the analysis. The highest skill self-ratings included sharing recovery stories (rated very strong by 80%); the lowest included vocational support (rated very strong by 33%). More than 75% were satisfied with their workplace supportiveness; less than one-half were satisfied with their promotion opportunities. When asked if they could generate adequate funds to address a common financial shock, 115 of 301 respondents (38%) were "certain" they could not, suggesting financial vulnerability. These results support developing career ladder opportunities for CPSSs.

Survey of Peer Support Specialists: Professional Activities, Self-Rated Skills, Job Satisfaction, and Financial Well-being.

Background: Individuals with severe mental illness have low employment rates, and the job interview presents a critical barrier for obtaining employment. Four randomized controlled trials (RCTs) revealed that virtual reality job interview training (VR-JIT) improved interviewing skills and the odds of obtaining a job offer among trainees with severe mental illness (i.e., schizophrenia and mood disorders) or autism spectrum disorder. This study assessed whether trainees across all four trials had greater odds than controls at receiving a job offer by 6-month follow-up. We also evaluated if interviewing skills mediated the relationship between virtual interview trial completion and receiving job offers by 6-month follow-up. 
 
Methods: VR-JIT trainees (n = 79) completed pre- and posttest role-plays and a brief survey approximately 6 months later to assess if trainees received a job offer. VR-JIT trainees completed up to 17 virtual interviews, while controls received services as usual. We used logistic regression to assess the odds of receiving a job offer. We also conducted mediational path model with Mplus 7.2 using a Bayesian estimator (with Sobel Test) to test if post-test interviewing skills mediated the relationship between virtual interviews completed and receiving job offers by 6-month follow-up. 
 
Results: The odds of receiving a job offer were higher for VR-JIT trainees across all four cohorts compared to the controls from across all four cohorts (OR = 2.68, 95% CI = 1.14–6.29; P = .03). As hypothesized, the relationship between number of virtual interviews completed and job offer attainment was fully mediated as indicated by the direct effect between completed interviews and job offer changing from significant (B = .09, P < .05; SD = .046, β = .30, 95% PCI:.01–.54) to nonsignificant (B = .07, P < .05; SD = .05, β = .23, 95% PCI:−.06 to −.49) in the mediation model when accounting for posttest job interview performance. In turn, the number of completed virtual interviews predicted posttest interviewing skills, which in turn predicted obtaining a job offer (Product-of-coefficients = .02, SD = .01, P < .05; 95% PCI:.01–.04). 
 
Conclusion: Results suggest that VR-JIT trainees have greater odds of receiving a job offer and may provide a mechanism of action that helps trainees across various psychiatric diagnoses obtain job offers in the community. Future research can evaluate the community-based effectiveness of this novel intervention.

183. Virtual Reality-Enhanced Job Interview Skills Help Individuals With Severe Mental Illness Obtain Job Offers

Adults with serious mental illnesses (e.g., Autism Spectrum Disorder [ASD], schizophrenia, post-traumatic stress disorder [PTSD]) often have difficulties obtaining employment. The Job Interview Training System with Molly Porter, developed in collaboration with Yale and Northwestern Universities and vocational rehabilitation specialists with funding from The National Institutes of Health (R43/44MH080496), allows learners to practice job interviews on computers in a stress free environment. The system includes user-driven educational materials, an interactive job application, a practice simulation with a fictional interviewer (Molly Porter), and extensive feedback. SIMmersion's PeopleSIM™ technology allows each conversation with Molly to provide a unique interview experience, enabling users to gain confidence while building skills. The on-screen coach provides insight during the conversation, and a comprehensive after-action review provides learners with feedback on the entire interview. In a randomized control trial, the system was proven effective at improving participants' interview skills and confidence. Ninety-six (96) unemployed adults with ASD (n=26), schizophrenia/other (n=37) or PTSD (n=33) were recruited. Participants were randomized into control (n=32) and experimental (n=64) conditions. The control group was "wait-listed" to receive training, and the experimental group used the training system with Molly Porter. Both groups completed pre- and post-intervention role-play interviews and self-assessment questionnaires. Analyses of covariance showed that the simulation provided a highly significant training effect, with experimental group participants scoring better in the role-play interviews and self-assessing higher than control group participants. By increasing skills and confidence, this system may ultimately reduce the length of unemployment for adults with mental illnesses.

Simulated job interview improves skills for adults with serious mental illnesses.

Virtual Reality Job Interview Training in Adults with Autism Spectrum Disorder

Audible Bleeding, the Vascular Surgery Podcast: Affecting the Practice of Vascular Surgery

Laparoscopic nephrectomy with ex vivo repair of aneurysm and autotransplantation

A Novel Intraoperative Method to Optically Assess Perfusion During Percutaneous Interventions of the Lower Extremity

Patient and Procedural Factors Impacting Discharge on New Anticoagulation After Below Knee Arterial Bypass

First Case Study for the Use of Diffuse Optical Spectroscopy during a Vascular Surgical Intervention in the Lower Limbs

PC114. The Role of the Vascular Surgeon in Open Oncologic Resection: Benefiting Everyone Involved

Objectives Upper extremity arterial access is often required for endovascular procedures, especially for antegrade access to the visceral aortic branches. Radial arterial access has been shown previously to have low complication rates, and patients tolerate the procedure well and are able to recover quickly. However, transradial access remains relatively uncommon amongst vascular surgeons. Methods The radial artery was evaluated by ultrasound to evaluate for adequate caliber, and to identify any aberrant anatomy or arterial loops. A modified Barbeau test was performed to ensure sufficient collateral circulation. A cocktail of nitroglycerin, verapamil and heparin was administered intra-arterially to combat vasospasm. Sheaths up to 6 French were utilized for interventions. On completion of the procedure, a compression band was used for hemostasis in all cases. Results Twenty-five interventions were performed in 24 patients. The left radial artery was used in 23/25 cases (92.0%). Procedures included visceral and renal artery interventions; stent graft repair of a renal artery aneurysm; embolization of splenic, pancreaticoduodenal and internal mammary aneurysms; embolization of bilateral hypogastric arteries following blunt pelvic trauma; interventions for peripheral arterial disease; delivery of a renal snorkel graft during endovascular aortic aneurysm repair, and access for diagnostic catheters during thoracic endovascular aortic aneurysm repair. Technical success was 92.0%. There was one post-operative radial artery occlusion (4.3%) which led to paresthesias but resolved with anticoagulation. There were no instances of arterial rupture, hematoma, or hand ischemia requiring intervention. Conclusions Using the transradial approach, we have demonstrated a high technical success rate over a range of clinical contexts with minimal morbidity and no significant complications such as bleeding or hand ischemia. The safety profile compares favorably to historical complication rates from brachial access. Radial access is a safe and useful skill for vascular surgeons to master.

Transradial interventions in contemporary vascular surgery practice

Previous studies have identified predictors of prolonged length of stay (LOS) following pulmonary lobectomy. LOS is typically described to have a direct relationship to postoperative complications. We sought to determine the LOS and factors associated with variability after uncomplicated pulmonary lobectomy.

METHODS
Analysing the State Inpatient Databases, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality database, we reviewed lobectomies performed (2009-11) on patients in California, Florida and New York. LOS and comorbidities were identified. Multivariable regression analysis (MVA) was used to determine factors associated with LOS greater than the median. Patients with postoperative complications or death were excluded.

RESULTS
Among 22 647 lobectomies performed, we identified 13 099 patients (58%) with uncomplicated postoperative courses (mean age = 66 years; 56% female; 76% white, 57% Medicare; median DEYO comorbidity score = 3, 55% thoracotomy, 45% thoracoscopy/robotic). There was a wide distribution in LOS [median LOS = 5 days; interquartile range (IQR) 4-7]. By MVA, predictors of prolonged LOS included, age ≥ 75 years [odds ratio (OR) 1.7, 95% confidence interval (CI) 1.4-2.0], male gender (OR 1.2, 95% CI 1.1-1.2), chronic obstructive pulmonary disease (OR 1.6, 95% CI 1.5-1.7) and other comorbidities, Medicaid payer (OR 1.7, 95% CI 1.4-2.1) versus private insurance, thoracotomy (OR 3.0, 95% CI 2.8-3.3) versus video-assisted thoracoscopic surgery/robotic approach and low hospital volume (OR 2.4, 95% CI 2.1-2.6).

Variability exists in LOS following even uncomplicated pulmonary lobectomy. Variability is driven by clinical factors such as age, gender, payer and comorbidities, but also by surgical approach and volume. All of these factors should be taken into account when designing clinical care pathways or when allocating payment resources. Attempts to define an optimal LOS depend heavily upon the patient population studied.

European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery

Variability in length of stay after uncomplicated pulmonary lobectomy: is length of stay a quality metric or a patient metric?†.

Objective: To standardise emergency response processes to life threatening maternal and fetal situations requiring activation of a category one Caesarean section (C1CS), with the aim of reducing decision to incision (D-I) and decision to delivery (D-D) times. Design: A prospective observational study following the introduction of a streamlined C1CS process. Setting: A tertiary public obstetric hospital Population: All women who had a C1CS process activated over a 14 month period. Methods: Data were collected prospectively on a newly developed C1CSResponse Management Plan with documentation of D-I and D-D times for multiple variables. Main outcome measures: D-I and D-D times. Results: The median D-I was 11 minutes (interquartile range (IR): 7 minutes). 83% (68/82) of calls which proceeded to C1CS had D-I within 15 minutes. The median D-D was 17 minutes (IR: 9 minutes). 76% (62/82) of calls, which proceeded to C1CS, had D-D within 20 minutes and 96% within 30 minutes. Factors which significantly decreased D-I and D-D (p<0.05) included: taking verbal rather than written consent, not performing bladder catheterisation, not performing pubic clipping, and not changing women into theatre attire. Seniority of the surgeon did not affect times. Conclusions: A streamlined C1CS process can achieve D-I and D-D times well within expected international standards.

A Category One Caesarean Section Process at an Australian Tertiary Obstetric Hospital: Planning to Reduce Decision to Delivery Time

Metal buildings (MB) are a prevalent form of low-rise construction in the U.S. They are built in a variety of geographic locations, including high seismic regions. It is desirable to understand the seismic performance of such a prevalent structural system. There is a general lack of experimental data available concerning the seismic performance of metal buildings and the web-tapered I- shaped beams of which they are typically composed. In order to improve the seismic performance of the moment resisting frames in these buildings new Seismic Force Resisting Systems (SFRS) need to be developed. But first, several key issues required research. The MB moment frames are often controlled by lateral-torsional buckling (LTB) and current design methodologies do not provide adequate LTB flexural strength prediction equations for the full range of member geometries commonly used. Single-story MB frames deviate significantly from the buildings used to define approximate fundamental period equations in the current building codes and the applicability of those equations to MB frames is questionable. Partial-floors, called mezzanines, are often attached to MB frames, yet no clear guidance is given in the current building codes to address the seismic analysis and design of these structures. Finally, experimental data for the dynamic characteristics of MB moment frames at the system level and their cyclic post-buckling behavior at the member level was needed. This research provided experimental data through two testing programs. Shake table testing was performed on two full-scale metal buildings. Results of those tests led to two concepts for new SFRS for MB frames, one of which relies on LTB for inelastic hinging. Experimental data was provided in support of the development of the new SFRS through cyclic tests of ten web-tapered rafter specimens. The cyclic performance of LTB was investigated and results used to outline a new design procedure. In addition, new approximate period equations and seismic design methods for mezzanines were developed. This research provides the necessary foundation for the development of new SFRS for MB moment frames which considers the available ductility of web-tapered rafters

Seismic Testing and Analytical Studies for the Development of New Seismic Force Resisting Systems for Metal Buildings

The Tertiary in Thailand is a period strongly affected by continental collisions, tectonic escape of continental blocks and extensional tectonics, which ultimately link back to the formation of the Himalayas. In NW Thailand metamorphic core complexes, major strikeslip faults and rift basins are contemporaneous. However structurally it is presently unclear how they relate to each other. Mapped core complexes exist west of Chiang Mai, their southerly extent will be investigated, along with the evolution of the Mae Ping strike-slip fault zone. Among other techniques apatite fission track dating will establish the uplift history of the area. Seismic interpretation of the Phitsanulok basin, focusing on timing and orientation of structural features especially inversion, will be integrated with the field data to determine the links between core complexes, strike-slip motion, rift basin development and paleostress evolution. On a basin scale understanding the magnitude and timing of uplift is useful for reconstructing sediment source areas and drainage patterns during the syn-rift stage. Constraining the timing of inversion is important for trap development and for identifying the location and timing of fault reactivation, which can lead to lateral seal destruction.

Structural geometry, evolution and relationships between strike-slip faults, metamorphic core complexes and rift basins in central Thailand

Abstract Caregiving strain often stems from caregivers’ unmet needs and is a risk factor for physical and psychological ill-health. This study aims to identify factors associated with caregiver strain among middle-aged and older African American and Hispanic male caregivers living with one or more chronic conditions. Data were collected from 431 male caregivers using a web-based survey (55% African American, 45% Hispanic). Linear regression models were fitted to assess factors associated with caregiver strain, which was measured using caregiving difficulty items from Behavioral Risk Factor Surveillance System. On average, participants were age 54.9(±9.51) years, they self-reported chronic conditions were 3.74(±2.62), and their caregiver strain was 14.7(±7.30). Among African American caregivers, higher caregiver strain was positively associated with living with children below age 18 (β=0.14, P=0.045) and feelings of social disconnectedness (β=0.16, P=0.018) and depression (β=0.15, P=0.035). Conversely, caregiver strain was negatively associated with having insurance coverage (β=-1.34, P=0.028) and disease self-management efficacy (β=-2.26, P=< 0.001. Among Hispanic caregivers, higher caregiver strain was negatively associated with age (β=-0.28, P=< 0.001) and positively associated with feelings of social disconnectedness (β=0.16, P=0.041). Findings suggest African American and Hispanic males with chronic conditions have differing caregiving experiences. Compared to Hispanic men, contributors to caregiving strain among African American men were multifaceted and associated with financial resources, household dynamics, mental health, and the ability to self-manage their chronic conditions. While bolstering social connectedness may offset caregiver strain, tailored mental health and disease-management programming are needed to meet the specific needs of African American and Hispanic male caregivers.

CAREGIVER STRAIN AMONG AFRICAN AMERICAN AND HISPANIC MALE CAREGIVERS WITH CHRONIC CONDITIONS

Abstract Demands of caregivers of persons living with dementia (PLWD) are often influenced by the context of their caregiving situation. This study examines factors associated with caregiving burden in terms of task time and task difficulty among paid and unpaid caregivers of PLWD. Cross-sectional baseline survey data were analyzed from 110 paid and unpaid caregivers of PLWD participating in a larger NIH-funded study assessing the feasibility of using a novel in-situ sensor system. Oberst Caregiving Burden Scale constructs of task time and task difficulty served as dependent variables. Two least squares regression models were fitted, controlling for contextual items related to the caregiver, care recipient, and caregiving logistics. Caregivers whose care recipients were female (B=-0.29, P=0.006), had more chronic conditions (B=0.31, P=0.011), and had lower Mini-Mental State Exam scores (B=-0.20, P=0.015) reported higher task time burdens. Caregivers whose care recipients had other paid caregivers (B=0.30, P=0.031) and spent more months/years caring for their care recipients (B=0.28, P=0.004) reported higher task time burdens. Caregivers’ task time burden was positively associated with their emotional stress level (B=0.30, P=0.020). Caregivers’ task difficulty burden was positively associated with their emotional stress (B=0.30, P=0.029) and depressive symptomatology (B=0.32, P=0.002). Results reinforce the relationship between caregiver burden and mental health. While the care recipient’s disease profile and needs were drivers of task time burden, which may also require coordination with other paid caregivers, task difficulty was emotionally driven. Findings highlight the importance of caregiver support services and programming for mental health.

CAREGIVING BURDENS OF TASK TIME AND TASK DIFFICULTY AMONG PAID AND UNPAID CAREGIVERS OF PERSONS LIVING WITH DEMENTIA

Abstract Recently, social workers have been identified as a key messenger group for promoting physical activity (PA) to disabled people. Also identified is the need to train social workers in PA promotion. In response, the purpose of this article is to inform the design of a training programme prototype aiming to support social workers to become active PA messengers. We conducted a three‐round Delphi study to identify the essential contents and teaching methods for the programme, as well as the challenges that may jeopardise its success. Qualified experts on physical activity and health, social work, and/or disability working in the UK were invited to partake in the study. The response rates were 55% (33/60) in the first round, 79% (26/33) in the second and 77% (20/26) in the third rounds. Following the last questionnaire round, the experts reached consensus on 8 contents, 7 teaching methods and 10 challenges to success. The top three most important contents were: benefits of PA (1.05 ± 0.22), what PA means to disabled people (1.15 ± 0.36) and person‐centred PA planning (1.35 ± 0.57). The most relevant teaching methods were interactive activities and discussions (1.20 ± 0.51) and case studies (1.25 ± 0.43). Blended learning (1.85 ± 0.57) was preferred to e‐learning (2.20 ± 0.60) and face‐to‐face learning (2.10 ± 0.70). Lack of time (1.30 ± 0.46) and confidence (1.45 ± 0.59) were deemed vital challenges. However, consensus around other potential barriers such as lack of interest and commitment (1.30 ± 0.46), lack of buy in from employers (1.75 ± 0.70) and professional inertia (2.05 ± 0.67) suggest that a major challenge for long‐term impact is to convince key people that social work and PA promotion make a good match. The results of this study provide a valuable starting point evidence base for PA curriculum development. Future research will delve into expert opinions using in‐depth qualitative interviews. Participatory approaches including knowledge cafés will also be used to add more views of stakeholders with experiential knowledge.

Designing a programme to train social workers on how to promote physical activity for disabled people: A Delphi study in the UK

 This study examines factors associated with self-reported worsening of depressive symptomatology since before the COVID-19 pandemic among caregivers of persons living with dementia (PLWD). Cross-sectional baseline survey data were analyzed from 76 paid and unpaid caregivers of PLWD participating in a larger NIH-funded study assessing the feasibility of using a novel in-situ sensor system. Using the PHQ-2, caregivers were asked to report their depressive symptomatology twice: (1) retrospectively before the COVID-19 pandemic started; and (2) since the COVID-19 pandemic. A change score was calculated, and whether or not caregivers’ depressive symptomatology worsened since before the pandemic served as the dependent variable. A logistic regression model was fitted, controlling for contextual items related to the caregiver, care recipient, and caregiving logistics. On average, caregivers were age 58.09(±16.92) and the majority was female (84.2%). Thirty percent of caregivers reported worse depressive symptomatology since the COVID-19 pandemic than before the COVID-19 pandemic started. Caregivers who were female (OR=25.86, P=0.028), not paid for caregiving (OR=14.59, P=0.047), had lower annual household incomes (OR=0.50, P=0.032), and whose care recipients had higher Mini-Mental State Exam scores (OR=1.78, P=0.005) were more likely to report worse depressive symptomatology since the COVID-19 pandemic. Results suggest that the COVID-19 pandemic intensified depressive symptomatology for many caregivers, and unpaid, female caregivers with fewer financial resources have been especially impacted. As the pandemic continues, support for caregivers of PLWD should be tailored to specifically meet their needs and circumstances.

WORSENING OF DEPRESSIVE SYMPTOMATOLOGY SINCE BEFORE COVID-19 AMONG CAREGIVERS OF PERSONS LIVING WITH DEMENTIA

 With a rapidly aging workforce and the rising prevalence of chronic conditions, efforts are needed to better understand the needs of older adult workers and how to create supportive working environments for them. This study examines factors associated with job satisfaction among full-time employed adults ages 60+ years with 1+ chronic conditions. Data were collected with an internet-delivered survey in January 2022. Analyses included 337 older adult workers with chronic conditions. An ordinal regression model was fitted to assess factors associated with higher levels of job satisfaction. The model adjusted for sociodemographics, disease characteristics, social engagement, work logistics, and perceptions about the workplace. On average, participants were age 65.14(±4.56) years and self-reported 3.05(±2.09) chronic conditions. Twenty-eight percent reported being very satisfied with their current job and 48.4% worked remotely 1+ days per work week. Higher job satisfaction levels were positively associated with being Hispanic (β=0.68, P=0.030), exhibiting stronger organizational citizenship behavior (β=0.16, P< 0.001), and working more days remotely (β=0.12, P=0.026). Higher job satisfaction levels were negatively associated with job-related stress (β=-0.26, P< 0.001), feelings of social disconnectedness (β=-0.12, P=0.010), and greater intentions of leaving current jobs within the next three months (β=-0.70, P< 0.001). Findings suggest that job satisfaction among older adult workers is rooted in their compatibility with their organizations’ work environment, management of job-related stressors, and opportunity to engage in meaningful and fulfilling interactions with others. Strategies such as remote working are encouraged to give older adults flexibility to promote work-life balance and self-manage their chronic conditions.

CORRELATES OF JOB SATISFACTION AMONG FULL-TIME EMPLOYED OLDER ADULTS WITH CHRONIC CONDITIONS

Abstract Objective: To examine differential relationships between communication technology use and social connectedness among paid and unpaid caregivers providing care for middle-aged and older adults. Methods: This nationwide study utilized a cross-sectional Qualtrics panel survey from caregivers, ages 50 years and older (n=504) of middle-aged and older adults. About 17% were paid (n=86) and 83% (n=418) were unpaid caregivers. Primary outcomes were caregivers’ sense of belonging to their local community and social bonds. The primary predictor of interest was caregivers’ use of communication technology (texting/communication applications). A multivariable regression analysis was performed to predict each outcome based on communication technology use, separately among paid and unpaid caregivers. Multivariable regression analyses were repeated after including the caregivers’ payment status (paid/unpaid) and the interaction term between the caregivers’ payment status and the use of communication technology. The models were adjusted for caregivers’ age, education, financial status, place of residence, and total weekly hours of caregiving. Results: Use of communication technology had a statistically-significant positive association with sense of belonging only among paid caregivers (b=25.8, p=.005). The relationship between use of communication technology and sense of belonging was significantly different between paid and unpaid caregivers (p=.005). Use of communication technology was significantly associated with social bonds only among unpaid caregivers (b=0.4, p<.001). There was no statistically-significant differential association between communication technology use and social bonds. Conclusion: Communication technology may play differential roles in linking paid and unpaid caregivers with their community and interpersonal groups. Additional efforts should examine mechanisms that provide meaningful caregiver support.

Social Connectedness and Communication Technology Among Paid and Unpaid Caregivers of Middle-Aged and Older Adults

Abstract Technological innovations are becoming commonplace in research among persons living with dementia (PLWD) and their caregivers. However, few studies attempt to validate technology’s ability to appropriately monitor functional assessment in dementia care research. Bringing together industry, academia, and health care, we demonstrate the feasibility of using a novel in-situ sensor system to continuously and accurately assess daily functions for PWLDs in home or assisted care settings. Phase1 revealed a high accuracy (~85%) of detecting and classifying ADLs between sensors and human loggers across 26 defined activities. Phase 2, which will target 140 PLWDs, has already demonstrated the value of such sensors in detecting safety concerns (e.g., no heat). Technology-driven research for PLWD and their caregivers have practical applications for assessing diverse forms of functional assessment and environmental conditions which can improve measurement precision over time and space and the ability to better tailor care plans for PLWDs and their caregivers.

Technology Innovations in Dementia Care: Improvements in Functional Assessments Through Background Sensing

Abstract Social connectedness is a multi-factorial concept encompassing structural, functional, and quality aspects. For those with chronic conditions, threats to social connectedness can exacerbate illness symptomology and impose barriers to disease self-management. This study identified factors associated social connectedness risk among Black men ages 40+ years with one or more chronic conditions. Data from 2019 were analyzed from a national sample of 1,200 Black males collected with an internet-delivered questionnaire. Three logistic regression models were fitted to assess factors associated with not having enough people to call for help (structural), feeling isolated from others (functional), and not being content with friendships/relationships (quality). All regression models were adjusted for age, education, marital status, number of chronic conditions, self-reported barriers to disease self-management, and having cut-down or skipped social activities because of health problems. On average, participants were age 56.7 (±9.7) years and self-reported 4.0 (±2.9) chronic conditions. Approximately 23% were ages 65+ years, 45.4% cut-down or skipped social activities because of health problems, 25.2% did not have enough people to call for help, 26.0% felt isolated from others, and 23.8% were not content with friendships/relationships. Across the three regression models, men who were middle-aged (P<0.05), never married (P<0.01), cut-down or skipped social activities because of health problems (P<0.001), and reported more barriers to disease self-management (P<0.001) were significantly more likely to report social connectedness risk. Findings suggest that efforts to improve the self-management of illness symptomology may mitigate threats to structural, functional, and quality aspects of social connectedness among this male population.

Social Connectedness Risk Among Middle-Aged and Older Black Men With Chronic Conditions

IMPACT OF A DISEASE SELF-MANAGEMENT PROGRAM ON EMPLOYEE HEALTH AND WORK PERFORMANCE: INTRODUCING WORKPLACE CDSMP

CAREGIVER PARTICIPATION IN CHRONIC DISEASE SELF-MANAGEMENT EDUCATION PROGRAMS: FINDINGS FROM A NATIONAL STUDY

This paper assesses and compares state-of-the-art filter technology to the next generation filter technology required for use in military multifunction systems. Military architectures are transitioning from federated systems to wideband multifunction systems which integrate radar, electronic warfare (EW), and communications through a common aperture. This is accomplished while performing in an increasingly dense spectral environment while on increasingly smaller platforms (e.g., small UAV). This evolution hae called for advances in digital beamforming, reconfigurable digital receiver exciters (DREX), wideband phased arrays with lower size, weight, power and cost (SWaP-C). One of the key challenges in next generation DREX architectures is integrating and miniaturizing filters in order to meet the new requirements. Moreover, as DREX moves on-chip and on wafer, filters must integrate at this level to achieve the desired level of miniaturization and channelization required by today's wide bandwidth complex signal environments. Notable strides have been made across many enabling technologies such as Si/CMOS/SiGe for affordability, GaN for power and linearity, InP HEMT for speed and low noise, MEMS for low loss switching and photonics for high speed distribution. Nonetheless, miniature filter challenges continue to elude full integration on-chip and in 3D wafer level stacks.

2012 IEEE International Conference on Wireless Information Technology and Systems (ICWITS)

Future trends in filter technology for military multifunction systems

An inter-digital slow-wave coplanar waveguide (CPW) geometry on silicon is described and its use in a new, low-loss transition from CPW to slot-line is discussed. The example transitions are designed for the 10–30 GHz frequency range and are approximately two times smaller than typical slot-stub designs.

For most radiometers, periodic calibration is essential to ensure sensor measurement accuracy. This paper describes the application of a unique active microwave circuit that simulates known radiated thermal temperatures over a stepped range of less than 105 K to over 300 K. The device, when connected or switched to the input of a receiver, can be incrementally stepped via a bias voltage from the coldest to the warmest temperature. It offers the potential to replace more complex and expensive external and internal calibration techniques. In addition to calibration, the device also serves to test the receiver linearity and measure receiver noise figure. The paper will identify significant advances in the area of modeling, design, development, and test of the stepped 'cold/warm' noise source. Several prototype FET circuits, using 150 and 300 micrometer InP devices, have been built and demonstrated at K-band frequencies of 18 - 22 GHz. Work is in progress to build and test the next device at 37 GHz. Tests have been conducted at Raytheon Systems, the University of South Florida (USF), and the National Institute of Science and Technology (NIST). The results illustrate good agreement between simulation and measurements. Block diagrams are included to show the method of calibrating radiometers, testing receiver linearity, and measuring receiver noise figure.

Microwave active cold/warm noise source for calibration of radiometer sensors

The GEOSAT follow-on (GFO) WVR provides correction factors to the GFO altimeter range measurements for path delays due to water vapor. Radiometric 'brightness temperatures' of 22.2 and 37.0 GHz are measured with a shared antenna that has pattern footprints that overlap the altimeter footprint. The antenna is a 1.1 m diameter off-set parabolic reflector with a corrugated tri-band feed. Main beam efficiency is 94% and near beam (plus or minus 10 degrees) efficiency is 97%. This total power radiometer system has fully redundant electronics, weighs 12.7 kg and consumes 18 watts. Channel sensitivities are less than 0.18 degrees Kelvin for a 1 sec sample period.

Water vapor radiometer for the U.S. Navy GEOSAT follow-on mission

PCB technology based on both rigid and flexible laminates is desirable for miniaturization of mobile devices and systems. The technology provides substantial flexibility in systems design. The ability to use flexible microsystems allows new sensing systems for mobile applications. Using this design, fabrication and construction approach allows lightweight, complex, and space efficient systems. Flex microsystems based on structurable, non-fiber filled laminates permits miniaturization to occur at two levels: at the micro scale with the embedding of microstructures in the substrate, and at the macro scale with the ability to flex the system across millimeter to centimeter lengths of real everyday objects. The macro scale systems further allows ultra large systems with high resolution features permitting novel sensor systems. Examples will be given where the technology has enabled devices, systems and packaging innovation across several spatial scales. Mobile (environmental, medical, portable, embedded) sens...

PCBMEMS as a Flexible Path to Devices and Systems across Spatial Scales

PCBMEMS have previously been incorporated within rigid substrates. Flexible laminates are also possible to incorporate PCBMEMS, called Flex PCBMEMS, and at times are desirable for maximum packing density and miniaturization. In this work demonstrations using 2D to 3D packaging transforms on a compact heated fluorometer block are presented. In one case the optoelectronic reference block is further integrated using flexible PCB/MEMS. The block is transformed with the insertion of a polyimide flex opto/mechanical/electrical interconnect skin. In a second example the block is further miniaturized into a mini tube using planar fabrication and flexible folding of the fluorometer system. This design, fabrication and construction approach allows lightweight, complex, space efficient systems. Flex PCBMEMS permits miniaturization to occur at two levels: at the micro scale with the embedding of microstructures in the substrate, and at the macro scale with the ability to flex the system across millimeter to centimeter lengths of real everyday objects. Using this path Flex PCBMEMS can approach the creativity and complexity of natural systems.

This study describes the use of the ChargeSwitch extraction technique as a method amenable to in-field RNA extraction and purification. The modified ChargeSwitch extractions were performed by lysing cells captured from filtration of 30 mL seawater sample spiked with cultured Karenia brevis and seawater samples from regions around a known red tide event. Extractions were compared to traditional laboratory-based silica spin columns by integration with real-time nucleic acid sequence-based amplification. The ChargeSwitch extraction method was equivalent to or was faster than traditional laboratory analysis whilst having the additional advantages of obtaining consistently higher RNA concentrations and requiring no specialized or powered equipment. This method represents a fast and field-able method for RNA extraction from K. brevis and potentially other organisms of public health significance. 
 
PRACTICAL APPLICATIONS 
 
This manuscript describes an RNA extraction method that utilizes ChargeSwitch technology suited for in-field use that can be performed without access to extensive laboratory infrastructure, requiring only magnetic separation equipment and adjustable pipettes. This research is both timely and important as a recent Alliance for Coastal Technologies' workshop on “Genetic Sensors for Environmental Water Quality” (January 5–7, 2005) highlighted in-field sample preparation as one of the major issues facing the advancement of in situ genetic assays. The method uses detection of the harmful, algal bloom-forming dinoflagellate Karenia brevis as a demonstration of the use of ChargeSwitch to extract RNA from complex environmental samples in the field. Combined with previously described portable analytical equipment, these techniques will prove invaluable in the advancement of on-site analysis, leading to faster decision making for public health officials and shellfish managers.

Extended abstract of a paper presented at Microscopy and Microanalysis 2007 in Ft. Lauderdale, Florida, USA, August 5 – August 9, 2007

The Autonomous Microbial Genosensor, an in situ Sensor for Marine Microbe Detection

A handheld NASBA analyzer for the field detection and quantification of Karenia brevis

An integrated portable hand-held analyser for real-time isothermal nucleic acid amplification.

Development and evaluation of a method to detect and quantify enteroviruses using NASBA and internal control RNA (IC-NASBA).

Increased precision of microbial RNA quantification using NASBA with an internal control.

Miniaturization of laboratory sensors has been enabled by continued evolution of technology. Field portable systems are often desired, because they reduce sample handling, provide rapid feedback capability, and enhance convenience. Fieldable sensor systems should include a method for initiating the analysis, storing and displaying the results, while consuming minimal power and being compact and portable. Low cost will allow widespread usage of these systems. In this paper, we discuss a reconfigurable Personal Data Assistant (PDA) based control and data collection system for use with miniature sensors. The system is based on the Handspring visor PDA and a custom designed motherboard, which connects directly to the PDA microprocessor. The PDA provides a convenient and low cost graphical user interface, moderate processing capability, and integrated battery power. The low power motherboard provides the voltage levels, data collection, and input/output (I/O) capabilities required by many MEMS and miniature sensors. These capabilities are relayed to connectors, where an application specific daughterboard is attached. In this paper, two applications are demonstrated. First, a handheld nucleic acid sequence-based amplification (NASBA) detection sensor consisting of a heated and optical fluorescence detection system is discussed. Second, an electrostatically actuated MEMS micro mirror controller is realized.

ABSTRACT Nucleic acid sequence-based amplification (NASBA) is an isothermal method of RNA amplification that has been previously used in clinical diagnostic testing. A real-time NASBA assay has been developed for the detection of rbcL mRNA from the red tide dinoflagellate Karenia brevis. This assay is sensitive to one K. brevis cell and 1.0 fg of in vitro transcript, with occasional detection of lower concentrations of transcript. The assay did not detect rbcL mRNA from a wide range of nontarget organisms and environmental clones, while 10 strains (all tested) of K. brevis were detected. By the use of standard curves based on time to positivity, concentrations of K. brevis in environmental samples were predicted by NASBA and classified into different levels of blooms per the Florida Fish and Wildlife Conservation Commission (FWC) system. NASBA classification matched FWC classification (based on cell counts) 72% of the time. Those samples that did not match were off by only one class. NASBA is sensitive, rapid, and effective and may be used as an additional or alternative method to detect and quantify K. brevis in the marine environment.

Detection and Quantification of the Red Tide Dinoflagellate Karenia brevis by Real-Time Nucleic Acid Sequence-Based Amplification

The Competitiveness of Orthopaedic Surgery Residency Programs: A Twenty-Year Analysis Utilizing a Normalized Competitive Index

Compliance with Electronic Patient Reported Outcome Measure System Data Collection Is 51% Two-years After Shoulder Arthroscopy

Abstract PS7-49: Assessment of patient out-of-pocket cost for palbociclib therapy in advanced breast cancer

Bilateral atypical fractures of the femur: Ten years AFTER ten years of bisphosphonate therapy

Evidence based management for paediatric burn: new approaches and improved scar outcomes.

Tea and coffee scalds in children: a British epidemic requiring a solution.

Does belonging to an undergraduate surgical society really improve students' surgical skills?

Microvascular decompression versus stereotactic radiosurgery for the primary treatment of idiopathic trigeminal neuralgia

PURPOSE
The purpose of this paper is to evaluate the common themes leading or contributing to clinical incidents in a UK teaching hospital.

DESIGN/METHODOLOGY/APPROACH
A root-cause analysis was conducted on patient safety incidents. Commonly occurring root causes and contributing factors were collected and correlated with incident timing and severity.

FINDINGS
In total, 65 root-cause analyses were reviewed, highlighting 202 factors implicated in the clinical incidents and 69 categories were identified. The 14 most commonly occurring causes (encountered in four incidents or more) were examined as a key-root or contributory cause. Incident timing was also analysed; common factors were encountered more frequently during out-hours--occurring as contributory rather than a key-root cause.

PRACTICAL IMPLICATIONS
In total, 14 commonly occurring factors were identified to direct interventions that could prevent many clinical incidents. From these, an "Organisational Safety Checklist" was developed to involve departmental level clinicians to monitor practice.

ORIGINALITY/VALUE
This study demonstrates that comprehensively investigating incidents highlights common factors that can be addressed at a local level. Resilience against clinical incidents is low during out-of-hours periods, where factors such as lower staffing levels and poor service provision allows problems to escalate and become clinical incidents, which adds to the literature regarding out-of-hours care provision and should prove useful to those organising hospital services at departmental and management levels.

Models are increasingly being used for training in invasive procedures in the field of medicine and surgery to prepare trainees to perform such interventions on patients. The removal of an epidermoid cyst is a simple procedure, but can be challenging when the cyst is located in a cosmetically sensitive area. Epidermoid cysts may also rupture, increasing the risk of infection. Although artificial models exist for simulation of this procedure, they are costly and permit single use only. Bowling and Botting published an ingenious, inexpensive solution in this journal using paint balls located in pork flesh to simulate an epidermoid cyst. This model provides optimal simulation of human skin, although it poses a number of difficulties. We have developed a related model based on a cheaply produced synthetic skin pad incorporating a similar paint ball-based epidermoid cyst simulation.

Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]

Modernising access to surgical research: The win-win answer for both student and clinician

Video Gaming: The Best Preparation for Surgical Training? or Should We Mourn the Death of Model Airplanes?

Laparoscopic simulation for all: two affordable, upgradable, and easy-to-build laparoscopic trainers.

Engineering the future of surgery: the place of the surgical engineering faculty.

The number and proportion of abstracts submitted to the 2012 ASiT conference across difficult surgical specialities

Despite recent challenges to attaining surgical exposure (e.g. after the introduction of the European Working Time Directive), trainees must keep a meticulous logbook detailing key intra-operative details; indeed, an ‘eLogbook’ service has been established for this purpose. Unfortunately, current provision is aimed at postgraduates. We argue that there are myriad reasons why undergraduates should document operations, and that handwritten logbooks offer an elegant solution. Medical students spend very little time in the operating theatre, so efforts should be made to maximise educational return. Encouraging undergraduates to catalogue their operative experiences introduces essential skills, such as the handwriting of ‘operative notes’ and the concept of diligent record keeping. Importantly, it provides a solid background to underpin future postgraduate portfolios and interviews: demonstrating the pursuit of personal educational improvement and an unparalleled commitment to surgery. Logbook maintenance encourages students to go beyond passively observing in theatre: providing opportunities to reflect on knowledge gained, and how this complements the extant curriculum.

Objective: 1) To report the process of management and 2-year disease-free survival statistics for laryngeal cancer cases presenting to a United Kingdom tertiary cancer center. 2) To investigate which modality of treatment is the most appropriate for specific stages of laryngeal cancer. Method: A retrospective cohort study was carried out on laryngeal cancer patients presenting to a tertiary head and neck center from 2007 to 2009. Information on primary tumor staging and management was collected using the Somerset Cancer Registry. Patient notes, imaging, and histology reports were consulted to complete data retrieval. Results: Forty-seven cases presented during the study period (2 stage-0, 8 stage-I, 12 stage-II, 13 stage-III, 12 stage-IV). Nodal disease was present in 10.6%, and 2.1% had metastatic disease at presentation. Overall 2-year disease-free survival was 100% for stage-0, 87.5% stage-I, 69.2% stage-II, 36.4% stage-III, and 32.2% for stage-IV disease. Stage-I/II cases were treated by transoral laser (36.8%) or radiotherapy (63.2%), with 85.7% and 83.3% 2-year disease-free survival rates, respectively. Stage-III/IV cases were treated by surgery (38.1%) or radiotherapy/chemoradiotherapy (61.9%) with 2-year disease-free survival rates of 62.5% and 21.4%, respectively. Conclusion: Early-stage disease is equally well treated with transoral laser or radiotherapy alone in line with other studies. Larynx preservation with chemoradiotherapy demonstrates significantly poorer outcomes compared to surgery in this study. Accurate contemporary data recording is required to allow critical review of treatment modalities.

Objective: To define the analgesic regimen given following tonsillectomy in a large otolaryngology center and correlate this with readmission for secondary complications. Method: Case notes for patients undergoing tonsillectomy were collected between February and August 2011. Information was collated and entered into a database including age, gender, operation type, indication, medications on discharge, and details of readmission. Data were assessed for correlations, particularly that between readmission and analgesic regimen given following tonsillectomy. Results: One hundred twenty-five patients underwent tonsillectomy during the six-month period (mean age of 13.8 years, range 3 months to 65 years). The most common indication for surgery was recurrent tonsillitis and with most carried out by bipolar dissection. A total of 64.8% of patients were discharged as day cases. Seventeen different postoperative analgesic regimens were identified with the most common being acetaminophen and ibuprofen in combination (26.4%). Of the patients, 20.0% had no documented analgesia on discharge. Thirteen patients (10.4%) were readmitted following discharge from hospital postoperatively, 4 (3.2%) for issues related to pain. There was no correlation between analgesic regimens and readmission, including those without formal analgesic prescriptions. Conclusion: No apparent link between readmission and analgesic regimen was identified. The lack of opioid analgesics does not appear to affect readmission rates. However the vast variation of analgesic regimens and lack of formal instructions for those advised over-the-counter analgesics has prompted development of a formal step-based protocol.

TEMPL3: a simple mnemonic for the diagnosis of temporal arteritis.

Objective: To investigate the presenting features of cases of laryngeal carcinoma to a large tertiary head and neck center over a 4-year period. Method: A retrospective cohort study was carried out on laryngeal cancer patients presenting to our head and neck center between 2007 and 2011. Information on sex, age, smoking status, presenting symptoms, tumor location, tumor staging, and histopathology was collected from the Somerset Cancer Registry, using hospital case notes for completion. Results: A total of 105 cases presented during the study period, of which 88.6% were male. The mean age was 66.1 years (range, 37-89). 89.6% of patients had a smoking history. The most common presenting symptom was voice change (79.1%), followed by throat pain (14.0%). 84.8% of tumors were glottic, with 15.2% supraglottic. 4.7% of tumors were diagnosed as stage-0, 30.8% stage-I, 22.4% stage-II, 18.7% stage-III, 9.3% stage-IVA, 9.3% stage-IVB, and 2.8% stage-IVC. Twelve (11.4%) presented with nodal disease, and 3 with distant metastases (2.9%). On histopathology, 29.2% of tumors were well differentiated, 52.8% moderately differentiated and 18.0% poorly differentiated squamous cell carcinomas. Conclusion: Advanced age, smoking history, and dysphonia remain the most common features of laryngeal carcinoma presentations. Detection of early disease is vital to improve prognosis. Results should help focus referral pathways and enable family physicians to most easily identify those at risk. Smoking cessation programs must continue to be a priority.

article reported about it in Malaysia settings. This study aimed to evaluate its psychometric properties in a sample of Malaysian medical students. It was designed to answer a few questions: (1) Is DREEM a valid and reliable tool to measure educational climate in the studied population?, (2) What is the best fit model of DREEM in the studied population? (3) Does internal consistency vary across years of study? The author carried out a cross-sectional study on 656 medical students. A total of 511 (77.9%) medical students completely responded to the DREEM: 156 (30.5%) first year, 196 (38.4%) third year and 159 (31.1%) fifth year. Majority of them were female (61.1%). Confirmatory factor analysis (CFA) and reliability analysis were analysed by SPSS version 18 and AMOS 19 to assess the construct validity and internal consistency. The CFA showed that the proposed five-factor structure of the original DREEM was not fit as all the goodness of fit indices did not signify for model fit. This finding consistent with previous studies reported that its construct validity was not well supported by the empirical data (Jakobsson et al. 2011). On further CFA, the author found that the five-factor structure of DREEM with 17 items (i.e. the shortened DREEM) was fit as all the indices signify for model fit. Cronbach’s alpha values across years of study for the subscales of both DREEM versions ranged between 0.53 and 0.82. Our study did not support the proposed five-factor structure of DREEM. The shortened version demonstrated a better fit with the proposed model and was found to be as reliable as the original version across years of study. Continued research is required to verify and maximize psychometric credentials of the DREEM across institutions and nationalities.

Defining Surgical Role Models and Their Influence on Career Choice

Surgical management of chronic subdural haematoma: one hole or two?

Developing an affordable simulator of laparoscopic techniques for undergraduate trainees

A personalized and specific orthopedic instrument for the patient, comprising a cutting board for specific and personalized femur for the patient (1400) comprising: (i) a front body (1402) having a surface facing the bone (1412 ) having a negative contour -Custom and specific to the patient- configured to receive a portion of an anterior side of a patient's femur that has a corresponding positive contour; the body has a cut groove (1432) which serves to guide the blade of a saw, and the cut groove is in the previous body or a cutting guide (1430) connected to the upper body and is made from a different material from the body; the cutting groove is positioned so as to allow a surgeon to perform a distal cut in the femur of a patient, (ii) a main tab (1404) leaves the body and extends rearwardly; the main tab has a surface facing the bone (1140) has a negative contour -Custom and specific to the patient- configured to receive a portion of the distal end of the patient's femur that has a corresponding positive contour, (iii) an edge main (1408) extending upward from the end of the main flange; the leading edge has a surface facing the bone (1472) has a negative contour -Custom and specific to the patient- configured to receive a portion of a posterior side of a patient's femur that has a corresponding positive contour, and that characterized by the fact that the instrument includes: (iv) a secondary tab (1406) leaves the body and extends towards the back; secondary tab has a surface facing the bone (1442) has a negative contour -Custom and specific to the patient- configured to receive a portion of the distal end of the patient's femur that has a corresponding positive contour, so that the tab main and secondary tab create an opening (1405) including, (v) a side edge (1410) extending upward from the end of the secondary tab; the edge has a main surface facing the bone (1474) has a negative contour -Custom and specific to the patient- configured to accommodate a portion of the back side of the patient's femur that has a corresponding positive contour, in which the edge and the secondary edge (1408, 1410) have a blind slot (1484) extending laterally from the side which faces the bone and is in a plane transverse to the cutting slot (118) of the front body, so that the blind grooves can accommodate the distal end of a saw blade that is inserted through the cutting slot of the front body.

Instrumental personalized and specific orthopedic surgery for the patient

Let us reflect for a moment on the leading causes of death: cardiac disease , cancer and trauma. Imagine the following proposal from January 2003 the population of Melbourne and Sydney will be served by 2.5 and 3.0 full time equivalent (FTE) cardiologists. It has been suggested that the system will be very organized with excellent prehospital triage bringing patients with suspected myocardial infarction to either one of two hospitals in Melbourne, and one of six in Sydney. In Sydney the 3.0 FTE cardiologists will however only be working at 3 hospitals one in both Liverpool and Westmead, and one to be appointed to St George. It is felt however that the cardiologists will be able to oversee the care of all patients in their respective hospitals. There will of course be excellent links with the smaller hospitals, and good rural support and liaison. To help the cardiac departments each cardiologist will have a secretary and a part time case manager. To ensure that positions will be competitive there will only be a 300% reduction in salary compared to equivalent private practice specialist. This will result in a significant lower tax burden for the new postions.

Use of Recombinant Factor VIIa in a Patient with Recalcitrant Coagulopathy

Proactive and Integrated Management and Empowerment in Parkinson’s Disease protocol for a randomised controlled trial (PRIME-UK) to evaluate a new model of care

Introduction People with parkinsonism are a highly heterogeneous group and the disease encompasses a spectrum of motor and non-motor symptoms which variably emerge and manifest across the disease course, fluctuate over time and negatively impact quality of life. While parkinsonism is not directly the result of ageing, it is a condition that mostly affects older people, who may also be living with frailty and multimorbidity. This study aims to describe the broad range of health needs for people with parkinsonism and their carers in relation to their symptomatology, disability, disease stage, comorbidities and sociodemographic characteristics. Methods and analysis In this single site cross-sectional study, people with parkinsonism will be sent a study information pack for themselves and their primary informal caregiver, if relevant. Data are collected via questionnaire, with additional support, if required, to maximise participation. A specific strategy has been developed to target and proactively recruit patients lacking capacity to consent, including those in residential care settings, with input from a personal consultee prior to completion of a bespoke questionnaire by a representative. Caregivers are also recruited to look at various health outcomes. Results will be displayed as descriptive statistics and regression models will be used to test simple associations and interactions. Ethics and dissemination This protocol was approved by the London—Brighton & Sussex Research Ethics Committee (REC reference 20/LO/0890). The results of this protocol will be disseminated through publication in an international peer-reviewed journal; presentation at academic meetings and conferences; and a lay summary uploaded to the PRIME-Parkinson website. Trial registration number ISRCTN11452969; Pre-results.

Needs of patients with parkinsonism and their caregivers: a protocol for the PRIME-UK cross-sectional study

Stimulation of the Tibial nerve Repetitively to Improve Incontinence in Parkinson’s Electronically (STRIPE trial): a randomised control trial of tibial nerve stimulation for bladder symptoms in Parkinson’s disease using a self-contained wearable device

Neuromodulation : journal of the International Neuromodulation Society

Neuromodulation for Storage Lower Urinary Tract Symptoms in Parkinson Disease: A Systematic Review.

Summary Hyperpyrexia syndrome in Parkinson's disease (PD) is a medical emergency requiring prompt action. This can be precipitated by numerous provoking factors, in particular withdrawal of dopaminergic medication. We report a case of a patient with PD presenting with confusion, dramatic worsening of PD symptoms and pyrexia in the context of a heatwave, potentially mediating its effect through dehydration and impaired medication absorption. Precipitous cooling and conversion of dopaminergic medication to a rotigotine patch due to drowsiness led to her rapid improvement. The possibility of infection was covered however no source of infection or evidence of inflammatory response was found, but remained an important differential. This case highlights the importance of recognising and managing hyperpyrexia syndrome in PD and the possibility of uncharacteristically hot weather being a cause.

An unwell patient with Parkinson's disease: Hyperpyrexia syndrome in a heatwave

Hypothesis: Disrupted Regulation of the Intracranial Vascular and Cerebrospinal Fluid Circulations Causes Nocturia

Dementia is the most common neurodegenerative disorder globally. Disease progression is marked by declining cognitive function accompanied by changes in mobility. Increased sedentary behaviour and, conversely, wandering and becoming lost are common. Global positioning system (GPS) solutions are increasingly used by caregivers to locate missing people with dementia (PwD) but also offer a non-invasive means of monitoring mobility patterns in PwD. We performed a systematic search across five databases to identify papers published since 2000, where wearable or portable GPS was used to monitor mobility in patients with common dementias or mild cognitive impairment (MCI). Disease and GPS-specific vocabulary were searched singly, and then in combination, identifying 3004 papers. Following deduplication, we screened 1972 papers and retained 17 studies after a full-text review. Only 1/17 studies used a wrist-worn GPS solution, while all others were variously located on the patient. We characterised the studies using a conceptual framework, finding marked heterogeneity in the number and complexity of reported GPS-derived mobility outcomes. Duration was the most frequently reported category of mobility reported (15/17), followed by out of home (14/17), and stop and trajectory (both 10/17). Future research would benefit from greater standardisation and harmonisation of reporting which would enable GPS-derived measures of mobility to be incorporated more robustly into clinical trials.

Wearable and Portable GPS Solutions for Monitoring Mobility in Dementia: A Systematic Review

Abstract Gait dysfunction is a key defining feature of Parkinson’s disease (PD), and is associated with symptoms of freezing and an increased risk of falls. In this narrative review, we cover the putative mechanisms of gait dysfunction in PD, the assessment of gait abnormalities, and the management of symptoms caused by the inherent difficulty in walking. Our understanding of the causes of gait problems in PD has progressed in recent times, moving from neurocognitive theory to correlates of affected neuronal pathways. In particular, this can be shown to correspond with abnormalities in responses to dual-task paradigms and dysfunction in cholinergic signaling. Great progress has been made in the sophistication and precision of gait assessment; however, it has firmly remained in the research domain. There is significant momentum behind wearable technologies that can be used by patients in their own environment, acting as digital biomarkers that can not only reflect progression but also independently discriminate PD from non-PD individuals. The treatment of gait dysfunction has historically relied on physical therapies and training combined with a view to mitigating the impact of such consequences as falls. Pharmacological therapies that are the mainstay of treatment in PD have tended to address symptoms like bradykinesia; however, optimization of dopaminergic therapies likely has a positive effect on quality of gait. Other targets have been assessed with the goal of improving gait, of which medications that improve cholinergic signaling appear most promising. Neuromodulation techniques are increasingly used in the form of deep-brain stimulation; however, standard targets, such as the globus pallidus interna, have a modest effect on gait. Considerable benefit has been seen through targeting the pedunculopontine nucleus, and a dual-target approach may be warranted. Stimulation of the spinal cord and brain through direct or magnetic approaches has been assessed, but requires further evidence.

Current Perspectives on the Assessment and Management of Gait Disorders in Parkinson’s Disease

Neurodegenerative disorders (NDDs) constitute an increasing global burden and can significantly impair an individual’s mobility, physical activity (PA), and independence. Remote monitoring has been difficult without relying on diaries/questionnaires which are more challenging for people with dementia to complete. Wearable global positioning system (GPS) sensors and accelerometers present a cost-effective and noninvasive way to passively monitor mobility and PA. In addition, changes in sensor-derived outcomes (such as walking behaviour, sedentary, and active activity) may serve as potential biomarkers of disease onset, progression, and response to treatment. We performed a systematic search across four databases to identify papers published within the past 5 years, in which wearable GPS or accelerometers were used to monitor mobility or PA in patients with common NDDs (Parkinson’s disease, Alzheimer’s disease, motor neuron diseases/amyotrophic lateral sclerosis, vascular parkinsonism, and vascular dementia). Disease and technology-specific vocabulary were searched singly, and then in combination, identifying 4985 papers. Following deduplication, we screened 3115 papers and retained 28 studies following a full text review. One study used wearable GPS and accelerometers, while 27 studies used solely accelerometers in NDDs. GPS-derived measures had been validated against current gold standard measures in one Parkinson’s cohort, suggesting that the technology may be applicable to other NDDs. In contrast, accelerometers are widely utilised in NDDs and have been operationalised in well-designed clinical trials.

Wearable GPS and Accelerometer Technologies for Monitoring Mobility and Physical Activity in Neurodegenerative Disorders: A Systematic Review

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease and affects about 1% of the population over the age of 60 years in industrialised countries. The aim of this review is to examine nutrition in PD across three domains: dietary intake and the development of PD; whole body metabolism in PD and the effects of PD symptoms and treatment on nutritional status. In most cases, PD is believed to be caused by a combination of genetic and environmental factors and although there has been much research in the area, evidence suggests that poor dietary intake is not a risk factor for the development of PD. The evidence about body weight changes in both the prodromal and symptomatic phases of PD is inconclusive and is confounded by many factors. Malnutrition in PD has been documented as has sarcopaenia, although the prevalence of the latter remains uncertain due to a lack of consensus in the definition of sarcopaenia. PD symptoms, including those which are gastrointestinal and non-gastrointestinal, are known to adversely affect nutritional status. Similarly, PD treatments can cause nausea, vomiting and constipation, all of which can adversely affect nutritional status. Given that the prevalence of PD will increase as the population ages, it is important to understand the interplay between PD, comorbidities and nutritional status. Further research may contribute to the development of interventional strategies to improve symptoms, augment care and importantly, enhance the quality of life for patients living with this complex neurodegenerative disease.

How often are patients with progressive supranuclear palsy really falling?

Waking up from sleep more than once to pass urine, known as nocturia, is an important nonmotor symptom in Parkinson's disease (PD). Very little is known about the cause for nocturia. The aim of this work was to evaluate lower urinary tract (LUT) symptoms in patients with PD reporting nocturia using standardized validated questionnaires and bladder diaries and to assess the impact of nocturia on quality of life and sleep.

Bladder and Bowel Dysfunction Is Common in Both Men and Women with Mutation of the ABCD1 Gene for X-Linked Adrenoleukodystrophy.

Bladder and bowel dysfunction in female carriers of X-linked adrenomyeloneuropathy

A 45 year-old male presented with acute onset urinary retention. 1.8L of urine was catheterised in A&E and he was found to have low grade fever. He was started on ciprofloxacin and an alpha-blocker under the presumptive diagnosis of prostatitis but failed to void after 2 weeks and began reporting sweats and lower back pain. He was diagnosed with Human Immunodeficiency Virus (HIV) infection in the past but was not antiretrovirals; CD4 count was 350 cells/mm3 and viral load 22,000 copies/mL. Without a urological cause being established, a neurological review was requested and examination suggested absent third and fourth sacral dermatomal sensations and anal reflex. MRI revealed suspicious enhancement over the lower thoracic cord. CSF protein was 1.44 g/L, glucose 2.3 mmol/l, 62 leukocytes (60% mononuclear), negative acid-fast bacilli, TB PCR and culture, cryptococcal antigen, and viral PCR. CSF HIV viral load was 140,000 copies/mL. He was started empirically on four-drug anti-tuberculosis regimen and prednisolone. After 6 weeks he began to urinate and discharged without catheter. At 2 months, he reported no voiding difficulties. Urinary retention may occasionally be the only apparent manifestation of an underlying neurological condition. Our patient was found to have chronic meningitis and symptoms improved with treatment.

Urinary retention is a common problem, most often due to an anatomical lesion in the urinary tract causing obstruction, such as a urethral stricture or prostate enlargement. However, a subset of patients have no structural urological lesion, and so require neurological evaluation. We present a patient with acute urinary retention who was found to have chronic meningitis, and review the neurological causes for urinary retention.

A 20‐year‐old man with normal motor milestones as an infant but subsequent progressive difficulty in walking in childhood, was genetically confirmed to have Becker muscular dystrophy (BMD) at age 13. He was independent in ambulation and activities of daily living. He was referred to the Department of Uro‐neurology for a 5‐year history of urinary urgency and incontinence. He would visit the toilet 10 times in the daytime and experience urinary urgency daily, often associated with incontinence. He did not report difficulties initiating voiding, stress incontinence, pain, or hematuria. There was no history of urinary tract infections. Muscle Nerve 47:464‐465, 2013

Hypothesis / aims of study Parkinson’s Disease (PD) is often associated with “non-motor symptoms”, the commonest being nocturia which is reported in up to 60% of patients. Nocturia in PD is poorly understood, and the aim of this study was to evaluate patients reporting nocturia using bladder diaries and urinary symptom and sleep questionnaires. Study design, materials and methods In this prospective service evaluation, consecutive patients with Parkinson’s disease referred for lower urinary tract symptoms and reporting nocturia (defined as waking one or more times at night to void) were included. Patients underwent a standard evaluation including review of history and examination, bladder scan and prostate evaluation (males). Participants filled out a three-day bladder diary, the Urinary Symptom Profile (USP), International Prostate Symptom Score (IPSS), Qualiveen Short Form (SF-Qualiveen), and Parkinson's Disease Sleep Scale (PDSS) questionnaires.

Nocturnal polyuria is common in patients with Parkinson's disease who report nocturia

Stress incontinence may be associated with benign joint hypermobility syndrome (BJHS), highlighting the importance of inquiring about such symptoms in nulliparous women.

Stress urinary incontinence as the presenting complaint of benign joint hypermobility syndrome

Hypothesis / aims of study Adrenomyeloneuropathy (AMN) is a specific phenotype of the metabolic disorder X-linked adrenoleukodystrophy, presenting with progressive paraparesis linked to non-inflammatory degeneration of spinal tracts and peripheral nerves, as well as adrenal insufficiency 1 . Symptoms of bladder dysfunction have also been described as part of the X-ALD spectrum of disorders in an increasing collection of case reports and series’, and represent a set of symptoms correlating strongly with reduced quality of life tha t are potentially treatable. AMN is classically thought to affect males as a sex linked disorder. However it is increasingly recognised that females heterzygotic for the mutated ABCD1 gene may suffer a degree of similar symptoms to males with AMN, however without the endocrine elements of the disorder Our study set out to catalogue the extent of urinary and bowel symptoms in a significant group of patients attending a dedicated national AMN clinic.

Bladder and bowel dysfunction in X-linked adrenomyeloneuropathy: males and females are affected

Version anglaise dans la bibliotheque: Artificial intelligence and human development : toward a research agenda

Intelligence artificielle et développement humain : vers un programme de recherche

A search for new phenomena in final states containing an $e^+e^-$ or $\mu^+\mu^-$ pair, jets, and large missing transverse momentum is presented. Thisadditional_resources: analysis makes use of proton-proton collision data, collected during 2015 and 2016 at a centre-of-mass energy $\sqrt{s}=13$ TeV with the ATLAS detector at the Large Hadron Collider, which corresponds to an integrated luminosity of 36.1 fb$^{-1}$. The search targets the pair production of supersymmetric coloured particles, squarks or gluinos, and their decays to final states containing an $e^+e^-$ or $\mu^+\mu^-$ pair and the lightest neutralino ($\tilde{\chi}_1^0$) via one of two next-to-lightest neutralino ($\tilde{\chi}_2^0$) decay mechanisms: $\tilde{\chi}_2^0 \rightarrow Z \tilde{\chi}_1^0$, where the $Z$ boson decays leptonically leading to a peak in the dilepton invariant mass distribution around the $Z$ boson mass; and $\tilde{\chi}_2^0 \rightarrow \ell^+\ell^- \tilde{\chi}_1^0$ with no intermediate $\ell^+\ell^-$ resonance, yielding a kinematic endpoint in the dilepton invariant-mass spectrum. The data are found to be consistent with the Standard Model expectation. Results are interpreted using simplified models, and exclude gluinos and squarks with masses as large as 1.85 TeV and 1.3 TeV at 95% confidence level, respectively.

L'invention concerne un agencement de pompe auto-lubrifiante qui comprend un agencement de guidage d'ecoulement de fluide concu pour acheminer le fluide du cote d'aspiration au cote d'evacuation de la pompe, et un agencement de guidage de fluide redirige concu pour acheminer une partie de l'ecoulement de fluide sortant qui est evacue et pour rediriger cette partie de l'ecoulement du fluide pour lubrifier l'arbre d'entrainement responsable de l'action de pompage de l'agencement de pompe auto-lubrifiante.

La presente invention concerne un distributeur de liquide qui comprend, d'une part un tube exterieur (2) a la paroi laterale pourvue d'un orifice de decharge, et d'autre part un tube interieur (4) partiellement recu a l'interieur du tube exterieur avec lequel il definit un espace annulaire accueillant un element d'etancheite annulaire (20) formant un joint peripherique entre le tube interieur et le tube exterieur. L'autre extremite du tube exterieur est concue pour se raccorder a un recipient a liquide. La paroi du tube interieur comporte un orifice d'ecoulement du liquide (30). Le tube interieur est mobile longitudinalement a l'interieur du tube exterieur entre une position ouverte, dans laquelle l'orifice d'ecoulement du liquide communique avec l'orifice de decharge (14), et une position fermee dans laquelle le passage d'ecoulement de liquide est hermetiquement ferme. Le tube interieur comporte un passage d'ecoulement d'air a deux extremites agence de facon qu'en position ouverte du tube interieur, l'une des extremites communique avec l'orifice de decharge et le passage d'ecoulement d'air.

L'invention concerne un procede d'encliquetage de couvercle sur un recipient (2) comprenant un col definissant le goulot du recipient, un epaulement dirige vers le bas (14) etant forme sur la surface exterieure dudit col. Ledit couvercle comprend egalement une plaque de fermeture (30, 32) reliee a une jupe peripherique dependante (18), une bride de retenue (20) etant reliee a cette jupe par une charniere souple (22). Le procede selon l'invention consiste a deplacer le couvercle et le recipient l'un vers l'autre, de sorte a mettre la bride de retenue (20) en contact avec le bord superieur du col (8), ce qui entraine la rotation de la bride (20) autour de la charniere (22) jusqu'a ce que l'extremite libre de la bride (20) depasse l'epaulement (14). La bride de retenue (20) est ensuite mise en rotation dans le sens oppose, en direction du col (8) du recipient, grâce a la souplesse de la charniere, et elle vient en contact en dessous de l'epaulement (14), ce qui permet de limiter le mouvement respectif du couvercle et du recipient lorsqu'ils s'eloignent l'un de l'autre. La surface laterale de l'extremite libre de la bride de retenue (20) est sollicitee en contact de fermeture avec la surface exterieure du col (8), grâce a la souplesse de la charniere (22), et l'extremite libre de la bride de retenue (20) est mise en contact de fermeture avec l'epaulement (14), par la contrainte de tension exercee dans la jupe (18), provoquee par la deformation du bouchon venant en contact avec la surface superieure du rebord (8).

Le connecteur electrique cylindrique selon l'invention, constitue d'une partie de connecteur formant fiche (1) et d'une partie de connecteur complementaire formant embase (15), laquelle recoit en accouplement de connexion electrique ladite partie formant fiche (1), est caracterise en ce que la partie de contact de la fiche est constituee d'au moins deux surfaces conductrices coaxiales (9a, 9b) et la partie de contact de l'embase comprend au moins deux autres surfaces conductrices (17a, 17b) complementaires desdites surfaces conductrices de la fiche et les recevant en contact de legere pression lors de l'enfichage d'accouplement de la fiche dans l'embase, lesdites surfaces de contact de la fiche et de l'embase etant adaptees en surface de contact d'accouplement a la quantite de courant ou au nombre de courants a transmettre par le connecteur.

Partant du probleme theorique du personnage romanesque, l'etude se confronte a l'episteme d'une autre epoque, et a l'œuvre de Jane Austen. L'inventaire de l'analyse stucturaliste du personnage est dresse. Si certaines notions restent valables, la semiotique reste dans l'en-deca du sens, et l'outil analytique de l'epreuve n'est operatoire qu'en connaissant les contrats axiologiques, culturels, et politiques qui cadrent le personnage. Ceux-ci sont explores en detail, faisant apparaitre les epreuves et les luttes qui construisent les personnages d'Austen. Sa distance ironique s'avere complementaire au didactisme plutot que subversif. Le personnage austenien est egalement codifie par le genre comique et par ses rapoorts avec la cohesion sociale et avec les paradigmes caracterologiques. Un classement exhaustif des occurrences du terme " character " dans l'œuvre revele un auteur lucide quant aux aspects narratifs, sociaux et politiques du concept, mais essentiellement conservateur modere.

Représentation et instrumentalisation du sujet narratif : "character" chez Jane Austen

Monitoring cerebral autoregulation at the respiration rate using near-infrared spectroscopy

Goal: Cerebrovascular impedance is modulated by a vasoactive autoregulative mechanism in response to changes in cerebral perfusion pressure. Characterization of impedance and the limits of autoregulation are important biomarkers of cerebral health. We developed a method to quantify impedance based on the spectral content of cerebral blood flow and volume at the cardiac frequency, measured with diffuse optical methods. Methods: In three non-human primates, we modulated cerebral perfusion pressure beyond the limits of autoregulation. Cerebral blood flow and volume were measured with diffuse correlation spectroscopy and near-infrared spectroscopy, respectively. Results: We show that impedance can be used to identify the lower and upper limits of autoregulation. Conclusions: This impedance method may be an alternative method to measure autoregulation and a way of assessing cerebral health non-invasively at the clinical bedside.

Cerebrovascular Impedance as a Function of Cerebral Perfusion Pressure

Biophotonics Congress: Biomedical Optics 2022 (Translational, Microscopy, OCT, OTS, BRAIN)

Estimation of Intracranial Pressure Using Cardiac Pulse Waveform Features with Near Infrared Spectroscopy

[This corrects the article on p. 1462 in vol. 11, PMID: 32206422.].

Erratum: Estimating intracranial pressure using pulsatile cerebral blood flow measured with diffuse correlation spectroscopy: erratum.

Near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS) measure cerebral hemodynamics, which in turn can be used to assess the cerebral metabolic rate of oxygen (CMRO2) and cerebral autoregulation (CA). However, current mathematical models for CMRO2 estimation make assumptions that break down for cerebral perfusion pressure (CPP)-induced changes in CA. Here, we performed preclinical experiments with controlled changes in CPP while simultaneously measuring NIRS and DCS at rest. We observed changes in arterial oxygen saturation (~10%) and arterial blood volume (~50%) with CPP, two variables often assumed to be constant in CMRO2 estimations. Hence, we propose a general mathematical model that accounts for these variations when estimating CMRO2 and validate its use for CA monitoring on our experimental data. We observed significant changes in the various oxygenation parameters, including the coupling ratio (CMRO2/blood flow) between regions of autoregulation and dysregulation. Our work provides an appropriate model and preliminary experimental evidence for the use of NIRS- and DCS-based tissue oxygenation and metabolism metrics for non-invasive diagnosis of CA health in CPP-altering neuropathologies.

Non-Invasive Spectroscopy for Measuring Cerebral Tissue Oxygenation and Metabolism as a Function of Cerebral Perfusion Pressure

Cerebral autoregulation ensures a stable average blood supply to brain tissue across steady state cerebral perfusion pressure (CPP) levels. Neurovascular coupling, in turn, relies on sufficient blood flow to meet neuronal demands during activation. These mechanisms break down in pathologies where extreme levels of CPP can cause dysregulation in cerebral blood flow. Here, we experimentally tested the influence of changes in CPP on neurovascular coupling in a hydrocephalus-type non-human primate model (n = 3). We recorded local neural and vascular evoked responses to a checkerboard visual stimulus, non-invasively, using electroencephalography and near-infrared spectroscopy respectively. The evoked signals showed changes in various waveform features in the visual evoked potentials and the hemodynamic responses, with CPP. We further used these signals to fit for a hemodynamic response function (HRF) to describe neurovascular coupling. We estimated n = 26 distinct HRFs at a subset of CPP values ranging from 40–120 mmHg across all subjects. The HRFs, when compared to a subject dependent healthy baseline (CPP 70–90 mmHg) HRF, showed significant changes in shape with increasing CPP (ρCPP = −0.55, p-valueCPP = 0.0049). Our study provides preliminary experimental evidence on the relationship between neurovascular coupling and CPP changes, especially when beyond the limits of static autoregulation.

Changes in neurovascular coupling with cerebral perfusion pressure indicate a link to cerebral autoregulation

Purpose Lamina cribrosa (LC) deformations caused by elevated intraocular pressure (IOP) are believed to contribute to glaucomatous neuropathy and have therefore been extensively studied, in many conditions from in-vivo to ex-vivo. We compare acute IOP-induced global and local LC deformations immediately before (pre-mortem) and after (post-mortem) sacrifice by exsanguination. Methods The optic nerve heads of three healthy monkeys 12-15 years old were imaged with spectral-domain optical coherence tomography under controlled IOP pre-mortem and post-mortem. Volume scans were acquired at baseline IOP (8-10 mmHg) and at 15, 30, and 40 mmHg IOP. A digital volume correlation technique was used to determine the IOP-induced 3D LC deformations (strains) in regions visible pre-mortem and post-mortem. Results Both conditions exhibited similar nonlinear relationships between IOP increases and LC deformations. Median effective and shear strains were, on average over all eyes and pressures, smaller post-mortem than pre-mortem, by 14% and 11%, respectively (P’s < 0.001). Locally, however, the differences in LC deformation between conditions were variable. Some regions were subjected pre-mortem to triple the strains observed post-mortem, and others suffered smaller deformations pre-mortem than post-mortem. Conclusions Increasing IOP acutely caused nonlinear LC deformations with an overall smaller effect post-mortem than pre-mortem. Locally, deformations pre-mortem and post-mortem were sometimes substantially different. We suggest that the differences may be due to weakened mechanical support from the unpressurized central retinal vessels post-mortem. Translational Relevance Additional to the important pre-mortem information, comparison with post-mortem provides a unique context essential to understand the translational relevance of all post-mortem biomechanics literature. Precis The authors compared in monkeys acute IOP-induced deformations of the lamina cribrosa pre-mortem and post-mortem. Deformation trends were similar pre-mortem and post-mortem, but deformations pre-mortem were generally smaller than those post-mortem, with substantial local variations. The differences are likely due to loss of vessel support post-mortem.

Comparing Acute IOP-Induced Lamina Cribrosa Deformations Premortem and Postmortem

Optical methods for non-invasive assessment of cerebral microvascular flow impedance

Abstract. Significance Intracranial pressure (ICP) measurements are important for patient treatment but are invasive and prone to complications. Noninvasive ICP monitoring methods exist, but they suffer from poor accuracy, lack of generalizability, or high cost. Aim We previously showed that cerebral blood flow (CBF) cardiac waveforms measured with diffuse correlation spectroscopy can be used for noninvasive ICP monitoring. Here we extend the approach to cardiac waveforms measured with near-infrared spectroscopy (NIRS). Approach Changes in hemoglobin concentrations were measured in eight nonhuman primates, in addition to invasive ICP, arterial blood pressure, and CBF changes. Features of average cardiac waveforms in hemoglobin and CBF signals were used to train a random forest (RF) regressor. Results The RF regressor achieves a cross-validated ICP estimation of 0.937r2, 2.703-mmHg2 mean squared error (MSE), and 95% confidence interval (CI) of   [    −  3.064  3.160  ]    mmHg on oxyhemoglobin concentration changes; 0.946r2, 2.301-mmHg2 MSE, and 95% CI of   [    −  2.841  2.866  ]    mmHg on total hemoglobin concentration changes; and 0.963r2, 1.688  mmHg2 MSE, and 95% CI of   [    −  2.450  2.397  ]    mmHg on CBF changes. Conclusions This study provides a proof of concept for the use of NIRS in noninvasive ICP estimation.

Using near-infrared spectroscopy and a random forest regressor to estimate intracranial pressure

Changes in Cerebral Metabolic Rate of Oxygen with Cerebral Perfusion Pressure

The brain's ability to maintain cerebral blood flow approximately constant despite cerebral perfusion pressure changes is known as cerebral autoregulation (CA) and is governed by vasoconstriction and vasodilation. Cerebral perfusion pressure is defined as the pressure gradient between arterial blood pressure and intracranial pressure. Measuring CA is a challenging task and has created a variety of evaluation methods, which are often categorized as static and dynamic CA assessments. Because CA is quantified as the performance of a regulatory system and no physical ground truth can be measured, conflicting results are reported. The conflict further arises from a lack of healthy volunteer data with respect to cerebral perfusion pressure measurements and the variety of diseases in which CA ability is impaired, including stroke, traumatic brain injury and hydrocephalus. To overcome these differences, we present a healthy non-human primate model in which we can control the ability to autoregulate blood flow through the type of anesthesia (isoflurane vs fentanyl). We show how three different assessment methods can be used to measure CA impairment, and how static and dynamic autoregulation compare under challenges in intracranial pressure and blood pressure. We reconstructed Lassen's curve for two groups of anesthesia, where only the fentanyl anesthetized group yielded the canonical shape. Cerebral perfusion pressure allowed for the best distinction between the fentanyl and isoflurane anesthetized groups. The autoregulatory response time to induced oscillations in intracranial pressure and blood pressure, measured as the phase lag between intracranial pressure and blood pressure, was able to determine autoregulatory impairment in agreement with static autoregulation. Static and dynamic CA both show impairment in high dose isoflurane anesthesia, while low isoflurane in combination with fentanyl anesthesia maintains CA, offering a repeatable animal model for CA studies.

Comparison of static and dynamic cerebral autoregulation under anesthesia influence in a controlled animal model.

Interplay between intraocular and intracranial pressure effects on the optic nerve head in vivo.

Intracranial pressure estimated non-invasively in non-human primates and pediatric critical care (Conference Presentation)

Measuring intracranial pressure (ICP) is necessary for the treatment of severe head injury but measurement systems are highly invasive and introduce risk of infection and complications. We developed a non-invasive alternative for quantifying ICP using measurements of cerebral blood flow (CBF) by diffuse correlation spectroscopy. The recorded cardiac pulsation waveform in CBF undergoes morphological changes in response to ICP changes. We used the pulse shape to train a randomized regression forest to estimate the underlying ICP and demonstrate in five non-human primates that DCS-based estimation can explain over 90% of the variance in invasively measured ICP.

Estimating intracranial pressure using pulsatile cerebral blood flow measured with diffuse correlation spectroscopy.

Intracranial pressure (ICP) has been proposed to play an important role in the sensitivity to intraocular pressure (IOP) and susceptibility to glaucoma. However, the in vivo effects of simultaneous, controlled, acute variations in ICP and IOP have not been directly measured. We quantified the deformations of the anterior lamina cribrosa (ALC) and scleral canal at Bruch’s membrane opening (BMO) under acute elevation of IOP and/or ICP. Four eyes of three monkeys were imaged in vivo with OCT under four pressure conditions: IOP and ICP either at baseline or elevated. The BMO and ALC were reconstructed from manual delineations. From these, we determined canal area at the BMO (BMO area), BMO aspect ratio and planarity, and ALC median depth relative to the BMO plane. To better account for the pressure effects on the imaging, we also measured ALC visibility as a percent of the BMO area. Further, ALC depths were analyzed only in regions where the ALC was visible in all pressure conditions. Bootstrap sampling was used to obtain mean estimates and confidence intervals, which were then used to test for significant effects of IOP and ICP, independently and in interaction. Response to pressure manipulation was highly individualized between eyes, with significant changes detected in a majority of the parameters. Significant interactions between ICP and IOP occurred in all measures, except ALC visibility. On average, ICP elevation expanded BMO area by 0.17mm2 at baseline IOP, and contracted BMO area by 0.02 mm2 at high IOP. ICP elevation decreased ALC depth by 10μm at baseline IOP, but increased depth by 7 μm at high IOP. ALC visibility decreased as ICP increased, both at baseline (−10%) and high IOP (−17%). IOP elevation expanded BMO area by 0.04 mm2 at baseline ICP, and contracted BMO area by 0.09 mm2 at high ICP. On average, IOP elevation caused the ALC to displace 3.3 μm anteriorly at baseline ICP, and 22 μm posteriorly at high ICP. ALC visibility improved as IOP increased, both at baseline (5%) and high ICP (8%). In summary, changing IOP or ICP significantly deformed both the scleral canal and the lamina of the monkey ONH, regardless of the other pressure level. There were significant interactions between the effects of IOP and those of ICP on LC depth, BMO area, aspect ratio and planarity. On most eyes, elevating both pressures by the same amount did not cancel out the effects. Altogether our results show that ICP affects sensitivity to IOP, and thus that it can potentially also affect susceptibility to glaucoma. Research Highlights - In vivo ONH deformations caused by acute, controlled, simultaneous changes in IOP and/or ICP can be directly visualized and measured in the monkey eye using OCT. - Acute changes of either IOP or ICP significantly deformed both the scleral canal and the lamina cribrosa, regardless of the other pressure level. - Pressures interacted, meaning that the effects of one pressure depended significantly on the level of the other pressure. - Elevating both pressures did not cancel out the effects of one of them being elevated. - Our results show that ICP affects sensitivity to IOP, and thus that it can potentially also affect susceptibility to glaucoma.

Interplay between intraocular and intracranial pressure effects on the optic nerve head in vivo

Role of cerebrovascular autoregulation in neurovascular coupling (Conference Presentation)

Measurements of static and dynamic cerebral autoregulation were performed in nonhuman primates. Comparison of changes in intracranial and arterial blood pressure are discussed for their influence on autoregulatory responses measured non-invasively with diffuse optical instruments.

Biophotonics Congress: Biomedical Optics 2020 (Translational, Microscopy, OCT, OTS, BRAIN)

Comparison of Dynamic and Static Assessment of Cerebral Autoregulation in Non-Human Primates

Measuring intracranial pressure (ICP) is typically a highly invasive procedure, in which a ventricular catheter or pressure sensor is placed into the brain. To improve the availability of ICP measurements in non-intensive care patients and research and to reduce the invasiveness and underlying risks of ICP sensing, we developed a non-invasive method to measure ICP with Diffuse Correlation Spectroscopy (DCS) and machine learning. ICP baseline changes were induced in non-human primates (Macaca mulatta) through adjusting the height of a saline reservoir connected to the lateral ventricle via a catheter. ICP was precisely measured with an invasive parenchymal pressure sensor. Cerebral blood flow (CBF) was measured with DCS. The DCS system was operated by a software correlator able to resolve cardiac pulse waves at a sampling rate of 100Hz. To increase signal-to-noise ratio, multiple cardiac pulse waves in CBF were averaged based on systolic peak maximum in invasively measured arterial blood pressure. We hypothesized that the cerebral blood flow pulse waves will change their shape with increasing ICP. The shape of the curve was expressed in numerical features and passed into a regression forest training algorithm. Preliminary results show successful prediction of underlying ICP baselines by the decision forest in one animal. The prediction of non-invasive ICP was achieved with a sampling rate of 1 Hz, an equivalent of about 120 averaged pulses. A larger data set for increased generalizability is the next step to push this approach further.

Diffuse correlation spectroscopy for intracranial pressure estimation through cardiac pulse waveform analysis

Guiding treatment in traumatic brain injury based on managing and optimizing cerebral perfusion pressure, which is the difference between mean arterial blood pressure and intracranial pressure (ICP), has been demonstrated to improve patient outcome. However, this requires ICP to be measured, which currently is only possible by placing pressure probes inside the brain. The feasibility of optical systems to measure ICP non-invasively has shown preliminary promising evidence of feasibility. To pursue the goal of non-invasive ICP acquisition further, an understanding of the influence of different pressure changes on the brain and their hemodynamic response is necessary. To investigate the frequency content of hemodynamic reactions to pressure changes in both ICP as well as arterial blood pressure (ABP), we induced changes of both pressures in non-human primates. We then demonstrate that ABP and ICP changes both influence cerebral blood flow and hemoglobin concentrations, measured with diffuse correlation spectroscopy (DCS) and near-infrared spectroscopy (NIRS), respectively. We found that the magnitude of induced oscillations is dependent on the frequency of the oscillation. Our data suggests, changes in ABP and ICP influence the hemodynamics differently, which we can use as a basis for non-invasive ICP measurements.

Frequency dependent hemodynamic response to intracranial pressure changes

Low-cost high temporal resolution diffuse correlation spectroscopy (Conference Presentation)

Intracranial pressure (ICP) is typically measured invasively through a sensor placed inside the brain or a needle inserted into the spinal canal, limiting the patient population on which this assessment can be performed. Currently, non-invasive methods are limited due to lack of sensitivity and thus only apply to extreme cases of increased ICP, instead of use in general clinical practice. We demonstrate a novel application for near-infrared spectroscopy (NIRS) to accurately estimate ICP changes over time. Using a non-human primate (Rhesus Macaque) model, we collected optical data while we induced ICP oscillations at multiple ICP levels obtained by manipulating the height of a fluid column connected via a catheter to the lateral ventricle. Hemodynamic responses to ICP changes were measured at the occipital pole and compared to changes detected by a conventional intraparenchymal ICP probe. We demonstrate that hemoglobin concentrations are highly correlated with induced ICP oscillations and that this response is frequency dependent. We translated the NIRS data into non-invasive ICP measurements via a fitted non-parametric transfer function, demonstrating a match in both magnitude and time alignment with an invasively measured reference. Our results demonstrate that NIRS has the potential for non-invasive ICP monitoring.

Fluctuations in intracranial pressure can be estimated non-invasively using near-infrared spectroscopy in non-human primates

Huong Tran, Jacob Wallace, Ziyi Zhu, Katie A. Lucy, Andrew P. Voorhees, Samantha E. Schmitt, Richard A. Bilonick, Joel S. Schuman, Matthew A. Smith, Gadi Wollstein, and Ian A. Sigal Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, United States Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States New York University Langone Eye Center, NYU School of Medicine, New York, New York, United States

Glaucoma Seeing the Hidden Lamina : Effects of Exsanguination on the Optic Nerve Head

In-Vivo Macro and Micro-Structure Optic Nerve Head Deformations Due to Gaze and Intracranial Pressure Changes

Purpose To introduce an experimental approach for direct comparison of the primate optic nerve head (ONH) before and after death by exsanguination. Method The ONHs of four eyes from three monkeys were imaged with spectral-domain optical coherence tomography (OCT) before and after exsanguination under controlled IOP. ONH structures, including the Bruch membrane (BM), BM opening, inner limiting membrane (ILM), and anterior lamina cribrosa (ALC) were delineated on 18 virtual radial sections per OCT scan. Thirteen parameters were analyzed: scleral canal at BM opening (area, planarity, and aspect ratio), ILM depth, BM depth; ALC (depth, shape index, and curvedness), and ALC visibility (globally, superior, inferior, nasal, and temporal quadrants). Results All four ALC quadrants had a statistically significant improvement in visibility after exsanguination (overall P < 0.001). ALC visibility increased by 35% globally and by 36%, 37%, 14%, and 4% in the superior, inferior, nasal, and temporal quadrants, respectively. ALC increased 4.1%, 1.9%, and 0.1% in curvedness, shape index, and depth, respectively. Scleral canals increased 7.2%, 25.2%, and 1.1% in area, planarity, and aspect ratio, respectively. ILM and BM depths averaged −7.5% and −55.2% decreases in depth, respectively. Most, but not all, changes were beyond the repeatability range. Conclusions Exsanguination allows for improved lamina characterization, especially in regions typically blocked by shadowing in OCT. The results also demonstrate changes in ONH morphology due to the loss of blood pressure. Future research will be needed to determine whether there are differences in ONH biomechanics before and after exsanguination and what those differences would imply.

Seeing the Hidden Lamina: Effects of Exsanguination on the Optic Nerve Head

The physiological relationship between electroencephalography (EEG), intercranial pressure (ICP), and cerebral hemodynamics is poorly understood. Here we demonstrate work in correlating EEG with hemodynamic responses during burst-suppression states in non-human primates.

Correlation of EEG with Intercranial Pressure and Cerebral Hemodynamics during Burst-Supression

Measuring intracranial pressure (ICP) is a highly invasive procedure. We show ICP changes calculated from non-invasive near-infrared spectroscopy-measured hemodynamics, using non-parametric transfer function analysis in a hydrocephalus model on non-human primates.

Intracranial Pressure Changes Derived from Near Infrared Spectroscopy Measurements in Non-Human Primates

Elevated intraocular pressure (IOP) deforms the lamina cribrosa (LC), a structure within the optic nerve head (ONH) in the back of the eye. Evidence suggests that these deformations trigger events that eventually cause irreversible blindness, and have therefore been studied in-vivo using optical coherence tomography (OCT), and ex-vivo using OCT and a diversity of techniques. To the best of our knowledge, there have been no in-situ ex-vivo studies of LC mechanics. Our goal was two-fold: to introduce a technique for measuring 3D LC deformations from OCT, and to determine whether deformations of the LC induced by elevated IOP differ between in-vivo and in-situ ex-vivo conditions. A healthy adult rhesus macaque monkey was anesthetized and IOP was controlled by inserting a 27- gauge needle into the anterior chamber of the eye. Spectral domain OCT was used to obtain volumetric scans of the ONH at normal and elevated IOPs. To improve the visibility of the LC microstructure the scans were first processed using a novel denoising technique. Zero-normalized cross-correlation was used to find paired corresponding locations between images. For each location pair, the components of the 3D strain tensor were determined using non-rigid image registration. A mild IOP elevation from 10 to 15mmHg caused LC effective strains as large as 3%, and about 50% larger in-vivo than in-situ ex-vivo. The deformations were highly heterogeneous, with substantial 3D components, suggesting that accurate measurement of LC microstructure deformation requires high-resolution volumes. This technique will help improve understanding of LC biomechanics and how IOP contributes to glaucoma.

Measuring in-vivo and in-situ ex-vivo the 3D deformation of the lamina cribrosa microstructure under elevated intraocular pressure

Combined NIRS and DCS measurements of cerebral hemodynamics during intracranial and blood pressure changes (Conference Presentation)

Formalin Fixation and Cryosectioning Cause Only Minimal Changes in Shape or Size of Ocular Tissues

There is increasing clinical evidence that the eye is not only affected by intraocular pressure (IOP), but also by intracranial pressure (ICP). Both pressures meet at the optic nerve head of the eye, specifically the lamina cribrosa (LC). The LC is a collagenous meshwork through which all retinal ganglion cell axons pass on their way to the brain. Distortion of the LC causes a biological cascade leading to neuropathy and impaired vision in situations such as glaucoma and idiopathic intracranial hypertension. While the effect of IOP on the LC has been studied extensively, the coupled effects of IOP and ICP on the LC remain poorly understood. We investigated in-vivo the effects of IOP and ICP, controlled via cannulation of the eye and lateral ventricle in the brain, on the LC microstructure of anesthetized rhesus monkeys eyes using the Bioptigen spectral-domain optical coherence tomography (OCT) device (Research Triangle, NC). The animals were imaged with their head upright and the rest of their body lying prone on a surgical table. The LC was imaged at a variety of IOP/ICP combinations, and microstructural parameters, such as the thickness of the LC collagenous beams and diameter of the pores were analyzed. LC microstructure was confirmed by histology. We determined that LC microstructure deformed in response to both IOP and ICP changes, with significant interaction between the two. These findings emphasize the importance of considering both IOP and ICP when assessing optic nerve health.

In-vivo effects of intraocular and intracranial pressures on the lamina cribrosa microstructure

Lamina cribrosa shape is different between humans and monkeys at baseline IOP and is changed differently with IOP elevations

Purpose To evaluate changes in monkey optic nerve head (ONH) morphology under acutely controlled intraocular pressure (IOP) and intracranial pressure (ICP). Methods Seven ONHs from six monkeys were imaged via optical coherence tomography while IOP and ICP were maintained at one of 16 conditions. These conditions were defined by 4 levels for each pressure: low, baseline, high and very high. Images were processed to determine scleral canal area, aspect ratio, and planarity and anterior lamina cribrosa (ALC) shape index and curvature. Linear mixed effect models were utilized to investigate the effects of IOP, ICP and their interactions on ONH morphological features. The IOP-ICP interaction model was compared with one based on translaminar pressure difference (TLPD). Results We observed complex, eye-specific, non-linear patterns of ONH morphological changes with changes in IOP and ICP. For all ONH morphological features, linear mixed effects models demonstrated significant interactions between IOP and ICP that were unaccounted for by TLPD. Interactions indicate that the effects of IOP and ICP depend on the other pressure. The IOP-ICP interaction model was a higher quality predictor of ONH features than a TLPD model. Conclusions In vivo modulation of IOP and ICP causes nonlinear and non-monotonic changes in monkey ONH morphology that depend on both pressures and is not accounted for by a simplistic TLPD. These results support and extend prior findings. Translational Relevance: A better understanding of ICP’s influence on the effects of IOP can help inform the highly variable presentations of glaucoma and effective treatment strategies.

In vivo Modulation of Intraocular and Intracranial Pressures Causes Nonlinear and Non-monotonic Deformations of the Lamina Cribrosa and Scleral Canal

High-resolution mapping of in-vivo stretch and compression of the lamina cribrosa in response to acute changes in intraocular and/or intracranial pressures

In-vivo 3D Deformation of Lamina Cribrosa Microstructure in Response to Acute Changes in Intraocular and Cerebrospinal Fluid Pressures

In-Vivo Laminar and Scleral Canal Displacements During Acute Intracranial and Intraocular Pressure Elevation in Monkeys

In vivo Visualization of Posterior Lamina Cribrosa (LC) using SD-OCT Validated with Histology

Introduction Nocturia is the commonest non-motor symptom of Parkinson's Disease (PD), having significant impact on sleep and quality of life. The cause for nocturia in PD is poorly understood; this study evaluates factors contributing to nocturia. Methods This was a cross-sectional survey of consecutive patients with PD referred for nocturia. Information about PD and medications were collected. Factors contributing to nocturia were evaluated, and questionnaires assessing bladder symptoms, quality of life, sleep and a 3 day bladder diary measuring voided volumes were filled. Results 23 patients participated (mean age 68.5 years, mean duration of PD 10.1 years, mean Hoehn and Yahr staging 3.0). 21 (91.3%) had moderate to severe bladder symptoms and in all, symptoms had a significant impact on quality of life. Bladder diaries revealed that 18 patients (78.3%) had nocturnal polyuria (NP, defined as >33% of urine output at night) (range 17.8–81.1%, mean 46.9%). 8 (34.7%) produced >50% of their urine output at night. Patients with NP more often had longer duration of disease and severity. Of patients with orthostatic hypotension (n=5), four had NP. Patients with NP had less overall fluid intake, increased mean nocturnal voided volume, worse overall bladder symptoms, worse quality of sleep and greater impact on quality of life from bladder symptoms. Conclusion In this preliminary study, nocturnal polyuria is likely to be an important factor contributing to nocturia in PD.

NOCTURNAL POLYURIA IN PARKINSON'S DISEASE PATIENTS PRESENTING WITH NOCTURIA

Social networks are typically constructed around an explicit and well-defined relationship among individuals. In this paper, we describe another class of social networks, known as Implicit Affinity Networks (IANs), where links are implicit in the patterns of natural affinities among individuals. Preliminary results with two Web communities, one focused on people's interests and one focused on people's blogs, exhibit rich dynamics and show interesting patterns of community evolution.

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz

Using Shapley values to assess the impact of temporary traffic restrictions on NO2 levels in Madrid urban area

We report the fabrication of hollow waveguide structures with various core geometries. These structures are suitable for low-loss anti-resonant reflecting (ARROW) and photonic crystal waveguides, and integration with microfluidic systems.

Hollow waveguides on planar substrates with selectable geometry cores

We discuss diierent methods of reducing symmetry in CSPs where the variables correspond to the cells of a matrix, and both the rows and the columns of the matrix are interchangeable. Two basic approaches are considered: adding symmetry-breaking constraints to the model, and breaking symmetry during search. We also show how the two approaches can be combined in this case. We empirically compare several diierent approximations to eliminating the symmetry and an exact method that eliminates the symmetry completely, but is only feasible for small matrices.

An experimental investigation into the operation of an electrically heated tobacco system

An active contour ImageJ plugin to monitor daughter cell size in 3D during cytokinesis.

A60. LET'S MEET AT DUPONT CIRCLE: NEW MOLECULAR TRAFFIC PATTERNS IN PULMONARY HYPERTENSION

The Mitochondrial Protein Mitoneet and Its Involvement With Iron Homeostasis and Metabolic Regulation in Pulmonary Hypertension

Eustachian tube (ET) dysfunction is a common but poorly understood cause of patient symptoms, and an important aetiological factor in the development of middle ear pathology. Despite this, there are no specific tests of ET function in widespread clinical use and no identified ‘gold standard’ with which to diagnose the disease.

 Introduction: Blacks/African-Americans (B/AAs) are disproportionately affected by prostate cancer, with higher incidence and mortality rates versus other racial/ethnic groups. Darolutamide (DARO) is a structurally distinct and highly potent androgen receptor inhibitor. In the ARASENS trial (NCT02799602), DARO in combination with androgen-deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5% (HR, 0.68; 95% CI 0.57–0.80; P<0.001) vs placebo (PBO) + ADT with docetaxel in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC). We present efficacy and safety of DARO + ADT and docetaxel in B/AAs from ARASENS. Methods: Pts with mHSPC were randomized 1:1 to DARO 600 mg or PBO twice daily in combination with ADT and docetaxel. The primary endpoint was overall survival (OS). Key secondary endpoints included time to castration-resistant prostate cancer (CRPC) and safety. Results: In ARASENS, 54 B/AAs received DARO (n=26) or PBO (n=28); 36/244 (14.8%) patients recruited in North America were B/AA. Baseline characteristics in the B/AA population were generally similar compared with the overall population, except for the proportion of pts who were <65 years of age (57.4% vs 36.6%), had ECOG performance status of 1 (37.0% vs 28.7%) and recurrent disease (24.1% vs 12.9%). Median prostate-specific antigen levels were similar (35.9 vs 27.6 μg/L), but alkaline phosphatase levels were lower in B/AAs (109.5 vs 143.0 U/L) vs all patients. In B/AAs, OS favored DARO + ADT + docetaxel vs PBO + ADT + docetaxel (stratified HR, 0.41; 95% CI, 0.17–1.02), with 4-year survival rates of 62% vs 41%. The DARO group also had longer time to CRPC vs PBO (median, not reached vs 12.6 months; HR, 0.09; 95% CI 0.02–0.30). The safety profile of DARO in B/AAs was consistent with that observed for all patients (grade 3/4 adverse events [AEs]: 57.7% vs 66.1%; serious AEs: 42.3% vs 44.8%). The occurrence of discontinuations of DARO/PBO due to AEs and AEs associated with androgen receptor pathway inhibitors (eg, fatigue/asthenia, vasodilation/flushing, hypertension, diabetes/hyperglycemia, cardiac disorders, fall, depressed mood disorders, rash, fracture, decreased weight, mental impairment, and breast disorders/gynecomastia) were similar between treatment groups in B/AAs and consistent with the overall population. Conclusions: In this small population of B/AAs with mHSPC from the ARASENS trial, DARO was associated with an improvement in OS and time to CRPC and was well tolerated. Efficacy and safety findings in B/AAs were consistent with the overall ARASENS population.
 Citation Format: Neal D. Shore, Maha H.A. Hussain, Fred Saad, Karim Fizazi, Cora N. Sternberg, E. David Crawford, Bertrand Tombal, Luke Nordquist, Michael Cookson, Jay Jhaveri, Silke Thiele, Shankar Srinivasan, Jorge Ortiz, Matthew R. Smith. Efficacy and safety of darolutamide in combination with androgen-deprivation therapy (ADT) and docetaxel in Black/African-American patients from the phase 3 ARASENS trial [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B131.

Abstract B131: Efficacy and safety of darolutamide in combination with androgen-deprivation therapy (ADT) and docetaxel in Black/African-American patients from the phase 3 ARASENS trial

Corrigendum to “What Experts Think About Prostate Cancer Management During the COVID-19 Pandemic: Report from the Advanced Prostate Cancer Consensus Conference 2021” [Eur Urol 82(1):6–11]

Efficacy and Safety of Darolutamide in Patients with Nonmetastatic Castration-resistant Prostate Cancer Stratified by Prostate-specific Antigen Doubling Time: Planned Subgroup Analysis of the Phase 3 ARAMIS Trial.

Management of Patients with Advanced Prostate Cancer: Report from the Advanced Prostate Cancer Consensus Conference 2021.

WHAT IS THIS SUMMARY ABOUT?
This is a summary of a publication about the ARASENS trial, which was published in the New England Journal of Medicine in February 2022. The trial includes 1,306 men with a type of prostate cancer called metastatic, hormone-sensitive prostate cancer (also called mHSPC). In the trial, researchers wanted to learn if combining a treatment called darolutamide (also known by the brand name Nubeqa®) with two other medicines called androgen deprivation therapy (also called ADT) and docetaxel (brand name Taxotere®) could help treat patients with mHSPC better than placebo plus ADT and docetaxel. ADT with docetaxel is a treatment used for patients with mHSPC. Darolutamide is an approved treatment for a different type of prostate cancer called non-metastatic, castration-resistant prostate cancer (also called nmCRPC).

WHAT WERE THE RESULTS?
The trial results showed that combining darolutamide with ADT and docetaxel increased the chance of survival and lowered the risk of death by 32.5% compared to combining ADT and docetaxel with placebo instead. Compared to patients who received the placebo, patients who received darolutamide had a delay in: their cancer becoming castration-resistant worsening pain having cancer-related bone fractures or related symptoms needing additional therapies for cancer The percentage of trial patients who had medical problems during the trial, also called adverse events, was similar between trial patients who received darolutamide and those who received the placebo.

WHAT DO THE RESULTS OF THE STUDY MEAN?
Combining darolutamide with ADT and docetaxel helped treat trial patients with mHSPC better than placebo with ADT and docetaxel. Darolutamide in combination with ADT and docetaxel could be a treatment option for patients with mHSPC. Patients should always talk to their doctors and nurses before making any decisions about their treatment. This summary also includes perspectives on the ARASENS trial and prostate cancer from 3 members of the patient community. ClinicalTrials.gov NCT number: NCT02799602.

Darolutamide and survival in metastatic, hormone-sensitive prostate cancer: a patient and caregiver perspective and plain language summary of the ARASENS study.

What Experts Think About Prostate Cancer Management During the COVID-19 Pandemic: Report from the Advanced Prostate Cancer Consensus Conference 2021

Erratum to "Efficacy and Safety of Darolutamide in Patients with Nonmetastatic Castration-resistant Prostate Cancer Stratified by Prostate-specific Antigen Doubling Time: Planned Subgroup Analysis of the Phase 3 ARAMIS Trial" [Eur Urol 2022].

73 Background: In phase 3 placebo (PBO)-controlled studies, addition of APA to androgen deprivation therapy (ADT) improved overall survival, resulted in rapid and deep PSA declines, and reduced risk of disease progression while preserving health-related quality of life (HRQoL) in nonmetastatic castration-resistant prostate cancer (nmCRPC; SPARTAN) and metastatic castration-sensitive prostate cancer (mCSPC; TITAN). This post hoc analysis evaluated the association of a deep PSA decline with PROs in these studies. Methods: Pts on ADT were randomized to APA (240 mg QD) or PBO: SPARTAN 2:1 (N = 1,207; APA n = 806), TITAN 1:1 (N = 1,052; APA n = 525). Each cycle was 28 d. PROs were assessed using Functional Assessment of Cancer Therapy-Prostate (FACT-P), Brief Pain Inventory-Short Form (BPI-SF; TITAN only), and Brief Fatigue Inventory (BFI; TITAN only) at baseline, specific cycles during study treatment, and post progression up to 1 yr. A landmark analysis at Month 3 evaluated association between deep PSA decline (≤ 0.2 ng/mL) and time to subsequent deterioration in PROs (defined as decrease ≥ 10 points FACT-P total, ≥ 3 points Physical Wellbeing, ≥ 30% baseline for BPI-SF worst pain, or ≥ 2 points for BFI worst fatigue). At time of the landmark analysis, only pts continuing treatment were included; all deep PSA responses after, and all PRO deterioration events before, were ignored. Time-to-event end points were analyzed by Kaplan-Meier method and Cox proportional hazards model. Results: Median treatment durations were 32.9 mo (SPARTAN) and 39.3 mo (TITAN). Per assessment, > 90% (SPARTAN, cycles 1-81) and > 50% (TITAN, cycles 1-33) of eligible pts completed FACT-P; BPI-SF and BFI, both > 62% (TITAN, cycles 1-33). Pts in either study who achieved PSA ≤ 0.2 ng/mL at Month 3 had a lower risk of deterioration in FACT-P total or Physical Wellbeing (Table). Pts in TITAN with PSA ≤ 0.2 ng/mL at Month 3 had a lower risk of BPI-SF worst pain intensity or BFI worst fatigue intensity progression (Table). Conclusions: Deep and rapid PSA responses with APA were associated with prolonged time to deterioration in HRQoL, FACT-P Physical Wellbeing, BPI-SF worst pain intensity, and BFI worst fatigue intensity in pts with advanced PC. Clinical trial information: NCT02489318 (TITAN); NCT01946204 (SPARTAN). [Table: see text]

Association between patient-reported outcomes (PROs) and changes in prostate-specific antigen (PSA) in patients (pts) with advanced prostate cancer treated with apalutamide (APA) in the SPARTAN and TITAN studies.

5020 Background: NIRA + AAP significantly improved outcomes in pts with mCRPC and HRR gene alterations in the Phase 3 MAGNTUDE study. There is a paucity of data supporting use of PARP inhibitors in pts with HRR gene alterations other than BRCA1/2. We report on the efficacy of NIRA + AAP in pts with mCRPC and a qualifying single gene HRR alteration other than BRCA1/2. Methods: A pre-specified analysis was undertaken of the primary endpoint (radiographic progression-free survival [rPFS] by BICR), secondary endpoints (time to cytotoxic chemotherapy [TCC], time to symptomatic progression [TSP], overall survival [OS]), as well as time to PSA progression (TPSA) and overall response rate (ORR) across 186 pts (91 randomized to NIRA + AAP, 95 to PBO + AAP) with an alteration in the ATM, BRIP1, CDK12, CHEK2, FANCA, HDAC2, or PALB2 gene (excluding cooccurring alterations) . This analysis of individual alterations was not powered for formal statistical inference. Given the rarity of some alterations, groups based on functional similarity are also presented. Results: (Table). Pts with PALB2 or CHEK2 alterations had consistent improvement across all endpoints. In pts with ATM alterations benefit was observed in TCC, TSP, TPSA and ORR. There was benefit only in TPSA and ORR for pts with CDK12 alterations. When combined into functional groups, pts with an alteration in the HRR-Fanconi pathway ( BRIP1, FANCA, and PALB2) as well as pts with a HRR associated alteration ( CHEK2 or HDAC2) showed improvement in all endpoints. Conclusions: These data support the overall conclusions of the MAGNITUDE primary analysis and support benefit of NIRA + AAP in pts with HRR mutations beyond BRCA1/2. Clinical trial information: NCT03748641. [Table: see text]

Gene-by-gene analysis in the MAGNITUDE study of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations.

Effects of metformin and statins on outcomes in men with castration-resistant metastatic prostate cancer: Secondary analysis of COU-AA-301 and COU-AA-302

and had persistent elevated prostate-speci ﬁ c antigen. Post-operative imaging and management strategies were collated. Probability of metastasis-free survival (MFS), prostate cancer speci ﬁ c survival (CSS) and overall survival (OS) among this cohort of men using Kaplan-Meier methods. RESULTS: We identi ﬁ ed 258 patients meeting the elgibility criteria, of which 128 patients developed metastasis. The 5-year and 10-year MFS probability was 52% (95% CI 45%, 58%) and 38% (95% CI 29%, 47%), respectively. We identi ﬁ ed 58 patients who died of any cause, 48 from disease. The 5 and 10-year survival probabilities from disease are 89% (95% CI 84%, 93%), and 68% (95% CI 58%, 76%), respectively; and from any cause are 87% (95% CI 81%, 91%), and 63% (95% CI 53%, 71%), respectively. Post-operative imaging was obtained for 77% of patients, of whom 87% had a negative scan. Post-operative treatment included hormonal deprivation in 88% of men, observation alone in 7%, adjuvant radiotherapy in 4%, and combined chemotherapy and hormonal therapy in 1%. CONCLUSIONS: In the absence of clear pre-existing data or guidelines, we highlight our experience of patients with nodal invasion and PSA persistence post-prostatectomy. We highlight compromised metastatases-free survival and overall survival. Further, we highlight the limited role for conventional imaging in this cohort. (nmCRPC) the phase 3 ARAMIS trial (NCT02200614). hoc analysis of ARAMIS, ef ﬁ cacy and safety of were evaluated in patients with nmCRPC with or without prior local therapy by radical prostatectomy (RP) or radiotherapy (RT) to determine if the impact of DARO on these was consistent or if prior local therapy altered the effects of DARO. Here, we report outcomes in the DARO treatment arm. METHODS: Patients with nmCRPC were randomized 2:1 to DARO or PBO while continuing androgen deprivation therapy (ADT). DARO patients who received prior RP or RT were compared with those who received neither therapy for overall survival (OS) and time to prostate-speci ﬁ c antigen (PSA) progression using adjusted Cox regression analysis. PSA response ( (cid:3) 50% decline from baseline) and adverse events (AEs) were summarized by use of prior RP or RT. RESULTS: In ARAMIS, 43.6% (416/954) of DARO patients were treated with prior RP or RT. The treatment bene ﬁ t of DARO on OS was consistent for patients on DARO with prior local therapy compared with patients on DARO with no prior local therapy. Median time to PSA progression in DARO-treated patients with prior local therapy was similar to those without prior local therapy (29.5 and 26.0 months; HR 0.96 [95% CI 0.77 e 1.20]). PSA response rates ( (cid:3) 50% decline from baseline) were similar for patients with and without local therapy in the DARO arm (85.6%, 83.8%). For RP/RT-treated and RP/RT-untreated patients receiving DARO, similar incidences of any AEs (87.7%, 84.2%), grade 3/4 AEs (26.7%, 26.0%), and discontinuations due to AEs (7.7%, 9.9%) were reported. CONCLUSIONS: The treatment bene ﬁ t of DARO on OS and PSA outcomes was consistent for patients with and without prior local therapy with RP or RT. The safety and tolerability pro ﬁ le of DARO was similar across the two subgroups. The primary endpoint was a description of the patients' characteristics with a description of complications at diagnosis. The secondary endpoint was progression-free survival. Kaplan-Meier survival and Cox proportional hazard analyses were performed. RESULTS: The median age at diagnosis was 71 years. The median PSA was 147 ng/ml and 37% of patients presented with a disease-related complication at diagnosis. The survival analysis according to treatment showed median survival of 15 months for the androgen deprivation (ADT) þ chemotherapy group, 20 months for the ADT þ new hormone therapy group, and 21.5 months for the ADT alone group, with no signi ﬁ cant difference between the three therapeutic options (log rank test: 0.27). In univariate analysis, none of the patient characteristics at diagnosis (i.e., age, PSA, bone lesions, visceral lesions) were signi ﬁ cantly associated with the risk of progression, regardless of the treatment. CONCLUSIONS: There was no signi ﬁ cant difference in terms of progression-free survival between currently validated treatments administered in the ﬁ rst line, regardless of the tumor volume or risk group. Future studies with larger numbers of patients and involving molecular factors are required to con ﬁ rm or invalidate these results and understand the evolution of prostate cancer in our population and thus better prevent complications related to the disease. clinicopathological upfront use of Abi combined with ADT resulted in favorable prognostic outcomes compared with conventional ADT with Bica. 1172CR cells were resistant to enzalutamide treatment and expressed high level of AKR1C3 and AR-V7. A novel AKR1C3 inhibitor (PB) which displayed superior potential to inhibit AKR1C3 activity and suppress enzalutamide resistant prostate cancer cell growth was tested in these models. At the same dose, PB signi ﬁ cantly suppressed 1172CR cell growth and colony formation compared to indomethacin and enzalutamide. PB also signi ﬁ cantly suppressed AR/AR-V7 protein expression compared to indomethacin in 1172CR cells.

MP27-05 EFFICACY AND SAFETY OF DAROLUTAMIDE IN NONMETASTATIC CASTRATION-RESISTANT PROSTATE CANCER PATIENTS WITH AND WITHOUT PRIOR LOCAL THERAPY WITH RADICAL PROSTATECTOMY OR RADIOTHERAPY

CONCLUSIONS: In this interim analysis, neoadjuvant Axitnib resulted in signi ﬁ cant reductions in tumor size and complexity, enabling partial nephrectomy in a cohort of highly complex renal masses, and with acceptable safety and functional preservation. Accrual is ongoing to reach a target of 50. 11 having had a cystectomy and 1 pending surgery. Pathological downstaging (yp < T2) was noted in 4 patients with 3 CRs (ypT0N0Mx) and 1 with residual ypTisN0Mx only. Of note, 1 CR was seen in a patient with locally advanced plasmacytoid variant. Participants tolerated treatment well with minimal treatment related AE/SAEs. CONCLUSIONS: Interim analysis of GCa-IVC NAC shows good tolerability with > 36% rate of downstaging. Of those with a pathological response, 75% achieved a CR. Continuation criteria has been met for stage 2. FACT-BI analysis and clinical follow up is ongoing and will be reported at study completion.

LBA01-07 OVERALL SAFETY AND INCIDENCES OF ADVERSE EVENTS BY TIME INTERVAL WITH DAROLUTAMIDE PLUS ANDROGEN-DEPRIVATION THERAPY AND DOCETAXEL IN THE PHASE 3 ARASENS TRIAL

Clinical characteristics associated with falls in patients with non-metastatic castration-resistant prostate cancer treated with apalutamide

 In the phase 2 GALAHAD study (NCT02854436), the PARP inhibitor (PARPi) niraparib, was evaluated in heavily pre-treated patients with mCRPC and DNA-repair gene defects (DRD) who progressed after androgen-receptor (AR) targeted therapy and taxane-based chemotherapy. The results showed that objective response rate (ORR) was 34.2% for patients with measurable disease having biallelic BRCA1/2 alterations (n=76). The development of BRCA reversion mutations, a type of secondary mutation that restores protein function, has been proposed as a key resistance mechanism to PARP inhibition. We aimed to evaluate the relationship between reversion mutations and treatment response in BRCA1/2 altered patients treated with niraparib in the GALAHAD study.
 Thirty-three patients with biallelic BRCA alterations (excluding patients with homozygous deletions) had donated an end-of-treatment (EOT) ctDNA sample. We performed sequencing to detect reversion mutations using the Resolution Bioscience ctDx-HRD assay. Mutation patterns at baseline included splice site, nonsense, missense, and frameshift mutations, with the latter being the most common (24/33; 73%). No reversions were detected at baseline and the baseline BRCA alterations were detected at EOT for every patient. Most BRCA patients (28/33; 85%) had at least 1 reversion mutation (range: 1-38 different BRCA alterations) at EOT. Of the 28 patients with reversions, 5 were classified as low reversions: 3 patients had only one reversion mutation, 1 patient had 2 reversions at low allele frequency and 1 patient had 4 reversions at low allele frequency. Patients with reversion mutations showed better composite response (defined as ORR by RECIST 1.1, or CTC conversion to <5/7.5 mL blood, or ≥50% decline in prostate specific antigen) (74.2% vs 25.8%, p=0.01) and longer duration on treatment (median 6.9 vs 3.7 mo, p<0.05) compared to those without or low reversions. Additionally, patients with reversions trended to have longer median radiographic progression-free survival compared to those without or low reversions (8.1 vs 5.5 mo, p=0.12). In conclusion, the high prevalence of patients with BRCA reversion mutations and the displayed longer benefit from niraparib underscores the dependence of these tumors on BRCA mutation as an oncogenic driver and reversion mutations as a marker of secondary resistance to niraparib treatment.
 Citation Format: Karen Urtishak, Gerhardt Attard, Tokuwa Kanno, Shibu Thomas, Gary E. Mason, Byron Espina, Eugene Zhu, Natalie Hutnick, Mary Guckert, Adam del Corral, Mark Li, Angela Lopez-Gitlitz, Kim Chi, William Kevin Kelly, Evan Y. Yu, Karim Fizazi, Matthew Smith. High prevalence and heterogeneity of emergence of BRCA reversion mutations at progression on niraparib treatment in BRCA-mutant metastatic castration-resistant prostate cancer (mCRPC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4133.

Abstract 4133: High prevalence and heterogeneity of emergence of BRCA reversion mutations at progression on niraparib treatment in BRCA-mutant metastatic castration-resistant prostate cancer (mCRPC) patients

618P Apalutamide (APA) for advanced prostate cancer in older patients (pts): Combined analysis of TITAN & SPARTAN

Importance
There is a need to identify prognostic biomarkers to guide treatment intensification in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC).

Objective
To examine whether molecular subtypes predict response to apalutamide, using archived primary tumor samples from the randomized, double-blind, phase 3 SPARTAN trial.

Design, Setting, and Participants
In this cohort study, gene expression data from 233 archived samples from patients with nmCRPC enrolled in the SPARTAN trial were generated using a human exon microarray. The present analysis was conducted from May 10, 2018, to October 15, 2020.

Interventions
Patients were randomized (2:1) to apalutamide, 240 mg/d, with androgen deprivation therapy (apalutamide+ADT) or placebo+ADT.

Main Outcomes and Measures
Patients were stratified into high-risk and low-risk categories for developing metastases based on genomic classifier (GC) scores for high (GC >0.6) and low to average (GC≤0.6) and into basal and luminal subtypes; associations between these molecular subtypes and metastasis-free survival (MFS), overall survival (OS), and progression-free survival 2 (PFS2) were evaluated using Cox proportional hazards regression and Kaplan-Meier analysis.

Results
Median age of the 233 included patients was 73 (range, 49-91) years. A total of 116 of 233 patients (50%) in the SPARTAN biomarker subset had high GC scores. Although all patients receiving apalutamide+ADT had improved outcomes, having high GC scores was associated with the greatest improvement in MFS (hazard ratio [HR], 0.21; 95% CI, 0.11-0.40; P < .001), OS (HR, 0.52; 95% CI, 0.29-0.94; P = .03), and PFS2 (HR, 0.39; 95% CI, 0.23-0.67; P = .001) vs placebo+ADT. In total, 152 of 233 patients (65%) had the basal molecular subtype. Although there were no significant differences in MFS, PFS2, or OS between patients with the luminal vs basal subtype in the placebo+ADT arm, patients with the luminal subtype in the apalutamide+ADT arm had a significantly longer MFS (apalutamide+ADT: HR, 0.40; 95% CI, 0.18-0.91; P = .03; placebo+ADT: HR, 0.66; 95% CI, 0.33-1.31; P = .23) compared with patients with basal subtype; similar trends were observed for OS (apalutamide+ADT: HR, 0.50; 95% CI, 0.25-0.98; P = .04; placebo+ADT: HR, 0.78; 95% CI, 0.38-1.60; P = .50), and PFS2 (apalutamide+ADT: HR, 0.71; 95% CI, 0.42-1.22; P = .22; placebo+ADT: HR, 0.72; 95% CI, 0.38-1.39; P = .33). In regression analysis, the luminal-basal subtype score was significantly associated with MFS in patients receiving apalutamide+ADT (HR, 2.65; 95% CI, 1.15-6.08; P = .02), whereas GC score was significantly associated with MFS in placebo+ADT recipients (HR, 2.09; 95% CI, 1.02-4.27; P = .04).

Conclusions and Relevance
The findings of this study suggest that the GC score and basal-luminal subtype derived from archived tumor specimens may be biomarkers of response to apalutamide+ADT in the nmCRPC setting. Although overall, the addition of apalutamide to ADT was beneficial, higher-risk and luminal subtypes appeared to benefit most. Obtaining GC scores may be useful for identifying patients for early treatment intensification with apalutamide, and basal-luminal subtyping may be a beneficial approach for patient selection for further treatment intensification in trials combining novel therapies with apalutamide.

Association of Molecular Subtypes With Differential Outcome to Apalutamide Treatment in Nonmetastatic Castration-Resistant Prostate Cancer.

630P Time course profile of adverse events of interest and serious adverse events with darolutamide in the ARAMIS trial

8Background: SPARTAN, a phase 3 placebo (PBO)-controlled study in patients (pts) with nmCRPC, showed that APA plus androgen deprivation therapy (ADT) significantly improves metastasis-free survival...

Molecular determinants associated with long-term response to apalutamide (APA) in nonmetastatic castration-resistant prostate cancer (nmCRPC).

5079 Background: Patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) need therapy that prolongs survival with little added toxicity, thus preserving quality of life. The second-generation androgen receptor inhibitors (ARIs) including DARO, apalutamide, and enzalutamide offer durable survival in nmCRPC but differences exist in AE profiles (eg, fatigue, falls, fractures, rash, mental impairment, and hypertension) that can limit daily activities. These AEs may require dose modifications and limit pts’ willingness to continue treatment, with an adverse impact on efficacy. DARO is a structurally distinct ARI that significantly extended metastasis-free survival and overall survival (OS) vs placebo (PBO) in ARAMIS (NCT02200614), with minimal AE risk. We report tolerability from extended follow-up and treatment response analyses from ARAMIS. Methods: Pts with nmCRPC (N=1509) were randomized 2:1 to DARO or PBO with androgen deprivation therapy. The ARAMIS trial was unblinded at the primary analysis, after which all pts could receive open-label (OL) DARO. Tolerability was assessed every 16 weeks. Pharmacodynamic modeling investigated the association between treatment response (maximum prostate-specific antigen [PSA] decline from baseline) and OS at 2 years using a Cox proportional hazards model. Results: As shown in the table, DARO remained well tolerated over the double-blind (DB) and OL periods: 98.8% of pts on DARO received the full planned dose and almost all pts with dose modifications were able to resume and re-establish the planned dose (DARO 89.6% vs PBO 89.7%). Discontinuation of DARO due to AEs increased slightly from the DB period (9.0%) to the DB+OL period (10.5%). Pharmacodynamic modeling showed that longer OS was positively associated with maximum PSA decline in DARO-treated pts. Conclusions: DARO remained well tolerated with extended treatment at the recommended dose of 600 mg twice daily. Almost all pts with nmCRPC were able to receive the full planned dose, increasing the likelihood of clinical benefit from effective disease control (PSA decline) and prolonged survival. Tolerability of different ARIs in the real world should be assessed. Clinical trial information: NCT02200614. [Table: see text]

Darolutamide (DARO) tolerability from extended follow up and treatment response in the phase 3 ARAMIS trial.

Health-related Quality of Life at the SPARTAN Final Analysis of Apalutamide for Nonmetastatic Castration-resistant Prostate Cancer Patients Receiving Androgen Deprivation Therapy.

How quality of life can help guide selection of androgen receptor inhibitors in nonmetastatic castration-resistant prostate cancer.

Darolutamide and health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: An analysis of the phase III ARAMIS trial.

TPS5086Background: In cancer cells, the cyclin-dependent kinases 4 and 6 (CDK4 & 6)/retinoblastoma protein (Rb) pathway is commonly altered, resulting in uncontrolled cell cycle entry and prolifera...

CYCLONE 1: A phase 2 study of abemaciclib in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a novel hormonal agent and taxane-based chemotherapy.

Lack of consensus identifies important areas for future clinical research: Advanced Prostate Cancer Consensus Conference (APCCC) 2019 findings.

New treatments for patients with non‐metastatic castration‐resistant prostate cancer: A nursing perspective

239Background: DARO is a structurally distinct androgen receptor inhibitor (ARI) approved for treating nmCRPC. In ARAMIS, DARO significantly reduced the risk of death by 31% (HR = 0.69; 95% CI: 0.5...

Safety of darolutamide (DARO) for nonmetastatic castration-resistant prostate cancer (nmCRPC) from extended follow-up in the phase III ARAMIS trial.

Purpose: In the placebo-controlled SPARTAN study, apalutamide added to androgen-deprivation therapy (ADT) improved metastasis-free survival, second progression-free survival (PFS2), and overall survival (OS) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). Mechanisms of resistance to apalutamide in nmCRPC require evaluation. Patients and Methods: In a subset of patients from SPARTAN, aberrations were assessed at baseline and end of study treatment (EOST) using targeted next-generation sequencing or qRT-PCR. Circulating-tumor DNA (ctDNA) levels were assessed qualitatively. Select aberrations in androgen receptor (AR) and other common PC-driving genes were detected and summarized by the treatment group; genomic aberrations were summarized in ctDNA-positive samples. Association between detection of aberrations in all patients and outcomes was assessed using Cox proportional-hazards models and multivariate analysis. Results: In 247 patients, the overall prevalence of ctDNA, AR aberrations, and TP53 inactivation increased from baseline (40.6%, 13.6%, and 22.2%) to EOST (57.1%, 25.4%, and 35.0%) and was comparable between treatment groups at EOST. In patients who received subsequent androgen signaling inhibition after study treatment, detectable biomarkers at EOST were significantly associated with poor outcomes: ctDNA with PFS2 or OS (HR, 2.01 or 2.17, respectively; P < 0.0001 for both), any AR aberration with PFS2 (1.74; P = 0.024), and TP53 or BRCA2 inactivation with OS (2.06; P = 0.003; or 3.1; P < 0.0001). Conclusions: Apalutamide plus ADT did not increase detectable AR/non-AR aberrations over ADT alone. Detectable ctDNA, AR aberrations, and TP53/BRCA2 inactivation at EOST were associated with poor outcomes in patients treated with first subsequent androgen signaling inhibitor.

Blood Biomarker Landscape in Patients with High-risk Nonmetastatic Castration-Resistant Prostate Cancer Treated with Apalutamide and Androgen-Deprivation Therapy as They Progress to Metastatic Disease

240Background: DARO is a structurally distinct androgen receptor inhibitor approved for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC) based on significantly prolonge...

Analysis of the effect of crossover from placebo (PBO) to darolutamide (DARO) on overall survival (OS) benefit in the ARAMIS Trial.

INTRODUCTION AND OBJECTIVE:The phase 3 TITAN and SPARTAN studies demonstrated improved outcomes with the addition of apalutamide (APA) to androgen deprivation therapy (ADT); outcomes included prolo...

PD34-11 PROSTATE-SPECIFIC ANTIGEN KINETICS IN PATIENTS WITH ADVANCED PROSTATE CANCER TREATED WITH APALUTAMIDE: RESULTS FROM THE TITAN AND SPARTAN STUDIES

5516Background: SPARTAN evaluated APA vs PBO in pts with nmCRPC and a prostate-specific antigen doubling time of ≤ 10 mo receiving androgen deprivation therapy (ADT). At primary end point analysis ...

Final survival results from SPARTAN, a phase III study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC).

1062Background: We assessed the antitumor activity of cabozantinib, a potent multi-receptor oral tyrosine kinase inhibitor with activity against MET, RET, VEGFR2, and AXL, in patients with hormone-...

A phase II trial of cabozantinib in hormone receptor-positive breast cancer with bone metastases.

Efficacy and safety of apalutamide in Japanese patients with nonmetastatic castration-resistant prostate cancer: a subgroup analysis of a randomized, double-blind, placebo-controlled, Phase-3 study

5562Background: PC is characterized by a relatively low prevalence of recurrent somatic point mutations. ctDNA is shed from PC and can be analyzed to profile somatic point mutations and copy number...

Association of detectable levels of circulating tumor DNA (ctDNA) with disease burden in prostate cancer (PC).

Efficacy and safety of darolutamide in Japanese patients with nonmetastatic castration-resistant prostate cancer: a sub-group analysis of the phase III ARAMIS trial

Purpose: To evaluate the relationship between exposure of apalutamide and its active metabolite, N-desmethyl-apalutamide, and selected clinical efficacy and safety parameters in men with high-risk nonmetastatic castration-resistant prostate cancer. Patients and Methods: An exploratory exposure–response analysis was undertaken using data from the 1,207 patients (806 apalutamide and 401 placebo) enrolled in the SPARTAN study, including those who had undergone dose reductions and dose interruptions. Univariate and multivariate Cox regression models evaluated the relationships between apalutamide and N-desmethyl-apalutamide exposure, expressed as area under the concentration–time curve at steady state, and metastasis-free survival (MFS). Univariate and multivariate logistic regression models assessed the relationship between apalutamide and N-desmethyl-apalutamide exposure and common treatment-emergent adverse events including fatigue, fall, skin rash, weight loss, and arthralgia. Results: A total of 21% of patients in the apalutamide arm experienced dose reductions diminishing the average daily dose to 209 mg instead of 240 mg. Within the relatively narrow exposure range, no statistically significant relationship was found between MFS and apalutamide and N-desmethyl-apalutamide exposure. Within apalutamide-treated subjects, skin rash and weight loss had a statistically significant association with higher apalutamide exposure. Conclusions: The use of apalutamide at the recommended dose of 240 mg once daily provided a similar delay in metastases across the SPARTAN patient population, regardless of exposure. The exploratory exposure–safety analysis supports dose reductions in patients experiencing adverse events.

Efficacy and Safety Exposure–Response Relationships of Apalutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer

Cabozantinib for Progressive Metastatic Castration-resistant Prostate Cancer Following Docetaxel: Combined Analysis of Two Phase 3 Trials.

Darolutamide is a structurally distinct androgen-receptor inhibitor that is approved for the treatment of nonmetastatic, castration-resistant prostate cancer. In the planned primary analysis of a phase 3 trial, the median metastasis-free survival was significantly longer with darolutamide (40.4 months) than with placebo (18.4 months). The data for the analysis of overall survival were immature at the time of the primary analysis.

METHODS
In this double-blind, placebo-controlled trial, we randomly assigned 1509 men, in a 2:1 ratio, to receive darolutamide (955 patients) or placebo (554 patients) while they continued to receive androgen-deprivation therapy. After the results of the primary end-point analysis were found to be positive, unblinding of the treatment assignments occurred, and patients in the placebo group were permitted to cross over to receive open-label darolutamide treatment. At the time of this prespecified final analysis, which had been planned to be performed after approximately 240 deaths had occurred, overall survival and all other secondary end points were evaluated.

RESULTS
The median follow-up time was 29.0 months. At the time of unblinding of the data, all 170 patients who were still receiving placebo crossed over to receive darolutamide; 137 patients who had discontinued placebo before unblinding had occurred received at least one other life-prolonging therapy. Overall survival at 3 years was 83% (95% confidence interval [CI], 80 to 86) in the darolutamide group and 77% (95% CI, 72 to 81) in the placebo group. The risk of death was significantly lower, by 31%, in the darolutamide group than in the placebo group (hazard ratio for death, 0.69; 95% CI, 0.53 to 0.88; P = 0.003). Darolutamide was also associated with a significant benefit with respect to all other secondary end points, including the time to first symptomatic skeletal event and the time to first use of cytotoxic chemotherapy. The incidence of adverse events after the start of treatment was similar in the two groups; no new safety signals were observed.

Among men with nonmetastatic, castration-resistant prostate cancer, the percentage of patients who were alive at 3 years was significantly higher among those who received darolutamide than among those who received placebo. The incidence of adverse events was similar in the two groups. (Funded by Bayer HealthCare and Orion Pharma; ARAMIS ClinicalTrials.gov number, NCT02200614.).

Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide.

TPS5588Background: Preclinical data suggest synergistic antitumor activity when the PARP inhibitor (PARPi) niraparib is combined with the androgen pathway inhibitor abiraterone acetate1. The additi...

A phase III randomized, placebo-controlled, double-blind study of niraparib plus abiraterone acetate and prednisone versus abiraterone acetate and prednisone in patients with metastatic prostate cancer (MAGNITUDE).

5514Background: DARO is a structurally distinct androgen receptor inhibitor with a favorable safety profile, approved for treating men with nmCRPC after demonstrating significantly prolonged metast...

Overall survival (OS) results of phase III ARAMIS study of darolutamide (DARO) added to androgen deprivation therapy (ADT) for nonmetastatic castration-resistant prostate cancer (nmCRPC).

TPS5591Background: Despite recent advances, nearly all patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) experience disease progression and cancer-specific mortality. Pers...

CYCLONE 2: A phase II, randomized, placebo-controlled study of abiraterone acetate plus prednisone with or without abemaciclib in patients with metastatic castration-resistant prostate cancer.

5521Background: In SPARTAN, APA + androgen deprivation therapy (ADT) prolonged metastasis-free survival (MFS) and improved PSA kinetics over placebo (PBO) + ADT in high-risk nmCRPC. All molecular s...

Molecular determinants of prostate specific antigen (PSA) kinetics and clinical response to apalutamide (APA) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) in SPARTAN.

5541Background: The phase III TITAN and SPARTAN studies demonstrated improved outcomes with the addition of apalutamide (APA) to androgen deprivation therapy (ADT); outcomes included prolonging ove...

Prostate-specific antigen (PSA) kinetics in patients (pts) with advanced prostate cancer treated with apalutamide: Results from the TITAN and SPARTAN studies.

Abstract Background We assessed the antitumor activity of cabozantinib, a potent multireceptor oral tyrosine kinase inhibitor, in patients with hormone receptor‐positive breast cancer with bone metastases. Patients and Methods In this single‐arm multicenter phase II study, patients received an initial starting dose of 100 mg, later reduced to 60 mg, per day. The primary endpoint was the bone scan response rate. Secondary endpoints included objective response rate by RECIST, progression‐free survival (PFS), and overall survival (OS). Results Of 52 women enrolled, 20 (38%) experienced a partial response on bone scan and 6 (12%) had stable disease. Prior to the first repeat bone scan at 12 weeks, 19 (35%) patients discontinued study treatment because of early clinical progression or unacceptable toxicity. RECIST evaluation based on best overall response by computed tomography revealed stable disease in extraosseous tissues in 26 patients (50%) but no complete or partial responses. In 25 patients with disease control on bone scan at 12 weeks, only 3 (12%) patients developed extraosseous progression. The median PFS was 4.3 months, and median OS was 19.6 months. The most common grade 3 or 4 toxicities were hypertension (10%), anorexia (6%), diarrhea (6%), fatigue (4%), and hypophosphatemia (4%). Conclusion Bone scans improved in 38% of patients with metastatic hormone receptor‐positive breast cancer and remained stable in an additional 12% for a minimum duration of 12 weeks on cabozantinib. Further investigations should assess the activity of cabozantinib in combination with other hormonal and other breast cancer therapies and determine whether bone scan responses correlate with meaningful antitumor effects. ClinicalTrials.gov identifier. NCT01441947 Implications for Practice Most patients with metastatic hormone receptor‐positive (HR+) breast cancer have bone involvement, and many have bone‐only disease, which is difficult to evaluate for response. This phase II single‐arm study evaluated the clinical activity of the small molecule MET/RET/VEGFR2 inhibitor cabozantinib in patients with metastatic HR+ breast cancer with bone metastases. This study met its primary endpoint, and cabozantinib treatment resulted in a significant bone scan response rate correlating with improved survival. This is the first study to use bone scan response as a primary endpoint in breast cancer. The results support further study of cabozantinib in HR+ breast cancer.

A Phase II Trial of Cabozantinib in Hormone Receptor‐Positive Breast Cancer with Bone Metastases

TPS257 Background: Preclinical data suggest synergistic antitumor activity when the PARP inhibitor (PARPi) niraparib is combined with the androgen pathway inhibitor abiraterone acetate. (1) The addition of a PARPi to abiraterone acetate plus prednisone (AAP) showed improved radiographic progression-free survival (rPFS) vs AAP alone in patients with mCRPC regardless of DNA repair gene defect (DRD) status. (2) Interim results from a phase 1 study support safety and tolerability of niraparib 200 mg combined with AAP in patients with mCRPC. (3) The objective of this Phase 3 study is to compare the efficacy and safety of niraparib plus AAP versus AAP with placebo as first-line therapy for mCRPC. Methods: This ongoing multicenter MAGNITUDE study will open in 300 sites across 28 countries and will enroll patients with mCRPC who have not received treatment in the metastatic castrate resistant setting other than ongoing androgen deprivation therapy [ADT] and ≤4 months of AAP. The DRD positive cohort (Cohort 1, n=400) will comprise patients whose tumors have DRD, as determined by a previously validated plasma or tissue assay. The cohort without DRD (Cohort 2, n=600) will enroll patients whose tumors are not found to have DRD. Enrollment began in February 2019. The primary objective of the study is to compare radiographic progression-free survival (rPFS) as assessed by blinded independent central radiology review for patients treated with niraparib and AAP versus placebo and AAP. To test superiority of the combination vs AAP, sample sizes were estimated to provide 92% power to detect HR≤0.65 rPFS in the DRD positive cohort and 94% power to detect HR≤0.67 in rPFS in the cohort without DRD, both at a 2-tailed level of significance of 0.05. The main secondary objectives are time to symptomatic progression, time to cytotoxic chemotherapy, and overall survival. Safety and pharmacokinetic profiles will be evaluated.1) Rajendra N, et al. Cancer Res 2019;79 (13 Suppl): Abstract nr 2134. 2) Clarke N, et al. Lancet Oncol. 2018;(7):975-986. 3) Saad, et al. Ann Oncol, 2018;29 (suppl 8), mdy284.043, https://doi.org/10.1093/annonc/mdy284.043 ). Clinical trial information: NCT03748641.

A phase III randomized, placebo-controlled, double-blind study of niraparib plus abiraterone acetate and prednisone versus abiraterone acetate and prednisone in patients with metastatic prostate cancer (NCT03748641).

118Background: Niraparib, a highly potent and selective poly (ADP-ribose) polymerase inhibitor (PARPi) received breakthrough designation by US FDA for treatment of pts with BRCA1,2 mutant mCRPC who...

Niraparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD): Correlative measures of tumor response in phase II GALAHAD study.

Management of Patients with Advanced Prostate Cancer: Report of the Advanced Prostate Cancer Consensus Conference 2019.

INTRODUCTION AND OBJECTIVES: The DECIPHER prostate test (GenomeDx Biosciences, Inc., San Diego, CA) is a clinical-grade mRNA-based test with a genomic classifier (GC) score that has been independently validated for predicting metastatic disease post radical prostatectomy in men with prostate cancer (Klein EA, et al. Eur Urol. 2013). Pts with high GC scores have significantly higher risk for metastasis than pts with low to average GC scores. APA, a next-generation androgen receptor inhibitor, improved metastasis-free survival (MFS) and other secondary end points in the SPARTAN study of pts with nmCRPC with prostate-specific antigen doubling time ⩽ 10 months who were receiving androgen deprivation therapy (ADT). We evaluated the effect of APA on MFS in a subgroup of SPARTAN pts grouped by DECIPHER GC score. METHODS: A high-density Affymetrix GeneChip platform (1.4 million genomic loci) was used to assess gene expression in 233 archived primary tumors from pts enrolled in SPARTAN who had been randomized 2:1 to APA+ADT or ADT alone. Gene expression values of 22 markers were used to generate GC scores (⩽ 0.6 [low to average] vs > 0.6 [high]) using prevalidated algorithms. Cox proportional hazard model was used to assess association of GC scores with clinical outcomes. RESULTS: Among 233 pts in SPARTAN, 50% had a high DECIPHER GC score. 78 and 39 in APA+ADT and ADT arms, respectively, had high GC scores; 76 and 40 pts in these arms, respectively, had low to average GC scores. Pts with high GC score, who typically have poor prognosis with standard of care (SoC) treatment, including ADT, had improved MFS when treated with APA+ADT vs ADT alone (hazard ratio [HR], 0.21; p < 0.0001). Pts with low to average GC score also had improved MFS with APA+ADT vs ADT alone (HR, 0.46; p = 0.031). There was no difference in MFS with APA+ADT among pts with high GC scores vs those receiving APA+ADT who had low to average GC scores (HR, 1.11; p = 0.741). Similar correlations between GC scores and second progression-free survival, overall survival, and symptomatic progression were observed. CONCLUSIONS: APA+ADT improved MFS and can overcome the negative prognosis associated with high GC scores. To our knowledge, this is the first report of application of the DECIPHER GC score at diagnosis to predict outcomes and therapeutic response in CRPC and the first SoC treatment to overcome negative prognosis. Source of Funding: Janssen Research & Development

PD11-03 RESPONSE TO APALUTAMIDE (APA) AMONG PATIENTS (PTS) WITH NONMETASTATIC CASTRATION-RESISTANT PROSTATE CANCER (NMCRPC) FROM SPARTAN BY DECIPHER GENOMIC CLASSIFIER (GC) SCORE

New androgen antagonists in non-metastatic castration-resistant prostate cancer

42 Background: The SPARTAN trial recently demonstrated that addition of APA to androgen deprivation therapy (ADT) improved metastasis-free survival (MFS) and second progression-free survival (PFS2) in nmCRPC pts. We performed transcriptome-wide profiling of available primary tumor samples from pts in SPARTAN to evaluate potential biomarkers of response or resistance to APA+ADT. Methods: Pts included in SPARTAN were at high risk of developing metastasis.We used a commercially available genomic assay (DECIPHER prostate test, GenomeDx Biosciences, Inc., San Diego, CA) to assess gene expression in 233 archived primary tumors from SPARTAN pts. Using a Cox proportional hazard model, we assessed the association between scores and subtypes from previously derived prognostic and predictive gene signatures, such as DECIPHER and basal (BA) vs luminal (LU) subtyping. Results: Pts with high DECIPHER scores had greater treatment effect with APA+ADT than those with low scores. Pts with LU, a subtype known to be sensitive to ADT, greatly benefited from APA+ADT. Pts with BA, typically resistant to ADT, also benefited from APA+ADT. Conclusions: DECIPHER score and BA or LU subtype may be biomarkers of response to APA+ADT. DECIPHER may be useful for identifying pts for early treatment intensification with APA or other agents, and molecular subtyping may be an effective approach for pt selection in trials combining novel therapies with APA. Clinical trial information: NCT01946204. [Table: see text]

Identifying molecular determinants of response to apalutamide (APA) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) in the SPARTAN trial.

Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; b Institut Gustave Roussy and University of Paris Sud, Villejuif, France; Department of Oncology and Hematology, Kantonsspital St. Gallen, Switzerland; University Hospital Aachen, Cologne, Germany; e The Royal Marsden Hospital and The Institute of Cancer Research, London, UK; Carolina Urologic Research Center and Atlantic Urology Clinics, Myrtle Beach, SC, USA; Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Cliniques Universitaires Saint Luc, Brussels, Belgium; Michigan Center for Translational Pathology, Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA E U RO P E AN U RO LOGY 7 5 ( 2 019 ) 2 8 5 – 2 9 3

– Prostate Cancer – Editor ’ s Choice Managing Nonmetastatic Castration-resistant Prostate Cancer

INTRODUCTION AND OBJECTIVES: SPARTAN, a randomized phase 3 placebo (PBO)-controlled study in pts with high-risk nmCRPC, demonstrated that APA added to androgen deprivation therapy (ADT) prolonged metastasis-free survival (MFS) by > 2 yrs (median 40.5 vs 16.2 mo; HR, 0.28; p < 0.0001) and provided a 55% reduction in the risk of symptomatic progression (HR, 0.45; 95% CI, 0.32-0.63; p < 0.0001) (Smith et al. N Engl J Med 2018). We examined whether treatment with APA, a next-generation androgen receptor inhibitor, provided the same benefit and safety profile in pts with or without prior RP and/or XRT (RP/XRT). METHODS: Pts with nmCRPC and a high risk of developing metastasis (prostate-specific antigen doubling time [PSADT] ⩽ 10 mo) were randomized 2:1 to APA (240 mg QD) + ADT or PBO + ADT. Pt outcomes were evaluated based on any RP/XRT prior to the study. Cox proportional hazard analysis was used to estimate the HR and 95% CI for MFS. RESULTS: 41% of pts in each arm (334/806 APA; 166/401 PBO) had prior RP/XRT. Pts with prior RP/XRT were younger with longer time since diagnosis, had lower PSA values, lower ECOG and Gleason scores, and were less likely to have renal impairment. Despite these baseline advantages in the PBO group, pts with prior RP/XRT had poorer outcomes. MFS was significantly shorter for PBO pts with vs without prior local therapy (HR, 1.73; p = 0.0002). This negative prognosis for pts with prior RP/XRT was overcome with APA (HR, 0.80; p = 0.13), which delayed development of metastases by 68%-84% vs PBO (Table). The relative magnitude of improvement with APA vs PBO was highest in pts with prior local therapy. No impact of prior local therapy was observed on incidence of grade 3/4 treatment-emergent adverse events with APA and PBO. Incidence of falls, fractures, hypothyroidism, seizures, and skin rash was similar in pts with or without prior RP/XRT. CONCLUSIONS: Regardless of prior local therapy, pts received highly significant MFS benefit from treatment with APA. Prior therapy did not have an impact on tolerability of APA. Table. No title available. Source of Funding: Funding: Janssen Research & Development

MP34-19 EFFICACY AND SAFETY OF APALUTAMIDE (APA) IN NONMETASTATIC CASTRATION-RESISTANT PROSTATE CANCER (NMCRPC) PATIENTS (PTS) WITH OR WITHOUT PRIOR RADICAL PROSTATECTOMY (RP) AND/OR EXTERNAL RADIOTHERAPY (XRT): POST HOC ANALYSIS OF SPARTAN

5000 Background: DARO is a structurally distinct androgen receptor antagonist for which in vitro and phase 1/2 studies suggest low risk of adverse events (AEs) and drug–drug interaction. In the ARAMIS study of DARO in nmCRPC, metastasis-free survival (MFS) was significantly prolonged vs placebo (PBO) (40.4 vs 18.4 mo; hazard ratio [HR] 0.41; 95% confidence interval [CI] 0.34–0.50; P < 0.001) and interim overall survival (OS) favored DARO (HR 0.71; 95% CI 0.50–0.99; P = 0.045). Methods: 1509 pts were randomized 2:1 to DARO 600 mg (two 300 mg tablets) twice daily (n = 955) or PBO (n = 554) while continuing androgen deprivation therapy (ADT). Primary endpoint was MFS. Secondary endpoints included OS and time to pain progression (assessed by Brief Pain Inventory Short Form). QoL was assessed by European Organisation for Research and Treatment of Cancer QoL Prostate Cancer module (EORTC-QLQ-PR25) at baseline (BL) and every 16 wks until end of treatment. Analysis of time to deterioration in EORTC-QLQ-PR25 subscales, defined as first occurrence of a minimally important difference (half the standard deviation of BL value), used Kaplan–Meier estimators and stratified Cox proportional hazard models. Results: DARO significantly delayed pain progression vs PBO (40.3 vs 25.4 mo; HR 0.65; 95% CI 0.53–0.79; P < 0.001); this was maintained beyond end of study treatment. Time to deterioration of EORTC-QLQ-PR25 outcomes showed statistically and clinically significant delays with DARO vs PBO for urinary symptoms (25.8 vs 14.8 mo; HR 0.64; 95% CI 0.54–0.76; P < 0.01). Time to deterioration of hormonal treatment-related symptoms was comparable with DARO vs PBO (18.9 vs 18.4 mo; HR 1.06; 95% CI 0.88–1.27; P = 0.52). DARO was well tolerated. Exposure-adjusted incidences (pts per 100 years’ exposure) of AEs of interest were similar/lower with DARO vs PBO (fatigue/asthenic conditions [11.3 vs 11.1], hypertension [4.7 vs 5.1], hot flush [3.7 vs 4.1], fracture [3.0 vs 3.5], falls [2.7 vs 4.1], cognitive disorder [0.3 vs 0.2], and seizure [0.2 vs 0.2]). Conclusions: For nmCRPC pts, DARO prolongs MFS, is well tolerated, maintains QoL, and delays worsening of pain and disease-related symptoms compared with PBO. Clinical trial information: NCT02200614.

Impact of darolutamide (DARO) on pain and quality of life (QoL) in patients (Pts) with nonmetastatic castrate-resistant prostate cancer (nmCRPC).

Evaluation of Clinically Relevant Drug–Drug Interactions and Population Pharmacokinetics of Darolutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer: Results of Pre-Specified and Post Hoc Analyses of the Phase III ARAMIS Trial

Prostate-specific membrane antigen positron-emission tomography (PSMA-PET) in high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC) SPARTAN-like patients (pts) negative by conventional imaging

INTRODUCTION AND OBJECTIVES: APA, a next-generation androgen receptor inhibitor, added to androgen deprivation therapy (ADT) improved MFS by > 2 years (median 40.5 vs 16.2 mo; p < 0.0001) in high-risk pts with nmCRPC in the phase 3 SPARTAN study. In this post hoc analysis, we examined clinical outcomes in APA-treated pts whose PSA declined to < 0.2 ng/mL. METHODS: In SPARTAN, pts with nmCRPC with PSA doubling time of ⩽ 10 months were randomized 2:1 to APA (240 mg QD) + ADT or placebo (PBO) + ADT. MFS, time to metastasis (mets) (TTM), and location of mets were evaluated as a function of PSA status (PSA decline to < 0.2 ng/mL at any time during the study, vs PSA not declining to < 0.2 ng/mL). Cox proportional hazard analysis estimated HRs and 95% CI. RESULTS: Following treatment with APA, PSA declined to < 0.2 ng/mL in 319/806 (40%) pts; 1 PBO pt had a decline in PSA to < 0.2 ng/mL. APA pts with a PSA decline to < 0.2 ng/mL had a 76% risk reduction for MFS (Figure) and TTM. Compared with pts who received PBO, the APA pts with PSA that declined to < 0.2 ng/mL had an 88% risk reduction for MFS and TTM. When mets developed, depth of PSA decline (to < 0.2 ng/mL vs not reaching < 0.2 ng/mL) was not associated with location of mets (bone: 53% vs 58%; nodes: 27% vs 31%). CONCLUSIONS: In nmCRPC pts treated with APA, a PSA decline to < 0.2 ng/mL occurred in 40% of pts, and was associated with an improvement in clinical end points, including MFS. Depth of PSA decline was not associated with a specific metastatic pattern. Figure. No caption available. Source of Funding: Janssen Research & Development

MP34-20 METASTASIS-FREE SURVIVAL (MFS) IN NONMETASTATIC CASTRATION-RESISTANT PROSTATE CANCER (NMCRPC) PATIENTS (PTS) WITH PROSTATE-SPECIFIC ANTIGEN (PSA) DECLINE TO < 0.2 NG/ML FOLLOWING APALUTAMIDE (APA) TREATMENT: POST HOC RESULTS FROM THE PHASE 3 SPARTAN STUDY

Apalutamide and overall survival in patients with nonmetastatic castration-resistant prostate cancer: Updated results from the phase 3 SPARTAN study

143 Background: Short-term measures of response that reflect clinical benefit are a critical unmet need for clinical trials for mCRPC. Using data from 5 randomized mCRPC trials, we showed that a response endpoint (RE) based on a change in CTC number using the FDA cleared CellSearch® (Menarini) platform from any, (≥ 1, CTC any) to 0 (CTC0) per 7.5 ml of blood was associated strongly with overall survival (OS). Here we explored whether different CTC and PSA REs could serve as “transitional surrogates” defined as a biomarker validated in phase 2 but not in phase 3 trials for overall survival (OS), using the baseline and week 13 prostate-specific antigen (PSA) level and CTC counts. Methods: Four 13-week REs were studied: (i) PSA50 (≥ 50% PSA decline from baseline), (ii) CTC0 (≥ 1 CTC/7.5 ml of blood at baseline and 0 CTCs at week 13), (iii) both PSA50 and CTC0, and (iv) either PSA50 or CTC0. The relative effectiveness of these REs as transitional surrogates for OS was evaluated at the patient level by discrimination, the separation between responder and non-responder survival curves, and at the trial level using explained variation, the accuracy in predicting k-month survival in a trial with the response proportion. Results: A total of 6081 pts were enrolled of whom 5660 (93%) survived until week 13 and among these patients 3080 (54%) had a baseline CTC count ≥ 1 and baseline PSA ≥ 5 ng/ml. At the patient level, separation between responder and non-responder survival curves over time was greater using CTC0 than PSA50 (average difference in survival probability 0.35 vs. 0.29, respectively). At the trial level, explained variation in survival over time was also greater for CTC0 than PSA50 (average R-squared 0.67 vs. 0.58, respectively). CTC/PSA combination REs did not improve on CTC0 at either level. Conclusions: The CTC0 RE provides stronger discrimination than PSA50 at the patient level and greater observed explained variation at the trial level. The results suggest that for the individual patient, a decrease in CTCs to zero at week 13 is a stronger indicator of longer term OS than the more widely used PSA50 and serves as a reasonably likely surrogate for OS in clinical trials.

Assessment of circulating tumor cell number as a transitional surrogate endpoint for survival in phase II trials for metastatic castration-resistant prostate cancer.

Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial.

Abstract Background In the phase 3 placebo (PBO)-controlled SPARTAN study, APA with ongoing androgen deprivation therapy (ADT) significantly improved metastasis-free survival (MFS) (HR, 0.28; 95% CI, 0.23-0.35; p  Methods Pts with nmCRPC and prostate-specific antigen doubling time of ≤ 10 months were randomized 2:1 to APA (240 mg QD) or PBO, with ongoing ADT. The OS effect of APA vs PBO was assessed using a group sequential testing procedure with O’Brien-Fleming-type alpha spending function. The required p value for statistical significance at IA2 was 0.0121. OS was analyzed by Kaplan-Meier method and Cox model. Results At 41 months’ median follow-up and 285 OS events, APA was associated with improved OS compared with PBO (HR, 0.75; 95% CI, 0.59-0.96; p = 0.0197). The 4-yr OS rates for APA and PBO were 72.1% and 64.7%, respectively. After unblinding the study and prior to IA2, 76 nonprogressing PBO pts (19%) crossed over to open-label APA. At IA2, the proportion of pts who received subsequent life-prolonging therapy was 68% in the PBO group and 38% in the APA group. Rates of discontinuation due to progressive disease and adverse events (AE) were 34% and 14%, for the APA group, and 74% and 8% for the PBO group. The rates of treatment-emergent AEs for APA at IA2 were similar to the rates previously reported at IA1. Conclusions At IA2, APA was associated with a 25% reduction in risk of death compared with PBO. This OS benefit for APA was observed despite crossover of PBO pts to APA and higher rates of subsequent life-prolonging therapy for PBO pts. APA safety profile remained unchanged. These results further support APA as a standard of care option for pts with high-risk nmCRPC. Clinical trial identification NCT01946204. Editorial acknowledgement William Turner, PAREXEL. Legal entity responsible for the study Janssen Research & Development. Funding Janssen Research & Development. Disclosure M.R. Smith: Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy, Research grant / Funding (self): Janssen Oncology; Advisory / Consultancy: Amgen; Advisory / Consultancy: Pfizer; Research grant / Funding (self): Gilead Sciences. F. Saad: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Janssen Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy: AstraZeneca/Medimmune; Honoraria (self): AbbVie; Honoraria (self), Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Oncogenex. S. Chowdhury: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Johnson & Johnson; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas Pharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Clovis. S. Oudard: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai. B.A. Hadaschik: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy: Bayer; Advisory / Consultancy: Lightpoint Medical; Research grant / Funding (self): Profound Medical; Research grant / Funding (self): German Cancer Aid; Research grant / Funding (self): German Research Foundation; Travel / Accommodation / Expenses: AstraZeneca. J.N. Graff: Honoraria (self), Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy: Exelixis; Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Sharp & Dohme; Travel / Accommodation / Expenses: Clovis Oncology; Licensing / Royalties: Oncoresponse: Exceptional responders; Honoraria (self): Astellas Medivation; Honoraria (self), Research grant / Funding (institution): Janssen Oncology; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Bristol-Myers Squibb. D. Olmos: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Clovis Oncology; Travel / Accommodation / Expenses: Ipsen; Honoraria (self): Sanofi; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Astellas Medivation; Research grant / Funding (institution): Tokai Pharmaceuticals. P.N. Mainwaring: Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy: Pfizer; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen Oncology; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Medivation/Astellas; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Licensing / Royalties: 4 patents on nanotechnology; Shareholder / Stockholder / Stock options: Xing Technologies; Research grant / Funding (self): Merck KGaA. H. Uemura: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Takeda; Advisory / Consultancy: AstraZeneca; Honoraria (self), Travel / Accommodation / Expenses: Sanofi; Honoraria (self): Daiichi-Sankyo; Honoraria (self): Merck Sharp Dohme. P. De Porre: Full / Part-time employment: Janssen Research & Development; Shareholder / Stockholder / Stock options: Johnson & Johnson. A. Smith: Full / Part-time employment: Janssen Research & Development; Shareholder / Stockholder / Stock options: Johnson & Johnson. K. Zhang: Full / Part-time employment: Janssen Research & Development; Shareholder / Stockholder / Stock options: Johnson & Johnson. A. Lopez-Gitlitz: Full / Part-time employment: Janssen Research & Development; Shareholder / Stockholder / Stock options: Johnson & Johnson. E.J. Small: Advisory / Consultancy, Shareholder / Stockholder / Stock options: Fortis; Advisory / Consultancy: Janssen Oncology; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Shareholder / Stockholder / Stock options: Harpoon Therapeutics. All other authors have declared no conflicts of interest.

Apalutamide (APA) and overall survival (OS) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC): Updated results from the phase III SPARTAN study

BACKGROUND Darolutamide is a structurally unique androgen‐receptor antagonist that is under development for the treatment of prostate cancer. We evaluated the efficacy of darolutamide for delaying metastasis and death in men with nonmetastatic, castration‐resistant prostate cancer. METHODS We conducted a randomized, double‐blind, placebo‐controlled, phase 3 trial involving men with nonmetastatic, castration‐resistant prostate cancer and a prostate‐specific antigen doubling time of 10 months or less. Patients were randomly assigned in a 2:1 ratio to receive darolutamide (600 mg [two 300‐mg tablets] twice daily) or placebo while continuing androgen‐deprivation therapy. The primary end point was metastasis‐free survival, with the presence of metastasis determined by independent central review of radiographic imaging every 16 weeks. RESULTS In total, 1509 patients underwent randomization (955 to the darolutamide group and 554 to the placebo group). In the planned primary analysis, which was performed after 437 primary end‐point events had occurred, the median metastasis‐free survival was 40.4 months with darolutamide, as compared with 18.4 months with placebo (hazard ratio for metastasis or death in the darolutamide group, 0.41; 95% confidence interval, 0.34 to 0.50; P<0.001). Darolutamide was also associated with benefits with regard to all secondary end points, including overall survival, time to pain progression, time to cytotoxic chemotherapy, and time to a symptomatic skeletal event. The incidence of adverse events that occurred or worsened during the treatment period and had a frequency of 5% or more or were of grade 3 or higher was similar in the two groups; all such events except fatigue occurred in less than 10% of patients in either group. The percentage of patients who discontinued the assigned regimen because of adverse events was 8.9% in the darolutamide group and 8.7% in the placebo group. Darolutamide was not associated with a higher incidence of seizures, falls, fractures, cognitive disorder, or hypertension than placebo. CONCLUSIONS Among men with nonmetastatic, castration‐resistant prostate cancer, metastasis‐free survival was significantly longer with darolutamide than with placebo. The incidence of adverse events was similar for darolutamide and placebo. (Funded by Bayer HealthCare and Orion Pharma; ARAMIS ClinicalTrials.gov number, NCT02200614.)

Darolutamide in Nonmetastatic, Castration‐Resistant Prostate Cancer

5024 Background: SPARTAN, a randomized phase 3 placebo (PBO)-controlled study in pts with high-risk nmCRPC and PSA doubling time ≤ 10 mo, showed that, compared with PBO, addition of APA to ongoing ADT treatment (tx) prolonged metastasis-free survival (MFS) by > 2 y, reduced the risk of symptomatic progression by 55%, and increased second progression-free survival (PFS2), which is the time from randomization to disease progression on first subsequent anticancer tx, or death. The impact of APA in terms of benefit and safety profile was evaluated in pts aged < 65, 65-74, and ≥ 75 y. Methods: Pts with nmCRPC were randomized 2:1 to APA (240 mg QD) or PBO; ADT was continuous. APA effect was analyzed by Cox models and Kaplan-Meier methods across age subgroups. Results: Baseline characteristics among age groups were similar, although ECOG PS 1 vs 0 increased with age. MFS benefit with APA was highly significant for all age subgroups (Table). In pts ≥ 75 y, MFS risk with APA vs PBO was reduced by 59%; MFS risk was reduced by 86% and 76% for pts < 65 and 65-74 y, respectively. Risk of PFS2 with APA vs PBO was reduced across all age subgroups. PFS2 in pts < 65, 65-74, and ≥ 75 y: HR, 0.09 (p < 0.0001); HR, 0.56 (p = 0.0343); HR, 0.59 (p = 0.0092), respectively. Risk of symptomatic progression was lessened with APA vs PBO for all age subgroups (Table). There was a similar increase in incidence of tx-emergent adverse events (TEAE) with age in both tx arms that remained higher with APA. Incidence of grade 3/4 TEAE (≥ 75 vs < 65 y): APA, 50% vs 37%; PBO, 37% vs 28%. Conclusions: Pts in all age subgroups with high-risk nmCRPC had significant improvement in MFS with APA + ongoing ADT. The safety profile of APA was similar across age subgroups. Clinical trial information: NCT01946204. [Table: see text]

Age-related efficacy and safety of apalutamide (APA) plus ongoing androgen deprivation therapy (ADT) in subgroups of patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC): Post hoc analysis of SPARTAN.

INTRODUCTION AND OBJECTIVES: Asymptomatic nonmetastatic castrate-resistant prostate cancer (nmCRPC) patients (pts) would benefit from treatments (Tx) that delay disease progression with minimal Tx-related adverse events (AEs). Darolutamide (DARO) is a structurally unique androgen receptor (AR) antagonist for which in vitro and phase I/II studies suggest low risk of AEs and drug-drug interaction. DARO prolonged metastasis-free survival (MFS) compared with placebo (PBO) (40 vs 18 mo; HR 0.41; 95% CI 0.34-0.50; P<0.001) in ARAMIS. Interim overall survival (OS) favored DARO (HR 0.71; 95% CI 0.50-0.99; P=0.045). DARO’s impact on prostate-specific antigen (PSA), disease progression, safety, and quality of life (QoL) in ARAMIS is reported here. METHODS: 1509 pts were randomized 2:1 to DARO 600 mg (two 300 mg tablets) twice daily (n=955) or PBO (n=554) while continuing androgen deprivation therapy. The primary end point was MFS. Secondary and exploratory endpoints included OS, time to cytotoxic chemotherapy, time to antineoplastic therapy, and safety. Exploratory endpoints included time to PSA progression and QoL, assessed by the Brief Pain Inventory-Short Form (BPI-SF), Functional Assessment of Cancer Therapy-Prostate (FACT-P), and the European Organisation for Research and Treatment of Cancer QoL Prostate Cancer module (EORTC-QLQ-PR25). RESULTS: DARO elicited an overall PSA response of ≥50% in 84% of pts vs 8% with PBO; 51% of pts had ≥90% PSA decline with DARO. DARO substantially delayed time to PSA progression (33 vs 7 mo; HR 0.13; 95% CI 0.11-0.16; P<0.001), time to cytotoxic chemotherapy (not reached [NR] vs 38 mo; HR 0.43; 95% CI 0.31-0.60; P<0.001), and time to antineoplastic therapy (NR vs NR; HR 0.33; 95% CI 0.23-0.47; P<0.001) compared with PBO. Incidences of Tx-emergent AEs with ≥5% frequency or grade 3-5 were comparable between study arms; only fatigue had an incidence of >10%. AE-related discontinuation rates were similar between study arms. AEs of interest (including fracture, falls, seizures, weight decrease, hypertension, and cognitive disorder) showed minimal or no difference in incidence between study arms. QoL was similar for DARO and PBO; differences in least-squares mean time-adjusted area under curve scores for BPI-SF, FACT-P, and EORTC-QLQ-PR25 subscales consistently favored DARO. CONCLUSIONS: DARO delays disease progression and subsequent Tx for metastatic CRPC compared with PBO, preserving QoL without increasing the prevalence of key AEs. Source of Funding: Bayer AG and Orion Pharma

LBA-09 DAROLUTAMIDE DELAYS PROSTATE-SPECIFIC ANTIGEN PROGRESSION AND TIME TO NEXT ANTICANCER THERAPIES IN PATIENTS WITH NONMETASTATIC CASTRATION-RESISTANT PROSTATE CANCER

202 Background: New therapies are needed for patients (pts) with mCRPC progressing after androgen-receptor signaling inhibitors (ARSIs) and taxane therapies. Niraparib is a once daily highly selective inhibitor of poly (ADP-ribose) polymerase (PARP-1 and 2). Methods: GALAHAD is an ongoing open label Ph 2 study assessing niraparib (300 mg daily) in pts with DRD progressing on/after ARSIs and taxane chemotherapy. Using a validated plasma assay, DRD status was defined as pathogenic mutations (including homozygous deletions) of BRCA1/2, ATM, FANCA, PALB2, CHEK2, BRIP1 or HDAC2. Composite response rate (RR) was defined as an objective response by RECIST 1.1 for measurable disease, circulating tumor cell (CTC) conversion to < 5/7.5 mL blood or prostate-specific antigen (PSA) decline of ≥50% (PSA50). Here, preliminary data on RR and adverse events (AEs) are reported in pts with biallelic DRD. Results: As of 10 Sep 2018, 123 pts with mCRPC and DRD were enrolled, of whom 39 had biallelic DRD (23 BRCA1/2). The median follow-up was 5.7 mo (2.0–23.7). Table depicts RRs for pts with biallelic DRD by BRCA status. Composite and objective RRs were 65% and 38% in pts with biallelic BRCA1/2, respectively. 3/8 pts (38% [2/5 BRCA1/2 and 1/3 non-BRCA]) with measurable visceral metastases showed objective response. Among the 20 biallelic responders, the duration of treatment (tx) has exceeded 4 mo in 13 pts and 6 mo in 8 pts; 14 pts remain on tx. The most common grade 3/4 hematologic AEs were anemia (25%) and thrombocytopenia (15%) (manageable by dose reduction/interruption). The most common grade 3/4 nonhematologic AEs were asthenia (6%) and hypertension (5%). Conclusions: These results suggest niraparib has compelling activity as monotherapy for pts with treatment-resistant mCRPC, particularly those with biallelic BRCA1/2 identified by a blood assay. Clinical trial information: NCT02854436. [Table: see text]

Phase II study of niraparib in patients with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD): Preliminary results of GALAHAD.

5025 Background: SPARTAN, a phase 3 study of APA vs placebo (PBO) added to ongoing ADT in pts with nmCRPC, demonstrated that APA significantly prolongs metastasis-free survival, time to symptomatic progression, and second progression free survival (Smith et al. NEJM 2018), with no decline in health-related quality of life (Saad et al. Lancet Oncol 2018). SPARTAN pts who received APA, vs PBO, with ongoing ADT had higher rates of falls (15.6% vs 9.0%) and fractures (11.7% vs 6.5%). An analysis was performed to identify clinical characteristics associated with falls and fractures in APA-treated SPARTAN pts. Methods: Of 1207 pts enrolled, 806 were randomized to APA. Univariate Cox proportional hazards model (UVA) assessed the association of 47 baseline clinical characteristics (demographics, comorbidities, and medication use, including bone-sparing agents) with time to fall or time to fracture. Characteristics with p values < 0.10 were included in a multivariate Cox proportional hazards model (MVA) to determine independent factors associated with these outcomes (p < 0.05). Results: Factors associated with time to both fall and fracture on UVA (p < 0.10) included older age, low serum albumin, and poor ECOG performance status (PS). Additional factors associated with time to fall were cerebrovascular accidents/transient ischemic attacks, neuropathy, depression, α-blocker use, and antidepressant use. On MVA, older age, poor ECOG PS, history of neuropathy, and α-blocker use were independently associated with falls; older age and low serum albumin were independently associated with fractures (Table). Conclusions: At initiation of APA added to ongoing ADT, nmCRPC pts with higher risk of falls and fractures can be identified and are candidates for intervention to reduce the risk for these events. Clinical trial information: NCT01946204. [Table: see text]

Predictors of falls and fractures in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) treated with apalutamide (APA) plus ongoing androgen deprivation therapy (ADT).

140 Background: Delaying metastases for nmCRPC patients, while minimizing the risk of adverse events, is an important treatment goal. Darolutamide, a structurally unique androgen receptor (AR) antagonist, is being evaluated for the treatment of advanced prostate cancer. The ARAMIS trial studied the efficacy and safety of darolutamide in nmCRPC patients. Methods: This double-blind, placebo-controlled phase III trial randomized nmCRPC patients in a 2:1 ratio to receive darolutamide 600 mg (two 300 mg tablets) twice-daily or placebo, while continuing androgen deprivation therapy. Patients were stratified by prostate-specific antigen doubling time (≤6 months or >6 months) and use of osteoclast-targeted therapy. The primary endpoint was metastasis-free survival (MFS), with independent central review of radiographic imaging every 16 weeks. Secondary endpoints include overall survival (OS), times to pain progression (assessed by Brief Pain Inventory), first cytotoxic chemotherapy and first symptomatic skeletal event, as well as safety profile. Results: In total, 1,509 patients were randomized (955 to darolutamide, 554 to placebo). Median MFS was 40.4 months with darolutamide vs 18.4 months with placebo (hazard ratio [HR] 0.41; 95% confidence interval [CI] 0.34–0.50; 2-sided p<0.0001). OS showed a trend in favor of darolutamide (HR 0.71, 95% CI 0.50–0.99, 2-sided p=0.045), as did time to pain progression (HR 0.65; 95% CI 0.53–0.79; 2-sided p<0.0001). Other secondary and exploratory efficacy endpoints also favored darolutamide. Incidences of treatment-emergent adverse events (AEs) with ≥5% frequency or grade 3–5 were comparable between darolutamide and placebo arms; none except fatigue occurred in >10%. Discontinuation rates due to AEs were 8.9% with darolutamide and 8.7% with placebo. Grouped terms for AEs noted with other AR inhibitors (including fracture, falls, seizures, weight decrease, hypertension, and cognitive disorder) showed minimal or no difference in incidence between study arms. Conclusion: Among men with nmCRPC, MFS was significantly longer with darolutamide than with placebo with a low incidence of treatment-related AEs in this asymptomatic patient population. Clinical trial information: NCT02200614.

ARAMIS: Efficacy and safety of darolutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC).

5023 Background: The addition of APA to ongoing ADT in pts with nmCRPC significantly prolonged metastasis-free survival (MFS), time to symptomatic progression (SymProg), and second progression-free survival (PFS2) in SPARTAN. We assessed the impact of APA on these end points in pts with or without BL CM. Methods: Using Cox proportional hazards models, treatment effect of APA was evaluated in SPARTAN pts with CM at BL, stratifying by the presence of BL diabetes/hyperglycemia (D/H), cardiovascular disease (CVD), hypertension (HTN), and renal insufficiency (RI). Results: Of 1207 SPARTAN pts, 1062 (88%) had ≥ 1 BL CM, including 703/806 (87%) APA pts and 359/401 (90%) PBO pts. A total of 226 (19%), 398 (33%), 798 (66%), and 774 (64%) pts had D/H, CVD, HTN, and RI, respectively; 323 (27%), 412 (34%), 259 (21%), and 68 (6%) pts had 1, 2, 3, and 4 CM, respectively. Incidence of CM was balanced between arms. Pts with CM were older than pts with no CM (median age, 75 vs 69 yrs, APA; 74 vs 69 yrs, PBO). MFS, SymProg, and PFS2 benefit with APA was significant in all CM subgroups, except PFS2 for pts with D/H (Table) and regardless of the number of CM. The incidence of any treatment-emergent AE was balanced between pts with and without CM. AEs with APA were not affected by any CM. Clinical trial information: NCT01946204. Conclusions: The benefit of APA + ongoing ADT in pts with nmCRPC was maintained in pts with D/H, CVD, HTN, and RI. The safety profile of APA was not affected by any CM.[Table: see text]

Efficacy of apalutamide (APA) plus ongoing androgen deprivation therapy (ADT) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) and baseline (BL) comorbidities (CM).

Background: The SPARTAN study recently demonstrated that the addition of APA to androgen deprivation therapy (ADT) improved metastasis-free survival (MFS) and second progression-free survival (PFS2) in pts with nmCRPC defined by conventional imaging. We performed transcriptome-wide profiling of available primary tumor samples from pts in SPARTAN to evaluate predictors of response or resistance to APA + ADT. Methods: We used a commercially available genomic assay (DECIPHER® prostate test, GenomeDx, San Diego, CA) to assess gene expression in archived primary tumors from SPARTAN pts. DECIPHER GC, a 22-marker mRNA-based genomic classifier (GC), was validated for predicting metastatic prostate cancer (Karnes RJ, et al. J Urol. 2013), and basal/luminal (BA/LU) subtyping was validated in prostate cancer (Zhao SG, et al. JAMA Oncol. 2017; Zhang D, et al. Nat Commun. 2016). Pts were stratified into high and low risk for developing metastases based on DECIPHER GC score high (GC > 0.6) and low to average (GC ≤ 0.6), respectively, and into BA and LU subtypes. Gene signatures representing key biological pathways associated with the BA subtype were also assessed. We analyzed the association between GC scores and subtypes and outcomes using a Cox proportional hazards model. Results: A total of 233 pts were assessed; 117 pts had high GC score. Pts with both high and low to average GC score had improved outcomes with APA + ADT vs ADT alone. Pts with poor-prognosis high GC score had improved MFS (HR = 0.21, p Conclusions: Molecular signatures derived from primary tumors, such as DECIPHER GC and BA/LU subtypes, stratify pts with nmCRPC who would benefit from APA + ADT despite the high risk for progression. DECIPHER GC may be useful for identifying pts for early treatment intensification with APA or other agents, and BA/LU subtyping may be an effective approach for pt selection in trials combining novel therapies with APA. Citation Format: Felix Feng, Shibu Thomas, Michael Gormley, Angela Lopez-Gitlitz, Margaret K. Yu, Shinta Cheng, Deborah S. Ricci, Brendan Rooney, Paul N. Mainwaring, David Olmos, Fred Saad, Simon Chowdhury, Boris Hadaschik, Nick Fishbane, Elai Davicioni, Yang Liu, Eric J. Small, Matthew R. Smith. Identifying molecular determinants of response to apalutamide (APA) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) in the SPARTAN study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT129.

Abstract CT129: Identifying molecular determinants of response to apalutamide (APA) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) in the SPARTAN study

INTRODUCTION AND OBJECTIVES: In SPARTAN, pts with nmCRPC assessed by conventional imaging benefited from apalutamide (APA). PSMA-PET detects localized and metastatic PC with superior sensitivity to conventional imaging. We retrospectively characterized the extent of disease using PSMA-PET in SPARTAN-like pts and compared the risk factors for M1 disease detected by PSMA-PET to those in SPARTAN. METHODS: A total of 200 pts with nmCRPC at high risk of developing metastases (prostate-specific antigen doubling time [PSADT] ⩽ 10 mo, or Gleason score ≥ 8) and no known extrapelvic metastases on prior conventional imaging were assessed with PSMA-PET. Detection rate on PSMA-PET, including local/pelvic and distant M1 disease, was determined. Association of baseline (BL) variables with M1 disease in the PSMA-PET cohort was assessed using univariate and multivariate analyses. SPARTAN pts were stratified according to risk factors for PSMA-PET-detected M1 disease and analyzed using Cox proportional-hazards models. RESULTS: BL characteristics of PSMA-PET and SPARTAN pts were generally similar. PSMA-PET detected PC in 196/200 (98%) pts; 55% had local recurrence, 54% had pelvic nodes (N1), 55% had any extrapelvic distant metastatic disease despite negative conventional imaging; 24% were diagnosed with local recurrence only, 29% with oligometastatic (1-3 lesions) and 46% with polymetastatic disease. PSA ≥ 5.5 ng/mL, pN1 disease, and prior local therapy were significantly associated with M1 disease detected by PSMA-PET (Table). All clinically relevant subgroups of SPARTAN pts, including pts with independent predictors of PSMA-PET-M1 disease, significantly benefited from APA (Table). CONCLUSIONS: PSMA-PET-positive CRPC pts were similar to those at high-risk of developing metastases in SPARTAN. APA showed significant benefit in all clinically relevant subgroups of SPARTAN pts, including pts with risk factors for distant metastases detected by PSMA-PET. Therefore, APA should be considered for pts negative by conventional imaging but positive by PSMA-PET (stage migration). The added value of PSMA-PET over PSADT in pts with high-risk nmCRPC should be explored in prospective studies. Table. No title available. Source of Funding: Janssen Research & Development: SPARTAN. Participating centers: PSMA-PET.

PD17-09 PROSTATE-SPECIFIC MEMBRANE ANTIGEN POSITRON EMISSION TOMOGRAPHY (PSMA-PET) IN HIGH-RISK NONMETASTATIC CASTRATION-RESISTANT PROSTATE CANCER (NMCRPC) SPARTAN-LIKE PATIENTS (PTS) NEGATIVE BY CONVENTIONAL IMAGING

Relationship Between Metastasis-free Survival and Overall Survival in Patients With Nonmetastatic Castration-resistant Prostate Cancer.

PURPOSE
The aim of this work is to provide evidence-based guidance on the management of osteoporosis in survivors of adult cancer.

METHODS
ASCO convened a multidisciplinary Expert Panel to develop guideline recommendations based on a systematic review of the literature.

RESULTS
The literature search of the 2018 systematic review by the US Preventive Services Task Force in the noncancer population was used as the evidentiary base upon which the Expert Panel based many of its recommendations. A total of 61 additional studies on topics and populations not covered in the US Preventive Services Task Force review were also included. Patients with cancer with metastatic disease and cancer survival outcomes related to bone-modifying agents are not included in this guideline.

RECOMMENDATIONS
Patients with nonmetastatic cancer may be at risk for osteoporotic fractures due to baseline risks or due to the added risks that are associated with their cancer therapy. Clinicians are advised to assess fracture risk using established tools. For those patients with substantial risk of osteoporotic fracture, the clinician should obtain a bone mineral density test. The bone health of all patients may benefit from optimizing nutrition, exercise, and lifestyle. When a pharmacologic agent is indicated, bisphosphonates or denosumab at osteoporosis-indicated dosages are the preferred interventions.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

Management of Osteoporosis in Survivors of Adult Cancers With Nonmetastatic Disease: ASCO Clinical Practice Guideline.

Purpose: Systemic androgen-signaling inhibition added to ongoing androgen-deprivation therapy (ADT) improved clinical outcomes in patients with nonmetastatic castration-resistant prostate cancer without detectable metastases by conventional imaging (nmCRPC). Prostate-specific membrane antigen ligand positron emission tomography (PSMA-PET) detects prostate cancer with superior sensitivity to conventional imaging, but its performance in nmCRPC remains largely unknown. We characterized cancer burden in high-risk patients with nmCRPC using PSMA-PET. Experimental Design: We retrospectively included 200 patients with nmCRPC, prostate-specific antigen (PSA) >2 ng/mL, and high risk for metastatic disease [PSA doubling time (PSADT) of ≤10 months and/or Gleason score of ≥8] from six high-volume PET centers. We centrally reviewed PSMA-PET detection rate for pelvic disease and distant metastases (M1). We further evaluated SPARTAN patients stratified by risk factors for PSMA-PET-detected M1 disease. Results: PSMA-PET was positive in 196 of 200 patients. Overall, 44% had pelvic diseases, including 24% with local prostate bed recurrence, and 55% had M1 disease despite negative conventional imaging. Interobserver agreement was very high (κ: 0.81–0.91). PSA ≥ 5.5 ng/mL, locoregional nodal involvement determined by pathology (pN1), prior primary radiation, and prior salvage radiotherapy independently predicted M1 disease (all P < 0.05). Conclusions: PSMA-PET detected any disease in nearly all patients and M1 disease in 55% of patients previously diagnosed with nmCRPC, including subgroups with PSADT of ≤10 months and Gleason score of ≥8. The value of PSMA-PET imaging for treatment guidance should be tested in future studies.

Prostate-Specific Membrane Antigen Ligand Positron Emission Tomography in Men with Nonmetastatic Castration-Resistant Prostate Cancer

144 Background: In the phase 3 SPARTAN study, compared with placebo (PBO), APA, a next-generation androgen receptor inhibitor, decreased the risk of distant metastasis or death by 72% (hazard ratio [HR], 0.28; p < 0.0001) in men with high-risk nmCRPC. After 1 year of additional follow-up, PFS2 and safety were reevaluated to ensure maintenance of benefit against potential harm. Methods: Pts with nmCRPC and prostate-specific antigen doubling time of ≤ 10 mos were randomized 2:1 to APA (240 mg QD) + androgen deprivation therapy (ADT) or PBO + ADT. All pts who developed distant metastasis, determined by blinded independent central review, were eligible to receive subsequent therapy including open-label treatment with abiraterone acetate + prednisone, provided by the sponsor. The exploratory PFS2 end point (time from randomization to disease progression on subsequent anticancer therapy or death) was evaluated, as was incidence of treatment-emergent adverse events (TEAEs). Results: Median treatment duration with APA was 25.7 mos; with PBO, 11.5 mos (original analysis, mos: APA, 19.2; PBO, 11.2). Pts randomized to APA continued to show significant benefit in PFS2 (HR, 0.5; 95% CI, 0.39-0.63; p < 0.0001) vs PBO (APA median time to PFS2 not reached vs PBO 39.3 mos). At a median follow-up of 32 mos, 51.3% of pts receiving APA, 8% of the 75 pts who crossed over from PBO to APA, and 99.7% of remaining PBO pts had discontinued study treatment. Rates of discontinuations due to progressive disease and AEs were 27.3% and 12.7%, respectively, in the APA group and 73.4% and 8.4% in the PBO group. There was no substantial change in the incidence of TEAEs in the APA group at the 1-year update. With regard to drug specific TEAEs, there were no grade 4 or 5 events; grade 3 TEAEs consisted of rash, 5.2%; falls, 2.4%; fractures, 3.1%; hypothyroidism, 0%; and seizures, 0%. Conclusions: APA was previously shown to result in an improvement in metastasis-free survival and symptomatic progression. With a median APA treatment duration of 25.7 mos, APA continues to show significant benefit in PFS2, and its safety profile remains unchanged. Clinical trial information: NCT01946204.

Updated analysis of progression-free survival with first subsequent therapy (PFS2) and safety in the SPARTAN study of apalutamide (APA) in patients (pts) with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC).

Evaluation of asymptomatic microscopic hematuria by renal ultrasound to detect upper tract malignancy: a 20-year experience in a community hospital.

Management of Patients with Advanced Prostate Cancer: The Report of the Advanced Prostate Cancer Consensus Conference APCCC 2017.

MP52-20 PATIENT REPORTED OUTCOMES (PROS) IN SPARTAN, A PHASE 3, DOUBLE-BLIND, RANDOMIZED STUDY OF APALUTAMIDE (APA) PLUS ANDROGEN DEPRIVATION THERAPY (ADT) VS PLACEBO PLUS ADT IN MEN WITH NONMETASTATIC CASTRATION-RESISTANT PROSTATE CANCER (NMCRPC)

PD10-04 A POPULATION-BASED STUDY OF THE ASSOCIATION OF PROSTATE-SPECIFIC ANTIGEN DOUBLING TIME (PSADT) WITH METASTASIS-FREE SURVIVAL (MFS) AND OVERALL SURVIVAL (OS) IN NONMETASTATIC CASTRATION-RESISTANT PROSTATE CANCER (NMCRPC) PATIENTS (PTS)

SPARTAN, a phase 3 double-blind, randomized study of apalutamide versus placebo in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC)

Purpose Measures of response that are clinically meaningful and occur early are an unmet need in metastatic castration-resistant prostate cancer clinical research and practice. We explored, using individual patient data, week 13 circulating tumor cell (CTC) and prostate-speci ﬁ c antigen (PSA) response end points in ﬁ ve prospective randomized phase III trials that enrolled a total of 6,081 patients — COU-AA-301, AFFIRM, ELM-PC-5, ELM-PC-4, and COMET-1 — ClinicalTrials.Gov identi ﬁ ers: NCT00638690, NCT00974311, NCT01193257, NCT01193244, and NCT01605227, respectively. Methods Eight response end points were explored. CTC nonzero at baseline and 0 at 13 weeks (CTC0); CTC conversion ( $ 5 CTCs at baseline, # 4 at 13 weeks — the US Food and Drug Administration cleared response measure); a 30%, 50%, and 70% decrease in CTC count; and a 30%, 50%, and 70% decrease in PSA level. Patients missing week-13 values were considered nonresponders. The discriminatory strength of each end point with respect to overall survival in each trial was assessed using the weighted c-index. Results Of the eight response end points, CTC0 and CTC conversion had the highest weighted c-indices, with smaller standard deviations. For CTC0, the mean (standard deviation) was 0.81 (0.04); for CTC conversion, 0.79 (0.03); for 30% decrease in CTC count, 0.72 (0.06); for 50% decrease in CTC count, 0.72 (0.06); for 70% decrease in CTC count, 0.73 (0.05); for 30% decrease in PSA level, 0.71 (0.03); for 50% decrease in PSA level, 0.72 (0.06); and for 70% decrease in PSA level, 0.74 (0.05). Seventy- ﬁ ve percent of eligible patients could be evaluated with the CTC0 end point, compared with 51% with the CTC conversion end point. Conclusion The CTC0 and CTC conversion end points had the highest discriminatory power for overall survival. Both are robust and meaningful response end points for early-phase metastatic castration-resistant prostate cancer clinical trials. CTC0 is applicable to a signi ﬁ cantly higher percentage of patients than CTC conversion. to develop intermediate end points for castration-resistant prostate cancer.

Circulating Tumor Cell Number as a Response Measure of Prolonged Survival for Metastatic Castration-Resistant Prostate Cancer: A Comparison With Prostate-Speci ﬁ c Antigen Across Five Randomized Phase III Clinical Trials

5034Background: Men with nmCRPC and prostate-specific antigen doubling time (PSADT) of ≤ 10 mo are at high risk for metastatic disease and associated death. Apalutamide (APA), a next-generation and...

Predicting disease progression in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC): An analysis from the phase 3 SPARTAN trial.

In the phase III ALSYMPCA trial, metastatic castration-resistant prostate cancer (mCRPC) patients had few prior life-prolonging therapies. Following ALSYMPCA, which demonstrated radium-223 survival benefit, and before radium-223 U.S. commercial availability, an expanded access program (EAP) providing early-access radium-223 allowed life-prolonging therapies in current use.

SUBJECTS, MATERIALS, AND METHODS
This phase II, open-label, single-arm, multicenter U.S. EAP (NCT01516762) enrolled patients with symptomatic mCRPC, ≥2 bone metastases, and no lung, liver, or brain metastases. Patients received radium-223 55 kBq/kg intravenously every 4 weeks × 6. Primary outcomes were acute and long-term safety. Additional analyses were done by number of radium-223 injections, and prior or concomitant abiraterone or enzalutamide use.

RESULTS
Of 252 patients, 184 received radium-223: 165/184 (90%) had Eastern Cooperative Oncology Group (ECOG) performance status 0-1; 183 (99%) had prior systemic anticancer therapy. Treatment-related adverse events occurred in 93/184 (51%) patients during treatment and 11 (6%) during follow-up. Median overall survival was 17 months, with 134/184 (73%) patients censored because of short follow-up due to radium-223 approval. In post hoc analyses, patients with ≥3 prior anticancer medications, baseline ECOG performance status ≥2, and lower baseline hemoglobin were less likely to receive 5-6 radium-223 injections and unlikely to benefit from radium-223. Radium-223 was well tolerated regardless of concurrent or prior abiraterone or enzalutamide.

CONCLUSION
Radium-223 was well tolerated, with no new safety concerns; safety was maintained with abiraterone or enzalutamide. Patients with more advanced disease were less likely to benefit from radium-223. Clinicians should consider baseline characteristics and therapy sequence for greatest clinical value.

IMPLICATIONS FOR PRACTICE
In this phase II U.S. expanded access program, radium-223 was well tolerated, with a median overall survival of 17 months in metastatic castration-resistant prostate cancer patients. In post hoc analyses, radium-223 was safe regardless of concurrent abiraterone or enzalutamide, and median overall survival appeared longer when radium-223 was used earlier in patients with less prior treatment. Patients with more advanced disease were less likely to benefit from radium-223. Clinicians should consider baseline clinical characteristics and therapy sequence to provide the greatest clinical value to patients.

Radium-223 Safety, Efficacy, and Concurrent Use with Abiraterone or Enzalutamide: First U.S. Experience from an Expanded Access Program.

Circulating Tumor Cell Number as a Response Measure of Prolonged Survival for Metastatic Castration-Resistant Prostate Cancer: Is Real Circulating Tumor Cell Number Superior to Prostate-Specific Antigen? Reply

Background Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration‐resistant prostate cancer who were at high risk for the development of metastasis. Methods We conducted a double‐blind, placebo‐controlled, phase 3 trial involving men with nonmetastatic castration‐resistant prostate cancer and a prostate‐specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo. All the patients continued to receive androgen‐deprivation therapy. The primary end point was metastasis‐free survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death. Results A total of 1207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after 378 events had occurred, median metastasis‐free survival was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (hazard ratio for metastasis or death, 0.28; 95% confidence interval [CI], 0.23 to 0.35; P<0.001). Time to symptomatic progression was significantly longer with apalutamide than with placebo (hazard ratio, 0.45; 95% CI, 0.32 to 0.63; P<0.001). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group. The following adverse events occurred at a higher rate with apalutamide than with placebo: rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2.0%), and fracture (11.7% vs. 6.5%). Conclusions Among men with nonmetastatic castration‐resistant prostate cancer, metastasis‐free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo. (Funded by Janssen Research and Development; SPARTAN ClinicalTrials.gov number, NCT01946204.)

Apalutamide Treatment and Metastasis‐free Survival in Prostate Cancer

225Background: Two phase III trials, COMET-1 and COMET-2, have reported that cabozantinib did not extend overall survival (OS) outcomes compared to prednisone and prednisone plus mitoxantrone respectively, in unselected post-docetaxel patients with mCRPC. We conducted a retrospective analysis of a combined dataset of these trials in an attempt to identify a benefit in subsets of patients based on prognostic risk factors. Methods: Baseline characteristics and survival data were combined for COMET-1 and COMET-2. Prognostic ability of baseline factors on survival was evaluated using Cox proportional hazards regression models, which incorporated the factors in the modern post-docetaxel nomogram and overall bone scan lesion area (BSLA) by computer-assisted analysis. Regression models included trial as a stratification factor. Evaluation of potentially benefited subsets was performed by the use of interaction terms between the factors and cabozantinib. The hazard ratio between cabozantinib and comparator arms w...

Cabozantinib for metastatic castration-resistant prostate cancer (mCRPC) following docetaxel: Combined analysis of two phase III trials.

TPS383Background: The addition of either docetaxel or abiraterone acetate plus prednisone to androgen deprivation therapy (ADT) improves overall survival (OS) compared with ADT alone in men with mHSPC. It is hypothesized that other androgen receptor (AR)-targeted therapies could be combined with docetaxel for mHSPC. Darolutamide (ODM-201) is an investigational oral AR antagonist with a unique chemical structure and negligible blood-brain barrier penetration that inhibits tumor growth by binding to AR and AR mutants (eg, W742L and F877L) with high affinity and specificity. In phase 1/2 ARADES and phase 1 ARAFOR trials, darolutamide demonstrated antitumor activity and was well tolerated in men with metastatic castration-resistant prostate cancer (mCRPC). ARASENS will evaluate the addition of darolutamide to standard ADT and docetaxel in men with mHSPC. Methods: This international, randomized, double-blind, placebo-controlled phase 3 trial (NCT02799602) is being conducted at > 300 sites in 23 countries. ~130...

ARASENS: A phase 3 trial of darolutamide in combination with docetaxel for men with metastatic hormone-sensitive prostate cancer (mHSPC).

161Background: Pts with nmCRPC are at risk for developing metastatic disease and cancer-specific mortality. There are no approved treatments for nmCRPC. APA is an orally administered next-generation androgen receptor inhibitor with antitumor activity in CRPC. SPARTAN evaluated the effects of APA on metastasis-free survival (MFS) in men with nmCRPC. Methods: Pts with nmCRPC and prostate-specific antigen doubling time (PSADT) of ≤ 10 mos were randomized 2:1 to APA (240 mg QD) or PBO. The primary end point was MFS, defined as the time from randomization to first radiographic distant metastasis (per blinded central review) or death. Secondary end points included time to metastasis (TTM), progression-free survival (PFS), time to symptomatic progression (SymProg), and overall survival (OS). Pts were eligible to receive study-provided abiraterone acetate plus prednisone after developing distant metastases. Second progression-free survival (PFS2, the time from randomization to disease progression or death after f...

SPARTAN, a phase 3 double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC).

5033Background: SPARTAN, a randomized placebo (PBO)-controlled phase 3 study, evaluated the effect of apalutamide (APA), an orally administered next-generation androgen receptor inhibitor, in men w...

Relationship of time to metastasis (TTM) and site of metastases in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC): Results from the phase 3 SPARTAN trial.

253Background: Metrics predicting a positive imaging test for men presumed M0 castration-resistant prostate cancer (CRPC) are not universally accepted/implemented. PREDICT (NCT01981109) evaluates characteristics predictive of a baseline (BL) imaging study positive for distant mets (M1) in men with presumed M0 CRPC, and follows those with confirmed M0 disease to M1 development. Methods: Men with no imaging in the previous 3 months (mos) were enrolled in the registry. Imaging modality to detect mets was at investigator’s discretion. Based on BL imaging, patients were classified as M0 or M1. Results: PREDICT enrolled 224 men, of whom 208 had BL scan/image data; 55 (25%) men presented with undetected M1. Visceral disease was noted in 11% of men presenting with M1 disease; 60% had bone only disease, 18% had nodal only disease and 11% had bone + nodal disease. Bone mets were found in 16% (25/160) of Tc99 scans vs 40% (19/48) of NaF PET (p = 0.0004). Of men with M0 at BL, 37/153 (24%) became M1 at a mean time fr...

Predict: Evaluation of baseline characteristics predictive of distant metastases in patients with castration-resistant prostate cancer—Updated data.

Effect of apalutamide on health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: an analysis of the SPARTAN randomised, placebo-controlled, phase 3 trial.

PD14-12 SECONDARY OUTCOMES OF A PROSPECTIVE RANDOMIZED TRIAL OF DIETARY CARBOHYDRATE RESTRICTION FOR MEN INITIATING ANDROGEN DEPRIVATION THERAPY: CARBOHYDRATE AND PROSTATE STUDY I (CAPS1)

Patient (pt) reported outcomes (PROs) in SPARTAN, a phase 3, double-blind, randomized study of apalutamide (APA) plus androgen deprivation therapy (ADT) vs placebo (PBO) plus ADT in men with nonmetastatic castration-resistant prostate cancer (nmCRPC)

e17010Background: Approved treatments for patients with mCRPC are associated with meaningful improvements in progression-free and overall survival. The burden of mCRPC remains high, however, as it ...

Impact of intervening in high-risk nonmetastatic castration-resistant prostate cancer (HRnmCRPC) on metastatic castration-resistant prostate cancer (mCRPC) disease burden.

Long‐Term Antitumor Activity and Safety of Enzalutamide Monotherapy in Hormone Naïve Prostate Cancer: 3‐Year Open Label Followup Results

PD10-11 PROSTATE-SPECIFIC ANTIGEN (PSA) OUTCOMES IN PATIENTS (PTS) WITH NONMETASTATIC CASTRATION-RESISTANT PROSTATE CANCER (NMCRPC) TREATED WITH APALUTAMIDE (APA): RESULTS FROM PHASE 3 SPARTAN STUDY

Introduction The next-generation AR inhibitor APA improves median metastasis-free survival by 2 yrs and second progression-free survival (PFS2; time from randomization to progression during the first mCRPC therapy or death) in men with nmCRPC and prostate-specific antigen doubling time ≤ 10 mos. AR anomalies (splice variants, ligand binding mutations, amplification) have been linked to AR signaling-targeted therapy resistance in mCRPC, but their relevance in nmCRPC is unknown. We assessed the frequency of AR anomalies after APA ± androgen deprivation therapy (ADT) and their effect on PFS2. Methods Pts received APA (240 mg QD) or placebo (PBO), with continuous ADT. ARv7 expression was tested using real-time PCR in 200 whole blood samples (end of treatment [EOT], first progression). Next-generation sequencing was performed on 240 EOT plasma samples to detect 5 clinically relevant AR mutations (L702H, W742C, H875Y, F877L, T878A) and AR amplification. Kaplan-Meier methods were used to estimate median PFS2, and Cox proportional hazard models to estimate HR and 95% CI. Results At EOT, 9.4% (9/96) of pts in the APA group and 12.5% (13/104) in the PBO group expressed ARv7. AR mutations were seen in 8.4% (10/118) and 6.5% (8/122) of pts in the APA and PBO groups, respectively. AR amplification occurred in 15.2% (18/118) and 14.7% (18/122) of pts in the APA and PBO groups, respectively. Although AR anomaly positivity had minimal impact on PFS2 with respect to APA, shorter median PFS2 was observed in AR anomaly-positive vs -negative pts, irrespective of treatment (Table). Conclusions APA treatment in nmCRPC pts did not increase the frequency of AR anomalies common in AR signaling-targeted therapy-resistant mCRPC. AR anomaly positivity was associated with shorter median PFS2 in the PBO group but not in the APA group. These preliminary findings suggest adding APA may circumvent mechanisms of resistance to standard ADT. Citation Format: Matthew R. Smith, Shibu Thomas, Simon Chowdhury, David Olmos, Jinhui Li, Paul N. Mainwaring, Stephane Oudard, Felix Y. Feng, Michael Gormley, Deborah S. Ricci, Brendan Rooney, Angela Lopez-Gitlitz, Margaret K. Yu, Eric J. Small. Androgen receptor (AR) anomalies and efficacy of apalutamide (APA) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) from the phase 3 SPARTAN study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2605.

Abstract 2605: Androgen receptor (AR) anomalies and efficacy of apalutamide (APA) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) from the phase 3 SPARTAN study

Clinical Development of Darolutamide: A Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer

5032Background: Intermediate clinical end points are needed for prostate cancer to inform clinical decisions and facilitate drug development. The international Intermediate Clinical Endpoints in Ca...

Association of metastasis-free survival (MFS) and overall survival (OS) in nonmetastatic castration-resistant prostate cancer (nmCRPC).

Purpose Measures of response that are clinically meaningful and occur early are an unmet need in metastatic castration-resistant prostate cancer clinical research and practice. We explored, using individual patient data, week 13 circulating tumor cell (CTC) and prostate-specific antigen (PSA) response end points in five prospective randomized phase III trials that enrolled a total of 6,081 patients-COU-AA-301, AFFIRM, ELM-PC-5, ELM-PC-4, and COMET-1- ClinicalTrials.Gov identifiers: NCT00638690, NCT00974311, NCT01193257, NCT01193244, and NCT01605227, respectively. Methods Eight response end points were explored. CTC nonzero at baseline and 0 at 13 weeks (CTC0); CTC conversion (≥ 5 CTCs at baseline, ≤ 4 at 13 weeks-the US Food and Drug Administration cleared response measure); a 30%, 50%, and 70% decrease in CTC count; and a 30%, 50%, and 70% decrease in PSA level. Patients missing week-13 values were considered nonresponders. The discriminatory strength of each end point with respect to overall survival in each trial was assessed using the weighted c-index. Results Of the eight response end points, CTC0 and CTC conversion had the highest weighted c-indices, with smaller standard deviations. For CTC0, the mean (standard deviation) was 0.81 (0.04); for CTC conversion, 0.79 (0.03); for 30% decrease in CTC count, 0.72 (0.06); for 50% decrease in CTC count, 0.72 (0.06); for 70% decrease in CTC count, 0.73 (0.05); for 30% decrease in PSA level, 0.71 (0.03); for 50% decrease in PSA level, 0.72 (0.06); and for 70% decrease in PSA level, 0.74 (0.05). Seventy-five percent of eligible patients could be evaluated with the CTC0 end point, compared with 51% with the CTC conversion end point. Conclusion The CTC0 and CTC conversion end points had the highest discriminatory power for overall survival. Both are robust and meaningful response end points for early-phase metastatic castration-resistant prostate cancer clinical trials. CTC0 is applicable to a significantly higher percentage of patients than CTC conversion.

Circulating Tumor Cell Number as a Response Measure of Prolonged Survival for Metastatic Castration-Resistant Prostate Cancer: A Comparison With Prostate-Specific Antigen Across Five Randomized Phase III Clinical Trials.

220Background: A phase 2 study of the androgen receptor inhibitor ENZ as monotherapy in patients with HNPC [NCT01302041] showed a high prostate-specific antigen (PSA) response rate, regardless of baseline metastases, and favorable tolerability. In a 1- and 2-year follow-up, ENZ maintained long-term reductions from baseline in PSA, with minimal impact on total-body bone mineral density (BMD). Herein, results from a pre-specified 3-year follow-up are reported. Methods: A total of67 patients with HNPC and non-castrate testosterone ( ≥ 230 ng/dL) received ENZ 160 mg/day until disease progression or unacceptable toxicity. The primary end point of PSA response ( ≥ 80% decline from baseline) was analyzed at week 25 and 1, 2, and 3 years. Other end points were best overall tumor response, BMD, body composition, quality of life, and safety. Results: At the 3-year visit, 42 (62.7%) patients remained on the study medication. Of those, 38 (90.5%; 95% confidence interval 77.4%, 97.3%) maintained a PSA response. Of the...

Long-term efficacy and safety of enzalutamide (ENZ) monotherapy in hormone-naïve prostate cancer (HNPC): 3-year, open-label, follow-up results.

Mortality and Androgen Deprivation Therapy as Salvage Treatment for Biochemical Recurrence after Primary Therapy for Clinically Localized Prostate Cancer

5007Background: Radiographic progression and overall survival (OS) are the traditional clinical benefit measures for mCRPC trials. Reliable indicators of response that occur early are a critical un...

Circulating tumor cell (CTC) number as a response endpoint in metastatic castration resistant (mCRPC) compared with PSA across five randomized phase 3 trials.

TPS5092Background: Androgen deprivation therapy (ADT) ± docetaxel is recommended first-line therapy for mHSPC, but most patients progress to castration-resistant PC (CRPC). BAY-1841788 (ODM-201) is...

ARASENS phase 3 trial of ODM-201 in men with metastatic hormone-sensitive prostate cancer (mHSPC).

Clinical Outcomes from Androgen Signaling-directed Therapy after Treatment with Abiraterone Acetate and Prednisone in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302.

A phase 3 randomized, double-blind, placebo-controlled trial of ODM-201 vs. placebo in combination with standard androgen deprivation therapy and docetaxel in patients with metastatic hormone-sensitive prostate cancer (ARASENS)

139Background: PD-L1 expression has been reported in 40% of gastroesophageal cancers, but little data exists with regards to expression of other immune checkpoints. Here, we examined baseline expression levels for multiple immune modulators in 31 resected esophageal adenocarcinomas (EAC) and investigated the change in expression levels post-chemoradiation. Methods: Slides were stained on a Ventana BenchMark ULTRA automated stainer for CTLA-4 (Santa Cruz Clone F-8, dilutions 1:100) and PD-L1 (Dako clone 22C3 prediluted). Tonsil tissue was used as a control for lymphocytes, and a provided tumor control was used for PD-L1. Positivity was classified as > 1%, and the stained cell type was recorded (lymphocytes or tumor). Additionally, laser capture microdissection was performed, and RNA was isolated and pre-amplified to determine expression levels of TIM-3, GITR, IDO-1, LAG-3, CD-137, OX-40, and KIR-3 using RT-PCR. Gene expression was calculated using the ΔΔ -Ct method, and intergroup comparisons were performe...

Checkpoint expression pre and post chemoradiation in operable esophageal cancer.

1470PDecisions and supports around clinical trial participation: A national study by Cancer Trials Ireland

bowel in eradicating the septic focus, which is consistent with the LOLA trial.1 Furthermore, the reoperation rate was significantly higher in the laparoscopic lavage group (20.3%) than in the resection group (5.7%). Dr Roberts questions the classification of reoperation as a severe complication. We would like to clarify that it was the event leading to reoperation that was considered a complication. In many cases, these were septic complications. Prolonged sepsis and repeated general anesthesia in severely ill patients is hazardous. The study did not include some of the most seriously ill patients, in whom it may have been even more important to get immediate control of the infective focus. Laparoscopic lavage carries the danger of recurrence because the diseased colon is left in-situ. Previous trials have shown that a delayed resection was necessary in several patients treated with laparoscopic lavage.1,2 Not resecting a perforated tumor, as in 4 patients in our study, is another major concern. We agree that a Hartmann procedure carries morbidity and perhaps primary anastomosis could be an option in more patients.3 In selected patients, laparoscopic lavage or nonoperative management may still be an option.4 However, further research is needed to find the right selection criteria. The long-term results of our trial are currently being collected and will hopefully enlighten these issues. Dr Mandrioli and colleagues question whether the preoperative randomization leading to the inclusion of some Hinchey grade I and II patients (n = 10 144) in this trial might have favored the resection group. We emphasize that 1 inclusion criterion was clinical indication for surgery. Furthermore, Hinchey grade I or II patients would probably have more benefit than harm from laparoscopic lavage compared with resection. This notion is supported by a study by Myers et al5 in which a higher proportion of Hinchey grade II patients were included and considerably better results were obtained with laparoscopic lavage. We consider intraoperative randomization to be more susceptible to bias because Hinchey grading is not always straightforward. Mandrioli and colleagues also question the choice of procedure for patients randomized to resection. Our aim was to compare laparoscopic lavage with common practice, which is why we chose a pragmatic design. The distribution of resection procedures was quite similar in included patients and patients treated outside the SCANDIV trial. Additionally, Mandrioli and colleagues are concerned regarding the technical skills of the surgeons in the laparoscopic lavage group. We included analysis of the variable “most experienced surgeon on the team” and it had no effect on the primary outcome. The frequency of secondary peritonitis, abdominal abscesses, and reoperations was similar in our trial and another recently published trial.1

Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer.

PURPOSE
Evolving treatments, disease phenotypes, and biology, together with a changing drug development environment, have created the need to revise castration-resistant prostate cancer (CRPC) clinical trial recommendations to succeed those from prior Prostate Cancer Clinical Trials Working Groups.

METHODS
An international expert committee of prostate cancer clinical investigators (the Prostate Cancer Clinical Trials Working Group 3 [PCWG3]) was reconvened and expanded and met in 2012-2015 to formulate updated criteria on the basis of emerging trial data and validation studies of the Prostate Cancer Clinical Trials Working Group 2 recommendations.

RESULTS
PCWG3 recommends that baseline patient assessment include tumor histology, detailed records of prior systemic treatments and responses, and a detailed reporting of disease subtypes based on an anatomic pattern of metastatic spread. New recommendations for trial outcome measures include the time to event end point of symptomatic skeletal events, as well as time to first metastasis and time to progression for trials in the nonmetastatic CRPC state. PCWG3 introduces the concept of no longer clinically benefiting to underscore the distinction between first evidence of progression and the clinical need to terminate or change treatment, and the importance of documenting progression in existing lesions as distinct from the development of new lesions. Serial biologic profiling using tumor samples from biopsies, blood-based diagnostics, and/or imaging is also recommended to gain insight into mechanisms of resistance and to identify predictive biomarkers of sensitivity for use in prospective trials.

PCWG3 moves drug development closer to unmet needs in clinical practice by focusing on disease manifestations most likely to affect prognosis adversely for therapeutics tested in both nonmetastatic and metastatic CRPC populations. Consultation with regulatory authorities is recommended if a trial is intended to seek support for drug approval.

Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3.

Cardiovascular Mortality Following Short-term Androgen Deprivation in Clinically Localized Prostate Cancer: An Analysis of RTOG 94-08.

Phase 2 Study of the Safety and Antitumor Activity of Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort

Modeling the Relationship Between Exposure to Abiraterone and Prostate-Specific Antigen Dynamics in Patients with Metastatic Castration-Resistant Prostate Cancer

PF1-091ARAMIS trial: Efficacy and safety of ODM-201 in men with high-risk nonmetastatic castration-resistant prostate cancer

TPS5094Background: Treatment for nonmetastatic castration-resistant prostate cancer (nmCRPC) other than continuing androgen deprivation therapy (ADT) remains an unmet need. There are no approved therapies for preventing metastatic disease in nmCRPC. Pts with nmCRPC who have shorter prostate-specific antigen doubling time (PSADT) are at higher risk for metastatic disease or death. ODM-201, a novel second-generation oral androgen receptor inhibitor, has demonstrated a tolerable safety profile and antineoplastic activity in progressive CRPC. The ARAMIS trial will evaluate the efficacy and safety of ODM-201 in high-risk nmCRPC pts. Methods: This randomized, double-blind, placebo-controlled phase 3 trial (NCT02200614) involves > 450 sites in > 33 countries. 1500 pts on ADT will be randomized 2:1 to ODM-201 600 mg or placebo BID. Pts will be stratified by PSADT and baseline bone-targeting agent use. Eligibility criteria include nmCRPC, PSADT ≤ 10 months, and screening PSA ≥ 2 ng/mL. 90% power to detect a target...

ARAMIS trial: Efficacy and safety of ODM-201 in men with high-risk nonmetastatic castration-resistant prostate cancer.

Use of androgen deprivation therapy as salvage treatment after primary therapy for clinically localized prostate cancer

ATLAS : A phase 3 trial evaluating the efficacy of apalutamide (ARN-509) in patients with high-risk localized or locally advanced prostate cancer receiving primary radiation therapy

Prostate cancer: A personalised approach through the development of patient-derived xenografts

168 Background: Treatment patterns of mCRPC have changed substantially in the last few years. In COU-AA-302 (chemotherapy-naive men with mCRPC), abiraterone acetate plus prednisone (AA) significantly improved radiographic progression-free survival and overall survival vs placebo plus prednisone (P). There is limited information about treatment patterns after AA. In this post hoc analysis of pts in the AA treatment arm who progressed, we characterized subsequent therapy after pts discontinued study drug. Methods: In COU-AA-302, 546 pts were randomized and received AA. Treatment patterns of pts receiving ≥ 1 subsequent therapy for mCRPC after progressing on AA were collected retrospectively and source verified. Results: As of March 2014, 8% (44/546) of pts continued on AA; 67% (365/546) received ≥ 1 subsequent therapy for mCRPC. 36% (194/546) and 15% (83/546) of pts had ≥ 2 and ≥ 3 subsequent therapies, respectively. 80% (435/543) of pts in the P arm had ≥ 1 subsequent therapy. Most frequent subsequent ther...

Treatment patterns after abiraterone acetate in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Post hoc analysis of COU-AA-302.

MP04-06 A PROSPECTIVE RANDOMIZED TRIAL OF DIETARY CARBOHYDRATE RESTRICTION FOR MEN INITIATING ANDROGEN DEPRIVATION THERAPY: CARBOHYDRATE AND PROSTATE STUDY I (CAPS1)

Purpose: Bone antiresorptive agents can significantly reduce bone turnover markers (BTM) in patients with advanced cancer. We evaluated association of changes in BTMs with overall survival (OS), disease progression (DP), and disease progression in bone (DPB) in patients with advanced cancer and bone metastases following denosumab or zoledronic acid treatment. Experimental Design: This is an integrated analysis of patient-level data from three identically designed, blinded, phase III trials with patients randomized to subcutaneous denosumab or intravenous zoledronic acid. Levels of the BTMs urinary N-telopeptide (uNTx) and serum bone-specific alkaline phosphatase (sBSAP) measured at study entry and month 3 were analyzed. OS, DP, and DPB were compared in patients with BTMs ≥ median versus < median based on month 3 assessments. Results: uNTx levels ≥ the median of 10.0 nmol/mmol at month 3 were associated with significantly reduced OS compared with levels < median (HR for death, 1.85; P < 0.0001). sBSAP levels ≥ median of 12.6 ng/mL were associated with significantly reduced OS compared with levels < median (HR, 2.44; P < 0.0001). uNTx and sBSAP levels ≥ median at month 3 were associated with significantly greater risk of DP (HR, 1.31; P < 0.0001 and HR, 1.71; P < 0.0001, respectively) and DPB (HR, 1.11; P = 0.0407 and HR, 1.27; P < 0.0001, respectively). Conclusions: BTM levels ≥ median after 3 months of bone antiresorptive treatment were associated with reduced OS and increased risk of DP and DPB. Assessment of uNTx and sBSAP levels after bone antiresorptive therapy may add to identification of patients at risk for worse clinical outcomes. Clin Cancer Res; 22(23); 5713–21. ©2016 AACR.

Changes in Bone Turnover Marker Levels and Clinical Outcomes in Patients with Advanced Cancer and Bone Metastases Treated with Bone Antiresorptive Agents

Prior Endocrine Therapy Impact on Abiraterone Acetate Clinical Efficacy in Metastatic Castration-resistant Prostate Cancer: Post-hoc Analysis of Randomised Phase 3 Studies.

TPS5087Background: At present, high-risk localized and locally advanced prostate cancer (PC) patients receiving primary radiation therapy (RT) and long-term androgen deprivation therapy (ADT; gonad...

ATLAS: A randomized, double-blind, placebo-controlled, phase 3 trial of apalutamide (ARN-509) in patients with high-risk localized or locally advanced prostate cancer receiving primary radiation therapy.

PURPOSE
Cabozantinib is an inhibitor of kinases, including MET and vascular endothelial growth factor receptors, and has shown activity in men with previously treated metastatic castration-resistant prostate cancer (mCRPC). This blinded phase III trial compared cabozantinib with prednisone in patients with mCRPC.

PATIENTS AND METHODS
Men with progressive mCRPC after docetaxel and abiraterone and/or enzalutamide were randomly assigned at a two-to-one ratio to cabozantinib 60 mg once per day or prednisone 5 mg twice per day. The primary end point was overall survival (OS). Bone scan response (BSR) at week 12 as assessed by independent review committee was the secondary end point; radiographic progression-free survival (rPFS) and effects on circulating tumor cells (CTCs), bone biomarkers, serum prostate-specific antigen (PSA), and symptomatic skeletal events (SSEs) were exploratory assessments.

RESULTS
A total of 1,028 patients were randomly assigned to cabozantinib (n = 682) or prednisone (n = 346). Median OS was 11.0 months with cabozantinib and 9.8 months with prednisone (hazard ratio, 0.90; 95% CI, 0.76 to 1.06; stratified log-rank P = .213). BSR at week 12 favored cabozantinib (42% v 3%; stratified Cochran-Mantel-Haenszel P < .001). rPFS was improved in the cabozantinib group (median, 5.6 v 2.8 months; hazard ratio, 0.48; 95% CI, 0.40 to 0.57; stratified log-rank P < .001). Cabozantinib was associated with improvements in CTC conversion, bone biomarkers, and post-random assignment incidence of SSEs but not PSA outcomes. Grade 3 to 4 adverse events and discontinuations because of adverse events were higher with cabozantinib than with prednisone (71% v 56% and 33% v 12%, respectively).

Cabozantinib did not significantly improve OS compared with prednisone in heavily treated patients with mCRPC and progressive disease after docetaxel and abiraterone and/or enzalutamide. Cabozantinib had some activity in improving BSR, rPFS, SSEs, CTC conversions, and bone biomarkers but not PSA outcomes.

Phase III Study of Cabozantinib in Previously Treated Metastatic Castration-Resistant Prostate Cancer: COMET-1.

TPS5088Background: Radium-223 dichloride (Ra-223), a first-in-class alpha-emitting radiopharmaceutical targeting bone metastases (mets), reduced risk of death and delayed time to first symptomatic ...

ERA 223: A phase 3 trial of radium-223 dichloride in combination with abiraterone acetate and prednisone in the treatment of asymptomatic or mildly symptomatic chemotherapy-naïve patients with bone-predominant metastatic castration-resistant prostate cancer.

Subsequent Chemotherapy and Treatment Patterns After Abiraterone Acetate in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302

668 Response to taxane chemotherapy as first subsequent therapy after abiraterone acetate in patients with metastatic castration-resistant prostate cancer (mCRPC): Post hoc analysis of COU-AA-302

139 Background: Cabo inhibits tyrosine kinases including MET and VEGFRs. In a phase 2 study in mCRPC pts, Cabo was associated with improvements in bone scans, pain, measurable disease, and circulating tumor cells. COMET-1 compared the effects of Cabo versus Pred on overall survival (OS) in men with progressive mCRPC and prior D and A and/or E. Methods: In this randomized, double-blind, controlled phase 3 study (NCT01605227), pts with mCRPC and prior D and A and/or E were randomized 2:1 to receive Cabo (60 mg qd) or Pred (5 mg bid). Pts were stratified by prior treatment with cabazitaxel, ECOG status, and presence of moderate to severe pain. The primary endpoint was OS. The study was designed to observe 578 deaths to provide 90% power to detect a hazard ratio (HR) of 0.75. A secondary endpoint was bone scan response at Week 12 (BSR) determined by central independent radiology committee, defined as a ≥30% decrease in the bone scan lesion area compared to baseline. Exploratory endpoints include PFS and OS su...

Final analysis of COMET-1: Cabozantinib (Cabo) versus prednisone (Pred) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) previously treated with docetaxel (D) and abiraterone (A) and/or enzalutamide (E).

247 Background: The ALSYMPCA study (Parker, NEJM, 2013) was the basis for regulatory approval of Ra-223 for the treatment of castrate-resistant prostate cancer (CRPC) patients (pts) with symptomatic bone metastases. The aim of this prospective EAP was to monitor acute and long-term safety of Ra-223. Pt profiles and findings in the EAP setting are presented. Methods: In the EAP, CRPC pts with symptomatic bone metastases who either received or were not eligible for docetaxel received Ra-223 50 kBq/kg by injection q4wks for 6 cycles. Primary endpts: ECOG PS, symptomatic skeletal-related events (SSE), treatment-emergent adverse events [TEAEs], routine laboratory tests including PSA. Exploratory endpts: overall survival (OS), SSE rates, changes in total ALP (tALP)/PSA responses, time to tALP normalization, and to tALP and PSA progression. Descriptive statistics were used. Results: 184 pts entered treatment; baseline characteristics were similar as seen in ALSYMPCA (N=600) (exceptions in table); 67% had total A...

Radium-223 dichloride (Ra-223) in U.S. expanded access program (EAP).

Impact of bone-targeted therapies in chemotherapy-naïve metastatic castration-resistant prostate cancer patients treated with abiraterone acetate: post hoc analysis of study COU-AA-302.

e22236 Background: Advanced cancer pts with metastatic bone disease typically have elevated BTM levels. Antiresorptive agents such as denosumab (DMAB) and zoledronic acid (ZA) can significantly reduce BTM levels. We evaluated BTM levels after treatment with these agents in advanced cancer pts with bone metastases. Methods: This post hoc analysis represents patient-level data from 3 identically designed, blinded, phase 3 trials with pts randomized to receive DMAB (120 mg SC) or ZA (4 mg IV, adjusted for creatinine clearance). The BTMs urinary N-telopeptide (uNTx) and bone-specific alkaline phosphatase (BSAP) were measured at study entry and 3 months. Disease progression (DP), overall survival (OS), and DP in the bone (DPB) were compared in pts with BTMs above and below median levels at month 3 by covariate analyses stratified by treatment and stratification factors based on month 3 assessments. Results: Pts with uNTx levels ≥ the median level of 10.04 nmol/mmol at month 3 had a significantly greater risk o...

Bone turnover marker (BTM) levels and clinical outcomes in advanced cancer patients (pts) treated with antiresorptive bone therapies.

Metastatic Prostate Cancer and the Bone: Significance and Therapeutic Options.

TPS5080 Background: There is no standard treatment for nmCRPC besides continuing androgen deprivation therapy (ADT). Preventing metastatic disease in nmCRPC is a major unmet need. Patients with nmC...

ARAMIS trial: Efficacy and safety phase 3 trial of ODM-201 in men with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC).

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA

Background: ARN-509 is a second-generation antiandrogen with antitumor activity in CRPC. Activating mutations in the AR ligand-binding domain (LBD) have been associated with resistance to first- (T877A) and second- (F876L) generation antiandrogens. We evaluated the type and frequency of relevant AR LBD mutations in ARN-509-treated CRPC pts at baseline (BL) and disease progression (PD).

Methods: ARN-509-001 was a phase I/II study that evaluated ARN-509 activity in nonmetastatic (M0), chemotherapy-naive, and post-AA CRPC. Of the 97 pts enrolled in phase II at a dose of 240 mg/d, 92 were evaluable for the mutation analysis at BL and 82 at PD. Relevant mutations in circulating tumor DNA were detected using a digital PCR method called BEAMing (Beads, Emulsification, Amplification, and Magnetics) (Richardson AL. Clin Cancer Res. 2012).

Results: Median duration of therapy was ∼16 months. One pt in the M0 cohort and one in the chemotherapy-naive cohort had the F876L mutation at BL. Two pts in the chemotherapy-naive cohort and one in the post-AA cohort acquired the AR F876L mutation during treatment. Pts with M0 CRPC did not acquire a mutation (Table 1). Three pts in the post-AA cohort had the T877A mutation at BL; the T877A mutation was not detected in any other cohort at BL. In the post-AA cohort, one pt acquired the T877A mutation during treatment while another lost the mutation (Table). The two pts with detectable F876L at BL developed prostate-specific antigen (PSA) progression at 4 and 6 months, respectively, compared with a median time to PSA progression of 16.4 months in the remainder of pts.

Conclusions: Pts with metastatic CRPC who were treated with ARN-509 had a low rate of acquisition of the AR F876L (3/82 = 4%) and AR T877A (1/82 = 1%) mutations. These results suggest that ARN-509 may be continued in the setting of a rising PSA. Larger studies are needed to confirm the prevalence of F876L, T877A, and the conversion rate.

| | | AR F876L | AR T877A |
|:------------------ | --------- | -------- | -------- | -------- |
| | Evaluable | BL | PD | Acquired | BL | PD | Acquired |
| | patients | n/N | n/N | | n/N | n/N | |
| Total | 92 | 2/92 | 5/82 | 3/82 | 3/92 | 3/82 | 1/82 |
| M0 | 49 | 1/49 | 1/47 | 0/47 | 0/50 | 0/47 | 0/47 |
| Chemotherapy-naive | 24 | 1/24 | 3/20 | 2/20 | 0/20 | 0/20 | 0/20 |
| Post-AA | 19 | 0/19 | 1/15 | 1/15 | 3/19 | 3/15 | 1/15 |

Citation Format: Dana E. Rathkopf, Matthew R. Smith, Emmanuel S. Antonarakis, Charles J. Ryan, William R. Berry, Neal D. Shore, Glenn Liu, Celestia Higano, Joshi J. Alumkal, Ralph Hauke, Ronald Tutrone, Mansoor Saleh, Edna Chow Maneval, Shibu Thomas, Deborah Ricci, Margaret K. Yu, Carla J. de Boer, Angela Trinh, Thian Kheoh, Rajesh Bandekar, Howard I. Scher. Androgen receptor (AR) mutations in patients (pts) with castration-resistant prostate cancer (CRPC) with and without prior abiraterone acetate (AA) treatment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT134. doi:10.1158/1538-7445.AM2015-CT134

Abstract CT134: Androgen receptor (AR) mutations in patients (pts) with castration-resistant prostate cancer (CRPC) with and without prior abiraterone acetate (AA) treatment

Data shown are the first of each SRE/SSE event type (radiation to bone, fracture, or surgery to bone, or spinal cord compression) without considering when the other event types first occurred. For SSE, the incidence of symptomatic pathologic fractures and symptomatic spinal cord compression is shown. For SRE, the incidence of pathologic fractures and spinal cord compression is shown. For first and subsequent skeletal events, regardless of whether assessed as SRE or SSE, only events occurring ≥21 days after the previous event were counted, and if multiple event types occurred on the same day, only one event was counted based on the following priority order (based on severity): (i) spinal cord compression, (ii) surgery to bone, (iii) fracture, and (iv) radiation to bone. For these reasons, some first and subsequent events may not have been counted, resulting in a lower incidence than first skeletal events (e.g. 15 versus 24 surgery to bone events assessed as SSE). co rr ig en du m corrigendum Annals of Oncology 26: 1274, 2015 doi:10.1093/annonc/mdv155

Denosumab for the prevention of skeletal complications in metastatic castration-resistant prostate cancer: comparison of skeletal-related events and symptomatic skeletal events

184 Background: In study COU-AA-302 of chemotherapy-naive men with mCRPC, AA plus prednisone (AA) significantly improved radiographic progression-free survival and overall survival vs placebo plus prednisone (P). There is limited information about response to subsequent therapy after AA. In this post hoc analysis of pts in the AA treatment arm who progressed, we evaluated the clinical outcome to chemotherapy as first subsequent therapy. Methods: In COU-AA-302, 546 pts were randomized and received AA. Clinical outcome and discontinuation data from pts receiving chemotherapy as first subsequent therapy after progressing on AA were collected retrospectively and source verified. Median time to prostate-specific antigen (PSA) progression was estimated using the Kaplan-Meier method. Results: 73% (365/502; 44 still continuing on AA) of pts in the AA treatment arm received ≥ 1 subsequent therapy. Chemotherapy, docetaxel (DOC) or cabazitaxel (CBZ), was the most common first subsequent therapy. As of March 2014, fo...

Response to taxane chemotherapy as first subsequent therapy after abiraterone acetate (AA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Post-hoc analysis of COU-AA-302.

5000 Background: The availability of new agents for men with CRPC, recognition of new disease phenotypes, and an evolving regulatory environment have created the need for new CRPC clinical trial gu...

The Prostate Cancer Working Group 3 (PCWG3) consensus for trials in castration-resistant prostate cancer (CRPC).

Risk of diabetes among patients receiving primary androgen deprivation therapy for clinically localized prostate cancer.

Effects of cabozantinib on pain and narcotic use in patients with castration-resistant prostate cancer: results from a phase 2 nonrandomized expansion cohort.

MP73-10 BONE TURNOVER MARKER LEVELS AND OUTCOMES IN MEN WITH PROSTATE CANCER AND BONE METASTASES TREATED WITH BONE ANTIRESORPTIVE AGENTS

e16028 Background: At diagnosis, most men with PC have localized disease with no distant metastases (M0) or regional lymphadenopathy (N0). After therapy, 20–40% of men have biochemical recurrence, often treated with androgen deprivation therapy (ADT). Other pts may receive primary ADT for N0/M0 disease. Both groups are at risk of CRPC, ie rising prostate-specific antigen (PSA) in absence of radiographic proven metastatic disease (M0). Metrics predicting a positive imaging test for men presumed M0 CRPC are not universally accepted/implemented. PREDICT’s primary objective is to evaluate characteristics predictive of a BL imaging study positive for distant metastases (M1) in men thought to have M0 CRPC. Methods: Eligible men have M0 CRPC, no prior M1, no imaging in > 3 mos and are classified as M0 or M1 based on BL bone and soft tissue imaging. Pts will be followed for 3 (M0) to 5 (M1) yrs after last pt registration. Results: Sixty-five men have BL scans and interim descriptive BL data. At BL, 18/65 (28%) me...

PREDICT, a study evaluating baseline (BL) disease characteristics predictive of a positive imaging study for distant metastases in patients (pts) with castration-resistant prostate cancer (CRPC): Preliminary data.

TPS5082 Background: Ra-223, a first-in-class alpha-emitting radiopharmaceutical targeting bone metastases, reduced risk of death by 30% and delayed time to first symptomatic skeletal event (SSE) ve...

ERA 223: A phase 3 trial of radium-223 dichloride (Ra-223) in combination with abiraterone acetate (abiraterone) and prednisone in the treatment of asymptomatic or mildly symptomatic chemotherapy-naïve patients (pts) with bone predominant metastatic castration-resistant prostate cancer (mCRPC).

5063 Background: The early-access program aimed to monitor acute and long-term Ra-223 safety. Herein the number of Ra-223 cycles was examined in relation to prior therapy with abiraterone (abi) and/or enzalutamide (enza). These agents were not approved at the time of the ALSYMPCA trial, the basis for Ra-223 approval. Methods: Symptomatic bone metastatic CRPC patients (pts) and no visceral mets were enrolled in the US if they were ineligible for (or refused) docetaxel (Doc), or had prior Doc. Ra-223 at 50 kBq/kg IV q 4weeks was planned for 6 cycles concomitant with "standard of care". We assessed the baseline characteristics and number of cycles administered in pts naive to, with prior use of either/or, and abi + enza. Results: Of 184 pts; 39 had prior abi + enza; 65 had abi or enza; 47 were naive. Notable differences in baseline demographics were seen in the prior abi + enza group with higher baseline median values for PSA, alk phos, and a higher % of pts with prior Doc (85%). The abi + enza pre-treated g...

Purpose: We constructed a biomarker-survival modeling framework to explore the relationship between prostate-specific antigen (PSA) kinetics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients following oral administration of 1,000 mg/day of abiraterone acetate (AA). Experimental Design: The PSA-survival modeling framework was based on data from two phase III studies, COU-AA-301 (chemotherapy pretreated, n = 1,184) and COU-AA-302 (chemotherapy naïve, n = 1,081), and included a mixed-effects tumor growth inhibition model and a Cox proportional hazards survival model. Results: The effect of AA on PSA kinetics was significant (P < 0.0001) and comparable between the chemotherapy-naïve and -pretreated patients. PSA kinetics [e.g., PSA nadir, PSA response rate (≥30%, 50%, and 90%), time to PSA progression, PSA doubling time (PSADT)] were highly associated with OS in both populations. The model-based posttreatment PSADT had the strongest association with OS (HR ∼0.9 in both populations). The models could accurately predict survival outcomes. After adjusting for PSA kinetic endpoints, the treatment effect of AA on survival was no longer statistically significant in both studies, and the Prentice criteria of surrogacy were met for the PSA kinetic endpoints. A strong correlation was also observed between PSA and radiographic progression-free survival. Conclusions: The analysis revealed a consistent treatment effect of AA on PSA kinetics and strong associations between PSA kinetics and OS in chemotherapy-pretreated and -naïve patients, thereby providing a rationale to consider PSA kinetics as surrogacy endpoints to indicate clinical benefit in AA-treated patients with mCRPC regardless of chemotherapy treatment. Clin Cancer Res; 21(14); 3170–7. ©2015 AACR.

Correlation between Prostate-Specific Antigen Kinetics and Overall Survival in Abiraterone Acetate–Treated Castration-Resistant Prostate Cancer Patients

267 Background: Denosumab, compared with ZA, has recently demonstrated significant benefits in preventing skeletal-related events (SREs) in a double-blind phase 3 study of men with castration-resistant PC and bone metastases (N=1901). This post hoc analysis was performed to determine if key bone metabolism biomarker levels correlated with time-to-first SRE. Methods: Time-to-Grade ≥2 increase in total serum alkaline phosphatase (ALP) was assessed for correlation with time-to-first SRE. Levels of urinary N-telopeptide (uNTX) and serum bone-specific alkaline phosphatase (BSAP) markers were measured at baseline and study week 13, and correlations with time-to-first SRE were assessed. Covariate analyses were performed using a Cox proportional hazards model, stratified by treatment group or (for baseline analyses) with treatment group as the independent variable. Results: Analysis of the relationship between time-to-Grade ≥2 increase in total ALP and time-to-first SRE demonstrated that Grade ≥2 increases in ALP...

Bone metabolism biomarkers in men with advanced prostate cancer (PC) and bone metastases treated with denosumab versus zoledronic acid (ZA).

Efficacy and Safety of Abiraterone Acetate in Elderly (75 Years or Older) Chemotherapy Naïve Patients with Metastatic Castration Resistant Prostate Cancer.

MP87-16 NOVEL ANTIANDROGEN ARN-509 IN HIGH-RISK NONMETASTATIC CASTRATION-RESISTANT PROSTATE CANCER

556 Abiraterone acetate improves overall survival in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC): Impact of crossover and baseline prognostic factors in the COU-AA-302 final analysis

672 Prior and concurrent use of abiraterone and enzalutamide with radium-223 dichloride (Ra-223) in US expanded access setting (EAP)

Adverse effects of androgen deprivation therapy and strategies to mitigate them.

Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study.

Active surveillance for low-risk prostate cancer: Need for intervention and survival at 10 years.

MP87-12 RADIUM-223 DICHLORIDE IN EXPANDED-ACCESS SETTING IN THE UNITED STATES: OVERALL AND CONCURRENT EXPERIENCE WITH ABIRATERONE OR ENZALUTAMIDE

Bone-related Parameters are the Main Prognostic Factors for Overall Survival in Men with Bone Metastases from Castration-resistant Prostate Cancer.

Long-term Efficacy and Safety of Enzalutamide Monotherapy in Hormone-naïve Prostate Cancer: 1- and 2-Year Open-label Follow-up Results.

142 Background: AA + prednisone (P) significantly increased OS, time to opiate use, and was well tolerated at the COU-AA-302 final analysis. Here we further characterize OS benefit adjusting for crossover therapy and for baseline prognostic factors. Methods: Patients (N = 1,088) were randomized 1:1 to receive AA (1 g) + P (5 mg po BID) vs P. Co-primary end points were radiographic progression-free survival and OS. Median time to events with 95% CI was estimated using the Kaplan-Meier method. Stratified log-rank test was used to test the difference in treatment effect. Adjustment for crossover utilized the iterative parameter estimate (IPE) and impact of baseline prognostic factors was examined via the multivariate Cox proportional hazard model. Results: With a median follow-up of 49.2 months and 741 deaths (96% of required), AA + P significantly reduced the risk of death vs P (19%) and prolonged median OS (34.7 vs 30.3 months) (Table). 44% of patients initially receiving P alone subsequently received AA +...

Impact of crossover and baseline prognostic factors on overall survival (OS) with abiraterone acetate (AA) in the COU-AA-302 final analysis.

253 Background: The aim of this prospective early-access program (EAP) was to monitor acute and long-term safety of Ra-223 CL2. The ALSYMPCA RA-223 phase III trial was completed prior to abiraterone (Abi) and enzalutamide (Enza) approval. Herein we provide experience with RA-223 in relationship to Abi and Enza. Methods: Symptomatic bone metastatic CRPC pts in the US who were ineligible for or had prior docetaxel were enrolled. Treatment included Ra-223 50 kBq/kg IV q4weeks for 6 cycles concomitant with standard of care medications. Analyses were conducted to assess safety and overall survival (OS) in pts with prior and concurrent Abi and Enza. Results: Of 184 treated, 120 (65%) had prior and 35 (19%) pts had concurrent Abi; 59 (32%) had prior and 25 (14%) pts had concurrent Enza. Baseline characteristics were generally balanced in the overall and across prior and concurrent groups. Pts with no concurrent Abi or Enza had a similar OS to the overall group (Abi 16m, Enza 17m, overall 17m). Due to a small num...

Prior and concurrent use of abiraterone and enzalutamide with Ra-223 in an expanded access setting.

869 Prevention of symptomatic skeletal events in patients with genitourinary (GU) tumours and bone metastases treated with denosumab or zoledronic acid

MP78-01 THE BURDEN OF SKELETAL-RELATED EVENTS ON PAIN OUTCOMES IN PATIENTS WITH CASTRATION-RESISTANT PROSTATE CANCER

TPS5100 Background: ADT is the standard of care for patients (pts) with metastatic prostate cancer and is frequently used in pts with non-metastatic prostate cancer. Initial ADT achieves responses in nearly all pts, but most progress to castration-resistant disease within a few years. Among men with M0-CRPC, a rising prostate-specific antigen (PSA) heralds the development of metastases and associated morbidity and mortality. Prevention of metastases is a major unmet medical need in M0-CRPC. ARN-509 (ARN) is a potent and selective androgen receptor (AR) antagonist that inhibits AR nuclear translocation and DNA binding without significant AR agonist properties (Clegg N et al. Cancer Res.2012). ARN demonstrates a 12- and 24-week PSA response rate of 91% in M0-CRPC pts and an excellent safety profile (Smith MR et al. ASCO GU 2013; Smith MR et al. ESMO 2013). Methods: This is a multicenter, double-blind, placebo-controlled, phase 3 trial evaluating the efficacy and safety of ARN in pts with M0-CRPC at high ris...

A randomized double-blind, comparative study of ARN-509 plus androgen deprivation therapy (ADT) versus ADT alone in nonmetastatic castration-resistant prostate cancer (M0-CRPC): The SPARTAN trial.

Androgen-deprivation therapy and diabetes control among diabetic men with prostate cancer.

58 Background: Abiraterone acetate (AA) is an effective therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). AA is metabolized to abiraterone, an androgen biosynthesis inhibitor. We performed population pharmacokinetic (PK) analyses to estimate PK parameters after a 1,000 mg/d oral dose of AA in patients with mCRPC with and without prior chemotherapy and after a one-time 1,000 mg dose in healthy volunteers, to determine consistency between groups. Methods: Studies included in analysis: COU-AA-302 (pre-chemotherapy mCRPC); COU-AA-301 and COU-AA-006 (post-docetaxel mCRPC); and COU-AA-008, COU-AA-009, and COU-AA-014 (healthy subjects). A total of 4,627 plasma concentrations from 360 subjects were analyzed using nonlinear mixed-effects modeling. Results: A two-compartment model with three-transit compartments following sequential zero-first order kinetics was used to characterize the systemic absorption of abiraterone. Absorption-related parameters were affected by food intake. A...

Population pharmacokinetic analysis of abiraterone acetate in healthy volunteers and chemotherapy-naive and chemotherapy-pretreated metastatic castration-resistant prostate cancer patients.

CONTEXT
Myostatin is a negative regulator of muscle growth. Androgen deprivation (ADT) is associated with muscle loss and increased body fat, and currently available therapies have limited efficacy to treat this complication. The antimyostatin peptibody (AMG 745/Mu-S) markedly attenuated muscle loss and decreased fat accumulation in orchiectomized mice.

OBJECTIVE
The objective of the study was to evaluate the safety, pharmacokinetics, and muscle efficacy of AMG 745 in men undergoing ADT for nonmetastatic prostate cancer.

METHODS
This was a randomized, blinded, placebo-controlled, multiple-dose, phase 1 study of AMG 745 given for 28 days. The end point of percentage change from baseline in lean body mass (LBM) as assessed by dual x-ray absorptiometry was prespecified.

RESULTS
Rates of adverse events (AMG 745 vs placebo) were the following: diarrhea (13% vs 9%), fatigue (13% vs 4%), contusion (10% vs 0%), and injection site bruising (6% vs 4%). Exposure increased linearly from 0.3 mg/kg to 3 mg/kg. AMG 745 significantly increased LBM in the 3 mg/kg vs the placebo groups on day 29 by 2.2% (±0.8% SE, P = 0.008); in exploratory fat mass analysis, a decrease of -2.5% (±1.0% SE, P = 0.021) was observed. Pharmacodynamic changes in muscle and fat were maintained at follow-up, 1 month after day 29.

Four weekly s.c. doses of AMG 745 were well tolerated and were associated with increased LBM and decreased fat in the men receiving ADT for nonmetastatic prostate cancer. RESULTS support further investigation of AMG 745 in clinical settings with muscle loss and atrophy.

Pharmacological inhibition of myostatin and changes in lean body mass and lower extremity muscle size in patients receiving androgen deprivation therapy for prostate cancer.

PURPOSE
Cabozantinib (XL184), an oral inhibitor of multiple receptor tyrosine kinases such as MET and VEGFR2, was evaluated in a phase II nonrandomized expansion study in castration-resistant prostate cancer (CRPC).

Patients received open-label cabozantinib at daily starting doses of 100 mg or 40 mg until disease progression or unacceptable toxicity. The primary end point was bone scan response, defined as ≥ 30% reduction in bone scan lesion area. Other efficacy end points included overall survival, pain, analgesic use, and biomarkers.

RESULTS
One hundred forty-four patients sequentially enrolled in either a 100-mg (n = 93) or 40-mg (n = 51) study cohort. Ninety-one patients (63%) had a bone scan response, often by week 6. Treatment resulted in clinically meaningful pain relief (57% of patients) and reduction or discontinuation of narcotic analgesics (55% of patients), as well as improvements in measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Improvements in each of these outcomes were observed in both cohorts: bone scan response in 73% and 45%, respectively; reductions in measurable soft tissue disease in 80% and 79%, respectively. Median overall survival was 10.8 months for the entire population. Most common grade 3 or 4 adverse events were fatigue (22%) and hypertension (14%). Fewer dose reductions because of toxicity were required in the 40-mg group.

The evidence suggests that cabozantinib has clinically meaningful activity in CRPC. Cabozantinib resulted in improvements in bone scans, pain, analgesic use, measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Taken together, these phase II observations warrant further development of cabozantinib in prostate cancer.

Cabozantinib in chemotherapy-pretreated metastatic castration-resistant prostate cancer: results of a phase II nonrandomized expansion study.

39 Background: Abiraterone, the active metabolite of abiraterone acetate (AA), is an effective androgen biosynthesis inhibitor for patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted a sequential exposure-biomarker-survival modeling analysis to explore the relationship between prostate-specific antigen (PSA) kinetics and overall survival (OS) and to establish the exposure response for PSA kinetics and OS in chemotherapy-naive and -pretreated patients with mCRPC following AA administration. Methods: The exposure-PSA-survival modeling framework was based on two phase III studies, COU-AA-301 (chemotherapy-pretreated, N = 1184) and COU-AA-302 (chemotherapy-naive, N = 1081), and included a mixed-effects tumor growth inhibition (TGI) model to describe PSA dynamics in response to AA and a Cox proportional hazards survival model to evaluate the relationship between relative risk of death and PSA dynamic end points. Results: The TGI model best described the longitudinal PSA dynamics...

Relationship between abiraterone exposure, prostate-specific antigen (PSA) kinetics, and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) .

12 Background: Patients with castration-resistant prostate cancer (CRPC) and bone metastases (BM) may experience debilitating pain that impacts daily functioning and diminishes the quality of life....

Denosumab or zoledronic acid (ZA) therapy on pain interference and cancer-specific quality of life (CSQoL) in patients with castrate-resistant prostate cancer (CRPC) and bone metastases (BM).

PURPOSE
Primary androgen-deprivation therapy (PADT) is often used to treat clinically localized prostate cancer, but its effects on cause-specific and overall mortality have not been established. Given the widespread use of PADT and the potential risks of serious adverse effects, accurate mortality data are needed to inform treatment decisions.

METHODS
We conducted a retrospective cohort study using comprehensive utilization and cancer registry data from three integrated health plans. All men were newly diagnosed with clinically localized prostate cancer. Men who were diagnosed between 1995 and 2008, were not treated with curative intent therapy, and received follow-up through December 2010 were included in the study (n = 15,170). We examined all-cause and prostate cancer-specific mortality as our main outcomes. We used Cox proportional hazards models with and without propensity score analysis.

RESULTS
Overall, PADT was associated with neither a risk of all-cause mortality (hazard ratio [HR], 1.04; 95% CI, 0.97 to 1.11) nor prostate-cancer-specific mortality (HR, 1.03; 95% CI, 0.89 to 1.19) after adjusting for all sociodemographic and clinical characteristics. PADT was associated with decreased risk of all-cause mortality but not prostate-cancer-specific mortality. PADT was associated with decreased risk of all-cause mortality only among the subgroup of men with a high risk of cancer progression (HR, 0.88; 95% CI, 0.78 to 0.97).

We found no mortality benefit from PADT compared with no PADT for most men with clinically localized prostate cancer who did not receive curative intent therapy. Men with higher-risk disease may derive a small clinical benefit from PADT. Our study provides the best available contemporary evidence on the lack of survival benefit from PADT for most men with clinically localized prostate cancer.

Effectiveness of primary androgen-deprivation therapy for clinically localized prostate cancer.

MP70-17 OPTIMAL TESTOSTERONE SUPPRESSION ON MEDICAL ANDROGEN DEPRIVATION THERAPY SHOULD STRIVE TO SUPPRESS FREE TESTOSTERONE LEVELS, TO LEVELS SIMILAR TO ORCHIECTOMY--WHAT IS THAT VALUE?

Association of alkaline phosphatase with clinical outcomes in chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC): results from COU-AA-302

27 Background: Prognostic models have been developed for men with mCRPC. In this analysis we undertook a pragmatic approach to focus on commonly obtained markers. Baseline ALP and normalization of elevated ALP post-docetaxel have prognostic value for overall survival (OS). We examined the association between ALP and prostate-specific antigen (PSA) elevation at baseline and after 4 cycles of therapy (C5D1), when both markers were assessed, with long-term clinical outcomes in COU-AA-302, a randomized phase 3 study of abiraterone acetate (AA) in chemotherapy-naive mCRPC pts. Methods: 1,088 pts were randomized 1:1 to AA (1 g) + prednisone (P) (5 mg BID) or placebo + P. Radiographic progression-free survival (rPFS) and OS were co-primary end points. The study design, as well as primary and secondary end point results obtained at the time of a prespecified interim analysis at 55% OS events, have been described in detail previously. The effect of elevated ALP (above upper limit of normal) and PSA (above 106.2 µg...

Association of alkaline phosphatase (ALP) with clinical outcomes in chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Results from COU-AA-302.

Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302).

62 Background: The efficacy and safety of enzalutamide (ENZA) monotherapy was assessed in hormone-naive men with prostate cancer (PC; any stage) eligible for androgen-deprivation therapy (ADT). The primary end point of prostate-specific antigen (PSA) response rate (80% or more decline), assessed at 25 weeks (wks), was 92.5% with a median (range) maximum decrease of –99% (–100, –86.5) (Tombal et al. ASCO-GU 2013). Here we present data from the extended follow-up at 49 wks. Methods: In an open-label, single-arm phase II study, men age 18 or older with histologically confirmed PC requiring ADT, non-castrate testosterone (8 nmol/L or more), PSA 2 ng/mL or more at screening and a life expectancy of 12 months or more, received 160 mg ENZA once daily (NCT01302041). Treatment continued until disease progression or unacceptable toxicity. Secondary end points included changes in endocrine levels, metabolic parameters, bone mineral density (BMD), quality of life, and safety. Results: Sixty seven men were enrolled. M...

Enzalutamide monotherapy: Extended follow-up of a phase II study in hormone-naive prostate cancer patients.

Mycophenolate mofetil therapy in the management of inflammatory bowel disease--a retrospective case series and review.

Prognostic impact of the neutrophil-to-lymphocyte ratio in men with metastatic castration-resistant prostate cancer.

Enzalutamide monotherapy in hormone-naive prostate cancer: primary analysis of an open-label, single-arm, phase 2 study.

Androgen-deprivation therapy and risk for biliary disease in men with prostate cancer.

9501 Background: There is an interest in identifying patients at risk for SREs who may benefit most from treatment with bone-targeted agents (BTA). Previous results from a subgroup analysis of three phase 3 trials demonstrated denosumab was superior to ZA in preventing SREs (pathologic fracture, radiation or surgery to bone, or spinal cord compression) regardless of baseline clinical pain symptoms or prior SRE status. This analysis assesses if denosumab is superior to ZA in delaying patients’ time to SREs across relevant baseline characteristics. Methods: Patients with metastatic bone disease were randomized 1:1 to receive either SC denosumab 120 mg + IV placebo (n=2,862) or IV ZA 4 mg (adjusted for CrCl) + SC placebo Q4W (n=2,861) in double-blinded phase 3 studies. Time to first on study SRE and time to first and subsequent SRE were evaluated in patients by several baseline variables: location of skeletal metastases (mets) (axial vs appendicular), presence of visceral mets (yes/no), urinary N-telopeptide...

Effect of denosumab versus zoledronic acid (ZA) in preventing skeletal-related events (SREs) in patients with metastatic bone disease: Subgroup analyses by baseline characteristics.

Risk of Diabetes Among Patients Exposed to Primary Androgen Deprivation Therapy for Clinically Localized Prostate Cancer

35 Background: In a randomized controlled trial of men with castration-resistant prostate cancer (CRPC) and bone metastases, denosumab was superior to zoledronic acid (ZA) for reducing skeletal-related events (SRE, defined as pathological fracture, surgery or radiation to bone [including the use of radioisotopes], or spinal cord compression) (Fizazi, et al. Lancet 2011;377:813-822.). Recently, the composite endpoint of symptomatic skeletal event (SSE, defined as symptomatic fracture, surgery or radiation to bone, or spinal cord compression) was introduced as an alternative term/clinical trial endpoint to describe skeletal morbidity. Methods: Men with CRPC, ≥ 1 bone metastasis, and no prior IV bisphosphonate use received either SC denosumab 120 mg or IV ZA 4 mg (adjusted for creatinine clearance) in a blinded fashion every 4 weeks. Oral calcium and vitamin D supplements were recommended. SSEs included pathologic fractures considered symptomatic by the investigator, spinal cord compression and surgery and r...

Denosumab for the prevention of symptomatic skeletal events in patients with castration-resistant advanced prostate cancer: A comparison with skeletal-related events.

861 Impact of prior endocrine therapy on radiographic progression-free survival (rPFS) in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer: Results from COU-AA-302

Population Pharmacokinetic Analysis of Abiraterone in Chemotherapy-Naïve and Docetaxel-Treated Patients with Metastatic Castration-Resistant Prostate Cancer

MP70-11 IMPACT OF PRIOR ENDOCRINE THERAPY ON CLINICAL BENEFIT OF ABIRATERONE ACETATE IN PATIENTS WITH CHEMOTHERAPY-NAÏVE METASTATIC CASTRATION-RESISTANT PROSTATE CANCER: RESULTS FROM COU-AA-302

Objective Endoscopic human thrombin injection appears to be a technically simple and efficacious alternative to tissue adhesives with fewer complications; however, data remain limited. We analysed our experience using endoscopic human thrombin injection for gastric varices in a tertiary referral liver unit. Methods Thirty patients received thrombin injection for gastric varices between December 2008 and January 2013. Twenty patients (67%) had active bleeding or signs of recent bleeding at endoscopy. Ten patients (33%) received thrombin for prophylaxis of rebleeding: secondary (eight patients) and primary (two patients). Results The mean thrombin dose/injection was 1100 IU (range 400–2500); the mean number of sessions was two (range 1–9), with no reported complications. Haemostasis was achieved in 18 out of 20 (90%) patients treated acutely. Failure to control bleeding (bleeding before day 5) was seen in seven patients: three died and four were managed successfully [two with further thrombin and two using a salvage transjugular intrahepatic portosystemic shunt (TIPSS)]. Rebleeding occurred in a further four patients, all managed successfully with salvage TIPSS. In the prophylaxis group, rebleeding occurred in two out of 10 patients. The median follow-up period was 672 days (interquartile range 92–1331). One patient underwent liver transplantation. Ten deaths occurred in total: four due to gastric variceal bleeding. Six-week survival was 83%. In cases in which TIPSS was precluded, 91% of patients (10 out of 11 patients) were managed successfully with thrombin. Conclusion Endoscopic thrombin therapy for gastric variceal bleeding may have most utility as a safe and easily applied bridge to more definitive therapy, in secondary prophylaxis of rebleeding and in cases in which TIPSS is precluded.

Outcomes of endoscopic human thrombin injection in the management of gastric varices

PD27-01 EFFICACY AND LONG-TERM SAFETY ANALYSIS OF STUDY COU-AA-302: ABIRATERONE ACETATE PLUS PREDNISONE IN CHEMOTHERAPY-NAÏVE METASTATIC CASTRATION-RESISTANT PROSTATE CANCER

PURPOSE
Zoledronic acid decreases the risk for skeletal-related events (SREs) in men with castration-resistant prostate cancer and bone metastases but its role earlier in the natural history of the disease is unknown. This phase III study evaluated the efficacy and safety of earlier treatment with zoledronic acid in men with castration-sensitive metastatic prostate cancer.

Men with castration-sensitive prostate cancer and bone metastases whose androgen-deprivation therapy was initiated within 6 months of study entry were randomly assigned in a blinded 1:1 ratio to receive zoledronic acid (4 mg intravenously every 4 weeks) or a placebo. After their disease progressed to castration-resistant status, all patients received open-label treatment with zoledronic acid. The primary end point was time to first SRE, defined as radiation to bone, clinical fracture, spinal cord compression, surgery to bone, or death as a result of prostate cancer. Target accrual was 680 patients. Primary analysis was planned after 470 SREs. The study was discontinued prematurely (645 patients; 299 SREs) after the corporate supporter withdrew study drug supply.

RESULTS
Early zoledronic acid was not associated with increased time to first SRE. The median time to first SRE was 31.9 months in the zoledronic acid group (95% CI, 24.2 to 40.3) and 29.8 months in the placebo group (95% CI, 25.3 to 37.2; hazard ratio, 0.97; 95% CI, 0 to 1.17; one-sided stratified log-rank P = .39). Overall survival was similar between the groups (hazard ratio, 0.88; 95% CI, 0.70 to 1.12; P = .29). Rates of adverse events were similar between the groups.

In men with castration-sensitive prostate cancer and bone metastases, early treatment with zoledronic acid was not associated with lower risk for SREs.

Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: results of CALGB 90202 (alliance).

144 Background: The goal of medical androgen deprivation therapy (ADT) for advanced prostate cancer is to provide an equivalency to orchiectomy based upon older assays for serum testosterone (T). Literature shows that based on more modern assays, medical ADT does not always provide optimal total T suppression equivalent to orchiectomy. With the understanding that free, or unbound, T is the biologically and clinically relevant component, the therapeutic goal of ADT should be to decrease free T to levels similar to orchiectomy. Free T has not been well studied in a substantial number of orchiectomized men. The purpose of this study was to examine a subpopulation of orchiectomized men in a clinical trial to determine the level of serum-free T in advanced prostate cancer. Methods: Baseline data was utilized from a double blind, randomized, placebo controlled trial (G300203) to determine the capacity of toremifene 80 mg to prevent bone fractures in men on ADT. This study included 1,389 men from 150 sites in th...

Optimal testosterone suppression on medical ADT should strive to suppress free testosterone levels to levels similar to orchiectomy: What is that value?

21 Background: In study COU-AA-302 of men with mCRPC and no prior chemotherapy, AA plus prednisone (hereafter AA) significantly increased radiographic progression-free survival. There is limited information about response to subsequent AS-directed therapies following AA. In this post hoc analysis of pts who received AA during study COU-AA-302, we evaluated clinical response to subsequent AA or enzalutamide (ENZ). Methods: In COU-AA-302, 546 pts were randomized and received AA. Subsequent response and discontinuation data from 88 pts receiving AS-directed therapy after study were collected retrospectively, source verified, and entered into the database. Median time to prostate-specific antigen (PSA) progression with 95% confidence intervals was estimated using the Kaplan-Meier method. Results: As of May 2013, following AA on study, 55 pts received subsequent AA and 33 received subsequent ENZ. 69% (38/55) of pts in the AA then AA group and 67% (22/33) pts in the AA then ENZ group received intervening chemot...

Response to androgen signaling (AS)-directed therapy after treatment with abiraterone acetate (AA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Post hoc analysis of study COU-AA-302.

5075 Background: In a randomized controlled trial of men with castration-resistant prostate cancer (CRPC) and bone metastases, denosumab was superior to zoledronic acid (ZA) for reducing skeletal-related events (SRE, defined as pathological fracture, surgery or radiation to bone [including the use of radioisotopes], or spinal cord compression) (Fizazi, et al. Lancet 2011;377:813-822.). Recently, the composite endpoint of symptomatic skeletal event (SSE, defined as symptomatic fracture, surgery or radiation to bone, or spinal cord compression) was introduced as an alternative term/clinical trial endpoint to describe skeletal morbidity. Methods: Men with CRPC, ≥ 1 bone metastasis, and no prior IV bisphosphonate use received either SC denosumab 120 mg or IV ZA 4 mg (adjusted for creatinine clearance) in a blinded fashion every 4 weeks. Oral calcium and vitamin D supplements were recommended. SSEs included pathologic fractures considered symptomatic by the investigator, spinal cord compression and surgery and...

Symptomatic skeletal events (SSE) in patients with advanced prostate cancer: Results from a phase III trial of denosumab for the prevention of skeletal-related events.

14 Background: Abiraterone acetate (AA), a prodrug of abiraterone, which is a selective androgen biosynthesis inhibitor, prolongs overall survival (OS) in mCRPC pts and is approved for use in this population. An exploratory analysis was conducted to determine the impact of prior endocrine therapy on clinical benefit of AA in COU-AA-302, a randomized phase 3 study of pts with chemotherapy-naive mCRPC. Methods: 1,088 pts (testosterone < 50 ng/dL; receiving continuous gonadotropin-releasing hormone [GnRH] agonist if not orchiectomized) were randomized 1:1 to AA (1 g) + prednisone (P) (5 mg BID) or placebo + P alone. rPFS and OS were co-primary end points. rPFS was defined as time to first occurrence of bone scan progression by PCWG2 criteria, progression by CT/MRI by modified RECIST 1.0 criteria, or death, whichever came first. Comparison of the treatment effect on rPFS (investigator review at 55% of OS events) was made for the subgroups above or below the median duration of prior endocrine therapy in 2 cate...

Impact of prior endocrine therapy on radiographic progression-free survival (rPFS) in patients (pts) with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC): Results from COU-AA-302.

P060 Enzalutamide monotherapy in patients with hormone-naive prostate cancer: 1-year extended follow-up of a Phase 2 study

Metabolic complications of androgen deprivation therapy for prostate cancer.

97 Updated interim analysis (IA): Results of randomized phase 3 study COU-AA-302 of abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) without prior chemotherapy

713 ABIRATERONE ACETATE IN METASTATIC CASTRATION-RESISTANT PROSTATE CANCER PATIENTS WITHOUT PRIOR CHEMOTHERAPY - INTERIM ANALYSIS OF THE COU-AA-302 PHASE 3 TRIAL

99 The impact of bone metastases on pain: Results from a phase III denosumab study in men with nonmetastatic castration-resistant prostate cancer

available at http://jurology.com/ Editorial Comment: The long-term metabolic effects of androgen deprivation therapy (ADT) re- main controversial, with conflicting literature on the subject. This study suggests that men with diabetes receiving ADT have worsening diabetes control with time as measured by hemoglobin A1c (HbA1c) levels compared to matched controls not receiving ADT. Among men on ADT it appears that diabetes control worsened during the course of the study as measured by increased use of oral hypoglycemic agents. I worry that the methodology of this study lends itself to a form of ascertain- ment bias in that men with diabetes with worsening control are more likely to undergo HbA1c measurements on a regular basis. In this study the authors used quarterly HbA1c measurements, although in cases where the quarterly measurement was missing they used predictive modeling to estimate the missing data point. They do not tell us, on my read, if the number of missing readings was different in either group. Nonetheless, the data are compelling and suggest that patients with diabetes may be at risk for worsening disease if placed on ADT. Whether this effect is direct or indirect, due to decreased activity or weight gain, is unknown. The impact of this effect on longevity is unknown as well. Int J Radiat Oncol Biol Phys 2013; 86: 64-71. Abstract available at http://jurology.com/ Editorial Comment: This retrospective series suggests that the addition of androgen deprivation therapy (ADT) to dose escalated radiation schemes improves overall survival among men treated for high risk disease. This finding is perhaps intuitive based on older data from randomized trials combining ADT with conventional dose radiation, although interestingly the use of ADT in men with high risk prostate cancer remains controversial in this country due to its potential long-term side effects. In this study men who received long-term ADT had a shorter followup (median 47 months)

Re: Retrospective Evaluation Reveals that Long-Term Androgen Deprivation Therapy Improves Cause-Specific and Overall Survival in the Setting of Dose-Escalated Radiation for High-Risk Prostate Cancer

5 Background: AA, a specific inhibitor of CYP17, blocks androgen biosynthesis and improves overall survival (OS) in mCRPC post-docetaxel (Lancet Oncol 2012;13:983-92). This pre-specified updated IA (55% total OS events) extends previous IA for COU-AA-302 evaluating clinical benefit of AA vs prednisone (P) in mildly symptomatic or asymptomatic pts with progressive mCRPC without prior chemotherapy.

METHODS
1088 pts were stratified by Eastern Cooperative Oncology Group performance status (ECOG-PS, 0 vs 1) and randomized 1:1 to AA 1000 mg + P 5 mg po BID vs Placebo + P. Co-primary endpoints: radiographic progression-free survival (rPFS) and OS. Median time with 95% CI was estimated using the Kaplan-Meier method. The O'Brien-Fleming Lan-DeMets α-spending function was used for OS.

RESULTS
At 55% IA, OS, rPFS and secondary endpoints all favored the AA arm (Table). Median follow-up = 27.1 mos. A post hoc sensitivity multivariate analysis for OS using known prognostic factors supported primary results (HR 0.74, P = 0.0017). Grade 3/4 AEs (AA, P) (%): hypertension 4.2 vs 3.1; hypokalemia 2.6 vs 1.9; ALT↑ 5.5 vs 0.7; AST↑ 3.1 vs 0.9.

In updated IA of COU-AA-302, improvement in rPFS (risk reduction 47%) remained statistically significant. Risk of death decreased by 21% but did not reach pre-specified efficacy boundary. Median OS for AA (35.3 mos) is the longest reported for this mCRPC population. Secondary endpoints were clinically and statistically significant; safety profile despite longer exposure remains favorable. Targeting extragonadal androgen synthesis reduces morbidity associated with disease progression in mCRPC pts without prior chemotherapy.

CLINICAL TRIAL INFORMATION
NCT00887198. [Table: see text].

Updated interim analysis (IA) of COU-AA-302, a randomized phase III study of abiraterone acetate (AA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) without prior chemotherapy.

fects. However, there is no evidence that metabolic effects of soy are involved in such protective activity. Thus, it seems unlikely that the amounts of calcium, protein, or sugars in the intervention and placebo products could have biased or diluted effects on biochemical occurrence because the amounts were identical in both products and the biochemical recurrence rate predicted based on data from the major clinical site (27%) was close to the rates observed in the 2 treatment groups (27.2%-29.5%).

RTOG 0518: Randomized Phase III Trial to Evaluate Zoledronic Acid for Prevention of Osteoporosis and Associated Fractures in Prostate Cancer Patients

5059 Background: The COU-AA-301 phase 3 trial showed significantly longer overall survival for AA + prednisone (P) than P alone in mCRPC pts refractory to docetaxel. This global EAP was conducted in the same setting to collect additional safety data. Methods: Open-label EAP in pts with mCRPC who progressed after 1 - 2 chemotherapy regimens (≥ 1 taxane), resided in areas where AA was unavailable and were ineligible for ongoing clinical trials of AA. Pts received AA (1000 mg PO/d) plus P (5 mg bid) in 28 d cycles until disease progression. Only serious or clinically important adverse events (AEs) were to be reported by investigators. First interim results (clinical cut-off date: December 31, 2011), reported as part of regulatory submissions, are presented. Results: 1079 pts from 15 countries were included: N. America (47%), Europe (29%), Australia (13%), Latin America (7%), and Asia (3%). Median age: 70 years (range: 47 – 93); 89% of pts were White. Median treatment exposure, incl. pts still on treatment (2...

Interim safety results of a global early access protocol (EAP) of abiraterone acetate (AA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) progressing after taxane-based chemotherapy.

P061 Efficacy and safety of enzalutamide monotherapy in hormone-naive prostate cancer (HNPC)

Studies suggest that low levels of vitamin D may be associated with prostate cancer, and darker skin reduces the body's ability to generate vitamin D from sunshine. The impact of sunshine on racial disparities in prostate cancer incidence and mortality is unknown.

Ultraviolet index and racial differences in prostate cancer incidence and mortality

5009 Background: AA, a CYP17 inhibitor, prolongs the lives of men with progressive pre- or post-chemotherapy treated mCRPC with a favorable safety profile (Rathkopf et al. ASCO-GU 2013. Abstr 5). This post hoc analysis examines the safety and tolerability of long-term treatment (≥ 24 mos) in study COU-AA-302. Methods: 1,088 pts were randomized 1:1 to AA 1000 mg + P 5 mg po BID vs placebo + P. Co-primary endpoints were radiographic progression-free survival (rPFS) and OS. Median times with 95% CI of the end points were estimated using the Kaplan-Meier (KM) method. Post hoc analysis of adverse events (AEs) was performed at pre-specified interim analysis (IA3) (55% OS events). Results: At a median follow-up = 27.1 mos (IA3): rPFS HR (95% CI) = 0.53 (0.45, 0.62), p < 0.0001 and OS was improved over P [0.79 (0.66, 0.96), p = 0.0151]; the latter did not reach the pre-specified efficacy boundary (p = 0.0035). All secondary endpoints favored the AA arm (Rathkopf et al. ASCO-GU 2013. Abstr 5). The incidence rate o...

Long-term safety and efficacy analysis of abiraterone acetate (AA) plus prednisone (P) in metastatic castration-resistant prostate cancer (mCRPC) without prior chemotherapy (COU-AA-302).

Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival in patients with metastatic castration-resistant prostate cancer after chemotherapy. We evaluated this agent in patients who had not received previous chemotherapy.

METHODS
In this double-blind study, we randomly assigned 1088 patients to receive abiraterone acetate (1000 mg) plus prednisone (5 mg twice daily) or placebo plus prednisone. The coprimary end points were radiographic progression-free survival and overall survival.

RESULTS
The study was unblinded after a planned interim analysis that was performed after 43% of the expected deaths had occurred. The median radiographic progression-free survival was 16.5 months with abiraterone-prednisone and 8.3 months with prednisone alone (hazard ratio for abiraterone-prednisone vs. prednisone alone, 0.53; 95% confidence interval [CI], 0.45 to 0.62; P<0.001). Over a median follow-up period of 22.2 months, overall survival was improved with abiraterone-prednisone (median not reached, vs. 27.2 months for prednisone alone; hazard ratio, 0.75; 95% CI, 0.61 to 0.93; P=0.01) but did not cross the efficacy boundary. Abiraterone-prednisone showed superiority over prednisone alone with respect to time to initiation of cytotoxic chemotherapy, opiate use for cancer-related pain, prostate-specific antigen progression, and decline in performance status. Grade 3 or 4 mineralocorticoid-related adverse events and abnormalities on liver-function testing were more common with abiraterone-prednisone.

Abiraterone improved radiographic progression-free survival, showed a trend toward improved overall survival, and significantly delayed clinical decline and initiation of chemotherapy in patients with metastatic castration-resistant prostate cancer. (Funded by Janssen Research and Development, formerly Cougar Biotechnology; ClinicalTrials.gov number, NCT00887198.).

Abiraterone in metastatic prostate cancer without previous chemotherapy.

Androgen‐deprivation therapy (ADT) causes bone loss and fractures. Guidelines recommend bone density testing before and during ADT to characterize fracture risk. The authors of the current report assessed bone density testing among men who received ADT for ≥ 1 year.

Bone density testing among prostate cancer survivors treated with androgen‐deprivation therapy

5010 Background: Abiraterone acetate (AA), an androgen biosynthesis inhibitor, prolongs overall survival (OS) in mCRPC patients and is approved for use in this population. The relationship of PSA k...

Relationship of baseline PSA and degree of PSA decline to radiographic progression-free survival (rPFS) in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC): Results from COU-AA-302.

PURPOSE
Denosumab, an anti-RANK ligand monoclonal antibody, significantly increases bone metastasis-free survival (BMFS; hazard ratio [HR], 0.85; P = .028) and delays time to first bone metastasis in men with nonmetastatic castration-resistant prostate cancer (CRPC) and baseline prostate-specific antigen (PSA) ≥ 8.0 ng/mL and/or PSA doubling time (PSADT) ≤ 10.0 months. To identify men at greatest risk for bone metastasis or death, we evaluated relationships between PSA and PSADT with BMFS in the placebo group and the efficacy and safety of denosumab in men with PSADT ≤ 10, ≤ 6, and ≤ 4 months.

A total of 1,432 men with nonmetastatic CRPC were randomly assigned 1:1 to monthly subcutaneous denosumab 120 mg or placebo. Enrollment began February 2006; primary analysis cutoff was July 2010, when approximately 660 men were anticipated to have developed bone metastases or died.

RESULTS
In the placebo group, shorter BMFS was observed as PSADT decreased below 8 months. In analyses by shorter baseline PSADT, denosumab consistently increased BMFS by a median of 6.0, 7.2, and 7.5 months among men with PSADT ≤ 10 (HR, 0.84; P = .042), ≤ 6 (HR, 0.77; P = .006), and ≤ 4 months (HR, 0.71; P = .004), respectively. Denosumab also consistently increased time to bone metastasis by PSADT subset. No difference in survival was observed between treatment groups for the overall study population or PSADT subsets.

Patients with shorter PSADT are at greater risk for bone metastasis or death. Denosumab consistently improves BMFS in men with shorter PSADT and seems to have the greatest treatment effects in men at high risk for progression.

Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time.

PURPOSE
Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. We evaluated the activity of cabozantinib in patients with castration-resistant prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort.

Patients received 100 mg of cabozantinib daily. Those with stable disease per RECIST at 12 weeks were randomly assigned to cabozantinib or placebo. Primary end points were objective response rate at 12 weeks and progression-free survival (PFS) after random assignment.

RESULTS
One hundred seventy-one men with CRPC were enrolled. Random assignment was halted early based on the observed activity of cabozantinib. Seventy-two percent of patients had regression in soft tissue lesions, whereas 68% of evaluable patients had improvement on bone scan, including complete resolution in 12%. The objective response rate at 12 weeks was 5%, with stable disease in 75% of patients. Thirty-one patients with stable disease at week 12 were randomly assigned. Median PFS was 23.9 weeks (95% CI, 10.7 to 62.4 weeks) with cabozantinib and 5.9 weeks (95% CI, 5.4 to 6.6 weeks) with placebo (hazard ratio, 0.12; P < .001). Serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen were reduced by ≥ 50% in 57% of evaluable patients. On retrospective review, bone pain improved in 67% of evaluable patients, with a decrease in narcotic use in 56%. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand-foot syndrome (8%).

Cabozantinib has clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in bone turnover markers, pain, and narcotic use.

Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial.

5001 Background: In locally-advanced prostate cancer, the antiandrogen bicalutamide (Bic) is used to maintain quality of life relative to castration therapy (LHRHa), but efficacy as a monotherapy i...

Efficacy and safety of enzalutamide (ENZA) monotherapy in hormone-naive prostate cancer (HNPC).

Cancer: ADT and acute kidney injury—causal or casual relationship?

18 Background: Enzalutamide (ENZA) is an oral androgen receptor inhibitor that has been approved in the US and shown to increase overall survival by 4.8 months over a placebo (HR, 0.63) in patients with metastatic castration resistant prostate cancer (CRPC) previously treated with docetaxel (Scher et al, N Engl J Med 2012;367:1187). Compared with bicalutamide in nonclinical studies, enzalutamide had higher androgen receptor-binding affinity, prevented nuclear translocation, showed no DNA binding, and induced apoptosis (Tran et al, Science 2009;324:787). In contrast to previous phase II and III studies that exclusively enrolled patients with CRPC receiving androgen deprivation therapy (ie, testosterone (T) levels ≤50 ng/dL), this phase II study assessed the efficacy and safety of ENZA monotherapy in patients who had never received hormone therapy; presenting with non-castrate T levels (≥230 ng/dL).

METHODS
This was a 25-wk, open-label, single-arm study of patients with hormone-naïve, histologically confirmed prostate cancer (all stages) requiring hormonal treatment, an ECOG PS score of 0, and a life expectancy >1 y. All patients received ENZA 160 mg/d without concomitment castration. Primary endpoint was PSA response (>80% decrease at wk 25). Secondary endpoints included changes in endocrine levels and safety/tolerability.

RESULTS
Among 67 men enrolled, the median (range) age was 73 (48, 86) y; 39% had metastases; 36% and 24% had undergone prostatectomy or radiotherapy before study entry. The PSA response rate (>80% PSA decline at wk 25) was 93%, with a median (range) decrease of -99% (-100, -57) at wk 25. Serum T and estrogen levels increased by a median (range) of 113% (-32, 300) and 58% (-49, 321) at wk 25, respectively, compared with baseline. 82% of men reported drug-related AEs (mostly Grade 1 or 2). Most frequent treatment-emergent AEs included gynaecomastia (36%), fatigue (34%), and hot flush (18%). 7% of men experienced SAEs; none were drug-related.

ENZA monotherapy (160 mg) was associated with significant PSA response in nearly all men with hormone-naïve prostate cancer. Endocrine level changes and most common AEs (gynecomastica, fatigue and hot flush) were consistent with potent AR inhibition.

NCT01302041.

Enzalutamide monotherapy: Phase II study results in patients with hormone-naive prostate cancer.

Toremifene to reduce fracture risk in men receiving androgen deprivation therapy for prostate cancer.

Does comorbidity influence the risk of myocardial infarction or diabetes during androgen-deprivation therapy for prostate cancer?

Urological Association: Endorsed by the American Society for Radiation Oncology Advisory From the American Heart Association, American Cancer Society, and American Androgen-Deprivation Therapy in Prostate Cancer and Cardiovascular Risk : A Science

5037 Background: BTT can delay symptomatic progression in cancer pts with bone metastases. In a post hoc analysis, we assessed the impact of concomitant BTT on outcomes in a recent large, multinational study in mCRPC pts without prior ctx. Methods: COU-AA-302 was a phase III trial in asymptomatic/mildly symptomatic pts with progressive mCRPC and no prior ctx. 1,088 pts were stratified by ECOG performance status (ECOG-PS, 0 vs 1) and randomized 1:1 to AA 1 g or placebo QD, plus prednisone 5 mg BID. Radiographic progression-free survival (rPFS) and overall survival (OS) were primary end points; secondary end points were times to opiate use, ctx, ECOG-PS deterioration, and PSA progression. The effect of concomitant use of BTT on all end points was assessed retrospectively using a stratified Cox regression model with factors for treatment, concomitant BTT, interaction of treatment and BTT, and baseline covariates. All data were obtained from a prespecified interim analysis at 55% OS events. Results: Median fo...

Impact of concomitant bone-targeted therapies (BTT) on outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) without prior chemotherapy (ctx) treated with abiraterone acetate (AA) or prednisone (P).

Background: Cabozantinib is an oral MET/VEGFR2 inhibitor. A recent phase II study of cabozantinib (100 mg daily) showed improved bone scans in subjects with metastatic castration-resistant prostate cancer (mCRPC), but adverse events (AE) caused frequent dose reductions. This study was designed to determine the efficacy and tolerability of cabozantinib at lower starting doses. Experimental Design: An adaptive design was used to determine the lowest active daily dose among 60, 40, and 20 mg. The primary endpoint was week 6 bone scan response, defined as ≥30% decrease in bone scan lesion area. The secondary endpoint was change in circulating tumor cells (CTC). Results: Among 11 evaluable subjects enrolled at 40 mg, there were 9 partial responses (PR), 1 complete response, and 1 stable disease (SD). Of 10 subjects subsequently enrolled at 20 mg, there were 1 PR, 5 SDs, and 4 with progressive disease. Among 13 subjects enrolled on the 40 mg expansion cohort, there were 6 PRs and 7 SDs. No subjects required dose reduction or treatment interruption at 6 or 12 weeks; 3 subjects at dose level 0 discontinued due to AEs by 12 weeks. At 40 mg, median treatment duration was 27 weeks. 58% of subjects with ≥5 CTCs/7.5mL at baseline converted to <5. Conclusions: Cabozantinib 40 mg daily was associated with a high rate of bone scan response. Cabozantinib 40 mg daily was associated with better tolerability than previously reported for cabozantinib 100 mg daily. These observations informed the design of phase III studies of cabozantinib in mCRPC. Clin Cancer Res; 19(11); 3088–94. ©2013 AACR.

A Dose-Ranging Study of Cabozantinib in Men with Castration-Resistant Prostate Cancer and Bone Metastases

Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: patient-reported outcome results of a randomised phase 3 trial.

Possible survival benefits from zoledronic acid treatment in patients with bone metastases from solid tumours and poor prognostic features—An exploratory analysis of placebo-controlled trials

New and emerging therapies for bone metastases in genitourinary cancers.

108 Denosumab in men with non-metastatic castration-resistant prostate cancer (CRPC) and PSA doubling time (PSADT) ≤6 months

Denosumab in men with non-metastatic castration-resistant prostate cancer (CRPC) and PSA doubling time (PSADT) <= 6 months - a post-hoc analysis of a randomised trial

784 THE IMPACT OF ABIRATERONE ACETATE THERAPY ON PATIENT-REPORTED PAIN AND FUNCTIONAL STATUS IN CHEMOTHERAPY-NAÏVE PATIENTS WITH PROGRESSIVE, METASTATIC CASTRATION-RESISTANT PROSTATE CANCER - RESULTS FROM AN UPDATED ANALYSIS

116 Background: Androgen-deprivation therapy (ADT) with a GnRH agonist is the foundational systemic therapy for prostate cancer but causes gain of fat mass, loss of muscle mass, adverse changes in serum lipid profile, and a decline in insulin sensitivity. It is unknown whether ADT causes a broader pattern of metabolic alterations. In order to better characterize the metabolic effects of ADT, we measured changes in plasma metabolomic profile during the first 3 months of ADT.

METHODS
Fasting plasma samples were drawn from 36 subjects at baseline and after 3 months (range: 71-112 days) of GnRH agonist therapy. Metabolomic analyses were performed by Metabolon, Inc (Durham, NC). Extracted samples were split into equal parts for analysis on the gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry platforms. Matched pairs t-test was used to identify biochemicals that differed between baseline and month 3.

RESULTS
Of the 504 identified metabolites, 88 changed significantly (p<0.05) from baseline to 3 months. Consistent changes in biochemicals were grouped as follows: (a) Multiple steroids were lower at 3 months, consistent with the effect of therapy on gonadal androgen synthesis. (b) Markers of lipid beta-oxidation (acetyl-carnitines and ketone bodies) and omega-oxidation were lower at 3 months. (c) Two previously-identified biomarkers of insulin resistance (2-hydroxybutyrate and branch chain keto-acid dehydrogenase complex products) were lower at 3 months. (d) Most bile acids and their metabolites were higher during treatment. Cholesterol levels changed very little (1.06 fold change, P = 0.029).

Unbiased metabolomic analyses on fasting plasma samples from men receiving GnRH agonist therapy revealed expected, unexpected, and novel results. Steroid levels fell, consistent with the effects of ADT. Biomarkers of lipid metabolism and insulin resistance also fell, unexpected results given that ADT has previously been shown to decrease insulin sensitivity. Finally, we observed evidence of increased levels of bile acids and bile acid metabolites. Further investigation of this novel finding is warranted.

Changes in plasma metabolomic profiles during the first 3 months of androgen-deprivation therapy for prostate cancer.

170 ANDROGEN DEPRIVATION THERAPY FOR NON-METASTATIC PROSTATE CANCER IS ASSOCIATED WITH AN INCREASED RISK OF PERIPHERAL ARTERIAL DISEASE AND VENOUS THROMBOEMBOLISM

4566 Background: Cabo (XL184) is an oral inhibitor of MET and VEGFR2. In a randomized discontinuation trial of cabo 100mg daily, 76% of men with CRPC and bone metastases had partial or complete res...

Investigator-sponsored trial of efficacy and tolerability of cabozantinib (cabo) at lower dose: A dose-finding study in men with castration-resistant prostate cancer (CRPC) and bone metastases.

4644 Background: A prognostic model for mCRPC post docetaxel is necessary to guide therapy. We retrospectively analyzed a phase III trial enrolling progressive mCRPC following docetaxel to construct a prognostic model. Additionally, we studied the impact of neutrophil-lymphocyte ratio (NLR), a potential marker for inflammatory and immune state. Methods: A phase III trial (SUN-1120) comparing prednisone combined with sunitinib (N=584) or placebo (N=289) for mCRPC following docetaxel-based chemotherapy was evaluated. The treatment arms were combined for analysis, since no statistical difference was observed in the primary endpoint of overall survival (OS). A logarithmic transformation was applied to non-normal factors. The Kaplan-Meier method was used for OS estimation. To identify an optimal prognostic model for survival, we used a Cox proportional hazards regression methods with forward stepwise selection, stratifying for ECOG PS, progression type (PSA or radiographic) and treatment group. A risk score wa...

Prognostic stratification of post-docetaxel metastatic castration resistant prostate cancer (mCRPC) from a phase III randomized trial.

18 Background: Androgen deprivation therapy (ADT) is associated with greater risk of diabetes and coronary heart disease in men with prostate cancer but there is significant controversy surrounding its potential impact on cardiovascular mortality especially among men with lower rates of cancer-specific death. We assessed the relationship between ADT and mortality in a large randomized trial of men treated with or without short-course ADT and radiation therapy (RT) for clinically-localized prostate cancer.

METHODS
Between 1994-2001, 1979 eligible men (median age 71) with clinically-localized (T1-2, PSA<20) prostate cancer were enrolled on a phase III trial (RTOG 94-08) and randomized to RT and 4 months of neoadjuvant/concurrent ADT or RT alone. Fine-Gray proportional hazards model was used to evaluate the relationship between treatment arm and mortality (disease-specific and cardiovascular). Covariates included PSA, Gleason score, T-stage, age, race, weight, prevalent cardiovascular disease (CVD), diabetes (DM), and hypertension.

RESULTS
After a median follow-up of 8.2 years, use of ADT improved overall and disease-specific survival but there was no ADT-related increase in cardiovascular mortality or non-prostate cancer death. There were a total of 191 cardiovascular-related deaths. At 10-years, cardiovascular mortality for men treated with RT+ADT was 9.8% vs 10.7% for men treated with RT alone. In multivariate analyses, treatment arm was not significantly associated with an increased risk of cardiovascular mortality [adjusted hazard ratio (HR)=0.93, 95% confidence interval (CI) 0.69-1.26, p=0.64]. Traditional cardiac risk factors, including prevalent CVD and DM, were significantly associated with greater cardiovascular mortality. Results were similar when limiting analyses to patient subsets at high risk for cardiovascular mortality and at low risk for disease-specific mortality.

Use of short-course ADT improves overall and disease-specific survival but does not appear to increase cardiovascular mortality in men with clinically-localized prostate cancer. Supported by RTOG grant U10 CA21661 and CCOP grant U10 CA37422 from NCI.

Cardiovascular mortality following short-term androgen deprivation in clinically localized prostate cancer: An analysis of RTOG 94-08.

Full Title: Prospective study of changes in the metabolomic profiles of men during their first three months of androgen deprivation therapy for prostate cancer Version Date: 4/2012 Abbreviated title: Metabolomic changes during ADT Authors: Philip J. Saylor, M.D. (corresponding author; contact for reprint requests) Division of Hematology-Oncology, Massachusetts General Hospital (MGH) Cancer Center, Boston, MA Massachusetts General Hospital Yawkey 7E 55 Fruit Street Boston, MA 02114 Fax: 617-726-8685 Phone: 617-724-4000 psaylor@partners.org Edward D. Karoly, Ph.D. Metabolon, Inc., Morrisville, NC ekaroly@metabolon.com Matthew R. Smith, M.D., Ph.D. Division of Hematology-Oncology, MGH Cancer Center, Boston, MA smith.matthew@mgh.harvard.edu

1822 NEED FOR INTERVENTION AND SURVIVAL IN A COHORT OF PATIENTS ON ACTIVE SURVEILLANCE FOR LOW-RISK PROSTATE CANCER

6 Background: Denosumab, an anti-RANK-ligand monoclonal antibody, has been shown to prolong BMFS by a median 4.2 months and with a 15% risk reduction vs. placebo in men with non-metastatic CRPC and baseline PSA value ≥ 8.0 ng/mL and/or PSA doubling time (DT) ≤ 10.0 months. To determine the efficacy of denosumab in men at greatest risk for bone metastases, we evaluated BMFS in a subset of men with PSADT < 6 months, a cutoff based on a previous report (Smith MR, et al: J Clin Oncol. 23:2918-2925, 2005).

METHODS
1432 men with non-metastatic CRPC (baseline [median] PSA: 12.3 ng/mL, PSADT: 5.1 months, ADT duration: 47.1 months) were randomized 1:1 to receive monthly subcutaneous denosumab 120 mg or placebo. The first patient enrolled February 2006; primary analysis cut-off was July 2010, when > 660 men had developed bone metastasis or died. The primary endpoint was BMFS (time to first bone metastasis or death from any cause). BMFS results are presented for men with baseline PSADT < 6 months.

RESULTS
Median BMFS in the placebo group of men with PSADT < 6 months was 6.5 months shorter than for the placebo group in the full population (18.7 months vs. 25.2 months), indicating that these men are at particularly high risk. In this group of men with PSADT < 6 months, denosumab prolonged BMFS by a median of 7.2 months and with a 23% reduction in risk compared with placebo (Table).

Patients with shortened PSADT are at higher risk of developing bone metastasis and denosumab is markedly effective at prolonging BMFS in this subset of patients. [Table: see text].

Effect of denosumab on prolonging bone-metastasis-free survival (BMFS) in men with nonmetastatic castrate-resistant prostate cancer (CRPC) presenting with aggressive PSA kinetics.

LBA4518 Background: AA is an androgen biosynthesis inhibitor that inhibits CYP17 and improves overall survival (OS) in post-docetaxel mCRPC. The primary objective of COU-AA-302 was to compare clinical benefit of AA + prednisone (P) vs placebo (PL) + P in chemo-naive, asymptomatic/mildly symptomatic mCRPC pts. Methods: 1088 pts (151 centers; 12 countries) were randomized 1:1 to AA (1 g) + P (5 mg BID) or PL + P. Co-primary endpoints: radiographic progression-free survival (rPFS) and OS. Median times estimated using K-M method including LR statistic for inference. The Lan-DeMets α-spending function was used for OS. Results:The Independent Data Monitoring Committee concluded that the OS, rPFS and secondary endpoints (Table) all favored the AA arm and unanimously recommended unblinding the study and crossing pts from PL to AA at IA (43% of total events). Median follow up = 22.2 mos. Grade 3/4 AEs (AA + P, PL + P) (%): hypertension 3.9 vs 3.0; hypokalemia 2.4 vs 1.9; ALT↑ 5.4 vs 0.7; AST↑ 3.0 vs 0.9. Conclusio...

Interim analysis (IA) results of COU-AA-302, a randomized, phase III study of abiraterone acetate in chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

Sunitinib, a tyrosine kinase inhibitor, produces discordant changes in 99mTc-MDP bone scans and serum PSA: A case series in prostate cancer patients

Association of Progression by Prostate Cancer Working Group (PCWG)-2 Criteria and Survival in Metastatic Castration Resistant Prostate Cancer

e11(1) n engl j med nejm.org C ase Vignet te A 55-year-old man presents to the primary care clinic for a routine health maintenance examination. He has hypertension, for which he takes a thiazide diuretic, and diabetes, which is well controlled with metformin therapy. He has no known allergies to medications. He does not smoke, and he drinks two to three beers each week. He works as an accountant and stays active by going to the gym five times a week. His blood pressure at this visit is 130/66 mm Hg. His glycated hemoglobin level, as measured recently, was 6.3%. His body-mass index (the weight in kilograms divided by the square of the height in meters) is 28. He has no symptoms of urinary frequency or difficulty voiding. He has never undergone prostate-specific antigen (PSA) testing, and at his most recent digital rectal examination, which was performed 5 years ago, no abnormalities were detected. He reports that one of his uncles recently received a diagnosis of prostate cancer at 75 years of age, and he is concerned that the disease might develop in him also. He admits that he is confused by conflicting reports he has read in the newspaper about whether prostate screening is actually beneficial. He asks whether he should be screened with a digital rectal examination and a PSA test. Which one of the following approaches would you find appropriate for this patient? Base your choice on the published literature, your own experience, recent guidelines, and other sources of information, as appropriate.

Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial

943 PAIN INTERFERENCE WITH DAILY FUNCTIONING IN PATIENTS WITH CASTRATE-RESISTANT PROSTATE CANCER: A COMPARISON OF DENOSUMAB AND ZOLEDRONIC ACID

Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer.

In the opening statement of Herman Melville's Moby Dick, the narrator unambiguously declares his identity with the words, “Call me Ishmael” [1]. It would serve us well to remember this injunction as we ponder the ambiguous status of prostate cancer. Consensus panels have offered us important advice about the management of prostate cancer in recent weeks, with the latest coming from a National Institutes of Health (NIH) panel convened to consider whether or not active surveillance is appropriate for low-grade (Gleason score ≤ 6), low-volume (prostate-specific antigen [PSA] <10 ng/mL) disease [2]. Their conclusion, that active surveillance is an acceptable strategy for many patients in this category, is eminently reasonable advice, particularly for elderly men with significant comorbidity and limited life expectancy. The majority of men currently diagnosed with prostate cancer have low-grade and low-volume disease, and many are advanced in age and will never experience morbidity or mortality as a result of this disease. However, the panel does advise us that a diagnosis of prostate cancer in any patient entails, at a minimum, active surveillance: careful follow-up with monitoring of PSA on an annual basis, or more frequently, and potentially, repeat biopsies, depending on the clinical setting. For the younger patient, active surveillance entails accepting some risk for later disease-related morbidity or mortality. This depends on the accuracy of the Gleason score (subject, of course, to sampling error and reader interpretation) and on patient compliance with the required surveillance. The advantages of active surveillance are obvious: it postpones or avoids costly, morbid, and potentially unnecessary treatment. A number of urologists and radiation oncologists participated in this panel, and one would have a hard time arguing with their conclusion. 
 
A more controversial aspect of the NIH panel's report was the statement that it may be a mistake to call low-grade low-volume prostate cancer a “cancer” in these patients. The panel's opinion is that the term causes unnecessary anxiety, and may prompt patients to take unnecessary action. Although we agree that the connotation of lethality for some patients is unfortunate, the diagnosis of cancer depends on pathological findings, specifically, pathological appearance and invasive behavior. Indolent cancers occur as part of the spectrum of breast cancers, lymphoma, and other forms of malignancy, and those will continue to be called cancer. Prostate cancer, in all its manifestations, is a real cancer. It is the second leading killer of men in the U.S., with incidence and mortality rates little different from those of breast cancer (Table 1). Approximately 15% of patients diagnosed with prostate cancer die from it. Although the PSA level and Gleason score are useful predictors for clinical behavior, curability, and survival, they are imperfect. Estimation of noncancer mortality, a critical step in assessing competing risks, is also notoriously unreliable. What is clear is that prostate cancer in patients with a favorable presentation usually progresses slowly and, for elderly men, a period of active surveillance may not place them in danger of eventual death resulting from cancer. The same can be said for small, estrogen receptor–positive breast cancers in elderly women, a presentation that may not require aggressive therapy [2]. However, for patients aged 15 years, the outcome of active surveillance is less certain. Much will depend on the judgment of the individual oncologist following the patient as to when to rebiopsy and when to intervene with treatment. The actual benefits of active surveillance, compared with aggressive intervention, in this younger age group remain to be proven by a clinical trial. An unknown number, perhaps 10%–20%, of such younger men with favorable findings at presentation if untreated will live long enough to develop metastatic disease, and some will die as a result of its dissemination. Because of this uncertainty, many younger patients will choose to proceed with treatment. 
 
Table 1. 
 
Cancer mortality rates, 1990 and 2007: Disease-specific death rates per 100,000 people 
 
A further ambiguity is posed by the lack of consistency of these recommendations with those of the U.S. Preventive Services Task Force, which, after reviewing available prospective trials, recently pronounced PSA measurement as having unproven value as a screening test for men aged <75 years and of no proven value for men aged ≥75 years [3]. Most oncologists agree that PSA screening is of unproven value for men aged ≥75 years. However, for younger men, without a PSA test, how will doctors detect the higher-grade prostate cancers, and how will physicians proceed with active surveillance for low-grade tumors? The active surveillance strategy itself depends on identifying patients early in the course of their disease and tailoring treatment decisions to the biopsy results. Urologists, radiation oncologists, and medical oncologists know that the digital rectal exam is not a tool for early detection of disease and is able to detect locally advanced disease, which in most cases is no longer curable. Some will argue that low-grade disease does not ever require treatment whereas advanced disease is unaffected by treatment, but if this is so, why undertake active surveillance at all? The fact is that prostate cancer treatment is effective in eradicating disease and delaying its progression, and early treatment is very likely contributing to the steady 4% yearly decline in mortality in the U.S. since the introduction of widespread PSA screening [4]. It is true that there is limited evidence from prospective clinical trials to prove that the decline in mortality is directly related to screening and early institution of therapy. The European screening trial did show a significantly higher prostate cancer-specific survival rate for men aged 55–69 years with regular PSA screening, but the Prostate, Lung, Colorectal, and Ovarian Cancer trial did not show this advantage [5, 6]. Both trials have been criticized for methodological flaws, and further prospective trials are warranted. 
 
Meanwhile, the oncologist (surgeon, radiation oncologist, medical oncologist) and primary care physician must sort out these conflicting messages and provide sensible advice for men at risk for prostate cancer. Prostate cancer is cancer. It has the potential to kill, and decisions to screen or not to screen, to treat or not to treat, may well affect an individual's survival and quality of life. Patients deserve to know this uncertainty, and to make informed decisions. Ignoring the fact that it is cancer, or renaming it something else, does not help the discussion.

PURPOSE
To characterize changes in lean body mass (LBM) in men with prostate cancer receiving androgen-deprivation therapy (ADT).

We prospectively evaluated LBM in a prespecified substudy of a randomized controlled trial of denosumab to prevent fractures in men receiving ADT for nonmetastatic prostate cancer. LBM was measured by total-body dual-energy x-ray absorptiometry at study baseline and at 12, 24, and 36 months. The analyses included 252 patients (132, denosumab; 120, placebo) with a baseline and at least one on-study LBM assessment. Patients were stratified by age (< 70 v ≥ 70 years) and by ADT duration (≤ 6 v > 6 months).

RESULTS
Median ADT duration was 20.4 months at study baseline. Mean LBM decreased significantly from baseline, by 1.0% at month 12 (95% CI, 0.4% to 1.5%; P < .001; n = 248), by 2.1% at month 24 (95% CI, 1.5% to 2.7%; P < .001; n = 205), and by 2.4% at month 36 (95% CI, 1.6% to 3.2%; P < .001; n = 168). Men age ≥ 70 years (n = 127) had significantly greater changes in LBM at all measured time points than younger men. At 36 months, LBM decreased by 2.8% in men age ≥ 70 years and by 0.9% in younger men (P = .035). Men with ≤ 6 months of ADT at study entry (n = 36) had a greater rate of decrease in LBM compared with men who had received more than 6 months of ADT at study entry (3.7% v 2.0%; P = .0645).

In men receiving ADT, LBM decreased significantly after 12, 24, and 36 months.

Sarcopenia during androgen-deprivation therapy for prostate cancer.

Androgen-deprivation therapy for nonmetastatic prostate cancer is associated with an increased risk of peripheral arterial disease and venous thromboembolism.

Hormone ablation therapy (HALT) for breast or prostate cancer accelerates the development of osteoporosis in both men and women by causing estrogen deficiency, which increases the risk for fracture by promoting bone resorption mediated by osteoclasts. Denosumab, a fully human monoclonal antibody that inhibits osteoclast formation and function, increases bone mass in patients undergoing hormone ablation therapy. In the HALT study of 1,468 men with prostate cancer on androgen-deprivation therapy, denosumab significantly reduced the risk of new vertebral fractures, increased bone mineral density (BMD), and reduced markers of bone turnover. In a study of 252 women with breast cancer undergoing adjuvant aromatase inhibitor (AI) therapy, denosumab increased BMD at 12 and 24 months, overall and in all patient subgroups. The overall rates of adverse events were similar to placebo. Clinicians should consider fracture risk assessment and therapies such as denosumab to increase bone mass in patients on hormone ablation therapy who are at high risk for fracture.

Treatment-Induced Bone Loss and Fractures in Cancer Patients Undergoing Hormone Ablation Therapy: Efficacy and Safety of Denosumab

ABSTRACT Background Androgen deprivation therapy (ADT) is the standard treatment of hormone-sensitive metastatic prostate cancer (HSMPC). We performed a phase III multicentre trial to compare ADT alone with ADT plus docetaxel (D) in HNMPC. Methods Patients (pts) with HSMPC were randomly assigned to either arm A (ADT + D: 75mg/m q3w, up to 9 cycles) or arm B (ADT). The primary endpoint was overall survival (OS). The planned number of pts was 378 to detect an improvement in OS with a hazard ratio (HR) of 0.62, a power of 80% and an alpha risk of 0.05 (two-sided test). Secondary endpoints were biological progression-free survival (PFS) and clinical PFS. Data on toxicity and quality of life have been previously presented. Results From October 2004 to December 2008, 385pts were included. Baseline characteristics were well balanced between the two arms. Median age was 63 years (43-84), median PSA was 26.4 ng/ml (0.1-11900), Gleason score was ≥ 8 in 57%. Prognostic classification was as follows: good prognosis (49%), intermediate (29%) and poor (22%). The majority of pts had metastases at the time of diagnosis (72%), 28% developed metastases after local treatment failure. Median number of D cycles was 8 (range 0-9). The median follow-up was 50 months (mo) [95%CI: 49-54]. At 6 mo, a higher PSA response (≥ 50%) in arm A (94% vs 85%, p = 0.0096) and a higher PSA progression (≥ 25%) in arm B (10% vs 1%, p = 0.0015) were observed. Biological PFS was significantly longer in arm A: 22.9 vs 12.9 mo, HR; 0.72 [95%CI: 0.57-0.91] (p = 0.005). Clinical PFS was increase in arm A: 23.46 vs 15.44 mo, HR: 0.75 [95CI: 0.59-0.94] (0.015). OS was not significantly different (median: 58.9 mo in arm A and 54.2 mo in arm B, HR: 1.01 [95%CI: 0.75-1.36]. The median OS for each prognostic group was 69.1 [95%CI: 60.9-NR], 46.5 [95%CI: 37.7-NR] and 36.6 [95%CI9: 28.5-58.9] mo respectively in the good, intermediate, and poor prognosis groups (p = 0.001), with no difference between the two arms. At the cut-off time, 65% of pts from the ADT arm had received docetaxel since they developed castrate-resistant prostate cancer. Conclusion Combining docetaxel and ADT improves PFS over ADT alone in pts with HSMPC. However, no difference in OS was observed between the two arms. Disclosure G. Gravis: I have expert testimony to disclose: Sanofi Aventis, uncompensated. K. Fizazi: Participation to advisory boards and speaker for Sanofi-Aventis. F. Joly Lobbedez: advisory board/board of directors position: Sanofi, Roche, Pfizer, Novartis, Ferring; compensated consultant relationship: Roche, Novartis; honoraria: Sanofi, Roche, Pfizer, Novartis, Ferring, Ipsen,Takeda; travel remuneration: ASCO by Novartis, ESMO by Janssen. S. Oudard: I have an advisory relationship and honoraria to disclose: Pfizer Oncology, Bayer-Schering Pharma, Hoffman La Roche, Glaxo SmithKline, Novartis Pharma, Sanofi Aventis. D. Pouessel: Consultant role and honoraria: Sanofi, P. Beuzeboc: Presentations: Avantis, All other authors have declared no conflicts of interest.

Diabetes and Cardiovascular Mortality in Men With Locally Advanced Prostate Cancer: Updated Analysis From RTOG 92-02

One of the central unanswered questions in prostate cancer research is the significance of tyrosine kinase inhibitor (TKI)–induced improvements in 99mTc-methylene diphosphonate (99mTc-MDP) bone scans. Multitargeted tyrosine kinase inhibition has recently shown promise in the management of castration-resistant prostate cancer. In some cases, TKI inhibition has produced unprecedented improvements in bone metastases as detected by 99mTc-MDP bone scans. The significance of these improvements is not known. In order to gain insight about the effects of TKIs on bone scans in prostate cancer, we systematically evaluated images from a phase II study of sunitinib, a multitargeted TKI. Methods: We analyzed images and data from a previously reported open-label phase II study that enrolled 34 men with advanced castration-resistant prostate cancer. Participants received sunitinib in 6-wk cycles (50 mg daily; 4 wk on, 2 wk off). We examined baseline and 12-wk bone scan images. Partial response was defined as an improvement of at least 50% in previous metastatic lesions subjectively or a change from prior diffuse skeletal metastases (superscan) to recognizable individual metastatic lesions. Our primary objective was to define the incidence of at least partial bone scan response. We also examined concomitant changes in CT and prostate-specific antigen (PSA) evidence of disease. Results: Analysis at 12 wk revealed 1 partial response by the response evaluation criteria in solid tumors (RECIST) and 2 confirmed PSA responses. There were 25 subjects who underwent bone scans at both time points (baseline and week 12) and who had bone metastases detectable at baseline. Within that group of 25, we found 5 bone scan partial responses and 1 complete response. None of those 6 subjects exhibited a PSA response (≥50% decline from baseline) or RECIST response. Conclusion: We found a relatively high rate of 99mTc-MDP bone scan response to sunitinib among men with metastatic prostate cancer. Further, we found that none of the subjects exhibiting bone scan responses experienced concordant improvements in PSA or CT evidence of disease by accepted criteria. This discordance argues that osteoblastic assessment provides an incomplete assessment of treatment-induced changes. Rational development of multitargeted TKIs for prostate cancer requires improved understanding of treatment-induced bone scan changes. Optimal imaging strategies may include evaluation of perfusion or direct tumor activity.

Multitargeted Tyrosine Kinase Inhibition Produces Discordant Changes Between 99mTc-MDP Bone Scans and Other Disease Biomarkers: Analysis of a Phase II Study of Sunitinib for Metastatic Castration-Resistant Prostate Cancer

Reply from Authors re: Ramdev Konijeti, Adam S. Kibel. Androgen Deprivation Therapy for Localized and Nonmetastatic Prostate Cancer: Too Much of a Good Thing? Eur Urol 2012;61:1129–30: Still Much to Understand About Androgen Deprivation Therapy and Cardiovascular Disease

Bone-targeted agents: preventing skeletal complications in prostate cancer.

INTRODUCTION
Angiogenesis and inflammation are both important to the pathogenesis of malignancies. Androgen deprivation therapy (ADT) for prostate cancer causes drastic hormonal changes that alter both disease and host factors. We measured inflammatory and angiogenic biomarkers in ADT-treated and control groups of men with prostate cancer.

MATERIALS AND METHODS
Baseline and 12-week plasma samples were collected from 37 ADT-naïve men with locally advanced or recurrent prostate cancer. Of those, 23 initiated ADT with a gonadotropin-releasing hormone (GnRH) agonist and 14 served as nontreatment controls. Samples were tested for a panel of angiogenic and inflammatory biomarkers.

RESULTS
The treatment group had significantly higher concentrations of the inflammatory biomarkers interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, and stromal cell-derived factor (SDF)-1α. None of the angiogenic biomarkers were significantly different between the groups at baseline. Among patients with a short prostate-specific antigen (PSA) doubling time (<6 months), the proangiogenic factor basic fibroblast growth factor (bFGF) was lower at baseline. In the treatment group, plasma placental growth factor (PlGF) increased and IL-6 decreased after 12 weeks of ADT. Moreover, the treatment group continued to have significantly higher concentrations of the inflammatory biomarkers IL-1β, IL-8, and SDF-1α as well as bFGF than controls.

DISCUSSION
These men were characterized by elevations in several traditional markers of aggressive disease and also by higher levels of several inflammatory biomarkers. Although ADT decreased IL-6 levels, IL-1β, IL-8, and SDF-1α remained significantly higher than in controls. The role of these biomarkers should be further explored.

Changes in biomarkers of inflammation and angiogenesis during androgen deprivation therapy for prostate cancer.

4642 Background: Prognostic models of OS in men with metastatic castrate-resistant prostate cancer (M+CRPC), have been limited. Here we present an analysis of baseline covariates associated with OS...

Baseline covariates impacting overall survival (OS) in a phase III study of men with bone metastases from castration-resistant prostate cancer.

6045 Background: Androgen deprivation therapy (ADT), the standard systemic treatment for prostate cancer, has adverse effects including bone loss and fractures. Current national guidelines suggest that men receiving ADT undergo dual energy x-ray absorptiometry (DXA) before and during ADT to better characterize fracture risk. We assessed receipt of DXA testing in a population-based cohort of men treated continuously with ADT for at least 1 year and identified factors associated with testing. Methods: Using Surveillance, Epidemiology, and End Results-Medicare data, we identified men aged >65 with local or regional prostate cancer diagnosed during 2001-2007 and followed through 2009 who received at least 1 year of continuous ADT. We identified receipt of DXA testing in the 18-month period beginning 6 months before the first dose of ADT. We used logistic regression to identify factors associated with DXA testing, including patient and tumor characteristics and the physicians with whom they had outpatient visi...

Osteoporosis screening among prostate cancer survivors treated with androgen deprivation therapy.

Purpose: Androgen deprivation therapy (ADT) for prostate cancer causes an increase in fasting insulin and adverse changes in body composition and serum lipid profile. It is unknown what other metabolic alterations are caused by ADT. To better characterize the metabolic effects of ADT, we measured changes in plasma metabolomic profile at baseline and after the first 3 months of therapy. Experimental Design: Fasting plasma samples were drawn from 36 subjects at baseline and after 3 months of gonadotropin releasing hormone (GnRH) agonist therapy. Extracted samples were split into equal parts for analysis on the gas chromatography-mass spectrometry and liquid chromatography/tandem mass spectrometry platforms. Results: Of the 292 identified metabolites, 56 changed significantly (P < 0.05) from baseline to 3 months. Notable changes were grouped as follows: (i) Multiple steroids were lower at 3 months, consistent with the effect of therapy on gonadal androgen synthesis. (ii) Most bile acids and their metabolites were higher during treatment. Cholesterol levels changed very little. (iii) Markers of lipid beta-oxidation (acetyl-carnitines and ketone bodies) and omega-oxidation were lower at 3 months. (iv) Two previously identified biomarkers of insulin resistance (2-hydroxybutyrate and branch chain keto-acid dehydrogenase complex products) were stable to lower at 3 months. Conclusions: Unbiased metabolomic analyses revealed expected, novel, and unexpected results. Steroid levels fell, consistent with the effects of ADT. Most bile acids and their metabolites increased during ADT, a novel finding. Biomarkers of lipid metabolism and insulin resistance fell, unexpected given that ADT has been shown to increase fasting insulin. Clin Cancer Res; 18(13); 3677–85. ©2012 AACR.

Prospective Study of Changes in the Metabolomic Profiles of Men during Their First Three Months of Androgen Deprivation Therapy for Prostate Cancer

LBA4518 Background: AA is an androgen biosynthesis inhibitor that inhibits CYP17 and improves overall survival (OS) in post-docetaxel mCRPC. The primary objective of COU-AA-302 was to compare clinical benefit of AA + prednisone (P) vs placebo (PL) + P in chemo-naive, asymptomatic/mildly symptomatic mCRPC pts.

METHODS
1088 pts (151 centers; 12 countries) were randomized 1:1 to AA (1 g) + P (5 mg BID) or PL + P. Co-primary endpoints: radiographic progression-free survival (rPFS) and OS. Median times estimated using K-M method including LR statistic for inference. The Lan-DeMets α-spending function was used for OS.

RESULTS
The Independent Data Monitoring Committee concluded that the OS, rPFS and secondary endpoints (Table) all favored the AA arm and unanimously recommended unblinding the study and crossing pts from PL to AA at IA (43% of total events). Median follow up = 22.2 mos. Grade 3/4 AEs (AA + P, PL + P) (%): hypertension 3.9 vs 3.0; hypokalemia 2.4 vs 1.9; ALT↑ 5.4 vs 0.7; AST↑ 3.0 vs 0.9.

AA + P produced a statistically significant improvement in rPFS and a strong trend for increased OS at this IA. AA resulted in clinically and statistically significant effects on all secondary endpoints. IA results confirmed the acceptable tolerability/safety profile of AA. This is the first randomized trial to demonstrate both OS and rPFS benefits in chemo-naive mCRPC and that inhibition of persistent extragonadal androgen synthesis significantly delays initiation of cytotoxic chemo. While median OS (AA arm) has not been reached, median PL arm OS (27.2 mos) is the longest measured in any phase III mCRPC study. [Table: see text].

Interim analysis (IA) results of COU-AA-302, a randomized, phase III study of abiraterone acetate (AA) in chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

MS In men with prostate cancer, bone is the dominant, and often the only, site of metastatic disease. Skeletal complications related to bone metastases are a dominant part of the clinical condition. Most men with fatal prostate cancer die either with or from complications of bone metastases. Bone metastases result in marked alterations in bone metabolism and impair the biomechanical integrity of bone, often leading to microfractures and poor hematopoiesis. There is also a risk that metastases will entrap nerves adjacent to the bone. Bone metastases may also encroach on the bone marrow space where new blood cells are made. Most of these complications involve pain, due to expansion of the bone metastasis or fractures that occur because of impaired biomechanical integrity of bone. Patients with progressive skeletal pain may require further systemic treatment, such as chemotherapy, or radiation to specific sites. Patients with generalized, diffuse bone pain may need treatment with radiopharmaceuticals. Another complication of bone metastasis is spinal cord compression caused by local extension of the tumor that compresses the spinal cord. This condition is uniformly painful and associated with neurologic compromise. It is one of the most devastating skeletal complications and can result in loss of mobility.

Racial differences in bone mineral density and fractures in men receiving androgen deprivation therapy for prostate cancer.

Denosumab in castration-resistant prostate cancer – Authors' reply

Secondary hyperparathyroidism is frequent in prostate cancer patients with bone metastases, and this condition is worsened by the administration of potent bisphosphonates. Serum parathyroid hormone (PTH) elevation can impair the efficacy of these drugs in terms of survival.

METHODS
The prognostic role of elevated serum PTH levels at baseline and after 3 months of zoledronic acid administration was assessed prospectively in 643 bone metastatic prostate cancer patients enrolled in a prospective randomized, placebo-controlled study.

RESULTS
On multivariate analysis, after adjusting for major prognostic factors and bone turnover markers, elevated baseline serum PTH level was negatively associated with overall survival (hazard ratio [HR], 1.448; 95% confidence interval [CI], 1.045-2.006; p < .03) in zoledronic acid-treated patients but not in placebo-treated patients. In patients with normal baseline PTH levels, there was a trend but insignificant association between zoledronic acid administration and a better survival outcome than with placebo (HR, 0.81; 95% CI, 0.65-1.01; p = .065), whereas a trend in the opposite direction was observed in patients with elevated PTH levels (HR, 1.45; 95% CI, 0.87-2.39; p = .151); interaction test, p = .040. Elevated serum PTH level after 3 months of zoledronic acid treatment was not significantly associated with survival outcome.

Secondary hyperparathyroidism has a negative prognostic impact in metastatic prostate cancer patients undergoing zoledronic acid administration. Counteracting elevated PTH levels by adequate doses of vitamin D may improve the efficacy of this drug.

Prognostic role of serum parathyroid hormone levels in advanced prostate cancer patients undergoing zoledronic acid administration.

1821 GLEASON UPGRADING AND INCREASED CANCER VOLUME ON REPEAT PROSTATE BIOPSY IN PATIENTS ON ACTIVE SURVEILLANCE

Biochemical markers of bone turnover and clinical outcomes in men with prostate cancer.

681 DENOSUMAB DELAYS DEVELOPMENT OF MULTIPLE BONE METASTASES IN MEN WITH CASTRATE-RESISTANT PROSTATE CANCER

4513 Background: Cabozantinib (cabo) inhibits MET and VEGFR2. High rates of bone scan resolution, pain relief and overall disease control, independent of PSA changes, were previously reported in a phase II study in mCRPC patients (pts). This is a NRE cohort in docetaxel (D)-pretreated pts with a novel primary endpoint of bone scan response based on computer-aided quantitative assessment of bone scan lesion area (BSLA) and a double-reader, independent, blinded review (Nucl Med Commun, in press). Methods: D-pretreated (≥225 mg/m2) CRPC pts with bone metastasis were required to have progressed in soft-tissue or bone within 6 months of last dose of D. Pts received 100 mg cabo qd. Tumor response was assessed q6 wks. Bone scan response (BSR) was defined by a ≥30% decline in BSLA. Pain intensity (worst pain over the past 24 hrs; BPI scale 0-10) and interference with sleep and daily activity were prospectively assessed using an IVR system. Analgesic use was collected by diary. Bone turnover markers and CTCs were ...

Cabozantinib (XL184) in chemotherapy-pretreated metastatic castration resistant prostate cancer (mCRPC): Results from a phase II nonrandomized expansion cohort (NRE).

Background: Cabozantinib is an orally available inhibitor of MET and VEGFR2. In a randomized discontinuation trial of cabozantinib (100 mg daily), 86% of men with mCRPC and bone metastases had partial or complete resolution of lesions on bone scan as early as week 6; dose reductions for AEs occurred in 51% of pts, and discontinuations in 10%.[1] The current study is designed to determine the efficacy and safety of cabozantinib at lower doses. Methods: The study uses an adaptive response scheme based on Sargent one-stage design [2] to determine the lowest effective cabozantinib dose among three dose levels: dose level +1 (60 mg daily), dose level 0 (40 mg daily), and dose level −1 (20 mg daily). Bone scan responses were assessed by comparison of baseline and week 6 bone scans using an automated FDA 510(k) approved computer-aided detection (CAD) system.[3] A decrease in total bone scan lesion area of ≥ 30% was defined as a response The first cohort was treated at dose level 0 (40 mg po QD). Using the adaptive design, the number of bone scan responses at dose level 0 (≥8 responses versus Results: The study has enrolled a total of 23 subjects. Twelve subjects were enrolled in the first study cohort and treated with cabozantinib 40 mg daily. Median followup is 14 weeks. One subject discontinued the study at week 2 because of anorexia and fatigue. Another subject discontinued at week 6 after experiencing a hip fracture. The remaining 10 subjects remain on treatment without dose reduction. Baseline and week 6 bone scans have been centrally reviewed for the first 10 evaluable subjects. There were 9 confirmed bone scan responses at week 6 including complete response. Median decrease in bone lesion area at week 6 was 69%. Eleven subjects were accrued to the second cohort and treated with cabozantinib 20 mg daily; all subjects remain on study. Conclusions: Cabozantinib 40 mg daily results in high rates of bone scan response in men with CRPC and bone metastases. Cabozantinib 40 mg daily is associated with improved tolerability compared to cabozantinib 100 mg daily. Evaluation of the efficacy and tolerability of cabozantinib 20 mg daily is ongoing. References: 1. Hussain, M., Smith M.R., Sweeney C., et al. Cabozantinib (XL184) in metastatic castration-resistant prostate cancer (mCRPC): Results from a phase II randomized discontinuation trial. Proc ASCO 2011 (Abstract 4516) 2. Sargent DJ, Chan V, Goldberg RM. A three-outcome design for phase II clinical trials. Control Clin Trials 2001;22:117–25. 3. Chu G. H., Brown M.S., Kim H.J., et al. Initial analytic validation of automated bone scan measures for treatment response assessment in patients with metastatic castration-resistant prostate cancer (CRPC). J Clin Oncol 29: 2011 (suppl; abstr e15174). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A90.

Abstract A90: Efficacy and tolerability of cabozantinib at lower dose: A dose finding study in men with castration-resistant prostate cancer and bone metastases.

Background: Cabozantinib is an oral inhibitor of MET and VEGFR2 and at a dose of 100 mg qd has demonstrated high rates of partial or complete bone scan resolution in CRPC patients with bone metastases, as assessed by manual visual reads. No accepted approach exists for the assessment of bone scan response in prostate cancer patients. An FDA 510(k) approved image analysis package has been developed that includes a computer-aided detection (CAD) system to detect pixels associated with bone lesions on bone scan with high accuracy, thus facilitating quantitative assessment of tumor burden with advantages of objectivity and consistency over manual approaches. A change in total Bone Scan Lesion Area of 30% or greater has been previously established as a cutoff point to distinguish responders from non-responders [1]. Methods: Original Digital Imaging and Communications in Medicine (DICOM) format images of baseline and week 6 bone scan assessments were collected and analyzed by the automated CAD system then reviewed by a physician experienced with bone scan interpretation as part of an ongoing clinical study of single agent cabozantinib at a lower starting dose of 40 mg qd in CRPC subjects with evidence of bone metastases. All subjects had undergone standard of care whole body scintigraphy, 2–4 hours post-injection of 20–25 mCi of Tc MDP. All images underwent intensity normalization to a bone scan reference to account for differences in radiotracer dosing levels and scan timing to improve reproducibility. Lesions consistent with metastatic foci of disease were automatically segmented based on anatomic region-specific intensity thresholds. Each segmented image was reviewed by a nuclear medicine physician for removal of any remaining false positive regions (e.g. areas of degenerative joint disease). Quantitative assessment of lesion burden was then determined. Results: 10 CRPC subjects showing evidence of bone metastasis were treated in an ongoing dose-ranging study with cabozantinib and were evaluable for bone scan response assessment at week 6. Reductions in the following parameters (median and range) were observed at week 6 relative to baseline: total Bone Scan Lesion Area (168.5 cm2 [20, 864] to 54 cm2 [0, 431]; 68% reduction), Bone Scan Lesion Count (34 [3, 74] to 3 [0, 64]; 91% reduction), and mean normalized Bone Scan Lesion Intensity (92.2 [56.5, 155.0] to 57.0 [0, 90.5]; 38% reduction). All 10 subjects had a reduction in Bone Scan Lesion Area, with 9 achieving a bone scan response at the week 6 timepoint as assessed by both the CAD system and visual review by the investigator. Conclusion: A significant reduction in apparent bone scan abnormality was demonstrated by the automated CAD system. The results demonstrate the potential for objective measurement of cabozantinib treatment effects in bone, laying the foundation for further validation against other clinically relevant outcome measures such as pain and overall survival. Reference: 1. G. H. Chu, M. S. Brown, H. J. Kim, M. Auerbach, C. Poon, B. Ramakrishna, A. Vidovic, D. W. Gjertson, M. J. Morris, S. M. Larson, J. G. Goldin, H. I. Scher. Initial analytic validation of automated bone scan measures for treatment response assessment in patients with metastatic castration-resistant prostate cancer (CRPC). J Clin Oncol 29: 2011 (suppl; abstr e15174). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B114.

Abstract B114: Cabozantinib effects on bone metastasis: Computer-aided quantitative bone scan assessment of prostate cancer treatment response.

711 EFFECTS OF DENOSUMAB AND ZOLEDRONIC ACID ON PAIN INTERFERENCE WITH DAILY FUNCTIONING IN PATIENTS WITH CASTRATE-RESISTANT PROSTATE CANCER

C176 PROLONGED BONE METASTASIS-FREE SURVIVAL IN MEN WITH CASTRATE-RESISTANT PROSTATE CANCER RECEIVING DENOSUMAB: RESULTS FROM A PHASE 3, RANDOMISED, DOUBLE-BLIND TRIAL

Dr. Philip J. Saylor (Medical Oncology): A 67-year-old man was seen in the multidisciplinary genitourinary cancer clinic at this hospital because of recurrent prostate cancer. Approximately 18 months earlier, needle biopsies of the prostate were performed because of an elevated level of prostate-specific antigen (PSA). A diagnosis of adenocarcinoma of the prostate was made, with a Gleason score of 7 (grade 3 plus grade 4). (The Gleason score is the sum of the two most prevalent histologic grades in a prostate tumor, each of which is rated on a scale of 1 to 5, with 5 being the most cytologically aggressive.) Two months later, radical retropubic prostatectomy and bilateral lymph-node sampling were performed. Pathological examination of the tissue revealed adenocarcinoma with a Gleason score of 8 (4 plus 4) in the right and left posterior quadrants of the prostate (with capsular penetration), extending to within 0.1 cm of the inked resection margins. The pathological stage was pT3N0. Three months after prostatectomy, the level of PSA was undetectable (<0.5 ng per milliliter; reference value for men after prostatectomy, <0.5). Adjuvant external-beam radiation therapy was administered. On routine follow-up at the cancer center at this hospital 18 months after prostatectomy, the PSA level was 17.2 ng per milliliter. The patient reported feeling well, with no urinary or bowel symptoms. He had a history of recurrent diverticulitis. Medications included acetylsalicylic acid daily. He had no known drug allergies. He was a widower and worked in an office. He drank alcohol occasionally and did not smoke or use illicit drugs. His mother had died at 94 years of age, his father at 60 years after a myocardial infarction, and his brother at 70 years, of leukemia; there was no other family history of cancer. A bone scan revealed marked right thoracic spinal scoliosis and nonspecific focal uptake of technetium-99m–labeled methylene diphosphonate within the right iliac crest and left distal radius. The location and pattern of the uptake were consistent with degenerative joint disease. A radiograph of the pelvis and a computed tomographic (CT) scan of the abdomen and pelvis showed no evidence of recurrent or metastatic carcinoma. A management decision was made. Case 16-2011: A 67-Year-Old Man with Recurrent Prostate Cancer

Case records of the Massachusetts General Hospital. Case 16-2011. A 67-year-old man with recurrent prostate cancer.

Results: 600 urologists replied; 570 currently perform BPH surgery. Table 1 shows procedure utilization. Urologists’ age, year of residency completion, and region of country had no infl uence on technique utilization, except in Northeastern (less monopolar TURP, p=0.04) and New York Sections (less PVP, p=0.01). Academic versus private settings were no different other than RP and Button which occur more often in academics (RP 7% vs 2%, button TURP 28% vs 21%). High volume surgeons are more likely to perform monopolar and bipolar TURP, whereas low volume surgeons are more likely to perform PVP, HoLAP, and HoLEP.

Phase 2 Study of Cabozantinib (XL184) in a Cohort of Patients With Castration-Resistant Prostate Cancer (CRPC) and Measurable Soft Tissue Disease

Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study

Purpose: Abiraterone is an oral inhibitor of CYP17, which is essential for androgen biosynthesis. This multicenter study assessed its efficacy in patients with castration-resistant prostate cancer (CRPC), without prior chemotherapy or CYP17-targeted therapy, and frequency of bone scans discordant with prostate-specific antigen (PSA) and clinical response. Experimental Design: Thirty-three patients received abiraterone acetate 1,000 mg daily with prednisone 5 mg twice daily in continuous 28-day cycles. Patients were evaluated monthly for efficacy and safety. Bone scan flare was defined as the combination, after 3 months of therapy, of an interpreting radiologist's report indicating “disease progression” in context of a 50% or more decline in PSA level, with scan improvement or stability 3 months later. Results: A 50% or more decline in PSA level at week 12 was confirmed in 22 of 33 (67%) patients. Declines in PSA level of 50% or more were seen in 26 of 33 (79%) patients. Undetectable PSA levels (≤0.1 ng/mL) occurred in 2 patients. Median time on therapy and time to PSA progression were 63 weeks and 16.3 months, respectively. Twenty-three patients were evaluable for bone scan flare. Progression was indicated in radiologist's report in 12 of 23 (52%), and 11 of 12 subsequently showed improvement or stability. As prospectively defined, bone scan flare was observed in 11 of 23 (48%) evaluable patients or 11 of 33 (33%) enrolled patients. Adverse events were typically grade 1/2 and consistent with prior published abiraterone reports. Conclusion: Clinical responses to abiraterone plus prednisone were frequent and durable in men with metastatic CRPC. Further investigation is needed to clarify the confounding effect of bone scan flare on patient management and interpretation of results. Clin Cancer Res; 17(14); 4854–61. ©2011 AACR.

Phase II Study of Abiraterone Acetate in Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer Displaying Bone Flare Discordant with Serologic Response

Skeletal morbidity is a prominent burden to men with advanced prostate cancer throughout the natural history of the disease. Bone metastases can cause pain and greatly elevate the risk for fractures and other structural complications. Distinct from the problem of metastases, treatment-related osteoporosis and associated fragility fractures are potential complications of androgen-deprivation therapy. Bone-targeted therapies for prostate cancer have therefore been the focus of considerable research and drug development efforts. The osteoclast is a validated therapeutic target in the management of prostate cancer. Osteoclast inhibition with zoledronic acid (a bisphosphonate) or with denosumab (a monoclonal antibody to RANK ligand) reduces risk for skeletal events in men with castration-resistant prostate cancer metastatic to bone. Osteoclast inhibition with any of several bisphosphonates improves bone mineral density, a surrogate for osteoporotic fracture risk. Denosumab and toremifene (a selective estrogen receptor modulator) have each been shown to reduce osteoporotic fracture risk among men receiving androgen-deprivation therapy. Beta-emitting radiopharmaceuticals reduce pain due to metastatic disease. Investigations involving alpha-emitting radium-223, endothelin-A receptor antagonists atrasentan and zibotentan, proto-oncogene tyrosine-protein kinase (SRC) inhibitor dasatinib, and tyrosine kinase inhibitor cabozantinib (XL184) are ongoing in clinical trials and are also discussed.

Emerging therapies to prevent skeletal morbidity in men with prostate cancer.

Male osteoporosis is an increasingly recognized problem in aging men. A common cause of male osteoporosis is hypogonadism. Thousands of men with prostate cancer are treated with androgen deprivation therapy, a treatment that dramatically reduces serum testosterone and causes severe hypogonadism. Men treated with androgen deprivation therapy experience a decline in bone mineral density and have an increased rate of fracture. This paper describes prostate cancer survivors as a model of hypogonadal osteoporosis and discusses the use of RANKL-targeted therapies in osteoporosis. Denosumab, the only RANKL-targeted therapy currently available, increases bone mineral density and decreases fracture rate in men with prostate cancer. Denosumab is also associated with delayed time to first skeletal-related event and an increase in bone metastasis-free survival in these men. It is reasonable to investigate the use of RANKL-targeted therapy in male osteoporosis in the general population.

RANKL-Targeted Therapies: The Next Frontier in the Treatment of Male Osteoporosis

1091 PAIN OUTCOMES IN PATIENTS WITH BONE METASTASES FROM CASTRATE-RESISTANT PROSTATE CANCER: RESULTS FROM A PHASE 3 TRIAL OF DENOSUMAB VS. ZOLEDRONIC ACID

The natural history of castration‐resistant nonmetastatic prostate cancer is poorly defined.

Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration‐resistant nonmetastatic prostate cancer

Gonadotropin-releasing hormone blockers and cardiovascular disease risk: analysis of prospective clinical trials of degarelix.

Treatment persistence with monthly zoledronic acid is associated with lower risk and frequency of skeletal complications in patients with breast cancer and bone metastasis.

Consensus on the utility of bone markers in the malignant bone disease setting.

Gonadotropin-Releasing Hormone Agonists and the Risks of Type 2 Diabetes and Cardiovascular Disease in Men with Prostate Cancer

718 LONG-TERM FOLLOW-UP OF A MULTICENTER PHASE II STUDY OF ABIRATERONE ACETATE (AA) + LOW-DOSE PREDNISONE (P) IN CHEMOTHERAPY-NAIVE MCRPC DEMONSTRATING RADIOGRAPHIC FLARES DISCORDANT WITH SEROLOGIC MEASURES OF RESPONSE

Denosumab versus zoledronic acid in patients with bone metastases from castration-resistant prostate cancer: Results from a phase 3 randomized trial

7003 ORAL Denosumab and Bone Metastasis-free Survival in Men With Castrate-resistant Prostate Cancer – Subgroup Analyses From an International, Double-blind, Randomized, Phase 3 Trial

648 BENEFIT OF DENOSUMAB THERAPY IN PATIENTS WITH BONE METASTASES FROM CASTRATE RESISTANT PROSTATE CANCER: A NUMBER-NEEDED-TO-TREAT (NNT) ANALYSIS

In 2010, prostate cancer was diagnosed in approximately 217,000 men in the United States. More than 90% of patients with newly diagnosed prostate cancer have localized (clinical stage T1 or T2) disease.1 Men with early-stage prostate cancer face the treatment dilemma posed by the urologist Dr. Willet Whitmore: “If treatment for cure is necessary, is it possible? If possible, is it necessary?” The Scandinavian Prostate Cancer Group Study 4 (SPCG-4) has provided important evidence that effective treatment is both necessary and possible for many men with early-stage prostate cancer. In a 2008 report of SPCG-4, radical prostatectomy, as compared with . . .

Effective treatment for early-stage prostate cancer--possible, necessary, or both?

Denosumab treatment for prolonging bone metastasis-free survival in men with castrate-resistant prostate cancer

Androgen deprivation therapy (ADT) for prostate cancer increases fracture risk, decreases bone mineral density, and increases bone turnover markers (BTMs) including serum type 1 C‐telopeptide (sCTX), tartrate‐resistant alkaline phosphatase 5b (TRAP‐5b), and procollagen‐1 N‐terminal telopeptide (P1NP). In a prespecified exploratory analysis of a phase 3, multicenter, double‐blind study, we evaluated the effects of denosumab (60 mg subcutaneously every 6 months for 3 years) versus placebo (1468 patients, 734 in each group) on BTM values. BTMs were measured at baseline, month 1, and predose at months 6, 12, 24, and 36 in the overall population. BTMs at month 1 are also reported for subgroups based on age (< 70 years versus ≥ 70 years), prior duration of ADT (≤ 6 months versus >6 months), and baseline BTM (≤ median versus > median BTM values). Treatment with denosumab provided a rapid and sustained decrease of BTM values compared with placebo. The median change in sCTX levels at month 1 was −90% in the denosumab group and −3% in the placebo group (p < 0.0001). The median change in TRAP‐5b levels at month 1 was −55% in the denosumab group and −3% in the placebo group (p < 0.0001). The maximal median change in P1NP was −64% in the denosumab group and −11% in the placebo group, (p < 0.0001). Significantly greater decreases in BTM for denosumab were also seen in subgroup analyses based on age, prior ADT treatment, and baseline BTM values. Suppression of bone turnover markers was consistent with marked increases in bone mineral density reported previously. © 2011 American Society for Bone and Mineral Research

Denosumab and changes in bone turnover markers during androgen deprivation therapy for prostate cancer

Treatment and prevention of bone complications from prostate cancer.

Factors associated with vertebral fractures in men treated with androgen deprivation therapy for prostate cancer.

Watchful waiting for localized prostate cancer in the PSA era: what have been the triggers for intervention?

Abstract Purpose: To evaluate the effects of timing and length of zoledronic acid (ZA) treatment on outcomes for patients with prostate cancer in clinical practice. Materials and methods: Patients with prostate cancer and first bone metastasis diagnosed from January 2003 to October 2006 were included. Patients were considered ‘untreated’ if no ZA was given, ‘early ZA-treated’ if ZA was initiated before skeletal complication (SC) occurrence or ‘late ZA-treated’ if one or more SC was documented before or at ZA initiation. Patients were classified with short (≤90 days), medium (91–180 days) or long (>180 days) treatment persistence. Assessments included follow-up duration (FUP) and risk of developing one or more SC. Results: Among eligible patients, 847 were untreated, 243 were early ZA-treated and 218 were late ZA-treated. For untreated versus early ZA-treated groups, median FUP was 263 versus 357 days (p < 0.0001), respectively, and time to first SC was 199 versus 273 days (p < 0.0001), respectively. ZA treatment was associated with significantly longer FUP and lower SC risk. The early ZA-treated group had significantly longer FUP versus the late ZA-treated group (median days, 357 vs. 299.5); the late ZA-treated group experienced significantly higher SC risk vs. the early ZA-treated group (odds ratio, 1.51). Compared with the long-persistence group, FUP was 56% and 40% shorter in the short and medium groups, respectively (p < 0.0001). Conclusion: Treatment with and early initiation of ZA for patients with prostate cancer and bone metastasis significantly prolonged time to and reduced risk of developing SC, while extending FUP.

Zoledronic acid therapy impacts risk and frequency of skeletal complications and follow-up duration in prostate cancer patients with bone metastasis

Toremifene decreases vertebral fractures in men younger than 80 years receiving androgen deprivation therapy for prostate cancer.

161 DETERMINATION OF CLINICAL CHARACTERISTICS FOR MEN ON ADT AS RELATED TO BASELINE SERUM TESTOSTERONE VALUES

9120 Background: Best supportive care in oncology should improve the most important symptoms. Proportions of patients who improve or worsen with usual care for symptoms over a 4-week period is unkn...

A prospective evaluation of symptom change over 4 weeks for outpatients with common solid tumors: Results from E2Z02 (the SOAPP study).

Skeletal complications are major causes of morbidity in patients with prostate cancer. Despite the osteoblastic appearance of prostate cancer bone metastases, elevated serum and urinary markers of bone resorption are indicative of high osteoclast activity. Increased osteoclast activity is independently associated with subsequent skeletal complications, disease progression, and death. Osteoclast-targeted therapies aim to reduce the risk for disease-related skeletal complications, bone metastases, and treatment-related fractures. This review focuses on recent advances in osteoclast-targeted therapies in the treatment and prevention of bone complications in prostate cancer. Osteoclast-targeted therapies have been extensively studied in men with prostate cancer. The potent bisphosphonate zoledronic acid significantly decreased the risk of skeletal complications in men with castration-resistant prostate cancer and bone metastases, and is Federal Drug Administration approved for this indication. Denosumab is a human monoclonal antibody that inhibits receptor activator of nuclear factor-κB (RANK) ligand, a critical mediator of osteoclast differentiation, activation, and survival. Data from recent phase III clinic trials demonstrate the emerging role for denosumab in the treatment of prostate cancer bone metastases and prevention of fractures associated with androgen deprivation therapy.

Contemporary therapeutic approaches targeting bone complications in prostate cancer.

75. 54. American Urological Association Education and Research, Inc. Best practice policy statement on cryosurgery for the treatment of localized prostate cancer. Linthicum (MD): American Urological Association Education and Research,

Androgen‐Deprivation Therapy in Prostate Cancer and Cardiovascular Risk: A Science Advisory From the American Heart Association, American Cancer Society, and American Urological Association: Endorsed by the American Society for Radiation Oncology

Most patients with bone metastases experience skeletal complications, resulting in significant morbidity and increased risk of death. Although the use of bisphosphonates is a well-established form of supportive care treatment for bone metastasis, complications arising from long-term use require schedule optimization and a search for alternative strategies. Moreover, the scope of use of bone-targeted agents in oncology has widened to include therapy-induced bone loss and antitumor effects. Indeed, bone provides a permissive niche to tumor growth, and targeting the interactions within the bone microenvironment is a promising antitumor strategy. In addition, the pathogenesis of cancer-related bone disease has been partially unraveled with a focus on the anabolic bone compartment, and the rapid bench-to-bedside translation has resulted in the identification of novel therapeutically amenable targets. This review focuses on studies optimizing bisphosphonate use and recent clinical data on denosumab in the treatment of bone disease. We also provide data on trials that have evaluated the antitumor effects of bisphosphonates and summarize the most recent discoveries on the role of the bone niche in cancer development, with insights into the preclinical rationale and clinical assessment of novel antiresorptive and anabolic bone-targeted agents. Clin Cancer Res; 16(16); 4084–93. ©2010 AACR.

PURPOSE
Abiraterone acetate is a prodrug of abiraterone, a selective inhibitor of CYP17, the enzyme catalyst for two essential steps in androgen biosynthesis. In castration-resistant prostate cancers (CRPCs), extragonadal androgen sources may sustain tumor growth despite a castrate environment. This phase I dose-escalation study of abiraterone acetate evaluated safety, pharmacokinetics, and effects on steroidogenesis and prostate-specific antigen (PSA) levels in men with CPRC with or without prior ketoconazole therapy.

Thirty-three men with chemotherapy-naïve progressive CRPC were enrolled. Nineteen patients (58%) had previously received ketoconazole for CRPC. Bone metastases were present in 70% of patients, and visceral involvement was present in 18%. Three patients (9%) had locally advanced disease without distant metastases. Fasted or fed cohorts received abiraterone acetate doses of 250, 500, 750, or 1,000 mg daily. Single-dose pharmacokinetic analyses were performed before continuous daily dosing.

RESULTS
Adverse events were predominantly grade 1 or 2. No dose-limiting toxicities were observed. Hypertension (grade 3, 12%) and hypokalemia (grade 3, 6%; grade 4, 3%) were the most frequent serious toxicities and responded to medical management. Confirmed > or = 50% PSA declines at week 12 were seen in 18 (55%) of 33 patients, including nine (47%) of 19 patients with prior ketoconazole therapy and nine (64%) of 14 patients without prior ketoconazole therapy. Substantial declines in circulating androgens and increases in mineralocorticoids were seen with all doses.

Abiraterone acetate was well tolerated and demonstrated activity in CRPC, including in patients previously treated with ketoconazole. Continued clinical study is warranted.

Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy.

Previous studies indicate that androgen deprivation therapy for prostate cancer is associated with diabetes and cardiovascular disease among older men. We evaluated the relationship between androgen deprivation therapy and incident diabetes and cardiovascular disease in men of all ages with prostate cancer.

METHODS
We conducted an observational study of 37,443 population-based men who were diagnosed with local or regional prostate cancer in the Veterans Healthcare Administration from January 1, 2001, through December 31, 2004, with follow-up through December 31, 2005. Cox proportional hazards models were used to assess whether androgen deprivation therapy with gonadotropin-releasing hormone (GnRH) agonists, oral antiandrogens, the combination of the two (ie, combined androgen blockade), or orchiectomy was associated with diabetes, coronary heart disease, myocardial infarction, sudden cardiac death, or stroke, after adjustment for patient and tumor characteristics. All statistical tests were two-sided.

RESULTS
Overall, 14,597 (39%) of the 37,443 patients were treated with androgen deprivation therapy. Treatment with GnRH agonists was associated with statistically significantly increased risks of incident diabetes (for GnRH agonist therapy, 159.4 events per 1000 person-years vs 87.5 events for no androgen deprivation therapy, difference = 71.9, 95% confidence interval [CI] = 71.6 to 72.2; adjusted hazard ratio [aHR] = 1.28, 95% CI = 1.19 to 1.38), incident coronary heart disease (aHR = 1.19, 95% CI = 1.10 to 1.28), myocardial infarction (12.8 events per 1000 person-years for GnRH agonist therapy vs 7.3 for no androgen deprivation therapy, difference = 5.5, 95% CI = 5.4 to 5.6; aHR = 1.28, 95% CI = 1.08 to 1.52), sudden cardiac death (aHR = 1.35, 95% CI = 1.18 to 1.54), and stroke (aHR = 1.22, 95% CI = 1.10 to 1.36). Combined androgen blockade was statistically significantly associated with an increased risk of incident coronary heart disease (aHR = 1.27, 95% CI = 1.05 to 1.53), and orchiectomy was associated with coronary heart disease (aHR = 1.40, 95% CI = 1.04 to 1.87) and myocardial infarction (aHR = 2.11, 95% CI = 1.27 to 3.50). Oral antiandrogen monotherapy was not associated with any outcome studied.

Androgen deprivation therapy with GnRH agonists was associated with an increased risk of diabetes and cardiovascular disease.

Application of a fracture risk algorithm to men treated with androgen deprivation therapy for prostate cancer.

Cardiovascular safety of degarelix: results from a 12-month, comparative, randomized, open label, parallel group phase III trial in patients with prostate cancer.

Purpose of reviewTo summarize the metabolic alterations associated with androgen deprivation therapy (ADT) for prostate cancer and to evaluate the evidence linking ADT with an increased risk of diabetes and cardiovascular disease. Recent findingsADT by either bilateral orchiectomy or treatment with gonadotropin-releasing hormone agonists causes changes in body composition, alterations in lipid profiles, and decreased insulin sensitivity. The spectrum of metabolic changes during ADT is distinct from classically described metabolic syndrome. Population-based, linked cancer registry studies have consistently reported significant associations between ADT and greater risk for diabetes mellitus. Some but not all studies have reported a link between ADT and cardiovascular disease risk. Most studies have reported no increase in cardiovascular mortality following ADT. SummaryADT appears causally associated with diabetes mellitus. ADT is also linked to cardiovascular morbidity, although there is less evidence that this relationship is causal.

Metabolic sequelae associated with androgen deprivation therapy for prostate cancer

4676 Background: The use of androgen deprivation therapy (ADT) in prostate cancer is associated with increased fracture risk. Previously we demonstrated in a phase III trial that toremifene, a selective estrogen receptor modulator (SERM), significantly decreased fracture incidence in men receiving ADT. Similar to other SERMs, there was an increase in venous thromboembolic events. This risk appeared to stratify to men ≥80 years of age. VTEs occurred in 1.5% and 2.5% of men <80, ≥80 respectively. To identify a patient population with the greatest benefit/risk profile we assessed the effect of toremifene in men <80 years. Methods: In this analysis of men <80 years of age receiving ADT for prostate cancer, 430 men received toremifene 80 mg and 417 received placebo (orally daily). All subjects were on ADT for ≥ 6 months, had a serum PSA ≤4 ng/mL, were ≥70 years of age or were at or below WHO thresholds for spine or hip (BMD). The primary endpoint was new vertebral fractures. Secondary endpoints included fragil...

Effect of toremifene on fracture risk in men younger than age 80 on androgen-deprivation therapy.

4671 Background: Abiraterone acetate (AA) is an inhibitor of CYP 17 (17α-hydroxylase and C17,20-lyase), a dual enzyme responsible for androgen synthesis. We have previously reported that a high proportion of patients (pts) with chemo-naive CRPC experience a clinical response to AA in combination with low-dose Pred, although median response duration had not yet been determined. Methods: Thirty-three (33) pts with progressive, metastatic chemo-naive CRPC, and normal organ function were prospectively treated with AA plus Pred (1000mg qd and 5mg bid, respectively). Pts previously treated with ketoconazole (keto) were excluded from the study. Results: Between Oct 2007 and May 2008, 33 men with CRPC were enrolled across five study centers. These patients had received a median of 2 prior hormonal therapies (range 2-4). PSA decline ≥ 50% was observed in 26 pts (79%) and sustained at 12 weeks in 22 pts (67%). At the time of analysis the median duration of therapy was 63 weeks. The median time to PSA progression (T...

Median time to progression in chemotherapy (chemo)-naive patients with castration-resistant prostate cancer (CRPC) treated with abiraterone acetate and low-dose prednisone (Pred).

Download st patients with bone metastases experience skeletal complications, resulting in significant morbidd increased risk of death. Although the use of bisphosphonates is a well-established form of supe care treatment for bone metastasis, complications arising from long-term use require schedule ization and a search for alternative strategies. Moreover, the scope of use of bone-targeted agents cology has widened to include therapy-induced bone loss and antitumor effects. Indeed, bone es a permissive niche to tumor growth, and targeting the interactions within the bone microenvint is a promising antitumor strategy. In addition, the pathogenesis of cancer-related bone disease een partially unraveled with a focus on the anabolic bone compartment, and the rapid benchside translation has resulted in the identification of novel therapeutically amenable targets. This focuses on studies optimizing bisphosphonate use and recent clinical data on denosumab in atment of bone disease. We also provide data on trials that have evaluated the antitumor effects phosphonates and summarize the most recent discoveries on the role of the bone niche in cancer of bis development, with insights into the preclinical rationale and clinical assessment of novel antiresorptive and anabolic bone-targeted agents. Clin Cancer Res; 16(16); 4084–93. ©2010 AACR.

Novel Bone-targeted Strategies in Oncology Scope of the Problem Biology of Bone Disease and Metastasis

Denosumab to Prevent Disease and Treatment-Related Skeletal Complications in Men with Prostate Cancer: Emerging Evidence

PURPOSE
Persistence of ligand-mediated androgen receptor signaling has been documented in castration-resistant prostate cancers (CRPCs). Abiraterone acetate (AA) is a potent and selective inhibitor of CYP17, which is required for androgen biosynthesis in the testes, adrenal glands, and prostate tissue. This trial evaluated the efficacy and safety of AA in combination with prednisone to reduce the symptoms of secondary hyperaldosteronism that can occur with AA monotherapy.

Fifty-eight men with progressive metastatic CRPC who experienced treatment failure with docetaxel-based chemotherapy received AA (1,000 mg daily) with prednisone (5 mg twice daily). Twenty-seven (47%) patients had received prior ketoconazole. The primary outcome was > or = 50% prostate-specific antigen (PSA) decline, with objective response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and changes in Eastern Cooperative Oncology Group (ECOG) performance status (PS) and circulating tumor cell (CTC) numbers. Safety was also evaluated.

RESULTS
A > or = 50% decline in PSA was confirmed in 22 (36%) patients, including 14 (45%) of 31 ketoconazole-naïve and seven (26%) of 27 ketoconazole-pretreated patients. Partial responses were seen in four (18%) of 22 patients with RECIST-evaluable target lesions. Improved ECOG PS was seen in 28% of patients. Median time to PSA progression was 169 days (95% CI, 82 to 200 days). CTC conversions with treatment from > or = 5 to < 5 were noted in 10 (34%) of 29 patients. The majority of AA-related adverse events were grade 1 to 2, and no AA-related grade 4 events were seen.

AA plus prednisone was well tolerated, with encouraging antitumor activity in heavily pretreated CRPC patients. The incidence of mineralocorticoid-related toxicities (hypertension or hypokalemia) was reduced by adding low-dose prednisone. The combination of AA plus prednisone is recommended for phase III investigations.

Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer.

Hormonal therapies: ADT for prostate cancer: true love or heartbreak?

132 SARCOPENIA IN MEN RECEIVING ANDROGEN DEPRIVATION THERAPY (ADT) FOR PROSTATE CANCER: A PROSPECTIVE 3-YEAR STUDY

In the late 1980s and early 1990s, the number of newly diagnosed prostate cancers in the United States increased dramatically, surpassing lung cancer as the most common cancer in men.1 Experts generally believe that these changes resulted from prostate-specific antigen (PSA) screening that detected many earlystage prostate cancers. For example, the percentage of patients with low-risk disease has increased (45.3% in 1999–2001 vs. 29.8% in 1989–1992; P < .0001).2 The incidence of prostate cancer increased 2.0% annually from 1995 to 2001 and has since declined. In 2009, an estimated 192,280 new cases were diagnosed and prostate cancer was expected to account for 25% of new cancer cases in men.1 Fortunately, the age-adjusted death rates from prostate cancer have also declined (–4.1% annually from 1994 to 2001).1 Researchers The NCCN

Researchers The NCCN Prostate Cancer Clinical Practice Guidelines in OncologyTM

Androgen deprivation therapy (ADT) plays a central role in the management of men with locally advanced, recurrent, and metastatic prostate cancer. Because most men diagnosed with prostate cancer will die of something other than their cancer, treatment-related adverse effects are highly relevant to their long-term health. Benefits of ADT in each clinical setting must be weighed against ADT-related adverse effects. ADT is detrimental to several metabolic end points and to bone health. ADT has been prospectively shown to cause decreased lean muscle mass, increased fat mass, weight gain, increased cholesterol and triglycerides, insulin resistance, and loss of bone mineral density. In population-based analyses it has been associated with an increased incidence of diabetes, clinical fractures, and cardiovascular disease. Data-driven recommendations for managing these adverse effects are needed. Currently the authors advocate the use of adapted practice guidelines developed to prevent diabetes, fractures, and coronary heart disease in the general population.

Adverse effects of androgen deprivation therapy: defining the problem and promoting health among men with prostate cancer.

4653 Background: Castration-resistant prostate cancer is a common but poorly characterized clinical disease state. To better understand the natural history, we analyzed data from the placebo group of a large randomized controlled trial. Methods: The 470 patients in these analyses were from the placebo group of a randomized controlled trial to evaluate atrasentan in men with prostate cancer, no radiographic evidence of metastases, and rising PSA levels despite androgen deprivation therapy (Nelson et al 2008 Cancer 113: 2478). Main outcomes were time to disease progression (defined as onset of metastases), time to first bone metastasis, and overall survival. Relationships between baseline covariates and clinical outcomes were assessed by Cox proportional hazard analyses. Covariates in the model were age, BMI, prior prostatectomy, prior bilateral orchiectomies, Gleason sum, PSA, PSA velocity, urinary NTx, serum BAP, albumin, lactate dehydrogenase, and hemoglobin. Results: Median time to disease progression, ...

Natural history of castration-resistant nonmetastatic prostate cancer: Secondary analyses of a multicenter randomized controlled trial.

TO THE EDITOR: In the September 1, 2009, issue of Journal of Clinical Oncology, McNeel et al reported the results of a phase I clinical trial of a DNA vaccine encoding prostatic acid phosphatase in men with nonmetastatic prostate cancer. They reported that nine of 22 (41%) participants developed prostatic acid phosphatase–specific T cell proliferation and seven of 22 (32%) had a post-treatment prostatespecific antigen doubling time (PSA DT) of greater than 200% of the baseline PSA DT. They offer the observed T cell responses and increased PSA DT as evidence of biologic activity and recommend a multi-institutional phase II trial to evaluate clinical efficacy. Although the observed T cell responses are compelling, the changes in PSA DT after vaccine treatment are similar to outcomes previously reported in placebo-treated participants. In two randomized controlled trials of men with rising PSA after prior surgery or radiation therapy for prostate cancer, post-treatment PSA DT of greater than 200% of the baseline PSA DT was observed in 20% to 31% of the participants assigned to placebo. The observed rates of positive PSA outcomes after placebo treatment appear to be explained primarily by variation in serial assessment of PSA DT. We conclude that the post-treatment changes in PSA DT after vaccine treatment do not provide evidence of biologic activity. Additional studies are necessary to assess the relationship between PSA kinetics and clinical outcomes and to evaluate the utility of post-treatment PSA DT or PSA velocity in the development of new drugs.

Current Opinion in Endocrinology, Diabetes & Obesity 2010, 17:240–246 Purpose of review To summarize the metabolic alterations associated with androgen deprivation therapy (ADT) for prostate cancer and to evaluate the evidence linking ADT with an increased risk of diabetes and cardiovascular disease. Recent findings ADT by either bilateral orchiectomy or treatment with gonadotropin-releasing hormone agonists causes changes in body composition, alterations in lipid profiles, and decreased insulin sensitivity. The spectrum of metabolic changes during ADT is distinct from classically described metabolic syndrome. Population-based, linked cancer registry studies have consistently reported significant associations between ADT and greater risk for diabetes mellitus. Some but not all studies have reported a link between ADT and cardiovascular disease risk. Most studies have reported no increase in cardiovascular mortality following ADT. Summary ADT appears causally associated with diabetes mellitus. ADT is also linked to cardiovascular morbidity, although there is less evidence that this relationship is causal.

C Metabolic consequences of ADT for prostate cancer Faris and Smith 241 Sarcopenic obesity Sarcopenic obesity

582 CARDIOVASCULAR SAFETY OF DEGARELIX: RESULTS FROM A 12-MONTH, COMPARATIVE, RANDOMIZED, OPEN-LABEL, PARALLEL-GROUP PHASE III TRIAL IN PROSTATE CANCER PATIENTS

583 TOREMIFENE IMPROVES PSA PROGRESSION FREE SURVIVAL IN CASTRATE MEN WITH DETECTABLE BASELINE PSA LEVELS

863 MULTIVARIATE ANALYSIS DEMONSTRATES TREATMENT WITH TOREMIFENE 80MG REDUCES FRACTURE RISK SIX MONTHS AFTER INITIATION OF ANDROGEN DEPRIVATION THERAPY (ADT)

Androgen-deprivation therapy (ADT) is a widely used treatment for prostate cancer. Recently, several studies have reported an association between ADT and an increased risk of cardiovascular events, including myocardial infarction and cardiovascular mortality.1-5 These reports have led to increased interest and discussion regarding the metabolic effects of ADT and its possible association with increased cardiovascular risk. In addition, likely as a result of these reports, internists, endocrinologists, and cardiologists are now being consulted regarding the evaluation and management of patients in whom ADT is being initiated. Most of these physicians are not aware of the possible effects of ADT on cardiovascular risk factors or the issues regarding ADT and cardiovascular disease. Therefore, this multidisciplinary writing group has been commissioned to review and summarize the metabolic effects of ADT, to evaluate the data regarding a possible relation between ADT and cardiovascular events in patients with prostate cancer, and to generate suggestions regarding the evaluation and management of patients, both with and without known cardiac disease, in whom ADT is being initiated (Table 1). 
 
TABLE 1 
 
Prospective Studies of the Effects of ADT on Cardiac Risk Factors 
 
ADT was first used in prostate cancer for patients with overt metastatic disease,7 and it remains the mainstay of therapy for this group. ADT combined with external-beam radiation therapy is a standard of care in the treatment of men with high-risk prostate cancer, on the basis of evidence that shows a survival benefit in multiple randomized controlled trials.8-13 However, ADT is also often used for other prostate cancer states (eg, for prostate volume reduction in men planning to undergo definitive local therapy with brachytherapy, or in the case of rising prostate-specific antigen after definitive local treatment),14,15 and in these cases, its role in prolonging survival is less certain.

Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology.

e18503 Background: Orbital lymphomas (OL) are rare and account for less than 1% of all cases of non-Hodgkin lymphoma. Radiotherapy (RT) alone provides good local control rates (97-100%) for extranodal marginal zone lymphoma (MALT) of the orbit. We report the outcomes of OL patients treated at FCCC. Methods: Between 1991 and 2008, 23 patients (28 eyes, 5 bilateral, 20%) treated at FCCC with local radiation therapy for orbital lymphoma were reviewed. Treatment consisted of 24-36 Gy,1.5-2.5 Gy per fraction (median 30 Gy in 20 fractions) of RT to the orbit using 6 MV photons. Patient, tumor and treatment related factors including age, stage, histology, type of treatment, RT details and late side effects were analyzed for the local control rates (LC), relapse free and overall survival (OS) by number of patients and orbits independently. Results: The median follow-up was 27 months (range: 1-123 months). The median age was 72 years (range: 37-87), 11 were females, 12 males. Most common presenting symptom was pro...

Curative radiation therapy for primary ocular lymphomas: Demonstration of dose response.

RANK Ligand-targeted Therapy: A Novel Approach to Prevent Bone Loss and Fractures in Men with Prostate Cancer

New opportunities for the management of cancer-related bone complications.

Introduction: Exercise improves functional outcome and symptoms for certain cancer populations, but the feasibility, efficacy, and safety of structured exercise in patients with lung cancer is unknown. In this study, we examined the feasibility of a hospital-based exercise program for patients with advanced non-small cell lung cancer. Methods: This study included patients with newly diagnosed advanced stage non-small cell lung cancer and Eastern Cooperative Oncology Group performance status 0–1. A physical therapist facilitated twice-weekly sessions of aerobic exercise and weight training over an 8-week period. The primary end point was feasibility of the intervention, defined as adherence to the exercise program. Secondary endpoints included functional capacity, measured by the 6-minute walk test and muscle strength, as well as quality of life, lung cancer symptoms and fatigue, measured by the Functional Assessment of Cancer Therapy-lung and Functional Assessment of Cancer Therapy-fatigue scales. Results: Between October 2004 and August 2007, 25 patients enrolled in the study. All participants received anticancer therapy during the study period. Twenty patients (80%) underwent the baseline physical therapy evaluation. Eleven patients (44%) completed all 16 sessions. An additional 6 patients attended at least 6 sessions (range, 6–15), and 2 patients only attended one session. Study completers experienced a significant reduction in lung cancer symptoms and no deterioration in their 6-minute walk test or muscle strength. Conclusions: Although the majority of participants attempted the exercise program, less than half were able to complete the intervention. Those who completed the program experienced an improvement in their lung cancer symptoms. Community-based or briefer exercise interventions may be more feasible in this population.

A Structured Exercise Program for Patients with Advanced Non-small Cell Lung Cancer

7005 Overall survival in men with and without prevalent vertebral fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer

Context: Androgen deprivation therapy (ADT) is increasingly used for the treatment of prostate cancer (PCa), even in clinical settings in which there is no evidence-based proof of prolonged overall survival (OS). ADT, however, may be associated with numerous side effects, including an increased therapy-related cardiovascular mortality. Objective: To discuss different clinical settings in which ADT is currently used and to critically weigh the benefits of ADT against its possible side effects. Evidence acquisition: A MEDLINE search was conducted to identify original articles and review articles addressing the efficacy and side effects of ADT for the treatment of PCa. Keywords consisted of prostate cancer, hormonal therapy, adverse effects, radical prostatectomy, and radiotherapy. The articles with the highest level of evidence for the various examined end points were identified with the consensus of all authors and were reviewed. Evidence synthesis: Even short-term use of ADT may lead to numerous side effects, such as osteoporosis, obesity, sarcopenia, lipid alterations, insulin resistance, and increased risk for diabetes and cardiovascular morbidity. Despite these side effects, ADT is commonly used in various clinical settings in which a clear effect on improved OS has not been shown. Conclusions: ADT is associated with an increased risk of multiple side effects that may reduce quality of life and/or OS. Consequently, these issues should be discussed in detail with patients and their families before initiation of ADT. ADT should be used with knowledge of its potential long-term side effects and with possible lifestyle interventions, especially in settings with the highest risk–benefit ratio, to alleviate comorbidities.

Collaborative Review - Prostate Cancer Androgen Deprivation Therapy for the Treatment of Prostate Cancer: Consider Both Benefits and Risks

Prostate Cancer Survivorship: Prevention and Treatment of the Adverse Effects of Androgen Deprivation Therapy

New opportunities in the management of prostate cancer–related bone complications

Bone health and maintenance of bone integrity are important components of comprehensive cancer care in both early and late stages of disease. Risk factors for osteoporosis are increased in patients with cancer, including women with chemotherapy-induced ovarian failure, those treated with aromatase inhibitors for breast cancer, men receiving androgen-deprivation therapy for prostate cancer, and patients undergoing glucocorticoid therapy. The skeleton is a common site of metastatic cancer recurrence, and skeletal-related events are the cause of significant morbidity. The National Comprehensive Cancer Network (NCCN) convened a multidisciplinary task force on Bone Health in Cancer Care to discuss the progress made in identifying effective screening and therapeutic options for management of treatment-related bone loss; understanding the factors that result in bone metastases; managing skeletal metastases; and evolving strategies to reduce bone recurrences. This report summarizes presentations made at the meeting.

846 A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF DENOSUMAB IN MEN RECEIVING ANDROGEN DEPRIVATION THERAPY FOR NON-METASTATIC PROSTATE CANCER

Natural history of malignant bone disease in breast cancer and the use of cumulative mean functions to measure skeletal morbidity

Androgen-deprivation therapy is well-established for treating prostate cancer but is associated with bone loss and an increased risk of fracture. We investigated the effects of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, on bone mineral density and fractures in men receiving androgen-deprivation therapy for nonmetastatic prostate cancer.

METHODS
In this double-blind, multicenter study, we randomly assigned patients to receive denosumab at a dose of 60 mg subcutaneously every 6 months or placebo (734 patients in each group). The primary end point was percent change in bone mineral density at the lumbar spine at 24 months. Key secondary end points included percent change in bone mineral densities at the femoral neck and total hip at 24 months and at all three sites at 36 months, as well as incidence of new vertebral fractures.

RESULTS
At 24 months, bone mineral density of the lumbar spine had increased by 5.6% in the denosumab group as compared with a loss of 1.0% in the placebo group (P<0.001); significant differences between the two groups were seen at as early as 1 month and sustained through 36 months. Denosumab therapy was also associated with significant increases in bone mineral density at the total hip, femoral neck, and distal third of the radius at all time points. Patients who received denosumab had a decreased incidence of new vertebral fractures at 36 months (1.5%, vs. 3.9% with placebo) (relative risk, 0.38; 95% confidence interval, 0.19 to 0.78; P=0.006). Rates of adverse events were similar between the two groups.

Denosumab was associated with increased bone mineral density at all sites and a reduction in the incidence of new vertebral fractures among men receiving androgen-deprivation therapy for nonmetastatic prostate cancer. (ClinicalTrials.gov number, NCT00089674.)

Denosumab in men receiving androgen-deprivation therapy for prostate cancer.

PURPOSE
Gonadotropin-releasing hormone (GnRH) agonists are associated with greater risk of coronary heart disease and myocardial infarction in men with prostate cancer, but little is known about potential impact on cardiovascular mortality. We assessed the relationship between GnRH agonists and cardiovascular mortality in a large randomized phase III trial of men treated with or without adjuvant goserelin after radiation therapy (RT) for locally advanced prostate cancer.

Between 1987 and 1992, 945 men with locally advanced prostate cancer were randomly assigned to RT and adjuvant goserelin or RT alone. Fine and Gray's regression was used to evaluate treatment effect on cardiovascular mortality. Covariates included age, prevalent cardiovascular disease (CVD), hypertension, diabetes mellitus (DM), body mass index, race, Gleason score, stage, acid phosphatase level, prostatectomy history, and nodal involvement.

RESULTS
After a median follow-up of 8.1 years, there were 117 cardiovascular-related deaths but no treatment-related increase in cardiovascular mortality. At 9 years, cardiovascular mortality for men receiving adjuvant goserelin was 8.4% v 11.4% for men treated without adjuvant goserelin (Gray's P = .17). In multiple regression analyses, treatment arm was not significantly associated with increased risk of cardiovascular mortality (adjusted hazard ratio [HR] = 0.73; 95% CI, 0.47 to 1.15; P = .16; when censoring at time of salvage goserelin therapy, HR = 0.99; 95% CI, 0.58 to 1.69; P = .97). Traditional cardiac risk factors, including prevalent CVD and DM, were significantly associated with greater cardiovascular mortality.

GnRH agonists do not seem to increase cardiovascular mortality in men with locally advanced prostate cancer. Further studies are warranted to evaluate adverse effects of GnRH agonists in men with lower cancer-specific mortality.

Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85-31.

Effects of denosumab on bone mineral density in men receiving androgen deprivation therapy for prostate cancer.

Cancer and its treatment can compromise bone health, leading to fracture, pain, loss of mobility, and hypercalcemia of malignancy. Bone metastasis occurs frequently in advanced prostate and breast cancers, and bony manifestations are commonplace in multiple myeloma. Osteoporosis and osteopenia may be consequences of androgen-deprivation therapy for prostate cancer, aromatase inhibition for breast cancer, or chemotherapy-induced ovarian failure. Osteoporotic bone loss and bone metastasis ultimately share a pathophysiologic pathway that stimulates bone resorption by increasing the formation and activity of osteoclasts. Important mediators of pathologic bone metabolism include substances produced by osteoblasts, such as RANKL, the receptor activator of nuclear factor kappa B ligand, which spurs osteoclast differentiation from myeloid cells. Available therapies are targeted to various steps in cascade of bone metastasis. (JNCCN 2009;7[Suppl 7]:S1–S29) more predictable pattern of spread is well recognized.4 Prostate cancer, breast cancer, and multiple myeloma have a particularly strong association with skeletal metastases and related bone loss, resulting in fracture, hypercalcemia, pain, and declines in mobility and performance status.5−7 Attention to bone health has emerged as an important and under-recognized component of comprehensive cancer care. Bone metastases most commonly affect the axial skeleton. Hematogenous spread is the most likely route, caused by venous drainage from visceral organs directly into the axial bones. Early postmortem studies of animals and humans by Batson8 showed that venous blood from the breasts and pelvic organs, like the prostate, flowed not only into the vena cava, but also into a vertebral-venous (Batson’s) plexus of vessels extending from the pelvis throughout the epidural and perivertebral veins. These direct hematogenous routes may explain in part the high proclivity of breast and prostate cancers to involve the axial skeleton. However, in the bone, it is the interaction between the molecular and cellular characteristics of the tumor cells and the bony microenvironment that ultimately influence metastatic skeletal growth.9,10 Morbidity associated with metastatic bony lesions can be extensive, regardless of the primary tumor origin.2,3 Osteolytic lesions, the type most commonly seen in breast cancer, can cause severe pain, pathologic fracture, and compression syndromes of the nerve root or spinal cord, as well as metabolic disturbances, such as hypercalcemia, phosphate imbalances, disruptions in Bone Disease: A Growing Problem Osteoporosis and osteopenia are common clinical problems associated with aging.1 Concurrent with these risks is malignant bony metastases. The skeleton is a frequent target of metastatic disease. It can be the first and sometimes the only site of advanced disease, contributing greatly to the burden of care in cancer patients.2,3 Bone metastases may complicate a wide range of malignancies, causing considerable morbidity and costly demands on health care resources. That certain tumors have a The Science and Practice of Bone Health in Oncology: Managing Bone Loss and Metastasis in Patients With Solid Tumors Allan Lipton, MD; Robert Uzzo, MD, FACS; Robert J. Amato, MD; Georgiana K. Ellis, MD; Behrooz Hakimian, MD; G. David Roodman, MD, PhD; and Matthew R. Smith, MD, PhD; Hershey, Pennsylvania; Philadelphia, Pennsylvania; Houston, Texas; Seattle, Washington; Los Angeles, California; Pittsburgh, Pennsylvania; and Boston, Massachusetts

EFFECTS OF TWICE-YEARLY SUBCUTANEOUS DENOSUMAB ON BONE MINERAL DENSITY IN MEN RECEIVING ANDROGEN-DEPRIVATION THERAPY FOR NON-METASTATIC PROSTATE CANCER

A RESPONDER ANALYSIS OF THE EFFECTS OF DENOSUMAB ON BONE MINERAL DENSITY IN MEN WITH PROSTATE CANCER RECEIVING ANDROGEN DEPRIVATION THERAPY

Prostate cancer: How can we improve the health of men who receive ADT?

Cancer and its treatment can compromise bone health, leading to fracture, pain, loss of mobility, and hypercalcemia of malignancy. Bone metastasis occurs frequently in advanced prostate and breast cancers, and bony manifestations are commonplace in multiple myeloma. Osteoporosis and osteopenia may be consequences of androgen-deprivation therapy for prostate cancer, aromatase inhibition for breast cancer, or chemotherapy-induced ovarian failure. Osteoporotic bone loss and bone metastasis ultimately share a pathophysiologic pathway that stimulates bone resorption by increasing the formation and activity of osteoclasts. Important mediators of pathologic bone metabolism include substances produced by osteoblasts, such as RANKL, the receptor activator of nuclear factor kappa B ligand, which spurs osteoclast differentiation from myeloid cells. Available therapies are targeted to various steps in cascade of bone metastasis.

The science and practice of bone health in oncology: managing bone loss and metastasis in patients with solid tumors.

Androgen deprivation therapy for the treatment of prostate cancer: consider both benefits and risks.

To assess factors associated with early or delayed androgen deprivation therapy (ADT) among men diagnosed with metastatic prostate cancer, and to assess the relationship between ADT and overall survival, as there is uncertainty about the ideal timing for initiating ADT in men with metastatic prostate cancer.

Use of androgen deprivation therapy for metastatic prostate cancer in older men

In 2006, we first reported that GnRH agonists were associated with a greater risk of diabetes and cardiovascular disease (CVD) in men with prostate cancer [1]. We studied the records of 73 196 men in the linked Surveillance, Epidemiology and End Results (SEER) and Medicare database who were diagnosed with local or local-regional prostate cancer during 1992–1999. Using a time-varying Cox proportional hazards model that adjusted for patient and tumour characteristics, the current use of a GnRH agonist was associated with a significantly greater risk of incident diabetes, coronary heart disease, myocardial infarction and sudden death. The adjusted hazard ratios for incident diabetes and coronary heart disease were 1.44 and 1.16, respectively. A subsequent study using SEER-Medicare data also reported a significant association between GnRH agonists and incident CVD [2]. 
 
Several mechanisms could contribute to greater risk of diabetes and CVD during GnRH-agonist therapy. GnRH agonists increase fat mass and decrease lean body mass [3–5]. Notably, subcutaneous fat accounts for most of the treatment-related fat accumulation [4,6]. GnRH agonists increase serum low- and high-density lipoprotein cholesterol, and triglycerides [4,7,8]. GnRH agonists increase fasting plasma insulin levels [8,9] and decrease insulin sensitivity [10], a marker of insulin resistance. 
 
Insulin resistance is a common metabolic abnormality that underlies type 2 diabetes mellitus and is prevalent in about a quarter of non-diabetic men [11]. Importantly, insulin resistance is an independent risk factor for CVD [12,13]. The metabolic syndrome refers to a clustering of specific CVD risk factors the pathophysiology of which appears to be related to insulin resistance. The National Cholesterol Education Program’s Adult Treatment Panel (NCEP ATP III) and WHO define the metabolic syndrome using different but related criteria [14], summarized in the Appendix. 
 
A recent cross-sectional study reported a higher prevalence of the metabolic syndrome (as defined by NCEP ATP III) in 18 men receiving a GnRH agonist than in age-matched control groups of untreated men with prostate cancer, and men without prostate cancer [15]. Men receiving GnRH agonist therapy were more likely to have increased abdominal girth, elevated triglycerides, and elevated fasting plasma glucose, consistent with results of prospective studies of GnRH agonist treatment. However, by contrast with the metabolic syndrome, prospective studies showed that GnRH agonists preferentially increase subcutaneous rather visceral abdominal fat, and increase rather than decrease high-density lipoprotein cholesterol [4]. In addition, the metabolic syndrome is characterized by low levels of adiponectin and elevated markers of inflammation, whereas GnRH agonists significantly increase serum adiponectin levels and do not alter levels of C-reactive protein or other markers of inflammation [6,16]. These observations from prospective trials suggest that GnRH agonists cause a pattern of metabolic changes that is distinct from the classically defined metabolic syndrome. 
 
What are the practical implications of distinguishing the phenotype of men receiving GnRH agonist treatment from the classic metabolic syndrome? The clinical use of the composite definition(s) of the metabolic syndrome centres on its potential value as a risk factor for CVD. However, the metabolic syndrome is imprecisely defined and might have limited independent value as a marker of CVD risk [17,18]. Given these limitations and the distinct metabolic changes associated with GnRH agonist treatment, we recommend evaluation and treatment of individual risk factors for diabetes and CVD with no regard for whether an individual meets the criteria for the diagnosis of metabolic syndrome. Also, these observations suggest that future research should focus on better characterizing the impact of treatment-related metabolic changes on clinical outcomes, and developing effective strategies to prevent treatment-related diabetes and CVD in prostate cancer survivors.

Gonadotrophin‐releasing hormone agonists, diabetes and cardiovascular disease in men with prostate cancer: which metabolic syndrome?

PURPOSE
Androgen-deprivation therapy (ADT) is associated with greater risk of incident coronary heart disease and hospital admission for myocardial infarction; treatment-related increases in serum lipids may contribute to greater cardiovascular disease risk. We evaluated the effects of toremifene, a selective estrogen-receptor modulator, on fasting serum lipid levels in men receiving ADT for prostate cancer.

In an ongoing, multicenter, double-blind, placebo-controlled phase III fracture-prevention study, 1,389 men receiving ADT for prostate cancer were randomly assigned to receive toremifene (80 mg/d) or placebo. In this interim analysis of 188 patients, changes in fasting serum lipids from baseline to month 12 were compared between the placebo and toremifene groups.

RESULTS
Changes in serum lipids differed significantly between the groups. Mean (+/- SE) total cholesterol decreased by 1.0% +/- 1.7% from baseline to month 12 in the placebo group and decreased by 8.1% +/- 1.4% in the toremifene group (P = .001 for between group comparison). Low-density lipoprotein (LDL) cholesterol increased by 0.8% +/- 2.5% in the placebo group and decreased by 8.2% +/- 2.5% in the toremifene group (P = .003). In contrast, high-density lipoprotein (HDL) cholesterol decreased by 4.9% +/- 1.2% in the placebo group and increased by 0.5% +/- 2.2% in the toremifene group (P = .018). Triglycerides increased by 6.9% +/- 4.2% in the placebo group and decreased by 13.2% +/- 3.6% in the toremifene group (P = .003).

Toremifene significantly decreased total cholesterol, LDL cholesterol, and triglycerides, and increased HDL cholesterol in men receiving ADT for prostate cancer.

Toremifene improves lipid profiles in men receiving androgen-deprivation therapy for prostate cancer: interim analysis of a multicenter phase III study.

Androgen deprivation therapy is the mainstay of treatment for metastatic prostate cancer. Among men with overt metastatic disease, androgen deprivation therapy by either bilateral orchiectomies or chronic treatment with a gonadotropin-releasing hormone agonist achieves responses in the vast majority, with a median response duration is approximately 1 to 2 years. Only rarely does androgen deprivation therapy result in prolonged remission or cure. Docetaxel is the standard first-line chemotherapy for men who develop disease progression despite androgen deprivation therapy. In two randomized controlled trials in men with castrate-resistant prostate cancer, docetaxel improved overall survival compared with treatment with mitoxantrone. For men with castrate-resistant disease, the current standard of care is to continue androgen deprivation therapy indefinitely, based on concerns that testosterone recovery might accelerate disease progression. The strategy of continuous androgen deprivation therapy and the addition of chemotherapy after emergence of hormone-resistant disease contrasts with the current paradigm of sequential hormone therapy and chemotherapy in breast cancer. In metastatic breast cancer, attempts to improve efficacy by combining hormone therapy and chemotherapy began decades ago. Several randomized controlled trials have compared hormone therapy to hormone therapy plus chemotherapy. Most studies report higher response rates for combination therapy; none report a significant improvement in survival. Other randomized controlled trials have compared chemotherapy alone to chemotherapy plus hormone therapy. Most of those studies reported significantly higher response rates for combination therapy but did not carefully evaluate the cumulative response rates for subjects who received sequential chemotherapy followed by hormone therapy at disease progression. None of the studies have reported a significant improvement in overall survival. An Australian study carefully evaluated concurrent and sequential chemotherapy and hormone therapy for metastatic breast cancer. In that study, 339 women with metastatic breast cancer were assigned randomly to one of three groups: tamoxifen, cyclophosphamide and doxorubicin (CA), or concurrent tamoxifen and CA. Women assigned to tamoxifen were treated with salvage chemotherapy at disease progression. The initial response rates to either CA (45%) or concurrent tamoxifen and CA (50%) were significantly higher than tamoxifen alone (22%). With salvage chemotherapy, however, the cumulative response rates were similar for each of the arms. Overall survival was also similar for each of the regimens. The North American Intergroup designed a study (Intergroup 0100/Southwest Oncology Group 8814) in the late 1980s to address the sequencing of hormone therapy and chemotherapy in the adjuvant setting. A total of 1,477 postmenopausal women with estrogen receptor–positive or progesterone receptor–positive nodepositive breast cancer were randomly assigned to tamoxifen alone, tamoxifen plus concurrent cyclophosphamide, doxorubicin, and fluorouracil (CAF), or CAF followed by tamoxifen. The combination of tamoxifen and CAF was superior to tamoxifen alone. Sequential CAF followed by tamoxifen, however, reduced the incidence of recurrence or death by approximately 50% compared with concurrent therapy. Based on these findings, most clinicians have adopted the strategy of administering chemotherapy followed by hormone therapy for the adjuvant treatment of estrogen receptor–positive breast cancer. Notably, other studies in both premenopausal and postmenopausal women have reported no difference between concurrent and sequential tamoxifen and chemotherapy in the adjuvant setting. In preclinical models of breast cancer, estrogens recruit dormant breast cancer cells into the cell cycle. In phase II studies of women with locally advanced or metastatic breast cancer, short-term pretreatment with estrogen before chemotherapy was associated with relatively high response rates. In one study, for example, estrogen priming and chemotherapy were also associated with comparatively long response duration and survival. A randomized controlled trial from the Netherlands, however, demonstrated no benefit from estrogen priming before chemotherapy. In that study, 318 women with stage II/IIIA breast cancer were assigned randomly to fluorouracil, doxorubicin, and cyclophosphamide with or without pretreatment with ethinyl estradiol. After a median follow-up of 6.8 years, there were no significant differences in relapse-free and overall survival between the groups. Similar results were observed in multivariate analyses that adjusted for subject and disease characteristics. The slow growth rate of prostate cancer may partially explain its limited sensitivity to chemotherapy. In the Dunning rat model of prostate cancer, androgen priming induces cell proliferation and increases sensitivity to chemotherapy compared with chemotherapy alone. The strategy of androgen priming to increase the efficacy of chemotherapy in men with prostate cancer was first evaluated more than two decades ago. In 1988, Manni et al reported the results of a small randomized controlled trial of men with castrate-resistant metastatic prostate cancer. A total of 85 men with disease progression despite bilateral orchiectomies were randomly assigned to monthly chemotherapy (CAF) or monthly chemotherapy preceded by three JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 18 JUNE 2

Rapid testosterone cycling and chemotherapy for prostate cancer: a way forward or return to the past?

5013 Background: Diabetes is associated with lower risk of prostate cancer. Most men with diabetes are obese and obesity is associated with greater prostate cancer mortality. Whether diabetes influ...

Diabetes and mortality in men with locally advanced prostate cancer: analyses of RTOG 92–02

A pilot study of an exercise program for patients with advanced non-small cell lung cancer

Introduction: Bone metastases from non-small cell lung cancer (NSCLC) are associated with skeletal-related events (SREs) and elevated levels of N-telopeptide of type I collagen (NTX) in some patients. Zoledronic acid (ZOL) reduces SRE risk and NTX levels. Methods: To assess effects of baseline variables, including NTX levels (normal = NTX < 64 nmol/mmol creatinine; high = NTX ≥ 64 nmol/mmol creatinine), on treatment effects in NSCLC patients, a retrospective analysis was performed in NSCLC patients with bone metastases (N = 382) treated with ZOL or placebo every 3 weeks in a 21-month randomized clinical trial in patients with NSCLC or other solid tumors. Cox proportional hazards models assessed relative risks (RRs) of SREs, bone lesion progression, and death. Multivariate models analyzed covariate effects on survival. Results: For both placebo- and ZOL-treated patients, high baseline NTX correlated with increased SRE risk (p = 0.068 and 0.012, respectively). Although high versus normal baseline NTX correlated with more than twofold increased risks of bone lesion progression and death in the placebo group (p = 0.039 and 0.001, respectively), correlations were weaker in the ZOL group (RR = 1.38; p = 0.0186 and RR = 1.27; p = 0.142, respectively), suggesting an interaction effect of ZOL and baseline NTX. Among patients with high baseline NTX, ZOL significantly reduced the RR of death by 35% versus placebo (p = 0.024). Per multivariate analysis, ZOL treatment (p = 0.005), higher lymphocyte count (p = 0.011), performance status 0 to 1 (p = 0.012), and absence of narcotic use (p = 0.016) correlated with improved survival. Conclusions: This retrospective analysis revealed statistically significant correlations between ZOL and increased survival versus placebo in NSCLC patients and high baseline NTX levels.

Zoledronic Acid and Survival in Patients with Metastatic Bone Disease from Lung Cancer and Elevated Markers of Osteoclast Activity

Bone markers and their prognostic value in metastatic bone disease: clinical evidence and future directions.

Impact of prior ketoconazole therapy on response proportion to abiraterone acetate, a 17-alpha hydroxylase C17,20-lyase inhibitor in castration resistant prostate cancer (CRPC)

Adipocytokines, obesity, and insulin resistance during combined androgen blockade for prostate cancer.

Osteoclast targeted therapy for prostate cancer: bisphosphonates and beyond.

PURPOSE
Diabetes is associated with lower risk of prostate cancer. Most men with diabetes are obese, and obesity is associated with greater prostate cancer mortality. Whether diabetes influences outcomes after prostate cancer diagnosis is unknown.

We assessed the relationship between prevalent diabetes and mortality using data from Radiation Therapy Oncology Group Protocol 92-02, a large randomized trial of men (N = 1,554) treated with radiation therapy and short-term versus long-term adjuvant goserelin for locally advanced prostate cancer. Regression and proportional hazard models were performed to evaluate relationships between prevalent diabetes and all-cause mortality, prostate cancer mortality, and non-prostate cancer mortality. Covariates included age, race, tumor stage, Gleason score, prostate-specific antigen, weight, and treatment arm.

RESULTS
There were a total of 765 deaths; 210 (27%) were attributed to prostate cancer. In univariate analyses, prevalent diabetes was associated with greater all-cause mortality and non-prostate cancer mortality but not prostate cancer mortality. After controlling for other covariates, prevalent diabetes remained significantly associated with greater all-cause mortality and non-prostate cancer mortality (hazard ratio [HR] = 2.12; 95% CI, 1.69 to 2.66; P < .0001) but not prostate cancer mortality (HR = 0.80; 95% CI, 0.51 to 1.25; P = .34). In contrast, weight was associated with greater prostate cancer mortality (HR = 1.77; 95% CI, 1.22 to 2.55; P = .002) but not all-cause or non-prostate cancer mortality.

Weight but not prevalent diabetes is associated with greater prostate cancer mortality in men receiving combined modality treatment for locally advanced disease. These observations suggest that the association between obesity and greater prostate cancer mortality is mediated by mechanism(s) other than the characteristic metabolic alterations of diabetes.

Diabetes and mortality in men with locally advanced prostate cancer: RTOG 92-02.

Androgen deprivation therapy and risk for diabetes and cardiovascular disease in prostate cancer survivors

Purpose: Summarize current knowledge, critical gaps in knowledge, and recommendations to advance the field of metastatic bone cancer. Experimental Design: A multidisciplinary consensus conference was convened to review recent progress in basic and clinical research, assess critical gaps in current knowledge, and prioritize recommendations to advance research in the next 5 years. The program addressed three principal topics: biology of metastasis, preserving normal bone health, and optimizing bone-targeted therapies. Results: A variety of specific recommendations were identified as important to advance research and clinical care over the next 5 years. Conclusions: Priorities for research in bone biology include characterizing components of the stem cell niche in bone, developing oncogenic immunocompetent animal models of bone metastasis, and investigating the unique contribution of the bone microenvironment to tumor growth and dormancy. Priorities for research in preserving normal bone health include developing methods to measure and characterize disseminating tumor cells, assessing outcomes from the major prevention trials currently in progress, and improving methodologies to assess risks and benefits of treatment. Priorities for optimizing bone-targeted therapies include advancing studies of serum proteomics and genomics to reliably identify patients who will develop bone metastases, enhancing imaging for early detection of bone metastases and early response evaluation, and developing new tests to evaluate response to bone-directed treatments.

Advancing Treatment for Metastatic Bone Cancer: Consensus Recommendations from the Second Cambridge Conference

Osteoporosis is an important but underappreciated problem in men worldwide. In the United States, 2 million men have osteoporosis and another 12 million are at risk for the disease. After age 50 years, one in four men experiences a clinical fracture. Men suffer one third of all hip fractures and are more likely than women to die after a hip fracture. Hypogonadism, chronic glucocorticoid therapy, and alcohol abuse are the major causes of acquired osteoporosis in men. These causes account for approximately one half of all cases of osteoporosis in men. Smoking, low dietary calcium intake, vitamin D deficiency, and sedentary lifestyle also contribute to risk for osteoporosis. Androgen-deprivation therapy (ADT) for prostate cancer is a leading cause of hypogonadism in men. ADT with a gonadotropinreleasing hormone (GnRH) agonist is the cornerstone of treatment for metastatic prostate cancer. GnRH agonists are also commonly used to treat men with earlier-stage disease. Approximately one third of the estimated 2 million prostate cancer survivors in the United States currently receive treatment with a GnRH agonist. GnRH agonists are associated with risk for clinical fractures. In large population-based studies, for example, men receiving GnRH agonist had a 21% to 45% relative increase in fracture risk compared with men who did not receive a GnRH agonist. Longer treatment duration conferred greater fracture risk. Age and comorbidity were also associated with higher fracture incidence. GnRH agonists increase bone turnover and decrease bone mineral density, a surrogate for fracture risk. Bone mineral density of the hip and spine decrease by approximately 2% to 3% per year during initial therapy. Most studies have reported that bone mineral density continues to decline steadily during long-term therapy. Some, but not all, men develop osteoporosis during ADT for prostate cancer. Pretreatment bone mineral density varies between men because of individual differences in peak bone mass and rates of adult bone loss. Accordingly, men begin treatment with different relative risks for developing osteoporosis. Duration of treatment and rates of bone loss during treatment also vary between individuals. Other mechanisms may also contribute to fracture risk. GnRH agonists significantly decrease muscle mass. Treatment-related sarcopenia appears to contribute to frailty and increased risk of falls in older men. Accordingly, GnRH agonists may increase fracture risk by decreasing both bone mineral density and muscle mass. Several small randomized controlled trials have demonstrated that bisphosphonates increase bone mineral density during GnRH agonist treatment. Intravenous pamidronate significantly decreased biochemical markers of bone turnover and increased bone mineral density of the hip and spine in men receiving GnRH agonist therapy. In a 12-month multicenter, placebo-controlled study of 106 men with prostate cancer, intravenous zoledronic acid increased bone mineral density of the hip and spine by 3.9% and 7.3%, respectively. Similar results have been reported with annual zoledronic acid. Oral bisphosphonates also increase bone mineral density during GnRH agonist therapy. In a randomized controlled trial of 112 men with prostate cancer, Greenspan et al reported that alendronate increased bone mineral density of the hip and spine by 2.3% and 5.1%, respectively, after 12 months. In this issue of Journal of Clinical Oncology, Greenspan et al report the second-year results of this partial crossover study. All participants initially assigned to placebo were treated with alendronate during the second year. Participants initially assigned to alendronate were randomly reassigned to receive either alendronate or placebo during year 2. In year 2, bone mineral density increased in the men assigned to alendronate and remained stable at most skeletal sites in men assigned to placebo. Over the entire study, bone mineral density increased more in the men who received alendronate for 2 years than those who received alendronate for only 1 year. Among men who were assigned to alendronate for 1 year, the net change in bone mineral density over the 2 year study was similar for men assigned to alendronate for the first year compared with men assigned to alendronate for the second year. The results of this welldesigned study confirm the expected increase in bone mineral density with continued bisphosphonate therapy and provide support for earlier intervention to prevent osteoporosis in this setting. Small randomized controlled trials have also demonstrated that selective estrogen-receptor modulators increase bone mineral density during GnRH agonist treatment for prostate cancer. In a 12-month open-label study, for example, raloxifene significantly increased bone mineral density of the hip and tended to increase bone mineral density of the spine. Raloxifene also significantly decreased biochemical markers of bone turnover. The results of this study are consistent with the key role of estrogens in bone metabolism in men. Taken together, these small randomized controlled trials have helped define the problem of osteoporosis in men with prostate cancer, understand the mechanisms of hypogonadal bone loss, and establish effective strategies to increase bone mineral density during GnRH agonist therapy. This groundbreaking work has also led to two large randomized placebo-controlled trials to prevent fractures during GnRH agonist therapy for prostate cancer. Final results of both studies will be reported this year. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 27 SEPTEMBER 2

Osteoporosis in men with prostate cancer: now for the fracture data.

P79. N-Telopeptide of type I collagen (NTX) levels and prognosis in patients with bone metastases from non-small cell lung cancer (NSCLC) receiving zoledronic acid (ZOL) or placebo

19003 Background: In a clinical trial of zoledronic acid (ZOL) vs placebo in patients (pts) with bone metastases from solid tumors (not breast or prostate cancer; N = 773), ∼50% of pts had non-smal...

Survival benefits of zoledronic acid in patients with bone metastases from non-small cell lung cancer and high NTX levels: The role of BALP

Cardiovascular mortality and duration of androgen deprivation for locally advanced prostate cancer: analysis of RTOG 92-02.

In men with prostate cancer, gonadotropin‐releasing hormone (GnRH) agonists increase fat mass, decrease insulin sensitivity, and increase triglycerides, features that are shared with metabolic syndrome. To the authors' knowledge, however, less is known regarding the effects of GnRH agonists on other attributes of the metabolic syndrome.

Metabolic changes during gonadotropin‐releasing hormone agonist therapy for prostate cancer

8106 Background: Lung cancer patients (pts) with bone metastasis are at high risk for skeletal complications (SCs). These SCs greatly compromise the patients’ quality of life, survival and add grea...

The impact of zoledronic acid treatment on frequency of skeletal complications experienced and on followup duration post diagnosis of bone metastasis in lung cancer patients

Prostate cancer is the most commonly diagnosed noncutaneous cancer in men in the United States. Treatment of men with prostate cancer commonly involves surgical, radiation, or hormone therapy. Most men with prostate cancer live for many years after diagnosis and may never suffer morbidity or mortality attributable to prostate cancer. The short‐term and long‐term adverse consequences of therapy are, therefore, of great importance. Adverse effects of radical prostatectomy include immediate postoperative complications and long‐term urinary and sexual complications. External beam or interstitial radiation therapy in men with localized prostate cancer may lead to urinary, gastrointestinal, and sexual complications. Improvements in surgical and radiation techniques have reduced the incidence of many of these complications. Hormone treatment typically consists of androgen deprivation therapy, and consequences of such therapy may include vasomotor flushing, anemia, and bone density loss. Numerous clinical trials have studied the role of bone antiresorptive therapy for prevention of bone density loss and fractures. Other long‐term consequences of androgen deprivation therapy may include adverse body composition changes and increased risk of insulin resistance, diabetes, and cardiovascular disease. Ongoing and planned clinical trials will continue to address strategies to prevent treatment‐related side effects and improve quality of life for men with prostate cancer.

To evaluate mifepristone (RU‐486) in patients with castration‐resistant prostate cancer (CRPC), with a correlative assessment of serum androgens and androgen metabolites

A phase II study of mifepristone (RU‐486) in castration‐resistant prostate cancer, with a correlative assessment of androgen‐related hormones

OBJECTIVE
Most breast cancer patients with bone metastases will receive bisphosphonate treatment. This post hoc analysis investigated whether early normalization of urinary N-telopeptide of type I collagen (NTX) levels during bisphosphonate therapy correlates with a long-term reduction in skeletal-related event (SRE) risk and mortality in patients with breast cancer.

METHODS
This was a retrospective subset analysis of a phase III randomized trial comparing i.v. zoledronic acid with pamidronate treatment in patients with bone metastases from breast cancer or multiple myeloma. Patients with breast cancer who had NTX assessments at baseline and at months 1 and 3 (n = 342) were classified as normal (NTX < 64 nmol/mmol creatinine) or elevated (NTX > or = 64 nmol/mmol creatinine). The relative risk for an SRE or death was estimated with Cox regression models.

RESULTS
Among the 328 evaluable patients treated with zoledronic acid, 196 patients (59.7%) had elevated baseline NTX, with 149 of those patients (76.0%) having normalized NTX levels and 31 patients (15.8%) having persistently elevated NTX levels at 3 months. The normalized NTX group had significantly lower risks for a first SRE, a first fracture or surgery to bone, or death than the group that had persistently elevated NTX levels.

These results suggest that early normalization of elevated baseline NTX while receiving zoledronic acid is associated with longer event-free and overall survival times compared with persistently elevated NTX. Further analyses in cancer patients with elevated marker levels are warranted to confirm the implications of these findings.

Zoledronic acid and survival in breast cancer patients with bone metastases and elevated markers of osteoclast activity.

5128 Background: Greater body mass index (BMI) is associated with shorter time to prostate-specific antigen (PSA) failure following radical prostatectomy. We investigated whether BMI is associated with prostate cancer-specific mortality (PCSM) in a large randomized trial of men treated with radiation therapy (RT) and androgen deprivation therapy (ADT) for locally advanced prostate cancer. Methods: Between 1987 and 1992, 945 eligible men with locally advanced prostate cancer were enrolled on a phase III trial (RTOG 85- 31) and randomized to RT and immediate goserelin (Arm I) or RT alone followed by goserelin at relapse (Arm II). Height and weight data were available at baseline for 788 (83%) subjects. Cox regression analyses were performed to evaluate the relationships between BMI and all-cause mortality, PCSM, and non-prostate cancer mortality. Covariates included age, race, treatment arm, history of prostatectomy, nodal involvement, Gleason score, clinical stage, and BMI. Results: The 5-year PCSM rate fo...

Body mass index and mortality in men treated for locally advanced prostate cancer: An analysis of RTOG 85–31

1015: Phase III Interim Analysis Demonstrates Toremifene Increases Bone Mineral Density in Men Receiving Androgen Deprivation Therapy for Prostate Cancer

304 ORAL Early normalization of elevated baseline bone resorption marker levels by zoledronic acid and improved survival in patients with bone metastases from solid tumors

Androgen deprivation therapy (ADT) is part of standard therapy for locally advanced or metastatic prostate cancer and is frequently used in men with a rising prostate-specific antigen following radical prostatectomy or radiation therapy. In some men, ADT may be administered for years or even decades. The intended therapeutic effect of ADT is testosterone deficiency. Because estrogen is a normal metabolite of testosterone, ADT also results in estrogen deficiency. ADT has a variety of adverse effects, many of which are primarily related to estrogen deficiency. Bone mineral density may decrease by 4% to 13% per year in men receiving ADT. The fracture rate for patients on ADT averages 5% to 8% per year of therapy. Hot flashes, gynecomastia, and breast tenderness are common side effects associated with ADT. In the clinic, minimum baseline testing should include weight measurement, blood pressure reading, and fasting lipid panel and serum glucose tests. Currently, there are no large outcome trials in men on ADT testing the available therapies for adverse effects. No therapies are specifically approved for treatment of adverse effects in men on ADT. Although some therapies can be used for a single indication (based upon small studies), there is currently no agent to treat the multiple estrogenic side effects of ADT.

Cardiovascular Mortality Following Androgen Deprivation Therapy in Men With Locally Advanced Prostate Cancer: An Analysis of RTOG 85-31

Purpose of reviewThe aim of this review is to summarize new concepts and concerns regarding treatment-related osteoporosis, diabetes, and cardiovascular disease in men receiving androgen deprivation therapy for prostate cancer. Recent findingsGonadotropin-releasing hormone agonists increase bone turnover, decrease bone mineral density, and increase fracture risk. Bisphosphonates, selective and estrogen receptor modulators significantly increase bone mineral density during androgen deprivation therapy. Ongoing randomized controlled trials will assess efficacy of denosumab, toremifene, and zoledronic acid to prevent fractures in this setting. Gonadotropin-releasing hormone agonists also increase fat mass, decrease insulin sensitivity, and increase serum lipoproteins. In contrast to the classical metabolic syndrome, however, the phenotype of men during androgen deprivation therapy is characterized by increased high-density lipoprotein cholesterol and preferential accumulation of subcutaneous fat. Gonadotropin-releasing hormone agonists are associated with greater risk of incident diabetes and cardiovascular disease in men with prostate cancer. SummaryAndrogen therapy increases risk of fractures, diabetes mellitus, and cardiovascular disease in men with prostate cancer. Current and planned studies will evaluate strategies to prevent these treatment-related adverse effects.

Androgen deprivation therapy for prostate cancer: new concepts and concerns

Osteolytic bone lesions from advanced multiple myeloma (MM) result in significant skeletal morbidity. Therefore, biochemical markers of bone metabolism, such as the N-terminal and C-terminal telopeptides of type I collagen, bone-specific alkaline phosphatase, and osteocalcin, have been investigated as tools for evaluating the extent of bone disease, risk of skeletal morbidity, and response to antiresorptive treatment. Several studies have shown that the majority of biochemical markers of bone metabolism are increased in patients with MM with osteolytic bone lesions, thus reflecting changes in bone metabolism associated with tumor growth. There is also a growing body of evidence that markers of bone metabolism correlate with the risk of skeletal complications, disease progression, and death. In addition, bone markers could potentially be used as a tool for early diagnosis of bone lesions. The aim of this review is to improve our understanding of bone markers as a clinical tool for the management of malignant bone disease in patients with MM.

Clinical utility of biochemical markers of bone metabolism for improving the management of patients with advanced multiple myeloma.

5116 Background: Androgen deprivation therapy (ADT) is the standard treatment for men with advanced prostate cancer. ADT decreases bone mineral density (BMD) and increases fracture risk although there is limited information about the prevalence of osteopenia and osteoporosis during ADT. We evaluated the baseline data from a large fracture prevention study to better characterize the prevalence of ostepenia and osteoporosis in men receiving ADT for prostate cancer. Methods: In an ongoing phase 3 fracture prevention study, 1,392 men = 50 years old with histologically documented prostate cancer and receiving ADT were randomized to placebo or toremifene 80 mg, a selective estrogen receptor modulator. The phase 3 study included men at increased risk of fracture based on age = 70 years or low baseline BMD of the hip or spine as assessed by dual energy x-ray absorptiometry. Subjects with metabolic bone disease or receiving treatment for osteoporosis were excluded. In the current analyses, we report the baseline B...

Prevalence of osteoporosis and osteopenia during androgen deprivation (ADT) for prostate cancer: Baseline data from a large randomized controlled trial

PURPOSE
Gonadotropin-releasing hormone (GnRH) agonists decrease bone mineral density (BMD) and increase fracture risk in men with prostate cancer. Annual zoledronic acid increases BMD in postmenopausal women, but its efficacy in hypogonadal men is not known.

In a 12-month study, 40 men with nonmetastatic prostate cancer who were receiving a GnRH agonist and had T scores more than -2.5 were randomly assigned to zoledronic acid (4 mg intravenously on day 1 only) or placebo. BMD of the posteroanterior lumbar spine and proximal femur were measured by dual-energy x-ray absorptiometry.

RESULTS
Mean (+/- SE) BMD of the posteroanterior lumbar spine decreased by 3.1% +/- 1.0% in men assigned to placebo and increased by 4.0% +/- 1.0% in men assigned to zoledronic acid (P < .001). BMD of the total hip decreased by 1.9% +/- 0.7% in men assigned to placebo and increased by 0.7% +/- 0.5% in men assigned to zoledronic acid (P = .004). Similar between-group differences were observed for the femoral neck and trochanter. Serum N-telopeptide, a marker of osteoclast activity, decreased significantly after zoledronic acid treatment.

In men receiving a GnRH agonist, a single treatment with zoledronic acid significantly increased BMD and durably suppressed serum N-telopeptide levels for 12 months. Annual zoledronic acid may be a convenient and effective strategy to prevent bone loss in hypogonadal men.

Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer.

Purpose: To evaluate effects of obesity on sex steroid levels during treatment with a gonadotropin-releasing hormone agonist in men with prostate cancer. Experimental Design: Forty-nine hormone-naïve men with recurrent or locally advanced prostate cancer were included in the analyses. All subjects were treated with leuprolide 3-month depot for 48 weeks. Serum levels of estradiol, sex hormone–binding globulin, total testosterone, and free testosterone were assessed at baseline, 24 weeks, and 48 weeks. Subjects were categorized by body mass index (BMI) and percent body fat. Results: Pretreatment serum sex hormone–binding globulin and total testosterone levels were significantly lower in overweight and obese men than in men with normal BMI. In the overall study population, mean serum testosterone concentrations decreased from 372 ± 18 ng/dL at baseline to 13 ± 1 ng/dL at week 48 (P < 0.001). Free testosterone decreased from 6.75 ± 0.33 ng/dL at baseline to 0.21 ± 0.02 ng/dL at week 48 (P < 0.001). During treatment with leuprolide, obese men had significantly higher total and free testosterone levels than men with normal BMI. Compared with normal men, total and free testosterone levels during treatment were 1.8-fold and 2.3-fold higher in obese men. Similar results were observed when subjects were categorized by body fat. Conclusions: Despite lower pretreatment serum testosterone levels, obese men have higher total and free testosterone levels during leuprolide treatment than men with normal BMI. These differences may contribute to the association between obesity and increased prostate cancer mortality.

Obesity and Sex Steroids during Gonadotropin-Releasing Hormone Agonist Treatment for Prostate Cancer

Effect of toremifene in lowering total cholesterol, LDL, and triglycerides and raising HDL in prostate cancer patients on androgen deprivation therapy

Greater body mass index (BMI) is associated with shorter time to prostate‐specific antigen (PSA) failure following radical prostatectomy and radiation therapy (RT). Whether BMI is associated with prostate cancer‐specific mortality (PCSM) was investigated in a large randomized trial of men treated with RT and androgen deprivation therapy (ADT) for locally advanced prostate cancer.

Obesity and mortality in men with locally advanced prostate cancer

Data from randomized, controlled trials of zoledronic acid were retrospectively analyzed to assess the effect of pathologic fractures on survival in patients with malignant bone disease.

Pathologic fractures correlate with reduced survival in patients with malignant bone disease

Predictors of skeletal complications in men with hormone-refractory metastatic prostate cancer.

6596 Background: Patients (pts) with bone metastasis are at high risk for skeletal related events (SREs), leading to increased morbidity, mortality, and decreased QOL. Methods: To study the impact ...

Solid tumor cancer patients treated with zoledronic acid experienced reduced skeletal related events as compared to untreated patients in clinical practice claims database

9119 Background: Cancer cachexia results in selective loss of skeletal muscle resulting in weakness, reduced physical activity and a lower quality of life. Cancer cachexia also diminishes response ...

Ostarine increases lean body mass and improves physical performance in healthy elderly subjects: Implications for cancer cachexia patients

Deregulation of the estrogen axis in humans prompts a series of tissue-specific events. In the breast and prostate, alterations in estrogen signalling lead to genotypic and phenotypic molecular alterations that result in dysplastic cellular appearance, deregulated cell growth and carcinoma. In bone, decreased estrogen leads to increased osteoclastogenesis and bone resorption, decreased bone mineral density and a significant fracture risk. Toremifene is a selective estrogen receptor modulator that exerts pharmacological activity in the breast, bone and prostate. An intense interest in developing this agent for prostate cancer chemoprevention is based on the reduction of premalignant and malignant prostate lesions in a transgenic model of prostate cancer. Biological and clinical activity was demonstrated in Phase II trials by the prevention of progression to prostate cancer in men with high-grade prostate intraepithelial neoplasia and through suppression of bone turnover biomarkers and increased bone mineral density in men on androgen deprivation therapy for prostate cancer.

Toremifene – a promising therapy for the prevention of prostate cancer and complications of androgen deprivation therapy

PURPOSE
Androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist is associated with increased fat mass and insulin resistance in men with prostate cancer, but the risk of obesity-related disease during treatment has not been well studied. We assessed whether androgen deprivation therapy is associated with an increased incidence of diabetes and cardiovascular disease.

Observational study of a population-based cohort of 73,196 fee-for-service Medicare enrollees age 66 years or older who were diagnosed with locoregional prostate cancer during 1992 to 1999 and observed through 2001. We used Cox proportional hazards models to assess whether treatment with GnRH agonists or orchiectomy was associated with diabetes, coronary heart disease, myocardial infarction, and sudden cardiac death.

RESULTS
More than one third of men received a GnRH agonist during follow-up. GnRH agonist use was associated with increased risk of incident diabetes (adjusted hazard ratio [HR], 1.44; P < .001), coronary heart disease (adjusted HR, 1.16; P < .001), myocardial infarction (adjusted HR, 1.11; P = .03), and sudden cardiac death (adjusted HR, 1.16; P = .004). Men treated with orchiectomy were more likely to develop diabetes (adjusted HR, 1.34; P < .001) but not coronary heart disease, myocardial infarction, or sudden cardiac death (all P > .20).

GnRH agonist treatment for men with locoregional prostate cancer may be associated with an increased risk of incident diabetes and cardiovascular disease. The benefits of GnRH agonist treatment should be weighed against these potential risks. Additional research is needed to identify populations of men at highest risk of treatment-related complications and to develop strategies to prevent treatment-related diabetes and cardiovascular disease.

Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer.

Metastatic prostate cancer is characterized by the presence of osteoblastic bone metastases. Bone metastases account for most of the morbidity from this disease. Inhibition of osteoclast activity with the potent bisphosphonate zoledronic acid reduces skeletal complications and decreases serum levels of biochemical bone turnover markers compared with placebo. Atrasentan is an investigational agent that inhibits endothelin‐1 receptor, resulting in decreased osteoblast activity.

Randomized phase II study of atrasentan alone or in combination with zoledronic acid in men with metastatic prostate cancer

CONTEXT
GnRH agonists markedly increase fat mass in men with prostate cancer, but little is known about the effects of treatment on insulin sensitivity.

OBJECTIVE
The objective of the study was to assess the effects of short-term GnRH agonist treatment on insulin sensitivity.

DESIGN
This was a prospective 12-wk study.

SETTING
The study was conducted at a general clinical research center.

We studied 25 men with locally advanced or recurrent prostate cancer, no radiographic evidence of metastases, no history of diabetes mellitus, and no evidence of diabetes mellitus at baseline visit.

INTERVENTION
Leuprolide depot and bicalutamide were used in the study.

Oral glucose tolerance tests and body composition assessment by dual-energy x-ray absorptiometry were performed at baseline and wk 12. The primary study outcome was change in insulin sensitivity index.

RESULTS
Mean (+/- se) percentage fat body mass increased by 4.3 +/- 1.3% from baseline to wk 12 (P = 0.002). Insulin sensitivity index decreased by 12.9 +/- 7.6% (P = 0.02). Insulin sensitivity by homeostatic model assessment decreased by 12.8 +/- 5.9% (P = 0.02). Fasting plasma insulin levels increased by 25.9 +/- 9.3% (P = 0.04). Mean glycosylated hemoglobin also increased significantly (P < 0.001).

Short-term treatment with leuprolide and bicalutamide significantly increased fat mass and decreased insulin sensitivity in men with prostate cancer. These observations suggest that GnRH agonists may increase the risk of diabetes mellitus and cardiovascular disease in older men.

Insulin sensitivity during combined androgen blockade for prostate cancer.

Risk of clinical fractures after gonadotropin-releasing hormone agonist therapy for prostate cancer.

PREDICTORS OF CLINICAL OUTCOME IN PATIENTS WITH PROSTATE CANCER AND BONE METASTASES: PROGNOSTIC SIGNIFICANCE OF FRACTURES AND BONE MARKERS

Bisphosphonates for metastatic bone disease [mdash] too much of a good thing?

PURPOSE
To assess the biologic activity of celecoxib, a selective cyclooxygenase-2 inhibitor, in men with recurrent prostate cancer using change in prostate-specific antigen (PSA) doubling time (PSADT) as the primary outcome variable.

Participants had histologically confirmed prostate cancer, no recent hormone therapy, rising serum PSA after radical prostatectomy and/or radiation therapy, and no radiographic evidence of metastases. Patients were randomly assigned to celecoxib (400 mg by mouth twice daily) or placebo. Treatment continued until disease progression or until adverse effects stopped treatment. A positive outcome was defined as post-treatment PSADT of more than 200% baseline PSADT with no new metastases.

RESULTS
The study was terminated early after information about the cardiovascular safety of celecoxib prompted review of ongoing clinical studies. Before discontinuation of the study, 78 men were assigned randomly to either celecoxib or placebo. Eight (20%) of 40 men in the placebo group and 15 (40%) of 38 men in the celecoxib group had post-treatment PSADT of more than 200% of baseline PSADT with no new metastases (P = .08). Mean PSA velocity increased by 3.0% for the placebo group and decreased by 3.4% for the celecoxib group (P = .02).

Although the primary efficacy objective was not met, this study provides some evidence for biologic activity of celecoxib in prostate cancer. Compared with placebo, celecoxib significantly decreased mean PSA velocity and tended to increase the proportion of men who doubled their PSADT.

Celecoxib versus placebo for men with prostate cancer and a rising serum prostate-specific antigen after radical prostatectomy and/or radiation therapy.

Purpose: To evaluate the relative prognostic value for specific markers of osteoblast and osteoclast activity while controlling for previously reported prognostic variables among men with hormone-refractory metastatic prostate cancer. Experimental Design: The 643 subjects in this report were participants in multicenter randomized controlled trial of zoledronic acid in men with metastatic prostate cancer. All subjects had bone metastases and disease progression despite medical or surgical castration. Relationships between baseline covariates and overall survival were examined by Cox proportional hazard model. Serum bone-specific alkaline phosphatase (BAP) and urinary N-telopeptide were assessed as representative specific markers of osteoblast and osteoclast activity, respectively. Other covariates in the model were age, log prostate-specific antigen, hemoglobin, lactate dehydrogenase, albumin, analgesic use, and Eastern Cooperative Oncology Group performance status. Results: Serum BAP was significantly correlated with urinary N-telopeptide (correlation coefficient = 0.674; 95% confidence interval, 0.628-0.715; P < 0.0001). In univariate analyses, higher levels of serum BAP and urinary N-telopeptide levels were significantly associated with shorter overall survival. After controlling for the other variables, including N-telopeptide, in multivariate models, higher serum BAP levels were consistently associated with shorter survival. In contrast, urinary N-telopeptide levels were not significantly associated with survival in multivariate analyses. Variables retained in the reduced multivariate model were age, log prostate-specific antigen, hemoglobin, lactate dehydrogenase, analgesic use, and BAP. Conclusions: Serum BAP significantly correlates with urinary N-telopeptide in men with androgen-independent prostate cancer and bone metastases. In multivariate models, higher levels of serum BAP but not urinary N-telopeptide are associated with shorter overall survival.

Markers of Bone Metabolism and Survival in Men with Hormone-Refractory Metastatic Prostate Cancer

ZOLEDRONIC ACID COMPARED WITH PAMIDRONATE IN PATIENTS WITH PROSTATE CANCER AND BONE METASTASES: EFFECTS ON SKELETAL COMPLICATIONS AND BONE MARKERS

Higher incidences of osteoporosis and osteopenia are found in cancer patients, particularly in women receiving aromatase inhibitors or with chemotherapy-induced ovarian failure, or in men with prostate cancer and androgen deprivation therapy. Therefore, management of long-term bone health is emerging as an important aspect of comprehensive cancer care. Patients with cancer typically have a number of additional risk factors for osteoporosis that should prompt screening, regardless of patient age or sex. Maintaining bone health requires a broad knowledge base, including understanding underlying bone metabolism and how it is affected by both cancer itself and the drugs used to treat cancer, the effect of chemotherapy-induced menopause on bone health, bone markers and imaging techniques used to assess bone health, therapeutic strategies to maintain bone health, and treatment of bone metastases, including surgery for pathologic fractures. Multiple members of the healthcare team may need to be involved in education and care of the patient. This report summarizes discussion of these and other issues regarding bone health and cancer care from the NCCN Bone Health and Cancer Care Task Force meeting in early 2006.

Purpose: To determine the safety and activity of weekly paclitaxel in combination with estramustine and carboplatin (TEC) in patients with advanced prostate cancer. Patients and Methods: In a dose-escalation study, patients with advanced prostate cancer were administered paclitaxel (weekly 1-hour infusions of 60 to 100 mg/m 2 ), oral estramustine (10 mg/kg), and carboplatin (area under the curve, 6 mg/mL-min every 4 weeks). Paclitaxel levels were determined 0, 30, 60, 90, and 120 minutes and 18 hours after infusion, and a concentration-time curve was estimated. Once a safe dose was established, a multi-institutional phase II trial was conducted in patients with progressive androgen-independent disease. Results: Fifty-six patients with progressive androgen-independent disease were treated for a median of four cycles. The dose of paclitaxel was escalated from 60 to 100 mg/m 2 without the occurrence of DLT. Posttherapy decreases in serum prostate-specific antigen levels of 50%, 80%, and 90% were seen in 67%, 48%, and 39% (95% confidence interval, 55% to 79%, 35% to 61%, 26% to 52%) of the patients, respectively. Of the 33 patients with measurable disease, two (6%) had a complete response and 13 (39%) had a partial response. The overall median time to progression was 21 weeks, and the median survival time for all patients was 19.9 months. Major grade 3 or 4 adverse effects were thromboembolic disease (in 25% of patients), hyperglycemia (in 38%), and hypophosphatemia (in 42%). Significant leukopenia, thrombocytopenia, and peripheral neuropathy were not observed. Conclusion: TEC has significant antitumor activity and is well tolerated in patients with progressive androgen-independent prostate cancer. J Clin Oncol 19:44-53. © 2001 by American Society of Clinical Oncology.

Paclitaxel, E stramustine P hosphate, a nd C arboplatin i n Patients W ith A dvanced P rostate C ancer

The First Cambridge Conference on Advances in Treating Metastatic Bone Cancer, a symposium held in Cambridge, Massachusetts, October 28 to 29, 2005, was convened to discuss recent advances and research related to the natural history of bone metastases and skeletal complications, bone cancer biology, treatment of myeloma and other solid tumors, and treatment-induced bone loss. The conference format combined brief presentations with extended periods of discussion. The conclusions reached during the 2-day meeting are summarized in this article and presented in more detail in the individual articles and accompanying discussion sessions that comprise the conference proceedings.

Advances in Treating Metastatic Bone Cancer: Summary Statement for the First Cambridge Conference

Therapy Insight: osteoporosis during hormone therapy for prostate cancer

PURPOSE
Gonadotropin-releasing hormone (GnRH) agonists decrease bone mineral density, a surrogate for fracture risk, in men with prostate cancer. We conducted a claims-based cohort study to characterize the relationship between GnRH agonists and risk for clinical fractures in men with nonmetastatic prostate cancer.

Using medical claims data from a 5% national random sample of Medicare beneficiaries, we identified a study group of men with nonmetastatic prostate cancer who initiated GnRH agonist treatment from 1992 to 1994 (n = 3,887). A comparison group of men with nonmetastatic prostate cancer who did not receive GnRH agonist treatment during the study period (n = 7,774) was matched for age, race, geographic location, and comorbidity. Clinical fractures were identified using inpatient, outpatient, and physician claims during 7 years of follow-up.

RESULTS
In men with nonmetastatic prostate cancer, GnRH agonists significantly increased fracture risk. The rate of any clinical fracture was 7.88 per 100 person-years at risk in men receiving a GnRH agonist compared with 6.51 per 100 person-years in matched controls (relative risk, 1.21; 95% CI, 1.14 to 1.29; P < .001). Rates of vertebral fractures (relative risk, 1.45; 95% CI, 1.19 to 1.75; P < .001) and hip/femur fractures (relative risk, 1.30; 95% CI, 1.10 to 1.53; P = .002) were also significantly higher in men who received a GnRH agonist. GnRH agonist treatment independently predicted fracture risk in multivariate analyses. Longer duration of treatment conferred greater fracture risk.

GnRH agonists significantly increase risk for any clinical fracture, hip fractures, and vertebral fractures in men with prostate cancer.

Gonadotropin-releasing hormone agonists and fracture risk: a claims-based cohort study of men with nonmetastatic prostate cancer.

BACKGROUND: Biochemical markers of bone metabolism provide valuable information about rates of bone turnover in patients with malignant bone disease. N-telopeptide of type I collagen (NTX) is released during osteolysis and is indicative of pathologic increases in bone resorption. Elevated NTX levels recently have been correlated with increased risks of skeletal-related events (SREs, defined as pathologic fracture, surgery to bone, spinal cord compression, hypercalcemia of malignancy, and the requirement for palliative radiotherapy), disease progression, and death in patients with bone metastases from solid tumors (Coleman RE, et al. J Clin Oncol.2005;23:4925–4935; Brown J, et al. J Natl Cancer Inst. 2005;97:59–69). METHODS: The current univariate analysis investigated the correlation between NTX levels at baseline and SREs (including palliative radiotherapy to bone) in patients with multiple myeloma who were treated with 4 mg zoledronic acid in a phase III clinical trial (Rosen LS, et al. Cancer J.2001;7:377–387). RESULTS: Forty-three patients had low NTX ( Conclusions: Multiple myeloma patients with elevated baseline NTX levels have a significantly increased risk of experiencing SREs.

Baseline N-Telopeptide Levels Correlate with Risk of Skeletal Morbidity in Patients with Multiple Myeloma during Zoledronic Acid Therapy.

BACKGROUND: Biochemical markers of bone metabolism are useful indicators of bone turnover in pts with malignant bone disease. Elevated N-telopeptide (NTX) levels were correlated with increased risks of skeletal-related events (SREs), disease progression, and death in pts with primary bone lesions from MM (Coleman RE, et al. J Clin Oncol. 2005). The prognostic value of other markers (eg, pyridinoline [PYD] and deoxypyridinoline [DXP]) in pts with MM is unknown. METHODS: This study investigated the association between NTX, PYD, DXP, and bone alkaline phosphatase (BAP) levels and risk of SRE or pathologic fracture in pts with MM who were treated with 4 mg zoledronic acid in a phase III clinical trial (Rosen LS, et al. Cancer J. 2001). Cut-off values for low, moderate, and high marker levels were based on prior reports and the investigators’ experience with bone marker data. Both univariate and multivariate analyses were performed and risk ratios were derived for pts with elevated levels of each bone marker relative to pts with low marker levels. RESULTS: By univariate analysis, moderate (50 to 100 nmol/mmol creatinine) and high (> 100 nmol/mmol creatinine) NTX levels corresponded with significantly increased risks of any SRE, onset of first SRE, or pathologic fracture. Elevated levels of PYD corresponded with a significantly increased risk of SREs, the onset of SREs, and pathologic fracture. Although there were some significant correlations, the association between DXP and BAP levels and risk of skeletal morbidity was inconsistent (Table). In multivariate models, only NTX and DXP were significant, and NTX had a stronger effect. CONCLUSIONS: Elevated baseline PYD, DXP, and BAP levels are significant predictors of an increased risk of some SREs and may therefore have clinical value. Elevated NTX levels are a consistent significant predictor of an increased risk of SREs and pathologic fractures. NTX levels may therefore aid in identifying patients at risk for skeletal complications.

Prognostic Significance of Biochemical Markers of Bone Metabolism in Patients with Bone Lesions from Multiple Myeloma (MM).

PURPOSE
To define the maximal tolerated dose, safety, and efficacy of docetaxel, carboplatin, and estramustine in patients with hormone-refractory prostate cancer (HRPC).

METHODS
Patients with HRPC received docetaxel for 3 weeks, followed by a rest week. Docetaxel (20, 25, 30, 36, or 43 mg/m2) was given on days 2, 9, and 16 of a 28-day cycle. Patients also received estramustine (140 mg p.o. three times daily on days 1-5, 8-12, and 15-19) and carboplatin [area under the curve, AUC (5) or (6) on day 2].

RESULTS
Thirty patients were treated. Five patients received carboplatin [AUC (6)] but experienced delayed thrombocytopenia. After a protocol amendment, 25 subsequent patients received carboplatin [AUC (5)]. Median age was 64 years. Median prostate-specific antigen (PSA) was 117 ng/mL. Fifty-three percent received prior ketoconazole and 10% had mitoxantrone. No dose-limiting toxicities were noted. Although maximal tolerated dose was not reached, docetaxel dose escalation was stopped at 43 mg/m2. Significant myelosuppression was not seen until the highest dose level, when seven and four patients experienced grade 3 and 4 toxicities, respectively. Among all patients, PSA declines of > or =50% occurred in 63%. At the recommended phase II dose, PSA declines of > or =50% occurred in 75% (95% confidence interval, 43-95). Four of 14 (29%) patients with measurable disease had partial responses. Median survival was 14.6 months.

Estramustine, docetaxel, and carboplatin are well tolerated and active in HRPC. Myelosuppression is the primary toxicity. The recommended phase II dose of docetaxel is 43 mg/m2 combined with estramustine and carboplatin. PSA declines were seen at every dose level.

Clinical cancer research : an official journal of the American Association for Cancer Research

A phase I study of estramustine, weekly docetaxel, and carboplatin chemotherapy in patients with hormone-refractory prostate cancer.

Bone metastases are a major cause of morbidity for men with prostate cancer. Complications of bone metastases include pain, fractures, and spinal cord compression. Although they appear osteoblastic by radiographic imaging, most bone metastases are characterized by excess osteoclast number and activity. In addition, pathologic osteoclast activation is associated with increased risk of skeletal complications. Zoledronic acid, a potent inhibitor of osteoclast activity, differentiation, and survival, decreases the risk of skeletal complications in men with androgen-independent prostate cancer and bone metastases. Other bisphosphonates, including pamidronate and clodronate, seem to be ineffective in this setting. The reduction in risk of skeletal complications with zoledronic acid must be weighed against potential adverse effects. Additional studies are needed to determine the optimal timing, schedule, and duration of treatment in men with bone metastases as well as the potential role of bisphosphonates in other settings including the prevention of bone metastases.

Bisphosphonates for treatment and prevention of bone metastases.

267: Gonadotropin-Releasing Hormone (GNRH) Agonist Therapy and Fracture Risk in Men with Prostate Cancer

PURPOSE
To describe the natural history of nonmetastatic prostate cancer and rising prostate-specific antigen (PSA) despite androgen deprivation therapy.

The 201 patients in this report were the placebo control group from an aborted randomized controlled trial to evaluate the effects of zoledronic acid on time to first bone metastasis in men with prostate cancer, no bone metastases, and rising PSA despite androgen deprivation therapy. Relationships between baseline covariates and clinical outcomes were assessed by Cox proportional hazard analyses. Covariates in the model were baseline PSA, Gleason sum, history of bilateral orchiectomies, regional lymph node metastases at diagnosis, prior prostatectomy, time from androgen deprivation therapy to random assignment, time from diagnosis to random assignment, and PSA velocity.

RESULTS
At 2 years, 33% of patients had developed bone metastases. Median bone metastasis-free survival was 30 months. Median time to first bone metastases and overall survival were not reached. Baseline PSA level greater than 10 ng/mL (relative risk, 3.18; 95% CI, 1.74 to 5.80; P < .001) and PSA velocity (4.34 for each 0.01 increase in PSA velocity; 95% CI, 2.30 to 8.21; P < .001) independently predicted shorter time to first bone metastasis. Baseline PSA and PSA velocity also independently predicted overall survival and metastasis-free survival. Other covariates did not consistently predict clinical outcomes.

Men with nonmetastatic prostate cancer and rising PSA despite androgen deprivation therapy have a relatively indolent natural history. Baseline PSA and PSA velocity independently predict time to first bone metastasis and survival.

Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer.

Now is the time to answer critical questions in the management of prostate cancer through enrollment in high-priority national phase 3 clinical trials. Studies of systemic therapy before and after local therapy are vitally important to determine whether early systemic interventions might delay cancer progression. Chemotherapy must be studied in earlier disease progression. Novel targeted therapies, such as vaccine therapy, angiogenesis inhibitors, and newer microtubule targeting agents, should be studied in all stages of progression. Despite these needs and the availability of systemic therapies, accrual to trials has been lagging. This article reviews the national cooperative group clinical trials, whether currently open or planned, and suggests practical strategies to improve accrual.

Zoledronic acid to prevent skeletal complications in cancer: corroborating the evidence.

From the Department of Urology, University of California School of Medicine, San Francisco (PRC) and University of California, San Francisco Comprehensive Cancer Center (JMLC), San Francisco, California; Departments of Radiation Oncology (AVD), Medical Oncology (PWK, WKO, WRS) and Pathology (MAR), Dana Farber Cancer Institute and Brigham and Women’s Hospital, Boston, Massachusetts; Lombardi Cancer Center, Georgetown University Medical Center, Washington, D. C. (EPG); Department of Urology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (PI); Memorial Sloan-Kettering Cancer Center, New York, New York, (NR); Sunnybrook & Women’s College Health Sciences Centre, Toronto, Ontario, Canada (LK); Shadyside Medical Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (JBN); Fred Hutchinson Cancer Research Center, Seattle, Washington (PSN); Johns Hopkins University, Baltimore, Maryland (WGN); University of Michigan Health Center, Ann Arbor, Michigan (HS); Massachusetts General Hospital Cancer Center, Boston, Massachusetts (MRS); Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina (JX); and InforMEDical, Inc., Carlisle, Massachusetts (MCM).

Consensus Summary FOURTH INTERNATIONAL CONFERENCE ON INNOVATIONS AND CHALLENGES IN PROSTATE CANCER: PREVENTION, DETECTION AND TREATMENT

4560 Background: In men with prostate cancer, GnRH agonists decreases bone mineral density, a major determinant of fracture risk. This retrospective population-based study evaluates the relationshi...

Risk factors for clinical fractures among men with non-metastatic prostate cancer

PURPOSE
Three large, randomized trials of patients with bone metastases recently demonstrated that zoledronic acid reduces the risk of skeletal-related events. These trials provide an opportunity for investigating the correlation between bone metabolism and clinical outcome during bisphosphonate therapy.

Urinary measurements of N-telopeptide (Ntx) and serum bone alkaline phosphatase (BAP) were obtained in 1,824 bisphosphonate-treated patients-1,462 with zoledronic acid (breast, 490; prostate, 411; myeloma, 210; non-small-cell lung, 183; other, 168) and 362 with pamidronate (breast, 254; myeloma, 108). This exploratory cohort analysis grouped patients by baseline and most recent levels of Ntx as low (< 50 nmol/mmol creatinine), moderate (50 to 99 nmol/mmol creatinine), or high (> or = 100 nmol/mmol creatinine), and BAP as low (< 146 U/L) or high (> or = 146 U/L). The relative risks for negative clinical outcomes were estimated for each group using multiple-event and Cox regression models with time-varying covariates.

RESULTS
Patients with high and moderate Ntx levels had 2-fold increases in their risk of skeletal complications and disease progression compared with patients with low Ntx levels (P < .001 for all). High Ntx levels in each solid tumor category were associated with a 4- to 6-fold increased risk of death on study, and moderate Ntx levels a 2- to 4-fold increased risk compared with low Ntx levels (P < .001 for all). Bone alkaline phosphatase also showed some correlation with risk of negative clinical outcomes.

The bone resorption marker Ntx provides valuable prognostic information in patients with bone metastases receiving bisphosphonates.

Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid.

Hormone-refractory prostate cancer (HRPC) remains true to its name: it is largely refractory to attempts to delay its progression. Although the number of men presenting with metastatic prostate cancer has decreased significantly over the last several years, the death rate for those men is essentially unchanged. To alter the currently inevitable progression of HRPC to death, new targets and new therapies are needed. This article reviews investigational therapies directed against standard targets (eg, the hypothalamic-pituitary-gonadal axis) as well as novel targets (eg, the endothelin axis).

Initial treatment with a gonadotropin‐releasing hormone (GnRH) agonist increases fat mass, decreases lean body mass, and decreases bone mineral density (BMD) in men with prostate carcinoma. To the authors' knowledge, little is known regarding either the long‐term effects of treatment or predictors of treatment‐related changes in BMD and body composition.

Changes in bone mineral density and body composition during initial and long‐term gonadotropin‐releasing hormone agonist treatment for prostate carcinoma

4517 Background: Trabectedin (T) is a novel, marine-derived cytotoxic agent that binds to the minor groove of DNA and induces apoptosis and cell cycle arrest. T has been studied in phase I and II c...

Phase II study of three hour, weekly infusion of trabectedin (ET-743) in men with metastatic, androgen-independent prostate carcinoma (AIPC)

Whether bone markers have prognostic value in patients with bone metastases is unknown. We investigated this question in patients with bone metastases secondary to prostate cancer and to non-small-cell lung cancer (NSCLC) and other solid tumors assigned to the placebo arms of two phase III trials of zoledronic acid.

METHODS
Levels of the urinary bone resorption marker N-telopeptide and the serum bone formation marker bone-specific alkaline phosphatase were assessed every 3 months for patients with prostate cancer (n = 203) or NSCLC or other solid tumors (n = 238) and were categorized as low or high. Patients were monitored for skeletal-related events, bone disease progression, and death. The relative risks (RRs) and 95% confidence intervals (CIs) for these outcomes were estimated for patients with high versus low levels of each marker using intensity-based multiple event and Cox regression models. All statistical tests were two-sided.

RESULTS
In each disease group and overall, high levels of each marker at the beginning of the study were statistically significantly associated with an increased risk of negative outcomes. Use of recent marker assessments as time-dependent covariates gave even greater prognostic significance. High N-telopeptide levels were a stronger prognostic indicator of negative outcomes than bone-specific alkaline phosphatase levels. In recent assessments, patients with high N-telopeptide levels had an increased relative risk of skeletal-related events (prostate cancer, RR = 3.25, 95% CI = 2.26 to 4.68, P<.001; NSCLC and other solid tumors, RR = 1.79, 95% CI = 1.15 to 2.79, P = .010), disease progression (prostate cancer, RR = 2.02, 95% CI = 1.48 to 2.74, P<.001; NSCLC and other solid tumors, RR = 1.91, 95% CI = 1.16 to 3.15, P = .011), and death (prostate cancer, RR = 4.59, 95% CI = 2.82 to 7.46, P<.001; NSCLC and other solid tumors, RR = 2.67, 95% CI = 1.85 to 3.85, P<.001) compared with patients with low N-telopeptide levels.

Baseline and recent bone marker levels were predictive of negative clinical outcomes in patients with bone metastases secondary to prostate cancer and to NSCLC and other solid tumors. N-telopeptide levels were more consistent prognostic indicators than bone-specific alkaline phosphatase for all tumor types, reflecting the key role of osteolysis in the development of skeletal complications.

Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors.

The intended therapeutic effect of gonadotropin-releasing hormone (GnRH) agonists is hypogonadism, which is a leading cause of osteoporosis in men. Consistent with this observation, GnRH agonists decrease bone mineral density and increase fracture risk in men with prostate cancer. GnRH agonists markedly decrease serum levels of both testosterone and estrogen. Estrogens play a central role in homeostasis of the normal male skeleton, and the available evidence suggests that estrogen deficiency rather than testosterone deficiency accounts for the adverse skeletal effects of GnRH agonists. The central role of estrogens in male bone metabolism provides a strong rationale to evaluate selective estrogen receptor modulators for prevention of treatment-related osteoporosis in men with prostate cancer. Preliminary evidence suggests that both raloxifene and toremifene increase bone mineral density in GnRH agonist-treated men. An ongoing pivotal study will evaluate the effects of toremifene on fractures and other complications of GnRH agonists in men with prostate cancer.

Selective estrogen receptor modulators to prevent treatment-related osteoporosis.

PURPOSE
A presentation on osteoporosis, obesity and obesity related disease at the Conference on Innovations and Challenges in Prostate Cancer: Prevention, Detection and Treatment is summarized.

A focused literature review was done.

RESULTS
Gonadotropin-releasing hormone (GnRH) agonists decrease bone mineral density and increase fracture risk. GnRH agonists also increase weight and fat mass, and decrease lean body mass. Treatment related changes in body composition may contribute to fatigue and fracture risk. The phenotype of men with GnRH agonist shares some features with the insulin resistance syndrome, raising the possibility that GnRH may also increase the risk of diabetes mellitus and cardiovascular disease.

The routine use of GnRH agonists in men with long life expectancy increases the importance of understanding and preventing the unintended adverse effects of treatment. Some adverse effects have the potential to impact not only quality of life, but also noncancer mortality. Additional research is needed to characterize better the unintended effects of androgen deprivation therapy and develop optimal strategies to prevent osteoporosis, obesity and obesity related disease.

Osteoporosis and obesity in men receiving hormone therapy for prostate cancer.

4507 Background: Androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist decreases bone mineral density in men with prostate cancer. Small retrospective studies have sugge...

Association between androgen deprivation therapy and fracture risk: A population-based cohort study in men with non-metastatic prostate cancer

The objective of this study was to assess the biologic activity of rosiglitazone, a peroxisome proliferator‐activated receptor γ agonist that has been approved to treat type 2 diabetes, in men with recurrent prostate carcinoma using change in prostate specific antigen (PSA) doubling time (PSADT) as the primary outcome variable.

Rosiglitazone versus placebo for men with prostate carcinoma and a rising serum prostate‐specific antigen level after radical prostatectomy and/or radiation therapy

Osteoporosis and Other Adverse Body Composition Changes during Androgen Deprivation Therapy for Prostate Cancer

PURPOSE
Gonadotropin-releasing hormone agonists decrease bone mineral density, lean mass, and muscle size and increase fat mass in men with prostate cancer. Less is known about the effects of bicalutamide monotherapy on bone mineral density and body composition.

In a 12-month, open-label study, we randomly assigned 52 men with prostate cancer and no bone metastases to receive either leuprolide or bicalutamide (150 mg by mouth daily). Bone mineral density and body composition were measured by dual energy x-ray absorptiometry and quantitative computed tomography.

RESULTS
Mean (+/- standard error) bone mineral density of the posterior-anterior lumbar spine decreased by 2.5% +/- 0.5% in the leuprolide group and increased by 2.5 +/- 0.5 in the bicalutamide group from baseline to 12 months (P <.001). Mean changes in bone mineral density of the total body, total hip, femoral neck, and trabecular bone of the lumbar spine also differed significantly between groups (P < or =.003 for each comparison). Fat mass increased by 11.1% +/- 1.3% in the leuprolide group and by 6.4% +/- 1.1% in the bicalutamide group (P =.01). Changes in lean mass, muscle size, and muscle strength were similar between the groups. Breast tenderness and enlargement were more common in the bicalutamide group than in the leuprolide group. Fatigue, loss of sexual interest, and vasomotor flushing were less common in the bicalutamide group than in the leuprolide group.

In men with prostate cancer, bicalutamide monotherapy increases bone mineral density, lessens fat accumulation, and has fewer bothersome side effects than treatment with a gonadotropin-releasing hormone agonist.

Bicalutamide monotherapy versus leuprolide monotherapy for prostate cancer: effects on bone mineral density and body composition.

Long-term bisphosphonate treatment of bone metastases from renal cell carcinoma.

PURPOSE
To evaluate the herbal combination, PC-SPES, and diethylstilbestrol (DES) in patients with androgen independent prostate cancer (AIPC).

A randomized phase II study was conducted with cross-over design. Patients were randomly assigned to receive either three PC-SPES capsules orally three times a day or DES 3 mg orally once a day. Prophylactic warfarin was administered. At clinical or prostate-specific antigen progression, patients received the other therapy. The study closed prematurely after PC-SPES was withdrawn from the market. Chemical analyses were performed on multiple lots of PC-SPES.

RESULTS
Ninety patients were enrolled, of whom 85 were assessable for response. Prostate-specific antigen declines > or = 50% were noted in 40% (95% CI, 25% to 56%) with PC-SPES, and 24% (95% CI, 12% to 39%) with DES. Median response duration was not reached with PC-SPES, and was 3.8 months with DES. Median time to progression for randomly assigned patients was 5.5 months for PC-SPES and 2.9 months for DES. Common toxicities included mild fatigue, gynecomastia, and mastodynia. Five thromboembolic events occurred (one PC-SPES, four DES). Responses in the cross-over phase were inconclusive. Four lots of PC-SPES had measurable quantities of DES, ranging from 0.01% to 3.1% of the dose used in the DES arm. Ethinyl estradiol was also detected in PC-SPES lots.

PC-SPES and DES demonstrate activity in AIPC and are well tolerated. However, the synthetic estrogens, DES and ethinyl estradiol, were detected in various lots of PC-SPES, including those used in this trial. Clinical trials that utilize herbal therapies must account for issues of purity and consistency.

Prospective, multicenter, randomized phase II trial of the herbal supplement, PC-SPES, and diethylstilbestrol in patients with androgen-independent prostate cancer.

Purpose: Biochemical markers of both osteoblast and osteoclast activity are elevated in men with osteoblastic metastases from prostate cancer. Androgen deprivation therapy (ADT), the mainstay of therapy for advanced prostate cancer, increases markers of osteoblast and osteoclast activity, even in the absence of bone metastases. Little is known about the relative contributions of ADT and skeletal metastases to elevated bone turnover in men with prostate cancer. Experimental Design: To evaluate the relative contributions of ADT and skeletal metastases to osteoblast and osteoclast activity, we performed a cross-sectional study in three groups of men with advanced prostate cancer: (a) hormone-naïve men without bone metastases; (b) castrate men without bone metastases; and (c) castrate men with bone metastases. The primary study end points were serum levels of bone-specific alkaline phosphatase (BSAP), a marker of osteoblast activity, and N-telopeptide (NTX), a marker of osteoclast activity. Results: Serum levels of both BSAP and NTX were significantly higher in groups of castrate men (groups 2 and 3) than in hormone-naïve men (group 1; P < 0.01 for all comparisons). Among castrate men, serum BSAP was significantly higher in men with bone metastases than in men without bone metastases (P = 0.01). In contrast, serum levels of NTX were similar in groups 2 and 3 (P = 0.33). Conclusions: The unintended effects of ADT on the skeleton are sufficient to explain increased osteoclast activity in castrate men with bone metastases. These results may have important implications for the optimal timing and schedule of osteoclast-targeted therapy in men with advanced prostate cancer.

Contribution of Androgen Deprivation Therapy to Elevated Osteoclast Activity in Men with Metastatic Prostate Cancer

A multi-institutional phase II trial of gemcitabine plus paclitaxel in patients with locally advanced or metastatic urothelial cancer.

438: Fracture Risk in Men with Prostate Cancer on Androgen Deprivation Therapy

The purpose of the study was to evaluate response and survival in patients with metastatic urothelial cancer treated with combination gemcitabine and paclitaxel administered on a biweekly schedule at doses of 3000 mg/m 2 and 150 mg/m 2 , respectively. Patients with adequate organ function and performance status were accrued through 7 institutions, stratified by prior therapy status, and treated as noted. Response was evaluated by 1979 bi-dimensional World Health Organization (WHO) criteria. Of 55 eligible patients, 17 had a partial and 5 had a complete response rate for an overall response rate of 40% (27‐54%). One complete response and one partial response were observed in the 6 previously treated patients. Overall median survival was 11.8 months (11.9 months in the chemonaive cohort). Grade 3 or 4 myelosuppression occurred in 56%, but only 4 serious infections were observed. We conclude that because of a lower than expected complete response rate, even when corrected for prognostic groupings, this regimen is not recommended for routine use in patients with metastatic urothelial cancer. Insufficient patients with poor renal function or prior therapy were accrued to reach conclusions regarding its utility in these subgroups. © 2004 Elsevier Inc. All rights reserved.

Original article A multi-institutional phase II trial of gemcitabine plus paclitaxel in patients with locally advanced or metastatic urothelial cancer

Primary and secondary osteoporosis are prevalent in more than 2 million American men. One of the main causes of this is hypogonadism, in turn brought upon by early androgen deprivation therapy used in prostate cancer treatment. Androgen deprivation therapy produces a host of adverse effects on the skeleton, including an increase in bone turnover, a decrease in bone mineral density, and an increase in fracture risk. In addition, based on observations in preclinical models, these adverse effects on the skeletal integrity may promote the development of or progression of metastasis to bone. Loss of bone due to androgen deprivation therapy is an important clinical issue for many men with prostate cancer, but osteoporosis is not an inevitable consequence of androgen deprivation therapy. Because of interpatient variations in peak bone mass as well as differences in rates of treatment-related bone loss, not all men with prostate cancer require treatment for osteoporosis. All men on androgen deprivation therapy should receive calcium and multivitamin supplements and should be considered for bisphosphonate therapy; this is particularly so for men with either a low baseline BMD or observed high rates of bone loss during androgen deprivation therapy.

The role of bisphosphonates in men with prostate cancer receiving androgen deprivation therapy.

Changes in fat and lean body mass during androgen-deprivation therapy for prostate cancer.

Androgen‐deprivation therapy (ADT) is prescribed with increasing frequency for men with prostate carcinoma. There is growing concern about the effects of such therapy on the skeleton. In the current review, the authors addressed the current research, diagnostic methods, and treatment recommendations for bone loss and osteoporosis in men with prostate carcinoma who received ADT.

Osteoporosis in men with prostate carcinoma receiving androgen‐deprivation therapy

Osteoporosis is an important complication of androgen-deprivation therapy (ADT) for prostate cancer. ADT by either bilateral orchiectomies or treatment with a gonadotropin-releasing hormone (GnRH) agonist decreases bone mineral density (BMD) and increases the risk of fracture. Prospective data about treatment or prevention of osteoporosis in men with prostate cancer are limited. Supplemental calcium and vitamin D are recommended. Additional therapy may be warranted for men with osteoporosis or fractures. Intravenous pamidronate prevents bone loss in the hip and spine during ADT. Intravenous zoledronic acid not only prevents bone loss but also increases BMD. Alendronate is approved to treatmen with osteoporosis although the efficacy of alendronate or other oral bisphosphonates has not been evaluated during ADT. Additional prospective studies are needed to evaluate the long-term effects of bisphosphonates and other the rapies on fracture risk and disease-related outcomes.

Fourth International Conference on Innovations and Challenges in Prostate Cancer: Prevention, Detection and Treatment.

GnRH agonists decrease bone mineral density and increase fracture risk in men with prostate cancer. Raloxifene increases bone mineral density in postmenopausal women, but its efficacy in hypogonadal men is not known. In a 12-month open-label study, men with nonmetastatic prostate cancer (n = 48) who were receiving a GnRH agonist were assigned randomly to raloxifene (60 mg/d) or no raloxifene. Bone mineral densities of the posteroanterior lumbar spine and proximal femur were measured by dual energy x-ray absorptiometry. Mean (+/-se) bone mineral density of the posteroanterior lumbar spine increased by 1.0 +/- 0.9% in men treated with raloxifene and decreased by 1.0 +/- 0.6% in men who did not receive raloxifene (P = 0.07). Bone mineral density of the total hip increased by 1.1 +/- 0.4% in men treated with raloxifene and decreased by 2.6 +/- 0.7% in men who did not receive raloxifene (P < 0.001). Similar between-group differences were observed in the femoral neck (P = 0.06) and trochanter (P < 0.001). In men receiving a GnRH agonist, raloxifene significantly increases bone mineral density of the hip and tends to increase bone mineral density of the spine.

Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial.

4656 Background: The purpose of this study was to define the maximal tolerated dose (MTD) of weekly docetaxel combined with carboplatin and estramustine in the treatment of patients with HRPC. Meth...

A phase I study of estramustine, weekly docetaxel and carboplatin (EDC) chemotherapy in patients with hormone refractory prostate cancer (HRPC)

As evidence accumulates in favor of androgen deprivation therapy (ADT) in patients with recurrent or metastatic prostate carcinoma, concern has increased regarding bone loss associated with therapeutic hypogonadism. The current study described the natural history of bone complications in men with prostate carcinoma who have initiated ADT.

Natural history of bone complications in men with prostate carcinoma initiating androgen deprivation therapy

Management of treatment-related osteoporosis in men with prostate cancer.

The role of bisphosphonates in the management of metastatic prostate cancer

Third international conference on innovations and challenges in prostate cancer: prevention, detection and treatment.

Androgens are important determinants of body composition in men. Androgen-deprivation therapy, the mainstay of treatment for advanced prostate cancer, increases fat mass and decreases lean body mass. These adverse changes in body composition may contribute to treatment-related fatigue, fracture risk, insulin resistance, and increased cardiovascular disease risk. Potential strategies to treat or prevent these adverse body composition changes include exercise training, alternative forms of hormonal therapy, and insulin-sensitizing agents.

Changes in body composition during hormonal therapy for prostate cancer.

Bisphosphonates to Prevent Osteoporosis in Men Receiving Androgen Deprivation Therapy for Prostate Cancer

PURPOSE
A multicenter double-blind, randomized, placebo controlled clinical trial was performed to assess the effect of zoledronic acid, a potent new bisphosphonate, on bone mineral density during androgen deprivation therapy for nonmetastatic prostate cancer.

Men with M0 (no distant metastases) prostate cancer beginning androgen deprivation therapy were randomly assigned to receive 4 mg. zoledronic acid or placebo intravenously every 3 months for 1 year. The primary efficacy variable was the percent change from baseline to 1 year in bone mineral density of the lumbar spine as measured by dual energy x-ray absorptiometry.

RESULTS
A total of 106 men were enrolled in the trial. Mean bone mineral density in the lumbar spine increased by 5.6% in men receiving zoledronic acid and decreased by 2.2% in those given placebo (mean difference 7.8%, 95% confidence interval 5.6%-10.0%, p <0.001). Mean bone mineral density of the femoral neck, trochanter and total hip also increased in the zoledronic acid group and decreased in the placebo group. Zoledronic acid was well tolerated.

Zoledronic acid increases bone mineral density in the hip and spine during androgen deprivation therapy for nonmetastatic prostate cancer.

Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer.

Cross-sectional study of bone turnover during bicalutamide monotherapy for prostate cancer.

Finasteride and flutamide therapy in patients with advanced prostate cancer: response to subsequent castration and long-term follow-up.

Purpose: We describe the practical technical aspects of magnetic resonance spectroscopic imaging (MRSI), and summarize the current and potential future status of magnetic resonance imaging (MRI) and MRSI in the diagnosis, localization, staging, treatment planning and posttreatment followup of prostate cancer. Materials and Methods: Contemporary series of patients with prostate cancer evaluated by MRI and MRSI were reviewed, with particular respect to imaging accuracy as evaluated by histopathological correlation, and the relationship between MRI and MRSI and outcome. Results: MRI and MRSI have a limited role in prostate cancer diagnosis but may be helpful for patients with a high index of suspicion and negative initial biopsy. High specificity can be achieved for sextant localization of cancer when sextant biopsy, MRI and MRSI are all positive. Volumetric localization is of limited accuracy for tumors less than 0.5 cc. Staging by MRI, which is improved by the addition of MRSI, is of incremental prognostic significance for patients with moderate and high risk tumors. MRI and MRSI may assist in surgical and radiation treatment planning, and posttreatment followup. In particular, the use of MRI to assist radiation treatment planning has been shown to improve outcome. Interventional MRI guided biopsy and therapy remain under investigation. Conclusions: Only MRI and MRSI allow combined structural and metabolic evaluation of prostate cancer location, aggressiveness and stage. MRI provides clinically and therapeutically relevant anatomical information. The technology remains in evolution, and continued advances in accuracy and use are likely.

Magnetic resonance imaging and spectroscopic imaging of prostate cancer. Discussion

PURPOSE
Bone metastases occur in approximately 80% of patients with advanced prostate cancer. Pain is common in these patients. The purpose of this study was to evaluate the effect of an intravenous bisphosphonate, pamidronate disodium, on pain control in metastatic prostate cancer patients.

Two multicenter, double-blind, randomized, placebo-controlled trials were conducted in patients with bone pain due to metastatic prostate cancer, with disease progression after first-line hormonal therapy. Intravenous pamidronate disodium (90 mg) or placebo was administered every 3 weeks for 27 weeks. Efficacy was measured via self-reported pain score (Brief Pain Inventory), analgesic use, the proportion of patients with a skeletal-related event (SRE; defined as pathologic fracture, radiation or surgery to bone, spinal cord compression, or hypercalcemia), and a pilot quantitative measurement of mobility. Laboratory evaluations included serum prostate-specific antigen, interleukin-6, bone alkaline phosphatase, and urinary bone resorption markers.

RESULTS
Results of the two trials were pooled. There were no sustained significant differences between the pamidronate and placebo groups in self-reported pain measurements, analgesic use, proportion of patients with an SRE, or mobility at week 9 or 27. Urinary bone resorption markers were suppressed in the pamidronate group compared with placebo.

Pamidronate disodium failed to demonstrate a significant overall treatment benefit compared with placebo in palliation of bone pain or reduction of SREs. Evaluation of more potent bisphosphonates in patients with prostate cancer is warranted.

Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer.

Purpose: Androgen refractory prostate cancer continues to evade effective treatment. The potent vasoconstrictor endothelin-1 is produced by prostate cancer and appears to have a role in prostate cancer progression and morbidity. Background on the endothelin axis (endothelin-1 and endothelin receptors ET A and ET B ), preclinical studies of its role in prostate cancer, results of phases I and II clinical trials, and future directions are reviewed. Materials and Methods: A review was conducted of the published data on the endothelin axis in prostate cancer. Results: Based on preclinical and clinical trial data, the endothelin axis is emerging as potentially important in the biology of prostate cancer progression and morbidity. Drugs targeting the endothelin axis, such as the potent ET A receptor antagonist atrasentan (ABT-627), have been studied in large clinical trials and appear to have an impact on disease progression and morbidity. Conclusions: The role of the endothelin axis in prostate cancer deserves further investigation in the laboratory and clinic. This new strategy for intervention is promising.

Endothelin inhibition: Novel therapy for prostate cancer. Discussion

PURPOSE
The literature on clinical trials of bisphosphonates in men with metastatic prostate cancer is reviewed to familiarize the reader with biology of bone metastases and rationale for use of bisphosphonates.

A MEDLINE review of the literature on prostate cancer and bisphosphonates was performed.

RESULTS
In uncontrolled clinical trials bisphosphonates improved pain and analgesic scores in men with symptomatic bone metastases. In a randomized controlled trial of men with bone metastases and progressive disease after first line hormonal therapy zoledronic acid decreased the skeletal related events, a composite end point defined as fracture, surgery or radiation therapy to bone, or change in antineoplastic therapy for bone pain. Randomized controlled trials with other bisphosphonates reported no significant benefit in men with bone metastases. Problems with the study populations, drug bioavailability and potency, statistical power and end point definition may have contributed to the negative results of these other studies.

Zoledronic acid decreases the risk of skeletal related events in men with bone metastases and disease progression after first line hormonal therapy. Additional clinical research is needed to evaluate the optimal timing, schedule and duration of bisphosphonate treatment in men with metastatic prostate cancer. Additional research is also necessary to determine whether bisphosphonates can prevent bone metastases in men with high risk nonmetastatic prostate cancer.

Bisphosphonates to prevent skeletal complications in men with metastatic prostate cancer.

We found limited evidence from RCTs suggesting that androgen deprivation reduced mortality compared with no initial treatment. One systematic review and one subsequent RCT found no evidence of a difference in effectiveness between different methods of androgen deprivation (orchidectomy, diethylstilbestrol, and gonadorelin analogues).

Bone metastases are a major cause of morbidity for patients with many types of cancer including multiple myeloma, breast cancer, prostate cancer, and other solid tumors. The clinical complications of bone metastases include pain, fracture, spinal cord compression, and hypercalcemia of malignancy.

Osteoporosis is a complication of androgen deprivation therapy in men with prostate carcinoma. Androgen deprivation therapy, caused by either bilateral orchiectomy or treatment with a gonadotropin‐releasing hormone agonist, decreases bone mineral density and increases fracture risk. Other factors including diet and lifestyle may contribute to bone loss. There is limited information regarding the best strategy to prevent osteoporosis in men with prostate carcinoma. Lifestyle modification including smoking cessation, moderation of alcohol consumption, and regular weight‐bearing exercise should be encouraged. Supplemental calcium and vitamin D are also recommended. Additional treatment may be warranted for men with osteoporosis, fractures, or high rates of bone loss during androgen deprivation therapy. Intravenous pamidronate, a second‐generation bisphosphonate, prevents bone loss during androgen deprivation therapy. Zoledronic acid, a more potent third‐generation bisphosphonate, not only prevents bone loss but also increases bone mineral density during androgen deprivation therapy. Other bisphosphonates may be effective although they have not been evaluated in this clinical setting. Treatment with estrogens or selective estrogen receptor modulators may also be effective. Monotherapy with bicalutamide or other antiandrogens may cause less bone loss than androgen deprivation therapy. Cancer 2003;97(3 Suppl):789–95. © 2003 American Cancer Society.

Diagnosis and management of treatment‐related osteoporosis in men with prostate carcinoma

Treatment options for patients with metastatic renal cell carcinoma are limited. Interferon-alpha has an overall response rate of 10–15% in phase II and III clinical trials and is considered a standard option for patients. Though the anti-estrogen toremifene has shown only modest single agent activity in renal cell carcinoma, evidence for synergy of anti-estrogens with interferon-alpha exists in renal cell and other cancers. Therefore, a phase II trial was undertaken to test the combination of interferon-alpha and toremifene in advanced renal cell carcinoma. Thirteen patients with measurable metastatic or unresectable local disease were treated with interferon-alpha at a dose of 5 million units/m2 three times a week and daily oral toremifene at 300 mg daily in divided doses. Patients were treated for 12 weeks and then restaged. Clinical response was the primary endpoint of the trial. Four patients (31%) had evidence of stable disease at 12 weeks, while the remaining nine patients (69%) progressed on treatment. Toxicity was moderate, with grade 2 or 3 fatigue, nausea and anorexia each noted in 31% of patients. We conclude that the combination of interferon-alpha plus toremifene demonstrates no significant activity in advanced renal cell carcinoma.

A Phase II Trial of Interferon-Alpha and Toremifene in Advanced Renal Cell Cancer Patients

Purpose: Prostate cancer is the most common malignancy in men and one of the leading causes of cancer death in men internationally. Treatment for prostate cancer frequently includes androgen deprivation therapy (ADT). Reports of depressive symptoms arising during ADT are emerging. This study examines the prevalence rates and risk factors associated with major depression in this population. Method: 45 men with prostate cancer receiving ADT at the MGH Cancer Center were surveyed for depression with the SCID for Axis I disorders for DSM‐IV and the Beck Depression Inventory. Results: Major depressive disorder was prevalent in 12.8% of the men with prostate cancer receiving ADT, eight times the national rate of depression in men, 32 times the rate in men over 65 years old. Major depression was not associated with worsening disease, medical response to ADT, receiving chemotherapy, or the type of ADT. Past history of depression was associated with current depression in this population (p<0.000). No first onset cases of depression occurred on ADT in this sample. Conclusion: This data suggests a significant rate of major depression in men with prostate cancer receiving ADT and that men with past histories of depression may be at particular risk for recurrence of their depression while undergoing this treatment. Copyright © 2002 John Wiley & Sons, Ltd.

Depression in Men Receiving Androgen Deprivation Therapy for Prostate Cancer: A Pilot Study

Osteoporosis and other adverse body composition changes during androgen deprivation therapy for prostate cancer : Clinical and translational research in prostate cancer, part II

Measurement of body fat by dual-energy X-ray absorptiometry and bioimpedance analysis in men with prostate cancer.

Osteoporosis during androgen deprivation therapy for prostate cancer.

Overview consensus statement. Newer approaches to androgen deprivation therapy in prostate cancer.

The aim of this study was to determine the effects of initial treatment with a GnRH agonist on body composition in asymptomatic men with nonmetastatic prostate cancer. Forty men with locally advanced, node-positive or biochemically recurrent prostate cancer, no radiographic evidence of metastases, and no prior androgen deprivation therapy were treated with leuprolide 3-month depot 22.5 mg im every 12 wk for 48 wk. The main outcome measures were percentage changes in weight, percentage fat body mass, percentage lean body mass, fat distribution, and muscle size after 48 wk. Thirty-two subjects were evaluable. Serum T concentrations decreased by 96.3% plus or minus 0.4% (P < 0.001). Weight increased by 2.4% plus or minus 0.8% (P = 0.005). Percentage fat body mass increased by 9.4% plus or minus 1.7% (P < 0.001), and percentage lean body mass decreased by 2.7% plus or minus 0.5% (P < 0.001). Cross-sectional areas of the abdomen and abdominal sc fat increased by 3.9% plus or minus 1.2% (P = 0.003) and 11.1% plus or minus 3.4% (P = 0.003), respectively. In contrast, the cross-sectional area of intraabdominal fat did not change significantly (P = 0.94). Cross-sectional paraspinal muscle area decreased by 3.2% plus or minus 1.3% (P = 0.02). GnRH agonists increase weight and percentage fat body mass and decrease percentage lean body mass and muscle size in men with nonmetastatic prostate cancer. Increased fatness resulted primarily from accumulation of sc rather than intraabdominal adipose tissue.

Changes in body composition during androgen deprivation therapy for prostate cancer.

Peroxisome Proliferator-Activated Receptor Gamma (PPARγ as a Novel Target for Prostate Cancer

The objective of this study was to determine the prevalence of low bone mineral density in men with prostate carcinoma and no history of androgen‐deprivation therapy.

Low bone mineral density in hormone‐naïve men with prostate carcinoma

Non‐destructive quantitation of spermine in human prostate tissue samples using HRMAS 1H NMR spectroscopy at 9.4 T

Purpose: Prostate-specific antigen (PSA) is a glycoprotein that is found almost exclusively in normal and neoplastic prostate cells. For patients with metastatic disease, changes in PSA will often antedate changes in bone scan. Furthermore, many but not all investigators have observed an association between a decline in PSA levels of 50% or greater and survival. Since the majority of phase II clinical trials for patients with androgenindependent prostate cancer (AIPC) have used PSA as a marker, we believed it was important for investigators to agree on definitions and values for a minimum set of parameters for eligibility and PSA declines and to develop a common approach to outcome analysis and reporting. We held a consensus conference with 26 leading investigators in the field of AIPC to define these parameters. Result: We defined four patient groups: (1) progressive measurable disease, (2) progressive bone metastasis, (3) stable metastases and a rising PSA, and (4) rising PSA and no other evidence of metastatic disease. The purpose of determining the number of patients whose PSA level drops in a phase II trial of AIPC is to guide the selection of agents for further testing and phase III trials. We propose that investigators report at a minimum a PSA decline of at least 50% and this must be confirmed by a second PSA value 4 or more weeks later. Patients may not demonstrate clinical or radiographic evidence of disease progression during this time period. Some investigators may want to report additional measures of PSA changes (ie, 75% decline, 90% decline). Response duration and the time to PSA progression may also be important clinical end point. Conclusion: Through this consensus conference, we believe we have developed practical guidelines for using PSA as a measurement of outcome. Furthermore, the use of common standards is important as we determine which agents should progress to randomized trials which will use survival as an end point. J Clin Oncol 17:3461‐3467. r 1999 by American Society of Clinical Oncology.

Eligibility a nd R esponse G uidelines f or P hase I I C linical Trials i n A ndrogen-Indepen dent P rostate C ancer: Recommendations F rom t he P rostate-Specifi c A ntigen Working G roup

Objectives: Estrogen receptors are expressed in healthy and malignant prostate epithelium. Previous studies of the antiestrogen tamoxifen (20–100 mg po qd) for recurrent or metastatic prostate cancer (CaP) reported response rates of 0–23%. These studies may have underestimated the activity of antiestrogens, however, because of their reliance on insensitive clinical and radiographic response criteria. In addition, treatment-related increases in androgen levels among men who initiated treatment with noncastrate testosterone levels may have confounded the results. The aims are to evaluate the activity of the antiestrogen toremifene, a triphenylethylene derivative antiestrogen related chemically and pharmacologically to tamoxifen, in men with androgen-independent CaP using prostate specific antigen (PSA) response criteria and to determine the effect of toremifene treatment on serum testosterone levels in castrated men. 
 
Materials and Methods: Fifteen men (median age 71 years; median PSA 58.5 ng/ml) with castrate testosterone levels, no disease-related symptoms, and rising PSA after androgen deprivation and antiandrogen withdrawal were treated with toremifene, 60 mg po qd, until it was determined that the patient was not responding to treatment. Nonresponse to treatment was defined as symptomatic disease progression or a PSA level 150% study nadir on two determinations at least 4 weeks apart. Response was defined as >50% PSA decrease on two determinations at least 4 weeks apart. 
 
Results: Twelve men were evaluable for response. Median time to determination of nonresponse to treatment was 16 weeks (range 8 to 19 weeks). There were no responses to treatment (response rate 0%; 95% confidence interval 0–22%). Treatment did not significantly change serum testosterone levels. 
 
Conclusions: These results indicate that toremifene is inactive for the treatment of androgen-independent CaP and suggest that antiestrogens should not be used routinely as secondary hormonal therapy. The treatment of castrated men with toremifene does not significantly change serum testosterone levels.

Phase II Trial of the Antiestrogen Toremifene for Androgen‐Independent Prostate Cancer

‘Tomudex’ (raltitrexed) 4.0 mg/m[2] as second- or third-line therapy in patients with advanced colorectal cancer: a Phase II study

PACLITAXEL(T), ESTRAMUSTINE(E) AND CARBOPLATIN(C) IN PATIENTS (Pts) WITH ADVANCED PROSTATE CANCER(PC):

Evolution of zygomycete secretomes and the origins of terrestrial fungal ecologies

Deconvoluting the XPS spectra for nitrogen-doped chars: An analysis from first principles

Microstructural analysis of nitrogen-doped char by Raman spectroscopy: Raman shift analysis from first principles

A handheld, spatially offset Raman spectroscopy (SORS) system was successfully used to obtain Surface‐enhanced Raman Scattering (SERS) spectra of fentanyl under simulated field conditions. A series of aqueous fentanyl solutions were prepared with commercially available gold nanoparticle solution, at concentrations ranging from 0.003 to 1697 μM. These SERS spectra were then used to generate two concentration calibration models (via a plot of peak area (1026 cm−1) versus concentration, and quantitative spectral decomposition using partial least squares (PLS1)). For both models, the relationship followed Langmuir adsorption and became non‐linear at concentrations above ~0.2 μM, with a limit of detection (LOD) of approximately 3 nM. The same technique was successfully used to measure fentanyl in the presence of two common “cutting agents,” heroin and glucose, at 1% and 2% fentanyl proportions (w/w). Fentanyl detection was successfully achieved, but mixture interference from the cutting agents prevented a calibration model being generated. Four fentanyl analogues were also investigated—butyrylfentanyl, furanylfentanyl, acetylfentanyl, and ocfentanyl. A concentration calibration model for each species was successfully generated, but differentiation from fentanyl proved more challenging, although several potential diagnostic peaks were identified. These results identified a pathway forward in using handheld equipment for the reliable detection of ultra‐low concentrations of fentanyl and fentanyl analogues via SERS, even when mixed with diluents. However, quantitative detection is negatively impacted in the presence of heroin and glucose. This also provides a starting point for a SERS‐based spectral library of fentanyl analogues, in combination with a range of different diluents.

A Semi‐quantitative method for the detection of fentanyl using surface‐enhanced Raman scattering (SERS) with a handheld Raman instrument

Core level binding energy for nitrogen doped char: XPS deconvolution analysis from first principles

Chemical and morphological evaluation of chars produced from primary biomass constituents: cellulose, xylan, and lignin.

Novel bio-char characterization strategies and their use to study the chemical and morphological evolution of material derived from xylan, cellulose and lignin

Effect of pyrolysis temperature on aromatic cluster size of cellulose char by quantitative multi cross-polarization 13C NMR with long range dipolar dephasing

54 POLYMERS CONTAINING OPTICAL 2,657,195 10/1953 Toland. BRIGHTENER COMPOUNDS 3,709,896 1/1973 Frischkorn et al.. COPOLYMERIZED THEREIN AND 3,912,697 10/1975 Pacifici. METHODS OF MAKING AND USING 4,095,939 6/1978 Pacifici et al.. THEREFOR 4,177,347 12/1979 Meyer. 4,803.241 2/1989 Weaver et al.. 75 Inventors: Richard Hsu-Shien Wang; James J. 4.882,412 11/1989 Weaver et al.. Krutak; Mahendra K. Sharma; 4.978.476 12/1990 Allen et al.. Barbara C. Jackson, all of Kingsport, 5,039,782 8/1991 Langer et al.. Tenn. 5,082.578 1/1992 Langer et al.. 5,292.855 3/1994 Krutak et al.. 5,336,714 8/1994 Krutak et al.. 73 Assignee: Eastman Chemical Company, 5,423,432 6/1995 Krutalk et all Kingsport, Tenn.

POLYMERS CONTAINING OPTICAL BRIGHTENER COMPOUNDS COPOLYMERIZED THEREIN AND METHODS OF MAKING AND USING THEREFOR FIELD OF THE INVENTION

Structural analysis of char by Raman spectroscopy: Improving band assignments through computational calculations from first principles

Improving the deconvolution and interpretation of XPS spectra from chars by ab initio calculations

by Matthew William Smith, Ph.D. Washington State University July 2016 Chair: Manuel Garcia Perez In this project the deconvolution of Raman, X-ray Photoelectron, and Nuclear Magnetic Resonance spectra of chars are examined. To support this work, spectra calculated for a wide variety of polyaromatic structures have been examined using density functional theory. Based on these results a new fitting and interpretation procedure for Raman spectra of chars has been proposed. This method identifies out of plane deformation, 5 membered ring systems, 7+ membered ring systems and heteroatom inclusions, in addition to monitoring the cluster size of aromatic domains. A modified deconvolution procedure has also been proposed for XPS spectra. This method utilizes sequential deconvolution of the O 1s and C 1s spectra. In this method the C 1s deconvolution is constrained by the results of the O 1s spectrum, using the maximum and minimum bonds of for carbon-oxygen bonds based on theoretical groupings. A new quantitative C multiple cross-polarization NMR technique was successfully applied to pyrolysis chars. Coupled with a REDOR type dephasing series this method was used to estimate the cluster size and number of atoms at each distance in a series of cellulose chars. This method provided results consistent with far more time intensive direct polarization studies. The methods developed have

Characterization and Modification of Biomass Pyrolysis Chars for Environmental Applications

Production and characterization of bio-oil and biochar from the pyrolysis of residual bacterial biomass from a polyhydroxyalkanoate production process.

Integrating Pyrolysis and Anaerobic Digestion in a Novel Biorefinery Concept

Predicting relative humidities of liquid-liquid phase separation, efflorescence & deliquescence of mixed particles of ammonium sulcate & organic material & water using organic-to-sulfate mass ratio of the particle & oxygen-to-carbon elemental ratio

Composite Energetic Materials Containing Nitrotriazalone Formed by Molecular Inclusion

Abstract : An accelerated ageing program was undertaken to analyse the suitability of ARX-4024 as a replacement for Composition B in Australian munitions. Testing was undertaken utilising two different conditions, namely the B2 cycle, which is representative of extreme conditions in northern Australia, and at a constant 60 deg C with ambient humidity. An analysis of the ingredient composition, sensitiveness, and mechanical strength was made at 3 month intervals over a period of 12 months, and the results compared to Composition B samples similiarly aged.

Abstract : Melt-castable NTO/TNT formulations have been identified as suitable IM candidates to replace existing Composition B main charges within the Australian inventory. Of this family, ARX-4O24 (65/35 NTO/TNT) has shown the greatest potential to pass IM criteria and allow Qualification for Australian service. It has shown processing properties suitable for large-scale production at ADI's Muiwala and Benalla plants. This report details results obtained from an IM test series of the 5"/54 Naval projectile filled with ARX-4024. The assessments were carried out on projectiles in their plugged logistical configuration and comprised of IM Slow Cook-Off, Liquid Fuel Fire, Bullet Imp act and Sympathetic Reaction tests. All four tests were successfully passed, with results providing a solid basis for further development

Insensitive Munitions Assessment of the 5"/54 Navel Artillery Shell Filled with ARX 4024

Abstract : Melt-castable NTO/TNT explosive formulations have been identified as possible candidates to replace RDX/TNT to meet Australian Insensitive Munitions obligations. Such formulations could be processed in existing ADI industrial facilities with minimal alterations to plant. A baseline 50:50 NTO/TNT formulation, designated ARX-4002, has been developed. ARX-4002 can be processed using traditional melt-cast techniques and exhibits reduced sensitiveness in comparison to Composition B and H-6. The molten slurry is less prone to sedimentation problems, however, viscosities are increased and lower solid loadings possible than for Grade A RDX. Velocity of detonation and detonation pressure were experimentally determined at 7370 m/s and 22.6 GPa respectively. Performance of ARX-4002 is thus less than for Composition B, however, the intrinsic sensitivity of ARX-4002 is expected to be greatly reduced as indicated by the large critical diameter (22.5-25.5 mm).

Abstract A thermal study of the dinitramide salts of lithium, sodium, potassium, rubidium and cesium is presented. The series displayed a complex set of DSC exothermic decays with the exception of ...

Abstract : 3-Nitro-1,2,4-triazol-5-one (NTO) is an explosive ingredient under investigation as a potential insensitive replacement for RDX in explosive formulations. Although its performance is slightly less than that of RDX, NTO is thermally more stable and less sensitive to hazard stimuli. Explosive compositions based on NTO are therefore more likely to be Extremely Insensitive Detonating Substances, and munitions filled with them may meet the criteria of both Insensitive Munitions (IM) and HD 1.6 classification for storage and transportation. This report examines the currently available literature on NTO and its use in explosive compositions, and recommends future work to explore the possible application of NTO in IM compliant explosives for the ADF.

Functionalization of poly(butylene adipate‐co‐terephthalate) with itaconic anhydride through graft copolymerization

Copper‐Catalyzed Covalent Dimerization of Near‐infrared Fluorescent Cyanine Dyes: Synergistic Enhancement of Photoacoustic Signals for Molecular Imaging of Tumor

Immobilization of Protein Probes on Graphene Field-Effect Transistors for Biomolecular Sensing

Decellularized extracellular matrix (dECM)–based biomaterials are of great clinical utility in soft tissue repair applications due to their regenerative properties. Multi-layered dECM devices have been developed for clinical indications where additional thickness and biomechanical performance are required. However, traditional approaches to the fabrication of multi-layered dECM devices introduce additional laminating materials or chemical modifications of the dECM that may impair the biological functionality of the material. Using an established dECM biomaterial, ovine forestomach matrix, a novel method for the fabrication of multi-layered dECM constructs has been developed, where layers are bonded via a physical interlocking process without the need for additional bonding materials or detrimental chemical modification of the dECM. The versatility of the interlocking process has been demonstrated by incorporating a layer of hyaluronic acid to create a composite material with additional biological functionality. Interlocked composite devices including hyaluronic acid showed improved in vitro bioactivity and moisture retention properties.

Further structural characterization of ovine forestomach matrix and multi-layered extracellular matrix composites for soft tissue repair

Comparison of Nylon Suture Versus 2 Fibrin Glue Products for Delayed Nerve Coaptation in an Animal Model.

Rheology and sheet extrusion of Novatein thermoplastic protein/polybutylene adipate‐co‐terephthalate blends

Novatein thermoplastic protein was extrusion blended with poly(butylene adipate-co-terephthalate) (PBAT) in the presence of dual compatibilizers to produce blends with greater energy absorbing properties than pure Novatein. Compatibilizer pairs were Joncryl ADR-4368 (glycidyl methacrylate-functionalized) with 2-methylimidazole (2MI), and poly-2-ethyl-2-oxazoline (PEOX) with polymeric diphenyl methane diisocyanate (pMDI). Uncompatibilized Novatein/PBAT blends had decreased tensile mechanical properties, attributed to phase separation, and poor interfacial adhesion. PBAT became finely dispersed in both compatibilized systems, but PEOX/pMDI blends showed embrittlement and large Novatein domains, which acted as stress concentrations. Tensile strength and elongation at break for Joncryl/2MI blends did not decrease compared with Novatein, even at 10 wt % PBAT, and impact strength increased threefold. Dynamic mechanical analysis and solvent extraction showed that PBAT coalesced in all systems, at compositions as low as 2 wt %. It was concluded that using Joncryl/2MI as a dual compatibilizer system can successfully produce a morphology that enhances energy absorption during fracture. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017, 134, 45808.

Compatibilization effects in thermoplastic protein/polyester blends

The self-assembly of micellar structures from diblock polymers that contain hydrophilic and hydrophobic domains has been of great interest for the encapsulation of drugs and other hydrophobic molecules. While most commercially used surfactants are derived from hydrocarbon sources, there have been recent efforts to replace these with biodegradable, nontoxic, biologically synthesized alternatives. Previous examples have primarily examined naturally occurring self-assembling proteins, such as silk and elastin-like sequences. Herein, we describe a new series of fusion proteins that have been developed to self-assemble spontaneously into stable micelles that are 27 nm in diameter after enzymatic cleavage of a solubilizing protein tag. The sequences of the proteins are based on a human intrinsically disordered protein, which has been appended with a hydrophobic segment. The micelles were found to form across a broad range of pH, ionic strength, and temperature conditions, with critical micelle concentration (CMC) values in the low micromolar range, 3 orders of magnitude lower than the CMC of commonly used surfactant sodium dodecyl sulfate (SDS). The reported micelles were found to solubilize hydrophobic metal complexes and organic molecules, suggesting their potential suitability for catalysis and drug delivery applications. Furthermore, the inherent flexibility in the design of these protein sequences enables the encoding of additional functionalities for many future applications. Overall, this work represents a new biomolecular alternative to traditional surfactants that are based on nonrenewable and poorly biodegradable hydrocarbon sources.

Self-Assembling Micelles Based on an Intrinsically Disordered Protein Domain.

Novatein thermoplastic protein was blended with 10 wt% poly(butylene adipate-co-terephthalate) (PBAT) compatibilized with Joncryl ADR-4368 and 2-methylimidazole (2MI). Morphology was tailored for favorable impact strength through changing viscosity ratio (λ) and interfacial tension (γ12). For uncompatibilized blends, λ decreased and γ12 increased with increasing Novatein water content, whereas compatibilizers caused a decrease in both λ and γ12. PBAT continuity was high when uncompatibilized, but dispersion improved with decreasing λ and increasing γ12. The dispersed domain size decreased in all compatibilized blends; PBAT continuity was lowest in samples with the smallest λ. Compatibilized blends had higher impact strength than Novatein and uncompatibilized blends through improved interfacial adhesion, smaller domain size, and increased dispersion. By altering λ and γ12, and with appropriate chemical interaction, a morphology can be created for improved impact strength. Increasing PBAT content showed further increases in impact strength; however, a cocontinuous morphology formed, demonstrating that composition can override the effect of λ and γ12.

Manipulating morphology in thermoplastic protein/polyester blends for improved impact strength

Improving Impact Properties of Novatein through Polymer Blending and Reactive Extrusion

As fossil fuels are increasingly linked to environmental damage, the development of renewable, affordable biological alternative fuels is vital. Shewanella oneidensis is often suggested as a potential component of bioelectrochemical cells because of its ability to act as an electron donor to metal surfaces. These microbes remain challenging to implement, though, due to inconsistency in biofilm formation on electrodes and therefore current generation. We have applied DNA hybridization-based cell adhesion to immobilize S. oneidensis on electrodes. High levels of current are reproducibly generated from these cell layers following only 30 min of immobilization without the need for the formation of a biofilm. Upon incorporation of DNA mismatches in the microbe immobilization sequence, significant attenuation in current production is observed, suggesting that at least part of the electron transfer to the electrode is DNA-mediated. This method of microbe assembly is rapid, reproducible, and facile for the production of anodes for biofuel cells.

DNA Hybridization To Interface Current-Producing Cells with Electrode Surfaces

Novatein thermoplastic protein embrittles quickly after processing due to desorption of plasticizer, leading to poor energy absorbing properties such as impact strength. However, impact modified Novatein blends, containing functionalized polyethylene or nano-scale core-shell particles exhibit increased energy absorbing properties. The phase distribution of reinforced blends, and the protein secondary structure changes as a result of blending and fracture was investigated using synchrotron FT-IR microspectroscopy. Morphological changes in Novatein/polyethylene blends were responsible for variations in mechanical properties, rather than changes in secondary structure. In contrast, a greater impact strength was correlated to an increase of disordered secondary structures in core-shell particle reinforced Novatein. Blends which exhibited greater elongation or yielding during fracture showed a significant difference between protein secondary structure in the bulk matrix and the yielded material after fracture. It was concluded that the change in conformation of protein structures during fracture is an energy absorbing mechanism that acts in conjunction with the free elongation of the matrix due to decreasing interparticle distance for materials reinforced with nano-particles. POLYM. ENG. SCI., 2017. © 2017 Society of Plastics Engineers

Structural changes and energy absorption mechanisms during fracture of thermoplastic protein blends using synchrotron FTIR

The interactions between microbes and surfaces provide critically important cues that control the behavior and growth of the cells. As our understanding of complex microbial communities improves, there is a growing need for experimental tools that can establish and control the spatial arrangements of these cells in a range of contexts. Recent improvements in methods to attach bacteria and yeast to nonbiological substrates, combined with an expanding set of techniques available to study these cells, position this field for many new discoveries. Improving methods for controlling the immobilization of bacteria provides powerful experimental tools for testing hypotheses regarding microbiome interactions, studying the transfer of nutrients between bacterial species, and developing microbial communities for green energy production and pollution remediation.

New Techniques for the Generation and Analysis of Tailored Microbial Systems on Surfaces.

A convenient enzymatic strategy is reported for the modification of proline residues in the N-terminal positions of proteins. Using a tyrosinase enzyme isolated from Agaricus bisporus (abTYR), phenols and catechols are oxidized to highly reactive o-quinone intermediates that then couple to N-terminal proline residues in high yield. Key advantages of this bioconjugation method include (1) the use of air-stable precursors that can be prepared on large scale if needed, (2) mild reaction conditions, including low temperatures, (3) the targeting of native functional groups that can be introduced readily on most proteins, and (4) the use of molecular oxygen as the sole oxidant. This coupling strategy was successfully demonstrated for the attachment of a variety of phenol-derivatized cargo molecules to a series of protein substrates, including self-assembled viral capsids, enzymes, and a chitin binding domain (CBD). The ability of the CBD to bind to the surfaces of yeast cells was found to be unperturbed by this modification reaction.

Enzymatic Modification of N-Terminal Proline Residues Using Phenol Derivatives.

Novatein thermoplastic protein was blended with modified polyethylene (containing either epoxy, carboxylic acid functionalities partially neutralised to produce zinc carboxylate salts, or maleic anhydride functionalities) to alter blend morphology and to manipulate thermal and mechanical properties. Up to 40 pphNovatein polyethylene (PE) was blended with Novatein by extrusion and injection moulding. Using zinc ionomer resulted in optimal properties and was compatible with a finely dispersed morphology at high content; high interfacial tension (σ) and a viscosity ratio (λ) of ~1 was observed. Unmodified blends and those containing epoxy functionalities showed co-continuity at low PE content. Whilst co-continuity appeared to increase impact resistance, other mechanical properties decreased due to lack of phase interaction. Maleic anhydride-grafted-polyethylene blends showed a finely dispersed PE phase, yet was less compatible. Zinc ionomer was deemed to be the most appropriate for modification of mechanical properties in Novatein.

The relationship between morphology development and mechanical properties in thermoplastic protein blends

Methods for Generating Microbial Cocultures that Grow in the Absence of Fixed Carbon or Nitrogen.

Microbial co‐cultures promise the development of more efficient bioproductions. However, the design of obligate mutualisms is complicated when using organisms that possess differing growth rates or incompatible media requirements. In this work, we investigate sucrose production by cscB Synechococcus elongatus PCC 7942 within a polyacrylate hydrogel matrix. This system secretes sucrose only when the hydrogel is spatially constrained, demonstrating a new utilization of hydrogel swelling pressure to control the osmotic strength of a microbial microenvironment. The sucrose produced via the constrained microbial hydrogel is used to grow the diazotrophic organism, Azotobacter vinelandii, in a mutually dependent fashion. The growth of this hydrogel‐based coculture has several advantages over batch cultures, including better growth over a longer period of time and decreased salt stress on A. vinelandii. Biotechnol. Bioeng. 2017;114: 1195–1200. © 2016 Wiley Periodicals, Inc.

Improving metabolite production in microbial co‐cultures using a spatially constrained hydrogel

DNA has unique capabilities for molecular recognition and self-assembly, which have fostered its widespread incorporation into devices that are useful in science and medicine. Many of these platforms rely on thiol groups to tether DNA to gold surfaces, but this method is hindered by a lack of control over monolayer density and by secondary interactions between the nucleotide bases and the metal. In this work, we report an electrochemically activated bioconjugation reaction as a mild, reagent-free strategy to attach oligonucleotides to gold surfaces. Aniline-modified DNA was coupled to catechol-coated electrodes that were oxidized to o-quinones using an applied potential. High levels of coupling could be achieved in minutes. By changing the reaction time and the underlying catechol content, the final DNA surface coverage could be specified. The advantages of this method were demonstrated through the electrochemical detection of the endocrine disruptor bisphenol A, as well as the capture of living nonadherent cells on electrode surfaces by DNA hybridization. This method not only improves the attachment of DNA to metal surfaces but also represents a new direction for the site-specific attachment of biomolecules to device platforms.

Microbial mutualisms play critical roles in a diverse number of ecosystems and have the potential to improve the efficiency of bioproduction for desirable chemicals. We investigate the growth of a photosynthetic cyanobacterium, Synechococcus elongatus PCC 7942, and a diazotroph, Azotobacter vinelandii, in coculture. From initial studies of the coculture grown in media with glutamate, we proposed a model of cross-feeding between these organisms. We then engineer a new microbial mutualism between Azotobacter vinelandii AV3 and cscB Synechococcus elongatus that grows in the absence of fixed carbon or nitrogen. The coculture cannot grow in the absence of a sucrose-exporting S. elongatus, and neither organism can grow alone without fixed carbon or nitrogen. This new system has the potential to produce industrially relevant products, such as polyhydroxybutyrate (PHB) and alginate, from air, water, phosphate, trace metals, and sunlight. We demonstrate the ability of the coculture to produce PHB in this work.

A Designed A. vinelandii-S. elongatus Coculture for Chemical Photoproduction from Air, Water, Phosphate, and Trace Metals.

Impact Modification and Fracture Mechanisms of Core–Shell Particle Reinforced Thermoplastic Protein

Differential scanning calorimetry (DSC) was used to study the curing reaction of bisphenol A diglycidyl ether (DGEBA) and Novatein thermoplastic protein (NTP). NTP is made from bloodmeal and is ∼60% protein. Activation energy (Eα), pre-exponential factor (ln Ao) and order of reaction (m + n) were calculated using the Kissinger, model-free isoconversional and autocatalytic models. Curing kinetics were almost independent of concentration and the addition of plasticizers and protein denaturants to bloodmeal caused a decrease in Eα of ∼50%. Increasing protein denaturants had little effect on the reaction; however, inclusion of salt proved detrimental. At NTP’s maximum processing temperature (∼450 K), using an equal molar ratio of epoxy groups to reactive amino acids, 75% conversion can be reached in 3 min based on the modeling done here.

Using infrared spectroscopy of a nitrile labeled phenylalanine and tryptophan fluorescence to probe the α-MSH peptide’s side-chain interactions with a micelle model membrane

A novel cellular homing/chemokine delivery system was developed, in which electrospun polydioxanone (PDO) scaffolds infused with Monocyte Chemotactic Protein-1 (MCP-1) were fabricated and examined for their potential to influence macrophage infiltration/adherence and for their potential to provide extended chemokine release. Over the course of 120 hours, MCP-1 released into supernatant peaked at 24 hours and was detectable by enzyme-linked immunosorbent assay (ELISA) when added to PDO solutions prior to electrospinning at 3000 ng/ml. PDO/MCP-1 hybrids were characterized for biological activity using a test tube ELISA procedure assessing macrophage adherence/infiltration of scaffolds. Results demonstrated an increasing dose-responsive trend with increasing MCP-1 concentration. These initial investigations suggest such hybrid materials have significant potential for use in and improvement of in situ tissue regeneration applications by acting as cellular homing devices.

Feasibility of Electrospun Polydioxanone — Monocyte Chemotactic Protein-1 (MCP-1) Hybrid Scaffolds as Potential Cellular Homing Devices

Suture-reinforced electrospun polydioxanone-elastin small-diameter tubes for use in vascular tissue engineering: a feasibility study.

While electrospinning had seen intermittent use in the textile industry from the early twentieth century, it took the explosion of the field of tissue engineering, and its pursuit of biomimetic extracellular matrix (ECM) structures, to create an electrospinning renaissance. Over the past decade, a growing number of researchers in the tissue engineering community have embraced electrospinning as a polymer processing technique that effectively and routinely produces non-woven structures of nanoscale fibers (sizes of 80nm to 1.5 µm). These nanofibers are of physiological significance as they closely resemble the structure and size scale of the native ECM (fiber diameters of 50 to 500nm). Attempts to replicate the many roles of native ECM have led to the electrospinning of a wide array of polymers, both synthetic (poly(glycolic acid), poly(lactic acid), polydioxanone, polycaprolactone, etc.) and natural (collagen, fibrinogen, elastin, etc.) in origin, for a multitude of different tissue applications. With various compositions, fiber dimensions and fiber orientations, the biological, chemical and mechanical properties of the electrospun materials can be tailored. In this review we highlight the role of electrospinning in the engineering of different tissues and applications (skin/wound healing, cartilage, bone, vascular tissue, urological tissues, nerve, and ligament), and discuss its potential role in future work.  2007 Society of Chemical Industry

Review Extracellular matrix regenerated: tissue engineering via electrospun biomimetic

While electrospinning had seen intermittent use in the textile industry from the early twentieth century, it took the explosion of the field of tissue engineering, and its pursuit of biomimetic extracellular matrix (ECM) structures, to create an electrospinning renaissance. Over the past decade, a growing number of researchers in the tissue engineering community have embraced electrospinning as a polymer processing technique that effectively and routinely produces non-woven structures of nanoscale fibers (sizes of 80 nm to 1.5 µm). These nanofibers are of physiological significance as they closely resemble the structure and size scale of the native ECM (fiber diameters of 50 to 500 nm). Attempts to replicate the many roles of native ECM have led to the electrospinning of a wide array of polymers, both synthetic (poly(glycolic acid), poly(lactic acid), polydioxanone, polycaprolactone, etc.) and natural (collagen, fibrinogen, elastin, etc.) in origin, for a multitude of different tissue applications. With various compositions, fiber dimensions and fiber orientations, the biological, chemical and mechanical properties of the electrospun materials can be tailored. In this review we highlight the role of electrospinning in the engineering of different tissues and applications (skin/wound healing, cartilage, bone, vascular tissue, urological tissues, nerve, and ligament), and discuss its potential role in future work. Copyright © 2007 Society of Chemical Industry

Extracellular matrix regenerated : tissue engineering via electrospun biomimetic nanofibers

Due primarily to cell sourcing issues, many in the field of tissue engineering have opted to create scaffolds that promote in situ regeneration, using the body as both the bioreactor and the cell source for the remodeling of scaffolds, resulting in the formation of native tissue. This practice raises many concerns, with the body's immune response to such an implant often being neglected as a potential problem in preliminary design and biocompatibility testing. More importantly, what happens over time in terms of the immune responses as the biodegradable scaffold structures being utilized to promote in situ regeneration begin to degrade, forming structural fragments and degradation products? In summary, immune response evaluations are critical considerations that must be conducted when evaluating bioresorbable scaffolds. In addition, it is essential that these evaluations analyze materials for their potential dose-response and time-course effects on the various components of innate and acquired immunity.

Immune Response Testing of Electrospun Polymers: An Important Consideration in the Evaluation of Biomaterials

Various concentrations of the globular protein hemoglobin were successfully electrospun to create micro-fibrous mats of varying physical and mechanical characteristics. The electrospinning parameters are reported. One concentration of myoglobin was electrospun into a mat for comparison to the hemoglobin mats. Scanning electron microscopy revealed ribbon-like morphologies for the hemoglobin and myoglobin structures. Mean fiber width and thickness for each mat electrospun from a different hemoglobin concentration increased from 2.68 ± 0.83 to 3.55 ± 1.49 μm and from 0.49 ± 0.08 to 0.99 ± 0.41 μm, respectively, for increasing hemoglobin solution concentrations (from 150 to 225 mg/mL). For calculations of surface area to volume ratio for the four different electrospun hemoglobin concentrations, there was a negative correlation (r = −0.84) with concentration; the surface area to volume ratio ranged between 0.50 ± 0.16 and 1.53 ± 0.24 m2/cm3. Also, there appears to be a positive correlation between electrospun hemoglobin concentration and porosity, which increased with increasing concentration from 69.5 to 83.3 %. Following cross-linking with glutaraldehyde, the mechanical properties of two constructs were evaluated via uniaxial tensile testing to demonstrate handling capability. Results indicated that increased cross-linking time produced stiffer structures, as peak stress and modulus increased while strain at break decreased when the mats were cross-linked for 30 minutes with glutaraldehyde versus the 20 minute cross-linking time.

Feasibility of Electrospinning the Globular Proteins Hemoglobin and Myoglobin

Road map for research on responsible artificial intelligence for development (AI4D) in African countries: The case study of agriculture

Artificial intelligence (AI) is beginning to live up to its promise of delivering real value, driven by recent advances in the availability of relevant data, computation and algorithms. In the present paper, I discuss the value to agriculture from AI over the next decade. The more immediate applications will be to improve precision information about what is happening on the farm by improving what is being detected and measured. A consequence of this are more accurate alerts to farmers. Another is an increased ability to understand why phenomena occur in farm systems, so as to improve their management. From improved data and understanding come improved predictions, enabling more optimal decisions about how to manage farm systems and stimulating the development of decision support and recommender systems. In many cases, robotics and automated systems will remove much of the need for human decision-making and improve farm efficiencies and farm health. Artificial intelligence will also be needed to enable organisations to harness the value of information distributed throughout supply chains, including farm data. Digital twins will also emerge as an important paradigm to improve how information about farm entities is organised to support decision-making. There are also likely to be negative impacts from AI, such as disruption to the roles and skills needed from farm workers, indicating the need to consider the social and ethical impacts of AI each time a new capability is introduced. I conclude that understanding these challenges more deeply tends to highlight new opportunities for positive change.

Every aspect of society and industry seems to be examining the potential benefits from applying artificial intelligence. In this paper I examine the likely benefits to agriculture from applying artificial intelligence and discuss some of the challenges. I end up identifying around 22 different areas, which imply that the highest value capabilities seem to be those where multiple different areas of AI developments are brought together to form new capabilities such as farm robots, digital twins and supply chain traceability.

Getting value from artificial intelligence in agriculture, over the next 10+ years

Meeting The Mentorship Needs Of International Students In The United States

Study to support the evaluation of the EU Adaptation Strategy : Final report

Library has French version: Evaluation axee sur l'utilisation : un manuel pour les evaluateurs

Sometimes a beacon, sometimes a nightmare, but always a dream, and nothing more: The American Dream in Chicano/Latino literature and film

Hostility, anger expression, cardiovascular responsivity, and social support

Mechanistic trait-based model predicts fitness of evergreen and deciduous trees

Specimens, parts and products of threatened species are commonly traded on the internet. This could threaten the survival of some wild populations. We outline 2 methods to monitor internet sales of species to assess potential threats and inform conservation actions. Our first method combines systematic monitoring of online offers of plants for sale with expert consultation. Our second method utilises a computational model, trained to expert-classified records using probabilistic inference, to predict unknown properties of the traded taxa. We used these methods to monitor internet trade in 5 genera of succulent plant species endemic to Madagascar, some of which have recently been listed for trade regulation under the Convention on International Trade in Endangered Species (CITES). This revealed potential threats to wild populations: for instance, almost all species recorded were of high conservation concern, yet most offers for live plants were of apparently wild-collected specimens (85%). Our model predicted with 89% accuracy whether the plants were classified as propagated or wild collected by an expert, although accuracy dropped for data collected in the following summer. Our results highlight potential threats by internet trade to the survival of some CITES and non-CITES listed plant species from Madagascar. These should be addressed by further conservation actions and policy. More generally, our results reveal how standardised internet surveys can provide information on levels of trade in wild-collected threatened species that could impact on natural populations, and can provide data that can be incorporated into models to facilitate future monitoring and enforcement.

Inferring diversity patterns along an elevation gradient from stacked SDMs: A case study on Mesoamerican ferns

With the volume of Earth observation data expanding rapidly, cloud computing is quickly changing the way these data are processed, analyzed, and visualized. Collocating freely available Earth observation data on a cloud computing infrastructure may create opportunities unforeseen by the original data provider for innovation and value-added data re-use, but existing systems at data centers are not designed for supporting requests for large data transfers. A lack of common methodology necessitates that each data center handle such requests from different cloud vendors differently. Guidelines are needed to support enabling all cloud vendors to utilize a common methodology for bulk-downloading data from data centers, thus preventing the providers from building custom capabilities to meet the needs of individual vendors. This paper presents recommendations distilled from use cases provided by three cloud vendors (Amazon, Google, and Microsoft) and are based on the vendors’ interactions with data systems at different Federal agencies and organizations. These specific recommendations range from obvious steps for improving data usability (such as ensuring the use of standard data formats and commonly supported projections) to non-obvious undertakings important for enabling bulk data downloads at scale. These recommendations can be used to evaluate and improve existing data systems for high-volume data transfers, and their adoption can lead to cloud vendors utilizing a common methodology.

Recommendations to Improve Downloads of Large Earth Observation Data

An ensemble of spatially explicit land-cover model projections: prospects and challenges to retrospectively evaluate deforestation policy

Ten years of monitoring air quality and ecological integrity using field-identifiable lichens at Kejimkujik National Park and National Historic Site in Nova Scotia, Canada

Abstract. Terrestrial ecosystems have absorbed roughly 30 % of anthropogenic CO2 emissions over the past decades, but it is unclear whether this carbon (C) sink will endure into the future. Despite extensive modeling and experimental and observational studies, what fundamentally determines transient dynamics of terrestrial C storage under global change is still not very clear. Here we develop a new framework for understanding transient dynamics of terrestrial C storage through mathematical analysis and numerical experiments. Our analysis indicates that the ultimate force driving ecosystem C storage change is the C storage capacity, which is jointly determined by ecosystem C input (e.g., net primary production, NPP) and residence time. Since both C input and residence time vary with time, the C storage capacity is time-dependent and acts as a moving attractor that actual C storage chases. The rate of change in C storage is proportional to the C storage potential, which is the difference between the current storage and the storage capacity. The C storage capacity represents instantaneous responses of the land C cycle to external forcing, whereas the C storage potential represents the internal capability of the land C cycle to influence the C change trajectory in the next time step. The influence happens through redistribution of net C pool changes in a network of pools with different residence times. Moreover, this and our other studies have demonstrated that one matrix equation can replicate simulations of most land C cycle models (i.e., physical emulators). As a result, simulation outputs of those models can be placed into a three-dimensional (3-D) parameter space to measure their differences. The latter can be decomposed into traceable components to track the origins of model uncertainty. In addition, the physical emulators make data assimilation computationally feasible so that both C flux- and pool-related datasets can be used to better constrain model predictions of land C sequestration. Overall, this new mathematical framework offers new approaches to understanding, evaluating, diagnosing, and improving land C cycle models.

Transient dynamics of terrestrial carbon storage: mathematical foundation and its applications

Next-generation soil decomposition models: representing ecological process complexity across scales

SimiVal, a multi-criteria map comparison tool for land-change model projections

Transit times and mean ages for nonautonomous and autonomous compartmental systems

Ecology studies the interactions between individuals, species and the environment. The ability to predict the dynamics of ecological systems would support the design and monitoring of control strategies and would help to address pressing global environmental issues. It is also important to plan for efficient use of natural resources and maintenance of critical ecosystem services. The mathematical modelling of ecological systems often includes nontrivial specifications of processes that influence the birth, death, development and movement of individuals in the environment, that take into account both biotic and abiotic interactions. To assist in the specification of such models, we introduce MELA, a process algebra for Modelling in Ecology with Location Attributes. Process algebras allow the modeller to describe concurrent systems in a high-level language. A key feature of concurrent systems is that they are composed of agents that can progress simultaneously but also interact - a good match to ecological systems. MELA aims to provide ecologists with a straightforward yet flexible tool for modelling ecological systems, with particular emphasis on the description of space and the environment. Here we present four example MELA models, illustrating the different spatial arrangements which can be accommodated and demonstrating the use of MELA in epidemiological and predator-prey scenarios.

Abstract Invasive species are a serious threat to biodiversity worldwide and predicting whether an introduced species will first establish and then become invasive can be useful to preserve ecosystem services. Establishment is influenced by multiple factors, such as the interactions between the introduced individuals and the resident community, and demographic and environmental stochasticity. Field observations are often incomplete or biased. This, together with an imperfect knowledge of the ecological traits of the introduced species, makes the prediction of establishment challenging. Methods that consider the combined effects of these factors on our ability to predict the establishment of an introduced species are currently lacking. We develop an inference framework to assess the combined effects of demographic stochasticity and parameter uncertainty on our ability to predict the probability of establishment following the introduction of a small number of individuals. We find that even moderate levels of demographic stochasticity influence both the probability of establishment, and, crucially, our ability to correctly predict that probability. We also find that estimation of the demographic parameters of an introduced species is fundamental to obtain precise estimates of the interaction parameters. For typical values of demographic stochasticity, the drop in our ability to predict an establishment can be 30% when having priors on the demographic parameters compared to having their accurate values. The results from our study illustrate how demographic stochasticity may bias the prediction of the probability of establishment. Our method can be applied to estimate probability of establishment of introduced species in field scenarios, where time series data and prior information on the demographic traits of the introduced species are available.

The effects of demographic stochasticity and parameter uncertainty on predicting the establishment of introduced species

Soil carbon (C) is a critical component of Earth system models (ESMs), and its diverse representations are a major source of the large spread across models in the terrestrial C sink from the third to fifth assessment reports of the Intergovernmental Panel on Climate Change (IPCC). Improving soil C projections is of a high priority for Earth system modeling in the future IPCC and other assessments. To achieve this goal, we suggest that (1) model structures should reflect real‐world processes, (2) parameters should be calibrated to match model outputs with observations, and (3) external forcing variables should accurately prescribe the environmental conditions that soils experience. First, most soil C cycle models simulate C input from litter production and C release through decomposition. The latter process has traditionally been represented by first‐order decay functions, regulated primarily by temperature, moisture, litter quality, and soil texture. While this formulation well captures macroscopic soil organic C (SOC) dynamics, better understanding is needed of their underlying mechanisms as related to microbial processes, depth‐dependent environmental controls, and other processes that strongly affect soil C dynamics. Second, incomplete use of observations in model parameterization is a major cause of bias in soil C projections from ESMs. Optimal parameter calibration with both pool‐ and flux‐based data sets through data assimilation is among the highest priorities for near‐term research to reduce biases among ESMs. Third, external variables are represented inconsistently among ESMs, leading to differences in modeled soil C dynamics. We recommend the implementation of traceability analyses to identify how external variables and model parameterizations influence SOC dynamics in different ESMs. Overall, projections of the terrestrial C sink can be substantially improved when reliable data sets are available to select the most representative model structure, constrain parameters, and prescribe forcing fields.

Toward more realistic projections of soil carbon dynamics by Earth system models

Citation for published version: Luisa Vissat, L, Hillston, J, Marion, G & Smith, MJ 2016, MELA: Modelling in Ecology with Location Attributes. in Fourteenth International Workshop on Quantitative Aspects of Programming Languages and Systems. pp. 82-97, Fourteenth International Workshop on Quantitative Aspects of Programming Languages and Systems, Eindhoven, Netherlands, 2/04/16. DOI: 10.4204/EPTCS.227.6

Abstract. Improving international food security under a changing climate and increasing human population will be greatly aided by improving our ability to modify, understand and predict crop growth. What we predominantly have at our disposal are either process-based models of crop physiology or statistical analyses of yield datasets, both of which suffer from various sources of error. In this paper, we present a generic process-based crop model (PeakN-crop v1.0) which we parametrise using a Bayesian model-fitting algorithm to three different sources: data–space-based vegetation indices, eddy covariance productivity measurements and regional crop yields. We show that the model parametrised without data, based on prior knowledge of the parameters, can largely capture the observed behaviour but the data-constrained model greatly improves both the model fit and reduces prediction uncertainty. We investigate the extent to which each dataset contributes to the model performance and show that while all data improve on the prior model fit, the satellite-based data and crop yield estimates are particularly important for reducing model error and uncertainty. Despite these improvements, we conclude that there are still significant knowledge gaps, in terms of available data for model parametrisation, but our study can help indicate the necessary data collection to improve our predictions of crop yields and crop responses to environmental changes.

The impacts of data constraints on the predictive performance of a general process-based crop model (PeakN-crop v1.0)

Geotemporal information, information associated with geographical space and time, has always been critical to climate and environmental science. However, this information is certainly not universally or easily accessible. In fact, obtaining and using geotemporal information often comes with a considerable technical overheads, impeding research progress. To address this, we introduce FetchClimate: a cloud service designed to provide easy, universal access to geotemporal information. FetchClimate enables and accelerates the use of geotemporal information by enabling it to be accessed programmatically from a Web service (such as the statistical software R) or non-programmatically using a Web browser. We intend the service to accelerate the pace of ecological and environmental research by eliminating the technical overheads currently needed to obtain geotemporal information. The software, online manual, and user support are freely available at .

1 Transient Dynamics of Terrestrial Carbon Storage : Mathematical foundation and Numeric 1 Examples 2 3

Terrestrial ecosystems absorb roughly 30% of anthropogenic CO2 emissions since preindustrial era, but it is unclear whether this carbon (C) sink will endure into the future. Despite extensive modeling, experimental, and observational studies, what fundamentally determines transient dynamics of terrestrial C storage under climate change is still not very clear. Here we develop a new framework for understanding transient dynamics of terrestrial C storage through mathematical analysis and numerical experiments. Our analysis indicates that the ultimate force driving ecosystem C storage change is the C storage capacity, which is jointly determined by ecosystem C input (e.g., net primary production, NPP) and residence time. Since both C input and residence time vary with time, the C storage capacity is time-dependent and acts as a moving attractor that actual C storage chases. The rate of change in C storage is proportional to the C storage potential, the difference between the current storage and the storage capacity. The C storage capacity represents instantaneous responses of the land C cycle to external forcing, whereas the C storage potential represents the internal capability of the land C cycle to influence the C change trajectory in the next time step. The influence happens through redistribution ofmore » net C pool changes in a network of pools with different residence times. Furthermore, this and our other studies have demonstrated that one matrix equation can exactly replicate simulations of most land C cycle models (i.e., physical emulators). As a result, simulation outputs of those models can be placed into a three-dimensional (3D) parameter space to measure their differences. The latter can be decomposed into traceable components to track the origins of model uncertainty. Moreover, the emulators make data assimilation computationally feasible so that both C flux- and pool-related datasets can be used to better constrain model predictions of land C sequestration. We also propose that the C storage potential be the targeted variable for research, market trading, and government negotiation for C credits.« less

Transient dynamics of terrestrial carbon storage: Mathematical foundation and numeric examples

Analyses of satellite-derived chlorophyll data indicate that the phase of rapid phytoplankton population growth in the North Atlantic (the “spring bloom”) is actually initiated in the winter rather than the spring, contradicting Sverdrup's critical depth hypothesis. An alternative disturbance-recovery hypothesis (DRH) has been proposed to explain this discrepancy, in which the rapid deepening of the mixed layer reduces zooplankton grazing rates sufficiently to initiate the bloom. We use Bayesian parameter inference on a simple Nutrient-Phytoplankton-Zooplankton (NPZ) model to investigate the DRH and also investigate how well the model can capture the multiyear and spatial dynamics of phytoplankton concentrations and population growth rates. Every parameter in our NPZ model was inferred as a probability distribution given empirical constraints, which provides a more objective method to identify a model parameterization given available empirical evidence, rather than fixing or tuning individual parameter values. Our model explains around 75% of variation in the seasonal dynamics of phytoplankton concentrations, 30% of variation in their population rates of change, and correctly predicts the phases of population growth and decline. Our parameter-inferred model supports the DRH, revealing the sustained reduction of grazing due to mixed-layer deepening as the driving mechanism behind bloom initiation, with the relaxation of nutrient limitation being another contributory mechanism. Our results also show that the continuation of the bloom is caused in part by the maintenance of phytoplankton concentrations below a level that can support positive zooplankton population growth. Our approach could be employed to formally assess alternative hypotheses for bloom formation.

Inferred support for disturbance-recovery hypothesis of North Atlantic phytoplankton blooms

Considerable efforts to quantify different sources of variation in climate change projections (some might say uncertainty) have led to a welcome set of additional information on which to base confidence about what and how different futures might unfold and how different types of mediating efforts might affect the future. Quantifying the impacts of these different sources of variation on key climate change projection metrics should be used in part to guide future model development efforts. I will report on several of my team’s recent research projects to better quantify and assess the importance of different sources of variation. I will show how we use inference techniques to estimate parameter uncertainty in land and marine carbon components of earth system models by comparing them with observational evidence and show how we propagate such uncertainty to better assess how such systems might respond to climate change and quantify the impact of reducing uncertainty for different applications. I will also show how we use such techniques on simulation models themselves to identify key sources of variation in their predictions: helping to pinpoint important focal areas for model improvement. Lastly, I will show a new software prototype being designed to enable any user to view climate model projections alongside historical and recent observational evidence while, importantly, also exposing some of the variation / uncertainty in the reported information.

Improving inferences about functional connectivity from animal translocation experiments

Abstract. A number of nonlinear microbial models of soil carbon decomposition have been developed. Some of them have been applied globally but have yet to be shown to realistically represent soil carbon dynamics in the field. A thorough analysis of their key differences is needed to inform future model developments. Here we compare two nonlinear microbial models of soil carbon decomposition: one based on reverse Michaelis–Menten kinetics (model A) and the other on regular Michaelis–Menten kinetics (model B). Using analytic approximations and numerical solutions, we find that the oscillatory responses of carbon pools to a small perturbation in their initial pool sizes dampen faster in model A than in model B. Soil warming always decreases carbon storage in model A, but in model B it predominantly decreases carbon storage in cool regions and increases carbon storage in warm regions. For both models, the CO2 efflux from soil carbon decomposition reaches a maximum value some time after increased carbon input (as in priming experiments). This maximum CO2 efflux (Fmax) decreases with an increase in soil temperature in both models. However, the sensitivity of Fmax to the increased amount of carbon input increases with soil temperature in model A but decreases monotonically with an increase in soil temperature in model B. These differences in the responses to soil warming and carbon input between the two nonlinear models can be used to discern which model is more realistic when compared to results from field or laboratory experiments. These insights will contribute to an improved understanding of the significance of soil microbial processes in soil carbon responses to future climate change.

Responses of two nonlinear microbial models to warming and increased carbon input

Abstract. Leaf seasonality impacts a variety of important biological, chemical, and physical Earth system processes, which makes it essential to represent leaf phenology in ecosystem and climate models. However, we are still lacking a general, robust parametrisation of phenology at global scales. In this study, we use a simple process-based model, which describes phenology as a strategy for carbon optimality, to test the effects of the common simplification in global modelling studies that plant species within the same plant functional type (PFT) have the same parameter values, implying they are assumed to have the same species traits. In a previous study this model was shown to predict spatial and temporal dynamics of leaf area index (LAI) well across the entire global land surface provided local grid cell parameters were used, and is able to explain 96 % of the spatial variation in average LAI and 87 % of the variation in amplitude. In contrast, we find here that a PFT level parametrisation is unable to capture the spatial variability in seasonal cycles, explaining on average only 28 % of the spatial variation in mean leaf area index and 12 % of the variation in seasonal amplitude. However, we also show that allowing only two parameters, light compensation point and leaf age, to be spatially variable dramatically improves the model predictions, increasing the model's capability of explaining spatial variations in leaf seasonality to 70 and 57 % of the variation in LAI average and amplitude, respectively. This highlights the importance of identifying the spatial scale of variation of plant traits and the necessity to critically analyse the use of the plant functional type assumption in Earth system models.

The effect of using the plant functional type paradigm on a data-constrained global phenology model

Optimal allocation in annual plants and its implications for drought response

Different representations of biological nitrogen fixation cause major variation in projected terrestrial biosphere responses to elevated levels of atmospheric CO 2

Microbes influence soil organic matter decomposition and the long‐term stabilization of carbon (C) in soils. We contend that by revising the representation of microbial processes and their interactions with the physicochemical soil environment, Earth system models (ESMs) will make more realistic global C cycle projections. Explicit representation of microbial processes presents considerable challenges due to the scale at which these processes occur. Thus, applying microbial theory in ESMs requires a framework to link micro‐scale process‐level understanding and measurements to macro‐scale models used to make decadal‐ to century‐long projections. Here we review the diversity, advantages, and pitfalls of simulating soil biogeochemical cycles using microbial‐explicit modeling approaches. We present a roadmap for how to begin building, applying, and evaluating reliable microbial‐explicit model formulations that can be applied in ESMs. Drawing from experience with traditional decomposition models, we suggest the following: (1) guidelines for common model parameters and output that can facilitate future model intercomparisons; (2) development of benchmarking and model‐data integration frameworks that can be used to effectively guide, inform, and evaluate model parameterizations with data from well‐curated repositories; and (3) the application of scaling methods to integrate microbial‐explicit soil biogeochemistry modules within ESMs. With contributions across scientific disciplines, we feel this roadmap can advance our fundamental understanding of soil biogeochemical dynamics and more realistically project likely soil C response to environmental change at global scales.

Explicitly representing soil microbial processes in Earth system models

Long‐term carbon (C) cycle feedbacks to climate depend on the future dynamics of soil organic carbon (SOC). Current models show low predictive accuracy at simulating contemporary SOC pools, which can be improved through parameter estimation. However, major uncertainty remains in global soil responses to climate change, particularly uncertainty in how the activity of soil microbial communities will respond. To date, the role of microbes in SOC dynamics has been implicitly described by decay rate constants in most conventional global carbon cycle models. Explicitly including microbial biomass dynamics into C cycle model formulations has shown potential to improve model predictive performance when assessed against global SOC databases. This study aimed to data‐constrained parameters of two soil microbial models, evaluate the improvements in performance of those calibrated models in predicting contemporary carbon stocks, and compare the SOC responses to climate change and their uncertainties between microbial and conventional models. Microbial models with calibrated parameters explained 51% of variability in the observed total SOC, whereas a calibrated conventional model explained 41%. The microbial models, when forced with climate and soil carbon input predictions from the 5th Coupled Model Intercomparison Project (CMIP5), produced stronger soil C responses to 95 years of climate change than any of the 11 CMIP5 models. The calibrated microbial models predicted between 8% (2‐pool model) and 11% (4‐pool model) soil C losses compared with CMIP5 model projections which ranged from a 7% loss to a 22.6% gain. Lastly, we observed unrealistic oscillatory SOC dynamics in the 2‐pool microbial model. The 4‐pool model also produced oscillations, but they were less prominent and could be avoided, depending on the parameter values.

Microbial models with data‐driven parameters predict stronger soil carbon responses to climate change

Abstract. Including a terrestrial nitrogen (N) cycle in Earth system models has led to substantial attenuation of predicted biosphere–climate feedbacks. However, the magnitude of this attenuation remains uncertain. A particularly important but highly uncertain process is biological nitrogen fixation (BNF), which is the largest natural input of N to land ecosystems globally. In order to quantify this uncertainty and estimate likely effects on terrestrial biosphere dynamics, we applied six alternative formulations of BNF spanning the range of process formulations in current state-of-the-art biosphere models within a common framework, the O-CN model: a global map of static BNF rates, two empirical relationships between BNF and other ecosystem variables (net primary productivity and evapotranspiration), two process-oriented formulations based on plant N status, and an optimality-based approach. We examined the resulting differences in model predictions under ambient and elevated atmospheric [CO2] and found that the predicted global BNF rates and their spatial distribution for contemporary conditions were broadly comparable, ranging from 108 to 148 Tg N yr−1 (median: 128 Tg N yr−1), despite distinct regional patterns associated with the assumptions of each approach. Notwithstanding, model responses in BNF rates to elevated levels of atmospheric [CO2] (+200 ppm) ranged between −4 Tg N yr−1 (−3 %) and 56 Tg N yr−1 (+42 %) (median: 7 Tg N yr−1 (+8 %)). As a consequence, future projections of global ecosystem carbon (C) storage (+281 to +353 Pg C, or +13 to +16 %) as well as N2O emission (−1.6 to +0.5 Tg N yr−1, or −19 to +7 %) differed significantly across the different model formulations. Our results emphasize the importance of better understanding the nature and magnitude of BNF responses to change-induced perturbations, particularly through new empirical perturbation experiments and improved model representation.

Variability of projected terrestrial biosphere responses to elevated levels of atmospheric CO 2 due to uncertainty in biological nitrogen fixation

Aim
Human impacts on the biosphere are a matter of urgent and growing concern, with ecologists increasingly being asked to project biodiversity futures. The Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES) is likely to comprehensively assess such projections, yet despite being widely used and potentially critical tools for analysing socio-environmental futures, integrated assessment models (IAMs) have received little attention from ecological modellers. We aim to raise awareness and understanding of IAMs among ecologists by describing the structure and composition of IAMs, assessing their utility for biodiversity projections and identifying limitations that hamper greater interaction between scientists using IAMs and those using ecological models. We also hope to inspire more accessible and applicable models by suggesting development needs for IAMs.

Methods
We conduct a systematic review of four state-of-the-art IAMs, which describes and contrasts key model features and analyses six aspects of IAMs that are of fundamental interest to ecologists.

Conclusions
IAMs could be valuable for modelling biodiversity futures; however, current IAMs were not developed for this application and challenges remain for ecologists looking to use their outputs. Separating and understanding the differences resulting from IAM formulation and those resulting from specific scenario assumptions is currently problematic, and current IAMs may be unable to accurately represent environmental conditions for both Earth-system projections and for building robust models of biodiversity because key ecological processes are absent. We suggest that model intercomparisons would identify differences in model dynamics, and detailed studies of how dynamical interactions between components influence behaviour would address why such differences arise. Bio-economic fisheries models and agriculture pollination models provide starting points for integrating key ecological feedbacks within IAMs. Ultimately, making IAMs more accessible within the multidisciplinary study of global change, drawing on user-centred research, would enable more resolved, reliable and accurate assessment of how Earth's socio-ecological system is approaching planetary boundaries.

Integrated assessment models for ecologists: the present and the future

Understanding and quantifying the temperature dependence of population parameters, such as intrinsic growth rate and carrying capacity, is critical for predicting the ecological responses to environmental change. Many studies provide empirical estimates of such temperature dependencies, but a thorough investigation of the methods used to infer them has not been performed yet. We created artificial population time series using a stochastic logistic model parameterized with the Arrhenius equation, so that activation energy drives the temperature dependence of population parameters. We simulated different experimental designs and used different inference methods, varying the likelihood functions and other aspects of the parameter estimation methods. Finally, we applied the best performing inference methods to real data for the species Paramecium caudatum. The relative error of the estimates of activation energy varied between 5% and 30%. The fraction of habitat sampled played the most important role in determining the relative error; sampling at least 1% of the habitat kept it below 50%. We found that methods that simultaneously use all time series data (direct methods) and methods that estimate population parameters separately for each temperature (indirect methods) are complementary. Indirect methods provide a clearer insight into the shape of the functional form describing the temperature dependence of population parameters; direct methods enable a more accurate estimation of the parameters of such functional forms. Using both methods, we found that growth rate and carrying capacity of Paramecium caudatum scale with temperature according to different activation energies. Our study shows how careful choice of experimental design and inference methods can increase the accuracy of the inferred relationships between temperature and population parameters. The comparison of estimation methods provided here can increase the accuracy of model predictions, with important implications in understanding and predicting the effects of temperature on the dynamics of populations.

Inferring the temperature dependence of population parameters: the effects of experimental design and inference algorithm

The quasi-steady-state approximation (or stochastic averaging principle) is a useful tool in the study of multiscale stochastic systems, giving a practical method by which to reduce the number of degrees of freedom in a model. The method is extended here to slow-fast systems in which the fast variables exhibit metastable behaviour. The key parameter that determines the form of the reduced model is the ratio of the timescale for the switching of the fast variables between metastable states to the timescale for the evolution of the slow variables. The method is illustrated with two examples: one from biochemistry (a fast-species-mediated chemical switch coupled to a slower varying species), and one from ecology (a predator-prey system). Numerical simulations of each model reduction are compared with those of the full system.

Model reduction for slow-fast stochastic systems with metastable behaviour.

Species distribution models (SDMs) are widely used to explain and predict species ranges and environmental niches. They are most commonly constructed by inferring species' occurrence–environment relationships using statistical and machine-learning methods. The variety of methods that can be used to construct SDMs (e.g. generalized linear/additive models, tree-based models, maximum entropy, etc.), and the variety of ways that such models can be implemented, permits substantial flexibility in SDM complexity. Building models with an appropriate amount of complexity for the study objectives is critical for robust inference. We characterize complexity as the shape of the inferred occurrence–environment relationships and the number of parameters used to describe them, and search for insights into whether additional complexity is informative or superfluous. By building ‘under fit’ models, having insufficient flexibility to describe observed occurrence–environment relationships, we risk misunderstanding the factors shaping species distributions. By building ‘over fit’ models, with excessive flexibility, we risk inadvertently ascribing pattern to noise or building opaque models. However, model selection can be challenging, especially when comparing models constructed under different modeling approaches. Here we argue for a more pragmatic approach: researchers should constrain the complexity of their models based on study objective, attributes of the data, and an understanding of how these interact with the underlying biological processes. We discuss guidelines for balancing under fitting with over fitting and consequently how complexity affects decisions made during model building. Although some generalities are possible, our discussion reflects differences in opinions that favor simpler versus more complex models. We conclude that combining insights from both simple and complex SDM building approaches best advances our knowledge of current and future species ranges.

What do we gain from simplicity versus complexity in species distribution models

Whirling disease dynamics: an analysis of intervention strategies.

Importance of modelling microbial dynamics in soil: evaluation of conventional and microbial soil models informed by observations across various plant functional types

New details about natural and anthropogenic processes are continually added to models of the Earth system, anticipating that the increased realism will increase the accuracy of their predictions. However, perspectives differ about whether this approach will improve the value of the information the models provide to decision makers, scientists, and societies. The present bias toward increasing realism leads to a range of updated projections, but at the expense of uncertainty quantification and model tractability. This bias makes it difficult to quantify the uncertainty associated with the projections from any one model or to the distribution of projections from different models. This in turn limits the utility of climate model outputs for deriving useful information such as in the design of effective climate change mitigation and adaptation strategies or identifying and prioritizing sources of uncertainty for reduction. Here we argue that a new approach to model development is needed, focused on the delive...

Changing How Earth System Modeling is Done to Provide More Useful Information for Decision Making, Science, and Society

Using species distribution models to inform IUCN Red List assessments

Functional and Structural Optimality in Plant Growth: A Crop Modelling Case Study

Abstract A process for the review of significant trade in species listed in CITES Appendix II was established to address problems with the application of CITES Article IV. Article IV states that international trade in Appendix II species requires a Scientific Authority of the state of export to determine that such trade will not be detrimental to the species’ survival in the wild. Such a review process was initiated for the plant species Galanthus woronowii Losinsk. as a result of continuing uncertainty over the sustainability of international exports of the plant from wild populations in Georgia, and the Georgian Management Authority was tasked with determining and reporting whether export levels conformed to Article IV. Here we report on the project that was established to address that task. Nationwide field surveys conducted in 2009 led to the recommendation of a conservative annual export quota of 15 million plants for the sites surveyed. Cultivated populations held significant stocks of harvestable plants but with varied cultivation histories, especially in relation to the extent and nature of supplementary planting. Future work should continue to monitor harvesting from wild populations and identify solutions for local communities wishing to cultivate the plant for international trade.

Assessing non-detrimental trade for a CITES Appendix II-listed plant species: the status of wild and cultivated Galanthus woronowii in Georgia

This paper presents the first mathematical model that attempts to represent the biology and behavior of all individual organisms globally, taking us a step closer to holistic ecological and conservation science founded on mechanistic predictions.

Emergent Global Patterns of Ecosystem Structure and Function from a Mechanistic General Ecosystem Model

The MaxEnt software package is one of the most popular tools for species distribution and environmental niche modeling, with over 1000 published applications since 2006. Its popularity is likely for two reasons: 1) MaxEnt typically outperforms other methods based on predictive accuracy and 2) the software is particularly easy to use. MaxEnt users must make a number of decisions about how they should select their input data and choose from a wide variety of settings in the software package to build models from these data. The underlying basis for making these decisions is unclear in many studies, and default settings are apparently chosen, even though alternative settings are often more appropriate. In this paper, we provide a detailed explanation of how MaxEnt works and a prospectus on modeling options to enable users to make informed decisions when preparing data, choosing settings and interpreting output. We explain how the choice of background samples reflects prior assumptions, how nonlinear functions of environmental variables (features) are created and selected, how to account for environmentally biased sampling, the interpretation of the various types of model output and the challenges for model evaluation. We demonstrate MaxEnt’s calculations using both simplified simulated data and occurrence data from South Africa on species of the flowering plant family Proteaceae. Throughout, we show how MaxEnt’s outputs vary in response to different settings to highlight the need for making biologically motivated modeling decisions.

A practical guide to MaxEnt for modeling species' distributions: what it does, and why inputs and settings matter

SUMMARY There is burgeoning interest in predicting road development because of the wide ranging important socioeconomic and environmental issues that roads present, including the close links between road development, deforestation and biodiversity loss. This is especially the case in developing nations, which are high in natural resources, where road development is rapid and often not centrally managed. Characterization of large scale spatio-temporal patterns in road network development has been greatly overlooked to date. This paper examines the spatio-temporal dynamics of road density across the Brazilian Amazon and assesses the relative contributions of local versus neighbourhood effects for temporal changes in road density at regional scales. To achieve this, a combination of statistical analyses and model-data fusion techniques inspired by studies of spatio-temporal dynamics of populations in ecology and epidemiology were used. The emergent development may be approximated by local growth that is logistic through time and directional dispersal. The current rates and dominant direction of development may be inferred, by assuming that roads develop at a rate of 55 km per year. Large areas of the Amazon will be subject to extensive anthropogenic change should the observed patterns of road development continue.

Large scale spatio-temporal patterns of road development in the Amazon rainforest

Landscape configuration influences gap-crossing decisions of northern flying squirrel (Glaucomys sabrinus)

Human societies, and their well-being, depend to a significant extent on the state of the ecosystems that surround them. These ecosystems are changing rapidly usually in response to anthropogenic changes in the environment. To determine the likely impact of environmental change on ecosystems and the best ways to manage them, it would be desirable to be able to predict their future states. We present a proposal to develop the paradigm of predictive systems ecology, explicitly to understand and predict the properties and behaviour of ecological systems. We discuss the necessary and desirable features of predictive systems ecology models. There are places where predictive systems ecology is already being practised and we summarize a range of terrestrial and marine examples. Significant challenges remain but we suggest that ecology would benefit both as a scientific discipline and increase its impact in society if it were to embrace the need to become more predictive.

Terrestrial ecosystems sequester roughly 30% of anthropogenic carbon emission. However this estimate has not been directly deduced from studies of terrestrial ecosystems themselves, but inferred from atmospheric and oceanic data. This raises a question: to what extent is the terrestrial carbon cycle intrinsically predictable? In this paper, we investigated fundamental properties of the terrestrial carbon cycle, examined its intrinsic predictability, and proposed a suite of future research directions to improve empirical understanding and model predictive ability. Specifically, we isolated endogenous internal processes of the terrestrial carbon cycle from exogenous forcing variables. The internal processes share five fundamental properties (i.e., compartmentalization, carbon input through photosynthesis, partitioning among pools, donor pool‐dominant transfers, and the first‐order decay) among all types of ecosystems on the Earth. The five properties together result in an emergent constraint on predictability of various carbon cycle components in response to five classes of exogenous forcing. Future observational and experimental research should be focused on those less predictive components while modeling research needs to improve model predictive ability for those highly predictive components. We argue that an understanding of predictability should provide guidance on future observational, experimental and modeling research.

Correction: The Effects of Sampling Bias and Model Complexity on the Predictive Performance of MaxEnt Species Distribution Models

In heterogeneous landscapes, physical barriers and loss of structural connectivity have been shown to reduce gene flow and therefore lead to population structuring. In this study, we assessed the influence of landscape features on population genetic structure and gene flow of a semiaquatic species, the muskrat. A total of 97 muskrats were sampled from three watersheds near Sudbury, Ontario, Canada. We estimated population genetic structure using 11 microsatellite loci and identified a single genetic cluster and no genetic differences were found among the watersheds as a result of high levels of gene flow. At finer scales, we assessed the correlation between individual pairwise genetic distances and Euclidean distance as well as different models of least cost path (LCP). We used a range of cost values for the landscape types in order to build our LCP models. We found a positive relationship between genetic distance and least cost distance when we considered roads as corridors for movements. Open landscapes and urban areas seemed to restrict but not prevent gene flow within the study area. Our study underlines the high-dispersal ability of generalist species in their use of landscape and highlights how landscape features often considered barriers to animal movements are corridors for other species.

Effects of structural connectivity on fine scale population genetic structure of muskrat, Ondatra zibethicus

Species distribution models (SDMs) trained on presence-only data are frequently used in ecological research and conservation planning. However, users of SDM software are faced with a variety of options, and it is not always obvious how selecting one option over another will affect model performance. Working with MaxEnt software and with tree fern presence data from New Zealand, we assessed whether (a) choosing to correct for geographical sampling bias and (b) using complex environmental response curves have strong effects on goodness of fit. SDMs were trained on tree fern data, obtained from an online biodiversity data portal, with two sources that differed in size and geographical sampling bias: a small, widely-distributed set of herbarium specimens and a large, spatially clustered set of ecological survey records. We attempted to correct for geographical sampling bias by incorporating sampling bias grids in the SDMs, created from all georeferenced vascular plants in the datasets, and explored model complexity issues by fitting a wide variety of environmental response curves (known as “feature types” in MaxEnt). In each case, goodness of fit was assessed by comparing predicted range maps with tree fern presences and absences using an independent national dataset to validate the SDMs. We found that correcting for geographical sampling bias led to major improvements in goodness of fit, but did not entirely resolve the problem: predictions made with clustered ecological data were inferior to those made with the herbarium dataset, even after sampling bias correction. We also found that the choice of feature type had negligible effects on predictive performance, indicating that simple feature types may be sufficient once sampling bias is accounted for. Our study emphasizes the importance of reducing geographical sampling bias, where possible, in datasets used to train SDMs, and the effectiveness and essentialness of sampling bias correction within MaxEnt.

The Effects of Sampling Bias and Model Complexity on the Predictive Performance of MaxEnt Species Distribution Models

International trade in species that are or may be endangered by collection from the wild is regulated under the Convention on International Trade in Endangered Species of wild fauna and flora (CITES) for 176 member States (Parties). Internet commerce is a relatively new route for such trade. In 2007, the CITES Secretariat asked Parties to collect information on internet wildlife trade and report problems and implemented regulations. The reports indicated it was difficult to even approximate the influence of e-commerce on CITES-listed species (CITES Secretariat 2009). We report a case study in which we quantified international transactions over an internet auction site of CITES-listed cacti and cross-checked them with CITES trade data. Our results were both surprising and alarming. 
 
Species protected under CITES are included in different CITES appendices according to their level of threat of extinction from international trade. Taxa listed in Appendix I are endangered and wild collection could cause their extinction, and taxa listed in Appendix II either may become endangered if wild collection is not regulated or are similar in appearance to other species listed in Appendix I or II (see http://www.cites.org for full definitions). The treaty operates through the issue and control of permits that apply to regular and internet trade. Trade in wild specimens is either prohibited (species listed in Appendix I) or regulated by permits (species listed in Appendix II), although some Parties implement stricter regulations. Export permits must also be issued for certified artificially propagated plants. International trade of plants listed in Appendix I is allowed only if they are artificially propagated. Plants listed in Appendix I that are artificially propagated for commercial purposes are included in Appendix II (Article VII, paragraph 4 of the Convention), and the exporting enterprises should be registered in accordance with Resolution of the Conference of the Parties 9.19 (Revised at CoP15). 
 
Parties must submit annual reports to the CITES Secretariat listing the number and type of permits and certificates granted, the States with which such trade occurred, and the quantities and types of specimens traded. Some Parties report actual trade, whereas others report the permits issued. Trade data from these reports are stored in the CITES Trade Database (CTD) (http://www.unep-wcmc-apps.org/citestrade/). We used this information to assess the implementation of the Convention for international trade in CITES species over the internet. We investigated e-commerce in 2010 for cacti as a case study. All members of the Cactaceae, with the exception of 3 genera (Pereskia, Pereskiopsis, and Quiabentia) are listed in either Appendix I or II. We also restricted our analyses to species listed in Appendix I because an export permit is mandatory to export and import live plants. 
 
We monitored buyer–seller interactions on an internet auction site (not identified here) and recorded sales of live plants that were successfully completed and for which we could identify the plant's country of origin and its destination. We compared this information with data on export permits for live plants in the CTD. Although these report trade data, rather than individual permits, they should reflect the internet trade if export permits were applied for, as required for all such transactions involving CITES Parties (the case for all transactions we recorded). Trade within the European Union does not require CITES permits, so we excluded these transaction and sales to Parties that have submitted official reservations against being regulated by CITES for certain cacti. All relevant exporting Parties had submitted their 2010 reports by the time of our analyses. 
 
We monitored 24 sellers over 6 months, twice weekly, until 1000 cacti listed in Appendix I had been sold. There were 978 such sales of a single plant, 1 sale with 6 plants, and 1 sale with 16 plants. We checked all scientific names and controlled for nomenclature differences between the names used in auctions and the official names used on CITES permits. Subspecies were noted if considered valid by the CITES cacti checklist. It is possible that the CTD records corresponding to a particular transaction actually corresponded to a different transaction with the same details. Our figures therefore represent the maximum number of transactions for which CITES export permits could have been issued. We did not check whether species were traded under permits spanning multiple years or under invalid permits, but we expected these would have only minor effects. 
 
Our data set contained roughly a quarter of the cactus plants for which CITES permits were issued in 2010. There were large discrepancies in the number of plants for which permits were issued and the number of plants traded in online transactions (Table 1). Our results suggest that only 10% of the plants traded were even potentially legal. Major discrepancies were also apparent in the number of species and number of importing and exporting countries between the online auctions and permits issued for that year (Table 1). 
 
Table 1 
 
Sales of cacti listed on CITES Appendix I on an internet auction site and permits issued by CITES Parties in 2010 
 
We suspect that most transactions we recorded were of artificially propagated plants. The United States was the only Range State recorded as exporting native species (approximately 8% of the recorded transactions). Few of the cacti sold that were pictured on the website had visible characteristics that could plausibly be associated with the plant being of wild origin. We therefore expect the recorded transactions to have only minor effects, if any, on wild populations. Nonetheless, an export permit is mandatory to export and import these plants. Therefore, the potentially wide scale of the illegal global trade that our results suggest should raise concerns about the adequacy of the protection for CITES species. For example, wild populations of some cacti listed in Appendix I may number only a few dozen individuals in their natural habitat (Hernandez et al. 2010), for which collectors are willing to pay high prices (Robbins 2003). Internet auction sites should be monitored more widely to investigate trade in CITES species with the aim of more effectively regulating trade in rare plants.

A number of nonlinear models have recently been proposed for simulating soil carbon decomposition. Their predictions of soil carbon responses to fresh litter input and warming differ significantly from conventional linear mod- els. Using both stability analysis and numerical simulations, we showed that two of those nonlinear models (a two-pool model and a three-pool model) exhibit damped oscillatory re- sponses to small perturbations. Stability analysis showed the

Oscillatory behavior of two nonlinear microbial models of soil carbon decomposition

Simulated crop yield in response to changes in climate and agricultural practices: results from a simple process based model

Biome vs. Species Traits: What Is the Best Scale for Phenology Models?

The feedback between climate and the terrestrial carbon cycle will be a key determinant of the dynamics of the Earth System (the thin layer that contains and supports life) over the coming decades and centuries. However, Earth System Model projections of the terrestrial carbon-balance vary widely over these timescales. This is largely due to differences in their terrestrial carbon cycle models. A major goal in biogeosciences is therefore to improve understanding of the terrestrial carbon cycle to enable better constrained projections. Utilising empirical data to constrain and assess component processes in terrestrial carbon cycle models will be essential to achieving this goal. We used a new model construction method to data-constrain all parameters of all component processes within a global terrestrial carbon model, employing as data constraints a collection of 12 empirical data sets characterising global patterns of carbon stocks and flows. Our goals were to assess the climate dependencies inferred for all component processes, assess whether these were consistent with current knowledge and understanding, assess the importance of different data sets and the model structure for inferring those dependencies, assess the predictive accuracy of the model and ultimately to identify a methodology by which alternative component models could be compared within the same framework in the future. Although formulated as differential equations describing carbon fluxes through plant and soil pools, the model was fitted assuming the carbon pools were in states of dynamic equilibrium (input rates equal output rates). Thus, the parameterised model is of the equilibrium terrestrial carbon cycle. All but 2 of the 12 component processes to the model were inferred to have strong climate dependencies, although it was not possible to data-constrain all parameters, indicating some potentially redundant details. Similar climate dependencies were obtained for most processes, whether inferred individually from their corresponding data sets or using the full terrestrial carbon model and all available data sets, indicating a strong overall consistency in the information provided by different data sets under the assumed model formulation. A notable exception was plant mortality, in which qualitatively different climate dependencies were inferred depending on the model formulation and data sets used, highlighting this component as the major structural uncertainty in the model. All but two component processes predicted empirical data better than a null model in which no climate dependency was assumed. Equilibrium plant carbon was predicted especially well (explaining around 70% of the variation in the withheld evaluation data). We discuss the advantages of our approach in relation to advancing our understanding of the carbon cycle and enabling Earth System Models to make better constrained projections.

The climate dependence of the terrestrial carbon cycle, including parameter and structural uncertainties

Predation effects on mean time to extinction under demographic stochasticity.

The rational design of synthetic cell populations with prescribed behaviours is a long-standing goal of synthetic biology, with the potential to greatly accelerate the development of biotechnological applications in areas ranging from medical research to energy production. Achieving this goal requires well-characterized components, modular implementation strategies, simulation across temporal and spatial scales and automatic compilation of high-level designs to low-level genetic parts that function reliably inside cells. Many of these steps are incomplete or only partially understood, and methods for integrating them within a common design framework have yet to be developed. Here, we address these challenges by developing a prototype framework for designing synthetic cells with prescribed population dynamics. We extend the genetic engineering of cells (GEC) language, originally developed for programming intracellular dynamics, with cell population factors such as cell growth, division and dormancy, together with spatio-temporal simulation methods. As a case study, we use our framework to design synthetic cells with predator–prey interactions that, when simulated, produce complex spatio-temporal behaviours such as travelling waves and spatio-temporal chaos. An analysis of our design reveals that environmental factors such as density-dependent dormancy and reduced extracellular space destabilize the population dynamics and increase the range of genetic variants for which complex spatio-temporal behaviours are possible. Our findings highlight the importance of considering such factors during the design process. We then use our analysis of population dynamics to inform the selection of genetic parts, which could be used to obtain the desired spatio-temporal behaviours. By identifying, integrating and automating key stages of the design process, we provide a computational framework for designing synthetic systems, which could be tested in future laboratory studies.

Towards the rational design of synthetic cells with prescribed population dynamics

A Fully Data-Constrained Benchmark Global Vegetation Model for Identifying Priority Sources of Uncertainty and Facilitating Rapid Model Refinement

Independent effects of connectivity predict homing success by northern flying squirrel in a forest mosaic

Assessing the impacts of international trade on CITES-listed species: Current practices and opportunities for scientific research

In their Policy Forum “Boosting CITES” (24 December 2010, p. [1752][1]), J. Phelps et al. propose improvements to the implementation of the Convention on International Trade in Endangered Species of Wild Flora and Fauna (CITES). Most of their recommendations would involve the negotiation of cross-Party agreements and procurement of additional financial resources, both of which are likely to delay or prevent their implementation. We suggest a more straightforward improvement to CITES implementation: Scientists should consider choosing CITES-listed taxa as model taxa for their research.

At a workshop in 2008, more than 100 scientists and regulators compiled 60 case studies covering a wide range of CITES-listed taxa. The group outlined how information on the biology, harvesting, and management could be used to determine whether international trade in CITES-listed taxa is detrimental to their survival in the wild. Most of those case studies (78%) mentioned that more basic information on the biology of the taxa in the wild (including taxonomy, biology, and ecology) would improve their ability to make this determination ([ 1 ][2]).

A lot of scientific research is done on species that are chosen out of convenience. We recommend that, all else being equal, scientists coordinate with national scientific authorities, local communities, and commercial traders to work on CITES-listed taxa instead. Such research could directly address sustainable exploitation practices or could simply aim to generate relevant information as a by-product (for example, by generating additional information on the basic taxonomy, biology, and ecology of taxa). Either way, those implementing CITES would benefit from the additional information and scientists would achieve additional impact from their research.

1. [↵][3] 1. M. J. Smith 2. et al
 ., Biol. Conserv. 144, 82 (2011).
 [OpenUrl][4][CrossRef][5][Web of Science][6]

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1. We review our ecological understanding of wildlife infectious diseases from the individual host to the ecosystem scale, highlighting where conceptual thinking lacks verification, discussing difficulties and challenges, and offering potential future research directions. 2. New molecular approaches hold potential to increase our understanding of parasite interactions within hosts. Also, advances in our knowledge of immune systems makes immunological parameters viable measures of parasite exposure, and useful tools for improving our understanding of causal mechanisms. 3. Studies of transmission dynamics have revealed the importance of heterogeneity in host behaviour and physiology, and of contact processes operating at different spatial and temporal scales. An important future challenge is to determine the key transmission mechanisms maintaining the persistence of different types of diseases in the wild. 4. Regulation of host populations is too complex to consider parasite effects in isolation from other factors. One solution is to seek a unified understanding of the conditions under which (and the ecological rules determining when) population scale impacts of parasites can occur. 5. Good evidence now shows that both direct effects of parasites, and trait mediated indirect effects, frequently mediate the success of invasive species and their impacts on recipient communities. A wider exploration of these effects is now needed. 6. At the ecosystem scale, research is needed to characterize the circumstances and conditions under which both fluxes in parasite biomass, and trait mediated effects, are significant in ecosystem processes, and to demonstrate that parasites do indeed increase 'ecosystem health'. 7. There is a general need for more empirical testing of predictions and subsequent development of theory in the classic research cycle. Experimental field studies, meta-analyses, the collection and analysis of long-term data sets, and data constrained modelling, will all be key to advancing our understanding. 8. Finally, we are only now beginning to understand the importance of cross-scale interactions associated with parasitism. Such interactions may offer key insights into bigger picture questions such as when and how different regulatory factors are important, when disease can cause species extinctions, and what characteristics are indicative of functionally resilient ecosystems.

Computational Scientists are both creators and end-users of scientific models. Different aspects to their work target different audiences and generally require different development approaches. The research of computational scientists typically involves the development of new computational models and methods often exposed as services. Complex multi-component models, usually bringing together previously developed and new services into a larger dynamical model, are now frequently developed. The communication of scientific models and their predictions is now a major area of science, with policy makers increasingly turning to scientists for predictions of complex dynamical systems. Scientific model development is also often done collaboratively, with different scientific teams working on components of the larger model, becoming analogous to professional software development. It is therefore not surprising that the majority of scientists consider developing scientific software as important for their own research. Despite the need for software to help conduct and communicate scientific research, computational scientists are generally "end-user programmers" with entirely different goals to Software Engineers when creating and composing software. Here we report outcomes of an experimental collaboration between Software Engineers and Computational Scientists to create a new development environment to encompass diverse end user groups.

A key aim in epidemiology is to understand how pathogens spread within their host populations. Central to this is an elucidation of a pathogen's transmission dynamics. Mathematical models have generally assumed that either contact rate between hosts is linearly related to host density (density-dependent) or that contact rate is independent of density (frequency-dependent), but attempts to confirm either these or alternative transmission functions have been rare. Here, we fit infection equations to 6 years of data on cowpox virus infection (a zoonotic pathogen) for 4 natural populations to investigate which of these transmission functions is best supported by the data. We utilize a simple reformulation of the traditional transmission equations that greatly aids the estimation of the relationship between density and host contact rate. Our results provide support for an infection rate that is a saturating function of host density. Moreover, we find strong support for seasonality in both the transmission coefficient and the relationship between host contact rate and host density, probably reflecting seasonal variations in social behavior and/or host susceptibility to infection. We find, too, that the identification of an appropriate loss term is a key component in inferring the transmission mechanism. Our study illustrates how time series data of the host–pathogen dynamics, especially of the number of susceptible individuals, can greatly facilitate the fitting of mechanistic disease models.

Host–pathogen time series data in wildlife support a transmission function between density and frequency dependence

Effects of abundance on infection in natural populations: field voles and cowpox virus.

The seasonality of recurrent epidemics has been largely neglected, especially where patterns are not driven by forces external to the population. Here, we use data on cowpox virus in field voles to explore the seasonal patterns in wildlife (variable abundance) populations and compare these with patterns previously found in humans. Timing in our system was associated with both the number and the rate of recruitment of susceptible hosts. A plentiful and sustained supply of susceptible hosts throughout the summer gave rise to a steady rise in infected hosts and a late peak. A meagre supply more limited in time was often insufficient to sustain an increase in infected hosts, leading to an early peak followed by a decline. These seasonal patterns differed from those found in humans, but the underlying association found between the timing and the supply of susceptible hosts was similar to that in humans. We also combine our data with a model to explore these differences between humans and wildlife. Model results emphasize the importance of the interplay between seasonal infection and recruitment and suggest that our empirical patterns have a relevance extending beyond our own system.

Seasonal host dynamics drive the timing of recurrent epidemics in a wildlife population

Question: What are the key physiological and life-history trade-offs responsible for the evolution of different suites of plant traits (strategies) in different environments? Experimental methods: Common-garden experiments were performed on physiologically realistic model plants, evolved in contrasting environments, in computer simulations. This allowed the identification of the trade-offs that resulted in different suites of traits (strategies). The environments considered were: resource rich, low disturbance (competitive); resource poor, low disturbance (stressed); resource rich, high disturbance (disturbed); and stressed environments containing herbivores (grazed). Results: In disturbed environments, plants increased reproduction at the expense of ability to compete for light and nitrogen. In competitive environments, plants traded off reproductive output and leaf production for vertical growth. In stressed environments, plants traded off vertical growth and reproductive output for nitrogen acquisition, contradicting Grime's (2001) theory that slow-growing, competitively inferior strategies are selected in stressed environments. The contradiction is partly resolved by incorporating herbivores into the stressed environment, which selects for increased investment in defence, at the expense of competitive ability and reproduction. Conclusion: Our explicit modelling of trade-offs produces rigorous testable explanations of observed associations between suites of traits and environments.

Identification of trade-offs underlying the primary strategies of plants

Paragraph The minimum criteria a population model should meet in order to aid in the making of non detriment findings (NDFs) should be a demonstrable ability to predict changes to the population size following actual harvesting regimes to a desired level of accuracy. This case study outlines how population models could be developed and used to aid in making NDFs for G. elwesii, the Turkish Giant Snowdrop. This taxon is particularly suited to developing such a quantitative framework because the populations are visited annually (facilitating data collection), they appear to have relatively stable abundances (suggesting relatively low stochasticity), and annual collections of relatively large quantities for international trade is likely to continue to for the foreseeable future. Furthermore, the establishment of such a quantitative framework will be a valuable example for those wishing to develop a similar system for other CITES taxa.

THE APPLICATION OF POPULATION MODELLING TECHNIQUES TO THE DEVELOPMENT OF NON-DETRIMENT FINDINGS FOR GALANTHUS ELWESII IN TURKEY

Mathematical investigations into the mechanisms driving the spatiotemporal dynamics of cyclic populations

The software program TreeSAAP measures the selective influences on 31 structural and biochemical amino acid properties during cladogenesis, and performs goodness-of-fit and categorical statistical tests.

TreeSAAP: Selection on Amino Acid Properties using phylogenetic trees

How biological form emerges from cell fate decisions and tissue remodelling is a fundamental question in development biology. However, an understanding of how these processes operate side-by-side to set precise and robust patterns is largely missing. Here, we investigate this interplay during the process of vein refinement in the Drosophila pupal wing. By following reporters of signalling activity dynamically, together with tissue flows, we show that longitudinal vein refinement arises from a combination of local tissue deformation and cell fate adjustments controlled by a signalling network involving Notch, Dpp, and EGFR. Perturbing large-scale convergence and extension tissue flows does not affect vein refinement, showing that pre-patterned vein domains are able to intrinsically refine to the correct width. A minimal biophysical description taking into account key signalling interactions recapitulates the intrinsic tissue ability to establish a thin, regular vein independently of large-scale tissue flows. Supporting this prediction, artificial proveins optogenetically generated orthogonal to the axis of wing elongation refine against large-scale flows. Overall, we find that signalling-mediated updating of cell fate is a key contributor to reproducible patterning.

Signalling-dependent refinement of cell fate choice during tissue remodelling

Segmenting cells within cellular aggregates in 3D is a growing challenge in cell biology, due to improvements in capacity and accuracy of microscopy techniques. Here we describe a pipeline to segment images of cell aggregates in 3D. The pipeline combines neural network segmentations with active meshes. We apply our segmentation method to cultured mouse mammary duct organoids imaged over 24 hours with oblique plane microscopy, a high-throughput light-sheet fluorescence microscopy technique. We show that our method can also be applied to images of mouse embryonic stem cells imaged with a spinning disc microscope. We segment individual cells based on nuclei and cell membrane fluorescent markers, and track cells over time. We describe metrics to quantify the quality of the automated segmentation. Our segmentation pipeline involves a Fiji plugin which implement active meshes deformation and allows a user to create training data, automatically obtain segmentation meshes from original image data or neural network prediction, and manually curate segmentation data to identify and correct mistakes. Our active meshes-based approach facilitates segmentation postprocessing, correction, and integration with neural network prediction. Statement of significance In vitro culture of organ-like structures derived from stem cells, so-called organoids, allows to image tissue morphogenetic processes with high temporal and spatial resolution. Three-dimensional segmentation of cell shape in timelapse movies of these developing organoids is however a significant challenge. In this work, we propose an image analysis pipeline for cell aggregates that combines deep learning with active contour segmentations. This combination offers a flexible and efficient way to segment three-dimensional cell images, which we illustrate with by segmenting datasets of growing mammary gland organoids and mouse embryonic stem cells.

Active mesh and neural network pipeline for cell aggregate segmentation

ECM degradation in the Drosophila abdominal epidermis initiates tissue growth that ceases with rapid cell-cycle exit

Proper orientation of the mitotic spindle plays a crucial role in embryos, during tissue development, and in adults, where it functions to dissipate mechanical stress to maintain tissue integrity and homeostasis. While mitotic spindles have been shown to reorient in response to external mechanical stresses, the subcellular cues that mediate spindle reorientation remain unclear. Here, we have used a combination of optogenetics and computational modelling to better understand how mitotic spindles respond to inhomogeneous tension within the actomyosin cortex. Strikingly, we find that the optogenetic activation of RhoA only influences spindle orientation when it is induced at both poles of the cell. Under these conditions, the sudden local increase in cortical tension induced by RhoA activation reduces pulling forces exerted by cortical regulators on astral microtubules. This leads to a perturbation of the torque balance exerted on the spindle, which causes it to rotate. Thus, spindle rotation in response to mechanical stress is an emergent phenomenon arising from the interaction between the spindle positioning machinery and the cell cortex.

Spindle reorientation in response to mechanical stress is an emergent property of the spindle positioning mechanisms

Mechanical constraints to cell-cycle progression in a pseudostratified epithelium

ECM Remodeling and an Abrupt, Stochastic Transition to Arrest Determine Tissue Growth Kinetics

ABSTRACT Proper control of division orientation and symmetry, largely determined by spindle positioning, is essential to development and homeostasis. Spindle positioning has been extensively studied in cells dividing in two-dimensional (2D) environments and in epithelial tissues, where proteins such as NuMA (also known as NUMA1) orient division along the interphase long axis of the cell. However, little is known about how cells control spindle positioning in three-dimensional (3D) environments, such as early mammalian embryos and a variety of adult tissues. Here, we use mouse embryonic stem cells (ESCs), which grow in 3D colonies, as a model to investigate division in 3D. We observe that, at the periphery of 3D colonies, ESCs display high spindle mobility and divide asymmetrically. Our data suggest that enhanced spindle movements are due to unequal distribution of the cell–cell junction protein E-cadherin between future daughter cells. Interestingly, when cells progress towards differentiation, division becomes more symmetric, with more elongated shapes in metaphase and enhanced cortical NuMA recruitment in anaphase. Altogether, this study suggests that in 3D contexts, the geometry of the cell and its contacts with neighbors control division orientation and symmetry. This article has an associated First Person interview with the first author of the paper.

Three-dimensional geometry controls division symmetry in stem cell colonies

Proper control of division orientation and symmetry, largely determined by spindle positioning, is essential to development and homeostasis. Spindle positioning has been extensively studied in cells dividing in 2-dimensional (2D) environments and in epithelial tissues, where proteins such as NuMA orient division along the cell's interphase long axis. However, little is known about how cells control spindle positioning in 3-dimensional (3D) environments, such as early mammalian embryos and a variety of adult tissues. Here, we use mouse embryonic stem (ES) cells, which grow in 3D colonies, as a model to investigate division in 3D. We observe that at the periphery of 3D colonies, ES cells display high spindle mobility and divide asymmetrically. Our data suggest that enhanced spindle movements are due to unequal distribution of the cell-cell junction protein E-Cadherin between future daughter cells. Interestingly, when cells progress towards differentiation, division becomes more symmetric, with more elongated shapes in metaphase and enhanced cortical NuMA recruitment in anaphase. Altogether, this study suggests that in 3D contexts, the geometry of the cell and its contacts with neighbors control division orientation and symmetry.

Three-dimensional geometry controls division symmetry in stem cell colonies.

SPIN90 associates with mDia1 and the Arp2/3 complex to regulate cortical actin organization

During development, multicellular organisms undergo stereotypical patterns of tissue growth to yield organs of highly reproducible sizes and shapes. How this process is orchestrated remains unclear. Analysis of the temporal dynamics of tissue growth in the Drosophila abdomen reveals that cell cycle times are spatially correlated and that growth termination occurs through the rapid emergence of a population of arrested cells rather than a gradual slowing down of cell cycle time. Reduction in apical tension associated with tissue crowding has been proposed as a developmental growth termination mechanism. Surprisingly, we find that growth arrest in the abdomen occurs while apical tension increases, showing that in this tissue a reduction in tension does not underlie the mechanism of growth arrest. However, remodeling of the extracellular matrix is necessary for tissue expansion. Thus, changes in the tissue microenvironment, and a rapid exit from proliferation, control the formation of the adult Drosophila abdomen.

ECM remodeling and spatial cell cycle coordination determine tissue growth kinetics

Nanoscale Organization of the Actomyosin Cortex during the Cell Cycle

Nanoscale architecture of the actomyosin cortex during cell division.

This paper introduces a new, easy-to-use method of fluorescence single-molecule speckle microscopy for actin with nanometer-scale accuracy. This new method reveals that actin flows in front of mature focal adhesions (FAs) are fast and biased toward FAs, suggesting that mature FAs are actively engaged in pulling and remodeling the local actin network.

New single-molecule speckle microscopy reveals modification of the retrograde actin flow by focal adhesions at nanometer scales

Model of Capping Protein and Arp2/3 Complex Turnover in the Lamellipodium based on Single Molecule Statistics

Distributed actin turnover in the lamellipodium and FRAP kinetics.

1 1 Actin polymerization and the lamellipodium 3 1.1 BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 1.1.1 Actin is part of the machinery of crawling cells . . . . . . . . . 3 1.1.2 Basics of actin polymerization . . . . . . . . . . . . . . . . . . 4 1.1.3 Regulation of actin polymerization . . . . . . . . . . . . . . . 7 1.1.4 Dendritic nucleation model . . . . . . . . . . . . . . . . . . . . 10 1.1.5 Fluorescence microscopy methods to study dynamics at the leading edge. . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 1.2 MOTIVATION AND OUTLINE . . . . . . . . . . . . . . . . . . . . . 14 1.2.1 Extracting filament structures from fluorescence microscopy images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 1.2.2 Particle tracking in fluorescence microscopy . . . . . . . . . . 15 1.2.3 Theoretical model of actin turnover in the lamellipodium . . . 16 2 Extracting filament structures from fluorescent microscopy images 17 2.

Visualizing Release of Single Fluorophores at Membrane Fusion Sites

Interactive, computer-assisted tracking of speckle trajectories in fluorescence microscopy: application to actin polymerization and membrane fusion.

An Autocatalytic Activator-Inhibitor Model of Actin Polymerization at the Leading Edge of Fibroblast Lamellipodia

We use open active contours to quantify cytoskeletal structures imaged by fluorescence microscopy in two and three dimensions. We developed an interactive software tool for segmentation, tracking, and visualization of individual fibers. Open active contours are parametric curves that deform to minimize the sum of an external energy derived from the image and an internal bending and stretching energy. The external energy generates (i) forces that attract the contour toward the central bright line of a filament in the image, and (ii) forces that stretch the active contour toward the ends of bright ridges. Images of simulated semiflexible polymers with known bending and torsional rigidity are analyzed to validate the method. We apply our methods to quantify the conformations and dynamics of actin in two examples: actin filaments imaged by TIRF microscopy in vitro, and actin cables in fission yeast imaged by spinning disk confocal microscopy. © 2010 Wiley‐Liss, Inc.

Segmentation and tracking of cytoskeletal filaments using open active contours

Turnover Dynamics of Diffuse Actin and Regulators At the Leading Edge

This paper presents an automated method for actin filament segmentation and tracking for measuring tip elongation rates in Total Internal Reflection Fluorescence Microscopy (TIRFM) images. The main contributions of the paper are: (i) we use a novel open active contour model for filament segmentation and tracking, which is fast and robust against noise; and (ii) different strategies are proposed to solve the filament intersection problem, which is shown to be the main difficulty in filament tracking. Application to experimental results demonstrated the robustness and effectiveness of this method.

2009 IEEE International Symposium on Biomedical Imaging: From Nano to Macro

Automated actin filament segmentation, tracking and tip elongation measurements based on open active contour models

Submitted for the MAR09 Meeting of The American Physical Society Mechanisms of large length fluctuations during actin filament growth MATTHEW B. SMITH, DIMITRIOS VAVYLONIS, Department of Physics, Lehigh University — Prior TIRF microscopy experiments monitoring the growth of single actin filaments have indicated that the magnitude of growth rate fluctuations, characterized by a “length diffusion coefficient” D, is much larger than the value expected from a simple monomer-by-monomer polymerization process. Several theoretical studies have explored mini-catastrophes or oligomeric annealing and fragmentation as sources of enhanced fluctuations. We used numerical simulations and analytical theory to examine additional mechanisms that contribute to length fluctuations. Fluctuations caused by cooperative kinetics, in which the rate of monomer addition and/or subtraction depends on the type of nucleotide bound to neighboring actin subunits exhibit qualitatively distinct dependence on actin monomer concentration and on concentration of phosphate than those caused by “short pauses.” By comparing to analysis of experimental data, we show that the experimentally measured D values can be distinguished from random noise. Further we propose experiments that will distinguish these sources of fluctuations. We relate our findings to other one-dimensional directed processes, such as in molecular motor walks. Matthew B. Smith Department of Physics, Lehigh University Date submitted: 07 Dec 2008 Electronic form version 1.4

Mechanisms of large length fluctuations during actin filament growth

In this paper, the Quiet Direct Simulation (QDS) method is used to model the unsteady jet development in a Pulsed Pressure Chemical Vapour Deposition (PP-CVD) reactor. QDS is a novel method of gas flow simulation which is able to compute true-direction fluxes of mass, momentum and energy in a computationally efficient and accurate manner. The scheme is ideal for the simulation of novel CVD processes like PP-CVD which include highly unsteady flow structures which has previously proved extremely difficult to simulate. Here, the axisymmetric QDS solver is outlined and the injection phase of a PP-CVD reactor is simulated.

CVD Flow Field Modeling Using the Quiet Direct Simulation (QDS) Method

In this study an explicit Finite Difference Method (FDM) based scheme is developed to solve the Maxwell’s equations in time domain for a lossless medium. This manuscript focuses on two unique aspects – the three dimensional time-accurate discretization of the hyperbolic system of Maxwell equations in three-point non-staggered grid stencil and it’s application to parallel computing through the use of Graphics Processing Units (GPU). The proposed temporal scheme is symplectic, thus permitting conservation of all Hamiltonians in the Maxwell equation. Moreover, to enable accurate predictions over large time frames, a phase velocity preserving scheme is developed for treatment of the spatial derivative terms. As a result, the chosen time increment and grid spacing can be optimally coupled. An additional theoretical investigation into this pairing is also shown. Finally, the application of the proposed scheme to parallel computing using one Nvidia K20 Tesla GPU card is demonstrated. For the benchmarks performed, the parallel speedup when compared to a single core of an Intel i7-4820K CPU is approximately 190x. AMS subject classifications: 35Q61, 65M06, 65Y05

Simulation of Maxwell's Equations on GPU Using a High-Order Error-Minimized Scheme

Analysis of the convergence properties for a non-linear implicit Equilibrium Flux Method using Quasi Newton-Raphson and BiCGStab techniques

Efficient methods for implementation of multi-level nonrigid mass-preserving image registration on GPUs and multi-threaded CPUs

A true-direction reconstruction of the quiet direct simulation method for inviscid gas flows

Extension of the uniform equilibrium flux method (UEFM) to second order accuracy and its graphics processing unit acceleration

The direction decoupled Quiet Direct Simulation method for rapid simulation of axisymmetric inviscid unsteady flow in pulsed pressure chemical vapour deposition

Development of a parallel semi-implicit two-dimensional plasma fluid modeling code using finite-volume method

Large-scale simulations on multiple Graphics Processing Units (GPUs) for the direct simulation Monte Carlo method

Presented is the multi‐dimensional extension of the Quiet Direct Simulation (QDS) method to general, higher order spatial accuracy. Due to the true directional nature of QDS, where volume‐to‐volume fluxes are computed as opposed to fluxes at cell interfaces, a volumetric reconstruction is required. In this approach, the conserved quantities are permitted to vary (according to a polynomial expression) across all simulated dimensions. Prior to flux computation, QDS particles are introduced using properties based on weighted moments taken over the polynomial reconstruction of conserved quantity fields. The resulting flux expressions are shown to exactly reproduce existing 2nd order extensions (for one‐dimensional flows) while providing means for true multi‐dimensional reconstruction and general higher order extensions. Here we will show a typical comparison among different spatial order extensions of QDS and other WENO (5th order accurate) based numerical scheme. The extension is demonstrated up to 5th order...

General Higher Order Extension to the Quiet Direct Simulation Method

Development of an improved spatial reconstruction technique for the HLL method and its applications

Fluxes of multiple species are implemented in the Quiet Direct Simulation (QDS) scheme for gas flows. Each molecular species streams independently. All species are brought to local equilibrium at the end of each time step. The multi species scheme is compared to DSMC simulation, on a test case of a Mach 20 flow of a xenon/helium mixture over a forward facing step. Depletion of the heavier species in the bow shock and the near‐wall layer are seen. The multi‐species QDS code is then used to model the flow in a pulsed‐pressure chemical vapour deposition reactor set up for carbon film deposition. The injected gas is a mixture of methane and hydrogen. The temporal development of the spatial distribution of methane over the substrate is tracked.

Multi‐Species Fluxes for the Parallel Quiet Direct Simulation (QDS) Method

Development of a semi-implicit fluid modeling code using finite-volume method based on Cartesian grids

Rapid optimization of blast wave mitigation strategies using Quiet Direct Simulation and Genetic Algorithm

An improved Quiet Direct Simulation method for Eulerian fluids using a second-order scheme

Overview Presented is a modified form of the Quiet Direct Simulation (QDS) method [1] adapted for application of Graphics Processing Units (GPU) for flux calculation. Fluxes between source and destination cells calculated by QDS are flux-vector split and (on a regular Cartesian grid) a function of the source cell alone. The resulting advantage is the rapid calculation of fluxes between cells without the prior exchange of information between them, allowing highly efficient calculation using GPU. Various flow problems have been solved and consistent speed-ups of over 35 times (when compared to an equivalent single CPU code) are reported.

Application of a Kinetic Theory based solver of the Euler Equations using GPU

Application of targeted maximum likelihood estimation in public health and epidemiological studies: a systematic review.

Background Multiple imputation is often used to reduce bias and gain efficiency when there is missing data. The most appropriate imputation method depends on the model the analyst is interested in fitting. Several imputation approaches have been proposed for when this model is a logistic regression model with an interaction term that contains a binary partially observed variable; however, it is not clear which performs best under certain parameter settings. Methods Using 1000 simulations, each with 10,000 observations, under six datagenerating mechanisms (DGM), we investigate the performance of four methods: (i) ’passive imputation’, (ii) ’just another variable’ (JAV), (iii) ’stratifyimputeappend’ (SIA), and (iv) ’substantive model compatible fully conditional specification’ (SMCFCS). The application of each method is shown in an empirical example using England-based cancer registry data. Results SMCFCS and SIA showed the least biased estimate of the coefficients for the fully, and partially, observed variable and the interaction term. SMCFCS and SIA showed good coverage and low relative error for all DGMs. SMCFCS had a large bias when there was a low prevalence of the fully observed variable in the interaction. SIA performed poorly when the fully observed variable in the interaction had a continuous underlying form. Conclusion SMCFCS and SIA give consistent estimation for logistic regression models with an interaction term when data are missing at random, and either can be used in most analyses. SMCFCS performed better than SIA when the fully observed variable in the interaction had an underlying continuous form. Researchers should be cautious when using SMCFCS when there is a low prevalence of the fully observed variable in the interaction.

Multiple imputation for logistic regression models: incorporating an interaction

Approximate statistical inference via determination of the asymptotic distribution of a statistic is routinely used for inference in applied medical statistics (e.g. to estimate the standard error of the marginal or conditional risk ratio). One method for variance estimation is the classical Delta-method but there is a knowl-edge gap as this method is not routinely included in training for applied medical statistics and its uses are not widely understood. Given that a smooth function of an asymptotically normal estimator is also asymptotically normally distributed, the Delta-method allows approximating the large-sample variance of a function of an estimator with known large-sample properties. In a more general setting, it is a technique for approximating the variance of a functional (i.e., an estimand) that takes a function as an input and applies another function to it (e.g. the expectation function). Speciﬁcally, we may approximate the variance of the function using the functional Delta-method based on the inﬂuence function (IF). The IF explores how a functional 𝜙 ( 𝜃 ) changes in response to small perturbations in the sample distribution of the estimator and allows to compute the empirical standard error of the distribution of the functional. The ongoing development of new methods and techniques may pose a challenge for applied statisticians who are interested in mastering the application of these methods. In this tutorial we review the use of the classical and functional Delta-method and their links to the IF from a practical perspective. We illustrate the methods using a cancer epidemiology example and we provide reproducible and commented code in R and Python using symbolic programming. The code can be accessed at https://github.com/migariane/DeltaMethodInﬂuenceFunction

The Delta-Method and Influence Function in Medical Statistics: a Reproducible Tutorial

Simple Summary There are inequalities in cancer survival between patients with or without comorbidities. The healthcare pathway (i.e., diagnostic route) of a patient is thought to explain some of these inequalities. We explore how much of the effect of comorbidity on survival of patients with diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) is explained by the diagnostic route (i.e., emergency diagnosis). We used mediation analysis to separate the effect of comorbidity on survival from its effect through diagnostic route. We found that, for DLBCL and FL, emergency diagnosis accounted for 24% and 16% of the inequalities in survival between comorbidity groups within 12 months since cancer diagnosis. This proportion reduced over time and was small after 5 years of follow up. Comorbidities can complicate the diagnosis and management of patients with DLBCL or FL. Our results show that greater research is needed to ensure patients with comorbidities have a timely diagnosis and will help to reduce the inequalities in cancer survival. Abstract Background: Socioeconomic inequalities in survival from non-Hodgkin lymphoma persist. Comorbidities are more prevalent amongst those in more deprived areas and are associated with diagnostic delay (emergency diagnostic route), which is also associated with poorer survival probability. We aimed to describe the effect of comorbidity on the probability of death mediated by diagnostic route (emergency vs. elective route) amongst patients with diffuse large B-cell (DLBCL) or follicular lymphoma (FL). Methods: We linked the English population-based cancer registry and hospital admission records (2005–2013) of patients aged 45–99 years. We decomposed the effect of comorbidity on survival into an indirect effect acting through diagnostic route and a direct effect not mediated by diagnostic route. Furthermore, we estimated the proportion of the comorbidity effect on survival mediated by diagnostic route. Results: For both DLBCL (n = 27,379) and FL (n = 14,043), those with any comorbidity, or living in more deprived areas, were more likely to experience diagnostic delay and poorer survival. The indirect effect of comorbidity on mortality through diagnostic route was highest at 12 months since diagnosis (DLBCL: Odds Ratio 1.10 [95% CI 1.07–1.13], FL: OR 1.09 [95% CI 1.04–1.14]). Within the first 12 months since diagnosis, emergency diagnostic route accounted for 24% (95% CI 17.5–29.5) and 16% (95% CI 6.0–25.6) of the comorbidity effect on mortality, for DLBCL and FL, respectively. Conclusion: Efforts to reduce diagnostic delay (emergency diagnosis) amongst patients with comorbidity would reduce inequalities in DLBCL and FL survival by 24% and 16%, respectively. Further public health programs and interventions are needed to reduce diagnostic delay amongst lymphoma patients with comorbidities.

Mediating Effects of Diagnostic Route on the Comorbidity Gap in Survival of Patients with Diffuse Large B-Cell or Follicular Lymphoma in England

The main purpose of many medical studies is to estimate the effects of a treatment or exposure on an outcome. However, it is not always possible to randomize the study participants to a particular treatment, therefore observational study designs may be used. There are major challenges with observational studies; one of which is confounding. Controlling for confounding is commonly performed by direct adjustment of measured confounders; although, sometimes this approach is suboptimal due to modeling assumptions and misspecification. Recent advances in the field of causal inference have dealt with confounding by building on classical standardization methods. However, these recent advances have progressed quickly with a relative paucity of computational‐oriented applied tutorials contributing to some confusion in the use of these methods among applied researchers. In this tutorial, we show the computational implementation of different causal inference estimators from a historical perspective where new estimators were developed to overcome the limitations of the previous estimators (ie, nonparametric and parametric g‐formula, inverse probability weighting, double‐robust, and data‐adaptive estimators). We illustrate the implementation of different methods using an empirical example from the Connors study based on intensive care medicine, and most importantly, we provide reproducible and commented code in Stata, R, and Python for researchers to adapt in their own observational study. The code can be accessed at https://github.com/migariane/Tutorial_Computational_Causal_Inference_Estimators.

Introduction to computational causal inference using reproducible Stata, R, and Python code: A tutorial

Simple Summary Diffuse large B-cell (DLBCL) and follicular lymphoma (FL) account for most non-Hodgkin lymphoma diagnoses: around 35% and 20% in England, respectively. Despite the vast contrast in survival between the subtypes, similar socioeconomic inequalities in survival have persisted over the past two decades, possibly due to the presence of comorbidities. The aim of our study was to assess the association between socioeconomic status and survival from DLBCL or FL accounting for patient and health system characteristics. We found that, for both DLBCL and FL, the most deprived patients had a higher excess mortality hazard compared to the least deprived, regardless of the comorbidity status. Our results show the need for the current framework of the National Health Service to improve the survival of DLBCL and FL patients in the most deprived areas of England, and further consideration is needed for patient-tailored management plans amongst patients with comorbidities or multimorbidities. Abstract (1) Background: Socioeconomic inequalities of survival in patients with lymphoma persist, which may be explained by patients’ comorbidities. We aimed to assess the association between comorbidities and the survival of patients diagnosed with diffuse large B-cell (DLBCL) or follicular lymphoma (FL) in England accounting for other socio-demographic characteristics. (2) Methods: Population-based cancer registry data were linked to Hospital Episode Statistics. We used a flexible multilevel excess hazard model to estimate excess mortality and net survival by patient’s comorbidity status, adjusted for sociodemographic, economic, and healthcare factors, and accounting for the patient’s area of residence. We used the latent normal joint modelling multiple imputation approach for missing data. (3) Results: Overall, 15,516 and 29,898 patients were diagnosed with FL and DLBCL in England between 2005 and 2013, respectively. Amongst DLBCL and FL patients, respectively, those in the most deprived areas showed 1.22 (95% confidence interval (CI): 1.18–1.27) and 1.45 (95% CI: 1.30–1.62) times higher excess mortality hazard compared to those in the least deprived areas, adjusted for comorbidity status, age at diagnosis, sex, ethnicity, and route to diagnosis. (4) Conclusions: Deprivation is consistently associated with poorer survival among patients diagnosed with DLBCL or FL, after adjusting for co/multimorbidities. Comorbidities and multimorbidities need to be considered when planning public health interventions targeting haematological malignancies in England.

Excess Mortality by Multimorbidity, Socioeconomic, and Healthcare Factors, amongst Patients Diagnosed with Diffuse Large B-Cell or Follicular Lymphoma in England

Objectives We aimed to assess the association between multimorbidity and deprivation on short-term mortality among patients with diffuse large B-cell (DLBCL) and follicular lymphoma (FL) in England. Setting The association of multimorbidity and socioeconomic deprivation on survival among patients diagnosed with DLBCL and FL in England between 2005 and 2013. We linked the English population-based cancer registry with electronic health records databases and estimated adjusted mortality rate ratios by multimorbidity and deprivation status. Using flexible hazard-based regression models, we computed DLBCL and FL standardised mortality risk by deprivation and multimorbidity at 1 year. Results Overall, 41 422 patients aged 45–99 years were diagnosed with DLBCL or FL in England during 2005–2015. Most deprived patients with FL with multimorbidities had three times higher hazard of 1-year mortality (HR: 3.3, CI 2.48 to 4.28, p<0.001) than least deprived patients without comorbidity; among DLBCL, there was approximately twice the hazard (HR: 1.9, CI 1.70 to 2.07, p<0.001). Conclusions Multimorbidity, deprivation and their combination are strong and independent predictors of an increased short-term mortality risk among patients with DLBCL and FL in England. Public health measures targeting the reduction of multimorbidity among most deprived patients with DLBCL and FL are needed to reduce the short-term mortality gap.

Association between multimorbidity and socioeconomic deprivation on short-term mortality among patients with diffuse large B-cell or follicular lymphoma in England: a nationwide cohort study

Investigating the inequalities in route to diagnosis amongst patients with diffuse large B-cell or follicular lymphoma in England

1Inequalities in Cancer Outcomes Network, Department of Non-communicable Disease Epidemiology. London School of Hygiene and Tropical Medicine, London, U.K. 2Department of Epidemiology and Biostatistics. Tehran University of Medical Sciences, Tehran, Iran. 3Department of Epidemiology. University of North Carolina at Chapel Hill, North Caroline, U.S. 4Non-communicable Disease and Cancer Epidemiology Group, Instituto de investigacion Biosanitaria de Granada (ibs.GRANADA), University of Granada, Granada, Spain 5Biomedical Network Research Centers of Epidemiology and Public Health (CIBERESP), Madrid, Spain.

Tutorial: Introduction to computational causal inference using reproducible Stata, R and Python code

Tutorial: Introduction to computational causal inference for applied researchers and epidemiologists using reproducible Stata code with translations to R and Python

Background: Acquiring real-world evidence is crucial to support health policy, but observational studies are prone to serious biases. An approach was recently proposed to overcome confounding and immortal-time biases within the emulated trial framework. This tutorial provides a step-by-step description of the design and analysis of emulated trials, as well as R and Stata code, to facilitate its use in practice. 
Methods: The steps consist in (i) specifying the target trial and inclusion criteria, (ii) cloning patients, (iii) defining censoring and survival times, (iv) estimating the weights to account for informative censoring introduced by design, and (v) analysing these data. These steps are illustrated with observational data to assess the benefit of surgery among 70-89 year-old patients diagnosed with early-stage lung cancer. 
Results: Because of the severe unbalance of the patient characteristics between treatment arms (surgery yes/no), a naive Kaplan-Meier survival analysis of the initial cohort severely overestimated the benefit of surgery on 1-year survival (22% difference), as did a survival analysis of the cloned dataset when informative censoring was ignored (17% difference). By contrast, the estimated weights adequately removed the covariate imbalance. The weighted analysis still showed evidence of a benefit, though smaller (11% difference), of surgery among older lung cancer patients on 1-year survival.
Conclusion: Complementing the CERBOT tool, this tutorial explains how to proceed to conduct emulated trials using observational data in the presence of immortal-time bias. The strength of this approach is its transparency and principles that are easily understandable by non-specialists.

A tutorial on trial emulation in the presence of immortal-time bias. Assessing the benefit of major surgery for elderly lung cancer patients using observational data

We Zhao et al. for their interest in our recent article 2 which aims to provide a step-by-step tutorial for the design and analysis of emulated target clinical trials from observational data, to prevent immortal-time bias. In particular, we would like to thank the authors for illustrating the versatility of the concept of cloning within the trial emulation framework by describing a wide range of applications. In their letter, Zhao et al. provide a useful classification of causal questions for which the clone-censor-weight approach is appropri-ate. According to the proposed classification, this approach is useful (i) when time of treatment initiation begins after the entry in the study or the start of follow-up; (ii) when treatment strategies differ in duration or time of onset; and (iii) when treatment strategies are dynamic, such as treatment switching or successions of treatment strategies. They apply their classification to published studies where the clone-censor-weight method has been applied for comparative effectiveness research. In all three categories, grace period(s) need to be defined to reflect different intervals of time during which treatment may be received following each arm’s specific definition. The categories differ by the role that time plays in the definition of the treatment strategies of interest.

Reply to: Versatility of the clone-censor-weight approach: response to ''trial emulation in the presence of immortal-time bias''.

Abstract Acquiring real-world evidence is crucial to support health policy, but observational studies are prone to serious biases. An approach was recently proposed to overcome confounding and immortal-time biases within the emulated trial framework. This tutorial provides a step-by-step description of the design and analysis of emulated trials, as well as R and Stata code, to facilitate its use in practice. The steps consist in: (i) specifying the target trial and inclusion criteria; (ii) cloning patients; (iii) defining censoring and survival times; (iv) estimating the weights to account for informative censoring introduced by design; and (v) analysing these data. These steps are illustrated with observational data to assess the benefit of surgery among 70–89-year-old patients diagnosed with early-stage lung cancer. Because of the severe unbalance of the patient characteristics between treatment arms (surgery yes/no), a naïve Kaplan-Meier survival analysis of the initial cohort severely overestimated the benefit of surgery on 1-year survival (22% difference), as did a survival analysis of the cloned dataset when informative censoring was ignored (17% difference). By contrast, the estimated weights adequately removed the covariate imbalance. The weighted analysis still showed evidence of a benefit, though smaller (11% difference), of surgery among older lung cancer patients on 1-year survival. Complementing the CERBOT tool, this tutorial explains how to proceed to conduct emulated trials using observational data in the presence of immortal-time bias. The strength of this approach is its transparency and its principles that are easily understandable by non-specialists.

Reflection on modern methods: trial emulation in the presence of immortal-time bias. Assessing the benefit of major surgery for elderly lung cancer patients using observational data

Emulating a randomised trial from registry data to evaluate the effect of surgical treatment on survival among older lung cancer patients : results and methodological challenges

It is unlikely that there is one single action that can end the present conflict in Ukraine without it being accompanied by significant unintended consequences. It is, however, highly likely that a particular combination of actions, if executed with precise timing, an acknowledgment of the centrality of the three principal actors—Russian President Vladimir Putin, Ukrainian President Volodymyr Zelenskyy, and the NATO alliance—and an awareness of amplifying effects, could deliver an end to the conflict on terms favourable to Ukraine. This paper analyses the central factors at the operational and strategic levels to highlight purposeful courses of action that could be developed: actions that are linked directly to sought-after changes in the system. This process is complex in the Ukraine situation due to the extraordinary levels of violence, destruction, and offensive actions that are violating the principle of proportionality in military operations. While the United Nations and the Security Council might be included as fourth and fifth actors, these institutions have thus far taken something of a spectator role in the conflict, and are apparently distracted by their own internal and somewhat underperforming mechanisms for arresting conflicts through assertive action, security resolutions, and other legitimate instruments. The invasion Ukraine 24 2022. when civilian West what

A Force for Greatness: Building Accountable, Data Driven Leaders and a Practice-Sharing Culture in the Birmingham City Schools

In the past, and currently, general contractors (GC) have been known to push the schedule to a point where a subcontractor (Sub) may overlook or deliberately take short cuts to meet deadlines. Taking a step back and looking at the larger picture, the goal for every project should be to build it safely, efficiently, and with quality, whether you are the GC or a Sub. The question we have to ask ourselves is “If the objectives of two companies run parallel then why is there so much resistance to working together as a team”. This paper will present some of the “best practices”, innovative ideas, and electrical summits that have been developed to help overcome the barriers between GC and Subs. To be clear, there are no “quick fixes” or a “magic pill” that a company can implement to solve this problem. A successful safety culture in a company requires a commitment starting at the top, and on a jobsite it starts with a GC taking the time to understand the process and facilitate a team environment.

Project team building to improve the safety culture and prevention of electrical incidents

(ProQuest: ... denotes non-USASCII text omitted.)Matthew L. SmithI. IntroductionThe United States' troubles in Asia began with the end of the Second World War and the beginning of the Cold War with the Soviet Union. After World War ?, the US became increasingly concerned with the threat of communism and adopted a foreign policy of containment as to prevent it from spreading to other nations (National Archives, 2012).1 While initially focused more on Europe after the fall of East Germany, America soon faced a new communist threat: with the emergence of Korea. In the 1950's, the Korean Peninsula fell by civil war, with Americans supporting the South, and its new threat, the Soviet Union, supporting the North.It was the fear of the Soviet Union more than the fear of communism, which fueled the conflict within Korea. The United States placed military troops south of the 38th parallel to prevent the Soviets from taking full control of the peninsula, while simultaneously removing Japanese presence (National Archives, 2012). Korea was then divided along this line, with Kim II Sung forming the communist Democratic People's Republic of Korea (DPRK) in the north, and Syngman Rhee establishing the democratic Republic of Korea (RoK).3 It was the intention of the two halves to reunite when the conflict between the United States and the Soviet Union subsided.Tensions rose, and ultimately reached the tipping point when war broke out on June 25, 1950 when North Korea attacked across the 38th parallel (National Archives, 2012). The UN Security Council declared this act to be a breach of peace and allowed nations to intervene (National Archives, 2012). Although US President Harry S. Truman sent troops, he did not have to acquire a declaration of war from Congress, as this was determined to be a "police action" on behalf of the UN (National Archives, 2012). This action by the US also conflicted with prior policy concerning Korea. Prior to the war, the US was in the process of removing its remaining troops from WWII, primarily because the Korean peninsula was beyond the boundary zone in which to prevent the spread of communism.The United States became involved with the Korean conflict for two major reasons: the Soviet Union successfully detonated a nuclear bomb in 1949, and in the same year, Mao Zedong led the Communists to power in the revolution in China (National Archives, 2012). Since the DPRK, with Soviet support, invaded the RoK, the US immediately saw this as another example of communism's expansion. President Truman even believed this was a plan by the Chinese to infiltrate the entire Korean peninsula. In light of these events, the US continued to provide the Republic of Korea military support under the guise of the United Nations in order to prevent the spread of communism. As of now and going forward, the United States will have to determine what is necessary for its own national security if it continues to support the Republic of Korea. Along with the strategic position of the RoK, (surrounded by China, the Russian Federation, and Taiwan), and the current conflicts they might entail, the US national security strategy needs to be revisited in order to create policies for the future.The conflict between the Democratic People's Republic of Korea and the Republic of Korea has been complicated and slow-moving in tangent of a solution towards the reunification of the peninsula. The US even supports the DPRK with humanitarian aid and food supplies, though Pyongyang and the military are the actual recipients of the aid. The US national security strategy will be determined on how each states behaves and how the US responds to the current political, economic, and military actions of the two Koreas.II. United States and North Korea RelationshipIn order to understand the current situation of North Korea, one must first briefly analyze its history and the position it currently holds. After Japanese occupation from 1905 to 1950, the DPRK was led by Kim ? …

Abstract : This thesis is an historical analysis of lessons learned concerning tank mobility, firepower, protection, command and control, and overall design during the major tank warfighting experience of the 20th Century. The aim of this study was to make a determination concerning the existence or non-existence of a common thread of lessons learned during individual and small unit (company size or smaller) tank fighting. The major tank warfare experiences examined were World War I, World War II, and the Arab-Israeli 1967 and 1973 Wars. The lessons learned were gleaned from sources written by soldiers, engineers, and historians who had either participated in or studied the particular tank warfare experience. Lessons are grouped into five areas; mobility, firepower, protection, command and control, and overall design. This study concludes that a common thread of lessons learned concerning individual and small unit (company size or smaller) tank fighting. The major tank warfare experiences examined were World War I, World War II, and the Arab-Israeli 1967 and 1973 Wars. The lessons learned were gleaned from sources written by soldiers, engineers, and historians who had either participated in or studied the particular tank warfare experience. Lessons are grouped into five areas; mobility, firepower, protection, command and control, and overall design. This study concludes that a common thread of lessons learned concerning individual and small unit tank fighting does exist throughout the major warfighting experiences of the 20th century.

Lessons Learned from 20th Century Tank Warfare: Does a Common Thread of Lessons Exist?

Abstract : Requirements for Future Force operations indicate that planning and wargaming must transition from a collocated, sequential, and staff-centered process to one that is distributed, simultaneous, and commander-centered. The present research developed a course of action analysis (wargaming) environment for exploring the human performance requirements associated with distributed wargaming activities characteristic of Future Force operations. This report describes the design, development, and initial evaluation of the multi-echelon distributed wargaming exercises and simulation tools comprising the wargaming research environment. Key design features of the research environment are identified which serve to rapidly guide command groups through the Action-Reaction- Counteraction wargaming cycle, minimizing the time required to orient participants to the tools, tasks, and background information necessary to wargaming. Four distributed wargaming exercises, including two Horizontal (Staff) and two Vertical (Command) exercises, were conducted with 20 Active Duty Officers - Majors and Captains. Results of the research provide a prototype example of an environment for distributed operations that can support Future Force research and training requirements. The results provide lessons learned for developing a distributed planning environment, including guidelines for the development of structured exercises, requirements for tools that facilitate collaboration, and measures for the assessment of wargaming performance.

Developing an Environment for Exploring Distributed Operations: A Wargaming Example

Abstract : This report documents the process and the products of a study examining training and training support for units involved in deployments for contingency operations. The purpose of this study was to assist U.S. Army leaders and training resource managers to better train units, staffs, leaders and soldiers based on the realities and challenges of the 21st century operational environment. It was completed in support of a specific request made by the U.S. Army Training and Doctrine Command (TRADOC) for assistance in providing training support to Army ground forces preparing for, participating in, or returning from contingency operations. The study began by surveying the existing body of knowledge concerning U.S. military contingency operations and military deployments conducted in the 1990s. The survey's purpose was to identify and codify full spectrum training and training resource requirements for units participating in contingency operations. The survey's findings were then used to develop an improved training model and associated templates, and to recommend changes in current training policies and procedures. The eight principal recommendations address training strategies, training documentation, resourcing, decision- making, and training management.

Abstract : It has been over thirty years since the passing of Major General John Fredrick Charles Fuller, a military genius who devoted his life's work to the study of warfare, military leadership and military history. An author of 45 books, along with numerous lectures, reviews and articles, MG Fuller contributed immensely to the body of knowledge concerning warfare. As a military scientist, MG Fuller attempted to do for warfare what Copernicus did for astronomy, Newton for physics, and Darwin for natural history: establish a higher order for the study warfare based on scientific analysis and methods. As a critic, MG Fuller challenged and influenced his and other countries' military and political establishments through two World Wars, one Cold War, and several military contingencies. As a prophet, MG Fuller successfully foretold the future of warfare for much of the twentieth century-from the days of horse-mounted cavalry through mechanization and into the nuclear age. Finally, as either a participant, observer, or commentator on every major military conflict of the early and mid- twentieth century, and as a military historian ranging back to the battles of antiquity, MG Fuller has rightfully earned consideration as one of the most knowledgeable and thought provoking military figures of all time.

Abstract : The purpose of this paper is to examine the current drug war and to determine if an operational artist's approach to planning and problem solving is applicable for the U.S. in its war against drugs. This paper is significant because the military's role in the drug was, while limited in the past, is increasing, and if the civilian agencies currently fighting the lion's share of the war continue to lose ground, then the military can expect to see its involvement significantly expanded. The following methodology was used in this study. First, a current estimate of the drug war is presented. Second, the central concepts of operational art are presented and discussed and a determination is made concerning their applicability. In addition, operational guidance for the design and conduct of an operational campaign plan is presented. This study concludes that the central concepts of operational art and an operational artist's planning methods are applicable and can help the U.S. turn the tide in its war on drugs. Keywords: Law enforcement; Military operations; Drug users; Drug trafficking; Drug interdiction; Operational concepts; Anti-drug campaign plan.

PRELIMINARY EXAMINATION OF THE PALEOCENE-EOCENE RECORD OF A MID-ATLANTIC SHALLOW-MARINE SECTION: THE WOODLAND BEACH CORE, DELAWARE

The Woodland Beach Core, Delaware: Paleocene-Eocene Record of a Mid-Atlantic Shoreline Sequence

Cenozoic stratigraphy of the North Carnarvon Basin: insights for the growth history of carbonate margins of the North West Shelf

Many cast-in-place reinforced concrete deck-girder (RCDG) bridges remain in the national inventory, and routine bridge evaluations are conducted to ensure operational performance. Current codes for rating and evaluation of bridges permit analysts to neglect axial force effects due to temperature and shrinkage effects when calculating load ratings for bridge components with well distributed reinforcement. The proportions and details of many older bridges, however, are unlikely to be considered well detailed. Additionally, available data regarding the behavior and strength of large girders subjected to axial tension is lacking. To develop new data on the influence of axial load on the shear-moment behavior of reinforced concrete girders, seven full-scale specimens were designed, constructed, and tested under combined axial tension and transverse applied forces until failure. Results showed that axial tension and the presence of flexural cutoffs reduced member stiffness and strength. Using these results, different analytical and design methods were compared with assessed member strength.

Effects of Axial Tension on Shear-Moment Capacity of Full-Scale Reinforced Concrete Girders

Toxicon : official journal of the International Society on Toxinology

Metabolic cost of venom replenishment by Prairie Rattlesnakes (Crotalus viridis viridis).

Many cast-in place reinforced concrete deck-girder (RCDG) bridges in the national inventory contain diagonal cracks typically associated with shear-moment interaction. Many transportation agencies use epoxy injection as a prophylactic to seal cracks. The shear-dominated performance of girders treated with epoxy injection is not well understood and the existing data regarding performance of members injected with epoxy have been gathered from reduced-scale test specimens. To provide new data on the shear performance of girders with epoxy injected diagonal cracks, five full-scale RCDG specimens were constructed to reflect 1950s proportions and details. The specimens were loaded to produce diagonal cracks, injected with epoxy under varying degrees of axial tension and service loading, and tested to failure. The test data indicated that epoxy injection resulted in minimal increased shear capacity. However, the epoxy injected specimens exhibited increased load magnitudes prior to crack re-initiation and reduced stirrup stresses at serviceability levels compared to the cracked condition prior to repair.

Behavior of Epoxy-Injected Diagonally Cracked Full-Scale Reinforced Concrete Girders

Gape‐limited predators are restricted in the shape and size of prey items they can ingest by their trophic morphology. Evolutionary theory predicts that gape‐limited predators, such as rattlesnakes, should possess plasticity in their trophic morphology to allow them to respond to environmental cues about their prey base. This study examined the effects of two possible influences over trophic morphology in the pit‐viper Crotalus viridis viridis. Snakes from six litters were exposed to diet manipulations performed over 480 days. By day 480, snakes from two prey‐size treatments exhibited significantly different head shapes. Snakes reared on whole rodents had broader heads, whereas snakes force‐fed homogenized prey had narrower heads. Shape differences varied among litters, suggesting that not all litters responded the same to diet manipulations. Results suggest that trophic morphology of rattlesnakes is plastic, at least in some litters, and can be induced by prey items. J. Morphol. 275:1339–1348, 2014. © 2014 Wiley Periodicals, Inc.

Induction of phenotypic plasticity in rattlesnake trophic morphology by diet manipulation

The trophic morphology of gape-limited predators constrains the shape and size of prey items they can ingest. Trophic morphology consists of any morphological feature that is involved in the handling and ingestion of food. Diet has a profound effect on the morphology of many gape-limited predators. Identifying how prey type and resource level affect the morphology of different populations is an essential step in understanding the mechanisms contributing to patterns of morphological diversity. Species interactions (Chapter 1) induce plasticity in morphology that can lead to increased fitness, morphological divergence, and eventually speciation. In Chapter 2, a laboratory study tested the effects of defensive strikes on snake trophic morphology. In conjunction with morphological measurements, the metabolic costs of replacing venom were quantified. Control and milked snakes had baseline metabolic rate and morphology quantified before treatment manipulation. Milked snakes showed no significant difference in metabolic rate after expending venom than. Trophic morphology was not significantly different after snakes struck defensively. Venom expenditure does not impose significant increases to metabolic rate or changes in trophic morphology. In Chapter 3, I quantified the effects of starvation on trophic morphology and its allometric relationship with body size. Starvation periods of short (100 days) and long (200 days) intervals were compared to control snakes. Shorter periods of starvation had no effect on morphology or its relationship with body size, but longer periods resulted in a significant shift in the relationship between head and body size. Results showed extended periods of starvation can significantly alter the allometry of trophic morphology in snakes. In Chapter 4, I studied the effects of prey size and resource level on trophic morphology. Juvenile snakes were raised for 480 days on varying biomasses and sizes of whole and homogenized rodents. Snakes exhibited significant differences in trophic morphology due to differences in prey size. Larger prey items induced relatively broader and deeper head shapes. Resource level and population also showed varied influences on the shape and size of trophic morphology. The results of this study provide insight into the plasticity in snake trophic morphology and possible ecological causes for observed patterns of variation. This dissertation is approved for recommendation to the Graduate Council Dissertation Director: _______________________________________ Dr. Steven J. Beaupre Dissertation Committee: _______________________________________ Dr. William J. Etges _______________________________________ Dr. Gary R. Huxel ______________________________________ Dr. Giovanni Petris DISSERTATION DUPLICATION RELEASE I hereby authorize the University of Arkansas Libraries to duplicate this dissertation when needed for research and/or scholarship. Agree ___________________________________ Matthew Thomas Smith Refused _________________________________ Matthew Thomas Smith ACKNOWLEDGEMENTS I thank Dr. Steve Beaupre for enduring six long years of my constant pestering and shenanigans. Thank you for taking a chance on me, supporting me, and giving me the opportunity to grow as a scientist. I have greatly benefited from your wisdom, experience, and insight as both a person and a professional. I truly believe that I am walking away from the University of Arkansas as a more complete and skilled scientist and that I have been provided all the tools I need to succeed. I cannot begin to quantify everything that your guidance has given me, nor can I convey how truly touched and grateful I am. I know there were times when you probably questioned your choice, but I have never regretted a day. I look forward to continued collaborations and hope that my career is a monument to all you have given me. I thank my dissertation committee (Drs. William Etges, Gary Huxel, and Giovanni Petris) for their input and guidance over my time at the University of Arkansas. My project, dissertation, knowledge, and ability have all significantly benefited from your role on my committee. Each of you has provided me with a unique insight into the world of science as well as presenting me with a set of challenges and benchmarks so that I could maximize my potential. Thank you for everything you have done for me. I thank my friends and colleagues Drs. Michael Collyer, Mark Davis, and Trevor Krabbenhoft for the years of comradery and scientific discussions. I have learned more from the three of you than a lifetime of degrees could ever instill. It has been a true pleasure being your friend, colleague, and fellow science enthusiast. I look forward to years of collaboration, discourse, good times, and of course the occasional beverage. I thank the past and present members of the Beaupre lab who have made my doctoral experience truly enjoyable: Rod Wittenberg, James Van Dyke, Lara Douglas, Joe Agugliaro, Marshall McCue, Jason Ortega, Craig Lind, and Brenna Levine. All of you have provided periods of great scientific debate, discussion, and insight along with enjoyable times of relaxation and fun in the field. Rod and Joe made my first years in Arkansas very enjoyable. The many trips to the field and adventures exploring for new sites will never be forgotten. The professional and person conversations had over beers at Grubs helped keep me focused and entertained. Joe, thank you for the great viridis collection trip of 2008, the field beard challenge, and exposure to some great music. I thank Jason for being just a great guy in general. You have always been the first to lend a helping hand, an ear to listen to my ideas and complaints, and a shoulder to lean on. I have enjoyed our time together and look forward to continued collaboration. I thank Craig for making me feel short and pushing me to be a better scientist and enjoy life more. Van, Marshall, and Lara, thank you for all of the great lab meetings and paper discussions. I thank all of the graduate students in the department (too numerous to name) that contributed to my experience here. I look forward to continuing the friendships and professional connections I have made here. I thank my family for all their love and support. My parents and all five of my siblings have always been there for me in my times of need and provided me with so many great memories. I know that much of who I am today is because of the experiences they have provided me as I have grown up. I am truly blessed to have such a great family. I thank Carrye for all of the love and support over an incredibly stressful period. Meeting you was one of the greatest aspects to my time here. We met during the most chaotic times of my career and I know you had to endure a lot of stress and turmoil. For that I thank you and can only hope to one day return the favor. DEDICATION I dedicate this dissertation and really the rest of my life to my father. I would be so much less of a person without your guidance. You were the greatest man I have ever known, and your life provides continual inspiration to become the best person I can. I could spend the rest of my dissertation detailing how much you have impacted my life and how grateful I am for all of the love and support. Since your passing, I have been a ship lost at sea and not a second goes by that I don’t think of you and wish that you were still with us. My deepest and greatest regret is that you could not be here to share this moment with me. I hope that I have made you proud and that I have not let you down. I will live every day for the rest of my life with you in my heart and with the desire to make you proud of your son. You are my coach, my father, and my hero; and I dedicate this dissertation and all my future accomplishments to you. TABLE OF CONTENTS INTRODUCTION 1 CHAPTER 1: A REVIEW OF PHENOTYPIC PLASTICITY, GAPE-LIMITED PREDATORS, AND PLASTIC RESPONSES IN TROPHIC MORPHOLOGY 3 Introduction 3 Phenotypic Plasticity Overview 5 What is Phenotypic Plasticity 5 When is Phenotypic Plasticity Favored 8 Costs and Benefits of Phenotypic Plasticity 9 Is Phenotypic Plasticity Adaptive? 10 The Importance of Phenotypic Plasticity 11 Speciation through Phenotypic Plasticity 13 Reciprocal Phenotypic Plasticity 15 Inducible Defenses 15 Inducible Offenses 18 Trophic Polymorphism in Fish 19 Trophic Polymorphisms in Amphibians and Birds 22 Trophic Polymorphisms in Snakes 24 Is Snake Trophic Morphology Adaptive? 27 Criticisms and Future Directions 30 Literature Cited 33 CHAPTER 2: METABOLIC AND MORPHOLOGICAL RESPONES TO VENOM EXPENDITURE BY PRAIRIE RATTLESNAKES (Crotalus viridis viridis) 47 Abstract 47 Introduction 47 Methods and Materials 53 Study Species 53 Experimental Design 54 Metabolic Measurements 55 Results 60 Venom Expenditure and Metabolic Response 60 Morphological Response to Venom Expenditure 62 Discussion 63 Acknowledgements 68 Literature Cited 70 FIGURES 76 FIGURE 1: Graph of pilot study data on the metabolic rate of Crotalus viridis viridis. 76 FIGURE 2: Graphs showing the predicted response in the cumulative difference in metabolic rate (CDMR) and the difference in metabolic rates (DMR) after milking. 77 FIGURE 3: Average RMR (ml CO2/h) values for all snakes plotted against snake body mass (g). 78 FIGURE 4: Graph of CDMR value over the 96 hours 79 FIGURE 5: Mean values for the cumulative difference in metabolic rate 80 FIGURE 6: Visual representation of the landmarks placed on the dorsal aspect of snake trophic morphology. 81 FIGURE 7: Visual representation of landmarks placed on the lateral aspect of snake trophic morphology. 82 FIGURE 8: Relative warp plot for the dorsal aspect of snake trophic morphology. 83 FIGURE 9: Plot of the first two relative warp scores for each TRT*Time group 85 TABLES 87 TABLE 1: Table summarizing the venom yields 87 TABLE 2: Tested covariance structures for the repeated measures ANCOVA 88 TABLE 3: Detailed informatio

Abstract : The United States active-duty military force is subject to an active duty retirement system that requires modernization especially considering the financial challenges facing the Department of Defense. Additionally, the United States military continues to lose highly experienced and valuable personnel at early points during one s service. This project explores aspects to include a future military retirement system such as being governed under an ERISA type structure with main characteristics being the advocacy of member savings, adopting portable retirement benefits, allowing for earlier vesting, and expanding survivorship benefits. Further, this project advocates innovative military retirement reform that includes benefits servicemembers can select and can carry with them for the duration of their careers no matter what the length of their careers may be. Several recommendations, as a result of this research, include a modified defined benefit plan, rewarding servicemembers for serving in combat, an option for a defined contribution plan, bonuses targeted at yearly service milestones in one s career, and separation pay with concessions made to allow the service member, and their benefits, to continue to seamlessly transfer to the Guard or Reserve.

Shear repair methods for conventionally reinforced concrete girders and bent caps : appendices.

Shear repair methods for conventionally reinforced concrete girders and bent caps : final report, December 2009.

approved: _____________________________________________________________________ Christopher C. Higgins Article 1: Behavior of Epoxy Injected Diagonally Cracked Full-Scale CRC Deck-Girders. Many cast-in place reinforced concrete deck-girder bridges (RCDG) remain in the national inventory and exhibit diagonal cracking. Epoxy injection has been in use for several decades as a method for sealing diagonal cracks, but the effects on girder behavior have not been validated. Much of the existing data regarding performance of members injected with epoxy have been gathered through testing of reduced-scale specimens. This investigation reports structural responses of five full-scale RCDG specimens constructed to reflect mid-twentieth century proportions and details. Specimens were loaded to produce diagonal cracks, injected with epoxy under varying degrees of axial tension and service loading, and tested to failure. The experimental results indicate that epoxy injection produced minimal capacity increase, increased crack re-initiation loads, and reduced stirrup serviceability stresses compared to original performance and the control specimen. The addition of cyclic live loading during injection and curing of epoxy produced variable pressures within the crack volume and also produced small bubbles within the epoxy matrix. These bubbles did not reduce performance for the loading considered. Article 2: Investigation of the Effects of Imposed Axial Tension on Diagonally Cracked Full-Scale CRC Deck-Girders. Many cast-in place reinforced concrete deck-girder bridges (RCDG) remain in the national inventory and are exhibiting significant diagonal cracking. Current codes for rating and evaluation of bridges permit analysts to neglect temperature and shrinkage effects when calculating load ratings for bridge components with well distributed reinforcement. The proportions and details of 1950’s vintage bridges are unlikely to be considered well detailed, and existing research regarding the performance of members subjected to axial tension is insufficient. Seven full-scale reinforced concrete specimens were constructed and tested to reflect mid-twentieth century proportions and detailing, including light shear reinforcement and straight flexural cutoff details. Specimens were loaded under combined axial tension and transverse forces. Results indicate that axial tension and flexural cutoffs reduce member capacity and stiffness and methods for predicting capacity were compared. © Copyright by Matthew T. Smith June 20, 2007 All Rights Reserved Investigation of the Behavior of Diagonally Cracked Full-Scale CRC Deck-Girders Injected with Epoxy Resin and Subjected to Axial Tension

Investigation of the behavior of diagonally cracked full-scale CRC deck-girders injected with epoxy resin and subjected to axial tension

Abstract : In the future, the US military cannot afford to be outmaneuvered by the enemy anywhere within the battlespace; freedom depends on our ability to retain the initiative and to subdue or annihilate the enemy at points of our choosing. Toward that end, we must continue to exploit fully joint warfighting theory and doctrine. We do this well enough in most areas, with the glaring exception of officer professional development. This research attempts to show that the Services do nothing substantial or systematic to instill joint-mindedness among all officers--the junior ranks most especially. This thesis ventures to illustrate that "joint" is a mere credential an officer attains at random points throughout his career. In doing so, Service core competencies and qualifications are established at the expense of joint mindedness and ultimately the joint force. The author provides analysis of each Service starting at the tactical career level and then proceeding on to the operational career level. The research culminates with an analysis of the strategic career level. Within these three career levels the author evaluates education (technical and professional military education), assignments, and exercises and operations. Finally, for each career level he provides his assessment and way ahead for the Services.

Dectin-1 signaling on colonic γδ T cells promotes psychosocial stress responses

Intermittent calorie restriction alters T cell subsets and metabolic markers in people with multiple sclerosis

Astrocytes are instrumental in maintaining central nervous system (CNS) homeostasis and responding to injury. A major limitation of studying neurodegenerative diseases like multiple sclerosis (MS) is lack of human pathological specimens obtained during the acute stages, thereby relegating research to post-mortem specimens obtained years after the initiation of pathology. Rodent reactive astrocytes have been shown to be cytotoxic to neurons and oligodendrocytes but may differ from human cells, especially in diseases with genetic susceptibility. Herein, we purified human CD49f+ astrocytes from induced pluripotent stem cells derived from individual patient and control peripheral leukocytes. We compared TNF and IL1α stimulated human reactive astrocytes from seven persons with MS and six non-MS controls and show their transcriptomes are remarkably similar to those described in rodents. The functional effect of astrocyte conditioned media (ACM) was examined in a human oligodendrocyte precursor cell (OPC) line differentiation assay. ACM was not cytotoxic to the OPCs but robustly inhibited the myelin basic protein (MBP) reporter. No differences were seen between MS and control stimulated astrocytes at either the transcript level or in ACM mediated OPC suppression assays. We next used RNAseq to interrogate differentially expressed genes in the OPC lines that had suppressed differentiation from the human ACM. Remarkably, not only was OPC differentiation and myelin gene expression suppressed, but we observed induction of several immune pathways in OPCs exposed to the ACM. These data support the notion that reactive astrocytes can inhibit OPC differentiation thereby limiting their remyelination capacity, and that OPCs take on an immune profile in the context of inflammatory cues.

Reactive Astrocytes Derived From Human Induced Pluripotent Stem Cells Suppress Oligodendrocyte Precursor Cell Differentiation

Evaluation of serum neurofilament light chain (sNfL), measured using high‐throughput assays on widely accessible platforms in large, real‐world MS populations, is a critical step for sNfL to be utilized in clinical practice.

Associations of sNfL with clinico‐radiological measures in a large MS population

CEST MRI and MALDI imaging reveal metabolic alterations in the cervical lymph nodes of EAE mice

To assess the effects of demographics, lifestyle factors, and comorbidities on serum neurofilament light chain (sNfL) levels in people without neurologic disease and establish demographic‐specific reference ranges of sNfL.

Contributors to Serum NfL Levels in People without Neurologic Disease

Astrocytes respond to injury, infection, and inflammation in the central nervous system by acquiring reactive states in which they may become dysfunctional and contribute to disease pathology. A sub-state of reactive astrocytes induced by proinflammatory factors TNF, IL-1α, and C1q (“TIC”) has been implicated in many neurodegenerative diseases as a source of neurotoxicity. Here, we used an established human induced pluripotent stem cell (hiPSC) model to investigate the surface marker profile and proteome of TIC-induced reactive astrocytes. We propose VCAM1, BST2, ICOSL, HLA-E, PD-L1, and PDPN as putative, novel markers of this reactive sub-state. We found that several of these markers colocalize with GFAP+ cells in post-mortem samples from people with Alzheimer’s disease. Moreover, our whole-cells proteomic analysis of TIC-induced reactive astrocytes identified proteins and related pathways primarily linked to potential engagement with peripheral immune cells. Taken together, our findings will serve as new tools to purify reactive astrocyte subtypes and to further explore their involvement in immune responses associated with injury and disease.

Proteomic Alterations and Novel Markers of Neurotoxic Reactive Astrocytes in Human Induced Pluripotent Stem Cell Models

Oligodendrocytes and their progenitors upregulate MHC pathways in response to inflammation, but the frequency of this phenotypic change is unknown and the features of these immune oligodendroglia are poorly defined. We generated MHC class I and II transgenic reporter mice to define their dynamics in response to inflammatory demyelination, providing a means to monitor MHC activation in diverse cell types in living mice and define their roles in aging, injury and disease.

MHC class I and MHC class II reporter mice enable analysis of immune oligodendroglia in mouse models of multiple sclerosis

Background and Objectives Serum neurofilament light chain (sNfL) and optical coherence tomography (OCT)–derived retinal measures (including peripapillary retinal nerve fiber layer [pRNFL] and macular ganglion cell layer/inner plexiform layer [GCIPL] thickness) have been proposed as biomarkers of neurodegeneration in multiple sclerosis (MS). However, studies evaluating the associations between sNfL and OCT-derived retinal measures in MS are limited. Methods In this retrospective analysis of a longitudinal, observational, single-center cohort study, sNfL levels were measured in people with MS and healthy controls (HCs) using single molecule array. Participants with MS were followed with serial OCT for a median follow-up of 4.5 years. Eyes with optic neuritis (ON) within 6 months of baseline OCT or ON during follow-up were excluded. Age-normative cutoffs of sNfL were derived using the HC data, and MS participants with sNfL greater than the 97.5th percentile for age were classified as having elevated sNfL (sNfL-E). Analyses were performed with mixed-effects linear regression models and adjusted for age, sex, race, and history of ON. Results A total of 130 HCs (age: 42.4 ± 14.2 years; 62% female) and 403 people with MS (age: 43.1 ± 12.0 years; 78% female) were included. Elevated sNfL levels were present at baseline in 80 participants with MS (19.9%). At baseline, sNfL-E participants had modestly lower pRNFL (−3.03 ± 1.50 μm; p = 0.044) and GCIPL thickness (−2.74 ± 1.02 μm; p = 0.007). As compared with those with sNfL within the reference range, eyes from NfL-E participants exhibited faster longitudinal thinning of the pRNFL (45% faster; −0.74 vs −0.51 μm/y; p = 0.015) and GCIPL (25% faster; −0.35 vs −0.28 μm/y; p = 0.021). Significant differences in rates of pRNFL and GCIPL thinning between sNfL groups were found only in those with relapsing-remitting MS but not progressive MS. Discussion Elevated baseline sNfL is associated with accelerated rates of retinal neuroaxonal loss in relapsing-remitting MS, independent of overt ON, but may be less reflective of retinal neurodegeneration in progressive MS.

Association of Serum Neurofilament Light Chain With Inner Retinal Layer Thinning in Multiple Sclerosis

Retinal pathology in spontaneous opticospinal experimental autoimmune encephalitis mice

Type of serum collection tube does not impact neurofilament light chain levels.

Multi-omic evaluation of metabolic alterations in multiple sclerosis identifies shifts in aromatic amino acid metabolism

Background: Sphingosine-1-phosphate receptor (S1P) modulators and antiCD20 therapies impair humoral responses to SARS-CoV-2 mRNA vaccines. Whether disease modifying therapies (DMTs) for multiple sclerosis (MS) also impact T cell immune response to vaccination is unknown. Methods: In 101 people with MS, we measured humoral responses via an immunoassay to measure IgG against the COVID-19 spike S1 glycoprotein in serum. We also measured T cell responses using FluoroSpot assay for interferon gamma (IFN-gamma; Mabtech,Sweden) using cryopreserved rested PBMCs and then incubated in cRPMI with 1microg/ml of pooled peptides spanning the entire spike glycoprotein (Genscript, 2 pools; 158 peptides each). Plates were read on an AID iSpot Spectrum to determine number of spot forming cells (SFC)/10 6 PBMCs. We tested for differences in immune responses across DMTs using linear models. Findings: Humoral responses were detected in 22/39 (56.4%) participants on anti-CD20 and in 59/63 (93.6%) participants on no or other DMTs. In a subset with immune cell phenotyping (n=88; 87%), T cell responses were detected in 76/88 (86%), including 32/33 (96.9%) participants on anti-CD20 therapies. AntiCD20 therapies were associated with an increase in IFN-gamma; SFC counts relative to those on no DMT or other DMTs (for antiCD20 vs. no DMT: 425.9% higher [95%CI: 109.6%, 1206.6%] higher; p<0.001; for antiCD20 vs. other DMTs: 289.6% [95%CI: 85.9%, 716.6%] higher; p<0.001). Interpretation: We identified a robust T cell response in individuals on anti-CD20 therapies despite a reduced humoral response to SARS-CoV-2 vaccination. Follow up studies are needed to determine if this translates to protection against COVID-19 infection.

Discordant humoral and T cell immune responses to SARS-CoV-2 vaccination in people with multiple sclerosis on anti-CD20 therapy

The goal of this exploratory study was to evaluate the effects of an exercise intervention – progressive resistance training (PRT) on the metabolome of people with MS (pwMS) and to link these to changes in clinical outcomes.

Exercise leads to metabolic changes associated with improved strength and fatigue in people with MS

Single-cell transcriptomic reveals molecular diversity and developmental heterogeneity of human stem cell-derived oligodendrocyte lineage cells

Complement component 3 from astrocytes mediates retinal ganglion cell loss during neuroinflammation

A lymphocyte–microglia–astrocyte axis in chronic active multiple sclerosis

Therapeutic Potential of a Novel Glucagon-like Peptide-1 Receptor Agonist, NLY01, in Experimental Autoimmune Encephalomyelitis

Targeting a sphingomyelin hydrolase improves the structure of remyelinated fibers in a mouse model of multiple sclerosis. Myelination requires a highly organized synthesis of multiple lipid species that regulate myelin curvature and compaction. For reasons that are not understood, central nervous system remyelinated axons often have thin myelin sheaths with a disorganized structure susceptible to secondary demyelination. We found that expression of the sphingomyelin hydrolase neutral sphingomyelinase 2 (nSMase2) during the differentiation of oligodendrocyte progenitor cells (OPCs) to myelinating oligodendrocytes changes their response to inflammatory cytokines. OPCs do not express nSMase2 and exhibit a protective/regenerative response to tumor necrosis factor–α and interleukin-1β. Oligodendrocytes express nSMase2 and exhibit a stress response to cytokine challenge that includes an overproduction of ceramide, a sphingolipid that forms negative curvatures in membranes. Pharmacological inhibition or genetic deletion of nSMase2 in myelinating oligodendrocytes normalized the ceramide content of remyelinated fibers and increased thickness and compaction. These results suggest that inhibition of nSMase2 could improve the quality of myelin and stabilize structure.

To investigate diffusion‐time dependency of diffusional kurtosis in the mouse brain using pulsed‐gradient spin‐echo (PGSE) and oscillating‐gradient spin‐echo (OGSE) sequences.

Diffusion‐time dependence of diffusional kurtosis in the mouse brain

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS) that results in variable severities of neurodegeneration. The understanding of MS has been limited by the inaccessibility of the affected cells and the lengthy timeframe of disease development. However, recent advances in stem cell technology have facilitated the bypassing of some of these challenges. Towards gaining a greater understanding of the innate potential of stem cells from people with varying degrees of disability, we generated induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells derived from stable and progressive MS patients, and then further differentiated them into oligodendrocyte (OL) lineage cells. We analyzed differentiation under both homeostatic and inflammatory conditions via sustained exposure to low-dose interferon gamma (IFNγ), a prominent cytokine in MS. We found that all iPSC lines differentiated into mature myelinating OLs, but chronic exposure to IFNγ dramatically inhibited differentiation in both MS groups, particularly if exposure was initiated during the pre-progenitor stage. Low-dose IFNγ was not toxic but led to an early upregulation of interferon response genes in OPCs followed by an apparent redirection in lineage commitment from OL to a neuron-like phenotype in a significant portion of the treated cells. Our results reveal that a chronic low-grade inflammatory environment may have profound effects on the efficacy of regenerative therapies.

iPSCs from people with MS can differentiate into oligodendrocytes in a homeostatic but not an inflammatory milieu

Glial pathology and retinal neurotoxicity in the anterior visual pathway in experimental autoimmune encephalomyelitis

Objective To measure the impact of JHU-083, a novel prodrug of the glutamine antagonist 6-diazo-5-oxo-l-norleucine, on immune cell proliferation and activation, along with physical and cognitive impairments associated with the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Methods Splenic-derived T cells and bone marrow–derived dendritic cells (DCs) were cultured, activated, and treated daily with vehicle or JHU-083. Proliferation and activation were measured via flow cytometry and IncuCyte live cell analysis. C57BL/6 mice were immunized for EAE. Vehicle or JHU-083 was administered orally every other day either from the time of immunization in the prevention paradigm or from the time of disease onset in the treatment paradigm. Disease scores and body weight were monitored. In the treatment paradigm, cognition was evaluated using the Barnes maze test. Results JHU-083 selectively inhibits T-cell proliferation and decreases T-cell activation, with no effect on DCs. In vivo, orally administered JHU-083 significantly decreases EAE severity in both prevention and treatment paradigms and reverses EAE-induced cognitive impairment. Conclusions JHU-083, a well-tolerated, brain penetrable glutamine antagonist, is a promising novel treatment for both the physical and cognitive deficits of MS.

Glutamine antagonism attenuates physical and cognitive deficits in a model of MS

Nucleotide-binding, leucine-rich repeat containing X1 (NLRX1) is a mitochondria-located innate immune sensor that inhibits major pro-inflammatory pathways such as type I interferon and nuclear factor-κB signaling. We generated a novel, spontaneous, and rapidly progressing mouse model of multiple sclerosis (MS) by crossing myelin-specific T-cell receptor (TCR) transgenic mice with Nlrx1−/− mice. About half of the resulting progeny developed spontaneous experimental autoimmune encephalomyelitis (spEAE), which was associated with severe demyelination and inflammation in the central nervous system (CNS). Using lymphocyte-deficient mice and a series of adoptive transfer experiments, we demonstrate that genetic susceptibility to EAE lies within the innate immune compartment. We show that NLRX1 inhibits the subclinical stages of microglial activation and prevents the generation of neurotoxic astrocytes that induce neuronal and oligodendrocyte death in vitro. Moreover, we discovered several mutations within NLRX1 that run in MS-affected families. In summary, our findings highlight the importance of NLRX1 in controlling the early stages of CNS inflammation and preventing the onset of spontaneous autoimmunity.

NLRX1 inhibits the early stages of CNS inflammation and prevents the onset of spontaneous autoimmunity

Trial of intrathecal rituximab in progressive multiple sclerosis patients with evidence of leptomeningeal contrast enhancement.

Multiple sclerosis (MS) is characterized by demyelinated lesions in the central nervous system. Destruction of myelin and secondary damage to axons and neurons leads to significant disability, particularly in people with progressive MS. Accumulating evidence suggests that the potential for myelin repair exists in MS, although for unclear reasons this process fails. The cells responsible for producing myelin, the oligodendrocytes, and their progenitors, oligodendrocyte precursor cells (OPCs), have been identified at the site of lesions, even in adults. Their presence suggests the possibility that endogenous remyelination without transplantation of donor stem cells may be a mechanism for myelin repair in MS. Strategies to develop novel therapies have focused on induction of signaling pathways that stimulate OPCs to mature into myelin-producing oligodendrocytes that could then possibly remyelinate lesions. We have been investigating pharmacological approaches to enhance OPC differentiation, and have identified that the combination of two agents, triiodothyronine (T3) and quetiapine, leads to an additive effect on OPC differentiation and consequent myelin production via both overlapping and distinct signaling pathways. While the ultimate production of myelin requires cholesterol biosynthesis, we identified that quetiapine enhances gene expression in this pathway more potently than T3. Two blockers of cholesterol production, betulin and simvastatin, reduced OPC differentiation into myelin producing oligodendrocytes. Elucidating the nature of agents that lead to complementary and additive effects on oligodendrocyte differentiation and myelin production may pave the way for more efficient induction of remyelination in people with MS.

Quetiapine has an additive effect to triiodothyronine in inducing differentiation of oligodendrocyte precursor cells through induction of cholesterol biosynthesis

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. Bile acids are cholesterol metabolites that can signal through receptors on cells throughout the body, including the CNS and immune system. Whether bile acid metabolism is abnormal in MS is unknown. Using global and targeted metabolomic profiling, we identified lower levels of circulating bile acid metabolites in multiple cohorts of adult and pediatric MS patients compared to controls. In white matter lesions from MS brain tissue, we noted the presence of bile acid receptors on immune and glial cells. To mechanistically examine the implications of lower levels of bile acids in MS, we studied the in vitro effects of an endogenous bile acid – tauroursodeoxycholic acid (TUDCA) on astrocyte and microglial polarization. TUDCA prevented neurotoxic (A1) polarization of astrocytes and pro-inflammatory polarization of microglia in a dose-dependent manner. TUDCA supplementation in experimental autoimmune encephalomyelitis reduced severity of disease, based on behavioral and pathological measures. We demonstrate that bile acid metabolism is altered in MS; bile acid supplementation prevents polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorates neuropathology in an animal model of MS. These findings identify dysregulated bile acid metabolism as a potential therapeutic target in MS.

Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation

For reasons that are not completely understood, remyelination is often incomplete, producing thin myelin sheaths with disorganized structure. We investigated the cellular basis for this altered myelin structure, and found that the response of oligodendrocyte progenitor cells (OPCs), and mature oligodendrocytes to TNFα and IL-1β is modified by the expression of the sphingomyelin hydrolase nSMase2. OPCs do not express nSMase2, and exhibit a protective response to these cytokines manifest by decreased ceramide, increased sphingosine 1-phosphate, and increased cell motility. Mature oligodendrocytes express nSMase2, and respond to TNFα and IL-1β with a stress phenotype, evidenced by increased ceramide, decreased sphingosine, and active caspase 3. Pharmacological inhibition or a targeted genetic deletion of nSMase2 in vivo increased myelin thickness, and enhanced myelin compaction. These results suggest that inhibition of nSMase2 improves the quality of new myelin by protecting maturing/myelinating oligodendrocytes. Pharmacological inhibition of nSMase2 following a demyelinating event could stabilize the structure of these newly formed myelin sheaths and protect them from secondary demyelination.

Inhibition of neutral sphingomyelinase-2 facilitates remyelination

Significance [11C]CPPC [5-cyano-N-(4-(4-[11C]methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide] is a PET radiotracer specific for CSF1R, a microglia-specific marker. This compound can be used as a noninvasive tool for imaging of reactive microglia, disease-associated microglia and their contribution to neuroinflammation in vivo. Neuroinflammation is posited to be an underlying pathogenic feature of a wide variety of neuropsychiatric disorders. [11C]CPPC may also be used to study specifically the immune environment of malignancies of the central nervous system and to monitor potential adverse neuroinflammatory effects of immunotherapy for peripheral malignancies. This PET agent will be valuable in the development of new therapeutics for neuroinflammation, particularly those targeting CSF1R, not only by providing a noninvasive, repeatable readout in patients but also by enabling measurement of drug target engagement. While neuroinflammation is an evolving concept and the cells involved and their functions are being defined, microglia are understood to be a key cellular mediator of brain injury and repair. The ability to measure microglial activity specifically and noninvasively would be a boon to the study of neuroinflammation, which is involved in a wide variety of neuropsychiatric disorders including traumatic brain injury, demyelinating disease, Alzheimer’s disease (AD), and Parkinson’s disease, among others. We have developed [11C]CPPC [5-cyano-N-(4-(4-[11C]methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide], a positron-emitting, high-affinity ligand that is specific for the macrophage colony-stimulating factor 1 receptor (CSF1R), the expression of which is essentially restricted to microglia within brain. [11C]CPPC demonstrates high and specific brain uptake in a murine and nonhuman primate lipopolysaccharide model of neuroinflammation. It also shows specific and elevated uptake in a murine model of AD, experimental allergic encephalomyelitis murine model of demyelination and in postmortem brain tissue of patients with AD. Radiation dosimetry in mice indicated [11C]CPPC to be safe for future human studies. [11C]CPPC can be synthesized in sufficient radiochemical yield, purity, and specific radioactivity and possesses binding specificity in relevant models that indicate potential for human PET imaging of CSF1R and the microglial component of neuroinflammation.

PET imaging of microglia by targeting macrophage colony-stimulating factor 1 receptor (CSF1R)

Multiple sclerosis is a heterogeneous disease with an unpredictable course and a wide range of severity; some individuals rapidly progress to a disabled state whereas others experience only mild symptoms. Though genetic studies have identified variants that are associated with an increased risk of developing multiple sclerosis, no variants have been consistently associated with multiple sclerosis severity. In part, the lack of findings is related to inherent limitations of clinical rating scales; these scales are insensitive to early degenerative changes that underlie disease progression. Optical coherence tomography imaging of the retina and low-contrast letter acuity correlate with and predict clinical and imaging-based outcomes in multiple sclerosis. Therefore, they may serve as sensitive phenotypes to discover genetic predictors of disease course. We conducted a set of genome-wide association studies of longitudinal structural and functional visual pathway phenotypes in multiple sclerosis. First, we assessed genetic predictors of ganglion cell/inner plexiform layer atrophy in a discovery cohort of 374 patients with multiple sclerosis using mixed-effects models adjusting for age, sex, disease duration, optic neuritis and genetic ancestry and using a combination of single-variant and network-based analyses. For candidate variants identified in discovery, we conducted a similar set of analyses of ganglion cell/inner plexiform layer thinning in a replication cohort (n = 376). Second, we assessed genetic predictors of sustained loss of 5-letters in low-contrast letter acuity in discovery (n = 582) using multivariable-adjusted Cox proportional hazards models. We then evaluated candidate variants/pathways in a replication cohort. (n = 253). Results of both studies revealed novel subnetworks highly enriched for connected genes in early complement activation linked to measures of disease severity. Within these networks, C3 was the gene most strongly associated with ganglion cell/inner plexiform layer atrophy (P = 0.004) and C1QA and CR1 were top results in analysis of sustained low-contrast letter acuity loss. Namely, variant rs158772, linked to C1QA, and rs61822967, linked to CR1, were associated with 71% and 40% increases in risk of sustained LCLA loss, respectively, in meta-analysis pooling discovery and replication cohorts (rs158772: hazard ratio: 1.71; 95% confidence interval 1.30-2.25; P = 1.3 × 10-4; rs61822967: hazard ratio: 1.40; 95% confidence interval: 1.16-1.68; P = 4.1 × 10-4). In conclusion, early complement pathway gene variants were consistently associated with structural and functional measures of multiple sclerosis severity. These results from unbiased analyses are strongly supported by several prior reports that mechanistically implicated early complement factors in neurodegeneration.

Early complement genes are associated with visual system degeneration in multiple sclerosis.

Oligodendrocyte precursor cells present antigen and are cytotoxic targets in inflammatory demyelination

Identify metabolic changes produced by dimethyl fumarate (DMF) treatment and link them to immunological effects.

Dimethyl fumarate treatment induces lipid metabolism alterations that are linked to immunological changes

Significance Multiple sclerosis (MS) is an inflammatory disease that targets the central nervous system and leads to severe neurologic disability. Bryostatin-1 is a naturally occurring, brain-penetrant compound that has undergone human testing in cancer and Alzheimer’s disease, but also has immunomodulatory properties that might provide benefit in MS. Here, we show that bryostatin-1 potently prevents disease and reverses neurologic deficits in the major mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Its benefit even in late-stage EAE further suggests potential in progressive forms of MS, in which much disability accrues but treatments are currently lacking. The established clinical safety profile of bryostatin-1 in humans could expedite its development as a therapeutic agent in MS. Multiple sclerosis (MS) is an inflammatory disorder targeting the central nervous system (CNS). The relapsing-remitting phase of MS is largely driven by peripheral activation of autoreactive T-helper (Th) 1 and Th17 lymphocytes. In contrast, compartmentalized inflammation within the CNS, including diffuse activation of innate myeloid cells, characterizes the progressive phase of MS, the most debilitating phase that currently lacks satisfactory treatments. Recently, bryostatin-1 (bryo-1), a naturally occurring, CNS-permeable compound with a favorable safety profile in humans, has been shown to act on antigen-presenting cells to promote differentiation of lymphocytes into Th2 cells, an action that might benefit Th1-driven inflammatory conditions such as MS. In the present study, we show that bryo-1 provides marked benefit in mice with experimental autoimmune encephalomyelitis (EAE), an experimental MS animal model. Preventive treatment with bryo-1 abolishes the onset of neurologic deficits in EAE. More strikingly, bryo-1 reverses neurologic deficits after EAE onset, even when treatment is initiated at a late stage of disease when peak adaptive immunity has subsided. Treatment with bryo-1 in vitro promotes an anti-inflammatory phenotype in antigen-presenting dendritic cells, macrophages, and to a lesser extent, lymphocytes. These findings suggest the potential for bryo-1 as a therapeutic agent in MS, particularly given its established clinical safety. Furthermore, the benefit of bryo-1, even in late treatment of EAE, combined with its targeting of innate myeloid cells suggests therapeutic potential in progressive forms of MS.

Dimethyl fumarate (DMF) treatment in multiple sclerosis (MS) increased the proportion of immunoregulatory CD56bright NK cells and this change was proportional to reductions in CD8+ memory T cells. DMF and monomethyl fumarate (MMF) treatment in vitro had directs effects on NK cells and promoted degranulation and cytotoxicity.

Dimethyl fumarate treatment alters NK cell function in multiple sclerosis

Oligodendrocyte precursor cells (OPCs) are abundant in the adult CNS and can be recruited to form new oligodendrocytes and myelin in response to injury or disease. However, in multiple sclerosis (MS), oligodendrocyte regeneration and remyelination are often incomplete, suggesting that recruitment and maturation of OPCs is impaired. MS and the rodent model experimental autoimmune encephalomyelitis (EAE) are characterized by infiltration of activated T-cells into the CNS. To investigate the mechanisms by which this neuroinflammatory process influences OPC mobilization, we performed in vivo fate tracing in an inflammatory demyelinating animal model. Results of our studies showed that the OPC differentiation and myelin production are inhibited by either adoptive transfer of CNS infiltrating cytokine producing effector T-cells or CNS production of interferon gamma (IFNγ), using an astrocyte specific IFNγ transgene model. In both systems, IFNγ changes the profile of OPCs by inducing functional expression of the immunoproteasome and upregulation of MHC class I. OPCs exposed to IFNγ are shown to cross present exogenous antigen to cytotoxic CD8 T-cells, which then produce proteases and FasL that results in subsequent caspase 3/7 activation and OPC death, both in vitro and in vivo. Cross presentation by OPCs is dependent on the cytosolic processing pathway and can be inhibited by small molecules targeting MHC class I antigen processing and the immunoproteasome subunits. Finally, the immunoproteasome subunit, PSMB8, is shown to be markedly increased on Sox10+ oligodendrocyte lineage cells only in the demyelinated white matter lesions from patients with MS. These findings support the notion that OPCs have multiple functions beyond differentiation into myelinating cells and adapt to their microenvironment by responding to local cues. In MS, OPCs may be co-opted by the immune system to perpetuate the autoimmune response. Strategies aimed at inhibiting the aberrant immune activation pathways in OPCs may allow more efficient remyelination in MS.

Oligodendrocyte Precursor Cells Are Co-Opted by the Immune System to Cross-Present Antigen and Mediate Cytotoxicity

The discovery that central nervous system (CNS)–targeted autoreactive T cells required a process of licensing in the lung revealed an unexpected relationship between these organs. The clinical and immunological significance of this finding is bidirectional in that it showed not only a mechanism by which T cells become pathogenic before entering the CNS, but also the potential for this process to influence lung immunity as well. Epidemiological studies have shown that people with multiple sclerosis (MS) suffer from increased morbidity and mortality from infectious diseases, independent of immunosuppressive therapies. Respiratory infections account for a large percentage of deaths of people with MS. In this study, to investigate the mechanisms responsible for this enhanced susceptibility, we established a comorbid model system in which mice with experimental autoimmune encephalomyelitis (EAE) were administered a sublethal dose of influenza. Whereas mice with either EAE alone or influenza alone survived, 70% of comorbid mice died as a result of uncontrolled viral replication. Immunological analyses revealed that the induction of EAE led to a surprising alteration of the lung milieu, converting an effective stimulatory influenza-reactive environment into a suppressive one. These results provide mechanistic information that may help to explain the unexpected immunological interactions.

CNS-targeted autoimmunity leads to increased influenza mortality in mice

The regeneration of oligodendrocytes is a crucial step in recovery from demyelination, as surviving oligodendrocytes exhibit limited structural plasticity and rarely form additional myelin sheaths. New oligodendrocytes arise through the differentiation of platelet‐derived growth factor receptor α (PDGFRα) expressing oligodendrocyte progenitor cells (OPCs) that are widely distributed throughout the CNS. Although there has been detailed investigation of the behavior of these progenitors in white matter, recent studies suggest that disease burden in multiple sclerosis (MS) is more strongly correlated with gray matter atrophy. The timing and efficiency of remyelination in gray matter is distinct from white matter, but the dynamics of OPCs that contribute to these differences have not been defined. Here, we used in vivo genetic fate tracing to determine the behavior of OPCs in gray and white matter regions in response to cuprizone‐induced demyelination. Our studies indicate that the temporal dynamics of OPC differentiation varies significantly between white and gray matter. While OPCs rapidly repopulate the corpus callosum and mature into CC1 expressing mature oligodendrocytes, OPC differentiation in the cingulate cortex and hippocampus occurs much more slowly, resulting in a delay in remyelination relative to the corpus callosum. The protracted maturation of OPCs in gray matter may contribute to greater axonal pathology and disease burden in MS.

Lineage tracing reveals dynamic changes in oligodendrocyte precursor cells following cuprizone‐induced demyelination

We evaluated the effect of dimethyl fumarate (DMF) treatment on B‐cell memory and cytokine production in 18 patients with relapsing remitting multiple sclerosis (RRMS) using peripheral blood mononuclear cells obtained prior to and at 6 months post‐DMF initiation. We noted a decline in the absolute B‐cell number with DMF treatment, with a preferential depletion of memory B cells and a concurrent increase in naïve B cells. We noted significant reductions in GM‐CSF, TNF‐α, and IL‐6 producing B cells with DMF treatment. These effects on the B‐cell compartment may underlie the beneficial effects of DMF in RRMS.

Dimethyl fumarate alters B‐cell memory and cytokine production in MS patients

Multiple sclerosis (MS) is a demyelinating disease of the CNS characterized by inflammation and neurodegeneration. Animal models that enable the study of remyelination in the context of ongoing inflammation are greatly needed for the development of novel therapies that target the pathological inhibitory cues inherent to the MS plaque microenvironment. We report the development of an innovative animal model combining cuprizone-mediated demyelination with transfer of myelin-reactive CD4+ T cells. Characterization of this model reveals both Th1 and Th17 CD4+ T cells infiltrate the CNS of cuprizone-fed mice, with infiltration of Th17 cells being more efficient. Infiltration correlates with impaired spontaneous remyelination as evidenced by myelin protein expression, immunostaining, and ultrastructural analysis. Electron microscopic analysis further reveals that demyelinated axons are preserved but reduced in caliber. Examination of the immune response contributing to impaired remyelination highlights a role for peripheral monocytes with an M1 phenotype. This study demonstrates the development of a novel animal model that recapitulates elements of the microenvironment of the MS plaque and reveals an important role for T cells and peripheral monocytes in impairing endogenous remyelination in vivo. This model could be useful for testing putative MS therapies designed to enhance remyelination in the setting of active inflammation, and may also facilitate modeling the pathophysiology of denuded axons, which has been a challenge in rodents because they typically remyelinate very quickly.

Transfer of Myelin-Reactive Th17 Cells Impairs Endogenous Remyelination in the Central Nervous System of Cuprizone-Fed Mice

Mesenchymal stem cells (MSCs) are pleiotropic cells with potential therapeutic benefits for a wide range of diseases. Because of their immunomodulatory properties they have been utilized to treat autoimmune diseases such as multiple sclerosis (MS), which is characterized by demyelination. The microenvironment surrounding MSCs is thought to affect their differentiation and phenotype, which could in turn affect the efficacy. We thus sought to dissect the potential for differential impact of MSCs on central nervous system (CNS) disease in T cell mediated and non-T cell mediated settings using the MOG35–55 experimental autoimmune encephalomyelitis (EAE) and cuprizone-mediated demyelination models, respectively. As the pathogeneses of MS and EAE are thought to be mediated by IFNγ-producing (TH1) and IL-17A-producing (TH17) effector CD4+ T cells, we investigated the effect of MSCs on the development of these two key pathogenic cell groups. Although MSCs suppressed the activation and effector function of TH17 cells, they did not affect TH1 activation, but enhanced TH1 effector function and ultimately produced no effect on EAE. In the non- T cell mediated cuprizone model of demyelination, MSC administration had a positive effect, with an overall increase in myelin abundance in the brain of MSC-treated mice compared to controls. These results highlight the potential variability of MSCs as a biologic therapeutic tool in the treatment of autoimmune disease and the need for further investigation into the multifaceted functions of MSCs in diverse microenvironments and the mechanisms behind the diversity.

Disparate Effects of Mesenchymal Stem Cells in Experimental Autoimmune Encephalomyelitis and Cuprizone-Induced Demyelination

Mesenchymal stem cells (MSC) have emerged as a promising candidate for inflammatory suppression and disease amelioration, especially of neuro‐inflammatory diseases such as multiple sclerosis (MS). Auto‐reactive CD4+ and CD8+ T cells acquire pathogenic IFNγ‐producing‐ (Type I) and IL‐17A‐producing‐ (Type 17) effector phenotypes in MS and its animal model experimental autoimmune encephalomyelitis (EAE). Although MSC have been extensively demonstrated to suppress pathogenic effector CD4+ T cells and CD4+ T cell‐mediated EAE, surprisingly few studies have addressed their modulation of effector CD8+ T cells represented in MS or their impact on CD8+ T cell‐mediated EAE. We find that MSC differentially modulate CD8+ T cell development depending on effector T cell subtype. MSC drive activated low‐IFNγ producers toward an enhanced high‐IFNγ Tc1‐like phenotype but strongly inhibit the production of IL‐17A and Tc17 polarization in vitro. These observations are underscored by differential MSC modulation of T cell activation, proliferation, and signature transcription factor up‐regulation. In addition, effector CD8+ T cells co‐cultured with MSC exhibited increased production of IL‐2, a molecule known to enhance IFNγ, yet suppress IL‐17A, production. Based on these in vitro effects on CD8+ T cells, we next evaluated their impact on the severity of EAE. To better evaluate CD8+ T cells, we immunized mice with MOG37‐50, which is a CD8‐targeted epitope. Our results revealed a worsening of disease, consistent with their in vitro stimulation of Tc1 cells. These findings highlight the emerging duality of MSC in immune modulation and provide implications for their future use in immune‐related diseases. Stem Cells 2014;32:2744–2755

Mesenchymal Stem Cells Differentially Modulate Effector CD8+ T Cell Subsets and Exacerbate Experimental Autoimmune Encephalomyelitis

 Auto-reactive T cells are a significant cause of myelin destruction and eventual axon loss in EAE and probably multiple sclerosis (MS). Both CD4+ and CD8+ T cells acquire pathogenic IFNγ-producing- (Type I) and IL-17A-producing- (Type 17) effector phenotypes in MS and EAE. On the frontier of MS therapy, mesenchymal stem cells (MSC) have emerged as a promising candidate for inflammatory suppression and disease amelioration. Although MSC have been extensively demonstrated to suppress pathogenic effector CD4+ T cells and CD4+ T cell-mediated EAE, surprisingly few studies have addressed their modulation of effector CD8+ T cells in MS or EAE. We find that MSC differentially modulate CD8+ T cell development depending on effector T cell subtype. MSC drive activated low-IFNγ producers toward an enhanced high-IFNγ Tc1-like phenotype but strongly inhibit the production of IL-17A and Tc17 polarization in vitro. These observations are underscored by differential MSC modulation of T cell activation, proliferation, and signature transcription factor up-regulation. In addition, MSC constitutively produced a panel of Type I inflammatory cytokines associated with the IFNγ/IL-17A axis.Based on these in vitro effects on CD8+ T cells, we next evaluated their impact on the severity of EAE. To better evaluate CD8+ T cells, we immunized mice with MOG 37-50, which is a CD8-targeted epitope. Our results revealed a disease worsening, consistent with the in vitro stimulation of Tc1 cells.

Mesenchymal stem cells differentially modulate effector CD8+ T cells and exacerbate EAE. (IRC8P.484)

Transforming growth factor-beta expression and signaling in the conducting airways of the rhesus macaque during postnatal development and in response to allergic airway disease

Mutant mice lacking both cyclin-dependent kinase (CDK) inhibitors p18 Ink4c and p27 Kip1 develop a tumor spectrum reminiscent of human multiple endocrine neoplasia (MEN) syndromes. To determine how p18 and p27 genetically interact with Men1 , the tumor suppressor gene mutated in familial MEN1, we characterized p18 - Men1 and p27-Men1 double mutant mice. Compared with their corresponding single mutant littermates, the p18 (cid:1) / (cid:1) ; Men1 (cid:2) / (cid:1) mice develop tumors at an accelerated rate and with an increased incidence in the pituitary, thyroid, parathyroid, and pancreas. In the pituitary and pancreatic islets, phosphorylation of the retinoblastoma (Rb) protein at both CDK2 and CDK4/6 sites was increased in p18 (cid:1) / (cid:1) and Men1 (cid:2) / (cid:1) cells and was further increased in p18 (cid:1) / (cid:1) ; Men1 (cid:2) / (cid:1) cells. The remaining wild-type Men1 allele was lost in most tumors from Men1 (cid:2) / (cid:1) mice but was retained in most tumors from p18 / ; Men1 (cid:2) / (cid:1) mice. Combined mutations of p27 (cid:1) / (cid:1) and Men1 (cid:2) / (cid:1) , in contrast, did not exhibit noticeable synergistic stimulation of Rb kinase activity, cell proliferation, and tumor growth. These results demonstrate that functional collaboration exists between p18 and Men1 and suggest that menin may regulate additional factor(s) that interact with p18 and p27 differently.

p18 Ink4c , but Not p27 Kip1 , Collaborates with Men1 To Suppress Neuroendocrine Organ Tumors (cid:1)

Elevating cortical serotonin (5-HT) in rats with clorgyline, a monoamine oxidase A (MAOA) inhibitor, from postnatal day (P-) 0 to P-6 delays the organization of thalamocortical afferent fibers into a vibrissae-related pattern in the somatosensory cortex (S-I). Despite continued elevation of cortical 5-HT, the thalamocortical fibers form a characteristic vibrissae pattern of barrels in layer IV of S-I by P-8. The growth-associated protein, GAP-43, is transiently expressed in developing S-I cortex of rats in a vibrissae related pattern until P-7. After P7, GAP-43 expression is reduced in the barrel centers and increased in the septa. The present study evaluated the effect of elevated 5-HT levels on the distribution of GAP-43 immunoreactivity in S-I. We employed 5-HT immunocytochemistry and 1,1’dioctadecyl-3,3,3”,3’tetramethylindocarbocyanine perchlorate (DiI) labeling of thalamic radiations to confirm a “barrelless” phenotype in P-6 clorgyline-treated animals and a recovered barrel pattern in treated animals allowed to survive until P-8 and P-10. GAP43 immunocytochemistry was used to evaluate the cortical distribution of this protein in similarly treated littermates. Continuous inhibition of MAOA from P-0 to P-6 resulted in a corresponding loss of the GAP-43 vibrissae-related pattern at P-6. Despite continued elevation of cortical 5-HT until P-8 and P-10, the characteristic vibrissae-complementary pattern of GAP-43 emerged with expression concentrated in the septa and rows. GAP-43 vibrissae-related thalamocortical axon pattern never appeared in the clorgyline-treated animals. Thus, while elevated 5-HT delays development of a vibrissae-related pattern of

Concentration in Neurosciences The Effects of Elevated Serotonin Levels on Patterns of GAP-43 Expression During Barrel Development in Rat Somatosensory Cortex

The sexually dimorphic number of cells expressing arginine vasopressin (AVP) in the bed nucleus of the stria terminalis and the density of AVP fibers within the lateral septum appear to be organized by pre- and postnatal androgens. Social recognition behaviors are also sexually dimorphic and AVP-dependent. Whereas AVP antagonists prevent males from recognizing familiar intruders by olfactory investigation of the anal-genital area, they have no effect in females. To test the hypothesis that the male's dependency upon AVP to form social recognition memories begins prior to birth, we compared the effectiveness of an AVP antagonist to block social recognition in control males and females with that seen in male offspring whose mothers were treated prenatally with an androgen antagonist (flutamide). In an initial study we showed that while sexual experience may enhance social recognition in males, virgin males exhibit the ability to recognize conspecifics and are sensitive to the memory blocking actions of AVP antagonists. In a second experiment, pregnant rats were treated daily for the last 10 days of gestation with either flutamide (10 mg) or control vehicle. Within 12 h of birth, male offspring from flutamide litters were injected with either testosterone proprionate (50 microg TP) or vehicle control. AVP-antagonist treatment in adults eliminated the ability of control males to recognize familiar juvenile intruders, but had no effect on males exposed prenatally to flutamide, regardless of whether these males were treated with TP or vehicle on day 1 of life. These data support the hypothesis that the development of the male's dependency upon AVP to express social recognition memories begins with the organizational actions of prenatal androgens.

Prenatal Flutamide Treatment Eliminates the Adult Male Rat's Dependency upon Vasopressin When Forming Social–Olfactory Memories

Enterprise and entrepreneurship education: Guidance for UK higher education providers

Evaluation of preparticipation forms for High schools and community colleges

Although the 'Third World' is not a formal subject and plays a minimal role in the National Curriculum Orders for England, this paper argues that in its constructions of 'self', 'world' and 'other', it is a potent element of the English school curriculum. Using ethnographic data from two schools and theoretical insights from post-colonialism, development studies and social theory, the paper conceptualises its communication in terms of debates around difference. Three perspectives are identified through which the 'Third World' is communicated in the curriculum-development, charity and multiculturalism. These are analysed in relation to their constructions of difference. The paper suggests that contradictions between and within them reflect a process of change in which a more critical knowledge of the 'Third World' in the curriculum is emerging. The paper concludes with some observations on the factors constraining this process and some recommendations for policy and further research.

Teaching the 'Third World': Unsettling discourses of difference in the school curriculum

This research explores the communication of the 'Third World' in the school 
curriculum, focusing particularly on its role, location and significance. Using data 
collected from two UK secondary schools the thesis combines ethnographic methods 
with theoretical perspectives from sociology, development studies and cultural 
studies. The conceptual focus of the research is on the ways the communication of the 
'Third World' constructs notions of difference and identity in the school curriculum, 
informed by its location within three frameworks of meaning: development; charity; 
multiculturalism. The communication of the 'Third World' through each of these is 
addressed in turn, focusing particularly on the variety of notions of 'self, 'world' and 
' other' which are constructed. Attention is also drawn to the epistemological 
foundations underpinning the different constructions of the 'Third World', and to the 
implications this has for engagements with notions of difference. 
The research seeks to explain the contradictions within and between the schools' 
communication of the 'Third World', emphasising the micro-politics of the schools 
and their location within a broader political context. In particular, attention is drawn to 
the role of the aims, structure, and organisation of the schools in informing the 
communication of the 'Third World', and to tensions between national and local 
curricular authority. 
It is argued that contradictions within and between the different constructions of the 
'Third World' reflect changes in how the 'Third World' and development are 
understood. However, the potential improvements in its communication that this 
suggests are being constrained at both local and national levels. Thus, the research 
concludes by identifying policy initiatives which can both build on this potential, and 
prevent further prejudiced and discriminatory constructions of the 'Third World'. It 
also suggests further research which will enhance our understanding in this area.

Teaching the 'Third World' : difference and development in the school curriculum

A quality engineering education is of utmost importance to undergraduate students seeking an engineering degree. Providing a quality education to these students is the responsibility of engineering faculty. The Department of Civil and Environmental Engineering at Utah State University (USU), in cooperation with the officers of the student chapter of the American Society of Civil Engineers (ASCE), has developed a series of six lessons focusing on teaching skills and faculty performance in the classroom. This series of lessons, known as the “Undergraduate Teaching Workshop”, is an effort to improve the teaching of the department faculty, and thereby the undergraduate education of its students. 
 
The lessons that make up this workshop range from student concerns to the use of learning resources and equipment. This paper discusses the workshop format and the experience we had with the workshop as it was conducted within our department.

Our Readers Wrote: What's the State of Education and English Teaching Today?

The objective of this work is to examine the feasibility of revision endoscopic posterior costal cartilage graft (EPCCG) placement for posterior glottic stenosis (PGS) and bilateral vocal fold immobility (BVFI). Revision and primary cases were compared with respect to decannulation rates, and it was hypothesized that there would be no difference in outcomes. Twenty-one patients met inclusion criteria (14 primary, 7 revision). Thirteen (62%) had a primary indication of PGS, and 8 (42%) were for BVFI. There were no differences between revision and primary groups with respect to age, gender, or comorbidities (p > .05). There was no difference between groups with respect to decannulation rate (85% primary vs 100% revision, p = .32). Thus, revision EPCCG appears to have comparable results to primary EPCCG with respect to decannulation rate and time to decannulation. EPCCG may be a feasible alternative to open airway reconstruction for PGS and BVFI in selected patients.

Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery

Revision Endoscopic Posterior Costal Cartilage Grafting: Is It Feasible?

We appreciate Dr. Healy’s comments regarding our article. The work Dr. Healy and his mentors had performed at that time were exceptional. Our group described several methods for creating an endoscopic subglottic injury and found that cauterization with prolonged intubation achieved a reproducible and safe model, which was sustainable during our study. We believe that prolonged intubation had a role in creating that injury. Although it is correct that CO2 laser could be beneficial, and some surgeons utilize it in airway endoscopic surgery our study’s objective was to create a subglottic scar tissue endoscopically and not to treat it. Nevertheless, we performed the subglottic injury with cauterization and prolonged intubation and not CO2 laser. Dohar and Hebda’s group had described in several articles their work in the wound healing process at the subglottic area after injury with CO2 laser 4–6 their work is fascinating and highly recommended to review. We agree that a thorough and updated literature review is key in every study performed. Thank you for recommending reviewing Maggio’s article.

In Reference to Establishing an Endoscopic Chronic Subglottic Stenosis Rabbit Model

OBJECTIVE
Tracheoesophageal fistula and esophageal atresia (TEA) and laryngeal cleft (LC) can coexist in some patients. The surgery-specific success rate of LC repair in children with associated TEA has not been well described. The aim of the study is to determine if the history of TEA alters the LC repair outcomes.

STUDY DESIGN
Case series with chart review.

SETTING
Single-institution academic medical center.

METHOD
A retrospective review was conducted of patients with LC with and without TEA repair between January 2001 and November 2020. Data collected and analyzed included demographics and clinical characteristics, LC type, and LC with TEA timing of repairs.

RESULTS
An overall 282 patients met the inclusion criteria of LC repair: LC (n = 242, 85.8%) and LC + TEA (n = 40, 14.2%). Revision repair was required in 43 patients (15.2%) with 8 (2.8%) needing a second revision repair. The first LC revision rate in the LC group was 36/242 (14.9%) as compared with 7/40 (17.5%) in the LC + TEA group (P = .67). The second LC revision rate in the LC and LC + TEA groups was 7 (2.9%) and 1 (2.4%), respectively. The median time to revision was 5.1 months (interquartile range, 3.45-10.6) in the LC group as compared with 29.2 months (interquartile range, 4.8-44.2) in the LC + TEA group (P = .06).

The incidence of TEA and LC was 14.2% in our study. Based on our findings, history of TEA repair is not associated with a higher revision rate vs LC alone. The history of TEA repair did not alter the outcomes of LC repair.

Does the History of Tracheoesophageal Fistula Repair Alter Outcomes of Laryngeal Cleft Repair?

ABSTRACT Introduction Laryngotracheal stenosis comprises a broad spectrum of congenital and acquired conditions that commonly cause pediatric airway obstruction. With the introduction and popularization of operative procedures such as laryngotracheoplasty, cricotracheal resection, and slide tracheoplasty more patients are presenting with airway issues at multiple anatomic levels. A combination of endoscopic and open techniques continues to be utilized for these complex issues. Additionally, there are specific long-term considerations for the post reconstruction patient. Areas covered This review highlights important aspects of the diagnosis, work up, and surgical treatment of pediatric laryngotracheal stenosis with updates for revision airway surgery and the post reconstruction patient. Important research articles and techniques within pediatric airway reconstruction are summarized and included in the review, in addition to recent articles from the last five years on pediatric laryngotracheal stenosis which were identified through a search of the PubMed database. Expert opinion The multidisciplinary concept of evaluation and treatment of laryngotracheal stenosis continues to be essential. Revision airway surgery presents unique challenges to improve the quality of life of patients as they age after reconstruction. Tracheal transplantation remains an important research area in the treatment of laryngotracheal stenosis.

Update on the diagnosis and management of pediatric laryngotracheal stenosis

To develop a reproducible and consistent chronic subglottic stenosis (SGS) in an endoscopic animal model.

Establishing an Endoscopic Chronic Subglottic Stenosis Rabbit Model

Evaluate swallowing and airway outcomes following laryngotracheoplasty with posterior grafting (LTP PCCG).

Airway and Swallowing Outcomes Following Laryngotracheoplasty With Posterior Grafting in Children

Determine surgical and swallowing outcomes after surgery for type III laryngotracheoesophageal cleft (LTEC).

Surgical Treatment of Type III Laryngotracheoesophageal Clefts: Techniques and Outcomes

Objective To determine if time to tracheostomy decannulation differs among children by socioeconomic status. Study Design Case series with chart review Setting Tertiary pediatric medical center. Methods Patients (≤21 years old) who underwent tracheostomy from January 1, 2011, to December 31, 2016. Patients were divided into 2 groups based on their socioeconomic status (SES), low SES and high SES. Principal components analysis was used to create an index for SES using census data obtained by the US Census Bureau’s American Community Survey 5 year data profile from 2013 to 2017. Statistical analysis was performed using a χ2 for categorical variables and Wilcoxon rank-sum test for continuous variables. A general linear model was constructed to control for clinical factors to understand the independent effect of SES on time to decannulation. Results In total, 215 patients were included; of these patients, 111 patients (52%) were included in the high-SES group and 104 patients (48%) were included in the low-SES group. There was a significant difference in the time to decannulation for children based on SES status, with those children in the low-SES group taking on average 10 months longer to decannulate (38.7 vs 28.0 months, P = .0007). Median follow-up was 44.1 months (interquartile range, 29.6-61.3 months). Conclusion Health care disparities appear to exist among children undergoing decannulation of their tracheostomy tube. Patients with lower SES had a significantly longer time to decannulation than those with higher SES.

The Impact of Socioeconomic Status on Time to Decannulation Among Children With Tracheostomies

Objectives: Examine the presentation and clinical course of patients with bacterial tracheitis (BT). Identify if socioeconomic differences exist among children who present with BT. Methods: This was a retrospective case series from a tertiary care pediatric medical center. The study group included patients less than 18 years old who were diagnosed with BT from January 2011 to March 2019. Patients with a tracheostomy and those who developed BT after prolonged hospitalization were excluded. Patient demographics were compared with the demographics of the counties surrounding the hospital. Results: 33 patients with BT met inclusion criteria. The most common presenting symptoms were difficulty breathing, stridor, and sore throat (81.8% each), followed by cough (78.8%). Median length of stay was 3 days [interquartile range (IQR):2-4]. 19 patients (57.5%) were admitted to the intensive care unit. Intubation was required for 13 patients (39.4%), for a median length of 2 days [IQR:2-2]. Methicillin sensitive staphylococcus aureus was the most common bacterial etiology (33%). Mean presenting age was 8.58 years [95% confidence interval:7.3-9.9] and 14 patients were female (42.4%). 31 patients were white (93.9%), 1 was black (3%), and 1 was Hispanic (3%). BT patients were more likely to have private insurance compared to comparison (81.8% vs 63.4%, P < .001). Conclusion: Children who presented with BT were more likely to be privately insured than a comparison population.

Demographic Characteristics of Children Diagnosed with Bacterial Tracheitis

Purpose of review The aim of this review is to provide an update on the management of pediatric tracheostomies. Recent findings Recent literature has focused on optimization of care for children with tracheostomies including prevention and management of skin breakdown, timing of tracheostomy tube changes, the role of multidisciplinary and team-based approaches to education and management of tracheostomy patients, ideal timing of surveillance endoscopy, and the emerging role of telemedicine in the care of tracheostomy patients. Summary A focus on quality improvement and a systematic, team-based approach to care has the potential to improve the quality of care for pediatric tracheostomy patients.

Objective To explore socioeconomic disparities in pediatric single-sided deafness (SSD) treatment. Study Design Retrospective chart review. Setting Tertiary referral academic center. Methods The charts of 190 pediatric patients with SSD were reviewed for demographic and clinical characteristics. Socioeconomic variables included race and insurance status. ZIP codes were used to obtain additional socioeconomic data from the American Community Survey, including mean and median income, percentage of families below the poverty level, and employment status. Socioeconomic status (SES) was classified by insurance status and income. Treatment outcomes were analyzed by socioeconomic variables. Results There were 105 males and 85 females with a mean follow-up of 55.2 months and a mean age at diagnosis of 4.4 years. Sixty-three percent of children received treatment at last follow-up. Thirty-five percent of children had public insurance and 65% had private insurance. Treatment rates were similar in the private and public insurance groups (60.6% vs 66.7%, P = .42), but device type was different between groups (P = .02). Consistent device use was associated with private insurance (47.5% vs 38.9%, P = .003) and high SES (94.4% vs 80%, P = .04) on univariate but not on multivariate analysis. Aided audiometry results were similar between SES groups. No association was found between sex, race, income level, poverty level, or employment status and treatment outcomes. Conclusion Insurance type and SES were not associated with SSD treatment outcomes in children, although device use may be higher in children with private insurance and higher SES. Further research should focus on strategies to reduce barriers to treatment and improve adherence.

Objective Congenital airway stenosis secondary to absent tracheal or bronchial rings is a rare congenital anomaly that is difficult to manage both clinically and surgically. This typically manifests as severe segmental tracheomalacia, and only isolated cases with short-term follow-up have been previously described. We aim to describe a series of children with absent tracheal or bronchial rings who underwent surgical management and had long-term follow-up. Study Design Case series with chart review. Setting Tertiary care pediatric hospital. Methods Patients with absent tracheal or bronchial rings from 2002 to 2016. Electronic and paper medical records were queried to obtain demographics, age at diagnosis and surgery, pre- and postoperative symptoms, location of absent rings, procedure performed, length of follow-up, and adjunctive procedures performed. Results Nine subjects were identified who underwent slide tracheoplasty for correction of congenital absent tracheal or bronchial rings. Age at diagnosis ranged from 10 days to 5 years of age (median, 4 weeks). Age at surgery ranged from 3 weeks to 5 years of age (median, 5 weeks). Six out of 9 subjects were extubated on postoperative day 1. Only 1 subject required additional intervention, which included balloon dilation, tracheobronchial stenting, and aortopexy to alleviate the obstruction. Mean follow-up time was 5.89 years. Conclusions This is the largest series of children with absent tracheal rings who underwent slide tracheoplasty with long-term follow-up presented to date. Slide tracheoplasty is an effective surgical intervention for the treatment of absent tracheal or bronchial rings in infants and young children.

Objective(s): To describe a single institution’s experience with the use of steroid-eluting stents after endoscopic transnasal repair of choanal atresia. Methods: A case series with review of children who underwent choanal atresia repair at a tertiary children’s hospital from June 2017 to January 2018 was performed. Those who had a mometasone drug-eluting stent (Propel® Mini, Intersect ENT Inc., Palo Alto, CA) placed after primary or secondary choanal atresia repair at our institution were included. The primary outcome measure was need for revision surgery due to stenosis. Postoperative regimens, duration of stenting, and need for return to the operating room (OR) were also assessed. Results: Five patients with a median age of 22 months at the time of repair met inclusion criteria. Two (40%) had bilateral atresia and 3 (60%) had confirmed CHARGE syndrome. A total of 6 mometasone drug-eluting stents were used in the 5 cases. Three patients were reassessed at least once in the OR; however, the majority (57.1%) of postoperative evaluations were able to be performed in the office or bedside setting. The first and last evaluations occurred a mean of 14 and 124 days after surgery, respectively. There were no instances of restenosis, repeat surgical interventions, or stent-related complications noted. Conclusion: Placement of a mometasone drug-eluting stent is a promising method to improve postoperative results and management of choanal atresia repair by limiting the need for repeat anesthetics and OR procedures, as well as the complications of traditional stents.

Use of Steroid-Eluting Stents after Endoscopic Repair of Choanal Atresia: A Case Series with Review

Our objective was to gather data that would enable us to suggest more specific guidelines for the management of children with airway disruption.

A 6‐month‐old female presented for 2 months of noisy breathing. Flexible laryngoscopy showed limited bilateral vocal fold abduction. Computed tomography revealed a non‐enhancing 3.6 × 2.3 × 3.5 cystic prevertebral mass spanning C2‐T. Using an endoscopic approach, the overlying mucosa was incised, and the cyst was freed and fully excised from the surrounding mucosa with blunt microlaryngeal instruments without complication. Three months postoperatively she had no respiratory issues and was eating well. Flexible laryngoscopy revealed bilateral vocal fold mobility. We propose that endoscopic removal of a cervical esophageal duplication cyst in selected cases is an alternative to open excision. Laryngoscope, 130:2053–2055, 2020

Objective To determine the optimal timing of the first posttracheostomy microlaryngoscopy and bronchoscopy (MLB). Study Design Case series with chart review. Setting Tertiary pediatric medical center. Subjects and Methods Patients (<21 years of age) who underwent tracheostomy placement from January 1, 2011, to December 31, 2016. Patients were divided into early and late posttracheostomy surveillance groups (<6 weeks vs 6 to 14 weeks, respectively) based on the timing of their first posttracheostomy MLB. The primary outcome was to ascertain the clinical yield of the initial posttracheostomy MLB by documenting whether a medical or surgical treatment decision was made based on MLB findings. Results In total, 202 patients were included; of these patients, 162 met criteria for placement in the early group and 40 met criteria for the late group. There was no significant difference between the early and late groups regarding whether a medical or surgical decision was made at the time of the first MLB (21.5% vs 19%, respectively; P = .49). Multiple logistic regression identified that the presence of tracheostomy-related symptoms prior to MLB (odds ratio, 6.75; 95% confidence interval, 2.78-16.39) was the sole predictor of a medical or surgical decision being made at the first posttracheostomy MLB. Conclusion The presence of tracheostomy-related symptoms was predictive of a medical or surgical decision being made using information obtained at the time of the first posttracheostomy MLB. We thus recommend that surveillance endoscopy be initiated when tracheotomized children start to develop tracheostomy-related symptoms.

Timing of Initial Posttracheostomy Surveillance Endoscopy in Pediatric Patients

Airway reconstruction for subglottic and tracheal stenosis is often successful in achieving tracheostomy decannulation and improving airway symptoms. However, one common reason for late failure is development of a tracheal A‐frame deformity, which can necessitate additional surgery. Although knowledge of this deformity exists, the incidence and risk factors have not been reported. This study seeks to determine the incidence of A‐frame following airway reconstruction and define factors that correlate with development of this deformity.

B53. SLEEP DISORDERED BREATHING AND LONG-TERM VENTILATION IN PEDIATRICS

Family Engagement in the Chronic Ventilator Population: Impact on Length of Stay and Education

CO2 laser supraglottic resurfacing for non-granulomatous chronic supraglottitis in two children.

1) Evaluate success rates for adults undergoing cervical slide tracheoplasty. 2) Examine complication rates of slide tracheoplasty in adults.

Cervical slide tracheoplasty in adults with laryngotracheal stenosis

We wish to address the manuscript entitled “The Role of Tonsillectomy in Adults with Tonsillar Hypertrophy and Obstructive Sleep Apnea,” by Smith et al. This is an excellent work; however, diseases of the nasal cavity and paranasal sinuses, in addition to adenoid hypertrophy, are also factors in adult cases of tonsillar hypertrophy and obstructive sleep apnea. Thus, an examination of the nasal cavity and nasopharynx was required for their patients. Tonsillectomy is a basic method for treating tonsillar hypertrophy and obstructive sleep apnea; however, some adults with tonsillar hypertrophy and obstructive sleep apnea are simultaneously affected by diseases of the nasal cavity and paranasal sinuses, as well as deviation of the nasal septum. In the study by Smith et al, although performing tonsillectomy alone without treating nasal cavity disease or nasal structural abnormalities reduced the apnea-hypopnea index (AHI) and improved sleep quality, it had no significant impact on snoring. A surgical response to treatment was defined as a >50% decrease in AHI and a decrease in the overall AHI to <20%; the authors found that 78% (14/18 subjects) of the cohort showed a surgical response to treatment. A complete surgical cure (AHI <5) was observed in 50% (n = 9) of the patients. Thus, we believe that the nasal cavity and paranasal sinuses should be examined in adults with tonsillar hypertrophy and obstructive sleep apnea. Simultaneous tonsillectomy and nasal surgery should be performed if severe diseases of the nasal cavity and paranasal sinuses, in addition to nasal structural abnormalities, are found; previous studies corroborated this opinion. Stow et al reported that the median AHI was significantly decreased, from 31.7 to 5.5 (P = .0002), when simultaneous tonsillectomy and nasal surgery were performed in adults with tonsillar hypertrophy and obstructive sleep apnea. In addition, adults with tonsillar hypertrophy usually have adenoid hypertrophy; thus, we believe that simultaneous endoscopic adenoidectomy and tonsillectomy should be done in adult cases of tonsillar and adenoid hypertrophy. Zheng-Cai Lou, MD Department of Otorhinolaryngology, The Affiliated YiWu Hospital of Wenzhou Medical University, Zhejiang, China

Response to Comments on “The Role of Tonsillectomy in Adults with Tonsillar Hypertrophy and Obstructive Sleep Apnea”

Granulomatosis with polyangiitis presenting as facial nerve palsy in a teenager.

ABSTRACT Introduction: Laryngotracheal stenosis comprises a broad spectrum of congenital and acquired conditions that commonly cause pediatric airway obstruction. Although the majority of these conditions were historically managed with endoscopic dilations, the introduction of operative procedures such as laryngotracheoplasty, cricotracheal resection, and slide tracheoplasty changed the treatment paradigm. The gradual evolution of endoscopic technology enabled surgeons to perform certain procedures endoscopically that were previously only able to be performed in an open fashion. Areas covered: This review highlights the important aspects of the diagnosis, workup, and surgical treatment of pediatric laryngotracheal stenosis. Important articles describing research and techniques within pediatric airway reconstruction are summarized and included in the review. Expert commentary: The importance of the multidisciplinary concept of treating laryngotracheal stenosis is evidenced by the establishment of aerodigestive centers internationally. In order to continue successfully treating complex cases of laryngotracheal stenosis, further airway research is needed. The application and feasibility of tracheal transplantation and replacement is likely the next frontier in the treatment of laryngotracheal stenosis.

Objective To determine if tonsillectomy alone is an effective treatment in improving obstructive sleep apnea in adult subjects with tonsillar hypertrophy and to evaluate the effect of tonsillectomy on patient-reported quality-of-life indices. Study Design Case series with planned data collection. Setting Academic hospital. Subjects and Methods Thirty-four subjects completed enrollment and intervention from January 2011 to January 2016. Subjects completed pre- and postoperative quality-of-life questionnaires, including the Insomnia Severity Index, Epworth Sleepiness Scale, and the Functional Outcomes of Sleep Questionnaire–10. Surgical response to treatment was defined by a >50% decrease in the Apnea-Hypopnea Index and a decrease in the overall Apnea-Hypopnea Index to <20. Wilcoxon matched-pairs signed-rank tests were used to test each variable to assess for a change from pre- to postintervention. Subjects were then split into 3 BMI subgroups, with results also evaluated by Wilcoxon matched-pairs signed-rank tests. Results There was a significant difference discovered between the mean preoperative Apnea-Hypopnea Index of 31.57 and the mean postoperative value of 8.12 (P < .001). All patient-reported outcomes improved significantly following tonsillectomy. After stratifying all outcome variables (Apnea-Hypopnea Index, Epworth Sleepiness Scale, Insomnia Severity Index, and Functional Outcomes of Sleep Questionnaire–10) by sex, race, and tonsil size, no statistically significant difference was noted among any of these subgroups. There was a 78% surgical response to treatment. Conclusion Tonsillectomy appears to be an effective treatment for obstructive sleep apnea in a select population of adults with tonsillar hypertrophy.

The Role of Tonsillectomy in Adults with Tonsillar Hypertrophy and Obstructive Sleep Apnea

Objective Determine if the noise levels of wind exposure experienced by cyclists reach levels that could contribute to noise-induced hearing loss. Study Design Industrial lab research. Setting Industrial wind tunnel. Subjects and Methods A commercial-grade electric wind tunnel was used to simulate different speeds encountered by a cyclist. A single cyclist was used during the simulation for audiometric measurements. Microphones attached near the ears of the cyclist were used to measure the sound (dB sound pressure level) experienced by the cyclist. Loudness levels were measured with the head positioned at 15-degree increments from 0 degrees to 180 degrees relative to the oncoming wind at different speeds (10-60 mph). Results Wind noise ranged from 84.9 dB at 10 mph and increased proportionally with speed to a maximum of 120.3 dB at 60 mph. The maximum of 120.3 dB was measured at the downwind ear when the ear was 90 degrees away from the wind. Conclusions Wind noise experienced by a cyclist is proportional to the speed and the directionality of the wind current. Turbulent air flow patterns are observed that contribute to increased sound exposure in the downwind ear. Consideration of ear deflection equipment without compromising sound awareness for cyclists during prolonged rides is advised to avoid potential noise trauma. Future research is warranted and can include long-term studies including dosimetry measures of the sound and yearly pre- and postexposure audiograms of cyclists to detect if any hearing loss occurs with long-term cycling.

Evaluation of Noise Exposure Secondary to Wind Noise in Cyclists

Trans-oral robotic surgical excision of an ectopic parathyroid adenoma

A 55-year-old Hispanic woman presented with a slow growing right-sided neck mass that was intermittently painful over the last year. There were no complaints of difficulty swallowing or breathing. Physical examination identified a four centimeter mobile, painless right submandibular neck mass. Computed tomography (CT) revealed a 3.1 cm lesion superficial to the platysma and fine needle aspiration was nondiagnostic. Excision of the mass confirmed a grey, well circumscribed mass with gritty consistency. Pathological examination revealed an epithelial neoplasm arranged in a nest of basaloid cells forming shadow cells among a multinucleate giant cell reaction. This neck mass was believed to be a pilomatrixoma, a rare, benign neoplasm arising from hair cortex cells. These masses most commonly arise in children, but can occur at any age in both males and females. Typically, pilomatrixomas are located on the eyebrows, scalp, trunk, and upper extremities. Symptoms typically include pain, tenderness, and inflammation from a solitary mass ranging from 0.5 to 3 centimeters. CT scan, ultrasound, and Magnetic Resonance Imaging (MRI) can all be used in the diagnosis, but fine needle aspiration is usually the test of choice. Pathology typically demonstrates ghost cells, basaloid cells, and calcium deposition. Treatment is complete surgical excision, and recurrence is as a low as 1% following excision.

Extraction of chewing gum obstructing the lower airways. A need for competence in bronchoscopy

Redox and metal profiles in human coronary endothelial and smooth muscle cells under hyperoxia, physiological normoxia and hypoxia: Effects of NRF2 signaling on intracellular zinc

Metallomic and redox profiling in human coronary smooth muscle cells under hyperoxia, physiological normoxia and hypoxia: crosstalk between Nrf2 signalling and zinc

Nitric oxide biosensor uncovers diminished ferrous iron-dependency of cultured cells adapted to physiological oxygen levels

Corrigendum to “Nitric oxide biosensor uncovers diminished ferrous iron-dependency of cultured cells adapted to physiological oxygen levels” [Redox Biol. 53 (2022) 102319]

Culturing bEnd.3 brain microvascular endothelial cells in normoxic conditions has direct consequences to hypoxia-reoxygenation injury

Nrf2-regulated redox signaling in human coronary smooth artery smooth muscle cells under hyperoxia, physiological normoxia and hypoxia

Ageing modulates human dermal fibroblast contractility: quantification using nano-biomechanical testing.

Effects of changes in ambient oxygen levels and hypoxia-reoxygenation on intracellular zinc levels in human coronary artery endothelial cells

Adapting bEnd.3 brain microvascular endothelial cells to defined ambient oxygen levels has direct consequences for hypoxia-reoxygenation injury

Nrf2-regulated redox signaling in brain endothelial cells adapted to physiological oxygen levels: Consequences for sulforaphane mediated protection against hypoxia-reoxygenation

UVA irradiation increases ferrous iron release from human skin fibroblast and endothelial cell ferritin: Consequences for cell senescence and aging.

Introduction Endothelial derived hyperpolarization (EDH) is an important path to vasodilatation especially in small arteries, and is more important in women and the elderly. Our previous work has shown that this becomes impaired in mice that had experienced a high fat diet during gestation up to weaning, with concomitant reduction in endothelial surface KCa3.1 expression.1 We have tested the idea that altered redox status affects the location of KCa3.1 in human dermal microvascular endothelial cells (HDMECs). Methods HDMECs were obtained from PromoCell (Heidelberg, Germany) and cultured in MV2 growth medium containing 1% penicillin-streptomycin in 5% O2, 5% CO2 at 37°C to passage 6 and 7 in the SCI-tive Physiological Oxygen Workstation from Baker Ruskinn (Maine, USA) for at least 5 days before experiments. The cells were plated on fibronectin (10 µg.ml-1) coated 8 well micro-slides (Ibidi, Martinsried, Germany) and incubated for 48 hour, treated with PBS or H2O2100 µM in PBS for 10 min., and fixed with 4% formalin. Immunofluorescence was performed by incubating with anti-KCa3.1 mouse monoclonal antibody (AL-051 Alomone, Israel) at 4°C overnight, with half of the wells being treated with 2% Triton-X to permeablize the cells. The Alexa 488 labelled anti-mouse antibody for 1 hour and Texas Red Lycopersicon Esculentum Lectin (to stain the cell surface) for 20 min, were applied to the cells at room temperature and finally the DAPI nuclear stain was applied for 3 min. The cells were examined using a x60 1.3 NA oil-immersion objective and images captured via a Hamamatsu RG3 camera into a computer. Using ImageHopper software and computer-driven focussing device (Prior Instruments, UK) we took 10 serial images of KCa3.1at 1.0 µm intervals, which were integrated using Image J. These images were analysed for the fractional area of an endothelial cell occupied by KCa3.1, defined as bright spots between 1 to 4 µm diameter in the relevant fluorescence channel. Results The density of channels on the surface, defined as the integrated image of non-permeablized KCa3.1 channels, was 9.5±0.68 µm-2 × 103 (mean ±sem), while in the permeablized cells the density within the whole cell area was 13.9±1.89 µm-2 × 103 (p<0.05, ‘t’ test, 4 experiments with 20 cells per experimental group) indicating that about 70% of the channels normally reside on the cell surface. Treatment with H2O2 had little effect on the total cell density (reduced to 12.3±1.56), but reduced the surface density to 5.25±0.47 (p<0.01) i.e. reduced to 43%. Conclusion Thus even a brief exposure to oxygen stress will result in the diminution of KCa3.1 on endothelial surface, and this may have implications for the ability of arterioles to dilate. Reference Stead R, et al. J Hypertens2016;34:452–63.

10 Evidence that altered redox status results in KCa3.1 channel reduced endothelial cell surface expression

Introduction To protect the cell from damaging oxidative stress induced by Fenton reactions, the cytosolic labile iron pool (LIP) is normally kept low and tightly regulated. These reactions are initiated by interactions between iron and hydrogen peroxide and can be prolonged and increased with ascorbate. The source of cytosolic labile iron is unclear. It has been suggested that lysosomes are the main source of iron, since protease inhibitors reduce leakage of lysosomal contents including iron after UVA (ultraviolet light) exposure. However, the time resolution of the changes in enzyme activity required to assess lysosomal leakage is too long to establish whether lysosomal damage occurs due to secondary response to iron release from other sources, particularly ferritin. Other methods are therefore required to clarify the source of cytosolic labile iron. Zinc is a redox-inert metal that has anti-oxidant, anti-inflammatory and anti-proliferative properties which is notably reduced in patients with subclinical carotid atherosclerosis, acute coronary syndrome and heart failure. Zinc is known to block iron diffusion via ferritin threefold channels and can therefore be used as a tool to examine UV-induced iron release from ferritin. Methods A fluorescence probe (FeRhoNox-1) specific for ferrous ion was used to determine the time dependent changes in human fibroblasts following exposure to UVA irradiation. Since it is known that low concentrations of zinc block iron diffusion via ferritin threefold channels, we reasoned that pre-incubating skin cells with low concentrations of ZnCl2 would inhibit iron release from ferritin after photo-activation by UVA. Confluent monolayers of human dermal fibroblasts were incubated overnight with 10 µM FeSO4 and 0, 10 and 40 µM ZnCl2, before being loaded with FeRhoNox-1 and exposed to UVA (360 nm) for 1–10 min (8–80 J/m2), with fluorescent readings gathered at 1 min intervals. Results The control cell iron dependent fluorescent signal increased by approximately 100% after 10 min UVA irradiation compared to pre-UV baseline (p<0.001). This UVA-dependent increase in cell iron is prevented by both 10 and 40 µM ZnCl2. Conclusions These Results suggest that UVA causes a significant increase in skin fibroblast LIP and hence oxidative stress which may exacerbate the ageing phenotype of dermal cells. This LIP is likely to be sourced mainly from ferritin since this is completely blocked by relatively low concentrations of extracellular ZnSO4.

6 Zinc attenuates UVA-dependent labile iron increase in human dermal fibroblasts: implications for skin ageing

38 Ageing is associated with increased vulnerability to environmental cold exposure. Previously, 39 we identified the role of the cold-sensitive transient receptor potential (TRP) A1, M8 receptors 40 as vascular cold sensors in mouse skin. We hypothesised that this dynamic cold-sensor 41 system may become dysfunctional in ageing. We show that behavioural and vascular 42 responses to skin local environmental cooling are impaired with even moderate ageing, with 43 reduced TRPM8 gene/protein expression especially. Pharmacological blockade of the 44 residual TRPA1/TRPM8 component substantially diminished the response in aged, compared 45 with young mice. This implies the reliance of the already reduced cold-induced vascular 46 response in ageing mice on remaining TRP receptor activity. Moreover, sympathetic-induced 47 vasoconstriction was reduced with downregulation of the α2c adrenoceptor expression in 48 ageing. The cold-induced vascular response is important for sensing cold and retaining body 49 heat and health. These findings reveal that cold sensors, essential for this neurovascular 50 pathway, decline as ageing onsets. 51 52 Introduction 53 Upon exposure to cold, depending on the type and intensity, several counterbalancing 54 responses are produced, such as shivering thermogenesis involving skeletal muscle, or non55 shivering thermogenesis in brown adipose tissue (BAT) and peripheral vasoconstriction in skin 56 (Señarís et al., 2018, Morrison, Shaun F., Nakamura, 2011, Morrison, S. F., Nakamura, 2019). 57 To produce such responses, thermo-sensors in the form of temperature sensitive sensory 58 receptors are distributed throughout the skin and are considered to work as a first line of 59 defence against cold, which makes peripheral cutaneous responses a fundamental event in 60 the defence against environmental thermal challenge. The sensory receptors in the skin 61 initiate the vascular cold constrictor response which acts to protect against body heat loss and 62 prevent hypothermia. This response is followed by the subsequent vasodilation, a restorative 63 response that is essential to protect the affected skin against cold-induced conditions, such 64 as chilblains, trench foot, frostbite, and Raynaud’s condition (Daanen, van der Struijs, Norbert 65 R., 2005, Keatinge, 1957, Lewis, 1930). It is a finely tuned well balanced response that 66 maintains cellular function and physiological homeostasis during cold exposure. Whilst this 67 response is relevant to all ages, physiological changes in ageing leads to dysfunctional 68 signalling which causes a reduced adaptation to cold exposure (Guergova, Dufour, 2011). 69 With the lack of physical activity in the elderly population, it exacerbates the fall in core body 70 temperature which can cause fatal cardiovascular and respiratory problems (Billeter et al., 71 2014, Stares, Kosatsky, 2015). This is normally the biggest cause behind the National Health 72 Service (NHS) excess winter deaths that we witness every year, where in 2018 it caused 73 approximately 11,000 deaths linked to cold exposure in England (Office for National Statistics, 74 2019). 75 We have previously delineated the primary roles of transient receptor potential (TRP) channels 76 in producing a distinctive biphasic vascular response to cold in the mouse paw consisting of a 77 TRP ankyrin 1 (TRPA1)/ melastatin 8 (TRPM8)-initiated sympathetic α2c adrenoceptor 78 mediated neuronal vasoconstriction and a distinct TRPA1-CGRP (Calcitonin gene-related 79 peptide) mediated sensory-vasodilator component (Aubdool et al., 2016). TRPA1 is a 80 biomolecular sensor for reduced temperatures especially noxious cold (<18C), mediating 81 aversive behaviour such as avoiding cold-induced pain, whilst also being involved in mediating 82 inflammatory pain (Kwan et al., 2006, Nassini et al., 2014, Jain et al., 2011, Gouin et al., 2017). 83 Additionally, it activates C and Aδ sensory nerves to release neuropeptides such as CGRP to 84 mediate neurogenic vasodilation (Aubdool et al., 2016, Story et al., 2003, Gentry et al., 2010). 85 TRPM8 on the other hand is sensitive to low or reduced temperatures such as cool 86 temperatures (<28C) (McKemy, Neuhausser & Julius, 2002, Peier et al., 2002). It is involved 87 in deep body cooling and suggested to supersede the role of TRPA1 (Gavva et al., 2012). 88 TRPM8 is also suggested to be a vasoactive stimulus (Bautista et al., 2007, Johnson et al., 89 2005, Silva et al., 2019). The other established receptor that plays a pivotal role in cold 90 signalling is the sympathetic α2c adrenoceptor, which mediates the vasoconstriction of the 91 blood vessels (Bailey et al., 2004). Whilst the sympathetic branch that is involved in the 92 vasoconstrictor component of the cold response has been shown to have reduced activity in 93 ageing humans (Holowatz, Thompson-Torgerson & Kenney, 2010, Degroot, Kenney, 2007), 94 little is known about the functionality of the cold receptors TRPA1 and TRPM8 in ageing. In 95 the current study we hypothesize that signalling via the cold receptors TRPA1 and TRPM8 96 deteriorates with ageing which causes an impaired vascular response to the cold. 97 The primary objective of this study is to investigate the cutaneous vascular response to cold 98 in ageing, focusing on the activity of the cold TRP receptors; TRPA1 and TRPM8. As 99 sympathetic-sensory neuronal signalling is key for the cutaneous vascular cold response in 100 ageing, we also searched for evidence of dysfunction within these systems. Here using in vivo, 101 ex vivo, genetic, and pharmacological approaches we show that TRPA1 and TRPM8 signalling 102 declines with ageing which affects the sensing as well as functional pathways involved in cold 103 signalling; all of which contribute to the impaired cold vascular response. Additionally, we 104 provide evidence that the α2c adrenoceptor as well as the TRPM8 receptor both play critical 105 roles to influence this outcome, as the expression of both diminishes significantly in ageing 106 which impacts the vascular response to cold. These important findings establish the dynamic 107 role of cold sensitive TRP receptors and sympathetic receptors in the cutaneous vascular 108 response to the cold as ageing occurs. 109 110 Results 111 Cold-induced vascular response is impaired in ageing. We analysed the cold induced vascular 112 response in wild-type (WT) CD1 females (Young: 2-3 months, Aged: 13-15 months) with a full113 field laser perfusion imager (FLPI) using the cold water immersion model (Figure 1a) 114 developed in our laboratory (Aubdool et al., 2014, Pan et al., 2018). After the baseline blood 115 flow was measured for 5 min, the ipsilateral hindpaw was immersed in cold water at 4C, a 116 temperature that produces a robust vascular response, for 5 min and blood flow was then 117 recorded for another 30 min. The cold treatment produced a typical vascular response of rapid 118 vasoconstriction followed by a prolonged recovery vasodilator response in both young and 119 aged mice (Figure 1b-c, Figure 1-figure supplement 1a). In young mice, the cold treatment 120 produced a maximum vasoconstriction of 51.1 ± 1.1%, however, in aged mice this was 121 significantly blunted with maximum vasoconstriction of 27.7 ± 3.0% (Figure 1d). These 122 changes were reflected in the area under the response curve (AUC) analysis with a 123 significantly greater response in young than aged mice (Figure 1e). The result was extended 124 by measurement of the blood flow recovery after the cold treatment. Although blood flow did 125 not fully recover back to the baseline, the initial rate of recovery immediately after maximum 126 vasoconstriction before it slowly plateaued off was significantly faster in the young mice 127 compared to the aged mice (Figure 1f). These results suggest that with ageing the cold 128 induced vascular response starts to diminish, which affects both parts of the vascular 129 response. We were surprized that these changes were observed with moderately aged mice, 130 equivalent to middle aged in human terms (Dutta, Sengupta, 2016). However, at this age there 131 is a clear evidence of elevated gene expression in dorsal root ganglion (DRG) and skin of 132 senescence markers associated with ageing, P16; INK4A, cyclin-dependent kinase inhibitor 133 2A (P16) and P21; Waf1, cyclin-dependent kinase inhibitor 1 (P21), (Figure 1g-h) also 134 confirmed by western blotting (Fig 1i). 135 To extend our mechanistic understanding, we also used a laser Doppler imager (VMS-LDF), 136 in addition to FLPI, which simultaneously measures the blood flow, skin temperature and 137 tissue oxygen saturation level at a single point, to investigate the vascular response to cold. 138 Similar to the results obtained using the FLPI, the environmental cold water treatment 139 produced an impaired vascular response in the paws of aged mice compared to the young 140 mice (Figure 2a). In young mice, the cold treatment produced a maximum vasoconstriction of 141 45.5 ± 3.0%, however in aged mice this was significantly lower with a maximum 142 vasoconstriction of 23.4 ± 4.7%, a result which was reflected in the AUC analysis (Figure 2b143 c). There was a trend of greater reduction in skin temperature of aged mice after the cold144 water treatment; however, the aged mice had a significantly higher skin temperature at 145 baseline. This suggests that they were losing more body heat and is consistent with the fact 146 that the ability to maintain core body temperature declines with ageing (Figure 2d-f). The tissue 147 oxygen saturation level underwent a similar reduction in both young and aged mice after the 148 cold exposure (Figure 2g-h) but recovered more robustly in the young mice compared to the 149 aged mice as shown by AUC analysis (Fig 2i). We also found evidence of increased cellular 150 stress as protein expression of 3-nitrotyrosine (3-NT), a biomarker of oxidative stress 151 produced

Dysfunctional TRPM 8 signalling in the vascular 1 response to environmental cold in ageing . 2 3

Conformational and functional interrelation between mitochondrial carrier proteins: UCP4, ANT, PiT.

Plastids are a dynamic class of organelle in plant cells that arose from an ancient cyanobacterial endosymbiont. Over the course of evolution, most genes encoding plastid proteins were transferred to the nuclear genome. In parallel, eukaryotic cells evolved a series of targeting pathways and complex proteinaceous machinery at the plastid surface to direct these proteins back to their target organelle. Chloroplasts are the most well-characterized plastids, responsible for photosynthesis and other important metabolic functions. The biogenesis and function of chloroplasts rely heavily on the fidelity of intracellular protein trafficking pathways. Therefore, understanding these pathways and their regulation is essential. Furthermore, the chloroplast outer membrane proteome remains relatively uncharted territory in our understanding of protein targeting. Many key players in the cytosol, receptors at the organelle surface, and insertases that facilitate insertion into the chloroplast outer membrane remain elusive for this group of proteins. In this review, we summarize recent advances in the understanding of well-characterized chloroplast outer membrane protein targeting pathways as well as provide new insights into novel targeting signals and pathways more recently identified using a bioinformatic approach. As a result of our analyses, we expand the known number of chloroplast outer membrane proteins from 117 to 138.

New Insights into the Chloroplast Outer Membrane Proteome and Associated Targeting Pathways

Higher concentration of protons in the mitochondrial intermembrane space compared to the matrix results in an electrochemical potential causing the back flux of protons to the matrix. This proton transport can take place through ATP synthase complex (leading to formation of ATP) or can occur via proton transporters of the mitochondrial carrier superfamily and/or membrane lipids. Some mitochondrial proton transporters, such as uncoupling proteins (UCPs), transport protons as their general regulating function; while others are symporters or antiporters, which use the proton gradient as a driving force to co-transport other substrates across the mitochondrial inner membrane (such as phosphate carrier, a symporter; or aspartate/glutamate transporter, an antiporter). Passage (or leakage) of protons across the inner membrane to matrix from any route other than ATP synthase negatively impacts ATP synthesis. The focus of this review is on regulated proton transport by UCPs. Recent findings on the structure and function of UCPs, and the related research methodologies, are also critically reviewed. Due to structural similarity of members of the mitochondrial carrier superfamily, several of the known structural features are potentially expandable to all members. Overall, this report provides a brief, yet comprehensive, overview of the current knowledge in the field.

TET proteins mediate DNA demethylation by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and other oxidative derivatives. We have previously demonstrated a dynamic enrichment of 5hmC during T and invariant natural killer T cell lineage specification. Here, we investigate shared signatures in gene expression of Tet2/3 DKO CD4 single positive (SP) and iNKT cells in the thymus. We discover that TET proteins exert a fundamental role in regulating the expression of the lineage specifying factor Th-POK, which is encoded by Zbtb7b. We demonstrate that TET proteins mediate DNA demethylation - surrounding a proximal enhancer, critical for the intensity of Th-POK expression. In addition, TET proteins drive the DNA demethylation of site A at the Zbtb7b locus to facilitate GATA3 binding. GATA3 induces Th-POK expression in CD4 SP cells. Finally, by introducing a novel mouse model that lacks TET3 and expresses full length, catalytically inactive TET2, we establish a causal link between TET2 catalytic activity and lineage specification of both conventional and unconventional T cells.

TET proteins regulate T cell and iNKT cell lineage specification in a TET2 catalytic dependent manner

It has been suggested that uncoupling proteins (UCPs) transport protons via interconversion between two conformational states: one in the "cytoplasmic state" and the other in the "matrix state". Matrix and cytoplasmic salt-bridge networks are key controllers of these states. This study proposes a mechanism for proton transport in tetrameric UCP2, with focus on the role of the matrix network. Eleven mutants were prepared to disrupt (K → Q or D → N mutations) or alter (K → D and D → K mutations) the salt-bridges in the matrix network. Proteins were recombinantly expressed in Escherichia coli membrane, reconstituted in model lipid membranes, and their structures and functions were analyzed by gel electrophoresis, circular dichroism spectroscopy, fluorescence assays, as well as molecular dynamics simulations. It is shown that the UCP2 matrix network contains five salt-bridges (rather than the previously reported three), and the matrix network can regulate the proton transport by holding the protein's transmembrane helices in close proximity, limiting the movement of the activator fatty acid(s). A biphasic two-state molecular model is proposed for proton transport in tetrameric (a dimer of stable dimers) UCP2, in which all the monomers are functional, and monomers in each dimer are in the same transport mode. Purine nucleotide (e.g., ATP) can occlude the internal pore of the monomeric units of UCP tetramers via interacting with positive residues at or in the proximity of the matrix network (K38, K141, K239, R88, R185, and R279) and prevent switching between cytoplasmic and matrix states, thus inhibiting the proton transport. This study provides new insights into the mechanism of proton transport and regulation in UCPs.

A Biphasic Molecular Model for Proton Transport in Tetrameric Uncoupling Proteins

Itaconate inhibits TET DNA dioxygenases to dampen inflammatory responses

ABSTRACT In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1

ABSTRACT While studies of the autophagy-related (ATG) genes in knockout models have led to an explosion of knowledge about the functions of autophagy components, the exact roles of LC3 and GABARAP family proteins (human ATG8 equivalents) are still poorly understood. A major drawback in understanding their roles is that the available interactome data has largely been acquired using overexpression systems. To overcome these limitations, we employed CRISPR/Cas9-based genome-editing to generate a panel of cells in which human ATG8 genes were tagged at their natural chromosomal locations with an N-terminal affinity epitope. This cellular resource was employed to map endogenous GABARAPL2 protein complexes using interaction proteomics. This approach identified the ER-associated protein and lipid droplet (LD) biogenesis factor ACSL3 as a stabilizing GABARAPL2-binding partner. GABARAPL2 bound ACSL3 in a manner dependent on its LC3-interacting regions, whose binding site in GABARAPL2 was required to recruit the latter to the ER. Through this interaction, the UFM1-activating enzyme UBA5 became anchored at the ER. Furthermore, ACSL3 depletion and LD induction affected the abundance of several ufmylation components and ER-phagy. Together these data allow us to define ACSL3 as a novel regulator of the enigmatic UFM1 conjugation pathway. Highlighted Article: Using endogenous tagging and interaction proteomics, we identified the ER-associated lipid droplet biogenesis factor ACSL3 as a GABARAPL2-binding partner that serves as novel regulator of the enigmatic UFM1 conjugation pathway.

ACSL3 is a novel GABARAPL2 interactor that links ufmylation and lipid droplet biogenesis

USP15 deubiquitinase inactivates TET2 to suppress tumor immunity and is a potential therapeutic target of immunotherapy. TET2 DNA dioxygenase is frequently mutated in human hematopoietic malignancies and functionally inactivated in many solid tumors through a nonmutational mechanism. We recently found that TET2 mediates the interferon-JAK-STAT pathway to stimulate chemokine expression and tumor infiltration of lymphocytes (TILs). TET2 is monoubiquitylated at K1299, which promotes its activity. Here, we report that USP15 is a TET2 deubiquitinase and inhibitor. USP15 catalyzes the removal of K1299-linked monoubiquitin and negatively regulates TET2 activity. Gene expression profiling demonstrates that TET2 and USP15 oppositely regulate genes involved in multiple inflammatory pathways, and TET2 is a major target of USP15 function. Deletion of Usp15 in melanoma stimulates chemokine expression and TILs in a TET2-dependent manner, leading to increased response to immunotherapy and extended life span of tumor-bearing mice. These results reveal a previously unknown regulator of TET2 activity and suggest USP15 as a potential therapeutic target for immunotherapy of solid tumors.

USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2

Proton Transport in Mitochondrial UCP2 is Regulated by a Matrix-Oriented Salt-Bridge Network

Evolutionarily conserved DCAF1 is a major substrate receptor for the DDB1-CUL4-ROC1 E3 ubiquitin ligase (CRL4) and controls cell proliferation and development. The molecular basis for these functions is unclear. We show here that DCAF1 loss in multiple tissues and organs selectively eliminates proliferating cells and causes perinatal lethality, thymic atrophy, and bone marrow defect. Inducible DCAF1 loss eliminates proliferating, but not quiescent, T cells and MEFs. We identify the ribosome assembly factor PWP1 as a substrate of the CRL4DCAF1 ligase. DCAF1 loss results in PWP1 accumulation, impairing rRNA processing and ribosome biogenesis. Knockdown or overexpression of PWP1 can rescue defects or cause similar defects as DCAF1 loss, respectively, in ribosome biogenesis. DCAF1 loss increases free RPL11, resulting in L11-MDM2 association and p53 activation. Cumulatively, these results reveal a critical function for DCAF1 in ribosome biogenesis and define a molecular basis of DCAF1 function in cell proliferation and development.

CRL4DCAF1/VprBP E3 ubiquitin ligase controls ribosome biogenesis, cell proliferation, and development.

Stoichiometry of uncoupling proteins (UCPs) and their coexistence as functional monomeric and associated forms in lipid membranes remain intriguing open questions. In this study, tertiary and quaternary structures of UCP2 were analyzed experimentally and through molecular dynamics (MD) simulations. UCP2 was overexpressed in the inner membrane of Escherichia coli, then purified and reconstituted in lipid vesicles. Structure and proton transport function of UCP2 were characterized by circular dichroism (CD) spectroscopy and fluorescence methods. Findings suggest a tetrameric functional form for UCP2. MD simulations conclude that tetrameric UCP2 is a dimer of dimers, is more stable than its monomeric and dimeric forms, is asymmetrical and induces asymmetry in the membrane's lipid structure, and a biphasic on-off switch between the dimeric units is its possible mode of transport. MD simulations also show that the water density inside the UCP2 monomer is asymmetric, with the cytoplasmic side having a higher water density and a wider radius. In contrast, the structurally comparable adenosine 5'-diphosphate (ADP)/adenosine 5'-triphosphate (ATP) carrier (AAC1) did not form tetramers, implying that tetramerization cannot be generalized to all mitochondrial carriers.

Functional Oligomeric Forms of Uncoupling Protein 2: Strong Evidence for Asymmetry in Protein and Lipid Bilayer Systems.

Regulation of Proton Transport in Tetrameric UCP2 by an Intramolecular Salt-Bridge Network

Loss-of-function mutations in genes encoding TET DNA dioxygenase occur frequently in hematopoietic malignancy, but rarely in solid tumors which instead commonly have reduced activity. The impact of decreased TET activity in solid tumors is not known. Here we show that TET2 mediates interferon γ (IFNγ)-JAK-STAT signaling pathway to control chemokine and PD-L1 expression, lymphocyte infiltration and cancer immunity. IFNγ stimulated STAT1 to bind TET2 and recruit TET2 to hydroxymethylate chemokine and PD-L1 genes. Reduced TET activity was associated with decreased TH1-type chemokines and tumor-infiltrating lymphocytes (TILs) and the progression of human colon cancer. Deletion of Tet2 in murine melanoma and colon tumor cells reduced chemokine expression and TILs, enabling tumors to evade anti-tumor immunity and to resist anti-PD-L1 therapy. Conversely, stimulating TET activity by systematic injection of its co-factor, ascorbate/vitamin C, increased chemokine and TILs, leading to enhanced anti-tumor immunity and anti-PD-L1 efficacy and extended lifespan of tumor-bearing mice. These results suggest an IFNγ-JAK-STAT-TET signaling pathway that mediates tumor response to anti-PD-L1/PD-1 therapy and is frequently disrupted in solid tumors. Our findings also suggest TET activity as a biomarker for predicting the efficacy and patient response to anti-PD-1/PD-L1 therapy, and stimulating TET activity as an adjuvant immunotherapy of solid tumors.

Tumor suppressor TET2 promotes cancer immunity and immunotherapy efficacy.

Nckipsd Coordinates Arp2/3 and Formin Nucleation of Actin Filaments in the Cell Cortex

Abstract ER stress-mediated induction of a new vertebrate-specific autophagy cargo receptor, CCPG1 (cell-cycle progression gene 1), drives degradation of endoplasmic reticulum. CCPG1 acts via ATG8-family interaction and, non-canonically, via discrete interactions with FIP200. CCPG1 ameliorates ER stress in the exocrine pancreas. This has potential implications for inflammation and cancer, discussed here.

CCPG1, an unconventional cargo receptor for ER-phagy, maintains pancreatic acinar cell health

ABSTRACT The importance of selective macroautophagy/autophagy in cellular health is increasingly evident. The selective degradation of portions of the endoplasmic reticulum (ER), or reticulophagy, is an emerging example but requires further mechanistic detail and broad evidence of physiological relevance. In a recent study, we identified CCPG1, an ER-resident transmembrane protein that can bind to Atg8-family proteins and, independently and discretely, to RB1CC1/FIP200. Both of these interactions are required to facilitate CCPG1's function as a reticulophagy cargo receptor. CCPG1 transcripts are inducible by ER stress, providing a direct link between ER stress and reticulophagy. In vivo, CCPG1 prevents the hyper-accumulation of insoluble protein within the ER lumen of pancreatic acinar cells and alleviates ER stress. Accordingly, CCPG1 loss sensitizes the exocrine pancreas to tissue injury.

CCPG1, a cargo receptor required for reticulophagy and endoplasmic reticulum proteostasis

Structure and Dynamics of the CheY Response Regulators from Rhodobacter sphaeroides

Tail-anchored (TA) proteins are a unique class of integral membrane proteins that possess a single C-terminal transmembrane domain and target post-translationally to the specific organelles at which they function. While significant advances have been made in recent years in elucidating the mechanisms and molecular targeting signals involved in the proper sorting of TA proteins, particularly to the endoplasmic reticulum and mitochondria, relatively little is known about the targeting of TA proteins to the plastid outer envelope. Here we show that several known or predicted plastid TA outer envelope proteins (OEPs) in Arabidopsis possess a C-terminal RK/ST sequence motif that serves as a conserved element of their plastid targeting signal. Evidence for this conclusion comes primarily from experiments with OEP7.2, which is a member of the Arabidopsis 7 kDa OEP family. We confirmed that OEP7.2 is localized to the plastid outer envelope and possesses a TA topology, and its C-terminal sequence (CTS), which includes the RK/ST motif, is essential for proper targeting to plastids. The CTS of OEP7.2 is functionally interchangeable with the CTSs of other TA OEPs that possess similar RK/ST motifs, but not with those that lack the motif. Further, a bioinformatics search based on a consensus sequence led to the identification of several new OEP TA proteins. Collectively, this study provides new insight into the mechanisms of TA protein sorting in plant cells, defines a new targeting signal element for a subset of TA OEPs and expands the number and repertoire of TA proteins at the plastid outer envelope.

An RK/ST C-Terminal Motif is Required for Targeting of OEP7.2 and a Subset of Other Arabidopsis Tail-Anchored Proteins to the Plastid Outer Envelope Membrane

Uncoupling proteins (UCP1s) are members of the mitochondrial carrier superfamily (MCF) that transport protons across the inner mitochondrial membrane, thereby uncoupling respiration from ATP synthesis. The proton transport mechanism in UCPs is not fully understood. It has been suggested that members of MCF possess matrix and cytoplasmic salt-bridge networks, which could control substrate transport via alternative conformational changes. In the current study the role of the matrix-facing salt-bridge network in proton transport function of UCP2 and its molecular state in membranes were analyzed. The role of the matrix network was evaluated by introducing single and double mutations of positively-charged lysine residues (K38Q, K141Q, K239Q, and K38Q/K239Q) into UCP2. Proteins were expressed in E. coli membranes and reconstituted in phosphatidylcholine vesicles. CD spectroscopy and fluorescence methods were employed to characterize protein structure and function, respectively. Proton transport was significantly increased in single mutants compared to the wild-type protein but did not change significantly in the double mutant, suggesting a regulatory role for the matrix network. Monomeric UCP2 self-associated into a tetrameric functional form after reconstitution in lipid vesicles. This result was further supported by molecular dynamics (MD) simulations. The molecular forms of UCP2 in liposomes were also compared to those of another conformationally relevant protein, ADP/ATP carrier. In contrast to UCP2, ADP/ATP carrier did not form tetramers in lipid membranes. Overall, tetrameric forms of UCP2 transported protons in lipid membranes and this transport was regulated by the matrix salt-bridge network.

The role of matrix-oriented salt-bridge on the proton transport in a multimeric uncoupling protein 2

Biological‐mediated conversion of pretreated lignocellulosic biomass to biofuels and biochemicals is a promising avenue toward energy sustainability. However, a critical impediment to the commercialization of cellulosic biofuel production is the high cost of cellulase enzymes needed to deconstruct biomass into fermentable sugars. One major factor driving cost is cellulase adsorption and inactivation in the presence of lignin, yet we currently have a poor understanding of the protein structure–function relationships driving this adsorption. In this work, we have systematically investigated the role of protein surface potential on lignin adsorption using a model monomeric fluorescent protein. We have designed and experimentally characterized 16 model protein variants spanning the physiological range of net charge (−24 to +16 total charges) and total charge density (0.28–0.40 charges per sequence length) typical for natural proteins. Protein designs were expressed, purified, and subjected to in silico and in vitro biophysical measurements to evaluate the relationship between protein surface potential and lignin adsorption properties. The designs were comparable to model fluorescent protein in terms of thermostability and heterologous expression yield, although the majority of the designs unexpectedly formed homodimers. Protein adsorption to lignin was studied at two different temperatures using Quartz Crystal Microbalance with Dissipation Monitoring and a subtractive mass balance assay. We found a weak correlation between protein net charge and protein‐binding capacity to lignin. No other single characteristic, including apparent melting temperature and 2nd virial coefficient, showed correlation with lignin binding. Analysis of an unrelated cellulase dataset with mutations localized to a family I carbohydrate‐binding module showed a similar correlation between net charge and lignin binding capacity. Overall, our study provides strategies to identify highly active, low lignin‐binding cellulases by either rational design or by computational screening genomic databases. Biotechnol. Bioeng. 2017;114: 740–750. © 2016 Wiley Periodicals, Inc.

Insights into cellulase‐lignin non‐specific binding revealed by computational redesign of the surface of green fluorescent protein

The endoplasmic reticulum (ER) is a key site for lipid biosynthesis and folding of nascent transmembrane and secretory proteins. These processes are maintained by careful homeostatic control of the environment within the ER lumen. Signalling sensors within the ER detect perturbations within the lumen (ER stress) and employ downstream signalling cascades that engage effector mechanisms to restore homeostasis. The most studied signalling mechanism that the ER employs is the unfolded protein response (UPR), which is known to increase a number of effector mechanisms, including autophagy. In this chapter, we will discuss the emerging role of autophagy as a UPR effector pathway. We will focus on the recently discovered selective autophagy pathway for ER, ER-phagy, with particular emphasis on the structure and function of known mammalian ER-phagy receptors, namely FAM134B, SEC62, RTN3 and CCPG1. Finally, we conclude with our view of where the future of this field can lead our understanding of the involvement of ER-phagy in ER homeostasis.

CCPG1 Is a Non-canonical Autophagy Cargo Receptor Essential for ER-Phagy and Pancreatic ER Proteostasis

WDTC1/Adp encodes an evolutionarily conserved suppressor of lipid accumulation. While reduced WDTC1 expression is associated with obesity in mice and humans, its cellular function is unknown. Here, we demonstrate that WDTC1 is a component of a DDB1‐CUL4‐ROC1 (CRL4) E3 ligase. Using 3T3‐L1 cell culture model of adipogenesis, we show that disrupting the interaction between WDTC1 and DDB1 leads to a loss of adipogenic suppression by WDTC1, increased triglyceride accumulation and adipogenic gene expression. We show that the CRL4WDTC1 complex promotes histone H2AK119 monoubiquitylation, thus suggesting a role for this complex in transcriptional repression during adipogenesis. Our results identify a biochemical role for WDTC1 and extend the functional range of the CRL4 complex to the suppression of fat accumulation.

The antiobesity factor WDTC1 suppresses adipogenesis via the CRL4WDTC1 E3 ligase

Uncoupling Proteins of the Central Nervous System:Comparative Biophysical Studies

Intracameral Delivery of Gene Therapy Vector scAAV2.MMP1 Results in Negligible to None Systemic Presence of Viral Genomes in a Large Animal Model.

WDTC1/Adp encodes an evolutionarily conserved suppressor of lipid accumulation. While reduced WDTC1 expression is associated with obesity in mice and humans, its cellular function is unknown. Here, we demonstrate that WDTC1 is a component of a DDB1-CUL4-ROC1 (CRL4) E3 ligase. Using 3T3-L1 cell culture model of adipogenesis, we show that disrupting the interaction between WDTC1 and DDB1 leads to a loss of adipogenic suppression by WDTC1, increased triglyceride accumulation and adipogenic gene expression. We show that the CRL4 complex promotes histone H2AK119 monoubiquitylation, thus suggesting a role for this complex in transcriptional repression during adipogenesis. Our results identify a biochemical role for WDTC1 and extend the functional range of the CRL4 complex to the suppression of fat accumulation.

The antiobesity factor WDTC 1 suppresses adipogenesis via the CRL 4 WDTC 1 E 3 ligase

Hypertension-associated C825T polymorphism impairs the function of Gβ3 to target GRK2 ubiquitination

Residing at the inner mitochondrial membrane, uncoupling protein-2 (UCP2) mediates proton transport from the intermembrane space (IMS) to the mitochondrial matrix and consequently reduces the rate of ATP synthesis in the mitochondria. The ubiquitous expression of UCP2 in humans can be attributed to the protein's multiple physiological roles in tissues, including its involvement in protective mechanisms against oxidative stress, as well as glucose and lipid metabolisms. Currently, the structural properties and ion transport mechanism of UCP2 and other UCP homologues remain poorly understood. UCP2-mediated proton transport is activated by fatty acids and inhibited by di- and triphosphate purine nucleotides. UCP2 also transports chloride and some other small anions. Identification of key amino acid residues of UCP2 in its ion transport pathway can shed light on the protein's ion transport function. On the basis of our previous studies, the second transmembrane helix segment (TM2) of UCP2 exhibited chloride channel activity. In addition, it was suggested that the positively charged residues on TM2 domains of UCPs 1 and 2 were important for their chloride transport activity. On this basis, to further understand the role of these positively charged residues on the ion transport activity of UCP2, we recombinantly expressed four TM2 mutants: R76Q, R88Q, R96Q, and K104Q. The wild type UCP2 and its mutants were purified and reconstituted into liposomes, and their conformation and ion (proton and chloride) transport activity were studied. TM2 Arg residues at the matrix interface of UCP2 proved to be crucial for the protein's anion transport function, and their absence resulted in highly diminished Cl(-) transport rates. On the other hand, the two other positively charged residues of TM2, located at the UCP2-IMS interface, could participate in the salt-bridge formation in the protein and promote the interhelical tight packing in the UCP2. Absence of these residues did not influence Cl(-) transport rates, but disturbed the dense packing in UCP2 and resulted in higher UCP2-mediated proton transport rates in the presence of long chain fatty acids. Overall, the outcome of this study provides a deeper and more detailed molecular image of UCP2's ion transport mechanism.

Role of positively charged residues of the second transmembrane domain in the ion transport activity and conformation of human uncoupling protein-2.

A Non-Canonical Function of Gβ as a Subunit of E3 Ligase in Targeting GRK2 Ubiquitylation.

Chloroplasts can be isolated from higher plants directly following homogenization; however, the resulting yield, purity, and intactness are often low, necessitating a large amount of starting material. This protocol is optimized to produce a high yield of pure chloroplasts from isolated Arabidopsis protoplasts. The two-part method is a simple, scaled-down, and low-cost procedure that readily provides healthy mesophyll protoplasts, which are then ruptured to release intact chloroplasts. Chloroplasts isolated using this method are competent for use in biochemical, cellular, and molecular analyses.

Molecular Physiology of Uncoupling Proteins in the Central Nervous System: Self-Association and Proton Transport

Uncoupling proteins (UCP)2, UCP4 and UCP5 transport protons across the inner membrane of mitochondria in the central nervous system (CNS). Novel recombinant protein expression allowed expression of UCPs in Escherichia coli membranes. Functional neuronal UCPs formed multimers in membranes and interacted with various fatty acids (FAs) to transport protons. Self-association and unique ion transport properties of UCPs distinguish their physiological roles in the CNS.

A biophysical study on molecular physiology of the uncoupling proteins of the central nervous system

BRCA1 mutation carriers are predisposed to developing basal-like breast cancers with high metastasis and poor prognosis. However, the mechanism underlying the function of BRCA1 in suppressing basal-like breast cancer remains unclear. We previously reported that deletion of p18Ink4c (p18), an inhibitor of CDK4 and CDK6, functionally inactivates the RB pathway, stimulates mammary luminal stem cell proliferation, and leads to spontaneous luminal tumor development whereas germline mutation of Brca1 alters the fate of luminal cells and causes luminal-to-basal mammary tumor transformation. We report here that disruption of Brca1 by both germline and epithelium-specific mutation of Brca1 in p18 deficient mice activates epithelial-to-mesenchymal transition (EMT) and induces basal-like breast tumors. Introduction of BRCA1 suppresses expression of EMT-inducing transcription factors (EMT-TFs) and inhibits EMT in mammary tumor cells. Knockdown of BRCA1 in human luminal cancer cells activates EMT and increases tumor formation potential. Consistently, EMT features are inversely correlated with BRCA1 in human breast cancers. These findings provide genetic evidence suggesting that BRCA1 suppresses EMT and inhibits basal-like tumor development. Citation Format: Xin-Hai Pei, Feng Bai, Ho Lam Chan, Alexandria Scott, Matthew D Smith, Cheng Fan, Jason I Herschkowitz, Charles M Perou, Alan S Livingstone, David J Robbins, Anthony J Capobianco. Genetic analysis of the role of Brca1 in suppression of basal-like breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-05-01.

Abstract P4-05-01: Genetic analysis of the role of Brca1 in suppression of basal-like breast cancer

development stem cell dedifferentiation during mammary and tumor BRCA 1 suppresses epithelial-to-mesenchymal transition and Updated

BRCA1 mutation carriers are predisposed to developing basal-like breast cancers with high metastasis and poor prognosis. Yet, how BRCA1 suppresses formation of basal-like breast cancers is still obscure. Deletion of p18(Ink4c) (p18), an inhibitor of CDK4 and CDK6, functionally inactivates the RB pathway, stimulates mammary luminal stem cell (LSC) proliferation, and leads to spontaneous luminal tumor development. Alternately, germline mutation of Brca1 shifts the fate of luminal cells to cause luminal-to-basal mammary tumor transformation. Here, we report that disrupting Brca1 by either germline or epithelium-specific mutation in p18-deficient mice activates epithelial-to-mesenchymal transition (EMT) and induces dedifferentiation of LSCs, which associate closely with expansion of basal and cancer stem cells and formation of basal-like tumors. Mechanistically, BRCA1 bound to the TWIST promoter, suppressing its activity and inhibiting EMT in mammary tumor cells. In human luminal cancer cells, BRCA1 silencing was sufficient to activate TWIST and EMT and increase tumor formation. In parallel, TWIST expression and EMT features correlated inversely with BRCA1 expression in human breast cancers. Together, our findings showed that BRCA1 suppressed TWIST and EMT, inhibited LSC dedifferentiation, and repressed expansion of basal stem cells and basal-like tumors. Thus, our work offers the first genetic evidence that Brca1 directly suppresses EMT and LSC dedifferentiation during breast tumorigenesis.

BRCA1 suppresses epithelial-to-mesenchymal transition and stem cell dedifferentiation during mammary and tumor development.

Post-translational import of nucleus-encoded chloroplast pre-proteins is critical for chloroplast biogenesis, and the Toc159 family of proteins serve as receptors for the process. Toc159 shares with other members of the family (e.g. Toc132), homologous GTPase (G−) and Membrane (M−) domains, but a highly dissimilar N-terminal acidic (A−) domain. Although there is good evidence that atToc159 and atToc132 from Arabidopsis mediate the initial sorting step, preferentially recognizing photosynthetic and non-photosynthetic preproteins, respectively, relatively few chloroplast preproteins have been assigned as substrates for particular members of the Toc159 family, which has limited the proof for the hypothesis. The current study expands the number of known preprotein substrates for members of the Arabidopsis Toc159 receptor family using a split-ubiquitin membrane-based yeast two-hybrid system using the atToc159 G-domain (Toc159G), atToc132 G-domain (Toc132G) and atToc132 A- plus G-domains (Toc132AG) as baits. cDNA library screening with all three baits followed by pairwise interaction assays involving the 81 chloroplast preproteins identified show that although G-domains of the Toc159 family are sufficient for preprotein recognition, they alone do not confer specificity for preprotein subclasses. The presence of the A-domain fused to atToc132G (Toc132AG) not only positively influences its specificity for non-photosynthetic preproteins, but also negatively regulates the ability of this receptor to interact with a subset of photosynthetic preproteins. Our study not only substantiates the fact that atToc132 can serve as a receptor by directly binding to chloroplast preproteins but also proposes the existence of subsets of preproteins with different but overlapping affinities for more than one member of the Toc159 receptor family.

A Split-Ubiquitin Yeast Two-Hybrid Screen to Examine the Substrate Specificity of atToc159 and atToc132, Two Arabidopsis Chloroplast Preprotein Import Receptors

Most nucleus-encoded chloroplast proteins rely on an N-terminal transit peptide (TP) as a post-translational sorting signal for directing them to the organelle. Although Toc159 is known to be a receptor for specific preprotein TPs at the chloroplast surface, the mechanism for its own targeting and integration into the chloroplast outer membrane is not completely understood. In a previous study, we identified a novel TP-like sorting signal at the C-terminus (CT) of a Toc159 homolog from the single-cell C4 species, Bienertia sinuspersici. In the current study, we have extended our understanding of the sorting signal using transient expression of fluorescently-tagged fusion proteins of variable-length, and with truncated and swapped versions of the CT. As was shown in the earlier study, the 56 residues of the CT contain crucial sorting information for reversible interaction of the receptor with the chloroplast envelope. Extension of this region to 100 residues in the current study stabilized the interaction via membrane integration, as demonstrated by more prominent plastid-associated signals and resistance of the fusion protein to alkaline extraction. Despite a high degree of sequence similarity, the plastid localization signals of the equivalent CT regions of Arabidopsis thaliana Toc159 homologs were not as strong as that of the B. sinuspersici counterparts. Together with computational and circular dichroism analyses of the CT domain structures, our data provide insights into the critical elements of the CT for the efficient targeting and anchorage of Toc159 receptors to the dimorphic chloroplasts in the single-cell C4 species.

The C-terminus of Bienertia sinuspersici Toc159 contains essential elements for its targeting and anchorage to the chloroplast outer membrane

Folding and self-association of atTic20 in lipid membranes: implications for understanding protein transport across the inner envelope membrane of chloroplasts

The translocon at the outer envelope membrane of chloroplasts (Toc) mediates the recognition and initial import into the organelle of thousands of nucleus-encoded proteins. These proteins are translated in the cytosol as precursor proteins with cleavable amino-terminal targeting sequences called transit peptides. The majority of the known Toc components that mediate chloroplast protein import were originally identified in pea, and more recently have been studied most extensively in Arabidopsis. With the completion of the tomato genome sequencing project, it is now possible to identify putative homologues of the chloroplast import components in tomato. In the work reported here, the Toc GTPase cDNAs from tomato were identified, cloned and analyzed. The analysis revealed that there are four Toc159 homologues (slToc159-1, -2, -3 and -4) and two Toc34 homologues (slToc34-1 and -2) in tomato, and it was shown that tomato Toc159 and Toc34 homologues share high sequence similarity with the comparable import apparatus components from Arabidopsis and pea. Thus, tomato is a valid model for further study of this system. The expression level of Toc complex components was also investigated in different tissues during tomato development. The two tomato Toc34 homologues are expressed at higher levels in non-photosynthetic tissues, whereas, the expression of two tomato Toc159 homologues, slToc159-1 and slToc159-4, were higher in photosynthetic tissues, and the expression patterns of slToc159-2 was not significantly different in photosynthetic and non-photosynthetic tissues, and slToc159-3 expression was limited to a few select tissues.

Molecular Characterization and Expression Analysis of Chloroplast Protein Import Components in Tomato (Solanum lycopersicum)

The translocon at the outer envelope membrane of chloroplasts (TOC) initiates the import of thousands of nuclear encoded preproteins required for chloroplast biogenesis and function. The multimeric TOC complex contains two GTP-regulated receptors, Toc34 and Toc159, which recognize the transit peptides of preproteins and initiate protein import through a β–barrel membrane channel, Toc75. Different isoforms of Toc34 and Toc159 assemble with Toc75 to form structurally and functionally diverse translocons, and the composition and levels of TOC translocons is required for the import of specific subsets of coordinately expressed proteins during plant growth and development. Consequently, the proper assembly of the TOC complexes is key to ensuring organelle homeostasis. This review will focus on our current knowledge of the targeting and assembly of TOC components to form functional translocons at the outer membrane. Our analyses reveal that the targeting of TOC components involves elements common to the targeting of other outer membrane proteins, but also include unique features that appear to have evolved to specifically facilitate assembly of the import apparatus.

Targeting and assembly of components of the TOC protein import complex at the chloroplast outer envelope membrane

ABSTRACT Pituitary tumors develop in about one-quarter of the population, and most arise from the anterior lobe (AL). The pituitary gland is particularly sensitive to genetic alteration of genes involved in the cyclin-dependent kinase (CDK) inhibitor (CKI)–CDK-retinoblastoma protein (Rb) pathway. Mice heterozygous for the Rb mutation develop pituitary tumors, with about 20% arising from the AL. Perplexingly, none of the CKI-deficient mice reported thus far develop pituitary AL tumors. In this study, we show that deletion of p19Ink4d (p19), a CKI gene, in mice results in spontaneous development of tumors in multiple organs and tissues. Specifically, more than one-half of the mutant mice developed pituitary hyperplasia or tumors predominantly in the AL. Tumor development is associated with increased cell proliferation and enhanced activity of Cdk4 and Cdk6 and phosphorylation of Rb protein. Though Cdk4 is indispensable for postnatal pituitary cell proliferation, it is not required for the hyperproliferative pituitary phenotype caused by p19 loss. Loss of p19 phosphorylates Rb in Cdk4−/− pituitary AL cells and mouse embryonic fibroblasts (MEFs) and rescues their proliferation defects, at least partially, through the activation of Cdk6. These results provide the first genetic evidence that p19 is a tumor suppressor and the major CKI gene that controls pituitary AL cell proliferation.

p19Ink4d Is a Tumor Suppressor and Controls Pituitary Anterior Lobe Cell Proliferation

Folding and Association of Human Uncoupling Protein-1 in Biological Membranes: Evidence for Multimeric Functional Forms

Microbially produced alkanes are a new class of biofuels that closely match the chemical composition of petroleum-based fuels. Alkanes can be generated from the fatty acid biosynthetic pathway by the reduction of acyl-ACPs followed by decarbonylation of the resulting aldehydes. A current limitation of this pathway is the restricted product profile, which consists of n-alkanes of 13, 15, and 17 carbons in length. To expand the product profile, we incorporated a new part, FabH2 from Bacillus subtilis , an enzyme known to have a broader specificity profile for fatty acid initiation than the native FabH of Escherichia coli . When provided with the appropriate substrate, the addition of FabH2 resulted in an altered alkane product profile in which significant levels of n-alkanes of 14 and 16 carbons in length are produced. The production of even chain length alkanes represents initial steps toward the expansion of this recently discovered microbial alkane production pathway to synthesize complex fuels. This work was conceived and performed as part of the 2011 University of Washington international Genetically Engineered Machines (iGEM) project.

Expanding the product profile of a microbial alkane biosynthetic pathway.

Intermolecular single-stranded DNA (ssDNA) ligation is important for various biotechnical applications, such as Ligation-Mediated PCR (LMPCR), and cDNA library construction, each of which requires a fixed sequence DNA oligonucleotide to ligate to an unknown 3’-end of a cDNA. Current ssDNA ligation protocols use Circligase I or T4 RNA ligase and suffer from slow kinetics, poor yield and severe nucleotide preference. Identification and remediation of nucleotide bias in ssDNA ligation is crucial because such bias can fail to quantitatively capture the original information stored in the DNA sample. Indeed, nucleotide preference in nucleic acid ligations can potentially lead to misinterpretation of gene expression levels.

Keywords/Field of Invention: DNA Recombinant Techniques and Nucleic Acids, Hybridization, Nucleotide preference Inventors:

evidently increased, suggesting the acidification between the membranesurface space. Additionally, the degree of the acidification was proportional to the concentration of uncaged ATP ranging from 0.2 mM to 0.7 mM. These results suggest that we successfully detected the proton pumping activity sensitively and quantitatively. As many kinds of Caged compounds and ion sensitive fluorescent dyes are commercially available, this technique can be applied to other ion pumps and transporters.

Ran GTPase-Independent and Stereochemical Control of Kinesin-1 and Mitochondrial Motility by Domains of Ran-Binding Protein-2

Tissue plasminogen activator, a serine protease encoded by the PLAT gene is present in the trabecular meshwork (TM) and other ocular tissues and has been reported to be downregulated by treatment with steroids in vitro. Steroids are known to cause changes in outflow facility of aqueous humor in many species. In the present study, we tested whether overexpression of PLAT can prevent and/or reverse the outflow facility of mouse eyes treated with steroids. Animals received bilateral injection with 20 µl of triamcinolone acetonide (TA) (40mg/ml) suspension subconjunctivally to induce outflow facility changes. Some animals received unilateral intracameral injection with 2 µl of adenoviral suspension [3-4x1012 virus genomes per milliliter (vg/ml)] carrying sheep PLAT cDNA (AdPLAT) either concurrently with TA injection or one week after TA injection, whereas others received bilateral intracameral injection with 2µl of adenoviral suspension (9x1012 vg/ml) carrying no transgene (AdNull) concurrently with TA injection. Animals were sacrificed one week after AdPLAT or AdNull treatment. Endogenous mRNA expression levels of mouse PAI-1 and MMP-2, -9 and -13 were also measured using qRT-PCR. Outflow facility one week after AdPLAT administration was increased by 60% and 63% respectively for animals that had not or had been pretreated with steroids. Overexpression of PLAT significantly upregulated expression of PAI-1, MMP-2, -9 and -13 compared to the levels found in TA only treated eyes. These findings suggest that overexpression of PLAT in TM of mouse eyes can both prevent and reverse the decrease in outflow facility caused by steroid treatment and is associated with upregulation of MMPs.

Tissue Plasminogen Activator in Trabecular Meshwork Attenuates Steroid Induced Outflow Resistance in Mice

Biophysical Characterization and Conformational Analysis of the GTPase Domain of Pre-Protein Import Receptors atToc33G and psToc34G

FUNCTIONAL ( UCP 1 ) in Lipid Membranes : EVIDENCE Activity of Human Uncoupling Protein-1 Expression , Folding , and Proton Transport Molecular Biophysics

Understanding the Structure, Charge, and Properties of Templated Vanadium Oxysalts

Background: UCP1 transports protons across the inner mitochondrial membrane and generates heat. Results: Oligomeric forms of UCP1 transported protons across phospholipid bilayers and the conformation and proton transport activity were affected by cardiolipin. Conclusion: UCP1 is functional in its monomeric and associated forms in membranes. Significance: Existence of functional associated forms of UCP1 provides insights into the mechanism of action of UCPs in mitochondria. Uncoupling protein-1 (UCP1) is abundantly expressed in the mitochondrial inner membrane of brown adipose tissues and has an important role in heat generation, mediated by its proton transport function. The structure and function of UCP1 are not fully understood, partially due to the difficulty in obtaining native-like folded proteins in vitro. In this study, using the auto-induction method, we have successfully expressed UCP1 in Escherichia coli membranes in high yield. Overexpressed UCP1 in bacterial membranes was extracted using mild detergents and reconstituted into phospholipid bilayers for biochemical studies. UCP1 was folded in octyl glucoside, as indicated by its high helical content and binding to ATP, a known UCP1 proton transport inhibitor. Reconstituted UCP1 in phospholipid vesicles also exhibited highly helical structures and proton transport that is activated by fatty acids and inhibited by purine nucleotides. Self-associated functional forms of UCP1 in lipid membranes were observed for the first time. The self-assembly of UCP1 into tetramers was unambiguously characterized by circular dichroism and fluorescence spectroscopy, analytical ultracentrifugation, and semi-native gel electrophoresis. In addition, the mitochondrial lipid cardiolipin stabilized the structure of associated UCP1 and enhanced the proton transport activity of the protein. The existence of the functional oligomeric states of UCP1 in the lipid membranes has important implications for understanding the structure and proton transport mechanism of this protein in brown adipose tissues as well as structure-function relationships of other mammalian UCPs in other tissues.

Expression, Folding, and Proton Transport Activity of Human Uncoupling Protein-1 (UCP1) in Lipid Membranes

On the Role of Positively Charged Residues of TM2 Domain in the Chloride Transport of Human UCP2

Effect of Tissue Plasminogen Activator on Outflow Facility of Steroid Injected Mouse Eyes

1134-Pos Board B26 Biophysical Characterization and Conformational Analysis of the GTPase Domain of Pre-Protein Import Receptors atToc33G and psToc34G Geetika Patel, Matthew D. Smith, Arthur G. Szabo. Wilfrid Laurier University, Waterloo, ON, Canada. atToc33 and psToc34 are GTPases-, that act as receptors for pre-protein import in the chloroplast outer envelope. Various lines of evidence suggest that the GTPase domain of atToc33 (atToc33G) dimerizes, including native PAGE studies (Weibel et al., 2003), gel-filtration experiments (Yeh et al., 2007) and filter binding assays (Koenig et al., 2008). The crystal structure of atToc33 shows that it is a monomer (Koenig et al., 2008) while psToc34 crystallizes as a dimer (Sun et al., 2002). The R130A atToc33 mutant apparently leads to monomer formation in vitro (Reddick et al., 2007; Weibel et al., 2003). Both-, atToc33-wt and atToc33-R130A bind GTP and GDP with high affinity and hydrolyse GTP with similar efficiencies (Weibel et al., 2003). To further investigate the conformations of these GTPases, and to characterize their optical spectroscopic properties, we first, expressed atToc33G and its R130A mutant in high yield. Initial characterization of these proteins by CD spectroscopy revealed significant a-helical content in their secondary structure.We also examined the effect of an increase in protein concentration of atToc33G and its R130Amutant using CD and fluorescence spectroscopy. CD spectral line shape does not change with increasing protein concentrations indicating that no or only small conformational changes occurs as the concentration increases. Fluorescence spectra for both proteins are superimposable with an intensity maximum at ~320nm. The addition of GDP to both the proteins leads to reduction of intensity. No wavelength shift in emission spectrum was observed. Our spectroscopic results and anisotropy experiments show that both atToc33G and atToc33G R130A are monomeric, irrespective of the protein concentration and also in presence of GDP or GTP. Experiments to compare atToc33G and atToc33G R130A with their corresponding homologues from Pisumsativum are also presented.

ATP Hydrolysis at One Site Drives the Dissociation of ATP-Binding Cassette Nucleotide-Binding Domains

Planarian flatworms are able to both regenerate their whole bodies and continuously adapt their size to nutrient status. Tight control of stem cell proliferation and differentiation during these processes is the key feature of planarian biology. Here we show that the planarian homolog of the phosphoinositide 3-kinase-related kinase (PIKK) family member SMG-1 and mTOR complex 1 components are required for this tight control. Loss of smg-1 results in a hyper-responsiveness to injury and growth and the formation of regenerative blastemas that remain undifferentiated and that lead to lethal ectopic outgrowths. Invasive stem cell hyper-proliferation, hyperplasia, hypertrophy, and differentiation defects are hallmarks of this uncontrolled growth. These data imply a previously unappreciated and novel physiological function for this PIKK family member. In contrast we found that planarian members of the mTOR complex 1, tor and raptor, are required for the initial response to injury and blastema formation. Double smg-1 RNAi experiments with tor or raptor show that abnormal growth requires mTOR signalling. We also found that the macrolide rapamycin, a natural compound inhibitor of mTORC1, is able to increase the survival rate of smg-1 RNAi animals by decreasing cell proliferation. Our findings support a model where Smg-1 acts as a novel regulator of both the response to injury and growth control mechanisms. Our data suggest the possibility that this may be by suppressing mTOR signalling. Characterisation of both the planarian mTORC1 signalling components and another PIKK family member as key regulators of regeneration and growth will influence future work on regeneration, growth control, and the development of anti-cancer therapies that target mTOR signalling.

SMG-1 and mTORC1 Act Antagonistically to Regulate Response to Injury and Growth in Planarians

Exploring the Biophysical Properties of Human Uncoupling Proteins: A Search for their Physiological Roles in the Central Nervous System

Their structural characterization by circular dichroism and ﬂuorescence emis- sion revealed a structure entirely analogous to that of SP-B puriﬁed in organic solvents. However, detergent-puriﬁed SP-B showed a much more oligomeric structure, as analyzed by blue-native electrophoresis, analytical centrifugation or electron microscopy. This SP-B complex has been reconstituted into surfac- tant phospholipids and the resulting lipid/protein complexes showed in the cap-tive bubble surfactometer (CBS) a similar surface active behaviour than provided by SP-B puriﬁed using the classic chloroform/methanol-based method. 3176-Pos Board Structural Flexibility of Cytoplasmic III Secretion Protein FlhB is Important for the Function of the Protein Bacterial ﬂagellum is a large complex organelle made up of more than 30 dif- ferent proteins. Most of the ﬂagellar proteins are localized outside of the cell and are exported across the cytoplasmic membrane by the ﬂagellar type III se- cretion system. The protein export is highly regulated. Membrane protein FlhB plays a key role in this regulation. The protein consists of two domains: a hy- drophobic N-terminal part (FlhB TM ), which is predicted to have four trans-membrane helices, and a C-terminal cytoplasmic domain (FlhB C ). Homologues of FlhB were found in all bacterial type III secretion systems. Sequences of these proteins are highly conserved suggesting that their function is also similar. In this study we have compared properties of FlhB from two organisms: Salmo- nella typhimurium and Aquifex aeolicus . Salmonella and Aquifex FlhB share 32% sequence identity. However, these proteins are evolutionarily very distant. Comparison of the two proteins may provide us with additional information about functionally important regions of FlhB. We have substituted ﬂhB gene in Salmonella by ﬂhB of A. aeolicus or by chi-mera gene encoding hybrid FlhB composed of the FlhB TM of S. typhimurium and FlhB C of A. aeolicus . Then we analyzed motility of the mutants on soft agar plates. Although all mutants showed some motility, they were substan- tially less motile than wild-type cells. We have found several spontaneous mutations in C-terminal part of FlhB that resulted in enhanced motility. To understand the effect of the mutations we have solved FlhB C structures from both organisms: Salmonella and Aquifex . We have also determined secondary structure and stability of the mutated FlhB C . Based on our ﬁndings we suggest that conformational ﬂexibility is important for FlhB function. in brown adipose tissues (BAT), uncoupling protein-1 (UCP1) facil- itates proton transport across the inner mitochondrial membrane, reducing the membrane potential and rate of ATP synthesis. The excessive proton ﬂux car- ried by UCP1 produces heat in BAT. Three other UCP homologues (UCP2, UCP4 and UCP5) are expressed in the central nervous system (CNS), but their physiological functions are not well understood. The goal of this study is to ex-plore the biophysical properties of neuronal UCPs reconstituted in liposomes to gain an insight into the speciﬁc roles of these proteins in the CNS. The three

Neuronal uncoupling proteins (UCP2, UCP4, and UCP5) have crucial roles in the function and protection of the central nervous system (CNS). Extensive biochemical studies of UCP2 have provided ample evidence of its participation in proton and anion transport. To date, functional studies of UCP4 and UCP5 are scarce. In this study, we show for the first time that, despite a low level of amino acid sequence identity with the previously characterized UCPs (UCP1-UCP3), UCP4 and UCP5 share their functional properties. Recombinantly expressed in Escherichia coli, UCP2, UCP4, and UCP5 were isolated and reconstituted into liposome systems, where their conformations and ion (proton and chloride) transport properties were examined. All three neuronal UCPs are able to transport protons across lipid membranes with characteristics similar to those of the archetypal protein UCP1, which is activated by fatty acids and inhibited by purine nucleotides. Neuronal UCPs also exhibit transmembrane chloride transport activity. Circular dichroism spectroscopy shows that these three transporters exist in different conformations. In addition, their structures and functions are differentially modulated by the mitochondrial lipid cardiolipin. In total, this study supports the existence of general conformational and ion transport features in neuronal UCPs. On the other hand, it also emphasizes the subtle structural and functional differences between UCPs that could distinguish their physiological roles. Differentiation between structure-function relationships of neuronal UCPs is essential for understanding their physiological functions in the CNS.

Toward understanding the mechanism of ion transport activity of neuronal uncoupling proteins UCP2, UCP4, and UCP5.

Copper-free click chemistry was employed to derivatize membrane bilayers. This approach uses an azido-lipid conjugate presented on liposomes, which can be labeled in bioorthogonal fashion via cyclooctyne-tagged reagents. An immobilization-based approach using streptavidin-coated microplates was exploited to evaluate membrane derivatization.

Membrane labeling and immobilization via copper-free click chemistry.

Past anthrax attacks in the United States have highlighted the need for improved measures against bioweapons. The virulence of anthrax stems from the shielding properties of the Bacillus anthracis poly-γ-d-glutamic acid capsule. In the presence of excess CapD, a B. anthracis γ-glutamyl transpeptidase, the protective capsule is degraded, and the immune system can successfully combat infection. Although CapD shows promise as a next generation protein therapeutic against anthrax, improvements in production, stability, and therapeutic formulation are needed. In this study, we addressed several of these problems through computational protein engineering techniques. We show that circular permutation of CapD improved production properties and dramatically increased kinetic thermostability. At 45 °C, CapD was completely inactive after 5 min, but circularly permuted CapD remained almost entirely active after 30 min. In addition, we identify an amino acid substitution that dramatically decreased transpeptidation activity but not hydrolysis. Subsequently, we show that this mutant had a diminished capsule degradation activity, suggesting that CapD catalyzes capsule degradation through a transpeptidation reaction with endogenous amino acids and peptides in serum rather than hydrolysis.

Improvement of a Potential Anthrax Therapeutic by Computational Protein Design*

Characterization of protein-membrane binding interactions via a microplate assay employing whole liposome immobilization.

SUMMARY Acute ammonia toxicity in vertebrates is thought to be characterized by a cascade of deleterious events resembling those associated with anoxic/ischemic injury in the central nervous system. A key event is the over-stimulation of neuronal N-methyl-D-aspartate (NMDA) receptors, which leads to excitotoxic cell death. The similarity between the responses to acute ammonia toxicity and anoxia suggests that anoxia-tolerant animals such as the goldfish (Carassius auratus Linnaeus) may also be ammonia tolerant. To test this hypothesis, the responses of goldfish were compared with those of the anoxia-sensitive rainbow trout (Oncorhynchus mykiss Walbaum) during exposure to high external ammonia (HEA). Acute toxicity tests revealed that goldfish are ammonia tolerant, with 96 h median lethal concentration (LC50) values of 199 μmol l–1 and 4132 μmol l–1 for NH3 and total ammonia ([TAmm]=[NH3]+[NH4+]), respectively. These values were ∼5–6 times greater than corresponding NH3 and TAmm LC50 values measured in rainbow trout. Further, the goldfish readily coped with chronic exposure to NH4Cl (3–5 mmol l–1) for 5 days, despite 6-fold increases in plasma [T] to ∼1300 μmol l–1 and 3-fold increases in brain [TAmm] to 6700 μmol l–1. Muscle [TAmm] increased by almost 8-fold from ∼900 μmol kg–1 wet mass (WM) to greater than 7000 μmol kg–1 WM by 48 h, and stabilized. Although urea excretion rates (JUrea) increased by 2–3-fold during HEA, the increases were insufficient to offset the inhibition of ammonia excretion that occurred, and increases in urea were not observed in the brain or muscle. There was a marked increase in brain glutamine concentration at HEA, from ∼3000 μmol kg–1 WM to 15,000 μmol kg–1 WM after 48 h, which is consistent with the hypothesis that glutamine production is associated with ammonia detoxification. Injection of the NMDA receptor antagonists MK801 (0.5–8 mg kg–1) or ethanol (1–8 mg kg–1) increased trout survival time by 1.5–2.0-fold during exposure to 2 mmol l–1 ammonia, suggesting that excitotoxic cell death contributes to ammonia toxicity in this species. In contrast, similar doses of MK801 or ethanol had no effect on ammonia-challenged (8–9.5 mmol l–1 TAmm) goldfish survival times, suggesting that greater resistance to excitotoxic cell death contributes to the high ammonia-tolerance of the goldfish. Whole-cell recordings measured in isolated brain slices of goldfish telencephalon during in vitro exposure to 5 mmol l–1 or 10 mmol l–1 TAmm reversibly potentiated NMDA receptor currents. This observation suggested that goldfish neurons may not be completely resistant to ammonia-induced excitotoxicity. Subsequent western blot and densitometric analyses revealed that NMDA receptor NR1 subunit abundance was 40–60% lower in goldfish exposed to 3–5 mmol l–1 TAmm for 5 days, which was followed by a restoration of NR1 subunit abundance after 3 days recovery in ammonia-free water. We conclude that the goldfish brain may be protected from excitotoxicity by downregulating the abundance of functional NMDA receptors during periods when it experiences increased internal ammonia.

The relationship between NMDA receptor function and the high ammonia tolerance of anoxia-tolerant goldfish

A wide range of cell stresses, including DNA damage, signal to p53 through posttranslational modification of p53. The cytoplasmic functions of p53 are emerging as an important constituent of role of p53 in tumor suppression. Here, we report that deletion of the Cul9 (formerly Parc) gene, which encodes an E3 ubiquitin ligase that binds to p53 and localizes in the cytoplasm, resulted in spontaneous tumor development, accelerated Eμ-Myc-induced lymphomagenesis, and rendered mice susceptible to carcinogenesis. Cul9-p53 double-mutant mice exhibited indistinguishable tumor phenotypes as p53 single-mutant mice, indicating that the function of Cul9 in tumor suppression is largely mediated by p53. Deletion of Cul9 had no significant effect on cell-cycle progression, but attenuated DNA damage-induced apoptosis. Ectopic expression of wild-type CUL9, but not a point mutant CUL9 deficient in p53 binding, promotes apoptosis. These results show CUL9 as a potential p53-activating E3 ligase in the cytoplasm.

Cytoplasmic CUL9/PARC ubiquitin ligase is a tumor suppressor and promotes p53-dependent apoptosis.

The expression of tumor suppressor Arf is tightly repressed during normal cell growth at a young age and is activated by oncogenic insults, and during aging, results in p53 activation and cell-cycle arrest to prevent hyperproliferation. The mechanisms of both transcriptional repression and activation of Arf are not understood. We show that p53 binds to and represses Arf expression and that this repression requires the function of both histone deacetylases (HDAC) and polycomb group (PcG) proteins. Inactivation of p53 leads to increased Arf transcription in both mouse embryonic fibroblasts (MEF) cultured in vitro and in tissues and organs of p53 null mice. Activation of endogenous p53 enhances Arf repression, and reintroduction of p53 back into p53 null MEFs restores Arf repression. Both DNA binding and transactivation activities of p53 are required for Arf repression. We show that p53 is required for both HDAC and PcG to repress Arf expression. Bindings of both HDAC and PcG to Arf are disrupted by inactivation of p53 and can be restored in p53 null MEFs by the reintroduction of wild-type, but not mutant, p53. These results indicate that p53 recruits both HDAC and PcG to Arf locus to repress its expression, and this repression constitutes a second feedback loop in p53 regulation.

p53 binds to and is required for the repression of Arf tumor suppressor by HDAC and polycomb.

A wide range of cell stresses, including DNA damage, signal to p53 through posttranslational modification of p53. The cytoplasmic functions of p53 are emerging as an important constituent of role of p53 in tumor suppression. Here, we report that deletion of the Cul9 (formerly Parc) gene, which encodes an E3 ubiquitin ligase that binds to p53 and localizes in the cytoplasm, resulted in spontaneous tumor development, accelerated EmMyc–induced lymphomagenesis, and rendered mice susceptible to carcinogenesis. Cul9-p53 double-mutant mice exhibited indistinguishable tumor phenotypes as p53 single-mutant mice, indicating that the function of Cul9 in tumor suppression is largely mediated by p53. Deletion of Cul9 had no significant effect on cell-cycle progression, but attenuated DNA damage–induced apoptosis. Ectopic expression of wild-type CUL9, but not a point mutant CUL9 deficient in p53 binding, promotes apoptosis. These results show CUL9 as a potential p53activating E3 ligase in the cytoplasm. Cancer Res; 71(8); 2969–77. 2011 AACR.

Cytoplasmic CUL 9 / PARC Ubiquitin Ligase Is a Tumor Suppressor and Promotes p 53-Dependent Apoptosis

Molecular Alignment and Temperature Effects on Photodriven, Mulitidimensional Oscillation of Azobenzene Liquid Crystalline Polymer Networks

Background Tail-anchored (TA) proteins are a distinct class of membrane proteins that are sorted post-translationally to various organelles and function in a number of important cellular processes, including redox reactions, vesicular trafficking and protein translocation. While the molecular targeting signals and pathways responsible for sorting TA proteins to their correct intracellular destinations in yeasts and mammals have begun to be characterized, relatively little is known about TA protein biogenesis in plant cells, especially for those sorted to the plastid outer envelope. Methodology/Principal Findings Here we investigated the biogenesis of three plastid TA proteins, including the 33-kDa and 34-kDa GTPases of the translocon at the outer envelope of chloroplasts (Toc33 and Toc34) and a novel 9-kDa protein of unknown function that we define here as an outer envelope TA protein (OEP9). Using a combination of in vivo and in vitro assays we show that OEP9 utilizes a different sorting pathway than that used by Toc33 and Toc34. For instance, while all three TA proteins interact with the cytosolic OEP chaperone/receptor, AKR2A, the plastid targeting information within OEP9 is distinct from that within Toc33 and Toc34. Toc33 and Toc34 also appear to differ from OEP9 in that their insertion is dependent on themselves and the unique lipid composition of the plastid outer envelope. By contrast, the insertion of OEP9 into the plastid outer envelope occurs in a proteinaceous-dependent, but Toc33/34-independent manner and membrane lipids appear to serve primarily to facilitate normal thermodynamic integration of this TA protein. Conclusions/Significance Collectively, the results provide evidence in support of at least two sorting pathways for plastid TA outer envelope proteins and shed light on not only the complex diversity of pathways involved in the targeting and insertion of proteins into plastids, but also the molecular mechanisms that underlie the delivery of TA proteins to their proper intracellular locations in general.

Distinct Pathways Mediate the Sorting of Tail-Anchored Proteins to the Plastid Outer Envelope

Mitochondrial uncoupling proteins of the nervous system (UCPs 2, 4, and 5) have potential roles in the function and protection of the central nervous system (CNS). In the absence of structural information, conformations of the hexahistidine-tagged versions of all five human UCPs in liposomes were investigated for the first time, using far- and near-UV CD and fluorescence spectroscopy. Highly pure UCPs 1-5 were reconstituted in detergents and stable small unilamellar vesicles, appropriate for spectroscopic studies. All UCPs formed dominantly helical conformations in negatively charged phospholipid vesicles (palmitoyloleoylphosphatidylcholine/palmitoyloleoylphosphatidylglycerol, 7:3 molar ratio). UCPs 2 and 5 exhibited comparable helical conformations with possible association in lipid bilayers, whereas UCP4 had a different helical profile that can be related to its less associated form. Interaction of reconstituted UCPs with GDP and GTP, inhibitors of the prototypic UCP1, was detected by near-UV CD and fluorescence spectroscopy, utilizing the sensitivity of these techniques to microenvironments around Trp residues close to the nucleotide binding site. Binding of UCP4 to purine nucleotides was also different from other UCPs. Binding of fatty acids, activators of proton transport in UCPs, to UCPs could not be unambiguously detected, implying a nonbinding conformation/orientation of the proteoliposomes. Interaction of CoA with UCPs was comparable to nucleotide binding, suggesting a possible binding of this molecule at the nucleotide binding site. Despite dissimilar primary sequences, neuronal UCPs share common structural and functional properties with UCPs 1 and 3, supporting a common physiological role in addition to their specific roles in the CNS.

A comparative study on conformation and ligand binding of the neuronal uncoupling proteins.

A modular photocurrent generation system, based on amphiphilic porphyrin and fullerene species assembled in a tethered lipid bilayer matrix, is reported here. The key findings are (1) the amount of photoactive species can be quantitatively controlled in each leaflet of the bilayer and (2) the sequential formation of the bilayer allows a directional organization of these agents on electrodes. Photocurrent generation from seven differently configured photoactive bilayers is studied, which reveals several critical factors in achieving efficient photoinduced electron transfer across lipid membranes. Detailed fluorescence characterization is performed on porphyrin samples either in liposomes or surface-tethered bilayers; and the observed fluorescence quenching is correlated with photocurrents generated from the electrode-immobilized lipid films. The potential usefulness of this lipid-based approach is discussed in connection to several existing molecular photovoltaic systems.

Photocurrent generation from porphyrin/fullerene complexes assembled in a tethered lipid bilayer.

Cellular membranes play key roles in the regulation of a range of important biological processes. However, the characterization of membrane involvement in these events is difficult to achieve due to the complexity of the membrane bilayer and the challenges associated with handling and analyzing these systems. As such, rapid and reliable approaches for characterizing membrane-based processes are necessary. To address this issue, we have first developed an azide-tagged modular lipid anchor scaffold (2) that can be conveniently derivatized via click chemistry to functionalize the membrane surface. This was used to access biotin- and fluorescein-lipid conjugates 1a and 1b, respectively. These compounds were then employed to perform and characterize the immobilization of liposomes containing biotin-anchor 1a onto streptavidin-coated microplates. Results from these studies indicated clean, biotin-dependent surface deposition. This strategy for liposome attachment was then applied to a microplate-based platform to detect the binding of receptor proteins to immobilized liposomes, specifically for the membrane binding of protein kinase Calpha (PKCalpha). The resulting data indicated direct detection of binding to the membrane-functionalized surface. The reported approaches provide efficient methods for the derivatization of the membrane surface, which is applicable to the study of membrane-based processes. Finally, the described microplate-based liposome binding assay allows for high-throughput analysis of important protein-membrane binding events.

Microplate-based analysis of protein-membrane binding interactions via immobilization of whole liposomes containing a biotinylated anchor.

Membrane lipids act as important regulators of a litany of important physiological and pathophysiological events. Many of them act as site-specific ligands for cytosolic proteins in binding events that recruit receptors to the cell surface and control both protein function and subcellular localization. Phosphatidylinositol phosphates (PIP(n)s) are a family of signaling lipids that regulate numerous cellular processes by interacting with a myriad of protein binding modules. Characterization of PIP(n)-binding proteins has been hampered by the lack of a rapid and convenient quantitative assay. Herein, microplate-based detection is presented as an effective approach to characterizing protein-PIP(n) binding interactions at the molecular level. With this assay, the binding of proteins to isolated PIP(n) headgroups is detected with high sensitivity using a platform that is amenable to high-throughput screening. In the studies described herein, biotinylated PI-(4,5)-P(2) headgroup analogue 1 was designed, synthesized, and immobilized onto 96-well streptavidin-coated microplates to study receptor binding. This assay was used to characterize the binding of the PH domain of beta-spectrin to this headgroup. The high affinity interaction that was detected for surface association (K(d, surf) = 6 nM +/- 3), demonstrates that receptor binding modules can form high affinity interactions with lipid headgroups outside of a membrane environment. The results also indicate the feasibility of the assay for rapid characterization of PIP(n)-binding proteins as well as the promise for high-throughput analysis of protein-PIP(n) binding interactions. Finally, this assay was also employed to characterize the inhibition of the binding of receptors to the PIP(n)-derivatized microplates using solution phase competitors. This showcases the viability of this assay for rapid screening of inhibitors of PIP(n)-binding proteins.

Microplate-based characterization of protein-phosphoinositide binding interactions using a synthetic biotinylated headgroup analogue.

Phosphatidic acid (PA) is an important signaling lipid that plays roles in a range of biological processes including both physiological and pathophysiological events. PA is one of a number of signaling lipids that can act as site-specific ligands for protein receptors in binding events that enforce membrane association and generally regulate both receptor function and subcellular localization. However, elucidation of the full scope of PA activities has proven problematic, primarily due to the lack of a consensus sequence among PA-binding receptors. Thus, experimental approaches, such as those employing lipid probes, are necessary for characterizing interactions at the molecular level. Herein, we describe an efficient modular approach to the synthesis of a range of PA probes that employs a late stage introduction of reporter groups. This strategy was exploited in the synthesis of PA probes bearing fluorescent and photoaffinity tags as well as a bifunctional probe containing both a photoaffinity moiety and an azide as a secondary handle for purification purposes. To discern the ability of these PA analogs to mimic the natural lipid in protein-binding properties, each compound was incorporated into vesicles for binding studies using a known PA receptor, the C2 domain of PKCalpha. In these studies, each compound exhibited binding properties that were comparable to those of synthetic PA, indicating their viability as probes for effectively studying the activities of PA in cellular processes.

Modular synthesis of biologically active phosphatidic acid probes using click chemistry.

Phosphatidylinositol polyphosphate lipids (PIPns) play key roles in important biological pathways, and defects in the signaling activities of these molecules have been implicated in a number of disease states. As such, it is necessary to understand the complex roles of these lipids in biological pathways, which often involve their actions as site-specific ligands that recruit receptors to the surfaces of cellular membranes. However, the complex structures of PIPn family members, of which seven biologically active isomers exist, complicate studies. Derivatized analogs of the PIPn structures are beneficial as chemical tools for elucidating signaling and binding activities. Herein, we present an efficient approach to probe the generation in which amino conjugates of PIPn headgroups can be conveniently functionalized in the final step of the synthesis to obtain a number of derivatized analogs of use for different studies. In addition to the application of this strategy to generate PI-(4,5)-P2 headgroup probes, we also report the synthesis of PIPn–amine conjugates corresponding to all seven naturally existing isomers. This approach will be invaluable for generating the range of probe structures that is required to elucidate the intricacies of PIPn signaling. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Synthesis of Modular Headgroup Conjugates Corresponding to All Seven Phosphatidylinositol Polyphosphate Isomers for Convenient Probe Generation

The acidic domains of the Toc159 chloroplast preprotein receptor family are intrinsically disordered protein domains

CDK inhibitor p18(INK4c) is a downstream target of GATA3 and restrains mammary luminal progenitor cell proliferation and tumorigenesis.

Expression, Reconstitution and Biophysical Studies of Neuronal Uncoupling Proteins: UCP4 and UCP5

Conformational analysis and folding of transmembrane and matrix peptide segments of the mitochondrial uncoupling proteins: a comparative study.

The Pea Nodulation Mutant R50 (sym16) Displays Altered Activity and Expression Profiles for Cytokinin Dehydrogenase

Conformations of the prototypic UCP-1 (uncoupling protein-1) and its TM (transmembrane) and ML (matrix-loop) domains were studied by CD spectroscopy. Recombinant, untagged mouse UCP-1 and a hexahistidine-tagged version of the protein were obtained in high purity following their overexpression in Escherichia coli. The TM and ML domains of hamster UCP-1 were chemically synthesized. Conformations of both recombinant UCP-1 proteins were dominantly helical (40-50%) in digitonin micelles. Binding of the purine nucleotides GDP and GTP to UCP-1, detected in the near-UV CD region, supported the existence of the functional form of the protein in digitonin micelles. All individual TM and ML peptides, except the third ML domain, adopted helical structures in aqueous trifluoroethanol, which implies that, in addition to six TM segments, at least two of the ML domains of the UCP-1 can form helical structures in membrane interface regions. TM and ML domains interacted with vesicles composed of the main phospholipids of the inner membrane of mitochondria, phosphatidylcholine, phosphatidylethanolamine and cardiolipin, to adopt dominantly beta- and/or unordered conformations. Mixtures of UCP-1 peptide domains spontaneously associated in aqueous, phospholipid vesicles and digitonin micelle environments to form ordered conformations, which exhibited common features with the conformations of the full-length proteins. Thermal denaturations of UCP-1 and its nine-peptide-domain assembly in digitonin were co-operative but not reversible. Assembly of six TM domains in lipid bilayers formed ion-conducting units with possible helical bundle conformations. Consequently, covalent connection between peptide domains, tight domain interactions and TM potential are essential for the formation of the functional conformation of UCP-1.

A CD study of uncoupling protein-1 and its transmembrane and matrix-loop domains.

Cell membrane lipids have been identified as key participants in cell signaling activities. One important role is their involvement as site-specific ligands in protein-membrane binding interactions, which result in the anchoring of peripheral proteins onto cellular membranes. These events generally regulate protein function and localization and have been implicated in both normal physiological processes and those pertaining to disease state onset. Thus, it is important to elucidate the details of interactions at the molecular level, such as lipid-binding specificities and affinities, the location of receptor binding domains and multivalency in binding. For this purpose, we have designed and developed azido-tagged lipid analogues as conveniently functionalizable lipid probe scaffolds. Herein, we report the design and synthesis of the initial structure of this type, diacylglycerol analogue 2, which contains an azide tag at the sn-1 position of the lipid headgroup. Direct functionalization of this compound with a range of reporter groups has been performed to illustrate the facile access to probes of use for characterizing binding. Quantitative lipid-binding studies using protein kinase C, a known DAG-binding receptor, demonstrate that these probes are active mimetics of natural DAG. Thus, these DAG probes will serve as robust sensors for studies aimed at understanding binding interactions and as precursors for the development of analogous probes of more complex phospholipids and glycolipids.

Synthesis and convenient functionalization of azide-labeled diacylglycerol analogues for modular access to biologically active lipid probes.

Phylogenetic profiling of amino acid substitution patterns in proteins has led many to conclude that most structural information is carried by interior core residues that are solvent inaccessible. This conclusion is based on the observation that buried residues generally tolerate only conserved sequence changes, while surface residues allow more diverse chemical substitutions. This notion is now changing as it has become apparent that both core and surface residues play important roles in protein folding and stability. Unfortunately, the ability to identify specific mutations that will lead to enhanced stability remains a challenging problem. Here we discuss two mutations that emerged from an in vitro selection experiment designed to improve the folding stability of a non-biological ATP binding protein. These mutations alter two solvent accessible residues, and dramatically enhance the expression, solubility, thermal stability, and ligand binding affinity of the protein. The significance of both mutations was investigated individually and together, and the X-ray crystal structures of the parent sequence and double mutant protein were solved to a resolution limit of 2.8 and 1.65 Å, respectively. Comparative structural analysis of the evolved protein to proteins found in nature reveals that our non-biological protein evolved certain structural features shared by many thermophilic proteins. This experimental result suggests that protein fold optimization by in vitro selection offers a viable approach to generating stable variants of many naturally occurring proteins whose structures and functions are otherwise difficult to study.

Structural Insights into the Evolution of a Non-Biological Protein: Importance of Surface Residues in Protein Fold Optimization

Mutant mice lacking both cyclin-dependent kinase (CDK) inhibitors p18(Ink4c) and p27(Kip1) develop a tumor spectrum reminiscent of human multiple endocrine neoplasia (MEN) syndromes. To determine how p18 and p27 genetically interact with Men1, the tumor suppressor gene mutated in familial MEN1, we characterized p18-Men1 and p27-Men1 double mutant mice and showed that p18, but not p27, functionally collaborates with Men1 in suppressing lung tumorigenesis. Lung tumors developed in both Men1(+/-) and p18(-/-);Men1(+/-) mice at a high penetrance and contain both neuroendocrine and nonneuroendocrine cells. The remaining wild-type Men1 allele was lost in most lung tumors from Men1(+/-) mice but was retained in most tumors from p18(-/-);Men1(+/-) mice, showing a functional collaboration between p18 and Men1 in lung tumor suppression. Phosphorylation of Rb protein at both CDK2 and CDK4/CDK6 sites were significantly increased in normal bronchial epithelia and tumor cells derived from p18(-/-);Men1(+/-) mice compared to those from single p18(-/-) or Men1(+/-) mice. Lung tumors developed in p18(-/-);Men1(+/-) mice were multifocal, more heterogeneous, and highly invasive compared to those developed in either p18(-/-) or Men1(+/-) mice. Bronchioalveolar stem cells are expanded in normal and tumorigenic lungs of p18(-/-) mice and are further expanded in p18(-/-);Men1(+/-) lung tumors. These results reveal a previously unrecognized function of p18 in lung tumor suppression through collaboration with Men1 to control lung stem cell proliferation.

p18Ink4c collaborates with Men1 to constrain lung stem cell expansion and suppress non-small-cell lung cancers.

Full-length cDNA corresponding to Arabidopsis (Arabidopsis thaliana) gene At2g31690, which has been annotated in GenBank as a putative triacylglycerol (TAG) lipase, was obtained by reverse transcription-polymerase chain reaction using RNA from senescing rosette leaves of Arabidopsis as a template. The cognate protein was found to contain the lipase active site sequence, and corresponding recombinant protein proved capable of deesterifying TAG. In vitro chloroplast import assays indicated that the lipase is targeted to chloroplasts. This was confirmed by confocal microscopy of rosette leaf tissue treated with fluorescein isocyanate-labeled, lipase-specific antibody, which revealed that lipase protein colocalizes with plastoglobular neutral lipids. Western-blot analysis indicated that the lipase is expressed in roots, inflorescence stems, flowers, siliques, and leaves and that it is strongly up-regulated in senescing rosette leaf tissue. Transgenic plants with suppressed lipase protein levels were obtained by expressing At2g31690 cDNA in antisense orientation under the regulation of a constitutive promoter. Transgenic plants bolted and flowered at the same time as wild-type plants, but were severely stunted and exhibited delayed rosette senescence. Moreover, the stunted growth phenotype correlated with irregular chloroplast morphology. The chloroplasts of transgenic plants were structurally deformed, had reduced abundance of thylakoids that were abnormally stacked, and contained more plastoglobular neutral lipids than chloroplasts of wild-type plants. These observations collectively indicate that this TAG lipase plays a role in maintaining the structural integrity of chloroplasts, possibly by mobilizing the fatty acids of plastoglobular TAG.

Characterization of a Plastid Triacylglycerol Lipase from Arabidopsis1[OA]

ABSTRACT Mutant mice lacking both cyclin-dependent kinase (CDK) inhibitors p18Ink4c and p27Kip1 develop a tumor spectrum reminiscent of human multiple endocrine neoplasia (MEN) syndromes. To determine how p18 and p27 genetically interact with Men1, the tumor suppressor gene mutated in familial MEN1, we characterized p18-Men1 and p27-Men1 double mutant mice. Compared with their corresponding single mutant littermates, the p18−/−; Men1+/− mice develop tumors at an accelerated rate and with an increased incidence in the pituitary, thyroid, parathyroid, and pancreas. In the pituitary and pancreatic islets, phosphorylation of the retinoblastoma (Rb) protein at both CDK2 and CDK4/6 sites was increased in p18−/− and Men1+/− cells and was further increased in p18−/−; Men1+/− cells. The remaining wild-type Men1 allele was lost in most tumors from Men1+/− mice but was retained in most tumors from p18−/−; Men1+/− mice. Combined mutations of p27−/− and Men1+/−, in contrast, did not exhibit noticeable synergistic stimulation of Rb kinase activity, cell proliferation, and tumor growth. These results demonstrate that functional collaboration exists between p18 and Men1 and suggest that menin may regulate additional factor(s) that interact with p18 and p27 differently.

p18Ink4c, but Not p27Kip1, Collaborates with Men1 To Suppress Neuroendocrine Organ Tumors

Chloroplasts are but one type of a diverse group of essential organelles that distinguish plant cells and house many critical biochemical pathways, including photosynthesis. The biogenesis of plastids is essential to plant growth and development and relies on the targeting and import of thousands of nuclear-encoded proteins from the cytoplasm. The import of the vast majority of these proteins is dependent on translocons located in the outer and inner envelope membranes of the chloroplast, termed the Toc and Tic complexes, respectively. The core components of the Toc and Tic complexes have been identified within the last 12 years; however, the precise functions of many components are still being elucidated, and new components are still being identified. In Arabidopsis thaliana (and other species), many of the components are encoded by more than one gene, and it appears that the isoforms differentially associate with structurally distinct import complexes. Furthermore, it appears that these complexes repres...

Chloroplasts are but one type of a diverse group of essential organelles that distinguish plant cells and house many critical biochemical pathways, including photosynthesis. The biogenesis of plastids is essential to plant growth and development and relies on the targeting and import of thousands of nuclear-encoded proteins from the cytoplasm. The im- port of the vast majority of these proteins is dependent on translocons located in the outer and inner envelope membranes of the chloroplast, termed the Toc and Tic complexes, respectively. The core components of the Toc and Tic complexes have been identified within the last 12 years; however, the precise functions of many components are still being eluci- dated, and new components are still being identified. In Arabidopsis thaliana (and other species), many of the components are encoded by more than one gene, and it appears that the isoforms differentially associate with structurally distinct im- port complexes. Furthermore, it appears that these complexes represent functionally distinct targeting pathways, and the regulation of import by these separate pathways may play a role in the differentiation and specific functions of distinct plastid types during plant growth and development. This review summarizes these recent discoveries and emphasizes the mechanisms of differential Toc complex assembly and substrate recognition.

Plastids represent a diverse group of organelles that perform essential metabolic and signaling functions within all plant cells. The differentiation of specific plastid types relies on the import of selective sets of proteins from among the approximately 2500 nucleus-encoded plastid proteins. The Toc159 family of GTPases mediates the initial targeting of proteins to plastids. In Arabidopsis thaliana, the Toc159 family consists of four genes: atTOC159, atTOC132, atTOC120, and atTOC90. In vivo analysis of atToc159 function indicates that it is required specifically for the import of proteins necessary for chloroplast biogenesis. In this report, we demonstrate that atToc120 and atToc132 represent a structurally and functionally unique subclass of protein import receptors. Unlike atToc159, mutants lacking both atToc120 and atToc132 are inviable. Furthermore, atToc120 and atToc132 exhibit preprotein binding properties that are distinct from atToc159. These data indicate that the different members of the Toc159 family represent distinct pathways for protein targeting to plastids and are consistent with the hypothesis that separate pathways have evolved to ensure balanced import of essential proteins during plastid development.

Members of the Toc159 import receptor family represent distinct pathways for protein targeting to plastids.

Most chloroplast outer-membrane proteins are synthesized at their mature size without cleavable targeting signals. Their insertion into the outer membrane is insensitive to thermolysin pretreatment of chloroplasts and does not require ATP. It has therefore been assumed that insertion of outer-membrane proteins proceeds through a different pathway from import into the interior of chloroplasts, which requires a thermolysin-sensitive translocon complex and ATP. Here, we show that a model outer-membrane protein, OEP14, competed with the import of a chloroplast interior protein, indicating that the two import pathways partially overlapped. Cross-linking studies showed that, during insertion, OEP14 was associated with Toc75, a thermolysin-resistant component of the outer-membrane protein–conducting channel that mediates the import of interior-targeted precursor proteins. Whereas almost no OEP14 inserted into protein-free liposomes, OEP14 inserted into proteoliposomes containing reconstituted Toc75 with a high efficiency. Taken together, our data indicate that Toc75 mediates OEP14 insertion, and therefore plays a dual role in the targeting of proteins to the outer envelope membrane and interior of chloroplasts.

Import Pathways of Chloroplast Interior Proteins and the Outer-Membrane Protein OEP14 Converge at Toc75

The members of the Toc159 family of GTPases act as the primary receptors for the import of nucleus-encoded preproteins into plastids. Toc159, the most abundant member of this family in chloroplasts, is required for chloroplast biogenesis (Bauer, J., K. Chen, A. Hiltbunner, E. Wehrli, M. Eugster, D. Schnell, and F. Kessler. 2000. Nature. 403:203–207) and has been shown to covalently cross-link to bound preproteins at the chloroplast surface (Ma, Y., A. Kouranov, S. LaSala, and D.J. Schnell. 1996. J. Cell Biol. 134:1–13; Perry, S.E., and K. Keegstra. 1994. Plant Cell. 6:93–105). These reports led to the hypothesis that Toc159 functions as a selective import receptor for preproteins that are required for chloroplast development. In this report, we provide evidence that Toc159 is required for the import of several highly expressed photosynthetic preproteins in vivo. Furthermore, we demonstrate that the cytoplasmic and recombinant forms of soluble Toc159 bind directly and selectively to the transit peptides of these representative photosynthetic preproteins, but not representative constitutively expressed plastid preproteins. These data support the function of Toc159 as a selective import receptor for the targeting of a set of preproteins required for chloroplast biogenesis.

atToc159 is a selective transit peptide receptor for the import of nucleus-encoded chloroplast proteins

The Toc complex at the outer envelope of chloroplasts initiates the import of nuclear-encoded preproteins from the cytosol into the organelle. The core of the Toc complex is composed of two receptor GTPases, Toc159 and Toc34, as well as Toc75, a β-barrel membrane channel. Toc159 is equally distributed between a soluble cytoplasmic form and a membrane-inserted form, suggesting that assembly of the Toc complex is dynamic. In the present study, we used the Arabidopsis thaliana orthologs of Toc159 and Toc34, atToc159 and atToc33, respectively, to investigate the requirements for assembly of the trimeric Toc complex. In addition to its intrinsic GTPase activity, we demonstrate that integration of atToc159 into the Toc complex requires atToc33 GTPase activity. Additionally, we show that the interaction of the two GTPase domains stimulates association of the membrane anchor of atToc159 with the translocon. Finally, we employ reconstituted proteoliposomes to demonstrate that proper insertion of the receptor requires both Toc75 and Toc34. Collectively these data suggest that Toc34 and Toc75 act sequentially to mediate docking and insertion of Toc159 resulting in assembly of the functional translocon.

The Roles of Toc34 and Toc75 in Targeting the Toc159 Preprotein Receptor to Chloroplasts*

This unit describes protocols for isolating chloroplasts from pea (Pisum sativum) and Arabidopsis thaliana for the study of nuclear‐encoded plastid precursor proteins. Chloroplasts from both preparations are competent for the in vitro import of recombinant preproteins synthesized using in vitro translation systems derived from reticulocyte or wheat germ lysates. These assays can be used to test whether a particular protein is targeted to chloroplasts, for analyzing the suborganellar location of newly imported preproteins, or to study the mechanism of import itself.

The import of nucleus-encoded preproteins into plastids requires the coordinated activities of membrane protein complexes that facilitate the translocation of polypeptides across the envelope double membrane. Tic20 was identified previously as a component of the import machinery of the inner envelope membrane by covalent cross-linking studies with trapped preprotein import intermediates. To investigate the role of Tic20 in preprotein import, we altered the expression of the Arabidopsis Tic20 ortholog (atTic20) by antisense expression. Several antisense lines exhibited pronounced chloroplast defects exemplified by pale leaves, reduced accumulation of plastid proteins, and significant growth defects. The severity of the phenotypes correlated directly with the reduction in levels of atTic20 expression. In vitro import studies with plastids isolated from control and antisense plants indicated that the antisense plastids are defective specifically in protein translocation across the inner envelope membrane. These data suggest that Tic20 functions as a component of the protein-conducting channel at the inner envelope membrane.

In Vivo Analysis of the Role of atTic20 in Protein Import into Chloroplasts

The multimeric translocon at the outer envelope membrane of chloroplasts (Toc) initiates the recognition and import of nuclear-encoded preproteins into chloroplasts. Two Toc GTPases, Toc159 and Toc33/34, mediate preprotein recognition and regulate preprotein translocation. Although these two proteins account for the requirement of GTP hydrolysis for import, the functional significance of GTP binding and hydrolysis by either GTPase has not been defined. A recent study indicates that Toc159 is equally distributed between a soluble cytoplasmic form and a membrane-inserted form, raising the possibility that it might cycle between the cytoplasm and chloroplast as a soluble preprotein receptor. In the present study, we examined the mechanism of targeting and insertion of the Arabidopsis thaliana orthologue of Toc159, atToc159, to chloroplasts. Targeting of atToc159 to the outer envelope membrane is strictly dependent only on guanine nucleotides. Although GTP is not required for initial binding, the productive insertion and assembly of atToc159 into the Toc complex requires its intrinsic GTPase activity. Targeting is mediated by direct binding between the GTPase domain of atToc159 and the homologous GTPase domain of atToc33, the Arabidopsis Toc33/34 orthologue. Our findings demonstrate a role for the coordinate action of the Toc GTPases in assembly of the functional Toc complex at the chloroplast outer envelope membrane.

The targeting of the atToc159 preprotein receptor to the chloroplast outer membrane is mediated by its GTPase domain and is regulated by GTP

Two homologous GTP-binding proteins, atToc33 and atToc159, control access of cytosolic precursor proteins to the chloroplast. atToc33 is a constitutive outer chloroplast membrane protein, whereas the precursor receptor atToc159 also exists in a soluble, cytosolic form. This suggests that atToc159 may be able to switch between a soluble and an integral membrane form. By transient expression of GFP fusion proteins, mutant analysis, and biochemical experimentation, we demonstrate that the GTP-binding domain regulates the targeting of cytosolic atToc159 to the chloroplast and mediates the switch between cytosolic and integral membrane forms. Mutant atToc159, unable to bind GTP, does not reinstate a green phenotype in an albino mutant (ppi2) lacking endogenous atToc159, remaining trapped in the cytosol. Thus, the function of atToc159 in chloroplast biogenesis is dependent on an intrinsic GTP-regulated switch that controls localization of the receptor to the chloroplast envelope.

Essential role of the G-domain in targeting of the protein import receptor atToc159 to the chloroplast outer membrane

Functional traits of lipid particles originating from thylakoid membranes

Release of Lipid Catabolites from Membranes by Blebbing of Lipid-Protein Particles

The lipid bilayers of plant membranes are normally liquid crystalline, reflecting the inherent rotational motion of membrane fatty acids at physiological temperature. With the onset of senescence, the chemical composition of membrane lipids changes resulting in lipid phase separations within the bilayer. These phase changes render the membranes leaky and lead to loss of essential ion gradients and impairment of cell function. The separation of lipid phases appears to be attributable to an accumulation of lipid metabolites in the bilayer that are formed during turnover and metabolism of membrane lipids. These metabolites are normally released from membranes as lipid–protein particles found in the cell cytosol and within organelles. The lipid–protein particles also contain catabolites of membrane proteins and appear to serve as a vehicle for removing lipid and protein metabolites that would otherwise destabilize the bilayer. They bear structural resemblance to oil bodies, which are abundant in oil seeds, an...

How do medical students want to learn ENT?: Perspectives from a consensus forum.

OBJECTIVE
This study aims to estimate the rate of postoperative meningitis (both immediate and long-term) in patients following cochlear implants (CIs). It aims to do so through a systematic review and meta-analysis of published studies tracking complications after CIs.

DATA SOURCES
MEDLINE, Embase, and Cochrane Library.

REVIEW METHODS
This review was performed in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies tracking complications following CIs in patients were included. Exclusion criteria included non-English language studies and case series reporting <10 patients. Bias risk was evaluated using the Newcastle-Ottawa Scale. Meta-analysis was performed through DerSimonian and Laird random-effects models.

RESULTS
A total of 116/1931 studies met the inclusion criteria and were included in the meta-analysis. Overall, there were 112 cases of meningitis in 58,940 patients after CIs. Meta-analysis estimated an overall rate of postoperative meningitis of 0.07% (95% confidence interval [CIs], 0.03%-0.1%; I2  = 55%). Subgroup meta-analysis showed this rate had 95% CIs crossing 0% in implanted patients who received the pneumococcal vaccine, antibiotic prophylaxis, those with postoperative acute otitis media (AOM), and those implanted less than 5 years.

Meningitis is a rare complication following CIs. Our estimated rates of meningitis after CIs appear lower than prior estimates based on epidemiological studies in the early 2000s. However, the rate still appears higher than the baseline rate in the general population. The risk was very low in implanted patients who received the pneumococcal vaccine, antibiotic prophylaxis, received unilateral or bilateral implantations, developed AOM, those implanted with a round window or cochleostomy techniques, and those under 5 years.

The Risk of Meningitis After Cochlear Implantation: A Systematic Review and Meta-Analysis.

Acute otitis media (AOM) and otitis externa (OE) are common ear infections which may warrant antibiotic therapy. For many infections, there is a rise in antimicrobial resistance, which is associated with treatment failure, morbidity, prolonged hospitalisation and mortality. This study aimed to identify longitudinal changes in microbiology and antimicrobial resistance in aural swabs taken from patients with AOM or OE.

DESIGN
Retrospective observational analysis.

SETTING
Aural samples processed at Manchester Medical Microbiology Partnership Laboratories between January 2008 and December 2018 were analysed to record organism isolated and antimicrobial sensitivity.

PARTICIPANTS
Individual aural swabs from 7200 patients.

Changes in the incidence of organisms and antimicrobial resistance between two time periods (2008-2012 and 2013-2018) were compared using the chi-squared test (alpha = 0.05).

RESULTS
From 7200 swabs, 2879 (40%) were from children. The most frequently isolated organisms were Staphylococcus aureus (25%), Pseudomonas aeruginosa (24.4%), yeast (9.1%), mixed anaerobes (7.9%) and Haemophilus influenzae (6.1%). In children aged 0-4 years, H. influenzae had particularly high incidence (25%). Overall, the incidence of P. aeruginosa decreased significantly with time (p = 0.05). Isolates displaying resistance to one or more antimicrobial agents increased significantly in number in the second time period for P. aeruginosa (p = 0.04) and H. influenzae (p =  0.03). There was increased resistance to amoxicillin for P. aeruginosa (p = 0.01) and to erythromycin for H. influenzae (p < 0.01).

Variations in type and frequency of organisms with increasing age likely result from differences in the preponderance of AOM compared to OE in children versus adults. We found increasing antimicrobial resistance for two organisms commonly isolated from AOM and OE infections, suggesting that aspects of current UK treatment practices and national recommendations may need to be revised.

Clinical otolaryngology : official journal of ENT-UK ; official journal of Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial Surgery

Changes in antimicrobial resistance in acute otitis media and otitis externa.

To estimate the prevalence of, and risk factors associated with electrode migration (EM) in cochlear implant (CI) recipients.

Frequency of electrode migration after cochlear implantation in the early postoperative period. What are associated risk factors?

Objective: To review the outcomes of cochlear implants (CI) in patients with neurofibromatosis type 2 (NF2) in a large cohort, and identify factors associated with poor hearing benefit. Study Design: Fifteen-year retrospective national observational case series. Setting: United Kingdom regional NF2 multidisciplinary teams. Patients: Consecutive patients with NF2 receiving a CI. Interventions: CI for hearing rehabilitation. Main outcome measures: 1) Audiometric performance at 9 to 12 months after implantation using City University of New York (CUNY) sentence recognition score, and Bamford- Kowal-Bench (BKB) word recognition score in quiet (BKBq), and in noise (BKBn). 2) CI use at most recent review. Results: Sixty four consecutive patients, median age 43 years, were included. Nine to 12 months mean audiometric scores were: CUNY 60.9%, BKBq 45.8%, BKBn 41.6%. There was no difference in audiometric outcomes between VS treatment modalities. At most recent review (median 3.6 years from implantation), 84.9% with device in situ/available data were full or part-time users. Between 9 and 12 months and most recent review there was an interval reduction in mean audiometric scores: CUNY −12.9%, BKBq −3.3%, BKBn −4.9%. Larger tumor size and shorter duration of profound hearing loss were the only variables associated with poorer audiometric scores. Tumor growth at the time of surgery was the only variable associated with CI non-use. Individual patient response was highly variable. Conclusions: CI can provide significant and sustained auditory benefits to patients with NF2 independent of tumor treatment modality, with the majority of those implanted becoming at least part-time users. Larger datasets are required to reliably assess the role of independent variables.

Cochlear Implantation in Neurofibromatosis Type 2: Experience From the UK Neurofibromatosis Type 2 Service

Objectives: Nurses are increasingly providing routine and emergency ENT care; yet there are often limited training opportunities. The aim of this study was to validate an intensive 1-day ENT emergency simulation course for nurses. Methods: The course included short lectures, practical skills stations and mannequin simulation scenarios. Sixteen nurse participants were video-recorded managing simulated scenarios before and after the course. Two assessors scored individual participant performance on a 15-point competency grid (maximum score 30), blinded to the timing of the recording. Participants also rated their confidence and skill before and immediately following the course across 11 items using a 5-point Likert score (maximum score 55). Results: Blinded assessor ratings for performance were significantly improved after the course compared to baseline (overall score 12 vs 7, respectively; P = .015). There was strong assessor inter-rater reliability (R = 0.965). Self-rated skills and confidence also increased following the course (46.7 vs 24.4 at baseline; P < .01). Conclusion: Simulation-based training is an effective and desirable method of teaching ENT emergency management to nurses, with greatest impact on participant confidence. Future courses need to refine the content and increase the validation sample size using a nurse-specific scoring system.

Validating a Simulated Emergency Course for Nurses Working in ENT

Objective Evidence for the management of acute otitis externa (AOE) is limited, with unclear diagnostic criteria and variably reported outcome measures that may not reflect key stakeholder priorities. We aimed to develop 1) a definition, 2) diagnostic criteria and 3) a core outcome set (COS) for AOE. Study design COS development according to Core Outcome Measures in Effectiveness Trials (COMET) methodology and parallel consensus selection of diagnostic criteria/definition. Setting Stakeholders from the United Kingdom. Subjects and methods Comprehensive literature review identified candidate items for the COS, definition and diagnostic criteria. Nine individuals with past AOE generated further patient-centred candidate items. Candidate items were rated for importance by patient and professional (ENT doctors, general practitioners, microbiologists, nurses, audiologists) stakeholders in a three-round online Delphi exercise. Consensus items were grouped to form the COS, diagnostic criteria, and definition. Results Candidate COS items from patients (n = 28) and literature (n = 25) were deduplicated and amalgamated to a final candidate list (n = 46). Patients emphasised quality-of-life and the impact on daily activities/work. Via the Delphi process, stakeholders agreed on 31 candidate items. The final COS covered six outcomes: pain; disease severity; impact on quality-of-life and daily activities; patient satisfaction; treatment-related outcome; and microbiology. 14 candidate diagnostic criteria were identified, 8 reaching inclusion consensus. The final definition for AOE was ‘diffuse inflammation of the ear canal skin of less than 6 weeks duration’. Conclusion The development and adoption of a consensus definition, diagnostic criteria and a COS will help to standardise future research in AOE, facilitating meta-analysis. Consulting former patients throughout development highlighted deficiencies in the outcomes adopted previously, in particular concerning the impact of AOE on daily life.

Acute otitis externa: Consensus definition, diagnostic criteria and core outcome set development

Nasal packing is the mainstay of epistaxis management; however, packs cause patient discomfort and can lead to hospital admission. Absorbable haemostats provide clotting factors or act as a substrate to stimulate clotting and represent a potential treatment alternative. A systematic review was performed to evaluate the efficacy of topical haemostats in the management of epistaxis.

Dissolvable intranasal haemostatic agents for acute epistaxis: A systematic review and meta‐analysis

The authors present the case of a 24-year-old female with neurofibromatosis type 2. Growth of the left vestibular schwannoma and progressive hearing loss prompted the decision to proceed to translabyrinthine resection with cochlear nerve preservation and cochlear implant insertion. Complete resection with preservation of the facial and cochlear nerves was achieved. The patient had grade 1 facial function and was discharged on postoperative day 4 following suturing of a minor CSF leak. This case highlights the feasibility of cochlear nerve preservation and cochlear implant insertion in appropriately selected patients, offering a combination of effective tumor control and hearing rehabilitation. The video can be found here: https://stream.cadmore.media/r10.3171/2021.7.FOCVID21122

Translabyrinthine resection of NF2 associated vestibular schwannoma with cochlear implant insertion

To explore the impact of COVID‐19 on the management and outcomes of acute paediatric mastoiditis across the UK.

Acute paediatric mastoiditis in the UK before and during the COVID‐19 pandemic: A national observational study

To investigate factors affecting the haemostatic success of non‐dissolvable intranasal packs in the management of acute epistaxis presenting to the emergency department (ED).

Objectives: To explore the relationship between aural symptoms during baro-challenge and the underlying measured Eustachian tube (ET) function. Two key questions were addressed. (1) In patients who have features of obstructive ET dysfunction, is there a measurable underlying difference in ET function between those who experience severe symptoms on baro-challenge and those that do not? (2) What is the diagnostic value of ET function tests in the identification of patients with severe symptoms on baro-challenge? Methods: Patients with symptoms of obstructive ET dysfunction were recruited, with the presence of aural symptoms on baro-challenge established via the clinical history and analysis of the Cambridge ET Dysfunction Assessment, a patient-reported outcome measure (PROM). ET function tests were assessed in each patient: 9 objective and semi-objective measures of ET opening, and 2 symptom-based PROMs. The tests’ results were grouped by type of ET opening assessed, generating passive and active dysfunction scores. Individual test results were assessed for diagnostic accuracy in reference to features in the history or PROM-based evidence of symptoms on baro-challenge. Results: Both passive and active opening of the ET was significantly reduced in ears with a history of pain on baro-challenge. Some patients had apparent severe obstructive ET dysfunction without symptoms on baro-challenge, whilst others had symptoms but normal test results. No individual test of ET opening was of diagnostic value in predicting those ears likely to experience pain or exacerbated symptoms on baro-challenge. Conclusion: The relationship between aural pain during baro-challenge and ET function appears more complex than had been assumed, with pain possibly related to factors other than just ET function.

Eustachian Tube Function in Patients with Symptoms on Baro-Challenge

To report changes in practice brought about by COVID‐19 and the implementation of new guidelines for the management of tonsillitis and peritonsillar abscess (PTA), and to explore factors relating to unscheduled re‐presentations for patients discharged from the emergency department (ED).

Admission avoidance in tonsillitis and peritonsillar abscess: A prospective national audit during the initial peak of the COVID‐19 pandemic

To assess the safety of paediatric tonsillectomy procedures conducted in NHS hospitals in England between 2008 and 2019.

Paediatric tonsillectomy in England: A cohort study of clinical practice and outcomes using Hospital Episode Statistics data (2008‐2019)

The mechanism of balloon Eustachian tuboplasty: a biomechanical study

The roles of Allied Health Care Professionals (AHPs) in Head and Neck Cancer (HNC) are wide ranging but not clearly defined. Inter‐regional variability in practice results from a lack of standardisation in approaches to the Multidisciplinary Team (MDT) make‐up and structure. Traditionally, the follow‐up of HNC patients is clinician led with multiple scheduled follow‐up appointments. The increasing population of HNC patients provides logistical, monetary and efficiency challenges.

The role of allied healthcare professionals in head and neck cancer surveillance: A systematic review

We aimed to audit current United Kingdom (UK) practice of Head and Neck Cancer (HNC) post‐treatment surveillance against national guidelines and determine the outcomes of these practices in detecting recurrence.

Post‐Treatment Head and Neck Cancer Care: National Audit and Analysis of Current Practice in the United Kingdom

There is a paucity of high-quality evidence relating to the management of epistaxis severe enough to require admission to a hospital. Previous studies of interventions for epistaxis have suffered from small sample sizes. They lacked the power to allow analysis of the effect of an intervention on epistaxis control that is independent of the condition severity or additional interventions given.

OBJECTIVE
To determine the effect of specialist treatments on the successful management of severe epistaxis METHODOLOGY: Secondary analysis of data collected from a national multi-centre audit of patients with epistaxis over 30 days in 2016. Data were entered prospectively, and patients were followed up for 30 days following hospital discharge. 1402 adults admitted for inpatient management of epistaxis were identified in 113 participating UK hospitals, with data entered prospectively during the 30-day audit window. Exposure variables assessed included treatment instigated at first ENT review, intervention strategy during hospitalization, disease factors (e.g. severity), patient risk factors (e.g. co-morbidities, medications) and treatment factors (grade of doctor, therapies initiated during hospital stay). Main Outcomes include treatment time (time from first ENT review to time haemostasis was achieved and patient was safe for hospital discharge) and 30-day hospital readmission rate.

RESULTS
834 patients had sufficient data for inclusion. Patients who did not receive nasal cautery at first specialist review had a treatment time greater than double the time of those who were cauterised: Adjusted ratio (aR) 2.5 (95% CI 1.7-3.3), after controlling for age, bleeding severity, and whether they received a nasal pack or not. Only 30% of patients received management that complied with new national guidance, but those that did were 87% more likely to be achieve haemostasis before those that did not, even after controlling for bleeding severity. Type of treatment, whether initial intervention or management strategy, did not affect 30-day re-attendance.

Analysis of national audit data suggest that cautery at first specialist review, and management according to national guidance can reduce hospital treatment times without compromising 30-day re-attendance. Future work should investigate why early nasal cautery is infrequently used, and how service delivery can be optimised to allow widespread implementation of evidence-based management for epistaxis.

National prospective observational study of inpatient management of adults with epistaxis - a National Trainee Research Collaborative delivered investigation.

Balloon dilatation of the Eustachian tube for obstructive Eustachian tube dysfunction in adults

Observational studies often represent the best available evidence for surgical practice. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) recommendations were generated in 2007 with the aim of improving the quality of reporting. This study was designed to assess whether publication of STROBE guidelines has improved the quality of reporting in observational otology and audiology studies.

EMBASE and MEDLINE were searched using a comprehensive keyword search developed in conjunction with a scientific librarian.

STUDY SELECTION
English language papers from six Otorhinolaryngology journals during two 6-month periods (2005 and 2016) were evaluated.

DATA EXTRACTION
Two reviewers independently analyzed papers according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

DATA SYNTHESIS
Percentage scores for the two periods were compared using Mann-Whitney U test.

Forty and 42 studies were returned for the 2005 and 2016 periods, respectively. The mean percentage of STROBE items that were met improved between 2005 and 2016 (58, 76%, respectively; p < 0.0001). Analysis indicated that improvements were greater in journals that endorsed STROBE guidelines (p = 0.02). This data suggests that STROBE has increased the reporting quality of observational studies; however, there are still significant further improvements to be met.

An Assessment of the Change in Compliance of Observational Otology and Audiology Studies With the STROBE Statement Guidelines: A Systematic Review.

OBJECTIVE
To develop and validate a novel patient-reported outcome measure (PROM) to distinguish patulous from obstructive Eustachian Tube Dysfunction (ETD). To determine accuracy of PROMs and ET function tests as diagnostic tools for ETD.

1) PROM development and validation. 2) Test case-control diagnostic accuracy study.

Cambridge ETD Assessment (CETDA) and ETDQ-7 PROMs, sonotubometry and tubomanometry ET function tests.

SETTING
Tertiary referral center.

PATIENTS
Cases with patulous (n = 7) or obstructive (n = 60) ETD, controls with either no ear symptoms (n = 33), or symptoms arising from hearing loss or Menière's disease (n = 24).

PROMs were assessed in terms of internal consistency, ceiling and floor effects, test-retest reliability and content, structural and criterion validity. PROMs and function test sensitivity and specificity was determined as diagnostic tests for ETD.

RESULTS
The 10-item CETDA was developed. CETDA validity and performance were good, though five items suffered floor effects. There was no difference in scores for either PROM in the patulous ETD, obstructive ETD, and symptomatic control groups. Both PROMS had excellent diagnostic accuracy using only healthy controls as comparator for ETD, but specificity was very poor when controls with other otological disorders were included. Both objective tests had sensitivity and specificity of 63% and 79% for obstructive ETD.

The CETDA and ETDQ-7 are not disease-specific and cannot distinguish obstructive from patulous ETD subtypes. A relatively weak correlation between sonotubometry and tubomanometry results, PROM scores, and the clinical diagnosis suggests that a varied core set of outcome measures is required to monitor response to treatments for ETD.

The Performance of Patient-reported Outcome Measures as Diagnostic Tools for Eustachian Tube Dysfunction.

In recent years, there has been a decline in the number of applications per ST3 post for ENT. The majority of medical students and foundation doctors have a limited exposure to ENT during undergraduate medical training. This is a common issue in smaller surgical specialties, and is acknowledged as one factor deterring students from surgical careers. This article is protected by copyright. All rights reserved.

Student and foundation doctor perspectives on promoting entry to ENT specialist training

Open minimally invasive versus video-assisted minimally invasive parathyroidectomy for primary hyperparathyroidism

The British Rhinological Society multidisciplinary consensus recommendations on the hospital management of epistaxis - ERRATUM.

Background and aims Eustachian tube dysfunction (ETD) is a commonly diagnosed disorder of Eustachian tube opening and closure, which may be associated with severe symptoms and middle ear disease. Currently the diagnosis of obstructive and patulous forms of ETD is primarily based on non-specific symptoms or examination findings, rather than measurement of the underlying function of the Eustachian tube. This has proved problematic when selecting patients for treatment, and when designing trial inclusion criteria and outcomes. This study aims to determine the correlation and diagnostic value of various tests of ET opening and patient reported outcome measures (PROMs), in order to generate a recommended diagnostic pathway for ETD. Methods Index tests included two PROMs and 14 tests of ET opening (nine for obstructive, five for patulous ETD). In the absence of an accepted reference standard two methods were adopted to establish index test accuracy: expert panel diagnosis and latent class analysis. Index test results were assessed with Pearson correlation and principle component analysis, and test accuracy was determined. Logistic regression models assessed the predictive value of grouped test results. Results The expert panel diagnosis and PROMs results correlated with each other, but not with ET function measured by tests of ET opening. All index tests were found to be feasible in clinic, and acceptable to patients. PROMs had very poor specificity, and no diagnostic value. Combining the results of tests of ET function appeared beneficial. The latent class model suggested tympanometry, sonotubometry and tubomanometry have the best diagnostic performance for obstructive ETD, and these are included in a proposed diagnostic pathway. Conclusions ETD should be diagnosed on the basis of clinical assessment and tests of ET opening, as PROMs have no diagnostic value. Currently diagnostic uncertainty exists for some patients who appear to have intermittent ETD clinically, but have negative index test results.

Eustachian tube dysfunction: A diagnostic accuracy study and proposed diagnostic pathway

Baro-challenge-induced Eustachian tube dysfunction (baro-induced ETD) is characterized by failure of the Eustachian tube (ET) to open adequately to permit middle-ear pressure regulation during ambient pressure changes. There are no well-characterized tests for identifying the condition, which makes both patient diagnosis and research into treatment efficacy challenging. This systematic review evaluates ET function tests as potential outcome measures for baro-induced ETD.

MEDLINE and CENTRAL were searched (database inception to March 2017) and reference lists reviewed for all relevant English Language articles.

Tests in included studies were required to measure ET function in patients reporting baro-induced ear symptoms or barotrauma.

Data were extracted in a standardized manner, and studies assessed according to Standards for Reporting of Diagnostic Accuracy Studies (STARD) criteria. The primary outcome of interest was the accuracy of ET function tests.

Heterogeneity of subject demographics, ET function test methodology, and reference standards only permitted narrative systematic review.

Sixteen studies involving seven different types of ET function tests were identified. The nine-step test was the most commonly used outcome measure, with overall test sensitivity and specificity ranges of 37 to 100% and 57 to 100%, respectively. Tympanometry test sensitivity was consistently poor (0-50%) while specificity was higher (52-97%). Published accuracy data for other ET function tests and test combinations were limited. Currently, no single test can be recommended for use in clinical practice. A combination of the nine-step test with other objective tests or patient-reported measures appears most promising as a core set of outcome measures for baro-induced ETD.

Outcome Measures for Baro-Challenge-Induced Eustachian Tube Dysfunction: A Systematic Review.

Many objective tests of eustachian tube (ET) function have been devised for clinical and research use but they have not been directly compared or characterized. As a first step to identifying tests to incorporate into an outcome set for ET dysfunction, we assessed repeatability of a panel of eight of these tests in healthy ears.

The repeatability of tests of eustachian tube function in healthy ears

Objective Balloon eustachian tuboplasty (BET) has entered clinical use as a treatment for eustachian tube dysfunction. Some surgeons perform myringotomy prior to BET due to concerns that the increase in middle ear (ME) pressure caused by BET may cause otic barotrauma. We investigated the ME pressure changes occurring during BET in cadavers. Study design Human cadaver investigation of a surgical technique Setting Laboratory study at a tertiary referral center. Subjects and Methods ME pressures were recorded from fresh-frozen cadavers, and BET was performed with the Bielefeld balloon catheter inflated to 10 bar. Peak ME pressures were recorded during catheter insertion, inflation, deflation, and removal. A second pressure measurement was taken 15 seconds after each stage to assess the residual pressures. All BET procedures were repeated at least once. Where transmastoid recordings were made, BET was repeated, measuring pressure via a myringotomy to ensure equivalence. Results Data from 25 procedures in 13 ears (9 heads) were analyzed. A consistent pattern of ME pressure change was observed in all cases. Positive pressures occurred on insertion (maximum, 26 daPa) and inflation (maximum, 99 daPa) and negative pressures on deflation (maximum, –46 daPa) and removal (maximum, –42 daPa). There were no significant pressure differences between first and second procedures, except at 15 seconds after insertion (P = .04). Conclusion In adult cadaveric specimens, BET induces ME pressures within the normal physiologic range. On this basis, routine myringotomy prior to BET in adults is not necessary.

Middle Ear Pressure Changes during Balloon Eustachian Tuboplasty

Objective Eustachian tube (ET) dysfunction is most frequently caused by a failure of the ET to adequately open; however, there is currently no reliable method of assessing this. Tubomanometry has recently shown good interindividual repeatability as a measure of ET function by measuring middle ear pressure after the application of regulated nasopharyngeal pressures during swallowing. We present the first reports of a novel test: middle ear impedance measurements during standard nasopharyngeal pressure application (tuboimpedance). We assess repeatability in healthy ears and any advantages over tubomanometry. Study Design Exploratory cohort diagnosis study. Setting Tertiary referral center. Subjects Twenty screened, healthy ears (10 volunteers). Methods Tubomanometry and tuboimpedance tests were performed while individuals swallowed with applied nasopharyngeal pressures of 20, 30, 40, and 50 mbar. Eustachian tube opening detection rate and test repeatability (measured by intraclass correlation coefficient [ICC]) for immediate and delayed repeats at each pressure were compared. Results ET opening was detected more frequently using tuboimpedance, with a 100% detection rate using a nasopharyngeal pressure of 30 mbar or more, compared to 88% to 96% with tubomanometry. Detection of ET opening at 20 mbar was possible with tuboimpedance. Repeatability of both tests was mostly strong (ICC >0.7) for both immediate and delayed repeats. Repeatability for the tubomanometry R value was only fair to moderate. Conclusion Tuboimpedance may provide a repeatable measure of ET opening that is easier to perform due to lower nasopharyngeal pressures required and fewer issues with poor ear-probe sealing. Further assessment in patients with different forms of ET dysfunction is required.

Open minimally invasive versus video‐assisted minimally invasive parathyroidectomy for primary hyperparathyroidism

OBJECTIVE
There is no agreement on the best clinical test for Eustachian tube (ET) dysfunction. Numerous tests have been developed to detect ET opening, and all require a patient to perform a Valsalva, Toynbee or sniff maneuver, or to swallow on demand. We aimed to characterize existing tests of ET function in healthy ears, and identify the optimal method and patient maneuver for each test. Our own normative data is presented alongside published comparisons.

Diagnostic test cohort study.

SETTING

PATIENTS
Seventy-five healthy ears from 42 volunteers.

Six tests of ET function, each performed using multiple different patient maneuvers.

MAIN OUTCOME MEASURE
Detected ET opening rate for each test-maneuver combination.

RESULTS
The highest detected opening rates were: Sonotubometry 94%; nine-step test inflation/deflation 93/94%; continuous impedance 88%, patient-reported opening 79%; observed tympanic membrane movement 78%; and Tubo-tympano-aerodynamic-graphy 76%. Valsalva maneuvers were most effective at opening the ET. Toynbee and swallow maneuvers were more effective when performed without water, when compared to with water. For Valsalva and sniff maneuvers, there was significant correlation between the peak nasopharyngeal pressure generated and the ET opening rate.

Based on ET opening detection rates, we recommend the use of dry swallows with sonotubometry and the nine-step test. When testing patient-reported opening and observed membrane movement, and when performing Tubo-tympano-aerodynamic-graphy and impedance tests, we recommend the use of Valsalva maneuvers. Further studies are required to explore the association between the test technique and results in ears with ET dysfunction.

Tests of Eustachian Tube Function: the Effect of Testing Technique on Tube Opening in Healthy Ears.

vestibular and and allow characterisation of the ECAPs. A new array and surgical approach to vestibular implantation developed. Auditory Brainstem Responses were also recorded to try and confirm preservation of hearing post. Patients were selected if they had recordable balance function and hearing in the tumour ear prior to surgery. Six patients were studied. situation, and the remaining symptoms were usually mild. Anyhow, the effect varied depending on the symptom. The most common preoperative symptoms were feeling that ears were “ clogged ” , muffled hearing, ear symptoms during a cold, crackling or popping sounds in the ears, and feeling of pressure in the ears. BET clearly alleviated these symptoms as at least 70 % of the affected patients reported improvement after long-term follow-up. On the other hand, ringing in the ears and the ability to release pressure in the ears by swallowing were improved only in about 40 % of the symptomatic patients. Overall patient satisfaction on BET was good and 79 % of the patients would choose to undergo BET again if their ear symptoms returned to the preoperative level. These results show that BET has significant subjective long-term benefits to the patients. available tests of Eustachian tube function, and how to optimise the techni-ques for clinical use. number of clinical tests able to Eustachian tube opening. The choice of patient manoeuvre each significant on tube our facilitate refine-ment testing Further to explore the association the test technique and

Tests of Eustachian Tube Function: The effects of different patient manoeuvres when testing healthy ears

Introduction: Eustachian tube (ET) dysfunction is a common and varied condition with significant associated morbidity. In most cases it is caused by a failure of the ET to adequately open, however there is currently no reliable method of assessing this opening. Tubomanometry is a test that has recently shown good inter-individual repeatability as a measure of ET opening and function, by measuring middle ear pressure after the application of regulated nasopharyngeal pressures during swallowing. We present the first reports of a novel test: middle ear impedance measurements during standardised nasopharyngeal positive pressure bursts (tuboimpedance). We assess repeatability in healthy ears, and whether this new assessment provides any advantages over tubomanometry.

Tympanic impedance measurement with standardised nasopharyngeal air pressures – a new test of Eustachian tube function

A 61‐year‐old man with a history of fish bone ingestion and poorly localized symptoms was seen. His clinical examination was unremarkable, but CT demonstrated a foreign body deeply embedded within his tongue. Intraoperative ultrasound (US) guidance facilitated identification of a bone, allowing a needle to be placed as a guide to dissection. Repeat US scanning through the incision permitted precisely targeted surgery. CT and US are the most effective imaging techniques for localizing fish bones. Intraoperative US can be used to accurately locate a submucosal fish bone in mobile tissue such as the tongue, and focused, image‐guided dissection can reduce surgical tissue trauma. © 2014 Wiley Periodicals, Inc. J Clin Ultrasound 42:565–568, 2014

Intraoperative ultrasound to facilitate removal of a submucosal foreign body

The morphometry of astrocytes in the arcuate nucleus exhibits cyclic changes during the estrous cycle leading to dynamic changes in the communication between neurotransmitters and neuropeptides that regulate pituitary hormone secretion. Data suggest that remodeling of direct and/or indirect inputs into GnRH neurons may influence the timing and/or amplitude of the preovulatory LH surge in young rats. We have previously found that aging alters the timing and amplitude of the LH surge. Therefore, the purpose of this study was to focus on the rostral preoptic area where GnRH cell bodies reside. We assessed the possibility that the morphometry of astrocytes in the rostral preoptic area displays time-related and age-dependent changes on proestrus. Our results demonstrate that, in young rats, astrocyte cell surface area decreases between 0800 h and 1200 h, before the initiation of the LH surge. Changes in surface area over the cycle were specific to astrocytes in close apposition to GnRH neurons. In contrast, in middle-aged rats astrocyte surface area was significantly less than in young rats and did not change during the day. These findings suggest that a loss of astrocyte plasticity could lead to the delayed and attenuated LH surge that has been previously observed in middle-aged rats.

The morphometry of astrocytes in the rostral preoptic area exhibits a diurnal rhythm on proestrus: relationship to the luteinizing hormone surge and effects of age.

The menopause marks the end of a woman's reproductive life. During the postmenopausal period, plasma estrogen concentrations decrease dramatically and remain low for the rest of her life, unless she chooses to take hormone replacement therapy. During the past 20 years, we have learned that changes in the central nervous system are associated with and may influence the timing of the menopause in women. Recently, it has become clear that estrogens act on more than just the hypothalamus, pituitary, ovary, and other reproductive organs. In fact, they play roles in a wide variety of nonreproductive functions. With the increasing life span of humans from approximately 50 to 80 years and the relatively fixed age of the menopause, a larger number of women will spend over one third of their lives in the postmenopausal state. It is not surprising that interest has increased in factors that govern the timing of the menopause and the repercussions of the lack of estrogen on multiple aspects of women's health. We have used animal models to better understand the complex interactions between the ovary and the brain that lead to the menopause and the repercussions of the hypoestrogenic state. Our results show that when rats reach middle age, the patterns and synchrony of multiple neurochemical events that are critical to the preovulatory gonadotropin-releasing hormone (GnRH) surge undergo subtle changes. The precision of rhythmic pattern of neurotransmitter dynamics depends on the presence of estradiol. Responsiveness to this hormone decreases in middle-aged rats. The lack of precision in the coordination in the output of neural signals leads to a delay and attenuation of the luteinizing hormone surge, which lead to irregular estrous cyclicity and, ultimately, to the cessation of reproductive cycles. We also have examined the impact of the lack of estrogen on the vulnerability of the brain to injury. Our work establishes that the absence of estradiol increases the extent of cell death after stroke-like injury and that treatment with low physiological levels of estradiol are profoundly neuroprotective. We have begun to explore the cellular and molecular mechanisms that underlie this novel nonreproductive action of estrogens. In summary, our studies show that age-related changes in the ability of estradiol to coordinate the neuroendocrine events that lead to regular preovulatory GnRH surges contribute to the onset of irregular estrous cycles and eventually to acyclicity. Furthermore, we have shown that the lack of estradiol increases the vulnerability of the brain to injury and neurodegeneration.

Neuroendocrine modulation and repercussions of female reproductive aging.

Localization of κ opioid receptors in oxytocin magnocellular neurons in the paraventricular and supraoptic nuclei

In mammals, the timing and occurrence of the preovulatory LH surge critically depends on the proper functioning of the suprachiasmatic nucleus (SCN). Recent evidence suggests that vasoactive intestinal polypeptide (VIP) conveys time of day information from the SCN to GnRH neurons. However, it is not completely clear whether this action is exerted directly at the level of the GnRH neuron. To determine if GnRH neurons are direct targets for VIP, triple-lable immunofluorescence was utilized to simultaneously localize GnRH, VIP and VIP2 receptor protein. The present results demonstrate that about 40% of all GnRH neurons analyzed contain VIP2 receptor immunoreactivity and that VIP-containing processes were seen in close apposition to a significant number of VIP2 receptor-positive GnRH neurons. GnRH neurons that exhibit immunoreactivity for the VIP2 receptor are located predominantly in the OVLT region and the rostral preoptic area. In the median eminence, where the majority of GnRH neurons terminate, VIP2 rece...

Localization of the VIP2 Receptor Protein on GnRH Neurons in the Female Rat.

The effect of blockade of κ-opioid receptors in the medial preoptic area on the luteinizing hormone surge in the proestrous rat

Further Studies on the Suppression of Luteinizing Hormone Release Due to Activation of Medial Preoptic-Anterior Hypothalamic Area μ-Opioid Receptors

The involvement of opioid peptides in the neural regulation of luteinizing hormone secretion in the female rat

" Evolutionary Computation in Data Mining " edited by Ashish Ghosh and Lakhmi C. Jain, published in the series on Studies in Fuzziness and Soft Computing by Springer contains twelve skillful papers, which show the advances and state of the art in the domain of evolutionary methods' application in data mining. Data mining is a relatively broad domain of automatic knowledge discovery from databases and is now one of the most developed fields in the area of artificial intelligence. A rapid growth of data collected in various realms of human activity and their potential usefulness in these realms requires appropriate and efficient tools to extract and use of the potentially gathered knowledge. Evolutionary algorithms are very powerful tools and can be utilized in many ways to make use of knowledge hidden in terabites of data collected in databases all over the world. In the Chapter 1 by Ashish Ghosh some essential aspects of application of evolutionary computation methods for rule generation are discussed. focuses on data preprocessing methods meant to minimize the size of data to be processed. Data reduction is obtained using a CHC evolutionary algorithm with stratification strategy to select representative instances of the processed data set. The presented evolutionary method outperforms the non-evolutionary ones and gives better instance reduction rates, higher accuracy and lower resources consumption. The next chapter by Matthew G. Smith and Larry Bull presents also a preprocessing method, where genetic programming is used to feature construction (inferring new features enables to find hidden relationships between them) and a genetic algorithm for feature selection from the set produced by the first stage. The preprocessing method with the C4.5 classification algorithm works significantly better than the single C4.5 method. Also the fourth chapter by Riyaz Sikora presents a multi-agent based method of feature selection and inductive learning. Genetic algorithms are treated as learning agents to discover solutions of small subproblems into which the whole data set is decomposed.

The use of machine learning techniques to automatically analyse data for information is becoming increasingly widespread. In this paper we examine the use of Genetic Programming and a Genetic Algorithm to pre-process data before it is classified by an external classifier. Genetic Programming is combined with a Genetic Algorithm to construct and select new features from those available in the data, a potentially significant process for data mining since it gives consideration to hidden relationships between features. We then examine techniques to improve the human readability of these new features and extract more information about the domain.

Improving the human readability of features constructed by genetic programming

Genetic Programming with a Genetic Algorithm for Feature Construction and Selection

GAP: Constructing and Selecting Features with Evolutionary Computing

Using Genetic Programming for Feature Creation with a Genetic Algorithm Feature Selector

Feature Construction and Selection Using Genetic Programming and a Genetic Algorithm

We performed a scoping review of literature on schools’ transfer of rights practices under the Individuals with Disabilities Education Act (IDEA) with respect to students with intellectual and developmental disabilities. The review found only limited empirical evidence of how IDEA transfer of rights policies are implemented in schools and affect students and parents. We found a substantial disconnect between this limited empirical evidence and generalizations about school practice made in recent literature that is not empirically based. In addition, we found some misunderstanding of relevant federal policy and little attention to variation in states’ policies and schools’ practices. Further research is needed to understand the intersection of relevant public policy, school practice, and student postsecondary education, employment, and independent living outcomes.

What Is Known About Schools’ Transfer of Rights Practices for Students With Intellectual and Developmental Disabilities

ABSTRACT Various forms of assistance are offered to help US Veterans achieve success in their post-military lives in recognition of their service. Despite the many successes, a significant number of Veterans continue to remain at risk for negative mental health outcomes, including suicidality and low levels of life satisfaction. These findings may be due to challenges arising from cultural identity dissonance. Problematic strategies used by Veterans to reduce this dissonance can result in a lack of belongingness, a key component in Joiner’s Interpersonal Theory of Suicide. The authors suggest that research on the immigrant experience of acculturation may provide a new perspective to better understand issues of identity and sense of belonging in Veterans. Given that most Veterans return to the culture in which they grew up, the authors offer the term “reculturation.” The authors propose clinical psychology focus on exploring the reculturation process of Veterans to support program engagement and suicide prevention.

Reculturation: A new perspective on military-civilian transition stress

The Disabled Contract: Severe Intellectual Disability, Justice and Morality by Jonas-Sébastien Beaudry (review)

Paternalistic attitudes about what is in the interests of a person with an intellectual disability have long led to abuses, and are embedded in the guardianship laws still in place in most countries. Self-advocates, who identify as people with intellectual or other disabilities and are committed to demanding their rights and educating others about them, are calling for a new approach. They have found support for reforms in the Convention on the Rights of Persons with Disabilities, adopted by the United Nations in 2006 and since acceded to by 182 countries. By supporting the fundamental right of those with disabilities to make decisions, it has enabled disability rights advocates to successfully challenge legal capacity restrictions and push for “supported decision-making.”

How Persons with Intellectual Disabilities Are Fighting for Decision-Making Rights

Lessons from United States school district policies and approaches to special education during the COVID-19 pandemic

Sexual Agency As a Rights-Based Imperative for Persons with Intellectual Disabilities

This Article explores the juridical implications of indigenous peoples’ right to legal capacity in the Inter-American system for cases involving the same right of persons with disabilities within that system and beyond. It explicates the Inter-American Court of Human Rights’ (IACtHR) three-factor test in Saramaka People v Suriname and analogizes its reasoning with rationales underpinning the right to legal capacity under the United Nations Convention on the Rights of Persons with Disabilities (crpd). It then demonstrates how the IACtHR can apply a Saramaka-style test to future cases brought by persons with disabilities challenging legal capacity restrictions. The Article further argues that the European Court of Human Rights (ECtHR) should also apply this rule to align its legal capacity jurisprudence with the crpd’s mandates. Finally, it suggests that the Committee on the Rights of Persons with Disabilities (crpd Committee) ought to consider this rule when resolving individual communications and thereby guide courts.

Connecting the Right of Collective Legal Capacity by Indigenous Peoples with the Right of Individual Legal Capacity by Persons with Disabilities

Article 30 of the CRPD as a Vehicle for Social Transformation: Harnessing the CRPD’s Potential for Persons with Intellectual Disabilities

Combating the Exclusion and Marginalisation of Persons with Intellectual Disabilities in Higher Education in the United States

This chapter analyses how Mexico’s Supreme Court has applied the Convention on the Rights of Persons with Disabilities (CRPD) to decide cases involving persons with disabilities following its 2011 constitutional reform. Although the Court has c to develop instructive case law on incorporating the CRPD into the domestic legal order, it has frequently failed to do so in an even-handed manner. Even when the Court has sided with petitioners with disabilities, its application of the CRPD to the facts of the case has been erratic, both making it difficult to predict how the Court will adjudicate future claims and also hindering the CRPD’s transformative potential for changing how individuals, organisations and society at large act towards persons with disabilities through its expressive value. Civil society organisations that have advocated for progressive rulings have a responsibility for educating the Court to develop workable judicial tests for CRPD-based claims.

Abstract The Global Fund to Fight AIDS, Tuberculosis and Malaria was created to greatly expand access to basic services to address the three diseases in its name. From its beginnings, its governance embodied some human rights principles: civil society is represented on its board, and the country coordination mechanisms that oversee funding requests to the Global Fund include representatives of people affected by the diseases. The Global Fund’s core strategies recognize that the health services it supports would not be effective or cost-effective without efforts to reduce human rights-related barriers to access and utilization of health services, particularly those faced by socially marginalized and criminalized persons. Basic human rights elements were written into Global Fund grant agreements, and various technical support measures encouraged the inclusion in funding requests of programs to reduce human rights-related barriers. A five-year initiative to provide intensive technical and financial support for the scaling up of programs to reduce these barriers in 20 countries is ongoing.

Human Rights and the Global Fund to Fight AIDS, Tuberculosis and Malaria

Same Old Game but with Some New Players – Assessing Argentina’s National Mental Health Law in Light of the Rights to Liberty and Legal Capacity under the UN Convention on the Rights of the Persons with Disabilities

The purpose of this thesis is to outline the relationship that existed in the past and exists in the present, between Australians and the War Graves and Memorials to the Missing. commemorations of Australians who died during the First World War. Their final resting places are scattered all over the world and provide a tangible record of the sacrifice of men and women in the war, and represent the final result by Official Agencies such as the Imperial, and later, Commonwealth War Graves Commission, and its agency representative, the Office of Australian War Graves, of an attempt to appropriately commemorate them. The study follows the path of history from the event of death of an individual in the First World War, through their burial; temporary grave or memorial commemoration; the permanent commemoration; the family and public reaction to the deaths; how the Official Agencies of related Commonwealth Governments dealt with the dead; and finally, how the Australian dead are represented on the battlefields of the world in the 21st century. Australia.s war dead of the First World War are scattered around the globe in more than 40 countries and are represented in war cemeteries and civil cemeteries; and listed on large „Memorials to the Missing., which commemorate the individuals devoid of a known graves or final resting place.

The relationship between Australians and the overseas graves of the First World War

Journal of American Association for Pediatric Ophthalmology and Strabismus

An analysis of medicaid reimbursement trends in pediatric ophthalmology in Arizona: 2015 to 2021

An audit of routine practice: a prospective study on the use of mouth props in oral surgery

Setting
Epidural hematoma rarely complicates interventional spine procedures. While anticoagulant and antiplatelet drugs increase bleeding risk, cessation may precipitate serious thromboembolic events. The Spine Intervention Society (SIS) and American Society of Regional Anesthesia and Pain Medicine (ASRA) put forth guidelines that dissent with regard to management of hemostatically active agents during commonly performed spinal injections.

Objective
To validate an antiplatelet/anticoagulant management table based on modifications of the SIS 2013 and ASRA 2015 guidelines.

Design
Prospective descriptive study.

Subjects
Patients undergoing interventional spine injections from a interventional physiatrist's practice.

Methods
A Modified SIS 2013-ASRA 2015 Antiplatelet & Anticoagulant (MSAAA) guideline table was devised and adopted. Patients undergoing interventional spine procedures were monitored for bleeding events.

Results
Of 4,253 injection sites, 197 (4.6%) were performed in 74 patients on antiplatelet/anticoagulants. No clinically evident bleeding events were observed in patients on antiplatelet/anticoagulant medications for lumbar transforaminal epidural (N = 90), posterior-approach facet joint (N = 62), lumbar intradiscal (N = 11), lumbar sympathetic (N = 3), and sacroiliac (N = 5) injections or in 26 radiofrequency neurotomy procedures. One in 2,026 (0.05%, 95% confidence interval = 0.00-0.31%) interlaminar epidural injections (cervical, thoracic, lumbar, and caudal) suffered epidural hematoma. This patient was not on an antiplatelet/anticoagulant drug. No patient in 191 cervicothoracic and 723 lumbar transforaminal injections experienced bleeding complications.

Continuing antiplatelet and anticoagulant medications for intermediate- to low-risk interventional spine procedures may be advisable. The MSAAA table may be a reasonable guideline reference for managing antiplatelet and anticoagulant drugs.

Anticoagulant and Antiplatelet Management for Spinal Procedures: A Prospective, Descriptive Study and Interpretation of Guidelines

Background. Chronic pain is a major health condition that has significant financial and lifestyle implications. Due to the complex etiologies of pain, it is difficult to find treatment modalities that would be universally applicable to the general population presenting for care. Mindfulness meditation is a complimentary treatment modality that has some preliminary, inconclusive evidence in support of its benefit on patients with chronic pain. Objectives. The purpose of this article is to systematically review the current literature for randomized controlled trials that assess the outcomes of mindfulness as an intervention for individuals with chronic pain. Methods. An electronic database search was performed for studies investigating the efficacy of mindfulness in treatment for chronic pain. The studies included were randomized controlled trials, published in English, from a peer-reviewed journal that identified mindfulness as the primary treatment focus for chronic pain in at least one group, and included participants with at least a 12-week history of symptoms. Results. The database search revealed 283 articles, of which 6 met the inclusion criteria. Conclusion. Mindfulness meditation appears to have minimal or statistically insignificant effects on chronic pain according to the current data. However, the effects of mindfulness on mental health scores are significant and may be an area for future trials to target. Well-conducted research is necessary before the effects of mindfulness on chronic pain can be definitively determined.

ABSTRACT LOW BACK PAIN (LBP) IS A COMMON CONDITION FOR WHICH INDIVIDUALS SEEK CARE. THE ASSOCIATED PHYSICAL LIMITATIONS OFTEN PERSIST BEYOND DISCHARGE FROM MEDICAL CARE, AND MANY OF THESE INDIVIDUALS WILL SEEK ADVICE FROM STRENGTH AND CONDITIONING PROFESSIONALS. ALTHOUGH THERE ARE MANY WAYS TO MANAGE PHYSICAL LIMITATIONS ASSOCIATED WITH LBP, A TRAINING PROGRAM THAT SERVES THE PURPOSE OF IMPROVING SPINAL CONDITIONING WHILE AVOIDING THE EXACERBATION AND RECURRENCE OF SYMPTOMS IS IDEAL. THEREFORE, THE PURPOSE OF THIS ARTICLE IS TO EDUCATE THE READER ON COMMON PATHOLOGIES ASSOCIATED WITH LBP AND GENERAL MOVEMENT PATTERNS THAT WOULD PREVENT THE EXACERBATION AND RECURRENCE OF SYMPTOMS.

Low Back Pain: Movement Considerations for Exercise and Training

A Comparison of Ultrasound and Magnetic Resonance Imaging Findings of a Morel‐Lavallée Lesion of the Knee

Objective: To review the existing literature regarding the nature of cervical spine degeneration, with specific emphasis on the Kirkaldy-Willis model. This information is presented and used to analyse the radiographic features of a case study demonstrating a classic representation of this model occurring over a 9-year period in the cervical spine of a patient. Case: A 42-year-old woman presents with a history of chronic neck pain. Her symptoms include reduced range of motion and pins and needles extending down the right arm and into the thumb. Radiological, CT and MRI findings indicate degenerative joint disease, intervertebral disc protrusion at C5/6, and C6/7 right lateral recess stenosis. Conclusion: This case presents a classic demonstration of the Kirkaldy-Willis model, and how degenerative joint disease affects the cervical spine in a patient, occurring over a 9-year period. By better understanding the pathophysiology of joint degeneration, and how degenerative changes in a 5-joint complex progress through 3 identifiable stages, practitioners can recognise early changes, which are visible on routine chiropractic x-rays, and predict the likely outcome of their patient's structural and functional state. This will enable practitioners to provide a better standard of care with emphasis on early preventative medicine.

Cervical Spine Degeneration: Radiographic Analysis Demonstrating the Kirkaldy-Willis Model - a Case Report

America's Religious Crossroads Faith and Community in the Emerging Midwest by Stephen T. Kissel (review)

Conflict between a captain and star player: An ethnodrama of interpersonal conflict experiences

ABSTRACT The purpose of this article is to gain greater understanding of interpersonal conflict between managers and players within an elite team sport environment. We consider conflict from multiple perspectives, and disseminate findings in an accessible way to encourage those involved in team sport to engage with the material. Through the adoption of a narrative inquiry approach, autobiographical extracts recalling incidences of conflict from a manager (Sir Alex Ferguson) and certain key players (e.g. David Beckham) have been analysed using reflexive thematic analysis, with finding presented through the mean of ethnodrama scenes. Such scenes were developed as a dialogue between Ferguson and his players, to illustrate the episodes of conflict through the eyes of both the players and Ferguson, with creative non-fiction techniques used to further bring the script to life. These scripts reflect the differences in the interpretation of the same conflict situations and allow the reader to reflect on the determinants of these conflicts, and the resulting consequences. It is hoped that the ethnodrama enhances further understanding of leader-athlete conflict in elite sport, through illustrating examples of conflict from different perspectives. In addition, the findings provide a stimulus for those working in sports teams to reflect on their own experiences of conflict and consider how such conflict might be prevented or managed.

Understanding coach-athlete conflict: an ethnodrama to illustrate conflict in elite sport

David Courtwright, The Age of Addiction: How Bad Habits Became Big Business

Rev. James McGready: Revival and Community in backcountry North Carolina and the Kentucky frontier

ABSTRACT: Analysing the urban renewal of Boston's West End during the 1950s, we examine how psychiatrists, social scientists and urban planners understood the relationship between the urban environment and mental health. For psychiatrist Erich Lindemann, the West End offered a unique opportunity to study how acute stress and loss affected populations, thus contributing to social psychiatry, which sought to prevent mental illness by addressing factors in the social and physical environment. While Lindemann's project provided a sophisticated response to the often simplistic arguments about the cities and mental health, it also highlighted the challenges of applying social psychiatric theory in practice.

Remembering the West End: social science, mental health and the American urban environment, 1939–1968

Universalism Not of God: An Examination of the System of Universalism; Its Doctrine, Arguments, and Fruits, with the Experience of the Author, During a Ministry of Twelve Years

Within children's geographies there has been an absence concerning sexuality and in particular how this can lead to the discimination and marginalisation of individuals. Similarly, within geographi ...

Placing Heteronormativity : A micro-geographical approach to the school as a space of heteronormative (re)production

Michael Mikulak, The Politics of the Pantry: Stories, Food, and Social Change (Montreal: McGill-Queen's University Press, 2013).

"IN THE LAND OF CANAAN:" RELIGIOUS REVIVAL AND REPUBLICAN POLITICS IN EARLY KENTUCKY

“In the Land of Canaan:” Religious Revival and Republican Politics in Early Kentucky

This chapter discusses the origins of hyperactivity in the United States. It is part of a collection of essays which focus on the dynamic relationship between health and place.

A place for hyperactivity : Sputnik, the cold war “brain race” and the origins of hyperactivity in the United States, 1957-1968

Leslie Iverson. Speed, Ecstasy, Ritalin: The Science of Amphetamines. Oxford: Oxford University Press, 2006.

Book Review: David Herzberg, Happy Pills in America: From Miltown to Prozac, The Johns Hopkins University Press: Baltimore, MD, 2009; x + 279 pp.: 9780801890307, £23.50

When "green" transport planners, cyclists and environmentalists consider the role of cycling in transport policy, many of them often look to cycling provision in China with a mixture of jealousy and encouragement and as an example to hold up to less enlightened, more doubting individuals. However, while it might be true that Europe can learn from studying the role of cycling in China with regard to the state of European policy (Smith, 1994), the situation is perhaps not as exemplary as one might think.

Optimism and Pragmatism in African Politics the Ghana Case 1946-1966

The development of a risk assessment model for the inhalation of brevetoxins

Design And Development Of A Silicon Carbide Chemical Vapor Deposition Reactor

Pregnancy-associated strokes are rare but can have detrimental effects on both mother and baby. A young female patient, 6 days postpartum, suffered a spontaneous intraparenchymal haemorrhage (IPH) and subarachnoid haemorrhage (SAH). The patient exhibited aphasia, right facial droop and right hemiparesis. Serial imaging showed no vascular malformation or other cause of her haemorrhages. Our pregnant patient presented with concurrent IPH and SAH. Given the timing of her stroke and the absence of underlying vascular lesion, it is possible her stroke was a case of IPH and SAH due to reversible cerebral vasoconstriction syndrome (RCVS). More specifically, it may reflect postpartum angiopathy, a subtype of RCVS presenting around 5 days postpartum. Alternatively, this could simply be a subarachnoid extension of a primary IPH.

Abstract Syphilis is a sexually transmitted infection caused by the bacterium Treponema pallidum. Tertiary syphilis, a late-stage multi-visceral complication of the disease is characterized by its diversity of clinical manifestations. Here, we present the first documented case of tertiary syphilis that clinically and radiologically mimicked primary rectal cancer with hepatic metastasis.

A 68-year-old male attended a regional emergency department with left lower quadrant abdominal pain and vomiting. Two days prior, the patient underwent elective colonoscopy for investigation of iron deficiency anaemia, which demonstrated diverticulosis with peridiverticular erythema. On presentation, the patient was febrile to 37.9, with a tender fluctuant swelling at the left lower quadrant suggestive of an abdominal wall abscess. This presentation was on a background of bilateral lung transplant in 2011 requiring immunosuppression with mycophenolate mofetil, tacrolimus and prednisolone. A CT abdomen-pelvis demonstrated bowel wall thickening and fat stranding of the sigmoid colon with an adjacent abdominal wall collection suggestive of a contained sigmoid perforation (Fig. 1). The patient was commenced on intravenous ceftriaxone and metronidazole and underwent incision and drainage of the abscess. Day two post-operatively, the patient developed septic shock with examination of the abdominal wound concerning for necrotising fasciitis, necessitating immediate return to theatre for aggressive debridement (Fig. 2). Post-operatively the patient was admitted to the intensive care unit intubated and on vasopressor support and transferred to an urban tertiary centre for ongoing management. Following transfer, the patient returned to theatre for reassessment of the wound. Faeculent discharge from an opening at the medial aspect of the wound bed was observed, highly suspicious for a colonic fistula. Insertion of a Foley catheter into the tract was performed to divert fistula output and reduce wound contamination. Significant bypassing around the catheter necessitated a laparotomy and Hartmann’s procedure for definitive source control. An approximately 15 cm phlegmonous mass involving the sigmoid colon was densely adhered to the abdominal wall. En bloc resection and end colostomy was performed. The resected specimen demonstrated two pericolic abscess cavities in communication with the bowel lumen, one of which was in continuity with the wound bed (Fig. 3). Serial debridement and VAC dressing changes were undertaken twice weekly. Antibiotics were rationalized to intravenous piperacillin-tazobactam given serial tissue culture isolates of Pseudomonas aeruginosa and Enterococcus faecalis. Sustained clinical improvement allowed step down to the general surgical ward one-week post-laparotomy. The patient was discharged following abdominal wall reconstruction. Necrotising fasciitis (NF) is a severe, rapidly progressive softtissue infection. It is associated with high morbidity and mortality, with early surgical debridement being the principal determinant of survival. NF occurring in association with an enterocutaneous fistula (ECF) is rare, limited to a small number of case reports.

Andrew Wakefield has been struck off by the General Medical Council for his research into a possible link between the Measles, Mumps and Rubella (MMR) vaccine and autism. Although he will appeal the verdict, it is another strike against him and his controversial theory.

To better understand the signaling complexity of AXL, a member of the TAM receptor tyrosine kinase family, we created a physical and functional map of AXL signaling interactions, phosphorylation events, and target-engagement of three AXL tyrosine kinase inhibitors (TKI). We assessed AXL protein-complexes using BioID, effects of AXL TKI on global phosphoproteins using mass spectrometry, and target engagement of AXL TKI using activity-based protein profiling. BioID identifies AXL-interacting proteins that are mostly involved in cell adhesion/migration. Global phosphoproteomics show that AXL inhibition decreases phosphorylation of peptides involved in phosphatidylinositol-mediated signaling and cell adhesion/migration. Comparison of three AXL inhibitors reveals that TKI RXDX-106 inhibits pAXL, pAKT and migration/invasion of these cells without reducing their viability, while Bemcentinib exerts AXL-independent phenotypic effects on viability. Proteomic characterization of these TKIs demonstrates that they inhibit diverse targets in addition to AXL, with Bemcentinib having the most off-targets. AXL and EGFR TKI co-treatment did not reverse resistance in cell line models of Erlotinib-resistance. However, a unique vulnerability was identified in one resistant clone, wherein combination of Bemcentinib and Erlotinib inhibited cell viability and signaling. We also show that AXL is overexpressed in ~30-40% of non-small but rarely in small-cell lung cancer. Cell lines have a wide range of AXL expression, with basal activation detected rarely. Implications: Our study defines mechanisms of action of AXL in lung cancers which can be used to establish assays to measure drug targetable active AXL-complexes in patient tissues and inform the strategy for targeting it's signaling as an anticancer therapy.

Integrated proteomics-based physical and functional mapping of AXL kinase signaling pathways and inhibitors define its role in cell migration.

Small molecule EGFR inhibitors have proven effective in treatment of Non-Small Cell Lung Cancer (NSCLC) with activating EGFR mutations, however there is minimal to no efficacy in wild-type EGFR NSCLC. Amivantamab, an EGFR/MET bispecific antibody, has demonstrated clinical activity across a diverse range of EGFR activating mutations in an ongoing Phase I trial and differentiates from anti-EGFR antibodies tested previously in NSCLC clinical trials due to dual targeting and enhanced interaction with Fc receptors on immune cells. As candidate biomarkers to predict response in wt EGFR disease, EGFR and MET expression (immunohistochemistry (IHC)) and signaling (proximity ligation assays (PLA)), as well as tumor associated macrophage (TAM) content, were assessed in 39 NSCLC wt EGFR patient-derived xenograft (PDX) models. A strong correlation (EGFR r=0.63; p Citation Format: Benjamin Henley, Kristen Chevalier, Matthew Smith, Smruthi Vijayaraghaven, Barbara Bushey, Gerald Chu, Joshua Curtin, Natasa Obermajer, Kathryn Packman, Sylvie Laquerre, Matthew Lorenzi, Eric Haura, Sheri Moores. Efficacy of amivantamab, a bispecific EGFR/MET antibody, correlates with EGFR expression and signaling in NSCLC models with wild-type EGFR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 953.

Abstract 953: Efficacy of amivantamab, a bispecific EGFR/MET antibody, correlates with EGFR expression and signaling in NSCLC models with wild-type EGFR

The ability to interrogate for the presence and distribution of protein-protein complexes (PPCs) is of high importance for the advancement of diagnostic capabilities such as determining therapeutic effects in the context of pharmaceutical development. Herein, we report a novel assay for detecting and visualizing PPCs on formalin-fixed, paraffin-embedded (FFPE) material using a caged hapten. To this end, we synthetically modified a nitropyrazole (NP) hapten with an al-kaline phosphatase (AP)-responsive self-immolative caging group. The AP-labile caging group abrogates antibody binding; however, upon exposure to AP, the native hapten is regenerated. These caged haptens were applied in a prox-imity assay format by the use of a first antibody labeled with caged haptens that can be uncaged by AP conjugated to the second antibody. Only when the two epitopes of interest are in close proximity to one another will the AP interact with the caged hapten and uncage it. The native hapten, which represents the population of PPCs, was then visualized by an anti-hapten antibody conjugated to horseradish peroxidase (HRP), followed by diaminobenzidine (DAB) detec-tion. We provide proof of concept for the detection of protein proximity pairs (β-Catenin:E-Cadherin and EGFR:GRB2), and confirm assay specificity through technical controls involving reagent omission experiments, and biologically by treatment with small molecule kinase inhibitors that interrupt kinase:adaptor complexes.

Fully Automated Protein Proximity Assay in FFPE Tissue using Caged Haptens.

Abstract 1883: Erlotinib resistance via a persister bottleneck results in mixed expression of EGFR T790M and EMT-like state with high AXL expression

Histone deacetylase 8 inhibition suppresses mantle cell lymphoma viability while preserving natural killer cell function.

Treatment options and risk stratification for esophageal adenocarcinomas (EAC) currently rely on pathological criteria such as tumor staging. However, with advancement in immune modulated treatments, there is a need for accurate predictive biomarkers that will help identify high-risk patients and provide novel therapeutic targets. Hence, we analyzed as prognostic classifiers a host of histopathological parameters in conjunction with novel immune biomarkers. Specifically, gene expression levels for CXCL9, IDO1, LAG3, and TIM3 were established in treatment naïve samples. Additionally, PD-L1 and CD8 positivity was determined by immunohistochemical staining. Based on our finding, a Cox model consisting of pathological complete response (CR), LAG3, and CXCL9 provided improved predictability for disease-free survival (DFS) compared to CR alone, and it demonstrated statistical significance for predictability of recurrence (p=0.0001). Likewise, for overall survival (OS), a Cox model constituted of TIM3, CR, and IDO1 performed better than CR alone, and it demonstrated statistical significance for predictability of survival (p = 0.0004). TIM3 was identified as the best predictor for OS (HR=4.43, p=0.0023). In conclusion, given the paucity of treatment options for EAC, evaluation of these biomarkers early in the disease course will lead to better risk stratification of patients and much needed alternatives for improved therapy.

Prognostic immune markers for recurrence and survival in locally advanced esophageal adenocarcinoma

Abstract 2632: Increased recurrence and clinical grade in renal cell carcinomas associated with novel EGFR splice variants

Abstract 1616: Novel caged hapten proximity assay platform enables detection of oncogenic signaling-associated complexes in the clinical pathology laboratory setting

During the last decade, our understanding of cancer cell signaling networks has significantly improved, leading to the development of various targeted therapies that have elicited profound but, unfortunately, short-lived responses. This is, in part, due to the fact that these targeted therapies ignore context and average out heterogeneity. Here, we present a mathematical framework that addresses the impact of signaling heterogeneity on targeted therapy outcomes. We employ a simplified oncogenic rat sarcoma (RAS)-driven mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase-protein kinase B (PI3K-AKT) signaling pathway in lung cancer as an experimental model system and develop a network model of the pathway. We measure how inhibition of the pathway modulates protein phosphorylation as well as cell viability under different microenvironmental conditions. Training the model on this data using Monte Carlo simulation results in a suite of in silico cells whose relative protein activities and cell viability match experimental observation. The calibrated model predicts distributional responses to kinase inhibitors and suggests drug resistance mechanisms that can be exploited in drug combination strategies. The suggested combination strategies are validated using in vitro experimental data. The validated in silico cells are further interrogated through an unsupervised clustering analysis and then integrated into a mathematical model of tumor growth in a homogeneous and resource-limited microenvironment. We assess posttreatment heterogeneity and predict vast differences across treatments with similar efficacy, further emphasizing that heterogeneity should modulate treatment strategies. The signaling model is also integrated into a hybrid cellular automata (HCA) model of tumor growth in a spatially heterogeneous microenvironment. As a proof of concept, we simulate tumor responses to targeted therapies in a spatially segregated tissue structure containing tumor and stroma (derived from patient tissue) and predict complex cell signaling responses that suggest a novel combination treatment strategy.

Cell signaling heterogeneity is modulated by both cell-intrinsic and -extrinsic mechanisms: An integrated approach to understanding targeted therapy

MA 12.05 Genomic Profiling of EGFR T790M Mutated Non-Small Cell Lung Cancer to Evaluate the Mechanisms of Resistance to Osimertinib

Objective: The aim of this study was to assess the impact of chemoradiation on the immune microenvironment to influence and optimally design future neoadjuvant clinical trials. Summary Background Data: Programmed death (PD)-1 inhibitors in metastatic gastroesophageal cancer have demonstrated response rates of approximately 25% in programmed death ligand-1 (PD-L1+) tumors. Unfortunately, the majority of patients do not respond. Therefore, a rationale strategy of combining immunotherapeutic agents with chemoradiation in earlier stage esophageal cancer may prevent metastatic disease in patients. Methods: To determine the effects of chemoradiation on resected esophageal adenocarcinomas, we examined the immune microenvironment pre- and post-chemoradiation using immunohistochemistry, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and functional analysis of tumor-infiltrating lymphocytes. Additionally, to assess the duration and dependency of radiation-induced PD-L1 upregulation, a surgical rat reflux model of esophageal adenocarcinoma is used. First, tumor-bearing animals were dosed with single-fraction 13Gy or 16Gy radiation to determine safety, dose correlation, and PD-L1 upregulation using qRT-PCR post-radiation. Next, longitudinal PD-L1 expression levels within individual animals were determined using serial endoscopic biopsies at baseline, 1, 5, and 9 weeks post 16Gy radiation. Results: The majority of cancers displayed enhanced interferon &ggr; and activated CD8+ T lymphocytes at the tumor stroma interface. These tumors also demonstrated enhanced upregulation of PD-L1 and multiple other immune checkpoints including TIM3, GITR, IDO1, LAG3, OX40, and KIR. The animal model results indicated PD-L1 upregulation is dose-dependent and transiently elevated post radiation exposure. Conclusions: Collectively, these findings provide insights into the evolving immune landscape after chemoradiation and have significant implications for neoadjuvant trial designs that will combine radiotherapy with immune checkpoint inhibitors.

The Dynamic and Transient Immune Microenvironment in Locally Advanced Esophageal Adenocarcinoma Post Chemoradiation

Oncogenic kinase fusions of ALK, ROS1, RET, and NTRK1 act as drivers in human lung and other cancers. Residual tumor burden following treatment of ALK or ROS1+ lung cancer patients with oncogene-targeted therapy ultimately enables the emergence of drug-resistant clones, limiting the long-term effectiveness of these therapies. To determine the signaling mechanisms underlying incomplete tumor cell killing in oncogene-addicted cancer cells, we investigated the role of EGFR signaling in drug-naïve cancer cells harboring these oncogene fusions. We defined three distinct roles for EGFR in the response to oncogene-specific therapies. First, EGF-mediated activation of EGFR blunted fusion kinase inhibitor binding and restored fusion kinase signaling complexes. Second, fusion kinase inhibition shifted adaptor protein binding from the fusion oncoprotein to EGFR. Third, EGFR enabled bypass signaling to critical downstream pathways such as MAPK. While evidence of EGFR-mediated bypass signaling has been reported after ALK and ROS1 blockade, our results extended this effect to RET and NTRK1 blockade and uncovered the other additional mechanisms in gene fusion-positive lung cancer cells, mouse models, and human clinical specimens before the onset of acquired drug resistance. Collectively, our findings show how EGFR signaling can provide a critical adaptive survival mechanism that allows cancer cells to evade oncogene-specific inhibitors, providing a rationale to cotarget EGFR to reduce the risks of developing drug resistance. Cancer Res; 77(13); 3551-63. ©2017 AACR.

EGFR Mediates Responses to Small-Molecule Drugs Targeting Oncogenic Fusion Kinases.

4060Background: PD-1 inhibitors in metastatic gastroesophageal cancer have demonstrated response rates of approximately 25%. Unfortunately, the majority of patients do not respond. Therefore, a rat...

Magnitude and duration of immune checkpoint up-regulation and changes in the immune microenvironment post chemo-radiation (CRT) in esophageal cancer.

Purpose: Targeting MET in cancer is hampered by lack of diagnostics that accurately reflect high MET signaling and dependence. We hypothesized that assays reflecting MET signaling associated protein complexes could redefine tumors dependent on MET and could add additional precision beyond genomic assessments. Experimental Design: We used biochemical approaches, cellular viability studies, and proximity ligation assays to assess MET dependence. We examined MET signaling complexes in lung cancer patient specimens (N = 406) and patient-derived xenograft (PDX) models of solid tumors (N = 308). We evaluated response to crizotinib in a MET-amplified cohort of PDX models of lung cancer (N = 6) and provide a case report of a lung cancer patient harboring a Δexon14 MET splice variant. Results: We found the interaction of MET with the adaptor protein GRB2 is necessary for oncogenic survival signaling by MET. MET-GRB2 complexes were identified only within MET-amplified PDX models and patient specimens but exhibit substantial variability. Lack of MET-GRB2 complexes was associated with lack of response to MET TKI in cell lines and PDX models. Presence of MET-GRB2 complexes can further subtype tumors with Δexon14 MET splice variants. Presence of these complexes correlated with response to crizotinib in one patient with Δexon14 MET lacking MET gene amplification. Conclusions: Proximity assays measuring MET-GRB2 signaling complexes provide novel insights into MET-mediated signaling and could complement current clinical genomics-based assay platforms. Clin Cancer Res; 23(22); 7084–96. ©2017 AACR.

MET–GRB2 Signaling-Associated Complexes Correlate with Oncogenic MET Signaling and Sensitivity to MET Kinase Inhibitors

Abstract A rat model of surgically induced reflux recapitulates the development and progression of human esophageal adenocarcinoma (EAC). In this study, reflux was induced in rats followed by postoperative endoscopy with biopsy, to diagnose and monitor disease progression. Overall, percentage agreement between visual endoscopy and gold standard histology was 95%, with disease-specific classification accuracies of 100% and 75% for Barrett’s with dysplasia and EAC, respectively. Additionally, the percentage agreement for biopsy in tumors >4 mm was 75%. Thereby, establishing endoscopic evaluation as a reliable tool to assess disease progression and provide biopsies for downstream correlates in a de novo EAC model.

Serial Endoscopic Evaluation of Esophageal Disease in a Cancer Model: A Paradigm Shift for Esophageal Adenocarcinoma (EAC) Drug Discovery and Development

INTRODUCTION: Patients with ALK-rearranged non-small cell lung cancer (NSCLC) derive significant anti-tumor responses when treated with ALK tyrosine kinase inhibitors (TKIs), such as crizotinib, the first-in-class ALK TKI. However despite the high response rates to these agents, acquired resistance to ALK TKI therapy remains a significant barrier to overcome in order to maximize therapeutic responses in patients with ALK+ lung cancer. In crizotinib-resistant tumors, EGFR activation has been demonstrated to mediate acquired resistance in several independent studies. The tumor suppressor gene product MIG-6 (encoded by ERFFI1) acts as a natural inhibitor of signaling through EGFR (ErbB1) and other ErbB family members. However, a role for MIG-6 in ALK+ lung cancer has not yet been elucidated. Here, we investigated the regulation of human MIG-6 in ALK+ lung cancer cells. DESIGN: MIG-6 expression, protein interaction and phosphorylation status were evaluated in ALK+ lung cancer cell lines and human tumor samples. The impact of MIG-6 loss and gain of function on ErbB receptor activity and on cell proliferation/survival were determined in several models of TKI-sensitive and TKI-resistant ALK+ lung cancer. RESULTS: MIG-6 protein level is regulated by EML4-ALK fusion protein at both transcriptional and post-translational levels. Genetic or pharmacologic knock-down of ALK significantly reduced MIG-6 protein levels in ALK+/TKI sensitive cells. We established a novel interaction between MIG-6 and ALK fusion proteins (both EML4-ALK and other fusion partners), and this association was dependent on ALK kinase activity. MIG-6 can also be tyrosine-phosphorylated by EML4-ALK and be threonine-phosphorylated through EML4-ALK-dependent MAPK activation. The reduced MIG-6 protein level was accompanied by increased total and phosphorylated ErbB family members (EGFR, HER2, and HER3) in ALK+/TKI sensitive lung cancer cells. Consistent with this observation, MIG-6 protein level is also attenuated in ALK+/TKI resistant cells, following the decreased EML4-ALK activity, while EGFR signaling activity is remarkably up-regulated in these resistant cells. Crizotinib-resistant cells were re-sensitized upon exposure to EGFR/HER2 inhibitors in combination with crizotinib. In addition, MIG-6 reconstitution impeded the development of early adaptive resistance in crizotinib-sensitive cells and was also able to inhibit the proliferation of crizotinib-resistant cells. CONCLUSION: Our study presents an in-depth mechanistic understanding of how ErbB family members, such as EGFR, are up-regulated at the time of crizotinib resistance and provides insights into the early escape mechanisms tumor may have to evade ALK TKI therapy. Citation Format: Huan Qiao, Yingjun Yan, Matthew A. Smith, Eric B. Haura, Marc Ladanyi, Christine M. Lovly. Novel role for MIG-6 in mediating TKI resistance in ALK -rearranged lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 311.

Abstract 311: Novel role for MIG-6 in mediating TKI resistance inALK-rearranged lung cancer

Non-small cell lung cancers (NSCLC) marked by EGFR mutations tend to develop resistance to therapeutic EGFR inhibitors, often due to secondary mutation EGFR(T790M) but also other mechanisms. Here we report support for a rationale to target IKBKE, an IκB kinase family member that activates the AKT and NF-κB pathways, as one strategy to address NSCLC resistant to EGFR inhibitors. While wild-type and mutant EGFR directly interacted with IKBKE, only mutant EGFR phosphorylated IKBKE on residues Y153 and Y179. The unphosphorylatable mutant IKBKE-Y153F/Y179-F that lost kinase activity failed to activate AKT and inhibited EGFR signaling. In clinical specimens of NSCLC with activating mutations of EGFR, we observed elevated levels of phospho-Y153 IKBKE. IKBKE ablation with shRNA or small-molecule inhibitor amlexanox selectively inhibited the viability of NSCLC cells with EGFR mutations in vitro In parallel, we found that these treatments activated the MAPK pathway due to attenuation of an IKBKE feedback mechanism. In vivo studies revealed that combining amlexanox with MEK inhibitor AZD6244 significantly inhibited the xenograft tumor growth of NSCLC cells harboring activating EGFR mutations, including EGFR(T790M) Overall, our findings define IKBKE as a direct effector target of EGFR and provide a therapeutic rationale to target IKBKE as a strategy to eradicate EGFR-TKI-resistant NSCLC cells. Cancer Res; 76(15); 4418-29. ©2016 AACR.

IKBKE Is a Substrate of EGFR and a Therapeutic Target in Non-Small Cell Lung Cancer with Activating Mutations of EGFR.

MET:GRB2 complexes define a subset of lung cancer with potential vulnerability to MET inhibition

Signaling pathways controlling cellular proliferation are major targets of cancer therapeutics, however, accurate assessment of activation status of targetable signaling cascades remains a challenge. We have developed proximity ligation assay (PLA)-based methodologies to detect signaling-associated complexes for a variety of receptor tyrosine kinases, intracellular adaptors and phosphorylation events in formalin-fixed, paraffin-embedded tissues. By assessing the degree of functional association of oncogenic kinases (such as EGFR and ALK) with intracellular adaptor molecules, it is possible to characterize the activation status of targetable kinase activity and monitor variations across tissue types, within tissues and in response to perturbations. Here, we present data for a panel of PLAs using cell lines, patient specimens and patient-derived xenografts models. We show that EGFR-GRB2 PLA reflects erlotinib pharmacodynamics and has predictive capacity for response to both erlotinib and cetuximab. We demonstrate that PLA can identify alterations in multiple bypass signaling cascades associated with therapeutic escape using both in vitro models of acquired resistance and patient specimens. We observe striking intratumoral variation in abundance of signaling-associated complexes, likely reflecting influences from the tumor microenvironment and phenotypic heterogeneity. We are currently expanding our PLA panel to include emerging therapeutic targets (MET and FGFR1) and evaluating performance of these assays to characterize signaling complexes in circulating tumor cells obtained from advanced stage non-small cell lung cancer patients. Collectively, our data suggests that PLA-based methodologies can be harnessed to explore the cancer interactome and can be important tools to enable precision medicine. Citation Format: Matthew A. Smith, Leah Clark, Richard Hall, Kate Fisher, Takeshi Yoshida, Vincent Vuaroqueaux, Heinz-Herbert Fiebig, Ann Chen, Eric B. Haura. Characterizing pathway vulnerabilities and tumor heterogeneity through signaling-associated complexes. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B54.

Abstract B54: Characterizing pathway vulnerabilities and tumor heterogeneity through signaling-associated complexes

A new assay could improve identification of tumors that are likely to respond to therapies that inhibit epidermal growth factor receptor (EGFR) signaling. Abstract This Podcast features an interview with Eric Haura and Matthew Smith, authors of a Research Article that appears in the 13 January 2015 issue of Science Signaling, about an assay that may expand the identification of tumors that are likely to respond to therapies that inhibit epidermal growth factor receptor (EGFR) signaling. EGFR is a transmembrane receptor tyrosine kinase that induces intracellular signaling in response to binding to extracellular ligands, such as growth factors and cytokines. EGFR signaling is abnormally highly active and drives tumor cell proliferation in diverse types of cancer. Drugs that target EGFR are used to treat some of these cancers. Aberrant EGFR signaling may result from activating mutations, which can be detected by genetic analysis of the tumor cells. However, there may be other causes for increased EGFR signaling in cancer cells in addition to those that can be detected by gene sequencing. Smith et al. have developed an assay that can detect increased EGFR signaling in cancer cells by measuring the interaction of EGFR with the adaptor protein GRB2, which is required for EGFR signaling. The assay detects aberrant EGFR signaling even in tumors with no activating mutations in EGFR. This assay could be used to improve identification and treatment of EGFR-driven cancers.

A method for detecting receptor tyrosine kinase signaling in patient tumor samples may improve diagnosis and therapy. Visualizing Protein Complexes in Clinical Samples Aberrant activation of receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR), plays a role in cancer initiation, progression, and acquired drug resistance. Genetic analysis may not always reveal aberrant activity of receptor tyrosine kinase signaling; thus, detecting active signaling through these kinases in clinical samples should improve prognostication and personalization of therapies. Diverse cancers, for example, those found in the lung, colon, or head and neck, can have aberrant activation of EGFR signaling, and EGFR-targeted therapies are used to treat these diseases. Smith et al. developed a proximity ligation assay (PLA) to detect the interaction between EGFR and the requisite signaling adaptor GRB2 (growth factor receptor–bound protein 2) in common clinical preparations. EGFR:GRB2 PLA recapitulated traditional readouts of active EGFR signaling in cultured cells, in a panel of tumor xenografts in mice derived from primary patient samples, and in samples from three large cohorts of human patients. Moreover, EGFR:GRB2 PLA detected increased EGFR signaling in tumors with wild-type EGFR, which would have been undetectable by genetic analysis, and was predictive of therapeutic response to EGFR inhibitors in both mice and humans. Thus, using PLA to detect signaling-associated protein complexes has the potential to improve current diagnostic measures. Strategies to measure functional signaling-associated protein complexes have the potential to augment current molecular biomarker assays, such as genotyping and expression profiling, used to annotate diseases. Aberrant activation of epidermal growth factor receptor (EGFR) signaling contributes to diverse cancers. We used a proximity ligation assay (PLA) to detect EGFR in a complex with growth factor receptor–bound protein 2 (GRB2), the major signaling adaptor for EGFR. We used multiple lung cancer cell lines to develop and characterize EGFR:GRB2 PLA and correlated this assay with established biochemical measures of EGFR signaling. In a panel of patient-derived xenografts in mice, the intensity of EGFR:GRB2 PLA correlated with the reduction in tumor size in response to the EGFR inhibitor cetuximab. In tumor biopsies from three cohorts of lung cancer patients, positive EGFR:GRB2 PLA was observed in patients with and without EGFR mutations, and the intensity of EGFR:GRB2 PLA was predictive of overall survival in an EGFR inhibitor–treated cohort. Thus, we established the feasibility of using PLA to measure EGFR signaling–associated protein complexes in patient-based materials, suggesting the potential for similar assays for a broader array of receptor tyrosine kinases and other key signaling molecules.

Annotation of human cancers with EGFR signaling–associated protein complexes using proximity ligation assays

Introduction: Interleukin-6 (IL-6) can activate downstream signaling pathways in lung cancer cells, such as the STAT3 pathway, and is reported to be produced by tumor cells with activating EGFR mutations. We examined IL-6/STAT3 in lung cancer tumor tissues and the effects of siltuximab, a neutralizing antibody to human IL-6, in mouse models of lung cancer. Methods: IL-6 and STAT3 activation levels were compared with tumor histology and presence of KRAS mutations in snap-frozen, non–small-cell lung cancer tumors. The effects of siltuximab alone or in combination with erlotinib were examined in mouse xenograft models constructed using three cell line xenograft models and one primary explant mouse model. We examined the influence of cancer-associated fibroblasts (CAFs) on tumor growth and siltuximab effects. Results: IL-6 levels were higher in tumors of squamous cell versus adenocarcinoma histology and were not associated with presence of KRAS mutations. Tyrosine phosphorylation status of STAT3 did not correlate with tumor IL-6 levels. Serine phosphorylation of STAT3 was correlated with KRAS mutation status. Both tumor and stromal cells contributed to total IL-6 within tumors. Siltuximab had minimal effect as a single agent in xenografts with tumor cells alone; however, in models coadministered with CAFs, siltuximab had more potent effects on tumor inhibition. We observed no effects of combined erlotinib and siltuximab. Conclusions: IL-6 is elevated in subsets of human NSCLCs, especially with squamous cell histology. Tumors supported by stromal production of IL-6 seem to be the most vulnerable to tumor growth inhibition by siltuximab.

Antitumor Efficacy of the Anti-Interleukin-6 (IL-6) Antibody Siltuximab in Mouse Xenograft Models of Lung Cancer

Purpose : Irreversible EGFR-tyrosine kinase inhibitors (TKIs) are thought to be one strategy to overcome EGFR-TKI resistance induced by T790M gate-keeper mutations in non-small cell lung cancer (NSCLC), yet they display limited clinical efficacy. We hypothesized that additional resistance mechanisms that cooperate with T790M could be identified by profiling tyrosine phosphorylation in NSCLC cells with acquired resistance to reversible EGFR-TKI and harboring T790M. Experimental Design: We profiled PC9 cells with TKI-sensitive EGFR mutation and paired EGFR-TKI-resistant PC9GR (gefitinib-resistant) cells with T790M using immunoaffinity purification of tyrosine-phosphorylated peptides and mass-spectrometry-based identification/quantification. Profiles of erlotinib perturbations were examined. Results: We observed a large fraction of the tyrosine phosphoproteome was more abundant in PC9- and PC9GR-erlotinib treated cells, including phosphopeptides corresponding to MET, IGF, and AXL signaling. Activation of these receptor tyrosine kinases by growth factors could protect PC9GR cells against the irreversible EGFR-TKI afatinib. We identified a Src-family kinase (SFK) network as EGFR-independent and confirmed that neither erlotinib nor afatinib affected Src phosphorylation at the activation site. The SFK-inhibitor dasatinib plus afatinib abolished Src phosphorylation and completely suppressed downstream phosphorylated Akt and Erk. Dasatinib further enhanced anti-tumor activity of afatinib or T790M-selective EGFR-TKI (WZ4006) in proliferation and apoptosis assays in multiple NSCLC cell lines with T790M mediated resistance. This translated into tumor regression in PC9GR xenograft studies with combined afatinib and dasatinib. Conclusions: Our results identified both co-drivers of resistance along with T790M and support further studies of irreversible or T790M-selective EGFR inhibitors combined with dasatinib in NSCLC patients with acquired T790M. a the molecular between EGFR-TKI-sensitive and -resistant pairs. The driving force this the limited efficacy of irreversible EGFR-TKIs in targeting T790M, as shown in both preclinical and clinical studies (8, 9, 12, 14-19), and the ability of other tyrosine kinases, especially RTKs, to limit EGFR-TKI efficacy. Through a systematic interrogation of pTyr peptides and proteins using LC-MS/MS, we identified both RTKs and non-RTKs able to be recruited to confer erlotinib sensitivity. In PC9GR cells, we identified higher levels of pTyr peptides corresponding to MET signaling, including more MET, ROR1, and Gab1/2 proteins. Interestingly, this coordinated activation of MET signaling was not secondary to MET gene amplification, as our FISH results revealed no amplification of the MET gene. The results with the basal phosphoproteome corresponded to HGF’s strong effects in protecting both PC9 and PC9GR cells from erlotinib or afatinib, respectively. Additionally, these results suggest a form of “lineage” addiction, whereby resistant cells with T790M can carry forward RTKs that can cooperate to drive resistance. Importantly, these results suggest that interrogating protein activation status or network signaling may highlight proteins that play a role in protecting cells against EGFR-TKI, especially when in a microenvironment rich with cognate growth factor ligands. Despite observing more AXL pTyr peptides in PC9GR cells, we demonstrated no ability of AXL pathway activation by Gas6 ligand to drive resistance to either erlotinib or afatinib. not clear, our of of pTyr peptides. adaptive resistance to targeted agents and could in some cases with factors, such as growth factors, to limit TKI efficacy. Collectively, these results suggest that cell intrinsic (receptors, signaling proteins) and extrinsic (ligands) factors can collaborate to drive resistance to kinase inhibitors in a systems-level manner. Our phosphoproteomics analyses in PC9 and PC9GR cells demonstrated that SFKs are also critical as an EGFR-independent co-signal in NSCLC cells with T790M. These results were enabled by tyrosine phosphorylation profiling combined with analysis of proteins based on known protein-protein interactions. We validated the inferences derived from the phosphoproteomics by showing that afatinib combined with dasatinib resulted in anti-tumor activity regarding cell proliferation and apoptosis in and HCC827-T790M cells (each harboring T790M). These results appear to be generalized to additional T790M EGFR-TKIs, as dasatinib demonstrated similar combination effects with the T790M-selective EGFR-TKI WZ4002 (40). We did not observe combination effects with afatinib plus dasatinib compared to either agent alone in cells with TKI-sensitive EGFR mutation only (PC9, HCC4006, and HCC827 cells) or wild-type EGFR (H460, A549, and H1299 cells). The enhanced apoptosis with combined afatinib and dasatinib in the cells with T790M translated into improved in vivo effects on tumor growth in PC9GR cells. Collectively, our results suggest that dasatinib can be generally used as a combination therapy with irreversible or T790M-selective EGFR-TKIs for NSCLC patients results of cell models. In addition, our mass spectrometry data from tumor samples with TKI-sensitive EGFR mutation demonstrated a high degree of overlap with results from cell models, thereby validating the overall approach. These results from tumor samples suggest that our results from lung cancer cell line models are applicable to translate in to the clinic. Our previous chemical and phosphoproteomic characterization identified nearly 40 different kinase targets of dasatinib and showed that SRC, FYN, and EGFR are relevant targets for dasatinib action in NSCLC (32). Our recent phase I/II study showed that dasatinib combined with erlotinib is tolerable, with 63% of advanced NSCLC patients showing disease control, including two having partial response and one having bone response (48). Another group also showed that dasatinib combined with erlotinib is safe and feasible in NSCLC Based on these clinical studies along with the experiments reported here, dasatinib has potential clinical activity in NSCLC treatment, but this is limited to combinations with T790M-targeted agents and in genotype-specific patients. This will be formally tested in a phase I trial of afatinib and dasatinib (NCT01999985). Our results also highlight the ability of phosphoproteomics to identify other important mediators of drug sensitivity, and examination of these proteins may be important in clinical studies of T790M-targeting agents.

Tyrosine phosphoproteomics identified both co-drivers and co-targeting strategies for T790M-related EGFR-TKI resistance in non-small cell lung cancer RUNNING TITLE: Phosphoproteomics of EGFR-TKI resistance

Purpose: Irreversible EGFR-tyrosine kinase inhibitors (TKI) are thought to be one strategy to overcome EGFR-TKI resistance induced by T790M gatekeeper mutations in non–small cell lung cancer (NSCLC), yet they display limited clinical efficacy. We hypothesized that additional resistance mechanisms that cooperate with T790M could be identified by profiling tyrosine phosphorylation in NSCLC cells with acquired resistance to reversible EGFR-TKI and harboring T790M. Experimental Design: We profiled PC9 cells with TKI-sensitive EGFR mutation and paired EGFR-TKI–resistant PC9GR (gefitinib-resistant) cells with T790M using immunoaffinity purification of tyrosine-phosphorylated peptides and mass spectrometry–based identification/quantification. Profiles of erlotinib perturbations were examined. Results: We observed a large fraction of the tyrosine phosphoproteome was more abundant in PC9- and PC9GR-erlotinib–treated cells, including phosphopeptides corresponding to MET, IGF, and AXL signaling. Activation of these receptor tyrosine kinases by growth factors could protect PC9GR cells against the irreversible EGFR-TKI afatinib. We identified a Src family kinase (SFK) network as EGFR-independent and confirmed that neither erlotinib nor afatinib affected Src phosphorylation at the activation site. The SFK inhibitor dasatinib plus afatinib abolished Src phosphorylation and completely suppressed downstream phosphorylated Akt and Erk. Dasatinib further enhanced antitumor activity of afatinib or T790M-selective EGFR-TKI (WZ4006) in proliferation and apoptosis assays in multiple NSCLC cell lines with T790M-mediated resistance. This translated into tumor regression in PC9GR xenograft studies with combined afatinib and dasatinib. Conclusions: Our results identified both codrivers of resistance along with T790M and support further studies of irreversible or T790M-selective EGFR inhibitors combined with dasatinib in patients with NSCLC with acquired T790M. Clin Cancer Res; 20(15); 4059–74. ©2014 AACR.

Tyrosine Phosphoproteomics Identifies Both Codrivers and Cotargeting Strategies for T790M-Related EGFR-TKI Resistance in Non–Small Cell Lung Cancer

In a report accompanying our article, Spigel et al present their findings on combining erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), with onartuzumab (MetMAb; Genentech, South San Francisco, CA), a humanized monovalent monoclonal antibody that blocks ligand activation of MET receptor tyrosine kinase (RTK). MET-positive patients (defined by immunohistochemistry) treated with erlotinib and onartuzumab demonstrated improved progression-free and overall survival, whereas MET-negative patients had worse outcomes. This article provides an overview of signaling control by EGFR and MET and the biologic rationale for cotargeting strategies. EGFR and MET are membrane-bound RTKs consisting of extracellular domains that bind to growth factors and intracellular domains that contain a kinase domain (Fig 1). MET is activated by its cognate ligand, hepatocyte growth factor (HGF), which is produced by stromal cells, also in an autocrine fashion. EGFR is activated by several ligands, including EGF, transforming growth factor alpha (TGF ), and heparin-binding EGF. On receptor binding of the ligands, the kinase domain becomes activated, leading to transautophosphorylation of tyrosine residues on the cytoplasmic tail. Phosphorylation of these tyrosine residues creates intramolecular docking sites for proteins containing Src homology 2 domains that serve as readers for tyrosine phosphorylation. This includes adaptor proteins such as growth factor receptor–bound protein 2 (GRB2), GAB1 (GRB2-associated binding protein 1), and Src homology 2–containing transforming protein 1 (SHC1). These proteins serve as scaffolds to support signal transduction to the mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), phospholipase C (PLC), and signal transducer and activator of transcription (STAT) pathways. EGFR and MET use a highly overlapping repertoire of signaling adaptors and downstream effector pathways, highlighting their combined ability to codrive oncogenic signaling. Three general approaches are being employed in clinic to target EGFR and MET. The first uses small-molecule TKIs, such as erlotinib for EGFR and crizotinib for MET, that bind the ATP-binding pocket in the kinase domain and inhibit the kinase function. The second approach uses antibody therapy directed against the extracellular domain of the MET receptor (onartuzumab) or the HGF ligand (ficlatuzumab). The third approach targets downstream proteins involved in signaling, such as inhibitors of PI3K, or molecules regulating receptor trafficking and degradation, such as heat shock proteins. The EGFR pathway can be activated in lung cancer through genomic events, such as activating EGFR mutations or gene amplification, or through tumor environmental events, such as autocrine production of EGFR-activating ligands. Likewise, MET activation occurs through HGF produced in the tumor microenvironment and through MET gene amplification. MET amplification by fluorescent in situ hybridization occurs in approximately 5% to 15% of lung adenocarcinomas. Increased MET is associated with advanced stage of disease, poor outcome, brain metastasis, and high levels of EGFR. Coactivation of EGFR and MET occurs in subsets of lung cancer cell lines and tumor tissues and is associated with aggressive disease. In cells lacking EGFR mutation or high levels of MET, activation of either receptor can produce extensive signaling crosstalk to the opposing RTK and downstream substrates. EGFR activation can induce accumulation of activated MET protein through a c-SRC– dependent mechanism, and dual MET/EGFR inhibition has shown increased activity in xenograft models. Phosphoproteomic analysis of lung tumors and cell lines can identify tumors with concomitant EGFR and MET activation. EGFR, either through mutation or ligand-mediated activation, can also regulate MET levels through hypoxia-inducible factor-1 . Importantly, MET signaling is one actionable mechanism driving resistance to EGFR TKIs. MET activation can drive intrinsic as well as acquired resistance to EGFR through genomic and tumor microenvironment–mediated mechanisms. Primary resistance to anti-EGFR antibody therapy has been associated with MET activation in primary explant models of lung cancer. Approximately 5% of EGFR mutation–positive tumors with acquired resistance to EGFR TKIs are found to have MET gene amplification. Mechanistically, amplified MET co-opts use of ERBB3 to maintain the PI3K pathway activation. Combining MET and EGFR TKIs or EGFR/HSP90 inhibition has been effective in mouse models of lung cancer with T790M EGFR and MET amplification. High levels of HGF are associated with intrinsic or acquired resistance to EGFR TKIs in patients with lung cancer with activating EGFR mutations and in those with other solid tumors. HGF production by stromal fibroblasts leads to fibroblast-induced JOURNAL OF CLINICAL ONCOLOGY U N D E R S T A N D I N G T H E P A T H W A Y VOLUME 31 NUMBER 32 NOVEMBER 1

Signaling control by epidermal growth factor receptor and MET: rationale for cotargeting strategies in lung cancer.

In the era of precision medicine, matching patients to targeted therapies is a critical goal and novel biomarker strategies must be implemented as new therapeutic options are introduced into the clinic. However, most traditional biomarkers fail to capture the actual signaling activity occurring within a patient's tumor. Proximity ligation assays (PLA) represent a novel approach to quantify receptor tyrosine kinase activity in clinical specimens, yielding a fluorescent readout of in situ signaling complexes. We have developed PLA assays for multiple receptor tyrosine kinase-adaptor pairs, including EGFR in complex with its major adaptor protein, GRB2. Here, we demonstrate robust performance of these assays in both cell lines and FFPE tissue specimens and provide evidence of predictive biomarker capacity for tyrosine kinase inhibitor response in lung cancer patients.

For EGFR-GRB2, we demonstrate PLA is highly sensitive and specific, reflecting kinase activity and not merely expression levels of EGFR or GRB2. In non-small cell lung cancer (NSCLC) cell lines, high PLA signal is associated with EGFR mutation status and levels of phospho-EGFR. PLA also correlates with results from co-immunoprecipitation experiments and is abrogated by erlotinib in a dose-dependent manner. In multiple cell line xenograft models, PLA signal is observed in cytokeratin-staining regions and reveals dissociation of EGFR-GRB2 signaling complexes in response to erlotinib. In patient-derived lung adenocarcinoma xenografts, significantly higher PLA signal is observed in EGFR mutant xenografts relative to wildtype xenografts and is strongly reduced with erlotinib treatment. We have analyzed three cohorts of mixed histology NSCLC tumor specimens (N =354 patients) and scored these on a 0-3+ scale, finding good agreement of incidence of ≥ 2 PLA score across the three cohorts. EGFR protein expression levels as determined by Automated Quantitative Analysis (AQUA) correlate with EGFR-GRB2 PLA signal, but clear instances are defined where PLA signals are discordant, indicating “value-added” over EGFR expression analysis. High PLA score was not limited to adenocarcinomas and was observed in multiple histologies, with significant enrichment in metastatic brain lesions (P<.0001). PLA signal was enriched in tumors with known EGFR mutation status (P<0.01 by x2), but we also identified high signal in 24.5% (13 of 53) of KRAS mutant lung cancers and in 34% (26 of 77) of lung cancers lacking either EGFR or KRAS mutations (WT/WT). Among erlotinib-treated patients with follow-up data (N=91), we identified a strong trend of higher EGFR-GRB2 PLA signal associated with improved overall survival (P = 0.127) and a near doubling in median survival (10 months vs. 20 months) which was not observed when EGFR expression was evaluated by AQUA. Furthermore, PLA assays can be used on archival specimens in which phospho-IHC fails and can also be conducted using brightfield microscopy detection.

Collectively, our data indicate that PLA assays measuring EGFR:GRB2 signaling complexes can serve as biomarkers for druggable kinase activity. We believe this novel proteome-level approach has the potential to be applied in a predictive capacity in multiple malignancies.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B27.

Citation Format: Matthew A. Smith, Richard Hall, Kate Fisher, Ann Chen, Eric B. Haura. Proximity ligation assays as biomarkers for receptor tyrosine kinase activity in lung tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B27.

Abstract B27: Proximity ligation assays as biomarkers for receptor tyrosine kinase activity in lung tumors.

Predictive biomarkers are critical to optimize the use of receptor tyrosine kinase (RTK) inhibitors for cancer therapy. Because multi-protein complexes are critical to maintain oncogenic signaling, we hypothesized that assays that measure protein-protein interactions could identify patients with RTK activity and predict RTK inhibitor response. We developed in situ proximity ligation assays (PLA) to assess the degree of active EGFR signaling in both non-small cell lung cancer (NSCLC) cell lines and formalin-fixed paraffin-embedded (FFPE) patient specimens with the goal of establishing PLA assays as biomarkers of erlotinib sensitivity. Using in situ PLA, we evaluated EGFR association with its signaling adaptors, GRB2 and SHC1. By confocal microscopy we observed increased PLA signals in EGFR mutant NSCLC cell lines (PC9, H1650, HCC4006, HCC827) relative to EGFR wildtype (H23, H1299, H322, A549), indicative of constitutively active signaling complexes in mutant cell lines. PLA signal intensity was independent of EGFR, GRB2 and SHC1 protein expression levels, but did correlate with co-IP and pEGFR immunoblot results. Erlotinib dose-dependently reduced PLA signals in PC9 cells. H1650 xenografts exhibited high PLA signals that were reduced by erlotinib, corresponding with tumor shrinkage. Conversely, low PLA signals were observed in xenografts from EGFR wildtype cell lines (H322, H157). In human xenografts, PLA signals were significantly higher in EGFR mutant xenografts and reduced by erlotinib. In human FFPE specimens, PLA signals were absent in normal non-epithelial tissues and low in epithelial portions. FFPE lung tumor specimens (N = 221) revealed a wide range of PLA signal intensities (scored as 0+ to 3+), which localized to cytokeratin-positive regions. High PLA signals were found in approximately 25% of specimens across multiple histological classifications, including adenocarcinoma, squamous and large cell carcinoma. Furthermore, specimens from metastatic brain lesions were highly enriched for high PLA signal (p 2+) in specimens with relatively low EGFR protein expression and low PLA signal ( Citation Format: Matthew A. Smith, Richard Hall, Scott Haake, Jiannong Li, Eric B. Haura. Proximity ligation assays reveal protein-protein interactions associated with oncogenic signaling and drug sensitivity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3502. doi:10.1158/1538-7445.AM2013-3502

Abstract 3502: Proximity ligation assays reveal protein-protein interactions associated with oncogenic signaling and drug sensitivity.

UNLABELLED
Interleukin-1β (IL-1β) has been shown to play an essential role in mediating intestinal inflammation of Crohn's disease and other inflammatory conditions of the gut. Previous studies from our laboratory have shown that IL-1β causes an increase in intestinal tight-junction permeability in Caco-2 monolayers in vitro. However, the IL-1β effect on the intestinal epithelial barrier in vivo remains unclear.

AIMS
the major aims of this study were to examine the effect of IL-1β on mouse intestinal epithelial barrier in vivo and to delineate the mechanisms involved using an in vivo model system consisting of a recycling perfusion of mouse small intestine. Intraperitonial injection of IL-1β at varying doses (0-10 μg) caused a concentration-dependent increase in mouse intestinal permeability to the paracellular marker dextran (10 KD), and the maximal increase in dextran flux occurred at IL-1β dose of 5 μg. IL-1β treatment caused an increase in myosin light-chain kinase (MLCK) mRNA and protein expression in the small intestinal tissue starting at 24 h, which continued up to 72 h. Additionally, IL-1β did not cause an increase in intestinal permeability in MLCK-deficient mice (C57BL/6 MLCK(-/-)). MLCK inhibitor ML-7 (2 mg/kg body weight) also inhibited the IL-1β-induced increase in small intestinal permeability. The IL-1β-induced increase in mouse intestinal permeability was associated with an increase in NF-κB activation. The intestinal tissue-specific silencing of NF-κB p65 inhibited the IL-1β-induced increase in intestinal permeability and increase in MLCK expression. These data show for the first time that IL-1β causes an increase in mouse intestinal permeability in vivo. These data suggested that the mechanism of IL-1β-induced increase in mouse intestinal permeability in vivo involved NF-κB p65-induced activation of the mouse enterocyte MLCK gene.

Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research

Mechanism of interleukin-1β induced-increase in mouse intestinal permeability in vivo.

Mitochondrial activity is critical for efficient function of the cardiovascular system. In response to cardiovascular injury, mitochondrial dysfunction occurs and can lead to apoptosis and necrosis. Calpains are a 15-member family of Ca(2+)-activated cysteine proteases localized to the cytosol and mitochondria, and several have been shown to regulate apoptosis and necrosis. For example, in endothelial cells, Ca(2+) overload causes mitochondrial calpain 1 cleavage of the Na(+)/Ca(2+) exchanger leading to mitochondrial Ca(2+) accumulation. Also, activated calpain 1 cleaves Bid, inducing cytochrome c release and apoptosis. In renal cells, calpains 1 and 2 promote apoptosis and necrosis by cleaving cytoskeletal proteins, which increases plasma membrane permeability and cleavage of caspases. Calpain 10 cleaves electron transport chain proteins, causing decreased mitochondrial respiration and excessive activation, or inhibition of calpain 10 activity induces mitochondrial dysfunction and apoptosis. In cardiomyocytes, calpain 1 activates caspase 3 and poly-ADP ribose polymerase during tumour necrosis factor-α-induced apoptosis, and calpain 1 cleaves apoptosis-inducing factor after Ca(2+) overload. Many of these observations have been elucidated with calpain inhibitors, but most calpain inhibitors are not specific for calpains or a specific calpain family member, creating more questions. The following review will discuss how calpains affect mitochondrial function and apoptosis within the cardiovascular system.

Mitochondrial calpain 10 is degraded by Lon protease after oxidant injury.

Calpain 10 is a ubiquitously expressed mitochondrial and cytosolic Ca(2+)-regulated cysteine protease in which overexpression or knockdown leads to mitochondrial dysfunction and cell death. We previously identified a potent and specific calpain 10 peptide inhibitor (CYGAK), but it was not efficacious in cells. Therefore, we created a homology model using the calpain 10 amino acid sequence and calpain 1 3-D structure and docked CYGAK in the active site. Using this model we modified the inhibitor to improve potency 2-fold (CYGAbuK). To increase cellular efficacy, we created CYGAK-S-phenyl-oleic acid heterodimers. Using renal mitochondrial matrix CYGAK, CYGAK-OC, and CYGAK-ON had IC(50)'s of 70, 90, and 875 nM, respectively. Using isolated whole renal mitochondria CYGAK, CYGAK-OC, and CYGAK-ON had IC(50)'s of 95, 196, and >10,000 nM, respectively. Using renal proximal tubular cells (RPTC) in primary culture, 30 min exposures to CYGAK-OC and CYGAbuK-OC decreased cellular calpain activity approximately 20% at 1 μM, and concentrations up to 100 μM had no additional effect. RPTC treated with 10 μM CYGAK-OC for 24 h induced accumulation of ATP synthase β and NDUFB8, two calpain 10 substrates. In summary, we used molecular modeling to improve the potency of CYGAK, while creating CYGAK-oleic acid heterodimers to improve efficacy in cells. Since calpain 10 has been implicated in type 2 diabetes and renal aging, the use of this inhibitor may contribute to elucidating the role of calpain 10 in these and other diseases.

Calpain 10 homology modeling with CYGAK and increased lipophilicity leads to greater potency and efficacy in cells.

Loss of calpain 10 causes mitochondrial dysfunction during chronic hyperglycemia.

Novel Roles for the Transcriptional Repressor PRDM1 in Human Natural Killer Cells and Identification of an Inhibitor of its Interacting Methyltransferase G9a

We review 3 pediatric cases of extramedullary hematopoietic disease occurring in the orbit, ethmoid sinuses, and parotid gland, and present a review of the literature. Each of the 3 patients was taken to the operating room, and the biopsy specimens obtained were successful in establishing the diagnosis in every case. Head and neck manifestations of extramedullary hematopoietic disease are rare, indeed. However, these cases demonstrate that it is important for otolaryngologists, pediatricians, primary-care physicians, radiologists, and pathologists to maintain a high index of suspicion for extramedullary presentations of hematopoietic disease in the head and neck. A coordinated multidisciplinary approach, including the appropriate surgical approach for biopsy, will facilitate determination of the diagnosis and treatment plan.

Pediatric Head and Neck Extramedullary Hematopoietic Disease: Case Series and Review of the Literature

Dendritic cells (DCs) are key mediators of immune function through robust and tightly regulated presentation of antigen in the context of the MHC Class II. MHC Class II expression is controlled by the transactivator CIITA. CIITA expression in conventional DCs is uniquely dependent on an uncharacterized myeloid cell-specific promoter, CIITApI. We now identify in vivo the promoter structure and factors regulating CIITApI. In immature DCs transcription requires binding of PU.1, IRF8, NFκB, and Sp1 to the promoter. PU.1 binds independently at one site and in a required heterodimer with IRF8 at a composite element. DCs from IRF8-null mice have an unoccupied CIITApI promoter that can be rescued by reconstitution with IRF8 in vitro. Furthermore, mutation of either PU.1 site or the IFR8 site inhibits transcriptional activation. In vivo footprinting and chromatin immunoprecipitation reveals that DC maturation induces complete disassociation of the bound activators paralleled by recruitment of PRDM1/Blimp-1 to the promoter. PRDM1 is a transcriptional repressor with essential roles in B cells, T cells, NK cells, and DCs. We show that PRDM1 co-repressors, G9a and HDAC2, are recruited to CIITApI, leading to a loss of histone acetylation and acquisition of histone H3K9 dimethylation and heterochromatin protein 1γ (HP1γ). PRDM1 binding also blocks IRF8-mediated activation dependent on the PU.1/IRF composite element. Together these findings reveal the mechanisms regulating CIITA and, thus, antigen presentation in DCs, demonstrating that PRDM1 and IRF8/PU.1 counter-regulate expression. The activity of PRDM1 in silencing all three cell type-specific CIITA promoters places it as a central regulator of antigen presentation.

Positive Regulatory Domain I (PRDM1) and IRF8/PU.1 Counter-regulate MHC Class II Transactivator (CIITA) Expression during Dendritic Cell Maturation*

NK cells are major effectors of the innate immune response through cytolysis and bridge to the adaptive immune response through cytokine release. The mediators of activation are well studied; however, little is known about the mechanisms that restrain activation. In this report, we demonstrate that the transcriptional repressor PRDM1 (also known as Blimp-1 or PRDI-BF1) is a critical negative regulator of NK function. Three distinct PRDM1 isoforms are selectively induced in the CD56dim NK population in response to activation. PRDM1 coordinately suppresses the release of IFN-γ, TNF-α, and TNF-β through direct binding to multiple conserved regulatory regions. Ablation of PRDM1 expression leads to enhanced production of IFN-γ and TNF-α but does not alter cytotoxicity, whereas overexpression blocks cytokine production. PRDM1 response elements are defined at the IFNG and TNF loci. Collectively, these data demonstrate a key role for PRDM1 in the negative regulation of NK activation and position PRDM1 as a common regulator of the adaptive and innate immune response.

PRDM1/Blimp-1 Controls Effector Cytokine Production in Human NK Cells

MDM2 recruitment of lysine methyltransferases regulates p53 transcriptional output

Mantle cell lymphoma (MCL) is an aggressive form of B-cell lymphoma with a poor disease-free survival rate. The proteasome inhibitor bortezomib is approved for the treatment of relapsed and refractory MCL and has efficacy in about 30% of patients. However, the precise mechanism of action of bortezomib is not well understood. This report establishes a requirement for the transcription repressor PR domain zinc finger protein 1 (PRDM1, Blimp1) in the response to bortezomib. Bortezomib rapidly induces transcription of PRDM1 as part of the apoptotic response in both cell lines and primary MCL tumor cells. Knockdown of PRDM1 blocks activation of NOXA and inhibits apoptosis, whereas ectopic expression of PRDM1 alone leads to apoptosis in MCL. Two novel direct targets of PRDM1 were identified in MCL cells: MKI67 (Ki67) and proliferating cell nuclear antigen (PCNA). Both MKI67 and PCNA are required for proliferation and survival. Chromatin immunoprecipitation and knockdown studies reveal that specific repression of MKI67 and PCNA is mediated by PRDM1 in response to bortezomib. Furthermore, promoter studies and mutation/deletion analysis show that PRDM1 functions through specific sites in the PCNA proximal promoter and an MKI67 distal upstream repression domain. Together, these findings establish PRDM1 as a key mediator of bortezomib activity in MCL. Mol Cancer Res; 8(6); 907–18. ©2010 AACR.

PRDM1 Is Required for Mantle Cell Lymphoma Response to Bortezomib

Authors' A Institute; 2 Sciences, a Florida, Tam Note: Sup Cancer Res Current ad esis, Natio Alexander Authors' c wrote the m M.A. Smith interpreted helped writ Correspon 12902 Mag 3918; Fax:

Signaling and Regulation Molecular Cancer Research PRDM 1 Is Required for Mantle Cell Lymphoma Response to Bortezomib

Lihong Chen, Zhenyu Li, Aleksandra K Zwolinska, Matthew A Smith, Brittany Cross, John Koomen, Zhi-Min Yuan, Thomas Jenuwein, Jean-Christophe Marine, Kenneth L Wright and Jiandong Chen* Molecular Oncology Department, Moffitt Cancer Center, Tampa, FL, USA, VIB-KULeuven, Laboratory for Molecular Cancer Biology, Leuven, Belgium, Immunotherapy Department, Moffitt Cancer Center, Tampa, FL, USA, Department of Radiation Oncology, University of Texas Health Science Center, San Antonio, TX, USA and Department of Epigenetics, Max-Planck Institute of Immunobiology, Freiburg, Germany

MDM 2 recruitment of lysine methyltransferases regulates p 53 transcriptional output

S1781 Mechanisms of TNF-α-Induced Increase in Intestinal Permeability in an In-Vivo Mouse Model: Role of Myosine Light Chain Kinase

 PRDI-BF1 (Positive Regulatory Domain I - Binding Factor 1,) is a zinc finger transcription factor, originally identified as a suppressor of interferon-beta in virally-infected human fibroblasts. It is most widely recognized as a key regulator of B-cell terminal differentiation into antibody-producing plasma cells. More recently, several reports have described functions in T-cell homeostasis. Here, we demonstrate that PRDI-BF1 is expressed in human natural killer (NK) cells and is involved in the attenuation of activation-induced cytokine gene transcription. Ex vivo stimulation of negatively-selected human CD56+ lymphocytes with activating cytokines increases levels of PRDI-BF1 mRNA and protein. This induction occurs primarily in the CD56dim population. The combination of IL-2, IL-12 and IL-18 leads to synergistic increases in PRDI-BF1 and IFN? as part of a global transcriptional profile that we have characterized via microarray analysis. Blockade of PRDI-BF1 induction via siRNA leads to enhanced TNFα and IFNγ transcription. Chromatin immunoprecipitation analysis of both NK cell lines and primary CD56+ lymphocytes reveals occupancy of several promoters, including IFNγ. Collectively, these data provide evidence for novel contributions of PRDI-BF1 to natural killer cell function and innate immunity.

PRDI-BF1/Blimp-1 Associates with Cytokine-Mediated Activation of Human Natural Killer Cells (136.25)

Restoring the functional immunogenicity of chronic lymphocytic leukemia using epigenetic modifiers.

Fluorescein‐conjugated bisindolylmaleimide inhibitor (FIM‐1) was used to identify protein kinase C (PKC) presence and activity in Marchantia polymorpha thalli. Fluorescence microscopy showed that PKC activity occurred in the membranes of parenchymous and chloroplast‐containing cells. PKC activity increased with distance from the thallus apex in untreated tissue. Spermine‐treated tissue displayed significantly higher levels of PKC activity in comparison with untreated tissue, and PKC activity decreased with distance from the apex of the thallus.

The Influence of Spermine on the In Situ Expression of a Protein Kinase Associated with Senescence in Marchantia polymorpha Thalli

Evaluation and implementation of a molecular-based protocol for the identification of enteroviruses at the Florida Department of Health - Tampa Laboratory

The Macrophage as the Demyelinative Agent: A Role for Antimyelin Antibodies

The Autobiography of Daniel ParkerFrontier Universalist ed. by David Torbett (review)

Impostors: Literary Hoaxes and Cultural Authenticity by Christopher L. Miller (review)

Abstract:In this essay, we identify and discuss three motifs that enable literary narrative to perform a shift from a phenomenological, common-sense understanding of the body to the far more challenging nonhuman corporeality articulated by poststructuralist theorists in dialogue with Deleuze and Guattari’s work. We argue that such reconceptualization of the body via narrative form aligns closely with contemporary debates surrounding the Anthropocene and material, as well as nonhuman, turns. We illustrate the three motifs—which we label metamorphosis, blending, and unraveling—through the analysis of passages from contemporary novels that engage, in deeply embodied terms, with environmental issues.

News of War: Civilian Poetry 1936–1945 by Rachel Galvin (review)

Beyond Pontiac’s Shadow: Michilimackinac and the Anglo-Indian War of 1763 by Keith R. Widder (review)

Abstract: This essay shows that translation has redefined the parameters of poetry in the United States through a case study of two works by the contemporary poets Andrew Zawacki and Bill Luoma. Both responded to the French translation of their poems with a revised or new work in English; whereas Zawacki takes advantage of this new pattern of circulation to enrich and embellish his poem, Luoma documents its obstacles and setbacks. In both cases, these works take up and re-examine the problems and challenges posed by translation. They also signal a new kind of poetry that directly engages with the foreign scene of its circulation.

This work offers a transnational perspective on the lively dialogue between French and American poetry since the 1970s. Focusing on the institutions and practices that mediate this exchange, I show how American and French poets take up, challenge or respond to shifts in the poetic field tied to new cross-cultural networks of circulation. In so doing, I also demonstrate how poets imagine and realize a diverse set of competing publics. The work is divided into three chapters. After analyzing in my introduction the web of poets and institutions that have enabled and sustained this exchange, I show in my first chapter how collaborations between writers and translators have greatly impacted recent poetry in a case study of two American works: Andrew Zawack’s Georgia (2009) and Bill Luoma’s My Trip to New York City (1994). Following the trajectory of these works as they move through different contexts and languages, I investigate the shifting meanings of poetry as it circulates through various spaces. I also move outside the traditional paradigm of translation studies: rather than a comparative textual analysis, I examine how these poets respond to the new set of circumstances created by the institutionalization of translation. In my second chapter I draw on two influential periodicals— La revue de litterature generale (1995-1996) in France and Chain (1994-2006) in the U.S.— to show how the periodical at once facilitates and troubles transnational exchange in contemporary poetry. I demonstrate that these two reviews redefine their respective poetic fields by working both within and against larger cultural institutions and technologies. I argue that each journal creates a new context for its poetry by defying larger structures of power, such as Jack Lang’s cultural policies in the case of RLG and the institutional forms of capital tied to the Poetics Program at SUNY-Buffalo and its use of the listserv with Chain. In my final chapter I examine the influence of the American poetry reading in France. I argue that the reception of the poetry reading in France has given rise to new “oral-centered” writing practices. In particular, I show how Jacques Roubaud’s experiments with “improvised prose” and oral performance developed as a response to the professionalized, American-style poetry reading. Through my reading of Roubaud, I complicate the myth of the poetry reading as a more authentic experience of poetry and call into question established notions of orality. The specific case studies of my dissertation open onto a field of larger questions concerning how modes of circulation in our globalized world are transforming poetry. These questions are further explored in a coda that closes my dissertation.

Patterns of Exchange: Translation, Periodicals and the Poetry Reading in Contemporary French and American Poetry

Understanding the effect of metamictization on the efficiency of zircon milling

Avoidance and diagnosis of problems associated with internal wall insulation

Exploring the effects of estrogen receptor beta polymorphisms on wound repair

Wound healing is a complicated and dynamic process. The aim of this study was to determine whether systemic administration of common anticoagulants retards or delays wound healing in an animal model.

Effects of anticoagulation on wound healing using a tensile test.

The ADP-ribosylation factor (ARF) family of GTPases are essential molecular switches that control a large variety of cellular processes. Here, we used classical proximity-dependent biotin identification (BioID) to comprehensively define the interactome of 28 out of 29 ARF proteins in two cell lines. The identification of ∼3000 high-confidence interactors allowed us to assign specific subcellular localization to the family members, uncovering previously undefined localization for ARL4D and ARL10. Clusterization analysis further showed the uniqueness in the set of interactors identified with these two ARF GTPases. We found that the expression of the understudied member ARL14 is restricted to the stomach and intestines and have identified phospholipase D1 (PLD1) and the ESCPE-1 complex, more precisely SNX1, as effectors. We showed that ARL14 can activate PLD1 in cellulo and is involved in the trafficking of cargos via the ESCPE-1 complex. Thus, the BioID data generated in this study represent a useful tool to dissect the intricacies of ARF signaling and its spatial organization.

ARF-family global interactome mapping uncovers spatial organization of cellular signaling pathways

Distinct functions mediated by members of the monopolar spindle-one-binder (MOB) family of proteins remain elusive beyond the evolutionary conserved and well-established roles of MOB1A and B in regulating the Hippo pathway. Since MOB proteins are adaptors, understanding how they engage in protein-protein interactions and complexes assembly is essential to define the full scope of their biological functions. To address this, we undertook a proximity-dependent biotin identification (BioID) approach to define the interactomes of all seven human MOB proteins in HeLa and HEK293 cell lines. We uncovered > 200 interactions, of which at least 70% are unreported on BioGrid. The generated dataset reliably recalled the bona fide interactors of the well-studied MOBs. We further defined the common and differential interactome between different MOBs on a subfamily and an individual level. We discovered a unique interaction between MOB3C and 7 out of 10 protein subunits of the RNase P complex, an endonuclease that catalyzes tRNA 5’ maturation. As a proof-of-principle for the robustness of the generated dataset, we validated the specific interaction of MOB3C with catalytically active RNase P by using affinity purification-mass spectrometry and pre-tRNA cleavage assays of MOB3C pulldowns. In summary, our data provide novel insights into the biology of MOB proteins and reveal the first interactors of MOB3C, components of the RNase P complex, and hence an exciting nexus with RNA biology.

Mapping the MOB proteins’ proximity network reveals a unique interaction between human MOB3C and the RNase P complex

Biasing the conformation of ELMO2 reveals that myoblast fusion can be exploited to improve muscle regeneration

RAS small GTPases regulate important signalling pathways and are notorious drivers of cancer development and progression. While most research to date has focused on understanding and addressing the oncogenic potential of three RAS oncogenes: HRAS, KRAS, and NRAS; the full RAS subfamily is composed of 35 related GTPases with diverse cellular functions. Most remain deeply understudied despite strong evolutionary conservation. Here, we highlight a group of 17 poorly characterized RAS GTPases that are frequently down-regulated in cancer and evidence suggests may function not as oncogenes, but as tumour suppressors. These GTPases remain largely enigmatic in terms of their cellular function, regulation, and interaction with effector proteins. They cluster within two families we designate as 'distal-RAS' (D-RAS; comprised of DIRAS, RASD, and RASL10) and 'CaaX-Less RAS' (CL-RAS; comprised of RGK, NKIRAS, RERG, and RASL11/12 GTPases). Evidence of a tumour suppressive role for many of these GTPases supports the premise that RAS subfamily proteins may collectively regulate cellular proliferation.

 Chromosomal rearrangements of the KMT2A gene are associated with acute leukemias and myelodysplastic syndromes. The large number of known KMT2A fusions (>100) renders a precise diagnosis a demanding task. More than 50% of all KMT2A partner genes have been analyzed at the DCAL, including the novel partner genes BCAS4, FAM13A, RANBP3, and STK4. Even though all KMT2A rearrangements are associated with high-risk acute leukemia, the outcome (poor or very poor) is influenced by the partner gene. So far, we have analyzed more than 3,200 patients positive for a KMT2A rearrangement. The breakpoints of these cases are located mainly in the major breakpoint cluster region (bcr1) and to a small extent in the recently described minor bcr (bcr2). A small number of breakpoints were also found outside of these two bcrs.
 Most of these patients were analyzed by long distance inverse (LDI)- or multiplex-PCR which only cover bcr1. More recently, we used targeted KMT2A-NGS with whole gene coverage in over 450 patients, which was initially applied selectively in patients negative by LDI- and multiplex-PCR and then used more widely.
 Within the KMT2A-NGS group, 410 patients had bcr1 breakpoints mainly between the KMT2A exons 7 and 13, while 46 patients bcr2 breakpoints mainly between exons 20 and 24. Of note, five patients had their breakpoint outside of these two bcrs: three of them within intron 2 and no functional KMT2A rearrangement; the other two within intron 35 and intron 36, fusing almost the whole KMT2A gene in frame to the respective partner genes ARHGEF12 and MLLT4. These two breakpoints may define a third and rare bcr (bcr3), although further cases are needed to support this hypothesis. Interestingly, 70 patients displayed a 3'-KMT2A deletion, indicating that the number of terminal deletions is higher than described previously. Two patients had a 5'-KMT2A deletion. All deletions started or ended in bcr1 and bcr2.
 We also observed a striking difference in the distribution of partner genes between bcr1 and bcr2. The most frequent translocation partners fused to bcr1 sites are transcription factors, while the partner genes linked to bcr2 sites generally code for cytosolic proteins. In bcr1, the 4 most frequent partner genes AFF1, MLLT3, MLLT1, and MLLT10, found in 80% of cases, all code for transcription factors that are part of the super elongation complex (SEC). These fusions therefore all lead to disruption of the hematopoietic lineage commitment.
 In contrast in bcr2, 3 partner genes USP2, MLLT4, and USP8 account for 85% of the cases. USP2 and USP8 are ubiquitin specific peptidases involved in cell signaling and exclusively fused to bcr2 in KMT2A. While MLLT4 is found as a partner in bcr1, bcr2 and bcr3 fusions; unlike other recurrent KMT2A partners linked to bcr1, it is not a transcription factor and it exerts oncogenic potential via dimerization like other cytosolic partners. We hypothesize that the oncogenic properties of USP2 and USP8 are dependent on dimerization like MLLT4 and that the most frequent fusions involving at different bcrs favor different oncogenic mechanisms: bcr1 transactivation and bcr2 dimerization. Further studies are needed to explain why USP2 and USP8 are exclusively associated with bcr2, and why the most frequent partner genes AFF1 and MLLT3 of the bcr1 are less frequent in bcr2.
 In conclusion, targeted NGS combined with bioinformatic analysis has expanded our knowledge of the KMT2A recombinome to include more fusion partners and has generated new hypotheses for future research on oncogenic mechanisms.
 
 No relevant conflicts of interest to declare.

Targeted Next Generation Sequencing Reveals a Third Breakpoint Cluster Region and New Partner Genes in the KMT2A Recombinome

Structure of the DOCK2−ELMO1 complex provides insights into regulation of the auto-inhibited state

RAS GTPases are fundamental regulators of development and drivers of an extraordinary number of human cancers. RAS oncoproteins constitutively signal through downstream effector proteins, triggering cancer initiation, progression and metastasis. In the absence of targeted therapeutics to mutant RAS itself, inhibitors of downstream pathways controlled by the effector kinases RAF and PI3K have become tools in the treatment of RAS-driven tumours. Unfortunately, the efficacy of this approach has been greatly minimized by the prevalence of acquired drug resistance. Decades of research have established that RAS signalling is highly complex, and in addition to RAF and PI3K these small GTPase proteins can interact with an array of alternative effectors that feature RAS binding domains. The consequence of RAS binding to these effectors remains relatively unexplored, but these pathways may provide targets for combinatorial therapeutics. We discuss here three candidate alternative effectors: RALGEFs, RASSF5 and AFDN, detailing their interaction with RAS GTPases and their biological significance. The metastatic nature of RAS-driven cancers suggests more attention should be granted to these alternate pathways, as they are highly implicated in the regulation of cell adhesion, polarity, cell size and cytoskeletal architecture.

RASSF proteins interact with distinct GTPase partners to regulate downstream Hippo and p53 signaling. Diversity among RASSFs GTPases of the RAS superfamily couple diverse stimuli to specific downstream pathways by interacting with various effectors that contain RAS-association (RA) domains, such as RA domain family (RASSF) proteins. Although RAS signaling is often associated with cellular proliferation, coupling to the RASSFs has been reported to promote apoptosis. Through binding studies in vitro and in cells, Dhanaraman et al. found that RASSFs 1 to 6 interacted with the Hippo ortholog MST1, and RASSFs 8 to 10 interacted with the p53 regulators ASPP1 and ASPP2. Only RASSF5 interacted with HRAS and KRAS, and RASSF1 interacted with members of the RGK subfamily of RAS GTPases and inhibited nuclear localization of the Hippo-responsive transcription factor YAP. This systematic analysis of RASSF binding partners is a valuable first step in defining the molecular mechanisms through which these RAS effectors couple different RAS family members to proapoptotic pathways. Small guanosine triphosphatases (GTPases) of the RAS superfamily signal by directly binding to multiple downstream effector proteins. Effectors are defined by a folded RAS-association (RA) domain that binds exclusively to GTP-loaded (activated) RAS, but the binding specificities of most RA domains toward more than 160 RAS superfamily GTPases have not been characterized. Ten RA domain family (RASSF) proteins comprise the largest group of related effectors and are proposed to couple RAS to the proapoptotic Hippo pathway. Here, we showed that RASSF1-6 formed complexes with the Hippo kinase ortholog MST1, whereas RASSF7-10 formed oligomers with the p53-regulating effectors ASPP1 and ASPP2. Moreover, only RASSF5 bound directly to activated HRAS and KRAS, and RASSFs did not augment apoptotic induction downstream of RAS oncoproteins. Structural modeling revealed that expansion of the RASSF effector family in vertebrates included amino acid substitutions to key residues that direct GTPase-binding specificity. We demonstrated that the tumor suppressor RASSF1A formed complexes with the RAS-related GTPases GEM, REM1, REM2, and the enigmatic RASL12. Furthermore, interactions between RASSFs and RAS GTPases blocked YAP1 nuclear localization. Thus, these simple scaffolds link the activation of diverse RAS family small G proteins to Hippo or p53 regulation.

RASSF effectors couple diverse RAS subfamily GTPases to the Hippo pathway

Small GTPases alternatively bind GDP/GTP guanine nucleotides to gate signaling pathways that direct most cellular processes. Numerous GTPases are implicated in oncogenesis, particularly the three RAS isoforms HRAS, KRAS, and NRAS and the RHO family GTPase RAC1. Signaling networks comprising small GTPases are highly connected, and there is some evidence of direct biochemical cross-talk between their functional G-domains. The activation potential of a given GTPase is contingent on a codependent interaction with the nucleotide and a Mg2+ ion, which bind to individual variants with distinct affinities coordinated by residues in the GTPase nucleotide-binding pocket. Here, we utilized a selective-labeling strategy coupled with real-time NMR spectroscopy to monitor nucleotide exchange, GTP hydrolysis, and effector interactions of multiple small GTPases in a single complex system. We provide insight into nucleotide preference and the role of Mg2+ in activating both WT and oncogenic mutant enzymes. Multiplexing revealed guanine nucleotide exchange factor (GEF), GTPase-activating protein (GAP), and effector-binding specificities in mixtures of GTPases and resolved that the three related RAS isoforms are biochemically equivalent. This work establishes that direct quantitation of the nucleotide-bound conformation is required to accurately determine an activation potential for any given GTPase, as small GTPases such as RAS-like proto-oncogene A (RALA) or the G12C mutant of KRAS display fast exchange kinetics but have a high affinity for GDP. Furthermore, we propose that the G-domains of small GTPases behave autonomously in solution and that nucleotide cycling proceeds independently of protein concentration but is highly impacted by Mg2+ abundance.

Conformational resolution of nucleotide cycling and effector interactions for multiple small GTPases determined in parallel

Small GTPase proteins alternatively bind GDP/GTP guanine nucleotides to gate signaling pathways that direct most cellular processes. Numerous GTPases are implicated in oncogenesis, particularly three RAS isoforms HRAS, KRAS and NRAS, and the RHO family GTPase RAC1. Signaling networks comprising small GTPases are highly connected, and there is evidence of direct biochemical crosstalk between the functional G-domains of these proteins. The activation potential of a given GTPase is contingent on a co-dependent interaction with nucleotide and a Mg2+ ion, which bind to individual variants via distinct affinities coordinated by residues in the nucleotide binding pocket. Here, we utilize a selective-labelling strategy coupled with real-time nuclear magnetic resonance (NMR) spectroscopy to monitor nucleotide exchange, GTP hydrolysis and effector interactions of multiple small GTPases in a single complex system. We provide new insight on nucleotide preference and the role of Mg2+ in activating both wild-type and oncogenic mutant enzymes. Multiplexing reveals GEF, GAP and effector binding specificity in mixtures of GTPases and establishes the complete biochemical equivalence of the three related RAS isoforms. This work establishes that direct quantitation of the nucleotide-bound conformation is required to accurately resolve GTPase activation potential, as GTPases such as RALA or the G12C mutant of KRAS demonstrate fast exchange kinetics but have a high affinity for GDP. Further, we propose that the G-domains of small GTPases behave autonomously in solution and nucleotide cycling proceeds independent of protein concentration but is highly impacted by Mg2+ abundance.

Conformational resolution of nucleotide cycling and effector interactions for multiple small GTPases in parallel

Evolution of AF6-RAS association and its implications in mixed-lineage leukemia

Inhibition of RAS function through targeting an allosteric regulatory site.

RAS-like protein expressed in many tissues 1 (RIT1) is a disease-associated RAS subfamily small guanosine triphosphatase (GTPase). Recent studies revealed that germ-line and somatic RIT1 mutations can cause Noonan syndrome (NS), and drive proliferation of lung adenocarcinomas, respectively, akin to RAS mutations in these diseases. However, the locations of these RIT1 mutations differ significantly from those found in RAS, and do not affect the three mutational “hot spots” of RAS. Moreover, few studies have characterized the GTPase cycle of RIT1 and its disease-associated mutants. Here we developed a real-time NMR-based GTPase assay for RIT1 and investigated the effect of disease-associated mutations on GTPase cycle. RIT1 exhibits an intrinsic GTP hydrolysis rate similar to that of H-RAS, but its intrinsic nucleotide exchange rate is ∼4-fold faster, likely as a result of divergent residues near the nucleotide binding site. All of the disease-associated mutations investigated increased the GTP-loaded, activated state of RIT1 in vitro, but they could be classified into two groups with different intrinsic GTPase properties. The S35T, A57G, and Y89H mutants exhibited more rapid nucleotide exchange, whereas F82V and T83P impaired GTP hydrolysis. A RAS-binding domain pulldown assay indicated that RIT1 A57G and Y89H were highly activated in HEK293T cells, whereas T83P and F82V exhibited more modest activation. All five mutations are associated with NS, whereas two (A57G and F82V) have also been identified in urinary tract cancers and myeloid malignancies. Characterization of the effects on the GTPase cycle of RIT1 disease-associated mutations should enable better understanding of their role in disease processes.

Biochemical Classification of Disease-associated Mutants of RAS-like Protein Expressed in Many Tissues (RIT1)*

It is proposed that the N-peptide plays a critical role in intracellular trafficking of syntaxin-1, which depends on the conformational state of this protein. Surprisingly, however, the N-peptide binding mode seems dispensable for SNARE-mediated exocytosis per se, as long as the protein is trafficked to the plasma membrane.

Conformational states of syntaxin-1 govern the necessity of N-peptide binding in exocytosis of PC12 cells and Caenorhabditis elegans

Significance KRAS (Kirsten rat sarcoma viral oncogene homolog) is frequently mutated in pancreatic, colon, and lung tumors, which predicts poor clinical outcome, whereas germ-line mutations are associated with developmental disorders, including Noonan syndrome. Although K-RAS is an attractive anticancer target, no clinically successful inhibitors are available. Most disease-associated mutations elevate the activated GTP-bound form of KRAS; however, some remain unexplained. KRAS signals from cellular membranes; however, our studies revealed that its association with the membrane surface sequesters its binding site for effector proteins, hampering signaling. Some disease-associated KRAS mutations disrupt this autoinhibition, identifying a new gain-of-function mechanism and explaining how certain Noonan syndrome mutations activate K-RAS signaling. Importantly, these findings open new avenues for therapeutic strategies to target oncogenic K-RAS through stabilizing autoinhibitory interactions with the membrane. K-RAS4B (Kirsten rat sarcoma viral oncogene homolog 4B) is a prenylated, membrane-associated GTPase protein that is a critical switch for the propagation of growth factor signaling pathways to diverse effector proteins, including rapidly accelerated fibrosarcoma (RAF) kinases and RAS-related protein guanine nucleotide dissociation stimulator (RALGDS) proteins. Gain-of-function KRAS mutations occur frequently in human cancers and predict poor clinical outcome, whereas germ-line mutations are associated with developmental syndromes. However, it is not known how these mutations affect K-RAS association with biological membranes or whether this impacts signal transduction. Here, we used solution NMR studies of K-RAS4B tethered to nanodiscs to investigate lipid bilayer-anchored K-RAS4B and its interactions with effector protein RAS-binding domains (RBDs). Unexpectedly, we found that the effector-binding region of activated K-RAS4B is occluded by interaction with the membrane in one of the NMR-observable, and thus highly populated, conformational states. Binding of the RAF isoform ARAF and RALGDS RBDs induced marked reorientation of K-RAS4B from the occluded state to RBD-specific effector-bound states. Importantly, we found that two Noonan syndrome-associated mutations, K5N and D153V, which do not affect the GTPase cycle, relieve the occluded orientation by directly altering the electrostatics of two membrane interaction surfaces. Similarly, the most frequent KRAS oncogenic mutation G12D also drives K-RAS4B toward an exposed configuration. Further, the D153V and G12D mutations increase the rate of association of ARAF-RBD with lipid bilayer-tethered K-RAS4B. We revealed a mechanism of K-RAS4B autoinhibition by membrane sequestration of its effector-binding site, which can be disrupted by disease-associated mutations. Stabilizing the autoinhibitory interactions between K-RAS4B and the membrane could be an attractive target for anticancer drug discovery.

Oncogenic and RASopathy-associated K-RAS mutations relieve membrane-dependent occlusion of the effector-binding site

Real-time NMR monitoring of biological activities in complex physiological environments.

Integrated RAS signaling defined by parallel NMR detection of effectors and regulators.

The Ras superfamily of small GTPases are important intracellular signaling molecules, the functions of which are determined by the binding of guanosine nucleotides (GTP = guanosine triphosphate and GDP = guanosine diphosphate). [1] The GTP-bound (“active”) states of these enzymes are capable of interacting with specific downstream effector proteins, thus eliciting a wide range of cellular responses. [2, 3] Mutations that reduce the rate of GTP hydrolysis and thus increase the lifetime of the active GTP-bound state are frequently oncogenic and contribute to the development and metastasis of human cancers. [4] Elegant 31 P NMR studies of GTP-bound Ras showed that the enzyme interconverts between two states, a minor conformer termed state 1 and a major species designated state 2. [5–9] Similar conformational dynamics have been observed in other Ras family GTPases as well. [10–12] State 2 is generally regarded as the conformation competent for binding effector proteins, whereas state 1 exhibits significantly reduced affinity for these molecules. [5–7, 13, 14] Stabilization of the low-affinity state 1 was

A comparative CEST NMR study of slow conformational dynamics of small GTPases complexed with GTP and GTP analogues.

Interaction Domains of Sos1/Grb2 Are Finely Tuned for Cooperative Control of Embryonic Stem Cell Fate

Defects in the RAS small G protein or its associated network of regulatory proteins that disrupt GTPase cycling are a major cause of cancer and developmental RASopathy disorders. Lack of robust functional assays has been a major hurdle in RAS pathway-targeted drug development. We used NMR to obtain detailed mechanistic data on RAS cycling defects conferred by oncogenic mutations, or full-length RASopathy-derived regulatory proteins. By monitoring the conformation of wild-type and oncogenic RAS in real-time, we show that opposing properties integrate with regulators to hyperactivate oncogenic RAS mutants. Q61L and G13D exhibited rapid nucleotide exchange and an unexpected susceptibility to GAP-mediated hydrolysis, in direct contrast with G12V, indicating different approaches must be taken to inhibit these oncoproteins. An NMR methodology was established to directly monitor RAS cycling by intact, multidomain proteins encoded by RASopathy genes in mammalian cell extracts. By measuring GAP activity from tumor cells, we demonstrate how loss of neurofibromatosis type 1 (NF1) increases RAS-GTP levels in NF1-derived cells. We further applied this methodology to profile Noonan Syndrome (NS)-derived SOS1 mutants. Combining NMR with cell-based assays allowed us to differentiate defects in catalysis, allosteric regulation, and membrane targeting of individual mutants, while revealing a membrane-dependent compensatory effect that attenuates dramatic increases in RAS activation shown by Y337C, L550P, and I252T. Our NMR method presents a precise and robust measure of RAS activity, providing mechanistic insights that facilitate discovery of therapeutics targeted against the RAS signaling network.

NMR-based functional profiling of RASopathies and oncogenic RAS mutations

Probing the GTPase cycle with real-time NMR: GAP and GEF activities in cell extracts.

Noboru Ishiyama,1 Seung-Hye Lee,3 Shuang Liu,1 Guang-Yao Li,1 Matthew J. Smith,1 Louis F. Reichardt,3 and Mitsuhiko Ikura1,2,* 1Division of Signaling Biology, Ontario Cancer Institute 2Department of Medical Biophysics, University of Toronto MaRS Toronto Medical Discovery Tower, Room 4-804, 101 College Street, Toronto, ON M5G 1L7, Canada 3Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA *Correspondence: mikura@uhnres.utoronto.ca DOI 10.1016/j.cell.2010.01.017

Dynamic and Static Interactions between p 120 Catenin and E-Cadherin Regulate the Stability of Cell-Cell Adhesion

Dynamic and Static Interactions between p120 Catenin and E-Cadherin Regulate the Stability of Cell-Cell Adhesion

The PTB domain of ShcA couples receptor activation to the cytoskeletal regulator IQGAP1

Solution structure of CA150 FF1 domain and FF1-FF2 interdomain linker

The Ras family of small GTPases control diverse signaling pathways through a conserved “switch” mechanism, which is turned on by binding of GTP and turned off by GTP hydrolysis to GDP. Full understanding of GTPase switch functions requires reliable, quantitative assays for nucleotide binding and hydrolysis. Fluorescently labeled guanine nucleotides, such as 2′(3′)-O-(N-methylanthraniloyl) (mant)-substituted GTP and GDP analogs, have been widely used to investigate the molecular properties of small GTPases, including Ras and Rho. Using a recently developed NMR method, we show that the kinetics of nucleotide hydrolysis and exchange by three small GTPases, alone and in the presence of their cognate GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors, are affected by the presence of the fluorescent mant moiety. Intrinsic hydrolysis of mantGTP by Ras homolog enriched in brain (Rheb) is ∼10 times faster than that of GTP, whereas it is 3.4 times slower with RhoA. On the other hand, the mant tag inhibits TSC2GAP-catalyzed GTP hydrolysis by Rheb but promotes p120 RasGAP-catalyzed GTP hydrolysis by H-Ras. Guanine nucleotide exchange factor-catalyzed nucleotide exchange for both H-Ras and RhoA was inhibited by mant-substituted nucleotides, and the degree of inhibition depends highly on the GTPase and whether the assay measures association of mantGTP with, or dissociation of mantGDP from the GTPase. These results indicate that the mant moiety has significant and unpredictable effects on GTPase reaction kinetics and underscore the importance of validating its use in each assay.

Real-time NMR Study of Three Small GTPases Reveals That Fluorescent 2′(3′)-O-(N-Methylanthraniloyl)-tagged Nucleotides Alter Hydrolysis and Exchange Kinetics*

Structural studies of FF domains of the transcription factor CA150 provide insights into the organization of FF domain tandem arrays.

Subcellular receptor redistribution and enhanced microspike formation by a Ret receptor preferentially recruiting Dok

ABSTRACT Shc family proteins serve as phosphotyrosine adaptor molecules in various receptor-mediated signaling pathways. In mammals, three distinct Shc genes have been described that encode proteins characterized by two phosphotyrosine-interaction modules, an amino-terminal phosphotyrosine binding (PTB) domain and a carboxy-terminal Src homology 2 domain. Here, we report the analysis of an uncharacterized fourth Shc family protein, ShcD/Shc4, that is expressed in adult brain and skeletal muscle. Consistent with this expression pattern, we find that ShcD can associate via its PTB domain with the phosphorylated muscle-specific kinase (MuSK) receptor tyrosine kinase and undergo tyrosine phosphorylation downstream of activated MuSK. Interestingly, additional sites of tyrosine phosphorylation, including a novel Grb2 binding site, are present on ShcD that are not found in other Shc family proteins. Activation of MuSK upon agrin binding at the neuromuscular junction (NMJ) induces clustering and tyrosine phosphorylation of acetylcholine receptors (AChRs) required for synaptic transmission. ShcD is coexpressed with MuSK in the postsynaptic region of the NMJ, and in cultured myotubes stimulated with agrin, expression of ShcD appears to be important for early tyrosine phosphorylation of the AChR. Thus, we have characterized a new member of the Shc family of docking proteins, which may mediate a specific aspect of signaling downstream of the MuSK receptor.

Analysis of a Shc Family Adaptor Protein, ShcD/Shc4, That Associates with Muscle-Specific Kinase

Modular interaction domains that recognize peptide motifs in target proteins can impart selectivity in signaling pathways. Phosphotyrosine binding (PTB) domains are components of cytoplasmic docking proteins that bind cell surface receptors through NPXY motifs. We have employed a library of human proteome-derived NXXY sequences to explore PTB domain specificity and function. SPOTS peptide arrays were used to create a comprehensive matrix of receptor motifs that were probed with a set of 10 diverse PTB domains. This approach confirmed that individual PTB domains have selective and distinct recognition properties and provided a means to explore over 2,500 potential PTB domain-NXXY interactions. The results correlated well with previously known associations between full-length proteins and predicted novel interactions, as well as consensus binding data for specific PTB domains. Using the Ret, MuSK, and ErbB2 receptor tyrosine kinases, we show that interactions of these receptors with PTB domains predicted to bind by the NXXY arrays do occur in cells. Proteome-based peptide arrays can therefore identify networks of receptor interactions with scaffold proteins that may be physiologically relevant.

Screening for PTB Domain Binding Partners and Ligand Specificity Using Proteome-Derived NPXY Peptide Arrays

ABSTRACT Modular interaction domains that recognize peptide motifs in target proteins can impart selectivity in signaling pathways. Phosphotyrosine binding (PTB) domains are components of cytoplasmic docking proteins that bind cell surface receptors through NPXY motifs. We have employed a library of human proteome-derived NXXY sequences to explore PTB domain specificity and function. SPOTS peptide arrays were used to create a comprehensive matrix of receptor motifs that were probed with a set of 10 diverse PTB domains. This approach confirmed that individual PTB domains have selective and distinct recognition properties and provided a means to explore over 2,500 potential PTB domain-NXXY interactions. The results correlated well with previously known associations between full-length proteins and predicted novel interactions, as well as consensus binding data for specific PTB domains. Using the Ret, MuSK, and ErbB2 receptor tyrosine kinases, we show that interactions of these receptors with PTB domains predicted to bind by the NXXY arrays do occur in cells. Proteome-based peptide arrays can therefore identify networks of receptor interactions with scaffold proteins that may be physiologically relevant.

Screening for PTB Domain Binding Partners and LigandSpecificity Using Proteome-Derived NPXY Peptide Arrays

The RET receptor tyrosine kinase is important for several different biological functions during development. The recruitment at the phosphorylated Tyr1062 site in RET of a number of different phosphotyrosine binding (PTB) domain-containing adaptor proteins, including Shc and Frs2, plays a dominant role for the multiple different biological functions of the RET receptor during development, including stimulation of cell survival. Here, we demonstrate that a competitive recruitment of Shc as opposed to Frs2 mediates the survival signaling arising from RET activation. Based on results from a peptide array, we have genetically engineered the PTB domain binding site of RET to rewire its recruitment of the PTB proteins Shc and Frs2. An engineered RET that has a competitive interaction with Shc at the expense of Frs2, but not a RET receptor that only recruits Frs2, activates cell survival signaling pathways and is protective from cell death in neuronal SK-N-MC cells. Thus, cell type-specific functions involve a competitive recruitment of different PTB adaptor molecules by RET that activate selective signaling pathways.

Engineering the Recruitment of Phosphotyrosine Binding Domain-containing Adaptor Proteins Reveals Distinct Roles for RET Receptor-mediated Cell Survival*

Modular interaction domains that recognize peptide motifs in target proteins can impart selectivity in signaling pathways. Phosphotyrosine binding (PTB) domains are components of cytoplasmic docking proteins that bind cell surface receptors through NPXY motifs. We have employed a library of human proteome-derived NXXY sequences to explore PTB domain speciﬁcity and function. SPOTS peptide arrays were used to create a comprehensive matrix of receptor motifs that were probed with a set of 10 diverse PTB domains. This approach conﬁrmed that individual PTB domains have selective and distinct recognition properties and provided a means to explore over 2,500 potential PTB domain-NXXY interactions. The results correlated well with previously known associations between full-length proteins and predicted novel interactions, as well as consensus binding data for speciﬁc PTB domains. Using the Ret, MuSK, and ErbB2 receptor tyrosine kinases, we show that interactions of these receptors with PTB domains predicted to bind by the NXXY arrays do occur in cells. Proteome-based peptide arrays can therefore identify networks of receptor interactions with scaffold proteins that may be physiologically relevant. in dimethyl- sulfoxide. Incorporation of biotin was assessed using HRP-conjugated streptavidin from Bio-Rad Laboratories (Mississauga, ON, Canada). Peptide synthesis and ﬂuorescence polarization. Peptides were synthesized on an AbiMed 431 synthesizer using the standard Fastmoc protocol. Authenticity of product was conﬁrmed by matrix-assisted laser desorption ionization mass spec-trometry. Equilibrium binding constant determination was carried out on a Beacon ﬂuorescence polarization system (Pan Vera, WI) equipped with a 100- (cid:6) l sample chamber. Fluorescein-labeled probes were prepared through the reaction of carboxy terminal peptides with 5-(and -6)-carboxyﬂuorescein succinimidyl ester (Molecular Probes, Eugene, OR). Binding studies were conducted with 5 nM ﬂuorescein-labeled probes dissolved in phosphate-buffered saline containing 100 (cid:6) g ml (cid:4) 1 bovine serum albumin and 1 mM dithiothreitol. Increasing quan- tities of protein were added up to 100 (cid:6) M. Reaction mixtures were allowed to equilibrate for 30 to 60 min at room temperature. All ﬂuorescence polarization measurements were conducted at 22°C.

Screening for PTB Domain Binding Partners and Ligand Speciﬁcity Using Proteome-Derived NPXY Peptide Arrays (cid:1) †

ABSTRACT The human transcription factor CA150 modulates human immunodeficiency virus type 1 gene transcription and contains numerous signaling elements, including six FF domains. Repeated FF domains are present in several transcription and splicing factors and can recognize phosphoserine motifs in the C-terminal domain (CTD) of RNA polymerase II (RNAPII). Using mass spectrometry, we identify a number of nuclear binding partners for the CA150 FF domains and demonstrate a direct interaction between CA150 and Tat-SF1, a protein involved in the coupling of splicing and transcription. CA150 FF domains recognize multiple sites within the Tat-SF1 protein conforming to the consensus motif (D/E)2/5-F/W/Y-(D/E)2/5. Individual FF domains are capable of interacting with Tat-SF1 peptide ligands in an equivalent and noncooperative manner, with affinities ranging from 150 to 500 μM. Repeated FF domains therefore appear to bind their targets through multiple weak interactions with motifs comprised of negatively charged residues flanking aromatic amino acids. The RNAPII CTD represents a consensus FF domain-binding site, contingent on generation of the requisite negative charges by phosphorylation of serines 2 and 5. We propose that CA150, through the dual recognition of acidic motifs in proteins such as Tat-SF1 and the phosphorylated CTD, could mediate the recruitment of transcription and splicing factors to actively transcribing RNAPII.

FF Domains of CA150 Bind Transcription and Splicing Factors through Multiple Weak Interactions

Abstract Virtual Reality Job Interview Training (VR-JIT) has increased employment rates for returning citizens when added to a successful prison-based employment readiness program. However, implementation preparation cost—expenses prior to offering VR-JIT to intended recipients—is unknown. We estimated the cost of implementation preparation activities (e.g., organizing workflow) for two prisons to deliver VR-JIT. We conducted a budget impact analysis and enumerated the labor costs incurred during this important stage of implementation. Labor costs were approximately $8,847 per prison. Our sensitivity analysis estimated the labor costs to replicate this effort in a new prison to range from $2,877 to $4,306 per prison. Thus, VR-JIT may be an affordable tool for prison-based employment readiness programs to improve gainful employment.

Implementation preparation costs of virtual reality job interview training in prisons: a budget impact analysis

This article examines current technology-aided instruction and intervention (TAII) available for autistic transition-age youth (TAY) and existing policies that may support or hinder the delivery of these interventions. Specifically, we focus on policies that might influence the delivery of TAII to autistic TAY. After a careful review of the literature, we observed that postsecondary policy guiding the delivery of TAII designed to support autistic TAY is lacking. TAII has demonstrated effectiveness, usability, sustainability, and cost-effectiveness, particularly with this population. We suggest possibilities for future policies to support the development, implementation, and evaluation of TAII for autistic TAY.

The Need for Technology-Aided Instruction and Intervention Policy for Autistic Youth

BACKGROUND: Autistic transition-age youth are employed at rates far lower than their non-disabled peers as well as youth with other disabilities. Meanwhile, very few studies have evaluated the implementation of job interviewing practices within pre-employment transition services. OBJECTIVE: We conducted an initial implementation evaluation as part of a Hybrid Type 1 randomized controlled effectiveness-implementation trial where we trained teachers to deliver Virtual Interview Training for Transition-Age Youth (VIT-TAY) within five pre-employment transition services programs. METHOD: We used mixed methods to evaluate leader (n = 5), teacher (n = 15) and autistic transition age youth (n = 48) perceptions of VIT-TAY. We used descriptive statistics and thematic network analysis to evaluate survey data. Mixed methods integration was then performed to make comparisons between quantitative and qualitative results. RESULTS: Quantitative survey data revealed that leaders and teachers found VIT-TAY to be highly acceptable and appropriate for pre-employment transition services; findings which were confirmed via thematic network analysis of qualitative interview data. Autistic students reported via quantitative surveys that VIT-TAY was acceptable and usable, which was confirmed via thematic network analysis of open-ended survey data. CONCLUSION: This initial implementation evaluation can be used to inform a larger scale implementation evaluation of VIT-TAY in schools.

Mixed methods implementation evaluation of virtual interview training for transition-age autistic youth in pre-employment transition services

This column shares strategies for implementing a technology-based intervention within secondary special education transition services. Virtual Interview Training for Transition-Age Youth is a web-based job interview training that uses educational content and virtual hiring managers to help teach job interview skills. Eight support strategies for implementing the training are described. Strategies include prepare for implementation, ensure administrative support, prioritize training and support, address logistical challenges, integrate the program into the curriculum, take advantage of the administrative center, individualize student support, and offer virtual delivery.

Implementing Virtual Interview Training for Transition-Age Youth: Practical Strategies for Educators

OBJECTIVE
Virtual Reality Job Interview Training (VR-JIT) is a computerized interview simulator with efficacy at enhancing interview skills and employment outcomes. A randomized controlled trial assessed VR-JIT effectiveness for participants in individual placement and support (IPS), in which approximately 55% of individuals with serious mental illness obtain employment.

METHODS
Ninety participants with serious mental illness were randomly assigned to IPS+VR-JIT (N=54) or IPS as usual (N=36), completing pretest-posttest assessments and an employment evaluation at 9 months. Intent-to-treat chi-square analysis, multivariable logistic regression, Cox proportional hazards models, and mixed-effects linear regressions were conducted. Fifty-one percent were IPS nonresponders (i.e., no employment within the first 90 days of IPS).

RESULTS
IPS+VR-JIT participants did not have significantly higher employment rates, compared with IPS-as-usual participants (43% versus 28%). IPS nonresponders (N=46) in the IPS+VR-JIT group had greater odds of obtaining employment (odds ratio [OR]=5.82, p=0.014) and shorter time to employment (hazard ratio=2.70, p=0.044) compared with IPS nonresponders in the IPS-as-usual group. Intent-to-treat mixed-effects linear analyses indicated that IPS+VR-JIT, compared with IPS as usual, significantly improved interview skills (p=0.006), interview confidence (p=0.013), and interview anxiety (p=0.019).

VR-JIT's potential benefits (increased employment in a shorter time) appeared to be specific to IPS nonresponders, whereas employment outcomes for recent IPS enrollees were not affected. VR-JIT could be a valuable resource for employment specialists to support IPS nonresponders, because 47% of participants engaged in mock interview training with their specialist. Future research should focus on evaluating the effectiveness and implementation of VR-JIT among IPS nonresponders.

An RCT of Virtual Reality Job Interview Training for Individuals With Serious Mental Illness in IPS Supported Employment.

Returning citizens struggle to obtain employment after release from prison and navigating job interviews is a critical barrier they encounter. Implementing evidence-based interview training is a major gap in prison-based vocational services. We conducted a randomized controlled trial (RCT) to evaluate the feasibility and initial effectiveness of Virtual Reality Job Interview Training (VR-JIT) within two prisons. Forty-four male returning citizens were randomized to receive service-as-usual (SAU) with VR-JIT (SAU + VR-JIT, n = 28) or SAU (n = 16). Participants reported VR-JIT was highly acceptable and usable. SAU + VR-JIT, compared with SAU, had significant improvements (with large effect sizes) in interview skills, interview training motivation, and interview anxiety (all p < .05; η p 2 > .15), and greater employment by 6-month follow-up (odds ratio [OR] = 7.4, p = .045). VR-JIT can potentially help fill a major gap in prison-based services. Future research is needed to validate VR-JIT effectiveness and evaluate VR-JIT implementation strategies within prisons.

Virtual Reality Job Interview Training for Adults Receiving Prison-Based Employment Services: A Randomized Controlled Feasibility and Initial Effectiveness Trial

In a previous randomized controlled trial (RCT), Virtual Interview Training for Transition Age Youth (VIT-TAY) enhanced employment for autistic youth receiving transition services. For this study, a nonrandomized hybrid effectiveness-implementation trial evaluated whether VIT-TAY maintained its core implementation and effectiveness functions when scaled out to students with disabilities in 32 schools. Also, we compared the implementation and effectiveness between VIT-TAY and Virtual Reality Job Interview Training (VR-JIT; developed for adults and previously evaluated in students with disabilities). Core implementation functions did not differ between VIT-TAY and VR-JIT. Greater engagement with either training was significantly associated with employment (both p < .05). Overall, VIT-TAY was feasibly implemented with high adherence and may be effective at enhancing employment for students with disabilities. Limitations and implications for research and practice are discussed.

Scaling Out Virtual Interview Training for Transition-Age Youth: A Quasi-Experimental Hybrid Effectiveness-Implementation Study

In this perspective, we argue that the regular use of diversity advisory boards in autism research will improve the inclusivity and participation of marginalized groups in autism research and intervention development. We define a diversity advisory board as a representative group of community members, scholars, policymakers, and area experts that specifically discuss and examine research and interventions for accurate representation and consideration of underrepresented and marginalized identities such as racial, gender, sexual minorities, and dis/abilities who are often excluded from the research process. We present three arguments for forming and integrating diversity advisory boards in autism research and intervention development. First, diversity advisory boards would encourage scholars and interventionists to be intentional in considering how their intervention will work for culturally, racially, gendered, and dis/ability diverse groups. Second, diversity advisory boards will lead to increased diverse samples of autistic participants if members of the board are incentivized to support recruitment efforts from their local communities and networks. Finally, the regular use of diversity advisory boards will improve the research-to-practice gap by including a wider range of community members in the early development and implementation of autism interventions. Recommended actions researchers could take to select, maintain, and meaningfully engage a diversity advisory board are included in this perspective. Lay abstract This article argues that using groups of individuals that specifically focus on addressing issues with diversity in autism research and autism intervention development are key in ensuring that a greater amount of racial, ethnic, and gender diverse autistic individuals are included in the research and that the research is addressing the needs of these individuals and groups. We call these groups a diversity advisory board. A diversity advisory board will help improve diversity in autism research and intervention development by making sure that autism researchers (1) are intentional about addressing issues of diversity in their research and (2) are able to recruit a greater number of autistic individuals with diverse identities, and (3) by giving greater consideration to the context of diverse autistic individuals which will help autism-focused interventions work better in community settings. We give a short description of these arguments and ideas for how to form and use a diversity advisory board.

Perspective: The role of diversity advisory boards in autism research

Abstract This study explored peer specialists’ perspectives on delivering vocational interventions, especially Virtual Reality Job Interview Training (VR-JIT). Five focus groups of peer specialists (N = 34) explored their beliefs about vocational services, including VR-JIT. We trained eight peer specialists to be VR-JIT “instructors” and interviewed them about using VR-JIT in their mental health practice. Generally, participants discussed tailoring their vocational services to include sharing their story of recovery. Specifically, participants perceived VR-JIT as acceptable and feasibly implemented within their practice. Overall, participants viewed VR-JIT as a higher level of service and they would be uniquely qualified to support consumers using the tool.

Acceptability and Feasibility of Peer Specialist-Delivered Virtual Reality Job Interview Training for Individuals with Serious Mental Illness: A Qualitative Study

Brief Report: Initial Evidence of Depressive Symptom Disparities among Black and White Transition Age Autistic Youth

Vocational outcomes among transition-age youth receiving special education services are critically poor and have only incrementally improved since the implementation of the Workforce Innovation Opportunity Act. Few studies highlight whether interviewing may be critical to obtaining vocational outcomes such as competitive employment or internships. This study evaluated vocational interviewing and outcomes among 656 transition-age youth receiving special education pre-employment transition services from 47 schools. Results suggest 20.8% of these youth were currently employed, and 88.8% of these employed youth interviewed prior to obtaining their job, which is higher than anecdotal evidence suggests and speaks to the importance of job interview skills as an intervention target for special education pre-employment transition services. We discuss the implications and directions for further study.

Job Interview and Vocational Outcomes Among Transition-Age Youth Receiving Special Education Pre-Employment Transition Services.

A pilot RCT of virtual reality job interview training in transition-age youth on the autism spectrum

Autistic transition age youth struggle with obtaining employment, and interviewing is a critical barrier to getting a job. We adapted an efficacious virtual reality job interview intervention to meet the needs of autistic transition age youth, called the Virtual Interview Training for Transition Age Youth. This study evaluated whether Virtual Interview Training for Transition Age Youth can be feasibly delivered in high school special education settings and whether Virtual Interview Training for Transition Age Youth improves job interview skills, job interview self-efficacy, job interview anxiety, and access to employment. Forty-eight autistic transition age youth received school-based pre-employment services as usual with Virtual Interview Training for Transition Age Youth, while 23 autistic transition age youth received services as usual only. Local teachers trained and supervised autistic transition age youth using Virtual Interview Training for Transition Age Youth. Participants reported Virtual Interview Training for Transition Age Youth was highly acceptable. Participants receiving services as usual and Virtual Interview Training for Transition Age Youth, compared to participants receiving services as usual only, had better job interview skills and lower job interview anxiety as well as greater access to jobs. Overall, Virtual Interview Training for Transition Age Youth appears to be effective at teaching job interview skills that are associated with accessing competitive jobs. Moreover, youth enjoyed Virtual Interview Training for Transition Age Youth and teachers feasibly implemented the tool within special education pre-employment transition services. Future research needs to better understand how autistic transition age youth from culturally diverse backgrounds and different social, behavioral, or mental health challenges may respond to Virtual Interview Training for Transition Age Youth. Lay abstract Autistic transition age youth struggle with obtaining employment, and interviewing is a critical barrier to getting a job. We adapted an efficacious virtual reality job interview intervention to meet the needs of autistic transition age youth, called the Virtual Interview Training for Transition Age Youth. This study evaluated whether Virtual Interview Training for Transition Age Youth can be feasibly delivered in high school special education settings and whether Virtual Interview Training for Transition Age Youth improves job interview skills, job interview self-efficacy, job interview anxiety, and access to employment. Forty-eight autistic transition age youth received school-based pre-employment services as usual with Virtual Interview Training for Transition Age Youth, while 23 autistic transition age youth received services as usual only. Local teachers trained and supervised autistic transition age youth using Virtual Interview Training for Transition Age Youth. Participants reported Virtual Interview Training for Transition Age Youth was highly acceptable. Participants receiving services as usual and Virtual Interview Training for Transition Age Youth, compared to participants receiving services as usual only, had better job interview skills and lower job interview anxiety as well as greater access to jobs. Overall, Virtual Interview Training for Transition Age Youth appears to be effective at teaching job interview skills that are associated with accessing competitive jobs. Moreover, youth enjoyed Virtual Interview Training for Transition Age Youth and teachers feasibly implemented the tool within special education pre-employment transition services. Future research needs to better understand how autistic transition age youth from culturally diverse backgrounds and different social, behavioral, or mental health challenges may respond to Virtual Interview Training for Transition Age Youth.

Virtual interview training for autistic transition age youth: A randomized controlled feasibility and effectiveness trial

Suicidal ideation in first-episode psychosis: Considerations for depression, positive symptoms, clinical insight, and cognition

11 “To Place Ourselves in History”: The Haitian Revolution in British West Indian Thought before The Black Jacobins

Computerized Clinical Training Simulations with Virtual Clients Abusing Alcohol: Initial Feasibility, Acceptability, and Effectiveness

Using community-engaged methods to adapt virtual reality job-interview training for transition-age youth on the autism spectrum.

Job interviewing is often the first big hurdle for people seeking employment and may be especially difficult for someone with a psychiatric disorder or disability. Performing well in a job interview often requires coping with the emotional demands of the interaction and having the necessary social skills to establish rapport with the interviewer in order to present oneself in a favorable way. Virtual Reality Job Interview Training (VR-JIT) was created specifically for people with severe and persistent mental illness (SPMI) and other potential employment handicaps (e.g., physical disability, felony convictions, first job) to help them overcome their fears, learn the necessary skills, and develop self-confidence to do well during a job interview. The chapter begins by reviewing vocational rehabilitation services for individuals with SPMI, explains the scientific foundations of the VR-JIT training program, describes the special features of the online tool, and presents research findings on its acceptability and efficacy among individuals with SPMI and other disabilities. The authors observed that trainees largely adhered to VR-JIT and could master the skills and earn excellent scores by the end of training. VR-JIT had a moderate to large effect on improving job interview skills in live role-play interviews and increasing self-confidence for job interviews. Moreover, 6-month follow-up survey results suggest that VR-JIT increased access to employment or other competitive volunteer positions as well as reduced the number of weeks to obtaining their employment goal

Virtual Reality Training in Job Interviewing for People with Mental Health Disorders or Disabilities

Enhancing vocational training in corrections: A type 1 hybrid randomized controlled trial protocol for evaluating virtual reality job interview training among returning citizens preparing for community re-entry

This study reports the results of a single-arm, noncontrolled, Type 3 hybrid effectiveness-implementation trial evaluating virtual reality job interview training (VR-JIT) delivered in five preemployment transition programs comprising 15 schools, 10 administrators, 23 teachers, and 279 youth ages 16–21 years receiving special education preemployment transition services. Fidelity, expected implementation feasibility, and teacher and student acceptance of VR-JIT were high. Youth completed virtual interviews (M = 10.8, SD = 7.4) over 6–8 weeks. At the 6-month follow-up, teachers reported that youth using VR-JIT had employment rates higher than current national employment rates for youth with disabilities. A multinomial logistic regression revealed VR-JIT engagement was associated with greater employment rates by 6-month follow-up (odds ratio = 1.63, p = .002). This study provides promising evidence that VR-JIT may be feasibly implemented with high fidelity in special education preemployment transition services and can potentially enhance employment outcomes among transition-age youth receiving special education services.

Virtual Reality Job Interview Training in Transition Services: Results of a Single-Arm, Noncontrolled Effectiveness-Implementation Hybrid Trial

Adapting Virtual Reality Job-Interview Training for Transition-Age Youth on the Autism Spectrum

RATIONAL, AIMS AND OBJECTIVES
Individual Placement and Support (IPS) is an evidence based strategy for facilitating employment among adults with severe mental illness (SMI) where staff may lead mock job interviews to prepare clients for real-world interviews (a method with limited scalability and cost effectiveness). A virtual reality job interview training program (VR-JIT)-delivered via the internet-has demonstrated efficacy for increasing employment among adults with SMI. Now, VR-JIT is being implemented with a community mental health agency (CMHA) and evaluated for its effectiveness within IPS. This study is a budget impact analysis, evaluating the costs of preparing a CMHA to implement VR-JIT.

METHOD
Implementation preparation occurred over 7 months from October 1, 2016 to April 30, 2017. CMHA staff (n = 15) and external research partners (n = 3) tracked their hours completing implementation preparation activities. Salaries plus a 28% fringe benefit rate were used to derive a per-hour salary amount for each individual and applied to each activity. Non-labor equipment costs were obtained from purchase receipts. A budget impact analysis evaluated the expenditures associated with preparing the CMHA to implement VRJIT.

RESULTS
The total implementation preparation costs equaled $25,482. Labor costs equaled $22,882 and non-labor costs equaled $2,600. In total, 655 person-hours were spent preparing for VR-JIT implementation (e.g., preparing lab space, training, and supervising operations).

This study presents an initial evaluation of the budget impact of preparing to implement VR-JIT in a CMHA. Cost considerations for future implementation preparation will be discussed. Given that the cost to prepare to implement an intervention can hinder its adoption, results provide an important analysis for decision-makers that may enhance uptake. Future work will determine the cost-effectiveness of VR-JIT implemented within IPS. This study is registered at http://clinicaltrials.gov, NCT = 03049813, "Virtual Reality Job Interview Training: An Enhancement to Supported Employment in Severe Mental Illness."

Costs of preparing to implement a virtual reality job interview training programme in a community mental health agency: A budget impact analysis.

S129. PRELIMINARY RESULTS OF A RANDOMIZED CONTROLLED TRIAL TO EVALUATE VIRTUAL REALITY JOB INTERVIEW AS AN ENHANCEMENT TO THE INDIVIDUAL PLACEMENT AND SUPPORT MODEL OF SUPPORTED EMPLOYMENT

Enhancing individual placement and support (IPS) - Supported employment: A Type 1 hybrid design randomized controlled trial to evaluate virtual reality job interview training among adults with severe mental illness.

Abstract:The passing of J. Michael Dash has left the academic community on both sides of the Atlantic in shock. As we come to terms with the weight of this loss, we should remember his many contributions to how we think, understand, and write about the Caribbean.

ABSTRACT The social work profession has not yet taken a leadership role in addressing the myriad of challenges that individuals on the autism spectrum encounter across the lifespan. In this essay, we argue that social workers are well equipped to engage in research and practice aimed at promoting full and meaningful inclusion in society, as well as social and economic justice, for individuals on the autism spectrum. We highlight short- and long-term goals that provide the social work profession with a framework to engage in research, practice, education, and advocacy aimed at supporting individuals on the autism spectrum and their families.

Autism spectrum disorder and the science of social work: A grand challenge for social work research

Poetic Relations: Intimacy and Faith in the English Reformation. Constance M. Furey. Chicago: University of Chicago Press, 2017. Pp. xvi+244.

OBJECTIVE
Four randomized controlled trials revealed that virtual-reality job interview training (VR-JIT) improved interviewing skills and the odds of obtaining a job offer among trainees with severe mental illness or autism spectrum disorder. This study assessed whether postintervention interviewing skills mediated the relationship between completion of virtual interviews and receiving job offers by six-month follow-up.

METHODS
VR-JIT trainees (N=79) completed pre- and posttest mock interviews and a brief survey approximately six months later to assess whether they received a job offer.

RESULTS
As hypothesized, analyses indicated that the number of completed virtual interviews predicted greater posttest interviewing skills (β=.20, 95% posterior credible interval [PCI]=.08-.33), which in turn predicted trainees' obtaining a job offer (β=.28, 95% PCI=.01-.53).

VR-JIT may provide a mechanism of action that helps trainees with various psychiatric diagnoses obtain job offers in the community. Future research can evaluate the community-based effectiveness of this novel intervention.

Mechanism of Action for Obtaining Job Offers With Virtual Reality Job Interview Training.

W e thank the author for recognizing the importance of developing and evaluating whether virtual reality job interview training can help enhance skills and the ability to obtain job offers. We agree that our analytic focus was limited to the primary outcome measures; however, wewere underpowered tomore fully evaluate the impact of symptoms and cognition on training. Moreover, the lack of correlations that we observed between cognition and improved performance could simply reflect that the training is not dependent on one's cognitive capacity and that someone with reduced cognitive ability could still benefit from training. We see this as a potential strength of the training, but the question of this relationship can only be answered by a sufficiently powered trial. The author also brings up an excellent point regarding the benefits of collecting qualitative data. We will be collecting additional qualitative measurements during future evalua-

Response: Importance of Virtual Reality Job Interview Training in Today's World.

Individuals with substance use disorders (SUDs) have low employment rates and job interviewing is a critical barrier to employment for them. Virtual reality training is efficacious at improving interview skills and vocational outcomes for several clinical populations.

OBJECTIVE
This study evaluated the acceptability and efficacy of virtual reality job interview training (VR-JIT) at improving interview skills and vocational outcomes among individuals with SUDs via a small randomized controlled trial (n=14 VR-JIT trainees, n=11 treatment-as-usual (TAU) controls).

METHODS
Trainees completed up to 10 hours of virtual interviews, while controls received services as usual. Primary outcome measures included two pre-test and two post-test video-recorded role-play interviews and vocational outcomes at six-month follow-up.

RESULTS
Trainees reported that the intervention was easy-to-use and helped prepared them for future interviews. While co-varying for pre-test role-play performance, trainees had higher post-test role-play scores than controls at the trend level (p<0.10). At 6-month follow-up, trainees were more likely than controls to attain a competitive position (78.6% vs. 44.4%, p<0.05, respectively). Trainees had greater odds of attaining a competitive position by 6 month follow-up compared to controls (OR: 5.67, p<0.05). VR-JIT participation was associated with fewer weeks searching for a position (r= -0.36, p<0.05).

There is preliminary evidence that VR-JIT is acceptable to trainees. Moreover, VR-JIT led to better vocational outcomes with trainees having greater odds of attaining a competitive position by 6-month follow-up. Future studies could evaluate the effectiveness of VR-JIT within community-based services.

Virtual Reality Job Interview Training and 6-Month Employment Outcomes for Individuals with Substance Use Disorders Seeking Employment.

“To Place Ourselves in History”: The Haitian Revolution in British West Indian Thought beforeThe Black Jacobins

OBJECTIVE
Individuals with severe mental illness have low employment rates, and the job interview presents a critical barrier for them to obtain competitive employment. Prior randomized controlled trials (RCTs) indicated that virtual reality job interview training (VR-JIT) improved job interviewing skills among trainees. This study assessed whether VR-JIT participation was associated with greater odds of receiving job offers in the six-months after completion of training.

METHODS
To assess the efficacy of VR-JIT, trainees (N=39) in the method and a comparison group (N=12) completed a brief survey approximately six months after participating in the RCTs. Primary vocational outcome measures included receiving a job offer and number of weeks searching for employment.

RESULTS
A larger proportion of trainees than comparison participants received a job offer (51% versus 25%, respectively). Trainees were more likely to receive a job offer than comparison participants (odds ratio=9.64, p=.02) after analyses accounted for cognition, recency of last job, and diagnosis. Trainees had greater odds of receiving a job offer for each completed VR-JIT trial (odds ratio=1.41, p=.04), and a greater number of completed VR-JIT trials predicted fewer weeks of searching for employment (β=-.74, p=.02).

Results provide preliminary support that VR-JIT is a promising intervention associated with enhanced vocational outcomes among individuals with severe mental illness. Given that participants had minimal access to standardized vocational services, future research could evaluate the effectiveness of VR-JIT among individuals with and without access to standardized vocational services as well as evaluate strategies to implement VR-JIT within a large community mental health service provider.

Job Offers to Individuals With Severe Mental Illness After Participation in Virtual Reality Job Interview Training.

Virtual reality job interview training and 6-month employment outcomes for individuals with schizophrenia seeking employment

Veterans with posttraumatic stress disorder (PTSD) have low employment rates and the job interview presents a critical barrier for them to obtain competitive employment.

OBJECTIVE
To evaluate the acceptability and efficacy of virtual reality job interview training (VR-JIT) among veterans with PTSD via a small randomized controlled trial (n=23 VR-JIT trainees, n=10 waitlist treatment-as-usual (TAU) controls).

METHODS
VR-JIT trainees completed up to 10 hours of simulated job interviews and reviewed information and tips about job interviewing, while wait-list TAU controls received services as usual. Primary outcome measures included two pre-test and two post-test video-recorded role-play interviews scored by blinded human resource experts and self-reported interviewing self-confidence.

RESULTS
Trainees attended 95% of lab-based VR-JIT sessions and found the intervention easy-to-use, helpful, and prepared them for future interviews. VR-JIT trainees demonstrated significantly greater improvement on role-play interviews compared with wait-list TAU controls (p=0.04) and demonstrated a large effect for within-subject change (Cohen's d=0.76). VR-JIT performance scores increased significantly over time (R-Squared=0.76). Although VR-JIT trainees showed a moderate effect for within-subject change on self-confidence (Cohen's d=0.58), the observed difference between conditions did not reach significance (p=0.09).

Results provide preliminary support that VR-JIT is acceptable to trainees and may be efficacious for improving job interview skills and self-confidence in veterans with PTSD.

Virtual Reality Job Interview Training for Veterans with Posttraumatic Stress Disorder.

For the past decade, we’ve been conducting research, writing, and working with companies on the topic of organizational health. Our work indicates that the health of an organization is based on the ability to align around a clear vision, strategy, and culture; to execute with excellence; and to renew the organization’s focus over time by responding to market trends. Health also has a hard edge: indeed, we’ve come to define it as the capacity to deliver— over the long term—superior financial and operating performance.

The hidden value of organizational health– and how to capture it

Abstract Services are available to help support existing employment for individuals with psychiatric disabilities; however, there is a gap in services targeting job interview skills that can help obtain employment. We assessed the feasibility and efficacy of Virtual Reality Job Interview Training (VR-JIT) in a randomized controlled trial. Participants were randomized to VR-JIT (n = 25) or treatment-as-usual (TAU) (n = 12) groups. VR-JIT consisted of 10 hours of simulated job interviews with a virtual character and didactic online training. The participants attended 95% of laboratory-based training sessions and found VR-JIT easy to use and felt prepared for future interviews. The VR-JIT group improved their job interview role-play performance (p ⩽ 0.05) and self-confidence (p ⩽ 0.05) between baseline and follow-up as compared with the TAU group. VR-JIT performance scores increased over time (R2 = 0.65). VR-JIT demonstrated initial feasibility and efficacy at improving job interview skills and self-confidence. Future research may help clarify whether this intervention is efficacious in community-based settings.

Virtual Reality Job Interview Training for Individuals With Psychiatric Disabilities

Content analysis of CMS Healthcare Innovation Awards from a physiatric perspective.

The spine journal : official journal of the North American Spine Society

Much of the change being sought in the United State’s health-care system is predicated on improving value. Value is most simply defined as quality divided by cost, and physicians increasingly rely on the quality-adjusted life year as the numerical measure to justify their services. However, there are many other definitions of value being advocated by various stakeholders in the health-care reform effort. Incentive programs and pilot studies implemented by private and public payers are steering much of the current change. Expanding our understanding of how value is defined by health-care economists and policy makers can help spine providers navigate the evolving healthcare landscape. 2013 Elsevier Inc. All rights reserved.

Sprague, Jeb. Paramilitarism and the Assault on Democracy in Haiti. New York: Monthly Review Press, 2012. 400 pp. US$23.95 (paperback).

"The Picador March" and "Nymphalin" of John Philip Sousa: Transcriptions and Editions for Historically-Informed Performance

Stage, cathedral, wagon, street: The grounds of belief in Shakespeare and Renaissance performance

Sacramental Poetics at the Dawn of Secularism: When God Left the World. By Regina Mara Schwartz.

This study examined health behaviors, utilization, and access to care among older Latina and Black American mothers who co-reside with a child with developmental disabilities. Using data from the National Health Interview Survey National Center for Health Statistics (2005a), we compared Latina and Black American caregivers to similar women who did not have caregiving responsibilities. Findings showed that Latina caregivers were more likely to smoke and have insurance; Black American caregivers were less likely to be able to afford medication and mental health care; and both groups were less likely to have seen a doctor in the past year than their noncaregiving counterparts. Findings suggest that service providers should consider developing programs that focus on health for caregivers of color. Furthermore, results suggest that providers should take into account differing trends across ethnicities when designing programs.

Health behaviors, service utilization, and access to care among older mothers of color who have children with developmental disabilities.

The impact of caring for a child with a developmental disability on the physical and mental health of Latina and Black American women was examined. We used the National Health Interview Survey to compare the health of older mothers who were co-residing with a child who had a developmental disability to the health of same age mothers without caregiving responsibilities. Findings show that for both groups, older adult caregivers were more likely to report having limitations from arthritis than their noncaregiving counterparts. Caregiving was associated with more depressive symptoms for Latinas, but this relationship was not found for Black American women. Findings suggest that physical and mental health of caregivers need more attention in research and practice.

Health outcomes of midlife and older Latina and black American mothers of children with developmental disabilities.

This article examined the emotional well-being of 108 Latina and non-Latina White mothers who were coresiding with a youth or adult with an autism spectrum disorder (ASD). It was hypothesized that Latina mothers would be more satisfied with coresidence than non-Latina White mothers, and that satisfaction with coresidence would mediate the relationship between ethnicity and outcomes. When controlling for demographic characteristics, non-Latina White mothers were more distressed and had lower levels of psychological well-being than Latina mothers. As hypothesized, satisfaction with coresidence mediated this difference. Qualitative analysis revealed that both groups of mothers valued family cohesion as a positive aspect of coresidence. However, Latina mothers were less likely to report negative aspects of coresidence than non-Latina White mothers.

Psychological distress and well-being of Latina and non-Latina White mothers of youth and adults with an autism spectrum disorder: cultural attitudes towards coresidence status.

OBJECTIVE
The first democratic government elected in South Africa in 1994 inherited huge inequalities in health status and health provision across all sections of the population. This study set out to assess, 4 years later, the influence of race and socioeconomic status (SES) on perceived quality of care from health care providers.

DESIGN
A 1998 countrywide survey of 3820 households assessed many aspects of health care delivery, including levels of satisfaction with health care providers among different segments of South African society.

RESULTS
Fifty-one percent (n = 1953) of the respondents had attended a primary care facility in the year preceding the interview and were retained in the analysis. Both race and SES were significant predictors of levels of satisfaction with the services of the health care provider, after adjusting for gender, age, and type of facility visited. White and high SES respondents were about 1.5 times more likely to report excellent service compared with Black and low SES respondents, respectively.

In South Africa, race and SES are not synonymous and can no longer be considered reliable proxy indicators of one another. Each has distinct and significant but different degrees of association with client satisfaction. Any assessment of equity-driven health policy in South Africa should consider the impacts of both race and SES on client satisfaction as one of the indicators of success.

International journal for quality in health care : journal of the International Society for Quality in Health Care

Patient satisfaction with health care providers in South Africa: the influences of race and socioeconomic status.

Abstract This article provides a critique of South Africa's attempt to transform apprenticeships using data from the 2004 Baseline Survey of the Learnership Programme in South Africa. The data suggests that Learnerships provide important opportunities for those in work to learn new theoretical and practical capabilities and thus deepen the skills base of the South African economy. They also provide key avenues for unemployed people to gain skills and work experience and improve their employability. Moreover, incentives have been set sufficiently high to encourage employer participation. However, this high overall level of satisfaction with the Learnerships may mask some of the underlying differences in levels of satisfaction across the different strata of the South African labour market. Without controlling for other factors, there were substantial differences in the levels of satisfaction with Learnerships across the employed versus unemployed and National Qualifications Framework (NQF) level divides. This suggests that a number of key challenges remain which the architects of the policy need to urgently address, including a more equitable spread of Learnerships across both spheres of the dual economy and strengthening the administrative and oversight capacity of SETAs.

Perspectives on learnerships: a critique of South Africa's transformation of apprenticeships

Book Review Editor’s Note: Having received these two books on reality television within just a few weeks of each other, I contacted Professors Andrejevic and Smith, who had not met prior to this, to collaborate on a “dialogue-inspired” review essay where they engage each other’s work. The following co-authored essay resulted, with the authorship of each section appearing in parentheses next to the section title.

Collaborative Review Essay: "Reality TV: The Work of Being Watched," by Mark Andrejevic and "Survivor Lessons: Essays on Communication and Reality Television," edited by Matthew J. Smith and Andrew F. Wood

The Manchester Massacre of 1819 and Chartist March of 1842: The emergence(y) of working class identity, representation, and history

 The traditional tiered security operation centre approach is flawed, writes Matthew Smith, Global Head of Cyber Security, St. James's Palace - simply because we are human. We must leverage the benefits of machine learning, user behaviour analytics and security automation to deliver effective detection and response in 2020 and beyond.

This article examines how contemporary artists respond to the technique of hydraulic fracturing, more commonly known as “fracking.” Drawing on examples of political protest and social activism, with special focus on the ways that artistic interventions challenge energy corporations in galleries and museums, Smith analyzes how artists fuse concerns over the environment with critical aesthetics. By doing so, they explore the problematic relationships between fracking and climate change, waste, environmental degradation, pollution, and public health. In the wake of new data, research, and dissent, it is argued that contemporary art visualizes protest and continues to play a role in picturing the potentially harmful effects of fracking. Accordingly, Smith proposes that artists formulate innovative ways to confront an authoritative fuel industry and translate key issues into new modes of understanding.

Kinngait in Scale: Embassy of Imagination and the Next Generation of Inuit Artists

(Forthcoming) Tell-Tale Signs: Unsanctioned Graffiti Interventions in Post-Apartheid Johannesburg

Scandalous Images, Divine Light: Photography and the Aesthetics of Scanography

Performative aPProPriation of video art on Youtube, vimeo and dailYmotion

Marie-Paula Robitaille (ed.), Journey to the Heart of the First Peoples Collection. Montreal: Baraka Books, 2014. 260 pages. ISBN 9781771860307. $49.95 hardcover.The Canadian Museum of Civilization (renamed the Canadian Museum of History in 2013) is a public cultural institution located in Gatineau, Quebec. The amendment of the museum's name serves to reposition Canada's historical events and cultural production within a framework that can include a special focus on its relationship to the global sphere. Established in 1856, the museum is not only one of the oldest cultural institutions in Canada, but it also holds the highest visitor attendance rate in Canada. The National Collection comprises over four million visual materials of relevance to scholarly disciplines including, but not limited to, art history, archeology, anthropology, geology, and ethnology.This edited volume comprises fifteen interdisciplinary essays by Aboriginal and non-Aboriginal artists, writers, curators, and scholars who engage broadly with the museum's collection of Aboriginal visual material and artwork titled the First Peoples collection. The editor and curator at the museum, Marie-Paule Robitaille, divides the work into five distinct sections. The first section, "The National Collection Built over Many Years," includes four essays that investigate the complex history behind growing the museum's substantial First Peoples collection. The first essay by Robitaille is arguably the most consequential because it maps the social origins of the museum -first opened as a display centre for the Geological Survey of Canada -as well as the often unrelated donations, purchasing, and collection practices that contribute to the heterogeneous scope of objects, artifacts, artworks, and specimens. The authors in this section do not shy away from the close relationship between collecting and colonialism, acknowledging that the participation between Aboriginal peoples and Canada's cultural institutions is a way into decolonization (48).Three essays comprise the second section "The Musees da la civilisation Working Closely with the Nations." Here, the texts employ a postcolonial methodology to explore ways that foster Aboriginal inclusivity in Canadian cultural institutions systematically, beginning with the active participation of Aboriginal peoples in exhibition and collecting planning, design, and execution. Though the authors cull from various experiences and sources, at the centre of their arguments is a desire to respectfully address the ways that progressive intellectual property rights, repatriation, and co-management policies hold potential for greater agency while facilitating cultural renewal. In particular, Boye G. Ladd's (Ho-Chunk Nation) essay on the traditional meaning of gift-giving offers a fresh perspective on how Aboriginal epistemology related to collecting is often in conflict with European values and conventions, the same values and conventions that still govern some Canadian cultural institutions."Collections and Exhibitions, a Vital Link" is the title of the third section, which includes both an essay and research notes. The first text examines how the 1991 exhibition "L'OEil amerindien regards sur l'animal" at the museum remains an archetypal example of a rigorous curatorial premise, selection of works, and design principles. In effect, the author argues that the exhibition's "content-container" relationship posits a useful strategy for ethnographic museology with suggestions as to how to adopt it for today's exhibitionary environment (147). "Museum Research Notes," written by Diane Dittemore, curator of the Arizona State Museum, in conjunction with Robitaille, illustrates the collaboration between the museum and the Arizona State Museum in providing collection inventories to Aboriginal peoples in the United States and Canada. …

Before and After the Horizon: Anishinaabe Artists of the Great Lakes

Notes on Curating Autobiographical Art / Notes sur le commissariat de l’art autobiographique

This paper argues that autobiographical video art radically transforms intersubjective relationships with viewers, and in doing so deconstructs critical spectatorship by positioning the viewer as an interlocutor. Here I draw attention to the work of visual artists Lisa Steele, Colin Campbell, Peter Kingstone, and Irene Loughlin, who help to reconceptualize the interlocutor subject position by using unorthodox transmedial aesthetic strategies.

Toronto-based artist Clive Holden engages the prospect of chance in various random compositions through his use of randomization algorithms. Combining new digital technologies with lo-fi analog formats, these sequences of possibility literalize Gilies Deleuze and Felix Guattari's notion of the rhizome (a philosophical concept relating to representation, among other things), which they describe as having "no beginning or end; it is always in the middle, between things, interbeing, intermezzo." (1) As such, Holden's work presents a strong challenge to the very idea of the static, immobile image because the work dramatizes the simple drift of time. For this reason Holden's images remain performative, quite literally making themselves anew every moment ad infinitum, a kind of controlled chaos. Recently, Holden has drawn his attention to random compositions created for media lightboxes, media walls, and projections, making them with web technology that's been modded for offline purposes. But he has also been addressing the internet more generally by creating digital paintings, website artworks, and videos. In his latest series INTERNET MOUNTAINS (2014--present), he appropriates found imagery from the World Wide Web to produce fantastical digital landscapes and accompanying moving image works. Similar to his earlier work, these too depend on randomization processes to determine their visual trajectory, yet their approach is radically different. In both the digital paintings and internet videos, sunspots, orbs, and other abstract forms traverse the frame in a collision of analog and digital, real and surreal. I spoke with Holden via email exchange in May and July of 2015 about his recent projects and whatever else came to mind. MATTHEW RYAN SMITH: I'd like to begin by tracing how you arrived at your recent series INTERNET MOUNTAINS. What concerned you then, and how did that translate into now? CLIVE HOLDEN: INTERNET MOUNTAINS showed up as an idea last summer. It's been a way to think about the relationship between real mountains--the kind one can climb--versus internet mountains that buzz with the power of the archetype they are, even if they've been dissolved into math and reconstituted into digital images. The project's tagline is: "Mountains versus the internet, who will win?" I've been thinking about this growing tension between objects and the ephemeral. It's one of the most interesting border zones for making art; there's lots of energy to work with there. Today, we're seeing a battle between the older world of art forms with mass and texture--everything from sculpture to works on paper--versus fleeting or weightless forms on the other, including post-cinema, website artworks and net.art, conceptual data-based work, and even "social media art." It's all performance in a way: work that's dynamic and continually producing unique moments. A year into the project, I know it has enough fuel to keep me interested until it's all made. Which is one of the ways I decide if I should make something. The project should be completed by 2017. We've always lived somewhere between mountains and idea. That relationship is basic to how we live, but now it's being expanded. We live partly online, but we still need food, air, some exercise, and physical human contact to function. MRS: Chance has driven your practice for several years. In 2013, I reviewed your show of Media, Mediated (March 2-30, 2013) at Stephen Bulger Gallery in Toronto for Afterimage [Ed. note: See the review in Afterimage 40, no. 6] and noted that "utilizing the randomization and dynamism found in nature serves to unsettle and reconfigure [your] installations, transforming them into ever-evolving media." Was this an accurate description, and how is your new work engaging chance through algorithms? CH: Nature is full of models for chance-based and dynamic structures. Ecosystems, for example--the way they continually adjust in response to events. …

A review of

Phillips, Ruth. 2011. Museum Pieces: Toward the Indigenization of Canadian Museums. Montreal/Kingston: McGill-Queen’s University Press.

Book Review: Museum Pieces: Toward the Indigenization of Canadian Museums

Book Review: "The Official Picture: The National Film Board of Canada's Still Photography Division and the Image of Canada, 1941-1971"

Blackbirds and Growing Pains: A Conversation with Rutherford Chang

Family Photography and the Documentation of Trauma in Contemporary Art

Canadian Journal of Film Studies-revue Canadienne D Etudes Cinematographiques

American Ethnographic Cinema and Personal Documentary: The Cambridge Turn By Scott Macdonald. Berkeley: University of California Press, 2013

Ghost Dance: The Crisis of Categorization in Contemporary Indigenous Art

Hennessy Youngman and the New Art Criticism / Hennessy Youngman et la nouvelle critique d’art

In 1983, the National Commission on Excellence in Education published A Nation at Risk in response to the growing perception that the public educational system in the United States was failing to a...

Character Education: Introduction, Evolution, and Current Trends

Book Review: "Gary Wyatt: Seekers and Travellers Contemporary Art of the Pacific Northwest Coast"

Book Review: Shapeshifting: Transformations in Native American Art

Relational Viewing: Affect, Trauma and the Viewer in Contemporary Autobiographical Art

PhD Thesis (Some images have been removed due to copyright issues. The thesis (and multimedia items accompanying it) can be viewed in full via the print copy at the University Library.)

Dale Chihuly: The Chandeliers and other Critical Insight into his Work

In 1954, George Spindler convened the first conference devoted to exploring the joint interests of anthropologists and educators. Since then, a sizable percentage of the Spindlers’ numerous written works have centered on these concerns. Due to this conference, their corpus of work, and their role in training large numbers of educators and educational anthropologists, they are recognized as founders of the field of anthropology and education. Before Louise Spindler’s death in 1997, she and her husband began to select the chapters for this anthology of their best work in the field. The foreword by Henry Trueba and previews by G. Spindler introduce the book’s sections and chapters. The latter provide reference and contextual materials on the larger studies that generated each chapter and include reflections on the state of research and theory in educational anthropology today and on continuities and changes in the Spindlers’ stances and practices. Ray McDermott and Frederick Erickson’s informal interviews further illuminate the Spindlers’ intellectual evolution, whereas a concluding chapter by Susan Parman outlines the Spindlers’ work in areas outside educational anthropology. Because the Spindlers’ work is macroethnographic (holistic and broad in scope), components of this work are present in each chapter. The anthology is organized into four sections and is loosely chronological. The first section introduces the main themes of the book as they

It is well documented that African Americans tend to score lower on cognitive ability tests than White Americans. The cause of this performance difference is still being hotly debated and actively researched. Recently, J. E. Helms (1992) argued that cognitive ability tests fail to adequately assess African American intelligence because they do not account for the emphasis placed on social relations and the effect of social context on reasoning in the African American culture. To evaluate this argument, racial subgroup performance differences on Wason conditional reasoning items presented in the standard form and in a social relationship form were examined. Contrary to Helms's argument, results indicate that presenting Wason conditional reasoning items in a social context did not reduce the difference between African American and White American performance.

Can Racial Differences in Cognitive Test Performance Be Reduced by Presenting Problems in a Social Context

Rehabilitation after primary reverse total shoulder arthroplasty (RTSA) is accepted to be an essential component to successful outcome achievement, but successful rehabilitation approaches have yet to be well described in the literature. This retrospective review documents the outcomes of a cohort of 29 patients undergoing RTSA surgery with rehabilitation following the Upper Limb Treatment and Rehabilitation Advice (ULTRA) guideline (Appendix 1). The Oxford Shoulder Score, Quick Disabilities of the Arm, Shoulder and Hand score, range of movement (degrees of flexion, abduction and external rotation) and numerical rating score for pain were prospectively collected pre-operatively and at one- and two-years post-operatively. Scores were then evaluated to establish whether or not there were any significant changes over time. Statistically significant improvements were seen in all outcome domains from pre-operative to one-year post-operative. All improvements met the threshold for achieving substantial clinical benefit as well as exceeding the minimum clinically important difference, and all improvements were maintained at the two-year post-operative time point. The present study showed that following the ULTRA guideline after elective RTSA can give statistically significant improvements in range of movement, pain score and patient-reported outcome at one-year post-operatively, which can be maintained up to two-years post-operatively.

Physiotherapy treatment for reverse total shoulder arthroplasty: Results of a patient-centred rehabilitation guideline using functional and patient-reported outcome measures

Background Deep infection remains a serious complication of orthopaedic surgery. Knowledge of infection rates and causative organisms is important to guide infection control measures. The aim of the present study was to determine infection rates and causative organisms in elective shoulder surgery. Methods Cases complicated by infection were identified and prospectively recorded over a 2-year period. All patients undergoing elective shoulder surgery in the concurrent period at a single Specialist Upper Limb Unit in the UK were identified from the hospital electronic database. Results In total, 1574 elective shoulder cases were performed: 1359 arthroscopic (540 with implant insertion) and 215 open (197 with implant insertion). The overall infection rate in open surgery of 2.5% was significantly higher than arthroscopic implant cases at 0.7% (p < 0.005). The overall infection rate in implant arthroscopic surgery was significantly higher at 0.7% compared to 0% in non-implant related surgery. (p < 0.05) Conclusions Patients undergoing open shoulder surgery have a significantly higher risk of infection compared to arthroscopic shoulder surgery. Arthroscopic surgery with implant insertion has a statistically significantly higher risk of developing deep infection compared to procedures with no implant insertion. We recommend prophylactic antibiotics in open shoulder surgery and arthroscopic shoulder surgery with implant insertion.

The incidence and causative organisms of infection in elective shoulder surgery

Introduction Shoulder and Elbow replacement was added to NJR data collection from 1st April 2012. We present an initial audit of our unit’s experience following the introduction of shoulder and elbow replacement to the NJR, followed by re-audit to complete the loop, summarizing our overall experience for 2012 and the recommendations for 2013. Method Patients who did not have any entry on the NJR system, or patients who whose information did not meet the minimum dataset for inclusion onto the NJR system were collated. The initial audit cycle ran form April 2012 to October 2012, after dissemination of these results; the second cycle ran from October 2012 to December 2012. Results In the initial period, only 49% of procedures were entered onto the NJR. In the period following, all procedures performed were added to the online system. However, despite this improvement consent rate for patient identifiable information to be entered onto the NJR remained low at 16%. Conclusion This audit represents our initial experience with the expansion of the UK’s NJR to shoulder and elbow replacement. In this initial period, the awareness of the expansion of the NJR was limited, hence the poor input. This was corrected in the second audit cycle, with an improvement in the submission rate.

Addition of Shoulder and Elbow replacement to the National Joint Register – an audit of initial experience in a large University teaching hospital

Metastatic pathological fracture of the surgical neck of humerus during manipulation under anaesthesia for adhesive capsulitis

Manipulation or intra-articular steroids in the management of adhesive capsulitis of the shoulder? A prospective randomized trial.

Fractures of the proximal humerus are common. Most can be treated conservatively with good results. However, there is no uniform treatment of displaced fractures. One option was the PlantTan Plate (PTP). We present a study of 65 patients with displaced proximal humeral fractures treated with the PTP. Patients were followed-up for 24 months assessing fracture healing, functional outcome, pain and postoperative complications. The mean patient age was 61 years (range: 17 to 86). Forty-six percent of the patients were aged over 65 years. The Constant-Murley shoulder score (CMS) to assess function and a visual analogue scale (VAS) assessing pain were used. At 24 months, the mean CMS was 76 (range: 34 to 100) for the fractured side and 85 (range: 66 to 100) for the uninjured side, the mean VAS was 22 (range: 0 to 78). We believe that this study shows that operative intervention is a viable option for displaced proximal humeral fractures.

Internal fixation of fractures of the proximal humerus with a humeral fixator plate (PlantTan Plate): a two year follow-up.

A 61-year-old male had a successful left total knee arthroplasty but one year later developed a deep diphtheroides infection of the joint following femoral percutaneous transluminal coronary angioplasty without antimicrobial prophylaxis. Diphtheroides is an uncommon organism to infect a joint replacement and it has not been reported in the medical literature previously to our knowledge. There is little evidence to support the routine use of prophylactic antibiotics to cover percutaneous transluminal coronary angioplasty in the general population; however, we would encourage its use, and the use of an alternative entry site (such as the radial artery) if a patient has a joint replacement in situ.

Diphtheroid infection of a total knee arthroplasty following femoral percutaneous transluminal coronary angioplasty.

We report a case of failed reduction of the distal tibiofibular syndesmosis following a Maisonneuve fracture due to interposition of an osteochondral fragment in the syndesmosis from the tibial plafond. The displaced fragment was not initially appreciated. It is suggested that surgeons consider this as a possible cause of an incompletely reduced diastasis after deltoid ligament interposition has been excluded.

The Journal of foot and ankle surgery : official publication of the American College of Foot and Ankle Surgeons

Persistent diastasis in a Maisonneuve fracture--interposition of a tibial osteochondral fragment: a case report.

In order to identify structural features of pyrimethamine (5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine) that contribute to its inhibitory activity (IC50 value) and chaperoning efficacy toward β-N-acetylhexosaminidase, derivatives of the compound were synthesized that differ at the positions bearing the amino, ethyl, and chloro groups. Whereas the amino groups proved to be critical to its inhibitory activity, a variety of substitutions at the chloro position only increased its IC50 by 2-3-fold. Replacing the ethyl group at the 6-position with butyl or methyl groups increased IC50 more than 10-fold. Surprisingly, despite its higher IC50, a derivative lacking the chlorine atom in the para-position was found to enhance enzyme activity in live patient cells a further 25% at concentrations >100 μM, while showing less toxicity. These findings demonstrate the importance of the phenyl group in modulating the chaperoning efficacy and toxicity profile of the derivatives.

Pyrimethamine Derivatives: Insight into Binding Mechanism and Improved Enhancement of Mutant β-N-acetylhexosaminidase Activity.

The presented procedure gives access to a broad scope of arylated enones and crotonic systems with reasonable yields by employment of a relative simple catalytic system compared to common protocols.

Selective Reactivity of Electron-Rich Aryl Iodides in the Heck Arylation of Disubstituted Alkenes Catalyzed by Palladium—Arylurea Complexes.

Pd‐Arylurea Complexes for the Heck Arylation of Crotonic and Cinnamic Substrates.

Pd–arylurea complexes for the Heck arylation of crotonic and cinnamic substrates

Selective reactivity of electron-rich aryl iodides in the Heck arylation of disubstituted alkenes catalyzed by palladium–arylurea complexes

Directed evolution and rational design of a de novo designed esterase toward improved catalysis. Northeast Structural Genomics Consortium (NESG) Target OR184

Reaction of in situ generated lithium phosphides with 0.5 eq. Cu(I) is employed as a means of targeting lithium phosphidocuprates of either Gilman- or Lipshutz-type formulation--e.g., (R(2)P)(2)CuLi·n(LiX) (n = 0, 1). For R = Ph, X = CN in toluene followed by thf or R = Ph, X = I in thf/toluene an unexpected product results. [(Ph(2)P)(6)Cu(4)][Li·4thf](2)1 reveals an ion-separated structure in the solid state, with solvated lithium cations countering the charge on an adamantyl dianion [(Ph(2)P)(6)Cu(4)](2-). Deployment of R = Ph, X = CN in thf affords a novel network based on the dimer of Ph(2)PCu(CN)Li·2thf 2 with trianions based on 6-membered (PCu)(3) rings acting as nodes in the supramolecular array and solvated alkali metal counter-ions completing the linkers. Cy(2)PLi (Cy = cyclohexyl) has been reacted with CuCN in thf/toluene to yield Gilman-type lithium bis(phosphido)cuprate (Cy(2)P)(2)CuLi·2thf 3 by the exclusion of in situ generated LiCN. A polymer is noted in the solid state.

Expanding the tools available for direct ortho cupration--targeting lithium phosphidocuprates.

Enzyme catalysts of a retroaldol reaction have been generated by computational design using a motif that combines a lysine in a nonpolar environment with water‐mediated stabilization of the carbinolamine hydroxyl and β‐hydroxyl groups. Here, we show that the design process is robust and repeatable, with 33 new active designs constructed on 13 different protein scaffold backbones. The initial activities are not high but are increased through site‐directed mutagenesis and laboratory evolution. Mutational data highlight areas for improvement in design. Different designed catalysts give different borohydride‐reduced reaction intermediates, suggesting a distribution of properties of the designed enzymes that may be further explored and exploited.

Robust computational design, optimization, and structural characterization of retroaldol enzymes

Interfacial storage of lithium in the nanostructure of SnO2 nanobaskets for capacities exceeding theoretical values

Carbenes derived from diazoimidazolecarboxylates 4 under thermal or photochemical conditions undergo O-H and N-H insertion reactions with alcohols and amines, respectively, in moderate yield, in competition with reduction in good H-donor solvents. Dichloromethane reacts to give the corresponding 4-chloroimidazole. Aromatic hydrocarbons are excellent traps for the imidazolylidene carbene and lead to a range of arylimidazole derivatives 7. Reaction with pyridine leads to the first example of a pyridinium ylide 8 formed from an imidazolylidene carbene, whereas irradiation in hexafluorobenzene gives the imidazoazocine 11, presumably by way of an initial norcaradiene intermediate.

Carbene reactivity of 4-diazo-4H-imidazoles toward nucleophiles and aromatic compounds.

Design, synthesis and biological evaluation of new tryptamine and tetrahydro-beta-carboline-based selective inhibitors of CDK4.

Optical transitions and dynamic properties of GaN wide bandgap semiconductors and quantum wells

DOES AN OPTIMAL LIFTING HEIGHT FOR THE PRODUCTION OF PEAK POWER OUTPUT DURING THE OLYMPIC POWER CLEAN EXIST

Measurement of the sound power output of machinery has typically assumed that the result required is independent of time. Indeed, if there are temporal variations most standardized methods1,2 would require averaging over a number of cycles of operation in order to give a single value figure. The main application of these measurements has been to establish noise exposures for a workforce, and therefore the long term energy exposure is the critical measure. The classical method depended on indirect measures of sound intensity, in an anechoic or reverberation chamber. With the development of direct methods for the measurement of sound intensity, measurements can often be made in situ, but, again the requirement exists for a continuous output, and, if present, a continuous uninterrupted level of background noise3.

TIME DOMAIN MEASUREMENT OF SOUND POWER OUTPUT FROM A VACUUM FABRICATION FACILITY

The present study examined the impact of reputation information on athletes’ behavioral responses to coaches within a naturalistic, field‐based setting. Using a between‐group design, male soccer players (n = 35) were assigned to one of three experimental conditions (i.e., experienced reputation, inexperienced reputation, no reputation) prior to taking part in a coaching session delivered by an unknown coach. Participants’ behaviors indicative of attention to coach instruction, effort and persistence, and willingness to participate in demonstrations were video recorded throughout the coaching session. Multivariate analyses of variance revealed that participants in the experienced reputation condition exhibited significantly greater attention to coach instruction, and greater effort and persistence during free practice than participants in the inexperienced reputation condition. Results related to participants’ willingness to participate in demonstrations failed to yield any significant differences. The results provide further evidence to support the contention that athletes use reputation information as a basis for their initial expectancies of coaches, and such expectancies have the potential to influence athletes’ behavior during coach–athlete interactions. The findings also indicate that expectancies based on positive information may be more powerful than negatively framed expectancies, and can be harnessed by coaches as a means of developing effective relationships with their athletes.

The influence of coach reputation on the behavioral responses of male soccer players

Cardiothoracic physiotherapists wanted – must be committed, motivated and competent in this specialty area

This article discusses the potential problem of latex allergy in the school, particularly among students with spina bifida. The origin of the problem, its symptoms, and prevention and management of latex allergy in the school environment are described. The individual roles of school administrator, school nurse, parent, student and other service providers are listed within an Individual Healthcare Plan (IHP). The IHP is proposed as a guide to schools to assist with identification of latex allergy reactions as well as response procedures if an allergic reaction is identified.

The Journal of school nursing : the official publication of the National Association of School Nurses

The problem of Doppler-based target position and velocity estimation using a sensor network is outlined. The minimum number of Doppler-shift measurements at distinct generic sensor positions in order to have a finite number of solutions, and later, a unique solution for the unknown target position and velocity are stated analytically. Furthermore we study the same problem, where not only Doppler-shift measurements are collected, but also other types of measurements are available, e.g,. bearing or distance to the target from each of the sensors. Later we study the Cramer-Rao inequality associated with the Doppler-shift measurements to a target in a sensor network, and we use the Cramer-Rao bound to illustrate some results on optimal placements of the sensors when the goal is to estimate the velocity of the target. Some simulation results are presented at the end.

This paper outlines the problem of doppler-based target position and velocity estimation using a sensor network. The minimum number of doppler shift measurements at distinct generic sensor positions to have a finite number of solutions, and later, a unique solution for the unknown target position and velocity is stated analytically, for the case when no measurement noise is present. Furthermore, we study the same problem where not only doppler shift measurements are collected, but also other types of measurements are available, e.g. bearing or distance to the target from each of the sensors. Subsequently, allowing nonzero measurement noise, we present an optimization method to estimate the position and the velocity of the target. An illustrative example is presented to show the validity of the analysis and the performance of the estimation method proposed. Some concluding remarks and future work directions are presented in the end.

Analysis of target velocity and position estimation via doppler-shift measurements

This paper outlines the problem of multi-static Doppler-based target position and velocity estimation. The Fisher information matrix is derived given a separate target illuminator and then given a target-based isotropic signal emission. Some remarks concerning the Cramer-Rao inequality and its relationship to the estimation problem are given. Some results concerning the placement of the receivers are given and some open problems are discussed.

2010 Sixth International Conference on Intelligent Sensors, Sensor Networks and Information Processing

Remarks on the Cramer-Rao inequality for Doppler-based target parameter estimation

This paper provides an investigation of the fundamental and practical distinctions between state estimates obtained by using the positional components of a phased array radar (PAR) measurements versus the estimate obtained by using the additional Doppler component. By employing the Doppler component of PAR measurements several significant improvements in tracking system performance are practically achievable including: lower state estimate uncertainty, increased measurement origin certainty, increased identifiability of target maneuvers and increased tracking system robustness.

Interpreting deep learning models typically relies on post-hoc saliency map techniques. However, these techniques often fail to serve as actionable feedback to clinicians, and they do not directly explain the decision mechanism. Here, we propose an inherently interpretable model that combines the feature extraction capabilities of deep neural networks with advantages of sparse linear models in interpretability. Our approach relies on straightforward but effective changes to a deep bag-of-local-features model (BagNet). These modifications lead to fine-grained and sparse class evidence maps which, by design, correctly reflect the model's decision mechanism. Our model is particularly suited for tasks which rely on characterising regions of interests that are very small and distributed over the image. In this paper, we focus on the detection of Diabetic Retinopathy, which is characterised by the progressive presence of small retinal lesions on fundus images. We observed good classification accuracy despite our added sparseness constraint. In addition, our model precisely highlighted retinal lesions relevant for the disease grading task and excluded irrelevant regions from the decision mechanism. The results suggest our sparse BagNet model can be a useful tool for clinicians as it allows efficient inspection of the model predictions and facilitates clinicians' and patients' trust.

This report documents the programme and the outcomes of Dagstuhl Seminar 22382"Machine Learning for Science: Bridging Data-Driven and Mechanistic Modelling". Today's scientific challenges are characterised by complexity. Interconnected natural, technological, and human systems are influenced by forces acting across time- and spatial-scales, resulting in complex interactions and emergent behaviours. Understanding these phenomena -- and leveraging scientific advances to deliver innovative solutions to improve society's health, wealth, and well-being -- requires new ways of analysing complex systems. The transformative potential of AI stems from its widespread applicability across disciplines, and will only be achieved through integration across research domains. AI for science is a rendezvous point. It brings together expertise from $\mathrm{AI}$ and application domains; combines modelling knowledge with engineering know-how; and relies on collaboration across disciplines and between humans and machines. Alongside technical advances, the next wave of progress in the field will come from building a community of machine learning researchers, domain experts, citizen scientists, and engineers working together to design and deploy effective AI tools. This report summarises the discussions from the seminar and provides a roadmap to suggest how different communities can collaborate to deliver a new wave of progress in AI and its application for scientific discovery.

Purpose The purpose of this study was to provide a comparison of performance and explainability of a multitask convolutional deep neuronal network to single-task networks for activity detection in neovascular age-related macular degeneration (nAMD). Methods From 70 patients (46 women and 24 men) who attended the University Eye Hospital Tübingen, 3762 optical coherence tomography B-scans (right eye = 2011 and left eye = 1751) were acquired with Heidelberg Spectralis, Heidelberg, Germany. B-scans were graded by a retina specialist and an ophthalmology resident, and then used to develop a multitask deep learning model to predict disease activity in neovascular age-related macular degeneration along with the presence of sub- and intraretinal fluid. We used performance metrics for comparison to single-task networks and visualized the deep neural network (DNN)-based decision with t-distributed stochastic neighbor embedding and clinically validated saliency mapping techniques. Results The multitask model surpassed single-task networks in accuracy for activity detection (94.2% vs. 91.2%). The area under the curve of the receiver operating curve was 0.984 for the multitask model versus 0.974 for the single-task model. Furthermore, compared to single-task networks, visualizations via t-distributed stochastic neighbor embedding and saliency maps highlighted that multitask networks’ decisions for activity detection in neovascular age-related macular degeneration were highly consistent with the presence of both sub- and intraretinal fluid. Conclusions Multitask learning increases the performance of neuronal networks for predicting disease activity, while providing clinicians with an easily accessible decision control, which resembles human reasoning. Translational Relevance By improving nAMD activity detection performance and transparency of automated decisions, multitask DNNs can support the translation of machine learning research into clinical decision support systems for nAMD activity detection.

Multitask Learning for Activity Detection in Neovascular Age-Related Macular Degeneration

Correction to: Probabilistic solvers enable a straight-forward exploration of numerical uncertainty in neuroscience models.

Distribution shifts remain a fundamental problem for the safe application of machine learning systems. If undetected, they may impact the real-world performance of such systems or will at least render original performance claims invalid. In this paper, we focus on the detection of subgroup shifts, a type of distribution shift that can occur when subgroups have a different prevalence during validation compared to the deployment setting. For example, algorithms developed on data from various acquisition settings may be predominantly applied in hospitals with lower quality data acquisition, leading to an inadvertent performance drop. We formulate subgroup shift detection in the framework of statistical hypothesis testing and show that recent state-of-the-art statistical tests can be effectively applied to subgroup shift detection on medical imaging data. We provide synthetic experiments as well as extensive evaluation on clinically meaningful subgroup shifts on histopathology as well as retinal fundus images. We conclude that classifier-based subgroup shift detection tests could be a particularly useful tool for post-market surveillance of deployed ML systems.

Deep Hypothesis Tests Detect Clinically Relevant Subgroup Shifts in Medical Images

In light of recent advances in machine learning for medical applications, the automation of medical diagnostics is imminent. That said, before machine learning algorithms find their way into clinical practice, various problems at the epistemic level need to be overcome. In this paper, we discuss different sources of uncertainty arising for clinicians trying to evaluate the trustworthiness of algorithmic evidence when making diagnostic judgments. Thereby, we examine many of the limitations of current machine learning algorithms (with deep learning in particular) and highlight their relevance for medical diagnostics. Among the problems we inspect are the theoretical foundations of deep learning (which are not yet adequately understood), the opacity of algorithmic decisions, and the vulnerabilities of machine learning models, as well as concerns regarding the quality of medical data used to train the models. Building on this, we discuss different desiderata for an uncertainty amelioration strategy that ensures that the integration of machine learning into clinical settings proves to be medically beneficial in a meaningful way.

Uncertainty, Evidence, and the Integration of Machine Learning into Medical Practice.

The number of publications in biomedicine and life sciences has rapidly grown over the last decades, with over 1.5 million papers now being published every year. This makes it difficult to keep track of new scientific works and to have an overview of the evolution of the field as a whole. Here we present a 2D map of the entire corpus of biomedical literature, and argue that it provides a unique and useful overview of the life sciences research. We based our atlas on the abstract texts of 21 million English articles from the PubMed database. To embed the abstracts into 2D, we used the large language model PubMedBERT, combined with t-SNE tailored to handle samples of our size. We used our atlas to study the emergence of the Covid-19 literature, the evolution of the neuroscience discipline, the uptake of machine learning, the distribution of gender imbalance in academic authorship, and the distribution of retracted paper mill articles. Furthermore, we present an interactive web version of our atlas that allows easy exploration and will enable further insights and facilitate future research.

Color is an important visual feature that informs behavior, and the retinal basis for color vision has been studied across various vertebrate species. While we know how color information is processed in visual brain areas of primates, we have limited understanding of how it is organized beyond the retina in other species, including most dichromatic mammals. In this study, we systematically characterized how color is represented in the primary visual cortex (V1) of mice. Using large-scale neuronal recordings and a luminance and color noise stimulus, we found that more than a third of neurons in mouse V1 are color-opponent in their receptive field center, while the receptive field surround predominantly captures luminance contrast. Furthermore, we found that color-opponency is especially pronounced in posterior V1 that encodes the sky, matching the statistics of mouse natural scenes. Using unsupervised clustering, we demonstrate that the asymmetry in color representations across cortex can be explained by an uneven distribution of green-On/UV-Off color-opponent response types that are represented in the upper visual field. This type of coloropponency in the receptive field center was not present at the level of the retinal output and, therefore, is likely computed in the cortex by integrating upstream visual signals. Finally, a simple model with natural scene-inspired parametric stimuli shows that green-On/UV-Off color-opponent response types may enhance the detection of “predatory”-like dark UV-objects in noisy daylight scenes. The results from this study highlight the relevance of color processing in the mouse visual system and contribute to our understanding of how color information is organized in the visual hierarchy across species. More broadly, they support the hypothesis that visual cortex combines upstream information towards computing neuronal selectivity to behaviorally-relevant sensory features.

Asymmetric distribution of color-opponent response types across mouse visual cortex supports superior color vision in the sky

Purpose: To automatically detect epiretinal membranes (ERM) in various OCT scans of the central and paracentral macula region and classify them by size using deep neural networks (DNNs). Methods: 11,061 OCT-images of 624 volume OCT scans (624 eyes of 461 patients) were included and graded according to the presence of an ERM and its size (small 100-1000m, large >1000m). The data set was divided into training, validation and test sets (comprising of 75%, 10%, 15% of the data, respectively). An ensemble of DNNs was trained and saliency maps were generated using Guided Backprob. OCT-scans were also transformed into a one-dimensional-value using t-SNE analysis. Results: The DNNs' receiver-operating-characteristics on the test set showed a high performance for no ERM, small ERM and large ERM cases (AUC: 0.99, 0.92, 0.99, respectively; 3-way accuracy: 89% ), with small ERMs being the most difficult ones to detect. t-SNE analysis sorted cases by size and, in particular, revealed increased classification uncertainty at the transitions between groups. Saliency maps reliably highlighted ERM, regardless of the presence of other OCT features (i.e. retinal thickening, intraretinal pseudo- cysts, epiretinal proliferation) and entities such as ERM-retinoschisis, macular pseudohole and lamellar macular hole. Conclusion: DNNs can reliably detect and grade ERMs according to their size not only in the fovea but also in the paracentral region. This is also achieved in cases of hard-to-detect, small ERMs. In addition, the generated saliency maps can be used effectively to highlight small ERMs that might otherwise be missed. The proposed model could be used for screening programs or decision support systems in the future.

Interpretable Detection of Epiretinal Membrane from Optical Coherence Tomography with Deep Neural Networks

The safe application of machine learning systems in healthcare relies on valid performance claims. Such claims are typically established in a clinical validation setting designed to be as close as possible to the intended use, but inadvertent domain or population shifts remain a fundamental problem. In particular, subgroups may be differently represented in the data distribution in the validation compared to the application setting. For example, algorithms trained on population cohort data spanning all age groups may be predominantly applied in elderly people. While these data are not “out-of distribution”, changes in the prevalence of different subgroups may have considerable impact on algorithm performance or will at least render original performance claims invalid. Both are serious problems for safely deploying machine learning systems. In this paper, we demonstrate the fundamental limitations of individual example out-of-distribution detection for such scenarios, and show that subgroup shifts can be detected on a population-level instead. We formulate population-level shift detection in the framework of statistical hypothesis testing and show that recent state-of-the-art statistical tests can be effectively applied to subgroup shift detection in a synthetic scenario as well as real histopathology images.

In medical image classification tasks like the detection of diabetic retinopathy from retinal fundus images, it is highly desirable to get visual explanations for the decisions of black-box deep neural networks (DNNs). However, gradient-based saliency methods often fail to highlight the diseased image regions reliably. On the other hand, adversarially robust models have more interpretable gradients than plain models but suffer typically from a significant drop in accuracy, which is unacceptable for clinical practice. Here, we show that one can get the best of both worlds by ensembling a plain and an adversarially robust model: maintaining high accuracy but having improved visual explanations. Also, our ensemble produces meaningful visual counterfactuals which are complementary to existing saliency-based techniques. Code is available under url{https://github.com/valentyn1boreiko/Fundus_VCEs}.

Visual explanations for the detection of diabetic retinopathy from retinal fundus images

We benchmarked different approaches for creating 2D visualizations of large document libraries, using the MEDLINE (PubMed) database of the entire biomedical literature as a use case (19 million scientific papers). Our optimal pipeline is based on log-scaled TF-IDF representation of the abstract text, SVD preprocessing

T WO - DIMENSIONAL VISUALIZATION OF LARGE DOCUMENT LIBRARIES USING T -SNE

To avoid the curse of dimensionality, a common approach to clustering high-dimensional data is to first project the data into a space of reduced dimension, and then cluster the projected data. Although effective, this twostage approach prevents joint optimization of the dimensionality-reduction and clustering models, and obscures how well the complete model describes the data. Here, we show how a family of such two-stage models can be combined into a single, hierarchical model that we call a hierarchical mixture of Gaussians (HMoG). An HMoG simultaneously captures both dimensionality-reduction and clustering, and its performance is quantified in closed-form by the likelihood function. By formulating and extending existing models with exponential family theory, we show how to maximize the likelihood of HMoGs with expectation-maximization. We apply HMoGs to synthetic data and RNA sequencing data, and demonstrate how they exceed the limitations of two-stage models. Ultimately, HMoGs are a rigorous generalization of a common statistical framework, and provide researchers with a method to improve model performance when clustering high-dimensional data.

Hierarchical mixtures of Gaussians for combined dimensionality reduction and clustering

Center-surround interactions underlie bipolar cell motion sensitivity in the mouse retina

Objective: Modeling of the ophthalmologist's decision-making process for activity detection in neovascular age-related macular degeneration with a multi-task convolutional deep neuronal network which takes intra- and subretinal fluid into account. Design: A cohort study to evaluate the multi-task deep learning model for activity detection. Participants: n = 70 patients (46 female, 24 male) attended the University Eye Hospital Tuebingen between 21.2.2018 and 27.6.2018. 3762 optical coherence tomography B-scans (right eye: 2011, left eye: 1751) were acquired from them with Heidelberg Spectralis, Heidelberg, Germany. Methods: B-scans were graded by a retina specialist and an ophthalmology resident, and then used to develop a multi-task deep learning model to concurrently predict disease activity in neovascular age-related macular degeneration along with the presence of sub- and intraretinal fluid. Main outcome measures: Performance metrics compared to single-task networks, visualization of the representation driving the DNN-based decisions using t-distributed stochastic neighbor embedding and analysis of the model's decisions via clinically validated saliency mapping techniques. Results: The multi-task model surpassed single-task networks in accuracy for activity detection. Visualizations via t-distributed stochastic neighbor embedding and saliency maps highlighted that the network's decisions for activity of neovascular age-related macular degeneration were based on the presence of sub- and intraretinal fluids, the optical coherence tomography characteristics used for treatment decision in clinical routine. Conclusion: Multi-task learning increases the performance of neuronal networks for predicting disease activity, while providing clinicians with an easily accessible decision control, which resembles human reasoning.

Multi-task learning for activity detection in neovascular age-related macular degeneration

The retina transforms patterns of light into visual feature representations supporting behaviour. These representations are distributed across various types of retinal ganglion cells (RGCs), whose spatial and temporal tuning properties have been extensively studied in many model organisms, including the mouse. However, it has been difficult to link the potentially nonlinear retinal transformations of natural visual inputs to specific ethological purposes. Here, we discover a novel selectivity to chromatic contrast in an RGC type that allows the detection of transitions of the horizon across a retinal region. We trained a convolutional neural network (CNN) model on large-scale functional recordings of RGC responses to natural mouse movies, and then used this model to search in silico for stimuli that maximally excite distinct types of RGCs. This procedure predicted centre colour-opponency in transient Suppressed-by-Contrast RGCs (tSbC), a cell type whose function is being debated. We confirmed experimentally that these cells indeed responded very selectively to Green-OFF, UV-ON contrasts, which we found to be characteristic of transitions from ground to sky in the visual scene, as might be elicited by head-or eye-movements across the horizon. Because tSbCs reliably detected these transitions, we suggest a role for this RGC type in providing contextual information (i.e. sky or ground) necessary for the selection of appropriate behavioural responses to other stimuli, such as looming objects. Our work showcases how a combination of experiments with natural stimuli and computational modelling allows discovering novel types of stimulus selectivity and identifying their potential ethological relevance.

A chromatic feature detector in the retina signals visual context changes

Zusammenfassung. Ungefähr ein Fünftel aller Kinder und Jugendlichen zeigt psychische Auffälligkeiten, doch nur ein geringer Teil der Betroffenen erhält professionelle Hilfe. Häufig gehen mit psychischen Beeinträchtigungen auch gravierende schulische Probleme einher. In dieser Studie untersuchten wir, ob es schulische Merkmale von Schülerinnen und Schülern gibt, die Hinweise auf eine psychische Auffälligkeit liefern können. Dazu wurden 185 Klinikschülerinnen und -schüler und 387 Schülerinnen und Schüler an Regelschulen zu ihrer schulischen Situation befragt. Außerdem wurde der Strengths and Difficulties Questionnaire (SDQ) genutzt, um eine Vergleichsgruppe mit ausschließlich psychisch unauffälligen Schülerinnen und Schülern bilden zu können. Wir verwendeten ein logistisches Regressionsmodell, um herauszufinden, welche Antwortitems eine gute Vorhersage auf psychische Auffälligkeiten ermöglichten. Der Klassifikator war in der Lage, psychisch auffällige und unauffällige Schülerinnen und Schüler mit hoher Genauigkeit zu unterscheiden (Genauigkeit .83, Sensitivität: .76; Spezifität: .87). Die Klassifikation basierte dabei – anders als vermutet werden könnte – nicht primär auf Aussagen zum Lern- und Leistungsverhalten der Schülerinnen und Schüler, sondern auf Aussagen zu schulvermeidendem Verhalten und ihrer sozialen Integration. Diese schulischen Prädiktoren waren auch unter Kontrolle von Alter und Geschlecht sehr stabil. Die Ergebnisse deuten darauf hin, dass Lehrkräfte eine bedeutsame Rolle bei der Früherkennung von psychischen Auffälligkeiten einnehmen können.

Schulische Prädiktoren für psychische Auffälligkeiten bei Kindern und Jugendlichen anhand einer Befragung von Schülerinnen und Schülern an Klinik- und Regelschulen

Probabilistic solvers enable a straight-forward exploration of numerical uncertainty in neuroscience models

Visualization methods based on the nearest neighbor graph, such as t-SNE or UMAP, are widely used for visualizing high-dimensional data. Yet, these approaches only produce meaningful results if the nearest neighbors themselves are meaningful. For images represented in pixel space this is not the case, as distances in pixel space are often not capturing our sense of similarity and therefore neighbors are not semantically close. This problem can be circumvented by self-supervised approaches based on contrastive learning, such as SimCLR, relying on data augmentation to generate implicit neighbors, but these methods do not produce two-dimensional embeddings suitable for visualization. Here, we present a new method, called t-SimCNE, for unsupervised visualization of image data. T-SimCNE combines ideas from contrastive learning and neighbor embeddings, and trains a parametric mapping from the high-dimensional pixel space into two dimensions. We show that the resulting 2D embeddings achieve classification accuracy comparable to the state-of-the-art high-dimensional SimCLR representations, thus faithfully capturing semantic relationships. Using t-SimCNE, we obtain informative visualizations of the CIFAR-10 and CIFAR-100 datasets, showing rich cluster structure and highlighting artifacts and outliers.

Unsupervised visualization of image datasets using contrastive learning

This report documents the programme and the outcomes of Dagstuhl Seminar 22382 “Machine Learning for Science: Bridging Data-Driven and Mechanistic Modelling”. Today’s scientific challenges are characterised by complexity. Interconnected natural, technological, and human systems are influenced by forces acting across time- and spatial-scales, resulting in complex interactions and emergent behaviours. Understanding these phenomena – and leveraging scientific advances to deliver innovative solutions to improve society’s health, wealth, and well-being – requires new ways of analysing complex systems. The transformative potential of AI stems from its widespread applicability across disciplines, and will only be achieved through integration across research domains. AI for science is a rendezvous point. It brings together expertise from AI and application domains; combines modelling knowledge with engineering know-how; and relies on collaboration across disciplines and between humans and machines. Alongside technical advances, the next wave of progress in the field will come from building a community of machine learning researchers, domain experts, citizen scientists, and engineers working together to design and deploy effective AI tools. This report summarises the discussions from the seminar and provides a roadmap to suggest how different communities can collaborate to deliver a new wave of progress in AI and its application for scientific discovery.

Machine Learning for Science: Bridging Data-Driven and Mechanistic Modelling (Dagstuhl Seminar 22382)

Deep neural networks (DNNs) have achieved physician-level accuracy on many imaging-based medical diagnostic tasks, for example classification of retinal images in ophthalmology. However, their decision mechanisms are often considered impenetrable leading to a lack of trust by clinicians and patients. To alleviate this issue, a range of explanation methods have been proposed to expose the inner workings of DNNs leading to their decisions. For imaging-based tasks, this is often achieved via saliency maps. The quality of these maps are typically evaluated via perturbation analysis without experts involved. To facilitate the adoption and success of such automated systems, however, it is crucial to validate saliency maps against clinicians. In this study, we used two different network architectures and developed ensembles of DNNs to detect diabetic retinopathy and neovascular age-related macular degeneration from retinal fundus images and optical coherence tomography scans, respectively. We used a variety of explanation methods and obtained a comprehensive set of saliency maps for explaining the ensemble-based diagnostic decisions. Then, we systematically validated saliency maps against clinicians through two main analyses --- a direct comparison of saliency maps with the expert annotations of disease-specific pathologies and perturbation analyses using also expert annotations as saliency maps. We found the choice of DNN architecture and explanation method to significantly influence the quality of saliency maps. Guided Backprop showed consistently good performance across disease scenarios and DNN architectures, suggesting that it provides a suitable starting point for explaining the decisions of DNNs on retinal images.

Clinical Validation of Saliency Maps for Understanding Deep Neural Networks in Ophthalmology

Analytic Pearson residuals for normalization of single-cell RNA-seq UMI data

Understanding neural computation on the mechanistic level requires biophysically realistic neuron models. To analyze such models one typically has to solve systems of coupled ordinary differential equations (ODEs), which describe the dynamics of the underlying neural system. These ODEs are solved numerically with deterministic ODE solvers that yield single solutions with either no or only a global scalar bound on precision. To overcome this problem, we propose to use recently developed probabilistic solvers instead, which are able to reveal and quantify numerical uncertainties, for example as posterior sample paths. Importantly, these solvers neither require detailed insights into the kinetics of the models nor are they difficult to implement. Using these probabilistic solvers, we show that numerical uncertainty strongly affects the outcome of typical neuroscience simulations, in particular due to the non-linearity associated with the generation of action potentials. We quantify this uncertainty in individual single Izhikevich neurons with different dynamics, a large population of coupled Izhikevich neurons, single Hodgkin-Huxley neuron and a small network of Hodgkin-Huxley-like neurons. For commonly used ODE solvers, we find that the numerical uncertainty in these models can be substantial, possibly jittering spikes by milliseconds or even adding or removing individual spikes from the simulation altogether. Author summary Computational neuroscience is built around computational models of neurons that allow the simulation and analysis of signal processing in the central nervous system. These models come typically in the form of ordinary differential equations (ODEs). The solution of these ODEs is computed using solvers with finite accuracy and, therefore, the computed solutions deviate from the true solution. If this deviation is too large but goes unnoticed, this can potentially lead to wrong scientific conclusions. A field in machine learning called probabilistic numerics has recently developed a set of probabilistic solvers for ODEs, which not only produce a single solution of unknown accuracy, but instead yield a distribution over simulations. Therefore, these tools allow one to address the problem state above and quantitatively analyze the numerical uncertainty inherent in the simulation process. In this study, we demonstrate how such solvers can be used to quantify numerical uncertainty in common neuroscience models. We study both Hodgkin-Huxley and Izhikevich neuron models and show that the numerical uncertainty in these models can be substantial, possibly jittering spikes by milliseconds or even adding or removing individual spikes from the simulation altogether. We discuss the implications of this finding and discuss how our methods can be used to select simulation parameters to trade off accuracy and speed.

Numerical uncertainty can critically affect simulations of mechanistic models in neuroscience

Integrating data from multiple experiments is common practice in systems neuroscience but it requires inter-experimental variability to be negligible compared to the biological signal of interest. This requirement is rarely fulfilled; systematic changes between experiments can drastically affect the outcome of complex analysis pipelines. Modern machine learning approaches designed to adapt models across multiple data domains offer flexible ways of removing inter-experimental variability where classical statistical methods often fail. While applications of these methods have been mostly limited to single-cell genomics, in this work, we develop a theoretical framework for domain adaptation in systems neuroscience. We implement this in an adversarial optimization scheme that removes inter-experimental variability while preserving the biological signal. We compare our method to previous approaches on a large-scale dataset of two-photon imaging recordings of retinal bipolar cell responses to visual stimuli. This dataset provides a unique benchmark as it contains biological signal from well-defined cell types that is obscured by large inter-experimental variability. In a supervised setting, we compare the generalization performance of cell type classifiers across experiments, which we validate with anatomical cell type distributions from electron microscopy data. In an unsupervised setting, we remove inter-experimental variability from data which can then be fed into arbitrary downstream analyses. In both settings, we find that our method achieves the best trade-off between removing inter-experimental variability and preserving biological signal. Thus, we offer a flexible approach to remove inter-experimental variability and integrate datasets across experiments in systems neuroscience. Code available at https://github.com/eulerlab/rave.

Removing Inter-Experimental Variability from Functional Data in Systems Neuroscience

For some years, we have been witnessing a steady stream of high-profile studies about machine learning (ML) algorithms achieving high diagnostic accuracy in the analysis of medical images. That said, facilitating successful collaboration between ML algorithms and clinicians proves to be a recalcitrant problem that may exacerbate ethical problems in clinical medicine. In this paper, we consider different epistemic and normative factors that may lead to algorithmic overreliance within clinical decision-making. These factors are false expectations, the miscalibration of uncertainties, non-explainability, and the socio-technical context within which the algorithms are utilized. Moreover, we identify different desiderata for bridging the gap between ML algorithms and clinicians. Further, we argue that there is an intriguing dialectic in the collaboration between clinicians and ML algorithms. While it is the algorithm that is supposed to assist the clinician in diagnostic tasks, successful collaboration will also depend on adjustments on the side of the clinician.

How competitors become collaborators-Bridging the gap(s) between machine learning algorithms and clinicians.

Many sensory systems use ribbon-type synapses to transmit their signals to downstream circuits. The properties of this synaptic transfer fundamentally dictate which aspects in the original stimulus will be accentuated or suppressed, thereby partially defining the detection limits of the circuit. Accordingly, sensory neurons have evolved a wide variety of ribbon geometries and vesicle pool properties to best support their diverse functional requirements. However, the need for diverse synaptic functions does not only arise across neuron types, but also within. Here we show that UV-cones, a single type of photoreceptor of the larval zebrafish eye, exhibit striking differences in their synaptic ultrastructure and consequent calcium to glutamate transfer function depending on their location in the eye. We arrive at this conclusion by combining serial section electron microscopy and simultaneous “dual-colour” 2-photon imaging of calcium and glutamate signals from the same synapse in vivo. We further use the functional dataset to fit a cascade-like model of the ribbon synapse with different vesicle pool sizes, transfer rates and other synaptic properties. Exploiting recent developments in simulation-based inference, we obtain full posterior estimates for the parameters and compare these across different retinal regions. The model enables us to extrapolate to new stimuli and to systematically investigate different response behaviours of various ribbon configurations. We also provide an interactive, easy-to-use version of this model as an online tool. Overall, we show that already on the synaptic level of single neuron types there exist highly specialized mechanisms which are advantageous for the encoding of different visual features.

Distinct synaptic transfer functions in same-type photoreceptors

Motion is a critical aspect of vision. We studied the representation of motion in mouse retinal bipolar cells and found, surprisingly, that some bipolar cells possess motion-sensing capabilities that rely on their center-surround receptive fields. Using a glutamate sensor, we directly observed motion-sensitive bipolar cell synaptic output, which was strongest for local motion and dependent on the motion’s origin. We characterized bipolar cell receptive fields and found that there are motion and non-motion sensitive bipolar cell types, the majority being motion sensitive. Next, we used these bipolar cell receptive fields along with connectomics to design biophysical models of downstream cells. The models and experiments demonstrated that bipolar cells pass motion-sensitive excitation to starburst amacrine cells through direction-specific signals mediated by bipolar cells’ center-surround receptive field structure. As bipolar cells provide excitation to most amacrine and ganglion cells, their motion sensitivity may contribute to motion processing throughout the visual system.

Center-surround interactions underlie bipolar cell motion sensing in the mouse retina

For the past century, the anatomy of a neuron has been considered one of its defining features: The shape of a neuron’s dendrites and axon fundamentally determines what other neurons it can connect to. These neurites have been described using mathematical tools e.g. in the context of cell type classification, but generative models of these structures have only rarely been proposed and are often computationally inefficient. Here we propose MorphVAE, a sequence-to-sequence variational autoencoder with spherical latent space as a generative model for neural morphologies. The model operates on walks within the tree structure of a neuron and can incorporate expert annotations on a subset of the data using semi-supervised learning. We develop our model on artificially generated toy data and evaluate its performance on dendrites of excitatory cells and axons of inhibitory cells of mouse motor cortex (M1) and dendrites of retinal ganglion cells. We show that the learned latent feature space allows for better cell type discrimination than other commonly used features. By sampling new walks from the latent space we can easily construct new morphologies with a specified degree of similarity to their reference neuron, providing an efficient generative model for neural morphologies.

MorphVAE: Generating Neural Morphologies from 3D-Walks using a Variational Autoencoder with Spherical Latent Space

Estimating smooth and sparse neural receptive fields with a flexible spline basis

Spatio-temporal receptive field (STRF) models are frequently used to approximate the computation implemented by a sensory neuron. Typically, such STRFs are assumed to be smooth and sparse. Current state-of-the-art approaches for estimating STRFs based empirical Bayes estimation encode such prior knowledge into a prior covariance matrix, whose hyperparameters are learned from the data, and thus provide STRF estimates with the desired properties even with little or noisy data. However, empirical Bayes methods are often not computationally efficient in high-dimensional settings, as encountered in sensory neuroscience. Here we pursued an alternative approach and encode prior knowledge for estimation of STRFs by choosing a set of basis function with the desired properties: a natural cubic spline basis. Our method is computationally efficient, and can be easily applied to Linear-Gaussian and Linear-Nonlinear-Poisson models as well as more complicated Linear-Nonlinear-Linear-Nonlinear cascade model or spike-triggered clustering methods. We compared the performance of spline-based methods to no-spline ones on simulated and experimental data, showing that spline-based methods consistently outperformed the no-spline versions. We provide a Python toolbox for all suggested methods (https://github.com/berenslab/RFEst/).

Summary. Many sensory systems use ribbon-type synapses to transmit their signals to downstream circuits. The properties of this synaptic transfer fundamentally dictate which aspects in the original stimulus will be accentuated or suppressed, thereby partially defining the detection limits of the circuit. Accordingly, 11 sensory neurons have evolved a wide variety of ribbon geometries 12 and vesicle pool properties to best support their diverse functional requirements. However, the need for diverse synaptic functions 14 does not only arise across neuron types, but also within . Here we show that UV-cones, a single type of photoreceptor of the larval zebrafish eye, exhibit striking differences in their synaptic 17 ultrastructure and consequent calcium to glutamate transfer 18 function depending on their location in the eye. We arrive at this 19 conclusion by combining serial section electron microscopy and 20 simultaneous “dual-colour” 2-photon imaging of calcium and 21 glutamate signals from the same synapse in vivo . We further use 22 the functional dataset to fit a cascade-like model of the ribbon 23 synapse with different vesicle pool sizes, transfer rates and other 24 synaptic properties. Exploiting recent developments in simulation- 25 based inference, we obtain full posterior estimates for the 26 parameters and compare these across different retinal regions. 27 The model enables us to extrapolate to new stimuli and to 28 systematically investigate different response behaviours of 29 various ribbon configurations. We also provide an interactive, 30 easy-to-use version of this model as an online tool. Overall, we show that already on the synaptic level of single neuron types 32 there exist highly specialized mechanisms which are 33 advantageous for the encoding of different visual features.

Eye-Region Specific Ribbon Tuning Supports 1 Distinct Modes of Synaptic Transmission 2 in Same-Type Cone-Photoreceptors

Ordinary diﬀerential equations (ODEs) play an important role in modeling dynamical systems in various scientiﬁc ﬁelds. Most ODEs cannot be solved in closed-form but various approximate algorithms exist, for instance Runge-Kutta methods. Usually, those methods neglect the fact that approximation necessarily introduces errors and instead, the approximated solution is used as if it was the true solution. Probabilistic numerical ODE solvers ﬁx this short-coming by augmenting the output of the solvers with appropriate uncertainty estimates. One of these classes of algorithms randomly perturbs the behaviour of non-probabilistic algorithms by a small amount. This results in a non-deterministic approximate solution. By repeatedly solving the ODE with such a randomized algorithm, the uncertainty associated with numerical approximation can be quantiﬁed. We ask two questions: 1) How well does the range of samples quantify the numerical uncertainty? 2) How many repetitions are required to reach asymptotic behavior? This work develops several metrics that benchmark the calibration of a probabilistic ODE solver. These metrics are then used to analyse the behaviour of two representative choices of such algorithms. It turns out that – perhaps surprisingly – few samples ( ≤ 16) quantify the numerical error as well as many samples do. Unfortunately, the quality of the quantiﬁcation depends crucially on speciﬁc parameters which need to be chosen manually. Therefore, the descriptiveness of the range of samples is ultimately problem- and user-dependent. These, and other phenomena are studied in the present thesis.

Master Thesis Computer Science Benchmarking Probabilistic ODE Solvers

Deep neural networks (DNNs) are able to predict a person's gender from retinal fundus images with high accuracy, even though this task is usually considered hardly possible by ophthalmologists. Therefore, it has been an open question which features allow reliable discrimination between male and female fundus images. To study this question, we used a particular DNN architecture called BagNet, which extracts local features from small image patches and then averages the class evidence across all patches. The BagNet performed on par with the more sophisticated Inception-v3 model, showing that the gender information can be read out from local features alone. BagNets also naturally provide saliency maps, which we used to highlight the most informative patches in fundus images. We found that most evidence was provided by patches from the optic disc and the macula, with patches from the optic disc providing mostly male and patches from the macula providing mostly female evidence. Although further research is needed to clarify the exact nature of this evidence, our results suggest that there are localized structural differences in fundus images between genders. Overall, we believe that BagNets may provide a compelling alternative to the standard DNN architectures also in other medical image analysis tasks, as they do not require post-hoc explainability methods.

Interpretable Gender Classification from Retinal Fundus Images using BagNets

In genomics, transcriptomics, and related biological fields (collectively known as omics), combinations of experimental techniques can yield multiple sets of features for the same set of biological replicates. One example is Patch‐seq, a method combining single‐cell RNA sequencing with electrophysiological recordings from the same cells. Here we present a framework based on sparse reduced‐rank regression (RRR) for obtaining an interpretable visualisation of the relationship between the transcriptomic and the electrophysiological data. We use elastic net regularisation that yields sparse solutions and allows for an efficient computational implementation. Using several Patch‐seq datasets, we show that sparse RRR outperforms both sparse full‐rank regression and non‐sparse RRR, as well as previous sparse RRR approaches, in terms of predictive performance. We introduce a bibiplot visualisation in order to display the dominant factors determining the relationship between transcriptomic and electrophysiological properties of neurons. We believe that sparse RRR can provide a valuable tool for the exploration and visualisation of paired multivariate datasets.

Journal of the Royal Statistical Society: Series C (Applied Statistics)

Sparse reduced‐rank regression for exploratory visualisation of paired multivariate data

In vivo recordings of cone photoreceptor outputs in a tetrachromate reveal efficient ancestral strategy for color processing.

Ancestral circuits for vertebrate color vision emerge at the first retinal synapse

Visual processing in the retina has been studied in great detail at all levels such that a comprehensive picture of the retina’s cell types and the many neural circuits they form is emerging. However, the currently best performing models of retinal function are black-box CNN models which are agnostic to such biological knowledge. In particular, these models typically neglect the role of the many inhibitory circuits involving amacrine cells and the biophysical mechanisms underlying synaptic release. Here, we present a computational model of temporal processing in the inner retina, including inhibitory feedback circuits and realistic synaptic release mechanisms. Fit to the responses of bipolar cells, the model generalized well to new stimuli including natural movie sequences, performing on par with or better than a benchmark black-box model. In pharmacology experiments, the model replicated in silico the effect of blocking specific amacrine cell populations with high fidelity, indicating that it had learned key circuit functions. Also, more in depth comparisons showed that connectivity patterns learned by the model were well matched to connectivity patterns extracted from connectomics data. Thus, our model provides a biologically interpretable data-driven account of temporal processing in the inner retina, filling the gap between purely black-box and detailed biophysical modeling.

System Identification with Biophysical Constraints: A Circuit Model of the Inner Retina

Phenotypic variation of transcriptomic cell types in mouse motor cortex

Patch-seq, a recently developed experimental technique, allows neuroscientists to obtain transcriptomic and electrophysiological information from the same neurons. Efficiently analyzing and visualizing such paired multivariate data in order to extract biologically meaningful interpretations has, however, remained a challenge. Here, we use sparse deep neural networks with and without a two-dimensional bottleneck to predict electrophysiological features from the transcriptomic ones using a group lasso penalty, yielding concise and biologically interpretable two-dimensional visualizations. In two large example data sets, this visualization reveals known neural classes and their marker genes without biological prior knowledge. We also demonstrate that our method is applicable to other kinds of multimodal data, such as paired transcriptomic and proteomic measurements provided by CITE-seq.

Sparse bottleneck neural networks for exploratory non-linear visualization of Patch-seq data

Neighbor embeddings are a family of methods for visualizing complex high-dimensional datasets using $k$NN graphs. To find the low-dimensional embedding, these algorithms combine an attractive force between neighboring pairs of points with a repulsive force between all points. One of the most popular examples of such algorithms is t-SNE. Here we empirically show that changing the balance between the attractive and the repulsive forces in t-SNE using the exaggeration parameter yields a spectrum of embeddings, which is characterized by a simple trade-off: stronger attraction can better represent continuous manifold structures, while stronger repulsion can better represent discrete cluster structures and yields higher $k$NN recall. We find that UMAP embeddings correspond to t-SNE with increased attraction; mathematical analysis shows that this is because the negative sampling optimisation strategy employed by UMAP strongly lowers the effective repulsion. Likewise, ForceAtlas2, commonly used for visualizing developmental single-cell transcriptomic data, yields embeddings corresponding to t-SNE with the attraction increased even more. At the extreme of this spectrum lie Laplacian Eigenmaps. Our results demonstrate that many prominent neighbor embedding algorithms can be placed onto the attraction-repulsion spectrum, and highlight the inherent trade-offs between them.

Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft

[Artificial intelligence in ophthalmology : Guidelines for physicians for the critical evaluation of studies].

For a long time, the anatomy of a neuron has been considered a defining feature of neural cell types. However, computational analysis of neuronal morphologies persists to be a challenging problem. It usually begins with choosing a feature representation in order to make individual morphologies amenable to statistical data analysis or to processing by machine learning methods. Over the years, many different feature representations have been suggested in the literature, such as density maps (Jefferis et al., 2007), single valued summary statistics (morphometrics) (BBP, n.d.; Scorcioni, Polavaram, & Ascoli, 2008) or, more recently, persistence images (Kanari et al., 2018; Li, Wang, Ascoli, Mitra, & Wang, 2017). Unfortunately, current software packages for extracting them from morphological data are often focused on solely one such representation and implemented across various programming languages.

MorphoPy: A python package for feature extraction of neural morphologies

Probing and predicting ganglion cell responses to smooth electrical stimulation in healthy and blind mouse retina

Correction to: Heavy-Tailed Kernels Reveal a Finer Cluster Structure in t-SNE Visualisations

Multicompartment models have long been used to study the biophysical mechanisms underlying neural information processing. However, it has been challenging to infer the parameters of such models from data. Here, we build on recent advances in Bayesian simulation-based inference to estimate the parameters of detailed models of retinal neurons whose anatomical structure was based on electron microscopy data. We demonstrate how parameters of a cone, an OFF- and an ON-cone bipolar cell model can be inferred from standard two-photon glutamate imaging with simple light stimuli. The inference method starts with a prior distribution informed by literature knowledge and yields a posterior distribution over parameters highlighting parameters consistent with the data. This posterior allows determining how well parameters are constrained by the data and to what extent changes in one parameter can be compensated for by changes in another. To demonstrate the potential of such data-driven mechanistic neuron models, we created a simulation environment for external electrical stimulation of the retina as used in retinal neuroprosthetic devices. We used the framework to optimize the stimulus waveform to selectively target OFF- and ON-cone bipolar cells, a current major problem of retinal neuroprothetics. Taken together, this study demonstrates how a data-driven Bayesian simulation-based inference approach can be used to estimate parameters of complex mechanistic models with high-throughput imaging data.

Bayesian inference for biophysical neuron models enables stimulus optimization for retinal neuroprosthetics

In recent years, increasingly large datasets with two different sets of features measured for each sample have become prevalent in many areas of biology. For example, a recently developed method called Patch-seq provides single-cell RNA sequencing data together with electrophysiological measurements of the same neurons. However, the efficient and interpretable analysis of such paired data has remained a challenge. As a tool for exploration and visualization of Patch-seq data, we introduce neural networks with a two-dimensional bottleneck, trained to predict electrophysiological measurements from gene expression. To make the model biologically interpretable and perform gene selection, we enforce sparsity by using a group lasso penalty, followed by pruning of the input units and subsequent fine-tuning. We applied this method to a recent dataset with $>$1000 neurons from mouse motor cortex and found that the resulting bottleneck model had the same predictive performance as a full-rank linear model with much higher latent dimensionality. Exploring the two-dimensional latent space in terms of neural types showed that the nonlinear bottleneck approach led to much better visualizations and higher biological interpretability.

Sparse Bottleneck Networks for Exploratory Analysis and Visualization of Neural Patch-seq Data

Despite variations in appearance we robustly recognize objects. Neuronal populations responding to objects presented under varying conditions form object manifolds and hierarchically organized visual areas untangle pixel intensities into linearly decodable object representations. However, the associated changes in the geometry of object manifolds along the cortex remain unknown. Using home cage training we showed that mice are capable of invariant object recognition. We simultaneously recorded the responses of thousands of neurons to measure the information about object identity across the visual cortex and found that lateral areas LM, LI and AL carry more linearly decodable object information compared to other visual areas. We applied the theory of linear separability of manifolds, and found that the increase in classification capacity is associated with a decrease in the dimension and radius of the object manifold, identifying the key features in the geometry of the population neural code that enable invariant object coding.

Object manifold geometry across the mouse cortical visual hierarchy

Fovea-like Photoreceptor Specializations Underlie Single UV Cone Driven Prey-Capture Behavior in Zebrafish

Potenzial von Methoden der künstlichen Intelligenz für die Qualitätssicherung

Neighbor embeddings are a family of methods for visualizing complex high-dimensional datasets using kNN graphs. To find the low-dimensional embedding, these algorithms combine an attractive force between neighboring pairs of points with a repulsive force between all points. One of the most popular examples of such algorithms is t-SNE. Here we show that changing the balance between the attractive and the repulsive forces in t-SNE yields a spectrum of embeddings, which is characterized by a simple trade-off: stronger attraction can better represent continuous manifold structures, while stronger repulsion can better represent discrete cluster structures. We show that UMAP embeddings correspond to t-SNE with increased attraction; this happens because the negative sampling optimisation strategy employed by UMAP strongly lowers the effective repulsion. Likewise, ForceAtlas2, commonly used for visualizing developmental single-cell transcriptomic data, yields embeddings corresponding to t-SNE with the attraction increased even more. At the extreme of this spectrum lies Laplacian Eigenmaps, corresponding to zero repulsion. Our results demonstrate that many prominent neighbor embedding algorithms can be placed onto this attraction-repulsion spectrum, and highlight the inherent trade-offs between them.

A Unifying Perspective on Neighbor Embeddings along the Attraction-Repulsion Spectrum

Cortical neurons exhibit astounding diversity in gene expression as well as in morphological and electrophysiological properties. Most existing neural taxonomies are based on either transcriptomic or morpho-electric criteria, as it has been technically challenging to study both aspects of neuronal diversity in the same set of cells. Here we used Patch-seq to combine patch-clamp recording, biocytin staining, and single-cell RNA sequencing of over 1300 neurons in adult mouse motor cortex, providing a comprehensive morpho-electric annotation of almost all transcriptomically defined neural cell types. We found that, although broad families of transcriptomic types (Vip, Pvalb, Sst, etc.) had distinct and essentially non-overlapping morpho-electric phenotypes, individual transcriptomic types within the same family were not well-separated in the morpho-electric space. Instead, there was a continuum of variability in morphology and electrophysiology, with neighbouring transcriptomic cell types showing similar morpho-electric features, often without clear boundaries between them. Our results suggest that neural types in the neocortex do not always form discrete entities. Instead, neurons follow a hierarchy consisting of distinct non-overlapping branches at the level of families, but can form continuous and correlated transcriptomic and morpho-electrical landscapes within families.

Phenotypic variation within and across transcriptomic cell types in mouse motor cortex

[Potential of methods of artificial intelligence for quality assurance].

Neural circuits in the mouse retina support color vision in the upper visual field

Author response: Cell type composition and circuit organization of clonally related excitatory neurons in the juvenile mouse neocortex

Background Standard preprocessing of single-cell RNA-seq UMI data includes normalization by sequencing depth to remove this technical variability, and nonlinear transformation to stabilize the variance across genes with different expression levels. Instead, two recent papers propose to use statistical count models for these tasks: Hafemeister and Satija (Genome Biol 20:296, 2019) recommend using Pearson residuals from negative binomial regression, while Townes et al. (Genome Biol 20:295, 2019) recommend fitting a generalized PCA model. Here, we investigate the connection between these approaches theoretically and empirically, and compare their effects on downstream processing. Results We show that the model of Hafemeister and Satija produces noisy parameter estimates because it is overspecified, which is why the original paper employs post hoc smoothing. When specified more parsimoniously, it has a simple analytic solution equivalent to the rank-one Poisson GLM-PCA of Townes et al. Further, our analysis indicates that per-gene overdispersion estimates in Hafemeister and Satija are biased, and that the data are in fact consistent with the overdispersion parameter being independent of gene expression. We then use negative control data without biological variability to estimate the technical overdispersion of UMI counts, and find that across several different experimental protocols, the data are close to Poisson and suggest very moderate overdispersion. Finally, we perform a benchmark to compare the performance of Pearson residuals, variance-stabilizing transformations, and GLM-PCA on scRNA-seq datasets with known ground truth. Conclusions We demonstrate that analytic Pearson residuals strongly outperform other methods for identifying biologically variable genes, and capture more of the biologically meaningful variation when used for dimensionality reduction.

A Systematic Evaluation of Interneuron Morphology Representations for Cell Type Discrimination

A multimodal cell census and atlas of the mammalian primary motor cortex

Clones of excitatory neurons derived from a common progenitor have been proposed to serve as elementary information processing modules in the neocortex. To characterize the cell types and circuit diagram of clonally related excitatory neurons, we performed multi-cell patch clamp recordings and Patch-seq on neurons derived from Nestin-positive progenitors labeled by tamoxifen induction at embryonic day 10.5. The resulting clones are derived from two radial glia on average, span cortical layers 2–6, and are composed of a random sampling of transcriptomic cell types. We find an interaction between shared lineage and connection type: related neurons are more likely to be connected vertically across cortical layers, but not laterally within the same layer. These findings challenge the view that related neurons show uniformly increased connectivity and suggest that integration of vertical intra-clonal input with lateral inter-clonal input may represent a developmentally programmed connectivity motif supporting the emergence of functional circuits.

Cell type composition and circuit organization of clonally related excitatory neurons in the juvenile mouse neocortex

Mouse dLGN Receives Functional Input from a Diverse Population of Retinal Ganglion Cells with Limited Convergence

Correction: Bayesian hypothesis testing and experimental design for two-photon imaging data

Summary Excitatory neurons arising from a common progenitor establish radially-oriented clonal units in the neocortex which have been proposed to serve as elementary information processing modules. To characterize the cell types and circuit diagram within these clonal units, we performed single-cell RNA-sequencing and multi-cell patch clamp recordings of neurons derived from Nestin-positive progenitors. We found that radial clones do not appear to be fate-restricted, but instead individual clones are composed of a random sampling of the transcriptomic cell types present in a particular cortical area. The effect of lineage on synaptic connectivity depends on the type of connection tested: pairs of clonally related neurons were more likely to be connected vertically, across cortical layers, but not laterally within the same layer, compared to unrelated pairs. We propose that integration of vertical input from related neurons with lateral input from unrelated neurons may represent a developmentally programmed motif for assembling neocortical circuits.

Cell type composition and circuit organization of neocortical radial clones

Layer 4 of mouse neocortex differs in cell types and circuit organization between sensory areas

Calcium (Ca2+) dysregulation has been linked to neuronal cell death, including in hereditary retinal degeneration. Ca2+ dysregulation is thought to cause rod and cone photoreceptor cell death. Spatial and temporal heterogeneities in retinal disease models have hampered validation of this hypothesis. We examined the role of Ca2+ in photoreceptor degeneration, assessing the activation pattern of Ca2+‐dependent calpain proteases, generating spatiotemporal maps of the entire retina in the cpfl1 mouse model for primary cone degeneration, and in the rd1 and rd10 models for primary rod degeneration. We used Gaussian process models to distinguish the temporal sequences of degenerative molecular processes from other variability sources.In the rd1 and rd10 models, spatiotemporal pattern of increased calpain activity matched the progression of primary rod degeneration. High calpain activity coincided with activation of the calpain‐2 isoform but not with calpain‐1, suggesting differential roles for both calpain isoforms. Primary rod loss was linked to upregulation of apoptosis‐inducing factor, although only a minute fraction of cells showed activity of the apoptotic marker caspase‐3. After primary rod degeneration concluded, caspase‐3 activation appeared in cones, suggesting apoptosis as the dominant mechanism for secondary cone loss. Gaussian process models highlighted calpain activity as a key event during primary rod photoreceptor cell death. Our data suggest a causal link between Ca2+ dysregulation and primary, nonapoptotic degeneration of photoreceptors and a role for apoptosis in secondary degeneration of cones, highlighting the importance of the spatial and temporal location of key molecular events, which may guide the evaluation of new therapies.

Systematic spatiotemporal mapping reveals divergent cell death pathways in three mouse models of hereditary retinal degeneration

The inherent noise of neural systems makes it difficult to construct models which accurately capture experimental measurements of their activity. While much research has been done on how to efficiently model neural activity with descriptive models such as linear-nonlinear-models (LN), Bayesian inference for mechanistic models has received considerably less attention. One reason for this is that these models typically lead to intractable likelihoods and thus make parameter inference difficult. Here, we develop an approximate Bayesian inference scheme for a fully stochastic, biophysically inspired model of glutamate release at the ribbon synapse, a highly specialized synapse found in different sensory systems. The model translates known structural features of the ribbon synapse into a set of stochastically coupled equations. We approximate the posterior distributions by updating a parametric prior distribution via Bayesian updating rules and show that model parameters can be efficiently estimated for synthetic and experimental data from in vivo two-photon experiments in the zebrafish retina. Also, we find that the model captures complex properties of the synaptic release such as the temporal precision and outperforms a standard GLM. Our framework provides a viable path forward for linking mechanistic models of neural activity to measured data.

Approximate Bayesian Inference for a Mechanistic Model of Vesicle Release at a Ribbon Synapse

Machine learning and knowledge discovery in databases : European Conference, ECML PKDD ... : proceedings. ECML PKDD

Heavy-tailed kernels reveal a finer cluster structure in t-SNE visualisations

Deep learning-based systems can achieve a diagnostic performance comparable to physicians in a variety of medical use cases including the diagnosis of diabetic retinopathy. To be useful in clinical practice, it is necessary to have well calibrated measures of the uncertainty with which these systems report their decisions. However, deep neural networks (DNNs) are being often overconfident in their predictions, and are not amenable to a straightforward probabilistic treatment. Here, we describe an intuitive framework based on test-time data augmentation for quantifying the diagnostic uncertainty of a state-of-the-art DNN for diagnosing diabetic retinopathy. We show that the derived measure of uncertainty is well-calibrated and that experienced physicians likewise find cases with uncertain diagnosis difficult to evaluate. This paves the way for an integrated treatment of uncertainty in DNN-based diagnostic systems.

Expert-validated estimation of diagnostic uncertainty for deep neural networks in diabetic retinopathy detection

Type-specific dendritic integration in mouse retinal ganglion cells

Saccades are ballistic eye movements that rapidly shift gaze from one location of visual space to another. Detecting saccades in eye movement recordings is important not only for studying the neural mechanisms underlying sensory, motor, and cognitive processes, but also as a clinical and diagnostic tool. However, automatically detecting saccades can be difficult, particularly when such saccades are generated in coordination with other tracking eye movements, like smooth pursuits, or when the saccade amplitude is close to eye tracker noise levels, like with microsaccades. In such cases, labeling by human experts is required, but this is a tedious task prone to variability and error. We developed a convolutional neural network to automatically detect saccades at human-level accuracy and with minimal training examples. Our algorithm surpasses state of the art according to common performance metrics and could facilitate studies of neurophysiological processes underlying saccade generation and visual processing. NEW & NOTEWORTHY Detecting saccades in eye movement recordings can be a difficult task, but it is a necessary first step in many applications. We present a convolutional neural network that can automatically identify saccades with human-level accuracy and with minimal training examples. We show that our algorithm performs better than other available algorithms, by comparing performance on a wide range of data sets. We offer an open-source implementation of the algorithm as well as a web service.

Human-level saccade detection performance using deep neural networks.

In the outer plexiform layer (OPL) of the mouse retina, two types of cone photoreceptors (cones) provide input to more than a dozen types of cone bipolar cells (CBCs). This transmission is modulated by a single horizontal cell (HC) type, the only interneuron in the outer retina. Horizontal cells form feedback synapses with cones and feedforward synapses with CBCs. However, the exact computational role of HCs is still debated. Along with performing global signaling within their laterally coupled network, HCs also provide local, cone-specific feedback. Specifically, it has not been clear which synaptic structures HCs use to provide local feedback to cones and global forward signaling to CBCs. Here, we reconstructed in a serial block-face electron microscopy volume the dendritic trees of five HCs as well as cone axon terminals and CBC dendrites to quantitatively analyze their connectivity. In addition to the fine HC dendritic tips invaginating cone axon terminals, we also identified “bulbs”, short segments of increased dendritic diameter on the primary dendrites of HCs. These bulbs are located well below the cone axon terminal base and make contact to other cells mostly identified as other HCs or CBCs. Using immunolabeling we show that HC bulbs express vesicular gamma-aminobutyric acid transporters and co-localize with GABA receptor γ2 subunits. Together, this suggests the existence of two synaptic strata in the mouse OPL, spatially separating cone-specific feedback and feedforward signaling to CBCs. A biophysics-based computational model of a HC dendritic branch supports the hypothesis that the spatial arrangement of synaptic contacts allows simultaneous local feedback and global feedforward signaling.

Retinal horizontal cells use different synaptic sites for global feedforward and local feedback signaling

Calcium (Ca2+) dysregulation has been linked to neuronal cell death, including in hereditary retinal degeneration. Ca2+ dysregulation is thought to cause rod and cone photoreceptor cell death. Spatial and temporal heterogeneities in retinal disease models have hampered validation of this hypothesis. We examined the role of Ca2+ in photoreceptor degeneration, assessing the activation pattern of Ca2+-dependent calpain proteases, generating spatio-temporal maps of the entire retina in the cpfl1 mouse model for primary cone degeneration, and in the rd1 and rd10 models for primary rod degeneration. We used Gaussian process models to distinguish the temporal sequences of degenerative molecular processes from other variability sources. In the rd1 and rd10 models, spatio-temporal pattern of increased calpain activity matched the progression of primary rod degeneration. High calpain activity coincided with activation of the calpain-2 isoform but not with calpain-1, suggesting differential roles for both calpain isoforms. Primary rod loss was linked to upregulation of apoptosis-inducing factor (AIF), although only a minute fraction of cells showed activity of the apoptotic marker caspase-3. After primary rod degeneration concluded, caspase-3 activation appeared in cones, suggesting apoptosis as the dominant mechanism for secondary cone loss. Gaussian process models highlighted calpain activity as a key event during primary rod photoreceptor cell death. Our data suggests a causal link between Ca2+ dysregulation and primary, non-apoptotic degeneration of photoreceptors and a role for apoptosis in secondary degeneration of cones, highlighting the importance of the spatial and temporal location of key molecular events, which may guide the evaluation of new therapies.

Systematic spatio-temporal mapping reveals divergent cell death pathways in three mouse models of hereditary retinal degeneration

One of the most important tasks for humans is the attribution of causes and effects in all wakes of life. The first systematical study of visual perception of causality—often referred to as phenomenal causality—was done by Albert Michotte using his now well-known launching events paradigm. Launching events are the seeming collision and seeming transfer of movement between two objects—abstract, featureless stimuli (“objects”) in Michotte’s original experiments. Here, we study the relation between causal ratings for launching events in Michotte’s setting and launching collisions in a photorealistically computer-rendered setting. We presented launching events with differing temporal gaps, the same launching processes with photorealistic billiard balls, as well as photorealistic billiard balls with realistic motion dynamics, that is, an initial rebound of the first ball after collision and a short sliding phase of the second ball due to momentum and friction. We found that providing the normal launching stimulus with realistic visuals led to lower causal ratings, but realistic visuals together with realistic motion dynamics evoked higher ratings. Two-dimensional versus three-dimensional presentation, on the other hand, did not affect phenomenal causality. We discuss our results in terms of intuitive physics as well as cue conflict.

In recent years, a plethora of high-profile scientific publications has been reporting about machine learning algorithms outperforming clinicians in medical diagnosis or treatment recommendations. This has spiked interest in deploying relevant algorithms with the aim of enhancing decision-making in healthcare. In this paper, we argue that instead of straightforwardly enhancing the decision-making capabilities of clinicians and healthcare institutions, deploying machines learning algorithms entails trade-offs at the epistemic and the normative level. Whereas involving machine learning might improve the accuracy of medical diagnosis, it comes at the expense of opacity when trying to assess the reliability of given diagnosis. Drawing on literature in social epistemology and moral responsibility, we argue that the uncertainty in question potentially undermines the epistemic authority of clinicians. Furthermore, we elucidate potential pitfalls of involving machine learning in healthcare with respect to paternalism, moral responsibility and fairness. At last, we discuss how the deployment of machine learning algorithms might shift the evidentiary norms of medical diagnosis. In this regard, we hope to lay the grounds for further ethical reflection of the opportunities and pitfalls of machine learning for enhancing decision-making in healthcare.

In the eye, the function of same-type photoreceptors must be regionally adjusted to process a highly asymmetrical natural visual world. Here we show that UV-cones in the larval zebrafish area temporalis are specifically tuned for UV-bright prey capture in their upper frontal visual field, which uses the signal from a single cone at a time. For this, UV-detection efficiency is regionally boosted 42-fold. Next, in vivo 2-photon imaging, transcriptomics and computational modelling reveal that these cones use an elevated baseline of synaptic calcium to facilitate the encoding of bright objects, which in turn results from expressional tuning of phototransduction genes. Finally, this signal is further accentuated at the level of glutamate release driving retinal networks. These regional differences tally with variations between peripheral and foveal cones in primates and hint at a common mechanistic origin. Together, our results highlight a rich mechanistic toolkit for the tuning of neurons.

Cellular and molecular mechanisms of photoreceptor tuning for prey capture in larval zebrafish

Author Correction: Layer 4 of mouse neocortex differs in cell types and circuit organization between sensory areas

For colour vision, retinal circuits must separate information about intensity and wavelength. This requires circuit-level comparison of at least two spectrally distinct photoreceptors. However, many vertebrates use four or more, and in those cases the nature and implementation of this computation remains poorly understood. Here, we establish the complete circuit architecture and function of outer retinal circuits underlying colour processing in the tetrachromatic larval zebrafish. Our findings reveal that the specific spectral tunings of the four cone types near optimally rotate the encoding of natural daylight in a principal component analysis (PCA)-like manner to yield one primary achromatic axis, two colour-opponent axes as well as a secondary UV-achromatic axis for prey capture. We note that fruit flies – the only other tetrachromat species where comparable circuit-level information is available - use essentially the same strategy to extract spectral information from their relatively blue-shifted terrestrial visual world. Together, our results suggest that rotating colour space into achromatic and chromatic axes at the eye’s first synapse may be a fundamental principle of colour vision when using more than two spectrally well-separated photoreceptor types.

Near-optimal rotation of colour space by zebrafish cones in vivo

Deep neural networks (DNNs) have revolutionized medical image analysis and disease diagnosis. Despite their impressive increase in performance, it is difﬁcult to generate well-calibrated probabilistic outputs for such networks such that state-of-the-art networks fail to provide reliable uncertainty estimates regarding their decisions. We propose a simple but effective method using traditional data augmentation methods such as geometric and color transformations at test time. This allows to examine how much the network output varies in the vicinity of examples in the input spaces. Despite its simplicity, our method yields useful estimates for the input-dependent predictive uncertainties of deep neural networks. We showcase the impact of our method via the well-known collection of fundus images obtained from a previous Kaggle competition.

Test-time Data Augmentation for Estimation of Heteroscedastic Aleatoric Uncertainty in Deep Neural Networks

Temporal filters of electrically stimulated retinal ganglion cells

Visual processing begins in the retina—a thin, multilayered neuronal tissue lining the back of the vertebrate eye. The retina does not merely read out the constant stream of photons impinging on its dense array of photoreceptor cells. Instead it performs a first, extensive analysis of the visual scene, while constantly adapting its sensitivity range to the input statistics, such as the brightness or contrast distribution. The functional organization of the retina abides to several key organizational principles. These include overlapping and repeating instances of both divergence and convergence, constant and dynamic range-adjustments, and (perhaps most importantly) decomposition of image information into parallel channels. This is often referred to as “parallel processing.” To support this, the retina features a large diversity of neurons organized in functionally overlapping microcircuits that typically uniformly sample the retinal surface in a regular mosaic. Ultimately, each circuit drives spike trains in the retina’s output neurons, the retinal ganglion cells. Their axons form the optic nerve to convey multiple, distinctive, and often already heavily processed views of the world to higher visual centers in the brain.

The Functional Organization of Vertebrate Retinal Circuits for Vision

In the mouse, the parallel output of more than 30 functional types of retinal ganglion cells (RGCs) serves as the basis for all further visual processing. Little is known about how the representation of visual information changes between the retina and the dorsolateral geniculate nucleus (dLGN) of the thalamus, the main relay station between the retina and cortex. Here, we functionally characterized responses of retrogradely labeled dLGN-projecting RGCs and dLGN neurons to the same set of visual stimuli. We found that many of the previously identified functional RGC types innervate the dLGN, which maintained a high degree of functional diversity. Using a linear model to assess functional connectivity between RGC types and dLGN neurons, we found that the responses of dLGN neurons could be predicted as a linear combination of inputs from on average five RGC types, but only two of those had the strongest functional impact. Thus, mouse dLGN receives input from a diverse population of RGCs with limited functional convergence.

Mouse dLGN receives input from a diverse population of retinal ganglion cells with limited convergence

When the brain has determined the position of a moving object, because of anatomical and processing delays the object will have already moved to a new location. Given the statistical regularities present in natural motion, the brain may have acquired compensatory mechanisms to minimize the mismatch between the perceived and real positions of moving objects. A well-known visual illusion-the flash lag effect-points toward such a possibility. Although many psychophysical models have been suggested to explain this illusion, their predictions have not been tested at the neural level, particularly in a species of animal known to perceive the illusion. To this end, we recorded neural responses to flashed and moving bars from primary visual cortex (V1) of awake, fixating macaque monkeys. We found that the response latency to moving bars of varying speed, motion direction, and luminance was shorter than that to flashes, in a manner that is consistent with psychophysical results. At the level of V1, our results support the differential latency model positing that flashed and moving bars have different latencies. As we found a neural correlate of the illusion in passively fixating monkeys, our results also suggest that judging the instantaneous position of the moving bar at the time of flash-as required by the postdiction/motion-biasing model-may not be necessary for observing a neural correlate of the illusion. Our results also suggest that the brain may have evolved mechanisms to process moving stimuli faster and closer to real time compared with briefly appearing stationary stimuli. NEW & NOTEWORTHY We report several observations in awake macaque V1 that provide support for the differential latency model of the flash lag illusion. We find that the equal latency of flash and moving stimuli as assumed by motion integration/postdiction models does not hold in V1. We show that in macaque V1, motion processing latency depends on stimulus luminance, speed and motion direction in a manner consistent with several psychophysical properties of the flash lag illusion.

Faster processing of moving compared with flashed bars in awake macaque V1 provides a neural correlate of the flash lag illusion.

Variability, stochastic or otherwise, is a central feature of neural circuits. Yet the means by which variation and uncertainty are derived from noisy observations of neural activity is often unprincipled, with too much weight placed on numerical convenience at the cost of statistical rigour. For two-photon imaging data, composed of fundamentally probabilistic streams of photon detections, the problem is particularly acute. Here, we present a complete statistical pipeline for the inference and analysis of neural activity using Gaussian Process Regression, applied to two-photon recordings of light-driven activity in ex vivo mouse retina. We demonstrate the flexibility and extensibility of these models, considering cases with non-stationary statistics, driven by complex parametric stimuli, in signal discrimination, hierarchical clustering and inference tasks. Sparse approximation methods allow these models to be fitted rapidly, permitting them to actively guiding the design of light stimulation in the midst of ongoing two-photon experiments.

Bayesian hypothesis testing and experimental design for two-photon imaging data

Mouse dLGN Receives Input from a Diverse Population of Retinal Ganglion Cells with Limited Functional Convergence

Manipulating Hippocampal Place Cell Activity by Single-Cell Stimulation in Freely Moving Mice.

Combining two photon microscopy and CMOS MEA to uncover the mechanism of aberrant activity in blind retina

In genomics, transcriptomics, and related biological fields (collectively known as ‘omics’), it is common to work with n ≪ p data sets with the dimensionality much larger than the sample size. In recent years, combinations of experimental techniques began to yield multiple sets of features for the same set of biological replicates. One example is Patch-seq, a method combining single-cell RNA sequencing with electrophysiological recordings from the same cells. Here we present a framework based on sparse reduced-rank regression for obtaining an interpretable visualization of the relationship between the transcriptomic and the electrophysiological data. We use an elastic net regularization penalty that yields sparse solutions and allows for an efficient computational implementation. Using several publicly available Patch-seq data sets, we show that sparse reduced-rank regression outperforms both sparse full-rank regression and non-sparse reduced-rank regression in terms of predictive performance, and can outperform existing methods for sparse partial least squares and sparse canonical correlation analysis in terms of out-of-sample correlations. We introduce a ‘bibiplot’ visualization in order to display the dominant factors determining the relationship between transcriptomic and electrophysiological properties of neurons. We believe that sparse reduced-rank regression can provide a valuable tool for the exploration and visualization of multimodal data sets, including Patch-seq.

Sparse reduced-rank regression for exploratory visualization of multimodal data sets

Functional recordings at the first synaptic layer of the visual system in vivo

Zebrafish Differentially Process Color across Visual Space to Match Natural Scenes

Saccades are ballistic eye movements that rapidly shift gaze from one location of visual space to another. Detecting saccades in eye movement recordings is important not only for studying the neural mechanisms underlying sensory, motor, and cognitive processes, but also as a clinical and diagnostic tool. However, automatically detecting saccades can be difficult, particularly when such saccades are generated in coordination with other tracking eye movements, like smooth pursuits, or when the saccade amplitude is close to eye tracker noise levels, like with microsaccades. In such cases, labeling by human experts is required, but this is a tedious task prone to variability and error. We developed a convolutional neural network (CNN) to automatically detect saccades at human-level performance accuracy. Our algorithm surpasses state of the art according to common performance metrics, and will facilitate studies of neurophysiological processes underlying saccade generation and visual processing.

Human-level saccade detection performance using deep neural networks

Data from: Zebrafish differentially process colour across visual space to match natural scenes

The ability to detect moving objects is an ethologically salient function. Direction-selective neurons have been identified in the retina, thalamus, and cortex of many species, but their homology has remained unclear. For instance, it is unknown whether direction-selective retinal ganglion cells (DSGCs) exist in primates and, if so, whether they are the equivalent to mouse and rabbit DSGCs. Here, we used a molecular/circuit approach in both sexes to address these issues. In mice, we identify the transcription factor Satb2 (special AT-rich sequence-binding protein 2) as a selective marker for three RGC types: On–Off DSGCs encoding motion in either the anterior or posterior direction, a newly identified type of Off-DSGC, and an Off-sustained RGC type. In rabbits, we find that expression of Satb2 is conserved in On–Off DSGCs; however, it has evolved to include On–Off DSGCs encoding upward and downward motion in addition to anterior and posterior motion. Next, we show that macaque RGCs express Satb2 most likely in a single type. We used rabies virus-based circuit-mapping tools to reveal the identity of macaque Satb2-RGCs and discovered that their dendritic arbors are relatively large and monostratified. Together, these data indicate Satb2-expressing On–Off DSGCs are likely not present in the primate retina. Moreover, if DSGCs are present in the primate retina, it is unlikely that they express Satb2. SIGNIFICANCE STATEMENT The ability to detect object motion is a fundamental feature of almost all visual systems. Here, we identify a novel marker for retinal ganglion cells encoding directional motion that is evolutionarily conserved in mice and rabbits, but not in primates. We show in macaque monkeys that retinal ganglion cells (RGCs) that express this marker comprise a single type and are morphologically distinct from mouse and rabbit direction-selective RGCs. Our findings indicate that On–Off direction-selective retinal neurons may have evolutionarily diverged in primates and more generally provide novel insight into the identity and organization of primate parallel visual pathways.

Molecular Fingerprinting of On–Off Direction-Selective Retinal Ganglion Cells Across Species and Relevance to Primate Visual Circuits

Manipulating Hippocampa l Place Cell Activity by Single-Cell Stimulation in Freely Moving Mice Graphical

Layer 4 (L4) of mammalian neocortex plays a crucial role in cortical information processing, yet a complete census of its cell types and connectivity remains elusive. Using whole-cell recordings with morphological recovery, we identified one major excitatory and seven inhibitory types of neurons in L4 of adult mouse visual cortex (V1). Nearly all excitatory neurons were pyramidal and all somatostatin-positive (SOM+) non-fast-spiking neurons were Martinotti cells. In contrast, in somatosensory cortex (S1), excitatory neurons were mostly stellate and SOM+ neurons were non-Martinotti. These morphologically distinct SOM+ interneurons corresponded to different transcriptomic cell types and were differentially integrated into the local circuit with only S1 neurons receiving local excitatory input. We propose that cell-type specific circuit motifs, such as the Martinotti/pyramidal and non-Martinotti/stellate pairs, are optionally used across the cortex as building blocks to assemble cortical circuits.

Neocortical layer 4 in adult mouse differs in major cell types and circuit organization between primary sensory areas

Animal eyes evolve to process behaviourally important visual information, but how retinas deal with statistical asymmetries in visual space remains poorly understood. Using hyperspectral imaging in the field, in-vivo 2-photon imaging of retinal neurons and anatomy, here we show that larval zebrafish use a highly anisotropic retina to asymmetrically survey their natural visual world. First, different neurons dominate different parts of the eye, and are linked to a systematic shift in inner retinal function: Above the animal, there is little colour in nature and retinal circuits are largely achromatic. Conversely, the lower visual field and horizon are colour-rich, and are predominately surveyed by chromatic and colour-opponent circuits that are spectrally matched to the dominant chromatic axes in nature. Second, above the frontal horizon, a high-gain ultraviolet-system piggy-backs onto retinal circuits, likely to support prey-capture. Our results demonstrate high functional diversity among single genetically and morphologically defined types of neurons.

Zebrafish differentially process colour across visual space to match natural scenes

Inhibition decorrelates visual feature representations in the inner retina

Abstract The retina in the eye performs complex computations, to transmit only behaviourally relevant information about our visual environment to the brain. These computations are implemented by numerous different cell types that form complex circuits. New experimental and computational methods make it possible to study the cellular diversity of the retina in detail – the goal of obtaining a complete list of all the cell types in the retina and, thus, its “building blocks”, is within reach. We review the current state of this endeavour and highlight possible directions for future research.

Was wir sehen, wird nicht erst im Gehirn verarbeitet. Bereits in der Netzhaut sind zahlreiche verschiedene Zelltypen dafür verantwortlich, visuell Wahrgenommenes in seine Komponenten zu zerlegen und diese auf verschiedenen Kanälen an das Gehirn weiterzuleiten. Dabei spielen die sogenannten Bipolarzellen eine zentrale Rolle, denn sie verarbeiten die Reize aus den lichtempfindlichen Zellen des Auges als erstes. Ihre Arbeitsweise haben Tübinger Neurowissenschaftler nun in einer Studie detailliert untersucht, die im Fachmagazin Nature veröffentlicht wird, DOI: 10.1038/nature21394.

Zusammenfassung Die Netzhaut im Auge führt bereits komplexe Berechnungen aus, um nur verhaltensrelevante Informationen aus unserer Umgebung an das Gehirn weiterzuleiten. Diese Berechnungen werden von zahlreichen Zelltypen durchgeführt, die sich zu komplexen Schaltkreisen zusammenschließen. Neue experimentelle und statistische Methoden erlauben es, die neuronale Vielfalt in der Netzhaut detailliert zu erfassen und zu verstehen – das Ziel, eine vollständige Liste der Zelltypen und damit der „Bauteile“ der Netzhaut zu erstellen, rückt nun in greifbare Nähe. In diesem Artikel geben wir einen Überblick über den aktuellen Stand dieses Unterfangens und zeigen mögliche zukünftige Forschungsrichtungen auf.

Standardizing and benchmarking data analysis for calcium imaging

Visual Neuroscience: A Retinal Ganglion Cell to Report Image Focus?

Photoreceptors form a sophisticated synaptic complex with bipolar and horizontal cells, transmitting the signals generated by the phototransduction cascade to downstream retinal circuitry. The cone photoreceptor synapse shows several characteristic anatomical connectivity motifs that shape signal transfer: typically, ON‐cone bipolar cells receive photoreceptor input through invaginating synapses; OFF‐cone bipolar cells form basal synapses with photoreceptors. Both ON‐ and OFF‐cone bipolar cells are believed to sample from all cone photoreceptors within their dendritic span. Electron microscopy and immunolabelling studies have established the robustness of these motifs, but have been limited by trade‐offs in sample size and spatial resolution, respectively, constraining precise quantitative investigation to a few individual cells. 3D‐serial electron microscopy overcomes these limitations and has permitted complete sets of neurons to be reconstructed over a comparatively large section of retinal tissue. Although the published mouse dataset lacks labels for synaptic structures, the characteristic anatomical motifs at the photoreceptor synapse can be exploited to identify putative synaptic contacts, which has enabled the development of a quantitative description of outer retinal connectivity. This revealed unexpected exceptions to classical motifs, including substantial interaction between rod and cone pathways at the photoreceptor synapse, sparse photoreceptor sampling and atypical contacts. Here, we summarize what was learned from this study in a more general context: we consider both the implications and limitations of the study and identify promising avenues for future research.

Connectomics of synaptic microcircuits: lessons from the outer retina

NeuroResource Benchmarking Spike Rate Inference in Population Calcium Imaging Highlights

The retina extracts visual features for transmission to the brain. Different types of bipolar cell split the photoreceptor input into parallel channels and provide the excitatory drive for downstream visual circuits. Anatomically, mouse bipolar cell types have been described down to the ultrastructural level, but a similarly deep understanding of their functional diversity is lacking. By imaging light-driven glutamate release from more than 11,000 bipolar cell axon terminals in the intact retina, we here show that bipolar cell functional diversity is generated by the balanced interplay of dendritic excitatory inputs and axonal inhibitory inputs. The resultant centre and surround components of bipolar cell receptive fields interact to decorrelate bipolar cell output in the spatial and temporal domain. Our findings highlight the importance of inhibitory circuits in generating functionally diverse excitatory pathways and suggest that decorrelation of parallel visual pathways begins already at the second synapse of the mouse visual system.

Balanced excitation and inhibition decorrelates visual feature representation in the mammalian inner retina

Cell Lineage Directs teh Precise Assembly of Excitatory Neocortical Circuits

The critique of Barth et al. centers on three points: (i) the completeness of our study is overstated; (ii) the connectivity matrix we describe is biased by technical limitations of our brain-slicing and multipatching methods; and (iii) our cell classification scheme is arbitrary and we have simply renamed previously identified interneuron types. We address these criticisms in our Response.

Response to Comment on “Principles of connectivity among morphologically defined cell types in adult neocortex”

Connectivity map of bipolar cells and photoreceptors in the outer mouse retina

Program Number: 582 Poster Board Number: B0055 Presentation Time: 1:30 PM–3:15 PM Time-lapse near infrared microscopy reveals stimulus-evoked photoreceptor outer segment shrinkage and shift Xincheng Yao1, 2, Xiaohui Zhao1, Damber Thapa1, Benquan Wang1, Yiming Lu1. 1Department of Bionengineering, University of Illinois at Chicago, Chicago, IL; 2Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL. Purpose: This study is to investigate biophysical mechanism of transient retinal phototropism (TRP). Oblique light stimulation evoked TRP has been observed in mouse and frog retinas. High resolution microscopy of freshly isolated retinas indicated that the TRP is predominated by rod photoreceptors. Comparative confocal microscopy and optical coherence tomography (OCT) revealed photoreceptor outer segment (OS) movement. However, biophysical mechanism of rod OS movement is still unknown. Methods: Frog retinal slices, which open a cross section of the photoreceptor and inner retinal layers, were used to test the effect of light stimulation on rod OS. High-speed and high-resolution near infrared (NIR) light microscopy was employed to monitor photoreceptor OS response evoked by a rectangular-shaped visible light flash. Stimulus-evoked photoreceptor OS length change and transverse distortion were quantitatively calculated. Results: High spatiotemporal resolution NIR imaging revealed rapid rod OS length change correlated with visible light stimulation. The magnitude and direction of the rod OS changes varied within the area covered by the rectangle-shaped stimulus pattern. In the center of the stimulus pattern, transient rod OS shrinkage was observed; while in the periphery of the stimulus pattern, transient rod tip shift towards the stimulus center was recorded. Conclusions: Our experimental result and theoretical analysis indicate that the TRP might reflect unbalanced rod OS disc-shape change due to localized pigment bleaching and phototransduction. Further investigation is required to understand biochemical mechanism of the observed rod OS kinetics. Better study of the TRP may provide a noninvasive biomarker to enable early detection of age-related macular degeneration (AMD) and other diseases that are known to produce retinal photoreceptor dysfunctions. Commercial Relationships: Xincheng Yao, The UAB Research Foundation (P); Xiaohui Zhao, None; Damber Thapa, None; Benquan Wang, None; Yiming Lu, None Support: NIH R01 EY023522, NIH R01 EY024628, NIH P30 EY001792 and NSF CBET-1055889

Time-lapse near infrared microscopy reveals stimulus-evoked photoreceptor outer segment shrinkage and shift

Author response: Sparse activity of identified dentate granule cells during spatial exploration

Leveraging uncertainty information from deep neural networks for disease detection

In the dentate gyrus – a key component of spatial memory circuits – granule cells (GCs) are known to be morphologically diverse and to display heterogeneous activity profiles during behavior. To resolve structure–function relationships, we juxtacellularly recorded and labeled single GCs in freely moving rats. We found that the vast majority of neurons were silent during exploration. Most active GCs displayed a characteristic spike waveform, fired at low rates and showed spatial activity. Primary dendritic parameters were sufficient for classifying neurons as active or silent with high accuracy. Our data thus support a sparse coding scheme in the dentate gyrus and provide a possible link between structural and functional heterogeneity among the GC population. DOI: http://dx.doi.org/10.7554/eLife.20252.001

Sparse activity of identified dentate granule cells during spatial exploration

Visual processing begins at the first synapse of the visual system. In the mouse retina, three different types of photoreceptors provide input to 14 bipolar cell (BC) types. Classically, most BC types are thought to contact all cones within their dendritic field; ON BCs would contact cones exclusively via so-called invaginating synapses, while OFF BCs would form basal synapses. By mining publically available electron microscopy data, we discovered interesting violations of these rules of outer retinal connectivity: ON BC type X contacted only ~20% of the cones in its dendritic field and made mostly atypical non-invaginating contacts. Types 5T, 5O and 8 also contacted fewer cones than expected. In addition, we found that rod BCs received input from cones, providing anatomical evidence that rod and cone pathways are interconnected in both directions. This suggests that the organization of the outer plexiform layer is more complex than classically thought.

Connectivity map of bipolar cells and photoreceptors in the mouse retina

Electrophysiological, transcriptomic and morphologic profiling of single neurons using Patch-seq

Functional characterization of the signal processing chain in the mouse early visual system

Sibling rivalry and cooperation among excitatory neurons in the neocortex

A census of neocortical neurons Despite the importance of the brain's neocortex, we still do not completely understand the diversity and functional connections of its cell types. Jiang et al. recorded, labeled, and classified over 1200 interneurons and more than 400 pyramidal neurons in the mature mouse visual cortex. Fifteen major classes of interneurons fell into three types: some connect to all neurons, some connect to other interneurons, and some form synapses with pyramidal neurons. Science, this issue p. 10.1126/science.aac9462 The connections between more than 10,000 pairs of individually classified neurons in the visual cortex of adult mice are mapped. INTRODUCTION The intricate microcircuitry of the cerebral cortex is thought to be a critical substrate from which arise the impressive capabilities of the mammalian brain. Until now, our knowledge of the stereotypical connectivity in neocortical microcircuits has been pieced together from individual studies of the connectivity between small numbers of neuronal cell types. Here, we provide unbiased, large-scale profiling of neuronal cell types and connections to reveal the essential building blocks of the cortex and the principles governing their assembly into cortical circuits. Using advanced techniques for tissue slicing, multiple simultaneous whole-cell recording, and morphological reconstruction, we are able to provide a comprehensive view of the connectivity between diverse types of neurons, particularly among types of γ-aminobutyric acid–releasing (GABAergic) interneurons, in the adult animal. RATIONALE We took advantage of a method for preparing high-quality slices of adult tissue and combined this technique with octuple simultaneous, whole-cell recordings followed by an improved staining method that allowed detailed recovery of axonal and dendritic arbor morphology. These data allowed us to perform a census of morphologically and electrophysiologically defined neuronal types (primarily GABAergic interneurons) in neocortical layers 1, 2/3, and 5 (L1, L23, and L5, respectively) and to observe their connectivity patterns in adult animals. RESULTS Our large-scale, comprehensive profiling of neocortical neurons differentiated 15 major types of interneurons, in addition to two lamina-defined types of pyramidal neurons (L23 and L5). Cortical interneurons comprise two types in L1 (eNGC and SBC-like), seven in L23 (L23MC, L23NGC, BTC, BPC, DBC, L23BC, and ChC), and six in L5 (L5MC, L5NGC, L5BC, SC, HEC, and DC) (see the figure). Each type has stereotypical electrophysiological properties and morphological features and can be differentiated from all others by cell type–specific axonal geometry and axonal projection patterns. Importantly, each type of neuron has its own characteristic input-output connectivity profile, connecting with other constituent neuronal types with varying degrees of specificity in postsynaptic targets, laminar location, and synaptic characteristics. Despite specific connection patterns for each cell type, we found that a small number of simple connectivity motifs are repeated across layers and cell types defining a canonical cortical microcircuit. CONCLUSION Our comprehensive profiling of neuronal cell types and connections in adult neocortex provides the most complete wiring diagram of neocortical microcircuits to date. Compared with current genetic labels for cell class, which paint the cortex in broad strokes, our analysis of morphological and electrophysiological properties revealed new cell classes and allowed us to derive a small number of simple connectivity rules that were repeated across layers and cell types. This detailed blueprint of cortical wiring should aid efforts to identify specific circuit abnormalities in animal models of brain disease and may eventually provide a path toward the development of comprehensive circuit-based, cell type–specific interventions. Connectivity among morphologically defined cell types in adult neocortex. (A) Simultaneous octuple whole-cell recording to study connectivity followed by morphological reconstruction. (B) Synaptic connectivity between morphologically distinct types of neurons, including pyramidal (P) neurons. (C) Connectivity from NGCs to other cell types. This connectivity is believed to be nonsynaptic and mediated by volume transmission. Martinotti cell, MC; neurogliaform cell, NGC; basket cell, BC; single-bouquet cell-like cell, SBC-like; bitufted cell, BTC; bipolar cell, BPC, double-bouquet cell, DBC; chandelier cell, ChC; shrub cell, SC; horizontally elongated cell, HEC; deep-projecting cell, DC. Since the work of Ramón y Cajal in the late 19th and early 20th centuries, neuroscientists have speculated that a complete understanding of neuronal cell types and their connections is key to explaining complex brain functions. However, a complete census of the constituent cell types and their wiring diagram in mature neocortex remains elusive. By combining octuple whole-cell recordings with an optimized avidin-biotin-peroxidase staining technique, we carried out a morphological and electrophysiological census of neuronal types in layers 1, 2/3, and 5 of mature neocortex and mapped the connectivity between more than 11,000 pairs of identified neurons. We categorized 15 types of interneurons, and each exhibited a characteristic pattern of connectivity with other interneuron types and pyramidal cells. The essential connectivity structure of the neocortical microcircuit could be captured by only a few connectivity motifs.

Principles of connectivity among morphologically defined cell types in adult neocortex

A fundamental challenge in calcium imaging has been to infer the timing of action potentials from the measured noisy calcium fluorescence traces. We systematically evaluate a range of spike inference algorithms on a large benchmark dataset recorded from varying neural tissue (V1 and retina) using different calcium indicators (OGB-1 and GCamp6). We show that a new algorithm based on supervised learning in flexible probabilistic models outperforms all previously published techniques, setting a new standard for spike inference from calcium signals. Importantly, it performs better than other algorithms even on datasets not seen during training. Future data acquired in new experimental conditions can easily be used to further improve its spike prediction accuracy and generalization performance. Finally, we show that comparing algorithms on artificial data is not informative about performance on real population imaging data, suggesting that a benchmark dataset may greatly facilitate future algorithmic developments.

Supervised learning sets benchmark for robust spike detection from calcium imaging signals

OrientationFine and Coarse Discrimination of From Another Angle: Differences in Cortical Coding

When the brain has determined the position of a moving object, due to anatomical and processing delays, the object will have already moved to a new location. Given the statistical regularities present in natural motion, the brain may have acquired compensatory mechanisms to minimize the mismatch between the perceived and the real position of a moving object. A well-known visual illusion — the flash lag effect — points towards such a possibility. Although many psychophysical models have been suggested to explain this illusion, their predictions have not been tested at the neural level, particularly in a species of animal known to perceive the illusion. Towards this, we recorded neural responses to flashed and moving bars from primary visual cortex (V1) of awake, fixating macaque monkeys. We found that the response latency to moving bars of varying speed, motion direction and luminance was shorter than that to flashes, in a manner that is consistent with psychophysical results. At the level of V1, our results support the differential latency model positing that flashed and moving bars have different latencies. As we found a neural correlate of the illusion in passively fixating monkeys, our results also suggest that judging the instantaneous position of the moving bar at the time of flash — as required by the postdiction/motion-biasing model — may not be necessary for observing a neural correlate of the illusion. Our results also suggest that the brain may have evolved mechanisms to process moving stimuli faster and closer to real time compared with briefly appearing stationary stimuli. New and Noteworthy We report several observations in awake macaque V1 that provide support for the differential latency model of the flash lag illusion. We find that the equal latency of flash and moving stimuli as assumed by motion integration/postdiction models does not hold in V1. We show that in macaque V1, motion processing latency depends on stimulus luminance, speed and motion direction in a manner consistent with several psychophysical properties of the flash lag illusion.

Faster processing of moving compared to flashed bars in awake macaque V1 provides a neural correlate of the flash lag illusion

Unexpected functional diversity among mouse retinal ganglion cell types

What the mouse eye tells the mouse brain: Fingerprinting the retinal ganglion cell types of the mouse retina

Following the visual signal across the entire mouse retina: From cone calcium to ganglion cell spikes

A fundamental challenge in calcium imaging has been to infer spike rates of neurons from the measured noisy calcium fluorescence traces. We systematically evaluate a range of spike inference algorithms on a large benchmark dataset (>100.000 spikes) recorded from varying neural tissue (V1 and retina) using different calcium indicators (OGB-1 and GCaMP6). We introduce a new algorithm based on supervised learning in flexible probabilistic models and show that it outperforms all previously published techniques. Importantly, it even performs better than other algorithms when applied to entirely new datasets for which no simultaneously recorded data is available. Future data acquired in new experimental conditions can easily be used to further improve its spike prediction accuracy and generalization performance. Finally, we show that comparing algorithms on artificial data is not informative about performance on real data, suggesting that benchmark datasets such as the one we provide may greatly facilitate future algorithmic developments.

Supervised learning sets benchmark for robust spike rate inference from calcium imaging signals

The rise of big data in modern research poses serious challenges for data management: Large and intricate datasets from diverse instrumentation must be precisely aligned, annotated, and processed in a variety of ways to extract new insights. While high levels of data integrity are expected, research teams have diverse backgrounds, are geographically dispersed, and rarely possess a primary interest in data science. Here we describe DataJoint, an open-source toolbox designed for manipulating and processing scientific data under the relational data model. Designed for scientists who need a flexible and expressive database language with few basic concepts and operations, DataJoint facilitates multiuser access, efficient queries, and distributed computing. With implementations in both MATLAB and Python, DataJoint is not limited to particular file formats, acquisition systems, or data modalities and can be quickly adapted to new experimental designs. DataJoint and related resources are available at http://datajoint.github.com.

Psychisch belastete Kinder und Jugendliche im Schulkontext – eine empirische Analyse schulischer Problemlagen anhand von Schulakten einer Klinikschule

Population code in mouse V1 facilitates read-out of natural scenes through increased sparseness

What the Mouse Eye Tells the Mouse Brain: A Semi-Supervised Clustering Approach for Fingerprinting the Retinal Ganglion Cell Types of the Mouse Retina

Recording the entire visual representation along the vertical pathway in the retina

Transmission of neural signals in the brain takes time due to the slow biological mechanisms that mediate it. During such delays, the position of moving objects can change substantially. The brain could use statistical regularities in the natural world to compensate neural delays and represent moving stimuli closer to real time. This possibility has been explored in the context of the flash lag illusion, where a briefly flashed stimulus in alignment with a moving one appears to lag behind the moving stimulus. Despite numerous psychophysical studies, the neural mechanisms underlying the flash lag illusion remain poorly understood, partly because it has never been studied electrophysiologically in behaving animals. Macaques are a prime model for such studies, but it is unknown if they perceive the illusion. By training monkeys to report their percepts unbiased by reward, we show that they indeed perceive the illusion qualitatively similar to humans. Importantly, the magnitude of the illusion is smaller in monkeys than in humans, but it increases linearly with the speed of the moving stimulus in both species. These results provide further evidence for the similarity of sensory information processing in macaques and humans and pave the way for detailed neurophysiological investigations of the flash lag illusion in behaving macaques.

Spikes in Mammalian Bipolar Cells Support Temporal Layering of the Inner Retina

Recording the entire visual representation along the vertical pathway in the mammalian retina

State Dependence of Noise Correlations in Macaque Primary Visual Cortex

Encoding of natural scene statistics in the primary visual cortex of the mouse

In Table 1, in the second column of the "Correct response?" row of "Training Phase II", there was a missing "x" symbol. The correct Table 2 can be viewed here:

Die Deutsche Forschungsgemeinschaft hat zum 1.1.2013 den ortständigen SFB 1080: Molekulare und zelluläre Mechanismen neuraler Homöostase im „rhine-main-neuroscience network“ (rmn2, www.rmn2.de) eingerichtet. Im rmn2 arbeiten die Johannes Gutenberg-Universität Mainz, die GoetheUniversität Frankfurt/M., das Institut für Molekulare Biologie Mainz (IMB), das Frankfurt Institute for Advanced Studies (FIAS) und in enger Kooperation mit den Max-Planck-Instituten für Biophysik und ForschungsFörderung

What information does the eye send to the brain? Recording the entire visual output at a single retinal location

Orientation tuning has been a classic model for understanding single-neuron computation in the neocortex. However, little is known about how orientation can be read out from the activity of neural populations, in particular in alert animals. Our study is a first step toward that goal. We recorded from up to 20 well isolated single neurons in the primary visual cortex of alert macaques simultaneously and applied a simple, neurally plausible decoder to read out the population code. We focus on two questions: First, what are the time course and the timescale at which orientation can be read out from the population response? Second, how complex does the decoding mechanism in a downstream neuron have to be to reliably discriminate between visual stimuli with different orientations? We show that the neural ensembles in primary visual cortex of awake macaques represent orientation in a way that facilitates a fast and simple readout mechanism: With an average latency of 30–80 ms, the population code can be read out instantaneously with a short integration time of only tens of milliseconds, and neither stimulus contrast nor correlations need to be taken into account to compute the optimal synaptic weight pattern. Our study shows that—similar to the case of single-neuron computation—the representation of orientation in the spike patterns of neural populations can serve as an exemplary case for understanding the computations performed by neural ensembles underlying visual processing during behavior.

The amount of information encoded by networks of neurons critically depends on the correlation structure of their activity. Neurons with similar stimulus preferences tend to have higher noise correlations than others. In homogeneous populations of neurons, this limited range correlation structure is highly detrimental to the accuracy of a population code. Therefore, reduced spike count correlations under attention, after adaptation, or after learning have been interpreted as evidence for a more efficient population code. Here, we analyze the role of limited range correlations in more realistic, heterogeneous population models. We use Fisher information and maximum-likelihood decoding to show that reduced correlations do not necessarily improve encoding accuracy. In fact, in populations with more than a few hundred neurons, increasing the level of limited range correlations can substantially improve encoding accuracy. We found that this improvement results from a decrease in noise entropy that is associated with increasing correlations if the marginal distributions are unchanged. Surprisingly, for constant noise entropy and in the limit of large populations, the encoding accuracy is independent of both structure and magnitude of noise correlations.

The Effect of Noise Correlations in Populations of Diversely Tuned Neurons

Cortical circuits perform the computations underlying rapid perceptual decisions within a few dozen milliseconds with each neuron emitting only a few spikes. Under these conditions, the theoretical analysis of neural population codes is challenging, as the most commonly used theoretical tool—Fisher information—can lead to erroneous conclusions about the optimality of different coding schemes. Here we revisit the effect of tuning function width and correlation structure on neural population codes based on ideal observer analysis in both a discrimination and a reconstruction task. We show that the optimal tuning function width and the optimal correlation structure in both paradigms strongly depend on the available decoding time in a very similar way. In contrast, population codes optimized for Fisher information do not depend on decoding time and are severely suboptimal when only few spikes are available. In addition, we use the neurometric functions of the ideal observer in the classification task to investigate the differential coding properties of these Fisher-optimal codes for fine and coarse discrimination. We find that the discrimination error for these codes does not decrease to zero with increasing population size, even in simple coarse discrimination tasks. Our results suggest that quite different population codes may be optimal for rapid decoding in cortical computations than those inferred from the optimization of Fisher information.

Reassessing optimal neural population codes with neurometric functions

Material for Decorrelated Neuronal Firing in Cortical Microcircuits

Local field potentials, BOLD and spiking activity: Relationships and physiological mechanisms

Correlated trial-to-trial variability in the activity of cortical neurons is thought to reflect the functional connectivity of the circuit. Many cortical areas are organized into functional columns, in which neurons are believed to be densely connected and to share common input. Numerous studies report a high degree of correlated variability between nearby cells. We developed chronically implanted multitetrode arrays offering unprecedented recording quality to reexamine this question in the primary visual cortex of awake macaques. We found that even nearby neurons with similar orientation tuning show virtually no correlated variability. Our findings suggest a refinement of current models of cortical microcircuit architecture and function: Either adjacent neurons share only a few percent of their inputs or, alternatively, their activity is actively decorrelated.

Directional data is ubiquitious in science. Due to its circular nature such data cannot be analyzed with commonly used statistical techniques. Despite the rapid development of specialized methods for directional statistics over the last fifty years, there is only little software available that makes such methods easy to use for practioners. Most importantly, one of the most commonly used programming languages in biosciences, MATLAB, is currently not supporting directional statistics. To remedy this situation, we have implemented the CircStat toolbox for MATLAB which provides methods for the descriptive and inferential statistical analysis of directional data. We cover the statistical background of the available methods and describe how to apply them to data. Finally, we analyze a dataset from neurophysiology to demonstrate the capabilities of the CircStat toolbox.

Second-order maximum-entropy models have recently gained much interest for describing the statistics of binary spike trains. Here, we extend this approach to take continuous stimuli into account as well. By constraining the joint second-order statistics, we obtain a joint Gaussian-Boltzmann distribution of continuous stimuli and binary neural firing patterns, for which we also compute marginal and conditional distributions. This model has the same computational complexity as pure binary models and fitting it to data is a convex problem. We show that the model can be seen as an extension to the classical spike-triggered average/covariance analysis and can be used as a non-linear method for extracting features which a neural population is sensitive to. Further, by calculating the posterior distribution of stimuli given an observed neural response, the model can be used to decode stimuli and yields a natural spike-train metric. Therefore, extending the framework of maximum-entropy models to continuous variables allows us to gain novel insights into the relationship between the firing patterns of neural ensembles and the stimuli they are processing.

A joint maximum-entropy model for binary neural population patterns and continuous signals

The relative merits of different population coding schemes have mostly been analyzed in the framework of stimulus reconstruction using Fisher Information. Here, we consider the case of stimulus discrimination in a two alternative forced choice paradigm and compute neurometric functions in terms of the minimal discrimination error and the Jensen-Shannon information to study neural population codes. We first explore the relationship between minimum discrimination error, Jensen-Shannon Information and Fisher Information and show that the discrimination framework is more informative about the coding accuracy than Fisher Information as it defines an error for any pair of possible stimuli. In particular, it includes Fisher Information as a special case. Second, we use the framework to study population codes of angular variables. Specifically, we assess the impact of different noise correlations structures on coding accuracy in long versus short decoding time windows. That is, for long time window we use the common Gaussian noise approximation. To address the case of short time windows we analyze the Ising model with identical noise correlation structure. In this way, we provide a new rigorous framework for assessing the functional consequences of noise correlation structures for the representational accuracy of neural population codes that is in particular applicable to short-time population coding.

Directional data is ubiquitious in science and medicine. Due to its circular nature such data cannot be analyzed with commonly used statistical techniques. Despite the rapid development of specialized methods for directional statistics over the last thirty years, there is not a lot of software available that makes such methods easy to use for users. Most importantly, one of the most commonly used programming languages in biosciences, Matlab, is currently not supporting directional statistics. To remedy this situation, we have implemented a toolbox in Matlab, which covers diverse aspects of the statistical analysis of directional data.

Pairwise Correlations and Multineuronal Firing Patterns in Primary Visual Cortex

The local field potential (LFP), comprised of low-frequency extra-cellular voltage fluctuations, has been used extensively to study the mechanisms of brain function. In particular, oscillations in the gamma-band (30–90 Hz) are ubiquitous in the cortex of many species during various cognitive processes. Surprisingly little is known about the underlying biophysical processes generating this signal. Here, we examine the relationship of the local field potential to the activity of localized populations of neurons by simultaneously recording spiking activity and LFP from the primary visual cortex (V1) of awake, behaving macaques. The spatial organization of orientation tuning and ocular dominance in this area provides an excellent opportunity to study this question, because orientation tuning is organized at a scale around one order of magnitude finer than the size of ocular dominance columns. While we find a surprisingly weak correlation between the preferred orientation of multi-unit activity and gamma-band LFP recorded on the same tetrode, there is a strong correlation between the ocular preferences of both signals. Given the spatial arrangement of orientation tuning and ocular dominance, this leads us to conclude that the gamma-band of the LFP seems to sample an area considerably larger than orientation columns. Rather, its spatial resolution lies at the scale of ocular dominance columns.

Comparing the Feature Selectivity of the Gamma-Band of the Local Field Potential and the Underlying Spiking Activity in Primate Visual Cortex

Extracellular voltage fluctuations (local field potentials, LFPs) reflecting neural mass action are ubiquitous across species and brain regions. Numerous studies have characterized the properties of LFP signals in the cortex to study sensory and motor computations as well as cognitive processes like attention, perception and memory. In addition, its extracranial counterpart – the electroencephalogram – is widely used in clinical applications. However, the link between LFP signals and the underlying activity of local populations of neurons remains largely elusive. Here, we review recent work elucidating the relationship between spiking activity of local neural populations and LFP signals. We focus on oscillations in the gamma-band (30–90 Hz) of the LFP in the primary visual cortex (V1) of the macaque that dominate during visual stimulation. Given that in area V1 much is known about the properties of single neurons and the cortical architecture, it provides an excellent opportunity to study the mechanisms underlying the generation of the LFP.

Feature Selectivity of the Gamma-Band of the Local Field Potential in Primate Primary Visual Cortex

On the spatial scale of the local field potential - orientation and ocularity tuning of the local field potential in the primary visual cortex of the macaque

Maximum entropy analysis of binary variables provides an elegant way for studying the role of pairwise correlations in neural populations. Unfortunately, these approaches suffer from their poor scalability to high dimensions. In sensory coding, however, high-dimensional data is ubiquitous. Here, we introduce a new approach using a near-maximum entropy model, that makes this type of analysis feasible for very high-dimensional data—the model parameters can be derived in closed form and sampling is easy. Therefore, our NearMaxEnt approach can serve as a tool for testing predictions from a pairwise maximum entropy model not only for low-dimensional marginals, but also for high dimensional measurements of more than thousand units. We demonstrate its usefulness by studying natural images with dichotomized pixel intensities. Our results indicate that the statistics of such higher-dimensional measurements exhibit additional structure that are not predicted by pairwise correlations, despite the fact that pairwise correlations explain the lower-dimensional marginal statistics surprisingly well up to the limit of dimensionality where estimation of the full joint distribution is feasible.

Near-Maximum Entropy Models for Binary Neural Representations of Natural Images

Recent advances in both electrophysiological recording techniques and hardware capabilities have enabled researchers to simultaneously record from a large number of neurons in different areas of the brain. This opens the door for a wide range of complex analyses potentially leading to a better understanding of the principles underlying neural network computations. At the same time, due to the increasing amount of data with increasing complexity, significantly more emphasis has to be put on the data analysis task. Although high-level scripting languages such as Matlab can speed up the development of analysis tools, in our experience, a too large amount of time is still spent on (re)structuring and (re)organizing data for specific analyses. Therefore, our goal was to develop a system which enables experimental neuroscientists to spend less time on organizing their data and more on data collection and creative analysis. We developed an object oriented Matlab toolbox which supplies the user with basic data types and functions to organize and structure various types of electrophysiological data. By using an object oriented, hierarchical layout, basic functionality, such as integration of metadata, or storage and retrieval of data and results, is implemented independent of specific data formats or experimental designs. This provides maximal flexibility and compatibility with future experiments and new data formats. All data and experimental results are stored in a database, so the experimenter can choose which data to keep in memory for faster access and which to save to disk to save resources. Additionally, we have created an extensive library of basic analysis and visualization tools that can be used to get an overview of the data.

Studying the effects of noise correlations on population coding using a sampling method

Oscillations in the local field potential (LFP) are abundant across species and brain regions. The possible relationship of these low-frequency extracelluar voltage fluctuations with the activity of the underlying local population of neurons remains largely elusive. To study this relationship, we used an array of chronically implanted tetrodes spanning a distance of 700 µm and simultaneously recorded action potentials from multiple well-isolated single units, multi unit activity (MUA) and LFP from area V1 of the awake, behaving macaque. Moving and static gratings of different orientations were used for visual stimulation. In agreement with previous studies we find that the increase of LFP gamma-band power is a function of the orientation of the stimulus. However, the power of the gamma-band contains much less information about the orientation of the stimulus than the MUA and SUA recorded at the same site (Figure 1A). The average discriminability d' between preferred and orthogonal orientation was 2.46 for MUA, 2.45 for SUA and 1.01 for the LFP. Moreover, in contrast to recent results from area MT (Liu and Newsome, 2006) we find only a weak correlation between the preferred orientation of the MUA tuning function and that of the LFP (Figure 1B, different colors indicate different animals). Interestingly, all nearby LFP recording sites in our array were tuned to a similar orientation while the preferred orientations of MUA tuning functions were widely scattered. These results suggest that the power of LFP signals does not capture local population activity at the scale of orientation columns in area V1.

Orientation tuning of the local field potential and multi-unit activity in the primary visual cortex of the macaque

Spikes are phase locked to the gamma-band of the local field potential oscillations in the primary visual cortex of the macaque

Combining the insights of archaeology, history and anthropology, this account ranges from the origins of the Khoikhoi to the contemporary politics of the Namaqualand 'reserves'. It explores the stereotype of the 'Hottentot', the conception that the Khoikhoi are a vanished people. "The Cape Herders" provides the first picture of the Khoikhoi people. In doing so, it fills a long-standing gap in the resources of Southern African studies, and at a time when interest in the indigenous populations of South Africa is growing daily. Combining the insights of archaeology, history and anthropology, this account ranges from the origins of the Khoikhoi in Southern Africa to the contemporary politics of the Namaqualand 'reserves'. The Cape Herders explodes a variety of South African myths - not least those surrounding the negative stereotype of the 'Hottentot', and those which contribute to the idea that the Khoikhoi are by now 'a vanished people'. The story it tells instead is one of enduring interest - the history of a herding people in Southern Africa, its society, economy and culture, its relationship to the indigenous hunters of the Cape, its encounters with European expeditions, and its subsequent exposure to the first effects of colonisation. It is a story of change and adaptation, and it confirms the Khoikhoi's central role in the making of today's South Africa.

We would rather decline an effortful option, but when compelled, will move only slowly to harvest. Why should economic variables such as reward and effort affect movement vigor? In theory, both our decisions and our movements contribute to a measure of fitness in which the objective is to maximize rewards minus efforts, divided by time. To explore this idea, we engaged marmosets in a foraging task in which on each trial they decided whether to work by making saccades to visual targets, thus accumulating food, or to harvest by licking what they had earned. We varied the effort cost of harvest by moving the food tube with respect to the mouth. Theory predicted that the subjects should respond to the increased effort costs by working longer, stockpiling food before commencing harvest, but reduce their movement vigor to conserve energy. Indeed, in response to the increased effort costs of harvest, marmosets increased their work duration but reduced their movement vigor. These changes in decisions and movements coincided with changes in pupil size. As the effort cost of harvest declined, work duration decreased, the pupils dilated, and lick and saccade vigor increased. Thus, when acquisition of reward became effortful, there was a global change in the state of the brain: the pupils constricted, the decisions exhibited delayed gratification, and the movements displayed reduced vigor. Significance statement Why do economic variables such as reward and effort affect both the decision-making and the motor-control circuits of the brain? Our results suggest that as the brainstem neuromodulatory circuits that control pupil size respond to effort costs, they alter computations in the brain regions that control decisions, encouraging work and delaying gratification, and the brain regions that control movements, suppressing energy expenditure and reducing vigor. This coordinated response may improve a variable relevant to fitness: the capture rate.

Effort cost of harvest affects decisions and movement vigor of marmosets during foraging

The cerebellar cortex performs computations that are critical for control of our actions, and then transmits that information via simple spikes of Purkinje cells (P-cells) to downstream structures. However, because P-cells are many synapses away from muscles, we do not know how their output affects behavior. Furthermore, we do not know the level of abstraction, i.e., the coordinate system of the P-cell’s output. Here, we recorded spiking activities of hundreds of P-cells in the oculomotor vermis of marmosets during saccadic eye movements and found that following the presentation of a visual stimulus, the olivary input to a P-cell encoded a probabilistic signal that coarsely described both the direction and the amplitude of that stimulus. When this input was present, the resulting complex spike briefly suppressed the P-cell’s simple spikes, disrupting the P-cell’s output during that saccade. Remarkably, this brief suppression altered the saccade’s trajectory by pulling the eyes toward the part of the visual space that was preferentially encoded by the olivary input to that P-cell. Thus, analysis of behavior in the milliseconds following a complex spike unmasked how the P-cell’s output influenced behavior: the preferred location in the coordinates of the visual system as conveyed probabilistically from the inferior olive to a P-cell defined the action in the coordinates of the motor system for which that P-cell’s simple spikes directed behavior. Significance We are lacking general principles that can describe how changes in a P-cell’s simple spikes might alter behavior. Here, we show that a brief suppression of a P-cell’s simple spikes in the oculomotor vermis consistently pulls the eyes in a direction that corresponds to the preferred location of the sensory space as conveyed probabilistically to that P-cell from the inferior olive. Thus, the inferior olive defines the coordinate system regarding the information that a P-cell is providing to the rest of the brain.

Complex spikes perturb movements, revealing the sensorimotor map of Purkinje cells

Background The decision of which arm to use to achieve a goal depends on energetic costs and performance abilities of each arm. Following a stroke, there is a reduction in the use of the more-impaired arm. Is it because the energetic costs of the more-impaired arm are increased, or because its use dictates a lower chance of success? Objective We sought to elucidate the impact of energetic cost and task success on the arm choice of stroke survivors. Methods Thirteen chronic stroke survivors and thirteen neurologically-intact subjects participated in an experiment where they reached towards visual targets in a virtual-reality environment. Energetic cost of reaching with their less-used arm (nondominant/more-impaired) was adjusted by amplifying the range of motion, while task accuracy requirement was independently modulated by changing target size. Results Reducing the energic cost of reaching increased the use of the less-used arms in both groups, but by a greater amount in the stroke survivors. In contrast, lowering task accuracy requirement altered arm choice similarly in the two groups. The time spent in decision-making (reaction time) reflected different impacts of energetic cost and task success on the arm choice of the two groups. Conversely, velocity changes were similar between the groups. Conclusions The impact of energetic cost on arm choice of stroke survivors is greater than neurologically-intact subjects. Thus, the reduction in the use of the impaired arm following stroke may be primarily due to a subjective increase in the effort it takes to use that arm.

Choice of Arm Use in Stroke Survivors is Largely Driven by the Energetic Cost of the Movement

Claiming agency is a prerequisite for taking responsibility: the brain must differentiate between the sensory events that are the erroneous consequences of our actions, and thus may be remedied if we change our behavior, and the many other events in our environment that consume our attention, but for which we have no means of influence. In the cerebellum, the firing rates of complex spikes of Purkinje cells signal that a sensory or a motor event has taken place, but do not specify if that event was the consequence of the animal’s action. Instead, to claim agency of a sensory outcome, the complex spikes synchronize within the population of Purkinje cells that guided that action. As a result, in the cerebellum the erroneous sensory consequences of movements are identified not via modulation of complex spike firing rates, but via synchronization of spikes.

Signaling the agency of an erroneous outcome via synchronization of spikes in the cerebellum

Moving and holding still have been posited to be under separate control regimes for both eye and arm movements. The paretic arm after stroke is notable for abnormalities both at rest and during movement, thus it provides an opportunity to address the relationships between control of reaching, stopping and stabilizing. Here, we asked whether independence of these behaviors is preserved in arm paresis. To address this question, we quantified resting postural abnormalities in stroke patients by measuring their biases in force production as they held their hand still in various locations in a planar workspace, and then assessed the influence of these resting force biases on active reaching in the same workspace. We found that patients had marked resting postural force biases at each location. However, these biases did not manifest during any phase of planar reaching movements in the setting of weight support: not during initial acceleration, not to mid-trajectory perturbations, and not during deceleration to a stop. Resting force biases only appeared to switch on after a movement had fully stopped. These findings in stroke suggest that moving and holding still are functionally separable modes of control. At the same time, we found that patients’ resting postural force biases mirrored characteristics of abnormal synergies active during movement: they markedly decreased when arm support was provided; they were higher in more distal positions which require breaking out of flexion; and they scaled with the Fugl-Meyer score for the upper extremity (a measure of intrusion of abnormal synergies during active movement). These three shared features suggest a common mechanism for resting postural biases and abnormal synergies, which appears to be a contradiction given the functional separation of moving and holding still observed in the same patients. To resolve this apparent paradox, we propose a model that predicts a breakdown in the functional separation between reaching and holding still when patients move in the absence of weight support. Thus, the model posits that synergies are the behavioral manifestation of a spillover of posture into movement. Mapping these functional systems onto anatomical and physiological details of lesioned substrate after stroke may provide implementation-level insight into how normal arm motor control is assembled.

Independence and interaction between the control of moving and holding still in post-stroke arm paresis

When variability is added to a sensorimotor perturbation, total adaptation is impaired. In Albert et al.1 we explored this phenomenon, and observed that it is the brain’s implicit, i.e., subconscious learning system that is most affected by perturbation variance. We observed that perturbation variability impaired implicit learning by downregulating its sensitivity to error. Recently, Wang et al.2 present an alternate viewpoint: implicit error sensitivity does not change with experience, only the errors observed by the implicit system change. Here we evaluated this alternate view by empirically measuring error sensitivity as a function of error size. We found that perturbation variability strongly downregulates implicit error sensitivity when controlling for error size, consistent with our original results, counter to the inflexible model argued by Wang et al. With that said, a pre-existing relationship between error sensitivity and error magnitude noted by Wang et al. can contribute at least in part to implicit behavior. State-space models that start with this pre-existing error sensitivity curve and then update it with training according to a ‘memory of errors’ most accurately tracked measured behavior.

Perturbation variance suppresses error sensitivity in the implicit learning system

During deliberation, as the brain considers its options, the neural activity representing the goodness of each option rises toward a threshold, and the choice is often dictated by the option for which the rise is fastest. Here we report a surprising correlate of these activities: saccade vigor. We engaged human subjects in a decision-making task in which they considered effortful options, each requiring walking various durations and inclines. As they deliberated, they made saccades between the symbolic representations of those options. These saccades had no bearing on the effort that they would later expend, yet as they deliberated, saccade velocities increased. The rate of rise in vigor was faster for saccades toward the option that they later indicated as their choice, and encoded the difference in the subjective value of the two effortful options. Once deliberation ended, following a brief delay the subjects indicated their choice by making another saccade. Remarkably, vigor for this saccade dropped to baseline and no longer encoded subjective value. These results are consistent with an urgency model of decision-making in which a global signal in the brain drives both the neural circuits that make decisions, and the neural circuits that make movements. Paradoxically, this common drive is shared between the oculomotor circuits and the decision-making circuits, even when the decision involves effortful expenditure during a future event. Significance There is a link between the decisions we make and the movements that follow. Not only do we prefer options of greater value, but we also move faster to acquire them. When deliberating between options, neural activity rises to a threshold and the option that wins this race is the one chosen. We report a potential correlate of this in the motor control circuits; during deliberation, saccade vigor to both options rise, but faster for the option ultimately chosen. Thus, our movements appear to mirror the neural activity conducting the decision-making process. Paradoxically, this is true even when the movements have no direct bearing on the decision at hand.

The vigor paradox: saccade velocity during deliberation encodes utility of effortful actions

A hedge fund billionaire's children are suffering from cerebellar disease. He invited a group of neuroscientists to plan a search for therapies. What resulted is the outline of an implantable neural emulator that might electronically replace the damaged part of the brain.

Saccade vigor reflects the rise of decision variables during deliberation

P-sort dataset: Purkinje cell electrophysiological recordings in three species

Analysis of electrophysiological data from Purkinje cells (P-cells) of the cerebellum presents unique challenges to spike sorting. Complex spikes have waveforms that vary significantly from one event to the next, raising the problem of misidentification. Even when complex spikes are detected correctly, the simple spikes may belong to a different P-cell, raising the danger of misattribution. To address these identification and attribution problems, we wrote an open-source, semi-automated software called P-sort, and then tested it by analyzing data from P-cells recorded in three species: marmosets, macaques, and mice. Like other sorting software, P-sort relies on nonlinear dimensionality reduction to cluster spikes. However, it also uses the statistical relationship between simple and complex spikes to merge disparate clusters and split a single cluster. In comparison with expert manual curation, occasionally P-sort identified significantly more complex spikes, as well as prevented misattribution of clusters. Three existing automatic sorters performed less well, particularly for identification of complex spikes. To improve development of analysis tools for the cerebellum, we provide labeled data for 313 recording sessions, as well as statistical characteristics of waveforms and firing patterns of P-cells in three species.

Analysis of electrophysiological data from Purkinje cells (P-cells) of the cerebellum presents challenges for spike detection. Complex spikes have waveforms that vary significantly from one event to the next, raising the problem of misidentification. Even when complex spikes are detected correctly, the simple spikes may belong to a different P-cell, raising the danger of misattribution. Here, we analyzed data from over 300 P-cells in marmosets, macaques, and mice, using an open-source, semi-automated software called P-sort that addresses the spike identification and attribution problems. Like other sorting software, P-sort relies on nonlinear dimensionality reduction to cluster spikes. However, it also uses the statistical relationship between simple and complex spikes to merge seemingly disparate clusters, or split a single cluster. In comparison with expert manual curation, occasionally P-sort identified significantly more complex spikes, as well as prevented misattribution of clusters. Three existing automatic sorters performed less well, particularly for identification of complex spikes. To improve development of analysis tools for the cerebellum, we provide labeled data for 313 recording sessions, as well as statistical characteristics of waveforms and firing patterns.

Abstract In science, as in life, one can only hope to both inform others, and be informed by them. The commentaries associated with our book Vigor have highlighted the many ways in which the theory that we proposed can be improved. For example, there are a myriad of factors that need to be considered in a fully encompassing objective function. The neural mechanisms underlying the links between movement and decision-making have yet to be unraveled. The implications of a two-way interaction between movement and decisions at both the individual and social levels remain to be understood. The commentaries outline future questions, and encouragingly highlight the diversity of science communities that may be linked via the concept of vigor.

Movement control, decision-making, and the building of Roman roads to link them

The information that the brain transmits from one region to another is often viewed through the lens of firing rates. However, if the output neurons could vary the timing of their spikes with respect to each other, then through synchronization they could highlight information that may be critical for control of behavior. In the cerebellum, the computations that are performed by the cerebellar cortex are conveyed to the nuclei via inhibition. Yet, synchronous activity entrains nucleus neurons, making them fire. Does the cerebellar cortex rely on spike synchrony within populations of Purkinje cells (P-cells) to convey information to the nucleus? We recorded from multiple P-cells while marmosets performed saccadic eye movements and organized them into populations that shared a complex spike response to error. Before movement onset, P-cells transmitted information via a rate code: the simple spike firing rates predicted the direction and velocity of the impending saccade. However, during the saccade, the spikes became temporally aligned within the population, signaling when to stop the movement. Thus, the cerebellar cortex relies on spike synchronization within a population of P-cells, not individual firing rates, to convey to the nucleus when to stop a movement.

Synchronous spiking of cerebellar Purkinje cells during control of movements

Significance Improving the process of learning from error can play a critical role in applied settings such as rehabilitation. Previous work has generally focused on reward as a variable that may modulate learning. However, in response to an erroneous movement, the nervous system often engages a reflex that corrects for that error, thus expending time and energy. Here, we modulated this cost of error and found that increasing the cost increased how much the brain learned from error. Thus, the landscape of the loss associated with the act of correcting for error regulates the rates of sensorimotor learning. Learning from error is often a slow process. In machine learning, the learning rate depends on a loss function that specifies a cost for error. Here, we hypothesized that during motor learning, error carries an implicit cost for the brain because the act of correcting for error consumes time and energy. Thus, if this implicit cost could be increased, it may robustly alter how the brain learns from error. To vary the implicit cost of error, we designed a task that combined saccade adaptation with motion discrimination: movement errors resulted in corrective saccades, but those corrections took time away from acquiring information in the discrimination task. We then modulated error cost using coherence of the discrimination task and found that when error cost was large, pupil diameter increased and the brain learned more from error. However, when error cost was small, the pupil constricted and the brain learned less from the same error. Thus, during sensorimotor adaptation, the act of correcting for error carries an implicit cost for the brain. Modulating this cost affects how much the brain learns from error.

gr ad ua l The common assumption is that this implicit system is driven by sensory prediction errors (SPE), which do not depend on explicit strategy (Eq. 2). With prolonged exposure to the rotation, this SPE learning creates an implicit steady-state that relies on the rotation alone and a learning gain (a scale factor between 0 and 1, which depends on and ). Because this steadystate is unaltered by explicit learning, we will refer to it as the independence equation (Eq. 3). Another salient error in these tasks is the target error: the discrepancy between the cursor and the target. Target errors depend on both implicit and explicit learning (Eq. 4). If both implicit and explicit systems are driven by a common target error, they will compete. That is, increases in explicit strategy will reduce target errors, siphoning away the driving force for implicit learning. With prolonged training these target errors yield the steady-state competition equation (Eq. 5). This equation predicts that implicit learning is increased by the rotation, but decreased by explicit strategy.

Adaptation as a competition between two distinct sensorimotor learning systems

During foraging, animals explore a site and harvest reward, and then abandon that site and travel to the next opportunity. One aspect of this behavior involves decision-making, while the other involves movement control. We recently proposed that control of decision-making and movements may be linked via a desire to maximize a single normative utility: the sum of all rewards acquired, minus all efforts expended, divided by time. If this is the case, then the history of rewards, and not just its immediate availability, should dictate how long one decides to stay and harvest reward, and how fast one travels to the next opportunity. We tested this theory in a series of experiments in which humans used their hand to harvest tokens at a reward patch, and then used their arm to reach toward a subsequent opportunity. Experiencing a history of poor rewards not only led people to forage longer, but they also reached slower toward the next reward site. Thus, reward history had a consistent effect on both the decision-making process regarding when to abandon a reward site, and the motor control process regarding how fast to move to the next opportunity.

As you read this text, your eyes make saccades that guide your fovea from one word to the next. Accuracy of these movements require the brain to monitor and learn from visual errors. A current model suggests that learning is supported by two different adaptive processes, one fast (high error sensitivity, low retention), and the other slow (low error sensitivity, high retention). Here, we searched for signatures of these hypothesized processes and found that following experience of a visual error, there was an adaptive change in the motor commands of the subsequent saccade. Surprisingly, this adaptation was not uniformly expressed throughout the movement. Rather, after experience of a single error, the adaptive response in the subsequent trial was limited to the deceleration period. After repeated exposure to the same error, the acceleration period commands also adapted, and exhibited resistance to forgetting during set-breaks. In contrast, the deceleration period commands adapted more rapidly, but suffered from poor retention during these same breaks. State-space models suggested that acceleration and deceleration periods were supported by a shared adaptive state which re-aimed the saccade, as well as two separate processes which resembled a two-state model: one that learned slowly and contributed primarily via acceleration period commands, and another that learned rapidly but contributed primarily via deceleration period commands.

Sensorimotor adaptation benefits from learning in two parallel systems: one that has access to explicit knowledge, and another that relies on implicit, unconscious correction. However, it is unclear how these systems interact: does enhancing one system’s contributions, for example through instruction, impair the other, or do they learn independently? Here we illustrate that certain contexts can lead to competition between implicit and explicit learning. In some cases, each system is responsive to a task-related visual error. This shared error appears to create competition between these systems, such that when the explicit system increases its response, errors are siphoned away from the implicit system, thus reducing its learning. This model suggests that explicit strategy can mask changes in implicit error sensitivity related to savings and interference. Other contexts suggest that the implicit system can respond to multiple error sources. When these error sources conflict, a second type of competition occurs. Thus, the data show that during sensorimotor adaptation, behavior is shaped by competition between parallel learning systems.

In numerous paradigms, from fear conditioning to motor adaptation, memory exhibits a remarkable property: acquisition of a novel behavior followed by its extinction results in spontaneous recovery of the original behavior. A current model suggests that spontaneous recovery occurs because learning is supported by two different adaptive processes: one fast (high error sensitivity, low retention), and the other slow (low error sensitivity, high retention). Here, we searched for signatures of these hypothesized processes in the commands that guided single movements. We examined human saccadic eye movements and observed that following experience of a visual error, there was an adaptive change in the motor commands of the subsequent saccade, partially correcting for the error. However, the error correcting commands were expressed only during the deceleration period. If the errors persisted, the acceleration period commands also changed. Adaptation of acceleration period commands exhibited poor sensitivity to error, but the learning was resistant to forgetting. In contrast, the deceleration period commands adapted with high sensitivity to error, and the learning suffered from poor retention. Thus, within a single saccade, a fast-like process influenced the deceleration period commands, whereas a slow-like process influenced the acceleration period commands. Following extinction training, with passage of time motor memory exhibited spontaneous recovery, as evidenced by return of saccade endpoints toward their initial adapted state. The temporal dynamics of spontaneous recovery suggested that a single saccade is controlled by two different adaptive controllers, one active during acceleration, and the other during deceleration. Significance statement A feature of memory in many paradigms is the phenomenon of spontaneous recovery: learning followed by extinction inevitably leads to reversion toward the originally learned behavior. A theoretical model posits that spontaneous recovery is a feature of memory systems that learn with two independent learning processes, one fast, and the other slow. However, there have been no direct measures of these putative processes. Here, we found potential signatures of the two independent adaptive processes during control of a single saccade. The results suggest that distinct adaptive controllers contribute to the acceleration and deceleration phases of a saccade, and that each controller is supported by a fast and a slow learning process.

Spontaneous recovery and the multiple timescales of human motor memory

The cerebellum resembles a feedforward, three-layer network of neurons in which the "hidden layer" consists of Purkinje cells (P-cells), and the output layer consists of deep cerebellar nucleus (DCN) neurons. In this analogy, the output of each DCN neuron is a prediction that is compared to the actual observation, resulting in an error signal that originates in the inferior olive. Efficient learning requires that the error signal reach the DCN neurons, as well as the P-cells that project onto them. However, this basic rule of learning is violated in the cerebellum: the olivary projections to the DCN are weak, particularly in adulthood. Instead, an extraordinarily strong signal is sent from the olive to the P-cells, producing complex spikes. Curiously, P-cells are grouped into small populations that converge onto single DCN neurons. Why are the P-cells organized in this way, and what is the membership criterion of each population? Here, I apply elementary mathematics from machine learning and consider the fact that P-cells that form a population exhibit a special property: they can synchronize their complex spikes, which in turn suppress activity of DCN neuron they project to. Thus, complex spikes can not only act as a teaching signal for a P-cell, but through complex spike synchrony a P-cell population may act as a surrogate teacher for the DCN neuron that produced the erroneous output. It appears that grouping of P-cells into small populations that share a preference for error satisfies a critical requirement of efficient learning: providing error information to the output layer neuron (DCN) that was responsible for the error, as well as the hidden layer neurons (P-cells) that contributed to it. This population coding may account for several remarkable features of behavior during learning, including multiple timescales, protection from erasure, and spontaneous recovery of memory.

Population coding in the cerebellum: a machine learning perspective.

Every movement ends in a period of stillness. Current models assume that commands that hold the limb at a target location do not depend on the commands that moved the limb to that location. Here, we report a surprising relationship between movement and posture in primates: on a within-trial basis, the commands that hold the arm and finger at a target location depend on the mathematical integration of the commands that moved the limb to that location. Following damage to the corticospinal tract, both the move and hold period commands become more variable. However, the hold period commands retain their dependence on the integral of the move period commands. Thus, our data suggest that the postural controller possesses a feedforward module that uses move commands to calculate a component of hold commands. This computation may arise within an unknown subcortical system that integrates cortical commands to stabilize limb posture.

Postural control of arm and fingers through integration of movement commands

Decisions are made based on the subjective value that the brain assigns to options. However, subjective value is a mathematical construct that cannot be measured directly, but rather inferred from choices. Recent results have demonstrated that reaction time, amplitude, and velocity of movements are modulated by reward, raising the possibility that there is a link between how the brain evaluates an option, and how it controls movements toward that option. Here, we asked people to choose among risky options represented by abstract stimuli, some associated with gain (points in a game), and others with loss. From their choices we estimated the subjective value that they assigned to each stimulus. In probe trials, a single stimulus appeared at center, instructing subjects to make a saccade to a peripheral target. We found that the reaction time, peak velocity, and amplitude of the peripherally directed saccade varied roughly linearly with the subjective value that the participant had assigned to the central stimulus: reaction time was shorter, velocity was higher, and amplitude was larger for stimuli that the participant valued more. Naturally, participants differed in how much they valued a given stimulus. Remarkably, those who valued a stimulus more, as evidenced by their choices in decision trials, tended to move with shorter reaction time and greater velocity in response to that stimulus in probe trials. Overall, the reaction time of the saccade in response to a stimulus partly predicted the subjective value that the brain assigned to that stimulus.

Saccade vigor and the subjective economic value of visual stimuli.

Author response: Postural control of arm and fingers through integration of movement commands

The cerebellum resembles a feedforward, three-layer network of neurons in which the “hidden layer” consists of Purkinje cells (P-cells), and the output layer consists of deep cerebellar nucleus (DCN) neurons. However, unlike an artificial network, P-cells are grouped into small populations that converge onto single DCN neurons. Why are the P-cells organized in this way, and what is the membership criterion of each population? To consider these questions, in this review I apply elementary mathematics from machine learning and assume that the output of each DCN neuron is a prediction that is compared to the actual observation, resulting in an error signal that originates in the inferior olive. This signal is sent to P-cells via climbing fibers that produce complex spikes. The same error signal from the olive must also guide learning in the DCN neurons, yet the olivary projections to the DCN are weak, particularly in adulthood. However, P-cells that form a population exhibit a special property: they can synchronize their complex spikes, which in turn suppresses activity of the DCN neuron that produced the erroneous output. Viewed in the framework of machine learning, it appears that the olive organizes the P-cells into populations so that through complex spike synchrony each population can act as a surrogate teacher for the DCN neuron it projects to. This error-dependent grouping of P-cells into populations gives rise to a number of remarkable features of behavior, including multiple timescales of learning, protection from erasure, and spontaneous recovery of memory.

Population coding in the cerebellum and its implications for learning from error

The decision regarding which arm to use to perform a task reflects a complex process that can be influenced by many factors, including effort requirements of acquiring the goal. In this study, we considered a virtual reality environment in which people reached to a visual target in 3D space. To vary the cost of reaching, we altered the visual feedback associated with motion of one arm but not the other. This altered the extent of motion that was required to reach, thus changing the effort required to acquire the goal. We then measured how that change in effort affected the decision regarding which arm to use, as well as the preparation time for the movement that ensued. As expected, with increased visual amplification of one arm (reduced effort to reach the goal), subjects increased the probability of choosing that arm. Surprisingly, however, the reaction times to start these movements were also reduced: despite constancy of the visual representation of the target, reaction times were shorter for movements with less effort. Thus, as the perceived effort associated with accomplishing a goal was reduced for a given limb, the decision-making process was biased toward use of that limb. Furthermore, movements that were perceived to be less effortful were performed with shorter reaction times. These results suggest that visual amplification can alter the perceived effort associated with using a limb, thus increasing frequency of use. This may provide a useful method to increase use of a limb during rehabilitation.

Perceived effort affects choice of limb and reaction time of movements.

Abstract Why do we run toward people we love, but only walk toward others? Why do people in New York seem to walk faster than other cities? Why do our eyes linger longer on things we value more? There is a link between how the brain assigns value to things, and how it controls our movements. This link is an ancient one, developed through shared neural circuits that on one hand teach us how to value things, and on the other hand control the vigor with which we move. As a result, when there is damage to systems that signal reward, like dopamine and serotonin, that damage not only affects our mood and patterns of decision-making, but how we move. In this book, we first ask why, in principle, evolution should have developed a shared system of control between valuation and vigor. We then focus on the neural basis of vigor, synthesizing results from experiments that have measured activity in various brain structures and neuromodulators, during tasks in which animals decide how patiently they should wait for reward, and how vigorously they should move to acquire it. Thus, the way we move unmasks one of our well-guarded secrets: how much we value the thing we are moving toward.

The common marmoset (Callithrix Jacchus) is a promising new model for study of neurophysiological basis of behavior in primates. Like other primates, it relies on saccadic eye movements to monitor and explore its environment. Previous reports have demonstrated some success in training marmosets to produce goal-directed actions in the laboratory. However, the number of trials per session has been relatively small, thus limiting the utility of marmosets as a model for behavioral and neurophysiological studies. Here, we report the results of a series of new behavioral training and neurophysiological protocols aimed at increasing the number of trials per session while recording from the cerebellum. To improve the training efficacy, we designed a precisely calibrated food regulation regime that motivated the subjects to perform saccade tasks, resulting in about a thousand reward-driven trials on a daily basis. We then developed a multi-channel recording system that used imaging to target a desired region of the cerebellum, allowing for simultaneous isolation of multiple Purkinje cells in the vermis. In this report, we describe (1) the design and surgical implantation of a CT guided, subject specific head-post, (2) the design of a CT and MRI guided alignment tool for trajectory guidance of electrodes mounted on an absolute encoder microdrive, (3) development of a protocol for behavioral training of subjects, and (4) simultaneous recordings from pairs of Purkinje cells during a saccade task.

Behavioral training of marmosets and electrophysiological recording from the cerebellum.

The common marmoset (Callithrix Jacchus) is a promising new model for study of neurophysiological basis of behavior in primates. Like other primates, it relies on saccadic eye movements to monitor and explore its environment. Previous reports have demonstrated some success in training marmosets to produce goal-directed actions in the laboratory. However, the number of trials per session has been relatively small, thus limiting the utility of marmosets as a model for behavioral and neurophysiological studies. Here, we report the results of a series of new behavioral training and neurophysiological protocols aimed at increasing the number of trials per session while recording from the cerebellum. To improve the training efficacy, we designed a precisely calibrated food regulation regime that motivated the subjects to perform saccade tasks, resulting in about a thousand reward-driven trials on a daily basis. We then developed a multi-channel recording system that used imaging to target a desired region of the cerebellum, allowing for simultaneous isolation of multiple Purkinje cells in the vermis. In this report, we describe (1) the design and surgical implantation of a CT guided, subject specific head-post, (2) the design of a CT and MRI guided alignment tool for trajectory guidance of electrodes mounted on an absolute encoder microdrive, (3) development of a protocol for behavioral training of subjects, and (4) simultaneous recordings from pairs of Purkinje cells during a saccade task. New and Noteworthy Marmosets present the opportunity to investigate genetically based neurological disease in primates; in particular, diseases that affect social behaviors, vocal communication, and eye movements. All of these behaviors depend on the integrity of the cerebellum. Here, we present training methods that better motivate the subjects, allowing for improved performance, and also present electrophysiological techniques that precisely target the subject’s cerebellum, allowing for simultaneous isolation of multiple Purkinje cells. In our parks, are there any trees more elegant and luxurious than the Purkinje cell from the cerebellum? Santiago Ramon y Cajal

Behavioral training of marmosets and electrophysiological recording from the cerebellum

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature

Faculty Opinions recommendation of Complex spike synchrony dependent modulation of rat deep cerebellar nuclear activity.

Adan Aguirre Zaitsev Aleksey Kaoru Amano Shaowen Bao Luis Basile Ihtisham Bukhari Ashley Bush Jose-Manuel Cancela Carlos Cepeda Allen Chan Marshall Dalton Attilio Della Torre Jun Ding Matteo Feurra Wim Fias Douglas Fields Christopher Frederickson Luca Gallelli Philip Gasquoine Michael Graziano Amanda Hampton Wary Javeria Hasmi Nicholas Hatsopoulos William Honer Yang Li Shane Liddelow Kyle Lillis Thomas Liu Daniel Llano Alexander Maier Pietro Mazzoni Anna Molofsky Nicole Neef Jeanne Nerbonne Daniel O”Connor John Ochoa Juan Pascual Mathieu Piche Samantha Pitt Mikhail Pletnikov Julien Puyal Simon Rinaldi Paul Rosenberg William Ross Makoto Sasaki Philipp Schwartenbeck Menahem Segal Reza Shadmehr Scott Shippy Dandan Sun James Tepper Maarten Titulaer Ugur Ture Raymond Scott Turner Robert Turner Evan Usler Vincent Valton Jaap Van Dieen Huaxi Xu Nadja Zeltner Quanguang Zhang 835165 NROXXX10.1177/1073858419835165The NeuroscientistReviewer List other2019

In many forms of motor adaptation, performance approaches a limit at which point learning stops, despite the fact that errors remain. What causes this adaptation limit? Here we found that while reach adaptation exhibited an asymptotic limit, this limit was not fixed: when the variance of the perturbation decreased, the adaptation limit increased, and performance improved. Moreover, the limit could be altered in real-time by changing perturbation variance. The same was true at low reaction times, indicating that implicit processes influenced the adaptation limit. Using a mathematical model that describes adaptation as a balance between learning and forgetting, we found that participants altered their adaptation limit by changing their sensitivity to reaching errors. Changes in error sensitivity were linked to the consistency of past errors. These observations suggest that during adaptation, time-varying error sensitivities compete with constant forgetting, setting the boundary conditions that produce an apparent limit in total adaptation.

Anterograde interference refers to the negative impact of prior learning on the propensity for future learning. Previous work has shown that subsequent adaptation to two perturbations of opposing sign, A and B, impairs performance in B. Here, we aimed to unveil the mechanism at the basis of anterograde interference by tracking its impact as a function of time through a 24h period. We found that the memory of A biased performance in B for all time intervals. Conversely, learning from error was hindered up to 1h following acquisition of A, with release from interference occurring at 6h. These findings suggest that poor performance induced by prior learning is driven by two distinct mechanisms: a long-lasting bias that acts as a prior and hinders the initial level of performance, and a short-lasting learning impairment that originates from a reduction in error-sensitivity. Our work provides insight into the timeline of memory stabilization in visuomotor adaptation.

The origins of anterograde interference in visuomotor adaptation

Every movement ends in a period of stillness. In current models of reaching, the commands that hold the arm still at a target, depend on the spatial location of the target, but not on the reach commands that moved the arm to the target. Contrary to this assumption, in a series of tasks in humans and non-human primates, we find that the commands that hold the arm still have a consistent mathematical relationship to the reach commands that moved the arm. With damage to the corticospinal tract, reach commands become impaired as expected, but remarkably, the mathematical dependence of hold commands upon the now imperfect reach commands remains intact. Therefore, we find that the brain uses a design principle in which its holding controller is not driven by the spatial location of the target. Rather, holding is obtained via mathematical integration of moving, potentially through a subcortical structure.

The capacity to move is essential for independence and declines with age. Limitations in mobility impact ~35% of adults over 70 and the majority of adults over 85. These limitations are highly associated with disability, dependency, and survival. More than 25-years ago the term “sarcopenia” was coined to highlight the age-related loss of muscle mass and strength with the assumption being that sarcopenia led to limitations in mobility. However, contrary to expectations, recent findings clearly indicate these variables only modestly explain limitations in mobility. One likely reason the current sarcopenia variables of muscle mass and strength do not discriminate, or predict, mobility limitations well is because they are heavily influenced by musculoskeletal mechanisms and do not incorporate measures reflective of the central neural control of mobility. Unfortunately, the precise central neural changes associated with aging that lead to decreased mobility are poorly understood. This knowledge gap has hampered the development of effective interventions for mobility limitations and the subsequent reduction of major functional disability for older adults. Here, we discuss the potential role of the motor control circuit of the dorsal basal ganglia as well as dopaminergic function in age-related reductions in mobility.

The Aging Brain & the Dorsal Basal Ganglia: Implications for Age-Related Limitations of Mobility

Decisions are made based on the subjective value that the brain assigns to options. However, subjective value is a mathematical construct that cannot be measured directly, but only inferred from choices. Is there another aspect of behavior that directly reflects subjective valuation of an option? Recent results have demonstrated that movement vigor is modulated by reward, raising the possibility that there is a link between how the brain evaluates an option, and how it controls movements toward that option. Alternatively, vigor may reflect salience and not value of the stimulus, growing larger for both stimuli that promise gain as well as stimuli that foretell loss. To dissociate between these possibilities, we asked people to choose among risky options represented by abstract stimuli, some associated with gain, others with loss. From their choices we estimated the subjective value that they assigned to each stimulus. In probe trials, they viewed only one stimulus at a time, and we measured their saccade vigor. We found that vigor was lowest for stimuli that promised loss, highest for stimuli that promised gain. This implied that vigor corresponded to value not salience. Naturally, a given stimulus was valued more by some participants. Remarkably, those who valued a given stimulus more tended to move with greater vigor in response to that stimulus. Thus, subjective value of a stimulus monotonically modulated the vigor with which the eyes moved to acquire a stimulus, suggesting that subjective valuation may be inferred from movement vigor. Significance statement Does vigor of movements in response to an option reflect the subjective value that the brain has assigned to that option? If this were the case, vigor may provide an objective assay of subjective value, obviating the need to infer this variable from measurements of choice. Here, we show that saccade vigor varies monotonically with subjective value: smallest for stimuli that predict economic loss, and highest for stimuli that predict economic gain. Notably, between-subject differences in valuation may be gleaned from the between-subject differences in their patterns of vigor. “A true theory of economy can only be attained by going back to the great springs of human action --- the feelings of pleasure and pain.” William Jevons (1866)

Saccade vigor as an implicit measure of subjective economic value

An implicit memory of errors limits human sensorimotor adaptation

Faculty Opinions recommendation of Cortico-cerebellar network involved in saccade adaptation.

Movement vigor, defined as the reciprocal of the latency from availability of reward to its acquisition, changes with reward magnitude: movements exhibit shorter reaction time and increased velocity when they are directed toward more rewarding stimuli. This invigoration may be due to release of dopamine before movement onset, which has been shown to be modulated by events that signal reward prediction error (RPE). Here, we generated an RPE event in the milliseconds before movement onset and tested whether there was a relationship between RPE and vigor. Human subjects (both sexes) made saccades toward an image. During execution of the primary saccade, we probabilistically changed the position and content of that image, encouraging a secondary saccade. On some trials, the content of the secondary image was more valuable than the first image, resulting in a positive RPE (+RPE) event that preceded the secondary saccade. On other trials, this content was less valuable (−RPE event). We found that reaction time of the secondary saccade was affected in an orderly fashion by the magnitude and direction of the preceding RPE event: the most vigorous saccades followed the largest +RPE, whereas the least vigorous saccades followed the largest −RPE. Presence of the secondary saccade indicated that the primary saccade had experienced a movement error, inducing trial-to-trial adaptation. However, this learning from movement error was not modulated by the RPE event. The data suggest that RPE events, which are thought to transiently alter the release of dopamine, modulate the vigor of the ensuing movement. SIGNIFICANCE STATEMENT Does dopamine release in response to a stimulus serve to invigorate the ensuing movement? To test this hypothesis, we relied on the fact that reward prediction error (RPE) is a strong modulator of dopamine. Our innovation was a task in which an RPE event occurred precisely before onset of a stimulus-driven movement. We probabilistically produced a combination of large or small, negative or positive RPE events and observed that saccade vigor carried a robust signature of the preceding RPE event: high vigor saccades followed +RPE events, whereas low vigor saccades followed −RPE events. This suggests that in humans, vigor is partly controlled through release of dopamine in the moments before onset of a movement.

A common aspect of individuality is our subjective preferences in evaluation of reward and effort. The neural circuits that evaluate these commodities influence circuits that control our movements, raising the possibility that vigor differences between individuals may also be a trait of individuality, reflecting a willingness to expend effort. In contrast, classic theories in motor control suggest that vigor differences reflect a speed-accuracy trade-off, predicting that those who move fast are sacrificing accuracy for speed. Here we tested these contrasting hypotheses. We measured motion of the eyes, head, and arm in healthy humans during various elementary movements (saccades, head-free gaze shifts, and reaching). For each person we characterized their vigor, i.e., the speed with which they moved a body part (peak velocity) with respect to the population mean. Some moved with low vigor, while others moved with high vigor. Those with high vigor tended to react sooner to a visual stimulus, moving both their eyes and arm with a shorter reaction time. Arm and head vigor were tightly linked: individuals who moved their head with high vigor also moved their arm with high vigor. However, eye vigor did not correspond strongly with arm or head vigor. In all modalities, vigor had no impact on end-point accuracy, demonstrating that differences in vigor were not due to a speed-accuracy trade-off. Our results suggest that movement vigor may be a trait of individuality, not reflecting a willingness to accept inaccuracy but demonstrating a propensity to expend effort. NEW & NOTEWORTHY A common aspect of individuality is how we evaluate economic variables like reward and effort. This valuation affects not only decision making but also motor control, raising the possibility that vigor may be distinct between individuals but conserved across movements within an individual. Here we report conservation of vigor across elementary skeletal movements, but not eye movements, raising the possibility that the individuality of our movements may be driven by a common neural mechanism of effort evaluation across modalities of skeletal motor control.

Faculty Opinions recommendation of Perceptual decisions are biased by the cost to act.

Encoding of error and learning to correct that error by the Purkinje cells of the cerebellum

A recent policy change at Journal of Neuroscience (JN) has significantly increased editorial “desk rejections”, reducing the number of papers that are considered for publication. Survey results from 130 scientists suggested that the new policy may have had a particularly large impact on studies that focused on human behavioral techniques. To quantify the effects of the new policy, we gathered data on all papers ever published in JN (~35,000), as well as all papers that had cited the JN papers (~2.7 million papers). We found that the recent change in editorial policy had disproportionately affected rejection rates of human behavioral papers: since 2015, the number of human behavioral papers as a proportion of all papers published in JN has seen a 30% decline. While there has been a long-term declining trend in the journal’s impact factor, we found that this declining impact factor was shared by both human behavioral papers as well as other papers in the journal. This suggested that whatever may have been the source of the declining impact factor at JN, this source was affecting the various areas of research equally. That is, it was unlikely that papers in any one field were responsible for the declining impact factor number at JN. Indeed, when impact was measured over the long-term, we found that the average human behavioral paper at JN consistently outperformed other papers, generating a significantly higher number of citations per year at 5 and 10 years post publication.

Making a movement may be thought of as an economic decision in which one spends effort to acquire reward. Time discounts reward, which predicts that the magnitude of reward should affect movement vigor: we should move faster, spending greater effort, when there is greater reward at stake. Indeed, saccade peak velocities are greater and reaction-times shorter when a target is paired with reward. In this study, we focused on human reaching and asked whether movement kinematics were affected by expectation of reward. Participants made out-and-back reaching movements to one of four quadrants of a 14-cm circle. During various periods of the experiment only one of the four quadrants was paired with reward, and the transition from reward to nonreward status of a quadrant occurred randomly. Our experiment design minimized dependence of reward on accuracy, granting the subjects wide latitude in self-selecting their movement speed, amplitude, and variability. When a quadrant was paired with reward, reaching movements had a shorter reaction time, higher peak velocity, and greater amplitude. Despite this greater vigor, movements toward the rewarded quadrant suffered from less variability: both reaction times and reach kinematics were less variable when there was expectation of reward. Importantly, the effect of reward on vigor was specific to the movement component that preceded the time of reward (outward reach), not the movement component that followed it (return reach). Our results suggest that expectation of reward not only increases vigor of human reaching but also decreases its variability. NEW & NOTEWORTHY Movements may be thought of as an economic transaction where the vigor of the movement represents the effort that the brain is willing to expend to acquire a rewarding state. We show that in reaching, reward discounts the cost of effort, producing movements with shorter reaction time, higher velocity, greater amplitude, and reduced reaction-time variability. These results complement earlier observations in saccades, suggesting a common principle of economics across modalities of motor control.

Vigor of reaching movements: reward discounts the cost of effort.

Decision letter: Cerebellar implementation of movement sequences through feedback

Faculty Opinions recommendation of Saccade metrics reflect decision-making dynamics during urgent choices.

Rabbits can learn the biological analogue of a simple recursive function by relying only on the neurons of the cerebellum.

Faculty Opinions recommendation of Frontal eye field inactivation diminishes superior colliculus activity, but delayed saccadic accumulation governs reaction time increases.

NEUROSCIENCE, PSYCHOLOGICAL AND COGNITIVE SCIENCES Correction for “Control of movement vigor and decision making during foraging,” by Tehrim Yoon, Robert B. Geary, Alaa A. Ahmed, and Reza Shadmehr, which was first published October 15, 2018; 10.1073/pnas.1812979115 (Proc Natl Acad Sci USA 115:E10476–E10485). The authors note that, due to a printer’s error, Fig. 2 appeared incorrectly. The corrected figure and its legend appear below.

Correction for Yoon et al., Control of movement vigor and decision making during foraging

Faculty Opinions recommendation of A Trial-by-Trial Window into Sensorimotor Transformations in the Human Motor Periphery.

Experience of a prediction error recruits multiple motor learning processes, some that learn strongly from error but have weak retention and some that learn weakly from error but exhibit strong retention. These processes are not generally observable but are inferred from their collective influence on behavior. Is there a robust way to uncover the hidden processes? A standard approach is to consider a state space model where the hidden states change following experience of error and then fit the model to the measured data by minimizing the squared error between measurement and model prediction. We found that this least-squares algorithm (LMSE) often yielded unrealistic predictions about the hidden states, possibly because of its neglect of the stochastic nature of error-based learning. We found that behavioral data during adaptation was better explained by a system in which both error-based learning and movement production were stochastic processes. To uncover the hidden states of learning, we developed a generalized expectation maximization (EM) algorithm. In simulation, we found that although LMSE tracked the measured data marginally better than EM, EM was far more accurate in unmasking the time courses and properties of the hidden states of learning. In a power analysis designed to measure the effect of an intervention on sensorimotor learning, EM significantly reduced the number of subjects that were required for effective hypothesis testing. In summary, we developed a new approach for analysis of data in sensorimotor experiments. The new algorithm improved the ability to uncover the multiple processes that contribute to learning from error. NEW & NOTEWORTHY Motor learning is supported by multiple adaptive processes, each with distinct error sensitivity and forgetting rates. We developed a generalized expectation maximization algorithm that uncovers these hidden processes in the context of modern sensorimotor learning experiments that include error-clamp trials and set breaks. The resulting toolbox may improve the ability to identify the properties of these hidden processes and reduce the number of subjects needed to test the effectiveness of interventions on sensorimotor learning.

Estimating properties of the fast and slow adaptive processes during sensorimotor adaptation.

Significance How long should one stay and accumulate reward, and then, how fast should one travel to the next reward site? Marginal value theorem describes the decision-making process: the brain compares the immediate rate of harvest with its global history of capture, deciding to leave when the immediate rate falls below the average. Here, we extended the theory, showing that the same principle can be used to control speed of movements: the brain should compare the immediate rate of energy expenditure during movement with the global capture rate, planning to arrive at the destination when the two become equal. Experimental results confirmed many of the predictions, suggesting that a shared principle may underlie decision making and control of movement vigor. During foraging, animals decide how long to stay at a patch and harvest reward, and then, they move with certain vigor to another location. How does the brain decide when to leave, and how does it determine the speed of the ensuing movement? Here, we considered the possibility that both the decision-making and the motor control problems aimed to maximize a single normative utility: the sum of all rewards acquired minus all efforts expended divided by total time. This optimization could be achieved if the brain compared a local measure of utility with its history. To test the theory, we examined behavior of people as they gazed at images: they chose how long to look at the image (harvesting information) and then moved their eyes to another image, controlling saccade speed. We varied reward via image content and effort via image eccentricity, and then, we measured how these changes affected decision making (gaze duration) and motor control (saccade speed). After a history of low rewards, people increased gaze duration and decreased saccade speed. In anticipation of future effort, they lowered saccade speed and increased gaze duration. After a history of high effort, they elevated their saccade speed and increased gaze duration. Therefore, the theory presented a principled way with which the brain may control two aspects of behavior: movement speed and harvest duration. Our experiments confirmed many (but not all) of the predictions, suggesting that harvest duration and movement speed, fundamental aspects of behavior during foraging, may be governed by a shared principle of control.

To interact with and manipulate the world around us, our bodies must be constantly in motion. Even now, as you read the words on this page, your nervous system is coordinating a series of rapid eye movements (saccades) that allow your eyes to scan the text in front of you. These saccades are an example of a goal-directed movement; your brain chooses an interesting location in space (i.e. the goal) and executes a movement to bring that spatial location into visual focus. Perhaps you might have a cup of coffee nearby. Periodically, your thirst (or your desire for a dose of caffeine) might drive you to interrupt your reading, and reach for your cup. This process of reaching, like moving your eyes, requires you to select a target in the world around you, and move your arm towards that target. Though this process of reaching may require little conscious effort on your part, moving towards an object in the space around you requires many different neural calculations.

When we hold an object in our hand, the mass of the object alters the physics of our arm, changing the relationship between motor commands that our brain sends to our arm muscles and the resulting motion of our hand. If the object is unfamiliar to us, our first movement will exhibit an error, producing a trajectory that is different from the one we had intended. This experience of error initiates learning in our brain, making it so that on the very next attempt our motor commands partially compensate for the unfamiliar physics, resulting in smaller errors. With further practice, the compensation becomes more complete, and our brain forms a model that predicts the physics of the object. This model is a motor memory that frees us from having to relearn the physics the next time that we encounter the object. The mechanism by which the brain transforms sensory prediction errors into corrective motor commands is the basis for how we learn the physics of objects with which we interact. The cerebellum and the motor cortex appear to be critical for our ability to learn physics, allowing us to use tools that extend our capabilities, making us masters of our environment.

In generating a point-to-point movement, the brain does more than produce the transient commands needed to move the body part; it also produces the sustained commands that are needed to hold the body part at its destination. In the oculomotor system, these functions are mapped onto two distinct circuits: a premotor circuit that specializes in generating the transient activity that displaces the eyes and a "neural integrator" that transforms that transient input into sustained activity that holds the eyes. Different parts of the cerebellum adaptively control the motor commands during these two phases: the oculomotor vermis participates in fine tuning the transient neural signals that move the eyes, monitoring the activity of the premotor circuit via efference copy, whereas the flocculus participates in controlling the sustained neural signals that hold the eyes, monitoring the activity of the neural integrator. Here, I review the oculomotor literature and then ask whether this separation of control between moving and holding is a design principle that may be shared with other modalities of movement. To answer this question, I consider neurophysiological and psychophysical data in various species during control of head movements, arm movements, and locomotion, focusing on the brain stem, motor cortex, and hippocampus, respectively. The review of the data raises the possibility that across modalities of motor control, circuits that are responsible for producing commands that change the sensory state of a body part are distinct from those that produce commands that maintain that sensory state.

Distinct neural circuits for control of movement vs. holding still.

The Editors give special thanks to an elite group of Outstanding Reviewers who have provided an extraordinary number of thoughtful reviews for JNeurosci during the past year.

The integrity of the cerebellum is critical for accurate eye movements. Disruption of neurons in either the cerebellar oculomotor vermis or its projections to the most medial output nucleus of the cerebellum, the caudal fastigial nucleus (cFN), results in significant saccadic dysmetria (Ritchie, 1976; Ohtsuka et al., 1994; Goffart et al., 2004; Buzunov et al., 2013). The relationship between cFN neuron firing rates and saccade kinematic parameters is quite variable across neurons (Hepp et al., 1982; Fuchs et al., 1993), suggesting that a direct encoding of saccade parameters may not occur in the responses of individual neurons of cFN. However, previous studies have generally agreed that saccaderelated cFN neurons tend to fire earlier for horizontal saccades made in the contraversive vs. ipsiversive directions (Ohtsuka & Noda, 1991; Fuchs et al., 1993; Helmchen & B€uttner, 1995; Kleine et al., 2003). Taken together, these results have led to the hypothesis that saccade properties are related to the timing of responses in cFN rather than response magnitude. Under this hypothesis, neurons should fire early for contraversive saccades, helping to accelerate the eye, whereas the delayed firing of ipsiversive neurons serves to decelerate and stop the eye at saccade termination. However, new data reported by Sun et al. (2016) call this view into question. Sun and colleagues recorded single-unit cFN neuron activity while primates made saccades of various magnitudes. These saccades included very small saccades, made during periods of fixation (microsaccades), as well as larger magnitude goal-directed saccades to peripheral targets. Their results suggest that cFN neuron responses exist on a continuum between these two types of saccades. That is, microand macrosaccades likely share common neural mechanisms of generation. Therefore, the responses of cFN neurons can be interpreted similarly across a large range of saccadic amplitudes (e.g. 0.5–15°). The duration of a typical saccade is on the order of 60 ms. Taking advantage of the temporally short nature of saccades, Sun et al. combined the responses of individual cFN neurons recorded across different sessions to yield an estimate of the firing of a population of simultaneously recorded neurons. This population response represents an estimate of the combined response of all saccade-related cFN neurons during a saccade. Strikingly, the timing of the population response did not occur earlier for contraversive compared to ipsiversive saccades, as would be anticipated by previous single-unit studies. Rather, both directions of saccades resulted in a population response that preceded the start of the saccade, and began at approximately the same time. How can these two deep nuclei be involved in saccade acceleration and deceleration when the timing of the responses to contraversive and ipsiversive saccades are not different? We recently suggested that populations of Purkinje cells (P-cells) in the oculomotor vermis (OMV) of the cerebellum encode the velocity and direction of an impending eye movement as a gain-field (Herzfeld et al., 2015). In this encoding, the population response of P-cells in OMV increases linearly with increasing eye velocity, whereas the direction is encoded as a cosine in which the population response is smallest for the direction of error that produces the highest probability of complex spikes (called CS-on), and highest for the direction of error that produces the lowest probability of complex spikes (CS-off). Given that inferior olive neurons project to the contralateral P-cells, P-cell simple spike encoding has the highest gain for contraversive saccades, and lowest gain for ipsiversive saccades. These P-cells inhibit neurons in cFN. Data from Sun et al. are consistent with this P-cell encoding, demonstrating that the cFN population response is larger for ipsiversive saccades than contraversive, a property which is not reliably found in the responses of individual cells. Combining this new experimental evidence with previous studies, it seems likely that the encoding of saccade kinematic parameters in cFN is not temporal in nature but rather results from differences in the magnitude of the overall cFN response. How can we interpret the results of previous studies in this framework? Goffart et al. (2004) have previously suggested that cFN inactivation and lesion studies could be understood by interpreting experimental results in the context of the bilaterality of cFN. Under this encoding scheme, cFN activity does not strictly encode acceleration and deceleration, but rather the two nuclei act as antagonists, in which one cFN can be thought of as ‘pushing’ the eye while the other cFN ‘pulls.’ In this framework, equal activity in the two nuclei does not result in horizontal movement of the eye – cerebellar-dependent movement results only when the magnitude of the responses in the two nuclei are different. In this way, the output of the cerebellum is defined by the difference in the activities of the two cFNs, providing a ‘correction’ on top of the current movement (Fuchs et al., 1993). The population-level analysis presented by Sun et al. further clarifies this hypothesis. During a saccade, both sides of OMV are simultaneously active with a higher gain on the contralateral side (Herzfeld et al., 2015). This, in turn, results in the opposite scenario for the fastigial nuclei: higher firing rates for the ipsilateral vs. contralateral sides, without any differences in the timing of the response. Projections from cFN synapse throughout the brainstem saccadic circuitry, particularly on inhibitory and excitatory burst neurons, eventually acting on the motor

Cerebellar output encodes a corrective saccadic command (Commentary on Sun et al.)

Previous research shows that human eye movements can serve as a valuable source of information about the structural elements of the oculomotor system and they also can open a window to the neural functions and cognitive mechanisms related to visual attention and perception. The research field of eye movement-driven biometrics explores the extraction of individual-specific characteristics from eye movements and their employment for recognition purposes. In this work, we present a study for the incorporation of dynamic saccadic features into a model of eye movement-driven biometrics. We show that when these features are added to our previous biometric framework and tested on a large database of 322 subjects, the biometric accuracy presents a relative improvement in the range of 31.6--33.5% for the verification scenario, and in range of 22.3--53.1% for the identification scenario. More importantly, this improvement is demonstrated for different types of visual stimulus (random dot, text, video), indicating the enhanced robustness offered by the incorporation of saccadic vigor and acceleration cues.

Biometric Recognition via Eye Movements: Saccadic Vigor and Acceleration Cues

When we experience an error during a movement, we update our motor commands to partially correct for this error on the next trial. How does experience of error produce the improvement in the subsequent motor commands? During the course of an erroneous reaching movement, proprioceptive and visual sensory pathways not only sense the error, but also engage feedback mechanisms, resulting in corrective motor responses that continue until the hand arrives at its goal. One possibility is that this feedback response is co-opted by the learning system and used as a template to improve performance on the next attempt. Here we used electromyography (EMG) to compare neural correlates of learning and feedback to test the hypothesis that the feedback response to error acts as a template for learning. We designed a task in which mixtures of error-clamp and force-field perturbation trials were used to deconstruct EMG time courses into error-feedback and learning components. We observed that the error-feedback response was composed of excitation of some muscles, and inhibition of others, producing a complex activation/deactivation pattern during the reach. Despite this complexity, across muscles the learning response was consistently a scaled version of the error-feedback response, but shifted 125 ms earlier in time. Across people, individuals who produced a greater feedback response to error, also learned more from error. This suggests that the feedback response to error serves as a teaching signal for the brain. Individuals who learn faster have a better teacher in their feedback control system. SIGNIFICANCE STATEMENT Our sensory organs transduce errors in behavior. To improve performance, we must generate better motor commands. How does the nervous system transform an error in sensory coordinates into better motor commands in muscle coordinates? Here we show that when an error occurs during a movement, the reflexes transform the sensory representation of error into motor commands. To learn from error, the nervous system scales this feedback response and then shifts it earlier in time, adding it to the previously generated motor commands. This addition serves as an update to the motor commands, constituting the learning signal. Therefore, by providing a coordinate transformation, the feedback system generates a template for learning from error.

The Neural Feedback Response to Error As a Teaching Signal for the Motor Learning System

Dynamics Model By Combined Impedance Control and Inverse Adaptation to Stable and Unstable Dynamics Achieved

Degeneration Cerebellar Dynamics in Huntington's Disease But Not Intact Ability to Learn Internal Models of Arm

In motor tasks, efficiency can be measured via the commands that are produced to accomplish a goal. To maximize efficiency, the nervous system should produce task-relevant motor commands while avoiding behaviors that are task-irrelevant. The current view is that this is achieved through training, i.e., the optimum motor commands are learned by trial and error. However, in contrast to this view, there are numerous examples in which during an experiment, task-irrelevant commands are continuously produced. To address this, we trained human volunteers to reach in a force field. With practice, they learned to produce forces that compensated for the field, generating task-relevant commands that were necessary to achieve success. As expected, training also resulted in generalization, the transfer of learning to other movements. We designed the task so that any forces produced as a result of generalization were unnecessary and therefore task-irrelevant. Importantly, there were no explicit cues to indicate that production of these forces was task-irrelevant. Rather, the only indicator was effort itself. Could this inefficiency of the motor commands be reduced? We found that even with extensive practice, the production of task-irrelevant forces persisted. However, if subjects were given sufficient time away from practice (6 or 24 h but not 3 or 30 min), they spontaneously reduced production of the task-irrelevant forces. Therefore, practice alone was insufficient to allow for increased efficiency of motor output. Time away from practice was a required element for optimization of effort.

Optimizing effort: increased efficiency of motor memory with time away from practice.

Patients With Cerebellar Degeneration Perturbation Is Correlated to Different Brain Areas in Adaptation to Visuomotor Rotation and Force Field

the Learning Event Persistence of Motor Memories Reflects Statistics of

In Parkinson's disease (PD), the human brain is capable of producing motor commands, but appears to require greater than normal subjective effort, particularly for the more-affected side. What is the nature of this subjective effort and can it be altered? We used an isometric task in which patients produced a goal force by engaging both arms, but were free to assign any fraction of that force to each arm. The patients preferred their less-affected arm, but only in some directions. This preference was correlated with lateralization of signal-dependent noise: the direction of force for which the brain was less willing to assign effort to an arm was generally the direction for which that arm exhibited greater noise. Therefore, the direction-dependent noise in each arm acted as an implicit cost that discouraged use of that arm. To check for a causal relationship between noise and motor cost, we used bilateral transcranial direct current stimulation of the motor cortex, placing the cathode on the more-affected side and the anode on the less-affected side. This stimulation not only reduced the noise on the more-affected arm, it also increased the willingness of the patients to assign force to that arm. In a 3 d double-blind study and in a 10 d repeated stimulation study, bilateral stimulation of the two motor cortices with cathode on the more-affected side reduced noise and increased the willingness of the patients to exert effort. This stimulation also improved the clinical motor symptoms of the disease. SIGNIFICANCE STATEMENT In Parkinson's disease, patients are less willing to assign force to their affected arm. Here, we find that this pattern is direction dependent: directions for which the arm is noisier coincide with directions for which the brain is less willing to assign force. We hypothesized that if we could reduce the noise on the affected arm, then we may increase the willingness for the brain to assign force to that arm. We found a way to do this via noninvasive cortical stimulation. In addition to reducing effort costs associated with the affected arm, the cortical stimulation also improved clinical motor symptoms of the disease.

Altering Effort Costs in Parkinson's Disease with Noninvasive Cortical Stimulation

Faculty Opinions recommendation of Dopamine reward prediction error responses reflect marginal utility.

Autism spectrum disorder is a developmental disorder characterized by deficits in social and communication skills and repetitive and stereotyped interests and behaviours. Although not part of the diagnostic criteria, individuals with autism experience a host of motor impairments, potentially due to abnormalities in how they learn motor control throughout development. Here, we used behavioural techniques to quantify motor learning in autism spectrum disorder, and structural brain imaging to investigate the neural basis of that learning in the cerebellum. Twenty children with autism spectrum disorder and 20 typically developing control subjects, aged 8-12, made reaching movements while holding the handle of a robotic manipulandum. In random trials the reach was perturbed, resulting in errors that were sensed through vision and proprioception. The brain learned from these errors and altered the motor commands on the subsequent reach. We measured learning from error as a function of the sensory modality of that error, and found that children with autism spectrum disorder outperformed typically developing children when learning from errors that were sensed through proprioception, but underperformed typically developing children when learning from errors that were sensed through vision. Previous work had shown that this learning depends on the integrity of a region in the anterior cerebellum. Here we found that the anterior cerebellum, extending into lobule VI, and parts of lobule VIII were smaller than normal in children with autism spectrum disorder, with a volume that was predicted by the pattern of learning from visual and proprioceptive errors. We suggest that the abnormal patterns of motor learning in children with autism spectrum disorder, showing an increased sensitivity to proprioceptive error and a decreased sensitivity to visual error, may be associated with abnormalities in the cerebellum.

Behavioural and neural basis of anomalous motor learning in children with autism.

During a Postural Task Mechanical Loads Applied to the Shoulder and Elbow Neural Activity in Primary Motor Cortex Related to

Energy Cost in Arm Movements The Central Nervous System Does Not Minimize

When movements are perturbed in adaptation tasks, humans and other animals show incomplete compensation, tolerating small but sustained residual errors that persist despite repeated trials. State-space models explain this residual asymptotic error as interplay between learning from error and reversion to baseline, a form of forgetting. Previous work using zero-error-clamp trials has shown that reversion to baseline is not obligatory and can be overcome by manipulating feedback. We posited that novel error-clamp trials, in which feedback is constrained but has nonzero error and variance, might serve as a contextual cue for recruitment of other learning mechanisms that would then close the residual error. When error clamps were nonzero and had zero variance, human subjects changed their learning policy, using exploration in response to the residual error, despite their willingness to sustain such an error during the training block. In contrast, when the distribution of feedback in clamp trials was naturalistic, with persistent mean error but also with variance, a state-space model accounted for behavior in clamps, even in the absence of task success. Therefore, when the distribution of errors matched those during training, state-space models captured behavior during both adaptation and error-clamp trials because error-based learning dominated; when the distribution of feedback was altered, other forms of learning were triggered that did not follow the state-space model dynamics exhibited during training. The residual error during adaptation appears attributable to an error-dependent learning process that has the property of reversion toward baseline and that can suppress other forms of learning.

Persistent Residual Errors in Motor Adaptation Tasks: Reversion to Baseline and Exploratory Escape

The Editors give special thanks to an elite group of Outstanding Reviewers who have provided an extraordinary number of thoughtful reviews for The Journal of Neuroscience during the past few years.

Interaction Between Posterior Parietal and Motor Adaptation to Visuomotor Rotation Through

During value-based decision-making, individuals consider the various options and select the one that provides the maximum subjective value. Although the brain integrates abstract information to compute and compare these values, the only behavioral outcome is often the decision itself. However, if the options are visual stimuli, during deliberation the brain moves the eyes from one stimulus to the other. Previous work suggests that saccade vigor, i.e., peak velocity as a function of amplitude, is greater if reward is associated with the visual stimulus. This raises the possibility that vigor during the free viewing of options may be influenced by the valuation of each option. Here, humans chose between a small, immediate monetary reward and a larger but delayed reward. As the deliberation began, vigor was similar for the saccades made to the two options but diverged 0.5 s before decision time, becoming greater for the preferred option. This difference in vigor increased as a function of the difference in the subjective values that the participant assigned to the delayed and immediate options. After the decision was made, participants continued to gaze at the options, but with reduced vigor, making it possible to infer timing of the decision from the sudden drop in vigor. Therefore, the subjective value that the brain assigned to a stimulus during decision-making affected the motor system via the vigor with which the eyes moved toward that stimulus. SIGNIFICANCE STATEMENT We find that, as individuals deliberate between two rewarding options and arrive at a decision, the vigor with which they make saccades to each option reflects a real-time evaluation of that option. With deliberation, saccade vigor diverges between the two options, becoming greater for the option that the individual will eventually choose. The results suggest a shared element between the network that assigns value to a stimulus during the process of decision-making and the network that controls vigor of movements toward that stimulus.

Multi-Joint, Arm Movements Persistence of Motor Adaptation During Constrained,

Cerebellar damage can profoundly impair human motor adaptation. For example, if reaching movements are perturbed abruptly, cerebellar damage impairs the ability to learn from the perturbation-induced errors. Interestingly, if the perturbation is imposed gradually over many trials, people with cerebellar damage may exhibit improved adaptation. However, this result is controversial, since the differential effects of gradual vs. abrupt protocols have not been observed in all studies. To examine this question, we recruited patients with pure cerebellar ataxia due to cerebellar cortical atrophy (n = 13) and asked them to reach to a target while viewing the scene through wedge prisms. The prisms were computer controlled, making it possible to impose the full perturbation abruptly in one trial, or build up the perturbation gradually over many trials. To control visual feedback, we employed shutter glasses that removed visual feedback during the reach, allowing us to measure trial-by-trial learning from error (termed error-sensitivity), and trial-by-trial decay of motor memory (termed forgetting). We found that the patients benefited significantly from the gradual protocol, improving their performance with respect to the abrupt protocol by exhibiting smaller errors during the exposure block, and producing larger aftereffects during the postexposure block. Trial-by-trial analysis suggested that this improvement was due to increased error-sensitivity in the gradual protocol. Therefore, cerebellar patients exhibited an improved ability to learn from error if they experienced those errors gradually. This improvement coincided with increased error-sensitivity and was present in both groups of subjects, suggesting that control of error-sensitivity may be spared despite cerebellar damage.

Modulation of error-sensitivity during a prism adaptation task in people with cerebellar degeneration.

Movement variability is often considered an unwanted byproduct of a noisy nervous system. However, variability can signal a form of implicit exploration, indicating that the nervous system is intentionally varying the motor commands in search of actions that yield the greatest success. Here, we investigated the role of the human basal ganglia in controlling reward-dependent motor variability as measured by trial-to-trial changes in performance during a reaching task. We designed an experiment in which the only performance feedback was success or failure and quantified how reach variability was modulated as a function of the probability of reward. In healthy controls, reach variability increased as the probability of reward decreased. Control of variability depended on the history of past rewards, with the largest trial-to-trial changes occurring immediately after an unrewarded trial. In contrast, in participants with Parkinson's disease, a known example of basal ganglia dysfunction, reward was a poor modulator of variability; that is, the patients showed an impaired ability to increase variability in response to decreases in the probability of reward. This was despite the fact that, after rewarded trials, reach variability in the patients was comparable to healthy controls. In summary, we found that movement variability is partially a form of exploration driven by the recent history of rewards. When the function of the human basal ganglia is compromised, the reward-dependent control of movement variability is impaired, particularly affecting the ability to increase variability after unsuccessful outcomes.

Motor Learning Size of Error Affects Cerebellar Contributions to

memory with time away from practice Optimizing effort: increased efficiency of motor

Electrifying the motor engram: effects of tDCS on motor learning and control

Practice makes perfect — or does it? How do we learn from past errors? Herzfeld et al. found that when we practice a movement, the human brain has a memory for errors that is then used to learn faster in new conditions. This memory for error exists in parallel with motor memory's two traditional forms: memory of actions and memory of external perturbations. They also proposed a mathematical model for learning from errors. This model explained previous experimental results and predicted other major findings that they later verified experimentally. Science, this issue p. 1349 The history of previously experienced motor errors changes the amount the brain is willing to learn from an error. The current view of motor learning suggests that when we revisit a task, the brain recalls the motor commands it previously learned. In this view, motor memory is a memory of motor commands, acquired through trial-and-error and reinforcement. Here we show that the brain controls how much it is willing to learn from the current error through a principled mechanism that depends on the history of past errors. This suggests that the brain stores a previously unknown form of memory, a memory of errors. A mathematical formulation of this idea provides insights into a host of puzzling experimental data, including savings and meta-learning, demonstrating that when we are better at a motor task, it is partly because the brain recognizes the errors it experienced before.

The Editors give special thanks to an elite group of Top Reviewers who have provided an extraordinary number of thoughtful reviews for The Journal of Neuroscience during the past few years.

Contributions of the cerebellum and the motor cortex to acquisition and retention of motor memories

If we assume that the purpose of a movement is to acquire a rewarding state, the duration of the movement carries a cost because it delays acquisition of reward. For some people, passage of time carries a greater cost, as evidenced by how long they are willing to wait for a rewarding outcome. These steep discounters are considered impulsive. Is there a relationship between cost of time in decision making and cost of time in control of movements? Our theory predicts that people who are more impulsive should in general move faster than subjects who are less impulsive. To test our idea, we considered elementary voluntary movements: saccades of the eye. We found that in humans, saccadic vigor, assessed using velocity as a function of amplitude, was as much as 50% greater in one subject than another; that is, some people consistently moved their eyes with high vigor. We measured the cost of time in a decision-making task in which the same subjects were given a choice between smaller odds of success immediately and better odds if they waited. We measured how long they were willing to wait to obtain the better odds and how much they increased their wait period after they failed. We found that people that exhibited greater vigor in their movements tended to have a steep temporal discount function, as evidenced by their waiting patterns in the decision-making task. The cost of time may be shared between decision making and motor control.

Alkis M. Hadjiosif, Sarah E. Criscimagna-Hemminger, Tricia L. Gibo, Allison M. Okamura, Reza Shadmehr, Amy J. Bastian and Maurice A. Smith A number of studies have shown that motor adaptation is impaired following cerebellar damage. However, the degree of impairment varies considerably from one study to another, with widely ranging results reported even within the same task. For example, three recent force field adaptation studies in reaching arm movements have reported very different levels of impairment ranging from 30-70%, as shown in Figure 1. Smith and Shadmehr (2005) reported a substantial 75% deficit in force field adaptation, but two more recent studies (Gibo et al 2013; Criscimagna-Hemminger et al 2010) found only 30-40% learning deficits in this task. Why would this be? Here we suggest that cerebellar damage reduces the temporal stability of motor memories. If this were the case, paradigms with longer inter-trial spacing might be more sensitive to cerebellar damage, as this damage would lead to greater decay of adaptation in the time interval between movements. Interestingly, the Smith and Shadmehr study was based on an 8-movement-direction paradigm whereas Gibo et al (2013) and Criscimagna-Hemminger et al (2010) employed only one or two movement directions, respectively. Correspondingly, the inter-trial intervals between consecutive movements in the same direction were 4-fold greater in the Smith and Shadmehr study, as shown in Figure 1.

We have two arms, many muscles in each arm, and numerous neurons that contribute to their control. How does the brain assign responsibility to each of these potential actors? We considered a bimanual task in which people chose how much force to produce with each arm so that the sum would equal a target. We found that the dominant arm made a greater contribution, but only for specific directions. This was not because the dominant arm was stronger. Rather, it was less noisy. A cost that included unimanual noise and strength accounted for both direction- and handedness-dependent choices that young people made. To test whether there was a causal relationship between unimanual noise and bimanual control, we considered elderly people, whose unimanual noise is comparable in the two arms. We found that, in bimanual control, the elderly showed no preference for their dominant arm. We noninvasively stimulated the motor cortex to produce a change in unimanual strength and noise, and found a corresponding change in bimanual control. Using the noise measurements, we built a neuronal model. The model explained the anisotropic distribution of preferred directions of neurons in the monkey motor cortex and predicted that, in humans, there are changes in the number of these cortical neurons with handedness and aging. Therefore, we found that coordination can be explained by the noise and strength of each effector, where noise may be a reflection of the number of task-related neurons available for control of that effector in the motor cortex.

Faculty of 1000 evaluation for Brain Systems for Probabilistic and Dynamic Prediction: Computational Specificity and Integration.

Faculty Opinions recommendation of Are muscle synergies useful for neural control

Both abrupt and gradually imposed perturbations produce adaptive changes in motor output, but the neural basis of adaptation may be distinct. Here, we measured the state of the primary motor cortex (M1) and the corticospinal network during adaptation by measuring motor-evoked potentials (MEPs) before reach onset using transcranial magnetic stimulation of M1. Subjects reached in a force field in a schedule in which the field was introduced either abruptly or gradually over many trials. In both groups, by end of the training, muscles that countered the perturbation in a given direction increased their activity during the reach (labeled as the on direction for each muscle). In the abrupt group, in the period before the reach toward the on direction, MEPs in these muscles also increased, suggesting a direction-specific increase in the excitability of the corticospinal network. However, in the gradual group, these MEP changes were missing. After training, there was a period of washout. The MEPs did not return to baseline. Rather, in the abrupt group, off direction MEPs increased to match on direction MEPs. Therefore, we observed changes in corticospinal excitability in the abrupt but not gradual condition. Abrupt training includes the repetition of motor commands, and repetition may be the key factor that produces this plasticity. Furthermore, washout did not return MEPs to baseline, suggesting that washout engaged a new network that masked but did not erase the effects of previous adaptation. Abrupt but not gradual training appears to induce changes in M1 and/or corticospinal networks.

Changes in corticospinal excitability during reach adaptation in force fields.

adaptation in force fields Changes in corticospinal excitability during reach

When motor commands are accompanied by an unexpected outcome, the resulting error induces changes in subsequent commands. However, when errors are artificially eliminated, changes in motor commands are not sustained but show decay. Why does the adaptation-induced change in motor output decay in the absence of error? A prominent idea is that decay reflects the stability of the memory. We show results that challenge this idea and instead suggest that motor output decays because the brain actively disengages a component of the memory. Humans adapted their reaching movements to a perturbation and were then introduced to a long period of trials in which errors were absent (error-clamp). We found that, in some subjects, motor output did not decay at the onset of the error-clamp block but a few trials later. We manipulated the kinematics of movements in the error-clamp block and found that, as movements became more similar to subjects' natural movements in the perturbation block, the lag to decay onset became longer and eventually reached hundreds of trials. Furthermore, when there was decay in the motor output, the endpoint of decay was not zero but a fraction of the motor memory that was last acquired. Therefore, adaptation to a perturbation installed two distinct kinds of memories: (1) one that was disengaged when the brain detected a change in the task and (2) one that persisted despite it. Motor memories showed little decay in the absence of error if the brain was prevented from detecting a change in task conditions.

16 It has been proposed that the brain predicts the sensory consequences of a movement and compares it to 17 the actual sensory feedback. When the two differ, an error signal is formed, driving adaptation. How 18 does an error in one trial alter performance in the subsequent trial? Here, we show that the sensitivity to 19 error is not constant, but declines as a function of error magnitude. That is, one learns relatively less from 20 large errors as compared to small errors. We performed an experiment in which humans made reaching 21 movements and randomly experienced an error in both their visual and proprioceptive feedback. 22 Proprioceptive errors were created using force fields, and visual errors were formed by perturbing the 23 cursor trajectory to create a visual error that was smaller, the same size, or larger than the proprioceptive 24 error. We measured single trial adaptation and calculated sensitivity to error, i.e., the ratio of the trial-to25 trial change in motor commands to error size. We found that for both sensory modalities, sensitivity 26 decreased with increasing error size. A reanalysis of a number of previously published psychophysical 27 results also exhibited this feature. Finally, we asked how the brain might encode sensitivity to error. We 28 reanalyzed previously published probabilities of cerebellar complex spikes (CS) and found that this 29 probability declined with increasing error size. From this we posit that a CS may be representative of the 30 sensitivity to error, and not error itself, a hypothesis which may explain conflicting reports about CSs and 31 their relationship to error. 32 33 34 Introduction 35 How we perceive the world is at the core of how we behave. As we make a movement, sensory 36 inputs from multiple modalities converge in our brain to create an understanding of the results of that 37 movement. Theory suggests movements may be planned using a forward model, which generates a 38 prediction of our sensory feedback based on the outgoing motor command (Wolpert et al., 1995). If a 39 movement has an unexpected sensory consequence, an error is experienced. Error feedback is rich in 40 nature, and can include the size, relevance, direction, sensory modality and other details about the error. 41 Despite the large number of studies on adaptation (Shadmehr and Mussa-Ivaldi, 1994;Smith et al., 42 2006;Pekny et al., 2011), little is known about how we adapt to a single error, nor how individual sensory 43 prediction errors are processed and combined. Of particular interest are visual and proprioceptive errors, 44 which arguably play the greatest role in control of movement. Here, we will explore the question of how 45 learning from error depends on error size and sensory modality. 46 In models of adaptation, it is generally assumed that learning scales linearly with error size 47 (Thoroughman and Shadmehr, 2000;Scheidt et al., 2001;Cheng and Sabes, 2006;Smith et al., 2006;van 48 Beers, 2009). This implies that sensitivity to error is constant as a function of error size. However, 49 experiments suggest that the brain alters sensitivity to error based on its uncertainty about its predictions 50 relative to its uncertainty about observations (Korenberg and Ghahramani, 2002;Burge et al., 2008). For 51 example, when visual feedback about the consequences of a movement is blurry, one is less likely to 52 change their motor commands as compared to when it is sharp (Izawa and Shadmehr, 2008). Even when 53 the quality of the sensory feedback is kept constant, the brain appears to modulate sensitivity to error as a 54 function of error size. For example, Robinson et al. (Robinson et al., 2003) found that adaptation to 55 saccadic errors declined as the error size increased. Additionally, in reaching tasks, both Fine and 56 Thoroughman (2006) and Wei and Kording (Wei and Kording, 2009) reported that trial-to-trial learning 57 from a force perturbation of increasing size or a visual perturbation of increasing size showed rapid 58 saturation, respectively. That is, learning did not increase linearly with error size. 59 From a neurophysiological perspective, it is also unclear how the brain encodes error sensitivity. 60 Error-dependent adaptation of movements is generally thought to require integrity of the cerebellum 61 (Martin et al., 1996;Maschke et al., 2004;Smith and Shadmehr, 2005;Rabe et al., 2009). Complex spikes 62 that are generated by climbing fiber inputs onto Purkinje cells of the cerebellum are considered to be the 63 biological representation of an error signal (Kitazawa et al., 1998). However, when the probability of a 64 complex spike was measured in response to various error sizes, the probability was high for small errors 65 but decreased for larger errors (Soetedjo et al., 2008). This result is inconsistent with the idea that 66 complex spikes encode an error, and instead indicates that error size may play a role in plasticity of 67 Purkinje cells. 68 In addition to errors having different sizes, errors can occur in multiple modalities. The most 69 commonly used adaptation paradigms rely on visual error alone (i.e., a visuomotor rotation) or visual and 70 proprioceptive error concurrently (i.e., a force field). Behavioral studies suggest that learning from visual 71 and proprioceptive errors may occur independently (Krakauer et al., 1999;Pipereit et al., 2006;Bock and 72 Thomas, 2011). Furthermore, a recent study of people with cerebellar damage demonstrated that 73 adaptation in these two paradigms relied on different regions of the cerebellum (Rabe et al., 74 2009;Donchin et al., 2012). Thus it is important to consider the relative contributions of visual and 75 proprioceptive error, and understand how the two interact. 76 Here we performed an experiment to measure sensitivity to error, defined as the ratio of the 77 change in motor output from trial 1 n − to trial 1 n + , to the error experienced in trial n . We aimed to 78 understand the role of error size and modality on sensitivity to error, in a way which unified the results of 79 past studies. To do so, we performed a one trial learning experiment in which we varied errors in vision, 80 proprioception, and size of discrepancy throughout the same task. Our results demonstrate that, 81 regardless of sensory modality, sensitivity to error declines with increasing error size. Furthermore, 82 discrepancy between modalities does not significantly modulate error sensitivity, thus learning from each 83 modality may occur independently. Finally, we show that the relationship between sensitivity and error 84 size is similar to the relationship between the probability of a complex spike and error size. This suggests 85 that the occurrence of a complex spike may be a reflection of sensitivity to error, and not the error itself. 86 87 Methods 88 Ten subjects (age 25.8 ± 3.7 years, 4 male) participated in the experiment. The protocol was 89 approved by the Johns Hopkins Institutional Review Board and all subjects provided written consent. All 90 subjects were healthy, right hand dominant and naive for the purpose of the experiment. Subjects held the 91 handle of a robotic manipulandum with their right hand below an opaque horizontal screen that prevented 92 view of their arm (Fig. 1A). An elastic force helped guide their hand to the start position, indicated by a 93 6x6mm green square. Once the hand was within 1 cm of the start box, a cursor indicating current hand 94 position was turned on. After stopping within the start box, a target box (6x6mm square) appeared at 8cm 95 distance and the start box disappeared. There was only a single target, always located 8 cm above the 96 start position. Subjects were required to make a ballistic movement through the target box (a shooting 97 movement), crossing through the target between 150 and 250 ms after the movement start, at which point 98 a ”pillow” force field cushioned and slowed their movement and the robot brought the hand back to the 99 target box. The cursor indicating hand position remained on until the hand was returned to the target box. 100 Subjects then received feedback regarding their movement. Feedback consisted of the target box turning 101 red, blue or “exploding,” indicating that the movement was too fast, too slow, or accurate and correctly 102 timed, respectively. For every target explosion, subjects gained a point towards their score. Subjects 103 were instructed to score as many points as possible. 104 The experiment lasted approximately 90 minutes. There were 10 blocks with 80 movements in 105 each. The experiment began with a warm-up period of 40 movements through a null field to acquaint the 106 subjects with the apparatus. 107 Perturbations 108 Subjects were exposed to 11 different perturbation types, each applied in both the left and right 109 directions. In each block, all of the possible 22 perturbation types appeared once in a random order (Fig. 110 1B). Thus not only was the overall experiment balanced, but each individual block as well. The 111 perturbation trials consisted of a force perturbation and a visual perturbation. The force perturbation was 112 caused by a velocity dependent curl force field that applied force perpendicular to the direction of 113 movement, 114 0 0 B B   =   −   f x 115 where x is hand velocity. There were three possible force perturbation sizes, causing a small 116 proprioceptive error ( B = ±6.5 N.s/m), a medium proprioceptive error ( B = ±13 N.s/m) or a large 117 proprioceptive error ( B = ±19.5 N.s/m) to the left or right. Fig. 1C shows sample hand trajectories for 118 rightward perturbations. For the small or medium force perturbation one of five possible visual gains 119 were applied to the cursor trajectory. The visual gain, , g scaled the lateral deviation of the hand from the 120 straight line to the target by 0, 0.5, 1, 1.5, or 2. Thus, the lateral trajectory taken by the cursor, x c , had 121 eith

The kinematics of elementary movements such as saccadic eye movements are highly regular across repeated movements and across individuals. Historically, saccades have been viewed as following a fixed kinematic pattern with a characteristic peak velocity and duration that varies only with the amplitude of movement. Here we show experimentally in humans that saccade peak velocity and duration can be modulated through presenting stimuli of differing intrinsic value, and that repetition of the same stimulus leads to a decline in saccade speed which we interpret as a decline in the value of that stimulus. Surprisingly, we find that, among saccades of comparable amplitude, faster movement is associated with lower variability - contradicting the idea of a speed-accuracy tradeoff. We consider these results in the context of theoretical models that attempt to account for saccade durations through balancing costs that penalize accuracy with costs that penalize movement duration.

2012 46th Annual Conference on Information Sciences and Systems (CISS)

Changes in saccade kinematics associated with the value and novelty of a stimulus

Faculty Opinions recommendation of Beside the point: motor adaptation without feedback-based error correction in task-irrelevant conditions.

Suppose that the purpose of a movement is to place the body in a more rewarding state. In this framework, slower movements may increase accuracy and therefore improve the probability of acquiring reward, but the longer durations of slow movements produce devaluation of reward. Here we hypothesize that the brain decides the vigor of a movement (duration and velocity) based on the expected discounted reward associated with that movement. We begin by showing that durations of saccades of varying amplitude can be accurately predicted by a model in which motor commands maximize expected discounted reward. This result suggests that reward is temporally discounted even in timescales of tens of milliseconds. One interpretation of temporal discounting is that the true objective of the brain is to maximize the rate of reward—which is equivalent to a specific form of hyperbolic discounting. A consequence of this idea is that the vigor of saccades should change as one alters the intertrial intervals between movements. We find experimentally that in healthy humans, as intertrial intervals are varied, saccade peak velocities and durations change on a trial-by-trial basis precisely as predicted by a model in which the objective is to maximize the rate of reward. Our results are inconsistent with theories in which reward is discounted exponentially. We suggest that there exists a single cost, rate of reward, which provides a unifying principle that may govern control of movements in timescales of milliseconds, as well as decision making in timescales of seconds to years.

Evidence for Hyperbolic Temporal Discounting of Reward in Control of Movements

The brain builds an association between action and sensory feedback to predict the sensory consequence of self‐generated motor commands. This internal model of action is central to our ability to adapt movements and may also play a role in our ability to learn from observing others. Recently, we reported that the spatial generalization patterns that accompany adaptation of reaching movements were distinct in children with autism spectrum disorder (ASD) as compared with typically developing (TD) children. To test whether the generalization patterns are specific to ASD, here, we compared the patterns of adaptation with those in children with attention deficit hyperactivity disorder (ADHD). Consistent with our previous observations, we found that in ASD, the motor memory showed greater than normal generalization in proprioceptive coordinates compared with both TD children and children with ADHD; children with ASD also showed slower rates of adaptation compared with both control groups. Children with ADHD did not show this excessive generalization to the proprioceptive target, but they did show excessive variability in the speed of movements with an increase in the exponential distribution of responses (τ) as compared with both TD children and children with ASD. The results suggest that slower rate of adaptation and anomalous bias towards proprioceptive feedback during motor learning are characteristics of autism, whereas increased variability in execution is a characteristic of ADHD. Autism Res 2012,••:••–••. © 2012 International Society for Autism Research, Wiley Periodicals, Inc.

Motor Learning Relies on Integrated Sensory Inputs in ADHD, but Over‐Selectively on Proprioception in Autism Spectrum Conditions

It has been proposed that the brain predicts the sensory consequences of a movement and compares it to the actual sensory feedback. When the two differ, an error signal is formed, driving adaptation. How does an error in one trial alter performance in the subsequent trial? Here we show that the sensitivity to error is not constant but declines as a function of error magnitude. That is, one learns relatively less from large errors compared with small errors. We performed an experiment in which humans made reaching movements and randomly experienced an error in both their visual and proprioceptive feedback. Proprioceptive errors were created with force fields, and visual errors were formed by perturbing the cursor trajectory to create a visual error that was smaller, the same size, or larger than the proprioceptive error. We measured single-trial adaptation and calculated sensitivity to error, i.e., the ratio of the trial-to-trial change in motor commands to error size. We found that for both sensory modalities sensitivity decreased with increasing error size. A reanalysis of a number of previously published psychophysical results also exhibited this feature. Finally, we asked how the brain might encode sensitivity to error. We reanalyzed previously published probabilities of cerebellar complex spikes (CSs) and found that this probability declined with increasing error size. From this we posit that a CS may be representative of the sensitivity to error, and not error itself, a hypothesis that may explain conflicting reports about CSs and their relationship to error.

Suppose that it is true that when the brain generates a motor command, it also predicts the sensory consequences. The state estimation framework that we developed in the last few chapters suggests that when the actual sensory measurements arrive, the brain should combine what it predicted with what it measured to form an estimate of the state of the body (and whatever else contributes to things that it can sense). By doing so, it can estimate this state better than if it were to rely on the sensors alone. For example, we can estimate the location of a visual stimulus better if we can predict its position as well as see it, as compared to if we can only see it but not predict it (Vaziri et al., 2006). However, this last statement is true only if the predictions that the brain makes are unbiased. Being an unbiased predictor is actually rather difficult, because our body and the objects we interact with have dynamics: inputs (motor commands) and outputs (sensory measurements) are not related via some static mapping. Rather, dynamics implies that state of the system changes both as a function of time (passive dynamics), and as a function of the input (active dynamics). What's more, the relationship between inputs and outputs can change (for example, muscles can fatigue), making it necessary for us to adjust our predictions. We saw that one way our brain can learn to make better predictions is to assume a generative model that describes the relationship between inputs and outputs via some hidden states (for example, the fatigue state of the muscle can be one of these states). The prediction errors can guide the process of estimating these hidden states, and thereby improving the predictions. The elephant in the room is the generative model itself. Where does the brain get such a model? That is, how does our brain go about finding (presumably, learning) a model that has a structure or topology that can in principle represent the relationship between inputs (e.g., motor commands) and observations (sensory measurements)? To accurately predict the sensory consequences of a motor command we need to be able to have a model that can approximate behavior of a dynamical system. We are no longer talking about the hidden states of some generic model, but rather the topology of the model itself. How do we discover this topology, or structure of …

Building Generative Models: Structural Learning and Identification of the Learner

In Biological Learning and Control, Reza Shadmehr and Sandro Mussa-Ivaldi present a theoretical framework for understanding the regularity of the brain's perceptions, its reactions to sensory stimuli, and its control of movements. They offer an account of perception as the combination of prediction and observation: the brain builds internal models that describe what should happen and then combines this prediction with reports from the sensory system to form a belief. Considering the brain's control of movements, and variations despite biomechanical similarities among old and young, healthy and unhealthy, and humans and other animals, Shadmehr and Mussa-Ivaldi review evidence suggesting that motor commands reflect an economic decision made by our brain weighing reward and effort. This evidence also suggests that the brain prefers to receive a reward sooner than later, devaluing or discounting reward with the passage of time; then as the value of the expected reward changes in the brain with the passing of time (because of development, disease, or evolution), the shape of our movements will also change. The internal models formed by the brain provide the brain with an essential survival skill: the ability to predict based on past observations. The formal concepts presented by Shadmehr and Mussa-Ivaldi offer a way to describe how representations are formed, what structure they have, and how the theoretical concepts can be tested.

Biological Learning and Control: How the Brain Builds Representations, Predicts Events, and Makes Decisions

When we use a novel tool, the motor commands may not produce the expected outcome. In healthy individuals, with practice the brain learns to alter the motor commands. This change depends critically on the cerebellum as damage to this structure impairs adaptation. However, it is unclear precisely what the cerebellum contributes to the process of adaptation in human motor learning. Is the cerebellum crucial for learning to associate motor commands with novel sensory consequences, called forward model, or is the cerebellum important for learning to associate sensory goals with novel motor commands, called inverse model? Here, we compared performance of cerebellar patients and healthy controls in a reaching task with a gradual perturbation schedule. This schedule allowed both groups to adapt their motor commands. Following training, we measured two kinds of behavior: in one case, people were presented with reach targets near the direction in which they had trained. The resulting generalization patterns of patients and controls were similar, suggesting comparable inverse models. In the second case, participants reached without a target and reported the location of their hand. In controls, the pattern of change in reported hand location was consistent with simulation results of a forward model that had learned to associate motor commands with new sensory consequences. In patients, this change was significantly smaller. Therefore, in our sample of patients, we observed that while adaptation of motor commands can take place despite cerebellar damage, cerebellar integrity appears critical for learning to predict visual sensory consequences of motor commands.

Cerebellar Contributions to Reach Adaptation and Learning Sensory Consequences of Action

In a voluntary movement, the nervous system specifies not only the motor commands but also the gains associated with reaction to sensory feedback. For example, suppose that, during reaching, a perturbation tends to push the hand to the left. With practice, the brain not only learns to produce commands that predictively compensate for the perturbation but also increases the long-latency reflex gain associated with leftward displacements of the arm. That is, the brain learns a feedback controller. Here, we wondered whether, during the preparatory period before the reach, the brain engaged this feedback controller in anticipation of the upcoming movement. If so, its signature might be present in how the motor system responds to perturbations in the preparatory period. Humans trained on a reach task in which they adapted to a force field. During the preparatory period before the reach, we measured how the arm responded to a pulse to the hand that was either in the direction of the upcoming field, or in the opposite direction. Reach adaptation produced an increase in the long-latency (45–100 ms delay) feedback gains with respect to baseline, but only for perturbations that were in the same direction as the force field that subjects expected to encounter during the reach. Therefore, as the brain prepares for a reach, it loads a feedback controller specific to the upcoming reach. With adaptation, this feedback controller undergoes a change, increasing the gains for the expected sensory feedback.

Preparing to Reach: Selecting an Adaptive Long-Latency Feedback Controller

Perhaps in no area of neuroscience is the cooperation between theory and data more fruitful than in the study of movements. The reason has much to do with the fact that movements of people and other animals tend to be highly reproducible. For example, reaching movements, eye movements, and walking each have distinct features that are present in all healthy people. A teenager may actively choose to dress very differently than his parents, but will not exhibit walking, reaching, or eye movements that are very different. Indeed, a persistent difference in movements is often a sign of a neurological disorder. Our aim here is to describe some of this regularity, and attempt to build a theory that may account for it. Over the last 25 years, a large body of experimental and computational work has been directed towards offering theories that attempt to explain why there is regularity in our movements. The approaches are reminiscent of physics and its earliest attempts to explain regularity in motion of celestial objects. Similar to physics, the search in the field of motor control has been for normative laws, or cost functions, that govern our behavior. Here, we will focus on a theory that assumes that the purpose of movements is to achieve a rewarding state at a minimum effort. That is, we are going to assume that we make movements in order to change the state of our body to something more valuable, and effort is the cost that we pay to acquire reward. Consider the behavior of the eyes during saccadic eye movements: when we are looking at an image, the brain shifts our gaze from location to location with saccades. During each saccade, the eyes move in a stereotypical trajectory, with temporal and spatial characteristics that are described in Fig. 10.3. These characteristics include a nearly linear relationship between saccade amplitude and duration (Fig. 10.3B), and a symmetric trajectory of eye velocities for small amplitude saccades but asymmetric velocities during large amplitude saccades (Fig. 10.3D). However, these characteristics are variable and the variability is not entirely due to random noise. For example, when we make a saccade to look at a face, the eyes move slightly faster and arrive at the target slightly sooner than if the goal of our saccade was to foveate another kind of image (Fig. 10.7). When monkeys are rewarded with juice for moving their eyes to …

Faculty Opinions recommendation of Response competition in the primary motor cortex: corticospinal excitability reflects response replacement during simple decisions.

When we applied a single pulse of transcranial magnetic stimulation (TMS) to any part of the human head during a saccadic eye movement, the ongoing eye velocity was reduced as early as 45 ms after the TMS, and lasted ∼32 ms. The perturbation to the saccade trajectory was not due to a mechanical effect of the lid on the eye (e.g., from blinks). When the saccade involved coordinated movements of both the eyes and the lids, e.g., in vertical saccades, TMS produced a synchronized inhibition of the motor commands to both eye and lid muscles. The TMS-induced perturbation of the eye trajectory did not show habituation with repetition, and was present in both pro-saccades and anti-saccades. Despite the perturbation, the eye trajectory was corrected within the same saccade with compensatory motor commands that guided the eyes to the target. This within-saccade correction did not rely on visual input, suggesting that the brain monitored the oculomotor commands as the saccade unfolded, maintained a real-time estimate of the position of the eyes, and corrected for the perturbation. TMS disrupted saccades regardless of the location of the coil on the head, suggesting that the coil discharge engages a nonhabituating startle-like reflex system. This system affects ongoing motor commands upstream of the oculomotor neurons, possibly at the level of the superior colliculus or omnipause neurons. Therefore, a TMS pulse centrally perturbs saccadic motor commands, which are monitored possibly via efference copy and are corrected via internal feedback.

TMS Perturbs Saccade Trajectories and Unmasks an Internal Feedback Controller for Saccades

When we adapt our movements to a perturbation, and then adapt to another perturbation, is the initial memory destroyed, or is it protected? Despite decades of experiments, this question remains unresolved. The confusion, in our view, is due to the fact that in every instance the approach has been to assay contents of motor memory by retesting with the same perturbations. When performance in retesting is the same as naive, this is usually interpreted as the memory being destroyed. However, it is also possible that the initial memory is simply masked by the competing memory. We trained humans in a reaching task in field B and then in field A (or washout) over an equal number of trials. To assay contents of motor memory, we used a new tool: after completion of training in A, we withheld reinforcement (i.e., reward) for a brief block of trials and then clamped movement errors to zero over a long block of trials. We found that this led to spontaneous recovery of B. That is, withholding reinforcement for the current motor output resulted in the expression of the competing memory. Therefore, adaptation followed by washout or reverse adaptation produced competing motor memories. The protection from unlearning was unrelated to sudden changes in performance errors that might signal a contextual change, as competing memories formed even when the perturbations were introduced gradually. Rather, reinforcement appears to be a critical signal that affords protection to motor memories, and lack of reinforcement encourages retrieval of a competing memory.

Faculty Opinions recommendation of Spontaneous activity signatures of morphologically identified interneurons in the vestibulocerebellum.

Voluntary motor commands produce two kinds of consequences. Initially, a sensory consequence is observed in terms of activity in our primary sensory organs (e.g., vision, proprioception). Subsequently, the brain evaluates the sensory feedback and produces a subjective measure of utility or usefulness of the motor commands (e.g., reward). As a result, comparisons between predicted and observed consequences of motor commands produce two forms of prediction error. How do these errors contribute to changes in motor commands? Here, we considered a reach adaptation protocol and found that when high quality sensory feedback was available, adaptation of motor commands was driven almost exclusively by sensory prediction errors. This form of learning had a distinct signature: as motor commands adapted, the subjects altered their predictions regarding sensory consequences of motor commands, and generalized this learning broadly to neighboring motor commands. In contrast, as the quality of the sensory feedback degraded, adaptation of motor commands became more dependent on reward prediction errors. Reward prediction errors produced comparable changes in the motor commands, but produced no change in the predicted sensory consequences of motor commands, and generalized only locally. Because we found that there was a within subject correlation between generalization patterns and sensory remapping, it is plausible that during adaptation an individual's relative reliance on sensory vs. reward prediction errors could be inferred. We suggest that while motor commands change because of sensory and reward prediction errors, only sensory prediction errors produce a change in the neural system that predicts sensory consequences of motor commands.

Learning from Sensory and Reward Prediction Errors during Motor Adaptation

It has been hypothesized that the generalization patterns that accompany learning carry the signatures of the neural systems that are engaged in that learning. Reach adaptation in force fields has generalization patterns that suggest primary engagement of a neural system that encodes movements in the intrinsic coordinates of joints and muscles, and lesser engagement of a neural system that encodes movements in the extrinsic coordinates of the task. Among the cortical motor areas, the intrinsic coordinate system is most prominently represented in the primary sensorimotor cortices. Here, we used transcranial direct current stimulation (tDCS) to alter mechanisms of synaptic plasticity and found that when it was applied to the motor cortex, it increased generalization in intrinsic coordinates but not extrinsic coordinates. However, when tDCS was applied to the posterior parietal cortex, it had no effects on learning or generalization in the force field task. The results suggest that during force field adaptation, the component of learning that produces generalization in intrinsic coordinates depends on the plasticity in the sensorimotor cortex.

Stimulation of the Human Motor Cortex Alters Generalization Patterns of Motor Learning

During adaptation, motor commands tend to repeat as performance plateaus. It has been hypothesized that this repetition produces plasticity in the motor cortex (M1). Here, we considered a force field reaching paradigm, varied the perturbation schedule to potentially alter the amount of repetition, and quantified the interaction between disruption of M1 using transcranial magnetic stimulation (TMS) and the schedule of perturbations. In the abrupt condition (introduction of the perturbation on a single trial followed by constant perturbation), motor output adapted rapidly and was then followed by significant repetition as performance plateaued. TMS of M1 had no effect on the rapid adaptation phase but reduced adaptation at the plateau. In the intermediate condition (introduction of the perturbation over 45 trials), disruption of M1 had no effect on the phase in which motor output changed but again impaired adaptation when performance had plateaued. Finally, when the perturbation was imposed gradually (over 240 trials), the motor commands continuously changed during adaptation and never repeated, and disruption of M1 had no effect on performance. Therefore, TMS of M1 appeared to reduce adaptation of motor commands during a specific phase of learning: when motor commands tended to repeat.

Contributions of the motor cortex to adaptive control of reaching depend on the perturbation schedule.

Why do movements take a characteristic amount of time, and why do diseases that affect the reward system alter control of movements? Suppose that the purpose of any movement is to position our body in a more rewarding state. People and other animals discount future reward as a hyperbolic function of time. Here, we show that across populations of people and monkeys there is a correlation between discounting of reward and control of movements. We consider saccadic eye movements and hypothesize that duration of a movement is equivalent to a delay of reward. The hyperbolic cost of this delay not only accounts for kinematics of saccades in adults, it also accounts for the faster saccades of children, who temporally discount reward more steeply. Our theory explains why saccade velocities increase when reward is elevated, and why disorders in the encoding of reward, for example in Parkinson's disease and schizophrenia, produce changes in saccade. We show that delay of reward elevates the cost of saccades, reducing velocities. Finally, we consider coordinated movements that include motion of eyes and head and find that their kinematics is also consistent with a hyperbolic, reward-dependent cost of time. Therefore, each voluntary movement carries a cost because its duration delays acquisition of reward. The cost depends on the value that the brain assigns to stimuli, and the rate at which it discounts this value in time. The motor commands that move our eyes reflect this cost of time.

Temporal Discounting of Reward and the Cost of Time in Motor Control

In the mid sixties, Feldman (1966) reported on experiments on feedback control processes that stabilize the human arm. In a typical test, the elbow flexors (or extensors) would be loaded and the subject was asked to maintain a predetermined elbow angle. After a sudden decrease of the load, the forearm would settle at a new position. The experiments were repeated for the same initial elbow position and load, but each time the change in the load was different. The set of points that resulted consisted of two variables: elbow angle θ and force ƒ. These points formed an exponential-like curve

Small errors may affect the process of learning in a fundamentally different way than large errors. For example, adapting reaching movements in response to a small perturbation produces generalization patterns that are different from large perturbations. Are distinct neural mechanisms engaged in response to large versus small errors? Here, we examined the motor learning process in patients with severe degeneration of the cerebellum. Consistent with earlier reports, we found that the patients were profoundly impaired in adapting their motor commands during reaching movements in response to large, sudden perturbations. However, when the same magnitude perturbation was imposed gradually over many trials, the patients showed marked improvements, uncovering a latent ability to learn from errors. On sudden removal of the perturbation, the patients exhibited aftereffects that persisted much longer than did those in healthy controls. That is, despite cerebellar damage, the brain maintained the ability to learn from small errors and the motor memory that resulted from this learning was strongly resistant to change. Of note was the fact that on completion of learning, the motor output of the cerebellar patients remained distinct from healthy controls in terms of its temporal characteristics. Therefore cerebellar degeneration impaired the ability to learn from large-magnitude errors, but had a lesser impact on learning from small errors. The neural basis of motor learning in response to small and large errors appears to be distinct.

Size of error affects cerebellar contributions to motor learning.

The neural systems that support motor adaptation in humans are thought to be distinct from those that support the declarative system. Yet, during motor adaptation changes in motor commands are supported by a fast adaptive process that has important properties (rapid learning, fast decay) that are usually associated with the declarative system. The fast process can be contrasted to a slow adaptive process that also supports motor memory, but learns gradually and shows resistance to forgetting. Here we show that after people stop performing a motor task, the fast motor memory can be disrupted by a task that engages declarative memory, but the slow motor memory is immune from this interference. Furthermore, we find that the fast/declarative component plays a major role in the consolidation of the slow motor memory. Because of the competitive nature of declarative and nondeclarative memory during consolidation, impairment of the fast/declarative component leads to improvements in the slow/nondeclarative component. Therefore, the fast process that supports formation of motor memory is not only neurally distinct from the slow process, but it shares critical resources with the declarative memory system.

The coordination of movement: optimal feedback control and beyond

Faculty Opinions recommendation of Responsibility assignment in redundant systems.

Motor control is the study of how organisms make accurate goal-directed movements. Here we consider two problems that the motor system must solve in order to achieve such control. The first problem is that sensory feedback is noisy and delayed, which can make movements inaccurate and unstable. The second problem is that the relationship between a motor command and the movement it produces is variable, as the body and the environment can both change. A solution is to build adaptive internal models of the body and the world. The predictions of these internal models, called forward models because they transform motor commands into sensory consequences, can be used to both produce a lifetime of calibrated movements, and to improve the ability of the sensory system to estimate the state of the body and the world around it. Forward models are only useful if they produce unbiased predictions. Evidence shows that forward models remain calibrated through motor adaptation: learning driven by sensory prediction errors.

Error correction, sensory prediction, and adaptation in motor control.

Faculty Opinions recommendation of Dissociating variability and effort as determinants of coordination.

Faculty Opinions recommendation of Statistics predict kinematics of hand movements during everyday activity.

Visual Targets on Earth Internal Model of Gravity for Hand Interception: Parametric Adaptation to Zero-Gravity (PDF)

The intrinsic value of visual information affects saccade velocities

Caudal Fastigial Nucleus in the Monkey Saccade Dysmetria in Head-Unrestrained Gaze Shifts After Muscimol Inactivation of the

Representation of internal models of action in the autistic brain

The cerebellum may monitor motor commands and through internal feedback correct for anticipated errors. Saccades provide a test of this idea because these movements are completed too quickly for sensory feedback to be useful. Earlier, we reported that motor commands that accelerate the eyes toward a constant amplitude target showed variability. Here, we demonstrate that this variability is not random noise, but is due to the cognitive state of the subject. Healthy people showed within-saccade compensation for this variability with commands that arrived later in the same saccade. However, in people with cerebellar damage, the same variability resulted in dysmetria. This ability to correct for variability in the motor commands that initiated a saccade was a predictor of each subject's ability to learn from endpoint errors. In a paradigm in which a target on the horizontal meridian jumped vertically during the saccade (resulting in an endpoint error), the adaptive response exhibited two timescales: a fast timescale that learned quickly from endpoint error but had poor retention, and a slow timescale that learned slowly but had strong retention. With cortical cerebellar damage, the fast timescale of adaptation was effectively absent, but the slow timescale was less impaired. Therefore, the cerebellum corrects for variability in the motor commands that initiate saccades within the same movement via an adaptive response that not only exhibits strong sensitivity to previous endpoint errors, but also rapid forgetting.

Cerebellar Contributions to Adaptive Control of Saccades in Humans

The saccadic system is an ideal model for the study of how the brain optimizes its motor behavior. Here we review some recent research that points to exciting new areas of investigation relative to the multiple time scales of and the influence of context and consolidation on motor learning. These findings suggest new ways of thinking about the processes that underlie the short‐term adaptive mechanisms that maintain accuracy of eye movements and so ensure optimal vision.

Learning to control a new tool (i.e., a novel environment) produces an internal model, i.e., a motor memory that allows the brain to implicitly predict the behavior of the tool. Data from a wide array of experiments suggest that formation of motor memory is not a single process, but one that is due to multiple adaptive processes with different time constants. Here we asked whether these time constants are invariant or are they influenced by the statistics of the learning event. To measure the time constants, we controlled the statistics of the learning event in a reaching task and then assayed the decay rates of motor output in a set of trials in which errors were effectively removed. We found that prior experience with a rapid change in the environment increased the decay rate of memories acquired later in response to a gradual change in the same environment. Prior experience in an environment that changed gradually reduced the decay rates of memories acquired later in response to a rapid change in that same environment. Indeed we found that by manipulating the prior statistics of the learning experience, we could readily alter the decay rates of a given motor memory. This suggests that time scales of processes that support motor memory are not constant. Rather decay of motor memory is the brain's implicit estimate of how likely it is that the environment will change with time. During motor learning, prior statistics that suggest changes are likely to be permanent result in slowly decaying memories, whereas prior statistics that suggest changes are transient result in rapidly decaying memories.

Persistence of motor memories reflects statistics of the learning event.

In a typical short-term saccadic adaptation protocol, the target moves intrasaccadically either toward (gain-down) or away (gain-up) from initial fixation, causing the saccade to complete with an endpoint error. A central question is how the motor system adapts in response to this error: are the motor commands changed to bring the eyes to a different goal, akin to a remapping of the target, or is adaptation focused on the processes that monitor the ongoing motor commands and correct them midflight, akin to changes that act via internal feedback? Here, we found that, in the gain-down paradigm, the brain learned to produce a smaller amplitude saccade by altering the trajectory of the saccade. The adapted saccades had reduced peak velocities, reduced accelerations, shallower decelerations, and increased durations compared with a control saccade of equal amplitude. These changes were consistent with a change in an internal feedback that acted as a forward model. However, in the gain-up paradigm, the brain learned to produce a larger amplitude saccade with trajectories that were identical with those of control saccades of equal amplitude. Therefore, whereas the gain-down paradigm appeared to induce adaptation via an internal feedback that controlled saccades midflight, the gain-up paradigm induced adaptation primarily via target remapping. Our simulations explained that, for each condition, the specific adaptation produced a saccade that brought the eyes to the target with the smallest motor costs.

Sequential neural changes during motor learning in schizophrenia

Can memories be unlearned, or is unlearning a form of acquiring a new memory that competes with the old, effectively masking it? We considered motor memories that were acquired when people learned to use a novel tool. We trained people to reach with tool A and quantified recall in error-clamp trials, i.e., trials in which the memory was reactivated but error-dependent learning was minimized. We measured both the magnitude of the memory and its resistance to change. With passage of time between acquisition and reactivation (up to 24 h), memory of A slowly declined, but with reactivation remained resistant to change. After learning of tool A, brief exposure to tool B brought performance back to baseline, i.e., apparent extinction. Yet, for up to a few minutes after A+B training, output in error-clamp trials increased from baseline to match those who had trained only in A. This spontaneous recovery and convergence demonstrated that B did not produce any unlearning of A. Rather, it masked A with a new memory that was very fragile. We tracked the memory of B as a function of time and found that within minutes it was transformed from a fragile to a more stable state. Therefore, a sudden performance error in a well-learned motor task does not produce unlearning, but rather installs a competing but fragile memory that with passage of time acquires stability. Learning not only engages processes that adapt at multiple timescales, but once practice ends, the fast states are partially transformed into slower states.

Our sensory observations represent a delayed, noisy estimate of the environment. Delay causes instability and noise causes uncertainty. To deal with these problems, theory suggests that the processing of sensory information by the brain should be probabilistic: to start a movement or to alter it midflight, our brain should make predictions about the near future of sensory states and then continuously integrate the delayed sensory measures with predictions to form an estimate of the current state. To test the predictions of this theory, we asked participants to reach to the center of a blurry target. With increased uncertainty about the target, reach reaction times increased. Occasionally, we changed the position of the target or its blurriness during the reach. We found that the motor response to a given second target was influenced by the uncertainty about the first target. The specific trajectories of motor responses were consistent with predictions of a “minimum variance” state estimator. That is, the motor output that the brain programmed to start a reaching movement or correct it midflight was a continuous combination of two streams of information: a stream that predicted the near future of the state of the environment and a stream that provided a delayed measurement of that state.

On-Line Processing of Uncertain Information in Visuomotor Control

Ballistic movements like saccades require the brain to generate motor commands without the benefit of sensory feedback. Despite this, saccades are remarkably accurate. Theory suggests that this accuracy arises because the brain relies on an internal forward model that monitors the motor commands, predicts their sensory consequences, and corrects eye trajectory midflight. If control of saccades relies on a forward model, then the forward model should adapt whenever its predictions fail to match sensory feedback at the end of the movement. Using optimal feedback control theory, we predicted how this adaptation should alter saccade trajectories. We trained subjects on a paradigm in which the horizontal target jumped vertically during the saccade. With training, the final position of the saccade moved toward the second target. However, saccades became increasingly curved, i.e., suboptimal, as oculomotor commands were corrected on-line to steer the eye toward the second target. The adaptive response had two components: (1) the motor commands that initiated the saccades changed slowly, aiming the saccade closer to the jumped target. The adaptation of these earliest motor commands displayed little forgetting during the rest periods. (2) Late in saccade trajectory, another adaptive response steered it still closer to the jumped target, producing curvature. Adaptation of these late motor commands showed near-complete forgetting during the rest periods. The two components adapted at different timescales, with the late-acting component displaying much faster rates. It appears that in controlling saccades, the brain relies on an internal feedback that has the characteristics of a fast-adapting forward model.

When we learn a new skill (e.g., golf) without a coach, we are "active learners": we have to choose the specific components of the task on which to train (e.g., iron, driver, putter, etc.). What guides our selection of the training sequence? How do choices that people make compare with choices made by machine learning algorithms that attempt to optimize performance? We asked subjects to learn the novel dynamics of a robotic tool while moving it in four directions. They were instructed to choose their practice directions to maximize their performance in subsequent tests. We found that their choices were strongly influenced by motor errors: subjects tended to immediately repeat an action if that action had produced a large error. This strategy was correlated with better performance on test trials. However, even when participants performed perfectly on a movement, they did not avoid repeating that movement. The probability of repeating an action did not drop below chance even when no errors were observed. This behavior led to suboptimal performance. It also violated a strong prediction of current machine learning algorithms, which solve the active learning problem by choosing a training sequence that will maximally reduce the learner's uncertainty about the task. While we show that these algorithms do not provide an adequate description of human behavior, our results suggest ways to improve human motor learning by helping people choose an optimal training sequence.

Children with autism exhibit a host of motor disorders including poor coordination, poor tool use and delayed learning of complex motor skills like riding a tricycle. Theory suggests that one of the crucial steps in motor learning is the ability to form internal models: to predict the sensory consequences of motor commands and learn from errors to improve performance on the next attempt. The cerebellum appears to be an important site for acquisition of internal models, and indeed the development of the cerebellum is abnormal in autism. Here, we examined autistic children on a range of tasks that required a change in the motor output in response to a change in the environment. We first considered a prism adaptation task in which the visual map of the environment was shifted. The children were asked to throw balls to visual targets with and without the prism goggles. We next considered a reaching task that required moving the handle of a novel tool (a robotic arm). The tool either imposed forces on the hand or displaced the cursor associated with the handle position. In all tasks, the children with autism adapted their motor output by forming a predictive internal model, as exhibited through after-effects. Surprisingly, the rates of acquisition and washout were indistinguishable from normally developing children. Therefore, the mechanisms of acquisition and adaptation of internal models in self-generated movements appeared normal in autism. Sparing of adaptation suggests that alternative mechanisms contribute to impaired motor skill development in autism. Furthermore, the findings may have therapeutic implications, highlighting a reliable mechanism by which children with autism can most effectively alter their behaviour.

Acquisition of internal models of motor tasks in children with autism.

It is possible that motor adaptation in timescales of minutes is supported by two distinct processes: one process that learns slowly from error but has strong retention, and another that learns rapidly from error but has poor retention. This two-state model makes the prediction that if a period of adaptation is followed by a period of reverse-adaptation, then in the subsequent period in which errors are clamped to zero (error-clamp trials) there will be a spontaneous recovery, i.e., a rebound of behavior toward the initial level of adaptation. Here we tested and confirmed this prediction during double-step, on-axis, saccade adaptation. When people adapted their saccadic gain to a magnitude other than one (adaptation) and then the gain was rapidly reversed back to one (reverse-adaptation), in the subsequent error-clamp trials (visual target placed on the fovea after the saccade) the gain reverted toward the initially adapted value and then gradually reverted toward normal. We estimated that the fast system was about 20-fold more sensitive to error than the slow system, but had a time constant of 28 s, whereas the slow system had a time constant of nearly 8 min. Therefore short-term adaptive mechanisms that maintain accuracy of saccades rely on a memory system that has characteristics of a multistate process with a logarithmic distribution of timescales.

Adaptation is sometimes viewed as a process in which the nervous system learns to predict and cancel effects of a novel environment, returning movements to near baseline (unperturbed) conditions. An alternate view is that cancellation is not the goal of adaptation. Rather, the goal is to maximize performance in that environment. If performance criteria are well defined, theory allows one to predict the reoptimized trajectory. For example, if velocity-dependent forces perturb the hand perpendicular to the direction of a reaching movement, the best reach plan is not a straight line but a curved path that appears to overcompensate for the forces. If this environment is stochastic (changing from trial to trial), the reoptimized plan should take into account this uncertainty, removing the overcompensation. If the stochastic environment is zero-mean, peak velocities should increase to allow for more time to approach the target. Finally, if one is reaching through a via-point, the optimum plan in a zero-mean deterministic environment is a smooth movement but in a zero-mean stochastic environment is a segmented movement. We observed all of these tendencies in how people adapt to novel environments. Therefore, motor control in a novel environment is not a process of perturbation cancellation. Rather, the process resembles reoptimization: through practice in the novel environment, we learn internal models that predict sensory consequences of motor commands. Through reward-based optimization, we use the internal model to search for a better movement plan to minimize implicit motor costs and maximize rewards.

We make errors when learning to use a new tool. However, the cause of error may be ambiguous: is it because we misestimated properties of the tool or of our own arm? We considered a well-studied adaptation task in which people made goal-directed reaching movements while holding the handle of a robotic arm. The robot produced viscous forces that perturbed reach trajectories. As reaching improved with practice, did people recalibrate an internal model of their arm, or did they build an internal model of the novel tool (robot), or both? What factors influenced how the brain solved this credit assignment problem? To investigate these questions, we compared transfer of adaptation between three conditions: catch trials in which robot forces were turned off unannounced, robot-null trials in which subjects were told that forces were turned off, and free-space trials in which subjects still held the handle but watched as it was detached from the robot. Transfer to free space was 40% of that observed in unannounced catch trials. We next hypothesized that transfer to free space might increase if the training field changed gradually, rather than abruptly. Indeed, this method increased transfer to free space from 40 to 60%. Therefore although practice with a novel tool resulted in formation of an internal model of the tool, it also appeared to produce a transient change in the internal model of the subject's arm. Gradual changes in the tool's dynamics increased the extent to which the nervous system recalibrated the model of the subject's own arm.

Reach adaptation: what determines whether we learn an internal model of the tool or adapt the model of our arm?

The cerebellum is an essential part of the neural network involved in adapting goal-directed arm movements. This adaptation might rely on two distinct signals: a sensory prediction error or a motor correction. Sensory prediction errors occur when an initial motor command is generated but the predicted sensory consequences do not match the observed values. In some tasks, these sensory errors are monitored and result in on-line corrective motor output as the movement progresses. Here we asked whether cerebellum-dependent adaptation of reaching relies on sensory or on-line motor corrections. Healthy controls and people with hereditary cerebellar ataxia reached during a visuomotor perturbation in two conditions: "shooting" movements without on-line corrections and "pointing" movements that allowed for on-line corrections. Sensory (i.e., visual) errors were available in both conditions. Results showed that the addition of motor corrections did not influence adaptation in control subjects, suggesting that only sensory errors were needed for learning. Cerebellar subjects were comparably impaired in both adaptation conditions relative to controls, despite abnormal and inconsistent on-line motor correction. Specifically, poor on-line motor corrections were unrelated to cerebellar subjects' adaptation deficit (i.e., adaptation did not worsen), further suggesting that only sensory prediction errors influence this process. Therefore adaptation to visuomotor perturbations depends on the cerebellum and is driven by the mismatch between predicted and actual sensory outcome of motor commands.

Sensory prediction errors drive cerebellum-dependent adaptation of reaching.

The function of the cerebellum in motor control is a long-standing puzzle because cerebellar damage is associated with both timing and coordination deficits. Timing is the ability to produce consistent intervals between movements based on an internal representation of time. Coordination, in contrast, is a state-dependent control process in which motor commands to one effector depend on the predicted state of another effector. Here we considered a task consisting of two components, an arm movement and an isometric press with the thumb. We found that when the two components temporally overlapped, the brain controlled the thumb using an estimate of the state of the arm. In contrast, when the components did not temporally overlap, the brain controlled the thumb solely based on an internal estimate of time. Using functional magnetic resonance imaging, we contrasted these two conditions and found that lobule V of the cerebellum ipsilateral to the arm movement was consistently more activated during state-dependent control. When the brain learned time-dependent control, no region of the cerebellum showed consistently increased activity compared with state-dependent control. Rather, the consistent activity associated with time-dependent control was found in language areas of the left cerebral hemisphere along the Sylvian fissure. We suggest that timing and coordination are behaviorally distinct modes of motor control and that the anterior cerebellum is a crucial node in state-dependent motor control, computing a predictive state estimate of one effector (e.g., the arm) to coordinate actions of another effector (the thumb).

Dissociating Timing and Coordination as Functions of the Cerebellum

When a movement results in error, the nervous system amends the motor commands that generate the subsequent movement. Here we show that this adaptation depends not just on error, but also on passage of time between the two movements. We observed that subjects learned a reaching task faster, i.e., with fewer trials, when the intertrial time intervals (ITIs) were lengthened. We hypothesized two computational mechanisms that could have accounted for this. First, learning could have been driven by a Bayesian process where the learner assumed that errors are the result of perturbations that have multiple timescales. In theory, longer ITIs can produce faster learning because passage of time might increase uncertainty, which in turn increases sensitivity to error. Second, error in a trial may result in a trace that decays with time. If the learner continued to sample from the trace during the ITI, then adaptation would increase with increased ITIs. The two models made separate predictions: The Bayesian model predicted that when movements are separated by random ITIs, the learner would learn most from a trial that followed a long time interval. In contrast, the trace model predicted that the learner would learn most from a trial that preceded a long time interval. We performed two experiments to test for these predictions and in both experiments found evidence for the trace model. We suggest that motor error produces an error memory trace that decays with a time constant of about 4 s, continuously promoting adaptation until the next movement.

Evolution of motor memory during the seconds after observation of motor error.

Faculty Opinions recommendation of Motor adaptation as a greedy optimization of error and effort.

Learning a visuomotor skill involves a distributed network which includes the primary motor cortex (M1). Despite multiple lines of evidence supporting the role of M1 in motor learning and memory, it is unclear whether M1 plays distinct roles in different aspects of learning such as acquisition and retention. Here, we investigated the nature and chronometry of that processing through a temporally specific disruption of M1 activity using single-pulse transcranial magnetic stimulation (TMS). We applied single-pulse TMS to M1 or dorsal premotor cortex (PMd) during adaptation of rapid arm movements (∼150 ms duration) to a visuomotor rotation. When M1 was stimulated either immediately after the end of each trial or with a 700 ms delay, subjects exhibited normal adaptation. However, whereas the memory of the subjects who received delayed-TMS showed normal rates of forgetting during deadaptation, the memory of those who received immediate TMS was more fragile: in the deadaptation period, they showed a faster rate of forgetting. Stimulation of PMd with adjusted (reduced) intensity to rule out the possibility of coactivation of this structure caused by the current spread from M1 stimulation did not affect adaptation or retention. The data suggest that, during the short time window after detection of movement errors, neural processing in M1 plays a crucial role in formation of motor memories. This processing in M1 may represent a slow component of motor memory which plays a significant role in retention.

Impairment of Retention But Not Acquisition of a Visuomotor Skill Through Time-Dependent Disruption of Primary Motor Cortex

Faculty Opinions recommendation of Time of day accounts for overnight improvement in sequence learning.

When the brain initiates a saccade, it uses a copy of the oculomotor commands to predict the visual consequences: for example, if one fixates a reach target, a peripheral saccade will produce an internal estimate of the new retinal location of the target, a process called remapping. In natural settings, the target likely remains visible after the saccade. So why should the brain predict the sensory consequence of the saccade when after its completion, the image of the target remains visible? We hypothesized that in the post-saccadic period, the brain integrates target position information from two sources: one based on remapping and another based on the peripheral view of the target. The integration of information from these two sources could produce a less variable target estimate than is possible from either source alone. Here, we show that reaching toward targets that were initially foveated and remapped had significantly less variance than reaches relying on peripheral target information. Furthermore, in a more natural setting where both sources of information were available simultaneously, variance of the reaches was further reduced as predicted by integration. This integration occurred in a statistically optimal manner, as demonstrated by the change in integration weights when we manipulated the uncertainty of the post-saccadic target estimate by varying exposure time. Therefore, the brain predicts the sensory consequences of motor commands because it integrates its prediction with the actual sensory information to produce an estimate of sensory space that is better than possible from either source alone.

Why Does the Brain Predict Sensory Consequences of Oculomotor Commands? Optimal Integration of the Predicted and the Actual Sensory Feedback

Dissociable effects of the implicit and explicit memory systems on learning control of reaching

Faculty Opinions recommendation of How a lateralized brain supports symmetrical bimanual tasks.

Lesion or degeneration of the cerebellum can profoundly impair adaptive control of reaching in humans. Computational models have proposed that internal models that help control movements form in the cerebellum and influence planned motor output through the cerebello-thalamo-cortical pathway. However, lesion studies of the cerebellar thalamus have not consistently found impairment in reaching or adaptation of reaching. To elucidate the role of the cerebellar thalamus in humans, we studied a group of essential tremor (ET) patients with deep brain stimulation (DBS) electrodes placed in the cerebellar thalamus. The stimulation can be turned on or off remotely and is thought to reduce tremor by blocking the spread of the pathological output from the cerebellum. We studied the effect of thalamic DBS on the ability to adapt arm movements to novel force fields. Although thalamic DBS resulted in a dramatic and significant reduction of tremor in ET, it also impaired motor adaptation: the larger the stimulation voltage, the greater the reduction in rates of adaptation. We next examined ET patients that had undergone unilateral thalamotomy in the cerebellar thalamus and found that adaptation with the contralateral arm was impaired compared with the ipsilateral arm. Therefore, although both lesion and electrical stimulation of the cerebellar thalamus are highly effective in reducing tremor, they significantly impair the ability of the brain to form internal models of action. Adaptive control of reaching appears to depend on the integrity of the cerebello-thalamo-cortical pathway.

Effects of human cerebellar thalamus disruption on adaptive control of reaching.

Generalization of motor learning refers to our ability to apply what has been learned in one context to other contexts. When generalization is beneficial, it is termed transfer, and when it is detrimental, it is termed interference. Insight into the mechanism of generalization may be acquired from understanding why training transfers in some contexts but not others. However, identifying relevant contextual cues has proven surprisingly difficult, perhaps because the search has mainly been for cues that are explicit. We hypothesized instead that a relevant contextual cue is an implicit memory of action with a particular body part. To test this hypothesis we considered a task in which participants learned to control motion of a cursor under visuomotor rotation in two contexts: by moving their hand through motion of their shoulder and elbow, or through motion of their wrist. Use of these contextual cues led to three observations: First, in naive participants, learning in the wrist context was much faster than in the arm context. Second, generalization was asymmetric so that arm training benefited subsequent wrist training, but not vice versa. Third, in people who had prior wrist training, generalization from the arm to the wrist was blocked. That is, prior wrist training appeared to prevent both the interference and transfer that subsequent arm training should have caused. To explain the data, we posited that the learner collected statistics of contextual history: all upper arm movements also move the hand, but occasionally we move our hands without moving the upper arm. In a Bayesian framework, history of limb segment use strongly affects parameter uncertainty, which is a measure of the covariance of the contextual cues. This simple Bayesian prior dictated a generalization pattern that largely reproduced all three findings. For motor learning, generalization depends on context, which is determined by the statistics of how we have previously used the various parts of our limbs.

Generalization of Motor Learning Depends on the History of Prior Action

Adaptation and generalization in acceleration-dependent force fields

Multiple processes may contribute to motor skill acquisition, but it is thought that many of these processes require sleep or the passage of long periods of time ranging from several hours to many days or weeks. Here we demonstrate that within a timescale of minutes, two distinct fast-acting processes drive motor adaptation. One process responds weakly to error but retains information well, whereas the other responds strongly but has poor retention. This two-state learning system makes the surprising prediction of spontaneous recovery (or adaptation rebound) if error feedback is clamped at zero following an adaptation-extinction training episode. We used a novel paradigm to experimentally confirm this prediction in human motor learning of reaching, and we show that the interaction between the learning processes in this simple two-state system provides a unifying explanation for several different, apparently unrelated, phenomena in motor adaptation including savings, anterograde interference, spontaneous recovery, and rapid unlearning. Our results suggest that motor adaptation depends on at least two distinct neural systems that have different sensitivity to error and retain information at different rates.

Interacting Adaptive Processes with Different Timescales Underlie Short-Term Motor Learning

When one moves one’s hand from one point to another, the brain guides the arm by relying on neural structures that estimate the physical dynamics of the task. For example, if one is about to lift a bottle of milk that appears full rather than empty, the brain takes into account the subtle changes in the dynamics of the task and this is reflected in the altered motor commands. The neural structures that compute the task’s dynamics are “internal models” that transform the desired motion into motor commands. Internal models are learned with practice and are a fundamental part of voluntary motor control. What do internal models compute, and which neural structures perform that computation? We approach these problems by considering a task where physical dynamics of reaching movements are altered by force fields that act on the hand. Experiments by a number of laboratories on this paradigm suggest that internal models are sensorimotor transformations that map a desired sensory state

We describe the design, testing and tools to build parametric models of a six-legged cockroach-like robot for velocity control without precise knowledge on the robot's geometry or its inertia. Robot legs were made by Shape Deposition Manufacturing and were compliant at the "knee". These kinds of robots usually have a limited number of actuators and a small number of low-cost sensors. Consequently, they are difficult to control with analytic models. Our goal was to design a very fast robot that could run in a straight line over short distances at a desired velocity. We incorporated such legs into a novel body design, where position and orientation of the legs were chosen to enhance static stability. Robot design proved to be robust, as the machine did not suffer any failure in over 20,000 runs. We found that body-pitch angle was a crucial parameter in the control of running speed. To control this angle, we built a parametric model that related leg orientation to pitch angle. We experimented with various leg stiffness parameters, and built a comprehensive parametric model that quantified performance as a function of this parameter, as well as body-pitch angle, ground slope, and body mass. When these parameters were optimized, the robot consistently achieved a speed of six body lengths per second, even when pulling a large load in the form of a trailer cart.

Parametric models for motion planning and control in biomimetic robotics

Two different compensatory mechanisms are engaged when the nervous system senses errors during a reaching movement. First, on-line feedback control mechanisms produce in-flight corrections to reduce errors in the on-going movement. Second, these errors modify the internal model with which the motor plan is transformed into motor commands for the subsequent movements. What are the neural mechanisms of these compensatory systems? In a previous study, we reported that while on-line error correction was disturbed in patients with Huntington's disease (HD), it was largely intact in patients with cerebellar degeneration. Here we altered dynamics of reaching and studied the effect of error in one trial on the motor commands that initiated the subsequent trial. We observed that in patients with cerebellar degeneration, motor commands changed from trial-to-trial by an amount that was comparable to control subjects. However, these changes were random and were uninformed by the error in the preceding trial. In contrast, the change in motor commands of HD patients was strongly related to the error in the preceding trial. This error-dependent change had a sensitivity that was comparable to healthy controls. As a result, HD patients exhibited no significant deficits in adapting to novel arm dynamics, whereas cerebellar subjects were profoundly impaired. These results demonstrate a double dissociation between on-line and trial-to-trial error correction suggesting that these compensatory mechanisms have distinct neural bases that can be differentially affected by disease.

Intact ability to learn internal models of arm dynamics in Huntington's disease but not cerebellar degeneration.

Reach errors may be broadly classified into errors arising from unpredictable changes in target location, called target errors, and errors arising from miscalibration of internal models (e.g., when prisms alter visual feedback or a force field alters limb dynamics), called execution errors. Execution errors may be caused by miscalibration of dynamics (e.g., when a force field alters limb dynamics) or by miscalibration of kinematics (e.g., when prisms alter visual feedback). Although all types of errors lead to similar on-line corrections, we found that the motor system showed strong trial-by-trial adaptation in response to random execution errors but not in response to random target errors. We used functional magnetic resonance imaging and a compatible robot to study brain regions involved in processing each kind of error. Both kinematic and dynamic execution errors activated regions along the central and the postcentral sulci and in lobules V, VI, and VIII of the cerebellum, making these areas possible sites of plastic changes in internal models for reaching. Only activity related to kinematic errors extended into parietal area 5. These results are inconsistent with the idea that kinematics and dynamics of reaching are computed in separate neural entities. In contrast, only target errors caused increased activity in the striatum and the posterior superior parietal lobule. The cerebellum and motor cortex were as strongly activated as with execution errors. These findings indicate a neural and behavioral dissociation between errors that lead to switching of behavioral goals and errors that lead to adaptation of internal models of limb dynamics and kinematics.

During reaching, the brain may rely on internal models to transform desired sensory outcomes into motor commands. This transformation depends on both the state of the limb and the cues that can identify the context of the movement. How are contextual cues and information about state of the limb combined in the computations of internal models? We considered a reaching task where forces on the hand depended on both the direction of movement (state of the limb) and order of that movement in a predefined sequence (contextual cue). When the cue was available, the motor system formed an internal model that used both serial order and target direction to program motor commands. Assuming that the internal model was formed by a population code through a combination of unknown basis elements, the sensitivity of the bases with respect to state of the limb and contextual cue should dictate how error in one type of movement affected all other movement types. Using a state-space theory, we estimated this generalization function and identified the adaptive system from trial-by-trial changes in performance. The results implied that the basis elements were tuned to direction of movement but output of each basis at its preferred direction was multiplicatively modulated by a weak tuning with respect to the contextual cue. Activity fields that multiplicatively encode diverse sources of information may serve as a general mechanism for a single network to produce context-dependent motor output.

Internal models and contextual cues: encoding serial order and direction of movement.

Faculty Opinions recommendation of Adaptation to visuomotor transformations: consolidation, interference, and forgetting.

(PPV) vs negative pressure ventilation (NPV) in providing ventilatory muscle rest for five normal subjects and six patients with chronic obstructive pulmonary disease (COPD). All participants underwent measurement of trans diaphragmatic pressure (Pdi), pressure time integral of the diaphragm (PT!), integrated diaphragmatic electromyo gram (iEMG), minute ventilation (VE), tidal volume (VT), and end-tidal CO (etCOÃ during 15 minutes of PPV and NPV. For each subject, ventilator adjustments were made to obtain VE similar to levels measured during quiet breathing (QB). We found that the iEMG, Pdi, P11, and average coefficient of variation of the tidal volume (CV-VT) were consistently lower during PPV as compared with NPV (p=O.O1). The iEMG normalized for VE and VT was also significantly lower during PPV (p0.O1). During PPV, subjects were mildly hyperventilated (lower etCO, and

Efficacyof Positivevs NegativePressure Ventilationin UnloadingtheRespiratory Muscles *

Studies of reaching suggest that humans adapt to novel arm dynamics by building internal models that transform planned sensory states of the limb, e.g., desired limb position and its derivatives, into motor commands, e.g., joint torques. Earlier work modeled this computation via a population of basis elements and used system identification techniques to estimate the tuning properties of the bases from the patterns of generalization. Here we hypothesized that the neural representation of planned sensory states in the internal model might resemble the signals from the peripheral sensors. These sensors normally encode the limb's actual sensory state in which movement errors occurred. We developed a set of equations based on properties of muscle spindles that estimated spindle discharge as a function of the limb's state during reaching and drawing of circles. We then implemented a simulation of a two-link arm that learned to move in various force fields using these spindle-like bases. The system produced a pattern of adaptation and generalization that accounted for a wide range of previously reported behavioral results. In particular, the bases showed gain-field interactions between encoding of limb position and velocity, very similar to the gain fields inferred from behavioral studies. The poor sensitivity of the bases to limb acceleration predicted behavioral results that were confirmed by experiment. We suggest that the internal model of limb dynamics is computed by the brain with neurons that encode the state of the limb in a manner similar to that expected of muscle spindle afferents.

Lesion or degeneration of the cerebellum can profoundly impair adaptive control of reaching in humans. Computational models have proposed that internal models for motor action form in the cerebellum and influence planned motor output through the cerebello-thalamo-cortical pathway. However, lesions in the cerebellar thalamus have not been consistently shown to result in motor adaptation impairment. To elucidate the role of the cerebellar thalamus in humans, we studied a group of essential tremor (ET) patients with deep brain stimulation (DBS) electrodes placed in the cerebellar thalamus. The stimulation can be turned on or off remotely, and is thought to reduce tremor by blocking the spread of the pathological output from the cerebellum. We found that while thalamic DBS resulted in a dramatic reduction in ET, it also led to impaired motor adaptation in the patients. Thus, human adaptive reaching motor control depends on the integrity of the thalamic nucleus that relays cerebellar output to the cerebral cortex

2005 IEEE Engineering in Medicine and Biology 27th Annual Conference

Effects of Deep Brain Stimulation on Adaptive Control of Reaching

Mechanisms and techniques disclose a system that provides access to data using a two part cache. The system receives a data access request containing a first data reference, such as an open systems request to access data. The system then obtains a history cache entry from a history cache based on the first data reference and obtains a partition cache entry from a partition cache based on the first data reference. Cache entries contain mappings between open systems reference locations and non-open systems references to locations in the data to be accessed. The system then performs a data access operation as specified by the data access request using a second data reference based upon either the history cache entry or the partition cache entry. Upon performance of the data access operation, the system then updates the history and partition caches with new cache entries and can resize the partition and history caches as needed.

Generalization as a behavioral window to the neural mechanisms of learning internal models.

Faculty Opinions recommendation of Discharge of inferior olive cells during reaching errors and perturbations.

An introduction to the computational biology of reaching and pointing, with an emphasis on motor learning. Neuroscience involves the study of the nervous system, and its topics range from genetics to inferential reasoning. At its heart, however, lies a search for understanding how the environment affects the nervous system and how the nervous system, in turn, empowers us to interact with and alter our environment. This empowerment requires motor learning. The Computational Neurobiology of Reaching and Pointing addresses the neural mechanisms of one important form of motor learning. The authors integrate material from the computational, behavioral, and neural sciences of motor control that is not available in any other single source. The result is a unified, comprehensive model of reaching and pointing. The book is intended to be used as a text by graduate students in both neuroscience and bioengineering and as a reference source by experts in neuroscience, robotics, and other disciplines. The book begins with an overview of the evolution, anatomy, and physiology of the motor system, including the mechanisms for generating force and maintaining limb stability. The sections that follow, "Computing Locations and Displacements", "Skills, Adaptations, and Trajectories", and "Predictions, Decisions, and Flexibility", present a theory of sensorially guided reaching and pointing that evolves organically based on computational principles rather than a traditional structure-by-structure approach. The book also includes five appendixes that provide brief refreshers on fundamentals of biology, mathematics, physics, and neurophysiology, as well as a glossary of relevant terms. The authors have also made supplemental materials available on the Internet. These web documents provide source code for simulations, step-by-step derivations of certain mathematical formulations, and expanded explanations of some concepts.

The Computational Neurobiology of Reaching and Pointing: A Foundation for Motor Learning

When the human motor system adapts to novel dynamics of the arm during reaching, hand trajectories tends to converge toward a roughly straight line. This straight line is thought to be the desired trajectory of the system. Trial-to-trial changes in performance are well described by a first order state-space model: errors in a given trial affect performance on the subsequent trial as a function of the distance in state space between the two trials. This function describes the generalization patterns that govern adaptation. Whereas the desired trajectory and the generalization function have been quantified for short-term adaptation, little is known about their behavior with long-term training. We report that when subjects are trained to reach in novel force fields over multiple days, the state-space model suggests that the desired trajectory undergoes systematic changes. In a constant field, the desired trajectory becomes curved. The direction of change of the desired trajectory is affected by the training protocol, such that occasional unperturbed trials (catch trials) caused subject to increasingly under-compensate for the perturbations whereas a lack of such trials caused subjects to increasingly overcompensate for the perturbations. We suggest that the desired trajectory is not constant, but is a result of an optimization that considers the success rate. In this optimization process, subjects weigh more heavily the importance of certain trials: either those that are infrequent or those that cause large errors.

The 26th Annual International Conference of the IEEE Engineering in Medicine and Biology Society

Change of desired trajectory caused by training in a novel motor task

During reaching movements, the brain's internal models map desired limb motion into predicted forces. When the forces in the task change, these models adapt. Adaptation is guided by generalization: errors in one movement influence prediction in other types of movement. If the mapping is accomplished with population coding, combining basis elements that encode different regions of movement space, then generalization can reveal the encoding of the basis elements. We present a theory that relates encoding to generalization using trial-by-trial changes in behavior during adaptation. We consider adaptation during reaching movements in various velocity-dependent force fields and quantify how errors generalize across direction. We find that the measurement of error is critical to the theory. A typical assumption in motor control is that error is the difference between a current trajectory and a desired trajectory (DJ) that does not change during adaptation. Under this assumption, in all force fields that we examined, including one in which force randomly changes from trial to trial, we found a bimodal generalization pattern, perhaps reflecting basis elements that encode direction bimodally. If the DJ was allowed to vary, bimodality was reduced or eliminated, but the generalization function accounted for nearly twice as much variance. We suggest, therefore, that basis elements representing the internal model of dynamics are sensitive to limb velocity with bimodal tuning; however, it is also possible that during adaptation the error metric itself adapts, which affects the implied shape of the basis elements.

Quantifying Generalization from Trial-by-Trial Behavior of Adaptive Systems that Learn with Basis Functions: Theory and Experiments in Human Motor Control

Accurate performance of reaching movements depends on adaptable neural circuitry that learns to predict forces and compensate for limb dynamics. In earlier experiments, we quantified generalization from training at one arm position to another position. The generalization patterns suggested that neural elements learning to predict forces coded a limb's state in an intrinsic, muscle-like coordinate system. Here, we test the sensitivity of these elements to the other arm by quantifying inter-arm generalization. We considered two possible coordinate systems: an intrinsic (joint) representation should generalize with mirror symmetry reflecting the joint's symmetry and an extrinsic representation should preserve the task's structure in extrinsic coordinates. Both coordinate systems of generalization were compared with a naïve control group. We tested transfer in right-handed subjects both from dominant to nondominant arm (D-->ND) and vice versa (ND-->D). This led to a 2 x 3 experimental design matrix: transfer direction (D-->ND/ND-->D) by coordinate system (extrinsic, intrinsic, control). Generalization occurred only from dominant to nondominant arm and only in extrinsic coordinates. To assess the dependence of generalization on callosal inter-hemispheric communication, we tested commissurotomy patient JW. JW showed generalization from dominant to nondominant arm in extrinsic coordinates. The results suggest that when the dominant right arm is used in learning dynamics, the information could be represented in the left hemisphere with neural elements tuned to both the right arm and the left arm. In contrast, learning with the nondominant arm seems to rely on the elements in the nondominant hemisphere tuned only to movements of that arm.

Learned dynamics of reaching movements generalize from dominant to nondominant arm.

The delays in sensorimotor pathways pose a formidable challenge to the implementation of stable error feedback control, and yet the intact brain has little trouble maintaining limb stability. How is this achieved? One idea is that feedback control depends not only on delayed proprioceptive feedback but also on internal models of limb dynamics. In theory, an internal model allows the brain to predict limb position. Earlier we had found that during reaching, the brain estimates hand position in real-time in a coordinate system that can be used for generating saccades. Here we tested the idea that the estimate of hand position, as expressed through saccades, depends on an internal model that adapts to dynamics of the arm. We focused on the behavior of the eyes as perturbations were applied to the unseen hand. We found that when the hand was perturbed from stable posture with a 100-ms force pulse of random direction and magnitude, a saccade was generated on average at 182 ms postpulse onset to a position that was an unbiased estimate of real-time hand position. To test whether planning of saccades depended on an internal model of arm dynamics, arm dynamics were altered either predictably or unpredictably during the postpulse period. When arm dynamics were predictable, saccade amplitudes changed to reflect the change in the arm's behavior. We suggest that proprioceptive feedback from the arm is integrated into an adaptable internal model that computes an estimate of current hand position in eye-centered coordinates.

Adaptability of reaching movements depends on a computation in the brain that transforms sensory cues, such as those that indicate the position and velocity of the arm, into motor commands. Theoretical consideration shows that the encoding properties of neural elements implementing this transformation dictate how errors should generalize from one limb position and velocity to another. To estimate how sensory cues are encoded by these neural elements, we designed experiments that quantified spatial generalization in environments where forces depended on both position and velocity of the limb. The patterns of error generalization suggest that the neural elements that compute the transformation encode limb position and velocity in intrinsic coordinates via a gain-field; i.e., the elements have directionally dependent tuning that is modulated monotonically with limb position. The gain-field encoding makes the counterintuitive prediction of hypergeneralization: there should be growing extrapolation beyond the trained workspace. Furthermore, nonmonotonic force patterns should be more difficult to learn than monotonic ones. We confirmed these predictions experimentally.

A Gain-Field Encoding of Limb Position and Velocity in the Internal Model of Arm Dynamics

Where r is robot, s is subject, p is robot joint angles, q is subject joint angles, I is an inertial matrix, G is a coriolis-centripetal matrix, and E and C are forces actively generated by the robot and subject respectively. Fhandle is a coupling term that represents the force that the robot and subject apply to each other. The active subject torques, called the controller, are governed by both the actual position and velocity and the desired trajectory q(t). The desired trajectories we used were minimum-jerk for displacements of 10cm of 0.5s (Flash and Hogan, 1985).

Supplementary Information: Quantifying Generalization from Trial-by-Trial behavior of Adaptive Systems that Learn with Basis Functions

Theoretical motor control predicts that because of delays in sensorimotor pathways, a neural system should exist in the brain that uses efferent copy of commands to the arm, sensory feedback, and an internal model of the dynamics of the arm to predict the future state of the hand (i.e., a forward model). We tested this theory under the hypothesis that saccadic eye movements, tracking an unseen reaching movement, would reflect the output of this state predictor. We found that in unperturbed reaching movements, saccade occurrence at any timet consistently provided an unbiased estimate of hand position at t + 196 msec. To investigate the behavior of this predictor during feedback error control, we applied 50 msec random-force perturbations to the moving hand. Saccades showed a sharp inhibition at 100 msec after perturbation. At ∼170 msec, there was a sharp increase in saccade probabilities. These postperturbation saccades were an unbiased estimator of hand position at saccade timet + 150 msec. The ability of the brain to guide saccades to the future position of the hand failed when a force field unexpectedly changed the dynamics of the hand immediately after perturbation. The behavior of the eyes suggested that during reaching movements, the brain computes an estimate of future hand position based on an internal model that relies on real-time proprioceptive feedback. When an error occurs in reaching movements, the estimate of future hand position is recomputed. The saccade inhibition period that follows the hand perturbation may indicate the length of time it takes for this computation to take place.

A Real-Time State Predictor in Motor Control: Study of Saccadic Eye Movements during Unseen Reaching Movements

This paper presents a method to control industrial redundant manipulators based on a method similar to the mechanism ascribed to the human motor system that adaptively combines motor primitives to control human body motions. The idea is to identify a set of local model primitives based on Runge-Kutta-Gill neural networks (RKGNNs) and control the manipulator based on an adaptive selection and fusion method. The adaptive selection is carried out using a resonance signal that recalls only the most relevant memory primitives given a situation, and adaptive fusion is carried out by a method based on fuzzy memberships. This method imitates few recent findings on how human motor skills are developed by adaptive combination of motor primitives. Experiments on an industrial manipulator with seven degrees of freedom shows that the proposed method is a potentially viable approach to model based control of redundant robot manipulators.

Proceedings of the IEEE Internatinal Symposium on Intelligent Control

Intelligent control of a 7-DOF manipulator based on model primitives

An internal model of the dynamics of a tool or an object is part of the motor memory acquired when learning to use the tool or to manipulate the object. Changes in synaptic efficacy may underlie acquisition and storage of memories. Here we studied the effect of pharmacological agents that interfere with synaptic plasticity on acquisition of new motor memories and on recall of a previously learned internal model. Forty-nine subjects, divided into six groups, made reaching movements while holding a robotic arm that applied forces to the hand. On day 1, all subjects learned to move in force field A. On day 2, each group of subjects was tested on their ability to recall field A and their ability to learn a new internal model in field B. Four groups participated in the experiments of day 2 under the effects of lorazepam (LZ; a GABA type A receptor-positive allosteric modulator), dextromethorphan [DM; an N-methyl-D-aspartate (NMDA) receptor blocker], lamotrigine (LG, a drug that blocks voltage-gated Na(+) and Ca(2+) channel), or scopolamine (SP; muscarinic receptor antagonist). Two control groups were tested in a drug-free condition: one group that was not exposed to additional experimental protocols (NP) and another group was tested under ~24 h of sleep deprivation between completion of learning on day 1 and start of testing on day 2 (SD). Recall of field A was normal in all groups. Learning of field B was reduced by LZ and DM but not by SP, LG, SD or in the NP condition. These results suggest that a 24-h sleep-deprivation period may have little or no effect on consolidation of this motor memory and that NMDA receptor activation and GABAergic inhibition are mechanisms operating in the acquisition but not recall of new motor memories in humans.

Mechanisms influencing acquisition and recall of motor memories.

Reaching movements require the brain to generate motor commands that rely on an internal model of the task's dynamics. Here we consider the errors that subjects make early in their reaching trajectories to various targets as they learn an internal model. Using a framework from function approximation, we argue that the sequence of errors should reflect the process of gradient descent. If so, then the sequence of errors should obey hidden state transitions of a simple dynamical system. Fitting the system to human data, we find a surprisingly good fit accounting for 98% of the variance. This allows us to draw tentative conclusions about the basis elements used by the brain in transforming sensory space to motor commands. To test the robustness of the results, we estimate the shape of the basis elements under two conditions: in a traditional learning paradigm with a consistent force field, and in a random sequence of force fields where learning is not possible. Remarkably, we find that the basis remains invariant.

Linking Motor Learning to Function Approximation: Learning in an Unlearnable Force Field

We investigated how an internal model is generalized when the dynamics of the arm is changed during reaching movements in a force field. We also investigated whether generalization occurs in intrinsic or extrinsic coordinates. Three regions of the workspace were used to train and test the subjects: Left, Right and Center. The subjects were trained in one region with a force field and then were tested in another region with the same force field. The results show substantial generalization in reaching movements when the applied force field is in joint-based (intrinsic) coordinates.

Long-term adaptation to dynamics of reaching movements: a PET study

Learning the dynamics of reaching movements results in the modification of arm impedance and long-latency perturbation responses

We investigated how the CNS learns to control movements in di erent dynamical conditions, and how this learned behavior is represented. In particular, we considered the task of making reaching movements in the presence of externally imposed forces from a mechanical environment. This environment was a force eld produced by a robot manipulandum, and the subjects made reaching movements while holding the end{e ector of this manipulandum. Since the force eld signi cantly changed the dynamics of the task, subjects' initial movements in the force eld were grossly distorted compared to their movements in free space. However, with practice, hand trajectories in the force eld converged to a path very similar to that observed in free space. This indicated that for reaching movements, there was a kinematic plan independent of dynamical conditions. The recovery of performance within the changed mechanical environment is motor adaptation. In order to investigate the mechanism underlying this adaptation, we considered the response to the sudden removal of the eld after a training phase. The resulting trajectories, named after{e ects, were approximately mirror images of those which were observed when the subjects were initially exposed to the eld. This suggested that the motor controller was gradually composing a model of the force eld, a model which the nervous system used to predict and compensate for the forces imposed by the environment. In order to explore the structure of the model, we investigated whether adaptation to a force eld, as presented in a small region, led to after{e ects in other regions of the workspace. We found that indeed there were after{e ects in workspace regions where no exposure to the eld had taken place, i.e., there was transfer beyond the boundary of the training data. This observation rules out the hypothesis that the subject's model of the force eld was constructed as a narrow association between visited states and experienced forces, i.e. adaptation was not via composition of a look{up table. In contrast, subjects modeled the force eld by a combination of computational elements whose output was broadly tuned across the motor state space. These elements formed a model which extrapolated to outside the training region in a coordinate system similar to that of the joints and muscles rather than endpoint forces. This geometric property suggests that the elements of the adaptive process represent dynamics of a motor task in terms of the intrinsic coordinate system of the sensors and actuators. Copyright c Massachusetts Institute of Technology, 1993 This research was supported in part by Grants from the NIH (NS09343 and AR26710), the ONR (N00014/90/J/1946), and the McDonnell{Pew Center for Cognitive Neuroscience. This report describes research done at the Dept. of Brain and Cognitive Sciences, the Center for Biological and Computational Learning, and the Arti cial Intelligence Laboratory of the Massachusetts Institute of Technology. Support for CBCL is provided in part by a grant from the NSF (ASC{9217041). Support for the laboratory's arti cial intelligence research is provided in part by the Advanced Research Projects Agency of the Dept. of Defense.

MASSACHUSETTS INSTITUTE OF TECHNOLOGY ARTIFICIAL INTELLIGENCE LABORATORY and CENTER FOR BIOLOGICAL AND COMPUTATIONAL LEARNING DEPARTMENT OF BRAIN AND COGNITIVE SCIENCES

Error correction and the basal ganglia Response to Lawrence (2000)

When subjects practice reaching movements in a force field, they learn a new sensorimotor map that associates desired trajectories to motor commands. The map is formed in the brain with elements that allow for generalization beyond the region of training. We quantified spatial generalization properties of these elements by training in one extreme of the reachable space and testing near another. Training resulted in rotations in the preferred direction (PD) of activation of some arm muscles. We designed force fields that maintained a constant rotation in muscle PDs as the shoulder joint rotated in the horizontal plane. In such fields, training in a small region resulted in generalization to near and far work spaces (80 cm). In one such field, the forces on the hand reversed directions for a given hand velocity with respect to the location of original training. Despite this, there was generalization. However, if the field was such that the change in the muscle PDs reversed as the work spaces changed, then performance was worse than performance of naive subjects. We suggest that the sensorimotor map of arm dynamics is represented in the brain by elements that globally encode the position of the arm but locally encode its velocity. The elements have preferred directions of movement but are modulated globally by the position of the shoulder joint. We suggest that tuning properties of cells in the motor system influence behavior and that this influence is reflected in the way that we learn dynamics of reaching movements.

Spatial Generalization from Learning Dynamics of Reaching Movements

Learning of action through adaptive combination of motor primitives

Motor disorder in Huntington's disease begins as a dysfunction in error feedback control

Theoretical and psychophysical studies have suggested that humans learn to make reaching movements in novel dynamic environments by building specific internal models (IMs). Here we have found electromyographic correlates of internal model formation. We recorded EMG from four muscles as subjects learned to move a manipulandum that created systematic forces (a “force field”). We also simulated a biomechanical controller, which generated movements based on an adaptive IM of the inverse dynamics of the human arm and the manipulandum. The simulation defined two metrics of muscle activation. The first metric measured the component of the EMG of each muscle that counteracted the force field. We found that early in training, the field-appropriate EMG was driven by an error feedback signal. As subjects practiced, the peak of the field-appropriate EMG shifted temporally to earlier in the movement, becoming a feedforward command. The gradual temporal shift suggests that the CNS may use the delayed error–feedback response, which was likely to have been generated through spinal reflex circuits, as a template to learn a predictive feedforward response. The second metric quantified formation of the IM through changes in the directional bias of each muscle’s spatial EMG function, i.e., EMG as a function of movement direction. As subjects practiced, co-activation decreased, and the directional bias of each muscle’s EMG function gradually rotated by an amount that was specific to the field being learned. This demonstrates that formation of an IM can be represented through rotations in the spatial tuning of muscle EMG functions. Combined with other recent work linking spatial tunings of EMG and motor cortical cells, these results suggest that rotations in motor cortical tuning functions could underlie representation of internal models in the CNS.

Electromyographic Correlates of Learning an Internal Model of Reaching Movements

Computational nature of human adaptive control during learning of reaching movements in force fields

Based on computational principles, the concept of an internal model for adaptive control has been divided into a forward and an inverse model. However, there is as yet little evidence that learning control by the CNS is through adaptation of one or the other. Here we examine two adaptive control architectures, one based only on the inverse model and other based on a combination of forward and inverse models. We then show that for reaching movements of the hand in novel force fields, only the learning of the forward model results in key characteristics of performance that match the kinematics of human subjects. In contrast, the adaptive control system that relies only on the inverse model fails to produce the kinematic patterns observed in the subjects, despite the fact that it is more stable. Our results provide evidence that learning control of novel dynamics is via formation of a forward model.

Evidence for a Forward Dynamics Model in Human Adaptive Motor Control

Functional properties of motor memory change with the passage of time. The time-dependent nature of memories in humans has also been demonstrated for certain "declarative" memories. When the declarative memory system is damaged, are the time-dependent properties associated with motor memories intact? To approach this question, we examined five subjects with global amnesia (AMN), including subject H.M., and a group of age-matched control subjects. The task was to make reaching movements to visually presented targets. We found that H.M. (but not the other subjects) was significantly impaired in the ability to perform the visuomotor kinematic transformations required in this task, to accurately move the hand in the direction specified by a target. With extensive practice, H.M.'s performance improved significantly. At this point, a force field was imposed on the hand. With practice in field A, H.M. and other AMN subjects developed aftereffects and maintained these aftereffects for 24 h. To quantify postpractice properties associated with motor memories, subjects learned field B on day 2 and at 5 min were retested in field A. In both subject groups, performance in field A was significantly worse than their own naive performance a day earlier. The aftereffects indicated persistence of the just-learned but now inappropriate motor memory. After 4 h of rest, subjects were retested in B. Performance was now at naive levels. The aftereffects at 4 h indicated a reduced influence of the memory of field A. The time-dependent patterns of motor memory perseveration, as measured at 5 min and 4 h, were not different in the AMN and normal control groups.

One can use a number of techniques (e.g., from videotaping to computer enhancement of the environment) to augment the feedback that a subject usually receives during training on a motor task. Although some forms of augmented feedback have been shown to enhance performance on isolated isometric tasks during training, when the feedback has been removed subjects have sometimes not been able to perform as well in the "real-world" task as controls. Indeed, for realistic, nonisometric motor tasks, improved skill acquisition because of augmented feedback has not been demonstrated. In the present experiments, subjects (Experiment 1, N = 42; Experiment 2, N = 21) performed with a system that was designed for teaching a difficult multijoint movement in a table tennis environment. The system was a fairly realistic computer animation of the environment and included paddles for the teacher and subject, as well as a virtual ball. Each subject attempted to learn a difficult shot by matching the pattern of movements of the expert teacher. Augmented feedback focused the attention of the subject on a minimum set of movement details that were most relevant to the task; feedback was presented in a form that required the least perceptual processing. Effectiveness of training was determined by measuring their performance in the real task. Subjects who received the virtual environment training performed significantly better than subjects who received a comparable amount of real-task practice or coaching. Kinematic analysis indicated that practice with the expert's trajectory served as a basis for performance on the real-world task and that the movements executed after training were subject-specific modifications of the expert's trajectory. Practice with this trajectory alone was not sufficient for transfer to the real task, however: When a critical component of the virtual environment was removed, subjects showed no transfer to the real task.

Augmented Feedback Presented in a Virtual Environment Accelerates Learning of a Difficult Motor Task.

Computational studies suggest that acquisition of a motor skill involves learning an internal model of the dynamics of the task, which enables the brain to predict and compensate for mechanical behavior. During the hours that follow completion of practice, representation of the internal model gradually changes, becoming less fragile with respect to behavioral interference. Here, functional imaging of the brain demonstrates that within 6 hours after completion of practice, while performance remains unchanged, the brain engages new regions to perform the task; there is a shift from prefrontal regions of the cortex to the premotor, posterior parietal, and cerebellar cortex structures. This shift is specific to recall of an established motor skill and suggests that with the passage of time, there is a change in the neural representation of the internal model and that this change may underlie its increased functional stability.

Previous research has demonstrated that the primate CNS has the ability to learn and store multiple and conflicting visuo-motor maps. Here we studied the ability of human subjects to learn to make reaching movements while interacting with one of two conflicting mechanical environments as produced by a robotic manipulandum. We demonstrate that two motor maps may be learned and retained, but only if the training sessions in the tasks are separated by an interval of ∼5 hr. If the interval is shorter, learning of the second map begins with an internal model appropriate for the first task and performance in the second task is significantly impaired. Analysis of the after-effects suggests that with a short temporal distance, learning of the second task leads to an unlearning of the internal model for the first. With the longer temporal distance, learning of the second task starts with an unbiased internal model, and performance approaches that of naives. Furthermore, the memory of the consolidated skill lasts for at least 5 months after training. These results argue for a distinct change in the state of resistance of motor memory (to disruption) within a few hours after acquisition. We suggest that motor practice results in memories that have at least two functional components: soon after completion of practice, one component fades while another is strengthened. A further experiment suggests that the hypothetical first stage is not merely a gateway to long-term memory, but also temporary storage for items of information, whether new or old, for use in the near-term. Our results raise the possibility that there are distinct neuronal mechanisms for representation of the two functional stages of motor memory.

Functional Stages in the Formation of Human Long-Term Motor Memory

Laboratory and clinical observations of patients with a large-fiber somatic sensory neuropathy indicate a dramatic inability of these patients to set accurate tonic or phasic levels of muscle activity needed to maintain static postures and to reproduce simple movements. These observations suggest that somatic sensation contributes to sensations of motor output, previously thought to be mediated by central mechanisms of corollary discharge. We review data describing psychophysical performance on weight-matching tasks and discuss new experiments on reaching tasks done by patients with a large-fiber sensory neuropathy and normal controls. In combination, the data show that patients with peripheral sensory deficits exhibit an impaired sense of muscular effort and the consequences of active movement. In addition, the data on weight matching indicate that the basis of disrupted effort sense relates to an inability to correlate psychophysical decisions with concomitant muscle activity. In new experiments, accuracy to match actively achieved arm end points by pointing was decreased in patients with large-fiber sensory neuropathy. The collective results suggest that appreciation of motor output is mediated in part by peripheral return from somatic sensory afferent systems.

Sense of muscular effort and somesthetic afferent information in humans.

We investigated how the CNS learns to control movements in different dynamical conditions, and how this learned behavior is represented. In particular, we considered the task of making reaching movements in the presence of externally imposed forces from a mechanical environment. This environment was a force field produced by a robot manipulandum, and the subjects made reaching movements while holding the end-effector of this manipulandum. Since the force field significantly changed the dynamics of the task, subjects' initial movements in the force field were grossly distorted compared to their movements in free space. However, with practice, hand trajectories in the force field converged to a path very similar to that observed in free space. This indicated that for reaching movements, there was a kinematic plan independent of dynamical conditions. The recovery of performance within the changed mechanical environment is motor adaptation. In order to investigate the mechanism underlying this adaptation, we considered the response to the sudden removal of the field after a training phase. The resulting trajectories, named aftereffects, were approximately mirror images of those that were observed when the subjects were initially exposed to the field. This suggested that the motor controller was gradually composing a model of the force field, a model that the nervous system used to predict and compensate for the forces imposed by the environment. In order to explore the structure of the model, we investigated whether adaptation to a force field, as presented in a small region, led to aftereffects in other regions of the workspace. We found that indeed there were aftereffects in workspace regions where no exposure to the field had taken place; that is, there was transfer beyond the boundary of the training data. This observation rules out the hypothesis that the subject's model of the force field was constructed as a narrow association between visited states and experienced forces; that is, adaptation was not via composition of a look-up table. In contrast, subjects modeled the force field by a combination of computational elements whose output was broadly tuned across the motor state space. These elements formed a model that extrapolated to outside the training region in a coordinate system similar to that of the joints and muscles rather than end-point forces. This geometric property suggests that the elements of the adaptive process represent dynamics of a motor task in terms of the intrinsic coordinate system of the sensors and actuators.

Adaptive representation of dynamics during learning of a motor task

Experiments were performed to reveal some of the computational properties of the human motor memory system. We show that as humans practice reaching movements while interacting with a novel mechanical environment, they learn an internal model of the inverse dynamics of that environment. Subjects show recall of this model at testing sessions 24 hours after the initial practice. The representation of the internal model in memory is such that there is interference when there is an attempt to learn a new inverse dynamics map immediately after an anticorrelated mapping was learned. We suggest that this interference is an indication that the same computational elements used to encode the first inverse dynamics map are being used to learn the second mapping. We predict that this leads to a forgetting of the initially learned skill.

Interference in Learning Internal Models of Inverse Dynamics in Humans

Biological sensorimotor systems are not static maps that transform input (sensory information) into output (motor behavior). Evidence from many lines of research suggests that their representations are plastic, experience-dependent entities. While this plasticity is essential for flexible behavior, it presents the nervous system with difficult organizational challenges. If the sensorimotor system adapts itself to perform well under one set of circumstances, will it then perform poorly when placed in an environment with different demands (negative transfer)? Will a later experience-dependent change undo the benefits of previous learning (catastrophic interference)? We explore the first question in a separate paper in this volume (Shadmehr et al. 1995). Here we present psychophysical and computational results that explore the question of catastrophic interference in the context of a dynamic motor learning task. Under some conditions, subjects show evidence of catastrophic interference. Under other conditions, however, subjects appear to be immune to its effects. These results suggest that motor learning can undergo a process of consolidation. Modular neural networks are well suited for the demands of learning multiple input/output mappings. By incorporating the notion of fast- and slow-changing connections into a modular architecture, we were able to account for the psychophysical results.

We consider the problem of how the CNS learns to control dynamics of a mechanical system. By using a paradigm where a subject's hand interacts with a virtual mechanical environment, we show that learning control is via composition of a model of the imposed dynamics. Some properties of the computational elements with which the CNS composes this model are inferred through the generalization capabilities of the subject outside the training data.

Computational Elements of the Adaptive Controller of the Human Arm

If muscles are viewed as spring-like torque generators, then the integral of torque with respect to joint angle is the potential energy of that muscle. An energy function for the musculoskeletal system can be defined by summing the energy contribution of each muscle and the potential energy stored in the limb. Any local minimum in this energy landscape is a possible equilibrium position for the limb. The gradient of this function with respect to joint angles is a torque field, and the task of postural control is to find a set of muscle activations to produce a desired field. We consider one technique by which this approximation may be achieved: A postural module is defined as a synergy of muscles that produce a class of torque functions that converge at a constant equilibrium position, but whose stiffness at this position varies as a function of activation of the postural module. For a single-joint system, we show that through control of two such modules it is possible to produce any stiffness at any desired equilibrium position. To extend this scheme to a multijoint system, we initially derive the mechanical constraints on the shape of the restoring force field when a multijoint limb is displaced from equilibrium. Next, we consider voluntary control of the force field when the human arm is displaced from equilibrium: Mussa-Ivaldi, Hogan, and Bizzi (1985) have suggested that subjects are unable to voluntarily change the shape and orientation of the field, although they can readily scale it. This suggests existence of a limitation on the independent recruitment of arm muscles. We show, through simulation, that the inability to voluntarily control the shape and orientation of the restoring force field can be attributed to an organization of postural modules that act as local stiffness controllers. We propose that through coactivation, postural modules coarsely encode the work space and serve as an intermediate control system in the motor control hierarchy.

Control of Equilibrium Position and Stiffness Through Postural Modules.

When a perturbation displaces the human hand from equilibrium, arm muscles respond by producing restoring forces. When a set of displacements are given at various directions from the same equilibrium position, the resulting restoring forces form a “postural force field.” It is not known whether these postural forces are related to those generated when a reaching movement is executed. However, if a movement is a consequence of a shift of the equilibrium position of the hand toward the target, then, from the postural force field, predictions can be made regarding the nature of the elastic forces acting on the hand during the movement. We have taken the first steps in testing this hypothesis by measuring the postural force field of a subject's arm over relatively large distances, and comparing these forces with the static forces generated at the hand while the subject attempted a reaching movement. Using a robot manipulandum, the hand was displaced at various directions from an equilibrium position. The measured restoring forces were fitted to a nonlinear model to define a postural force field for that equilibrium position. This field was used to predict elastic forces generated when the subject attempted to move the manipulandum from a point on the circumference of a circle to a target at its center--the center corresponded to the equilibrium position at which the postural field was measured. In some of the movement trials, the manipulandum was locked during approximately the first 120 msec of the program for motion and the resulting static “evoked” forces measured. We found that (1) the evoked forces did not point to the target, but were a function of the configuration of the arm and rotated with the shoulder joint, and (2) the magnitude of the evoked forces varied systematically, even though the movements were of the same magnitude. These patterns were remarkably similar to those observed in the postural forces. Our results provide experimental evidence linking maintenance of posture in a multijoint system to that of generating a movement. The evidence is consistent with the hypothesis that the CNS programs a reaching movement by shifting the equilibrium position of the hand toward the target.

Postural force fields of the human arm and their role in generating multijoint movements

The objects with which the hand interacts with may significantly change the dynamics of the arm. How does the brain adapt control of arm movements to this new dynamics? We show that adaptation is via composition of a model of the task''s dynamics. By exploring generalization capabilities of this adaptation we infer some of the properties of the computational elements with which the brain formed this model: the elements have broad receptive fields and encode the learned dynamics as a map structured in an intrinsic coordinate system closely related to the geometry of the skeletomusculature. The low--level nature of these elements suggests that they may represent a set of primitives with which a movement is represented in the CNS.

A mathematical analysis of the force-stiffness characteristics of muscles in control of a single joint system

We report on a simple technique that characterizes the effect of process parameters (i.e., pressure, RF power, and gas mixture) on the optical emission and mass spectra of CHFJO2 plasma. This technique is sensitive to changes in chamber contamination levels (e.g., formation of Teflon-like thin-film), and appears to be a promising tool for real-time monitoring and control of reactive ion etching. Through principal component analysis, we observe that 99% of the variance in the more than 1100 optical and mass spectra channels are accounted for by the first four principal components of each sensor. Projection of the mass spectrum on its principal components suggests a strong linear relationship with respect to chamber pressure. This representation also shows that the effect of changes in thin-film levels, gas mixture, and RF power on the mass spectrum is complicated, but predictable. To model the nonlinear relationship between these process parameters and the principal component projections, a feedforward, multi-layered neural network is trained and is shown to be able to predict all process parameters from either the mass or the optical spectrum. The projections of the optical emission spectrum on its principal components suggest that optical emission spectroscopy is much more sensitive to changes in RF power than the mass spectrum, as measured by the residual gas analyzer. Model performance can be significantly improved if both the optical and mass spectrum projections are used (so called sensor fusion). Our analysis indicates that accurate estimates of process parameters and chamber conditions can be made with relatively simple neural network models which fuse the principal components of the measured optical emission and mass spectra. In the reactive ion etching (RIE) process, plasma characteristics depend on many parameters; some of these parameter values are set by the tool operator, e.g., chamber pressure, RF power, and gas flow, while others are internal to the condition of the chamber, e.g., thin-film thickness on the chamber walls, or the amount of material etched. Plasma characteristics can be observed using in situ measurements, e.g., via optical emission spectroscopy (OES) or residual gas analysis (RGA). How these measurements can be used to estimate the process parameters is the question

Principal Component Analysis of Optical Emission Spectroscopy and Mass Spectrometry: Application to Reactive Ion Etch Process Parameter Estimation Using Neural Networks

Our goal is to describe a computational framework for control of posture and movement in multijoint limb, consistent with the constraints imposed by the neural and mechanical properties of the system. We search for a coherent way of organizing a pre-motoneuron, spinal based control system which can translate relatively high-level commands from the supra-spinal centers into the language of the muscles. A derivation is provided which supports the hypothesis that the static response of a muscle and its reflex system can be viewed as a non-linear spring with an adjustable resting length. Citing experimental data, the class of models where a muscle is viewed as a non-linear spring with an adjustable stiffness can be rejected. The issue of actuator redundancy and postural stability with muscles is examined through control of an inverted pendulum and a multi-joint structure. The potential energy of the musculo-skeletal system is derived and it is suggested that the task of postural control can be viewed as sculpting an energy landscape so that there is a local minimum associated with the desired limb configuration. An algorithm for producing this landscape is proposed: We define a postural module as a synergy of muscles which can be activated to produce a class of torque functions which all have a zero value at a specified equilibrium position. Postural modules form a distributed set of stiffness controllers, and by co-activation of these modules it is possible to encode the reachable space and control the limb's stiffness. We describe a computational framework in which postural modules can account for the observed limitations in voluntary control of stiffness in man, EMG during initiation of movement, and perceptual errors which exist when subjects are asked to guess the characteristics of compliant objects. Movements of kinematically redundant limbs are considered in light of this framework in the frog wiping reflex. Finally, a learning algorithm is applied to compensate for the dynamics of a limb during rapid movements through production of a virtual equilibrium trajectory. (Copies available exclusively from Micrographics Department, Doheny Library, USC, Los Angeles, CA 90089-0182.)

A computational theory for control of posture and movement in a multijoint limb

Two procedures were used to estimate the relative contribution of neurotransmission failure (NF) to fatigue of the rat diaphragm at different rates of phrenic nerve stimulation. In one, direct muscle stimulation was intermittently superimposed on neural stimulation of the diaphragm, and the relative contribution of NF was estimated by the difference in generated tension. In a second procedure, diaphragm fatigue was induced by using either direct muscle stimulation (with complete blockade of the neuromuscular junction by d-tubocurare) or phrenic nerve stimulation. The relative contribution of NF to diaphragm fatigue was then estimated by comparing the force loss during these two modes of stimulation. With both procedures, it was observed that 1) the relative contribution of NF to diaphragm fatigue was less than 45% at each frequency of phrenic nerve stimulation; 2) the relative contribution of NF to diaphragm fatigue increased at higher rates of phrenic stimulation, reaching a maximum at 75 pulses/s; and 3) the relative contribution of NF to diaphragm fatigue reached a plateau after 2 min of repetitive stimulation.

Relative contribution of neurotransmission failure to diaphragm fatigue.

We compared the efficacy of positive pressure ventilation (PPV) vs negative pressure ventilation (NPV) in providing ventilatory muscle rest for five normal subjects and six patients with chronic obstructive pulmonary disease (COPD). All participants underwent measurement of transdiaphragmatic pressure (Pdi), pressure time integral of the diaphragm (PTI), integrated diaphragmatic electromyogram (iEMG), minute ventilation (Ve), tidal volume (Vt), and end-tidal CO2 (etCO2) during 15 minutes of PPV and NPV. For each subject, ventilator adjustments were made to obtain Ve similar to levels measured during quiet breathing (QB). We found that the iEMG, Pdi, PTI, and average coefficient of variation of the tidal volume (CV-Vt) were consistently lower during PPV as compared with NPV (p = 0.01). The iEMG normalized for Ve and Vt was also significantly lower during PPV (p = 0.01). During PPV, subjects were mildly hyperventilated (lower etCO2 and higher Ve) compared with QB and NPV, but no significant correlation was noted between the change in etCO2 and the change in iEMG. The change in PTI was significantly correlated with the change in iEMG (p less than 0.01). We conclude that in the short term, PPV is more effective than NPV in reducing diaphragmatic activity. Positive pressure ventilation may be the preferred method of assisted ventilation in future studies of ventilatory muscle rest therapy.

Efficacy of positive vs negative pressure ventilation in unloading the respiratory muscles.

The cerebellar model articulation controller (CMAC) (Albus 1975) is applied for learning the inverse dynamics of a simulated two joint, planar arm. The actuators were antagonistic muscles, which acted as feedback controllers for each joint. We use this example to demonstrate some limitations of the control paradigm used in earlier applications of the CMAC (e.g., Miller et al. 1987, 1990): the CMAC learns dynamics of the arm and not those of the feedback system. We suggest an alternate approach, one in which the CMAC learns to manipulate the feedback controller's input, producing a virtual trajectory, rather the controller's output, which is torque. Several experiments are performed that suggest that the CMAC learns to compensate for the dynamics of the plant, as well as the controller.

Learning Virtual Equilibrium Trajectories for Control of a Robot Arm

The feasibility of developing a neural network to perform nonlinear Bayesian estimation from sparse data is explored using an example from clinical pharmacology. The problem involves estimating parameters of a dynamic model describing the pharmacokinetics of the bronchodilator theophylline from limited plasma concentration measurements of the drug obtained in a patient. The estimation performance of a backpropagation trained network is compared to that of the maximum likelihood estimator as well as the maximum a posteriori probability estimator. In the example considered, the estimator prediction errors (model parameters and outputs) obtained from the trained neural network were similar to those obtained using the nonlinear Bayesian estimator.

A Neural Network for Nonlinear Bayesian Estimation in Drug Therapy

We have studied the scratch reflex in order to better understand the strategy that the spinal neural structures use to program limb movements. A network is proposed for the positioning and rhythmic portions of the scratch reflex in the deafferented preparation. This model is based on Berkinblit's hypotheses regarding organization of neurons constituting the spinal central pattern generator (CPG) for this behavior. We offer a mechanism by which the initial position of the hindlimb can influence the output of the CPG in the immobilized animal.

A Neural Model for Generation of Some Behaviors in the Fictive Scratch Reflex

A connectionist model (adaptive neural network) is developed for estimating the pharmacokinetic properties of a drug from plasma concentrations measured during the course of therapy. The back-propagation algorithm was used to determine the weights in a three-layered network model from simulated sets of kinetic parameters and drug concentrations. The estimation performance of the connectionist model is shown to compare well to that of maximum-likelihood and Bayesian estimators.<<ETX>>

Images of the Twenty-First Century. Proceedings of the Annual International Engineering in Medicine and Biology Society,

Connectionist modeling vs. Bayesian procedures for sparse data pharmacokinetic parameter estimation

Summary form only given. A mathematical model of the neuromuscular system is built to describe some of the consequences of the equilibrium trajectory hypothesis (ETH) regarding the role of spinal control structures in movement. This model builds on the assumption that the spring-like reaction of the arm to small disturbances is mainly due to the length-tension properties of the muscles and not the length-dependent spinal reflexes. In order to explore point-to-point movements, a two-joint model of the arm is constructed, and its inverse dynamics are solved to predict movement trajectories for developed muscular forces. ETH suggests that movement is controlled by the central nervous system through gradual shifting of the arm's equilibrium point. A minimum jerk criterion function is used to define this virtual trajectory. An algorithm is suggested for assigning firing rates for a given virtual trajectory. To determine the role of the spinal reflexes, the model is tested in the case where no afferent information is available, so the virtual trajectory serves as the only source of neuromuscular activation.<<ETX>>

An implementation of the equilibrium trajectory hypothesis for movement generation in the arm

Neural model for modifiable pattern generation in the scratch reflex

To overcome the problem of altered breathing strategy during resistive ventilatory muscle training (VMT), we used a single-orifice inspiratory resistance together with a target feedback device (TFD) in patients with chronic obstructive pulmonary disease (COPD). In a preliminary study (study A), we showed that the resistance plus TFD was effective in controlling breathing strategy. We subsequently used the resistor plus TFD in a 5-wk study (study B) of VMT in 17 COPD patients who were randomized into high-intensity (HI) and low-intensity (LI) training groups. Compared with the LI group, the HI group showed significant increases in static maximal inspiratory pressure (21.3 vs. 5.0 cmH2O), maximal sustained ventilatory capacity (MSVC, 3.2 vs -0.1 l/min, sustained maximal mouth pressure (12.1 vs. 0.6 cmH2O), mean mouth pressure (6.9 vs. 3.9 cmH2O), peak inspiratory flow rate (12.3 vs. 4.0 l/min), and maximal sustained work rate (12.2 vs. 4.2 cmH2O.l-1.min-1). We conclude that targeted VMT with control of breathing strategy improves both ventilatory muscle strength and endurance.

Targeted resistive ventilatory muscle training in chronic obstructive pulmonary disease.

The authors approach the problem of translating sensory information to a coordinated pattern of muscular activation by presenting a model for the initial positioning and rhythmic behavior of the hindlimb in the scratch reflex. This model draws heavily on a set of hypotheses proposed by M.B. Berkinblit et al. (1978) regarding apparent localization of the pattern generator in lamina VII of the fourth and fifth lumbar segments of the spinal cord. The authors propose a network based exclusively on interneurons residing in this area. Given a tonic input, the activities of the network's neurons produce the initial positioning phase. This in turn leads to a rhythmic phase that correlates well with the required motor output during a scratch cycle. A mechanism is suggested for varying the length of the initial positioning phase (and presumably location of the hindlimb), independent of the period of the rhythmic phase.<<ETX>>

L'invention concerne un appareil et un procede permettant d'enseigner des mouvements a un etre humain, l'apprentissage par l'etudiant reposant sur l'imitation du mouvement de l'enseignant. Le mouvement de l'enseignant est detecte par un dispositif de detection de mouvements, puis numerise par un ordinateur et enfin enregistre dans une memoire. L'ordinateur genere une sequence d'images virtuelles de l'enseignant sur l'ecran d'affichage de l'enseignant pour avoir une interaction dans l'environnement virtuel genere par l'ordinateur afin que l'etudiant visualise et imite le mouvement de l'enseignant. Le meme dispositif de detection de mouvements utilise pour enregistrer le mouvement de l'enseignant suit le mouvement de l'eleve et l'ordinateur cree une sequence d'images virtuelles sur l'affichage correspondant aux mouvements de l'eleve et son interaction avec l'environnement virtuel en temps reel, tout en fournissant simultanement une sequence d'images du mouvement de l'enseignant. Le travail de l'eleve consiste a imiter le mouvement de l'enseignant. Ce processus est repete jusqu'a ce que les trajectoires de l'enseignant et de l'eleve correspondent parfaitement dans l'espace et dans le temps.

Systeme d'apprentissage des trajectoires par l'homme dans des environnements virtuels

Systeme d'apprentissage des mouvements du corps utilisant des environnements virtuels

Dans un dispositif et procede permettant de donner une dexterite motrice a un etre humain, l'apprentissage par un eleve est base sur l'imitation d'un mouvement du professeur, lequel est capte par un dispositif capteur de mouvements, numerise par un ordinateur puis enregistre dans une memoire remanente d'ordinateur. L'ordinateur genere sur l'ecran une sequence d'images du professeur afin que l'eleve puisse la regarder et l'imiter. Pour enregistrer le mouvement de l'eleve, on utilise le meme capteur que celui utilise pour enregistrer le mouvement du professeur, et l'ordinateur cree sur l'ecran une sequence d'images correspondant au mouvement de l'eleve, tout en produisant en meme temps une sequence d'images du mouvement du professeur. L'entrainement de l'eleve est base sur l'affichage a l'ecran du mouvement preenregistre du professeur. La tâche de l'eleve consiste a imiter le mouvement du professeur. Ce processus est repete jusqu'a ce que la trajectoire de l'eleve et celle du professeur coincident dans l'espace et dans le temps.

The computational neurobiology of reaching and pointing , The computational neurobiology of reaching and pointing , کتابخانه دیجیتال جندی شاپور اهواز

63. Kongress der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin e. V.

Junge Patientin mit AV-Block III. Grades bei starker FDG-Anreicherung im Bereich des interventrikulären Septums

We present the class of Hida-Matérn kernels, which is the canonical family of covariance functions over the entire space of stationary Gauss-Markov Processes. It extends upon Matérn kernels, by allowing for flexible construction of priors over processes with oscillatory components. Any stationary kernel, including the widely used squared-exponential and spectral mixture kernels, are either directly within this class or are appropriate asymptotic limits, demonstrating the generality of this class. Taking advantage of its Markovian nature we show how to represent such processes as state space models using only the kernel and its derivatives. In turn this allows us to perform Gaussian Process inference more efficiently and side step the usual computational burdens. We also show how exploiting special properties of the state space representation enables improved numerical stability in addition to further reductions of computational complexity.

Latent Gaussian process (GP) models are widely used in neuroscience to uncover hidden state evolutions from sequential observations, mainly in neural activity recordings. While latent GP models provide a principled and powerful solution in theory, the intractable posterior in non-conjugate settings necessitates approximate inference schemes, which may lack scalability. In this work, we propose cvHM, a general inference framework for latent GP models leveraging Hida-Mat\'ern kernels and conjugate computation variational inference (CVI). With cvHM, we are able to perform variational inference of latent neural trajectories with linear time complexity for arbitrary likelihoods. The reparameterization of stationary kernels using Hida-Mat\'ern GPs helps us connect the latent variable models that encode prior assumptions through dynamical systems to those that encode trajectory assumptions through GPs. In contrast to previous work, we use bidirectional information filtering, leading to a more concise implementation. Furthermore, we employ the Whittle approximate likelihood to achieve highly efficient hyperparameter learning.

Linear Time GPs for Inferring Latent Trajectories from Neural Spike Trains

Latent variable models have become instrumental in computational neuroscience for reasoning about neural computation. This has fostered the development of powerful offline algorithms for extracting latent neural trajectories from neural recordings. However, despite the potential of real time alternatives to give immediate feedback to experimentalists, and enhance experimental design, they have received markedly less attention. In this work, we introduce the exponential family variational Kalman filter (eVKF), an online recursive Bayesian method aimed at inferring latent trajectories while simultaneously learning the dynamical system generating them. eVKF works for arbitrary likelihoods and utilizes the constant base measure exponential family to model the latent state stochasticity. We derive a closed-form variational analogue to the predict step of the Kalman filter which leads to a provably tighter bound on the ELBO compared to another online variational method. We validate our method on synthetic and real-world data, and, notably, show that it achieves competitive performance.

REAL-TIME VARIATIONAL METHOD FOR LEARNING NEURAL TRAJECTORY AND ITS DYNAMICS

Brain asymmetry in the sensitivity to spectrotemporal modulation is an established functional feature that underlies the perception of speech and music. The left auditory cortex (ACx) is believed to specialize in processing fast temporal components of speech sounds, and the right ACx slower components. However, the circuit features and neural computations behind these lateralized spectrotemporal processes are poorly understood. To answer these mechanistic questions we use mice, an animal model that captures some relevant features of human communication systems. In this study, we screened for circuit features that could subserve temporal integration differences between the left and right ACx. We mapped excitatory input to principal neurons in all cortical layers and found significantly stronger recurrent connections in the superficial layers of the right ACx compared to the left. We hypothesized that the underlying recurrent neural dynamics would exhibit differential characteristic timescales corresponding to their hemispheric specialization. To investigate, we recorded spike trains from awake mice and estimated the network time constants using a statistical method to combine evidence from multiple weak signal-to-noise ratio neurons. We found longer temporal integration windows in the superficial layers of the right ACx compared to the left as predicted by stronger recurrent excitation. Our study shows substantial evidence linking stronger recurrent synaptic connections to longer network timescales. These findings support speech processing theories that purport asymmetry in temporal integration is a crucial feature of lateralization in auditory processing.

Differences in temporal processing speeds between the right and left auditory cortex reflect the strength of recurrent synaptic connectivity

The macaque middle temporal (MT) area is well known for its visual motion selectivity and relevance to motion perception, but the possibility of it also reflecting higher-level cognitive functions has largely been ignored. We tested for effects of task performance distinct from sensory encoding by manipulating subjects' temporal evidence-weighting strategy during a direction discrimination task while performing electrophysiological recordings from groups of MT neurons in rhesus macaques (one male, one female). This revealed multiple components of MT responses that were, surprisingly, not interpretable as behaviorally relevant modulations of motion encoding, or as bottom-up consequences of the readout of motion direction from MT. The time-varying motion-driven responses of MT were strongly affected by our strategic manipulation—but with time courses opposite the subjects' temporal weighting strategies. Furthermore, large choice-correlated signals were represented in population activity distinct from its motion responses, with multiple phases that lagged psychophysical readout and even continued after the stimulus (but which preceded motor responses). In summary, a novel experimental manipulation of strategy allowed us to control the time course of readout to challenge the correlation between sensory responses and choices, and population-level analyses of simultaneously recorded ensembles allowed us to identify strong signals that were so distinct from direction encoding that conventional, single-neuron-centric analyses could not have revealed or properly characterized them. Together, these approaches revealed multiple cognitive contributions to MT responses that are task related but not functionally relevant to encoding or decoding of motion for psychophysical direction discrimination, providing a new perspective on the assumed status of MT as a simple sensory area. SIGNIFICANCE STATEMENT This study extends understanding of the middle temporal (MT) area beyond its representation of visual motion. Combining multineuron recordings, population-level analyses, and controlled manipulation of task strategy, we exposed signals that depended on changes in temporal weighting strategy, but did not manifest as feedforward effects on behavior. This was demonstrated by (1) an inverse relationship between temporal dynamics of behavioral readout and sensory encoding, (2) a choice-correlated signal that always lagged the stimulus time points most correlated with decisions, and (3) a distinct choice-correlated signal after the stimulus. These findings invite re-evaluation of MT for functions outside of its established sensory role and highlight the power of experimenter-controlled changes in temporal strategy, coupled with recording and analysis approaches that transcend the single-neuron perspective.

Sensory and Choice Responses in MT Distinct from Motion Encoding

Development of a restraining wall and screw-extractor discharge system for continuous jig separation of mixed plastics

Cortical neurons emit seemingly erratic trains of action potentials or “spikes,” and neural network dynamics emerge from the coordinated spiking activity within neural circuits. These rich dynamics manifest themselves in a variety of patterns, which emerge spontaneously or in response to incoming activity produced by sensory inputs. In this Review, we focus on neural dynamics that is best understood as a sequence of repeated activations of a number of discrete hidden states. These transiently occupied states are termed “metastable” and have been linked to important sensory and cognitive functions. In the rodent gustatory cortex, for instance, metastable dynamics have been associated with stimulus coding, with states of expectation, and with decision making. In frontal, parietal, and motor areas of macaques, metastable activity has been related to behavioral performance, choice behavior, task difficulty, and attention. In this article, we review the experimental evidence for neural metastable dynamics together with theoretical approaches to the study of metastable activity in neural circuits. These approaches include (i) a theoretical framework based on non-equilibrium statistical physics for network dynamics; (ii) statistical approaches to extract information about metastable states from a variety of neural signals; and (iii) recent neural network approaches, informed by experimental results, to model the emergence of metastable dynamics. By discussing these topics, we aim to provide a cohesive view of how transitions between different states of activity may provide the neural underpinnings for essential functions such as perception, memory, expectation, or decision making, and more generally, how the study of metastable neural activity may advance our understanding of neural circuit function in health and disease.

Understanding the nature of representation in neural networks is a goal shared by neuroscience and machine learning. It is therefore exciting that both fields converge not only on shared questions but also on similar approaches. A pressing question in these areas is understanding how the structure of the representation used by neural networks affects both their generalization, and robustness to perturbations. In this work, we investigate the latter by juxtaposing experimental results regarding the covariance spectrum of neural representations in the mouse V1 (Stringer et al) with artificial neural networks. We use adversarial robustness to probe Stringer et al's theory regarding the causal role of a 1/n covariance spectrum. We empirically investigate the benefits such a neural code confers in neural networks, and illuminate its role in multi-layer architectures. Our results show that imposing the experimentally observed structure on artificial neural networks makes them more robust to adversarial attacks. Moreover, our findings complement the existing theory relating wide neural networks to kernel methods, by showing the role of intermediate representations.

For stimuli near perceptual threshold, the trial-by-trial activity of single neurons in many sensory areas is correlated with the animal’s perceptual report. This phenomenon has often been attributed to feedforward readout of the neural activity by the downstream decision-making circuits. The interpretation of choice-correlated activity is quite ambiguous, but its meaning can be better understood in the light of population-wide correlations among sensory neurons. Using a statistical nonlinear dimensionality reduction technique on single-trial ensemble recordings from the middle temporal (MT) area during perceptual-decision-making, we extracted low-dimensional latent factors that captured the population-wide fluctuations. We dissected the particular contributions of sensory-driven versus choice-correlated activity in the low-dimensional population code. We found that the latent factors strongly encoded the direction of the stimulus in single dimension with a temporal signature similar to that of single MT neurons. If the downstream circuit were optimally utilizing this information, choice-correlated signals should be aligned with this stimulus encoding dimension. Surprisingly, we found that a large component of the choice information resides in the subspace orthogonal to the stimulus representation inconsistent with the optimal readout view. This misaligned choice information allows the feedforward sensory information to coexist with the decision-making process. The time course of these signals suggest that this misaligned contribution likely is feedback from the downstream areas. We hypothesize that this non-corrupting choice-correlated feedback might be related to learning or reinforcing sensory-motor relations in the sensory population.

Odor tracking in aquatic organisms: the importance of temporal and spatial intermittency of the turbulent plume

Brain dynamics can exhibit narrow-band nonlinear oscillations and multistability. For a subset of disorders of consciousness and motor control, we hypothesized that some symptoms originate from the inability to spontaneously transition from one attractor to another. Using external perturbations, such as electrical pulses delivered by deep brain stimulation devices, it may be possible to induce such transition out of the pathological attractors. However, the induction of transition may be non-trivial, rendering the current open-loop stimulation strategies insufficient. In order to develop next-generation neural stimulators that can intelligently learn to induce attractor transitions, we require a platform to test the efficacy of such systems. To this end, we designed an analog circuit as a model for the multistable brain dynamics. The circuit spontaneously oscillates stably on two periods as an instantiation of a 3-dimensional continuous-time gated recurrent neural network. To discourage simple perturbation strategies, such as constant or random stimulation patterns from easily inducing transition between the stable limit cycles, we designed a state-dependent nonlinear circuit interface for external perturbation. We demonstrate the existence of nontrivial solutions to the transition problem in our circuit implementation.

Birhythmic Analog Circuit Maze: A Nonlinear Neurostimulation Testbed

Studies in visual, auditory, and somatosensory cortices have revealed that different cell types as well as neurons located in different laminae display distinct stimulus response profiles. The extent to which these layer and cell type-specific distinctions generalize to gustatory cortex (GC) remains unknown. In this study, we performed extracellular recordings in adult female mice to monitor the activity of putative pyramidal and inhibitory neurons located in deep and superficial layers of GC. Awake, head-restrained mice were trained to lick different tastants (sucrose, salt, citric acid, quinine, and water) from a lick spout. We found that deep layer neurons show higher baseline firing rates (FRs) in GC with deep-layer inhibitory neurons displaying highest FRs at baseline and following the stimulus. GC's activity shows robust modulations before animals' contact with tastants, and this phenomenon is most prevalent in deep-layer inhibitory neurons. Furthermore, we show that licking activity strongly shapes the spiking pattern of GC pyramidal neurons, eliciting phase-locked spiking across trials and tastants. We demonstrate that there is a greater percentage of taste-coding neurons in deep versus superficial layers with chemosensitive neurons across all categories showing similar breadth of tuning, but different decoding performance. Lastly, we provide evidence for functional convergence in GC, with neurons that can show prestimulus activity, licking-related rhythmicity and taste responses. Overall, our results demonstrate that baseline and stimulus-evoked firing profiles of GC neurons and their processing schemes change as a function of cortical layer and cell type in awake mice. SIGNIFICANCE STATEMENT Sensory cortical areas show a laminar structure, with each layer composed of distinct cell types embedded in different circuits. While studies in other primary sensory areas have elucidated that pyramidal and inhibitory neurons belonging to distinct layers show distinct response properties, whether and how response properties of gustatory cortex (GC) neurons change as a function of their laminar position and cell type remains uninvestigated. Here, we show that there are several notable differences in baseline, prestimulus, and stimulus-evoked response profiles of pyramidal and inhibitory neurons belonging to deep and superficial layers of GC.

Layer- and Cell Type-Specific Response Properties of Gustatory Cortex Neurons in Awake Mice

The standard approach to fitting an autoregressive spike train model is to maximize the likelihood for one-step prediction. This maximum likelihood estimation (MLE) often leads to models that perform poorly when generating samples recursively for more than one time step. Moreover, the generated spike trains can fail to capture important features of the data and even show diverging firing rates. To alleviate this, we propose to directly minimize the divergence between neural recorded and model generated spike trains using spike train kernels. We develop a method that stochastically optimizes the maximum mean discrepancy induced by the kernel. Experiments performed on both real and synthetic neural data validate the proposed approach, showing that it leads to well-behaving models. Using different combinations of spike train kernels, we show that we can control the trade-off between different features which is critical for dealing with model-mismatch.

For stimuli near perceptual threshold, the trial-by-trial activity of single neurons in many sensory areas is correlated with the animal’s perceptual report. This phenomenon has often been attributed to feedforward readout of the neural activity by the downstream decision-making circuits. The interpretation of choice-correlated activity is quite ambiguous, but its meaning can be better understood in the light of population-wide correlations among sensory neurons. Using a statistical nonlinear dimensionality reduction technique on single-trial ensemble recordings from the middle temporal area during perceptual-decision-making, we extracted low-dimensional neural tra jectories that captured the population-wide fluctuations. We dissected the particular contributions of sensory-driven versus choice-correlated activity in the low-dimensional population code. We found that the neural trajectories strongly encoded the direction of the stimulus in single dimension with a temporal signature similar to that of single MT neurons. If the downstream circuit were optimally utilizing this information, choice-correlated signals should be aligned with this stimulus encoding dimension. Surprisingly, we found that a large component of the choice information resides in the subspace orthogonal to the stimulus representation inconsistent with the optimal readout view. This misaligned choice information allows the feedforward sensory information to coexist with the decision-making process. The time course of these signals suggest that this misaligned contribution likely is feedback from the downstream areas. We hypothesize that this non-corrupting choice-correlated feedback might be related to learning or reinforcing sensory-motor relations in the sensory population. Author summary In sensorimotor decision-making, internal representation of sensory stimuli is utilized for the generation of appropriate behavior for the context. Therefore, the correlation between variability in sensory neurons and perceptual decisions is sometimes explained by a causal, feedforward role of sensory noise in behavior. However, this correlation could also originate via feedback from decision-making mechanisms downstream of the sensory representation. This cannot be resolved by analyzing single unit responses, but requires a population level analysis. Area MT contains both sensory and choice information and is known to be the key sensory area for visual motion perception. Thus the decision-making process may be corrupting the sensory representation. However, we find that the sensory stimuli and choice variables are separate at the population level,contradicting the previous interpretations based on single unit recordings. This new insight postulates how neural systems can maintain a mixed representation while allows learning and adaptation.

Nonlinear state-space models are powerful tools to describe dynamical structures in complex time series. In a streaming setting where data are processed one sample at a time, simultaneous inference of the state and its nonlinear dynamics has posed significant challenges in practice. We develop a novel online learning framework, leveraging variational inference and sequential Monte Carlo, which enables flexible and accurate Bayesian joint filtering. Our method provides an approximation of the filtering posterior which can be made arbitrarily close to the true filtering distribution for a wide class of dynamics models and observation models. Specifically, the proposed framework can efficiently approximate a posterior over the dynamics using sparse Gaussian processes, allowing for an interpretable model of the latent dynamics. Constant time complexity per sample makes our approach amenable to online learning scenarios and suitable for real-time applications.

Gated recurrent units (GRUs) are specialized memory elements for building recurrent neural networks. Despite their incredible success on various tasks, including extracting dynamics underlying neural data, little is understood about the specific dynamics representable in a GRU network. As a result, it is both difficult to know a priori how successful a GRU network will perform on a given task, and also their capacity to mimic the underlying behavior of their biological counterparts. Using a continuous time analysis, we gain intuition on the inner workings of GRU networks. We restrict our presentation to low dimensions, allowing for a comprehensive visualization. We found a surprisingly rich repertoire of dynamical features that includes stable limit cycles (nonlinear oscillations), multi-stable dynamics with various topologies, and homoclinic bifurcations. At the same time we were unable to train GRU networks to produce continuous attractors, which are hypothesized to exist in biological neural networks. We contextualize the usefulness of different kinds of observed dynamics and support our claims experimentally.

Gated Recurrent Units Viewed Through the Lens of Continuous Time Dynamical Systems

Exploding and vanishing gradient are both major problems often faced when an artificial neural network is trained with gradient descent. Inspired by the ubiquity and robustness of nonlinear oscillations in biological neural systems, we investigate the properties of their artificial counterpart, the stable limit cycle neural networks. Using a continuous time dynamical system interpretation of neural networks and backpropagation, we show that stable limit cycle neural networks have non-exploding gradients, and at least one effective nonvanishing gradient dimension. We conjecture that limit cycles can support the learning of long temporal dependence in both biological and artificial neural networks.

2019 53rd Asilomar Conference on Signals, Systems, and Computers

Recent work on critical initializations of deep neural networks has shown that by constraining the spectrum of input-output Jacobians allows for fast training of very deep networks without skip connections. The current understanding of this class of initializations is limited with respect to classical notions from optimization. In particular, the connections between Jacobian eigenvalues and curvature of the parameter space are unknown. Similarly, there is no firm understanding of the effects of maintaining orthogonality during training. With this work we complement the existing understanding of critical initializations and show that the curvature is proportional to the maximum singular value of the Jacobian. Furthermore we show that optimization under orthogonality constraints ameliorates the dependence on choice of initial parameters, but is not strictly necessary.

The Expressive Power of Gated Recurrent Units as a Continuous Dynamical System

New technologies for recording the activity of large neural populations during complex behavior provide exciting opportunities for investigating the neural computations that underlie perception, cognition, and decision-making. Non-linear state space models provide an interpretable signal processing framework by combining an intuitive dynamical system with a probabilistic observation model, which can provide insights into neural dynamics, neural computation, and development of neural prosthetics and treatment through feedback control. This brings with it the challenge of learning both latent neural state and the underlying dynamical system because neither are known for neural systems a priori. We developed a flexible online learning framework for latent non-linear state dynamics and filtered latent states. Using the stochastic gradient variational Bayes approach, our method jointly optimizes the parameters of the non-linear dynamical system, the observation model, and the black-box recognition model. Unlike previous approaches, our framework can incorporate non-trivial distributions of observation noise and has constant time and space complexity. These features make our approach amenable to real-time applications and the potential to automate analysis and experimental design in ways that testably track and modify behavior using stimuli designed to influence learning.

State space models provide an interpretable framework for complex time series by combining an intuitive dynamical system model with a probabilistic observation model. We developed a flexible online learning framework for latent nonlinear state dynamics and filtered latent states. Our method utilizes the stochastic gradient variational Bayes method to jointly optimize the parameters of the nonlinear dynamics, observation model, and the recognition model. Unlike previous approaches, our framework can incorporate non-trivial observation noise models and infer in real-time. We test our method on point process observations driven by continuous attractor dynamics, demonstrating its ability to recover the phase portrait, filtered trajectory, and produce long-term predictions for neuroscience applications.

Recursive Variational Bayesian Dual Estimation for Nonlinear Dynamics and Non-Gaussian Observations

Manipulating the dynamics of neural systems through targeted stimulation is a frontier of research and clinical neuroscience; however, the control schemes considered for neural systems are mismatched for the unique needs of manipulating neural dynamics. An appropriate control method should respect the variability in neural systems, incorporating moment to moment “input” to the neural dynamics and behaving based on the current neural state, irrespective of the past trajectory. We propose such a controller under a nonlinear state-space feedback framework that steers one dynamical system to function as through it were another dynamical system entirely. This “myopic” controller is formulated through a novel variant of a model reference control cost that manipulates dynamics in a step-wise manner, omitting the need to pre-calculate a rigid and computationally costly neural feedback control solution. To demonstrate the breadth of this control’s utility, two examples with distinctly different applications in neuroscience are studied. First an unhealthy motor-like system containing an unwanted beta-oscillation spiral attractor is controlled to function as a healthy motor system, a relevant clinical example for neurological disorders. Second, we show the myopic control’s utility to probe the causal dynamics of cognitive processes by transforming a winner-take-all decision-making system to operate as a robust neural integrator of evidence.

Generalized linear models (GLMs) are useful tools to capture the characteristic features of spiking neurons; however, the long-term prediction of an autoregressive GLM inferred through maximum likelihood (ML) can be subject to runway self-excitation. We explain here that this runaway excitation is a consequence of the one-step-ahead ML inference used in estimating the parameters of the GLM. Alternatively, inference techniques that incorporate the likelihood of spiking multiple steps ahead in the future can alleviate this instability. We formulate a multi-step log-likelihood (MSLL) as an alternative objective for fitting spiking data. We maximize MSLL to infer an autoregressive GLM for individual spiking neurons recorded from the lateral intraparietal (LIP) area of monkeys during a perceptual decision-making task. While ML inference is shown to produce a GLM with poor fits of the neuron's interspike intervals and autocorrelation, in addition to its runaway excitation, MSLL fit models show a substantial improvement in interval statistics and stable spiking.

2017 8th International IEEE/EMBS Conference on Neural Engineering (NER)

Multistep inference for generalized linear spiking models curbs runaway excitation

New technologies for recording the activity of large neural populations during complex behavior provide exciting opportunities for investigating the neural computations that underlie perception, cognition, and decision-making. Nonlinear state-space models provide an interpretable signal processing framework by combining an intuitive dynamical system with a probabilistic observation model, which can provide insights into neural dynamics, neural computation, and development of neural prosthetics and treatment through feedback control. It yet brings the challenge of learning both latent neural state and the underlying dynamical system because neither is known for neural systems a priori. We developed a flexible online learning framework for latent nonlinear state dynamics and filtered latent states. Using the stochastic gradient variational Bayes approach, our method jointly optimizes the parameters of the nonlinear dynamical system, the observation model, and the black-box recognition model. Unlike previous approaches, our framework can incorporate non-trivial distributions of observation noise and has constant time and space complexity. These features make our approach amenable to real-time applications and the potential to automate analysis and experimental design in ways that testably track and modify behavior using stimuli designed to influence learning.

Abstract The mammalian visual system consists of several anatomically distinct areas, layers, and cell types. To understand the role of these subpopulations in visual information processing, we analyzed neural signals recorded from excitatory neurons from various anatomical and functional structures. For each of 186 mice, one of six genetically tagged cell types and one of six visual areas were targeted while the mouse was passively viewing various visual stimuli. We trained linear classifiers to decode one of six visual stimulus categories with distinct spatiotemporal structures from the population neural activity. We found that neurons in both the primary visual cortex and secondary visual areas show varying degrees of stimulus-specific decodability, and neurons in superficial layers tend to be more informative about the stimulus categories. Additional decoding analyses of directional motion were consistent with these findings. We observed synergy in the population code of direction in several visual areas suggesting area-specific organization of information representation across neurons. These differences in decoding capacities shed light on the specialized organization of neural information processing across anatomically distinct subpopulations, and further establish the mouse as a model for understanding visual perception.

Canonical correlations reveal co-variability between spike trains and local field potentials in area MT)

Latent variable time-series models are among the most heavily used tools from machine learning and applied statistics. These models have the advantage of learning latent structure both from noisy observations and from the temporal ordering in the data, where it is assumed that meaningful correlation structure exists across time. A few highly-structured models, such as the linear dynamical system with linear-Gaussian observations, have closed-form inference procedures (e.g. the Kalman Filter), but this case is an exception to the general rule that exact posterior inference in more complex generative models is intractable. Consequently, much work in time-series modeling focuses on approximate inference procedures for one particular class of models. Here, we extend recent developments in stochastic variational inference to develop a `black-box' approximate inference technique for latent variable models with latent dynamical structure. We propose a structured Gaussian variational approximate posterior that carries the same intuition as the standard Kalman filter-smoother but, importantly, permits us to use the same inference approach to approximate the posterior of much more general, nonlinear latent variable generative models. We show that our approach recovers accurate estimates in the case of basic models with closed-form posteriors, and more interestingly performs well in comparison to variational approaches that were designed in a bespoke fashion for specific non-conjugate models.

The kernel least mean squares (KLMS) algorithm is a computationally efficient nonlinear adaptive filtering method that “kernelizes” the celebrated (linear) least mean squares algorithm. We demonstrate that the least mean squares algorithm is closely related to the Kalman filtering, and thus, the KLMS can be interpreted as an approximate Bayesian filtering method. This allows us to systematically develop extensions of the KLMS by modifying the underlying state-space and observation models. The resulting extensions introduce many desirable properties such as “forgetting”, and the ability to learn from discrete data, while retaining the computational simplicity and time complexity of the original algorithm.

The spatial and temporal characteristics of the visual and acoustic sensory input are indispensable attributes for animals to perform scene analysis. In contrast, research in olfaction has focused almost exclusively on how the nervous system analyzes the quality and quantity of the sensory signal and largely ignored the spatiotemporal dimension especially in longer time scales. Yet, detailed analyses of the turbulent, intermittent structure of water- and air-borne odor plumes strongly suggest that spatio-temporal information in longer time scales can provide major cues for olfactory scene analysis for animals. We show that a bursting subset of primary olfactory receptor neurons (bORNs) in lobster has the unexpected capacity to encode the temporal properties of intermittent odor signals. Each bORN is tuned to a specific range of stimulus intervals, and collectively bORNs can instantaneously encode a wide spectrum of intermittencies. Our theory argues for the existence of a novel peripheral mechanism for encoding the temporal pattern of odor that potentially serves as a neural substrate for olfactory scene analysis.

Intermittency Coding in the Primary Olfactory System: A Neural Substrate for Olfactory Scene Analysis

Antonio R. C. Paiva, Il Park, Jose C. Pŕincipe, and Justin C. Sanchez 1 Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, UT arpaiva@sci.utah.edu 2 Center for Perceptual System and Institute for Neuroscience, University of Texas, Austin, TX memming@austin.utexas.edu 3 Dept. of Electrical and Computer Engineering, University of Florida, Gainesville, FL principe@cnel.ufl.edu 4 Dept. of Biomedical Engineering, University of Miami, Coral Gables, FL jcsanchez@miami.edu

Instantaneous Cross-Correlation Analysis of Neural Ensembles with High Temporal Resolution

The precise control of spiking in a population of neurons via applied electrical stimulation is a challenge due to the sparseness of spiking responses and neural system plasticity. We pose neural stimulation as a system control problem where the system input is a multidimensional time-varying signal representing the stimulation, and the output is a set of spike trains; the goal is to drive the output such that the elicited population spiking activity is as close as possible to some desired activity, where closeness is defined by a cost function. If the neural system can be described by a time-invariant (homogeneous) model, then offline procedures can be used to derive the control procedure; however, for arbitrary neural systems this is not tractable. Furthermore, standard control methodologies are not suited to directly operate on spike trains that represent both the target and elicited system response. In this paper, we propose a multiple-input multiple-output (MIMO) adaptive inverse control scheme that operates on spike trains in a reproducing kernel Hilbert space (RKHS). The control scheme uses an inverse controller to approximate the inverse of the neural circuit. The proposed control system takes advantage of the precise timing of the neural events by using a Schoenberg kernel defined directly in the space of spike trains. The Schoenberg kernel maps the spike train to an RKHS and allows linear algorithm to control the nonlinear neural system without the danger of converging to local minima. During operation, the adaptation of the controller minimizes a difference defined in the spike train RKHS between the system and the target response and keeps the inverse controller close to the inverse of the current neural circuit, which enables adapting to neural perturbations. The results on a realistic synthetic neural circuit show that the inverse controller based on the Schoenberg kernel outperforms the decoding accuracy of other models based on the conventional rate representation of neural signal (i.e., spikernel and generalized linear model). Moreover, after a significant perturbation of the neuron circuit, the control scheme can successfully drive the elicited responses close to the original target responses.

Adaptive Inverse Control of Neural Spatiotemporal Spike Patterns With a Reproducing Kernel Hilbert Space (RKHS) Framework

An emerging idea in olfaction is that temporal coding of odor specificity can be intrinsic to the primary olfactory receptor neurons (ORNs). As a first step towards understanding whether lobster ORNs are capable of generating odor-specific temporal activity and what mechanisms underlie any such heterogeneity in discharge pattern, we characterized different patterns of activity in lobster ORNs individually and ensemble using patch-clamp recording and calcium imaging. We demonstrate that lobster ORNs show tonic excitation, tonic inhibition, phaso-tonic excitation, and bursting, and that these patterns are faithfully reflected in the calcium signal. We then demonstrate that the various dynamic patterns of response are inherent in the cells, and that this inherent heterogeneity is largely determined by heterogeneity in the underlying intrinsic conductances. Copyright: ß 2012 Bobkov et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Correction: Cellular Basis for Response Diversity in the Olfactory Periphery

Exploratory tools that are sensitive to arbitrary statistical variations in spike train observations open up the possibility of novel neuroscientific discoveries. Developing such tools, however, is difficult due to the lack of Euclidean structure of the spike train space, and an experimenter usually prefers simpler tools that capture only limited statistical features of the spike train, such as mean spike count or mean firing rate. We explore strictly positive-definite kernels on the space of spike trains to offer both a structural representation of this space and a platform for developing statistical measures that explore features beyond count or rate. We apply these kernels to construct measures of divergence between two point processes and use them for hypothesis testing, that is, to observe if two sets of spike trains originate from the same underlying probability law. Although there exist positive-definite spike train kernels in the literature, we establish that these kernels are not strictly definite and thus do not induce measures of divergence. We discuss the properties of both of these existing nonstrict kernels and the novel strict kernels in terms of their computational complexity, choice of free parameters, and performance on both synthetic and real data through kernel principal component analysis and hypothesis testing.

Strictly Positive-Definite Spike Train Kernels for Point-Process Divergences

This paper quantifies and comparatively validates functional connectivity between neurons by measuring the statistical dependence between their firing rates. Based on statistical analysis of the pairwise functional connectivity, we estimate, exclusively from neural data, the neural assembly functional connectivity given a behavior task, which provides a quantifiable representation of the dynamic nature during the behavioral task. Because of the time scale of behavior (100-1000 ms), a statistical method that yields robust estimators for this small sample size is desirable. In this work, the temporal resolutions of four estimators of functional connectivity are compared on both simulated data and real neural ensemble recordings. The comparison highlights how the properties and assumptions of statistical-based and phase-based metrics affect the interpretation of connectivity. Simulation results show that mean square contingency (MSC) and mutual information (MI) create more robust quantification of functional connectivity under identical conditions than cross correlation (CC) and phase synchronization (PhS) when the sample size is 1 s. The results of the simulated analysis are extended to real neuronal recordings to assess the functional connectivity in monkey's cortex corresponding to three movement states in a food reaching task and construct the assembly graph given a movement state and the activation degree of a state-related assembly over time using the statistical test exclusively from neural data dependencies. The activation degree of a given state-related assembly reaches the peak repeatedly when the specific movement states occur, which also reveals the network of interactions among the neurons are key for the operation of a specific behavior.

Functional Connectivity Dynamics Among Cortical Neurons: A Dependence Analysis

This paper proposes a unified framework for several available measures of independence by generalizing the concept of information theoretic learning (ITL). The key component of ITL is the use of inner product between two density functions as a measure of similarity between two random variables. We show that by generalizing the inner product using a symmetric strictly positive-definite kernel and by choosing appropriate kernels, it is possible to reproduce a number of popular measures of independence. This unified framework also allows the design of new strictly positive-definite kernels and corresponding measures of independence. Following this framework we explore a new measure of independence and apply it in the context of linear independent component analysis (ICA). An attractive property of the proposed method is that it does not involve any free parameter and we demonstrate that it performs equally well compared to the existing methods for ICA.

Optimization in Reproducing kernel Hilbert Spaces of Spike Trains

Inner products for representation and learning in the spike train domain

This paper discusses an information theoretic approach of designing sparse kernel adaptive filters. To determine useful data to be learned and remove redundant ones, a subjective information measure called surprise is introduced. Surprise captures the amount of information a datum contains which is transferable to a learning system. Based on this concept, we propose a systematic sparsification scheme, which can drastically reduce the time and space complexity without harming the performance of kernel adaptive filters. Nonlinear regression, short term chaotic time-series prediction, and long term time-series forecasting examples are presented.

An Information Theoretic Approach of Designing Sparse Kernel Adaptive Filters

ICASSP 2023 - 2023 IEEE International Conference on Acoustics, Speech and Signal Processing (ICASSP)

Multimodal Microscopy Image Alignment Using Spatial and Shape Information and a Branch-and-Bound Algorithm

High-density electrophysiology probes have opened new possibilities for systems neuroscience in human and non-human animals, but probe motion (or drift) while recording poses a challenge for downstream analyses, particularly in human recordings. Here, we improve on the state of the art for tracking this drift with an algorithm termed DREDge (Decentralized Registration of Electrophysiology Data) with four major contributions. First, we extend previous decentralized methods to exploit multiband information, leveraging the local field potential (LFP), in addition to spikes detected from the action potentials (AP). Second, we show that the LFP-based approach enables registration at sub-second temporal resolution. Third, we introduce an efficient online motion tracking algorithm, allowing the method to scale up to longer and higher spatial resolution recordings, which could facilitate real-time applications. Finally, we improve the robustness of the approach by accounting for the nonstationarities that occur in real data and by automating parameter selection. Together, these advances enable fully automated scalable registration of challenging datasets from both humans and mice.

Robust Online Multiband Drift Estimation in Electrophysiology Data

Understanding whole-brain-scale electrophysiological recordings relies on the collective work of many labs. Because two labs recording from the same region can reach different conclusions, it is critical to quantify and control features that hinder reproducibility. To address this, we formed a multi-lab collaboration using a shared, open-source behavioral task and experimental apparatus. Experimenters in ten laboratories repeatedly targeted Neuropixels probes to the same location (spanning secondary visual areas, hippocampus, and thalamus) in mice making decisions. After applying quality-control criteria, we found that neuronal yield, firing rates, spike amplitudes, and task-modulated neuronal activity were largely reproducible across laboratories. To quantify variance in neural activity explained by task variables, we developed a multi-task neural network model, and found that within- and between-lab random effects captured by this model were comparable. Our results demonstrate that across-lab standardization can produce reproducible results from large-scale Neuropixels recordings. Our dataset, code, and protocols are openly accessible.

Reproducibility of in-vivo electrophysiological measurements in mice

Pose estimation algorithms are shedding new light on animal behavior and intelligence. Most existing models are only trained with labeled frames (supervised learning). Although effective in many cases, the fully supervised approach requires extensive image labeling, struggles to generalize to new videos, and produces noisy outputs that hinder downstream analyses. We address each of these limitations with a semi-supervised approach that leverages the spatiotemporal statistics of unlabeled videos in two different ways. First, we introduce unsupervised training objectives that penalize the network whenever its predictions violate smoothness of physical motion, multiple-view geometry, or depart from a low-dimensional subspace of plausible body configurations. Second, we design a new network architecture that predicts pose for a given frame using temporal context from surrounding unlabeled frames. These context frames help resolve brief occlusions or ambiguities between nearby and similar-looking body parts. The resulting pose estimation networks achieve better performance with fewer labels, generalize better to unseen videos, and provide smoother and more reliable pose trajectories for downstream analysis; for example, these improved pose trajectories exhibit stronger correlations with neural activity. We also propose a Bayesian post-processing approach based on deep ensembling and Kalman smoothing that further improves tracking accuracy and robustness. We release a deep learning package that adheres to industry best practices, supporting easy model development and accelerated training and prediction. Our package is accompanied by a cloud application that allows users to annotate data, train networks, and predict new videos at scale, directly from the browser.

Lightning Pose: improved animal pose estimation via semi-supervised learning, Bayesian ensembling, and cloud-native open-source tools

Two-photon optogenetics has transformed our ability to probe the structure and function of neural circuits. However, achieving precise optogenetic control of neural ensemble activity has remained fundamentally constrained by the problem of off-target stimulation (OTS): the inadvertent activation of nearby non-target neurons due to imperfect confinement of light onto target neurons. Here we propose a novel computational approach to this problem called Bayesian target optimisation. Our approach uses nonparametric Bayesian inference to model neural responses to optogenetic stimulation, and then optimises the laser powers and optical target locations needed to achieve a desired activity pattern with minimal OTS. We validate our approach in simulations and using data from in vitro experiments, showing that Bayesian target optimisation substantially reduces OTS across all conditions we test. Together, these results establish our ability to overcome OTS, enabling optogenetic stimulation with significantly improved precision.

Bayesian target optimisation for high-precision holographic optogenetics

Learning Probabilistic Piecewise Rigid Atlases of Model Organisms via Generative Deep Networks

Discovering how neural computations are implemented in the cortex at the level of monosynaptic connectivity requires probing for the existence of synapses from possibly thousands of presynaptic candidate neurons. Two-photon optogenetics has been shown to be a promising technology for mapping such monosynaptic connections via serial stimulation of neurons with single-cell resolution. However, this approach is limited in its ability to uncover connectivity at large scales because stimulating neurons one-by-one requires prohibitively long experiments. Here we developed novel computational tools that, when combined, enable learning of monosynaptic connectivity from high-speed holographic neural ensemble stimulation. First, we developed a model-based compressed sensing algorithm that identifies connections from postsynaptic responses evoked by stimulation of many neurons at once, considerably increasing the rate at which the existence and strength of synapses are screened. Second, we developed a deep learning method that isolates the postsynaptic response evoked by each stimulus, allowing stimulation to rapidly switch between ensembles without waiting for the postsynaptic response to return to baseline. Together, our system increases the throughput of monosynaptic connectivity mapping by an order of magnitude over existing approaches, enabling the acquisition of connectivity maps at speeds needed to discover the synaptic circuitry implementing neural computations.

Rapid learning of neural circuitry from holographic ensemble stimulation enabled by model-based compressed sensing

Multi-animal pose estimation is essential for study-ing animals’ social behaviors in neuroscience and neuroethology. Advanced approaches have been proposed to support multi-animal estimation. How-ever, these models rarely exploit unlabeled data during training, even though real world applica-tions have exponentially more unlabeled frames than labeled frames. Manually adding dense annotations for a large number of images or videos is costly and labor-intensive, especially for multiple instances. Given these deﬁciencies, we propose a novel semi-supervised architecture for multi-animal pose estimation, leveraging the abundant structures pervasive in unlabeled frames in behavior videos to enhance training, particularly in the context of sparsely-labeled problems. The resulting algorithm provides superior multi-animal pose estimation results on three animal experiments compared to existing baselines, and exhibits more predictive power in sparsely-labeled data regimes.

SemiMultiPose: A Semi-supervised Multi-animal Pose Estimation Framework

Reconstruction of neocortex: Organelles, compartments, cells, circuits, and activity

A key aspect of neuroscience research is the development of powerful, general-purpose data analyses that process large datasets. Unfortunately, modern data analyses have a hidden dependence upon complex computing infrastructure (e.g., software and hardware), which acts as an unaddressed deterrent to analysis users. Although existing analyses are increasingly shared as open-source software, the infrastructure and knowledge needed to deploy these analyses efficiently still pose significant barriers to use. In this work, we develop Neuroscience Cloud Analysis As a Service (NeuroCAAS): a fully automated open-source analysis platform offering automatic infrastructure reproducibility for any data analysis. We show how NeuroCAAS supports the design of simpler, more powerful data analyses and that many popular data analysis tools offered through NeuroCAAS outperform counterparts on typical infrastructure. Pairing rigorous infrastructure management with cloud resources, NeuroCAAS dramatically accelerates the dissemination and use of new data analyses for neuroscientific discovery.

Neuroscience Cloud Analysis As a Service: An open-source platform for scalable, reproducible data analysis

Tracking body parts in behaving animals, extracting fluorescence signals from cells embedded in deforming tissue, and analyzing cell migration patterns during development all require tracking objects with partially correlated motion. As dataset sizes increase, manual tracking of objects becomes prohibitively inefficient and slow, necessitating automated and semi-automated computational tools. Unfortunately, existing methods for multiple object tracking (MOT) are either developed for specific datasets and hence do not generalize well to other datasets, or require large amounts of training data that are not readily available. This is further exacerbated when tracking fluorescent sources in moving and deforming tissues, where the lack of unique features and sparsely populated images create a challenging environment, especially for modern deep learning techniques. By leveraging technology recently developed for spatial transformer networks, we propose ZephIR, an image registration framework for semi-supervised MOT in 2D and 3D videos. ZephIR can generalize to a wide range of biological systems by incorporating adjustable parameters that encode spatial (sparsity, texture, rigidity) and temporal priors of a given data class. We demonstrate the accuracy and versatility of our approach in a variety of applications, including tracking the body parts of a behaving mouse and neurons in the brain of a freely moving C. elegans. We provide an open-source package along with a web-based graphical user interface that allows users to provide small numbers of annotations to interactively improve tracking results.

Versatile Multiple Object Tracking in Sparse 2D/3D Videos Via Diffeomorphic Image Registration

Neuropixels (NP) probes are dense linear multi-electrode arrays that have rapidly become essential tools for studying the electrophysiology of large neural populations. Unfortunately, a number of challenges remain in analyzing the large datasets output by these probes. Here we introduce several new methods for extracting useful spiking information from NP probes. First, we use a simple point neuron model, together with a neural-network denoiser, to efficiently map single spikes detected on the probe into three-dimensional localizations. Previous methods localized individual spikes in two dimensions only; we show that the new localization approach is significantly more robust and provides an improved feature set for clustering spikes according to neural identity (“spike sorting”). Next, we denoise the resulting three-dimensional point-cloud representation of the data, and show that the resulting 3D images can be accurately registered over time, leading to improved tracking of time-varying neural activity over the probe, and in turn, crisper estimates of neural clusters over time. Open source code is available at https://github.com/int-brain-lab/spikes_localization_registration.git.

Three-dimensional spike localization and improved motion correction for Neuropixels recordings

Sex differences in the brain are prevalent throughout the animal kingdom and particularly well appreciated in the nematode C. elegans. While 294 neurons are shared between the two sexes, the nervous system of the male contains an additional 93 malespecific neurons, most of which have received very little attention so far. To make these neurons amenable for future study, we describe here how a multicolor, multipromoter reporter transgene, NeuroPAL, is capable of visualizing the distinct identities of all male specific neurons. We used this tool to visualize and characterize a number of features of the male-specific nervous system. We provide several proofs of concept for using NeuroPAL to identify the sites of expression of gfp-tagged reporter genes. We demonstrate the usage of NeuroPAL for cellular fate analysis by analyzing the effect of removal of developmental patterning genes, including a HOX cluster gene (egl-5), a miRNA (lin-4) and a proneural gene (lin-32/Ato), on neuronal identity acquisition within the male-specific nervous system. We use NeuroPAL and its intrinsic cohort of more than 40 distinct differentiation markers to show that, even though male-specific neurons are generated throughout all four larval stages, they execute their terminal differentiation program in a coordinated manner in the fourth larval stage that is concomitant with male tale retraction. This wave of differentiation couples neuronal maturation programs with the appearance of sexual organs. We call this wave “just-in-time” differentiation by its analogy to the mechanism of “just-in-time” transcription of metabolic pathway genes.

Visualizing the organization and differentiation of the male-specific nervous system of C. elegans

High-fidelity estimates of spikes and subthreshold waveforms from 1-photon voltage imaging in vivo.

A popular approach to quantifying animal behavior from video data is through discrete behavioral segmentation, wherein video frames are labeled as containing one or more behavior classes such as walking or grooming. Sequence models learn to map behavioral features extracted from video frames to discrete behaviors, and both supervised and unsupervised methods are common. However, each approach has its drawbacks: supervised models require a time-consuming annotation step where humans must hand label the desired behaviors; unsupervised models may fail to accurately segment particular behaviors of interest. We introduce a semi-supervised approach that addresses these challenges by constructing a sequence model loss function with (1) a standard supervised loss that classifies a sparse set of hand labels; (2) a weakly supervised loss that classifies a set of easy-to-compute heuristic labels; and (3) a self-supervised loss that predicts the evolution of the behavioral features. With this approach, we show that a large number of unlabeled frames can improve supervised segmentation in the regime of sparse hand labels and also show that a small number of hand labeled frames can increase the precision of unsupervised segmentation.

Semi-supervised sequence modeling for improved behavioral segmentation

Cellular barcoding methods offer the exciting possibility of ‘infinite-pseudocolor’ anatomical reconstruction — i.e., assigning each neuron its own random unique barcoded ‘pseudocolor,’ and then using these pseudocolors to trace the microanatomy of each neuron. Here we use simulations, based on densely-reconstructed electron microscopy microanatomy, with signal structure matched to real barcoding data, to quantify the feasibility of this procedure. We develop a new blind demixing approach to recover the barcodes that label each neuron. We also develop a neural network which uses these barcodes to reconstruct the neuronal morphology from the observed fluorescence imaging data, ‘connecting the dots’ between discontiguous amplicon signals. We find that accurate recovery should be feasible, provided that the barcode signal density is sufficiently high. This study suggests the possibility of mapping the morphology and projection pattern of many individual neurons simultaneously, at high resolution and at large scale, via conventional light microscopy.

Blind demixing methods for recovering dense neuronal morphology from barcode imaging data

What are the spatial and temporal scales of brainwide neuronal activity, and how do activities at different scales interact? We used SCAPE microscopy to image a large fraction of the central brain of adult Drosophila melanogaster with high spatiotemporal resolution while flies engaged in a variety of behaviors, including running, grooming and flailing. This revealed neural representations of behavior on multiple spatial and temporal scales. The activity of most neurons across the brain correlated (or, in some cases, anticorrelated) with running and flailing over timescales that ranged from seconds to almost a minute. Grooming elicited a much weaker global response. Although these behaviors accounted for a large fraction of neural activity, residual activity not directly correlated with behavior was high dimensional. Many dimensions of the residual activity reflect the activity of small clusters of spatially organized neurons that may correspond to genetically defined cell types. These clusters participate in the global dynamics, indicating that neural activity reflects a combination of local and broadly distributed components. This suggests that microcircuits with highly specified functions are provided with knowledge of the larger context in which they operate, conferring a useful balance of specificity and flexibility.

Flygenvectors: The spatial and temporal structure of neural activity across the fly brain

Recent neuroscience studies demonstrate that a deeper understanding of brain function requires a deeper understanding of behavior. Detailed behavioral measurements are now often collected using video cameras, resulting in an increased need for computer vision algorithms that extract useful information from video data. Here we introduce a new video analysis tool that combines the output of supervised pose estimation algorithms (e.g. DeepLabCut) with unsupervised dimensionality reduction methods to produce interpretable, low-dimensional representations of behavioral videos that extract more information than pose estimates alone. We demonstrate this tool by extracting interpretable behavioral features from videos of three different head-fixed mouse preparations, as well as a freely moving mouse in an open field arena, and show how these interpretable features can facilitate downstream behavioral and neural analyses. We also show how the behavioral features produced by our model improve the precision and interpretation of these downstream analyses compared to using the outputs of either fully supervised or fully unsupervised methods alone.

Partitioning variability in animal behavioral videos using semi-supervised variational autoencoders

Gaussian Processes (GPs) provide powerful probabilistic frameworks for interpolation, forecasting, and smoothing, but have been hampered by computational scaling issues. Here we investigate data sampled on one dimension (e.g., a scalar or vector time series sampled at arbitrarily-spaced intervals), for which state-space models are popular due to their linearly-scaling computational costs. It has long been conjectured that state-space models are general, able to approximate any one-dimensional GP. We provide the first general proof of this conjecture, showing that any stationary GP on one dimension with vector-valued observations governed by a Lebesgue-integrable continuous kernel can be approximated to any desired precision using a specifically-chosen state-space model: the Latent Exponentially Generated (LEG) family. This new family offers several advantages compared to the general state-space model: it is always stable (no unbounded growth), the covariance can be computed in closed form, and its parameter space is unconstrained (allowing straightforward estimation via gradient descent). The theorem’s proof also draws connections to Spectral Mixture Kernels, providing insight about this popular family of kernels. We develop parallelized algorithms for performing inference and learning in the c ©2021 Jackson Loper, David Blei, John P. Cunningham, Liam Paninski. License: CC-BY 4.0, see https://creativecommons.org/licenses/by/4.0/. Attribution requirements are provided at http://jmlr.org/papers/v22/21-0072.html. Loper, Blei, Cunningham, and Paninski LEG model, test the algorithm on real and synthetic data, and demonstrate scaling to datasets with billions of samples.

A general linear-time inference method for Gaussian Processes on one dimension

Multi-electrode arrays such as "Neuropixels" probes enable the study of neuronal voltage signals at high temporal and single-cell spatial resolution. However, in vivo recordings from these devices often experience some shifting of the probe (due e.g. to animal movement), resulting in poorly localized voltage readings that in turn can corrupt estimates of neural activity. We introduce a new registration method to partially correct for this motion. In contrast to previous template-based registration methods, the proposed approach is decentralized, estimating shifts of the data recorded in multiple timebins with respect to one another, and then extracting a global registration estimate from the resulting estimated shift matrix. We find that the resulting decentralized registration is more robust and accurate than previous template-based approaches applied to both simulated and real data, but nonetheless some significant non-stationarity in the recovered neural activity remains that should be accounted for by downstream processing pipelines. Open source code is available at https://github.com/evarol/NeuropixelsRegistration.

ICASSP 2021 - 2021 IEEE International Conference on Acoustics, Speech and Signal Processing (ICASSP)

Decentralized Motion Inference and Registration of Neuropixel Data

Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention

Non-parametric Vignetting Correction for Sparse Spatial Transcriptomics Images

Sex differences in the brain are prevalent throughout the animal kingdom and particularly well appreciated in the nematode C. elegans, where male animals contain a little studied set of 93 male-specific neurons. To make these neurons amenable for future study, we describe here how a multicolor reporter transgene, NeuroPAL, is capable of visualizing the distinct identities of all male specific neurons. We used NeuroPAL to visualize and characterize a number of features of the male-specific nervous system. We provide several proofs of concept for using NeuroPAL to identify the sites of expression of gfp-tagged reporter genes and for cellular fate analysis by analyzing the effect of removal of several developmental patterning genes on neuronal identity acquisition. We use NeuroPAL and its intrinsic cohort of more than 40 distinct differentiation markers to show that, even though male-specific neurons are generated throughout all four larval stages, they execute their terminal differentiation program in a coordinated manner in the fourth larval stage. This coordinated wave of differentiation, which we call "just-in-time" differentiation, couples neuronal maturation programs with the appearance of sexual organs.

Visualizing the organization and differentiation of the male-specific nervous system of C. elegans.

Rapid mesoscale volumetric imaging of neural activity with synaptic resolution

Demixing Calcium Imaging Data in C. elegans via Deformable Non-negative Matrix Factorization

Disentangled sticky hierarchical Dirichlet process hidden Markov model

A major goal of computational neuroscience is the development of powerful data analyses that operate on large datasets. These analyses form an essential toolset to derive scientific insights from new experiments. Unfortunately, a major obstacle currently impedes progress: novel data analyses have a hidden dependence upon complex computing infrastructure (e.g. software dependencies, hardware), acting as an unaddressed deterrent to potential analysis users. While existing analyses are increasingly shared as open source software, the infrastructure needed to deploy these analyses – at scale, reproducibly, cheaply, and quickly – remains totally inaccessible to all but a minority of expert users. In this work we develop Neuroscience Cloud Analysis As a Service (NeuroCAAS): a fully automated analysis platform that makes state-of-the-art data analysis tools accessible to the neuroscience community. Based on modern large-scale computing advances, NeuroCAAS is an open source platform with a drag-and-drop interface, entirely removing the burden of infrastructure purchase, configuration, deployment, and maintenance from analysis users and developers alike. NeuroCAAS offers two major scientific benefits to any data analysis. First, NeuroCAAS provides automatic reproducibility of analyses at no extra effort to the analysis developer or user. Second, NeuroCAAS cleanly separates tool implementation from usage, allowing for immediate use of arbitrarily complex analyses, at scale. We show how these benefits drive the design of simpler, more powerful data analyses. Furthermore, we show that many popular data analysis tools offered through NeuroCAAS outperform typical analysis solutions (in terms of speed and cost) while improving ease of use, dispelling the myth that cloud compute is prohibitively expensive and technically inaccessible. By removing barriers to fast, efficient cloud computation, NeuroCAAS can dramatically accelerate both the dissemination and the effective use of cutting-edge analysis tools for neuroscientific discovery.

Chronic, cortex-wide imaging of specific cell populations during behavior

Spike sorting is a critical first step in extracting neural signals from large-scale multi-electrode array (MEA) data. This manuscript presents several new techniques that make MEA spike sorting more robust and accurate. Our pipeline is based on an efficient multi-stage “triage-then-cluster-then-pursuit” approach that initially extracts only clean, high-quality waveforms from the electrophysiological time series by temporarily skipping noisy or “collided” events (representing two neurons firing synchronously). This is accomplished by developing a neural network detection and denoising method followed by efficient outlier triaging. The denoised spike waveforms are then used to infer the set of spike templates through nonparametric Bayesian clustering. We use a divide-and-conquer strategy to parallelize this clustering step. Finally, we recover collided waveforms with matching-pursuit deconvolution techniques, and perform further split-and-merge steps to estimate additional templates from the pool of recovered waveforms. We apply the new pipeline to data recorded in the primate retina, where high firing rates and highly-overlapping axonal units provide a challenging testbed for the deconvolution approach; in addition, the well-defined mosaic structure of receptive fields in this preparation provides a useful quality check on any spike sorting pipeline. We show that our pipeline improves on the state-of-the-art in spike sorting (and outperforms manual sorting) on both real and semi-simulated MEA data with > 500 electrodes; open source code can be found at https://github.com/paninski-lab/yass.

YASS: Yet Another Spike Sorter applied to large-scale multi-electrode array recordings in primate retina

We present a semi-automated reconstruction of L2/3 mouse primary visual cortex from 3 million cubic microns of electron microscopic images, including pyramidal and inhibitory neurons, astrocytes, microglia, oligodendrocytes and precursors, pericytes, vasculature, mitochondria, and synapses. Visual responses of a subset of pyramidal cells are included. The data are being made publicly available, along with tools for programmatic and 3D interactive access. The density of synaptic inputs onto inhibitory neurons varies across cell classes and compartments. We uncover a compartment-specific correlation between mitochondrial coverage and synapse density. Frequencies of connectivity motifs in the graph of pyramidal cells are predicted quite accurately from node degrees using the configuration model of random graphs. Cells receiving more connections from nearby cells exhibit stronger and more reliable visual responses. These example findings illustrate the resource’s utility for relating structure and function of cortical circuits as well as for neuronal cell biology.

Multiscale and multimodal reconstruction of cortical structure and function

Extracting calcium traces from populations of neurons is a critical step in the study of the large-scale neural dynamics that govern behavior. Accurate activity extraction requires the correction of motion and movement-induced deformations as well as demixing of signals that may overlap spatially due to limitations in optical resolution. Traditionally, non-negative matrix factorization (NMF) methods have been successful in demixing and denoising cellular calcium activity in relatively motionless or pre-registered videos. However, standard NMF methods fail in animals undergoing significant non-rigid motion; similarly, standard image registration methods based on template matching can fail when large changes in activity lead to mismatches with the image template. To address these issues simultaneously, we introduce a deformable non-negative matrix factorization (dNMF) framework that jointly optimizes registration with signal demixing. On simulated data and real semi-immobilized C. elegans microscopy videos, dNMF outperforms traditional demixing methods that account for motion and demixing separately. Finally, following the extraction of neural traces from multiple imaging experiments, we develop a quantile regression time-series normalization technique to account for varying neural signal intensity baselines across different animals or different imaging setups. Open source code implementing this pipeline is available at https://github.com/amin-nejat/dNMF.

Extracting neural signals from semi-immobilized animals with deformable non-negative matrix factorization

Modern spatial transcriptomics methods can target thousands of different types of RNA transcripts in a single slice of tissue. Many biological applications demand a high spatial density of transcripts relative to the imaging resolution, leading to partial mixing of transcript rolonies in many pixels; unfortunately, current analysis methods do not perform robustly in this highly-mixed setting. Here we develop a new analysis approach, BARcode DEmixing through Non-negative Spatial Regression (BarDensr): we start with a generative model of the physical process that leads to the observed image data and then apply sparse convex optimization methods to estimate the underlying (demixed) rolony densities. We apply Bar-Densr to simulated and real data and find that it achieves state of the art signal recovery, particularly in densely-labeled regions or data with low spatial resolution. Finally, BarDensr is fast and parallelizable. We provide open-source code as well as an implementation for the ‘NeuroCAAS’ cloud platform. Author Summary Spatial transcriptomics technologies allow us to simultaneously detect multiple molecular targets in the context of intact tissues. These experiments yield images that answer two questions: which kinds of molecules are present, and where are they located in the tissue? In many experiments (e.g., mapping RNA expression in fine neuronal processes), it is desirable to increase the signal density relative to the imaging resolution. This may lead to mixing of signals from multiple RNA molecules into single imaging pixels; thus we need to demix the signals from these images. Here we introduce BarDensr, a new computational method to perform this demixing. The method is based on a forward model of the imaging process, followed by a convex optimization approach to approximately ‘invert’ mixing induced during imaging. This new approach leads to significantly improved performance in demixing imaging data with dense expression and/or low spatial resolution.

BARcode DEmixing through Non-negative Spatial Regression (BarDensr)

Probabilistic Joint Segmentation and Labeling of C. elegans Neurons

Learning community structures in graphs has broad applications across scientific domains. While graph neural networks (GNNs) have been successful in encoding graph structures, existing GNN-based methods for community detection are limited by requiring knowledge of the number of communities in advance, in addition to lacking a proper probabilistic formulation to handle uncertainty. We propose a simple framework for amortized community detection, which addresses both of these issues by combining the expressive power of GNNs with recent methods for amortized clustering. Our models consist of a graph representation backbone that extracts structural information and an amortized clustering network that naturally handles variable numbers of clusters. Both components combine into well-defined models of the posterior distribution of graph communities and are jointly optimized given labeled graphs. At inference time, the models yield parallel samples from the posterior of community labels, quantifying uncertainty in a principled way. We evaluate several models from our framework on synthetic and real datasets and demonstrate superior performance to previous methods. As a separate contribution, we extend recent amortized probabilistic clustering architectures by adding attention modules, which yield further improvements on community detection tasks.

Modern recording techniques can generate large-scale measurements of multiple neural populations over extended time periods. However, it remains a challenge to model non-stationary interactions between high-dimensional populations of neurons. To tackle this challenge, we develop recurrent switching linear dynamical systems models for multiple populations. Here, each high-dimensional neural population is represented by a unique set of latent variables, which evolve dynamically in time. Populations interact with each other through this low-dimensional space. We allow the nature of these interactions to change over time by using a discrete set of dynamical states. Additionally, we parameterize these discrete state transition rules to capture which neural populations are responsible for switching between interaction states. To fit the model, we use variational expectation-maximization with a structured mean-field approximation. After validating the model on simulations, we apply it to two different neural datasets: spiking activity from motor areas in a non-human primate, and calcium imaging from neurons in the nematode C. elegans. In both datasets, the model reveals behaviorally-relevant discrete states with unique inter-population interactions and different populations that predict transitioning between these states.

Recurrent Switching Dynamical Systems Models for Multiple Interacting Neural Populations

NeuroPAL: A Multicolor Atlas for Whole-Brain Neuronal Identification in C. elegans

The ability to probe the membrane potential of multiple genetically defined neurons simultaneously would have a profound impact on neuroscience research. Genetically encoded voltage indicators are a promising tool for this purpose, and recent developments have achieved high signal to noise ratio in vivo with 1-photon fluorescence imaging. However, these recordings exhibit several sources of noise that present analysis challenges, namely light scattering, out-of-focus sources, motion, and blood flow. We present a novel signal extraction methodology, Spike-Guided Penalized Matrix Decomposition-Nonnegative Matrix Factorization (SGPMD-NMF), which resolves supra- and sub-threshold voltages with high fidelity, even in the presence of correlated noise. The method incorporates biophysical constraints (shared soma profiles for spiking and subthreshold dynamics) and optical constraints (smoother spatial profiles from defocused vs. in-focus sources) to cleave signal from background. We validated the pipeline using simulated and composite datasets with realistic noise properties. We demonstrate applications to mouse hippocampus expressing paQuasAr3-s or SomArchon, mouse cortex expressing SomArchon or Voltron, and zebrafish spine expressing zArchon1.

High fidelity estimates of spikes and subthreshold waveforms from 1-photon voltage imaging in vivo

Noninvasive behavioral tracking of animals is crucial for many scientific investigations. Recent transfer learning approaches for behavioral tracking have considerably advanced the state of the art. Typically these methods treat each video frame and each object to be tracked independently. In this work, we improve on these methods (particularly in the regime of few training labels) by leveraging the rich spatiotemporal structures pervasive in behavioral video — specifically, the spatial statistics imposed by physical constraints (e.g., paw to elbow distance), and the temporal statistics imposed by smoothness from frame to frame. We propose a probabilistic graphical model built on top of deep neural networks, Deep Graph Pose (DGP), to leverage these useful spatial and temporal constraints, and develop an efficient structured variational approach to perform inference in this model. The resulting semi-supervised model exploits both labeled and unlabeled frames to achieve significantly more accurate and robust tracking while requiring users to label fewer training frames. In turn, these tracking improvements enhance performance on downstream applications, including robust unsupervised segmentation of behavioral “syllables,” and estimation of interpretable “disentangled” low-dimensional representations of the full behavioral video. Open source code is available at https://github.com/paninski-lab/deepgraphpose.

Deep Graph Pose: a semi-supervised deep graphical model for improved animal pose tracking

Decoding sensory stimuli from neural activity can provide insight into how the nervous system might interpret the physical environment, and facilitates the development of brain-machine interfaces. Nevertheless, the neural decoding problem remains a significant open challenge. Here, we present an efficient nonlinear decoding approach for inferring natural scene stimuli from the spiking activities of retinal ganglion cells (RGCs). Our approach uses neural networks to improve upon existing decoders in both accuracy and scalability. Trained and validated on real retinal spike data from > 1000 simultaneously recorded macaque RGC units, the decoder demonstrates the necessity of nonlinear computations for accurate decoding of the fine structures of visual stimuli. Specifically, high-pass spatial features of natural images can only be decoded using nonlinear techniques, while low-pass features can be extracted equally well by linear and nonlinear methods. Together, these results advance the state of the art in decoding natural stimuli from large populations of neurons. Author summary Neural decoding is a fundamental problem in computational and statistical neuroscience. There is an enormous literature on this problem, applied to a wide variety of brain areas and nervous systems. Here we focus on the problem of decoding visual information from the retina. The bulk of previous work here has focused on simple linear decoders, applied to modest numbers of simultaneously recorded cells, to decode artificial stimuli. In contrast, here we develop a scalable nonlinear decoding method to decode natural images from the responses of over a thousand simultaneously recorded units, and show that this decoder significantly improves on the state of the art.

Nonlinear decoding of natural images from large-scale primate retinal ganglion recordings

Combining two-photon calcium imaging (2PCI) and electron microscopy (EM) provides arguably the most powerful current approach for connecting function to structure in neural circuits. Recent years have seen dramatic advances in obtaining and processing CI and EM data separately. In addition, several joint CI-EM datasets (with CI performed in vivo, followed by EM reconstruction of the same volume) have been collected. However, no automated analysis tools yet exist that can match each signal extracted from the CI data to a cell segment extracted from EM; previous efforts have been largely manual and focused on analyzing calcium activity in cell bodies, neglecting potentially rich functional information from axons and dendrites. There are two major roadblocks to solving this matching problem: first, dense EM reconstruction extracts orders of magnitude more segments than are visible in the corresponding CI field of view, and second, due to optical constraints and non-uniform brightness of the calcium indicator in each cell, direct matching of EM and CI spatial components is nontrivial. In this work we develop a pipeline for fusing CI and densely-reconstructed EM data. We model the observed CI data using a constrained nonnegative matrix factorization (CNMF) framework, in which segments extracted from the EM reconstruction serve to initialize and constrain the spatial components of the matrix factorization. We develop an efficient iterative procedure for solving the resulting combined matching and matrix factorization problem and apply this procedure to joint CI-EM data from mouse visual cortex. The method recovers hundreds of dendritic components from the CI data, visible across multiple functional scans at different depths, matched with densely-reconstructed three-dimensional neural segments recovered from the EM volume. We publicly release the output of this analysis as a new gold standard dataset that can be used to score algorithms for demixing signals from 2PCI data. Finally, we show that this database can be exploited to (1) learn a mapping from 3d EM segmentations to predict the corresponding 2d spatial components estimated from CI data, and (2) train a neural network to denoise these estimated spatial components. This neural network denoiser is a stand-alone module that can be dropped in to enhance any existing 2PCI analysis pipeline.

Gaussian Processes (GPs) provide a powerful probabilistic framework for interpolation, forecasting, and smoothing, but have been hampered by computational scaling issues. Here we prove that for data sampled on one dimension (e.g., a time series sampled at arbitrarily-spaced intervals), approximate GP inference at any desired level of accuracy requires computational effort that scales linearly with the number of observations; this new theorem enables inference on much larger datasets than was previously feasible. To achieve this improved scaling we propose a new family of stationary covariance kernels: the Latent Exponentially Generated (LEG) family, which admits a convenient stable state-space representation that allows linear-time inference. We prove that any continuous integrable stationary kernel can be approximated arbitrarily well by some member of the LEG family. The proof draws connections to Spectral Mixture Kernels, providing new insight about the flexibility of this popular family of kernels. We propose parallelized algorithms for performing inference and learning in the LEG model, test the algorithm on real and synthetic data, and demonstrate scaling to datasets with billions of samples.

General linear-time inference for Gaussian Processes on one dimension

Amortized approaches to clustering have recently received renewed attention thanks to novel objective functions that exploit the expressiveness of deep learning models. In this work we revisit a recent proposal for fast amortized probabilistic clustering, the Clusterwise Clustering Process (CCP), which yields samples from the posterior distribution of cluster labels for sets of arbitrary size using only O(K) forward network evaluations, where K is an arbitrary number of clusters. While adequate in simple datasets, we show that the model can severely underfit complex datasets, and hypothesize that this limitation can be traced back to the implicit assumption that the probability of a point joining a cluster is equally sensitive to all the points available to join the same cluster. We propose an improved model, the Attentive Clustering Process (ACP), that selectively pays more attention to relevant points while preserving the invariance properties of the generative model. We illustrate the advantages of the new model in applications to spike-sorting in multi-electrode arrays and community discovery in networks. The latter case combines the ACP model with graph convolutional networks, and to our knowledge is the first deep learning model that handles an arbitrary number of communities.

Widefield calcium imaging enables recording of large-scale neural activity across the mouse dorsal cortex. In order to examine the relationship of these neural signals to the resulting behavior, it is critical to demix the recordings into meaningful spatial and temporal components that can be mapped onto well-defined brain regions. However, no current tools satisfactorily extract the activity of the different brain regions in individual mice in a data-driven manner, while taking into account mouse-specific and preparation-specific differences. Here, we introduce Localized semi-Nonnegative Matrix Factorization (Lo-caNMF), a method that efficiently decomposes widefield video data and allows us to directly compare activity across multiple mice by outputting mouse-specific localized functional regions that are significantly more interpretable than more traditional decomposition techniques. Moreover, it provides a natural subspace to directly compare correlation maps and neural dynamics across different behaviors, mice, and experimental conditions, and enables identification of task- and movement-related brain regions. Author summary While recording from multiple regions of the brain, how does one best incorporate prior information about anatomical regions while accurately representing the data? Here, we introduce Localized semi-NMF (LocaNMF), an algorithm that efficiently decomposes widefield video data into meaningful spatial and temporal components that can be decoded and compared across different behavioral sessions and experimental conditions. Mapping the inferred components onto well-defined brain regions using a widely-used brain atlas provides an interpretable, stable decomposition. LocaNMF allows us to satisfactorily extract the activity of the different brain regions in individual mice in a data-driven manner, while taking into account mouse-specific and preparation-specific differences.

Localized semi-nonnegative matrix factorization (LocaNMF) of widefield calcium imaging data

We introduce a neural architecture to perform amortized approximate Bayesian inference over latent random permutations of two sets of objects. The method involves approximating permanents of matrices of pairwise probabilities using recent ideas on functions defined over sets. Each sampled permutation comes with a probability estimate, a quantity unavailable in MCMC approaches. We illustrate the method in sets of 2D points and MNIST images.

Reinforcement Learning Recruits Somata and Apical Dendrites across Layers of Primary Sensory Cortex

A new method to analyze the variations of neural tuning and its application to primate V1

Probabilistic clustering models (or equivalently, mixture models) are basic building blocks in countless statistical models and involve latent random variables over discrete spaces. For these models, posterior inference methods can be inaccurate and/or very slow. In this work we introduce deep network architectures trained with labeled samples from any generative model of clustered datasets. At test time, the networks generate approximate posterior samples of cluster labels for any new dataset of arbitrary size. We develop two complementary approaches to this task, requiring either O(N) or O(K) network forward passes per dataset, where N is the dataset size and K the number of clusters. Unlike previous approaches, our methods sample the labels of all the data points from a well-defined posterior, and can learn nonparametric Bayesian posteriors since they do not limit the number of mixture components. Moreover, the algorithms are easily parallelized with a GPU. As a scientific application, we present a novel approach to neural spike sorting for high-density multielectrode arrays.

Comprehensively resolving single neurons and their cellular identities from whole-brain fluorescent images is a major challenge. We achieve this in C. elegans through the engineering and use of a multicolor transgene called NeuroPAL (a Neuronal Polychromatic Atlas of Landmarks). NeuroPAL worms share a stereotypical multicolor fluorescence map for the entire hermaphrodite nervous system that allows comprehensive determination of neuronal identities. Neurons labeled with NeuroPAL do not exhibit fluorescence in the green, cyan, or yellow emission channels, allowing the transgene to be used with numerous reporters of gene expression or neuronal dynamics. Here we showcase three studies that leverage NeuroPAL for nervous-system-wide neuronal identification. First, we determine the brainwide expression patterns of all metabotropic receptors for acetylcholine, GABA, and glutamate, completing a map of this communication network. Second, we uncover novel changes in cell fate caused by transcription factor mutations. Third, we record brainwide activity in response to attractive and repulsive chemosensory cues, characterizing multimodal coding and novel neuronal asymmetries for these stimuli. We present a software package that enables semi-automated determination of all neuronal identities based on color and positional information. The NeuroPAL framework and software provide a means to design landmark atlases for other tissues and organisms. In conclusion, we expect NeuroPAL to serve as an invaluable tool for gene expression analysis, neuronal fate studies, and for mapping whole-brain activity patterns.

NeuroPAL: A Neuronal Polychromatic Atlas of Landmarks for Whole-Brain Imaging in C. elegans

We address the problem of marginal inference for an exponential family defined over the set of permutation matrices. This problem is known to quickly become intractable as the size of the permutation increases, since its involves the computation of the permanent of a matrix, a #P-hard problem. We introduce Sinkhorn variational marginal inference as a scalable alternative, a method whose validity is ultimately justified by the so-called Sinkhorn approximation of the permanent. We demonstrate the effectiveness of our method in the problem of probabilistic identification of neurons in the worm C.elegans.

Modern recording techniques enable large-scale measurements of neural activity in a variety of model organisms. The dynamics of neural activity shed light on how organisms process sensory information and generate motor behavior. Here, we study these dynamics using optical recordings of neural activity in the nematode C. elegans. To understand these data, we develop state space models that decompose neural time-series into segments with simple, linear dynamics. We incorporate these models into a hierarchical framework that combines partial recordings from many worms to learn shared structure, while still allowing for individual variability. This framework reveals latent states of population neural activity, along with the discrete behavioral states that govern dynamics in this state space. We find stochastic transition patterns between discrete states and see that transition probabilities are determined by both current brain activity and sensory cues. Our methods automatically recover transition times that closely match manual labels of different behaviors, such as forward crawling, reversals, and turns. Finally, the resulting model can simulate neural data, faithfully capturing salient patterns of whole brain dynamics seen in real data.

Hierarchical recurrent state space models reveal discrete and continuous dynamics of neural activity in C. elegans

Future neural interfaces will read and write population neural activity with high spatial and temporal resolution, for diverse applications. For example, an artificial retina may restore vision to the blind by electrically stimulating retinal ganglion cells. Such devices must tune their function, based on stimulating and recording, to match the function of the circuit. However, existing methods for characterizing the neural interface scale poorly with the number of electrodes, limiting their practical applicability. This work tests the idea that using prior information from previous experiments and closed-loop measurements may greatly increase the efficiency of the neural interface. Large-scale, high-density electrical recording and stimulation in primate retina were used as a lab prototype for an artificial retina. Three key calibration steps were optimized: spike sorting in the presence of stimulation artifacts, response modeling, and adaptive stimulation. For spike sorting, exploiting the similarity of electrical artifact across electrodes and experiments substantially reduced the number of required measurements. For response modeling, a joint model that captures the inverse relationship between recorded spike amplitude and electrical stimulation threshold from previously recorded retinas resulted in greater consistency and efficiency. For adaptive stimulation, choosing which electrodes to stimulate based on probability estimates from previous measurements improved efficiency. Similar improvements resulted from using either non-adaptive stimulation with a joint model across cells, or adaptive stimulation with an independent model for each cell. Finally, image reconstruction revealed that these improvements may translate to improved performance of an artificial retina.

Efficient characterization of electrically evoked responses for neural interfaces

Voltage imaging and optogenetics reveal behaviour-dependent changes in hippocampal dynamics

Calcium imaging is a critical tool for measuring the activity of large neural populations. Much effort has been devoted to developing “pre-processing” tools applied to calcium video data, addressing the important issues of e.g., motion correction, denoising, compression, demixing, and deconvolution. However, computational modeling of deconvolved calcium signals (i.e., the estimated activity extracted by a pre-processing pipeline) is just as critical for interpreting calcium measurements. Surprisingly, these issues have to date received significantly less attention. To fill this gap, we examine the statistical properties of the deconvolved activity estimates, and propose several density models for these random signals. These models include a zero-inflated gamma (ZIG) model, which characterizes the calcium responses as a mixture of a gamma distribution and a point mass which serves to model zero responses. We apply the resulting models to neural encoding and decoding problems. We find that the ZIG model out-performs simpler models (e.g., Poisson or Bernoulli models) in the context of both simulated and real neural data, and can therefore play a useful role in bridging calcium imaging analysis methods with tools for analyzing activity in large neural populations.

A zero-inflated gamma model for post-deconvolved calcium imaging traces

We present a novel approach to spike sorting for high-density multielectrode probes using the Neural Clustering Process (NCP), a recently introduced neural architecture that performs scalable amortized approximate Bayesian inference for efficient probabilistic clustering. To optimally encode spike waveforms for clustering, we extended NCP by adding a convolutional spike encoder, which is learned end-to-end with the NCP network. Trained purely on labeled synthetic spikes from a simple generative model, the NCP spike sorting model shows promising performance for clustering multi-channel spike waveforms. The model provides higher clustering quality than an alternative Bayesian algorithm, finds more spike templates with clear receptive fields on real data, and recovers more ground truth neurons on hybrid test data compared to a recent spike sorting algorithm. Furthermore, NCP is able to handle the clustering uncertainty of ambiguous small spikes by GPU-parallelized posterior sampling. The source code is publicly available [1].

Voltage imaging and optogenetics reveal behavior dependent changes in hippocampal dynamics

Recent advances in optical voltage sensors have brought us closer to a critical goal in cellular neuroscience: imaging the full spatiotemporal voltage on a dendritic tree. However, current sensors and imaging approaches still face significant limitations in SNR and sampling frequency; therefore statistical denoising and interpolation methods remain critical for understanding single-trial spatiotemporal dendritic voltage dynamics. Previous denoising approaches were either based on an inadequate linear voltage model or scaled poorly to large trees. Here we introduce a scalable fully Bayesian approach. We develop a generative nonlinear model that requires few parameters per compartment of the cell but is nonetheless flexible enough to sample realistic spatiotemporal data. The model captures different dynamics in each compartment and leverages biophysical knowledge to constrain intra- and inter-compartmental dynamics. We obtain a full posterior distribution over spatiotemporal voltage via an augmented Gibbs sampling algorithm. The nonlinear smoother model outperforms previously developed linear methods, and scales to much larger systems than previous methods based on sequential Monte Carlo approaches.

Scalable Bayesian inference of dendritic voltage via spatiotemporal recurrent state space models

A fundamental goal of systems neuroscience is to understand the relationship between neural activity and behavior. Behavior has traditionally been characterized by low-dimensional, task-related variables such as movement speed or response times. More recently, there has been a growing interest in automated analysis of high-dimensional video data collected during experiments. Here we introduce a probabilistic framework for the analysis of behavioral video and neural activity. This framework provides tools for compression, segmentation, generation, and decoding of behavioral videos. Compression is performed using a convolutional autoencoder (CAE), which yields a low-dimensional continuous representation of behavior. We then use an autoregressive hidden Markov model (ARHMM) to segment the CAE representation into discrete "behavioral syllables." The resulting generative model can be used to simulate behavioral video data. Finally, based on this generative model, we develop a novel Bayesian decoding approach that takes in neural activity and outputs probabilistic estimates of the full-resolution behavioral video. We demonstrate this framework on two different experimental paradigms using distinct behavioral and neural recording technologies.

BehaveNet: nonlinear embedding and Bayesian neural decoding of behavioral videos

†These authors contributed equally to this work 1Center for the Neural Basis of Cognition and Machine Learning Department, Carnegie 8 Mellon University, Pittsburgh, United States of America; 2Departments of Statistics and 9 Neuroscience, Grossman Center for the Statistics of Mind, Center for Theoretical 10 Neuroscience, Kavli Institute for Brain Science, and NeuroTechnology Center, Columbia 11 University, New York, United States of America; 3Department of Psychiatry, University of 12 North Carolina at Chapel Hill, Chapel Hill, United States of America; 4Departments of 13 Neuroscience & Psychiatry, Columbia University, New York, United States of America; 14 5Division of Integrative Neuroscience, Department of Psychiatry, New York State 15 Psychiatric Institute, New York, United States of America; 6Howard Hughes Medical 16 Institute, Department of Neurobiology, Harvard Medical School, Boston, United States of 17 America; 7Center for Computational Biology, Flatiron Institute, Simons Foundation, New 18 York, United States of America; 8Neuroscience Center, Department of Cell Biology and 19 Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States of 20 America; 9Neuroscience Graduate Program, Weill Institute for Neurosciences, Kavli 21 Institute for Fundamental Neuroscience, Department of Psychiatry, University of 22 California, San Francisco, United States of America; 10Department of Statistics, Carnegie 23 Mellon University, Pittsburgh, United States of America 24

The Spatiotemporal Organ ization of the Striatum Encodes Action Space Highlights

Calcium imaging (CI) has become the dominant method for recording from large populations of neurons, due to several well-known advantages: CI offers sub-cellular spatial resolution with cell-type specificity and can be coupled easily with a variety of genetic tools; CI has proven scalability to record simultaneously from O(10) neurons in vivo; finally, CI allows for longitudinal tracking of cellular activity across multiple days. At the same time, CI presents some important analysis challenges: calcium signals represent a slow, nonlinear encoding of the underlying spike train signals of interest, and therefore it is necessary to denoise, temporally deconvolve, and spatially demix calcium video data into estimates of neural activity. In addition, CI produces datasets that can be quite large (hundreds of GB per hour in some cases); thus analysis methods must be scalable and as automated and reproducible as possible. This chapter presents a (non-exhaustive) review of current state of the art analysis methods for CI data, with a focus on data recorded at single-neuron resolution. We will also touch briefly on the analysis of voltage imaging data and widefield CI data, both of which come with their own related but distinct analysis challenges.

Analysis of functional imaging data at single-cellular resolution ∗

Visualizing neuronal activity in vivo Imaging the changes in fluorescence of voltage-sensitive reagents would enable monitoring of the activity of neurons in vivo. Abdelfattah et al. created such a voltage indicator by designing a protein that combines the voltage sensor domain from microbial rhodopsin with a domain that captures a dye molecule with exceptional brightness and photostability. When the protein was expressed in mice, flies, or zebrafish, they could monitor single action potentials in dozens of neurons simultaneously for many minutes. Science, this issue p. 699 Improved speed, brightness, and photostability of voltage sensors allows simultaneous imaging of many neurons. Genetically encoded voltage indicators (GEVIs) enable monitoring of neuronal activity at high spatial and temporal resolution. However, the utility of existing GEVIs has been limited by the brightness and photostability of fluorescent proteins and rhodopsins. We engineered a GEVI, called Voltron, that uses bright and photostable synthetic dyes instead of protein-based fluorophores, thereby extending the number of neurons imaged simultaneously in vivo by a factor of 10 and enabling imaging for significantly longer durations relative to existing GEVIs. We used Voltron for in vivo voltage imaging in mice, zebrafish, and fruit flies. In the mouse cortex, Voltron allowed single-trial recording of spikes and subthreshold voltage signals from dozens of neurons simultaneously over a 15-minute period of continuous imaging. In larval zebrafish, Voltron enabled the precise correlation of spike timing with behavior.

Bright and photostable chemigenetic indicators for extended in vivo voltage imaging

We develop methods for efficient amortized approximate Bayesian inference over posterior distributions of probabilistic clustering models, such as Dirichlet process mixture models. The approach is based on mapping distributed, symmetry-invariant representations of cluster arrangements into conditional probabilities. The method parallelizes easily, yields iid samples from the approximate posterior of cluster assignments with the same computational cost of a single Gibbs sampler sweep, and can easily be applied to both conjugate and non-conjugate models, as training only requires samples from the generative model.

Latent variable models have been widely applied for the analysis and visualization of large datasets. In the case of sequential data, closed-form inference is possible when the transition and observation functions are linear. However, approximate inference techniques are usually necessary when dealing with nonlinear dynamics and observation functions. Here, we propose a novel variational inference framework for the explicit modeling of time series, Variational Inference for Nonlinear Dynamics (VIND), that is able to uncover nonlinear observation and transition functions from sequential data. The framework includes a structured approximate posterior, and an algorithm that relies on the fixed-point iteration method to find the best estimate for latent trajectories. We apply the method to several datasets and show that it is able to accurately infer the underlying dynamics of these systems, in some cases substantially outperforming state-of-the-art methods.

Calcium imaging has revolutionized systems neuroscience, providing the ability to image large neural populations with single-cell resolution. The resulting datasets are quite large (with scales of TB/hour in some cases), which has presented a barrier to routine open sharing of this data, slowing progress in reproducible research. State of the art methods for analyzing this data are based on non-negative matrix factorization (NMF); these approaches solve a non-convex optimization problem, and are highly effective when good initializations are available, but can break down e.g. in low-SNR settings where common initialization approaches fail. Here we introduce an improved approach to compressing and denoising functional imaging data. The method is based on a spatially-localized penalized matrix decomposition (PMD) of the data to separate (low-dimensional) signal from (temporally-uncorrelated) noise. This approach can be applied in parallel on local spatial patches and is therefore highly scalable, does not impose non-negativity constraints or require stringent identifiability assumptions (leading to significantly more robust results compared to NMF), and estimates all parameters directly from the data, so no hand-tuning is required. We have applied the method to a wide range of functional imaging data (including one-photon, two-photon, three-photon, widefield, somatic, axonal, dendritic, calcium, and voltage imaging datasets): in all cases, we observe ~2-4x increases in SNR and compression rates of 20-300x with minimal visible loss of signal, with no adjustment of hyperparameters; this in turn facilitates the process of demixing the observed activity into contributions from individual neurons. We focus on two challenging applications: dendritic calcium imaging data and voltage imaging data in the context of optogenetic stimulation. In both cases, we show that our new approach leads to faster and much more robust extraction of activity from the video data.

Penalized matrix decomposition for denoising, compression, and improved demixing of functional imaging data

Many data generating processes involve latent random variables over discrete combinatorial spaces whose size grows factorially with the dataset. In these settings, existing posterior inference methods can be inaccurate and/or very slow. In this work we develop methods for efficient amortized approximate Bayesian inference over discrete combinatorial spaces, with applications to random permutations, probabilistic clustering (such as Dirichlet process mixture models) and random communities (such as stochastic block models). The approach is based on mapping distributed, symmetry-invariant representations of discrete arrangements into conditional probabilities. The resulting algorithms parallelize easily, yield iid samples from the approximate posteriors, and can easily be applied to both conjugate and nonconjugate models, as training only requires samples from the generative model.

Neuroprosthetic brain-computer interfaces function via an algorithm which decodes neural activity of the user into movements of an end effector, such as a cursor or robotic arm. In practice, the decoder is often learned by updating its parameters while the user performs a task. When the user’s intention is not directly observable, recent methods have demonstrated value in training the decoder against a surrogate for the user’s intended movement. We describe how training a decoder in this way is a novel variant of an imitation learning problem, where an oracle or expert is employed for supervised training in lieu of direct observations, which are not available. Specifically, we describe how a generic imitation learning meta-algorithm, dataset aggregation (DAgger, [1]), can be adapted to train a generic brain-computer interface. By deriving existing learning algorithms for brain-computer interfaces in this framework, we provide a novel analysis of regret (an important metric of learning efficacy) for brain-computer interfaces. This analysis allows us to characterize the space of algorithmic variants and bounds on their regret rates. Existing approaches for decoder learning have been performed in the cursor control setting, but the available design principles for these decoders are such that it has been impossible to scale them to naturalistic settings. Leveraging our findings, we then offer an algorithm that combines imitation learning with optimal control, which should allow for training of arbitrary effectors for which optimal control can generate goal-oriented control. We demonstrate this novel and general BCI algorithm with simulated neuroprosthetic control of a 26 degree-of-freedom model of an arm, a sophisticated and realistic end effector.

M L ] 1 4 M ar 2 01 6 Neuroprosthetic decoder training as imitation learning

Latent variable models have been widely applied for the analysis and visualization of time series that result from techniques in experimental neuroscience. These are datasets in which the evolution of the observations is relatively smooth and possibly nonlinear. In this work we present Variational Inference for Nonlinear Dynamics (VIND), a variational inference framework that is able to uncover nonlinear, smooth latent dynamics from sequential data. The framework is a direct extension of PfLDS; including a structured approximate posterior describing spatially-dependent linear dynamics, as well as an algorithm that re- lies on the fixed-point iteration method to achieve convergence. We apply VIND to electrophysiology, single-cell voltage and widefield imaging datasets with state-of-the-art results in reconstruction error. In single-cell voltage data, VIND finds a 5D latent space, with variables akin to those of Hodgkin-Huxley-like models. The quality of VIND’s learned dynamics is further quantified by using it to predict future neural activity. VIND excels in this task, in some cases substantially outperforming current methods.

Nonlinear Evolution via Spatially-Dependent Linear Dynamics for Electrophysiology and Calcium Data

Many important datasets in physics, chemistry, and biology consist of noisy sequences of images of multiple moving overlapping particles. In many cases, the observed particles are indistinguishable, leading to unavoidable uncertainty about nearby particles’ identities. Exact Bayesian inference is intractable in this setting, and previous approximate Bayesian methods scale poorly. Non-Bayesian approaches that output a single “best” estimate of the particle tracks (thus discarding important uncertainty information) are therefore dominant in practice. Here we propose a flexible and scalable amortized approach for Bayesian inference on this task. We introduce a novel neural network method to approximate the (intractable) filter-backward-sample-forward algorithm for Bayesian inference in this setting. By varying the simulated training data for the network, we can perform inference on a wide variety of data types. This approach is therefore highly flexible and improves on the state of the art in terms of accuracy; provides uncertainty estimates about the particle locations and identities; and has a test run-time that scales linearly as a function of the data length and number of particles, thus enabling Bayesian inference in arbitrarily large particle tracking datasets.

Scalable approximate Bayesian inference for particle tracking data

The neocortex is organized into discrete layers of excitatory neurons: layer 4 receives the densest ‘bottom up’ projection carrying external sensory data, while layers 2/3 and 5 receive ‘top down’ inputs from higher cortical areas that may convey sensory expectations and behavioral goals. A subset of cortical somatostatin (SST) neurons gate top down input and control sensory computation by inhibiting the apical dendrites of pyramidal cells in layers 2/3 and 5. However, it is unknown whether an analogous inhibitory mechanism separately and specifically controls activity in layer 4. We hypothesized that distinct SST circuits might exist to inhibit specific cortical layers. By enforcing layer-specific inhibition, distinct SST subnetworks could mediate pathway-specific gain control, such as regulating the balance between bottom up and top down input. Employing a combination of high precision circuit mapping, in vivo optogenetic perturbations, and single cell transcriptional profiling, we reveal distinct and complementary SST circuits that specifically and reciprocally interconnect with excitatory cells in either layer 4 or layers 2/3 and 5. Our data further define a transcriptionally distinct SST neuronal sub-class that powerfully gates bottom up sensory activity during active sensation by regulating layer 4 activity. This integrated paradigm further represents a potentially generalizable approach to identify and characterize neuronal cell types and reveal their in vivo function.

Complementary networks of cortical somatostatin interneurons enforce layer specific control

This paper studies measurement linkage. An example from cell biology helps explain the problem: imagine for a given cell we can either sequence the cell’s RNA or we can examine its morphology, but not both. Given a cell’s morphology, what do we expect to see in its RNA? Given a cell’s RNA, what do we expect in its morphology? More broadly, given a measurement of one type, can we predict measurements of the other type? This measurement linkage problem arises in many scientific and technological fields. To solve this problem, we develop a nonparametric approach we dub the “Markov link method” (MLM). The MLM makes a conditional independence assumption that holds in many multi-measurement contexts and provides a a way to estimate the link, the conditional probability of one type of measurement given the other. We derive conditions under which the MLM estimator is consistent and we use simulated data to show that it provides accurate measures of uncertainty. We evaluate the MLM on real data generated by a pair of single-cell RNA sequencing techniques. The MLM characterizes the link between them and helps connect the two notions of cell type derived from each technique. Further, the MLM reveals that some aspects of the link cannot be determined from the available data, and suggests new experiments that would allow for better estimates.

The Markov link method: a nonparametric approach to combine observations from multiple experiments

The Spatiotemporal Organization of the Striatum Encodes Action Space

Spike sorting is a critical first step in extracting neural signals from large-scale electrophysiological data. This manuscript describes an efficient, reliable pipeline for spike sorting on dense multi-electrode arrays (MEAs), where neural signals appear across many electrodes and spike sorting currently represents a major computational bottleneck. We present several new techniques that make dense MEA spike sorting more robust and scalable. Our pipeline is based on an efficient multi-stage “triage-then-cluster-then-pursuit” approach that initially extracts only clean, high-quality waveforms from the electrophysiological time series by temporarily skipping noisy or “collided” events (representing two neurons firing synchronously). This is accomplished by developing a neural network detection method followed by efficient outlier triaging. The clean waveforms are then used to infer the set of neural spike waveform templates through nonparametric Bayesian clustering. Our clustering approach adapts a “coreset” approach for data reduction and uses efficient inference methods in a Dirichlet process mixture model framework to dramatically improve the scalability and reliability of the entire pipeline. The “triaged” waveforms are then finally recovered with matching-pursuit deconvolution techniques. The proposed methods improve on the state-of-the-art in terms of accuracy and stability on both real and biophysically-realistic simulated MEA data. Furthermore, the proposed pipeline is efficient, learning templates and clustering much faster than real-time for a ≃ 500-electrode dataset, using primarily a single CPU core.

Optical imaging methods using calcium indicators are critical for monitoring the activity of large neuronal populations in vivo. Imaging experiments typically generate a large amount of data that needs to be processed to extract the activity of the imaged neuronal sources. While deriving such processing algorithms is an active area of research, most existing methods require the processing of large amounts of data at a time, rendering them vulnerable to the volume of the recorded data, and preventing realtime experimental interrogation. Here we introduce OnACID, an Online framework for the Analysis of streaming Calcium Imaging Data, including i) motion artifact correction, ii) neuronal source extraction, and iii) activity denoising and deconvolution. Our approach combines and extends previous work on online dictionary learning and calcium imaging data analysis, to deliver an automated pipeline that can discover and track the activity of hundreds of cells in real time, thereby enabling new types of closed-loop experiments. We apply our algorithm on two large scale experimental datasets, benchmark its performance on manually annotated data, and show that it outperforms a popular offline approach.

Vocal communication evokes robust responses in primary auditory cortex (A1) of songbirds, and single neurons from superficial and deep regions of A1 have been shown to respond selectively to songs over complex, synthetic sounds. However, little is known about how this song selectivity arises and manifests itself on the level of networks of neurons in songbird A1. Here, we examined the network-level coding of song and synthetic sounds in A1 by simultaneously recording the responses of multiple neurons in unanesthetized zebra finches. We developed a latent factor model of the joint simultaneous activity of these neural populations, and found that the shared variability in the activity has a surprisingly simple structure; it is dominated by an unobserved latent source with one degree-of-freedom. This simple model captures the structure of the correlated activity in these populations in both spontaneous and stimulus-driven conditions, and given both song and synthetic stimuli. The inferred latent variability is strongly suppressed under stimulation, consistent with similar observations in a range of mammalian cortical regions.

A Statistical Model of Shared Variability in the Songbird Auditory System

Modern large - scale multineuronal recording methodologies, including multielectrode arrays, calcium imaging, and optogenetic techniques, produce single - neuron resolution data of a magnitude and precision that were the realm of science fiction twenty years ago. The major bottlenecks in systems and circuit neuroscience no longer lie in simply collecting data from large neural populations, but also in understanding this data: developing novel scientific questions, with corresponding analysis techniques and experimental designs to fully harness these new capabilities and meaningfully interrogate these questions. Advances in methods for signal processing, network analysis, dimensionality reduction, and optimal control – developed in lockstep with advances in experimental neurotechnology - - promise major breakthroughs in multiple fundamental neuroscience problems. These trends are clear in a broad array of subfields of modern neuroscience; this review focuses on recent advances in methods for analyzing neural time - series data with single - neuronal precision. Figure 1. The central role of data science in modern large - scale neuroscience. Topics reviewed herein are indicated in black.

Neural data science: accelerating the experiment-analysis-theory cycle in large-scale neuroscience

Cerebellar granule cells acquire a widespread predictive feedback signal during motor learning

Decoding sensory stimuli from neural signals can be used to reveal how we sense our physical environment, and is critical for the design of brain-machine interfaces. However, existing linear techniques for neural decoding may not fully reveal or exploit the fidelity of the neural signal. Here we develop a new approximate Bayesian method for decoding natural images from the spiking activity of populations of retinal ganglion cells (RGCs). We sidestep known computational challenges with Bayesian inference by exploiting “amortized inference” via artificial neural networks developed for computer vision, which enables nonlinear decoding that incorporates natural scene statistics implicitly. We use a decoder architecture that first linearly reconstructs an image from RGC spikes, then applies a convolutional autoencoder to enhance the image. The resulting decoder, trained on natural images, significantly outperforms state-of-the-art linear decoding, as well as simple point-wise nonlinear decoding. Additionally, the decoder trained on natural images performs nearly as accurately on a subset of natural stimuli (faces) as a decoder trained specifically for the subset, a feature not observed with a linear decoder. These results provide a tool for the assessment and optimization of retinal prosthesis technologies, and reveal that the neural output of the retina may provide a more accurate representation of the visual scene than previously appreciated.

Many matching, tracking, sorting, and ranking problems require probabilistic reasoning about possible permutations, a set that grows factorially with dimension. Combinatorial optimization algorithms may enable efficient point estimation, but fully Bayesian inference poses a severe challenge in this high-dimensional, discrete space. To surmount this challenge, we start with the usual step of relaxing a discrete set (here, of permutation matrices) to its convex hull, which here is the Birkhoff polytope: the set of all doubly-stochastic matrices. We then introduce two novel transformations: first, an invertible and differentiable stick-breaking procedure that maps unconstrained space to the Birkhoff polytope; second, a map that rounds points toward the vertices of the polytope. Both transformations include a temperature parameter that, in the limit, concentrates the densities on permutation matrices. We then exploit these transformations and reparameterization gradients to introduce variational inference over permutation matrices, and we demonstrate its utility in a series of experiments.

Reparameterizing the Birkhoff Polytope for Variational Permutation Inference

Decoding sensory stimuli from neural signals can be used to reveal how we sense our physical environment, and is valuable for the design of brain-machine interfaces. However, existing linear techniques for neural decoding may not fully reveal or exploit the fidelity of the neural signal. Here we develop a new approximate Bayesian method for decoding natural images from the spiking activity of populations of retinal ganglion cells (RGCs). We sidestep known computational challenges with Bayesian inference by exploiting artificial neural networks developed for computer vision, enabling fast nonlinear decoding that incorporates natural scene statistics implicitly. We use a decoder architecture that first linearly reconstructs an image from RGC spikes, then applies a convolutional autoencoder to enhance the image. The resulting decoder, trained on natural images and simulated neural responses, significantly outperforms linear decoding, as well as simple point-wise nonlinear decoding. These results provide a tool for the assessment and optimization of retinal prosthesis technologies, and reveal that the retina may provide a more accurate representation of the visual scene than previously appreciated.

Neural Networks for Efficient Bayesian Decoding of Natural Images from Retinal Neurons

Fluorescent calcium indicators are a popular means for observing the spiking activity of large neuronal populations, but extracting the activity of each neuron from raw fluorescence calcium imaging data is a nontrivial problem. We present a fast online active set method to solve this sparse non-negative deconvolution problem. Importantly, the algorithm 3progresses through each time series sequentially from beginning to end, thus enabling real-time online estimation of neural activity during the imaging session. Our algorithm is a generalization of the pool adjacent violators algorithm (PAVA) for isotonic regression and inherits its linear-time computational complexity. We gain remarkable increases in processing speed: more than one order of magnitude compared to currently employed state of the art convex solvers relying on interior point methods. Unlike these approaches, our method can exploit warm starts; therefore optimizing model hyperparameters only requires a handful of passes through the data. A minor modification can further improve the quality of activity inference by imposing a constraint on the minimum spike size. The algorithm enables real-time simultaneous deconvolution of O(105) traces of whole-brain larval zebrafish imaging data on a laptop.

Many natural systems, such as neurons firing in the brain or basketball teams traversing a court, give rise to time series data with complex, nonlinear dynamics. We can gain insight into these systems by decomposing the data into segments that are each explained by simpler dynamic units. Building on switching linear dynamical systems (SLDS), we develop a model class and Bayesian inference algorithms that not only discover these dynamical units but also, by learning how transition probabilities depend on observations or continuous latent states, explain their switching behavior. Our key innovation is to design these recurrent SLDS models to enable recent Pólya-gamma auxiliary variable techniques and thus make approximate Bayesian learning and inference in these models easy, fast, and scalable.

Bayesian Learning and Inference in Recurrent Switching Linear Dynamical Systems

Bayesian Sparse Regression Analysis Documents the Diversity of Spinal Inhibitory Interneurons

Reconstruction of neuroanatomy is a fundamental problem in neuroscience. Stochastic expression of colors in individual cells is a promising tool, although its use in the nervous system has been limited due to various sources of variability in expression. Moreover, the intermingled anatomy of neuronal trees is challenging for existing segmentation algorithms. Here, we propose a method to automate the segmentation of neurons in such (potentially pseudo-colored) images. The method uses spatio-color relations between the voxels, generates supervoxels to reduce the problem size by four orders of magnitude before the final segmentation, and is parallelizable over the supervoxels. To quantify performance and gain insight, we generate simulated images, where the noise level and characteristics, the density of expression, and the number of fluorophore types are variable. We also present segmentations of real Brainbow images of the mouse hippocampus, which reveal many of the dendritic segments.

Automated scalable segmentation of neurons from multispectral images

and show the results in Figure 7. The raw data is typically dense when averaged over either time or space, as can be seen from the low intensity of the raw data correlation and mean image (Figures 7A–7C).We initialize randomly using a large number of components (in this case 50) and then order the inferred components as before. The top 23 of these components together with the background and the corresponding temporal traces in DF/F units are shown in Figures 7D–7F. These components are sparse in both space and time, with the temporal components extracting temporally localized bursts visible in the raw video data, and the spatial components extracting segments of the apparent dendritic structures visible in the video data (see also Movie S9). The results show the effectiveness of the sparse CNMFprocedure in obtaining separated spatiotemporal components given dendritic imaging data in which the degree of overlap is very high and the spatial components are not localized.

NeuroResource Simultaneous Denoising , D econvolution , and Demixing of Calcium Imaging Data Highlights

Partition functions of probability distributions are important quantities for model evaluation and comparisons. We present a new method to compute partition functions of complex and multimodal distributions. Such distributions are often sampled using simulated tempering, which augments the target space with an auxiliary inverse temperature variable. Our method exploits the multinomial probability law of the inverse temperatures, and provides estimates of the partition function in terms of a simple quotient of Rao-Blackwellized marginal inverse temperature probability estimates, which are updated while sampling. We show that the method has interesting connections with several alternative popular methods, and offers some significant advantages. In particular, we empirically find that the new method provides more accurate estimates than Annealed Importance Sampling when calculating partition functions of large Restricted Boltzmann Machines (RBM); moreover, the method is sufficiently accurate to track training and validation log-likelihoods during learning of RBMs, at minimal computational cost.

Super-resolution microscopy methods (e.g. STORM or PALM imaging) have become essential tools in biology, opening up a variety of new questions that were previously inaccessible with standard light microscopy methods. In this paper we develop new Bayesian image processing methods that extend the reach of super-resolution microscopy even further. Our method couples variational inference techniques with a data summarization based on Laplace approximation to ensure computational scalability. Our formulation makes it straightforward to incorporate prior information about the underlying sample to further improve accuracy. The proposed method obtains dramatic resolution improvements over previous methods while retaining computational tractability.

Population-Level Representation of a Temporal Sequence Underlying Song Production in the Zebra Finch

Developing accurate predictive models of sensory neurons is vital to understanding sensory processing and brain computations. The current standard approach to modeling neurons is to start with simple models and to incrementally add interpretable features. An alternative approach is to start with a more complex model that captures responses accurately, and then probe the fitted model structure to understand the neural computations. Here, we show that a multitask recurrent neural network (RNN) framework provides the flexibility necessary to model complex computations of neurons that cannot be captured by previous methods. Specifically, multilayer recurrent neural networks that share features across neurons outperform generalized linear models (GLMs) in predicting the spiking responses of parasol ganglion cells in the primate retina to natural images. The networks achieve good predictive performance given surprisingly small amounts of experimental training data. Additionally, we present a novel GLM-RNN hybrid model with separate spatial and temporal processing components which provides insights into the aspects of retinal processing better captured by the recurrent neural networks.

Multilayer Recurrent Network Models of Primate Retinal Ganglion Cell Responses

Imaging the neuronal activity throughout the brain with high temporal and spatial resolution is an important step in understanding how the brain works. Two-photon laser scanning microscopy with fluorescent calcium indicators has enabled this type of experiments in vivo. Most of these microscopes acquire images serially, with a single laser beam, limiting the overall imaging speed. To overcome this limit, multiple beamlets can be used to image in parallel multiple regions. Here, we demonstrate a novel scheme of a two-photon laser-scanning microscope that can simultaneously record neuronal activity at multiple planes of the sample with a single photomultiplier tube. A spatial light modulator is used to generate the designated multiple beamlets, and a constrained non-negative matrix factorization algorithm is used to demix the signals from multiple scanned planes. We simultaneously record neuronal activity of multiple layers of a mouse cortex at 10 fps in vivo. This novel imaging scheme provides a powerful tool for mapping the brain activity.

Two-photon multiplane imaging of neural circuits (Conference Presentation)

Fluorescent calcium indicators are a popular means for observing the spiking activity of large neuronal populations, but extracting the activity of each neuron from raw fluorescence calcium imaging data is a nontrivial problem. We present a fast online active set method to solve this sparse non-negative deconvolution problem. Importantly, the algorithm progresses through each time series sequentially from beginning to end, thus enabling real-time online estimation of neural activity during the imaging session. Our algorithm is a generalization of the pool adjacent violators algorithm (PAVA) for isotonic regression and inherits its linear-time computational complexity. We gain remarkable increases in processing speed: more than one order of magnitude compared to currently employed state of the art convex solvers relying on interior point methods. Our method can exploit warm starts; therefore optimizing model hyperparameters only requires a handful of passes through the data. A minor modification can further improve the quality of activity inference by imposing a constraint on the minimum spike size. The algorithm enables real-time simultaneous deconvolution of $O(10^5)$ traces of whole-brain larval zebrafish imaging data on a laptop.

Fast Active Set Methods for Online Deconvolution of Calcium Imaging Data

A common analytical problem in neuroscience is the interpretation of neural activity with respect to sensory input or behavioral output. This is typically achieved by regressing measured neural activity against known stimuli or behavioral variables to produce a "tuning function" for each neuron. Unfortunately, because this approach handles neurons individually, it cannot take advantage of simultaneous measurements from spatially adjacent neurons that often have similar tuning properties. On the other hand, sharing information between adjacent neurons can errantly degrade estimates of tuning functions across space if there are sharp discontinuities in tuning between nearby neurons. In this paper, we develop a computationally efficient block Gibbs sampler that effectively pools information between neurons to de-noise tuning function estimates while simultaneously preserving sharp discontinuities that might exist in the organization of tuning across space. This method is fully Bayesian and its computational cost per iteration scales sub-quadratically with total parameter dimensionality. We demonstrate the robustness and scalability of this approach by applying it to both real and synthetic datasets. In particular, an application to data from the spinal cord illustrates that the proposed methods can dramatically decrease the experimental time required to accurately estimate tuning functions.

Robust and scalable Bayesian analysis of spatial neural tuning function data

Many natural systems, such as neurons firing in the brain or basketball teams traversing a court, give rise to time series data with complex, nonlinear dynamics. We can gain insight into these systems by decomposing the data into segments that are each explained by simpler dynamic units. Building on switching linear dynamical systems (SLDS), we present a new model class that not only discovers these dynamical units, but also explains how their switching behavior depends on observations or continuous latent states. These "recurrent" switching linear dynamical systems provide further insight by discovering the conditions under which each unit is deployed, something that traditional SLDS models fail to do. We leverage recent algorithmic advances in approximate inference to make Bayesian inference in these models easy, fast, and scalable.

Fluorescent calcium indicators are a popular means for observing the spiking activity of large neuronal populations. Unfortunately, extracting the spike train of each neuron from raw fluorescence calcium imaging data is a nontrivial problem. We present a fast online active set method to solve this sparse nonnegative deconvolution problem. Importantly, the algorithm progresses through each time series sequentially from beginning to end, thus enabling real-time online spike inference during the imaging session. Our algorithm is a generalization of the pool adjacent violators algorithm (PAVA) for isotonic regression and inherits its linear-time computational complexity. We gain remarkable increases in processing speed: more than one order of magnitude compared to currently employed state of the art convex solvers relying on interior point methods. Our method can exploit warm starts; therefore optimizing model hyperparameters only requires a handful of passes through the data. The algorithm enables real-time simultaneous deconvolution of $O(10^5)$ traces of whole-brain zebrafish imaging data on a laptop.

Fast Active Set Methods for Online Spike Inference from Calcium Imaging

In vivo calcium imaging through microendoscopic lenses enables imaging of previously inaccessible neuronal populations deep within the brains of freely moving animals. However, it is computationally challenging to extract single-neuronal activity from microendoscopic data, because of the very large background fluctuations and high spatial overlaps intrinsic to this recording modality. Here, we describe a new constrained matrix factorization approach to accurately separate the background and then demix and denoise the neuronal signals of interest. We compared the proposed method against previous independent components analysis and constrained nonnegative matrix factorization approaches. On both simulated and experimental data recorded from mice, our method substantially improved the quality of extracted cellular signals and detected more well-isolated neural signals, especially in noisy data regimes. These advances can in turn significantly enhance the statistical power of downstream analyses, and ultimately improve scientific conclusions derived from microendoscopic data.

Efficient and accurate extraction of in vivo calcium signals from microendoscopic video data

Simultaneous Denoising, Deconvolution, and Demixing of Calcium Imaging Data

Simultaneous electrical stimulation and recording using multi-electrode arrays can provide a valuable technique for studying circuit connectivity and engineering neural interfaces. However, interpreting these measurements is challenging because the spike sorting process (identifying and segregating action potentials arising from different neurons) is greatly complicated by electrical stimulation artifacts across the array, which can exhibit complex and nonlinear waveforms, and overlap temporarily with evoked spikes. Here we develop a scalable algorithm based on a structured Gaussian Process model to estimate the artifact and identify evoked spikes. The effectiveness of our methods is demonstrated in both real and simulated 512-electrode recordings in the peripheral primate retina with single-electrode and several types of multi-electrode stimulation. We establish small error rates in the identification of evoked spikes, with a computational complexity that is compatible with real-time data analysis. This technology may be helpful in the design of future high-resolution sensory prostheses based on tailored stimulation (e.g., retinal prostheses), and for closed-loop neural stimulation at a much larger scale than currently possible. Author Summary Simultaneous electrical stimulation and recording using multi-electrode arrays can provide a valuable technique for studying circuit connectivity and engineering neural interfaces. However, interpreting these recordings is challenging because the spike sorting process (identifying and segregating action potentials arising from different neurons) is largely stymied by electrical stimulation artifacts across the array, which are typically larger than the signals of interest. We develop a novel computational framework to estimate and subtract away this contaminating artifact, enabling the large-scale analysis of responses of possibly hundreds of cells to tailored stimulation. Importantly, we suggest that this technology may also be helpful for the development of future high-resolution neural prosthetic devices (e.g., retinal prostheses).

Electrical stimulus artifact cancellation and neural spike detection on large multi-electrode arrays

Novel Model-based identification of retinal ganglion cell subunits

Progress in modern neuroscience critically depends on our ability to observe the activity of large neuronal populations with cellular spatial and high temporal resolution. However, two bottlenecks constrain efforts towards fast imaging of large populations. First, the resulting large video data is challenging to analyze. Second, there is an explicit tradeoff between imaging speed, signal-to-noise, and field of view: with current recording technology we cannot image very large neuronal populations with simultaneously high spatial and temporal resolution. Here we describe multi-scale approaches for alleviating both of these bottlenecks. First, we show that spatial and temporal decimation techniques provide order-of-magnitude speedups in spatiotemporally demixing calcium video data into estimates of single-cell neural activity. Second, once the shapes of individual neurons have been identified (e.g., after an initial phase of conventional imaging with standard temporal and spatial resolution), we find that the spatial/temporal resolution tradeoff shifts dramatically: after demixing we can accurately recover neural activity from data that has been spatially decimated by an order of magnitude. This offers a cheap method for compressing this large video data, and also implies that it is possible to either speed up imaging significantly, or to “zoom out” by a corresponding factor to image order-of-magnitude larger neuronal populations with minimal loss in accuracy or temporal resolution. Author Summary The voxel rate of imaging systems ultimately sets the limit on the speed of data acquisition. These limits often mean that only a small fraction of the activity of large neuronal populations can be observed at high spatio-temporal resolution. For imaging of very large populations with single cell resolution, temporal resolution is typically sacrificed. Here we propose a multi-scale approach to achieve single cell precision using fast imaging at reduced spatial resolution. In the first phase the spatial location and shape of each neuron is obtained at standard spatial resolution; in the second phase imaging is performed at much lower spatial resolution. We show that we can apply a demixing algorithm to accurately recover each neuron’s activity from the low-resolution data by exploiting the high-resolution cellular maps estimated in the first imaging phase. Thus by decreasing the spatial resolution in the second phase, we can compress the video data significantly, and potentially acquire images over an order-of-magnitude larger area, or image at significantly higher temporal resolution, with minimal loss in accuracy of the recovered neuronal activity. We evaluate this approach on real data from light-sheet and 2-photon calcium imaging.

Multi-scale approaches for high-speed imaging and analysis of large neural populations

Advances in optical recording technologies allow whole-brain recordings with single cell resolution of small animals, such as larval zebrafish. A crucial step for further neural analysis is the move from voxel-space to neural-space, i.e. the detection of all neurons and extraction/demixing of how each neurons activity evolves in time. The sheer amount of data has led experimenters towards simple but fast methods such as averaging voxels in a small neighborhood around identified neuron centers. More statistically-principled methods based on non-negative matrix factorization (NMF) better conserve information, yielding higher signal-to-noise ratio and more recovered neurons, and allow the demixing of overlapping neurons. However, previous implementations of these methods have been too slow for the large data sizes obtained with calcium imaging and have not yet been employed routinely in practice. Here we exploit advances in NMF paired with downsampling schemes for the specific data at hand to obtain a fast NMF method. Given access to a small cluster, processing of the data takes the same time as the experiment. Though we focus on batch processing performed after the experiment, our method opens the way to online real-time processing.

Fast Constrained Non-negative Matrix Factorization for Whole-Brain Calcium Imaging Data

We introduce a novel stochastic version of the non-reversible, rejection-free Bouncy Particle Sampler (BPS), a Markov process whose sample trajectories are piecewise linear. The algorithm is based on simulating first arrival times in a doubly stochastic Poisson process using the thinning method, and allows efficient sampling of Bayesian posteriors in big datasets. We prove that in the BPS no bias is introduced by noisy evaluations of the log-likelihood gradient. On the other hand, we argue that efficiency considerations favor a small, controllable bias in the construction of the thinning proposals, in exchange for faster mixing. We introduce a simple regression-based proposal intensity for the thinning method that controls this trade-off. We illustrate the algorithm in several examples in which it outperforms both unbiased, but slowly mixing stochastic versions of BPS, as well as biased stochastic gradient-based samplers.

A body of recent work in modeling neural activity focuses on recovering low-dimensional latent features that capture the statistical structure of large-scale neural populations. Most such approaches have focused on linear generative models, where inference is computationally tractable. Here, we propose fLDS, a general class of nonlinear generative models that permits the firing rate of each neuron to vary as an arbitrary smooth function of a latent, linear dynamical state. This extra flexibility allows the model to capture a richer set of neural variability than a purely linear model, but retains an easily visualizable low-dimensional latent space. To fit this class of non-conjugate models we propose a variational inference scheme, along with a novel approximate posterior capable of capturing rich temporal correlations across time. We show that our techniques permit inference in a wide class of generative models.We also show in application to two neural datasets that, compared to state-of-the-art neural population models, fLDS captures a much larger proportion of neural variability with a small number of latent dimensions, providing superior predictive performance and interpretability.

Linear dynamical neural population models through nonlinear embeddings

Inferring Spike Trains, Neural Filters, and Network Circuits from in vivo Calcium Imaging

Neuroprosthetic brain-computer interfaces function via an algorithm which decodes neural activity of the user into movements of an end effector, such as a cursor or robotic arm. In practice, the decoder is often learned by updating its parameters while the user performs a task. When the user’s intention is not directly observable, recent methods have demonstrated value in training the decoder against a surrogate for the user’s intended movement. Here we show that training a decoder in this way is a novel variant of an imitation learning problem, where an oracle or expert is employed for supervised training in lieu of direct observations, which are not available. Specifically, we describe how a generic imitation learning meta-algorithm, dataset aggregation (DAgger), can be adapted to train a generic brain-computer interface. By deriving existing learning algorithms for brain-computer interfaces in this framework, we provide a novel analysis of regret (an important metric of learning efficacy) for brain-computer interfaces. This analysis allows us to characterize the space of algorithmic variants and bounds on their regret rates. Existing approaches for decoder learning have been performed in the cursor control setting, but the available design principles for these decoders are such that it has been impossible to scale them to naturalistic settings. Leveraging our findings, we then offer an algorithm that combines imitation learning with optimal control, which should allow for training of arbitrary effectors for which optimal control can generate goal-oriented control. We demonstrate this novel and general BCI algorithm with simulated neuroprosthetic control of a 26 degree-of-freedom model of an arm, a sophisticated and realistic end effector.

Inferring connectivity in neuronal networks remains a key challenge in statistical neuroscience. The common input problem presents a major roadblock: it is di cult to reliably distinguish causal connections between pairs of observed neurons versus correlations induced by common input from unobserved neurons. Available techniques allow us to simultaneously record, with su cient temporal resolution, only a small fraction of the network. Consequently, naive connectivity estimators that neglect these common input e ects are highly biased. In a recent work [1] we propose a shotgun experimental design, in which we observe multiple sub-networks brie y, in a serial manner. Thus, while the full network cannot be observed simultaneously at any given time, we may be able to observe much larger subsets of the network over the course of the entire experiment, thus ameliorating the common input problem. To perform network inference given this type of data, in which only a small fraction of the network is observed in each time bin, we developed a scalable Bayesian method. The method is derived using a cavity-style approximation to the gradient of the expected loglikelihood in a generalized linear model for a spiking recurrent neural network. Simulation demonstrated that the shotgun experimental design can eliminate the biases induced by common input e ects. Networks with thousands of neurons, in which only a small fraction of the neurons is observed in each time bin, can be quickly and accurately estimated, achieving orders of magnitude speed up over previous approaches. [1] Soudry, D., Keshri, S., Stinson, P., Oh, M., Iyengar, G., & Paninski, L. (2015). E cient Shotgun Inference of Neural Connectivity from Highly Sub-sampled Activity Data. PLOS Computational Biology, 11(10), e1004464.

Implementing e cient "shotgun" inference of neural connectivity from highly sub-sampled activity data

Main Results Calcium imaging is quickly becoming a prominent paradigm to collect data in neuroscience. We have developed a fully automatic method for processing data of this kind, ie, given a calcium movie, we provide the most likely spike trains for all the neurons in the movie, their stimulus filters, and a functional connectivity matrix. Code is available upon request. References [V09] Vogelstein JT, Watson BO, Packer AM, Yuste R, Jedynak B, and Paninski L. Spike inference from calcium imaging using sequential Monte Carlo methods. In Press at Biophysical Journal. [N03] Neal RM, Beal MJ, Roweis, ST. Inferring State Sequences for Non-linear Systems with Embedded Hidden Markov Mdels. NIPS, 2003.

Towards Inferring Neural Circuits from Calcium Population Imaging

Primacy of Flexor Locomotor Pattern Revealed by Ancestral Reversion of Motor Neuron Identity

Fi (t) = αi Ci (t) Ci (t) + kd + βi + σ F i et τ c i dCi (t) dt = −Ci (t) + Cb i + Ai ni (t) + σ c i et ni (t) ∼ Binomial[ f (bi + ki s(t) + i wi j hi j (t))] τ h dh j (t) dt = −h j (t) + n j (t) + σ et θ = {θi }i≤N , θi = {αi ,βi , σ F i , τ c i , Cb i , Ai , σ c i , τ h i , σ h i } X = {Xi }i≤N , Xi = {Xi (t)}t≤T , Xi (t) = {Ci (t), ni (t), hi (t)} aim given only a set of fluorescence traces collected simultaneously from a small (eg ≈ 100 neurons) population of neurons, obtain the spike trains for each of the neurons, and the effective connectivity matrix for the observed population.

Towards Confirming Neural Circuit Inference from Population Calcium Imaging. NIPS Workshop on Connectivity Inference in Neuroimaging

Motivation Calcium imaging is quickly becoming a prominent paradigm to collect data in neuroscience. To maximally utilize the power of this technique, complementary analytical tools can be built. Goal We aim to develop analytical tools to facilitate inferring spike trains from fluorescent observations, fitting tuning curves, and inferring population connectivity, given only short sequences of possibly very noisy, low temporal resolution, and saturating fluorescence images. Solution By framing the problem as a state-space problem, we can utilize tools developed by the statistics community for related problems. In particular, we develop a (i) fast filter utilizing a tridiagonal trick and interior point methods to approximate the MAP spike train, (ii) particle filter to infer the probability of spiking in each frame, (iii) a population version of our particle filter to infer connectivity. Conclusions Our fast filter can accurately approximate the most likely spike train given the fluorescence data inO(T ) time. When fluorescence saturates, stimuli are present, or temporal resolution is unsatisfactorily slow, our particle filter can infer the probability of a spike in each time bin. If a small population of neurons are imaged simultaneously, our population particle filter can learn the effective connectivity of the observable neurons. References 1) Vogelstein JT, Watson BO, Packer AM, Yuste R, Jedynak B, and Paninski L. Spike inference from calcium imaging using sequential Monte Carlo methods. In Press at Biophysical Journal. 2) Vogelstein JT, Babadi B, Packer AM, Yuste R, and Paninski L. Fast methods for spike inference from calcium imaging. In preparation. Acknowldgments Support for JTV was provided by NIDCD DC00109. LP is supported by an NSF CAREER award, by an Alfred P. Sloan Research Fellowship, and a McKnight Scholar Award. 1. simple

Inferring connectivity in neuronal networks remains a key challenge in statistical neurosci-ence. The " common input " problem presents a major roadblock: it is difficult to reliably distinguish causal connections between pairs of observed neurons versus correlations induced by common input from unobserved neurons. Available techniques allow us to simultaneously record, with sufficient temporal resolution, only a small fraction of the network. Consequently , naive connectivity estimators that neglect these common input effects are highly biased. This work proposes a " shotgun " experimental design, in which we observe multiple sub-networks briefly, in a serial manner. Thus, while the full network cannot be observed simultaneously at any given time, we may be able to observe much larger subsets of the network over the course of the entire experiment, thus ameliorating the common input problem. Using a generalized linear model for a spiking recurrent neural network, we develop a scalable approximate expected loglikelihood-based Bayesian method to perform network inference given this type of data, in which only a small fraction of the network is observed in each time bin. We demonstrate in simulation that the shotgun experimental design can eliminate the biases induced by common input effects. Networks with thousands of neurons, in which only a small fraction of the neurons is observed in each time bin, can be quickly and accurately estimated, achieving orders of magnitude speed up over previous approaches. Optical imaging of the activity in a neuronal network is limited by the scanning speed of the imaging device. Therefore, typically, only a small fixed part of the network is observed during the entire experiment. However, in such an experiment, it can be hard to infer from the observed activity patterns whether (1) a neuron A directly affects neuron B, or (2) another, unobserved neuron C affects both A and B. To deal with this issue, we propose a " shotgun " observation scheme, in which, at each time point, we observe a small changing access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. subset of the neurons from the network. Consequently, many fewer neurons remain completely unobserved during the entire experiment, enabling us to eventually distinguish between cases (1) and (2) given sufficiently long experiments. Since previous inference algorithms cannot efficiently handle so many missing observations, we …

Correction: Efficient "Shotgun" Inference of Neural Connectivity from Highly Sub-sampled Activity Data

Inferring Spike Trains, Learning Tuning Curves, and Estimating Connectivity from Calcium Imaging

Neuroprosthetic brain-computer interfaces are systems that decode neural activity into useful control signals for effectors, such as a cursor on a computer screen. It has long been recognized that both the user and decoding system can adapt to increase the accuracy of the end effector. Co-adaptation is the process whereby a user learns to control the system in conjunction with the decoder adapting to learn the user's neural patterns. We provide a mathematical framework for co-adaptation and relate co-adaptation to the joint optimization of the user's control scheme ("encoding model") and the decoding algorithm's parameters. When the assumptions of that framework are respected, co-adaptation cannot yield better performance than that obtainable by an optimal initial choice of fixed decoder, coupled with optimal user learning. For a specific case, we provide numerical methods to obtain such an optimized decoder. We demonstrate our approach in a model brain-computer interface system using an online prosthesis simulator, a simple human-in-the-loop pyschophysics setup which provides a non-invasive simulation of the BCI setting. These experiments support two claims: that users can learn encoders matched to fixed, optimal decoders and that, once learned, our approach yields expected performance advantages.

Maximum Likelihood Inference of Neuronal Dynamics under Noisy and Intermittent Observations using Sequential Monte Carlo EM Algorithms

Inferring connectivity in neuronal networks remains a key challenge in statistical neuroscience. The “common input” problem presents a major roadblock: it is difficult to reliably distinguish causal connections between pairs of observed neurons versus correlations induced by common input from unobserved neurons. Available techniques allow us to simultaneously record, with sufficient temporal resolution, only a small fraction of the network. Consequently, naive connectivity estimators that neglect these common input effects are highly biased. This work proposes a “shotgun” experimental design, in which we observe multiple sub-networks briefly, in a serial manner. Thus, while the full network cannot be observed simultaneously at any given time, we may be able to observe much larger subsets of the network over the course of the entire experiment, thus ameliorating the common input problem. Using a generalized linear model for a spiking recurrent neural network, we develop a scalable approximate expected loglikelihood-based Bayesian method to perform network inference given this type of data, in which only a small fraction of the network is observed in each time bin. We demonstrate in simulation that the shotgun experimental design can eliminate the biases induced by common input effects. Networks with thousands of neurons, in which only a small fraction of the neurons is observed in each time bin, can be quickly and accurately estimated, achieving orders of magnitude speed up over previous approaches.

Efficient "Shotgun" Inference of Neural Connectivity from Highly Sub-sampled Activity Data

The function of a neural circuit is shaped by the computations performed by its interneurons, which in many cases are not easily accessible to experimental investigation. Here, we elucidate the transformation of visual signals flowing from the input to the output of the primate retina, using a combination of large-scale multi-electrode recordings from an identified ganglion cell type, visual stimulation targeted at individual cone photoreceptors, and a hierarchical computational model. The results reveal nonlinear subunits in the circuity of OFF midget ganglion cells, which subserve high-resolution vision. The model explains light responses to a variety of stimuli more accurately than a linear model, including stimuli targeted to cones within and across subunits. The recovered model components are consistent with known anatomical organization of midget bipolar interneurons. These results reveal the spatial structure of linear and nonlinear encoding, at the resolution of single cells and at the scale of complete circuits. DOI: http://dx.doi.org/10.7554/eLife.05241.001

Mapping nonlinear receptive field structure in primate retina at single cone resolution

High-dimensional, simultaneous recordings of neural spiking activity are often explored, analyzed and visualized with the help of latent variable or factor models. Such models are however ill-equipped to extract structure beyond shared, distributed aspects of firing activity across multiple cells. Here, we extend unstructured factor models by proposing a model that discovers subpopulations or groups of cells from the pool of recorded neurons. The model combines aspects of mixture of factor analyzer models for capturing clustering structure, and aspects of latent dynamical system models for capturing temporal dependencies. In the resulting model, we infer the subpopulations and the latent factors from data using variational inference and model parameters are estimated by Expectation Maximization (EM). We also address the crucial problem of initializing parameters for EM by extending a sparse subspace clustering algorithm to integer-valued spike count observations. We illustrate the merits of the proposed model by applying it to calcium-imaging data from spinal cord neurons, and we show that it uncovers meaningful clustering structure in the data.

We present a structured matrix factorization approach to analyzing calciumimaging recordings of large neuronal ensembles. Our goal is to simultaneouslyidentify the locations of the neurons, demix spatially overlapping components,and denoise and deconvolve

A structured matrix factorization framework for large scale calcium imaging data analysis

The BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative aims to produce a sophisticated understanding of the link between brain and behavior and to uncover new ways to treat, prevent and cure brain disorders.1 Success in meeting these multifaceted challenges will require scientific and technological paradigms that incorporate novel statistical methods for data acquisition and analysis. Our purpose here is to substantiate this proposition, and to identify implications for training.

Kalman filtering-smoothing is a fundamental tool in statistical time-series analysis. However, standard implementations of the Kalman filter-smoother require O(d3) time and O(d2) space per time step, where d is the dimension of the state variable, and are therefore impractical in high-dimensional problems. In this article we note that if a relatively small number of observations are available per time step, the Kalman equations may be approximated in terms of a low-rank perturbation of the prior state covariance matrix in the absence of any observations. In many cases this approximation may be computed and updated very efficiently (often in just O(k2d) or O(k2d + kdlog d) time and space per time step, where k is the rank of the perturbation and in general k ≪ d), using fast methods from numerical linear algebra. We justify our approach and give bounds on the rank of the perturbation as a function of the desired accuracy. For the case of smoothing, we also quantify the error of our algorithm because of the low-rank approximation and show that it can be made arbitrarily low at the expense of a moderate computational cost. We describe applications involving smoothing of spatiotemporal neuroscience data. This article has online supplementary material.

Fast Kalman Filtering and Forward–Backward Smoothing via a Low-Rank Perturbative Approach

Detailed conductance-based neuron models can reproduce electrophysiological measurements to a high degree of accuracy, but because of their intrinsic complexity these models are difficult to analyze. For this reason, simple phenomenological spiking neuron models are highly popular for studies of neural coding, memory, and network dynamics. In this chapter we discuss formal threshold models of neuronal firing, also called integrate-andfire models. The shape of the action potential of a given neuron is rather stereotyped with very little change between one spike and the next. Thus, the shape of the action potential which travels along the axon to a postsynaptic neuron cannot be used to transmit information; rather, from the point of view of the receiving neuron, action potentials are “events” which are fully characterized by the arrival time of the spike at the synapse. Note that spikes from different neuron types can have different shapes and the duration and shape of the spike does influence neurotransmitter release; but the spikes that arrive at a given synapse all come from the same presynaptic neuron and – if we neglect effects of fatigue of ionic channels in the axon – we can assume that its time course is always the same. Therefore we make no effort to model the exact shape of an action potential. Rather, spikes are treated as events characterized by their firing time – and the task consists in finding a model so as to reliably predict spike timings.

Abstract Parametric models of the conditional intensity of a point process (e.g., generalized linear models) are popular in statistical neuroscience, as they allow us to characterize the variability in neural responses in terms of stimuli and spiking history. Parameter estimation in these models relies heavily on accurate evaluations of the log likelihood and its derivatives. Classical approaches use a discretized time version of the spiking process, and recent work has exploited the existence of a refractory period (during which the conditional intensity is zero following a spike) to obtain more accurate estimates of the likelihood. In this brief letter, we demonstrate that this method can be improved significantly by applying classical quadrature methods directly to the resulting continuous-time integral.

The primary aim of this chapter is to introduce several elementary notions of neuroscience, in particular the concepts of action potentials, postsynaptic potentials, firing thresholds, refractoriness, and adaptation. Based on these notions a preliminary model of neuronal dynamics is built and this simple model (the leaky integrate-and-fire model) will be used as a starting point and reference for the generalized integrate-and-fire models, which are the main topic of the book, to be discussed in Parts II and III. Since the mathematics used for the simple model is essentially that of a one-dimensional linear differential equation, we take this first chapter as an opportunity to introduce some of the mathematical notation that will be used throughout the rest of the book. Owing to the limitations of space, we cannot – and do not want to – give a comprehensive introduction to such a complex field as neurobiology. The presentation of the biological background in this chapter is therefore highly selective and focuses on those aspects needed to appreciate the biological background of the theoretical work presented in this book. For an in-depth discussion of neurobiology we refer the reader to the literature mentioned at the end of this chapter. After the review of neuronal properties in Sections 1.1 and 1.2 we will turn, in Section 1.3, to our first mathematical neuron model. The last two sections are devoted to a discussion of the strengths and limitations of simplified models.

From a biophysical point of view, action potentials are the result of currents that pass through ion channels in the cell membrane. In an extensive series of experiments on the giant axon of the squid, Hodgkin and Huxley succeeded in measuring these currents and described their dynamics in terms of differential equations. Their paper published in 1952, which presents beautiful experiments combined with an elegant mathematical theory (Hodgkin and Huxley, 1952), was rapidly recognized as groundbreaking work and eventually led to the Nobel Prize for Hodgkin and Huxley in 1963. In this chapter, the Hodgkin–Huxley model is reviewed and its behavior illustrated by several examples. The Hodgkin–Huxley model in its original form describes only three types of ion channel. However, as we shall see in Section 2.3 it can be extended to include many other ion channel types. The Hodgkin–Huxley equations are the basis for detailed neuron models which account for different types of synapse, and the spatial geometry of an individual neuron. Synaptic dynamics and the spatial structure of dendrites are the topics of Chapter 3. The Hodgkin–Huxley model is also the starting point for the derivation of simplified neuron models in Chapter 4 and will serve as a reference throughout the discussion of generalized integrate-and-fire models in Part II of the book. Before we can turn to the Hodgkin–Huxley equations, we need to give some additional information on the equilibrium potential of ion channels.

Spatiotemporal receptive fields of barrel cortex revealed by reverse correlation of synaptic input

We present a unified approach to unsupervised Bayesian learning of factor models for binary data with binary and spike-and-slab latent factors. We introduce a non-negative constraint in the spike-and-slab prior that eliminates the usual sign ambiguity present in factor models and lowers the generalization error on the datasets tested here. For the generative models we use probit functions, which can be sampled without tuning parameters, unlike previous works that used logistic functions. The posterior distributions involve mixtures of binary and truncated Gaussian variables, for which we present exact Hamiltonian Monte Carlo samplers and compare their properties to Gibbs samplers.

Bayesian Sparse Unsupervised Learning for Probit Models of Binary Data

In the ten preceding chapters, we have come a long way: starting from the biophysical basis of neuronal dynamics we arrived at a description of neurons that we called generalized integrate-and-fire models. We have seen that neurons contain multiple types of ion channels embedded in a capacitive membrane (Chapter 2). We have seen how basic principles regulate the dynamics of electrical current and membrane potential in synapses, dendrites and axons (Chapter 3). We have seen that sodium and potassium ion channels form an excitable system characterized by a threshold mechanism (Chapter 4) and that other ion channels shape the spike after-effects (Chapter 6). Finally, we have seen in Chapters 4, 5 and 6 how biophysical models can be reduced by successive approximations to other, simpler, models such as the LIF, EIF, AdEx, and SRM. Moreover, we have added noise to our neuron models (Chapters 7 and 9). At this point, it is natural to step back and check whether our assumptions were too stringent, whether the biophysical assumptions were well-founded, and whether the generalized models can explain neuronal data. We laid out the mathematical groundwork in Chapter 10; we can now set out to apply these statistical methods to real data. We can test the performance of these, and other, models by using them as predictive models of encoding .

Neuronal Dynamics: Estimating parameters of probabilistic neuron models

What happens in our brain when we make a decision? What triggers a neuron to send out a signal? What is the neural code? This textbook for advanced undergraduate and beginning graduate students provides a thorough and up-to-date introduction to the fields of computational and theoretical neuroscience. It covers classical topics, including the Hodgkin-Huxley equations and Hopfield model, as well as modern developments in the field such as Generalized Linear Models and decision theory. Concepts are introduced using clear step-by-step explanations suitable for readers with only a basic knowledge of differential equations and probabilities, and are richly illustrated by figures and worked-out examples. End-of-chapter summaries and classroom-tested exercises make the book ideal for courses or for self-study. The authors also give pointers to the literature and an extensive bibliography, which will prove invaluable to readers interested in further study.

Neuronal Dynamics: From Single Neurons To Networks And Models Of Cognition

Neuronal Dynamics: Continuity equation and the Fokker–Planck approach

Fast state-space methods for inferring dendritic synaptic connectivity

Fast inference in generalized linear models via expected log-likelihoods

We investigate Bayesian methods for optimal decoding of noisy or incompletely-observed spike trains. Information about neural identity or temporal resolution may be lost during spike detection and sorting, or spike times measured near the soma may be corrupted with noise due to stochastic membrane channel effects in the axon. We focus on neural encoding models in which the (discrete) neural state evolves according to stimulus-dependent Markovian dynamics. Such models are sufficiently flexible that we may incorporate realistic stimulus encoding and spiking dynamics, but nonetheless permit exact computation via efficient hidden Markov model forward-backward methods. We analyze two types of signal degradation. First, we quantify the information lost due to jitter or downsampling in the spike-times. Second, we quantify the information lost when knowledge of the identities of different spiking neurons is corrupted. In each case the methods introduced here make it possible to quantify the dependence of the information loss on biophysical parameters such as firing rate, spike jitter amplitude, spike observation noise, etc. In particular, decoders that model the probability distribution of spike-neuron assignments significantly outperform decoders that use only the most likely spike assignments, and are ignorant of the posterior spike assignment uncertainty.

Computing loss of efficiency in optimal Bayesian decoders given noisy or incomplete spike trains

We present efficient Bayesian methods for extracting neuronal spiking information from calcium imaging data. The goal of our methods is to sample from the posterior distribution of spike trains and model parameters (baseline concentration, spike amplitude etc) given noisy calcium imaging data. We present discrete time algorithms where that the existence of a spike at each time bin using Gibbs methods, as well as continuous time algorithms that sample over the number of spikes and their locations at an arbitrary resolution using Metropolis-Hastings methods for point processes. We provide Rao-Blackwellized extensions that (i) marginalize over several model parameters and (ii) provide smooth estimates of the marginal spike posterior distribution in continuous time. Our methods serve as complements to standard point estimates and allow for quantification of uncertainty in estimating the underlying spike train and model parameters.

In a closed-loop brain-computer interface (BCI), adaptive decoders are used to learn parameters suited to decoding the user's neural response. Feedback to the user provides information which permits the neural tuning to also adapt. We present an approach to model this process of co-adaptation between the encoding model of the neural signal and the decoding algorithm as a multi-agent formulation of the linear quadratic Gaussian (LQG) control problem. In simulation we characterize how decoding performance improves as the neural encoding and adaptive decoder optimize, qualitatively resembling experimentally demonstrated closed-loop improvement. We then propose a novel, modified decoder update rule which is aware of the fact that the encoder is also changing and show it can improve simulated co-adaptation dynamics. Our modeling approach offers promise for gaining insights into co-adaptation as well as improving user learning of BCI control in practical settings.

A multi-agent control framework for co-adaptation in brain-computer interfaces

We present a new approach to sample from generic binary distributions, based on an exact Hamiltonian Monte Carlo algorithm applied to a piecewise continuous augmentation of the binary distribution of interest. An extension of this idea to distributions over mixtures of binary and possibly-truncated Gaussian or exponential variables allows us to sample from posteriors of linear and probit regression models with spike-and-slab priors and truncated parameters. We illustrate the advantages of these algorithms in several examples in which they outperform the Metropolis or Gibbs samplers.

Auxiliary-variable Exact Hamiltonian Monte Carlo Samplers for Binary Distributions

Fast state-space methods for inferring dendritic synaptic
 connectivity

Inferring connectivity in neuronal networks remains a key challenge in statistical neuroscience. The `common input' problem presents the major roadblock: it is difficult to reliably distinguish causal connections between pairs of observed neurons from correlations induced by common input from unobserved neurons. Since available recording techniques allow us to sample from only a small fraction of large networks simultaneously with sufficient temporal resolution, naive connectivity estimators that neglect these common input effects are highly biased. This work proposes a `shotgun' experimental design, in which we observe multiple sub-networks briefly, in a serial manner. Thus, while the full network cannot be observed simultaneously at any given time, we may be able to observe most of it during the entire experiment. Using a generalized linear model for a spiking recurrent neural network, we develop scalable approximate Bayesian methods to perform network inference given this type of data, in which only a small fraction of the network is observed in each time bin. We demonstrate in simulation that, using this method: (1) The shotgun experimental design can eliminate the biases induced by common input effects. (2) Networks with thousands of neurons, in which only a small fraction of the neurons is observed in each time bin, could be quickly and accurately estimated. (3) Performance can be improved if we exploit prior information about the probability of having a connection between two neurons, its dependence on neuronal cell types (e.g., Dale's law), or its dependence on the distance between neurons.

A shotgun sampling solution for the common input problem in neural connectivity inference

We propose a compressed sensing (CS) calcium imaging framework for monitoring large neuronal populations, where we image randomized projections of the spatial calcium concentration at each timestep, instead of measuring the concentration at individual locations. We develop scalable nonnegative deconvolution methods for extracting the neuronal spike time series from such observations. We also address the problem of demixing the spatial locations of the neurons using rank-penalized matrix factorization methods. By exploiting the sparsity of neural spiking we demonstrate that the number of measurements needed per timestep is significantly smaller than the total number of neurons, a result that can potentially enable imaging of larger populations at considerably faster rates compared to traditional raster-scanning techniques. Unlike traditional CS setups, our problem involves a block-diagonal sensing matrix and a non-orthogonal sparse basis that spans multiple timesteps. We provide tight approximations to the number of measurements needed for perfect deconvolution for certain classes of spiking processes, and show that this number undergoes a "phase transition," which we characterize using modern tools relating conic geometry to compressed sensing.

Sparse nonnegative deconvolution for compressive calcium imaging: algorithms and phase transitions

Recordings from large populations of neurons make it possible to search for hypothesized low-dimensional dynamics. Finding these dynamics requires models that take into account biophysical constraints and can be fit efficiently and robustly. Here, we present an approach to dimensionality reduction for neural data that is convex, does not make strong assumptions about dynamics, does not require averaging over many trials and is extensible to more complex statistical models that combine local and global influences. The results can be combined with spectral methods to learn dynamical systems models. The basic method extends PCA to the exponential family using nuclear norm minimization. We evaluate the effectiveness of this method using an exact decomposition of the Bregman divergence that is analogous to variance explained for PCA. We show on model data that the parameters of latent linear dynamical systems can be recovered, and that even if the dynamics are not stationary we can still recover the true latent subspace. We also demonstrate an extension of nuclear norm minimization that can separate sparse local connections from global latent dynamics. Finally, we demonstrate improved prediction on real neural data from monkey motor cortex compared to fitting linear dynamical models without nuclear norm smoothing.

Robust learning of low-dimensional dynamics from large neural ensembles

With the advent of modern stimulation techniques in neuroscience, the opportunity arises to map neuron to neuron connectivity. In this work, we develop a method for efficiently inferring posterior distributions over synaptic strengths in neural microcircuits. The input to our algorithm is data from experiments in which action potentials from putative presynaptic neurons can be evoked while a subthreshold recording is made from a single postsynaptic neuron. We present a realistic statistical model which accounts for the main sources of variability in this experiment and allows for significant prior information about the connectivity and neuronal cell types to be incorporated if available. Due to the technical challenges and sparsity of these systems, it is important to focus experimental time stimulating the neurons whose synaptic strength is most ambiguous, therefore we also develop an online optimal design algorithm for choosing which neurons to stimulate at each trial.

Bayesian Inference and Online Experimental Design for Mapping Neural Microcircuits

Statistical analysis of neural data : Regression approaches for modeling neural responses and stimulus decoding

It has recently become possible to identify cone photoreceptors in primate retina from multi-electrode recordings of ganglion cell spiking driven by visual stimuli of sufficiently high spatial resolution. In this paper we present a statistical approach to the problem of identifying the number, locations, and color types of the cones observed in this type of experiment. We develop an adaptive Markov Chain Monte Carlo (MCMC) method that explores the space of cone configurations, using a Linear-Nonlinear-Poisson (LNP) encoding model of ganglion cell spiking output, while analytically integrating out the functional weights between cones and ganglion cells. This method provides information about our posterior certainty about the inferred cone properties, and additionally leads to improvements in both the speed and quality of the inferred cone maps, compared to earlier “greedy” computational approaches.

Monte Carlo methods for localization of cones given multielectrode retinal ganglion cell recordings

A Bayesian compressed-sensing approach for reconstructing neural connectivity from subsampled anatomical data

A major goal for brain machine interfaces is to allow patients to control prosthetic devices with high degrees of independent movements. Such devices like robotic arms and hands require this high dimensionality of control to restore the full range of actions exhibited in natural movement. Current BMI strategies fall well short of this goal allowing the control of only a few degrees of freedom at a time. In this paper we present work towards the decoding of 27 joint angles from the shoulder, arm and hand as subjects perform reach and grasp movements. We also extend previous work in examining and optimizing the recording depth of electrodes to maximize the movement information that can be extracted from recorded neural signals.

Decoding arm and hand movements across layers of the macaque frontal cortices

Constructing tractable dependent probability distributions over structured continuous random vectors is a central problem in statistics and machine learning. It has proven difficult to find general constructions for models in which ecient exact inference is possible, outside of the classical cases of models with restricted graph structure (chain, tree, etc.) and linear-Gaussian or discrete potentials. In this work we identify a graphical model class in which exact inference can be performed efficiently, owing to a certain “low-rank” structure in the potentials. While we focus on the case of tree graphical models, the lowrank treatment can also be applied for ecient exact inference in certain sparsely-loopy models. We explore this new class of models by applying the resulting inference methods to neural spike rate estimation and motioncapture joint-angle smoothing tasks.

We present a Hamiltonian Monte Carlo algorithm to sample from multivariate Gaussian distributions in which the target space is constrained by linear and quadratic inequalities or products thereof. The Hamiltonian equations of motion can be integrated exactly and there are no parameters to tune. The algorithm mixes faster and is more efficient than Gibbs sampling. The runtime depends on the number and shape of the constraints but the algorithm is highly parallelizable. In many cases, we can exploit special structure in the covariance matrices of the untruncated Gaussian to further speed up the runtime. A simple extension of the algorithm permits sampling from distributions whose log-density is piecewise quadratic, as in the “Bayesian Lasso” model.

Exact Hamiltonian Monte Carlo for Truncated Multivariate Gaussians

Inferring synaptic inputs given a noisy voltage trace via sequential Monte Carlo methods

Sensory neurons have been hypothesized to efficiently encode signals from the natural environment subject to resource constraints. The predictions of this efficient coding hypothesis regarding the spatial filtering properties of the visual system have been found consistent with human perception, but they have not been compared directly with neural responses. Here, we analyze the information that retinal ganglion cells transmit to the brain about the spatial information in natural images subject to three resource constraints: the number of retinal ganglion cells, their total response variances, and their total synaptic strengths. We derive a model that optimizes the transmitted information and compare it directly with measurements of complete functional connectivity between cone photoreceptors and the four major types of ganglion cells in the primate retina, obtained at single-cell resolution. We find that the ganglion cell population exhibited 80% efficiency in transmitting spatial information relative to the model. Both the retina and the model exhibited high redundancy (∼30%) among ganglion cells of the same cell type. A novel and unique prediction of efficient coding, the relationships between projection patterns of individual cones to all ganglion cells, was consistent with the observed projection patterns in the retina. These results indicate a high level of efficiency with near-optimal redundancy in visual signaling by the retina.

We discuss methods for fast spatiotemporal smoothing of calcium signals in dendritic trees, given single-trial, spatially localized imaging data obtained via multi-photon microscopy. By analyzing the dynamics of calcium binding to probe molecules and the effects of the imaging procedure, we show that calcium concentration can be estimated up to an affine transformation, i.e., an additive and multiplicative constant. To obtain a full spatiotemporal estimate, we model calcium dynamics within the cell using a functional approach. The evolution of calcium concentration is represented through a smaller set of hidden variables that incorporate fast transients due to backpropagating action potentials (bAPs), or other forms of stimulation. Because of the resulting state space structure, inference can be done in linear time using forward-backward maximum-a-posteriori methods. Non-negativity constraints on the calcium concentration can also be incorporated using a log-barrier method that does not affect the computational scaling. Moreover, by exploiting the neuronal tree structure we show that the cost of the algorithm is also linear in the size of the dendritic tree, making the approach applicable to arbitrarily large trees. We apply this algorithm to data obtained from hippocampal CA1 pyramidal cells with experimentally evoked bAPs, some of which were paired with excitatory postsynaptic potentials (EPSPs). The algorithm recovers the timing of the bAPs and provides an estimate of the induced calcium transient throughout the tree. The proposed methods could be used to further understand the interplay between bAPs and EPSPs in synaptic strength modification. More generally, this approach allows us to infer the concentration on intracellular calcium across the dendritic tree from noisy observations at a discrete set of points in space.

Fast Spatiotemporal Smoothing of Calcium Measurements in Dendritic Trees

Optimal experimental design for sampling voltage on dendritic trees in the low-SNR regime

A constrained point-process filtering mechanism for prediction of electromyogram (EMG) signals from multichannel neural spike recordings is proposed here. Filters from the Kalman family are inherently suboptimal in dealing with non-Gaussian observations, or a state evolution that deviates from the Gaussianity assumption. To address these limitations, we modeled the non-Gaussian neural spike train observations by using a generalized linear model that encapsulates covariates of neural activity, including the neurons' own spiking history, concurrent ensemble activity, and extrinsic covariates (EMG signals). In order to predict the envelopes of EMGs, we reformulated the Kalman filter in an optimization framework and utilized a nonnegativity constraint. This structure characterizes the nonlinear correspondence between neural activity and EMG signals reasonably. The EMGs were recorded from 12 forearm and hand muscles of a behaving monkey during a grip-force task. In the case of limited training data, the constrained point-process filter improved the prediction accuracy when compared to a conventional Wiener cascade filter (a linear causal filter followed by a static nonlinearity) for different bin sizes and delays between input spikes and EMG output. For longer training datasets, results of the proposed filter and that of the Wiener cascade filter were comparable.

EMG Prediction From Motor Cortical Recordings via a Nonnegative Point-Process Filter

We present an algorithm for fast posterior inference in penalized high-dimensional state-space models, suitable in the case where a few measurements are taken in each time step. We assume that the state prior and observation likelihoods are log-concave and have a special structure that allows fast matrix-vector operations. We derive a second-order algorithm for computing the maximum a posteriori state path estimate, where the cost per iteration scales linearly both in time and memory. This is done by computing an approximate Newton direction using an efficient forward-backward scheme based on a sequence of low rank updates. We formalize the conditions under which our algorithm is applicable and prove its stability and convergence. We show that the state vector can be drawn from a large class of prior distributions without affecting the linear complexity of our algorithm. This class includes both Gaussian and nonsmooth sparse and group sparse priors for which we employ an interior point modification of our algorithm. We discuss applications in text modeling and neuroscience.

Fast interior-point inference in high-dimensional sparse, penalized state-space models

Sequential Monte Carlo (“particle filtering”) methods provide a powerful set of tools for recursive optimal Bayesian filtering in state-space models. However, these methods are based on importance sampling, which is known to be non-robust in several key scenarios, and therefore standard particle filtering methods can fail in these settings. We present a filtering method which solves the key forward recursion using a reparameterized Gibbs sampling method, thus sidestepping the need for importance sampling. In many cases the resulting filter is much more robust and efficient than standard importance-sampling particle filter implementations. We illustrate the method with an application to a nonlinear, non-Gaussian model from neuroscience.

Robust particle filters via sequential pairwise reparameterized Gibbs sampling

Birdsong is comprised of rich spectral and temporal organization, which might be used for vocal perception. To quantify how this structure could be used, we have reconstructed birdsong spectrograms by combining the spike trains of zebra finch auditory midbrain neurons with information about the correlations present in song. We calculated maximum a posteriori estimates of song spectrograms using a generalized linear model of neuronal responses and a series of prior distributions, each carrying different amounts of statistical information about zebra finch song. We found that spike trains from a population of mesencephalicus lateral dorsalis (MLd) neurons combined with an uncorrelated Gaussian prior can estimate the amplitude envelope of song spectrograms. The same set of responses can be combined with Gaussian priors that have correlations matched to those found across multiple zebra finch songs to yield song spectrograms similar to those presented to the animal. The fidelity of spectrogram reconstructions from MLd responses relies more heavily on prior knowledge of spectral correlations than temporal correlations. However, the best reconstructions combine MLd responses with both spectral and temporal correlations.

Incorporating Naturalistic Correlation Structure Improves Spectrogram Reconstruction from Neuronal Activity in the Songbird Auditory Midbrain

Given recent experimental results suggesting that neural circuits may evolve through multiple firing states, we develop a framework for estimating state-dependent neural response properties from spike train data. We modify the traditional hidden Markov model (HMM) framework to incorporate stimulus-driven, non-Poisson point-process observations. For maximal flexibility, we allow external, time-varying stimuli and the neurons own spike histories to drive both the spiking behavior in each state and the transitioning behavior between states. We employ an appropriately modified expectation-maximization algorithm to estimate the model parameters. The expectation step is solved by the standard forward-backward algorithm for HMMs. The maximization step reduces to a set of separable concave optimization problems if the model is restricted slightly. We first test our algorithm on simulated data and are able to fully recover the parameters used to generate the data and accurately recapitulate the sequence of hidden states. We then apply our algorithm to a recently published data set in which the observed neuronal ensembles displayed multistate behavior and show that inclusion of spike history information significantly improves the fit of the model. Additionally, we show that a simple reformulation of the state space of the underlying Markov chain allows us to implement a hybrid half-multistate, half-histogram model that may be more appropriate for capturing the complexity of certain data sets than either a simple HMM or a simple peristimulus time histogram model alone.

Hidden Markov Models for the Stimulus-Response Relationships of Multistate Neural Systems

Kalman filtering is a fundamental tool in statistical time series analysis: it is computationally tractable in many real-world situations, implements the optimal Bayesian filter in the linear-Gaussian setting, and serves as a key step in the inference algorithms for a wide variety of nonlinear and non-Gaussian models. However, standard implementations of the Kalman filter require O(N 3 ) time and O(N 2 ) space per timestep, where N is the dimension of the state variable, and are therefore impractical in many high-dimensional problems. In this paper we note that if a relatively small number of observations with low signal-to-noise (SNR) are available per time step, the Kalman equations may be approximated in terms of a low-rank perturbation of the prior state covariance matrix in the absence of any observations. In many cases this approximation may be computed and updated very efficiently (often in justO(N) or O(N log N) time and space per timestep), using fast methods from numerical linear algebra. This opens up the possibility of real-time adaptive experimental design and optimal control in systems of much larger dimension than was previously feasible. We describe an application involving smoothing of spatiotemporal neuroscience data.

Kalman filter mixture model for spike sorting of non-stationary data

In the auditory system, the stimulus-response properties of single neurons are often described in terms of the spectrotemporal receptive field (STRF), a linear kernel relating the spectrogram of the sound stimulus to the instantaneous firing rate of the neuron. Several algorithms have been used to estimate STRFs from responses to natural stimuli; these algorithms differ in their functional models, cost functions, and regularization methods. Here, we characterize the stimulus-response function of auditory neurons using a generalized linear model (GLM). In this model, each cell's input is described by: 1) a stimulus filter (STRF); and 2) a post-spike filter, which captures dependencies on the neuron's spiking history. The output of the model is given by a series of spike trains rather than instantaneous firing rate, allowing the prediction of spike train responses to novel stimuli. We fit the model by maximum penalized likelihood to the spiking activity of zebra finch auditory midbrain neurons in response to conspecific vocalizations (songs) and modulation limited (ml) noise. We compare this model to normalized reverse correlation (NRC), the traditional method for STRF estimation, in terms of predictive power and the basic tuning properties of the estimated STRFs. We find that a GLM with a sparse prior predicts novel responses to both stimulus classes significantly better than NRC. Importantly, we find that STRFs from the two models derived from the same responses can differ substantially and that GLM STRFs are more consistent between stimulus classes than NRC STRFs. These results suggest that a GLM with a sparse prior provides a more accurate characterization of spectrotemporal tuning than does the NRC method when responses to complex sounds are studied in these neurons.

A Generalized Linear Model for Estimating Spectrotemporal Receptive Fields from Responses to Natural Sounds

Automating the design of informative sequences of sensory stimuli

Deducing the structure of neural circuits is one of the central problems of modern neuroscience. Recently-introduced calcium fluorescent imaging methods permit experimentalists to observe network activity in large populations of neurons, but these techniques provide only indirect observations of neural spike trains, with limited time resolution and signal quality. In this work, we present a Bayesian approach for inferring neural circuitry given this type of imaging data. We model the network activity in terms of a collection of coupled hidden Markov chains, with each chain corresponding to a single neuron in the network and the coupling between the chains reflecting the network’s connectivity matrix. We derive a Monte Carlo ExpectationMaximization algorithm for fitting the model parameters; to obtain the sufficient statistics in a computationally-efficient manner, we introduce a specialized blockwise-Gibbs algorithm for sampling from the joint activity of all observed neurons given the observed fluorescence data. We perform large-scale simulations of randomly connected neuronal networks with biophysically realistic parameters and find that the proposed methods can accurately infer the connectivity in these networks given reasonable experimental and computational constraints. In addition, the estimation accuracy may be improved significantly by incorporating prior knowledge about the sparseness of connectivity in the network, via standard L1 penalization methods.

A Bayesian approach for inferring neuronal connectivity from calcium fluorescent imaging data

Monte Carlo approaches have recently been proposed to quantify connectivity in neuronal networks. The key problem is to sample from the conditional distribution of a single neuronal spike train, given the activity of the other neurons in the network. Dependencies between neurons are usually relatively weak; however, temporal dependencies within the spike train of a single neuron are typically strong. In this paper we develop several specialized Metropolis--Hastings samplers which take advantage of this dependency structure. These samplers are based on two ideas: (1) an adaptation of fast forward--backward algorithms from the theory of hidden Markov models to take advantage of the local dependencies inherent in spike trains, and (2) a first-order expansion of the conditional likelihood which allows for efficient exact sampling in the limit of weak coupling between neurons. We also demonstrate that these samplers can effectively incorporate side information, in particular, noisy fluorescence observations in the context of calcium-sensitive imaging experiments. We quantify the efficiency of these samplers in a variety of simulated experiments in which the network parameters are closely matched to data measured in real cortical networks, and also demonstrate the sampler applied to real calcium imaging data.

Efficient methods for sampling spike trains in networks of coupled neurons

Many fundamental questions in theoretical neuroscience involve optimal decoding and the computation of Shannon information rates in populations of spiking neurons. In this paper, we apply methods from the asymptotic theory of statistical inference to obtain a clearer analytical understanding of these quantities. We find that for large neural populations carrying a finite total amount of information, the full spiking population response is asymptotically as informative as a single observation from a Gaussian process whose mean and covariance can be characterized explicitly in terms of network and single neuron properties. The Gaussian form of this asymptotic sufficient statistic allows us in certain cases to perform optimal Bayesian decoding by simple linear transformations, and to obtain closed-form expressions of the Shannon information carried by the network. One technical advantage of the theory is that it may be applied easily even to non-Poisson point process network models; for example, we find that under some conditions, neural populations with strong history-dependent (non-Poisson) effects carry exactly the same information as do simpler equivalent populations of non-interacting Poisson neurons with matched firing rates. We argue that our findings help to clarify some results from the recent literature on neural decoding and neuroprosthetic design.

Information Rates and Optimal Decoding in Large Neural Populations

Recent advances in experimental stimulation methods have raised the following important computational question: how can we choose a stimulus that will drive a neuron to output a target spike train with optimal precision, given physiological constraints? Here we adopt an approach based on models that describe how a stimulating agent (such as an injected electrical current or a laser light interacting with caged neurotransmitters or photosensitive ion channels) affects the spiking activity of neurons. Based on these models, we solve the reverse problem of finding the best time-dependent modulation of the input, subject to hardware limitations as well as physiologically inspired safety measures, that causes the neuron to emit a spike train that with highest probability will be close to a target spike train. We adopt fast convex constrained optimization methods to solve this problem. Our methods can potentially be implemented in real time and may also be generalized to the case of many cells, suitable for neural prosthesis applications. With the use of biologically sensible parameters and constraints, our method finds stimulation patterns that generate very precise spike trains in simulated experiments. We also tested the intracellular current injection method on pyramidal cells in mouse cortical slices, quantifying the dependence of spiking reliability and timing precision on constraints imposed on the applied currents.

Inference From Population Calcium Imaging Fast Nonnegative Deconvolution for Spike Train

Population decoding of motor cortical activity using a generalized linear model with hidden states

Relay neurons in the lateral geniculate nucleus (LGN) receive direct visual input predominantly from a single retinal ganglion cell (RGC), in addition to indirect input from other sources including interneurons, thalamic reticular nucleus (TRN), and the visual cortex. To address the extent of influence of these indirect sources on the response properties of the LGN neurons, we fit a Generalized Linear Model (GLM) to the spike responses of cat LGN neurons driven by spatially homogeneous spots that were rapidly modulated by a pseudorandom luminance sequence. Several spot sizes were used to probe the spatial extent of the indirect visual effects. Our extracellular recordings captured both the LGN spikes and the incoming RGC input (S potentials), allowing us to divide the inputs to the GLM into two categories: the direct RGC input and the indirect input to which we have access through the luminance of the visual stimulus. For spots no larger than the receptive field center, the effect of the indirect input is negligible, while for larger spots its effect can, on average, account for 5% of the variance of the data and for as much as 25% in some cells. The polarity of the indirect visual influence is opposite to that of the linear receptive field of the neurons. We conclude that the indirect source of response modulation of the LGN relay neurons arises from inhibitory sources, compatible with thalamic interneurons or TRN.

A generalized linear model of the impact of direct and indirect inputs to the lateral geniculate nucleus.

1 Systems Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 2 Santa Cruz Institute for Particle Physics, University of California, Santa Cruz, CA 3 Department of Physics and Astronomy, University of Glasgow, Glasgow, UK 4 Faculty of Physics and Applied Computer Science, AGH University of Science and Technology, 23 30-059, Krakow, Poland 5 Department of Statistics and Center for Theoretical Neuroscience, Columbia University, New York, NY * These authors contributed equally.

Mapping a Neural Circuit : A Complete Input-Output Diagram in the Primate Retina

Functional connectivity in the retina at the resolution of photoreceptors

Understanding dendritic computation remains a key problem in cellular and computational neuroscience. The main challenge is in recording physiological signals (particularly voltage) with sufficient spatiotemporal resolution on dendrites, either via multiple-electrode recordings or imaging techniques. Statistical techniques can alleviate this difficulty, by de-noising the data and inferring the voltage in unobserved compartments.

Near-optimal experimental design for sampling voltage on dendritic trees

We present the design and characterization of a single-photon avalanche diode (SPAD) fabricated with a standard 0.13 μm complementary metal-oxide-semiconductor process. We have developed a figure of merit for SPADs when these detectors are employed in high frame-rate fluorescent lifetime imaging microscopy, which allows us to specify an optimal bias point for the diode and compare our diode with other published devices. At its optimum bias point at room temperature, our SPAD achieves a photon detection probability of 29% while exhibiting a dark count rate of only 231 Hz and an impulse response of 198 ps.

A low-noise, single-photon avalanche diode in standard 0.13 μm complementary metal-oxide-semiconductor process

Estimating two-dimensional firing rate maps is a common problem, arising in a number of contexts: the estimation of place fields in hippocampus, the analysis of temporally nonstationary tuning curves in sensory and motor areas, the estimation of firing rates following spike-triggered covariance analyses, etc. Here we introduce methods based on Gaussian process nonparametric Bayesian techniques for estimating these two-dimensional rate maps. These techniques offer a number of advantages: the estimates may be computed efficiently, come equipped with natural errorbars, adapt their smoothness automatically to the local density and informativeness of the observed data, and permit direct fitting of the model hyperparameters (e.g., the prior smoothness of the rate map) via maximum marginal likelihood. We illustrate the method's flexibility and performance on a variety of simulated and real data.

Efficient, adaptive estimation of two-dimensional firing rate surfaces via Gaussian process methods

Efficient computation of the maximum a posteriori path and parameter estimation in integrate-and-fire and more general state-space models

Fluorescent calcium indicators are becoming increasingly popular as a means for observing the spiking activity of large neuronal populations. Unfortunately, extracting the spike train of each neuron from a raw fluorescence movie is a nontrivial problem. This work presents a fast nonnegative deconvolution filter to infer the approximately most likely spike train of each neuron, given the fluorescence observations. This algorithm outperforms optimal linear deconvolution (Wiener filtering) on both simulated and biological data. The performance gains come from restricting the inferred spike trains to be positive (using an interior-point method), unlike the Wiener filter. The algorithm runs in linear time, and is fast enough that even when simultaneously imaging >100 neurons, inference can be performed on the set of all observed traces faster than real time. Performing optimal spatial filtering on the images further refines the inferred spike train estimates. Importantly, all the parameters required to perform the inference can be estimated using only the fluorescence data, obviating the need to perform joint electrophysiological and imaging calibration experiments.

Fast nonnegative deconvolution for spike train inference from population calcium imaging.

The understanding of neuronal circuits has been, and will continue to be, greatly advanced by the simultaneous imaging of action potentials in neuronal ensembles. This protocol describes "bulk" loading of brain slices with acetoxymethyl (AM) ester calcium indicators in order to monitor action potential activity in large populations of neurons simultaneously. The imaging of calcium influx into neurons provides an indirect, but accurate, measure of action potential generation in individual neurons. Single-cell resolution, and thus the easy identification of every active cell, is the key advantage of the technique.

Adaptively optimizing experiments has the potential to significantly reduce the number of trials needed to build parametric statistical models of neural systems. However, application of adaptive methods to neurophysiology has been limited by severe computational challenges. Since most neurons are high-dimensional systems, optimizing neurophysiology experiments requires computing high-dimensional integrations and optimizations in real time. Here we present a fast algorithm for choosing the most informative stimulus by maximizing the mutual information between the data and the unknown parameters of a generalized linear model (GLM) that we want to fit to the neuron's activity. We rely on important log concavity and asymptotic normality properties of the posterior to facilitate the required computations. Our algorithm requires only low-rank matrix manipulations and a two-dimensional search to choose the optimal stimulus. The average running time of these operations scales quadratically with the dimensionality of the GLM, making real-time adaptive experimental design feasible even for high-dimensional stimulus and parameter spaces. For example, we require roughly 10 milliseconds on a desktop computer to optimize a 100-dimensional stimulus. Despite using some approximations to make the algorithm efficient, our algorithm asymptotically decreases the uncertainty about the model parameters at a rate equal to the maximum rate predicted by an asymptotic analysis. Simulation results show that picking stimuli by maximizing the mutual information can speed up convergence to the optimal values of the parameters by an order of magnitude compared to using random (nonadaptive) stimuli. Finally, applying our design procedure to real neurophysiology experiments requires addressing the nonstationarities that we would expect to see in neural responses; our algorithm can efficiently handle both fast adaptation due to spike history effects and slow, nonsystematic drifts in a neuron's activity.

Biophysically detailed models of single cells are difficult to fit to real data. Recent advances in imaging techniques allow simultaneous access to various intracellular variables, and these data can be used to significantly facilitate the modelling task. These data, however, are noisy, and current approaches to building biophysically detailed models are not designed to deal with this. We extend previous techniques to take the noisy nature of the measurements into account. Sequential Monte Carlo (“particle filtering”) methods, in combination with a detailed biophysical description of a cell, are used for principled, model-based smoothing of noisy recording data. We also provide an alternative formulation of smoothing where the neural nonlinearities are estimated in a non-parametric manner. Biophysically important parameters of detailed models (such as channel densities, intercompartmental conductances, input resistances, and observation noise) are inferred automatically from noisy data via expectation-maximisation. Overall, we find that model-based smoothing is a powerful, robust technique for smoothing of noisy biophysical data and for inference of biophysical parameters in the face of recording noise.

Smoothing of, and Parameter Estimation from, Noisy Biophysical Recordings

The Kalman filter has been proposed as a model to decode neural activity measured from the motor cortex in order to obtain real-time estimates of hand motion in behavioral neurophysiological experiments. However, currently used linear state-space models underlying the Kalman filter do not take into account other behavioral states such as muscular activity or the subject's level of attention, which are often unobservable during experiments but may play important roles in characterizing neural controlled hand movement. To address this issue, we depict these unknown states as one multidimensional hidden state in the linear state-space framework. This new model assumes that the observed neural firing rate is directly related to this hidden state. The dynamics of the hand state are also allowed to impact the dynamics of the hidden state, and vice versa. The parameters in the model can be identified by a conventional expectation-maximization algorithm. Since this model still uses the linear Gaussian framework, hand-state decoding can be performed by the efficient Kalman filter algorithm. Experimental results show that this new model provides a more appropriate representation of the neural data and generates more accurate decoding. Furthermore, we have used recently developed computationally efficient methods by incorporating a priori information of the targets of the reaching movement. Our results show that the hidden-state model with target-conditioning further improves decoding accuracy.

Neural Decoding of Hand Motion Using a Linear State-Space Model With Hidden States

A major open problem in systems neuroscience is to understand the relationship between behavior and the detailed spiking properties of neural populations. We assess how faithfully velocity information can be decoded from a population of spiking model retinal neurons whose spatiotemporal receptive fields and ensemble spike train dynamics are closely matched to real data. We describe how to compute the optimal Bayesian estimate of image velocity given the population spike train response and show that, in the case of global translation of an image with known intensity profile, on average the spike train ensemble signals speed with a fractional standard deviation of about 2% across a specific set of stimulus conditions. We further show how to compute the Bayesian velocity estimate in the case where we only have some a priori information about the (naturalistic) spatial correlation structure of the image but do not know the image explicitly. As expected, the performance of the Bayesian decoder is shown to be less accurate with decreasing prior image information. There turns out to be a close mathematical connection between a biologically plausible "motion energy" method for decoding the velocity and the Bayesian decoder in the case that the image is not known. Simulations using the motion energy method and the Bayesian decoder with unknown image reveal that they result in fractional standard deviations of 10% and 6%, respectively, across the same set of stimulus conditions. Estimation performance is rather insensitive to the details of the precise receptive field location, correlated activity between cells, and spike timing.

Journal of the Optical Society of America. A, Optics, image science, and vision

The relationship between optimal and biologically plausible decoding of stimulus velocity in the retina.

Recent experimental results suggest that neural networks are associated with multiple firing regimes, or states, such as tonic and burst modes in thalamus (for review, see Sherman, Trends in Neuroscience, 2001) and UP and DOWN states in cortex (e.g. Anderson et al., Nature Neuroscience, 2000). It is reasonable to speculate that neurons in multi-state networks that are involved in sensory processing might display differential firing behaviors in response to the same stimulus in each of the states of the system, and, indeed, Bezdudnaya et al. (Neuron, 2006) showed that temporal receptive field properties change between tonic and burst states for relay cells in rabbit thalamus. Motivated by these results, we previously presented a general framework for estimating state-dependent neural response properties from paired spike-train and stimulus data assuming that neuronal assemblies transition between several discrete hidden states (Escola and Paninski, Cosyne, 2007). We modified the traditional hidden Markov model (HMM) framework to permit point-process observables such as spike-trains, and, for maximal flexibility in our model, we allowed an external, time-varying stimulus, if present, and the neurons’ own spike histories to drive both the spiking behavior in each state and the transitioning behavior between states. We showed that an appropriately modified expectation-maximization algorithm could be constructed to learn the model parameters and gave preliminary results with simulated data. Although HMMs have been used previously to analyze neuronal data (e.g. Abeles et al., Proceedings of the National Academy of Sciences, 1995; Chen et al., Neural Computation, 2009), our model is an extension to the stimulus and history-dependent regime.

Hidden Markov models for the stimulus-response relationships of multi-state neurons

Spike inference from calcium imaging using sequential Monte Carlo methods.

There has recently been a great deal of interest in inferring network connectivity from the spike trains in populations of neurons. One class of useful models that can be fit easily to spiking data is based on generalized linear point process models from statistics. Once the parameters for these models are fit, the analyst is left with a nonlinear spiking network model with delays, which in general may be very difficult to understand analytically. Here we develop mean-field methods for approximating the stimulus-driven firing rates (in both the time-varying and steady-state cases), auto- and cross-correlations, and stimulus-dependent filtering properties of these networks. These approximations are valid when the contributions of individual network coupling terms are small and, hence, the total input to a neuron is approximately gaussian. These approximations lead to deterministic ordinary differential equations that are much easier to solve and analyze than direct Monte Carlo simulation of the network activity. These approximations also provide an analytical way to evaluate the linear input-output filter of neurons and how the filters are modulated by network interactions and some stimulus feature. Finally, in the case of strong refractory effects, the mean-field approximations in the generalized linear model become inaccurate; therefore, we introduce a model that captures strong refractoriness, retains all of the easy fitting properties of the standard generalized linear model, and leads to much more accurate approximations of mean firing rates and cross-correlations that retain fine temporal behaviors.

Mean-Field Approximations for Coupled Populations of Generalized Linear Model Spiking Neurons with Markov Refractoriness

A major open problem in systems neuroscience is to understand the relationship between behavior and the detailed spiking properties of neural populations. In this work, we assess how faithfully velocity information can be decoded from a population of spiking model retinal neurons whose spatiotemporal receptive fields and ensemble spike-train dynamics are closely matched to real data. We describe how to compute the optimal Bayesian estimate of image velocity given the population spike train response, and show that, given complete information about the displayed image, the spike train ensemble signals speed with an average relative precision of about 2% across a specific set of stimulus conditions. We further show how to compute the Bayesian velocity estimate in the case where we only have some a priori information about the (naturalistic) correlation structure of the image, but do not know the image explicitly. As expected, the performance of the Bayesian decoder is shown to be less accurate with decreasing prior image information. There turns out to be a close mathematical connection between a biologically-plausible “motion energy” method for decoding the velocity and the optimal Bayesian decoder in the case that the image is not known. Simulations using the motion energy method reveal that it results in an average relative precision of only 10% across the same set of stimulus conditions. Estimation performance is rather insensitive to the details of the precise receptive field location, correlated activity between cells, and spike timing. c © 2009 Optical Society of America OCIS codes: 330.4060, 330.4150, 330.7310, 330.5310.

Optimal decoding of stimulus velocity using a probabilistic model of ganglion cell populations in primate retina

Signal-to-noise ratios in physical systems can be significantly degraded if the outputs of the systems are highly variable. Biological processes for which highly stereotyped signal generations are necessary features appear to have reduced their signal variabilities by employing multiple processing steps. To better understand why this multistep cascade structure might be desirable, we prove that the reliability of a signal generated by a multistate system with no memory (i.e., a Markov chain) is maximal if and only if the system topology is such that the process steps irreversibly through each state, with transition rates chosen such that an equal fraction of the total signal is generated in each state. Furthermore, our result indicates that by increasing the number of states, it is possible to arbitrarily increase the reliability of the system. In a physical system, however, an energy cost is associated with maintaining irreversible transitions, and this cost increases with the number of such transitions (i.e., the number of states). Thus, an infinite-length chain, which would be perfectly reliable, is infeasible. To model the effects of energy demands on the maximally reliable solution, we numerically optimize the topology under two distinct energy functions that penalize either irreversible transitions or incommunicability between states, respectively. In both cases, the solutions are essentially irreversible linear chains, but with upper bounds on the number of states set by the amount of available energy. We therefore conclude that a physical system for which signal reliability is important should employ a linear architecture, with the number of states (and thus the reliability) determined by the intrinsic energy constraints of the system.

A Bayesian method to predict the optimal diffusion coefficient in random fixational eye movements

Statistical analysis of neural data : Discrete-space hidden Markov models

Experimental research seeking to quantify neuronal structure constantly contends with restrictions on image resolution and variability. In particular, experimentalists often need to analyze images with very low signal-to-noise ratio (SNR). In many experiments, dye toxicity scales with the light intensity; this leads experimentalists to reduce image SNR in order to preserve the viability of the specimen. In this paper, we present a Bayesian approach for estimating the neuronal shape given low-SNR observations. This Bayesian framework has two major advantages. First, the method effectively incorporates known facts about 1) the image formation process, including blur and the Poisson nature of image noise at low intensities, and 2) dendritic shape, including the fact that dendrites are simply-connected geometric structures with smooth boundaries. Second, we may employ standard Markov chain Monte Carlo techniques for quantifying the posterior uncertainty in our estimate of the dendritic shape. We describe an efficient computational implementation of these methods and demonstrate the algorithm's performance on simulated noisy two-photon laser-scanning microscopy images.

Bayesian Image Recovery for Dendritic Structures Under Low Signal-to-Noise Conditions

1 Autoregressive models and Kalman filter models are Gaussian Markov and hidden Markov models, respectively 3 1.1 Example: voltage smoothing and interpolation; inferring biophysical parameters 5 1.2 We may perform inference in the Kalman model either via the forward-backwards recursion or by direct optimization methods . . . . . . . . . . . . . . . . . . . 9 1.3 The Kalman model is only identifiable up to linear transformations of the state variable . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 1.4 Examples: intermittent, noisy, filtered, nonlinearly transformed voltage observations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 1.5 Example: spike sorting given nonstationary data using a mixture-of-Kalmanfilters model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Statistical analysis of neural data : Continuous-space models ( First 2 / 3 )

Integral equation methods for computing likelihoods and their derivatives in the stochastic integrate-and-fire model

This article reviews an earlier recursive approach for computing such reach trajectories and presents a new nonrecursive approach, with computations that may be performed analytically for the most part, leading to a significant gain in the accuracy of the inferred trajectory while imposing a very small computational burden. Extensions of the approach are discussed including the incorporation of multiple target observations at different times, and multiple possible target locations.

We develop a ldquoplug-inrdquo kernel estimator for the differential entropy that is consistent even if the kernel width tends to zero as quickly as 1/N, where N is the number of independent and identically distributed (i.i.d.) samples. Thus, accurate density estimates are not required for accurate kernel entropy estimates; in fact, it is a good idea when estimating entropy to sacrifice some accuracy in the quality of the corresponding density estimate.

Sequential optimal design methods hold great promise for improving the efficiency of neurophysiology experiments. However, previous methods for optimal experimental design have incorporated only weak prior information about the underlying neural system (e.g., the sparseness or smoothness of the receptive field). Here we describe how to use stronger prior information, in the form of parametric models of the receptive field, in order to construct optimal stimuli and further improve the efficiency of our experiments. For example, if we believe that the receptive field is well-approximated by a Gabor function, then our method constructs stimuli that optimally constrain the Gabor parameters (orientation, spatial frequency, etc.) using as few experimental trials as possible. More generally, we may believe a priori that the receptive field lies near a known sub-manifold of the full parameter space; in this case, our method chooses stimuli in order to reduce the uncertainty along the tangent space of this sub-manifold as rapidly as possible. Applications to simulated and real data indicate that these methods may in many cases improve the experimental efficiency.

Designing neurophysiology experiments to optimally constrain receptive field models along parametric submanifolds

We describe a class of models that predict how the instantaneous firing rate of a neuron depends on a dynamic stimulus. The models utilize a learnt pointwise nonlinear transform of the stimulus, followed by a linear filter that acts on the sequence of transformed inputs. In one case, the nonlinear transform is the same at all filter lag-times. Thus, this “input nonlinearity” converts the initial numerical representation of stimulus value to a new representation that provides optimal input to the subsequent linear model. We describe algorithms that estimate both the input nonlinearity and the linear weights simultaneously; and present techniques to regularise and quantify uncertainty in the estimates. In a second approach, the model is generalized to allow a different nonlinear transform of the stimulus value at each lag-time. Although more general, this model is algorithmically more straightforward to fit. However, it has many more degrees of freedom than the first approach, thus requiring more data for accurate estimation. We test the feasibility of these methods on synthetic data, and on responses from a neuron in rodent barrel cortex. The models are shown to predict responses to novel data accurately, and to recover several important neuronal response properties.

Movements Under Resistive and Assistive Force Fields Encoding of Movement Dynamics by Purkinje Cell Simple Spike Activity During Fast Arm

How many independent samples <i>N</i> do we need from a distribution <i>p</i> to decide that <i>p</i> is epsiv-distant from uniform in an L<sub>1</sub> sense, Sigma<sub>i=1</sub> <sup>m</sup> |<i>p</i>(<i>i</i>) - 1/<i>m</i>| > epsiv? (Here <i>m</i> is the number of bins on which the distribution is supported, and is assumed known <i>a</i> <i>priori</i>.) Somewhat surprisingly, we only need <i>N</i> epsiv<sup>2</sup> Gt <i>m</i> <sup>1/2</sup> to make this decision reliably (this condition is both sufficient and necessary). The test for uniformity introduced here is based on the number of observed ldquocoincidencesrdquo (samples that fall into the same bin), the mean and variance of which may be computed explicitly for the uniform distribution and bounded nonparametrically for any distribution that is known to be epsiv-distant from uniform. Some connections to the classical birthday problem are noted.

A Coincidence-Based Test for Uniformity Given Very Sparsely Sampled Discrete Data

Statistical analysis of neural data : Monte Carlo techniques for decoding spike trains

We use multilinear methods to extend traditional neural encoding models in various directions: the linear encoding model is extended to include an “input nonlinearity” (a nonlinear transformation of stimulus value applied before temporal filtering [1]); such a nonlinearity is also added to the LNP model [2], resulting in the “NLNP model”. In the auditory domain, when STRF models [3] are extended with the input nonlinearity, the resulting structure allows for the identification of new inseparabilities in sound processing (such as inseparabilities in time and sound level) beyond the traditionally studied time-frequency inseparability.

Multilinear neural encoding models capture nonlinearities and contextual influences in cortical responses

Statistical methods for understanding complex biophysical neural data

4: Two applications of the point process likelihood formula Two-alternative forced choice (2AFC) discrimination. Let’s assume we have some model that assigns some conditional intensity function λ~x(t) to any given stimulus ~x. We may use this model to perform discrimination tasks: given the observed spike train data D = {ti}, which of the two stimuli ~x1 or ~x2 are more likely to have produced this spike train? (The detection task is a special case: here we would like to know whether ~x0 or ~x = 0 produced the observed response.) According to Neyman-Pearson, we should simply compare loglikelihoods:

Statistical analysis of neural data: Addenda to Brown's point process notes

0.1 Generalized linear models for spike trains; relationship to the standard linear Gaussian model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 0.2 Generalized linear models for images in low-light conditions; incorporating nonnegativity constraints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 0.3 Sampling properties of the MLE; connections to spike-triggered averaging . . 5 0.4 Incorporating nonlinear terms . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 0.5 Incorporating spike history effects and interneuronal interactions . . . . . . . 7 0.6 Example: fitting time-varying terms / PSTH estimation . . . . . . . . . . . . 8 0.7 Multiplicative models of spike history-dependence; connections to renewal models 9 0.8 Connection to biophysical models: soft-threshold integrate-and-fire models . . 12 0.9 Avoiding overfitting: training error, generalization, and cross-validation . . . 14 0.10 Reducing the number of parameters can increase the prediction accuracy; basis choice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 0.11 Low-rank approximations provide a useful method for reducing the number of parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 0.12 Regularization; maximum penalized likelihood; maximum a posteriori estimation 22 0.13 The Fisher information matrix is useful for large-sample approximations of confidence ellipses and errorbars . . . . . . . . . . . . . . . . . . . . . . . . . 27 0.14 The Fisher information matrix may be used to help select stimuli adaptively 29 0.15 Extensions: latent variable models . . . . . . . . . . . . . . . . . . . . . . . . 31

Statistical analysis of neural data : Generalized linear models for spike trains

Recent developments in multi-electrode recordings enable the simultaneous measurement of the spiking activity of many neurons. Analysis of such multineuronal data is one of the key challenge in computational neuroscience today. In this work, we develop a multivariate point-process model in which the observed activity of a network of neurons depends on three terms: (1) the experimentally-controlled stimulus; (2) the spiking history of the observed neurons; and (3) a hidden term that corresponds, for example, to common input from an unobserved population of neurons that is presynaptic to two or more cells in the observed population. We consider two models for the network firing-rates, one of which is computationally and analytically tractable but can lead to unrealistically high firing-rates, while the other with reasonable firing-rates imposes a greater computational burden. We develop an expectation-maximization algorithm for fitting the parameters of both the models. For the analytically tractable model the expectation step is based on a continuous-time implementation of the extended Kalman smoother, and the maximization step involves two concave maximization problems which may be solved in parallel. The other model that we consider necessitates the use of Monte Carlo methods for the expectation as well as maximization step. We discuss the trade-off involved in choosing between the two models and the associated methods. The techniques developed allow us to solve a variety of inference problems in a straightforward, computationally efficient fashion; for example, we may use the model to predict network activity given an arbitrary stimulus, infer a neuron's ring rate given the stimulus and the activity of the other observed neurons, and perform optimal stimulus decoding and prediction. We present several detailed simulation studies which explore the strengths and limitations of our approach.

Statistical analysis of neural data: Hidden Markov models and applications to multi-state neural models ∗

3 The “Fokker-Planck” equation is a partial differential equation that controls the evolution of the forward (and backward) probabilities 9 3.1 Deriving the “free” Fokker-Planck equation (no spike observations) . . . . . . 10 3.1.1 Conductance-based model . . . . . . . . . . . . . . . . . . . . . . . . . 12 3.1.2 Computing mean firing rates in a network of GLM neurons . . . . . . 13 3.2 Incorporating spike observations into the Fokker-Planck equation . . . . . . . 14 3.2.1 Soft threshold integrate-and-fire model . . . . . . . . . . . . . . . . . . 15 3.2.2 Hard threshold IF model . . . . . . . . . . . . . . . . . . . . . . . . . 16 3.2.3 Leaky integrate-and-fire cell driven by white current noise . . . . . . . 17 3.2.4 Noiseless leaky integrate-and-fire cell . . . . . . . . . . . . . . . . . . . 17 3.2.5 Leaky integrate and fire cell with Poisson conductance inputs . . . . . 18 3.3 A similar “backwards” equation holds for the backwards probabilities . . . . 18

Statistical analysis of neural data : The integrate-and-fire neuron and other continuous-time state-space models

Decoding algorithms, which translate neural activity into command signals for external devices such as robotic limbs and computer cursors, are a key component of neural prosthetic devices. Classically, a linear state-space model, with bayesian inferencing methods, has been used as it enables real-time implementation. This model is based on a linear Gaussian approximation between neural firing rates and hand motion, and an autoregressive representation for the hand kinematics over time. In this work we suggest two key modifications to the classical model in order to improve decoding accuracy.

Neural decoding of goal-directed movements using a linear state-space model with hidden states

We develop an expectation-maximization (EM) algorithm for a class of noisy integrate-and-fire models, in which the voltage evolves according to the linear stochastic differential equation dV (t) = (g (t)V (t) + I(t))dt + σdBt, with Bt standard Brownian motion, and V (t) is reset after each spike (Paninski et al., 2004; Pillow et al., 2005). The functions I(t) and g(t) (the input current and membrane conductance, respectively) are given by I(t) = P aiIi(t) and g(t) = P bjgj(t), where the functions Ii(t) and gj(t) are assumed known; thus the unknown parameters that we want to estimate are θ = {~ a, ~ b, σ}. (The reset and threshold voltage parameters may be assumed known, by the usual change of variables.) We fit the parameters θ via maximum likelihood, given only the functions {Ii(t)}, {gj(t)}, and the observed spike times; no intracellular currents or voltages are observed. We previously (Paninski et al., 2004) described methods for computing the likelihood and directly ascending the likelihood by a hill-climbing procedure. In (Paninski et al., 2005) we proposed an alternate method to compute the likelihood, which facilitates the computation of gradient information. However, the computational complexity of this gradient method scales as O(d 3 ), where d is the number of time points a given inter-spike interval is divided into (the larger d is, the higher the numerical precision of the calculation). By casting the model as a hidden Markov model in continuous time and space (Paninski, 2006), we may adapt standard EM approaches to derive a method for computing likelihood gradients that only requires O(d 2 ) time (Salakhutdinov et al., 2003). In addition, the EM algorithm provides a good “warm start” for optimization via conjugate gradient ascent. The E-step of the algorithm requires the solution of a forward and backward Fokker-Planck equation with time-dependent coefficients; we derive an efficient and unconditionally stable algorithm for solving this partial differential equation.

An expectation-maximization Fokker-Planck algorithm for the noisy integrate-and-fir e model

Statistical analysis of neural data: Classification-based approaches: spike-triggered averaging, spike-triggered covariance, and the linear-nonlinear cascade model

First, we discuss methods for optimally inferring the synaptic inputs to an electrotonically compact neuron, given intracellular voltage-clamp or current-clamp recordings from the postsynaptic cell. These methods are based on sequential Monte Carlo techniques (“particle filtering”). We demonstrate on model data that these methods can accurately recover the time course of excitatory and inhibitory synaptic inputs on a single trial; no averaging over multiple trials is necessary. Once these synaptic input time courses are recovered, it becomes possible to fit (via tractable convex optimization techniques) simple models describing the relationship between the sensory stimulus and the observed synaptic input. We develop an expectationmaximization (EM) algorithm that consists of alternating iterations between these synaptic recovery and model estimation steps. These proposed methods have direct and immediate applications to understanding the balance between excitation and inhibition in sensory processing in vivo.

2 Maximum a posteriori neural decoding 3 2.1 Gaussian approximations to the posterior p(~x|D) are tractable and useful . . 4 2.1.1 Moment-matching provides an alternative method for constructing the Gaussian approximation . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.2 Numerical implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 2.3 MAP decoding examples: correlated and spatial stimuli . . . . . . . . . . . . 7 2.4 Decoding Poisson image observations . . . . . . . . . . . . . . . . . . . . . . . 11

Statistical analysis of neural data : Maximum a posteriori techniques for decoding spike trains

0.1 Bound optimization; auxiliary functions . . . . . . . . . . . . . . . . . . . . . 2 0.2 The EM algorithm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 0.3 EM may be used to optimize the log-posterior instead of the log-likelihood . . 5 0.4 Example: Mixture models and spike sorting . . . . . . . . . . . . . . . . . . . 5 0.5 Example: Spike sorting given stimulus observations . . . . . . . . . . . . . . . 7 0.6 Example: LNP models with spike-timing jitter . . . . . . . . . . . . . . . . . 8 0.7 Fitting hierarchical generalized linear models for spike trains . . . . . . . . . 11 0.8 Connection between EM algorithm and computing gradients of the marginal likelihood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Statistical analysis of neural data : The expectation-maximization ( EM ) algorithm

Noise is an omnipresent issue that is often handled suboptimally. For example, noise is an issue in voltagesensitive imaging – even the best dyes achieve signal-to-noise ratios of no more than ∼ 1 − 6%. Averaging noise out is not always possible and sometimes not even desirable. Missing data are often burdensome too: in voltage dye experiments, the laser has to be moved between sites of interest and thus the data is not acquired simultaneously, leading to gaps in the data. Despite advances, this problem becomes more prominent the more sites one attempts to record from. More generally, we might even be interested in a variable that has not been observed directly at all, such as the voltage in a Ca ++imaging experiment. Principled methods to filter out noise, to interpolate between data points and to infer unobserved variables could substantially complement advances in data acquisition methodology.

Model-based smoothing of noisy, intermittent, biophysical signals

We present an efficient algorithm for selecting optimal stimuli for estimating the conditional response function of a neuron. Stimuli are selected by optimizing an objective function which quantifies the expected reduction in uncertainty about the unknown response function. Our objective function is based on mutual information and leads to an optimality criterion known as D-optimality [1]. Our implementation overcomes the computational hurdles of sequential optimal experimental design in this setting. Simulations show that using optimally chosen stimuli can reduce the number of trials needed to estimate the conditional response function by more than an order of magnitude.

An Efficient Algorithm for Sequential Optimal Design of Neuro- physiology Experiments

Active learning can significantly reduce the amount of training data required to fit parametric statistical models for supervised learning tasks. Here we present an efficient algorithm for choosing the optimal (most informative) query when the output labels are related to the inputs by a generalized linear model (GLM). The algorithm is based on a Laplace approximation of the posterior distribution of the GLM’s parameters. The algorithm requires only low-rank matrix manipulations and a single two-dimensional search to choose the optimal query and has complexity O(n) (with n the dimension of the feature space), making active learning with GLMs feasible even for high-dimensional feature spaces. In certain cases the twodimensional search may be reduced to a onedimensional search, further improving the algorithm’s efficiency. Simulation results show that the model parameters can be estimated much more efficiently using the active learning technique than by using randomly chosen queries. We compute the asymptotic posterior covariance semi-analytically and demonstrate that the algorithm empirically achieves this asymptotic convergence rate, which is generally better than the convergence rate in the random-query setting. Finally, we generalize the approach to efficiently handle both output history effects (for applications to time-series models of autoregressive type) and slow, non-systematic drifts in the model parameters. Introduction Active learning refers to the problem of selecting the optimal training set for a learning agent, given our prior knowledge and any previously observed examples. Active learning is particularly useful in settings 1) for which it is expensive to obtain labeled training examples (e.g. user ratings systems or geophysical applications), or 2) for which we have limited time to collect data (e.g. biological applications). Optimal inputs are typically selected by optimizing an objective function which quantifies the expected utility of measuring the response to a particular input. One important objective function is the expected mutual information between the response and the parameters of the model being fitted to the data (Fedorov, 1972; Mackay, 1992; Chaloner and Verdinelli, 1995). Previous work has shown that constructing a training set using this criterion is in general asymptotically more efficient and never less efficient than using a randomly constructed training set (Paninski, 2005). Active learning, however, is limited by the computational challenges of the required optimization (Cohn et al., 1996; Gilad-Bachrach et al., 2005). In particular, there are two major computational hurdles. First, the utility of each possible input depends on what has already been learned from labeled examples. Therefore, we need to be able to rapidly update the fitted model as we add new points to the training set. Second, evaluating and optimizing the mutual information over the (high-dimensional) space of unlabeled examples requires a high-dimensional integration followed by a search over the possible inputs. In general, the complexity of both the integration and optimization scales exponentially with the dimensionality. As emphasized above, many applications require that we perform these tasks in near-real time. We present methods for solving these problems using generalized linear models (GLM) for the input-output relationship and certain Gaussian approximations of the posterior distribution of the model parameters. Our emphasis is on developing techniques that scale well in high dimensions. We solve the first problem by using efficient rank-one update methods to update the Gaussian approximation to the posterior, and the second problem by a reduction to a highly tractable twodimensional optimization problem. Our results show that the resulting algorithm produces a training set which can be up to an order of magnitude more informative than the set produced by random sampling. Moreover, the algorithm is efficient enough for near real-time implementation.

Statistical analysis of neural data : State-space models and applications to optimal voltage smoothing , tracking nonstationarities , and recursive decoding

Using calcium sensitive fluorescence to study neural dynamics is becoming increasingly popular both in vitro and in vivo, at the level of individual spines, dendrites, boutons, neurons, or populations of neurons. While the data collected from these experiments are time-varying fluorescence images, the signals of interest are the precise spike times and/or the intracellular calcium concentrations, [Ca]t, of the observable neurons. Unfortunately, determining the true value of these hidden signals is a difficult problem for a number of reasons. First, observations are noisy. This is a problem unlikely to be solved in the near future, as a major source of the noise is photon shot noise, which reflects the quantal nature of light. Second, observations may be undersampled. When using epifluorescence, this problem can be solved with faster cameras. Similarly, when using confocal microscopy, faster cameras and spinning disk technology enable sufficiently fast imaging. However, when using two-photon microscopy (2PM), images are reconstructed from serial scans across the imaging plane. Array based technologies and faster scanning can help alleviate this problem, but may also exacerbate the third problem: low signal-to-noise ratio. Fourth, the relationship between fluorescence observations and [Ca]t is nonlinear, especially for fluorescent proteins. This has placed undesirable and unnecessary restrictions on the calcium indicators used for analysis, as the standard analytical tools assume a linear relationship between [Ca]t and fluorescence.

Model-based optimal inference of spike times and calcium dy- namics given noisy and intermittent calcium-fluorescence imag- ing

Biophysically accurate multicompartmental models of individual neurons have significantly advanced our understanding of the input-output function of single cells. These models depend on a large number of parameters that are difficult to estimate. In practice, they are often hand-tuned to match measured physiological behaviors, thus raising questions of identifiability and interpretability. We propose a statistical approach to the automatic estimation of various biologically relevant parameters, including 1) the distribution of channel densities, 2) the spatiotemporal pattern of synaptic input, and 3) axial resistances across extended dendrites. Recent experimental advances, notably in voltage-sensitive imaging, motivate us to assume access to: i) the spatiotemporal voltage signal in the dendrite and ii) an approximate description of the channel kinetics of interest. We show here that, given i and ii, parameters 1-3 can be inferred simultaneously by nonnegative linear regression; that this optimization problem possesses a unique solution and is guaranteed to converge despite the large number of parameters and their complex nonlinear interaction; and that standard optimization algorithms efficiently reach this optimum with modest computational and data requirements. We demonstrate that the method leads to accurate estimations on a wide variety of challenging model data sets that include up to about 10(4) parameters (roughly two orders of magnitude more than previously feasible) and describe how the method gives insights into the functional interaction of groups of channels.

Random-Access Multiphoton (RAMP) Microscopy Fast Functional Imaging of Single Neurons Using

We apply an adaptive approach to optimal experimental design in the context of estimating the unknown parameters of a model of a neuron's response. We present an algorithm to choose the optimal (most informative) stimulus on each trial; this algorithm can be implemented efficiently even for high-dimensional stimulus and parameter spaces (in particular, no high-dimensional numerical optimizations or integrations are required). Our simulation results show that model parameters can be estimated much more efficiently using this adaptive algorithm rather than random sampling. We also show that this adaptive approach leads to superior performance in the case that the model parameters are nonstationary, as would be expected in real experiments

2006 International Conference of the IEEE Engineering in Medicine and Biology Society

Model­based optimal interpolation and filtering for noisy, intermittend, biophysical signals

Motor Cortex and Cerebellum Linear Encoding of Muscle Activity in Primary

We present methods for making better use of currently obtainable data, focusing upon algorithms for twophoton laser scanning microscopy (TPLSM) image recovery. In the low signal to noise regime (SNR), imaging can be modeled as a Poisson process which introduces a blur per pixel (PSF) and additive noise by: Imageout = Poiss{Imagein ∗ psf + noise} . Many groups have contributed to the general problem of restoring noisy blurred images. With various refinements, maximum likelihood (ML) techniques have been particularly successful for image restoration [3].

We compute the exact spike-triggered average (STA) of the voltage for the nonleaky integrate-and-fire (IF) cell in continuous time, driven by gaussian white noise. The computation is based on techniques from the theory of renewal processes and continuous-time hidden Markov processes (e.g., the backward and forward Fokker-Planck partial differential equations associated with first-passage time densities). From the STA voltage, it is straightforward to derive the STA input current. The theory also gives an explicit asymptotic approximation for the STA of the leaky IF cell, valid in the low-noise regime 0. We consider both the STA and the conditional average voltage given an observed spike doublet event, that is, two spikes separated by some fixed period of silence. In each case, we find that the STA as a function of time-preceding-spike, , has a square root singularity as approaches zero from below and scales linearly with the scale of injected noise current. We close by briefly examining the discrete-time case, where similar phenomena are observed.

The Spike-Triggered Average of the Integrate-and-Fire Cell Driven by Gaussian White Noise

Adaptively optimizing experiments can significantly reduce the number of trials needed to characterize neural responses using parametric statistical models. However, the potential for these methods has been limited to date by severe computational challenges: choosing the stimulus which will provide the most information about the (typically high-dimensional) model parameters requires evaluating a high-dimensional integration and optimization in near-real time. Here we present a fast algorithm for choosing the optimal (most informative) stimulus based on a Fisher approximation of the Shannon information and specialized numerical linear algebra techniques. This algorithm requires only low-rank matrix manipulations and a one-dimensional linesearch to choose the stimulus and is therefore efficient even for high-dimensional stimulus and parameter spaces; for example, we require just 15 milliseconds on a desktop computer to optimize a 100-dimensional stimulus. Our algorithm therefore makes real-time adaptive experimental design feasible. Simulation results show that model parameters can be estimated much more efficiently using these adaptive techniques than by using random (nonadaptive) stimuli. Finally, we generalize the algorithm to efficiently handle both fast adaptation due to spike-history effects and slow, non-systematic drifts in the model parameters.

Real-time adaptive information-theoretic optimization of neurophysiology experiments

The activity of neurons in primary motor cortex (M1) and cerebellum is known to correlate with extrinsic movement parameters, including hand position and velocity. Relatively few studies have addressed the encoding of intrinsic parameters, such as muscle activity. Here we applied a generalized regression analysis to describe the relationship of neurons in M1 and cerebellar dentate nucleus to electromyographic (EMG) activity from hand and forearm muscles, during performance of precision grip by macaque monkeys. We showed that cells in both M1 and dentate encode muscle activity in a linear fashion, and that EMG signals provide predictions of neural discharge that are equally accurate to those from kinematic information under these task conditions. Neural activity in M1 was significantly more correlated with both EMG and kinematic signals than was activity in dentate nucleus. Furthermore, the analysis enabled us to look at the temporal properties of muscle encoding. Cells were broadly tuned to muscle activity as a function of the lag between spiking and EMG and there was considerable heterogeneity in the optimal delay among individual neurons. However, a single lag (40 ms) was generally sufficient to provide good fits. Finally, incorporating spike history effects in our model offered no advantage in predicting novel spike trains, reinforcing the simple nature of the muscle encoding that we observed here.

Linear encoding of muscle activity in primary motor cortex and cerebellum.

The most likely voltage path and large deviations approximations for integrate-and-fire neurons

A fundamental goal of neuroscience is to be able to construct models of a population of neurons acting in concert to perform nonlinear operations. A primary difficulty hindering progress towards this goal is the paucity of computational tools designed with population data in mind. Cross-correlation based ideas become computationally intractable due to the combinatorial explosion. Fitting phenomenological models to multicell data has received some attention, but we take a more biophysically realistic approach. Our models have two distinguishing features to this effect. First, we consider experimentally derived noise distributions act on the neurons, which can be non-Gaussian (e.g., synaptic failures). Second, we assume the existence of unobserved data (i.e., hidden states), in addition to the observed data (or states). These qualities naturally lead to a Sequential Monte Carlo Expectation-Maximization approach (SMC-EM). The expectation step requires computing the likelihood of the joint probability of both the hidden and observed state trajectories. By assuming that the hidden states are Markov, these distributions are approximated using SMC. The maximization step requires computing the maximum likelihood estimates (MLEs) of the model parameters. By choosing models with likelihood functions that are jointly convex in the parameters, we can guarantee convergence. The MLEs for those parameters for which no closed-form solutions exist are determined using standard convex optimization tools.

Inferring the Structure of Populations of Neurons using a Sequential Monte Carlo EM Algorithm

Noise is an omnipresent issue that is often handled suboptimally. For example, noise is an issue in voltagesensitive imaging – even the best dyes achieve signal-to-noise ratios of no more than ∼ 1 − 6% (Djurisic and Zecevic, 2005). Averaging noise out is not always possible and sometimes not even desirable. Missing data are often burdensome too: in voltage dye experiments, the laser has to be moved between sites of interest and thus the data is not acquired simultaneously, leading to gaps in the data. Despite advances (Bullen et al., 1997), this problem becomes more prominent the more sites one attempts to record from. More generally, we might even be interested in a variable that has not been observed directly at all, such as the voltage in a Caimaging experiment. Principled methods to filter out noise, to interpolate between data points and to infer unobserved variables could substantially complement advances in data acquisition methodology. Here we show how, when time series recordings of a dynamical system (eg the voltage of a cell) are made, knowledge of the dynamical system can be used to both filter and interpolate between the measurements, providing a principled alternative to heuristics such as temporal smoothing or low-pass filtering. Neural dynamics are usually specified as Markov chains. If these dynamics are hidden (due to noisy or indirect measurements), the task of recovering the distribution over the true underlying state evolution s0:T of the neurone over time p(s0:T |V0:T ) is equivalent to inference in nonlinear state space models. These models, together with their discrete analogues such as intermittent Kalman filters and Hidden Markov Models have been analysed extensively and are very well understood. In particular, if the hidden variables do indeed evolve in a Markovian manner (as is often the case), a number of algorithms from the machine learning literature allow efficient sampling from p(s0:T |V0:T ) (cf. Doucet et al., 2001; Godsill et al., 2004), despite the huge size of this state space (O(N T ) for a state space of size N). In particular, we find that the combination of a nonlinear Gaussian state space model with Gaussian observation noise and the forward-backward particle filter, a simple algorithm frequently applied to Hidden Markov Models allows us to recover the true voltage of a Fitzhugh-Nagumo (FHN) spiking model very well.

Model-based optimal interpolation and ltering for noisy, intermittent biophysical recordings

A major function of the whisker thalamus (ventro posterior medial nucleus, VPM) is to transmit signals about surface texture to the barrel cortex. Different textures are known to induce characteristic “kinetic signatures” of whisker vibration, which are transduced as corresponding temporal sequences of precisely timed spikes by mechanoreceptors in the whisker follicle. However, it is not known how dynamic whisker vibrations are encoded by neurons in the thalamus.

REVERSE CORRELATION ANALYSIS OF THALAMIC RESPONSES TO DYNAMIC WHISKER STIMULATION

A number of studies of the motor system suggest that the majority of primary motor cortical neurons represent simple movement-related kinematic and dynamic quantities in their time-varying activity patterns. An example of such an encoding relationship is the cosine tuning of firing rate with respect to the direction of hand motion. We present a systematic development of statistical encoding models for movement-related motor neurons using multielectrode array recordings during a two-dimensional (2-D) continuous pursuit-tracking task. Our approach avoids massive averaging of responses by utilizing 2-D normalized occupancy plots, cascaded linear-nonlinear (LN) system models and a method for describing variability in discrete random systems. We found that the expected firing rate of most movement-related motor neurons is related to the kinematic values by a linear transformation, with a significant nonlinear distortion in about 1/3 of the neurons. The measured variability of the neural responses is markedly non-Poisson in many neurons and is well captured by a "normalized-Gaussian" statistical model that is defined and introduced here. The statistical model is seamlessly integrated into a nearly-optimal recursive method for decoding movement from neural responses based on a Sequential Monte Carlo filter.

Statistical encoding model for a primary motor cortical brain-machine interface

Our understanding of the input-output function of single cells has been substantially advanced by biophysically accurate multi-compartmental models. The large number of parameters needing hand tuning in these models has, however, somewhat hampered their applicability and interpretability. Here we propose a simple and well-founded method for automatic estimation of many of these key parameters: 1) the spatial distribution of channel densities on the cell's membrane; 2) the spatiotemporal pattern of synaptic input; 3) the channels' reversal potentials; 4) the intercompartmental conductances; and 5) the noise level in each compartment. We assume experimental access to: a) the spatiotemporal voltage signal in the dendrite (or some contiguous subpart thereof, e.g. via voltage sensitive imaging techniques), b) an approximate kinetic description of the channels and synapses present in each compartment, and c) the morphology of the part of the neuron under investigation. The key observation is that, given data a)-c), all of the parameters 1)-4) may be simultaneously inferred by a version of constrained linear regression; this regression, in turn, is efficiently solved using standard algorithms, without any "local minima" problems despite the large number of parameters and complex dynamics. The noise level 5) may also be estimated by standard techniques. We demonstrate the method's accuracy on several model datasets, and describe techniques for quantifying the uncertainty in our estimates.

Large-scale biophysical parameter estimation in single neurons via constrained linear regression

We discuss a method for obtaining a subject's a priori beliefs from his/her behavior in a psychophysics context, under the assumption that the behavior is (nearly) optimal from a Bayesian perspective. The method is nonparametric in the sense that we do not assume that the prior belongs to any fixed class of distributions (e.g., Gaussian). Despite this increased generality, the method is relatively simple to implement, being based in the simplest case on a linear programming algorithm, and more generally on a straightforward maximum likelihood or maximum a posteriori formulation, which turns out to be a convex optimization problem (with no non-global local maxima) in many important cases. In addition, we develop methods for analyzing the uncertainty of these estimates. We demonstrate the accuracy of the method in a simple simulated coin-flipping setting; in particular, the method is able to precisely track the evolution of the subject's posterior distribution as more and more data are observed. We close by briefly discussing an interesting connection to recent models of neural population coding.

Nonparametric inference of prior probabilities from Bayes-optimal behavior

We discuss an idea for collecting data in a relatively efficient manner. Our point of view is Bayesian and information-theoretic: on any given trial, we want to adaptively choose the input in such a way that the mutual information between the (unknown) state of the system and the (stochastic) output is maximal, given any prior information (including data collected on any previous trials). We prove a theorem that quantifies the effectiveness of this strategy and give a few illustrative examples comparing the performance of this adaptive technique to that of the more usual nonadaptive experimental design. In particular, we calculate the asymptotic efficiency of the information-maximization strategy and demonstrate that this method is in a well-defined sense never less efficientand is generically more efficientthan the nonadaptive strategy. For example, we are able to explicitly calculate the asymptotic relative efficiency of the staircase method widely employed in psychophysics research and to demonstrate the dependence of this efficiency on the form of the psychometric function underlying the output responses.

Recent work has examined the estimation of models of stimulus-driven neural activity in which some linear filtering process is followed by a nonlinear, probabilistic spiking stage. We analyze the estimation of one such model for which this nonlinear step is implemented by a known parametric function; the assumption that this function is known speeds the estimation process considerably. We investigate the shape of the likelihood function for this type of model, give a simple condition on the nonlinearity ensuring that no non-global local maxima exist in the likelihood—leading, in turn, to efficient algorithms for the computation of the maximum likelihood estimator—and discuss the implications for the form of the allowed nonlinearities. Finally, we note some interesting connections between the likelihood-based estimators and the classical spike-triggered average estimator, discuss some useful extensions of the basic model structure, and provide two novel applications to physiological data.

Maximum likelihood estimation of cascade point-process neural encoding models

Consider a sequence p/sub N/ of discrete probability measures, supported on m/sub N/ points, and assume that we observe N independent and identically distributed (i.i.d.) samples from each p/sub N/. We demonstrate the existence of an estimator of the entropy, H(p/sub N/), which is consistent even if the ratio N/m/sub N/ is bounded (and, as a corollary, even if this ratio tends to zero, albeit at a sufficiently slow rate).

We develop a family of upper and lower bounds on the worst-case expected KL loss for estimating a discrete distribution on a finite number m of points, given N i.i.d. samples. Our upper bounds are approximation-theoretic, similar to recent bounds for estimating discrete entropy; the lower bounds are Bayesian, based on averages of the KL loss under Dirichlet distributions. The upper bounds are convex in their parameters and thus can be minimized by descent methods to provide estimators with low worst-case error; the lower bounds are indexed by a one-dimensional parameter and are thus easily maximized. Asymptotic analysis of the bounds demonstrates the uniform KL-consistency of a wide class of estimators as c = N/m → ∞ (no matter how slowly), and shows that no estimator is consistent for c bounded (in contrast to entropy estimation). Moreover, the bounds are asymptotically tight as c → 0 or ∞, and are shown numerically to be tight within a factor of two for all c. Finally, in the sparse-data limit c → 0, we find that the Dirichlet-Bayes (add-constant) estimator with parameter scaling like - c log(c) optimizes both the upper and lower bounds, suggesting an optimal choice of the "add-constant" parameter in this regime.

Variational Minimax Estimation of Discrete Distributions under KL Loss

Log-concavity is an important property in the context of optimization, Laplace approximation, and sampling; Bayesian methods based on Gaussian process priors have become quite popular recently for classification, regression, density estimation, and point process intensity estimation. Here we prove that the predictive densities corresponding to each of these applications are log-concave, given any observed data. We also prove that the likelihood is log-concave in the hyperparameters controlling the mean function of the Gaussian prior in the density and point process intensity estimation cases, and the mean, covariance, and observation noise parameters in the classification and regression cases; this result leads to a useful parameterization of these hyperparameters, indicating a suitably large class of priors for which the corresponding maximum a posteriori problem is log-concave.

Log-concavity Results on Gaussian Process Methods for Supervised and Unsupervised Learning

A pursuit-tracking task (PTT) and multielectrode recordings were used to investigate the spatiotemporal encoding of hand position and velocity in primate primary motor cortex (MI). Continuous tracking of a randomly moving visual stimulus provided a broad sample of velocity and position space, reduced statistical dependencies between kinematic variables, and minimized the nonstationarities that are found in typical "step-tracking" tasks. These statistical features permitted the application of signal-processing and information-theoretic tools for the analysis of neural encoding. The multielectrode method allowed for the comparison of tuning functions among simultaneously recorded cells. During tracking, MI neurons showed heterogeneity of position and velocity coding, with markedly different temporal dynamics for each. Velocity-tuned neurons were approximately sinusoidally tuned for direction, with linear speed scaling; other cells showed sinusoidal tuning for position, with linear scaling by distance. Velocity encoding led behavior by about 100 ms for most cells, whereas position tuning was more broadly distributed, with leads and lags suggestive of both feedforward and feedback coding. Individual cells encoded velocity and position weakly, with comparable amounts of information about each. Linear regression methods confirmed that random, 2-D hand trajectories can be reconstructed from the firing of small ensembles of randomly selected neurons (3-19 cells) within the MI arm area. These findings demonstrate that MI carries information about evolving hand trajectory during visually guided pursuit tracking, including information about arm position both during and after its specification. However, the reconstruction methods used here capture only the low-frequency components of movement during the PTT. Hand motion signals appear to be represented as a distributed code in which diverse information about position and velocity is available within small regions of MI.

Spatiotemporal tuning of motor cortical neurons for hand position and velocity.

Neural activity in primary motor cortex (MI) is known to correlate with hand position and velocity. Previous descriptions of this tuning have (1) been linear in position or velocity, (2) depended only instantaneously on these signals, and/or (3) not incorporated the effects of interneuronal dependencies on firing rate. We show here that many MI cells encode a superlinear function of the full time-varying hand trajectory. Approximately 20% of MI cells carry information in the hand trajectory beyond just the position, velocity, and acceleration at a single time lag. Moreover, approximately one-third of MI cells encode the trajectory in a significantly superlinear manner; as one consequence, even small position changes can dramatically modulate the gain of the velocity tuning of MI cells, in agreement with recent psychophysical evidence. We introduce a compact nonlinear “preferred trajectory” model that predicts the complex structure of the spatiotemporal tuning functions described in previous work. Finally, observing the activity of neighboring cells in the MI network significantly increases the predictability of the firing rate of a single MI cell; however, we find interneuronal dependencies in MI to be much more locked to external kinematic parameters than those described recently in the hippocampus. Nevertheless, this neighbor activity is approximately as informative as the hand velocity, supporting the view that neural encoding in MI is best understood at a population level.

Superlinear Population Encoding of Dynamic Hand Trajectory in Primary Motor Cortex

We discuss an idea for collecting data in a relatively efficient manner. Our point of view is Bayesian and information-theoretic: on any given trial, we want to adaptively choose the input in such a way that the mutual information between the (unknown) state of the system and the (stochastic) output is maximal, given any prior information (including data collected on any previous trials). We prove a theorem that quantifies the effectiveness of this strategy and give a few illustrative examples comparing the performance of this adaptive technique to that of the more usual nonadaptive experimental design. For example, we are able to explicitly calculate the asymptotic relative efficiency of the "staircase method" widely employed in psychophysics research, and to demonstrate the dependence of this efficiency on the form of the "psychometric function" underlying the output responses.

Sequential movement representations based on correlated neuronal activity

We present some new results on the nonparametric estimation of entropy and mutual information. First, we use an exact local expansion of the entropy function to prove almost sure consistency and central limit theorems for three of the most commonly used discretized information estimators. The setup is related to Grenander's method of sieves and places no assumptions on the underlying probability measure generating the data. Second, we prove a converse to these consistency theorems, demonstrating that a misapplication of the most common estimation techniques leads to an arbitrarily poor estimate of the true information, even given unlimited data. This inconsistency theorem leads to an analytical approximation of the bias, valid in surprisingly small sample regimes and more accurate than the usual formula of Miller and Madow over a large region of parameter space. The two most practical implications of these results are negative: (1) information estimates in a certain data regime are likely contaminated by bias, even if bias-corrected estimators are used, and (2) confidence intervals calculated by standard techniques drastically underestimate the error of the most common estimation methods. Finally, we note a very useful connection between the bias of entropy estimators and a certain polynomial approximation problem. By casting bias calculation problems in this approximation theory framework, we obtain the best possible generalization of known asymptotic bias results. More interesting, this framework leads to an estimator with some nice properties: the estimator comes equipped with rigorous bounds on the maximum error over all possible underlying probability distributions, and this maximum error turns out to be surprisingly small. We demonstrate the application of this new estimator on both real and simulated data.

We analyse the convergence properties of three spike-triggered data analysis techniques. Our results are obtained in the setting of a probabilistic linear–nonlinear (LN) cascade neural encoding model; this model has recently become popular in the study of the neural coding of natural signals. We start by giving exact rate-of-convergence results for the common spike-triggered average technique. Next, we analyse a spike-triggered covariance method, variants of which have been recently exploited successfully by Bialek, Simoncelli and colleagues. Unfortunately, the conditions that guarantee that these two estimators will converge to the correct parameters are typically not satisfied by natural signal data. Therefore, we introduce an estimator for the LN model parameters which is designed to converge under general conditions to the correct model. We derive the rate of convergence of this estimator, provide an algorithm for its computation and demonstrate its application to simulated data as well as physiological data from the primary motor cortex of awake behaving monkeys. We also give lower bounds on the convergence rate of any possible LN estimator. Our results should prove useful in the study of the neural coding of high-dimensional natural signals.1http://www.cns.nycu/edu/∼liam2A brief summary of some of the results presented here is to appear in the NIPS02 Conference Proceedings (Paninski 2002).

Convergence properties of three spike-triggered analysis techniques

Fairhall et al. (2001) recently reported on variance adaptation processes in cells of the fly visual system, and qualitatively similar effects have been observed in various vertebrate preparations. To better understand the contributions of somatic mechanisms to this kind of adaptation, we recorded intracellularly from neurons of rat sensorimotor cortex while stimulating with a noise current whose standard deviation was varied parametrically. We observed systematic variance-dependent adaptation (where adaptation is defined as a scaling of a nonlinear transfer function), similar in many respects to the effects observed The fact that similar adaptive phenomena could be observed in such different preparations led us to investigate a simple model of stochastic stimulus-driven neural activity. The simplest such model, the leaky integrate-and-fire (LIF) cell driven by noise current, permits us to analytically compute many quantities relevant to our observations on adaptation; we show that the LIF model displays "adaptive" behavior which is quite similar to the effects observed and .

Brain-machine interface: Instant neural control of a movement signal

We analyse the convergence properties of three spike-triggered data analysis techniques. Our results are obtained in the setting of a probabilistic linear-nonlinear (LN) cascade neural encoding model; this model has recently become popular in the study of the neural coding of natural signals. We start by giving exact rate-of-convergence results for the common spike-triggered average technique. Next, we analyse a spike-triggered covariance method, variants of which have been recently exploited successfully by Bialek, Simoncelli and colleagues. Unfortunately, the conditions that guarantee that these two estimators will converge to the correct parameters are typically not satisfied by natural signal data. Therefore, we introduce an estimator for the LN model parameters which is designed to converge under general conditions to the correct model. We derive the rate of convergence of this estimator, provide an algorithm for its computation and demonstrate its application to simulated data as well as physiological data from the primary motor cortex of awake behaving monkeys. We also give lower bounds on the convergence rate of any possible LN estimator. Our results should prove useful in the study of the neural coding of high-dimensional natural signals.

Convergence Properties of Some Spike-Triggered Analysis Techniques

Although neuronal synchronization has been shown to exist in primary motor cortex (MI), very little is known about its possible contribution to coding of movement. By using cross-correlation techniques from multi-neuron recordings in MI, we observed that activity of neurons commonly synchronized around the time of movement initiation. For some cell pairs, synchrony varied with direction in a manner not readily predicted by the firing of either neuron. Information theoretic analysis demonstrated quantitatively that synchrony provides information about movement direction beyond that expected by simple rate changes. Thus, MI neurons are not simply independent encoders of movement parameters but rather engage in mutual interactions that could potentially provide an additional coding dimension in cortex.

Information about movement direction obtained from synchronous activity of motor cortical neurons.

How do temporal stimulus correlations influence the performance of population codes

A generalized linear model for estimating receptive fields from midbrain responses to natural sounds

Given recent experimental results suggesting that neural circuits may evolve through multiple firing states, we develop a framework for estimating state-dependent neural response properties from spike-train data. We modify the traditional hidden Markov model (HMM) framework to incorporate stimulus-driven, non-Poisson point process observations. For maximal flexibility, we allow external, time-varying stimuli and the neurons’ own spike histories to drive both the spiking behavior in each state and the transitioning behavior between states. We employ an appropriately modified expectation-maximization algorithm to estimate the model parameters. The expectation step is solved by the standard forward-backward algorithm for HMMs. The maximization step reduces to a set of separable concave optimization problems if the model is restricted slightly. We first test our algorithm on simulated data and are able both to fully recover the parameters used to generate the data and to accurately recapitulate the sequence of hidden states. We then apply our algorithm to a recently published data set in which the observed neuronal ensembles displayed multi-state behavior and show that inclusion of spike-history information significantly improves the fit of the model. Additionally, we show that a simple reformulation of the state-space of the underlying Markov chain allows us to implement a hybrid half-multistate/half-histogram model which may be more appropriate for capturing the complexity of certain data sets than either a simple HMM or a simple peri-stimulus time histogram (PSTH) model alone.

Hidden Markov models for the stimulus-response relationships of multi-state neural systems

Methods for neural circuit inference from population calcium imaging data

A common-input model of a complete network of ganglion cells in the primate retina.

Decoding of stimulus velocity using a model of ganglion cell populations in primate retina.

Inferring functional connectivity in an ensemble of retinal ganglion cells sharing a common input

Towards inferring neural circuits from population calcium imaging

A decoder-based spike train metric for analyzing the neural code in the retina

Hidden Markov models for the complex stimulus-response relationships of multi-state neurons

Incentives tend to drive improvements in performance. But when incentives get too high, we can “choke under pressure” and underperform when it matters most. What neural processes might lead to choking under pressure? We studied Rhesus monkeys performing a challenging reaching task in which they underperform when an unusually large “jackpot” reward is at stake. We observed a collapse in neural information about upcoming movements for jackpot rewards: in the motor cortex, neural planning signals became less distinguishable for different reach directions when a jackpot reward was made available. We conclude that neural signals of reward and motor planning interact in the motor cortex in a manner that can explain why we choke under pressure. One-Sentence Summary In response to exceptionally large reward cues, animals can “choke under pressure”, and this corresponds to a collapse in the neural information about upcoming movements.

The most prominent role of motor cortex is generating patterns of neural activity that lead to movement, but it is also active when we simply imagine movements in the absence of actual motor output. Despite decades of behavioral and imaging studies, it is unknown how the specific activity patterns and temporal dynamics within motor cortex during covert motor imagery relate to those during motor execution. Here we recorded intracortical activity from the motor cortex of two people with residual wrist function following incomplete spinal cord injury as they performed both actual and imagined isometric wrist extensions. We found that we could decompose the population-level activity into orthogonal subspaces such that one set of components was similarly active during both action and imagery, and others were only active during a single task type—action or imagery. Although they inhabited orthogonal neural dimensions, the action-unique and imagery-unique subspaces contained a strikingly similar set of dynamical features. Our results suggest that during motor imagery, motor cortex maintains the same overall population dynamics as during execution by recreating the missing components related to motor output and/or feedback within a unique imagery-only subspace.

Motor cortex retains and reorients neural dynamics during motor imagery

Feedforward and feedback interactions between visual cortical areas use different population activity patterns

Dimensionality reduction of calcium-imaged neuronal population activity

Tracking momentary fluctuations in human attention with a cognitive brain-machine interface

How are we able to learn new behaviors without disrupting previously learned ones? To understand how the brain achieves this, we used a brain-computer interface (BCI) learning paradigm, which enables us to detect the presence of a memory of one behavior while performing another. We found that learning to use a new BCI map altered the neural activity that monkeys produced when they returned to using a familiar BCI map, in a way that was specific to the learning experience. That is, learning left a “memory trace.” This memory trace co-existed with proficient performance under the familiar map, primarily by altering dimensions of neural activity that did not impact behavior. Such a memory trace could provide the neural underpinning for the joint learning of multiple motor behaviors without interference.

Learning alters neural activity to simultaneously support memory and action

Disentangling the flow of signals between populations of neurons

Brain function relies on the coordination of activity across multiple, recurrently connected brain areas. For instance, sensory information encoded in early sensory areas is relayed to, and further processed by, higher cortical areas and then fed back. However, the way in which feedforward and feedback signaling interact with one another is incompletely understood. Here we investigate this question by leveraging simultaneous neuronal population recordings in early and midlevel visual areas (V1–V2 and V1–V4). Using a dimensionality reduction approach, we find that population interactions are feedforward-dominated shortly after stimulus onset and feedback-dominated during spontaneous activity. The population activity patterns most correlated across areas were distinct during feedforward- and feedback-dominated periods. These results suggest that feedforward and feedback signaling rely on separate “channels”, which allows feedback signals to not directly affect activity that is fed forward. How cortical areas interact via feedforward and feedback signaling remains unclear. Here, the authors recorded from V1 and V2/V4 in macaque visual cortex and found that feedforward and feedback interactions vary with stimulus drive and involve different neuronal population activity patterns.

Attention often requires maintaining a stable mental state over time while simultaneously improving perceptual sensitivity. These requirements place conflicting demands on neural populations, as sensitivity implies a robust response to perturbation by incoming stimuli, which is antithetical to stability. Functional specialization of cortical areas provides one potential mechanism to resolve this conflict. We reasoned that attention signals in executive control areas might be highly stable over time, reflecting maintenance of the cognitive state, thereby freeing up sensory areas to be more sensitive to sensory input (i.e., unstable), which would be reflected by more dynamic attention signals in those areas. To test these predictions, we simultaneously recorded neural populations in prefrontal cortex (PFC) and visual cortical area V4 in rhesus macaque monkeys performing an endogenous spatial selective attention task. Using a decoding approach, we found that the neural code for attention states in PFC was substantially more stable over time compared with the attention code in V4 on a moment-by-moment basis, in line with our guiding thesis. Moreover, attention signals in PFC predicted the future attention state of V4 better than vice versa, consistent with a top-down role for PFC in attention. These results suggest a functional specialization of attention mechanisms across cortical areas with a division of labor. PFC signals the cognitive state and maintains this state stably over time, whereas V4 responds to sensory input in a manner dynamically modulated by that cognitive state. SIGNIFICANCE STATEMENT Attention requires maintaining a stable mental state while simultaneously improving perceptual sensitivity. We hypothesized that these two demands (stability and sensitivity) are distributed between prefrontal and visual cortical areas, respectively. Specifically, we predicted attention signals in visual cortex would be less stable than in prefrontal cortex, and furthermore prefrontal cortical signals would predict attention signals in visual cortex in line with the hypothesized role of prefrontal cortex in top-down executive control. Our results are consistent with suggestions deriving from previous work using separate recordings in the two brain areas in different animals performing different tasks and represent the first direct evidence in support of this hypothesis with simultaneous multiarea recordings within individual animals.

A Stable Population Code for Attention in Prefrontal Cortex Leads a Dynamic Attention Code in Visual Cortex

Statistical methods for dissecting interactions between brain areas

Stabilization of a brain–computer interface via the alignment of low-dimensional spaces of neural activity

Principles of Corticocortical Communication: Proposed Schemes and Design Considerations

An animal’s decision depends not only on incoming sensory evidence but also on its fluctuating internal state. This internal state is a product of cognitive factors, such as fatigue, motivation, and arousal, but it is unclear how these factors influence the neural processes that encode the sensory stimulus and form a decision. We discovered that, over the timescale of tens of minutes during a perceptual decision-making task, animals slowly shifted their likelihood of reporting stimulus changes. They did this unprompted by task conditions. We recorded neural population activity from visual area V4 as well as prefrontal cortex, and found that the activity of both areas slowly drifted together with the behavioral fluctuations. We reasoned that such slow fluctuations in behavior could either be due to slow changes in how the sensory stimulus is processed or due to a process that acts independently of sensory processing. By analyzing the recorded activity in conjunction with models of perceptual decision-making, we found evidence for the slow drift in neural activity acting as an impulsivity signal, overriding sensory evidence to dictate the final decision. Overall, this work uncovers an internal state embedded in the population activity across multiple brain areas, hidden from typical trial-averaged analyses and revealed only when considering the passage of time within each experimental session. Knowledge of this cognitive factor was critical in elucidating how sensory signals and the internal state together contribute to the decision-making process.

Slow Drift of Neural Activity as a Signature of Impulsivity in Macaque Visual and Prefrontal Cortex

Two commonly used approaches to study interactions among neurons are spike count correlation, which describes pairs of neurons, and dimensionality reduction, applied to a population of neurons. While both approaches have been used to study trial-to-trial correlated neuronal variability, they are often used in isolation and have not been directly related. We first established concrete mathematical and empirical relationships between pairwise correlation and metrics of population-wide covariability based on dimensionality reduction. Applying these insights to macaque V4 population recordings, we found that the previously reported decrease in mean pairwise correlation associated with attention stemmed from three distinct changes in population-wide covariability. Overall, our work builds the intuition and formalism to bridge between pairwise correlation and population-wide covariability and presents a cautionary tale about the inferences one can make about population activity by using a single statistic, whether it be mean pairwise correlation or dimensionality.

Significance Consider a skill you would like to learn, like playing the piano. How do you progress from “Chopsticks” to Chopin? As you learn to do something new with your hands, does the brain also do something new? We found that monkeys learned new skilled behavior by generating new neural activity patterns. We used a brain–computer interface (BCI), which directly links neural activity to movement of a computer cursor, to encourage animals to generate new neural activity patterns. Over several days, the animals began to exhibit new patterns of neural activity that enabled them to control the BCI cursor. This suggests that learning to play the piano and other skills might also involve the generation of new neural activity patterns. Learning has been associated with changes in the brain at every level of organization. However, it remains difficult to establish a causal link between specific changes in the brain and new behavioral abilities. We establish that new neural activity patterns emerge with learning. We demonstrate that these new neural activity patterns cause the new behavior. Thus, the formation of new patterns of neural population activity can underlie the learning of new skills.

Cortical Areas Interact thr ough a Communication Subspace Highlights

Mathematical and statistical models have played important roles in neuroscience, especially by describing the electrical activity of neurons recorded individually, or collectively across large networks. As the field moves forward rapidly, new challenges are emerging. For maximal effectiveness, those working to advance computational neuroscience will need to appreciate and exploit the complementary strengths of mechanistic theory and the statistical paradigm.

of Statistics and Its Application Computational Neuroscience : Mathematical and Statistical Perspectives

Distinct population codes for attention in the absence and presence of visual stimulation

Millions of neurons drive the activity of hundreds of muscles, meaning many different neural population activity patterns could generate the same movement. Studies have suggested that these redundant (i.e. behaviorally equivalent) activity patterns may be beneficial for neural computation. However, it is unknown what constraints may limit the selection of different redundant activity patterns. We leveraged a brain-computer interface, allowing us to define precisely which neural activity patterns were redundant. Rhesus monkeys made cursor movements by modulating neural activity in primary motor cortex. We attempted to predict the observed distribution of redundant neural activity. Principles inspired by work on muscular redundancy did not accurately predict these distributions. Surprisingly, the distributions of redundant neural activity and task-relevant activity were coupled, which enabled accurate predictions of the distributions of redundant activity. This suggests limits on the extent to which redundancy may be exploited by the brain for computation.

Bridging large-scale neuronal recordings and large-scale network models using dimensionality reduction

Computational Neuroscience: Mathematical and Statistical Perspectives.

Adaptive sampling methods in neuroscience have primarily focused on maximizing the firing rate of a single recorded neuron. When recording from two or more neurons, it is usually not possible to find a single stimulus that maximizes the firing rates of all neurons. This motivates an objective function that takes into account the recorded population of neurons together. We propose ``Adept,'' an adaptive sampling method that can optimize population objective functions. In simulated experiments, we first confirmed that population objective functions elicited more varied stimulus responses than those of single-neuron objective functions. Then, we tested Adept in a closed-loop electrophysiological experiment in which population activity was recorded from macaque V4, a cortical area known for mid-level visual processing. Adept uses the outputs of a deep convolutional neural network model as feature embeddings to predict neural responses. Adept elicited mean stimulus responses 20\% larger than those for randomly-chosen natural images, as well as a larger scatter of stimulus responses. Such adaptive sampling methods can enable new scientific discoveries when recording from a population of neurons with heterogeneous response properties.

Adaptive stimulus selection methods in neuroscience have primarily focused on maximizing the firing rate of a single recorded neuron. When recording from a population of neurons, it is usually not possible to find a single stimulus that maximizes the firing rates of all neurons. This motivates optimizing an objective function that takes into account the responses of all recorded neurons together. We propose “Adept,” an adaptive stimulus selection method that can optimize population objective functions. In simulations, we first confirmed that population objective functions elicited more diverse stimulus responses than single-neuron objective functions. Then, we tested Adept in a closed-loop electrophysiological experiment in which population activity was recorded from macaque V4, a cortical area known for mid-level visual processing. To predict neural responses, we used the outputs of a deep convolutional neural network model as feature embeddings. Images chosen by Adept elicited mean neural responses that were 20% larger than those for randomly-chosen natural images, and also evoked a larger diversity of neural responses. Such adaptive stimulus selection methods can facilitate experiments that involve neurons far from the sensory periphery, for which it is often unclear which stimuli to present.

Adaptive stimulus selection for optimizing neural population responses

A Path to Understanding How Motor Cortex Influences Muscle Activity

We propose a dimensionality reduction method to identify linear projections that capture interactions between two or more sets of variables. The method, distance covariance analysis (DCA), can detect both linear and nonlinear relationships, and can take dependent variables into account. On previous testbeds and a new testbed that systematically assesses the ability to detect both linear and nonlinear interactions, DCA performs better than or comparable to existing methods, while being one of the fastest methods. To showcase the versatility of DCA, we also applied it to three different neurophysiological datasets.

In many experiments, neuroscientists tightly control behavior, record many trials, and obtain trial-averaged firing rates from hundreds of neurons in circuits containing billions of behaviorally relevant neurons. Di-mensionality reduction methods reveal a striking simplicity underlying such multi-neuronal data: they can be reduced to a low-dimensional space, and the resulting neural trajectories in this space yield a remarkably insightful dynamical portrait of circuit computation. This simplicity raises profound and timely conceptual questions. What are its origins and its implications for the complexity of neural dynamics? How would the situation change if we recorded more neurons? When, if at all, can we trust dynamical portraits obtained from measuring an infinitesimal fraction of task relevant neurons? We present a theory that answers these questions, and test it using physiological recordings from reaching monkeys. This theory reveals conceptual insights into how task complexity governs both neural dimensionality and accurate recovery of dynamic portraits, thereby providing quantitative guidelines for future large-scale experimental design.

A theory of multineuronal dimensionality, dynamics and measurement

Many studies use population analysis approaches, such as dimensionality reduction, to characterize the activity of large groups of neurons. To date, these methods have treated each neuron equally, without taking into account whether neurons are excitatory or inhibitory. We studied population activity structure as a function of neuron type by applying factor analysis to spontaneous activity from spiking networks with balanced excitation and inhibition. Throughout the study, we characterized population activity structure by measuring its dimensionality and the percentage of overall activity variance that is shared among neurons. First, by sampling only excitatory or only inhibitory neurons, we found that the activity structures of these two populations in balanced networks are measurably different. We also found that the population activity structure is dependent on the ratio of excitatory to inhibitory neurons sampled. Finally we classified neurons from extracellular recordings in the primary visual cortex of anesthetized macaques as putative excitatory or inhibitory using waveform classification, and found similarities with the neuron type-specific population activity structure of a balanced network with excitatory clustering. These results imply that knowledge of neuron type is important, and allows for stronger statistical tests, when interpreting population activity structure.

Population activity structure of excitatory and inhibitory neurons

Recent studies have applied dimensionality reduction methods to understand how the multi-dimensional structure of neural population activity gives rise to brain function. It is unclear, however, how the results obtained from dimensionality reduction generalize to recordings with larger numbers of neurons and trials or how these results relate to the underlying network structure. We address these questions by applying factor analysis to recordings in the visual cortex of non-human primates and to spiking network models that self-generate irregular activity through a balance of excitation and inhibition. We compared the scaling trends of two key outputs of dimensionality reduction—shared dimensionality and percent shared variance—with neuron and trial count. We found that the scaling properties of networks with non-clustered and clustered connectivity differed, and that the in vivo recordings were more consistent with the clustered network. Furthermore, recordings from tens of neurons were sufficient to identify the dominant modes of shared variability that generalize to larger portions of the network. These findings can help guide the interpretation of dimensionality reduction outputs in regimes of limited neuron and trial sampling and help relate these outputs to the underlying network structure.

Scaling Properties of Dimensionality Reduction for Neural Populations and Network Models

Brain–computer interfaces for dissecting cognitive processes underlying sensorimotor control

Dimensionality reduction has been applied in various brain areas to study the activity of populations of neurons. To interpret the outputs of dimensionality reduction, it is important to first understand its outputs for brain areas for which the relationship between the stimulus and neural response is well characterized. Here, we applied principal component analysis (PCA) to trial-averaged neural responses in macaque primary visual cortex (V1) to study two fundamental, population-level questions. First, we characterized how neural complexity relates to stimulus complexity, where complexity is measured using relative comparisons of dimensionality. Second, we assessed the extent to which responses to different stimuli occupy similar dimensions of the population activity space using a novel statistical method. For comparison, we performed the same dimensionality reduction analyses on the activity of a recently-proposed V1 receptive field model and a deep convolutional neural network. Our results show that the dimensionality of the population response changes systematically with alterations in the properties and complexity of the visual stimulus.

Stimulus-Driven Population Activity Patterns in Macaque Primary Visual Cortex

firing patterns, e.g. by producing stochastic drift in grid attractor networks. Recently, Hardcastle et al. (Neuron, 2015) proposed that border cells may provide one mechanism for correcting such drift. We construct a model in which experience-dependent Hebbian plasticity during exploration allows border cells to self-organize their responses, while also learning connectivity to grid cells which maintain their activity through an attractor network. We show that border cells in this learned network effectively correct for grid drift despite stochasticity of border cell firing. This error-correction is robust with respect to environmental shape including squares and circles. Furthermore, it survives insertion of barriers within an enclosure (consistent with Solstad et al., 2008) even though a given border cell can fire ambiguously at multiple boundaries with the same allocentric orientation (Solstad et al, 2008; Lever et al, 2009). In our mechanism, the learned border-grid connectivity pattern compensates for such ambiguities. Upon deformation of an environment, e.g., by shrinking or changing shape, the error correction initially fails and grid drift resumes. However, in our model the border-grid connectivity adapts to boundaries of the deformed environment, restoring error correction after a characteristic timescale. Our results demonstrate a class of self-organized mechanisms that achieve robust path integration. These mechanisms predict that: (a) disrupting synaptic plasticity between grid cells and border cells will cause grid patterns to drift in a random walk, and (b) deforming an environment will initially lead to grid drift, which is subsequently stabilized.

Time-warped PCA : simultaneous alignment and dimensionality reduction of neural data

Noisy, high-dimensional time series observations can often be described by a set of low-dimensional latent variables. Commonly used methods to extract these latent variables typically assume instantaneous relationships between the latent and observed variables. In many physical systems, changes in the latent variables manifest as changes in the observed variables after time delays. Techniques that do not account for these delays can recover a larger number of latent variables than are present in the system, thereby making the latent representation more difficult to interpret. In this work, we introduce a novel probabilistic technique, time-delay gaussian-process factor analysis (TD-GPFA), that performs dimensionality reduction in the presence of a different time delay between each pair of latent and observed variables. We demonstrate how using a gaussian process to model the evolution of each latent variable allows us to tractably learn these delays over a continuous domain. Additionally, we show how TD-GPFA combines temporal smoothing and dimensionality reduction into a common probabilistic framework. We present an expectation/conditional maximization either (ECME) algorithm to learn the model parameters. Our simulations demonstrate that when time delays are present, TD-GPFA is able to correctly identify these delays and recover the latent space. We then applied TD-GPFA to the activity of tens of neurons recorded simultaneously in the macaque motor cortex during a reaching task. TD-GPFA is able to better describe the neural activity using a more parsimonious latent space than GPFA, a method that has been used to interpret motor cortex data but does not account for time delays. More broadly, TD-GPFA can help to unravel the mechanisms underlying high-dimensional time series data by taking into account physical delays in the system.

Extracting Low-Dimensional Latent Structure from Time Series in the Presence of Delays

To successfully guide limb movements, the brain takes in sensory information about the limb, internally tracks the state of the limb, and produces appropriate motor commands. It is widely believed that this process uses an internal model, which describes our prior beliefs about how the limb responds to motor commands. Here, we leveraged a brain-machine interface (BMI) paradigm in rhesus monkeys and novel statistical analyses of neural population activity to gain insight into moment-by-moment internal model computations. We discovered that a mismatch between subjects’ internal models and the actual BMI explains roughly 65% of movement errors, as well as long-standing deficiencies in BMI speed control. We then used the internal models to characterize how the neural population activity changes during BMI learning. More broadly, this work provides an approach for interpreting neural population activity in the context of how prior beliefs guide the transformation of sensory input to motor output. DOI: http://dx.doi.org/10.7554/eLife.10015.001

Internal models for interpreting neural population activity during sensorimotor control

First, note that by assumption rank{A} > 0. Let Ω1 = ρ1 × ρ1 and Ω2 = ρ2 × ρ2 be the two index sets in the theorem. By assumption we have ρ1 × ρ1 ∪ ρ2 × ρ2 = Ω and Ω 6= [n]× [n]. If A1 is not met, then ρ1 ∪ ρ2 6= [n], and from lemma 6 we can conclude recovery of A is impossible. If ρ1 ∪ ρ2 = [n], but A2 is not met then ι2 = |ρ1 ∩ ρ2| < r so it must be that rank{A(ι2, ι2)} < r. Further, by assumption rank{A(ρ1, ρ1)} = rank{A(ρ2 \ ι2, ρ2 \ ι2)} = r. By lemma 6, we can again conclude that matrix recovery is impossible. Finally, if A3 is not met, then again rank{A(ι2, ι2)} < r and we can conclude matrix recovery is impossible.

Appendix for Deterministic Symmetric Positive Semidefinite Matrix Completion

Author response: Internal models for interpreting neural population activity during sensorimotor control

the Upcoming Reach'' in Premotor and Motor Cortex Reflects the Speed of . Focus on ''Preparatory Activity Preparing for Speed

Developments in neural recording technology are rapidly enabling the recording of populations of neurons in multiple brain areas simultaneously, as well as the identification of the types of neurons being recorded (e.g., excitatory vs. inhibitory). There is a growing need for statistical methods to study the interaction among multiple, labeled populations of neurons. Rather than attempting to identify direct interactions between neurons (where the number of interactions grows with the number of neurons squared), we propose to extract a smaller number of latent variables from each population and study how these latent variables interact. Specifically, we propose extensions to probabilistic canonical correlation analysis (pCCA) to capture the temporal structure of the latent variables, as well as to distinguish within-population dynamics from across-population interactions (termed Group Latent Auto-Regressive Analysis, gLARA). We then applied these methods to populations of neurons recorded simultaneously in visual areas V1 and V2, and found that gLARA provides a better description of the recordings than pCCA. This work provides a foundation for studying how multiple populations of neurons interact and how this interaction supports brain function.

Extracting Latent Structure From Multiple Interacting Neural Populations

implications for brain-machine interface control Motor cortical control of movement speed with

Objective. Intracortical brain–computer interface (BCI) decoders are typically retrained daily to maintain stable performance. Self-recalibrating decoders aim to remove the burden this may present in the clinic by training themselves autonomously during normal use but have only been developed for continuous control. Here we address the problem for discrete decoding (classifiers). Approach. We recorded threshold crossings from 96-electrode arrays implanted in the motor cortex of two rhesus macaques performing center-out reaches in 7 directions over 41 and 36 separate days spanning 48 and 58 days in total for offline analysis. Main results. We show that for the purposes of developing a self-recalibrating classifier, tuning parameters can be considered as fixed within days and that parameters on the same electrode move up and down together between days. Further, drift is constrained across time, which is reflected in the performance of a standard classifier which does not progressively worsen if it is not retrained daily, though overall performance is reduced by more than 10% compared to a daily retrained classifier. Two novel self-recalibrating classifiers produce a ∼15%?> increase in classification accuracy over that achieved by the non-retrained classifier to nearly recover the performance of the daily retrained classifier. Significance. We believe that the development of classifiers that require no daily retraining will accelerate the clinical translation of BCI systems. Future work should test these results in a closed-loop setting.

Self-recalibrating classifiers for intracortical brain–computer interfaces

Motor cortex plays a substantial role in driving movement, yet the details underlying this control remain unresolved. We analyzed the extent to which movement-related information could be extracted from single-trial motor cortical activity recorded while monkeys performed center-out reaching. Using information theoretic techniques, we found that single units carry relatively little speed-related information compared with direction-related information. This result is not mitigated at the population level: simultaneously recorded population activity predicted speed with significantly lower accuracy relative to direction predictions. Furthermore, a unit-dropping analysis revealed that speed accuracy would likely remain lower than direction accuracy, even given larger populations. These results suggest that the instantaneous details of single-trial movement speed are difficult to extract using commonly assumed coding schemes. This apparent paucity of speed information takes particular importance in the context of brain-machine interfaces (BMIs), which rely on extracting kinematic information from motor cortex. Previous studies have highlighted subjects' difficulties in holding a BMI cursor stable at targets. These studies, along with our finding of relatively little speed information in motor cortex, inspired a speed-dampening Kalman filter (SDKF) that automatically slows the cursor upon detecting changes in decoded movement direction. Effectively, SDKF enhances speed control by using prevalent directional signals, rather than requiring speed to be directly decoded from neural activity. SDKF improved success rates by a factor of 1.7 relative to a standard Kalman filter in a closed-loop BMI task requiring stable stops at targets. BMI systems enabling stable stops will be more effective and user-friendly when translated into clinical applications.

Motor cortical control of movement speed with implications for brain-machine interface control.

We consider the problem of recovering a symmetric, positive semidefinite (SPSD) matrix from a subset of its entries, possibly corrupted by noise. In contrast to previous matrix recovery work, we drop the assumption of a random sampling of entries in favor of a deterministic sampling of principal submatrices of the matrix. We develop a set of sufficient conditions for the recovery of a SPSD matrix from a set of its principal submatrices, present necessity results based on this set of conditions and develop an algorithm that can exactly recover a matrix when these conditions are met. The proposed algorithm is naturally generalized to the problem of noisy matrix recovery, and we provide a worst-case bound on reconstruction error for this scenario. Finally, we demonstrate the algorithm's utility on noiseless and noisy simulated datasets.

Objective. Analyzing and interpreting the activity of a heterogeneous population of neurons can be challenging, especially as the number of neurons, experimental trials, and experimental conditions increases. One approach is to extract a set of latent variables that succinctly captures the prominent co-fluctuation patterns across the neural population. A key problem is that the number of latent variables needed to adequately describe the population activity is often greater than 3, thereby preventing direct visualization of the latent space. By visualizing a small number of 2-d projections of the latent space or each latent variable individually, it is easy to miss salient features of the population activity. Approach. To address this limitation, we developed a Matlab graphical user interface (called DataHigh) that allows the user to quickly and smoothly navigate through a continuum of different 2-d projections of the latent space. We also implemented a suite of additional visualization tools (including playing out population activity timecourses as a movie and displaying summary statistics, such as covariance ellipses and average timecourses) and an optional tool for performing dimensionality reduction. Main results. To demonstrate the utility and versatility of DataHigh, we used it to analyze single-trial spike count and single-trial timecourse population activity recorded using a multi-electrode array, as well as trial-averaged population activity recorded using single electrodes. Significance. DataHigh was developed to fulfil a need for visualization in exploratory neural data analysis, which can provide intuition that is critical for building scientific hypotheses and models of population activity.

DataHigh: graphical user interface for visualizing and interacting with high-dimensional neural activity

Much work in optimal control and inverse control has assumed that the controller has perfect knowledge of plant dynamics. However, if the controller is a human or animal subject, the subject's internal dynamics model may differ from the true plant dynamics. Here, we consider the problem of learning the subject's internal model from demonstrations of control and knowledge of task goals. Due to sensory feedback delay, the subject uses an internal model to generate an internal prediction of the current plant state, which may differ from the actual plant state. We develop a probabilistic framework and exact EM algorithm to jointly estimate the internal model, internal state trajectories, and feedback delay. We applied this framework to demonstrations by a nonhuman primate of brain-machine interface (BMI) control. We discovered that the subject's internal model deviated from the true BMI plant dynamics and provided significantly better explanation of the recorded neural control signals than did the true plant dynamics.

A High-Performance Neural Prosthesis Enabled by Control Algorithm Design

The activity of tens to hundreds of neurons can be succinctly summarized by a smaller number of latent variables extracted using dimensionality reduction methods. These latent variables define a reduced-dimensional space in which we can study how population activity varies over time, across trials, and across experimental conditions. Ideally, we would like to visualize the population activity directly in the reduced-dimensional space, whose optimal dimensionality (as determined from the data) is typically greater than 3. However, direct plotting can only provide a 2D or 3D view. To address this limitation, we developed a Matlab graphical user interface (GUI) that allows the user to quickly navigate through a continuum of different 2D projections of the reduced-dimensional space. To demonstrate the utility and versatility of this GUI, we applied it to visualize population activity recorded in premotor and motor cortices during reaching tasks. Examples include single-trial population activity recorded using a multi-electrode array, as well as trial-averaged population activity recorded sequentially using single electrodes. Because any single 2D projection may provide a misleading impression of the data, being able to see a large number of 2D projections is critical for intuition-and hypothesis-building during exploratory data analysis. The GUI includes a suite of additional interactive tools, including playing out population activity timecourses as a movie and displaying summary statistics, such as covariance ellipses and average timecourses. The use of visualization tools like the GUI developed here, in tandem with dimensionality reduction methods, has the potential to further our understanding of neural population activity.

DataHigh: Graphical user interface for visualizing and interacting with high-dimensional neural activity

We present a novel brain machine interface (BMI) control algorithm, the recalibrated feedback intention-trained Kalman filter (ReFIT-KF). The design of ReFIT-KF is motivated from a feedback control perspective applied to existing BMI control algorithms. The result is two design innovations that alter the modeling assumptions made by these algorithms and the methods by which these algorithms are trained. In online neural control experiments recording from a 96-electrode array implanted in M1 of a macaque monkey, the ReFIT-KF control algorithm demonstrates large performance improvements over the current state of the art velocity Kalman filter, reducing target acquisition time by a factor of two, while maintaining a 500 ms hold period, thereby increasing the clinical viability of BMI systems.

A brain machine interface control algorithm designed from a feedback control perspective

Internal models have been proposed to explain the brain’s ability to compensate for sensory feedback delays by predicting the sensory consequences of movement commands. Single-neuron studies in the oculomotor and vestibulo-ocular systems have provided evidence of internal models, as have behavioral studies in the skeletomotor system. Here, we present evidence of internal models from simultaneously recorded population activity underlying closed-loop brain-computer interface (BCI) control. We studied cursor-based BCI control by a nonhuman primate implanted with a multi-electrode array in motor cortex. Using a novel BCI task, we measured the visual feedback processing delay to be about 125 ms. By examining the task-based appropriateness of the population activity at different time lags, we found evidence that the subject compensates for the feedback delay by predicting upcoming cursor positions, suggesting the use of an internal forward model. Lastly, we examined the time course of internal model adaptation after altering the mapping between population activity and cursor movements. This study suggests that closedloop BCI experiments combined with novel statistical analyses can provide insight into the neural substrates of feedback motor control and motor learning.

Internal Models in Closed-loop Brain-computer Interfaces: Evidence and Implications

Internal models have been proposed to explain the brain's ability to compensate for sensory feedback delays by predicting the sensory consequences of movement commands. Single-neuron studies in the oculomotor and vestibulo-ocular systems have provided evidence of internal models, as have behavioral studies in the skeletomotor system. Here, we present evidence of internal models from simultaneously recorded population activity underlying closed-loop brain-computer interface (BCI) control. We studied cursor-based BCI control by a nonhuman primate implanted with a multi-electrode array in motor cortex. Using a novel BCI task, we measured the visual feedback processing delay to be about 130 milliseconds. By examining the task-based appropriateness of the population activity at different time lags, we found evidence that the subject compensates for the feedback delay by predicting upcoming cursor positions, suggesting the use of an internal forward model. Lastly, we examined the time course of internal model adaptation after altering the mapping between population activity and cursor movements. This study suggests that closed-loop BCI experiments combined with novel statistical analyses can provide insight into the neural substrates of feedback motor control and motor learning.

Simultaneous recordings of many neurons embedded within a recurrently-connected cortical network may provide concurrent views into the dynamical processes of that network, and thus its computational function. In principle, these dynamics might be identified by purely unsupervised, statistical means. Here, we show that a Hidden Switching Linear Dynamical Systems (HSLDS) model— in which multiple linear dynamical laws approximate a nonlinear and potentially non-stationary dynamical process—is able to distinguish different dynamical regimes within single-trial motor cortical activity associated with the preparation and initiation of hand movements. The regimes are identified without reference to behavioural or experimental epochs, but nonetheless transitions between them correlate strongly with external events whose timing may vary from trial to trial. The HSLDS model also performs better than recent comparable models in predicting the firing rate of an isolated neuron based on the firing rates of others, suggesting that it captures more of the "shared variance" of the data. Thus, the method is able to trace the dynamical processes underlying the coordinated evolution of network activity in a way that appears to reflect its computational role.

Dynamical segmentation of single trials from population neural data

[PDF] [Full Text] [Abstract] , April , 2010; 103 (4): 2124-2138. J Neurophysiol Joo-Hyun Song and Robert M. McPeek Selection and Movement Production Roles of Narrowand Broad-Spiking Dorsal Premotor Area Neurons in Reach Target [PDF] [Full Text] [Abstract] , May 18, 2010; 10 (5): . J Vis Fabrice R. Sarlegna and Jean Blouin by amplitude control Visual guidance of arm reaching: Online adjustments of movement direction are impaired [PDF] [Full Text] [Abstract] , August , 2010; 104 (2): 799-810. J Neurophysiol Stephen I. Ryu and Krishna V. Shenoy Matthew T. Kaufman, Mark M. Churchland, Gopal Santhanam, Byron M. Yu, Afsheen Afshar, Roles of Monkey Premotor Neuron Classes in Movement Preparation and Execution [PDF] [Full Text] [Abstract] , January , 2011; 105 (1): 454-473. J Neurophysiol Scheidt Xiaolin Liu, Kristine M. Mosier, Ferdinando A. Mussa-Ivaldi, Maura Casadio and Robert A. Scaling of a Newly Learned Sensorimotor Transformation Reorganization of Finger Coordination Patterns During Adaptation to Rotation and [PDF] [Full Text] [Abstract] , January , 2011; 105 (1): 45-59. J Neurophysiol Wilsaan M. Joiner, Obafunso Ajayi, Gary C. Sing and Maurice A. Smith Anisotropic, Gain-Encoding Primitives for Motor Adaptation Linear Hypergeneralization of Learned Dynamics Across Movement Speeds Reveals

Memorized-Delay Reaching Task With Direction and Amplitude During a Covariation of Primate Dorsal Premotor Cell Activity

Neural prostheses, or brain-computer interfaces (BCIs), have the potential to substantially increase quality of life for people suffering from motor disorders, including paralysis and amputation. These systems translate recorded neural signals into control signals that guide a paralyzed arm, artificial limb, or computer cursor. Although current laboratory demonstrations provide a compelling proof-ofconcept, the field must continue to increase performance to achieve clinical viability. Many BCIs use activity from motor and/or premotor cortex to achieve continuous control. These BCIs can be viewed from a feedback control perspective, as the motor field has done for the native limb: the brain is the controller of a new plant, defined by the BCI. This perspective leads us to two advances that result in significant qualitative and quantitative performance improvements. We tested these advances in closed loop with one rhesus macaque trained in a virtual 3D workspace. On each trial he used a cursor, controlled by the native contralateral limb or a BCI, to acquire a target on a 2D plane within an allotted time period. Neural data were recorded from a 96-electrode array (Blackrock) implanted spanning PMd and M1. Our designs are informed by a feedback model, which assumes the user develops a volitional control signal to achieve a goal given the current state of the world. This signal and task-unconstrained signals (such as sensory feedback, attention) give rise to neural firing, which we record. Finally, the decoding algorithm estimates desired cursor movements from the neural firing, and updates the workspace. By applying the assumptions of this simple feedback model, we augment a basic position/velocity Kalman filter. We consider the position/velocity Kalman filter to represent "baseline" as it meshes with the performance of and is algorithmically similar to methods common in the literature (e.g., Kim et al., 2008). All experiments used spike counts generated by a threshold detector without spike sorting. Such a system has clinical appeal, particularly for arrays with potentially decreased SNR (these experiments were 22-24 months post implantation). Design iterations were tested within the same experimental session using a blocked "ABA" design. Through this design process, we made two advances that substantially improve performance. First, using a standard Kalman filter, we fit neural data to a guess of the desired volitional control signal, instead of observed or instructed kinematics. Second, we developed a modified velocity-only Kalman filter, whose observation model incorporates cursor position as feedback. The new BCI appears more controllable and produces straighter reaches and crisper stops. Compared to the standard Kalman BCI, mean time to target is reduced by nearly a factor of two. This system can run freely for hundreds to thousands of trials, making point-toAdditional Materials

Stimulus onset quenches neural variability: a widespread cortical phenomenon

Neural prostheses, which are also termed brain–machine and brain–computer interfaces, offer the potential to substantially increase the quality of life for people suffering from motor disorders, including paralysis and amputation. Such devices translate electrical neural activity from the brain into control signals for guiding paralyzed upper limbs, prosthetic arms, and computer cursors. Several research groups have now demonstrated that monkeys (e.g., Serruya et al., 2002; Taylor et al., 2002; Carmena et al., 2003; Musallam et al., 2004; Santhanam et al., 2006; Mulliken et al., 2008; Velliste et al., 2008) and humans (e.g., Kennedy et al., 2000a; Leuthardt et al., 2004; Wolpaw and McFarland, 2004b; Hochberg et al., 2006; Kim et al., 2008; Schalk et al., 2008) can learn to move computer cursors and robotic arms to various target locations simply by activating neural populations that participate in natural arm movements. Figure 7.1 illustrates the basic operating principle of neural prosthetic systems. Neural activity from various arm movement–related brain regions (e.g., Wise et al., 1997) is electronically processed to create control signals for enacting the desired movement. Non invasive sensors can collect neural signals representing the average activity of many neurons. When invasive permanently implanted arrays of electrodes are employed, as depicted, it is possible to use waveform shape differences to discriminate individual neurons (e.g., Lewicki, 1998; Santhanam et al., 2004). After determining how each neuron responds before and during a movement, which is typically accomplished by correlating arm movements made during a behavioral task with

Dorsal premotor cortex (PMd) is known to be involved in the planning and execution of reaching movements. However, it is not understood how PMd plan activity-often present in the very same neurons that respond during movement-is prevented from itself producing movement. We investigated whether inhibitory interneurons might "gate" output from PMd, by maintaining high levels of inhibition during planning and reducing inhibition during execution. Recently developed methods permit distinguishing interneurons from pyramidal neurons using extracellular recordings. We extend these methods here for use with chronically implanted multi-electrode arrays. We then applied these methods to single- and multi-electrode recordings in PMd of two monkeys performing delayed-reach tasks. Responses of putative interneurons were not generally in agreement with the hypothesis that they act to gate output from the area: in particular it was not the case that interneurons tended to reduce their firing rates around the time of movement. In fact, interneurons increased their rates more than putative pyramidal neurons during both the planning and movement epochs. The two classes of neurons also differed in a number of other ways, including greater modulation across conditions for interneurons, and interneurons more frequently exhibiting increases in firing rate during movement planning and execution. These findings provide novel information about the greater responsiveness of putative PMd interneurons in motor planning and execution and suggest that we may need to consider new possibilities for how planning activity is structured such that it does not itself produce movement.

Roles of monkey premotor neuron classes in movement preparation and execution.

Preparation and Execution Roles of Monkey Premotor Neuron Classes in Movement

Neural prostheses aim to provide treatment options for individuals with nervous-system disease or injury. It is necessary, however, to increase the performance of such systems before they can be clinically viable for patients with motor dysfunction. One performance limitation is the presence of correlated trial-to-trial variability that can cause neural responses to wax and wane in concert as the subject is, for example, more attentive or more fatigued. If a system does not properly account for this variability, it may mistakenly interpret such variability as an entirely different intention by the subject. We report here the design and characterization of factor-analysis (FA)-based decoding algorithms that can contend with this confound. We characterize the decoders (classifiers) on experimental data where monkeys performed both a real reach task and a prosthetic cursor task while we recorded from 96 electrodes implanted in dorsal premotor cortex. The decoder attempts to infer the underlying factors that comodulate the neurons' responses and can use this information to substantially lower error rates (one of eight reach endpoint predictions) by <or=75% (e.g., approximately 20% total prediction error using traditional independent Poisson models reduced to approximately 5%). We also examine additional key aspects of these new algorithms: the effect of neural integration window length on performance, an extension of the algorithms to use Poisson statistics, and the effect of training set size on the decoding accuracy of test data. We found that FA-based methods are most effective for integration windows >150 ms, although still advantageous at shorter timescales, that Gaussian-based algorithms performed better than the analogous Poisson-based algorithms and that the FA algorithm is robust even with a limited amount of training data. We propose that FA-based methods are effective in modeling correlated trial-to-trial neural variability and can be used to substantially increase overall prosthetic system performance.

Factor-analysis methods for higher-performance neural prostheses.

Markov Models for Motor Cortical Prostheses Detecting Neural-State Transitions Using Hidden

We consider the problem of extracting smooth, low-dimensional neural trajectories that summarize the activity recorded simultaneously from many neurons on individual experimental trials. Beyond the benefit of visualizing the high-dimensional, noisy spiking activity in a compact form, such trajectories can offer insight into the dynamics of the neural circuitry underlying the recorded activity. Current methods for extracting neural trajectories involve a two-stage process: the spike trains are first smoothed over time, then a static dimensionality-reduction technique is applied. We first describe extensions of the two-stage methods that allow the degree of smoothing to be chosen in a principled way and that account for spiking variability, which may vary both across neurons and across time. We then present a novel method for extracting neural trajectories-Gaussian-process factor analysis (GPFA)-which unifies the smoothing and dimensionality-reduction operations in a common probabilistic framework. We applied these methods to the activity of 61 neurons recorded simultaneously in macaque premotor and motor cortices during reach planning and execution. By adopting a goodness-of-fit metric that measures how well the activity of each neuron can be predicted by all other recorded neurons, we found that the proposed extensions improved the predictive ability of the two-stage methods. The predictive ability was further improved by going to GPFA. From the extracted trajectories, we directly observed a convergence in neural state during motor planning, an effect that was shown indirectly by previous studies. We then show how such methods can be a powerful tool for relating the spiking activity across a neural population to the subject's behavior on a single-trial basis. Finally, to assess how well the proposed methods characterize neural population activity when the underlying time course is known, we performed simulations that revealed that GPFA performed tens of percent better than the best two-stage method.

Gaussian-process factor analysis for low-dimensional single-trial analysis of neural population activity

Neural prosthetic interfaces use neural activity related to the planning and perimovement epochs of arm reaching to afford brain-directed control of external devices. Previous research has primarily centered on accurately decoding movement intention from either plan or perimovement activity, but has assumed that temporal boundaries between these epochs are known to the decoding system. In this work, we develop a technique to automatically differentiate between baseline, plan, and perimovement epochs of neural activity. Specifically, we use a generative model of neural activity to capture how neural activity varies between these three epochs. Our approach is based on a hidden Markov model (HMM), in which the latent variable (state) corresponds to the epoch of neural activity, coupled with a state-dependent Poisson firing model. Using an HMM, we demonstrate that the time of transition from baseline to plan epochs, a transition in neural activity that is not accompanied by any external behavior changes, can be detected using a threshold on the a posteriori HMM state probabilities. Following detection of the plan epoch, we show that the intended target of a center-out movement can be detected about as accurately as that by a maximum-likelihood estimator using a window of known plan activity. In addition, we demonstrate that our HMM can detect transitions in neural activity corresponding to targets not found in training data. Thus the HMM technique for automatically detecting transitions between epochs of neural activity enables prosthetic interfaces that can operate autonomously.

Detecting neural-state transitions using hidden Markov models for motor cortical prostheses.

Neural prosthetic systems have been designed to estimate continuous reach trajectories (motor prostheses) and to predict discrete reach targets (communication prostheses). In the latter case, reach targets are typically decoded from neural spiking activity during an instructed delay period before the reach begins. Such systems use targets placed in radially symmetric geometries independent of the tuning properties of the neurons available. Here we seek to automate the target placement process and increase decode accuracy in communication prostheses by selecting target locations based on the neural population at hand. Motor prostheses that incorporate intended target information could also benefit from this consideration. We present an optimal target placement algorithm that approximately maximizes decode accuracy with respect to target locations. In simulated neural spiking data fit from two monkeys, the optimal target placement algorithm yielded statistically significant improvements up to 8 and 9% for two and sixteen targets, respectively. For four and eight targets, gains were more modest, as the target layouts found by the algorithm closely resembled the canonical layouts. We trained a monkey in this paradigm and tested the algorithm with experimental neural data to confirm some of the results found in simulation. In all, the algorithm can serve not only to create new target layouts that outperform canonical layouts, but it can also confirm or help select among multiple canonical layouts. The optimal target placement algorithm developed here is the first algorithm of its kind, and it should both improve decode accuracy and help automate target placement for neural prostheses.

Increasing the performance of neural prostheses is necessary for assuring their clinical viability. One performance limitation is the presence of correlated trial-to-trial variability that can cause neural responses to wax and wane in concert as the subject is, for example, more attentive or more fatigued. We report here the design and characterization of a Factor- Analysis-based decoding algorithm that is able to contend with this confound. We characterize the decoder (classifier) on a previously reported dataset where monkeys performed both a real reach task and a prosthetic cursor movement task while we recorded from 96 electrodes implanted in dorsal pre- motor cortex. In principle, the decoder infers the underlying factors that co-modulate the neurons' responses and can use this information to function with reduced error rates (1 of 8 reach target prediction) of up to ~75% (~20% total prediction error using independent Gaussian or Poisson models became ~5%). Such Factor-Analysis based methods appear to be effective when attempting to combat directly unobserved trial-by-trial neural variabiliy.

2008 IEEE International Conference on Acoustics, Speech and Signal Processing

A factor-analysis decoder for high-performance neural prostheses

We have developed a virtual integration environment (VIE) for the development of neural prosthetic systems. This paper, the second of two companion articles, describes the use of the VIE as a common platform for the implementation of neural decode algorithms. In this paper, a linear filter decode and a recursive Bayesian algorithm are implemented as separate signal analysis modules of the VIE for the real-time decode of end effector trajectory. The process of implementing each algorithm is described and the real-time behavior as well as computational cost for each algorithm is examined. This is the first report of the real-time implementation of the Mixture of Trajectory Models decode [10]. These real-time algorithms can be easily interfaced with pre-existing modules of the VIE to control simulated and real devices.

2008 30th Annual International Conference of the IEEE Engineering in Medicine and Biology Society

The use of a virtual integration environment for the real-time implementation of neural decode algorithms

Evidence for smooth and inertial dynamics in the evolution of neural state

Toward Optimal Estimates of Neural Firing Rates from Spike Trains

Neural prostheses aim to improve the quality of life of severely disabled patients by translating neural activity into control signals for guiding prosthetic devices or computer cursors. We recently demonstrated that plan activity from premotor cortex, which specifies the endpoint of the upcoming arm movement, can be used to swiftly and accurately guide computer cursors to the desired target locations. However, these systems currently require additional, non-neural information to specify when plan activity is present. We report here the design and performance of state estimator algorithms for automatically detecting the presence of plan activity using neural activity alone. Prosthesis performance was nearly as good when state estimation was used as when perfect plan timing information was provided separately (∼5 percentage points lower, when using 200 ms of plan activity). These results strongly suggest that a completely neurally-driven high-performance brain–computer interface is possible.

Neural spike trains present challenges to analytical efforts due to their noisy, spiking nature. Many studies of neuroscientific and neural prosthetic importance rely on a smoothed, denoised estimate of the spike train's underlying firing rate. Current techniques to find time-varying firing rates require ad hoc choices of parameters, offer no confidence intervals on their estimates, and can obscure potentially important single trial variability. We present a new method, based on a Gaussian Process prior, for inferring probabilistically optimal estimates of firing rate functions underlying single or multiple neural spike trains. We test the performance of the method on simulated data and experimentally gathered neural spike trains, and we demonstrate improvements over conventional estimators.

Inferring Neural Firing Rates from Spike Trains Using Gaussian Processes

Probabilistic decoding techniques have been used successfully to infer time-evolving physical state, such as arm trajectory or the path of a foraging rat, from neural data. A vital element of such decoders is the trajectory model, expressing knowledge about the statistical regularities of the movements. Unfortunately, trajectory models that both 1) accurately describe the movement statistics and 2) admit decoders with relatively low computational demands can be hard to construct. Simple models are computationally inexpensive, but often inaccurate. More complex models may gain accuracy, but at the expense of higher computational cost, hindering their use for real-time decoding. Here, we present a new general approach to defining trajectory models that simultaneously meets both requirements. The core idea is to combine simple trajectory models, each accurate within a limited regime of movement, in a probabilistic mixture of trajectory models (MTM). We demonstrate the utility of the approach by using an MTM decoder to infer goal-directed reaching movements to multiple discrete goals from multi-electrode neural data recorded in monkey motor and premotor cortex. Compared with decoders using simpler trajectory models, the MTM decoder reduced the decoding error by 38 (48) percent in two monkeys using 98 (99) units, without a necessary increase in running time. When available, prior information about the identity of the upcoming reach goal can be incorporated in a principled way, further reducing the decoding error by 20 (11) percent. Taken together, these advances should allow prosthetic cursors or limbs to be moved more accurately toward intended reach goals.

Mixture of trajectory models for neural decoding of goal-directed movements.

Some movements that animals and humans make are highly stereotyped, repeated with little variation. The patterns of neural activity associatedwithrepeatsofamovementmaybehighlysimilar,orthesamemovementmayarisefromdifferentpatternsofneuralactivity, if the brain exploits redundancies in the neural projections to muscles. We examined the stability of the relationship between neural activityandbehavior.Weaskedwhetherthevariabilityinneuralactivitythatweobservedduringrepeatedreachingwasconsistentwith anoisybutstablerelationship,orwithachangingrelationship,betweenneuralactivityandbehavior.Monkeysperformedhighlysimilar reachesundertightbehavioralcontrol,whilemanyneuronsinthedorsalaspectofpremotorcortexandtheprimarymotorcortexwere simultaneouslymonitoredforseveralhours.Neuralactivitywaspredominantlystableovertimeinallmeasuredproperties:firingrate, directional tuning, and contribution to a decoding model that predicted kinematics from neural activity. The small changes in neural activitythatwedidobservecouldbeaccountedforprimarilybysubtlechangesinbehavior.Weconcludethattherelationshipbetween neural activity and practiced behavior is reasonably stable, at least on timescales of minutes up to 48 h. This finding has significant implicationsforthedesignofneuralprostheticsystemsbecauseitsuggeststhatdevicerecalibrationneednotbeoverlyfrequent,Italso hasimplicationsforstudiesofneuralplasticitybecauseastablebaselinepermitsidentificationofnonstationaryshifts.

Neural Decoding of Movements: From Linear to Nonlinear Trajectory Models

Techniques for extracting single-trial activity patterns from large-scale neural recordings

Some movements that animals and humans make are highly stereotyped, repeated with little variation. The patterns of neural activity associated with repeats of a movement may be highly similar, or the same movement may arise from different patterns of neural activity, if the brain exploits redundancies in the neural projections to muscles. We examined the stability of the relationship between neural activity and behavior. We asked whether the variability in neural activity that we observed during repeated reaching was consistent with a noisy but stable relationship, or with a changing relationship, between neural activity and behavior. Monkeys performed highly similar reaches under tight behavioral control, while many neurons in the dorsal aspect of premotor cortex and the primary motor cortex were simultaneously monitored for several hours. Neural activity was predominantly stable over time in all measured properties: firing rate, directional tuning, and contribution to a decoding model that predicted kinematics from neural activity. The small changes in neural activity that we did observe could be accounted for primarily by subtle changes in behavior. We conclude that the relationship between neural activity and practiced behavior is reasonably stable, at least on timescales of minutes up to 48 h. This finding has significant implications for the design of neural prosthetic systems because it suggests that device recalibration need not be overly frequent, It also has implications for studies of neural plasticity because a stable baseline permits identification of nonstationary shifts.

Single-Neuron Stability during Repeated Reaching in Macaque Premotor Cortex

When a human or animal reaches out to grasp an object, the brain rapidly computes a pattern of muscular contractions that can acquire the target. This computation involves a reference frame transformation because the target's position is initially available only in a visual reference frame, yet the required control signal is a set of commands to the musculature. One of the core brain areas involved in visually guided reaching is the dorsal aspect of the premotor cortex (PMd). Using chronically implanted electrode arrays in two Rhesus monkeys, we studied the contributions of PMd to the reference frame transformation for reaching. PMd neurons are influenced by the locations of reach targets relative to both the arm and the eyes. Some neurons encode reach goals using limb-centered reference frames, whereas others employ eye-centered reference fames. Some cells encode reach goals in a reference frame best described by the combined position of the eyes and hand. In addition to neurons like these where a reference frame could be identified, PMd also contains cells that are influenced by both the eye- and limb-centered locations of reach goals but for which a distinct reference frame could not be determined. We propose two interpretations for these neurons. First, they may encode reach goals using a reference frame we did not investigate, such as intrinsic reference frames. Second, they may not be adequately characterized by any reference frame.

Reference frames for reach planning in macaque dorsal premotor cortex.

We present experiments and analyses designed to test the idea that firing rates in premotor cortex become optimized during motor preparation, approaching their ideal values over time. We measured the across-trial variability of neural responses in dorsal premotor cortex of three monkeys performing a delayed-reach task. Such variability was initially high, but declined after target onset, and was maintained at a rough plateau during the delay. An additional decline was observed after the go cue. Between target onset and movement onset, variability declined by an average of 34%. This decline in variability was observed even when mean firing rate changed little. We hypothesize that this effect is related to the progress of motor preparation. In this interpretation, firing rates are initially variable across trials but are brought, over time, to their “appropriate” values, becoming consistent in the process. Consistent with this hypothesis, reaction times were longer if the go cue was presented shortly after target onset, when variability was still high, and were shorter if the go cue was presented well after target onset, when variability had fallen to its plateau. A similar effect was observed for the natural variability in reaction time: longer (shorter) reaction times tended to occur on trials in which firing rates were more (less) variable. These results reveal a remarkable degree of temporal structure in the variability of cortical neurons. The relationship with reaction time argues that the changes in variability approximately track the progress of motor preparation.

Neural Variability in Premotor Cortex Provides a Signature of Motor Preparation

Neural activity unfolding over time can be modeled using non-linear dynamical systems [1]. As neurons communicate via discrete action potentials, their activity can be characterized by the numbers of events occurring within short pre-defined time-bins (spike counts). Because the observed data are high-dimensional vectors of non-negative integers, non-linear state estimation from spike counts presents a unique set of challenges. In this paper, we describe why the expectation propagation (EP) framework is particularly well-suited to this problem. We then demonstrate ways to improve the robustness and accuracy of Gaussian quadrature-based EP. Compared to the unscented Kalman smoother, we find that EP-based state estimators provide more accurate state estimates.

Expectation Propagation for Inference in Non-Linear Dynamical Models with Poisson Observations

Neural prostheses have received considerable attention due to their potential to dramatically improve the quality of life of severely disabled patients. Cortically-controlled prostheses are able to translate neural activity from cerebral cortex into control signals for guiding computer cursors or prosthetic limbs. Non-invasive and invasive electrode techniques can be used to measure neural activity, with the latter promising considerably higher levels of performance and therefore functionality to patients. We review here some of our recent experimental and computational work aimed at establishing a principled design methodology to increase electrode-based cortical prosthesis performance to near theoretical limits. Studies discussed include translating unprecedentedly brief periods of "plan" activity into high information rate (6.5 bits/s)control signals, improving decode algorithms and optimizing visual target locations for further performance increases, and recording from chronically implanted arrays in freely behaving monkeys to characterize neuron stability. Taken together, these results should substantially increase the clinical viability of cortical prostheses.

Neural prosthetic systems have been designed to estimate continuous reach trajectories as well as discrete reach targets. In the latter case, reach targets are typically decoded from neural activity during an instructed delay period, before the reach begins. We have recently characterized the decoding speed and accuracy achievable by such a system. The results were obtained using canonical target layouts, independent of the tuning properties of the neurons available. Here we seek to increase decode accuracy by judiciously selecting the locations of the reach targets based on the characteristics of the neural population at hand. We present an optimal target placement algorithm that approximately maximizes decode accuracy with respect to target locations. Using maximum likelihood decoding, the optimal target placement algorithm yielded up to 11 and 12% improvement for two and sixteen targets, respectively. For four and eight targets, gains were more modest (5 and 3%, respectively) as the target layouts found by the algorithm closely resembled the canonical layouts. Thus, the algorithm can serve not only to find target layouts that outperform canonical layouts, but it can also confirm or help select among multiple canonical layouts. These results indicate that the optimal target placement algorithm is a valuable tool for designing high-performance prosthetic systems

Cortical neural activity can be used to position computer cursors on visually presented targets. We wished to investigate the following questions central to the clinical viability of such prostheses: how quickly and accurately can targets be selected; how performance differs when running online; and whether performance is limited by electrode count or other factors. Experiments were performed with two rhesus macaques trained on an instructed-delay center-out reach task (2, 4, 8 or 16 target locations). Single and multi-unit activity was recorded from a 96-electrode array in premotor cortex. The desired target was estimated using 50-275 ms of delay activity (Tint epoch) starting 150 ms after target onset (Tskip epoch). If the target prediction was correct a cursor was positioned, the monkey received a reward, and the next target appeared immediately. Tskip was estimated in control experiments in order to exclude noise or visual transients from the Tint estimation window. With one monkey, we recently performed a series of online experiments where Tint was swept to understand the effect of this parameter on the maximum information transmission rate (bits/s) between the requested and the estimated target. Offline analyses using data from trials with targets presented ~2 sec apart indicated that 8.1 bits/s could be achieved under these conditions. For online experiments, the maximum average sustained performance achieved was 6.5 bits/s (8 targets, Tint=100 ms). The difference between offline (8.1) and online (6.5) performance appears to result from changes in neural tuning curves when targets are presented in rapid succession (Kalmar et al. in this volume). We also report results from modeling efforts to understand the prospect for higher information throughput afforded by adding electrodes to the system. This suggests that the maximum achievable throughput (~10 bits/s) is limited by task and decoding design, as opposed to the total number of recording electrodes.

Spiking activity from neurophysiological experiments often exhibits dynamics beyond that driven by external stimulation, presumably reflecting the extensive recurrence of neural circuitry. Characterizing these dynamics may reveal important features of neural computation, particularly during internally-driven cognitive operations. For example, the activity of premotor cortex (PMd) neurons during an instructed delay period separating movement-target specification and a movement-initiation cue is believed to be involved in motor planning. We show that the dynamics underlying this activity can be captured by a low-dimensional non-linear dynamical systems model, with underlying recurrent structure and stochastic point-process output. We present and validate latent variable methods that simultaneously estimate the system parameters and the trial-by-trial dynamical trajectories. These methods are applied to characterize the dynamics in PMd data recorded from a chronically-implanted 96-electrode array while monkeys perform delayed-reach tasks.

At present, the best view of the activity of a neural circuit is provided by multiple-electrode extracellular recording technologies. These technologies are able to simultaneously measure spike trains from up to a few hundred cells in one or more brain areas during each trial. However, characterizing the dynamics of the circuit from such data is made difficult, both by the point-like nature of the spikes and by the variability in the responses to identical repeated trials. By their nature, spikes give us only an occasional view of the process from which they are generated.

Extracting Dynamical Structure Embedded in Motor Preparatory Activity

leftward reaches have a mean firing rate of 3.4 1.1). To explore this finding, two different multivariate Poisson models were generated. The first model assumes independence between the firing rate of each unit. The second model assumes the firing rate of each unit is coupled to the population's mean firing rate; accordingly, the model scales the expected firing rate of each unit by this mean firing rate on each trial. These models were fit offline to the first 200 trials of the day and were tested on trials from the remainder of the day. For monkey G (H), when decoding on 150ms of delay period activity, the first and second model correctly classify reach direction on 55% (75%) and 66% (78%) of the trials, respectively (chance=12.5%). Across multiple daily data sets collected over a period of several weeks, the second model consistently outperforms the first model. If we adjust the expected firing rate of individual neurons according to mean firing rate, we may improve discrete classification and continuous estimation of reaches from neural activity. Improving these processes will move us closer to realizing effective neural prosthetic systems.

Trial - by - trial mean normalization improves plan period reach target decoding

We consider the problem of decoding time-evolving physical parameters, such as hand position, from neural data when there is prior information available about the desired final state, such as reach endpoint. For reach trajectories, it has been shown that the desired reach endpoint can be reliably decoded from neural activity that occurs before the reach begins. In this work, we incorporate this goal information into a recursive Bayesian framework to improve average estimation error across the entire trajectory. While most recursive Bayesian estimators to date have modeled the state evolution as a random walk defined by a static covariance matrix, we show how to use this goal information to transform the state evolution into a directed random walk defined by a dynamically adapting covariance matrix. We applied this technique to decoding hand trajectories from neural recordings in monkey pre-motor cortex and found that using an adaptive random walk model gave 45.5% lower estimation error than using a static random walk model. This result indicates that goal-directed trajectory estimation can be significantly improved if prior information about the intended goal location is available and is incorporated into the estimator. Recursive Bayesian techniques represent a class of state-of-the-art methods for decoding time-evolving physical parameters from neural data. These methods include the Kalman filter , the switching Kalman filter, and the particle filter, which have all been used to decode hand trajectory. Another such method is a point process-driven Bayes’ filter which has been used to decode the position of a freely foraging rat. There are two major advantages of using recursive Bayesian techniques. First, Bayesian estimation requires formal statistical models for the generation of neuronal spike trains or spike counts (the observation model) and for the time-evolution of the relevant physical parameters (the state model). If the modeling assumptions are satisfied, then Bayesian estimation makes optimal use of the observed data. Second, recursive algorithms provide estimates as the observed data stream in, as opposed to batch algorithms which wait for all data to arrive before outputing the first estimate. This sequence of predictions is critical for real-time decoding applications, such as neural prosthetics. Furthermore, recursive algorithms have smaller storage requirements and can be designed to track adaptively varying model parameters. In previous work (Brockwell et al. J Neurophysiol, 2004; Brown et al. J Neurosci, 1998), the state model is defined to be a zero-mean Gaussian random walk, which refers to the time-evolution of the physical parameters contained in the state vector (such as position, velocity, or acceleration). The random walk is typically described by a static covariance matrix, which is fit to the training data and remains unchanged across all time steps. Using a static covariance matrix is a logical approach for decoding an arbitrary trajectory through state space when there is no additional knowledge about the trajectory being estimated beyond what is contained in the training data. However, for goal-directed trajectories, there is usually an additional piece of information: the intended trajectory endpoint. Examples of goal-directed trajectories include a hand reaching for an object or a rat running towards a food source. For reaching trajectories, it has been shown that the desired reach endpoint can be reliably decoded from neural activity in the pre-motor and parietal cortices before the reach begins. We asked how this prior goal information can be used to improve the average estimation error across the entire impending trajectory. The recursive Bayesian paradigm provides a natural framework for incorporating this goal information. Instead of using a static random walk covariance matrix, we can dynamically adapt this covariance matrix at each time step based on the error vector between the current state estimate and the goal. We propose such a technique that adapts the random walk covariance matrix based on the current state estimate and its uncertainty. We then applied this technique to decoding hand reach trajectories from neural data recorded in monkey pre-motor cortex (96-electrode array). The monkey performed a ’delayed-reach’ center-out task wherein a random delay period (750 or 1000 ms) was inserted between the appearance and eye fixation of a reach target and the appearance of an arm-movement initiation “go” cue. We decoded reach trajectories using peri-movement neural activity and showed that, when taking into account goal information decoded from the delay activity (last 700 or 950 ms of delay period), average trial-by-trial RMS error decreased by 45.5% (Wilcoxon paired-sample test, p < 0.001). This result indicates that goaldirected trajectory estimation can be significantly improved by using goal information when it is available.

Feedback-Directed State Transition for Recursive Bayesian Estimation of Goal-Directed Trajectories

INTRODUCTION It will be possible to decode cortical motor signals to enable a robotic arm to accurately and quickly assist spinal cord injured patients. Understanding how quickly the brain plans reaches is important to quantify the performance limits of such a system. METHODS We trained a rhesus monkey to touch a center point on a video screen and to hold for 200-1000 ms while one of several targets arranged around a circle on a touch screen was shown. These included layouts with 2, 4, or 8 directions at a 10 cm radial distance and layouts with 4 or 8 directions at 6 and 12 cm radial distances. After a cue, he then performed reaches out to the specified target. Given a target location, the distribution of spike rates for each trial was modeled as a multivariate Gaussian. Models were computed on neural data from a microsurgically implanted a 96-channel electrode array into the premotor cortex. We then computationally predicted the upcoming reach from 100-275 ms of neural activity starting 150 ms after the target was shown. Given a successful prediction, the subject was rewarded without executing a real reach. RESULTS Using just 200 ms of neural activity the correct target location could be predicted using a maximum likelihood estimator on 80% of trials for the 1 of 8 target layout. When wrong, the predicted target was typically adjacent to the actual target. Prediction computation required ~20 ms. Up to 10 targets in a row were predicted from neural planning activity alone with no real reaches performed. Over 3.5 reach plans could be decoded in under one second for the 1 of 2 target layout. CONCLUSIONS Our prosthetic system is capable of fast and accurate positioning of prosthetic icons, faster than real reach capabilities.

785 The Speed at Which Reach Movement Plans Can Be Decoded from the Cortex and Its Implications for High-performance Neural Prosthetic Arm Systems

Multiple-subcarrier modulation (MSM) offers several potential advantages for optical wireless systems. MSM makes it possible to perform frequency-division multiplexing, while maintaining the simplicity of intensity modulation and direct detection. Indoor optical wireless systems may be subject to multipath distortion; in such systems, MSM enables transmission at high bit rates with minimal intersymbol interference. The average-power efficiency of MSM is lower than that of baseband modulation techniques, such as on-off-keying or pulse-position modulation, however. We present a technique for improving the average-power efficiency of multiple-subcarrier systems using binary or quadrature phase-shift keying (BPSK, QPSK) with bandlimited pulses, which are, necessarily, not time-limited. In order to insure the non-negativity of the transmitted intensity signal, we use a time-varying bias signal, which is a baseband pulse-amplitude modulation signal also using these pulses. We focus on the problem of designing this time-varying bias signal, which is complicated by the fact that the pulses are not time-limited. We show that the proposed scheme can significantly enhance power efficiency, with only a minimal increase in implementation complexity.

Power-Efficient Multiple-Subcarrier Modulation Scheme for Optical Wireless Communications

We present a technique for average power reduction in intensity-modulated optical systems using multiple BPSK or QPSK subcarriers with bandlimited pulses, which are, necessarily, not time-limited. In order to insure the non-negativity of the transmitted intensity signal, we use a time-varying bias signal, which is a baseband pulse-amplitude modulation signal also using these pulses. We focus on the problem of designing this time-varying bias signal, which is complicated by the fact that the pulses are not time-limited. We consider pulses whose Fourier transform is a root-raised cosine with rolloff factor , where . We use a heuristic approach in which, during a given symbol interval, the bias amplitude is computed considering the multiple-subcarrier amplitudes during that symbol interval, as well as several neighboring symbol intervals. We consider three cases in detail: with BPSK, with BPSK, and with QPSK. We show that, although using these pulses requires slightly more power than using rectangular pulses, the use of a time-varying bias yields a large gain in average power efficiency over a fixed bias, especially when the number of subcarriers is large.

Average Power Reduction Using Time-Varying Bias with Bandlimited Pulses in Multiple-Subcarrier Intensity-Modulated Optical Systems

In this paper, we describe an application, PubCloud that uses tagclouds for the summarization of results from queries over thePubMed database of biomedical literature. PubCloud responds toqueries of this database with tag clouds generated from wordsextracted from the abstracts returned by the query. The results ofa user study comparing the PubCloud tag-cloud summarization ofquery results with the standard result list provided by PubMedindicated that the tag cloud interface is advantageous in presenting descriptive information and in reducing user frustrationbut that it is less effective at the task of enabling users to discoverrelations between concepts.

Serial analysis of gene expression (SAGE) not only is a method for profiling the global expression of genes, but also offers the opportunity for the discovery of novel transcripts. SAGE tags are mapped to known transcripts to determine the gene of origin. Tags that map neither to a known transcript nor to the genome were hypothesized to span a splice junction, for which the exon combination or exon(s) are unknown. To test this hypothesis, we have developed an algorithm, SAGE2Splice, to efficiently map SAGE tags to potential splice junctions in a genome. The algorithm consists of three search levels. A scoring scheme was designed based on position weight matrices to assess the quality of candidates. Using optimized parameters for SAGE2Splice analysis and two sets of SAGE data, candidate junctions were discovered for 5%–6% of unmapped tags. Candidates were classified into three categories, reflecting the previous annotations of the putative splice junctions. Analysis of predicted tags extracted from EST sequences demonstrated that candidate junctions having the splice junction located closer to the center of the tags are more reliable. Nine of these 12 candidates were validated by RT-PCR and sequencing, and among these, four revealed previously uncharacterized exons. Thus, SAGE2Splice provides a new functionality for the identification of novel transcripts and exons. SAGE2Splice is available online at http://www.cisreg.ca.

iHOPerator: user-scripting a personalized bioinformatics Web, starting with the iHOP website

We analyzed 8.55 million LongSAGE tags generated from 72 libraries. Each LongSAGE library was prepared from a different mouse tissue. Analysis of the data revealed extensive overlap with existing gene data sets and evidence for the existence of approximately 24,000 previously undescribed genomic loci. The visual cortex, pancreas, mammary gland, preimplantation embryo, and placenta contain the largest number of differentially expressed transcripts, 25% of which are previously undescribed loci.

A mouse atlas of gene expression: large-scale digital gene-expression profiles from precisely defined developing C57BL/6J mouse tissues and cells.

CGMIM: Automated text-mining of Online Mendelian Inheritance in Man (OMIM) to identify genetically-associated cancers and candidate genes

We derive a modified version of factor analysis for data that is poisson (rather than gaussian) distributed. This modified approach may better fit certain classes of data, including neuronal spiking data commonly collected in electrophysiology experiments.

The McGovern Institute for Brain Research at MIT is led by a team of world-renowned neuroscientists committed to meeting two great challenges of modern science: understanding how the brain works and discovering new ways to prevent or treat brain disorders. Patrick J. McGovern and Lore Harp McGovern, committed to improving human welfare, communication, and understanding through their support for neuroscience research, established the McGovern Institute in 2000. Patrick McGovern passed away in March 2014.

Leitfahigkeitsdetektor
(AP1) fur
ein Fluid in einem Kanal (118) mit einer Kanalwand (117, der folgende
Merkmale umfast: eine
erste Erdungselektrode (113), die mit dem Fluid durch die Kanalwand
kapazitiv gekoppelt und auf einem Massepotential gehalten wird; eine
Signalelektrode (109), die mit dem Fluid durch die Kanalwand (117)
kapazitiv koppelt, so dass die erste Erdungselektrode (113) und
die Signalelektrode (109) uber
das Fluid elektrisch gekoppelt sind; einen Empfanger (107),
der mit der Signalelektrode elektrisch verbunden ist, um ein Ausgangssignal
als Funktion eines sich an der Signalelektrode entwickelnden Signals
zu liefern; einen Erfassungswiderstand (105), der mit der Signalelektrode
(109) elektrisch verbunden ist; und einen Wechselsignalsender
(103), der durch den Erfassungswiderstand (105) mit der Signalelektrode
(109) elektrisch verbunden ist.

Kontaktloser Leitfähigkeitsdetektor mit Sender-Empfänger-Elektrode

The availability of both anatomical connectivity and brain-wide neural activity measurements in C. elegans make the worm a promising system for learning detailed, mechanistic models of an entire nervous system in a data-driven way. However, one faces several challenges when constructing such a model. We often do not have direct experimental access to important modeling details such as single-neuron dynamics and the signs and strengths of the synaptic connectivity. Further, neural activity can only be measured in a subset of neurons, often indirectly via calcium imaging, and signiﬁcant trial-to-trial variability has been observed. To address these challenges, we introduce a connectome-constrained latent variable model (CC-LVM) of the unobserved voltage dynamics of the entire C. elegans nervous system and the observed calcium signals. We used the framework of variational autoencoders to ﬁt parameters of the mechanistic simulation constituting the generative model of the LVM to calcium imaging observations. A variational approximate posterior distribution over latent voltage traces for all neurons is efﬁciently inferred using an inference network, and constrained by a prior distribution given by the biophysical simulation of neural dynamics. We applied this model to an experimental whole-brain dataset, and found that connectomic constraints enable our LVM to predict the activity of neurons whose activity were withheld signiﬁcantly better than models unconstrained by a connectome. We explored models with different degrees of biophysical detail, and found that models with realistic conductance-based synapses provide markedly better some

Connectome-constrained Latent Variable Model of Whole-Brain Neural Activity

This paper presents an unsupervised deep learning method for complex object reconstruction in severely undersampled Fourier ptychographic microscopy. The method requires no ground truth objects, only a dataset of undersampled measurements.

Imaging and Applied Optics Congress 2022 (3D, AOA, COSI, ISA, pcAOP)

Physics-Informed Variational Autoencoder for Undersampled Fourier Ptychography

Differentiable simulations of optical systems can be combined with deep learning-based reconstruction networks to enable high performance computational imaging via end-to-end (E2E) optimization of both the optical encoder and the deep decoder. This has enabled imaging applications such as 3D localization microscopy, depth estimation, and lensless photography via the optimization of local optical encoders. More challenging computational imaging applications, such as 3D snapshot microscopy which compresses 3D volumes into single 2D images, require a highly non-local optical encoder. We show that existing deep network decoders have a locality bias which prevents the optimization of such highly non-local optical encoders. We address this with a decoder based on a shallow neural network architecture using global kernel Fourier convolutional neural networks (FourierNets). We show that FourierNets surpass existing deep network based decoders at reconstructing photographs captured by the highly non-local DiffuserCam optical encoder. Further, we show that FourierNets enable E2E optimization of highly non-local optical encoders for 3D snapshot microscopy. By combining FourierNets with a large-scale multi-GPU differentiable optical simulation, we are able to optimize non-local optical encoders 170$\times$ to 7372$\times$ larger than prior state of the art, and demonstrate the potential for ROI-type specific optical encoding with a programmable microscope.

FourierNets enable the design of highly non-local optical encoders for computational imaging

Many animals produce distinct sounds or substrate-borne vibrations, but these signals have proved challenging to segment with automated algorithms. We have developed SongExplorer, a web-browser based interface wrapped around a deep-learning algorithm that supports an interactive workflow for (1) discovery of animal sounds, (2) manual annotation, (3) supervised training of a deep convolutional neural network, and (4) automated segmentation of recordings. Raw data can be explored by simultaneously examining song events, both individually and in the context of the entire recording, watching synced video, and listening to song. We provide a simple way to visualize many song events from large datasets within an interactive low-dimensional visualization, which facilitates detection and correction of incorrectly labelled song events. The machine learning model we implemented displays higher accuracy than existing heuristic algorithms and similar accuracy as two expert human annotators. We show that SongExplorer allows rapid detection of all song types from new species and of novel song types in previously well-studied species.

SongExplorer: A deep learning workflow for discovery and segmentation of animal acoustic communication signals

3D snapshot microscopy enables fast volumetric imaging by capturing a 3D volume in a single 2D camera image and performing computational reconstruction. Fast volumetric imaging has a variety of biological applications such as whole brain imaging of rapid neural activity in larval zebrafish. The optimal microscope design for this optical 3D-to-2D encoding is both sampleand task-dependent, with no general solution known. Deep learning based decoders can be combined with a differentiable simulation of an optical encoder for end-to-end optimization of both the deep learning decoder and optical encoder. This technique has been used to engineer local optical encoders for other problems such as depth estimation, 3D particle localization, and lensless photography. However, 3D snapshot microscopy is known to require a highly non-local optical encoder which existing UNet-based decoders are not able to engineer. We show that a neural network architecture based on global kernel Fourier convolutional neural networks can efficiently decode information from multiple depths in a volume, globally encoded across a 3D snapshot image. We show in simulation that our proposed networks succeed in engineering and reconstructing optical encoders for 3D snapshot microscopy where the existing state-of-the-art UNet architecture fails. We also show that our networks outperform the state-of-the-art learned reconstruction algorithms for a computational photography dataset collected on a prototype lensless camera which also uses a highly non-local optical encoding.

Programmable 3D snapshot microscopy with Fourier convolutional networks

Automatic detection of synaptic partners in a whole-brain Drosophila electron microscopy data set

In this paper, an approach for improving active shape segmentation of medical images using machine learning techniques which can achieve high segmentation accuracy is described. A statistical shape model is created from a training dataset which is used to search for an object of interest in an image. Active shape model has shown over time to be a reliable image segmentation methodology, but its segmentation accuracy is hindered especially by poor initialization which can&apos;t be guaranteed to always be perfect. In our methodology, we extract features for each landmark using haarfilters[9]. We train a classifier with these features and use the classifier to classify points around the final points of an Active shape model search. The aim of this approach is to better place points that might have been wrongly placed from the ASM search. We have used the simple, yet effective K-Nearest Neighbour machine learning algorithm, and have demonstrated the ability of this method to improve segmentation accuracy by segmenting 2d images of the lateral ventricles of the brain.

Deep learning describes a class of machine learning algorithms that are capable of combining raw inputs into layers of intermediate features. These algorithms have recently shown impressive results across a variety of domains. Biology and medicine are data-rich disciplines, but the data are complex and often ill-understood. Hence, deep learning techniques may be particularly well-suited to solve problems of these elds. We examine applications of deep learning to a variety of biomedical problems—patient classi cation, fundamental biological processes, and treatment of patients—and discuss whether deep learning will be able to transform these tasks or if the biomedical sphere poses unique challenges. Following from an extensive literature review, we nd that deep learning has yet to revolutionize biomedicine or de nitively resolve any of the most pressing challenges in the eld, but promising advances have been made on the prior state of the art. Even though improvements over previous baselines have been modest in general, the recent progress indicates that deep learning methods will provide valuable means for speeding up or aiding human investigation. Though progress has been made linking a speci c neural network’s prediction to input features, understanding how users should interpret these models to make testable hypotheses about the system under study remains an open challenge. Furthermore, the limited amount of labeled data for training presents problems in some domains, as do legal and privacy constraints on work with sensitive health records. Nonetheless, we foresee deep learning enabling changes at both bench and bedside with the potential to transform several areas of biology and medicine. Introduction to deep learning Biology and medicine are rapidly becoming data-intensive. A recent comparison of genomics with social media, online videos, and other data-intensive disciplines suggests that genomics alone will equal or surpass other elds in data generation and analysis within the next decade [1]. The volume and complexity of these data present new opportunities, but also pose new challenges. Automated algorithms that extract meaningful patterns could lead to actionable knowledge and change how we develop treatments, categorize patients, or study diseases, all within privacy-critical environments. The term deep learning has come to refer to a collection of new techniques that, together, have demonstrated breakthrough gains over existing best-in-class machine learning algorithms across several elds. For example, over the past ve years these methods have revolutionized image classi cation and speech recognition due to their exibility and high accuracy [2]. More recently, deep learning algorithms have shown promise in elds as diverse as high-energy physics [3], computational chemistry [4], dermatology [5], and translation among written languages [6]. Across elds, “o -theshelf” implementations of these algorithms have produced comparable or higher accuracy than previous best-in-class methods that required years of extensive customization, and specialized implementations are now being used at industrial scales. Deep learning approaches grew from research on arti cial neurons, which were rst proposed in 1943 [7] as a model for how the neurons in a biological brain process information. The history of arti cial neural networks—referred to as “neural networks” throughout this article—is interesting in its own right [8]. In neural networks, inputs are fed into the input layer, which feeds into one or more hidden layers, which eventually link to an output layer. A layer consists of a set of nodes, sometimes called “features” or “units,” which are connected via edges to the immediately earlier and the immediately deeper layers. In some special neural network architectures, nodes can connect to themselves with a delay. The nodes of the input layer generally consist of the variables being measured in the dataset of interest—for example, each node could represent the intensity value of a speci c pixel in an image or the expression level of a gene in a speci c transcriptomic experiment. The neural networks used for deep learning have multiple hidden layers. Each layer essentially performs feature construction for the layers before it. The training process used often allows layers deeper in the network to contribute to the re nement of earlier layers. For this reason, these algorithms can automatically engineer features that are suitable for many tasks and customize those features for one or more speci c tasks. Deep learning does many of the same things as more familiar machine learning approaches. In particular, deep learning approaches can be used both in supervised applications—where the goal is to accurately predict one or more labels or outcomes associated with each data point—in the place of regression approaches, as well as in unsupervised, or “exploratory” applications—where the goal is to summarize, explain, or identify interesting patterns in a data set—as a form of clustering. Deep learning methods may in fact combine both of these steps. When su cient data are available and labeled, these methods construct features tuned to a speci c problem and combine those features into a predictor. In fact, if the dataset is “labeled” with binary classes, a simple neural network with no hidden layers and no cycles between units is equivalent to logistic regression if the output layer is a sigmoid (logistic) function of the input layer. Similarly, for continuous outcomes, linear regression can be seen as a single-layer neural network. Thus, in some ways, supervised deep learning approaches can be seen as an extension of regression models that allow for greater exibility and are especially well-suited for modeling non-linear relationships among the input features. Recently, hardware improvements and very large training datasets have allowed these deep learning techniques to surpass other machine learning algorithms for many problems. In a famous and early example, scientists from Google demonstrated that a neural network “discovered” that cats, faces, and pedestrians were important components of online videos [9] without being told to look for them. What if, more generally, deep learning takes advantage of the growth of data in biomedicine to tackle challenges in this eld? Could these algorithms identify the “cats” hidden in our data—the patterns unknown to the researcher—and suggest ways to act on them? In this review, we examine deep learning’s application to biomedical science and discuss the unique challenges that biomedical data pose for deep learning methods. Several important advances make the current surge of work done in this area possible. Easy-to-use software packages have brought the techniques of the eld out of the specialist’s toolkit to a broad community of computational scientists. Additionally, new techniques for fast training have enabled their application to larger datasets [10]. Dropout of nodes, edges, and layers makes networks more robust, even when the number of parameters is very large. Finally, the larger datasets now available are also su cient for tting the many parameters that exist for deep neural networks. The convergence of these factors currently makes deep learning extremely adaptable and capable of addressing the nuanced di erences of each domain to which it is applied. Figure 1: Neural networks come in many di erent forms. Left: a key for the various types of nodes used in neural networks. Simple FFNN: a feed forward neural network in which inputs are connected via some function to an output node and the model is trained to produce some output for a set of inputs. MLP: the multi-layer perceptron is a feed forward neural network in which there is at least one hidden layer between the input and output nodes. CNN: the convolutional neural network is a feed forward neural network in which the inputs are grouped spatially into hidden nodes. In the case of this example, each input node is only connected to hidden nodes alongside their neighboring input node. Autoencoder: a type of MLP in which the neural network is trained to produce an output that matches the input to the network. RNN: a deep recurrent neural network is used to allow the neural network to retain memory over time or sequential inputs. This gure was inspired by the Neural Network Zoo by Fjodor Van Veen. This review discusses recent work in the biomedical domain, and most successful applications select neural network architectures that are well suited to the problem at hand. We sketch out a few simple example architectures in Figure 1. If data have a natural adjacency structure, a convolutional neural network (CNN) can take advantage of that structure by emphasizing local relationships, especially when convolutional layers are used in early layers of the neural network. Other neural network architectures such as autoencoders require no labels and are now regularly used for unsupervised tasks. In this review, we do not exhaustively discuss the di erent types of deep neural network architectures; an overview of the principal terms used herein is given in Table 1. Table 1 also provides select example applications, though in practice each neural network architecture has been broadly applied across multiple types of biomedical data. A recent book from Goodfellow et al. covers neural network architectures in detail [11], and LeCun et al. provide a more general introduction [2].

Opportunities and obstacles for deep learning in biology and medicine [update in progress]

How neuron types encode behavioral states What is the contribution of molecularly defined cell types to neural coding of stimuli and states? Xu et al. aimed to evaluate neural representation of multiple behavioral states in the mouse paraventricular hypothalamus. To achieve this goal, they combined deep-brain two-photon imaging with post hoc validation of gene expression in the imaged cells. The behavioral states could be well predicted by the neural response of multiple neuronal clusters. Some clusters were broadly tuned and contributed strongly to the decoding of multiple behavioral states, whereas others were more specifically tuned to certain behaviors or specific time windows of a behavioral state. Science, this issue p. eabb2494 An imaging method can merge molecular and systems neuroscience to reveal combinatorial cell type coding of essential survival behaviors. INTRODUCTION Brain function is often compared to an orchestral ensemble, where subgroups of neurons that have similar activity are analogous to different types of instruments playing a musical score. Brains are composed of specialized neuronal subtypes that can be efficiently classified by gene expression profiles measured by single-cell RNA sequencing (scRNA-seq). Are these molecularly defined cell types the “instruments” in the neural ensemble? To address this question, we examined the neural ensemble dynamics of the hypothalamic paraventricular nucleus (PVH), a small brain region that is important for behavior states such as hunger, thirst, and stress. Past work has emphasized specialized behavioral state–setting roles for different PVH cell types, but it is not clear whether the dynamics of the PVH ensemble support this view. RATIONALE We considered three possibilities for how PVH neurons could be involved in encoding behavioral states: (i) PVH neurons of a molecularly defined cell type may respond similarly and be specialized for a behavioral state as a “labeled-line,” (ii) molecularly defined cell types may show unrelated activity patterns and be irrelevant to behavioral state coding, and (iii) molecularly defined neurons may respond similarly within a type, but behavioral state may be encoded by combinations of cell types. To evaluate the role of molecularly defined cell types in the neural ensemble, it is important to monitor activity in many individual neurons with subsecond temporal resolution along with quantitative gene expression information about each cell. For this, we developed the CaRMA (calcium and RNA multiplexed activity) imaging platform in which deep-brain two-photon calcium imaging of neuron activity is performed in mice during multiple behavioral tasks. This is followed by ex vivo multiplexed RNA fluorescent in situ hybridization to measure gene expression information in the in vivo–imaged neurons. RESULTS We simultaneously imaged calcium activity in hundreds of PVH neurons from 10 cell types across 11 behavioral states. Within a molecularly defined cell type, neurons often showed similar activity patterns such that we could predict functional responses of individual neurons solely from their quantitative gene expression information. Behavioral states could be decoded with high accuracy based on combinatorial assemblies of PVH cell types, which we called “grouped-ensemble coding.” Labeled-line coding was not observed. The neuromodulatory receptor gene neuropeptide receptor neuropeptide Y receptor type 1 (Npy1r) was usually the most predictive gene for neuron functional response and was expressed in multiple cell types, analogous to the “conductor” of the PVH neural ensemble. CONCLUSION Our results validated molecularly defined neurons as important information processing units in the PVH. We found correspondence between the gene expression hierarchies used for molecularly defined cell type classification and functional activity hierarchies involving coordination by neuromodulation. CaRMA imaging offers a solution to the problem of how to rapidly evaluate the function of the panoply of cell types being uncovered with scRNA-seq. CaRMA imaging bridges a gap between the abstract digital elements typically described in systems neuroscience with the “wetware” associated with traditional molecular neuroscience. Merging these two areas is essential to understanding the relationships of gene expression, brain function, behavior, and ultimately neurological diseases. CaRMA imaging reveals combinatorial cell type coding of behavior states. CaRMA imaging records calcium dynamics of PVH neurons across multiple behavioral states followed by gene expression profiling. Combinatorial assemblies of PVH cell types encoded behavioral states. The PVH neural activity ensemble was split by Npy1r expression into two main cell classes that were subdivided into cell types. Thus, neuromodulation coordinates cell types for grouped-ensemble coding to represent different survival behaviors such as eating, drinking, and stress. Brains encode behaviors using neurons amenable to systematic classification by gene expression. The contribution of molecular identity to neural coding is not understood because of the challenges involved with measuring neural dynamics and molecular information from the same cells. We developed CaRMA (calcium and RNA multiplexed activity) imaging based on recording in vivo single-neuron calcium dynamics followed by gene expression analysis. We simultaneously monitored activity in hundreds of neurons in mouse paraventricular hypothalamus (PVH). Combinations of cell-type marker genes had predictive power for neuronal responses across 11 behavioral states. The PVH uses combinatorial assemblies of molecularly defined neuron populations for grouped-ensemble coding of survival behaviors. The neuropeptide receptor neuropeptide Y receptor type 1 (Npy1r) amalgamated multiple cell types with similar responses. Our results show that molecularly defined neurons are important processing units for brain function.

Behavioral state coding by molecularly defined paraventricular hypothalamic cell type ensembles

The Importance Weighted Auto Encoder (IWAE) objective has been shown to improve the training of generative models over the standard Variational Auto Encoder (VAE) objective. Here, we derive importance weighted extensions to AVB and AAE. These latent variable models use implicitly defined inference networks whose approximate posterior density q_\phi(z|x) cannot be directly evaluated, an essential ingredient for importance weighting. We show improved training and inference in latent variable models with our adversarially trained importance weighting method, and derive new theoretical connections between adversarial generative model training criteria and marginal likelihood based methods. We apply these methods to the important problem of inferring spiking neural activity from calcium imaging data, a challenging posterior inference problem in neuroscience, and show that posterior samples from the adversarial methods outperform factorized posteriors used in VAEs.

Importance Weighted Adversarial Variational Autoencoders for Spike Inference from Calcium Imaging Data

We present a method combining affinity prediction with region agglomeration, which improves significantly upon the state of the art of neuron segmentation from electron microscopy (EM) in accuracy and scalability. Our method consists of a 3D U-Net, trained to predict affinities between voxels, followed by iterative region agglomeration. We train using a structured loss based on Malis, encouraging topologically correct segmentations obtained from affinity thresholding. Our extension consists of two parts: First, we present a quasi-linear method to compute the loss gradient, improving over the original quadratic algorithm. Second, we compute the gradient in two separate passes to avoid spurious gradient contributions in early training stages. Our predictions are accurate enough that simple learning-free percentile-based agglomeration outperforms more involved methods used earlier on inferior predictions. We present results on three diverse EM datasets, achieving relative improvements over previous results of 27, 15, and 250 percent. Our findings suggest that a single method can be applied to both nearly isotropic block-face EM data and anisotropic serial sectioned EM data. The runtime of our method scales linearly with the size of the volume and achieves a throughput of $\sim$∼ 2.6 seconds per megavoxel, qualifying our method for the processing of very large datasets.

Large Scale Image Segmentation with Structured Loss Based Deep Learning for Connectome Reconstruction

Molecular profiles of neurons influence information processing, but bridging the gap between genes, circuits and behavior has been very difficult. Furthermore, the behavioral state of an animal continuously changes across development and as a result of sensory experience. How behavioral state influences molecular cell state is poorly understood. Here we present a complete atlas of the Drosophila larval nervous system. We develop polyseq, a python analysis package, and use single molecule RNA-FISH to validate our scRNAseq findings. To investigate how internal state affects cell state, we altered internal state with high-throughput behaviour protocols designed to mimic wasp sting and over activation of the memory system. We found nervous system-wide gene expression changes related to cell state. This work advances our understanding of how genes, neurons, and circuits generate behavior. One Sentence Summary Single cell genomics and modulation of internal state reveal how genes, neurons, and circuits produce behavior.

Comparative single-cell transcriptomics of complete insect nervous systems

The study of neural circuits requires the reconstruction of neurons and the identification of synaptic connections between them. To scale the reconstruction to the size of whole-brain datasets, semi-automatic methods are needed to solve those tasks. Here, we present an automatic method for synaptic partner identification in insect brains, which uses convolutional neural networks to identify post-synaptic sites and their pre-synaptic partners. The networks can be trained from human generated point annotations alone and require only simple post-processing to obtain final predictions. We used our method to extract 244 million putative synaptic partners in the fifty-teravoxel full adult fly brain (FAFB) electron microscopy (EM) dataset and evaluated its accuracy on 146,643 synapses from 702 neurons with a total cable length of 312 mm in four different brain regions. The predicted synaptic connections can be used together with a neuron segmentation to infer a connectivity graph with high accuracy: between 92% and 96% of edges linking connected neurons are correctly classified as weakly connected (less than five synapses) and strongly connected (at least five synapses). Our synaptic partner predictions for the FAFB dataset are publicly available, together with a query library allowing automatic retrieval of up- and downstream neurons.

Automatic Detection of Synaptic Partners in a Whole-Brain Drosophila EM Dataset

Constraining computational models using electron microscopy wiring diagrams

Deep learning describes a class of machine learning algorithms that are capable of combining raw inputs into layers of intermediate features. These algorithms have recently shown impressive results across a variety of domains. Biology and medicine are data-rich disciplines, but the data are complex and often ill-understood. Hence, deep learning techniques may be particularly well-suited to solve problems of these elds. We examine applications of deep learning to a variety of biomedical problems—patient classi cation, fundamental biological processes, and treatment of patients—and discuss whether deep learning will be able to transform these tasks or if the biomedical sphere poses unique challenges. Following from an extensive literature review, we nd that deep learning has yet to revolutionize biomedicine or de nitively resolve any of the most pressing challenges in the eld, but promising advances have been made on the prior state of the art. Even though improvements over previous baselines have been modest in general, the recent progress indicates that deep learning methods will provide valuable means for speeding up or aiding human investigation. Though progress has been made linking a speci c neural network’s prediction to input features, understanding how users should interpret these models to make testable hypotheses about the system under study remains an open challenge. Furthermore, the limited amount of labeled data for training presents problems in some domains, as do legal and privacy constraints on work with sensitive health records. Nonetheless, we foresee deep learning enabling changes at both bench and bedside with the potential to transform several areas of biology and medicine. Introduction to deep learning Biology and medicine are rapidly becoming data-intensive. A recent comparison of genomics with social media, online videos, and other data-intensive disciplines suggests that genomics alone will equal or surpass other elds in data generation and analysis within the next decade [1]. The volume and complexity of these data present new opportunities, but also pose new challenges. Automated algorithms that extract meaningful patterns could lead to actionable knowledge and change how we develop treatments, categorize patients, or study diseases, all within privacy-critical environments. The term deep learning has come to refer to a collection of new techniques that, together, have demonstrated breakthrough gains over existing best-in-class machine learning algorithms across several elds. For example, over the past ve years these methods have revolutionized image classi cation and speech recognition due to their exibility and high accuracy [2]. More recently, deep learning algorithms have shown promise in elds as diverse as high-energy physics [3], computational chemistry [4], dermatology [5], and translation among written languages [6]. Across elds, “o -the-shelf” implementations of these algorithms have produced comparable or higher accuracy than previous best-in-class methods that required years of extensive customization, and specialized implementations are now being used at industrial scales. Deep learning approaches grew from research on arti cial neurons, which were rst proposed in 1943 [7] as a model for how the neurons in a biological brain process information. The history of arti cial neural networks— referred to as “neural networks” throughout this article—is interesting in its own right [8]. In neural networks, inputs are fed into the input layer, which feeds into one or more hidden layers, which eventually link to an output layer. A layer consists of a set of nodes, sometimes called “features” or “units,” which are connected via edges to the immediately earlier and the immediately deeper layers. In some special neural network architectures, nodes can connect to themselves with a delay. The nodes of the input layer generally consist of the variables being measured in the dataset of interest—for example, each node could represent the intensity value of a speci c pixel in an image or the expression level of a gene in a speci c transcriptomic experiment. The neural networks used for deep learning have multiple hidden layers. Each layer essentially performs feature construction for the layers before it. The training process used often allows layers deeper in the network to contribute to the re nement of earlier layers. For this reason, these algorithms can automatically engineer features that are suitable for many tasks and customize those features for one or more speci c tasks. Deep learning does many of the same things as more familiar machine learning approaches. In particular, deep learning approaches can be used both in supervised applications—where the goal is to accurately predict one or more labels or outcomes associated with each data point—in the place of regression approaches, as well as in unsupervised, or “exploratory” applications—where the goal is to summarize, explain, or identify interesting patterns in a data set—as a form of clustering. Deep learning methods may in fact combine both of these steps. When su cient data are available and labeled, these methods construct features tuned to a speci c problem and combine those features into a predictor. In fact, if the dataset is “labeled” with binary classes, a simple neural network with no hidden layers and no cycles between units is equivalent to logistic regression if the output layer is a sigmoid (logistic) function of the input layer. Similarly, for continuous outcomes, linear regression can be seen as a single-layer neural network. Thus, in some ways, supervised deep learning approaches can be seen as an extension of regression models that allow for greater exibility and are especially well-suited for modeling non-linear relationships among the input features. Recently, hardware improvements and very large training datasets have allowed these deep learning techniques to surpass other machine learning algorithms for many problems. In a famous and early example, scientists from Google demonstrated that a neural network “discovered” that cats, faces, and pedestrians were important components of online videos [9] without being told to look for them. What if, more generally, deep learning takes advantage of the growth of data in biomedicine to tackle challenges in this eld? Could these algorithms identify the “cats” hidden in our data—the patterns unknown to the researcher—and suggest ways to act on them? In this review, we examine deep learning’s application to biomedical science and discuss the unique challenges that biomedical data pose for deep learning methods. Several important advances make the current surge of work done in this area possible. Easy-to-use software packages have brought the techniques of the eld out of the specialist’s toolkit to a broad community of computational scientists. Additionally, new techniques for fast training have enabled their application to larger datasets [10]. Dropout of nodes, edges, and layers makes networks more robust, even when the number of parameters is very large. Finally, the larger datasets now available are also su cient for tting the many parameters that exist for deep neural networks. The convergence of these factors currently makes deep learning extremely adaptable and capable of addressing the nuanced di erences of each domain to which it is applied. Figure 1: Neural networks come in many di erent forms. Left: a key for the various types of nodes used in neural networks. Simple FFNN: a feed forward neural network in which inputs are connected via some function to an output node and the model is trained to produce some output for a set of inputs. MLP: the multi-layer perceptron is a feed forward neural network in which there is at least one hidden layer between the input and output nodes. CNN: the convolutional neural network is a feed forward neural network in which the inputs are grouped spatially into hidden nodes. In the case of this example, each input node is only connected to hidden nodes alongside their neighboring input node. Autoencoder: a type of MLP in which the neural network is trained to produce an output that matches the input to the network. RNN: a deep recurrent neural network is used to allow the neural network to retain memory over time or sequential inputs. This gure was inspired by the Neural Network Zoo by Fjodor Van Veen. This review discusses recent work in the biomedical domain, and most successful applications select neural network architectures that are well suited to the problem at hand. We sketch out a few simple example architectures in Figure 1. If data have a natural adjacency structure, a convolutional neural network (CNN) can take advantage of that structure by emphasizing local relationships, especially when convolutional layers are used in early layers of the neural network. Other neural network architectures such as autoencoders require no labels and are now regularly used for unsupervised tasks. In this review, we do not exhaustively discuss the di erent types of deep neural network architectures; an overview of the principal terms used herein is given in Table 1. Table 1 also provides select example applications, though in practice each neural network architecture has been broadly applied across multiple types of biomedical data. A recent book from Goodfellow et al. covers neural network architectures in detail [11], and LeCun et al. provide a more general introduction [2].

Opportunities and obstacles for deep learning in biology and medicine: 2019 update

Each training step for a variational autoencoder (VAE) requires us to sample from the approximate posterior, so we usually choose simple (e.g. factorised) approximate posteriors in which sampling is an efficient computation that fully exploits GPU parallelism. However, such simple approximate posteriors are often insufficient, as they eliminate statistical dependencies in the posterior. While it is possible to use normalizing flow approximate posteriors for continuous latents, some problems have discrete latents and strong statistical dependencies. The most natural approach to model these dependencies is an autoregressive distribution, but sampling from such distributions is inherently sequential and thus slow. We develop a fast, parallel sampling procedure for autoregressive distributions based on fixed-point iterations which enables efficient and accurate variational inference in discrete state-space latent variable dynamical systems. To optimize the variational bound, we considered two ways to evaluate probabilities: inserting the relaxed samples directly into the pmf for the discrete distribution, or converting to continuous logistic latent variables and interpreting the K-step fixed-point iterations as a normalizing flow. We found that converting to continuous latent variables gave considerable additional scope for mismatch between the true and approximate posteriors, which resulted in biased inferences, we thus used the former approach. Using our fast sampling procedure, we were able to realize the benefits of correlated posteriors, including accurate uncertainty estimates for one cell, and accurate connectivity estimates for multiple cells, in an order of magnitude less time.

Discrete flow posteriors for variational inference in discrete dynamical systems

What can we learn from a connectome? We constructed a simplified model of the first two stages of the fly visual system, the lamina and medulla. The resulting hexagonal lattice convolutional network was trained using backpropagation through time to perform object tracking in natural scene videos. Networks initialized with weights from connectome reconstructions automatically discovered well-known orientation and direction selectivity properties in T4 neurons and their inputs, while networks initialized at random did not. Our work is the first demonstration, that knowledge of the connectome can enable in silico predictions of the functional properties of individual neurons in a circuit, leading to an understanding of circuit function from structure alone.

A Connectome Based Hexagonal Lattice Convolutional Network Model of the Drosophila Visual System

Synaptic partner prediction from point annotations in insect brains

Biological systems are often complex nonlinear and time-varying. The modeling of biological systems, therefore, presents significant challenges that are not overcome by the classical linear methods. In recent decades, intensive research has begun to produce methods for analyzing and modeling isolated classes of nonlinear systems. However, this vast class of models still presents many challenges, especially in complex biological systems. In this research, two novel methods are introduced for analyzing time series resulting from nonlinear systems.

In Toto Imaging and Reconstruction of Post-Implantation Mouse Development at the Single-Cell Level

Resource In Toto Imaging and Reconstruction of Post-Implantation Mouse Development at the Single-Cell Level Graphical

Author(s): Huang, Furong; Anandkumar, Animashree; Borgs, Christian; Chayes, Jennifer; Fraenkel, Ernest; Hawrylycz, Michael; Lein, Ed; Ingrosso, Alessandro; Turaga, Srinivas | Abstract: Cataloging the neuronal cell types that comprise circuitry of individual brain regions is a major goal of modern neuroscience and the BRAIN initiative. Single-cell RNA sequencing can now be used to measure the gene expression profiles of individual neurons and to categorize neurons based on their gene expression profiles. While the single-cell techniques are extremely powerful and hold great promise, they are currently still labor intensive, have a high cost per cell, and, most importantly, do not provide information on spatial distribution of cell types in specific regions of the brain. We propose a complementary approach that uses computational methods to infer the cell types and their gene expression profiles through analysis of brain-wide single-cell resolution in situ hybridization (ISH) imagery contained in the Allen Brain Atlas (ABA). We measure the spatial distribution of neurons labeled in the ISH image for each gene and model it as a spatial point process mixture, whose mixture weights are given by the cell types which express that gene. By fitting a point process mixture model jointly to the ISH images, we infer both the spatial point process distribution for each cell type and their gene expression profile. We validate our predictions of cell type-specific gene expression profiles using single cell RNA sequencing data, recently published for the mouse somatosensory cortex. Jointly with the gene expression profiles, cell features such as cell size, orientation, intensity and local density level are inferred per cell type.

Discovering Neuronal Cell Types and Their Gene Expression Profiles Using a Spatial Point Process Mixture Model

The field of connectomics has recently produced neuron wiring diagrams from relatively large brain regions from multiple animals. Most of these neural reconstructions were computed from isotropic (e.g., FIBSEM) or near isotropic (e.g., SBEM) data. In spite of the remarkable progress on algorithms in recent years, automatic dense reconstruction from anisotropic data remains a challenge for the connectomics community. One significant hurdle in the segmentation of anisotropic data is the difficulty in generating a suitable initial over-segmentation. In this study, we present a segmentation method for anisotropic EM data that agglomerates a 3D over-segmentation computed from the 3D affinity prediction. A 3D U-net is trained to predict 3D affinities by the MALIS approach. Experiments on multiple datasets demonstrates the strength and robustness of the proposed method for anisotropic EM segmentation.

Anisotropic EM Segmentation by 3D Affinity Learning and Agglomeration

Population activity measurement by calcium imaging can be combined with cellular resolution optogenetic activity perturbations to enable the mapping of neural connectivity in vivo. This requires accurate inference of perturbed and unperturbed neural activity from calcium imaging measurements, which are noisy and indirect, and can also be contaminated by photostimulation artifacts. We have developed a new fully Bayesian approach to jointly inferring spiking activity and neural connectivity from in vivo all-optical perturbation experiments. In contrast to standard approaches that perform spike inference and analysis in two separate maximum-likelihood phases, our joint model is able to propagate uncertainty in spike inference to the inference of connectivity and vice versa. We use the framework of variational autoencoders to model spiking activity using discrete latent variables, low-dimensional latent common input, and sparse spike-and-slab generalized linear coupling between neurons. Additionally, we model two properties of the optogenetic perturbation: off-target photostimulation and photostimulation transients. Using this model, we were able to fit models on 30 minutes of data in just 10 minutes. We performed an all-optical circuit mapping experiment in primary visual cortex of the awake mouse, and use our approach to predict neural connectivity between excitatory neurons in layer 2/3. Predicted connectivity is sparse and consistent with known correlations with stimulus tuning, spontaneous correlation and distance.

Model-based Bayesian inference of neural activity and connectivity from all-optical interrogation of a neural circuit

Deep learning, which describes a class of machine learning algorithms, has recently showed impressive results across a variety of domains. Biology and medicine are data rich, but the data are complex and often ill-understood. Problems of this nature may be particularly well-suited to deep learning techniques. We examine applications of deep learning to a variety of biomedical problems -- patient classification, fundamental biological processes, and treatment of patients -- to predict whether deep learning will transform these tasks or if the biomedical sphere poses unique challenges. We find that deep learning has yet to revolutionize or definitively resolve any of these problems, but promising advances have been made on the prior state of the art. Even when improvement over a previous baseline has been modest, we have seen signs that deep learning methods may speed or aid human investigation. More work is needed to address concerns related to interpretability and how to best model each problem. Furthermore, the limited amount of labeled data for training presents problems in some domains, as can legal and privacy constraints on work with sensitive health records. Nonetheless, we foresee deep learning powering changes at the bench and bedside with the potential to transform several areas of biology and medicine.

Opportunities and obstacles for deep learning in biology and medicine

We present a deep structured learning method for neuron segmentation from 3D electron microscopy (EM) which improves significantly upon the state of the art in terms of accuracy and scalability. Our method consists of a 3D U-Net classifier predicting affinity graphs on voxels, followed by iterative region agglomeration. We train the U-Net using a new structured loss based on MALIS that encourages topological correctness. Our extension consists of two parts: First, an $O(n\log(n))$ method to compute the loss gradient, improving over the originally proposed $O(n^2)$ algorithm. Second, we compute the gradient in two separate passes to avoid spurious contributions in early training stages. Our affinity predictions are accurate enough that simple agglomeration outperforms more involved methods used earlier on inferior predictions. We present results on three datasets (CREMI, FIB, and SegEM) of different imaging techniques and animals and achieve improvements over previous results of 27%, 15%, and 250%. Our findings suggest that a single 3D segmentation strategy can be applied to both isotropic and anisotropic EM data. The runtime of our method scales with $O(n)$ in the size of the volume and achieves a throughput of about 2.6 seconds per megavoxel, allowing processing of very large datasets.

A Deep Structured Learning Approach Towards Automating Connectome Reconstruction from 3D Electron Micrographs

To stimulate progress in automating the reconstruction of neural circuits, we organized the first international challenge on 2D segmentation of electron microscopic (EM) images of the brain. Participants submitted boundary maps predicted for a test set of images, and were scored based on their agreement with a consensus of human expert annotations. The winning team had no prior experience with EM images, and employed a convolutional network. This “deep learning” approach has since become accepted as a standard for segmentation of EM images. The challenge has continued to accept submissions, and the best so far has resulted from cooperation between two teams. The challenge has probably saturated, as algorithms cannot progress beyond limits set by ambiguities inherent in 2D scoring and the size of the test dataset. Retrospective evaluation of the challenge scoring system reveals that it was not sufficiently robust to variations in the widths of neurite borders. We propose a solution to this problem, which should be useful for a future 3D segmentation challenge.

Crowdsourcing the creation of image segmentation algorithms for connectomics

Space-time wiring specificity supports direction selectivity in the retina

Erratum: Connectomic reconstruction of the inner plexiform layer in the mouse retina (Nature (2013) 500 (168-174) DOI:10.1038/nature12346))

Mapping social behavior-induced brain activation at cellular resolution in the mouse.

Connectomic reconstruction of the inner plexiform layer in the mouse retina

Extended abstract of a paper presented at Microscopy and Microanalysis 2011 in Nashville, Tennessee, USA, August 7–August 11, 2011.

Development of High-Throughput, High-Resolution 3D Reconstruction of Large-Volume Biological Tissue Using Automated Tape Collection Ultramicrotomy and Scanning Electron Microscopy

An agglomerative clustering algorithm merges the most similar pair of clusters at every iteration. The function that evaluates similarity is traditionally hand-designed, but there has been recent interest in supervised or semisupervised settings in which ground-truth clustered data is available for training. Here we show how to train a similarity function by regarding it as the action-value function of a reinforcement learning problem. We apply this general method to segment images by clustering superpixels, an application that we call Learning to Agglomerate Superpixel Hierarchies (LASH). When applied to a challenging dataset of brain images from serial electron microscopy, LASH dramatically improved segmentation accuracy when clustering supervoxels generated by state of the boundary detection algorithms. The naive strategy of directly training only supervoxel similarities and applying single linkage clustering produced less improvement.

Machines that learn to segment images: a crucial technology for connectomics

Many image segmentation algorithms first generate an affinity graph and then partition it. We present a machine learning approach to computing an affinity graph using a convolutional network (CN) trained using ground truth provided by human experts. The CN affinity graph can be paired with any standard partitioning algorithm and improves segmentation accuracy significantly compared to standard hand-designed affinity functions. We apply our algorithm to the challenging 3D segmentation problem of reconstructing neuronal processes from volumetric electron microscopy (EM) and show that we are able to learn a good affinity graph directly from the raw EM images. Further, we show that our affinity graph improves the segmentation accuracy of both simple and sophisticated graph partitioning algorithms. In contrast to previous work, we do not rely on prior knowledge in the form of hand-designed image features or image preprocessing. Thus, we expect our algorithm to generalize effectively to arbitrary image types.

Convolutional Networks Can Learn to Generate Affinity Graphs for Image Segmentation

Images can be segmented by first using a classifier to predict an affinity graph that reflects the degree to which image pixels must be grouped together and then partitioning the graph to yield a segmentation. Machine learning has been applied to the affinity classifier to produce affinity graphs that are good in the sense of minimizing edge misclassification rates. However, this error measure is only indirectly related to the quality of segmentations produced by ultimately partitioning the affinity graph. We present the first machine learning algorithm for training a classifier to produce affinity graphs that are good in the sense of producing segmentations that directly minimize the Rand index, a well known segmentation performance measure. The Rand index measures segmentation performance by quantifying the classification of the connectivity of image pixel pairs after segmentation. By using the simple graph partitioning algorithm of finding the connected components of the thresholded affinity graph, we are able to train an affinity classifier to directly minimize the Rand index of segmentations resulting from the graph partitioning. Our learning algorithm corresponds to the learning of maximin affinities between image pixel pairs, which are predictive of the pixel-pair connectivity.

In this thesis I present new contributions to the fields of neuroscience and computer science. The neuroscientific contribution is a new technique for automatically reconstructing complete neural networks from densely stained 3d electron micrographs of brain tissue. The computer science contribution is a new machine learning method for image segmentation and the development of a new theory for supervised hierarchy learning based on ultrametric distance functions. It is well-known that the connectivity of neural networks in the brain can have a dramatic influence on their computational function . However, our understanding of the complete connectivity of neural circuits has been quite impoverished due to our inability to image all the connections between all the neurons in biological network. Connectomics is an emerging field in neuroscience that aims to revolutionize our understanding of the function of neural circuits by imaging and reconstructing entire neural circuits. In this thesis, I present an automated method for reconstructing neural circuitry from 3d electron micrographs of brain tissue. The cortical column, a basic unit of cortical microcircuitry, will produce a single 3d electron micrograph measuring many 100s terabytes once imaged and contain neurites from well over 100,000 different neurons. It is estimated that tracing the neurites in such a volume by hand would take several thousand human years. Automated circuit tracing methods are thus crucial to the success of connectomics. In computer vision, the circuit reconstruction problem of tracing neurites is known as image segmentation. Segmentation is a grouping problem where image pixels belonging to the same neurite are clustered together. While many algorithms for image segmentation exist, few have parameters that can be optimized using groundtruth data to extract maximum performance on a specialized dataset. In this thesis, I present the first machine learning method to directly minimize an image segmentation error. It is based the theory of ultrametric distances and hierarchical clustering. Image segmentation is posed as the problem of learning and classifying ultrametric distances between image pixels. Ultrametric distances on point set have the special property that

Learning image segmentation and hierarchies by learning ultrametric distances

Convolutional networks have achieved a great deal of success in high-level vision problems such as object recognition. Here we show that they can also be used as a general method for low-level image processing. As an example of our approach, convolutional networks are trained using gradient learning to solve the problem of restoring noisy or degraded images. For our training data, we have used electron microscopic images of neural circuitry with ground truth restorations provided by human experts. On this dataset, Markov random field (MRF), conditional random field (CRF), and anisotropic diffusion algorithms perform about the same as simple thresholding, but superior performance is obtained with a convolutional network containing over 34,000 adjustable parameters. When restored by this convolutional network, the images are clean enough to be used for segmentation, whereas the other approaches fail in this respect. We do not believe that convolutional networks are fundamentally superior to MRFs as a representation for image processing algorithms. On the contrary, the two approaches are closely related. But in practice, it is possible to train complex convolutional networks, while even simple MRF models are hindered by problems with Bayesian learning and inference procedures. Our results suggest that high model complexity is the single most important factor for good performance, and this is possible with convolutional networks.

Supervised Learning of Image Restoration with Convolutional Networks

Multipath propagation in shallow water can lead to mismatch losses when single-path replicas are used for horizontal array beamforming. Matched field processing (MFP) seeks to remedy this by using full-field acoustic propagation models to predict the multipath arrival structure. Ideally, MFP can give source localization in range and depth as well as detection gains, but robustly estimating range and depth is difficult in practice. The approach described here seeks to collapse full-field replica outputs to bearing, which is robustly estimated, while retaining any signal gains provided by the full-field model. Cluster analysis is used to group together full-field replicas with similar responses. This yields a less redundant “sampled field” describing a set of representative multipath structures for each bearing. A detection algorithm is introduced that uses clustering to collapse beamformer outputs to bearing such that signal gains are retained while increases in the noise floor are minimized. Horizontal ar...

Cluster analysis and robust use of full-field models for sonar beamforming

Cluster analysis provides a tool for mapping out regions of ambiguous response in sparse array beamforming problems. This paper discusses clustering and its application to matched field processing (MFP) problems in ocean acoustics. The map of the ambiguity volume provided by clustering can be used for improved interpretation and postprocessing. By peak-picking in cluster space, rather than in spatial dimensions, we are able to identify and discard ambiguous peaks that result from the presence of a strong source. As shown in a data example, clustering can help collapse 3-D MFP output to bearings-only while preserving signal gains obtained by accounting for multipath. Clustering can also provide computational gains by allowing elimination of highly redundant replicas. 1. OVERVIEW OF MATCHED FIELD Matched field processing has been extensively explored for use in detecting and localizing underwater sources. MFP uses ocean propagation models to account for multipath when generating replica vectors. If accurate environmental information is available, sources can be localized in range, depth, and bearing. Accurately modeling multipath can also yield mismatch reduction and detection gains as compared to direct-path beamformers. A significant problem for MFP is that the beamformer output often displays high ambiguities in range and depth, with a single source leading to multiple spatial peaks. This is particularly true for arrays without significant vertical aperture because of their limited ability to resolve multipath. MFP for these arrays can be thought of as a form of sparse array processing with resultant high ambiguities. Many of the ambiguous peaks may be within a few dB of the overall peak, so they are not easily suppressed with adaptive beamforming. This work was sponsored by DARPA-ATO under Air Force Contract F19628-00-C-0002. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the United States Government. MFP replicas are generated for a set of look directions in range, depth, and azimuth. If we define Θ = (r, φ, z) as the look direction, the MFP output for an N element array at frequency f0, time t0, and direction Θ is given by

Abstract : Cluster analysis provides a tool for mapping out regions of ambiguous response in sparse array beam forming problems. This paper discusses clustering and its application to matched field processing (MFP) problems in ocean acoustics. The map of the ambiguity volume provided by clustering can be used for improved interpretation and postprocessing. By peak-picking in cluster space, rather than in spatial dimensions, the authors are able to identify and discard ambiguous peaks that result from the presence of a strong source. As shown in a data example, clustering can help collapse three-dimensional MFP output to bearings-only while preserving signal gains obtained by accounting for multipath. Clustering also can provide computational gains by allowing the elimination of highly redundant replicas.

Statistical Clustering Methods Applied to Adaptive Matched Field Processing

Matched field processing (MFP) offers the possibility of improved sonar performance through range/depth discrimination of contacts. One challenge is that arrays with limited vertical aperture can often resolve only a small number of multipath arrivals. This paper explores ways to capture the array resolution by re-parametrizing the set of MFP replicas. A variant on beam-space processing can be created by performing a singular value decomposition (SVD) on the MFP replica set. Clustering techniques can be used to identify MFP ”clusters”, or regions of similar response. Beamforming can then be done on only one representative of the cluster, with output mapped to other cluster members. These parametrizations are applied to adaptive MFP algorithms to show speed and performance gains.

We present an efficient Monte Carlo algorithm for simulating diffusion in tight-fitting host–guest systems, based on using zeolite normal modes. Computational efficiency is gained by sampling framework distortions using normal-mode coordinates, and by exploiting the fact that zeolite distortion energies are well approximated by harmonic estimates. Additional savings are obtained by performing local normal-mode analysis, i.e., only including the motions of zeolite atoms close to the jumping molecule, hence focusing the calculation on zeolite distortions relevant to guest diffusion. We performed normal-mode analysis on various silicalite structures to demonstrate the accuracy of the harmonic approximation. We computed free energy surfaces for benzene in silicalite, finding excellent agreement with previous theoretical studies. Our method is found to be orders-of-magnitude faster than comparable Monte Carlo calculations that use conventional forcefields to quantify zeolite distortion energies. For tight-fitt...

Calculating free energies for diffusion in tight-fitting zeolite-guest systems: Local normal-mode Monte Carlo

Matched field processing (MFP) offers the possibility of improved towed array performance at endfire through range/depth discrimination of contacts. One challenge is that arrays with limited vertical aperture can often resolve only a small number of multipath arrivals. This paper explores ways to capture the array resolution by re‐parametrizing the set of MFP replicas. A reduced beamset can be created by performing a singular value decomposition on the MFP replica set. Alternatively, clustering techniques can be used to generate MFP cell families, or regions of similar response. These parametrizations are applied to adaptive MFP algorithms to show speed and performance gains. The use of cell families/regions instead of individual MFP cells also provides a framework for increasing the robustness of MFP by defocusing the MFP beamforming operation. The techniques are demonstrated for shallow‐water towed array scenarios. [Work sponsored by DARPA‐ATO under Air Force Contract No. F19628‐00‐C‐0002. Opinions, int...

I study the emergent behavior in the self-play of simple value function based reinforcement learning algorithms in an iterative two player general-sum game. The players are assumed to have limited knowledge of the game. Therefore learning algorithms only use information about their own choice and recieved reward histories to compute a value function based on which actions are chosen stochastically. Two related algorithms are studied, with fixed points that correspond to matching and Nash equilibria respectively. Linear stability analysis is used to probe the dynamics about the fixed points. Linear analysis shows that the matching equilibrium is stable, while the algorithm with the Nash equilibrium has marginal stability. Numerical simulations suggest that the Nash equilibrium is unstable for this class of algorithms and that algorithms with equilibria lying near the matching equilibrium are progressively more stable.

Convergence Analysis of Certain Reinforcement Learning Algorithms in Self-Play

AIMS
The aim of this study was to assess the clinical value of biomarkers to identify TAVI patients at high risk for adverse outcome, to assess whether these biomarkers provide prognostic information beyond that of established clinical risk scores, and to assess whether a combined multi-marker strategy can improve clinical decision making.

METHODS AND RESULTS
In 683 TAVI patients, biomarkers reflecting various pathophysiologic systems were measured before TAVI. The primary endpoint was one-year all-cause mortality. Other outcomes were recorded according to the VARC-2 criteria. Thirty-day and one-year mortality was 2.9% and 12.0%, respectively. Non-survivors at one year had higher risk scores and increased median biomarker levels. Logistic EuroSCORE in combination with hs-CRP had the highest predictive value for 30-day (AUC 0.740 [95% CI: 0.667-0.812], p=0.1117) and one-year mortality (AUC 0.631 [95% CI: 0.569-0.693], p=0.0403). In multivariate regression analysis, logistic EuroSCORE in combination with hs-CRP showed the strongest association with one-year mortality. Combinations of increasing medians of logistic EuroSCORE results and hs-CRP levels allowed the stratification of the TAVI patients into subgroups with one-year mortality rates ranging from 6.6% up to 18.2%.

hs-CRP alongside the logistic EuroSCORE was an independent predictor of one-year all-cause mortality in TAVI patients. A combination of both might help to predict procedural risk and outcome better.

EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology

Combination of high-sensitivity C-reactive protein with logistic EuroSCORE improves risk stratification in patients undergoing TAVI.

Atherosclerosis and COPD are both systemic inflammatory diseases that may influence each other. The aim of the present study was to determine the prevalence of COPD in patients with cerebral and/or peripheral artery disease and to assess factors associated with the presence of COPD. Following the diagnosis of cerebral and/or peripheral artery disease by means of duplex sonography, 166 consecutive patients underwent body plethysmography with capillary blood gas analysis. Thereafter, blood tests with determination of different parameters such as lipid profile, inflammatory and coagulation markers were conducted in remaining 136 patients who fulfilled inclusion criteria of the study. Thirty-six out of 136 patients suffered from COPD, mostly in early stages of the disease. Residual volume indicating emphysema was increased (162.9%±55.9% vs 124.5%±37.0%, p<0.05) and diffusion capacity was decreased (55.1%±19.5% vs 75.3%±18.6%, p<0.05) in COPD patients vs non-COPD group. In capillary blood gas analysis, COPD patients had lower partial pressure of oxygen (70.9±11.5 vs 75.2±11.0 mmHg, p<0.05) and higher partial pressure of carbon dioxide (36.8±7.5 vs 34.4±4.4 mmHg, p<0.05) compared with non-COPD individuals. Presence of COPD was associated with predominance of diabetes mellitus, interleukin-8-related systemic neutrophilic inflammation and anemia. In conclusion, COPD is highly prevalent in patients with atherosclerotic artery disease.

High prevalence of obstructive pulmonary diseases in patients with peripheral artery disease

Zusammenfassung Die Verarbeitung sensorischer Information kann sowohl im Kortex als auch im Thalamus durch den Verhaltenskontext, z. B. durch aktive Fortbewegung, moduliert werden. Solch aktives Verhalten verbessert die Kodierung sensorischer Reize und die Wahrnehmung, besonders während Aktivitäten von moderater Intensität. Der Modulation sensorischer Verarbeitung durch Fortbewegung scheint eine Kombination von Mechanismen zugrunde zu liegen, unter anderem neuromodulatorische Einflüsse, die Aktivität spezifischer, inhibitorischer Interneurone, sowie top-down- oder motorische Rückprojektionen. Neue experimentelle Ansätze, die es Mäusen erlauben, sich trotz Kopffixation auf Laufbällen oder –bändern fortzubewegen, ermöglichte es in den letzten Jahren, die neuronalen Schaltkreise und zellulären Elemente, die der Modulation durch Verhaltenskontext zugrunde liegen, eingehend zu untersuchen. Dieser Übersichtsartikel fasst den momentanen Stand dieser Studien zusammen und beleuchtet wichtige offenen Fragen.

Der Einfluss von Fortbewegung auf die sensorische Informationsverarbeitung und die zugrunde liegenden neuronalen Schaltkreise

DIE MEGAKARYOPOESEAKTIVITAT IM ZYTOLOGISCHEN KNOCHENMARK-PRAPARAT DES HUNDES : BEI AUTOIMMUNBEDINGTER THROMBOZYTOPENIE UND EHRLICHIA-CANIS-INFEKTION I M VERGLEICH ZUM GESUNDEN HUND

For about 10 years, many individual crack diagnoses have been registered during inspections on shaft-side fir tree-type mountings of the blading of the large low-pressure sections of turbines. In the meantime, the results of non-destructive crack tests on a larger number of comparable plants have become available. No connection is to be established with the number of hours of operation or start-ups. The detailed design of the fir tree-type mountings is not the cause of the cracks, as numerous crack-free plants with many start-ups and hours of operation demonstrate. Metallographic investigations show that it is a question of cracks which are initiated hy corrosion pitting, the cause of which is seen to be mainly in the trcatment of shut-down machines and less in on-load operation.

Une reserve de puissance active pendant quelques secondes est indispensable pour assurer le bon equilibre de charge d'un reseau electrique. Un changement de combustible d'une chaudiere demande quelques minutes pour la reprise de charge. Le maintien de la puissance se fait par liberation d'une reserve de vapeur contenue dans la chaudiere. En meme temps, les soupapes de reglage de la turbine sont maintenues levees. L'importance de ce type de reserve pour la regulation de la charge d'une tranche est indiquee

Sekundenleistungsreserve und Wärmeverbrauch bei verschiedenen Betriebsarten von Dampfturbinen

Neural networks: Explaining animal behavior with prior knowledge of the world

Due to the staggering complexity of the brain and its neural circuitry, neuroscientists rely on the analysis of mathematical models to elucidate its function. From Hodgkin and Huxley's detailed description of the action potential in 1952 to today, new theories and increasing computational power have opened up novel avenues to study how neural circuits implement the computations that underlie behavior. Computational neuroscientists have developed many models of neural circuits that differ in complexity, biological realism, or emergent network properties. With recent advances in experimental techniques for detailed anatomical reconstructions of large-scale activity recordings, precise biological data has become more available. The challenge when building network models is to reflect experimental results, either through a high level of detail or by finding an appropriate level of abstraction. Meanwhile, machine learning has facilitated the development of artificial neural networks (ANN), which are trained to perform specific tasks. While they have proven successful at achieving task-oriented behavior, they are often abstract constructs that differ in many features from the physiology of brain circuits. Thus, it is unclear whether the mechanisms underlying computation in biological circuits can be investigated by analyzing artificial networks that accomplish the same function but differ in their mechanisms. Here, we argue that building biologically realistic network models is crucial to establishing causal relationships between neurons, synapses, circuits, and behavior. More specifically, we advocate for network models that consider the connectivity structure and the recorded activity dynamics while evaluating task performance.

How to incorporate biological insights into network models and why it matters.

Neurons in the dorsolateral geniculate nucleus (dLGN) of the thalamus receive a substantial proportion of modulatory inputs from corticothalamic (CT) feedback and brain stem nuclei. Hypothesizing that these modulatory influences might be differentially engaged depending on the visual stimulus and behavioral state, we performed in vivo extracellular recordings from mouse dLGN while optogenetically suppressing CT feedback and monitoring behavioral state by locomotion and pupil dilation. For naturalistic movie clips, we found CT feedback to consistently increase dLGN response gain and promote tonic firing. In contrast, for gratings, CT feedback effects on firing rates were mixed. For both stimulus types, the neural signatures of CT feedback closely resembled those of behavioral state, yet effects of behavioral state on responses to movies persisted even when CT feedback was suppressed. We conclude that CT feedback modulates visual information on its way to cortex in a stimulus-dependent manner, but largely independently of behavioral state.

Robust effects of corticothalamic feedback and behavioral state on movie responses in mouse dLGN

SPP2411: ‘Sensing LOOPS: cortico-subcortical interactions for adaptive sensing’

Significance The relation between structure and function is particularly fascinating in neural networks. Direct connectivity measurements in the mouse primary visual cortex show large variability across experimental reports. Can various synaptic connectivity matrices lead to similar firing patterns recorded in the cortex? Vice versa, can observations of firing rate activity constrain possible synaptic wiring patterns? We show that model-based connectivity inference from activity recorded in the thalamus and primary visual cortex reveals hidden ascending order in the strengths of otherwise diverse experimentally reported cortical connections. Thus, diverse cortical connectivity patterns contain mutual motifs that support canonical neural computations observed across cortices and experiments.

In vivo extracellular recordings of thalamic and cortical visual responses reveal V1 connectivity rules

Neural system identification aims at learning the response function of neurons to arbitrary stimuli using experimentally recorded data, but typically does not leverage normative principles such as efficient coding of natural environments. Visual systems, however, have evolved to efficiently process input from the natural environment. Here, we present a normative network regularization for system identification models by incorporating, as a regularizer, the efficient coding hypothesis, which states that neural response properties of sensory representations are strongly shaped by the need to preserve most of the stimulus information with limited resources. Using this approach, we explored if a system identification model can be improved by sharing its convolutional filters with those of an autoencoder which aims to efficiently encode natural stimuli. To this end, we built a hybrid model to predict the responses of retinal neurons to noise stimuli. This approach did not only yield a higher performance than the “stand-alone” system identification model, it also produced more biologically-plausible filters. We found these results to be consistent for retinal responses to different stimuli and across model architectures. Moreover, our normatively regularized model performed particularly well in predicting responses of direction-of-motion sensitive retinal neurons. In summary, our results support the hypothesis that efficiently encoding environmental inputs can improve system identification models of early visual processing.

Efficient coding of natural scenes improves neural system identification

The way in which sensory systems encode information, even at early processing stages, is modulated according to the internal state of the animal. Internal states, such as arousal, are often characterized by relating neural variables to a single “level” of arousal, defined using a behavioral variable such as locomotion or pupil size. Here, we extend the notion of arousal-related modulation by showing that multifaceted aspects of pupil size dynamics can predict changes in neural activity. Specifically, we show that the phases of pupil size fluctuations occurring over multiple timescales modulate firing mode in the dorsal lateral geniculate nucleus (dLGN) of mice. Increased firing rates, driven by a preponderance of tonic spiking, occurred during pupil dilations, while burst spikes preferentially occurred during contractions. We further find that these activity modulations could not be explained solely by pupil size per se, or by transitions between overt locomotion and quiescence, and extend to periods of patterned stimulus viewing. We conclude that dLGN spiking activity is modulated by pupil-indexed arousal processes on various timescales, with implications for the determination of arousal-related cortical rhythms, and for the transfer of sensory information to the cortex.

Modulation of dLGN firing mode across multiple timescales is predicted by pupil size dynamics

Should I stay or should I go? A thalamic circuit for modulating behavioral responses to visual threat

Choosing an action in response to visual cues relies on cognitive processes, such as perception, evaluation, and prediction, which can modulate visual representations even at early processing stages. In the mouse, it is challenging to isolate cognitive modulations of sensory signals because concurrent overt behavior patterns, such as locomotion, can also have brainwide influences. To address this challenge, we designed a task, in which head-fixed mice had to evaluate one of two visual cues. Choosing an action in response to visual cues relies on cognitive processes, such as perception, evaluation, and prediction, which can modulate visual representations even at early processing stages. In the mouse, it is challenging to isolate cognitive modulations of sensory signals because concurrent overt behavior patterns, such as locomotion, can also have brainwide influences. To address this challenge, we designed a task, in which head-fixed mice had to evaluate one of two visual cues. While their global shape signaled the opportunity to earn reward, the cues provided equivalent local stimulation to receptive fields of neurons in primary visual (V1) and anterior cingulate cortex (ACC). We found that mice evaluated these cues within few hundred milliseconds. During this period, ∼30% of V1 neurons became cue-selective, with preferences for either cue being balanced across the recorded population. This selectivity emerged in response to the behavioral demands because the same neurons could not discriminate the cues in sensory control measurements. In ACC, cue evaluation affected a similar fraction of neurons; emerging selectivity, however, was stronger than in V1, and preferences in the recorded population were biased toward the cue promising reward. Such a biased selectivity regime might allow the mouse to infer the promise of reward simply by the overall level of activity. Together, these experiments isolate the impact of task demands on neural responses in mouse cerebral cortex, and document distinct neural signatures of cue evaluation in V1 and ACC. SIGNIFICANCE STATEMENT Performing a cognitive task, such as evaluating visual cues, not only recruits frontal and parietal brain regions, but also modulates sensory processing stages. We trained mice to evaluate two visual cues, and show that, during this task, ∼30% of neurons recorded in V1 became selective for either cue, although they provided equivalent visual stimulation. We also show that, during cue evaluation, mice frequently move their eyes, even under head fixation, and that ignoring systematic differences in eye position can substantially obscure the modulations seen in V1 neurons. Finally, we document that modulations are stronger in ACC, and biased toward the reward-predicting cue, suggesting a transition in the neural representation of task-relevant information across processing stages in mouse cerebral cortex.

Evaluating Visual Cues Modulates Their Representation in Mouse Visual and Cingulate Cortex

Pupil size is a commonly used proxy for waking brain states such as arousal, and has been related to activity modulations in cortical sensory areas. Here, we asked whether the dorsolateral geniculate nucleus (dLGN), which provides sensory input to the visual cortex, is modulated by pupil-indexed arousal. Observing that the pupil oscillates at multiple timescales, we developed a method to show that the spiking mode of the dLGN is predicted by pupil size oscillations over several of these timescales. Overall, we found that tonic spikes preferentially occurred during pupil dilation, while bursts occurred during contraction. These preferences could not be explained solely by pupil size per se or by the locomotion of the animal, and were also present during periods of stimulus viewing. We conclude that dLGN spiking activity is modulated by pupil-indexed arousal processes on various timescales, influencing the mode in which sensory signals are passed on to the cortex.

Pupil Size Dynamics Predict dLGN Firing Mode Over a Wide Range of Timescales

Natural environment statistics in the upper and lower visual field are reflected in mouse retinal specializations

Corticothalamic feedback sculpts visual spatial integration in mouse thalamus

Pressures for survival drive sensory circuit adaption to a species’ habitat, making it essential to statistically characterise natural scenes. Mice, a prominent visual system model, are dichromatic with enhanced sensitivity to green and UV. Their visual environment, however, is rarely considered. Here, we built a UV-green camera to record footage from mouse habitats. We found chromatic contrast to greatly diverge in the upper but not the lower visual field, an environmental difference that may underlie the species’ superior colour discrimination in the upper visual field. Moreover, training an autoencoder on upper but not lower visual field scenes was sufficient for the emergence of colour-opponent filters. Furthermore, the upper visual field was biased towards dark UV contrasts, paralleled by more light-offset-sensitive cells in the ventral retina. Finally, footage recorded at twilight suggests that UV promotes aerial predator detection. Our findings support that natural scene statistics shaped early visual processing in evolution. Lead contact Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Thomas Euler (thomas.euler@cin.uni-tuebingen.de)

Mouse retinal specializations reflect knowledge of natural environment statistics

Neurons in the dorsolateral geniculate nucleus (dLGN) of the thalamus are contacted by a large number of feedback synapses from cortex, whose role in visual processing is poorly understood. Past studies investigating this role have mostly used simple visual stimuli and anesthetized animals, but corticothalamic (CT) feedback might be particularly relevant during processing of complex visual stimuli, and its effects might depend on behavioral state. Here, we find that CT feedback robustly modulates responses to naturalistic movie clips by increasing response gain and promoting tonic firing mode. Compared to these robust effects for naturalistic movies, CT feedback effects on firing rates were less consistent for grating stimuli. Finally, while CT feedback and locomotion affected dLGN responses in similar ways, we found their effects to be largely independent. We propose that CT feedback and behavioral state use separate circuits to modulate visual information on its way to cortex in a stimulus-dependent manner.

Robust effects of corticothalamic feedback during naturalistic visual stimulation

Neurons in the dorsolateral geniculate nucleus (dLGN) of the thalamus are contacted by a large number of feedback synapses from cortex, whose role in visual processing is poorly understood. Past studies investigating this role have mostly used simple visual stimuli and anesthetized animals, but corticothalamic (CT) feedback might be particularly relevant during processing of complex visual stimuli, and its effects might depend on behavioral state. Here, we find that CT feedback robustly modulates responses to naturalistic movie clips by increasing response gain and promoting tonic firing mode. Compared to these robust effects for naturalistic movies, CT feedback effects were less consistent for simple grating stimuli. Finally, while CT feedback and locomotion affected dLGN responses in similar ways, we found their effects to be largely independent. We propose that CT feedback and behavioral state use separate routes to powerfully modulate visual information on its way to cortex.

Robust effects of cortical feedback on thalamic firing mode during naturalistic stimulation

To establish useful representations of the environment, primary visual cortex (V1) integrates inputs from various spatial locations. Spatial integration is a fundamental, context-dependent neural operation involving extensive neural circuits that span across all cortical layers of a V1 column and reflects both feedforward and feedback processing. How spatial integration is dynamically coordinated across cortical layers remains poorly understood. We recorded single- and multi-unit activity and local field potentials across V1 layers of awake mice while they viewed stimuli of varying size, and used dynamic Bayesian model comparisons to identify when laminar activity and inter-laminar functional interactions showed surround suppression, the hallmark of spatial integration. We found that surround suppression is strongest in layer 3 (L3) and L4, where suppression is established within ~10 ms after response onset, and that receptive fields dynamically sharpen while suppression strength increases. Importantly, we also found that specific inter-laminar functional connections resembled a surround-suppressed tuning curve, parametrically driving target layers depending on stimulus context. Taken together our results shed light on how L3 dynamically coordinates activity across a cortical column and on the different functional roles of cortical layers in spatial integration.

Layer 3 dynamically coordinates columnar activity during spatial integration in mouse V1

Abstract Processing of sensory information can be modulated in both cortex and thalamus by behavioral context, such as locomotion. During active behaviors, coding of sensory stimuli and perception are improved, in particular during physical activity of moderate intensity. These locomotion-related modulations seem to arise from a combination of mechanisms, including neuromodulation, the recruitment of inhibitory interneurons, and specific top-down or motor-related inputs. The application of new experimental methods in mice during walking under head-fixation on treadmills made it possible to study the circuit and cellular basis underlying modulations by behavioral context with unprecedented detail. This article reviews the current state of these studies and highlights some important open questions.

The influence of locomotion on sensory processing and its underlying neuronal circuits

To reduce statistical redundancy of natural inputs and increase the sparseness of coding, neurons in primary visual cortex (V1) show tuning for stimulus size and surround suppression. This integration of spatial information is a fundamental, context-dependent neural operation involving extensive neural circuits that span across all cortical layers of a V1 column, and reflects both feedforward and feedback processing. However, how spatial integration is dynamically coordinated across cortical layers remains poorly understood. We recorded single- and multiunit activity and local field potentials across V1 layers of awake mice (both sexes) while they viewed stimuli of varying size and used dynamic Bayesian model comparisons to identify when laminar activity and interlaminar functional interactions showed surround suppression, the hallmark of spatial integration. We found that surround suppression is strongest in layer 3 (L3) and L4 activity, where suppression is established within ∼10 ms after response onset, and receptive fields dynamically sharpen while suppression strength increases. Importantly, we also found that specific directed functional connections were strongest for intermediate stimulus sizes and suppressed for larger ones, particularly for connections from L3 targeting L5 and L1. Together, the results shed light on the different functional roles of cortical layers in spatial integration and on how L3 dynamically coordinates activity across a cortical column depending on spatial context. SIGNIFICANCE STATEMENT Neurons in primary visual cortex (V1) show tuning for stimulus size, where responses to stimuli exceeding the receptive field can be suppressed (surround suppression). We demonstrate that functional connectivity between V1 layers can also have a surround-suppressed profile. A particularly prominent role seems to have layer 3, the functional connections to layers 5 and 1 of which are strongest for stimuli of optimal size and decreased for large stimuli. Our results therefore point toward a key role of layer 3 in coordinating activity across the cortical column according to spatial context.

Layer 3 Dynamically Coordinates Columnar Activity According to Spatial Context

A substantial portion of our sensory experience happens during active behaviors such as walking around or paying attention. How do sensory systems work during such behaviors? Neural processing in sensory systems can be shaped by behavior in multiple ways ranging from a modulation of responsiveness or sharpening of tuning to a dynamic change of response properties or functional connectivity. Here, we review recent findings on the modulation of sensory processing during active behaviors in different systems: insect vision, rodent thalamus, and rodent sensory cortices. We discuss the circuit-level mechanisms that might lead to these modulations and their potential role in sensory function. Finally, we highlight the open questions and future perspectives of this exciting new field.

Processing of Feedforward and Feedback Signals in the Lateral Geniculate Nucleus of the Thalamus

A fundamental property of visual cortex is to enhance the representation of those stimuli that are relevant for behavior, but it remains poorly understood how such enhanced representations arise during learning. Using classical conditioning in adult mice of either sex, we show that orientation discrimination is learned in a sequence of distinct behavioral stages, in which animals first rely on stimulus appearance before exploiting its orientation to guide behavior. After confirming that orientation discrimination under classical conditioning requires primary visual cortex (V1), we measured, during learning, response properties of V1 neurons. Learning improved neural discriminability, sharpened orientation tuning, and led to higher contrast sensitivity. Remarkably, these learning-related improvements in the V1 representation were fully expressed before successful orientation discrimination was evident in the animals' behavior. We propose that V1 plays a key role early in discrimination learning to enhance behaviorally relevant sensory information. SIGNIFICANCE STATEMENT Decades of research have documented that responses of neurons in visual cortex can reflect the behavioral relevance of visual information. The behavioral relevance of any stimulus needs to be learned, though, and little is known how visual sensory processing changes, as the significance of a stimulus becomes clear. Here, we trained mice to discriminate two visual stimuli, precisely quantified when learning happened, and measured, during learning, the neural representation of these stimuli in V1. We observed learning-related improvements in V1 processing, which were fully expressed before discrimination was evident in the animals' behavior. These findings indicate that sensory and behavioral improvements can follow different time courses and point toward a key role of V1 at early stages in discrimination learning.

Learning Enhances Sensory Processing in Mouse V1 before Improving Behavior

Subcortical Source and Modulation of the Narrowband Gamma Oscillation in Mouse Visual Cortex

Visual processing along the primate ventral stream takes place in a hierarchy of areas, characterized by an increase in both complexity of neuronal preferences and invariance to changes of low-level stimulus attributes. A basic type of invariance is form-cue invariance, where neurons have similar preferences in response to first-order stimuli, defined by changes in luminance, and global features of second-order stimuli, defined by changes in texture or contrast. Whether in mice, a now popular model system for early visual processing, visual perception can be guided by second-order stimuli is currently unknown. Here, we probed mouse visual perception and neural responses in areas V1 and LM using various types of second-order, contrast-modulated gratings with static noise carriers. These gratings differ in their spatial frequency composition and thus in their ability to invoke first-order mechanisms exploiting local luminance features. We show that mice can transfer learning of a coarse orientation discrimination task involving first-order, luminance-modulated gratings to the contrast-modulated gratings, albeit with markedly reduced discrimination performance. Consistent with these behavioral results, we demonstrate that neurons in area V1 and LM are less responsive and less selective to contrast-modulated than to luminance-modulated gratings, but respond with broadly similar preferred orientations. We conclude that mice can, at least in a rudimentary form, use second-order stimuli to guide visual perception. SIGNIFICANCE STATEMENT To extract object boundaries in natural scenes, the primate visual system does not only rely on differences in local luminance but can also take into account differences in texture or contrast. Whether the mouse, which has a much simpler visual system, can use such second-order information to guide visual perception is unknown. Here we tested mouse perception of second-order, contrast-defined stimuli and measured their neural representations in two areas of visual cortex. We find that mice can use contrast-defined stimuli to guide visual perception, although behavioral performance and neural representations were less robust than for luminance-defined stimuli. These findings shed light on basic steps of feature extraction along the mouse visual cortical hierarchy, which may ultimately lead to object recognition.

Mice Can Use Second-Order, Contrast-Modulated Stimuli to Guide Visual Perception

Behavioral and neural effects of visual masking and optogenetic V1 suppression in mice

Temporal predictability of visual target onset by audition leads to decrease in evoked neural activity in mouse V1

Representation of Concurrent Stimuli by Population Activity in Visual Cortex

Effects of Locomotion Extend throughout the Mouse Early Visual System

Responses of many neurons in primary visual cortex (V1) are suppressed by stimuli exceeding the classical receptive field (RF), an important property that might underlie the computation of visual saliency. Traditionally, it has proven difficult to disentangle the underlying neural circuits, including feedforward, horizontal intracortical, and feedback connectivity. Since circuit-level analysis is particularly feasible in the mouse, we asked whether neural signatures of spatial integration in mouse V1 are similar to those of higher-order mammals and investigated the role of parvalbumin-expressing (PV+) inhibitory interneurons. Analogous to what is known from primates and carnivores, we demonstrate that, in awake mice, surround suppression is present in the majority of V1 neurons and is strongest in superficial cortical layers. Anesthesia with isoflurane-urethane, however, profoundly affects spatial integration: it reduces the laminar dependency, decreases overall suppression strength, and alters the temporal dynamics of responses. We show that these effects of brain state can be parsimoniously explained by assuming that anesthesia affects contrast normalization. Hence, the full impact of suppressive influences in mouse V1 cannot be studied under anesthesia with isoflurane-urethane. To assess the neural circuits of spatial integration, we targeted PV+ interneurons using optogenetics. Optogenetic depolarization of PV+ interneurons was associated with increased RF size and decreased suppression in the recorded population, similar to effects of lowering stimulus contrast, suggesting that PV+ interneurons contribute to spatial integration by affecting overall stimulus drive. We conclude that the mouse is a promising model for circuit-level mechanisms of spatial integration, which relies on the combined activity of different types of inhibitory interneurons.

Title: Spatial integration in mouse primary visual cortex 1 2 Authors and author addresses: 3 Agne Vaiceliunaite1,2, Sinem Erisken1, Florian Franzen1, Steffen Katzner1, and 4 Laura Busse1 5 6 1Werner Reichardt Centre for Integrative Neuroscience, University of Tübingen, 7 Germany 8 2Department of Neurobiology Biophysics, Faculty of Natural Sciences, Vilnius 9 University, Lithuania 10 11 Running head: Spatial integration in mouse visual cortex 12 13 Contact information: 14 Laura Busse 15 Centre for Integrative Neuroscience 16 University of Tübingen 17 Otfried-Müller-Str. 25 18 72076 Tübingen 19 Germany 20 laura.busse@cin.uni-tuebingen.de 21 22 Articles in PresS. J Neurophysiol (May 29, 2013). doi:10.1152/jn.00138.2013

Title: Spatial Integration in Mouse Primary Visual Cortex 1 2 Spatial Integration in Mouse Primary

One of the key features of active perception is the ability to predict critical sensory events. Humans and animals can implicitly learn statistical regularities in the timing of events and use them to improve behavioral performance. Here, we used a signal detection approach to investigate whether such improvements in performance result from changes of perceptual sensitivity or rather from adjustments of a response criterion. In a regular sequence of briefly presented stimuli, human observers performed a noise-limited motion detection task by monitoring the stimulus stream for the appearance of a designated target direction. We manipulated target predictability through the hazard rate, which specifies the likelihood that a target is about to occur, given it has not occurred so far. Analyses of response accuracy revealed that improvements in performance could be accounted for by adjustments of the response criterion; a growing hazard rate was paralleled by an increasing tendency to report the presence of a target. In contrast, the hazard rate did not affect perceptual sensitivity. Consistent with previous research, we also found that reaction time decreases as the hazard rate grows. A simple rise-to-threshold model could well describe this decrease and attribute predictability effects to threshold adjustments rather than changes in information supply. We conclude that, even under conditions of full attention and constant perceptual sensitivity, behavioral performance can be optimized by dynamically adjusting the response criterion to meet ongoing changes in the likelihood of a target.

Improving behavioral performance under full attention by adjusting response criteria to changes in stimulus predictability.

Cortical circuits encode sensory stimuli through the firing of neuronal ensembles, and also produce spontaneous population patterns in the absence of sensory drive. This population activity is often characterized experimentally by the distribution of multineuron “words” (binary firing vectors), and a match between spontaneous and evoked word distributions has been suggested to reflect learning of a probabilistic model of the sensory world. We analyzed multineuron word distributions in sensory cortex of anesthetized rats and cats, and found that they are dominated by fluctuations in population firing rate rather than precise interactions between individual units. Furthermore, cortical word distributions change when brain state shifts, and similar behavior is seen in simulated networks with fixed, random connectivity. Our results suggest that similarity or dissimilarity in multineuron word distributions could primarily reflect similarity or dissimilarity in population firing rate dynamics, and not necessarily the precise interactions between neurons that would indicate learning of sensory features.

Population Rate Dynamics and Multineuron Firing Patterns in Sensory Cortex

Numerous studies have revealed traveling waves of activity in sensory cortex, both following sensory stimulation and during ongoing activity. We contributed to this body of work by measuring the spike-triggered average of the local field potential (stLFP) at multiple concurrent locations (Nauhaus et al., 2009) in the visual cortex of anesthetized cats and macaques. We found the stLFP to be progressively delayed at increasing distances from the site of the triggering spikes, and interpreted this as a traveling wave of depolarization originating from that site. Our results were criticized, however, on two grounds. First, a study using the same recording techniques in the visual cortex of awake macaques reported an apparent lack of traveling waves, and proposed that traveling waves could arise artifactually from excessive filtering of the field potentials (Ray and Maunsell, 2011). Second, the interpretability of the stLFP was questioned (Kenneth Miller, personal communication), as the stLFP must reflect not only interactions between spike trains and field potentials, but also correlations within and across the spike trains. Here, we show that our data and interpretation are not imperiled by these criticisms. We reanalyzed our field potentials to remove any possible artifact due to filtering and to discount the effects of correlations within and across the triggering spike trains. In both cases, we found that the traveling waves were still present. In fact, closer inspection of Ray and Maunsell's (2011) data from awake cortex shows that they do agree with ours, as they contain clear evidence for traveling waves.

Robustness of Traveling Waves in Ongoing Activity of Visual Cortex

The mouse is becoming a key species for research on the neural circuits of the early visual system. To relate such circuits to perception, one must measure visually guided behavior and ask how it depends on fundamental stimulus attributes such as visual contrast. Using operant conditioning, we trained mice to detect visual contrast in a two-alternative forced-choice task. After 3–4 weeks of training, mice performed hundreds of trials in each session. Numerous sessions yielded high-quality psychometric curves from which we inferred measures of contrast sensitivity. In multiple sessions, however, choices were influenced not only by contrast, but also by estimates of reward value and by irrelevant factors such as recent failures and rewards. This behavior was captured by a generalized linear model involving not only the visual responses to the current stimulus but also a bias term and history terms depending on the outcome of the previous trial. We compared the behavioral performance of the mice to predictions of a simple decoder applied to neural responses measured in primary visual cortex of awake mice during passive viewing. The decoder performed better than the animal, suggesting that mice might not use optimally the information contained in the activity of visual cortex.

GABAA inhibition is thought to play multiple roles in sensory cortex, such as controlling responsiveness and sensitivity, sharpening selectivity, and mediating competitive interactions. To test these proposals, we recorded in cat primary visual cortex (V1) after local iontophoresis of gabazine, the selective GABAA antagonist. Gabazine increased responsiveness by as much as 300%. It slightly decreased selectivity for stimulus orientation and direction, often by raising responses to all orientations. Strikingly, gabazine affected neither contrast sensitivity nor cross-orientation suppression, the competition seen when stimuli of different orientation are superimposed. These results were captured by a simple model in which GABAA inhibition has the same selectivity as excitation and keeps responses to unwanted stimuli below threshold. We conclude that GABAA inhibition in V1 helps enhance stimulus selectivity but is not responsible for competition among superimposed stimuli. It controls the sensitivity of V1 neurons by adjusting their response gain, without affecting their input gain.

Stimulus contrast modulates functional connectivity in visual cortex

Directing visual attention to spatial locations or to non-spatial stimulus features can strongly modulate responses of individual cortical sensory neurons. Effects of attention typically vary in magnitude, not only between visual cortical areas but also between individual neurons from the same area. Here, we investigate whether the size of attentional effects depends on the match between the tuning properties of the recorded neuron and the perceptual task at hand. We recorded extracellular responses from individual direction-selective neurons in the middle temporal area (MT) of rhesus monkeys trained to attend either to the color or the motion signal of a moving stimulus. We found that effects of spatial and feature-based attention in MT, which are typically observed in tasks allocating attention to motion, were very similar even when attention was directed to the color of the stimulus. We conclude that attentional modulation can occur in extrastriate cortex, even under conditions without a match between the tuning properties of the recorded neuron and the perceptual task at hand. Our data are consistent with theories of object-based attention describing a transfer of attention from relevant to irrelevant features, within the attended object and across the visual field. These results argue for a unified attentional system that modulates responses to a stimulus across cortical areas, even if a given area is specialized for processing task-irrelevant aspects of that stimulus.

Attention to the Color of a Moving Stimulus Modulates Motion-Signal Processing in Macaque Area MT: Evidence for a Unified Attentional System

In sensory neurophysiology, reverse correlation analyses have advanced our understanding of the spatio-temporal structure of receptive fields (RFs) and the tuning properties of individual neurons. Here, we used a psychophysical variant of the motion reverse correlation technique to investigate how visual selective attention influences human perceptual tuning curves for direction of motion. Direction tuning functions were computed by reverse correlating speeded target-present responses of human observers with a random sequence of brief, fully coherent motion impulses. We found that attention enhanced the amplitude of perceptual tuning curves for direction of motion, while tuning width remained unaffected. Furthermore, the full direction tuning profile across time could be well fitted by a separable model of direction and temporal tuning. Attention enhanced both the direction tuning and its temporal profile, without shifts or changes in shape. Thus, attention exerts a multiplicative effect on human perceptual tuning curves for direction of motion. An analysis of second-order correlations revealed a boost in the likelihood of responses to the target direction when it was followed by a motion impulse in the opposite direction. This perceptual effect might be mediated by biphasic neurons that are preferentially activated by a rapid succession of opposite motion directions.

Effects of attention on perceptual direction tuning curves in the human visual system.

Dynamically shifting attention between behaviorally relevant stimuli in the environment is a key condition for successful adaptive behavior. Here, we investigated how exogenous (reflexive) and endogenous (voluntary) shifts of visual spatial attention interact to modulate activity of single neurons in extrastriate area MT. We used a double-cueing paradigm, in which the first cue instructed two macaque monkeys to covertly attend to one of three moving random dot patterns until a second cue, whose unpredictable onset exogenously captured attention, either signaled to shift or maintain the current focus of attention. The neuronal activity revealed correlates of both exogenous and endogenous attention, which could be well distinguished by their characteristic temporal dynamics. The earliest effect was a transient interruption of the focus of endogenous attention by the onset of the second cue. The neuronal signature of this exogenous capture of attention was a short-latency decrease of responses to the stimulus attended so far. About 70 ms later, the influence of exogenous attention leveled off, which was reflected in two concurrent processes: responses to the newly cued stimulus continuously increased because of allocation of endogenous attention, while, surprisingly, there was also a gradual rebound of attentional enhancement of the previously relevant stimulus. Only after an additional 110 ms did endogenous disengagement of attention from this previously relevant stimulus become evident. These patterns of attentional modulation can be most parsimoniously explained by assuming two distinct attentional mechanisms drawing on the same capacity-limited system, with exogenous attention having a much faster time course than endogenous attention.

Temporal dynamics of neuronal modulation during exogenous and endogenous shifts of visual attention in macaque area MT

Spatial and feature-based effects of exogenous cueing on visual motion processing

Electrophysiological activity underlying inhibitory control processes in normal adults

Editor's Note: These short reviews of a recent paper in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to mimic the journal clubs that exist in your own departments or institutions. For more information on the format and purpose of the Journal Club, please see Review of Khayat et al. At any instant, we are confronted with more information than we can fully process , because our sensory and cognitive resources are limited. To cope with this avalanche we use selective attention to enhance information from the environment that we care about and suppress the rest. Extracellular single-unit recordings in the visual cortex of awake, behaving ma-caques have provided detailed information about the mechanisms of " sustained " attention. In these studies, attention was directed to a visual stimulus or a stream of visual stimuli for up to several seconds. Little is known, though, about " shifts " in attention. This is an important gap in our knowledge because attention must operate on millisecond time scales. Imagine driving along a busy road. While keeping your eyes on the road, you also have to attend to cars on each side, pedestrians crossing the street, upcoming signs and changing traffic lights. In such a situation, accident-free driving is only possible because we are able to quickly shift our focus of attention, thereby temporarily " lightening up " representations of the most relevant objects in the visual scene. A recent study by Khayat et al. activity from the primary visual cortex (V1) in two macaque monkeys while the animals performed a variant of the " curve-tracking " task, an elegant paradigm developed by Roelfsema et al. (1998) (Fig. 1 A). On each trial, the monkey was presented with two curved lines, only one of which was connected via a small segment to the fixation point [Khayat et al., 2006, their Fig. 1a The monkey's task was to maintain its gaze on the fixation point for 800 ms and then saccade to the end of the target curve, the line connected to the fixation point. Roelfsema et al. (1998) have shown previously that neurons in V1 respond more strongly to such task-relevant curves, compared with distractor curves (i.e., curves that are task-irrelevant because they are not connected to the fixation point) [see also Khayat et al., 2006, their Fig. 2a– dtive modulation has been interpreted as a neuronal correlate of …

In four variants of a speeded target detection task, we investigated the processing of color and motion signals in the human visual system. Participants were required to attend to both a particular color and direction of motion in moving random dot patterns (RDPs) and to report the appearance of the designated targets. Throughout, reaction times (RTs) to simultaneous presentations of color and direction targets were too fast to be reconciled with models proposing separate and independent processing of such stimulus dimensions. Thus, the data provide behavioral evidence for an integration of color and motion signals. This integration occurred even across superimposed surfaces in a transparent motion stimulus and also across spatial locations, arguing against object- and location-based accounts of attentional selection in such a task. Overall, the pattern of results can be best explained by feature-based mechanisms of visual attention.

Feature-based attentional integration of color and visual motion.

Attentional modulation of psychophysical tuning curves for direction of motion

The topic of this thesis is centered on the question of how cognition influences the processing of sensory information. The main part of this work consists of seven research articles and manuscripts. Three of these articles are published in scientific journals, and the remaining four have been prepared for submission. To study the cognitive influences on the processing of sensory information I have used, as a model system, the highly-developed ability of primates to process visual motion. In this work, I have combined two different, but complementary techniques: One the one hand, I have performed extracellular recordings in the cortical motion-sensitive middle temporal area (MT) of macaque monkeys to investigate how attention changes the neural representation of motion information. On the other hand, I have used psychophysical methods to study how human motion perception is altered by various cognitive factors, such as attention or expectation. Together, these contributions show that cognitive influences strongly modulate the sensory processing of visual motion.

Effects of Selective Attention on Sensory Processing of Visual Motion

Attending to a stimulus is known to enhance the neural responses to that stimulus. Recent experiments on visual attention have shown that this modulation can have object-based characteristics, such that, when certain parts of a visual object are attended, other parts automatically also receive enhanced processing. Here, we investigated whether visual attention can modulate neural responses to other components of a multisensory object defined by synchronous, but spatially disparate, auditory and visual stimuli. The audiovisual integration of such multisensory stimuli typically leads to mislocalization of the sound toward the visual stimulus (ventriloquism illusion). Using event-related potentials and functional MRI, we found that the brain's response to task-irrelevant sounds occurring synchronously with a visual stimulus from a different location was larger when that accompanying visual stimulus was attended versus unattended. The event-related potential effect consisted of sustained, frontally distributed, brain activity that emerged relatively late in processing, an effect resembling attention-related enhancements seen at earlier latencies during intramodal auditory attention. Moreover, the functional MRI data confirmed that the effect included specific enhancement of activity in auditory cortex. These findings indicate that attention to one sensory modality can spread to encompass simultaneous signals from another modality, even when they are task-irrelevant and from a different location. This cross-modal attentional spread appears to reflect an object-based, late selection process wherein spatially discrepant auditory stimulation is grouped with synchronous attended visual input into a multisensory object, resulting in the auditory information being pulled into the attentional spotlight and bestowed with enhanced processing.

The spread of attention across modalities and space in a multisensory object.

The ERP omitted stimulus response to “no-stim” events and its implications for fast-rate event-related fMRI designs

The representation of visual objects in short-term memory has been shown to be related to increased gamma-band activity in the electroencephalogram. Using a similar paradigm, we investigated oscillatory magnetoencephalographic activity in human subjects during a delayed matching-to-sample task requiring working memory of auditory spatial information. The memory task involved same–different judgments about the lateralization angle of pairs of filtered noise stimuli (S1 and S2) separated by 800 msec delays of background noise. This was compared with a control condition requiring the detection of a possible change in the background noise volume appearing instead of S2 (volume task). Statistical probability mapping revealed increased spectral activity at 59 Hz over left parietal cortex during the delay phase of the memory condition. In addition, 59 Hz coherence was enhanced between left parietal and right frontal sensors. During the end of the delay and during the presentation of S2, enhanced gamma-band activity at 67 Hz was observed over right frontal and later over midline parietal areas. In contrast, the volume task was characterized by increased left inferior frontotemporal 59 Hz spectral amplitude after S1. Apparently representation of the spatial position of a sound source is associated both with synchronization of networks in parietal areas involved in the auditory dorsal stream and with increased coupling between networks serving representation of audiospatial information and frontal executive systems. The comparison with S2 seemed to activate frontal and parietal neuronal ensembles. Gamma-band activity during the volume task may reflect auditory pattern encoding in auditory ventral stream areas.

Dynamics of Gamma-Band Activity during an Audiospatial Working Memory Task in Humans

The temporal dynamics of the effects in occipital cortex of visual-spatial selective attention.

Implications of the ERP omitted stimulus response to null events in fast-rate event-related fMRI designs

Gamma-band activity along the dorsal "where" stream during an auditory memory task

Three synthesized syllables differing in place of articulation ([bɑ], [dɑ], and [gɑ]) were used in a three‐alternative identification task. Preliminary trials established the range of stimulus levels at which each S's performance, for each syllable, varied from below 50% to nearly 100% correct. Each of the three syllables was presented at five different intensities differing in 5‐dB steps. The three syllables and the five levels for each syllable were presented in intermixed random orders. Listeners (18–23 and 60–75 years old) all had normal hearing for their ages. Syllable identification thresholds (i.e., levels required for 50% correct performance) were higher for the older adults, as might be expected because of their poorer sensitivity. Older listeners also exhibited more shallow identification functions—an outcome that cannot be attributed to sensitivity differences since stimulus levels were adjusted for individual subjects. Possible explanations for these shallow slopes are considered. [Work supported, in part, by NSF.]

Esse artigo teve como principal objetivo analisar o impacto da assistência estudantil na permanência dos(as) estudantes do PROEJA, no Instituto Federal do Amapá. O tipo de pesquisa, quanto ao objetivo, foi uma pesquisa descritiva e quanto ao procedimento técnico, configurou-se em estudo de campo. Os sujeitos da pesquisa foram os(as) estudantes da turma do curso Técnico em Logística, na modalidade PROEJA, na forma integrada, presencial, ingressante no ano de 2016.2. O locus da pesquisa foi o Instituto Federal do Amapá, Campus Santana. Baseada no método dialético, a pesquisa se configurou como uma pesquisa de campo e teve abordagem qualitativa, utilizando-se também de dados quantitativos. O instrumento utilizado para a coleta de dados foi a aplicação de questionário de natureza semiestruturada. Dentre os resultados obtidos, verificou-se que em relação aos fatores que contribuem para a permanência os(as) estudantes não trazem a assistência estudantil como fator primordial para permanência. Porém, a esperança da empregabilidade e o desejo de um futuro melhor constituem-se como prioridades para permanência no curso. Percebe-se que os(as) estudantes ainda relacionam a assistência estudantil com ajuda, apoio ou favor, descaracterizando-a da forma de direito conquistado e vinculando-a mais uma vez a benesse do Estado. Ou seja, não se reconhece que garantias como transporte, alimentação, saúde sejam dever do Estado garantir. Assim, este estudo revelou que os programas de assistência estudantil ainda são pontuais e insuficientes para se garantir a permanência e o êxito na Instituição.

Educitec - Revista de Estudos e Pesquisas sobre Ensino Tecnológico

Análise do impacto da Política de Assistência Estudantil na permanência dos(as) estudantes do PROEJA no Instituto Federal do Amapá – Campus Santana

Gestão Curricular e Educação Profissional: a perspectiva da coordenação pedagógica

A literatura contemporânea tem evocado como singularidade da Geografia a estruturação de uma forma de pensar específica denominada Pensamento Geográfico. Todavia, se há uma ampla defesa da Geografia como forma de pensar, contraditoriamente, ainda são poucos os trabalhos que conceituam o que é esse Pensamento Geográfico, seus processos de estruturação e constituição. Este artigo visa contribuir com o avanço do debate teórico reduzindo a lacuna sobre o tema na literatura brasileira. A discussão está balizada nas seguintes questões: o que é o Pensamento Geográfico? Como se desenvolve? Que processos cognitivos o caracterizam? Para tanto, realizou-se pesquisa bibliográfica nos campos da Psicologia e da Geografia relacionando a cognição humana e suas especificidades a partir da aprendizagem e da formação dos conceitos geográficos pelos indivíduos. Por fim, observou-se como essa relação culmina na constituição de uma forma singular de pensar.

Por uma singularidade da Geografia: desenvolvimento do Pensamento Geográfico

The present study aims to address the multiplicity of research fields made possible by the documentary typology devassa from the analysis of the characteristics identified in the manuscripts that are part of the collection of the historical event entitled Conjuration Baiana, an important movement of revolutionary intent that took place in colonial Brazil in the 18th century which motivated vast documentary production currently held, mostly, by the Public Archive of the State of Bahia and by the Manuscripts Division of the National Library. Alluding to the need for a rigorous scientific systematization that takes care of the preparation of this type of material, at the level of paleographic and diplomatic editing, which values the scientific rigor that it demands, the aim is to draw the attention of researchers to the need for editions of historical sources are carried out in order to guarantee the reliability of the original sources, establishing a bridge between the physical and digital document.

Devassas em devassa: uma fonte para a reconstituição da história da cultura escrita no Brasil Colonial e Imperial

APLICAÇÃO DA FERRAMENTA DMAIC PARA REDUÇÃO DE CUSTOS EM UMA EMPRESA MULTINACIONAL AUTOMOTIVA

A Educação Ambiental (EA) é um processo permanente, no qual os indivíduos e a sociedade se conscientizam da condição do seu ambiente e adquirem os conhecimentos que os tornam aptos a agirem individual e coletivamente. Na região sul de Santa Catarina, temos a Reserva Biológica Estadual do Aguaí (REBIO), Unidade de Conservação (UC) de proteção integral, fundamental para o abastecimento humano e função ecológica. O estudo objetivou possibilitar o envolvimento da comunidade escolar em ações de integração da Reserva Biológica Estadual do Aguaí no contexto educacional, desenvolvendo atividades pedagógicas com estudantes de ensino médio dos municípios de Nova Veneza, Siderópolis e Treviso (SC). Os estudantes mostraram seu protagonismo durante a participação no projeto.
 
Educação Ambiental com enfoque na preservação da Reserva Biológica Estadual do Aguaí (SC)

Palmas, capital do estado do Tocantins, e a ultima cidade brasileira construida com base em um projeto de planificacao. O inicio de sua construcao data de Maio de 1990, portanto apos a Constituicao de 1988 que garante o direito a moradia. Apesar desses fatores, planejamento e direito a moradia constitucionalizado, Palmas conta com um deficit habitacional significativo ao longo da sua Historia. Mesmo seguindo o modelo de cidades ja planejadas, Palmas e composta por diversos e grandes vazios urbanos, e mesmo assim ha diversas pessoas com problemas relacionados a moradia, entende-se que nao houve a instalacao inicial do planejamento da capital que previa uma boa qualidade de vida para todos os moradores. O presente trabalho tem por objetivo central discutir como ocorreram as mobilizacoes de ocupacoes urbanas da cidade, atraves de aspectos historicos e sociais, diante dos problemas habitacionais. Temos como objetivo nesse trabalho de desnaturalizar discursos que avaliam deficit habitacional a questoes de ordem individual, assim, analisamos movimentos de luta pela moradia e suas estrategias de resistencia a um planejamento urbano excludente sendo as ocupacoes urbanas um exemplo pragmatico.

O descarte irregular de resíduos sólidos em áreas de disposição inadequada constitui uma realidade no Brasil, gerando impactos ao meio ambiente (no solo e nas águas subterrâneas e superficiais) e risco à saúde pública. Nesse sentido, o objetivo desta pesquisa foi avaliar a qualidade das águas subterrâneas e superficial adjacentes do antigo lixão de Tangará da Serra-MT. A metodologia consistiu em realizar análises físicas, químicas e microbiológicas das águas subterrâneas e superficial no período chuvoso e seco compreendidos entre setembro de 2019 e junho de 2020. Foram avaliados quatro poços de monitoramento (P1, P2, P3 e P4) com distância de 100 a 2.000 metros do lixão. A avaliação da água superficial ocorreu no Córrego do Meio, (P5) próximo ao lixão (nascente) e a (P6) a jusante. Foram realizados a avaliação da qualidade da água utilizando o Índice de Qualidade da Água (IQA). Os resultados obtidos nos poços de monitoramento mostraram maiores valores nos parâmetros (cor real, cor aparente, condutividade elétrica, nitrito, nitrato, fósforo, dureza total, demanda bioquímica de oxigênio (DBO) e demanda química de oxigênio (DQO)) no período de seca, em todos os poços, evidenciando que com a redução do volume de água na seca ocorre um aumento da concentração. Nas águas superficiais os dados de nitrato, resíduos totais e Escherichia coli, demostraram maior valores à jusante, em função da vegetação alterada por ações antrópica e do carreamento de partículas na área da nascente verificou-se a melhor qualidade das águas devido a conservação da vegetação na área. Por consequência, os valores de (IQA) do Córrego do Meio classificaram as águas da nascente (P5) como boas e as da jusante (P6) como regular. Os resultados obtidos inferem não haver carreamento de poluentes do antigo lixão capaz de impactar na qualidade das águas subterrâneas e superficial para os parâmetros estudados.

Qualidade da água na área de entorno do antigo lixão de Tangará da Serra (MT)

É DE MENINA OU MENINO? Imagens de gêneros, sexualidades e educação

Objetivo : avaliar criticamente conteúdos de publicações sobre nascimento e nascimento em páginas sobre o assunto na rede social facebook®.  Método : estudo quantitativo, descritivo, realizado no Brasil entre os meses de março e abril de 2019. Foram publicadas oito páginas e selecionadas como cinco publicações recentes sobre nascimento e nascimento, analisadas criticamente de acordo com o instrumento que buscou verificar as estatísticas de seleção na escolha do tipo de parto, uma concordância com a literatura dos conteúdos das publicações; os tipos de publicações, período das postagens e localização dos criadores das páginas; e como repercussões das publicações. Esses dados foram tabulados usando o Microsoft Excel® 2016. Resultados :das 40 publicações, apenas três não apresentadas que pudessem indicar um tipo de partição específica, 28 infladas sobre a partição normal, dez apresentadas embasamento científico e 34 estavam de acordo com a literatura. Conclusão : a maioria das publicações estava em concordância com a literatura e, quanto às repercussões, apesar do grande número de curtidas e compartilhadas, com poucos comentários. Essas informações podem ser usadas na construção de um estreitamento de relações entre a tecnologia e a saúde, para tornar o facebook® um aliado na promoção da saúde.

Introdução: A resistência bacteriana pode ocorrer como estratégia de defesa das bactérias. A bactéria Pseudomonas aeruginosa se sobressai entre o grupo de bactérias gram-negativas, pois constantemente está relacionada com altas taxas de morbimortalidade em pacientes na unidade de emergência. Objetivo: Identificar quais antissépticos utilizados na unidade de emergência promovem maior risco de colonização e resistência da Pseudomonas aeruginosa. Método: Trata-se de uma revisão integrativa da literatura realizada no período de março a julho de 2020. Resultados: Alguns antissépticos utilizados na unidade de emergência, como fenóis sintéticos, compostos quaternários de amônio, clorexidina e polihexametileno biguanida, não possuem boa eficácia contra a bactéria gram-negativa P. aeruginosa, primeira a manifestar fenótipos multirresistentes a muitos antimicrobianos. Conclusão: É cada vez mais crescente o risco da resistência de P. aeruginosa aos antissépticos. Onde a proliferação dessa bactéria na unidade de emergência, pode desencadear um quadro de infecção hospitalar no paciente, com complicações e óbito.

IDENTIFICAÇÃO DO RISCO DA RESISTÊNCIA DE PSEUDOMONAS AERUGINOSA A ANTISSÉPTICOS EM UNIDADES DE EMERGÊNCIA: UMA REVISÃO DE LITERATURA

EDUCAÇÃO E ENSINO EM TEMPOS ATUAIS: aprendizagem virtual, metodologias ativas e ensino híbrido

Observa-se nos últimos anos um movimento de retorno ao espaço público construído das cidades. Esse movimento, sob a ótica do planejamento urbano, respalda o que chamamos nesta pesquisa de ativismo projetual, em contraponto a movimentos espontâneos de ocupação daqueles espaços. Portanto, o presente artigo objetiva investigar se o que denominamos de ativismo projetual tem definido as intervenções que vêm sendo propostas para esses espaços em particular. Para tanto, trabalha-se com a hipótese de que ações projetuais, quando advindas desse ativismo, contribuem para tornar o espaço público edificado objeto-mercadoria dentro do sistema capitalista. Tendo como referência teórica a noção de dispositivos técnicos e disposições sociais, argumenta-se, ao final, que o ativismo projetual coloca em debate a lógica do planejamento urbano, seu caráter homogeneizante, midiático e privatista em detrimento da condição do espaço enquanto lugar do encontro e do debate.

O espaço público construído das cidades brasileiras: o ativismo projetual do planejamento urbano versus ocupação

Este artigo analisa o uso variável do modo imperativo no português popular da Bahia, fundamentado no enquadramento teórico-metodológico da Sociolinguística Variacionista (WEINREICH; LABOV; HERZOG 2006 [1968]; LABOV, 2008 [1972]).  O trabalho apresenta a alternância entre formas morfologicamente associadas ao indicativo (canta/não canta) e ao subjuntivo (cante/não cante) na expressão do modo imperativo em dados de fala de comunidades rurais da Bahia (Santo Antônio de Jesus, Poções, Barra e Bananal, Cinzento, Sapé e Helvécia). A análise quantitativa aponta a prevalência das formas do indicativo (canta) nessas comunidades. Esse resultado amplia o conhecimento acerca dos falares da Bahia e abre novas perspectivas de investigação acerca das isoglossas do imperativo ao apontar a complexidade da distribuição do fenômeno no estado.

EVIDÊNCIAS SOCIOLINGUÍSTICAS SOBRE OS USOS DO IMPERATIVO NO INTERIOR DA BAHIA

RESUMO O presente estudo teve como objetivo comparar o efeito de um protocolo de exercícios cinesiofuncionais (ECF) isolados ou associados a corrente interferencial (CI) ou corrente aussie (CA), sobre a intensidade da dor, a mobilidade/flexibilidade, a funcionalidade e a qualidade de vida (QV) de indivíduos com dor lombar inespecífica crônica. Trata-se de um ensaio clínico não randomizado, em que foram selecionados 42 sujeitos aleatorizados em três grupos: GI (treinamentos cinesiofuncional; n=14), GII (treinamentos cinesiofuncional + CI; n=14) e GIII (treinamento cinesiofuncional + CA; n=14). Os indivíduos foram submetidos a dez sessões de tratamento ao longo de 5 semanas e foram avaliados pré e pós-intervenção, usando escala visual analógica de dor (EVA); avaliação da QV pelo questionário SF-36; avaliação da mobilidade/flexibilidade lombar pelo teste de Schober modificado e o teste de sentar e alcançar com o banco de Wells; avaliação da incapacidade funcional através do índice Oswestry; e, para os aspectos depressivos, inventário de depressão de Beck (IDB). Na reavaliação, percebeu-se que houve melhora significativa em todos os grupos experimentais na intensidade da dor (p<0,0001) e na mobilidade/flexibilidade. No SF-36, verificamos que apenas os indivíduos tratados com exercícios associados à corrente elétrica apresentaram melhora dos domínios capacidade física, aspectos físicos e dor. A avaliação do IDB não apresentou modificações pré e pós-intervenção. Conclui-se que a associação das técnicas terapêuticas apresentou maior benefício aos indivíduos da amostra, uma vez que produziu melhora sobre as variáveis avaliadas, como dor, mobilidade/flexibilidade e qualidade de vida.

A eletroterapia pode aprimorar o efeito de exercícios cinesiofuncionais no tratamento da dor lombar inespecífica crônica?

Manejo Nutricional na Candidíase Vulvovaginal: Uma revisão de literatura

The purpose of this article is to show that in research on the schooling of children with disabilities or chronically ill, intersectionality with issues of gender, race, social class and ethnicity are fundamental. The analysis was conducted based on this assumption, considered here as structuring of inclusive education. In order to carry out a narrative that validates this assumption, methodologically, information obtained in long ethnographic efforts with adults who accompany children registered as a target audience for special education in their respective schools was used. The conclusion we reached was that without criticizing the frameworks of gender, race and class that we witness the corporealities in question would not have been analyzed in an inclusive perspective.

INTERSECCIONALIDADES E A EDUCAÇÃO ESPECIAL NA PERSPECTIVA DA EDUCAÇÃO INCLUSIVA

A resiliência se apresenta como um fator imprescindível para que os profissionais de saúde possam realizar as suas funções com êxito. O objetivo do estudo foi conhecer os mecanismos institucionais e neurofisiológicos que ajudam os profissionais da saúde na promoção da resiliência. Trata-se de uma revisão sistemática realizada a partir da pesquisa com os descritores “Equipe de Assistência ao Paciente”, “Neurofisiologia” e “Resiliência Psicológica”, combinados com o descritor booleano “AND”, nas bases de dados BVS, SciELO, PubMed e Portal de Periódicos CAPES, foram encontrados 3.047 artigos. Os critérios de inclusão dos artigos definidos foram: textos disponíveis online, na íntegra e gratuitamente, em idioma português, inglês e espanhol, publicados entre os anos 2014 a 2020. Após aplicar os critérios de inclusão e de exclusão restaram 1.082, ao realizar a leitura do título e do resumo apenas 73 estudos foram selecionados para leitura integral, desses escolheu-se 10 para compor a base de dados dessa revisão. A resiliência entre profissionais da saúde que atuam na emergência é menor do que o das outras especialidades. Diversos estudos identificaram o papel protetor da resiliência pessoal durante eventos de desastre e surto de doenças, sugerindo que o fortalecimento dos níveis de resistência e habilidades de enfrentamento pode ajudá-los a gerenciar e lidar com situações estressantes de forma eficaz. A resiliência é relevante para os profissionais da saúde, pois proporciona melhoria da performance do profissional no ambiente de trabalho e ajuda no enfrentamento de diversas situações estressoras. Dado isso, percebeu-se a necessidade da implementação de medidas que promovam o desenvolvimento da resiliência para esses indivíduos.

A parte comestivel do caju, o pseudofruto, e considerada residuo da industria processadora de castanhas. Ao final do processo, estima-se a geracao de ate 90% desse residuo, no entanto, trata-se de uma matriz complexa altamente nutritiva e que possui grande potencial de aproveitamento. Uma das formas mais comuns e viaveis para esse aproveitamento e a producao de cajuina, bebida tradicional muito apreciada na regiao Nordeste do Brasil, que e obtida a partir da clarificacao do suco extraido dos pedunculos dos cajus. Apos ser tombada como Patrimonio Cultural Brasileiro da Producao Tradicional e Praticas Socioculturais, em 2014, no Piaui, a cajuina vem ganhando visibilidade em outros estados e regioes. O aumento do consumo resultou na necessidade de garantir uma bebida segura e com qualidade, e essa foi a principal razao para a elaboracao desse estudo, que teve como objetivo identificar os principais perigos existentes na producao de cajuina e como controla-los de acordo com o plano APPCC (Analise de Perigos e Pontos Criticos de Controle). A presente revisao foi escrita levando em consideracao artigos cientificos, teses e dissertacoes disponibilizadas em base de dados. Os perigos foram identificados de acordo com a sua natureza: quimicos (residuo de defensivos agricolas); fisicos (corpos estranhos e fragmentos de vidro); biologicos (microrganismos patogenicos presentes na producao da bebida). Apos a identificacao dos perigos, medidas preventivas, formas de controle e verificacao foram determinadas baseadas em dados existentes na literatura. Dessa forma, depreende-se que e possivel implementar a ferramenta APPCC no processamento de cajuina.

Análise dos componentes que influenciam no processamento seguro da cajuína sob a ótica do APPCC: uma revisão

Esta pesquisa propos-se a investigar como tem sido desenvolvida a formacao 
da lideranca e da gestao no Colegio Anchieta/RS, evidenciando as enfases oferecidas 
e verificando como elas se coadunam as competencias socioemocionais e aos 
principios da formacao jesuitica. A fundamentacao teorica buscou a compreensao da 
lideranca inaciana, seus principios e fundamentos – baseada em Lowney, Custodio 
Filho, Ospina, Ullman e Bohnen, e Dupla –; do percurso da gestao – apoiada em 
Sander, Paro, Akkari, Luck Libâneo e Minioli –; e das competencias e da formacao 
dos lideres para a eficacia na gestao e a etica do cuidado – em que se destacam as 
contribuicoes de Boff; Goleman, Boyatzis e Mckee; Morin; Maturana; Dutra; 
Perrenoud; Moscovici e Senge. A abordagem metodologica foi a qualitativa. O 
levantamento de dados ocorreu mediante entrevistas com nove gestores membros da 
direcao e coordenacoes. Alem disso, analisaram-se os principais documentos 
institucionais e jesuitas, que contribuiram e nortearam muitas escolhas nesta pesquisa 
– Regimento Escolar, Projeto Politico-Pedagogico, Projeto Educativo Comum e as 
Constituicoes Jesuiticas. A analise dos dados apoiou-se na tecnica de analise de 
conteudo e na construcao de mapas conceituais. A investigacao, no formato proposto 
e com as bases teoricas selecionadas, aponta para os desafios da gestao no seculo 
XXI, o que exige dos profissionais nao somente competencias tecnicas e 
instrumentais, mas habilidades e competencias socioemocionais para ter a excelencia 
nos objetivos educacionais, com vistas a educacao integral de qualidade. A proposta 
de intervencao sugerida nesta pesquisa versa sobre a fundamental formacao 
permanente dos gestores diretivos e intermediarios na instituicao, focada na lideranca 
jesuita e articulada para o desenvolvimento das competencias socioemocionais na 
gestao, e apresenta-se como uma producao tecnica em que ja estao previstos tempos, 
abordagens e tematicas relevantes.

Formação para a liderança e a gestão no Colégio Anchieta: análise e possibilidades

Even after the end of the Apartheid regime, South Africa continued to be a country divided internally and with a negative image outside its borders. Nelson Mandela, elected president of the country, had in his hands the mission to unite South-Africans, without distinction of skin color, and reinsert the country internationally. That is when right before the rugby World Cup of 1995, to be hosted by South Africa, he realized the political potential of the sport. This article has as general objective analyze how rugby was used, in Nelson Mandela’s policy, to construct an unified nation and reinsert the country in the international scenery. For that, were worked the definitions of nationalism, prestige politics and soft power, focusing on the role of the sport; right after it was portrayed the political period after apartheid and the role of rugby in the country. It is concluded that the strategy to use rugby as a political instrument was successful, opening paths to overcome apartheid and reinsert South Africa in the International Scenery.

'Um time, uma nação': o rúgbi como instrumento de união da África do Sul pós-apartheid

The theme of this article is The Judicialization of Health: Challenging the Effectivation of the Fundamental Guarantee. The following problem was investigated: "Does judicialization cause injustice?" The following hypothesis was considered: “It is not injustice to the extent that the State does not offer health effectively.” The overall objective is to "Demonstrate the leading cause of judicialization." The specific objectives are: “Investigate the sector most affected by the lack of care”; “Examine the State as a guarantor of rights”; “Demonstrate the reasons of judicialization”. This work is important from an individual perspective because of the number of people dead awaiting emergency health care; for science, it is relevant because it provokes the perception that investing in emergency care is essential to reduce judicialization; It adds to society for the fact that such a premise saves lives, the most valuable asset within the legal system, essential for the Democratic Rule of Law. This is a theoretical qualitative research lasting six months.

A JUDICIALIZAÇÃO DA SAÚDE: DESAFIO DA EFETIVAÇÃO DESSA GARANTIA FUNDAMENTAL

A internet e basicamente uma rede de dispositivos espalhados por todo o mundo, que sao unidos atraves de um protocolo comum e, dessa forma, podem trocar dados e mensagens que seus usuarios desejarem. Essa rede acaba por ter diversos problemas internos, como roubo de dados, anuncios irritantes, travamentos dentre outros, que causam muitos desajustes no dia a dia. O objetivo deste estudo e mostrar os principais inconvenientes da internet, o que as pessoas acham deles e como lidar/resolve-los. https://eventos.textolivre.org/moodle/mod/forum/discuss.php?d=1222

Este artigo tem como foco de discussao a territorialidade da pesca artesanal em Atins, uma localidade do Parque Nacional dos Lencois Maranhenses. Na realizacao dessa tarefa, algumas estrategias metodologicas foram mobilizadas para aprimorar a pesquisa etnograﬁca de modo a dar conta da forma como os agentes sociais do universo empirico estudado percebem e representam os ambientes por meio de desenhos, contribuindo para uma melhor compreensao do seu territorio pesqueiro. Na situacao estudada, apresentamos reﬂexoes a partir da pesquisa etnograﬁca, utilizando alem das informacoes obtidas por meio da observacao direta e participante, fotograﬁas, imagens de satelite e tambem desenhos feitos por pescadores artesanais do povoado Atins que apontam as transformacoes nos ambientes onde realizam as atividades de pesca e mariscagem provocados pela agencia da natureza. Tais representacoes auxiliam na compreensao da territorialidade da pesca artesanal.

ETNOGRAFIA E TERRITORIALIDADE NA PESCA ARTESANAL NO PARQUE NACIONAL DOS LENÇÓIS MARANHENSES – O CASO DE ATINS

Uma interpretação alegórica e simbólica da Bíblia segundo Gregório de Nissa

Trata-se de uma ação extensionista que busca possibilitar a união entre teoria e prática na criação e gerenciamento de ideias e negócios inovadores. Envolve alunos, servidores, comunidade e outras entidades parceiras. Visa agregar conhecimentos e estimular um intercâmbio de ideias entre a comunidade acadêmica, difundindo, dessa forma, a cultura da inovação e do empreendedorismo. Atua por meio de cursos, minicursos, palestras, seminários, oficinas e apresentação de “cases de sucesso”.

Empreendedor IF: desenvolvendo a cultura da inovação e do empreendedorismo no Campus Juiz de Fora

ISOFLAVONOIDS OF THE TRIBE DALBERGIEAE: A CHEMOSYSTEMATIC CONTRIBUTION TO THE SUBFAMILY PAPILIONOIDEAE. Plants from Fabaceae family have several secondary metabolites and high biological potential. The subfamily Papilionoideae (Fabaceae) has 28 tribes, of which Dalbergieae comprises 49 genera and 1325 species. Isoflavonoids are chemotaxonomic markers of Papilionoideae and have important biological properties. This review describes the isoflavonoids and biological activities from the tribe Dalbergieae (Fabaceae–Papilionoideae) species, in the period of 1945 to 2019. A total of 240 isoflavonoids were found in 69 species and in 15 genera. Formononetin, biochanin A and medicarpin were the most frequent isoflavonoids in this tribe. Dalbergia, Machaerium, Andira and Pterocarpus genera had a high number of species with occurrence of isoflavonoids. A total of 81 isoflavanoids and 46 species showed biological activities. This suggests that more works are necessary to evaluate the potential of this tribe. The present study contributes to the taxonomic classification of genus or species in the family, subfamily or tribe, once the correlation between secondary metabolites and morphological data is an important tool for the classification, phylogeny and evolution of species. This compilation also contributes to extend and update the researched period on the occurrence of isoflavonoids in species of the tribe Dalbergieae, described in the literature in other bibliographic reviews.

ISOFLAVONOIDES DA TRIBO DALBERGIEAE: UMA CONTRIBUIÇÃO QUIMIOSSISTEMÁTICA PARA A SUBFAMÍLIA PAPILIONOIDEAE

TECNOLOGIAS COMO MEIO AUXILIAR PARA O ENSINO E APRENDIZAGEM: UMA REVISÃO BIBLIOGRÁFICA CATEGORIZADA DAS PUBLICAÇÕES DA REVISTA FÍSICA NA ESCOLA

Apos o advento da Constituicao Federal de 1988, o Direito de Familia passou por mudancas radicais, ao passo que a sociedade tambem mudou. Dessa forma, ao contemplar o afeto como principio juridico e, principalmente, como formador de familia, ocorreu o fenomeno da desbiologizacao da paternidade. Nesse sentido, a denominada parentalidade socioafetiva passou a ser reconhecida pelo ordenamento juridico brasileiro. Ademais, tendo em vista o carater eudemonista que marca a nova concepcao de familia, foi proferido o revolucionario acordao 898/060, reconhecendo a possibilidade da existencia concomitante entre as duas formas de parentalidade, a socioafetiva e a biologica. Dessarte, busca-se fazer uma abordagem da multiparentalidade como nova realidade juridica bem como seus efeitos juridicos. Palavras-chave: Desbiologizacao. Multiparentalidade. Parentalidade socioafetiva. Principio da afetividade.

A DESBIOLOGIZAÇÃO DA PATERNIDADE: o reconhecimento concomitante da parentalidade socioafetiva e a biológica e seus efeitos jurídicos.

LESÃO POR PRESSÃO: REVISÃO, FORMATAÇÃO, PUBLICAÇÃO DE CONTEÚDO INTERATIVO EM UM AMBIENTE VIRTUAL DE APRENDIZAGEM

O estudo trata da otimizacao da rota de coleta de lixo em um municipio da regiao do Alto Paranaiba. Para tanto, este foi pautado no problema do carteiro chines, que consiste na construcao de uma rota que passe por todas as ruas  pelo menos uma vez, minimizando a distância total percorrida. Alem disso, teve por objetivo a reducao da distância percorrida pelos caminhoes responsaveis pela coleta. Frente a isso, utilizou-se um modelo de programacao linear inteira desenvolvido na linguagem GAMS que, posteriormente, foi submetido ao servidor NEOS onde foram utilizados os solvers CPLEX, MOSEK, GUROBI e CBC. A partir do resultado obtido pelo NEOS utilizou-se o algoritmo Hierholzer para gerar a rota otimizada. Por fim, os resultados obtidos foram satisfatorios, uma vez que foi proposta uma rota otimizada para a realizacao da coleta de lixo, a qual reduziu em 28% a distância necessaria para a coleta de residuos solidos. Palavras-chave: Pesquisa Operacional. Problema do Carteiro Chines. Programacao Linear Inteira. Residuos Solidos Urbanos. Roteirizacao de Veiculos. ABSTRACT This study deals with the optimization of the garbage collection route in a municipality in the Alto Paranaiba region. To this end, it was based on the problem of the Chinese postman, which consists of the construction of a route that passes through all the streets at least once, minimizing the total distance traveled. In addition, it aimed to reduce the distance traveled by the trucks responsible for the collection. Therefore, a linear programming model was developed using the GAMS language, which was later submitted to the NEOS service where the CPLEX, MOSEK, GUROBI and CBC solvers were used. From the results obtained from NEOS, the Hierholzer algorithm was used to generate the optimized route. Finally, the results obtained were satisfactory, since an optimized route was proposed to perform the garbage collection, which reduced by 28% the distance required for solid waste collection. Keywords: Operational Research. Chinese Postman Problem. Integer Linear Programming. Urban Solid Waste. Vehicle Routing.

Otimização da Rota de Coleta de Lixo na Região do Alto Paranaíba: Uma Pesquisa Aplicada / Optimization of the Trash Collection Route in the Alto Paranaíba Region: An Applied Research

AVALIAÇÃO DA VIABILIDADE DAS MÍDIAS SOCIAIS PARA ORIENTAÇÃO DA POPULAÇÃO SOBRE TEMAS RELACIONADOS À SAÚDE

Esperanças provenientes de um contato tardio com a obra “Pedagogia do Oprimido” de Paulo Freire

This article aims to analyze the elements that enhance the teaching of statistical concepts through a teaching sequence with the theme potable water, elaborated with the phases of the Investigative Cycle for the initial years of Elementary Education. In order to achieve this objective, we rely on the Statistical Literacy proposed by Gal and on Vergnaud’s Conceptual Field Theory. The sequence was developed in a group of third-grade students at a public school, in the southern region of Bahia, and the five phases of the Investigative Cycle proposed by Wild and Pfannkuch are adopted in this study’s methodology. The sequence was planned during a formative process and it was developed by a teacher in her classroom. The result of the research reveals that the elements of the cognitive component (mathematical and statistical knowledge) and of the attitudinal component proposed by Gal for the development of Statistical Literacy (critical posture, beliefs, and attitudes) were enhanced. It also signaled that the sequence provided the students with the learning of statistical concepts when addressing a daily theme and being developed according to the Investigative Cycle phases.

Uma sequência de ensino para a formação de conceitos estatísticos nos anos iniciais do Ensino Fundamental

A fraude como elemento essencial para a configuração da tipicidade objetiva dos crimes contra a ordem tributária praticados por particulares (Lei 8.137/90, artigos 1º e 2º)

As facilidades e os desafios trazidos pela tecnologia e a evolucao tem colocado em questao metodos de trabalho e administracoes de procedimentos. Tendo em vista a pouca aplicabilidade de projetos tecnologicos em alguns segmentos, o presente artigo procura apresentar conceitos relacionados a administracao do conhecimento, sua relacao com a tecnologia e a tematica de cidades inteligentes. O trabalho e desenvolvido com base em estudos sobre a aplicabilidade e iniciativas de municipios em implantar conceitos de cidades inteligentes, a fim de otimizarem processos e atenderem de forma mais eficaz a populacao. Utilizou-se como metodologia o levantamento bibliografico na apresentacao de conceitos e teorias e uma abordagem exploratoria ao analisar dados ja coletados em trabalhos cientificos. Pode-se concluir que diversos processos e metodos de trabalhos podem ser aplicados, a luz da gestao do conhecimento, em municipios que, claramente, demonstraram evolucao e sucesso na maneira em que desenvolviam tarefas, proporcionando o eficiente atendimento a populacao e aos orgaos responsaveis.

A importância da Gestão do Conhecimento no desenvolvimento de Cidades Inteligentes

As neoplasias de pele do tipo melanoma sao consideradas graves devido a sua alta letalidade e ao grande risco de metastase. Existem diversas opcoes de tratamentos convencionais, porem nenhum deles apresenta um bom prognostico. Nesse contexto, tem-se estudado  terapias biologicas com inibidores de vias de sinalizacao e anticorpos monoclonais no tratamento de melanoma, buscando resultados mais eficazes. O presente estudo discorre sobre as terapias biologicas mais utilizadas e a acao no tratamento de melanomas. A metodologia utilizada foi revisao literaria em bases de dados cientificos. Os resultados mostram que o melhor prognostico para melanoma ainda esta relacionado ao diagnostico precoce. Contudo, o estudo das terapias biologicas no tratamento do melanoma pode proporcionar indices maiores de cura e diminuir os riscos de metastase. Entre os inibidores de vias de sinalizacao intracelulares para tratamento de melanomas tem destaque os  inibidores de quinases como BRAF. Entre os anticorpos monoclonais, destacam-se os anticorpos direcionados para as moleculas PD-1 e CTLA-4.

O novo coronavirus coloca o Brasil, pais com grandes desigualdades sociais, em um contexto de incertezas no enfrentamento durante e pos-pandemia. A formacao em servico nesse contexto tem grande relevância na garantia da atencao integral a saude viabilizada por projetos de intervencao baseados em analise da situacao de saude, com olhar multiprofissional e interdisciplinar, de forma a atender as necessidades sociais e epidemiologicas da populacao. Nesse relato e problematizado o potencial positivo e negativo das atividades cotidianas, a partir da cartilha “Orientacoes, atividades e rotinas para toda a familia no periodo de afastamento social devido a transmissao do coronavirus (Covid-19)”. Abstract The new coronavirus places Brazil, a country with great social inequalities, in a context of uncertainties in the confrontation during and after the pandemic. In-service forming in this context has great relevance in guaranteeing comprehensive health care made possible by intervention projects based on analysis of the health situation, with a multidisciplinary and interdisciplinary perspective, in order to meet the social and epidemiological needs of the population. In this report, the positive and negative potential of daily activities is problematized, based on the booklet “Guidelines, activities and routines for the whole family during the period of social withdrawal due to the transmission of the coronavirus (Covid-19)”. Key words: Coronavirus, Cotidianity, Health Residence, Occupational Therapy. Resumen El nuevo coronavirus coloca a Brasil, un pais con grandes desigualdades sociales, en un contexto de incertidumbres en la confrontacion durante y despues de la pandemia. La capacitacion en el servicio en este contexto tiene una gran relevancia para garantizar la atencion integral de la salud hecha posible mediante proyectos de intervencion basados en el analisis de la situacion de la salud, con una perspectiva multidisciplinaria e interdisciplinaria, con el fin de satisfacer las necesidades sociales y epidemiologicas de la poblacion. En este informe, el potencial positivo y negativo de las actividades diarias se problematiza, segun el folleto "Directrices, actividades y rutinas para toda la familia durante el periodo de abstinencia social debido a la transmision del coronavirus (Covid-19)". Palabras clave: Coronavirus, Cotidianidad, Residencia de salud, Terapia ocupacional.

Cotidianidades frente ao coronavírus em uma resiência em saúde: possibilidades construídas junto a terapeutas ocupacionais/“Quotidianity” in the face of the coronavirus in a health residence: possibilities built with occupational therapists

Este trabalho e uma investigacao teorica e etnografica sobre uma etica no candomble. A 
pesquisa assumiu como questao de partida a existencia nao apenas de uma etica dentro do 
terreiro, mas tambem com efeitos sobre a sociedade mais ampla. Inicialmente, apresenta-se, 
no primeiro capitulo, um panorama da discussao do tema da etica no candomble trazendo, de 
um lado, os autores que consideram que ele e uma religiao aetica e, de outro, autores que 
defendem haver uma etica nessa religiao. Prossegue-se, no segundo capitulo, com uma 
apresentacao de teorias e autores que subsidiaram a pesquisa de campo. Por fim, no terceiro 
capitulo, faz-se uma descricao de nossa etnografia sobre a existencia de uma etica cotidiana 
no candomble. Conclui-se haver uma etica de cuidado e de responsabilidade no candomble, 
que tem como fundamento o axe e o ciclo da dadiva; e defende-se que ela e incorporada pelos 
adeptos em sua experiencia religiosa e que e acionada, na vida cotidiana, “alem dos muros do 
terreiro”

Além dos muros dos terreiros: relacionalidade, corporificação e cuidado na ética do Candomblé

This study proposed to apply the checklist of good practices for food services and a questionnaire to identify the presence of the nutritionist in seven restaurants in a district of the city of Palhoca, Santa Catarina. The relation of the presence of the nutritionist with the hygienic-sanitary quality in Food and Nutrition Units. In this analysis were accomplished averages and test of conformities, relating to the presence or not of the nutritionist in the units. As a result, it was observed that the presence of the nutritionist was positive in relation to the conformities and in the units that did not present the professional; several unconformities were evidenced, such as the lack of a Good Practices Manual and sample collection in many of them.

Relatorio de Estagio do Mestrado em Ensino de Ingles e de Lingua Estrangeira no 3o ciclo do Ensino Basico e no Ensino Secundario, nas areas de especializacao de Alemao ou de Espanhol ou de Frances apresentado a Faculdade de Letras

A Didatização da Imagem: o contributo da exploração visual para o desenvolvimento de competências no ensino de LE

RESENHA SIMONETTE, Marcel Jacques. Fatores humanos na engenharia do software . Tese (Doutorado) – Escola Politecnica da Universidade de Sao Paulo. Departamento de Engenharia de Computacao e Sistemas Digitais. Sao Paulo, 2015. 210 p.

Agroindustrial activities in Southeastern Para produce many organic residues that can be recycled economically through composting processes. This study aimed to evaluate the reproduction rate, survival and density of Eisenia Andrei in different agroindustrial wastes. Pre-composting organic waste piles were implanted with ovine manure and waste from fruit pulps, being the variation source triturated acai seed (Treatment 1); sawdust (Treatment 2); and babacu coconut (Treatment 3). After 50 days of pre-composting, vermicomposting reactors with three populational levels of Eisenia Andrei for the three treatments were built, being evaluated the temperature, reproduction and survival indices of earthworms in the reactors for 35 days. Results showed that the temperature remained within the acceptable range (lower than 35 oC) during the experiment. For the reproduction, it was verified that the sawdust composting propitiated favorable conditions for increased earthworm density, while for the presence of cocoons only the initial quantities of earthworms showed positive effects; for both variables the time was significant. No treatments had earthwarms that escaped or died due to the waste composition, thus establishing the use of such residues as a viable alternative for vermiculture.

Reprodução e sobrevivência de Eisenia andrei sob diferentes resíduos agroindustriais

A IMPLEMENTAÇÃO DA EDUCAÇÃO EM DIREITOS HUMANOS PARA A DIMINUIÇÃO DO BULLYING NO AMBIENTE ESCOLAR

Fatores envolvidos na identificaÃ§Ã£o dos sinais de risco e intervenÃ§Ã£o precoce para o transtorno do espectro autista: uma revisÃ£o integrativa da literatura

Diante da demanda cada vez maior para que pessoas mais adequadas e produtivas possam ocupar postos de trabalho, de acordo com as suas caracteristicas, o Instituto de Psicologia da Aeronautica [IPA] desenvolveu, a partir da metodologia de analise profissiografica, o perfil do piloto militar de acrobacias aereas da Forca Aerea Brasileira [FAB], dando inicio a atividade de assessoramento na selecao de aviadores do Esquadrao de Demonstracao Aerea [EDA], tambem conhecido como Esquadrilha da Fumaca. O presente artigo trata do relato de experiencia da primeira participacao do IPA na selecao, englobando a avaliacao psicologica das caracteristicas de personalidade em pilotos candidatos a integrarem esse importante Esquadrao. Apos produzido o levantamento do perfil, deu-se inicio ao planejamento e implementacao do processo seletivo, que contou com uso de testes psicologicos de personalidade, dentre outros, bem como de Tecnicas de Entrevista Individual e Dinâmica de Grupo. Nesse primeiro processo seletivo , o IPA indicou tres do total de 12 candidatos a aviadores do EDA. Inumeros sao os desafios para uma selecao que busca priorizar a seguranca na aviacao e a adaptacao de pilotos a seu grupo de trabalho, assim como ao trabalho em equipe. Dentre eles, o mais complexo envolve lidar com a carencia de ferramentas e / ou testes psicologicos apropriados a esse publico especifico de profissionais, cuja existencia, certamente, poderia contribuir para uma operacao aerea mais segura.

A participação do Instituto de Psicologia da Aeronáutica no processo de seleção de aviadores para o Esquadrão de Demonstração Aérea no Brasil

O trabalho visou a produção e seleção de linhagens de Bacillus sp LBA produtoras de α-amilase com potencial para a aplicação na indústria de alimentos. De 108 linhagens estudadas as linhagens 03; 16; 25; 27; 68; 107; 108 e 113 foram selecionadas, apresentando atividade enzimática de 44,0 U/mL; 35,1 U/mL; 38,2u/mL; 51,3 U/mL; 42,9 U/mL; 50,7 U/mL; 50,3 U/mL; e 43,0 U/mL, respectivamente. Bacillus sp 107 e 108 foram selecionadas para a caracterização enzimática.

Estudo da produção e caracterização de enzimas para aplicação em alimentos

O desenvolvimento de novas tecnologias, baseadas na utilizacao de materiais lignocelulosicos, vem crescendo com o aprimoramento de metodologias ja utilizadas para o bagaco de cana-de-acucar. Entretanto, o pre-tratamento apresenta-se como desafio a ser consolidado ao se utilizar diferentes biomassas. O coco, promissor para tal aplicacao, possui 85% de seu peso bruto descartado, cujo reaproveitamento, esta associado ao baixo custo de obtencao, colabora com a reducao dos impactos ambientais. O presente trabalho analisou a eficiencia do pre-tratamento da fibra do mesocarpo do coco, por explosao a vapor, em diferentes condicoes de temperatura (160 °C, 205 °C e 215 °C) e tempos de residencia (2 min, 6 min e 10 min). A partir dos resultados obtidos, verificou-se que o pre-tratamento por explosao a vapor conseguiu solubilizar, 92,71% de hemicelulose (215 °C/10 min) e, 14,15% de lignina (160 °C/10 min.). As analises de espectroscopia foram realizadas atraves da tecnica de Refletância Difusa na Regiao do Infravermelho com Transformada de Fourier (DRIFT).

ANÁLISE DA EFICIÊNCIA DO PRÉ-TRATAMENTO POR EXPLOSÃO A VAPOR DA FIBRA DO MESOCARPO DO COCO

Introducao -  durante anos as gestantes diabeticas, ou respondiam aos controles dieteticos e mudanca nos habitos de vida, ou entravam no regime de insulina. Paralelamente mulheres nao gravidas se beneficiavam da comodidade dos hipoglicemiantes orais. De uma decada para ca, os organismos internacionais de pesquisa e de controle do uso de drogas liberaram seu uso para o periodo gestacional. Objetivo – fazer revisao com intuito de garantir a liberalizacao destas medicacoes, alem de escolher, e consequentemente protocolar, seu uso na maternidade do Hospital de Clinicas de Teresopolis. Metodo -  pesquisa nos principais sitios de busca em Medicina, usando como descritores Metformina; Diabetes gestacional; Diabetes mellitus. Aceitos artigos em lingua inglesa, portuguesa e espanhola, com criterio de tempo nos ultimos 5 anos. Resultados – varios foram os artigos encontrados, inclusive ja com revisoes sistematicas e metanalises. Estes artigos recomendam a metformina como o melhor hipoglicemiante oral na gestacao, com comprovada ausencia de teratogenicidade, com uso a partir do primeiro trimestre, mas com um percentual de falhas de cerca de 30%. A maioria dos autores indica a necessidade de estudos clinicos para acompanhamento destas criancas submetidas a metformina intra-utero.  Conclusoes - predilecao pela metformina pela facilidade de uso com maior adesao ao tratamento;  segura em todos os trimestres, pois nao tem relacao com teratogenese; em casos de falha, insulina pode ser associada ao tratamento conferindo os efeitos beneficos de ambas as drogas; precisamos aguardar os ensaios que avaliarao os recem-natos que entraram em contato com a metformina, no seu desenvolvimento a longo prazo.

ANÁLISE MICROCLIMÁTICA DA ÁREA URBANA NO MUNICÍPIO DE DOM ELISEU-PA

Com a crescente demanda energetica atual, existe a necessidade de desenvolver maneiras mais eficientes de se converter as relativamente abundantes fontes de calor em trabalho. Para os motores de combustao interna existem varias tecnologias promissoras nesse mercado dentre elas o motor a cinco tempos, cujo objetivo e obter eficiencias energeticas maiores que as dos motores tradicionais de quatro tempos predominantes no mercado, atraves da expansao estendida dos gases de escape em um quinto tempo, no proprio motor. Modelos de ciclo motores a cinco tempos sao ainda escassos em razao de sua invencao ser relativamente recente. A Modelagem de tempofinito de adicao de calor (FTHA) e uma tecnica recente de modelagem de ciclos motores Otto que incorpora importantes parâmetros construtivos dos motores enquanto mantem a simplicidade de uma modelagem padrao a ar. Este trabalho propoe aliar a modelagem de tempo-finito de adicao de calor aos casos de motores a cinco tempos.

Modelagem padrão a ar de motores a cinco tempos com ignição por centelha com tempo finito de adição de calor (FTHA)

Sergio Assad, Odair Assad (Duo Assad) e a cantora e violonista Badi Assad desenvolvem carreiras musicais notorias na cena musical mundial. Jorge Assad, bandolinista autodidata e pai desses músicos, registrou em fita magnética o início de suas carreiras, além de performances de amigos artistas quando se reuniam em sua casa. Este projeto de iniciação científica teve como objetivo transpor este registro para o formato digital.

RESUMO: Este artigo trata do tema “trabalho docente” e tem como objetivo geral verificar como o professor é representado no processo de apropriação da gamificação como instrumento, a partir de textos produzidos pelo e para o professor. Os dados utilizados para análise consistem em diários reflexivos escritos pela professora-pesquisadora e produzidos antes e após aulas que tiveram elementos da gamificação envolvidos. Baseamos nossa análise, primeiramente, no posicionamento epistemológico do Interacionismo Sociodiscursivo (ISD) e é a partir desta base que o corpus será analisado, privilegiando os níveis enunciativos e semânticos da análise de elementos linguístico-discursivos. A partir do gênero diários pode-se ver observar o trabalho real, além das as capacidades mobilizadas para o agir, postura do professor diante dos impedimentos e o desenvolvimento dentro de uma aula desde seu planejamento, à execução e avaliação. O que nos leva a concluir que o professor, em seu trabalho real é ator do seu trabalho e agir, baseando ações em suas intenções e motivos.  

Professor como ator do agir docente – Uma análise de diários reflexivos

Trabalho de Conclusao de Curso (Especializacao Lato Sensu em Microbiologia) – Coordenacao de Pos-Graduacao do Centro Universitario Sao Lucas – UniSL, 2019. 
Orientacao Profa. Me. Tatiane Silva de Carvalho.

O uso racional de antimicrobianos em ambiente hospitalar consiste no resultado de uma prescricao medica correta e uma dispensacao feita pelo profissional farmaceutico mediante instrucoes adequadas e o uso apropriado do medicamento. Este trabalho teve como objetivo demonstrar as consequencias da prescricao irracional de antimicrobianos em hospitais. Foi realizada uma revisao de literatura sistematica, com base em pesquisa bibliografica em bancos de dados cientificos Os resultados evidenciaram que a terapia antimicrobiana em hospitais e de predominância profilatica e que nos casos especificos quando a escolha do antimicrobiano se norteia por testes laboratoriais microbiologicos a terapia e mais especifica e eficaz.. O uso de antimicrobianos em ambiente hospitalar tem sido analisado como inadequado e exagerado, acarretando muitos problemas aos pacientes com as indicacoes irracionais desses medicamentos.

A hipertensao arterial sistemica (HAS) e considerada um problema de saude publica que se caracteriza em valores elevados e constantes de pressao arterial. Para o seu controle o tratamento terapeutico tem sido de grande relevância, e o maleato de enalapril, um inibidor da enzima conversora de angiotensina (IECA), e um dos anti-hipertensivos mais utilizados. Por isso acha-se necessario realizar um controle de qualidade desse medicamento para avaliar se ele tem as propriedades e caracteristicas esperadas. A metodologia utilizada foi uma pesquisa experimental, atraves de analise fisico-quimica de peso medio, friabilidade, desintegracao e dureza, de acordo com a metodologia descrita na farmacopeia brasileira. O objetivo foi avaliar a qualidade dos medicamentos de referencia generico e similar, dispensados nas farmacias privadas da cidade de Uberlândia, municipio do Triângulo Mineiro, atraves dos testes fisico-quimicos. As amostras analisadas nos testes foram aprovadas em todos os testes realizados, estando aptos para o consumo. E as bulas apresentam as informacoes necessarias para o paciente e para os profissionais de saude.

CONTROLE DE QUALIDADE FÍSICO – QUÍMICO DO MALEATO DE ENALAPRIL 10MG: REFERÊNCIA, GENÉRICO E SIMILAR, DISPENSADOS NA REDE PRIVADA DE UBERLÂNDIA – MG.

The era arising after the technical-scientific revolution is characterized by the massive use of 
communication technologies and the production of data. We lives in an information society, 
which dynamics forces law to face new questions and social facts that need its discipline and 
pacification. Among them is the fate of data and information added and produced by people 
on the Internet, resources such as social networks and cloud storage. The institute of the 
inheritance is millenarian, but the doctrine and the law have not yet adapted to the current 
reality. The digital collection is still an area of uncertainty. The present work was elaborated 
with the survey of the history and legal discipline of the right of succession. Next, we 
discussed the origins of computers and the Internet, to explain how the formation of the 
computerized and connected society took place. Finally, it was a question of analyzing the 
virtual goods and their aptitude to integrate the collection left by the de cujus, denominated 
digital inheritance. Three questions guided the thinking: if there are virtual goods (recognition 
of existence); whether these assets are part of the individual assets (recognition as individual 
assets); and, integrating, if these assets are part of the inheritance (recognition as transferable 
patrimony causa mortis). The methodology used was the bibliographical and documentary 
research.

Herança digital: análise do pertencimento do acervo digital ao mundo jurídico e da possibilidade de transmissão causa mortis

Abordagem clínica e anestésica de felinos machos com obstrução uretral

Satisfação dos familiares com os serviços prestados por um centro de atenção psicossocial infantojuvenil = Family Satisfaction with Services Provided by the Social and Psychological Care Center to Children and Youth (CAPSI)

O trabalho tem como tema “Dificuldade de Aprendizagem da Leitura e Escrita: desafios e possibilidades na comunidade Sao Pedro-Santa Maria do Para”. Justifica-se, pois a tematica e uma reflexao de minha inquietacao diante de uma realidade educacional dos alunos da Escola MEIF. Antonio Henrique de Oliveira. Destaca-se que a problematica surgiu da necessidade de entender melhor, que na construcao do desenvolvimento intelectual de cada aluno, ha fatores que interferem no processo de aprendizagem, ocasionando problemas ou dificuldades de aprendizagem serias a sua vida escolar. Tem-se como objetivo geral: Analisar os fatores principais que dificultam a leitura e a escrita dos alunos do segundo ano na turma multisserie do Ensino Fundamental da Escola M. E. I. F. Antonio Henrique de Oliveira, na comunidade Travessa Sao Pedro, Santa Maria do Para. E como objetivos especificos: Identificar quais as principais dificuldades de leitura e escrita sao apresentadas pelos alunos do segundo ano do Ensino Fundamental. Constatar que fatores que contribuem para a manutencao das principais dificuldades de leitura e escrita sao apresentadas pelos alunos do segundo ano do Ensino Fundamental. Perceber as praticas pedagogicas da professora pode colaborar para a aprendizagem da leitura e escrita. Sao autores: Antunes (2003), Fernandes (2006), Ferreiro (2004), Kleiman (2005), Lajolo (1999), Oliveira (1996), Silveira (1997), Soares (2005/2004/2009/2010), Teberosky (2008), Vigotski (2007), e outros. Conclui-se que, foi possivel identificar que as principais dificuldades de leitura e escrita sao apresentadas pelos alunos do segundo ano do EF na escola em questao, sao as de manter a concentracao e atencao no contexto da turma multisserie onde as faixas de idade sao grandes, tanto quanto os conteudos a serem trabalhados, o que ocasiona desestimulo e desmotivacao.

Dificuldade de aprendizagem da leitura e escrita: desafios e possibilidades na Comunidade São Pedro - Santa Maria do Pará

O Estado do Amapa se destaca em escala nacional e internacional pelo quantitativo de areas legalmente protegidas, como Areas de Preservacao Permanente, Reservas Legais, Territorios Remanescentes de Quilombos, Terras Indigenas e principalmente Unidades de Conservacao. E interessante lembrar que e o unico Estado em que todas as Terras Indigenas estao homologadas. Com relacao as Unidades de Conservacao, estas representam 61,95% de seu territorio. A Area de Protecao Ambiental da Fazendinha, a unidade objeto desta pesquisa foi a primeira unidade de conservacao criada no estado e a pesquisa teve como objetivo: identificar os conflitos socioambientais existente nessa area. As tecnicas de pesquisa utilizadas foram: o levantamento do referencial teorico, trabalhos de campo com observacao participativa, e posteriormente se trabalhou os dados obtidos; as transcricoes de entrevista semiestruturadas realizadas com a gestao da area e moradores, alem de analises de documentos e as demais informacoes disponiveis. Constatou-se a ingerencia da area, com a inexistencia do Plano de Manejo, dificuldades em gerir o territorio em conjunto com a populacao residente, gerando problemas de regularizacao fundiaria e degradacao socioambiental. Engendrando um cenario oposto ao proposto pelo Sistema Nacional de Unidade de Conservacao da Natureza.

DIAGNÓSTICOS DOS CONFLITOS SOCIOAMBIENTAIS PERTINENTES A ÁREA DE PROTEÇÃO AMBIENTAL DA FAZENDINHA- AP

O objetivo deste estudo e investigar o processo de destinacao final dos residuos solidos urbanos na cidade de Porto Nacional - TO. A pesquisa e um estudo de caso com abordagens qualitativa e quantitativa sobre a disposicao dos residuos solidos urbanos e o seu descarte. Os resultados verificados, por meio de diferentes percepcoes, demonstram problemas com relacao ao lixo acumulado e ao seu volume significativo disposto em varios pontos da cidade, principalmente nas ruas e nos espacos vazios. Em busca do objetivo geral proposto, foi necessario identificar os habitos da populacao no manuseio dos Residuos Solidos Domiciliares (RSDs) na cidade de Porto Nacional; selecionar alguns setores censitarios para estudo; delimitar os principais tipos de residuos solidos urbanos descartados indevidamente; e localizar os pontos de maior ocorrencia de descarte indevido de residuos solidos urbanos; para assim, relacionar a disposicao final desses residuos e suas consequencias socioambientais. A metodologia utilizada baseia-se no estudo de caso em oito setores censitarios selecionados. Para obtencao dos dados, moradores dos setores e coletores de lixo responderam aos questionarios; bem como realizaram-se entrevistas com gestores municipais. Na mesma intencao, fez-se a observacao direta nos setores com a localizacao de coordenadas dos pontos com disposicao inadequada de lixo, e a visita ao lixao da cidade. A partir dos questionarios, da visita de campo e das entrevistas, percebeu-se que os residuos solidos gerados sao encaminhados para a coleta convencional, tendo como destino final o lixao municipal. Constatou-se um numero elevado de disposicao inadequada de residuos solidos nos setores com maior numero de espacos vazios e de baixa infraestrutura de vias; e ainda que, no local do aterro sanitario, existe um lixao a ceu aberto. Buscou-se, com o presente trabalho, conhecer como ocorre o descarte de residuos solidos na area urbana de Porto Nacional, e dessa forma, contribuir com informacoes uteis as acoes de planejamento e gestao ambiental da cidade.

Lixo urbano: um estudo da disposição inadequada dos resíduos sólidos urbanos na cidade de Porto Nacional – TO

A reducao das areas verdes nas cidades devido ao crescimento urbano 
colabora no processo de degradacao ambiental. Sendo assim, torna-se 
necessaria a busca de alternativas sustentaveis de construcao que diminuam os 
impactos causados no meio ambiente. Desta forma, o sistema de telhado verde 
surge como alternativa de minimizar os efeitos da degradacao ambiental, como 
as ilhas de calor. O trabalho tem como objetivo, atraves de revisao bibliografica, 
definir e apresentar as vantagens e desvantagens de telhados verdes 
extensivos, comparar o desempenho em relacao ao conforto termico de sistemas 
construtivos tradicionais e sistemas construtivos de telhado verde extensivos e, 
ao final, fazer uma analise comparativa de custos entre sistemas de telhados 
verdes e um sistema tradicional. A comparacao de custos com a intencao de 
verificar a viabilidade economica da implantacao de um telhado verde na cidade 
de Barra do Garcas, MT, foi realizada atraves da composicao do orcamento da 
cobertura de cada sistema atraves da tabela SINAPI e de dados fornecidos por 
empresas especializadas, utilizando de base a mesma residencia padrao. 
Conclui-se que a aplicacao do telhado verde tem custo inicial na faixa de 32% 
maior que um sistema tradicional, mas torna-se viavel na cidade quando se 
considera seus beneficios a longo prazo, como a economia de energia gerada e 
o aumento da vida util da cobertura, alem de todos os beneficios ambientais 
gerados.

Análise do custo benefício da implantação do sistema construtivo de telhado verde em uma edificação no município de Barra do Garças - MT

The attributes of Primary Health Care (PHC) are structuring axes of the care process, associated with the quality of services, effectiveness and efficiency of health interventions. Most studies on PHC assessment have been conducted in developed countries and there is little evidence on the positive impact of PHC in developing countries, especially in Latin America. In Brazil, the APS evaluation process is still in its infancy. A bibliographic search was carried out in national and international databases, in order to identify the validated APS evaluation instruments currently used in Brazil, the evaluation scope of each instrument and its results. There was no restriction of languages or period of publication. We included studies that used validated instruments for the evaluation of PHC in Brazil. We excluded articles that assessed the quality of life of PHC users, who were directed to a specific health event and who performed the validation of the instruments. 3,575 articles were found in total search. After reading the abstracts, 55 studies were selected for analysis, being 53 on PCATool, 1 on EUROPEP and 1 on CCAENA. It was concluded that all attributes are capable of assessing PHC in Brazil, but there is a prominence for PCATool due to its ability to evaluate all the attributes of this level of attention and its greater adaptation to the reality of Brazilian public health units

Instrumentos de Avaliação da Atenção Primária em Saúde no Brasil: uma revisão da literatura

A Escola Normal de Feira de Santana (ENFSA), fundada em 1927, enquanto instituição destinada à formação profissional de professoras para a região interiorana da Bahia, teve um papel fundamental na História da Educação feirense e de sua região (SOUSA, 2002).O objetivo desta pesquisa é identificar se ocorreu a incorporação dos ideais pedagógicos anisianos nas propostas de formação de professoras na ENFSA, e se estes são visíveis em modificações curriculares e disciplinares, a partir dos registros desta instituição, entre 1945 a 1950, no contexto da redemocratização do Governo de Octavio Mangabeira e da gestão de Anísio Teixeira. Um segundo objetivo é buscar se estas ideias pedagógicos repercutiram na sociedade de forma mais ampla, sendo registradas no periódico Folha do Norte.As reformas que propunham melhorias e ampliação das escolas primárias, assim como, a formação de professores e o aperfeiçoamento nos métodos de ensino, com a promulgação da Constituição Federal de 1946 – assegurando o direito a todos a educação –, era necessário levar a pratica esse ideário de educação. Com o regresso de Anísio a Educação Baiana em 1947 - agora como então Secretário da Educação, poderia fazer com que houvesse a partir do Estado um esforço para aplicar esses ideais.

A REDEMOCRATIZAÇÃO DO PERIODO MANGABEIRA (1945 A 1950) NA ESCOLA NORMAL DE FEIRA DE SANTANA: FORMAÇÃO DOCENTE E PROJETOS EDUCACIONAIS

Neste trabalho, apresentamos questoes ligadas a feminilidade das lavadeiras do Jequitinhonha atraves da analise do lexico presente nas cancoes inseridas em tres CDs: Batukim Brasileiro (FARIAS, 2001), Aqua (FARIAS, 2004) e Devocao (FARIAS, 2013). Nas cancoes analisadas vemos tracos de cantigas de amigo da Era Medieval. Os poetas medievais eram homens, mas utilizavam o ponto de vista feminino nas cantigas de amigo, que tem como tema o sofrimento por amor, motivado normalmente pela ausencia do “amigo” (que neste caso e o namorado). A voz poetica e a de uma jovem que relata as suas vivencias amorosas, ora num monologo, ora num dialogo com suas amigas, irmas ou inclusive com a mae. Os sentimentos sao diversos e incluem a alegria pela chegada do amigo, a tristeza pela sua ausencia ou a ansiedade pelo seu regresso, o desejo de vinganca, ciumes e outros. Os ambientes nos quais acontecem os fatos sao o campo, o mar, a casa, a fonte aonde vao procurar agua ou o rio onde lavam roupas. PALAVRAS-CHAVE: cantigas de amigo; jovem; feminilidade; desejo; desencanto

Este trabalho visa analisar como a Pedagogia da Alternância baseada no aprender-acao entre escola, familia e comunidade auxilia para que os sujeitos camponeses que vivem no campo possam pensar e transformar a educacao e a realidade em que vivem. A metodologia pauta-se no estudo da historia da educacao no campo, da pedagogia da alternância e da importância dessa pedagogia aplicada na Escola Familia Agricola localizada no municipio de Japoata/Sergipe. Verifica-se como essa estrutura favorece a reproducao e resignificacao dos educandos que vivem no campo. Conclui-se que e necessario pensar uma educacao nao somente no campo, mas tambem para o campo, para que os sujeitos camponeses possam ter acesso a uma educacao de qualidade e que leve em consideracao o meio em que estao inseridos.

A PEDAGOGIA DA ALTERNÂNCIA COMO ESTRATÉGIA PARA A REPRODUÇÃO DO HOMEM CAMPONÊS NO SEU ESPAÇO DE VIDA

Este trabalho trata sobre o processo identitario dos alunos da escola Municipal Francisco Pereira Leite, localizada na comunidade serra das Viuvas, municipio de Agua Branca/Alagoas. O interesse em pesquisar a tematica surgiu a partir da curiosidade de conhecer uma comunidade Quilombola, em especial a Serra das Viuvas, bastante falada pelos visitantes e apesar de morar na mesma cidade, desconhecia sua realidade, seu modo de vida, seus costumes. Entendemos que e de fundamental importância conhecer como ocorrem os processos identitarios dos alunos da comunidade Quilombola, uma forma dos alunos se perceberem enquanto sujeitos da sociedade em que vivem e entenderem que eles possuem uma historia de vida diferenciada, fazem parte de uma familia, de grupos sociais e pertencem a uma comunidade. Dentro desse contexto levantaremos algumas inquietacoes como: O que e ser quilombola? Como as criancas se identificam nesse processo e como se deu ou e se da a luta pelos seus direitos? Qual o elo entre a escola e a comunidade quilombola? Inicialmente realizamos pesquisas de campo para observar os alunos e professores, acompanhando e registrando as atividades relacionadas aos processos identitarios desenvolvidos em sala de aula. Em seguida, fizemos entrevistas com a lider da comunidade e alguns moradores que vivenciaram o processo historico pela qual a mesma perpassou, ate ser reconhecida como comunidade Quilombola. Para fundamentar nosso estudo recorremos a algumas Leis e autores que serviram de aportes teoricos para nossa pesquisa tais como; a Lei de Diretrizes e Bases da Educacao Nacional – LDB no 9394/96: as Diretrizes Curriculares Nacionais para a Educacao Quilombola, o Artigo 68 do ADCT e 215 e 216 da Constituicao da Republica que determina a regularizacao territorial das comunidades quilombolas e protegem suas culturas; o Decreto no 4887 de 20 de novembro de 2003, que regulamenta o procedimento para identificacao, reconhecimento, delimitacao, demarcacao e titulacao das terras ocupadas por remanescentes das comunidades dos quilombos, a Constituicao Federal de 1988. Utilizamos ainda os seguintes autores: Haall (2006), Castells (1999), Johnson (2006), Braga e Duarte, (2014); Silva (2015) alem de teses, dissertacoes e TCCs. Referencias cujo enfoque teorico permite apresentar questoes conceituais importantes no âmbito da educacao Quilombola. O objetivo principal deste trabalho e analisar os processos identitarios de um grupo de criancas da escola 
Municipal Francisco Pereira Leite da comunidade Serra das Viuvas - Agua Branca Alagoas. 
Assim como, conhecer o processo historico de formacao da comunidade e analisar a insercao da escola Municipal neste contexto. Consideramos que o trabalho desenvolvido podera ser de grande valia para a comunidade serra das Viuvas, assim como auxiliar os docentes e discentes nas atividades pedagogicas, colaborando com a sociedade a tecer reflexoes sobre a formacao das comunidades Quilombolas e as formas de afirmacao identitaria no ambiente escolar, suas potencialidades e principais desafios.

Quem sou eu, quem somos nós? conhecendo os processos identitários dos alunos da escola municipal Francisco Pereira Leite da comunidade Serra das Viúvas, Água Branca - Alagoas

O presente artigo tem como objetivo apresentar nossas experiAancias como bolsistas da Revista SOLETRAS, sob orientaA§A£o da professora Maria Cristina Cardoso Ribas (editora gerente) e do professor Paulo CA©sar Silva de Oliveira (editor-adjunto); mostrar que, mesmo com as dificuldades que possam surgir, a atividade como bolsista no processo de editoraA§A£o A© engrandecedora, tanto pessoal quanto profissionalmente e academicamente, abrindo nossas mentes durante a graduaA§A£o e apresentando novos caminhos dentro da nossa futura profissA£o. Apresentaremos, singularmente, as experiAancias, jAi que somos bolsistas de diferentes modalidades â€“ ExtensA£o e EstAigio Interno Complementar â€“; e compartilharemos tais experiAancias com os colegas graduandos. Falaremos sobre esta modalidade de trabalho, o que aprendemos e como estas prAiticas vAam nos ajudando a crescer na graduaA§A£o. Falaremos ainda sobre nossa participaA§A£o na 26Âa UERJ Sem Muros (setembro de 2015), na qual apresentamos banners com base em nossas pesquisas do projeto e no trabalho feito desde o inA­cio, alA©m de discorrermos mais detalhadamente sobre os cursos, leituras e aA§Aµes desenvolvidos durante o trabalho de editoraA§A£o e publicaA§A£o. De maneira geral, o artigo pretende mostrar nosso trabalho, como bolsistas na graduaA§A£o, a partir do nosso prA³prio ponto de vista. Esperamos que a experiAancia aqui compartilhada fique o mais prA³ximo possA­vel da realidade dos colegas graduandos â€“ para que acessem periA³dicos acadAamicos como importante fonte de pesquisa. Palavras-chave: Bolsistas. ExtensA£o. EstAigio Interno. Revista SOLETRAS UERJ. EditoraA§A£o e publicaA§A£o.

EnglishAsking about the meaning and the concrete role of Philosophy teaching in High School, at a time when this discipline, which has just arrived at the curriculum, is already threatened to leave it, it is necessary to show the justifications already which debated to the framework of required subjects. It is argued here that one of the tasks of Philosophy teaching is to promote the students' mental extension. This pretension requires appropriate methodologies, such as the proposal presented in this text of debates, in a didactic sequence that would occupy an entire two-month period, around the theme of freedom. This experience elaborated as a proposal and tried out as experience, represents in itself the exercise of philosophy, a political position and a professional improvement. portuguesPerguntando-se sobre o significado e o papel concreto do ensino de Filosofia no ensino medio, num tempo em que esta disciplina, recem-chegada ao curriculo, ja esta ameacada de sair dele, ve-se a necessidade de evidenciar as justificativas ja debatidas que a levaram ao quadro das disciplinas obrigatorias. Defende-se aqui que uma das tarefas do ensino de Filosofia e promover a amplitude mental dos estudantes. Essa pretensao exige metodologias adequadas, tal como a proposta presente neste texto de debates, numa sequencia didatica que ocuparia todo um bimestre, em torno do tema da liberdade. Essa experiencia elaborada como proposta e vivenciada como experiencia representa, por si so, o exercicio do filosofar, um posicionamento politico e um aprimoramento profissional.

Possibilidades de abordagens filosóficas sobre o tema da liberdade como caminho para exercitar a amplitude mental

Considerando a implantacao da UHE Belo Monte e consequente enchimento do Reservatorio Xingu, foi executado monitoramento da dinâmica e qualidade das aguas subterrâneas no âmbito do Programa de Monitoramento das Aguas Subterrâneas. Os estudos realizados na area do bairro Jardim Independente I, localizado na cidade de Altamira - PA partiram da demanda de se avaliar a existencia ou nao de um aquifero suspenso e de se verificar a relacao de causa-efeito entre a formacao do reservatorio Xingu (UHE Belo Monte) e consequente elevacao dos niveis freaticos com a elevacao e flutuacao do nivel da agua da “lagoa” localizada no bairro em referencia. O regime de chuvas e o principal parâmetro para explicar as variacoes dos niveis freaticos dos pocos de monitoramento em toda a area urbana de Altamira. Apos longos periodos com chuvas acumuladas, superiores a media historica, ha uma tendencia dos niveis freaticos se elevarem de forma consistente, padrao observado em toda a area urbana de Altamira antes, durante e apos o enchimento do Reservatorio. A chuva tambem e o principal parâmetro para explicar a variacao da elevacao da lâmina d'agua da lagoa existente na regiao do bairro Jardim Independente I; onde o nivel se eleva a partir das chuvas que caem diretamente sobre a lâmina d'agua e pelo escoamento superficial da agua, no entorno da lagoa e em sua direcao. os dados ainda permitem concluir que nao ha conexao hdraulica entre o Reservatorio Xingu e o aquifero local situado sob a lagoa, que por sua vez esta vinculada a exposicao do nivel freatico de um aquifero suspenso com localizacao restrita. Em sintese, os dados e analises mostram que ha um aquifero suspenso, materializado por i) diferenca de carga hidraulica deste com o aquifero local; ii) padroes de qualidade das aguas distintos entre os mesmos, iii) existencia deum aquitarde constituido por camda de argila interposto entre ambos, com espessura entre 3,5 e 8m, portanto sem conexao direta do aquifero suspenso com o Reservatorio.

ESTUDO DE POTENCIOMETRIA PARA A VERIFICAÇÃO DE EXISTÊNCIA DE AQUÍFERO SUSPENSO: CASO DO BAIRRO JARDIM INDEPENDENTE I (ALTAMIRA, PA)

O puerperio e o periodo do ciclo gravido-puerperal em que tanto as modificacoes locais quanto sistemicas ocorridas no periodo da gravidez e parto, retornam a situacao do estado pre-gravidico, o periodo puerperal exige uma atencao do enfermeiro (a) para o acolhimento, orientacoes e duvidas, garantindo um acompanhamento ao servico de saude que se faz necessario para entender e conhecer como ocorre a atuacao do (a) enfermeiro (a) nos cuidados as puerperas. Objetivo: Identificar como e prestada a assistencia as puerperas pelo enfermeiro. Metodologia: Trata-se de um estudo de revisao integrativa de literatura. Foram encontrados um total de 215 artigos, pre-selecionados 31 artigos para uma leitura detalhada dos titulos e resumos das publicacoes, e apos leitura foram excluidos 24 artigos por nao contemplarem os criterios de inclusao e o tema do estudo, restando sete artigos. Foram incluidos tambem no trabalho sete artigos com buscas a partir das seguintes palavras e combinacoes: Puerperio, consulta puerperal e mortes maternas no puerperio. Desta forma totalizaram 14 artigos para analise. Resultados: Os estudos mostraram que em relacao a qualidade de assistencia prestada pelo enfermeiro nos artigos estudados 85,7% demonstraram insatisfacao com a assistencia prestada, tendo como primeiro indicador o foco da assistencia ser voltado para o recem-nascido, seguido de comunicacao ineficaz entre os profissionais e as mulheres. Consideracoes finais: O estudo revelou que ha uma ausencia de informacoes quanto aos cuidados que devem ser feitos, a importância da consulta puerperal e, principalmente, cuidados relacionados a puerpera, pois no estudo comprova-se que o cuidado e direcionado em sua grande maioria ao recem-nascido.

A relacao entre as dimensoes evangelistica e social da missao sempre se constituiram de forma tensa na historia da Igreja Crista. Esse legado dicotomico entre Deus-mundo, espirito-corpo vem desde os gregos, Agostinho e hoje e reforcado pela mentalidade iluminista. Assim essa heranca sustenta e possibilita interpretacoes como por exemplo, politica e acao social sao coisas terrenas; a missao suprema da igreja e a pregacao oral; as melhorias das condicoes sociais e resultado do bom exito da evangelizacao. Entretanto, na historia do metodismo brasileiro sao encontradas iniciativas em favor de mudancas na compreensao e na pratica missionaria a partir dos anos 60, mas e so nos anos 80 que as reflexoes atingem uma visao mais ampla sobre a missao ao ser inspirado na realidade social brasileira e na heranca wesleyana. Este processo ficou conhecido por Vida e Missao, o que resultou na construcao do Plano para a Vida e Missao da Igreja em 1982. Tal documento permanece como um paradigma missiologico da Igreja Metodista do Brasil, e dentre seu conteudo encontra-se no “Plano para areas de vida e trabalho” da Igreja a Area de Acao Social, a qual e de interesse neste estudo, pois e reconhecida como parte da missao e construcao do Reino de Deus atraves de acoes de amor e justica em favor da renovacao do ser humano e das estruturas sociais. A intencao e de conhecer e investigar como se da essa relacao entre as diretrizes trazidas no Plano com a pratica, por isso foi eleita a Igreja Metodista em Pocos de Caldas, devido seu envolvimento com a praxis social e missionaria. Para este fim, foi realizada pesquisa bibliografica sobre a historia do metodismo brasileiro com enfase aos elementos que conduziram a construcao do Plano. No segundo momento o recorte historico esta voltado para a cidade de Pocos de Caldas, a chegado do metodismo, as acoes sociais e missionarias desenvolvidas pelos membros no municipio, e em especial, um olhar mais detalhado para as atividades que estao em desenvolvimento para contrapor com as diretrizes contidas no Plano. Por isso o capitulo dois traz o mapeamento das acoes atraves da pesquisa documental. Ja no ultimo capitulo sao apresentadas as analises da praxis social e missionaria dos metodistas pocos-caldenses, mas para isso foi necessario primeiro conceituar o termo praxis, por isso a discussao percorre a filosofia e a teologia pratica para entender como atividade transformadora. Entretanto, observou que essa dimensao politica, social e economica da praxis esta presente nas acoes dos metodistas, porem, essa consciencia esta centralizada muitas vezes nos dirigentes da Associacao Metodista de Acao Social, acredita-se que justamente pelo contato direto com a pratica, circunstancias cotidianas e o contato com o que sofre. Assim, diante dessa realidade diagnosticada, encerra-se a pesquisa elevando a discussao para o debate do ministerio diaconal da Igreja de Cristo, onde todo cristao tem a responsabilidade do servico de amor ao proximo.

A VIDA NA MISSÃO DO METODISMO POÇOS-CALDENSE: uma análise crítica sobre a práxis missionária no âmbito da ação social à luz do Plano para a Vida e Missão

Cirurgia bariátrica e qualidade de vida de trabalhadores da saúde

ABSTRACT The objective of this study is to observe the importance of affectivity in the teacher-student relationship in elementary level education of the final years at Santos Dumont Municipal School. We seek to question how the affectivity in the teacher and student relationship can favor the learning of children and adolescents, as well as the possible relationships between these subjects that collaborate for their educational development processes. Also, we seek to find some answers by identifying basic points in the conceptions that can stimulate a coexistence between teachers and students, aimed at understanding the daily development of affectivity in the classroom that is in collaboration for quality learning. That is, for an education in which the student can have satisfactory stimuli to be in the room. The question is how this affective relationship between teacher and student in the classroom can help in learning by finding a foundation in the works of Wallon, Vygotsky, and Piaget, who defend the dimension of affectivity in the teaching-learning process and points out the teacher's action as factor in this process. Regarding the methodology, we highlight bibliographical research and field research, using a qualitative approach. Questionnaires with open and closed questions were applied to teachers and students at the school. We hope that the research results demonstrate how affectivity has been worked in schools and how important it is in student learning. Reinforcing the affective relationship in the classroom facilitates learning and stimulates the learner.

A afetividade como ferramenta mediadora da aprendizagem na relação professor-aluno

ABSTRACT Objective : to identify the factors associated with risk for cardiovascular diseases in hypertensive primary health care (PHC) users. Method : quantitative and cross-sectional study conducted with 115 hypertensive users enrolled in a Brazilian primary health center (UBS). Data were recorded in a semi-structured questionnaire. A descriptive and inferential analysis was performed (Student’s t -test and multivariate logistic regression). P values 60 years) (66.1%), continuous users of diuretic drugs (65.2%). By stratifying PHC users according to the risk for cardiovascular diseases, we observed that the majority showed high risk (59.1%), medium risk (26.1%), and low risk (14.8%). Hypertensive patients with diabetes mellitus (DM) ( p = 0.000), acute myocardial infarction (AMI) ( p = 0.000), congestive heart failure (CHF) ( p = 0.000), and those using diuretic drugs ( p = 0,001) are associated with an increased risk for cardiovascular events. Conclusion : hypertensive patients with DM, AMI, CHF, and those using diuretic drugs evolved with a greater risk for a cardiovascular event. In this context, there is a need for providing an integrated and preventive care based on prevention not only to minimize the occurrence of complications, but mainly to extend the life of hypertensive PHC users on a qualitative basis. Descriptors : Hypertension; Cardiovascular Diseases; Primary Health Care; Risk Factors; Office Nursing; Delivery of Health Care.                                                        RESUMO Objetivo : identificar os fatores associados ao risco de doencas cardiovasculares em usuarios da atencao primaria a saude (APS) hipertensos. Metodo : estudo quantitativo e transversal realizado com 115 usuarios hipertensos cadastrados em uma unidade basica de saude (UBS). Os dados foram registrados em questionariosemiestruturado. Realizou-se analise descritiva e inferencial (teste t de Student e regressao logistica multivariada). Valores p 60 anos) (66,1%), em uso continuo de diureticos (65,2%). Ao estratificar os usuarios da APS de acordo com o risco para doencas cardiovasculares, observou-se que a maioria apresentou risco elevado (59,1%), risco medio (26,1%) e baixo risco (14,8%). Estao associados ao maior risco de eventos cardiovasculares os hipertensos com diabetes mellitus (DM) ( p = 0,000), infarto agudo do miocardio (IAM) ( p = 0,000), insuficiencia cardiaca congestiva (ICC) ( p = 0,000) e aqueles em uso de diureticos ( p = 0,001). Conclusao : usuarios da APS hipertensos com DM, IAM, ICC e em uso de diureticos evoluiram com maior risco de evento cardiovascular. Nesse contexto, faz-se necessario proporcionar uma assistencia integrada e pautada na prevencao nao apenas para minimizar a ocorrencia de complicacoes, mas principalmente para prolongar qualitativamente a vida dos usuarios da APS hipertensos. Descritores : Hipertensao; Doencas Cardiovasculares; Atencao Primaria a Saude; Fatores de Risco; Consulta de Enfermagem; Assistencia a Saude. RESUMEN Objetivo : identificar los factores asociados con el riesgo de enfermedades cardiovasculares en usuarios de la atencion primaria de salud (APS) hipertensos. Metodo : estudio cuantitativo y transversal realizado con 115 usuarios hipertensos inscritos en un centro de salud primaria (UBS) brasileno. Los datos se registraron en un cuestionario semi-estructurado. Se realizo un analisis descriptivo e inferencial (prueba t de Student y regresion logistica multivariable). Los valores p 60 anos) (66,1%), usuarios continuos de diureticos (65,2%). Al estratificar a usuarios de la APS de acuerdo con el riesgo de enfermedades cardiovasculares, observamos que la mayoria mostraba alto riesgo (59,1%), medio riesgo (26,1%) y bajo riesgo (14,8%). Los pacientes hipertensos con diabetes mellitus (DM) ( p = 0,000), infarto agudo de miocardio (IAM) ( p = 0,000), insuficiencia cardiaca congestiva (ICC) ( p = 0,000) y aquellos que usan diureticos ( p = 0,001) estan asociados con un mayor riesgo de eventos cardiovasculares. Conclusion : pacientes hipertensos con DM, IAM, ICC y aquellos que usan diureticos evolucionaron con un mayor riesgo de evento cardiovascular. En este contexto, existe la necesidad de proporcionar una atencion integrada y preventiva basada en la prevencion no solo para minimizar la aparicion de complicaciones, sino principalmente para extender la vida de los usuarios de la APS hipertensos sobre una base cualitativa. Descriptores : Hipertension; Enfermedades Cardiovasculares; Atencion Primaria de Salud; Factores de Riesgo; Enfermeria de Consulta; Prestacion de Atencion de Salud.

Risco cardiovascular em usuários hipertensos da atenção primária à saúde

Movimentos neonazistas na Suécia e na Finlândia : o caso do Nordic Resistance Movement

RESUMO INTRODUCAO: A dirofilariose canina, vulgarmente conhecida como “doenca do verme do coracao” e uma doenca parasitaria cujo agente etiologico e um nematoda filarioide da especie Dirofilaria immitis , de distribuicao cosmopolita e que pode, ocasionalmente parasitar o homem. A D. immitis e um parasita com ciclo heteroxeno, e os mosquitos dos generos Anopheles, Aedes e Culex , sao os principais hospedeiros intermediarios. Testes de sorologia, PCR, e outros especificos como o da gota espessa e de Knott sao os mais indicados para o diagnostico, que pode ser associado aos achados de hematimetria e exames de imagem. O principio do tratamento baseia-se na melhora clinica do animal e na eliminacao de todas as formas nos diferentes estagios do parasita. OBJETIVOS: O presente projeto tem por objetivo analisar a ocorrencia da dirofilariose nos caes atendidos no Hospital Veterinario da UNISO. DELINEAMENTO DO ESTUDO: Experimental e observacional com animais atendidos na rotina ambulatorial do Hospital Veterinario da Universidade de Sorocaba. METODOS: Os caes foram selecionados a partir da rotina ambulatorial do Hospital Veterinario da Universidade de Sorocaba, e que apresentaram manifestacoes clinicas compativeis com a doenca. Foram avaliados os prontuarios clinicos dos animais suspeitos e exames hematologicos, de bioquimica serica e sorologia, realizados nas amostras sanguineas desses animais. RESULTADOS PARCIAIS: Ate o presente momento dois animais foram testados com os testes ELISA, Knott e Gota Espessa, apresentando resultados negativos em ambos os testes para dirofilariose. Entretanto, um dos animais apresentou resultado positivo para anaplasma pela tecnica de ELISA pelo Kit SNAP 4Dx (SNAP 4Dx Plus, IDEXX Laboratories, 2009), que tambem avalia a presenca de anticorpos anti- Ehrlichia canis , anti- Anaplasma phagocytophilum , anti- Anaplasma platys , anti- Borrelia burgdorferi e anti- Ehrlichia ewingii . Alem dos testes ELISA, Knott e Gota Espessa, foram avaliadas a hematimetria, leucometria, contagem de plaquetas, perfil hepatico, proteina total, albumina, globulina e perfil renal destes animais.

ESTUDO DA OCORRÊNCIA DA DIROFILARIOSE EM CÃES NO MUNICÍPIO DE SOROCABA - SP

Controles “sinérgicos” sobre pressão parcial do CO2 na Baía do Almirantado, Península Antártica Norte, durante a primavera de 2013

A pesquisa tem como objetivo maior propor a utilizacao de tecnicas de ultrassom como ferramenta adicional na preservacao do patrimonio historico. Edificacoes como o Museu da Lingua Portuguesa, desde que nao adequadamente preservadas, sofrem processo de desgaste, naturalmente com o tempo. E por meio destes testemunhos materiais que uma sociedade pode preservar sua cultura e historia. Assim, ao descobrir as patologias construtivas atraves de inspecoes sistematizadas pode-se buscar a perpetuacao do objeto, bem como o resgate da identidade do patrimonio tombado.

ENSAIOS NÃO DESTRUTIVOS APLICADOS À ESTRUTURAS DE MADEIRA NO MUSEU DA LÍNGUA PORTUGUESA

It proposes a theoretical study that pervade the concepts of Archivology, Information Science and History, in order to bring the discussions Archivology field, two other disciplines, namely: History and Information Science. These disciplines which in recent years, it is recurrent in academic debates, given that the methods and techniques have been incorporated into each other in a true interdisciplinary dynamics. Even though it realizes that the Information Science has to appropriate much of the debates and speeches, especially of history, then the Archivology, aiming to form its epistemological scope. This is an eminently literature with literature review, seeking to promote a theoretical debate from an interdisciplinary relationship. For this explains the discussions of Information Science, then and History, discusses the idea of interdisciplinarity. Finally seeks to present the dialogue between these three fields of knowledge.

Diálogos entre Arquivologia, Ciência da Informação e história: uma conversa possível

A sindrome do espectro autista e caracterizada por desordem de cunho neurologico e comunicativo, que em sua totalidade atinge areas de cognicao, fala, interacao social e desenvolvimento neuropsicomotor. Enxergando o autismo como de causa multifatorial, torna-se imprescindivel que a partir da descoberta da sindrome, o paciente esteja acolhido por uma equipe de profissionais, incluindo o nutricionista. O presente artigo teve como objetivo analisar como o uso da nutricao em pacientes autistas pode contribuir no tratamento e reabilitacao dos sintomas. A metodologia utilizada constou de pesquisa bibliografica e foi realizada em fontes secundarias: artigos, textos publicados na internet e livros.

Não sejA burro!: o preconceito linguístico e a intolerância no discurso de Marcela Tavares

This paper made a reflection of the reforms influence that had undertaken in Brazil during the government of Luiz Inacio Lula da Silva and Dilma Vana Rousseff. The aim is to analyze how the public sector reforms that took place in the country throughout the twentieth century were inserted in both government. It also sought to understand what was the government view in terms of building a societal public administration. The theoretical framework was built from the three public sector reforms experienced in the country: 1930, 1967 and 1995. Then the news published with the term "reform" on the website of the Ministerio do Planejamento, Orcamento e Gestao were analyzed. The thematic analysis was used for addressing the data. In Lula government particularly, there were progress toward civil population participation in the federal government decisions, but that still require improvements.

Administração Pública Brasileira no Século XXI - Caminhamos para Alguma Reforma?

Este artigo apresenta um estudo exploratorio e teorico sobre o valor do objeto, relacionando as teorias com os objetos ja analisados durante a pesquisa maior realizada para o Trabalho de Conclusao de Curso, realizado junto aos cursos de Design Grafico da Universidade Federal de Pelotas, que tem por objetivo apresentar um estudo sobre a Mauricio de Sousa Producoes a partir de sua historia e evidenciando sua transformacao editorial ao longo de sua trajetoria. O artigo apresentado corresponde ao capitulo no qual abordamos o valor sentimental que o colecionador possui em relacao ao objeto.

Orientador: Prof. Dr. Mauricio Paes Landim. 1o Membro Interno: Prof. Dr. Eucario Leite Monteiro Alves. 2o Membro Interno: Prof. Dr. Viriato Campelo.

ANÁLISE ESPACIAL DA MORTALIDADE POR DOENÇAS DO APARELHO CIRCULATÓRIO EM TERESINA, PIAUÍ

The application of biocatalysis using isolated enzymes and entire cells is a powerful tool to transform a wide range of organic compounds in chemo-, regioand stereoselective mode. In this work, we applied the biocatalysis in the chemical enzymatic synthesis of α-methyl-βhydroxy ester using Saccharomyces cerevisiae by the reduction of α-methylene-β-keto ester and 4-thiazolidinones by a one-pot multicomponent reaction combined biocatalysts. This work is composed by a general introduction followed by two chapters of experimental work, results and discussion. The α-methyl-β-hydroxy ester is an important compound for asymmetric organic synthesis, where they are applied as building blocks to the synthesis of several compounds. This synthesis is getting attention following appropriate methodologies and high selectivity. In the most studied strategies, the asymmetric reduction of α-methylene-β-keto ester in the chemical or enzymatic path are one of the most investigated approaches. The synthesis route to the formation of α-methylene-β-keto ester was the conversion of α-methylene-β-hydroxy ester by Morita-Baylis-Hillman reaction (yields of 64 to 96%), followed by an oxidation reaction using IBX (yields of 88 to 95%). The α-methylene-β-keto ester substrates were exposed as a reactant to the reduction reaction applying Saccharomyces cerevisiae. The product α-methyl-β-hydroxy ester were produced with 66 to 99% of conversion, the diasteroselectivity of 91:9 and enantiomeric excess higher than 99% to all diasteroisomers. Concluding, the S. cerevisiae could reduce the α-methylene-β-keto ester to α-methyl-β-hydroxy ester with high diastereoand enantioselectivity. The 4-thiazolidinones are an important heterocyclic scaffolds present in many biologically and pharmacologically active compounds. Therefore, the development of a proper methodology to synthesize this compound is an actual concern. The efficiency of multicomponent reactions combined with the sustainable feature of biocatalysis were employed in the synthesis of these compounds. A collection of microbial cells, isolated enzymes and bovine serum albumin were screened for catalytic activities. The solvent influence, stoichiometric relations between substrates and the aromatic ring substitutes in the aldehydes were evaluated either. The stoichiometric relation were the greater in the proportion of 1 : 1 : 3 aldehyde : amine : carboxylic acid. The relation between the aldehyde aromatic ring substitutes and the reaction rate was not clear, since the conversions vary with the tested biocatalysts. Summarizing, the 4-thiazolidinones were obtained with good and moderate yields (52 to 69%), under mild reaction conditions.

Sínteses quimioenzimáticas de moléculas bioativas: uma abordagem à química verde

O estudo e o entusiasmo pela robotica tem crescido nos ultimos anos. Entretanto, estudantes e entusiastas possuem restricoes de acesso as tecnologias de montagem e programacao de robos devido aos custos de compra de equipamentos desta area serem considerados inacessiveis. Instituicoes de ensino publicas e privadas podem ate promover aulas e oficinas de robotica, porem a disponibilidade destas tecnologias fica restrita a estas ocasioes e instituicoes. Com a finalidade de solucionar este problema, o presente artigo apresenta uma analise comparativa de custo-beneficio entre laboratorios presenciais e laboratorios de experimentacao remota, destinados a pratica da programacao de robos. Para esta analise, iniciou-se a implementacao do experimento remoto RoboRex que tem por objetivo permitir o experimentador programar um robo para cumprir tarefas como: seguir uma linha e desviar de obstaculos. Conclui-se que a abordagem de experimentacao remota proposta tem menor custo financeiro para a instituicao de ensino, e prove maiores beneficios aos alunos e entusiastas, quando comparada com um laboratorio presencial que tem objetivo similar.

Uma Análise de Custo-benefício entre Experimento Remoto e Laboratório Presencial na Programação de Robôs

A Cannabis sativa vem sendo utilizada ha seculos na medicina por seus efeitos depressores do SNC. Recentemente o uso de um dos seus principios ativos, o Canabidiol (CBD), foi autorizado para uso terapeutico pela ANVISA e pelo CFM, para casos de epilepsia refrataria ao tratamento conservador. A definicao de ansiedade para Castilho, e um sentimento vago e desagradavel de medo, apreensao, caracterizado por tensao ou desconforto derivado de antecipacao de perigo de algo desconhecido ou estranho, passando a ser patologico quando sao exagerados, em relacao ao estimulo, prejudicando o controle emocional, bem como o desempenho diario do individuo. Em relacao aos efeitos ansioliticos do CBD, foram feitos estudos em animais e humanos para avaliacao do efeito terapeutico da droga. Os pacientes com TAS que receberam o CBD nao apresentaram diferencas significativas dos pacientes saudaveis (grupo controle), porem quando comparados aos pacientes com TAS que receberam o placebo, esses pacientes apresentaram “menores niveis de ansiedade nas fases antecipatoria e de performance do teste, alem de menos sintomas somaticos e menos auto avaliacao negativa. Apesar de haver evidencias do efeito ansiolitico do canabidiol, os estudos clinicos, ate o momento, foram feitos com individuos saudaveis que se submeteram a uma situacao que provocava estresse e ansiedade. A substituicao do tratamento classico dos transtornos de ansiedade pelo uso dos derivados da Cannabis sativa, expoe os pacientes a riscos nao conhecidos, alem de nao garantir uma terapeutica eficaz.

O sistema de precedentes judiciais vinculantes no Código de Processo Civil de 2015: um instrumento para concretizar o princípio da segurança jurídica = The binding judicial precedente sistem in 2015 Civil Procedure Code: a mechanism to realise the legal safety

De acordo com o Ministerio da Saude, a Hipertensao Arterial Sistemica (HAS) afeta 600 milhoes de pessoas no mundo, cerca de 25% da populacao brasileira adulta apresenta hipertensao e na terceira idade aumenta para 50%. A HAS e caracterizada como um estado clinico que envolve multiplos fatores e elevado nivel da Pressao Arterial (PA), associada a alteracoes na estrutura e funcionamento de orgaos-alvo (encefalo, coracao, rins e vasos sanguineos), aumentando assim os riscos de acidentes cardiovasculares que podem levar ou nao a obito o individuo. O tratamento farmacologico tem como finalidade primordial, evitar a morbidade e diminuir a mortalidade por eventos cardiovasculares relacionados a HAS. Considerando esses dados o presente estudo tem como objetivo conhecer o perfil farmacologico de pacientes hipertensos cadastrados na Unidade de Saude da Familia no Municipio de Nova Canaa-BA, atraves de um questionario que envolve a idade, medicamento, tempo de uso e as queixas relatadas pelo paciente.

Perfil farmacológico de pacintes Hipertensos Cadastrados em uma Unidade de Saúde da Família no Município de Nova Canaã-BA

Descreve-se caso de um potro Quarto de Milha recem-nascido com malformacao cardiaca complexa, diagnosticada atraves do exame ecodopplercardiografico e necropsia. Os achados morfologicos incluiram atresia de valva tricuspide, comunicacao interventricular, persistencia de forame oval e aplasia de cuspide pulmonar. Havia alteracao do fluxo sanguineo cardiaco, com fluxo turbulento interventricular, interatrial e na arteria pulmonar. Apesar do aspecto complexo das malformacoes, os achados diferiram tanto morfologicamente como pela analise do fluxo sanguineo dos casos de tetralogia de Fallot ou suas derivacoes, por nao haver dextroposicao da aorta, concomitante hipertrofia do ventriculo direito, e pelas ocorrencias de atresia de tricuspide e persistencia do forame oval.

Diagnóstico ecocardiográfico de malformação cardíaca complexa em potro quarto de milha

Epidemiological studies have shown that the pathologies that affect the periodontium are the most common chronic diseases of the human being, affecting 5 to 30% of the adult population in the age group of 25 to 75 years. Non-surgical periodontal therapy is the first stage of the treatment and has proved to be effective for the control of gingival and peridontal diseases, eliminating etiological factors and preventing disease progression, restoring health and function to the patient. Non-surgical periodontal therapy includes instructions for oral hygiene, patient motivation, and scaling and root planing. This study aims to evaluate the outcome of non-surgical periodontal therapy in patients treated in the Periodontal Maintenance extension project, which takes place on Fridays at the Faculty of Dentistry of UFU.

Resultado da terapia periodontal não cirúrgica em pacientes tratados no projeto manutenção periodontal da FOUFU

Antigamente as civilizações se deparavam com dificuldades práticas, do dia a dia, a exemplo disso: medição de terras, distribuição de bens ou até mesmo cálculos de impostos. Contavam então com os sistemas de equações lineares para solucionar esses problemas, conhecido atualmente como álgebra linear. Eram cálculos simples relacionando diferentes variáveis e solucionando atividades corriqueiras. Cada civilização criou seu método, a China desenvolveu seus cálculos para resolver os sistemas lineares em 263 a.C, foi com Chiu Chang Suan Shu que pode-se aprender como a álgebra linear realmente funcionava. Ele então criou um livro com 246 problemas e todos resolvidos. Seu livro “Os Nove Capítulos da Arte Matemática” foi organizado e finalizado por Liu Hui em 263 d.C. Em um dos seus capítulos, Chiu mostra um método muito parecido com a eliminação gaussiana, que foi elaborada na Europa no século XIX. Neste método, é utilizado um exemplo para classes de milho, onde temos a primeira, segunda e terceira classe. Essas medidas são denominadas X, Y, Z formando um sistema linear com três equações e três incógnitas, lembrando que há um resultado para cada equação. Uma das maneiras de resolução era utilizar os coeficientes positivos representando-os por varas pretas, os negativos por varas vermelhas e os coeficientes nulos em espaços vazios. A tabela para o cálculo era adaptado em colunas, utilizando os valores do problema juntamente com as incógnitas. Após isso, o número de varas era ajustado: (1) duas vezes os números da terceira coluna eram subtraídos em três vezes os números da segunda coluna e (2) os números da terceira coluna eram subtraídos de três vezes os números da primeira coluna. Depois, os números da segunda coluna eram subtraídos de cinco vezes os números da primeira coluna. A cada vez que este procedimento era feito, as colunas diminuíam, alguns quadrantes zeravam, e quando uma incógnita poderia ser isolada, era feito o cálculo com base na mesma, ou seja, o Z era isolado obtendo seu resultado, e com esse resultado era possível descobrir o valor de Y e consequentemente o de X. Esse método também era conhecido como Método Fangcheng, foi de extrema importância na China, pois foi com ele que os cálculos puderam ser resolvidos com mais facilidade e exatidão.

In this paper we intend to demonstrate the operation of the customs and the composition of their royal employees mainly using the Pernambuco example as from the documentation available in Brazil. The Pernambuco Ombudsman of the Royal Treasury and the Customs were overlapped in the first half of the eighteenth century. In the first part we will try to demonstrate the power of the administrator of these two institutions and how his family remained for many generations in the Ombudsman’s office and the Customs Judge. In the second we will seek clarify the internal operation of Pernambuco’s Customs; the changes in the context of his officers; the concern of the crown as the suitability of the officership; quarrels between the senior managers of the crown in Pernambuco.

Provedoria da Fazenda Real e Alfândega de Pernambuco: Administração e Funcionamento 1701-1725

As DTM’s sao alteracoes funcionais e dolorosas da articulacao temporomandibular e do sistema mastigatorio com etiologia multifatorial. Uma das alteracoes importantes relacionadas com essa disfuncao sao as alteracoes posturais da coluna cervical. O objetivo deste estudo foi verificar, atraves de uma revisao bibliografica, a relacao entre DTMs e as alteracoes posturais da coluna cervical e verificar os efeitos da fisioterapia nos casos de DTMs. Foi realizada uma pesquisa nas bases de dados Scientific Electronic Library Online (Scielo), Google Academico e Biblioteca Virtual em Saude (BVS)/Lilacs a fim de selecionar artigos relevantes sobre o assunto. Os artigos foram selecionados no periodo de 2005 a 2015. Encontrou-se um total de 339 artigos sendo que somente 12 foram selecionados. Com base nos achados do presente estudo concluiu-se que ha uma relacao da DTM com a alteracao postural da coluna cervical e que a fisioterapia se mostrou eficaz na reabilitacao destes pacientes.

ALTERAÇÕES POSTURAIS DA COLUNA CERVICAL NO DESENVOLVIMENTO DAS DISFUNÇÕES TEMPOROMANDIBULARES

Um checklist anotado de Helmintos parasitos de anuros de cinco localidades da Floresta Atlântica no Sul do Brasil

Tendo em vista o aumento da programacao infantil nas midias digitais, como no site Youtube, o presente estudo tem como objetivo identificar as dificuldades da regulamentacao no que tange a publicidade veiculada para criancas no âmbito nacional. Para tanto, foram realizadas pesquisas bibliograficas a respeito da legislacao brasileira, a fim de entender conceitos e explicacoes juridicas; pesquisa descritiva, para realizar o estudo de caso referente a programacao online da marca de calcados infantis Pampili; e para obter mais informacoes a respeito do assunto abordado, foram realizadas entrevistas com Denise Fabretti, profissional de Legislacao Publicitaria, e com o Instituto Alana, ONG responsavel pelo projeto Crianca e Consumo. PALAVRAS-CHAVE: midias digitais, publicidade, publico infantil, regulamentacao.

PUBLICIDADE DIRIGIDA ÀS CRIANÇAS: A REGULAMENTAÇÃO NA ERA DIGITAL

OBJETIVO: Analisar a producao cientifica nacional e internacional referente ao uso de ventilacao nao invasiva em pacientes com insuficiencia respiratoria aguda, de modo a conhecer os seus efeitos e identificar os fatores associados ao sucesso e falha deste metodo. METODOLOGIA: Trata-se uma revisao integrativa realizada atraves de pesquisa de artigos de 2013 a 2017 nas bases de dados SciELO, LILACS e PubMed. RESULTADOS: Os principais achados em relacao aos efeitos da ventilacao nao invasiva em pacientes com IRA foram a diminuicao da permanencia na UTI e hospital, reducao do trabalho respiratorio e diminuicao da intubacao endotraqueal. Os principais fatores associados a falha da VNI foram a idade, o aumento da frequencia respiratoria, escores de APACHE II e Escala de Coma de Glaslow e presenca de condicoes cronicas e infeccoes. CONSIDERACOES FINAIS: No geral, a VNI e benefica para o tratamento de IRA, entretanto suas taxas de sucesso e falha estao associadas a diversos fatores, requerendo maiores investigacoes para comprovar a sua eficacia.

Efeitos da ventilação não invasiva em pacientes com insuficiência respiratória aguda: uma revisão integrativa

Ao falar de agricultura familiar ouve-se muito tambem sobre a sucessao rural das dificuldade de estimular os jovens a seguir os passos dos pais para a conducao da propriedade familiar. Este tema e importante para os agricultores mais velhos cuja a vontade e ter os filhos perto para poder tocar a propriedade. Diante desse cenario, o tema central desta monografia e levantar possibilidades para este impasse envolvendo a comunicacao, mais precisamente a publicidade. O presente estudo e construido a partir de uma pesquisa bibliografica e de uma pesquisad com abordagem qualitativa. Para obtencao dos resultados foram entrevistados 8 jovens agricultores com idade entre 18 e 25 anos dos municipios de Tapejara, Santa Cecilia do Sul e Ibiaca. Quanto aos resultados, destaca-se a opiniao quase unânime dos jovens de que a publicidade nao influencia diretamente na decisao de permanencia no campo, mas pode haver mudancas nos anuncios para que os jovens sintam-se mais valorizados quanto a profissao que exercem.

Publicidade e sucessão da atividade rural: Um estudo sobre a influência da publicidade na permanência do jovem agricultor no campo

Os beneficios de um programa de atividade fisica regular ja foram comprovados em diversos estudos, beneficios esses, relacionados ao bem estar social, emocional e fisico, favorecendo individuos saudaveis bem como em condicoes patologicas, buscando uma melhora da qualidade de vida e consequentemente melhor performance. Os efeitos da fotobiomodulacao com a terapia de Laser e/ou Diodos Emissores de luz de baixa potencia em humanos, tem sido amplamente estudados quanto a melhora do desempenho e recuperacao muscular, porem seus efeitos a longo prazo e o momento ideal de aplicacao da tecnica ainda precisam ser melhor definidos. O objetivo desse estudo foi investigar o momento ideal para aplicacao da irradiacao com Lasers e LEDs, associado a um treinamento aerobio regular, no intuito de otimizar a performance muscular. Foram recrutados 96 voluntarios, de ambos os sexos, com idade entre 18 e 35 anos, submetidos a um protocolo em esteira ergometrica, associado a fotobiomodulacao ativa ou placebo, antes e/ou depois de cada sessao de treinamento, realizado durante 12 semanas, 3 sessoes por semana, com avaliacoes feitas antes do inicio do protocolo e apos 4, 8 e 12 semanas. Para a irradiacao foi utilizado um cluster de 12 diodos, sendo 4 diodos de laser super pulsado infravermelho de 905 nm, 4 diodos de LED infravermelho 875 nm e 4 diodos de LED vermelho de 640 nm, fabricado pela Multi Radiance Medica TM, com dose de 30 J por local de irradiacao, em 17 locais distintos em cada membro inferior, sendo avaliados aspectos referentes ao desempenho aerobio dos voluntarios (VO2max e tempo ate exaustao) e a composicao corporal (percentual de gordura). Os voluntarios do grupo PBMT+PBMT, apresentaram melhora significante quanto ao tempo ate exaustao (119,19±10,07%) e consumo maximo de oxigenio (120,20±16,62) comparado ao grupo Placebo+Placebo (109,75±9,64% e 106,41±19,54%) e queda com significância estatistica no percentual de gordura (86,13±12,56 x 96,11±11,20%), na decima segunda semana. Nao houve diferenca estatistica nas comparacoes feitas entre os outros grupos. Concluimos que a aplicacao da fotobiomodulacao associada ao exercicio aerobio melhora a performance se aplicada antes e apos as sessoes de treinamento.

Fototerapia aplicada em associação ao treinamento aeróbio: avaliação de diferentes protocolos de irradiação

Este artigo apresenta o trabalho de formacao continuada de professores e alunos da modalidade de Educacao de Jovens e Adultos (Educacao Basica) dos municipios do Baixo do Sao Francisco de Sergipe. Apresenta analise de acoes realizadas por bolsistas e colaboradores do TRANSEJA2 Transdisciplinaride na Literacia e Numeracia de Jovens e Adultos do Semiarido Sergipano, projeto do Observatorio de Educacao da Universidade Tiradentes (OBEDUC/Unit/ CAPES). Trata do subprojeto Oficinas Pedagogicas de Direitos humanos com uso de Tecnologias Digitais na Educacao de Jovens e Adultos do Semiarido Sergipano que contempla quatro oficinas : direitos humanos educacao e cidadania; direitos dos povos – um desafio para a educacao; direitos humanos da crianca e do adolescente educacao e escola; praticas pedagogicas e transformacao, com alunos e professores da rede municipal.

DIREITOS HUMANOS COMO CONTEÚDO TRANSVERSAL NO CURRICULO DA EJA: UMA EXPERIÊNCIA NO BAIXO SÃO FRANCISCO SERGIPANO

No grupo dos repteis, a capacidade de formar memorias e ainda muito discutida e dados neuroanatomicos tem sugerido a existencia de homologias entre as areas do hipocampo e amigdala de mamiferos e estruturas correlatas no telencefalo de repteis. Contudo, existem poucas evidencias funcionais dessas estruturas reptelianas para que fornecam suporte a essa proposta de homologia. Diante de tal conjuntura, esse trabalho teve como objetivo realizar uma avaliacao comportamental e neurobiologica da memoria em lagartos da especie Tropidurus hispidus. Para isso foram utilizados 50 lagartos machos adultos, que apos 4 dias de acomodacao, foram distribuidos em dois experimentos: o Experimento 1, de memoria aversiva (n=40); e o Experimento 2, de memoria espacial (n=10). No Experimento 1 os animais foram divididos em tres grupos (Controle, n=8; Estimulo Neutro, n=16; Estimulo Aversivo, n=16). O grupo controle nao participou das etapas comportamentais, ja o grupo Estimulo Neutro foi exposto a uma gaiola metalica vazia, enquanto o grupo Estimulo Aversivo foi exposto a um gato domestico. Em seguida, todos os animais do grupo Controle e metade dos animais dos grupos Estimulo Neutro e Estimulo Aversivo tiveram seus cerebros perfundidos com paraformaldeido 4% para posterior analise. Os animais restantes dos grupos Estimulo Neutro e Estimulo Aversivo foram colocados de volta no terrario de acomodacao e apos 24 horas passaram por uma reexposicao ao local da exibicao dos estimulos, entao tambem tiveram seus cerebros perfundidos com paraformaldeido 4%. Apos a fixacao, todos os cerebros coletados foram submetidos a uma tecnica de deteccao imustotoquimica de Zif-268, uma proteina envolvida na mediacao da plasticidade que ocorre durante a formacao de memorias. Verificamos que, durante a exposicao ao gato, os lagartos do grupo Estimulo Aversivo apresentaram um maior tempo de congelamento (p<0,001) e um menor numero de deslocamentos iniciados (p<0,001) e de quadrantes visitados (p<0,001), quando comparados com o grupo Estimulo Neutro. Verificamos tambem que, durante a reexposicao ao contexto aversivo, os animais do grupo Estimulo Aversivo apresentaram um maior tempo de congelamento (p<0,001) e um menor numero de deslocamentos iniciados (p<0,001) e de quadrantes visitados (p<0,001), sugerindo assim que a exposicao ao gato atuou adequadamente como um estimulo aversivo. Observou-se tambem um aumento do numero de celulas Zif-268 positivas nas regioes do hipocampo reptiliano e na amigdala dos lagartos do grupo Estimulo Aversivo, durante a exposicao ao gato (p=0,005 e p=0,039, respectivamente) e na reexposicao ao contexto aversivo (p=0,001 e p=0,009, respectivamente). No experimento 2, os lagartos foram submetidos a uma adaptacao do labirinto aquatico de Morris, onde, 3 vezes por dia, durante 19 dias, os animais realizaram tentativas de encontrar uma plataforma submersa. Constatamos uma correlacao negativa (p=0,012) do tempo para chegar a plataforma e o passar dos dias, indicando uma melhoria no desempenho dos lagartos na tarefa. Assim, o presente estudo forneceu indicios que machos de T. hispidus sao capazes de formar memorias aversivas e espaciais, e que ha um envolvimento do hipocampo e amigdala na memoria.

Avaliação comportamental e neurobiológica da memória no lagarto Tropidurus hispidus (SPIX, 1825 ; Squamata : Tropiduridae)

A hipertensao arterial sistemica e definida por niveis elevados e sustentados da pressao arterial, tendo como valor limite 140/90mmHg de valor pressorico. Comprometendo o sistema funcional a curto e longo prazo, afetando orgaos como o coracao, rins, encefalo e vasos sanguineos, tendo por decorrencia o acidente vascular encefalico, patologias cardiovasculares, insuficiencia renal entre outros. Uma nova opcao de tratamento esta sendo utilizada em alguns casos, principalmente na hipertensao esistente- Denervacao simpatica renal-, utilizando o cateter de ablacao por radiofrequencia na arteria renal. O objetivo desta revisao integrativa foi avaliar os estudos que tenha-se utilizado a denervacao no tratamento da hipertensao resistente, e o trabalho do profissional enfermeiro envolvido no procedimento. Na busca realizada nas bases de dados foram selecionados cinco estudos. Foi evidenciado que maiores estudos sao necessarios para embasar a realizacao do procedimentos, a maioria dos estudos publicados sao discrepantes e controversos sem suas conclusoes

Análise da eficácia da denervação simpática renal notratamento da hipertensão resistente

INTRODUCAO: Educacao ambiental e um processo dinâmico, criativo e permanente, proporcionando a sociedade uma mentalidade critica e global do ambiente, com intuito de despertar valores e novas atitudes, proporcionando individuos conscientes, participativos e transformadores, a respeito do meio ambiente e dos problemas que lhe sao associados. Os profissionais da saude, realizam atividades com diversas pessoas com costumes e crencas no que diz espeito ao meio ambiente, mas mesmo assim, passam ensinos a comunidade, sobre nocoes basicas de cuidados com a moradia, englobando a higiene ambiental, o controle da contaminacao hidrica, edafica e aerea, os cuidados com esgotamento sanitario e o lixo ajudando assim na prevencao de determinadas doencas. OBJETIVO: Relatar a relevância das praticas de educacao em saude envolvendo a questao do meio ambiente junto a comunidade. METODOLOGIA: Trata-se de um relato de experiencia executado na disciplina Internato I-Saude Coletiva junto a comunidade cadastrada no Programa de Saude da Familia (PSF), no periodo de janeiro a abril de 2015, desenvolvida na Unidade Basica de Saude (UBS) Artur de Oliveira Reis no povoado Brasilia pertencente ao municipio de Lagarto/SE. Adicionalmente foi realizado um levantamento bibliografico nos bancos de dados da Bireme (Biblioteca virtual em saude) foi selecionado diversos artigos publicados e disponibilizados no Scielo. DISCUSSAO: Os resultados observados apresentam que os profissionais da saude devem envolver-se na orientacao sobre as questoes ambientais, pois influencia diretamente na qualidade de vida e no bem estar da comunidade. Pois sao eles os responsaveis por instruir a comunidade a qual trabalha atraves de mecanismo de educacao em saude, a qual sempre esteve inerente a todos os niveis de atencao, mas ganha significado especial na atencao primaria, pois atraves dela pode embasar acoes preventivas e inovadoras, melhorando assim a saude da comunidade ao redor e preservando o meio ambiente. CONCLUSAO: O estudo possibilitou um amadurecimento sobre a inclusao do profissional da enfermagem, nas praticas de educacao envolvendo as tematicas ambientais no contexto da promocao da saude a comunidade, ja que os agravos ambientais constituem algum comum do cotidiano e influencia diretamente na saude.

O NOVO OLHAR DOS PROFISSIONAIS DA SAÚDE SOBRE EDUCAÇÃO AMBIENTAL

O Prosseguimento do Processo Penal para o Réu Revel Citado por Edital à Luz dos Princípios Constitucionais do Contraditório e da Ampla Defesa

A doenca falciforme e uma enfermidade hereditaria e genetica. Com alta morbimortalidade, pode levar a anemia cronica, a quadros graves de infeccao, a crises intensas de dor, entre outras complicacoes. Este estudo objetivou identificar, por meio de uma pesquisa bibliografica, repercussoes da doenca falciforme no cotidiano do adolescente e como o autocuidado pode minimiza-las. A busca eletronica dos artigos ocorreu entre os meses de setembro a novembro de 2014, orientada pelos Descritores “Doenca Falciforme”, “Adolescentes” e “Autocuidado”, mediante consulta as bases de dados Literatura Latino-Americana e do Caribe em Ciencias da Saude (LILACS), na Base de Dados de Enfermagem (BDENF) e tambem atraves da Scientifc Electronic Library (SciELO). A partir dessas buscas, e de acordo com os criterios de inclusao e exclusao, foram selecionados 14 artigos para analise e interpretacao dos dados. Os resultados foram apresentados por meio de 04 categorias tematicas: repercussoes fisicas, atraves das crises algicas, baixa estatura e magreza, e deficit de desenvolvimento; repercussoes emocionais, evidenciadas por disturbio da autoestima, autoimagem e autoconceito; sociais, destacando os conﬂitos internos e o cotidiano da familia do adolescente com doenca falciforme. Diante dessas repercussoes, fica clara a importância de trabalhar o autocuidado, visando proporcionar melhor qualidade de vida aos adolescentes com DF. ABSTRACT Sickle cell disease (SCD) is an inherited and genetic disease. With high morbidity and mortality, it can lead to chronic anemia, severe infection, intense pain, and other complications. This study aimed to identify the repercussions of sickle cell disease in the adolescent’s daily life and how self-care can minimize them. It is a bibliographic research. The electronic search occurred between September and November 2014, guided by the Health Sciences Descriptors (DECS) “Sickle Disease”, “Adolescents” and “Self Care”, through consultation to Latin American and Caribbean Health Sciences (LILACS), Nursing Database (BDENF), and Scientifc Electronic Library (SciELO). From these searches and according to the inclusion and exclusion criteria, 14 articles were selected for analysis and interpretation of the data. The results were presented through 04 thematic categories: physical repercussions, through pain crises, short stature and thinness and development defcit; The emotional ones, evidenced by disturbance of the self-esteem, self-image and selfconcept; and the social ones, highlighting the internal conﬂicts and the daily life of the family of adolescente with DF family. In the face of these repercussions, it is clear the importance of working self-care, aiming to provide a better quality of life for adolescents with DF.

REPERCUSSÕES DA DOENÇA FALCIFORME E O AUTOCUIDADO NO COTIDIANO DO ADOLESCENTE: REVISÃO BIBLIOGRÁFICA

O presente estudo reflete sobre a producao da punicao e dos limites e possibilidades de um julgamento, pautado pela equidade, no âmbito da justica juvenil atuante na esfera da socioeducacao. O campo da pesquisa e o Juizado da Infância e Juventude da Comarca de Goiânia. Trata-se de uma investigacao qualitativa, realizada por meio da observacao direta de oitivas informais da promotoria e audiencias, e tambem entrevistas semiestruturadas com profissionais desta justica: defensores, promotores e magistrada. Pierre Bourdieu e Michel Foucault sao autores centrais para este estudo; Bourdieu e de grande valia para pensar a forma como esta organizada a justica juvenil da comarca estudada, enquanto Foucault contribui para a analise dos discursos. No caso de Bourdieu, os conceitos de Illusio (jogo) e aqueles muito proximos dele, como campo/subcampo, tambem nomos e doxa, alem do habitus, sao aqui mobilizados em diferentes intensidades; no caso de Foucault, privilegia-se as dobras ou duplos sucessivos, providenciados pelas praticas de exame, associados ao Poder de Normalizacao. Entende-se que a extensao do poder punitivo, operado nas dobras que incidem sobre o julgamento da justica juvenil, so pode ser enfrentada por meio da combinacao entre medidas socioeducativas e medidas protetivas, recurso este disponibilizado pela legislacao que informa esta justica. Analisa-se, entao, a realidade desta possibilidade que vai ao encontro de um julgamento afinado a perspectiva da equidade. Para alem disso, a introducao e as consideracoes finais deste trabalho se ocupam em coloca-lo em dialogo com temas que estao na pauta da cena sociopolitica contemporânea, a reducao da maioridade penal e o recrudescimento punitivo no âmbito do direito juvenil.

Qual é a medida? Um estudo sobre punição e equidade no julgamento da justiça juvenil

Analise do papel do Estado-Juiz no combate ao dumping social, sob a perspectiva do ativismo judicial e da aplicacao de indenizacoes punitivas, e sua importância para a reducao da litigância e efetivacao dos direitos sociais trabalhistas, pressupostos para a construcao e consolidacao do Estado Democratico de Direito. Dentro dessa tematica, propoe-se uma reflexao acerca do papel do Juiz do Trabalho na atualidade, sobretudo em tempos de crise do denominado Estado Social, visando ao aprimoramento da prestacao jurisdicional atraves de uma nova racionalidade juridica, que impoe uma postura mais ativa do Magistrado com vistas a garantir a efetivacao dos direitos fundamentais, a realizacao dos principios constitucionais e a afirmacao da autoridade estatal no cumprimento da legislacao trabalhista.

Femvertising: o empoderamento da mulher na propaganda sob a ótica das receptoras

Metodologia para produção de animação publicitária: adequações projetuais para potenciais mercados

Senhoras e senhores, com vocês, os palhaços grotescos Doutor, Capitão e Woyzeck!

A MULHER SEGUNDO O PENSAMENTO ULTRAMONTANO: CONSERVADORISMO OU INOVAÇÃO?

Com mais de 134 anos de existencia no Brasil, a soja (Glycine max L.) Merril e cultivada em praticamente todo o territorio brasileiro, hoje destaca-se como a mais importante oleaginosa cultivada no mundo. Possui um alto teor de proteina (38%) e oleo (18%), o que lhe confere multiplas utilizacoes, sendo largamente utilizado pela 
industria esmagadora para a producao do oleo de soja, mas um dos desafios da industria consiste em obter um grao com baixos teores de acidez titulavel e clorofila. Tendo em vista a necessidade de estudar a qualidade do grao de soja, objetivou-se neste trabalho quantificar os niveis de acidez titulavel e clorofila dos graos de soja da safra de 2014/2015 em nove estados do Brasil. Buscou-se avaliar o percentual de acidez titulavel e clorofila dos graos da safra 2014/2015 de nove estados do Brasil. Analisou-se 408 amostras de graos de soja, cultivadas nos estados do Rio Grande do Sul, Santa Catarina, Parana, Mato Grosso do Sul, Sao Paulo, Mato Grosso, Goias, Minas Gerais e Bahia, por meio de analises para quantificacao de acidez 
titulavel e determinacao dos teores de clorofila a,b e total atraves da espectrofotometria UV-VIS. Os resultados obtidos demonstraram que as amostras dos estados de Santa Catarina, Parana e Rio Grande do Sul respectivamente, alcancaram os menores resultados de acidez titulavel, na faixa de 1 a 1,5% e o estado de Goias na regiao centro-oeste foi o que obteve a maior media, proximo a 4,5%, demonstrando que o teor de acidez aumentou com o aumento de latitude. Os resultados podem ter sido influenciados por altas temperaturas, ataque de percevejos ou manejo inadequado. Para as analises que quantificaram o teor de 
clorofila no grao de soja, os estados de Santa Catarina e Mato Grosso obtiveram os menores valores, com menos de 2,00 mg.g-1 e o estado da Bahia obteve o maior valor entre os nove estados, com media superior a 10,00 mg.g-1. Fatores como estresse, morte prematura da planta, baixo desenvolvimento do grao, doencas que afetam a raiz, hastes e folhas da planta, assim como o deficit hidrico e presenca de pragas podem ter colaborado para os altos resultados encontrados.

Perda da qualidade do grão de soja no Brasil em função dos altos teores de acidez e clorofila

Este trabalho estudou o Programa Nacional de Inclusao de Jovens – Pro-Jovem, com  objetivo de analisar as contribuicoes socioeconomica, laboral e cultural do Programa ProJovem Urbano na (re)insercao dos setores vulneraveis , mediante detalhamento de seus objetivos, metas, acoes e estrategias. Para uma melhor compreensao sobre esta politica publica, ha uma descricao sobre a realidade da adolescencia e da juventude brasileira; descricao do ProJovem Urbano e o Programa em Vitoria da Conquista/BA. Como resultado da pesquisa, atraves do levantamento bibliografico e documental e da analise de publicacoes ja existentes na area, a pesquisa observou que, das mudancas percebidas pelos jovens, algumas sao mais valorizadas que outras, pois lhes trouxeram novas perspectivas e aumento da autoestima e confianca, indo muito alem das suas expectativas. Ja para a cidade de Vitoria da Conquista, o programa ainda enfrentara inumeros desafios, tanto na sua gestao quanto na sua avaliacao, analise e monitoramento. Mas, a partir do momento em que esses problemas forem sendo sanados atraves de estrategias, acoes e melhoramento do suporte tecnico e administrativo, alem da adequacao de suas estruturas, o projeto tera condicoes reais de modificar a vida de seu publico-alvo e das comunidades, nao sendo mais apenas um programa fadado ao fracasso.

As contribuições socioeconômica, laboral e cultural do programa projovem urbano na (re)inserção dos setores vulneráveis

Inclusão social pelo trabalho: estudo comparativo entre as políticas públicas de saúde mental do Brasil e da Inglaterra

Este trabalho prop˜oe m´eto do num´erico de simula¸c˜ao e otimiza¸c˜ao do temp o de esp era 
nas filas da emergˆencia hospitalar. O estudo de caso ´e realizado em hospital da rede 
particular, do munic´ipio de Goiˆania. Utiliza-se a mo delagem de sistemas a eventos 
discretos como simulador computacional e dois m´eto dos heur´isticos de otimiza¸c˜ao: 
o Algoritmo de For¸ca Bruta e o Algoritmo Gen´etico. Os resultados da otimiza¸c˜ao 
s˜ao comparados com as diretivas encontradas na Resolu¸c˜ao CFM no 2077/2014, na 
tentativa de adequar o sistema a esta resolu¸c˜ao. De posse dos resultados obtidos, 
observa-se que o m´etodo de simula¸c˜ao e os m´etodos de otimiza¸c˜ao s˜ao eficientes para 
minimiza¸c˜ao de filas em sistema de emergˆencia hospitalar.

Otimização do atendimento médico-hospitalar emergencial utilizando sistema a eventos discretos

O presente artigo apresenta alguns resultados de pesquisa de mestrado cujo objetivo foi investigar “A Avaliacao Como Instrumento Diagnostico ‘Reflexivo’ do Processo Ensino-Aprendizagem do Aluno do Ensino Medio da EJA da Escola Estadual de Ensino Fundamental e Medio ‘Arlindo Ferreira Lopes’ do Municipio de Serra/ES.” Procura-se aqui apresentar uma investigacao de que forma o docente da Escola Estadual de Ensino Fundamental e Medio ‘Arlindo Ferreira Lopes’ do Municipio de Serra/ES, compreende a avaliacao como instrumento diagnostico ‘reflexivo’ no processo de ensino-aprendizagem do aluno da EJA no Ensino Medio. A abordagem metodologica utilizada para a realizacao do estudo foi de cunho descritivo correlacional e nao experimental, cujo enfoque da investigacao e qualitativo com ajuda de tecnicas quantitativas. Para coleta de dados foram realizadas aplicacoes de questionarios com perguntas abertas, fechadas e semiabertas. Os resultados permitem constatar que a proposta pedagogica da escola campo com relacao ao trabalho direcionado a avaliacao tem sido um instrumento diagnostico ‘reflexivo’ no processo de ensino-aprendizagem do aluno, impulsionado aos professores uma metodologia diferenciada e eficaz, fato esse que os professores se esforcam para que avaliacao contribua com o ensino do aluno. Bem como foi constatado que o aspecto da revisao de conteudo contribui muito para o sucesso e melhoria do aprendizado. Assim como a implementacao de novas metodologias contribuem para uma educacao de excelencia.

A AVALIAÇÃO COMO INSTRUMENTO DIAGNÓSTICO ‘REFLEXIVO’ DO PROCESSO ENSINO- APRENDIZAGEM DO ALUNO DO ENSINO MÉDIO DA EJA.

Integração dos imigrantes da República Democrática do Congo no Bairro Camama 1 em Luanda

O presente tem por escopo evidenciar a problematica do superendividamento e analisar, a estreita relacao dos vulneraveis com os contratos bancarios de mutuo onerosos. O estudo parte de uma analise do caso de superendividamento dos vulneraveis, ou seja, dos consumidores como a parte mais fraca da relacao consumerista, dispoe sobre a oferta demasiada de credito no mercado. E em ultimo momento trata da relacao dos superendividados com os contratos bancarios de mutuo oneroso e da revisao contratual como instrumento juridico para assegurar a protecao do consumidor na ausencia de normas especificas que tratem a situacao de superendividamento. A abordagem do assunto foi realizada atraves de um metodo dedutivo, por meio de analise doutrinaria e literatura especializada, mediante aplicacao de tecnica de pesquisa bibliografica, com utilizacao de referencias fisicas e eletronicas.

O SUPERENDIVIDAMENTO DE VULNERÁVEIS E OS CONTRATOS BANCARIOS DE MÚTUO ONEROSOS

Na disciplina de Planejamento de Relacoes Publicas, do Curso de Comunicacao Social da UNISC, realizada no semestre de 2015, os academicos Tatiane Conrad, Gabriele Ayres e Lucas Jardim realizaram um plano, projeto e programa de Relacoes Publicas para a empresa M.M. Maquinas Industriais, situada na cidade de Santa Cruz do Sul. Inicialmente foi aplicada uma pesquisa institucional, que ofereceu os elementos necessarios para uma analise da organizacao e de sua comunicacao. Os objetivos deste trabalho foram: ampliar e melhorar a comunicacao da empresa com seus publicos, reforcando a comunicacao externa; aprimorar a comunicacao interna; melhorar a comunicacao organizacional; divulgar a empresa em grande escala; e aumentar as vendas. A empresa M. M. Maquinas Industriais funciona ha mais de sete anos no mercado, com 11 funcionarios fixos, alem do proprio dono, de um representante comercial e dos prestadores de servico. A empresa participa de todos os trabalhos da producao dos elevadores, instalacao e manutencao. Por ser a unica empresa proxima aos Vales do Rio Pardo e do Taquari, possui uma grande area para atuacao, mas necessita de mais divulgacao. Atraves do diagnostico concluimos que a divulgacao da empresa se da prioritariamente por meio de um representante comercial, uma pagina no Facebook e folders que estao dispostos na sede da empresa. Nao ha nenhuma comunicacao por meio de jornal, radio ou TV. Alem disso, a empresa possui cinco veiculos, para visitas, entregas e instalacoes, alem da manutencao. Nenhum dos carros possui algum tipo de comunicacao visual para divulgar a empresa com midia espontânea. Estabelecer os conceitos de missao, visao e valores para a empresa sera de grande valia, pois trara todos os envolvidos na empresa para um mesmo foco. Assim espera-se que o comprometimento dentro de suas funcoes diarias e das metas a cumprir seja levado mais a serio. Para o plano de comunicacao estrategico, decidiu-se pela criacao dos conceitos de missao, visao e valores para que a empresa possua claramente definido qual seu proposito; utilizacao da midia digital com a criacao de um site alem da manutencao da pagina do Facebook; adesivagem dos veiculos da empresa e da familia; realizacao de um mural interno; realizacao de confraternizacao em datas festivas e aniversarios; producao de material grafico e do cartao RP. Foi feito um quadro com cronograma anual e a estimativa de orcamento de cada item. O projeto de comunicacao mercadologica foi definido com prioridade em aumentar as vendas, gerando mais visibilidade e divulgando-a em grande escala. Para este projeto, estipulou-se um cronograma semestral para aplica-lo, bem como uma estimativa de investimento. Para a elaboracao do programa de comunicacao foi escolhido a criacao da pagina na web, pois seria um canal completo e traria uma imagem mais seria a empresa. Alem de oferecer informacoes importantes antes do primeiro contato, o site tambem disponibilizara uma opcao para orcamento, facilitanto o contato com a empresa. Dessa forma finaliza-se este trabalho com as metas estabelecidas de forma clara e objetiva para que a empresa possa trabalhar com foco nas necessidades, a fim de reestruturar sua imagem e aumentar suas vendas.

The Care System Nursing (ASN) is a method for organizing actions systematized and interrelated, aiming at nursing care of the highest quality human being. Aiming to report the authors' experience during hospital practice in order to expand the technical and scientific knowledge of nursing professionals on the topic and show the importance of drawing a SAE effective in reducing complications in intra-and postoperatively. This is an experience report done from a curricular course of Nursing, University of Para, in Ophir Loyola Hospital in the city of Belem, in the year 2012. In developing the SAE used as a data source anamnesis, physical examination, systematic reading of the records and information obtained from the monitoring period in intra-and postoperative patient. Patients with a history of colorectal cancer, about 2 years, underwent colostomy due to pathology, returns to the hospital for restoration of intestinal transit (RTI). The postoperative period was uneventful. This experience allowed us to know about aspects of the pathology studied, learn to draw a SAE to customer quality, enhance nursing care to surgical patients and patients with colostomy, and contribute constructively to our training. KEY WORDS: Colostomy, Nursing Care, Perioperative Period. ______________________________________________________________________

Assistência De Enfermagem ao Paciente Colostomizado Submetido à Reconstrução De Trânsito Intestinal

Even with the consolidation of communication protocols network on the market, such as File Transfer Protocol (FTP), communication between software systems has always been a challenging task. The Java Message Service (JMS) came up with the same order, so that applications written in the Java language could create, send and receive messages from other applications. The company of road control systems VELSIS chose to start with FTP as a protocol communication between their equipment. However, given the constraints encountered due to this technology the company felt the need for more stable alternatives. This article presents the results and the experience gained by the migration of FTP to JMS as a communication between systems. The positives and negatives points will be presented and some possible solutions to the problems that came to

JAVA MESSAGE SERVICE, UMA ALTERNATIVA ENTRE COMUNICAÇÃO DE SISTEMAS: UMA ABORDAGEM PRÁTICA.

O presente trabalho de conclusao de curso se remete ao espaco urbano de Caico/RN, cujo objetivo geral foi interpretar suas formas de espacializacao comercial e de servicos evidenciadas a partir da teoria dos circuitos da economia urbana. Apos o processo de urbanizacao, com enfase na expansao urbana de 1970, sao destacados as acoes e os objetos inseridos na forma de concentracao na urbe caicoense. O espaco geografico, entendido como banal (espaco de todos os homens e todos os fenomenos) e os diversos usos do territorio sao elementos chave dessa interpretacao. A partir dessa interrelacao de conceitos sao evidenciados e percebidos os processos de concentracao e centralidade exercidos no bairro Centro, principalmente pelos agentes do circuito superior, mas tambem pelo circuito inferior. Este subespaco e caracterizado como o mais dinâmico e luminoso da urbe para o uso comercial. Os atores hegemonicos tambem agem e adjetivam o espaco central como de alto status. Em contrapartida, tambem foram evidenciados a partir da expansao urbana os processos de periferizacao e uma tentativa de descentralizacao comercial de forma espontânea pelos agentes do circuito inferior nos subespacos opacos da urbe. Estes agentes do circuito inferior periferico nao promovem a mesma espacializacao comercial quando se compara ao processo no centro, mas nao se podem negligenciar os dinamismos da economia e do territorio periferico. Aliado a essa intensa fragmentacao do espaco urbano caicoense foi indicada a coexistencia tambem do processo de segregacao socioespacial. De um lado, os atores hegemonicos agem nos subespacos concentrados (os luminosos) e promovem a sua autossegregacao. Do outro, os nao hegemonicos sobrevivem a partir de variadas estrategias nas descontinuidades perifericas (os subespacos opacos) e sao indicados como os segregados da urbe. Tem-se, pois, uma cidade profundamente desigual e fragmentada evidenciada a partir da localizacao dos circuitos da economia urbana. Entende-se que a cidade nao esta dividida em duas, mas em varias parcelas. Finalmente, a insuficiencia no direcionamento das acoes do Estado (incluindo o poder publico municipal) e percebida. A lei e os dispositivos constitucionais que indicam que todos os homens tem direito ao uso da cidade em sua totalidade sao questionados. O espaco urbano capitalista caicoense e territorio no qual os hegemonicos concentram-se na forma de centralidade urbana e os agentes nao hegemonicos sao afastados da concentracao em direcao as periferias. O mercado e o consumo pensados neste periodo globalizado, a partir do meio tecnico-cientifico-informacional, mostram que nem todas as parcelas e todas as pessoas tem acesso a totalidade citadina. Os circuitos da economia urbana e os conceitos que sao discutidos neste trabalho evidenciam tais processos.

O centro e as novas centralidades: considerações a partir dos circuitos da economia urbana na cidade de Caicó/RN

A agricultura de precisao (AP) e um sistema de gestao da producao agricola que, baseados em estudos da variabilidade de solos e clima de dados especificos de areas geograficamente referenciadas, implanta-se o processo de automacao agricola para que as lavouras e sistemas de producao sejam otimizados para uma maior producao com menores custos. No setor canavieiro, o recurso tecnologico mais aplicado da agricultura de precisao (AP) e o Piloto Automatico (PA) em que, utilizando o posicionamento por satelite, e capaz de conduzir os conjuntos mecanizados, como preparo do solo, plantio e colheita em um trajeto definido pelo operador em campo. As principais partes que compoe um tipico aparelho de piloto automatico agricola sao; monitor FMX (tela); antena; controladora (NaveControl); fluxometro e sensor de roda. Portanto, com a aplicacao da PA e outros recursos tecnologicos nas lavouras canavieiras espera-se a divulgacao e disseminacao da Agricultura de precisao para as demais culturas no Estado de Mato Grosso do Sul. Este estudo teve o objetivo de caracterizar a aplicacao do PA em lavouras comerciais de uma Usina Sucroenergetica da regiao de Rio Brilhante/MS e diagnosticar, atraves de um questionario aplicado em diferentes turnos, as principais dificuldades encontradas pelos operadores e as suas causas. O piloto automatico esta sendo utilizado nestas lavouras na topografia, plantio mecanizado e quebra lombo (cultivo). O operador agricola deve executar as seguintes operacoes para o uso do PA: Ligar, selecionar ou criar novo trabalho, verificar o sinal GPS e RTK, verificar calibracao do GPS, identificar cintilacao, tirar reta ou curva AB, ativar o PA, identificar o numero de leiras, selecionar outra area, identificar a distância fora da linha, verificar falha e troca de canal da base para a repetidora. Atualmente, a Usina possui 18 operadores agricolas distribuidos nos tres turnos de trabalho apresentando uma media de: idade de 33 anos, experiencia profissional de 7 anos e 2 anos de trabalho em piloto automatico (PA) sendo que as maiores dificuldades na configuracao do PA foi apagar a falha e a troca de canal da base para a repetidora.

MANUTENÇÃO E DIFICULDADES DA OPERAÇÃO DO PILOTO AUTOMÁTICO AGRÍCOLA NO PLANTIO MECANIZADO DE CANA-DE-AÇÚCAR

Este presente artigo tem como principal objetivo analisar a campanha publicitaria da marca Assolan produzida e veiculada nos anos de 2002 e 2003. Intitulada “O fenomeno”, a campanha trabalhou com Comunicacao Integrada de Marketing (CIM) a fim de obter o resultado desejado: o aumento de vendas e um novo posicionamento de Mercado. Palavras-Chave: Assolan. Comunicacao Integrada de Marketing (CIM). Campanha Publicitaria. Posicionamento.

Assolan: “O fenômeno”: estudo de caso de Comunicação Integrada de Marketing (CIM)

Monografia apresentada ao Curso de Direito da Universidade Federal do Maranhao para obtencao do grau de Bacharel em Direito.

O presente trabalho toma como objeto de estudo os tipos de discurso, umas das nocoes centrais do Interacionismo Sociodiscursivo (ISD). Segundo o ISD, a linguagem assume um ponto central no desenvolvimento do ser humano e o texto e concebido como uma unidade comunicativa global que movimenta recursos linguisticos de determinada lingua natural, adotando e adaptando determinado modelo textual (os generos textuais). Os tipos de discurso sao definidos como segmentos, em numero finito, que entram necessariamente na composicao dos generos e, consequentemente, de cada texto empirico, nos quais semiotizam diferentes mundos discursivos particulares ou diferentes atitudes de locucao. A identificacao dos tipos de discurso e possivel a partir das unidades linguisticas que neles ocorrem. Considerando essas nocoes, partimos da hipotese formulada por Miranda (2008) segundo a qual, de acordo com os generos, os tipos de discurso apresentam especificidades no plano da configuracao do tipo linguistico, que, por sua vez, podem variar nas diferentes linguas naturais. Nosso objetivo e, portanto, detectar o tipo de discurso que predomina no genero painel do leitor e depreender as unidades e mecanismos linguisticos que se associam ao tipo de discurso ou tipos de discurso predominantes, comparativamente em relacao ao portugues e ao espanhol. O trabalho se caracteriza por sua natureza exploratoria e pretende tratar a questao com vistas a torna-la mais explicita para a discussao de hipoteses. Para atingir esse objetivo, analisamos um corpus composto por 30 paineis de leitores, 15 extraidos do jornal El periodico de Catalunya, em lingua espanhola, e 15 do jornal Folha de Sao Paulo, em lingua portuguesa.

Tipos de discurso e recursos linguísticos: análise comparativa entre português e espanhol

Ligas metálicas solidificadas divergem em suas propriedades mecânicas através de sua macroestrutura, microestrutura, porosidades e quanto a produtos de segregação. Estes são definidos na solidificação da liga. A verificação dos parâmetros microestruturais como espaçamento entre as células ou espaçamentos dentríticos, são uma forma de se prever o comportamento mecânico de determinada liga. [Pinto, 2000; Siqueira, 2002].

Análise Microestrutural de uma Liga Hipereutética Al-Si Solidificada Unidirecionalmente em Regime Transitório

Planejamento simplex-centróide na produção de protease de Bacillus amyloliquefaciens MO.04b em resíduos da agro-indústria

Article published in the Diario de Noticias journal, in 1943 in Rio de Janeiro. The paper presents characteristics of Nietzsche's moral philosophy and shows the German as a philosopher that sought to understand the "want-to-live", i.e. the expansion of life. Lucio builds up his text exclusively on the basis of Thus spoke Zarathustra.

Compreendendo o Homem sob uma perspectiva transdisciplinar, o estudo
tem como objetivo principal entender o papel da educacao ecologica na formacao
humana, cidada e, sobretudo, multiplice dos seres humanos, tornando-os capazes
de pensar o mundo complexo de forma responsavel e sustentavel. Para tal, buscouse
elaborar uma pesquisa transdisciplinar baseada em autores que trabalham as
questoes terrestres e humanas da atualidade e a educacao ecologica como
ferramenta de transformacao, como Edgar Morin, Francisco Gutierrez, Humberto
Maturana, Francisco Varela e Moacir Gadotti. O trabalho inicia-se com um
preâmbulo em que se demonstra o surgimento da vida no planeta, elucida-se a
necessidade de se pensar o planeta como uma entidade viva e autonoma e as
relacoes dentro dele como multiplas e complexas. A partir deste entendimento, o
trabalho divide-se em tres partes, sendo a primeira focada nas definicoes e
conceitos que se voltam a crise socioecologica que assola o planeta hoje, a
sustentabilidade e a educacao ecologica dentro de um quadro de complexidade
mundial. Na segunda parte, situa-se a elaboracao da analise das experiencias
Ecopedagogicas realizadas pela pesquisadora no ano de 2011, no Centro
Educacional Unificado (CEU) Pera Marmelo, e, por fim, a terceira parte fecha o
estudo, trazendo as consideracoes finais e apontando a necessaria mudanca de
paradigma para que a educacao que acreditamos seja responsavel pela mudanca
de postura e forma de enxergar e agir no mundo atual

Este trabalho objetivou relatar as concepcoes e praticas de Educacao em Saude e sua relacao com a promocao a saude pelas equipes integrantes de uma unidade de saude da familia e conduzir a acao-reflexao sobre a abordagem dialogica e emancipatoria educativas, por meio de discussoes grupais. Tratou-se de uma pesquisa-acao com base teorico-metodologica dos Circulos de Cultura de Paulo Freire. As percepcoes dos participantes, quanto as praticas educativas, nao sao atuais e evidencia a mudanca de paradigma que estamos vivendo, do metodo tradicional para o dialogico. Por meio da reflexao sobre o modelo dialogico e o modelo bancario foi possivel pensar sobre as praticas dos profissionais da area da saude e a possibilidade de muda-las.

A PRÁTICA EDUCATIVA NA ESTRATÉGIA SAÚDE DA FAMÍLIA: ESTRATÉGIA PARA REPENSAR E RECONSTRUIR AÇÕES DIALÓGICAS

__________________________________________________________ Anacampserotaceae belongs to the order Caryophyllales, suborder Portulacineae, currently consists of three genus (Anacampseros L., Grahamia Gill ex Hook and Talinopsis A. Gray) formerly circumscribed to the family Portulacaceae. Anacampserotaceae representatives presents lignified axillary structures very distinctive, like trichomes, scales and bristles and also WBT cells that is presented only by two other families of Caryophyllales, Aizoaceae e Cactaceae. The axillary characters are very informative for the ACPT clade (Anacampserotaceae, Cactaceae, Portulacaceae and Talinaceae) and has been revealing important data for the phylogenetic studies on the Portulacineae suborder, nevertheless, there is a controversy regarding the Anacampserotaceae axillary structures ontogenetic origin, what may lead to misguided interpretations for the ACPT phylogenetic relationships. Before it, this research have accomplished the ontogenetic study of the structures present on the leaf axil of eight Anacampserotaceae species and examined stem and leaf WBTs, as for its secondary thickening type and quantitative measurements of six species. The results points 1) that at least one structure (scale) has leaf origin instead of protodermic origin, as stated by some authors; 2) first report of prophylls for the family and 3) WBTs occur in Anacampseros but they are absent in Talinopsis, a basal group of Anacampserotaceae.

Ontogênese das estruturas axilares em Anacampserotaceae (Caryophyllales)

The American Civil War (1861-1865) was the result of deep differences – territorial, political, social and economic – that were all tied up in one fundamental question: slavery. Slavery was the deepest point of divergence within the nation and the question about its expansion to the west became fundamental from the Mexican-American War in 1846. The issue involving the addition of new slave states in the Union created a new alignment of forces, exacerbating the division between projects from Republicans and Democrats. Based on this, the article seeks to contribute to an understanding of the issue based on the analysis of a series of seven debates between Abraham Lincoln and Stephen Douglas, candidates representing the two parties in the Illinois state campaign for U.S. Senator in 1858.

Uma nação dividida: Escravidão e política partidária nos Estados Unidos as vésperas da guerra civil

O tema tratado e sobre a violencia domestica contra a mulher por companheiro. A vitima que sofre desde seculos passados, aos poucos, foi ganhando espaco na sociedade, atraves dos movimentos sociais, principalmente o movimento feminista. Porem, mesmo com o advento de tal conquista, o numero de casos da violencia continua elevado. Os agressores, geralmente seus parceiros, sentem-se no poder de domina-las e agredi-las. Os tipos de violencia que irao ser vistos no artigo, irao alem do fisico, como tambem as consequencias trazidas por esses atos. Algumas medidas de prevencao contra a violencia ja foram tomadas e a que esta em vigor atualmente e a Lei Maria da Penha, que embora ameace os agressores, nao ha fatos comprovando a diminuicao dos casos.

A Violência Doméstica contra Mulher por Companheiro e a Lei Maria da Penha

O anistiado politico se configura como aquele que recebeu o perdao do Estado por um crime cometido contra o Estado. O texto da Lei 6.683/79 (Lei da Anistia) instaura a posicao-sujeito anistiado e a divide em dois grupos: criminosos politicos e criminosos conexos , criando, ao mesmo tempo, a posicao-sujeito nao anistiado , a qual engloba a figura do subversivo, que permaneceu no imaginario popular como aquele que recebeu a anistia, ou aquele a quem a anistia seria destinada. Entretanto, o texto da Lei segue na direcao contraria a essa expectativa, e a memoria historica forma um sujeito que nao teve direito ao perdao do Estado no primeiro momento da abertura governamental, quando o combate ao Regime Militar passou a ser considerado um ato licito. Este estudo analisa, a partir de pressupostos teoricos da AD francesa de vertente pecheutiana, a instauracao da posicao-sujeito anistiado politico e, ao mesmo tempo o aparecimento do nao anistiado , por oposicao, a partir de dominios de memoria relacionados ao entorno da designacao anistiado , bem como do texto legal que regulamenta socialmente a condicao de anistiado.

O direito penal moderno, no limiar da sociedade de risco, busca cada vez mais o equilibrio entre a protecao de bens juridicos e sua funcao garantidora da sociedade, bem como o respeito entre os direitos e garantias fundamentais do cidadao. Nao ha sociedade sem crime e nao ha sociedade justa e pacifica sem as devidas sancoes para estes crimes para que consigamos viver em paz e harmonia. Dessa feita, o direito penal e legitimo para intervir na esfera da tutela dos bens juridicos dos cidadaos, atraves da sua funcao pacificadora, quando o mal causado por ele e menor que o mal que o agente causa a sociedade. A emergencia para a protecao de certos bens juridicos nos quais o dano causado e insustentavel para a vitima e para a sociedade como um todo, requer uma protecao especial do direito penal, uma protecao antecipada, para que esse dano nao se concretize e o bem juridico permaneca num raio de seguranca. Atraves da figura dos delitos de perigo abstrato, e possivel a protecao dos bens juridico-penais mais importantes a vida, a integridade fisica, o patrimonio, a paz social-, antes da sua nadificacao pelo cometimento do delito. Frente a essa realidade fatica e que neste trabalho trataremos dos crimes de perigo abstrato, desenvolvendo seus elementos principiologicos e teoricos, estrutura elementar e sua aplicacao na legislacao penal brasileira.

Os crimes de perigo abstrato no âmbito da legislação penal brasileira

Caracterizacao do problema abordado: A Universidade possui a responsabilidade de formar profissionais capazes de promoverem mudancas conceituais e estruturais no "fazer" saude, a partir do reconhecimento da saude como um bem publico e conhecimento da epidemiologia e das necessidades sociais de saude da populacao. Para tanto, e essencial o desenvolvimento de praticas que levem-nos a reconhecer o territorio, a realidade e os atores sociais que compoem o contexto. Alem disso, a articulacao entre as instituicoes de ensino superior e os servicos publicos de saude fortalecer a formacao de recursos humanos na perspectiva do SUS. Por isto, o curso de Fonoaudiologia da UFBA adotou os Estagios em Saude Coletiva I e II, com vistas a formacao atraves da integracao ensino-servico-comunidade na Atencao Basica. Descricao da experiencia: Trata-se de uma experiencia dos estudantes de Fonoaudiologia que cursaram o Estagio em Saude Coletiva I, e vivenciaram a dinâmica de uma Unidade de Saude da Familia (USF), em uma comunidade no municipio de Salvador/BA. A insercao dos estudantes nesse campo de pratica foi desafiador, devido a relacao fragil entre o ensino e o servico, o que parece ser reflexo da ausencia de politicas municipais que responsabilizem os servicos de saude como local de formacao dos futuros profissionais do setor. Entrementes, superando as dificuldades, foram realizadas atividades de analise de situacao de saude e territorializacao, tais como reconhecimento do territorio adscrito a USF, entrevista com  usuarios da unidade, e o  levantamento de indicadores atraves  das fichas de cadastramento das familias, as Fichas A. Aprendizados obtidos: A partir do vivenciado, foi possivel compreender a relevância do ordenamento das acoes da ESF a partir das necessidades em saude, adotando a promocao da saude como pratica potencial no enfrentamento dos determinantes sociais em saude. Observa-se a necessidade da consolidacao do trabalho em equipe, valorizacao do agente comunitario de saude, superacao das praticas centradas na tecnica e no biomedico, e da  integracao ensino-servico-comunidade Recomendacoes: A formacao atraves da vivencia nos servicos e uma importante estrategia na formacao dos profissionais de saude. Contudo, faz-se necessario a criacao de politicas e de praticas que fortalecam a integracao ensino-servico-comunidade, e de reorientacao do modelo de atencao vigente no municipio, em busca da formacao de um profissional critico, reflexivo e humanizado.

A percepção dos estudantes de Fonoaudiologia da UFBA sobre o primeiro contato com uma Unidade de Saúde da Família: relato de experiência

Este artigo visita as tres fases da telenovela brasileira – sentimental, realista e naturalista – com o intuito de examinar a natureza dos viloes desse tipo de producao, personagens geralmente representados como pessoas extremamente atraentes e abastadas. Tendo como base os estudos de algumas das principais pesquisadoras da area, o trabalho investiga a funcao da vilania na estrutura narrativa das novelas televisivas e como beleza, riqueza e maldade sao caracteristicas associadas ha mais de sessenta anos de teledramaturgia.

A REPRESENTAÇÃO DOS VILÕES ATRAVÉS DAS FASES DA TELENOVELA BRASILEIRA

Em Ecologia e usual descrever-se uma comunidade atraves de sua composicao em especies, o que permite determinar padroes espaciais e temporais e suas possiveis conexoes com fatores ambientais. Classificacoes funcionais dos organismos vem sendo propostas como complemento ou alternativa aos descritores taxonomicos, tendo como base suas caracteristicas biologicas e ecologicas, que sao essenciais para entender e prever as consequencias de mudancas em comunidades e ecossistemas. No presente estudo, foram selecionadas quatro lagoas com diferentes niveis de trofia que sofrem impactos variados, localizadas dentro dos limites do Parque Estadual do Rio Doce (Carioca, Dom Helvecio e Gambazinho) e em sua regiao de entorno (Jacare), com o objetivo de analisar as comunidades de macroinvertebrados bentonicos utilizando as abordagens taxonomica e funcional. As comunidades zoobentonicas e parâmetros fisicos e quimicos da agua e do sedimento das lagoas foram amostrados sazonalmente entre 2011 e 2013. Riqueza de taxa (71) e abundância de individuos (25.367) apresentaram variacao sazonal, e refletiram um padrao associado as condicoes de preservacao ambiental das lagoas, tendo os ambientes mais preservados apresentado maior numero de taxa e de individuos. A composicao e estrutura das comunidades tambem diferiram entre as lagoas, com dominância do molusco invasor Melanoides tuberculatus nas lagoas Dom Helvecio e Jacare, mais impactadas, e da familia de diptera Chironomidae nas lagoas Carioca e Gambazinho, mais preservadas. Os diferentes grupos taxonomicos associaram-se aos parâmetros ambientais abioticos, confirmando a influencia das condicoes do habitat na distribuicao dos organismos. A analise funcional resultou em agrupamento dos organismos com maior semelhanca em suas caracteristicas, dando origem a oito Tipos Funcionais (TFs), os quais apresentaram correlacao com as variaveis ambientais. A composicao de TFs nao diferiu muito entre as lagoas, mas a estrutura de cada comunidade e distinta, com o TF dominante nas lagoas Dom Helvecio e Jacare apresentando caracteristicas de acordo com o esperado para locais impactados (como rapido crescimento populacional, presenca de hemoglobina, entre outros). De forma diferente, nas lagoas Carioca e Gambazinho, apenas parte das caracteristicas esperadas para organismos de locais preservados foram encontradas nos taxa mais dominantes nesses locais. Os pontos de Dom Helvecio e Jacare apresentaram maior variacao na composicao de TFs entre si do que os pontos das outras lagoas, provavelmente devido a maior heterogeneidade ambiental encontrada naqueles locais.

Macroinvertebrados bentônicos em lagoas do médio rio Doce, MG: estrutura e composição taxonômica e funcional das comunidades

Este trabalho tem objetivo de incentivar as criancas a pratica da leitura, ressaltando o valor da leitura infantil na formacao de futuros leitores, e o quanto e relevante o incentivo das instituicoes para o crescimento de individuos criticos para formacao de leitores competentes. Ressalta a leitura e os beneficios que trazem ao desenvolvimento do conhecimento e a grandiosidade da pratica da leitura permitindo que a crianca possa usar a imaginacao, uma experiencia tao presente durante a infância. Destaca como e dada a leitura no Brasil, enfatizando a realidade em que a educacao brasileira se encontra, destacando o livre acesso a informacao e o descaso das escolas que nao possuem ou nao utilizam as bibliotecas como fonte de conhecimento. Comenta o excesso da tecnologia como fator predominante na desvalorizacao da leitura e do livro, onde sera apresentado o Blog “Final Feliz” como fonte de incentivo a pratica leitora, em seguida traremos a influencia dos livros infantis nos primeiros anos de vida da crianca. A construcao deste trabalho efetivou-se a partir da necessidade de levarmos ao conhecimento da sociedade o poder do habito a leitura, onde atraves da pesquisa bibliografica, documental e participativa buscou-se subsidios para a conscientizacao das instituicoes a leitura no âmbito infantil, aplicado por meio de um recurso eletronico para que ocorra interacao e troca de conhecimento junto ao Blog. Conclui-se que a leitura infantil influi em todos os aspectos da formacao do ser humano, na educacao e nas areas de extrema importância para sua formacao intelectual e social.

Leitura infantil: o valor da leitura para a formação de futuros leitores

Uma forma de transmissao de conteudo esta comecando a crescer nos ultimos anos emcanais do Youtube e em outras plataformas. O video interativo esta aos poucos sedestacando gracas a novas tecnologias. Este artigo e resultante dos estudos do Grupo dePesquisa em Linguagem Interativa Gestual e mostra as tentativas de encontrar ummodelo para producao do video interativo em meio as novas midias, possibilitandomudancas na forma de assistir producoes audiovisuais. Palavras-chave: Audiovisual. Interatividade. Midias. Narrativa interativa. Tablet

O presente artigo, fruto de pesquisa em andamento, esta ancorado no Projeto de Iniciacao Cientifica intitulado ?Modos de educar: praticas escolares e cultura escolar no territorio do Alto Sertao Sergipano? que tem por objetivo compreender os modos de educar desenvolvidos por professores da regiao. Por meio da metodologia da historia oral, de acordo com Verena Alberti (2011), elegemos como objeto de analise as narrativas de historia de vida das professoras Maria Luiza Barbosa da Silva de 59 anos, residente na cidade de Poco Redondo e Maria Lima Santos Aragao de 69 anos, residente na cidade de Gararu. Assim ao fazer uso da narrativa e da memoria de nossas entrevistadas elegemos como objetivo compreender a cultura material das escolas isoladas na realidade vivida pelas professoras no decorrer de sua trajetoria escolar. Foi possivel apreender mesmo que parcialmente as formas de organizacao do cotidiano escolar e as formas com as quais as professoras primarias se valiam para ministrar suas aulas: a disciplina e a organizacao material da sala de aula tomando como enfase os bancos escolares as quais faziam adaptacoes com tijolos e madeiras que serviam de assentos por conta do elevado numero de alunos que estudavam em uma unica sala. A luz das categorias de analises, ?Cultura Escolar? de Dominique Julia (2001), ?Praticas Escolares? de Faria Filho e Vidal (2000) e ?Cultura Material? Silva (2012), foi possivel considerar a dinâmica do cotidiano escolar e a atuacao dos seus agentes. Assim concluimos que a partir do dialogo dos professores e suas intencoes previamente estabelecidas com a materialidade escolar revela a cultura escolar e praticas escolares de um tempo e espaco, a saber, que o material escolar e a fonte pedagogica do professor e do aluno.

A cultura material das escolas isoladas do território do alto sertão sergipano (1950-1960)

Os servicos de agua e esgoto organizados e universalizados sao fundamentais para o desenvolvimento regional, pois impactam diretamente na qualidade de vida da populacao e crescimento economico. Neste sentido o trabalho demonstrou e analisou o resultado referente ao ano de 2009 de seis indicadores basicos: tarifa media, indice de perdas na distribuicao, atendimento com agua tratada, atendimento com esgotamento sanitario, indice de tratamento de esgoto e indice de hidrometracao, relativos as concessionarias regionais do Brasil de servicos de agua e esgoto. Utilizou o metodo e tecnica de analise regional Sistema de Informacao Geografica (SIG) e o software Philcarto para a confeccao dos mapas. O estudo possibilitou observar disparidades nas acoes e investimentos no saneamento (agua e esgoto) em cada Estado do Brasil e a necessidade de resolver problemas publicos deste setor tao importante para as questoes nacionais de saude, direitos humanos, infraestrutura, meio ambiente e economia. Palavras-chave: concessionarias regionais, indicadores de saneamento, politicas publicas, servicos de agua e esgoto.

SERVIÇOS DE ÁGUA E ESGOTO DISPONIBILIZADO POR CONCESSIONÁRIAS REGIONAIS NO BRASIL

DOI  http://dx.doi.org/10.12957/cosmopolitan.2014.14943 Trata-se de medidas provisorias decididas pelo Tribunal Internacional do Direito do Mar em lide entre Paises Baixos e Federacao Russa, paises que nao escolheram o mesmo procedimento de solucao de controversias da Convencao das Nacoes Unidas do Direito do Mar, aceitando assim a jurisdicao do Tribunal Arbitral.

Tribunal Internacional para o Direito do Mar: Reino dos Países Baixos versus Federação Russa: O Caso do Arctic Sunrise

ÉTICA E BIOÉTICA NA FORMAÇÃO PROFISSIONAL NA ÁREA DA BIOMEDICINA

Sistema automatizado para controle de umidade e temperatura em cultura de morangos aplicados aos pequenos produtores

O presente trabalho considera irregular a anistia concedida aos que cometeram determinados crimes no periodo ditatorial iniciado no Brasil em 1964. Visa a mostrar a irregularidade da concessao da anistia e a necessidade de ser revisada. O trabalho foi realizado por meio de uma pesquisa exploratoria, baseada em pesquisas bibliograficas e no metodo hipotetico-dedutivo. Anistia e o esquecimento de fatos criminosos que o Poder Publico teve dificuldades de punir ou preferiu nao punir. No periodo do Regime Militar foram criados varios Atos Institucionais que embasavam as acoes do governo da epoca e lhes concediam poderes absolutos, inclusive, contrariando a Constituicao Federal. Com base nesses atos procuravam esmagar qualquer oposicao e para isso havia um sistema de repressao, a censura foi instaurada e houve em todo o pais uma sucessao de prisoes arbitrarias, perseguicoes, torturas e desaparecimentos. Ambas as Constituicoes Federais de 1946, Art. 141 e 1967, Art. 150, garantem a inviolabilidade dos direitos concernentes a vida e a seguranca, assim como o tratado da ONU, do qual o Brasil ja fazia parte. O proprio Ato institucional no5, o qual legitimava a adocao de medidas necessarias para garantir o governo, assegura autentica ordem democratica baseada na liberdade e no respeito a dignidade humana. A Lei no 6.683/79 afirma que se excetuam dos beneficios da anistia os que praticaram crimes de sequestro e atentado pessoal. A Lei No 4.898/65 afirma que constitui atentado qualquer pratica contra a incolumidade fisica. Portanto, os atos de tortura praticados durante o regime militar nao poderiam ter legitimidade nem ser anistiados. Diante dessas consideracoes percebe-se a necessidade de rever a decisao que concedeu anistia no periodo ditatorial.

A REVISÃO DA ANISTIA CONCEDIDA NA DITADURA BRASILEIRA DA DÉCADA DE 60

Cultura e Lazer Operários em Gaia, entre o final da Monarquia e o início da República (1893-1914)

O presente artigo tem como objetivo discorrer de forma panorâmica sobre a estreita relacao entre as Politicas Publicas Sociais e a Educacao, no sentido de demonstrar de que forma essa relacao contribui para o desenvolvimento socioeconomico do pais. Nesse sentido, sao levantadas duas questoes problemas: Qual e a relacao entre as politicas sociais e a educacao? Sera que as politicas sociais erradicam a pobreza ou a educacao e fundamental para se atingir este objetivo? Buscando responde-las, foi realizada uma analise da acao governamental “Brasil Carinhoso”, no municipio de Brumado, no estado da Bahia, uma vez que o programa visa, alem da complementacao da renda e de beneficiar a saude, incentivar a educacao basica com a ampliacao do acesso a creche, a Pre-Escola. 
Trata-se de um estudo que pretende mostrar a importância da educacao para a erradicacao da pobreza, em um contexto capitalista, no qual o conhecimento e a capacitacao tornaram-se o diferencial para a insercao das pessoas no mercado de trabalho e, alem disso, a educacao e a responsavel pela formacao do cidadao consciente do seu papel na sociedade e de que ao exercer sua cidadania plenamente e capaz de sair da condicao de pobreza em que se encontra. 
 
Palavras-chave: Politicas Publicas Sociais; Educacao; Brasil Carinhoso.

UMA BREVE CONSIDERAÇÃO SOBRE A RELAÇÃO ENTRE A POLÍTICA PÚBLICA SOCIAL E A EDUCAÇÃO: UM OLHAR SOBRE O PROGRAMA BRASIL CARINHOSO NO MUNICÍPIO DE BRUMADO/BA

Voluntariado empresarial: motivações dos empregados em participar nos programas de voluntariado empresarial

Narrativas da exceção: como o discurso jornalístico da Folha de São Paulo tratou a atuação policial em novembro de 2012

Justiça e verdade: a interpretação heideggeriana da alegoria da caverna de Platão

O presente trabalho tem por objetivo geral um estudo aprofundado de uma das causas de perda de modo unilateral do direito de propriedade imobiliaria, qual seja: a renuncia a que alude o inc. II do art. 1.275 do Codigo Civil. Todavia, para a boa compreensao da pesquisa proposta, sobretudo para a compreensao dos efeitos de tal renuncia, primeiramente decidiu-se por algumas consideracoes sobre o direito de propriedade de uma forma geral e, mais especificamente, da propriedade imobiliaria. Como objetivo especifico procurou-se descobrir quais os motivos ou situacoes que podem levar alguem a renunciar ao direito de propriedade sobre imovel registrado na serventia imobiliaria, Mas, inserido ainda no citado objetivo geral promoveu-se tambem um estudo comparativo entre renuncia e abandono da propriedade, uma vez que o segundo e uma consequencia natural da primeira. Entrementes, o presente trabalho nao ficou restrito apenas ao citado problema propulsor da pesquisa, pois no desenvolvimento do tema, outros, de menor, igual ou ate de maior relevância exsurgiram e por isso tambem foram analisados. O presente trabalho demonstra a utilidade teorica-pratica da renuncia em questao, comprovando que se bem compreendida e empregada podera deixar de ser a letra-morta da lei que praticamente e. Para sustentar o trabalho utilizou-se da legislacao, doutrina, jurisprudencia e de argumentacao critica propria, assim como tanto dos metodos dedutivo e dialetico.

Da renúncia da propriedade imóvel (breve comparativo com o abandono)

O Conselho Federal da Ordem dos Advogados do Brasil ingressou com Arguicao de Descumprimento de Preceito Fundamental (no153) perante o Supremo Tribunal Federal para questionar o recebimento, pela Constituicao Federal de 1988, do disposto no § 1o do artigo 1o da Lei federal no 6.683, de 28 de agosto de 1979, e obter declaracao no sentido de que a anistia concedida aos crimes politicos ou conexos nao se estende aos crimes comuns praticados pelos agentes publicos contra opositores politicos, durante o regime militar. A Secretaria-Geral de Contencioso prestou informacoes, defendendo a amplitude da anistia concedida, inclusive quanto aos crimes comuns praticados por agentes politicos, as quais foram aprovadas pelo Advogado-Geral da Uniao e encaminhadas ao Supremo Tribunal Federal juntamente com manifestacoes divergentes elaboradas no âmbito de Secretarias federais e Ministerios. Alem de orgaos federais, o debate tambem envolveu diversos setores da sociedade civil, evidenciando, assim, a grande controversia existente em torno da tematica discutida na acao. No entanto, os argumentos expostos pela Secretaria-Geral de Contencioso foram amplamente acolhidos pelo Supremo Tribunal Federal, que, por maioria de votos, em sua composicao plenaria, julgou improcedente o pedido formulado pelo Conselho Federal da Ordem dos Advogados do Brasil.

JUSTIÇA DE TRANSIÇÃO – LEI DE ANISTIA ARGUIÇÃO DE DESCUMPRIMENTO DE PRECEITO FUNDAMENTAL Nº 153

Objetivamos com o presente artigo recuperar, de forma modesta, as contribuicoes sociologica de Walter Benjamin presentes em um pequeno fragmento de sua obra, desta forma, focamos nossa atencao em um texto especifico "As teses do conceito de historia" por entender que neste pequeno trabalho, no que se refere ao numero de caracteres escritos, podemos encontrar profundas contribuicoes para pensar questoes contemporâneas, como os processos de mudanca e producao da memoria social e ao mesmo tempo entender algumas determinacoes politicas e sociais na narracao da historia como se apresenta.

Contribuições sociológicas de Walter Benjamin para pensar a contemporaneidade: uma breve leitura das Teses sobre o Conceito de História.

Este estudo teve como objetivo apresentar os principais fatores que interfere na 
participacao dos alunos nas aulas de Educacao Fisica no Ensino Fundamental e 
Medio, e as competencias do professor como motivador e suas estrategias, visando 
que o planejamento de aulas desperte o maior interesse possivel dos alunos e que 
os mesmos se conscientizem da importância da pratica da Educacao Fisica e seus 
beneficios, e que busquem melhorar a qualidade de vida. Trata-se de um artigo de 
revisao bibliografica, as fontes de pesquisa utilizadas foram os seguintes portais: 
Google academico, pubmed, scielo, portal capes, livros e sites acerca do tema. Os 
resultados demonstraram que a motivacao auxilia na aplicacao do conhecimento 
teorico e pratico, ja que apenas o conhecimento nao e suficiente para garantir uma 
boa aula. Sendo assim e pressuposto do professor de Educacao Fisica Escolar ter 
ciencia de seu papel motivador e saber aplicar a teorias motivadoras em sua filosofia 
de ensino.

Introducao: A Estrategia Saude da Familia (ESF), implantado em 1994, prioriza acoes de protecao e promocao da saude. Cada equipe de saude e levada a conhecer a realidade das familias pelas, por meio do cadastramento e da identificacao de suas caracteristicas, tornando-se mais sensivel as suas necessidades, facilitando a criacao de vinculos, a identificacao e o atendimento dos problemas de saude da comunidade. Objetivos: Acredita-se que o conceito de familia sustenta aspectos relacionados a abordagem familiar na ESF. O artigo objetiva identificar o conceito de familia e fatores associados a abordagem familiar na ESF por meio de uma revisao em documentos oficiais do Ministerio da Saude (MS) e na literatura cientifica Metodologia ou Descricao da Experiencia: No periodo de julho a setembro de 2008 foi realizado o estudo de documentos oficiais na base de dados da Biblioteca Virtual em Saude do MS. Foram selecionados tres documentos encontrados por abordarem as principais diretrizes da ESF. A revisao de literatura realizada incluiu artigos que apresentaram consideracoes sobre o cuidado a familia na ESF, indexados nas bases de dados LILACS E MEDLINE. Apos a leitura analitica destes artigos, 10 foram selecionados como objeto de estudo, por apresentarem aspectos que respondiam a questao norteadora, e a analise do conteudo permitiu a organizacao dos dados em categorias tematicas. Resultados: A analise do conteudo resultou em 4 categorias tematicas: 1) O conceito de familia nos documentos norteadores da ESF; 2) O perfil e a capacitacao dos profissionais para atuarem com familias; 3) A abordagem da familia na ESF; 4) O potencial da ESF para desenvolver o trabalho com familias. Embora os documentos oficiais apresentem diversas recomendacoes, nao ha orientacoes e normatizacoes de como conduzir a acao profissional diante de questoes sobre a dinâmica familiar e nao e especificada a forma como deve acontecer, a definicao de instrumentos para a avaliacao e intervencao em familias e o preparo dos profissionais para esta pratica assistencial. Conclusao ou Hipoteses: Ha a falta de estudos sobre o trabalho dos profissionais da ESF com familias para evidenciar como o mesmo ocorre na pratica cotidiana. No entanto, acredita-se que a oportunidade apresentada pela ESF de superacao em direcao a uma pratica de atencao a saude com foco na familia e unica e ha a necessidade da criacao de instrumentos teoricos que abordem questoes da dinâmica familiar de modo efetivo.

O presente artigo [1] tem por objetivo realizar uma critica a centralidade da familia nas politicas sociais brasileiras no âmbito da sociedade capitalista. Identificando de que maneira a mesma e utilizada pelo Capital em prol de sua manutencao, atraves de acoes focalizadoras de cunho controlador, que apenas minimizam a condicao de pauperismo em que vem sendo submetida a familia da classe trabalhadora brasileira, tornando-as cada vez mais dependentes dessas acoes que sao compreendidas como caridade e que eliminam o carater de direito que possuem as Politicas Sociais. [1] E uma sistematizacao do Trabalho de conclusao de curso, apresentado no curso de Servico Social da Faculdade Integrada Tiradentes no 2o semestre de 2011, que teve como titulo: “Uma critica a centralidade da familia nas politicas sociais Brasileiras” sob orientacao da Profa. Msc. Maria Alcina T. Lins.

Xiphopenaeus kroyeri is considered to be overfished in the southern and southeastern regions, due to intensive fishing, with juveniles being caught in shallower waters, near beaches, in bays and inlets, whilst adults occur at depths of about 20 m. This study aims to analyze the space/time distribution of captures of sea-bob-shrimp in the ship-yard/surfzone of the Armacao do Itapocoroy, Penha, SC, during one full year. Monthly catches (one sample being divided in two), lasting 15 minutes, were undertaken at depths of 10, 20 and 30 meters between July 2010 and June 2011, using a whaling-boat. The population of X. kroyeri presented seasonal variations, the greatest concentrations and adults were observed at 20 metres. The rare caught at 30 meters front of the high sampling effort indicated that the species probably doesn’t use this isobath as living area in the study region. The action of the fishing fleet in the shallower areas in Armacao Itapocoroy, mainly during recruitment which starts in November, raises concern about the maintenance of species stocks, given the high abundance of juveniles in these shallow sites and their importance in the continuity of this kind of fisheries.

Distribuição espaço-temporal das capturas do camarão sete-barbas na armação do itapocoroy, Penha, SC

Introducao: A hernia diafragmatica congenita e a falha do fechamento embrionario do musculo diafragmatico, resultando em um defeito de continuidade. Esta patologia pode ocorrer pela passagem de estruturas do abdome atraves de um defeito no diafragma, ou haver herniacao parcial do estomago atraves do hiato esofagico, paralisia frenica com deslocamento do conteudo abdominal para cima, mas sem herniacao, e, eventracao do diafragma. Casuistica: Foi relatado um caso de hernia diafragmatica congenita, hernia de Bochdalek, em um recem – nascido do sexo feminino, que nos ultra-sonografias da gestante apresentavam sem alteracoes. O diagnostico da patologia foi feito apenas apos a realizacao de raios-X de torax e abdome para confirmar a posicao do cateterismo umbilical venoso. Discussao/Conclusao: A apresentacao clinica da hernia de diafragmatica congenita inclui desconforto respiratorio moderado a grave com repercussao sistemica. O diagnostico, em cerca de 80% dos casos, e feito por ultrassom pre-natal. O tratamento proposto foi intubacao endotraqueal com ventilacao mecânica e programacao para correcao cirurgica da hernia. Apos correcao cirurgica da patologia, a paciente permaneceu na unidade de terapia intensiva neonatal por 21 dias para acompanhamento de pos – operatorio e intercorrencias na evolucao. Palavras-chave: hernia diafragmatica congenita, recem-nascido, hernia de Bochdalek ABSTRACT Introduction: Congenital diaphragmatic hernia is the failure of embryonic closure of the diaphragm, resulting in a lack of continuity. This condition can occur by passing structures of the abdomen through a defect in the diaphragm, or be part herniation of the stomach through the esophageal hiatus, phrenic paralysis with displacement of abdominal contents up but no herniation, and eventration of the diaphragm. Case Report: We report a case congenital diaphragmatic hernia, such as Bochdalek hernia, in a new - born female that in ultrasounds of pregnant women showed without change. The diagnosis of the disease was made only after conducting X-ray of the chest and abdomen to confirm the position of umbilical venous catheterization. Discussion/Conclusion: Clinical presentation of congenital diaphragmatic hernia includes moderate to severe respiratory distress with systemic repercussions. The diagnosis in about 80% of the cases is done by ultrasound prenatally. The proposed treatment was endotracheal intubation with mechanical ventilation and programming for surgical correction of the hernia. After surgical pathology, the patient remained in neonatal intensive care unit for 21 days to monitor post - operative complications and evolution. Keywords : congenital diaphragmatic hernia, newborn, Bochdalek hernia

Hérnia Diafragmática Congênita: Relato de Caso/ Congenital Diaphragmatic Hernia: Case Report

Cinema, Personagem, Importância parte da analise feita por Susan Sontag das fotografias de Diane Arbus em seu celebre On Photography para, em seguida, pensar o documentario Grey Gardens. Um dos principais trabalhos dos cineastas Albert e David Maysles, o filme nos permite debater uma possivel forma pela qual o cinema documentario constroi sua encenacao, seus personagens e confere importância aqueles outrora esquecidos.

A publicidade nas redes sociais: percepções e respostas dos utilizadores

As organizacoes estao diante de uma nova economia, mais evidente a cada dia, podendo-se perceber uma intensidade maior de aplicacao de conhecimento aos negocios na atualidade do que se percebia ha 50 anos. Capital Intelectual pode ser considerado como a soma de todos os ativos de conhecimento que interagem em uma organizacao, sendo especificamente o que lhe confere vantagem competitiva. O estudo teve como objetivo principal elaborar modelo de avaliacao do capital intangivel, baseado em medidas nao financeiras. Foi elaborada uma pesquisa bibliografica acerca do assunto com a consequente avaliacao dos principais elementos constitutivos dos principais modelos, no intuito de consolidar uma concepcao teorica sobre o tema. Constatou-se que existe um numero significativo de empresas que estao desenvolvendo e experimentando novas tecnicas e modelos de mensuracao do capital intelectual, mas o grande desafio ainda e documentar estas praticas e experiencias e compartilhar com outras empresas, no intuito de tirar vantagem desta inovacao em termos de modelos de avaliacao que estao surgindo.

Uma proposta de avaliação de capital intangível baseado em medidas não financeiras

O presente trabalho tem por objetivo apresentar uma sistematizacao do pensamento
juridico sobre a eficacia horizontal dos direitos fundamentais elencados na Constituicao
Brasileira de 1988, isto e, se tais direitos podem vir a ser aplicados nas relacoes juridicas
privadas e, em caso positivo, de que forma se dara a aplicacao de tais direitos nessas relacoes.
Tal tema ganhou forca nos dias atuais, pois se verificou que nao so o Estado e capaz
de violar os direitos fundamentais, sendo que, muitas das violacoes verificadas, tem como
agente violador entes privados, como empresas multinacionais, bancos, sindicatos, etc.
Dessa forma, pretendemos analisar de que forma e de que modo e possivel sustentar,
com base no ordenamento juridico brasileiro em vigencia, uma eficacia horizontal dos direitos
fundamentais. Para tanto, foi feito um estudo da doutrina e da jurisprudencia, tanto nacional,
quanto estrangeira.
Da analise do texto se depreende que pretendemos fornecer um modelo de aplicacao
de tais direitos, em especial os de primeira dimensao, nas relacoes privadas, especificando de
que forma e de que maneira os particulares se vinculam a esses direitos, alem de tracar
parâmetros verificaveis intersubjetivamente para a aplicacao dos direitos nas relacoes entre
privados.
Ao final, lancamos algumas consideracoes sobre a necessidade de se reconhecer essa
vinculacao, bem como a necessidade de estruturar um modelo que facilite a aplicacao dos
direitos fundamentais nas relacoes entre particulares

Aplicação dos direitos fundamentais de 1ª dimensãonas relações jurídicas privadas

O presente trabalho teve como objetivo refletir sobre a finalidade, desafios e possibilidades do ensino da disciplina Lingua Espanhola no curriculo integrado do Instituto Federal de Educacao, Ciencia e Tecnologia Baiano (IFBaiano), espaco criado para a formacao de seres humanos em harmonia com os arranjos produtivos locais. Para alcancar o objetivo, tracei um breve historico do IFBaiano, com o proposito de ressaltar a identidade desse segmento da educacao no contexto politico, social e cultural; para so entao entrar na proposta de refletir sobre curriculo integrado e ensino aprendizagem do Espanhol como Lingua Estrangeira dentro desse contexto. Para tanto, procurei desenvolver estudos teoricos e metodologicos com a finalidade de embasar, justificar e concretizar essa adequacao, buscando apoio nos conceitos de bases teoricas que defendem o desenvolvimento integral e emancipatorio do cidadao. Espero com este estudo contribuir para uma reflexao entre a necessidade de unir os saberes tecnologicos aos das ciencias humanas na vida escolar e social do aprendiz.

Educação profissional, currículo integrado e Espanhol como Língua Estrangeira: desafios e possibilidades para o IFBaiano

Animacao em stop motion com papel - Duracao: 3:03 - Ano: 2012 Produzido na Oficina de Video-Historia de 2012-2.

PURPOSE: To verify the effectiveness of an educational action in the form of training, emphasizing the importance of hearing protection for workers exposed to occupational noise. METHODS: The study included 78 male individuals. All participants answered a questionnaire before they were submitted to audiological evaluation. For the second application of the questionnaire, participants were randomly divided into two groups: Research Group, constituted by 44 subjects that received educational training before the second questionnaire application, and Control Group, comprising 34 individuals that answered the questionnaire before the educational training. Training was based on material with graphic images and text, in the form of conversation. The topics covered included: the importance of hearing, noise effects on health, importance of preventing hearing loss and using hearing protection, conservation and cleaning of hearing protectors, levels of noise in the workplace and noise attenuation provided by hearing protectors. The questionnaire contained 14 multiple choice questions that addressed the same themes explored in the educational training. RESULTS: There was a significant increase of correct responses in the second application of the questionnaire, only in the Research Group, in all comparisons. CONCLUSION: Educational action performed with workers exposed to occupational noise are effective, and the questionnaire is a stable and viable tool to evaluate the effectiveness of educational programs

Verificação da efetividade de uma ação educativa sobre proteção auditiva para trabalhadores expostos a ruído

Impacto das projeções das mudanças climáticas no balanço hídrico do solo e da soja (Glycine max) no PAD/DF - Distrito Federal

O objetivo com este trabalho e elaborar um panorama socio-economico da localidade Piranheira no Assentamento Agroextrativista Praia Alta-Piranheira em Nova Ipixuna, Para. Para a caracterizacao da localidade Piranheira foram entrevistados 18 agricultores com um questionario fechado, abrangendo todas as familias moradoras da localidade, alem de dados secundarios de orgao oficiais. Este Assentamento e regularizado pelo INCRA com o titulo de Agro-extrativista, possui um plano de desenvolvimento que combina tanto as atividades dos sistemas de producao agropecuaria como as do extrativismo de produtos florestais. A localidade possui lotes com uma area media de 86 ha, em relacao a cobertura vegetal destes estabelecimentos, 52,9% e pasto, 23,3% mata e 5,8% vegetacao secundaria. Mesmo com a peculiaridade da exploracao agricola e extrativista projetada para este assentamento, o que acontece e a mesma degradacao pelo processo de pecuarizacao e desmatamento dos assentamentos da regiao.

11676 - Panorama sócio-econômico da localidade Piranheira no Assentamento Agroextrativista Praia Alta-Piranheira, Nova Ipixuna – Pará.

Este trabalho tem como objetivo propor a reestruturacao, ampliacao e modernizacao do 
Terminal de Passageiros do Aeroporto Bartolomeu Lisandro, em Campos dos Goytacazes, 
norte do estado do Rio de Janeiro. Em funcao do atual cenario de desenvolvimento regional a 
partir, principalmente, da construcao do Porto do Acu e levando em conta o crescimento do 
setor de transporte aereo em todo o Brasil, torna-se extremamente importante adequar o 
espaco do terminal de passageiros do aeroporto a essa nova demanda. E importante, ainda, 
chamar a atencao para o fato de que a democratizacao do transporte aereo tem permitido que 
esse tipo de transporte ja nao seja apenas utilizado por segmentos limitados da populacao. 
Dessa forma, a ampliacao do terminal de passageiros do Bartolomeu Lisandro torna-se 
necessaria e urgente.

Esta dissertacao apresenta uma investigacao sobre os significados atribuidos por um grupo de um colegio privado e nao confessional localizado na cidade de Ponta Grossa (PR). um dos grandes obstaculos pedagogicos, comprometer o processo de ensino-aprendizagem e fragilizar a relacao professor-aluno. m compreender os significados da indisciplina, atribuidos por grupo de sujeitos, referencial teorico, um conjunto de conceitos desenvolvidos por Basil Bernstein. Para o desenvolvimento do trabalho de campo utilizamos de pesquisa qualitativa. A selecao dos sujeitos entrevistados empregou criterio de amostragem por variacao maxima. Participaram dessa pesquisa, coordenadores, professores e alunos que ingressaram recentemente no colegio e aqueles ja a um longo . Como metodo de analise dos dados, utilizamos uma forma de Analise de Conteudo, que derivou as seguintes categorias para interpretar a indisciplina: a) ausencia de disposicoes socioafetivas; b) desconexao com o ambiente de aprendizagem coletiva; c) esvaziamento do processo de ensino-aprendizagem d) consequencia da provisoriedade da acao docente; e) reflexo da incompletude do papel formativo exercido pela familia. O texto esta estruturado da seguinte forma. Inicialmente, sobre alguns conceitos oriundos das teorizacoes de Basil Bernstein. Em seguida, a construcao da indisciplina na escola, o conceito de indisciplina sob a otica de . Na sequencia, apresentamos pesquisa empirica, o tipo de amostragem, a selecao dos sujeitos pesquisados e do contexto estudado. Em seguida, a analise do conteudo das entrevistas e na ultima as consideracoes finais. A pesquisa fornece um conjunto de leituras sobre a indisciplina escolar, que iluminam algumas de seus possiveis significados. Em destaque, a nocao de indisciplina como uma ausencia de disposicoes socioafetivas dos alunos. Alem disso, seria um reflexo da provisoriedade da acao docente em sala de aula, bem como uma consequencia do esvaziamento do processo de ensino-aprendizagem. A investigacao tambem sugere o cruzamento de fatores familiares e escolares na producao da indisciplina, pois existiria uma descontinuidade entre a acao formativa da familia e as praticas pedagogicas da escola.

Pretendemos pesquisar a possibilidade de um trabalho integrado entre a escola e a familia objetivando desenvolver o habito da leitura em alunos na faixa etaria de 7 a 9 anos. Atraves de livros da literatura infantil os alunos poderao conhecer um pouco mais sobre as historias que de geracao em geracao sao contadas. Somos leitores de historias que nossos pais ja conhecem e que em varias escolas sao utilizadas para o comeco da aprendizagem da leitura. Neste sentido, para as criancas adentrarem nesse mundo magico proporcionado pela literatura infantil, e essencial a leitura dos contos de fadas e demais historias infantis , onde ha animais e personagens misticos, folcloricos falam. Lobos, fadas, reis e rainhas despertam na crianca seus primeiros interesses a leitura e, assim ao longo do tempo a crianca se torna um leitor daquilo que realmente deseja. Acreditamos que esse habito de ler deve ser cultivado desde muito cedo primeiramente pela familia e depois pela instituicao escolar, pois contribuira para o seu desenvolvimento e sua formacao. Lembramos que nao somente as criancas mas, tambem os adultos que, somos exposto a muitos outros fatores e acontecimentos do cotidiano que nos desviam da leitura, tais como: a TV, o radio, o video-game entre outros. Uma tarefa dificil, mas, e preciso ter o habito da leitura para sabermos administrar o nosso dia, nosso tempo, temos que saber que a hora da leitura e uma aprendizagem essencial para nossa vida de formacao enquanto cidadao participante da sociedade. A escola e a principal orientadora entre o conhecimento, a motivacao e a busca pela aprendizagem do aluno. A iniciativa dos pais e a contribuicao que as instituicoes escolares atribuem aos livros nas bibliotecas, a sala de leitura, o momento para as atividades que relacionam a leitura e essencial na escola, podendo fazer com que a professora busque atividades diversas para incentivar e motivar seus alunos, buscando o individual e a socializacao entre eles. As primeiras etapas na vida de cada crianca e: falar, ler e escrever e cultivar a leitura e a escrita cria um habito que consequentemente a ajudara muito em seu cotidiano e assim contribuira para o seu desenvolvimento pessoal e profissional. Quanto mais incentivo a crianca tiver em seus primeiros anos de vida, mais havera interesse no futuro, podendo se manter firme em seus estudos que a levaram ao sucesso. Ao se deparar com os livros as criancas se encantam pelas ilustracoes que estao na capa, assim o comeco para uma grande amizade entre o aluno e o livro, apos varios capitulos o aluno passa a buscar o interesse para saber o final e isso o incentiva a continuar a leitura. A literatura infantil contribui para essa alianca entre a leitura e o aluno que caminharao juntos por muito tempo. Atraves da pesquisa bibliografica e se necessario de campo visamos estabelecer um contato maior entre o aluno e a leitura, e o caminho que o aluno vai precisar para a sua aprendizagem, buscar informacoes, conhecimentos novos que auxiliariam em sua caminhada para o desenvolvimento do habito da leitura. Ao decorrer do tempo vamos notar que os pais e professores sao os nossos orientadores, e atraves deles que vamos aprender mais e mais. A cada dia que passa livros novos sao lancados no mercado contribuindo para nos leitores que necessitamos de novas historias, novas emocoes que nos incentivem a querer que os autores nunca deixem de escrever e assim possam contribuir cada vez mais momentos propicios de aprendizagem no ambiente escolar e familiar para haver interesse e despertar o habito da leitura nos alunos.

OBJECTIVE: To prospectively evaluate the pulmonary function in patients undergoing reduction mammaplasty. METHODS: Twelve female patients with Gigantomastia and without medical antecedents were submitted to reduction mammaplasty at our University Hospital. The patients underwent lung function testing and arterial blood gas measurements in the preoperative and postoperative period (three to six months). The data were analyzed using the Wilcoxon test and the level of statistical significance was p <0.05. As for lung function tests,total lung capacity and residual volume were higher postoperatively (p <0.05). RESULTS: As for the arterial gases, there was no statistically significant difference. CONCLUSION: The increase in total lung capacity and residual volume may suggest a better lung function after reduction mammaplasty for Gigantomastia treatment, although not altering blood gases in healthy patients.

Avaliação da função pulmonar em pacientes submetidas à mastoplastia redutora

The focusing on issues relating to the paradigms of the Literary Theory in those texts produced within a certain ethical-aesthetical context most often makes it impossible to understand the literary productions from outside the Eurocentric axis. As a disciplinary field, and due to the very building of its aesthetic criteria, Literary Theory tends to let aside the most recent literary production, mainly that from the emerging peripheries. By analyzing some poems by Ana Paula Tavares, a poet from Angola, the present essay will discuss the limits of the Literary Theory in face of the postcolonial literary production.

A lírica menor: por uma Teoria da Literatura das Literaturas Africanas de Língua Portuguesa

A presente pesquisa aborda a questao do turismo em terras e comunidades indigenas a partir da analise das politicas de turismo elaboradas no âmbito do Estado brasileiro. Essa abordagem elegeu como foco de analise as propostas e politicas para o desenvolvimento do turismo na Amazonia e junto aos povos indigenas da regiao, identificando como agentes principais o SPVEA, a SUDAM, os Ministerios do Turismo e Meio Ambiente e a FUNAI. Na perspectiva de compreender esse campo politico do indigenismo, elegemos tambem posicionamentos de conferencias dos povos indigenas. A reflexao central desse trabalho esta na comunidade etnica Satere-Mawe Sahu-Ape, localizada no municipio de Iranduba, Amazonas. Trata-se de um grupo que esta no centro dessas politicas desenvolvimentistas e indigenistas e que definiram estrategias proprias para gestao do turismo e da etnicidade.

O melanoma cutaneo e um tumor originado a partir da proliferacao descontrolada de melanocitos. A incidencia do melanoma maligno tem aumentado significativamente nas ultimas decadas e se tornado um problema de saude publica em muitos paises. Na imunoterapia contra o cancer, anticorpos monoclonais (mAbs) sao utilizados como ferramentas para diagnostico, monitoramento e tratamento da doenca. A descoberta de novos alvos terapeuticos para mAbs em celulas tumorais, e a determinacao dos mecanismos de citotoxicidade gerados pelos mesmos pode ampliar significativamente as possibilidades e o sucesso dos tratamentos. Anteriormente em nosso laboratorio, Dobroff e colaboradores (2002) isolaram um mAb (mAb A4) que foi citotoxico in vitro sobre celulas de melanoma murino B16F10-Nex2 e sobre algumas celulas tumorais humanas, efeito independente do complemento, mas aumentado por este. O mAb A4 reduziu o desenvolvimento do melanoma murino B16F10-Nex2 in vivo, aumentando a sobrevida dos animais. O alvo do mAb A4 na superficie celular e a proteina Protocaderina A13 (PCDHA13), membro da superfamilia das caderinas. A interacao entre ambos levou as celulas tumorais a morte, em processo sugestivo de apoptose (Dobroff et. al., 2010, em publicacao). Neste trabalho, verificamos a reatividade do mAb A4 com celulas do melanoma murino e com algumas outras linhagens tumorais humanas atraves de ELISAQuimioluminescente e Imunofluorescencia Indireta. A expressao do gene PcdhA13 foi verificada por RT-PCR nao quantitativo e a expressao da proteina PCDHA13, por Immunoblotting. Verificou-se que, somente celulas que expressam a proteina PCDHA13 na membrana plasmatica sao suscetiveis a acao do mAb A4. O mAb A4 foi citotoxico in vitro contra o melanoma murino e contra linhagens tumorais humanas, incluindo melanoma, carcinoma de colon, carcinoma de cervice uterino e glioblastoma. O mAb A4 nao foi citotoxico contra linhagens humanas de carcinoma de mama e contra a linhagem de melanocitos murinos imortalizados melan A, que nao expressam a PCDHA13. A interacao do mAb A4 com celulas B16F10-Nex2.1 in vitro ocasionou a endocitose do mAb A4 em vesiculas, rapida reducao nos niveis de A-catenina livre no citoplasma e do fator de transcricao TCF-4, redistribuicao da A-catenina para a periferia celular, ativacao das caspases-9, -3 e -6, exposicao de fosfatidilserina na membrana plasmatica, condensacao da cromatina e degradacao internucleossomal do DNA, corroborando a inducao de um processo de morte por apoptose pela via intrinseca nessa celula tumoral. Adicionalmente, observou-se o aumento da producao de especies reativas de oxigenio, que podem amplificar o processo apoptotico. A inibicao da via de sinalizacao da A-catenina sugere que vias de sinalizacao intracelular que regulam o crescimento e a sobrevivencia foram inibidas pela interacao entre o mAb A4 e seu alvo na celula. A presenca de vesiculas sugestivas de autofagossomos nas imagens de microscopia de transmissao eletronica pode indicar a inducao de um processo de autofagia em paralelo ao processo apoptotico.…

Mecanismo de Citotoxicidade do Anticorpo Monoclonal A4, que Reconhece Protocaderina À13, em Celulas Tumorais Murinas e Humanas

Gestão de recursos e reservas para aumento do aproveitamento do folhelho pirobetuminoso e aumento da recuperação de sua matéria orgânica na forma dos derivados óleo e gás.

Significados sobre autonomia de idosos participantes de um Processo de Inclusão Digital (PID)

A sociedade tem demonstrado uma crescente preocupacao com o meio ambiente, pois compreendeu que os recursos que dele usufrui sao de vital importância para a atual e para as futuras geracoes. O homem passou, entao, a entender que era necessario utilizar tais recursos de modo consciente, garantindo o desenvolvimento sustentavel, um equilibrio entre o desenvolvimento, com a satisfacao das necessidades do homem, e a conservacao do meio ambiente. Um dos recursos naturais que o homem mais utiliza e a agua. Este recurso hidrico tem valor economico por ser considerado escasso e e com a necessidade de garantir tal recurso a todos que o direito impoe restricoes administrativas e financeiras a sua utilizacao. A Constituicao de 1988 traz em seu bojo os principios de valorizacao da agua como um bem essencial para a sobrevivencia do homem, tornando constitucional seu uso correto. Essas normas possibilitaram o estabelecimento da Politica Nacional dos Recursos Hidricos, que ordena tanto o gerenciamento quanto o controle administrativo dos recursos. A questao da conservacao dos recursos naturais provem de uma conscientizacao do homem, que, so atraves da educacao ambiental, atua em consonância com principios de protecao ao meio ambiente, os quais estao regulamentados no ordenamento juridico.

O objetivo deste trabalho foi isolar proantocianidinas de folhas de barbatimao e avaliar a 
atividade citotoxica para celulas de tumor mamario humano, MCF-7 (ER+) e MDA-MB-435 
(ER-). As proantocianidinas foram isoladas da fracao aquosa de folhas de barbatimao, 
utilizando-se cromatografia em coluna de Sephadex LH-20 e metanol (10-100% ) e acetona 
(70%) como eluentes. A presenca de proantocianidinas, nas fracoes obtidas, foi monitorada 
por cromatografia de camada delgada e esta revelou que a fracao eluida com metanol 100% 
(usada nos experimentos) apresentou o maior teor de proantocianidinas. A despolimerizacao 
acida permitiu quantificar as procianidinas na amostra e a analise por HPLC revelou a 
presenca de acido galico, procianidina dimerica B1 e (-)-epicatequina-3-O-galato. A fracao 
apresentou atividade antioxidante, sendo que a capacidade antioxidante total foi de 470,28 ± 
14,36 mg acido ascorbico/g de fracao. A atividade sequestrante de radicais livres DPPH 50% 
foi de 12 μg/mL e a atividade inibidora maxima da oxidacao de proteinas foi obtida com 50 
μg/mL de fracao. A fracao apresentou atividade citotoxica para celulas de tumor mamario 
MCF-7 e MDA-MB-435. O tratamento das celulas com a fracao aumentou a atividade 
redutora de MTT, o que indica aumento da viabilidade celular. Entretanto, a analise 
morfologica revelou intensa vacuolizacao citoplasmatica dependente da concentracao da 
fracao. Os vacuolos acumularam MTT, indicando tratarem-se de vacuolos autofagicos. Outras 
alteracoes morfologicas observadas com o tratamento foram a perda da morfologia celular 
tipica, condensacao da cromatina (principalmente formacao de nucleo picnotico), alteracoes 
na membrana plasmatica e apos 48 h de tratamento houve marcante diminuicao do tamanho 
das celulas. Nao foi observado o padrao de DNA escada caracteristico de apoptose nos 
diversos tratamentos. Os resultados parecem indicar que a fracao isolada pode induzir 
autofagia nos dois tipos celulares estudados. A autofagia pode potencializar os efeitos 
antitumorais de quimioterapicos, o que pode ser util na terapia contra o câncer e as folhas de 
barbatimao parecem ser uma valiosa fonte de substâncias bioativas.

Obtenção de proantocianidinas do barbatimão e avaliação da toxicidade sobre células de tumor mamário humano MDA-MB-435 e MCF-7

Avaliação histopatológica de botões corneanos provenientes de falência de transplante penetrante

This study had the objective of verifving the influence of Kundalini Yoga practice upon health condition, physical fitness and upon state and trace anxiety levels in women with Fibromyalgia Syndrome that is a rheumatic disease characterized by diffuse muscle pain, specific pain sites, associated frequently to sleeping disosders, fatigue, chronic headache, anxiety, depression and stress. Methods: The study group was composed by 7 women with Fibromyalgia, that didn’t practice Yoga, with a mean age of 52,6 years old. The health condition, physical fitness and trace-anxiety were evaluated before and after 8 weeks of practice, with these instruments, respectively Fibromyalgia Impact Questionnaire, Walking Test and a Trace Anxiety Questionnaire. The variable state-anxiety was verified with a State- Anxiety Questionnaire, one time a week before and after the Kundalini Yoga session. Results: With the statistical analysis done through the Wilcoxon Test, the results of the study showed, for a p<0,05, that there was a significant diffrence upon the variables helath condition, trace-anxiety and state anxiety, and there was no statistically significant difference upon the physical fitness.

A INFLUÊNCIA DA PRÁTICA REGULAR DE KUNDALINI YOGA SOBRE VARIÁVEIS FUNCIONAIS EM INDIVÍDUOS PORTADORES DA SÍNDROME DA FIBROMIALGIA

Este trabalho consiste na conclusao do primeiro ciclo da pesquisa que estamos realizando. A proposta dessa pesquisa e abordar a memoria e os conceitos que a norteiam segundo a perspectiva psicanalitica. Neste texto, especificamente, apresentamos o inicio da preocupacao de Freud com a questao do registro, bem como a maneira pela qual o autor concebe a memoria. Preocupamo-nos tambem em levantar os aspectos que confirmam a centralidade da memoria na abordagem do aparelho psiquico.

Visando a contribuir para a compreensao de um importante momento da historia da alfabetizacao em nosso pais e para o desenvolvimento de pesquisas correlatas, apresentam-se neste artigo resultados de pesquisa de iniciacao cientifica, em que se enfocou a Cartilha da infancia: ensino da leitura, de Thomaz Paulo do Bom Sucesso Galhardo (1855 – 1904). Mediante abordagem historica centrada em pesquisa documental e bibliografica, desenvolvida por meio de procedimentos de localizacao, recuperacao, reuniao, selecao e ordenacao de fontes documentais e de leitura da bibliografia especializada sobre o tema, analisou-se a configuracao textual da cartilha, com base na hipotese segundo a qual essa cartilha se apresenta como uma concretizacao do metodo da silabacao defendido pelo autor da cartilha como o metodo mais eficiente e mais adequado a esse ensino naquele momento historico e que influenciou, por mais de oito decadas, geracoes de professores e alunos do curso primario, no Brasil.

Um estudo sobre a cartilha da infância (188?), de Thomaz Galhardo

Resumo A escrita da Historia foi tomada nos ultimos anos pela desconfianca. Os debates em torno da verdade e das possibilidades de apreensao da realidade historica seguem ruidosos. Entretanto, o perigo dos extremismos pode ser minimizado atraves da analise dos conceitos aplicados as pesquisas. As discussoes em torno do eurocentrismo em Historia e das construcoes narrativas acerca das populacoes originarias brasileiras constituem pontos de partida para experiencias deste tipo, sendo este o foco do presente artigo. Palavras-chave: Populacoes originarias brasileiras, conceitos, eurocentrismo. Abstract Suspiciousness is the word which best describes the writing of the History over the past few years. The debates around the truth and around the possibilities of historical reality apprehension remain thorny. However, the danger of extremisms can be minimized by the analysis of concepts applied in researches. The discussions around eurocentrism along the History and also narratives constructions on the original Brazilian population represent starting points for this kind of experiences, being the focus of this article. Keywords: original Brazilian population, concepts, eurocentrism.

A herança colonial: fontes históricas, conceitos e eurocentrismo.

Desempenho produtivo, características seminais e morfométricas do testículo de coelhos alimentados com farelo de canola (Brassica sp.) até 180 dias de idade

Este trabalho apresenta uma reflexao historica que engloba novos sistemas para explicar a participacao do Brasil na II Guerra Mundial. Consideramos que, em cada sequencia de acontecimentos, existe uma mistura intrinseca de finalidade e causalidade, e desta forma articulamos um conceito ao outro, a partir de mecanismos relacionados a estrutura nacional brasileira. Tais pressupostos sao estabelecidos a partir das formulacoes teoricas de Jean Baptiste Duroselle, em seu trabalho Todo Imperio Perecera. A estrutura nacional que se instaura no Brasil a partir de 1930 possibilitou apresentar nacionalismo e autoritarismo como politicas complementares na formacao da nova estrutura nacional do Estado brasileiro. Desta forma, as decisoes do dirigente (finalidade), tomadas independentes dos posicionamentos do povo, seguiam as orientacoes politico-ideologicas de um projeto organizado. O Sistema da causalidade por sua vez, disponibilizou dispositivos de forcas que impulsionaram o pais para a guerra. Brasileiros sofreram a forca de pulsao em funcao dos ataques aos navios mercantes brasileiros, nascendo assim um sentimento revanchista que foi asseverado pela campanha de entrada do Brasil na Guerra, organizada pelo governo federal brasileiro do periodo, como uma forca de pressao, a partir da criacao de aparatos proprios para a difusao ideologica - Departamento de Imprensa e Propaganda (DIP), por exemplo - o governo foi capaz de difundir a imagem do Estado Novo, e, a partir de 1942, conscientizar e mobilizar a sociedade brasileira a favor da participacao brasileira na Segunda Guerra Mundial, consagrando tal posicao na Revista Cultura Politica, em sua edicao extraordinaria, intitulada, O Brasil na Guerra, de agosto de 1943. Uma vez no front de guerra a Forca Expedicionaria Brasileira FEB, grupamento real especifico, foi submetida, nao apenas as pressoes e pulsoes do conjunto da nacao, mas tambem a uma guerra psicologica, em comunicacoes em forma de panfletos, escritos em portugues, onde os inimigos buscavam reforcar o moral dos seus, erodir o dos brasileiros e causar boa impressao aos neutros.

Há algo de novo no front: a participação do Brasil na Segunda Guerra Mundial

Resumen pt: A abordagem psicologica do paciente infantil representa uma das bases do atendimento em odontopediatria. Muitas tecnicas sao propostas para criancas que...

Avaliação da técnicade condicionamento psicológico"mão-sobre-a-boca" no Municípiode Porto Alegre/RS

Esta pesquisa investigou as concepcoes do professor de Matematica sobre o Ensino de Algebra , comparando-as as concepcoes sobre Algebra propostas por Usiskin e com as abordagens para o ensino de Algebra sugeridas por Bednarz, Kieran e Lee. Foram feitas analises qualitativa, utilizando-se o software C.H.I.C. (Classificacao Hierarquica Implicativa e Coesitiva), e quantitativa das respostas dos professores ao questionario, chegando-se as seguintes conclusoes: a maioria dos professores concebe a Algebra como estudo de procedimentos para resolver certos tipos de problemas , conforme Usiskin, bem como aborda a Algebra como Regras de Transformacoes e solucoes de equacoes , conforme Bednarz, Kieran e Lee; todos os professores concebem a Algebra como Aritmetica generalizada , conforme Usiskin, e abordam a Algebra como generalizacao das leis que regem os numeros , conforme Bednarz, Kieran e Lee; uma pequena parte do grupo de professores concebem a Algebra como estudo de relacoes entre grandezas , conforme Usiskin, bem como, abordam a Algebra como introducao do conceito de variavel e funcao , conforme Bednarz, Kieran e Lee. Nestas tres concepcoes emitidas pelos professores pesquisados evidenciaram-se afirmacoes da teoria ausubeliana em relacao a aprendizagem significativa implicita na concepcao Algebra como Aritmetica generalizada ; como tambem, a aprendizagem mecânica que pode associar-se a concepcao de Algebra como procedimento , se abordada apenas como regras a serem memorizadas. Alem disso, ao conceberem o Ensino de Algebra , segundo as tres concepcoes citadas, os professores oportunizam a seus alunos abordar o ente algebrico em situacoes diversas referentes a cada uma das tres concepcoes.

Estrutura eletrônica e caracterização espectroscópica da molécula SiP

Esse artigo se propoe a apresentar a realidade brasileira em termos de exclusao digital, mostrar as vantagens do Software Livre (SL) na otica da inclusao digital, informar iniciativas brasileiras de uso do SL na alfabetizacao digital e apresentar uma proposta de combate a exclusao digital na Bahia.

Trabalhar o romance aqui em discussao nao e tarefa facil, principalmente quando a leitura e feita nos dias de hoje e percebemos que grande parte desta representacao alude a um periodo da historia do Brasil que provoca muitos estudos: o golpe militar de 64. A medida que lemos a obra, parece que encontramos uma parte dessa nossa realidade historica representada em uma forma romanesca de ha 24 anos. Uma forma tao antiga de se abordar no tecido metaforico do texto literario aspectos relacionados a sociologia, a realidade que nos circunda, nos faz construir este ensaio, cuja discussao e relacionada como a forma literaria, muitas vezes presa a modelos esteticos, a nocoes de genero, representa a nocao de sociedade e seus varios complexos e paradoxos configurados na imagem do personagem Souza, nosso sujeito problematico, heroi degradado, sujeito pos-modemo. Baseados em Candido (1965), formulamos hipoteses acerca da representatividade de aspectos historicos na forma literaria. A literatura, segundo este critico, sempre foi uma especie de 'lugar' onde realidades podem adquirir outras conotacoes, servindo como equilibrio intelectual a medida que nao discutimos temas de sociologia somente em tratados de sociologia ou similares, mas atraves da ficcionalizacao do discurso. DOI: 10.28998/0103-6858.2003v1n31p197-228

Forma literária e conteúdo social: uma representação em "Não verás país nenhum"

Spinning : relações entre tipos de aula, freqüência cardíaca e esforço percebido

The xerogel p-anisidinepropylsilica was obtained. This solid presents some residual paraffin and also a small fraction of high organofunctionalized material that was leached in polar solvent. The xerogel purification could be achieved by exhaustively washing with hexane and dichloromethane solvents, or submitting the xerogel to thermal treatment up to 300 oC, in vacuum. The resulting purified xerogel material present an appreciable thermal stability and resistance to leaching by solvents.

Xerogel p-anisidinapropilsílica: estudo da estabilidade térmica e da resistência à lixiviação com solventes

A violencia domestica e um tema bastante discutido na atualidade. Este artigo trata da situacao economica como fator capaz de contribuir para o aumento desta violencia. O estudo e ilustrado por uma pesquisa realizada na Delegacia da Mulher de Florianopolis, onde fica clara a posicao das mulheres e as dificuldades que tem de perceberem seus direitos. Mas e necessario debater o tema, pois assim poderemos contribuir para que as mulheres rompam com as formas de submissao que marcam suas vidas e entendam, que a conquista da independencia economica e o primeiro passo para estabelecerem relacoes de igualdade entre os generos.

A situação econômica como fator agravante da violência doméstica: um estudo na Delegacia da Mulher de Florianópolis

Isolamento e identificação de alcalóides da Psychotria suterella

A presente pesquisa e resultado da experiencia de estagio curricular supervisionado realizado num abrigo para criancas e adolescentes em risco pessoal e social conforme determina o Estatuto da Crianca e do Adolescente (ECA). Tivemos como principal categoria os vinculos familiares das criancas e dos adolescentes institucionalizados. Durante a realizacao do estagio a nossa preocupacao foi com as criancas e adolescentes que muitas vezes sao retirados do convivio familiar. Lembramos que, o Estatuto da Crianca e do Adolescente (ECA), trouxe avancos, no que tange a questao da convivencia familiar e comunitaria, e podemos traduzir essa convivencia como vinculo, mas nem sempre, no entanto, esse direito e lembrado; em nome da "protecao" a criancas e adolescentes, oriundos, principalmente de familias em situacao economica e social deficitarias, eles sao institucionalizados, dessa forma ferindo o texto legal. Sendo que, em seu artigo 23, o ECA contempla que "a falta ou carencia de recursos materiais, nao constitui motivo suficiente para a perda ou suspensao do patrio poder". E ainda mais: nao existindo outro motivo, que por si so autorize a decretacao da medida, a crianca ou o adolescente sera mantido em sua familia de origem, a qual devera obrigatoriamente ser incluida em programas oficiais de auxilio. Assim, dada a miserabilidade em que vive hoje um grande contingente da populacao brasileira, podemos concluir que, se existe abandono dos filhos por parte dos pais, abandono ainda maior se da por parte do Estado em relacao as familias. Por tudo isso, pensar em atender a crianca, hoje, significa tambem atender sua familia, que muitas vezes e obrigada a transformar a instituicao no unico refugio para seus filhos.

O binômio mãe-filho e incentivo ao aleitamento materno uma proposta assistencial baseada nas necessidades humanas básicas de Wanda de Aguiar Horta

OS COLEGIADOS DE DESENVOLVIMENTO TERRITORIAL E SUA IMPORTÂNCIA NA EFETIVAÇÃO DE POLÍTICAS PÚBLICAS NA AMAZÔNIA: UMA ANÁLISE DO COLEGIADO DO BAIXO AMAZONAS, PARÁ

To interpret the sensory environment, the brain combines ambiguous sensory measurements with knowledge that reflects context-specific prior experience. But environmental contexts can change abruptly and unpredictably, resulting in uncertainty about the current context. Here we address two questions: how should context-specific prior knowledge optimally guide the interpretation of sensory stimuli in changing environments, and do human decision-making strategies resemble this optimum? We probe these questions with a task in which subjects report the orientation of ambiguous visual stimuli that were drawn from three dynamically switching distributions, representing different environmental contexts. We derive predictions for an ideal Bayesian observer that leverages knowledge about the statistical structure of the task to maximize decision accuracy, including knowledge about the dynamics of the environment. We show that its decisions are biased by the dynamically changing task context. The magnitude of this decision bias depends on the observer’s continually evolving belief about the current context. The model therefore not only predicts that decision bias will grow as the context is indicated more reliably, but also as the stability of the environment increases, and as the number of trials since the last context switch grows. Analysis of human choice data validates all three predictions, suggesting that the brain leverages knowledge of the statistical structure of environmental change when interpreting ambiguous sensory signals.

During visually guided behavior, the prefrontal cortex plays a pivotal role in mapping sensory inputs onto appropriate motor plans [1]. When the sensory input is ambiguous, this involves deliberation. It is not known whether the deliberation is implemented as a competition between possible stimulus interpretations [2, 3] or between possible motor plans [4, 5, 6]. Here we study neural population activity in prefrontal cortex of macaque monkeys trained to flexibly report categorical judgments of ambiguous visual stimuli. Our task design allowed for the dissociation of neural predictors of the upcoming categorical choice and the upcoming motor response used to report this choice. We find that the population activity initially represents the formation of a categorical choice before transitioning into the stereotypical representation of the motor plan. We show that stimulus strength and prior expectations both bear on the formation of the categorical choice, but not on the formation of the action plan. These results suggest that prefrontal circuits involved in action selection are also used for the deliberation of abstract propositions divorced from a specific motor plan, thus providing a crucial mechanism for abstract reasoning.

Abstract deliberation by visuomotor neurons in prefrontal cortex

To interpret the sensory environment, the brain combines ambiguous sensory measurements with context-specific prior experience. But environmental contexts can change abruptly and unpredictably, resulting in uncertainty about the current context. Here we address two questions: how should context-specific prior knowledge optimally guide the interpretation of sensory stimuli in changing environments, and do human decision-making strategies resemble this optimum? We probe these questions with a task in which subjects report the orientation of ambiguous visual stimuli that were drawn from three dynamically switching distributions, representing different environmental contexts. We derive predictions for an ideal Bayesian observer that leverages the statistical structure of the task to maximize decision accuracy and show that its decisions are biased by task context. The magnitude of this decision bias is not a fixed property of the sensory measurement but depends on the observer’s belief about the current context. The model therefore predicts that decision bias will grow with the reliability of the context cue, the stability of the environment, and with the number of trials since the last context switch. Analysis of human choice data validates all three predictions, providing evidence that the brain continuously updates probabilistic representations of the environment to best interpret an uncertain, ever-changing world. SIGNIFICANCE The brain relies on prior knowledge to make perceptual inferences when sensory information is ambiguous. However, when the environmental context changes, the appropriate prior knowledge often changes with it. Here, we develop a Bayesian observer model to investigate how to make optimal perceptual inferences when sensory information and environmental context are both uncertain. The behavioral signature of this strategy is a context-appropriate decision bias whose strength grows with the reliability of the context cue, the stability of the environment, and with the number of decisions since the most recent change in context. We identified exactly this pattern in the behavior of human subjects performing a dynamic orientation discrimination task. Together, our results suggest that the brain continuously updates probabilistic representations of the environment to make perceptual decisions in the face of uncertainty over both sensory and contextual information.

Perceptual decisions exhibit hallmarks of dynamic Bayesian inference

Decisions vary in difficulty. Humans know this and typically report more confidence in easy than in difficult decisions. However, confidence reports do not perfectly track decision accuracy, but also reflect response biases and difficulty misjudgments. To isolate the quality of confidence reports, we developed a model of the decision-making process underlying choice-confidence data. In this model, confidence reflects a subject’s estimate of the reliability of their decision. The quality of this estimate is limited by the subject’s uncertainty about the uncertainty of the variable that informs their decision (“meta-uncertainty”). This model provides an accurate account of choice-confidence data across a broad range of perceptual and cognitive tasks, revealing that meta-uncertainty varies across subjects, is stable over time, generalizes across some domains, and can be manipulated experimentally. The model offers a parsimonious explanation for the computational processes that underlie and constrain the sense of confidence.

Representation of visual uncertainty through neural gain variability

In the article “Compound Stimuli Reveal the Structure of Visual Motion Selectivity in Macaque MT Neurons,” by Andrew D. Zaharia, Robbe L. T. Goris, J. Anthony Movshon, and Eero P. Simoncelli, which published online on October 11, 2019, a passage of text in the Discussion section needed clarification. The sentence on page 16, “Linear weighting alone in the velocity-separable model is sufficient to capture the unimodality of constant frequency plaid (pattern) direction tuning, but not in the frequency-separable model (Fig. 11A, lightest red and blue traces, respectively).” is modified to be: “If the velocity plaid responses are not included during model fitting, linear weighting alone in the velocity-separable model is sufficient to capture the unimodality of constant frequency plaid (pattern) direction tuning, but not in the frequencyseparable model (unpublished data). However, when all data are included, linear weighting alone is not sufficient for either model to capture this unimodality (Fig. 11A, lightest red and blue traces).” This correction does not affect the conclusions of the article. The text has been corrected in the online record.

Erratum: Zaharia et al., Compound Stimuli Reveal the Structure of Visual Motion Selectivity in Macaque MT Neurons

Optogenetic activation of corticogeniculate feedback stabilizes response gain and increases information coding in LGN neurons

Decision letter: Development of visual motion integration involves coordination of multiple cortical stages

Uncertainty is intrinsic to perception. Neural circuits which process sensory information must therefore also represent the reliability of this information. How they do so is a topic of debate. We propose a view of visual cortex in which average neural response strength encodes stimulus features, while cross-neuron variability in response gain encodes the uncertainty of these features. To test our theory, we studied spiking activity of neurons in macaque V1 and V2 elicited by repeated presentations of stimuli whose uncertainty was manipulated in distinct ways. We show that gain variability of individual neurons is tuned to stimulus uncertainty, that this tuning is invariant to the source of uncertainty, and that it is specific to the features encoded by these neurons. We demonstrate that this behavior naturally arises from known gain-control mechanisms, and derive how downstream circuits can jointly decode stimulus features and their uncertainty from sensory population activity.

Abstract Motion selectivity in primary visual cortex (V1) is approximately separable in orientation, spatial frequency, and temporal frequency (“frequency-separable”). Models for area MT neurons posit that their selectivity arises by combining direction-selective V1 afferents whose tuning is organized around a tilted plane in the frequency domain, specifying a particular direction and speed (“velocity-separable”). This construction explains “pattern direction-selective” MT neurons, which are velocity-selective but relatively invariant to spatial structure, including spatial frequency, texture and shape. We designed a set of experiments to distinguish frequency-separable and velocity-separable models and executed them with single-unit recordings in macaque V1 and MT. Surprisingly, when tested with single drifting gratings, most MT neurons’ responses are fit equally well by models with either form of separability. However, responses to plaids (sums of two moving gratings) tend to be better described as velocity-separable, especially for pattern neurons. We conclude that direction selectivity in MT is primarily computed by summing V1 afferents, but pattern-invariant velocity tuning for complex stimuli may arise from local, recurrent interactions.

Compound Stimuli Reveal the Structure of Visual Motion Selectivity in Macaque MT Neurons

Sensory neurons represent stimulus information with sequences of action potentials that differ across repeated measurements. This variability limits the information that can be extracted from momentary observations of a neuron's response. It is often assumed that integrating responses over time mitigates this limitation. However, temporal response correlations can reduce the benefits of temporal integration. We examined responses of individual orientation-selective neurons in the primary visual cortex of two macaque monkeys performing an orientation-discrimination task. The signal-to-noise ratio of temporally integrated responses increased for durations up to a few hundred milliseconds but saturated for longer durations. This was true even when cells exhibited little or no adaptation in their response levels. These observations are well explained by a statistical response model in which spikes arise from a Poisson process whose stimulus-dependent rate is modulated by slow, stimulus-independent fluctuations in gain. The response variability arising from the Poisson process is reduced by temporal integration, but the slow modulatory nature of variability due to gain fluctuations is not. Slow gain fluctuations therefore impose a fundamental limit on the benefits of temporal integration.

Slow gain fluctuations limit benefits of temporal integration in visual cortex

Responses of individual task-relevant sensory neurons can predict monkeys' trial-by-trial choices in perceptual decision-making tasks. Choice-correlated activity has been interpreted as evidence that the responses of these neurons are causally linked to perceptual judgments. To further test this hypothesis, we studied responses of orientation-selective neurons in V1 and V2 while two macaque monkeys performed a fine orientation discrimination task. Although both animals exhibited a high level of neuronal and behavioral sensitivity, only one exhibited choice-correlated activity. Surprisingly, this correlation was negative: when a neuron fired more vigorously, the animal was less likely to choose the orientation preferred by that neuron. Moreover, choice-correlated activity emerged late in the trial, earlier in V2 than in V1, and was correlated with anticipatory signals. Together, these results suggest that choice-correlated activity in task-relevant sensory neurons can reflect postdecision modulatory signals. SIGNIFICANCE STATEMENT When observers perform a difficult sensory discrimination, repeated presentations of the same stimulus can elicit different perceptual judgments. This behavioral variability often correlates with variability in the activity of sensory neurons driven by the stimulus. Traditionally, this correlation has been interpreted as suggesting a causal link between the activity of sensory neurons and perceptual judgments. More recently, it has been argued that the correlation instead may originate in recurrent input from other brain areas involved in the interpretation of sensory signals. Here, we call both hypotheses into question. We show that choice-related activity in sensory neurons can be highly variable across observers and can reflect modulatory processes that are dissociated from perceptual decision-making.

Dissociation of Choice Formation and Choice-Correlated Activity in Macaque Visual Cortex

Uncoupling choice formation and choice-correlated activity in early visual cortex

Origin and Function of Tuning Diversity in Macaque Visual Cortex

Origin and Function of Tun ing Diversity in Macaque Visual Cortex Highlights

What determines the shape of the spatiotemporal tuning curves of visual neurons? In V1, direction-selective simple cells have selectivity that is roughly separable in orientation, spatial frequency, and temporal frequency ("frequency separable"). Models for tuning in area MT predict that signals from V1 inputs with suitable spatial and temporal frequency selectivity are combined to create tuning curves organized around tilted planes through the origin, representing stimuli translating at a particular direction and speed ("velocity separable"). In these models, this transformation is critical to build "pattern selective" neurons, which are neurons that respond best to simple and compound stimuli moving with the preferred velocity. We measured spatiotemporal frequency selectivity in single macaque MT neurons responding to sinusoidal gratings whose drift direction varied while their drift rate was either held constant (frequency separable organization) or varied along the preferred velocity plane (velocity separable). Most MT neurons' grating tuning was fit equally well by both the frequency and velocity separable model, regardless of the degree of pattern selectivity. We also measured responses to plaids (sums of two gratings oriented 120º apart). MT responses to velocity separable plaids were stronger and more broadly tuned than those to frequency separable plaids. Velocity separable model fits to these plaid responses were better than corresponding frequency separable model fits for almost every cell. Fitting the velocity separable model to gratings alone failed to predict pattern selectivity, whereas fitting to plaids alone predicted pattern selectivity well. We conclude that velocity separable models better describe the responses of most MT cells, though this superiority is only evident when complex stimuli are used to expose the nonlinear elements of these models. Meeting abstract presented at VSS 2015.

Compound stimuli reveal velocity separability of spatiotemporal receptive fields in macaque area MT.

Responses of sensory neurons represent stimulus information, but are also influenced by internal state. For example, when monkeys direct their attention to a visual stimulus, the response gain of specific subsets of neurons in visual cortex changes. Here, we develop a functional model of population activity to investigate the structure of this effect. We fit the model to the spiking activity of bilateral neural populations in area V4, recorded while the animal performed a stimulus discrimination task under spatial attention. The model reveals four separate time-varying shared modulatory signals, the dominant two of which each target task-relevant neurons in one hemisphere. In attention-directed conditions, the associated shared modulatory signal decreases in variance. This finding provides an interpretable and parsimonious explanation for previous observations that attention reduces variability and noise correlations of sensory neurons. Finally, the recovered modulatory signals reflect previous reward, and are predictive of subsequent choice behavior.

Neural responses are highly variable, and some portion of this variability arises from fluctuations in modulatory factors that alter their gain, such as adaptation, attention, arousal, expected or actual reward, emotion, and local metabolic resource availability. Regardless of their origin, fluctuations in these signals can confound or bias the inferences that one derives from spiking responses. Recent work demonstrates that for sensory neurons, these effects can be captured by a modulated Poisson model, whose rate is the product of a stimulus-driven response function and an unknown modulatory signal. Here, we extend this model, by incorporating explicit modulatory elements that are known (specifically, spike-history dependence, as in previous models), and by constraining the remaining latent modulatory signals to be smooth in time. We develop inference procedures for fitting the entire model, including hyperparameters, via evidence optimization, and apply these to simulated data, and to responses of ferret auditory midbrain and cortical neurons to complex sounds. We show that integrating out the latent modulators yields better (or more readily-interpretable) receptive field estimates than a standard Poisson model. Conversely, integrating out the stimulus dependence yields estimates of the slowly-varying latent modulators.

A model of sensory neural responses in the presence of unknown modulatory inputs

Compound stimuli reveal velocity separability of spatiotemporal receptive fields in macaque area MT

Responses of sensory neurons represent stimulus information, but are also influenced by internal state. For example, when monkeys direct their attention to a visual stimulus, the response gain of specific subsets of neurons in visual cortex changes. Here, we develop a functional model of population activity to investigate the structure of this effect. We fit the model to the spiking activity of bilateral neural populations in area V4, recorded while the animal performed a stimulus discrimination task under spatial attention. The model reveals four separate time-varying shared modulatory signals, the dominant two of which each target task-relevant neurons in one hemisphere. In attention-directed conditions, the associated shared modulatory signal decreases in variance. This finding provides an interpretable and parsimonious explanation for previous observations that attention reduces variability and noise correlations of sensory neurons. Finally, the recovered modulatory signals reflect previous reward, and are predictive of subsequent choice behavior. DOI: http://dx.doi.org/10.7554/eLife.08998.001

Model modulation index Figure 1 (a) An input image is convolved with a model V1 front-end with units tuned to different orientations and spatial frequencies. The first V2 stage computes derivatives over the activation map of V1 across space, as well as orientation and spatial frequency. We modelled “V2 simple cells” as the rectified output of these filters. The final V2 stage pools and rectifies the output of these “V2 simple cells”. (b,c) Single unit modulation indices for V1 and V2 cells adapted from Freeman et al. (2013). The modulation index represents the normalized difference in firing rate between naturalistic and control stimuli. The V1 neurons show an average modulation close to zero, whereas the V2 population was consistently positive. (d,e) Modulation indices for a simulated population of V2 “simple” and “complex” cells. Units were simulated to have random parameters for derivative and pooling weights. While “V2 simple” cells had a slightly positive modulation index on average, “V2 complex” cells approached the magnitude of the recorded V2 population. (f) The average modulation of “V2 simple” cells failed to account for the strength of V2 modulation across different categories of naturalistic images, (g) while The average modulation of “V2 complex” cells across categories was correlated with recorded V2 population. Characterizing receptive field selectivity in area V2 Corey M Ziemba, Robbe LT Goris, J Anthony Movshon, Eero P Simoncelli New York University

Author response: Attention stabilizes the shared gain of V4 populations

On the diversity of orientation selectivity in macaque visual cortex

Pattern detection is the bedrock of modern vision science. Nearly half a century ago, psychophysicists advocated a quantitative theoretical framework that connected visual pattern detection with its neurophysiological underpinnings. In this theory, neurons in primary visual cortex constitute linear and independent visual channels whose output is linked to choice behavior in detection tasks via simple read-out mechanisms. This model has proven remarkably successful in accounting for threshold vision. It is fundamentally at odds, however, with current knowledge about the neurophysiological underpinnings of pattern vision. In addition, the principles put forward in the model fail to generalize to suprathreshold vision or perceptual tasks other than detection. We propose an alternative theory of detection in which perceptual decisions develop from maximum-likelihood decoding of a neurophysiologically inspired model of population activity in primary visual cortex. We demonstrate that this theory explains a broad range of classic detection results. With a single set of parameters, our model can account for several summation, adaptation, and uncertainty effects, thereby offering a new theoretical interpretation for the vast psychophysical literature on pattern detection.

Several studies have reported optimal population decoding of sensory responses in two-alternative visual discrimination tasks. Such decoding involves integrating noisy neural responses into a more reliable representation of the likelihood that the stimuli under consideration evoked the observed responses. Importantly, an ideal observer must be able to evaluate likelihood with high precision and only consider the likelihood of the two relevant stimuli involved in the discrimination task. We report a new perceptual bias suggesting that observers read out the likelihood representation with remarkably low precision when discriminating grating spatial frequencies. Using spectrally filtered noise, we induced an asymmetry in the likelihood function of spatial frequency. This manipulation mainly affects the likelihood of spatial frequencies that are irrelevant to the task at hand. Nevertheless, we find a significant shift in perceived grating frequency, indicating that observers evaluate likelihoods of a broad range of irrelevant frequencies and discard prior knowledge of stimulus alternatives when performing two-alternative discrimination.

A New Perceptual Bias Reveals Suboptimal Population Decoding of Sensory Responses

Superiority of angle discrimination to orientation discrimination for bisecting lines

Sensory neurons encode information probabilistically: repeated stimulus presentations elicit variable firing. This variability is often described using a cascade model, in which spikes arise from a Poisson process whose rate is a deterministic function of the stimulus. However, it has recently been shown that time-dependent rate variability is a wide-spread phenomenon in cortex (Churchland et al 2010, 2011). Consequently, the Poisson noise model commonly underestimates the variability of visual cortical recordings, which can lead to systematic errors in inferring neuronal characteristics. We measured responses to a variety of stimuli in visual cortex in anesthetized and alert monkeys. The fluctuations in neural responsiveness that typically occur over the timescale of these experiments are significantly greater than predicted by a Poisson model – estimated Fano factors as high as 10 occur in the acute preparation. We propose a doubly stochastic model, in which the stimulus-driven firing rate is modulated according to a stimulus-independent gamma-distributed random variable. This fluctuating rate generates spikes according to a Poisson process. Fitting the resulting mixture of Poisson processes to neural data reveals that the model is statistically superior for all neurons, and therefore provides an improved framework for analyzing neuronal tuning. The framework offers two further advantages over existing methods. First, it provides a natural means of estimating and tracking fluctuations in responsiveness (state changes) that occur during the course of an experiment. Second, it offers an efficient and accurate estimate of the upper bound on discrimination performance that can be supported by each neuron. Application of this new method can substantially improve the analysis of neuronal data, both in fitting explicit models and in assessing the limits of neuronal performance.

Using a doubly-stochastic model to analyze neuronal activity in the visual cortex

A new perceptual bias reveals suboptimal Bayesian decoding of sensory responses

Inferring characteristics of stimulus encoding mechanisms using rippled noise stimuli

Early Stages in Spatial Vision - Psychophysical Data and Computational Models of Contrast Perception

Visual object recognition is remarkably accurate and robust, yet its neurophysiological underpinnings are poorly understood. Single cells in brain regions thought to underlie object recognition code for many stimulus aspects, which poses a limit on their invariance. Combining the responses of multiple non-invariant neurons via weighted linear summation offers an optimal decoding strategy, which may be able to achieve invariant object recognition. However, because object identification is essentially parameter optimization in this model, the characteristics of the identification task trained to perform are critically important. If this task does not require invariance, a neural population-code is inherently more selective but less tolerant than the single-neurons constituting the population. Nevertheless, tolerance can be learned – provided that it is trained for – at the cost of selectivity. We argue that this model is an interesting null-hypothesis to compare behavioral results with and conclude that it may explain several experimental findings.

Invariance in Visual Object Recognition Requires Training: A Computational Argument

The pedestal effect is the improvement in the detectability of a sinusoidal grating in the presence of another grating of the same orientation, spatial frequency, and phase-usually called the pedestal. Recent evidence has demonstrated that the pedestal effect is differently modified by spectrally flat and notch-filtered noise: The pedestal effect is reduced in flat noise but virtually disappears in the presence of notched noise (G. B. Henning & F. A. Wichmann, 2007). Here we consider a network consisting of units whose contrast response functions resemble those of the cortical cells believed to underlie human pattern vision and demonstrate that, when the outputs of multiple units are combined by simple weighted summation-a heuristic decision rule that resembles optimal information combination and produces a contrast-dependent weighting profile-the network produces contrast-discrimination data consistent with psychophysical observations: The pedestal effect is present without noise, reduced in broadband noise, but almost disappears in notched noise. These findings follow naturally from the normalization model of simple cells in primary visual cortex, followed by response-based pooling, and suggest that in processing even low-contrast sinusoidal gratings, the visual system may combine information across neurons tuned to different spatial frequencies and orientations.

A neurophysiologically plausible population code model for human contrast discrimination.

Neural mechanisms underlying invariant behaviour such as object recognition are not well understood. For brain regions critical for object recognition, such as inferior temporal cortex (ITC), there is now ample evidence indicating that single cells code for many stimulus aspects, implying that only a moderate degree of invariance is present. However, recent theoretical and empirical work seems to suggest that integrating responses of multiple non-invariant units may produce invariant representations at population level. We provide an explicit test for the hypothesis that a linear read-out mechanism of a pool of units resembling ITC neurons may achieve invariant performance in an identification task. A linear classifier was trained to decode a particular value in a 2-D stimulus space using as input the response pattern across a population of units. Only one dimension was relevant for the task, and the stimulus location on the irrelevant dimension (ID) was kept constant during training. In a series of identification tests, the stimulus location on the relevant dimension (RD) and ID was manipulated, yielding estimates for both the level of sensitivity and tolerance reached by the network. We studied the effects of several single-cell characteristics as well as population characteristics typically considered in the literature, but found little support for the hypothesis. While the classifier averages out effects of idiosyncratic tuning properties and inter-unit variability, its invariance is very much determined by the (hypothetical) ‘average’ neuron. Consequently, even at population level there exists a fundamental trade-off between selectivity and tolerance, and invariant behaviour does not emerge spontaneously.

Neural Representations that Support Invariant Object Recognition

Computational models of spatial vision typically make use of a (rectified) linear filter, a nonlinearity and dominant late noise to account for human contrast discrimination data. Linear-nonlinear cascade models predict an improvement in observers' contrast detection performance when low, subthreshold levels of external noise are added (i.e., stochastic resonance). Here, we address the issue whether a single contrast gain-control model of early spatial vision can account for both the pedestal effect, i.e., the improved detectability of a grating in the presence of a low-contrast masking grating, and stochastic resonance. We measured contrast discrimination performance without noise and in both weak and moderate levels of noise. Making use of a full quantitative description of our data with few parameters combined with comprehensive model selection assessments, we show the pedestal effect to be more reduced in the presence of weak noise than in moderate noise. This reduction rules out independent, additive sources of performance improvement and, together with a simulation study, supports the parsimonious explanation that a single mechanism underlies the pedestal effect and stochastic resonance in contrast perception.

Modelling contrast discrimination data suggest both the pedestal effect and stochastic resonance to be caused by the same mechanism.

The standard psychophysical model of our early visual system consists of a linear filter stage, followed by a nonlinearity and an internal noise source. If a rectification mechanism is introduced at the output of the linear filter stage, as has been suggested on some occasions, this model actually predicts that human performance in a classical contrast detection task might benefit from the addition of weak levels of noise. Here, this prediction was tested and confirmed in two contrast detection tasks. In Experiment 1, observers had to discriminate a low-contrast Gabor pattern from a blank. In Experiment 2, observers had to discriminate two low-contrast Gabor patterns identical on all dimensions, except for orientation (-45 degrees vs. +45 degrees). In both experiments, weak-to-modest levels of 2-D, white noise were added to the stimuli. Detection thresholds vary nonmonotonically with noise power, i.e., some noise levels improve contrast detection performance. Both simple uncertainty reduction and an energy discrimination strategy can be excluded as possible explanations for this effect. We present a quantitative model consistent with the effects and discuss the implications.

Optimal noise levels enhance sensitivity to weak signals in the human visual system

COPYRIGHT © 2023 Yang, Shew, Yu, Luczak, Stringer and Okun. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Editorial: Deciphering population neuronal dynamics: from theories to experiments

Editorial: Deciphering population neuronal dynamics: from theories to experiments

Spike sorting is the computational process of extracting the firing times of single neurons from recordings of local electrical fields. This is an important but hard problem in neuroscience, complicated by the non-stationarity of the recordings and the dense overlap in electrical fields between nearby neurons. To solve the spike sorting problem, we have continuously developed over the past eight years a framework known as Kilosort. This paper describes the various algorithmic steps introduced in different versions of Kilosort. We also report the development of Kilosort4, a new version with substantially improved performance due to new clustering algorithms inspired by graph-based approaches. To test the performance of Kilosort, we developed a realistic simulation framework which uses densely sampled electrical fields from real experiments to generate non-stationary spike waveforms and realistic noise. We find that nearly all versions of Kilosort outperform other algorithms on a variety of simulated conditions, and Kilosort4 performs best in all cases, correctly identifying even neurons with low amplitudes and small spatial extents in high drift conditions.

A surprising finding of recent studies in mouse is the dominance of widespread movement-related activity throughout the brain, including in early sensory areas. In awake subjects, failing to account for movement risks misattributing movement-related activity to other (e.g., sensory or cognitive) processes. In this article, we (1) review task designs for separating task-related and movement-related activity, (2) review three “case studies” in which not considering movement would have resulted in critically different interpretations of neuronal function, and (3) discuss functional couplings that may prevent us from ever fully isolating sensory, motor, and cognitive-related activity. Our main thesis is that neural signals related to movement are ubiquitous, and therefore ought to be considered first and foremost when attempting to correlate neuronal activity with task-related processes.

The Importance of Accounting for Movement When Relating Neuronal Activity to Sensory and Cognitive Processes

Not so spontaneous: Multi-dimensional representations of behaviors and context in sensory areas

Recent studies in mice have shown that orofacial behaviors drive a large fraction of neural activity across the brain. To understand the nature and function of these signals, we need better computational models to characterize the behaviors and relate them to neural activity. Here we developed Facemap, a framework consisting of a keypoint tracking algorithm and a deep neural network encoder for predicting neural activity. We used the Facemap keypoints as input for the deep neural network to predict the activity of ∼50,000 simultaneously-recorded neurons and in visual cortex we doubled the amount of explained variance compared to previous methods. Our keypoint tracking algorithm was more accurate than existing pose estimation tools, while the inference speed was several times faster, making it a powerful tool for closed-loop behavioral experiments. The Facemap tracker was easy to adapt to data from new labs, requiring as few as 10 annotated frames for near-optimal performance. We used Facemap to find that the neuronal activity clusters which were highly driven by behaviors were more spatially spread-out across cortex. We also found that the deep keypoint features inferred by the model had time-asymmetrical state dynamics that were not apparent in the raw keypoint data. In summary, Facemap provides a stepping stone towards understanding the function of the brainwide neural signals and their relation to behavior.

Facemap: a framework for modeling neural activity based on orofacial tracking

Omnipose: a high-precision morphology-independent solution for bacterial cell segmentation

Many biological applications require the segmentation of cell bodies, membranes and nuclei from microscopy images. Deep learning has enabled great progress on this problem, but current methods are specialized for images that have large training datasets. Here we introduce a generalist, deep learning-based segmentation method called Cellpose, which can precisely segment cells from a wide range of image types and does not require model retraining or parameter adjustments. Cellpose was trained on a new dataset of highly varied images of cells, containing over 70,000 segmented objects. We also demonstrate a three-dimensional (3D) extension of Cellpose that reuses the two-dimensional (2D) model and does not require 3D-labeled data. To support community contributions to the training data, we developed software for manual labeling and for curation of the automated results. Periodically retraining the model on the community-contributed data will ensure that Cellpose improves constantly. Cellpose is a generalist, deep learning-based approach for segmenting structures in a wide range of image types. Cellpose does not require parameter adjustment or model retraining and outperforms established methods on 2D and 3D datasets.

Single neurons in visual cortex provide unreliable mea-surements of visual features due to their high trial-to-trial variability. It is not known if this “noise” extends its effects over large neural populations to impair the global encoding of sensory stimuli. We recorded simultaneously from ∼ 20,000 neurons in mouse visual cortex and found that the neural population had discrimination thresholds of 0.3 ◦ in an orientation decoding task. These thresholds are ∼ 100 times smaller than those reported behaviorally in mice. The discrepancy between neural and behavioral discrimination could not be explained by the types of stimuli we used, by behavioral states or by the sequential nature of trial-by-trial perceptual learning tasks. These results imply that the limits of sensory perception in mice are not set by neural noise in sensory cortex, but by the limitations of downstream decoders.

Computational processing of neural recordings from calcium imaging data

Single neurons in visual cortex provide unreliable measurements of visual features due to their high trial-to-trial variability. It is not known if this “noise” extends its effects over large neural populations to impair the global encoding of stimuli. We recorded simultaneously from ∼20,000 neurons in mouse primary visual cortex (V1) and found that the neural populations had discrimination thresholds of ∼0.34° in an orientation decoding task. These thresholds were nearly 100 times smaller than those reported behaviorally in mice. The discrepancy between neural and behavioral discrimination could not be explained by the types of stimuli we used, by behavioral states or by the sequential nature of perceptual learning tasks. Furthermore, higher-order visual areas lateral to V1 could be decoded equally well. These results imply that the limits of sensory perception in mice are not set by neural noise in sensory cortex, but by the limitations of downstream decoders.

High-dimensional geometry of population responses in visual cortex

Vertical drift (Z-drift) is a major confound for neural recordings during behavior. The brain floats in liquid, and
movements of tens of microns can easily occur, even in head-fixed animals. In the mouse, for instance, postural
changes such as locomotion can cause vertical brain movements of up to 20 microns. This displacement creates
an apparent change in the activity of neurons recorded with either electrode arrays or two-photon calcium
imaging. Here, we present methods to estimate and correct the drift in both optical and electrical recordings. We
demonstrate three methods to recover Z-drift in 2-photon calcium imaging. (1) Alignment to a densely-scanned
reference volume (z-stack). (2) Estimation from a non-functional channel- such as tdTomato expressed in a neuronal
subclass. (3) Estimation from changes in the shape of identified cells in functional recordings. We validate
methods 2 and 3 by comparing to method 1, which provides ground truth. We then develop correction methods
that remove the effects of Z-drift, and show that correlations of neuronal activity with running are significantly
decreased. Finally, we develop a convenient online module for drift correction that eliminates Z-drift at sub-micron
resolution. Z-drift also affects electrophysiological recordings. The amplitude and shape of extracellular action potentials
changes when the electrode moves relative to the brain, and neurons may even disappear altogether from
the set of recorded channels. Fortunately, new electrodes such as Neuropixels have dense arrays of channels,
with inter-site spacings as low as 20um. We found that we could estimate the drift in extracellular recordings with
linear electrodes by tracking neuronal waveform shifts, and corrected for it by spatially interpolating the raw data
prior to spike sorting. In summary, the algorithms presented here provide effective methods to remove Z-drift, a
major confound for neural recordings during behavioral experiments. We provide the code as part of the Suite2p
and Kilosort pipelines.

Drift correction for electrophysiology and two-photon calcium imaging

Sensory cortices are active in the absence of external sensory stimuli. To understand the nature of this ongoing activity, we used two-photon calcium imaging to record from over 10,000 neurons in the visual cortex of mice awake in darkness while monitoring their behavior videographically. Ongoing population activity was multidimensional, exhibiting at least 100 signiﬁcant dimensions, some of which were related to the spontaneous behaviors of the mice. The largest single dimension was correlated with the running speed and pupil area, while a 16-dimensional summary of orofacial behaviors could predict ∼ 45% of the explainable neural variance. Electrophysiological recordings with 8 simultaneous Neuropixels probes revealed a similar encoding of high-dimensional orofacial behaviors across multiple forebrain regions. Representation of motor variables continued uninterrupted during visual stimulus presentation, occupying dimensions nearly orthogonal to the stimulus responses. Our results show that a multidimensional representation of motor state is encoded across the forebrain, and is integrated with visual input by neuronal populations in primary visual cortex.

Spontaneous behaviors drive multidimensional, brain-wide neural activity

Our brains contain billions of neurons, which are continually producing electrical signals to relay information around the brain. Yet most of our knowledge of how the brain works comes from studying the activity of one neuron at a time. Recently, studies of multiple neurons have shown that they tend to be active together. These coordinated dynamics vary across brain states and impact the way that external sensory information is processed. To investigate the network-level mechanisms that underlie these dynamics, we developed novel computational techniques to fit a deterministic spiking network model directly to multi-neuron recordings from different rodent species, sensory modalities, and behavioral states. We found that inhibition modulates the interactions between intrinsic dynamics and sensory inputs to control the reliability of sensory representations. We next recorded from awake mice using calcium imaging techniques, and acquired activity from 10,000 neurons simultaneously in visual cortex while presenting 2,800 different natural images. In awake mice, these intrinsic population-wide fluctuations were suppressed and responses to visual stimuli were reliable. The stimulus-related information was stored in a high-dimensional neural space: 1,000 dimensions of neural activity accounted for 90\% of the variance. Although awake mice lacked large population-wide fluctuations in activity, we observed several dozen dimensions of spontaneous activity. These dimensions of spontaneous activity were not spatially organized in cortex. Instead they were related to the orofacial behaviors of the mouse: over 50\% of the shared variability of the network could be predicted from the facial movements of the mouse. In simulations of high-dimensional network activity, flexible patterns of activity were reproduced only if the network contained multiple dimensions of inhibitory activity. We tested this hypothesis in our recordings and found that inhibitory neuron activity did track excitatory neuron activity across multiple dimensions.

Discovering structure in multi-neuron recordings through network modelling

Neuron activity across the brain How is it that groups of neurons dispersed through the brain interact to generate complex behaviors? Three papers in this issue present brain-scale studies of neuronal activity and dynamics (see the Perspective by Huk and Hart). Allen et al. found that in thirsty mice, there is widespread neural activity related to stimuli that elicit licking and drinking. Individual neurons encoded task-specific responses, but every brain area contained neurons with different types of response. Optogenetic stimulation of thirst-sensing neurons in one area of the brain reinstated drinking and neuronal activity across the brain that previously signaled thirst. Gründemann et al. investigated the activity of mouse basal amygdala neurons in relation to behavior during different tasks. Two ensembles of neurons showed orthogonal activity during exploratory and nonexploratory behaviors, possibly reflecting different levels of anxiety experienced in these areas. Stringer et al. analyzed spontaneous neuronal firing, finding that neurons in the primary visual cortex encoded both visual information and motor activity related to facial movements. The variability of neuronal responses to visual stimuli in the primary visual area is mainly related to arousal and reflects the encoding of latent behavioral states. Science, this issue p. eaav3932, p. eaav8736, p. eaav7893; see also p. 236 Neurons in the primary visual cortex encode both visual information and motor activity. INTRODUCTION In the absence of sensory inputs, the brain produces structured patterns of activity, which can be as large as or larger than sensory-driven activity. Ongoing activity exists even in primary sensory cortices and has been hypothesized to reflect recapitulation of previous sensory experiences, or expectations of possible sensory events. Alternatively, ongoing activity could be related to behavioral and cognitive states. RATIONALE Much previous work has linked spontaneous neural activity to behavior through one-dimensional measures like running speed and pupil diameter. However, mice perform diverse behaviors consisting of whisking, licking, sniffing, and other facial movements. We hypothesized that there exists a multidimensional representation of behavior in visual cortex and that previously reported “noise” during stimulus presentations may in fact be behaviorally driven. To investigate this, we recorded the activity of ~10,000 neurons in visual cortex of awake mice using two-photon calcium imaging, while simultaneously monitoring the facial movements using an infrared camera. In a second set of experiments, we recorded the activity of thousands of neurons across the brain using eight simultaneous Neuropixels probes, again videographically monitoring facial behavior. RESULTS First, we found that ongoing activity in visual cortex is high dimensional: More than a hundred latent dimensions could be reliably extracted from the population activity. We found that a third of this activity could be predicted by a multidimensional model of the mouse’s behavior, extracted from the face video. This behaviorally related activity was not limited to visual cortex. We observed multidimensional representations of behavior in electrophysiological recordings from frontal, sensorimotor, and retrosplenial cortex; hippocampus; striatum; thalamus; and midbrain. Even though both behavior and neural activity contained fast–time scale fluctuations on the order of 200 ms, they were only related to each other at a time scale of about 1 s. We next investigated how this spontaneous, behavior-related signal interacts with stimulus responses. The representation of sensory stimuli and behavioral variables was mixed in the same neurons: The fractions of each neuron’s variance explained by stimuli and by behavior were only slightly negatively correlated, and neurons with similar stimulus responses did not have more similar behavioral correlates. Nevertheless, at a population level, the neural dimensions encoding motor variables overlapped with those encoding visual stimuli along only one dimension, which coherently increased or decreased the activity of the entire population. Activity in all other behaviorally driven dimensions continued unperturbed regardless of sensory stimulation. CONCLUSION The brainwide representation of behavioral variables suggests that information encoded nearly anywhere in the forebrain is combined with behavioral state variables into a mixed representation. We found that these multidimensional signals are present both during ongoing activity and during passive viewing of a stimulus. This suggests that previously reported noise during stimulus presentations may consist primarily of behavioral-state information. What benefit could this ubiquitous mixing of sensory and motor information provide? The most appropriate behavior for an animal to perform at any moment depends on the combination of available sensory data, ongoing motor actions, and purely internal variables such as motivational drives. Integration of sensory inputs with motor actions must therefore occur somewhere in the nervous system. Our data indicate that it happens as early as primary sensory cortex. Large-scale neural population recordings can be predicted from behavior. We used new recording technologies to simultaneously monitor the activity of ~10,000 neurons in a single brain area and ~3000 neurons from across the brain (top left). These neurons showed slow–time scale patterns of coactivation restricted to subsets of neurons which were distributed across the brain (top right). The patterns of neural activity appeared to be driven by specific spontaneous behaviors that the animals engaged in during the experiment. We tracked these spontaneous behaviors by projecting a video recording of the mouse face onto a set of canonical “eigenfaces” (bottom left) and used these projections to predict a large fraction of the neural activity (bottom right). t, time; PC, principal component. Neuronal populations in sensory cortex produce variable responses to sensory stimuli and exhibit intricate spontaneous activity even without external sensory input. Cortical variability and spontaneous activity have been variously proposed to represent random noise, recall of prior experience, or encoding of ongoing behavioral and cognitive variables. Recording more than 10,000 neurons in mouse visual cortex, we observed that spontaneous activity reliably encoded a high-dimensional latent state, which was partially related to the mouse’s ongoing behavior and was represented not just in visual cortex but also across the forebrain. Sensory inputs did not interrupt this ongoing signal but added onto it a representation of external stimuli in orthogonal dimensions. Thus, visual cortical population activity, despite its apparently noisy structure, reliably encodes an orthogonal fusion of sensory and multidimensional behavioral information.

Spontaneous behaviors drive multidimensional, brainwide activity

Calcium imaging is a powerful method to record the activity of neural populations in many species, but inferring spike times from calcium signals is a challenging problem. We compared multiple approaches using multiple datasets with ground truth electrophysiology and found that simple non-negative deconvolution (NND) outperformed all other algorithms on out-of-sample test data. We introduce a novel benchmark applicable to recordings without electrophysiological ground truth, based on the correlation of responses to two stimulus repeats, and used this to show that unconstrained NND also outperformed the other algorithms when run on “zoomed out” datasets of ∼10,000 cell recordings from the visual cortex of mice of either sex. Finally, we show that NND-based methods match the performance of a supervised method based on convolutional neural networks while avoiding some of the biases of such methods, and at much faster running times. We therefore recommend that spikes be inferred from calcium traces using simple NND because of its simplicity, efficiency, and accuracy. SIGNIFICANCE STATEMENT The experimental method that currently allows for recordings of the largest numbers of cells simultaneously is two-photon calcium imaging. However, use of this powerful method requires that neuronal firing times be inferred correctly from the large resulting datasets. Previous studies have claimed that complex supervised learning algorithms outperform simple deconvolution methods at this task. Unfortunately, these studies suffered from several problems and biases. When we repeated the analysis, using the same data and correcting these problems, we found that simpler spike inference methods perform better. Even more importantly, we found that supervised learning methods can introduce artifactual structure into spike trains, which can in turn lead to erroneous scientific conclusions. Of the algorithms we evaluated, we found that an extremely simple method performed best in all circumstances tested, was much faster to run, and was insensitive to parameter choices, making incorrect scientific conclusions much less likely.

Calcium imaging is a powerful method to record the activity of neural populations, but inferring spike times from calcium signals is a challenging problem. We compared multiple approaches using multiple datasets with ground truth electrophysiology, and found that simple non-negative deconvolution (NND) outperformed all other algorithms. We introduce a novel benchmark applicable to recordings without electrophysiological ground truth, based on the correlation of responses to two stimulus repeats, and used this to show that unconstrained NND also outperformed the other algorithms when run on “zoomed out” datasets of ~10,000 cell recordings. Finally, we show that NND-based methods match the performance of a supervised method based on convolutional neural networks, while avoiding some of the biases of such methods, and at much faster running times. We therefore recommend that spikes be inferred from calcium traces using simple NND, due to its simplicity, efficiency and accuracy.

Robustness of spike deconvolution for calcium imaging of neural spiking

Two-photon microscopy of calcium-dependent sensors has enabled unprecedented recordings from vast populations of neurons. While the sensors and microscopes have matured over several generations of development, computational methods to process the resulting movies remain inefficient and can give results that are hard to interpret. Here we introduce Suite2p: a fast, accurate and complete pipeline that registers raw movies, detects active cells, extracts their calcium traces and infers their spike times. Suite2p runs on standard workstations, operates faster than real time, and recovers ~2 times more cells than the previous state-of-the-art method. Its low computational load allows routine detection of ~10,000 cells simultaneously with standard two-photon resonant-scanning microscopes. Recordings at this scale promise to reveal the fine structure of activity in large populations of neurons or large populations of subcellular structures such as synaptic boutons.

Suite2p: beyond 10,000 neurons with standard two-photon microscopy

Cortical networks exhibit intrinsic dynamics that drive coordinated, large-scale fluctuations across neuronal populations and create noise correlations that impact sensory coding. To investigate the network-level mechanisms that underlie these dynamics, we developed novel computational techniques to fit a deterministic spiking network model directly to multi-neuron recordings from different species, sensory modalities, and behavioral states. The model generated correlated variability without external noise and accurately reproduced the wide variety of activity patterns in our recordings. Analysis of the model parameters suggested that differences in noise correlations across recordings were due primarily to differences in the strength of feedback inhibition. Further analysis of our recordings confirmed that putative inhibitory neurons were indeed more active during desynchronized cortical states with weak noise correlations. Our results demonstrate that network models with intrinsically-generated variability can accurately reproduce the activity patterns observed in multi-neuron recordings and suggest that inhibition modulates the interactions between intrinsic dynamics and sensory inputs to control the strength of noise correlations.

Inhibitory control of correlated intrinsic variability in cortical networks

dynamical systems [Curto et al., 2009] or probabilistic frameworks in which variability is modelled as stochastic and correlated variability arises through abstract latent variables whose origin is assumed to lie either in unspecified circuit processes [Ecker et al., 2014, Macke et al., 2011, Pachitariu et al., 2013] or elsewhere in the brain [Goris et al., 2014, de la Rocha et al., 2007]. While these models are able to accurately reproduce many features of cortical activity and provide valuable summaries of the phenomenological and computational properties of cortical networks, their parameters are difficult to interpret at a biophysical level. One alternative to these abstract stochastic models is a biophysical spiking network, which can generate variable neural activity through chaotic amplification of different initial conditions [van Vreeswijk and Sompolinsky, 1996, Amit and Brunel, 1997, Renart et al., 2010, Litwin-Kumar and Doiron, 2012, Wolf et al., 2014]. These networks can be designed to have interpretable parameters, but have not yet been fit directly to multi-neuron recordings and, thus, their use has been limited to attempts to explain qualitative features of cortical dynamics through manual tuning of network parameters. This approach has revealed a number of different network features that are capable of controlling dynamics, such as clustered connectivity [Litwin-Kumar and Doiron, 2012], synaptic coupling strength [Ostojic, 2014], or adaptation currents [Latham et al., 2000, Destexhe, 2009], but the inability to fit the networks directly to recordings has made it difficult to identify which network features play an important role in vivo. To overcome this limitation, we used a novel computational approach that allowed us to fit a spiking network directly to individual multi-neuron recordings. By taking advantage of the computational power of graphics processing units (GPUs), we were able to sample from the network with millions of different parameter values to find those that best reproduced the activity in a given recording. We developed a biophysical spiking network with intrinsic variability and a small number of parameters that was able to capture the apparently doubly chaotic structure of cortical activity [Churchland and Abbott, 2012]. Like classical excitatory-inhibitory networks, the model generates deterministic microscopic trial-totrial variability in the spike times of individual neurons [van Vreeswijk and Sompolinsky, 1996], as well as 3 peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/041103 doi: bioRxiv preprint first posted online Feb. 24, 2016;

Inhibitory control of correlated variability in cortical networks

The combination of two-photon microscopy recordings and powerful calcium-dependent fluorescent sensors enables simultaneous recording of unprecedentedly large populations of neurons. While these sensors have matured over several generations of development, computational methods to process their fluorescence remain inefficient and the results hard to interpret. Here, we introduce a set of practical methods based on novel clustering algorithms, and provide a complete pipeline from raw image data to neuronal calcium traces to inferred spike times. We formulate a generative model of the fluorescence image, incorporating spike times and a spatially smooth neuropil signal, and solve the inference and learning problems using a fast algorithm. This implementation scales linearly with the number of recorded cells, and the complete pipeline runs in approximately one hour for typical two-hour long recordings, on commodity GPUs. Furthermore, this method recovers twice as many cells as a previous standard method. This allowed us to routinely record and detect ∼10,000 cells simultaneously from the visual cortex of awake mice using standard two-photon resonant-scanning microscopes. The software is publicly available at github.com/cortex-lab/Suite2P, together with a graphical user interface that allows rapid manual curation of the results.

Suite 2 p : beyond 10 , 000 neurons with standard two-photon microscopy

Changes in inhibition explain variability in cortical activity and its role in sensory representations.

There are an estimated 1.7 million Americans living with limb loss; further, spinal cord injuries afflict 250,000 Americans [1]. Many patients lose their jobs and their quality of life plummets. Fortunately there have been significant advancements in the design of prosthetic limbs in the last few decades. A noteworthy achievement is the direct integration of a prosthetic device with the brain, termed a neuroprosthesis device. An electrode is implanted in the brain of the patient which records the electrical activity of the neurons associated with motor movement and controls the prosthetic device. These have been successfully implemented for simple upper limb movements [2]. However, efficient and cost-effective lower limb prosthetic devices have not yet appeared on the market. Investigating passive dynamic walking determines the extent to which the natural human gait depends on passive dynamics. More efficient prosthetic models can be developed from these principles. A thorough mathematical investigation of passive dynamic walking is necessary to replicate the stability of the human locomotor system. This requires an understanding of the physical basis of walking and an understanding of the biological processes underlying motor movement. The first model investigated was a passive walking model based on a double pendulum which exhibits a single stable periodic solution. The robustness of this solution was investigated as the angle of incline and the weights of the feet were varied. Continuation of the solution was also performed as the incline angle and mass distribution were continuously varied. The second model investigated was a passive walking model with rockers on its feet, which rolled without slipping on the surface. McGeer terms it the ”walking wheel” [5]. This model’s regions of stability were much larger than those of the simple pendulum model.

Equilibrium formally can be represented as an ensemble of uncoupled systems undergoing unbiased dynamics in which detailed balance is maintained. Many nonequilibrium processes can be described by suitable subsets of the equilibrium ensemble. Here, we employ the “weighted ensemble” (WE) simulation protocol [Huber and Kim, Biophys. J.1996, 70, 97–110] to generate equilibrium trajectory ensembles and extract nonequilibrium subsets for computing kinetic quantities. States do not need to be chosen in advance. The procedure formally allows estimation of kinetic rates between arbitrary states chosen after the simulation, along with their equilibrium populations. We also describe a related history-dependent matrix procedure for estimating equilibrium and nonequilibrium observables when phase space has been divided into arbitrary non-Markovian regions, whether in WE or ordinary simulation. In this proof-of-principle study, these methods are successfully applied and validated on two molecular systems: explicitly solvated methane association and the implicitly solvated Ala4 peptide. We comment on challenges remaining in WE calculations.

Simultaneous Computation of Dynamical and Equilibrium Information Using a Weighted Ensemble of Trajectories

Equilibrium Sampling using a Weighted Ensemble of Dynamical Trajectories

REASONS FOR PERFORMING STUDY
Water treadmill exercise is often incorporated into rehabilitation programmes for horses yet little is known about the biomechanical and physiological responses to water walking.

To establish whether stride frequency (SF) reached steady state as a result of 6 introductory water treadmill sessions and then to investigate the effect of increasing water height on SF, stride length (SL) and heart rate (HR).

METHODS
Nine horses with no previous experience of water treadmills completed 6 sessions of walking for between 15 and 30 min. Each horse was fitted with a leg mounted accelerometer to measure SF. The effect of session on SF was tested using univariate ANOVA. Eight horses completed 3 further sessions at each of the following water heights; proximal interphalangeal joint (PIP), carpus and ulna. SF, SL and HR at each water height were compared to a control (hoof height) using univariate ANOVA.

RESULTS
When SF during introductory sessions 4-6 were compared, there was no significant effect of session on SF (P > 0.05). In the second part of the experiment, SF was 0.57 ± 0.03 strides/s at control, 0.54 ± 0.03 strides/s at the PIP joint, 0.51 ± 0.02 strides/s at the carpus and 0.52 ± 0.03 strides/s at the ulna. Stride frequency at carpal and ulna height was significantly lower than at control (P < 0.05). Stride length was 1.53 ± 0.09 m for control, 1.63 ± 0.10 m at the PIP joint, 1.71 ± 0.08 m at the carpus and 1.68 ± 0.10 m at the ulna. Stride length at carpal and ulna height was significantly greater than control (P < 0.05). There was no significant difference between HR during control and any other water height (P > 0.05).

Horses reached steady state gait within the first 6 sessions of water treadmill exercise. Walking in water at the level of the carpus or ulna resulted in a lower SF compared to walking in water at hoof height.

The effect of water height on stride frequency, stride length and heart rate during water treadmill exercise.

Quaternary ammonium compounds (QACs) are vital disinfectants for the neutralization of pathogenic bacteria in clinical, domestic, and commercial settings. After decades of dependence on QACs, the emergence of antimicrobial resistance to this class of compounds threatens the ability of existing QAC products to effectively manage rising bacterial threats. The need for new disinfectants is therefore urgent, with quaternary phosphonium compounds (QPCs) emerging as a new class of promising antimicrobials that boast significant activity against highly resistant bacteria. Reported here is a series of twenty-one novel QPCs that replace phenyl substituents on the phosphorus center with alkyl groups yet allow for rapid synthetic routes in high yields. Within this series are structures containing methyl, ethyl, or cyclohexyl phosphonium substituents on bisphosphane scaffolds bearing ethyl linkers, affording atom economical structures and ones that represent exact analogs to nitrogenous amphiphiles. The resultant bisQPC structures display high antibacterial efficacy enjoyed by comparably constructed QACs, with three structures in the single-digit micromolar activity range despite structural simplification.

Atom Economical QPCs: Phenyl-Free Biscationic Quaternary Phosphonium Compounds as Potent Disinfectants

Designing molecules with desired biological properties remains an outstanding challenge both in the wet and dry laboratories. Meeting this challenge promises great translational impacts across drug discovery, material sciences, biotechnology, and more. Recent momentum in deep learning promises to advance our computational capabilities on molecule generation. In particular, deep graph generative models which treat molecule design as a graph generation problem are allowing us to directly learn from existing databases of small molecules and generate novel, valid molecules. Currently, these models have many shortcomings, including poor controllability of desired molecular properties, especially in practical application where the training data is usually small, noisy, and incomplete. This paper focuses on equipping graph variational autoencoders with the ability to control for desired properties and its practical application in a practical application which is the generation of Quaternary Ammonium Compounds (QAC). Several controllable graph generation mechanisms are investigated for their effectiveness. A general framework is then proposed to extend these mechanisms by our newly proposed objective function to handle the challenges in practical applications where the property value annotations are usually censored and not fully available in all training samples. The experimental evaluation considers an experimentally-characterized dataset of antimicrobial small molecules with wet-lab characterized activity against antibiotic-resistant bacteria. Extensive experiments demonstrate the superiority of the proposed models and control of desired properties.

2022 IEEE International Conference on Bioinformatics and Biomedicine (BIBM)

Property-Controllable Generation of Quaternary Ammonium Compounds

Quaternary ammonium compounds (QACs) serve as mainstays in the formulation of disinfectants and antiseptics. However, an over-reliance and misuse of our limited QAC arsenal has driven the development and spread of resistance to these compounds, as well as co-resistance to common antibiotics. Extensive use of these compounds throughout the COVID-19 pandemic thus raises concern for the accelerated proliferation of antimicrobial resistance and demands for next-generation antimicrobials with divergent architectures that may evade resistance. To this end, we endeavored to expand beyond canonical ammonium scaffolds and examine quaternary phosphonium compounds (QPCs). Accordingly, a synthetic and biological investigation into a library of novel QPCs unveiled biscationic QPCs to be effective antimicrobial scaffolds with improved broad-spectrum activities compared to commercial QACs. Notably, a subset of these compounds was found to be less effective against a known QAC-resistant strain of MRSA. Bioinformatic analysis revealed the unique presence of a family of small multiresistant transporter proteins, hypothesized to enable efflux-mediated resistance to QACs and QPCs. Further investigation of this resistance mechanism through efflux-pump inhibition and membrane depolarization assays illustrated the superior ability of P6P-10,10 to perturb the cell membrane and exert the observed broad-spectrum potency compared to its commercial counterparts. Collectively, this work highlights the promise of biscationic phosphonium compounds as next-generation disinfectant molecules with potent bioactivities, thereby laying the foundation for future studies into the synthesis and biological investigation of this nascent antimicrobial class.

Quaternary Phosphonium Compounds: An Examination of Non-Nitrogenous Cationic Amphiphiles That Evade Disinfectant Resistance.

Activity characterization, optimization, and generation of small molecules are increasingly active areas of research at the intersection of molecular chemistry and machine learning. Large datasets of small molecules have allowed training deep models that have been shown capable of exploring the underlying chemical space and generating valid, novel, and unique molecules. While this is a noteworthy achievement, what impedes operationalizing these models in the wet laboratory is the ability to link the chemical and biological space of small molecules. A central challenge to this is the lack of activity data on these entities. In this paper we relate a computational pipeline that permits linking the chemical and biological space of an important class of small molecules, quaternary ammonium compounds (QACs). Our experimental collaborators have characterized the activity of many QACs against Staphylococcus aureus. We train various generative models and evaluate their ability to generate valid, novel, and unique QACs. We then leverage classification models trained over activity data to evaluate the generated QACs. The resulting pipeline identifies valid, novel, unique, membrane-active QACs. This work opens the way to further avenues of research in machine learning models capable of jointly sampling the chemical and biological space of small molecules.

Generation and Characterization of Quaternary Ammonium Compounds via Deep Learning

Background Aromatase inhibitors (AIs) are recommended as adjuvant treatment for estrogen-receptor positive breast carcinoma in postmenopausal women. Studies demonstrate mixed results as to the impact of AIs on cardiovascular (CV) events and overall survival. With the increasing number of pre- and postmenopausal women on AIs for five to ten years, understanding the long-term impact of AIs on blood vessels and CV risk in cancer survivors is vital. Methods A single arm longitudinal study of 14 postmenopausal women with ER+ breast cancer prescribed adjuvant AIs at the University of Minnesota. Subjects with a history of tobacco use, hypertension, or hyperlipidemia were excluded. Participants underwent routine labs, blood pressure assessments, and vascular testing at baseline (prior to starting AIs) and at six months. Vascular assessment was performed using the EndoPAT 2000 and HDI/PulseWave CR-2000 Cardiovascular Pro ling System and pulse contour analysis on two occasions as previously described. Vascular measurements were conducted by one trained vascular technician. Assessments were performed in triplicate, and the mean indices were used for analyses. All subjects were on an AI at the follow-up visit. The protocol was approved by the UMN Institutional Review Board and all participants were provided written informed consent. Baseline and follow-up characteristics were compared using Wilcoxon signed-rank tests. Analyses were performed using R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria). Results After six months of AI treatment, EndoPAT® ratio declined to a median 1.12 (Q1: 0.85, Q3: 1.86; p=0.045) and median estradiol levels decreased to 2 pg/mL (Q1: 2, Q3: 3; p=0.052). There was no evidence of association between change in EndoPAT® and change in estradiol level (p=0.91). There were no statistically significant changes in small or large arterial elasticity. Conclusion Endovascular dysfunction is an early sign for atherosclerosis and vascular impairment. This study suggests that postmenopausal breast cancer survivors on aromatase inhibitor therapy develop endothelial dysfunction as early as six months which is a predictor of adverse CV disease. We hypothesize that long-term use of AIs can lead to persistent endothelial dysfunction. It is unclear if these changes are reversible once AI use is discontinued and further investigation is necessary.

Endothelial Dysfunction in Breast Cancer Survivors on Aromatase Inhibitors: Changes over Time

Simple Summary When ovarian cancer is detected early, the survival rate is high. Unfortunately, existing blood tests are neither sensitive nor specific enough to screen women for ovarian cancer. The purpose of this study was to determine the levels of 92 cancer-related proteins in the blood of women with ovarian cancer compared to healthy women in order to develop a test for ovarian cancer detection. We tested the blood of more than 400 women and identified four proteins that, when combined, successfully detected over 90% of the women with ovarian cancer. We then tested more than 700 additional blood samples and found that the combination of the four proteins successfully distinguished the majority of the blood samples from women with both early and late stages of ovarian cancer compared to healthy women. These four proteins show promise in the development of a test to detect the early stages of ovarian cancer. Abstract Background: Individual serum biomarkers are neither adequately sensitive nor specific for use in screening the general population for ovarian cancer. The purpose of this study was to develop a multiprotein classifier to detect the early stages of ovarian cancer, when it is most treatable. Methods: The Olink Proseek Multiplex Oncology II panel was used to simultaneously quantify the expression levels of 92 cancer-related proteins in sera. Results: In the discovery phase, we generated a multiprotein classifier that included CA125, HE4, ITGAV, and SEZ6L, based on an analysis of sera from 116 women with early stage ovarian cancer and 336 age-matched healthy women. CA125 alone achieved a sensitivity of 87.9% at a specificity of 95%, while the multiprotein classifier resulted in an increased sensitivity of 91.4%, while holding the specificity fixed at 95%. The performance of the multiprotein classifier was validated in a second cohort comprised of 192 women with early stage ovarian cancer and 467 age-matched healthy women. The sensitivity at 95% specificity increased from 74.5% (CA125 alone) to 79.2% with the multiprotein classifier. In addition, the multiprotein classifier had a sensitivity of 95.1% at 98% specificity for late stage ovarian cancer samples and correctly classified 80.5% of the benign samples using the 98% specificity cutpoint. Conclusions: The inclusion of the proteins HE4, ITGAV, and SEZ6L improved the sensitivity and specificity of CA125 alone for the detection of early stages of ovarian cancer in serum samples. Furthermore, we identified several proteins that may be novel biomarkers of early stage ovarian cancer.

Development of a Multiprotein Classifier for the Detection of Early Stage Ovarian Cancer

Surveillance for environmental contamination of antineoplastic drugs has been recommended by authoritative bodies such as the United States Pharmacopeia and the National Association of Pharmacy Regulatory Authorities. Clear guidance is needed on how to develop sampling strategies that align with surveillance objectives efficiently and effectively. We conducted a series of simulations using previously collected surveillance data from nine cancer treatment centers to evaluate different sampling strategies. We evaluated the impact of sampling 2, 5, 10, or 20 surfaces, at monthly, quarterly, semi-annual, and annual frequencies, while employing either a random or sentinel surface selection strategy to assess contamination by a single antineoplastic drug (AD) or by a panel of three ADs. We applied two different benchmarks: a binary benchmark of above or below the limit of detection and AD-specific hygienic guidance values, based on 90th percentile values as quantitative benchmarks. The use of sentinel surfaces to evaluate a three-drug panel relative to 90th percentile hygienic guidance values (HGVs) resulted in the most efficient and effective surveillance strategy.

Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners

Developing wipe sampling strategy guidance for assessing environmental contamination of antineoplastic drugs.

Differentiation of human induced pluripotent stem cells (hiPSCs) generates cell phenotypes valuable for cell therapy and personalized medicine. Successful translation of these hiPSC-derived therapeutic products will rely upon effective cryopreservation at multiple stages of the manufacturing cycle. From the perspective of cryobiology, we attempted to understand how the challenge of cryopreservation evolves between cell phenotypes along an hiPSC-to-sensory neuron differentiation trajectory. Cells were cultivated at three different stages to represent intermediate, differentiated, and matured cell products. All cell stages remained ≥90% viable in a dimethyl sulfoxide (DMSO)-free formulation but suffered ≥50% loss in DMSO before freezing. Raman spectroscopy revealed higher sensitivity to undercooling in hiPSC-derived neuronal cells with lower membrane fluidity and higher sensitivity to suboptimal cooling rates in stem cell developmental stages with larger cell bodies. Highly viable and functional sensory neurons were obtained following DMSO-free cryopreservation. Our study also demonstrated that dissociating adherent cultures plays an important role in the ability of cells to survive and function after cryopreservation.

Differentiation of Human iPS Cells Into Sensory Neurons Exhibits Developmental Stage-Specific Cryopreservation Challenges

The impact of using adjuvant chemotherapy following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with appendiceal adenocarcinoma is not known. The aim of this study was to assess the impact of adjuvant chemotherapy following complete cytoreduction in patients with appendiceal adenocarcinoma.

Impact of adjuvant chemotherapy on outcomes in appendiceal cancer

The two bes- known ovarian cancer biomarkers, CA125 and HE4, are neither adequately sensitive nor specific to be used to screen the general population for early stages of ovarian cancer. The purpose of this study was to develop a multiprotein classifier that would combine additional protein biomarkers with CA125 and HE4 in order to increase their sensitivity and specificity. We used the Olink Proseek Multiplex Oncology II panel to simultaneously quantify the expression levels of 92 cancer-related proteins using proximity extension assay technology. We analyzed serum from two institutions: 143 women with early-stage (I/II) ovarian cancer (serous, endometrioid, clear-cell, mucinous, and others) and compared the values obtained to 341 age-matched healthy women. We identified 24 proteins whose relative expression between cancers and controls was significantly different between the samples from the two institutions; therefore, we removed these proteins from downstream analysis. Principle Component Analysis and T-distributed Stochastic Neighbor Embedding separated the ovarian cancer samples from the healthy controls, with minimal misclassification. Data from the Proseek plates for CA125 levels exhibited a strong correlation with previously measured clinical values for CA125 (correlation coefficient of 0.81). CA125 and HE4 were detected at low levels in samples from healthy women, while higher levels were observed in the early-stage ovarian cancer cases. We identified 31 proteins that differed significantly (p Citation Format: Amy P. Skubitz, Kristin L. Boylan, Timothy K. Starr, Xuan Pu, Qing Cao, Kate Geschwind, Robert C. Bast, Jr., Karen H. Lu, Joseph Celestino, Ashley J. Petersen. A serum protein biomarker signature for the detection of early stages of ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B43.

Abstract B43: A serum protein biomarker signature for the detection of early stages of ovarian cancer

Abstract P1-12-06: Endothelial dysfunction in breast cancer survivors on aromatase inhibitors (AIs) over time

The increased treatment of metastatic castration-resistant prostate cancer (mCRPC) with second-generation antiandrogen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost dependence on androgen receptor (AR) signaling. These AR-independent tumors may also transdifferentiate to express neuroendocrine lineage markers and are termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing several AR-independent to AR-dependent prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-independent cell lines. Clinical NEPC patient samples and NEPC patient-derived xenografts displayed upregulated RET transcript and RET pathway activity. Genetic knockdown or pharmacologic inhibition of RET kinase in multiple mouse and human models of NEPC dramatically reduced tumor growth and decreased cell viability. Our results suggest that targeting RET in NEPC tumors with high RET expression could be an effective treatment option. Currently, there are limited treatment options for patients with aggressive neuroendocrine prostate cancer and none are curative. Implications: Identification of aberrantly expressed RET kinase as a driver of tumor growth in multiple models of NEPC provides a significant rationale for testing the clinical application of RET inhibitors in patients with AVPC.

e12525Background: AIs reduce breast cancer-related mortality however they may increase cardiovascular (CV) risk. We previously presented data demonstrating women on AIs have endothelial dysfunction, a measure of increased CV risk. Here, we present data of AIs on endothelial function over time. Methods: 19 healthy women (controls) and 18 women with locally advanced breast cancer and taking an AI (cases) underwent vascular testing at baseline and > 6 months (median follow up 7 months controls, 24 months cases). Subjects with tobacco use, hypertension or hyperlipidemia were excluded. Consented subjects underwent biomarker analysis and radial artery pulse wave analysis using the HDI/Pulse Wave CR-2000 CV Profiling System and pulse contour analysis using the Endo-PAT2000 system. Reductions in EndoPAT ratio, small artery elasticity (SAE) and large artery elasticity (LAE) are associated with worsening endothelial dysfunction. Functional test markers were compared between cases and controls using Wilcoxon Rank-Su...

Longitudinal follow-up of endothelial function in breast cancer survivors on aromatase inhibitors (AIs).

Developing an In Vitro System to Mimic the Natural Germinal Center Reaction an Ovine and Human Model

PURPOSE
Clinical studies suggest that carcinoembryonic antigen (CEA) is associated with metastatic progression of colon cancer. However, the biological function of CEA is not well understood. We have established an approach that allows studying of CEA function within the intact pathophysiological context of human colon cancer cells.

EXPERIMENTAL DESIGN
We expressed CEA-targeted ribozymes under control of a tet-off promoter system in human HT29 colon cancer cells. This approach allows regulation of CEA levels on the mRNA and protein level by 50% and enables screening analysis of CEA-mediated changes of gene expression by cDNA microarray analysis.

RESULTS
Comprehensive analysis of 273 genes revealed that CEA affects expression of various groups of cancer-related genes, in particular cell cycle and apoptotic genes. Although cell cycle gene expression showed a balanced bidirectional dysregulation, apoptotic genes were unidirectionally down-regulated by CEA. In parallel phenotypic studies, CEA did not affect cell cycle or proliferation rate. However, CEA significantly protected HT29 cells from undergoing apoptosis under various conditions, including confluent growth, UV light, IFN-gamma treatment, and treatment with 5-fluorouracil.

Our study suggests that CEA has an important regulatory role in apoptosis, and we propose that CEA is a survival factor for colon cancer cells.

Controlled ribozyme targeting demonstrates an antiapoptotic effect of carcinoembryonic antigen in HT29 colon cancer cells.

Health halo effects are a form of biased processing, wherein a particular product claim bleeds over to other categories of analysis or to an overall healthier impression. This study tests whether the term tobacco-free nicotine triggers a health halo effect. Through an experiment with middle school youth (n = 599), we vary the flavor (tobacco vs. fruit) and nicotine source information (nicotine/tobacco-free nicotine/nicotine from tobacco) on the warning label of the vaping product participants viewed. We evaluate product measures (nicotine content beliefs, nicotine source beliefs, and risk perceptions) and comparative nicotine source misperceptions (addictiveness, safety, and risk). Findings show that the term tobacco-free nicotine triggers inaccurate nicotine content beliefs, nicotine source beliefs, and misperceptions associated with addictiveness, safety, and risk. We conclude with theoretical and regulatory implications.

Tobacco Free Nicotine Vaping Products: A Study of Health Halo Effects Among Middle School Youth

Minimal Detectable Width of Tooth Fractures Using Magnetic Resonance Imaging and Method to Measure.

The health risks of exposure to antineoplastic drugs (ADs) are well established, and healthcare professionals can be exposed while caring for cancer patients receiving AD therapy. Studies conducted worldwide over the past two decades indicate continuing widespread surface contamination by ADs. No occupational exposure limits have been established for ADs, but concerns over exposures have led to the development of guidelines, such as United States Pharmacopeia (USP) General Chapter <800> Hazardous Drugs-Handling in Healthcare. While recommending regular surveillance for surface contamination by ADs these guidelines do not provide guidance on sampling strategies. Better characterization of spatial and temporal variability of multidrug contamination would help to inform such strategies. We conducted surface-wipe monitoring of nine cancer care centers in Alberta, Canada and Minnesota, USA, with each center sampled eight times over a 12-month period. Twenty surfaces from within pharmacy and drug administration areas were sampled, and 11 drugs were analyzed from each wipe sample. Exposure data were highly left-censored which restricted data analysis; we examined prevalence of samples above limit of detection (LOD), and used the 90th percentile of the exposure distribution as a measure of level of contamination. We collected 1984 wipe samples over a total of 75 sampling days resulting in 21 824 observations. Forty-five percent of wipe samples detected at least one drug above the LOD, but only three of the drugs had more than 10% of observations above the LOD: gemcitabine (GEM) (24%), cyclophosphamide (CP) (16%), and paclitaxel (13%). Of 741 wipe samples with at least one drug above LOD, 60% had a single drug above LOD, 19% had two drugs, and 21% had three drugs or more; the maximum number of drugs found above LOD on one wipe was 8. Surfaces in the compounding area of the pharmacy and in the patient area showed the highest prevalence of samples above the LOD, including the compounding work surface, drug fridge handle, clean room cart, passthrough tray, and hazardous drug room temperature storage, the IV pump keypad, patient washroom toilet handle, patient washroom door handle, nurses' storage shelf/tray, and patient side table. Over the course of the study, both 90th percentiles and prevalence above LOD varied without clear temporal patterns, although some centers appeared to show decreasing levels with time. Within centers, the degree of variability was high, with some centers showing changes of two to three orders of magnitude in the 90th percentile of drug concentrations month to month. A clear difference was observed between the six centers located in Alberta and the three in Minnesota, with Minnesota centers having substantially higher percentages of samples above the LOD for CP and GEM. Other factors that were associated with significant variability in exposures were drug compounding volume, size of center, number of patients seen, and age of the center. We hope that demonstrating variability associated with drug, surface, clinic-factors, and time will aid in a better understanding of the nature of AD contamination, and inform improved sampling strategies.

Spatial and Temporal Variability in Antineoplastic Drug Surface Contamination in Cancer Care Centers in Alberta and Minnesota.

Bupropion for postpartum smoking relapse: A remote protocol for a two-arm, double-blind, placebo-controlled randomized clinical trial.

Clinical presentation of oromandibular dystonia (OMD) is variable that can be further complicated by the presence of temporomandibular disorder (TMD) symptoms. We sought to evaluate variations in the clinical presentation of OMD patients, particularly TMD-related characteristics, in two clinical settings.

METHODS
In a cross-sectional study design, a Web-based data collection survey was provided to eligible patients with OMD from movement disorder (MD) and oro-facial pain (OFP) clinics. The survey questionnaire was designed to collect information on demographic characteristics, clinical presentation particularly related to TMD, quality of life and treatment outcomes. Validated questionnaires were used when available such as the TMD Pain Screener, EuroQol 5-Dimensions 5-Levels (EQ-5D-5L), Jaw Functional Limitation Scale and Global Rating of Change Scale.

RESULTS
Of 53 eligible patients, 31 responded to the survey for a 58% response rate. Forty-eight per cent of patients in the MD clinic and 60% of patients in the OFP clinic reported jaw pain along with involuntary movements. Of those, 90% from the MD group and 83% from the OFP group screened positive with the TMD Pain Screener at the onset of symptoms based on recall. Positive TMD Pain Screener response was observed in about 40% of patients in both clinics within 30 days of questionnaire response. No statistically significant differences were observed between two groups for any measured variables.

Patients with OMD have features of TMD, irrespective of the clinical setting in which they seek and receive care. OMD patients from both clinics were similar in terms of clinical presentation, quality of life and treatment outcomes.

Temporomandibular disorder-related characteristics and treatment outcomes in Oromandibular Dystonia patients in two different clinical settings: A cross-sectional study.

Purpose: Obstructive sleep apnea (OSA) is a common breathing disorder; however, many individuals remain undiagnosed. The purpose of this study was to assess the comfort level of community-dwelling adults to participate in OSA screening in a dental office setting and survey the OSA risk levels of an adult population.Methods: This cross-sectional study was conducted among adults presenting at the University of Minnesota Driven to Discover Research Facility during the 2018 Minnesota State Fair. Participants completed a brief survey including the eight-item STOP-Bang questionnaire for OSA screening. Electronic tablets were used for data capture. Data analyses included descriptive statistics, t-tests, and Chi-square tests.Results: A total of 639 adults met the survey inclusion criteria (n=639). The majority of participants (88%) reported no prior OSA diagnosis. Based on STOP-Bang criteria, 61% (n=344) of the participants were at low, 29% (n=161) intermediate, and 10% (n= 56) high risk of OSA. A majority (64%) of participants reported being either "comfortable" or "very comfortable'"with OSA screening performed in a dental office setting.Conclusion: Over one third of participants with no prior OSA diagnosis were at moderate to high risk for OSA, and the majority stated that they would be comfortable undergoing OSA screening in a dental office setting. Dental hygienists screening patients for OSA with the STOP-BANG questionnaire are likely to have a high level of patient acceptance. Referring patients to the appropriate health care provider for further testing may increase timely diagnoses and treatment of OSA.

Acceptance of Dental Office Obstructive Sleep Apnea Screening among Minnesota State Fair Attendees.

Abstract Objective: Examine pre-existing learning disorders (LD) and attention deficit/hyperactivity disorders (ADHD) as risk factors for prolonged recovery and increased symptomology following pediatric mild traumatic brain injury (mTBI). Methods: We conducted a retrospective cohort study of children/adolescents (5-17 years) with mTBI who presented to a Children’s Minnesota Concussion Clinic between April 2018 and March 2019. Differences across strata of pre-existing conditions (present vs. absent) in time to recovery measures were estimated via Kaplan–Meier and Cox proportional hazards analyses and differences in symptom trajectories were examined via linear mixed-effects regression models. Regression models were adjusted for age, sex and other confounders. Results: In our cohort of 680 mTBI patients, those with LD (n = 70) or ADHD (n = 107) experienced significantly longer median durations of symptoms (58 and 68 days, respectively) than those without (43 days). Accordingly, LD was significantly associated with delayed symptom recovery (adjusted hazard ratio (aHR) = 1.63, 95% CI: 1.16–2.29), return to school (1.47, 1.08–2.00), and return to physical activity (1.50, 1.10–2.04). Likewise, ADHD was associated with delayed recovery (1.69, 1.28–2.23), return to school (1.52, 1.17–1.97) and physical activity (1.55, 1.19–2.01). Further, patients with LD or ADHD reported, on average, significantly more concussion symptoms and higher vision symptom scores throughout recovery versus those without. There was no evidence that concussion or vision symptom recovery trajectories varied over time between those with/without LD or ADHD (joint P-interactions > 0.05). Conclusion: Pre-existing LD and ADHD are risk factors for prolonged and more symptomatic mTBI recovery in youth. These results can inform clinical concussion management and recovery expectations.

Learning and Attention Deficit/Hyperactivity Disorders as Risk Factors for Prolonged Concussion Recovery in Children and Adolescents

Introduction Racial and socioeconomic disparities in health access and outcomes for many conditions is well known. However, for time-sensitive high-acuity diseases such as traumatic injuries, disparities in access and outcomes should be significantly diminished. Our primary objective was to characterize racial disparities across majority, mixed-race, and minority hospitals for African American ([AA] vs White) males with high-grade splenic injuries. Methods Data from the National Trauma Data Bank were utilized from 2007 to 2015; 24 855 AA or White males with high-grade splenic injuries were included. Multilevel mixed-effects regression analysis was used to evaluate disparities in outcomes and resource allocation. Results Mortality was significantly higher for AA males at mixed-race (OR 1.6; 95% CI 1.3-2.1; P < .001) and minority (OR 2.1; 95% CI 1.5-3.0; P < .001) hospitals, but not at majority hospitals. At minority hospitals, AA males were significantly less likely to be admitted to the intensive care unit (OR 0.7; 95% CI, 0.49-0.97; P = .04) and experienced a significantly longer time to surgery (IRR 1.5; P = .02). Minority hospitals were significantly more likely to have failures from angiographic embolization requiring operative intervention (OR 2.2, P = .009). At both types of nonmajority hospitals, AA males with penetrating injuries were more likely to be managed with angiography (mixed-race hospitals: OR 1.7; P = .046 vs minority hospitals: OR 1.6; P = .08). Discussion While multiple studies have shown that minority hospitals have increased mortality compared to majority hospitals, this study found this disparity only existed for AAs.

The role of subjective responses in electronic cigarette uptake and substitution in adult smokers.

Introduction Racial and socioeconomic disparities in health access and outcomes for many conditions are well known. However, for time-sensitive high-acuity diseases such as traumatic injuries, disparities in access and outcomes should be significantly diminished. Our primary objective was to characterize racial disparities across majority, mixed-race, and minority hospitals for African American (AA) versus white males with high-grade splenic injuries. Methods Data from the National Trauma Data Bank was utilized from 2007 to 2015. A total of 24 855 AA or white males with high-grade splenic injuries were included. Multilevel mixed effects regression analysis was used to evaluate disparities in outcomes and resource allocation. Results Mortality was significantly higher for AA males at mixed-race (odds ratio [OR] 1.6; 95% CI 1.3-2.1; P < .001) and minority (OR 2.1; 95% CI 1.5-3.0; P < .001) hospitals, but not at majority hospitals. At minority hospitals, AA males were significantly less likely to be admitted to the intensive care unit (OR 0.7; 95% CI 0.49-0.97; P = .04) and experienced a significantly longer time to surgery (IRR 1.5; P = .02). Minority hospitals were significantly more likely to have failures from angiographic embolization requiring operative intervention (OR 2.2; P = .009). At both types of nonmajority hospitals, AA males with penetrating injuries were more likely to be managed with angiography (mixed-race hospitals: OR 1.7; P = .046 vs minority hospitals: OR 1.6; P = .08). Discussion While multiple studies have shown that minority hospitals have increased mortality compared to majority hospitals, this study found this disparity only existed for AAs.

Racial Disparities at Mixed-Race and Minority Hospitals: Treatment of African American Males With High-Grade Splenic Injuries

Impact of gastroesophageal reflux on longitudinal lung function and quantitative computed tomography in the COPDGene cohort

Objective To examine pre-existing anxiety disorders as a risk factor for increased concussion symptomology and prolonged recovery in children and adolescents. Methods In this retrospective cohort study, we abstracted medical record data for 637 children/adolescents (5–17 years) presenting to three tertiary concussion clinics between April 2018 and March 2019. Primary outcomes were mean concussion symptom and vision symptom severity scores measured at clinic visits. Linear mixed-effects regression models were employed to investigate differences in average symptom load, vision symptom score and symptom recovery trajectories across anxiety strata, adjusted for random effects (time), age and sex. Secondary outcomes, time to concussion symptom recovery and time to return to academics and sports, respectively, were examined via log-rank tests and multivariable Cox regression. Results Among 637 eligible concussion patients, 155 (24%) reported pre-existing anxiety. On average, patients with anxiety reported an additional 2.64 (95% CI 1.84 to 3.44) concussion symptoms and 7.45 (95% CI 5.22 to 9.68) higher vision symptom severity scores throughout recovery versus those without, after adjusting for age and sex. There was no evidence that concussion or vision symptom trajectories varied over time between those with/without anxiety after accounting for baseline dissimilarities in symptom scores (all pinteraction >0.05). Anxiety was significantly associated with delayed symptom recovery (adjusted HR 3.34, 95% CI 2.18 to 5.12), return to school (adjusted HR 2.01, 95% CI 1.59 to 2.53) and return to physical activity (adjusted HR 1.88, 95% CI 1.49 to 2.37). Conclusions Pre-existing anxiety disorders were associated with more severe symptomology and prolonged recovery after concussion in children and adolescents. These results can be referenced by providers to manage patients’ recovery expectations.

Concussion symptomology and recovery in children and adolescents with pre-existing anxiety

Effect of exogenous progesterone administration on smoking topography.

The Association of Social Determinants of Health with Somali Refugee Mother–Child Caries

Longitudinal Evaluation of Self-Reported Gastroesophageal Reflux Disease (GERD) and Lung Function Decline in the COPDGene Cohort

Preclinical and clinical literature suggest that sex hormones impact tobacco use behaviors in women. The goal of this double-blind crossover laboratory study was to examine the effect of oral exogenous progesterone (200 mg twice per day) versus placebo on nicotine response using measures of motor speed and cognitive function in women following overnight smoking abstinence. We hypothesized that increased progesterone would blunt the nicotine response whereby producing less change in motor speed and cognition in response to nicotine exposure. Female smokers, age 18-35, were randomized to participate in two 9-day crossover testing weeks. Participants completed a lab session following overnight abstinence where they were administered nicotine nasal spray and asked to complete measures of immediate memory (IMT), delayed memory (DMT), word recall (WR), and finger tapping speed (FT). After the first 9-day testing week, participants resumed smoking and returned the following month to complete the identical lab session in the crossover condition. Forty-seven women were included in this analysis (n = 47). We found no differences in the magnitude of response for IMT, DMT, and WR between conditions. For FT, women had a blunted response to nicotine during the placebo condition. When examining the association between hormone levels and relative performance, we found increases in DMT, WR, and FT but decreases in IMT during the progesterone condition. We observed differences between progesterone versus placebo in relative change in some measures of nicotine response following overnight abstinence. Future studies are needed to further characterize this response. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Response to nicotine following overnight smoking abstinence during short-term progesterone treatment in women.

Smoking-related symptomatology in pregnant smokers during ad libitum smoking and following overnight smoking abstinence

The aim of this project was to investigate the prevalence of nutrition consultation (NC) in U.S. intensive care units (ICUs) and to examine its association with patient outcomes.

METHODS
Data from the Healthcare Cost and Utilization Project's state inpatient databases was utilized from 2010 - 2014. A multilevel logistic regression model was used to evaluate the relationship between NC and clinical outcomes.

RESULTS
Institutional ICU NC rates varied significantly (mean: 14%, range: 0.1%-73%). Significant variation among underlying disease processes was identified, with burn patients having the highest consult rate (P < 0.001, mean: 6%, range: 2%-25%). ICU patients who received NC had significantly lower in-hospital mortality (odds ratio [OR] 0.59, 95% confidence interval [CI] 0.48-0.74, P < 0.001), as did the subset with malnutrition (OR 0.72, 95% CI 0.53-0.99, P = 0.047) and the subset with concomitant physical therapy consultation (OR 0.53, 95% CI 0.38-0.74, P < 0.001). NC was associated with significantly lower rates of intubation, pulmonary failure, pneumonia, and gastrointestinal bleeding (P < 0.05). Furthermore, patients who received NC were more likely to receive enteral or parenteral nutrition (ENPN) (OR 1.8, 95% CI 1.4-2.3, P < 0.001). Patients who received follow-up NC were even more likely to receive ENPN (OR 3.0, 95% CI 2.1-4.2, P < 0.001).

Rates of NC were low in critically ill patients. This study suggests that increased utilization of NC in critically ill patients may be associated with improved clinical outcomes.

Utilization of Intensive Care Unit Nutrition Consultation Is Associated With Reduced Mortality.

Supplemental Digital Content is available in the text. Purpose: Pulmonary nodules, found either incidentally or on lung cancer screening, are common. Evaluating the benign or malignant nature of these nodules is costly in terms of patient risk and expense. The presence of both global and regional emphysema has been linked to increased lung cancer risk. We sought to determine whether the measurement of emphysema directly adjacent to a lung nodule could inform the likelihood of a nodule being malignant. Materials and Methods: Within a population of Veterans at high risk for lung cancer, 58 subjects with malignant nodules found on computerized tomographic chest scans were matched by lobe and nodule size to 58 controls. Lung densitometry was measured via determination of the low attenuation area percentage at −950 Hounsfield units (LAA950) and the Hounsfield unit (HU) value at which 15% of lung voxels have a lower lung density (Perc15), at predefined lung volumes that encompassed the nodule to evaluate both perinodular and regional lung fields. The association between measured lung density and malignancy was investigated using conditional logistic regression models, with densitometry measurements used as the primary predictor, adjusting for age alone, or age and computerized tomographic scan characteristics. Results: No significant differences in emphysema measurements between malignant and benign nodules were identified at lung volumes encompassing both perinodular and regional emphysema. Furthermore, emphysema quantification remained stable across lung volumes within individuals. Conclusions: In this study, quantifying the degree of perinodular or regional emphysema did not offer any benefit in the risk stratification of lung nodules.

Quantification of Perinodular Emphysema in High-risk Patients Offers No Benefit in Lung Nodule Risk-Stratification of Malignancy Potential

Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons

Factors Associated With the Mental Health and Satisfaction of Oral and Maxillofacial Surgery Residents in the United States: A Cross-Sectional Study and Analysis.

Background There has been limited research on the relationship between contraception and child growth in low-income and middle-income countries (LMICs). This study examines the association between contraception and child linear growth in Guatemala, an LMIC with a very high prevalence of child stunting. We hypothesise that contraceptive use is associated with better child linear growth and less stunting in Guatemala. Methods Using representative national data on 12 440 children 0–59 months of age from the 2014–2015 Demographic and Health Survey in Guatemala, we constructed multivariable linear and Poisson regression models to assess whether child linear growth and stunting were associated with contraception variables. All models were adjusted for a comprehensive set of prespecified confounding variables. Results Contraceptive use was generally associated with modest, statistically significant greater height-for-age z-score. Current use of a modern method for at least 15 months was associated with a prevalence ratio of stunting of 0.87 (95% CI 0.81 to 0.94; p<0.001), and prior use of a modern method was associated with a prevalence ratio of stunting of 0.93 (95% CI 0.87 to 0.98; p<0.05). The severe stunting models found generally similar associations with modern contraceptive use as the stunting models. There was no significant association between use of a modern method for less than 15 months and the prevalence ratio of stunting or severe stunting. Conclusions Contraceptive use was associated with better child linear growth and less child stunting in Guatemala. In addition to the human rights imperative to expand contraceptive access and choice, family planning merits further study as a strategy to improve child growth in Guatemala and other countries with high prevalence of stunting.

Associations between contraception and stunting in Guatemala: secondary analysis of the 2014–2015 Demographic and Health Survey

Effect of exogenous progesterone administration on cigarette smoking-related symptomology in oral contraceptive users who smoke.

Introduction: Poor oral health has been implicated as an independent risk factor for the development of COPD, but few studies have evaluated the association between oral health and COPD exacerbations. We aimed to determine if poor oral health is associated with COPD exacerbations and/or worse respiratory health. Methods: We performed a case-control study of oral health among COPD exacerbators and non-exacerbators. Cases (exacerbators) had experienced ≥1 exacerbation in the previous 12 months, while controls (non-exacerbators) had no exacerbations in the previous 24 months. We excluded those with <4 teeth. We evaluated the global oral health assessment, Oral Health Impact Profile (OHIP-5), dental symptoms/habits, and St. George’s Respiratory Questionnaire (SGRQ). In a subset, we performed blinded dental exams to measure bleeding on probing, probing depth, clinical attachment loss, periodontitis severity, plaque index, gingival index, and carries risk. We evaluated associations between oral health and COPD exacerbations using logistic regression. Linear regression was used to assess relationships between oral health and SGRQ scores. Results: Screened non-exacerbators (n=118) were significantly more likely to have <4 teeth, compared to screened exacerbators (n=100) (44% vs 30%, respectively; p=0.046). After excluding those with <4 teeth, there were 70 cases and 66 controls. Self-reported oral health and objective dental exam measures did not vary significantly between cases vs controls. However, the odds of severe COPD exacerbations requiring hospitalizations and/or emergency department visits trended higher in those with worse dental exam compared to those with better dental exam. Worse OHIP-5 was strongly associated with worse SGRQ scores. Conclusions: Oral health status was not related to COPD exacerbations, but was associated with self-reported respiratory health. Non-exacerbators were more likely to be edentate or have ≤4 teeth compared to exacerbators. Larger studies are needed to address oral health as a potential method to improve respiratory health in patients with COPD.

1Pulmonary Section, Minneapolis Veterans Affairs Health Care System, Minneapolis, MN, USA; 2Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, USA; 3TMD, Orofacial Pain, and Dental Sleep Medicine, University of Minnesota, Minneapolis, MN, USA; 4Dental Section, Minneapolis Veterans Affairs Health Care System, Minneapolis, MN, USA; 5Division of Biostatistics, University of Minnesota, Minneapolis, MN, USA; 6Infectious Disease Section, Minneapolis Veterans Affairs Health Care System, Minneapolis, MN, USA; 7Division of Infectious Disease, Department of Medicine, University of Minnesota, Minneapolis, MN, USA Introduction: Poor oral health has been implicated as an independent risk factor for the development of COPD, but few studies have evaluated the association between oral health and COPD exacerbations. We aimed to determine if poor oral health is associated with COPD exacerbations and/or worse respiratory health. Methods: We performed a case-control study of oral health among COPD exacerbators and non-exacerbators. Cases (exacerbators) had experienced ≥1 exacerbation in the previous 12 months, while controls (non-exacerbators) had no exacerbations in the previous 24 months. We excluded those with <4 teeth. We evaluated the global oral health assessment, Oral Health Impact Profile (OHIP-5), dental symptoms/habits, and St. George’s Respiratory Questionnaire (SGRQ). In a subset, we performed blinded dental exams to measure bleeding on probing, probing depth, clinical attachment loss, periodontitis severity, plaque index, gingival index, and carries risk. We evaluated associations between oral health and COPD exacerbations using logistic regression. Linear regression was used to assess relationships between oral health and SGRQ scores. Results: Screened non-exacerbators (n=118) were significantly more likely to have <4 teeth, compared to screened exacerbators (n=100) (44% vs 30%, respectively; p=0.046). After excluding those with <4 teeth, there were 70 cases and 66 controls. Self-reported oral health and objective dental exam measures did not vary significantly between cases vs controls. However, the odds of severe COPD exacerbations requiring hospitalizations and/or emergency department visits trended higher in those with worse dental exam compared to those with better dental exam. Worse OHIP-5 was strongly associated with worse SGRQ scores. Conclusions: Oral health status was not related to COPD exacerbations, but was associated with self-reported respiratory health. Non-exacerbators were more likely to be edentate or have ≤4 teeth compared to exacerbators. Larger studies are needed to address oral health as a potential method to improve respiratory health in patients with COPD.

This study aims to generate a predictive model stratifying the probability of requiring hospitalization and inpatient respiratory intervention for croup patients presenting to the emergency department (ED), and secondarily to compare the model's performance with that of ED providers.

METHODS
Retrospective data was collected on croup patients presenting to the EDs of 2 pediatric and 1 community hospital from 2019 to 2020, including demographics, preexisting conditions, and history of croup. The ED length of stay, previous dexamethasone administration, time to ED dexamethasone, number of ED racemic epinephrine doses, viral testing, and ED revisits were also recorded. Westley croup scores were derived at ED presentation and final disposition. For admitted patients, any respiratory interventions were recorded. Admission need was defined as either admitted and required an inpatient intervention or not admitted with ED revisit. A prediction model for admission need was fit using L1-penalized logistic regression.

RESULTS
We included 2951 patients in the study, 68 (2.3%) of which needed admission. The model's predictors were disposition Westley croup scores, number of ED racemic epinephrine doses, previous dexamethasone administration, and history of intubation. The model's sensitivity was 66%, specificity was 91%, positive predictive value was 15%, and negative predictive value was 99%. ED providers' performance had a sensitivity of 72%, a specificity of 94%, a positive predictive value of 23%, and a negative predictive value of 99%.

The croup admission need predictive model appears to support clinical decision making in the ED, with the potential to improve decision making when pediatric expertise is limited.

The Impact of Increased Chest Compression Fraction on Survival for Out-of-Hospital Cardiac Arrest Patients with a Non-Shockable Initial Rhythm.

BACKGROUND Traumatic arrests have historically had poor survival rates. Identifying salvageable patients and ideal management is challenging. We aimed to (1) describe the management and outcomes of prehospital traumatic arrests; (2) determine regional variation in survival; and (3) identify Advanced Life Support (ALS) procedures associated with survival. METHODS This was a secondary analysis of cases from the Resuscitation Outcomes Consortium Epistry-Trauma and Prospective Observational Prehospital and Hospital Registry for Trauma (PROPHET) registries. Patients were included if they had a blunt or penetrating injury and received cardiopulmonary resuscitation. Logistic regression analyses were used to determine the association between ALS procedures and survival. RESULTS We included 2,300 patients who were predominately young (Epistry mean [SD], 39 [20] years; PROPHET mean [SD], 40 [19] years), males (79%), injured by blunt trauma (Epistry, 68%; PROPHET, 67%), and treated by ALS paramedics (Epistry, 93%; PROPHET, 98%). A total of 145 patients (6.3%) survived to hospital discharge. More patients with blunt (Epistry, 8.3%; PROPHET, 6.5%) vs. penetrating injuries (Epistry, 4.6%; PROPHET, 2.7%) survived. Most survivors (81%) had vitals on emergency medical services arrival. Rates of survival varied significantly between the 12 study sites (p = 0.048) in the Epistry but not PROPHET (p = 0.14) registries. Patients in the PROPHET registry who received a supraglottic airway insertion or intubation experienced decreased odds of survival (adjusted OR, 0.27; 95% confidence interval, 0.08–0.93; and 0.37; 95% confidence interval, 0.17–0.78, respectively) compared to those receiving bag-mask ventilation. No other procedures were associated with survival. CONCLUSIONS Survival from traumatic arrest may be higher than expected, particularly in blunt trauma and patients with vitals on emergency medical services arrival. Although limited by confounding and statistical power, no ALS procedures were associated with increased odds of survival. LEVEL OF EVIDENCE Prognostic study, level IV.

Prehospital traumatic cardiac arrest: Management and outcomes from the resuscitation outcomes consortium epistry-trauma and PROPHET registries

Early prediction of outcome after severe traumatic brain injury: a simple and practical model

Traumatic cardiac arrest has traditionally been associated with a dismal prognosis, but emerging evidence suggests that survival may be better than expected. The objectives for this study were to 1) describe the contemporary management and outcomes of traumatic arrest; and 2) identify prehospital interventions associated with survival to hospital discharge. We completed a secondary analysis of traumatic arrest cases in the ROC Epistry-Trauma and PROPHET registries. Patients were included if they suffered a blunt or penetrating injury and received chest compressions in the field, regardless of whether they were ultimately transported to the hospital. Multivariable logistic regression analyses were used to generate odds ratios for survival to hospital discharge for the following interventions: advanced life support care, prehospital times, bag-mask ventilation, intubation, supraglottic airway, needle thoracostomy, hemorrhage control, and IV/IO fluids. The study population included 2248 traumatic arrest patients who were predominately young (mean 39 ± 20 years), males (78%), with blunt injuries (68%), without vital signs on EMS arrival (67%), and attended to by advanced life support paramedic crews (87%). A total of 193 patients (8.6%) survived to hospital discharge. More patients with blunt trauma (11%) compared to penetrating trauma (4.5%) survived. The majority (87%) of survivors had at least one vital sign on EMS arrival. Frequently performed procedures were bag-mask ventilation (86%), intubation (55%), and IV fluids (53%). All other procedures were performed in ≤ 15% of patients. Bag-mask ventilation (adjusted OR: 0.26, 95% CI 0.15, 0.44), intubation (adjusted OR: 0.45, 95% CI 0.265 to 0.764), and hemorrhage control (adjusted OR: 0.43, 95% CI 0.20 to 0.93) were all associated with a decreased odds of surviving to hospital discharge following blunt traumatic arrest. No other procedures significantly altered the odds of surviving to hospital discharge. We conclude that survival from traumatic arrest may be higher than previously thought, particularly in blunt trauma, and in those with at least one vital sign on EMS arrival. Frequently performed prehospital interventions were not associated with improved survival from traumatic arrest.

Abstract 17: Prehospital Interventions Associated with Survival from Traumatic Cardiac Arrest

Objective: We investigate whether changes in vital signs between the prehospital scene and emergency department (ED) can be used to develop triage tools to predict the need for life-saving interventions (LSI) and survival in trauma patients. Methods: We analyzed a prospective cohort with any prehospital systolic blood pressure (SBP) ≤ 90 mmHg or Glasgow Coma Scale ≤ 8 who were admitted to an ED at 11 sites of the Resuscitation Outcomes Consortium. The primary outcome was the need for in-hospital LSI (e.g. invasive airway management, invasive bleeding control, blood transfusion, craniotomy, cardiopulmonary resuscitation). Secondary outcome was survival to hospital discharge. Changes in heart rate (HR), SBP, shock index (SI), and respiratory rate (RR) from first prehospital assessment to first ED assessment were considered as predictors in addition to sex, age, mechanism of injury, trauma center level, duration of transport, type of transport, and prehospital fluid volume. Decision trees for each outcome we...

Abstract 343: Prediction of Lifesaving Interventions Using Changes in Vital Signs from Prehospital Scene to Emergency Department

During a two year period, general practitioners in a local area were called to all 112 alarms (the number dialled in Denmark in emergencies) in order to improve the prognosis of patients with cardiac arrest. In 55% of the calls, the practitioners arrived within five minutes, whereas the ambulance arrived within five minutes in only 16% of the cases (p < 0.01). Three of ten patients with cardiac arrest survived without cerebral damage. In 23% of the cases final treatment was completed by the local practitioner.

[Efforts of general practitioners in the treatment of heart arrest in a rural area. A prospective pilot study].

 Device-related infection is the most common serious complication in patients with cardiac implantable electronic devices (CIED). Staphylococcus aureus accounts for up to 30% of CIED-related infections. There is a lack of scientific literature investigating risk of Staphylococcus aureus bacteremia (SAB) in CIED-patients.
 
 We aimed to describe the risk of SAB in Danish patients with a CIED through the years 2000–2018 compared to the background population.
 
 Patients who received a CIED from 2000–2018 were identified from The Danish National Pacemaker and ICD Register. Patients were matched 1:5 on age and gender with the background population. We identified the primary endpoint of first time SAB from The National Danish Staphylococcus Aureus Bacteremia Database. The cumulative incidence of SAB was calculated using the Aalen-Johansen estimator, adding competing risk of death into account. Hazard ratios were estimated by Cox regression models adjusting for age and gender. Crude rates of relapse SAB, defined as a new SAB episode 14–180 days after first SAB, and device extractions were reported for all patients who survived 14 days from SAB diagnosis.
 
 We identified 79,324 CIED-patients (pacemaker (PM) = 61,227; Implantable Cardioverter Defibrillator (ICD) = 11,635; Cardiac resynchronization therapy, PM or ICD (CRT) = 6,364 and 396,590 matched controls (median age 75.5±13.3 years; 61% males). Age and gender distribution differed significantly by device type (age: PM 76.1±12.1; ICD 62.4±13.4; CRT 68.0±11.1; males: PM: 55.6%, ICD% 75.5: CRT: 80.9%). Across a mean follow-up of 5.9 (±4.6) years, we observed first episode of SAB in 1,430 (1.8%) CIED-patients, compared to 2,599 (0.7%) patients in the control population (p<0.001).
 The 10-year cumulative incidence of SAB was 1.0% for controls and 2.2% for CIED patients. The risk of SAB differed substantially by device type (Figure 1). Compared to controls and adjusted for age and gender, increasing hazard ratios for SAB were observed with more advanced devices: PM 1.12 (1.11–1.13); ICD 1.36 (1.33–1.39); CRT 1.55 (1.51–1.59). However, CIED-patients with SAB did not have higher 30-day mortality rates than the non-CIED control population with SAB (Controls 34.8%; PM 35.1%; ICD 28.1% CRT 26.1%, p=0.016). Out of all SAB patients who survived 14 days from SAB diagnosis (Controls=1,672; CIED=1,107), relapse SAB occurred in 52 (3.1%) controls and in 51 (4.6%) CIED-patients (PM 4.0%; ICD 5.8%; CRT 6.3%). Device extraction within 14 and 30 days from SAB diagnosis was undertaken in less than 30% of the CIED-patients (PM: 11.3/13.6%; ICD: 22.7/27.5%; CRT: 17.4/20.1%).
 
 The occurrence of SAB was higher in CIED patients compared with controls and increased with more advanced devices. There was no difference in 30-day mortality after SAB between CIED patients and controls. Relapse SAB occurred in less than 7%, despite a low percentage of early device extractions.
 
 Type of funding sources: None.

Staphylococcus aureus bacteremia in Danish patients with cardiac implantable electronic devices: an explorative epidemiological study

Introduction: Catheter ablation for atrial fibrillation (PVI) is being performed with increasing frequency. This time and labor-intensive procedure is under increasing scrutiny as we look for means to decrease costs of delivering care. Performing these procedures on therapeutic warfarin could shorten hospital stays, eliminate costly low-molecular weight heparin (LMW) use, and decrease procedural heparin administration which could reduce hemorrhage from access sites.

Methods: Over a six-year period, 180 patients, 138 M/42 F, mean age 43 yr (18-77 yr), underwent PVI for persistent - 99 pts., and paroxysmal - 81 pts. atrial fibrillation. Mean INR was 2.2 (1.5 - 4.2). Procedures were performed with standard radiofrequency (RF) catheters - 132, Cryoablation - 27, and Ablation Frontiers RF - 21. Procedural time, fluoroscopy time, hospital stays, outcomes, and complications were tracked.

Results: 127 of 180 pts. were discharged the day of procedure (OP) from the outpatient unit, 51 pts. stayed one night post-procedure (IP), 2 patients stayed 4 days, one for pulmonary treatment and one for CVA. Mean procedural length was 3.3 hours, mean fluoro time was 52 min. Mean time from hospital admit to discharge was 17.3 hr. Mean time from procedure end to discharge was 11.0 hr. 77% of pts. were free from AF on follow-up on no meds or “pill-in-the-pocket”. 6 complications occurred - 1 phrenic nerve paralysis (resolved), 2 CVAs (one was 72 hrs post PVI), 1 perforation/tamponade, 1 groin bleed requiring evacuation, 1 PV stenosis. There was no difference in outcome for patients discharged OP vs IP. Cost savings by continuing warfarin were LMW = $205/dose X 6 doses - $1230/pt. Cost savings by same day discharge = $1330/day.

Conclusions: PVI can be safely performed as an outpatient procedure on therapeutic warfarin with good clinical outcomes. Significant cost savings can be realized from OP PVI from reduced staff, medication, and facilities utilization.

Abstract P65: Outpatient Atrial Fibrillation Ablation on Therapeutic Warfarin - Safety, Efficacy, and Cost Savings

Efficacy and safety of prolonged thromboprophylaxis with a low molecular weight heparin (dalteparin) after total hip arthroplasty--the Danish Prolonged Prophylaxis (DaPP) Study.

Developing deep generative models has been an emerging field due to the ability to model and generate complex data for various purposes, such as image synthesis and molecular design. However, the advancement of deep generative models is limited by challenges to generate objects that possess multiple desired properties: 1) the existence of complex correlation among real-world properties is common but hard to identify; 2) controlling individual property enforces an implicit partially control of its correlated properties, which is difficult to model; 3) controlling multiple properties under various manners simultaneously is hard and under-explored. We address these challenges by proposing a novel deep generative framework that recovers semantics and the correlation of properties through disentangled latent vectors. The correlation is handled via an explainable mask pooling layer, and properties are precisely retained by generated objects via the mutual dependence between latent vectors and properties. Our generative model preserves properties of interest while handling correlation and conflicts of properties under a multi-objective optimization framework. The experiments demonstrate our model's superior performance in generating data with desired properties.

Multi-objective Deep Data Generation with Correlated Property Control

In this paper, we consider fitting a flexible and interpretable additive regression model in a data‐rich setting. We wish to avoid pre‐specifying the functional form of the conditional association between each covariate and the response, while still retaining interpretability of the fitted functions. A number of recent proposals in the literature for nonparametric additive modeling are data adaptive, in the sense that they can adjust the level of flexibility in the functional fits to the data at hand. For instance, the sparse additive model makes it possible to adaptively determine which features should be included in the fitted model, the sparse partially linear additive model allows each feature in the fitted model to take either a linear or a nonlinear functional form, and the recent fused lasso additive model and additive trend filtering proposals allow the knots in each nonlinear function fit to be selected from the data. In this paper, we combine the strengths of each of these recent proposals into a single proposal that uses the data to determine which features to include in the model, whether to model each feature linearly or nonlinearly, and what form to use for the nonlinear functions. We establish connections between our approach and recent proposals from the literature, and we demonstrate its strengths in a simulation study.

video. We propose a dictionary learning approach for this task. First, we perform image segmentation to develop a dictionary containing a huge number of candidate neurons. Next, we refine the dictionary using clustering. Finally, we apply the dictionary to select neurons and estimate their corresponding activity over time, using a sparse group lasso optimization problem. We assess performance on simulated calcium imaging data and apply our proposal to three calcium imaging data sets. Our proposed approach is implemented in the R package scalpel, which is available on CRAN.

Submitted to the Annals of Applied Statistics SCALPEL : EXTRACTING NEURONS FROM CALCIUM IMAGING DATA By

In the past few years, new technologies in the field of neuroscience have made it possible to simultaneously image activity in large populations of neurons at cellular resolution in behaving animals. In mid-2016, a huge repository of this so-called "calcium imaging" data was made publicly available. The availability of this large-scale data resource opens the door to a host of scientific questions for which new statistical methods must be developed. In this paper we consider the first step in the analysis of calcium imaging data-namely, identifying the neurons in a calcium imaging video. We propose a dictionary learning approach for this task. First, we perform image segmentation to develop a dictionary containing a huge number of candidate neurons. Next, we refine the dictionary using clustering. Finally, we apply the dictionary to select neurons and estimate their corresponding activity over time, using a sparse group lasso optimization problem. We assess performance on simulated calcium imaging data and apply our proposal to three calcium imaging data sets. Our proposed approach is implemented in the R package scalpel, which is available on CRAN.

We consider the problem of predicting an outcome variable on the basis of a small number of covariates, using an interpretable yet non-additive model. We propose convex regression with interpretable sharp partitions (CRISP) for this task. CRISP partitions the covariate space into blocks in a data-adaptive way, and fits a mean model within each block. Unlike other partitioning methods, CRISP is fit using a non-greedy approach by solving a convex optimization problem, resulting in low-variance fits. We explore the properties of CRISP, and evaluate its performance in a simulation study and on a housing price data set.

Data-Adaptive Modeling using Convex Regression Ashley Petersen Co-Chairs of the Supervisory Committee: Dr. Daniela Witten Departments of Biostatistics and Statistics Dr. Noah Simon Department of Biostatistics The collection and storage of large amounts of data has greatly increased in recent years, which has led to a greater interest in developing methods to explore and model this data. In settings in which little is known about the relationship among variables in advance, exploratory data analysis is particularly important. Furthermore, when the number of covariates is large, traditional exploratory data analysis becomes challenging. In this setting, fitting flexible and interpretable models can be a useful tool for visualizing the conditional relationships between the covariates and outcome. In Chapter 2, we present a method that adaptively selects covariates to include in the model and for those included, models their conditional associations with the outcome as piecewise constant functions with adaptivelychosen knots. In Chapter 3, we present a related method that is useful in settings in which interactions between pairs of covariates are of particular interest. In Chapter 4, we turn our attention to a specific type of data: calcium imaging data, which measures large populations of neurons at cellular resolution in behaving animals. As a first step of analyzing calcium imaging data, two goals must be accomplished: neuron identification and calcium quantification. Through combining image segmentation, clustering, and convex regression, we are able to extract the locations of neurons in the field of view, as well as estimate the neurons’ intracellular calcium concentrations over time. This extracted data is useful in downstream analyses, which aim to provide unprecedented insight into neural activity.

We consider the problem of predicting an outcome variable using p covariates that are measured on n independent observations, in a setting in which additive, flexible, and interpretable fits are desired. We propose the fused lasso additive model (FLAM), in which each additive function is estimated to be piecewise constant with a small number of adaptively chosen knots. FLAM is the solution to a convex optimization problem, for which a simple algorithm with guaranteed convergence to a global optimum is provided. FLAM is shown to be consistent in high dimensions, and an unbiased estimator of its degrees of freedom is proposed. We evaluate the performance of FLAM in a simulation study and on two datasets. Supplemental materials are available online, and the R package flam is available on CRAN.

Incorporating prior knowledge to increase the power of genome-wide association studies.

Gene-based tests of association are frequently applied to common SNPs (MAF>5%) as an alternative to single-marker tests. In this analysis we conduct a variety of simulation studies applied to five popular gene-based tests investigating general trends related to their performance in realistic situations. In particular, we focus on the impact of non-causal SNPs and a variety of LD structures on the behavior of these tests. Ultimately, we find that non-causal SNPs can significantly impact the power of all gene-based tests. On average, we find that the “noise” from 6–12 non-causal SNPs will cancel out the “signal” of one causal SNP across five popular gene-based tests. Furthermore, we find complex and differing behavior of the methods in the presence of LD within and between non-causal and causal SNPs. Ultimately, better approaches for a priori prioritization of potentially causal SNPs (e.g., predicting functionality of non-synonymous SNPs), application of these methods to sequenced or fully imputed datasets, and limited use of window-based methods for assigning inter-genic SNPs to genes will improve power. However, significant power loss from non-causal SNPs may remain unless alternative statistical approaches robust to the inclusion of non-causal SNPs are developed.

Assessing Methods for Assigning SNPs to Genes in Gene-Based Tests of Association Using Common Variants

Evaluating methods for combining rare variant data in pathway-based tests of genetic association

Evaluating methods for the analysis of rare variants in sequence data

Abstract While correlated data methods (like random effect models and generalized estimating equations) are commonly applied in practice, students may struggle with understanding the reasons that standard regression techniques fail if applied to correlated outcomes. To this end, this article presents an in-class activity using results from Monte Carlo simulations to introduce the impact of ignoring the correlation between outcomes by applying standard regression techniques. This activity is used at the beginning of a graduate course on statistical methods for analyzing correlated data taken by students with limited mathematical backgrounds. Students gain the intuition that analyzing correlated outcomes using methods for independent data produces invalid inference (i.e., confidence intervals and p-values) due to underestimated or overestimated standard errors of the effect estimates, even though the effect estimates themselves are still valid. While this standalone 90-minute in-class activity can be added at the beginning of an existing course on statistical methods for correlated data without any further changes, techniques for reinforcing students’ intuition throughout the course and applying this intuition to teach sample size and power calculations for correlated outcomes are also discussed. Supplementary materials for this article are available online.

Developing Students’ Intuition on the Impact of Correlated Outcomes

A soluble truncated tau species related to cognitive dysfunction is elevated in the brain of cognitively impaired human individuals

Author Correction: A soluble truncated tau species related to cognitive dysfunction is elevated in the brain of cognitively impaired human individuals

A soluble tau fragment generated by caspase-2 is associated with dementia in Lewy body disease

A soluble truncated tau species related to cognitive dysfunction and caspase-2 is elevated in the brain of Huntington’s disease patients

Whether novelty-flavored vaping devices should be available in the marketplace has been a hotly contested debate. From one perspective, the variety of different flavors, such as fruit and mint, may help adult cigarette smokers who are seeking to switch to reduced-harm nicotine products. However, these flavors are also wildly popular among youth, creating concerns about new nicotine product use among minors.

METHODS
This experiment (n = 176) tests whether vaping flavors (tobacco vs. fruit) and flavor representations on packages (flavor color, flavor image) influence how middle school youth perceive vaping products.

RESULTS
While results show no difference in risk perceptions based on condition, novelty perceptions (e.g., how fun, interesting) and susceptibility to vaping are highest among those who view the fruit-flavored vaping product with flavor color and flavor image. Those who viewed this condition reported higher novelty perceptions and susceptibility than those who viewed the fruit-flavored vaping product with no flavor color and no flavor image. Additionally, they reported higher novelty perceptions than those who viewed the tobacco-flavored vaping product with flavor color and flavor image. A post-hoc analysis in supplemental data shows that youth who report lower risk perceptions and higher susceptibility have higher behavioral intentions to vape in the next year.

Findings suggest that restricting flavor representation on packaging might reduce how fun and interesting youth perceive these products to be and how susceptible they are to using them.

IMPLICATIONS
While there is debate over the regulation of flavored vaping products, this study suggests that restricting the use of the flavor color and flavor image on the packaging is associated with lower levels of novelty perceptions and susceptibility. This might be an alternative approach to minimize the appeal of vaping products among youth.

Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco

Vaping Flavors and Flavor Representation: A Test of Youth Risk Perceptions, Novelty Perceptions, and Susceptibility.

A new prescription platform to manage emerging and diverse pathogens

Bioinformatics as a tool in prescription platform vaccine development

Additives that help cells survive the stresses of freezing and thawing are known as cryoprotective agents (CPAs). Two different types of CPAs have been identified: penetrating and non-penetrating. Common penetrating CPAs include dimethylsulfoxide (DMSO) and glycerol. The location of a CPA (intracelluar or extracellular) is important for understanding the molecular mechanisms of action for the agent. Low-temperature Raman spectroscopy is a label-free method of detecting the location of CPAs at low temperature with high spatial resolution and chemical specificity. To this end, cells cryopreserved in DMSO using a variety of cooling rates and DMSO concentrations and imaged using Raman spectroscopy were analyzed using automated image analysis to determine the partitioning ratio (concentration of DMSO outside/concentration of DMSO inside the cell). The partitioning ratio was roughly 1 for Jurkat cells frozen at 1°C/min in varying concentrations of DMSO with the exception of 1% DMSO which had a partitioning ratio of 0.2. The partitioning ratio increased from 1 to 1.3 as the cooling rate increased from 1°C to 5°C/min. Different cell types, specifically sensory neurons cells and human induced pluripotent stem cells, exhibited differences in partitioning ratio when frozen in 10% DMSO and 1°C/min suggesting that differences in freezing response may result from differences in solute partitioning. The presence of intracellular ice changed the distribution of DMSO inside the cell and also the partitioning ratio.

Characterizing cellular membrane partitioning of DMSO using low-temperature Raman spectroscopy

Characterizing the “sweet spot” for the preservation of a T-cell line using osmolytes

Solution Structure of the Integral Human Membrane Protein VDAC-1 in Detergent Micelles

ABSTRACT The relevance of the acyl homoserine lactone (acyl-HSL) quorum signals N-3-oxododecanoyl-homoserine lactone (3OC12HSL) and N-butanoyl-homoserine lactone to the biology and virulence of Pseudomonas aeruginosa is well investigated. Previously, P. aeruginosa was shown to degrade long-chain, but not short-chain, acyl-HSLs as sole carbon and energy sources (J. J. Huang, J.-I. Han, L.-H. Zhang, and J. R. Leadbetter, Appl. Environ. Microbiol. 69:5941-5949, 2003). A gene encoding an enzyme with acyl-HSL acylase activity, pvdQ (PA2385), was identified, but it was not required for acyl-HSL utilization. This indicated that P. aeruginosa encodes another acyl-HSL acylase, which we identify here. A comparison of total cell proteins of cultures grown with long-acyl acyl-HSLs versus other substrates implicated the involvement of a homolog of PvdQ, the product of gene PA1032, for which we propose the name QuiP. Transposon mutants of quiP were defective for growth when P. aeruginosa was cultured in medium containing decanoyl-HSL as a sole carbon and energy source. Complementation with a functional copy of quiP rescued this growth defect. When P. aeruginosa was grown in buffered lysogeny broth, constitutive expression of QuiP in P. aeruginosa led to decreased accumulations of the quorum signal 3OC12HSL, relative to the wild type. Heterologous expression of QuiP was sufficient to confer long-chain acyl-HSL acylase activity upon Escherichia coli. Examination of gene expression patterns during acyl-HSL-dependent growth of P. aeruginosa further supported the involvement of quiP in signal decay and revealed other genes also possibly involved. It is not yet known under which “natural” conditions quiP is expressed or how P. aeruginosa balances the expression of its quorum-sensing systems with the expression of its acyl-HSL acylase activities.

Identification of QuiP, the Product of Gene PA1032, as the Second Acyl-Homoserine Lactone Acylase of Pseudomonas aeruginosa PAO1

Certain members of the fluorescent pseudomonads produce and secrete phenazines. These heterocyclic, redox‐active compounds are toxic to competing organisms, and the cause of these antibiotic effects has been the focus of intense research efforts. It is largely unknown, however, how pseudomonads themselves respond to – and survive in the presence of – these compounds. Using Pseudomonas aeruginosa DNA microarrays and quantitative RT‐PCR, we demonstrate that the phenazine pyocyanin elicits the upregulation of genes/operons that function in transport [such as the resistance‐nodulation‐cell division (RND) efflux pump MexGHI‐OpmD] and possibly in redox control (such as PA2274, a putative flavin‐dependant monooxygenase), and downregulates genes involved in ferric iron acquisition. Strikingly, mexGHI‐opmD and PA2274 were previously shown to be regulated by the PA14 quorum sensing network that controls the production of virulence factors (including phenazines). Through mutational analysis, we show that pyocyanin is the physiological signal for the upregulation of these quorum sensing‐controlled genes during stationary phase and that the response is mediated by the transcription factor SoxR. Our results implicate phenazines as signalling molecules in both P. aeruginosa PA14 and PAO1.

The phenazine pyocyanin is a terminal signalling factor in the quorum sensing network of Pseudomonas aeruginosa

Sensitivity and Specificity of MRI Versus CBCT to Detect Vertical Root Fractures Using MicroCT as a Reference Standard.

International Journal of Computer Assisted Radiology and Surgery

Bidirectional long short-term memory for surgical skill classification of temporally segmented tasks

Purpose: Previous research has shown that obtaining non-expert crowd evaluations of surgical performances concords with the gold standard of expert surgeon review, and that faster playback speed increases ratings for videos of higher-skilled surgeons in laparoscopic simulation. The aim of this research is to extend this investigation to real surgeries that use non-expert crowd evaluations. We address two questions (1) whether crowds award more favorable ratings to videos shown at increased playback speeds, and (2) if crowd evaluations of the first minute of a surgical procedure differ from crowd evaluations of the entire performance. Methods: A set of 56 videos of practicing surgeons were used to evaluate the technical skill of the surgeons at each video playback speed used for the first minute of the previously rated performance, using the GEARS assessment criteria. Results: Crowds on average did rate videos higher as playback speed was increased. This effect was observed for both proficient and expert surgeons. Each increase in the playback speed by 0.8x was associated with, on average, a 0.16-point increase in the GEARS score for expert surgeons and a 0.27-point increase in GEARS score for proficient surgeons, with both groups being perceived as obtaining relatively equal skill at the fastest playback speed. It was also found that 22 out of the 56 surgeons were perceived to be significantly different in skill when just viewing the first minute of performance. Conclusion: The observed increase in skill ratings with video playback speed replicates findings for laparoscopy in [2], and extends to real robotic surgeries. Furthermore, the large differences in skill labels when comparing the first minute of surgery to the entire 15 minute video warrants further investigation into how much perceived skill ratings vary in time (sub-task level) vs. summative metrics (task level).

The Effect of Video Playback Speed on Perception of Technical Skill in Robotic Surgery

The effect of video playback speed on surgeon technical skill perception

Interpretable methods for extracting meaningful building blocks (BBs) underlying multi-dimensional time series are vital for discovering valuable insights in complex systems. Existing techniques, however, encounter limitations that restrict their applicability to real-world systems, like reliance on orthogonality assumptions, inadequate incorporation of inter- and intra-state variability, and incapability to handle sessions of varying duration. Here, we present a framework for Similarity-driven Building Block Inference using Graphs across States (SiBBlInGS). SiBBlInGS employs a graph-based dictionary learning approach for BB discovery, simultaneously considers both inter- and intra-state relationships in the data, can extract non-orthogonal components, and allows for variations in session counts and duration across states. Additionally, SiBBlInGS allows for cross-state variations in BB structure and per-trial temporal variability, can identify state-specific vs state-invariant BBs, and offers both supervised and data-driven approaches for controlling the level of BB similarity between states. We demonstrate SiBBlInGS on synthetic and real-world data to highlight its ability to provide insights into the underlying mechanisms of complex phenomena and its applicability to data in various fields.

SiBBlInGS: Similarity-driven Building-Block Inference using Graphs across States

Given a set of overlapping local views (patches) of a dataset, we consider the problem of finding a rigid alignment of the views that minimizes a $2$-norm based alignment error. In general, the views are noisy and a perfect alignment may not exist. In this work, we characterize the non-degeneracy of an alignment in the noisy setting based on the kernel and positivity of a certain matrix. This leads to a polynomial time algorithm for testing the non-degeneracy of a given alignment. Consequently, we focus on Riemannian gradient descent for minimization of the error and obtain a sufficient condition on an alignment for the algorithm to converge (locally) linearly to it. In the case of noiseless views, a perfect alignment exists, resulting in a realization of the points that respects the geometry of the views. Under a mild condition on the views, we show that the non-degeneracy of a perfect alignment is equivalent to the local rigidity of the resulting realization. By specializing the characterization of a non-degenerate alignment to the noiseless setting, we obtain necessary and sufficient conditions on the overlapping structure of the views for a locally rigid realization. Similar results are also obtained in the context of global rigidity.

A common challenge in applying graph machine learning methods is that the underlying graph of a system is often unknown. Although different graph inference methods have been proposed for continuous graph signals, inferring the graph structure underlying other types of data, such as discrete counts, is under-explored. In this paper, we generalize a graph signal processing (GSP) framework for learning a graph from smooth graph signals to the exponential family noise distribution to model various data types. We propose an alternating algorithm that estimates the graph Laplacian as well as the unobserved smooth representation from the noisy signals. We demonstrate in synthetic and real-world data that our new algorithm outperforms competing Laplacian estimation methods under noise model mismatch.

Finding meaningful representations and distances of hierarchical data is important in many fields. This paper presents a new method for hierarchical data embedding and distance. Our method relies on combining diffusion geometry, a central approach to manifold learning, and hyperbolic geometry. Specifically, using diffusion geometry, we build multi-scale densities on the data, aimed to reveal their hierarchical structure, and then embed them into a product of hyperbolic spaces. We show theoretically that our embedding and distance recover the underlying hierarchical structure. In addition, we demonstrate the efficacy of the proposed method and its advantages compared to existing methods on graph embedding benchmarks and hierarchical datasets.

Hyperbolic Diffusion Embedding and Distance for Hierarchical Representation Learning

Dimensionality reduction techniques are a key component of most microbiome studies, providing both the ability to tractably visualize complex microbiome datasets and the starting point for additional, more formal, statistical analyses. In this review, we discuss the motivation for applying dimensionality reduction techniques, the special characteristics of microbiome data such as sparsity and compositionality that make this difficult, the different categories of strategies that are available for dimensionality reduction, and examples from the literature of how they have been successfully applied (together with pitfalls to avoid). We conclude by describing the need for further development in the field, in particular combining the power of phylogenetic analysis with the ability to handle sparsity, compositionality, and non-normality, as well as discussing current techniques that should be applied more widely in future analyses.

Applications and Comparison of Dimensionality Reduction Methods for Microbiome Data

Emotion regulation habits have long been implicated in risk for depression. However, research in this area traditionally adopts an approach that ignores the multifaceted nature of emotion regulation strategies, the clinical heterogeneity of depression, and potential differential relations between emotion regulation features and individual symptoms. To address limitations associated with the dominant aggregate-level approach, this study aimed to identify which features of key emotion regulation strategies are most predictive and when those features are most predictive of individual symptoms of depression across different time lags. Leveraging novel developments in the field of machine learning, artificial neural network models with feature selection were estimated using data from 460 participants who participated in a 20-wave longitudinal study with weekly assessments. At each wave, participants completed measures of repetitive negative thinking, positive reappraisal, perceived stress, and depression symptoms. Results revealed that specific features of repetitive negative thinking (wondering "why cannot I get going?" and having thoughts or images about feelings of loneliness) and positive reappraisal (looking for positive sides) were important indicators for detecting various depressive symptoms, above and beyond perceived stress. These features had overlapping and unique predictive relations with individual cognitive, affective, and somatic symptoms. Examining temporal fluctuations in the predictive utility, results showed that the utility of these emotion regulation features was stable over time. These findings illuminate potential pathways through which emotion regulation features may confer risk for depression and help to identify actionable targets for its prevention and treatment. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Which features of repetitive negative thinking and positive reappraisal predict depression? An in-depth investigation using artificial neural networks with feature selection.

Probabilistic generative models provide a ﬂexible and systematic framework for learning the underlying geometry of data. However, model selection in this setting is challenging, particularly when selecting for ill-deﬁned qualities such as disentanglement or interpretability. In this work, we address this gap by introducing a method for ranking generative models based on the training dynamics exhibited during learning. Inspired by recent theoretical characterizations of disentanglement, our method does not require supervision of the underlying latent factors. We evaluate our approach by demonstrating the need for disentanglement metrics which do not require labels—the underlying generative factors. We additionally demonstrate that our approach correlates with baseline supervised methods for evaluating disentanglement. Finally, we show that our method can be used as an unsupervised indicator for downstream performance on reinforcement learning and fairness-classiﬁcation problems.

Evaluating Disentanglement in Generative Models Without Knowledge of Latent Factors

There has been great interest in enhancing the robustness of neural network classiﬁers to defend against adversarial perturbations through adversarial training, while balancing the trade-off between robust accuracy and standard accuracy. We propose a novel adversarial training framework that learns to reweight the loss associated with individual training samples based on a notion of class-conditioned margin, with the goal of improving robust generalization. We formulate weighted adversarial training as a bilevel optimization problem with the upper-level problem corresponding to learning a robust classiﬁer, and the lower-level problem corresponding to learning a parametric function that maps from a sample’s multi-class margin to an importance weight. Extensive experiments demonstrate that our approach consistently improves both clean and robust accuracy compared to related methods and state-of-the-art baselines.

Learning Sample Reweighting for Accuracy and Adversarial Robustness

Probabilistic generative models provide a flexible and systematic framework for learning the underlying geometry of data. However, model selection in this setting is challenging, particularly when selecting for ill-defined qualities such as disentanglement or interpretability. In this work, we address this gap by introducing a method for ranking generative models based on the training dynamics exhibited during learning. Inspired by recent theoretical characterizations of disentanglement, our method does not require supervision of the underlying latent factors. We evaluate our approach by demonstrating the need for disentanglement metrics which do not require labels—the underlying generative factors. We additionally demonstrate that our approach correlates with baseline supervised methods for evaluating disentanglement. Finally, we show that our method can be used as an unsupervised indicator for downstream performance on reinforcement learning and fairness-classification problems.

Selecting subsets of features that differentiate between two conditions is a key task in a broad range of scientific domains. In many applications, the features of interest form clusters with similar effects on the data at hand. To recover such clusters we develop DiSC, a data-driven approach for detecting groups of features that differentiate between conditions. For each condition, we construct a graph whose nodes correspond to the features and whose weights are functions of the similarity between them for that condition. We then apply a spectral approach to compute subsets of nodes whose connectivity differs significantly between the condition-specific feature graphs. On the theoretical front, we analyze our approach with a toy example based on the stochastic block model. We evaluate DiSC on a variety of datasets, including MNIST, hyperspectral imaging, simulated scRNA-seq and task fMRI, and demonstrate that DiSC uncovers features that better differentiate between conditions compared to competing methods.

Many machine learning algorithms depend on weights that quantify row and column similarities of a data matrix. The choice of weights can dramatically impact the effectiveness of the algorithm. Nonetheless, the problem of choosing weights has arguably not been given enough study. When a data matrix is completely observed, Gaussian kernel affinities can be used to quantify the local similarity between pairs of rows and pairs of columns. Computing weights in the presence of missing data, however, becomes challenging. In this paper, we propose a new method to construct row and column affinities even when data are missing by building off a co‐clustering technique. This method takes advantage of solving the optimization problem for multiple pairs of cost parameters and filling in the missing values with increasingly smooth estimates. It exploits the coupled similarity structure among both the rows and columns of a data matrix. We show these affinities can be used to perform tasks such as data imputation, clustering, and matrix completion on graphs.

Statistical Analysis and Data Mining: The ASA Data Science Journal

Multi‐scale affinities with missing data: Estimation and applications

Abstract. Functional optical imaging in neuroscience is rapidly growing with the development of optical systems and fluorescence indicators. To realize the potential of these massive spatiotemporal datasets for relating neuronal activity to behavior and stimuli and uncovering local circuits in the brain, accurate automated processing is increasingly essential. We cover recent computational developments in the full data processing pipeline of functional optical microscopy for neuroscience data and discuss ongoing and emerging challenges.

Review of data processing of functional optical microscopy for neuroscience

Given the exponential growth of the volume of the ball w.r.t. its radius, the hyperbolic space is capable of embedding trees with arbitrarily small distortion and hence has received wide attention for representing hierarchical datasets. However, this exponential growth property comes at a price of numerical instability such that training hyperbolic learning models will sometimes lead to catastrophic NaN problems, encountering unrepresentable values in floating point arithmetic. In this work, we carefully analyze the limitation of two popular models for the hyperbolic space, namely, the Poincar\'e ball and the Lorentz model. We first show that, under the 64 bit arithmetic system, the Poincar\'e ball has a relatively larger capacity than the Lorentz model for correctly representing points. Then, we theoretically validate the superiority of the Lorentz model over the Poincar\'e ball from the perspective of optimization. Given the numerical limitations of both models, we identify one Euclidean parametrization of the hyperbolic space which can alleviate these limitations. We further extend this Euclidean parametrization to hyperbolic hyperplanes and exhibits its ability in improving the performance of hyperbolic SVM.

Graphons are general and powerful models for generating graphs of varying size. In this paper, we propose to directly model graphons using neural networks, obtaining Implicit Graphon Neural Representation (IGNR). Existing work in modeling and reconstructing graphons often approximates a target graphon by a fixed resolution piece-wise constant representation. Our IGNR has the benefit that it can represent graphons up to arbitrary resolutions, and enables natural and efficient generation of arbitrary sized graphs with desired structure once the model is learned. Furthermore, we allow the input graph data to be unaligned and have different sizes by leveraging the Gromov-Wasserstein distance. We first demonstrate the effectiveness of our model by showing its superior performance on a graphon learning task. We then propose an extension of IGNR that can be incorporated into an auto-encoder framework, and demonstrate its good performance under a more general setting of graphon learning. We also show that our model is suitable for graph representation learning and graph generation.

Convex clustering is an appealing approach to many classical clustering problems. It stands out among standard methods as it enjoys the existence of a unique global optimal solution. Despite this advantage, convex clustering has not been widely adopted, due to its computationally intensive nature. To address this obstacle, especially in the “big data” setting, we introduce a Scalable cOnvex cLustering AlgoRithm via Parallel Coordinate Descent Method (SOLAR-PCDM) that improves the algorithm’s scalability by combining a parallelizable algorithm with a compression strategy. This idea is in line with the rise and ever increasing availability of high performance computing systems built around multi-core processors, GPU-accelerators, and computer clusters. SOLARPCDM consists of two parts. In the first part, we develop a method called weighted convex clustering to recover the solution path by formulating a sequence of smaller equivalent optimization problems. In the second part, we utilize the Parallel Coordinate Descent Method (PCDM) to solve a specific convex clustering problem. We demonstrate the correctness and scalability of our algorithm on both simulated and real data examples.

Large‐scale brain dynamics are believed to lie in a latent, low‐dimensional space. Typically, the embeddings of brain scans are derived independently from different cognitive tasks or resting‐state data, ignoring a potentially large—and shared—portion of this space. Here, we establish that a shared, robust, and interpretable low‐dimensional space of brain dynamics can be recovered from a rich repertoire of task‐based functional magnetic resonance imaging (fMRI) data. This occurs when relying on nonlinear approaches as opposed to traditional linear methods. The embedding maintains proper temporal progression of the tasks, revealing brain states and the dynamics of network integration. We demonstrate that resting‐state data embeds fully onto the same task embedding, indicating similar brain states are present in both task and resting‐state data. Our findings suggest analysis of fMRI data from multiple cognitive tasks in a low‐dimensional space is possible and desirable.

Nonlinear manifold learning in functional magnetic resonance imaging uncovers a low‐dimensional space of brain dynamics

Magnetic resonance imaging (MRI) and Ecological Momentary Assessment (EMA) are two powerful methods to study psychological processes that have become increasingly popular in the last two decades. Though each method is valuable in its own right, their complementary strengths have the potential to further advance our understanding of typical and atypical human behavior. Despite the increase in the number of studies that combine these methods over the last decade, there are no existing recommendations for best practices or norms for conducting and reporting the findings from these types of studies. To address the absence of such standards in the field, we conducted a systematic review of papers that combine these methods. A systematic search of peer-reviewed papers using Google Scholar resulted in a pool of 11,558 articles. Inclusion criteria were 1) data-based study in which 2) participants completed (a) Structural or functional MRI and (b) an EMA protocol that included self-report. Seventy-one papers met inclusion criteria. The following review compares these studies based on several key parameters (e.g., population age and type, type of MRI scans and EMA assessments, sample size) with the aim of determining feasibility and current standards for design and reporting in the field. The review concludes with recommendations for future research guidelines. A special focus is given to the ways in which the two methods are combined on an analytical level and suggestions for novel computational methods that could further advance the field.

Better together: A systematic review of studies combining Magnetic Resonance Imaging with Ecological Momentary Assessment

Deep neural networks are known to be vulnerable to adversarial examples, where a perturbation in the input space leads to an amplified shift in the latent network representation. In this paper, we combine canonical supervised learning with selfsupervised representation learning, and present Self-supervised Online Adversarial Purification (SOAP), a novel defense strategy that uses a self-supervised loss to purify adversarial examples at test-time. Our approach leverages the labelindependent nature of self-supervised signals, and counters the adversarial perturbation with respect to the self-supervised tasks. SOAP yields competitive robust accuracy against state-of-the-art adversarial training and purification methods, with considerably less training complexity. In addition, our approach is robust even when adversaries are given knowledge of the purification defense strategy. To the best of our knowledge, our paper is the first that generalizes the idea of using self-supervised signals to perform online test-time purification.

Experimental work across a variety of species has demonstrated that spontaneously generated behaviors are robustly coupled to variation in neural activity within the cerebral cortex. Indeed, functional magnetic resonance imaging (fMRI) data suggest that functional connectivity in cortical networks varies across distinct behavioral states, providing for the dynamic reorganization of patterned activity. However, these studies generally lack the temporal resolution to establish links between cortical signals and the continuously varying fluctuations in spontaneous behavior typically observed in awake animals. Here, we took advantage of recent developments in wide-field, mesoscopic calcium imaging to monitor neural activity across the neocortex of awake mice. We develop a novel “graph of graphs” approach to quantify rapidly time-varying functional connectivity and show that spontaneous behaviors are represented by fast changes in both the activity and correlational structure of cortical network activity. Combining mesoscopic imaging with simultaneous cellular resolution 2-photon microscopy also demonstrated that the correlations among neighboring neurons and between local and large-scale networks also encodes behavior. Finally, the dynamic functional connectivity of mesoscale signals revealed subnetworks that are not predicted by traditional anatomical atlas-based parcellation of the cortex. These results provide new insight into how behavioral information is represented across the mammalian neocortex and demonstrate an analytical framework for investigating time-varying functional connectivity in neural networks.

Rapid fluctuations in functional connectivity of cortical networks encode spontaneous

Microbiome data are sparse and high dimensional, so effective visualization of these data requires dimensionality reduction. To date, the most commonly used method for dimensionality reduction in the microbiome is calculation of between-sam-ple microbial differences (beta diversity), followed by principal-coordinate analysis (PCoA). Uniform Manifold Approximation and Projection (UMAP) is an alternative method that can reduce the dimensionality of beta diversity distance matrices. Here, we demonstrate the bene ﬁ ts and limitations of using UMAP for dimensionality reduction on microbiome data. Using real data, we demonstrate that UMAP can improve the representation of clusters, especially when the clusters are composed of multiple sub-groups. Additionally, we show that UMAP provides improved correlation of biological variation along a gradient with a reduced number of coordinates of the resulting embedding. Finally, we provide parameter recommendations that emphasize the preservation of global geometry. We therefore conclude that UMAP should be routinely used as a complementary visualization method for microbiome beta diversity studies. IMPORTANCE UMAP provides an additional method to visualize microbiome data. The method is extensible to any beta diversity metric used with PCoA, and our results demonstrate that UMAP can indeed improve visualization quality and correspondence with biological and technical variables of interest. The software to perform this analysis is available under an open-source license and can be obtained at https://github.com/ knightlab-analyses/umap-microbiome-benchmarking; additionally, we have provided a QIIME 2 plugin for UMAP at https://github.com/biocore/q2-umap.

Manifold Projection Reveals Composite Patterns and Resolves Visualization Artifacts in Microbiome Data.

Deep neural networks are known to be vulnerable to adversarial examples, where a perturbation in the input space leads to an ampliﬁed shift in the latent network representation. In this paper, we combine canonical supervised learning with self-supervised representation learning, and present Self-supervised Online Adversarial Puriﬁcation (SOAP), a novel defense strategy that uses a self-supervised loss to purify adversarial examples at test-time. Our approach leverages the label-independent nature of self-supervised signals

Online Adversarial Purification based on Self-supervised Learning

To understand the relationship between behavior and neural activity, experiments in neuroscience often include an animal performing a repeated behavior such as a motor task. Recent progress in computer vision and deep learning has shown great potential in the automated analysis of behavior by leveraging large and high-quality video datasets. In this paper, we design Disentangled Behavior Embedding (DBE) to learn robust behavioral embeddings from unlabeled, multi-view, high-resolution behavioral videos across different animals and multiple sessions. We further combine DBE with a stochastic temporal model to propose Variational Disentangled Behavior Embedding (VDBE), an end-to-end approach that learns meaningful discrete behavior representations and generates interpretable behavioral videos. Our models learn consistent behavior representations by explicitly disentangling the dynamic behavioral factors (pose) from time-invariant, non-behavioral nuisance factors (context) in a deep autoencoder, and exploit the temporal structures of pose dynamics. Compared to competing approaches, DBE and VDBE enjoy superior performance on downstream tasks such as ﬁne-grained behavioral motif generation and behavior decoding.

We present Low Distortion Local Eigenmaps (LDLE), a manifold learning technique which constructs a set of low distortion local views of a data set in lower dimension and registers them to obtain a global embedding. The local views are constructed using the global eigenvectors of the graph Laplacian and are registered using Procrustes analysis. The choice of these eigenvectors may vary across the regions. In contrast to existing techniques, LDLE can embed closed and non-orientable manifolds into their intrinsic dimension by tearing them apart. It also provides gluing instruction on the boundary of the torn embedding to help identify the topology of the original manifold. Our experimental results will show that LDLE largely preserved distances up to a constant scale while other techniques produced higher distortion. We also demonstrate that LDLE produces high quality embeddings even when the data is noisy or sparse.

Optical imaging of calcium signals in the brain has enabled researchers to observe the activity of hundreds-to-thousands of individual neurons simultaneously. Current methods predominantly focus on matrix factorization and aim at detecting neurons in the imaged field-of-view, and then inferring the corresponding time-traces. The explicit locality constraints on the cell shapes additionally limits the applicability to optical imaging at different scales (i.e., dendritic or widefield data). Here we present a new method that frames the problem of isolating independent fluorescing components as a dictionary learning problem. Specifically, we focus on the time-traces, which are the main quantity used in scientific discovery, and learn the dictionary of time traces with the spatial maps acting as the presence coefficients encoding which pixels the time traces are active in. Furthermore, we present a novel graph filtering model which redefines connectivity between pixels in terms of their shared temporal activity, rather than spatial proximity. This model greatly eases the ability of our method to handle data with complex non-local spatial structure, such as dendritic imaging. We demonstrate important properties of our method, such as robustness to initialization, implicitly inferring number of neurons and simultaneously detecting different neuronal types, on both synthetic data and real data examples. Specifically, we demonstrate applications of our method to calcium imaging both at the dendritic, somatic, and widefield scales.

GraFT: Graph Filtered Temporal Dictionary Learning for Functional Neural Imaging

Biclustering is a generalization of clustering used to identify simultaneous grouping patterns in observations (rows) and features (columns) of a data matrix. Recently, the biclustering task has been formulated as a convex optimization problem. While this convex recasting of the problem has attractive properties, existing algorithms do not scale well. To address this problem and make convex biclustering a practical tool for analyzing larger data, we propose an implementation of fast convex biclustering called COBRAC to reduce the computing time by iteratively compressing problem size along the solution path. We apply COBRAC to several gene expression datasets to demonstrate its effectiveness and efficiency. Besides the standalone version for COBRAC, we also developed a related online web server for online calculation and visualization of the downloadable interactive results.

AVAILABILITY
The source code and test data are available at https://github.com/haidyi/cvxbiclustr or https://zenodo.org/record/4620218. The web server is available at https://cvxbiclustr.ericchi.com.

SUPPLEMENTARY INFORMATION
Supplementary data are available at Bioinformatics online.

COBRAC: a fast implementation of convex biclustering with compression

UMAP provides an additional method to visualize microbiome data. The method is extensible to any beta diversity metric used with PCoA, and our results demonstrate that UMAP can indeed improve visualization quality and correspondence with biological and technical variables of interest. ABSTRACT Microbiome data are sparse and high dimensional, so effective visualization of these data requires dimensionality reduction. To date, the most commonly used method for dimensionality reduction in the microbiome is calculation of between-sample microbial differences (beta diversity), followed by principal-coordinate analysis (PCoA). Uniform Manifold Approximation and Projection (UMAP) is an alternative method that can reduce the dimensionality of beta diversity distance matrices. Here, we demonstrate the benefits and limitations of using UMAP for dimensionality reduction on microbiome data. Using real data, we demonstrate that UMAP can improve the representation of clusters, especially when the clusters are composed of multiple subgroups. Additionally, we show that UMAP provides improved correlation of biological variation along a gradient with a reduced number of coordinates of the resulting embedding. Finally, we provide parameter recommendations that emphasize the preservation of global geometry. We therefore conclude that UMAP should be routinely used as a complementary visualization method for microbiome beta diversity studies. IMPORTANCE UMAP provides an additional method to visualize microbiome data. The method is extensible to any beta diversity metric used with PCoA, and our results demonstrate that UMAP can indeed improve visualization quality and correspondence with biological and technical variables of interest. The software to perform this analysis is available under an open-source license and can be obtained at https://github.com/knightlab-analyses/umap-microbiome-benchmarking; additionally, we have provided a QIIME 2 plugin for UMAP at https://github.com/biocore/q2-umap.

Uniform Manifold Approximation and Projection (UMAP) Reveals Composite Patterns and Resolves Visualization Artifacts in Microbiome Data

Graph signal processing (GSP) is an important methodology for studying data residing on irregular structures. Because acquired data are increasingly taking the form of multiway tensors, new signal processing tools are needed to maximally utilize the multiway structure within the data. In this article, we review modern signal processing frameworks that generalize GSP to multiway data, starting from graph signals coupled to familiar regular axes, such as time in sensor networks, and then extending to general graphs across all tensor modes. This widely applicable paradigm motivates reformulating and improving classical problems and approaches to creatively address the challenges in tensor-based data. We synthesize common themes arising from current efforts to combine GSP with tensor analysis and highlight future directions in extending GSP to the multiway paradigm.

Multiway Graph Signal Processing on Tensors: Integrative Analysis of Irregular Geometries

A low-dimensional dynamical system is observed in an experiment as a high-dimensional signal, for example, a video of a chaotic pendulums system. Assuming that we know the dynamical model up to some unknown parameters, can we estimate the underlying system's parameters by measuring its time-evolution only once? The key information for performing this estimation lies in the temporal inter-dependencies between the signal and the model. We propose a kernel-based score to compare these dependencies. Our score generalizes a maximum likelihood estimator for a linear model to a general nonlinear setting in an unknown feature space. We estimate the system's underlying parameters by maximizing the proposed score. We demonstrate the accuracy and efficiency of the method using two chaotic dynamical systems-the double pendulum and the Lorenz '63 model.

Kernel-based parameter estimation of dynamical systems with unknown observation functions

Poincaré Embedding Reveals Edge-Based Functional Networks of the Brain

Large-scale brain dynamics are believed to lie in a latent, low-dimensional space. Typically, the embeddings of brain scans are derived independently from different cognitive tasks or resting-state data, ignoring a potentially large—and shared—portion of this space. Here, we establish that a shared, robust, and interpretable low-dimensional space of brain dynamics can be recovered from a rich repertoire of task based fMRI data. This occurs when relying on non-linear approaches as opposed to traditional linear methods. The embedding maintains proper temporal progression of the tasks, revealing brain states and the dynamics of network integration. We demonstrate that resting-state data embeds fully onto the same task embedding, indicating similar brain states are present in both task and resting-state data. Our findings suggest analysis of fMRI data from multiple cognitive tasks in a low-dimensional space is possible and desirable, and our proposed framework can thus provide an interpretable framework to investigate brain dynamics in the low-dimensional space.

Non-linear manifold learning in fMRI uncovers a low-dimensional space of brain dynamics

Calcium imaging has become a fundamental neural imaging technique, aiming to recover the individual activity of hundreds of neurons in a cortical region. Current methods (mostly matrix factorization) are aimed at detecting neurons in the field-of-view and then inferring the corresponding time-traces. In this paper, we reverse the modeling and instead aim to minimize the spatial inference, while focusing on finding the set of temporal traces present in the data. We reframe the problem in a dictionary learning setting, where the dictionary contains the time-traces and the sparse coefficient are spatial maps. We adapt dictionary learning to calcium imaging by introducing constraints on the norms and correlations of the time-traces, and incorporating a hierarchical spatial filtering model that correlates the time-trace usage over the field-of-view. We demonstrate on synthetic and real data that our solution has advantages regarding initialization, implicitly inferring number of neurons and simultaneously detecting different neuronal types.

ICASSP 2019 - 2019 IEEE International Conference on Acoustics, Speech and Signal Processing (ICASSP)

Learning Spatially-correlated Temporal Dictionaries for Calcium Imaging

Optical calcium imaging is a versatile imaging modality that permits the recording of neural activity, including deep neural populations as well as single dendrites and spines using two-photon microscopy (TPM). Calcium imaging analysis relies on extracting the temporal fluorescence fluctuations of each component (e.g., spines, cell bodies or dendrites) from the full video. Current methods rely on strong a-priori spatial and temporal regularization to isolate each component, which can bias time-trace estimation and restrict applicability across imaging scales. We reverse the modeling and instead aim to minimize the spatial inference, while focusing on finding the set of temporal traces present in the data. We reframe the problem in a dictionary learning setting, where the dictionary contains the time-traces and the sparse coefficient are spatial maps. Our method is based on spatiallyfiltered Laplacian-scale mixture models, and we introduce additional constraints to implicitly infer the number of components and suppress their redundancy. We demonstrate our approach on calcium imaging at two different scales: population and dendritic imaging. First we compare our method to a current state-of-the-art algorithm, Suite2p, on the publicly available Neurofinder dataset. The flexible spatial constraints allows our model to isolate both disconnected portions of the same neuron and small components otherwise over-shadowed by stronger components. This latter case is important as such configurations can cause scientifically-misleading false transients. On dendritic data we demonstrate how our method isolates spines and dendritic firings.

Spatially-filtered temporal dictionary learning for calcium imaging analysis

Understanding why and how certain neural networks outperform others is key to guiding future development of network architectures and optimization methods. To this end, we introduce a novel visualization algorithm that reveals the internal geometry of such networks: Multislice PHATE (M-PHATE), the first method designed explicitly to visualize how a neural network's hidden representations of data evolve throughout the course of training. We demonstrate that our visualization provides intuitive, detailed summaries of the learning dynamics beyond simple global measures (i.e., validation loss and accuracy), without the need to access validation data. Furthermore, M-PHATE better captures both the dynamics and community structure of the hidden units as compared to visualization based on standard dimensionality reduction methods (e.g., ISOMAP, t-SNE). We demonstrate M-PHATE with two vignettes: continual learning and generalization. In the former, the M-PHATE visualizations display the mechanism of "catastrophic forgetting" which is a major challenge for learning in task-switching contexts. In the latter, our visualizations reveal how increased heterogeneity among hidden units correlates with improved generalization performance. An implementation of M-PHATE, along with scripts to reproduce the figures in this paper, is available at this https URL.

A Hierarchical Manifold Learning Framework for High-Dimensional Neuroimaging Data

Representation learning is typically applied to only one mode of a data matrix, either its rows or columns. Yet in many applications, there is an underlying geometry to both the rows and the columns. We propose utilizing this coupled structure to perform co-manifold learning: uncovering the underlying geometry of both the rows and the columns of a given matrix, where we focus on a missing data setting. Our unsupervised approach consists of three components. We first solve a family of optimization problems to estimate a complete matrix at multiple scales of smoothness. We then use this collection of smooth matrix estimates to compute pairwise distances on the rows and columns based on a new multi-scale metric that implicitly introduces a coupling between the rows and the columns. Finally, we construct row and column representations from these multi-scale metrics. We demonstrate that our approach outperforms competing methods in both data visualization and clustering.

Investigation of the moment-to-moment changes in brain activity using functional magnetic resonance imaging (fMRI) is an emerging field. However, one of the major problems is how to represent and evaluate these temporal relationships from the high-dimensional fMRI data. While many linear approaches have been proposed, nonlinear dimensionality reduction approaches may offer better solutions for these high-dimensional data. In this work, we propose a hierarchical, dimensionality reduction framework for time-synchronized fMRI data based on diffusion maps—a type of nonlinear embedding—labeled 2step diffusion maps (2sDM). For evaluation, we apply the framework to task fMRI during a working memory task for two large, independent datasets. By applying the embedding on the time domain, we show that our framework can detect brain states as defined by task blocks. By applying the embedding on the subjects domain, we show that subjects can be separated by their working memory performance. Together, these results show the promise of 2sDM as a nonlinear embedding framework for fMRI data.

Hierarchical nonlinear embedding reveals brain states and performance differences during working memory tasks

The extraction of clusters from a dataset which includes multiple clusters and a significant background component is a non-trivial task of practical importance. In image analysis this manifests for example in anomaly detection and target detection. The traditional spectral clustering algorithm, which relies on the leading K eigenvectors to detect K clusters, fails in such cases. In this paper we propose the spectral embedding norm which sums the squared values of the first I normalized eigenvectors, where I can be significantly larger than K. We prove that this quantity can be used to separate clusters from the background in unbalanced settings, including extreme cases such as outlier detection. The performance of the algorithm is not sensitive to the choice of I, and we demonstrate its application on synthetic and real-world remote sensing and neuroimaging datasets.

Spectral Embedding Norm: Looking Deep into the Spectrum of the Graph Laplacian

Recent advances in experimental methods in neuroscience enable measuring in-vivo activity of large populations of neurons at cellular level resolution. To leverage the full potential of these complex datasets and analyze the dynamics of individual neurons, it is essential to extract high-resolution regions of interest, while addressing demixing of overlapping spatial components and denoising of the temporal signal of each neuron. In this paper, we propose a data-driven solution to these challenges, by representing the spatiotemporal volume as a graph in the image plane. Based on the spectral embedding of this graph calculated across trials, we propose a new clustering method, Local Selective Spectral Clustering, capable of handling overlapping clusters and disregarding clutter. We also present a new nonlinear mapping which recovers the structural map of the neurons and dendrites, and global video denoising. We demonstrate our approach on in-vivo calcium imaging of neurons and apical dendrites, automatically extracting complex structures in the image domain, and denoising and demixing their time-traces.

Automated cellular structure extraction in biological images with applications to calcium imaging data

Diffusion maps, when applied to large datasets, are typically constructed by a process of sampling and out-of-sample function extension. However, the performance of anomaly detection in large data when using diffusion maps is sensitive to the chosen samples. In this paper we propose an iterative data-driven approach to improve the sample set and diffusion maps representation. By updating the sample set with suspicious points detected in the previous iteration, the constructed diffusion maps better separate the anomaly from the normal points in each iteration. Experimental results in side-scan sonar images demonstrate the improvement gained by our iterative sampling compared to random sampling and other competing detection algorithms.

If we pick n random points uniformly in [0, 1] d and connect each point to its c d log n-nearest neighbors, where d ≥ 2 is the dimension and c d is a constant depending on the dimension, then it is well known that the graph is connected with high probability. We prove that it suffices to connect every point to c d,1 log log n points chosen randomly among its c d,2 log n-nearest neighbors to ensure a giant component of size n - o(n) with high probability. This construction yields a much sparser random graph with ~ n log log n instead of ~ n log n edges that has comparable connectivity properties. This result has nontrivial implications for problems in data science where an affinity matrix is constructed: instead of connecting each point to its k nearest neighbors, one can often pick k' ≪ k random points out of the k nearest neighbors and only connect to those without sacrificing quality of results. This approach can simplify and accelerate computation; we illustrate this with experimental results in spectral clustering of large-scale datasets.

Randomized Near Neighbor Graphs, Giant Components, and Applications in Data Science

We consider the analysis of high-dimensional data given in the form of a matrix with columns consisting of observations and rows consisting of features. Often the data is such that the observations do not reside on a regular grid, and the given order of the features is arbitrary and does not convey a notion of locality. Therefore, traditional transforms and metrics cannot be used for data organization and analysis. In this paper, our goal is to organize the data by defining an appropriate representation and metric such that they respect the smoothness and structure underlying the data. We also aim to generalize the joint clustering of observations and features in the case the data does not fall into clear disjoint groups. For this purpose, we propose multiscale data-driven transforms and metrics based on trees. Their construction is implemented in an iterative refinement procedure that exploits the co-dependencies between features and observations. Beyond the organization of a single dataset, our approach enables us to transfer the organization learned from one dataset to another and to integrate several datasets together. We present an application to breast cancer gene expression analysis: Learning metrics on the genes to cluster the tumor samples into cancer subtypes and validating the joint organization of both the genes and the samples. We demonstrate that using our approach to combine information from multiple gene expression cohorts, acquired by different profiling technologies, improves the clustering of tumor samples.

IEEE Transactions on Signal and Information Processing over Networks

Recently, a supervised graph-based target detection method was proposed based on a new affinity measure between a set of target training patches and a test image. In this paper, we propose a new high-resolution detection score, which enhances the performance of the previous method by utilizing the known locations of the targets in the training images. We show that our new score is more reliable and spatially accurate, not only improving the detection resolution of true targets, but also reducing the number of false alarms. The method is successfully tested on side-scan sonar images of sea-mines, demonstrating an improved true detection rate. Our approach is general and can improve the detection resolution of the target in other patch-based detection algorithms for various signals and applications.

2016 IEEE International Conference on Acoustics, Speech and Signal Processing (ICASSP)

In this paper, we propose a detection method based on data-driven target modeling, which implicitly handles variations in the target appearance. Given a training set of images of the target, our approach constructs models based on local neighborhoods within the training set. We present a new metric using these models and show that, by controlling the notion of locality within the training set, this metric is invariant to perturbations in the appearance of the target. Using this metric in a supervised graph framework, we construct a low-dimensional embedding of test images. Then, a detection score based on the embedding determines the presence of a target in each image. The method is applied to a data set of side-scan sonar images and achieves impressive results in the detection of sea mines. The proposed framework is general and can be applied to different target detection problems in a broad range of signals.

In the wake of recent advances in experimental methods in neuroscience, the ability to record in-vivo neuronal activity from awake animals has become feasible. The availability of such rich and detailed physiological measurements calls for the development of advanced data analysis tools, as commonly used techniques do not suffice to capture the spatio-temporal network complexity. In this paper, we propose a new hierarchical coupled-geometry analysis that implicitly takes into account the connectivity structures between neurons and the dynamic patterns at multiple time scales. Our approach gives rise to the joint organization of neurons and dynamic patterns in data-driven hierarchical data structures. These structures provide local to global data representations, from local partitioning of the data in flexible trees through a new multiscale metric to a global manifold embedding. The application of our techniques to in-vivo neuronal recordings demonstrate the capability of extracting neuronal activity patterns and identifying temporal trends, associated with particular behavioral events and manipulations introduced in the experiments.

Hierarchical Coupled-Geometry Analysis for Neuronal Structure and Activity Pattern Discovery

Detection of defects on patterned semiconductor wafers is a critical step in wafer production. Many inspection methods and apparatus have been developed for this purpose. We recently presented an anomaly detection approach based on geometric manifold learning techniques. This approach is data-driven, with the separation of the anomaly from the background arising from the intrinsic geometry of the image, revealed through the use of diffusion maps. In this paper, we extend our algorithm to 3D data in multichannel wafer defect detection. We test our algorithm on a set of semiconductor wafers and demonstrate that our multiscale multi-channel algorithm has superior performance when compared to single-scale and single-channel approaches.

2014 IEEE 28th Convention of Electrical & Electronics Engineers in Israel (IEEEI)

Recently, we presented a multiscale approach to anomaly detection in images, combining diffusion maps for dimensionality reduction and a nearest-neighbor-based anomaly score in the reduced dimension. When applying diffusion maps to images, usually a process of sampling and out-of-sample extension is used, which has limitations in regards to anomaly detection. To overcome the limitations, a multiscale approach was proposed, which drives the sampling process to ensure separability of the anomaly from the background clutter. In this paper, we propose a new anomaly score used in the diffusion map space, which shows increased performance. We show that this algorithm enables improved detection when tested on side-scan sonar images of sea-mines and compare it with competing algorithms.

2014 IEEE International Conference on Acoustics, Speech and Signal Processing (ICASSP)

Multiscale anomaly detection using diffusion maps and saliency score

We propose a multiscale approach to anomaly de- tection in images, combining spectral dimensionality reduction and a nearest-neighbor-based anomaly score. We use diffusion maps to embed the data in a low dimensional representation, which separates the anomaly from the background. The diffusion distance between points is then used to estimate the local density of each pixel in the new embedding. The diffusion map is constructed based on a subset of samples from the image and then extended to all other pixels. Due to the interpolative nature of extension methods, this may limit the ability of the diffusion map to reveal the presence of the anomaly in the data. To overcome this limitation, we propose a multiscale approach based on Gaussian pyramid representation, which drives the sampling process to ensure separability of the anomaly from the background clutter. The algorithm is successfully tested on side-scan sonar images of sea-mines.

We propose a multiscale approach to anomaly detection in images, combining spectral dimensionality reduction and a nearest-neighbor-based anomaly score. We use diffusion maps to embed the data in a low dimensional representation, which separates the anomaly from the background. The diffusion distance between points is then used to estimate the local density of each pixel in the new embedding. The diffusion map is constructed based on a subset of samples from the image and then extended to all other pixels. Due to the interpolative nature of extension methods, this may limit the ability of the diffusion map to reveal the presence of the anomaly in the data. To overcome this limitation, we propose a multiscale approach based on Gaussian pyramid representation, which drives the sampling process to ensure separability of the anomaly from the background clutter. The algorithm is successfully tested on side-scan sonar images of sea-mines.

Compositional and texture-independent 3D orientation coding in visual cortex

Hunger or thirst state-uncertainty is resolved by outcome evaluation in medial prefrontal cortex to guide decision-making

Survey of spiking in the mouse visual system reveals functional hierarchy

Decision letter: Reconciling functional differences in populations of neurons recorded with two-photon imaging and electrophysiology

Electrode pooling can boost the yield of extracellular recordings with switchable silicon probes

Brains must represent the outside world so that animals survive and thrive. In early sensory systems, neural populations have diverse receptive fields structured to detect important features in inputs, yet significant variability has been ignored in classical models of sensory neurons. We model neuronal receptive fields as random, variable samples from parameterized distributions and demonstrate this model in two sensory modalities using data from insect mechanosensors and mammalian primary visual cortex. Our approach leads to a significant theoretical connection between the foundational concepts of receptive fields and random features, a leading theory for understanding artificial neural networks. The modeled neurons perform a randomized wavelet transform on inputs, which removes high frequency noise and boosts the signal. Further, these random feature neurons enable learning from fewer training samples and with smaller networks in artificial tasks. This structured random model of receptive fields provides a unifying, mathematically tractable framework to understand sensory encodings across both spatial and temporal domains.

Structured random receptive fields enable informative sensory encodings

For many
studies, especially those focusing on learning and plasticity, it is important
to track the activity of neurons over long periods. Prolonged recordings can be
achieved with two-photon imaging, but this method is difficult in deep brain
structures and has limited temporal resolution. Here we asked whether neurons
could be reliably tracked across recordings with Neuropixels probes, which
allow access not only to the cortex but also to deep brain structures and can
resolve individual spikes.We
chronically implanted mice with prototype version 2.0 Neuropixels probes.
They can have one shank or four shanks, and have tightly spaced recording sites
aligned in two columns, as shown in the methods section. Neuropixels devices
can be carried by mice for months without any
observed problems. We
implanted the probes vertically through primary visual cortex and cemented them
to the cranium. For recordings, mice were head-fixed in front of computer screens. Recordings were performed at
regular intervals for more than half a year. To characterize the
neurons, during each recording we presented a library of natural images.
Recordings yielded many neurons across more than 6 months as demonstrated in section
1, but there was substantial drift of the probe relative to the brain tissue across
sessions. To compensate for it, we used a specially adapted version of
Kilosort2 spike-sorting program that detects and corrects for such drifts in
spliced recordings. Many V1 neurons responded to the presented images and
showed a pattern of preferences that constituted a unique signature, as shown in
section two. Figure 5 shows responses of all selective neurons on a day of
recording and a consecutive day. They look similar, but how similar are they?
In order to quantify that, we took pairs of recordings and spike sorted them
together. For each signature on the first day, we find the signature from the
second day that correlates with it the most. For most responsive neurons, it is
the same neuron’s signature, because most dots on figure 6 are situated on the diagonal.
This is true across days, weeks and even months. We are able to track
significantly higher percentage of neurons than previous state-of-the-art
methods. Moreover, our method, unlike previous ones, does not require
continuous recording. To conclude, the new Neuropixels probe, whose geometry is
particularly helpful for tracking
drifts, and the adapted Kilosort 2 algorithm allow to track same
cortical neurons over the course of days, weeks and months. The ability to
follow large populations of individual neurons over extended periods opens new
possibilities in the study of learning and plasticity.

Recording from the same cortical neurons over months with Neuropixels probes

Recording many neurons for a long time The ultimate aim of chronic recordings is to sample from the same neuron over days and weeks. However, this goal has been difficult to achieve for large populations of neurons. Steinmetz et al. describe the development and testing of Neuropixels 2.0. This new electrophysiological recording tool is a miniaturized, high-density probe for both acute and long-term experiments combined with sophisticated software algorithms for fully automatic post hoc computational stabilization. The technique also provides a strategy for extending the number of recorded sites beyond the number of available recording channels. In freely moving animals, extremely large numbers of individual neurons could thus be followed and tracked with the same probe for weeks and occasionally months. Science, this issue p. eabf4588 An approach has been developed that allows recording from the same neurons in a freely behaving animal for weeks and months. INTRODUCTION Electrode arrays based on complementary metal-oxide semiconductor silicon fabrication technology, such as Neuropixels probes, have enabled recordings of thousands of individual neurons in the living brain. These tools have led to discoveries about the brain-wide correlates of perception and action, primarily when used in acute, head-fixed recordings. To study the dynamics of neuronal processing across time scales, however, it is necessary to record from neurons over weeks and months, ideally during unrestrained behavior and in small animals, such as mice. RATIONALE To this end, we designed a miniaturized probe, called Neuropixels 2.0, with 5120 recording sites distributed over four shanks. The probe and headstage were miniaturized to about one-third of the original size (i.e., the size of the Neuropixels 1.0 probe), so that two probes and their single headstage weigh only ~1.1 g, without loss of channel count (384 channels per probe). Using two four-shank probes provides 10,240 recording sites in one implant. To achieve stable recordings despite brain movement, we optimized the recording site arrangement. The probe has a denser, linearized geometry that allows for post hoc computational motion correction using a newly designed algorithm. This algorithm, implemented in the Kilosort 2.5 software package, determines the motion over time from the spiking data and corrects it with spatial resampling, as in image registration. RESULTS To validate these probes for long-term recordings, we implanted them chronically in 21 rats and mice in six laboratories. Twenty of these 21 implants succeeded and yielded neurons over weeks and months while retaining good signal quality. The probes were reliably recoverable using newly engineered implant fixture designs. To test the performance of the motion correction algorithm, we performed recordings with known imposed motion of the probe relative to the brain. The algorithm improved the yield of stable neurons and largely eliminated the impact of motion on the recording. A version of this algorithm allowed the recording of neurons stably across days. We assessed this by “fingerprinting” individual chronically recorded neurons in the primary visual cortex using their distinctive visual responses to a battery of images. Neuron tracking was >90% successful for up to 2 weeks and >80% successful for up to 2 months. CONCLUSION This work demonstrates a suite of electrophysiological tools comprising a miniaturized high-density probe, recoverable chronic implant fixtures, and algorithms for automatic post hoc motion correction. These tools enable an order-of-magnitude increase in the number of sites that can be recorded in small animals, such as mice, and the ability to record from them stably over long time scales. Neuropixels 2.0 probes allow unprecedented recordings. (A) Comparison of the Neuropixels 1.0 and 2.0 device designs. The Neuropixels 2.0 device is miniaturized and has four shanks. Two probes can be hosted per headstage. (B) Pattern of spiking activity across the cortex (Ctx), hippocampus (HC), and thalamus (Th) recorded over >300 days. (C) Example spiking rasters from two Neuropixels 2.0 probes chronically implanted in a mouse, showing spikes recorded on 6144 of the 10,240 sites available across the two probes. Eight sequential recordings (different colors) were performed from 768 channels each. Measuring the dynamics of neural processing across time scales requires following the spiking of thousands of individual neurons over milliseconds and months. To address this need, we introduce the Neuropixels 2.0 probe together with newly designed analysis algorithms. The probe has more than 5000 sites and is miniaturized to facilitate chronic implants in small mammals and recording during unrestrained behavior. High-quality recordings over long time scales were reliably obtained in mice and rats in six laboratories. Improved site density and arrangement combined with newly created data processing methods enable automatic post hoc correction for brain movements, allowing recording from the same neurons for more than 2 months. These probes and algorithms enable stable recordings from thousands of sites during free behavior, even in small animals such as mice.

Neuropixels 2.0: A miniaturized high-density probe for stable, long-term brain recordings

Neuron activity across the brain How is it that groups of neurons dispersed through the brain interact to generate complex behaviors? Three papers in this issue present brain-scale studies of neuronal activity and dynamics (see the Perspective by Huk and Hart). Allen et al. found that in thirsty mice, there is widespread neural activity related to stimuli that elicit licking and drinking. Individual neurons encoded task-specific responses, but every brain area contained neurons with different types of response. Optogenetic stimulation of thirst-sensing neurons in one area of the brain reinstated drinking and neuronal activity across the brain that previously signaled thirst. Gründemann et al. investigated the activity of mouse basal amygdala neurons in relation to behavior during different tasks. Two ensembles of neurons showed orthogonal activity during exploratory and nonexploratory behaviors, possibly reflecting different levels of anxiety experienced in these areas. Stringer et al. analyzed spontaneous neuronal firing, finding that neurons in the primary visual cortex encoded both visual information and motor activity related to facial movements. The variability of neuronal responses to visual stimuli in the primary visual area is mainly related to arousal and reflects the encoding of latent behavioral states. Science, this issue p. eaav3932, p. eaav8736, p. eaav7893; see also p. 236 Water deprivation establishes a brainwide activity state that gates how sensory stimuli produce behavioral responses. INTRODUCTION Motivational drives are internal states that can explain why animals adaptively display distinct behaviors in response to the same external stimulus. Physiological needs (e.g., for food and water) are thought to produce specific drives that engage particular goal-directed behaviors to promote survival. These drives are established through the activity of populations of hypothalamic neurons that sense physiological variables and relay this information to other parts of the brain. However, it is unclear how the activity of these hypothalamic neurons activates and coordinates other brain systems involved in sensation, decision-making, and action in order to produce the appropriate goal-directed behavior. The cellular dynamics of brainwide states underlying basic survival drives have heretofore remained inaccessible. RATIONALE Understanding the neural basis of motivated behavior would require measuring activity within distributed neural circuits in the brain and studying how this activity is regulated by the animal’s motivational state. Recent advances in extracellular electrophysiological recording technology have enabled large-scale measurements of neuronal activity throughout the brains of behaving animals. This technology could lead to a spatiotemporal map of activity flow across the brain as an animal senses and responds to stimuli under different conditions. By examining the animal in different motivational states, we could determine how these states are represented in diverse brain regions and how these states influence neuronal activity across the brain to alter behavior. RESULTS We recorded the activity of ~24,000 neurons throughout 34 brain regions during thirst-motivated choice behavior; these recordings were performed across 87 sessions from 21 mice as they gradually consumed water and became sated. We found that more than half of recorded neurons were modulated by this task, with a rapid and widespread response to a water-predicting olfactory cue preceding sustained activity related to water acquisition. The animal’s satiety state gated this wave of activity: In satiated mice, the same sensory cue produced only a transient change in activity and no behavioral response. Surprisingly, the spontaneous baseline activity of neurons across many brain regions was also modulated by the animal’s satiety state. We found diverse correlates of the task at the single-neuron level, with many neurons’ activity correlating with specific sensory cues or behavior, and some of them highly modulated by satiety state. Neurons from each of these groups were distributed throughout the brain, with each brain area differing in the relative proportions of different types of neurons. We separated the high-dimensional population activity dynamics into lower-dimensional state-, cue-, and behavior-related modes. Whereas the cue- and behavior-related modes were primarily modulated by the task in a satiety state–dependent manner, activity along the state mode was persistent throughout the trial, including the period before odor onset. Thus, there existed a brainwide representation of satiety state that appeared to gate the flow of activity in response to sensory inputs. Finally, as a causal test of the role of this widespread encoding of satiety state, we optogenetically stimulated hypothalamic thirst neurons and caused mice to perform more trials after reaching satiety. We found that this focal stimulation returned the behavior, brainwide single-neuron within-trial dynamics, and brainwide single-neuron correlates of satiety state back to the state corresponding to thirst. Stimulation also specifically modulated activity along the satiety-related mode in a subset of brain areas. CONCLUSION Our experiments revealed a global representation of the thirst motivational state throughout the brain, which appears to gate the brainwide propagation of sensory information and its subsequent transformation into behavioral output. Brainwide dynamics of thirst motivational drive. Top left: Potential models for widespread or selective regulation of neural dynamics by thirst. Bottom left: Tracks of Neuropixels electrodes used to record activity from different brain regions during thirst-motivated behavior. Center: Brainwide activity dynamics of individual neurons in response to a sensory cue while a mouse was thirsty and sated. Top right: Neural activity correlated with satiety state. Bottom right: Low-dimensional dynamics of task-related activity. Physiological needs produce motivational drives, such as thirst and hunger, that regulate behaviors essential to survival. Hypothalamic neurons sense these needs and must coordinate relevant brainwide neuronal activity to produce the appropriate behavior. We studied dynamics from ~24,000 neurons in 34 brain regions during thirst-motivated choice behavior in 21 mice as they consumed water and became sated. Water-predicting sensory cues elicited activity that rapidly spread throughout the brain of thirsty animals. These dynamics were gated by a brainwide mode of population activity that encoded motivational state. After satiation, focal optogenetic activation of hypothalamic thirst-sensing neurons returned global activity to the pre-satiation state. Thus, motivational states specify initial conditions that determine how a brainwide dynamical system transforms sensory input into behavioral output.

Thirst regulates motivated behavior through modulation of brainwide neural population dynamics

The operating mode of the visual system depends on behavioural states such as arousal1,2. This dependence is seen both in primary visual cortex3–7 (V1) and in subcortical brain structures receiving direct retinal input4,8. Here we show that this effect arises as early as in the output of the retina. We first measured activity in a region that receives retinal projections9, the superficial superior colliculus (sSC), and found that this activity strongly depended on behavioural state. This modulation was not mediated by feedback inputs from V1 as it was immune to V1 inactivation. We then used Neuropixels probes10 to record activity in the optic tract, and we found some retinal axons whose activity significantly varied with arousal, even in darkness. To characterize these effects on a larger sample of retinal outputs, we imaged the activity of retinal boutons11,12 in sSC during behaviour using a calcium indicator. The activity of these boutons correlated with arousal as strongly as that of sSC neurons, and this correlation persisted also during darkness. These results reveal a novel property of retinal function in mice, which could be observed only during behaviour: retinal outputs are modulated by behavioural state before they reach the rest of the brain.

The mammalian visual system, from retina to neocortex, has been extensively studied at both anatomical and functional levels. Anatomy indicates the cortico-thalamic system is hierarchical, but characterization of cellular-level functional interactions across multiple levels of this hierarchy is lacking, partially due to the challenge of simultaneously recording activity across numerous regions. Here, we describe a large, open dataset (part of the Allen Brain Observatory) that surveys spiking from units in six cortical and two thalamic regions responding to a battery of visual stimuli. Using spike cross-correlation analysis, we find that inter-area functional connectivity mirrors the anatomical hierarchy from the Allen Mouse Brain Connectivity Atlas. Classical functional measures of hierarchy, including visual response latency, receptive field size, phase-locking to a drifting grating stimulus, and autocorrelation timescale are all correlated with the anatomical hierarchy. Moreover, recordings during a visual task support the behavioral relevance of hierarchical processing. Overall, this dataset and the hierarchy we describe provide a foundation for understanding coding and dynamics in the mouse cortico-thalamic visual system.

A survey of spiking activity reveals a functional hierarchy of mouse corticothalamic visual areas

State-of-the-art silicon probes for electrical recording from neurons have thousands of recording sites. However, due to volume limitations there are typically many fewer wires carrying signals off the probe, which restricts the number of channels that can be recorded simultaneously. To overcome this fundamental constraint, we propose a novel method called electrode pooling that uses a single wire to serve many recording sites through a set of controllable switches. Here we present the framework behind this method and an experimental strategy to support it. We then demonstrate its feasibility by implementing electrode pooling on the Neuropixels 1.0 electrode array and characterizing its effect on signal and noise. Finally we use simulations to explore the conditions under which electrode pooling saves wires without compromising the content of the recordings. We make recommendations on the design of future devices to take advantage of this strategy.

Electrode pooling: boosting the yield of extracellular recordings with switchable silicon probes

Populations of neurons in primary visual cortex (V1) transform direct thalamic inputs into a cortical representation which acquires new spatio-temporal properties. One of these properties, motion selectivity, has not been strongly tied to putative neural mechanisms, and its origins remain poorly understood. Here we propose that motion selectivity is acquired through the recurrent mechanisms of a network of strongly connected neurons. We first show that a bank of V1 spatiotemporal receptive fields can be generated accurately by a network which receives only instantaneous inputs from the retina. The temporal structure of the receptive fields is generated by the long timescale dynamics associated with the high magnitude eigenvalues of the recurrent connectivity matrix. When these eigenvalues have complex parts, they generate receptive fields that are inseparable in time and space, such as those tuned to motion direction. We also show that the recurrent connectivity patterns can be learnt directly from the statistics of natural movies using a temporally-asymmetric Hebbian learning rule. Probed with drifting grating stimuli and moving bars, neurons in the model show patterns of responses analogous to those of direction-selective simple cells in primary visual cortex. These computations are enabled by a specific pattern of recurrent connections, that can be tested by combining connectome reconstructions with functional recordings.* Author summary Dynamic visual scenes provide our eyes with enormous quantities of visual information, particularly when the visual scene changes rapidly. Even at modest moving speeds, individual small objects quickly change their location causing single points in the scene to change their luminance equally fast. Furthermore, our own movements through the world add to the velocities of objects relative to our retinas, further increasing the speed at which visual inputs change. How can a biological system process efficiently such vast amounts of information, while keeping track of objects in the scene? Here we formulate and analyze a solution that is enabled by the temporal dynamics of networks of neurons.

Fully integrated silicon probes for high-density recording of neural activity

New silicon technology is enabling large-scale electrophysiological recordings in vivo from hundreds to thousands of channels. Interpreting these recordings requires scalable and accurate automated methods for spike sorting, which should minimize the time required for manual curation of the results. Here we introduce KiloSort, a new integrated spike sorting framework that uses template matching both during spike detection and during spike clustering. KiloSort models the electrical voltage as a sum of template waveforms triggered on the spike times, which allows overlapping spikes to be identified and resolved. Unlike previous algorithms that compress the data with PCA, KiloSort operates on the raw data which allows it to construct a more accurate model of the waveforms. Processing times are faster than in previous algorithms thanks to batch-based optimization on GPUs. We compare KiloSort to an established algorithm and show favorable performance, at much reduced processing times. A novel post-clustering merging step based on the continuity of the templates further reduced substantially the number of manual operations required on this data, for the neurons with near-zero error rates, paving the way for fully automated spike sorting of multichannel electrode recordings.

Fast and accurate spike sorting of high-channel count probes with KiloSort

Advances in silicon probe technology mean that in vivo electrophysiological recordings from hundreds of channels will soon become commonplace. To interpret these recordings we need fast, scalable and accurate methods for spike sorting, whose output requires minimal time for manual curation. Here we introduce Kilosort, a spike sorting framework that meets these criteria, and show that it allows rapid and accurate sorting of large-scale in vivo data. Kilosort models the recorded voltage as a sum of template waveforms triggered on the spike times, allowing overlapping spikes to be identified and resolved. Rapid processing is achieved thanks to a novel low-dimensional approximation for the spatiotemporal distribution of each template, and to batch-based optimization on GPUs. A novel post-clustering merging step based on the continuity of the templates substantially reduces the requirement for subsequent manual curation operations. We compare Kilosort to an established algorithm on data obtained from 384-channel electrodes, and show superior performance, at much reduced processing times. Data from 384-channel electrode arrays can be processed in approximately realtime. Kilosort is an important step towards fully automated spike sorting of multichannel electrode recordings, and is freely available (github.com/cortex-lab/Kilosort).

Kilosort: realtime spike-sorting for extracellular electrophysiology with hundreds of channels

In the mouse primary visual cortex (V1), sensory responses are shaped by behavioral factors such as locomotion. These factors are thought to control a disinhibitory circuit, whereby interneurons expressing vasoactive intestinal peptide (Vip) inhibit those expressing somatostatin (Sst), disinhibiting pyramidal cells (Pyr). We measured the effect of locomotion on these neurons and on interneurons expressing parvalbumin (Pvalb) in layer 2/3 of mouse V1, and found in-consistencies with the disinhibitory model. In the presence of large stimuli, locomotion increased Sst cell responses without suppressing Vip cells. In the presence of small stimuli, locomotion increased Vip cell responses without suppressing Sst cells. A circuit model could reproduce each cell type’s activity from the measured activity of other cell types, but only if we allowed locomotion to increase feedforward synaptic weights while modulating recurrent weights. These results suggest that locomotion alters cortical function by changing effective synaptic connectivity, rather than only through disinhibition.

Vision and Locomotion Shape the Interactions between Neuron Types in Mouse Visual Cortex

Sensory function is mediated by interactions between external stimuli and intrinsic cortical dynamics that are evident in the modulation of evoked responses by cortical state. A number of recent studies across different modalities have demonstrated that the patterns of activity in neuronal populations can vary strongly between synchronized and desynchronized cortical states, i.e., in the presence or absence of intrinsically generated up and down states. Here we investigated the impact of cortical state on the population coding of tones and speech in the primary auditory cortex (A1) of gerbils, and found that responses were qualitatively different in synchronized and desynchronized cortical states. Activity in synchronized A1 was only weakly modulated by sensory input, and the spike patterns evoked by tones and speech were unreliable and constrained to a small range of patterns. In contrast, responses to tones and speech in desynchronized A1 were temporally precise and reliable across trials, and different speech tokens evoked diverse spike patterns with extremely weak noise correlations, allowing responses to be decoded with nearly perfect accuracy. Restricting the analysis of synchronized A1 to activity within up states yielded similar results, suggesting that up states are not equivalent to brief periods of desynchronization. These findings demonstrate that the representational capacity of A1 depends strongly on cortical state, and suggest that cortical state should be considered as an explicit variable in all studies of sensory processing.

Many essential neural computations are implemented by large populations of neurons working in concert. Recent studies have sought both to monitor increasingly large groups of neurons and to characterise their collective behaviour, but the standard computational approaches available to identify the collective dynamics scale poorly with the size of the dataset. We develop new efficient methods for discovering the low-dimensional dynamics that underlie simultaneously-recorded spike trains from a neural population. We use the new models to analyze two different sets of population recordings, one from motor cortex and another from auditory cortex. In motor cortex, we describe the nature of the trial-by-trial spontaneous fluctuations identified by the model and connect these fluctuations to behavioral events. The spatio-temporal structure of the spontaneous events was tracked by three trajectories identified by the model. These trajectories followed similar dynamics during hand reaches as they did when the hands were stationary. The structure of the models we developed allow them to be used as decoders of hand position from neural activity, significantly improving upon previous state-of-the-art methods. The decoders were able to predict information about the direction, onset time and speed profile of movements. In auditory cortex, we use the statistical models to identify population dynamics under different brain states. We report major differences in dynamics and stimulus coding between synchronized and desychronized brain states. Synchronized but not desynchronized brain states imposed constraints on neural dynamics such that a four-dimensional system accounted for most of the dynamical structure of population events. We used the low-dimensional representation of the data to construct network simulations that reproduced the patterns present in the recordings. The simulations suggest that the overall level of feedback inhibition controls the stability of each local cortical network, with unstable dynamics resulting in synchronized brain states. Finally we propose a functional role for dynamics in the representation of visual motion in visual cortex.

Learning Enhances Senso ry and Multiple Non-sensory Representations in Primary Visual Cortex Highlights

Learning Enhances Sensory and Multiple Non-sensory Representations in Primary Visual Cortex

Population neural recordings with long-range temporal structure are often best understood in terms of a common underlying low-dimensional dynamical process. Advances in recording technology provide access to an ever-larger fraction of the population, but the standard computational approaches available to identify the collective dynamics scale poorly with the size of the dataset. We describe a new, scalable approach to discovering low-dimensional dynamics that underlie simultaneously recorded spike trains from a neural population. We formulate the Recurrent Linear Model (RLM) by generalising the Kalman-filter-based likelihood calculation for latent linear dynamical systems to incorporate a generalised-linear observation process. We show that RLMs describe motor-cortical population data better than either directly-coupled generalised-linear models or latent linear dynamical system models with generalised-linear observations. We also introduce the cascaded generalised-linear model (CGLM) to capture low-dimensional instantaneous correlations in neural populations. The CGLM describes the cortical recordings better than either Ising or Gaussian models and, like the RLM, can be fit exactly and quickly. The CGLM can also be seen as a generalisation of a low-rank Gaussian model, in this case factor analysis. The computational tractability of the RLM and CGLM allow both to scale to very high-dimensional neural data.

Recurrent linear models of simultaneously-recorded neural populations

Neural language models (LMs) based on recurrent neural networks (RNN) are some of the most successful word and character-level LMs. Why do they work so well, in particular better than linear neural LMs? Possible explanations are that RNNs have an implicitly better regularization or that RNNs have a higher capacity for storing patterns due to their nonlinearities or both. Here we argue for the first explanation in the limit of little training data and the second explanation for large amounts of text data. We show state-of-the-art performance on the popular and small Penn dataset when RNN LMs are regularized with random dropout. Nonetheless, we show even better performance from a simplified, much less expressive linear RNN model without off-diagonal entries in the recurrent matrix. We call this model an impulse-response LM (IRLM). Using random dropout, column normalization and annealed learning rates, IRLMs develop neurons that keep a memory of up to 50 words in the past and achieve a perplexity of 102.5 on the Penn dataset. On two large datasets however, the same regularization methods are unsuccessful for both models and the RNN's expressivity allows it to overtake the IRLM by 10 and 20 percent perplexity, respectively. Despite the perplexity gap, IRLMs still outperform RNNs on the Microsoft Research Sentence Completion (MRSC) task. We develop a slightly modified IRLM that separates long-context units (LCUs) from short-context units and show that the LCUs alone achieve a state-of-the-art performance on the MRSC task of 60.8%. Our analysis indicates that a fruitful direction of research for neural LMs lies in developing more accessible internal representations, and suggests an optimization regime of very high momentum terms for effectively training such models.

Regularization and nonlinearities for neural language models: when are they needed?

Biological tissue is often composed of cells with similar morphologies replicated throughout large volumes and many biological applications rely on the accurate identification of these cells and their locations from image data. Here we develop a generative model that captures the regularities present in images composed of repeating elements of a few different types. Formally, the model can be described as convolutional sparse block coding. For inference we use a variant of convolutional matching pursuit adapted to block-based representations. We extend the K-SVD learning algorithm to subspaces by retaining several principal vectors from the SVD decomposition instead of just one. Good models with little cross-talk between subspaces can be obtained by learning the blocks incrementally. We perform extensive experiments on simulated images and the inference algorithm consistently recovers a large proportion of the cells with a small number of false positives. We fit the convolutional model to noisy GCaMP6 two-photon images of spiking neurons and to Nissl-stained slices of cortical tissue and show that it recovers cell body locations without supervision. The flexibility of the block-based representation is reflected in the variability of the recovered cell shapes.

Extracting regions of interest from biological images with convolutional sparse block coding

We introduce the Recurrent Generalized Linear Model (R-GLM), an extension of GLMs based on a compact representation of the spiking history through a linear recurrent neural network. R-GLMs match the predictive likelihood of Linear Dynamical Systems (LDS) with linear-Gaussian observations. We also address a disadvantage of GLMs, including the R-GLM, that they cannot model instantaneous correlations. The LDS however allows for extra correlated variability through the new innovation in the latent space. To improve GLMs we introduce a class of correlated output distributions which can be used with any type of multivariate data: binary, counts or continuous. The correlated Bernoulli distribution matches the predictive likelihood of Ising models for static binarized spike data. The correlated Poisson distribution offers significant improvements in predictive likelihood for GLMs and R-GLMs. We evaluate the performance of the models on a dataset recorded from a Utah array implanted into motor areas of a macaque monkey during a delayed reaching task. We report that the R-GLM consistently finds long timescales (of up to several seconds) of correlated activity similar to those found by LDS and longer than the timescales learnt by standard GLMs (up to 400 ms). Like all GLMs, the proposed model can be used with any link function and any output distribution. This is unlike models based on LDS which require careful approximations to be trained with Poisson outputs.

Recurrent generalized linear models with correlated Poisson observations

We present a dynamic nonlinear generative model for visual motion based on a latent representation of binary-gated Gaussian variables. Trained on sequences of images, the model learns to represent different movement directions in different variables. We use an online approximate inference scheme that can be mapped to the dynamics of networks of neurons. Probed with drifting grating stimuli and moving bars of light, neurons in the model show patterns of responses analogous to those of direction-selective simple cells in primary visual cortex. Most model neurons also show speed tuning and respond equally well to a range of motion directions and speeds aligned to the constraint line of their respective preferred speed. We show how these computations are enabled by a specific pattern of recurrent connections learned by the model.

We found that cortical neurons in a rat premotor area called the Frontal Orienting Fields (FOF) have ISI distributions well matched by Gamma(k, θ), where k averaged 3.07 ± 1.09 (mean ± sd). The gamma shape estimator which we use (k) is based on the statistics of ratios of pairs of consecutive intervals and can be easily fit nonparametrically as a function of either time in the trial or firing rate (r) or both. The kestimator is more robust to outliers than estimators obtained from probabilistic models fitted with GLMs. We found that k(r) was approximately constant for 329/504 neurons, increasing for 135/504 neurons and had a peak for 44/504 neurons. There were also significant interactions between behavior and regularity, not accounted for by firing rate modulations alone. For example, some neurons fired more regularly during the execution of movements. Others fired more regularly when a reward was delivered but not when it was absent. We then showed that a simple linear leaky integrate and fire (LLIF) model with a calcium activated K+ current (IAHP ) and a relatively long membrane time constant accounts well for gamma distributions of ISIs of a wide range of shapes and means. By fitting a single parameter of the AHP-LLIF model we obtain a model with the properties: 1) k(r) is constant unless 2) τAHP is too short or too long, in which cases k(r) is increasing and peaked respectively; 3) the scale of the synaptic noise sets k but has little influence on r. Thus, one fitted parameter qualitatively accounts for the entire heterogeneous range of observed FOF firing statistics. In a theoretical framework, assuming an arbitrary stochastic LLIF neuron defined by τmdV/dt = −(V − EL) + f(t) + dW with known synaptic noise statistics dW , time constant τm and ISI distribution p(t)dt but unknown input f(t) and unknown threshold Vt, we show how to numerically determine f(t) and Vt. For p(t) ∼ Gamma(k, θ) we obtained f(t) ≈ −A exp(−t/B), A,B > 0 which prompted us to model f(t) as a negative AHP current. Conversely, we produced gamma distributions of various shapes and means from the AHP-LLIF model defined by τmdV/dt = −(V − EL) − A exp(−t/τAHP ) + dW when τAHP ∈ [10, 40] ms and τm ∈ [40, 100] ms, but not for other settings of the time constants. We determined the Fisher information and the Shannon channel capacity for AHP-LLIF neurons and found that in principle both measures of coding efficiency increase indefinitely with the amplitude and duration of IAHP , even though we kept the mean firing rates fixed. We postulate that if the AHP-LLIF model is correct for real neurons, there must exist evolutionary disadvantages to having regularly firing neurons. One commonly held assumption is that regularly firing neurons respond sluggishly to quickly changing inputs. The AHP-LLIF neuron (a population of these) in fact responds quickly and accurately to rising transients (as a population), but inaccurately to falling transients and to fluctuating high inputs. The AHP-LLIF model predicts that sustained firing should enhance the K current by accumulation of residual calcium, thereby increasing k. We saw this trend clearly in 69% of the FOF neurons as an upwards shift of the fitted k(r) curves. The average size of the effect was a 24% increase of k. k fitted as a function of r− and r+ for a single neuron in a cubic spline basis with no interaction terms. Error bars were computed by bootstrapping. We also fit k as a function of r− (r just before the time of the observation) and r+ (r just after the observation). These fits revealed peaks in k(r−, r+) for 40% of the neurons (see figure for one such example). The peaks were clustered around (15.34, 15.60) ± (4.38, 4.20) Hz (5 outliers excluded). We are unsure at the moment whether the AHP-LLIF model alone can capture the full amplitude of these peaks. On top of firing rate modulations and modulations from sustained firing, we also found interactions between k and behavior. We believe the interactions are caused by different network states which result in different dW noise inputs. Scaling dW in the model results in scaling k with little effect on r. Therefore k provides to us (and to all downstream neurons) a measure of the variance of the input, just like r provides a measure of the mean input. This might or might not have a computational role for networks of neurons, but for us (r(t),k(t)) is a useful joint measure of single cell activity which can be correlated with behavior.

Title of dissertation: A LATENT VARIABLE MODELING FRAMEWORK FOR ANALYZING NEURAL POPULATION ACTIVITY Matthew R. Whiteway Doctor of Philosophy, 2018 Dissertation directed by: Professor Daniel A. Butts Department of Biology Neuroscience is entering the age of big data, due to technological advances in electrical and optical recording techniques. Where historically neuroscientists have only been able to record activity from single neurons at a time, recent advances allow the measurement of activity from multiple neurons simultaneously. In fact, this advancement follows a Moore’s Law-style trend, where the number of simultaneously recorded neurons more than doubles every seven years, and it is now common to see simultaneous recordings from hundreds and even thousands of neurons. The consequences of this data revolution for our understanding of brain structure and function cannot be understated. Not only is there opportunity to address old questions in new ways, but more importantly these experimental techniques will allow neuroscientists to address new questions entirely. However, addressing these questions successfully requires the development of a wide range of new data analysis tools. Many of these tools will draw on recent advances in machine learning and statistics, and in particular there has been a push to develop methods that can accurately model the statistical structure of high-dimensional neural activity. In this dissertation I develop a latent variable modeling framework for analyzing such high-dimensional neural data. First, I demonstrate how this framework can be used in an unsupervised fashion as an exploratory tool for large datasets. Next, I extend this framework to incorporate nonlinearities in two distinct ways, and show that the resulting models far outperform standard linear models at capturing the structure of neural activity. Finally, I use this framework to develop a new algorithm for decoding neural activity, and use this as a tool to address questions about how information is represented in populations of neurons. A LATENT VARIABLE MODELING FRAMEWORK FOR ANALYZING NEURAL POPULATION ACTIVITY

A latent variable modeling framework for analyzing neural population activity

A common approach to characterizing a sensory neuron’s response to stimuli is to use a probabilistic modeling approach. These models use both the stimulus and the neuron’s response to the stimulus to estimate the probability of the neuron spiking, given a particular stimulus. This project will investigate some of the well known approaches, starting with simple linear models and progressing to more complex nonlinear models. One technique for fitting the parameters of the model uses the idea of a “linear receptive field” to characterize a feature subspace of the stimulus in which the neuron’s response is dependent. Another parameter fitting technique that has been used with success is a likelihood-based method that can lead to efficient model parameter estimation. This project will examine both linear and nonlinear models, and use both the feature subspace technique and the maximum likelihood technique to fit the parameters of the appropriate model.

We investigate the effects that network topology, natural frequency distribution, and system size have on the path to global synchronization as the overall coupling strength between oscillators is increased in a Kuramoto network. In particular, we study the scenario recently found by Gómez-Gardeñes et al. [Phys. Rev. E 73, 056124 (2006)] in which macroscopic global synchronization emerges through a process whereby many small synchronized clusters form, grow, and merge, eventually leading to a macroscopic giant synchronized component. Our main result is that this scenario is robust to an increase in the number of oscillators or a change in the distribution function of the oscillators' natural frequencies, but becomes less prominent as the number of links per oscillator increases.

Local synchronization in complex networks of coupled oscillators.

Abstract:In the 1980s a new, extraordinarily productive way of reasoning about algorithms emerged. In this paper, we introduce the term “outcome reasoning” to refer to this form of reasoning. Though outcome reasoning has come to dominate areas of data science, it has been under-discussed and its impact under-appreciated. For example, outcome reasoning is the primary way we reason about whether “black box” algorithms are performing well. In this paper we analyze outcome reasoning’s most common form (i.e., as “the common task framework”) and its limitations. We discuss why a large class of prediction-problems are inappropriate for outcome reasoning. As an example, we find the common task framework does not provide a foundation for the deployment of an algorithm in a real world situation. Building off of its core features, we identify a class of problems where this new form of reasoning can be used in deployment. We purposefully develop a novel framework so both technical and non-technical people can discuss and identify key features of their prediction problem and whether or not it is suitable for outcome reasoning.

The Baum-Welch (B-W) algorithm is the most widely accepted method for inferring hidden Markov models (HMM). However, it is prone to getting stuck in local optima, and can be too slow for many real-time applications. Spectral learning of HMMs (SHMM), based on the method of moments (MOM) has been proposed in the literature to overcome these obstacles. Despite its promises, asymptotic theory for SHMM has been elusive, and the long-run performance of SHMM can degrade due to unchecked propagation of error. In this paper, we (1) provide an asymptotic distribution for the approximate error of the likelihood estimated by SHMM, (2) propose a novel algorithm called projected SHMM (PSHMM) that mitigates the problem of error propagation, and (3) develop online learning variants of both SHMM and PSHMM that accommodate potential nonstationarity. We compare the performance of SHMM with PSHMM and estimation through the B-W algorithm on both simulated data and data from real world applications, and find that PSHMM not only retains the computational advantages of SHMM, but also provides more robust estimation and forecasting.

Bridging the Usability Gap: Theoretical and Methodological Advances for Spectral Learning of Hidden Markov Models

Abstract Introduction: Pilot projects (“pilots”) are important for testing hypotheses in advance of investing more funds for full research studies. For some programs, such as Clinical and Translational Science Awards (CTSAs) supported by the National Center for Translational Sciences, pilots also make up a significant proportion of the research projects conducted with direct CTSA support. Unfortunately, administrative data on pilots are not typically captured in accessible databases. Though data on pilots are included in Research Performance Progress Reports, it is often difficult to extract, especially for large programs like the CTSAs where more than 600 pilots may be reported across all awardees annually. Data extraction challenges preclude analyses that could provide valuable information about pilots to researchers and administrators. Methods: To address those challenges, we describe a script that partially automates extraction of pilot data from CTSA research progress reports. After extraction of the pilot data, we use an established machine learning (ML) model to determine the scientific content of pilots for subsequent analysis. Analysis of ML-assigned scientific categories reveals the scientific diversity of the CTSA pilot portfolio and relationships among individual pilots and institutions. Results: The CTSA pilots are widely distributed across a number of scientific areas. Content analysis identifies similar projects and the degree of overlap for scientific interests among hubs. Conclusion: Our results demonstrate that pilot data remain challenging to extract but can provide useful information for communicating with stakeholders, administering pilot portfolios, and facilitating collaboration among researchers and hubs.

An analysis of the Clinical and Translational Science Award pilot project portfolio using data from Research Performance Progress Reports

Transformer networks (Vaswani et al., 2017) are the de facto standard architecture in natural language processing. To date, there are no theoretical analyses of the Transformer’s ability to capture tree structures. We focus on the ability of Transformer networks to learn tree structures that are important for tree transduction problems. We first analyze the theoretical capability of the standard Transformer architecture to learn tree structures given enumeration of all possible tree backbones, which we define as trees without labels. We then prove that two linear layers with ReLU activation function can recover any tree backbone from any two nonzero, linearly independent starting backbones. This implies that a Transformer can learn tree structures well in theory. We conduct experiments with synthetic data and find that the standard Transformer achieves similar accuracy compared to a Transformer where tree position information is explicitly encoded, albeit with slower convergence. This confirms empirically that Transformers can learn tree structures.

Trees in transformers: a theoretical analysis of the Transformer's ability to represent trees

Text Analytics: Advances and Challenges Domenica Fioredistella Iezzi, Damon Mayaffre and Michelangelo Misuraca Springer, 2020, xi + 302 pages, £95.50, eBook ISBN: 978‐3‐030‐52680‐1

Abstract:Instead of two cultures, the story of the last couple decades of data science is about the interplay between three different types of reasoning using data. Two of these types of reasoning were well known when Breiman wrote his Two Cultures paper – warranted reasoning (e.g., randomized trials and sampling) and model reasoning (e.g., linear models). Breiman, though he does not appear to have realized it fully, was in fact describing the dynamics arising in a data community that was making progress using the newest, third type of reasoning – outcome reasoning. In this commentary we clarify this dynamic a bit, and suggest some useful language for identifying and differentiating types of problems better suited for outcome reasoning.

In the 1980s a new, extraordinarily productive way of reasoning about algorithms emerged. In this paper, we introduce the term"outcome reasoning"to refer to this form of reasoning. Though outcome reasoning has come to dominate areas of data science, it has been under-discussed and its impact under-appreciated. For example, outcome reasoning is the primary way we reason about whether ``black box'' algorithms are performing well. In this paper we analyze outcome reasoning's most common form (i.e., as"the common task framework") and its limitations. We discuss why a large class of prediction-problems are inappropriate for outcome reasoning. As an example, we find the common task framework does not provide a foundation for the deployment of an algorithm in a real world situation. Building off of its core features, we identify a class of problems where this new form of reasoning can be used in deployment. We purposefully develop a novel framework so both technical and non-technical people can discuss and identify key features of their prediction problem and whether or not it is suitable for outcome reasoning.

When black box algorithms are (not) appropriate: a principled prediction-problem ontology

Black-box algorithms have had astonishing success in some settings. But their unpredictable brittleness has provoked serious concern and increased scrutiny. For any given black-box algorithm understanding where it might fail is extraordinarily challenging. In contrast, understanding which settings are not appropriate for black-box deployment requires no more than understanding simply how they are developed. We introduce a framework that isolates four problem-features -- measurement, adaptability, resilience, and agnosis -- which need to be carefully considered before selecting an algorithm. This paper lays out a principled framework, justified through careful decomposition of the system components used to develop black-box algorithms, for people to understand and discuss where black-box algorithms are appropriate and, more frequently, where they are not appropriate.

The Principled Prediction-Problem Ontology: when black box algorithms are (not) appropriate

Many tasks in natural language processing require the alignment of word embeddings. Embedding alignment relies on the geometric properties of the manifold of word vectors. This paper focuses on supervised linear alignment and studies the relationship between the shape of the target embedding. We assess the performance of aligned word vectors on semantic similarity tasks and find that the isotropy of the target embedding is critical to the alignment. Furthermore, aligning with an isotropic noise can deliver satisfactory results. We provide a theoretical framework and guarantees which aid in the understanding of empirical results.

The problem of identifying functional connectivity from multiple time series data recorded in each of two or more brain areas arises in many neuroscientific investigations. For a single stationary time series in each of two brain areas statistical tools such as cross-correlation and Granger causality may be applied. On the other hand, to examine multivariate interactions at a single time point, canonical correlation, which finds the linear combinations of signals that maximize the correlation, may be used. We report here a new method that produces interpretations much like these standard techniques and, in addition, 1) extends the idea of canonical correlation to 3-way arrays (with dimensionality number of signals by number of time points by number of trials), 2) allows for nonstationarity, 3) also allows for nonlinearity, 4) scales well as the number of signals increases, and 5) captures predictive relationships, as is done with Granger causality. We demonstrate the effectiveness of the method through simulation studies and illustrate by analyzing local field potentials recorded from a behaving primate. NEW & NOTEWORTHY Multiple signals recorded from each of multiple brain regions may contain information about cross-region interactions. This article provides a method for visualizing the complicated interdependencies contained in these signals and assessing them statistically. The method combines signals optimally but allows the resulting measure of dependence to change, both within and between regions, as the responses evolve dynamically across time. We demonstrate the effectiveness of the method through numerical simulations and by uncovering a novel connectivity pattern between hippocampus and prefrontal cortex during a declarative memory task.

This paper presents a novel variant of hierarchical hidden Markov models (HMMs), the multiscale hidden Markov model (MSHMM), and an associated spectral estimation and prediction scheme that is consistent, finds global optima, and is computationally efficient. Our MSHMM is a generative model of multiple HMMs evolving at different rates where the observation is a result of the additive emissions of the HMMs. While estimation is relatively straightforward, prediction for the MSHMM poses a unique challenge, which we address in this paper. Further, we show that spectral estimation of the MSHMM outperforms standard methods of predicting the asset covariance of stock prices, a widely addressed problem that is multiscale, non-stationary, and requires processing huge amounts of data.

Abstract Much attention has been paid to the question of how Bayesian integration of information could be implemented by a simple neural mechanism. We show that population vectors based on point-process inputs combine evidence in a form that closely resembles Bayesian inference, with each input spike carrying information about the tuning of the input neuron. We also show that population vectors can combine information relatively accurately in the presence of noisy synaptic encoding of tuning curves.

Population Vectors Can Provide Near Optimal Integration of Information

While technological progress made more content readily available to learners, the information load makes it hard to navigate the content space and attain learning goals. The exponential growth of specialized knowledge challenges learners, scholars, teachers, and educational institutions. For novice learners, knowing where to start and what courses contribute towards educational goals, and in what sequence, are key problems. For scholars and researchers, keeping abreast of latest developments in their field, embarking on new or interdisciplinary research, or gaining deeper understanding of the foundations of a field, all require understanding of how the knowledge space is structured and connected. For educators and educational institutions, developing curricula of proper coverage and design implies knowledge of content mapping, overlap, and dependency. For emerging online learning organizations, course recommendation and personalization of the learning experience require complex learner-content modeling. As the space of knowledge grows in scope and connections, new questions arise: How do we define coherent “modules” or “topics” in this ever growing space? How do we represent content at different levels of abstraction? Can we discover latent patterns and relations in the content space? What are the characteristics of well-designed curricula? Can we formalize and guide the personalization of learning paths? Can we automate curriculum planning and generation? What is common between all these questions is the their relevance to content. In this thesis, we propose to model content at the concept, module, and curriculum levels which we define in detail in this proposal. At each of these levels, we focus on three main problems: representation, (planning and) generation, and evaluation. We propose models, methods, and evaluation criteria and metrics for the specific tasks we define to tackle these main problems. The representation, data structures, results and resources at each level serve to solve problems in the next level. Ultimately, the goal is to fully automate the navigation of the knowledge space given specific educational goals (coverage) and constraints defined on the learner’s resources.

From Concepts to Curricula : Content Exploration , Generation , and Evaluation

This thesis extends and improves methods for estimating key quantities of hidden Markov models through spectral method-of-moments estimation. Unlike traditional estimation methods like EM and Gibbs sampling, the set of estimation methods, which we call spectral HMMs (sHMMs), are incredibly fast, do not require multiple restarts, and come with provable guarantees. Our first result improves upon the original spectral estimation of hidden Markov models algorithm by estimating the parameters from fully reduced data. We also show that the parameters developed in the fully reduced dimensional version can be estimated using various forms of regression, which can lead to major speed gains, as well as allowing flexibility in the estimation scheme. We then extend the algorithm beyond basic hidden Markov models to latent variable tree structures that have linguistic applications, especially dependency parsing, and finally to hidden Markov models in which the output is a high-dimensional, continuously distributed variable. We show that spectral estimation of hidden Markov models can be factored into two major componentsestimation of the hidden state space dynamics, and estimation of the observation probability distributions. This leads to extremely flexible estimation procedures that can be tailored precisely for the task of interest. These tools are all simple to implement, fast, and naturally incorporate dimension reduction, which allows them to scale gracefully as the dimension of the data increases. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Statistics First Advisor Dean Foster Subject Categories Statistics and Probability This dissertation is available at ScholarlyCommons: http://repository.upenn.edu/edissertations/1423 SPECTRAL ESTIMATION OF HIDDEN MARKOV MODELS

Locating recombination hotspots in genomic data is an important but difficult task. Current methods frequently rely on estimating complicated models at high computational cost. In this paper we develop an extremely fast, scalable method for inferring recombination hot spots in a population of genomic sequences that is based on the singular value decomposition. Our method performs well in several synthetic data scenarios. We also apply our technique to a real data investigation of the evolution of drug therapy resistance in a population of HIV genomic sequences. Finally, we compare our method both on real and simulated data to a state of the art algorithm.

Locating recombination hot spots in genomic sequences through the singular value decomposition

Unlabeled data is often used to learn representations which can be used to supplement baseline features in a supervised learner. For example, for text applications where the words lie in a very high dimensional space (the size of the vocabulary), one can learn a low rank "dictionary" by an eigendecomposition of the word co-occurrence matrix (e.g. using PCA or CCA). In this paper, we present a new spectral method based on CCA to learn an eigenword dictionary. Our improved procedure computes two set of CCAs, the first one between the left and right contexts of the given word and the second one between the projections resulting from this CCA and the word itself. We prove theoretically that this two-step procedure has lower sample complexity than the simple single step procedure and also illustrate the empirical efficacy of our approach and the richness of representations learned by our Two Step CCA (TSCCA) procedure on the tasks of POS tagging and sentiment classification.

Two Step CCA: A new spectral method for estimating vector models of words

Recently there has been substantial interest in using spectral methods to learn generative sequence models like HMMs. Spectral methods are attractive as they provide globally consistent estimates of the model parameters and are very fast and scalable, unlike EM methods, which can get stuck in local minima. In this paper, we present a novel extension of this class of spectral methods to learn dependency tree structures. We propose a simple yet powerful latent variable generative model for dependency parsing, and a spectral learning method to efficiently estimate it. As a pilot experimental evaluation, we use the spectral tree probabilities estimated by our model to re-rank the outputs of a near state-of-the-art parser. Our approach gives us a moderate reduction in error of up to 4.6% over the baseline re-ranker.

Unlabeled data is often used to learn representations which can be used to supplement baseline features in a supervised learner. For example, for text applications where the words lie in a very high dimensional space (the size of the vocabulary), one can learn a low rank “dictionary” by an eigendecomposition of the word co-occurrence matrix (e.g. using PCA or CCA). In this paper, we present a new spectral method based on CCA to learn an eigenword dictionary. Our improved procedure computes two set of CCAs, the first one between the left and right contexts of the given word and the second one between the projections resulting from this CCA and the word itself. We prove theoretically that this two-step procedure has lower sample complexity than the simple single step procedure and also illustrate the empirical efficacy of our approach and the richness of representations learned by our Two Step CCA (TSCCA) procedure on the tasks of POS tagging and sentiment classification.

Using CCA to improve CCA: A new spectral method for estimating vector models of words

Hidden Markov Models (HMMs) can be accurately approximated using co-occurrence frequencies of pairs and triples of observations by using a fast spectral method in contrast to the usual slow methods like EM or Gibbs sampling. We provide a new spectral method which significantly reduces the number of model parameters that need to be estimated, and generates a sample complexity that does not depend on the size of the observation vocabulary. We present an elementary proof giving bounds on the relative accuracy of probability estimates from our model. (Correlaries show our bounds can be weakened to provide either L1 bounds or KL bounds which provide easier direct comparisons to previous work.) Our theorem uses conditions that are checkable from the data, instead of putting conditions on the unobservable Markov transition matrix.

Neighborhoods of points in R n where a positive linear combination of C 1 vector fields sum to zero contain, generically, cyclic trajectories that switch between the vector fields. Such points are called stasis points, and the approximating switching cycle can be chosen so that the timing of the switches exactly matches the positive linear weighting. In the case of two vector fields, the stasis points form one-dimensional C 1 manifolds containing nearby families of two-cycles. The generic case of two flows in R 3 can be dieomorphed to a standard form with cubic curves as trajectories.

NLP researchers have long computed the singular vectors of matrices of words and the documents or contexts they occur in, and used these singular vectors as low dimension representations of the words [1, 2]. When the immediate context of words–the words before and after each target word– are used, the projections of words onto their corresponding singular vectors forms the basis of a spectral method for estimating HMMs [3, 4].

Prospective Running Assessments Among Collegiate Cross-Country Athletes

Physical therapy in sport : official journal of the Association of Chartered Physiotherapists in Sports Medicine

Prospective running assessments among division I cross-country athletes.

Objectives To assess the effects of a 4-week randomised controlled trial comparing an outdoor gait-training programme to reduce contact time in conjunction with home exercises (contact time gait-training feedback with home exercises (FBHE)) to home exercises (HEs) alone for runners with exercise-related lower leg pain on sensor-derived biomechanics and patient-reported outcomes. Design Randomised controlled trial. Setting Laboratory and field-based study. Participants 20 runners with exercise-related lower leg pain were randomly allocated into FBHE (4 male (M), 6 female (F), 23±4 years, 22.0±4.3 kg/m2) or HE groups (3 M, 7 F, 25±5 years, 23.6±3.9 kg/m2). Interventions Both groups completed eight sessions of HEs over 4 weeks. The FBHE group received vibrotactile feedback through wearable sensors to reduce contact time during outdoor running. Primary and secondary outcome measures Patient-reported outcome measures (PROMs) and outdoor gait assessments were conducted for both groups at baseline and 4 weeks. PROMs were repeated at 6 weeks, and feedback retention was assessed at 6 weeks for the FBHE group. Repeated measures analyses of variance were used to assess the influence of group and timepoint on primary outcomes. Results The FBHE group reported increased function and recovery on PROMs beyond the HE group at 6 weeks (p<0.001). There was a significant group by time interaction for Global Rating of Change (p=0.004) and contact time (p=0.002); the FBHE group reported greater subjective improvement and reduced contact time at 4 and 6 weeks compared with the HE group and compared with baseline. The FBHE group had increased cadence (mean difference: 7 steps/min, p=0.01) at 4 weeks during outdoor running compared with baseline. Conclusion FBHE was more effective than HE alone for runners with exercise-related lower leg pain, manifested with improved PROMs, reduced contact time and increased cadence. Trial registration number NCT04270565.

Sensor-based gait training to reduce contact time for runners with exercise-related lower leg pain: a randomised controlled trial

ABSTRACT Introduction/Purpose Running-related injuries are prevalent among competitive runners. In a previous prospective descriptive assessment of in situ running biomechanics in collegiate cross-country athletes, a subset of athletes developed repetitive stress lower extremity injuries during study participation. The purpose of this preliminary, observational study was to assess sensor-derived biomechanics in the several days leading up to injury (n = 8; 4 female, 4 male) compared with runners who remained healthy (n = 14; 9 female, 5 male) over a single cross-country season. Methods Wearable sensors were used to collect running biomechanics during two weekly runs, and surveys were used to capture wellness and injury. Individual z scores of biomechanical measures were assessed for runners who developed injuries and compared against healthy male and female z scores. Results Of the eight injuries, four were categorized as bone stress injuries (three female, one male), and four as soft tissue injuries (one female, three male). Bone injury cases had increased contact time, loading, and pronation, and decreased cadence and stride length preceding injury. Hamstring injury cases (n = 2) had increased stride length, whereas foot and ankle soft tissue injuries had increased pronation velocity and decreased shock and braking. Conclusions This assessment of injury cases illuminates several biomechanical patterns associated with running-related injury development. This study sets the precedent for larger-scale prospective running-related injury evaluations.

Running-Related Injuries Captured Using Wearable Technology during a Cross-Country Season: A Preliminary Study

Use of wearable sensors to identify biomechanical alterations in runners with Exercise-Related lower leg pain.

Abstract Boxplots have become an extremely popular display of distribution summaries for collections of data, especially when we need to visualize summaries for several collections simultaneously. The whiskers in the boxplot show only the extent of the tails for most of the data (with outside values denoted separately); more detailed information about the shape of the tails, such as skewness and “weight” relative to a standard reference distribution, is much better displayed via quantile–quantile (q-q) plots. We incorporate the q-q plot’s tail information into the traditional boxplot by replacing the boxplot’s whiskers with the tails from a q-q plot, and display these tails with confidence bands for the tails that would be expected from the tails of the reference distribution. We describe the construction of the “q-q boxplot” and demonstrate its advantages over earlier proposed boxplot modifications on data from economics and neuroscience, which illustrate the q-q boxplots’ effectiveness in showing important tail behavior especially for large datasets. The package qqboxplot (an extension to the ggplot2 package) is available for the R programming language. Supplementary files for this article are available online.

Neurons in navigational brain regions provide information about position, orientation, and speed relative to environmental landmarks. These cells also change their firing patterns (“remap”) in response to changing contextual factors such as environmental cues, task conditions, and behavioral state, which influence neural activity throughout the brain. How can navigational circuits preserve their local computations while responding to global context changes? To investigate this question, we trained recurrent neural network models to track position in simple environments while at the same time reporting transiently-cued context changes. We show that these combined task constraints (navigation and context inference) produce activity patterns that are qualitatively similar to population-wide remapping in the entorhinal cortex, a navigational brain region. Furthermore, the models identify a solution that generalizes to more complex navigation and inference tasks. We thus provide a simple, general, and experimentally-grounded model of remapping as one neural circuit performing both navigation and context inference.

Remapping in a recurrent neural network model of navigation and context inference

Many animal species use vocalizations to communicate social information and previous experiments in rodents have identified a range of vocal types that may be used for this purpose. However, social vocalizations are typically acquired during brief interactions between animals with no prior social relationship, and under environmental conditions with limited ethological relevance. Here, we establish long-term acoustic recordings from Mongolian gerbil families, a core social group that uses an array of sonic and ultrasonic vocalizations which vary with social context. Three separate gerbil families (two parents and four pups) were transferred to an enlarged environment and continuous 20-day audio recordings were obtained. We leveraged deep-learning based unsupervised analysis of 583,237 vocalizations to show that gerbils exhibit a more complex vocal repertoire than has been previously reported. Furthermore, gerbils displayed family-specific vocal repertoires, including differences in vocal type usage and transitions. Since gerbils live naturally as extended families in complex underground burrows that are adjacent to other families, these results suggest the presence of a vocal dialect which could be exploited by animals to represent kinship. These findings offer insight into the naturalistic vocal tendencies of gerbil families and position the Mongolian gerbil as a compelling animal to study the neural basis of vocal communication.

Unsupervised discovery of family specific vocal usage in the Mongolian gerbil

Discovering Precise Temporal Patterns in Large-Scale Neural Recordings through Robust and Interpretable Time Warping

Quantifying similarity between neural representations -- e.g. hidden layer activation vectors -- is a perennial problem in deep learning and neuroscience research. Existing methods compare deterministic responses (e.g. artificial networks that lack stochastic layers) or averaged responses (e.g., trial-averaged firing rates in biological data). However, these measures of _deterministic_ representational similarity ignore the scale and geometric structure of noise, both of which play important roles in neural computation. To rectify this, we generalize previously proposed shape metrics (Williams et al. 2021) to quantify differences in _stochastic_ representations. These new distances satisfy the triangle inequality, and thus can be used as a rigorous basis for many supervised and unsupervised analyses. Leveraging this novel framework, we find that the stochastic geometries of neurobiological representations of oriented visual gratings and naturalistic scenes respectively resemble untrained and trained deep network representations. Further, we are able to more accurately predict certain network attributes (e.g. training hyperparameters) from its position in stochastic (versus deterministic) shape space.

Representational dissimilarity metric spaces for stochastic neural networks

Neyman-Scott processes (NSPs) are point process models that generate clusters of points in time or space. They are natural models for a wide range of phenomena, ranging from neural spike trains to document streams. The clustering property is achieved via a doubly stochastic formulation: first, a set of latent events is drawn from a Poisson process; then, each latent event generates a set of observed data points according to another Poisson process. This construction is similar to Bayesian nonparametric mixture models like the Dirichlet process mixture model (DPMM) in that the number of latent events (i.e. clusters) is a random variable, but the point process formulation makes the NSP especially well suited to modeling spatiotemporal data. While many specialized algorithms have been developed for DPMMs, comparatively fewer works have focused on inference in NSPs. Here, we present novel connections between NSPs and DPMMs, with the key link being a third class of Bayesian mixture models called mixture of finite mixture models (MFMMs). Leveraging this connection, we adapt the standard collapsed Gibbs sampling algorithm for DPMMs to enable scalable Bayesian inference on NSP models. We demonstrate the potential of Neyman-Scott processes on a variety of applications including sequence detection in neural spike trains and event detection in document streams.

Spatiotemporal Clustering with Neyman-Scott Processes via Connections to Bayesian Nonparametric Mixture Models

Dynamic and reversible remapping of network representations in an unchanging environment

A core goal in systems neuroscience and neuroethology is to understand how neural circuits generate naturalistic behavior. One foundational idea is that complex naturalistic behavior may be composed of sequences of stereotyped behavioral syllables, which combine to generate rich sequences of actions. To investigate this, a common approach is to use autoregressive hidden Markov models (ARHMMs) to segment video into discrete behavioral syllables. While these approaches have been successful in extracting syllables that are interpretable, they fail to account for other forms of behavioral variability, such as differences in speed, which may be better described as continuous in nature. To overcome these limitations, we introduce a class of warped ARHMMs (WARHMM). As is the case in the ARHMM, behavior is modeled as a mixture of autoregressive dynamics. However, the dynamics under each discrete latent state (i.e. each behavioral syllable) are additionally modulated by a continuous latent “warping variable.” We present two versions of warped ARHMM in which the warping variable affects the dynamics of each syllable either linearly or nonlinearly. Using depth-camera recordings of freely moving mice, we demonstrate that the failure of ARHMMs to account for continuous behavioral variability results in duplicate cluster assignments. WARHMM achieves similar performance to the standard ARHMM while using fewer behavioral syllables. Further analysis of behavioral measurements in mice demonstrates that WARHMM identifies structure relating to response vigor.

Distinguishing discrete and continuous behavioral variability using warped autoregressive HMMs

Understanding the operation of biological and artificial networks remains a difficult and important challenge. To identify general principles, researchers are increasingly interested in surveying large collections of networks that are trained on, or biologically adapted to, similar tasks. A standardized set of analysis tools is now needed to identify how network-level covariates -- such as architecture, anatomical brain region, and model organism -- impact neural representations (hidden layer activations). Here, we provide a rigorous foundation for these analyses by defining a broad family of metric spaces that quantify representational dissimilarity. Using this framework we modify existing representational similarity measures based on canonical correlation analysis to satisfy the triangle inequality, formulate a novel metric that respects the inductive biases in convolutional layers, and identify approximate Euclidean embeddings that enable network representations to be incorporated into essentially any off-the-shelf machine learning method. We demonstrate these methods on large-scale datasets from biology (Allen Institute Brain Observatory) and deep learning (NAS-Bench-101). In doing so, we identify relationships between neural representations that are interpretable in terms of anatomical features and model performance.

Medial entorhinal cortex (MEC) supports a wide range of navigational and memory related behaviors. Well-known experimental results have revealed specialized cell types in MEC — e.g. grid, border, and head-direction cells — whose highly stereo-typical response profiles are suggestive of the role they might play in supporting MEC functionality. However, the majority of MEC neurons do not exhibit stereotypical firing patterns. How should the response profiles of these more “heterogeneous” cells be described, and how do they contribute to behavior? In this work, we took a computational approach to addressing these questions. We first performed a statistical analysis that shows that heterogeneous MEC cells are just as reliable in their response patterns as the more stereotypical cell types, suggesting that they have a coherent functional role. Next, we evaluated a spectrum of candidate models in terms of their ability to describe the response profiles of both stereotypical and heterogeneous MEC cells. We found that recently developed task-optimized neural network models are substantially better than traditional grid cell-centric models at matching most MEC neuronal response profiles — including those of grid cells themselves — despite not being explicitly trained for this purpose. Specific choices of network architecture (such as gated nonlinearities and an explicit intermediate place cell representation) have an important effect on the ability of the model to generalize to novel scenarios, with the best of these models closely approaching the noise ceiling of the data itself. We then performed “in-silica” experiments on this model to address questions involving the relative functional relevance of various cell types, finding that heterogeneous cells are likely to be just as involved in downstream functional outcomes (such as path integration) as grid and border cells. Finally, inspired by recent data showing that, going beyond their spatial response selectivity, MEC cells are also responsive to non-spatial rewards, we introduce a new MEC model that performs reward-modulated path integration. We find that this unified model matches neural recordings across all variable-reward conditions. Taken together, our results point toward a conceptually principled goal-driven modeling approach for moving future experimental and computational efforts beyond overly-simplistic single-cell stereotypes.

Explaining heterogeneity in medial entorhinal cortex with task-driven neural networks

Sparse sequences of neural spikes are posited to underlie aspects of working memory, motor production, and learning. Discovering these sequences in an unsupervised manner is a longstanding problem in statistical neuroscience. Promising recent work utilized a convolutive nonnegative matrix factorization model to tackle this challenge. However, this model requires spike times to be discretized, utilizes a sub-optimal least-squares criterion, and does not provide uncertainty estimates for model predictions or estimated parameters. We address each of these shortcomings by developing a point process model that characterizes fine-scale sequences at the level of individual spikes and represents sequence occurrences as a small number of marked events in continuous time. This ultra-sparse representation of sequence events opens new possibilities for spike train modeling. For example, we introduce learnable time warping parameters to model sequences of varying duration, which have been experimentally observed in neural circuits. We demonstrate these advantages on experimental recordings from songbird higher vocal center and rodent hippocampus.

Point process models for sequence detection in high-dimensional neural spike trains

In response to environmental changes, the medial entorhinal cortex alters its single-cell firing properties. This flexibility in neural coding is hypothesized to support navigation and memory by dividing sensory experience into unique contextual episodes. However, it is unknown how the entorhinal circuit transitions between different representations, particularly when sensory information is not delineated into discrete contexts. Here, we describe spontaneous and abrupt transitions between multiple spatial maps of an unchanging task and environment. These remapping events were synchronized across hundreds of medial entorhinal neurons and correlated with changes in running speed. While remapping altered spatial coding in individual neurons, we show that features of the environment were statistically preserved at the population-level, enabling simple decoding strategies. These findings provoke a reconsideration of how medial entorhinal cortex dynamically represents space and broadly suggest a remarkable capacity for higher-order cortical circuits to rapidly and substantially reorganize their neural representations.

Recordings from large neural populations are becoming an increasingly popular and accessible method in experimental neuroscience. While the activity of individual neurons is often too stochastic to interrogate circuit function on a moment-by-moment basis, multi-neuronal recordings enable us to do so by pooling statistical power across many cells. For example, groups of neurons often exhibit correlated gain or amplitude modulation across trials, which can be statistically formalized in a tensor decomposition framework (Williams et al. 2018). Additionally, the time course of neural population dynamics can be shifted or stretched/compressed, which can be modeled by time warping methods (Williams et al. 2020). Here, I describe how these two modeling frameworks can be combined, and show some evidence that doing so can be highly advantageous for practical neural data analysis—for example, the presence of random time shifts hampers the performance and interpretability of tensor decomposition, while a time-shifted variant of this model corrects for these disruptions and uncovers ground truth structure in simulated data.

Combining tensor decomposition and time warping models for multi-neuronal spike train analysis

The brain has a remarkable, yet poorly understood, capacity to perform rapid dynamic switching between different cognitive states. Absence epilepsy, characterized by sudden transitions to and from highly synchronous thalamocortical oscillations, provides a unique window to investigate rapid state switching. Here we explored the transition into seizures in detail using simultaneous extracellular unit recordings from the thalamocortical circuit in the Scn8a mouse, a validated murine model of absence epilepsy. We find that trial-averaged neural firing in the thalamus, but not cortex, was transiently elevated several seconds prior to seizure onset. However, we observed large single-trial variability in pre-ictal dynamics both within and across subjects, suggesting possible heterogeneous transition dynamics into absence seizures. To quantify the single-trial amplitude and temporal variability, we developed a statistical model, which revealed that individual seizures are preceded by low dimensional neural dynamics that vary in amplitude and time across seizures. Interestingly, the single-trial pre-seizure amplitude modulation uncovered by the model showed strong periodicity over trials, suggesting that pre-ictal dynamics may co-modulate with arousal state. To our knowledge, our results are the first characterization of single-unit pre-ictal firing dynamics across the thalamocortical circuit in absence epilepsy. Our results argue that seizure-monitoring devices may be able to capitalize on seizure-by-seizure changes in pre-ictal activity to better predict seizure onset, and that the thalamus may be a source of clinically useful pre-ictal signatures.

Thalamic activity patterns unfolding over multiple time scales predict seizure onset in absence epilepsy

Recurrent neural networks (RNNs) are a widely used tool for modeling sequential data, yet they are often treated as inscrutable black boxes. Given a trained recurrent network, we would like to reverse engineer it-to obtain a quantitative, interpretable description of how it solves a particular task. Even for simple tasks, a detailed understanding of how recurrent networks work, or a prescription for how to develop such an understanding, remains elusive. In this work, we use tools from dynamical systems analysis to reverse engineer recurrent networks trained to perform sentiment classification, a foundational natural language processing task. Given a trained network, we find fixed points of the recurrent dynamics and linearize the nonlinear system around these fixed points. Despite their theoretical capacity to implement complex, high-dimensional computations, we find that trained networks converge to highly interpretable, low-dimensional representations. In particular, the topological structure of the fixed points and corresponding linearized dynamics reveal an approximate line attractor within the RNN, which we can use to quantitatively understand how the RNN solves the sentiment analysis task. Finally, we find this mechanism present across RNN architectures (including LSTMs, GRUs, and vanilla RNNs) trained on multiple datasets, suggesting that our findings are not unique to a particular architecture or dataset. Overall, these results demonstrate that surprisingly universal and human interpretable computations can arise across a range of recurrent networks.

Reverse engineering recurrent networks for sentiment classification reveals line attractor dynamics

Though the temporal precision of neural computation has been studied intensively, a data-driven determination of this precision remains a fundamental challenge. Reproducible spike time patterns may be obscured on single trials by uncontrolled temporal variability in behavior and cognition, or may not even be time locked to measurable signatures in either behavior or local field potentials (LFP). To overcome these challenges, we describe a general-purpose time warping framework that reveals precise spike-time patterns in an unsupervised manner, even when spiking is decoupled from behavior or is temporally stretched across single trials. We demonstrate this method across diverse systems: cued reaching in nonhuman primates, motor sequence production in rats, and olfaction in mice. This approach flexibly uncovers diverse dynamical firing patterns, including pulsatile responses to behavioral events, LFP-aligned oscillatory spiking, and even unanticipated patterns, like 7 Hz oscillations in rat motor cortex that are not time-locked to measured behaviors or LFP.

Identifying recurring patterns in high-dimensional time series data is an important problem in many scientific domains. A popular model to achieve this is convolutive nonnegative matrix factorization (CNMF), which extends classic nonnegative matrix factorization (NMF) to extract short-lived temporal motifs from a long time series. Prior work has typically fit this model by multiplicative parameter updates---an approach widely considered to be suboptimal for NMF, especially in large-scale data applications. Here, we describe how to extend two popular and computationally scalable NMF algorithms---Hierarchical Alternating Least Squares (HALS) and Alternatining Nonnegative Least Squares (ANLS)---for the CNMF model. Both methods demonstrate performance advantages over multiplicative updates on large-scale synthetic and real world data.

Fast Convolutive Nonnegative Matrix Factorization Through Coordinate and Block Coordinate Updates

Task-based modeling with recurrent neural networks (RNNs) has emerged as a popular way to infer the computational function of different brain regions. These models are quantitatively assessed by comparing the low-dimensional neural representations of the model with the brain, for example using canonical correlation analysis (CCA). However, the nature of the detailed neurobiological inferences one can draw from such efforts remains elusive. For example, to what extent does training neural networks to solve common tasks uniquely determine the network dynamics, independent of modeling architectural choices? Or alternatively, are the learned dynamics highly sensitive to different model choices? Knowing the answer to these questions has strong implications for whether and how we should use task-based RNN modeling to understand brain dynamics. To address these foundational questions, we study populations of thousands of networks, with commonly used RNN architectures, trained to solve neuroscientifically motivated tasks and characterize their nonlinear dynamics. We find the geometry of the RNN representations can be highly sensitive to different network architectures, yielding a cautionary tale for measures of similarity that rely on representational geometry, such as CCA. Moreover, we find that while the geometry of neural dynamics can vary greatly across architectures, the underlying computational scaffold-the topological structure of fixed points, transitions between them, limit cycles, and linearized dynamics-often appears universal across all architectures.

Universality and individuality in neural dynamics across large populations of recurrent networks

Recurrent neural networks (RNNs) are a powerful tool for modeling sequential data. Despite their widespread usage, understanding how RNNs solve complex problems remains elusive. Here, we characterize how popular off-the-shelf architectures (including LSTMs, GRUs, and vanilla RNNs) perform document-level sentiment classification. Despite their theoretical capacity to implement complex, high-dimensional computations, we find that all architectures converge to highly interpretable, low-dimensional representations. We identify a simple mechanism, integration along an approximate line attractor, and find this mechanism present across RNN architectures (including LSTMs, GRUs, and vanilla RNNs). Overall, these results demonstrate that surprisingly universal and human interpretable computations can arise across a range of RNNs.

Line attractor dynamics in recurrent networks for sentiment classiﬁcation

NeuroResource Unsupervised Discovery o f Demixed , Low-Dimensional Neural Dynamics across Multiple Timescales through Tensor Component Analysis Graphical

Deep feedforward neural networks are associated with complicated, nonconvex objective functions. Yet, simple optimization algorithms can identify parameters that generalize well to held-out data. We currently lack detailed descriptions of this learning process, even on a qualitative level. We propose a simple tensor decomposition model to study how hidden representations evolve over learning. This approach precisely extracts the correct dynamics of learning in linear networks, which admit closed form solutions. On deep, nonlinear architectures performing image classification (CIFAR-10), we find empirically that a low-rank tensor model can explain a large fraction of variance while extracting meaningful features, such as stage-like learning and selectivity to inputs.

Learning Dynamics of Deep Networks Admit Low-Rank Tensor Descriptions

Identifying low-dimensional features that describe large-scale neural recordings is a major challenge in neuroscience. Repeated temporal patterns (sequences) are thought to be a salient feature of neural dynamics, but are not succinctly captured by traditional dimensionality reduction techniques. Here we describe a software toolbox—called seqNMF—with new methods for extracting informative, non-redundant, sequences from high-dimensional neural data, testing the significance of these extracted patterns, and assessing the prevalence of sequential structure in data. We test these methods on simulated data under multiple noise conditions, and on several real neural and behavioral data sets. In hippocampal data, seqNMF identifies neural sequences that match those calculated manually by reference to behavioral events. In songbird data, seqNMF discovers neural sequences in untutored birds that lack stereotyped songs. Thus, by identifying temporal structure directly from neural data, seqNMF enables dissection of complex neural circuits without relying on temporal references from stimuli or behavioral outputs.

Unsupervised discovery of temporal sequences in high-dimensional datasets, with applications to neuroscience

Perceptions, thoughts and actions unfold over millisecond timescales, while learned behaviors can require many days to mature. While recent experimental advances enable large-scale and long-term neural recordings with high temporal fidelity, it remains a formidable challenge to extract unbiased and interpretable descriptions of how rapid single-trial circuit dynamics change slowly over many trials to mediate learning. We demonstrate a simple tensor components analysis (TCA) can meet this challenge by extracting three interconnected low dimensional descriptions of neural data: neuron factors, reflecting cell assemblies; temporal factors, reflecting rapid circuit dynamics mediating perceptions, thoughts, and actions within each trial; and trial factors, describing both long-term learning and trial-to-trial changes in cognitive state. We demonstrate the broad applicability of TCA by revealing insights into diverse datasets derived from artificial neural networks, large-scale calcium imaging of rodent prefrontal cortex during maze navigation, and multielectrode recordings of macaque motor cortex during brain machine interface learning.

Unsupervised Discovery of Demixed, Low-Dimensional Neural Dynamics across Multiple Timescales through Tensor Component Analysis

related with an animal’s perceptual report [1]. The interpretation of this phenomenon (often summarized as choice probability (CP)) is complicated by the presence of correlations between neurons [2], which are often lowdimensional and shared across many neurons [3, 4, 5]. Here we extracted single-trial low-dimensional neural trajectory using variational latent Gaussian process (vLGP) algorithm [6] from population recordings in area MT [7] to understand how stimulus and choice are encoded across the population. The recovered neural trajectory captures the slow covariation in the population spike trains. The generative model of vLGP assumes multiplicative interaction among the latent processes in addition to an autoregressive point process observation model for each spike train. vLGP decomposes the population response as the shared variability (represented as neural trajectory) and individual neuron’s private noise. We found that the neural trajectories strongly encoded the direction of the stimulus with similar temporal signature as single MT neurons. We then computed a time-weighted CP for the neural trajectories; this “population CP” was much higher than any single MT unit CP and increased over time unlike single MT unit CP. Most of the explanatory power of neural trajectories came from 2 latent dimensions, which were spatially localized along the recording electrode, suggesting anatomical organization correlated with functional information representation. Taken together, these observations offer new interpretive frameworks for population level activity in relation to perception.

Dimension reduction of multi-trial neural data by tensor decomposition

Nervous system function requires intracellular transport of channels, receptors, mRNAs, and other cargo throughout complex neuronal morphologies. Local signals such as synaptic input can regulate cargo trafficking, motivating the leading conceptual model of neuron-wide transport, sometimes called the “sushi-belt model” (Doyle and Kiebler, 2011). Current theories and experiments are based on this model, yet its predictions are not rigorously understood. We formalized the sushi belt model mathematically, showing how it can achieve arbitrarily complex spatial distributions of cargo in reconstructed morphologies. However, the model also predicts an unavoidable, morphology dependent tradeoff between speed, precision and metabolic efficiency of cargo transport. With experimental estimates of trafficking kinetics, the model predicts delays of many hours or days for modestly accurate and efficient cargo delivery throughout a dendritic tree. These findings challenge current understanding of the efficacy of nucleus-to-synapse trafficking and may explain the prevalence of local biosynthesis in neurons.

Dendritic trafficking faces physiologically critical speed-precision tradeoffs

ABSTRACT Many neuropeptides are members of peptide families, with multiple structurally similar isoforms frequently found even within a single species. This raises the question of whether the individual peptides serve common or distinct functions. In the accompanying paper, we found high isoform specificity in the responses of the lobster (Homarus americanus) cardiac neuromuscular system to members of the pyrokinin peptide family: only one of five crustacean isoforms showed any bioactivity in the cardiac system. Because previous studies in other species had found little isoform specificity in pyrokinin actions, we examined the effects of the same five crustacean pyrokinins on the lobster stomatogastric nervous system (STNS). In contrast to our findings in the cardiac system, the effects of the five pyrokinin isoforms on the STNS were indistinguishable: they all activated or enhanced the gastric mill motor pattern, but did not alter the pyloric pattern. These results, in combination with those from the cardiac ganglion, suggest that members of a peptide family in the same species can be both isoform specific and highly promiscuous in their modulatory capacity. The mechanisms that underlie these differences in specificity have not yet been elucidated; one possible explanation, which has yet to be tested, is the presence and differential distribution of multiple receptors for members of this peptide family. Summary: Crustaceans typically possess multiple pyrokinins; in the lobster, all isoforms tested similarly activated the gastric mill rhythm, suggesting that the pyrokinin receptor(s) in the stomatogastric nervous system is relatively promiscuous.

Distinct or shared actions of peptide family isoforms: II. Multiple pyrokinins exert similar effects in the lobster stomatogastric nervous system

the Neuromuscular Transform Optimization of Rhythmic Behaviors by Modulation of

Erratum to: "Cell Types, Network Homeostasis, and Pathological Compensation from a Biologically Plausible Ion Channel Expression Model" [Neuron 82, (2014) 809-821; May 21]

Excitability in Neurons of the Deep Cerebellar Nuclei Morphological Correlates of Intrinsic Electrical

Whole-cell models that explicitly represent all cellular components at the molecular level have the potential to predict phenotype from genotype. However, even for simple bacteria, whole-cell models will contain thousands of parameters, many of which are poorly characterized or unknown. New algorithms are needed to estimate these parameters and enable researchers to build increasingly comprehensive models. We organized the Dialogue for Reverse Engineering Assessments and Methods (DREAM) 8 Whole-Cell Parameter Estimation Challenge to develop new parameter estimation algorithms for whole-cell models. We asked participants to identify a subset of parameters of a whole-cell model given the model’s structure and in silico “experimental” data. Here we describe the challenge, the best performing methods, and new insights into the identifiability of whole-cell models. We also describe several valuable lessons we learned toward improving future challenges. Going forward, we believe that collaborative efforts supported by inexpensive cloud computing have the potential to solve whole-cell model parameter estimation.

Summary of the DREAM8 Parameter Estimation Challenge: Toward Parameter Identification for Whole-Cell Models

Production of Functional Rhythmic Behaviors The Neuromuscular Transform Constrains the

Individual Central Pattern Generator Neurons Membrane Potential and Spiking Activity in Cycle Period of a Network Oscillator Is Independent of

Cell Types, Network Homeostasis, and Pathological Compensation from a Biologically Plausible Ion Channel Expression Model

Neurons in cold-blooded animals remarkably maintain their function over a wide range of temperatures, even though the rates of many cellular processes increase twofold, threefold, or many-fold for each 10°C increase in temperature. Moreover, the kinetics of ion channels, maximal conductances, and Ca2+ buffering each have independent temperature sensitivities, suggesting that the balance of biological parameters can be disturbed by even modest temperature changes. In stomatogastric ganglia of the crab Cancer borealis, the duty cycle of the bursting pacemaker kernel is highly robust between 7 and 23°C (Rinberg et al., 2013). We examined how this might be achieved in a detailed conductance-based model in which exponential temperature sensitivities were given by Q10 parameters. We assessed the temperature robustness of this model across 125,000 random sets of Q10 parameters. To examine how robustness might be achieved across a variable population of animals, we repeated this analysis across six sets of maximal conductance parameters that produced similar activity at 11°C. Many permissible combinations of maximal conductance and Q10 parameters were found over broad regions of parameter space and relatively few correlations among Q10s were observed across successful parameter sets. A significant portion of Q10 sets worked for at least 3 of the 6 maximal conductance sets (∼11.1%). Nonetheless, no Q10 set produced robust function across all six maximal conductance sets, suggesting that maximal conductance parameters critically contribute to temperature robustness. Overall, these results provide insight into principles of temperature robustness in neuronal oscillators.

Many Parameter Sets in a Multicompartment Model Oscillator Are Robust to Temperature Perturbations

You might find this additional info useful...This article cites 40 articles, 20 of which can be accessed free at:/content/91/1/397.full.html#ref-list-1 This article has been cited by 17 other HighWire hosted articles, the first 5 are:€[Abstract] [Full Text] [PDF] Integr. Comp. Biol., December , 2011; 51 (6): 845-855.Ronald L. Calabrese, Brian J. Norris, Angela Wenning and Terrence M. WrightCoping with Variability in Small Neuronal Networks€[Abstract] [Full Text] [PDF] J Neurophysiol, March 15, 2012; 107 (6): 1681-1693.Rebecca C. Roffman, Brian J. Norris and Ronald L. CalabresegeneratorAnimal-to-animal variability of connection strength in the leech heartbeat central pattern€[Abstract] [Full Text] [PDF] J Exp Biol, June 15, 2012; 215 (12): 2108-2116.Daniel Kueh and John A. JelliesTargeting a neuropeptide to discrete regions of the motor arborizations of a single neuron€[Abstract] [Full Text] [PDF] J Neurophysiol, May 15, 2013; 109 (10): 2451-2465.and Patsy S. DickinsonAlex H. Williams, Molly A. Kwiatkowski, Adam L. Mortimer, Eve Marder, Mary Lou Zeemanexperimental and computational analysisAnimal-to-animal variability in the phasing of the crustacean cardiac motor pattern: an€[Abstract] [Full Text] [PDF] J Neurophysiol, July 1, 2014; 112 (1): 95-109.Angela Wenning, Brian J. Norris, Anca Doloc-Mihu and Ronald L. CalabreseVariation in motor output and motor performance in a centrally generated motor patternUpdated information and services including high resolution figures, can be found at:/content/91/1/397.full.html Additional material and information about Journal of Neurophysiology can be found at:http://www.the-aps.org/publications/jnThis information is current as of December 23, 2014.€

The cardiac ganglion (CG) of Homarus americanus is a central pattern generator that consists of two oscillatory groups of neurons: "small cells" (SCs) and "large cells" (LCs). We have shown that SCs and LCs begin their bursts nearly simultaneously but end their bursts at variable phases. This variability contrasts with many other central pattern generator systems in which phase is well maintained. To determine both the consequences of this variability and how CG phasing is controlled, we modeled the CG as a pair of Morris-Lecar oscillators coupled by electrical and excitatory synapses and constructed a database of 15,000 simulated networks using random parameter sets. These simulations, like our experimental results, displayed variable phase relationships, with the bursts beginning together but ending at variable phases. The model suggests that the variable phasing of the pattern has important implications for the functional role of the excitatory synapses. In networks in which the two oscillators had similar duty cycles, the excitatory coupling functioned to increase cycle frequency. In networks with disparate duty cycles, it functioned to decrease network frequency. Overall, we suggest that the phasing of the CG may vary without compromising appropriate motor output and that this variability may critically determine how the network behaves in response to manipulations.

Animal-to-animal variability in the phasing of the crustacean cardiac motor pattern: an experimental and computational analysis.

Significance A deep puzzle in neuroscience is how neurons maintain their electrical properties despite continuous ion channel turnover and activity perturbations. Previous work proposed that activity-dependent homeostatic rules ensure robust development of excitability by regulating channel density, although it is not understood how these rules shape the distribution of ion channel types nor how finely tuned these rules must be. We show that generic homeostatic regulation rules impose correlations in the steady-state distribution of ion channels, as has been recently observed experimentally. Specific correlations depend on relative expression rates, and the regulation rules themselves are far more robust than previously thought. Experimental observations reveal that the expression levels of different ion channels vary across neurons of a defined type, even when these neurons exhibit stereotyped electrical properties. However, there are robust correlations between different ion channel expression levels, although the mechanisms that determine these correlations are unknown. Using generic model neurons, we show that correlated conductance expression can emerge from simple homeostatic control mechanisms that couple expression rates of individual conductances to cellular readouts of activity. The correlations depend on the relative rates of expression of different conductances. Thus, variability is consistent with homeostatic regulation and the structure of this variability reveals quantitative relations between regulation dynamics of different conductances. Furthermore, we show that homeostatic regulation is remarkably insensitive to the details that couple the regulation of a given conductance to overall neuronal activity because of degeneracy in the function of multiple conductances and can be robust to “antihomeostatic” regulation of a subset of conductances expressed in a cell.

Correlations in ion channel expression emerge from homeostatic tuning rules

How conductance distributions are shaped by activity-dependent regulation rules

Motor neuron activity is transformed into muscle movement through a cascade of complex molecular and biomechanical events. This nonlinear mapping of neural inputs to motor behaviors is called the neuromuscular transform (NMT). We examined the NMT in the cardiac system of the lobster Homarus americanus by stimulating a cardiac motor nerve with rhythmic bursts of action potentials and measuring muscle movements in response to different stimulation patterns. The NMT was similar across preparations, which suggested that it could be used to predict muscle movement from spontaneous neural activity in the intact heart. We assessed this possibility across semi-intact heart preparations in two separate analyses. First, we performed a linear regression analysis across 122 preparations in physiological saline to predict muscle movements from neural activity. Under these conditions, the NMT was predictive of contraction duty cycle but was unable to predict contraction amplitude, likely as a result of uncontrolled interanimal variability. Second, we assessed the ability of the NMT to predict changes in motor output induced by the neuropeptide C-type allatostatin. Wiwatpanit et al. (2012) showed that bath application of C-type allatostatin produced either increases or decreases in the amplitude of the lobster heart contractions. We show that an important component of these preparation-dependent effects can arise from quantifiable differences in the basal state of each preparation and the nonlinear form of the NMT. These results illustrate how properly characterizing the relationships between neural activity and measurable physiological outputs can provide insight into seemingly idiosyncratic effects of neuromodulators across individuals.

The Neuromuscular Transform of the Lobster Cardiac System Explains the Opposing Effects of a Neuromodulator on Muscle Output

Motor neuron activity is transformed into muscle movement through a cascade of complex molecular and biomechanical events. This nonlinear mapping of neural inputs to motor behaviors is called the neuromuscular transform (NMT). We examined the NMT in the cardiac system of the lobster Homarus americanus by stimulating a cardiac motor nerve with rhythmic bursts of action potentials and measuringmusclemovementsinresponsetodifferentstimulationpatterns.TheNMTwassimilaracrosspreparations,whichsuggested thatitcouldbeusedtopredictmusclemovementfromspontaneousneuralactivityintheintactheart.Weassessedthispossibilityacross semi-intact heart preparations in two separate analyses. First, we performed a linear regression analysis across 122 preparations in physiological saline to predict muscle movements from neural activity. Under these conditions, the NMT was predictive of contraction dutycyclebutwasunabletopredictcontractionamplitude,likelyasaresultofuncontrolledinteranimalvariability.Second,weassessed the ability of the NMT to predict changes in motor output induced by the neuropeptide C-type allatostatin. Wiwatpanit et al. (2012) showedthatbathapplicationofC-typeallatostatinproducedeitherincreasesordecreasesintheamplitudeofthelobsterheartcontractions.Weshowthatanimportantcomponentofthesepreparation-dependenteffectscanarisefromquantifiabledifferencesinthebasal state of each preparation and the nonlinear form of the NMT. These results illustrate how properly characterizing the relationships betweenneuralactivityandmeasurablephysiologicaloutputscanprovideinsightintoseeminglyidiosyncraticeffectsofneuromodulatorsacrossindividuals.

Homeostatic principles are consistent with sensitivity analysis of neuronal rhythmicity

There is a growing interest in extending crowdwork beyond traditional desktop-centric design to include mobile devices (e.g., smartphones). However, mobilizing crowdwork remains significantly tedious due to a lack of understanding about the mobile usability requirements of human intelligence tasks (HITs). We present a taxonomy of characteristics that defines the mobile usability of HITs for smartphone devices. The taxonomy is developed based on findings from a study of three consecutive steps. In Step 1, we establish an initial design of our taxonomy through a targeted literature analysis. In Step 2, we verify and extend the taxonomy through an online survey with Amazon Mechanical Turk crowdworkers. Finally, in Step 3 we demonstrate the taxonomy’s utility by applying it to analyze the mobile usability of a dataset of scraped HITs. In this paper, we present the iterative development of the taxonomy, highlighting the observed practices and preferences around mobile crowdwork. We conclude with the implications of our taxonomy for accessibly and ethically mobilizing crowdwork not only within the context of smartphone devices, but beyond them.

Proceedings of the 2022 CHI Conference on Human Factors in Computing Systems

Mobilizing Crowdwork:A Systematic Assessment of the Mobile Usability of HITs

We present a design fiction, which is set in the near future as significant Mars habitation begins. Our goal in creating this fiction is to address current work-life issues on Earth and Mars in the future. With shelter-in-place measures, established norms of productivity and relaxation have been shaken. The fiction creates an opportunity to explore boundaries between work and life, which are changing with shelter-in-place and will continue to change. Our work includes two primary artifacts: (1) a propaganda recruitment poster and (2) a fictional narrative account. The former paints the work-life on Mars as heroic, fulfilling, and fun. The latter provides a contrast that depicts the lived experience of early Mars inhabitants. Our statement draws from our design fiction in order to reflect on the structure of work, stress identification and management, family and work-family communication, and the role of automation.

Non-workstation devices provide mobility in the sense that they enable work and play in less constrained environments and configurations. Workers have different needs and preferences in terms of work practices that impact work-life balance. One way to increase mobility is to allow for more choices in both workstation and non-workstation devices. This paper investigates whether workers’ preferences for using different devices are distinct. To understand whether these differences in preference exist, we use data from an exploratory qualitative survey of 150 crowdworkers from Amazon Mechanical Turk. We first identify the aspects that influence crowdworkers’ preferences in using non-workstation devices. Next, our thematic analysis of open-ended data indicates that different workers have different preferences for multi-device configuration. Finally, this leads to a discussion of how people have different preferences which would require different non-workstation devices.

Adjunct Proceedings of the 2022 ACM International Joint Conference on Pervasive and Ubiquitous Computing and the 2022 ACM International Symposium on Wearable Computers

Beyond a One-Size-Fits-All Approach: Towards Personalizing Multi-device Setups in Crowdwork

Working from home has become common practice for many, especially since the global pandemic has forced many office workers to relocate their work spaces to a home environment. While working from home can have benefits, it requires self-discipline and can be a challenge to stay motivated. Changes in motivation about work may impact people's sense of productivity and well-being. We used a mixed-methods study using diaries and interviews with 25 informants to investigate perceived challenges during remote work from home. A grounded theory analysis revealed that people's work motivation had shifted from being people-centric to being work-centric. In the office, informants were motivated by working and interacting with others and being at their desk signaled work engagement to others. At home, motivation was mainly driven by personal work responsibilities. We identify four clusters of worker strategies to address the shift in work motivation. While some informants' perspectives on motivation made them reflect inward on their work performance and enjoyment, other informants' perspectives were outward-facing and involved performance and enjoyment in relation to others. We conclude that there needs to be better support for sustaining work motivation at home that can be tailored to different individuals, specifically in terms of managing time and detaching from work. We conclude by considering new pathways for supporting remote work.

Motivated to Work or Working to Stay Motivated: A Diary and Interview Study on Working From Home

With the growing prevalence of affective computing applications, Automatic Emotion Recognition (AER) technologies have garnered attention in both research and industry settings. Initially limited to speech-based applications, AER technologies now include analysis of facial landmarks to provide predicted probabilities of a common subset of emotions (e.g., anger, happiness) for faces observed in an image or video frame. In this paper, we study the relationship between AER outputs and self-reports of affect employed by prior work, in the context of information work at a technology company. We compare the continuous observed emotion output from an AER tool to discrete reported affect obtained via a one-day combined tool-use and diary study (N = 15). We provide empirical evidence showing that these signals do not completely align, and find that using additional workplace context only improves alignment up to 58.6%. These results suggest affect must be studied in the context it is being expressed, and observed emotion signal should not replace internal reported affect for affective computing applications.

“I Didn’t Know I Looked Angry”: Characterizing Observed Emotion and Reported Affect at Work

People regularly share retellings of their personal events through social media websites to elicit feedback about the reasonability of their actions in the event's context. In this paper, we explore how learning approaches can be used toward the goal of classifying reasonability in personal retellings of events shared on social media. We collect 13,748 community-labeled posts from /r/AmITheAsshole, a subreddit in which Reddit users share retellings of personal events which are voted upon by community members. We build and evaluate a total of 21 machine learning models across seven types of models and three distinct feature sets. We find that our best-performing model can predict the reasonability of a post with an F1 score of .76. Our findings suggest that features derived from the post and author metadata were more predictive than simple linguistic features like the post sentiment and types of words used. We conclude with a discussion on the implications of our findings as they relate to sharing retellings of personal events on social media and beyond.

Classifying Reasonability in Retellings of Personal Events Shared on Social Media: A Preliminary Case Study with /r/AmITheAsshole

Voice assistants are fundamentally changing the way we access information. However, voice assistants still leverage little about the web beyond simple search results. We introduce Firefox Voice, a novel voice assistant built on the open web ecosystem with an aim to expand access to information available via voice. Firefox Voice is a browser extension that enables users to use their voice to perform actions such as setting timers, navigating the web, and reading a webpage’s content aloud. Through an iterative development process and use by over 12,000 active users, we find that users see voice as a way to accomplish certain browsing tasks efficiently, but struggle with discovering functionality and frequently discontinue use. We conclude by describing how Firefox Voice enables the development of novel, open web-powered voice-driven experiences.

Proceedings of the 2021 CHI Conference on Human Factors in Computing Systems

Firefox Voice: An Open and Extensible Voice Assistant Built Upon the Web

Open surgery for abdominal aortic aneurysms in the UK is usually performed via a midline transperitoneal incision. However, the left retroperitoneal (RP) approach may be beneficial for juxtarenal abdominal aortic aneurysms and certain physiological reasons. One potential disadvantage is that the left kidney usually requires mobilization anteromedially risking injury to the renal tract and possibly the ureter.

Ureteric complications and left retroperitoneal abdominal aortic surgery

The contributors listed below made the opening of the World Chess Hall of Fame and Sidney Samole Museum in Miami possible.

1 Lengthening the chain in diphenylacetylcholine decreases affinity for muscarinic cholinoceptors in guinea‐pig ileum. Diphenylacetoxypropyldimethylamine and its quaternary trimethylammonium salt are roughly equiactive: the dimethylamine and the piperidine have some selectivity for ileum compared with atria, but are not as active nor as selective as 4‐diphenylacetoxy‐N‐methylpiperidine (4‐DAMP) methobromide (MeBr). With the weaker diphenylacetoxybutyl compounds the base is more active than the quaternary salt. 2 The diphenylacetoxybutyl‐, cis‐butenyl and trans‐butenyl compounds have similar affinities. The quaternary salts are less active than the tertiary bases, but they are less selective than the butynyl analogues studied in earlier work. 3 1,1‐Diphenyl‐1‐hydroxy‐2,4‐hexadiynyl dimethylamine and its trimethylammonium salt are inactive in concentrations below 100 μm, as are the (+)‐camphor‐sulphonyl ester of 4‐hydroxy‐N‐methyl piperidine and its methiodide. The (±)‐phenylcyclopentylacetyl ester of 4‐hydroxy‐N‐methylpiperidine methobromide is more active than its cyclohexyl analogue and than 4‐DAMP MeBr but it is less selective than 4‐DAMP MeBr. 4 The high selectivity of p‐fluoro‐hexahydrosila‐diphenidol is confirmed but this compound has relatively low affinity (for ileum log K = 7.8). 5 The results indicate steric constraints to binding at muscarinic receptors which could be used to check molecular modelling of the receptor based on its known amino acid sequence. The group binding the charged nitrogen is probably at the mouth of a cavity which can accommodate two large rings (as in 4‐DAMP MeBr) but with a depth less than about 7 Å so that the rod‐like hexadiynes cannot fit. Differences between types of receptor may only involve small changes in geometry secondary to differences in amino acids not directly involved in binding and the production of selectivity depends upon finding substituents which interfere with binding more at one type of receptor than at another.

Effects of chain‐length and unsaturation on affinity and selectivity at muscarinic receptors

Hydroxylase cofactor in human CSF--an index of central aminergic activity.

Abstract Arguments against providing fiscal aid to state governments usually rely on a simplistic moral hazard argument: supporting states through a cyclical downturn encourages them to overspend. This argument undergirds the policy recommendations made by the mainstream literature on Fiscal Federalism. I argue that these accounts are predicated on a misunderstanding of what it means to be an agent with respect to one’s budget over the business cycle. Basic corporate finance theory teaches us that in order to have control over the relative movement of income and expenditure in the current period, one must be able to design one’s own capital structure. US State governments are institutionally and constitutionally prevented from designing their own capital structures, and as such, cannot be judged to have budgetary agency across the business cycle. I show that the moral hazard problem presented in the fiscal finance literature is ill-posed, and obscures a second, more important problem of moral hazard. Namely, that politicians at the federal level reap the political rewards of pursuing austerity at the state level while remaining insulated from any political, economic, or social costs or responsibility. This second moral hazard problem admits of a simple solution: trigger-based fiscal aid to state governments.

This paper explores the benefits and value of college students’ conducting critical family history (CFH) projects, which may serve as curricular material to expand students’ understanding of complex aspects of history and immigration. This article unpacks how one student came to see herself and others from a deeper perspective, particularly through the lens of someone who chose to continue digging into her enslaved ancestors’ roots. Using narrative inquiry, a college instructor and former student collaboratively reflect on the lessons learned from using a CFH project in a college-level class primarily for preservice teachers. A unique aspect of this paper is that it gives voice to a former student in the class, which provides a way of seeing the complexities and dehumanizing components of the lives of enslaved Africans in the U.S.—often sanitized out of history books. In addition, a university librarian suggests approaches to genealogical research, by focusing more on the lived experiences of ancestors that go beyond dates and locations. The perspectives from both a former student and the college instructor add multiple dimensions on lessons learned from a critical family history project, which uses students’ family histories as funds of knowledge as the primary curriculum.

There Has Been No Remorse over It: A Narrative Inquiry Exploring Enslaved Ancestral Roots through a Critical Family History Project

Political Hegemony and Social Complexity: Mechanisms of Power After Gramsci

Abstract The key claims of left accelerationism are grounded upon a network of concepts. Crucial here have been the notions of hegemony (the genesis of which exists within the work of Antonio Gramsci); strategy (a notably polyvalent concept); and rationality (which has strong roots in the contemporary analytic tradition but which has been widely critiqued within the Continental one). Though the concepts of hegemony–strategy and strategy–rationality have received wide treatment, the hegemony and rationality pair has received minimal attention. Yet to render the core arguments of left accelerationism explicable requires that these three ideas are placed in some concrete relation. To put the issue another way: what is the relationship between power (hegemony) and rationality? This article will argue that many of the critiques which the left accelerationist position has received are bound up in misunderstanding this relationship. To remedy such misnomers, we will argue that it is a more sophisticated understanding of strategy that can help bridge these two domains. This leads us to delineate a form of strategy-without-a-strategiser, a distributed and emergent strategic orientation which mediates the power/rationality binary.

The way out of institutional complexity: Transport for London (TfL)

This dissertation tests previous unsubstantiated accusations that newspapers intentionally draw their circulation boundaries to exclude minority areas to make their audience look more white and affluent to increase advertising revenue. Analyzing 328 daily newspapers from 2002 – 2015, this dissertation compares the demographics of the zip codes a newspaper serves to the neighboring zip codes a newspaper does not serve. Mirroring how the Department of Justice has defined redlining under the legal theory of disparate impact, I argue that newspapers who serve minority residents at less than 4/5’s the rate of white residents have created discriminatory practices. Using this measurement, I find that in 2014/2015, 15% of daily newspapers with circulations over 10,000 were redlining African American residents, 14% were redlining Asian American residents, and 10% were redlining Hispanic residents. I then show that since 2002, the percentage of papers engaging in redlining has decreased and that newspapers who stopped redlining were most likely to do so after decreasing their service boundaries by more than 25 miles. Using logistic regression, I then show that depending on the racial group, region, residential segregation, and circulation size are significant predictors of whether a paper will engage in redlining. I conclude by arguing that more research is needed to explore whether redlining shapes news coverage and the process in which newspapers set their service boundaries. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Communication First Advisor Victor W. Pickard

Despite academics and media critics warning that cutbacks from the journalism crisis may be harming democratic values, a majority of the public is unaware of the financial struggles plaguing the industry. In this article, I argue that more communication scholars should publish research that is accessible to the broader public to help raise public awareness of this pivotal issue. Political economy, I argue, is well suited to this task, given its emphasis on merging research with action. I detail three key ways scholars can help the public connect to the journalism crisis: (1) by “localizing” the data to allow people to see how the crisis is impacting their community, (2) by “humanizing” the research to make the findings more relatable, and (3) by testing and refuting common refrains related to the crisis.

COMPASS| Measuring the Journalism Crisis: Developing New Approaches That Help the Public Connect to the Issue

Deleuze’s concept of the control society presciently sketches a world of power as ‘universal modulation’. This article investigates the applicability of this understanding of control to today’s socio-technical systems. It examines Deleuze’s control society through the philosophy of cybernetics, situating a restrictive interpretation with reference to Norbert Weiner’s theory of control systems in animals and machines. We argue that in maintaining a concept of control-as-homeostatic feedback modulation, cybernetic readings tend to ignore the constructive, enabling dimension of control. To remedy this, we analyse a recent concept developed in the field of business studies of information technology: the platform. Extrapolating beyond the existing literature of platform design, we develop a generalised theory of the platform as an alternative model of control, through the concept of generative entrenchment.

The recent global financial crisis has underscored the importance of sound bank liquidity management. This paper analyzes the performance of Jamaica’s banking system by looking at the impact of the banks’ liquid assets holdings on profitability with a bid to improving financial system soundness. To measure performance of the deposit taking institutions (DTIs), the paper used return on assets (ROA) as a proxy for profitability performance. Two econometric approaches were conducted to make inferences, an Ordinary Least Square (OLS) for each bank sub-sector and a 2-step General Method of Moments (GMM) Dynamic Panel for the banking system. The results suggest that there is an inverse relationship between profitability and liquid assets holdings for the sub-sectors. In addition, the result for commercial banks was more robust when an interactive dummy was utilized in the panel. The panel consisted of quarterly data from 2000Q1-2012Q1 for six commercial banks, four building societies and two FIA licensees. Macroeconomic variables were also included to test the profitability performance of banks when the economy deteriorated. It was found that when the country’s debt level continued on its deterministic trend, the impact on profitability was negative. In addition, the relationship between non-performing loans and profitability suggests an indirect link to unemployment.

The Creative Industries are a significant sector for the success of the UK economy contributing £87.4bn GVA in 2015 (DCMS). It is therefore important that we use the research funds allocated to university support for this sector (over £46 million in 2015) as effectively as possible. To do this, we must understand the distinctive nature of knowledge exchange relationships between universities and enterprises within this sector.

The Hidden Story : understanding knowledge exchange partnerships with the creative economy

The aim of this section organised by the Design Innovation Management Special Interest Group with themed track on the Design Policy was to explore Changing Design Policies and Practices. Design has played a vital role in the development of economies, societies and cultures globally. Governments in nations – such as Korea, Denmark and the UK – have long recognised the contribution design makes towards success and have employed a wide variety of approaches to create environments conducive to design. Different national contexts have called for differing tactics to encourage companies to use design more strategically but have met barriers. Yet research into those policies (defined here as ‘political visions into programmes and actions to develop national design resources and encourage their effective use’ (Raulik-Murphy, 2014) and their ability to unlock the potential of the design industry to respond to social challenges is both recent and scant. 
This section starts by identifying and critically examining national and regional design policies, which guide the interaction of design capacities, seen as a stimulus for economic and social change. Looking to the future, there is significant interest in how design policies may be instrumental in catalysing national responses to global challenges re: poverty, ageing and health; conflict and security; climate change; and in the ‘movement of everything’ (Cooper, 2015). 
The section then moves on to consider how design approaches address this. One of the triggers for, and consequences of, this change is an incorporation of co-design as a process in which designers and users collaborate as ‘equals’ to develop innovative solutions. The UK Design Council is, for example, advocating the use of co-design methods to support the development of practical innovative solutions to social problems such as increased cost of elderly care or tackling child poverty (Design Council, n.d.). 
The involvement of users in developing solutions acknowledges that their take up is dependent on the ways users make and negotiate meanings of objects and services (Vossoughi, 2013). Research suggests that a move to incorporate co-design processes will have significant implications on future designers’ and researchers’ practices (Sanders & Stappers, 2008). So we proposed to explore the following question: how we design, what we design, and who designs? 
This leads to questions as to how we best facilitate, resource, and grow such cooperative practices, in both the cultural and organizational senses. This leads us consider issues of support, co-location and clustering, and ultimately back to consideration of policy, and the extent to which this is/should be top-down (market failure driven) or bottom-up (ecological). 
Authors contributing to this section consider points such as: 
 Emergent trends in design policy 
 Understanding how such policies might be embedded within the private, public and service sectors 
 The value of design, its dimensions and influences, and how differing design approaches address this 
 An exploration of sense-making and meaning within innovation 
 Evaluations of participatory methods which facilitate co-design processes 
 The challenges for stakeholders within co-design, and the support needs of local communities and start-ups 
 The significance of resourcing and clustering, and the implications best practice has on policy formation. 
Unpacking this discourse in more detail, the papers are presented under four sub-themes: emergent thinking in design policy; the value of design and how design approaches might address this; the emergence of co-design in addressing social challenges; and the significance of resourcing and clustering.

Deleuze’s concept of the control society presciently sketches a world of power as ‘universal modulation’. This article investigates the applicability of this understanding of control to today’s socio-technical systems. It investigates Deleuze’s control society by reference to the philosophy of cybernetics, situating a restrictive interpretation with reference to Norbert Weiner’s theory of control systems in animals and machines. We argue that in maintaining a concept of control-as-homeostatic feedback modulation, cybernetic readings tend to ignore the constructive, enabling dimension of control. To remedy this, we analyse a recent concept developed in the field of business studies of information technology: the platform. Extrapolating beyond the existing literature of platform design, we develop a generalised theory of the platform as an alternative model of control, through the concept of generative entrenchment.

Against the confused understanding of our high-tech world by both the right and the left, this book claims that the emancipatory and future-oriented possibilities of our society can be reclaimed.

"The future needs to be constructed. It has been demolished by neoliberal capitalism and reduced to a cut-​price promise of greater inequality, conflict, and chaos. This collapse in the idea of the future is symptomatic of the regressive historical status of our age, rather than, as cynics across the political spectrum would have us believe, a sign of sceptical maturity. The future must be cracked open once again, unfastening our horizons towards the universal possibilities of the Outside."

This paper reviews the evolution of the design industry globally in the context of Porter's Competitive Advantage of Nations theory, & its migration through resource exploitation, investment, innovation & wealth creation stages. The paper posits a further stage of economic development & reviews design's role at each juncture. Taking industry case illustrations across Africa, Asia, Europe & the US, the paper explores innovation, design utility & value across these differing stages, & identifies discrete design challenges within each scenario relating to infrastructure, cost bases, knowledge, strategic value, IP & entrepreneurship. A key element in each study is the recognition of emergent client sectors, the diversification of expertise, strategic partnerships, routes-to-market, challenges & evolving business models, & how these relate both to existing theories of design agglomeration & to new drivers exemplified by globalization, long tail economics & the digital economy. The paper culminates in an exploration of design & innovation policy within each specific context, & examines the implications of such policies going forward, particularly on design businesses, & in doing so, proposes a model for evaluating such policies.

A review of global design economies: Implications for the future of the profession & for policy formation

This paper locates Ecologically Sustainable Development (ESD) as the only credible overarching policy objective for contemporary planning systems and presents six key policy and governance areas where a planning system's ability to implement ESD is determined. Through the analysis of face-to-face interviews, the paper provides a snapshot of the issues and concerns of local government planners regarding the ability of the NSW planning system to implement ESD. It is found that, despite the content of aspirational documents and in the context of reform agendas that prioritise economic growth, the NSW planning system is currently not well placed to implement ESD. A degree of consensus is found regarding the particular legislative, structural and cultural factors that work to impede the implementation of ESD in NSW: an overly narrow view of the role of planning; a focus on development assessment at the expense of strategic planning; insufficient statutory weight given to ESD; and a lack of policy integration at State government level. Perhaps most significantly, given the review of planning legislation currently being undertaken in NSW, this paper identifies a package of policy and governance reform directions that together will promote more effective implementation of ESD in the future.

Experience talks: the views of planners regarding the ability of the New South Wales planning system to implement ecologically sustainable development (ESD)

Purpose – This paper sets out to identify key success criteria for e‐business and consider emergent models which integrate the most value‐adding characteristics in response to the requirements of both consumers and business organisations.Design/methodology/approach – In assessing differing models of B2C/C2C, the paper uses an adapted evaluation framework which brings together key factors identified from the literature. A Likert scale exercise undertaken enables the authors to subsequently rank models.Findings – Analysis of the results from the differing models identifies 14 primary success factors from which the paper develops a modified ontology of e‐business. This is attributed to the evolving role of internet communities and social networking; the impact of “mobbing” and demand aggregation on rate of growth; and the effects of the “long tail” in differentiating markets into high‐diversity short‐run products.Research limitations/implications – It is recognised that the scoring exercise is based on a lim...

A comparison of e‐business models from a value chain perspective

Design management in the UK has developed significantly since the early 1990s, with design managers now operating across both design consultancies and within businesses. These organizations operate in a dynamic global environment; as such it is necessary to respond to changes, especially in the business environment in which the design industry itself operates. This chapter draws on the results of a study conducted by the authors and colleagues into the future of the UK design industry, which considers the implications for design management in the design consultancy sector as well as design management in its client base. The study described in this chapter, Design 2020, identifies challenges and opportunities that the UK design industry will face in the second decade of the twenty-first century and presents a framework to signpost and support change.1 The remainder of this chapter explains the research context, the findings of each stage of the study, followed by discussion of the results with implications and recommendations for those involved in design management.

New design business models - Implications for the future of design management

ABSTRACT Design management is a relatively new concept compared with either design practice or management science. There have been various approaches which have tried to conceptualize design management issues, but most of these have considered design management in an organizational perspective, in isolation from the context in which the design profession is practised – the design industry – and thus are unlikely to capture the emerging issues driven by design industry trends. This suggests a need for a design management model that conceptualizes design management practice in addressing the issues of concern to various stakeholders within the sector. This paper develops a conceptual framework by positioning design management within the design industry's knowledge supply chain. It defines design management as the management of the interface between design practice and other industry forces. The proposed conceptual framework is evaluated by comparing it with existing theoretical concepts and models. It concludes by identifying roles missing from classical design management theory, and suggesting region-specific design management remits, which recognize how the emerging role for design managers is likely to differ.

This report focuses on the outlook for the development of existing and new economic activity in the Arctic marine region, and on a range of different sectors.

The future of Arctic enterprise : long-term outlook and implications

Despite a growing body of research on Chinese business practices and consumer market development, little has been written on the significance of new product development (NPD) within Chinese organizations. In addition, there has been little analysis of the influence of Chinese industry structures and national culture on approaches to NPD. A key assumption has been that it will mirror Western experience. This paper will establish whether a Western interpretation of NPD is appropriate to indigenous Chinese enterprises engaged in high technology sectors. Further, it will provide an overview of the nature of the NPD process within Chinese organizations, contextualized within the Chinese economy. The authors subsequently present the findings of a case study conducted within a high technology state-owned enterprise. The study focuses on its engagement with NPD in both market and organizational contexts, and its relationship to research and development (R&D), production systems, and technology transfer, in particular. The paper concludes by proposing a model of the NPD process specific to Chinese organizations, and suggests that future development of the Chinese economy will necessitate greater engagement with NPD, albeit in a differing form.

Strategic New Product Development in Chinese Organizations: A Case Study in the High Technology Sector

The objective of this study is to examine the future of the UK design industry. It aims to identify challenges and opportunities facing the UK design industry over the next decade and to develop a framework to signpost and support change. The project focuses on the UK design consultancy sector, with specific reference to brand and corporate identity, multimedia, new product development, packaging, and service design. The project does not consider designer-makers or craft-based designers. Research has been conducted in two stages. The first involved a review of literature and focus group research, which identified key issues and concerns within the sector, and has informed the development of a conceptual framework and scenario tools. A second stage involved interviews and focus groups with three sets of stakeholders: (i) design practitioners and design consultancies, (ii) design buyers/clients (including both private and public sectors), (iii) design policymakers and design educators. These stakeholders were consulted in order to establish the nature of the transactions between all parties in the knowledge supply chain. The findings present a conceptual framework as a model of the business context for design that identifies the driving forces in the market. Four future scenarios are described as well as the design industry’s response to these which include the development of ten potential business models for the sector. Five of these models were identified as viable by policy maker respondents: Small Independents, Specialist Design Groups, Mega Design Corps, and Design Strategists. All of these business models which exist to some extent today. However a new model thought to be likely to gain credibility was the Special Interest Groups (SIG) Niche Network. Design respondents identified with five models: UK Design Centres in BRIC Economies, Specialised Innovation Services, Design Strategists, UK Export Engine,and Mega Design Corps. Analysis of the responses to these scenarios and models revealed the dimensions of the framework that required further attention which included: revising design education, creating a single professional body for accreditation, and encouraging design companies to radically rethink their business models.

Design 2020: The Future of the UK Design Industry – An investigation into the threats and opportunities for the UK design industry over the next 10 to 15 years

New product development implementation in indigenous Chinese organisations

Fabrication and evaporation time investigation of water treatment membranes using green solvents and recycled polyethylene terephthalate

PbTe is a premiere mid-range temperature thermoelectric material and recent studies have proven nanostructing as an effective approach to reduce thermal conductivity of alloys. Whereas, little attention has been given to long-term thermal stability of secondary phases and microstructural evolution. Interestingly, replacing Te with S in PbTe provides an opportunity to form nanostructures in the bulk material through spinodal decomposition, which appears in binary phase diagrams of the PbTe–PbS system. Herein, the critical composition of PbTe0.38S0.62 alloy is fabricated to n-type by chlorine doping. Thermoelectric transport properties of the alloy are investigated in the 300–850 K temperature range and the maximum zT achieved at 800 K is 0.75 with a predicted zT ∼ 0.85 at 750 K from single parabolic band model. The microstructure of the sintered samples was studied by FEG-SEM for both the as sintered and post transport properties measurement. The experimental results are compared with estimates from the parallel and series models for heterogeneous composites of single phase PbTe and PbS. The Seebeck coefficient is in agreement with the models predictions, but the resistivity is higher and the thermal conductivity is much lower than predicted values. We propose that this is attributed to the phonon and electron scattering on solute atoms in solid solutions and at interfaces.

Thermoelectric Properties and Microstructure Studies of Spinodally Decomposed PbTe 0 . 38 S 0 . 62 Alloy

Effect of SCM combinations on paste rheology and its relationship to particle characteristics of the mixture

PbTe is a premiere mid-range temperature thermoelectric material and recent studies have proven nanostructing as an effective approach to reduce thermal conductivity of alloys. Whereas, little attention has been given to long-term thermal stability of secondary phases and microstructural evolution. Interestingly, replacing Te with S in PbTe provides an opportunity to form nanostructures in the bulk material through spinodal decomposition, which appears in binary phase diagrams of the PbTe–PbS system. Herein, the critical composition of PbTe_(0.38)S_(0.62) alloy is fabricated to n-type by chlorine doping. Thermoelectric transport properties of the alloy are investigated in the 300–850 K temperature range and the maximum zT achieved at 800 K is 0.75 with a predicted zT ∼ 0.85 at 750 K from single parabolic band model. The microstructure of the sintered samples was studied by FEG-SEM for both the as sintered and post transport properties measurement. The experimental results are compared with estimates from the parallel and series models for heterogeneous composites of single phase PbTe and PbS. The Seebeck coefficient is in agreement with the models predictions, but the resistivity is higher and the thermal conductivity is much lower than predicted values. We propose that this is attributed to the phonon and electron scattering on solute atoms in solid solutions and at interfaces.

Thermoelectric properties and microstructure studies of spinodally decomposed PbTe0.38S0.62 alloy

Microstructural characteristics of cerium oxide conversion coatings obtained by various aqueous deposition methods

INTRODUCTION In the last fifty years geophysical methods have become increasingly important in site investigation, since mastering the equipment is fairly simple, large amounts of data can be quickly obtained and processed, and scientists can study subsurface areas of interest without physically altering the landscape. Geophysical results do not produce conclusive, explicit results, but rather show subsurface variations in physical properties (Breiner, 1973). Magnetic and conductivity surveys are among the most commonly used methods. The magnetometer, which penetrates the ground down to 6 meters, is designed to measure the total field magnetic intensity, which includes the magnetivity of subsurface features as well as background magnetization from the Earth. Subsurface variations cause anomalous readings that fall above or below background levels of 55,000 nanoTeslas (nT) in Pennsylvania. A dipole anomaly, a combination of a low measurement directly north of an abnormally high measurement, could indicate metallic objects below the surface. Ground conductivity surveys are useful in studying subsurface variations. A conductivity meter utilizes a transmitter which produces a magnetic current that is sent, about 1 meter into the ground, and is measured by a receiver at the other end of the instrument. Changes in the subsurface are detected by differences in conductivity readings; for example, metallic objects effectuate higher values (Bevan, 1983). The Baker Woodlands research site is a 60-acre tract of land approximately one mile west of Franklin and Marshall College in Lancaster, Pennsylvania. In the past, varying sections of the site were used: for agriculture, by a brickworks company, as a landfill, and as open woodlands. Today, most of the site is a woodland area, with some grassy zones, and a small wetland. Four sites of varying sizes were selected for geophysical analysis, two in the industrial landfill (Grids 1 and 2) and two in the former brickworks area (Grids 3 and 4). The two sites in the landfill are adjacent to the previously studied transect L-4 ( de Wet et al., 1998).

Geophysical Investigation of a former landfill and brickworks area, Baker Woodlands Research Site Lancaster, Pennsylvania

Use of Larval Zebrafish Model to Study Within-Host Infection Dynamics.

Human skin commensals augment Staphylococcus aureus pathogenesis

A "sweet-spot" for fluid-induced oscillations in the conditioning of stem cell-based engineered heart valve tissues.

To slow the inexorable rise of antibiotic resistance we must understand how drugs impact on pathogenesis and influence the selection of resistant clones. Staphylococcus aureus is an important human pathogen with populations of antibiotic-resistant bacteria in hospitals and the community. Host phagocytes play a crucial role in controlling S. aureus infection, which can lead to a population “bottleneck” whereby clonal expansion of a small fraction of the initial inoculum founds a systemic infection. Such population dynamics may have important consequences on the effect of antibiotic intervention. Low doses of antibiotics have been shown to affect in vitro growth and the generation of resistant mutants over the long term, however whether this has any in vivo relevance is unknown. In this work, the population dynamics of S. aureus pathogenesis were studied in vivo using antibiotic-resistant strains constructed in an isogenic background, coupled with systemic models of infection in both the mouse and zebrafish embryo. Murine experiments revealed unexpected and complex bacterial population kinetics arising from clonal expansion during infection in particular organs. We subsequently elucidated the effect of antibiotic intervention within the host using mixed inocula of resistant and sensitive bacteria. Sub-curative tetracycline doses support the preferential expansion of resistant microorganisms, importantly unrelated to effects on growth rate or de novo resistance acquisition. This novel phenomenon is generic, occurring with methicillin-resistant S. aureus (MRSA) in the presence of β-lactams and with the unrelated human pathogen Pseudomonas aeruginosa. The selection of resistant clones at low antibiotic levels can result in a rapid increase in their prevalence under conditions that would previously not be thought to favor them. Our results have key implications for the design of effective treatment regimes to limit the spread of antimicrobial resistance, where inappropriate usage leading to resistance may reduce the efficacy of life-saving drugs.

Clonal Expansion during Staphylococcus aureus Infection Dynamics Reveals the Effect of Antibiotic Intervention

Rhythmic electrical oscillations in neuronal networks underlie important cognitive processes and motor functions. Rhythmic oscillations can be achieved by a variety of biophysical mechanisms and, as a result, biological networks display a wide variety of behaviors. However, this natural variability is often not incorporated into model neuronal networks in order to facilitate mathematical analysis. In particular, model networks are often assumed to be homogenous – i.e. being constituted of identical model neurons. Though this assumption can be useful in certain circumstances, it can break down in the simplest biological systems. We demonstrate the significance of non-identical oscillators in a computational model of the crustacean cardiac ganglion (CG) – a small neuronal network that controls heart beating in decapods. We modeled the oscillations in these networks by a system of differential equations that we adapted from previous theoretical work. 7,500 model networks were simulated using standard numerical techniques. Results show that mechanisms controlling heart rate operate drastically different in networks with asynchronous activity – indicative of non-homogenous networks – than those with synchronous oscillations – representative of homogenous networks. In particular, decoupling the oscillators generally resulted in an increase in heart rate for the asynchronous networks, while the opposite effect was observed in synchronous networks. Because asynchrony has largely been ignored by previous research, these results have broad implications for the field of theoretical neuroscience.

The significance of asynchrony within a small neuronal network: a computational model of the crustacean cardiac ganglion.

The innate immune system is the primary defence against the versatile pathogen, Staphylococcus aureus. How this organism is able to avoid immune killing and cause infections is poorly understood. Using an established larval zebrafish infection model, we have shown that overwhelming infection is due to subversion of phagocytes by staphylococci, allowing bacteria to evade killing and found foci of disease. Larval zebrafish coinfected with two S. aureus strains carrying different fluorescent reporter gene fusions (but otherwise isogenic) had bacterial lesions, at the time of host death, containing predominantly one strain. Quantitative data using two marked strains revealed that the strain ratios, during overwhelming infection, were often skewed towards the extremes, with one strain predominating. Infection with passaged bacterial clones revealed the phenomenon not to bedue to adventitious mutations acquired by the pathogen. After infection of the host, all bacteria are internalized by phagocytes and the skewing of population ratios is absolutely dependent on the presence of phagocytes. Mathematical modelling of pathogen population dynamics revealed the data patterns are consistent with the hypothesis that a small number of infected phagocytes serve as an intracellular reservoir for S. aureus, which upon release leads to disseminated infection. Strategies to specifically alter neutrophil/macrophage numbers were used to map the potential subpopulation of phagocytes acting as a pathogen reservoir, revealing neutrophils as the likely ‘niche’. Subsequently in a murine sepsis model, S. aureus abscesses in kidneys were also found to be predominantly clonal, therefore likely founded by an individual cell, suggesting a potential mechanism analogous to the zebrafish model with few protected niches. These findings add credence to the argument that S. aureus control regimes should recognize both the intracellular as well as extracellular facets of the S. aureus life cycle.

A privileged intraphagocyte niche is responsible for disseminated infection of Staphylococcus aureus in a zebrafish model

For many years, scientists were puzzled as to how cells regulate gene expression. How could a cell produce different amounts of genetic product at different times? How could a cell start and stop production of specific genetic products? Conducting a wide variety of experiments using techniques including polymerase chain reactions, various blotting and recombinant techniques; scientists discovered operons. While the area is still open to much study, a lot has been learned about operons thus far. A few examples discussed below include how operons can be influenced by antibiotics, how operons can be modified to completely repress expression, and how gene expression is influenced by the distance from the gene to the end of the operon. The results found from these experiments are exciting, and could one day potentially aid in curing diseases and disorders, as well as answering many questions about genetic expression.

Understanding Gene Regulation-Operons and their key importance to cellular functionality

An investigation of the kinetics for the fast pyrolysis of Loblolly pine woody biomass

Residence Time Influence on the Fast Pyrolysis of Loblolly Pine Biomass

Background: The use of 2-chloro-4,4,5,5-tetramethyl-1,3,2-dioxaphospholane followed by 31P-NMR analysis has been frequently employed to quantitatively characterize the structure of hydroxyl groups in lignin and, more recently, biodiesel. This technique serves as a valuable tool to determine aliphatic hydroxyls, phenolics and carboxylic acid groups in lignin and aliphatic hydroxyl groups in partially substituted glycerols. Results: This study demonstrates the application of this analytical technique to pyrolysis oils to allow efficient analysis and identification of important functional groups present in bio-oils and the measurement of moisture content. Conclusion: Phosphitylation followed by 31P-NMR analysis was used to show that the moisture content of the loblolly pine bio-oil used in this study was 11.94%. The results also established that the bio-oils obtained from loblolly pine cellulose had higher levoglucosan content than the bio-oil obtained from the starting pine itself. In addition, the total phenolic content of bio-oil derived from loblolly pine milled wood lignin was greater than that obtained from the bio-oil from the loblolly pine cellulose. The data also highlighted the ability to track chemical transitions that take place during pyrolysis using 31P-NMR.

31P-NMR analysis of bio-oils obtained from the pyrolysis of biomass

The search for fossil fuel alternatives has been one of increasing interest in recent years and one method which shows evidence of feasibility on a large scale is the production of bio-oil through the pyrolysis of biomass. In order to mathematically characterize biomass pyrolysis reactions for the purpose of process modeling, reaction descriptors in the form of Arrhenius coefficients are frequently utilized. Due to the complexity and inhomogeneity of biomass molecular structures, strictly analytically derived Arrhenius coefficients are not capable of predicting pyrolysis behaviors and outcomes. Typically thermogravimetric analysis (TGA) is employed as a method of extracting mass conversion data as a function of temperature from which bulk reaction descriptors following the form of Arrhenius reaction coefficients are derived. The preceding time and temperature history, however, will have a significant impact on the biomass conversion processes at each subsequent data point. This renders derived process predictors from TGA incapable of approximating fast pyrolysis reactions which have a markedly different time and temperature history than is seen utilizing TGA methods. Experimentally derived reaction descriptors of the Arrhenius form for the fast pyrolysis of biomass have been investigated utilizing a novel isothermal fast pyrolysis reactor. Multiple reaction durations and reaction temperatures for Pinus Taeda were tested resulting in measurements of biomass conversion. Reaction coefficients derived from the data are compared to coefficients derived utilizing TGA data and their predictions for mass conversion are contrasted.Copyright © 2010 by ASME

Experimentally Derived Arrhenius Coefficients for the Reaction Modeling of Fast Pyrolysis

A Microreactor System for the Analysis of the Fast Pyrolysis of Biomass

Bio-oils were produced within a fast-pyrolysis micro-reactor at 400°C from Loblolly Pine (Pinus Taeda) with varying residence times. This preliminary study has considered two boundary values for the residence time, evaluating the products of the reaction at 20 seconds and 120 seconds. The collected bio-oils were analyzed for their calorific values (LHV) and biomass conversion efficiencies. Heating rates greater than 100°C/s were achieved for the biomass, allowing for isothermal conditions to exist throughout the majority of the reaction despite short residence times. This study shows the effect that reaction duration has on the mass of the bio-oil yield and energy content present for the isothermal fast pyrolysis of Loblolly Pine and evaluates the predictive capabilities of TGA derived Arrhenius coefficients.Copyright © 2009 by ASME

Investigation Into the Effects of Reaction Duration on the Isothermal Fast Pyrolysis of Biomass

This paper presents the latest results in the design, development and performance characterization of a novel prototype micro-reactor system that is uniquely capable of capturing the transient product evolution history of the fast pyrolysis of biomass products. With strong demand driving the technological development of sustainable energy solutions, the consideration of optimal conversion methodologies for biomass energy feedstocks has received a great deal of attention recent years. [1, 2] The pyrolysis of soft woods, in particular spruce and pine, has emerged as a credible alternative to bio-digestive strategies that are reliant on fermentation processes, typically of corn feedstocks. The design objectives for the micro-reactor system are reviewed, highlighting the multi-physics and multi-disciplinary complexity in designing for transient characterization of the pyrolized products by the micro-reactor system. One of the dominant challenges in the design of the micro-reactor for fast pyrolysis reactions is the requirement of very high heating rates for the feedstock, on the order of 100°C/s. A 1D transient thermal model of the reactor is developed that considers the average particle size and morphology, the initial surface temperature of the reaction surface within the micro-reactor, the heat loss to the ambient atmosphere in the reactor, the heat loss through the contact resistance between the sample and the reaction surface and the thermal capacitance of the reaction surface. A parametric evaluation of the design space was performed using the 1D model in order to identify a preferred range of particle size, reactor surface area and thermal input power. Based on the results for the domain reduction study, multi-physics thermo-mechanical 3D FEA was used to undertake a brute-force optimization process of the final design. The key metric considered in the FEA study was the maximum thermal gradient in the reaction surface and was driven to a minimum value. The thermal response of the prototype micro-reactor has been evaluated using infra-red thermography measurement techniques. Thermographical analysis of the results has demonstrated negligible thermal gradients in the reaction plane up to the maximum reaction setpoint of 450°C. Based on the results of the thermal testing of the micro-reactor, the achieved peak heating rates of the sample have been estimated to be on the order of 400°C/s, meeting and exceeding the design requirement.Copyright © 2008 by ASME

Design, Development and Characterization of a Micro-Reactor for Fast Pyrolysis of Biomass Feedstocks

Machine learning dissection of human accelerated regions in primate neurodevelopment

Behavioral states affect neuronal responses throughout the cortex and influence visual processing. Quiet wakefulness (QW) is a behavioral state during which subjects are quiescent, but awake and connected to the environment. Here, we examined the effects of pre-stimulus arousal variability on post-stimulus neural activity in primary visual cortex (V1) and posterior parietal cortex (PPc) in awake ferrets, using the pupil diameter as an indicator of arousal. We observed that during low arousal, low- frequency power increases during visual stimulation, and that the peak alpha frequency shifted depending on the arousal state. High arousal increased gamma power as well as low-frequency inter- and intra-areal coherence. Using a simplified model of laminar circuits, we show that this connectivity pattern is compatible with feedback signals targeting infragranular layers in area PPc and supragranular layers in V1. Neurons in V1 displayed higher firing rates at their preferred orientations on high-arousal trials. Broad-spiking cells in V1 entrained to high-frequency oscillations (>80 Hz), whereas narrow-spiking neurons phase-locked to low (12-18 Hz) and high-frequency (>80 Hz) rhythms. These results indicate that the variability and sensitivity of post-stimulus cortical responses and coherence depend on the pre-stimulus behavioral state and account for the neuronal response variability observed during repeated stimulation.

Spontaneous variations in arousal modulate subsequent visual processing and local field potential dynamics in the ferret during quiet wakefulness

Humans are uniquely capable of adapting to highly changing environments by updating relevant information and adjusting ongoing behaviour accordingly. Here we show how this ability —termed cognitive flexibility— is differentially modulated by high and low arousal fluctuations. We implemented a probabilistic reversal learning paradigm in healthy participants as they transitioned towards sleep or physical extenuation. The results revealed, in line with our pre-registered hypotheses, that low arousal leads to diminished behavioural performance through increased decision volatility, while performance decline under high arousal was attributed to increased perseverative behaviour. These findings provide evidence for distinct patterns of maladaptive decision-making on each side of the arousal inverted u-shaped curve, differentially affecting participants’ ability to generate stable evidence-based strategies, and introduces wake-sleep and physical exercise transitions as complementary experimental models for investigating neural and cognitive dynamics.

Different underlying mechanisms for high and low arousal in probabilistic learning in humans

World Scientific Series in Grand Public Policy Challenges of the 21st Century

These are some informal notes for a chalk-talk tutorial given at Janelia as part of the junior scientist workshop on theoretical neuroscience. The goal of these notes is to give a very direct and to-the-point introduction of these topics to scientists in biology and neuroscience. Many of these topics are reviewed in greater technical detail in [14] (for matrix decompositions) and [8] (for tensor decompositions).

La gauche devrait se mobiliser autour d’un consensus sur le post-travail. Cela lui permettrait de viser non seulement des gains appreciables – tels que la reduction de la corvee et de la pauvrete – mais aussi la construction, chemin faisant, d’une puissance politique. Cela implique au moins trois revendications : l’automation aussi complete que possible, une reduction du temps de travail sans reduction des salaires et l’instauration d’un revenu de base universel.

The Left should mobilize around a post-work consensus. Our first demand is for a fully-automated economy. Our second demand is for reducing the length of the working week. Our third demand calls for the implementation of a universal basic income.

Full employment is a tenet of classic social democracy – but what if that just isn't applicable anymore? Nick Srnicek and Alex Williams survey the state of the British labour market and ask how a modern Labour party might reframe the issue of work so that it is sustainable and sustaining in the face of technological change.

On Cunning Automata: Financial Acceleration at the Limits of the Dromological

Correct interpretation of accuracy ensures that results are judged neither overly optimistically nor unduly pessimistically.

Infection remains a significant problem associated with biomedical implants and orthopedic surgeries, especially in revision total joint replacements. Recent advances in antibiotic-releasing bone void fillers (BVF) provide new opportunities to address these types of device-related orthopedic infections that often lead to substantial economic burdens and reduced quality of life. We report improvements made in fabrication and scalability of an antibiotic-releasing polycaprolactone-calcium carbonate/phosphate ceramic composite BVF using a new solvent-free, molten-cast fabrication process. This strategy provides the ability to tailor drug release kinetics from the BVF composite based on modifications of the inorganic substrate and/or the polymeric component, allowing extended tobramycin release at bactericidal concentrations. The mechanical properties of the new BVF composite are comparable to many reported BVFs and validate the relative homogeneity of fabrication. Most importantly, fabrication quality controls are correlated with favorable drug release kinetics, providing bactericidal activity to 10 weeks in vitro when the polycaprolactone component exceeds 98% w/w of the total polymer fraction. Furthermore, in a time kill study, tobramycin-releasing composite fragments inhibited S. aureus growth over 48 h at inoculums as high as 10(9) CFU/mL. This customizable antibiotic-releasing BVF polymer-inorganic biomaterial should provide osseointegrative and osteoconductive properties while contributing antimicrobial protection to orthopedic sites requiring the use of bone void fillers.

Journal of biomedical materials research. Part B, Applied biomaterials

Molded polymer-coated composite bone void filler improves tobramycin controlled release kinetics.

To determine if a combination of the Charlson Comorbidity Index (CCI) and quick‐Sequential Organ Failure Assessment (qSOFA) score is superior to qSOFA alone for predicting the outcome of ED patients with suspected infection.

Effect of age and comorbidity on the ability of quick‐Sequential Organ Failure Assessment score to predict outcome in emergency department patients with suspected infection

The Oscillatory Shear Index: Quantifications for Valve Tissue Engineering and a Novel Interpretation for Calcification

A shortcut review was carried out to establish whether routine use of bispectral index monitoring in emergency department conscious sedation was effective in improving patient safety. Thirteen unique papers were found using the reported searches, of which three presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of this paper are tabulated. It is concluded that there is currently insufficient evidence to support the routine use of bispectral index monitoring during conscious sedation and further studies are needed to investigate its exact benefits.

BET 1: The use of bispectral index monitoring (BIS) in conscious sedation

Introduction: Venous thrombo-embolism (VTE) is commonly encountered in the emergency department (ED). Due to the potential severity of a missed diagnosis and the particularly varied presentation of PE, there has been an increasing reliance on D-dimers in the ED. The British Thoracic Society (BTS) suggest this is potentially leading to over-investigation of patients for possible PE (British Thoracic Society. Thorax 2003; 58: 470-484).

Aims and objectives: This audit aimed to establish whether BTS guidelines were followed when D-dimers were requested in the ED, and whether D-dimers were requested appropriately by reviewing indication for the test, co-morbidities and documented end diagnosis.

Methods: A retrospective analysis of patients with positive D-dimers performed in ED or the acute medical unit in January 2010. 147 case notes were reviewed with a view to Well's score documentation; indication for request; further investigation for venous thrombo-embolism; end diagnosis.

Results: Of the 147 patients, 90 had a D-dimer performed for possible PE, 47 for possible DVT. Only two patients had a Well's score documented at any point during their hospital admission. Although 100% patients with D-dimer performed for possible DVT had further investigation, only 51% of patients with a D-dimer requested for possible PE went on to have any further investigation for PE, leading to an end diagnosis of PE in eight. The modal diagnosis in the patients reviewed was pneumonia.

Conclusions: Overuse of D-dimer testing in our ED leads to over-investigation of patients resulting in unnecessary radiation exposure. Guidelines for the use of D-dimer testing together with bedside testing will be implemented.

Are D-dimers requested appropriately in the emergency department? A retrospective audit

N (NWs) and nanopillars (NPs) have been the subject of intense study in the past decade due to their potential for new functionality and materials properties. In particular, a strong emphasis has been placed on the applicability of NWs to nanophotonics and photonic integrated circuits (PICs). Single NW lasers, light-emitting diodes (LEDs), and photodetectors have been demonstrated. NW-based lasers pose a unique challenge over other optoelectronic components because they require a carefully designed and fabricated resonant optical cavity. Several different approaches have been taken to form cavities for NW lasers, including plasmonic waveguides, Fabry Perot resonators, microring racetrack resonators, and top-down etched photonic crystal cavities. However, these devices were fabricated by mechanical removal of the NWs from the growth substrate and random placement on a host substrate. Alignment of subsequent process steps was done to each NW individually. Currently there is no feasible manufacturingmethod to place the NWs on the host substrate with the necessary precision to fabricate these devices at the wafer scale. An alternative approach to integration of NWs and NPs with PICs is lithographic control of the growth position and diameter. This allows for photonic crystal (PC) waveguides, resonant cavities, and active gain regions to be formed entirely by NPs grown simultaneously. These PC devices correspond to the dielectric rods in air structure, which differs from the more conventional air holes in a dielectric slab structure in that the photonic band gap occurs for TM polarization rather than TE polarization. PC waveguides of this type with no active gain have been reported previously using vapor liquid solid (VLS) grown NWs patterned by nanoimprint lithography. However, this method suffers from limited variability in the NW diameter due to the Au catalyst particle size, the tapered profile of the NWs, and defect growth between the NWs that will result in optical losses. These problems can be avoided by growth of NPs via catalyst-free selective-area epitaxy (SAE). Furthermore, the SAE patterns include optical alignment marks for device integration. In this work, we exploit the ability to design device parameters with SAE to enable two-dimensional (2D) photonic crystal devices. Control of both NP pitch and diameter allow for the photonic band gap (PBG) region and defect cavity active region to be comprised entirely of III V NPs grown simultaneously. The SAE grown NPs offer a unique advantage due to their hexagonal cross sections with side-wall facets consisting of the {1-10} family of crystal planes. These side-walls are completely vertical and have atomic scale roughness, avoiding two of the largest contributors to cavity losses in top-down fabricated photonic crystals. The growth of pure axial GaAs/InGaAs/ GaAs heterostructures allows for the appropriate placement of gain material within the cavities at the antinodes of the electric field. Furthermore, the ability to grow lattice matched InGaP shells over the NPs provides effective in situ surface passivation

We present evidence of cavity quantum electrodynamics from a sparse density of strongly quantum-confined Pb-chalcogenide nanocrystals (between 1 and 10) approaching single-dot levels on moderately high-Q mesoscopic silicon optical cavities. Operating at important near-infrared (1500-nm) wavelengths, large enhancements are observed from devices and strong modifications of the QD emission are achieved. Saturation spectroscopy of coupled QDs is observed at 77K, highlighting the modified nanocrystal dynamics for quantum information processing.

Cryogenic spectroscopy of ultra-low density colloidal lead chalcogenide quantum dots on chip-scale optical cavities towards single quantum dot near-infrared cavity QED.

ABSTRACT The present study aimed to examine the affordances and constraints of small-group discussions in relation to student teachers’ learning of science. By drawing on variation theory, this study focused explicitly on the student teachers themselves as the primary agents for providing opportunities for their own learning of science. The results show that student teachers were more likely to arrive at a common understanding of the object of learning when they adopted explorative talk, which included asking questions, testing ideas, and presenting differing views. Furthermore, explorative talk indicated a higher density in patterns of variation within and between relevant dimensions of variation. These results have implications for facilitating small-group discussions as part of student teachers learning process.

Student Teachers’ Collaborative Learning of Science in Small-Group Discussions

ABSTRACT In Swedish teacher education, student teachers commonly work with assignments in small groups. To enable student teachers to grow, both personally and professionally, they need to reflect both individually and collectively with their teacher educators and fellow student teachers. However, research shows that there is a risk in teacher education to narrow reflection into a tool for teacher learning, and not recognizing it as an activity that challenges thought. To avoid this risk, the approach to video-stimulated reflection (VSR) explored in this study, considers not only the notion of reflection, but also the reflective process itself, and its potential for growing student teachers to create a reflective space collaboratively. Three groups of student teachers participated in the VSR on a field practice at a local science center. Two of the groups were preparing for teaching science in lower and upper primary school. The third group was preparing for teaching science in secondary school. A reflective cycle analysis was applied to detect reflection in the VSR interviews. The results demonstrate that the approach to VSR enabled a reflective process in all three groups. The affordances and constraints of the VSR and the role of the facilitator are discussed.

Growing student teachers’ reflective practice: explorations of an approach to video-stimulated reflection

Accélérer le futur : post-travail & post-capitalisme (Éd. revisée et mise à jour) Nick Srnicek & Alex Williams ; traduit [de l'anglais] par Laurent Bury

Accélérons ! : manifeste pour une politique accélérationniste / Nick Srnicek et Alex Williams

Le travail que nous presentons est compose de deux etudes. La premiere partie porte sur les mecanismes propres a l'apprentissage en general, nous y etudions un ensemble de caracteristiques necessaires a la mise en oeuvre des systemes capables d'apprendre. Nous arguons que pour parvenir a ce but il faut etre en mesure de memoriser ses experiences passees, suite a cela nous presentons une recompilation et caracterisation des recherches sur l'apprentissage dans le domaine de l'intelligence artificielle. La deuxieme partie concerne la mise en oeuvre d'un systeme qui apprend des comportements proceduraux par memorisation des experiences dans la resolution des problemes. Nous utilisons la technique du Morcellement (Rosenbloom, 1983) et de generation automatique des sous-buts (Laird, 1983). Le Morcellement etant une methode de choix des informations pertinentes a la description d'une situation rencontree et la generation automatique des sous-buts est une methode generale de resolution des problemes qui permet, entre autres, d'utiliser le Morcellement. Le resultat est un systeme semblable a SOAR (Laird, Rosenbloom, Newell 1986a).

Apprentissage par mémorisation d'expériences dans la résolution des problèmes

I will define Higher Education as post‐school studies which are set at a standard above English “A”‐level or Scottish “H”‐grade. Using this definition, engineering courses in higher education in Scotland are available in six universities, five central institutions (the Scottish equivalent of polytechnics) and in 37 Regional Authority further education colleges

Constitutional Law - Conflict of Twenty-First Amendment and Import-Export Clause - State Tax on Foreign Liquor

Cases in Paediatric Critical Care Transfer and Retrieval Medicine

Purpose
Although green management has gained legitimacy as a sustainable business practice, little is known about the elements that will lead to the long-term success of the movement. To identify these elements, this study aims to review the existing literature on social movements and analyzes archival data from a specific social undertaking, the Hispanic Civil Rights movement in the USA.

A historiographical approach was used in which systematic combining used abductive logic to developed a provisional framework based on the interpretation of secondary sources of data concerning the Hispanic Civil Rights movement. Subsequently, an ethnomethodologically informed interpretation of primary data based on the League of United Latin American Citizens (LULAC) archives refined the provisional framework.

Findings
The authors identified common elements that are critical to the success of social movements, as supported by both secondary data on the Hispanic Civil Rights movement and primary data based on the LULAC archives. These elements consist of: ideology, identity, mobilization, goals, leadership and integration. Using these results, a pseudo-gap analysis approach was completed by systematically comparing the interpretive data with current knowledge of the green management movement to identify the missing gaps and to offer guidance for further development of green management as a contemporary movement.

Social implications
Applying the lessons learned from social movements will help the development and prosperity of the green movement in current business organizations. Such applications are important, given that local and global environmental crises can have profound implications on ecosystems, economics and social systems.

Social movements are an important means by which societal concerns such as injustices are addressed. By identifying the important elements needed for the green management movement to be successful in the long term, managers will know where to put their efforts. Such actions may help environmental awareness in business organizations to become more than a fad or marketing tool.

Lessons for green management from the Hispanic Civil Rights movement: a pseudo-gap analysis

ABSTRACT The theoretical basis of Situational Crime Prevention (SCP) posits that to reduce crime it is first necessary to understand the interaction between the physical environment and criminal decision making. Situational efforts are commonly applied to specific crimes that are frequent in nature and, due to regular interaction with situational determinants, occur within temporal and spatial clusters. However, SCP is also regularly employed to prevent less frequent crimes, such as terrorist events. The application of SCP has potential to be highly effective for the now common occurrence of ideologically-motivated vehicle ramming attacks (VRAs). However, as SCP measures must be targeted and specific to crime events, it is necessary to first identify common features of the events under scrutiny. One analytical method used to inform the application of SCP through identification of common features of VRAs is crime scripting. This paper develops a crime script of twenty VRAs between 2008 and 2019. The results are analyzed to evaluate the effectiveness of existing SCP initiatives, and identify further opportunities to implement SCP to prevent and mitigate against the impact of VRAs.

Vehicular Ramming Attacks: Assessing the Effectiveness of Situational Crime Prevention Using Crime Script Analysis

State regulatory efforts in protecting a surrogate's bodily autonomy.

A guide to information about fiction and other leisure reading resources for Centralian Senior College students.

A guide to information and resources on a variety of literature including film, poetry and creative writing. Tools to search library resources.

A guide to sources of information on Women and Work for Centralian Senior College students.

A guide to sources of information on Australian Aboriginal literature for Centralian Senior College students.

A guide to information on Ancient Greek and Roman Material Culture for Centralian Senior College students.

LibGuides: Ancient Greek and Roman Material Culture Guide: Architecture

A guide to information and resources on a variety of literature including film, poetry and creative writing.

LibGuides: Ancient Greek and Roman Material Culture Guide: Sculpture

A guide to information on current issues in society for Centralian Senior College students.

LibGuides: Women in the Islamic World Guide: Women in Afghanistan

LibGuides: Moving Between Cultures Guide: Australian Values & Lifestyle

LibGuides: Moving Between Cultures Guide: Intercultural Understanding

A guide to information on the use of drugs in sport for Centralian Senior College students.

A guide to information on representations of women in cultural texts for Centralian Senior College students.

LibGuides: Representations of Women in Cultural Texts Guide: Websites

Guide contains links to useful resources for students studying China including Chinese language, history, politics and art. Print and eBooks on related topics.

A guide to information, services and resources for students studying Creative Arts and Humanities.

Effects of Diaphragmatic Breathing Patterns on Balance: A Preliminary Clinical Trial

Colonoscopy Follow-up Compliance Rates in a Private Practice Setting: 2134

turbinate flap for repair of nasal septal perforation. Laryngoscope 113, 1425–1428 5 Hier M.P., Yoskovitch A. & Panje W.R. (2002) Endoscopic repair of a nasal septal perforation. J. Otolaryngol. 31, 323–326 6 Goh A.Y. & Hussain S.S.M. (2007) Different surgical treatments for nasal septal perforation and their outcomes. J. Laryngol. Otol. 121, 419–426 7 Romo T. (1999) A gradual approach to the repair of nasal septal perforations. Plast. Reconstr. Surg. 103, 66–75

Hand hygiene compliance in otolaryngology outpatients: how we do it

An investigation into the causes of non-compliance by patients using eyedrops has been undertaken by questionnaire, ability tests, and by tests oneyedrop bottles. The results indicate a high prevalence of non-compliance, compounded by an inability adequately to instil a' drop into the eye. About half the patients had difficulty aiming the drop, and other problems including squeezing the bottle, blinking, and seeing the tip of the bottle. Ability tests included a measurement of the grip strength of patients to complement measurement of the force required to expel a drop from a bottle. Some patients, particularly those with arthritis, could not generate enough force to squeeze a bottle. These same patients also had difficulty with the other movements required to administer drops. While some attempts have been made to produce devices to assist with eyedrops which can improve the aim of the patient, none give assistance in expelling a drop. An additional problem found was the reluctance of patients to admit to medical staff that they experienced any difficulty with their drops. Pharmacy and Medicines Research Unit, School of Pharmacy, Robert Gordon's Institute of Technology, Aberdeen AB9 1FR A J Winfield D Jessiman Aberdeen Royal Infirmary, Aberdeen, Pharmacy Department A Williams Ophthalmology Outpatients Department L Esakowitz Correspondence to: Dr A J Winfield, School of Pharmacy, Robert Gordon's Institute of Technology, Schoolhill, Aberdeen AB9 1FR. Accepted for publication 1 March 1990 It is well established that compliance of patients with a prescribed treatment is often inadequate. This may be due to a complex interaction of factors, prime among them being lack of knowledge, inability, or disinterest. Eye preparations are no exception.' Several teams have undertaken studies in an attempt both to enumerate the extent of the problem and to understand its

TPS9145 Background: Pharmacological and clinical data suggest standard regimens for anti-PD1 agents nivo and pembro result in overtreatment. These agents have high target affinity, saturate PD1 at very low concentrations and maintain receptor occupancy for up to 30 wks following discontinuation. Clinical studies suggest no dose-response relationship in the wide range tested (0.1 – 10 mg/kg) and retrospective data suggest the efficacy of lower doses or longer administration frequency. Given their high costs and important implications for pt quality of life and toxicity, new approaches to optimise treatment regimens are required. However, conventional 2-arm non-inferiority designs require large numbers of patients, explore a single alternative to the standard of care and potentially require multiple trials to establish optimal parameters such as dose or frequency. Here we present a new multi-arm trial design to tackle this problem, implemented in the UK multicentre phase III REFINE-Lung study that aims to determine the optimal treatment frequency of pembro in NSCLC. Pts who are progression free after 6 months of standard therapy are randomised to 5 pembro frequency reduced arms (q6w, q9w, q12w, q15w and q18w). By evaluation of the frequency-response relationship, we will determine the longest frequency that is equivalent to standard of care within a pre-defined margin. Methods: The REFINE-Lung trial (NCT05085028) is a multicentre, randomised open-label, phase III trial in advanced NSCLC. REFINE-Lung utilises a novel Multi-Arm Multi-Stage Response Over Continuous Interventions (MAMS-ROCI) design to determine the optimal dose frequency of pembro. 1750 pts aged ≥18 and progression free at six months into 1st line pembro and planning to continue, will be enrolled from up to UK 35 hospital groups. Pts will be randomised across 5 arms to determine the optimal dose frequency. To assess safety, pts will initially be randomised 1:1 into q6w (control) and q12w arms. Interim analysis will be conducted once 37 progression free events are observed in the control arm. If PFS in the q12w arm is not significantly reduced, the remaining q9w, q15w and q18w arms will be opened. Pts who progress on a frequency reduced arm may re-escalate to q6w therapy. The primary objective is to determine the optimal continuing dose frequency of pembro, defined as the longest dose interval non-inferior to standard therapy using 2-year survival as the primary outcome. Secondary endpoints include OS, PFS, ORR, duration of response, adverse events, quality of life and cost effectiveness. An exploratory sub-study will explore fundamental aspects of cancer immunotherapy and develop novel biomarkers of response, resistance, toxicity and patient suitability for dose frequency de-escalation. Recruitment is ongoing and the trial is open at 16 centres at time of submission. Clinical trial information: NCT05085028 .

REFINE-Lung: A multicentre phase III study to determine the optimal frequency of pembrolizumab in non-small cell lung cancer utilising a novel multi-arm design.

Performing classification on noisy, crowdsourced image datasets can prove challenging even for the best neural networks. Two issues which complicate the problem on such datasets are class imbalance and ground-truth uncertainty in labeling. The AL-ALL and AL-PUB datasets -- consisting of tightly cropped, individual characters from images of ancient Greek papyri -- are strongly affected by both issues. The application of ensemble modeling to such datasets can help identify images where the ground-truth is questionable and quantify the trustworthiness of those samples. As such, we apply stacked generalization consisting of nearly identical ResNets with different loss functions: one utilizing sparse cross-entropy (CXE) and the other Kullback-Liebler Divergence (KLD). Both networks use labels drawn from the crowdsourced consensus. For the second network, the KLD is calculated with respect to the proposed Normalized Distribution of Annotations (NDA). For our ensemble model, we apply a k-nearest neighbors model to the outputs of the CXE and KLD networks. Individually, the ResNet models have approximately 93% accuracy, while the ensemble model achieves an accuracy of>95%. We also perform an analysis of the Shannon entropy of the various models' output distributions to measure classification uncertainty. Our results suggest that entropy is useful for predicting model misclassifications.

An Approach for Noisy, Crowdsourced Datasets Utilizing Ensemble Modeling, Normalized Distributions of Annotations, and Entropic Measures of Uncertainty

Character recognition models rely substantially on image datasets that maintain a balance of class samples. However, achieving a balance of classes is particularly challenging for ancient manuscript contexts as character instances may be significantly limited. In this paper, we present findings from a study that assess the efficacy of using synthetically generated character instances to augment an existing dataset of ancient Greek character images for use in machine learning models. We complement our model exploration by engaging professional papyrologists to better understand the practical opportunities afforded by synthetic instances. Our results suggest that synthetic instances improve model performance for limited character classes, and may have unexplored effects on character classes more generally. We also find that trained papyrologists are unable to distinguish between synthetic and non-synthetic images and regard synthetic instances as valuable assets for professional and educational contexts. We conclude by discussing the practical implications of our research.

Dataset Augmentation in Papyrology with Generative Models: A Study of Synthetic Ancient Greek Character Images

Noisy, crowdsourced image datasets prove challenging, even for the best neural networks. Two issues which compli-cate classiﬁcation on such datasets are class imbalance and ground-truth uncertainty in labeling. The AL-ALL and AL-PUB datasets—consisting of tightly cropped, individual char- acters from images of ancient Greek papyri—are strongly affected by both issues. The application of ensemble mod- eling to such a dataset can help identify images where the ground-truth is questionable and quantify the trustworthiness of those samples. We apply stacked generalization consisting of nearly identical ResNets: one utilizing cross-entropy (CXE) and the other Kullback-Liebler Divergence (KLD). The CXE network uses standard labeling drawn from the crowdsourced consensus. In contrast, the KLD network uses probabilistic labeling for each image derived from the distri- bution of crowdsourced annotations. We refer to this labeling as the Human Softmax (HSM) distribution. For our ensem- ble model, we apply a k -nearest neighbors model to the outputs of the CXE and KLD networks. Individually, the ResNet models have approximately 93% accuracy, while the ensemble model achieves an accuracy of > 95%. We also perform an analysis of the Shannon entropy of the various models’ output distributions to measure classiﬁcation uncertainty.

An Approach for Noisy, Crowdsourced Datasets Utilizing Ensemble Modeling, 'Human Softmax' Distributions, and Entropic Measures of Uncertainty

The central dogma of handwritten character recognition remains inextricably linked to optical character recognition methods for print media. Alongside their reliance on proprietary data and lack of open-access software, the applicability of these optical character recognition methods to handwritten characters from low-quality documents (e.g., that are damaged) remains unknown. In this paper, we compare and contrast the performance of state-of-the-art optical character recognition tools for print and learning models engineered with state-of-the-art machine learning toolkits trained on handwritten inputs. Using Tesseract OCR as a baseline, we build, optimize, and evaluate three types of convolutional neural networks that are trained on the AL-ALLand AL-PUBdatasets, a collection of images of handwritten ancient Greek characters that were labeled by volunteers through the Ancient Lives online citizen science project. We find our best-performing machine learning model to be 92.57% accurate compared to Tesseract OCR’s 11.15%. Following our analysis, we present a brief examination of our models’ shortcomings, introduce the publicly-available AL-PUBdataset, and, describe Theia, a web-based tool that democratizes our machine learning models for public use. We conclude by discussing the promise of our findings for advancing research at the intersection of machine learning, manuscript transcription, and the digital humanities.

Exploring Learning Approaches for Ancient Greek Character Recognition with Citizen Science Data

Information workers perform jobs that demand constant multitasking, leading to context switches, productivity loss, stress, and unhappiness. Systems that can mediate task transitions and breaks have the potential to keep people both productive and happy. We explore a crucial initial step for this goal: finding opportune moments to recommend transitions and breaks without disrupting people during focused states. Using affect, workstation activity, and task data from a three-week field study (N=25), we build models to predict whether a person should continue their task, transition to a new task, or take a break. The R-squared values of our models are as high as 0.7, with only 15% error cases. We ask users to evaluate the timing of recommendations provided by a recommender that relies on these models. Our study shows that users find our transition and break recommendations to be well-timed, rating them as 86% and 77% accurate, respectively. We conclude with a discussion of the implications for intelligent systems that seek to guide task transitions and manage interruptions at work.

Proceedings of the 2020 CHI Conference on Human Factors in Computing Systems

Optimizing for Happiness and Productivity: Modeling Opportune Moments for Transitions and Breaks at Work

Task management tools allow people to record, track, and manage task-related information across their work and personal contexts. As work contexts have shifted amid the COVID-19 pandemic, it has become important to understand how these tools are continuing or failing to support peoples’ work-related and personal needs. In this article, we examine and probe practices for managing task-related information across the work–life boundary. We report findings from an online survey deployed to 150 information workers during Summer 2019 (i.e., pre-pandemic) and 70 information workers at the same organization during Summer 2020 (i.e., mid-pandemic). Across both survey cohorts, we characterize these cross-boundary task management practices, exploring the central role that physical and digital tools play in managing task-related information that arises at inopportune times. We conclude with a discussion of the opportunities and challenges for future productivity tools that aid people in managing task-related information across their personal and work contexts.

Managing Tasks across the Work–Life Boundary: Opportunities, Challenges, and Directions

Web browsers allow people to find, organize, and manage information on the web. While voice interaction research has evaluated the support of web search, the broader role of voice interactions within the browser have yet to be explored at depth. We report findings from a preliminary exploration of the challenges, opportunities, and directions of voice assistants embedded in modern web browsers. We drive our inquiry with Firefox Voice, a browser extension that implements a voice assistant into the Firefox desktop browser. Through a think-aloud study (n = 5), we explore the strengths and shortcomings of Firefox Voice to better understand the role that voice interaction can play in supporting people both in the browser and beyond it.

Proceedings of the 2nd Conference on Conversational User Interfaces

Toward Voice-Assisted Browsers: A Preliminary Study with Firefox Voice

In chronically injured humans and rodents with spinal cord injury (SCI) cardiac function is impaired. It is unknown whether such dysfunction is present acutely post‐SCI and if so whether it contributes to reduced spinal cord oxygenation. The aims of the present study, therefore, were to 1) define the acute cardiac and hemodynamic response to SCI, and 2) test the efficacy of a cardiac‐centered hemodynamic management strategy (β1‐receptor agonist dobutamine, DOB) vs. a traditional vasopressor‐based strategy (norepinephrine, NE) on intraparenchymal spinal cord oxygenation.

Acute Spinal Cord Injury Causes Cardiac Contractile Dysfunction that when Treated Aids Spinal Cord Oxygenation

There has been considerable research on how software can enhance programmers' productivity within their workspace. In this paper, we instead explore how software might help programmers make productive use of their time while away from their workspace. We interviewed 10 software engineers and surveyed 78 others and found that while programmers often do work while mobile, their existing mobile work practices are primarily exploratory (e.g., capturing thoughts or performing online research). In contrast, they want to be doing work that is more grounded in their existing code (e.g., code review or bug triage). Based on these findings, we introduce Mercury, a system that guides programmers in making progress on-the-go with auto-generated microtasks derived from their source code's current state. A study of Mercury with 20 programmers revealed that they could make meaningful progress with Mercury while mobile with little effort or attention. Our findings suggest an opportunity exists to support the continuation of programming tasks across devices and help programmers resume coding upon returning to their workspace.

Proceedings of the 32nd Annual ACM Symposium on User Interface Software and Technology

Mercury: Empowering Programmers' Mobile Work Practices with Microproductivity

Crowdworkers regularly support their work with scripts, extensions, and software to enhance their productivity. Despite their evident significance, little is understood regarding how these tools affect crowdworkers' quality of life and work. In this study, we report findings from an interview study (N=21) aimed at exploring the tooling practices used by full-time crowdworkers on Amazon Mechanical Turk. Our interview data suggests that the tooling utilized by crowdworkers (1) strongly contributes to the fragmentation of microwork by enabling task switching and multitasking behavior; (2) promotes the fragmentation of crowdworkers' work-life boundaries by relying on tooling that encourages a 'work-anywhere' attitude; and (3) aids the fragmentation of social ties within worker communities through limited tooling access. Our findings have implications for building systems that unify crowdworkers' work practice in support of their productivity and well-being.

While having a step-by-step breakdown for a task-an action plan-helps people complete tasks, prior work has shown that people prefer not to make action plans for their own tasks. Getting planning support from others could be beneficial, but it is limited by how much domain knowledge people have about the task and how available they are. Our goal is to incorporate the benefits of having action plans in the complex domain of writing, while mitigating the time and effort costs of creating plans. To mitigate these costs, we introduce a vocabulary-a finite set of functions pertaining to writing tasks-as a cognitive scaffold that enables people with necessary context (e.g. collaborators) to generate action plans for others. We develop this vocabulary by analyzing 264 comments, and compare plans created using it with those created without any aid, in an online study with 768 comments (N=145) and a lab study with 96 comments (N=8). We show that using a vocabulary reduces planning time and effort and improves plan quality compared to unstructured planning, and opens the door for automation and task sharing for complex tasks.

Creating Better Action Plans for Writing Tasks via Vocabulary-Based Planning

Supplementary material from "Herbarium specimens reveal substantial and unexpected variation in phenological sensitivity across the eastern United States"

Phenology is a key biological trait that can determine an organism's survival and provides one of the clearest indicators of the effects of recent climatic change. Long time-series observations of plant phenology collected at continental scales could clarify latitudinal and regional patterns of plant responses and illuminate drivers of that variation, but few such datasets exist. Here, we use the web tool CrowdCurio to crowdsource phenological data from over 7000 herbarium specimens representing 30 diverse flowering plant species distributed across the eastern United States. Our results, spanning 120 years and generated from over 2000 crowdsourcers, illustrate numerous aspects of continental-scale plant reproductive phenology. First, they support prior studies that found plant reproductive phenology significantly advances in response to warming, especially for early-flowering species. Second, they reveal that fruiting in populations from warmer, lower latitudes is significantly more phenologically sensitive to temperature than that for populations from colder, higher-latitude regions. Last, we found that variation in phenological sensitivities to climate within species between regions was of similar magnitude to variation between species. Overall, our results suggest that phenological responses to anthropogenic climate change will be heterogeneous within communities and across regions, with large amounts of regional variability driven by local adaptation, phenotypic plasticity and differences in species assemblages. As millions of imaged herbarium specimens become available online, they will play an increasingly critical role in revealing large-scale patterns within assemblages and across continents that ultimately can improve forecasts of the impacts of climatic change on the structure and function of ecosystems. This article is part of the theme issue ‘Biological collections for understanding biodiversity in the Anthropocene’.

Herbarium specimens reveal substantial and unexpected variation in phenological sensitivity across the eastern United States

Research has shown that productivity is mediated by an individual's ability to detach from their work at the end of the day and reattach with it when they return the next day. In this paper we explore the extent to which structured dialogues, focused on individuals' work-related tasks or emotions, can help them with the detachment and reattachment processes. Our inquiry is driven with SwitchBot, a conversational bot which engages with workers at the start and end of their work day. After preliminarily validating the design of a detachment and reattachment dialogue frame-work with 108 crowdworkers, we study SwitchBot's use in-situ for 14 days with 34 information workers. We find that workers send fewer e-mails after work hours and spend a larger percentage of their first hour at work using productivity applications than they normally would when using SwitchBot. Further, we find that productivity gains were better sustained when conversations focused on work-related emotions. Our results suggest that conversational bots can be effective tools for aiding workplace detachment and reattachment and help people make successful use of their time on and off the job.

Proceedings of the 2018 CHI Conference on Human Factors in Computing Systems

Supporting Workplace Detachment and Reattachment with Conversational Intelligence

Having a step-by-step list of instructions for completing a task - a plan - enables people to make progress on challenging tasks, but making plans for tasks is a tedious job. Asking crowdworkers to make plans for others' tasks only works for independent (context-free) tasks, and asking people who have context (e.g., friends or collaborators) has social costs and quality concerns. Our goal is to reduce the costs and improve quality of planning by people who have context in the context-rich domain of writing. We introduce a vocabulary (a finite set of functions pertaining to writing tasks) to aid the planning process. We develop a writing vocabulary by analyzing 264 comments, and compare plans created using this vocabulary to those created without any aid, in a study with 768 comments (N=145). We show that using a vocabulary reduces the planning time and effort compared to unstructured planning, and opens the door for automation and task sharing for complex tasks.

Extended Abstracts of the 2018 CHI Conference on Human Factors in Computing Systems

Using Vocabularies to Collaboratively Create Better Plans for Writing Tasks

Citizen science is a form of collaboration that engages non-professionals as contributors to scientific research, typically through the processes of gathering, transforming or analyzing data. To date, research has documented examples of hugely successful citizen science projects, such as Zooniverse and eBird, but citizen science also includes hundreds of smaller citizen science and functionally similar digital humanities projects, operating from small-scale web platforms and in-person collaborative teams. Yet, it is unclear what the "science" of citizen science entails: What are the core research questions and methodologies for answering them? What theories and concepts have been associated with citizen science research to date? What are the technology needs for supporting successful research collaboration among diverse stakeholders and across distinctive types of citizen science projects? In this workshop, our goal is to (i) bring together researchers studying citizen science to form a coherent map summarizing the theories, methodologies and platforms that currently defines citizen science research, with a special focus on CHI and CSCW relevant topics (ii) brainstorm a list of fundamental open questions and ways to tackle them, and (iii) form a multidisciplinary community to build synergies for further collaboration.

Companion of the 2017 ACM Conference on Computer Supported Cooperative Work and Social Computing

The Science of Citizen Science: Theories, Methodologies and Platforms

Curiosity is a ubiquitous characteristic of humans and a central mechanism for motivating learning, information seeking behaviors, and sustained engagements with everyday artifacts, such as artistic creations, commercial products, interactive displays and persuasive health technologies, etc. Researchers from a variety of disciplines, e.g., psychology, education, economics, have studied the concept of curiosity, yet the question of how we can systematically design curiosity-inducing behaviors into user interfaces and interactions remains unexplored. In this workshop, our goal is to (i) bring together researchers from a variety of disciplines (e.g., psychology, AI/robotics, HCI, marketing) who study curiosity, as well as practitioners (e.g., architects, designers) who employ the concept of curiosity in their artistic creations, (ii) discuss the idea of curiosity from these diverse perspectives, and (iii) form a multidisciplinary community to build synergies for further collaboration.

Proceedings of the 2017 CHI Conference Extended Abstracts on Human Factors in Computing Systems

Phenology is a key aspect of plant success. Recent research has demonstrated that herbarium specimens can provide important information on plant phenology. Massive digitization efforts have the potential to greatly expand herbarium-based phenological research, but also pose a serious challenge regarding efficient data collection. Here, we introduce CrowdCurio, a crowdsourcing tool for the collection of phenological data from herbarium specimens. We test its utility by having workers collect phenological data (number of flower buds, open flowers and fruits) from specimens of two common New England (USA) species: Chelidonium majus and Vaccinium angustifolium. We assess the reliability of using nonexpert workers (i.e. Amazon Mechanical Turk) against expert workers. We also use these data to estimate the phenological sensitivity to temperature for both species across multiple phenophases. We found no difference in the data quality of nonexperts and experts. Nonexperts, however, were a more efficient way of collecting more data at lower cost. We also found that phenological sensitivity varied across both species and phenophases. Our study demonstrates the utility of CrowdCurio as a crowdsourcing tool for the collection of phenological data from herbarium specimens. Furthermore, our results highlight the insight gained from collecting large amounts of phenological data to estimate multiple phenophases.

CrowdCurio: an online crowdsourcing platform to facilitate climate change studies using herbarium specimens.

 Consistency is a practical metric that evaluates an instrument's reliability based on its ability to yield the same output when repeatedly given a particular input. Despite its broad usage, little is understood about the feasibility of using consistency as a measure of worker reliability in crowdwork. In this paper, we explore the viability of measuring a worker's reliability by their ability to conform to themselves. We introduce and describe Deja Vu, a mechanism for dynamically generating task queues with consistency probes to measure the consistency of workers who repeat the same task twice. We present a study that utilizes Deja Vu to examine how generic characteristics of the duplicate task - such as placement, difficulty, and transformation - affect a worker’s task consistency in the context of two unique object detection tasks. Our findings provide insight into the design and use of consistency-based reliability metrics.
 
Deja Vu: Characterizing Worker Reliability Using Task Consistency

Audio annotation is key to developing machine-listening systems; yet, effective ways to accurately and rapidly obtain crowdsourced audio annotations is understudied. In this work, we seek to quantify the reliability/redundancy trade-off in crowdsourced soundscape annotation, investigate how visualizations affect accuracy and efficiency, and characterize how performance varies as a function of audio characteristics. Using a controlled experiment, we varied sound visualizations and the complexity of soundscapes presented to human annotators. Results show that more complex audio scenes result in lower annotator agreement, and spectrogram visualizations are superior in producing higher quality annotations at lower cost of time and human labor. We also found recall is more affected than precision by soundscape complexity, and mistakes can be often attributed to certain sound event characteristics. These findings have implications not only for how we should design annotation tasks and interfaces for audio data, but also how we train and evaluate machine-listening systems.

Numerous crowdsourcing platforms are now available to support research as well as commercial goals. However, crowdsourcing is not yet widely adopted by researchers for generating, processing or analyzing research data. This study develops a deeper understanding of the circumstances under which crowdsourcing is a useful, feasible or desirable tool for research, as well as the factors that may influence researchers' decisions around adopting crowdsourcing technology. We conducted semi-structured interviews with 18 researchers in diverse disciplines, spanning the humanities and sciences, to illuminate how research norms and practitioners' dispositions were related to uncertainties around research processes, data, knowledge, delegation and quality. The paper concludes with a discussion of the design implications for future crowdsourcing systems to support research.

Proceedings of the 2017 ACM Conference on Computer Supported Cooperative Work and Social Computing

Crowdsourcing as a Tool for Research: Implications of Uncertainty

Music transcription is a highly complex task that is difficult for automated algorithms, and equally challenging to people, even those with many years of musical training. Furthermore, there is a shortage of high-quality datasets for training automated transcription algorithms. In this research, we explore a semi-automated, crowdsourced approach to generate music transcriptions, by first running an automatic melody transcription algorithm on a (polyphonic) song to produce a series of discrete notes representing the melody, and then soliciting the crowd to correct this melody. We present a novel web-based interface that enables the crowd to correct transcriptions, report results from an experiment to understand the capabilities of non-experts to perform this challenging task, and characterize the characteristics and actions of workers and how they correlate with transcription performance.

Ensemble: A Hybrid Human-Machine System for Generating Melody Scores from Audio

Permission to make digital or hard copies of all or part of this work for personal or classroom use is granted without fee provided that copies are not made or distributed for profit or commercial advantage and that copies bear this notice and the full citation on the first page. Copyrights for components of this work owned by others than ACM must be honored. Abstracting with credit is permitted. To copy otherwise, or republish, to post on servers or to redistribute to lists, requires prior specific permission and/or a fee. Request permissions from permissions@acm.org. CHI’16, May7–May 11, 2016, San Jose, California. Copyright © 2015 ACM ISBN/14/04...$15.00. DOI string from ACM form confirmation Author Biographies Edith Law is an assistant professor in the School of Computer Science at University of Waterloo. Previously, she was a postdoctoral fellow at Harvard University. She holds a Ph.D. in Machine Learning from Carnegie Mellon University, M.Sc. in Computer Science at McGill University, and B.Sc. in Computer Science at the University of British Columbia.

The Big Picture : Preserving Context in the Decomposition of Complex Expert Tasks

Over the past few decades, discovery based on sequence homology has become a widely accepted practice. Consequently, comparative accuracy of retrieval algorithms (e.g., BLAST) has been rigorously studied for improvement. Unlike most components of retrieval algorithms, the E-value threshold criterion has yet to be thoroughly investigated. An investigation of the threshold is important as it exclusively dictates which sequences are declared relevant and irrelevant. In this paper, we introduce the false discovery rate (FDR) statistic as a replacement for the uniform threshold criterion in order to improve efficacy in retrieval systems. Using NCBI's BLAST and PSI-BLAST software packages, we demonstrate the applicability of such a replacement in both non-iterative (BLASTFDR) and iterative (PSI-BLASTFDR) homology searches. For each application, we performed an evaluation of retrieval efficacy with five different multiple testing methods on a large training database. For each algorithm, we choose the best performing method, Benjamini-Hochberg, as the default statistic. As measured by the threshold average precision, BLASTFDR yielded 14.1 percent better retrieval performance than BLAST on a large (5,161 queries) test database and PSI-BLASTFDR attained 11.8 percent better retrieval performance than PSI-BLAST. The C++ source code specific to BLASTFDR and PSI-BLASTFDR and instructions are available at http://www.cs.mtsu.edu/~hcarroll/blast_fdr/.

IEEE/ACM Transactions on Computational Biology and Bioinformatics

Improving Retrieval Efficacy of Homology Searches Using the False Discovery Rate

Scholars working on vast archives of ancient fragmentary manuscripts have long faced the problem of managing and intuitively interfacing the exponential growth of data as fragments are re-edited over time. Multiple readings, multiple versions, and the reality of a multi-text are concepts not well-suited to the physical codex. Current digital archives and libraries for ancient Greek and Latin texts provide only a single reading of a text. Furthermore, the current information model for these digital texts fails to include the vital components necessary to create complete born digital critical editions which are citable and usable in Classics. Collectively, these problems have undermined the effectiveness and reputability of digital editions on the World Wide Web. In this paper, we introduce Proteus, a platform designed to facilitate the creation and scholarly use of complete born digital critical editions of literary and subliterary papyri.

Proteus: A platform for born digital critical editions of literary and subliterary papyri

In the late nineteenth century, two excavators from the University of Oxford uncovered a vast trove of naturally deteriorated papyri, numbering over 500,000 fragments, from the city of Oxyrhynchus. With varying levels and forms of deterioration, the identification of a papyrus fragment can become a repetitive, long, and exhausting process for a professional papyrologist. The University of Oxford's Ancient Lives project aims to accelerate the identification process through citizen science (or crowdsourcing). In the Ancient Lives interface, volunteer users identify letters by clicking on a location in the image to designate the presence of a letter. To date, over 7 million letter identifications from users across the world have been recorded in the Ancient Lives database. In this paper, we present a computational pipeline for converting crowdsourced letter identifications made through the Ancient Lives interface into digital consensus transcriptions of papyrus fragments. We conclude by explaining the usefulness of the pipeline output in the context of additional computational projects that aim to further accelerate the identification process.

A computational pipeline for crowdsourced transcriptions of Ancient Greek papyrus fragments

Papyrologists analyze, transcribe, and edit papyrus fragments in order to enrich modern lives by better understanding the linguistics, culture, and literature of the ancient world. One of their common tasks is to match an unknown fragment to a known manuscript. This is especially challenging when the fragments are damaged and contain only limited information (e.g., due to deterioration). In the last 100 years, only about 10% of the more than 500,000 fragments recovered from the Egyptian village of Oxyrhynchus have been edited. We do not know what new ancient texts might be found and what can be learned from them, but using current methods of identification this process will take in excess of 1000 years. The identification of an anonymous string of characters with a collection of known text sequences is ubiquitous in computational biology. Genes are often represented by a sequence of continuous characters, each of which denotes an amino acid. Relationships are inferred by finding multi-letter patterns shared between the anonymous sequence and a known sequence. This process is commonly referred to as genetic sequence alignment. In this paper, we introduce a novel methodology that uses modern genetic sequence alignment algorithms as a method for identifying Ancient Greek text fragments. This application will offer papyrologists and other professionals in the humanities the ability to rapidly identify severely damaged texts. This approach leverages a new form of non-contextual, multi-line text identification for the Greek language that can greatly accelerate the tedious task of transcription and identification.

Identification of Ancient Greek Papyrus Fragments Using Genetic Sequence Alignment Algorithms

The biological concept of bilateral symmetry as a marker of developmental stability and good health is well established. Although most individuals deviate slightly from perfect symmetry, humans are essentially considered bilaterally symmetrical. Consequently, increased fluctuating asymmetry of paired structures could be an indicator of disease. There are several published studies linking bilateral breast size asymmetry with increased breast cancer risk. These studies were based on radiologists’ manual measurements of breast size from mammographic images. We aim to develop a computerized technique to assess fluctuating breast volume asymmetry in screening mammograms and investigate whether it correlates with the presence of breast cancer. Using a large database of screening mammograms with known ground truth we applied automated breast region segmentation and automated breast size measurements in CC and MLO views using three well established methods. All three methods confirmed that indeed patients with breast cancer have statistically significantly higher fluctuating asymmetry of their breast volumes. However, statistically significant difference between patients with cancer and benign lesions was observed only for the MLO views. The study suggests that automated assessment of global bilateral asymmetry could serve as a breast cancer risk biomarker for women undergoing mammographic screening. Such biomarker could be used to alert radiologists or computer-assisted detection (CAD) systems to exercise increased vigilance if higher than normal cancer risk is suspected.

Automated assessment of bilateral breast volume asymmetry as a breast cancer biomarker during mammographic screening

Exergames are increasingly being proposed for physical rehabilitation in chronic pain. They can be engaging, fun and can facilitate the setting of targets and evaluating performances through body movement tracking and multimodal feedback. While these attributes are important, it is also essential that psychological factors that lead to avoidance of physical activity are addressed in the game design. Anxiety about increased pain and/or of further damage often causes people to behave in a self-protective manner (e.g., guarding movement) and to avoid particular movements. Protective behaviour may itself cause increased pain or strain. In this paper we investigate the possibility to automatically detect such behavior. Automatic detection of protective behaviour can be used to adapt the exergame at run time to alleviate anxiety and increase treatment efficacy.

Automatic Recognition of Protective Behaviour in Chronic Pain Rehabilitation

Re-Engineering Hegemony: Glass Bead in conversation with Mat Dryhurst, Holly Herndon and Alex Williams — Glass Bead

Miscellaneous personal letters from Geoffrey J. Judge of Zeehan in regard to repairs to T. Gibbins' shop, lack of mining jobs and mines "commencing to look up" dated 1 July and 19 August 1894. From James Duncan regarding the tenancy of Williams' property at Zeehan dated 12 September 1896. From Ada Proctor of Sandy Bay on hearing 
 ALW was about to leave Hobart to thank him for all he did for her Aunt dated 29 August 1897. From E.A Lorkin of North Lyell regarding the lease, amalgamation, and section not complying with labour clause written on 18 October 1897. From J. McDonald of Strahan, correspondence regarding mill timber and accompanying list of measurements of logs dated 6 September 1897. These personal letters of Alex Lachlan Williams 1894-1897 are from the papers of Oscar Jones, solicitor of Murdoch & Jones Queenstown branch and his predecessor Alex Lachlan Williams, apparently found at Strathelie at Broadmarsh formerly the Jones family home. The Queenstown practice was established by Alex Lachlan Williams in 1896. Later Charles Page became a partner and established an office at Zeehan. George Murdoch of the Stone Buildings, Hobart, later Murdoch and Jones, acted as Hobart agent and early in 1898 the two firms merged as Williams and Page of Hobart, Queenstown and Zeehan. In April 1899, however, Williams sold out to Murdoch and Jones, Oscar Jones managed the Queenstown branch and by July the firm's name was changed to Murdoch & Jones. Williams & Page remained in Zeehan, under C.S. Page. 
 Private Deposit Collection M14/13 
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Miscellaneous personal letters of Alex Lachlan Williams, 1894-1897

Root and Rhizosphere Processes under Drought: Digging Deeper to Enhance Ecosystem Resilience

Climate change and an increasing population, present a massive global challenge with respect to environmentally sustainable nutritious food production. Crop yield enhancements, through breeding, are decreasing, whilst agricultural intensification is constrained by emerging, re-emerging, and endemic pests and pathogens, accounting for ~30% of global crop losses, as well as mounting abiotic stress pressures, due to climate change. Metabolomics approaches have previously contributed to our knowledge within the fields of molecular plant pathology and plant–insect interactions. However, these remain incredibly challenging targets, due to the vast diversity in metabolite volatility and polarity, heterogeneous mixtures of pathogen and plant cells, as well as rapid rates of metabolite turn-over. Unravelling the systematic biochemical responses of plants to various individual and combined stresses, involves monitoring signaling compounds, secondary messengers, phytohormones, and defensive and protective chemicals. This demands both targeted and untargeted metabolomics approaches, as well as a range of enzymatic assays, protein assays, and proteomic and transcriptomic technologies. In this review, we focus upon the technical and biological challenges of measuring the metabolome associated with plant stress. We illustrate the challenges, with relevant examples from bacterial and fungal molecular pathologies, plant–insect interactions, and abiotic and combined stress in the environment. We also discuss future prospects from both the perspective of key innovative metabolomic technologies and their deployment in breeding for stress resistance.

Unravelling Plant Responses to Stress—The Importance of Targeted and Untargeted Metabolomics

Comparing root exudate collection techniques: An improved hybrid method

Plant root exudation is a crucial means through which plants communicate with soil microbes and influence rhizosphere processes. Exudation can also underlie ecosystem response to changing environmental conditions. Different plant species vary in their root exudate quantity and quality, but our understanding of the plant characteristics that drive these differences is fragmentary. We hypothesised that root exudates would be under phylogenetic control and fit within an exploitative root nutrient uptake strategy, specifically that high rates of root exudation would link to root traits indicative of exploitative growth. We collected root exudates from plants grown in field soil, as well as leachates of the entire plant–soil system, to assess both the quantity and quality of root exudates, and their interaction with the soil metabolome, across 18 common grassland species. We found that exudation varied with plant functional group and that differences were trait dependent. Particularly, root diameter, root tissue density and root nitrogen content explained much of the variation in exudate metabolome, along with plant phylogeny. Specific root exudation rate was highest in forbs and was negatively correlated with root tissue density, a trait indicative of conservative resource‐use strategy, and positively correlated with root diameter, which is associated with microbial collaboration and resource uptake ‘outsourcing’. Synthesis. We provide novel insight into species‐specific differences in root exudates and identify root functional traits that might underlie these differences. Our results show that root exudation fits, although not entirely, within current models of the root economic space, with strong positive relationships to outsourcing traits like high root diameter. Determining the role of root exudates as a key facet of the resource‐outsourcing strategy necessitates further research into the fundamental controls on root exudation quantity and quality, particularly during environmental change.

Root functional traits explain root exudation rate and composition across a range of grassland species

Root-associated microbes can improve plant growth, and they offer the potential to increase crop resilience to future drought. Although our understanding of the complex feedbacks between plant and microbial responses to drought is advancing, most of our knowledge comes from non-crop plants in controlled experiments. We propose that future research efforts should attempt to quantify relationships between plant and microbial traits, explicitly focus on food crops, and include longer-term experiments under field conditions. Overall, we highlight the need for improved mechanistic understanding of the complex feedbacks between plants and microbes during, and particularly after, drought. This requires integrating ecology with plant, microbiome, and molecular approaches and is central to making crop production more resilient to our future climate.

Harnessing rhizosphere microbiomes for drought-resilient crop production

Root exudates are a pathway for plant-microbial communication and play a key role in ecosystem response to environmental change. Here, we collate recent evidence that shows that plants of different growth strategies differ in their root exudation, that root exudates can select for beneficial soil microbial communities, and that drought affects the quantity and quality of root exudation. We use this evidence to argue for a central involvement of root exudates in plant and microbial response to drought and propose a framework for understanding how root exudates influence ecosystem form and function during and after drought. Specifically, we propose that fast-growing plants modify their root exudates to recruit beneficial microbes that facilitate their regrowth after drought, with cascading impacts on their abundance and ecosystem functioning. We identify outstanding questions and methodological challenges that need to be addressed to advance and solidify our comprehension of the importance of root exudates in ecosystem response to drought.

Plant root exudation under drought: implications for ecosystem functioning.

The analysis of chemical diversity in non-sterile rhizosphere soil has been a pressing methodological challenge for years. Rhizosphere-enriched chemicals (i.e., rhizochemicals) include root exudation chemicals, (microbial) breakdown products thereof, and de novo produced metabolites by rhizosphere-inhabiting microbes, all of which can play an important role in plant-soil interactions. The power and resolution of analytical methods and statistical analysis pipelines allow for better acquisition, separation and identification of rhizochemicals, thus providing unprecedented insight into the biochemistry underpinning plant-soil interactions. The current protocol describes a recently developed method to characterize rhizochemical profiles from plants, including crops, and is modular and customizable, allowing for application across a range of different plant-soil combinations. The protocol provides in-depth details about the experimental system for sample collection, data acquisition by liquid chromatography coupled to mass spectrometry, and analytical pipeline, which statistically selects for rhizochemicals by statistical comparison between metabolite profiles from plant-containing soil and plant-free soil. Moreover, the optional addition of chemical standards permits a semi-targeted approach, which improves the annotation of chemical signatures and identification of single rhizochemicals.

An Adjustable Protocol to Analyze Chemical Profiles of Non-sterile Rhizosphere Soil.

Summary Root exudates play an important role in ecosystem response to climate change, but the functional consequences of drought‐induced changes in the quality of root exudates are unknown. Here, we addressed this knowledge gap in a unique experimental approach. We subjected two common grassland species that differ widely in their growth strategies and root systems, the grass Holcus lanatus and the forb Rumex acetosa, to 2 wk of drought. We collected root exudates and soils at the end of the drought and after 2 wk of recovery and readded all root exudates to all soils in a fully reciprocal set‐up to measure root‐exudate‐induced respiration. We found that soil treatment was unimportant for determining root‐exudate‐induced respiration. By contrast, root exudates collected from plants that had experienced drought clearly triggered more soil respiration than exudates from undroughted plants. Importantly, this increased respiration compensated for the lower rates of root exudation in droughted plants. Our findings reveal a novel mechanism through which drought can continue to affect ecosystem carbon cycling, and a potential plant strategy to facilitate regrowth through stimulating microbial activity. These findings have important implications for understanding plant and ecosystem response to drought.

Changes in root‐exudate‐induced respiration reveal a novel mechanism through which drought affects ecosystem carbon cycling

Concerns over rising atmospheric CO2 concentrations have led to growing interest in the effects of global change on plant-microbe interactions. As a primary substrate of plant metabolism, atmospheric CO2 influences below-ground carbon allocation and root exudation chemistry, potentially affecting rhizosphere interactions with beneficial soil microbes. In this study, we have examined the effects of different atmospheric CO2 concentrations on Arabidopsis rhizosphere colonization by the rhizobacterial strain Pseudomonas simiae WCS417 and the saprophytic strain Pseudomonas putida KT2440. Rhizosphere colonization by saprophytic KT2440 was not influenced by sub-ambient (200 ppm) and elevated (1,200 ppm) concentrations of CO2, irrespective of the carbon (C) and nitrogen (N) content of the soil. Conversely, rhizosphere colonization by WCS417 in soil with relatively low C and N content increased from sub-ambient to elevated CO2. Examination of plant responses to WCS417 revealed that plant growth and systemic resistance varied according to atmospheric CO2 concentration and soil-type, ranging from growth promotion with induced susceptibility at sub-ambient CO2, to growth repression with induced resistance at elevated CO2. Collectively, our results demonstrate that the interaction between atmospheric CO2 and soil nutritional status has a profound impact on plant responses to rhizobacteria. We conclude that predictions about plant performance under past and future climate scenarios depend on interactive plant responses to soil nutritional status and rhizobacteria.

Impacts of Atmospheric CO2 and Soil Nutritional Value on Plant Responses to Rhizosphere Colonization by Soil Bacteria

Over recent years, an increasing body of evidence has suggested that elevated atmospheric CO2 concentrations can alter plant microbial interactions. However, there is limited consensus whether these impacts will be positive or negative for plants in terms of disease resistance. Accordingly, there is a pressing need to gain a better understanding of the molecular and physiological mechanisms by which CO2 shapes the plant’s ability to interact with its biotic environment, which is essential to predict impacts of future climate scenarios on crop production. 
The work described in this thesis has used a range of CO2 concentrations, from past through present to future predicted concentrations, to study the immune response of the model plant Arabidopsis thaliana to aboveground pathogens and belowground rhizosphere bacteria. Furthermore, a novel developmental correction was established, which enables assessing the direct immunological effects of CO2 on microbial interactions without bias from age-related resistance arising from the stimulatory effects of CO2 on plant development. 
Changes in disease resistance at elevated CO2 (eCO2), against the necrotrophic fungus Plectosphaerella cucumerina (Pc) and the obligate biotrophic oomycete Hyaloperonospora arabidopsidis (Hpa) were associated with changes in production and sensitivity of the phytohormones jasmonic acid (JA and salicylic acid (SA), respectively. However, priming of SA-dependent defence was not the only mechanisms contributing to eCO2-induced resistance against Hpa. The increased resistance to Hpa at sub-ambient CO2 (saCO2) against Hpa operated independently of SA signaling and was associated with changes in cellular redox state and priming of pathogen-inducible intracellular ROS. Based on the defence phenotypes of knock-down mutants in glycolate oxidase, the H2O2-generating enzyme of the photorespiration cycle, and transcriptional profiling of the peroxisomal catalase gene CAT2, it is proposed that the enhanced Hpa resistance at saCO2 is controlled by photorespiratory ROS. 
Below-ground, the root colonisation of a specialised rhizobacterial strain Pseudomonas simiae WCS417 was found to be dependent on CO2 concentration 
vi 
and soil-nutritional status, whereas root colonisation by the soil saprophytic strain Pseudomonas putida KT2440 was largely unaffected by these variables. Hence, changes in atmospheric CO2 have a greater impact on specialist rhizosphere microbes. Furthermore, the ability of P. simiae WCS417 to promote plant growth and elicit an induced systemic resistance (ISR) was highly dependent on CO2 and nutritional status of the soil. These results suggest that the effects of atmospheric CO2 on rhizosphere microbes depend on the rhizosphere species in question and the nutritional status of the soil. 
To obtain a more global impression of the impacts of CO2 on rhizosphere interactions, rhizosphere soil was studied for bacterial community diversity and composition using PCR-based community profiling techniques. This revealed that CO2 has a measurable impact on microbial communities in a time-point dependent manner, whereby the effects of eCO2 are more pronounced at earlier stages and the effects of saCO2 are more pronounced at later stages. To study the biochemical basis of these CO2 effects on the rhizosphere effect, a new mass spectrometry-based method was developed to study quantitative and qualitative impacts of CO2 on non-sterile rhizosphere chemistry. These experiments revealed that the diversity of chemical signals greatly increases with rising CO2 concentrations, and that saCO2 and eCO2 are associated with rhizosphere enrichment of different classes of chemicals. 
Together, the results presented in this thesis provide novel insights into the mechanisms by which plants have adapted to past CO2 climates, and the potential impacts by which future CO2 scenarios will affect interactions with hostile and beneficial microbes. Further research is required to explore the combined impacts of eCO2 and other environmental changes due to global climate change, such as elevated temperatures and drought.

Impacts of sub-ambient and elevated CO2 on above- and below-ground microbial interactions with Arabidopsis.

Summary The impacts of rising atmospheric CO2 concentrations on plant disease have received increasing attention, but with little consensus emerging on the direct mechanisms by which CO2 shapes plant immunity. Furthermore, the impact of sub‐ambient CO 2 concentrations, which plants have experienced repeatedly over the past 800 000 yr, has been largely overlooked. A combination of gene expression analysis, phenotypic characterisation of mutants and mass spectrometry‐based metabolic profiling was used to determine development‐independent effects of sub‐ambient CO 2 (sa CO 2) and elevated CO 2 (eCO 2) on Arabidopsis immunity. Resistance to the necrotrophic Plectosphaerella cucumerina (Pc) was repressed at sa CO 2 and enhanced at eCO 2. This CO 2‐dependent resistance was associated with priming of jasmonic acid (JA)‐dependent gene expression and required intact JA biosynthesis and signalling. Resistance to the biotrophic oomycete Hyaloperonospora arabidopsidis (Hpa) increased at both eCO 2 and sa CO 2. Although eCO 2 primed salicylic acid (SA)‐dependent gene expression, mutations affecting SA signalling only partially suppressed Hpa resistance at eCO 2, suggesting additional mechanisms are involved. Induced production of intracellular reactive oxygen species (ROS) at sa CO 2 corresponded to a loss of resistance in glycolate oxidase mutants and increased transcription of the peroxisomal catalase gene CAT2, unveiling a mechanism by which photorespiration‐derived ROS determined Hpa resistance at saCO2. By separating indirect developmental impacts from direct immunological effects, we uncover distinct mechanisms by which CO 2 shapes plant immunity and discuss their evolutionary significance.

Mechanisms of glacial‐to‐future atmospheric CO 2 effects on plant immunity

Summary Rhizosphere chemistry is the sum of root exudation chemicals, their breakdown products and the microbial products of soil‐derived chemicals. To date, most studies about root exudation chemistry are based on sterile cultivation systems, which limits the discovery of microbial breakdown products that act as semiochemicals and shape microbial rhizosphere communities. Here, we present a method for untargeted metabolic profiling of non‐sterile rhizosphere soil. We have developed an experimental growth system that enables the collection and analysis of rhizosphere chemicals from different plant species. High‐throughput sequencing of 16S rRNA genes demonstrated that plants in the growth system support a microbial rhizosphere effect. To collect a range of (a)polar chemicals from the system, we developed extraction methods that do not cause detectable damage to root cells or soil‐inhabiting microbes, thus preventing contamination with cellular metabolites. Untargeted metabolite profiling by UPLC‐Q‐TOF mass spectrometry, followed by uni‐ and multivariate statistical analyses, identified a wide range of secondary metabolites that are enriched in plant‐containing soil, compared with control soil without roots. We show that the method is suitable for profiling the rhizosphere chemistry of Zea mays (maize) in agricultural soil, thereby demonstrating the applicability to different plant–soil combinations. Our study provides a robust method for the comprehensive metabolite profiling of non‐sterile rhizosphere soil, which represents a technical advance towards the establishment of causal relationships between the chemistry and microbial composition of the rhizosphere.

Slugs and snails are parasitised by a range of organisms including nematodes, bacteria, microsporidia, mites and flies (Barker, 2004). Of these, the nematodes are the most numerous and diverse as 108 species have evolved to parasitise molluscs (Grewal et al., 2003). One of these nematodes (Phasmarhabditis hermaphrodita) is a lethal parasite of a range of pestiferous slugs and snails including Deroceras reticulatum, Arion ater and Helix aspersa (Wilson et al., 1993). P. hermaphrodita has been formulated into a biocontrol agent (Nemaslug®) by Becker Underwood-BASF available for farmers and gardeners (Rae et al., 2007). Nematodes are mixed with water and applied using spraying equipment to soil where then go and search for potential gastropod hosts. They are attracted to slug mucus and faeces (Rae et al., 2006, 2009) and upon discovery they penetrate through the slugs’ mantle and kill it between 4 and 21 days (Wilson et al., 1993; Tan & Grewal, 2001).

Cepaea nemoralis (Linnaeus, 1758) uses its shell as a defence mechanism to trap and kill parasitic nematodes

La presente invention concerne une composition amelioree d'inhibiteur de nitrification et son utilisation dans des applications agricoles.

This study investigated the relationship between microbial communities in differently sized colonies of the massive coral Coelastrea aspera at Phuket, Thailand where colony size could be used as a proxy for age. Results indicated significant differences between the bacterial diversity (ANOSIM, R = 0.76, p = 0.001) of differently sized colonies from the same intertidal reef habitat. Juvenile and small colonies (<6cm mean diam) harboured a lower bacterial richness than medium (~10cm mean diam) and large colonies (>28 cm mean diam). Bacterial diversity increased in a step-wise pattern from juveniles<small<medium colonies, which was then followed by a slight decrease in the two largest size classes. These changes appear to resemble a successional process which occurs over time, similar to that observed in the ageing human gut. Furthermore, the dominant bacterial ribotypes present in the tissues of medium and large sized colonies of C. aspera, (such as Halomicronema, an Oscillospira and an unidentified cyanobacterium) were also the dominant ribotypes found within the endolithic algal band of the coral skeleton; a result providing some support for the hypothesis that the endolithic algae of corals may directly influence the bacterial community present in coral tissues.

Universal cervical cancer control through a right to health lens: refocusing national policy and programmes on underserved women

Introduction: In this article we consider Ontario policy responses to an aging population and highlight lessons learned about the challenges of sustaining policy change in unstable sub-sectors. We consider the case of community based long-term care (LTC) policy in Ontario over the past decade analyzing the trajectory and legacy of what has been referred to as “Aging at Home” strategy. Description of the innovation or study: Aging at Home policies aim to maintain persons as independently as possible, for as long as possible, in their own homes through coordinated access to home and community care (HC and secondly, health policy change can be contingent on competing policy agendas in other sub-sectors of health systems. Key Lessons: Sub-sectors within healthcare systems will have divergent political dynamics, institutional arrangements and policy histories. We suggest that existing theoretical frameworks for policy change can be too general to account for important differences. Competing policy agendas in marginalized sectors can be appropriated by competing policy agendas in other prevailing sectors. In the case of Aging at Home, findings suggest it was largely appropriated by the interests of more dominant actors in the Mainstream sector. Conclusion: Ontario's experience with the Strategy has been quintessential, rather than novel; it shifted to expand capacity of institutional care. In redefining the role of the H&CC sector moving forward – as informed by the participants – we need to leverage interests of dominant players, ‘share risk’, and structurally reform funding and delivery of H&CC services.

Reform but no change: The case of aging at home policy in Ontario, Canada

Introduction : In Ontario, Canada publicly funded healthcare extends across siloed sub-systems, spanning acute, primary, home and community care (HC however, within each system there are multiple and less distinct subsystems related to broader health making the identification of relevant subsystems for CBPHC extremely complex. Suggestions for Future Research : A cross-jurisdictional comparative policy analysis with Quebec and New Zealand is planned to increase understanding of the extent to which cross-boundary issues influence the ability to offer integrated CBPHC and recommendations to address them.

iCOACH: Integrated care as boundary spanning: Organizational workarounds in the delivery of community based primary health care

Introduction: Community-based primary health care (CBPHC) describes a model of service provision that is oriented to the population health needs and wants of service users and communities, and has particular relevance to supporting the growing proportion of the population with multiple chronic conditions. Internationally, aspirations for CBPHC have stimulated local initiatives and influenced the design of policy solutions. However, the ways in which these ideas and influences find their way into policy and practice is strongly mediated by policy settings and institutional path dependencies. This paper compares key features of the policy and institutional environments relevant to community-based primary health care in Ontario, Quebec and New Zealand. Theory/Methods: Drawing on existing literature and our collective expertise, we sought to identify the key organisational landscapes, service models, integrating mechanisms, and relevant policy developments within each jurisdiction. From these descriptions we develop a comparative analysis of enablers and facilitators. Results: Our analysis suggests that Ontario has the most significant institutional barriers to organisational integration and the fewest available policy levers, whilst New Zealand has the most conducive organisational landscape and strongest policy levers. Quebec has significant capacity for reform the structure of the health system, but reforms to date these have not incorporated primary health care. Conclusions: (comprising key findings) Our analysis suggests that two key conditions include the integration of relevant health and social sector organisations, and the range of policy levers available and used by governments. On both dimensions, the New Zealand environment appears to offer the largest scope, with Ontario’s environment significantly less conducive, with Quebec situated in between. Nevertheless, in each case there remain important institutional barriers to implementation of policies that promote CBPHC. Lessons Learned: Although New Zealand has more powerful policy levers, the effectiveness of levers is largely dependent on implementation strategies. Here the differences between New Zealand, Quebec and Ontario are less marked. Limitations: This research constitutes a preliminary, high-level understanding of the complex policy environments of three comparable policy and institutional environments. However, the degree to which the factors identified are key facilitators and inhibitors of CBPHC requires empirical investigation such that other significant policy and institutional constraints and enablers can be identified. Suggestions for Future Research: This research serves to inform the broader iCoach research collaboration, which investigates a range of specific local CBPHC initiatives and embedded practices that focus on older adults with complex conditions. Moving forward our research will focus on the analysis of key stakeholder interviews conducted within Ontario, Quebec and New Zealand to identify key institutional and policy settings that may enable and constrain the implementation and diffusion of these initiatives.

A comparison of the policy and institutional environment relevant to community-based primary health care in Ontario, Quebec and New Zealand

Background Increasing evidence has suggested that major depression (MD) is associated with an increased risk of ischemic heart disease (IHD). We examined this association in Chinese adults using data from the China Kadoorie Biobank study. Methods and Results Over 0.5 million adults aged 30 to 79 years were followed from baseline interview (2004–2008) until December 31, 2013. Past year MD was measured with the modified Chinese version of Composite International Diagnostic Interview‐Short Form at baseline. Incident IHD cases were identified through linkage to related medical databases, and defined as having International Statistical Classification of Diseases and Related Health Problems 10th Revision codes of I20 to I25. Cox proportional hazards regression models were used to estimate hazard ratios and 95% CIs for the MD‐IHD association with adjustment for sociodemographic variables and established cardiovascular risk factors. During 3 423 542 person‐years of follow‐up, 24 705 incident IHD cases were documented. Higher IHD incidence was observed in participants with MD compared with those without (8.76 versus 7.21 per 1000 person‐years), and the multivariable‐adjusted hazard ratio was 1.32 (95% CI 1.15–1.53). Geographic location modified the association (P for interaction=0.005), and a positive association was observed in urban residents (hazard ratio 1.72; 95% CI 1.39–2.14) but not rural residents (1.13; 0.93–1.37). Compared with participants without depressive symptoms, the hazard ratio (95% CI) of IHD was 1.13 (1.04–1.23) for those with depressive symptoms only and 1.33 (1.15–1.53) for those with MD. Conclusions Past year major depression was associated with an increased risk of IHD in Chinese adults, independent of other major cardiovascular risk factors.

Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Association of Major Depression With Risk of Ischemic Heart Disease in a Mega‐Cohort of Chinese Adults: The China Kadoorie Biobank Study

On the record. Looking at ordinary people's tales of living with their mental illness.

This paper reflects on older teenagers’ engagement with leisure reading as an unanticipated outcome of a university library-based study centre for secondary school students. In 2013, the author, a university Liaison Librarian, was employed to manage a study centre for secondary school students as part of a wider initiative to increase the university participation rates of students from low socioeconomic backgrounds in the Northern Territory (NT), Australia. In addition to supporting the academic needs of students, the Into Uni Study Centre program places a strong focus on fostering the social-emotional wellbeing of older teenagers accessing the service. The Study Centre has inadvertently given rise to an ‘accidental book club’, which has presented opportunities to foster a culture of reading through serendipitous promotion of the library collection. This has led to a number of positive outcomes, including a more targeted approach to developing the library’s young adult fiction collection, increased circulation of leisure reading materials and students’ increased knowledge of library services and confidence in accessing library staff. The author argues that library-based programs which explicitly support social-emotional needs can encourage older teenagers to engage with reading in a flexible and authentic way, as opposed to more traditional book club programs which focus on the uptake of reading as the primary desired outcome.

The accidental book club: Getting older teenagers to engage with leisure reading without really meaning to

In the ECE sector, & indeed in our wider society, there is a growing awareness that the current dearth of men teaching in the ECE context is neither ‘natural’ nor ‘as it should be’. The profound lack of men working in ECE merely reflects, & ultimately upholds, unhelpful, limiting & out-dated notions of what constitutes men’s & women’s work. This presentation draws on recent research to unpack some of the factors that might attract men into ECE, to consider some of the circumstances that may create opportunities for men to join ECE & to consider, from a distinctly male perspective, some of the intrinsic rewards found in a career in ECE. This information provides an informed platform from which to engage with men in conversations about ECE & to encourage men to consider ECE as a viable & attractive vocation. UNDERSTANDING WHY THERE ARE SO FEW MALE ECE TEACHERS: 1. ECE as an extension of ‘mothering’ ECE has long being seen as a natural extension of the mothering role – a role that women do ‘naturally’ & one that men are in some way inferior at. 2. The fear of accusation It has been argued that men shy away from the ECE context due to fears of being accused of ‘inappropriate behaviour’. The reduction in male ECE teachers as a result of the Christchurch Civic Crèche case supports this view. However the fact that men continue to be involved in wide range of other contexts involving children (ie children’s sports, Cub groups & primary teaching etc) suggests this is not the primary reason for the lack of men in ECE.

Encouraging Men into the ECE Sector. Having Informed Conversations.

Background Drinking alcohol has a long tradition in Chinese culture. However, data on the prevalence and patterns of alcohol consumption in China, and its main correlates, are limited. Methods During 2004–08 the China Kadoorie Biobank recruited 512 891 men and women aged 30–79 years from 10 urban and rural areas of China. Detailed information on alcohol consumption was collected using a standardized questionnaire, and related to socio-demographic, physical and behavioural characteristics in men and women separately. Results Overall, 76% of men and 36% of women reported drinking some alcohol during the past 12 months, with 33% of men and 2% of women drinking at least weekly; the prevalence of weekly drinking in men varied from 7% to 51% across the 10 study areas. Mean consumption was 286 g/week and was higher in those with less education. Most weekly drinkers habitually drank spirits, although this varied by area, and beer consumption was highest among younger drinkers; 37% of male weekly drinkers (12% of all men) reported weekly heavy drinking episodes, with the prevalence highest in younger men. Drinking alcohol was positively correlated with regular smoking, blood pressure and heart rate. Among male weekly drinkers, each 20 g/day alcohol consumed was associated with 2 mmHg higher systolic blood pressure. Potential indicators of problem drinking were reported by 24% of male weekly drinkers. Conclusion The prevalence and patterns of drinking in China differ greatly by age, sex and geographical region. Alcohol consumption is associated with a number of unfavourable health behaviours and characteristics.

Alcohol consumption in 0.5 million people from 10 diverse regions of China: prevalence, patterns and socio-demographic and health-related correlates

Purpose – The paper is a follow-up to a personal account published in this journal 12 months ago. The purpose of this paper is to highlight job retention through support measures during a period of crisis, contrasted with factors which undermine a quicker return to good mental health. Design/methodology/approach – The paper is a personal account of difficulties experienced within and outside the workplace for someone who has been through long-term mental distress and is in her first, proper, paid job. The author reflects on becoming unwell while in full-time work with fears of dismissal by the employer as well as rejection by mental health services. Due to a supportive employer the author is still employed but is more aware of distress triggers. Findings – Helpful approaches which make job sustainment possible include the use of independent occupational health services, supported employment advice, phased returns, income maximisation through Disability Living Allowance and employer flexibility. The factor...

Purpose – This article aims to explore what are likely to be key factors in a successful journey to employment for someone who has experienced long‐term mental distress.Design/methodology/approach – The article is a personal account of entering and sustaining employment by someone who has experienced long‐term mental distress and use of secondary mental health services. The writer reflects on a hard fought journey to start paid work in the hope that readers may understand this process for themselves and others in similar positions.Findings – Key factors in the transition to employment are hard work, workplace support, specialist vocational advice, individual determination and willing employers. Support needs to be flexible, personalised, ongoing and sometimes intensive. Time is measured in years rather than months.Practical implications – The integration of specialist vocational advice within mental health teams may be an effective approach.Research implications – Further research into the practical and p...

Managers can have personal afflictions that may interfere with their role as managers in an organization. One of these maladies is obsessive-compulsive disorder (OCD), a condition frequently identified with excessive patterns of seemingly unnecessary behavior. OCD compels individuals to seek "perfection" in the accomplishment of primarily routine tasks. This overt routine of behaviors distracts individuals from accomplishing their goals and those they manage. This paper examines the role of self-concept as being central in identifying and understanding the characteristics of the behavioral disorder OCD and how to modify the self-concept to prevent disruption in the workplace. In addition, the paper explores how to measure OCD and the impact of maladies on peers, subordinates, and superiors in the organization. I've learned...that we should be glad God doesn't give us everything we pray for-My father.

Assessing the role of the self-concept on the destructive impact of obsessive–compulsive disorder in managers

Seeing a new perspective: Alex Williams was getting her life back on track when tragedy struck, but the support of healthcare staff has been crucial in helping her to cope

Impaired employees: Lessons learned from The Wonderful Wizard of Oz

The highly gendered nature of early childhood education is highlighted by the statistical reality that currently less than one percent of early childhood educators in New Zealand are men. This situation is of significant concern and has potentially negative implications, not only for the early childhood educational experiences for both boys and girls but also for the sector as a whole. This paper explores the notion that men in the early childhood sector, as a statistical minority, may be perceived in terms of being unusual, different and even perhaps as outsiders. An analysis of nine 'Personal Stories' posted on the TeachNZ (the recruiting arm of the Ministry of Education) website was conducted to gain an insight into how men in early childhood education can be unintentionally positioned as outside the norm and how the differences between men and women early childhood educators can be accentuated within this specific context (i.e., the TeachNZ website). This paper considers how such positioning of men within the early childhood education sector not only highlights the difference and otherness of men within the sector but may also actively contribute to the perpetuation of such a perception.

Mapping the State of the Art: Integrating Care for Vulnerable Older Populations

The purpose of this article is to offer a new approach to measuring person-organization (P-O) fit, referred to here as “Latent fit.” Respondents were administered unidimensional forced choice items and were asked to choose the statement in each pair that better reflected the correspondence between their values and those of the organization; scaling was done using an item response theory (IRT) model for stimulus endorsement. An empirical study comparing this new approach to two traditional P-O fit measurement approaches was also conducted. The results indicated that the Latent fit approach had merit, with the fit scores exhibiting theoretically expected patterns of relations with other variables and incremental validity in predicting intentions to leave.

Latent Trait Theory Approach to Measuring Person-Organization Fit: Conceptual Rationale and Empirical Evaluation

Integrating community-based health and social care has grabbed international attention as a way of addressing the needs of aging populations while contributing to health systems' sustainability. However, integrating initiatives in different jurisdictions work (or do not work) within very various institutional and structural dynamics. The question is, what transferable lessons can we learn to guide policy makers and policy innovators at the local level? In this paper, we consider "aging at home" as a policy option in Ontario, and beyond. In the first section, we focus on the problem, in effect, what not to do. Here, we briefly review findings from national and international research literature and from our own research in Ontario that identify the costs and consequences of non-systems of care for older persons. In the second part, we turn to solutions, in effect, what to do. Drawing on our recent scoping review of the international literature, we identify three guiding principles, as well as a number of recommendations, for integrating care for older persons, knowing that important details of how to put such initiatives "on the ground" will be provided by other contributors to this journal edition.

Aging at home: integrating community-based care for older persons.

My mental health: Alex Williams has worked hard to overcome her mental health problems, and with the support of a community psychiatric nurse she is now looking forward to making up for the lost years

User-entrepreneurship and innovation: does customer involvement and learning orientation matter?

The purpose of this paper is twofold. First, this paper seeks to formalize a definition of activist entrepreneurship and differentiate it from social entrepreneurship. Second, this paper proposes a model that explains how the storytelling process, in the form of the message and means of communication, influences the activist identity process and consequently the legitimacy of the activist entrepreneur.,This paper explains the historical method and offers an overview of the unique case of Madam C.J. Walker and analyzes how she gained legitimacy as an activist entrepreneur by conveying psychological capital (Psycap) concepts in her message and political skill in the means of her communication. The paper also analyzed books being written on her and also letters that were exchanged between herself and her lawyer F.B. Ransom.,The authors have found out that Madam Walker used Psycap elements such as self-efficacy, hope, resiliency and optimism as message and elements of political skill such as social astuteness, interpersonal skill, networking ability and apparent sincerity as means to communicate the message toward her followers and built a legitimate social identity where she had won the trust of them.,The primary limitation of this paper is that it is theoretical in nature and uses only one case study to support the theoretical model. However, when analyzing complex relationships, historical cases offer a wealth of insight to solve the problem at hand.,By using the elements of the model discussed in the research paper properly, people could create a legitimate identity for themselves where any message they give to their employees, colleagues and sub-ordinates would be viewed as a selfless one and that would increase the chances of their messages or orders being accepted and obeyed by the followers.

Abstract Research has typically explained the positive intrapsychic influence of political skill using Conservation of Resources (COR) theory. However, research explaining the possible negative intrapsychic consequences of high levels of political skill is lacking. Therefore, we introduce Cognitive Activation Theory (CAT) to the political skill literature to explain possible negative outcomes of political skill. In testing this theory, we used two hierarchical moderated multiple regressions to examine the relationship between affective and continuance commitment, life satisfaction, and political skill in a large, privately owned, financial services firm in Ecuador. Aligned with prior research, affective commitment positively affected life satisfaction; however, contrary to our hypothesis, continuance commitment also positively affected life satisfaction. Furthermore, consistent with both Conservation of Resources and Cognitive Activation Theory, results indicated that political skill strengthened the relationship between affective commitment and life satisfaction. However, contrary to Cognitive Activation Theory, political skill did not significantly weaken the relationship between continuance commitment and life satisfaction.

A dark side of political skill? Awareness and life satisfaction in a Latin American Business

Although trait narcissism has been related to entrepreneurial tendencies, research regarding the influence of narcissism on the entrepreneur’s intrapsychic and interpersonal processes is limited. F...

The Intrapsychic and Interpersonal Processes of a Self-deceptive Narcissistic Serial Entrepreneur

Purpose 
 
The purpose of this study is to narratively explore the influence of leader narcissism on leader/follower social exchange. Moreover, while researchers acknowledge that narcissistic personality is a dimensional construct, the preponderance of extant literature approaches the concept of narcissistic leadership categorically by focusing on the reactive or constructive narcissistic extremes. This bimodal emphasis ignores self-deceptive forms of narcissistic leadership, where vision orientation and communication could differ from leaders with more reactive or constructive narcissistic personalities. 
 
Design/methodology/approach 
 
The authors argue that they encountered a compelling example of a communal, self-deceiving narcissist during archival research of Robert Owen’s collective experiment at New Harmony, Indiana. To explore Owen’s narcissistic leadership, they utilize an analytically structured history approach to interpret his leadership, as he conveyed his vision of social reform in America. 
 
Findings 
 
Approaching data from a ‘history to theory’ perspective and via a communicative lens, the authors use insights from their abductive analysis to advance a cross-paradigm, communication-centered process model of narcissistic leadership that accounts for the full dimensional nature of leader narcissism and the relational aspects of narcissistic leadership. 
 
Research limitations/implications 
 
Scholars maintaining a positivist stance might consider this method a limitation, as historical case-based research places greater emphasis on reflexivity than replication. However, from a constructionist perspective, a focus on generalization might be considered inappropriate or premature, potentially hampering the revelation of insights. 
 
Originality/value 
 
Through a multi-paradigmatic analysis of the historical case of Robert Owen and his visionary communal experiment at New Harmony, the authors contribute to the extant literature by elaborating a comprehensive, dimensional and relational process framework of narcissistic leadership. In doing so, the authors have heeded calls to better delineate leader narcissism, embrace process and relational aspects of leadership and consider leader communication as constitutive of leadership.

Disharmony in New Harmony: insights from the narcissistic leadership of Robert Owen

DeRue and Ashford (2010) proposed a social process of leadership identity construction, asserting that leadership identity is co-constructed by way of claims and grants of leader and follower identities. In addition, these authors suggested that the collective endorsement of the broader social context might serve as a catalyst to initiate the leader identity construction process. As a result, they called for qualitative studies to further develop this idea. During archival research of James Meredith’s historic integration of the University of Mississippi, we discovered evidence to support and extend their theoretical arguments. Accordingly, we interpret the archival evidence of support and opposition of Meredith’s defiant integration to contrast the leader identity construction processes of Meredith with his contemporary antagonist, former Mississippi Governor Ross Barnett. We use this analysis to illustrate how the distinctive social context broadly recognized the key element of defiance and collectively endorsed Meredith as a leader, thereby initiating his leader identity construction process.

The collective endorsement of James Meredith: Initiating a leader identity construction process

IntroductionINCREASED DISSATISFACTION WITH TRADITIONAL INSTITUTIONS towards addressing social needs has motivated entrepreneurs to identify and pursue ventures aimed at creating value by tackling pressing social issues (London, 2008; Mason, 2010). While many social ventures have considerable impact on their constituent stakeholder group (Seanor & Meaton, 2007), unfortunately, very few survive their first succession (Adams, 2004; Froelich, McKee, & Rathge, 2011). The failed succession of a social venture, unlike the failure of successions in other contexts (e.g., commercial or family firms), primarily affects a non-financially vested targeted social group towards which the organizational mission intends to benefit. This is concerning because social ventures "are more consequential than generating income, as people's lives may be in the balance" (Miller et al., 2012, p. 362). However, despite the increased importance of social entrepreneurship in general and the poor succession rates of social ventures, research on the succession of founding social entrepreneurs has been neglected (Balser & Carmin, 2009; Block & Rosenberg, 2002; Froelich, McKee, & Rathge, 2011).Succession in social ventures differs from succession in other contexts because the primary purpose of the organization is social value creation and not personal wealth accumulation (Carsrud & Brannback, 2011; Fauchart & Gruber, 2011). This difference is important because it reflects divergent founder motivations and contrasting assumptions of the 'model of man' underlying agency and stewardship theories (Donaldson & Davis, 1991). Furthermore, the elevated failure rates of social ventures after the succession of the founder suggest that measures should be taken to prepare the organization for such an event.Through their ability to develop policies and engage in practices reflecting their values, founders of social ventures have a significant and enduring influence on organizational culture (Eddleston, 2008; Fauchart & Gruber, 2011). Therefore, in this paper we posit that by espousing the assumptions of stewardship theory and creating a steward-based organizational culture, social entrepreneurs may facilitate effective succession. This line of research contributes to the extant literature by using the framework developed by Davis, Schoorman, and Donaldson (1997) to explain how social entrepreneurs can use situational mechanisms to influence the psychological mechanisms of internal stakeholders, thereby creating a stewardship culture that results in an effective succession process.The Social Entrepreneur and SuccessionSocial entrepreneurship is an emerging field of inquiry (Short, Moss, & Lumpkin, 2009) that is still at a pre-paradigmatic stage without an agreed upon definition (Zahra, Gedajlovic, Neubaum, & Shulman, 2009). Broader conceptualizations suggest that social entrepreneurship "encompasses the activities and processes undertaken to discover, define, and exploit opportunities in order to enhance social wealth by creating new ventures or managing existing organizations in an innovative manner" (Zahra et al., 2009, p. 519). However, while the broad social entrepreneurship definitions encompass ventures in the for-profit sector, most social entrepreneurial activity takes place in the non-sector (Weerawardena & Mort, 2006). Due to the emphasis placed on satisfying social constituents over wealth creation, most social ventures explicitly state this emphasis in their mission statement. An organizational mission that lends primacy to social value creation over economic accumulation has important implications for corporate governance and consequently on succession (Gedajlovic, Lubatkin, & Schulze, 2004).Succession is the transfer process of leadership and ownership (Le BretonMiller, Miller, & Steier, 2004), and is recognized as "an important mechanism for organizational renewal" (Steier, Chrisman, & Chua, 2004, p. …

Effective Succession of Social Entrepreneurs: A Stewardship-Based Model

IntroductionOrganizations operating in dynamic industries are faced with a large amount of uncertainty regarding strategic options, and thus, must maintain the flexibility to respond to changes in the external environment and capitalize on the opportunities they provide (Teece, Pisano, & Schuen, 1997). Increasingly, organizations are managing environmental uncertainty and achieving strategic organizational goals by forming alliances with partners who offer strengths not maintained by the primary organization (Schreiner, Kale, & Corsten, 2009). Healthcare organizations, in particular, operate in an extremely dynamic environment due to frequent changes in the regulatory demands. The dynamism has never been more evident than with the recent passage of the Affordable Care Act. This act promotes an accountable care organization (ACO) model that encourages hospitals, physicians and other healthcare providers to collaborate to ensure cost effective delivery of patient care. Creating and maintaining these ACO alliances in addition to the many other non-ACO alliances in a cohesive and efficient manner is challenging as managers must account for not only the dynamics of each alliance, but also for how each dyadic relationship influences the overall portfolio of alliances (Wassmer, 2010). Healthcare alliances have historically not been equipped to manage these types of portfolios and to date no specific insight to healthcare strategic alliance portfolio management has been proffered.In order to address this opening in the literature this paper sets out to examine the phenomenon of healthcare alliance portfolios from two perspectives. First, we utilize resource dependence theory (RDT) (Pfeffer & Salancik, 1978) to derive the options of strategic alliances that healthcare administrators can form based on the value and congruence of the resources that the alliance relationship could provide. Second, we use the resource-based view (RBV) (Barney, 1991) to explicate the options that administrators can use to manage the coordination, communication, and bonding of the formed strategic alliances. We then integrate these two perspectives and explain how effective management of the individual dyadic relationships and the overall alliance portfolio is important for establishing a competitive strategic position within the healthcare industry.Analyzing portfolios of alliances requires hospital management to step back from the day-to-day management of transactional contracts and adopt a broader perspective to ensure that the overall portfolio configuration is congruent with the organization's strategic goals (Gulati, Lavie, & Singh, 2009). Many organizations enter into alliance relationships without considering the impact of the relationship on the overall portfolio or how the specific alliance improves the alignment of the overall portfolio of alliances with the organization's strategic plan (Bamford & Ernst, 2002). Healthcare reform and the surrounding legislation suggests the need for real and significant changes to the way healthcare is delivered, yet leaves healthcare leaders in a quandary as to how to make the necessary changes. In addition to the changing definitions of reform itself there is "a lack of knowledge and experience on the part of providers" (McClellan, McKethan, Lewis, Roski & Fisher, 2010 p.987) on the structure of the organization and the essential relationships necessary to implement the changes required or encouraged by the reform legislation. Similar to other organizational leaders, healthcare administrators may not fully consider how newly forged ACO alliances may contribute to their current alliance portfolio. With the ever-changing dynamic of the healthcare industry, not only the composition of the portfolio but also the management of the relationships is increasingly difficult. The national strategy for healthcare reform calls on ACOs to continue to examine the effectiveness of the relationships they create both within and outside the patient care area with an eye on clinical care and economic responsibility. …

Managing Healthcare Alliance Portfolios: A Theory-Based Typology

Servant leadership is a paradox ... How can a person be a leader and a servant at the same time? Although servant leadership seems contradictory and challenges our traditional beliefs about leadership, it is an approach that offers a unique perspective.(Northouse, 2013: 219)I was still shy then ... However, I was assertive in our assignments, going above and beyond ... and driving our team to achieve excellence. Years later, I would find this approach written about in business management textbooks: it was a leadership style known as "servant leadership."(Fu & Fox, 2012: 64)The paradoxical notion of the servant leader was originated by Greenleaf (1970), largely based on his belief that service towards others is an essential element of human nature (Leduc, 2003). "However, despite its introduction four decades ago and empirical studies that started more than 10 years ago (Laub, 1999), there is still no consensus about a definition and theoretical framework of servant leadership" (van Dierendonck, 2011: 1229). In an attempt to resolve this conceptual confusion, van Dierendonck (2011) analyzed the plethora of models inspired by Greenleaf's ideas, to offer a broad framework emphasizing the antecedents, processes, and outcomes of servant leadership. Regrettably, we still lack sufficient studies that describe servant leadership in practice, as the preponderance of servant leader writing has been prescriptive (Northouse, 2013). This leaves many fundamental questions unanswered (Parris & Peachey, 2013). As a result, Whetstone (2002: 390) suggested that the questions surrounding servant leadership might be "best answered by observing leaders genuinely adopting servant leadership."The above autobiographical reference to her own servant leadership style was made by an extraordinary entrepreneurial leader, Ping Fu, the founder and CEO of Geomagic, a 3D digital technology company. As we will show, the story of her strength, courage, and resilience in serving those in her sphere of influence is remarkable. With current calls for more examinations of leaders actually practicing servant leadership, we argue that consideration of a contemporary leader whose philosophy, motivations, and practices resonate with, and in some ways reconcile, the paradoxical concept of leader as servant is warranted. Accordingly, we analyzed her life- stories (Shamir & Eilam, 2005) to further inform the servant leadership debate.We begin by describing the assumptions of logic, method, and theoretical lens directing our interpretive study. We then briefly review the current state of servant leadership theory, focusing on the recent theoretical framework proposed by van Dierendonck (2011). Next, we introduce Ping Fu and attempt to situate her leadership motives, attributes, and behaviors within van Dierendonck's (2011) conceptual model of servant leadership. Finally, noting the unique and incongruous aspects of Fu's servant leadership, we integrate insights gleaned from her case to illustrate the servant leader core emerging from her life-stories.Assumptions and ApproachAlthough studies of contemporary organizational leaders can be phenomenological, tending to favor realism over internal validity (Chatman & Flynn, 2005), Shamir and Eilam (2005) argued that the experiences chosen by a leader to appear in their life-stories reflects the leader's self-concepts, their concept of leadership, and the processes that enable their leadership practice. From this perspective, objectivity in the recounting of events is of lesser importance than the construction and interpretation of events (Neisser, 1994), as leaders select the elements of their stories. In doing so, they often ascribe meaning to prior events that may not have held significant meaning at the time of manifestation (Josselson, 1993). Thus, life-stories can be examined as "depositories of meaning" (Gabrial, 2000: 15) and "analyzed to discover those meanings" (Shamir & Eilam, 2005: 413). …

Servant Leadership: Approaching the Paradox from the Life-Stories of Ping Fu

Prior research has typically explained the positive intrapsychic influence of political skill using Conservation of Resources (COR) theory. However, theoretical and empirical research explaining possible negative intrapsychic consequences of maintaining a high level of political skill is lacking in the literature. Therefore, we introduce Cognitive Activation Theory (CAT) to the political skill literature to theoretically explain possible negative outcomes of political skill. In order to test this theory, we examined the relationship between affective and continuance commitment, life satisfaction, and political skill in a large Latin American organization. Consistent with both COR and CAT, results indicated that political skill strengthened the relationship between affective commitment and life satisfaction. However, contrary to COR, but in line with CAT, political skill weakened the relationship between continuance commitment and life satisfaction.

The Dark Side of Political Skill: When Awareness Reduces Life Satisfaction

In extremisleadership of Sartrean authenticity: Examples from Xenophon’s Anabasis

Purpose – The purpose of this paper is to extend the body of knowledge of authentic leadership in extreme contexts by developing a framework grounded in the Sartrean existentialist perspective on authenticity and illustrating this framework using the works of Xenophon. Design/methodology/approach – The authors use Sartre’s existential view of authenticity to develop a framework of authentic leadership in extreme contexts. They then use this framework to examine Xenophon’s recount of the retreat of the 10,000 in the classic work, Anabasis. For this analysis, the authors iterate between the ideas of the past and the concepts of the present to understand how this classic has influenced and informed the current body of knowledge about leadership. Findings – Using a Sartrean existentialist lens, “in extremis” authentic leaders exhibit an awareness of context extremity, responsibility in leading and following to share risks in extreme contexts and self-determination that inspires mutual trust and loyalty. Pract...

IntroductionAt the beginning of the 21st century, various corporate scandals brought heightened scrutiny of organizations by their internal and external stakeholders (Evans, Novicevic, Buckley, & Buckley, 2008). The increasing pressures stemming from these multiple constituent groups eventually resulted in the U.S. Congress passing the Sarbanes-Oxley Act (SOX) in 2002. This legislation was passed with the aim of regaining general confidence of publicly traded firms by mandating greater transparency and more stringent internal controls of critical financial and operational events (BNA, 2006; Donaldson, 2005). In particular, SOX demands strict corporate governance, including the conduct of company executives, auditors (both internal and external), middle and lower-level managers, and financial analysts. The Act's far-reaching tenets have resulted in major changes in organizational functions and processes, not only in publicly traded firms, but also in private companies and non-for-profit organizations that voluntarily followed suit in order to attract quality stakeholders (Fletcher, 2005; Lieber, 2007). For all of these organizations, the more stringent demands of SOX require tighter internal controls, emphasizing the need to implement effective information systems and processes (Sherman, 2005).HR departments have increasingly taken a protagonist role within organizations (Shilpa & Gopal, 2011) and are particularly instrumental in establishing organizational compliance with SOX due to their centrality within the organizational structure (Ready, Novicevic, & Evans, 2009). The purview of HR departments spans throughout the organization and includes the responsibility of establishing and controlling policies and procedures (e.g., compensation and training) directly addressed by SOX. Such boundary-spanning has necessitated the move to electronic human resource management systems within the HR function.Despite the increased public interest (Stone & Dulebohn, 2013), as well as the growing academic literature concerning the benefits of electronic human resource management (e-HRM) (Ruel & van der Kaap, 2012), there is surprisingly little research on the strategic benefits of e- HRM (Marler & Fisher, 2013; Stone & Dulebohn, 2013). E-HRM has been defined as organization-wide information systems (i.e., internet or intranet) that allow stakeholders to access HR information and perform HR functions (Stone & Dulebohn, 2013). While past research studies on SOX compliance have addressed the benefits of implementing organization- wide information systems, little is known specifically about how e-HRM systems enable organizations to integrate HR management with internal controls for compliance with SOX demands. Towards that end, we explain how e-HRM facilitates SOX compliance by assisting HR departments to: 1) pursue more stringently the general guidelines of the new proposed COSO framework (developed by the Committee of Sponsoring Organizations of the Treadway Commission for enhancing internal controls - see Appendix) and 2) follow more efficiently the prescriptions offered by Dailey and Brookmire (2005) concerning the role of HR in SOX compliance. Therefore, we contribute to the extant literature by explaining how human resource departments can enhance SOX compliance through the implementation of e-HRM systems.This article is structured as follows: first, we discuss the regulatory framework of organizational conduct and the related implications of SOX for internal controls and HRM policies and practices. Second, we offer a brief overview of the e-HRM literature followed by an explanation of the newly proposed COSO framework and how e-HRM can complement the general guiding principles and contribute to the initiatives of strengthening internal controls. Third, we discuss the five behaviors suggested by Dailey and Brookmire (2005) for how HR departments can enhance SOX compliance and extend their work by explaining how e-HRM can play an instrumental role by making this process more effective and efficient. …

Implication of SOX Compliance for HRM: Enhancing Internal Controls with E-HRM

Theoretical and empirical research has taken great strides towards understanding the antecedents of entrepreneurial intentions. However, much less is understood about how social entrepreneurial intentions are formed. While the Theory of Planned Behavior (TPB) has been one of the dominant theoretical frameworks offered to explain entrepreneurial intentions, the social psychology literature suggests the inclusion of personal norms to predict intentions with a moral consideration. Therefore, the purpose of this paper is to introduce to the entrepreneurship literature this extension of the TPB and explain how attitudes, social norms, perceived behavioral control, and personal norms might provide a parsimonious model for entrepreneurial intentions that have a social inclination. We provide support for the revised TPB framework by analyzing the rich life story of Juliette Gordon (Daisy) Low, the founder of the Girl Scouts, to help map an understanding of how a middle aged, divorced, nearly deaf woman during the...

Towards a Model of Social Entrepreneurial Intentions: Evidence from the Case of Daisy Low

Purpose – The purpose of this paper is to examine Chester Barnard's decisional model utilizing the lens of image theory. The main claim is that the individual decision‐making model proposed by Barnard in his Notes on the Significance of Decisive Behavior can be evaluated within the framework of image theory.Design/methodology/approach – The paper performed a comparative analysis of Barnard's and image theory's models of decision making to outline congruence and incongruence between Barnard's early conceptualization of individual decision making and the contemporary understanding of image theory.Findings – The findings provide support to the claim that image theory is an appropriate framework to describe Barnard's model.Originality/value – The unique contribution of this study is that it provides the first theoretical analysis of Barnard's model of individual decision making. Barnard's model of individual decision making is little known because it was posthumously published in his Notes on the Significance...

Barnard's model of decision making: a historical predecessor of image theory

Abstract The current literature is replete with calls for greater discernment of more positive forms of leadership. In particular, leader authenticity has been proposed as a significant predictor of follower satisfaction and performance and proponents have suggested researchers attempt to theoretically integrate the construct of authentic leadership with other related leadership literatures. While theoretical advances are critical to the discipline, management historians recognize the latent value of ideas presented in classical writings for contemporary theory development. Accordingly, we interpret the historical meanings conveyed by the works of the ancient Athenian Xenophon (c.430–354 BC), a pupil of Socrates, to propose a process by which leader authenticity augments transformational leadership to transcend hedonic satisfaction and promote eudaemonic follower well-being.

Towards the augmenting role of authenticity: Xenophon as leadership theorist

Purpose – This paper analyzes Chandler's biography of Henry Varnum Poor to assess Chandler's contribution to management history as a biographer.Design/methodology/approach – Using Winter's content thematic analysis, measure Poor's motivational needs for achievement, affiliation‐intimacy, and power, as they are depicted by Chandler throughout the stages of Poor's career as a business editor, analyst, and reformer.Findings – Our analysis shows that Chandler views Poor's motivation as stable throughout Poor's three professional roles. This paper found that Chandler views Poor as primarily driven by his need for power, followed by a significant need for achievement, and a minor need for affiliation throughout his working life.Originality/value – This research is unique because it provides the first social‐scientific assessment of Chandler's contribution to management history as a biographer.

Chandler as a biographer: content thematic analysis of Chandler's biography of Henry Varnum Poor

Purpose – The purpose of this paper is to commemorate Alfred Chandler, a truly outstanding business historian, through the unique lens of his revisionists.Design/methodology/approach – By developing a classifying framework, Chandler's revisionists is analyzed based on the extent to which they critique Chandler's interpretation of the role of managers in large organizations.Findings – The revisionist critiques of Chandler's works is traced and examine how they can contribute to the intent of commemorating Chandler and his works.Practical implications – The most relevant revisionists of Chandler's works are highlighted in a manner that might be valuable for the understanding of how Chandler's revisionists can be interpreted within both functional and critical paradigms.Originality/value – The unique contributions of this study is its focus on providing a specific form of commemoration through the lens of Chandler's revisionists and thus putting “Chandler in a larger frame” of management history.

Every state includes nurses as mandated reporters of suspected child maltreatment, and each state has its own law and policy regarding what is reportable and reporting requirements. These differences mean that generic training on child abuse and reporting needs to be augmented by practical state-specific information. In nearly every study of nurses, participants report having inadequate child abuse training. This paper presents an analysis of the information states post on their websites to educate nurses to appropriately identify and report suspected child abuse or neglect. Specifically, this study aims to answer the following questions: (1) how do mandated reporting laws that apply to nurses vary by state, (2) what information do states provide on their child protection and Board of Nursing websites about child maltreatment and mandatory reporting, and (3) what training resources do states make available on their websites to educate nurse mandatory reporters to ably fulfill their obligation? Data on state-by-state practices regarding mandated reporting of child abuse were gathered from the Rape, Abuse, & Incest National Network (RAINN) database, review of state statutes, Child Welfare Information Gateway, Board of Nursing sites, and the Nursing Licensure Compact (NLC) website. This analysis found that states provide little guidance or education about their child maltreatment laws, and few have resources targeted for nurses. Given rising membership in the NLC it is critical for nurses to have education about state specific mandated reporting requirements. States should consider adding mandatory reporting training as a requirement for licensure and for continuing education.

How do States Inform Nurses of Their Policies for Mandatory Reporting of Child Maltreatment?

Identifying intensive care staff cultural, spiritual, and ethical beliefs to successfully implement a dying pathway: A two stage mixed methods sequential design

Low socioeconomic status, ethnicity and geographical location confers high risk of significant accidental burns injuries in London

Aim: The primary aim of this study was to evaluate the impact of a targeted, practical education intervention on paediatric nurses' knowledge of appropriate breastfeeding management in an acute practice setting. Background: Breastfeeding provides the optimal method for infant growth and nutrition, yet studies have demonstrated knowledge deficits of Australian paediatric nurses regarding the management of the mother-infant breastfeeding dyad. Limited evidence is available evaluating which educational approach is effective in the dynamic and busy acute care setting. Design: This study was a two-phased, mixed-method design, conducted in a large, tertiary, metropolitan children's hospital in south-east Queensland, Australia. Methods: Reference groups were conducted in Phase One to advise development of the resource kit. Phase Two was the experimental phase and included a pre-test knowledge survey, the educational intervention, and a post-test knowledge survey. Results: Pre- and post-test response rates of 75% (n=49) and 34% (n=23) respectively were achieved from the population of 67 eligible participants. Post-intervention study results demonstrated knowledge improvement in four key breastfeeding management areas: importance of baby-led feeding; reduction in otitis media risk for breastfed infants; ongoing management of maternal milk supply when breastfeeding is interrupted; and the correct storage and management of expressed breast milk. Areas for further knowledge improvement included management of more complex breastfeeding scenarios, such as mastitis. Conclusion: The implementation of a resource kit and brief education series has improved the knowledge of paediatric nurses in some areas of breastfeeding practice and management.

Improving knowledge of breastfeeding management: A practice development intervention for paediatric nurses

Does the Emergency Triage Education Kit improve triage consistency: A paediatric emergency department's experience

When opportunity knocks...jab it? Opportunistic immunising in the emergency department

Introduction Barriers to safe sleeping (SS) recommendation uptake by health professionals and parents include perceptions that babies placed supine to sleep have an increased aspiration risk and are more difficult to settle. Aim To develop, implement and evaluate teaching methods that support and promote supine infant sleep positions used by health professionals and parents. Method A pre-test/post-test intervention design evaluated knowledge and practices relating to SS recommendations in a sample of nurses and midwives caring for families with infants (n=393): a) pre-test survey and audit (observational and chart); b) educational intervention including safety of supine positioning; c) post-test survey and audit. Results Comparison of paired responses (n=102 paired) for nurses/midwives who completed both pre and post-tests demonstrated that the intervention significantly improved documentation and practice (p=0.04); and achieved positive changes in knowledge of risk factors (p<0.05), parent advice relating to recommended infant sleep position (p=0.005) particularly for infants with reflux (p=0.003), and safe wrapping as a strategy to support supine sleep (p=0.02). Education including bed-side teaching tools comprising a lariat card, poster, cot card and an on-line resource developed to facilitate health professional and parent understanding of the importance of supine sleep are included in the resource suite. SS audit indicators have been included in state-wide maternity clinical pathways for on-going monitoring. Conclusion Innovative teaching tools that significantly and positively impact health professional knowledge and practice relating to SS recommendations will directly impact the support parents receive to use infant care practices that reduce risk of sudden unexpected infant death.

Improving uptake of safe infant sleeping recommendations: Teaching tools for parents and health professionals

When opportunity knocks…give it your best shot!—Opportunistic immunising in the Paediatric Emergency Department

Objectives: This study aims to provide a better understanding of the motivations and actions of parents of children with non-urgent injury or illness who attend the emergency department at a tertiary paediatric hospital seeking care. Design: A prospective questionnaire-based survey of 355 parents aimed to ascertain information about parent care-giving and care-seeking behaviours prior to presentation at the emergency department with their child. Results: A total of 355 parents were surveyed, representing 8% of the parents/carers presenting to the emergency department in a 3-month period for non-urgent (Australasian Triage System 4 and 5) care of their child. The factors identified were: parents rated their child’s condition as moderate to very serious (242 (68%)); two-thirds of parents (234 (66%)) had sought advice prior to attending the emergency department; 54% (77) of the 137 children who attended with an injury presented promptly to emergency (ie, within 4 h of injury) whereas of the 216 presenting with an illness, 41% (88) presented within 2–7 days of the onset of the illness. Conclusions: This study displayed the accuracy of “parental triage,” that is, parents assess their child’s health and generally engage in appropriate care-giving and care-seeking behaviours before presenting to a paediatric emergency department. Highlighted are the deficiencies in current primary care services available to families and the perception that not all cases deemed as non-urgent by the emergency department are able to be dealt with in a primary care setting.

Making choices: why parents present to the emergency department for non-urgent care

Sleeping babies safely: Consistent and collaborative approaches to reduce preventable deaths

Sleeping Babies Safely: Achievements and lessons learned in using a multi-agency approach to positively impact health professional and public knowledge about safe infant sleeping recommendations

Consistent and collaborative approaches to reduce preventable deaths: a Safe Infant Sleeping educational resource designed for health professionals

Safe Infant Sleeping Education Program for Health Professionals Update on Current Study

Developing a critical mass to sustain evidence-based practice change in a child health setting: practice development models in action

Safe Sleeping for Infants: an Education Intervention Designed to Positively Impact Nursing and Midwifery Knowledge, Attitudes and Practice (Oral presentation)

Safe sleeping for infants: A multi-agency team approach to positively impact health professional and public knowledge about safe infant sleeping messages

Safe infant sleeping: a multi-agency team approach to positively impact health professional knowledge about safe infant sleeping messages

To determine knowledge about bladder care among junior medical staff and allied health professionals, and to examine any difference in knowledge among the subgroups.

Knowledge of female bladder care among medical staff, nurses and midwives: results of a questionnaire survey

AIMS
To provide a synthesis of the experience of nursing in the Vietnam War.

RATIONALE
War and nursing are linked unequivocally. As battles have raged over the centuries, nurses have attended the ill and wounded soldiers, nursing them back to health or into death and the study of this phenomenon forms a significant part of Australia's nursing history. However, a review of the Australian scholarly nursing and military history literature revealed that the experiences of Australian nurses in the Vietnam War has not been widely published. In an attempt to redress this gap in Australian nursing and military history, the aim of this study was to analyse the nature of the nursing work in the Vietnam War, and to increase awareness and understanding of the experience of nurses in the war within the nursing profession.

METHODS
Using oral history interviews, this study investigated the nature of nursing work as experienced by 17 Australian Army nurses who served in the Australian Military Hospital in Vung Tau between 1967 and 1971.

FINDINGS
The vast majority of the nursing sisters sent to Vietnam knew little about the type of work or the environment into which they were entering and were, therefore, clinically unprepared. It appeared that, by virtue of their being a nurse, it was an expectation that the nurses would adapt to the nature of their work in the war zone. However, this study also revealed that, although the nurses adapted professionally, their memories of their experiences have affected many personally.

This paper will increase current knowledge significantly regarding the phenomenon of nursing in the Vietnam War, enabling a greater understanding of the experience.

The wartime experience of Australian Army nurses in Vietnam, 1967-1971.

The knowledge and attitudes of healthcare professionals in accident and emergency departments in Australia are poorly understood. The authors assessed knowledge of and attitudes toward HIV/AIDS and homophobia were assessed in a convenience sample of 111 healthcare professionals in three New South Wales teaching hospitals. Results indicated that respondents with low knowledge of HIV/AIDS used the media as their major source of education and had higher levels of fear of infection than their colleagues with higher knowledge. The study findings imply that quality health care for people with HIV/AIDS requires programs that provide correct information and address the fear of infection.

HIV/AIDS: knowledge and attitudes of accident and emergency healthcare professionals.

In summary it would appear that Australian and Canadian nursing students, at least in these limited samples, generally have similar knowledge and attitudes regarding AIDS. This study, with its acknowledged limitations, could be regarded as a pilot study for future collaborative comparative research, targeting a wider population of nursing students in two very similar countries.

The Canadian journal of nursing research = Revue canadienne de recherche en sciences infirmieres

AIDS: knowledge and attitudes of student nurses in Australia and Canada.

Perceptions of nursing care: effects of written and verbal instructional methods on families of head injury patients.

To determine the diagnostic accuracy of urinary cytology to diagnose bladder cancer and upper tract urothelial cancer (UTUC) as well as the outcome of patients with a positive urine cytology and normal haematuria investigations in patients in a multicentre prospective observational study of patients investigated for haematuria.

We present a methodology and an example of preparing an order of merit list to rank terrorist targets based upon decision-maker weights. We used an old terrorist data set as our base data to keep the information unclassified. This data is used to demonstrate this methodology. We perform numerical iterative criteria weight sensitivity analysis to show the effects on the model’s outputs in changes in the weights. We identify the critical criterion.

The Journal of Defense Modeling and Simulation: Applications, Methodology, Technology

Vice-Chairman St. Pierre called the meeting to order and requested Captain Mangas of the US Army Special Forces to lead the forum in saying the Pledge of Allegiance.

The Traditional Protection of Civil Liberties in Britain and the Impact of the Human Rights Act 1998

Text, Cases and Materials on Public Law and Human Rights integrates a diverse and contemporary collection of cases and materials with an authoritative narrative commentary from two leading academics in the fields of public law and human rights. The text intersperses extracts from leading cases, academic commentary and parliamentary and governmental material to produce an all-encompassing student companion to constitutional, administrative and UK human rights law. 
 
This third edition has been fully updated and includes coverage of: the Governance of Britain reform package and the Constitutional Reform and Governance Act 2010, the Constitutional Reform Act and the new Supreme Court, the Serious Organised Crime and Policing Act 2005 and the impact of anti-terrorism legislation on the rule of law and police powers. There is comprehensive coverage of the Jackson case, Bancoult and the royal prerogative, the 2008 White Paper on Lords reform, the impact of the Parliamentary Standards Act 2009 and the Kelly Report on parliamentary privilege, and of the Wright Committee Reforms on the Commons. There is in-depth discussion of the latest leading cases in judicial review and key decisions under the Freedom of Information Act. Furthermore, the book includes extensive coverage and analysis of a range of recent developments in the human rights field, including the key Human Rights Act cases of Belmarsh, Re P, Huang and YL and the Strasbourg decisions in the Marper (DNA) case and A v UK on detention without trial; the Austin and Laporte decisions on public order in the House of Lords are discussed together with the latest leading cases on freedom of expression. The possibilities of repeal of the Human Rights Act and of the future introduction of a British Bill of Rights are given consideration.

A key feature of British rule in India was the formation of a class of elite metropolitan lawyers who had an outsized role within the legal profession and a prominent position in Indian politics. This paper analyzes the response of these legal elites to the shifting social and political terrain of post-colonial India, arguing that the advent of the Indian nation-state shaped the discursive strategies of elite lawyers in two crucial ways. First, in response to the slipping grasp of lawyers on Indian political life and increasing competition from developmentalist economics, the elite bar turned their attention towards the consolidation of a national professional identity, imagining an ‘Indian advocate’ as such, whose loyalty would ultimately lie with the nation-state. Second, the creation of the Supreme Court of India, the enactment of theConstitution of India, and the continuous swelling of the post-colonial regulatory welfare state partially reoriented the legal elite towards public law, particularly towards the burgeoning field of administrative law.

Imagining the Post-colonial Lawyer: Legal Elites and the Indian Nation-State, 1947–1967

3. The discussion that follows is valuable for two reasons. First, it helps advance the ongoing debate about how to draft the legislation that is set to replace the HRA in future. Although the BBOR project has been shelved while the government concentrates its efforts on negotiating Brexit, it has not been abandoned altogether. The HRA has been in Conservative crosshairs for years, and the 2017 Tory manifesto contained a pledge to “consider our human rights legal framework when the process of leaving the EU concludes”. The BBOR issue will doubtless resurface before the next general election in 2022.

Responds to the article by Colin D. Campbell entitled "Monopoly power as public power for the purposes of judicial review", L.Q.R. 2009, 125(Jul), 491-521, by questioning the practicability of its monopoly power test for determining if the exercise of a power is amenable to judicial review. Argues that any test of a public function should concentrate on the nature of the power being exercised rather than its source.

In this article I explore the amenability of private bodies to European Convention (ECHR) challenge under the Human Rights Act 1998 (HRA), in particular the meaning of a public function and the rea...

1. The vexed question of which functions are public and amenable to judicial review has generated considerable volumes of case law and academic discussion over the years. In this article I consider...

Assesses the lessons offered by the Australian Capital Territory's Human Rights Act 2004 and the Victorian Charter of Human Rights and Responsibilities Act 2006 for the possible development of a British Bill of Rights to replace the Human Rights Act 1998, noting that they were drafted in the light of the UK experience. Considers the ways in which the Australian instruments have addressed the perceived flaws of the 1998 Act.

Emotional Inhibition in Adolescents' Friendships: The Moderating Role of Gender

This thesis investigates the problematic of social and political complexity. It attempts to answer the question of how power operates in a world of complex and globalised social, political, and economic systems. The basic claims of the thesis are as follows. Firstly, we can find the tools to understand social complexity in complexity theory. In turn, the conceptual innovations of complexity theory can be deployed to rethink the pre-existing political theoretical tradition of hegemony. We argue that the most significant existing theories of hegemony have been produced in relation to moments of increasing real world social complexity, and that there exists an under-developed seam of thinking already within the tradition which evokes key concepts from complexity theory. Therefore, the flaws in existing theories of hegemony can be remedied by conceptualising the complexity of hegemony in a rigorous way using the formal resources of complexity theory. To do so, the thesis first defines the necessary conditions for and properties of complex systems, as investigated by complexity science. It then outlines a general theory of social and political complexity. It develops an original reading of Gramscian hegemony, while critically appraising Laclau and Mouffe’s articulatory variant of the concept. It then brings together insights from the field of complexity theory to rethink the basic concepts of hegemony, before applying the theory to the investigation of the persistence of Neoliberalism after the 2008 financial crisis. In so doing, it establishes the grounds for a new theory of complex hegemony, reworking existing political theory to better explain the complex dynamics of our contemporary world.

Complexity & Hegemony: Technical Politics in an Age of Uncertainty

Purpose – The purpose of this paper is to explore crisis management in terms of the spiritual aspects of victim recovery. The paper focuses, in particular, on victims of serious crime. Design/methodology/approach – The paper reviews the available literature on crisis management, serious crime, spirituality and pastoral support to determine their impact on trauma recovery. Semi-structured interviews were also conducted with a number of police chaplains and a hospital chaplain, in addition to police family liaison officers and witness care officers, who have in-depth involvement with victims of serious crime, to explore the support available and identify gaps against existing theory. Findings – Spiritual/pastoral support is available to police officers in the form of police chaplains. Their support is reported to be valuable in the crisis recovery process. Hospital patients report such support as integral to mental and emotional well-being and recovery. Victims of serious crime are not offered such pastoral...

Crisis management: the spiritual aspects of victim recovery in serious crime

Disclaimer: This document is published under the sole responsibility of the organizers of the meeting and does not in any way constitute a document emanating from the UN Geneva Professional Delegation (DPU), nor does it bind the delegation or its members in any way. The references to the DPU's participation are maintained with a view to faithfully and accurately reflecting the content and the context of the meeting.

Career prospects and demographic challenges in the UN Geneva Sub-sector

This article chronicles the recent history of the debate in the United States over digital paywalls, a model often hailed as newspapers’ savior. We show how this debate has evolved from emphasizing industry-wide adoption to focusing on individual experiments. While highlighting potential legal, economic, and democratic concerns with paywalls, we examine the empirical record of three prominent newspaper paywall models: the Arkansas Democrat-Gazette, the Dallas Morning News, and the New York Times. While each has enjoyed varying levels of success, our analysis suggests that paywalls are unable to offset steep losses in advertising revenue. We conclude by briefly discussing non-commercial alternatives.

The question of whether humans are free willed has been on our minds for many years, not solely approached by academic philosophers, but considered by every reflective and inquisitive human who wants to know more about the truth of the world. Max Scheler put forth the notion that humans have obtained ‘Spirit’ at some point in their evolution, an idea that ties incredibly well into William James’ views on experience, truth and reality. I will argue that ‘Spirit’ is one of the most significant differences between humans and other animals, and is the main source of our apparent free will. The ideas put forth by Scheler and James that I will evaluate in this essay have a similar point of origin in the works of Charles Darwin, through the notion of flexibility, which shall be expanded on at a later point. As well as attempting to present a unique interpretation on human free will through the above philosophers, I will address the differences between humans and other animals according to what we can learn from Scheler and James, as well as asking how other animals differ from us in terms of free will. With the information obtained from the above discussions, I will assess our treatment of other animals and present a perspective on whether our current methods are justified or if we should change our ways.

The Existence of Free Will in Humans and Other Animals Through Their Obtaining of 'Spirit'

This thesis explores the public-private divide. Its primary focus is on two distinct but interlinked contexts: the amenability of bodies to judicial review in domestic law and the notion of ‘public authority’ under s 6 of the Human Rights Act 1998 (HRA). It also focuses secondarily on the notion of the governmental organisation in Strasbourg. The aim is to re-order the law in all three areas, providing an account of the law that is both doctrinally accurate and normatively defensible. The core argument is that, in both of the primary contexts, at the root of the public-private distinction lies an approach that defines ‘public’ activity as the exercise of legally-authorised coercive power. This is called the ‘LACPA’ for short. The LACPA is functional in outlook and sufficiently flexible to bring private bodies performing delegated public functions within the purview of public law. As such, this thesis challenges the orthodox view that the courts’ approach to the public-private divide is ill-equipped to deal with trends in modern governance and needs a major overhaul. Instead, fine-tuning and a better judicial appreciation of the existing law are all that is required.

Throughout his career, Lacan struggles to present a coherent thesis of time and its place in psychoanalytic theory and practice. Partly this is because he wishes to remain faithful to Freud’s theory that the unconscious knows no time. The antagonism that results from this struggle means that any reference to time in Lacan’s oeuvre is both clouded by ambiguity and brief. By concentrating on Lacan’s notion of the pause, as presented in his 1945 essay on Logical Time, I aim to solve this antagonism and thus allow a Lacanian thesis of time to blossom fully.

Doing Time: A Sideways Glance at the Pauses and Hesitations in Jacques Lacan’s Essay on Logical Time

An analysis of when the HRA subjects private bodies to the Convention is highly germane to any discourse concerning the impact of the HRA on private law. The common law horizontal effect mechanism is one route through which to hold private bodies, albeit indirectly, to Convention standards. Another route is through the hybrid public authority scheme – if a private body performs ‘functions of a public nature’ under s 6(3)(b), it is regarded during its public activity as a public authority and must respect the Convention. 
 
This chapter builds on earlier work which attempts to coax the judges into adopting a wider interpretation of s 6(3)(b). Its central message is that there is no need for the courts to construe that provision as restrictively as they have done since the HRA entered into force. Whilst ostensibly public in nature, hybrid public authorities are institutionally private bodies. The crucial effect of this, coupled with a close analysis of relevant Strasbourg jurisprudence, is that hybrids enjoy Convention rights themselves under the HRA, even during the performance of their public functions. They can therefore assert their own Convention rights as a defence to Convention-based challenges by claimants in court – a powerful method of self-protection which, once properly appreciated, should help ease judicial reluctance to widen the scope of s 6(3)(b) to encompass a greater range of functions performed by private bodies.

Public authorities : what is a hybrid public authority under the HRA ?

This article offers a new interpretation – the ‘constitutional constraint’ model – of the duty the Human Rights Act imposes on the courts to give horizontal effect to European Convention rights through the common law. The model requires courts to develop the common law compatibly with the Convention, but only where compatibility can be achieved by incremental development. We argue that models requiring more than incremental development are unsustainable; that deep constitutional norms compel the constraint of incrementalism, which is preserved under the HRA; and that by virtue of section 2 of the HRA, Convention rights function as principles rather than hard-edged rights in this context. This further undermines the idea that the courts must strictly apply Convention rights and cannot allow them to be overridden by non-Convention factors. The final section explores the nature of incrementalism in this context and the impact of the model on the doctrine of judicial precedent.

Publisher's copyright statement: This is a pre-copyedited, author-produced version of an article accepted for publication inPublic lawfollowing peer review. The de nitive published versionWilliams, Alexander (2011) 'A fresh perspective on hybrid public authorities under the Human Rights Act : private contractors, rights-stripping and 'chameleonic' horizontal e ect.', Public law. (1). pp. 139-163is available online onWestlaw UKor fromThomson Reuters DocDel service.

A Fresh Perspective on Hybrid Public Authorities under the Human Rights Act: Private Contractors, Rights-Stripping and "Chameleonic" Horizontal Effect

Strasbourg jurisprudence and hybrid public authorities under the HRA 1998 : introducing chameleonic horizontal effect.

Section 6 of the human rights act 1998: the meaning of 'public authority'

ed beyond the power of the individual (21). H.C. Robinson reported that Blake considered the Atonement in the ordinary Calvinistic sense” a “horrible doctrine; if another pay your debt, I do not forgive it,” but in the effort to correct an endless chain in the law of retribution from one man to another (“Dye hee [man] or Justice must,” PL 3.210), Milton provides a redemption of Original Sin through self-annihilation rather than the “Druidical” blood sacrifice God demanded before offering the grace of forgiveness, “unless for him...death for death...just th’ unjust to save” (210215), not through the requirement of an abstract verdict, but available for humanity in another context. As for Blake’s portrayal of Milton himself, Milton, “who walkd about in Eternity...pondring the intricate mazes of Providence” (2.16-17), is associated with the fallen angels of Paradise Lost who “reason’d high / Of 6 Bentley, G.E., Jr., Blake Records (Oxford: Claredon Press, 1969), p.548 Providence, Foreknowledge, Will and Fate...And found no end, in wandring mazes lost” (II.559-61), and wanders in moralistic labyrinths as his Selfhood-breaking imagination does not let him rest peacefully. Furthermore, Blake employs Adam’s rhetorical musings to align Milton with a fallen state of humanity as well, “all my evasions vain, / And reasonings, though through Mazes, lead me still to my own conviction” (X.829-31), yet this lapsed power shall be absolved not by the Son, but by Milton when he descends from the Elect in Heaven to undergo self-annihilation. The description of Milton as “Unhappy tho in Heaven, he obey’d, he murmur’d not, he was silent” (2.18), directly echoes Milton’s original theme “Of Man’s Disobedience” (PL I.1), but this is adapted by Blake as his central matter and suggests that Milton was “mistaken” in believing God requires obedience over all. Although the historical Milton is known to have rejected Calvinist predestination of the Elect in De Doctrina Christina (first published in 1823, after Blake’s final revisions of Milton), Blake sought to correct what Milton’s God ambiguously decrees, “Some I have chosen of peculiar grace / Elect above all the rest” (III.183-84) while others untouched by conscience will “hard be hard’n’d, blind be blinded even more, / That they may stumble on and deeper fall” (ll.199-201). Blake inverts this traditional paradigm through an Elect “who cannot Believe in Eternal Life except by Miracle & a New Birth” while the Reprobate, those such as Blake’s Jesus who transgress old codes of Urizenic restraint and obedience in favor of liberating revolutionary desire, “never cease to Believe” in the holiness of the regenerative imagination (Milton 25:31). Yet Blake does not fall into unchangeable categories of divine predestination, for humankind can both fall and liberate themselves between “the pulses of an artery” (3/29:3) without the Atonement The traditional paradigm of the Elect, Redeemed and Reprobate is developed by Blake further, rendering immanent the individual as intercessor through the process of self-annihilation and the coming of the Last Judgment. Although Milton rejects the Pelagian controversy, which heretically relocated the power of salvation through individual works and faith without redeeming grace, by voicing through the Father that “Man shall not quite be lost, but sav’d who will, / Yet not of will in him, but grace in me / Freely voutsaft” (PL III.17375), Blake adopts this controversy and provides an instruction on how to “Judge then of thy Own Self...What is Eternal & what Changeable? & what Annihilable?” (35/32:30-31). As Milton’s epic revolves around the end of the cycle of guilt perpetuated by the Atonement aforementioned and divinely predestined salvation or condemnation, Blake employs the Michael/Adam instructional dialogue of Paradise Lost through Hillel/Milton to reveal what will come to pass not in the distant future, but within mere moments. In the philosophical conversation that follows, Hillel tells Milton that “Satan & Adam are States Created in Twenty-seven Churches / And thou O Milton art a State about to be created” (25-26), for as “States Change: but Individual Identities never change nor cease,” Milton can freely judge himself and annihilate his delusional Satanic-Elect state/class. Rather than “to [God] ow, / All his deliv’rance, and to none but [God]” (PL III.181-82) at the end of mortal existence, or wait until the Son “Shall bruise the head of Satan, crush his strength / Defeating Sin and Death, his two main arms” (XII.430-31), Milton will willingly undergo a Last Judgment of his Selfhood. By annihilating the current state within which Milton resides and creating a new state that will encompass the rejection of Selfhood and the reclaiming of his Emanation, Ololon (man’s female counterpart, for Milton composed of a composite of his poems, his sexual impulses, and his three wives and daughters), the “Eternal Humanity Divine” will no longer be divided within itself, but re-harmonize in the final battle between Milton and Satan. Blake initiates a revolutionary awakening of consciousness of not only Miltonic Selfhood, but the universal phenomenon of institutional oppression found in conventional Christian doctrine when Milton awakens from false-consciousness among the Elect by the Bard’s Song that equates him with Satan. After realizing that the Poetic Genius is the Eternal Divine Humanity, aforementioned in the invocation of the Daughters of Beulah, Milton “took off the robe of the promise, & ungirded himself from the oath of God” (15/14:13), or the “garments of salvation” and the “robe of righteousness” of Isaiah (61:10). In realizing that his assertion of “Eternal Providence” and justification of “the wayes of God to men” (PL I.25-26) was rooted in Selfhood, he ontologically identifies himself with Satan, “I in my Selfhood am that Satan: I am that Evil One! / He is my Spectre! in my obedience to loose him from my Hells / To claim the Hells, my Furnaces, I go to Eternal Death” (15/14:30-32). As if literalizing the request to “Return me to my native element” (PL VII.15), Milton descends back to earth to reclaim the energy he had poured into his erroneous representation of evil in Paradise Lost and correct the history restrained desire. As Mary Lynn Johnson explains in “Milton and its Contexts,” the “instantaneous revelation of ‘Truth or Eternity” could, for Blake, “occur at any time, with the burning up of error ‘the Moment Men cease to behold it’” (241), and it is this moment of previously unfathomable identification that compels Milton to redeem himself immediately. For unlike the Satan of Paradise Lost, however, who realizes his ontological fall is irreversible, “Which way I flie is Hell; my self am Hell” there is a place yet for redemption, but attainable by the Last Judgment, or the momentous casting off of error obfuscating the immortal spirit that institutionalized Christianity rendered abstract and faintly perceivable. Now able to identify Satan as his self-hood, Milton provides an exemplarly model for the disobedience he condemned by not only repudiating Satan, but the conventional Christian image of God. In Milton’s coming to “discover before Heaven & Hell the Self righteousness / In all its Hypocritic turpitude,” Satan attempts to imitate himself further with the conventional God of Paradise Lost, “I am God the judge of all, the living & the dead / Fall down therefore and worship me, submit thy supreme / Dictate, to my eternal Will” (43/38:43-44;51-53), an echo of the selfrighteous “God-like imitated State” (PL II.511). Milton, however, rejects the discourse of rationality and natural religion that led him to contemplate this false god Urizen. By “cast[ing] off Rational Demonstration by Faith in the Saviour” (48/41:3), Milton disobediently repudiates Raphael’s imperative to faith and works modeled on the rational chain of being in Paradise Lost, “one Almightie is, from whom / All things proceed, and up from him return” (V.469-70). Continuing this purgation of false doctrine bred by Selfhood, Milton then casts off the repressive Muse of restrained history, or Urania whom he invokes throughout Paradise Lost, “the rotten rags of Memory by Inspiration” (48/41:4). This second repudiation is in accordance with Blake’s Daughters of Memory, offering subjective vision over unchangeable decree. Furthermore, Milton then casts off the Enlightenment dialectic of the passionate body contra rational soul and harmonizes the one as extension of the other by rejecting “Bacon, Locke & Newton from Albion’s covering” (5) thus providing a model for imaginative regeneration to complete Blake/Milton’s personal theodicy and, by extension, combating institutional repression by granting a universal vision of redemption. Milton for Blake was as Virgil to Dante insofar as Blake echoed Milton’s condemnation of “Hirelings in the Camp, the Court, & the University: who would if they could, for ever depress Mental & prolong Corporeal War” (147), but Blake believed that Milton’s task had remained unfulfilled. Milton’s epiphany that moves him from the Elect status in Heaven, “I in my Selfhood am that Satan: I am that Evil One!” (15/14.30) reveals that his history of the restraint of desire in Paradise Lost was but a “Spectre” (15/14.31), or the product of Selfhood determined to justify selfish desires under false reasoning that ultimately inhibit, rather than unite, humanity and its universal divinity. For it is through this adaptation of Paradise Lost that Blake thought he and the spirit of Milton could correct the nations that “still / follow after the detestable Gods of Priam; in pomp of warlike selfhood, contradicting and blaspheming” (15/14.15-16) and answer England’s call for a poetic liberator. As T.S. Eliot commented on the artistry that posits there is not much difference “between identifying oneself with the Universe and identifying the Universe with oneself,”; this progressi

Paradise Re-Envisioned: William Blake's Milton as the Redemption of Selfhood

This analysis examines the recent House of Lords ruling on the interpretation of ‘functions of a public nature’ under s 6(3)(b) of the Human Rights Act 1998. It criticises the reasoning and result, suggesting that the ruling has failed satisfactorily to settle the law and that the provision of care and accommodation by a private provider pursuant to contract with a local authority acting under s 21 of the National Assistance Act 1948 should be regarded as a function of a public nature. It concludes by assessing the ruling’s impact, briefly commenting on the new Human Rights Act 1998 (Meaning of Public Function) Bill and highlighting remaining issues for future judicial and legislative consideration.

YL v Birmingham City Council : contracting out and 'functions of a public nature'.

Pension — pension scheme — jurisdiction of Pensions Ombudsman — complaint to Pensions Ombudsman — maladministration of pension scheme — Court of Appeal holding that Ombudsman having no jurisdiction to hear complaint — decision statutorily reversed and complainant making fresh complaint to Ombudsman based on same facts as first complaint — Ombudsman upholding complaint but concluding that maladministration causing no injustice — whether Ombudsman having jurisdiction to hear complaint — whether respondent having right of appeal against determination of maladministration not causing injustice In 1993 H, a former employee of the appellant local authority, made a complaint of maladministration to the Pensions Ombudsman concerning the authority's severance scheme. The complaint, relating to events in 1991, eventually reached the Court of Appeal, which rejected it on the grounds that H had not been entitled to long service benefits under the scheme, that therefore he was not a member of the scheme within the meaning of s. 146(7) of the Pension Schemes Act 1993 and that accordingly the complaint fell outside the Ombudsman's jurisdiction. That decision was statutorily reversed by reg 9 of the Personal and Occupational Pension Schemes (Miscellaneous Amendments) (No. 2) Regulations 1997, made under the 1993 Act, which provided that, for the purposes of s. 146(7), "a person shall be regarded as a member of a scheme if he is, or had been, entitled to benefits under it". In 1998, relying on that provision, H brought a fresh complaint before the Ombudsman, based on the same facts as the 1993 complaint. The authority challenged the Ombudsman's jurisdiction to hear the complaint, contending that reg 9 did not have retrospective effect. Alternatively, it contended that the Court of Appeal's decision gave rise to a res judicata precluding a further complaint identical to the 1993 complaint, that in any event the complaint had been made outside the three-year limitation period prescribed by reg 5(1) of the Personal and Occupational Pension Schemes (Pensions Ombudsman) Regulations 1996 and that the Ombudsman was not entitled to invoke reg 5(3) which allowed him to investigate and determine a complaint made out of time if, in his view, it was reasonable to bring the complaint outside the limitation period. Those contentions were rejected by the Ombudsman who further held that the authority had been guilty of maladministration, that that maladministration had not caused H injustice consisting of financial loss, that he had suffered injustice consisting of distress and inconvenience but that it was inappropriate to make a direction for payment of compensation for

On August 1, 1986, Rule 48 of the National Collegiate Athletic Association (NCAA) will become effective. Just what will be the actual effect of its implementation is as yet unknown. However, it is more than mere conjecture that Rule 48 will have a major impact upon the black athlete with college aspirations. Moreover, few will dispute the notion that this impact will foster profound litigious ramifications. Will the impact of Rule 48 be positive or negative? The response to such an inquiry lies in one's point of view concerning both the role of athletics in the educational system and the validity of the proposed standards under Rule 48 in measuring worthiness to attend college. With the invocation of Rule 48, educators, academicians, lawyers, civil rights leaders, coaches, and athletes have postulated their varied views on these two issues. Some would argue that Rule 48 is long overdue, that black student athletes have been exploited in the past and will be beneficiaries of more stringent academic requirements.1 Others argue, however, that the rule will

The Impact of Rule 48 Upon the Black Student Athlete: A Comment.

Cloud-Based Framework for Performing Digital Forensic Investigations

Provenance in computing systems is the key to establishing data integrity. It provides a historical ledger of data's life cycle through creation, ownership, consumption, and manipulation. With provenance in hand, it is possible to reverse engineer the state of the data that can lead to understanding how it was derived and verify its accuracy. This need for data integrity is extremely critical in scientific workflows to ensure verifiability and repeatability of the derived results. Due to the vast computational power required by scientific workflows, many operate within high performance computing (HPC) environments, where data is consumed and manipulated by a multitude of processes running on highly distributed infrastructure. The current landscape of HPC environments range from on-premise systems to cloud and grid based solutions. While the majority of research in digital provenance has been focused on standalone HPC environments, provenance in a heterogeneous HPC environment remains a challenge. In this paper we propose HyperProvenance, a high level system architecture especially for next generation heterogeneous HPC environments, which aims to increase confidence in workflow result accuracy through secure provenance collection.

2021 IEEE 12th Annual Information Technology, Electronics and Mobile Communication Conference (IEMCON)

Scientific Workflow Provenance Architecture for Heterogeneous HPC Environments

In recent years, there has been a dramatic change in attitude towards computers and the use of computer resources in general. Cloud and Edge computing have emerged as the most widely used technologies, including fog computing and the Internet of Things (IoT). There are several benefits in exploiting Cloud and Edge computing paradigms, such as lower costs and higher efficiency. It provides data computation and storage where data are processed, enables better data control, faster understanding and actions, and continuous operation. However, though these benefits seem to be appealing, their effects on computer forensics are somewhat undesirable. The complexity of the Cloud and Edge environments and their key features present many technical challenges from multiple stakeholders. This paper seeks to establish an in-depth understanding of the impact of Cloud and Edge computing-based environmental factors. Software and hardware tools used in the digital forensic process, forensic methods for handling tampered sound files, hidden files, image files, or images with steganography, etc. The technical/legal challenges and the open design problems (such as distributed maintenance, multitasking and practicality) highlight the various challenges for the digital forensics process.

Cloud and Edge Computing-Based Computer Forensics: Challenges and Open Problems

p-Poincaré inequality versus ∞-Poincaré inequality: some counterexamples

Este libro es un nuevo y atrevido manifiesto por la vida despues del capitalismo. Los autores nos hablan de una economia postcapitalista capaz de mejorar el nivel de vida de las personas y de liberar a la humanidad del trabajo, desarrollando tecnologias que expandan nuestra libertad

"Répons", de Pierre Boulez: ¿fantasmagoría o articulación de espacio?

Calculation of the expanded uncertainty for large uncertainties using the lognormal distribution

Eurachem workshop on quality in analytical measurements: from specification to decision

Part 1 of this history of EURACHEM deals with the development of the initial idea and the early consultations within Europe that led to definition of its aims and objectives, cumulating with its formal establishment in July 1989, followed by the signing of the MoU by sixteen countries by the end of 1990. Part 2 will describe the subsequent developments. Foreword This history of the first ten years of EURACHEM must by its nature be a personal one, since I have been so closely involved in its creation and development that I would find it very difficult to write it in any other way. The development of EURACHEM has depended upon the efforts and ideas of many people. I hope that their invaluable contributions will be brought out as this history unfolds, but I apologise that if, due to oversight or lack of completeness in my research, I have omitted to include some important stages or contributions. I have been fortunate to have access to two important sources of information, first the working files of myself and my colleagues at The Laboratory of the Government Chemist (LGC), during the formation stage of EURACHEM and the excellent records kept by the secretariat of all that has happened since EURACHEM was launched. The idea is born

EURACHEM/CITAC workshop on recent developments in measurement uncertainty

Principles of the EURACHEM/CITAC guide “Use of uncertainty information in compliance assessment”

EURACHEM/CITAC Uncertainty Guide does cover use of validation data

The article contains sections titled: 
 
1. The Evolution of Analytical Chemistry 
2. The Functional Organization of Analytical Chemistry 
3. Analysis Today 
4. Computers 
5. Analytical Tasks and Structures 
5.1. Formulating the Analytical Problem 
5.2. Research and Application 
5.3. An Organogram 
5.4. Physical Organization of the Analytical Laboratory 
5.5. The Target of Analysis 
6. Definitions and Important Concepts 
6.1. Sensitivity, Limit of Detection, and Detection Power 
6.2. Reliability - Measurement Uncertainty 
6.3. Elemental Analysis 
6.4. Elementary Analysis 
6.5. Microanalysis and Micro Procedures 
6.6. Stereochemical and Topochemical Analysis 
6.7. Microdistribution Analysis 
6.8. Surface Analysis 
6.9. Trace Analysis 
6.10. Trace Elements 
6.11. Multistep Procedures 
6.12. Hyphenated Methods 
6.13. Radioanalytical Methods and Activation Analysis 
6.14. Species Analysis (Speciation) 
6.15. Chemometrics 
6.16. DNA Analysis

Traceability and uncertainty – A comparison of their application in chemical and physical measurement

Traceability and uncertainty — A comparison of their application in chemical and physical measurement

Analytical Chemistry: Purpose and Procedures. Quality Assurance in Instrumentation. Chemometrics. Weighing. Sampling. Sample Preparation for Trace Analysis. Trace Analysis. Radionuclides in Analytical Chemistry. Enzyme and Immunoassays. Basic Principles of Chromatography. Gas Chromatography. Liquid Chromatography. Thin Layer Chromatography. Electrophoresis. Structure Analysis by Diffraction. Ultraviolet and Visible Spectroscopy. Infrared and Raman Spectroscopy. Nuclear Magnetic Resonance and Electron Spin Resonance Spectroscopy. Mossbauer Spectroscopy. Mass Spectrometry. Atomic Spectrometry. Laser Analytical Spectrometry. X--Ray Fluorescence Spectrometry. Activation Analysis. Analytical Voltammetry and Polarography. Thermal Analysis and Calorimetry. Surface Analysis. Chemical and Biochemical Sensors. Microscopy. Techniques for DNA Analysis. Subject Index.

Measurement uncertainty and its implications for collaborative study method validation and method performance parameters

Despite or perhaps because of the tremendous amount of work contained in this book the reviewer cannot recommend it to other than a very few fracture specialists of a highly mathematical turn of mind. The tone is perhaps set in the preface by the phrases ‘Today, scientists are studying the phenomena of fracture . . . The aim of these studies is to describe major features of fracture . . . by means of rigorously formulated models’. There is no room for either the practising engineer or the metallurgist in the treatment that follows. For purposes of understanding the outlines of fracture mechanics and then applying it to cover cases of design, inspection, safety assessment and so on, as is the near daily task of some engineers, a host of Western literature from standards to textbooks is much to be proferred. If your interests are in stress analysis of cracks, including visco-elastic case or fracture in the presence of electromagnetic fields, read on! There is much work covered here not well known in Western literature, or at least not covered in Western texts on engineering fracture mechanics. For those with the reviewer’s level of mathematics it would take days of careful study to grasp the contents of several of the chapters. In the main, this is due to the nature of the text with minimal physical explanation for many pages of mathematical formulation, an aspect not helped by the great difficulty of following up the mainly Russian references. To some extent, it also seems due to inadequacies in translation and presentation. As an example of the first, the wellknown formula for J in terms of the area A under the load-displacement diagram and cross-section of the ligament is introduced by one sentence on limit loads and the formula ‘J = aA/t(w 1) where a is a coefficient (a = 2 in bending . . .)’. As far as the reader could discover, there is no other guidance to what is the rationale for 01, or what are the limitations of this interpretation of J. The translation also contains some infelicitations, rather inevitable in a text of this complexity, sometimes leaving the reader with a smile but other times wondering whether he has understood what the authors mean. As an example of what is less familiar and may repay study, the authors present a model for dynamic crack propagation employing a ‘crackon’. Since they argue that a ‘crack tip may be considered as a quasi-particle . . . having a mass, m, and a force, F, acting upon it’. The conventional Western treatment is that a crack is an inertia-less particle but the authors then say, ‘the crackon mass is a measurement of its resistance to motion , . . interrelated with the rate of energy variation.’ It therefore appears to be a device to include toughness in the equation of dynamic energy balance yet still allowing Newton’s Law of Motion to be used. Without more study than yet given, it is not clear whether the authors recommend this method or just describe it. No references at all are given in support and no comparisons are offered for the results shown. Finally a criticism of the editors. Many of the Russian references would be difficult to obtain, but the main list stops at 321 (although there is also a supplementary list for particular sections). However, the text has references such as 430, 446. The upper limit is not clear since the numbering sequence is an inscrutable mixture of alphabetical and sequential, the first on page 3 being Ioffe (Yoffe), reference 64, and the fifth on page 6 being Griffiths, reference 347 . . . neither apparently indexed. In short an immense amount of work has been put in by both authors and translators but it would need a large effort for even a specialist reader to penetrate beyond what is better found elsewhere. This book is certainly not recommended bed-time reading for the engineer, metallurgist or even research worker with practical problems in mind.

Proceedings of the Institution of Mechanical Engineers, Part C: Journal of Mechanical Engineering Science

It is now becoming recognised in the measurement community that as well as reporting the measured value it is also essential to give its uncertainty. Without a knowledge of the uncertainty, it is impossible for the users of the result to know what confidence can be placed in it and it is also impossible to assess the comparability of different measurements of the same parameter. However, problems arise with the use of such terminology as error, accuracy, inaccuracy and uncertainty that has everyday connotations as well as formal definitions for use in metrology. The paper gives a resume of the reasons why it is important to evaluate and report the uncertainty on a result in a consistent manner. A description is given of the concept of uncertainty, which highlights the difference between it and error, accuracy or inaccuracy. This is followed by a discussion of the recommendations made by the “ISO – Guide to the Expression of Uncertainty in Measurement” for the evaluation and reporting of uncertainty. The methodology for evaluating uncertainty is described and the advantages of using suitable reference materials are discussed. Finally, the benefits to both the analytical laboratory and the user of the results from the evaluation and reporting of uncertainty are considered.

Untargeted metabolomics is a powerful tool for measuring and understanding complex biological chemistries. However, employment, bioinformatics and downstream analysis of mass spectrometry (MS) data can be daunting for inexperienced users. Numerous open-source and free-to-use data processing and analysis tools exist for various untargeted MS approaches, including liquid chromatography (LC), but choosing the ‘correct’ pipeline isn’t straight-forward. This tutorial, in conjunction with a user-friendly online guide presents a workflow for connecting these tools to process, analyse and annotate various untargeted MS datasets. The workflow is intended to guide exploratory analysis in order to inform decision-making regarding costly and time-consuming downstream targeted MS approaches. We provide practical advice concerning experimental design, organisation of data and downstream analysis, and offer details on sharing and storing valuable MS data for posterity. The workflow is editable and modular, allowing flexibility for updated/changing methodologies and increased clarity and detail as user participation becomes more common. Hence, the authors welcome contributions and improvements to the workflow via the online repository. We believe that this workflow will streamline and condense complex mass-spectrometry approaches into easier, more manageable, analyses thereby generating opportunities for researchers previously discouraged by inaccessible and overly complicated software.

Untangling the Complexities of Processing and Analysis for Untargeted LC-MS Data Using Open-Source Tools

REFINE-Lung implements a novel multi-arm randomised trial design to address possible immunotherapy overtreatment.

Author response for "Root functional traits explain root exudation rate and composition across a range of grassland species"

Health and fitness content intended to inspire people to live healthy lives (e.g. "fitspiration") has been linked to negative body image among girls and young women. Fitness influencers purport wanting to motivate healthy behaviors. This study seeks to examine the presence of strategies known to positively influence health behaviors (e.g. attitudes, self-efficacy) as well as of content known to have a negative influence (e.g. objectification) among fitness influencers. We conducted a content analysis (N = 441) of a random sample of one year of posts from four Instagram fitness influencers popular with girls and young women in the United States. The main analysis consisted of codes related to objectification, health promotion strategies, health-related content, and social engagement (i.e., likes). We found that fitness influencers included content that conveyed constructs previously found to positively influence health behaviors (e.g., attitudes and self-efficacy), but objectification was frequently present, in more than half of the posts. Additionally, we found that the presence of objectification in posts was negatively associated with likes, a form of social endorsement. We suggest health communicators aim to work in tandem with fitness influencers to include content that may motivate positive health behaviors and improve media literacy and that influencers aim to reduce the amount of objectifying content included in their posts. Our findings shed light on content being conveyed and possible insights into the negative effects associated with viewing such content.

An Exploratory Content Analysis of the Use of Health Communication Strategies and Presence of Objectification in Fitness Influencer Social Media Posts.

ABSTRACT Developing artificial intelligence (AI) equitably necessitates understanding how nonexperts conceptualize and share news about technoscientific risk. We examine a model predicting AI information sharing online from an interaction of framing strategies, through psychological proximity to the impacts of AI and perceived AI risk. A panel of N = 412 participants were exposed to either a control message; or one of four manipulated messages related to AI risks. Contrary to expectations, thematically framed explicit risk news primed psychological proximity compared to both a control message and episodic frame condition. Meanwhile, episodic explicit risk frames did not prime psychological proximity over a control message. These results contest the notion that episodic frames should be associated with psychological proximity to a risk over more general framing strategies. Our results support prior research suggesting that where risk-news primes psychological proximity, the decrease in distance is in-turn associated with greater risk perception and increased likelihood of news sharing online.

The Indirect Effects of Episodic-Thematic Framing on Information Sharing About the Economic Threat of Artificial Intelligence

American Indian and Alaska Native (AI/AN) people infrequently participate in Alzheimer's disease (AD) research, despite the rapidly increasing population of AI/AN people aged 65 and older.

Alzheimer's & Dementia : Translational Research & Clinical Interventions

Communication about Alzheimer's disease and research among American Indians and Alaska Natives

YouTube videos have been used to inform and misinform the public about the safety of vaccines related to health threats such as measles and COVID-19. Understanding how such videos can promote the sharing of accurate vaccine safety information is of the utmost importance if health researchers are to combat the spread of misinformation and encourage widespread uptake of vaccines. Through the lens of prospect theory, this study conducted a 2 (framing: loss v. gain) x 2 (evidence type: episodic v. thematic) x 2 (speaker expertise: expert v. non-expert) between-subject factorial experiment in which a sample of N = 400 US adults over the age of 18 recruited through MTurk were asked their intention to share vaccine safety information with others after watching a manipulated YouTube video. The results showed that loss framing was associated with perceived MMR severity which was, in turn, associated with the likelihood that participants would share MMR vaccine information with others, via any means. However, this process varied depending on the type of evidence delivered, and the expertise of the speaker. Results and limitations are discussed in the context of vaccine communication and social media.

Vaccine Videos and Information Sharing: The Effects of Framing, Evidence Type, and Speaker Expertise

The spread of science misinformation harms efforts to mitigate threats like climate change or coronavirus. Construal-level theory suggests that mediated messages can prime psychological proximity to threats, having consequences for behavior. Via two MTurk experiments, I tested a serial mediation process model predicting misinformation sharing from lexical concreteness, through psychological proximity and perceived threat. In Study 1, concrete misinformation primed psychological proximity which, in turn, increased perceived threat. Perceived threat then increased the likelihood that misinformation would be shared. Source credibility was also shown to positively influence misinformation sharing. Study 2 advanced this by showing this process was moderated by subjective knowledge. Specifically, the effect of perceived threat on misinformation sharing was stronger for those with higher subjective knowledge. Furthermore, the indirect effect of lexical concreteness on misinformation sharing was stronger for those with higher subjective knowledge. Results and limitations are discussed within the lens of construal-level theory and science communication.

The spread of fake science: Lexical concreteness, proximity, misinformation sharing, and the moderating role of subjective knowledge.

Abstract Public opinion on critical issues, such as technology deployment aimed at reducing greenhouse gases or increasing energy efficiency, may be impacted through information disseminated through the media. It is therefore increasingly important to understand the role media plays in spreading misinformation to the public. Through this study, we add to the growing body of literature on misinformation by exploring the relationship between media attention, risk perceptions, knowledge of, and support for smart meter technology. Smart meter deployment has been hindered, in part, due to beliefs that the technology causes cancer or can lead to incorrect electricity billing. To examine the relationship between misinformation and support for smart meter technology, we analyzed a quota sample of 1,046 people living in the U.S. Results show that paying attention to smart meter stories is related to familiarity with false information about smart meters. Familiarity with false information is also associated with misperceiving risks regarding the technology (e.g. those who are aware of false information about health problems associated with smart meters are more concerned about health-related problems associated with this technology). Ultimately, reporting higher levels of concern about smart meters is associated with lower support for government and industry policies aimed at increasing smart meter installation. However, the relationship for misperceptions, which decreased support for smart meters, was only present among those with low knowledge levels of the technology. Results indicate that knowledge may be a protective factor in terms of mitigating the effects that misinformation could have on outcomes such as support for policies or technological developments.

Understanding public support for smart meters: media attention, misperceptions, and knowledge

Part I: The Environment: Regulation and the Mortgage Market The Etiology of Risk in Mortgage Portfolios Part II: Risk Reduction Through Portfolio Diversification Controlling Risk in Mortgage Portfolios Part III: Residential Mortgages: Single- and Multifamily Mortgage Risk Analysis: The Regression Method Linear Probability Model Cohort Analysis of Delinquency Risk Discriminant Function Analysis Classification Risk Indexes Evaluating Commercial and Industrial Properties

IN THIS PAPER WE have developed a model which uses duration and price elasticity to estimate security price risk. The focus is on the volatility of security prices, and how this affects the return to the investor. The investor's return is made up of the dividend yield and the proportional change in the asset price. Historically, dividends have been relatively constant, which would imply that most of the volatility in the investor's return is derived from the volatility in the price of the stock. We are, therefore, interested in the change in price, as measured by its elasticity, and how the elasticity, in turn, affects the investor's return. Hicks [1939] derived the equivalent "average period" measuring the "elasticity of asset prices with respect to a discount ratio." His interest at the time was focused on fixed income securities such as bonds. Macaulay [1938] had proposed the concept of "duration" to represent the "essence of time element of a loan" with risk proxying properties. Hicks' "average period" and Macaulay's "duration" are equivalent concepts. We have also used duration, or the average period, to measure the elasticity of security prices. Malkiel [1963] first considered the theoretical relationships of price volatility of a share of common stock. Malkiel concluded that as the general level of share prices change, the prices of growth stocks must fluctuate more than proportionately. Haugen and Wichern [1974] examined the relative response of value in common stocks to changes in the level of interest rates and concluded that the elasticity of share price with respect to parameter changes can be simply and directly related to the "duration" of the stream of payments accruing to the security. Boquist, Racette and Schlarbaum [1975] examined the time-risk relationship as measured by duration. There is some similarity between the term structure of interest rates and the structure of equity prices. For a given change in interest rates it is known that

Estimating Security Price Risk Using Duration and Price Elasticity

Default Risk in Urban Mortgages: A Pittsburgh Prototype Analysis

Extension of O'Leary et al. (2014) homeostatic neuron model to two-compartments

Design and Structural Features of the SH-2F Composite Main Rotor Blade

Field Performance of Asian Pear Cultivars in the Hot, Humid Summer Conditions of the Mid-Atlantic Region of the United States

Mutations of FLT3/ITD confer resistance to multiple tyrosine kinase inhibitors

Fishers from four river systems, Bonny, New Calabar, Sombreiro and Andoni in Bonny area of Niger Delta were identified. A characteristic of fishers, being a very mobile group was evident from the total of 10 ethnic groups identified, five of which were not indigenous to the area. Age structure ranged from <10 to 74 years. Seven main fisheries exploited were big fish, catfish, shrimp, croaker, sardine and shark. Thirteen different gear types used in the exploitation of the fishery ranged from gill nets of various mesh size, hand and purse seines, and hook and lines; eight were passive and five active. The fisheries resources were exploited within eight fishing grounds in Rivers (Bonny, New Calabar, Sombreiro and Andoni) and in creeks, estuaries and the Atlantic Ocean off these river systems. Estimated CPUE showed highest average from the Ocean fishing grounds with lowest values being obtained from rivers and creeks. Exploitation strategies employing higher number of passive gears, and allowing escape of smaller sizes of fish coupled with highest average CPUE from the Atlantic Ocean fishing grounds where larger sizes were found, are significant for resource sustainability. Encountered exploitation strategies were in compliance with the dictates of responsible fisheries which is being advocated for sustainability of all fisheries resources globally.

Fishers and Fisheries: issues of Sustainable Resource Exploitation. A Case Study of Bonny Area In Nigeria

Sex-specific investment in pathogen resistance and immunity has been widely reported in animals and to a much lesser degree in plants. Here, we investigated the incidence of fungal pathogens in dioecious versus hermaphroditic plant species. We found that direct studies on differences between males and females in disease resistance or pathogen incidence were rare or non-existent in plants, but if we made the prediction that if such differences exist (e.g. if males are less resistant than females), dioecious species should have a higher variation in pathogen diversity than hermaphrodites. Comparative studies on paired dioecious and hermaphrodite species from multiple plant families showed that hermaphrodites had a higher average pathogen load than dioecious species, consistent with the idea that higher outcrossing is beneficial to resistance to a greater diversity of pathogens. There was however no support for dioecious species also having a greater variance in pathogen diversity. Our results are consistent with dioecy providing a benefit in terms of pathogen resistance, but the data were insufficient to resolve if the male and female plants showed sex-specific investment in resistance.

Recruitment pattern of Macrobrachium vollenhovenii in the Lagos – Lekki Lagoon System was estimated from a time series length-frequency data of two years (April 2002 – May 2004). The annual recruitment pattern was estimate through back-projection, along a trajectory defined by the von Bertalanffy Growth Formula (VBGF) of the restructured data onto the time axis. M. vollenhovenii from the Lagos Lagoon exhibited two peaks of unequal pulse strength. The peaks of the smaller sized prawn for M. vollenhovenii were noted in September to November and in February. The recruitment pattern exhibited, revealed that for sustainability of this resource exploitation should be avoided in the months of September to November and also in February, as this would allow the young recruits to grow and reproduce thereby ensuring resource sustainability. Keywords : Recruitment Pattern, Pulse Strength, Macrobrachium vollenhovenii , Resource Sustainability, Lagos – Lekki Lagoon System. The Zoologist Vol. 6 2008: pp. 55-60

Recruitment Pattern Of Macrobrachium vollenhovenii In The Lagos – Lekki Lagoon System, Nigeria

Length-Weight Relationship and Condition Factor of Macrobrachium macrobrachion in the Lagos-Lekki Lagoon System, Nigeria

Assessment of fish by-catch species from coastal artisanal shrimp beam trawl fisheries in Nigeria

The physico-chemical features and phytoplankton community of selected fishponds in Lagos State, Nigeria were studied between November 1998 and August 1999. pH of water in all the ponds ranged between 6.50 ± 0.24 and 7.90 ± 0.40, while dissolved oxygen concentration and temperature ranged from 2.40 ± 0.36 to 5.95 ± 1.31 mgl-1 and 27.3 ± 1.08 to 29.4 ± 0.970C respectively. Three families of phytoplankton were encountered. These were Bacilliariophyceae, Cyanophyceae and Chlorophyceae. The phytoplankton community was predominated by Cyanophyceae which constituted more than 40% of the total phytoplankton population. The predominant taxa were Spirulina sp., Lepocindis sp., Merimospedia sp., Anabena sp. and Coclastrum sp. Anabena sp. was present in all the farms and throughout the months. Phytoplankton were more abundant during the dry season than rainy season. Key words : Physico-chemical parameters, Phytoplankton community, Fishponds 
Journal of Aquatic Sciences Vol.18(1) 2003: 53-58

Physico-Chemical Parameters and Phytoplankton Community of Some Selected Fishponds in Lagos State, Nigeria

Existing chemical models of bacteria are complicated, due to the thousands of interacting chemical reactions within the cell. To gain a higher level of understanding, more transparent and abstract models are needed. In this paper an intentional dynamic modelling approach is introduced and used to simulate the behaviour of Escherichia coli. A model of the entire cell is presented that covers E. coli’s behaviour, including its intracellular processes and their control. The intentional state properties used in the model are in a one-to-one correspondence to chemical state properties: concentrations of specific substances within the cell. Via these correspondences the dynamic relationships between intentional state properties are justified by chemical laws. A software environment has been developed for simulation and automated analysis of such a model.

Pareiasaurus karpinskii Amalitzky, 1922 (currently Scutosaurus karpinskii; Reptilia, Pareiasauria): Proposed conservation of the specific name

A New Species Of Mud Shrimp, Upogebia Toralae, From Veracruz, Mexico

Occurrence Of Three Species Of Mud Shrimps In Aquaculture Ponds On Caribbean Coasts Of Venezuela And Colombia, With A Redescription Of Upogebia Omissago Williams, 1993 (Decapoda: Upogebiidae)

Two New Species And A Range Extension Of Mud Shrimps, Upogebia, From Pacific Costa Rica And Mexico (Decapoda : Thalassinidea : Upogebiidae)

Comments On The Proposed Conservation Of The Generic Names Monstrilla Dana, 1849 And Thaumaleus Kroyer, 1849 (Crustacea, Copepoda)

—Epilobocera wetherbeei, a new species of pseudothelphusid crab, is described from the Dominican Republic. The species can be easily distinguished from other species of Epilobocera by its small size, absence of anterolateral spinulation and characters of the first male gonopods. SEM microphotographs of the first and second male gonopods of E. wetherbeei, E. sinuatifrons, E. haytensis and E. gertraudae are provided. The apex of the second male gonopod in all species of Epilobocera studied is hollow, transversely truncate, with a prominent internal rib provided with spines. These characters distinctly separate Epilobocera from species in the subfamily Pseudothelphusinae where the gonopodal apex is spoon-shaped and provided with long setae. The new observations are incorporated into amended diagnoses of the subfamilies Epilobocerinae and Pseudothelphusinae. The genus Epilobocera Stimpson, 1860, comprises six species of freshwater crabs restricted to the Greater Antilles and some nearby islands: E. sinuatifrons A. Milne Edwards, 1866, inhabits Puerto Rico and Saint Croix Island; E. haytensis Rathbun, 1893, is confined to Hispaniola; Cuba has three species, E. armata Smith, 1870, E. cubensis Stimpson, 1860, and the troglobic E. gertraudae Pretzmann, 1965; E. gilmani (Smith 1870), possibly conspecific with E. cubensis, has been described from Isla de Pinos. One species, E. granulata Rathbun, 1893, was described from an immature male labeled "West Indies'" and the first male gonopod was not illustrated. Chace & Hobbs (1969) stated that "the material is now virtually macerated" and suggested that "In view of the immaturity of these specimens and the lack of specific type-locality, the species may remain a species inquirenda indefinitely unless it can be shown to be a synonym of E. armata."' The genus has been the object of recent revisions by Chace & Hobbs (1969), Pretzmann (1972) and Rodriguez (1982). Due to the accessibility and small area of the Greater Antilles, their freshwater fauna is fairly well known. For this reason it has been noteworthy to find a new species of freshwater crab in the material recently collected by Dr. David Wetherbee during his explorations of the Cordillera Central of Hispaniola. Materials and Methods The materials used for the description of Epilobocera wetherbeei were collected as two separate lots. The first lot included the male holotype and one juvenile specimen collected on 2 Oct 1990, and sent to the junior author in the National Museum of Natural VOLUME 108, NUMBER 1 77 History, Smithsonian Institution, Washington (USNM). The specimens were received in semi-dry condition, and the coloration was carefully noted at the time of reception (see "Color"). The specimens were subsequently placed in alcohol and shipped to the senior author for further study. The second lot was collected on 12 Jul 1991, at the type locality, and was shipped to the senior author by Dr. Wetherbee. The lot included two males and five ripe or ovigerous females. These specimens were in poor condition and almost all pereiopods and some carapaces have become dislocated. The specimens are deposited at the USNM and the Reference Collection of the Instituto Venezolano de Investigaciones Cientificas, Caracas (IVIC). Other abbreviations used are cb for carapace breadth, and cl for carapace length. For comparative purposes we have studied the first and second gonopods of other species of Epilobocera deposited in IVIC, namely E. sinuatifrons, 1 male, cl 55.6 mm, from El Yunque, Coca Falls, Luquillo, Puerto Rico, collected 5 Feb 1972; E. haytensis, 1 male cl 43.2 mm, from Barahona, Dominican Republic, collected 3 Feb 1967; E. gertraudae, 1 male cl 31.5 mm, from Cueva Superior Majaguas, Sierra de San Carlos, Pinar del Rio, Cuba, collected 2 Aug 1977. The first and second gonopods of the holotype of E. wetherbeei and all the species recorded above were dried, coated with platinum, and photographed on a scanning electron microscope Hitachi S-500. Pointdrying was not used due to the extreme brittleness of the material. For the gonopods of E. armata and E. cubensis we have relied on drawings and notes made on the material already reported by Rodriguez (1982). Subfamily Epilobocerinae Smalley, 1964 Genus Epilobocera Stimpson, 1860 Epilobocera wetherbeei, new species Figs. 1, 2A, B, 3A, 4A Material. —Rio Magua, tributary of Rio Mao, Sierra Platicos, northern slopes of the Cordillera Central, near the water divide, Provincia Santiago, Dominican Republic, at waterfall, 2300 m alt., 2 Oct 1990, leg. David Wetherbee, 1 male holotype, cl 16.5 mm, cb 26.6 mm, 1 juvenile (USNM).— Same data, 12 Jul 1991, 1 male paratype, cl 15.0 mm, cb 23.5 mm (IVIC), 1 male, broken carapace, cl approximately 12.5 mm, cb approximately 20.1 mm; 4 ovigerous female paratypes, cl 14.7, 15.5, 16.1 and 16.8 mm, cb 24.6, 25.8, 25.7 and 28.1 mm, 1 adult female broken carapace cl 14.2 mm, cb approximately 24.0 mm (USNM). Description. —Carapace wide (cb/cl =1.61 in holotype), strongly convex on anteroposterior axis. Cervical groove absent, only in female cl 15.5 mm indicated by thin line on left side of carapace. Antero-lateral margin without conspicuous depression behind antero-external angle, entire or slightly festooned on anterior portion, with occasional small papillae in holotype and male paratype, smooth or with 12 to 16 poorly-defined papillae in females. Postfrontal lobes absent, their position indicated only by rounded scars; median groove thin and shallow, obsolescent. Front lacks upper border, but surface of carapace in this area rounded off to lower margin. Lower margin clearly visible in dorsal view, slightly arched; strongly sinuous in frontal view. Surface of carapace smooth and polished, with regions not marked. No tooth present at aperture of efferent branchial channel. Largest cheliped elongated, ischium overreaching by % of its length margin of carapace. Palm moderately inflated, lower margin of palm and fixed finger sinuous; fingers arched, widely gaping. Walking legs slender, ischium of third pair 4.7 as long as wide. Third maxilliped with merus wide, anterolateral border evenly rounded; exopod devoid of flagellum, overreaching ischium of endognath, its tip rounded, provided with plumose setae. First male gonopod long and slender. Margin (sensu Smalley 1964a) progressively twisted dextrally, its middle portion direct78 PROCEEDINGS OF THE BIOLOGICAL SOCIETY OF WASHINGTON Fig. 1. Epilobocera wetherbeei, new species, holotype male, dorsal view of carapace and pereiopods. ed mesially and its apical portion directed to cephalic side. Margin developed distally into strong recurved mesial lobe. Apex club shaped; bulging lateral process ("globulus" sensu Pretzmann 1972) with 7 strong hooked spines; finger-like caudal process ("nasus" sensu Pretzmann 1972) devoid of spines, apex with crenulations on inner side; mesial process ("caudaler Kamm" sensu Pretzmann 1972) consists of 5 spines disposed in comb-like structure directed externally; intermediate plate ("Querkamm" sensu Pretzmann 1972) with 5 slender spines; cephalic margin with few tiny proximal papillae, ending mesially in acute angle (broken in our SEM illustration of Fig. 3a). Second male gonopod straight, apex hollow, transversely truncate, prominent internal rib provided with spines. Color. —According to field notes taken by the collector, the color in live specimens "varies from brown in some to orange. Orange specimens have maroon (reddish purple) walking legs and white claws." In the holotype specimen preserved in alcohol the color is as follows. Overall color carapace salmon pink. Walking legs lighter. Chelipeds still lighter, buff, articular membranes between merus and carpus, between carpus and propodus, and at base of dactyl, salmon pink and contrasting with buff of articles; membrane at either end of carpus darker than those at base of dactyl; membranes of major right chela darker than those of minor (left). The fifth left leg is detached; articular membranes not colored on this or any other of the walking legs. Underside of the walking legs only slightly lighter in color than other sides. VOLUME 108, NUMBER 1 Fig. 2. Epilobocera wetherbeei, new species, holotype male: a, third maxilliped, right; b, apical portion of left first gonopod, cephalic view, ml, mesial lobe; lp, lateral process; cp, caudal process; s, spines of mesial process; ip, intermediate plate; cm, cephalic margin; ma, mesial angle of cephalic margin; tp, terminal process. Underparts of body lighter than dorsum, but flush of salmon pink on sternal plate between chelipeds and third maxillipeds, with similar color on exposed articles of third maxilliped, pterygostomian and subhepatic regions. Abdomen not salmon pink, but of somewhat darker hue than adjacent sternites to each side. Size. —The species is small for the members of the genus. Our largest male has a cl 26.6 mm, and females reach maturity at cl 24.6 mm. Remarks. — The small size distinguishes this species from all others in the genus; in fact Epilobocera sinuatifrons and E. haytensis, are among the largest Pseudothelphusidae on record (cb 103.3 mm and 100.4 mm, Rodriguez 1982). The largest specimens recorded for E. armata and E. cubensis have a cb of 85.2 mm and 84 mm, respectively (Rodriguez 1982). The specimen of E. gertraudae examined by us has a cb of 53.8 mm. The absence of teeth on the antero-lateral margin and the smoothness of carapace characteristic of E. wetherbeei are only observed in E. cubensis, but while in this last species the margin has some rudimentary papillae, in E. wetherbeei it has none. The coloration observed in this species has not been reported for other Epilobocera. The characteristic tooth present at the aperture of the efferent branchial channel in other species of Epilobocera (see Rodriguez 1982, fig. 3h-l), and which can be clearly seen through the channel aperture, is missing in this species. The most important differences from

Epilobocera wetherbeei, a new species of freshwater crab (Decapoda: Brachyura: Pseudothelphusidae) from Hispaniola

Epilobocera wetherbeeic a new species of freshwater crab lDecapodac Brachyurac Pseudothelphusidaer from Hispaniola

A marine natural product, patellamide D, reverses multidrug resistance in a human leukemic cell line.

Comments On The Proposed Conservation Of The Specific Name Of Artemia Franciscana Kellogg, 1906 (Crustacea, Branchiopoda)

^fo^rac^—Deepwater trapping in the Mariana Archipelago, western North Pacific Ocean, included incidental catches of a spider crab and a homoloid crab with novel characteristics. Bothromaia griffini, new genus and species, family Majidae, subfamily Inachinae, represented by a male and female, seems most closely related to the genus Pleistacantha Miers, containing several species distributed in Indo-Pacific waters. The new species resembles members of this genus with respect to presence of pseudorostral horns, and shape of eyestalks, basal antennal article, epistome, third maxilliped, male stemites and pleopod 1, but differs from them in shape of pseudorostral horns, carapace, male pleopod, and in proportions of the ambulatory legs. Descriptions, illustrations, and comparative discussion are presented. Notes on the homoloid crab, Poupinia hirsuta Guinot, include locality data, measurements, remarks on distribution, and discussion of features distinguishing the families of Homoloidea, including a key for their identification.

Crabs from the Mariana Archipelago : Bothromaia griffini new genus and species (Brachyura : Majidae), and remarks on Poupinia hirsuta Guinot (Homoloidea, Poupiniidae)

Upogebia spinistipula, a new burrowing shrimp from the Florida shelf, northeastern gulf of Mexico (Decapoda: Thalassinidea: Upogebiidae)

Abnormal phenotype associated with an inherited and apparently balanced x autosome translocation prenatal and postnatal late x replication studies

— Panopeus margentus new species, a xanthid crab from warm, temperate, marine Argentine waters is described, illustrated, and compared with the recently described Panopeus mirajloresensis from the Pacific side of the Panama Canal. The first male pleopods and carapace of these species are similar and resemble these features in P. bermudensis. Notes on associated

Panopeus margentus, a new crab from the Argentine warm temperate subregion (Decapoda : Xanthidae)

A new species of Munidopsis from submarine thermal vents of the east Pacific Rise at 21°N (Anomura : Galatheidae)

Reassessment Of Northern Geographic Limits For Decapod Crustacean Species In The Carolinian Province Usa Some Major Range Extensions Itemized

—Mimilambrus wileyi, new genus and new species is described from nearshore waters of Man-of-War Bay, Tobago, West Indies. Mimilambrus represents a new family that combines characters of the Parthenopidae, Leucosiidae and Calappidae. Its placement, therefore, lies between the Oxystomata and Brachygnatha, probably within the Oxyrhyncha.

A New Crab Family From Shallow Waters Of The West indies Crustacea Decapoda Brachyura

Transfer To Pseudomedaeus Of The Xanthid Crab Micropanope-Distinctus

Distinction Between A Gulf Of Mexico And A Carolinian Atlantic Species Of The Swimming Crab Ovalipes Decapoda Portunidae

Two new axiids lCrustaceac Decapodac Thalassinidaec Calocarisr from North Carolina and the Straits of Florida

A New Species Of Hypsophrys Decapoda Homolidae From The Straits Of Florida Usa With Notes On Related Crabs

Central nervous system (CNS) autonomic network plays an important role in energy homeostasis, and cardiovascular function with important pathophysiological implications. Previous studies employing ...

Abstract P106: Polysynaptic Neurotracing Of Autonomic Nuclei Projecting To Cardiovascular And Metabolic Organs

In this article I share some of my experiences of practising Korean Zen meditation and how, without ever mentioning the word ‘mindfulness,’ this practice helps us to become mindful. This leads me to suggest that the main ingredients of Buddhist meditation are samatha (which I will translate here as ‘concentration’) and vipassanā (which I will call ‘experiential enquiry’). No matter which Buddhist tradition one follows, the practice of samatha and vipassanā will lead to the cultivation of mindfulness. I also intend to show how the traditional doctrine of the ‘four great efforts’ is very close to therapeutic methods advocated in MBCT. I will also propose that the Buddha’s five methods of dealing with difficult thoughts as presented in the Vitakkhasa _ n _ thāna Sutta (Majjhima Nikāya 20) are examples of an early Buddhist cognitive behavioural strategy.

Cette invention concerne des esters de colophane. Les esters de colophane selon l'invention peuvent manifester une couleur amelioree ( p. ex. ., l'ester de colophane peut avoir une valeur nette de 4 ou moins sur l'echelle de couleurs Gardner), une stabilite a l'oxydation amelioree ( p. ex. ., quand 1000 ppm ou moins d'un antioxydant sont presentes en combinaison avec l'ester de colophane, l'ester de colophane peut manifester un temps d'induction d'oxydation a 130°C d'au moins 30 minutes), une stabilite de couleur amelioree ( p. ex. ., l'ester de colophane peut conserver une valeur nette de 5 ou moins sur l'echelle de couleurs Gardner quand il est chauffe a une temperature de 160°C pendant une periode de trois heures), ou leurs combinaisons. Des compositions polymeres comprenant lesdits esters de colophane ainsi que des procedes de production desdits esters de colophane sont en outre decrits.

Background: Sar1 mediates the onward transport of ER cargo. Results: Sar1B promotes VLDL secretion, whereas Sar1A antagonizes this activity, and a deficit of both reduces cholesterol biosynthesis. Conclusion: Sar1B independently of and through its lipoprotein secretion function promotes the expression of genes regulating cholesterol biosynthesis. Significance: Sar1B-mediated transport activities contribute to both the functional integrity of the ER membrane and blood cholesterol levels. Triglycerides and cholesterol are essential for life in most organisms. Triglycerides serve as the principal energy storage depot and, where vascular systems exist, as a means of energy transport. Cholesterol is essential for the functional integrity of all cellular membrane systems. The endoplasmic reticulum is the site of secretory lipoprotein production and de novo cholesterol synthesis, yet little is known about how these activities are coordinated with each other or with the activity of the COPII machinery, which transports endoplasmic reticulum cargo to the Golgi. The Sar1B component of this machinery is mutated in chylomicron retention disorder, indicating that this Sar1 isoform secures delivery of dietary lipids into the circulation. However, it is not known why some patients with chylomicron retention disorder develop hepatic steatosis, despite impaired intestinal fat malabsorption, and why very severe hypocholesterolemia develops in this condition. Here, we show that Sar1B also promotes hepatic apolipoprotein (apo) B lipoprotein secretion and that this promoting activity is coordinated with the processes regulating apoB expression and the transfer of triglycerides/cholesterol moieties onto this large lipid transport protein. We also show that although Sar1A antagonizes the lipoprotein secretion-promoting activity of Sar1B, both isoforms modulate the expression of genes encoding cholesterol biosynthetic enzymes and the synthesis of cholesterol de novo. These results not only establish that Sar1B promotes the secretion of hepatic lipids but also adds regulation of cholesterol synthesis to Sar1B's repertoire of transport functions.

The Endoplasmic Reticulum Coat Protein II Transport Machinery Coordinates Cellular Lipid Secretion and Cholesterol Biosynthesis*

Dimethylzinc adduct chemistry revisited: MOCVD of vertically aligned ZnO nanowires using the dimethylzinc 1,4-dioxane adduct

The dimethylzinc-bidentate ether adducts [Me2Zn(1,4-dioxane)] (1), [Me2Zn(1,2-dimethoxyethane)] (2) and [Me2Zn(1,4-thioxane)] (3) are used as precursors for the growth of vertically aligned zinc oxide (ZnO) nanowires (NWs) by liquid-injection, metal-organic (MO)CVD. The ZnO NWs are deposited on Si(111) and F-doped SnO2/glass substrates in the absence of a seed catalyst. The precursors (1) and (2) are used to deposit ZnO NWs at substrate temperatures of 450 °C and 500 °C, whilst higher deposition temperatures of 550–600 °C are necessary to obtain ZnO NWs using (3). X-ray diffraction (XRD) data show that the NWs grown from all three adduct precursors are deposited in the wurtzitic ZnO phase. Room-temperature photoluminescence (PL) data for the ZnO NWs grown using (1) and (2) show an intense peak at 3.28 eV due to near band-edge emission with a very low intensity of defect-related green luminescence at 2.42 eV. In contrast, room-temperature PL data for the ZnO NWs deposited using (3) is dominated by deep centre, defect-related emission at 2.42 eV. Auger electron spectroscopy (AES) shows that the ZnO films deposited from (1) and (2) are high purity with no detectable carbon, but the ZnO films grown from (3) are contaminated with sulfur (1 at.-%). Single-crystal X-ray structures show that (1) is polymeric containing bridging 1,4-dioxane ligands while (2) is a monomeric complex featuring a chelating 1,2-dimethoxyethane ligand. The wide [Me-Zn-Me] bond angles in (1) and (2) (152.0(3)° and 154.5(2)°, respectively) suggest moderately weak [Me2Zn]-ligand interactions. Complex (3) is polymeric and exhibits nearly linear [Me-Zn-Me] bond angles, indicative of much weaker [Me2Zn]-ligand interactions.

MOCVD of Vertically Aligned ZnO Nanowires Using Bidentate Ether Adducts of Dimethylzinc

L'invention concerne un procede de formation d'un film a teneur en metal par depot d'une couche atomique. Le procede comprend l'utilisation (a) d'au moins un precurseur de β-dicetonate fluore metallique ; et (b) d'un co-reactif comprenant au moins une hydrazine facultativement substituee.

Procédés de préparation de films minces par dépôt d'une couche atomique à l'aide d'hydrazines

Crystal Structure of Bi(OCMe2CH2OMe)3 and Its Use in the MOCVD of Bi2O3.

Conjugated linoleic acid (CLA) and n‐3 fatty acids (FA) have been proposed as an important pharmaconutrient for modulating cancer and obesity. We investigated effect of CLA and n‐3 FA alone or in combination to modulate bone loss and liver steaotosis in aging C57Bl/6 mice. Twelve months old C57Bl/6 mice were fed with 10% corn oil (CO) as control, with or without 0.5 % CLA (50:50 mixture of c9t11 and t10c12 isomers), 5% n‐3 FA and a combination of 0.5 % CLA and 5% n‐3 FA for 6 months. After 6 months dietary intervention, CLA and CLA+n‐3 FA fed mice reduced body weight and maintained bone mineral density compared to CO group. Importantly, CLA induced liver hypertrophy or steatosis was completely prevented by incorporation of n‐ 3 FA in CLA diet. The liver histology revealed that lipid filled vacuoles were significantly less in n‐3 FA and CLA+n‐3 FA diet fed mice compared to CO and CLA fed mice. The inherited property of n‐3 FA to reduce triglycerides may be responsible in modulating the liver hypertrophy induced by CLA. The DXA results showed that CLA and CLA+n‐3 FA diet also increased the lean mass in the hind leg. Furthermore, femoral bone histological sections stained with oil red O showed that CLA and CLA+n‐3 FA diet prevented bone adiposity. These findings demonstrate that CLA with n‐3 FA can be used for obesity as well as osteoporosis prevention strategy. Further studies in higher species and humans are needed to confirm this observation.

Effect of conjugated linoleic acid and n‐3 fatty acids on body composition and bone loss in aging C57Bl/6 mice

Procédés de préparation de films minces contenant du titane par dépôt de couches atomiques à l'aide de précurseurs à base de monocyclopentadiényltitane

Procédés de préparation de films minces par dépôt de couches atomiques à l'aide de précurseurs de monocyclopentadiényl triamino zirconium

Verfahren zur herstellung von dünnen filmen durch atomlagenabscheidung unter verwendung von monocyclopentadnieyltriaminozirconium-vorläufern

La presente invention concerne des precurseurs appropries pour un depot en phase vapeur, plus particulierement un depot d’une couche atomique (DCA), d'oxyde d'hafnium ou d'oxyde de zirconium, repondant a la formule generale (I) : (R1Cp)2MR2R3 dans laquelle Cp represente un ligand cyclopentadienyle, R1 represente H ou un groupe alkyle, un groupe alcoxy ou un groupe amido de substitution sur le ligand Cp, R2 et R3 representent un groupe alkyle, un groupe alcoxy ou un groupe amido et M represente l’hafnium ou le zirconium.

Précurseurs d'hafnium et de zirconium de type cyclopentadiényle et leur utilisation dans le dépôt atomique d'une couche

Précurseurs d'hafnium et de zirconium de type cyclopentadiényle et leur utilisation dans le dépôt en couches atomiques

Mo-W6:3 Genetics of intracellular lipid transport and familial combined hyperlipidemia

A precursor suitable for chemical vapour deposition, especially ALD, of hafnium oxide or zirconium oxide has the formula: (R Cp)2MR wherein Cp is a cyclopentadienyl ring; R ,is H, alkyl, alkoxy, amide; R is alkyl, alkoxy, amide; M is hafnium or zirconium. In another aspect, a precursor has the formula: Cp2MR R wherein Cp is as above; R , R are the same or different and are selected from alkyl, alkoxy, amide; M is as above. In another aspect, a precursor has the formula: (R Cp)2MR R wherein Cp is as above; R , R are the same or different and are selected from alkyl, alkoxy; R is alkyl, alkoxy, amide; M is as above. The precursors can be used in ALD techniques for applications including DRAM and CMOS for memory and logic applications in silicone chips.

A range of “single source” Sr-Nb and Sr-Ta heterometal alkoxides precursors are investigated as potential sources for liquid injection MOCVD (metalorganic chemical vapour deposition) and ALD (atomic layer deposition) of SrBi 2 Ta 2 O 9 (SBT) and SrBi 2 (T x Nb 1-x ) 2 O 9 (SBTN). These “single source” precursors are designed to alleviate the mis-match between conventional Sr and Ta or Sr and Nb sources. Strontium-tantalate and strontium-niobate thin films were deposited on silicon using the “single source” alkoxide precursors [Sr{Ta(OEt) 5 (dmae} 2 ] and [Sr{Nb(OEt) 5 (dmae)} 2 ] (dmae = OCH 2 CH 2 NMe 2 ), and the optimum temperatures for deposition of stoichiometric SrTa 2 O 6 and SrNb 2 O 6 were determined. Separate ALD studies of [Sr{Ta(OEt) 5 (dmae)} 2 ] and [Sr{Ta(OEt) 5 (mee)} 2 ] (mee = OCH 2 CH 2 OMe) for the growth of strontium-tantalate were carried out to assess precursor suitability for this technique. Liquid injection MOCVD of Bi-oxide films using Bi(mmp) 3 indicates similar decomposition behaviour to the Sr-Ta and Sr-Nb alkoxides, demonstrating its suitability as a complementary source of Bi for SBT, SBN and SBTN.

Liquid injection MOCVD and ALD studies of “single source” Sr-Nb and Sr-Ta precursors

Thin films of HfO 2 have been deposited by liquid-injection metal-organic (MO)CVD using two nitrogen-containing precursors [Hf(NMe 2 ) 4 ] and [Hf(ONEt 2 ) 4 ]. The [Hf(NMe 2 ) 4 ] precursor deposits oxide at lower growth temperatures and over a wider temperature range than [Hf(ONEt 2 ) 4 ]. Varying levels of residual carbon and nitrogen were detected in the films grown from each precursor. Analysis by X-ray diffraction (XRD) indicates that films grown from both precursors exist predominantly in the thermodynamically stable monoclinic phase. Scanning electron microscopy (SEM) shows that the morphology of the HfO 2 films from each precursor is markedly different, with films deposited from [Hf(NMe 2 ) 4 ] having a well-defined columnar crystalline structure, whereas films grown from [Hf(ONEt 2 ) 4 ] are smoother with little evidence of columnar structure. Full crystal structure data for [Hf(NMe 2 ) 4 ] are given, and the dielectric properties of [Al/HfO 2 /n-Si(100)] MOS capacitors, fabricated using each precursor, are also reported.

Growth of Hafnium Dioxide Thin Films by Liquid‐Injection MOCVD Using Alkylamide and Hydroxylamide Precursors

Bismuth titanate, Bi4Ti3O12, is a layered perovskite with a number of useful ferroelectric and electro-optic properties, and has potential applications in non-volatile memory devices and ferroelectric-effect transistors. MOCVD is a promising technique for the deposition of Bi4Ti3O12 which has applications in non-volatile ferroelectric computer memories. To exploit the full potential of the technique it is essential to employ precursors with the appropriate physical characteristics and decomposition behaviour. A variety of precursor combinations have been used for the MOCVD of Bi4Ti3O12, such as BiPh3 in combination with Ti(OPr)4 or BiMe3 with Ti(OPr)4, but these are poorly matched. In particular, the Bi precursor has a number of disadvantages, which has restricted progress in the development of a MOCVD process. For instance, BiPh3 has a significantly higher thermal stability than Ti alkoxides, which can cause problems in controlling compositional uniformity across the substrate, and although the less thermally stable complex BiMe3 has proved to be a better match to the Ti(OR)4 precursor, it is highly reactive and potentially explosive, which limits its widespread application. Simple bismuth alkoxides, Bi(OR)3 form low volatility polymeric [Bi(OR)3]n aggregates, unsuited to MOCVD, but the sterically hindered bidentate ligand [OCMe2CH2OMe] (mmp) is highly effective in reducing polymerisation in metal alkoxides and the complex Bi(mmp)3 is a volatile monomer. In this paper we report for the first time the use of Bi(mmp)3 for the liquid injection MOCVD of Bi4Ti3O12 thin films. We have also sought alternatives to conventional Ti(OR)4 precursors, as they are highly moisture sensitive due to their unsaturated 4-coordinate Ti centres. This can cause difficulty in handling and places stringent requirements on the purity and water content of the solvent in liquid injection MOCVD. Our initial investigation focused on [Ti(OPr)2(thd)2], which contains the chelating [thd] group, making it more fully saturated and less moisture sensitive than the parent Ti(OPr)4. Another approach to increasing the coordinative saturation of a metal alkoxide complex and reducing its moisture sensitivity is to introduce bidentate alkoxide ligands, such as [mmp] and in this paper we report the synthesis and characterisation of the new Ti alkoxides, Ti(OPr)2(mmp)2 and Ti(mmp)4 , both of which prove to be well matched to Bi(mmp)3 with similar physical properties and decomposition characteristics. A further advantage of the Bi(mmp)3 / Ti(mmp)4 precursor system is the presence of the same ligand in each complex, which can be expected to minimise unfavourable precursor interactions in solution. In this paper we describe the use of Bi(mmp)3 in combination with Ti(OPr)2(thd)2, Ti(OPr)2(mmp)2 and Ti(mmp)4 for the deposition of Bi4Ti3O12 by liquid injection MOCVD. Thermogravimetric analysis (TGA) (Fig. 1) showed that all complexes have well-matched volatilities, evaporating over a similar temperature range, with all complexes being fully evaporated at < 300C.

Development of Improved Precursors for the MOCVD of Bismuth Titanate

Thin films of ZrO 2 and HfO 2 have been deposited by liquid injection metal-organic (MO)CVD using a range of new alkoxide precursors, [Zr(O t Bu) 2 (mmp) 2 ] (1), [Hf(O t Bu) 2 (mmp) 2 ] (2), [Zr(mmp) 4 ] (3), and [Hf(mmp) 4 ] (4): (mmp = 1-methoxy-2-methyl-2-propanolate, OCMe 2 CH 2 OMe). The complexes are mononuclear and volatile, and are significantly less reactive to air and moisture than existing Zr and Hf alkoxide precursors such as [Zr(O t Bu) 4 ] and [Hf(O t Bu) 4 ]. The ZrO 2 and HfO 2 films were grown over a wide range of substrate temperatures (350-650 °C), and analysis by laser Raman spectroscopy shows that the films were deposited in the thermodynamically stable α- or monoclinic phase.

Novel Mononuclear Alkoxide Precursors for the MOCVD of ZrO2 and HfO2 Thin Films

Thin films of tantalum oxide and niobium oxide have been deposited by liquid injection MOCVD using solutions of Ta(OEt) 4 (dbm) (1) or Nb(OEt) 4 (dbm) (2) (dbm = dibenzoyl methanate = 1,3-diphenyl-1,3-propanedionate). The presence of the dbm ligand imparts unusual thermal stability to the complexes, allowing oxide films to be deposited at relatively high substrate temperatures (650°C and higher). Single-crystal X-ray diffraction (XRD) shows the complexes to be mononuclear, with distorted octahedral configurations.

The unusual thermal stabilization of MOCVD precursors by the dibenzoyl methanate group: Liquid injection MOCVD of tantalum oxide and niobium oxide using M(OEt)4(dbm) precursors

The alkoxide and alkylamide complexes [Hf(mmp)4] and [Hf(NMe2)4]2 are both promising precursors for the MOCVD of HfO2. A comparison has shown that [Hf(NMe2)4]2 deposits oxide at lower temperatures and over a wider temperature range then [Hf(mmp)4].

The novel complexes [Zr(OBut)2(OCMe2CH2OMe)2] 
(1) and [Hf(OBut)2(OCMe2CH2OMe)2] 
(2) are mononuclear and volatile, and are highly promising precursors for the deposition of zirconium dioxide and hafnium dioxide thin films by metalorganic chemical vapour deposition (MOCVD).

Novel mononuclear zirconium and hafnium alkoxides; improved precursors for the MOCVD of ZrO2 and HfO2

Atomic-Layer Deposition of ZrO2 Thin Films Using New Alkoxide Precursors

Characterization of Steady-State Wear in All-Alumina THR to 20 MC

The new titanium alkoxy–diolate precursors [Ti(OCH2CH2O)(OCH2CH2NMe2)2]2 
(1) and [Ti(OCMe2CMe2O)(OCH2CH2NMe2)2]2 
(2) have been prepared and structurally characterised by single crystal X-ray diffraction. Both compounds exhibit binuclear centrosymmetric structures with bridging alkoxide groups, containing two six-coordinate Ti atoms in distorted octahedral environments. In (1) the oxygen from the ethylene glycolate ligand is involved in bridging, whereas in (2) the bridging oxygen is provided by the dimethylamino ethoxide ligand. Complexes (1) and (2) are potential precursors for Ti-containing oxides and both complexes have been investigated as precursors for the deposition of TiO2 thin films by liquid injection metalorganic chemical vapour deposition (MOCVD). Significantly, only complex (2) led to reproducible TiO2 deposition in the temperature range 325–450 °C, whilst complex (1) exhibited a marked pre-reaction leading to highly irreproducible film growth. The difference in MOCVD behaviour between the complexes is rationalised in terms of their molecular structure.

Synthesis and crystal structures of two new titanium alkoxy-diolate complexes. Potential precursors for oxide ceramics

Abstract Liquid injection MOCVD is an attractive technique for the deposition of SrBi2Ta2O9 (SBT), SrBi2Nb2O9 (SBN) and SrBi2(Ta1-xNbx)2O9 (SBTN), but progress has been limited by a lack of suitable precursors. To alleviate the mismatch between the Sr and Ta or Nb precursors, “single-source” precursors such as Sr[Ta(OEt)6]2 and Sr[Nb(OEt)6]2 have been used, but these still have a tendency to dissociate in the vapour phase leading to an excess of the Ta or Sr component in the deposited film. The insertion of a donor functionalised ligand such as dimethylaminoethoxide (dmae) or bis-dmap into the complex leads to a more fully saturated Sr centre and binds the Sr atom more closely to the Ta or Nb atoms. In this paper we describe the development of the new single-source precursors, Sr[Ta(OEt)5(dmae)]2, Sr[Nb(OEt)5(dmae)]2 and Sr[Nb(OEt)5(bis-dmap)]2, and present structural data for each complex.

The polymerization reaction and its side reactions were investigated in the synthesis of 4-acetoxybenzoic acid (ABA) and 6-acetoxy-2-naphthoic acid (ANA) copolymers by the measurement of byproducts and polymer molecular weight and the study of polymer end groups and model reactions. A method was developed to isolate and collect the byproducts produced in the polymerization. These byproducts, acetic anhydride, phenol, phenyl acetate, ketene, and carbon dioxide, were detected using HPLC and GC/MS. The existence of acetoxy, carboxy, phenyl ester, and phenolic hydroxyl end groups on the polymer chain was confirmed by direct measurement of end groups and polymer molecular weight and by the study of model reactions, such as the decarboxylation of 4-(benzoyloxy)benzoic acid and the decomposition of ABA methyl ester. For the bulk copolymerization of ABA and ANA at temperatures ranging from 195 to 325 °C under nitrogen, the classical acidolysis mechanism changes to a phenolysis mechanism in the late stages of the ...

A Change in Mechanism from Acidolysis to Phenolysis in the Bulk Copolymerization of 4-Acetoxybenzoic Acid and 6-Acetoxy-2-naphthoic Acid

Kinetics of the initial stages of the bulk polymerization of 4-acetoxybenzoic acid (ABA) and 6-acetoxy-2-naphthoic acid (ANA) were investigated. A method to analyze the kinetics by measuring the amount of evolved acetic acid trapped in a sodium hydroxide solution by titrimetry was developed. All polymerizations followed second-order reaction kinetics up to 70% conversion. Two kinetic regions were observed in the homopolymerization of ABA and copolymerization of ABA and ANA in the melt, visible by a break in the time−conversion curve. The average degree of polymerization at the change of mechanism point from a homogeneous to a heterogeneous system was 3.5. The time of the change in mechanism and the reaction rate were dependent on the temperature and the initial concentration ratio of ABA and ANA used in the polymerization. The higher the temperature and the concentration of ABA, the earlier the break takes place and the faster the reaction proceeds. The corresponding reaction rate constants and activation...

Kinetics of the Polymerization of 4-Acetoxybenzoic Acid and 6-Acetoxy-2-naphthoic Acid

A novel synthetic route to poly(quinone imines) has been developed. Reaction of anthraquinone (AQ) with aromatic diamines in the presence of TiCl 4 and DABCO as base in refluxing chloro- or o-dichlorobenzene led to high molecular weight polymers with the poly(quinone diimine) structure. Polymerization of AQ with methylene-4,4'-dianiline resulted in a mixture of high molecular weight polymer (M w 15 000) and oligomeric macrocycles. The polymerization of AQ was also accomplished with 4,4'-oxy- and 4,4'-thiodianiline, as well as with p-phenylenediamine. The latter polymer is the dibenzo analog of the pernigraniline base form of polyaniline. tert-Butylanthraquinone was also successfuly used as a comonomer with the various aromatic diamines. All these polymers are red in color, soluble in organic solvents, and film-forming. Polymerizations of the aromatic diamines with heterocyclic-substituted benzoquinones, such has benzo[1,2-b:4,5-b']dithiophene-4,8-dione, 2,2'-dialkylbenzo[1,2-d:5,4-d']dioxazole-4,8-dione, and N,N',2,2'-tetraalkylbenzo[1,2-d:5,4-d']imidazole-4,8-dione, were also investigated

The structures of model compounds for the polyaromatic quinone diimine polymers were determined. These polymers were obtained by polycondensation of tricyclic quinones with aromatic diamines in the presence of TiCl 4 and DABCO. The N-phenyldiimine and monoimine derivatives of the following quinones were synthesized: naphthoquinone, 2-methyl- and 2-tert-butyloxazolonaphthoquinone, 2,2'-dimethylbis(oxazolo)benzoquinone, and bisthiophenobenzoquinone. X-ray single-crystal structure determinations are reported for the following derivatives: N,N'-bis(p-fluorophenyl)naphthoquinone 1,4-diimine, N-phenyl-2-tert-butylnaphtho[2,3-d]oxazole-4,9-dione 4-imine and 9-imine, N-(p-fluorophenyl)-2-tert-butylnaphtho[2,3-d]oxazole-9-one 4-imine, N-phenyl-2-isobutylnaphtho[2,3-d]oxazole-9-one diimine, and N,N'-diphenylbenzo[1,2-b:4,5-b']dithiophene-4,8-dione diimine. The following common features are observed for these structures: the central ring systems are planar in contrast to the anthraquinone diimine derivatives in which the central ring system is buckled, the N-phenyl ring is twisted out of the plane of the central ring system, and the N-phenyl rings are twisted toward the ring with the heteroatom and away from the C-H group on the adjacent ring. Molecular modeling calculations are found to be in agreement with the X-ray structures. The implications of the crystal structures of the model compounds for the polymeric structures are discussed

Synthesis and structure of heterocyclic quinone arylimines as model compounds for polyaromatic quinone imines

The clean synthesis of soluble, tractable, moderately high molecular weight poly(arylanthraquinone imines) via the condensation between aromatic diamines and anthraquinone is described.

CONTEXT/OBJECTIVE
The risk for cardiovascular disease is amplified following spinal cord injury, but whether risk differs between the sexes remains unknown. Here, we evaluated sex differences in the prevalence of heart disease among individuals with spinal cord injury, and compared sex differences with able-bodied individuals.

DESIGN
The design was a cross-sectional study. Multivariable logistic regression analysis was conducted, using inverse probability weighting to account for the sampling method and to adjust for confounders.

SETTING
Canada.

Individuals who participated in the national Canadian Community Health Survey.

Not applicable.

OUTCOME MEASURES
Self-reported heart disease.

RESULTS
Among 354 individuals with spinal cord injury, the weighted prevalence of self-reported heart disease was 22.9% in males and 8.7% in females, with an inverse-probability weighted odds ratio of 3.44 (95% CI 1.70-6.95) for males versus females. Among 60,605 able-bodied individuals, the prevalence of self-reported heart disease was 5.8% in males and 4.0% in females, with an inverse probability weighted odds ratio of 1.62 (95% CI 1.50-1.75) for males versus females. The effect of male sex on increasing heart disease prevalence was about two times higher among individuals with spinal cord injury than able-bodied individuals (relative difference in inverse probability weighted odds ratios = 2.12, 95% CI 1.08-4.51).

Males with spinal cord injury exhibit a significantly higher prevalence of heart disease, compared with females with spinal cord injury. Moreover, relative to able-bodied individuals, spinal cord injury amplifies sex-related differences in heart disease. Overall, this work will inform targeted cardiovascular prevention strategies, and may also inform a better understanding of cardiovascular disease progression in both able-bodied and individuals with spinal cord injury.

Sex differences in heart disease prevalence among individuals with spinal cord injury: A population-based study.

. Chronic high‐level spinal cord injury (SCI) results in a complex phenotype of cardiovascular consequences, notably impairments to cardiac contractile function and baroreflex control of blood pressure. Recently, our group has demonstrated that hemodynamic management targeting the heart (i.e. dobutamine, DOB), rather than standard vasopressor treatment (i.e. norepinephrine, NE) improves cord oxygenation and mitigates hemorrhage in a porcine model of acute T2 SCI. Yet, the potential long‐term cardiovascular benefits of acute cardio‐centric hemodynamic management remain elusive.

Preserved Cardio‐Inotropic Baroreflex Function Following Optimized Hemodynamic Management in High‐Thoracic Spinal Cord Injury

Spinal cord injury impairs cardiac function due to impaired bulbospinal sympathetic control

Over the last 100 years, high‐altitude researchers have amassed a comprehensive understanding of the global cardiac responses to acute, prolonged and lifelong hypoxia. When lowlanders are exposed to hypoxia, the drop in arterial oxygen content demands an increase in cardiac output, which is facilitated by an elevated heart rate at the same time as ventricular volumes are maintained. As exposure is prolonged, haemoconcentration restores arterial oxygen content, whereas left ventricular filling and stroke volume are lowered as a result of a combination of reduced blood volume and hypoxic pulmonary vasoconstriction. Populations native to high‐altitude, such as the Sherpa in Asia, exhibit unique lifelong or generational adaptations to hypoxia. For example, they have smaller left ventricular volumes compared to lowlanders despite having larger total blood volume. More recent investigations have begun to explore the mechanisms underlying such adaptive responses by combining novel imaging techniques with interventions that manipulate cardiac preload, afterload, and/or contractility. This work has revealed the contributions and interactions of (i) plasma volume constriction; (ii) sympathoexcitation; and (iii) hypoxic pulmonary vasoconstriction with respect to altering cardiac loading, or otherwise preserving or enhancing biventricular systolic and diastolic function even amongst high altitude natives with excessive erythrocytosis. Despite these advances, various areas of investigation remain understudied, including potential sex‐related differences in response to high altitude. Collectively, the available evidence supports the conclusion that the human heart successfully adapts to hypoxia over the short‐ and long‐term, without signs of myocardial dysfunction in healthy humans, except in very rare cases of maladaptation.

A change of heart: Mechanisms of cardiac adaptation to acute and chronic hypoxia

The assessment of left ventricular (LV) contractility in animal models is useful in various experimental paradigms, yet obtaining such measures is inherently challenging and surgically invasive. In a cross‐species study using small and large animals, we comprehensively tested the agreement and validity of multiple single‐beat surrogate metrics of LV contractility against the field‐standard metrics derived from inferior vena cava occlusion (IVCO). Fifty‐six rats, 27 minipigs and 11 conscious dogs underwent LV and arterial catheterization and were assessed for a range of single‐beat metrics of LV contractility. All single‐beat metrics were tested for the various underlying assumptions required to be considered a valid metric of cardiac contractility, including load‐independency, sensitivity to inotropic stimulation, and ability to diagnose contractile dysfunction in cardiac disease. Of all examined single‐beat metrics, only LV maximal pressure normalized to end‐diastolic volume (EDV), end‐systolic pressure normalized to EDV, and the maximal rate of rise of the LV pressure normalized to EDV showed a moderate‐to‐excellent agreement with their IVCO‐derived reference measure and met all the underlying assumptions required to be considered as a valid cardiac contractile metric in both rodents and large‐animal models. Our findings demonstrate that single‐beat metrics can be used as a valid, reliable method to quantify cardiac contractile function in basic/preclinical experiments utilizing small‐ and large‐animal models

A cross‐species validation of single‐beat metrics of cardiac contractility

What is the central question of this study? How does hypoxic pulmonary vasoconstriction and the response to supplemental oxygen change over time at high altitude? What is the main finding and its importance? Lowlanders and partially de‐acclimatized Sherpa both demonstrated pulmonary vascular responsiveness to supplemental oxygen that was maintained for 12 days’ exposure to progressively increasing altitude. An additional 2 weeks’ acclimatization at 5050 m altitude rendered the pulmonary vasculature minimally responsive to oxygen similar to the fully acclimatized non‐ascent Sherpa. Additional hypoxic exposure at that time point did not augment hypoxic pulmonary vasoconstriction.

Pulmonary vascular reactivity to supplemental oxygen in Sherpa and lowlanders during gradual ascent to high altitude

Cervical spinal cord injury (C‐SCI) negatively impacts cardiac and respiratory function. As the heart and lungs are linked via the pulmonary circuit these systems are interdependent. Here, we utilized inspiratory and expiratory loading to assess whether augmenting the respiratory pump improves left‐ventricular (LV) filling and output in individuals with motor‐complete C‐SCI. We hypothesized LV end‐diastolic volume (LVEDV) would increase and decrease with inspiratory and expiratory loading, respectively. Participants (C‐SCI: 7M/1F, 35 ± 7 years; able‐bodied: 7M/1F, 32 ± 6 years) were assessed under five conditions during 45° head‐up tilt; unloaded, inspiratory loading with −10 and −20 cmH2O oesophageal pressure (Poes) on inspiration, and expiratory loading with +10 and +20 cmH2O Poes on expiration. An oesophageal balloon catheter monitored Poes, and LV structure and function were assessed by echocardiography. In C‐SCI only, (1) +20 cmH2O reduced LVEDV vs. unloaded (81 ± 15 vs. 88 ± 11 ml, P = 0.006); (2) heart rate was higher during +20 cmH2O compared to unloaded (P = 0.001) and +10 cmH2O (P = 0.002); (3) cardiac output was higher during +20 cmH2O than unloaded (P = 0.002); and (4) end‐expiratory lung volume was higher during +20 cmH2O vs. unloaded (63 ± 10 vs. 55 ± 13% total lung capacity, P = 0.003) but was unaffected by inspiratory loading. In both groups, −10 and −20 cmH2O had no significant effect on LVEDV. These findings suggest greater expiratory positive pressure acutely impairs LV filling in C‐SCI, potentially via impaired venous return, mediastinal constraint and/or direct ventricular interaction subsequent to dynamic hyperinflation. Inspiratory loading did not significantly improve LV function in C‐SCI and neither inspiratory nor expiratory loading affected cardiac function or lung volumes in able‐bodied participants.

Influence of respiratory loading on left‐ventricular function in cervical spinal cord injury

Background Spinal cord injury (SCI) leads to a loss of descending motor and sympathetic control below the level of injury (LOI), which ultimately results in chronically altered cardiovascular function and remodeling. While supervised, laboratory-based exercise training can generate cardiovascular adaptations in people with SCI, it is unknown whether behavioral community-based interventions effectively generate such adaptations for individuals with SCI. Objective Examine the effects of a tailored behavioral physical activity (PA) intervention on cardiac and vascular structure and function in individuals with SCI. Methods In this randomized controlled trial, 32 participants with SCI (18-65 years, SCI >1 year) were assigned to PA (8-week behavioral intervention) or control (CON) groups. At baseline and postintervention, measures of resting left ventricular (LV) structure and function, carotid intima-media thickness and pulse-wave velocity were assessed with ultrasound and tonometry. Results Twenty-eight participants completed the study (n = 14/group). Across the full study cohort there were no significant changes in indices of LV or vascular structure and function, despite notable improvements in peak power and oxygen uptake in the PA group. However, in a subanalysis for LOI, individuals in the PA group with LOIs below T6 had evidence of altered LV geometry (ie, increased LV internal diameter, reduced sphericity index and relative wall thickness; group × time P < 0.05 for all), which was not seen in individuals with higher LOIs at or above T6. Conclusion An 8-week behavioral PA intervention appears to promote adaptations in cardiac geometry more readily in individuals with lower level SCI than those with higher-level SCI.

Effects of a Tailored Physical Activity Intervention on Cardiovascular Structure and Function in Individuals With Spinal Cord Injury

The high-altitude maladaptation syndrome known as chronic mountain sickness (CMS) is characterized by polycythemia and is associated with proteinuria despite unaltered glomerular filtration rate. However, it remains unclear if indigenous highlanders with CMS have altered volume regulatory hormones. We assessed N-terminal pro-B-type natriuretic peptide (NT pro-BNP), plasma aldosterone concentration, plasma renin activity, kidney function (urinary microalbumin, glomerular filtration rate), blood volume, and estimated pulmonary artery systolic pressure (ePASP), in Andean males without (n=14; age=39±11) and with (n=10; age=40±12) CMS at 4330 meters (Cerro de Pasco, Peru). Plasma renin activity (non-CMS: 15.8±7.9 vs. CMS: 8.7±5.4 ng/ml; p=0.025) and plasma aldosterone concentration (non-CMS: 77.5±35.5 vs. CMS: 54.2±28.9 pg/ml; p=0.018) were lower in highlanders with CMS compared to non-CMS, while NT pro-BNP was not different between groups (non-CMS: 1394.9±214.3 vs. CMS: 1451.1±327.8 pg/ml; p=0.15). Highlanders had similar total blood volume (non-CMS: 90±15 vs. CMS: 103±18 ml • kg-1; p=0.071), but Andeans with CMS had greater total red blood cell volume (non-CMS: 46±10 vs. CMS 66±14 ml • kg-1; p<0.01) and smaller plasma volume (non-CMS 43±7 vs. CMS 35±5 ml • kg-1; p=0.03) compared to non-CMS. There were no differences in ePASP between groups (non-CMS 32±9 vs. CMS 31±8 mmHg; p=0.6). A negative correlation was found between plasma renin activity and glomerular filtration rate in both groups (group: r=-0.66; p<0.01; non-CMS: r=-0.60; p=0.022; CMS: r=-0.63; p=0.049). A smaller plasma volume in Andeans with CMS may indicate an additional CMS maladaptation to high-altitude, causing potentially greater polycythemia and clinical symptoms.

American journal of physiology. Regulatory, integrative and comparative physiology

Global REACH 2018: Volume regulation in high-altitude Andeans with and without chronic mountain sickness.

Haemoconcentration can influence hypoxic pulmonary vasoconstriction (HPV) via increased frictional force and vasoactive signalling from erythrocytes, but whether the balance of these mechanism is modified by the duration of hypoxia remains to be determined. We performed three sequential studies: (i) at sea level, in normoxia and isocapnic hypoxia with and without isovolumic haemodilution (n=10, aged 29±7 years); (ii) at altitude (6±2 days acclimatization at 5050 m), before and during hypervolumic haemodilution (n=11, aged 27±5 years) with room air and additional hypoxia (FiO2 = 0.15), and; (iii) at altitude (4340 m) in Andean high-altitude natives with excessive erythrocytosis (EE; n=6, aged 39±17 years), before and during isovolumic haemodilution with room air and hyperoxia (end-tidal PO2 = 100 mmHg). Results: At sea level, haemodilution mildly increased pulmonary artery systolic pressure (PASP; +1.6±1.5 mmHg, P=0.01) and pulmonary vascular resistance (PVR; +0.7±0.8 wu, P=0.04). In contrast, after acclimation to 5050 m, haemodilution did not significantly alter PASP (22.7±5.2 vs. 24.5±5.2 mmHg, P=0.14) or PVR (2.2±0.9 vs. 2.3±1.2 wu, p=0.77), although both remained sensitive to additional acute hypoxia. In Andeans with EE at 4340 m, haemodilution lowered PVR in room air (2.9±0.9 vs. 2.3±0.8 wu, P=0.03), but PASP remained unchanged (31.3±6.7 vs. 30.9±6.9 mmHg, P=0.80) due to an increase in cardiac output. Collectively, our series of studies reveal that HPV is modified by the duration of exposure and the prevailing haematocrit level. In application, these findings emphasize the importance of accounting for haematocrit and duration of exposure when interpreting the pulmonary vascular responses to hypoxemia.

American journal of physiology. Heart and circulatory physiology

The influence of hemoconcentration on hypoxic pulmonary vasoconstriction in acute, prolonged and life-long hypoxemia.

End‐systolic elastance (Ees) derived from sequential pressure‐volume (PV) loops acquired during inferior vena cava occlusion (IVCO) is the reference for quantification of in vivo left ventricular (LV) contractile performance. Given the challenges associated with midline laparotomy surgeries in animal models and the barriers of performing such measures in clinical practice, a number of single‐beat estimations of LV contractile function have been proposed. Here, we examined the agreement between two single‐beat estimates of Ees obtained from basal LV and arterial hemodynamics in rats and pigs and the Ees obtained from IVCO (Ees(IVC)). We also tested whether a novel approach of leveraging the respiratory‐induced oscillations in cardiac PV (i.e., changes in intrathoracic pressure) during mechanical ventilation enables a “naturally” occurring change in cardiac preload and the subsequent estimation of Ees (Ees(RES)).

Validity of Assessing in vivo Cardiac Contractility Using A “Less‐Invasive” Approach during Mechanical Ventilation: Insights from Small and Large Animal Models

Iron acts as a cofactor in the stabilization of the hypoxic‐inducible factor family, and plays an influential role in the modulation of hypoxic pulmonary vasoconstriction. It is uncertain whether iron regulation is altered in lowlanders during either (1) ascent to high altitude, or (2) following partial acclimatization, when compared to high‐altitude adapted Sherpa. During ascent to 5050 m, the rise in pulmonary artery systolic pressure (PASP) was blunted in Sherpa, compared to lowlanders; however, upon arrival to 5050 m, PASP levels were comparable in both groups, but the reduction in iron bioavailability was more prevalent in lowlanders compared to Sherpa. Following partial acclimatization to 5050 m, there were differential influences of iron status manipulation (via iron infusion or chelation) at rest and during exercise between lowlanders and Sherpa on the pulmonary vasculature.

Influence of iron manipulation on hypoxic pulmonary vasoconstriction and pulmonary reactivity during ascent and acclimatization to 5050 m

Commentaries on Point:Counterpoint: Investigators should/should not control for menstrual cycle phase when performing studies of vascular control.

Cardio-centric hemodynamic management improves spinal cord oxygenation and mitigates hemorrhage in acute spinal cord injury

Left ventricular (LV) twist mechanics are augmented with both acute and chronic hypoxemia. Although the underlying mechanisms remain unknown, sympathetic activation and a direct effect of hypoxemia on the myocardium have been proposed, the latter of which may produce subendocardial dysfunction that is masked by larger subepicardial torque. This study therefore sought to (1) determine the individual and combined influences of β1-AR (β1-adrenergic receptor) stimulation and peripheral O2 saturation (Spo2) on LV twist in acute and chronic hypoxia and (2) elucidate whether endocardial versus epicardial mechanics respond differently to hypoxia.

METHODS
Twelve males (27±4 years) were tested near sea level in acute hypoxia (Spo2=82±4%) and following 3 to 6 days at 5050 m (high altitude; Spo2=83±3%). In both settings, participants received infusions of β1-AR blocker esmolol and volume-matched saline (double-blind, randomized). LV mechanics were assessed with 2-dimensional speckle-tracking echocardiography, and region-specific analysis to compare subendocardial and subepicardial mechanics.

RESULTS
At sea level, compared with baseline (14.8±3.0°) LV twist was reduced with esmolol (11.2±3.3°; P=0.007) and augmented during hypoxia (19.6±4.9°; P<0.001), whereas esmolol+hypoxia augmented twist compared with esmolol alone (16.5±3.3°; P<0.001). At 5050 m, LV twist was increased compared with sea level (19.5±5.4°; P=0.004), and reduced with esmolol (13.0±3.8°; P<0.001) and Spo2 normalization (12.8±3.4°; P<0.001). Moreover, esmolol+normalized Spo2 lowered twist further than esmolol alone (10.5±3.1°; P=0.036). There was no mechanics-derived evidence of endocardial dysfunction with hypoxia at sea level or high altitude.

These findings suggest LV twist is augmented in hypoxia via β1-AR-dependent and β1-AR-independent mechanisms (eg, α1-AR stimulation), but does not appear to reflect endocardial dysfunction.

Left Ventricular Twist Is Augmented in Hypoxia by β1-Adrenergic-Dependent and β1-Adrenergic-Independent Factors, Without Evidence of Endocardial Dysfunction.

In contrast to Andean natives, high-altitude Tibetans present with a lower hemoglobin concentration that correlates with reproductive success and exercise capacity. Decades of physiological and genomic research have assumed that the lower hemoglobin concentration in Himalayan natives results from a blunted erythropoietic response to hypoxia (i.e., no increase in total hemoglobin mass). In contrast, herein we test the hypothesis that the lower hemoglobin concentration is the result of greater plasma volume, rather than an absence of increased hemoglobin production. We assessed hemoglobin mass, plasma volume and blood volume in lowlanders at sea level, lowlanders acclimatized to high altitude, Himalayan Sherpa, and Andean Quechua, and explored the functional relevance of volumetric hematological measures to exercise capacity. Hemoglobin mass was highest in Andeans, but also was elevated in Sherpa compared with lowlanders. Sherpa demonstrated a larger plasma volume than Andeans, resulting in a comparable total blood volume at a lower hemoglobin concentration. Hemoglobin mass was positively related to exercise capacity in lowlanders at sea level and in Sherpa at high altitude, but not in Andean natives. Collectively, our findings demonstrate a unique adaptation in Sherpa that reorientates attention away from hemoglobin concentration and toward a paradigm where hemoglobin mass and plasma volume may represent phenotypes with adaptive significance at high altitude.

The overlooked significance of plasma volume for successful adaptation to high altitude in Sherpa and Andean natives

What is the central question of this study? The aim was to evaluate the degree to which increases in haematocrit alter cerebral blood flow and cerebral oxygen delivery during acclimatization to high altitude. What is the main finding and its importance? Through haemodilution, we determined that, after 1 week of acclimatization, the primary mechanism contributing to the cerebral blood flow response during acclimatization is an increase in haemoglobin and haematocrit. The remaining contribution to the cerebral blood flow response during acclimatization is likely to be attributable to ventilatory acclimatization.

UBC‐Nepal Expedition: Haemoconcentration underlies the reductions in cerebral blood flow observed during acclimatization to high altitude

We have developed a novel porcine model of high‐thoracic midline contusion spinal cord injury (SCI) at the T2 spinal level. We describe this model and the ensuing cardiovascular and neurohormonal responses, and demonstrate the model is efficacious for studying clinically relevant cardiovascular dysfunction post‐SCI. We demonstrate that the high‐thoracic SCI model, but not a low‐thoracic SCI model, induces persistent hypotension along with a gradual reduction in plasma noradrenaline and increases in plasma aldosterone and angiotensin II. We additionally conducted a proof‐of‐concept long‐term (12 weeks) survival study in animals with T2 contusion SCI demonstrating the potential utility of this model for not only acute experimentation but also long‐term drug studies prior to translation to the clinic.

A porcine model for studying the cardiovascular consequences of high‐thoracic spinal cord injury

The effect of combined inspiratory and expiratory muscle training on resting and reflexive cardiac function, as well as exercise capacity, in individuals with cervical spinal cord injury (SCI) is presently unknown. Six weeks of combined inspiratory and expiratory muscle training enhances both inspiratory and expiratory muscle strength in highly‐trained athletes with cervical SCI with no significant effect on lung function. There was a significant decrease in left‐ventricular filling and stroke volume at rest in response to 45° head‐up tilt, which is irreversible by respiratory muscle training. Combined inspiratory and expiratory muscle training increased peak aerobic work rate and reduced end‐expiratory lung volumes during exercise, which may have implications for left‐ventricular filling during exercise.

Respiratory muscle training in athletes with cervical spinal cord injury: effects on cardiopulmonary function and exercise capacity

It remains unclear if the human coronary vasculature is inherently sensitive to changes in arterial Po2 and Pco2 or if coronary vascular responses are the result of concomitant increases in myocardial O2 consumption/demand ([Formula: see text]). We hypothesized that the coronary vascular response to Po2 and Pco2 would be attenuated in healthy men when [Formula: see text] was attenuated with β1-adrenergic receptor blockade. Healthy men (age: 25 ± 1 yr, n = 11) received intravenous esmolol (β1-adrenergic receptor antagonist) or volume-matched saline in a double-blind, randomized crossover study and were exposed to poikilocapnic hypoxia, isocapnic hypoxia, and hypercapnic hypoxia. Measurements made at baseline and after 5 min of steady state at each gas manipulation included left anterior descending coronary blood velocity (LADV; Doppler echocardiography), heart rate, and arterial blood pressure. LADV values at the end of each hypoxic condition were compared between esmolol and placebo. The rate-pressure product (RPP) and left ventricular mechanical energy (MELV) were calculated as indexes of [Formula: see text]. All gas manipulations augmented RPP, MELV, and LADV, but only RPP and MELV were attenuated (4-18%) after β1-adrenergic receptor blockade ( P < 0.05). Despite attenuated RPP and MELV responses, β1-adrenergic receptor blockade did not attenuate the mean LADV vasodilatory response compared with placebo during poikilocapnic hypoxia (29.4 ± 2.2 vs. 27.3 ± 1.6 cm/s) and isocapnic hypoxia (29.5 ± 1.5 vs. 30.3 ± 2.2 cm/s). Hypercapnic hypoxia elicited a feedforward coronary dilation that was blocked by β1-adrenergic receptor blockade. These results indicate a direct influence of arterial Po2 on coronary vascular regulation that is independent of [Formula: see text]. NEW & NOTEWORTHY In humans, arterial hypoxemia led to an increase in epicardial coronary artery blood velocity. β1-Adrenergic receptor blockade did not diminish the hypoxemic coronary response despite reduced myocardial O2 demand. These data indicate hypoxemia can regulate coronary blood flow independent of myocardial O2 consumption. A plateau in the mean left anterior descending coronary artery blood velocity-rate-pressure product relationship suggested β1-adrenergic receptor-mediated, feedforward epicardial coronary artery dilation. In addition, we observed a synergistic effect of Po2 and Pco2 during hypercapnic hypoxia.

Influence of myocardial oxygen demand on the coronary vascular response to arterial blood gas changes in humans.

Left ventricular (LV) twist mechanics differ between men and women during acute physiological stress, which may be partly mediated by sex differences in autonomic control. While men appear to have greater adrenergic control of LV twist, the potential contribution of vagal modulation to sex differences in LV twist remains unknown. Therefore, the present study examined the role of vagal control on sex differences in LV twist during graded lower body negative pressure (LBNP) and supine cycling. On two separate visits, LV mechanics were assessed using two-dimensional speckle-tracking echocardiography in 18 men (22 ± 2 yr) and 17 women (21 ± 4 yr) during -40- and -60-mmHg LBNP and 25% and 50% of peak supine cycling workload with and without glycopyrrolate (vagal blockade). LV twist was not different at baseline but was greater in women during -60 mmHg in both control (women: 16.0 ± 3.4° and men: 12.9 ± 2.3°, P = 0.004) and glycopyrrolate trials (women: 17.7 ± 5.9° and men: 13.9 ± 3.3°, P < 0.001) due to greater apical rotation during control (women: 11.9 ± 3.6° and men: 7.8 ± 1.5°, P < 0.001) and glycopyrrolate (women: 11.6 ± 4.9° and men: 7.1 ± 3.6°, P = 0.009). These sex differences in LV twist consistently coincided with a greater LV sphericity index (i.e., ellipsoid geometry) in women compared with men. In contrast, LV twist did not differ between the sexes during exercise with or without glycopyrrolate. In conclusion, women have augmented LV twist compared with men during large reductions to preload, even during vagal blockade. As such, differences in vagal control do not appear to contribute to sex differences in the LV twist responses to physiological stress, but they may be related to differences in ventricular geometry. NEW & NOTEWORTHY This is the first study to specifically examine the role of vagal autonomic control on sex-related differences in left ventricular (LV) mechanics. Contrary to our hypothesis, vagal control does not appear to primarily determine sex differences in LV mechanical or hemodynamic responses to acute physiological stress. Instead, differences in LV geometry may be a more important contributor to sex differences in LV mechanics.

Influence of vagal control on sex-related differences in left ventricular mechanics and hemodynamics.

Friends in high places: Researchers go global to reach for answers at high altitude

Association of Epidural Stimulation With Cardiovascular Function in an Individual With Spinal Cord Injury The application of epidural electrical stimulation to the lumbosacral spinal cord in individuals with a spinal cord injury (SCI) facilitates supraspinal control of paralyzed limbs.1 There is a growing interest in studying whether epidural stimulation can be leveraged to also abrogate cardiovascular dysfunction, as evidenced by ongoing randomized clinical trials on this topic (NCT02037620; NCT03026816). Here, we investigated whether lumbosacral epidural stimulation could be optimized to control cardiovascular functions in the short term, a top health priority and primary cause of death,2 in 1 individual with a motorcomplete cervical SCI. Methods | A man in his early 30s with a chronic C5 motorcomplete SCI (ASIA impairment scale B) who was previously (12 months prior) fitted with an epidural spinal cord stimulation unit and 16-electrode array (Restore-ADVANCED and Specify 5-6-5; Medtronic) at T11-L1 vertebral levels was assessed. The placement was confirmed via radiography (Figure 1A). The participant gave his written informed consent. This study was approved by the University of British Columbia Clinical Research Ethics Board. We first conducted a series of tests (over 2 weeks) to determine the optimum stimulation parameters to increase blood pressure (BP) in the seated position, ultimately selecting a widefield stimulation configuration (Figure 1A; frequency, 35 Hz; pulse width, 300 milliseconds; intensity, 3.5 V). On the main experimental day, we assessed beat-by-beat BP via finger photoplethysmography (Finometer PRO; Finapres Medical Sys-

Association of Epidural Stimulation With Cardiovascular Function in an Individual With Spinal Cord Injury

Objective Conduct a meta-analysis to determine the impact of traumatic spinal cord injury (SCI) on echocardiographic measurements of left ventricular (LV) structure and function. Methods MEDLINE and Embase were used for primary searches of studies reporting LV echocardiographic data in individuals with SCI. Of 378 unique citations, 36 relevant full-text articles were retrieved, and data from 27 studies were extracted for meta-analyses. Literature searches, article screening and data extraction were completed by two independent reviewers and compared for agreement. Primary analyses compared echocardiographic indices between individuals with SCI and able-bodied individuals, using a random effects model. Results Data are reported as pooled effect estimates (95% CI). Data from 22 articles (474 participants) were included in the primary meta-analysis. Compared with able-bodied individuals, individuals with SCI had reductions to LV stroke volume of 11.8 mL (95% CI −17.8 to −5.9, p<0.001), end-diastolic volume of 19.6 mL (95% CI −27.2 to −11.9, p<0.001) and LV massindex of −7.7 g/m2 (95% CI −11.6 to −3.8, p<0.001), but ejection fraction was not different between the groups (95% CI −2.6% to 0.6%, p=0.236). Individuals with SCI also had altered indices of diastolic function, specifically a lowered ratio of early-to-late filling velocities (p=0.039), and augmented ratio of early diastolic flow-to-tissue velocities (p=0.021). Conclusions Individuals with SCI have smaller LV volumes and mass, and altered systolic and diastolic function. While this meta-analysis demonstrates important alterations to echocardiographic measures of cardiac structure and function at rest, future work should consider the impacts of SCI on the heart’s capacity or ‘reserve’ to respond to physiological challenges. PROSPERO registration number CRD42017072333.

Cardiac consequences of spinal cord injury: systematic review and meta-analysis

Volume loading increases left ventricular (LV) stroke volume (LVSV) through series interaction, but may paradoxically reduce LVSV in the presence of large increases in right ventricular (RV) afterload because of direct ventricular interaction (DVI). RV afterload is often increased in chronic obstructive pulmonary disease (COPD) as a result of pathological changes to respiratory mechanics, namely increased negative intrathoracic pressure (nITP), dynamic lung hyperinflation (DH), and increased pulmonary vascular resistance (PVR). These hallmarks of COPD negatively impact LV hemodynamics in normovolemia. However, it is unknown how these heart-lung interactions are impacted by acute volume loading. Twenty healthy subjects (23 ± 2 yr) completed the study protocol, involving acute volume loading via 20° head-down tilt (HDT) in isolation and with 1) inspiratory resistance of -20 cmH2O (HDT+nITP) and 2) nITP, expiratory resistance to induce DH and hypoxic-mediated increases in PVR (HDT+COPD model). LV volumes and geometry were assessed using triplane echocardiography. HDT significantly increased LVSV by 10 ± 10% through an 8 ± 6% increase in LV end-diastolic volume (LVEDV). HDT+nITP paradoxically decreased LVSV by 11 ± 12% and LVEDV by 6 ± 9% from supine baseline, or -14 ± 10% LVSV and -15 ± 13% LVEDV from HDT (P < 0.001). HDT+COPD model decreased LVSV (21 ± 10% and 28 ± 11%) and LVEDV (16 ± 10% and 22 ± 10%) from both supine and HDT, respectively (P < 0.001). Under all conditions, significant septal flattening (increased radius of septal curvature) occurred, indicating DVI. Thus, when RV afterload is increased and/or an external constraint to ventricular filling exists, acute volume loading appears to paradoxically reduce LVSV. These findings have important implications for understanding how volume status impacts cardiopulmonary interactions in COPD.NEW & NOTEWORTHY Volume loading may exacerbate adverse cardiopulmonary interaction in COPD; however, the mechanisms remain unclear. We found that when negative intrathoracic pressure is increased, acute volume loading paradoxically reduces stroke volume. This reduction in stroke volume is considerably greater in a model of COPD, owing to the effects of lung hyperinflation.

Acute volume loading exacerbates direct ventricular interaction in a model of COPD.

Sex differences in left ventricular (LV) mechanics occur during acute physiological challenges; however, it is unknown whether sex differences in LV mechanics are fundamentally regulated by differences in adrenergic control. Using two‐dimensional echocardiography and speckle tracking analysis, this study compared LV mechanics in males and females matched for LV length during post‐exercise ischaemia (PEI) and β1‐adrenergic receptor blockade. Our data demonstrate that while basal rotation was increased in males, LV twist was not significantly different between the sexes during PEI. In contrast, during β1‐adrenergic receptor blockade, LV apical rotation, twist and untwisting velocity were reduced in males compared to females. Significant relationships were observed between LV twist and LV internal diameter and sphericity index in females, but not males. These findings suggest that LV twist mechanics may be more sensitive to alterations in adrenergic stimulation in males, but more highly influenced by ventricular structure and geometry in females.

The influence of adrenergic stimulation on sex differences in left ventricular twist mechanics

Our aim was to quantify the end-tidal-to-arterial gas gradients for O2 (PET-PaO2) and CO2 (Pa-PETCO2) during a CO2 reactivity test to determine their influence on the cerebrovascular (CVR) and ventilatory (HCVR) response in subjects with (PFO+, n = 8) and without (PFO-, n = 7) a patent foramen ovale (PFO). We hypothesized that 1) the Pa-PETCO2 would be greater in hypoxia compared with normoxia, 2) the Pa-PETCO2 would be similar, whereas the PET-PaO2 gradient would be greater in those with a PFO, 3) the HCVR and CVR would be underestimated when plotted against PETCO2 compared with PaCO2, and 4) previously derived prediction algorithms will accurately target PaCO2. PETCO2 was controlled by dynamic end-tidal forcing in steady-state steps of -8, -4, 0, +4, and +8 mmHg from baseline in normoxia and hypoxia. Minute ventilation (V̇E), internal carotid artery blood flow (Q̇ICA), middle cerebral artery blood velocity (MCAv), and temperature corrected end-tidal and arterial blood gases were measured throughout experimentation. HCVR and CVR were calculated using linear regression analysis by indexing V̇E and relative changes in Q̇ICA, and MCAv against PETCO2, predicted PaCO2, and measured PaCO2. The Pa-PETCO2 was similar between hypoxia and normoxia and PFO+ and PFO-. The PET-PaO2 was greater in PFO+ by 2.1 mmHg during normoxia (P = 0.003). HCVR and CVR plotted against PETCO2 underestimated HCVR and CVR indexed against PaCO2 in normoxia and hypoxia. Our PaCO2 prediction equation modestly improved estimates of HCVR and CVR. In summary, care must be taken when indexing reactivity measures to PETCO2 compared with PaCO2.

Measuring the human ventilatory and cerebral blood flow response to CO2: a technical consideration for the end-tidal-to-arterial gas gradient.

Compared to males, females have smaller left ventricular (LV) dimensions and volumes, higher ejection fractions (EF), and higher LV longitudinal and circumferential strain. LV twist mechanics determine ventricular function and are preload-dependent. Therefore, the sex differences in LV structure and myocardial function may result in different mechanics when preload is altered. This study investigated sex differences in LV mechanics during acute challenges to preload. With the use of conventional and speckle-tracking echocardiography, LV structure and function were assessed in 20 males (24 ± 6.2 yr) and 20 females (23 ± 3.1 yr) at baseline and during progressive levels of lower body negative pressure (LBNP). Fourteen participants (8 males, 6 females) were also assessed following a rapid infusion of saline. LV end-diastolic volume, end-systolic volume, stroke volume (SV), and EF were reduced in both groups during LBNP (P < 0.001). While males had greater absolute volumes (P < 0.001), there were no sex differences in allometrically scaled volumes at any stage. Sex differences were not detected at baseline in basal rotation, apical rotation, or twist. Apical rotation and twist increased in both groups (P < 0.001) with LBNP. At -60 mmHg, females had greater apical rotation (P = 0.009), twist (P = 0.008), and torsion (P = 0.002) and faster untwisting velocity (P = 0.02) than males. There were no differences in mechanics following saline infusion. Females have larger LV twist and a faster untwisting velocity than males during large reductions to preload, supporting that females have a greater reliance on LV twist mechanics to maintain SV during severe reductions to preload.

Females have greater left ventricular twist mechanics than males during acute reductions to preload.

Chronic obstructive pulmonary disease (COPD) is associated with dynamic lung hyperinflation (DH), increased pulmonary vascular resistance (PVR), and large increases in negative intrathoracic pressure (nITP). The individual and interactive effect of these stressors on left ventricular (LV) filling, emptying, and geometry and the role of direct ventricular interaction (DVI) in mediating these interactions have not been fully elucidated. Twenty healthy subjects were exposed to the following stressors alone and in combination: 1) inspiratory resistive loading of -20 cmH2O (nITP), 2) expiratory resistive loading to cause dynamic hyperinflation (DH), and 3) normobaric-hypoxia to increase PVR (hPVR). LV volumes and geometry were assessed using triplane echocardiography. LV stroke volume (LVSV) was reduced during nITP by 7 ± 7% (mean ± SD; P < 0.001) through a 4 ± 5% reduction in LV end-diastolic volume (LVEDV) (P = 0.002), while DH reduced LVSV by 12 ± 13% (P = 0.001) due to a 9 ± 10% reduction in LVEDV (P < 0.001). The combination of nITP and DH (nITP+DH) caused larger reductions in LVSV (16 ± 16%, P < 0.001) and LVEDV (12 ± 10%, P < 0.001) than nITP alone (P < 0.05). The addition of hPVR to nITP+DH did not further reduce LV volumes. Significant septal flattening (indicating DVI) occurred in all conditions, with a significantly greater leftward septal shift occurring with nITP+DH than either condition alone (P < 0.05). In summary, the interaction of nITP and DH reduces LV filling through DVI. However, DH may be more detrimental to LV hemodynamics than nITP, likely due to mediastinal constraint of the heart amplifying DVI.

Heart-lung interaction in a model of COPD: importance of lung volume and direct ventricular interaction.

heavy exercise are related to changes in muscle activity kinetics during 2 Effects of prior heavy exercise onV?o

old and young men is associated with improved kinetics with endurance training in 2 Speeding of V?o

Michael M. Tymko, Ryan L. Hoiland, Tomas Kuca, Lindsey M. Boulet, Joshua C. Tremblay, Bryenna K. Pinske, Alexandra M. Williams, and X Glen E. Foster Centre for Heart, Lung, and Vascular Health, School of Health and Exercise Science, University of British Columbia, Kelowna, Canada; and Department of Anesthesia, Pain and Perioperative Medicine, Department of Critical Care Medicine, Dalhousie University, Halifax, Canada

Hypoxia 2015 Measuring the human ventilatory and cerebral blood flow response to CO 2 : a technical consideration for the end-tidal-to-arterial gas gradient

lower region of the moderate-intensity exercise domain deoxygenation are slowed in the upper compared with uptake, leg blood flow, and muscle

work test to exercise endurance during the work Ischemic preconditioning accelerates muscle deoxygenation dynamics and enhances

metabolic rates transitions initiated from low and elevated baseline deoxygenation, during moderate-intensity exercise uptake, but not muscle 2 of pulmonary O High-intensity interval training speeds the adjustment

During step transitions in work rate (WR) within the moderate-intensity (MOD) exercise domain, pulmonary O2 uptake (Vo2p) kinetics are slowed, and Vo2p gain (ΔVo2p/ΔWR) is greater when exercise is initiated from an elevated metabolic rate. High-intensity interval training (HIT) has been shown to speed Vo2p kinetics when step transitions to MOD exercise are initiated from light-intensity baseline metabolic rates. The effects of HIT on step transitions initiated from elevated metabolic rates have not been established. Therefore, this study investigated the effects of HIT on Vo2p kinetics during transitions from low and elevated metabolic rates, within the MOD domain. Eight young, untrained men completed 12 sessions of HIT (spanning 4 wk). HIT consisted of 8-12 1-min intervals, cycling at a WR corresponding to 110% of pretraining maximal WR (WRmax). Pre-, mid- and posttraining, subjects completed a ramp-incremental test to determine maximum O2 uptake, WRmax, and estimated lactate threshold (θL). Participants additionally completed double-step constant-load tests, consisting of step transitions from 20 W → Δ45% θL [lower step (LS)] and Δ45 → 90% θL [upper step (US)]. HIT led to increases in maximum O2 uptake (P < 0.05) and WRmax (P < 0.01), and τVo2p of both lower and upper MOD step transitions were reduced by ∼40% (LS: 24 s → 15 s; US: 45 s → 25 s) (P < 0.01). However, the time course of adjustment of local muscle deoxygenation was unchanged in the LS and US. These results suggest that speeding of Vo2p kinetics in both the LS and US may be due, in part, to an improved matching of muscle O2 utilization to microvascular O2 delivery within the working muscle following 12 sessions of HIT, although muscle metabolic adaptations cannot be discounted.

High-intensity interval training speeds the adjustment of pulmonary O2 uptake, but not muscle deoxygenation, during moderate-intensity exercise transitions initiated from low and elevated baseline metabolic rates.

Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Abstract Summary DeepPheWAS is an R package for phenome-wide association studies that creates clinically curated composite phenotypes and integrates quantitative phenotypes from primary care data, longitudinal trajectories of quantitative measures, disease progression and drug response phenotypes. Tools are provided for efficient analysis of association with any genetic input, under any genetic model, with optional sex-stratified analysis, and for developing novel phenotypes. Availability and implementation The DeepPheWAS R package is freely available under GNU general public licence v3.0 from at https://github.com/Richard-Packer/DeepPheWAS. Supplementary information Supplementary data are available at Bioinformatics online.

DeepPheWAS: an R package for phenotype generation and association analysis for phenome-wide association studies

Thyroid hormones play a critical role in regulation of multiple physiological functions and thyroid dysfunction is associated with substantial morbidity. Electronic health records were used to undertake the largest genome-wide association study of thyroid-stimulating hormone (TSH) levels, with a total sample size of 247,107. We identified 158 novel signals, more than doubling the number of known associations with TSH, and implicating 112 putative causal genes, of which 78 were not previously implicated. For the first time, we demonstrate that a polygenic score for TSH was associated with TSH levels in all ancestries in UK Biobank, and strongly predicted age of onset of hypothyroidism and hyperthyroidism in European ancestry participants. We developed pathway-specific genetic risk scores for TSH levels and used these in phenome-wide association studies to identify potential consequences of pathway perturbation. Together, these findings demonstrate the potential utility of genetic associations to inform future therapeutics and risk prediction for thyroid diseases.

Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease susceptibility and age-of-onset

Rationale Eosinophils are associated with airway inflammation in respiratory disease. Eosinophil production and survival is controlled partly by interleukin-5: anti-interleukin-5 agents reduce asthma and response correlates with baseline eosinophil counts. However, whether raised eosinophils are causally related to chronic obstructive pulmonary disease (COPD) and other respiratory phenotypes is not well understood. Objectives We investigated causality between eosinophils and: lung function, acute exacerbations of COPD, asthma-COPD overlap (ACO), moderate-to-severe asthma and respiratory infections. Methods We performed Mendelian randomisation (MR) using 151 variants from genome-wide association studies of blood eosinophils in UK Biobank/INTERVAL, and respiratory traits in UK Biobank/SpiroMeta, using methods relying on different assumptions for validity. We performed multivariable analyses using eight cell types where there was possible evidence of causation by eosinophils. Measurements and main results Causal estimates derived from individual variants were highly heterogeneous, which may arise from pleiotropy. The average effect of raising eosinophils was to increase risk of ACO (weighted median OR per SD eosinophils, 1.44 (95%CI 1.19 to 1.74)), and moderate-severe asthma (weighted median OR 1.50 (95%CI 1.23 to 1.83)), and to reduce forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and FEV1 (weighted median estimator, SD FEV1/FVC: −0.054 (95% CI −0.078 to −0.029), effect only prominent in individuals with asthma). Conclusions Broad consistency across MR methods may suggest causation by eosinophils (although of uncertain magnitude), yet heterogeneity necessitates caution: other important mechanisms may be responsible for the impairment of respiratory health by these eosinophil-raising variants. These results could suggest that anti-IL5 agents (designed to lower eosinophils) may be valuable in treating other respiratory conditions, including people with overlapping features of asthma and COPD.

Mendelian randomisation of eosinophils and other cell types in relation to lung function and disease

Summary: Deep-PheWAS is a platform for phenome wide association studies that creates clinically-curated composite phenotypes, and integrates quantitative phenotypes from primary care data, longitudinal trajectories of quantitative measures, disease progression, and drug response phenotypes. Tools are provided for efficient analysis of association with any genetic input, under any genetic model, with optional sex-stratified analysis, and for developing novel phenotypes.

Deep-PheWAS: a pipeline for phenotype generation and association analysis for phenome-wide association studies.

Background Chronic sputum production impacts on quality of life and is a feature of many respiratory diseases. Identification of the genetic variants associated with chronic sputum production in a disease agnostic sample could improve understanding of its causes and identify new molecular targets for treatment. Methods We conducted a genome-wide association study (GWAS) of chronic sputum production in UK Biobank. Signals meeting genome-wide significance (P<5x10-8) were fine-mapped and putative causal genes identified by gene expression analysis. GWAS of respiratory traits were interrogated to identify whether the signals were driven by existing respiratory disease amongst the cases and variants were further investigated for wider pleiotropic effects using phenome-wide association studies (PheWAS). Findings From a GWAS of 9,714 cases and 48,471 controls, we identified six novel genome-wide significant signals for chronic sputum production including the Human Leukocyte Antigen (HLA) locus, chromosome 11 mucin locus (containing MUC2, MUC5AC and MUC5B) and the FUT2 locus. The mucin locus signal had previously been reported for association with moderate-to-severe asthma. The HLA signal was fine-mapped to an amino-acid change of threonine to arginine (frequency 36.8%) in HLA-DRB1 (HLA-DRB1*03:147). The signal near FUT2 was associated with expression of several genes including FUT2, for which the direction of effect was tissue dependent. Our PheWAS identified a wide range of associations. Interpretation Novel signals at the FUT2 and mucin loci highlight mucin flucosylation as a driver of chronic sputum production even in the absence of diagnosed respiratory disease and provide genetic support for this pathway as a target for therapeutic intervention.

Genome-wide association study of chronic sputum production implicates loci involved in mucus production and infection

Assessment of causal relationships between eosinophils and respiratory disease using Mendelian randomization

A first update on mapping the human genetic architecture of COVID-19

Background Electronic health record (EHR) databases provide rich, longitudinal data on interactions with healthcare providers and can be used to advance research into respiratory conditions. However, since these data are primarily collected to support health care delivery, clinical coding can be inconsistent, resulting in inherent challenges in using these data for research purposes. Methods We systematically searched existing international literature and UK code repositories to find respiratory disease codelists for asthma from January 2018, and chronic obstructive pulmonary disease and respiratory tract infections from January 2020, based on prior searches. Medline searches using key terms provided in article lists. Full-text articles, supplementary files, and reference lists were examined for codelists, and codelists repositories were searched. A reproducible methodology for codelists creation was developed with recommended lists for each disease created based on multidisciplinary expert opinion and previously published literature. Results Medline searches returned 1126 asthma articles, 70 COPD articles, and 90 respiratory infection articles, with 3%, 22% and 5% including codelists, respectively. Repository searching returned 12 asthma, 23 COPD, and 64 respiratory infection codelists. We have systematically compiled respiratory disease codelists and from these derived recommended lists for use by researchers to find the most up-to-date and relevant respiratory disease codelists that can be tailored to individual research questions. Conclusion Few published papers include codelists, and where published diverse codelists were used, even when answering similar research questions. Whilst some advances have been made, greater consistency and transparency across studies using routine data to study respiratory diseases are needed.

Deriving a Standardised Recommended Respiratory Disease Codelist Repository for Future Research

Background: Globally, respiratory infections contribute to significant morbidity and mortality. However, genetic determinants of respiratory infections are understudied and remain poorly understood. Methods: We conducted a genome-wide association study in 19,459 hospitalised respiratory infection cases and 101,438 controls from UK Biobank. We followed-up well-imputed top signals from the UK Biobank discovery analysis in 50,912 respiratory infection cases and 150,442 controls from 11 cohorts. We aggregated effect estimates across studies using inverse variance-weighted meta-analyses. Additionally, we investigated the function of the top signals in order to gain understanding of the underlying biological mechanisms. Results: In the discovery analysis, we report 56 signals at P<5×10-6, one of which was genome-wide significant (P<5×10-8). The genomewide significant signal was in an intron of PBX3, a gene that encodes pre-B-cell leukaemia transcription factor 3, a homeodomaincontaining transcription factor. Further, the genome-wide significant signal was found to colocalise with gene-specific expression quantitative trait loci (eQTLs) affecting expression of PBX3 in lung tissue, where the respiratory infection risk alleles were associated with decreased PBX3 expression in lung tissue, highlighting a possible biological mechanism. Of the 56 signals, 40 were well-imputed in UK Biobank and were investigated in the 11 follow-up cohorts. None of the 40 signals replicated, with effect estimates attenuated. Conclusions: Our discovery analysis implicated PBX3 as a candidate causal gene and suggests a possible role of transcription factor binding activity in respiratory infection susceptibility. However, the PBX3 signal, and the other well-imputed signals, did not replicate when aggregating effect estimates across 11 independent cohorts. Significant phenotypic heterogeneity and differences in study ascertainment may have contributed to this lack of statistical Open Peer Review Reviewer Status AWAITING PEER REVIEW Any reports and responses or comments on the article can be found at the end of the article. Page 2 of 15 Wellcome Open Research 2021, 6:290 Last updated: 30 NOV 2021

Genome-wide association study of susceptibility to hospitalised respiratory infections [version 1; peer review: awaiting peer review]

Background: Globally, respiratory infections contribute to significant morbidity and mortality. However, genetic determinants of respiratory infections are understudied and remain poorly understood. Methods: We conducted a genome-wide association study in 19,459 hospitalised respiratory infection cases and 101,438 controls from UK Biobank. We followed-up well-imputed top signals from the UK Biobank discovery analysis in 50,912 respiratory infection cases and 150,442 controls from 11 cohorts. We aggregated effect estimates across studies using inverse variance-weighted meta-analyses. Additionally, we investigated the function of the top signals in order to gain understanding of the underlying biological mechanisms. Results: In the discovery analysis, we report 56 signals at P<5×10-6, one of which was genome-wide significant (P<5×10-8). The genome-wide significant signal was in an intron of PBX3, a gene that encodes pre-B-cell leukaemia transcription factor 3, a homeodomain-containing transcription factor. Further, the genome-wide significant signal was found to colocalise with gene-specific expression quantitative trait loci (eQTLs) affecting expression of PBX3 in lung tissue, where the respiratory infection risk alleles were associated with decreased PBX3 expression in lung tissue, highlighting a possible biological mechanism. Of the 56 signals, 40 were well-imputed in UK Biobank and were investigated in the 11 follow-up cohorts. None of the 40 signals replicated, with effect estimates attenuated. Conclusions: Our discovery analysis implicated PBX3 as a candidate causal gene and suggests a possible role of transcription factor binding activity in respiratory infection susceptibility. However, the PBX3 signal, and the other well-imputed signals, did not replicate when aggregating effect estimates across 11 independent cohorts. Significant phenotypic heterogeneity and differences in study ascertainment may have contributed to this lack of statistical replication. Overall, our study highlighted putative associations and possible biological mechanisms that may provide insight into respiratory infection susceptibility.

Genome-wide association study of susceptibility to hospitalised respiratory infections

Background: New data collection in established longitudinal population studies provides an opportunity for studying the risk factors and sequelae of the novel coronavirus disease 2019 (COVID-19), plus the indirect impacts of the COVID-19 pandemic on wellbeing. The Extended Cohort for E-health, Environment and DNA (EXCEED) cohort is a population-based cohort (N>11,000), recruited from 2013 in Leicester, Leicestershire and Rutland. EXCEED includes consent for electronic healthcare record (EHR) linkage, spirometry, genomic data, and questionnaire data. Methods: Between May 2020 and July 2021, a new questionnaire was deployed in EXCEED, which captured COVID-19 symptoms, general physical and mental health, plus socioeconomic and environmental factors during the pandemic. An online system was developed to invite new participants to join EXCEED, with informed consent being provided online. New and existing participants then completed the COVID-19 questionnaire online. A subset of the new questionnaire respondents were invited to participate in COVID-19 serology substudies, using home antibody testing kits. Results: In total, 3,693 participants provided COVID-19 infection status (median age 62.9 (IQR 54.7-69.2), 58.9% female). Trends of monthly incidence proportions of COVID-19 in EXCEED (self-report or symptom-predicted) approximated local and national figures. Regression analysis of 2,768 participants with linked EHR data showed no obvious monotonic relationship between number of chronic diseases (of 16 pre-specified diseases) and COVID-19 infection. There were 2,144 participants with valid results from a kit allowing differentiation between antibodies due to vaccination or infection. Of these, 8.5% had results consistent with previous COVID-19 infection, and 85.9% had evidence of COVID-19 vaccination, but without evidence of infection. Conclusions: Enriching EXCEED with a new COVID-19 questionnaire and serology data may improve understanding of the risk factors, clinical sequelae and broader impacts of the COVID-19 pandemic in the general population. Controlled access to these data for bona fide researchers is via application to the EXCEED study.

Extended Cohort for E-health, Environment and DNA (EXCEED) COVID-19 focus

Background: Eosinophils are granulocytes associated with airway inflammation in respiratory disease. Eosinophil production and survival is controlled by interleukin-5: anti-interleukin-5 agents reduce asthma and COPD exacerbation frequency, and response correlates with baseline eosinophil counts. However, causal relationships between eosinophils and other respiratory phenotypes are less studied. Methods: We investigated causality between eosinophils and: lung function, acute exacerbations of COPD (AECOPD), asthma-COPD overlap (ACO), moderate-to-severe asthma, and respiratory infections. We performed Mendelian randomization (MR) using 151 genetic variants from genome-wide association studies of blood eosinophil counts in UK Biobank/INTERVAL, and respiratory data from UK Biobank, using MR methods relying on different assumptions for validity. Multivariable MR using eight blood cell type exposures was performed for outcomes showing evidence of causation by eosinophils. Findings: There was evidence that higher eosinophils reduce FEV1/FVC and FEV1 (weighted median estimator, SD change FEV1/FVC per SD eosinophils: -0.054 [95%CI -0.078,-0.029]. There was also evidence that eosinophils cause ACO (weighted median OR 1.44 [95%CI 1.19,1.74]), and asthma (weighted median OR 1.50 [95%CI 1.23,1.83]). Multivariable MR for FEV1/FVC, FEV1, ACO and asthma suggested that eosinophils were the cell type with the most important effect. Causal estimates of individual variants were heterogeneous, which may arise from pleiotropy. Interpretation: We found evidence that eosinophils reduce lung function, and increase ACO and asthma risk, on average over the set of genetic variants studied. Eosinophils appear to be causal determinants of fixed airflow obstruction among individuals with features of both asthma and COPD.

Mendelian randomisation analyses of eosinophils and other blood cell types in relation to lung function and disease.

Genetic and clinical characteristics of treatment-resistant depression using primary care records in two UK cohorts

Cohort Profile: Extended Cohort for E-health, Environment and DNA (EXCEED) Catherine John,* Nicola F Reeve , Robert C Free, Alexander T Williams, Ioanna Ntalla and Aliki-Eleni Farmaki, Jane Bethea, Linda M Barton, Nick Shrine, Chiara Batini, Richard Packer, Sarah Terry, Beverley Hargadon, Qingning Wang, Carl A Melbourne, Emma L Adams, Catherine E Bee, Kyla Harrington, José Miola, Nigel J Brunskill, Christopher E Brightling, Julian Barwell, Susan E Wallace, Ron Hsu, David J Shepherd, Edward J Hollox, Louise V Wain and Martin D Tobin Department of Health Sciences, University of Leicester, Leicester, UK, NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK, Department of Respiratory Sciences, University of Leicester, Leicester, UK, Department of Clinical Pharmacology, William Harvey Research Institute, Barts & The London Medical School, Queen Mary University of London, Charterhouse Square, London, UK, Department of Population Science and Experimental Medicine, Institute of Cardiovascular Science, University College London, London, UK, Department of Haematology, University Hospitals of Leicester NHS Trust, Leicester, UK, Leicester Law School, University of Leicester, Leicester, UK, Department of Cardiovascular Sciences University of Leicester, Leicester, UK and Department of Genetics and Genome Biology, University of Leicester, Leicester, UK

Corrigendum to: Cohort profile: Extended Cohort for E-health, Environment and DNA (EXCEED)

EXCEED is a longitudinal population-based cohort which facilitates investigation of genetic, environmental and lifestyle-related determinants of a broad range of diseases and of multiple morbidity through data collected at baseline and via electronic healthcare record linkage. Recruitment has taken place in Leicester, Leicestershire and Rutland since 2013 and is ongoing, with 10 156 participants aged 30-69 to date. The population of Leicester is diverse and additional recruitment from the local South Asian community is ongoing. Participants have consented to follow-up for up to 25 years through electronic health records (EHR). Data available includes baseline demographics, anthropometry, spirometry, lifestyle factors (smoking and alcohol use) and longitudinal health information from primary care records, with additional linkage to other EHR datasets planned. Patients have consented to be contacted for recall-by-genotype and recall-by-phenotype sub-studies, providing an important resource for precision medicine research. We welcome requests for collaboration and data access by contacting the study management team via exceed@le.ac.uk.

Cohort Profile: Extended Cohort for E-health, Environment and DNA (EXCEED)

Evaluation of Okra (Abelmoschus Esculentus) Lines for Fruit Quality and Yield Performances Under Open-Field and Greenhouse Conditions

Producing enough tomato to meet market demand 
sustainably has not been feasible in the tropics like Ghana. Attempts to 
improve production using greenhouse 
facilities have not addressed the challenge because of high-temperature 
conditions in the greenhouse, which are difficult to manage. Heat stress, 
arising from high temperatures, hinder the performance of tomato in terms of 
fruit set and yield. Moreover, the impending climate change is expected to 
impose more unfavorable environmental conditions on crop production. An experiment was conducted in (greenhouse at 
Chiba University, Japan) summer period, which has similar 
high-temperature conditions like Ghana. This work sought to increase the yield 
of a heat-tolerant tomato using a 
state-of-the-art hydroponic system through high-density planting. The 
outcome of this work was intended for adoption and practice in Ghana. A 
Heat-tolerant tomato “Nkansah HT” along with Lebombo and Jaguar cultivars, were 
grown at high and low plant densities (4.1 and 2.7 plants m-2 respectively). Each 
plant was grown in a low substrate volume culture (0.5 L plant-1) in a recirculating nutrient film technique (NFT) 
hydroponic system. Parameters measured were plant growth and dry 
matter assimilation at 12 weeks after 
transplanting, and the generative components. Results showed that a high 
plant density increased plant height but reduced chlorophyll content by 9.6%. Under temperature stress conditions, the three 
cultivars recorded more than 95% fruit 
set, but plant density did not affect the fruit set and the incidence of 
blossom end rot (BER). The incidence of BER reduced the marketable yield 
of the Jaguar cultivar by 51% but, this physiological disorder was not recorded 
in the HT and the Lebombo cultivars. A high-density planting increased the 
yield per unit area increased by 38.9%. However, it is uneconomical to 
cultivate the Jaguar cultivar under a heat stress condition due to its high 
susceptibility to blossom end rot. To improve the yield of tomatoes under 
tropical heat stress with a threatening climate change condition, the HT is a 
better cultivar suited for high-density planting. This study shows that high-density 
cultivation of the HT cultivar in NFT hydroponic system has the potential to 
increase Ghana’s current tomato yield by 4.8 times.

Effect of Plant Density on the Yield of Hydroponically Grown Heat-Tolerant Tomato under Summer Temperature Conditions

The low-node pinching order at a high-density plant cultivation system (LN&HD) is now widely adopted for increasing tomato yield and fruit quality. The LN&HD cultivation period spans 70–120 days, employs the use of a small amount of substrate (low substrate volume), and plants are usually topped between the first and the fourth truss. Using a small amount of substrate in cultivation induces root restriction. Increasing the extent of root restriction in small pots has been adopted for increasing the fruit quality of tomato in some advanced countries. However, improving fruit quality at the expense of yield becomes a major drawback for adopting the LN&HD in Ghana. The LN&HD was introduced into Ghana mainly to increase tomato yield sustainably at a cost-effective level. This study aimed to manipulate or reduce the extent of root restriction to increase tomato yield. Information related to manipulating or reducing the extent of root restriction has not been extensively reported. Thus, an experiment was conducted (between 21 April 2019 and 11 August 2019) in the greenhouse of the University of Ghana Forest and Horticultural Research Centre, Kade-Ghana. Plants of two tomato cultivars (Jaguar and Momotaro York) were subjected to four root restriction conditions. The extent of root restriction were (1) complete root restriction in a 1.0 L volume capacity pot, (2) complete root restriction in a 1.5 L volume capacity pot, (3) partial root restriction in Rockwool-like cultivation, otherwise referred to as Cocowool, and (4) No root restriction in a trough containing 1.5 L of the substrate. The experiment was laid out in a 2 x 4 factorial in a randomized complete block. Results showed that partial root restriction in Cocowool and unrestricted roots in the trough produced the highest tomato yield and total dry matter compared to the plants that received complete root restrictions in the 1.0 and 1.5 L pots. However, the tomato’s total soluble solids increased with a complete root restriction in the 1.0 L pot. Reducing the extent of root restriction increased the yield and total dry matter of tomato. With the LN&HD, a small amount of substrate could be used (at a reduced cost) with a partial root restriction to increase the yield of tropical tomato cultivars grown in Ghana.

Effect of Root Restriction on the Performance of Three-Truss Cultivated Tomato in the Low-Node Pinching Order at High-Density Cultivation System

The issue of low tomato production in the tropics like Ghana has been a long-standing challenge. The advent of greenhouse technology has not significantly improved the yield of tomato compared to Japan and the Netherlands. Immediate technological interventions are needed. Through hydroponics, the low-node order pinching at a high-density planting system has been recommended in some studies. This system was intended to be established in Ghana, and it would be expected to improve the yield and fruit quality of tomato. In effect, a study was carried out in the greenhouse, at Chiba University using this system. A tropical tomato cultivar (Jaguar) was evaluated with Momotaro York at 3.8 m s2 and pinched at the fourth truss. Data collected were water and nutrient use efficiencies, plant growth rate, dry matter partitioning, and fruit yield and quality, as well as some physiological characteristics. The experiment was laid out in a randomized complete block design with three replications. Results showed that Jaguar cultivar was two times more efficient in water and nutrient use than Momotaro York at first harvest. Root tissue density recorded in Jaguar was significantly lower compared to Momotaro York. The net assimilation rate (NAR) recorded was markedly higher in Jaguar than Momotaro York at last harvest. All the physiological attributes recorded in both cultivars were not significantly different. Plant dry mass (DM) recorded was similar in the two cultivars; however, the DM partitioned to fruits was 55% in Jaguar compared to 46.5% DM for Momotaro York. Fruit yield per area did not differ in the two cultivars. Fruit yields of 28.8 and 30 kg m−2 per year were recorded in Jaguar and Momotaro York, respectively. In comparison, this yield result is 1.2–1.25 times less and 14.4–15 times higher than current tomato yields recorded in Japan (greenhouse) and Ghana, respectively. Fruit quality, in terms of total soluble solids recorded in Jaguar cultivar being 5.4 %Brix, was within the 3.5–5.6 %Brix recorded in Ghana. This system could effectively enhance the yield and quality of tomato in the tropics as well as economising on the use of resources.

Evaluation of Tropical Tomato for Growth, Yield, Nutrient, and Water Use Efficiency in Recirculating Hydroponic System

Production of tomato in the tropics especially in Ghana is beset with lots of setbacks thereby causing low yields per hectare. Greenhouse cultivation systems are promising yet yields of tropical tomato cultivars are hampered by adverse temperature conditions. In order to mitigate this, an experiment was conducted during the extreme summer temperature conditions in the greenhouse at Kashiwanoha Campus of Chiba University, Japan. The study was conducted between May 23, 2018 and September20, 2018. The low substrate volume production system of 500mL in closed recirculated hydroponics (sub-irrigation) method was employed. Three tropical tomato cultivars (Jaguar, Lebombo and Lindo) were evaluated for yields. Plants were spaced at 20cm (4.2 plants m-2) and 30cm (2.8 plants m-2). At 7 and 9WAT, plants were topped at 2nd and 4th nodes respectively. The 3x2x2 factorial in Randomised Complete Block design in three replications was adopted. Some parameter collected were; 1. Morphometrics such as plant height, girth, leaf number and chlorophyll content, days to 50% flowering and fruit set 2. Yield components and fruit quality such as fruit number, marketable yield, yield per area, yield per hectare, percent blossom end rot, fruit TSS, TA, TSS/TA ratio and 3. Dry matter partitioning at last harvest, 11WAT. Results showed that blossom end rot reduced the yields of Jaguar and Lindo almost by 50% while Lebombo recorded less than 1%. Lebombo produced significantly the highest plant dry mass of 125g of which 57.7% was converted to vegetative growth compared to the Jaguar. For Jaguar however, 53.7% of total plant dry mass was allocated to fruits. This in effect was translated to the highest yield of 93tons ha-1 year-1 for Jaguar plants that were pinched at 4th truss in high density planting of 4.2 plant m-2.

Effect of Spacing and Topping on the Performance of Hydroponically Grown Tomato Under Tropical Conditions

Field experiments were conducted at the Teaching and Research farm of the University of Ghana Forest and Horticultural Crop Research Centre (FOHCREC), Okumaning-Kade to investigate the effect of grafting on growth, yield, disease resistance and fruit quality of tomatoes grafted onto two different African eggplant rootstocks. Two commercial tomato varieties (‘Tropimech’ and ‘Roma’) were used as scions and two African eggplant varieties (‘Aworoworo’ and ‘Green’) were used as rootstocks. The scion/rootstock combinations or treatments were ‘Roma/Green’, ‘Tropimech/Green’, ‘Roma/Aworoworo’, ‘Tropimech/Aworoworo’, ‘Roma/Roma’, ‘Tropimech/Tropimech’, and Roma non-grafted (control) and Tropimech nongrafted (control). The results indicated that, grafted tomatoes on African eggplant rootstocks performed better in terms of growth, yield, earliness, disease incidence and shelf life than non-grafted or control plants. Pooled mean data indicated signifi cant differences in terms of percent fruit set, fruit number and weight among the treatments. Percent fruit set was higher for tomato on Africa eggplant (67.9) compared to the self grafted (58.7) and the control (52.6). Fruit number/plant and yield of tomato on the African eggplant was 16.2 and 1120.7g/plant compared to the control (10.8 and 916g/plant) while the self grafted had 13.2 and 1064.9g/plant, respectively. The shelf life of grafted tomatoes onto egg plant was signifi cantly higher (25.4 days) compared to control (13.6 days). Grafting did not signifi cantly affect Brix (%), pH and acidity of tomato. Grafted plants signifi cantly recorded low disease incidence compared to non-grafted ones. The study indicated that the use of grafting on eggplant in the humid forest zone of Ghana can boost tomato production considerably.

Grafting onto African eggplant enhances growth, yield and fruit quality of tomatoes in tropical Forest ecozones

Genetic Diversity among Local and Introduced Avocado Germplasm Based on Morpho-agronomic Traits

Objective : To evaluate the growth and yield performance of Bird Eye pepper ( Capsicum frutescence) in the forest ecological zone of Ghana. Methodology and results: Field experiments were conducted at the teaching and research farm of the University of Ghana Forest and Horticultural Crops Research Centre, Kade during the rainy seasons of 2009 and 2010. The treatments were randomized in complete block design and replicated three times. The parameters assessed were: plant height, number of leaves/plant, number of branches/plant, stem girth, fruit number, fruit weight and yield as well as quantitative characters. Results showed that there were significant differences in growth parameters as well as in the yield and yield components of the four cultivars and in both seasons. Plant heights were highest in cultivar 7777 and local in both seasons. Cultivar 7777 had significantly higher number of branches, canopy girth, fruit number and weight compared to the other cultivars. In terms of fruit colour, cultivar 7777 had dark green colour, a characteristics required in the export industry. Based on the results, cultivar 7777 is recommended for release to farmers and stakeholders in the vegetable industry in Ghana due to its colour, yield and consumer preference on the export and local market. Conclusion and application: The use of this cultivar will increase the foreign exchange earnings of Ghana and well-being of farmers not forgetting that it is going to be a good material for breeding purposes.

Growth and yield performance of bird eye pepper in the forest ecological zone of Ghana

This report describes an Equity Lens Protocol and its use to guide partners’ systematic reflection on harms and mitigation strategies of the COVID-19 response in a local public health system. This process evaluation tool is based on the Guidance document for assuring an equitable response to COVID-19 prepared by the Pan American Health Organization. We used a participatory approach to engage public health partners in systematically reflecting on harms, mitigation strategies, and lessons learned and implications for practice. Outputs from using this tool included identified: (a) specific harms (e.g., loss of income and challenges to learning) related to particular COVID-19 response measures (e.g., home confinement and school closure) and (b) mitigation strategies implemented to reduce harms. In response to the protocol’s guiding questions, partners also identified lessons learned and practice recommendations for strengthening equity work in public health responses (e.g., an equitable response requires an investment in people, structures, and relationships before a crisis). This report—and accompanying protocol—illustrates use of a practical method for systematic reflection on public health responses through an equity lens.

Equity Lens Protocol: Reflecting on Harms From the COVID-19 Response and Mitigation Strategies Implemented in a Local Public Health System

Division of Gastroenterology and NutritionQuestion: A7-month-old infant pre-sented to the hospitalwith vomiting andabdominal distensionfor 3 days. On exami-nation, the baby waswell developed andalert. Abdomen wasnontender and dis-tended with hypo-active bowel sounds.Faint, localized yellowdiscoloration wasnoted over the bilat-eral ﬂanks (Figure A).Laboratory results revealed the following: white blood cell count, 11.2 K/cumm (29.6% neutrophils, 58.4% lympho-cytes, 11.0% monocytes, 0.5% eosinophils, 0.5% basophils); hemoglobin, 10.0 g/dL; platelet count, 333 K/cumm; alkalinephosphatase, 83 U/L; total protein, 4.3 g/dL; albumin, 2.9 g/dL; aspartate aminotransferase, 33 U/L; alanine amino-transferase, 14 U/L; total bilirubin, 1.5 U/L; direct bilirubin, 1.0 U/L; amylase, 103; and lipase, 30. Urine analysis wasicototest positive. Fecal occult blood test was guaiac negative. Plain abdominal radiograph showed dilated small and largebowel suggestive of partial obstruction versus ileus (Figure B). Abdominal ultrasonography was ordered.What is the diagnosis?Look on page 000 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for moreinformation on submitting your favorite image to Clinical Challenges and Images in GI.

Yellow flank discoloration and abdominal distension in an infant.

Comparacion de dos tecnicas hidroponicas, flujo laminar de nutrientes y raiz flotante para la produccion de lechuga (Lactuca sativa L.) en el Centro Experimental de Cota Cota

Austrostipa (Poaceae) in Western Australia: new species, new records, keys, and character notes

The spread of fake science: Lexical concreteness, proximity, misinformation sharing, and the moderating role of subjective knowledge

If you are about to leave school, or about to leave home for the first time, this is the ONLY guide you need to pop into your backpack or handbag ?
Welcome to the Real World! is the only book you will need to guide you through the challenges of becoming a grown-up. With practical advice on topics including travel, accommodation, studies, employment, finance, and personal health and safety, and written by two young women who have been there, done that, no one about to leave home for the first time should be without it. Easy to dip into to find the right advice at the right time, with this book in hand you will never have to call your parents in despair and hear the words: ?Why don?t you know this?? Essential reading if you are about to embark on the journey of a lifetime ?

Welcome to the Real World! : A young person's guide to figuring it all out Ed. 1

Does a change in end-tidal carbon dioxide level predict high altitude mountain sickness?

Perceptions and Misconceptions: How are International and UK Law Perceived to Affect Military Commanders and Their Subordinates on Operations?

Cultural values at work on the advanced command and staff course (ACSC)

The Political-Military Interface: Friction in the Conduct of British Army Operations in North Africa 1940-1942

Can the Current Ministry of Defence Performance Management Regime Cope With Cognitive Effects

The ‘Clash of Civilisations’ Thesis as a Tool for Explaining Conflicts in the Contemporary World

‘Can We Stop The Next 9/11’1 read the headline of Time Magazine in the aftermath of the events of September 11, 2001. As the bombing in Bali later indicated, international terrorist attacks of this...

Does 9/11 mark the end of deterrence and the birth of ‘detercion’?

Assessing the Reasons for Failure: 1st British Airborne Division Signal Communications during Operation ‘Market Garden’

A command philosophy for the information age: The continuing relevance of mission command

Assess the importance of Measures of Effectiveness (MOE) for the further development of UK information operations

Asymmetry: What is it and what does it mean for the British armed forces?

Is Osama Bin Laden's ‘Fatwa urging Jihad against Americans’ dated 23 February 1998 justified by Islamic law?

The 14th army in Burma: A case study in delivering fighting power

Is the West's Reliance on Technology the Panacea for Future Conflict or its Achilles' Heel?

Memorias IV Congreso Internacional en Gestión Organizacional. La Empresa del Siglo XXI

El proyecto tiene como finalidad que el cohete sonda Libertador I sea recuperado y 
tenga un descenso controlado con la menor velocidad posible de impacto, por 
medio de un sistema que reduzca la velocidad de descenso para el impacto en la 
superficie de la Tierra por medio de un paracaidas desplegable y eyectable que 
presente una mayor fuerza de arrastre, una menor area proyectada y un menor 
volumen, cumpliendo con los requisitos de diseno del cohete sonda Libertador I. 
Debido a lo anterior se plantea la siguiente pregunta de investigacion: 
?Como debe ser el diseno y construccion del sistema de recuperacion para que 
cumpla con los requerimientos del cohete sonda Libertador I?

Diseño, desarrollo y pruebas del sistema de recuperación para el cohete sonda LIBERTADOR I.

Este trabajo de grado esta inscrito en el enfasis de Tecnologia Digital en la Ensenanza y el Aprendizaje de las Matematicas, de la Maestria en Docencia de la Matematica de la Universidad Pedagogica Nacional. Surge con el proposito de aportar a la linea de investigacion Conceptos y procesos del Calculo, particularmente al desarrollo del pensamiento variacional en la escuela. Para lograr lo anterior, se aplica un conjunto de tareas mediadas por el uso de tecnologia computacional, a grupos de estudiantes de grado noveno y decimo, con el objetivo de obtener informacion sobre los esquemas de accion instrumentada, asociadas al pensamiento variacional, evidentes en los gestos, senalamientos, movimientos corporales, expresiones linguisticas. Para poder lograr la indagacion planteada, se emplean los esquemas de accion instrumentada, para articular los tres referentes teoricos utilizados en este trabajo: los procesos del pensamiento variacional, la mediacion instrumental y la teoria de objetivacion. Por tal razon, se exponen las diferentes fases llevadas a cabo para la elaboracion de este documento y se da cuenta y razon, de los alcances, logros y aspectos por mejorar al hacer uso de la tecnologia computacional en la escuela.

La mediación instrumental y el cuerpo: una aproximación al pensamiento variacional

Centro de pedagogía rural alternativo (P.R.A) en la zona rural de Chaparral Tolima. Propuesta para el retorno de la población campesina a sus territorios en el marco del posconflicto colombiano

El consumo de varias sustancias por una gestante aumenta el riesgo de que el bebe nazca con sindrome de abstinencia, este se caracteriza por un conjunto de sintomas que se originan en un bebe que ha estado expuesto durante la gestacion a diversas sustancias toxicas en el momento que se separa de su madre o en el momento en que la gestante deja de recibir dichas sustancias, esto se produce porque estas sustancias toxicas que ha consumido la madre han atravesado las paredes de la placenta y han llegado al embrion, haciendo que de esta manera el bebe depende de ellas despues del parto o cuando la gestante deja de recibirlas, para ello siempre sera necesario propiciar y facilitar la adquisicion de conocimientos y las habilidades necesarias para que la enfermeria actue de manera coherente con la evidencia cientifica acerca del tema. Tambien sera de gran utilidad contar con un programa estructurado que marque las pautas elementales de la atencion enfermera.

¿Cuáles son los cuidados de enfermería eficaces que se pueden implementar para neonatos hijos de madres con antecedentes de consumo de SPA, alcohol y opioides para limitar el síndrome de abstinencia?

1. Introduccion. -- 2. Objetivos del sg – sst de la empresa creaciones aquis s.a.s. -- 2.1. Objetivo general. -- 2.2. Objetivos especificos. -- Marco conceptual. -- 3. Organizacion del sistema de gestion en seguridad y salud en el trabajo. -- 3.1. Descripcion de la Empresa. -- 3.1.1. Clasificacion de la Empresa. -- 3.1.2. Mision Creaciones AQUIS S.A.S. -- 3.1.3. Vision Creaciones AQUIS S.A.S. -- 3.1.4. Estructura Organizacional. -- 3.1.5. Centros de trabajo. -- 3.1.6. Jornada laboral. -- 3.1.7. Materia prima y equipos utilizados en el proceso. -- 3.1.8. Servicios Sanitarios. -- 3.1.9. Cobertura del Sistema de Riesgos Laborales. -- 3.1.10. Capacitacion en Seguridad y Salud en el Trabajo – SST. -- 3.2. Responsabilidades de la Empresa frente al Sistema de Gestion en Seguridad y Salud en el Trabajo. -- 
3.3. Direccion del Sistema de Gestion de Seguridad y Salud en el Trabajo en Creaciones AQUIS S.A.S. -- 3.3.1. Responsabilidades del Vigia de Seguridad y Salud en el Trabajo. -- 3.3.2. Capacitacion obligatoria al responsable del SG SST. -- 3.3.3. Obligaciones del empleador. -- 3.3.4. Responsabilidades de los trabajadores. -- 3.3.5. Responsabilidades de la direccion de SST. -- 3.3.6. Obligaciones de las Administradoras de Riesgos Laborales. -- 3.3.7. Responsabilidades del Comite de Convivencia Laboral. -- 3.4. Perfil socio demografico. -- 3.5. Diagnostico de las condiciones de salud. -- 3.5.1. Hallazgos de Morbilidad sentida. -- 3.5.2. Morbilidad. -- 3.5.3. Plan de analisis y priorizacion. -- 3.6. Requisitos Legales. -- 4. Planificacion del sistema de gestion seguridad y salud en el trabajo del nombre de la empresa. -- 4.1. Identificacion de Peligros, Evaluacion y Valoracion de los Riesgos. -- 
4.1.1. Identificacion y diagnostico de los factores de riesgos y peligros. -- 4.1.2. Priorizacion, evaluacion y control de los factores de riesgo y peligro. -- 4.2. Evaluacion Inicial del Sistema de Gestion de la Seguridad y Salud en el Trabajo del nombre de la empresa. -- 4.3. Reglamento de Higiene y Seguridad Industrial. -- 4.4. Planeacion, Organizacion y Ejecucion del SG – SST. -- 4.5. Indicadores del Sistema de Gestion de la Seguridad y Salud en el Trabajo. (Decreto 1072 de 2015, Capitulo 6 – Articulo 19). -- 4.5.1. Indicadores de Estructura del Sistema de Gestion de Seguridad y Salud en el Trabajo. (Decreto 1072 de 2015, Capitulo 6 – Articulo 20). -- 4.5.2. Indicadores de Proceso del Sistema de Gestion de Seguridad y Salud en el Trabajo. (Decreto 1072 de 2015, Capitulo 6 – Articulo 21). -- 4.5.3. Indicadores de Resultado del Sistema de Gestion de Seguridad y Salud en el Trabajo. (Decreto 1072 de 2015, Capitulo 6 – Articulo 22). -- 4.5.4. Indicadores Minimos de Seguridad y Salud en el Trabajo. (Resolucion 1111de 2017, Articulo 15). -- 4.5.5. Documentacion. -- 4.5.6. Conservacion de los documentos. -- 4.5.7. Comunicacion. -- 5. Aplicacion. -- 5.1. Plan de Trabajo Anual y Programas para la Gestion del Riesgo. -- 5.2. Programa de Gestion del Cambio. -- 5.2.1. Plan de medidas de prevencion, mejora y control. -- 5.3. Programa Medicina Preventiva y del Trabajo. -- 5.3.1. Subprograma de Evaluaciones Medicas Ocupacionales. -- 5.3.2. Subprograma de Vigilancia Epidemiologica. -- 5.3.3. Subprograma de Caracterizacion del ausentismo. -- 5.4. Programa de Higiene y Seguridad Industrial. -- 5.4.1. Reglamento de Higiene y Seguridad Industrial. -- 5.4.2. Subprograma de Investigacion de incidentes y/o accidentes. -- 5.4.3. Subprograma de Elementos de Proteccion Personal EPP. -- 5.4.4. Subprograma de Mantenimiento de las Instalaciones, Equipos y Herramientas. (Decreto 1072 de 2015, Capitulo 6 – Articulo 24 Paragrafo 2.). -- 5.4.5. Subprograma de Reporte de actos y condiciones inseguras. -- 5.5. Programa de Prevencion, Preparacion y Respuesta ante Emergencias. -- Recursos para emergencias. -- Primeros Auxilios. -- 5.6. Programa de Capacitacion, Entrenamiento y Formacion. -- 5.6.1. Subprograma Capacitacion continuada general a todos los trabajadores. -- 5.6.2. Subprograma de Induccion. -- 5.6.3. Subprograma de Capacitacion Especifica. -- 5.7. Programa de Adquisiciones (Proveedores y Contratistas). -- 5.7.1. Contratacion. -- 5.8. Programa de Saneamiento Basico Industrial y proteccion al medio ambiente. -- 5.8.1. Hojas de Seguridad para productos quimicos. -- 6. Auditoria y revision por gerencia. -- 6.1. Programa de Auditoria. -- 6.2. Alcance de la Auditoria. -- 6.2.1. Indicadores de seguridad y salud en el trabajo para evaluacion (Resolucion 1016). -- 6.3. Revision por Alta Direccion. -- 7. Mejoramiento. -- 7.1. Acciones Preventivas, Acciones Correctivas. -- 7.2. Eficacia de los controles en la Matriz de Riesgos. -- 7.3. Mejora Continua. -- 8. Bibliografia.

Propuesta de un sistema de salud y seguridad en el trabajo para creaciones Aquis S.A

ABSTRACT 
The objective of the present investigation was to determine how to achieve the application and primacy of the private autonomy of the parties in the leasing contract without ignoring the will, freedom and equality of the tenant. For the verification of the hypothesis, a sample constituted by 10 experts in financial leasing contract analysis divided into: 06 users and 04 financial entities was considered. As well as the statistical reports of the financial leasing contracts of the ASBAC, 2016-2017, and the regulations that regulate it. In order to obtain the information, the techniques of documentary analysis, the signing and the survey were used, with their respective data collection instruments. This information was organized and presented in tables and frequency figures. Likewise, the inductive-deductive, analysis-synthesis and hermeneutic methods were used to discuss the information obtained from the elements of the sample. The results allowed to conclude that the application and primacy of the Principle of Private Autonomy of the tenant, in the financial leasing contract within the framework of constitutionally regulated contractual freedom, is achieved by granting personal decision to the tenant in the free pact of the minimum insurance conditions that covers the goods subject of financial leasing, since Legislative Decree 299 is distorted, coerces the contractual freedom and imposes the financial obligation on the business need.

El presente articulo tiene como finalidad analizar los impactos que genera la implementacion de las normas que regulan la Responsabilidad Social Universitaria (R.S.U), que se desarrollan a nivel nacional, con el fin de encaminar un correcto proceso de gestion dentro de las instituciones de educacion superior. A traves de un proceso investigativo de las diferentes normas, convenciones, leyes y demas decretos existentes que estan siendo aplicados obligatoriamente o por iniciativa propia en el territorio nacional y cuya poblacion objeto de estudio son las instituciones educativas colombianas. El resultado de esta documentacion es el impacto organizacional, educativo, cognitivo y social, que se genera a raiz de la implementacion de las normas. Se concluye que la actividad universitaria no puede centrarse exclusivamente en la practica academica, sino que deben estar basada en las acciones socialmente responsable, el caracter etico, y formacion de profesionales con etica, que busquen el bien comun y esten orientados al desarrollo sostenible.

Impacto de las normas que regulan la responsabilidad social en las instituciones de educación superior

La investigacion acerca de Estrategias metodologicas para desarrollar la comprension lectora en los alumnos de quinto grado A del turno matutino de la Escuela Jose Maria Villaseca, distrito III, municipio de Managua, en el I semestre del ano 2019. El grupo de objeto de estudio, a nivel externo, pertenece a una escuela subvencionada, que esta ubicada en Managua el barrio Altagracia, cuya poblacion estudiantil procede de hogares pudientes y tambien de escasos recursos economicos, a estos ultimos se les proporciona beca completa. A nivel interno, el dato mas significativo indica que presenta un bajo desempeno en comprension lectora, afectando su rendimiento academico en las diferentes asignaturas. Es debido a lo anterior que la investigacion se planteo la finalidad de analizar las estrategias metodologicas que se implementan en la practica, su pertenencia respecto a las competencias que se espera desarrollen los estudiantes objetos de estudio y en relacion a las caracteristicas de estos ultimos, con vista a determinar las necesidades en base a las cuales se elaboraron recomendaciones que permitan asegurar en los estudiantes, fuertes habilidades de comprension lectora. 
El estudio se realizo con enfoque cualitativo, de tipo descriptivo porque analiza las estrategias de comprension lectora que aplica el docente con los estudiantes de quinto grado, transversal porque fue realizado en un periodo de 3 meses, utilizando las tecnicas de observacion y entrevista para recolectar la informacion, la cual se analizo mediante la tecnica de triangulacion de la perspectiva teorica y los resultados de observaciones, entrevista y la prueba diagnostica a los estudiantes partir de lo cual se establecieron las conclusiones y recomendaciones. 
Los hallazgos indican que en el aula se aplican estrategias esquematicas y tradicionales de ensenanza que no facilitan el desarrollo de la comprension lectora de los estudiantes en forma significativa. Por tanto, se recomienda a la direccion del centro, desarrollar estrategias para el fortalecimiento de los niveles de comprension lectora en los estudiantes. Al docente del aula en particular, se le propone asumir una actitud proactiva para el mejoramiento de su labor docente. Ambos aspectos son requisitos basicos para lograr una evolucion real de las capacidades de los estudiantes en la educacion y en la vida

Estrategias metodológicas para desarrollar la comprensión lectora en los estudiantes de quinto grado del turno matutino de la escuela José María Villaseca, ubicado en el distrito III, en el departamento de Managua en el I semestre del año 2019

The present literature review was carried out with the objective of identifying the care provided by professional staff to neonates with hyperbilirubinemia in phototherapy treatment, through the analysis of previous studies on the care of users with this pathology. Considering the activities performed by the nursing professional within the health units, providing quality care especially to priority groups such as neonates, this disease is attributed to a physiological or pathological process that affects premature newborns as a term, positioning itself as one of the main causes of morbidity; The present bibliographical revision is carried out entitled: Nursing care in the neonate with hyperbilirubinemia, Ecuador 2018. Fifteen documents obtained from the bibliographical bases were selected: Scielo, Lilacs, Redalyc, VHL, visits on official websites of the World Health Organization (WHO) and Ministry of Public Health of Ecuador (MSP), published between 2014 and 2019. Triangulation and analysis of each one was carried out to obtain the pertinent information, carrying out the discussion and respective study, determining nursing care, among those that stand out: general care such as promotion and prevention activities, promotion of breastfeeding, continuous education to the family, hydration, vital sign control, interpretation of laboratory data and use of the Kramer scale; phototherapy activities: skin care, eye and genital protection, thermoregulation and postural changes; while for exanginotransfusion: glucose control, evaluate signs of hemolysis and continue with phototherapy to prevent rebound effect.

Cuidados de Enfermería en el Neonato con Hiperbilirrubinemia. Ecuador, 2018

espanolSe presenta una investigacion cualitativa desde el marco teorico psicoanalitico con el fin de realizar un analisis de los 101 audios publicados por el portal IDL Reporteros acerca de la corrupcion del Consejo Nacional de la Magistratura del Peru. El marco psicoanalitico permite analizar la presencia de mecanismos inconscientes inscritos en los vinculos instituidos de los protagonistas de los audios, tambien denominados «hermanitos». El trabajo plantea un recorrido por las ideas psicoanaliticas relacionadas con fenomenos de grupos e instituciones, desde Freud hasta autores contemporaneos como Kaes y Ulloa. De los trabajos de Freud se recogen mecanismos psiquicos inconscientes como proyeccion, idealizacion e identificacion. Posteriormente, Kaes plantea que existen mecanismos de grupo tales como el pacto denegativo y el contrato narcisista. Ulloa, por su parte, destaca la encerrona tragica, un dispositivo para perpetuar la crueldad donde no hay tercero que interceda.Los resultados arrojan ocho categorias, las cuales fueron obtenidas a partir del metodo de analisis tematico. Sobre la base de ello, se describe el funcionamiento de la estructura de poder del grupo de los hermanitos, sostenida en la corrupcion y en un desmedido afan de apoderamiento y explotacion del otro —elemento caracteristico de fantasias omnipotentes que se expresan en pactos denegativos o acuerdos que intentan ubicar al sujeto por encima del malestar en la cultura—. Respecto de su funcionamiento, podemos notar un lenguaje comun y un habla en codigos que dan cohesion al grupo y permiten dar cuenta de los vinculos entre sujetos. El grupo es reflejo de una estructura de poder vertical, en la cual los subordinados son explotados y violentados, siempre en una posicion de dependencia. En el destacan alianzas inconscientes con resortes familiares evidentes, que aseguran su continuidad gracias a actividades de disfrute en lugares exclusivos. Asimismo, las amenazas externas generan fantasias paranoides que refuerzan un habla en codigo, a la vez que colocan fuera un perseguidor que amenaza la perpetuacion de dicha estructura. EnglishThis study presents a qualitative research based on the psychoanalytic theoretical framework with the purpose of realize an analysis of the 101 audios published by the IDL Reporteros website, about corruption in the Consejo Nacional de la Magistratura of Peru. The psychoanalytic framework allows to analyze the presence of unconscious mechanisms inscribed in the instituted links between the main characters of these audios, also called «hermanitos». The research presents a route of the psychoanalytic ideas related to group and institution phenomena, from Sigmund Freud to contemporary authors like Kaes and Ulloa. Freud’s work allows to analyze unconscious mechanisms like projection, idealization and identification. Kaes proposes group mechanisms like denied pact and narcissistic contract, and Ulloa highlights the tragic entrapment, an institutional and social device that perpetuates cruelty where there’s no other that intercede. The results show the emergence of eight categories obtained through thematic analysis. Based on the results, we describe the functioning of the power structure of the hermanito’s group, maintained on corruption and an excessive seizure desire and exploitation of others, characteristic of omnipotent fantasies expressed on denied pacts or agreements that pretend to be above civilization and its discontents. About its functioning, we can remark a common language and speaking in code that brings cohesion to the group and allows observing the relationship between subjects. The group reflects a vertical power structure in which subordinates are exploited and forced, as well as dependents. In it stand outs unconscious alliances with evident family springs that ensure its continuity by activities of enjoyment and exclusivity. Likewise, external threats generate paranoid fantasies that reinforce speaking in code, as well as place out a persecutor that threats the perpetration of this structure.

Antimicrobial resistance in the city of Ayacucho is a frequent public health problem, therefore a descriptive investigation was carried out to determine the prevalence of Escherichia coli and Klebsiella pneumoniae producing extended-spectrum betalactamases and Ampc of hospitalized and outpatient patients in the Regional Hospital of Ayacucho from January 2015 to October 2016 and also evaluate the resistance patterns in vitro against the different groups of antibiotics such as quinolones, carbapenems, aminoglycosides and furans, in addition to doing this screening for the determination of producing strains of Extended Spectrum Beta Lactamases (BLEE), AmpC and their confirmation by the Hodge method, inhibitors and the Vitek system. The urine cultures of patients who went to the Microbiology area with the corresponding request were analyzed, performing the urine culture and the antibiogram by the diffusion disk method and vitek 2, in addition to screening for beta-lactamase-producing strains and their confirmation by the Hogde method and inhibitors. We analyzed 2728 samples of which 474 urine cultures were positive with growth greater than 100,000 CFU / ml, the most frequent microorganism being Escherichia coli with 69.4%, Klebsiella pneumoniae 7.6%, other microorganisms 23% of the total cases, having more incidence in women with 64%. A resistance of Escherichia coli to quinolones of 79.1% to ciprofloxacin, 79.4% to Levofloxacin. A resistance to carbapenems of 0%, a resistance to aminoglycosides of 43.8% for gentamicin, 3.7% for Amikacin and Torbamycin 64.7%. In addition, 47.7% of Escherichia coli strains were found to be (BLEE) positive which were confirmed by Hogde and Inhibitor methods and 3.9% of AmpC positive results. In the case of Klebsiella pneumoniae, I have a resistance of 83.3% to ciprofloxacin, 83.3% to levofloxacin, resistance to carbapenems of 0%, resistance to aminoglycosides of 75.1% for gentamicin, 2.7% for amikacin and tobramycin 86.1%. In addition, 83.3% of Klebsiella pneumoniae strains were found to be BLEE positive, which were confirmed by Hogde and Inhibitor methods and 0.0% of Klebsiella pneumoniae were AmpC negative.

Prevalencia de Betalactamasas de Espectro Extendido y AMPC en Escherichia coli y Klebsiella pneumoniae Aislados de Muestras de Orina de Pacientes Hospitalizados y Ambulatorios en el Hospital Regional de Ayacucho Febrero 2015 – Octubre 2016.

Este proyecto se basa en los elementos para la medicion de huella de carbono en una 
Institucion de educacion superior a nivel nacional para asimismo poder realizar la 
implementacion ya que es una herramienta de mejora continua en la parte ambiental, es 
importante generar concientizacion para la disminucion de la huella de carbono, de esta 
forma contribuir positivamente a la mitigacion del impacto al medio ambiente y ser 
reconocido entre las universidades como generador de buenas practicas y contribuyente de 
forma positiva al medio ambiente. 
A Traves de diferentes herramientas de analisis y que permitieron recolectar la 
informacion como las matrices vistas en cada uno de los modulos de la especializacion en 
gestion ambiental en la Uniagustiniana se diligenciaron ingresando los aspectos e impactos 
identificando los mas significativos para la institucion, revision de la normatividad legal en 
Colombia aplicada al componente ambiental y por ultimo un diagnostico general las 
condiciones ambientales, identificando el alcance la importancia que tiene la reduccion de 
huella de carbono en las instituciones de educacion superior, y asi mismo se fortalece la 
investigacion con el concepto huella de carbono en las IES a nivel nacional.

Elementos para la medición de huella de carbono en la Uniagustiniana

DOI: 107764/Horiz_Enferm.29.2.75-88 El presente estudio se enmarca en el Programa Mas Adultos Mayores Autovalentes (MAS AMA) enmarcado en las politicas publicas de salud en Chile, implementado el ano 2015 en Atencion Primaria con el proposito de influir de forma positiva en la calidad de vida de las personas mayores, con un enfoque preventivo y promocional. Esta investigacion pretende indagar en las percepciones psicosociales de las personas mayores tras su participacion en el programa. Para ello mediante una metodologia cualitativa, fenomenologica y exploratoria, se describen aspectos psicosociales de los adultos mayores del Programa, ofrecido en el CESFAM Dr. Pedro Jauregui, de la ciudad de Osorno. Se seleccionaron 10 adultos mayores mediante un muestreo por conveniencia, realizando entrevistas semiestructuradas previo firma de consentimiento. Estas fueron transcritas y analizadas segun la Teoria Fundamentada utilizando el software ATLAS.ti ® . Los resultados demuestran que el Programa contribuye a un incremento en los niveles de socializacion de los sujetos en estudio; en la autopercepcion del estado y manejo de su salud y en el bienestar psicologico al enfrentar estados depresivos, contribuyendo asi a un envejecimiento activo. Finalmente, se obtiene informacion relevante para ser utilizada por los equipos de salud de atencion primaria y asi aumentar la cobertura del Programa MAS AMA, siendo ejecutado en todos los CESFAM a nivel local, ya que los beneficios que se obtienen responden a las politicas publicas de autonomia y de envejecimiento saludable.

PERCEPCIONES PSICOSOCIALES DE ADULTOS MAYORES PARTICIPANTES DEL PROGRAMA “MÁS ADULTOS MAYORES AUTOVALENTES” DEL CESFAM “Dr. Pedro Jáuregui”, OSORNO, CHILE PSYCHOSOCIAL PERCEPTIONS OF OLDER ADULTS PARTICIPATING IN THE "MORE ADULTS OF OLDER AUTOVALENTS" PR

La Formacion y Desarrollo de personal en las organizaciones resulta esencial en el entorno actual donde el conocimiento es vital para las relaciones laborales, las empresas deben comenzar a evolucionar si es que desean contar con los mejores elementos que les ayuden a cumplir con sus objetivos, el entorno laboral de hoy no es el mismo de hace 20 anos, los empleados actualmente buscan ademas de una estabilidad laboral, un empleo que les permita crecer no solo en lo laboral, sino tambien en lo personal, profesional y familiar, con impacto en su calidad de vida. Se genera una competencia entre las organizaciones para contar con el mejor talento humano, recurren a universidades, oficinas de colocacion y a todos los medios necesarios que les de la seguridad de contar con el conocimiento que requieren.

Programa de formación y desarrollo del componente humano del CUNorte

Técnica pilates como alternativa para el tratamiento fisioterapéutico

Implementación de un Data Center Virtual en Cloud Computing para mejorar los servicios del departamento de TI en la Empresa Venus peruana S.A.C

espanolCronica testimonial politica del lider comunista Franklin Chacon Estrada, en San Isidro del General. Guerra Civil de 1948. La Cronica politica de un lider comunista desde los primeros dias de la guerra civil de 1948, en la ciudad de San Isidro del General de la provincia de San Jose de Costa Rica. Memoria politica de los preparativos de lo que seria el ataque militar por fuerzas extranjeras y nacionales para el control de esta ciudad y de este modo inicia la guerra civil. Esta ciudad fue defendida por varios dias por fuerzas leales al gobierno calderonista y por grupos comunistas finalmente son vencidos, teniendo muchas perdidas humanas, y los lideres militares de la Legion del Caribe controlan a la poblacion, haciendo presos politicos a muchos como el autor de este testimonio que narra con autenticidad los s dias de carcel y episodios sobresalientes, como el del fusilamiento abortado por el companerismo mason. Y los actos valerosos de los hombres al mando de Carlos Luis Fallas Sibaja y Comandante Tijerino. EnglishChronic political testimonial of the communist leader Franklin Chacon Estrada, in San Isidro del General. Civil War of 1948. The political Chronicle of a communist leader from the first days of the 1948 civil war, in the city of San Isidro del General of the province of San Jose de Costa Rica. Political memory of the preparations of what would be the military attack by foreign and national forces for the control of this city and in this way initiates the civil war. This city was defended for several days by forces loyal to the Calderonist government and by communist groups finally defeated, taking many human losses, and the military leaders of the Caribbean Legion control the population, making political prisoners to many as the author of this testimony that narrates with authenticity the days of jail and outstanding episodes, such as the one of the execution aborted by the masonic companionship and the valiant acts of the men under the command of Carlos Luis Fallas Sibaja and Commander Tijerino.

Memoria del Secretario Político del Partido Vanguardia Popular, San Isidro de EL GENERAL, San José, 1948 TESTIMONIO DE FRANKLIN CHACON ESTRADA EN LA GUERRA CIVIL DE 1948

Uso efectivo del material educativo en el aprendizaje del área de Matemática en la I.E. 2046 Virgen de las Mercedes

Introduccion: El sedentarismo es un factor de riesgo que favorece la presencia de enfermedades no transmisibles, principalmente la cardiopatia isquemica, que es la segunda causa de mortalidad en todo el mundo; no obstante, la actividad fisica moderada y/o vigorosa como intervencion estandarizada podria modificar o controlarlo.

REVISIÓN SISTEMATIZADA DE LAS INTERVENCIONES EDUCATIVAS PARA REDUCIR EL SEDENTARISMO EN PACIENTES CON CARDIOPATÍA ISQUÉMICA

In the cultivation of the coffee, green fruit residues are present, these residues can be exploited by their phenolic contents 12 . In this research, a coagulant was evaluated from coffee bean of species coffea arabica coffee residues in natural water samples from the Carbonera creek, in the Subia village, in the municipality of Silvania - Cundinamarca. Taking into account initial and final parameters of the Chemical Oxygen Demand (COD), Biochemical Oxygen Demand (BOD) and turbidity. The initial turbidity data for the creek during the dry season and rain corresponded to 3.86 and 367 NTU. Subsequently, the coagulant extraction process was performed using the ultrasound-assisted extraction technique for a time of 60 minutes and 40kHz; The final concentration of polyphenols was determined by the Follin Ciocalteu quantification method, obtaining an extract concentration of 385.4 mg GAE / g of coffee on a dry basis.

Evaluación fisicoquímica del tratamiento primario de agua, mediante el uso de un coagulante obtenido a partir de residuos de café

La situacion de representacion mediada por el titere no solo responde a las ideas tradicionales de movilizar contenidos linguisticos, axiologicos, culturales. Desde la perspectiva de la teoria de la accion didactica conjunta (TADC), las acciones del profesor estan reguladas por la construccion de medios didacticos que contribuyen a lograr los aprendizajes. Este trabajo de investigacion aposto por las posibilidades de abordaje corporal, desde las diferentes tecnicas de titeres para desarrollar contenidos como: reconocimiento corporal, ubicacion espacial, relaciones con los pares, los objetos y su entorno, lateralidad, disociacion, confianza, sensibilizacion, entre otros aspectos fundamentales en el desarrollo de la infancia. Por esto se respondio a la pregunta ?Como el titere, como medio didactico, aporta a los procesos corporales, la construccion de corporeidad y al movimiento corporal de los ninos y ninas de jardin 2 del Colegio Atanasio Girardot? La metodologia que se implemento fue la IAPE (investigacion accion pedagogica educativa); donde se propone que el docente transforme el aula de clase, cree y mantenga una practica reflexiva. Se desarrollo de los anos 2015 a 2017 con los grados de jardin y transicion. En conclusion, esta investigacion ofrece elementos teoricos en relacion con las tecnicas de titeres, su funcion en la escuela, como medio didactico, reflexiones sobre el cuerpo y las diferentes miradas que se tienen sobre el; y practicos para llevarlos al aula y consolidar procesos de ensenanza- aprendizaje sobre el cuerpo; la prevencion, el cuidado, la conciencia del mismo, la relacion con el otro y con los otros y el acercamiento al mundo del teatro por medio del titere 
dentro de la situacion de representacion.

El títere, un medio didáctico para los procesos corporales, la corporeidad y el movimiento en la educación inicial

Evidenciar la influencia de las pautas de crianza en el desarrollo social del nino entre edades de dos a cuatro anos en el jardin infantil Blanco y Negro.

Prevalencia de Leptospira interrogans y Serovariedades en Pacientes con Sindrome Febril en el Distrito de Olmos – Lambayeque – Septiembre - 2016.

Análisis de los problemas del cálculo mental en las decisiones de consumo de un grupo de individuos en la ciudad de Bogotá

Incidencia de los trastornos hipertensivos del embarazo en gestantes diagnosticadas con infección de vías urinarias en el Hospital Infantil Universitario de San José y Hospital de San José, durante el año 2015

Evaluacion de las posibles fuentes opticas de ancho espectro que pueden ser utilizadas junto con dispositivos de fragmentado espectral (AWGs), con el fin de ser utilizadas en enlaces de larga distancia como portadoras de informacion, logrando un reduccion de costos en este tipo de transmisiones.

Evaluación del Fragmentado Espectral como Técnica de Generación de Portadoras Ópticas

The familiar subsidy that some personsenjoy in Colombia, is a juridical figurecreated in France to protect the largefamilies. Colombia implemented thefamiliar subsidy with the expedition ofthe decree 118 of 1957, signed by themilitary junta and across the law 21 of1982 recognizes it as a payable socialsecurity benefit in money and I spread.In this one article treats only the payablefamiliar subsidy in money for spouse,permanent partner and children to theprofessional soldiers of the National Army of Colombia, being these thecentral population of this one analysisbecause only familiar subsidy isrecognized after him until the year2000, later in the year 2009 benefit isdeprived to them of this one becausedue to the way in which the law wasinterpreted, it became untenablefinancially keeping on recognizing it,and in the year 2014 one returns themto recognize the right after the familiarsubsidy but in a less percentage, leavingthem initially in an inequality opposite toprofessional soldiers sheltered underthe decree 1794/2000, official,subofficial and civil linked to the militaryforces.

Subsidio familiar en compensación económica para hijos y cónyuge o compañera permanente de soldados profesionales ¿Derecho a la Igualdad o jerarquía militar?

Estudio de factibilidad para la creación de una empresa de consultoría de soluciones en business intelligence especializada en el área de ventas y finanzas en grandes empresas de transporte de carga

Background: Current business scenarios and market mechanics have positioned innovative activity as one of the most required management strategies to reinvent the form of business relationships and value that organizations create with their customers and other interest groups, of the same In this way, the relationship with these actors in the environment is no longer seen as an isolated phenomenon that does not affect business activity, but on the contrary, each interest group has an impact on the company's value chain. In this sense and from a macroeconomic perspective, the theories of endogenous development have highlighted two key dynamics to create capacities that allow the generation of value, knowledge and technology that improve the quality of life of the inhabitants, as well as favorable business scenarios and contributors to the growth of the regions, the relationship between three actors stands out in the first instance: universities, industry and government. Objective: To diagnose the current state of the University-Industry-Government linkage as a contribution to generation of open innovation, identifying its most outstanding features in the regional system of the department Atlantico. Materials and Methods: Methodologically, the study has focused on diagnosing the current state of the regional innovation system from the main actors of the triple helix, using tools supported by the documentary review and secondary information about 50 sources that have allowed to nurture the initiatives, projects and figures related to the key aspects per actor linked to the innovative activity and to what extent it has been developed openly, dimensioned from a diagnostic process, assessment of key elements and definition of improvement opportunities for the system. Results: The findings of the document review process have made it possible to identify that the innovation system has achieved achievements by having a platform of institutions of higher education recognized as universities (seven), highly innovative companies (four) and actions undertaken by territorial administrations (governorate and mayorships), presented outstanding performance and progress over previous studies of the system; Regarding the approach of open innovation, its application in the actions of the actors has not been identified, however, this is presented as a tool in view of the improvement opportunities that allow to enhance the department's results and position the regional innovation system from Atlantico as a benchmark for business and competitive intelligence at the national level. Conclusions: Regarding innovation, organizations such as the OECD internationally emphasize the relevance that the concept combined with research and development has acquired as a factor of competitiveness and sustainability, innovation theories display different ways by which strategies can be adopted and implemented innovative in organizations, highlighting open innovation as a way of co-creating solutions, products or processes by transferring knowledge of the environment to the system, so that the contributions of different interest groups nurture the innovative activity from the organization towards the environment in the so-called collaborative workspaces. Key-Words: University-Industry-Governement Linkage, Triple Helix, Open innovation, Regional systems. REFERENCIAS 1. Abello, R. et al. (2013). Plan estratégico departamental de ciencia, tecnología e innovación del Atlántico (PEDCTI) 2012–2022. Disponible en: https://goo.gl/Xk1j53 2. Amar, P. & Diazgranados, J. F. (2006). Modelo de relación estado-mercado para el fomento de la innovación. Investigación & Desarrollo, 14(1), 200-225. 3. Amar, P. & Miranda, R. (2014). Hacia dónde vamos En: Amar, P. et al. CUEE Caribe: una estrategia para fomentar la transferencia tecnológica en la región (pp. 133-145). Barranquilla, Colombia: Ediciones Universidad Simón Bolívar. 4. Amar, P. (2017). Los desafíos de la innovación y el emprendimiento en Colombia. En J. M. Mendoza (presidencia). I Coloquio del Doctorado en Administración. Universidad Simón Bolívar, Barranquilla, Colombia 5. Amar, P., Angulo, G., Ortega, M., & Quintero, J. (2006). El sistema de innovación del departamento del atlántico: una mirada desde la cibernética organizacional. Revista GTI, 5(12), 55-62. 6. Azagra-Caro, J. M., & Consoli, D. (2016). Knowledge flows, the influence of national R&D structure and the moderating role of public–private cooperation. The Journal of Technology Transfer, 41(1), 152-172. 7. Behar, D. (2008). Introducción a la metodología de la investigación. Lima, Perú: Ediciones Shalom. 8. Bolívar, A. (2001). Los centros educativos como organizaciones que aprenden: una mirada crítica. Contexto Educativo, 3(18), 1-11. 9. Brunner, J. J. (2011). Gobernanza universitaria: tipología, dinámicas y tendencias. Revista de Educación, 355, 137-159. 10. Coe, N. & Letza, S. (2014). Two decades of the balanced scorecard: A review of developments. The Poznan University of Economics Review, 14(1), 63-75. 11. COLCIENCIAS (2016a). El estado de la ciencia en Colombia – Convocatoria 737. Disponible en: https://sites.google.com/a/colciencias.gov.co/estado-de-laciencia-2015/ 12. COLCIENCIAS (2016b). Guía para la selección de las empresas altamente innovadoras. Recuperado desde: http://www.colciencias.gov.co/sites/default/files/ckeditor_files/guiatecnicapilotoeais.pdf 13. COLCIENCIAS (2017). Documento de actualización de los sistemas de indexación y resumen SIR. Recuperado desde: http://www.colciencias.gov.co/sites/default/files/upload/convocatoria/documento -sires-abril-2017.pdf 14. Cortés, F. A. (2006). La relación universidad-entorno socioeconómico y la innovación. Ingeniería e Investigación, 26(2), 94-101. 15. Chesbrough, H. (2013). Open business models: how to thrive in the new innovation landscape. Boston, USA: Harvard Business Press. 16. Christensen, C. (2013). The innovator’s dilemma: when new technologies cause great firms to fail. Boston, USA: Harvard Business Press. 17. DANE (2016). Cuentas departamentales Producto Interno Bruto 2016. Recuperado desde: https://www.dane.gov.co/files/investigaciones/pib/departamentales/B_2005/pre s_2016preliminar.pdf 18. DNP (2015). Índice Departamental de Innovación para Colombia (IDIC). Recuperado desde: https://colaboracion.dnp.gov.co/CDT/Prensa/Publicaciones/%C3%8Dndice%20 de%20Innovaci%C3%B3n%20Departamental%20para%20Colombia.pdf 19. Etzkowitz, H. & Leydesdorff, L. (2000). The Dynamics of Innovation: From National Systems and “Mode 2” to a Triple Helix of University-IndustryGovernment Relations. Research Policy, 29(2), 109–123. 20. Fernández de Lucio, I., Conesa, F., Garea, M., Castro, E., Gutiérrez, A., & Bodegas, M. A. (1996). Estructuras de interfaz en el sistema español de innovación. Su papel en la difusión de tecnología. Valencia, España: Centro de Transferencia de Tecnología Universidad Politécnica de Valencia. 21. González-Ramos, M. I., Donate-Manzanares, M. J., Guadamillas-Gómez, F. & Alegre-Vidal, J. (2014). Relación entre el dinamismo percibido, la postura tecnológica y los resultados de innovación. Journal of Technology Management & Innovation, 9(2), 131-144. 22. González-Sánchez, R. & García-Muiña, F. (2010). Innovación abierta: un modelo preliminar desde la gestión del conocimiento. Intangible capital, 7(1), 82-115. 23. Hernández, R., Fernández, C. & Baptista, P. (2014). Metodología de la investigación. (6a ed). México: McGraw-Hill. 24. Jiménez, F., Fernández de Lucio, I. & Menéndez, A. (2011). Los Sistemas Regionales de Innovación: experiencias concretas en América Latina. En: Llisterri, J. & Pietrobelli, C. (eds). Los Sistemas Regionales de Innovación en América Latina (pp. 58-103) Nueva York, EE.UU: Banco Interamericano de Desarrollo. 25. Kerry, C. & Danson, M. (2016). Open Innovation, Triple Helix and Regional Innovation Systems: Exploring CATAPULT Centres in the UK. Industry and Higher Education, 30(1), 67-78. doi: https://doi.org/10.5367/ihe.2016.0292 26. Ley 1530 “Por la cual se regula la organización y el funcionamiento del Sistema General de Regalías”. Congreso de la Republica de Colombia. Bogotá, D.C. 17 de mayo de 2012. 27. Leydesdorff, L. & Ivanova, I. A. (2016). 'Open Innovation' and 'Triple Helix' models of innovation: can synergy in innovation systems be measured? Journal of Open Innovation: Technology, Market, and Complexity, 2(11), 1-12. doi: https://doi.org/10.1186/s40852-016-0039-7 28. Luengo, M. J. & Obeso, M. (2013). El efecto de la triple hélice en los resultados de innovación. RAE-Revista de Administração de Empresas, 53(4), 388-399. 29. Márquez, A. & Pérez, L. (2015). Análisis relacional entre capital intelectual y el desarrollo organizacional en la universidad. Gestión y Gerencia, 9(3), 48-74. 30. Martínez, D., Melamed, E., Rodríguez, I., Amar, P., Miranda, R., & Quintero, V. (2017). Dinámicas de innovación y relacionamiento universidad-empresa-Estado para el desarrollo del turismo de negocios. En: V. Quintero y R. Miranda (Comp.). Turismo corporativo y TIC: una puerta a la competitividad, 213-244. 31. Martínez, D., Miranda, R. & Rodríguez, I. (2014). ¿Dónde estamos? En: Amar, P. et al. CUEE Caribe: una estrategia para fomentar la transferencia tecnológica en la región (pp. 59-115). Barranquilla, Colombia: Ediciones Universidad Simón Bolívar. 32. Mazzucato, M. (2015). The entrepreneurial state: debunking public vs private sector myths. London, UK: Anthem Press. 33. Melamed-Varela, E. & Miranda-Medina, C. (2016). Transferencia tecnológica en la educación. Educación y Humanismo, 18(31), 180-182. doi: https://doi.org/10.17081/eduhum.18.31.2357 34. Méndez, R. (2002). Innovación y desarrollo territorial: algunos debates teóricos recientes. EURE, Revista Latinoamericana De Estudios Urbano-Regionales, 28(84), 63-83. http://dx.doi.org/10.4067/S0250-71612002008400004 35. Miguel, S., Chinchilla-Rodríguez, Z. & De Moya-Anegón, F. (2011). Open access and Scopus: a new approach t

Vínculo universidad-empresa-estado e innovación abierta: diagnóstico en el sistema regional del departamento del Atlántico

Introduccion: Desde los primeros reportes de VIH infantil en Latinoamerica en el ano 1987 hasta el dia de hoy, ha sido concienzuda la investigacion y clasificacion de las distintas patologias que han presentado los pacientes VIH positivos. Lamentablemente en nuestro pais no existe una publicacion oficial la cual describa cuales son las enfermedades oportunistas mas frecuentes. Es importante conocerlas, pues esto nos permite poder empezar un tratamiento oportuno y eficaz. Objetivo: Establecer la prevalencia de infecciosas oportunistas en pacientes pediatricos VIH positivos en el Hospital del Nino Dr. Francisco de Icaza Bustamante desde enero 2012 hasta diciembre 2016. Materiales y metodos: El presente documento se trata de un estudio de prevalencia, observacional, descriptivo, de 173 pacientes pediatricos VIH positivos, del Hospital del Nino Dr. Francisco de Icaza Bustamante. Se revisaron historias clinicas para poder determinar cuales eran las infecciones oportunistas que se presentan con mayor frecuencia. Resultados y discusion: Como resultado del estudio se obtuvo que la tuberculosis fue la infeccion oportunista mas frecuente (37%) y que, de las variables, el sexo mostro ser estadisticamente significativa (p 0.001), siendo el sexo masculino mas propenso a contraer una infeccion oportunista. Conclusion: la prevalencia de infecciones oportunistas destaca a la TB como su enfermedad principal en pacientes VIH positivos, tambien que los varones son mas propensos a estas infecciones. Tambien se concluyo que la edad no es un factor estadisticamente significativo.

Prevalencia de infecciones oportunistas en pacientes pediátricos VIH positivos en el hospital del niño Dr. Francisco de Icaza Bustamante desde enero 2012 hasta diciembre 2016.

Gasto público en niñas, niños y adolescentes en el Perú : estudio de caso del análisis del gasto público en los espacios amazónicos 2013-2015

Comparamos dos tipos de recorridos guiados en el Museo Nacional de Historia Natural (La Paz, Bolivia) en relacion a seis variables de respuesta medidas en grupos de estudiantes de 4o a 6o de primaria. Uno de los recorridos (GT) incluye una metodologia tradicional de transmision del conocimiento del guia al visitante. El otro recorrido (SI) utiliza la metodologia de Senderos de Indagacion, basado en la construccion del conocimiento por parte del visitante, facilitada por el guia. En los recorridos SI registramos mayor porcentaje de estudiantes atentos, que participaron de manera reflexiva sobre lo observado y que participaron reflexionando sobre su entorno en relacion a lo observado. No encontramos diferencias entre los recorridos en el porcentaje de estudiantes que participaron en relacion a lo observado. No encontramos diferencias cuantitativas, pero si cualitativas, en el numero de respuestas sobre aprendizajes nuevos y sobre cambios que podrian hacer en su entorno. Concluimos que la metodologia de los SI es mas apropiada para generar cambios de actitud en los visitantes en relacion a la conservacion de la naturaleza.Palabras clave: Educacion para la conservacion de la naturaleza; Museos; Metodos de guiaje; Senderos de indagacion.Comparison of traditionally and indagatory guided visits to the Museo Nacional de Historia Natural, La Paz - BoliviaWe compared two types of guided visits to short trails at the Museo Nacional de Historia Natural (La Paz, Bolivia), in relation to six response variables measured in groups of 4th to 6th grade children. One of the trails followed the traditional way of guidance with knowledge transmission from the guide to the visitor (GT). The other one used the Trails of Inquiry methodology, based on the knowledge building by the visitor, eased by the guide (SI). A larger percentage of attentive children, children that reflexively participated of the observations, and those that made reflexive comments about what they observed in relation to their own close environment. There was no difference between groups in the percentage of children participating in relation to the observations. Furthermore, there was no quantitative difference in the number of answers about either newly acquired knowledge, or changes that children could do for their own environment, but there was a qualitative difference. We conclude that the SI trails is more appropriate if we want to generate changes in attitudes in the visitors, in relation to nature conservation.Keywords: Conservation education; Museums; guidance methods; inquiry trails.

Comparación entre recorridos guiados tradicionales y recorridos guiados indagatorios en el Museo Nacional de Historia Natural, La Paz-Bolivia

This Current research has the purpose of presenting a detailed structure of the different existing systems for the management of materials in the retail sector in Colombia, depending on the commercial activity. 
An investigation of the state of art is carried out, which must be taken into account for an adequate handling of the materials, the concepts that are revealed in this chapter are: Storage of merchandise, the distribution channels that we find in the chain of Supply, the functions of a warehouse, general inventory model; These are basic knowledge that business owners must not get over costs in their processes. It presents a classification of the different types of warehouses and the normativity to realize the planes of the corridors. 
Storage in companies is usually done with shelves, the procedure basically consists of placing the products on the shelves according to the method used to keep inventories, a structure of the systems for the management of materials is made depending on the nature of the company , A detailed description of each of the equipment and its respective images is elaborated to give a greater clarity to the reader. 
In addition, it makes a matrix of the most representative suppliers of the country, in which the availability of equipment for the handling of materials against existing suppliers in Colombia that offer such systems is evaluated, in addition a short description of each one is elaborated with their respective contact details such as, the address, telephone, web page and city, in order to provide better information from each Colombian supplier

Caracterización de los sistemas para el manejo de materiales en el sector retail en Colombia

1. Resumen Para las marcas, la abundancia de canales de comunicacion en la actualidad no solo supone un mayor numero de vias para acceder a su publico objetivo, sino un escenario competitivo cada vez mas congestionado. Las competencias deportivas y particularmente el futbol se han convertido en fenomenos transnacionales con millones de espectadores en donde las marcas invierten millones de dolares anualmente. Mediante un cuestionario aplicado a 395 personas se evaluo si los altos niveles de inversion se ven justificados por el impacto real del patrocinio deportivo a partir de variables como la pertinencia, la notoriedad y el impacto en la percepcion de las marcas expuestas en el contexto de una competencia deportiva.

Evaluación de la eficiencia de las marcas en los eventos deportivos – “sponsorship”: aplicación en el contexto colombiano

Perfiles de competencia informacional en los estudiantes del VII ciclo de educación básica regular de una institución educativa pública de la provincia de Barranca

Efectos de los reparos tributarios para el cálculo del impuesto a la renta de la empresa laboratorio farmacéutico San Joaquín Roxfarma

La ERC ha adquirido las proporciones de una verdadera epidemia, es una situacion morbida que afecta la poblacion general. Se estima que el 10% de la poblacion mundial sufre de ERC. (Flores, y otros, 2009) En Nicaragua se registro en 1996 un total de 1,721 casos, con una prevalencia estimada del 70% para el 2006-2007, desde el 2002 al 2006 se reportan 127 ninos. (Ministerio de Salud, 2009) 
Se estudiaron 20 pacientes registrados en el Programa de Cronicos de Enfermedades no Transmisibles, del puesto de salud de Los Laureles, Tipitapa, en el periodo de estudio. Esto corresponde al 100% del universo. El tipo de diseno es No experimental cuantitativo. De acuerdo al alcance del estudio es observacional, descriptivo, de serie de casos. Muestreo de tipo no probabilistico por conveniencia. A partir de los datos que se recolectaron, se diseno la base datos correspondientes, utilizando el software estadistico SPSS, v. 20 para Windows. Una vez que se realizo el control de calidad de los datos registrados, se hicieron los analisis estadisticos pertinentes. 
Las edades mas dominantes fueron los pacientes mayores de 50 anos, del sexo masculino, procedente de la comunidad de Los Laureles, que sabe leer, ama de casa. El Estadio 3 fue el mas dominante, se le realizaron examenes completos de laboratorio, siendo la creatinina el examen mas comun. La mayoria de los pacientes presentaron antecedentes patologicos, siendo la Diabetes Mellitus el antecedente mas comun. Lo mismo sucedio con respecto a los antecedentes patologicos familiares. La mayoria no presentaba ningun antecedente personal no patologico. Y de los que presentaron algun antecedente, el mayor fue el consumo de alcohol.

Factores asociados a Enfermedad Renal Crónica (ERC) en pacientes atendidos en el Programa de Crónicos de Enfermedades no Transmisibles del Puesto de Salud Los Laureles, Tipitapa, 2014

RESUMEN: El presente trabajo de investigacion considera identificar los estilos de liderazgo en los coordinadores academicos de una institucion educativa, para que en una investigacion posterior se puedan determinar las fortalezas, capacidades, habilidades que debe manifestar un lider con un gran numero de personas a su cargo. Para llegar a este proposito de investigacion se mostro el Test de Liderazgo Situacional de Hershey y Blanchard, el cual tiene como objetivo encontrar el estilo de Liderazgo para los coordinadores academicos, para posteriormente y siendo objeto de otro proyecto de investigacion que de continuidad al presente se planea 
llevar a cabo su aplicacion para descubrir el estilo de representar las fortalezas necesarias para una disciplina fundamental y un liderazgo efectivo; propiciando un entorno laboral mas saludable y estable.

Estudio del liderazgo para fomentar un ambiente laboral estable.

La crisis economica que vive hoy el Ecuador es resultado de una conjuncion de politicas gubernamentales y de una nueva crisis internacional, agravandose por la dependencia del petroleo, por el elevado endeudamiento y por los gastos burocraticos y suntuarios en los que incurrio el gobierno. El principal afectado, por el momento, es el presupuesto fiscal que ha perdido liquidez y llevo al gobierno a tomar medidas de ajuste a lo largo de este ano.

Reformas a la Ley de Seguridad Social son una regresión de derechos para el docente y el trabajador ecuatorianos

Centro de interacción cultural de Sugamuxi : estrategia de intervención para la integración regional Provincia de Sugamuxi

Análisis de la marca de Pastas Nicolini, al cierre del 2014 y propuesta de plan comercial para su relanzamiento

Este articulo muestra los resultados del proyecto Geinve v1.0, el cual busca fortalecer los procesos automatizados de la universidad ECCI, con el apoyo de su grupo de investigacion Sistema de Gestion Cientifica y Tecnologia, Sigcienty, y los semilleros Mente Viva y Aprovechando la Web. Ademas se responde a la pregunta de investigacion: ?cuales son las estrategias para la construccion de un prototipo inicial para un modelo integral en la gestion investigativa en la Universidad ECCI, orientado hacia el esquema de negocio? Dando alcance a la estructura organizacional de la Universidad y a la Gerencia de Proyectos de la Vicerrectoria de Investigacion, se tomo como base para el desarrollo de este trabajo, la metodologia RUP, con el acompanamiento del lenguaje del modelo unificado-UML y la metodologia Proyect Management Body of Knowledge –PMBOK-, con el fin de administrar y controlar la gestion de los proyectos de investigacion desde el area de negocios y las especificaciones metricas de un sistema de informacion (software), respectivamente. En el avance de dicha gestion se implemento un prototipo funcional en linea a traves de un sitio web, como metodo de prueba del avance de dichas metodologias, logrando dar una iniciativa al interior de la Universidad ECCI sobre la organizacion y valorizacion de los productos de investigacion de la comunidad cientifica y academica en la ciudad de Bogota, Colombia.

Estrategias en la construcción de un prototipo como modelo integral en la gestión investigativa orientado hacia el esquema de negocio

Clima familiar social y rendimiento académico en ciencia tecnología y ambiente de estudiantes del primer grado de secundaria de tres instituciones educativas, Comas, 2014

La leptospirosis es una de las zoonosis mas comunes y un importante problema de salud publica, aunque se desconoce la prevalencia real de esta enfermedad . [] La infeccion es comunmente transmitida a humanos cuando agua que ha sido contaminada por orina animal se pone en contacto directo con lesiones en la piel, ojos o por las mucosas. En zonas no tropicales, los casos de leptospirosis muestran relativamente marcadas estaciones, donde la mayoria ocurren entre agosto y septiembre o entre febrero y marzo. Con el objetivo de caracterizar el comportamiento epidemiologico en el Hospital Regional de Mandeville en el periodo comprendido entre Julio del 2011 y Julio del 2012 se realizo un estudio retrospectivo, descriptivo de los pacientes ingresados con esta entidad en el servicio de medicina, tomando como universo a los 57 pacientes ingresados con sospecha de la misma siendo la muestra representativa de 49 pacientes los cuales se confirmo positiva la enfermedad donde el 87.7% de los casos correspondian al sexo masculino, el grupo etareo mas vulnerable es el 51 a 60 anos, predominando la incidencia de esta enfermedad en los meses de Noviembre y Diciembre, procediendo la mayoria de los pacientes del parish Manchester de las zonas rurales y semiurbanas, falleciendo solamente 5 pacientes en el estudio que representan un 10.2%. Palabras Claves Leptospirosis, caracterizacion, epidemiologia, comportamiento.

Leptospirosis, comportamiento epidemiológico en Mandeville Regional Hospital. Julio 2011-2012

Objetivo : Realizar la validacion de contenido y adaptacion del cuestionario FANTASTICO a traves de la tecnica Delphi para caracterizar los estilos de vida en adolescentes escolarizados. Materiales y metodos : Estudio de validacion y adaptacion con 12 expertos utilizando la tecnica Delphi de consenso a tres rondas; un Alpha de Cronbach > 0,80 se considero como valor optimo de fiabilidad para la pertinencia, relevancia, utilidad, redaccion y claridad. Resultados: Los 30 items incluidos en el cuestionario evaluan conductas en diez dimensiones del estilo de vida - familiares y amigos, asociatividad y actividad fisica, nutricion,  toxicidad, alcohol, sueno y estres, tipo de personalidad y actividades,  imagen interior, control de la salud y sexualidad y orden - , los puntajes obtenidos en el Alpha de Cronbach fueron: pertinencia: 0,932; relevancia: 0,904; utilidad: 0,948; redaccion: 0,846 y claridad 0,800. Conclusiones: El cuestionario FANTASTICO se adapta como una herramienta breve y util para la aproximacion a los estilos de vida de adolescentes escolarizados desde un enfoque holistico. Es un instrumento fiable para esta poblacion.

Validación de contenido y adaptación del cuestionario FANTÁSTICO por técnica Delphi

A study of 167 patients with anorectal fistula simple and complex from the Workers' Hospital of Lima, for the period 1952-1956 is made. Anorectal fistulas are the 15.39% of all anorectal conditions and continue in numerical importance to hemorrhoids that come first. Independent of age, has found them more often between 25 and 58 years of age, 98.8% of patients were male. Virtually all are mestizos, there are only three black patients.

El presente proyecto de grado, tuvo como proposito estudiar el Impuesto a la Riqueza contenido en el Capitulo I de la Ley 1739 de 2014 para el desarrollo de un manual en el que se explica, de forma detallada y de facil entendimiento, el funcionamiento, los efectos y las implicaciones que trae consigo. Para dar cumplimiento a este objetivo, se planteo una investigacion con una metodologia tipo critica y analitica, la cual sirvio para construir una propuesta de optimizacion que oriente a aquellas personas interesadas en definir y conocer como es el tratamiento tributario para el patrimonio en lo concerniente al Impuesto a la Riqueza. Aqui se desarrollo, una comparacion entre la reciente ley y la legislacion anterior relacionada con esta imposicion tributaria.

Introduccion: La timpanoplastia esta orientada a la reconstruccion anatomofuncional del oido medio que realizada en la membrana timpanica se denomina miringoplastia. 
Objetivo: Determinar la eficacia de Miringoplastia con parche de papel en pacientes que acuden al servicio de otorrinolaringologia del Hospital Antonio Lenin Fonseca 
en el periodo Diciembre 2013 a Diciembre 2014. 
Material y metodo: Estudio prospectivo, descriptivo y de enfoque cuantitativo de fichas de 10 pacientes entre 9 y 65 anos. Universo: 10 oidos, muestra: 10 oidos. Se evaluaron resultados segun sexo, edad, ubicacion, nivel ocioeconomico, 
localizacion y tipo de perforacion, y mejoria funcional objetivada por audiometria. 
Resultados: La integridad anatomica posquirurgica es de 50% con predominio del sexo masculino. En todos los casos, las perforaciones fueron centrales de la pars tensa, de predominio oido izquierdo con un 60%, siendo plastias fallidas 30% derecho y 20% izquierdo. No hay estudios que demuestren diferencias entre oido con el cierre completo de la perforacion. En todos los pacientes el procedimiento fue 
bien tolerado sin efectos secundarios o complicaciones. El 70% logro mejorar el componente auditivo conductivo, sin embargo demostraron en las audiometrias posquirurgicas afectacion neurosensorial variable Conclusion: El parche papel es un medio eficaz y seguro para el cierre de la 
membrana timpanica, ya que reduce la lista de espera quirurgica, beneficiando al paciente, al medico y al hospital en tiempo quirurgico, economia y riesgos propios 
de la anestesia y la cirugia. Siendo una tecnica ideal que conserva la estructura de la membrana timpanica para futuras intervenciones. 
Palabras clave: Miringoplastia, parche de papel, perforacion timpanica

Eficacia de miringoplastía con parche de papel en pacientes que acuden al servicio de otorrinolaringología del Hospital Antonio Lenin Fonseca en el periodo Diciembre 2013 a Diciembre 2014

En Colombia por su riqueza hidrica presenta un gran potencial en el cultivo acuicola, pero debido a el desconocimiento de los procesos y al poco control que hacen los organismos competentes de los factores que afecta esta actividad, generan pocas ganancias a sus cultivadores y grandes dificultades para realizarla. Este articulo describe el desarrollo de un sistema de alimentacion programable, el cual cuenta con un sensor de oxigeno de la empresa Atas Scientific denominado Dissolved Oxygen Kit y un sensor de temperatura tipo sonda denominado DS18B20, que se encargan de obtener sus respectivos valores para enviarlo a un micro controlador CY8CKIT-059 PSoC® 5LP Prototyping Kit el cual lo transfiere por medio de un modulo Zigbee a un computador, este cuenta con una interfaz grafica desarrollada en Python la cual almacena y organiza todos los datos obtenidos tanto por los sensores como por el usuario, dicha interfaz se encarga de enviarle al micro controlador 3 horas en las cuales el usuario desea alimentar a los peces y organiza toda la informacion obtenida en una base de datos que el usuario puede consultar[1][2]

Este proyecto esta desarrollado con el fin de determinar la Prefactibilidad tecnico- economica para el montaje de una planta procesadora de aceite de cocina usado, recolectado en las localidades de Usaquen y Chapinero, que permita reutilizar en un proceso industrial dicha materia prima. Para lograr lo anterior se realizaron tres estudios: de mercado, tecnico y economico. El primero de ellos permitio determinar la disponibilidad de 22,4 Ton de aceite de cocina usado / mes en las localidades, con un costo de compra $365 COP/litro; adicionalmente se realizo el analisis de la oferta y la demanda con el fin de examinar la competencia y los posibles precios de venta del producto. El segundo estudio permitio determinar la infraestructura, equipos, mano de obra y los recursos necesarios para llevar a cabo el proceso tecnico asi como la distribucion y ubicacion de la planta.

Estudio De Prefactibilidad Técnico Económica Para La Instalación De Una Planta Procesadora De Aceite Usado De Cocina Obtenido De Las Localidades De Usaquén Y Chapinero En Bogotá

En el siguiente trabajo se presenta una secuencia de ensenanza, planteada como un problema autentico para alumnos de tercer ano de una escuela secundaria de Rio Gallegos. La propuesta se inicia debido al interes de los estudiantes por las areas en las que realizan actividades recreativas y esta ajustada a los contenidos disciplinares previstos para los espacios de Biologia, Quimica y Educacion Fisica. El problema que la origina es el estudio del nivel de contaminacion en cinco lagunas urbanas. Para ello se realizaron recorridos por los alrededores de los cuerpos de agua; se tomaron, muestras, en las que, se evaluaron parametros fisicos y quimicos de las lagunas; se registro mediante fotografias la presencia de residuos solidos y otros contaminantes. Los resultados de los analisis de laboratorio, se tabularon, graficaron, analizaron, y se obtuvieron conclusiones. Se realizo un informe escrito y el trabajo se expuso en las jornadas institucionales. Durante el desarrollo los alumnos se comprometieron con las actividades; buscaron informacion; se interesaron por las especies de aves y otros grupos de seres vivos que relevaron; hicieron uso adecuado de graficos y tablas, y del material de laboratorio, pero sobre todo le otorgaron sentido a muchos contenidos desarrollados.

Experiencias Prácticas en la Naturaleza. Muestreo y Analisis de parámetros del agua en lagunas urbanas.

Informe de labores--Universidad de Costa Rica, Vicerrectoria de Accion Social, Trabajo Comunal Universitario. 2013. Para mayor informacion puede escribir a accion.social@ucr.ac.cr

Actividades lúdicas de promoción de la calidad de vida en personas con discapacidad, enfermedad crónica y su familia

La Universidad Tecnologica de Tula – Tepeji ubicada en el Estado de Hidalgo, Mexico; inicio inicio sus actividades academicas en septiembre de 1991, es una de las instituciones de educacion superior en el estado de mayor matricula y desde 2005 esta inmersa en procesos de evaluacion externa para todos los programas educativos lo que le ha permitido recibir del gobierno federal en los ultimos anos reconocimientos por su buena calidad, ademas de estar certificada por la norma ISO 9001:2008 para el proceso educativo. En este sentido, la institucion comprometida con la calidad educativa atiende las areas de oportunidad que resultan de cada evaluacion externa, ademas de buscar la eficiencia en los procesos administrativos y que estos faciliten el quehacer academico. El personal de la institucion esta sujeto a evaluaciones externas que permiten conocer su nivel de habilitacion, su perfil y que para los docentes muestran la evidencia de su produccion academica; cumplir con los requisitos de cada organismo evaluador externo es una tarea que puede resultar redundante, conjuntar estos documentos requiere de una inversion alta en el tiempo y recursos como el papel; no es una tarea sencilla el garantizar que todo el personal de la institucion tenga actualizado su expediente, ni tampoco generar los indicadores del personal en tiempo y forma cuando la institucion esta en constante movimiento y el area de recursos humanos espera a que cada persona acuda a entregar sus evidencias y cumplir entonces con los requisitos de los marcos normativos externos; es asi como se identifica la necesidad de mejorar el proceso de actualizacion de los expedientes de todo el personal de la institucion. El Sistema de Curriculum Digital de la Universidad Tecnologica de Tula – Tepeji, es una aplicacion informatica que se realizo con la intencion de contar con un curriculo actualizado y accesible del personal docente y administrativo; ademas de contribuir a la estrategia de sustentabilidad institucional por que todos los documentos estan digitalizados; eficienta el acceso a la informacion y los tiempos de respuesta para procesos de Evaluacion Externa en los que se participa como: PROMEP, CIEES Y COPAES; cuenta con un generador de la estadistica y reportes que se pueden exportar en diferentes formatos, asi como los indicadores definidos en el Sistema de Gestion de Calidad. El personal accesa desde la pagina web de la institucion a la aplicacion en Intranet institucional y actualiza la informacion que le corresponde, generando con ello la trayectoria de cada persona en la institucion; para el caso del personal docente el contar con toda la evidencia digitalizada le facilita su participacion en las convocatorias de PROMEP, ademas de que la interior esta directamente documentado su protafolio de evidencias, ya que registran su produccion academica. Se tiene la proyeccion de vincular este sistema con el de evaluacion al personal docente y al programa de estimulos, contribuyendo con ello al cumplimiento de la mision y vision institucional.

El Curriculum Digital, un sistema de información que eficenta las evidencias para las evaluaciones externas en la Universidad Tecnológica de Tula – Tepeji.

Rol del complejo formado por el Intercambiador Cl - /HCO 3 - AE3 y la anhidrasa carbónica XIV en procesos patológicos cardíacos

The legislation on occupational health and occupational hazards becomes a social concern for stipulating regulations designed to promote the physical and mental welfare of workers seeking to avoid the occurrence of accidents and occupational diseases; however, the construction area is classified as a risky and dangerous activity, due to the high incidence of accidents, where the current legislation proposes a comprehensive approach to minimize all risks, where the participation of everyone in the company is required to create a culture of prevention . Its goal is to report on the implementation of occupational health in the construction industry in the town of Armenia, Quindío. It applied a methodology through literature reviews and the regulatory development discussed in social security in Colombia, specifically occupational health, to find the results, some interviews and surveys were made with the application of different statistical tools, it allowed determine the level of compliance of construction companies in Armenia’s occupational health regulations. All results lead us to consider that companies have an acceptable degree of compliance; however, weaknesses observed in the Plan-Do -Check-Act cycle as the accident rate in Quindío, according to information the occupational health administration remains high and a large percentage of accidents belong to the construction area.

Aplicación de la salud ocupacional en el sector de la construcción en Armenia, Quindío

Practica dirigida (licenciatura en geografia)--Universidad de Costa Rica. Facultad de Ciencias Sociales. Escuela de Geografia, 2014

Análisis biofísico de la subcuenca del Río Chirripó Pacífico para satisfacer la demanda futura de agua de la ciudad de San Isidro del General, Pérez Zeledón, Costa Rica, 2013

Desarrollo del lenguaje escrito en niños con discapacidad auditiva que tienen audífono o implante coclear

Intervenciones fisioterapeuticas en el control postural en pacientes con lesión de sistema nervioso central.

Objective: Identify the prevalence of musculoskeletal disorders in the administrative officials of the municipality of Chia from 2009 to 2011. Methods : We have performed a quantitative, descriptive retrospective and transversal study to identify cases of musculoskeletal disorder in a period of time between years 2009-2011, through the creation of a database, result of the collection of information on medical disabilities, database from the town hall of Chia and an occupational health matrix , from which the record was made in a matrix of Microsoft Excel, including information as: identification number, gender, age, antiquity, department, absence days, CIE10 code, diagnosis, body part affected, type of disease and social security, with the purpose of identify the prevalence of MSD, which as described above are common in administrative workers. Results: we show that the entire population of the Municipality of Chia who were unable to work, 11% is diagnosed with some type of DME, being Lumbago radiculopathy and most common, being the trunk body segment most affected with 80%, the number of women with DME prevailed on the number of men doing administrative work, finally the year with the highest incidence of DME was medical disabilities by 2011.

PREVALENCIA DE DESÓRDENES MÚSCULO ESQUELÉTICOS EN FUNCIONARIOS ADMINISTRATIVOS DE LA ALCALDÍA DE CHÍA, EN EL PERÍODO 2009-2011

This descriptive correlational research aims to determine the relationship between the leadership style of a group of Principals and the Organizational Climate in the schools they lead. The study was conducted in four schools that belong to the Religious Network Sacred Heart of Jesus (RSCJ) located in Metropolitan Lima. The sample of the study consisted of 167 teachers who work at these schools. They were given a questionnaire based on the Rensis Lickert scale to obtain information about the Leadership Style and Organizational Climate perceived by teachers. The research formulated a general hypothesis that has been confirmed by the existence of a positive relationship between Leadership and Organizational Climate perceived by teachers. The results revealed that, both in the level of the Principals´ Leadership and Organizational Climate of the four Sacred Heart schools, the highest percentage is in the medium level with significant differences between the institutions investigated. Results that fit with a positive relationship between a consultative leadership style and Organizational Climate show confidence and commitment among its members.

Relación entre el liderazgo de las directoras y el clima organizacional de las instituciones educativas del Sagrado Corazón en Lima Metropolitana: estudio realizado con personal docente de las instituciones educativas de la red del Sagrado Corazón en Lima Metropolitana

Cuidado ético a la adolescente en situación de aborto, Chiclayo 2012

El nuevo sistema de transferencias adoptado a partir de 2001, mejor conocido como Sistema General de Participaciones, ha significado para los entes territoriales una menor disponibilidad de recursos que se ha reflejado en el sector salud (y en el HURGV) y ha perjudicado nocivamente el crecimiento futuro de las tasas de cobertura, al mismo tiempo que ha condicionado el proposito de aumentar la eficiencia y equidad en la prestacion de los servicios sociales basicos a la comunidad de que trata el Sistema General de Seguridad Social en Salud (SGSSS). Sin embargo la nueva formula de calculo no es el problema si existe una disciplina fiscal en la eficiencia del gasto publico nacional y territorial. Asi como las transferencias no son las unicas comprometidas con el deficit, a diferencia de lo que muchos solian pensar, el deficit fiscal en su conjunto pese a estar involucrado con la actual crisis economica, no es tampoco la causa absoluta de esta.

ESTUDIO, SEGUIMIENTO Y EVALUACION AL SISTEMA GENERAL DE PARTICIPACIONES PARA EL SECTOR SALUD EN SANTANDER : EL CASO DEL HURGV

Los procesos de inclusion educativa de las personas en condicion de discapacidad, PCD, se han convertido en uno de los mayores retos para las Instituciones de Educacion Superior (IES). Por ende, el derecho a la educacion es un derecho humano esencial, un derecho fundamental que se encuentra contemplado en la legislacion nacional e internacional, el cual debe ser garantizado a todos y todas, dentro de unos principios basicos que materialicen una igualdad sustancial en la que se reconoce y acepta la diferencia. (Constitucional, 1980).

Diseño de un instrumento para caracterizar el desarrollo moral en aspirantes y funcionarios de la Policía Nacional de Colombia

El presente estudio del Corregimiento tres de Floridablanca intenta identificar las principales caracteristicas socioeconomicas de la poblacion que lo conforma. Con este proyecto se organiza la informacion generada por los diferentes instrumentos utilizados por la alcaldia y se espera sea una util herramienta para la creacion del plan de desarrollo rural del municipio por parte del consejo municipal de desarrollo rural el cual se esta creando. En la parte inicial se plasma las diferentes problematicas que se plantearon tanto para America Latina como para Colombia desde la perspectiva del desarrollo rural y desarrollo endogeno, teniendo en cuenta los objetivos y principios de actuacion del desarrollo rural. Luego se continua con el estudio de las diferentes variables tanto a nivel social como economico, para determinar la calidad de vida de la poblacion y observar las falencias principales que impiden un mejor desarrollo integral de la misma. Por ultimo luego de un profundo analisis del comportamiento de las diversas variables estudiadas se plantean una serie de recomendaciones o propuestas las cuales se espera tengan eco en las decisiones adoptadas por el consejo municipal de desarrollo.

ESTUDIO SOCIO-ECONOMICO EN EL CORREGIMIENTO TRES DE FLORIDABLANCA

This research was oriented to created a system SCADA, including an electromagnetic sensor (EMS) conductivity for the analysis of wastewater in the Electrocoagulation Process (ECP) and thus ensure a reducction of power consumption. The EMS should deliver a feedback signal to enable online control and monitoring of effluents in order to increase efficiency of the wastewater purification stage, with economical viability, so the main target is to improve the mass and energy balance of the ECP, while the metals are removing successfully. The experimental results confirmed the feasibility of monitoring and system control to remove a 99,54%, of metals in the water spending 0.25 €/m3, rising in this way the effectiveness compared with traditional Electrocoagulation in Batch as well the traditional chemical process. The project was developed within cooperation between RWTH Aachen University and its Colombian partner Pontificia Bolivariana University UPB, enabling projects towards process automation of industrial wastewater treatment using the electrocoagulation process and with economical support from the DAAD and COLCIENCIAS.

Control en línea de una planta piloto de tratamiento de aguas residuales por electrocoagulación

espanolLa presente investigacion analiza los tipos de intervenciones implementados por los Gobiernos con los Pueblos Indigenas en Paraguay, desde la apertura democratica del ano 1989 hasta el Gobierno actual 2008/2013. Como resultado mas significativo de la investigacion se encuentra que el relacionamiento y la intervencion del Estado con los Pueblos Indigenas se caracterizan por un indigenismo de enfoque asimilacionista e integracionista y solo en algunos discursos se incorpora el enfoque de derecho. En lineas generales las evidencias permiten senalar que existe una ausencia de Politicas Publicas, y si bien el INDI (Instituto Nacional del Indigena) cuenta con lineamientos basicos, elaborados sin la participacion de los Pueblos Indigenas, no responden, sin embargo, a las demandas de los mismos, principalmente en cuanto al aseguramiento y legalizacion de la Tierra/Territorio, elemento fundamental para la continuidad y existencia de los Pueblos Indigenas. EnglishThis research analyzes the types of interventions implemented by the Governments with Indigenous Peoples in Paraguay, since the democratic opening in 1989 until the present Government 2008/2013. The most significant outcome of the investigation is that the relationship and government intervention with Indigenous Peoples are characterized by an indigenism with an assimilationist and integrationist focus and only in some discussions incorporating a focus on rights. In general, the evidence indicates that there is an absence of public policy, and although the INDI (National Indigenous Institute) has basic guidelines, prepared without the participation of Indigenous Peoples, they nevertheless do not respond to the their need primarily in terms of assurance and legalization of the Earth / Land, fundamental for the continuity and existence of Indigenous Peoples.

Intervenciones implementadas por los gobiernos con pueblos indígenas en Paraguay desde la apertura democrática (años 1989-2008/2013)

Oportunidades de financiación e inversión en la bolsa mercantil de Colombia

INTRODUCCION: La ERGE es considerada como la causa de morbilidad digestiva mas frecuente en la poblacion, siendo la erosion dental una manifestacion extra esofagica en la cavidad bucal. OBJETIVOS: determinar la asociacion entre erosiones dentales y esofagitis por reflujo gastroesofagico de acuerdo al grado de esofagitis, grado de erosion dental, sexo y edad. MATERIALES Y METODOS: Estudio descriptivo, transversal, observacional y correlacional en 150 pacientes con ERGE diagnosticados endoscopicamente como esofagitis por reflujo gastroesofagico (graduados segun clasificacion de Los Angeles) en el Servicio de Gastroenterologia del Hospital Arzobispo Loayza (2011-2012). Posterior a la endoscopia los pacientes fueron sometidos a una evaluacion clinica dental a fin de investigar la presencia de erosiones dentales previa firma de consentimiento informado. RESULTADOS: Se obtuvo una prevalencia de 30% (45 pacientes) con erosiones dentales y ERGE, el 100% manifesto acidez en la boca y regurgitacion acida. Respecto al sexo, el femenino presento un promedio de 2.35 erosiones en el sector anterior en la superficie palatina en grado 1 mientras que en el sexo masculino se encontro un promedio de 1.86 erosiones en el sector anterior de la superficie palatina en grado 2. De acuerdo a la edad se obtuvo un promedio de 3.50 erosiones en la superficie incisal grado 1 en el sector anterior en pacientesmayores de 70 anos seguida de un promedio de 3.11 erosiones en la superficie palatina grado 1 en pacientes de 20 a 30 anos. De acuerdo al total de superficies evaluadas el grupo etario comprendido entre 30 y 40 anos conforman la mayoria de poblacion afectada. Respecto al grado de esofagitis por reflujo gastroesofagico se encontro en el grupo de Esofagitis por reflujo Los Angeles “D” un promedio de 6.0 erosiones en el sector anterior en la superficie palatina grado 2 y en el sector anterior en la superficie palatina grado 1 y en el grupo de pacientes con esofagitis Los Angeles “A” y “B” con promedios respectivos de 2.3 y 2.2 y en el sector anterior en la superficie incisal Grado 1. y esofagitis Los Angeles “D”. Existe asociacion significativa (p=0.002) entre el grado de esofagitis por reflujo gastroesofagico y grado de erosion dental. CONCLUSIONES: en el presente estudio se ha encontrado clara asociacion entre el grado de las erosiones dentarias y el grado esofagitis por reflujo gastroesofagico. Las erosiones dentarias son mas frecuentes en varones mayores de 70 anos, en quienes las erosiones dentales se dieron en el sector anterior en la superficie incisal grado 1. Las superficies mas erosionadas se encontraron en mujeres en el sector anterior en la superficie palatina grado 1. En pacientes con esofagitis por reflujo gastroesofagico Los Angeles “A”,” B” y “C” se observa mayor numero de piezas dentarias erosionadas sea de grado 1 o 2. Los sintomas: acidez en la boca y regurgitaciones acidas que llegan hasta la boca son un indicador importante para la presencia de erosiones dentarias en pacientes con ERGE. La superficie palatina de las piezas antero superiores fueron las que tuvieron mayor presencia de erosiones en pacientes con ERGE.

Erosiones dentales en pacientes con diagnóstico de enfermedad por reflujo gastroesofágico en el Hospital Nacional Arzobispo Loayza

Necesidad de las enfermeras de ofrecer cuidados para el bienestar de los recién nacidos bajo efectos de sedación- relajación, en la unidad de cuidado intensivo neonatal de la Clínica FOSCAL (Bucaramanga)

Frecuencia de resistencia a fármacos antirretrovirales en pacientes con infección por VIH

This document includes the application and analysis of the modernization model of organizational management (MMGO ®) to the company Chia Auto Service Ltd., it was review about 13 key components that operates in an integrated form. With the application of the matrix MMGO ® was diagnosed each component, with the idea for planning of improvement plans that focus on the components of: Strategic Management, Marketing Management, Human Resources and Organizational Culture, finding that the area of finance and operations management is strengthened by a new manager who arrived with definite plans for these areas.

Análisis situacional y propuesta de ruta de mejoramiento para la empresa Auto Servicio Chía Ltda.

Programa para el fortalecimiento de la autoestima positiva en los niños del club de patinaje Juventud XXI del barrio Camilo Desepaz en la ciudad de Cali-Valle

Es ampliamente reconocido el beneficio de los arboles para proveer servicios ecosistemicos en sistemas agroforestales. El objetivo de este estudio fue determinar, a partir de la base del conocimiento local, los servicios ecosistemicos en sistemas agroforestales en fincas de pequenos productores de cafe del sur de Colombia. La base de conocimiento se construyo usando el programa Agroecological Knowledge Toolkit AKT5®. Entre otras, se relacionaron variables del manejo del cultivo, incidencia de las especies de sombrio sobre la produccion y calidad de taza, relacion entre los arboles y el suelo. La base incluyo 547 estamentos de los cuales el 74,50 % son de Atributo-Valor, 24,60 % como causales y el restante corresponde a estamentos de Comparacion y Link. De acuerdo a la percepcion del productor se reconocen 49 especies de arboles asociadas al cultivo del cafe que inciden sobre las caracteristicas fisicas y organolepticas, asi mismo, sobre las caracteristicas del suelo y el mantenimiento de la biodiversidad. En general, un productor con una base de conocimiento sobre los servicios ecosistemicos en sistemas agroforestales, tomara una adecuada decision de la inclusion de los arboles dentro de las configuraciones de produccion de cafe.

CONOCIMIENTO LOCAL DE LOS SERVICIOS ECOSISTÉMICOS EN ARREGLOS AGROFORESTALES DE CAFÉ (Coffea arabica L.) DEL SUR DE COLOMBIA

Defectos más frecuentes por los que no se admite un recurso de casación

Evaluación del uso de recubrimientos lipídicos, poliméricos y refrigeración para prolongar la vida útil del Yacón (Smallantus Sonchifolius)

Resumen es: El objetivo de este trabajo fue probar la efectividad de las tecnicas de relajacion, terapia ocupacional y dinamicas grupales para mejorar la autoestima ...

INCREMENTO DE LA AUTOESTIMA EN LOS ADULTOS MAYORES DE UN HOGAR DE JUBILADOS

Plan estratégico para el desarrollo económico y social de los artesanos del cantón Pedernales a través de la elaboración de artículos a base de la corteza de coco

Programa "Encuentro de los adultos y adultas mayores con el arte y la cultura"

La brucelosis es la enfermedad zoonotica mas extendida en el mundo que afecta diversos animales, incluyendo especies domesticas y de vida silvestre. Es causada por una bacteria perteneciente al genero Brucella, el cual incluye nueve especies distintas e infectantes de mamiferos terrestres y marinos. Cada especie de Brucella presenta variaciones en la secuencia de ADN que afectan a los nucleotidos en una posicion especifica del genoma. A estas variaciones se les llama polimorfismo. El polimorfismo de las especies de Brucella localizado en los genes que codifican para las proteinas glk, omp25 y trpE, se utilizo para desarrollar un ensayo multiple basado en la extension de cebadores, el cual permite identificar un aislamiento como miembro de una de las nueve especies reconocidas. Los metodos tradicionales para la identificacion de Brucella a nivel de especie consumen mucho tiempo y ponen en riesgo al personal laboratorial. Es por ello que la finalidad de este trabajo es evitar la ambiguedad, agilizar el procedimiento, disminuir el tiempo de respuesta y generar una herramienta laboratorial mas efectiva para mejorar la vigilancia epidemiologica, el diagnostico y el abordaje de la brucelosis en Costa Rica. El siguiente trabajo presenta la estandarizacion del protocolo para la extraccion de ADNde Brucella, asi como de una serie de amplificaciones de fragmentos de genes de interes por medio de la reaccion en cadena de la polimerasa (PCR) y la estandarizacion de la reaccion de extension de cebadores.

Estandarización de un protocolo de caracterización molecular para la identificación de especie de cepas terrestres de bacterias del género Brucella

Evaluación de la eficacia in vitro e in vivo de las [la] aplicación de silice en frutos de mango (Mangifera indica) VAR. Tommy Atkins para el control de enfermedades poscosecha

En la busqueda del enriquecimiento y la optimizacion de la formacion de los futuros profesionales en psicologia se pretende analizar la efectividad de un entrenamiento holistico, que integre los aportes de las diferentes corrientes y campos de accion. El quehacer interdisciplinario y transdisciplinario requiere una formacion amplia y abierta.La Escuela de Psicologia de la Universidad Latina Campus Heredia se inspira en dicho modelo. Desde el quehacer en las aulas hasta la formacion de un pensamiento critico y contextuado en la cotidianidad, que le da sentido a traves de la practica supervisada y la investigacion como ejes integrados y correlacionados de aprendizaje.

Situación socioeconómica, laboral y profesional de los optómetras que laboran en las ópticas habilitadas en los departamentos de Casanare y Meta durante el primer periodo de 2009

In the present project they were studied the phytotoxic effects on the Lactuca sativa seed, these were done in batteries of test in order to determine the concentration of average inhibition of the chrome (CE50). Initially 20 tests were carried out with dicromato of potassium, because is necessary to determine the sensibility of the seed opposite to the toxin, in base with the results that are throw in previous projects. Then of this the hexavalente chrome patron was define with the tests of dicromato of potassium, because this has in its compound as an element to chrome in +6 state. Finally and how the phytotoxic tests need an applicability, was necessary to analyze the behaviour of the Lactuca sativa on the chrome poured, that it come of the galvanic industry, to evaluated its toxicity, it was necessary to do some preliminaries tests, but then it was define with definitive test with a total of 5. Later it was necessary to do a pre-treatment used the chemical rainfall, because was necessary to reduce the concentration of the metal in the poured, as to reduce the grade of toxicity for the seed, its mean its concentration of average inhibition (CE50), to this procedure it’s was necessary 5 tests too.

Determinación de la concentración de inhibición media (CE50) de cromo para la semilla lactuca sativa mediante ensayos de toxicidad

TGFβ1 Previene la Muerte por Apoptosis Inducida por Estrés de Retículo Endoplasmático en los Fibroblastos Cardiacos de Ratas Neonatas

La idea dominante acerca de la globalizacion -asi elaborada desde la ideologia neoliberal- la presenta como un proceso inevitable, que se despliega y avanza al margen de toda voluntad humana. Esta concepcion, sin embargo, posee un estatuto metafisico, no cientifico. En cambio, admitir el caracter social y politico de la globalizacion, es decir, el hecho de que esta es simplemente resultante del pensamiento, las acciones y decisiones de seres humanos que interactuan de forma compleja, implica admitir que la globalizacion no es mas evitable o inevitable de lo pueda ser cualquier fenomeno humano. Este articulo diserta teoricamente sobre esta problematica, e intenta desarrollar, en sus aspectos mas generales, una elaboracion teorica que haga inteligibles las categorias principales de actores y el entramado sistemico a que las interrelaciones entre esos actores da lugar, todo lo cual constituye, a fin de cuentas, las fuerzas sociales -y por lo tanto humanas- que subyacen a la globalizacion.

Actores sociales y relaciones de poder: la globalización como proceso y fenómeno socio-político

El presente trabajo de investigacion, se realizo en la Parroquia San Pablo, Canton 
Archidona provincia de Napo, en una organizacion Kichwa llamado, Cooperativa de 
produccion agropecuaria San Pedro Ltda. De Rukullakta. En donde realizo un estudio de 
factibilidad sobre el cultivo, siembra, produccion y la comercializacion de la naranjilla 
hibrida ancestral. 
La naranjilla es producto amazonico que se encuentra cultivada por los pobladores de las 
comunidades indigenas de alto Napo, de esta region ancestral amazonica, especialmente en 
nuestras tierras orientales, son ricas en recursos Naturales, posee la biodiversidad flora y 
fauna ;ademas son aptos para el cultivo de productos agroecologicos amazonicos, como la 
naranjilla hibrida que es un producto ancestral hubo antes de las venidas de los espanoles, 
los pueblos originarios ya cultivaban la plantacion (naranjilla) para el consumo humano en 
diferentes pueblos y nacionalidades indigenas de la Amazonia Ecuatoriana. 
En los actuales momentos la mayor parte de los agricultores se dedican a la actividad 
productiva agricola de la naranjilla hibrida, especialmente en nuestra Provincia de Napo, las 
organizaciones de base de la Cooperativa Produccion Agropecuaria San Pedro Ltda. Rukullakta, tiene una fuerte demanda de produccion de la naranjilla

Implementación de una unidad de producción y comercialización de la Naranjilla Hibrida nativa amazónica: Solanum Hirtum, en la cooperativa de producición agropecuria San Pedro de Rukullakta

El presente estudio tuvo como objetivo identificar las estrategias didacticas empleadas por los docentes para orientar el proyecto integrador de los semestres primero a cuarto de la Facultad de Psicologia de la Universidad de San Buenaventura, sede Bogota, D. C. Se realizo una investigacion descriptiva. Los participantes fueron los 8 profesores de materia nucleo y de pensamiento investigativo que orientan el proyecto integrador. El instrumento disenado y aplicado previa validacion por jueces, fue una encuesta para determinar los procedimientos, los metodos, las estrategias metodologicas y las ayudas educativas empleadas por los docentes en el trabajo integrador la cual consta de 33 items agrupados en dichas categorias. Los resultados indicaron que el procedimiento mas utilizado por los docentes en el proyecto integrador es el trabajo colectivo. En cuanto a los metodos empleados, hay una tendencia a utilizar todos ellos (analitico, sintetico, deductivo, inductivo, analogico, verbalistico, intuitivo, sistematico y globalizado). Respecto a las estrategias metodologicas, se emplean principalmente el mapa conceptual, la clase participativa, la clase magistral, la tutoria, el empleo de preguntas y el taller. En relacion con las ayudas educativas, el tablero es la principal herramienta utilizada por los docentes. La coleccion de trabajos elaborados por los estudiantes como ensayos, consultas, articulos, biografias que hacen parte del portafolio, tiene una incidencia igualmente importante, al igual que los medios audiovisuales

ESTRATEGIAS DIDÁCTICAS DESARROLLADAS POR LOS DOCENTES PARA ORIENTAR EL TRABAJO INTEGRADOR EN LA FACULTAD DE PSICOLOGÍA

En los ultimos anos muchas poblaciones de El Salvador experimentaron un crecimiento poblacional desmesurado, focalizado en aquellas areas que les permitia seguridad y acceso a muchos servicios, mientras otras poblaciones quedaban completamente deshabitadas y esto era debido al fenomeno de la guerra interna en El Salvador, factor que predomino durante doce anos. La zona que mas experimento estas migraciones internas fue el oriente del pais y las areas urbanas con sus mismas infraestructuras pasaron a hacer mayormente pobladas; lo que llevo a un periodo de auge de viviendas el cual genero desorden poblacional, falta de organizacion y ocupacion de areas especificas especiales para recargas o purificacion del aire. Formular una propuesta ante el crecimiento urbano de la ciudad de La Union y moderar el desarrollo habitacional, mediante la orientacion del crecimiento de la ciudad, hacia el municipio de Conchagua es el objetivo general. La metodologia consiste en la recopilacion de informacion para despues hacer un analisis ordenado y poder determinar cuales son las necesidades del lugar y establecer una propuesta que solvente las problematicas encontradas. Los aspectos a utilizar seran por medio de un sistema ordenado, el cual trata de aprovechar al maximo todos los recursos bibliograficos y estudios de campo, con los cuales se cuentan y luego ser analizados de manera especifica. La metodologia a usar consta de cinco etapas que se detallan de la siguiente manera: etapa i: perfil etapa ii: marco referencial etapa iii: diagnostico etapa iv: pronostico etapa v: propuesta. Las conclusiones son Se presenta una alternativa para el desarrollo del crecimiento urbano ubicado en los cuadrantes en las coordenadas Lamberth de latitud 244 000 y 245 500; y en las coordenadas longitudinales 622 500 y 624 000, que segun las proyecciones del estudio es hacia donde apunta el desarrollo habitacional de la ciudad de La Union. La presente propuesta de desarrollo habitacional se enmarca en los aspectos de desarrollo vial, infraestructura y logistica; que conlleva a un proceso ordenado del desarrollo urbano para que sea armonico con el medio ambiente y que este le da un aspecto de convivencia con la biodiversidad mas aceptable.

Propuesta de crecimiento urbano de ciudad La Unión hacia el municipio de Conchagua

Zonificación de la amenaza por deslizamiento en la zona urbana del distrito turístico, cultural e histórico de Santa Marta según la metodología de Rodríguez (1999)

El presente estudio cualitativo esta orientado a explicar las actividades magico – religiosas dentro de la intervencion de problemas de salud mental en pobladores de la ciudad de Cajamarca. Se diseno y aplico  una  entrevista  semi  estructurada  ocho  mujeres,  en  donde  se  encontro  que  las  actividades magico – religiosas estan presentes y son primordiales en las actividades diarias de las entrevistadas, asimismo  seis  de  las  participantes  senalaron  resultados  beneficios.  Mediante  el  presente  estudio tambien  se  identifico  los  ritos  magicos  religiosos  mas  populares  y  arraigados  en  la  region  de Cajamarca. Palabras claves: Cajamarca, pensamiento magico religioso, maestro curandero.

A partir de una excelente fundamentacion teorica desde la perspectiva de las finanzas corporativas y bursatiles, los autores realizan un ejercicio estadistico para 14 empresas que cotizan en la Bolsa Mexicana de Valores y miden el efecto informativo en los precios de las acciones de esas emisoras ante anuncios de dividendos. El ejercicio se enmarcan en el debate aun no resuelto de los trabajos pioneros de John E. Kirshman y de Modigliani y Miller sobre la relevancia de la politica de dividendos en el valor de la empresa y el patrimonio de los accionistas, trabajos que derivaron en las metodologias que miden el valor de las corporaciones.

La política de dividendos en el valor bursátil: Los modelos de Gordon y Lintner

Nuevo modelo de atención integral en salud: la problemática de falta de cupo por morbilidad

Fourteen samples of blood (10 L each) were collected at the bleeding line of a slaughter house (Federal Inspected Plant) in Hermosillo, Mexico. This plant complies with the HACCP (Hazard Analysis and Critical Control Points) system. Serum fractions were freeze dried for further analysis. Proximate composition of serum indicated 2.3% moisture, 84.3% protein, 4.0% lipids and 4.6%.minerals. Lipid content were greater (P<0.05) in winter samples than in other months, while no variation was found in protein content. Similar concentrations of IgA, IgG and IgM were found in fresh and lyophilized porcine serum. All samples tested presented less than 10 CFU per gram of total viable mesophilic aerobes, and less than 3 MPN/g of coliforms. No bacteria colonies indicating the presence of Salmonella spp or Staphyloccocus aureus were observed. The excellent quality of serum indicates the optimum sanitary conditions at the slaughterhouse and the potential of use of porcine blood fractions.

CARACTERIZACIÓN DEL SUERO PORCINO PRODUCIDO BAJO CONDICIONES CONTROLADAS EN UN RASTRO DE LA CIUDAD DE HERMOSILLO, MÉXICO Characterization of Porcine Serum Obtained Under Controlled Conditions in a Slaughterhouse of Hermosillo, México

Implementacion de un programa nacional para el tratamiento del cancer infantil en Chile

Este articulo resume los principales resultados, las conclusiones y recomendaciones de la investigacion titulada La Capacidad Resolutiva para la Atencion Integral de la Salud: Un abordaje desde el Nivel Local. El proposito general del estudio consistio en la caracterizacion la capacidad resolutiva de las organizaciones gubernamentales y no gubernamentales, con el fin de identificar el potencial de la cogestion para la Atencion Integral de la Salud y proponer algunas orientaciones generales que definan el funcionamiento de un Sistema de Gestion Local de Salud en el Area de Salud de La Union. La investigacion se realizo en el segundo semestre de 1998, en el Area de Salud del Canton de la Union, Cartago. Esta Area de Salud plantea un terreno propicio para incorporar el mejoramiento del sistema de gestion local de salud mediante las acciones de intersectorialidad e interinstitucionalidad, por el conjunto de organizaciones gubernamentales y no gubernamentales, asi como grupos organizados de la comunidad, presentes en este espacio local. Este estudio procura ofrecer opciones para mejorar las condiciones de vida de la poblacion y se constituye en una base esencial que puede ser incorporada en otras Areas de Salud del pais. Se partio de la necesidad de la reactivacion del Sistema Nacional de Salud, pues desde su consolidacion colocaba en el plano central la urgencia de brindarle un tratamiento distinto a la salud, el cual trataba de trascender lo puramente biologico en la busqueda de la atencion integral de la salud

La capacidad resolutiva para la atención integral: un abordaje desde el nivel local

El 5 de octubre de 1989 la Asamblea Legislativa aprobo la Ley de la Jurisdiccion Constitucional (No 7135, publicada en el Alcance No 34 a La Gaceta No 198 del 19 de octubre de 1989), creando el marco juridico de la Sala Constitucional de la Corte Suprema de Justicia. Dicha ley reformo el articulo 490 del Codigo de Procedimientos Penales vigente, el cual establece las causales del recurso de revision, agregando un nuevo inciso que determina que procedera la revision contra una sentencia firme.

El Derecho a defensa letrada como parte del debido proceso en materia penal (Análisis de los juicios de Clarence Earl Gideon - Florida, 1961 - 1963 y Ernesto Miranda - Arzona, 1963 - 1967)

Acute lymphoblastic leukemia (ALL) is the most frequent childhood cancer. The leukemic cells of ALL patients show several well defined numeric and structural chromosomal abnormalities which are universally known for its prognostic implications. We studied a group of 44 children with ALL, to investigate the incidence of chromosome aberrations in ALL, its lymphocyte lineage and some clinical feature associations, and the finding of non previously described aberrations. A high proportion of patients (79.5%) showed chromosomal abnormalities. Most of them had a pseudodiploid karyotype (46 chromosomes), characterized mainly by a translocation. In relation to chromosome number, 27% of them were hyperdiploid with more than 50; 9% hyperdiploid between 47-50 and 7% hypodiploid (less than 46). Among structural aberrations found, were the following recurrent translocations: t (1; 19), t (4; 11), t (9; 22) in 6.8%, 9.1% and 2.3% of cases respectively, all related to an early B immunophenotype. Other translocations found, compromised regions 7q22, 9p21 - 24. Two new translocations in ALL were found: t (1; 5)(q23; q33), apparently balanced, and t (13; 21)(q14; q22), unbalanced. Other recurrent structural changes found were: deletion (6q), (7q), (9p), (11q), (12p), inversion (3q), isochromosome (7q), maker chromosomes and double minutes. The distribution of chromosome abnormalities in this group of patients was in agreement with previous reports from other investigators.

Estudios citogenéticos en niños chilenos con leucemia linfoblástica aguda.

La crisis económica y las respuestas de las mujeres a través de las organizaciones de sobrevivencia

Con miras permanentes a disminuir la incidencia de las toxicosis gravidicas en el Instituto, hemos adoptado en forma rutinaria una estrecha vigilancia de las pacientes exceptuando las deficiencias debidas al grado de cultura y a la mentalidad de la clientela hospitaliaria. Desgraciadamente es dificil llevar esta vigilancia hasta el punto deseado, ya que con frecuencia ocurre la falta de colaboracion e interes por parte de la mayoria de las pacientes. Es lamentable tener que reconocer que. a pesar de la larga trayectoria de los servicios de maternidad en Bogota, aun las mismas pacientes, tratadas en varias oportunidades en el Instituto, menosprecian y descuidan sus problemas obstetricos y permanecen sin vigilancia alguna o lo que es peor se entregan a los cuidados de comadronas ignorantes y solo concurren a la consulta medica cuando se ven enfrentadas a una complicacion o accidente que las haga temer por su vida. Por otra parte la generalidad de las embarazadas ni siquiera consideran que sea util acudir al medico en los primeros meses. salvo que sufran alguna complicacion que las haga sentirse enfermas.

Employing equivariance in neural networks leads to greater parameter efficiency and improved generalization performance through the encoding of domain knowledge in the architecture; however, the majority of existing approaches require an a priori specification of the desired symmetries. We present a neural network architecture, Linear Group Networks (LGNs), for learning linear groups acting on the weight space of neural networks. Linear groups are desirable due to their inherent interpretability, as they can be represented as finite matrices. LGNs learn groups without any supervision or knowledge of the hidden symmetries in the data and the groups can be mapped to well known operations in machine learning. We use LGNs to learn groups on multiple datasets while considering different downstream tasks; we demonstrate that the linear group structure depends on both the data distribution and the considered task.

Latent Gaussian models have a rich history in statistics and machine learning, with applications ranging from factor analysis to compressed sensing to time series analysis. The classical method for maximizing the likelihood of these models is the expectation-maximization (EM) algorithm. For problems with high-dimensional latent variables and large datasets, EM scales poorly because it needs to invert as many large covariance matrices as the number of data points. We introduce probabilistic unrolling, a method that combines Monte Carlo sampling with iterative linear solvers to circumvent matrix inversion. Our theoretical analyses reveal that unrolling and backpropagation through the iterations of the solver can accelerate gradient estimation for maximum likelihood estimation. In experiments on simulated and real data, we demonstrate that probabilistic unrolling learns latent Gaussian models up to an order of magnitude faster than gradient EM, with minimal losses in model performance.

Probabilistic Unrolling: Scalable, Inverse-Free Maximum Likelihood Estimation for Latent Gaussian Models

The identification of interesting substructures within jets is an important tool for searching for new physics and probing the Standard Model at colliders. Many of these substructure tools have previously been shown to take the form of optimal transport problems, in particular the Energy Mover's Distance (EMD). In this work, we show that the EMD is in fact the natural structure for comparing collider events, which accounts for its recent success in understanding event and jet substructure. We then present a Shape Hunting Algorithm using Parameterized Energy Reconstruction (SHAPER), which is a general framework for defining and computing shape-based observables. SHAPER generalizes N-jettiness from point clusters to any extended, parametrizable shape. This is accomplished by efficiently minimizing the EMD between events and parameterized manifolds of energy flows representing idealized shapes, implemented using the dual-potential Sinkhorn approximation of the Wasserstein metric. We show how the geometric language of observables as manifolds can be used to define novel observables with built-in infrared-and-collinear safety. We demonstrate the efficacy of the SHAPER framework by performing empirical jet substructure studies using several examples of new shape-based observables.

The classical sparse coding model represents visual stimuli as a linear combination of a handful of learned basis functions that are Gabor-like when trained on natural image data. However, the Gabor-like filters learned by classical sparse coding far overpredict well-tuned simple cell receptive field (SCRF) profiles. A number of subsequent models have either discarded the sparse dictionary learning framework entirely or have yet to take advantage of the surge in unrolled, neural dictionary learning architectures. A key missing theme of these updates is a stronger notion of \emph{structured sparsity}. We propose an autoencoder architecture whose latent representations are implicitly, locally organized for spectral clustering, which begets artificial neurons better matched to observed primate data. The weighted-$\ell_1$ (WL) constraint in the autoencoder objective function maintains core ideas of the sparse coding framework, yet also offers a promising path to describe the differentiation of receptive fields in terms of a discriminative hierarchy in future work.

The problem of sparse multichannel blind deconvolution (S-MBD) arises frequently in many engineering applications such as radar/sonar/ultrasound imaging. To reduce its computational and implementation cost, we propose a compression method that enables blind recovery from much fewer measurements with respect to the full received signal in time. The proposed compression measures the signal through a filter followed by subsampling, allowing for a significant reduction in implementation cost. We derive theoretical guarantees for the identifiability and recovery of a sparse filter from compressed measurements. Our results allow for the design of a wide class of compression filters. We, then, propose a data-driven unrolled learning framework to learn the compression filter and solve the S-MBD problem. The encoder is a recurrent inference network that maps compressed measurements into an estimate of sparse filters. We demonstrate that our unrolled learning method is more robust to choices of source shapes and has better recovery performance compared to optimization-based methods. Finally, in data-limited applications (fewshot learning), we highlight the superior generalization capability of unrolled learning compared to conventional deep learning.

Understanding the activity of single neurons in relation to features in the environment is the first step in many neuroscience studies. We propose a method using algorithm unrolling, an emerging technique in interpretable deep learning, to deconvolve single-trial neuronal activity into interpretable components. Specifically, we model the firing rates of single neurons using a set of kernels characterizing neurons’ responses to time-sensitive sparse events/stimuli. The kernels can be either unique or shared across the population and are weighted by codes whose amplitude and timing are trial-specific. Our inference results in a deep sparse deconvolutional encoder and, unlike sequential deep encoder approaches, is based on a generative model; hence, the learned parameters and encoding are directly interpretable. First, we characterize the performance regime of our method; this guides end users to understand the model’s accuracy and limitations. Second, we apply our method to deconvolve overlapping signals in the response of dopaminergic neurons to rewards of varying size. Previous studies have suggested that reward prediction error responses of dopaminergic neurons are modulated by two components: salience and value. However, this multiplexing is often ignored or analyzed using ad-hoc windows to estimate the two contributions. Here, we deconvolve the two factors in an unsupervised manner; one kernel corresponds to salience whose code is common across reward sizes and another to value whose code changes as a function of reward amount. We show that the inferred codes are more informative than firing rates estimated using ad-hoc windows. Third, we study the response of piriform cortex neurons to brief odor pulses delivered at random time across trials. Based on the learned neural impulse responses, we uncover 3 clusters of response types across the population. Overall, we propose a novel method to deconvolve into interpretable components the factors driving neural activity in single trials. Methods. Given a neuron’s activity, the spikes at trial j are binned at B ms resolution and modeled using the

Unsupervised sparse deconvolutional learning of features driving neural activity∗

—The problem of sparse multichannel blind decon- volution (S-MBD) arises frequently in many engineering applications such as radar/sonar/ultrasound imaging. To reduce its computational and implementation cost, we propose a compression method that enables blind recovery from much fewer measurements with respect to the full received signal in time. The proposed compression measures the signal through a ﬁlter followed by a subsampling, allowing for a signiﬁcant reduction in implementation cost. We derive theoretical guarantees for the identiﬁability and recovery of a sparse ﬁlter from compressed measurements. Our results allow for the design of a wide class of compression ﬁlters. We, then, propose a data-driven unrolled learning framework to learn the compression ﬁlter and solve the S-MBD problem. The encoder is a recurrent inference network that maps compressed measurements into an estimate of sparse ﬁlters. We demonstrate that our unrolled learning method is more robust to choices of source shapes and has better recovery performance compared to optimization-based methods. Finally, in applications with limited data (fewshot learning), we highlight the superior generalization capability of unrolled learning compared to conventional deep learning.

Deep neural networks lack straightforward ways to incorporate domain knowledge and are notoriously considered black boxes. Prior works attempted to inject domain knowledge into architectures implicitly through data augmentation. Building on recent advances on equivariant neural networks, we propose networks that explicitly encode domain knowledge, speciﬁcally equivariance with respect to rotations. By using unfolded architectures, a rich framework that originated from sparse coding and has theoretical guarantees, we present interpretable networks with sparse activations. The equivariant unfolded networks compete favorably with baselines, with only a fraction of their parameters, as showcased on (rotated) MNIST and CIFAR-10.

Sparse Bayesian learning (SBL) is a powerful framework for tackling the sparse coding problem. However, the most popular inference algorithms for SBL become too expensive for high-dimensional settings, due to the need to store and compute a large covariance matrix. We introduce a new inference scheme that avoids explicit construction of the covariance matrix by solving multiple linear systems in parallel to obtain the posterior moments for SBL. Our approach couples a little-known diagonal estimation result from numerical linear algebra with the conjugate gradient algorithm. On several simulations, our method scales better than existing approaches in computation time and memory, especially for structured dictionaries capable of fast matrix-vector multiplication.

ICASSP 2022 - 2022 IEEE International Conference on Acoustics, Speech and Signal Processing (ICASSP)

High-Dimensional Sparse Bayesian Learning without Covariance Matrices

The dictionary learning problem, representing data as a combination of a few atoms, has long stood as a popular method for learning representations in statistics and signal processing. The most popular dictionary learning algorithm alternates between sparse coding and dictionary update steps, and a rich literature has studied its theoretical convergence. The success of dictionary learning relies on access to a"good"initial estimate of the dictionary and the ability of the sparse coding step to provide an unbiased estimate of the code. The growing popularity of unrolled sparse coding networks has led to the empirical finding that backpropagation through such networks performs dictionary learning. We offer the theoretical analysis of these empirical results through PUDLE, a Provable Unrolled Dictionary LEarning method. We provide conditions on the network initialization and data distribution sufficient to recover and preserve the support of the latent code. Additionally, we address two challenges; first, the vanilla unrolled sparse coding computes a biased code estimate, and second, gradients during backpropagated learning can become unstable. We show approaches to reduce the bias of the code estimate in the forward pass, and that of the dictionary estimate in the backward pass. We propose strategies to resolve the learning instability by tuning network parameters and modifying the loss function. Overall, we highlight the impact of loss, unrolling, and backpropagation on convergence. We complement our findings through synthetic and image denoising experiments. Finally, we demonstrate PUDLE's interpretability, a driving factor in designing deep networks based on iterative optimizations, by building a mathematical relation between network weights, its output, and the training set.

State-of-the-art approaches for clustering high-dimensional data utilize deep auto-encoder architectures. Many of these networks require a large number of parameters and suffer from a lack of interpretability, due to the black-box nature of the auto-encoders. We introduce Mixture Model Auto-Encoders (MixMate), a novel architecture that clusters data by performing inference on a generative model. Built on ideas from sparse dictionary learning and mixture models, MixMate comprises several auto-encoders, each tasked with reconstructing data in a distinct cluster, while enforcing sparsity in the latent space. Through experiments on various image datasets, we show that MixMate achieves competitive performance versus state-of-the-art deep clustering algorithms, while using orders of magnitude fewer parameters.

Mixture Model Auto-Encoders: Deep Clustering Through Dictionary Learning

Convolutional dictionary learning (CDL), the problem of estimating shift-invariant templates from data, is typically conducted in the absence of a prior/structure on the templates. In data-scarce or low signal-to-noise ratio (SNR) regimes, learned templates overfit the data and lack smoothness, which can affect the predictive performance of downstream tasks. To address this limitation, we propose GPCDL, a convolutional dictionary learning framework that enforces priors on templates using Gaussian Processes (GPs). With the focus on smoothness, we show theoretically that imposing a GP prior is equivalent to Wiener filtering the learned templates, thereby suppressing high-frequency components and promoting smoothness. We show that the algorithm is a simple extension of the classical iteratively reweighted least squares algorithm, independent of the choice of GP kernels. This property allows one to experiment flexibly with different smoothness assumptions. Through simulation, we show that GPCDL learns smooth dictionaries with better accuracy than the unregularized alternative across a range of SNRs. Through an application to neural spiking data, we show that GPCDL learns a more accurate and visually-interpretable smooth dictionary, leading to superior predictive performance compared to non-regularized CDL, as well as parametric alternatives.

Recent approaches in the theoretical analysis of model-based deep learning architectures have studied the convergence of gradient descent in shallow ReLU networks that arise from generative models whose hidden layers are sparse. Motivated by the success of architectures that impose structured forms of sparsity, we introduce and study a group-sparse autoencoder that accounts for a variety of generative models, and utilizes a group-sparse ReLU activation function to force the non-zero units at a given layer to occur in blocks. For clustering models, inputs that result in the same group of active units belong to the same cluster. We proceed to analyze the gradient dynamics of a shallow instance of the proposed autoencoder, trained with data adhering to a group-sparse generative model. In this setting, we theoretically prove the convergence of the network parameters to a neighborhood of the generating matrix. We validate our model through numerical analysis and highlight the superior performance of networks with a group-sparse ReLU compared to networks that utilize traditional ReLUs, both in sparse coding and in parameter recovery tasks. We also provide real data experiments to corroborate the simulated results, and emphasize the clustering capabilities of structured sparsity models.

Sparse Bayesian learning (SBL) is a powerful framework for tackling the sparse coding problem while also providing uncertainty quantification. The most popular inference algorithms for SBL exhibit prohibitively large computational costs for high-dimensional problems due to the need to maintain a large covariance matrix. To resolve this issue, we introduce a new method for accelerating SBL inference – named covariance-free expectation maximization (CoFEM) – that avoids explicit computation of the covariance matrix. CoFEM solves multiple linear systems to obtain unbiased estimates of the posterior statistics needed by SBL. This is accomplished by exploiting innovations from numerical linear algebra such as preconditioned conjugate gradient and a little-known diagonal estimation rule. For a large class of compressed sensing matrices, we provide theoretical justifications for why our method scales well in high-dimensional settings. Through simulations, we show that CoFEM can be up to thousands of times faster than existing baselines without sacrificing coding accuracy. Through applications to calcium imaging deconvolution and multi-contrast MRI reconstruction, we show that CoFEM enables SBL to tractably tackle high-dimensional sparse coding problems of practical interest.

The dictionary learning problem, representing data as a combination of a few atoms, has long stood as a popular method for learning representations in statistics and signal processing. The most popular dictionary learning algorithm alternates between sparse coding and dictionary update steps, and rich literature has studied its theoretical convergence. The growing popularity of neurally plausible unfolded sparse coding networks has led to the empirical finding that backpropagation through such networks performs dictionary learning. This paper offers the theoretical proof for these empirical results through PUDLE, a Provable Unfolded Dictionary LEarning method. We provide sufficient conditions on the network initialization and data distribution for model recovery. We highlight the impact of loss, unfolding, and backpropagation on convergence. We discuss proper initializations and strategies to resolve the instability issue concerning backpropagated gradient. This is achieved through tuning network parameters and modification of loss function. We complement our findings through synthetic and image denoising experiments. Finally, we highlight the interpretability of PULDE by deriving a mathematical relation between network weights, its output, and the training data.

PUDLE: Implicit Acceleration of Dictionary Learning by Backpropagation

Sparse manifold learning algorithms combine techniques in manifold learning and sparse optimization to learn features that could be utilized for downstream tasks. The standard setting of compressive sensing can not be immediately applied to this setup. Due to the intrinsic geometric structure of data, dictionary atoms might be redundant and do not satisfy the restricted isometry property or coherence condition. In addition, manifold learning emphasizes learning local geometry which is not reflected in a standard ℓ1 minimization problem. We propose weighted ℓ0 and weighted ℓ1 regularizations that encourage representation via neighborhood atoms suited for dictionary based manifold learning. Assuming that the data is generated from Delaunay triangulation, we show the equivalence of weighted ℓ1 and weighted ℓ0. We discuss an optimization program that learns the dictionaries and sparse co-efficients and demonstrate the utility of our regularization on synthetic and real datasets.

Sparse manifold learning algorithms combine techniques in manifold learning and sparse optimization to learn features that could be utilized for downstream tasks. The standard setting of compressive sensing can not be immediately applied to this setup. Due to the intrinsic geometric structure of data, dictionary atoms might be redundant and do not satisfy the restricted isometry property or coherence condition. In addition, manifold learning emphasizes learning local geometry which is not reﬂected in a standard (cid:96) 1 minimization problem. We propose weighted (cid:96) 0 and weighted (cid:96) 1 metrics that encourage representation via neighborhood atoms suited for dictionary based manifold learning. Assuming that the data is generated from Delaunay triangulation, we show the equivalence of weighted (cid:96) 1 and weighted (cid:96) 0 . We discuss an optimization program that learns the dictionaries and sparse coeﬃcients and demonstrate the utility of our regularization on synthetic and real datasets.

Weighed $\ell_1$ on the simplex: Compressive sensing meets locality

Given a continuous-domain signal that can be modeled as the superposition of localized events from multiple sources, the goal of Convolutional Dictionary Learning (CDL) is to identify the location of the events–by Convolutional Sparse Coding (CSC)–and learn the template for each source–through a Convolutional Dictionary Update (CDU) step. In practice, because we observe samples of the continuous-domain signal on a discrete grid, classical CSC methods can only produce estimates of the locations of the events on this grid, which degrades the performance of the CDU step. We introduce a CDL framework that significantly reduces the errors arising from performing the estimation on the grid. Specifically, we construct an expanded dictionary that comprises, not only discrete shifts of the templates, but also variants shifted by a non-integer amount and smoothly interpolated, that enable CSC and CDU to operate at a finer resolution than that of the original sampling grid. We term this approach CDL with grid refinement. For CSC, we develop a novel computationally efficient algorithm, termed Convolutional Orthogonal Matching Pursuit with an interpolated dictionary (COMP-INTERP). We use simulated data to compare COMP-INTERP to state-of-the-art CSC algorithms for estimating off-the-grid events, and demonstrate that it 1) achieves a competitive level of accuracy, and 2) is one order of magnitude faster. For CDU, we derive a novel procedure to update the templates given sparse codes that can occur both on and off the sampling grid. We also show that 3) dictionary update with the overcomplete dictionary yields more accurate templates. Finally, we demonstrate the competitive performance of the algorithms in two applications, namely spike sorting and super-resolution microscopy.

To capture the slowly time-varying spectral content of real-world time series, a common paradigm is to partition the data into approximately stationary intervals and perform inference in the time-frequency domain. This approach, however, lacks a corresponding nonstationary time-domain generative model for the entire data and thus, time-domain inference, such as sampling from the posterior, occurs in each interval separately. This results in distortion/discontinuity around interval boundaries and, consequently, can lead to erroneous inferences based on any quantities derived from the posterior, such as the phase. To address these shortcomings, we propose the Piecewise Locally Stationary Oscillation (PLSO) generative model for decomposing time-series data with slowly time-varying spectra into several oscillatory, piecewise-stationary processes. PLSO, being a nonstationary time-domain generative model, enables inference on the entire time-series, without boundary effects, and, at the same time, provides a characterization of its time-varying spectral properties. We propose a novel two-stage inference algorithm that combines the classical Kalman filter and the recently-proposed accelerated proximal gradient algorithm to optimize the nonconvex Whittle likelihood from PLSO. We demonstrate these points through experiments on simulated data and real neural data from the rat and the human brain.

PLSO: A generative framework for decomposing nonstationary time-series into piecewise stationary oscillatory components

The sparse representation model has been successfully utilized in a number of signal and image processing tasks; however, recent research has highlighted its limitations in certain deep-learning architectures. This paper proposes a novel dense and sparse coding model that considers the problem of recovering a dense vector $\mathbf{x}$ and a sparse vector $\mathbf{u}$ given linear measurements of the form $\mathbf{y} = \mathbf{A}\mathbf{x}+\mathbf{B}\mathbf{u}$. Our first theoretical result proposes a new natural geometric condition based on the minimal angle between subspaces corresponding to the measurement matrices $\mathbf{A}$ and $\mathbf{B}$ to establish the uniqueness of solutions to the linear system. The second analysis shows that, under mild assumptions and sufficient linear measurements, a convex program recovers the dense and sparse components with high probability. The standard RIPless analysis cannot be directly applied to this setup. Our proof is a non-trivial adaptation of techniques from anisotropic compressive sensing theory and is based on an analysis of a matrix derived from the measurement matrices $\mathbf{A}$ and $\mathbf{B}$. We begin by demonstrating the effectiveness of the proposed model on simulated data. Then, to address its use in a dictionary learning setting, we propose a dense and sparse auto-encoder (DenSaE) that is tailored to it. We demonstrate that a) DenSaE denoises natural images better than architectures derived from the sparse coding model ($\mathbf{B}\mathbf{u}$), b) training the biases in the latter amounts to implicitly learning the $\mathbf{A}\mathbf{x} + \mathbf{B}\mathbf{u}$ model, and c) $\mathbf{A}$ and $\mathbf{B}$ capture low- and high-frequency contents, respectively.

We propose a learned-structured unfolding neural network for the problem of compressive sparse multichannel blind-deconvolution. In this problem, each channel’s measurements are given as convolution of a common source signal and sparse filter. Unlike prior works where the compression is achieved either through random projections or by applying a fixed structured compression matrix, this paper proposes to learn the compression matrix from data. Given the full measurements, the proposed network is trained in an unsupervised fashion to learn the source and estimate sparse filters. Then, given the estimated source, we learn a structured compression operator while optimizing for signal reconstruction and sparse filter recovery. The efficient structure of the compression allows its practical hardware implementation. The proposed neural network is an autoencoder constructed based on an unfolding approach: upon training, the encoder maps the compressed measurements into an estimate of sparse filters using the compression operator and the source, and the linear convolutional decoder reconstructs the full measurements. We demonstrate that our method is superior to classical structured compressive sparse multichannel blind-deconvolution methods in terms of accuracy and speed of sparse filter recovery.

Unfolding Neural Networks for Compressive Multichannel Blind Deconvolution

We introduce a neural-network architecture, termed the constrained recurrent sparse autoencoder (CRsAE), that solves convolutional dictionary learning problems, thus establishing a link between dictionary learning and neural networks. Specifically, we leverage the interpretation of the alternating-minimization algorithm for dictionary learning as an approximate expectation-maximization algorithm to develop autoencoders that enable the simultaneous training of the dictionary and regularization parameter (ReLU bias). The forward pass of the encoder approximates the sufficient statistics of the E-step as the solution to a sparse coding problem, using an iterative proximal gradient algorithm called FISTA. The encoder can be interpreted either as a recurrent neural network or as a deep residual network, with two-sided ReLU nonlinearities in both cases. The M-step is implemented via a two-stage backpropagation. The first stage relies on a linear decoder applied to the encoder and a norm-squared loss. It parallels the dictionary update step in dictionary learning. The second stage updates the regularization parameter by applying a loss function to the encoder that includes a prior on the parameter motivated by Bayesian statistics. We demonstrate in an image-denoising task that CRsAE learns Gabor-like filters and that the EM-inspired approach for learning biases is superior to the conventional approach. In an application to recordings of electrical activity from the brain, we demonstrate that CRsAE learns realistic spike templates and speeds up the process of identifying spike times by ${900}\times $ compared with algorithms based on convex optimization.

Deep Residual Autoencoders for Expectation Maximization-Inspired Dictionary Learning

A recent line of work shows that a deep neural network with ReLU nonlinearities arises from a finite sequence of cascaded sparse-coding models, the outputs of which, except for the last element in the cascade, are sparse and unobservable. We show here, using techniques from the dictionary-learning literature that, if the measurement matrices in the cascaded sparse-coding model (a) satisfy RIP and (b) all have sparse columns except for the last, they can be recovered with high probability. We propose two algorithms: one that recovers the matrices in a forward sequence, and another that recovers them in a backward sequence. The method of choice in deep learning to solve this problem is by training an auto-encoder. Our algorithms provide a sound alternative, with theoretical guarantees, and upper bounds on sample complexity. The theory shows that the learning complexity of the forward algorithm depends on the number of hidden units at the deepest layer and the number of active neurons at that layer (sparsity). In addition, the theory relates the number of hidden units in successive layers, thus giving a practical prescription for designing deep ReLU neural networks. Because it puts fewer restrictions on the architecture, the backward algorithm requires more data. We use simulated data and patches from natural images to demonstrate the deep dictionary-learning algorithm. Finally, we conjecture a lower bound on sample complexity that gives some insight as to why deep networks require more data to train than shallow ones.

We introduce a novel clustering algorithm for data sampled from a union of nonlinear manifolds. Our algorithm extends a popular manifold clustering framework, which first computes a sparse similarity graph over the input data and then uses spectral methods to find clusters in this graph. While previous manifold learning algorithms directly compute similarity scores between pairs of data points, our algorithm first augments the data set with a small handful of representative atoms and then computes similarity scores between data points and atoms. To measure similarity, we express each data point as sparse convex combination of nearby atoms. To learn the atoms, we employ algorithm unrolling, an increasingly popular technique for structured deep learning. Ultimately, this departure from established manifold learning techniques leads to improvements in clustering accuracy and scalability.

Discriminative features extracted from the sparse coding model have been shown to perform well for classiﬁcation and reconstruction. Recent deep learning architectures have further improved reconstruction in inverse problems by considering new dense priors learned from data. We propose a novel dense and sparse coding model that integrates both representation capability and discriminative features. The model considers the problem of recovering a dense vector x and a sparse vector u given measurements of the form y = Ax + Bu . Our ﬁrst analysis proposes a natural geometric condition based on the minimal angle between spanning subspaces corresponding to the measurement matrices A and B to establish the uniqueness of solutions to the linear system. The second analysis shows that, under mild assumptions, a convex program recovers the dense and sparse components. We validate the eﬀectiveness of the proposed model on simulated data and propose a dense and sparse autoencoder (DenSaE) tailored to learning the dictionaries from the dense and sparse model. We demonstrate that a) DenSaE denoises natural images better than architectures derived from the sparse coding model ( Bu ), b) in the presence of noise, training the biases in the latter amounts to implicitly learning the Ax + Bu model, c) A and B capture low-and high-frequency contents, respectively, and d) compared to the sparse coding model, DenSaE oﬀers a balance between discriminative power and representation.

Towards improving discriminative reconstruction via simultaneous dense and sparse coding

Electroencephalographam (EEG) monitoring of neural activity is widely used for identifying underlying brain states. For inference of brain states, researchers have often used Hidden Markov Models (HMM) with a fixed number of hidden states and an observation model linking the temporal dynamics embedded in EEG to the hidden states. The use of fixed states may be limiting, in that 1) pre-defined states might not capture the heterogeneous neural dynamics across individuals and 2) the oscillatory dynamics of the neural activity are not directly modeled. To this end, we use a Hierarchical Dirichlet Process Hidden Markov Model (HDP-HMM), which discovers the set of hidden states that best describes the EEG data, without a-priori specification of state number. In addition, we introduce an observation model based on classical asymptotic results of frequency domain properties of stationary time series, along with the description of the conditional distributions for Gibbs sampler inference. We then combine this with multitaper spectral estimation to reduce the variance of the spectral estimates. By applying our method to simulated data inspired by sleep EEG, we arrive at two main results: 1) the algorithm faithfully recovers the spectral characteristics of the true states, as well as the right number of states and 2) the incorporation of the multitaper framework produces a more stable estimate than traditional periodogram spectral estimates.

2019 41st Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC)

We introduce a class of auto-encoder neural networks tailored to data from the natural exponential family (e.g., count data). The architectures are inspired by the problem of learning the filters in a convolutional generative model with sparsity constraints, often referred to as convolutional dictionary learning (CDL). Our work is the first to combine ideas from convolutional generative models and deep learning for data that are naturally modeled with a non-Gaussian distribution (e.g., binomial and Poisson). This perspective provides us with a scalable and flexible framework that can be re-purposed for a wide range of tasks and assumptions on the generative model. Specifically, the iterative optimization procedure for solving CDL, an unsupervised task, is mapped to an unfolded and constrained neural network, with iterative adjustments to the inputs to account for the generative distribution. We also show that the framework can easily be extended for discriminative training, appropriate for a supervised task. We demonstrate 1) that fitting the generative model to learn, in an unsupervised fashion, the latent stimulus that underlies neural spiking data leads to better goodness-of-fit compared to other baselines, 2) competitive performance compared to state-of-the-art algorithms for supervised Poisson image denoising, with significantly fewer parameters, and 3) gradient dynamics of shallow binomial auto-encoder.

Convolutional dictionary learning based auto-encoders for natural exponential-family distributions

Convolutional dictionary learning (CDL) has become a popular method for learning sparse representations from data. State-of-the-art algorithms perform dictionary learning (DL) through an optimization-based alternating-minimization procedure that comprises a sparse coding and a dictionary update step respectively. Here, we draw connections between CDL and neural networks by proposing an architecture for CDL termed the constrained recurrent sparse auto-encoder (CRsAE). We leverage the interpretation of the alternating-minimization algorithm for DL as an Expectation-Maximization algorithm to develop auto-encoders (AEs) that, for the first time, enable the simultaneous training of the dictionary and regularization parameter. The forward pass of the encoder, which performs sparse coding, solves the E-step using an encoding matrix and a soft-thresholding non-linearity imposed by the FISTA algorithm. The encoder in this regard is a variant of residual and recurrent neural networks. The M-step is implemented via a two-stage back-propagation. In the first stage, we perform back-propagation through the AE formed by the encoder and a linear decoder whose parameters are tied to the encoder. This stage parallels the dictionary update step in DL. In the second stage, we update the regularization parameter by performing back-propagation through the encoder using a loss function that includes a prior on the parameter motivated by Bayesian statistics. We leverage GPUs to achieve significant computational gains relative to state-of-the-art optimization-based approaches to CDL. We apply CRsAE to spike sorting, the problem of identifying the time of occurrence of neural action potentials in recordings of electrical activity from the brain. We demonstrate on recordings lasting hours that CRsAE speeds up spike sorting by 900x compared to notoriously slow classical algorithms based on convex optimization.

Deep Residual Auto-Encoders for Expectation Maximization-based Dictionary Learning

We consider the problem of learning recurring convolutional patterns from data that are not necessarily real valued, such as binary or count-valued data. We cast the problem as one of learning a convolutional dictionary, subject to sparsity constraints, given observations drawn from a distribution that belongs to the canonical exponential family. We propose two general approaches towards its solution. The first approach uses the $\ell_0$ pseudo-norm to enforce sparsity and is reminiscent of the alternating-minimization algorithm for classical convolutional dictionary learning (CDL). The second approach, which uses the $\ell_1$ norm to enforce sparsity, generalizes to the exponential family the recently-shown connection between CDL and a class of ReLU auto-encoders for Gaussian observations. The two approaches can each be interpreted as an auto-encoder, the weights of which are in one-to-one correspondence with the parameters of the convolutional dictionary. Our key insight is that, unless the observations are Gaussian valued, the input fed into the encoder ought to be modified iteratively, and in a specific manner, using the parameters of the dictionary. Compared to the $\ell_0$ approach, once trained, the forward pass through the $\ell_1$ encoder computes sparse codes orders of magnitude more efficiently. We apply the two approaches to the unsupervised learning of the stimulus effect from neural spiking data acquired in the barrel cortex of mice in response to periodic whisker deflections. We demonstrate that they are both superior to generalized linear models, which rely on hand-crafted features.

Given a continuous-time signal that can be modeled as the superposition of localized, time-shifted events from multiple sources, the goal of Convolutional Dictionary Learning (CDL) is to identify the location of the events--by Convolutional Sparse Coding (CSC)--and learn the template for each source--by Convolutional Dictionary Update (CDU). In practice, because we observe samples of the continuous-time signal on a uniformly-sampled grid in discrete time, classical CSC methods can only produce estimates of the times when the events occur on this grid, which degrades the performance of the CDU. We introduce a CDL framework that significantly reduces the errors arising from performing the estimation in discrete time. Specifically, we construct an expanded dictionary that comprises, not only discrete-time shifts of the templates, but also interpolated variants, obtained by bandlimited interpolation, that account for continuous-time shifts. For CSC, we develop a novel computationally efficient CSC algorithm, termed Convolutional Orthogonal Matching Pursuit with interpolated dictionary (COMP-INTERP). We benchmarked COMP-INTERP to Contiunuous Basis Pursuit (CBP), the state-of-the-art CSC algorithm for estimating off-the-grid events, and demonstrate, on simulated data, that 1) COMP-INTERP achieves a similar level of accuracy, and 2) is two orders of magnitude faster. For CDU, we derive a novel procedure to update the templates given sparse codes that can occur both on and off the discrete-time grid. We also show that 3) dictionary update with the overcomplete dictionary yields more accurate templates. Finally, we apply the algorithms to the spike sorting problem on electrophysiology recording and show their competitive performance.

Filter banks are a popular tool for the analysis of piecewise smooth signals such as natural images. Motivated by the empirically observed properties of scale and detail coefficients of images in the wavelet domain, we propose a hierarchical deep generative model of piecewise smooth signals that is a recursion across scales: the low pass scale coefficients at one layer are obtained by filtering the scale coefficients at the next layer, and adding a high pass detail innovation obtained by filtering a sparse vector. This recursion describes a linear dynamic system that is a non-Gaussian Markov process across scales and is closely related to multilayer-convolutional sparse coding (ML-CSC) generative model for deep networks, except that our model allows for deeper architectures, and combines sparse and non-sparse signal representations. We propose an alternating minimization algorithm for learning the filters in this hierarchical model given observations at layer zero, e.g., natural images. The algorithm alternates between a coefficient-estimation step and a filter update step. The coefficient update step performs sparse (detail) and smooth (scale) coding and, when unfolded, leads to a deep neural network. We use MNIST to demonstrate the representation capabilities of the model, and its derived features (coefficients) for classification.

2019 IEEE 8th International Workshop on Computational Advances in Multi-Sensor Adaptive Processing (CAMSAP)

Principal component analysis, dictionary learning, and auto-encoders are all unsupervised methods for learning representations from a large amount of training data. In all these methods, the higher the dimensions of the input data, the longer it takes to learn. We introduce a class of neural networks, termed RandNet, for learning representations using compressed random measurements of data of interest, such as images. RandNet extends the convolutional recurrent sparse auto-encoder architecture to dense networks and, more importantly, to the case when the input data are compressed random measurements of the original data. Compressing the input data makes it possible to fit a larger number of batches in memory during training. Moreover, in the case of sparse measurements, training is more efficient computationally. We demonstrate that, in unsupervised settings, RandNet performs dictionary learning using compressed data. In supervised settings, we show that RandNet can classify MNIST images with minimal loss in accuracy, despite being trained with random projections of the images that result in a 50% reduction in size. Overall, our results provide a general principled framework for training neural networks using compressed data.

2019 IEEE 29th International Workshop on Machine Learning for Signal Processing (MLSP)

Given a convolutional dictionary underlying a set of observed signals, can a carefully designed auto-encoder recover the dictionary in the presence of noise? We introduce an auto-encoder architecture, termed constrained recurrent sparse auto-encoder (CRsAE), that answers this question in the affirmative. Given an input signal and an approximate dictionary, the encoder finds a sparse approximation using FISTA. The decoder reconstructs the signal by applying the dictionary to the output of the encoder. The encoder and decoder in CRsAE parallel the sparse-coding and dictionary update steps in optimization-based alternating-minimization schemes for dictionary learning. As such, the parameters of the encoder and decoder are not independent, a constraint which we enforce for the first time. We derive the back-propagation algorithm for CRsAE. CRsAE is a framework for blind source separation that, only knowing the number of sources (dictionary elements), and assuming sparsely-many can overlap, is able to separate them. We demonstrate its utility in the context of spike sorting, a source separation problem in computational neuroscience. We demonstrate the ability of CRsAE to recover the underlying dictionary and characterize its sensitivity as a function of SNR.

2018 IEEE 28th International Workshop on Machine Learning for Signal Processing (MLSP)

SCALABLE CONVOLUTIONAL DICTIONARY LEARNING WITH CONSTRAINED RECURRENT SPARSE AUTO-ENCODERS

We present a compartmentalized approach to finding the maximum a posteriori (MAP) estimate of a latent time series that obeys a dynamic stochastic model and is observed through noisy measurements. We specifically consider modern signal processing problems with non-Markov signal dynamics (e.g., group sparsity) and/or non-Gaussian measurement models (e.g., point process observation models used in neuroscience). Through the use of auxiliary variables in the MAP estimation problem, we show that a consensus formulation of the alternating direction method of multipliers enables iteratively computing separate estimates based on the likelihood and prior and subsequently “averaging” them in an appropriate sense using a Kalman smoother. As such, this can be applied to a broad class of problem settings and only requires modular adjustments when interchanging various aspects of the statistical model. Under broad log-concavity assumptions, we show that the separate estimation problems are convex optimization problems and that the iterative algorithm converges to the MAP estimate. As such, this framework can capture non-Markov latent time series models and non-Gaussian measurement models. We provide example applications involving 1) group-sparsity priors, within the context of electrophysiologic specrotemporal estimation, and 2) non-Gaussian measurement models, within the context of dynamic analyses of learning with neural spiking and behavioral observations.

A Modularized Efficient Framework for Non-Markov Time Series Estimation

We propose a general statistical framework for clustering multiple time series that exhibit nonlinear dynamics into an a-priori-unknown number of sub-groups. Our motivation comes from neuroscience, where an important problem is to identify, within a large assembly of neurons, subsets that respond similarly to a stimulus or contingency. Upon modeling the multiple time series as the output of a Dirichlet process mixture of nonlinear state-space models, we derive a Metropolis-within-Gibbs algorithm for full Bayesian inference that alternates between sampling cluster assignments and sampling parameter values that form the basis of the clustering. The Metropolis step employs recent innovations in particle-based methods. We apply the framework to clustering time series acquired from the prefrontal cortex of mice in an experiment designed to characterize the neural underpinnings of fear.

Clustering Time Series with Nonlinear Dynamics: A Bayesian Non-Parametric and Particle-Based Approach

Spike sorting refers to the problem of assigning action potentials observed in extra-cellular recordings of neural activity to the neuron(s) from which they originate. We cast this problem as one of learning a convolutional dictionary from raw multi-electrode waveform data, subject to sparsity constraints. In this context, sparsity refers to the number of neurons that are allowed to spike simultaneously. The convolutional dictionary setting, along with its assumptions (e.g. refractoriness) that are motivated by the spike-sorting problem, let us give theoretical bounds on the sample complexity of spike sorting as a function of the number of underlying neurons, the rate of occurrence of simultaneous spiking, and the firing rate of the neurons. We derive memory/computation-efficient convolutional versions of OMP (cOMP) and KSVD (cKSVD), popular algorithms for sparse coding and dictionary learning respectively. We demonstrate via simulations that an algorithm that alternates between cOMP and cKSVD can recover the underlying spike waveforms successfully, assuming few neurons spike simultaneously, and is stable in the presence of noise. We also apply the algorithm to extra-cellular recordings from a tetrode in the rat Hippocampus.

Corticoamygdala Transfer of Socially Derived Information Gates Observational Learning

A recent line of work shows that a deep neural network with ReLU nonlinearities arises from a finite sequence of cascaded sparse coding models, the outputs of which, except for the last element in the cascade, are sparse and unobservable. That is, intermediate outputs deep in the cascade are sparse, hence the title of this manuscript. We show here, using techniques from the dictionary learning literature that, if the measurement matrices in the cascaded sparse coding model (a) satisfy RIP and (b) all have sparse columns except for the last, they can be recovered with high probability. We propose two algorithms for this purpose: one that recovers the matrices in a forward sequence, and another that recovers them in a backward sequence. The method of choice in deep learning to solve this problem is by training an auto-encoder. Our algorithms provide a sound alternative, with theoretical guarantees, as well upper bounds on sample complexity. The theory shows that the learning complexity of the forward algorithm depends on the number of hidden units at the deepest layer and the number of active neurons at that layer (sparsity). In addition, the theory relates the number of hidden units in successive layers, thus giving a practical prescription for designing deep ReLU neural networks. Because it puts fewer restrictions on the architecture, the backward algorithm requires more data. We demonstrate the deep dictionary learning algorithm via simulations. Finally, we use a coupon-collection argument to conjecture a lower bound on sample complexity that gives some insight as to why deep networks require more data to train than shallow ones.

Deeply-Sparse Signal rePresentations ($\text{D}\text{S}^2\text{P}$)

A separable two-dimensional random field model of binary response data from multi-day behavioral experiments

Electroencephalographic (EEG) monitoring of neural activity is widely used for sleep disorder diagnostics and research. The standard of care is to manually classify 30-second epochs of EEG time-domain traces into 5 discrete sleep stages. Unfortunately, this scoring process is subjective and time-consuming, and the defined stages do not capture the heterogeneous landscape of healthy and clinical neural dynamics. This motivates the search for a data-driven and principled way to identify the number and composition of salient, reoccurring brain states present during sleep. To this end, we propose a Hierarchical Dirichlet Process Hidden Markov Model (HDP-HMM), combined with wide-sense stationary (WSS) time series spectral estimation to construct a generative model for personalized subject sleep states. In addition, we employ multitaper spectral estimation to further reduce the large variance of the spectral estimates inherent to finite-length EEG measurements. By applying our method to both simulated and human sleep data, we arrive at three main results: 1) a Bayesian nonparametric automated algorithm that recovers general temporal dynamics of sleep, 2) identification of subject-specific "microstates" within canonical sleep stages, and 3) discovery of stage-dependent sub-oscillations with shared spectral signatures across subjects.

A fundamental problem in neuroscience is to characterize the dynamics of spiking from the neurons in a circuit that is involved in learning about a stimulus or a contingency. A key limitation of current methods to analyze neural spiking data is the need to collapse neural activity over time or trials, which may cause the loss of information pertinent to understanding the function of a neuron or circuit. We introduce a new method that can determine not only the trial-to-trial dynamics that accompany the learning of a contingency by a neuron, but also the latency of this learning with respect to the onset of a conditioned stimulus. The backbone of the method is a separable two-dimensional (2D) random field (RF) model of neural spike rasters, in which the joint conditional intensity function of a neuron over time and trials depends on two latent Markovian state sequences that evolve separately but in parallel. Classical tools to estimate state-space models cannot be applied readily to our 2D separable RF model. We develop efficient statistical and computational tools to estimate the parameters of the separable 2D RF model. We apply these to data collected from neurons in the prefrontal cortex in an experiment designed to characterize the neural underpinnings of the associative learning of fear in mice. Overall, the separable 2D RF model provides a detailed, interpretable characterization of the dynamics of neural spiking that accompany the learning of a contingency.

Estimating a Separably Markov Random Field from Binary Observations

The problem of detecting changes in firing patterns in neural data is studied. The problem is formulated as a quickest change detection (QCD) problem. Important algorithms from the literature are reviewed. A new algorithmic technique is discussed to detect deviations from learned baseline behavior. The algorithms studied can be applied to both spike and local field potential data. The algorithms are applied to mice spike data to verify the presence of behavioral learning.

2019 9th International IEEE/EMBS Conference on Neural Engineering (NER)

With ever-increasing advancements in technology, neuroscientists are able to collect data in greater volumes and with finer resolution. The bottleneck in understanding how the brain works is consequently shifting away from the amount and type of data we can collect and toward what we actually do with the data. There has been a growing interest in leveraging this vast volume of data across levels of analysis, measurement techniques, and experimental paradigms to gain more insight into brain function. Such efforts are visible at an international scale, with the emergence of big data neuroscience initiatives, such as the BRAIN initiative (Bargmann et al., 2014), the Human Brain Project, the Human Connectome Project, and the National Institute of Mental Health's Research Domain Criteria initiative. With these large-scale projects, much thought has been given to data-sharing across groups (Poldrack and Gorgolewski, 2014; Sejnowski et al., 2014); however, even with such data-sharing initiatives, funding mechanisms, and infrastructure, there still exists the challenge of how to cohesively integrate all the data. At multiple stages and levels of neuroscience investigation, machine learning holds great promise as an addition to the arsenal of analysis tools for discovering how the brain works.

Spectral properties of the electroencephalogram (EEG) are commonly analyzed to characterize the brain's oscillatory properties in basic science and clinical neuroscience studies. The spectrum is a function that describes power as a function of frequency. To date inference procedures for spectra have focused on constructing confidence intervals at single frequencies using large sample-based analytic procedures or jackknife techniques. These procedures perform well when the frequencies of interest are chosen before the analysis. When these frequencies are chosen after some of the data have been analyzed, the validity of these conditional inferences is not addressed. If power at more than one frequency is investigated, corrections for multiple comparisons must also be incorporated. To develop a statistical inference approach that considers the spectrum as a function defined across frequencies, we combine multitaper spectral methods with a frequency-domain bootstrap (FDB) procedure. The multitaper method is optimal for minimizing the bias-variance tradeoff in spectral estimation. The FDB makes it possible to conduct Monte Carlo based inferences for any part of the spectrum by drawing random samples that respect the dependence structure in the EEG time series. We show that our multitaper FDB procedure performs well in simulation studies and in analyses comparing EEG recordings of children from two different age groups receiving general anesthesia.

A macaque monkey is trained to perform two different kinds of tasks, memory aided and visually aided. In each task, the monkey saccades to eight possible target locations. A classifier is proposed for direction decoding and task decoding based on local field potentials (LFP) collected from the prefrontal cortex. The LFP time-series data is modeled in a nonparametric regression framework, as a function corrupted by Gaussian noise. It is shown that if the function belongs to Besov bodies, then the proposed wavelet shrinkage and thresholding based classifier is robust and consistent. The classifier is then applied to the LFP data to achieve high decoding performance. The proposed classifier is also quite general and can be applied for the classification of other types of time-series data as well, not necessarily brain data.

2018 IEEE International Conference on Acoustics, Speech and Signal Processing (ICASSP)

Wavelet Shrinkage and Thresholding Based Robust Classification for Brain-Computer Interface

Significance Rapid growth in sensor and recording technologies is spurring rapid growth in time series data. Nonstationary and oscillatory structure in time series is commonly analyzed using time-varying spectral methods. These widely used techniques lack a statistical inference framework applicable to the entire time series. We develop a state-space multitaper (SS-MT) framework for time-varying spectral analysis of nonstationary time series. We efficiently implement the SS-MT spectrogram estimation algorithm in the frequency domain as parallel 1D complex Kalman filters. In analyses of human EEGs recorded under general anesthesia, the SS-MT paradigm provides enhanced denoising (>10 dB) and spectral resolution relative to standard multitaper methods, a flexible time-domain decomposition of the time series, and a broadly applicable, empirical Bayes’ framework for statistical inference. Time series are an important data class that includes recordings ranging from radio emissions, seismic activity, global positioning data, and stock prices to EEG measurements, vital signs, and voice recordings. Rapid growth in sensor and recording technologies is increasing the production of time series data and the importance of rapid, accurate analyses. Time series data are commonly analyzed using time-varying spectral methods to characterize their nonstationary and often oscillatory structure. Current methods provide local estimates of data features. However, they do not offer a statistical inference framework that applies to the entire time series. The important advances that we report are state-space multitaper (SS-MT) methods, which provide a statistical inference framework for time-varying spectral analysis of nonstationary time series. We model nonstationary time series as a sequence of second-order stationary Gaussian processes defined on nonoverlapping intervals. We use a frequency-domain random-walk model to relate the spectral representations of the Gaussian processes across intervals. The SS-MT algorithm efficiently computes spectral updates using parallel 1D complex Kalman filters. An expectation–maximization algorithm computes static and dynamic model parameter estimates. We test the framework in time-varying spectral analyses of simulated time series and EEG recordings from patients receiving general anesthesia. Relative to standard multitaper (MT), SS-MT gave enhanced spectral resolution and noise reduction (>10 dB) and allowed statistical comparisons of spectral properties among arbitrary time series segments. SS-MT also extracts time-domain estimates of signal components. The SS-MT paradigm is a broadly applicable, empirical Bayes’ framework for statistical inference that can help ensure accurate, reproducible findings from nonstationary time series analyses.

A fundamental problem in neuroscience is to characterize the dynamics of spiking from the neurons in a circuit that is involved in learning about a stimulus or a contingency. A key limitation of current methods to analyze neural spiking data is the need to collapse neural activity over time or trials, which may cause the loss of information pertinent to understanding the function of a neuron or circuit. We introduce a new method that can determine not only the trial-to-trial dynamics that accompany the learning of a contingency by a neuron, but also the latency of this learning with respect to the onset of a conditioned stimulus. The backbone of the method is a separable two-dimensional (2D) random field (RF) model of neural spike rasters, in which the joint conditional intensity function of a neuron over time and trials depends on two latent Markovian state sequences that evolve separately but in parallel. Classical tools to estimate state-space models cannot be applied readily to our 2D separable RF model. We develop efficient statistical and computational tools to estimate the parameters of the separable 2D RF model. We apply these to data collected from neurons in the pre-frontal cortex (PFC) in an experiment designed to characterize the neural underpinnings of the associative learning of fear in mice. Overall, the separable 2D RF model provides a detailed, interpretable, characterization of the dynamics of neural spiking that accompany the learning of a contingency.

Estimating a Separably-Markov Random Field (SMuRF) from Binary Observations

A problem of classification of local field potentials (LFPs), recorded from the prefrontal cortex of a macaque monkey, is considered. An adult macaque monkey is trained to perform a memory based saccade. The objective is to decode the eye movement goals from the LFP collected during a memory period. The LFP classification problem is modeled as that of classification of smooth functions embedded in Gaussian noise. It is then argued that using minimax function estimators as features would lead to consistent LFP classifiers. The theory of Gaussian sequence models allows us to represent minimax estimators as finite dimensional objects. The LFP classifier resulting from this mathematical endeavor is a spectrum based technique, where Fourier series coefficients of the LFP data, followed by appropriate shrinkage and thresholding, are used as features in a linear discriminant classifier. The classifier is then applied to the LFP data to achieve high decoding accuracy. The function classification approach taken in the paper also provides a systematic justification for using Fourier series, with shrinkage and thresholding, as features for the problem, as opposed to using the power spectrum. It also suggests that phase information is crucial to the decision making.

Classification of Local Field Potentials using Gaussian Sequence Model

Classical time-evolving spectral analysis techniques utilize a sliding window approach that fails to exploit overarching spectrotemporal structures that are known to occur in many real-world signals. In particular, many biological signals have the distinct quality of having few defining spectral characteristics. We propose an algorithm for efficiently estimating a low-rank spectrotemporal decomposition. While existing approaches yield such representations by penalizing a group norm of successive differences, our insight is that a penalty that promotes low-rank yields more flexible representations and an efficient distributed implementation. We demonstrate on simulated time series data and human electroencephalogram (EEG) recordings that this low-rank spectrotemporal decomposition can provide a spectral representation of time series that highlights salient features and reduces the effects of noise.

BACKGROUND:Although emergence from general anesthesia is clinically treated as a passive process driven by the pharmacokinetics of drug clearance, agents that hasten recovery from general anesthesia may be useful for treating delayed emergence, emergence delirium, and postoperative cognitive dysfunction. Activation of central monoaminergic neurotransmission with methylphenidate has been shown to induce reanimation (active emergence) from general anesthesia. Cholinergic neurons in the brainstem and basal forebrain are also known to promote arousal. The objective of this study was to test the hypothesis that physostigmine, a centrally acting cholinesterase inhibitor, induces reanimation from isoflurane anesthesia in adult rats. METHODS:The dose-dependent effects of physostigmine on time to emergence from a standardized isoflurane general anesthetic were tested. It was then determined whether physostigmine restores righting during continuous isoflurane anesthesia. In a separate group of rats with implanted extradural electrodes, physostigmine was administered during continuous inhalation of 1.0% isoflurane, and the electroencephalogram changes were recorded. Finally, 2.0% isoflurane was used to induce burst suppression, and the effects of physostigmine and methylphenidate on burst suppression probability (BSP) were tested. RESULTS:Physostigmine delayed time to emergence from isoflurane anesthesia at doses ≥0.2 mg/kg (n = 9). During continuous isoflurane anesthesia (0.9% ± 0.1%), physostigmine did not restore righting (n = 9). Blocking the peripheral side effects of physostigmine with the coadministration of glycopyrrolate (a muscarinic antagonist that does not cross the blood–brain barrier) produced similar results (n = 9 each). However, during inhalation of 1.0% isoflurane, physostigmine shifted peak electroencephalogram power from &dgr; (<4 Hz) to &thgr; (4–8 Hz) in 6 of 6 rats. During continuous 2.0% isoflurane anesthesia, physostigmine induced large, statistically significant decreases in BSP in 6 of 6 rats, whereas methylphenidate did not. CONCLUSIONS:Unlike methylphenidate, physostigmine does not accelerate time to emergence from isoflurane anesthesia and does not restore righting during continuous isoflurane anesthesia. However, physostigmine consistently decreases BSP during deep isoflurane anesthesia, whereas methylphenidate does not. These findings suggest that activation of cholinergic neurotransmission during isoflurane anesthesia produces arousal states that are distinct from those induced by monoaminergic activation.

Physostigmine and Methylphenidate Induce Distinct Arousal States During Isoflurane General Anesthesia in Rats

Significance Neurons represent both signal and noise in binary electrical discharges termed action potentials. Hence, the standard signal-to-noise ratio (SNR) definition of signal amplitude squared and divided by the noise variance does not apply. We show that the SNR estimates a ratio of expected prediction errors. Using point process generalized linear models, we extend the standard definition to one appropriate for single neurons. In analyses of four neural systems, we show that single neuron SNRs range from −29 dB to −3 dB and that spiking history is often a more informative predictor of spiking propensity than the signal or stimulus activating the neuron. By generalizing the standard SNR metric, we make explicit the well-known fact that individual neurons are highly noisy information transmitters. The signal-to-noise ratio (SNR), a commonly used measure of fidelity in physical systems, is defined as the ratio of the squared amplitude or variance of a signal relative to the variance of the noise. This definition is not appropriate for neural systems in which spiking activity is more accurately represented as point processes. We show that the SNR estimates a ratio of expected prediction errors and extend the standard definition to one appropriate for single neurons by representing neural spiking activity using point process generalized linear models (PP-GLM). We estimate the prediction errors using the residual deviances from the PP-GLM fits. Because the deviance is an approximate χ2 random variable, we compute a bias-corrected SNR estimate appropriate for single-neuron analysis and use the bootstrap to assess its uncertainty. In the analyses of four systems neuroscience experiments, we show that the SNRs are −10 dB to −3 dB for guinea pig auditory cortex neurons, −18 dB to −7 dB for rat thalamic neurons, −28 dB to −14 dB for monkey hippocampal neurons, and −29 dB to −20 dB for human subthalamic neurons. The new SNR definition makes explicit in the measure commonly used for physical systems the often-quoted observation that single neurons have low SNRs. The neuron’s spiking history is frequently a more informative covariate for predicting spiking propensity than the applied stimulus. Our new SNR definition extends to any GLM system in which the factors modulating the response can be expressed as separate components of a likelihood function.

Significance Classical spectral estimation techniques use sliding windows to enforce temporal smoothness of the spectral estimates of signals with time-varying spectrotemporal representations. This widely applied approach is not well-suited to signals that have low-dimensional, highly structured time–frequency representations. We develop a new Bayesian spectral decomposition framework—spectrotemporal pursuit—to compute spectral estimates that are smooth in time and sparse in frequency. We use a statistical interpretation of sparse recovery to derive efficient algorithms for computing spectrotemporal pursuit spectral estimates. We apply spectrotemporal pursuit to achieve a more precise delineation of the oscillatory structure of human electroencephalogram and neural spiking data under propofol general anesthesia. Spectrotemporal pursuit offers a principled alternative to existing methods for decomposing a signal into a small number of oscillatory components. Classical nonparametric spectral analysis uses sliding windows to capture the dynamic nature of most real-world time series. This universally accepted approach fails to exploit the temporal continuity in the data and is not well-suited for signals with highly structured time–frequency representations. For a time series whose time-varying mean is the superposition of a small number of oscillatory components, we formulate nonparametric batch spectral analysis as a Bayesian estimation problem. We introduce prior distributions on the time–frequency plane that yield maximum a posteriori (MAP) spectral estimates that are continuous in time yet sparse in frequency. Our spectral decomposition procedure, termed spectrotemporal pursuit, can be efficiently computed using an iteratively reweighted least-squares algorithm and scales well with typical data lengths. We show that spectrotemporal pursuit works by applying to the time series a set of data-derived filters. Using a link between Gaussian mixture models, ℓ1 minimization, and the expectation–maximization algorithm, we prove that spectrotemporal pursuit converges to the global MAP estimate. We illustrate our technique on simulated and real human EEG data as well as on human neural spiking activity recorded during loss of consciousness induced by the anesthetic propofol. For the EEG data, our technique yields significantly denoised spectral estimates that have significantly higher time and frequency resolution than multitaper spectral estimates. For the neural spiking data, we obtain a new spectral representation of neuronal firing rates. Spectrotemporal pursuit offers a robust spectral decomposition framework that is a principled alternative to existing methods for decomposing time series into a small number of smooth oscillatory components.

Robust spectrotemporal decomposition by iteratively reweighted least squares

An important problem in computational neuro-science is to design algorithms that can capture robustly abrupt changes in the conditional intensity function (CIF) of a stochastic point process model of neural spiking data. Towards this end, we advocate the use of a point process analogue of the total variation denoising algorithm, which trades off the point process likelihood with a total variation prior on the parameters of a log-linear model of the CIF. We propose an iteratively re-weighted least squares (IRLS) algorithm, termed Point process Re-weighted Iterative SMoothing (PRISM), to solve the point process total variation denoising (PPTVD) problem. PRISM can be implemented using well-established point process smoothing algorithms, which are point process analogues of the Kalman smoother. We use a connection between the Expectation-Maximization (EM) algorithm and IRLS to prove that the sequence generated by PRISM converges and that its limit point coincides with the unique stationary point of the PPTVD problem. We apply PRISM to 123 and 41 neuronal units acquired from two separate epileptic patients during general anesthesia induced using the drug propofol. The PRISM algorithm is able to capture robustly the onset of loss of consciousness at the millisecond time scale.

Neural spike train denoising by point process re-weighted iterative smoothing

Likelihood-based encoding models founded on point processes have received significant attention in the literature because of their ability to reveal the information encoded by spiking neural populations. We propose an approximation to the likelihood of a point-process model of neurons that holds under assumptions about the continuous time process that are physiologically reasonable for neural spike trains: the presence of a refractory period, the predictability of the conditional intensity function, and its integrability. These are properties that apply to a large class of point processes arising in applications other than neuroscience. The proposed approach has several advantages over conventional ones. In particular, one can use standard fitting procedures for generalized linear models based on iteratively reweighted least squares while improving the accuracy of the approximation to the likelihood and reducing bias in the estimation of the parameters of the underlying continuous-time model. As a result, the proposed approach can use a larger bin size to achieve the same accuracy as conventional approaches would with a smaller bin size. This is particularly important when analyzing neural data with high mean and instantaneous firing rates. We demonstrate these claims on simulated and real neural spiking activity. By allowing a substantive increase in the required bin size, our algorithm has the potential to lower the barrier to the use of point-process methods in an increasing number of applications.

In this paper, we study the theoretical properties of iteratively re-weighted least squares (IRLS) algorithms and their utility in sparse signal recovery in the presence of noise. We demonstrate a one-to-one correspondence between the IRLS algorithms and a class of Expectation-Maximization (EM) algorithms for constrained maximum likelihood estimation under a Gaussian scale mixture (GSM) distribution. The EM formalism, as well as the connection to GSMs, allow us to establish that the IRLS algorithms minimize smooth versions of the lν `norms', for . We leverage EM theory to show that the limit points of the sequence of IRLS iterates are stationary points of the smooth lν “norm” minimization problem on the constraint set. We employ techniques from Compressive Sampling (CS) theory to show that the IRLS algorithm is stable, if the limit point of the iterates coincides with the global minimizer. We further characterize the convergence rate of the IRLS algorithm, which implies global linear convergence for ν = 1 and local super-linear convergence for . We demonstrate our results via simulation experiments. The simplicity of IRLS, along with the theoretical guarantees provided in this contribution, make a compelling case for its adoption as a standard tool for sparse signal recovery.

Convergence and Stability of Iteratively Re-weighted Least Squares Algorithms

Understanding how ensembles of neurons represent and transmit information in the patterns of their joint spiking activity is a fundamental question in computational neuroscience. At present, analyses of spiking activity from neuronal ensembles are limited because multivariate point process (MPP) models cannot represent simultaneous occurrences of spike events at an arbitrarily small time resolution. Solo recently reported a simultaneous-event multivariate point process (SEMPP) model to correct this key limitation. In this paper, we show how Solo's discrete-time formulation of the SEMPP model can be efficiently fit to ensemble neural spiking activity using a multinomial generalized linear model (mGLM). Unlike existing approximate procedures for fitting the discrete-time SEMPP model, the mGLM is an exact algorithm. The MPP time-rescaling theorem can be used to assess model goodness-of-fit. We also derive a new marked point-process (MkPP) representation of the SEMPP model that leads to new thinning and time-rescaling algorithms for simulating an SEMPP stochastic process. These algorithms are much simpler than multivariate extensions of algorithms for simulating a univariate point process, and could not be arrived at without the MkPP representation. We illustrate the versatility of the SEMPP model by analyzing neural spiking activity from pairs of simultaneously-recorded rat thalamic neurons stimulated by periodic whisker deflections, and by simulating SEMPP data. In the data analysis example, the SEMPP model demonstrates that whisker motion significantly modulates simultaneous spiking activity at the 1 ms time scale and that the stimulus effect is more than one order of magnitude greater for simultaneous activity compared with non-simultaneous activity. Together, the mGLM, the MPP time-rescaling theorem and the MkPP representation of the SEMPP model offer a theoretically sound, practical tool for measuring joint spiking propensity in a neuronal ensemble.

Algorithms for the analysis of ensemble neural spiking activity using simultaneous-event multivariate point-process models

In this paper, we study the theoretical properties of a class of iteratively re-weighted least squares (IRLS) algorithms for sparse signal recovery in the presence of noise. We demonstrate a one-to-one correspondence between this class of algorithms and a class of Expectation-Maximization (EM) algorithms for constrained maximum likelihood estimation under a Gaussian scale mixture (GSM) distribution. The IRLS algorithms we consider are parametrized by 0 < ν ≤ 1 and ε > 0. The EM formalism, as well as the connection to GSMs, allow us to establish that the IRLS(ν, ε) algorithms minimize ε-smooth versions of the ℓ ν 'norms'. We leverage EM theory to show that, for each 0 < ν ≤ 1, the limit points of the sequence of IRLS(ν, ε) iterates are stationary point of the ε-smooth ℓ ν 'norm' minimization problem on the constraint set. Finally, we employ techniques from Compressive sampling (CS) theory to show that the class of IRLS(ν, ε) algorithms is stable for each 0 < ν ≤ 1, if the limit point of the iterates coincides the global minimizer. For the case ν = 1, we show that the algorithm converges exponentially fast to a neighborhood of the stationary point, and outline its generalization to super-exponential convergence for ν < 1. We demonstrate our claims via simulation experiments. The simplicity of IRLS, along with the theoretical guarantees provided in this contribution, make a compelling case for its adoption as a standard tool for sparse signal recovery.

IEEE transactions on signal processing : a publication of the IEEE Signal Processing Society

Convergence and Stability of a Class of Iteratively Re-weighted Least Squares Algorithms for Sparse Signal Recovery in the Presence of Noise.

Ising models are routinely used to quantify the second order, functional structure of neural populations. With some recent exceptions, they generally do not include the influence of time varying stimulus drive. Yet if the dynamics of network function are to be understood, time varying stimuli must be taken into account. Inclusion of stimulus drive carries a heavy computational burden because the partition function becomes stimulus dependent and must be separately calculated for all unique stimuli observed. This potentially increases computation time by the length of the data set. Here we present an extremely fast, yet simply implemented, method for approximating the stimulus dependent partition function in minutes or seconds. Noting that the most probable spike patterns (which are few) occur in the training data, we sum partition function terms corresponding to those patterns explicitly. We then approximate the sum over the remaining patterns (which are improbable, but many) by casting it in terms of the stimulus modulated missing mass (total stimulus dependent probability of all patterns not observed in the training data). We use a product of conditioned logistic regression models to approximate the stimulus modulated missing mass. This method has complexity of roughly O(LNNpat) where is L the data length, N the number of neurons and Npat the number of unique patterns in the data, contrasting with the O(L2N) complexity of alternate methods. Using multiple unit recordings from rat hippocampus, macaque DLPFC and cat Area 18 we demonstrate our method requires orders of magnitude less computation time than Monte Carlo methods and can approximate the stimulus driven partition function more accurately than either Monte Carlo methods or deterministic approximations. This advance allows stimuli to be easily included in Ising models making them suitable for studying population based stimulus encoding.

Missing mass approximations for the partition function of stimulus driven Ising models

We consider the problem of recovering a sequence of vectors, $(x_k)_{k=0}^K$, for which the increments $x_k-x_{k-1}$-1 are Sk-sparse (with Sk typically smaller than S1), based on linear measurements $(y_k = A_k x_k + e_k)_{k=1}^K$, where Ak and ek denote the measurement matrix and noise, respectively. Assuming each Ak obeys the restricted isometry property (RIP) of a certain order—depending only on Sk—we show that in the absence of noise a convex program, which minimizes the weighted sum of the l1-norm of successive differences subject to the linear measurement constraints, recovers the sequence $(x_k)_{k=1}^K$ exactly. This is an interesting result because this convex program is equivalent to a standard compressive sensing problem with a highly-structured aggregate measurement matrix which does not satisfy the RIP requirements in the standard sense, and yet we can achieve exact recovery. In the presence of bounded noise, we propose a quadratically-constrained convex program for recovery and derive bounds on the reconstruction error of the sequence. We supplement our theoretical analysis with simulations and an application to real video data. These further support the validity of the proposed approach for acquisition and recovery of signals with time-varying sparsity.

Exact and Stable Recovery of Sequences of Signals with Sparse Increments via Differential _1-Minimization

In this paper, we study the theoretical properties of a class of iteratively re-weighted least squares (IRLS) algorithms for sparse signal recovery in the presence of noise. We demonstrate a one-toone correspondence between this class of algorithms and a class of Expectation-Maximization (EM) algorithms for constrained maximum likelihood estimation under a Gaussian scale mixture (GSM) distribution. The IRLS algorithms we consider are parametrized by 0 < ν ≤ 1 and ε > 0. The EM formalism, as well as the connection to GSMs, allow us to establish that the IRLS(ν, ε) algorithms minimize ε-smooth versions of the lν ‘norms’. We leverage EM theory to show that, for each 0 < ν ≤ 1, the limit points of the sequence of IRLS(ν,ε) iterates are stationary point of the ε-smooth lν ‘norm’ minimization problem on the constraint set. Finally, we employ techniques from Compressive sampling (CS) theory to show that the class of IRLS(ν,ε) algorithms is stable for each 0 < ν ≤ 1, if the limit point of the iterates coincides the global minimizer. For the case ν = 1, we show that the algorithm converges exponentially fast to a neighborhood of the stationary point, and outline its generalization to super-exponential convergence for ν < 1. We demonstrate our claims via simulation experiments. The simplicity of IRLS, along with the theoretical guarantees provided in this contribution, make a compelling case for its adoption as a standard tool for sparse signal recovery. (1) Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139 (2) Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114 (3) Harvard-MIT Division of Health, Sciences and Technology Emails: Behtash Babadi (behtash@nmr.mgh.harvard.edu), Demba Ba (demba@mit.edu), Patrick L. Purdon (patrickp@nmr.mgh.harvard.edu), and Emery N. Brown (enb@neurostat.mit.edu)

Convergence and Stability of Iteratively Re-weighted Least Squares Algorithms for Sparse Signal Recovery in the Presence of Noise

We consider the problem of recovering a sequence of vectors, (xk)k=0, for which the incrementsxk−xk−1 areSk-sparse (withSk typically smaller thanS1), based on linear measurements (yk = Akxk + ek)k=1, whereAk andek denote the measurement matrix and noise, respectively. Assuming each Ak obeys the restricted isometry property (RIP) of a certain order—depending only o Sk—we show that in the absence of noise a convex program, which minimizes the weighted sum of the l1-norm of successive differences subject to the linear measu r ment constraints, recovers the sequence (xk)k=1 exactly. This is an interesting result because this convex program is equivalent to a standard compre ssive sensing problem with a highly-structured aggregate measurement matrix wh ch does not satisfy the RIP requirements in the standard sense, and yet we can ach ieve exact recovery. In the presence of bounded noise, we propose a quadratic ally-constrained convex program for recovery and derive bounds on the reconst ruction error of the sequence. We supplement our theoretical analysis with simu lations and an application to real video data. These further support the vali dity of the proposed approach for acquisition and recovery of signals with timevarying sparsity.

Exact and stable recovery of sequences of signals with sparse increments via differential ℓ [subscript 1]-minimization

The geometry of an acoustic environment can be an important information in many audio signal processing applications. To estimate such a geometry, previous work has relied on large microphone arrays, multiple test sources, moving sources or the assumption of a 2-D room. In this paper, we lift these requirements and present a novel method that uses a compact microphone array to estimate a 3-D room geometry, delivering effective estimates with low-cost hardware. Our approach first probes the environment with a known test signal emitted by a loudspeaker co-located with the array, from which the room impulse responses (RIRs) are estimated. It then uses an ℓ1-regularized least-squares minimization to fit synthetically generated reflections to the RIRs, producing a sparse set of reflections. By enforcing structural constraints derived from the image model, these are classified into first-, second-, and third-order reflections, thereby deriving the room geometry. Using this method, we detect walls using off-the-shelf teleconferencing hardware with a typical range resolution of about 1 cm. We present results using simulations and data from real environments.

Geometrically Constrained Room Modeling With Compact Microphone Arrays

The formulation of multivariate point-process (MPP) models based on the Jacod likelihood does not allow for simultaneous occurrence of events at an arbitrarily small time resolution. In this thesis, we introduce two versatile representations of a simultaneous-event multivariate point-process (SEMPP) model to correct this important limitation. The first one maps an SEMPP into a higher-dimensional multivariate point-process with no simultaneities, and is accordingly termed the disjoint representation. The second one is a marked point-process representation of an SEMPP, which leads to new thinning and time-resealing algorithms for simulating an SEMPP stochastic process. Starting from the likelihood of a discrete-time form of the disjoint representation, we present derivations of the continuous likelihoods of the disjoint and MkPP representations of SEMPPs. 
For static inference, we propose a parametrization of the likelihood of the disjoint representation in discrete-time which gives a multinomial generalized linear model (mGLM) algorithm for model fitting. For dynamic: inference, we derive generalizations of point-process adaptive filters. The MPP time-resealing theorem can be used to assess model goodness-of-fit. 
We illustrate the features of our SEMPP model by simulating SEMPP data and by analyzing neural spiking activity from pairs of simultaneously-recorded rat thalamic neurons stimulated by periodic whisker deflections. The SEMPP model demonstrates a strong effect of whisker motion on simultaneous spiking activity at the one millisecond time scale. Together, the MkPP representation of the SEMPP model, the inGLM and the MPP time-resealing theorem offer a theoretically sound, practical tool for measuring joint spiking propensity in a neuronal ensemble. (Copies available exclusively from MIT Libraries, Rm. 14-0551, Cambridge, MA 02139-4307. Ph. 617-253-5668; Fax 617-253-1690.)

Algorithms and inference for simultaneous-event multivariate point-process, with applications to neural data

Acoustic room modeling has several applications. Recent results using large microphone arrays show good performance, and are helpful in many applications. For example, when designing a better acoustic treatment for a concert hall, these large arrays can be used to help map the acoustic environment and aid in the design. However, in real-time applications - including de-reverberation, sound source localization, speech enhancement and 3D audio - it is desirable to model the room with existing small arrays and existing loudspeakers. In this paper we propose a novel room modeling algorithm, which uses a constrained room model and ℓ1-regularized least-squares to achieve good estimation of room geometry. We present experimental results on both real and synthetic data.

2010 IEEE International Conference on Acoustics, Speech and Signal Processing

Sound Source Localization (SSL) based on microphone arrays has numerous applications, and has received significant research attention. Common to all published research is the observation that the accuracy of SSL degrades with reverberation. Indeed, early (strong) reflections can have amplitudes similar to the direct signal, and will often interfere with the estimation. In this paper, we show that reverberation is not the enemy, and can be used to improve estimation. More specifically, we are able to use early reflections to significantly improve range and elevation estimation. The process requires two steps: during setup, a loudspeaker integrated with the array emits a probing sound, which is used to obtain estimates of the ceiling height, as well as the locations of the walls. In a second step (e.g., during a meeting), the device incorporates this knowledge into a maximum likelihood SSL algorithm. Experimental results on both real and synthetic data show huge improvements in range estimation accuracy.

Turning enemies into friends: Using reflections to improve sound source localization

Sound source localization (SSL) is an essential task in many applications involving speech capture and enhancement. As such, speaker localization with microphone arrays has received significant research attention. Nevertheless, existing SSL algorithms for small arrays still have two significant limitations: lack of range resolution, and accuracy degradation with increasing reverberation. The latter is natural and expected, given that strong reflections can have amplitudes similar to that of the direct signal, but different directions of arrival. Therefore, correctly modeling the room and compensating for the reflections should reduce the degradation due to reverberation. In this paper, we show a stronger result. If modeled correctly, early reflections can be used to provide more information about the source location than would have been available in an anechoic scenario. The modeling not only compensates for the reverberation, but also significantly increases resolution for range and elevation. Thus, we show that under certain conditions and limitations, reverberation can be used to improve SSL performance. Prior attempts to compensate for reverberation tried to model the room impulse response (RIR). However, RIRs change quickly with speaker position, and are nearly impossible to track accurately. Instead, we build a 3-D model of the room, which we use to predict early reflections, which are then incorporated into the SSL estimation. Simulation results with real and synthetic data show that even a simplistic room model is sufficient to produce significant improvements in range and elevation estimation, tasks which would be very difficult when relying only on direct path signal components.

Using Reverberation to Improve Range and Elevation Discrimination for Small Array Sound Source Localization

Identification of multiple simultaneously recorded neural spike train recordings is an important task in understanding neuronal dependency, functional connectivity, and temporal causality in neural systems. An assessment of the functional connectivity in a group of ensemble cells was performed using a regularized point process generalized linear model (GLM) that incorporates temporal smoothness or contiguity of the solution. An efficient convex optimization algorithm was then developed for the regularized solution. The point process model was applied to an ensemble of neurons recorded from the cat motor cortex during a skilled reaching task. The implications of this analysis to the coding of skilled movement in primary motor cortex is discussed.

A regularized point process generalized linear model for assessing the connectivity in the cat motor cortex

2009 Annual International Conference of the IEEE Engineering in Medicine and Biology Society

A regularized point process generalized linear model for assessing the functional connectivity in the cat motor cortex

In distributed meeting applications, microphone arrays have been widely used to capture superior speech sound and perform speaker localization through sound source localization (SSL) and beamforming. This paper presents a unified maximum likelihood framework of these two techniques, and demonstrates how such a framework can be adapted to create efficient SSL and beamforming algorithms for reverberant rooms and unknown directional patterns of microphones. The proposed method is closely related to steered response power-based algorithms, which are known to work extremely well in real-world environments. We demonstrate the effectiveness of the proposed method on challenging synthetic and real-world datasets, including over six hours of recorded meetings.

Maximum Likelihood Sound Source Localization and Beamforming for Directional Microphone Arrays in Distributed Meetings

Microphone arrays based on the minimum variance distortionless response (MVDR) beamformer are among the most popular for speech enhancement applications. The original MVDR is excessively sensitive to source location and microphone gains. Previous research has made MVDR practical by successfully increasing the robustness of MVDR to source location, and MVDR-based microphone arrays are already commercially available. Nevertheless, MVDR performance is still weak in cases where microphone gain variations are too large, e.g., for circular arrays of directional microphones. In this paper we propose an improved MVDR beamformer which takes into account the effect of sensors (e.g. microphones) with arbitrary, potentially directional responses. Specifically, we form estimates of the relative magnitude responses of the sensors based on the data received at the array and include those in the original formulation of the MVDR beamforming problem. Experimental results on real-world audio data show an average 2.4 dB improvement over conventional MVDR beamforming, which does not account for the magnitude responses of the sensors.

This paper introduces a family of integer-to-integer approximations to the Cartesian-to-polar coordinate transformation and analyzes its application to lossy compression. A high-rate analysis is provided for an encoder that first uniformly scalar quantizes, then transforms to "integer polar coordinates," and finally separately entropy codes angle and radius. For sources separable in polar coordinates, the performance (at high rate) is shown to match that of entropy-constrained unconstrained polar quantization - where the angular quantization is allowed to depend on the radius. Thus, for sources separable in polar coordinates but not separable in rectangular coordinates - including certain Gaussian scale mixtures - the proposed system performs better than any transform code. Furthermore, unlike unconstrained polar quantization, integer polar coordinates are appropriate for lossless compression of integer-valued vectors. Combination of integer polar coordinates with integer-to-integer transform coding is also discussed.

In conventional transform coding, the importance of preserving desirable quantization partition cell shapes prevents one from considering the use of a nonlinear change of variables. If no linear transformation of a given source would yield independent components, this means having to encode it at a rate higher than its entropy, i.e. suboptimally. This thesis proposes a new transform coding technique where the source samples are first uniformly scalar quantized and then transformed with an integerto-integer approximation to a nonlinear transformation that would give independent components. In particular, we design a family of integer-to-integer approximations to the Cartesian-to-polar transformation and analyze its behavior for high rate transform coding. Among the benefits of such an approach is the ability to achieve redundancy reduction beyond decorrelation without limitation to orthogonal linear transformations of the original variables. A high resolution analysis is given, and for source models inspired by a sensor network application and by image compression, simulations show improvements over conventional transform coding. A comparison to state-of-the-art entropy-coded polar quantization techniques is also provided. Thesis Supervisor: Vivek K Goyal Title: Assistant Professor of Electrical Engineering

Summary form only given. We designed a family of integer-to-integer (i2i) approximations to the Cartesian-to-polar transformation and analyzed its behavior for high-rate transform coding. Denoting (ordinary, continuous) polar coordinates by (r, 0), our precise high-rate analysis relates the performance to the differential entropies of r2 and 0, which are often easy to evaluate. One may thus predict when there is an improvement over linear transform coding. The analysis matches our simulations for coding of Gaussian scale mixtures and other polar-separable sources. The advantage over the best linear transform coder can be large. Our hope is to extend the polar-coordinate results to a general theory for nonlinear transform coding based on i2i implementations of arbitrary nonlinear transformations

Nonlinear Transform Coding with Lossless Polar Coordinates by Demba Elimane

English Title: Biological profile of inactive carriers of the hepatitis B virus in Abidjan 
L’objectif etait de decrire le profil de FH chez les patients porteurs chroniques inactifs du VHB. Il s’agit d’une etude retrospective transversale (fevrier 2014 a Decembre 2017). Soixante-dix-sept dossiers de patients inactifs du VHB ont ete colliges. Les parametres recueillis etaient demographiques (âge sexe), biologiques (antigenemie HBs, charge virale B, plaquettes et transaminases sanguines) et elastometrique (valeur du fibroscan). La fibrose hepatique a ete evaluee selon 4 tests (APRI, TREAT B, FIB 4 et Fibroscan (FS)).L’âge moyen etait de 42,4 ans. Le sex ratio etait a 1,43. La mediane des transaminases etait respectivement de 24 UI/L et de 21 UI/L pour les ASAT et ALAT. Les dix patients ayant eu un dosage du genotype du VHB avaient tous un genotype E. Aucun patient dans notre etude n’avait de fibrose hepatique significative au score APRI. Respectivement 5,1%, 11,4%, 27,8% avaient une fibrose hepatique significative selon le score TREAT B, FS, FIB 4. Il existait une correlation positive significative entre les transaminases et le score APRI et, entre le score APRI et le score FIB. Il n’existait pas de correlation entre le FS et, le score FIB 4, le score APRI et le taux de transaminases ni entre les transaminases et le FIB 4. L’evaluation de la fibrose hepatique est necessaire chez tout sujet porteur chronique du VHB AgHBe negatif quel que soit la charge virale et le taux des transaminases en Afrique noire. Le choix du test non invasif influence le diagnostic de fibrose hepatique significative et par consequent l’initiation du traitement antiviral. 
Mots cles : porteurs chroniques inactifs du VHB, fibrose hepatique, Fibroscan, TREAT B, APRI, FIB 4.

Profil biologique des porteurs inactifs du virus de l’hépatite B à Abidjan

Contexte : La prevalence de l’infection gastrique a Helicobacter pylori (Hp) en milieu endoscopique a Abidjan en 1994 etait de 74,45% ;  majoritairement chez des hommes de moins de 40 ans admis pour epigastralgies chroniques.But : Decrire une decennie apres l’etude d’Attia et al, dans le meme service, le profil epidemiologique et clinique des patients infectes par Hp.Patients et Methodes : Il s’agit d’une etude prospective qui s’est deroulee du 9 fevrier au 9 aout 2002 dans l’unite d’endoscopie du CHU de  Yopougon. Durant cette periode, 90 patients ont ete tires au sort et ont fait l’objet de biopsies gastriques systematiques au cours de l’endoscopie digestive pour diagnostic histologique de l’infection a Hp. Les parametres etudies etaient epidemiologiques et cliniques.Resultats : Parmi les 90 patients ayant eu des biopsies gastriques durant la periode d’etude, 52 patients avaient une infection a Hp, soit une prevalence de 57,8%. Les hommes infectes par Hp etaient au nombre de 23 (sex-ratio 0,79). L’âge de nos patients infecte variait de 17 et 84 ans avec une moyenne de 37,5± 14,17 ans et une mediane de 34,5 ans. Les tranches d’âge les plus touchees etaient celles comprises entre 21 et 40 ans (57,7% des cas). Dans notre serie, les employes de la fonction publique, les employes du prive et les femmes au foyer etaient les plus infectes (n= 22 ; 42,3%). Les epigastralgies constituaient le principal motif de l’examen endoscopique (82,7% des cas ; n=43). Respectivement 17,3% (n=9), 9,6% (n=5) et 12,6% (n=7) ont pris un medicament gastrotoxique, un antibiotique ou un antisecretoire gastrique les 4 semaines qui precedaient l’examen endoscopique.Conclusion : Bien qu’elle ait diminue en une decennie, Hp reste endemique chez les patients vus en endoscopie digestive. Elle predomine toujours chez les sujets de moins de 40 ans mais majoritairement chez les femmes se plaignant d’epigastralgies chroniques.Mots cles: Epidemiologie, profil clinique, Helicobacter Pylori, endoscopie, Abidjan English Title: Epidemiological and clinical profile of patients with Helicobacter pylori gastric infection in the digestive endoscopy unit of the Yopougon University Hospital CenterBackground: A 74.45% prevalence of helicobacter pylori (Hp) gastric infection had been reported in 1994 in Abidjan endoscopic unit. This infection was predominant in men under 40 years admitted for chronic epigastralgia.Aim: To describe try in the same department, ten years later, epidemiological and clinical profile of patients infected with Hp.Patients and methods: This is a prospective study that was conducted from February 9 to August 9, 2002 in the endoscopy unit of Yopougon University Hospital. During this period, 90 patients were treated and subjected to systematic gastric biopsies during digestive endoscopy for histological analysis. The studied parameters were epidemiological and clinical.Results: Among the 90 patients included, 52 had Hp infection (prevalence of 57.8%). Men infected with Hp were 23 (sex ratio 0.79). Age of infected patients varied to 17 and 84 years old with an average of 37.5 14.17 years and a median of 34.5 years. The age groups associated with these include between 21 and 40 years, 57.7% of the cases. In our series, public service employees, private employees and housewives were the most infected (n = 22, 42.3%). Epigastralgia was the main reason for endoscopic endamenic (82.7% of cases, n = 43). Respectively 17.3% (n = 9), 9.6% (n = 5) and 12.6% (n = 7) took a gastrotoxic drug, an antibiotic or an endoscopic gastric antisecretory.Conclusion: Although you have decreased in 10 years, Hp remains endemic in patients seen in digestive endoscopy. It still predominates in subjects under 40 years of age but mostly in women who complain of chronic epigastralgia.Keywords: Epidemiology, clinical profile, Helicobacter Pylori, endoscopy, Abidjan

Profil épidémiologique et clinique des patients porteurs d’infection gastrique à Helicobacter pylori dans l’unité d’endoscopie digestive du centre hospitalier universitaire de Yopougon.

Le carcinome hepatocellulaire et l’immunodepression peuvent reveler une infection occulte par le virus de l’hepatite B chez le patient noir Africain. Nous vous rapportons un cas de carcinome hepatocellulaire consecutif a une infection virale B occulte chez un patient de 47 ans vu en consultation pour hepatalgies inexpliquees. Les examens biologiques hepatiques montraient une elevation des transaminases, une cholestase icterique et une positivite des anticorps anti HBc totaux isolement. Les explorations radiologiques notamment scannographiques montraient un foie d’allure fibreux non dysmorphique, sans signe de degenerescence neoplasique. La numeration formule sanguine, le taux de prothrombine et l’alpha foeto proteine etaient normaux. Les serologies VIH et du virus de l’hepatite C etaient negatives. La charge virale du virus de l’hepatite B etait de 5,24 logs (175 764 copies/mL), et le genotype E. L’examen histologique du prelevement biopsique hepatique concluait a un carcinome hepatocellulaire infiltrant sur cirrhose. Mots cles : Virus de l’hepatite B, infection occulte, carcinome hepatocellulaire, Afrique sub saharienne.

Un carcinome hépatocellulaire infiltrant révélant une infection virale B occulte chez un patient noir Africain

Background: The effect of eradicating Helicobacter pylori on the course of chronic gastritis (CG) is controversial. The aim of this study was to assess the impact of H. pylori eradication treatment on CG. Materials and Methods: This was a retrospective (January 2016 to December 2018) multicenter study. All medical records of patients treated with a quadruple therapy to eradicate H. pylori who were confirmed with histology at least 4 weeks after the end of treatment were included. The evolution of the CG ratings after treatment was analyzed. Results: The records of 170 patients (male/female ratio 0.95, average age 49.3 ± 12.2 years) were included. Respectively, inflammation and H. pylori levels decreased (P < 0.001) in antrum (2.09 to 1.45; 1.95 to 0.63) and fundus (1.82 to 1.27; 1.76 to 0.55). Gastric atrophy levels regressed in antrum (0.28 to 0.18; P = 0.0655) and fundus (0.19 to 0.09; P = 0.0096) on sequential quadruple therapy (0.42 to 0.26; P = 0.2384), with bismuth (0.27 to 0.1l8; P = 0.6232) or with concomitant therapy for 14 days (0.20 to 0.13; P = 0.1288). Gastric intestinal metaplasia progressed in the antrum (0.05 to 0.06; P = 0.5930) and the fundus (0.02 to 0.03; P = 0.2568); in sequential quadruple therapy (0.04 to 0.07; P = 0.3173) and in bismuth therapy groups (0.04 to 0.09; P = 0.5637) even after eradication of H. pylori (0.03 to 0.09; P = 0.0455). Conclusions: The eradication treatment for H. pylori improved elements of the Sydney CG system except for intestinal metaplasia.

Impact of quadruple eradication therapy on the elements of the Sydney system in chronic Helicobacter pylori gastritis in Abidjan (Ivory Coast)

Introduction: Purulent pleurisy is a severe form of acute respiratory infection. They are a major concern in pediatric practice. The aim of our work is to study the epidemiological, clinical, therapeutic and progressive profile of purulent pleurisy (PP) in children in Senegal. 
 
Patients and methods: This is a retrospective and descriptive study, including children aged 0 to 15 years hospitalized for PP from January 2014 to December 2017 at the Albert Royer Hospital Center. The positive diagnosis of PP was retained in front of the purulent, cloudy or citrine aspect of the pleural puncture fluid with the presence of altered neutrophilic polymorphonuclear cells. 
 
Results: The hospital frequency of PP was 0.6%. Sex ratio 1.42. The average age was 49 months. The age group of 6 to 36 months was the most represented. Malnutrition was present in 13 patients. In 91% of cases pleurisy was unilateral and right in 59% of cases. Pneumonia was radiologically associated in 54 children and pneumothorax in 19 children. The lethality was 6.6% (8 patients). The low socioeconomic level (p=0.0001) and the appearance of frankly purulent pleural fluid (p=0.002) were statistically significant associated with this mortality. 
 
Conclusion: Purulent pleurisy is associated with significant morbidity and mortality. Prevention involves vaccination, strengthening strategies to combat malnutrition and supplementation with zinc and vitamin A.

Aim: To assess the predictive value of the Baveno VI criteria for the diagnosis of large esophageal varices (EV) in Black African patient with compensated hepatitis B related cirrhosis. Methods: We carried out a cross-sectional study from January 2 to July 3 (2016), in Department of Gastroenterology at University Hospitals of Cocody (CHUC) and Yopougon (CHUY). All the black African patients included were more than 15 years old and their liver elasticity score (LES) was carried out at Yopougon University Hospital. Hepatitis B related cirrhosis was defined by LES ≥ 11 kPa (FibroScan® (Echosens, France)) with positive HBs antigen (HBsAg) and anti HBc antibody. All the patients with hepatitis B related cirrhosis performed a gastroscopy at Cocody University Hospital and esophageal varices were ranked according to societe francaise d’endoscopie digestive (SFED) classification. Data analysis was performed by SPSS model 20.0 statistics software (SPSS Inc., Chicago, IL, United States). Diagnostic performance of LES 150,000/mmm3 (Baveno VI criteria) for the diagnosis of large EV by gastroscopy was studied (area under the ROC curve, specificity (Sp), sensitivity (Se), positive predictive value (PPV) and negative predictive value (NPV). Results: During the study period, 720 patients achieved liver FibroScan® at CHUY. Of these, 60 respondents to our inclusion criteria were prospectively included in our study. Twelve (20%) of these 60 patients met the Baveno VI criteria. EV were present in 40% of cases (n = 24) with 6.7% (n = 4), 15% (n = 9) and 18.3% (n = 11) of grade 1, 2 and 3, respectively. (66.7% (n = 40) without EV or with small EV) and 33.3% (n = 20) with large EV. The Baveno VI criteria had a Se, Sp, PPV and NPV of 100%, 41.6%, 30% and 100% respectively for the diagnosis of large EV. The area under the ROC curve of a platelet count greater than 150,000/mm3, a liver elasticity score of less than 20 kPa and combination of both were respectively 0.763 [0.645 - 0.880; P = 0.272]; 0.588 [0.436 - 0.739; P = 0.01] and 0.650 [0.513 - 0.787 P = 0.005]. Conclusion: The combination of liver elasticity score 150,000/mm3, allowed the exclusion of large esophageal varices at gastroscopy with a 100 % NPV in Black African patients with compensated hepatitis B related cirrhosis.

Liver Transient Elastography Combined to Platelet Count (Baveno VI) Predict High Esophageal Varices in Black African Patient with Compensated Hepatitis B Related Cirrhosis

Introduction: The state of epilepticus in children is considered as a medical emergency which involves the vital and functional prognosis of the patient. The difficulties of this support in our country are linked to the lack of pediatric intensive care unit. The aim of our study is to evaluate the clinical, therapeutic, scalable and etiological states of epilepticus in children at Hospital Albert Royer National Children, Dakar. 
Methods: This is a prospective study which includes all patients aged between 2 months and 16 years who were hospitalized between 1 August, 2014 and 31 May, 2015 for a prolonged convulsion over 5 minutes and/or with at least 3 episodes of successive convulsions. We have not included the newborns and non-convulsive state epilepticus patients. The treatment protocol consists of the use of diazepam as first line, after 60 minutes if the crisis persists; diazepam phenobarbital was associated with the second line. 
Results: We collected 53 cases of state epilepticus (29 boys and 24 girls), which turned out to be a hospital incidence of 4.2%. The mean age was 48.5 months. Three quarters of our patients (n=40) were received emergency beyond 30 minutes after the onset of convulsions where the generalized seizures (n=42) were more common than partial seizures (n=11). The convulsions occurred in a context of fever in 38 patients. The metabolic balance was in favor of hyponatremia in 13 cases. Twenty-four patients (45.3%) have received only phenobarbital diazepam combination within 60 minutes after the onset of seizures. 
Conclusions: The state epilepticus cases are frequent in the hospital emergency department especially for infants from 2 months to 3 years. It was observed that the patients unfortunately received emergency in late beyond 30 minutes after the onset of convulsions.

Assessment of State of Convulsive Child in Hospital National Children Albert Royer, Dakar

A regional network of dialogue and exchange platforms to improve the identification of farmers' needs and dissemination of new varieties of Banana and plantain: the case of Cameroon

En Basse-Casamance, la mangrove constitue un écosystème particulier qui abrite de nombreuses ressources et reste le siège des principales activités rurales. Dans la zone d’Oussouye, cette mangrove a connu une régression importante au cours des décennies 1970 et 1980. L’étude de sa dynamique spatio-temporelle, à partir des outils de la géomatique couplés à des enquêtes de terrain, a permis d’appréhender son déclin, entre 1972 et 1994 de -42 % ; et son évolution positive de +22,44 % entre 1994-2018. Les facteurs à l’origine de la régression durant les années 70 et 80 sont principalement le déficit pluviométrique avec comme conséquences la salinisation et l’acidification des terres, et la faiblesse de la régénération naturelle. L’étude a aussi montré que les actions anthropiques telles que la coupe du bois pour diverses raisons et des racines échasses ont longtemps porté préjudice aux écosystèmes de mangrove. La reprise constatée au cours des dernières décennies est à replacer dans le contexte du retour de la pluviométrie à une situation meilleure et à la prise de conscience des populations du rôle stratégique et important de la mangrove.

Dynamique de la mangrove et perceptions locales dans le Département d’Oussouye (Basse-Casamance, Sénégal) entre 1972 et 2018

Stratégies des acteurs et gouvernance des écosystèmes face aux plantes envahissantes dans le Delta du fleuve Sénégal

Vulnérabilité et résilience des socio-écosystèmes littoraux d’Afrique de l’Ouest : état des connaissances actuelles et interrogation sur le devenir du littoral sénégalo-bissau-guinéen

Cette etude propose une approche cartographique et statistique qui permet de calculer les taux de variation historique du trait de cote avec le plug-in DSAS dans la partie nord de l’estuaire de la Casamance au Senegal. Pour ce faire, une methode statistique d’extrapolation et de calcul de tendances est mise en place, basee sur le traitement des images satellitaires Landsat acquises entre 2004 et 2019. Cette methode a permis d’obtenir une representation cartographique et graphique des resultats statistiques sur l’evolution du trait de cote de l’estuaire nord de la Casamance.

Approche cartographique de l’évolution du trait de côte dans l’estuaire de la Casamance

Situee en zone frontaliere entre le Senegal et la Gambie, la partie nord de la Haute-Casamance (actuelle region de Kolda) fait l’objet d’une importante deforestation. Les modifications qui y sont observees resultent, pour l’essentiel, de la destruction des massifs forestiers pour l’agriculture et des coupes massives de bois a destination, surtout, de la Gambie voisine. C’est dans ce contexte que notre etude se propose d’analyser la dynamique de la deforestation dans la zone frontaliere nord de la Haute-Casamance, ainsi que les principaux facteurs explicatifs. L’etude est basee sur une cartographie diachronique de l’occupation des sols entre 1987 et 2018 a partir des images satellitaires Landsat (TM 1987, ETM+ 1999, TM 2010 et OLI 2018), sur le calcul des Indices Standardises des Precipitations (ISP), et sur les travaux de terrain. Les resultats indiquent, qu’entre 1987 et 2018, la foret claire et la savane boisee ont perdu respectivement 66 485,5 ha et 36 470,6 ha de leur superficie en faveur principalement des zones de culture qui ont augmente de 71 995,9 ha, et de la savane arboree a arbustive qui a augmente de 48 711,6 ha. L’analyse des principaux facteurs a l’origine de la deforestation a montre qu’il s’agit des defrichements pour les besoins agricoles, l’augmentation de la population, les coupes non controlees de bois, et l’evolution des conditions pluviometriques.

Dynamique de la déforestation en zone frontalière au nord de la Haute-Casamance (Sénégal)

Au Senegal, la prevalence de l’asthme n’est pas encore evaluee. Les caracteristiques sociodemographiques, epidemiologiques et la provenance des patients asthmatiques consultes au Centre Hospitalier National Universitaire (CHNU) de Fann demeurent peu connues. Cet article contribue a la connaissance du profil des patients asthmatiques admis au CHNU. Il s’est agi d’une etude retrospective, prospective et transversale a avisee analytique associant l’approche quantitative et qualitative qui s’est deroulee de janvier 1999 a aout 2017 a la clinique de pneumologie du CHNU. La population d’etude etait constituee des asthmatiques recus en consultation. Les parametres analyses concernent les caracteristiques de la population etudiee (âge, sexe, profession et statut matrimonial). Au total 296 patients asthmatiques, soit 36,5% d’hommes contre 63,5% de femmes, ont ete enregistres avec un âge median qui etait de 35 ans. 234 repondants a la variable categorie socioprofessionnelle, etaient composes de menageres (24,8%), d’eleves et d’etudiants (20,1%), de commercants (17,5%), de bureaucrates (6,8%), de personnel de sante (6%) et d’enseignants et de maitres coraniques (3,8%). A cela s’ajoutait, des ouvriers (3,8%), des couturiers (3,4%), des coiffeurs (3%), des chauffeurs (2,6%), des agriculteurs et eleveurs (2,6%), des mecaniciens et garagistes (1,3%), des pecheurs et marins (1,3%), des restaurateurs et restauratrices (1,3%) et d’autres (1,7%). Selon le statut matrimonial, 54,3% etaient des maries, 42,7% de celibataires et 3% de divorces. Parmi les 296 asthmatiques, 250 residaient en milieu urbain dakarois. Les antecedents se resumaient sur les signes et les symptomes des patients avec de la toux (34%), de la dyspnee expiratoire nocturne (34%), des expectorations nummulaires (18%) et des crises d’asthme (14%). Le profil des patients asthmatiques presente une population jeune avec une predominance feminine. 
In Senegal, the prevalence of asthma has not yet been assessed. The socio-demographic, epidemiological and provenance characteristics of asthmatic patients consulted at the National Hospital University Center (CHNU) remain little known. This article contributes to the knowledge of the profile of asthmatic patients admitted to the CHNU. This was a retrospective, prospective and cross-sectional, analytical wise study combining the quantitative and qualitative approach which took place from January 1999 to august 2017 at the CHNU pulmonology clinic. The study of asthmatics received in consultation. The parameters analyzed relate to the characteristics of the population studied (age, sex, profession and marital status). A total of 296 asthmatic patients, or 36.5% male versus 63.5% female, were registered with a median age of 35 years. 234 respondents to the socio-professional category variable, were made up of housewives (24.8%), pupils and students (20.1%), traders (17.5%), bureaucrats (6.8%), health personnel (6%) and koranic teachers and teachers (3.8%). In addition, workers (3.8%), dressmakers (3.4%), hairdressers (3%), drivers (2.6%), farmers and ranchers (2.6%), mechanics and mechanics (1.3%), fishermen and sailors (1.3%), restaurateurs and restorers (1.3%), and others (1.7%). According to marital status, 54.3% were married, 42.7% were single and 3% were divorced. Among the 296 asthmatics, 250 resided in an urban Dakar environment. The history was summarized by the signs and symptoms of patients with cough (34%), nocturnal expiratory dyspnea (34%), sputum (18%) and asthma attacks (14%). The profile of asthmatic patients presents a young population with a female predominance.

Profil De L’asthmatique Admis Au Centre Hospitalier National Universitaire De Fann (CHNU) A Dakar (Senegal)

Located south-west of the Senegalese coast, the mouth of the Casamance River is under the influence of natural hydrodynamic factors. Thus, the beaches of the villages located around this mouth are characterized by a highly variable mobility. The purpose of this article is to analyze the variation of the position of the coastline around the mouth of the Casamance River. The methodology is based on the superimposition of a series of multidate images (aerial photographs, Landsat images and Google Earth image). Scanning jobs were done with ArcGIS 10.5 software. From there, the statistical calculations of the rates of evolution of the coastline are made with the model of DSAS4.3. The results obtained through the calculation of the mobility indices (EPR and LRR) showed a very variable dynamics of the coastline revealing two trends: a first period between 1968 and 1986, characterized generally by a progradation and a second period (1986- 2017) characterized in general by a decline in the beach, but with a slower decline between 2004 and 2017. Situee au sud-ouest du littoral senegalais, l’embouchure du fleuve Casamance est sous l’influence des facteurs hydrodynamiques naturels. Ainsi, les plages des villages situes au tour de cette embouchure sont caracterisees par une mobilite tres variable. L’objectif de cet article est d’analyser la variation de la position du trait de cote autour de l’embouchure du fleuve Casamance. La methodologie est basee sur la superposition d’une serie d’images multi-dates (photographies aeriennes, images Landsat et image Google Earth). Lestravaux de numerisation ont ete faits avec le logiciel ArcGIS 10.5. A partir de la, les calculs statistiques des vitesses d’evolution du trait de cote sont effectues avec le modele de DSAS4.3. Les resultats obtenus a travers le calcul des indices de mobilite (EPR et LRR) ont montre une dynamique tres variable du trait de cote degageant deux tendances : une premiere periode, comprise entre 1968 et 1986, caracterisee globalement par une progradation et une seconde periode (1986-2017) caracterisee globalement par un recul de la plage, mais avec un recul moins rapide entre 2004 et 2017.

Analyse Spatiale de l’évolution du Trait de Côte Autour de l’embouchure du Fleuve Casamance (Sénégal) de 1968 à 2017, à Partir de l’outil DSAS

RESUME Objectif. L’objectif de cette etude etait de decrire les aspects epidemiologiques des affections buccodentaires observees chez les scolaires du district de Bamako. Methodologie. Nous avons realise une etude transversale, analytique basee sur l’observation de l’etat buccodentaire des eleves du district de Bamako pendant trois mois. Nous avons utilise l'indice de plaque pour apprecier la qualite de l'hygiene buccodentaire, l’indice gingival de Loe et Silness pour l'inflammation gingivale et l’indice de Mulhemann pour la mobilite dentaire. Les donnees ont ete recueillies a partir d’une fiche d'enquete, saisies puis analysees sur le logiciel SPSS version 19.0. Resultats. Sur 625 eleves recrutes, 51% etait de sexe masculin et 49 % de feminin. Leur âge moyen etait de 12 ans avec des extremes de 5 a 18 ans. Parmi ces eleves, 6,24 % ne se brossaient jamais les dents et 46,40 % le faisaient insuffisamment. La technique de brossage etait mauvaise chez 91,15 % d’entre eux. L’indice de plaque chez les eleves etait faible ou « mauvais » dans 9,76 % des cas. Les affections buccodentaires les plus frequentes etaient la carie dentaire (95,00 %), les parodontopathies (87,84 %), la malocclusion (62,88 %) et la mobilite dentaire (21,60 %). un frein pathologique a ete note chez 35,00 % des eleves et une fluorose dentaire chez 6,24 %. Ils avaient dans 30,24 % des cas effectue au moins une consultation chez le Chirurgien dentiste. Nous n’avons pas trouve de lien statistiquement significatif entre le sexe, le niveau d'alphabetisation, l'hygiene buccodentaire et l'indice plaque; la malocclusion et le sexe, la mobilite dentaire. Conclusion. La frequence des affections buccodentaires est elevee en milieu scolaire dans le district de Bamako. Des efforts de promotion, de prevention et de depistage precoce de ces pathologies sont necessaires. ABSTRACT Aim: To describe the dental and periodontal disorders in schoolchildren in Bamako. Materials and methods. We carried out an analytical cross-sectional study based on the observation of the oral state of the pupils of Bamako during three months. We collected data by questionnaire administration and oral examination by the interviewer. Quality of orodental hygiene was assesses by the plaque score, gingival inflammation was assessed by the gingival index of Loe et Silness and tooth mobility was assessed by Mulhemann score. The data were analyzed on the SPSS software version 19.0. Statistical test was performed with Pearson's Chi-2 with an alpha risk of less than or equal to 0.05. Results. Among the 625 students, 51% were male and 49% female. The average age was 12 years with extremes of 5 to 18 years. We found that 6.24% of pupils never brushed their teeth while 46.4% of students did not do it properly. The brushing technique was poor in 91.15% of students. The plaque index among students was low or "bad" in 9.76% of cases. The main dental anomalies were tooth decay (95.00%), periodontal disease (87.84%); malocclusion (62.88%) and tooth mobility (21.60%). Students had a pathological impairment in 35.00% and 6.24% of cases of dental fluorosis. In 30.24% of cases they had at least one consultation with the dental surgeon. There were no statistical significant link between sex, literacy level, oral hygiene and plaque index, malocclusion and sex, dental mobility. Conclusion. Dental and periodontal diseases are common among school children of Bamako. Promotion, prevention and early detection of these pathologies are mandatory.

Prévalence des Maladies Dentaires et Parodontales chez les Élèves de Bamako

L'Afrique de l'Ouest subit, depuis plus d'une quarantaine d'annees, une degradation des paysages agricoles. La forte variabilite climatique de ces dernieres decennies est un des facteurs determinants de ces transformations. Elle se traduit par une diminution des precipitations et une importante occurrence des periodes de deficit pluviometrique dont les repercussions sont manifestes sur les systemes agraires. Les terroirs rizicoles de Basse-Casamance, emblematique des "civilisations agraires" d'Afrique de l'Ouest, traduisent les dynamiques en cours dans les "Rivieres du Sud". Ces espaces, qui concentrent de nombreuses activites humaines, presentent de fortes contraintes naturelles et socioeconomiques qui ont des consequences sur les systemes rizicoles. L'analyse des terroirs rizicoles de Basse-Casamance, par une approche des paysages combinant des donnees geospatiales et des travaux de terrain, montre des dynamiques contrastees entre l'activite rizicole et son environnement biophysique et socio-economique. L'analyse des photographies aeriennes et des images Google Earth, en particulier, fait apparaitre un recul des terroirs rizicoles induit par la forte variabilite climatique, la salinisation et l'acidification des eaux et des terres, et par l'insuffisante main d'oeuvre liee a l'exode des jeunes qui se traduit par le manque d'entretien des digues de protection des parcelles rizicoles. Elle revele ainsi l'existence de fortes interactions entre activites agricoles, ecosystemes exploites et environnement socio-economique.

Permanences et mutations dans les terroirs rizicoles de Basse-Casamance (Sénégal)

Manifestations parodontales chez la femme enceinte : Etude de 208 grossesses au CHU Gabriel Touré, Bamako

Ameloblastoma: a study of 51 cases. Objective: The objective of this study was to describe the social- demographic, clinical, pathological and therapeutic aspects of patients with mandibular ameloblastoma in the Odonto-Stomatology Teaching Hospital (CHU OS) in Bamako, Mali. Materials and Methods: We conducted a retrospective study over a three-year period (from January 2011 to December 2013), on successive cases of mandibular ameloblastoma. Clinical, radiological and pathological data were collected from medical records, entered and analyzed with SPSS software. Results: The tumor lesions involved 25 men and 26 women with a sex ratio of 0.94. The most frequent reason for consultation was bone swelling, in 90.20% of cases. The left hemi- mandible was the most frequent anatomical location in 47.06% of cases, and the area of predilection was the mandibular horizontal branch in 37.26% of cases. Conservative surgery was performed in 56.86% of cases and radical surgery in 43.14% of cases. Primary recurrence occurred in 11.77% of cases. Conclusion: This study shows a high incidence of mandibular ameloblastoma among patients attending the CHU OS in Bamako, Mali, but a low recurrence. Mots cles : ameloblastome / mandibule /chirurgie / recidive

Objectif  : Cette etude avait pour objectif de decrire les aspects sociodemographiques, cliniques, anatomopathologiques et therapeutiques, des patients presentant un ameloblastome mandibulaire, au centre hospitalier universitaire d’odontostomatologie (CHU OS) de Bamako, au Mali. Materiels et methode  : Nous avons realise une etude retrospective sur une periode de trois ans (de janvier 2011 a decembre 2013), sur des cas successifs d’ameloblastome mandibulaire, confirmes par un examen clinique, radiologique et anatomopathologique. Les donnees ont ete recueillies a partir des dossiers medicaux, saisies et analysees avec le logiciel SPSS version 3.22. Resultats  : Les lesions tumorales ont concerne 25 hommes et 26 femmes avec un sex-ratio de 0,94. Le motif de consultation le plus frequent a ete la tumefaction osseuse dans 90,20 % des cas. La localisation anatomique la plus frequente a ete l’hemimandibule gauche dans 47,06 % des cas, et la zone de predilection a ete la branche horizontale mandibulaire dans 37,26 % des cas. La chirurgie conservatrice a ete realisee chez 56,86 % des patients et la chirurgie radicale dans 43,14 % des cas. La recidive primaire a concerne 11,77 % des patients. Conclusion  : Cette etude montre une frequence elevee de l’ameloblastome mandibulaire, chez les patients consultant au service de chirurgie buccale du CHU OS a Bamako, au Mali, mais peu de recidives.

INTRODUCTION : Les maladies parodontales sont des maladies infectieuses dues a la presence de micro-organismes contenus dans la plaque dentaire situee entre la gencive et la dent. Elles sont frequentes, le plus souvent silencieuses et decouvertes lors d'une visite chez le chirurgien-dentiste. OBJECTIF : L’objectif de cette etude etait de decrire les aspects epidemiologiques, de l’infection parodontale observee chez les scolaires du district de Bamako et d’analyser les besoins de traitement. MATERIELS ET METHODE : Nous avons realise une etude transversale, analytique basee sur l’observation de l’etat parodontal des eleves du district de Bamako, sur une periode de trois mois (1er avril au 30 juin 2013). Les donnees ont ete recueillies a partir d’une fiche d'enquete elaboree pour la circonstance, saisies puis analysees sur le logiciel SPSS version 19.0. Les calculs statistiques ont ete effectues avec le chi-2 de Pearson avec un risque alpha inferieur ou egal a 0,05. RESULTATS : Nous avons enregistre 549 cas de maladies parodontales soit une frequence de 87,84 %. La moyenne d’âge etait de 12 ans avec des extremes de 5 a 18 ans. Le sex-ratio etait 1,04. Les eleves du primaire etaient de 54,65 %, 45,35 % pour ceux du secondaire. La plaque dentaire sur au moins une dent a ete observee chez 66,08 % des eleves. Une inflammation gingivale a ete retrouvee chez 87,84 % des eleves dont, 14,72 % avaient au moins une dent avec des poches parodontales de 4 a 5mm de profondeur et 2,40 % avaient au moins une dent avec des poches parodontales de 6mm. Le score 2 CPITN (Enseignement en hygiene bucco-dentaire et detartrage) a ete de 67,52 %. CONCLUSION : Cette etude a montre une frequence elevee des affections parodontales en milieu scolaire dans le district de Bamako. Les actions de prevention, de promotion de la sante buccodentaire et de depistage precoce des affections permettront d'ameliorer la sante des eleves, d'ou la necessite de renforcer les programmes sur la sante buccodentaire en milieu scolaire.

L’INFECTION PARODONTALE EN MILIEU SCOLAIRE DU DISTRICT DE BAMAKO : 625 OBSERVATIONS

Territorialisation du développement local au Sénégal:: impensés, cheminements, enjeux et limites d’un concept et d’une approche

Objectif : L’objectif de ce travail etait d’analyser les circonstances de diagnostic et la prise en charge therapeutique des affections mediastinales a point de depart cervical. Patients et methodes : Nous avons mene une etude descriptive longitudinale pro et retrospective dans le service d’ORL du CHU Gabriel Toure de Bamako et qui a concerne les dossiers des patients traites pour mediastinite compliquant une cellulite cervico-faciale de janvier 2011 a Avril 2014. Resultats : Huit patients ont repondu a nos criteres d’inclusion. L’âge median etait de 29 ans, l’ecart type etait de 10,23 ans avec des extremes de 25 et 57 ans. La porte d’entree a ete dentaire dans tous les cas. Le delai median de consultation etait de 13 jours avec des extremes de 10 et 1 mois. Six patients avaient eu des anti-inflammatoires non steroidiens avant leur admission dans le service. Le scanner a permis d’orienter diagnostic, en montrant des signes en faveur de mediastinite, dans tous les cas. Sept patients ont beneficie d’un drainage du mediastin par voie de cervicotomie, 3 patients ont beneficie d’un drainage pleural percutane sous guidage echographique. Nous avons eu deux deces. Conclusion : La mediastinite au cours de la cellulite cervicale represente une pathologie infectieuse grave avec une mortalite qui reste elevee. Le drainage mediastinal a ete effectue par voie cervicale. La prevention repose sur la sensibilisation de la population et sur l’importance de l’hygiene dentaire et la prise en charge correcte et precoce des caries dentaires.

Médiastinite compliquant une cellulite cervicale : à propos de 8 cas observés dans le service ORL du CHU Gabriel Touré de Bamako (Mali)

A la suite de beaucoup d’autres pays, ceux de l’Union economique et monetaire ouest africaine (UEMOA) ont adopte le systeme de gestion par la performance des politiques publiques. Il s’agit d’un systeme global qui inclut, en phase d’elaboration des politiques publiques – declinees en missions, programmes et actions -, de reconnaitre la contrainte budgetaire qui s’impose partout, de definir le perimetre de ces politiques, d’en degager les priorites et d’envisager leur execution dans un cadre pluriannuel. En phase d’execution, la gestion par la performance implique d’accorder plus de liberte aux gestionnaires, notamment dans l’utilisation des ressources tant humaines que materielles. En contrepartie de cette liberte, se trouve la responsabilite des gestionnaires. En phase de controle enfin, la gestion par la performance suppose la modernisation des controles a posteriori traditionnels par leur inclusion dans les controles preventifs manageriaux que sont le controle interne, le controle de gestion, l’audit. Elle suppose enfin un usage plus systematique de l’evaluation.

Finances publiques et gestion par la performance dans les pays membres de l'UEMOA : étude de cas du Sénégal

AIMS: The aim of this study was to determinate sociodemographics, clinical and therapeutic aspects of isolated mandibular fractures in the CHU-OS of Bamako. MATERIALS AND METHODS: We carried out a four months follow-up study involving 55 cases of isolated mandibular fractures, confirmed by a clinical and radiological examination. Our data were entered and analyzed using Epiinfo.fr 6.0 software. RESULTS: The lesions were more frequent in men (42) than women (13) with a sex ratio of 3.23. Age group of 21-30 was the most reached with 47.30%. The main cause was found to be road traffic accidents with 72.72 %. The fractures of the mandible at the level of horizontal branch were the most frequent with 34.54 %, and the orthopedic treatment was used in 72.72 % of the cases, with a good and very good results. CONCLUSION: This study shows the high frequency of isolated fractures of the mandible mainly from road traffic accidents, and among young adults.

Etude des fractures isolées de la mandibule au CHU d’odontostomatologie de bamako : à propos de 55 cas.

Objective: Study the therapeutic aspects and prognosis of volvulus of the sigmoid colon in the
surgical departments A and B. Patients and methods: Our study was retrospective from january
2000 to december 2009 (10 years). All patients who underwent sigmoid volvulus were taken into
account. Results: We recorded 96 patients operated for volvulus of sigmoid 882 cases of bowel
obstruction or a rate of 10.9%. The average age was 47.2 years ± 18, 9. In per-operative, there was
necrosis of colon in 16.7% (14). Performed surgical treatment modalities were: sigmoidectomy with
primary anastomosis in 29.2% (28), followed by sigmoidectomy and colostomy anastomosis secondary
in 60.4 % (58) and 10.4 devolvulation simple % (10/ 96). The immediate postoperative period were
marked by a morbidity rate of 7.3% (7/) and a mortality rate of 7.3% (7). Conclusion:
In spite of various therapeutic modalities of volvulus of the sigmoid colon, the rates of postoperative
morbidity and mortality are rising in the general surgery of the teaching Hospital of Point G.

Volvulus du colon sigmoïde: traitement chirurgical et pronostic dans les services de chirurgie générale du CHU du Point G

Pouvoir, ressources et développement dans le delta central du Niger

Cette these propose une analyse geographique de l'agriculture et de l'alimentation au Senegal. Elle interroge les politiques economiques et agricoles et elle met en evidence leurs impacts dans le processus de transformation de l'agriculture et de la consommation alimentaire. Par le biais des bilans agricoles et des bilans de couverture cerealiere, elle demontre la fragilite de la securite alimentaire et explique le caractere chronique de certains deficits cerealiers. Face aux besoins alimentaires, les systemes agricoles s'averent inadaptes et les strategies paysannes limitees pour faire face a la crise cerealiere et alimentaire. En combinant les espaces naturels et les territoires de developpement crees depuis l'accession du pays a l'independance, cette these permet d'envisager l'agriculture senegalaise, jusque-la fondee sur le modele de agro-exportation, dans une perspective veritablement endogene pour assurer une securite alimentaire durable. Elle invite a la creation de nouveaux espaces alimentaire fonctionnels, bases sur la production de cereales.

Etude géographique de l'agriculture en Afrique noire : analyse des productions céréalières et des systèmes alimentaires au Sénégal

Un essai d'analyse des échanges extérieurs du Sénégal pour une politique du commerce extérieur : étude

ABSTRACT Violent clashes between Fulani and Dogon have recently escalated in the Seeno plains in central Mali. After failing to defeat a “jihadist” insurgency dominated by Fulani, the Malian army has sponsored and trained a Dogon militia, which has systematically attacked Fulani villages, and again caused counterattacks. In addition, internal conflicts within Fulani and Dogon society have emerged. This demonstrates the complexities of the current crisis in Mali and how simplistic narratives about its causes are unhelpful. It also shows how views of the enemy as “terrorists” or “jihadists” are dangerous and able to further fuel violent conflicts.

Fulani-Dogon Killings in Mali: Farmer-Herder Conflicts as Insurgency and Counterinsurgency

On October 6, 2020, an armed group broke into the village of Kourmari (Niono circle, Segou region, central Mali) during the weekly fair. They took twenty civilian hostages and blocked all access to the village, which they have continuously besieged for several months. The identity of the assailants varies according to sources: initially the local villagers said they were bandits. Later, the gunmen who carried out the attack claimed to be affiliated with the jihadist group, Katiba Macina, which is linked to alQaeda in the Islamic Maghreb (AQIM) and is primarily active in central Mali. After months of continuous attacks, traditional chiefs, community leaders, the mayors of Niono and donso hunters, a community militia and self-defense group, began negotiating with the jihadists. This negotiation, which lasted four months, was conducted under the mediation of the High Islamic Council of Mali, an institution that groups and represents all Muslims and Muslim associations in Mali. The parties agreed to a temporary cease-fire for one month that later became definitive for the entire Niono circle. This article analyzes the situation of the conflict between Katiba Macina jihadists and donsos in the Niono area (Segou region, central Mali), and the peace accord process between the groups. The conflict dynamics and the peace accord provide insight into the complex violence mechanisms in central Mali.

Central Mali: The Niono Accord, from hope for peace, to a resurgence of conflict

In West Africa, as in many other estuaries, enormous volumes of marine water are entering the continent. Fresh water discharge is very low, and it is commonly strongly linked to rainfall level. Some of these estuaries are inverse estuaries. During the Great Sahelian Drought (1968–1993), their hyperhaline feature was exacerbated. This paper aims to describe the evolution of the two main West African inverse estuaries, those of the Saloum River and the Casamance River, since the end of the drought. Water salinity measurements were carried out over three to five years according to the sites in order to document this evolution and to compare data with the historical ones collected during the long dry period at the end of 20th century. The results show that in both estuaries, the mean water salinity values have markedly decreased since the end of the drought. However, the Saloum estuary remains a totally inverse estuary, while for the Casamance River, the estuarine turbidity maximum (ETM) is the location of the salinity maximum, and it moves according to the seasons from a location 1–10 km downwards from the upstream estuary entry, during the dry season, to a location 40–70 km downwards from this point, during the rainy season. These observations fit with the functioning of the mangrove, the West African mangrove being among the few in the world that are markedly increasing since the beginning of the 1990s and the end of the dry period, as mangrove growth is favored by the relative salinity reduction. Finally, one of the inverse estuary behavior factors is the low fresh water incoming from the continent. The small area of the Casamance and Saloum basins (20,150 and 26,500 km² respectively) is to be compared with the basins of their two main neighbor basins, the Gambia River and the Senegal River, which provide significant fresh water discharge to their estuary.

Inverse Estuaries in West Africa: Evidence of the Rainfall Recovery?

Botanical field-study and remote sensing to describe mangrove resilience in the Saloum Delta (Senegal) after 30 years of degradation narrative

Coastline dynamics of the northern Lower Casamance (Senegal) and southern Gambia littoral from 1968 to 2017

ABSTRACT Since 2015 jihadist groups have taken control of the Mopti region in central Mali. We ask how such a radical development has been possible in a country previously praised as a bulwark against radical Islam in Africa. While the dominant literature on the crisis in Mali has focused on how global political economic developments and international jihadist thinking and organisation relate to national dynamics, we take a materialist political ecology approach to explain the current situation. By focusing on the micro-politics of two land-use conflicts and how these conflicts are affected by the jihadist expansion, we seek to explain peasant (or pastoral) logics behind joining these armed groups. In particular, pastoralists seem to support the jihadist takeover, because of an anti-state, anti-elite and pro-pastoral jihadist discourse, because they have become increasingly fatigued by and disgruntled with a predatory and corrupt state, and because the development model imposed by the state and international donors has not responded to pastoral priorities. Rent-seeking by government officials has been especially intense in relation to conflicts over pastoral land, environmental management and the fight against desertification. This happened while the international community continued to praise Mali as a model of African democracy.

Why do pastoralists in Mali join jihadist groups? A political ecological explanation

L’Afrique de l’Ouest subit, depuis plusieurs annees, une degradation des paysages agricoles. La forte variabilite climatique de ces dernieres decennies est un des facteurs determinants de ces transformations qui y sont observees. Les terroirs rizicoles de Basse-Casamance, emblematiques des « civilisations agraires » ouest-africaines, traduisent les dynamiques dans cette region. Ces espaces, aux nombreuses activites humaines, presentent de fortes contraintes naturelles et socio-economiques qui se repercutent sur les systemes rizicoles. L’analyse des terroirs rizicoles, par une approche des paysages combinant donnees geospatiales et travaux de terrain, montre des dynamiques contrastees entre l’activite rizicole et son environnement socio-biophysique. Il ressort de l’analyse un recul des terroirs rizicoles en relation avec les changements globaux. La faiblesse de la main-d’œuvre se traduit par le manque d’entretien des digues de protection des parcelles rizicoles. L’analyse revele ainsi l’existence de fortes interactions entre activites agricoles, ecosystemes exploites et environnement socio-economique.

Stability and change in rice-growing areas in Basse-Casamance (Senegal)

Emerging from a severe political crisis that had encapsulated the country for almost a year and a half, Mali staged a remarkably comeback when the country held successful presidential elections. Behind the (for Mali) exceptionally high turnout of 48.9%, there was a strong sentiment of national revival. The winner was Ibrahim Boubacar Keita, and the 77.7% of the vote he collected proved that he has gained a legitimate mandate that should allow him the political space necessary to implement the difficult reforms needed to overcome the crisis. The challenges are, however, still huge. Political and administrative institutions must be rebuilt. The army must be brought under constitutional control and Keita must find a constructive way of dealing with the Tuareg rebels in the north. His main challenge in this regard is that his room for manoeuvre and negotiation is quite limited, because many of his own supporters will not accept a deal that gives autonomy to the Tuareg areas, while the Tuareg rebels have high expectations of what they want to achieve from the peace process. It is therefore essential that Keita also brings the political opposition into this process in order to avoid the negotiations becoming politicised.

Executive summary By Boubacar Ba and Morten Bøås The Mali presidential elections : outcomes and challenges

This study aims to explain a farmer–herder conflict in the inland Niger delta of Mali. We focus on the interests and motivations of the actors involved in the conflict and the rent seeking of the local administration in handling the conflict. Since independence, the customary pastoral leaders (the jowros) have gradually lost power and wealth to the benefit of previously underprivileged farmers (the rimaybe). We argue that this process is mainly the result of national policies and laws giving priority to agricultural development at the expense of pastoralism. The result has been large-scale conversions of dry season pastures to rice fields. This pastoral marginalisation also results in increased land use conflicts between herders and farmers. In addition, rent seeking by local officials is perpetuating land use conflicts in the area. Hence, officials are benefiting from conflicts, while especially pastoralists, but also farmers, are losing out. The droughts of the 1970s and 1980s, leading to a more rapid encroachment of rice fields on pastures, as well as the power vacuum that emerged in the early days of the decentralisation process, further aggravated land disputes. Finally, we use this case study to call for an inclusion of issues of rent seeking and corruption more centrally in political ecology.

Farmer–herder conflicts, pastoral marginalisation and corruption: a case study from the inland Niger delta of Mali

The SSE Programme - Project review of Arid Zone Agricultural Project (DAZA) in Macina Cercle in the region of Segou, Mali.

AN APPROACH TO PATHWISE STOCHASTIC INTEGRATION IN FRACTIONAL BESOV-TYPE SPACES BY KRYLOV INEQUALITY

In this paper, we study some models without jumps of stochastic differential equations directed by a fractional Brownian motion.

STUDY OF MODELS WITHOUT JUMPS WITH RESPECT TO FRACTIONAL BROWNIAN MOTION

In this paper, we study the problem of estimating the unknow parameters in a long memory process based on the maximum likelihood method. We consider again a diffusion model involving fractional Brownian motion. Our goal is to study the consistency of the drift parameter estimates depending on the form of the model.

CONSISTENCY OF THE DRIFT PARAMETERS ESTIMATES IN THE FRACTIONAL BROWNIAN DIFFUSION MODEL AND ESTIMATION OF THE HURST PARAMETER BY MAXIMUM LIKELIHOOD METHOD

In this paper, we study several properties of the bifractional Brownian motion introduced by Houdr\'{e} and Villa.

Since the pioneering work of Hurst, and Mandelbrot, the fractional brownian motions have played and increasingly important role in many fields of application such as hydrology, economics and telecommunications. For every value of the Hurst index H ∈ (0,1) we define a stochastic integral with respect to fractional Brownian motion of index H. This process is called a (standard) fractional Brownian motion with Hurst parameter H. To simplify the presentation, it is always assumed that the fractional Brownian motion is 0 at t=0. If H = 1/2, then the corresponding fractional Brownian motion is the usual standard Brownian motion. If 1/2 < H < 1, Fractional Brownian motion (FBM) is neither a finite variation nor a semi-martingale. Consequently, the standard Ito calculus is not available for stochastic integrals with respect to FBM as an integrator if 1/2 < H < 1. The classic methods (Ito and Stiliege) are excluted. The most studied case is that where H is between 0 and 1/2. Several attempts to define the stochastic integral are made. But so far some difficulties subjust. We give in this paper, several construction methods. So for the construction, we will use other tools to deal with such situations.

Method of Construction of the Stochastic Integral with Respect to Fractional Brownian Motion

In this paper we define the multifractional Brownian motion and we give some properties. we study the uniform Convergence of the Serie expansion. After having determined the covariance function, we give in proposition 2 another proof of almost sure uniform convergence on compact K of the series. We will finish by showing that the m.B.f is locally astymptotically self-similar, with field or fractional Brownian field with Hurst exposant H. One of the problem, for application of multifractional Brownian motion, is the regularity of the function. In the filtered white noise model the increments are no more homogeneous as in fractional Brownian field case. It is obvious when we consider the tangent field associated with a function. Still the multifractional function in the previous model is constant and it is not convient for many applications. We show the uniform convergence of the series on K. We deduce from the previous questions the almost sure uniform convergence of the series to a mBm.

Uniform Convergence of the Series Expansion of the Multifractional Brownian Motion

Pneumonie lipidique exogène du nourrisson atteint de maladie de Hirschsprung: aspects radiographiques et tomodensitométriques.

Introduction: Prematurity is one of the leading causes of neonatal death in Africa. The objective of this work was to assess the preterm birth at the pediatric service of the regional hospital of Ziguinchor. Material and methods: This was a prospective, descriptive and analytical study of the case of hospitalized newborns whose age was between 32 SA to 36SA + 6 days. The study was conducted from May 21, 2013 to May 21, 2014. We included all premature infants at age ≥ 32SA.Those presenting a malformation were not included. We studied maternal socio-demographic, obstetric and neonatal parameters. Results: We have identified 140 newborns out of a total of 342 Preterm births and 2292 maternity births, a prevalence of 40.9% compared to preterm infants and 6.10% in relation to all births. 51.4 percent of mothers came from urban areas, 63.5 percent were between 20 and 34 years of age, not attending school in 45.7 percent, married in 72.9 percent and without work in 94.3 percent. The average gestures represented 3.09 . Arterial hypertension was the most common medical condition (67.7%). The followup was done by a midwife (82.1%) and 23.5% had received at least 4 NPC. Eclampsia and pre-eclampsia (48.9%) and RPM (42.8%) were common obstetric pathologies. The delivery was by caesarian (51.4%), hospital (92.1%), cephalic presentation (80%), with an average weight of 1816.79 g. An RCIU (16.4%), an RPM (61.9%). At birth, a DR (16.4%) was noted due to MMH (43.7%) and transitory tachypnea (50%). Asphyxia was reported in 3.5%. During hospitalization (6.7 days on average), 6.4% had RD caused by infection (77.7%). Other complications were infection (64.4%), hypoglycemia (28.5%), digestive hemorrhage (7.01%). The fatality rate was 7.9% due to infection (63.3%), DR (18%), haemorrhage (9%). The anthropometric measurements at the exit: P 1887.9g, T: 38.3cm, PC: 30.9cm; at 1 month P: 2387.1g, T: 46.6cm, PC: 32.8cm; at 30 months P: 12.1kg, T: 89.5cm, PC: 48.4cm. Conclusion: Moderate preterm birth accounts for almost half of the cases of prematurity in our series. Their optimal management would go through a better obstetric-neonatal collaboration but above all by the installation of kangaroo mother units

Evaluation De La Prematurite Superieure Ou Egale A 32 Semaine D’amenorhée A L’hopital Regional De Ziguinchor Au Sud Du Senegal (Afrique De L’ouest)

Generalized extreme value regression model is widely used when the dependent variable Y represents a rare event. The quantile function of the GEV distribution is used as link function to investigate the relationship between the binary outcome Y and a set of potential predictors X. In this article we develop a maximum likelihood estimation procedure int he generalized extreme value regression model. We establish the asymptotic properties (existence, consistency and asymptotic normality) of the proposed maximum likelihood estimator.

Maximum likelihood estimation in the generalized extreme value regression model for binary data

RFID (Radio Frequency Identification) UHF (Ultra High Frequency) is a wireless identification technology that has many advantages. The technology’s tags are most often attached to the objects to be tagged for tracking and identification. The miniaturization of the antenna allows to reduce the size of the antennas. A novel meandering dipole antenna for RFID applications is presented in this paper. The miniaturization of this antenna is achieved by bending the inductive lines creating a capacitive effect between these lines. A T-shaped matching circuit as well as shorting lines drawn from top to bottom on both sides of the matching circuit allowed us to obtain a good match between the antenna and the NXP UCODE G2XL chip (Z=16-j156 $\Omega$) at 867MHz. The miniature antenna, which resonates at 867MHz in the European band, presented is designed based on copper of thickness e=35$ \mu$m which is printed on an FR4 epoxy substrate of thickness h=1.6 mm. The prototype is simulated on several complex environments and the results are presented in this paper. The 3D electromagnetic simulator HFSS (High Frequency Structure Simulator) allowed us to simulate the antenna performance such as input impedance, return loss, radiation pattern and antenna gain.

2022 International Conference on Electrical, Computer and Energy Technologies (ICECET)

A new broadband compact meander dipole antenna for RFID applications

A miniature PIFA RFID tag antenna for metal surface applications is presented in this article. The RFID tag antenna has a compact size ($45\text{mm}\times 45\text{mm}\times 5.162\text{mm}$) UHF, with a high gain of 4.2dB and a long maximum read range of 25m. The designed antenna is a two-substrate PIFA whose radiating plane, made of copper, is printed on Rogers RT / duroid 5880 ($\varepsilon_{r}=2.2,\ \text{tan}\ \sigma=0.0009$), the artificial magnetic conductor (AMC) and the ground plane are printed on top and bottom of FR4 epoxy substrate ($\varepsilon_{r}=4.4,\ \text{tan}\ \sigma=0.02$) respectively. The antenna is connected to the Monza R6 chip of impedance $\mathrm{Z}=13.6-\mathrm{j}\ 127$ at 866 MHz. It covers a bandwidth of 780 MHz (570 MHz-1.35 GHz) and therefore it covers the entire European UHF RFID band. To test its robustness, this tag antenna is simulated on different metal plates but these do not affect the performance of the tag.

Miniaturized PIFA RFID UHF Tag Antenna for Metal Surface Applications

With a widely attended virtual kickoff event on January 29, 2021, the National Cancer Institute (NCI) and the Department of Energy (DOE) launched a series of 4 interactive, interdisciplinary workshops—and a final concluding “World Café” on March 29, 2021—focused on advancing computational approaches for predictive oncology in the clinical and research domains of radiation oncology. These events reflect 3,870 human hours of virtual engagement with representation from 8 DOE national laboratories and the Frederick National Laboratory for Cancer Research (FNL), 4 research institutes, 5 cancer centers, 17 medical schools and teaching hospitals, 5 companies, 5 federal agencies, 3 research centers, and 27 universities. Here we summarize the workshops by first describing the background for the workshops. Participants identified twelve key questions—and collaborative parallel ideas—as the focus of work going forward to advance the field. These were then used to define short-term and longer-term “Blue Sky” goals. In addition, the group determined key success factors for predictive oncology in the context of radiation oncology, if not the future of all of medicine. These are: cross-discipline collaboration, targeted talent development, development of mechanistic mathematical and computational models and tools, and access to high-quality multiscale data that bridges mechanisms to phenotype. The workshop participants reported feeling energized and highly motivated to pursue next steps together to address the unmet needs in radiation oncology specifically and in cancer research generally and that NCI and DOE project goals align at the convergence of radiation therapy and advanced computing.

Predictive Radiation Oncology – A New NCI–DOE Scientific Space and Community

The RFID (Radio Frequency Identification) technology is evolving strongly with the emergence of cognitive sensor networks and notably the Internet of Things. A significant indicator of this evolution is that the tags are equipped with new capabilities and functions such as more powerful sensors, actuators, etc. This evolution of the RFID requires more energy consumption, and the continued passive nature of tags could be threated. Indeed, the tag needs more and more energy, and the energy received from the only reader can be insufficient. To address this issue, the proposed concept is to exploit the reflected energy by the tags near to the “target” tag. In this paper, we develop the associated theory for far-field conditions. The theoretical development is illustrated and the impact of the relative position between the tags on the total energy captured by the “target” tag is emphasized.

2021 IEEE International Conference on RFID Technology and Applications (RFID-TA)

Wireless Power Transfer of Passive UHF RFID Uplink in the Case of Tags Network

Zero-inflated regression models have had wide application recently and have provenuseful in modeling data with many zeros. Zero-inflated Binomial (ZIB) regression model is an extension of the ordinary binomial distribution that takes into account the excess of zeros. In comparing the probit model to the logistic model, many authors believe that there is little theoretical justification in choosing one formulation over the other in most circumstances involving binary responses. The logit model is considered to be computationally simpler but it is based on a more restrictive assumption of error independence, although many other generalizations have dealt with that assumption as well. By contrast, the probit model assumes that random errors have a multivariate normal distribution. This assumption makes the probit model attractive because the normal distribution provides a good approximation to many other distributions. In this paper, we develop a maximum likelihood estimation procedure for the parameters of a zero-inflated Binomial regression model with probit link function for both component of the model. We establish the existency, consistency and asymptotic normality of the proposed estimator.

ASYMPTOTIC PROPERTIES IN THE PROBIT-ZERO-INFLATED BINOMIAL REGRESSION MODEL

ABSTRACT We consider the problem of parameter estimation by the observations of the inhomogeneous Poisson processes. We suppose that the intensity function of these processes is a smooth function of the unknown parameter and as a method of estimation we take the minimum distance approach. We are interested by the behavior of estimators in non Hilbertian situation and we define the minimum distance estimation (MDE) with the help of the Lp metrics. We show that (under regularity conditions) the MDE is consistent and we describe its limit distribution.

On minimum Lp-distance estimation for inhomogeneous Poisson processes

Estimate by the L 2 Norm of a Parameter Poisson Intensity Discontinuous

Study of an Estimate of the Minimum Distance for a Multidimensional Model of a Poisson Process

Specializing in the export of products made intensively from relatively abundant factors of production and in the import of those made from relatively scarce ones has had a lot of traction in international trade practice. Ample evidence, however, now shows that some nations are gaining a comparative advantage in new areas that they never had before. Consequently, the traditional policy option of many African countries of continuing to specialize in areas in which they already have a comparative advantage (such as exports of primary commodities) is complemented with that of moving to new areas (such as high technology manufacturing) in which they could gain some advantage even though they may not enjoy any at the moment. Trade strategies are therefore now being formulated specifically to transition economies from a state of non-competitiveness to a state of relative competitiveness. This transitioning is what we call dynamic competitiveness in this paper. Empirically, we determine this by analysing the growth of the World Economic Forumi¯s Global Competitiveness Index of 27 African countries. This is complemented with the analysis of the growth of trade and transport costs using the World Bank Doing Business data. The study finds, among others, that even though the selected Sub-Saharan African countries are improving their (static) competitiveness over time, they cannot be said to be achieving dynamic competitiveness.

Depuis son entree en vigueur, le 1er janvier 1988, la convention de vienne constitue, en france, le droit commun de la vente internationale de marchandises. En raison des progres technique qu'elle renferme, de sa pretention a la simplification, precision, adaptation aux pratiques et besoins du commerce, la convention de vienne aura des incidences theoriques et pratiques reelles dans le devenir du droit positif interne francais. Les regles substantielles de la convention ne different pas fondamentalement des lois uniformes de la haye de 1964. Cependant et en depit de ses qualites formelles ainsi que d'une meilleure coordination entre les regles uniformes et les regles de conflit de lois, la convention de vienne est d'un grand conservatisme. Sa contribution a l'instauration d'un nouvel ordre economique international est plus que modeste.

La vente internationale de marchandises. Etude de la convention des nations unies sur les contrats de vente internationale de marchandises (vienne, 11 avril 1980)

Background: The diagnosis of tuberculosis (TB) has mostly been relied on a long-used method called sputum smear microscopy. In 2010, Xpert MTB/RIF assay was approved by the World Health Organization for simultaneous TB diagnosis and detection of resistance. Our current study was undertaken to compare the diagnostic performance of Xpert MTB/RIF assay to auramine staining-based light-emitting diode-Fluorescence Microscopy (LED-FM) considering culture as the gold standard method for pulmonary and extrapulmonary TB. Method: Pulmonary and extrapulmonary specimens of suspected TB patients were examined in this study. From January 2016 to June 2019, sputum, urine, superficial swabs, gastric aspirates, and pleural infusion specimens were collected from new and previously treated TB individuals. Specimens were examined using Xpert MTB/RIF, LED-FM, and Mycobacterium culture techniques to evaluate their performance. Results: A total of 697 suspected TB samples were included in this analysis, and of these, 469 (67.29%) were positive for all three used methods. The overall sensitivities, specificities, and positive and negative predictive values were 99.6%, 62.0%, 88.4%, and 98.2% for Xpert MTB/RIF and 88.0%, 95.6%, 99.0%, and 60.7% for LED-FM, respectively, compared to culture method. Conclusion: The sensitivity of Xpert MTB/RIF assay was observed to be higher than the LED-FM method, thus suggesting this molecular technique as a promising tool for the diagnosis of pulmonary and extrapulmonary TB, which will help in the management of TB infections in developing countries such as Mali.

Performance of Xpert MTB/RIF in comparison with light-emitting diode-fluorescence microscopy and culture for detecting tuberculosis in pulmonary and extrapulmonary specimens in Bamako, Mali

Pulmonary hypoplasia is a rare disease characterized by a defect of lung development more often unilateral. The diagnosis requires several exams to eliminate other causes of pulmonary retraction. We report two cases at the department of pneumophtisiology of the University Teaching Hospital of Point G. The first case is a young adult who was complaining of a chronic cough. Etiological investigation required several exams including spirometry and Computed tomographic scan (CT scan). After elimination of all suspected causes of pulmonary opacity, the diagnosis of pulmonary hypoplasia was retained. The second case is a 2-year-old girl who was born with congenital cardiopathy whose respiratory complications were increasing during her childhood and respiratory explorations discovered pulmonary agenesis. Pulmonary hypoplasia is rare in our medical practice, but attention must be drawn to a retractile pulmonary opacity in young age after elimination of all infectious causes in TB endemic area.

Pulmonary Hypoplasia: A Rare Cause of Chronic Cough in TB Endemic Area

Cet article présente la preuve de concept du premier assistant vocal automatique en wolof, première langue véhiculaire parlée au Sénégal. Ce bot vocal est le résultat d’un projet de recherche collaboratif entre Orange Innovation en France, Orange Sénégal (alias Sonatel) et ADNCorp, une petite société informatique basée à Dakar, au Sénégal. Le but du bot vocal est de fournir des informations aux clients d’Orange sur le programme de fidélité Sargal d’Orange Sénégal en utilisant le moyen le plus naturel de communiquer : la parole. Le bot vocal reçoit la demande orale du client, qui est traitée par un moteur de compréhension de la parole, et répond avec des messages audio préenregistrés. Les premiers résultats de cette preuve de concept sont encourageants : nous avons obtenu un WER de 22 % pour la tâche de reconnaissance vocale et une F-mesure de 78 % pour la tâche de compréhension.

Preuve de concept d’un bot vocal dialoguant en wolof (Proof-of-Concept of a Voicebot Speaking Wolof)

Cet article étudie l’intégration de la production photovoltaïque au réseau électrique faible. Les objectifs de cet article sont d’intégrer le système PV au réseau électrique faible et proposer une stratégie de contrôle pour l’injection au réseau. Dans ce travail, une stratégie de limitation des fluctuations de puissance est proposée. La simulation de l’ensemble système photovoltaïque, onduleur triphasé, réseau faible a été réalisé dans matlab/simulink. Le contrôle de la puissance injectée a été implémenté et simulé. Les résultats de simulation ont montré que la stratégie de contrôle implémentée permet de fournir la puissance maximale et d'injecter l'énergie au réseau à un facteur de puissance unitaire avec un faible taux de distorsion harmonique.

Injection de puissance photovoltaïque au réseau électrique faible 

Le cancer de l'œsophage est une tumeur de mauvais pronostic. Sa gravité est liée au retard de diagnostic qui se fait le plus souvent au stade de métastase en Afrique. Les métastases costales de ce cancer sont rares. Nous rapportons un cas de carcinome épidermoïde du bas œsophage avec métastases costales lytiques chez une patiente sénégalaise de 38 ans. Il s’agissait de madame TD, âgée de 38 ans admise pour une tuméfaction douloureuse de l’hémithorax droit dans un contexte d’amaigrissement. La patiente signalait par ailleurs une dysphagie d’allure mécanique évoluant depuis 4 mois qui n’avait pas motivé de consultation. L’examen objectivait un mauvais état général, une tuméfaction dure, sensible mesurant 3 cm de grand axe, siégeant sur la face antérolatérale de l’hémithorax droit en regard de la 5ème côte. Les examens biologiques mettaient en évidence une anémie normochrome normocytaire avec un taux d’hémoglobine à 9,4 g/dl, un syndrome inflammatoire biologique non spécifique et une hypercalcémie (calcémie corrigée= 107 mg/l). L’endoscopie oeso-gastroduodénale objectivait une lésion ulcéro bourgeonnante sténosante à 32 cm des arcades dentaires. L’examen anatomopathologique des biopsies mettait en évidence un carcinome épidermoïde moyennement différencié. La tomodensitométrie thoraco-abdomino pelvienne montrait en plus de la tumeur œsophagienne, une lyse osseuse de l’arc antérieure de la 5ème côte, des nodules pulmonaires carcinomateuses et un épanchement pleural bilatéral. La ponction exploratrice du liquide pleural ramenait un liquide sérohématique et l’examen cytologique de ce liquide objectivait des cellules carcinomateuses. Le diagnostic de carcinome épidermoïde du bas œsophage avec métastases costales, pleurales et pulmonaires était retenu et un traitement palliatif instauré. L’évolution était marquée par le décès de la patiente survenu 3 mois après la réalisation de la gastrostomie, dans un tableau de détresse respiratoire. L’originalité de cette observation tient au siège atypique des métastases de ce cancer de l’œsophage; mais aussi le terrain de survenue de cette tumeur. Le cancer de l’œsophage du sujet jeune est un problème majeur en Afrique. Le challenge est de déterminer ses facteurs de risque afin de prévenir sa survenue.

Métastase costale révélant un carcinome épidermoïde de l’œsophage

Baaba Maal : le message en chantant : réflexions sur l'homme et son oeuvre / Oumar Demba Ba ; préface de Felwine Sarr

Introduction Le tabagisme est un puissant facteur de risque cardio-vasculaire. Son sevrage semble moins bien pris en compte chez les coronariens. Les objectifs de ce travail étaient d’évaluer la prévalence du tabagisme et le sevrage tabagique au décours d'un infarctus du myocarde dans un service de cardiologie au Sénégal. Méthodes Il s'agit d'une étude transversale et descriptive réalisée entre janvier 2008 et juin 2010. Nous avons recruté les patients hospitalisés pour infarctus du myocarde puis les fumeurs actifs ont été inclus dans notre enquête. Les malades étaient sensibilisés pour l'arrêt du tabac puis suivis à 3 mois, 6 mois et 12 mois pour évaluer le sevrage tabagique. Résultats Nous avons recensé 82 patients hospitalisés pour un infarctus du myocarde, parmi eux 26 sujets (25 hommes) étaient fumeurs (31,7%). L’âge moyen des sujets fumeurs était de 56±11,5 ans. La consommation moyenne de tabac était de 32±14 paquets-année et le score moyen de Fagerström de 8. Tous les patients ont arrêté le tabac pendant l'hospitalisation. Après un suivi de 3 mois, 45% des patients ont repris le tabac, 65% à 6 mois et 85% à 12 mois. Conclusion Le tabagisme est assez fréquent chez les patients sénégalais présentant un infarctus du myocarde. Le taux de sevrage tabagique à court et moyen termes est faible. Le sevrage tabagique devrait alors constituer un objectif privilégié dans la prévention des maladies cardio-vasculaires.

Faible taux de succès du sevrage tabagique à court et moyen termes au décours d'un infarctus aigu du myocarde dans un service de cardiologie de Dakar au Sénégal

Cette etude a pour objet l'evolution de la politique agricole du senegal pendant la colonisation et apres les independances. Elle devrait nous fournir des explications ou nous aider a comprendre la situation economique et sociale de l'aof, en general, et du senegal en particulier. Nous avons par l'exemple de la vallee du fleuve senegal a cause, d'une part, de la presence du fleuve, d'autre part des travaux importants qui y sont realises sous l'egide de l'organisation pour la mise en valeur du senegal (omvs) et enfin des annees successives de secheresse. Ainsi, nous avons distingue quelques etapes correspondant chacune a une evolution politique. --l'abolition de l'esclavage et les exigences du "jeune" systeme capitaliste. --la crise de 1929 et le role du front populaire. --l'apres deuxieme guerre et la naissance des etats africains (independances) --les annees 1970 et la naissance de l'omvs (importance des organisations non-gouvernementales et des organisations gouvernementales). Nous constations que chaque fois que l'agriculture fut sollicitee c'etait au lendemain d'une crise (passage du mercantilisme au capitalisme, crise de 1929-30, crise d'apres la deuxieme guerre et enfin secheresse et chocs petroliers). L'agriculture etait, et, est consideree comme un remede et non comme une base necessaire au developpement des pays. Ces differentes politiques sont souvent definies en fonction des besoins de l'etranger. On note aussi une certaine constante politique, les populations concernees sont toujours tenues a l'ecart des choix des politiques et des produits. Ce dernier point nous avait amene a effectuer une enquete dans la region a l'issue de laquelle nous avions note une similitude entre les principales critiques et les preocupations des populations. Les independances de 1960 ne sont pas une rupture ; elles permettent a la france de se liberer du poids colonial tout en gardant l'essentiel. Elles repondent a un besoin pressant d'une tranches des industriels francais et a une incontournable volonte des populations a acceder a leur independance. Les solutions existent. Mais la aussi nous avions avance qu'au dela de toute teintes politiques, elles doivent obligatoirement tenir compte des populations qui devront etre le point de depart et le point d'arrivee de toute politique.

Politique agricole du senegal de 1936 a nos jours : le cas du fleuve senegal

La Penetration Francaise au Cayor. Du Rente de Birima N'gone Latyr a l'Intronisation de Madiodo Deguene Cadou. Tome I: Premiere et Deuxieme Parties, 16 Decembre 1854-28 Mai 1861

La pénétration française au Cayor : du règne de Birima N'Goné Latyr à l'intronisation de Madiodo Dèguène Codou

Une figure eurafricaine : le chef de province Baila Birane Wane (Sénégal et Mauritanie).

Petit lexique peul-français de la faune et de la flore du Fouta Toro

Ba Oumar. Dix-huit poemes peul modernes, presentes par Pierre F. Lacroix. In: Cahiers d'etudes africaines, vol. 2, n°8, 1962. pp. 536-550.

Médicaments responsables de toxidermie chez des enfants de phototype foncé à Dakar

Résumé La pandémie de COVID-19 a eu un impact sur le fonctionnement des systèmes de santé dont les modes d’adaptation et de réponse sur le terrain sont encore peu documentés et en cours d’évolution. Le Centre de Prise en charge Intégrée des Addictions de Dakar (CEPIAD) met en œuvre depuis 2014 la réduction des risques auprès d’usagers de drogues. La pandémie de COVID-19 et les mesures de santé publique ont été un obstacle à sa fréquentation par les patients, notamment du fait de la limitation des déplacements. Outre la mise en place de mesures préventives et l’application des gestes barrières dans le centre, le CEPIAD a eu recours à l’emport à domicile de la méthadone habituellement dispensée chaque jour dans ses locaux. Le centre a aussi pris en charge des usagers de cannabis incarcérés après leur amnistie. Plusieurs aspects de l’expérience du CEPIAD, perçue positivement, pourraient être pertinents hors du contexte pandémique.

Assurer la continuité des soins au temps de la COVID-19 : défis pour le centre de traitement des addictions à Dakar

Introduction la pandémie COVID-19 a poussé le monde à mettre en œuvre des méthodes de prévention drastiques basées sur la limitation des mouvements des populations ayant un impact sur les politiques de santé publique comme la vaccination. L´objectif de ce travail était d´évaluer l´impact de ces mesures de prévention sur la vaccination de routine en milieu hospitalier depuis l´avènement de cette pandémie au Sénégal. Méthodes il s´agit d´une étude transversale rétrospective réalisée en août 2020 dans l´unité de vaccination du centre hospitalier Abass NDAO. Nous avons comparé les données de l´unité de vaccination durant la période allant de mars à août des trois dernières années (2018, 2019 et 2020). Le paramètre étudié était le nombre de dose de vaccins administrée pour les différentes périodes selon le programme élargi de vaccination. Résultats pour les vaccins administrés à la sixième semaine en avril, le nombre de dose était de 36 en 2018, 29 en 2019 et 15 en 2020 soit une baisse de 50% par rapport au mois de mars. Au mois de juillet le nombre de dose administrée était de 40 en 2018, 35 en 2019 et 15 en 2020 soit une réduction de 42% par rapport à 2019. Conclusion les mesures de lutte contre cette pandémie ne devraient pas faire oublier la vaccination de routine surtout dans nos pays à ressources limitées. Il est indispensable de poursuivre la vaccination pour les enfants et d´identifier les enfants qui ont raté des doses vaccinales pour un rattrapage.

Impact de la COVID-19 sur la vaccination de routine en milieu hospitalier au Sénégal

La déshydratation hypernatrémique du nouveau-né au service de néonatologie du centre hospitalier National d’Enfants Albert Royer de Dakar

Résumé Entre le XIVe et le XVe siècle, le Portugal et l’Espagne ont fini de mûrir les conditions technologiques et pré-capitalistiques qui leur permettront d’initier l’ouverture atlantique et la mise en place du commerce transatlantique. Face à cette nouvelle donne, le commerce transsaharien s’adapte par différentes modalités d’accommodation qui vont s’intensifier et se complexifier jusqu’au XIXe siècle. Ce papier identifie et étudie ces modalités d’accommodation en s’appuyant sur une analyse historiographique: superposition de circuits commerciaux, naissance de circuits religieux, captage de nouveaux produits commerciaux, signature de nouveaux traités, initiation du shurbubba

Le commerce transsaharien et ses logiques d’accommodation par rapport au commerce transatlantique entre le XVe et le XIXe siècle

Impact de la pollution particulaire (PM10 et PM2.5) sur la survenue des cas des exacerbations aiguës d’asthme de l’enfant hôpital Albert Royer de Dakar

Aspect épidémiologique, clinique, microbiologique thérapeutique et évolutif des affections respiratoires aiguës de l’enfant à propos d’une étude prospective au centre Albert-Royer de Dakar

La cystinurie chez l’enfant peut être fatale en cas de retard diagnostic

Apports de l’observation du bébé selon la méthode Esther Bick pour la psychiatrie au Sénégal: La place du regard dans la culture sénégalaise

Le bébé africain du ventre au dos : la fonction du portage du bébé en milieu sénégalais

INTRODUCTION: La malnutrition carentielle est un probleme de sante publique au Senegal. Notre objectif etait d’etudie les facteurs qui lui sont associes. METHODES: nous avons mene une etude prospective a l’Institut de Pediatrie Social (IPS) de Pekin, du 1er Decembre 2016 au 1er Mars 2017. Nous avons inclus tous les enfants de 06 a 36 mois, suivis en ambulatoire. Nous n’avons pas inclus ceux dont la prise en charge necessitait une hospitalisation. Nous avons etudie les donnees sociodemographiques, l’alimentation et l’etat nutritionnel. L’analyse etait faite avec Excel et EPI INFO 7. RESULTATS: nous avons recrute 70 enfants, avec un sex ratio a 0,52. L’âge moyen etait de 14,6 ± 4,6 mois. Chez les meres, 39% n’etait pas instruites et 73% etaient sans emploi. L’Allaitement Maternel Exclusif (AME) etait pratique par 64% d’entre elles. L’âge moyen de la diversification alimentaire etait de 6,4 ± 2,8 mois. Chez ces enfants, 84% n’avaient pas les apports alimentaires minimums acceptables. L’âge moyen au sevrage etait de 15,8 ± 3,5 mois. Une malnutrition aigue etait observee chez 91% des enfants, la malnutrition chronique chez 53% et l’insuffisance ponderale chez 98%. CONCLUSION: a l’IPS de Pekin, les facteurs associes a la malnutrition sont multiples. Les strategies de lutte devraient integrer les realites socio-culturelles locales.

Facteurs associés à la malnutrition en milieu péri urbain Dakarois

Les nouveau-nés de mère diabétique au service de néonatologie du chu de Dakar (Sénégal)

Resume Depuis son ouverture en 2006, le service de pedopsychiatrie fait face chaque annee a une demande de plus en plus croissante de prise en charge d’enfants ou de preadolescentes victimes d’abus sexuels. Il s’agit ici d’un travail original car tres peu d’etudes sur les aspects psychologiques et sociaux des abus sexuels ont ete menees dans notre pays. A partir de sept cas cliniques, les auteurs tentent de decrire les realites psychosociales liees au contexte du viol chez des mineures et leurs familles suivies pour viol au service de pedopsychiatrie du CHNPT de juillet a decembre 2012.

Aspects psychologiques et sociaux chez des mineures victimes d’abus sexuels :

Introduction L'hyperthyroïdie de l'enfant semble rare et constitue un problème de par son retentissement psychosomatique. L’objectif était de faire le point sur ses aspects épidémiologiques et diagnostiques chez l’enfant à Dakar. Méthodes Il s'agissait d'une étude multicentrique, descriptive sur 15 ans. Etaient analysés les aspects épidémiologiques, cliniques et étiologiques. Résultats 239 patients sélectionnés avec une prévalence de 2.4%, un sex ratio (H/F) de 0.36, un âge moyen de 10.8 ans. À l'inclusion, il s'agissait d'un ainé de famille (26.3%), d'une croissance avancée (36.9%), retardée (12.5%), d'une corpulence insuffisante (40.1%). L'étiologie était la maladie de Basedow dans 90.3% avec un facteur psychoaffectif dans 22.1%. Sur le plan clinique, prédominaient la tachycardie (92.4%), le goitre (91.1%), l'exophtalmie (81.8%), l'amaigrissement (69.8%) avec cependant une énurésie (30.2%) et des manifestations psychiques (3.1%). Les manifestations cardiovasculaires et cutanées étaient positivement associées avec l'âge (p < 0.05). Le goitre était associé au sexe féminin (p = 0.005), aux signes cardiovasculaires (p = 0.02), neuropsychiques (p = 0.03), cutanées (p = 0.03) et à la diarrhée (p = 0.03). La T4 libre était corrélée à l'âge (p = 0.007), la diarrhée (p = 0.021), l'anxiété (p = 0.024), la fréquence cardiaque (p = 0.00) et la maladie de Basedow (p = 0.04). Plus le goitre était volumineux, plus était augmentée la T4 libre (p = 0.007). Conclusion Conclusion: L'hyperthyroïdie de l'enfant se différencie de celle de l'adulte par les facteurs d'induction, les perturbations sur la croissance et l'énurésie. L’âge et le sexe semble favoriser le tableau clinique de thyrotoxicose et les signes associés.

L’hyperthyroïdie de l’enfant au centre hospitalier universitaire de Dakar (Sénégal)

Ostéopétrose maligne infantile révélée par une atrésie des choanes : à propos d’un cas

Les nombreux problemes sociaux (violence, delinquance, etc.) que connaissent nos villes aujourd’hui ne cessent d’interroger les politiques et les professionnels de l’enfance et de l’adolescence. Les transformations profondes de nos societes ont bouleverse les familles africaines, tant dans leurs structures que dans leur fonctionnement. L’auteur, a travers une description de la societe traditionnelle africaine, met en evidence la place de l’enfant au sein de la communaute, ainsi que le role et les responsabilites de cette derniere aupres de l’enfant dans le but d’en faire l’adulte de demain.

Comment penser l’enfance ici et ailleurs ?: Faut-il vraiment tout un village pour élever un enfant ?

Iconographies supplémentaires de l'article : Ostéopétrose maligne infantile révélée par une atrésie des choanes : à propos d’un cas

L’abces du foie est une infection grave, pouvant entrainer des complications mettant en jeu le pronostic vital. Objectif : D ecrire les aspects epidemiologique, diagnostique et evolutif des abces du foie au CHNEAR de Dakar. Methode : Il s’agissait d’une etude retrospective monocentrique, sur une periode de cinq ans (1 er Janvier  2010 au  31 Decembre 2014). Tous les enfants âges de 0 a 15 ans, hospitalises pour  abces hepatique, avec confirmation echographique, etaient inclus. Nous avons recueilli les donnees sociodemographiques, cliniques, paracliniques, therapeutiques ainsi que l’evolution  Les donnees etaient analysees avec le logiciel SPSS version. Resultats : nous avons collige 26 cas d’abces hepatiques, soit une prevalence hospitaliere de 100 cas  pour 100 000 admissions. Le sex-ratio etait de 1,36 et l’âge moyen etait de 7,2 ans. Le faible niveau socio-economique et l’hygiene de vie precaire constituaient les facteurs favorisants. L’anemie (69,2%), la malnutrition  (42,3%), et le traumatisme abdominal (15,3) etaient les principaux terrains retrouves. La triade de Fontan caracteristique de l’abces du foie etait retrouvee dans 57,7% des cas. A l’echographie, l’abces etait unique dans 24 cas. Il siegeait au niveau du lobe droit dans 18 cas, et le segment VI (15,4%) etait le plus concerne. Sur le plan bacteriologique, il s’agissait d’un abces a pyogene dans 17 cas et d’un abces amibien dans  9 cas. Les principaux pyogenes retrouves etaient  Klebsiella pneumoniae (3 cas), Pseudomonas aeruginosa  (1 cas), Steptococcus pneumoniae (1 cas) et Staphylococus aureus (1 cas). La duree moyenne de l’antibiotherapie etait de 14,5 jours. Le drainage etait realise dans 92,3% des cas. L’evolution  etait favorable chez tous les enfants. Conclusion : La prevalence de l’abces foie au CHNEAR est relativement elevee, comparee aux donnees de la litterature. La malnutrition et les mauvaises conditions de vie representent les principaux facteurs de risque. Le pronostic est favorable. Mots cles : Abces du foie ; Enfants ; Germes a pyogene; Amibiase hepatique; Senegal.

Abcès du foie chez l’enfant au Sénégal : description d’une série de 26 cas.

L’hypothyroïdie de l’enfant é été peu étudiée au Sénégal. Le but de cette étude était d’évaluer les aspects épidémiologiques, diagnostiques et évolutifs de l’hypothyroïdie congénitale. Il s’agissait d’une étude rétrospective descriptive et analytique portant sur tous les enfants suivis pour hypothyroïdie congénitale au Centre Hospitalier National d’Enfants Albert Royer sur la période de 2001 à 2014 (14 ans). A partir des dossiers des malades, nous avons recueilli et analysé les données sociodémographiques, cliniques et évolutives. Au total, 28 patients ont été inclus, soit une moyenne de 2 cas par an. L’âge moyen de découverte de l’hypothyroïdie était de 54,25 ± 43 mois avec une prédominance féminine (Sex- ratio 0,47). Seuls 2 cas d’hypothyroïdie ont été diagnostiqués dans la période néonatale. La consanguinité était présente chez 68% des patients. Les signes cliniques étaient dominés par le retard des acquisitions psychomotrices (96%), l’hypothermie (46%), la dysmorphie cranio-faciale (43%) et le goitre (39%). Le retard statural était constant au-delà de 6 mois. Les étiologies étaient dominées par les troubles de l’hormonosynthèse (84,21%). Dans l’évolution, la taille moyenne des patients était passée de -3,5 DS à -2,25 DS pour une durée de traitement moyenne de 28 mois. La débilité mentale était présente dans 73% des cas. Le retard de croissance et la débilité mentale étaient d’autant plus sévères que le diagnostic était tardif. Nos résultats confirment l’insuffisance d’une prise en charge précoce des patients. Il urge de mettre en place un système de dépistage néonatale systématique, afin d’améliorer le pronostic mental de cette affection.

Family collective poisoning carbon monoxide in Dakar The carbon monoxide poisoning (CO) is a serious and potentially fatal accident, domestic or professional origin. It is still common in developing countries, favored by the use of charcoal as cooking fuel. We report a dramatic collective intoxication family history, occurred in a small family of five, living in the suburbs of Dakar. On the day of the poisoning, the whole family slept in the same room, heated by a stove with coal badly burned, doors and windows closed. The mother was the first to wake up in the morning, with headache and vomiting transient. The father and the youngest 12 month-girl, who were lying on a bed in height, were found dead. The carboxyhemoglobinemia post mortem was high for both (23.3% to 50.8% for father and daughter). The boys, aged 4 and 5 years who had slept on the floor with mom, had survived but had presented a neurological symptoms (impaired consciousness, irritability) and gastrointestinal (vomiting, elevated liver enzymes) with respiratory alkalosis. This family drama is proof that CO poisoning is a reality in Senegal, because the risks associated with incorrect use of coal are still largely unknown by the population. Awareness campaigns must be organized to prevent such serious accidents. Population's habitat conditions must also be improved.

Médecine d'Afrique Noire 1ère Revue Médicale Internationale Panafricaine Intoxication collective familiale à l'oxyde de carbone à Dakar

Particularités des abcès du foie chez l’enfant au Sénégal : description d’une série de 26 cas

Le syndrome hémolytique et urémique (SHU) est une cause fréquente d'insuffisance rénale aiguë (IRA) organique chez l'enfant. C'est une complication évolutive des gastroentérites aiguës (GEA) en particulier à Escherichia coli de l'enfant. Notre objectif était de décrire les aspects cliniques, thérapeutiques et évolutifs de cette affection chez quatre enfants. Nous avions colligé quatre cas de SHU. L’âge moyen était de 10,5 mois (5-15mois) exclusivement des garçons. L'examen clinique retrouvait une anémie de type hémolytique (pâleur et ictére), un syndrome oedémateux avec oligo-anurie (2 cas), une hypertension artérielle (1 patient), une GEA avec déshydratation sévère et choc hypovolémique (2 patients), des troubles de conscience. L'IRA était notée chez tous les patients de même que la thrombopénie et les schizocytes au frottis. Le Coombs direct était négatif. Il y avait une hyperkaliémie (3patients) dont 1 patient supérieure à 9,2 mmol/l, une hyponatrémie à 129mmol/l(1 patient) et une hypernatrémie à 153mmol/l (1 patient). Le shu était secondaire à une pneumonie à pneumocoque (1 patient), une GEA à E. coli (1 patient). Le traitement était essentiellement symptomatique et comprenait la restriction hydrique, la transfusion de concentrés érythrocytaires, les diurétiques, la dialyse péritonéale et l'hémodialyse. L’évolution était marquée par la survenue d'une insuffisance rénale chronique (1 patient) après 6 mois de suivi et la guérison (1 cas). Nous avions noté 3décés. Le SHU est la cause la plus fréquente d'IRA organique du nourrisson. Le diagnostic est essentiellement biologique, le traitement est surtout symptomatique.

Syndrome hémolytique et urémique de l'enfant au Centre Hospitalier Universitaire (CHU) de Dakar: à propos de quatre observations

L’hématome sous-galéal chez le nouveau-né : circonstances de survenue et pronostic au centre hospitalier d’enfants Albert Royer de Dakar

Masse bombante de la fontanelle postérieure : penser à la veine de Galien

Les troubles psychiatriques chez les adolescents ont fait l’objet de peu d’etudes au Senegal. Les auteurs, a partir de l’analyse de cinq situations cliniques d’adolescents recus au service de pedopsychiatrie du Centre hospitalier national psychiatrique de Thiaroye, montrent comment les perturbations presentees par ces adolescents peuvent etre en lien avec l’histoire du developpement psychique de l’enfant en phase de devenir adulte mais aussi avec l’histoire meme de la parentalite meme de ses parents.

Psychopathologie des troubles psychiques chez les adolescents au Sénégal

La cytostéatonécrose du nouveau-né : à propos de trois observations

SFCP P-102 - Malnutrition et hospitalisation chez les moins de cinq ans

La formation a la methode d’observation des bebes d’Esther Bick a debute au Senegal avec beaucoup d’apprehension du fait de croyances culturelles et des representations sociales. En effet, au Senegal, « le mauvais œil » et « la mauvaise langue » sont tres souvent convoques pour expliquer des difficultes, des maladies dans les populations. Tres rapidement, le sujet en question est designe comme ayant ete l’objet du mauvais regard, du regard qui tue et de la mechante langue, celle qui nuit. L’on comprend aisement alors les apprehensions a mettre en place une methode basee exclusivement sur l’observation, quand on sait que la croissance d’un bebe est jalonnee de petites affections, en allant des poussees de fievre a celles dentaires. Au terme de deux annees de formation a l’observation du bebe, les auteurs se proposent, a partir du materiel clinique recueilli au cours de l’observation de deux bebes, de revenir sur les differents moments ou le mauvais œil et la mauvaise langue ont pu etre evoques.

L'observation du bébé au Sénégal : entre mauvais œil et mauvaise langue

Au Senegal et en Afrique, les formations en matiere de psychotherapie d’enfant sont quasi inexistantes. Les seules formations disponibles se limitent a un classique enseignement des bases anatomophysiologiques du fonctionnement cerebral, de la nosologie et de la pharmacologie psychiatrique. L’introduction au Senegal de la formation a l’observation du bebe selon Esther Bick depuis 2009 a permis d’ouvrir une autre voie pour la formation des specialistes en sante mentale de l’enfant. Pour l’auteur, l’Observation de Bebe offre ainsi une nouvelle opportunite pour la formation des specialistes en sante mentale de l’enfant au Senegal et en Afrique.

L'observation des bébés selon Esther Bick : un nouveau paradigme pour la formation des spécialistes en santé mentale au Sénégal

Dans le couple, le processus de crise est introduit par la deception eprouvee par le sujet en face d’une defaillance supposee de l’objet, en general le conjoint. Le contexte de la polygamie est souvent mal vecu par celles qui en font l’experience. Dans ce travail, les auteurs mettent en evidence la souffrance morale d’une femme intellectuelle dont le mode de vie s’inscrit dans une certaine orthodoxie religieuse. Son epoux la confronte a l’experience de la polygamie dont le vecu douloureux se dissimule soigneusement derriere des crises de possession bruyantes dont elle impute la responsabilite a une force mystique. Le refus d’exprimer ouvertement sa desapprobation et son desir de divorce obeit a une logique de se conformer a sa religion qui autorise la polygamie. Des entretiens psychotherapiques reguliers ont permis d’espacer nettement les crises et d’en attenuer considerablement l’intensite.

Souffrance psychique féminine et crises de possession dans l'expérience de la polygamie d'une Sénégalaise

Le role devolu a l'aine dans la famille senegalaise, a celui qui montre le chemin de la vie, comme celui de la mort, est particulierement difficile a tenir. L'aine est le seul, a qui il est demande d'etre plus, d'exercer le pouvoir. La reconnaissance par le pere, par la mere, les cadets, de son statut d'aine est le seul facteur qui pourra l'aider a conforter sa position et a asseoir son identite. Les auteurs rapportent a travers ce cas clinique la fragilite psychologique qui entoure l'aine dans son statut. La decompensation depressive survient quand cette absence de reconnaissance se traduit par une disqualification implicite de sa mere, angoissee par l'echec professionnel de son fils. Les auteurs abordent par ailleurs, la dimension psychopathologique dont l'enjeu majeur se structure autour de la rivalite œdipienne au pere.

La position d'aîné à l'épreuve d'un contexte familial déstructurant: une observation au CHU de Fann à Dakar

Les auteurs decrivent dans ce travail, les mecanismes qui sous-tendent l'exclusion sociale d'un schizophrene auteur d'un double parricide dans un village. Il est place en internement psychiatrique par decision administrative. Le probleme de sa reinsertion socio-familiale se pose avec acuite face a une famille dont l'identite sociale est remise en question par une communaute villageoise fortement superstitieuse. Cette communaute est confortee par l'idee longtemps entretenue selon laquelle la famille est sorciere-anthropophage au regard du crime atroce et incomprehensible commis par un de ses membres. L'expulsion implicite du patient de son environnement familial par les siens parait obeir a une logique de rehabilitation qui passe par un refus de remettre le patient dans le lien familial.Ce dernier se retrouve seul et evolue dans une situation qui assombrit le pronostic de sa maladie.

Problématique de la réinsertion d'un patient auteur de parricide dans un contexte de sorcellerie

Au Senegal, les phenomenes d'agressions sexuelles ont connu une certaine recrudescence liee soit a une frequence accrue, soit a une mediatisation outranciere. Cependant, les desastres psychologiques font des ravages parmi les victimes du fait de la tendance de certaines familles a passer le phenomene sous silence par crainte de la stigmatisation sociale ou au nom du maintien de la cohesion familiale. Nous rapportons l'observation d'une femme mariee de 47 ans, victime de viol par le fils de son employeur. Sa famille, qui lui a recommande de se taire, interprete les phenomenes de reviviscence traumatique comme relevant de la magie et de l'ensorcellement, justifiant un recours a la medecine traditionnelle sans succes. Ses troubles s'aggravent de deux tentatives de suicide et de troubles psychopathologiques d'allure schizophrenique. L'hospitalisation a ete l'enjeu therapeutique essentiel par une mise a distance de son epoux dont la cohabitation a represente un des facteurs de chronicisation des troubles inherents a l'agression sexuelle malgre un traitement ambulatoire bien conduit.

PARTICULARITÉ CLINIQUE ET THÉRAPEUTIQUE D UN TRAUMATISME PSYCHIQUE: ÉTUDE D UN CAS DE VIOL CHEZ UNE SÉNÉGALAISE

Crises hystériformes collectives, crise scolaire, crise sociale et nouvelle problématique de la féminité au Sénégal

Continuité ou discontinuité de la présence juive à Walâta et dans le Sahel ouest-africain du XVe au XIXe siècle

La depression du post-partum occupe une place importante parmi les accidents psychiatriques de la puerperalite. Les auteurs rapportent les differents aspects cliniques, therapeutiques et evolutifs de la depression du post-partum dans une serie de onze cas senegalais. Il s’agit d’un travail mene a partir des observations medicales et des registres d’hospitalisation. Les symptomes de depression etaient faits principalement d’irritabilite, de troubles de la concentration, de plaintes somatiques multiples, d’insomnie d’endormissement, de perte des interets habituels. Pour la prise en charge, toutes les patientes ont beneficie d’une psychotherapie de soutien et d’un traitement antidepresseur, associes a un traitement tranquillisant dans six cas. L’evolution etait favorable au bout de 29 a 43 jours d’hospitalisation.

Aspects cliniques et psychopathologiques de la dépression du post-partum : rapport d'une série de onze cas sénégalais

La tuberculose méningée en milieu pédiatrique sénégalais : à propos de 14 cas

Dans la migration, la culture se « reconstruit », puisqu’elle n’est pas un etat mais un processus dynamique. La condition de migrant expose souvent a des conditions de vie nouvelles. Le sujet doit faire des efforts permanents d’adaptation du moins au debut, pour annihiler le decalage culturel. L’echec de cette operation risque de conferer un caractere agressif au flot envahissant des stimuli etrangers. Cette etude souligne quelques particularites de la perturbation de l’identite culturelle chez des emigres senegalais qui ont trait a l’usage exclusif d’attribut traditionnel dans un but expiatoire et de reference anxieuse a des chefs religieux.

Particularités de la perturbation de l'identité chez les émigrés sénégalais - À propos de 3 cas

La mise en place de populations semites, en Afrique du Nord et dans le Sahara septentrional, remonte a l'antiquite. Certaines communautes juives se rattachent meme au Premier Temple. Unis devant l'oppression romaine, Juifs et Berberes operent un rapprochement tactique qui inscrit leur resistance dans la duree et facilite d'importants transferts culturels. Du IXe au XIVe siecle, le role des Juifs dans le commerce transsaharien se limite a la redistribution vers le nord des produits soudanais. Aux XIVe - XVe siecles, leur implication dans ce commerce est intense et directe, avant que l' Askya Mohammed ne brise une dynamique qui ne se remettra en place qu'au XVIIIe siecle. Ainsi, retrouve-t-on, a des periodes differentes, des communautes juives ou des commercants juifs, dans le Sahara mauritanien et le Sahel ouest –africain, en particulier dans la boucle du Niger. Le commerce aidant, les transferts culturels sont feconds, amenant l 'historien a deceler dans la question des origines semitiques, de la judeite ou de la judaisation de peuples sahariens ou soudanais une part importante de reappropriation de mythes bibliques et de rattachement a l’Islam, par une reecriture de l’histoire.

Présence juive au Sahara et au Soudan au Moyen-âge : perceptions et réalités

La problématique de la présence juive au Sahara et au Soudan d'après Jean Léon l'Africain

John Leo Africanus\' description of Africa offers a set of rich and diverse references which lead one to re-consider some of the arguments and clues which imply and implicate Jewish participation in the trans-Saharan trade and their settlement in the Western Sudan during the late Middle Ages. An analysis of the document reveals the commercial orientation of North African and Saharan mellahs, their role in the implantation of points along the primary and secondary trans-Saharan routes and their termini, and the professional specialization of Jewish artisans. The major axis which linked Morocco to the Upper Niger Delta consisted of two major routes: Fes - Timbuktu and Tafilalet/Dar\'a – Walata/Timbuctu. Indeed, Jewish occupations are intimately linked to the transformation of gold, to metalworking and to the import of other primary products from the Western Sudan. In Leo\'s description, there are references to Jewish tradesmen involved in the trans-Saharan trade. Moreover this activity appears as the principal source of personal enrichment in the Jewish communities. To quench their covetousness and to ensure the security of their properties and persons, Jewish communities and tradesmen were forced to pay local and specific taxes above and beyond the legal and traditional djizya. Sometimes, despite these added taxes, particularly during periods of crisis, politico-religious figures instigated popular persecution against them. Leo cites a sadly but widely known example: the persecution of the Jewish community of the Touat in 1492 instigated by al-Maghili. When considered in tandem, in principle two of the references analyzed in Leo are sufficient to verify the existence of a Sudanese Jewish community: on the one hand the involvement of the Jews in the trans-Saharan trade and on the other the regular persecution of Jews living in the North African and Saharan Mellahs. We can add to these two references a solid argument. According to Leo, \'the king of Timbuktu\' (who at the time of Leo\'s visit was the Songhay ruler Askya Muhammad) declared a policy of exclusion towards the Jewish traders. As a consequence, they were declared persona non grata in Timbuktu, and by extension, throughout the region of his rule. This reference, which implies that Jewish traders attracted by the wealth of the country lived there at the end of the fifteen century and perhaps during the early sixteen century, is validated by comparison with early documents and sources from the same period (e.g. Valentim Fernandes, Ahmed Bâba, the Tarikh al-Fattâsh), and with local traditions collected in the Kurmina region at Tendirma, Morikoyra, Arham, among others. Lagos Historical Review , vol. 5 (2005), 146-176

La problématique de la présence juive au Sahara et au Soudan d\'après Jean Léon l\'Africain

Rift Valley fever, Mauritania, 2020: Lessons from a one health approach

Place de la scintigraphie des récepteurs de la somatostatine couplée à la tomodensitométrie dans la prise en charge des tumeurs neuroendocrines du pancréas

TEP-TDM : radioprotection et contraintes d’aménagement d’une nouvelle unité

Introduction: Anemia is a public health problem throughout the world with disastrous consequences on the health and cognitive and socio-economic development of populations. Objective: To study the socio-demographic, health and nutritional aspects of children aged 6-59 months with anemia followed at the pediatric social institute (PSI). Methods: This is a cross-sectional study carried out at PSI from 1 November 2018 to 20 February 2019. Children aged 6-59 months with anemia were included. Results: A total of 280 children had anemia among 467 who had a blood count, determining a prevalence of 59.9%. The mean age was 21.34 months 10.82 with a sex ratio of 1.52. Food diversification was started before 4 months (40.7%), between 4 and 5 months (16.1%) and from 6 months (43.2%). Cereals predominated in the diet (66.4%) followed by dairy products (59.6%). The mean hemoglobin level was 9.72±5.12 g/dl. The anemia J Pediatr Perinatol Child Health 2021; 5 (3): 158-163 DOI: 10.26502/jppch.74050074 Journal of Pediatrics, Perinatology and Child Health 159 was mild (48.9%), moderate (48.9%) and severe (2.2%). Microcytic hypochromia was present in 92.1% of the children. Acute malnutrition was present in 9.3% of children. Conclusion: The prevalence of anemia is high in Senegalese suburban areas. It is most often microcytic hypochromic, most probably reflecting an iron deficiency related to errors in food diversification.

Anemia in among Children Aged 6-59 Months at the Institute of Social Pediatric (ISP) in Dakar Suburban Area

Ischemic Stroke Complicating Neuromeningeal and Pulmonary Tuberculosis in Children: About a Case in Senegal

Particularities of Tuberculosis in Children and Adolescents with Sickle Cell Disease in Senegal

Prevalence of Renal Failure in Children and the Need for Dialysis in Paediatric Nephrology in a Developing Country

Background: Atopic dermatitis (AD) is the most common inflammatory skin disease of childhood. Yet, in sub-Saharan Africa, data on AD in children is scarce. Herein, we aimed to determine the prevalence, clinical features, and risk factors of severity of AD in Senegalese children with skin phototype VI. Materials and Methods: This was a cross-sectional study including children with AD and skin phototype VI younger than fifteen years old seen in two dermatology centers in Senegal over a period of six months. The diagnosis of AD was based on the United Kingdom Working Party (UKWP) criteria. The severity of AD was evaluated with SCORing of Atopic Dermatitis (SCORAD). Results: Among the 630 children consulted during the study period, 104 had AD, yielding a hospital prevalence of 16.5%. The mean age of children with AD was 36 months with a sex ratio of 1. A personal and family history of atopic disease was reported in 86.5% and 84.6% of the patients, respectively. Xerosis was the most common clinical feature, observed in 80.8% of. Post-inflammatory hyperpigmentation and keratosis pilaris were observed in 44.2% and 37.5%, respectively. Severe AD was noted in 12.5%. Risk factors associated with the severity of AD were exposure to incense smoke, an age of onset before 24 months, food allergies, and impetiginisatio. Daily use of shea butter was a protective factor. Conclusion: Our study showed a high hospital prevalence of AD in Senegalese children with skin phototype VI. The result observed with shea butter as a protective factor against severe AD is highly important, although it needs to be confirmed by randomized studies.

Atopic dermatitis in Senegalese children with skin phototype VI: Prevalence, clinical features, and risk factors of severity

Coronavirus disease (COVID-19) is a highly contagious infectious disease. First case was reported at the end of 2019 in China. Children and neonate population appears to be relatively free of the virus. We reported a severe and fatal neonate case of COVID-19 in a 22 days old neonate female due to the delta variant strain during the third wave outbreak. She presented with fever, cough, grunting and diarrhea started 5 days before admission. Physical exam’s revealed severe respiratory distress, hypoxia and bilateral pulmonary condensation. PCR test for COVID-19 was positive. Chest X-ray found bilateral infiltrates. Chest CT showed diffuse ground glass images with 75% of lung parenchymal involvement. She was treated with antibiotics, corticostoid, respiratory support (CPAP and oxygen). Death occurred after 15 days of hospitalization in the context of multiple organ failure and pulmonary hypertension.

Bacteriological Profile of Acute Respiratory Infections in Children: About a Prospective Study at the Albert Royer Hospital in Dakar

Pelvic Tuberculosis Simulating an Ovarian Tumor at a Stage of Peritoneal Carcinosis

Background: Primary Immune Deficiencies (PID) are rare, 
under-determined diseases particularly in sub-Saharan Africa. The 
diagnosis is often suspected with uncommon clinical signs. Infections are the 
main diagnostic circumstances in infants. Confirmation is often difficult 
because some additional examinations are unavailable in many of our countries. Aim: Our aim was to share the challenge of diagnosis and treatment in PID. Case 
Presentation: It is about two infants, a boy and a girl, with early several 
infections. Both of them presented a hypo-gammaglobulinemia and to the boy, the 
immuno-phenotyping lymphocyte showed a decreased level of lymphocytes CD19. We are looking for 
genetic confirmation but it is not easy. The treatment of these infants requires a substitution for life 
of immunoglobulin which is unavailable in our 
countries. Conclusion: PID are suspected with atypical clinical signs. 
Confirmation genetic diagnosis is difficult in low income countries. To improve 
the follow up, we need to strengthen clinical-biological collaboration.

The main objective of this study was to focus on the microbiological aspects of acute respiratory infections (ARI) in children in Senegalese hospitals The hospital frequency of acute respiratory infections in children was 3 7% The average age was 23 7 months with extremes between 1 month and 144 months Peaks of consultations were found in August, March and April with 22%, 15 6%, and 12 8% respectively Fever, respiratory distress and pulmonary condensation syndrome were the main signs found on examination in our patients Bacteriology was positive in 82 6% of the samples and the most frequently found bacteria were: Streptococcus pneumoniae in 38 5%, Haemophilus influenza b in 32 1% and Moraxella catarrhalis in 25 7% Virological tests were positive in 80 7% The viruses most frequently found in the samples were Rhinovirus in 33% of the samples, Human respiratory syncytial virus in 24 8% and coronavirus in 15 6% On mycological examination, only 4 samples out of 109 were positive, i e 3 7% The only fungi found was Pneumocystis with its two serotypes Pneumocystis jirovecii and Pneumocystis pneumonia in equal proportions Among the diagnoses retained, pneumonia was predominant and found in 61 of the cases, with a prevalence of 59 9%, followed by acute bronchiolitis with a prevalence of 16 51% The average length of hospitalization was 10 days Lethality was 1 8% or 2 cases Acute respiratory infections in children still remain a public health problem in developing countries, with children under 5 years of age being the most affected, hence the need to strengthen programs to combat ARI

Acute respiratory infections in children: prospective study on 109 cases at the University Hospital of Dakar, Senegal

Congenital cyanogenic heart disease (CCHD) is a malformation of the heart 
and large vessels characterized by an oxygen desaturation in the arterial 
blood, responsible for cyanosis. The general objective was to study the profile 
of CCHD in Senegalese hospitals. This is a retrospective study carried out over 
a period of 8 years (January 1, 2010 - December 31, 2017) and including all children 
aged 0 to 16 years followed for a CCHD. The hospital prevalence was 0.87% for 
420 cases collected. The sex ratio was 1.44 and the average age at diagnosis 
was 16 months. First degree parental consanguinity was noted in 36 cases (30.78%). The main reasons for 
consultation were breathing difficulty in 242 cases (57.62%) and fever 
in 136 patients (32.36%). Apart from cyanosis, the clinical signs were 
dominated by the heart murmur in 313 cases (74.7%), tachycardia in 283 cases 
(67.38%) and digital hippocratism in 162 cases (38.57%). Cardiomegaly was found 
in 239 patients (83.36%). The main types of CCHD were tetralogy of Fallot and 
transposition of the large vessels. In biology, 206 patients (49.05%) presented 
polyglobulia. A complete surgical cure was carried out in 22 patients (5.24%). 
Complications were anoxic crisis (52 cases) and hemorrhagic syndrome (17 
cases). There were 97 deaths (28.28%) during hospitalization. The diagnosis of 
CCHD is late in our country and surgical management is poor explaining the high 
mortality.

Congenital Cyanogenic Heart Disease in Children: About 420 Cases in Africa

 Objective:

Primary immunodeficiencies are rarely related in sub-Saharan Africa. The aim of this study was to identify their different clinical patterns, to describe their biological phenotypes and to analyse treatment. A cross-sectional observational study over a period of 4 years and 2 months in 5 Senegalese paediatric departments was conducted. Children were recruited according to the recommendations of African society for immunodeficiencies (ASID) or the 10 warning signs for PID's diagnosis. Biological explorations were performed in these patients.
Results:

30 cases of PID were recorded. The sex ratio was 1:1; with a median age at diagnosis of 24 months. The most common clinical patterns were respiratory infections (18 patients) including tuberculosis pneumonia in almost one-third of cases (22%), followed by digestive and then cutaneous manifestations. This signs occurs in a specific context; as inbreeding (36, 7% of cases), death in sibling (30% of cases), or previous hospitalizations (66, 7%). Biological exploration made it possible to obtain immunological confirmation in 10 children, including one genetically confirmed. The most common category of PID was syndromic PID. Treatment was based mainly on antibiotic prophylaxis. PID are a reality in Senegal, but are certainly underestimated. Continue recruitment will enable advocacy for access to certain treatment.

Primary Immunodeficiencies Diseases (Pid) In Senegalese Children: A Cross Sectional Observational Study

Introduction: Acute respiratory infections (ARIs) are a global public health priority. They are the leading cause of 
 morbidity and mortality in children, especially in developing countries. The main objective of this study was to see 
 mainly the virological aspects in ARI in children in Senegalese hospitals 
Methodology: We had conducted a prospective descriptive mono-centric study over a period of one year (from July 
 01, 2017 to June 30, 2018) at the Albert Royer National Children's Hospital in Dakar. 
Results: The hospital frequency for acute respiratory infections in children was 3.7%. The average age was 23.7 
 months with extremes between 1 month and 144 months. The peaks of consultations were found in August, March 
 and April with respectively 22%, 15.6% and 12.8%. Fever, respiratory distress and pulmonary condensation 
 syndrome were the main signs found on examination in our patients. Virologic tests were positive in 80.7%. The 
 viruses most frequently found in the samples were the Rhinovirus in 33% of the samples, the respiratory syncytial 
 virus in 24.8% and the coronavirus in 15.6%. Among the diagnoses retained, pneumonia was predominant and 
 found in 61 of the cases, or a prevalence of 59.9%, followed by acute bronchiolitis with a prevalence of 16.51%. The 
 average length of hospital stay was 10 days. 
Conclusion: Acute respiratory infections in children are still a public health problem in developing countries; 
 children under the age of five years are the most affected, hence the need to strengthen programs to fight ARI. The 
 identification of germs is essential in the treatment and epidemiological surveillance in our regions.

Virological Profile of Acute Respiratory Infections in Children at Dakar CHU

The COVID 19 pandemic has prompted the world to implement drastic prevention methods based on limiting population movements that have an impact on public health policies such as vaccination. The objective of this work was to evaluate the impact of these prevention measures on routine vaccination in hospitals since the advent of the pandemic in Senegal. Methodology: This is a retrospective cross-sectional study carried out in August 2020 in the vaccination unit of the Abass NDAO hospital centre. We compared data from the vaccination unit during the period from March to August of the last three years (2018, 2019 and 2020). The parameter studied was the number of vaccine doses administered for the different periods according to the expanded programme of immunization. Results: For the vaccines administered in the sixth week in April, the number of doses was 36 in 2018, 29 in 2019 and 15 in 2020, i.e. a 50% drop compared to March. In July the number of doses administered was 40 in 2018, 35 in 2019 and 15 in 2020, a reduction of 42% compared to 2019. Conclusion: Measures to fight this pandemic should not make us forget routine vaccination, especially in our resource-constrained countries. It is essential to continue vaccination for children and to identify children who have missed vaccine doses for catch-up. Keywords: COVID19, Vaccination, Impact, Children, Senegal

Impact of COVID19 on Routine Immunization: A Cross-Sectional Study in Senegal

the COVID-19 pandemic has pushed the world to implement drastic prevention methods based on limiting population movements that have an impact on public health policies, such as vaccination. The purpose of this work was to assess the effect of these preventive measures on routine immunization schedules in hospitals after the outbreak of this pandemic in Senegal.

Methods
we conducted a retrospective cross-sectional study in the Vaccination Unit of the Abass NDAO hospital center in August 2020. We compared data from the Vaccination Unit over the period March-August of the last three years (2018, 2019 and 2020). The parameter studied was the number of vaccine doses administered in the different periods according to the expanded immunization program.

Results
in April, the number of doses of vaccines given at 6 weeks was 36 in 2018, 29 in 2019 and 15 in 2020, reflecting a decrease of 50% compared to March. In July, the number of doses given was 40 in 2018, 35 in 2019 and 15 in 2020, reflecting a reduction of 42% compared to 2019.

Conclusion
measures to combat this pandemic should not affect routine immunization programmes, especially in our resource-constrained country. It is essential to continue vaccination schedule for children and to identify children who have missed vaccine doses in order to implement catch-up vaccination.

[Effect of COVID-19 on routine immunization schedule in Senegalese hospitals].

Introduction: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases characterized by enzymatic deficiencies in the biosynthesis of adrenal steroids. The most common 21-hydroxylase deficiency is characterized by a cortisol deficiency and an excess of androgens, with or without aldosterone deficiency. In our countries, in the absence of neonatal screening, the diagnosis is most often late leading to life-threatening complications. The aim of this study was to describe the diagnostic features of CAH at the Albert Royer National Children’s Hospital (ARNCH) in Dakar. Patients and method: We conducted a retrospective, descriptive study carried out at the pediatric endocrinology department of ARNCH from 2015 to 2019. All children aged under 15 with a form of CAH were included. Socio-demographic data, family history, clinical and biochemical data at presentation were collected. Patients were noted as presenting with Disorder of Sexual Development (DSD) with dehydration, DSD without dehydration, dehydration without DSD, precocious puberty. The Prader’s scale was used to determine the degree of external virilization. These data were entered and analyzed with Epi Info version 7.2. Results: A total of 32 patients were included, representing 74.41% of the causes of disorder of sexual development (DSD) and 84.21% of the causes of adrenal insufficiency. These were 27 girls (84.37%) and 5 boys (15.63%). The mean age was 19 ± 34.6 months. DSD was the main finding (87.5%). It was associated with dehydration in 22 cases (68.75%). 21-hydroxylase deficiency represented 93.75% of the cases with salt wasting in 73.33% of the cases. Conclusion: The diagnosis of CAH was delayed leading to life-threatening adrenal crises. In the absence of neonatal screening for CAH in Senegal, there is a need to train healthcare workers to recognize neonates with DSD early and refer them timeously for specialist care.

Congenital Adrenal Hyperplasia: Diagnostic Features in a Limited Resource Country, Senegal

Blackfan Diamon anemia is the only known congenital erythroblastopenia. Following the discovery of the genes 
involved, it has become the leader in ribosomal diseases and this has opened the way to a great deal of basic research 
into erythropoiesis. It is defined by severe erythroblastopenia with less than five percent of erythroid precursors in a 
single-cell marrow. Blackfan Diamon's anemia manifests early before the age of two and its incidence is low in Africa, 
we report a case with early onset in a 03-month-old infant with RPS19 mutation. The diagnosis often remains 
difficult due to the unavailability of genetic tests. Corticosteroid therapy was prescribed for two weeks without 
significant improvement. The patient is currently on a transfusion routine while awaiting a bone marrow transplant.

Anemia of Blacfan Diamon in an infant at the Albert Royer National Children's Hospital in Dakar and Review of the Literature

Introduction: Unconjugated bilirubin 
jaundice is a common symptom in neonatal period. In some babies, excessive serum 
bilirubin concentrations can place them at risk of acute bilirubin 
encephalopathy (BE) when the unconjugated pigment crosses the blood-brain 
barrier. Our study aimed to describe epidemiology, diagnosis and prognosis of 
BE at the Neonatology Department of Albert Royer Children’s Hospital of Dakar. Materials 
and Methods: It was a retrospective, descriptive study of cases of BE from 
January 1, 2015 to June 30, 2019. 
Obstetric and perinatal data as well as 
postnatal jaundice data (onset time, associated signs, signs of encephalopathy, 
treatment and evolution) were collected and analyzed by SPSS software 
version 2.0. Almost all newborns (27 cases; 90%) were exclusively breastfed. At 
admission, all children exhibited blunt jaundice and signs of encephalopathy 
dominated by the abolition of archaic reflexes (76.7%), low suction (22 cases; 
73.3%), central apnea (12 cases, 40%). The mean serum bilirubinemia was 322 mg/litre. Neonatal infection (10 cases; 33.3%) and fetal-maternal 
incompatibility (16 cases; 53.3%) were the main causes. All children received 
intensive phototherapy and exsanguino transfusion was performed for 7 newborns (23.3%). Nine children 
died (30% mortality rate). Conclusion: Only better organisation of 
perinatal care with enhanced postnatal follow-up can reduce the incidence of 
EB.

Neonatal Bilirubin Encephalopathy: Study of 30 Cases at Albert Royer National Children Hospital of Dakar

Graves’ disease is the most common cause of hyperthyroidism. Adequate management is an area of controversy, especially when it comes to children. The objective of our study was to assess the outcome of Graves’ disease treatment in Albert Royer Children Hospital of Dakar. This was a retrospective study conducted from 2001 to 2015, and which involved all children between 0 to 15 years of age who were being monitored in the Albert Royer National Children Hospital. The evolutionary modalities were: stability, remission, failure, relapse, lost to follow-up and death. The data were analyzed with SPSS software version 20.0. For the comparisons, the KHI 2 or Fisher test was used with a significance threshold (p < 0.05). During the study period, 88 children were enrolled. The average age was 8.6 years [ranging from 8 months to 15 years]. The consultation delay was 11.36 months. In our study, 61.4% of the patients were regular in the follow-up, the observance was good in 40.9% of the cases and 19 patients (21.6%) were lost to follow-up. Clinical courses of 69 children after treatment with Carbimazole for 37 months were promising in 21 cases (30.43%), with 17 cases of remission (24.63%) and 4 cases of stability (5.8%). Age older than 10, the initial ATD dose greater than 1 mg/kg/day and the initial free T4 lower than 50 pmol/l were significantly associated with remission with a p value of 0.01; 0.024 and 0.004.

Evolutionary Profile of Graves’ Disease in Children at Albert Royer National Children Hospital in Dakar

Abstract Background Bacterial meningitis is a major cause of mortality among children under 5 years of age. Senegal is part of World Health Organization–coordinated sentinel site surveillance for pediatric bacterial meningitis surveillance. We conducted this analysis to describe the epidemiology and etiology of bacterial meningitis among children less than 5 years in Senegal from 2010 and to 2016. Methods Children who met the inclusion criteria for suspected meningitis at the Centre Hospitalier National d’Enfants Albert Royer, Senegal, from 2010 to 2016 were included. Cerebrospinal fluid specimens were collected from suspected cases examined by routine bacteriology and molecular assays. Serotyping, antimicrobial susceptibility testing, and whole-genome sequencing were performed. Results A total of 1013 children were admitted with suspected meningitis during the surveillance period. Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus accounted for 66% (76/115), 25% (29/115), and 9% (10/115) of all confirmed cases, respectively. Most of the suspected cases (63%; 639/1013) and laboratory-confirmed (57%; 66/115) cases occurred during the first year of life. Pneumococcal meningitis case fatality rate was 6-fold higher than that of meningococcal meningitis (28% vs 5%). The predominant pneumococcal lineage causing meningitis was sequence type 618 (n = 7), commonly found among serotype 1 isolates. An ST 2174 lineage that included serotypes 19A and 23F was resistant to trimethoprim-sulfamethoxazole. Conclusions There has been a decline in pneumococcal meningitis post–pneumococcal conjugate vaccine introduction in Senegal. However, disease caused by pathogens covered by vaccines in widespread use still persists. There is need for continued effective monitoring of vaccine-preventable meningitis.

Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America

Changes in the Molecular Epidemiology of Pediatric Bacterial Meningitis in Senegal After Pneumococcal Conjugate Vaccine Introduction

Senegal introduced a 13-valent pneumococcal conjugate vaccine (PCV13) in October 2013, given at 6, 10, and 14 weeks of age. We document trends of meningitis and pneumonia after the PCV13 introduction.

METHODS
From October 2010-October 2016, hospitalization data for clinical meningitis and pneumonia in children aged <5 years were collected from logbooks at a large, tertiary, pediatric hospital in Dakar. We used a set of predetermined keywords to define hospitalizations for extraction from hospital registers. We conducted a time-series analysis and compared hospitalizations before and after the PCV13 introduction, accounting for seasonality. The initial PCV13 uptake period (October 2013-September 2014) was considered to be transitional and was excluded.

RESULTS
Over the 7-year period, 1836 and 889 hospitalizations with a discharge diagnosis of pneumonia and meningitis, respectively, occurred in children aged <5 years. In children aged <12 months, a small, significant reduction in pneumonia was observed post-PCV13 (-3.8%, 95% confidence interval [CI] -1.5 to -5.9%). No decline was observed among children aged 12-59 months (-0.7%, 95% CI -0.8 to 2.2%). Meningitis hospitalizations remained stable for children aged <12 months (1.8%, 95% CI -0.9 to 4.4%) and 12-59 months (-0.5%, 95% CI -3.6 to 2.6%).

We used data from 1 hospital to detect a small, significant reduction in all-cause pneumonia hospitalizations 2 years post-PCV13 introduction in infants; the same trend was not measurable in children aged 12-59 months or in meningitis cases. There is a need for continued surveillance to assess the long-term impact of sustained PCV13 use and to monitor how pneumococcus is causing disease in the meningitis belt.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

Impact of 13-Valent Pneumococcal Conjugate Vaccine on Meningitis and Pneumonia Hospitalizations in Children aged <5 Years in Senegal, 2010-2016.

Hyperthyroidism in children is rare and constitutes a problem because of its psychosomatic impact. This study aimed to present an overview of the state of knowledge on these aspects in children from Dakar.

Methods
We conducted a multicenter, descriptive study over a period of 15 years. We evaluated the epidemiological, clinical and etiologic aspects of hyperthyroidism in children.

Results
239 patients were included in the study with a prevalence of 2.4%, a sex ratio (M/F) of 0.36 and an average age of 10.8 years. The inclusion criteria were being the eldest son in a family(26.3%), being advanced (36.9%) or delayed (12.5%) in maturation, having short stature (40.1%). It was caused by Graves' disease in 90.3% of cases with psychoaffective factor in 22.1%. On a clinical point of view tachycardia (92.4%), goiter (91.1%), exophthalmia (81.8%), weight loss (69.8%) prevailed but with bed-wetting (30.2%) and psychic manifestations (3.1%). Cardiovascular and cutaneous manifestations were positively associated with age (p < 0.05). Goiter was associated with female sex (p = 0.005), cardiovascular (p = 0.02), neuropsychic (p = 0.03), skin (p = 0.03) signs and diarrhea (p = 0.03). Free T4 was correlated with age (p = 0.007), diarrhea (p = 0.021), anxiety (p = 0.024), heart rate (p = 0.00) and Graves' disease (p = 0.04). More voluminous the goiter, higher the free T4 (p = 0.007).

Hyperthyroidism in children differs from that in adults because of induction factors, growth disturbances and enuresis. Age and sex seem to favor the clinical picture of thyrotoxicosis and its associated signs.

[Hyperthyroidism in children at the University Hospital in Dakar (Senegal)].

Impact of rotavirus vaccine on acute gastroenteritis in children under 5 years in Senegal: Experience of sentinel site of the Albert Royer Children's Hospital in Dakar.

Archives de pediatrie : organe officiel de la Societe francaise de pediatrie

[Particularities of liver abscesses in children in Senegal: Description of a series of 26 cases].

Hemolytic-uremic syndrome (HUS) is a common cause of organic acute renal failure (ARF) in children. It is a progressive complication of acute gastroenteritis (AGE), especially caused by Escherichia coli in children. This study aimed to describe the clinical, therapeutic and evolutionary aspects of this affection in four children. We collected four cases of HUS. The average age was 10,5 months (5-15mois), exclusively boys. Clinical examination revealed a hemolytic anemia (pallor and jaundice), oligoanuria and edematous syndrome (2 cases), arterial hypertension (1 patient), AGE associated with severe dehydration and hypovolemic shock (2 patients), consciousness disorders. ARF was found in all patients as well as thrombocytopenia and schizocytes smear. Direct Coombs test was negative. Hyperkalemia was found in 3 patients, of whom 1 with hyperkalemia level of more than 9.2 mmol/L, hyponatremia at 129 mmol/l (1 patient) and hypernatremia at 153 mmol/l (1 patient). HUS was secondary to pneumococcal pneumonia (1 patient) while AGE was secondary to E. coli (1 patient). The treatment was mainly symptomatic and included fluid restriction, transfusion of red cell concentrates, diuretics, peritoneal dialysis and hemodialysis. The evolution was marked by the onset of chronic renal failure (1 patient) after 6 months of follow-up and by recovery (1 case). Three patients died. HUS is the most common cause of organic acute renal failure in newborns. Diagnosis is essentially biological, treatment is mostly symptomatic.

[Hemolytic-uremic syndrome (HUS) in children at the University Hospital Center in Dakar: about four cases].

Child hypothyroidism has been little studied in Senegal. The aim of this study was to evaluate the epidemiological, diagnostic and evolutionary aspects of congenital hypothyroidism. We conducted a descriptive-analytical retrospective study of all children treated for congenital hypothyroidism at the Albert-Royer National Children's Hospital Center over the period from 2001 to 2014 (14 years). We collected and analyzed socio-demographic, clinical and evolutionary data from patient medical records. A total of 28 patients were included in the study, an average of 2 cases per year. The average age of discovery of hypothyroidism was 54.25 ± 43 months with a female predominance (Sex-ratio 0.47). Only 2 cases of hypothyroidism were diagnosed in the neonatal period. Consanguinity was present in 68% of patients. Clinical signs were dominated by the delay in psychomotor acquisitions (96%), hypothermia (46%), cranio-facial dysmorphia (43%) and goiter (39%). Growth retardation was constant beyond 6 months. The etiologies were dominated by hormonosynthesis disorders (84.21%). During the study period, mean SD of patients had decreased from -3.5 SD to -2.25 SD for a median treatment duration of 28 months. Mental retardation was present in 73% of cases. Growth retardation and mental retardation were more severe as the diagnosis was late. Our results confirm the inadequacy of early management of patients. It is urgent to implement a routine neonatal screening system in order to improve the mental prognosis of this condition.

[Malignant infantile osteopetrosis revealed by choanal atresia: A case report].

Abstract Ischemic stroke is infrequent in childhood. Etiological factors depend on epidemiological context. The purpose of this study is to determine risk factors, clinical and radiological features and outcome of arterial ischemic stroke in a cohort of Senegalese infants. We carried out a retrospective study of medical data of children hospitalized with arterial ischemic stroke in the neurological department of Fann teaching hospital and at Children's Hospital Albert Royer, from July 2003 to July 2011. Forty-eight cases were included in this study with ages ranging from 2 months to 18 yr, with a female/male ratio of 0.71. Mean age at the time of occurrence stroke was 89.37 mo. The most common symptoms were hemiparesis (93.75%), motor partial seizures (24.44%), and Broca's aphasia (33.3%). The middle cerebral artery was mostly affected (87.5%). Risk factors were predominantly sickle cell disease, anemia, embolic heart disease, meningoencephalitis and head trauma. 8.33% of patients died. After discharge, 16.66% of patients were lost follow-up and 62.5% of the total cohort had neurological impairments. Treatment was essentially symptomatic and secondary prevention was provided by treatment with anticoagulants or anti-platelets agents depending on the etiology of ischemic stroke.

Immune reconstitution syndrome in a child with disseminated tuberculosis

Immune reconstitution syndrome (IRIS) in a child with disseminated tuberculosis

[Tuberculosis meningitis in a Senegalese pediatric hospital: report of 14 cases].

The functional domain of the human cerebellum has expanded beyond motor control to also include cognitive and affective functions. In line with this notion, cerebellar volume has increased over recent primate evolution and cerebellar alterations have been linked to heritable mental disorders. In order to map the genetic architecture of human cerebellar morphology, we studied a large imaging genetics sample from the UK Biobank (n discovery = 27,302; n replication: 11,264) with state-of-the art neuroimaging and biostatistics tools. Multivariate GWAS (MOSTest) on empirically derived regional cerebellar MRI features yielded 351 significant genetic loci (228 novel, 94% replicated) showing both shared and specific effects across regions. Gene level analyses revealed enrichment for genes associated with human-specific evolution over the last 6-8 million years, to a similar or higher degree than cerebral comparison phenotypes. We also observed genetic overlap between cerebellar morphology and major mental disorders, supporting cerebellar involvement in psychopathology.

The genetic architecture of human cerebellar morphology supports a key role for the cerebellum in recent human evolution and psychopathology

Despite numerous studies, there is little agreement about what brain changes accompany motor sequence learning, partly because of a general publication bias that favors novel results. We therefore decided to systematically reinvestigate proposed functional magnetic resonance imaging (fMRI) correlates of motor learning in a preregistered longitudinal study with four scanning sessions over 5 weeks of training. Activation decreased more for trained than untrained sequences in premotor and parietal areas, without any evidence of learning-related activation increases. Premotor and parietal regions also exhibited changes in the fine-grained, sequence-specific activation patterns early in learning, which stabilized later. No changes were observed in the primary motor cortex (M1). Overall, our study provides evidence that human motor sequence learning occurs outside of M1. Furthermore, it shows that we cannot expect to find activity increases as an indicator for learning, making subtle changes in activity patterns across weeks the most promising fMRI correlate of training-induced plasticity.

fMRI signatures of motor sequence learning: A critical re-evaluation

Abstract Recovery of skilled movement after stroke is assumed to depend on motor learning. However, the capacity for motor learning and factors that influence motor learning after stroke have received little attention. In this study, we first compared motor skill acquisition and retention between well-recovered stroke patients and age- and performance-matched healthy controls. We then tested whether beta oscillations (15–30 Hz) from sensorimotor cortices contribute to predicting training-related motor performance. Eighteen well-recovered chronic stroke survivors (mean age 64 ± 8 years, range: 50–74 years) and 20 age- and sex-matched healthy controls were trained on a continuous tracking task and subsequently retested after initial training (45–60 min and 24 h later). Scalp electroencephalography was recorded during the performance of a simple motor task before each training and retest session. Stroke patients demonstrated capacity for motor skill learning, but it was diminished compared to age- and performance-matched healthy controls. Furthermore, although the properties of beta oscillations prior to training were comparable between stroke patients and healthy controls, stroke patients did show less change in beta measures with motor learning. Lastly, although beta oscillations did not help to predict motor performance immediately after training, contralateral (ipsilesional) sensorimotor cortex post-movement beta rebound measured after training helped predict future motor performance, 24 h after training. This finding suggests that neurophysiological measures such as beta oscillations can help predict response to motor training in chronic stroke patients and may offer novel targets for therapeutic interventions.

Sensorimotor cortex beta oscillations reflect motor skill learning ability after stroke

Beyond being essential for long-term motor-skill development, movement repetition has immediate benefits on performance, increasing the speed and accuracy of a second execution. While such repetition effects have been reported for single reaching movements, whether they apply to movement sequences, or whether they affect planning or execution processes, has yet to be determined. We addressed these questions in two behavioral experiments using a discrete sequence production (DSP) task in which human volunteers had to perform short sequences of finger movements. In Experiment 1, participants were presented with random sequences and we manipulated whether participants had to execute the sequence (Go), or not (No-Go), and whether the sequence was repeated on the next trial. We establish that repeating a sequence of movements led to immediate improvements in speed without associated accuracy costs. The biggest benefit was observed in the middle part of a sequence, suggesting that the repetition effect likely results from facilitated online planning. This claim was further supported by Experiment 2, in which we kept a set of sequences fixed allowing participants to develop sequence-specific learning: once learning reduced the need for online planning, the benefit of repetition disappeared. Finally, we found that repetition-related improvements only occurred for the trials that had been preceded by sequence production, suggesting that action selection and sequence pre-planning may not be sufficient to reap the benefits of repetition. Together, our results highlight the importance of motor practice for enhancing our ability to link individual sequence elements into skilled sequential behavior. Significance Statement Even for overlearned motor skills such as reaching, repeating the same movement improves subsequent performance. How exactly brain processes associated with motor planning and execution might benefit from repetition, however, remains unclear. Here we report the novel finding of repetition effects for sequential movements. Our results indicate that this benefit of repetition is tied to faster and more accurate online planning of upcoming sequence elements. We also highlight how recent movement experience appears to be required to observe the repetition effect, suggesting that actual practice might be more beneficial to the human sensorimotor system than mental rehearsal for producing short-term performance improvements.

Repetita iuvant: repetition facilitates online planning of sequential movements

Abstract We investigated motor skill learning using a path tracking task, where human subjects had to track various curved paths at a constant speed while maintaining the cursor within the path width. Subjects’ accuracy increased with practice, even when tracking novel untrained paths. Using a “searchlight” paradigm, where only a short segment of the path ahead of the cursor was shown, we found that subjects with a higher tracking skill took a longer section of the future path into account when performing the task. An optimal control model with a fixed horizon (receding horizon control) that increases with tracking skill quantitatively captured the subjects’ movement behaviour. These findings demonstrate that human subjects increase their planning horizon when acquiring a motor skill.

There is compelling evidence that the human cerebellum is engaged in a wide array of motor and cognitive tasks. A fundamental question centers on whether the cerebellum is organized into distinct functional sub-regions. To address this question, we employed a rich task battery, designed to tap into a broad range of cognitive processes. During four functional magnetic resonance imaging (fMRI) sessions, participants performed a battery of 26 diverse tasks comprising 47 unique conditions. Using the data from this multi-domain task battery, we derived a comprehensive functional parcellation of the cerebellar cortex, and evaluated it by predicting functional boundaries in a novel set of tasks. The new parcellation successfully identified distinct functional sub-regions, providing significant improvements over existing parcellations derived from task-free data. Lobular boundaries, commonly used to summarize functional data, did not coincide with functional subdivisions. This multi-domain task approach offers novel insights into the functional heterogeneity of the cerebellar cortex.

A Multi-Domain Task Battery Reveals Functional Boundaries in the Human Cerebellum

Hand and finger movements are mostly controlled through crossed corticospinal projections from the contralateral hemisphere. During unimanual movements, activity in the contralateral hemisphere is increased while the ipsilateral hemisphere is suppressed below resting baseline. Despite this suppression, unimanual movements can be decoded from ipsilateral activity alone. This indicates that ipsilateral activity patterns represent parameters of ongoing movement, but the origin and functional relevance of these representations is unclear. Here, we asked whether human ipsilateral representations are caused by active movement, or whether they are driven by sensory input. Participants alternated between performing single finger presses and having fingers passively stimulated, while we recorded brain activity using high-field (7T) functional imaging. We contrasted active and passive finger representations in sensorimotor areas of ipsilateral and contralateral hemispheres. Finger representations in the contralateral hemisphere were equally strong under passive and active conditions, highlighting the importance of sensory information in feedback control. In contrast, ipsilateral finger representations were stronger during active presses. Furthermore, the spatial distribution of finger representations differed between hemispheres: the contralateral hemisphere showed the strongest finger representations in Brodmann area 3a and 3b, while the ipsilateral hemisphere exhibited stronger representations in premotor and parietal areas. This suggests that finger representations in the two hemispheres have different origins – contralateral representations are driven by both active movement and sensory stimulation, whereas ipsilateral representations are mainly engaged during active movement. This suggests that a possible contribution of the ipsilateral hemisphere lies in movement planning, rather than in the dexterous feedback control of the movement. Significance statement Movements of the human body are mostly controlled by contralateral cortical regions. However, activity in ipsilateral sensorimotor regions is also modulated during active movements. The origin and functional relevance of these ipsilateral representations is unclear. Here we used high-field neuroimaging to investigate how human contralateral and ipsilateral hemispheres represent active finger presses and passive finger stimulation. We report that while the contralateral hemisphere was equally strongly recruited during active and passive conditions, the ipsilateral hemisphere was mostly recruited during active movement. We propose that the ipsilateral hemisphere may play a role in bilateral movement planning.

Ipsilateral finger representations are engaged in active movement, but not sensory processing

Cerebellar volume and cerebellocerebral structural covariance in schizophrenia: a multisite mega-analysis of 983 patients and 1349 healthy controls

Thirty years of research have provided compelling evidence that the human cerebellum is engaged in a wide array of cognitive tasks. Understanding the functional contributions of this structure to cognition remains a subject of considerable debate. Previous studies have generally taken a piecemeal approach, employing a limited number of tasks to test specific hypotheses. Here we take a different approach, seeking to identify a detailed characterization of functional subdivisions across the extent of the cerebellar cortex. During fMRI scanning, 24 participants performed a large task battery designed to tap into a broad range of cognitive processes (e.g., attention, memory, social cognition). These heterogeneous task patterns were leveraged to derive a multi-task parcellation of the cerebellum. We then developed a novel tool to evaluate the strength of functional boundaries, employing out-of-sample generalization. We tested our novel, multi-task parcellation, along with existing resting state and anatomical parcellations. We find that the multi-task parcellation successfully identifies functional subregions within the cerebellum, and provides a significant improvement over boundaries identified with resting state data. Surprisingly, lobular boundaries, the current standard for assigning functional activations, do not coincide with functional boundaries. The multi-task parcellation offers a novel functional map for analyzing and reporting cerebellar activations.

While previous studies have revealed an extended network of cortical regions associated with motor sequence production, the specific role of each of these areas is still elusive. To address this issue, we designed a novel behavioural paradigm that allowed us to experimentally manipulate the structure of motor sequences representations in individual participants. We then conducted fMRI while participants executed 8 trained sequences to examine how this structure is reflected in the associated activity patterns. Both model-based and model-free approaches revealed a clear distinction between primary and non-primary motor cortices in their representational contents, with M1 specifically representing individual finger movements, and premotor and parietal cortices showing a mixture of chunk, sequence and finger transition representations. Using model-free representational parcellation, we could divide these non-primary motor cortices into separate clusters, each with a unique representation along the stimulus-to-action gradient. These results provide new insights into how human neocortex organizes movement sequences.

Parcellation of motor sequence representations in the human neocortex

Statistics of natural hand use only partially explains structure of stimulation-evoked muscle activity

Sudden emergence of categoricality at the lateral-occipital stage of ventral visual processing

Cell Death Neurons in Close Temporal Relationship to Purkinje Mediated Conductance in Cerebellar Nuclei - -Receptor A Mice Exhibit Potentiation of GABA Lurcher

V16. MRI abnormalities of the cerebellar cortex and nuclei in SCA3, SCA6, and Friedreich’s ataxia

The g-ratio, quantifying the ratio between the inner and outer diameters of a fiber, is an important microstructural characteristic of fiber pathways and is functionally related to conduction velocity. We introduce a novel method for estimating the MR g-ratio non-invasively across the whole brain using high-fidelity magnetization transfer (MT) imaging and single-shell diffusion MRI. These methods enabled us to map the MR g-ratio in vivo across the brain's prominent fiber pathways in a group of 37 healthy volunteers and to estimate the inter-subject variability. Effective correction of susceptibility-related distortion artifacts was essential before combining the MT and diffusion data, in order to reduce partial volume and edge artifacts. The MR g-ratio is in good qualitative agreement with histological findings despite the different resolution and spatial coverage of MRI and histology. The MR g-ratio holds promise as an important non-invasive biomarker due to its microstructural and functional relevance in neurodegeneration.

Whole-Brain In-vivo Measurements of the Axonal G-Ratio in a Group of 37 Healthy Volunteers

Spinocerebellar ataxia type 3, spinocerebellar ataxia type 6 and Friedreich’s ataxia are common hereditary ataxias. Different patterns of atrophy of the cerebellar cortex are well known. Data on cerebellar nuclei are sparse. Whereas cerebellar nuclei have long been thought to be preserved in spinocerebellar ataxia type 6, histology shows marked atrophy of the nuclei in Friedreich’s ataxia and spinocerebellar ataxia type 3. In the present study susceptibility weighted imaging was used to assess atrophy of the cerebellar nuclei in patients with spinocerebellar ataxia type 6 (n = 12, age range 41–76 years, five female), Friedreich’s ataxia (n = 12, age range 21–55 years, seven female), spinocerebellar ataxia type 3 (n = 10, age range 34–67 years, three female), and ageand gender-matched controls (total n = 23, age range 22–75 years, 10 female). T1-weighted magnetic resonance images were used to calculate the volume of the cerebellum. In addition, ultra-high field functional magnetic resonance imaging was performed with optimized normalization methods to assess function of the cerebellar cortex and nuclei during simple hand movements. As expected, the volume of the cerebellum was markedly reduced in spinocerebellar ataxia type 6, preserved in Friedreich’s ataxia, and mildy reduced in spinocerebellar ataxia type 3. The volume of the cerebellar nuclei was reduced in the three patient groups compared to matched controls (P-values5 0.05; two-sample t-tests). Atrophy of the cerebellar nuclei was most pronounced in spinocerebellar ataxia type 6. On a functional level, hand-movement-related cerebellar activation was altered in all three disorders. Within the cerebellar cortex, functional magnetic resonance imaging signal was significantly reduced in spinocerebellar ataxia type 6 and Friedreich’s ataxia compared to matched controls (P-values50.001, bootstrap-corrected cluster-size threshold; two-sample t-tests). The difference missed significance in spinocerebellar ataxia type 3. Within the cerebellar nuclei, reductions were significant when comparing spinocerebellar ataxia type 6 and Friedreich’s ataxia to matched controls (P5 0.01, bootstrap-corrected cluster-size threshold; two-sample t-tests). Susceptibility weighted imaging allowed depiction of atrophy of the cerebellar nuclei in patients with Friedreich’s ataxia and spinocerebellar ataxia type 3. In spinocerebellar ataxia type 6, pathology was not restricted to the cerebellar cortex but also involved the cerebellar nuclei. Functional magnetic resonance imaging data, on the other hand, revealed that pathology in Friedreich’s ataxia and spinocerebellar ataxia type 3 is not restricted to the cerebellar nuclei. There was functional involvement of the cerebellar cortex despite no or little structural changes.

Structural and functional MRI abnormalities of cerebellar cortex and nuclei in SCA 3 , SCA 6 and Friedreich ’ s ataxia

Spinocerebellar ataxia type 3, spinocerebellar ataxia type 6 and Friedreich's ataxia are common hereditary ataxias. Different patterns of atrophy of the cerebellar cortex are well known. Data on cerebellar nuclei are sparse. Whereas cerebellar nuclei have long been thought to be preserved in spinocerebellar ataxia type 6, histology shows marked atrophy of the nuclei in Friedreich's ataxia and spinocerebellar ataxia type 3. In the present study susceptibility weighted imaging was used to assess atrophy of the cerebellar nuclei in patients with spinocerebellar ataxia type 6 (n = 12, age range 41-76 years, five female), Friedreich's ataxia (n = 12, age range 21-55 years, seven female), spinocerebellar ataxia type 3 (n = 10, age range 34-67 years, three female), and age- and gender-matched controls (total n = 23, age range 22-75 years, 10 female). T1-weighted magnetic resonance images were used to calculate the volume of the cerebellum. In addition, ultra-high field functional magnetic resonance imaging was performed with optimized normalization methods to assess function of the cerebellar cortex and nuclei during simple hand movements. As expected, the volume of the cerebellum was markedly reduced in spinocerebellar ataxia type 6, preserved in Friedreich's ataxia, and mildy reduced in spinocerebellar ataxia type 3. The volume of the cerebellar nuclei was reduced in the three patient groups compared to matched controls (P-values < 0.05; two-sample t-tests). Atrophy of the cerebellar nuclei was most pronounced in spinocerebellar ataxia type 6. On a functional level, hand-movement-related cerebellar activation was altered in all three disorders. Within the cerebellar cortex, functional magnetic resonance imaging signal was significantly reduced in spinocerebellar ataxia type 6 and Friedreich's ataxia compared to matched controls (P-values < 0.001, bootstrap-corrected cluster-size threshold; two-sample t-tests). The difference missed significance in spinocerebellar ataxia type 3. Within the cerebellar nuclei, reductions were significant when comparing spinocerebellar ataxia type 6 and Friedreich's ataxia to matched controls (P < 0.01, bootstrap-corrected cluster-size threshold; two-sample t-tests). Susceptibility weighted imaging allowed depiction of atrophy of the cerebellar nuclei in patients with Friedreich's ataxia and spinocerebellar ataxia type 3. In spinocerebellar ataxia type 6, pathology was not restricted to the cerebellar cortex but also involved the cerebellar nuclei. Functional magnetic resonance imaging data, on the other hand, revealed that pathology in Friedreich's ataxia and spinocerebellar ataxia type 3 is not restricted to the cerebellar nuclei. There was functional involvement of the cerebellar cortex despite no or little structural changes.

Structural and functional MRI abnormalities of cerebellar cortex and nuclei in SCA3, SCA6 and Friedreich's ataxia.

Proprioception in motor learning: lessons from a deafferented subject

Movement velocity during training influences recovery mechanisms after stroke

Widespread age-related differences in the human brain microstructure revealed by quantitative magnetic resonance imaging☆

P357: Motor learning differences due to training with an emphasis on fast movement or movement accuracy for reaching movements after stroke

The cerebellum is a compact structure that has about one-ninth of the volume of the neocortex, but comprises more than half of the neurons in the central nervous system. While the cerebel‐ lum has historically been understood to assist with movement and balance (e.g., Holmes, 1917, 1939), today we know that the cerebellum is also involved in non-motor functions (for review, see Stoodley & Schmahmann, 2009). Indeed, the cerebellum appears to play a role in nearly as many separate functions as the neocortex. This functional diversity within a restricted area poses unique challenges for the study of the cerebellum using functional magnetic resonance imaging (fMRI).

There is broad consensus that the prefrontal cortex supports goal-directed, model-based decision-making. Consistent with this, we have recently shown that model-based control can be impaired through transcranial magnetic stimulation of right dorsolateral prefrontal cortex in humans. We hypothesized that an enhancement of model-based control might be achieved by anodal transcranial direct current stimulation of the same region. We tested 22 healthy adult human participants in a within-subject, double-blind design in which participants were given Active or Sham stimulation over two sessions. We show Active stimulation had no effect on model-based control or on model-free (‘habitual’) control compared to Sham stimulation. These null effects are substantiated by a power analysis, which suggests that our study had at least 60% power to detect a true effect, and by a Bayesian model comparison, which favors a model of the data that assumes stimulation had no effect over models that assume stimulation had an effect on behavioral control. Although we cannot entirely exclude more trivial explanations for our null effect, for example related to (faults in) our experimental setup, these data suggest that anodal transcranial direct current stimulation over right dorsolateral prefrontal cortex does not improve model-based control, despite existing evidence that transcranial magnetic stimulation can disrupt such control in the same brain region.

Transcranial Direct Current Stimulation of Right Dorsolateral Prefrontal Cortex Does Not Affect Model-Based or Model-Free Reinforcement Learning in Humans

A 7T fMRI study of cerebellar activation in sequential finger movement tasks

Effects of focal basal ganglia lesions on timing and force control

Bimanual cross-talk during reaching movements is primarily related to response selection, not the specification of motor parameters

Previous studies have suggested that the cerebellum and basal ganglia may play a critical role in interval timing. In the first part of the chapter, we review this literature, focusing on production and perception tasks involving intervals in the hundreds of millisecond range. Overall, the neuropsychological and neuroimaging evidence consistently points to the involvement of the cerebellum in such tasks; the evidence is less consistent with respect to the basal ganglia. In the second half of the chapter, we present an experiment in which patients with either cerebellar or basal ganglia pathology were tested on a repetitive tapping task. Unlike previous studies, a pacing signal was provided, allowing an evaluation of variability associated with internal timing, motor implementation, and error correction. The results suggest a dissociation between the two groups: the patients with cerebellar lesions exhibited noisy internal timing while the gain in error correction was reduced in Parkinson patients. In combination with previous work, these results indicate how the cerebellum and basal ganglia may make differential contributions to tasks that require consistent timing.

While fMRI studies have documented cerebellar activity across a wide array of tasks, the functional contribution of the cerebellum within these task domains remains unclear. Here we present a new framework to address this problem, asking if neocortical inputs to the cerebellum are gated in a task-dependent manner. We tested this idea in the context of finger movements, where the integrity of the cerebellum has been shown to be essential for the coordination of rapid alternating movements but not grip force generation. While neocortical and cerebellar activity both increased with increasing speed and force, the changes in cerebellar activity associated with speed were larger than predicted by an optimized cortico-cerebellar connectivity model. This suggests a task-specific recruitment of the cerebellum through gating of information between the cerebellum and neocortex. More generally, this framework offers a new approach to identify cerebellar contributions to function using fMRI. Significance statement Previous functional imaging studies have shown the cerebellum is activated across a large range of tasks. However, drawing specific inferences about cerebellar function from this work has been difficult because activation patterns in the cerebellum are strongly constrained by its anatomical connectivity with the neocortex. As activity in the neocortex increases, corresponding changes should be expected in the cerebellum, regardless of whether the cerebellum is functionally involved in the task or not. We present a new framework to address this problem, comparing cerebellar activations with that predicted by a task-general cortico-cerebellar connectivity model. Applying this approach in the motor domain, we show that the input to the cerebellum is preferentially upregulated for the coordination of rapid, alternating finger movements.

Selective recruitment: Evidence for task-dependent gating of inputs to the cerebellum

One important barrier in the development of complex models of human brain organization is the lack of a large and comprehensive task-based neuro-imaging dataset. Therefore, current atlases of functional brain organization are mainly based on single and homogeneous resting-state datasets. Here, we propose a hierarchical Bayesian framework that can learn a probabilistically defined brain parcellation across numerous task-based and resting-state datasets, exploiting their combined strengths. The framework is partitioned into a spatial arrangement model that defines the probability of a specific individual brain parcellation, and a set of dataset-specific emission models that defines the probability of the observed data given the individual brain organization. We show that the framework optimally combines information from different datasets to achieve a new population-based atlas of the human cerebellum. Furthermore, we demonstrate that, using only 10 min of individual data, the framework is able to generate individual brain parcellations that outperform group atlases.

A hierarchical Bayesian brain parcellation framework for fusion of functional imaging datasets

What happens once a cortical territory becomes functionally redundant? We addressed brain and behavioural adaptations for the intact hand in individuals with a missing hand. Previous studies reported increased ipsilateral activity in the somatosensory territory of the missing hand (i.e., remapping) in acquired amputees, but not in individuals with a congenitally missing hand (one-handers). It is unclear whether remapping in amputees involves recruiting more neural resources to support the intact hand, and whether such activity is increased in tasks that demand greater motor control. We investigated sensorimotor learning and neural representation of the intact hand in one-handers and amputees using a multi-finger configuration task, as well as univariate and multivariate fMRI. We found that ipsilateral activity increased with motor demand - but only in the amputees group. However, these changes did not reflect behavioural differences. The representation of the finger configurations, as revealed by multivariate analysis, was stronger in amputees and closer to the typical representation found in controls’ contralateral hand territory, compared to one-handers. This collaborative contra-ipsilateral activity may reflect the intact hand’s efference copy. One-handers struggled to learn difficult finger configurations, but this did not translate to differences in univariate or multivariate activity relative to controls. Together with a supplementary structural white matter analysis, our results suggest that enhanced activity in the missing hand territory may not reflect intact hand function. Instead, we suggest that plasticity is more restricted than generally assumed and may depend on the availability of homologous pathways acquired early in life. Significant Statement We studied whether brain resources in the missing-hand territory support demanding intact hand motor control in people who were born with one hand or lost a hand later in life. We found that amputees had increased activity in the brain area used for the missing hand, but no improvement in the performance of their intact hand. This collaborative contra-ipsilateral activity may reflect the intact hand’s efference copy. One-handers showed slight deficits while learning to perform complex motor movements, but no brain activity differences in the missing hand territory, compared to controls. Our results suggest that brain plasticity is limited and may depend on early life experiences.

Does ipsilateral remapping following hand loss impact motor control of the intact hand?

The cortical alterations underpinning the acquisition of motor skills remain debated. In this longitudinal study in younger adults, we acquired performance and neuroimaging (7T MRI) measures weekly over the course of 6 weeks to investigate neural changes associated with learning sequences of simultaneous finger presses executed with the non-dominant hand. Both the intervention group (n = 33) and the control group (n = 30) showed general performance improvements, but performance improved more and became more consistent for sequences that were intensively trained by the intervention group, relative to those that were not. Brain activity for trained sequences decreased compared with untrained sequences in the bilateral parietal and premotor cortices. No training-related changes in the primary sensorimotor areas were detected. The similarity of activation patterns between trained and untrained sequences decreased in secondary, but not primary, sensorimotor areas, while the similarity of the activation patterns between different trained sequences did not show reliable changes. Neither the variability of activation patterns across trials, nor the estimates of brain structure displayed practice-related changes that reached statistical significance. Overall, the main correlate of learning configural sequences was a reduction in brain activity in secondary motor areas.

Cortical changes during the learning of sequences of simultaneous finger presses

In the past, the cerebellum has been best known for its crucial role in motor function. However, increasingly more findings highlight the importance of cerebellar contributions in cognitive functions and neurodevelopment. Using large scale, population-wide neuroimaging data, we describe and provide detailed, openly available models of cerebellar development in childhood and adolescence, an important time period for brain development and onset of neuropsychiatric disorders. Next to a traditionally used anatomical parcellation of the cerebellum, we generated growth models based on a recently proposed functional parcellation. In both, we find an anterior-posterior growth gradient mirroring the age-related improvements of underlying behavior and function, which is analogous to cerebral maturation patterns and offers new evidence for directly related cerebello-cortical developmental trajectories. Finally, we illustrate how the current approach can be used to detect cerebellar abnormalities in clinical samples.

Large Data on the Small Brain: Population-wide Cerebellar Growth Models of Children and Adolescents

When performing movements in rapid succession, the brain needs to coordinate preparation of an upcoming action with ongoing execution. Here we identify the processes and brain areas involved in this ability. Human participants performed pairs of single-finger presses or three-finger chords in settings where they had to prepare the second movement before or after the first response. Despite matched perceptual and movement requirements, 7T functional MRI revealed increased brain activity in regions along the intra-parietal sulcus and ventral visual stream when actions overlapped. Multivariate analyses suggested that these areas were involved in stimulus identification and action selection. In contrast, the dorsal premotor cortex, known to be involved in planning upcoming movements, showed no discernible signs of heightened activity. This observation suggests that the bottleneck during simultaneous action control and preparation arises at the level of stimulus identification and action selection, whereas movement planning in the premotor cortex can unfold concurrently with execution without interference between the two processes. Summary The brain’s ability to prepare for upcoming actions while controlling ongoing movements is a crucial evolutionary adaptation of the action system. However, the neural basis of online action preparation remains largely unknown. We found that superior-parietal and occipito-temporal areas exhibited heightened activation during online preparation. Surprisingly, the dorsal premotor cortex, known to be a crucial structure in motor planning, did not display additional activation for overlapping actions. These findings imply that while motor planning within the premotor cortex can occur in parallel with the execution of ongoing movement, the parallel stimulus identification and action selection in the posterior parietal cortex requires additional neural processes. Highlights Individuals prepare upcoming actions while simultaneously controlling ongoing movement When these two processes overlap, superior-parietal and occipito-temporal areas show increased activation Multivariate analysis suggests that increased activation arises to resolve simultaneous stimulus identification and action selection The premotor cortex, known to be involved in motor planning, coordinates simultaneous planning and execution without extra neural engagement

CerebNet: A fast and reliable deep-learning pipeline for detailed cerebellum sub-segmentation

Actions involving fine control of the hand, for example grasping an object, rely heavily on sensory information from the fingertips. While the integration of feedback during the execution of individual movements is well understood, less is known about the use of sensory feedback in the control of skilled movement sequences. To address this gap, we trained participants to produce sequences of finger movements on a keyboard-like device over a four-day training period. Participants received haptic, visual, and auditory feedback indicating the occurrence of each finger press. We then either transiently delayed or advanced the feedback for a single press by a small amount of time (30 or 60ms). We observed that participants rapidly adjusted their ongoing finger press by either accelerating or prolonging the ongoing press, in accordance with the direction of the perturbation. Furthermore, we could show that this rapid behavioural modulation was driven by haptic feedback. While these feedback-driven adjustments reduced in size with practice, they were still clearly present at the end of training. In contrast to the directionally-specific effect we observed on the perturbed press, a feedback perturbation resulted in a delayed onset of the subsequent presses irrespective of perturbation direction or feedback modality. This observation is consistent with a hierarchical organization of even very skilled and fast movement sequences, with different levels reacting distinctly to sensory perturbations.

The role of feedback in the production of skilled finger sequences.

Predicting brain activation maps for arbitrary tasks with cognitive encoding models

While resting-state fMRI studies have provided a broad picture of the connectivity between human neocortex and cerebellum, the degree of convergence of cortical inputs onto cerebellar circuits remains unknown. Does each cerebellar region receive input from a single cortical area or convergent inputs from multiple cortical areas? Here we use task-based fMRI data to build a range of cortico-cerebellar connectivity models, each allowing for a different degree of convergence. We compared these models by their ability to predict cerebellar activity patterns for novel Task Sets. Models that allow some degree of convergence provided the best predictions, arguing for convergence of multiple cortical inputs onto single cerebellar voxels. Importantly, the degree of convergence varied across the cerebellum with the highest convergence observed in areas linked to language, working memory, and social cognition. These findings suggest important differences in the way that functional subdivisions of the cerebellum support motor and cognitive function. Highlights Models of cortico-cerebellar connectivity are quantified using task-based fMRI Convergent rather than sparse inputs best characterize cortico-cerebellar connectivity Cerebellar areas linked to cognition receive high convergence of cortical inputs Models successfully generalize to new tasks and new participants

A task-general connectivity model reveals variation in convergence of cortical inputs to functional regions of the cerebellum

To achieve fast feedback control of voluntary movements, the visual consequences of our motor commands need to be quickly identified and analyzed by the motor control processes in the brain. These processes work remarkably well even in complex visual environments and in the face of discrepancies between physical actuator and visually perceived effect, e.g. when moving a computer mouse on a visually crowded screen. Here we use an ambiguous situation in which a single cursor could be controlled by either the left or the right hand to determine the visual and cognitive factors that determine the assignment of a visual stimulus to the corresponding motor command. Our results demonstrate that the visuomotor system is exquisitely sensitive to the spatio-temporal correlation between cursor and hands, learning the appropriate mapping implicitly within several minutes. In contrast, spatial proximity between end effector and visual consequence has an immediate but only transient effect on the assignment process. Finally, an explicit instruction about which hand controls the cursor only has a minor influence when the instruction is presented first. These findings provide insight into the relative importance of the factors that determine the binding of visual information to the corresponding motor structures to enable fast feedback control.

Factors governing the assignment of visual consequence to the corresponding action.

We investigated motor skill learning using a path tracking task, where human subjects had to track various curved paths at a constant speed while maintaining the cursor within the path width. Subjects' accuracy increased with practice, even when tracking novel untrained paths. Using a "searchlight" paradigm, where only a short segment of the path ahead of the cursor was shown, we found that subjects with a higher tracking skill differed from the novice subjects in two respects. First, they had lower movement variability, in agreement with previous findings. Second, they took a longer section of the future path into account when performing the task, i.e. had a longer planning horizon. We estimate that between one third and one half of the performance increase in the expert group was due to the longer planning horizon. An optimal control model with a fixed horizon (receding horizon control) that increases with tracking skill quantitatively captured the subjects' movement behaviour. These findings demonstrate that human subjects not only increase their motor acuity but also their planning horizon when acquiring a motor skill.

Motor skill learning decreases movement variability and increases planning horizon.

Multiple lines of research provide compelling evidence for a role of the cerebellum in a wide array of cognitive and affective functions, going far beyond its historical association with motor control. Structural and functional neuroimaging studies have further refined understanding of the functional neuroanatomy of the cerebellum beyond its anatomical divisions, highlighting the need for the examination of individual cerebellar subunits in healthy variability and neurological diseases. This paper presents a standardized pipeline for examining cerebellum grey matter morphometry that combines high-resolution, state-of-the-art approaches for optimized and automated cerebellum parcellation (Automatic Cerebellum Anatomical Parcellation using U-Net Locally Constrained Optimization; ACAPULCO) and voxel-based registration of the cerebellum (Spatially Unbiased Infra-tentorial Template; SUIT) for volumetric quantification. The pipeline has broad applicability to a range of neurological diseases and is fully automated, with manual intervention only required for quality control of the outputs. The pipeline is freely available, with substantial accompanying documentation, and can be run on Mac, Windows, and Linux operating systems. The pipeline is applied in a cohort of individuals with Friedreich ataxia (FRDA), and representative results, as well as recommendations on group-level inferential statistical analyses, are provided. This pipeline could facilitate reliability and reproducibility across the field, ultimately providing a powerful methodological approach for characterizing and tracking cerebellar structural changes in neurological diseases.

A Standardized Pipeline for Examining Human Cerebellar Grey Matter Morphometry using Structural Magnetic Resonance Imaging.

One important approach to human brain mapping is to define a set of distinct regions that can be linked to unique functions. Numerous brain parcellations have been proposed, using cytoarchitectonic, structural or functional Magnetic Resonance Imaging (fMRI) data. The intrinsic smoothness of brain data, however, poses a problem for current methods seeking to compare different parcellations. For example, criteria that simply compare within-parcel to between-parcel similarity provide even random parcellations with a high value. Furthermore, the evaluation is biased by the spatial scale of the parcellation. To address this problem, we propose the Distance Controlled Boundary Coefficient (DCBC), an unbiased criterion to evaluate discrete parcellations. We employ this new criterion to evaluate existing parcellations of the human neocortex in their power to predict functional boundaries for an fMRI data set with many different tasks, as well as for resting-state data. We find that common anatomical parcellations do not perform better than chance, suggesting that task-based functional boundaries do not align well with sulcal landmarks. Parcellations based on resting-state fMRI data perform well; in some cases, as well as a parcellation defined on the evaluation data itself. Finally, multi-modal parcellations that combine functional and anatomical criteria perform substantially worse than those based on functional data alone, indicating that functionally homogeneous regions often span major anatomical landmarks. Overall, the DCBC advances the field of functional brain mapping by providing an unbiased metric that compares the predictive ability of different brain parcellations to define brain regions that are functionally maximally distinct.

Evaluating brain parcellations using the distance‐controlled boundary coefficient

Abstract When performing a long chain of actions in rapid sequence, future movements need to be planned concurrently with ongoing action. However, how far ahead we plan, and whether this ability improves with practice, is currently unknown. Here, we designed an experiment in which healthy volunteers produced sequences of 14 finger presses quickly and accurately on a keyboard in response to numerical stimuli. On every trial, participants were only shown a fixed number of stimuli ahead of the current keypress. The size of this viewing window varied between 1 (next digit revealed with the pressing of the current key) and 14 (full view of the sequence). Participants practiced the task for 5 days, and their performance was continuously assessed on random sequences. Our results indicate that participants used the available visual information to plan multiple actions into the future, but that the planning horizon was limited: receiving information about more than three movements ahead did not result in faster sequence production. Over the course of practice, we found larger performance improvements for larger viewing windows and an expansion of the planning horizon. These findings suggest that the ability to plan future responses during ongoing movement constitutes an important aspect of skillful movement. Based on the results, we propose a framework to investigate the neuronal processes underlying simultaneous planning and execution.

Neuroscience has recently made much progress, expanding the complexity of both neural-activity measurements and brain-computational models. However, we lack robust methods for connecting theory and experiment by evaluating our new big models with our new big data. Here we introduce a new inferential methodology to evaluate models based on their predictions of representational geometries. The inference can handle flexible parametrized models and can treat both subjects and conditions as random effects, such that conclusions generalize to the respective populations of subjects and conditions. We validate the inference methods using extensive simulations with deep neural networks and resampling of calcium imaging and functional MRI data. Results demonstrate that the methods are valid and conclusions generalize correctly. These data analysis methods are available in an open-source Python toolbox.

It has been proposed that a form of cortical reorganization (changes in functional connectivity between brain areas) can be assessed with resting-state (rs) fMRI. Here we report a longitudinal data-set collected from 19 patients with subcortical stroke and 11 controls. Patients were imaged up to five times over one year. We found no evidence, using rs-fMRI, for post-stroke cortical connectivity changes despite substantial behavioral recovery. These results could be construed as questioning the value of resting-state imaging. Here we argue instead that they are consistent with other emerging reasons to challenge the idea of motor recovery-related cortical reorganization post-stroke when conceived of as changes in connectivity between cortical areas.

No evidence for motor-recovery-related cortical connectivity changes after stroke using resting-state fMRI

Actions involving fine control of the hand, for example grasping an object, rely heavily on sensory information from the fingertips. While the integration of feedback during execution of individual movements is well understood, less is known about the use of sensory feedback in the control of skilled movement sequences. To address this gap, we trained participants to produce sequences of finger movements on a keyboard-like device over a four-day training period. Participants received haptic, visual, and auditory feedback indicating the occurrence of each finger press. We then either transiently delayed or advanced the feedback for a single press by a small amount of time (30 or 60 ms). We observed that participants rapidly adjusted their ongoing finger press by either accelerating or prolonging the ongoing press, in accordance with the direction of the perturbation. Furthermore, we could show that this rapid behavioural modulation was driven by haptic feedback. While these feedback-driven adjustments reduced in size with practice, they were still clearly present at the end of training. In contrast to the directionally-specific effect we observed on the perturbed press, a feedback perturbation resulted in a delayed onset of the subsequent presses irrespective of perturbation direction or feedback modality. This observation is consistent with a hierarchical organization of skilled movement sequences, with different levels reacting distinctly to sensory perturbations.

The role of feedback in the production of skilled finger sequences

Given that new therapeutic options for spinocerebellar ataxias are on the horizon, there is a need for markers that reflect disease‐related alterations, in particular, in the preataxic stage, in which clinical scales are lacking sensitivity.

Movement disorders : official journal of the Movement Disorder Society

Regional Brain and Spinal Cord Volume Loss in Spinocerebellar Ataxia Type 3

How does the brain change during learning? In functional magnetic resonance imaging (fMRI) studies, both multivariate pattern analysis (MVPA) and repetition suppression (RS) have been used to detect changes in neuronal representations. In the context of motor sequence learning, the two techniques have provided discrepant findings: pattern analysis showed that only premotor and parietal regions, but not primary motor cortex (M1), develop a representation of trained sequences. In contrast, RS suggested trained sequence representations in all these regions. Here, we applied both analysis techniques to a five-week finger sequence training study, in which participants executed each sequence twice before switching to a different sequence. Both RS and pattern analysis indicated learning-related changes for parietal areas, but only RS showed a difference between trained and untrained sequences in M1. A more fine-grained analysis, however, revealed that the RS effect in M1 reflects a fundamentally different process than in parietal areas. On the first execution, M1 represents especially the first finger of each sequence, likely reflecting preparatory processes. This effect dramatically reduces during the second execution. In contrast, parietal areas represent the identity of a sequence, and this representation stays relatively stable on the second execution. These results suggest that the RS effect does not reflect a trained sequence representation in M1, but rather a preparatory signal for movement initiation. More generally, our study demonstrates that across regions RS can reflect different representational changes in the neuronal population code, emphasizing the importance of combining pattern analysis and RS techniques. SIGNIFICANCE STATEMENT Previous studies using pattern analysis have suggested that primary motor cortex (M1) does not represent learnt sequential actions. However, a study using repetition suppression (RS) has reported M1 changes during motor sequence learning. Combining both techniques, we first replicate the discrepancy between them, with learning-related changes in M1 in RS, but not pattern dissimilarities. We further analyzed the representational changes with repetition, and found that the RS effects differ across regions. M1's activity represents the starting finger of the sequence, an effect that vanishes with repetition. In contrast, activity patterns in parietal areas exhibit sequence dependency, which persists with repetition. These results demonstrate the importance of combining RS and pattern analysis to understand the function of brain regions.

Combining Repetition Suppression and Pattern Analysis Provides New Insights into the Role of M1 and Parietal Areas in Skilled Sequential Actions

The integration of somatosensory signals across fingers is essential for dexterous object manipulation. Previous experiments suggest that this integration occurs in neural populations in the primary somatosensory cortex (S1). However, the integration process has not been fully characterized, as previous studies have mainly used 2-finger stimulation paradigms. Here, we addressed this gap by stimulating all 31 single- and multifinger combinations. We measured population-wide activity patterns evoked during finger stimulation in human S1 and primary motor cortex (M1) using 7T fMRI in female and male participants. Using multivariate fMRI analyses, we found clear evidence of unique nonlinear interactions between fingers. In Brodmann area (BA) 3b, interactions predominantly occurred between pairs of neighboring fingers. In BA 2, however, we found equally strong interactions between spatially distant fingers, as well as interactions between finger triplets and quadruplets. We additionally observed strong interactions in the hand area of M1. In both M1 and S1, these nonlinear interactions did not reflect a general suppression of overall activity, suggesting instead that the interactions we observed reflect rich, nonlinear integration of sensory inputs from the fingers. We suggest that this nonlinear finger integration allows for a highly flexible mapping from finger sensory inputs to motor responses that facilitates dexterous object manipulation. SIGNIFICANCE STATEMENT Processing of somatosensory information in primary somatosensory cortex (S1) is essential for dexterous object manipulation. To successfully handle an object, the sensorimotor system needs to detect complex patterns of haptic information, which requires the nonlinear integration of sensory inputs across multiple fingers. Using multivariate fMRI analyses, we characterized brain activity patterns evoked by stimulating all single- and multifinger combinations. We report that progressively stronger multifinger interactions emerge in posterior S1 and in the primary motor cortex (M1), with interactions arising between inputs from neighboring and spatially distant fingers. Our results suggest that S1 and M1 provide the neural substrate necessary to support a flexible mapping from sensory inputs to motor responses of the hand.

Mapping the Integration of Sensory Information across Fingers in Human Sensorimotor Cortex

When reaching for an object with the hand, the gaze is usually directed at the target. In a laboratory setting, fixation is strongly maintained at the reach target until the reaching is completed, a phenomenon known as "gaze-anchoring". While conventional accounts of such tight eye-hand coordination have often emphasized the internal synergetic linkage between both motor systems, more recent optimal control theories regard motor coordination as the adaptive solution to task requirements. We here investigated to what degree gaze control during reaching is modulated by task demands. We adopted a gaze-anchoring paradigm in which participants had to reach for a target location. During the reach, they additionally had to make a saccadic eye movement to a salient visual cue presented at locations other than the target. We manipulated the task demands by independently changing reward contingencies for saccade reaction time (RT) and reaching accuracy. On average, both saccade RTs and reach error varied systematically with reward condition, with reach accuracy improving when the saccade was delayed. The distribution of the saccade RTs showed two types of eye movements: fast saccades with short RTs, and voluntary saccade with longer RTs. Increased reward for high reach accuracy reduced the probability of reflexive fast saccades, but left their latency unchanged. The results suggest that gaze-anchoring acts through a suppression of fast saccades, a mechanism that can be adaptively adjusted to the current task demands.

Gaze control during reaching is flexibly modulated to optimize task outcome.

Musicians dystonia presents with a persistent deterioration of motor control during musical performance. A predominant hypothesis has been that this is underpinned by maladaptive neural changes to the somatotopic organisation of finger representations within primary somatosensory cortex. Here, we tested this hypothesis by investigating the finger-specific activity patterns in the primary somatosensory and motor cortex using functional magnetic resonance (fMRI) in nine musicians with dystonia and nine healthy musicians. A purpose-built keyboard device allowed fMRI characterisation of activity patterns elicited during passive extension and active finger presses of individual fingers. We analysed the data using both traditional spatial analysis and state-of-the art multivariate analyses. Our analysis reveals that digit representations in musicians were poorly captured by spatial measures. An optimised spatial metric found clear somatotopy but no difference in the spatial geometry between fingers. Representational similarity analysis was confirmed as a highly reliable technique and more consistent than all spatial metrics evaluated. Significantly, the dissimilarity architecture was equivalent for musicians with and without dystonia and no expansion or spatial shift of digit representation maps were found in the symptomatic group. Our results therefore suggest that the neural representation of generic finger maps in primary sensorimotor cortex is intact in Musicians dystonia. These results are against the idea that task-specific dystonia is associated with a distorted hand somatotopy and suggests that task-specific dystonia is due to a higher order disruption of skill encoding. Such a formulation can better explain the task-specific deficit and offers mechanistic insight for therapeutic interventions.

Intact finger representation within primary sensorimotor cortex of musician’s dystonia

Representational similarity analysis (RSA) tests models of brain computation by investigating how neural activity patterns reflect experimental conditions. Instead of predicting activity patterns directly, the models predict the geometry of the representation, as defined by the representational dissimilarity matrix (RDM), which captures to what extent experimental conditions are associated with similar or dissimilar activity patterns. RSA therefore first quantifies the representational geometry by calculating a dissimilarity measure for each pair of conditions, and then compares the estimated representational dissimilarities to those predicted by each model. Here we address two central challenges of RSA: First, dissimilarity measures such as the Euclidean, Mahalanobis, and correlation distance, are biased by measurement noise, which can lead to incorrect inferences. Unbiased dissimilarity estimates can be obtained by crossvalidation, at the price of increased variance. Second, the pairwise dissimilarity estimates are not statistically independent, and ignoring this dependency makes model comparison statistically suboptimal. We present an analytical expression for the mean and (co)variance of both biased and unbiased estimators of the squared Euclidean and Mahalanobis distance, allowing us to quantify the bias-variance trade-off. We also use the analytical expression of the covariance of the dissimilarity estimates to whiten the RDM estimation errors. This results in a new criterion for RDM similarity, the whitened unbiased RDM cosine similarity (WUC), which allows for near-optimal model selection combined with robustness to correlated measurement noise.

Comparing representational geometries using whitened unbiased-distance-matrix similarity

Abstract How does the brain change during learning? Functional magnetic resonance imaging studies have used both pattern analysis and repetition suppression (RS) to detect changes in neuronal representations. In the context of motor sequence learning, the two techniques have provided discrepant findings. Specifically, pattern analysis showed that only premotor and parietal regions, but not primary motor cortex (M1), develop a representation of trained sequences. In contrast, RS suggested trained sequence representations in all these regions. Here we applied both analysis techniques to data from a 5-week finger sequence training study, in which participants executed each sequence twice before switching to a different sequence. While we replicated both previously reported findings in the same paradigm, a more fine-grained analysis revealed that the RS effect in M1 and parietal areas reflect fundamentally different processes. On the first execution, M1 represents especially the first finger of each sequence, which might reflect preparatory processes, and this effect dramatically reduces during the second execution. In contrast, parietal areas represent the identity of a sequence, and this representation stays relatively stable on the second execution, only reducing proportionally to the reduction in overall activity. These results suggest that the RS effect in M1 does not reflect trained sequence representation, but rather the altered communication with higher-order areas. More generally, our study demonstrates that RS can reflect different representational changes in the underlying neuronal population code across regions, emphasizing the importance of combining pattern analysis and RS techniques.

The role of primary motor cortex in sequence learning: resolving conflicting fMRI evidence from repetition suppression and pattern analysis

Humans have the remarkable ability to hold, grasp, and manipulate objects. Previous work has reported rapid and coordinated reactions in hand and shoulder muscles in response to external perturbations to the arm during object manipulation; however, little is known about how somatosensory feedback of an object slipping in the hand influences responses of the arm. We built a hand-held device to stimulate the sensation of slipping at all five fingertips. The device was integrated into an exoskeleton robot that supported it against gravity. The setup allowed us to decouple somatosensory stimulation in the fingers from forces applied to the arm- two variables that are highly interdependent in real-world scenarios. Fourteen participants performed three experiments in which we measured their arm feedback responses during slip stimulation. Slip stimulations were applied horizontally, in one of two directions, and participants were either instructed to follow the slip direction, or to move the arm in the opposite direction. Participants showed shoulder muscle responses within ~67 ms of slip onset when following the direction of slip, but significantly slower responses when instructed to move in the opposite direction. Shoulder responses were modulated by the speed but not the distance of the slip. Finally, when slip stimulation was combined with mechanical perturbations to the arm, we found that sensory information from the fingertips significantly modulated the shoulder feedback responses. Overall, the results demonstrate the existence of a rapid feedback system that stabilizes hand-held objects.

Sensory information from a slipping object elicits a rapid and automatic shoulder response.

Author response: A critical re-evaluation of fMRI signatures of motor sequence learning

Representational similarity analysis (RSA) tests models of brain computation by investigating how neural activity patterns change in response to different experimental conditions. Instead of predicting activity patterns directly, the models predict the geometry of the representation, i.e. to what extent experimental conditions are associated with similar or dissimilar activity patterns. RSA therefore first quantifies the representational geometry by calculating a dissimilarity measure for all pairs of conditions, and then compares the estimated representational dissimilarities to those predicted by the model. Here we address two central challenges of RSA: First, dissimilarity measures such as the Euclidean, Mahalanobis, and correlation distance, are biased by measurement noise, which can lead to incorrect inferences. Unbiased dissimilarity estimates can be obtained by crossvalidation, at the price of increased variance. Second, the pairwise dissimilarity estimates are not statistically independent. Ignoring the dependency makes model comparison with RSA statistically suboptimal. We present an analytical expression for the mean and (co-)variance of both biased and unbiased estimators of Euclidean and Mahalanobis distance, allowing us to exactly quantify the bias-variance trade-off. We then use the analytical expression of the co-variance of the dissimilarity estimates to derive a simple method correcting for this covariance. Combining unbiased distance estimates with this correction leads to a novel criterion for comparing representational geometries, the unbiased distance correlation, which, as we show, allows for near optimal model comparison.

Comparing representational geometries using the unbiased distance correlation

Motor planning plays a critical role in producing fast and accurate movement. Yet, the neural processes that occur in human primary motor and somatosensory cortex during planning, and how they relate to those during movement execution, remain poorly understood. Here we used 7T functional magnetic resonance imaging (fMRI) and a delayed movement paradigm to study single finger movement planning and execution. The inclusion of no-go trials and variable delays allowed us to separate what are typically overlapping planning and execution brain responses. Although our univariate results show widespread deactivation during finger planning, multivariate pattern analysis revealed finger-specific activity patterns in contralateral primary somatosensory cortex (S1), which predicted the planned finger action. Surprisingly, these activity patterns were as informative as those found in contralateral primary motor cortex (M1). Control analyses ruled out the possibility that the detected information was an artifact of subthreshold movements during the preparatory delay. Furthermore, we observed that finger-specific activity patterns during planning were highly correlated to those during execution. These findings reveal that motor planning activates the specific S1 and M1 circuits that are engaged during the execution of a finger press, while activity in both regions is overall suppressed. We propose that preparatory states in S1 may improve movement control through changes in sensory processing or via direct influence of spinal motor neurons. Significance statement Motor planning is important for good behavioral performance, yet it is unclear which neural processes underlie the preparation of the nervous system for an upcoming movement. Using high-resolution functional neuroimaging, we investigated how motor planning for finger presses changes the activity state in primary motor and primary somatosensory cortex, and how brain responses during planning and execution relate to each other. We show that planning leads to finger-specific activation in both M1 and S1, which is highly similar to the finger-specific activity patterns elicited during execution. Our findings suggest that S1 is being specifically prepared for an upcoming action, either to actively contribute to the outflowing motor command or to enable action-specific sensory gating.

Motor planning brings human primary somatosensory cortex into action-specific preparatory states

Selecting hand actions to manipulate an object is affected both by perceptual factors and by action goals. Affordances are associated with the automatic potentiation of motor representations to an object, independent of the goal of the actor. In previous studies, we have demonstrated an influence of the congruency between hand and object orientations on response times when reaching to turn an object, such as a cup. In this study, we investigated how the representation of hand postures triggered by planning to turn a cup were influenced by this congruency effect, in an fMRI scanning environment. Healthy participants were asked to reach and turn a real cup that was placed in front of them either in an upright orientation or upside down. They were instructed to use a hand orientation that was either congruent or incongruent with the cup orientation. As expected, the motor responses were faster when the hand and cup orientations were congruent. There was increased activity in a network of brain regions involving object-directed actions during action planning, which included bilateral primary and extrastriate visual, medial and superior temporal areas, as well as superior parietal, primary motor and premotor areas in the left hemisphere. Specific activation of the dorsal premotor cortex (PMd) was associated with hand-object orientation congruency during planning, and prior to any action taking place. Activity in that area and its connectivity with the lateral occipito-temporal cortex (LOTC) increased when planning incongruent actions. The increased activity in premotor areas in trials where the orientation of the hand was incongruent to that of the object suggests a role in eliciting competing representations specified by hand postures in LOTC.

Neural correlates of hand-object congruency effects during action planning

Individual fingers in the primary somatosensory cortex (S1) are known to be represented separately and adjacently, forming a cortical hand map. Electrophysiological studies in monkeys show that finger amputation triggers increased selectivity to the neighbouring fingers within the deprived S1, causing local reorganisation. Neuroimaging research in humans, however, shows persistent S1 finger representation of the missing hand, even decades after amputation. We aimed to resolve these apparently contrasting evidence by examining finger representation in humans following pharmacological ‘amputation’ using single-finger nerve block and 7T neuroimaging. We hypothesised that beneath the apparent selectivity of individual fingers in the hand map, peripheral and central processing is distributed across fingers. If each finger contributes to the cortical representation of the others, then localised input loss will weaken finger representation across the hand map. For the same reason, the non-blocked fingers will stabilise the blocked finger’s representation, resulting in persistent representation of the blocked finger. Using univariate selectivity profiling, we replicated the electrophysiological findings of local S1 reorganisation. However, more comprehensive analyses confirmed that local blocking reduced representation of all fingers across the entire hand area. Importantly, multivariate analysis demonstrated that despite input loss, representation of the blocked finger remained persistent and distinct from the unblocked fingers. Computational modelling suggested that the observed findings are driven by distributed processing underlying the topographic map, combined with homeostatic mechanisms. Our findings suggest that the long-standing depiction of the somatosensory hand map is misleading. As such, accounts for map reorganisation, e.g. following amputation, need to be reconsidered.

Malleability of the cortical hand map following a finger nerve block

Significance The cerebellum has long been recognized as a partner of the cerebral cortex, and both have expanded greatly in human evolution. The thin cerebellar cortex is even more tightly folded than the cerebral cortex. By scanning a human cerebellum specimen at ultra-high magnetic fields, we were able to computationally reconstruct its surface down to the level of the smallest folds, revealing that the cerebellar cortex has almost 80% of the surface area of the cerebral cortex. By performing the same procedure on a monkey brain, we found that the surface area of the human cerebellum has expanded even more than that of the human cerebral cortex, suggesting a role in characteristically human behaviors, such as toolmaking and language. The surface of the human cerebellar cortex is much more tightly folded than the cerebral cortex. It was computationally reconstructed for the first time to the level of all individual folia from multicontrast high-resolution postmortem MRI scans. Its total shrinkage-corrected surface area (1,590 cm2) was larger than expected or previously reported, equal to 78% of the total surface area of the human neocortex. The unfolded and flattened surface comprised a narrow strip 10 cm wide but almost 1 m long. By applying the same methods to the neocortex and cerebellum of the macaque monkey, we found that its cerebellum was relatively much smaller, approximately 33% of the total surface area of its neocortex. This suggests a prominent role for the cerebellum in the evolution of distinctively human behaviors and cognition.

The human cerebellum has almost 80% of the surface area of the neocortex

How does the brain change during skill learning? We previously conducted a longitudinal fMRI motor sequence learning study and, using multivariate techniques, found learning-related changes in premotor and parietal areas, but not in the primary motor cortex (M1) (1). However, a study using repetition suppression (RS) had previously suggested that M1 represents learned sequences. Here we replicate this discrepancy in a single experiment, allowing us to investigate the differences between RS and multivariate pattern analysis in detail. We found that the RS effect in M1 and parietal areas reflect fundamentally different processes. M1’s activity represents the starting finger of the sequence, an effect that vanishes with repetition. In contrast, activity patterns in parietal areas exhibit sequence dependency, which persists with repetition. These findings demonstrate that combining RS and pattern analysis can provide novel functional insights, here specifically into the relative contribution of cortical motor areas to sequence production.

Discrepancy between repetition suppression and pattern analysis provides new insights into the role of M1 and parietal areas in sequence learning

Despite numerous studies, there is little agreement about what brain changes accompany motor sequence learning, partly because of a general publication bias that favors novel results. We therefore decided to systematically reinvestigate proposed functional magnetic resonance imaging correlates of motor learning in a preregistered longitudinal study with four scanning sessions over 5 weeks of training. Activation decreased more for trained than untrained sequences in premotor and parietal areas, without any evidence of learning-related activation increases. Premotor and parietal regions also exhibited changes in the fine-grained, sequence-specific activation patterns early in learning, which stabilized later. No changes were observed in the primary motor cortex (M1). Overall, our study provides evidence that human motor sequence learning occurs outside of M1. Furthermore, it shows that we cannot expect to find activity increases as an indicator for learning, making subtle changes in activity patterns across weeks the most promising fMRI correlate of training-induced plasticity.

A critical re-evaluation of fMRI signatures of motor sequence learning

How is the primary motor cortex (M1) organized to control fine finger movements? We investigated the population activity in M1 for single finger flexion and extension, using 7T functional magnetic resonance imaging (fMRI) in female and male human participants and compared these results to the neural spiking patterns recorded in two male monkeys performing the identical task. fMRI activity patterns were distinct for movements of different fingers, but were quite similar for flexion and extension of the same finger. In contrast, spiking patterns in monkeys were quite distinct for both fingers and directions, which is similar to what was found for muscular activity patterns. The discrepancy between fMRI and electrophysiological measurements can be explained by two (non-mutually exclusive) characteristics of the organization of finger flexion and extension movements. Given that fMRI reflects predominantly input and recurrent activity, the results can be explained by an architecture in which neural populations that control flexion or extension of the same finger produce distinct outputs, but interact tightly with each other and receive similar inputs. Additionally, neurons tuned to different movement directions for the same finger (or combination of fingers) may cluster closely together, while neurons that control different finger combinations may be more spatially separated. When measuring this organization with fMRI at a coarse spatial scale, the activity patterns for flexion and extension of the same finger would appear very similar. Overall, we suggest that the discrepancy between fMRI and electrophysiological measurements provides new insights into the general organization of fine finger movements in M1. SIGNIFICANCE STATEMENT The primary motor cortex (M1) is important for producing individuated finger movements. Recent evidence shows that movements that commonly co-occur are associated with more similar activity patterns in M1. Flexion and extension of the same finger, which never co-occur, should therefore be associated with distinct representations. However, using carefully controlled experiments and multivariate analyses, we demonstrate that human fMRI activity patterns for flexion or extension of the same finger are highly similar. In contrast, spiking patterns measured in monkey M1 are clearly distinct. This suggests that populations controlling opposite movements of the same finger, while producing distinct outputs, may cluster together and share inputs and local processing. These results provide testable hypotheses about the organization of hand control in M1.

Structure of Population Activity in Primary Motor Cortex for Single Finger Flexion and Extension

Decision letter: Movement initiation and grasp representation in premotor and primary motor cortex mirror neurons

Many motor skills are learned with the help of instructions. In the context of complex motor sequences, instructions often break down the movement into chunks which can then be practiced in isolation. Thus, instructions shape an initial cognitive representation of the skill, which in turn guides practice. Are there ways of breaking up a motor sequence that are better than others? If participants are instructed in a way that hinders performance, how much practice does it take to overcome the influence of the instruction? To answer these questions, we used a paradigm in which participants were asked to perform finger sequences as fast and accurately as possible on a keyboard-like device. In the initial phases of training, participants had to explicitly remember and practice 2-or 3-digit chunks. These chunks were then combined to form seven 11-digit sequences that participants practiced for the remainder of the study. Each sequence was broken up into chunks in a way that was either aligned or misaligned with the basic execution-level constraints. We found that misaligned chunk instruction led to an initial performance deficit compared to aligned instruction. Overall, instructions still influenced the temporal pattern of performance after 10 days of subsequent training, with shorter inter-press-intervals within a chunk compared to between chunks. However, for the misaligned instructed sequences, this temporal pattern was altered more rapidly, such that participants could overcome the induced performance deficit in the last week. In the end of training, participants found idiosyncratic, but inter-individually stable ways of performing each sequence.

Beyond being essential for long-term motor-skill development, movement repetition has immediate benefits on performance, increasing speed and accuracy of a second execution. While repetition effects have been reported for single reaching movements, it has yet to be determined whether they also occur for movement sequences, and what aspects of sequence production are improved. We addressed these questions in two behavioral experiments using a discrete sequence production (DSP) task in which human volunteers had to perform short sequences of finger movements. In Experiment 1, we presented participants with randomly varying sequences and manipulated 1) whether the same sequence was repeated on successive trials, and 2) whether participants had to execute the sequence (Go), or not (No-Go). We establish that sequence repetition led to immediate improvements in speed without associated accuracy costs. The largest benefit was observed in the middle part of a sequence, suggesting that sequence repetition facilitated online planning. This claim was further supported by Experiment 2, in which we kept a set of sequences fixed throughout the experiment, thus allowing participants to develop sequence-specific learning: once the need for online planning decreased, the benefit of repetition disappeared. Finally, we found that repetition-related improvements only occurred for the trials that had been preceded by sequence production, suggesting that action selection and sequence pre-planning may not be sufficient to reap the benefits of repetition. Together, these results show that repetition can enhance representations at the level of movement sequences (rather than of individual movements) and facilitate online planning.

Repetita iuvant: repetition facilitates online planning of sequential movements.

Functional boundaries in the human cerebellum revealed by a multi-domain task battery

Reply: Further evidence for a non-cortical origin of mirror movements after stroke.

Hand and finger movements are mostly controlled through crossed corticospinal projections from the contralateral hemisphere. During unimanual movements, activity in the contralateral hemisphere is increased while the ipsilateral hemisphere is suppressed below resting baseline. Despite this suppression, unimanual movements can be decoded from ipsilateral activity alone. This indicates that ipsilateral activity patterns represent parameters of ongoing movement, but the origin and functional relevance of these representations is unclear. In this study, we asked whether ipsilateral representations are caused by active movement or whether they are driven by sensory input. Participants alternated between performing single finger presses and having fingers passively stimulated while we recorded brain activity using high-field (7T) functional imaging. We contrasted active and passive finger representations in sensorimotor areas of ipsilateral and contralateral hemispheres. Finger representations in the contralateral hemisphere were equally strong under passive and active conditions, highlighting the importance of sensory information in feedback control. In contrast, ipsilateral finger representations in the sensorimotor cortex were stronger during active presses. Furthermore, the spatial distribution of finger representations differed between hemispheres: the contralateral hemisphere showed the strongest finger representations in Brodmann areas 3a and 3b, whereas the ipsilateral hemisphere exhibited stronger representations in premotor and parietal areas. Altogether, our results suggest that finger representations in the two hemispheres have different origins: contralateral representations are driven by both active movement and sensory stimulation, whereas ipsilateral representations are mainly engaged during active movement. NEW & NOTEWORTHY Movements of the human body are mostly controlled by contralateral cortical regions. The function of ipsilateral activity during movements remains elusive. Using high-field neuroimaging, we investigated how human contralateral and ipsilateral hemispheres represent active and passive finger presses. We found that representations in contralateral sensorimotor cortex are equally strong during both conditions. Ipsilateral representations were mostly present during active movement, suggesting that sensorimotor areas do not receive direct sensory input from the ipsilateral hand.

Ipsilateral finger representations in the sensorimotor cortex are driven by active movement processes, not passive sensory input.

Decision letter: Motor cortex signals for each arm are mixed across hemispheres and neurons yet partitioned within the population response

Sign and Speech Share Partially Overlapping Conceptual Representations

The ability to perform complex sequences of movements quickly and accurately is critical for many motor skills. While training improves performance in a large variety of motor-sequence tasks, the precise mechanisms behind such improvements are poorly understood. Here we investigated the contribution of single-action selection, sequence pre-planning, online planning, and motor execution to performance in a discrete sequence production (DSP) task. Five visually-presented numbers cued a sequence of five finger presses, which had to be executed as quickly and accurately as possible. To study how sequence planning influenced sequence production, we manipulated the amount of time that participants were given to prepare each sequence by using a forced-response paradigm. Over 4 days, participants were trained on 10 sequences and tested on 80 novel sequences. Our results revealed that participants became faster in selecting individual finger presses. They also preplanned 3-4 sequence items into the future, and the speed of pre-planning improved for trained, but not for untrained, sequences. Because pre-planning capacity remained limited, the remaining sequence elements had to be planned online during sequence execution, a process that also improved with sequence-specific training. Overall, our results support the view that motor sequence learning effects are best characterized by improvements in planning processes that occur both before and concurrently with motor execution. New & Noteworthy Complex skills often require the production of sequential movements. While practice improves performance, it remains unclear how these improvements are achieved. Our findings show that learning effects in a sequence production task can be attributed to an enhanced ability to plan upcoming movements. These results shed new light on planning processes in the context of movement sequences, and have important implications for our understanding of the neural mechanisms that underlie skill acquisition.

The ability to perform complex sequences of movements quickly and accurately is critical for many motor skills. Although training improves performance in a large variety of motor sequence tasks, the precise mechanisms behind such improvements are poorly understood. Here we investigated the contribution of single-action selection, sequence preplanning, online planning, and motor execution to performance in a discrete sequence production task. Five visually presented numbers cued a sequence of five finger presses, which had to be executed as quickly and accurately as possible. To study how sequence planning influenced sequence production, we manipulated the amount of time that participants were given to prepare each sequence by using a forced-response paradigm. Over 4 days, participants were trained on 10 sequences and tested on 80 novel sequences. Our results revealed that participants became faster in selecting individual finger presses. They also preplanned three or four sequence items into the future, and the speed of preplanning improved for trained, but not for untrained, sequences. Because preplanning capacity remained limited, the remaining sequence elements had to be planned online during sequence execution, a process that also improved with sequence-specific training. Overall, our results support the view that motor sequence learning effects are best characterized by improvements in planning processes that occur both before and concurrently with motor execution. NEW & NOTEWORTHY Complex skills often require the production of sequential movements. Although practice improves performance, it remains unclear how these improvements are achieved. Our findings show that learning effects in a sequence production task can be attributed to an enhanced ability to plan upcoming movements. These results shed new light on planning processes in the context of movement sequences and have important implications for our understanding of the neural mechanisms that underlie skill acquisition.

A key question in neuroscience is how cortical organisation relates to experience. Previously we showed that amputees experiencing highly vivid phantom sensations maintain cortical representation of their missing hand (Kikkert et al., 2016). Here, we examined the role of sensory hand experience on persistent hand representation by studying individuals with acquired and congenital hand loss. We used representational similarity analysis in primary somatosensory and motor cortex during missing and intact hand movements. We found that key aspects of acquired amputees’ missing hand representation persisted, despite varying vividness of phantom sensations. In contrast, missing hand representation of congenital one-handers, who do not experience phantom sensations, was significantly reduced. Across acquired amputees, individuals’ reported motor control over their phantom hand positively correlated with the extent to which their somatosensory hand representation was normally organised. We conclude that once cortical organisation is formed, it is remarkably persistent, despite long-term attenuation of peripheral signals.

Obtaining and maintaining cortical hand representation as evidenced from acquired and congenital handlessness

Patients with chronic stroke have been shown to have failure to release interhemispheric inhibition (IHI) from the intact to the damaged hemisphere before movement execution (premovement IHI). This inhibitory imbalance was found to correlate with poor motor performance in the chronic stage after stroke and has since become a target for therapeutic interventions. The logic of this approach, however, implies that abnormal premovement IHI is causal to poor behavioral outcome and should therefore be present early after stroke when motor impairment is at its worst. To test this idea, in a longitudinal study, we investigated interhemispheric interactions by tracking patients’ premovement IHI for one year following stroke.

Rethinking interhemispheric imbalance as a target for stroke neurorehabilitation

Universal Transform or Multiple Functionality? Understanding the Contribution of the Human Cerebellum across Task Domains

Humans have the remarkable ability to hold, grasp, and manipulate objects. Previous work has reported rapid and coordinated reactions in hand and shoulder muscles in response to external perturbations to the arm during object manipulation; however, little is known about how somatosensory feedback of an object slipping in the hand influences responses of the arm. We built a hand-held device to stimulate the sensation of slipping at all five fingertips. The device was integrated into an exoskeleton robot that supported it against gravity. The setup allowed us to decouple somatosensory stimulation in the fingers from forces applied to the arm— two variables that are highly interdependent in real-world scenarios. Fourteen participants performed three experiments in which we measured their arm feedback responses during slip stimulation. Slip stimulations were applied horizontally, in one of two directions, and participants were either instructed to follow the slip direction, or to move the arm in the opposite direction. Participants showed responses within ∼67 ms of slip onset when following the direction of slip, but significantly slower responses when instructed to move in the opposite direction. Arm responses were modulated by the speed but not the distance of the slip. Finally, when slip stimulation was combined with mechanical perturbations to the arm, we found that sensory information from the fingertips significantly modulated the shoulder feedback response. Overall, the results demonstrate the existence of a rapid feedback system that stabilizes hand-held objects. NEW & NOTHEWORTHY We tested whether the sensation of an object slipping from the fingers modulates shoulder feedback responses. We found rapid shoulder feedback responses when participants were instructed to follow the slip direction with the arm. Shoulder responses following mechanical joint perturbations were also potentiated when combined with slipping. These results demonstrate the existence of fast and automatic feedback responses in the arm in reaction to sensory input to the fingertips that maintain grip on hand-held objects.

Sensory information from a slipping object elicits a rapid and automatic shoulder response

Neural Organization of Hie rarchical Motor Sequence Representations in the Human Neocortex Highlights

1 Brain and Mind Institute, Western University, London, Canada 2 Department of Neurology and Neurosciences, Johns Hopkins University, Baltimore, MD, USA 3 Department of Neurology, University of Zurich, Zurich, Switzerland 4 Department of Physical Medicine and Rehabilitation, Johns Hopkins University, Baltimore, MD, USA 5 Department of Neurology, New York University, NY, USA 6 Cereneo Center for Neurology and Rehabilitation, Vitznau, Switzerland 7 Department of Radiology, Johns Hopkins University, Baltimore, MD, USA

Cortical beta oscillations are associated with motor performance following visuomotor learning

The brain's function is to enable adaptive behavior in the world. To this end, the brain processes information about the world. The concept of representation links the information processed by the brain back to the world and enables us to understand what the brain does at a functional level. The appeal of making the connection between brain activity and what it represents has been irresistible to neuroscience, despite the fact that representational interpretations pose several challenges: We must define which aspects of brain activity matter, how the code works, and how it supports computations that contribute to adaptive behavior. It has been suggested that we might drop representational language altogether and seek to understand the brain, more simply, as a dynamical system. In this review, we argue that the concept of representation provides a useful link between dynamics and computational function and ask which aspects of brain activity should be analyzed to achieve a representational understanding. We peel the onion of brain representations in search of the layers (the aspects of brain activity) that matter to computation. The article provides an introduction to the motivation and mathematics of representational models, a critical discussion of their assumptions and limitations, and a preview of future directions in this area.

Do different languages evoke different conceptual representations? If so, greatest divergence might be expected between languages that differ most in structure, such as sign and speech. Unlike speech bilinguals, hearing sign-speech bilinguals use languages conveyed in different modalities. We used functional magnetic resonance imaging and representational similarity analysis (RSA) to quantify the similarity of semantic representations elicited by the same concepts presented in spoken British English and British Sign Language in hearing, early sign-speech bilinguals. We found shared representations for semantic categories in left posterior middle and inferior temporal cortex. Despite shared category representations, the same spoken words and signs did not elicit similar neural patterns. Thus, contrary to previous univariate activation-based analyses of speech and sign perception, we show that semantic representations evoked by speech and sign are only partially shared. This demonstrates the unique perspective that sign languages and RSA provide in understanding how language influences conceptual representation.

Evidence for shared conceptual representations for sign and speech

Cortical reorganization has been suggested as mechanism for recovery after stroke. It has been proposed that a form of cortical reorganization (changes in functional connectivity between brain areas) can be assessed with resting-state fMRI. Here we report the largest longitudinal data-set in terms of overall sessions in 19 patients with subcortical stroke and 11 controls. Patients were imaged up to 5 times over one year. We found no evidence for post-stroke cortical reorganization despite substantial behavioral recovery. These results could be construed as questioning the value of resting-state imaging. Here we argue instead that they are consistent with other emerging reasons to challenge the idea of motor recovery-related cortical reorganization post-stroke when conceived as changes in connectivity between cortical areas.

No evidence for motor recovery-related cortical reorganization after stroke using resting-state fMRI

Neural Organization of Hierarchical Motor Sequence Representations in the Human Neocortex

We investigated motor skill learning using a path tracking task, where human subjects had to track various curved paths at a constant speed while maintaining the cursor within the path width. Subjects’ accuracy increased with practice, even when tracking novel untrained paths. Using a “searchlight” paradigm, where only a short segment of the path ahead of the cursor was shown, we found that subjects with a higher tracking skill differed from the novice subjects in two respects. First, they had lower motor variability, in agreement with previous findings. Second, they took a longer section of the future path into account when performing the task, i.e. had a longer planning horizon. We estimate that between one third and one half of the performance increase was due to the increase in planning horizon. An optimal control model with a fixed horizon (receding horizon control) that increases with tracking skill quantitatively captured the subjects’ movement behaviour. These findings demonstrate that human subjects not only increase their motor acuity but also their planning horizon when acquiring a motor skill. New and Noteworthy We show that when learning a motor skill humans are using information about the environment from an increasingly longer amount of the movement path ahead to improve performance. Crucial features of the behavioural performance can be captured by modelling the behavioural data with a receding horizon optimal control model.

Motor skill learning decreases motor variability and increases planning horizon

Human primary motor cortex (M1) is essential for producing dexterous hand movements. Although distinct subpopulations of neurons are activated during single-finger movements, it remains unknown whether M1 also represents sequences of multiple finger movements. Using novel multivariate functional magnetic resonance imaging (fMRI) analysis techniques and combining evidence from both 3T and 7T fMRI data, we found that after 5 d of intense practice, premotor and parietal areas encoded the different movement sequences. There was little or no evidence for a sequence representation in M1. Instead, activity patterns in M1 could be fully explained by a linear combination of patterns for the constituent individual finger movements, with the strongest weight on the first finger of the sequence. Using passive replay of sequences, we show that this first-finger effect is due to neuronal processes involved in the active execution, rather than to a hemodynamic nonlinearity. These results suggest that M1 receives increased input from areas with sequence representations at the initiation of a sequence, but that M1 activity itself relates to the execution of component finger presses only. These results improve our understanding of the representation of finger sequences in the human neocortex after short-term training and provide important methodological advances for the study of long-term skill development. SIGNIFICANCE STATEMENT There is clear evidence that human primary motor cortex (M1) is essential for producing individuated finger movements, such as pressing a button. Over and above its involvement in movement execution, it is less clear whether M1 also plays a role in learning and controlling sequences of multiple finger movements, such as when playing the piano. Using cutting-edge multivariate fMRI analysis and carefully controlled experiments, we demonstrate here that, while premotor areas clearly show a sequence representation, activity patterns in M1 can be fully explained from the patterns for individual finger movements. The results provide important new insights into the interplay of M1 and premotor cortex for learning of sequential movements.

The Role of Human Primary Motor Cortex in the Production of Skilled Finger Sequences

Many complex behaviors consist of sequentially ordered actions. When acquiring a novel sequential skill, the transition between actions can be performed with increasing speed. This observation has led to the idea that the elementary actions are bound together during the learning process. Two ideas for this process have been proposed: First, statistical probabilities between different elementary actions could be acquired. Secondly, discrete groupings of elementary actions – so-called chunks could emerge with learning. We discuss the differences between these two ideas and compare the ability of the two models to predict inter-press time intervals (IPIs) measured by a discrete sequence production task. We find a greater ability of the chunk model to predict participants’ IPIs throughout learning.

Evidence for chunking vs. statistical learning in motor sequence production

Repetition suppression (RS) provides an important tool to investigate brain representations. Repetition of the same stimulus evokes a reduction in elicited brain activity. While the reduction in activity is consistently observed across modalities and species, it is unclear what mechanisms drive this effect. Several models of RS have been proposed, which vary in their prediction of stimulus ‘tuning’ in the second repetition. Here we examined RS mechanisms in two motor cortical areas and the striatum while participants executed motoric finger sequences, twice in a row. We distinguished the RS models by investigating the changes in the sequence-dependent fMRI activity patterns in concert with the changes in overall activity. In the striatum, we observed that the tuning for individual sequences is ‘sharpened’ on the second execution, whereas in the cortex we found a ‘fatigued’ representation. This dissociation might indicate different computational roles along the cortico-striatal circuitry, with the striatum solving the selection problem, and signaling its novelty to the cortex.

Repetition Suppression during Movement Execution Reflects Different Mechanisms in the Striatum than in the Neocortex

Stability of representational geometry across a wide range of fMRI activity levels

Skill learning involves the formation of stable motor patterns. In musical and athletic training, however, the formation of bad habits can impede the attainment of high levels of performance. We developed a novel experimental paradigm to induce a specific motor habit in a sequence production task and investigated how it affected subsequent optimization over a 3-week training period. Participants initially practiced small segments of 2 to 3 finger movements, which were then combined to form longer sequences. This initial training induced a persistent chunking behavior, with shorter intervals between presses within a chunk and longer presses at chunk boundaries. By aligning these chunks with biomechanically easy or difficult transitions, we were able to induce chunking habits that were either beneficial or detrimental to performance. We found that participants overcame detrimental habits using two kinds of optimization processes. Failure to change detrimental chunk structures predicted lower levels of final performance.

Discovering how the human brain gives rise to intelligent behaviour, complex thought, creativity, and our 4 rich conscious experiences is one of the most daunting scientific challenges of our time. How do neurons 5 represent and process information? In trying to answer this question, an experimental approach inspired 6 by system identification (Marmarelis and Marmarelis, 1978) has been long dominant across many fields of 7 neuroscience. In this approach the researcher independently varies the stimuli presented to the nervous 8 system and repeatedly measures the activity of a neuron under these conditions. The collected responses 9 of the neuron are analyzed as a tuning function or activity profile across the experimental conditions. The 10 goal of the approach is then to discover the mapping between the stimulus characteristics and the neuronal 11 response. 12

Concentric radiofrequency arrays to increase the statistical power of resting-state maps in monkeys

Unique degeneration signatures in the cerebellar cortex for spinocerebellar ataxias 2, 3, and 7

As a sequence of movements is learned, serially ordered actions get bound together into sets to reduce computational complexity during planning and execution. Here, we investigated how actions become naturally bound over the course of learning and how this learning affects cortical representations of individual actions. Across 5 weeks of practice, neurologically healthy human subjects learned either a complex 32-item sequence of finger movements (trained group, n = 9; 3 female) or randomly ordered actions (control group, n = 9; 3 female). Over the course of practice, responses during sequence production in the trained group became temporally correlated, consistent with responses being bound together under a common command. These behavioral changes, however, did not coincide with plasticity in the multivariate representations of individual finger movements, assessed using fMRI, at any level of the cortical motor hierarchy. This suggests that the representations of individual actions remain stable, even as the execution of those same actions become bound together in the context of producing a well learned sequence. SIGNIFICANCE STATEMENT Extended practice on motor sequences results in highly stereotyped movement patterns that bind successive movements together. This binding is critical for skilled motor performance, yet it is not currently understood how it is achieved in the brain. We examined how binding altered the patterns of activity associated with individual movements that make up the sequence. We found that fine finger control during sequence production involved correlated activity throughout multiple motor regions; however, we found no evidence for plasticity of the representations of elementary movements. This suggests that binding is associated with plasticity at a more abstract level of the motor hierarchy.

Binding During Sequence Learning Does Not Alter Cortical Representations of Individual Actions

Author response: Obtaining and maintaining cortical hand representation as evidenced from acquired and congenital handlessness

Decision letter: Individuals physically interacting in a group rapidly coordinate their movement by estimating the collective goal

Following a stroke, mirror movements are unintended movements that appear in the non-paretic hand when the paretic hand voluntarily moves. Mirror movements have previously been linked to overactivation of sensorimotor areas in the non-lesioned hemisphere. In this study, we hypothesized that mirror movements might instead have a subcortical origin, and are the by-product of subcortical motor pathways upregulating their contributions to the paretic hand. To test this idea, we first characterized the time course of mirroring in 53 first-time stroke patients, and compared it to the time course of activities in sensorimotor areas of the lesioned and non-lesioned hemispheres (measured using functional MRI). Mirroring in the non-paretic hand was exaggerated early after stroke (Week 2), but progressively diminished over the year with a time course that parallelled individuation deficits in the paretic hand. We found no evidence of cortical overactivation that could explain the time course changes in behaviour, contrary to the cortical model of mirroring. Consistent with a subcortical origin of mirroring, we predicted that subcortical contributions should broadly recruit fingers in the non-paretic hand, reflecting the limited capacity of subcortical pathways in providing individuated finger control. We therefore characterized finger recruitment patterns in the non-paretic hand during mirroring. During mirroring, non-paretic fingers were broadly recruited, with mirrored forces in homologous fingers being only slightly larger (1.76 times) than those in non-homologous fingers. Throughout recovery, the pattern of finger recruitment during mirroring for patients looked like a scaled version of the corresponding control mirroring pattern, suggesting that the system that is responsible for mirroring in controls is upregulated after stroke. Together, our results suggest that post-stroke mirror movements in the non-paretic hand, like enslaved movements in the paretic hand, are caused by the upregulation of a bilaterally organized subcortical system.

Evidence for a subcortical origin of mirror movements after stroke: a longitudinal study

In this chapter, I discuss models that specify how neuronal population activity relates to things that happen in the world i.e., models of neuronal representations. Focussing on the application to functional magnetic resonance imaging (fMRI) data, I discuss current approaches to estimate and test such models. Encoding models conceptualize representations in terms of sets of underlying features. We show that these models ultimately test hypotheses about the distribution of activity profiles in the space of the experimental conditions, and that the exact choice of feature sets is to some degree arbitrary. Over-interpreting the significance of specific feature sets constitutes an intellectual dead-end, termed here “feature fallacy”. The same representational models can also be tested using a Bayesian approach, Pattern component modelling (PCM), which abstract from the underlying features and allows direct model evaluation. It also provides a powerful means to test more flexible representational models, including models that consist of combinations of different feature sets.

Copyright Hagura et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Abstract Perceptual decisions are classically thought to depend mainly on the stimulus characteristics, probability and associated reward. However, in many cases, the motor response is considered to be a neutral output channel that only reflects the upstream decision. Contrary to this view, we show that perceptual decisions can be recursively influenced by the physical resistance applied to the response. When participants reported the direction of the visual motion by left or right manual reaching movement with different resistances, their reports were biased towards the direction associated with less effortful option. Repeated exposure to such resistance on hand during perceptual judgements also biased subsequent judgements using voice, indicating that effector-dependent motor costs not only biases the report at the stage of motor response, but also changed how the sensory inputs are transformed into decisions. This demonstrates that the cost to act can influence our decisions beyond the context of the specific action.

Decoupling between the hand territory and the default mode network after bilateral arm transplantation: four-year follow-up case study

Pattern component modeling: A flexible approach for understanding the representational structure of brain activity patterns

[This corrects the article on p. 1228 in vol. 35, PMID: 25609637.].

Correction: Thürling et al., “Cerebellar Cortex and Cerebellar Nuclei Are Concomitantly Activated during Eyeblink Conditioning: A 7T fMRI Study in Humans”

Human primary motor cortex (M1) is an essential structure for the production of dexterous hand movements. While distinct sub-populations of neurons are activated during single finger movements, it remains unknown whether M1 also represents sequences of multiple finger movements. Using novel multivariate fMRI analysis techniques, we show here that even after 5 days of intense practice there was little or no evidence for a true sequence representation in M1. Rather, the activity patterns for sequences in M1 could be explained by linear combination of patterns associated with the constituent individual finger movements, with the strongest weight on the finger making the first response of the sequence. These results suggest that M1 only represents single finger movements, but receives increased input at the start of a sequence. In contrast, the reliable differences between different sequences in premotor and parietal areas could not be explained by a strong weighting of the first finger, supporting the view that these regions exhibit a true representation of sequences.

Does human primary motor cortex represent sequences of finger movements?

Reaching movements are comprised of the coordinated action across multiple joints. The human skeleton is redundant for this task because different joint configurations can lead to the same endpoint in space. How do people learn to use combinations of joints that maximize success in goal-directed motor tasks? To answer this question, we used a 3-degree-of-freedom manipulandum to measure shoulder, elbow and wrist joint movements during reaching in a plane. We tested whether a shift in the relative contribution of the wrist and elbow joints to a reaching movement could be learned by an implicit reinforcement regime. Unknown to the participants, we decreased the task success for certain joint configurations (wrist flexion or extension, respectively) by adding random variability to the endpoint feedback. In return, the opposite wrist postures were rewarded in the two experimental groups (flexion and extension group). We found that the joint configuration slowly shifted towards movements that provided more control over the endpoint and hence higher task success. While the overall learning was significant, only the group that was guided to extend the wrist joint more during the movement showed substantial learning. Importantly, all changes in movement pattern occurred independent of conscious awareness of the experimental manipulation. These findings suggest that the motor system is generally sensitive to its output variability and can optimize joint-space solutions that minimize task-relevant output variability. We discuss biomechanical biases (e.g. joint’s range of movement) that could impose hurdles to the learning process.

Minimizing endpoint variability through reinforcement learning during reaching movements involving shoulder, elbow and wrist

Background. Recovery from stroke is often said to have “plateaued” after 6 to 12 months. Yet training can still improve performance even in the chronic phase. Here we investigate the biomechanics of accuracy improvements during a reaching task and test whether they are affected by the speed at which movements are practiced. Method. We trained 36 chronic stroke survivors (57.5 years, SD ± 11.5; 10 females) over 4 consecutive days to improve endpoint accuracy in an arm-reaching task (420 repetitions/day). Half of the group trained using fast movements and the other half slow movements. The trunk was constrained allowing only shoulder and elbow movement for task performance. Results. Before training, movements were variable, tended to undershoot the target, and terminated in contralateral workspace (flexion bias). Both groups improved movement accuracy by reducing trial-to-trial variability; however, change in endpoint bias (systematic error) was not significant. Improvements were greatest at the trained movement speed and generalized to other speeds in the fast training group. Small but significant improvements were observed in clinical measures in the fast training group. Conclusions. The reduction in trial-to-trial variability without an alteration to endpoint bias suggests that improvements are achieved by better control over motor commands within the existing repertoire. Thus, 4 days’ training allows stroke survivors to improve movements that they can already make. Whether new movement patterns can be acquired in the chronic phase will need to be tested in longer term studies. We recommend that training needs to be performed at slow and fast movement speeds to enhance generalization.

Chronic Stroke Survivors Improve Reaching Accuracy by Reducing Movement Variability at the Trained Movement Speed

Representational models specify how activity patterns in populations of neurons (or, more generally, in multivariate brain-activity measurements) relate to sensory stimuli, motor responses, or cognitive processes. In an experimental context, representational models can be defined as hypotheses about the distribution of activity profiles across experimental conditions. Previous studies have used three different methods to test such hypotheses: encoding analysis, pattern component modeling (PCM), and representational similarity analysis (RSA). Here we develop a common mathematical framework for understanding the relationship of these three methods, which all share one core commonality: all three evaluate the second moment of the distribution of activity profiles, which determines how well any feature can be linearly decoded from population activity. Using simulated data for three different experimental designs, we compare the power of the methods to adjudicate between competing representational models. PCM implements a likelihood-ratio test and therefore provides the most powerful test if its assumptions hold. However, the other two approaches – when conducted appropriately – can perform similarly. In encoding analysis, the linear model needs to be appropriately regularized, which effectively imposes a prior on the activity profiles. With such a prior, an encoding model specifies a well-defined distribution of activity profiles. In RSA, the unequal variances and statistical dependencies of the dissimilarity estimates need to be taken into account to enable near-optimal inference. The three methods render different aspects of the information explicit (e.g. single-response tuning in encoding analysis and population-response representational dissimilarity in RSA) and have specific advantages in terms of computational demands, ease of use, and extensibility. The three methods are properly construed as complementary components of a comprehensive data-analytical toolkit for understanding neural representations on the basis of multivariate brain-activity data. Author Summary Modern neuroscience can measure activity of many neurons or the local blood oxygenation of many brain locations simultaneously. As the number of simultaneous measurements grows, we can better investigate how the brain represents and transforms information, to enable perception, cognition, and behavior. Recent studies go beyond showing that a brain region is involved in some function. They use representational models that specify how different perceptions, cognitions, and actions are encoded in brain-activity patterns. In this paper. we provide a general mathematical framework for such representational models, which clarifies the relationships between three different methods that are currently used in the neuroscience community. All three methods evaluate the same core feature of the data, but each has distinct advantages and disadvantages. Pattern component modelling (PCM) implements the most powerful test between models, and is analytically tractable and expandable. Representational similarity analysis (RSA) provides a highly useful summary statistic (the dissimilarity) and enables model comparison with weaker distributional assumptions. Finally, encoding models characterize individual responses and enable the study of their layout across cortex. We argue that these methods should be considered components of a larger toolkit for testing hypotheses about the way the brain represents information.

Representational models: A common framework for understanding encoding, pattern-component, and representational-similarity analysis

Perceptual decisions are classically thought to depend mainly on the stimulus characteristics, probability and associated reward. However, in many cases, the motor response is considered to be a neutral output channel that only reflects the upstream decision. Contrary to this view, we show that perceptual decisions can be recursively influenced by the physical resistance applied to the response. When participants reported the direction of the visual motion by left or right manual reaching movement with different resistances, their reports were biased towards the direction associated with less effortful option. Repeated exposure to such resistance on hand during perceptual judgements also biased subsequent judgements using voice, indicating that effector-dependent motor costs not only biases the report at the stage of motor response, but also changed how the sensory inputs are transformed into decisions. This demonstrates that the cost to act can influence our decisions beyond the context of the specific action. DOI: http://dx.doi.org/10.7554/eLife.18422.001

When training bimanual skills, such as playing piano, people sometimes practice each hand separately and at a later stage combine the movements of the two hands. This poses the critical question of whether motor skills can be acquired by separately practicing each subcomponent or should be trained as a whole. In the present study, we addressed this question by training human subjects for 4 days in a unimanual or bimanual version of the discrete sequence production task. Both groups were then tested on trained and untrained sequences on both unimanual and bimanual versions of the task. Surprisingly, we found no evidence of transfer from trained unimanual to bimanual or from trained bimanual to unimanual sequences. In half the participants, we also investigated whether cuing the sequences on the left and right hand with unique letters would change transfer. With these cues, untrained sequences that shared some components with the trained sequences were performed more quickly than sequences that did not. However, the amount of this transfer was limited to ∼10% of the overall sequence-specific learning gains. These results suggest that unimanual and bimanual sequences are learned in separate representations. Making participants aware of the interrelationship between sequences can induce some transferrable component, although the main component of the skill remains unique to unimanual or bimanual execution.NEW & NOTEWORTHY Studies in reaching movement demonstrated that approximately half of motor learning can transfer across unimanual and bimanual contexts, suggesting that neural representations for unimanual and bimanual movements are fairly overlapping at the level of elementary movement. In this study, we show that little or no transfer occurred across unimanual and bimanual sequential finger movements. This result suggests that bimanual sequences are represented at a level of the motor hierarchy that integrates movements of both hands.

Restricted transfer of learning between unimanual and bimanual finger sequences.

Accumulating behavioural and neurophysiological evidence suggests that upper-limb control relies on contributions from both cortical and subcortical motor circuits, with cortical inputs providing fine-finger function and subcortical inputs providing the ability for gross movements, respectively. During recovery of function after stroke, the relative contributions from these pathways may shift. Here we propose that mirror movements that appear after stroke provide a non-invasive assay through which relative contributions from cortical and subcortical pathways towards hand recovery can be studied. We hypothesized that mirror movements, like hand function, are generated by summed contributions from cortical and subcortical pathways, and suggest that subcortical contributions should be characterized by a broad recruitment of fingers, while cortical contributions primarily recruit the homologous finger in the passive hand. In a longitudinal stroke recovery study (Xu et al., 2016), we quantified mirror movements and paretic hand function in 53 stroke patients in the year following unilateral stroke. Mirror movements in the non-paretic hand were exaggerated early after damage (week 2), with paretic finger presses broadly recruiting multiple fingers in the non-paretic hand. On average, however, mirroring in homologous fingers was 1.76 times larger than in non-homologous fingers. Over the year, mirroring in the non-paretic hand progressively normalized with a time-course that mimicked that for the fine-finger deficits in the paretic hand. In comparison, during non-paretic finger presses, the homologous component of mirroring in the paretic hand was reduced early after stroke (week 2) but progressively normalized. Altogether, we conclude that the pattern of mirror movements across homologous and non-homologous fingers reflect the summed contributions of both cortical and subcortical systems, and we discuss the implications of our results towards hand recovery after stroke.

Finger recruitment patterns during mirror movements suggest two systems for hand recovery after stroke

Classical delay eyeblink conditioning is likely the most commonly used paradigm to study cerebellar learning. As yet, few studies have focused on extinction and savings of conditioned eyeblink responses (CRs). Saving effects, which are reflected in a reacquisition after extinction that is faster than the initial acquisition, suggest that learned associations are at least partly preserved during extinction. In this study, we tested the hypothesis that acquisition‐related plasticity is nihilated during extinction in the cerebellar cortex, but retained in the cerebellar nuclei, allowing for faster reacquisition. Changes of 7 T functional magnetic resonance imaging (fMRI) signals were investigated in the cerebellar cortex and nuclei of young and healthy human subjects. Main effects of acquisition, extinction, and reacquisition against rest were calculated in conditioned stimulus‐only trials. First‐level β values were determined for a spherical region of interest (ROI) around the acquisition peak voxel in lobule VI, and dentate and interposed nuclei ipsilateral to the unconditioned stimulus. In the cerebellar cortex and nuclei, fMRI signals were significantly lower in extinction compared to acquisition and reacquisition, but not significantly different between acquisition and reacquisition. These findings are consistent with the theory of bidirectional learning in both the cerebellar cortex and nuclei. It cannot explain, however, why conditioned responses reappear almost immediately in reacquisition following extinction. Although the present data do not exclude that part of the initial memory remains in the cerebellum in extinction, future studies should also explore changes in extracerebellar regions as a potential substrate of saving effects. Hum Brain Mapp 38:3957–3974, 2017. © 2017 Wiley Periodicals, Inc.

Modulation of 7 T fMRI Signal in the Cerebellar Cortex and Nuclei During Acquisition, Extinction, and Reacquisition of Conditioned Eyeblink Responses

justed life gained as a result of thrombolytic therapy for acute ischemic stroke. Stroke 2010; 41: 471–77. Kakuda W, Lansberg MG, Thijs VN, Kemp SM, Bammer R, Wechsler LR, et al. DEFUSE Investigators. Optimal definition for PWI/DWI mismatch in acute ischemic stroke patients. J Cereb Blood Flow Metab 2008; 28: 887–91. Kawano H, Bivard A, Lin L, Ma H, Cheng X, Aviv R, et al. Perfusion computed tomography in patients with stroke thrombolysis. Brain 2017; 140: 684–91. McFarquhar G. Raindrop size distribution and evolution. In: Testik FY, Gebremichael M, eds. Rainfall: State of the Science. Geophys Monogr Ser 2010; 191; 49–60. Meretoja A, Keshtkaran M, Saver JL, Tatlisumak T, Parsons MW, Kaste M, et al. Stroke thrombolysis: save a minute, save a day. Stroke 2014; 45: 1053–8.

Impaired hand function after stroke is a major cause of long-term disability. We developed a novel paradigm that quantifies two critical aspects of hand function, strength, and independent control of fingers (individuation), and also removes any obligatory dependence between them. Hand recovery was tracked in 54 patients with hemiparesis over the first year after stroke. Most recovery of strength and individuation occurred within the first 3 mo. A novel time-invariant recovery function was identified: recovery of strength and individuation were tightly correlated up to a strength level of ~60% of estimated premorbid strength; beyond this threshold, strength improvement was not accompanied by further improvement in individuation. Any additional improvement in individuation was attributable instead to a second process that superimposed on the recovery function. We conclude that two separate systems are responsible for poststroke hand recovery: one contributes almost all of strength and some individuation; the other contributes additional individuation.NEW & NOTEWORTHY We tracked recovery of the hand over a 1-yr period after stroke in a large cohort of patients, using a novel paradigm that enabled independent measurement of finger strength and control. Most recovery of strength and control occurs in the first 3 mo after stroke. We found that two separable systems are responsible for motor recovery of hand: one contributes strength and some dexterity, whereas a second contributes additional dexterity.

Separable systems for recovery of finger strength and control after stroke.

Author response: Perceptual decisions are biased by the cost to act

Loss of hand function after stroke is a major cause of long-term disability. Hand function can be partitioned into strength and independent control of fingers (individuation). Here we developed a novel paradigm, which independently quantifies these two aspects of hand function, to track hand recovery in 54 patients with hemiparesis over the first year after their stroke. Most recovery of both strength and individuation occurred in the first three months after stroke. Improvement in strength and individuation were tightly correlated up to a strength level of approximately 60% of the unaffected side. Beyond this threshold, further gains in strength were not accompanied by improvements in individuation. Any observed improvements in individuation beyond the 60% threshold were attributable instead to a second independent stable factor. Lesion analysis revealed that damage to the hand area in motor cortex and the corticospinal tract (CST) correlated more with individuation than with strength. CST involvement correlated with individuation even after factoring out the strength-individuation correlation. The most parsimonious explanation for these behavioral and lesion-based findings is that most strength recovery, along with some individuation, can be attributed to descending systems other than the CST, whereas further recovery of individuation is CST dependent.

Recovery of hand function after stroke: separable systems for finger strength and control

Reliability of dissimilarity measures for multi-voxel pattern analysis

We present analytical expressions for the means and covariances of the sample distribution of the cross-validated Mahalanobis distance. This measure has proven to be especially useful in the context of representational similarity analysis (RSA) of neural activity patterns as measured by means of functional magnetic resonance imaging (fMRI). These expressions allow us to construct a normal approximation to the estimated distances, which in turn enables powerful inference on the measured statistics. Using the results, the difference between two distances can be statistically assessed, and the measured structure of the distances can be efficiently compared to predictions from computational models.

What is the role of ipsilateral motor and premotor areas in motor learning? One view is that ipsilateral activity suppresses contralateral motor cortex and, accordingly, that inhibiting ipsilateral regions can improve motor learning. Alternatively, the ipsilateral motor cortex may play an active role in the control and/or learning of unilateral hand movements. We approached this question by applying double-blind bihemispheric transcranial direct current stimulation (tDCS) over both contralateral and ipsilateral motor cortex in a between-group design during 4 d of unimanual explicit sequence training in human participants. Independently of whether the anode was placed over contralateral or ipsilateral motor cortex, bihemispheric stimulation yielded substantial performance gains relative to unihemispheric or sham stimulation. This performance advantage appeared to be supported by plastic changes in both hemispheres. First, we found that behavioral advantages generalized strongly to the untrained hand, suggesting that tDCS strengthened effector-independent representations. Second, functional imaging during speed-matched execution of trained sequences conducted 48 h after training revealed sustained, polarity-independent increases in activity in both motor cortices relative to the sham group. These results suggest a cooperative rather than competitive interaction of the two motor cortices during skill learning and suggest that bihemispheric brain stimulation during unimanual skill learning may be beneficial because it harnesses plasticity in the ipsilateral hemisphere. SIGNIFICANCE STATEMENT Many neurorehabilitation approaches are based on the idea that is beneficial to boost excitability in the contralateral hemisphere while attenuating that of the ipsilateral cortex to reduce interhemispheric inhibition. We observed that bihemispheric transcranial direct current stimulation (tDCS) with the excitatory anode either over contralateral or ipsilateral motor cortex facilitated motor learning nearly twice as strongly as unihemispheric tDCS. These increases in motor learning were accompanied by increases in fMRI activation in both motor cortices that outlasted the stimulation period, as well as increased generalization to the untrained hand. Collectively, our findings suggest a cooperative rather than a competitive role of the hemispheres and imply that it is most beneficial to harness plasticity in both hemispheres in neurorehabilitation of motor deficits.

Cooperation Not Competition: Bihemispheric tDCS and fMRI Show Role for Ipsilateral Hemisphere in Motor Learning

High-resolution functional imaging is providing increasingly rich measurements of brain activity in animals and humans. A major challenge is to leverage such data to gain insight into the brain's computational mechanisms. The first step is to define candidate brain-computational models (BCMs) that can perform the behavioural task in question. We would then like to infer which of the candidate BCMs best accounts for measured brain-activity data. Here we describe a method that complements each BCM by a measurement model (MM), which simulates the way the brain-activity measurements reflect neuronal activity (e.g. local averaging in functional magnetic resonance imaging (fMRI) voxels or sparse sampling in array recordings). The resulting generative model (BCM-MM) produces simulated measurements. To avoid having to fit the MM to predict each individual measurement channel of the brain-activity data, we compare the measured and predicted data at the level of summary statistics. We describe a novel particular implementation of this approach, called probabilistic representational similarity analysis (pRSA) with MMs, which uses representational dissimilarity matrices (RDMs) as the summary statistics. We validate this method by simulations of fMRI measurements (locally averaging voxels) based on a deep convolutional neural network for visual object recognition. Results indicate that the way the measurements sample the activity patterns strongly affects the apparent representational dissimilarities. However, modelling of the measurement process can account for these effects, and different BCMs remain distinguishable even under substantial noise. The pRSA method enables us to perform Bayesian inference on the set of BCMs and to recognize the data-generating model in each case. This article is part of the themed issue ‘Interpreting BOLD: a dialogue between cognitive and cellular neuroscience’.

Philosophical Transactions of the Royal Society B: Biological Sciences

Inferring brain-computational mechanisms with models of activity measurements

Goal-directed reaching movements are guided by visual feedback from both target and hand. The classical view is that the brain extracts information about target and hand positions from a visual scene, calculates a difference vector between them, and uses this estimate to control the movement. Here we show that during fast feedback control, this computation is not immediate, but evolves dynamically over time. Immediately after a change in the visual scene, the motor system generates independent responses to the errors in hand and target location. Only about 200 ms later, the changes in target and hand positions are combined appropriately in the response, slowly converging to the true difference vector. Therefore, our results provide evidence for the temporal evolution of spatial computations in the human visuomotor system, in which the accurate difference vector computation is first estimated by a fast approximation. SIGNIFICANCE STATEMENT The dominant view regarding the neural control of reaching is that the visuomotor system controls movement based on the difference vector—the difference between the positions of the hand and target. We directly test this theory by measuring the responses to visual perturbations over a large range of possible variations in both target and hand displacements. By modeling the nonlinearity of the feedback response, we were able to reveal the temporal evolution of the underlying computations. The visuomotor system first uses an approximation to the difference vector computation, simply combining the nonlinear responses to cursor and target displacements, only arriving at the correct difference vector calculation 200 ms later.

Temporal Evolution of Spatial Computations for Visuomotor Control

Hand use predicts the structure of representations in sensorimotor cortex

The dissociable effects of punishment and reward on motor learning

Representations of Motor Synergy and Sequence Learning Bihemispheric Transcranial Direct Current Stimulation Enhances Effector-Independent

Manipulating motor performance and memory through real-time fMRI neurofeedback

The paper presents a flat representation of the human cerebellum, useful for visualizing functional imaging data after volume-based normalization and averaging across subjects. Instead of reconstructing individual cerebellar surfaces, the method uses a white- and grey-matter surface defined on volume-averaged anatomical data. Functional data can be projected along the lines of corresponding vertices on the two surfaces. The flat representation is optimized to yield a roughly proportional relationship between the surface area of the 2D-representation and the volume of the underlying cerebellar grey matter. The map allows users to visualize the activation state of the complete cerebellar grey matter in one concise view, equally revealing both the anterior-posterior (lobular) and medial-lateral organization. As examples, published data on resting-state networks and task-related activity are presented on the flatmap. The software and maps are freely available and compatible with most major neuroimaging packages.

Surface-Based Display of Volume-Averaged Cerebellar Imaging Data

RepresentationFrontal Lobe and Action-Oriented Learning of Sequences of Finger Movements and

redundant reaching movements Mechanisms of responsibility assignment during

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Motivation in Motor Learning : Dissociable effect of Punishment and Reward

There are controversies whether learning of conditioned eyeblink responses primarily takes place within the cerebellar cortex, the interposed nuclei, or both. It has also been suggested that the cerebellar cortex may be important during early stages of learning, and that there is a shift to the cerebellar nuclei during later stages. As yet, human studies have provided little to resolve this question. In the present study, we established a setup that allows ultra-high-field 7T functional magnetic resonance imaging (fMRI) of the cerebellar cortex and interposed cerebellar nuclei simultaneously during delay eyeblink conditioning in humans. Event-related fMRI signals increased concomitantly in the cerebellar cortex and nuclei during early acquisition of conditioned eyeblink responses in 20 healthy human subjects. ANOVAs with repeated-measures showed significant effects of time across five blocks of 20 conditioning trials in the cortex and nuclei (p < 0.05, permutation corrected). Activations were most pronounced in, but not limited to, lobules VI and interposed nuclei. Increased activations were most prominent at the first time the maximum number of conditioned responses was achieved. Our data are consistent with a simultaneous and synergistic two-site model of learning during acquisition of classically conditioned eyeblinks. Because increased MRI signal reflects synaptic activity, concomitantly increased signals in the cerebellar nuclei and cortex are consistent with findings of learning related potentiation at the mossy fiber to nuclear cell synapse and mossy fiber to granule cell synapse. Activity related to the expression of conditioned responses, however, cannot be excluded.

Cerebellar Cortex and Cerebellar Nuclei Are Concomitantly Activated during Eyeblink Conditioning: A 7T fMRI Study in Humans

When we learn a novel task, the motor system needs to acquire both feedforward and feedback control. Currently, little is known about how the learning of these two mechanisms relate to each other. In the present study, we tested whether feedforward and feedback control need to be learned separately, or whether they are learned as common mechanism when a new control policy is acquired. Participants were trained to reach to two lateral and one central target in an environment with mirror (left-right)-reversed visual feedback. One group was allowed to make online movement corrections, whereas the other group only received visual information after the end of the movement. Learning of feedforward control was assessed by measuring the accuracy of the initial movement direction to lateral targets. Feedback control was measured in the responses to sudden visual perturbations of the cursor when reaching to the central target. Although feedforward control improved in both groups, it was significantly better when online corrections were not allowed. In contrast, feedback control only adaptively changed in participants who received online feedback and remained unchanged in the group without online corrections. Our findings suggest that when a new control policy is acquired, feedforward and feedback control are learned separately, and that there may be a trade-off in learning between feedback and feedforward controllers.

Learning feedback and feedforward control in a mirror-reversed visual environment.

A recent study suggests that reafferent hand-related visual information utilizes a privileged, attention-independent processing channel for motor control. This process was termed visuomotor binding to reflect its proposed function: linking visual reafferences to the corresponding motor control centers. Here, we ask whether the advantage of processing reafferent over exafferent visual information is a specific feature of the motor processing stream or whether the improved processing also benefits the perceptual processing stream. Human participants performed a bimanual reaching task in a cluttered visual display, and one of the visual hand cursors could be displaced laterally during the movement. We measured the rapid feedback responses of the motor system as well as matched perceptual judgments of which cursor was displaced. Perceptual judgments were either made by watching the visual scene without moving or made simultaneously to the reaching tasks, such that the perceptual processing stream could also profit from the specialized processing of reafferent information in the latter case. Our results demonstrate that perceptual judgments in the heavily cluttered visual environment were improved when performed based on reafferent information. Even in this case, however, the filtering capability of the perceptual processing stream suffered more from the increasing complexity of the visual scene than the motor processing stream. These findings suggest partly shared and partly segregated processing of reafferent information for vision for motor control versus vision for perception.

Processing reafferent and exafferent visual information for action and perception.

Decoding neural signals of intention and movement should guide the development of neural prosthetics [Also see Report by Aflalo et al.] Imagine a world in which your smartphone can read your mind. Just at the moment that you decide to move your finger to delete a message, it is already gone. This sounds like science fiction, but for one human in California, this fantasy is becoming reality. On page 906 of this issue, Aflalo et al. (1) report the case of a tetraplegic individual (called “EGS”) who volunteered to have his brain implanted with two small silicon chips that allow researchers to read his intentions directly from his brain activity. The chips—initially developed at the University of Utah (2) and now commercially available and approved for human use by the U.S. Food and Drug Administration—consist of a matrix of 96 microscopic electrodes that can record the activity of about 100 nerve cells at the same time.

A Dedicated Binding Mechanism for the Visual Control of Movement

Skilled performance is characterized by precise and flexible control of movement sequences in space and time. Recent theories suggest that integrated spatio-temporal trajectories are generated by intrinsic dynamics of motor and premotor networks. This contrasts with behavioural advantages that emerge when a trained spatial or temporal feature of sequences is transferred to a new spatio-temporal combination arguing for independent neural representations of these sequence features. We used a new fMRI pattern classification approach to identify brain regions with independent vs integrated representations. A distinct regional dissociation within motor areas was revealed: whereas only the contralateral primary motor cortex exhibited unique patterns for each spatio-temporal sequence combination, bilateral premotor areas represented spatial and temporal features independently of each other. These findings advocate a unique function of higher motor areas for flexible recombination and efficient encoding of complex motor behaviours. DOI: http://dx.doi.org/10.7554/eLife.03043.001

Human premotor areas parse sequences into their spatial and temporal features

When performing a skill such as throwing a dart, many different combinations of joint motions suffice to hit the target. The motor system adapts rapidly to reduce bias in the desired outcome (i.e., the first-order moment of the error); however, the essence of skill is to produce movements with less variability (i.e., to reduce the second-order moment). It is easy to see how feedback about success or failure could sculpt performance to achieve this aim. However, it is unclear whether the dimensions responsible for success or failure need to be known explicitly by the subjects, or whether learning can proceed without explicit awareness of the movement parameters that need to change. Here, we designed a redundant, two-dimensional reaching task in which we could selectively manipulate task success and the variability of action outcomes, whilst also manipulating awareness of the dimension along which performance could be improved. Variability was manipulated either by amplifying natural errors, leaving the correlation between the executed movement and the visual feedback intact, or by adding extrinsic noise, decorrelating movement and feedback. We found that explicit, binary, feedback about success or failure was only sufficient for learning when participants were aware of the dimension along which motor behavior had to change. Without such awareness, learning was only present when extrinsic noise was added to the feedback, but not when task success or variability was manipulated in isolation; learning was also much slower. Our results highlight the importance of conscious awareness of the relevant dimension during motor learning, and suggest that higher-order moments of outcome signals are likely to play a significant role in skill learning in complex tasks.

When Money Is Not Enough: Awareness, Success, and Variability in Motor Learning

[PDF] [Full Text] [Abstract] , March 5, 2014; 34 (10): 3622-3631. J. Neurosci. Benjamin A. Philip and Scott H. Frey Unilateral Amputees Compensatory Changes Accompanying Chronic Forced Use of the Nondominant Hand by [PDF] [Full Text] [Abstract] , April 2, 2014; 34 (14): 5054-5064. J. Neurosci. Tobias Wiestler, Sheena Waters-Metenier and Jorn Diedrichsen Reference Frames Effector-Independent Motor Sequence Representations Exist in Extrinsic and Intrinsic [PDF] [Full Text] [Abstract] , August 15, 2014; 112 (4): 999-1009. J Neurophysiol Cathrin M. Buetefisch, Kate Pirog Revill, Linda Shuster, Benjamin Hines and Michael Parsons Motor demand-dependent activation of ipsilateral motor cortex [PDF] [Full Text] [Abstract] , October 1, 2014; 2 (10): . PHY2 Takuya Morishita, Shinji Kubota, Masato Hirano and Kozo Funase motor manipulation task − resting primary motor cortex during a fine latency interhemispheric inhibition from active to − and long − Different modulation of short

Hand Movements Relates to Task Complexity Ipsilateral Motor Cortex Activity During Unimanual

Motor learning tasks are often classified into adaptation tasks, which involve the recalibration of an existing control policy (the mapping that determines both feedforward and feedback commands), and skill-learning tasks, requiring the acquisition of new control policies. We show here that this distinction also applies to two different visuomotor transformations during reaching in humans: Mirror-reversal (left-right reversal over a mid-sagittal axis) of visual feedback versus rotation of visual feedback around the movement origin. During mirror-reversal learning, correct movement initiation (feedforward commands) and online corrections (feedback responses) were only generated at longer latencies. The earliest responses were directed into a nonmirrored direction, even after two training sessions. In contrast, for visual rotation learning, no dependency of directional error on reaction time emerged, and fast feedback responses to visual displacements of the cursor were immediately adapted. These results suggest that the motor system acquires a new control policy for mirror reversal, which initially requires extra processing time, while it recalibrates an existing control policy for visual rotations, exploiting established fast computational processes. Importantly, memory for visual rotation decayed between sessions, whereas memory for mirror reversals showed offline gains, leading to better performance at the beginning of the second session than in the end of the first. With shifts in time-accuracy tradeoff and offline gains, mirror-reversal learning shares common features with other skill-learning tasks. We suggest that different neuronal mechanisms underlie the recalibration of an existing versus acquisition of a new control policy and that offline gains between sessions are a characteristic of latter.

Mirror Reversal and Visual Rotation Are Learned and Consolidated via Separate Mechanisms: Recalibrating or Learning De Novo?

Multivariate pattern analysis has become an important approach in the analysis of fMRI data, as it allows inferences not only about the relative size of activation in different regions but also about their representational content. The field currently uses a wide variety of multivariate analysis techniques, including classification, representational similarity analysis, MANOVA, and pattern component modeling. This makes it very hard for the novice to judge the relative strengths and weaknesses of these approaches, and to understand their deeper relationship. Here, we present a generative model framework, which unifies various approach and analysis techniques under a single roof, and provides a set of simple, yet powerful, ways of testing representational hypotheses on distributed activity patterns.

Many daily activities rely on the ability to produce meaningful sequences of movements. Motor sequences can be learned in an effector-specific fashion (such that benefits of training are restricted to the trained hand) or an effector-independent manner (meaning that learning also facilitates performance with the untrained hand). Effector-independent knowledge can be represented in extrinsic/world-centered or in intrinsic/body-centered coordinates. Here, we used functional magnetic resonance imaging (fMRI) and multivoxel pattern analysis to determine the distribution of intrinsic and extrinsic finger sequence representations across the human neocortex. Participants practiced four sequences with one hand for 4 d, and then performed these sequences during fMRI with both left and right hand. Between hands, these sequences were equivalent in extrinsic or intrinsic space, or were unrelated. In dorsal premotor cortex (PMd), we found that sequence-specific activity patterns correlated higher for extrinsic than for unrelated pairs, providing evidence for an extrinsic sequence representation. In contrast, primary sensory and motor cortices showed effector-independent representations in intrinsic space, with considerable overlap of the two reference frames in caudal PMd. These results suggest that effector-independent representations exist not only in world-centered, but also in body-centered coordinates, and that PMd may be involved in transforming sequential knowledge between the two. Moreover, although effector-independent sequence representations were found bilaterally, they were stronger in the hemisphere contralateral to the trained hand. This indicates that intermanual transfer relies on motor memories that are laid down during training in both hemispheres, but preferentially draws upon sequential knowledge represented in the trained hemisphere.

Effector-Independent Motor Sequence Representations Exist in Extrinsic and Intrinsic Reference Frames

movement sequences Interaction of temporal and ordinal representations in

Complex manual tasks—everything from buttoning up a shirt to playing the piano—fundamentally involve two components: (1) generating specific patterns of muscle activity (here, termed “synergies”); and (2) stringing these into purposeful sequences. Although transcranial direct current stimulation (tDCS) of the primary motor cortex (M1) has been found to increase the learning of motor sequences, it is unknown whether it can similarly facilitate motor synergy learning. Here, we determined the effects of tDCS on the learning of motor synergies using a novel hand configuration task that required the production of difficult muscular activation patterns. Bihemispheric tDCS was applied to M1 of healthy, right-handed human participants during 4 d of repetitive left-hand configuration training in a double-blind design. tDCS augmented synergy learning, leading subsequently to faster and more synchronized execution. This effect persisted for at least 4 weeks after training. Qualitatively similar tDCS-associated improvements occurred during training of finger sequences in a separate subject cohort. We additionally determined whether tDCS only improved the acquisition of motor memories for specific synergies/sequences or whether it also facilitated more general parts of the motor representations, which could be transferred to novel movements. Critically, we observed that tDCS effects generalized to untrained hand configurations and untrained finger sequences (i.e., were nonspecific), as well as to the untrained hand (i.e., were effector-independent). Hence, bihemispheric tDCS may be a promising adjunct to neurorehabilitative training regimes, in which broad transfer to everyday tasks is highly desirable.

Bihemispheric Transcranial Direct Current Stimulation Enhances Effector-Independent Representations of Motor Synergy and Sequence Learning

Author response: Human premotor areas parse sequences into their spatial and temporal features

The human motor system is remarkably proficient in the online control of visually guided movements, adjusting to changes in the visual scene within 100 ms [1–3]. This is achieved through a set of highly automatic processes [4] translating visual information into representations suitable for motor control [5, 6]. For this to be accomplished, visual information pertaining to target and hand need to be identified and linked to the appropriate internal representations during the movement. Meanwhile, other visual information must be filtered out, which is especially demanding in visually cluttered natural environments. If selection of relevant sensory information for online control was achieved by visual attention, its limited capacity [7] would substantially constrain the efficiency of visuomotor feedback control. Here we demonstrate that both exogenously and endogenously cued attention facilitate the processing of visual target information [8], but not of visual hand information. Moreover, distracting visual information is more efficiently filtered out during the extraction of hand compared to target information. Our results therefore suggest the existence of a dedicated visuomotor binding mechanism that links the hand representation in visual and motor systems.

The production of movement sequences requires an accurate control of muscle activation in time. How does the nervous system encode the precise timing of these movements? One possibility is that the timing of movements (temporal sequence) is an emergent property of the dynamic state of the nervous system and therefore intimately linked to a representation of the sequence of muscle commands (ordinal sequence). Alternatively, timing may be represented independently of the motor effectors and would be transferable to a new ordinal sequence. Some studies have found that a learned temporal sequence cannot be transferred to a new ordinal sequence, thus arguing for an integrated representation. Others have observed temporal transfer across movement sequences and have advocated an independent representation of temporal information. Using a modified serial reaction time task, we tested alternative models of the representation of temporal structure and the interaction between the output of separate ordinal and temporal sequence representations. Temporal transfer depended on whether a novel ordinal sequence was fixed within each test block. Our results confirm the presence of an independent representation of temporal structure and advocate a nonlinear multiplicative neural interaction of temporal and ordinal signals in the production of movements.

Interaction of temporal and ordinal representations in movement sequences.

Mechanisms of responsibility assignment during redundant reaching

How does the motor system choose the speed for any given movement? Many current models assume a process that finds the optimal balance between the costs of moving fast and the rewards of achieving the goal. Here, we show that such models also need to take into account a prior representation of preferred movement speed, which can be changed by prolonged practice. In a time-constrained reaching task, human participants made 25-cm reaching movements within 300, 500, 700, or 900 ms. They were then trained for 3 days to execute the movement at either the slowest (900-ms) or fastest (300-ms) speed. When retested on the 4th day, movements executed under all four time constraints were biased toward the speed of the trained movement. In addition, trial-to-trial variation in speed of the trained movement was significantly reduced. These findings are indicative of a use-dependent mechanism that biases the selection of speed. Reduced speed variability was also associated with reduced errors in movement amplitude for the fast training group, which generalized nearly fully to a new movement direction. In contrast, changes in perpendicular error were specific to the trained direction. In sum, our results suggest the existence of a relatively stable but modifiable prior of preferred movement speed that influences the choice of movement speed under a range of task constraints.

24 How does the motor system choose the speed for any given movement? Many current 25 models assume a process that finds the optimal balance between the costs of moving fast and the 26 rewards of achieving the goal. Here we show that such models also need to take into account a prior 27 representation of preferred movement speed, which can be changed by prolonged practice. In a 28 time-constrained reaching task, human participants made 25cm-reaching movements within 300, 29 500, 700 or 900ms. They were then trained for 3 days to execute the movement at either the 30 slowest (900ms) or fastest (300ms) speed. When retested on the fourth day, movements executed 31 under all four time constraints were biased towards the speed of the trained movement. In addition, 32 trial-to-trial variation in speed of the trained movement was significantly reduced. These findings are 33 indicative of a use-dependent mechanism that biases the selection of speed. Reduced speed 34 variability was also associated with reduced errors in movement amplitude for the fast training 35 group, which generalized nearly fully to a new movement direction. In contrast, changes in 36 perpendicular error were specific to the trained direction. In sum, our results suggest the existence 37 of a relatively stable, but modifiable prior of preferred movement speed that influences the choice 38 of movement speed under a range of task constraints. 39 40 Introduction 41 Individuals tend to move at a preferred speed: some talk slowly while others walk fast 42 (Slijper et al., 2009). Theoretical models suggest that the chosen speed is a compromise between the 43 importance or reward value of the goal state (Xu-Wilson et al., 2009), the effort or energy needed to 44 execute the movement (Mazzoni et al., 2007), and the cost of the wait before the goal is reached 45 (Tanaka et al., 2006;Shadmehr, 2010;Shadmehr et al., 2010;Haith et al., 2012). The motor system 46 chooses a speed that optimizes a cost function (Todorov and Jordan, 2002) representing a 47 2 Movement speed is biased by prior experience combination of these factors. For example, speed of walking with an arthritic hip could be a 48 compromise between reaching the goal of catching the bus, and minimising pain. 49 Here we ask whether the choice of movement speed, rather than being an optimal solution 50 to an internal cost function, is also determined by the habit of moving at a specific movement speed 51 that has formed during prior repetitive training. Previous studies have shown that a use-dependent 52 learning mechanism strongly influences spatial characteristics (Diedrichsen et al., 2010;Verstynen 53 and Sabes, 2011). When Verstynen and Sabes (2011) trained people to move repeatedly in one 54 direction, the variability of reaches in the trained direction decreased substantially. However, this 55 came at the cost of biasing movements in less frequently cued directions towards the trained 56 direction. Therefore, movement speed may also be habitual in that a certain speed may be chosen 57 because recent movements have tuned the system to this trained speed. If this habitual preference 58 can be imposed by previous training, this would have important implications for ongoing training 59 and treatment programmes. 60 Our hypothesis was that training movements at a specific speed could similarly bias the 61 speed of subsequent movements. Over three consecutive days of practice, a group of healthy young 62 volunteers practised a centre-out arm reaching task; half of them were trained to move fast whereas 63 the others were trained to move slowly. Before and after the training sessions, participants were 64 required to make reaching movements within 4 different time windows. One of these was the same 65 as the trained task; the 3 others were different. At the end of training, people in both training groups 66 made more accurate movements at less variable speeds, but this came at the cost of biasing the 67 speed in the untrained movements. Those who had been trained to move slowly tended to move 68 slower than before training, whereas those who had been trained to move fast did the opposite. The 69 changes in speed preference generalized to other movement directions, indicating that the 70 underlying adjustment is relatively global. 71 72 3 Movement speed is biased by prior experience Materials and Methods 73 Subjects 74 Eighteen healthy adults (mean age: 30.4 +/-8.30 SD years, 7 males) without a history of 75 upper limb neurological or musculoskeletal disorder attended for 5 consecutive days. Experimental 76 and consent procedures were approved by the University College London ethics committee. 77 Apparatus and stimuli 78 Participants were seated with their forehead supported on a headrest. Their semipronated 79 right hand gripped a manipulandum underneath a horizontally suspended mirror. The mirror 80 prevented direct vision of the hand and arm, but showed a reflection of a computer monitor 81 mounted above that appeared to be in the same plane as the hand. The visual display (Fig. 4 A1) 82 comprised a 1 cm diameter starting box, a cursor (0.5 cm diameter) representing the position of the 83 manipulandum and a circular 10 cm diameter target with a small black cross at its centre, which was 84 located 25cm from the start box at an angle of either 0 or 45 degrees. At the start of a trial a motor 85 moved the participants’ arm, and thereby the cursor, into the start box presented in midline. The 86 gleno-humeral joint was in ̴30 degrees of elevation through flexion, and 45 degrees of abduction, 87 and the elbow at ̴ 90 degrees flexion. The duration of each trial was identical irrespective of the 88 allowed movement time (i.e. 2320ms) but reaction time was not enforced and was not included in 89 the trial time. The starting signal, a change from the target (Fig 4A) from an outline to a solid colour, 90 appeared 100ms after trial initiation. Participants were instructed to start moving in their own time 91 after the starting signal. At movement onset the cursor disappeared, and reappeared, showing the 92 hand position, when the allowed movement time had passed. Reappearance of the cursor indicated 93 the end of the trial and provided feedback of reach end-point accuracy. The feedback was displayed 94 for 300ms after which the robotic manipulandum moved the arm back to the starting position. The 95 hand was held in the starting position until the end of the trial time. Shorter movement times 96 therefore had longer wait times at the end of a trial for initiation of the next trial. Participants 97 4 Movement speed is biased by prior experience familiarized themselves with the task by performing 10 reaches with continual visual feedback at 98 900ms and 300ms as well as 10 reaches without visual feedback at 300ms. 99 Preand post-test 100 On day one and day five (preand post-training) reaching accuracy was established at four 101 different movement times, 300, 500, 700 and 900ms, by performing blocks of 45 trials presented in a 102 random order. We performed the reaches at comfortable reaching speeds (500 and 700ms) 103 (Soechting et al., 1995) as well as very fast (300ms) movement times and slow movements (900ms) 104 (Nishikawa et al., 1999). The first five trials of each block were used for practice and the subsequent 105 40 trials were analyzed. All four movement times were performed with targets at 0 or 45 degrees 106 (Fig. 4A1 and 5A) and the order of conditions was randomized. In all cases the aim was to end the 107 movement as close as possible to the cross in the center of the target. 108 Participants were instructed to perform the reach within a pre-determined movement time. 109 The movement time was enforced by “dropping” the cursor at the hand position that was achieved 110 when the allowed movement time had passed, whether the hand had stopped moving or not. This 111 cursor position was used for determining endpoint error. Any further corrective movement after this 112 time did not influence the measurement. This arrangement means that movement times cannot be 113 longer than the allowed time although shorter movement times are possible. 114

0 Movement speed is biased by prior experience 1 Movement speed is biased by prior experience 2 3

An important observation in motor physiology is that even the fastest feedback responses can be modified in a task-dependent manner. However, whether or not such responses in one limb can be modulated based on online sensory feedback from other limbs is still unknown. We tested this using a bimanual postural control task, in which the two hands either controlled two separate cursors (double-cursor task) or a single cursor displayed at the spatial average between the hands (single-cursor task). In the first experiment, the two hands were symmetrically perturbed outwards. In the double-cursor task, the participants therefore had to return their hands to the targets, whereas in the single-cursor task no correction was necessary. Within 50 ms, the electromyographic activity showed significantly smaller responses in the single- compared with the double-cursor task. In the second experiment, the perturbation direction of the left hand (inward/outward) was randomized, such that participants could not preplan their response before perturbation onset. Results show that the behavior of the right arm in the one-cursor task depended on online feedback coming from the left arm: the muscular response was modulated within 75 ms based on directionally specific information of the left arm. These results suggest that sensory feedback from one limb can quickly modify the perturbation response of another limb in a task-dependent manner.

Author response: Skill learning strengthens cortical representations of motor sequences

When the two hands act together to achieve a goal, the redundancy of the system makes it necessary to distribute the responsibility for error corrections across the two hands. In an experiment in which participants control a single cursor with the movements of both hands, we show that right-handed individuals correct for movement errors more with their nondominant left hand than with their right hand, even though the dominant right hand corrects the same errors more quickly and efficiently when each hand acts in isolation. By measuring the responses to rapid cursor and target displacements using force channels, we demonstrate that this shift is due to a modulation of the feedback gains of each hand rather than to a shift in the onset of the corrective response. We also show that the shift toward left-hand corrections is more pronounced for errors that lead to adaptation (cursor displacements) than for perturbations that do not (target displacements). This finding provides some support for the idea that the motor system assigns the correction to the most likely source of the error to induce learning and to optimize future performance. Finally, we find that the relative strength of the feedback corrections in the redundant task correlates positively with those found for the nonredundant tasks. Thus the process of responsibility assignment modulates the processes that normally determine the gains of feedback correction rather than completely overwriting them.

Mechanisms of responsibility assignment during redundant reaching movements.

To produce skilled movements, the brain flexibly adapts to different task requirements and movement contexts. Two core abilities underlie this flexibility. First, depending on the task, the motor system must rapidly switch the way it produces motor commands and how it corrects movements online, i.e. it switches between different (feedback) control policies. Second, it must also adapt to environmental changes for different tasks separately. Here we show these two abilities are related. In a bimanual movement task, we show that participants can switch on a movement-by-movement basis between two feedback control policies, depending only on a static visual cue. When this cue indicates that the hands control separate objects, reactions to force field perturbations of each arm are purely unilateral. In contrast, when the visual cue indicates a commonly controlled object, reactions are shared across hands. Participants are also able to learn different force fields associated with a visual cue. This is however only the case when the visual cue is associated with different feedback control policies. These results indicate that when the motor system can flexibly switch between different control policies, it is also able to adapt separately to the dynamics of different environmental contexts. In contrast, visual cues that are not associated with different control policies are not effective for learning different task dynamics.

Flexible Switching of Feedback Control Mechanisms Allows for Learning of Different Task Dynamics

A multivariate method to determine the dimensionality of neural representation from population activity

Motor-skill learning can be accompanied by both increases and decreases in brain activity. Increases may indicate neural recruitment, while decreases may imply that a region became unimportant or developed a more efficient representation of the skill. These overlapping mechanisms make interpreting learning-related changes of spatially averaged activity difficult. Here we show that motor-skill acquisition is associated with the emergence of highly distinguishable activity patterns for trained movement sequences, in the absence of average activity increases. During functional magnetic resonance imaging, participants produced either four trained or four untrained finger sequences. Using multivariate pattern analysis, both untrained and trained sequences could be discriminated in primary and secondary motor areas. However, trained sequences were classified more reliably, especially in the supplementary motor area. Our results indicate skill learning leads to the development of specialized neuronal circuits, which allow the execution of fast and accurate sequential movements without average increases in brain activity. DOI: http://dx.doi.org/10.7554/eLife.00801.001

Skill learning strengthens cortical representations of motor sequences

A central tenet of motor neuroscience is that the cerebellum learns from sensory prediction errors. Surprisingly, neuroimaging studies have not revealed definitive signatures of error processing in the cerebellum. Furthermore, neurophysiologic studies suggest an asymmetry, such that the cerebellum may encode errors arising from unexpected sensory events, but not errors reflecting the omission of expected stimuli. We conducted an imaging study to compare the cerebellar response to these two types of errors. Participants made fast out-and-back reaching movements, aiming either for an object that delivered a force pulse if intersected or for a gap between two objects, either of which delivered a force pulse if intersected. Errors (missing the target) could therefore be signaled either through the presence or absence of a force pulse. In an initial analysis, the cerebellar BOLD response was smaller on trials with errors compared with trials without errors. However, we also observed an error-related decrease in heart rate. After correcting for variation in heart rate, increased activation during error trials was observed in the hand area of lobules V and VI. This effect was similar for the two error types. The results provide evidence for the encoding of errors resulting from either the unexpected presence or unexpected absence of sensory stimulation in the human cerebellum.

Studies with patients and functional magnetic resonance imaging investigations have demonstrated that the cerebellum plays an essential role in adaptation to visuomotor rotation and force field perturbation. To identify cerebellar structures involved in the two tasks, we studied 19 patients with focal lesions after cerebellar infarction. Focal lesions were manually traced on magnetic resonance images and normalized using a new spatially unbiased template of the cerebellum. In addition, we reanalyzed data from 14 patients with cerebellar degeneration using voxel-based morphometry. We found that adjacent regions with only little overlap in the anterior arm area (lobules IV to VI) are important for adaptation in both tasks. Although adaptation to the force field task lay more anteriorly (lobules IV and V), lobule VI was more important for the visuomotor task. In addition, regions in the posterolateral cerebellum (Crus I and II) contributed to both tasks. No consistent involvement of the posterior arm region (lobule VIII) was found. Independence of the two kinds of adaptation is further supported by findings that performance in one task did not correlate to performance in the other task. Our results show that the anterior arm area of the cerebellum is functionally divided into a more posterior part of lobule VI, extending into lobule V, related to visuomotor adaption, and a more anterior part including lobules IV and V, related to force field adaption. The posterolateral cerebellum may process common aspects of both tasks.

Cerebellar regions involved in adaptation to force field and visuomotor perturbation.

Should skill re-learning after stroke focus on movement speed or accuracy?

and visuomotor perturbation Cerebellar regions involved in adaptation to force field

Movements of the upper limb are controlled mostly through the contralateral hemisphere. Although overall activity changes in the ipsilateral motor cortex have been reported, their functional significance remains unclear. Using human functional imaging, we analyzed neural finger representations by studying differences in fine-grained activation patterns for single isometric finger presses. We demonstrate that cortical motor areas encode ipsilateral movements in 2 fundamentally different ways. During unimanual ipsilateral finger presses, primary sensory and motor cortices show, underneath global suppression, finger-specific activity patterns that are nearly identical to those elicited by contralateral mirror-symmetric action. This component vanishes when both motor cortices are functionally engaged during bimanual actions. We suggest that the ipsilateral representation present during unimanual presses arises because otherwise functionally idle circuits are driven by input from the opposite hemisphere. A second type of representation becomes evident in caudal premotor and anterior parietal cortices during bimanual actions. In these regions, ipsilateral actions are represented as nonlinear modulation of activity patterns related to contralateral actions, an encoding scheme that may provide the neural substrate for coordinating bimanual movements. We conclude that ipsilateral cortical representations change their informational content and functional role, depending on the behavioral context.

Two Distinct Ipsilateral Cortical Representations for Individuated Finger Movements

For smooth and efficient motor control, the brain needs to make fast corrections during the movement to resist possible perturbations. It also needs to adapt subsequent movements to improve future performance. It is important that both feedback corrections and feedforward adaptation need to be made based on noisy and often ambiguous sensory data. Therefore, the initial response of the motor system, both for online corrections and adaptive responses, is guided by prior assumptions about the likely structure of perturbations. In the context of correcting and adapting movements perturbed by a force field, we asked whether these priors are hard wired or whether they can be modified through repeated exposure to differently shaped force fields. We found that both feedback corrections to unexpected perturbations and feedforward adaptation to a new force field changed, such that they were appropriate to counteract the type of force field that participants had experienced previously. We then investigated whether these changes were driven by a common mechanism or by two separate mechanisms. Participants experienced force fields that were either temporally consistent, causing sustained adaptation, or temporally inconsistent, causing little overall adaptation. We found that the consistent force fields modified both feedback and feedforward responses. In contrast, the inconsistent force field modified the temporal shape of feedback corrections but not of the feedforward adaptive response. These results indicate that responses to force perturbations can be modified in a structural manner and that these modifications are at least partly dissociable for feedback and feedforward control.

Previous anatomical studies in monkeys have shown that forelimb motor representation is located caudal to hindlimb representation within the dorso‐rostral dentate nucleus. Here we investigate human dentate nucleus motor somatotopy by means of ultra‐highfield (7 T) functional magnetic brain imaging (fMRI). Twenty five young healthy males participated in the study. Simple finger and foot movement tasks were performed to identify dentate nucleus motor areas. Recently developed normalization procedures for group analyses were used for the cerebellar cortex and the cerebellar dentate nucleus. Cortical activations were in good accordance with the known somatotopy of the human cerebellar cortex. Dentate nucleus activations following motor tasks were found in particular in the ipsilateral dorso‐rostral nucleus. Activations were also present in other parts of the nucleus including the contralateral side, and there was some overlap between the body part representations. Within the ipsilateral dorso‐rostral dentate, finger activations were located caudally compared to foot movement‐related activations in fMRI group analysis. Likewise, the centre of gravity (COG) for the finger activation was more caudal than the COG of the foot activation across participants. A multivariate analysis of variance (MANOVA) on the x, y, and z coordinates of the COG indicated that this difference was significant (P = 0.043). These results indicate that in humans, the lower and upper limbs are arranged rostro‐caudally in the dorsal aspect of the dentate nucleus, which is consistent with studies in non‐human primates. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.

Evidence for a motor somatotopy in the cerebellar dentate nucleus—An FMRI study in humans

The cerebellum is thought to play a key role in the integration of sensory and motor events. Little is known, however, about how sensory and motor maps in the cerebellum superimpose. In the present study we investigated the relationship between these two maps for the representation of single fingers. Participants made isometric key presses with individual fingers or received vibratory tactile stimulation to the fingertips while undergoing high-resolution functional magnetic resonance imaging (fMRI). Using multivariate analysis, we have demonstrated that the ipsilateral lobule V and VIII show patterns of activity that encode, within the same region, both which finger pressed and which finger was stimulated. The individual finger-specific activation patches are smaller than 3 mm and only show a weak somatotopic organization. To study the superposition of sensory and motor maps, we correlated the finger-specific patterns across the two conditions. In the neocortex, sensory stimulation of one digit led to activation of the same patches as force production by the same digit; in the cerebellum, these activation patches were organized in an uncorrelated manner. This suggests that, in the cerebellum, a movement of a particular finger is paired with a range of possible sensory outcomes. In summary, our results indicate a small and fractured representation of single digits in the cerebellum and suggest a fundamental difference in how the cerebellum and the neocortex integrate sensory and motor events.

Integration of sensory and motor representations of single fingers in the human cerebellum.

Evidence for a motor and a non-motor domain in the human dentate nucleus — An fMRI study

The nervous system continuously predicts the sensory consequences of self-generated actions. These predictions can be used to cancel self-generated sensory information. It has been hypothesized that this cancellation process may serve to increase the perceptual sensitivity to unpredicted external events. Here, we provide the first empirical evidence for this idea. Participants were required to detect coherent motion in a random dot motion display. The task was made more difficult by a set of superimposed distractor dots that had to be ignored. When these distractors moved congruently with an active arm movement, perceptual performance in detecting the coherent motion was superior compared to a condition in which the distractor motion did not match the arm movement. To test whether this difference was due to sensory cancellation of matching distractors, or to the attentional enhancement of non-matching distractors, we introduced a control condition without any overt movement. Our results indicate that improvements in the detection of visual motion are indeed caused by sensory cancellation of self-generated events. In conjunction with other recent results, our data therefore suggest that the nervous system is able to attenuate or facilitate self-generated visual stimuli in a task-dependent manner.

Sensory cancellation of self-movement facilitates visual motion detection.

Comparing the similarity and spatial structure of neural representations: A pattern-component model

single fingers in the human cerebellum Integration of sensory and motor representations of

A comparison of volume-based and surface-based multi-voxel pattern analysis

Imaging the deep cerebellar nuclei: A probabilistic atlas and normalization procedure

Grip force regulates hand impedance to optimize object stability in high impact loads

The path from perception to action involves the transfer of information across various reference frames. Here we applied a functional magnetic resonance imaging (fMRI) repetition suppression paradigm to determine the reference frame(s) in which the cortical activity is coded at several phases of the sensorimotor transformation for a saccade, including sensory processing, saccade planning, and saccade execution. We distinguished between retinal (eye-centered) and nonretinal (e.g., head-centered) coding frames in three key regions: the intraparietal sulcus (IPS), frontal eye field (FEF), and supplementary eye field (SEF). Subjects (n = 18) made delayed saccades to one of five possible peripheral targets, separated at intervals of 9° visual angle. Target locations were chosen pseudorandomly, based on a 2 × 2 factorial design, with factors retinal and nonretinal coordinates and levels novel and repeated. In all three regions, analysis of the blood oxygenation level dependent dynamics revealed an attenuation of the fMRI signal in trials repeating the location of the target in retinal coordinates. The amount of retinal suppression varied across the three phases of the trial, with the strongest suppression during saccade planning. The paradigm revealed only weak traces of nonretinal coding in these regions. Further analyses showed an orderly representation of the retinal target location, as expressed by a contralateral bias of activation, in the IPS and FEF, but not in the SEF. These results provide evidence that the sensorimotor processing in these centers reflects saccade generation in eye-centered coordinates, irrespective of their topographic organization.

Repetition suppression dissociates spatial frames of reference in human saccade generation.

Many lines of evidence point to a tight linkage between the perceptual and motoric representations of actions. Numerous demonstrations show how the visual perception of an action engages compatible activity in the observer's motor system. This is seen for both intransitive actions (e.g., in the case of unconscious postural imitation) and transitive actions (e.g., grasping an object). Although the discovery of “mirror neurons” in macaques has inspired explanations of these processes in human action behaviors, the evidence for areas in the human brain that similarly form a crossmodal visual/motor representation of actions remains incomplete. To address this, in the present study, participants performed and observed hand actions while being scanned with functional MRI. We took a data-driven approach by applying whole-brain information mapping using a multivoxel pattern analysis (MVPA) classifier, performed on reconstructed representations of the cortical surface. The aim was to identify regions in which local voxelwise patterns of activity can distinguish among different actions, across the visual and motor domains. Experiment 1 tested intransitive, meaningless hand movements, whereas experiment 2 tested object-directed actions (all right-handed). Our analyses of both experiments revealed crossmodal action regions in the lateral occipitotemporal cortex (bilaterally) and in the left postcentral gyrus/anterior parietal cortex. Furthermore, in experiment 2 we identified a gradient of bias in the patterns of information in the left hemisphere postcentral/parietal region. The postcentral gyrus carried more information about the effectors used to carry out the action (fingers vs. whole hand), whereas anterior parietal regions carried more information about the goal of the action (lift vs. punch). Taken together, these results provide evidence for common neural coding in these areas of the visual and motor aspects of actions, and demonstrate further how MVPA can contribute to our understanding of the nature of distributed neural representations.

Surface-Based Information Mapping Reveals Crossmodal Vision–Action Representations in Human Parietal and Occipitotemporal Cortex

Human motor behavior is constantly adapted through the process of error-based learning. When the motor system encounters an error, its estimate about the body and environment will change, and the next movement will be immediately modified to counteract the underlying perturbation. Here, we show that a second mechanism, use-dependent learning, simultaneously changes movements to become more similar to the last movement. In three experiments, participants made reaching movements toward a horizontally elongated target, such that errors in the initial movement direction did not have to be corrected. Along this task-redundant dimension, we were able to induce use-dependent learning by passively guiding movements in a direction angled by 8° from the previous direction. In a second study, we show that error-based and use-dependent learning can change motor behavior simultaneously in opposing directions by physically constraining the direction of active movements. After removal of the constraint, participants briefly exhibit an error-based aftereffect against the direction of the constraint, followed by a longer-lasting use-dependent aftereffect in the direction of the constraint. In the third experiment, we show that these two learning mechanisms together determine the solution the motor system adopts when learning a motor task.

The brain integrates visual and haptic information from different spatial locations when using a tool

Deciding which hand to use for an action is one of the most frequent decisions people make in everyday behavior. Using a speeded reaching task, we provide evidence that hand choice entails a competitive decision process between simultaneously activated action plans for each hand. We then show that single-pulse transcranial magnetic stimulation to the left posterior parietal cortex biases this competitive process, leading to an increase in ipsilateral, left hand reaches. Stimulation of the right posterior parietal cortex did not alter hand choice, suggesting a hemispheric asymmetry in the representations of reach plans. These results are unique in providing causal evidence that the posterior parietal cortex is involved in decisions of hand choice.

Transcranial magnetic stimulation of posterior parietal cortex affects decisions of hand choice

PURPOSE OF REVIEW
A quarter century of functional neuroimaging has provided a number of insights into the function of the human cerebellum. However, progress has been relatively slow, partly because cerebellar imaging poses a number of unique challenges for functional magnetic resonance imaging (fMRI). This review provides a guide to problems and recent solutions in the design, analysis and interpretation of neuroimaging studies of the human cerebellum.

RECENT FINDINGS
One major problem in the interpretation of functional imaging studies is that it is still unclear what type of neural activity is reflected in the cerebellar blood-oxygenation-level-dependent signal. We summarize recent work that has provided partly contradictory insights. We then highlight some technical challenges, specifically the susceptibility to physiological artifacts, and recently developed techniques to account for them. Furthermore, the small size and functional heterogeneity of the cerebellum poses a challenge for normalization and atlas methods, which demands different analysis techniques than those used in the neocortex. Finally, we highlight some novel results assessing anatomical and functional connectivity with the neocortex.

SUMMARY
Although these results clearly show the limitations of current approaches, they also show the potential of anatomical and functional MRI for the study of the human cerebellum.

Evolution of the cerebellar cortex: The selective expansion of prefrontal-projecting cerebellar lobules

Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, 11 NL 6500 HE, Nijmegen, The Netherlands. 12 University College London, Institute of Cognitive Neuroscience; 17 Queen Square, 13 London WC1N 3AR, United Kingdom 14 15 16 *Corresponding author: 17 Radboud University Nijmegen 18 Donders Institute for Brain, Cognition and Behaviour 19 P.O. Box 9104, NL-6500 HE, Nijmegen 20 The Netherlands 21 Phone: +31 24 366 8495 22 FAX: +31 24 361 0989 23 Email: stan.vanpelt@donders.ru.nl 24 25 June 8, 2010 (revised version) 26 27 # Figures: 6 28 # Tables: 2 29 # Pages: 36 30 31 32 33 34 35 36 Articles in PresS. J Neurophysiol (June 30, 2010). doi:10.1152/jn.00393.2010

Redundancy is a fundamental feature of biological motor systems. For example, when touching an object, many different combinations of movements of the shoulder, elbow, wrist, and finger joints result in the same movement at the fingertip [1]. Exploiting this redundancy, the motor system distributes work across effectors to minimize signal-dependent noise and effort [2–4]. When an error occurs, however, the motor system must assign the error to specific effectors, even though it may be ambiguous which effector caused them. Here, we studied the principles of responsibility assignment by using a bimanual task, in which the left and right hands jointly moved a visual cursor. We found that participants assigned errors, which were induced by visual rotation of the cursor, in a unified manner for correction and adaptation; the hand that corrected more for the error within the current movement also showed a bigger adaptive change in the next movement. Righthanded participants corrected errors more with their left hands, even though they corrected faster with their right hands in nonredundant tasks. Further experiments show that the motor system assigns responsibility preferentially to the hand that was previously exposed to larger errors. Our results show that responsibility assignment is a flexible process that attributes errors to the most likely cause.

27 Many lines of evidence point to a tight linkage between the perceptual and 28 motoric representations of actions. Numerous demonstrations show how the visual 29 perception of an action engages compatible activity in the observer’s motor system. 30 This is seen for both intransitive actions (e.g. in the case of unconscious postural 31 imitation) and for transitive actions (e.g. grasping an object). While the discovery of 32 “mirror neurons” in macaques has inspired explanations of these processes in human 33 action behaviours, the evidence for areas in the human brain that similarly form a 34 crossmodal visual/motor representation of actions remains incomplete. To address 35 this, in the present study, participants performed and observed hand actions while 36 being scanned with fMRI. We took a data-driven approach by applying whole-brain 37 information mapping using a multi-voxel pattern analysis (MVPA) classifier, 38 performed on reconstructed representations of the cortical surface. The aim was to 39 identify regions in which local voxel-wise patterns of activity can distinguish among 40 different actions, across the visual and motor domains. Experiment 1 tested 41 intransitive, meaningless hand movements, while Experiment 2 tested object-directed 42 actions (all right-handed). Our analyses of both experiments revealed crossmodal 43 action regions in the lateral occipitotemporal cortex (bilaterally) and in the left 44 postcentral gyrus/anterior parietal cortex. Furthermore, in Experiment 2 we identified 45 a gradient of bias in the patterns of information in the left hemisphere postcentral / 46 parietal region. The postcentral gyrus carried more information about the effectors 47 used to carry out the action (fingers vs whole hand), while anterior parietal regions 48 carried more information about the goal of the action (lift vs punch). Taken together, 49 these results provide evidence for common neural coding in these areas of the visual 50 and motor aspects of actions, and demonstrate further how MVPA can contribute to 51 our understanding of the nature of distributed neural representations. 52 53 Introduction 54 There is increasing evidence for a direct link between perception and action: 55 perceiving another person’s action activates the same representations as does the 56 actual performance of the action. Such common codes between perceiving and 57 producing actions enable humans to embody the behavior of others and to infer the 58 internal states driving it (e.g., Barsalou et al. 2003). That is, by creating common 59 representations between ourselves and another person, we have a deeper 60 understanding of their current states, and are better able to predict their future 61 behaviour, facilitating complex social interactions. However, the basis of the brain’s 62 crucial ability to relate one’s own actions to those of others remains poorly 63

Crossmodal action representations 1 2 Surface-based information mapping reveals crossmodal vision-action 3 representations in human parietal and occipitotemporal cortex 4 5 6

Visual-haptic integration: Evidence for dynamic rescaling of visual and haptic signals during tool use

Bimanual coordination as task-dependent linear control policies.

s Friday Special Symposium: Beyond the Perception/Action Dissociation Dissociations and interactions of two visual processing-streams in sensori-motor control The dissociation of visual processing for sensori-motor control (the dorsal stream) and for conscious perception and cognitive processing (the ventral stream) has emerged as one of the important concepts in contemporary cognitive neuroscience. However, motor control processes are able to take into account information from memory and context-dependent representations normally attributed to the ventral stream. This symposium will explore issues related to the integration of these two streams for adaptive motor control. Bernhard Hommel, University of Leiden How we do what we want Voluntary actions are performed to achieve intended goals, suggesting that they are controlled through anticipating the effects they are expected to produce (the ideo-motor principle). According to the two-phase model of voluntary action proposed by Hommel and colleagues (Hommel, 1997; Elsner & Hommel, 2001) performing a movement leads to the automatic integration of its sensory effects and the motor pattern producing them. The resulting action concept, a truly sensorimotor structure, can then be used in the reverse direction: to activate the motor pattern by priming the effect representations. I present old and new evidence supporting this two-phase model from behavioral experiments in adults and infants, and from a PET study.

Cognitive Science Association for Interdisciplinary Learning Thursday, July 26 7:30 Pm Adjourn for Evening Special Symposium Continued the Functional Mechanism by Which Alcohol Reduces Inhibition 7:40 Pm Adjourn for Evening Inhibitory Control during Learning: Suppressing Interference from Semantic K

When integrating signals from vision and haptics the brain must solve a "correspondence problem" so that it only combines information referring to the same object. An invariant spatial rule could be used when grasping with the hand: here the two signals should only be integrated when the estimate of hand and object position coincide. Tools complicate this relationship, however, because visual information about the object, and the location of the hand, are separated spatially. We show that when a simple tool is used to estimate size, the brain integrates visual and haptic information in a near-optimal fashion, even with a large spatial offset between the signals. Moreover, we show that an offset between the tool-tip and the object results in similar reductions in cross-modal integration as when the felt and seen positions of an object are offset in normal grasping. This suggests that during tool use the haptic signal is treated as coming from the tool-tip, not the hand. The brain therefore appears to combine visual and haptic information, not based on the spatial proximity of sensory stimuli, but based on the proximity of the distal causes of stimuli, taking into account the dynamics and geometry of tools.

When coordinating movements, the nervous system often has to decide how to distribute work across a number of redundant effectors. Here, we show that humans solve this problem by trying to minimize both the variability of motor output and the effort involved. In previous studies that investigated the temporal shape of movements, these two selective pressures, despite having very different theoretical implications, could not be distinguished; because noise in the motor system increases with the motor commands, minimization of effort or variability leads to very similar predictions. When multiple effectors with different noise and effort characteristics have to be combined, however, these two cost terms can be dissociated. Here, we measure the importance of variability and effort in coordination by studying how humans share force production between two fingers. To capture variability, we identified the coefficient of variation of the index and little fingers. For effort, we used the sum of squared forces and the sum of squared forces normalized by the maximum strength of each effector. These terms were then used to predict the optimal force distribution for a task in which participants had to produce a target total force of 4–16 N, by pressing onto two isometric transducers using different combinations of fingers. By comparing the predicted distribution across fingers to the actual distribution chosen by participants, we were able to estimate the relative importance of variability and effort of 1∶7, with the unnormalized effort being most important. Our results indicate that the nervous system uses multi-effector redundancy to minimize both the variability of the produced output and effort, although effort costs clearly outweighed variability costs.

Dissociating Variability and Effort as Determinants of Coordination

We show that fast bimanual coordinative feedback responses can be reversed with changes in task goals. Participants moved a flexible virtual object across a finish line with an upward movement of both hands. In one condition, the middle of the object had to be aligned with a spatial goal at the end of the movement. In the second condition, the object had to be kept at a specific length. During the movement, a velocity-dependent force field was applied randomly to one of the hands to the left or to the right. Depending on the task condition, the unperturbed hand showed fast feedback corrections, either in or against the direction of the force field on the other hand. In the object-length condition we found evidence for a mixture of task goals: early in the movement the correction of the unperturbed hand was aimed at stabilizing object length; later in the movement, the correction reversed direction to reach a symmetric body posture in the end of the movement. The observed differences in feedback responses between task conditions also influenced the covariance structure of unperturbed movements and the adaptation when a specific force field was applied repeatedly to one of the hands. The results are congruent with the notion that coordination is established flexibly through a representation of the task-relevant controlled variables, rather than through a direct interaction between motor commands.

Reversal of bimanual feedback responses with changes in task goal.

Pattern classifiers reveal sensory-motor representation of single digits in the human cerebellum

We tested the hypothesis that saccade gains adapt to minimize error between the visual target and the saccade endpoint of every saccade we make even when the errors on sequential saccades are not directionally consistent. We utilized a state-space model that estimated the degree to which saccade gains were modified by the magnitude and direction of errors made on the previous trial. Importantly, to show that learning did not depend on the accumulation of directionally consistent errors, we fit the model to saccades made to targets that were displaced in a random direction during the saccade, thereby inducing errors with directions that were not sequentially the same. Saccade gains clearly adapted on a trial-by-trial basis despite that the perturbations were random, and the average amount of learning per trial was of similar magnitude as that found in a constant displacement of the target. These results indicate that saccade adaptation is a rapid and obligatory process that does not require conscious awareness.

Neural substrates of visuomotor learning based on improved feedback control and prediction

Object manipulation requires rapid increase in grip force to prevent slippage when the load force of the object suddenly increases. Previous experiments have shown that grip force reactions interact between the hands when holding a single object. Here we test whether this interaction is modulated by the object dynamics experienced before the perturbation of the load force. We hypothesized that coupling of grip forces should be stronger when holding a single object than when holding separate objects. We measured the grip force reactions elicited by unpredictable load perturbations when participants were instructed to hold one single or two separate objects. We simulated these objects both visually and dynamically using a virtual environment consisting of two robotic devices and a calibrated stereo display. In contrast to previous studies, the load forces arising from a single object could be uncoupled at the moment of perturbation, allowing for a pure measurement of grip force coupling. Participants increased grip forces rapidly (onset approximately 70 ms) in response to perturbations. Grip force increases were stronger when the load force on the other hand also increased. No such coupling was present in the reaction of the arms to the load force increase. Surprisingly, however, the grip force interaction did not depend on the nature of the manipulated object. These results show fast obligatory coupling of bimanual grip force responses. Although this coupling may play a functional role for providing stability in bimanual object manipulation, it seems to constitute a relatively hard-wired modulation of a reflex.

Hand interactions in rapid grip force adjustments are independent of object dynamics.

Optimal Task-Dependent Changes of Bimanual Feedback Control and Adaptation

Internal predictions influence the perception of force. When we support an object with one hand and lift it up with the other, we expect the force to disappear from the first, postural hand. In a virtual reality system, we violated this prediction by maintaining the force on the postural hand, whereas the object was still seen and felt to be lifted by the lifting hand. In this situation, participants perceived an illusionary increase in force on the postural hand, which was, in reality, constant. We test three possible mechanisms of how force perception may be influenced in this context. First, we showed that part of the illusion can be linked to a sensorimotor prediction--the predicted sensory consequences based on an efference copy of the lifting action. The illusion is reduced when the object is lifted by an external force. We also showed that the illusion changes on a trial-by-trial basis, paralleling the fast adaptation of the postural response. Second, motor errors that arise from a miscalibrated forward model do not contribute to the illusion; the illusion was unchanged even when we prevented motor errors by supporting the postural hand. Finally, visual information signaling the removal of the object is sufficient to elicit part of the illusion. These results argue that both sensorimotor predictions and visual object information, but not motor errors, influence force perception.

Illusions of force perception: the role of sensori-motor predictions, visual information, and motor errors.

Intermanual interactions during initiation and production of rhythmic and discrete movements in individuals lacking a corpus callosum

Patients with focal lesions in the left (n = 7) and right (n = 4) prefrontal cortex were compared with controls (n = 16) in a task-switching experiment using four different, simple spatial tasks. Each of these tasks involved a left-right decision, either regarding an arrow, the word left or right, a circle position, or the direction of a moving line. We compared performance on trials that required rule switches versus rule repetitions (local switch costs) and we compared performance between blocks with bivalent stimuli (two dimensions present) and blocks with univalent stimuli (only one dimension present) to assess global switch costs. Patients with left prefrontal lesions, but not patients with right prefrontal lesions, exhibited increased costs on trials in which the relevant dimension switched (local switch costs), but also on no-switch trials with bivalent stimuli (global costs). We also assessed task-set inhibition in the form of the backward-inhibition effect [increased response times to recently abandoned tasks; Mayr, U., & Keele, S. Changing internal constraints on action: The role of backward inhibition. Journal of Experimental Psychology: General, 129, 4-26, 2000]. Although left frontal patients showed normal inhibition, right frontal patients showed no evidence for inhibition. These results suggest a neurocognitive dissociation between task-set selection and inhibition.

Dissociating Task-set Selection from Task-set Inhibition in the Prefrontal Cortex

Anticipatory postural adjustments (APA) during bimanual actions can be observed when participants hold an object in one hand and then lift it with the other hand. The postural force used to hold the object is reduced in anticipation of unloading, indicating an accurate prediction of the change in load. We examined patients with unilateral or bilateral cerebellar damage as well as two individuals lacking the corpus callosum on the bimanual unloading task. The acallosal patients showed an intact APA, suggesting subcortical integration of motor signals for anticipatory adjustments during bimanual actions. Contrary to the hypothesis that the cerebellum is critical for predicting and compensating for the consequences of our actions, we found that the well-learned APA in this task was largely intact in cerebellar patients. However, cerebellar damage abolished short-term adaptation of the APA, and the patients were unable to acquire an APA in a similar but previously untrained situation. These results indicate that while over-learned anticipatory adjustments are preserved after cerebellar lesions, adaptation of this response and the acquisition of a novel coordination requires the cerebellum ipsilateral to the postural hand. Furthermore, this structure appears to be essential for the accurate timing of previously learned behaviors. The patients with cerebellar damage showed poorly timed adjustments with the APA beginning earlier than in healthy participants.

Cerebellar involvement in anticipating the consequences of self-produced actions during bimanual movements.

Functional imaging studies have revealed recruitment of ipsilateral motor areas during the production of sequential unimanual finger movements. This phenomenon is more prominent in the left hemisphere during left-hand movements than in the right hemisphere during right-hand movements. Here we investigate whether this lateralization pattern is related specifically to the sequential structure of the unimanual action or generalizes to other complex movements. Using event-related fMRI, we measured activation changes in the motor cortex during three types of unimanual movements: repetitions of a sequence of movements with multiple fingers, repetitive "chords" composed of three simultaneous key presses, and simple repetitive tapping movements with a single finger. During sequence and chord movements, strong ipsilateral activation was observed and was especially pronounced in the left hemisphere during left-hand movements. This pattern was evident for both right-handed and, to a lesser degree, left-handed individuals. Ipsilateral activation was less pronounced in the tapping condition. The site of ipsilateral activation was shifted laterally, ventrally, and anteriorly with respect to that observed during contralateral movements and the time course of activation implied a role in the execution rather than planning of the movement. A control experiment revealed that strong ipsilateral activity in left motor cortex is specific to complex movements and does not depend on the number of required muscles. These findings indicate a prominent role of left hemisphere in the execution of complex movements independent of the sequential nature of the task.

Ipsilateral motor cortex activity during unimanual hand movements relates to task complexity.

Conflict during bimanual movements can arise during the selection of movement goals or during movement planning and execution. We demonstrate a behavioral and neural dissociation of these 2 types of conflict. During functional magnetic resonance imaging scanning, participants performed bimanual reaching movements with symmetric (congruent) or orthogonal (incongruent) trajectories. The required movements were indicated either spatially, by illuminating the targets, or symbolically, using centrally presented letters. The processing of symbolic cues led to increased activation in a left hemisphere network including the intraparietal sulcus, premotor cortex, and inferior frontal gyrus. Reaction time cost for incongruent movements was substantially larger for symbolic than for spatial cues, indicating that the cost was primarily associated with the selection and assignment of movement goals, demands that are minimized when goals are directly specified by spatial cues. This goal-selection conflict increased activity in the pre-supplementary motor area and cingulate motor areas. Both cueing conditions led to larger activation for incongruent movements in the convexity of the superior parietal cortex, bilaterally, making this region a likely neural site for conflict that arises during the planning and execution of bimanual movements. These results suggest distinct neural loci for 2 forms of constraint on our ability to perform bimanual reaching movements.

Goal-selection and movement-related conflict during bimanual reaching movements.

Many studies on bimanual coordination have shown that people exhibit a preference for mirror‐symmetric movements. We demonstrate that this constraint is absent when bimanual reaching movements are made to visual targets. We investigated the ability of humans to make on‐line adjustments during such movements when one or both targets were displaced during the initial phase of the movements. Adjustments were as efficient during bimanual as unimanual movements, even when two adjustments had to be made simultaneously. When one target was displaced in the bimanual condition, the hand reaching to that target adjusted efficiently to the displacement. However, a small transient perturbation in the trajectory of the other hand was also observed. This perturbation was in the same direction as the displacement, rather than in mirror‐symmetric direction. A control experiment demonstrated that these perturbations could be elicited by visual information alone, but that they were also influenced by whether an adjustment was required in the trajectory of the other hand. Our results demonstrate near independent control of the two arms during visually guided reaching. The subtle interference observed between the arms reflects interactions between target‐related representations in visual coordinates rather than between movement‐related representations in joint‐ or muscle‐coordinates.

Independent on‐line control of the two hands during bimanual reaching

A Cognitive Neuroscience Perspective on Bimanual Coordination and Interference

Immediate spatial distortions of pointing movements induced by visual landmarks

Three experiments were conducted to identify the locus of bimanual interference observed during the production of reaching movements. The movements had either the same or different amplitude and were directed towards identically or differently colored target circles. In Experiment 1, reaction times for movements of different amplitudes to targets of the same color were faster than for movements of the same amplitude to targets of different colors. This indicates that the cost to initiate responses of unequal amplitudes arises during selection of the target of the movement rather than during motor programming. Experiments 2 and 3 further specify the sources of interference found in target selection. Reaction time costs are found with unimanual responses when the target is presented among distractors associated with responses for the other hand. This indicates that the costs may arise through an assignment problem of response-rules to the respective hands. BIMANUAL INTERFERENCE IN TARGET SELECTION 3 Bimanual interference associated with the selection of movement targets We typically use our two hands in a coordinated fashion to achieve a common goal. When unscrewing a bottle or tying a knot, the actions of the two hands have to be finely tuned in relation to each other. Constraints on bimanual performance become apparent when we use our hands to achieve different goals at the same time. Consider for example the task of picking out good cherries among rotten ones from a tray in the supermarket, with either one or two hands. If our hands could work perfectly independently, we should be able to pick out twice as many cherries with both hands than with only one. This, however, is not the case. This limitation may be due to our inability to plan or execute independent movements with the two hands at the same time. Alternatively, we may have problems in selecting in parallel the goals of the two reaching movements based on a number of criteria as size, color, smoothness, etc. for the two hands. The focus of the present article is to determine the processing stage that gives rise to the performance limitations during bimanual movements. In the laboratory, these limitations of bimanual performance have been studied with tasks that require the simultaneous production of two movements with either symmetric or differing spatial characteristics. Compared to when the movements are the same for the two hands, producing different movements with the two hands prolongs initiation times (Franz, Eliassen, Ivry, & Gazzaniga, 1996; Spijkers, Heuer, Kleinsorge, & van der Loo, 1997) and significant distortions of the spatial trajectories can be observed (Franz, Zelaznik, & McCabe, 1991; Kelso, Putnam, & Goodman, 1983; Sherwood, 1990; Spijkers & Heuer, 1995). Spijkers and his associates have explored the question of when limitations arise in a series of papers (1997; Spijkers, Heuer, Steglich, & Kleinsorge, 2000). In one study, participants were required to execute fast lateral movements (outward and back) with their arms. The target amplitude of each movement was cued by the presentation of two bars, one on the left and one on the right of a computer monitor. Each bar could either be short or long. Reaction times were nearly 100 ms longer when the two movements were incongruent (i.e., one short and the other long) compared to when the two movements were congruent (i.e., both short or both long). The authors proposed that this increase BIMANUAL INTERFERENCE IN TARGET SELECTION 4 reflected interference at the stage of motor programming (see Rosenbaum, 1980; Rosenbaum & Kornblum, 1982). Programming was fast when the only unknown parameter, movement amplitude, was set to the same value for each hand. When different parameters needed to be specified, cross talk was hypothesized to occur between the programming process required for the right arm and that required for the left arm. This cross talk presumably led to the increase in RT on incongruent trials. A challenge to the programming interpretation comes from a recent study in which the target locations were specified directly (Diedrichsen, Hazeltine, Kennerley, & Ivry, in press). That is, visual signals were presented on the table surface and the participants were instructed to move as quickly as possible to the target locations. Under these conditions, no differences were found in RT between congruent and incongruent movements, regardless of whether incongruency was defined as a difference in movement amplitude or direction. Indeed, the RT on bimanual trials with direct cues was as fast as on unimanual trials. Assuming that motor programming and execution processes are similar for direct and symbolically cued movements, these results indicate that the interference observed in earlier studies is unlikely to be attributed to either of these stages. Rather, the interference visible in the RT data is likely due to a processing stage associated with identification of the stimulus and/or selection of the appropriate response. Although rarely discussed as such, bimanual reaching studies constitute a form of a dual-task paradigm. Limitations in dual task performance have been one of the central topics in cognitive psychology and have played a critical role in the development of analytic tools for specifying processing stages across a range of tasks (Pashler, 1998b). One example is the literature on the psychological refractory period (McCann & Johnston, 1992; Pashler, 1994; Telford, 1931). In these studies, participants have to respond to two stimuli in rapid succession. When the stimulus onset asynchrony (SOA) between the tasks is short, the RT for the second task is delayed. This limitation has been attributed to a response-selection bottleneck (but see Meyer & Kieras, 1997; Pashler, 1984, 1998a). By this view, it is assumed that stimulus identification and response execution for the two tasks can occur in parallel; the limitation is hypothesized to arise due to overlapping demands of the two tasks on a common response selection process. BIMANUAL INTERFERENCE IN TARGET SELECTION 5 Response selection for one task must be completed before this operation can be performed for the other task. With short SOAs, this delay will be manifest as an increase in RT for the second task. Spijkers et al. (2000) used a PRP paradigm with bimanual reversal movements of same or different amplitudes. They found that at short SOA the initiation of the second movement was considerably delayed, when the movement amplitudes were incongruent. They interpreted their results as interference of temporally overlapping motor programming processes. With their symbolic bar stimuli as cues, however, the cost on incongruent trials might be associated with the demands associated with processing nonidentical cues or because non-identical "abstract" movement codes had to be selected. The first hypothesis was ruled out by a control condition in which the first stimulus had to be identified, but no response was required. The participants showed similar RTs in this condition on congruent and incongruent trials. The second possibili ty was considered by the authors, but dismissed because “the distinction between response selection and amplitude specification is inappropriate for our experimental paradigm [...]. As argued by Rosenbaum (1983), selection of a movement is equivalent to specifying its parameters” (Spijkers et al., 2000, p. 1103 ). This argument may be valid in cases in which the movements are not directed to specific targets but are instead determined by symbolic stimuli that specify the movement in terms of kinematic parameters. Under these symbolic conditions, movements may be mentally represented in terms of these task-defined movement parameters. That is, when participants are told to make a long or short movement in response to the letter “L” or “S” , then they likely represent possible action as either a “long movement” or “short movement” . Selection of the response then operates on codes in terms of movement parameters. Bimanual interference arises when two actions with different representations have to be selected. However, when the movement is directed towards an object, the response code may encompass characteristics of the goal object rather than the movement parameters. For example, imagine you want retrieve a tool from a cluttered tool drawer. Deciding which object you want to pick out would constitute a response-selection process. The location of that object and its orientation would then dictate the motor programming requirements, a process that would follow selection. In this way, the BIMANUAL INTERFERENCE IN TARGET SELECTION 6 selection of the movement goal and the specification of the movement parameters to get to the goal can be separated. This distinction suggests two possible loci for bimanual interference. If cross talk arises during the selection of responses, then the pattern of interference should depend heavily on how the possible actions are represented. If cross talk arises during the specification of motor parameters, then the interference should be determined by the kinematic properties of the movements. In Experiment 1 participants were instructed to select an object for each hand and then directly reach for it. The reaches could require movements of the same or different amplitudes. The goal of this study was to examine whether the interference should be attributed to early stages (stimulus identification and response selection) as has been hypothesized in PRP studies and our earlier direct reaching study (Diedrichsen et al., in press) or late stages (motor programming and motor execution) as has been assumed in most bimanual reaching studies. Experiment 1 The experiment was conducted in an apparatus which allowed participants to reach directly for visually presented targets (Figure 1). Four target locations were defined on each trial by the presentation of four colored circles that forme

Bimanual interference associated with the selection of movement targets

Spatial distortions induced by multiple visual landmarks: How local distortions combine to produce complex distortion patterns

Four experiments were conducted to identify the locus of interference observed during the preparation of bimanual reaching movements. Target locations were specified by color, and the right-hand and left-hand targets could be either the same or a different color. Movements of different amplitudes (Experiment 1) or different directions (Experiment 2) to targets of the same color were initiated more quickly than symmetric movements to targets of different colors. These results indicate that costs observed during bimanual movements arise during target selection rather than during motor programming. Experiments 3 and 4 further examined the interference associated with target selection. Reaction time costs were found with unimanual movements when the target was presented among distractors associated with responses for the other hand. Interference observed during bimanual reaching appears to reflect difficulty in segregating the response rules assigned to each hand.

Journal of experimental psychology. Human perception and performance

Bimanual interference associated with the selection of target locations.

Patients with cerebellar damage are known to exhibit deficits in the temporal control of movements. We report that these deficits are restricted to discontinuous movements. Cerebellar patients exhibited no deficit in temporal variability when producing continuous, rhythmic movements. We hypothesize that the temporal properties of continuous movements are emergent and reflect the operation of other control parameters not associated with the cerebellum. In contrast, discontinuous movements require an explicit representation of the temporal goal, a function of the cerebellum. The requirement for explicit temporal representation provides a parsimonious account of cerebellar involvement in a range of tasks.

Disrupted Timing of Discontinuous But Not Continuous Movements by Cerebellar Lesions

Two split-brain patients, a patient with callosal agenesis, and 6 age-matched control participants were tested on a bimanual force production task. The participants produced isometric responses with their index fingers, attempting to match the target force specified by a visual stimulus. On unimanual trials, the stimuli were presented in either the left or right visual field and the response was made with the ipsilateral hand. On bimanual trials, two stimuli were presented, one on each side, and the target forces could be either identical or different. Bimanual responses of the control subjects showed strong evidence of coupling. Forces produced by one hand were influenced by the forces produced by the other hand with positive correlations observed for all target force combinations. These assimilation effects and correlations were greatly attenuated in the acallosal group, with similar results observed for the split-brain patients and participant with callosal agenesis. Furthermore, the processes involved in selecting and planning the two responses occurred independently in the acallosal group; in contrast to the controls, the three acallosal participants exhibited no differences in reaction times or accuracy between bimanual trials in which the two target forces were the same or different. We also found a striking temporal desynchronization of the responses in the split-brain patients, indicating that in this context, temporal coupling is impaired after callosotomy. These results are congruent with the hypothesis that interference related to response selection and planning of bimanual force pulses arises from callosal interactions.

The role of the corpus callosum in the coupling of bimanual isometric force pulses.

We argue that bimanual coordination and interference depends critically on how these actions are represented on a cognitive level. We first review the literature on spatial interactions, focusing on the difference between movements directed at visual targets and movements cued symbolically. Interactions manifest during response planning are limited to the latter condition. These results suggest that interactions in the formation of the trajectories of the two hands are associated with processes involved in response selection, rather than interactions in the motor system. Neuropsychological studies involving callosotomy patients argue that these interactions arise from transcallosal interactions between cortically-based spatial codes. The second half of the chapter examines temporal constraints observed in bimanual movements. We propose that most bimanual movements are marked by a common event structure, an explicit representation that ensures temporal coordination of the movements. The translation of an abstract event structure into a movement with a particular timing pattern is associated with cerebellar function, although the resulting temporal coupling during bimanual movements may be due to the operation of other subcortical mechanisms. For rhythmic movements that do not entail an event structure, timing may be an emergent property. Under such conditions, both spatial and temporal coupling can be absent. The emphasis on abstract levels of constraint makes clear that limitations in bimanual coordination overlap to a considerable degree with those observed in other domains of cognition.

Abstract: Damage to the cerebellum disrupts performance on a range of tasks that require precise timing including the production of skilled movements, eyeblink conditioning, and perceptual tasks such as duration discrimination. We hypothesize that such tasks involve event timing, a form of representation in which the temporal goals are explicitly represented. For example, during finger tapping, the goal to produce evenly paced intervals invokes an explicit temporal representation of the time between successive contact points with the tapping surface. In contrast, timing can be an emergent property in other actions, reflecting temporal consistencies that arise through the control of other movement parameters. One example is continuous circle drawing, a task in which temporal consistency can be achieved by maintaining a constant angular velocity or minimizing higher‐order derivatives (e.g., jerk). Temporal consistency on event and emergent timing tasks is not correlated and patients with cerebellar damage show no increase in temporal variability during continuous circle drawing. While the cerebellum likely contributes to performance of a wide range of skilled behaviors, it appears to be especially important when the tasks entail event timing.

Anticipatory adjustments in the unloading task: Is an efference copy necessary for learning?

Callosotomy patients exhibit temporal uncoupling during continuous bimanual movements

Does the Cerebellum Preferentially Control Discrete and Not Continuous Movements?

The theory of event coding by Hommel et al. proposes that feature binding is a central component of action planning. To evaluate the binding hypothesis, we consider findings from studies of action-perception interference and bimanual movements. We argue that although binding of action features may be a valuable concept, interference from partial feature overlap does not provide a parsimonious account for the observed phenomena.

The theory of event coding by Hommel et al. proposes that feature binding is a central component of action planning. To evaluate the binding hypothesis, we consider findings from studies of action-perception interference and bimanual movement. We argue that although binding of action features may be a valuable concept, interference from partial feature overlap does not provide a parsimonious account for the observed phenomena.

Unifying by binding: will binding really bind? A commentary on Hommel et al. (2001).

Interference is frequently observed during bimanual movements if the two hands perform nonsymmetric actions. We examined the source of bimanual interference in two experiments in which we compared conditions involving symmetric movements with conditions in which the movements were of different amplitudes or different directions. The target movements were cued either symbolically by letters or directly by the onset of the target locations. With symbolic cues, reaction times were longer when the movements of the two hands were not symmetric. With direct cues, reaction times were the same for symmetric and nonsymmetric movements. These results indicate that directly cued actions can be programmed in parallel for the two hands. Our results challenge the hypothesis that the cost to initiate nonsymmetric movements is due to spatial interference in a motor-programming stage. Rather, the cost appears to be caused by stimulus identification, response-selection processes connected to the processing of symbolic cues, or both.

Moving to Directly Cued Locations Abolishes Spatial Interference During Bimanual Actions

When presented with a red T and a green O, observers occasionally make conjunction responses and indicate that they saw a green T. These errors have been interpreted as reflecting separable processing stages of feature detection and integration with the illusory conjunctions arising from a failure at the integration stage. Recently, M. Donk (1999) asserted that the phenomenon of illusory conjunctions is an artifact. Conjunction reports are actually the result of confusing a nontarget item (O in the example above) for a target item (the letter T) and (correctly) reporting the color associated with the (incorrectly) selected target. The authors demonstrate that although target-nontarget confusion errors are a potential source of conjunction reports, there is a plethora of findings that cannot be accounted for by this confusion model. A review of the literature indicates that in many studies, illusory conjunctions do result from a failure to properly integrate features.

Illusory conjunctions are alive and well: a reply to Donk (1999).

Four experiments were conducted using a flanker task with 1 distractor appearing either on the left or right side of a central target. Responses were made on a keyboard aligned parallel to the displays. A larger flanker effect was obtained when the distractor was on the same side as the response. Two factors account for this asymmetry. First, when the flanker and target are identical, the 2 form a group that is assigned a spatial tag, creating a form of the Simon effect on the basis of the compatibility between the response keys and the group. Second, preparation of a lateralized response appears to entail a shift of visual attention in the corresponding direction, thus enhancing processing of the flanker on the response side. Consistent with the 2nd hypothesis, participants were more likely to correctly recognize letters that were briefly presented at the distractor position on the same side as the response.

Asymmetries in a unilateral flanker task depend on the direction of the response: the role of attentional shift and perceptual grouping.

From action goals to movement: How do we decide which hand to use when reaching for an object?

Why we need a more realistic muscle model for optimal control theory: Lessons from a deafferented patient

Verarbeitung visueller Informationen zur motorischen Kontrolle: Agency und Aufmerksamkeit

eLife is changing its editorial process to emphasize public reviews and assessments of preprints by eliminating accept/reject decisions after peer review.

Everything else being equal, simpler models should be preferred over more complex ones. In reinforcement learning (RL), simplicity is typically quantified on an action-by-action basis -- but this timescale ignores temporal regularities, like repetitions, often present in sequential strategies. We therefore propose an RL algorithm that learns to solve tasks with sequences of actions that are compressible. We explore two possible sources of simple action sequences: Sequences that can be learned by autoregressive models, and sequences that are compressible with off-the-shelf data compression algorithms. Distilling these preferences into sequence priors, we derive a novel information-theoretic objective that incentivizes agents to learn policies that maximize rewards while conforming to these priors. We show that the resulting RL algorithm leads to faster learning, and attains higher returns than state-of-the-art model-free approaches in a series of continuous control tasks from the DeepMind Control Suite. These priors also produce a powerful information-regularized agent that is robust to noisy observations and can perform open-loop control.

Pavlovian influences notoriously interfere with operant behaviour; various such may be associated with the release of the neuromodulator dopamine in the nucleus accumbens. One role for cognitive control is suppressing these influences. Here, using the examples of active avoidance and omission behaviour, we examine the possibility that one instrument of control is direct manipulation of the dopamine signal itself.

Reframing dopamine: Controlling the controller at the limbic-motor interface

When we exercise sequences of actions, their execution becomes more fluent and precise. Here, we consider the possibility that exercised action sequences can also be used to make planning faster and more accurate by focusing expansion of the search tree on paths that have been frequently used in the past, and by reducing deep planning problems to shallow ones via multi-step jumps in the tree. To capture such sequences, we use a flexible Bayesian action chunking mechanism which finds and exploits statistically reliable structure at different scales. This gives rise to shorter or longer routines that can be embedded into a Monte-Carlo tree search planner. We show the benefits of this scheme using a physical construction task patterned after tangrams.

Formalising social representation to explain psychiatric symptoms

Reply to ‘Post-encounter freezing during approach–avoidance conflict: the role of the hippocampus’

Exploration is vital for animals and artificial agents who face uncertainty about their environments due to initial ignorance or subsequent changes. Their choices need to balance exploitation of the knowledge already acquired, with exploration to resolve uncertainty [1, 2]. However, the exact algorithmic structure of exploratory choices in the brain still remains largely elusive. A venerable idea in reinforcement learning is that agents can plan appropriate exploratory choices offline, during the equivalent of quiet wakefulness or sleep. Although offline processing in humans and other animals, in the form of hippocampal replay and preplay, has recently been the subject of highly successful modelling [3–5], existing methods only apply to known environments. Thus, they cannot predict exploratory replay choices during learning and/or behaviour in dynamic environments. Here, we extend the theory of Mattar & Daw [3] to examine the potential role of replay in approximately optimal exploration, deriving testable predictions for the patterns of exploratory replay choices in a paradigmatic spatial navigation task. Our modelling provides a normative interpretation of the available experimental data suggestive of exploratory replay. Furthermore, we highlight the importance of sequence replay, and license a range of new experimental paradigms that should further our understanding of offline processing.

Paying attention to particular aspects of the world or being more vigilant in general can be interpreted as forms of ‘internal’ action. Such arousal-related choices come with the benefit of increasing the quality and situational appropriateness of information acquisition and processing, but incur potentially expensive energetic and opportunity costs. One implementational route for these choices is widespread ascending neuromodulation, including by acetylcholine (ACh). The key computational question that elective attention poses for sensory processing is when it is worthwhile paying these costs, and this includes consideration of whether sufficient information has yet been collected to justify the higher signal-to-noise ratio afforded by greater attention and, particularly if a change in attentional state is more expensive than its maintenance, when states of heightened attention ought to persist. We offer a partially observable Markov decision-process treatment of optional attention in a detection task, and use it to provide a qualitative model of the results of studies using modern techniques to measure and manipulate ACh in rodents performing a similar task.

Vigilance, arousal, and acetylcholine: Optimal control of attention in a simple detection task

After Debussy is ambitious, timely, courageous, and invigoratingly combative. It is written against ‘the tendency of all musicology to become like Golaud, bitter and bewildered, dragging Mélisande around by the hair and demanding that she speak “la vérité”’ (p. 305). It situates itself as much on the margins of musicology as on those of philosophy, acutely observing how musicology was born, as Musikwissenschaft, of a certain kind of philosophical thinking that shies away from those margins, seeking always the linguistic security of instrumental reason, refusing to admit the existence of any kind of truth that cannot be spoken. This logocentrism is fundamental to the academic critical tradition, so it cannot be attacked directly from within one’s own academic critical discourse. Julian Johnson’s strategy is to enlist allies from three camps outside academe. The first camp consists of Debussy and his like-minded contemporaries, who, Johnson tells us, ‘inaugurated an aesthetic attitude that is wholly at odds with the world view of Musikwissenschaft’ (p. 304). This attitude leads, in music, to a concrete thinking in sound, a writing that is with and of the body (in Debussy’s case, notably as it engages with the keys of the piano and the culture of pianism). This type of creativity is concerned not with making things appear, but with the process of cominginto-appearance itself. Johnson does not merely make this argument in the abstract; he develops it through quite precise analysis of specific art works by Debussy. What convinced me of the pertinence of his method was simply listening to the pieces Johnson discusses after reading his analyses; they gave me a new sense of how this music works. Among Debussy’s contemporaries, Mallarmé is the most often cited. His analysis of poetry, music, and dance are often inspirations for Johnson. In that context, to me, perhaps the least persuasive aspect of Johnson’s argument is his notion that music should be considered ‘a mode of knowing the world, of thinking the world sensually’ (p. 285). The world is not, for Mallarmé, the object of the knowing and thinking that art embodies. But to do justice to that object (which is, in fact, not really an object at all) as conceived of by Mallarmé and Debussy, not to mention Derrida, would take, perhaps, another book. Johnson’s second set of allies consists of philosophers in reaction against positive or rationalist philosophy, beginning with Henri Bergson but concentrated in the period of what one might call ‘French theory’, between the 1950s and the 1980s, from Vladimir Jankélévitch and Maurice Merleau-Ponty to Roland Barthes, Jacques Derrida, and Jean-Luc Nancy, including Susan Sontag. These writers, he contends, showed to the literary and philosophical world the limits of the dominant human-scientific discourse, and the possibility of another kind of writing. However, ‘fifty years after Derrida’s Of Grammatology, Anglo-American musicology has not even begun to think through its consequences for music. Indeed, if anything, it has reembraced the very phonocentrism that Derrida calls into question’ (p. 205). The connection between Mallarmé’s thinking and that of theorists such as Derrida is of course explicit enough; what Johnson does is to couple Debussy’s musical aesthetics to Mallarmé’s and thence to Derrida’s, so that the literary theory of the

After Debussy: Music, Language, and the Margins of Philosophy by Julian Johnson (review)

Freezing revisited: coordinated autonomic and central optimization of threat coping

Gravity and Grace: Essays for Roger Pearson by Charlie Louth Patrick McGuinness (review)

P243. The Cognitive and Neural Impact of Uncontrollable Stress on Reward-Learning

Inferring causes of the good and bad events that we experience is part of the process of building models of our own capabilities and of the world around us. Making such inferences can be difficult because of complex reciprocal relationships between attributions of the causes of particular events, and beliefs about the capabilities and skills that influence our role in bringing them about. Abnormal causal attributions have long been studied in connection with psychiatric disorders, notably depression and paranoia; however, the mechanisms behind attributional inferences and the way they can go awry are not fully understood. We administered a novel, challenging, game of skill to a substantial population of healthy online participants, and collected trial-by-trial time series of both their beliefs about skill and attributions about the causes of the success and failure of real experienced outcomes. We found reciprocal relationships that provide empirical confirmation of the attribution-self representation cycle theory. This highlights the dynamic nature of the processes involved in attribution, and validates a framework for developing and testing computational accounts of attribution-belief interactions.

Interactions between attributions and beliefs at trial-by-trial level: Evidence from a novel computer game task

Learning the contingencies of a complex experiment is not easy. Individuals learn in an idiosyncratic manner, revising their strategies multiple times as they are shaped, or shape themselves. They may even end up with different asymptotic strategies. This long-run learning is therefore a tantalizing tar-get for the sort of quantitatively individualized characteriza-tion that descriptive models can provide. However, any such model requires a flexible and extensible structure which can capture the rapid introduction of radically new behaviours as well as slow changes in existing ones. We suggest a dynamic input-output infinite hidden semi-Markov model whose latent states are associated with specific behavioural patterns. This model encompasses a countably infinite number of potential states, and so can capture new behaviours by introducing states; equally, dynamical evolution of the behavioural pattern specified by a single state allows tracking of slow adaptations in existing behaviours. We fit this model to around 10,000 trials per mouse as they learned to perform a contrast detection task over multiple stages. We quantify different stages of learning via the number and psychometric characteristics of behavioural states, providing comprehensive insight into the highly individualised learning trajectories of animals.

Understanding Learning Trajectories With Infinite Hidden Markov Models

Individuals prone to anxiety and depression often report beliefs and make judgements about themselves that are more negative than those reported by others. We use computational modeling of a richly naturalistic task to disentangle the role of negative priors versus negatively biased belief updating and to investigate their association with different dimensions of Internalizing psychopathology. Undergraduate participants first provided profiles for a hypothetical tech internship. They then viewed pairs of other profiles and selected the individual they would prefer to work alongside out of each pair. In a subsequent phase of the experiment, participants made judgments about their relative popularity as hypothetical internship partners both before any feedback and after each of 20 items of feedback revealing whether or not they had been selected as the preferred teammate from a given pairing. Scores on latent factors of general negative affect, anxiety-specific affect and depression-specific affect were estimated using participants’ self-report scores on standardized measures of anxiety and depression together with factor loadings from a bifactor analysis conducted previously. Higher scores on the depression-specific factor were linked to more negative prior beliefs but were not associated with differences in belief updating. In contrast, higher scores on the anxiety-specific factor were associated with a negative bias in belief updating but no difference in prior beliefs. These findings indicate that, to at least some extent, distinct processes may impact the formation of belief priors and in-the-moment belief updating and that these processes may be differentially disrupted in depression and anxiety. Future directions for enquiry include examination of the possibility that prior beliefs biases in depression might reflect generalization from prior experiences or global schema whereas belief updating biases in anxiety might be more situationally specific.

Biased belief priors versus biased belief updating: Differential correlates of depression and anxiety

We use internal models of the external world to guide behavior, but little is known about how these cognitive maps are created. The orbitofrontal cortex (OFC) is typically thought to access these maps to support model-based decision-making, but it has recently been proposed that its critical contribution may be instead to integrate information into existing and new models. We tested between these alternatives using an outcome-specific devaluation task and a high-potency chemogenetic approach. We found that selectively inactivating OFC principal neurons when rats learned distinct cue-outcome associations, but prior to outcome devaluation, disrupted subsequent model-based inference, confirming that the OFC is critical for creating new cognitive maps. However, OFC inactivation surprisingly led to generalized devaluation. Using a novel reinforcement learning framework, we demonstrate that this effect is best explained not by a switch to a model-free system, as would be traditionally assumed, but rather by a circumscribed deficit in defining credit assignment precision during model construction. We conclude that the critical contribution of the OFC to learning is regulating the specificity of associations that comprise cognitive maps. One Sentence Summary OFC inactivation impairs learning of new specific cue-outcome associations without disrupting model-based learning in general.

Inferring causes of the good and bad events that we experience is part of the process of building models of our own capabilities and of the world around us. Making such inferences can be dicult because of complex reciprocal relationships between attributions of the causes of particular events, and beliefs about the capabilities and skills that influence our role in bringing them about. Abnormal causal attributions have long been studied in connection with psychiatric disorders, notably depression and paranoia; however, the mechanisms behind attributional inferences and the way they can go awry are not fully understood. We administered a novel, challenging, game of skill to a substantial population of online participants, and collected trial-by-trial time series of both their beliefs about skill and attributions about the causes of the success and failure of real experienced outcomes. We found reciprocal relationships that provide empirical confirmation of the attribution-self representation cycle theory. This highlights the dynamic nature of the processes involved in attribution, and validates a framework for developing and testing computational accounts of attribution-belief interactions.

Interactions between attributions and beliefs at high temporal resolution : evidence from a novel task

In evaluating our choices, we often suffer from two tragic relativities. First, when our lives change for the better, we rapidly habituate to the higher standard of living. Second, we cannot escape comparing ourselves to various relative standards. Habituation and comparisons can be very disruptive to decision-making and happiness, and till date, it remains a puzzle why they have come to be a part of cognition in the first place. Here, we present computational evidence that suggests that these features might play an important role in promoting adaptive behavior. Using the framework of reinforcement learning, we explore the benefit of employing a reward function that, in addition to the reward provided by the underlying task, also depends on prior expectations and relative comparisons. We find that while agents equipped with this reward function are less happy, they learn faster and significantly outperform standard reward-based agents in a wide range of environments. Specifically, we find that relative comparisons speed up learning by providing an exploration incentive to the agents, and prior expectations serve as a useful aid to comparisons, especially in sparsely-rewarded and non-stationary environments. Our simulations also reveal potential drawbacks of this reward function and show that agents perform sub-optimally when comparisons are left unchecked and when there are too many similar options. Together, our results help explain why we are prone to becoming trapped in a cycle of never-ending wants and desires, and may shed light on psychopathologies such as depression, materialism, and overconsumption.

The pursuit of happiness: A reinforcement learning perspective on habituation and comparisons

Spatial preferences account for inter-animal variability during the continual learning of a dynamic cognitive task

One of the most important and challenging application areas for complex machine learning methods is to predict, characterize and model rich, multi-dimensional, neural data. Recent advances in neural recording techniques have made it possible to monitor the activities of a large number of neurons across different brain regions as animals perform behavioural tasks. This poses the critical challenge of establishing links between neural activity at a microscopic scale, which might for instance represent sensory input, and at a macroscopic scale, which then generates behaviour. Predominant modeling methods apply rather disjoint techniques to these scales; by contrast, we suggest an end-to-end model which exploits recent developments of flexible, but tractable, neural network point-process models to characterize dependencies between stimuli, actions, and neural data. We apply this model to a public dataset collected using Neuropixel probes in mice performing a visually-guided behavioural task as well as a synthetic dataset produced from a hierarchical network model with reciprocally connected sensory and integration circuits intended to characterize animal behaviour in a fixed-duration motion discrimination task. We show that our model outperforms previous approaches and contributes novel insights into the relationships between neural activities and behaviour.

P242. Anxiety Associated with Perceived Lack of Control Over Stress During the COVID-19 Pandemic Impairs Reward Learning

A computational process-tracing method for measuring people’s planning strategies and how they change over time

: Cognitive maps represent relational structures and are taken to be important for generalization and optimal decision making in spatial as well as non-spatial domains. While many studies have investigated the benefits of cognitive maps, how these maps are learned from experience has remained less clear. We introduce a new graph-structured sequence task to better understand how cognitive maps are learned. Participants observed sequences of episodes followed by a reward, thereby learning about the underlying transition structure and fluctuating reward contingencies. Importantly, the task structure allowed participants to generalize value from some episode sequences to others, and generalizability was either signaled by episode similarity or had to be inferred more indirectly. Behavioral data demonstrated participants ` ability to learn about signaled and unsignaled generalizability with different speed, indicating that the formation of cognitive maps partially relies on exploiting observable similarities across episodes. We hypothesize that a possible neural mechanism involved in learning cognitive maps as described here is experience replay.

Representation learning facilitates different levels of generalization

Humans can implicitly learn complex perceptuo-motor skills over the course of large numbers of trials. This likely depends on our becoming better able to take advantage of ever richer and temporally deeper predictive relationships in the environment. Here, we offer a novel characterization of this process, fitting a non-parametric, hierarchical Bayesian sequence model to the reaction times of human participants’ responses over ten sessions, each comprising thousands of trials, in a serial reaction time task involving higher-order dependencies. The model, adapted from the domain of language, forgetfully updates trial-by-trial, and seamlessly combines predictive information from shorter and longer windows onto past events, weighing the windows proportionally to their predictive power. As the model defines a prior over window depths, we were able to determine the extent to which the internal predictions of individual participant depended on how many previous elements. Already in the first session, the model showed that participants had begun to rely on two previous elements (i.e., trigrams), thereby successfully adapting to the most prominent higher-order structure in the task. The extent to which local statistical fluctuations influenced participants’ responses waned over subsequent sessions, as subjects forgot the trigrams less and evidenced skilled performance. By the eighth session, a subset of participants shifted their prior further to consider a context deeper than two previous elements. Finally, participants showed resistance to interference and slow forgetting of the old sequence when it was changed in the final sessions. Model parameters for individual subjects covaried appropriately with independent measures of working memory. In sum, the model offers the first principled account of the adaptive complexity and nuanced dynamics of humans’ internal sequence representations during long-term implicit skill learning. Author summary A central function of the brain is to predict. One challenge of prediction is that both external events and our own actions can depend on a variably deep temporal context of previous events or actions. For instance, in a short motor routine, like opening a door, our actions only depend on a few previous ones (e.g., push the handle if the key was turned). In longer routines such as coffee making, our actions require a deeper context (e.g., place the moka pot on the hob if coffee is ground, the pot is filled and closed, and the hob is on). We adopted a model from the natural language processing literature that matches humans’ ability to learn variable-length relationships in sequences. This model explained the gradual emergence of more complex sequence knowledge and individual differences in an experiment where humans practiced a perceptual-motor sequence over 10 weekly sessions.

Tracking human skill learning with a hierarchical Bayesian sequence model

The role of the lateral orbitofrontal cortex in creating cognitive maps

Psychological and neural distinctions between the technical concepts of “liking” and “wanting” pose important problems for motivated choice for goods. Why could we “want” something that we do not “like,” or “like” something but be unwilling to exert effort to acquire it? Here, we suggest a framework for answering these questions through the medium of reinforcement learning. We consider “liking” to provide immediate, but preliminary and ultimately cancellable, information about the true, long-run worth of a good. Such initial estimates, viewed through the lens of what is known as potential-based shaping, help solve the temporally complex learning problems faced by animals.

“Liking” as an early and editable draft of long-run affective value

Efficiency and prioritization of inference-based credit assignment

The controllability of our social environment has a profound impact on our behavior and mental health. Nevertheless, neurocomputational mechanisms underlying social controllability remain elusive. Here, 48 participants performed a task where their current choices either did (Controllable), or did not (Uncontrollable), influence partners’ future proposals. Computational modeling revealed that people engaged a mental model of forward thinking (FT; i.e., calculating the downstream effects of current actions) to estimate social controllability in both Controllable and Uncontrollable conditions. A largescale online replication study (n=1342) supported this finding. Using functional magnetic resonance imaging (n=48), we further demonstrated that the ventromedial prefrontal cortex (vmPFC) computed the projected total values of current actions during forward planning, supporting the neural realization of the forwardthinking model. These findings demonstrate that humans use vmPFCdependent FT to estimate and exploit social controllability, expanding the role of this neurocomputational mechanism beyond spatial and cognitive contexts.

Author response: Humans use forward thinking to exploit social controllability

Significance Credit assignment (CA) to relevant actions poses a challenge because one is often flooded with reward feedback that is not easily causally attributed. We addressed this issue in a reinforcement learning framework wherein choice is mutually controlled by value-caching model-free (MF) and prospective, planning model-based (MB) systems. We find knowledge, stored in a cognitive map, filters exuberant reward feedback to guide CA in both systems but based on different attribute dimensions. In MF, CA is boosted for outcomes that are relevant (causally related) to one’s choice, whereas in MB, CA is enhanced for outcomes that attract greater attention during the deliberation process that preceded a choice. We consider normative and mechanistic accounts, including how these processes are instrumental to adaptation. An influential reinforcement learning framework proposes that behavior is jointly governed by model-free (MF) and model-based (MB) controllers. The former learns the values of actions directly from past encounters, and the latter exploits a cognitive map of the task to calculate these prospectively. Considerable attention has been paid to how these systems interact during choice, but how and whether knowledge of a cognitive map contributes to the way MF and MB controllers assign credit (i.e., to how they revaluate actions and states following the receipt of an outcome) remains underexplored. Here, we examine such sophisticated credit assignment using a dual-outcome bandit task. We provide evidence that knowledge of a cognitive map influences credit assignment in both MF and MB systems, mediating subtly different aspects of apparent relevance. Specifically, we show MF credit assignment is enhanced for those rewards that are related to a choice, and this contrasted with choice-unrelated rewards that reinforced subsequent choices negatively. This modulation is only possible based on knowledge of task structure. On the other hand, MB credit assignment was boosted for outcomes that impacted on differences in values between offered bandits. We consider mechanistic accounts and the normative status of these findings. We suggest the findings extend the scope and sophistication of cognitive map-based credit assignment during reinforcement learning, with implications for understanding behavioral control.

Dopamine is implicated in signalling model-free (MF) reward prediction errors and various aspects of model-based (MB) credit assignment and choice. Recently, we showed that cooperative interactions between MB and MF systems include guidance of MF credit assignment by MB inference. Here, we used a double-blind, placebo-controlled, within-subjects design to test the hypothesis that enhancing dopamine levels, using levodopa, boosts the guidance of MF credit assignment by MB inference. We found that levodopa enhanced retrospective guidance of MF credit assignment by MB inference, without impacting on MF and MB influences per se. This drug effect positively correlated with working memory, but only in a context where reward needed to be recalled for MF credit assignment. The dopaminergic enhancement in MB-MF interactions correlated negatively with a dopamine-dependent change in MB credit assignment, possibly reflecting a potential trade-off between these two components of behavioural control. Thus, our findings demonstrate that dopamine boosts MB inference during guidance of MF learning, supported in part by working memory, but trading-off with a dopaminergic enhancement of MB credit assignment. The findings highlight a novel role for a DA influence on MB-MF interactions.

Dopamine enhances model-free credit assignment through boosting of retrospective model-based inference

The pursuit of happiness is not easy. Habituation to positive changes in lifestyle and constant comparisons leave us unhappy even in the best of conditions. Given their disruptive impact, it remains a puzzle why habituation and comparisons have come to be a part of cognition in the first place. Here, we present computational evidence that suggests that these features might play an important role in promoting adaptive behavior. Using the framework of reinforcement learning, we explore the benefit of employing a reward function that, in addition to the reward provided by the underlying task, also depends on prior expectations and relative comparisons. We find that while agents equipped with this reward function are less "happy", they learn faster and significantly outperform standard reward-based agents in a wide range of environments. The fact that these features provide considerable adaptive benefits might explain why we have the propensity to keep wanting more, even if it contributes to depression, materialism, and overconsumption.

Why it is hard to be happy with what we have: A reinforcement learning perspective

Foraging is a common decision problem in natural environments. When new exploitable sites are always available, a simple optimal strategy is to leave a current site when its return falls below a single average reward rate. Here, we examined foraging in a more structured environment, with a limited number of sites that replenished at different rates and had to be revisited. When participants could choose sites, they visited fast-replenishing sites more often, left sites at higher levels of reward, and achieved a higher net reward rate. Decisions to exploit-or-leave a site were best explained with a computational model that included both the average reward rate for the environment and reward information about the unattended sites. This suggests that unattended sites influence leave decisions, in foraging environments where sites can be revisited. Highlights Being able to select sites during foraging increased visits to high value sites This visitation pattern was efficient, producing higher average reward rates Decisions to leave a site were influenced by information about alternative sites Graphical Abstract

Neural encoding of perceived patch value during competitive and hazardous virtual foraging

Many behavioral tasks have been developed to identify brain areas, genes, andmolecular pathways involved in cognitive processes and neurological conditions. For example, the open-field test is used to investigate contributors to anxiety, the Morris water maze tests spatial learning, and spatial alternation tasks measure working memory. But performance on these tasks requires multiple nervous system functions. Some of these, such as locomotion, vision, and motivation, are well recognized, and their contributions to impaired task performance under specific experimental conditions are usually assessed. Yet other cognitive processes might make contributions as well. For example, Kastner et al. have identified two cognitive components that influence spatial alternation. Spatial alternation tasks typically use mazes with three connected arms. To receive rewards, animals starting in the central arm must proceed to the left or right arm, return to the center alley, and then visit the third arm. The animals must use working memory to remember which outer arm they visited most recently. To determine whether working memory is sufficient to explain rats’ behavior on this task, Kastner et al. created a reinforcement-learning-based computational model incorporating working memory, and they compared the model’s performance with that of rats. Even when the model was given perfect memory, it did not learn the task as quickly as rats. Moreover, the pattern of errors made by the model differed from that made by rats. Rats learned to go to the middle arm after visiting an outer arm more quickly than they learned to go to the appropriate outer arm after visiting the middle arm; in contrast, the model learned the middle-to-outer rule more quickly than the outer-to-middle rule. But when the model was augmented to include preferences for particular arms and for transitions between arms, and when it was initialized to reflect an estimate of prior starting biases, its performance more closely matched the pattern and rate of learning in rats. These results suggest that performance on the spatial alternation task is determined by other cognitive factors in addition to working memory. The work identifies a set of preferences that can explain the pattern of errors rats make, but future work will be needed to determine which factors actually influence learning in animals.

Author Correction: Reward and punisher experience alter rodent decision-making in a judgement bias task

The poems Verlaine published up to 1886 contain very frequent references to song, and many references to the nation. But only three poems refer to both; and in all three cases, the relationship between song and the nation is presented as necessarily archaic, belonging to a lost monarchic time. For Verlaine, in his own time, the poet must keep song and the nation strictly separate. Song must be a transnational ideal, always identified with the pure azure of the sky, always already beyond the nation. This ideal song is divorced from the real, audible popular songs that Verlaine knew, sang, and occasionally evokes in his poetry. Those popular songs are national in the sense that they are in a specific national language. Precisely for that reason, he refuses to dignify them with the title of song, ‘chanson’ or ‘chant’. Verlaine’s transnational idealism, expressed in his concept of wordless, transnational song, turns out to be inseparable from his violent misogyny. He wanted to see his wife as pure song, as pure as the azure of the sky; when she turned out to have a voice in a national language, his love turned to violent revenge.

Why Song in Verlaine’s Verse is Always Already Beyond the Nation

The replay of task-relevant trajectories is known to contribute to memory consolidation and improved task performance. A wide variety of experimental data show that the content of replayed sequences is highly specific and can be modulated by reward as well as other prominent task variables. However, the rules governing the choice of sequences to be replayed still remain poorly understood. One recent theoretical suggestion is that the prioritization of replay experiences in decision-making problems is based on their effect on the choice of action. We show that this implies that subjects should replay sub-optimal actions that they dysfunctionally choose rather than optimal ones, when, by being forgetful, they experience large amounts of uncertainty in their internal models of the world. We use this to account for recent experimental data demonstrating exactly pessimal replay, fitting model parameters to the individual subjects’ choices.

Abstract Good translatability of behavioral measures of affect (emotion) between human and nonhuman animals is core to comparative studies. The judgment bias (JB) task, which measures “optimistic” and “pessimistic” decision-making under ambiguity as indicators of positive and negative affective valence, has been used in both human and nonhuman animals. However, one key disparity between human and nonhuman studies is that the former typically use secondary reinforcers (e.g., money) whereas the latter typically use primary reinforcers (e.g., food). To address this deficiency and shed further light on JB as a measure of affect, we developed a novel version of a JB task for humans using primary reinforcers. Data on decision-making and reported affective state during the JB task were analyzed using computational modeling. Overall, participants grasped the task well, and as anticipated, their reported affective valence correlated with trial-by-trial variation in offered volume of juice. In addition, previous findings from monetary versions of the task were replicated: More positive prediction errors were associated with more positive affective valence, a higher lapse rate was associated with lower affective arousal, and affective arousal decreased as a function of number of trials completed. There was no evidence that more positive valence was associated with greater “optimism,” but instead, there was evidence that affective valence influenced the participants' decision stochasticity, whereas affective arousal tended to influence their propensity for errors. This novel version of the JB task provides a useful tool for investigation of the links between primary reward and punisher experience, affect, and decision-making, especially from a comparative perspective.

Using Primary Reinforcement to Enhance Translatability of a Human Affect and Decision-Making Judgment Bias Task

The metacognitive sense of confidence can play a critical role in regulating decisionmaking. In particular, a lack of confidence can justify the explicit, potentially costly, instrumental acquisition of extra information that might resolve the underlying uncertainty. Recent work has suggested a statistically sophisticated tapestry behind the information governing both the making and monitoring of choices. Here, we extend this tapestry to reveal extra richness in the use of confidence for controlling information seeking. We thereby highlight how different models of metacognition can generate diverse relationships between action, confidence, and information search. More broadly, our work shows how crucial it can be to treat metacognitive monitoring and control together.

Metacognitive Computations for Information Search: Confidence in Control

Conditional value-at-risk (CVaR) precisely characterizes the influence that rare, catastrophic events can exert over decisions. Such characterizations are important for both normal decision-making and for psychiatric conditions such as anxiety disorders – especially for sequences of decisions that might ultimately lead to disaster. CVaR, like other well-founded risk measures, compounds in complex ways over such sequences – and we recently formalized three structurally different forms in which risk either averages out or multiplies. Unfortunately, existing cognitive tasks fail to discriminate these approaches well; here, we provide examples that highlight their unique characteristics, and make formal links to temporal discounting for the two of the approaches that are time consistent. These examples can ground future experiments with the broader aim of characterizing risk attitudes, especially for longer horizon problems and in psychopathological populations.

Distributional reinforcement learning (RL) – in which agents learn about all the possible long-term consequences of their actions, and not just the expected value – is of great recent interest. One of the most important affordances of a distributional view is facilitating a modern, measured, approach to risk when outcomes are not completely certain. By contrast, psychological and neuroscientific investigations into decision making under risk have utilized a variety of more venerable theoretical models such as prospect theory that lack axiomatically desirable properties such as coherence. Here, we consider a particularly relevant risk measure for modeling human and animal planning, called conditional value-at-risk (CVaR), which quantifies worst-case outcomes (e.g., vehicle accidents or predation). We first adopt a conventional distributional approach to CVaR in a sequential setting and reanalyze the choices of human decision-makers in the well-known two-step task, revealing substantial risk aversion that had been lurking under stickiness and perseveration. We then consider a further critical property of risk sensitivity, namely time consistency, showing alternatives to this form of CVaR that enjoy this desirable characteristic. We use simulations to examine settings in which the various forms differ in ways that have implications for human and animal planning and behavior.

Risk occupies a central role in both the theory and practice of decision-making. Although it is deeply implicated in many conditions involving dysfunctional behavior and thought, modern theoretical approaches to understanding and mitigating risk, in either one-shot or sequential settings, have yet to permeate fully the fields of neural reinforcement learning and computational psychiatry. Here we use one prominent approach, called conditional value-at-risk (CVaR), to examine optimal risk-sensitive choice and a form of optimal, risk-sensitive offline planning. We relate the former to both a justified form of the gambler’s fallacy and extremely risk-avoidant behavior resembling that observed in anxiety disorders. We relate the latter to worry and rumination.

People invest precious time and resources on experiences such as watching movies or listening to music. Yet, we still have a poor understanding of how such sensed experiences gain aesthetic value. We propose a model of aesthetic value that integrates existing theories with literature on conventional primary and secondary rewards such as food and money. We assume that the states of observers' sensory and cognitive systems adapt to process stimuli effectively in both the present and the future. These system states collectively comprise a probabilistic generative model of stimuli in the environment. Two interlinked components generate value: immediate sensory reward and the change in expected future reward. An immediate sensory reward is taken as the fluency with which a stimulus is processed, quantified by the likelihood of that stimulus given an observer's state. The change in expected future reward is taken as the change in fluency with which likely future stimuli will be processed. It is quantified by the change in the divergence between the observer's system state and the distribution of stimuli that the observer expects to see over the long term. Simulations show that a simple version of the model can account for empirical data on the effects of exposure, complexity, and symmetry on aesthetic value judgments. Taken together, our model melds processing fluency theories (immediate reward) and learning theories (change in expected future reward). Its application offers insight as to how the interplay of immediate processing fluency and learning gives rise to aesthetic value judgments. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Abstract We use neural reinforcement learning concepts including Pavlovian versus instrumental control, liking versus wanting, model-based versus model-free control, online versus offline learning and planning, and internal versus external actions and control to reflect on putative conflicts between short-term temptations and long-term goals.

The controllability of our social environment has a profound impact on our behavior and mental health. Nevertheless, neurocomputational mechanisms underlying social controllability remain elusive. Here, 48 participants performed a task where their current choices either did (Controllable), or did not (Uncontrollable), influence partners’ future proposals. Computational modeling revealed that people engaged a mental model of forward thinking (FT; i.e., calculating the downstream effects of current actions) to estimate social controllability in both Controllable and Uncontrollable conditions. A large-scale online replication study (n=1342) supported this finding. Using functional magnetic resonance imaging (n=48), we further demonstrated that the ventromedial prefrontal cortex (vmPFC) computed the projected total values of current actions during forward planning, supporting the neural realization of the forward-thinking model. These findings demonstrate that humans use vmPFC-dependent FT to estimate and exploit social controllability, expanding the role of this neurocomputational mechanism beyond spatial and cognitive contexts.

To benefit from social interactions, people need to predict how their social partners will behave. Such predictions arise through integrating prior expectations with evidence from observations, but where the priors come from and whether they influence the integration is not clear. Furthermore, this process can be affected by factors such as paranoia, in which the tendency to form biased impressions of others is common. Using a modified social value orientation (SVO) task in a large online sample (n=697), we showed that participants used a Bayesian inference process to learn about partners, with priors that were based on their own preferences. Paranoia was associated with preferences for earning more than a partner and less flexible beliefs regarding a partner’s social preferences. Alignment between the preferences of participants and their partners was associated with better predictions and with reduced attributions of harmful intent to partners.

The self as a prior for the other: social learning under paranoia

A critical facet of adjusting one’s behaviour after succeeding or failing at a task is assigning responsibility for the ultimate outcome. Humans have trait- and state-like tendencies to implicate aspects of their own behaviour (called ‘internal’ ascriptions) or facets of the particular task or Lady Luck (’chance’). However, how these tendencies interact with actual performance is unclear. We designed a novel task in which subjects had to learn the likelihood of achieving their goals, and the extent to which this depended on their efforts. High internality (Levenson I-score) was associated with decision making patterns that are less vulnerable to failure. Our computational analyses suggested that this depended heavily on the adjustment in the perceived achievability of riskier goals following failure. We found beliefs about chance not to be explanatory of choice behaviour in our task. Beliefs about powerful others were strong predictors of behaviour, but only when subjects lacked substantial influence over the outcome. Our results provide an evidentiary basis for heuristics and learning differences that underlie the formation and maintenance of control expectations by the self.

Internality and the internalisation of failure: Evidence from a novel task

Corpus callosum dysgenesis is one of the most common congenital neurological malformations. Despite being a clear and identifiable structural alteration of the brains white matter connectivity, the impact of corpus callosum dysgenesis on cognition and behavior has remained unclear. Here we build upon past clinical observations in the literature to define the clinical phenotype of corpus callosum dysgenesis better using unadjusted and adjusted group differences compared with a neurotypical sample on a range of social and cognitive measures that have been previously reported to be impacted by a corpus callosum dysgenesis diagnosis. Those with a diagnosis of corpus callosum dysgenesis (n = 22) demonstrated significantly higher persuadability, credulity, and insensitivity to social trickery than neurotypical (n = 86) participants, after controlling for age, sex, education, autistic-like traits, social intelligence, and general cognition. To explore this further, machine learning, utilizing a set neurotypical sample for training the normative covariance structure of our psychometric variables, was used to test whether these dimensions possessed the capability to discriminate between a test-set of neurotypical and corpus callosum dysgenesis participants. We found that participants with a diagnosis of corpus callosum dysgenesis were best classed within dimension space along the same axis as persuadability, credulity, and insensitivity to social trickery after controlling for age and sex, with Leave-One-Out-Cross-Validation across 250 training-set permutations providing a mean accuracy of 71.7 percent. These results have wide-reaching implications for a) the characterization of corpus callosum dysgenesis, and b) the role of the corpus callosum in social inference.

Increased persuadability and credulity in people with corpus callosum dysgenesis

The psychological and neural distinctions between the technical concepts of 'liking' and 'wanting' pose some important problems for motivated choice for goods. Why should it be that we could `want' something that we do not `like', or `like' something that we would not be willing to exert any effort to acquire? Here, we suggest a framework for answering these questions through the medium of reinforcement learning. We consider 'liking' to provide immediate, but preliminary and ultimately cancellable, information about the true, long-run worth of a good. Such preliminary estimates, viewed through the lens of what is known as potential-based shaping, generally facilitate the temporally complex learning problems that animals face.

The varied effect of unsupervised information on human category learning

Animals and humans replay neural patterns encoding trajectories through their environment, both whilst they solve decision-making tasks and during rest. Both on-task and off-task replay are believed to contribute to flexible decision making, though how their relative contributions differ remains unclear. We investigated this question by using magnetoencephalography to study human subjects while they performed a decision-making task that was designed to reveal the decision algorithms employed. We characterized subjects in terms of how flexibly each adjusted their choices to changes in temporal, spatial and reward structure. The more flexible a subject, the more they replayed trajectories during task performance, and this replay was coupled with re-planning of the encoded trajectories. The less flexible a subject, the more they replayed previously and subsequently preferred trajectories during rest periods between task epochs. The data suggest that online and offline replay both participate in planning but support distinct decision strategies.

Adversarial examples are carefully crafted input patterns that are surprisingly poorly classified by artificial and/or natural neural networks. Here we examine adversarial vulnerabilities in the processes responsible for learning and choice in humans. Building upon recent recurrent neural network models of choice processes, we propose a general framework for generating adversarial opponents that can shape the choices of individuals in particular decision-making tasks towards the behavioural patterns desired by the adversary. We show the efficacy of the framework through two experiments involving action selection and response inhibition. We further investigate the strategy used by the adversary in order to gain insights into the vulnerabilities of human choice. The framework may find applications across behavioural sciences in helping detect and avoid flawed choice.

The Anterior Cingulate Cortex Predicts Future States to Mediate Model-Based Action Selection

Monte-Carlo Tree Search (MCTS) is one of the most-widely used methods for planning, and has powered many recent advances in artificial intelligence. In MCTS, one typically performs computations (i.e., simulations) to collect statistics about the possible future consequences of actions, and then chooses accordingly. Many popular MCTS methods such as UCT and its variants decide which computations to perform by trading-off exploration and exploitation. In this work, we take a more direct approach, and explicitly quantify the value of a computation based on its expected impact on the quality of the action eventually chosen. Our approach goes beyond the "myopic" limitations of existing computation-value-based methods in two senses: (I) we are able to account for the impact of non-immediate (ie, future) computations (II) on non-immediate actions. We show that policies that greedily optimize computation values are optimal under certain assumptions and obtain results that are competitive with the state-of-the-art.

Neural Network Poisson Models for Behavioural and Neural Spike Train Data

Learning rules 
 
 How We Learn: Why Brains Learn Better Than Any Machine…for Now Stanislas Dehaene (Viking, New York, NY; 2020) ISBN: 978-0-525-55988-7

The anterior cingulate cortex (ACC) is implicated in learning the value of actions, but it remains poorly understood whether and how it contributes to model-based mechanisms that use action-state predictions and afford behavioural flexibility. To isolate these mechanisms, we developed a multi-step decision task for mice in which both action-state transition probabilities and reward probabilities changed over time. Calcium imaging revealed ramps of choice-selective neuronal activity, followed by an evolving representation of the state reached and trial outcome, with different neuronal populations representing reward in different states. ACC neurons represented the current action-state transition structure, whether state transitions were expected or surprising, and the predicted state given chosen action. Optogenetic inhibition of ACC blocked the influence of action-state transitions on subsequent choice, without affecting the influence of rewards. These data support a role for ACC in model-based reinforcement learning, specifically in using action-state transitions to guide subsequent choice. Highlights A novel two-step task disambiguates model-based and model-free RL in mice. ACC represents all trial events, reward representation is contextualised by state. ACC represents action-state transition structure, predicted states, and surprise. Inhibiting ACC impedes action-state transitions from influencing subsequent choice.

Anterior cingulate cortex represents action-state predictions and causally mediates model-based reinforcement learning in a two-step decision task

Background Real-life decisions are often complex because they involve making sequential choices that constrain future options. We have previously shown that to render such multi-step decisions manageable, people “prune” (i.e. selectively disregard) branches of decision trees that contain negative outcomes. We have theorized that sub-optimal pruning contributes to depression by promoting an oversampling of branches that result in unsavoury outcomes, which results in a negatively-biased valuation of the world. However, no study has tested this theory in depressed individuals. Methods Thirty unmedicated depressed and 31 healthy participants were administered a sequential reinforcement-based decision-making task to determine pruning behaviours, and completed measures of depression and anxiety. Computational, Bayesian and frequentist analyses examined group differences in task performance and relationships between pruning and depressive symptoms. Results Consistent with prior findings, participants robustly pruned branches of decision trees that began with large losses, regardless of the potential utility of those branches. However, there was no group difference in pruning behaviours. Further, there was no relationship between pruning and levels of depression/anxiety. Limitations The relatively small sample size limited the examination of individual differences. The use of other heuristics that are used to render complex decisions feasible, such as memoization and fragmentation, were not examined. Conclusions We found no evidence that sub-optimal pruning is evident in depression. Future research could determine whether maladaptive pruning behaviours are observable in specific sub-groups of depressed patients (e.g. in treatment-resistant individuals), or whether misuse of other heuristics may contribute to depression.

A comparison of ‘pruning’ during multi-step planning in depressed and healthy individuals

Hippocampal-midbrain circuit boosts the utility of anticipation in the prefrontal cortex and drives information-seeking behavior. Having something to look forward to is a keystone of well-being. Anticipation of future reward, such as an upcoming vacation, can often be more gratifying than the experience itself. Theories suggest the utility of anticipation underpins various behaviors, ranging from beneficial information-seeking to harmful addiction. However, how neural systems compute anticipatory utility remains unclear. We analyzed the brain activity of human participants as they performed a task involving choosing whether to receive information predictive of future pleasant outcomes. Using a computational model, we show three brain regions orchestrate anticipatory utility. Specifically, ventromedial prefrontal cortex tracks the value of anticipatory utility, dopaminergic midbrain correlates with information that enhances anticipation, while sustained hippocampal activity mediates a functional coupling between these regions. Our findings suggest a previously unidentified neural underpinning for anticipation’s influence over decision-making and unify a range of phenomena associated with risk and time-delay preference.

The value of what’s to come: Neural mechanisms coupling prediction error and the utility of anticipation

That we shape our environment, and our environment shapes us, are truisms with deep and complicated consequences. The resulting feedback interaction leads to a substantial form of what is known as path dependency. This is that small initial variations, stemming from individual differences or even just the vicissitudes of chance, can potentially result in large and persistent divergence in outcomes. This has implications for the nature and interpretation of adaptive and maladaptive choice. This chapter offers a simple formulation in terms of active observers—a formalization of decision-making problems in which actors have the choice of whether and how to gather information to improve what happens. The chapter notes that, according to Bayesian decision theory, it is often optimal for active observers to remain incorrectly calibrated with their surroundings; it explores consequences of this in non-interactive environments, and environments containing other people who might compete or cooperate. The chapter draws loose parallels with the literature on active and evocative gene–environment correlations.

The first steps on long marches: The costs of active observation

Links between affective states and risk-taking are often characterised using summary statistics from serial decision-making tasks. However, our understanding of these links, and the utility of decision-making as a marker of affect, needs to accommodate the fact that ongoing (e.g., within-task) experience of rewarding and punishing decision outcomes may alter future decisions and affective states. To date, the interplay between affect, ongoing reward and punisher experience, and decision-making has received little detailed investigation. Here, we examined the relationships between reward and loss experience, affect, and decision-making in humans using a novel judgement bias task analysed with a novel computational model. We demonstrated the influence of within-task favourability on decision-making, with more risk-averse/‘pessimistic’ decisions following more positive previous outcomes and a greater current average earning rate. Additionally, individuals reporting more negative affect tended to exhibit greater risk-seeking decision-making, and, based on our model, estimated time more poorly. We also found that individuals reported more positive affective valence during periods of the task when prediction errors and offered decision outcomes were more positive. Our results thus provide new evidence that (short-term) within-task rewarding and punishing experiences determine both future decision-making and subjectively experienced affective states.

Dissecting the links between reward and loss, decision-making, and self-reported affect using a computational approach

Author response: Impaired adaptation of learning to contingency volatility in internalizing psychopathology

Reward and punisher experience alter rodent decision-making in a judgement bias task

Having something to look forward to is a keystone of well-being. Anticipation of future reward, such as an upcoming vacation, can often be more gratifying than the experience itself. Theories suggest the utility of anticipation underpins various behaviors, ranging from beneficial information-seeking to harmful addiction. However, how neural systems compute anticipatory utility remains unclear. We analyzed the brain activity of human participants as they performed a task involving choosing whether to receive information predictive of future pleasant outcomes. Using a computational model, we show three brain regions orchestrate anticipatory utility. Specifically, ventromedial prefrontal cortex tracks the value of anticipatory utility, dopaminergic midbrain correlates with information that enhances anticipation, while sustained hippocampal activity mediates a functional coupling between these regions. Our findings suggest a previously unidentified neural underpinning for anticipation's influence over decision-making and unify a range of phenomena associated with risk and time-delay preference.

The value of what's to come: Neural mechanisms coupling prediction error and the utility of anticipation.

Recent theoretical and experimental results suggest that the dopamine system implements distributional temporal difference backups, allowing learning of the entire distributions of the long-run values of states rather than just their expected values. However, the distributional codes explored so far rely on a complex imputation step which crucially relies on spatial non-locality: in order to compute reward prediction errors, units must know not only their own state but also the states of the other units. It is far from clear how these steps could be implemented in realistic neural circuits. Here, we introduce the Laplace code: a local temporal difference code for distributional reinforcement learning that is representationally powerful and computationally straightforward. The code decomposes value distributions and prediction errors across three separated dimensions: reward magnitude (related to distributional quantiles), temporal discounting (related to the Laplace transform of future rewards) and time horizon (related to eligibility traces). Besides lending itself to a local learning rule, the decomposition recovers the temporal evolution of the immediate reward distribution, indicating all possible rewards at all future times. This increases representational capacity and allows for temporally-flexible computations that immediately adjust to changing horizons or discount factors.

A Local Temporal Difference Code for Distributional Reinforcement Learning

A critical facet of adjusting one’s behaviour after succeeding or failing at a task is assigning responsibility for the ultimate outcome. Humans have trait- and state-like tendencies to implicate aspects of their own behaviour (called ‘internal’ ascriptions) or facets of the particular task or Lady Luck (‘chance’). However, how these tendencies interact with actual performance is unclear. We designed a novel task in which subjects had to learn the likelihood of achieving their goals, and the extent to which this depended on their efforts. High internality (Levenson I-score) was associated with decision making patterns that are less vulnerable to failure, and at the same time less oriented to more rewarding achievements. Our computational analyses suggested that this depended heavily on the adjustment in the perceived achievability of riskier goals following failure. We found beliefs about chance not to be explanatory of choice behaviour in our task. Beliefs about powerful others were strong predictors of behaviour, but only when subjects lacked substantial influence over the outcome. Our results provide an evidentiary basis for heuristics and learning differences that underlie the formation and maintenance of control expectations by the self.

Subjective Beliefs In, Out, and About Control: A Quantitative Analysis

Animal behavior provides context for understanding disease models and physiology. However, that behavior is often characterized subjectively, creating opportunity for misinterpretation and misunderstanding. For example, spatial alternation tasks are treated as paradigmatic tools for examining memory; however, that link is actually an assumption. To test this assumption, we simulated a reinforcement learning (RL) agent equipped with a perfect memory process. We found that it learns a simple spatial alternation task more slowly and makes different errors than a group of male rats, illustrating that memory alone may not be sufficient to capture the behavior. We demonstrate that incorporating spatial biases permits rapid learning and enables the model to fit rodent behavior accurately. Our results suggest that even simple spatial alternation behaviors reflect multiple cognitive processes that need to be taken into account when studying animal behavior. SIGNIFICANCE STATEMENT Memory is a critical function for cognition whose impairment has significant clinical consequences. Experimental systems aimed at testing various sorts of memory are therefore also central. However, experimental designs to test memory are typically based on intuition about the underlying processes. We tested this using a popular behavioral paradigm: a spatial alternation task. Using behavioral modeling, we show that the straightforward intuition that these tasks just probe spatial memory fails to account for the speed at which rats learn or the types of errors they make. Only when memory-independent dynamic spatial preferences are added can the model learn like the rats. This highlights the importance of respecting the complexity of animal behavior to interpret neural function and validate disease models.

Memory Alone Does Not Account for the Way Rats Learn a Simple Spatial Alternation Task

Significance Humans cannot help but turn their gaze to objects that catch their attention. Our knowledge of the factors that govern this seizure, or of its effects in the context of learned decision making, is currently rather incomplete. We therefore monitored the gaze of human subjects as they learned to choose between multiple options whose value was initially unknown. We found evidence that attention was influenced by uncertainty and that the use of, and reduction in, uncertainty were, in turn, influenced by attention. Our findings provide evidence for approximately optimal models of learning and choice and uncover an intricate interplay between learning, choice, and attentional processes. Uncertainty plays a critical role in reinforcement learning and decision making. However, exactly how it influences behavior remains unclear. Multiarmed-bandit tasks offer an ideal test bed, since computational tools such as approximate Kalman filters can closely characterize the interplay between trial-by-trial values, uncertainty, learning, and choice. To gain additional insight into learning and choice processes, we obtained data from subjects’ overt allocation of gaze. The estimated value and estimation uncertainty of options influenced what subjects looked at before choosing; these same quantities also influenced choice, as additionally did fixation itself. A momentary measure of uncertainty in the form of absolute prediction errors determined how long participants looked at the obtained outcomes. These findings affirm the importance of uncertainty in multiple facets of behavior and help delineate its effects on decision making.

Animal behavior provides context for understanding disease models and physiology. 31 However, that behavior is often characterized subjectively, creating opportunity for 32 misinterpretation and misunderstanding. For example, spatial alternation tasks are treated as 33 paradigmatic tools for examining memory; however, that link is actually an assumption. To test this assumption, we simulated a reinforcement learning agent equipped with a perfect 35 memory process. We found that it is unable to learn a simple spatial alternation task as 36 rapidly as a group of male rats, illustrating that memory alone may not be sufficient to 37 capture the behavior. We demonstrate that incorporating spatial biases permits rapid 38 learning and enables the model to fit rodent behavior accurately. Our results suggest that 39 even simple spatial alternation behaviors likely reflect multiple cognitive processes and that 40 complexity needs to be taken into account when studying animal behavior.

Memory alone does not account for the speed of learning of a simple spatial alternation task in rats

Explicit knowledge of task structure is a primary determinant of human model-based action

Using a contingency volatility manipulation, we tested the hypothesis that difficulty adapting probabilistic decision-making to second-order uncertainty might reflect a core deficit that cuts across anxiety and depression and holds regardless of whether outcomes are aversive or involve reward gain or loss. We used bifactor modeling of internalizing symptoms to separate symptom variance common to both anxiety and depression from that unique to each. Across two experiments, we modeled performance on a probabilistic decision-making under volatility task using a hierarchical Bayesian framework. Elevated scores on the common internalizing factor, with high loadings across anxiety and depression items, were linked to impoverished adjustment of learning to volatility regardless of whether outcomes involved reward gain, electrical stimulation, or reward loss. In particular, high common factor scores were linked to dampened learning following better-than-expected outcomes in volatile environments. No such relationships were observed for anxiety- or depression-specific symptom factors.

Impaired adaptation of learning to contingency volatility in internalizing psychopathology

Significance “What I cannot efficiently break, I cannot understand.” Understanding the vulnerabilities of human choice processes allows us to detect and potentially avoid adversarial attacks. We develop a general framework for creating adversaries for human decision-making. The framework is based on recent developments in deep reinforcement learning models and recurrent neural networks and can in principle be applied to any decision-making task and adversarial objective. We show the performance of the framework in three tasks involving choice, response inhibition, and social decision-making. In all of the cases the framework was successful in its adversarial attack. Furthermore, we show various ways to interpret the models to provide insights into the exploitability of human choice. Adversarial examples are carefully crafted input patterns that are surprisingly poorly classified by artificial and/or natural neural networks. Here we examine adversarial vulnerabilities in the processes responsible for learning and choice in humans. Building upon recent recurrent neural network models of choice processes, we propose a general framework for generating adversarial opponents that can shape the choices of individuals in particular decision-making tasks toward the behavioral patterns desired by the adversary. We show the efficacy of the framework through three experiments involving action selection, response inhibition, and social decision-making. We further investigate the strategy used by the adversary in order to gain insights into the vulnerabilities of human choice. The framework may find applications across behavioral sciences in helping detect and avoid flawed choice.

Space, Time, and Fear: Survival Computations along Defensive Circuits

Abstract Bayesian decision theory provides a simple formal elucidation of some of the ways that representation and representational abstraction are involved with, and exploit, both prediction and its rather distant cousin, predictive coding. Both model-free and model-based methods are involved.

Avoidant behavior and pathological worry as optimal policies and optimal offline planning given individually exaggerated risk preferences

In group foraging organisms, optimizing the conflicting demands of competitive food loss and safety is critical. We demonstrate that humans select competition avoidant and risk diluting strategies during foraging depending on socially adjusted value. We formulate a mathematically grounded quantification of socially adjusted value in foraging environments and show using multivariate fMRI analyses that socially adjusted value is encoded by mid-cingulate and ventromedial prefrontal cortices, regions that integrate value and action signals.

Neural encoding of socially adjusted value during competitive and hazardous foraging

We consider the problem of learning to communicate using multi-agent reinforcement learning (MARL). A common approach is to learn off-policy, using data sampled from a replay buffer. However, messages received in the past may not accurately reflect the current communication policy of each agent, and this complicates learning. We therefore introduce a 'communication correction' which accounts for the non-stationarity of observed communication induced by multi-agent learning. It works by relabelling the received message to make it likely under the communicator's current policy, and thus be a better reflection of the receiver's current environment. To account for cases in which agents are both senders and receivers, we introduce an ordered relabelling scheme. Our correction is computationally efficient and can be integrated with a range of off-policy algorithms. It substantially improves the ability of communicating MARL systems to learn across a variety of cooperative and competitive tasks.

Retrospective model-based inference guides model-free credit assignment

Rewards and uncertainty jointly drive the attention dynamics in reinforcement learning

Having something to look forward to is a keystone of well-being. Anticipation of a future reward, like an upcoming vacation, can often be more gratifying than the very experience itself. Theories of anticipation have described how it induces behaviors ranging from beneficial information-seeking through to harmful addiction. However, it remains unclear how neural systems compute an attractive value from anticipation, instead of from the reward itself. To address this gap, we administered a decision-making task to human participants that allowed us to analyze brain activity during receipt of information predictive of future pleasant outcomes. Using a computational model of anticipatory value that captures participants’ decisions, we show that an anticipatory value signal is orchestrated by influences from three brain regions. Ventromedial prefrontal cortex (vmPFC) tracks the value of anticipation; dopaminergic midbrain responds to information that enhances anticipation, while sustained hippocampal activity provides a functional coupling between these regions. This coordinating function of the hippocampus is consistent with its known role in episodic future thinking. Our findings shed new light on the neural underpinnings of anticipation’s influence over decision-making, while also unifying a range of phenomena associated with risk and time-delay preference.

The value of what’s to come: neural mechanisms coupling prediction error and reward anticipation

Pupil-linked phasic arousal evoked by violation but not emergence of regularity within rapid sound sequences

Successful navigation can require realizing the current path choice was a mistake and the best strategy is to retreat along the recent path: ‘back-track’. Despite the wealth of studies on the neural correlates of navigation little is known about backtracking. To explore the neural underpinnings of backtracking we tested humans during functional magnetic resonance imaging on their ability to navigate to a set of goal locations in a virtual desert island riven by lava which constrained the paths that could be taken. We found that on a subset of trials, participants spontaneously chose to backtrack and that the majority of these choices were optimal. During backtracking, activity increased in frontal regions and the dorsal anterior cingulate cortex, while activity was suppressed in regions associated with the core default-mode network. Using the same task, magnetoencephalography and a separate group of participants, we found that power in the alpha band was significantly decreased immediately prior to such backtracking events. These results highlight the importance for navigation of brain networks previously identified in processing internally-generated errors and that such error-detection responses may involve shifting the brain from default-mode states to aid successful spatial orientation.

Backtracking during navigation is correlated with enhanced anterior cingulate activity and suppression of alpha oscillations and the ‘default-mode’ network

Individual characteristics in human decision-making are often quantified by fitting a parametric cognitive model to subjects' behavior and then studying differences between them in the associated parameter space. However, these models often fit behavior more poorly than recurrent neural networks (RNNs), which are more flexible and make fewer assumptions about the underlying decision-making processes. Unfortunately, the parameter and latent activity spaces of RNNs are generally high-dimensional and uninterpretable, making it hard to use them to study individual differences. Here, we show how to benefit from the flexibility of RNNs while representing individual differences in a low-dimensional and interpretable space. To achieve this, we propose a novel end-to-end learning framework in which an encoder is trained to map the behavior of subjects into a low-dimensional latent space. These low-dimensional representations are used to generate the parameters of individual RNNs corresponding to the decision-making process of each subject. We introduce terms into the loss function that ensure that the latent dimensions are informative and disentangled, i.e., encouraged to have distinct effects on behavior. This allows them to align with separate facets of individual differences. We illustrate the performance of our framework on synthetic data as well as a dataset including the behavior of patients with psychiatric disorders.

How does the brain learn how to plan? We reverseengineer people’s underlying learning mechanisms by combining rational process models of cognitive plasticity with recently developed empirical methods that allow us to trace the temporal evolution of people’s planning strategies. We find that our Learned Value of Computation model (LVOC) accurately captures people’s average learning curve. However, there were also substantial individual differences in metacognitive learning that are best understood in terms of multiple different learning mechanisms – including strategy selection learning. Furthermore, we observed that LVOC could not fully capture people’s ability to adaptively decide when to stop planning. We successfully extended the LVOC model to address these discrepancies. Our models broadly capture people’s ability to improve their decision mechanisms and represent a significant step towards reverseengineering how the brain learns increasingly effective cognitive strategies through its interaction with the environment.

Investigating animal affect and welfare using computational modelling

Altered learning under uncertainty in unmedicated mood and anxiety disorders

Humans and other animals are able to discover underlying statistical structure in their environments and exploit it to achieve efficient and effective performance. However, such structure is often difficult to learn and use because it is obscure, involving long-range temporal dependencies. Here, we analysed behavioural data from an extended experiment with rats, showing that the subjects learned the underlying statistical structure, albeit suffering at times from immediate inferential imperfections as to their current state within it. We accounted for their behaviour using a Hidden Markov Model, in which recent observations are integrated with evidence from the past. We found that over the course of training, subjects came to track their progress through the task more accurately, a change that our model largely attributed to improved integration of past evidence. This learning reflected the structure of the task, decreasing reliance on recent observations, which were potentially misleading.

Visual selective attention acts as a filter on perceptual information, facilitating learning and inference about important events in an agent’s environment. A role for visual attention in reward-based decisions has previously been demonstrated, but it remains unclear how visual attention is recruited during aversive learning, particularly when learning about multiple stimuli concurrently. This question is of particular importance in psychopathology, where enhanced attention to threat is a putative feature of pathological anxiety. Using an aversive reversal learning task that required subjects to learn, and exploit, predictions about multiple stimuli, we show that the allocation of visual attention is influenced significantly by aversive value but not by uncertainty. Moreover, this relationship is bidirectional in that attention biases value updates for attended stimuli, resulting in heightened value estimates. Our findings have implications for understanding biased attention in psychopathology and support a role for learning in the expression of threat-related attentional biases in anxiety.

We investigate how reinforcement learning agents can learn to cooperate. Drawing inspiration from human societies, in which successful coordination of many individuals is often facilitated by hierarchical organisation, we introduce Feudal Multi-agent Hierarchies (FMH). In this framework, a 'manager' agent, which is tasked with maximising the environmentally-determined reward function, learns to communicate subgoals to multiple, simultaneously-operating, 'worker' agents. Workers, which are rewarded for achieving managerial subgoals, take concurrent actions in the world. We outline the structure of FMH and demonstrate its potential for decentralised learning and control. We find that, given an adequate set of subgoals from which to choose, FMH performs, and particularly scales, substantially better than cooperative approaches that use a shared reward function.

Feudal Multi-Agent Hierarchies for Cooperative Reinforcement Learning

Dissociating neural learning signals in human sign- and goal-trackers

Uncertainty plays a critical role in reinforcement learning and decision making. However, exactly how it influences behaviour remains unclear. Multi-armed bandit tasks offer an ideal test-bed, since computational tools such as approximate Kalman filters can closely characterize the interplay between trial-by-trial values, uncertainty, learning, and choice. To gain additional insight into learning and choice processes we obtained data from subjects' overt allocation of gaze. The estimated value and estimation uncertainty of options influenced what subjects looked at before choosing; these same quantities also influenced choice, as additionally did fixation itself. A momentary measure of uncertainty in the form of absolute prediction errors determined how long participants looked at the obtained outcomes. These findings affirm the importance of uncertainty in multiple facets of behaviour, and help delineate its effects on decision making.

The Good, The Bad, and Something Inbetween: Dopamine in Active Avoidance

Forming global estimates of self-performance from local confidence

Semi-Supervised Categorisation: Input Representations Determine Necessity of Feedback

Pavlovian-instrumental interactions in active avoidance: The bark of neutral trials

Popular computational models of decision-making make specific assumptions about learning processes that may cause them to underfit observed behaviours. Here we suggest an alternative method using recurrent neural networks (RNNs) to generate a flexible family of models that have sufficient capacity to represent the complex learning and decision- making strategies used by humans. In this approach, an RNN is trained to predict the next action that a subject will take in a decision-making task and, in this way, learns to imitate the processes underlying subjects’ choices and their learning abilities. We demonstrate the benefits of this approach using a new dataset drawn from patients with either unipolar (n = 34) or bipolar (n = 33) depression and matched healthy controls (n = 34) making decisions on a two-armed bandit task. The results indicate that this new approach is better than baseline reinforcement-learning methods in terms of overall performance and its capacity to predict subjects’ choices. We show that the model can be interpreted using off-policy simulations and thereby provides a novel clustering of subjects’ learning processes—something that often eludes traditional approaches to modelling and behavioural analysis.

Models that learn how humans learn: The case of decision-making and its disorders

Affiliations: 1Institute of Cognitive Neuroscience, University College London, 17 Queen Square, London, WC1N 3AR, United Kingdom. 2Wellcome Trust Centre for Neuroimaging, University College London, 12 Queen Square, London, WC1N 3BG, United Kingdom. 3Computational and Biological Learning Lab, Department of Engineering, University of Cambridge, Trumpington Street, Cambridge CB2 1PZ, United Kingdom. 4LREN, Département des neurosciences cliniques, CHUV, University of Lausanne, Lausanne, Switzerland. 5Gatsby Computational Neuroscience Unit, Alexandra House, 17 Queen Square, WC1N 3AR, United Kingdom.

Title: The habenula encodes motivation associated with primary punishment in humans

The dynamical interaction between attribution and belief: Evidence from a novel task

Having something to look forward to is a keystone of well-being. Anticipation of a future reward, like an upcoming vacation, can be more gratifying than the experience of reward itself. Theories of anticipation have described how it causes behaviors ranging from beneficial information-seeking to harmful addiction. Here, we investigated how the brain generates and enhances anticipatory pleasure, by analyzing brain activity of human participants who received information predictive of future pleasant outcomes in a decision-making task. Using a computational model of anticipation, we show that three regions orchestrate anticipatory pleasure. We show ventromedial prefrontal cortex (vmPFC) tracks the value of anticipation; dopaminergic midbrain responds to information that enhances anticipation, while the sustained activity in hippocampus provides for functional coupling between these regions. This coordinating role for hippocampus is consistent with its known role in the vivid imagination of future outcomes. Our findings throw new light on the neural underpinnings of how anticipation influences decision-making, while also unifying a range of phenomena associated with risk and time-delay preference.

Hippocampal-midbrain circuit enhances the pleasure of anticipation in the prefrontal cortex

Individual characteristics in human decision-making are often quantified by fitting a parametric cognitive model to subjects’ behavior and then studying differences between them in the associated parameter space. However, these models often fit behavior more poorly than recurrent neural networks (RNNs), which are more flexible and make fewer assumptions about the underlying decision-making processes. Unfortunately, the parameter and latent activity spaces of RNNs are generally high-dimensional and uninterpretable, making it hard to use them to study individual differences. Here, we show how to benefit from the flexibility of RNNs while representing individual differences in a low-dimensional and interpretable space. To achieve this, we propose a novel end-to-end learning framework in which an encoder is trained to map the behavior of subjects into a low-dimensional latent space. These low-dimensional representations are used to generate the parameters of individual RNNs corresponding to the decision-making process of each subject. We introduce terms into the loss function that ensure that the latent dimensions are informative and disentangled, i.e., encouraged to have distinct effects on behavior. This allows them to align with separate facets of individual differences. We illustrate the performance of our framework on synthetic data as well as a dataset including the behavior of patients with psychiatric disorders.

Central to the concept of the “cognitive map” is that it confers behavioral flexibility, allowing animals to take efficient detours, exploit shortcuts, and avoid alluring, but unhelpful, paths. The neural underpinnings of such naturalistic and flexible behavior remain unclear. In two neuroimaging experiments, we tested human participants on their ability to navigate to a set of goal locations in a virtual desert island riven by lava, which occasionally spread to block selected paths (necessitating detours) or receded to open new paths (affording real shortcuts or false shortcuts to be avoided). Detours activated a network of frontal regions compared with shortcuts. Activity in the right dorsolateral PFC specifically increased when participants encountered tempting false shortcuts that led along suboptimal paths that needed to be differentiated from real shortcuts. We also report modulation in event-related fields and theta power in these situations, providing insight to the temporal evolution of response to encountering detours and shortcuts. These results help inform current models as to how the brain supports navigation and planning in dynamic environments.

Prefrontal Dynamics Associated with Efficient Detours and Shortcuts: A Combined Functional Magnetic Resonance Imaging and Magnetoencenphalography Study

In February 2019 a workshop was convened at the Banbury Centre at Cold Spring Harbor, NY. The purpose of the meeting was to identify key developments required in the practice and infrastructure of computational psychiatry research to accelerate its ability to address real world clinical problems in the near future. This report provides a summary of the conclusions of the meeting. At its core are suggestions to improve the measurement properties of computational assays through a rapid, iterative process that leverages coordinated waves of online and clinical testing, followed by deployment of the assays in innovative study designs to address clinically relevant questions. We particularly focus on theory-driven tasks but, where possible, the potential of data-driven approaches is also highlighted. Finally, the report suggests that for the promise of computational psychiatry to be realized, the research environment must be developed to encourage large-scale, collaborative, interdisciplinary consortia.

Realizing the Clinical Potential of Computational Psychiatry: Report From the Banbury Center Meeting, February 2019

Anticipation, imagination and information seeking via mid-brain, hippocampal, and prefrontal interactions

The really refreshing, and indeed exemplary, aspect of this book is its courage, openness and honesty in confronting a magnificently rich and disorientating topic. In choosing to analyse settings o...

In novel situations, behavior necessarily reduces to latent biases. How these biases interact with new experiences to enable subsequent behavior remains poorly understood. We exposed rats to a family of spatial alternation contingencies and developed a series of reinforcement learning agents to describe the behavior. The performance of these agents shows that accurately describing the learning of individual animals requires accounting for their individual dynamic preferences as well as general, shared, cognitive processes. Agents that include only memory of past choice do not account for the behavior. Adding an explicit representation of biases allows agents to perform the task as rapidly as the rats, to accurately predict critical facets of their behavior on which it was not fitted, and to capture individual differences quantitatively. Our results illustrate the value of making explicit models of learning and highlight the importance of considering the initial state of each animal in understanding behavior.

Dynamic preferences account for inter-animal variability during the continual learning of a cognitive task

O8. Computational Phenotyping in Borderline Personality Using a Role-Based Social Hierarchy Probe

Contemporary reinforcement learning (RL) theory suggests that potential choices can be evaluated by strategies that may or may not be sensitive to the computational structure of tasks. A paradigmatic model-free (MF) strategy simply repeats actions that have been rewarded in the past; by contrast, model-sensitive (MS) strategies exploit richer information associated with knowledge of task dynamics. MF and MS strategies should typically be combined, because they have complementary statistical and computational strengths; however, this tradeoff between MF/MS RL has mostly only been demonstrated in humans, often with only modest numbers of trials. We trained rhesus monkeys to perform a two-stage decision task designed to elicit and discriminate the use of MF and MS methods. A descriptive analysis of choice behaviour revealed directly that the structure of the task (of MS importance) and the reward history (of MF and MS importance) significantly influenced both choice and response vigour. A detailed, trial-by-trial computational analysis confirmed that choices were made according to a combination of strategies, with a dominant influence of a particular form of model sensitivity that persisted over weeks of testing. The residuals from this model necessitated development of a new combined RL model which incorporates a particular credit assignment weighting procedure. Finally, response vigor exhibited a subtly different collection of MF and MS influences. These results provide new illumination onto RL behavioural processes in non-human primates.

Combined model-free and model-sensitive reinforcement learning in non-human primates

Social control, the ability to exert influence over others, is critical in interpersonal interactions yet uninvestigated. Here, we used functional neuroimaging and a social exchange paradigm in which people’s current choices either did, or did not, influence their partners’ proposals in the future. Computational modeling revealed that participants used forward thinking and calculated the downstream effects of their current actions regardless of the controllability of the social environment. Furthermore, greater levels of estimated control correlated with better performance in controllable interactions and less illusory beliefs about control in uncontrollable interactions. Neural instantiation of trial-by-trial values of social controllability were tracked in the ventromedial prefrontal cortex (vmPFC), striatum, and insula for controllable interactions, but only in vmPFC for uncontrollable interactions. These findings demonstrate that humans use forward thinking, a strategy similar to model-based planning, to guide social choices; and that subjective beliefs about social controllability might not be grounded in reality.

The long and the short of serotonergic stimulation: The learning rate for rewards

Humans and other animals are able to discover underlying statistical structure in their environments and exploit it to achieve efficient and effective performance. However, such structure is often difficult to learn and use because it is obscure, involving long-range temporal dependencies. Here, we analysed behavioural data from an extended experiment with rats, showing that the subjects learned the underlying statistical structure, albeit suffering at times from immediate inferential imperfections as to their current state within it. We accounted for their behaviour using a Hidden Markov Model, in which recent observations are integrated with the recollections of an imperfect memory. We found that over the course of training, subjects came to track their progress through the task more accurately, a change that our model largely attributed to decreased forgetting. This ‘learning to remember’ decreased reliance on recent observations, which may be misleading, in favour of a longer-term memory. Author summary Humans and other animals possess the remarkable ability to find and exploit patterns and structures in their experience of a complex and varied world. However, such structures are often temporally extended and latent or hidden, being only partially correlated with immediate observations of the world. This makes it essential to integrate current and historical information, and creates a challenging statistical and computational problem. Here, we examine the behaviour of rats facing a version of this challenge posed by a brain-stimulation reward task. We find that subjects learned the general structure of the task, but struggled when immediate observations were misleading. We captured this behaviour with a model in which subjects integrated evidence from their observations together with a memory whose imperfections accounted for their errors. The subjects’ performance improved markedly over successive sessions, allowing them to overcome misleading observations. According to the model, this arose from a process of ‘learning to remember’ in which subjects became better at employing more reliable past observations to determine the hidden state of the world.

Decodability of Reward Learning Signals Predicts Mood Fluctuations

Neuroscience studies of human decision-making abilities commonly involve sub-jects completing a decision-making task while BOLD signals are recorded using fMRI. Hypotheses are tested about which brain regions mediate the effect of past experience, such as rewards, on future actions. One standard approach to this is model-based fMRI data analysis, in which a model is fitted to the behavioral data, i.e., a subject’s choices, and then the neural data are parsed to find brain regions whose BOLD signals are related to the model’s internal signals. However, the internal mechanics of such purely behavioral models are not constrained by the neural data, and therefore might miss or mischaracterize aspects of the brain. To address this limitation, we introduce a new method using recurrent neural network models that are flexible enough to be jointly fitted to the behavioral and neural data. We trained a model so that its internal states were suitably related to neural activity during the task, while at the same time its output predicted the next action a subject would execute. We then used the fitted model to create a novel visualization of the relationship between the activity in brain regions at different times following a reward and the choices the subject subsequently made. Finally, we validated our method using a previously published dataset. We found that the model was able to recover the underlying neural substrates that were discovered by explicit model engineering in the previous work, and also derived new results regarding the temporal pattern of brain activity.

Integrated accounts of behavioral and neuroimaging data using flexible recurrent neural network models

An effect of serotonergic stimulation on learning rates for rewards apparent after long intertrial intervals

The development of a functional nervous system requires tight control of neurite growth and guidance by extracellular chemical cues. Neurite growth is astonishingly sensitive to shallow concentration gradients, but a widely observed feature of both growth and guidance regulation, with important consequences for development and regeneration, is that both are only elicited over the same relatively narrow range of concentrations. Here we show that all these phenomena can be explained within one theoretical framework. We first test long-standing explanations for the suppression of the trophic effects of nerve growth factor at high concentrations, and find they are contradicted by experiment. Instead we propose a new hypothesis involving inhibitory signalling among the cell bodies, and then extend this hypothesis to show how both growth and guidance can be understood in terms of a common underlying signalling mechanism. This new model for the first time unifies several key features of neurite growth regulation, quantitatively explains many aspects of experimental data, and makes new predictions about unknown details of developmental signalling.

Control of neurite growth and guidance by an inhibitory cell-body signal

Early childhood investment impacts social decision-making four decades later

Significance Locus coeruleus (LC) integrity in cognitively normal older adults is a potentially important preclinical marker in dementia. Our study establishes a link between variability in LC integrity and cognitive decline related to noradrenergic modulation in old age. We find that in older adults, reduced LC integrity explains lower memory performance. This effect was more pronounced for memory related to negative events, and accompanied by increased pupil diameter size in response to negative events. The study provides a strong motivation for future research investigating the role of LC integrity in healthy, as well as in pathological, aging. The locus coeruleus (LC) is the principal origin of noradrenaline in the brain. LC integrity varies considerably across healthy older individuals, and is suggested to contribute to altered cognitive functions in aging. Here we test this hypothesis using an incidental memory task that is known to be susceptible to noradrenergic modulation. We used MRI neuromelanin (NM) imaging to assess LC structural integrity and pupillometry as a putative index of LC activation in both younger and older adults. We show that older adults with reduced structural LC integrity show poorer subsequent memory. This effect is more pronounced for emotionally negative events, in accord with a greater role for noradrenergic modulation in encoding salient or aversive events. In addition, we found that salient stimuli led to greater pupil diameters, consistent with increased LC activation during the encoding of such events. Our study presents novel evidence that a decrement in noradrenergic modulation impacts on specific components of cognition in healthy older adults. The findings provide a strong motivation for further investigation of the effects of altered LC integrity in pathological aging.

Locus coeruleus integrity in old age is selectively related to memories linked with salient negative events

Author Correction: Assessing animal affect: an automated and self-initiated judgement bias task based on natural investigative behaviour

Magnetoencephalography decoding reveals structural differences within integrative decision processes

Amir-Homayoun Javadi*, Eva Zita Patai*, Aaron Margois, Heng-Ru M. Tan, Dharshan Kumaran, Marko Nardini, Will Penny6, Emrah Duzel, Peter Dayan, Hugo J. Spiers 1Institute of Behavioural Neuroscience, University College London, London, UK 2School of Psychology, University of Kent, Canterbury, UK 3Institute of Cognitive Neuroscience, University College London, London, UK 4Google Deepmind 5Department of Psychology, Durham University, UK 6School of Psychology, University of East Anglia, UK 7Institute of Cognitive Neurology and Dementia Research (IkND), University Hospital Magdeburg, Germany

Neural signatures of detours , shortcuts and backtracking during navigation Abbreviated Title : Neural responses to detours , shortcuts and backtracking

Arbitrating between timely choice and extended information gathering is critical in effective decision making. Aberrant information gathering behaviour is said to be a feature of psychiatric disorders such as schizophrenia and obsessive-compulsive disorder. We know little about the neurocognitive control mechanisms that drive such information gathering. In a double-blind placebo-controlled drug study with 60 healthy humans (30 female), we examined the effects of noradrenaline and dopamine antagonism on information gathering. We show that modulating noradrenaline function with propranolol leads to decreased information gathering behaviour and this contrasts with no effect following a modulation of dopamine function. Using a Bayesian computational model, we show sampling behaviour is best explained when including an urgency signal that promotes commitment to an early decision. We demonstrate that noradrenaline blockade promotes the expression of this decision-related urgency signal during information gathering. We discuss the findings with respect to psychopathological conditions that are linked to aberrant information gathering. Significance Statement Knowing when to stop gathering information and commit to an option is non-trivial. This is an important element in arbitrating between information gain and energy conservation. In this double-blind, placebo-controlled drug study, we investigated to role of catecholamines noradrenaline and dopamine on sequential information gathering. We found that blocking noradrenaline led to a decrease in information gathering, with no effect seen following dopamine blockade. Using a Bayesian computational model, we show that this noradrenaline effect is driven by an increased decision urgency, a signal that reflects an escalating subjective cost of sampling. The observation that noradrenaline modulates decision urgency suggests new avenues for treating patients that show information gathering deficits.

Noradrenaline modulates decision urgency during sequential information gathering

Correct wiring is crucial for the proper functioning of the nervous system. Molecular gradients provide critical signals to guide growth cones, which are the motile tips of developing axons, to their targets. However, in vitro, growth cones trace highly stochastic trajectories, and exactly how molecular gradients bias their movement is unclear. Here, we introduce a mathematical model based on persistence, bias, and noise to describe this behaviour, constrained directly by measurements of the detailed statistics of growth cone movements in both attractive and repulsive gradients in a microfluidic device. This model provides a mathematical explanation for why average axon turning angles in gradients in vitro saturate very rapidly with time at relatively small values. This work introduces the most accurate predictive model of growth cone trajectories to date, and deepens our understanding of axon guidance events both in vitro and in vivo. DOI: 10.7554/eLife.12248.001

Retraction: A mathematical model explains saturating axon guidance responses to molecular gradients

Shadow Images Moving to Music: La Tentation de saint Antoine in Montmartre

Central to the concept of the 'cognitive map' is that it confers flexibility in behaviour allowing animals to take efficient detours, exploit shortcuts and realise when they need to back-track rather than continue on a poorly chosen route. Currently the neural underpinnings of such behaviour remains unclear. During fMRI we tested human subjects on their ability to navigate to a set of goal locations in a virtual desert island riven by lava, which occasionally shifted to block selected paths (necessitating detours) or receded to open new paths (affording shortcuts). We found that detours activated a wide network of frontal regions compared to shortcuts. Activity in right dorsolateral prefrontal cortex specifically also increased when participants encountered new paths that appeared to provide a shortcut in the direction of the goal but which added distance to the path (false short-cuts). During spontaneous back-tracking events, activity increased in frontal regions and the dorsal anterior cingulate cortex, while activity in regions associated with the core default-mode network were suppressed. These results help inform current models as to how the brain supports navigation and planning.

Neural signatures of detours, shortcuts and back-tracking during navigation

Existing Bayesian treatments of neural networks are typically characterized by weak prior and approximate posterior distributions according to which all the weights are drawn independently. Here, we consider a richer prior distribution in which units in the network are represented by latent variables, and the weights between units are drawn conditionally on the values of the collection of those variables. This allows rich correlations between related weights, and can be seen as realizing a function prior with a Bayesian complexity regularizer ensuring simple solutions. We illustrate the resulting meta-representations and representations, elucidating the power of this prior.

When planning to survive goes wrong: predicting the future and replaying the past in anxiety and PTSD

Mind Games: Recursive Predictions about Untrustworthy Intentional Others

Computational models of learning and decision-making processes in the brain play an important role in many domains. Such models typically have a constrained structure and make specific assumptions about the underlying human learning processes; these may make them underfit observed behaviours. Here we suggest an alternative method based on learning-to-learn approaches, using recurrent neural networks (RNNs) as a flexible family of models that have sufficient capacity to represent the complex learning and decision-making strategies used by humans. In this approach, an RNN is trained to predict the next action that a subject will take in a decision-making task, and in this way, learns to imitate the processes underlying subjects’ choices and their learning abilities. We demonstrate the benefits of this approach with a new dataset containing behaviour of uni-polar depression (n=34), bipolar (n=33) and control (n=34) participants in a two-armed bandit task. The results indicate that the new approach is better than baseline reinforcement-learning methods in terms of overall performance and its capacity to predict subjects’ choices. We show that the model can be interpreted using off-policy simulations, and thereby provide a novel clustering of subjects’ learning processes – something that often eludes traditional approaches to modelling and behavioural analysis.

Models that learn how humans learn: the case of depression and bipolar disorders

Humans build models of their environments and act according to what they have learnt. In simple experimental environments, such model-based behaviour is often well accounted for as if subjects are ideal Bayesian observers. However, more complex probabilistic tasks require more sophisticated forms of inference that are sufficiently computationally and statistically taxing as to demand approximation. Here, we study properties of two approximation schemes in the context of a serial reaction time task in which stimuli were generated from a hierarchical Markov chain. One, pre-existing, scheme was a generically powerful variational method for hierarchical inference which has recently become popular as an account of psychological and neural data across a wide swathe of probabilistic tasks. A second, novel, scheme was more specifically tailored to the task at hand. We show that the latter model fit significantly better than the former. This suggests that our subjects were sensitive to many of the particular constraints of a complex behavioural task. Further, the tailored model provided a different perspective on the effects of cholinergic manipulations in the task. Neither model fit the behaviour on more complex contingencies that competently. These results illustrate the benefits and challenges that come with the general and special purpose modelling approaches and raise important questions of how they can advance our current understanding of learning mechanisms in the brain.

Forget-me-some: General versus special purpose models in a hierarchical probabilistic task

Neural networks trained with backpropagation often struggle to identify classes that have been observed a small number of times. In applications where most class labels are rare, such as language modelling, this can become a performance bottleneck. One potential remedy is to augment the network with a fast-learning non-parametric model which stores recent activations and class labels into an external memory. We explore a simplified architecture where we treat a subset of the model parameters as fast memory stores. This can help retain information over longer time intervals than a traditional memory, and does not require additional space or compute. In the case of image classification, we display faster binding of novel classes on an Omniglot image curriculum task. We also show improved performance for word-based language models on news reports (GigaWord), books (Project Gutenberg) and Wikipedia articles (WikiText-103) --- the latter achieving a state-of-the-art perplexity of 29.2.

Dissecting the contributions of rewards and effort on motivation

48. A Computational Approach to Understanding Motivational Symptoms in Depression

Foraging for foundations in decision neuroscience: insights from ethology

The Protective Action Encoding of Serotonin Transients in the Human Brain

The capacity to take efficient detours and exploit novel shortcuts during navigation is thought to be supported by a cognitive map of the environment. Despite advances in understanding the neural basis of the cognitive map, little is known about the neural dynamics associated with detours and shortcuts. Here, we recorded magnetoencephalography from humans as they navigated a virtual desert island riven by shifting lava flows. The task probed their ability to take efficient detours and shortcuts to remembered goals. We report modulation in event-related fields and theta power as participants identified real shortcuts and differentiated these from false shortcuts that led along suboptimal paths. Additionally, we found that a decrease in alpha power preceded ‘back-tracking’ where participants spontaneously turned back along a previous path. These findings help advance our understanding of the fine-grained temporal dynamics of human brain activity during navigation and support the development of models of brain networks that support navigation.

Spotting the path that leads nowhere: Modulation of human theta and alpha oscillations induced by trajectory changes during navigation

Ideal decision-makers should constantly assess all sources of information about opportunities and threats, and be able to redetermine their choices promptly in the face of change. However, perpetual monitoring and reassessment impose inordinate sensing and computational costs, making them impractical for animals and machines alike. The obvious alternative of committing for extended periods of time to limited sensory strategies associated with particular courses of action can be dangerous and wasteful. Here, we explore the intermediate possibility of making provisional temporal commitments whilst admitting interruption based on limited broader observation. We simulate foraging under threat of predation to elucidate the benefits of such a scheme. We relate our results to diseases of distractibility and roving attention, and consider mechanistic substrates such as noradrenergic neuromodulation.

Interrupting behaviour: Minimizing decision costs via temporal commitment and low-level interrupts

The long and the short of serotonergic stimulation: Selective effects on the learning rate of rewards

Assessing animal affect: an automated and self-initiated judgement bias task based on natural investigative behaviour

The music of Dada follows Kurt Schwitters to Holland (bypassing Berlin) and ends in the Ursonate

Humans possess a rich repertoire of abstract concepts about which they can often judge their confidence. These judgements help guide behaviour, but the mechanisms underlying them are still poorly understood. Here, we examine the evolution of people’s sense of confidence as they engage in probabilistic concept learning. Participants learned a continuous function of four continuous features, reporting their predictions and confidence about these predictions. Participants indeed had insight into their uncertainties: confidence was correlated with the accuracy of predictions, increasing as learning progressed. There were substantial individual differences. In contrast to many classical models that try to explain only the predictions, we formalized human function learning in Bayesian terms as Gaussian process inference. This model generates posterior distributions, allowing us to link predictions and confidence judgements. Gaussian process inference well matched participants’ predictions, and also the confidence judgements of metacognitively competent participants. Our results show that human confidence judgements during learning are tied to uncertainty, suggesting that concept learning is fundamentally probabilistic.

Are you sure about that? On the origins of confidence in concept learning

Substantial evidence indicates that subjective value is adapted to the statistics of reward expected within a given temporal context. However, how these contextual expectations are learned is poorly understood. To examine such learning, we exploited a recent observation that participants performing a gambling task adjust their preferences as a function of context. We show that, in the absence of contextual cues providing reward information, an average reward expectation was learned from recent past experience. Learning dependent on contextual cues emerged when two contexts alternated at a fast rate, whereas both cue-independent and cue-dependent forms of learning were apparent when two contexts alternated at a slower rate. Motivated by these behavioral findings, we reanalyzed a previous fMRI data set to probe the neural substrates of learning contextual reward expectations. We observed a form of reward prediction error related to average reward such that, at option presentation, activity in ventral tegmental area/substantia nigra and ventral striatum correlated positively and negatively, respectively, with the actual and predicted value of options. Moreover, an inverse correlation between activity in ventral tegmental area/substantia nigra (but not striatum) and predicted option value was greater in participants showing enhanced choice adaptation to context. The findings help understanding the mechanisms underlying learning of contextual reward expectation.

Previous research has shown that short-term fasting in healthy individuals (HIs) is associated with changes in risky decision-making. The current experiment was designed to examine the influence of short-term fasting in HIs on four types of impulsivity: reflection impulsivity, risky decision-making, delay aversion, and action inhibition. HIs were tested twice, once when fasted for 20 hours, and once when satiated. Participants demonstrated impaired action inhibition when fasted; committing significantly more errors of commission during a food-related Affective Shifting Task. Participants also displayed decreased reflection impulsivity when fasted, opening significantly more boxes during the Information Sampling Task (IST). There were no significant differences in performance between fasted and satiated sessions for risky decision-making or delay aversion. These findings may have implications for understanding eating disorders such as Bulimia Nervosa (BN). Although BN has been characterised as a disorder of poor impulse control, inconsistent findings when comparing individuals with BN and HIs on behavioural measures of impulsivity question this characterisation. Since individuals with BN undergo periods of short-term fasting, the inconsistent findings could be due to differences in the levels of satiation of participants. The current results indicate that fasting can selectively influence performance on the IST, a measure of impulsivity previously studied in BN. However, the results from the IST were contrary to the original hypothesis and should be replicated before specific conclusions can be made.

Short-Term Fasting Selectively Influences Impulsivity in Healthy Individuals

Individual animals use distinct strategies in a changing spatial memory task

Pavlovian influences are important in guiding decision-making across health and psychopathology. There is an increasing interest in using concise computational tasks to parametrise such influences in large populations, and especially to track their evolution during development and changes in mental health. However, the developmental course of Pavlovian influences is uncertain, a problem compounded by the unclear psychometric properties of the relevant measurements. We assessed Pavlovian influences in a longitudinal sample using a well characterised and widely used Go-NoGo task. We hypothesized that the strength of Pavlovian influences and other ‘psychomarkers’ guiding decision-making would behave like traits. As reliance on Pavlovian influence is not as profitable as precise instrumental decision-making in this Go-NoGo task, we expected this influence to decrease with higher IQ and age. Additionally, we hypothesized it would correlate with expressions of psychopathology. We found that Pavlovian effects had weak temporal stability, while model-fit was more stable. In terms of external validity, Pavlovian effects decreased with increasing IQ and experience within the task, in line with normative expectations. However, Pavlovian effects were poorly correlated with age or psychopathology. Thus, although this computational construct did correlate with important aspects of development, it does not meet conventional requirements for tracking individual development. We suggest measures that might improve psychometric properties of task-derived Pavlovian measures for future studies.

Change, stability, and instability in the Pavlovian guidance of behaviour from adolescence to young adulthood

Arbitrating between timely choice and extended information gathering is critical for effective decision making. Aberrant information gathering behavior is thought to be a feature of psychiatric disorders such as schizophrenia and obsessive-compulsive disorder, but we know little about the underlying neurocognitive control mechanisms. In a double-blind, placebo-controlled drug study involving 60 healthy human subjects (30 female), we examined the effects of noradrenaline and dopamine antagonism on information gathering during performance of an information sampling task. We show that modulating noradrenaline function with 40 mg of the β-blocker propranolol leads to decreased information gathering behavior. Modulating dopamine function via a single dose of 400 mg of amisulpride revealed some effects that were intermediate between those of propranolol and placebo. Using a Bayesian computational model, we show that sampling behavior is best explained by inclusion of a nonlinear urgency signal that promotes commitment to an early decision. Noradrenaline blockade promotes the expression of this decision-related urgency signal during information gathering. We discuss the findings with respect to psychopathological conditions that are linked to aberrant information gathering. SIGNIFICANCE STATEMENT Knowing when to stop gathering information and commit to a choice option is nontrivial. This is an important element in arbitrating between information gain and energy conservation. In this double-blind, placebo-controlled drug study, we investigated the role of catecholamines noradrenaline and dopamine on sequential information gathering. We found that blockade of noradrenaline led to a decrease in information gathering. Dopamine blockade showed an intermediate, but nonsignificant, effect. Using a Bayesian computational model, we show that this noradrenaline effect is driven by increased decision urgency, a signal that reflects an escalating subjective cost of sampling. The observation that noradrenaline modulates decision urgency suggests new avenues for treating patients that show information gathering deficits.

Beta-Blocker Propranolol Modulates Decision Urgency During Sequential Information Gathering

Central to the concept of the ‘cognitive map’ is that it confers behavioural flexibility, allowing animals to take efficient detours, exploit shortcuts and realise the need to back-track rather than persevere on a poorly chosen route. The neural underpinnings of such naturalistic and flexible behaviour remain unclear. During fMRI we tested human subjects on their ability to navigate to a set of goal locations in a virtual desert island riven by lava, which occasionally shifted to block selected paths (necessitating detours) or receded to open new paths (affording shortcuts). We found that during self-initiated back-tracking, activity increased in frontal regions and the dorsal anterior cingulate cortex, while activity in regions associated with the core default-mode network was suppressed. Detours activated a network of frontal regions compared to shortcuts. Activity in right dorsolateral prefrontal cortex specifically increased when participants encountered new plausible shortcuts but which in fact added to the path (false shortcuts). These results help inform current models as to how the brain supports navigation and planning in dynamic environments. Significance Statement Adaptation to change is important for survival. Although real-world spatial environments are prone to continual change, little is known about how the brain supports navigation in dynamic environments where flexible adjustments to route plans are needed. Here, we used fMRI to examine the brain activity elicited when humans took forced detours, identified shortcuts and spontaneously back-tracked along their recent path. Both externally and internally generated changes in the route activated the fronto-parietal attention network, whereas only internally generated changes generated increased activity in the dorsal anterior cingulate cortex with a concomitant disengagement in regions associated with the default-mode network. The results provide new insights into how the brain plans and re-plans in the face of a changing environment.

Human back-tracking behaviour is associated with suppression of default-mode region activity and enhanced dorsal anterior cingulate activity

The ability to track the statistics of our surroundings is a key computational challenge. A prominent theory (Dayan & Yu, 2006) proposes that the brain monitors for ‘unexpected uncertainty’ – events which deviate substantially from model predictions, indicating model failure. Norepinephrine (NE) is thought to play a key role in this process by serving as an interrupt signal, initiating model-resetting. However, evidence is from paradigms where participants actively monitored stimulus statistics. To determine whether NE routinely reports the statistical structure of our surroundings, even when not behaviourally relevant, we used rapid tone-pip sequences that contained perceptually salient pattern-changes associated with abrupt structural violations vs. emergence of regular structure. Phasic pupil dilations (PDR) were monitored to assess NE. We reveal a remarkable specificity: When not behaviourally relevant, only abrupt structural violations evoked a PDR. The results demonstrate that NE tracks ‘unexpected uncertainty’ on rapid time scales relevant to sensory signals.

Phasic norepinephrine is a neural interrupt signal for unexpected events in rapidly unfolding sensory sequences – evidence from pupillometry

Betwixt fast and slow: Integrating model-free and model-based decision-making

Author response: Attenuation of dopamine-modulated prefrontal value signals underlies probabilistic reward learning deficits in old age

Cooperation and competition between human players in repeated microeconomic games offer a window onto social phenomena such as the establishment, breakdown and repair of trust. However, although a suitable starting point for the quantitative analysis of such games exists, namely the Interactive Partially Observable Markov Decision Process (I-POMDP), computational considerations and structural limitations have limited its application, and left unmodelled critical features of behavior in a canonical trust task. Here, we provide the first analysis of two central phenomena: a form of social risk-aversion exhibited by the player who is in control of the interaction in the game; and irritation or anger, potentially exhibited by both players. Irritation arises when partners apparently defect, and it potentially causes a precipitate breakdown in cooperation. Failing to model one’s partner’s propensity for it leads to substantial economic inefficiency. We illustrate these behaviours using evidence drawn from the play of large cohorts of healthy volunteers and patients. We show that for both cohorts, a particular subtype of player is largely responsible for the breakdown of trust, a finding which sheds new light on borderline personality disorder.

A model of risk and mental state shifts during social interaction

In Drosophila, as in other animals, the circadian clock is a singular entity in name and concept only. In reality, clock functions emerge from multiple processes and anatomical substrates. One distinction has conventionally been made between a central clock (in the brain) and peripheral clocks (e.g., in the gut and the eyes). Both types of clock generate robust circadian oscillations, which do not require external input. Furthermore, the phases of these oscillations remain exquisitely sensitive to specific environmental cues, such as the daily changes of light and temperature. When these cues conflict with one another, the central clock displays complex forms of sensory integration; how peripheral clocks respond to conflicting input is unclear. We therefore explored the effects of light and temperature misalignments on peripheral clocks. We show that under conflict, peripheral clocks preferentially synchronize to the light stimulus. This photic dominance requires the presence of the circadian photoreceptor, Cryptochrome.

Light Dominates Peripheral Circadian Oscillations in Drosophila melanogaster During Sensory Conflict

Modeling Avoidance in Mood and Anxiety Disorders Using Reinforcement Learning

Serotonin plays an influential, but computationally obscure, modulatory role in many aspects of normal and dysfunctional learning and cognition. Here, we studied the impact of optogenetic stimulation of dorsal raphe serotonin neurons in mice performing a non-stationary, reward-driven, foraging task. We report that activation of serotonin neurons significantly boosted learning rates for choices following long inter-trial-intervals that were driven by the recent history of reinforcement.

The Long and the Short of Serotonergic Stimulation: Optogenetic activation of dorsal raphe serotonergic neurons changes the learning rate for rewards

The anterior cingulate cortex (ACC) is implicated in learning the value of actions, and thus in allowing past outcomes to influence the current choice. However, it is not clear whether or how it contributes to the two major ways such learning is thought to happen: model-based mechanisms that learn action-state predictions and use these to infer action values; or model-free mechanisms which learn action values directly through reward prediction errors. Having confirmed, using a classical probabilistic reversal learning task, that optogenetic inhibition of ACC neurons on single trials indeed affected reinforcement learning, we examined the consequence of this manipulation in a novel two-step decision task designed to dissociate model-free and model-based learning mechanisms in mice. On the two-step task, silencing spared the influence of the trial outcome but reduced the influence of the experienced state transition. Analysis using reinforcement learning models indicated that ACC inhibition disrupted model-based RL mechanisms.

Single-Trial Inhibition of Anterior Cingulate Disrupts Model-based Reinforcement Learning in a Two-step Decision Task.

Humans possess rich knowledge of the structure of the world, including co-occurrences among entities, and covariation among their discrete and continuous features. But how people learn, infer and predict this structure is not well understood. Here we explore everyday scene understanding as a case study of people’s structural knowledge and reasoning. We introduce a probabilistic model over scene graphs that can learn the relational structure of objects and their arrangements and support inference and generation. Our model was able to learn the underlying structure of real-world scenes, and use it for inference and compression. In two human psychophysical experiments we found that a corresponding computational cognitive model was able to explain how people learn novel scene distributions and use it for classification and construction. Our work represents the first computational theory of human scene understanding that can account for people’s rich capacity for learning and reasoning about structure.

A model of structure learning, inference, and generation for scene understanding

Prior preferences beneficially influence social and non-social learning

Trials-with-fewer-errors: Feature-based learning and exploration

Pavlovian influences on learning differ between rats and mice in a counter-balanced Go/NoGo judgement bias task

Increased decision thresholds trigger extended information gathering across the compulsivity spectrum

Probabilistic reward learning is characterised by individual differences that become acute in aging. This may be due to age-related dopamine (DA) decline affecting neural processing in striatum, prefrontal cortex, or both. We examined this by administering a probabilistic reward learning task to younger and older adults, and combining computational modelling of behaviour, fMRI and PET measurements of DA D1 availability. We found that anticipatory value signals in ventromedial prefrontal cortex (vmPFC) were attenuated in older adults. The strength of this signal predicted performance beyond age and was modulated by D1 availability in nucleus accumbens. These results uncover that a value-anticipation mechanism in vmPFC declines in aging, and that this mechanism is associated with DA D1 receptor availability.

Attenuation of dopamine-modulated prefrontal value signals underlies probabilistic reward learning deficits in old age

Interrupting Options: Minimizing Decision Costs via Temporal Commitment and Low-Level Interrupt

Patients with obsessive-compulsive disorder (OCD) can be described as cautious and hesitant, manifesting an excessive indecisiveness that hinders efficient decision making. However, excess caution in decision making may also lead to better performance in specific situations where the cost of extended deliberation is small. We compared 16 juvenile OCD patients with 16 matched healthy controls whilst they performed a sequential information gathering task under different external cost conditions. We found that patients with OCD outperformed healthy controls, winning significantly more points. The groups also differed in the number of draws required prior to committing to a decision, but not in decision accuracy. A novel Bayesian computational model revealed that subjective sampling costs arose as a non-linear function of sampling, closely resembling an escalating urgency signal. Group difference in performance was best explained by a later emergence of these subjective costs in the OCD group, also evident in an increased decision threshold. Our findings present a novel computational model and suggest that enhanced information gathering in OCD can be accounted for by a higher decision threshold arising out of an altered perception of costs that, in some specific contexts, may be advantageous.

Increased decision thresholds enhance information gathering performance in juvenile Obsessive-Compulsive Disorder (OCD)

 The Edinburgh Companion to Literature and Music provides a pioneering interdisciplinary overview of the literature and music of nine centuries. Bringing together seventy-one newly commissioned chapters by specialists in literature and musicology, it presents the most recent interdisciplinary research. In five parts, the chapters cover relations between literature and music from the intermediality of the Middle Ages through to the broadening definitions of what constitutes ‘literature’ or ‘music’ in the present. 
The volume introduction and methodology chapters define key concepts for investigating the interdependence of the two art forms and a concluding chapter looks to the future of this interdisciplinary field. An editorial introduction to each historical part explains the main features of the relationships between literature and music in the period and outlines recent developments in scholarship. Contributions represent a multiplicity of approaches: theoretical, contextual and close reading. Case studies reach beyond literature and music to engage with related fields including philosophy, history of science, theatre, broadcast media and popular culture.
The volume charts and extends work in this expanding interdisciplinary field and is an essential resource for researchers with an interest in literature and other media.

Importance Major depressive disorder (MDD) is associated with deficits in representing reward prediction errors (RPEs), which are the difference between experienced and predicted reward. Reward prediction errors underlie learning of values in reinforcement learning models, are represented by phasic dopamine release, and are known to affect momentary mood. Objective To combine functional neuroimaging, computational modeling, and smartphone-based large-scale data collection to test, in the absence of learning-related concerns, the hypothesis that depression attenuates the impact of RPEs. Design, Setting, and Participants Functional magnetic resonance imaging (fMRI) data were collected on 32 individuals with moderate MDD and 20 control participants who performed a probabilistic reward task. A risky decision task with repeated happiness ratings as a measure of momentary mood was also tested in the laboratory in 74 participants and with a smartphone-based platform in 1833 participants. The study was conducted from November 20, 2012, to February 17, 2015. Main Outcomes and Measures Blood oxygen level–dependent activity was measured in ventral striatum, a dopamine target area known to represent RPEs. Momentary mood was measured during risky decision making. Results Of the 52 fMRI participants (mean [SD] age, 34.0 [9.1] years), 30 (58%) were women and 32 had MDD. Of the 74 participants in the laboratory risky decision task (mean age, 34.2 [10.3] years), 44 (59%) were women and 54 had MDD. Of the smartphone group, 543 (30%) had a depression history and 1290 (70%) had no depression history; 918 (50%) were women, and 593 (32%) were younger than 30 years. Contrary to previous results in reinforcement learning tasks, individuals with moderate depression showed intact RPE signals in ventral striatum (z = 3.16; P = .002) that did not differ significantly from controls (z = 0.91; P = .36). Symptom severity correlated with baseline mood parameters in laboratory (&rgr; = −0.54; P < 1 × 10−6) and smartphone (&rgr; = −0.30; P < 1 × 10−39) data. However, participants with depression showed an intact association between RPEs and happiness in a computational model of momentary mood dynamics (z = 4.55; P < .001) that was not attenuated compared with controls (z = −0.42; P = .67). Conclusions and Relevance The neural and emotional impact of RPEs is intact in major depression. These results suggest that depression does not affect the expression of dopaminergic RPEs and that attenuated RPEs in previous reports may reflect downstream effects more closely related to aberrant behavior. The correlation between symptom severity and baseline mood parameters supports an association between depression and momentary mood fluctuations during cognitive tasks. These results demonstrate a potential for smartphones in large-scale computational phenotyping, which is a goal for computational psychiatry.

Association of Neural and Emotional Impacts of Reward Prediction Errors With Major Depression

Modelling avoidance in mood and anxiety disorders using reinforcement-learningReinforcement learning of avoidance in mood and anxiety

We train a generator by maximum likelihood and we also train the same generator architecture by Wasserstein GAN. We then compare the generated samples, exact log-probability densities and approximate Wasserstein distances. We show that an independent critic trained to approximate Wasserstein distance between the validation set and the generator distribution helps detect overfitting. Finally, we use ideas from the one-shot learning literature to develop a novel fast learning critic.

Comparison of Maximum Likelihood and GAN-based training of Real NVPs

Human sign- but not goaltrackers show a Nucleus accumbens response to Pavlovian cues

Important real-world decisions are often arduous as they frequently involve sequences of choices, with initial selections affecting future options. Evaluating every possible combination of choices is computationally intractable, particularly for longer multistep decisions. Therefore, humans frequently use heuristics to reduce the complexity of decisions. We recently used a goal-directed planning task to demonstrate the profound behavioral influence and ubiquity of one such shortcut, namely aversive pruning, a reflexive Pavlovian process that involves neglecting parts of the decision space residing beyond salient negative outcomes. However, how the brain implements this important decision heuristic and what underlies individual differences have hitherto remained unanswered. Therefore, we administered an adapted version of the same planning task to healthy male and female volunteers undergoing functional magnetic resonance imaging (fMRI) to determine the neural basis of aversive pruning. Through both computational and standard categorical fMRI analyses, we show that when planning was influenced by aversive pruning, the subgenual cingulate cortex was robustly recruited. This neural signature was distinct from those associated with general planning and valuation, two fundamental cognitive components elicited by our task but which are complementary to aversive pruning. Furthermore, we found that individual variation in levels of aversive pruning was associated with the responses of insula and dorsolateral prefrontal cortices to the receipt of large monetary losses, and also with subclinical levels of anxiety. In summary, our data reveal the neural signatures of an important reflexive Pavlovian process that shapes goal-directed evaluations and thereby determines the outcome of high-level sequential cognitive processes. SIGNIFICANCE STATEMENT Multistep decisions are complex because initial choices constrain future options. Evaluating every path for long decision sequences is often impractical; thus, cognitive shortcuts are often essential. One pervasive and powerful heuristic is aversive pruning, in which potential decision-making avenues are curtailed at immediate negative outcomes. We used neuroimaging to examine how humans implement such pruning. We found it to be associated with activity in the subgenual cingulate cortex, with neural signatures that were distinguishable from those covarying with planning and valuation. Individual variations in aversive pruning levels related to subclinical anxiety levels and insular cortex activation. These findings reveal the neural mechanisms by which basic negative Pavlovian influences guide decision-making during planning, with implications for disrupted decision-making in psychiatric disorders.

On the danger of pushing poetry towards music: The successes and failures of Hugo Ball, René Ghil, and Stéphane Mallarmé

The influence of contextual reward statistics on risk preference

Significance Solving complex tasks often requires estimates of the future consequences of current actions. Estimates could be learned from past experience, but they then risk being out of date, or they could be calculated by a form of planning into the future, a process that is computationally taxing. We show that humans integrate learned estimates into their planning calculations, saving mental effort and time. We also show that increasing time pressure leads to reliance on learned estimates after fewer steps of planning. We suggest a normative rationale for this effect using a computational model. Our results provide a perspective on how the brain combines different decision processes collaboratively to exploit their comparative computational advantages. Behavioral and neural evidence reveal a prospective goal-directed decision process that relies on mental simulation of the environment, and a retrospective habitual process that caches returns previously garnered from available choices. Artificial systems combine the two by simulating the environment up to some depth and then exploiting habitual values as proxies for consequences that may arise in the further future. Using a three-step task, we provide evidence that human subjects use such a normative plan-until-habit strategy, implying a spectrum of approaches that interpolates between habitual and goal-directed responding. We found that increasing time pressure led to shallower goal-directed planning, suggesting that a speed-accuracy tradeoff controls the depth of planning with deeper search leading to more accurate evaluation, at the cost of slower decision-making. We conclude that subjects integrate habit-based cached values directly into goal-directed evaluations in a normative manner.

Adaptive integration of habits into depth-limited planning defines a habitual-goal–directed spectrum

Sensory Conflict Disrupts Activity of the Drosophila Circadian Network

Successful interaction with the environment requires flexible updating of our beliefs about the world. By estimating the likelihood of future events, it is possible to prepare appropriate actions in advance and execute fast, accurate motor responses. According to theoretical proposals, agents track the variability arising from changing environments by computing various forms of uncertainty. Several neuromodulators have been linked to uncertainty signalling, but comprehensive empirical characterisation of their relative contributions to perceptual belief updating, and to the selection of motor responses, is lacking. Here we assess the roles of noradrenaline, acetylcholine and dopamine within a single, unified computational framework of uncertainty. Using pharmacological interventions in a sample of 128 healthy human volunteers and a hierarchical Bayesian learning model, we characterise the influences of noradrenergic, cholinergic and dopaminergic receptor antagonism on individual computations of uncertainty during a probabilistic serial reaction time task. We propose that noradrenaline influences learning of uncertain events arising from unexpected changes in the environment. In contrast, acetylcholine balances attribution of uncertainty to chance fluctuations within an environmental context, defined by a stable set of probabilistic associations, or to gross environmental violations following a contextual switch. Dopamine supports the use of uncertainty representations to engender fast, adaptive responses.

Charting the landscape of priority problems in psychiatry, part 1: classification and diagnosis.

Observing seeking observing: How prediction errors boost anticipation

Background Changes in reflexive emotional responses are hallmarks of depression, but how emotional reflexes make an impact on adaptive decision-making in depression has not been examined formally. Using a Pavlovian-instrumental transfer (PIT) task, we compared the influence of affectively valenced stimuli on decision-making in depression and generalized anxiety disorder compared with healthy controls; and related this to the longitudinal course of the illness. Method A total of 40 subjects with a current DSM-IV-TR diagnosis of major depressive disorder, dysthymia, generalized anxiety disorder, or a combination thereof, and 40 matched healthy controls performed a PIT task that assesses how instrumental approach and withdrawal behaviours are influenced by appetitive and aversive Pavlovian conditioned stimuli (CSs). Patients were followed up after 4–6 months. Analyses focused on patients with depression alone (n = 25). Results In healthy controls, Pavlovian CSs exerted action-specific effects, with appetitive CSs boosting active approach and aversive CSs active withdrawal. This action-specificity was absent in currently depressed subjects. Greater action-specificity in patients was associated with better recovery over the follow-up period. Conclusions Depression is associated with an abnormal influence of emotional reactions on decision-making in a way that may predict recovery.

The specificity of Pavlovian regulation is associated with recovery from depression

Deep brain stimulation of the subthalamic nucleus modulates sensitivity to decision outcome value in Parkinson’s disease

Using social information to infer on one’s own taste in the important case of temporal discounting

When people anticipate uncertain future outcomes, they often prefer to know their fate in advance. Inspired by an idea in behavioral economics that the anticipation of rewards is itself attractive, we hypothesized that this preference of advance information arises because reward prediction errors carried by such information can boost the level of anticipation. We designed new empirical behavioral studies to test this proposal, and confirmed that subjects preferred advance reward information more strongly when they had to wait for rewards for a longer time. We formulated our proposal in a reinforcement-learning model, and we showed that our model could account for a wide range of existing neuronal and behavioral data, without appealing to ambiguous notions such as an explicit value for information. We suggest that such boosted anticipation significantly drives risk-seeking behaviors, most pertinently in gambling. DOI: http://dx.doi.org/10.7554/eLife.13747.001

The modulation of savouring by prediction error and its effects on choice

Successful interaction with the environment requires flexible updating of our beliefs about the world. By estimating the likelihood of future events, it is possible to prepare appropriate actions in advance and execute fast, accurate motor responses. According to theoretical proposals, agents track the variability arising from changing environments by computing various forms of uncertainty. Several neuromodulators have been linked to uncertainty signalling, but comprehensive empirical characterisation of their relative contributions to perceptual belief updating, and to the selection of motor responses, is lacking. Here we assess the roles of noradrenaline, acetylcholine, and dopamine within a single, unified computational framework of uncertainty. Using pharmacological interventions in a sample of 128 healthy human volunteers and a hierarchical Bayesian learning model, we characterise the influences of noradrenergic, cholinergic, and dopaminergic receptor antagonism on individual computations of uncertainty during a probabilistic serial reaction time task. We propose that noradrenaline influences learning of uncertain events arising from unexpected changes in the environment. In contrast, acetylcholine balances attribution of uncertainty to chance fluctuations within an environmental context, defined by a stable set of probabilistic associations, or to gross environmental violations following a contextual switch. Dopamine supports the use of uncertainty representations to engender fast, adaptive responses.

Author response: The modulation of savouring by prediction error and its effects on choice

Positive and negative moods can be treated as prior expectations over future delivery of rewards and punishments. This provides an inferential foundation for the cognitive (judgement) bias task, now widely-used for assessing affective states in non-human animals. In the task, information about affect is extracted from the optimistic or pessimistic manner in which participants resolve ambiguities in sensory input. Here, we report a novel variant of the task aimed at dissecting the effects of affect manipulations on perceptual and value computations for decision-making under ambiguity in humans. Participants were instructed to judge which way a Gabor patch (250ms presentation) was leaning. If the stimulus leant one way (e.g. left), pressing the REWard key yielded a monetary WIN whilst pressing the SAFE key failed to acquire the WIN. If it leant the other way (e.g. right), pressing the SAFE key avoided a LOSS whilst pressing the REWard key incurred the LOSS. The size (0–100 UK pence) of the offered WIN and threatened LOSS, and the ambiguity of the stimulus (vertical being completely ambiguous) were varied on a trial-by-trial basis, allowing us to investigate how decisions were affected by differing combinations of these factors. Half the subjects performed the task in a ‘Pleasantly’ decorated room and were given a gift (bag of sweets) prior to starting, whilst the other half were in a bare ‘Unpleasant’ room and were not given anything. Although these treatments had little effect on self-reported mood, they did lead to differences in decision-making. All subjects were risk averse under ambiguity, consistent with the notion of loss aversion. Analysis using a Bayesian decision model indicated that Unpleasant Room subjects were (‘pessimistically’) biased towards choosing the SAFE key under ambiguity, but also weighed WINS more heavily than LOSSes compared to Pleasant Room subjects. These apparently contradictory findings may be explained by the influence of affect on different processes underlying decision-making, and the task presented here offers opportunities for further dissecting such processes.

Cognitive Bias in Ambiguity Judgements: Using Computational Models to Dissect the Effects of Mild Mood Manipulation in Humans

Serious and debilitating symptoms of anxiety are the most common mental health problem worldwide, accounting for around 5% of all adult ‘years lived with disability’ in the developed world. Avoidance behaviour –avoiding social situations for fear of embarrassment, for instance–is a core feature of such anxiety. However, as for many other psychiatric symptoms, the biological mechanisms underlying avoidance remain unclear. Reinforcement-learning models provide formal and testable characterizations of the mechanisms of decision-making; here, we examine avoidance in these terms. One hundred and one healthy and pathologically anxious individuals completed an approach-avoidance go/no-go task under stress induced by threat of unpredictable shock. We show an increased reliance in the anxious group on a parameter of our reinforcement-learning model that characterizes a prepotent (Pavlovian) bias to withhold responding in the face of negative outcomes. This was particularly the case when the anxious individuals were under stress. This formal description of avoidance within the reinforcement-learning framework provides a new means of linking clinical symptoms with biophysically plausible models of neural circuitry and, as such, takes us closer to a mechanistic understanding of pathological anxiety.

Modelling avoidance in pathologically anxious humans using reinforcement-learning

Computations Underlying Social Hierarchy Learning: Distinct Neural Mechanisms for Updating and Representing Self-Relevant Information

Multiple value signals in dopaminergic midbrain and their role in avoidance contexts

Editorial overview: Computational modeling: After the Middle Ages of computational neuroscience

Significance Our ability to learn how to avoid harm is critical for maintaining physical and mental health. However, excessive harm avoidance can be maladaptive, as evident in psychiatric disorders such as avoidant personality disorder and obsessive-compulsive disorder. We therefore investigated the neural factors underlying individual imbalances in harm avoidance behavior. Our findings show that such imbalances can be predicted by the function and structure of an individual’s striatum, a brain region that is critical for goal-directed decisionmaking. Moreover, the neural signals expressed in this region revealed key processes through which individuals learn to avoid harm. These findings highlight a neural basis for imbalanced harm avoidance behavior, extreme forms of which may contribute to psychiatric pathology. Pain is an elemental inducer of avoidance. Here, we demonstrate that people differ in how they learn to avoid pain, with some individuals refraining from actions that resulted in painful outcomes, whereas others favor actions that helped prevent pain. These individual biases were best explained by differences in learning from outcome prediction errors and were associated with distinct forms of striatal responses to painful outcomes. Specifically, striatal responses to pain were modulated in a manner consistent with an aversive prediction error in individuals who learned predominantly from pain, whereas in individuals who learned predominantly from success in preventing pain, modulation was consistent with an appetitive prediction error. In contrast, striatal responses to success in preventing pain were consistent with an appetitive prediction error in both groups. Furthermore, variation in striatal structure, encompassing the region where pain prediction errors were expressed, predicted participants’ predominant mode of learning, suggesting the observed learning biases may reflect stable individual traits. These results reveal functional and structural neural components underlying individual differences in avoidance learning, which may be important contributors to psychiatric disorders involving pathological harm avoidance behavior.

Striatal structure and function predict individual biases in learning to avoid pain

Charting the landscape of priority problems in psychiatry, part 2: pathogenesis and aetiology.

Higher-level cognition depends on the ability to learn models of the world. We can characterize this at the computational level as a structure-learning problem with the goal of best identifying the prevailing causal relationships among a set of relata. However, the computational cost of performing exact Bayesian inference over causal models grows rapidly as the number of relata increases. This implies that the cognitive processes underlying causal learning must be substantially approximate. A powerful class of approximations that focuses on the sequential absorption of successive inputs is captured by the Neurath’s ship metaphor in philosophy of science, where theory change is cast as a stochastic and gradual process shaped as much by people’s limited willingness to abandon their current theory when considering alternatives as by the ground truth they hope to approach. Inspired by this metaphor and by algorithms for approximating Bayesian inference in machine learning, we propose an algorithmic-level model of causal structure learning under which learners represent only a single global hypothesis that they update locally as they gather evidence. We propose a related scheme for understanding how, under these limitations, learners choose informative interventions that manipulate the causal system to help elucidate its workings. We find support for our approach in the analysis of 3 experiments.

Formalizing Neurath’s Ship: Approximate Algorithms for Online Causal Learning

Abstract The hippocampus plays a central role in the approach‐avoidance conflict that is central to the genesis of anxiety. However, its exact functional contribution has yet to be identified. We designed a novel gambling task that generated approach‐avoidance conflict while controlling for spatial processing. We fit subjects’ behavior using a model that quantified the subjective values of choice options, and recorded neural signals using functional magnetic resonance imaging (fMRI). Distinct functional signals were observed in anterior hippocampus, with inferior hippocampus selectively recruited when subjects rejected a gamble, to a degree that covaried with individual differences in anxiety. The superior anterior hippocampus, in contrast, uniquely demonstrated value signals that were potentiated in the context of approach‐avoidance conflict. These results implicate the anterior hippocampus in behavioral avoidance and choice monitoring, in a manner relevant to understanding its role in anxiety. Our findings highlight interactions between subregions of the hippocampus as an important focus for future study.

Parsing the Role of the Hippocampus in Approach–Avoidance Conflict

The weight with which a specific outcome feature contributes to preference quantifies a person’s ‘taste’ for that feature. However, far from being fixed personality characteristics, tastes are plastic. They tend to align, for example, with those of others even if such conformity is not rewarded. We hypothesised that people can be uncertain about their tastes. Personal tastes are therefore uncertain beliefs. People can thus learn about them by considering evidence, such as the preferences of relevant others, and then performing Bayesian updating. If a person’s choice variability reflects uncertainty, as in random-preference models, then a signature of Bayesian updating is that the degree of taste change should correlate with that person’s choice variability. Temporal discounting coefficients are an important example of taste–for patience. These coefficients quantify impulsivity, have good psychometric properties and can change upon observing others’ choices. We examined discounting preferences in a novel, large community study of 14–24 year olds. We assessed discounting behaviour, including decision variability, before and after participants observed another person’s choices. We found good evidence for taste uncertainty and for Bayesian taste updating. First, participants displayed decision variability which was better accounted for by a random-taste than by a response-noise model. Second, apparent taste shifts were well described by a Bayesian model taking into account taste uncertainty and the relevance of social information. Our findings have important neuroscientific, clinical and developmental significance.

How People Use Social Information to Find out What to Want in the Paradigmatic Case of Inter-temporal Preferences

Distinguishing different psychiatric populations based on a social hierarchy paradigm

Abstract Background The effects of acute tryptophan depletion on human decision-making suggest that serotonin modulates the processing of rewards and punishments. However, few studies have assessed which of the many types of serotonin receptors are responsible. Methods Using a within-subject, double-blind, sham-controlled design in 26 subjects, we examined whether individual differences in serotonin system gene transcription, measured in peripheral blood, predicted the effect of acute tryptophan depletion on decision-making. Participants performed a task in which they chose between successive pairs of fixed, lower-stakes (control) and variable, higher-stakes (experimental) gambles, each involving wins or losses. In 21 participants, mRNA from 9 serotonin system genes was measured in whole blood prior to acute tryptophan depletion: 5-HT1B, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT3A, 5-HT3E, 5-HT7 (serotonin receptors), 5-HTT (the serotonin transporter), and tryptophan hydroxylase 1. Results Acute tryptophan depletion did not significantly influence participants’ sensitivity to probability, wins, or losses, although there was a trend for a lower tendency to choose experimental gambles overall following depletion. Significant positive correlations, which survived correction for multiple comparisons, were detected between baseline 5-HT1B mRNA levels and acute tryptophan depletion-induced increases in both the overall tendency to choose the experimental gamble and sensitivity to wins. No significant relationship was observed with any other peripheral serotonin system markers. Computational analyses of decision-making data provided results consistent with these findings. Conclusions These results suggest that the 5-HT1B receptor may modulate the effects of acute tryptophan depletion on risky decision-making. Peripheral levels of serotonin markers may predict response to treatments that act upon the serotonin system, such as selective serotonin reuptake inhibitors.

Peripheral Serotonin 1B Receptor Transcription Predicts the Effect of Acute Tryptophan Depletion on Risky Decision-Making

The neuromodulator dopamine has a well established role in reporting appetitive prediction errors that are widely considered in terms of learning. However, across a wide variety of contexts, both phasic and tonic aspects of dopamine are likely to exert more immediate effects that have been less well characterized. Of particular interest is dopamine's influence on economic risk taking and on subjective well-being, a quantity known to be substantially affected by prediction errors resulting from the outcomes of risky choices. By boosting dopamine levels using levodopa (l-DOPA) as human subjects made economic decisions and repeatedly reported their momentary happiness, we show here an effect on both choices and happiness. Boosting dopamine levels increased the number of risky options chosen in trials involving potential gains but not trials involving potential losses. This effect could be better captured as increased Pavlovian approach in an approach–avoidance decision model than as a change in risk preferences within an established prospect theory model. Boosting dopamine also increased happiness resulting from some rewards. Our findings thus identify specific novel influences of dopamine on decision making and emotion that are distinct from its established role in learning.

Dopaminergic Modulation of Decision Making and Subjective Well-Being

Substantial evidence suggests that the phasic activity of dopamine neurons represents reinforcement learning’s temporal difference prediction error. However, recent reports of ramp-like increases in dopamine concentration in the striatum when animals are about to act, or are about to reach rewards, appear to pose a challenge to established thinking. This is because the implied activity is persistently predictable by preceding stimuli, and so cannot arise as this sort of prediction error. Here, we explore three possible accounts of such ramping signals: (a) the resolution of uncertainty about the timing of action; (b) the direct influence of dopamine over mechanisms associated with making choices; and (c) a new model of discounted vigour. Collectively, these suggest that dopamine ramps may be explained, with only minor disturbance, by standard theoretical ideas, though urgent questions remain regarding their proximal cause. We suggest experimental approaches to disentangling which of the proposed mechanisms are responsible for dopamine ramps.

Tamping Ramping: Algorithmic, Implementational, and Computational Explanations of Phasic Dopamine Signals in the Accumbens

Dopamine plays a key role in motivation. Phasic dopamine response reflects a reinforcement prediction error (RPE), whereas tonic dopamine activity is postulated to represent an average reward that mediates motivational vigor. However, it has been hard to find evidence concerning the neural encoding of average reward that is uncorrupted by influences of RPEs. We circumvented this difficulty in a novel visual search task where we measured participants' button pressing vigor in a context where information (underlying an RPE) about future average reward was provided well before the average reward itself. Despite no instrumental consequence, participants' pressing force increased for greater current average reward, consistent with a form of Pavlovian effect on motivational vigor. We recorded participants' brain activity during task performance with fMRI. Greater average reward was associated with enhanced activity in dopaminergic midbrain to a degree that correlated with the relationship between average reward and pressing vigor. Interestingly, an opposite pattern was observed in subgenual cingulate cortex, a region implicated in negative mood and motivational inhibition. These findings highlight a crucial role for dopaminergic midbrain in representing aspects of average reward and motivational vigor.

The Dopaminergic Midbrain Mediates an Effect of Average Reward on Pavlovian Vigor

Correct wiring is crucial for the proper functioning of the nervous system. Molecular gradients provide critical signals to guide growth cones, which are the motile tips of developing axons, to their targets. However, in vitro, growth cones trace highly stochastic trajectories, and exactly how molecular gradients bias their movement is unclear. Here, we introduce a mathematical model based on persistence, bias, and noise to describe this behaviour, constrained directly by measurements of the detailed statistics of growth cone movements in both attractive and repulsive gradients in a microfluidic device. This model provides a mathematical explanation for why average axon turning angles in gradients in vitro saturate very rapidly with time at relatively small values. This work introduces the most accurate predictive model of growth cone trajectories to date, and deepens our understanding of axon guidance events both in vitro and in vivo. DOI: http://dx.doi.org/10.7554/eLife.12248.001

A mathematical model explains saturating axon guidance responses to molecular gradients

Chemotaxis, or directed motion in chemical gradients, is critical for various biological processes. Many eukaryotic cells perform spatial sensing, i.e. they detect gradients by comparing spatial differences in binding occupancy of chemosensory receptors across their membrane. In many theoretical models of spatial sensing, it is assumed, for the sake of simplicity, that the receptors concerned do not move. However, in reality, receptors undergo diverse modes of diffusion, and can traverse considerable distances in the time it takes such cells to turn in an external gradient. This sets a physical limit on the accuracy of spatial sensing, which we explore using a model in which receptors diffuse freely over the membrane. We find that the Fisher information carried in binding and unbinding events decreases monotonically with the diffusion constant of the receptors.

A Research Project Submitted to the Department of Applied Economics in Partial Fulfillment of the Requirements for the Award of Degree of Master of Economics (Finance) of Kenyatta University, November 2015

An overarching view of adaptive behavior is that humans and animals seek to maximize reward and minimize punishment in their choices. Solutions to such value-based decision problems fall along a crude spectrum. At one end, on-the-fly planning, based on a model of the relevant domain, can determine which of the available actions lead to a desired outcome. Finding optimal actions in this type of choice context, for instance, by searching the branches of a decision tree for the best outcome, poses severe demands on computation and memory and rapidly becomes intractable with growing complexity. This end of the planning spectrum is of particular importance when we have relatively little experience in an environment or where its aspects change quickly. In contrast, when subjects have extensive practice in a relatively stable domain, they can directly learn from experience about the affective consequences of different actions. Decision-making at this end of the spectrum can become highly automated and need no longer be based on a complex representational model of the world. One of the main results in the field of reinforcement learning1, and indeed one of the earliest insights in artificial intelligence2, is that it is possible to learn optimal actions in complex, but stable, domains by making and measuring errors in predictions over the course of extended experience. A rich body of work on value-based decision-making in humans has focused on learning on the basis of prediction errors3,4. Although there has been extensive investigation of various tasks involving planning, such as the Tower of London5, these tasks have typically not focused on value and have not been designed to compare the two ends of the spectrum referred to above. More recent investigations targeting this spectrum6–8 have been revealing, but have not directly addressed the computational mechanisms or neural encoding of value-based planning, or the integration of extensive training and planning–based evaluation and choice. We designed a value-based choice task for human subjects and used functional magnetic resonance imaging (fMRI) to examine the neural mechanisms underlying forward planning and choices based on learned values after extensive behavioral training. Our task allowed us to separately index planning and extensively trained contexts, which allowed us to specifically investigate value representations in the brain associated with the computational processes of each type of choice. We found that medial striatum was more strongly engaged during planning and lateral striatum was more strongly engaged during choices in extensively trained contexts. Notably, the blood oxygen level–dependent signals in caudate pertained to individual computational components of planned choice values, whereas signals in posterior putamen selectively fluctuated with the values during extensively trained responses. Our results provide direct evidence in humans for multiple decision systems that operate independently and in parallel and recruit neural structures along a medio-lateral axis in basal ganglia. Furthermore, prefrontal cortex, specifically ventromedial prefrontal cortex (vmPFC), represented the value of the chosen option across systems, highlighting its possible role as a value comparator across both decision systems.

the statistical significance of all results in the main text is based on a priori region of interests ( see Table S 5 ) . x y z Z voxels p ( FWE ) Region Hemi Planning

Social norms and their enforcement are fundamental to human societies. The ability to detect deviations from norms and to adapt to norms in a changing environment is therefore important to individuals' normal social functioning. Previous neuroimaging studies have highlighted the involvement of the insular and ventromedial prefrontal (vmPFC) cortices in representing norms. However, the necessity and dissociability of their involvement remain unclear. Using model-based computational modeling and neuropsychological lesion approaches, we examined the contributions of the insula and vmPFC to norm adaptation in seven human patients with focal insula lesions and six patients with focal vmPFC lesions, in comparison with forty neurologically intact controls and six brain-damaged controls. There were three computational signals of interest as participants played a fairness game (ultimatum game): sensitivity to the fairness of offers, sensitivity to deviations from expected norms, and the speed at which people adapt to norms. Significant group differences were assessed using bootstrapping methods. Patients with insula lesions displayed abnormally low adaptation speed to norms, yet detected norm violations with greater sensitivity than controls. Patients with vmPFC lesions did not have such abnormalities, but displayed reduced sensitivity to fairness and were more likely to accept the most unfair offers. These findings provide compelling computational and lesion evidence supporting the necessary, yet dissociable roles of the insula and vmPFC in norm adaptation in humans: the insula is critical for learning to adapt when reality deviates from norm expectations, and that the vmPFC is important for valuation of fairness during social exchange.

Necessary, Yet Dissociable Contributions of the Insular and Ventromedial Prefrontal Cortices to Norm Adaptation: Computational and Lesion Evidence in Humans

The recently developed ‘two-step’ behavioural task promises to differentiate model-based or goal-directed from model-free or habitual reinforcement learning, while generating neurophysiologically-friendly decision datasets with parametric variation of decision variables. These desirable features have prompted widespread adoption of the task. However, the signatures of model-based control can be elusive – here, we investigate model-free learning methods that, depending on the analysis strategy, can masquerade as being model-based. We first show that unadorned model-free reinforcement learning can induce correlations between action values at the start of the trial and the subsequent trial events in such a way that analysis based on comparing successive trials can lead to erroneous conclusions. We also suggest a correction to the analysis that can alleviate this problem. We then consider model-free reinforcement learning strategies based on different state representations from those envisioned by the experimenter, which generate behaviour that appears model-based under these, and also more sophisticated, analyses. The existence of such strategies is of particular relevance to the design and interpretation of animal studies using the two-step task, as extended training and a sharp contrast between good and bad options are likely to promote their use. Author Summary Planning is the use of a predictive model of the consequences of actions to guide decision making. Planning plays a critical role in human behaviour but isolating its contribution is challenging because it is complemented by control systems which learn values of actions directly from the history of reinforcement, resulting in automatized mappings from states to actions often termed habits. Our study examined a recently developed behavioural task which uses choices in a multi-step decision tree to differentiate planning from value-based control. Using simulation, we demonstrated the existence of strategies which produce behaviour that resembles planning but in fact arises as a fixed mapping from particular sorts of states to actions. These results show that when a planning problem is faced repeatedly, sophisticated automatization strategies may be developed which identify that there are in fact a limited number of relevant states of the world each with an appropriate fixed or habitual response. Understanding such strategies is important for the design and interpretation of tasks which aim to isolate the contribution of planning to behaviour. Such strategies are also of independent scientific interest as they may contribute to automatization of behaviour in complex environments.

Simple Plans or Sophisticated Habits? State, Transition and Learning Interactions in the Two-Step Task

Roger Kowalski's poem ‘L'autre face’, published in 1960, was set to music by Jean-Claude Risset some two decades later in a piece with the same title for soprano and computer-generated tape. The poem is a powerfully self-reflexive piece, foregrounding its status as a work on paper, in which the voice of the poet becomes audible only through an imaginative act of interpretation. This relationship between paper, voice, and interpretation is fundamental to the aesthetic tradition which the poem belongs. Risset's soprano part, like classical music generally, is similarly a work on paper, awaiting a voice; but his computer-generated tape is not. Does this mean we cannot interpret it in the same way? This essay argues that Kowalski's work and Risset's, despite the latter's new medium, both belong to a high art tradition in which ghostly voices emerge from beyond the physical substance of the work—whatever that substance may be.

Taming the shrewdness of neural function: methodological challenges in computational psychiatry

Significance Many problems, particularly sequential planning problems, are computationally very demanding. How humans combine strategies to approximate and simplify these problems is not understood. Using modelling to unpick performance in a planning task, we find that humans are able to exploit the structure of the task to subdivide it and reduce processing requirements nearly optimally. Subtasks are combined in a simple, greedy manner, however, and within subtasks there is evidence of inhibitory reflexes in response to losses. Humans routinely formulate plans in domains so complex that even the most powerful computers are taxed. To do so, they seem to avail themselves of many strategies and heuristics that efficiently simplify, approximate, and hierarchically decompose hard tasks into simpler subtasks. Theoretical and cognitive research has revealed several such strategies; however, little is known about their establishment, interaction, and efficiency. Here, we use model-based behavioral analysis to provide a detailed examination of the performance of human subjects in a moderately deep planning task. We find that subjects exploit the structure of the domain to establish subgoals in a way that achieves a nearly maximal reduction in the cost of computing values of choices, but then combine partial searches with greedy local steps to solve subtasks, and maladaptively prune the decision trees of subtasks in a reflexive manner upon encountering salient losses. Subjects come idiosyncratically to favor particular sequences of actions to achieve subgoals, creating novel complex actions or “options.”

Psychiatric disorders profoundly impair many aspects of decision making. Poor choices have negative consequences in the moment and make it very hard to navigate complex social environments. Computational neuroscience provides normative, neurobiologically informed descriptions of the components of decision making that serve as a platform for a principled exploration of dysfunctions. Here, we identify and discuss three classes of failure modes arising in these formalisms. They stem from abnormalities in the framing of problems or tasks, from the mechanisms of cognition used to solve the tasks, or from the historical data available from the environment.

P. Read Montague, Raymond J. Dolan, Karl J. Friston and Peter Dayan 1 Virginia Tech Carilion Research Institute and Department of Physics, Virginia Tech, 2 Riverside Circle, Roanoke, VA 24016, USA 2 Wellcome Trust Centre for Neuroimaging, University College London, 12 Queen Square, London, WC1N 3BG, UK 3 Gatsby Computational Neuroscience Unit, Alexandra House, 17 Queen Square, London, WC1N 3AR, UK

Special Issue : Cognition in Neuropsychiatric Disorders Computational psychiatry

Electrophysiological data disclose rich dynamics in patterns of neural activity evoked by sensory objects. Retrieving objects from memory reinstates components of this activity. In humans, the temporal structure of this retrieved activity remains largely unexplored, and here we address this gap using the spatiotemporal precision of magnetoencephalography (MEG). In a sensory preconditioning paradigm, 'indirect' objects were paired with 'direct' objects to form associative links, and the latter were then paired with rewards. Using multivariate analysis methods we examined the short-time evolution of neural representations of indirect objects retrieved during reward-learning about direct objects. We found two components of the evoked representation of the indirect stimulus, 200 ms apart. The strength of retrieval of one, but not the other, representational component correlated with generalization of reward learning from direct to indirect stimuli. We suggest the temporal structure within retrieved neural representations may be key to their function. DOI: http://dx.doi.org/10.7554/eLife.04919.001

Dissociable Effects of Serotonin and Dopamine on the Valuation of Harm in Moral Decision Making

Neurons that produce serotonin respond in a number of different and complex ways in anticipation and receipt of rewards or punishments.

Causal models are key to flexible and efficient exploitation of the environment. However, learning causal structure is hard, with massive spaces of possible models, hard-to-compute marginals and the need to integrate diverse evidence over many instances. We report on two experiments in which participants learnt about probabilistic causal systems involving three and 
four variables from sequences of interventions. Participants were broadly successful, albeit exhibiting sequential dependence and floundering under high background noise. We capture their behavior with a simple model, based on the “Neurath’s ship” metaphor for scientific progress, that neither maintains a probability distribution, nor computes exact likelihoods.

Staying afloat on Neurath's boat - Heuristics for sequential causal learning

INSIGHT NEUROPHYSIOLOGY Serotonin's many meanings elude simple theories Neurons that produce serotonin respond in a number of different and complex ways in anticipation and receipt of rewards or punishments. Serotonergic neurons signal reward and punishment on multiple timescales. Image Serotonin (cyan) and channelrho-dopsin (magenta) labelled in the midbrain of a mouse D opamine and serotonin are neuromodula-tors. Produced by small assemblies (or nuclei) of neurons deep in the brain stem, these molecules are projected throughout the brain to regulate the excitability and plasticity of broad neural networks via a fiendishly complex cast of receptor types. The importance of neuromodulators is underscored by their involvement in a wealth of neurological and psychiatric diseases. What has been harder to pin down are the details of their computational roles, particularly the semantics of what they signal. Now, in eLife, Jeremiah Cohen, Mackenzie Amoroso and Naoshige Uchida add much-needed data about the activity of neurons that release serotonin in a task involving predictable rewards and punishments (Cohen et al., 2015). These data nicely muddy the theoretical waters. The past two decades have ascribed dopa-mine a particularly crisp computational role. Seminal electrophysiological recordings suggested that the phasic activity of dopamine-producing neurons—the brief spikes in electrical activity seen after a stimulus is applied—closely resembles a sophisticated form of 'prediction error' that can be used to learn how much reward to expect and then influence the choice of appropriate actions. Interpreting electrophysiological recordings, however , has always been difficult. Neuromodulatory neurons reside in complex nuclei that harbour many different types of neurons, raising doubts about whether any recorded electrophysiological activity can really be related to particular neuromodulators. Such doubts have largely been settled for dopamine by Cohen, Uchida and co-workers at Harvard University (Cohen et al., 2012) using optogenetic tagging: this technique allows the dopamine neurons to be electrophysiologically identified by genetically modifying them so that they can be stimulated with light (Lima et al., 2009). Serotonin, by comparison, has been more elusive. There is a rather broad, though not completely self-consistent, cluster of electro-physiological, pharmacological, depletion-and lesion-based results suggesting that serotonin might play a critical role in preventing active behaviours or deciding to withdraw from a situation. In this role, it is often associated with the anticipation and/or delivery of a punishment More recent optoge-netic evidence that serotonin is involved in patience could be at least partially related to this (Miyazaki et al., 2014). Along with …

Serotonin's many meanings elude simple theories Neurons that produce serotonin respond in a number of different and complex ways in anticipation and receipt of rewards or punishments.

The manifold symptoms of depression are common and often transient features of healthy life that are likely to be adaptive in difficult circumstances. It is when these symptoms enter a seemingly self-propelling spiral that the maladaptive features of a disorder emerge. We examine this malignant transformation from the perspective of the computational neuroscience of decision making, investigating how dysfunction of the brain's mechanisms of evaluation might lie at its heart. We start by considering the behavioral implications of pessimistic evaluations of decision variables. We then provide a selective review of work suggesting how such pessimism might arise via specific failures of the mechanisms of evaluation or state estimation. Finally, we analyze ways that miscalibration between the subject and environment may be self-perpetuating. We employ the formal framework of Bayesian decision theory as a foundation for this study, showing how most of the problems arise from one of its broad algorithmic facets, namely model-based reasoning.

Erratum: Harm to others outweighs harm to self in moral decision making (Proc Natl Acad Sci USA (2014) 111 (17320-17325) DOI: 10.1073/pnas.1408988111)

This is the second biography of Tzara to be published. It is very different in style from the first, François Buot’s Tristan Tzara: l’homme qui inventa la révolution Dada (Paris: Grasset, 2002): Marius Hentea’s book is shorter, simpler, more straightforwardly chronological, more evocatively illustrated, and more readable for the non-specialist. Buot gives space to the evocation of the various social and artistic milieux surrounding Tzara; in Hentea’s more direct narrative, the figure of Tzara himself is more consistently centre stage. Hentea devotes three chapters to Tzara’s childhood and adolescence; six to the Dada years, from 1915 to 1923; and four to the forty years of Tzara’s life after Dada. Tzara’s writings are not infrequently cited as illustrations of the points being made about his life. Given the elusive style of his poetry, and the difficulties of reading it in English translation (the original language is rarely cited), readers may find these illustrations problematic. But what comes out very clearly, from beginning to end, through the very problematic nature of those illustrations, is the constancy of Tzara’s obstinate and durable devotion to art. His turbulent times, one discovers, shaped his political and personal actions, but had relatively limited purchase on his aesthetic principles. His constant promotion of ‘primitive’ art; his defence of poetry as an activity that must reject all attempts at objective definition, if necessary by strategic incoherence and paradox; his absorption in the physical substance of words as a plastic material for artistic creation (materialized, towards the end of his life, in his work on anagrams in Villon, so curiously reminiscent of Saussure’s last obsession); his practice of publishing his poetry in books with small print runs, collaborating with visual artists from Arp to Picasso; the curious contrast between his passionate advocacy of art and an apparently limited interest in popularizing his own — all these add up to a strikingly coherent artistic personality. The clearest rupture in his career seems to come in 1923, when Breton and Éluard violently disrupted the Soirée du Cœur à barbe in Paris. Never again did Tzara attempt to stage such an event. Dada as a performing enterprise was over for him, but the spirit of Dada lived on in his publications. There are some errors of fact in Hentea’s book: for example, Tzara is buried in Montparnasse not Père-Lachaise, and Hentea is fooled, like many before him, into thinking the ninth Dada soirée actually took place, when in fact it was a hoax perpetrated on journalists by Dadaists. Nonetheless, the copious documentation of this biography, with its photographs and endnotes, forms a fascinating and instructive contrast with the tone of the poetry cited, so thoroughly divorced from what we like to think of as reality, so confident that, in fact, poetry itself is reality, as Hentea indeed remarks (p. 272). This book provides a foil to that poetic reality, which genuinely does help in reading it; and anything that helps anyone to read Tzara’s poetry is to be welcomed.

TaTa Dada: The Real Life and Celestial Adventures of Tristan Tzara by Marius Hentea (review)

It is normally, if tacitly, assumed that nature came before poetry, and music somewhere in between the two. Mallarmé’s ‘Bucolique’, in the folds of its syntax, demonstrates why this belief is unsustainable. None of those concepts really functions unless, at a more or less hidden level, each can behave as if it were both anterior to and born of the others. Mallarmé does not assert this as a rational truth; rather, he shows this behaviour at work. Poetry, in this view, is both the consequence and the precondition of nature — and vice versa. Hence, perhaps, ecopoetry is the only poetry.

Which Came First? Nature, Music, and Poetry in Mallarmé’s ‘Bucolique’

Working memory plays a key role in cognition, and yet its mechanisms remain much debated. Human performance on memory tasks is severely limited; however, the two major classes of theory explaining the limits leave open questions about key issues such as how multiple simultaneously-represented items can be distinguished. We propose a palimpsest model, with the occurrent activity of a single population of neurons coding for several multi-featured items. Using a probabilistic approach to storage and recall, we show how this model can account for many qualitative aspects of existing experimental data. In our account, the underlying nature of a memory item depends entirely on the characteristics of the population representation, and we provide analytical and numerical insights into critical issues such as multiplicity and binding. We consider representations in which information about individual feature values is partially separate from the information about binding that creates single items out of multiple features. An appropriate balance between these two types of information is required to capture fully the different types of error seen in human experimental data. Our model provides the first principled account of misbinding errors. We also suggest a specific set of stimuli designed to elucidate the representations that subjects actually employ.

Reciprocating interactions represent a central feature of all human exchanges. They have been the target of various recent experiments, with healthy participants and psychiatric populations engaging as dyads in multi-round exchanges such as a repeated trust task. Behaviour in such exchanges involves complexities related to each agent’s preference for equity with their partner, beliefs about the partner’s appetite for equity, beliefs about the partner’s model of their partner, and so on. Agents may also plan different numbers of steps into the future. Providing a computationally precise account of the behaviour is an essential step towards understanding what underlies choices. A natural framework for this is that of an interactive partially observable Markov decision process (IPOMDP). However, the various complexities make IPOMDPs inordinately computationally challenging. Here, we show how to approximate the solution for the multi-round trust task using a variant of the Monte-Carlo tree search algorithm. We demonstrate that the algorithm is efficient and effective, and therefore can be used to invert observations of behavioural choices. We use generated behaviour to elucidate the richness and sophistication of interactive inference.

Monte Carlo Planning Method Estimates Planning Horizons during Interactive Social Exchange

David Marr's theory of the archicortex, a brain structure now more commonly known as the hippocampus and hippocampal formation, is an epochal contribution to theoretical neuroscience. Addressing the problem of how information about 10 000 events could be stored in the archicortex during the day so that they can be retrieved using partial information and then transferred to the neocortex overnight, the paper presages a whole wealth of later empirical and theoretical work, proving impressively prescient. Despite this impending success, Marr later apparently grew dissatisfied with this style of modelling, but he went on to make seminal suggestions that continue to resonate loudly throughout the field of theoretical neuroscience. We describe Marr's theory of the archicortex and his theory of theories, setting them into their original and a contemporary context, and assessing their impact. This commentary was written to celebrate the 350th anniversary of the journal Philosophical Transactions of the Royal Society.

Memory, modelling and Marr: a commentary on Marr (1971) ‘Simple memory: a theory of archicortex’

Cognitive biases: dissecting the influence of affect on decision-making under ambiguity in humans and animals

Humans frequently need to allocate resources across multiple time-steps. Economic theory proposes that subjects do so according to a stable set of intertemporal preferences, but the computational demands of such decisions encourage the use of formally less competent heuristics. Few empirical studies have examined dynamic resource allocation decisions systematically. Here we conducted an experiment involving the dynamic consumption over approximately 15 minutes of a limited budget of relief from moderately painful stimuli. We had previously elicited the participants’ time preferences for the same painful stimuli in one-off choices, allowing us to assess self-consistency. Participants exhibited three characteristic behaviors: saving relief until the end, spreading relief across time, and early spending, of which the last was markedly less prominent. The likelihood that behavior was heuristic rather than normative is suggested by the weak correspondence between one-off and dynamic choices. We show that the consumption choices are consistent with a combination of simple heuristics involving early-spending, spreading or saving of relief until the end, with subjects predominantly exhibiting the last two.

Anticipation and Choice Heuristics in the Dynamic Consumption of Pain Relief

Significance Concern for the welfare of others is a key component of moral decision making and is disturbed in antisocial and criminal behavior. However, little is known about how people evaluate the costs of others’ suffering. Past studies have examined people’s judgments in hypothetical scenarios, but there is evidence that hypothetical judgments cannot accurately predict actual behavior. Here we addressed this issue by measuring how much money people will sacrifice to reduce the number of painful electric shocks delivered to either themselves or an anonymous stranger. Surprisingly, most people sacrifice more money to reduce a stranger’s pain than their own pain. This finding may help us better understand how people resolve moral dilemmas that commonly arise in medical, legal, and political decision making. Concern for the suffering of others is central to moral decision making. How humans evaluate others’ suffering, relative to their own suffering, is unknown. We investigated this question by inviting subjects to trade off profits for themselves against pain experienced either by themselves or an anonymous other person. Subjects made choices between different amounts of money and different numbers of painful electric shocks. We independently varied the recipient of the shocks (self vs. other) and whether the choice involved paying to decrease pain or profiting by increasing pain. We built computational models to quantify the relative values subjects ascribed to pain for themselves and others in this setting. In two studies we show that most people valued others’ pain more than their own pain. This was evident in a willingness to pay more to reduce others’ pain than their own and a requirement for more compensation to increase others’ pain relative to their own. This ‟hyperaltruistic” valuation of others’ pain was linked to slower responding when making decisions that affected others, consistent with an engagement of deliberative processes in moral decision making. Subclinical psychopathic traits correlated negatively with aversion to pain for both self and others, in line with reports of aversive processing deficits in psychopathy. Our results provide evidence for a circumstance in which people care more for others than themselves. Determining the precise boundaries of this surprisingly prosocial disposition has implications for understanding human moral decision making and its disturbance in antisocial behavior.

Bayes-adaptive planning offers a principled solution to the exploration-exploitation trade-off under model uncertainty. It finds the optimal policy in belief space, which explicitly accounts for the expected effect on future rewards of reductions in uncertainty. However, the Bayes-adaptive solution is typically intractable in domains with large or continuous state spaces. We present a tractable method for approximating the Bayes-adaptive solution by combining simulation-based search with a novel value function approximation technique that generalises appropriately over belief space. Our method outperforms prior approaches in both discrete bandit tasks and simple continuous navigation and control tasks.

Bayes-Adaptive Simulation-based Search with Value Function Approximation

Nonpolitical Images Evoke Neural Predictors of Political Ideology

Although seemingly irrational choice abounds, the rules governing these mis-steps that might provide hints about the factors limiting normative behavior are unclear. We consider three experimental tasks, which probe different aspects of non-normative choice under uncertainty. We argue for systematic statistical, algorithmic, and implementational sources of irrationality, including incomplete evaluation of long-run future utilities, Pavlovian actions, and habits, together with computational and statistical noise and uncertainty. We suggest structural and functional adaptations that minimize their maladaptive effects.

Model-based and model-free Pavlovian reward learning: Revaluation, revision, and revelation

Dividing limited time between work and leisure when both have their attractions is a common everyday decision. We provide a normative control-theoretic treatment of this decision that bridges economic and psychological accounts. We show how our framework applies to free-operant behavioural experiments in which subjects are required to work (depressing a lever) for sufficient total time (called the price) to receive a reward. When the microscopic benefit-of-leisure increases nonlinearly with duration, the model generates behaviour that qualitatively matches various microfeatures of subjects’ choices, including the distribution of leisure bout durations as a function of the pay-off. We relate our model to traditional accounts by deriving macroscopic, molar, quantities from microscopic choices.

Optimal indolence: a normative microscopic approach to work and leisure

Corrigendum: Dopamine restores reward prediction errors in old age

Disorders of compulsivity: a common bias towards learning habits

Correction: Disentangling the Roles of Approach, Activation and Valence in Instrumental and Pavlovian Responding

Significance Organisms must learn adaptively about environmental cue–outcome associations to survive. Studies in nonhuman primates suggest that a small phylogenetically conserved brain structure, the habenula, encodes the values of cues previously paired with aversive outcomes. However, such a role for the habenula has never been demonstrated in humans. We establish that the habenula encodes associations with aversive outcomes in humans, specifically that it tracks the dynamically changing negative values of cues paired with painful electric shocks, consistent with a role in learning. Importantly, habenula responses predicted the extent to which individuals withdrew from or approached negative and positive cues, respectively. These results suggest that the habenula plays a central role in driving aversively motivated learning and behavior in humans. Learning what to approach, and what to avoid, involves assigning value to environmental cues that predict positive and negative events. Studies in animals indicate that the lateral habenula encodes the previously learned negative motivational value of stimuli. However, involvement of the habenula in dynamic trial-by-trial aversive learning has not been assessed, and the functional role of this structure in humans remains poorly characterized, in part, due to its small size. Using high-resolution functional neuroimaging and computational modeling of reinforcement learning, we demonstrate positive habenula responses to the dynamically changing values of cues signaling painful electric shocks, which predict behavioral suppression of responses to those cues across individuals. By contrast, negative habenula responses to monetary reward cue values predict behavioral invigoration. Our findings show that the habenula plays a key role in an online aversive learning system and in generating associated motivated behavior in humans.

The habenula encodes negative motivational value associated with primary punishment in humans

An increasing wealth of experimental detail is becoming available about the development and nature of addiction. Critical issues such as the varying vulnerabilities of individuals who develop addiction are being illuminated across levels of phenomenological, psychological and neurobiological detail. Furthermore, a rich theoretical understanding is emerging in the field of neural reinforcement learning, with glimmers as to how this might be related to the subjective experience of those individuals affected. In this chapter, we consider some particuarly pressing current issues in the interface between experiment and theory, notably the so-called “compulsive” phase of drug taking.

Neurobiology and computational structure of decision-making in addiction

Significance A common question in the social science of well-being asks, “How happy do you feel on a scale of 0 to 10?” Responses are often related to life circumstances, including wealth. By asking people about their feelings as they go about their lives, ongoing happiness and life events have been linked, but the neural mechanisms underlying this relationship are unknown. To investigate it, we presented subjects with a decision-making task involving monetary gains and losses and repeatedly asked them to report their momentary happiness. We built a computational model in which happiness reports were construed as an emotional reactivity to recent rewards and expectations. Using functional MRI, we demonstrated that neural signals during task events account for changes in happiness. The subjective well-being or happiness of individuals is an important metric for societies. Although happiness is influenced by life circumstances and population demographics such as wealth, we know little about how the cumulative influence of daily life events are aggregated into subjective feelings. Using computational modeling, we show that emotional reactivity in the form of momentary happiness in response to outcomes of a probabilistic reward task is explained not by current task earnings, but by the combined influence of recent reward expectations and prediction errors arising from those expectations. The robustness of this account was evident in a large-scale replication involving 18,420 participants. Using functional MRI, we show that the very same influences account for task-dependent striatal activity in a manner akin to the influences underpinning changes in happiness.

A computational and neural model of momentary subjective well-being

A venerable history of classical work on autoassociative memory has significantly shaped our understanding of several features of the hippocampus, and most prominently of its CA3 area, in relation to memory storage and retrieval. However, existing theories of hippocampal memory processing ignore a key biological constraint affecting memory storage in neural circuits: the bounded dynamical range of synapses. Recent treatments based on the notion of metaplasticity provide a powerful model for individual bounded synapses; however, their implications for the ability of the hippocampus to retrieve memories well and the dynamics of neurons associated with that retrieval are both unknown. Here, we develop a theoretical framework for memory storage and recall with bounded synapses. We formulate the recall of a previously stored pattern from a noisy recall cue and limited-capacity (and therefore lossy) synapses as a probabilistic inference problem, and derive neural dynamics that implement approximate inference algorithms to solve this problem efficiently. In particular, for binary synapses with metaplastic states, we demonstrate for the first time that memories can be efficiently read out with biologically plausible network dynamics that are completely constrained by the synaptic plasticity rule, and the statistics of the stored patterns and of the recall cue. Our theory organises into a coherent framework a wide range of existing data about the regulation of excitability, feedback inhibition, and network oscillations in area CA3, and makes novel and directly testable predictions that can guide future experiments.

Optimal Recall from Bounded Metaplastic Synapses: Predicting Functional Adaptations in Hippocampal Area CA3

Despite many debates in the first half of the twentieth century, it is now largely a truism that humans and other animals build models of their environments and use them for prediction and control. However, model-based (MB) reasoning presents severe computational challenges. Alternative, computationally simpler, model-free (MF) schemes have been suggested in the reinforcement learning literature, and have afforded influential accounts of behavioural and neural data. Here, we study the realization of MB calculations, and the ways that this might be woven together with MF values and evaluation methods. There are as yet mostly only hints in the literature as to the resulting tapestry, so we offer more preview than review.

The influence of receptor positioning on chemotactic information.

Objective The lateral habenula (LHb) has been shown to respond to cues that predict aversive stimuli in non-human primates (Matsumoto & Hikosaka, 2009, Nat Neurosci, 12 (1), 77–84) and has been implicated in reinforcement processing and the pathophysiology of major depression (MDD) (Roiser et al, Biol Psychiatry, 66 (5), 441–450), possibly via reciprocal connections with monoaminergic nuclei. We report the first high-resolution fMRI investigation of haemodynamic responses during appetitive and aversive conditioning in the LHb in unipolar MDD. Additionally, we report the first assessment of tonic habenula function using quantitative Arterial Spin Labelling (ASL) in MDD. Method Unmedicated MDD patients (n=26) and matched controls (n=26) performed a Pavlovian conditioning task where they were exposed to conditioned stimuli (CSs) that preceded reinforcing outcomes (win £1; lose £1; and painful electric shock) in a probabilistic manner. Neural responses were monitored using high-resolution T2* echo-planar imaging (1.5 mm isotropic), and T1-weighted (0.77mm isotropic) images were obtained to accurately identify the habenula (Lawson, et al., 2013, NeuroImage, 64 (0), 722/727). Breathing and heart-rate data were collected to correct for pulse-related artefacts. Using a temporal difference learning algorithm, trial-by-trial values for win, loss and shock predicting CSs were derived for each subject and used as parametric modulators in the fMRI analysis. Additionally, to investigate tonic habenula function, high-resolution ASL images were acquired to quantitatively assess baseline blood flow in the habenula. Results We replicated our previous result that habenula responses were positive to shock-predicting CSs in healthy volunteers (Lawson et al, submitted). We found no significant group differences in habenula responses to win and loss CSs (Ps>0.7), but surprisingly habenula responses to the value of shock CSs were negative in MDD subjects (P<0.05) and significantly different to controls (p<0005). However, there were no significant group differences in baseline blood flow (P>0.6) or habenula volume (P>0.5), ruling out tonic habenula function or grey matter volume differences as an explanation for our functional results. Conclusion These surprising results, which cannot be accounted for by group differences in tonic habenula activity or habenula volume, reflect a difference in how depressed patients process aversive stimuli and have important implications for understanding the constructs of anhedonia and learned helplessness.

HABENULA RESPONSES DURING APPETITIVE AND AVERSIVE CONDITIONING IN MAJOR DEPRESSIVE DISORDER

The computational costs of inference and planning have confined Bayesian model-based reinforcement learning to one of two dismal fates: powerful Bayes-adaptive planning but only for simplistic models, or powerful, Bayesian non-parametric models but using simple, myopic planning strategies such as Thompson sampling. We ask whether it is feasible and truly beneficial to combine rich probabilistic models with a closer approximation to fully Bayesian planning. First, we use a collection of counterexamples to show formal problems with the over-optimism inherent in Thompson sampling. Then we leverage state-of-the-art techniques in efficient Bayes-adaptive planning and non-parametric Bayesian methods to perform qualitatively better than both existing conventional algorithms and Thompson sampling on two contextual bandit-like problems.

Given the option, humans and other animals elect to distribute their time between work and leisure, rather than choosing all of one and none of the other. Traditional accounts of partial allocation have characterised behavior on a macroscopic timescale, reporting and studying the mean times spent in work or leisure. However, averaging over the more microscopic processes that govern choices is known to pose tricky theoretical problems, and also eschews any possibility of direct contact with the neural computations involved. We develop a microscopic framework, formalized as a semi-Markov decision process with possibly stochastic choices, in which subjects approximately maximise their expected returns by making momentary commitments to one or other activity. We show macroscopic utilities that arise from microscopic ones, and demonstrate how facets such as imperfect substitutability can arise in a more straightforward microscopic manner.

Some Work and Some Play: Microscopic and Macroscopic Approaches to Labor and Leisure

sonance, also provide insightful links between literature and language. Other contributions are less directly related to this theme: these include André Guyaux’s otherwise interesting essay on Baudelaire’s early reception history, and Marisa Verna’s analysis of the Port de Carquethuit scene in Proust in light of the novelist’s published reactions to Baudelaire and Mallarmé. Some of the essays offer much less of an original or insightful analysis, at times falling into summaries of familiar symbolist texts or leaning heavily on, without necessarily building upon, older, established work by other critics. Regrettably, this is most noticeably the case in the essays devoted to Mallarmé’s engagement with linguistics in texts such as Notes sur le langage and Les Mots anglais, which might have held great promise for the announced subject of the volume. The summaries, rather than analysis, of the symbolist poets’ well-known ideas in several of the articles suggest an ambiguity about the intended audience for these essays. Too specialized for the general reader, they are often too introductory to be of value to specialists, with the possible exception of those essays dedicated to minor figures such as Jean Lahor, Max Elskamp, Charles Guérin, and Camille Mauclair.

Aesthetic Rivalries: Word and Image in France, 1880–1926 by Linda Goddard (review)

Hierarchical deconstruction and memoization of goal-directed plans

Exploration from Generalization Mediated by Multiple Controllers

Differential, but not opponent, effects of l-DOPA and citalopram on action learning with reward and punishment

Only rich statistical models are adequate for agents that must learn to navigate complex environments. However, it has not been clear how methods for planning can take advantage of these models. Myopic methods such as Thompson Sampling have shortcomings that we illustrate with formal counter-examples. We show that Bayes-Adaptive planning can be combined in a principled way with approximate sampling, and demonstrate the power of the resulting method in a challenging task involving safe exploration. This highlights the importance of propagating beliefs in realistic cases involving trade-offs between exploration and exploitation.

It has long been recognised that statistical dependencies in neuronal activity need to be taken into account when decoding stimuli encoded in a neural population. Less studied, though equally pernicious, is the need to take account of dependencies between synaptic weights when decoding patterns previously encoded in an auto-associative memory. We show that activity-dependent learning generically produces such correlations, and failing to take them into account in the dynamics of memory retrieval leads to catastrophically poor recall. We derive optimal network dynamics for recall in the face of synaptic correlations caused by a range of synaptic plasticity rules. These dynamics involve well-studied circuit motifs, such as forms of feedback inhibition and experimentally observed dendritic nonlinearities. We therefore show how addressing the problem of synaptic correlations leads to a novel functional account of key biophysical features of the neural substrate.

Correlations strike back (again): the case of associative memory retrieval

Receptive fields acquired through unsupervised learning of sparse representations of natural scenes have similar properties to primary visual cortex (V1) simple cell receptive fields. However, what drives in vivo development of receptive fields remains controversial. The strongest evidence for the importance of sensory experience in visual development comes from receptive field changes in animals reared with abnormal visual input. However, most sparse coding accounts have considered only normal visual input and the development of monocular receptive fields. Here, we applied three sparse coding models to binocular receptive field development across six abnormal rearing conditions. In every condition, the changes in receptive field properties previously observed experimentally were matched to a similar and highly faithful degree by all the models, suggesting that early sensory development can indeed be understood in terms of an impetus towards sparsity. As previously predicted in the literature, we found that asymmetries in inter-ocular correlation across orientations lead to orientation-specific binocular receptive fields. Finally we used our models to design a novel stimulus that, if present during rearing, is predicted by the sparsity principle to lead robustly to radically abnormal receptive fields.

Sparse Coding Can Predict Primary Visual Cortex Receptive Field Changes Induced by Abnormal Visual Input

Dividing limited time between work and leisure when both have their attractions is a common everyday decision. We provide a normative control-theoretic treatment of this decision that bridges economic and psychological accounts. We show how our framework applies to free-operant behavioural experiments in which subjects are required to work (depressing a lever) for sufficient total time (called the price) to receive a reward. When the microscopic benefit-of-leisure increases non-linearly with duration, the model generates behaviour that qualitatively matches various microfeatures of subjects’ choices, including the distribution of leisure bout durations as a function of the payoff. We relate our model to traditional accounts by deriving macroscopic, molar, quantities from microscopic choices.

The company they keep: Background similarity influences transfer of aftereffects from second- to first-order stimuli

Habenula Responses in Major Depression: A High-Resolution FMRI Study

Dopaminergic modulation of value-based decision making and subjective wellbeing

Structured Cognitive Representations and Complex Inference in Neural Systems Samuel J. Gershman, Joshua B. Tenenbaum ({sjgershm,jbt}@mit.edu) Department of Brain and Cognitive Sciences, MIT Cambridge, MA 02139 USA Alexandre Pouget (Alexandre.Pouget@unige.ch) Department of Neuroscience, University of Geneva CH-1211 Geneva 4 Switzerland Matthew Botvinick (matthewb@princeton.edu) Department of Psychology, Princeton University Princeton, NJ 08540 USA Peter Dayan (dayan@gatsby.ucl.ac.uk) Gatsby Computational Neuroscience Unit, University College London London WC1N 3AR United Kingdom This symposium addresses the question: how do neural cir- cuits acquire and compute with structured representations? This question is examined from a number of angles. Ger- shman introduces the basic issues and discusses attempts to articulate a neurally plausible theory of structured cogni- tion. Pouget describes recent work on implementing com- plex probabilistic computations in neural circuits. Botvinick shows how neural circuits can be used to discover hierarchical task structure in the environment. Finally, Dayan discusses work on wedding richly structured models of semantics with representations of individual episodes. Each talk will be 20 minutes long, followed by a 20 minute panel discussion with speakers moderated by Tenenbaum. Keywords: Bayesian models, rational analysis, perception, ol- faction, memory Summary The dream of cognitive neuroscience has always been a seam- less integration of cognitive representations with neural ma- chinery, but—despite decades of work—fundamental gaps remain. Part of the problem is that many contemporary the- ories of cognition are formulated in terms of representations and computations that are quite different from those used in computational neuroscience. Bridging this gap requires more than simply a translation between theoretical concepts in the two fields; what is needed is a more radical updating of neu- roscience’s theoretical vocabulary. What should this vocabulary look like? Some important features of representations and computations used in contem- porary cognitive theories are: Gershman: from knowledge to neurons How can neurons express the structured knowledge represen- tations central to intelligence? This problem has been at- tacked many times from various angles. I discuss the history of these attempts and situate our current understanding of the problem. I then outline a new approach based on the idea of compressing structured knowledge using neurons in a way that supports probabilistic inference. I illustrate this approach using examples from motion perception and value-based de- cision making. • Compositional, recursive and relational representations (Fodor, 1975; Smolensky, 1990; Hummel & Holyoak, 2003; Stewart et al., 2011). • Flexible use of different structural forms (e.g., taxonomic vs. causal knowledge; Kemp & Tenenbaum, 2009). • Multiple levels of abstraction (Tenenbaum et al., 2011). Pouget: modeling the neural basis of complex intractable inference • Knowledge partitioning / clustering (Lewandowsky & Kirsner, 2000). It is becoming increasingly clear that neural computation can be formalized as a form of probabilistic inference. Several hypotheses have emerged regarding the neural basis of these inferences, including one based on a type of code known as probabilistic population codes or PPCs (Ma et al., 2006). PPCs have been used to model simple forms for multisensory integration, attentional search, perceptual decision making or causal inference, for which human subjects have been shown to be nearly optimal. However, most inferences performed by the brain are too complex be solved optimally in a reasonable • Complex intuitive theories (e.g., naive physics, theory of mind; Carey, 2009). • Algorithms that operate on these representations (e.g., dy- namic programming, Monte Carlo methods; Griffiths et al., These representations and computations are “structured” in the sense that they incorporate rich domain knowledge and strong constraints (Tenenbaum et al., 2011).

Structured cognitive representations and complex inference in neural systems

Neural representations of the effort deployed in performing actions, and the valence of the outcomes they yield, form the foundation of action choice. To discover whether brain areas represent effort and outcome valence together or if they represent one but not the other, we examined these variables in an explicitly orthogonal way. We did this by asking human subjects to exert one of two levels of effort to improve their chances of either winning or avoiding the loss of money. Subjects responded faster both when exerting greater effort and when exerting effort in anticipation of winning money. Using fMRI, we inspected BOLD responses during anticipation (before any action was executed) and when the outcome was delivered. In this way, we indexed BOLD signals associated with an anticipated need to exert effort and its affective consequences, as well as the effect of executed effort on the representation of outcomes. Anterior cingulate cortex and dorsal striatum (dorsal putamen) signaled the anticipation of effort independently of the prospect of winning or losing. Activity in ventral striatum (ventral putamen) was greater for better-than-expected outcomes compared with worse-than-expected outcomes, an effect attenuated in the context of having exerted greater effort. Our findings provide evidence that neural representations of anticipated actions are sensitive to the expected demands, but not to the expected value of their consequence, whereas representations of outcome value are discounted by exertion, commensurate with an integration of cost and benefit so as to approximate net value.

Effort and Valuation in the Brain: The Effects of Anticipation and Execution

Some work and some play: a normative, microscopic approach to allocating time between work and leisure

Introduction We propose a normative model of the behaviour of human subjects playing a dynamic foraging game containing a time-stochastic threat. The game is intended to capture the essence of the conflict between approach and avoidance. The realistic nature of the task makes planning challenging; we therefore rely on recent innovations in model-based methods to approximate the optimal policy, and on Approximate Bayesian Computation to fit our models.

A normative theory of approach-avoidance conflicts during dynamic foraging in humans

Mapping anhedonia onto reinforcement learning: a behavioural meta-analysis

T he latter half of the long nineteenth century was the golden age of the idea of absolute music; which is, to put it at its simplest, the notion that music can have a kind of meaning that is inaccessible to words, that cannot be translated into any other medium, or indeed translated at all. Innumerable composers and poets of the period (and of the subsequent two or three decades), including a disproportionate number of those who remain the most famous, expressed, in words of course, solidarity with this idea. However, all of them, as far as I know, also acknowledged that music nonetheless normally does appear to have the kind of meaning accessible to words. This is most obvious when words are set to music, or when music imitates extra-musical sounds or rhythms – the sound of the cuckoo, or the rhythm of rowing, for example; but in the nineteenth century generally, it was recognized as a wider phenomenon. It seemed to be a natural human instinct to associate music, almost as soon as it was written or heard, with words or images. For an intellectually intransigent and obstinately lucid composer such as Erik Satie, this posed a challenge. How could one, in one's music, both make it clear that music has a kind of meaning inaccessible to words, and take into account the fact that music was generally received as if its meaning could be expressed in words?

Losing Sense, Making Music: What Erik Satie's Music and Poetry do for Each Other

Bayesian planning is a formally elegant approach to learning optimal behaviour under model uncertainty, trading off exploration and exploitation in an ideal way. Unfortunately, planning optimally in the face of uncertainty is notoriously taxing, since the search space is enormous. In this paper we introduce a tractable, sample-based method for approximate Bayes-optimal planning which exploits Monte-Carlo tree search. Our approach avoids expensive applications of Bayes rule within the search tree by sampling models from current beliefs, and furthermore performs this sampling in a lazy manner. This enables it to outperform previous Bayesian model-based reinforcement learning algorithms by a significant margin on several well-known benchmark problems. As we show, our approach can even work in problems with an in finite state space that lie qualitatively out of reach of almost all previous work in Bayesian exploration.

Scalable and Efficient Bayes-Adaptive Reinforcement Learning Based on Monte-Carlo Tree Search

When planning a series of actions, it is usually infeasible to consider all potential future sequences; instead, one must prune the decision tree. Provably optimal pruning is, however, still computationally ruinous and the specific approximations humans employ remain unknown. We designed a new sequential reinforcement-based task and showed that human subjects adopted a simple pruning strategy: during mental evaluation of a sequence of choices, they curtailed any further evaluation of a sequence as soon as they encountered a large loss. This pruning strategy was Pavlovian: it was reflexively evoked by large losses and persisted even when overwhelmingly counterproductive. It was also evident above and beyond loss aversion. We found that the tendency towards Pavlovian pruning was selectively predicted by the degree to which subjects exhibited sub-clinical mood disturbance, in accordance with theories that ascribe Pavlovian behavioural inhibition, via serotonin, a role in mood disorders. We conclude that Pavlovian behavioural inhibition shapes highly flexible, goal-directed choices in a manner that may be important for theories of decision-making in mood disorders.

Bonsai Trees in Your Head: How the Pavlovian System Sculpts Goal-Directed Choices by Pruning Decision Trees

Spatial context in images induces perceptual phenomena associated with salience and modulates the responses of neurons in primary visual cortex (V1). However, the computational and ecological principles underlying contextual effects are incompletely understood. We introduce a model of natural images that includes grouping and segmentation of neighboring features based on their joint statistics, and we interpret the firing rates of V1 neurons as performing optimal recognition in this model. We show that this leads to a substantial generalization of divisive normalization, a computation that is ubiquitous in many neural areas and systems. A main novelty in our model is that the influence of the context on a target stimulus is determined by their degree of statistical dependence. We optimized the parameters of the model on natural image patches, and then simulated neural and perceptual responses on stimuli used in classical experiments. The model reproduces some rich and complex response patterns observed in V1, such as the contrast dependence, orientation tuning and spatial asymmetry of surround suppression, while also allowing for surround facilitation under conditions of weak stimulation. It also mimics the perceptual salience produced by simple displays, and leads to readily testable predictions. Our results provide a principled account of orientation-based contextual modulation in early vision and its sensitivity to the homogeneity and spatial arrangement of inputs, and lends statistical support to the theory that V1 computes visual salience.

Cortical Surround Interactions and Perceptual Salience via Natural Scene Statistics

Intermediality and the Refusal of Interdisciplinarity in Stravinsky's Music

© Oxford University Press, 2008. All rights reserved. This chapter considers the question of how learning adapts to changing environments, with particular reference to animal studies of operant and classical conditioning. It discusses a variety of probabilistic models, with different assumptions concerning the environment; and contrasts this type of model with a model by Kruschke (2006) which carries out local, approximate, Bayesian inference. It further suggests that it may be too early to incorporate mechanistic limitations into models of conditioning - enriching the understanding of the environment, and working with a 'pure' Bayesian rational analysis for that environment, may provide an alternative, and perhaps theoretically more elegant, way forward.

Establishing a function for the neuromodulator serotonin in human decision-making has proved remarkably difficult because if its complex role in reward and punishment processing. In a novel choice task where actions led concurrently and independently to the stochastic delivery of both money and pain, we studied the impact of decreased brain serotonin induced by acute dietary tryptophan depletion. Depletion selectively impaired both behavioral and neural representations of reward outcome value, and hence the effective exchange rate by which rewards and punishments were compared. This effect was computationally and anatomically distinct from a separate effect on increasing outcome-independent choice perseveration. Our results provide evidence for a surprising role for serotonin in reward processing, while illustrating its complex and multifarious effects.

Serotonin Selectively Modulates Reward Value in Human Decision-Making

Multi-level visual adaptation: Dissociating curvature and facial-expression aftereffects produced by the same adapting stimuli

Peut-on concevoir Uspud, ballet chretien, d’Erik Satie, comme une mystification ? Non, dans la mesure ou Satie ne voulut ni ne reussit a mystifier personne lorsqu’il chercha a faire representer Uspud a l’Opera de Paris. Il etait clair pour tous qu’Uspud etait comique, grotesque, inadapte, ridicule, caricatural – bref, une mystification ; et une mystification qui s’affiche comme telle n’en est sans doute pas une. Mais Satie reussit parfaitement a mystifier les hommes qui dirigeaient les institutions musicales de l’epoque, dans la mesure ou ceux-ci ne virent pas qu’un chef-d’œuvre revolutionnaire leur passait sous le nez. Leur incomprehension devait etre, pour Satie, un gage de la valeur de son ballet ; car toute œuvre vraiment neuve doit paraitre mystificatrice aux yeux des hommes en place.

Dopamine is widely observed to signal anticipation of future rewards and thus thought to be a key contributor to affectively charged decision making. However, the experiments supporting this view have not dissociated rewards from the actions that lead to, or are occasioned by, them. Here, we manipulated dopamine pharmacologically and examined the effect on a task that explicitly dissociates action and reward value. We show that dopamine enhanced the neural representation of rewarding actions, without significantly affecting the representation of reward value as such. Thus, increasing dopamine levels with levodopa selectively boosted striatal and substantia nigra/ventral tegmental representations associated with actions leading to reward, but not with actions leading to the avoidance of punishment. These findings highlight a key role for dopamine in the generation of appetitively motivated actions.

Action controls dopaminergic enhancement of reward representations

Computational, Cognitive, and Neural Models of Decision-making Biases Jonathan Malmaud (malmaud@mit.edu), Joshua B. Tenenbaum (jbt@mit.edu) Brain and Cognitive Sciences, 43 Vassar St. Cambridge, MA 02139 USA Peter Dayan (dayan@gatsby.ucl.ac.uk) Laurence T. Maloney (laurence.maloney@nyu.edu) Gatsby Computational Neuroscience Unit 17 Queen Square London, WCIN 3AR England Dept. of Psychology, 6 Washington Place New York, NY 10030 USA Edward Vul (evul@ucsd.edu) Nick Chater (n.chater@ucl.ac.uk) Dept. of Psychology, 9500 Gilman Dr. 0109 La Jolla, CA 92093 USA Division of Psychology and Language Sciences 26 Bedform Way London, WC1H 0AP England forms and parameters seem to be greatly affected by seem- ingly irrelevant factors of the task framing and setup, such as whether the outcome probabilities are presented numerically in tables or learned through experience and why the evalua- tion of individual gambles seems to be highly effected by the properties of other gambles in the choice set. More broadly, these theories fail to explain why in day-to-day life human decision-making seems to generally be highly robust and ef- fective while sharply contrasting with normative predictions in the simple, stylized decision tasks commonly used in JDM experiments. This symposium brings together researchers who repre- sent a variety of perspectives on ways cognitive science can inform our understanding of decision biases to address these challenges, with relevance at all three Marr levels of analysis. Malmaud and Tenenbaum, and Dayan both offer computational-level Bayesian accounts that explain decision- making biases as resulting from reasoning with priors that are adapted for real-world or evolutionary-relevant decision tasks. Malmaud and Tenenbaum explain choices in terms of advanced models from the AI planning literature and animal foraging theory. Dayan offers a neurobiological implementa- tion of inference that spans the Marr levels. Other approaches relate to algorithms levels of the Marr hierarchy with links to lower and higher levels. Vul offers an algorithmic description of biases as resulting from cogni- tive limitations associated with reasoning using only a limited number of samples from a posterior over decision parame- ters. Maloney and Chater link high-level decision-making to known properties of perception and cognition, such as scale- invariance. Maloney gives a unifying account of the prob- ability weighting function as arising from the same princi- ples as perception of continuous quantities in psychophysics. Chater explores the origin of subjective utility and tempo- ral discounting through connections to broader cognitive pro- cesses. One general idea that cuts across all these approaches is that human decision-making can be modeled in a unified way as the result of general cognitive principles that offer prin- Keywords: Computational modeling; Rational analysis; Judg- ment and decision-making; Biases and heuristics Summary The question for the symposium is how best to understand bi- ases in decision-making, going beyond traditional judgment and decision-making (JDM) accounts such as prospect theory to take a more modern reverse-engineering perspective bridg- ing rational computational, algorithmic, and neural levels of explanation, and viewing decision-making under risk and un- certainty not just as a simple matter of evaluating lotteries but in the context of cognition more broadly, taking seriously learning, perception, motor control, memory, and action plan- ning. The dominant normative approach to studying decision- making under risk is axiomatic expected utility theory, which argues that any agent obeying seemingly reasonable axioms of choice consistency can be modeled as maximizing the ex- pected utility of its decisions. From decades of research that analyzes people’s choices between simple gambles in the lab, it is known that humans routinely violate these axioms. This has forced decision theorists to adopt descriptive models of choice that lack a normative rational in order to account for observed patterns of choice, the most prominent of which is Khaneman’s and Tversky’s prospect theory for one-shot de- cisions under risk with immediate outcomes and hyperbolic discounting for decisions involving delayed outcomes. There are several challenges not addressed by prospect the- ory and its variants. First, they are silent on the issue of the cognitive mechanisms that are actually responsible for hu- man choice behavior. Second, they do not seem as a prac- tical matter to scale to real-world decision problems, where the space of possible outcomes and actions is not sharply de- fined, the effects of actions are highly uncertain, and the ex- plicit calculation of expected values is impractical. Third, they do not strongly constrain or give an underlying rationale for the probability weighting function, temporal discounting function, or utility function featured in prospect theory. Thus these models cannot explain why these functions’ estimated

Computational, Cognitive, and Neural Models of Decision-making Biases

The role dopamine plays in decision-making has important theoretical, empirical and clinical implications. Here, we examined its precise contribution by exploiting the lesion deficit model afforded by Parkinson’s disease. We studied patients in a two-stage reinforcement learning task, while they were ON and OFF dopamine replacement medication. Contrary to expectation, we found that dopaminergic drug state (ON or OFF) did not impact learning. Instead, the critical factor was drug state during the performance phase, with patients ON medication choosing correctly significantly more frequently than those OFF medication. This effect was independent of drug state during initial learning and appears to reflect a facilitation of generalization for learnt information. This inference is bolstered by our observation that neural activity in nucleus accumbens and ventromedial prefrontal cortex, measured during simultaneously acquired functional magnetic resonance imaging, represented learnt stimulus values during performance. This effect was expressed solely during the ON state with activity in these regions correlating with better performance. Our data indicate that dopamine modulation of nucleus accumbens and ventromedial prefrontal cortex exerts a specific effect on choice behaviour distinct from pure learning. The findings are in keeping with the substantial other evidence that certain aspects of learning are unaffected by dopamine lesions or depletion, and that dopamine plays a key role in performance that may be distinct from its role in learning.

Dopamine and performance in a reinforcement learning task: evidence from Parkinson’s disease

Robustness is a prominent concept in technical sciences and engineering. It has also been recognized as an important principle in evolutionary biology. In this chapter, it is proposed that the term “robustness” be used to characterize the extent to which a natural or artifi cial system can maintain its function when facing perturbation and that this concept is relevant in considerations of Darwinian decision theory. Situations in which the action of natural selection is liable to lead to the evolution of robust behavioral strategies are highlighted along with some psychological mechanisms that might lead to robust decision-making processes. Robustness describes a property of a system varying on a continuous scale rather than existing as a dichotomous feature. Degree of robustness depends on the details of the interaction of system characteristics and environmental contingencies, as well as the specifi c types and extents of perturbations to which the system may be subjected. A system can be robust in one domain while remaining highly vulnerable to perturbations in others. As defi ned here, robustness is related to, yet distinct from, fl exibility and optimality. The sorts of environmental variation, and hence perturbations, that an organism or technology is liable to face are described, as is the cost-benefi t trade-off of robustness. Finally, the robustness of decision making at the level of social groups is considered.

The twelve essays that make up this volume cover a greater range than the title suggests. They begin with two on pre-Revolutionary France, and end with one on Belgian literary journals in the 1920s. The models of collaboration considered fall broadly into four categories. The first corresponds most closely with the volume’s subtitle: writings composed by more than one person. Interestingly, these are all presented as, to some extent, artistic failures. According to Lawrence Schehr, ‘no aesthetic works and no vision of art emerge’ from the Goncourt brothers’ Manette Salomon ‘other than a condescending view of “realism” that leads nowhere’ (p. 166). Erkmann-Chatrian’s ‘smooth collaboration’, as described by Julia Przybos, created a popular writing style with a ‘single and unequivocal message’ (p. 56) that, doubtless for that very reason, was not taken seriously as literature by the literary giants of the time. Joseph Acquisto’s wonderfully evocative and suggestive study of La Muse à Bibi recounts both the history and the aesthetic consequences of presenting a collaborative work as if it were by one person, and shows why, as the twentieth century approached, and with the ‘renegotiation’ of the ‘author function’ (p. 104), the idea of a literal division between two writers gave way to a sense of the author as split personality, an understanding more in tune with the times. The second type of collaboration examined in this volume confirms both the attraction of working together and the difficulty of creating a convincing aesthetic whose contradictions and qualities do not appear to the reader internal to one author: books, albums, and journals bringing together many works from different pens, from the Tombeau de Théophile Gautier to the Album zutique, the Soirées de Médan or the Revue wagnérienne, all presented as fascinating but unequal, containing great works by great writers and lesser works by lesser writers. The third type of collaboration is the ‘cénacle’, or social grouping of writers, vital to the acquisition of sociocultural capital by new literary movements, yet repeatedly foundering as the expressed solidarity between like-minded artists comes into conflict with an aesthetic principle that remains powerful throughout the century: that art is radically heterogeneous to social communication between individuals. Two essays also discuss collaboration between writers and illustrators. Here too the most successful work appears to arise where communication is least evident: in Maurice Denis’s illustrations for Gide’s Voyage d’Urien, where, as Frédéric Canovas shows, Denis refuses to play ‘any useful or helpful role in turning Gide’s narrative into a coherent and unequivocal story for the readers’ (p. 133). Like so many collaborative volumes, this one might leave its own readers with a sense of disappointment that the themes common to the different essays are not more steadily developed as the book progresses. However, this frustration seems strangely in tune with the book’s underlying lesson, and it resonates strikingly with current tensions in academia: for social reasons, collaboration is highly valued (institutionally as well as by the AHRC); yet the works that we admire most unequivocally tend to be read as the products of a single pen.

Models of Collaboration in Nineteenth-Century French Literature: Several Authors, One Pen (review)

Recent notions about the vigour of responding in operant conditioning suggest that the long‐run average rate of reward should control the alacrity of action in cases in which the actual cost of speed is balanced against the opportunity cost of sloth. The average reward rate is suggested as being reported by tonic activity in the dopamine system and thereby influencing all actions, including ones that do not themselves lead directly to the rewards. This idea is syntactically problematical for the case of punishment. Here, we broaden the scope of the original suggestion, providing a two‐factor analysis of obviated punishment in a variety of operant circumstances. We also consider the effects of stochastically successful actions, which turn out to differ rather markedly between appetitive and aversive cases. Finally, we study how to fit these ideas into nascent treatments that extend concepts of opponency between dopamine and serotonin from valence to invigoration.

Thursday 10 May, morning Neuro-Physiology Session A. David Redish (University of Minnesota, USA) "Differences in information processing between decision-making systems" When rats come to spatial choice points, they sometimes pause and look back-and-forth, a phenomenon identified in the 1930s as "vicarious trial and error" (VTE). I will present our work on information processing during VTE events and non-VTE events that suggests that VTE is evidence of decisionmaking through deliberative/flexible/search-based processes, while non-VTE is evidence of decisionmaking through slowly-learned situation-action or action-action sequences. If there is time, I will present our new neuroeconomic data on the presence of VTE under different valuation conditions. Brian Lau (CRICM Paris / Columbia University, USA) "The amygdala combines space and value to guide attentional selection" Seeing a salient object can trigger both emotional and cognitive responses. Scientists commonly assume that the amygdala mediates emotional responses but not cognitive ones such as the top-down direction of attention to object locations. I will present data that suggest that amygdala activity is in fact appropriate for directing attention towards motivationally relevant locations, encoding information about both the motivational value and location of visual cues. Moreover, neural responses were correlated with trial-totrial fluctuations in the allocation of spatial attention. These results highlight a novel role for the amygdala in directing attention towards motivationally significant stimuli. Amygdala dysfunction may therefore contribute to symptoms of psychiatric disorders such as schizophrenia and autism, where patients have difficulties directing attention according to the emotional relevance of stimuli. Francesca Sargolini (Université de Provence Aix-Marseille 1, France) "Learning to dissociate spatial trajectories: different contributions of the dorsomedial and the dorsolateral striatum" Several studies on instrumental conditioning suggest the existence of two independent decision-making processes, one inflexible and dependent upon DLS activity, the other based on flexible goal-oriented responses and mediated by the DMS. However, very few studies have investigated whether a similar dissociation exists in more complex behaviors, such as spatial learning. The present study examined the role of the two structures in this behavior 1) by analyzing the effects of excitotoxic DMS and DLS lesions and 2) by comparing DMS and DLS neuronal activity, during the acquisition and extinction of a spatial alternation behavior in a continuous alternation T-maze task, originally employed to characterize hippocampal place cells activity. We first demonstrated that DMS and DLS lesions have opposite effects, the first impairing and the second improving rats performance during learning and extinction. Secondly, neurons from the two brain areas displayed different task-related responses. In particular, DMS provides a signal necessary to dissociate different spatial trajectories, whereas the DLS preferentially activate for egocentric movements and reward delivery, irrespective of left/right goal position. Taken together, these results indicate that the DMS and DLS may support in different ways the acquisition and performance of a spatial goal-directed behaviour, and suggest that DMSand DLSmediated learning strategies develop in parallel and compete for the control of the behavioral response during learning. Thomas Boraud (CNRS Université Victor Segalen Bordeaux 2, France) "Why is the striatum silent?" Thursday 10 May, afternoon Neuro-Computations Session Kenji Doya (Okinawa Institute of Science and Technology, Japon; Invited Professor at Université Pierre et Marie Curie, Paris) "Multiple Strategies for Decision Making" The theory of reinforcement learning prescribes two major strategies of decision making: model-based and model-free. The dichotomy has been helpful in searching for the computational bases for goaldirected and habitual behaviors, conscious and unconscious actions, and so forth (e.g., Daw et al., 2005). Both model-based and model-free strategies, however, have several different algorithms for implementation and we are assessing which of them are used in what stage of learning, and by what neural mechanisms. In the analysis of rats' binary choice sequences under probabilistic reward, we had earlier showed that action value-based models predicted rats' choices better than higher-order Markov models (Ito & Doya, 2009). However, recent analysis of a new set of data revealed that finite state-based models predict rats' choices better than action value-based models. Analysis of striatal neural firing revealed both action valuecoding and finite state-coding neurons in the dorsomedial striatum. In a human fMRI experiment requiring multiple steps of actions to the goal, we found the evidence of model-based action planning in the intermediate stage of learning, when the activities were seen in not only the cortical areas (parietal, premotor, prefrontal), but also the anterior basal ganglia and the lateral cerebellum. Behaviors in both early and late stages of learning can be considered as model-free, but the performance as well as the brain activation during the two stages were largely different. The results suggest the need for considering at least two different sub-types of model-free decision making, namely, value-based and procedure-based. The neural implementation of model-based decision making may not just involve the prefrontal cortex, but also the basal ganglia and the cerebellum (Doya, 1999). Benoît Girard (CNRS Université Pierre et Marie Curie Paris 6, France) "Interactions of model-based & model-free learning processes in rodent navigation" Kevin Gurney (University of Sheffield, UK) "Modeling the basal ganglia at multiple levels of description: from spikes to rate codes algorithms and

Mapping value based planning and extensively trained choice in the human brain

Go and no-go learning in reward and punishment: Interactions between affect and effect

Reciprocating exchange with other humans requires individuals to infer the intentions of their partners. Despite the importance of this ability in healthy cognition and its impact in disease, the dimensions employed and computations involved in such inferences are not clear. We used a computational theory-of-mind model to classify styles of interaction in 195 pairs of subjects playing a multi-round economic exchange game. This classification produces an estimate of a subject's depth-of-thought in the game (low, medium, high), a parameter that governs the richness of the models they build of their partner. Subjects in each category showed distinct neural correlates of learning signals associated with different depths-of-thought. The model also detected differences in depth-of-thought between two groups of healthy subjects: one playing patients with psychiatric disease and the other playing healthy controls. The neural response categories identified by this computational characterization of theory-of-mind may yield objective biomarkers useful in the identification and characterization of pathologies that perturb the capacity to model and interact with other humans.

Computational Phenotyping of Two-Person Interactions Reveals Differential Neural Response to Depth-of-Thought

Psychostimulant Addiction: Evidence for a Model of Habit Formation

Bayesian model-based reinforcement learning is a formally elegant approach to learning optimal behaviour under model uncertainty, trading off exploration and exploitation in an ideal way. Unfortunately, finding the resulting Bayes-optimal policies is notoriously taxing, since the search space becomes enormous. In this paper we introduce a tractable, sample-based method for approximate Bayes-optimal planning which exploits Monte-Carlo tree search. Our approach outperformed prior Bayesian model-based RL algorithms by a significant margin on several well-known benchmark problems - because it avoids expensive applications of Bayes rule within the search tree by lazily sampling models from the current beliefs. We illustrate the advantages of our approach by showing it working in an infinite state space domain which is qualitatively out of reach of almost all previous work in Bayesian exploration.

Efficient Bayes-Adaptive Reinforcement Learning using Sample-Based Search

Erratum: Computational psychiatry [Trends in Cognitive Sciences 16 (2012), 72–80]

Word and Music Studies: Essays on Performativity and on Surveying the Field

Humans and animals are exquisitely, though idiosyncratically, sensitive to risk or variance in the outcomes of their actions. Economic, psychological, and neural aspects of this are well studied when information about risk is provided explicitly. However, we must normally learn about outcomes from experience, through trial and error. Traditional models of such reinforcement learning focus on learning about the mean reward value of cues and ignore higher order moments such as variance. We used fMRI to test whether the neural correlates of human reinforcement learning are sensitive to experienced risk. Our analysis focused on anatomically delineated regions of a priori interest in the nucleus accumbens, where blood oxygenation level-dependent (BOLD) signals have been suggested as correlating with quantities derived from reinforcement learning. We first provide unbiased evidence that the raw BOLD signal in these regions corresponds closely to a reward prediction error. We then derive from this signal the learned values of cues that predict rewards of equal mean but different variance and show that these values are indeed modulated by experienced risk. Moreover, a close neurometric–psychometric coupling exists between the fluctuations of the experience-based evaluations of risky options that we measured neurally and the fluctuations in behavioral risk aversion. This suggests that risk sensitivity is integral to human learning, illuminating economic models of choice, neuroscientific models of affective learning, and the workings of the underlying neural mechanisms.

Neural Prediction Errors Reveal a Risk-Sensitive Reinforcement-Learning Process in the Human Brain

Intermedial Arts: Disrupting, Remembering, and Transforming Media

Dynamic decision making: neuronal, computational, and cognitive underpinnings Peter Dayan (dayan@gatsby.ucl.ac.uk) Gatsby computational neuroscience unit, University College London Nigel Harvey (n.harvey@ucl.ac.uk), Maarten Speekenbrink* (m.speekenbrink@ucl.ac.uk) Cognitive, Perceptual and Brain Sciences, University College London Magda Osman* (m.osman@qmul.ac.uk) Experimental Biology and Psychology Centre, Queen Mary University Masataka Watanabe (watanabe-ms@igakuken.or.jp) Department of Physiological Psychology, Tokyo Metropolitan Institute of Medical Science Keywords: Dynamic Decision Making, Computational models of reinforcement learning, Animal learning, Applied decision making Challenging Issues As complexity in our everyday environment increases (e.g., mobile applications for monitoring energy consumption), how do we adapt and react to the changing demands placed on us? In dynamic decision making (DDM) problems, the environment changes over time due to previous decisions made and/or factors outside the control of the decision-maker. To maximize his/her reward, an agent effectively needs to control a complex dynamic system. This often involves planning in the face of uncertainty about how decisions change the state of the system and the rewards that can be obtained. Thus, DDM refers to a process by which an agent selects a course of action in a manner that achieves or maintains a desired state in a dynamic environment. This includes balancing exploration and exploitation, distinguishing between different sources of variability within the environment, and tracking the current state of the environment (i.e., filtering). Thus far there has been little attempt at a synthesis of the amassing research from different areas of cognitive science directed towards understanding DDM. The objective of this symposium is to bring together the latest theoretical approaches and empirical research investigating DDM. The speakers range in expertise from comparative (Prof Watanabe), applied (Prof Harvey) and cognitive psychology (Dr Osman), computational neuroscience (Prof Dayan), and computational learning theory (Dr Speekenbrink). By bringing these diverse approaches together, the aim is to generate discussion around the following critical question: What are the processes/mechanisms that enable us to adapt to changes in uncertain environments in terms of the information we process, the decisions we make, and the intrinsic and extrinsic goals that we pursue? The symposium will consist of a general introduction (Osman), three talks (Dayan, Harvey, Wanatabe) and an extended discussion (moderated by Speekenbrink) involving all participants. Peter Dayan Peter Dayan’s work in computational and experimental neuroscience has contributed significantly to our understanding of the neural mechanisms underlying DDM and the learning of reward structures therein. Dayan is an expert on reinforcement learning and in recent work, has elucidated the distinction between “model-based” and “model-free” learning and the neural circuits supporting these. Model-based learning, usually associated with declarative task-knowledge, can support complex planning. Model-free learning, due to its more procedural nature, supports quick and habitual decisions, but will not cope well in an environment that undergoes rapid, abrupt changes. Dayan's recent work has shown how both processes work concurrently to support effective DDM.

Dynamic decision making: neuronal, computational, and cognitive underpinnings

Hard-wired, Pavlovian, responses elicited by predictions of rewards and punishments exert significant benevolent and malevolent influences over instrumentally-appropriate actions. These influences come in two main groups, defined along anatomical, pharmacological, behavioural and functional lines. Investigations of the influences have so far concentrated on the groups as a whole; here we take the critical step of looking inside each group, using a detailed reinforcement learning model to distinguish effects to do with value, specific actions, and general activation or inhibition. We show a high degree of sophistication in Pavlovian influences, with appetitive Pavlovian stimuli specifically promoting approach and inhibiting withdrawal, and aversive Pavlovian stimuli promoting withdrawal and inhibiting approach. These influences account for differences in the instrumental performance of approach and withdrawal behaviours. Finally, although losses are as informative as gains, we find that subjects neglect losses in their instrumental learning. Our findings argue for a view of the Pavlovian system as a constraint or prior, facilitating learning by alleviating computational costs that come with increased flexibility.

Disentangling the Roles of Approach, Activation and Valence in Instrumental and Pavlovian Responding

Storing a new pattern in a palimpsest memory system comes at the cost of interfering with the memory traces of previously stored items. Knowing the age of a pattern thus becomes critical for recalling it faithfully. This implies that there should be a tight coupling between estimates of age, as a form of familiarity, and the neural dynamics of recollection, something which current theories omit. Using a normative model of autoassociative memory, we show that a dual memory system, consisting of two interacting modules for familiarity and recollection, has best performance for both recollection and recognition. This finding provides a new window onto actively contentious psychological and neural aspects of recognition memory.

Two is better than one: distinct roles for familiarity and recollection in retrieving palimpsest memories

Background Bradykinesia is a cardinal feature of Parkinson’s disease (PD). Despite its disabling impact, the precise cause of this symptom remains elusive. Recent thinking suggests that bradykinesia may be more than simply a manifestation of motor slowness, and may in part reflect a specific deficit in the operation of motivational vigour in the striatum. In this paper we test the hypothesis that movement time in PD can be modulated by the specific nature of the motivational salience of possible action-outcomes. Methodology/Principal Findings We developed a novel movement time paradigm involving winnable rewards and avoidable painful electrical stimuli. The faster the subjects performed an action the more likely they were to win money (in appetitive blocks) or to avoid a painful shock (in aversive blocks). We compared PD patients when OFF dopaminergic medication with controls. Our key finding is that PD patients OFF dopaminergic medication move faster to avoid aversive outcomes (painful electric shocks) than to reap rewarding outcomes (winning money) and, unlike controls, do not speed up in the current trial having failed to win money in the previous one. We also demonstrate that sensitivity to distracting stimuli is valence specific. Conclusions/Significance We suggest this pattern of results can be explained in terms of low dopamine levels in the Parkinsonian state leading to an insensitivity to appetitive outcomes, and thus an inability to modulate movement speed in the face of rewards. By comparison, sensitivity to aversive stimuli is relatively spared. Our findings point to a rarely described property of bradykinesia in PD, namely its selective regulation by everyday outcomes.

The Effect of Motivation on Movement: A Study of Bradykinesia in Parkinson’s Disease

Chemotaxis plays a crucial role in many biological processes, including nervous system development. However, fundamental physical constraints limit the ability of a small sensing device such as a cell or growth cone to detect an external chemical gradient. One of these is the stochastic nature of receptor binding, leading to a constantly fluctuating binding pattern across the cell's array of receptors. This is analogous to the uncertainty in sensory information often encountered by the brain at the systems level. Here we derive analytically the Bayes-optimal strategy for combining information from a spatial array of receptors in both one and two dimensions to determine gradient direction. We also show how information from more than one receptor species can be optimally integrated, derive the gradient shapes that are optimal for guiding cells or growth cones over the longest possible distances, and illustrate that polarized cell behavior might arise as an adaptation to slowly varying environments. Together our results provide closed-form predictions for variations in chemotactic performance over a wide range of gradient conditions.

There is a peculiar paradox in Apollinaire’s attitude to music. On the one hand, he took little apparent interest in the music of his (or any) time; he clearly did not appreciate it much, and his enjoyment of concerts was at best ambiguous. On the other hand, music as an abstract concept (including what he calls, in his poems, “le chant”) stands, in his writing, for the very essence of art: there is no higher praise for a poem or a painting, in Apollinaire’s vocabulary, than to say it is, or is analogous to, music. This essay seeks to explain why actual works of music, of specific audible music, have such a low position in Apollinaire’s value system, while the concept of music has such a dominant one. The answer is to be found in the relationship between art and the dynamics of representation, as Apollinaire understood them. Works of art, for him, are born of a struggle between reality and creativity. In that struggle, music, which never represents reality, stands for the purely creative pole; hence, it figures the goal of all truly modern art, which refuses simply to imitate what exists. However, actual successful works of music are difficult for Apollinaire to imagine, precisely because the struggle with reality seems to him absent from music. The result is an aesthetic system in which the highest value can never be realised in a work, and a poetics in which unrealistic ambition is as essential as frustration.

Two fundamental questions underlie the expression of behavior, namely what to do and how vigorously to do it. The former is the topic of an overwhelming wealth of theoretical and empirical work particularly in the fields of reinforcement learning and decision-making, with various forms of affective prediction error playing key roles. Although vigor concerns motivation, and so is the subject of many empirical studies in diverse fields, it has suffered a dearth of computational models. Recently, Niv et al. [Niv, Y., Daw, N. D., Joel, D., & Dayan, P. Tonic dopamine: Opportunity costs and the control of response vigor. Psychopharmacology (Berlin), 191, 507–520, 2007] suggested that vigor should be controlled by the opportunity cost of time, which is itself determined by the average rate of reward. This coupling of reward rate and vigor can be shown to be optimal under the theory of average return reinforcement learning for a particular class of tasks but may also be a more general, perhaps hard-wired, characteristic of the architecture of control. We, therefore, tested the hypothesis that healthy human participants would adjust their RTs on the basis of the average rate of reward. We measured RTs in an odd-ball discrimination task for rewards whose magnitudes varied slowly but systematically. Linear regression on the subjects' individual RTs using the time varying average rate of reward as the regressor of interest, and including nuisance regressors such as the immediate reward in a round and in the preceding round, showed that a significant fraction of the variance in subjects' RTs could indeed be explained by the rate of experienced reward. This validates one of the key proposals associated with the model, illuminating an apparently mandatory form of coupling that may involve tonic levels of dopamine.

Vigor in the Face of Fluctuating Rates of Reward: An Experimental Examination

Contents: Introduction: the five laws of the interart aesthetic Whistler's poetry Satie's art Apollonaire's art Braque's music Ponge's music Stravinsky's poetry Conclusion: 'that's of course what poetry is': painting in Paris and London, December 2009 Bibliography Index.

Art as Music, Music as Poetry, Poetry as Art, from Whistler to Stravinsky and Beyond

The acquisition of reward and the avoidance of punishment could logically be contingent on either emitting or withholding particular actions. However, the separate pathways in the striatum for go and no-go appear to violate this independence, instead coupling affect and effect. Respect for this interdependence has biased many studies of reward and punishment, so potential action–outcome valence interactions during anticipatory phases remain unexplored. In a functional magnetic resonance imaging study with healthy human volunteers, we manipulated subjects' requirement to emit or withhold an action independent from subsequent receipt of reward or avoidance of punishment. During anticipation, in the striatum and a lateral region within the substantia nigra/ventral tegmental area (SN/VTA), action representations dominated over valence representations. Moreover, we did not observe any representation associated with different state values through accumulation of outcomes, challenging a conventional and dominant association between these areas and state value representations. In contrast, a more medial sector of the SN/VTA responded preferentially to valence, with opposite signs depending on whether action was anticipated to be emitted or withheld. This dominant influence of action requires an enriched notion of opponency between reward and punishment.

Action Dominates Valence in Anticipatory Representations in the Human Striatum and Dopaminergic Midbrain

Model-based influences on humans’ choices and striatal prediction errors

This report documents the program and the outcomes of Dagstuhl Seminar 11131 ``Exploration and Curiosity in Robot Learning and Inference''. This seminar was concerned with answering the question: how should a robot choose its actions and experiences so as to maximise the effectiveness of its learning?}. The seminar brought together workers from three fields: machine learning, robotics and computational neuroscience. The seminar gave an overview of active research, and identified open research problems. In particular the seminar identified the difficulties in moving from theoretically well grounded notions of curiosity to practical robot implementations.

Exploration and Curiosity in Robot Learning and Inference (Dagstuhl Seminar 11131)

Seeing Words and Music as a Painter Might: The Interart Aesthetic

Introduction. When deciding about the cause underlying serially presented events, patients with delusions utilise fewer events than controls, showing a “Jumping-to-Conclusions” bias. This has been widely hypothesised to be because patients expect to incur higher costs if they sample more information. This hypothesis is, however, unconfirmed. Methods. The hypothesis was tested by analysing patient and control data using two models. The models provided explicit, quantitative variables characterising decision making. One model was based on calculating the potential costs of making a decision; the other compared a measure of certainty to a fixed threshold. Results. Differences between paranoid participants and controls were found, but not in the way that was previously hypothesised. A greater “noise” in decision making (relative to the effective motivation to get the task right), rather than greater perceived costs, best accounted for group differences. Paranoid participants also deviated from ideal Bayesian reasoning more than healthy controls. Conclusions. The Jumping-to-Conclusions Bias is unlikely to be due to an overestimation of the cost of gathering more information. The analytic approach we used, involving a Bayesian model to estimate the parameters characterising different participant populations, is well suited to testing hypotheses regarding “hidden” variables underpinning observed behaviours.

Bayesian modelling of Jumping-to-Conclusions bias in delusional patients

EFFICIENT DECISION-MAKING IS DEPENDENT ON THE EFFICIENT PRUNING OF DECISION TREES

Contrast discrimination functions for simple gratings famously look like a dipper. Discrimination thresholds are lower than detection thresholds for moderate pedestal contrasts, and the rate of growth of thresholds as the pedestal contrast gets larger typically lies between the values implied by two popular treatments of noise. Here, we suggest a new normative treatment of the dipper, showing how it emerges from Bayesian inference based on the responses of a population of orientation-tuned units. Our central assumption concerns the noise corrupting the outputs of these units as a function of the contrast: We suggest that it has the shape of a hinge. We show the match to the psychophysical data and discuss the neurobiological and statistical rationales for this form of noise. Finally, we relate our model to other major accounts of contrast discrimination.

When good decisions go bad: Reinforcement learning and computational psychiatry

Synapses with short-term plasticity are optimal estimators of presynaptic membrane potentials

States versus Rewards: Dissociable Neural Prediction Error Signals Underlying Model-Based and Model-Free Reinforcement Learning

Subjects typically choose to be presented with stimuli that predict the existence of future reinforcements. This so-called ‘observing behavior’ is evident in many species under various experimental conditions, including if the choice is expensive, or if there is nothing that subjects can do to improve their lot with the information gained. A recent study showed that the activities of putative midbrain dopamine neurons reflect this preference for observation in a way that appears to challenge the common prediction-error interpretation of these neurons. In this paper, we provide an alternative account according to which observing behavior arises from a small, possibly Pavlovian, bias associated with the operation of working memory.

One standard interpretation of networks of cortical neurons is that they form dynamical attractors. Computations such as stimulus estimation are performed by mapping inputs to points on the networks' attractive manifolds. These points represent population codes for the stimulus values. However, this standard interpretation is hard to reconcile with the observation that the firing rates of such neurons constantly change following presentation of stimuli. We have recently suggested an alternative interpretation according to which computations are realized by systematic changes in the states of such networks over time. This way of performing computations is fast, accurate, readily learnable, and robust to various forms of noise. Here we analyze the computation of stimulus discrimination in this change-based setting, relating it directly to the computation of stimulus estimation in the conventional attractor-based view. We use a common linear approximation to compare the two methods and show that perfect performance at estimation implies chance performance at discrimination.

Shout line Traces rhythm in literature in the analysable patterns of metrical verse as it unfolds in the work of post-crisis writers Before the 'crise de vers' which Mallarme diagnosed in the 1880s, just as rhythm in music had to do with note values and repeated patterns, so rhythm in literature could be safely sought in the analysable patterns of metrical verse. The crisis abolished that security yet the conviction that rhythm is fundamental to literature survived that destruction. Tracing rhythm as it unfolds in the work of post-crisis writers from Valery, Woolf, Campana, and the Dadaists, via the strange history of Russian verse under Communism, to Reda, Cortazar, and John Wilkinson, this volume seeks to found such a theory precisely in the space between rhythm's elusiveness as a general concept, and the continuing specific force of its presence in the works of literature. Before the 'crise de vers' which Mallarme diagnosed in the 1880s, just as rhythm in music had to do with note values and repeated patterns, so rhythm in literature could be safely sought in the analysable patterns of metrical verse. The crisis abolished that security: free verse and prose poetry destroyed the privilege of the old countable rhythms. Yet the conviction that rhythm is fundamental to literature survived that destruction. How? Why? Is there really anything one can say, any theory that can measure up to rhythm since the crisis, to a rhythm that cannot be localised in measurable convention? Tracing rhythm as it unfolds in the work of post-crisis writers from Valery, Woolf, Campana, and the Dadaists, via the strange history of Russian verse under Communism, to Reda, Cortazar, and John Wilkinson, this volume seeks to found such a theory precisely in the space between rhythm's elusiveness as a general concept, and the continuing specific force of its presence in the works of literature.

Medial Self-Reference between Words and Music in Erik Satie's Piano Piece's

Declarative memory is remarkably adaptive in the way it maintains sensitivity to relative novelty in both unknown and highly familiar environments. However, the neural mechanisms underlying this contextual adaptation are poorly understood. On the basis of emerging links between novelty processing and reinforcement learning mechanisms, we hypothesized that responses to novelty will be adaptively scaled according to expected contextual probabilities of new and familiar events, in the same way that responses to prediction errors for rewards are scaled according to their expected range. Using functional magnetic resonance imaging in humans, we show that the influence of novelty and reward on memory formation in an incidental memory task is adaptively scaled and furthermore that the BOLD signal in orbital prefrontal and medial temporal cortices exhibits concomitant scaled adaptive coding. These findings demonstrate a new mechanism for adjusting gain and sensitivity in declarative memory in accordance with contextual probabilities and expectancies of future events. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.

Motion-gradient defined facial expressions and the nature of face representation

Opponency Revisited: Competition and Cooperation Between Dopamine and Serotonin

The brain exhibits remarkable facility in exerting attentional control in most circumstances, but it also suffers apparent limitations in others. The authors' goal is to construct a rational account for why attentional control appears suboptimal under conditions of conflict and what this implies about the underlying computational principles. The formal framework used is based on Bayesian probability theory, which provides a convenient language for delineating the rationale and dynamics of attentional selection. The authors illustrate these issues with the Eriksen flanker task, a classical paradigm that explores the effects of competing sensory inputs on response tendencies. The authors show how 2 distinctly formulated models, based on compatibility bias and spatial uncertainty principles, can account for the behavioral data. They also suggest novel experiments that may differentiate these models. In addition, they elaborate a simplified model that approximates optimal computation and may map more directly onto the underlying neural machinery. This approximate model uses conflict monitoring, putatively mediated by the anterior cingulate cortex, as a proxy for compatibility representation. The authors also consider how this conflict information might be disseminated and used to control processing.

Dynamics of attentional selection under conflict: toward a rational Bayesian account.

Axon guidance by molecular gradients plays a crucial role in wiring up the nervous system. However, the mechanisms axons use to detect gradients are largely unknown. We first develop a Bayesian “ideal observer” analysis of gradient detection by axons, based on the hypothesis that a principal constraint on gradient detection is intrinsic receptor binding noise. Second, from this model, we derive an equation predicting how the degree of response of an axon to a gradient should vary with gradient steepness and absolute concentration. Third, we confirm this prediction quantitatively by performing the first systematic experimental analysis of how axonal response varies with both these quantities. These experiments demonstrate a degree of sensitivity much higher than previously reported for any chemotacting system. Together, these results reveal both the quantitative constraints that must be satisfied for effective axonal guidance and the computational principles that may be used by the underlying signal transduction pathways, and allow predictions for the degree of response of axons to gradients in a wide variety of in vivo and in vitro settings.

A Bayesian model predicts the response of axons to molecular gradients

The maxim “no pain, no gain” summarizes scenarios in which an action leading to reward also entails a cost. Although we know a substantial amount about how the brain represents pain and reward separately, we know little about how they are integrated during goal-directed behavior. Two theoretical models might account for the integration of reward and pain. An additive model specifies that the disutility of costs is summed linearly with the utility of benefits, whereas an interactive model suggests that cost and benefit utilities interact so that the sensitivity to benefits is attenuated as costs become increasingly aversive. Using a novel task that required integration of physical pain and monetary reward, we examined the mechanism underlying cost–benefit integration in humans. We provide evidence in support of an interactive model in behavioral choice. Using functional neuroimaging, we identify a neural signature for this interaction such that, when the consequences of actions embody a mixture of reward and pain, there is an attenuation of a predictive reward signal in both ventral anterior cingulate cortex and ventral striatum. We conclude that these regions subserve integration of action costs and benefits in humans, a finding that suggests a cross-species similarity in neural substrates that implement this function and illuminates mechanisms that underlie altered decision making under aversive conditions.

How Humans Integrate the Prospects of Pain and Reward during Choice

A central hypothesis about early visual processing is that it represents inputs in a coordinate system matched to the statistics of natural scenes. Simple versions of this lead to Gabor-like receptive fields and divisive gain modulation from local surrounds; these have led to influential neural and psychological models of visual processing. However, these accounts are based on an incomplete view of the visual context surrounding each point. Here, we consider an approximate model of linear and non-linear correlations between the responses of spatially distributed Gabor-like receptive fields, which, when trained on an ensemble of natural scenes, unifies a range of spatial context effects. The full model accounts for neural surround data in primary visual cortex (V1), provides a statistical foundation for perceptual phenomena associated with Li's (2002) hypothesis that V1 builds a saliency map, and fits data on the tilt illusion.

Statistical Models of Linear and Nonlinear Contextual Interactions in Early Visual Processing

Abstract It is certainly true that Satie, in his later years, did not tire of repeating that there is ‘no Truth in Art’; and in saying so, he was doubtless very much in tune with the spirit of his artistic milieu, which included, after all, such aesthetic anarchists as Picabia and Tzara, as well as the great artistic revolutionaries of the time, Picasso and Stravinsky, for whom he had unbounded admiration. And every time he did so, he was careful to attribute the erroneous belief that there is a Truth in Art to that class of writers whom he variously called ‘critiques’, ‘pédagogues’, ‘Pontifes’, ‘pions’: people of the serious persuasion, who think it is possible to teach or describe what makes a piece of art good or bad. Attacks against this tribe are, in fact, the staple of Satie's writings. It might appear sensible to infer from this that it would be foolish for a critic to look for Truth in Erik Satie's writings about art. Nonetheless, that is what I shall be doing in this article. I shall argue that, while there may, for Satie, be no truth in art, there are truths about art, susceptible of at least indirect expression, which Satie himself maintained with remarkable adroitness. Whether those truths are peculiar to the aesthetics of Satie's writings; whether they are relevant to the way we might appreciate his music; and whether they have echoes in the thought of his artistic companions (especially those mentioned above) – these are questions that will remain open; but I would like at least to suggest that they are worth asking.

The tilt illusion is a paradigmatic example of contextual influences on perception. We analyze it in terms of a neural population model for the perceptual organization of visual orientation. In turn, this is based on a well-found treatment of natural scene statistics, known as the Gaussian Scale Mixture model. This model is closely related to divisive gain control in neural processing and has been extensively applied in the image processing and statistical learning communities; however, its implications for contextual effects in biological vision have not been studied. In our model, oriented neural units associated with surround tilt stimuli participate in divisively normalizing the activities of the units representing a center stimulus, thereby changing their tuning curves. We show that through standard population decoding, these changes lead to the forms of repulsion and attraction observed in the tilt illusion. The issues in our model readily generalize to other visual attributes and contextual phenomena, and should lead to more rigorous treatments of contextual effects based on natural scene statistics.

A striking recent finding is that monkeys behave maladaptively in a class of tasks in which they know that reward is going to be systematically delayed. This may be explained by a malign Pavlovian influence arising from states with low predicted values. However, by very carefully analyzing behavioral data from such tasks, La Camera and Richmond (2008) observed the additional important characteristic that subjects perform differently on states in the task that are at equal distances from the future reward, depending on what has happened in the recent past. The authors pointed out that this violates the definition of state value in the standard reinforcement learning models that are ubiquitous as accounts of operant and classical conditioned behavior; they suggested and analyzed an alternative temporal difference (TD) model in which past and future are melded. Here, we show that, in fact, a standard TD model can actually exhibit the same behavior, and that this avoids deleterious consequences for choice. At the heart of the model is the average reward per step, which acts as a baseline for measuring immediate rewards. Relatively subtle changes to this baseline occasioned by the past can markedly influence predictions and thus behavior.

Synapses exhibit an extraordinary degree of short-term malleability, with release probabilities and effective synaptic strengths changing markedly over multiple timescales. From the perspective of a fixed computational operation in a network, this seems like a most unacceptable degree of added variability. We suggest an alternative theory according to which short-term synaptic plasticity plays a normatively-justifiable role. This theory starts from the commonplace observation that the spiking of a neuron is an incomplete, digital, report of the analog quantity that contains all the critical information, namely its membrane potential. We suggest that a synapse solves the inverse problem of estimating the pre-synaptic membrane potential from the spikes it receives, acting as a recursive filter. We show that the dynamics of short-term synaptic depression closely resemble those required for optimal filtering, and that they indeed support high quality estimation. Under this account, the local postsynaptic potential and the level of synaptic resources track the (scaled) mean and variance of the estimated presynaptic membrane potential. We make experimentally testable predictions for how the statistics of subthreshold membrane potential fluctuations and the form of spiking non-linearity should be related to the properties of short-term plasticity in any particular cell type.

practices and the figure of the modern woman in the paintings of Manet and the Impressionists. It seems that print media images such as fashion plates, illustrated department store catalogues and advertising posters, along with street signs, store fronts and other manifestations of the rampant marchandisement of Paris so saturated everyday life that this consumerism became enmeshed in the economies of avantgarde art production and spectatorship. Iskin uses the lens of consumerism to survey an assortment of subjects, including Manet’s A Bar at the Folies-Bergère, the millinery paintings of Degas, the treatment of boulevards and cityscapes by various Impressionists, the market scenes of Caillebotte and Pissarro and finally the phenomenon of the chic Parisienne, as registered in high and low art. An important aspect of Iskin’s project is its reconsideration of women’s place within modernism and its representations. In contrast to much of the feminist scholarship devoted to this topic, which tends to emphasize the objectification and exclusion of women, this book posits that women were often presented as active agents in Impressionist paintings, and that in some instances, female viewers seem to have been a target audience. Such revisionist approaches are gaining traction, as evidenced by the catalogue essays accompanying two recent exhibitions on women and Impressionism, and Iskin’s advocacy for female agency and subjectivity as engendered in ‘consumerist’ Impressionist art is a significant enterprise. Particularly convincing are Iskin’s discussions on the intersections of commodity display and female spectatorship inManet’s Bar, along with Degas’s suite of millinery works and their relationship to the spaces (literal and otherwise) of female fashion consumerism. The author’s exploration of lesser known paintings of urban and village marketplaces, which engage in notions of natural and artificial modes of display and consumption, is also noteworthy. There is an abundance of new material offered in this book and scholars will profit from the author’s assiduous research. That said, there were ambiguities as to the relationship between consumer culture and avant-garde art that at times left this reader wanting. Iskin’s conclusion that there were aspects of resistance, ambivalence and absorption vis-à-vis commodity culture in Impressionist art is convincing; however, the complexity of this dynamic is too often minimized in both its theoretical framings as well as in the analyses of several key paintings. Moreover, the inconsistent treatment of the subject of modern women—which is positioned as this study’s focus in the introduction and yet all but disappears in two of its six chapters— is a bit problematic. These criticisms aside, this ambitious and revisionist book is sure to generate reappraisals of the Impressionist movement, the œuvre of its individual artists and women’s place in the public sphere of the late nineteenth century.

Reconstructing Woman: From Fiction to Reality in the Nineteenth-Century French Novel (review)

Cross-adaptation is widely used to probe whether different stimuli share common neural mechanisms. For example, that adaptation to second-order stimuli usually produces little aftereffect on first-order stimuli has been interpreted as reflecting their separate processing. However, such results appear to contradict the cue-invariant responses of many visual cells. We tested the novel hypothesis that the null aftereffect arises from the large difference in the backgrounds of first- and second-order stimuli. We created second-order faces with happy and sad facial expressions specified solely by local directions of moving random dots on a static-dot background, without any luminance-defined form cues. As expected, adaptation to such a second-order face did not produce a facial-expression aftereffect on the first-order faces. However, consistent with our hypothesis, simply adding static random dots to the first-order faces to render their backgrounds more similar to that of the adapting motion face led to a significant aftereffect. This background similarity effect also occurred between different types of first-order stimuli: real-face adaptation transferred to cartoon faces only when noise with correlation statistics of real faces or natural images was added to the cartoon faces. These findings suggest the following: (1) statistical similarities between the featureless backgrounds of the adapting and test stimuli can influence aftereffects, as in contingent adaptation; (2) weak or null cross-adaptation aftereffects should be interpreted with caution; and (3) luminance- and motion-direction-defined forms, and local features and global statistics, converge in the representation of faces.

Of course, ‘bien sur’ . . . Derrida would never have found the time to finish anything, to get to the end of anything, to see anything through properly, to do what he would have wanted to do. But perhaps the time that he would never have had was only one kind: the philosophical kind, the kind we are aware of as distinctively human. Perhaps there is another time, animal and poetic, which he did find. The paragraph from L’animal que donc je suis (The Animal That Therefore I am) of which I have quoted the first sentence continues thus:

A Bayesian model of behaviour in sequential economic games with applications to computational psychiatry

Dopamine is intimately linked with the modes of action of drugs of addiction. However, although its role in the initiation of drug abuse seems relatively uncomplicated, its possible involvement in the development of compulsive drug taking, and indeed vulnerability and relapse, is less clear. We first describe a modern reinforcement learning view of affective control, focusing on the roles for dopamine. We then use this as a framework to sketch various notions of the neuromodulator's possible participation in initiation and compulsion. We end with some pointers towards future theoretical developments.

Serotonin is a neuromodulator that is extensively entangled in fundamental aspects of brain function and behavior. We present a computational view of its involvement in the control of appetitively and aversively motivated actions. We first describe a range of its effects in invertebrates, endowing specific structurally fixed networks with plasticity at multiple spatial and temporal scales. We then consider its rather widespread distribution in the mammalian brain. We argue that this is associated with a more unified representational and functional role in aversive processing that is amenable to computational analyses with the kinds of reinforcement learning techniques that have helped elucidate dopamine's role in appetitive behavior. Finally, we suggest that it is only a partial reflection of dopamine because of essential asymmetries between the natural statistics of rewards and punishments.

Serotonin modulates choice stickiness through an outcome-independent striatal mechanism.

Values, rewards, and costs play a central role in economic, statistical, and psychological notions of decision making. They also have surprisingly direct neural realizations. This chapter discusses the ways in which different value systems interact with different decision-making systems to fashion and shape affectively appropriate behavior in complex environments. Forms of deliberative and automatic decision making are interpreted as sharing a common purpose rather than serving different or non-normative goals.

Aversive processing plays a central role in human phobic fears and may also be important in some symptoms of psychosis. We developed a temporal-difference model of the conditioned avoidance response, an important experimental model for aversive learning which is also a central pharmacological model of psychosis. In the model, dopamine neurons reported outcomes that were better than the learner expected, typically coming from reaching safety states, and thus controlled the acquisition of a suitable policy. The model accounts for normal conditioned avoidance learning, the persistence of responding in extinction, and critical effects of dopamine blockade, notably that subjects experiencing shocks under dopamine blockade, and hence failing to avoid them, nevertheless develop avoidance responses when both shocks and dopamine blockade are subsequently removed. These postulated roles of dopamine in aversive learning can thus account for many of the effects of dopaminergic modulation seen in laboratory models of psychopathological processes.

Adaptation is ubiquitous in sensory processing. Although sensory processing is hierarchical, with neurons at higher levels exhibiting greater degrees of tuning complexity and invariance than those at lower levels, few experimental or theoretical studies address how adaptation at one hierarchical level affects processing at others. Nevertheless, this issue is critical for understanding cortical coding and computation. Therefore, we examined whether perception of high-level facial expressions can be affected by adaptation to low-level curves (i.e., the shape of a mouth). After adapting to a concave curve, subjects more frequently perceived faces as happy, and after adapting to a convex curve, subjects more frequently perceived faces as sad. We observed this multilevel aftereffect with both cartoon and real test faces when the adapting curve and the mouths of the test faces had the same location. However, when we placed the adapting curve 0.2° below the test faces, the effect disappeared. Surprisingly, this positional specificity held even when real faces, instead of curves, were the adapting stimuli, suggesting that it is a general property for facial-expression aftereffects. We also studied the converse question of whether face adaptation affects curvature judgments, and found such effects after adapting to a cartoon face, but not a real face. Our results suggest that there is a local component in facial-expression representation, in addition to holistic representations emphasized in previous studies. By showing that adaptation can propagate up the cortical hierarchy, our findings also challenge existing functional accounts of adaptation.

Adaptation across the Cortical Hierarchy: Low-Level Curve Adaptation Affects High-Level Facial-Expression Judgments

Decision making is a core competence for animals and humans acting and surviving in environments they only partially comprehend, gaining rewards and punishments for their troubles. Decision-theoretic concepts permeate experiments and computational models in ethology, psychology, and neuroscience. Here, we review permeate experiments and computational models in ethology, psychology, and neuroscience. Here, we review a welln known, coherent Bayesian approach to decision making, showing how it unifies issues in Markovian decision problems, signal detection psychophysics, sequential sampling, and optimal exploration and discuss paradigmatic psychological and neural examples of each problem. We discuss computational issues concerning what subjects know about their task and how ambitious they are in seeking optimal solutions; we address algorithmic topics concerning model-based and model- free methods for making choices; and we highlight key aspects o t e eu a p e e tat o o dec s o a g. aspects of the neural implementation of decision making.

CONNECTIONS BETWEEN C N OMPUTATIONAL AND NEUROBIOLOGICAL PERSPECTIVES ON DECISION MAKING Decision theory, reinforcement learning, and the brain

Interart Contraband: What passed between Garcia, Sand, and Liszt in Le Contrebandier

Selective attention is a most intensively studied psychological phenomenon, rife with theoretical suggestions and schisms. A critical idea is that of limited capacity, the allocation of which has produced continual conflict about such phenomena as early and late selection. An influential resolution of this debate is based on the notion of perceptual load (Lavie, 2005), which suggests that low-load, easy tasks, because they underuse the total capacity of attention, mandatorily lead to the processing of stimuli that are irrelevant to the current attentional set; whereas high-load, difficult tasks grab all resources for themselves, leaving distractors high and dry. We argue that this theory presents a challenge to Bayesian theories of attention, and suggest an alternative, statistical, account of key supporting data.

Acetylcholine contributes through muscarinic receptors to attentional modulation in V1

Recent advances in the cognitive neuroscience of motivation and learning have demonstrated a critical role for midbrain dopamine and its targets in reward prediction. Converging evidence suggests that midbrain dopamine neurons signal a reward prediction error, allowing an organism to predict, and to act to increase, the probability of reward in the future. This view has been highly successful in accounting for a wide range of reinforcement learning phenomena in animals and humans. However, while current theories of midbrain dopamine provide a good account of behavior known as habitual or stimulus-response learning, we review evidence suggesting that other neural and cognitive processes are involved in motivated, goal-directed behavior. We discuss how this distinction resembles the classic distinction in the cognitive neuroscience of memory between nondeclarative and declarative memory systems, and discuss common themes between mnemonic and motivational functions. Finally, we present data demonstrating links between mnemonic processes and reinforcement learning.

Abstract:This article is the first literary critical analysis of Satie's poetry. It starts from his "Trois poèmes d'amour", whose verse form and musical setting place exaggerated emphasis on the 'e muet' of feminine rhymes. The 'e muet' and sounds connoted as feminine play an equally important role in Satie's 'drame symphonique' "Socrate": they suggest a symbolist prolongation of the voice beyond the point where its function is to make sense, as it fades into music or silence. Playing the conventions of verse against those of musical notation, Satie configures a poet whose problems of self-expression become those of poetry itself.

Our aim is to derive analytical approximations for the performance of a modelbased controller in tree-structured Markov decision processes. 1 Paradigm for analysis A controller navigating an initially unknown environment (defined as a Markov decision process, MDP) needs to have two component algorithms: a learning algorithm that defines a mapping from the history of experienced state-action transitions and obtained rewards to some internal representation (eg a value function), and an action selection algorithm (policy) that defines a mapping from this internal representation and the current state to an action (or, in the case of stochastic action choice, a distribution over actions).1 Thus, the performance of a controller depends on how close to optimal its two component algorithms are: how efficiently it uses sample data points when learning, and how accurately it selects actions based on the knowledge it acquired about its environment so far. There is a theoretically optimal, but of course hugely impractical, solution to this problem: a controller which has an explicit statistical model of its environment, learns it by Bayesian updating (assuming it has the correct priors), and then uses this model to exhaustively simulate all possible outcomes of its actions. Here we analyse the performance of such a controller to derive upper bounds on the performance of any other controller, and also investigate how the performance of this model-based controller breaks down if action selection (but not learning!) involves approximations rendering it imperfect – which is one obvious way to approach practicality. Since our ultimate interest lies in analyzing the trade-offs between multiple alternative controllers that might be available to the same agent, we consider off-policy controllers that are able to learn from experience even if it was gathered while following a policy other than the controller’s own. For a general introduction to the topic and definitions of all terms not defined here see [1]. Direct policy improvement algorithms are also possible and if the authors were hard-pressed those would be considered as a special case of this general scheme, in which the ‘policy’ that is being improved is the internal representation in our terms, and action selection just looks up the action for the current state.

Hippocampal Contributions to Control : The Third Way – Supporting Material –

The vigor with which a participant performs actions that produce valuable outcomes is subject to a complex set of motivational influences. Many of these are believed to involve the amygdala and the nucleus accumbens, which act as an interface between limbic and motor systems. One prominent class of influences is called pavlovian–instrumental transfer (PIT), in which the motivational characteristics of a predictor influence the vigor of an action with respect to which it is formally completely independent. We provide a demonstration of behavioral PIT in humans, with an audiovisual predictor of the noncontingent delivery of money inducing participants to perform more avidly an action involving squeezing a handgrip to earn money. Furthermore, using functional magnetic resonance imaging, we show that this enhanced motivation was associated with a trial-by-trial correlation with the blood oxygenation level-dependent (BOLD) signal in the nucleus accumbens and a subject-by-subject correlation with the BOLD signal in the amygdala. Our data dovetails well with the animal literature and sheds light on the neural control of vigor.

Interart Contraband: What Passed between García, Fiszt and Sand in “Le Contrebandier”

Complex cognitive tasks present a range of computational and algorithmic challenges for neural accounts of both learning and inference. In particular, it is extremely hard to solve them using the sort of simple policies that have been extensively studied as solutions to elementary Markov decision problems. There has thus been recent interest in architectures for the instantiation and even learning of policies that are formally more complicated than these, involving operations such as gated working memory. However, the focus of these ideas and methods has largely been on what might best be considered as automatized, routine or, in the sense of animal conditioning, habitual, performance. Thus, they have yet to provide a route towards understanding the workings of rule-based control, which is critical for cognitively sophisticated competence. Here, we review a recent suggestion for a uniform architecture for habitual and rule-based execution, discuss some of the habitual mechanisms that underpin the use of rules, and consider a statistical relationship between rules and habits.

Naturally occurring sensory stimuli are dynamic. In this letter, we consider how spiking neural populations might transmit information about continuous dynamic stimulus variables. The combination of simple encoders and temporal stimulus correlations leads to a code in which information is not readily available to downstream neurons. Here, we explore a complex encoder that is paired with a simple decoder that allows representation and manipulation of the dynamic information in neural systems. The encoder we present takes the form of a biologically plausible recurrent spiking neural network where the output population recodes its inputs to produce spikes that are independently decodeable. We show that this network can be learned in a supervised manner by a simple local learning rule.

Decision making lies at the very heart of many psychiatric diseases. It is also a central theoretical concern in a wide variety of fields and has undergone detailed, in-depth, analyses. We take as an example Major Depressive Disorder (MDD), applying insights from a Bayesian reinforcement learning framework. We focus on anhedonia and helplessness. Helplessness—a core element in the conceptualizations of MDD that has lead to major advances in its treatment, pharmacological and neurobiological understanding—is formalized as a simple prior over the outcome entropy of actions in uncertain environments. Anhedonia, which is an equally fundamental aspect of the disease, is related to the effective reward size. These formulations allow for the design of specific tasks to measure anhedonia and helplessness behaviorally. We show that these behavioral measures capture explicit, questionnaire-based cognitions. We also provide evidence that these tasks may allow classification of subjects into healthy and MDD groups based purely on a behavioural measure and avoiding any verbal reports.

Psychiatry: Insights into depression through normative decision-making models

A novel method for automated classification of epileptiform activity in the human electroencephalogram-based on independent component analysis

In the last two of its four chapters, this book does something rather daring and unusual. It examines the poetic theory and practice of two late Symbolists, René Ghil and Jean Royère, who are generally considered inferior poets and whose work has been little read for the last half century; not in order to rehabilitate them (Acquisto does not hesitate to describe their poems as failures), nor simply in order to put them in their literary historical place, but to look for the instructive flaws in their poetic reasoning. Taking it as axiomatic that we believe that Baudelaire and Mallarmé produced better poetry than Royère and Ghil, Acquisto tries to show why; where, exactly, the difference lies. He finds it by contrasting the dogmatism of Ghil and Royère with a certain openness in their great predecessors: ‘successful writers are ultimately those whose works yield themselves easily to inventive recombinations and rereadings’ (p. 157). This, in itself, is perhaps not an original insight. However, it is arrived at through a thoroughly original analysis of how these poets use the concept of music. Roughly summarized: in reading Baudelaire and Mallarmé, it often becomes difficult to say exactly what music is, where it starts and stops, whether or not it is to be identified with its physical manifestation as musical notes; nonetheless, there is also a constant movement to distance music from poetry, as poetry’s other, whether or not it also seems an ideal goal. Acquisto demonstrates this ambiguous distinction of music through careful investigation of the dynamics of reading which the poetry of Baudelaire and Mallarmé invites, playing on the functions of memory, and increasingly requiring the reader to engage performatively with the text. Ghil and Royère, on the other hand, fail to maintain the distinctiveness, the distance of music, the distance between music and poetry. Worse still, the collapse of that distance is followed by a general collapse of the functions of metaphor and synecdoche, so that similarity is no longer distinguished from identity. In Royère’s writing, ‘pure poetry is musicism, musicism is poetry, poetry is music and is also life, in addition to being language and the rhythm of language’ (p. 130). This dogmatic indistinction is fatal to the symbolist idea of poetry. It is therefore hardly suprising, Acquisto implies, that Royère largely gave up writing about literature and turned instead to pro-Mussolini propaganda. Acquisto’s book is not without its faults at the level of detail (including occasional errors in quotation and questionable translation), but the general argument becomes steadily more engrossing and persuasive as it progresses. It is refreshing to read a work that addresses so carefully the question of how poetry created its own values in the nineteenth century, especially when it also asks why those values ceased to be productive for poets, and yet remain highly functional for readers today.

Classical game theoretic approaches that make strong rationality assumptions have difficulty modeling human behaviour in economic games. We investigate the role of finite levels of iterated reasoning and non-selfish utility functions in a Partially Observable Markov Decision Process model that incorporates game theoretic notions of interactivity. Our generative model captures a broad class of characteristic behaviours in a multi-round Investor-Trustee game. We invert the generative process for a recognition model that is used to classify 200 subjects playing this game against randomly matched opponents.

Under a conventional view of information processing in recurrently connected populations of neurons, computations consist in mapping inputs onto terminal attractor states of the dynamical interactions. However, there is evidence that substantial information representation and processing can occur over the course of the initial evolution of the dynamical states of such populations, a possibility that has attractive computational properties. Here, we suggest a model that explores one such property, namely, the invariance to an irrelevant feature dimension that arises from monitoring not the state of the population, but rather (a statistic of) the change in this state over time. We illustrate our proposal in the context of the bisection task, a paradigmatic example of perceptual learning for which an attractor-state recurrent model has previously been suggested. We show a change-based inference scheme that achieves near optimal performance in the task (with invariance to translation), is robust to high levels of dynamical noise and variations of the synaptic weight matrix, and indeed admits a computationally straightforward learning rule.

Decision making involves selection from sets of options based on current evidence about the state of the world and estimates of the value or utility of different outcomes. The neural correlates of evidence assessment that guide simple perceptual judgments are now well understood, and we argue that this process can serve as a simple model for organizing behavioral and neural correlates of decision making in more complex contexts, including those that involve economic transactions, social interaction, emotional stimulation, and conscious awareness. Bridging the methodological and theoretical gaps between simple and more complicated decision problems remains a fundamental, but in our view soluble, challenge for understanding the neurobiology of decision making.

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It is a commonplace that psychiatric disorders such as depression and sc hizophrenia involve substantial disturbances to affectively-charged decision-making. Although our unde rstanding of the latter has substantially advanced, with theoretical concepts drawn from reinforcement learnin g (RL) providing a normatively-sound framework within which to link psychological, neurobiological and pharmaco logical results, there have hitherto been only a few applications to psychiatry. Here, we use RL to identify c omponents of decision-making that are key in depression, the psychiatric disease that is one of the world ’s biggest scourges.

An unsupervised learning model of neural plasticity: Orientation selectivity in goggle-reared kittens

Reviews Symphony by the German critic Adolph-Bernard Marx. Vogel does well to draw attention to this analysis, from which Berlioz quotes at length in the three-part biography of Beethoven he published in 1829, and from which he drew support for his early intuition of Beethoven as a self-expressive, implicitly “autobiographical” composer (a notion he later explicitly applies to the Fifth Symphony): Marx suggestively interprets the Ninth Symphony as a depiction of the creative act itself. But I am wholly unconvinced by the textual analogies Vogel attempts to tease out (complete with chart) between the Marxian analysis and the Berliozian scenario. Nothing could be more foreign to Berlioz’s manner and taste – he despised the very word “aesthetics” – than Marx’s lofty philosophical abstractions. What Vogel might rather have pointed out is that Marx’s idea of distributing copies of his “program” for the Ninth Symphony whenever the work was performed precisely anticipates what Berlioz was to do with the Fantastique. Marx’s suggestion is thus worth stressing as a sign that Berlioz, in using a program, not only continued a well-worn practice among earlier symphonic composers, but also followed a contemporary precedent associated with Beethoven. Although academic German is not for the faint of heart, I recommend this book as rewarding the plunge. Vogel writes ably, even entertainingly, with an understated humor well suited to his subject. Helpfully, many of his translations come accompanied by the original French, and synoptic charts guide the way. A French or English translation would nonetheless greatly benefit Berlioz scholarship, and bear the further advantage of enabling the author to correct the slips and errors that creep into rapidly published dissertations (this one was obviously rushed into print to coincide with the bicentennial). For Vogel’s book is a new sine qua non in the study of early Berlioz, complementing Cairns’s riveting treatment of the composer’s youth. No Berlioz scholar, certainly, can afford to ignore it, and nineteenth-century French scholars in general will find it eminently worth their while.

Unsupervised learning models applied to natural scene statistics almost ubiquitously generate V1-like receptive fields. To assess further how well these models describe the functional goals of its neural representation, we applied such a model to the V1 responses of animals raised in environments with unnatural statistics, namely the recent sustained goggle-rearing experiments of Tanaka [2]. We show that an over-complete product-of-experts model (POE) [1] captures well many characteristics of V1 simple cells observed under both normal and goggle-reared input.

Orientation selectivity in goggle-reared kittens: An overcomplete unsupervised learning model

Erratum: Space and time in visual context (Nature Reviews Neuroscience (2007) 8, (522-535))

Selection amongst potentially conflicting inputs is a critical facet of many decision making tasks. According to Bayesian optimality principles, the attentional suppression of irrelevant inputs and inappropriate responses should reflect implicitly encoded prior assumptions about the statistical structure of sensory inputs. This argument has particularly interesting ramifications for experimental tasks that violate the statistics of the natural environment. Here, we provide a Bayesian formulation for dynamic attentional selection that elucidates this problem, and consider the consequences for behavioral performance. We illustrate these issues using the Eriksen flanker task, a classical paradigm that explores the effects of competing sensory inputs on response tendencies. In this task, the presence of conflicting flanker stimuli has been shown to interfere with the processing of a central target stimulus, especially on short reaction-time trials. We show how two distinct Bayesian inferential principles can explain the detrimental effects of competition in speeded decisions. The first rests on the notion that the brain may be wired, through either evolutionary adaptation or developmental learning, to encode a compatibility bias: that is, the prior belief that spatially proximate items in a visual scene tend to be featurally similar. The second emphasizes the spatial uncertainty induced by overlapping receptive fields of visual sensory processes, which can give rise to a confusion of stimulus identity early on during visual presentation. We also elaborate a simpler, approximate, inference model that formalizes previous work suggesting that different neural structures are involved in the monitoring of conflict and the detection of unexpected events. Finally, we suggest explicit experimental tests to resolve the remaining conflicts between the models.

Pavlovian predictions of future aversive outcomes lead to behavioral inhibition, suppression, and withdrawal. There is considerable evidence for the involvement of serotonin in both the learning of these predictions and the inhibitory consequences that ensue, although less for a causal relationship between the two. In the context of a highly simplified model of chains of affectively charged thoughts, we interpret the combined effects of serotonin in terms of pruning a tree of possible decisions, (i.e., eliminating those choices that have low or negative expected outcomes). We show how a drop in behavioral inhibition, putatively resulting from an experimentally or psychiatrically influenced drop in serotonin, could result in unexpectedly large negative prediction errors and a significant aversive shift in reinforcement statistics. We suggest an interpretation of this finding that helps dissolve the apparent contradiction between the fact that inhibition of serotonin reuptake is the first-line treatment of depression, although serotonin itself is most strongly linked with aversive rather than appetitive outcomes and predictions.

Methods in Mind.Cognitive Neuroscience.Edited byCarl Senior,, Tamara Russell, and, Michael S Gazzaniga.Cambridge (Massachusetts): MIT Press. $55.00. xi + 382 p + 18 pl; ill.; index. ISBN: 0‐262‐19541‐0. 2006.

Mate Lengyel1,2*, Peter Dayan1 1Gatsby Computational Neuroscience Unit, UCL, UK; 2Collegium Budapest, Institute for Advanced Study, Hungary *lmate@gatsby.ucl.ac.uk Abstract ______________________ The mammalian brain possesses multiple memory systems, including the striatum, the locus of procedural memories underlying habits, the neocortex, the main site for long-term general perceptual and semantic knowledge, and the hippocampus, the area largely responsible for storing and processing specific autobiographical memories. These three systems and their interactions have been extensively studied, both empirically and theoretically, but their collective roles in guiding optimal behavior have only rarely been addressed. The contribution of episodic memory is particularly mysterious. Here, we develop a normative framework of control in the face of uncertainty, in which it plays a precisely delineated part. Results _______________________________________________ Performance of the different controllers at varying task complexity and amount of experience

Context exerts a dramatic influence on neural processing and sensory experience. Perceptually, the presence of contextual information at a given point can elicit striking misjudgements of local features, such as orientation and motion. This is manifest in illusions and aftereffects, which have been a topic of intensive study for decades. Perceptual illusions are most puzzling when contexts induce distortions that appear inconsistent with their statistically normative implications, as their functional role then is quite mysterious.

The tilt illusion, population decoding, and natural scene statistics

Blum andAbbott (1995) recently proposed an algorithm for learned navigation that is based on Hebbian changes to adaptive connections between place cells in the hippocampus. This paper suggests using a temporal difference rule (Sutton, 1988) for synaptic plasticity instead, and shows how this alters the resulting behaviour. It also recasts the problem of navigation into the reinforcement learning context of adaptive optimising control, and shows how to learn new trajectories that are not based only on averaging old ones. Preference: Oral Category: Theory and Analysis; Learning and Memory

DETERMINANTS OF MATERNAL AND INFANTICIDAL BEHAVIOR IN FEMALE MOUSE F1 HYBRIDS

The EUROPEAN BRAIN AND BEHAVIOUR SOCIETY has held its 39th Annual General Meeting in Trieste, in the campus next to the Miramare castle and its park, co-hosted by SISSA, the International School for Advanced Studies, and ICTP, the Abdus Salam International Centre for Theoretical Physics. Alessandro Treves (SISSA) was the head and inspiration of the Local Organizing committee, supported by P. Battaglini, L. Chelazzi, M. Diamond and G. Vallortigara. All approaches relating brain and behaviour were represented at the meeting, which aimed to further expand the wide spectrum of previous EBBS AGMs, and to bring together integrative, system, cognitive, computational neuroscientists. See also the societies home page: http://www.ebbs-science.org/.

Line attractor networks have become standard workhorses of computational accounts of neural population processing for optimal perceptual inference, working memory, decision making and more. Such networks are defined by possessing a one(line) or multi-dimensional (surface) manifold in the high dimensional space of the activities of all the neurons in the net, to a point on which the state of the network is projected in a non-linear manner by the network’s dynamics. The standard view that the network represents information by the location of the point on this manifold at which it sits [1] is only appropriate if the computation to be performed by the network is aligned with the underlying symmetry implied by the manifold. In interesting cases, the computation that must be performed is orthogonal to this symmetry structure, and so an alternative computational view is required. Here, we illustrate the problem using a well-studied visual hyperacuity task, and suggest solutions involving different classes of computations during the network’s transient evolution.

Mechanisms and neuropharmacology of visual attention in the primate

Recent experimental studies have focused on the specialization of different neural structures for different types of instrumental behavior. Recent theoretical work has provided normative accounts for why there should be more than one control system, and how the output of different controllers can be integrated. Two particlar controllers have been identified, one associated with a forward model and the prefrontal cortex and a second associated with computationally simpler, habitual, actor-critic methods and part of the striatum. We argue here for the normative appropriateness of an additional, but so far marginalized control system, associated with episodic memory, and involving the hippocampus and medial temporal cortices. We analyze in depth a class of simple environments to show that episodic control should be useful in a range of cases characterized by complexity and inferential noise, and most particularly at the very early stages of learning, long before habitization has set in. We interpret data on the transfer of control from the hippocampus to the striatum in the light of this hypothesis.

Introduction. Theories of delusions often underplay the role of their content. With respect to persecutory delusions, taking threat as fundamental suggests that models of threat-related, aversive learning, such as the Conditioned Avoidance Response (CAR) task, might offer valid insights into the underlying normal and abnormal processes. In this study, we reappraise the psychological significance of the CAR model of antipsychotic drug action; and we relate this to contemporary psychological theories of paranoia. Methods. Review and synthesis of literature. Results. Anticipation and recall of aversive events are abnormally accentuated in paranoia. Safety (avoidance) behaviours may help perpetuate and fix persecutory ideas by preventing their disconfirmation. In addition, patients may explain negative events in a paranoid way instead of making negative self-attributions (i.e., in an attempt to maintain self-esteem). This defensive function only predominates in the overtly psychotic patients. The “safety behaviours” of paranoid patients, their avoidance of negative self-attributions, and the antiparanoid effect of antipsychotic medication all resonate with aspects of the CAR. Conclusions. The CAR appears to activate some normal psychological and biological processes that are pathologically activated in paranoid psychosis. Paranoid psychological defences may be a result of basic aversive learning mechanisms, which are accentuated during acute psychosis.

Persecutory delusions and the conditioned avoidance paradigm: Towards an integration of the psychology and biology of paranoia

Studies on human monetary prediction and decision making emphasize the role of the striatum in encoding prediction errors for financial reward. However, less is known about how the brain encodes financial loss. Using Pavlovian conditioning of visual cues to outcomes that simultaneously incorporate the chance of financial reward and loss, we show that striatal activation reflects positively signed prediction errors for both. Furthermore, we show functional segregation within the striatum, with more anterior regions showing relative selectivity for rewards and more posterior regions for losses. These findings mirror the anteroposterior valence-specific gradient reported in rodents and endorse the role of the striatum in aversive motivational learning about financial losses, illustrating functional and anatomical consistencies with primary aversive outcomes such as pain.

Computational Models of Aversive Processing: Serotonin, Dopamine and Stress

Tonic dopamine: opportunity costs and the control of response vigor

Uncertainty coming from the noise in its neurons and the ill-posed nature of many tasks plagues neural computations. Maybe surprisingly, many studies show that the brain manipulates these forms of uncertainty in a probabilistically consistent and normative manner, and there is now a rich theoretical literature on the capabilities of populations of neurons to implement computations in the face of uncertainty. However, one major facet of uncertainty has received comparatively little attention: time. In a dynamic, rapidly changing world, data are only temporarily relevant. Here, we analyze the computational consequences of encoding stimulus trajectories in populations of neurons. For the most obvious, simple, instantaneous encoder, the correlations induced by natural, smooth stimuli engender a decoder that requires access to information that is nonlocal both in time and across neurons. This formally amounts to a ruinous representation. We show that there is an alternative encoder that is computationally and representationally powerful in which each spike contributes independent information; it is independently decodable, in other words. We suggest this as an appropriate foundation for understanding time-varying population codes. Furthermore, we show how adaptation to temporal stimulus statistics emerges directly from the demands of simple decoding.

David Marr famously enjoined (theoretical) psychologists and neuroscientists to think about the computational structures of the tasks whose behavioural and neural underpinning they were studying. Since essentially all the tasks these investigtors consider, be they sensory, motor or cognitive, involve hosts of uncertainties coming from external and internal noise and ignorance, these computational structures have probability and statistics at their very hearts. Bayes theorem is just a simple identity in basic probability theory; however, by providing a foundational probabilistic pedestal, it has acquired a significance and notoriety for modelling well beyond its surface importance. This is as true for machine learning, artificial intelligence, robotics and the like as theoretical neuroscience, thus there are rich potential and actual interdisciplinary links among approaches, methods and ideas. Further, uncertainties, albeit of rather different sorts, also plague the analysis of neural data. Thus, again, Bayesian methods have an important part to play in our budding understanding of neural coding, and ways of treating experimental observations of neural activity, including spikes, local field potentials, and functional magnetic resonance images (fMRI). This edited volume contains contributions from many top experts across the range of Bayesian approaches to both these classes of problems. Bayes theorem requires us to perform inference about an unknown quantity by combining prior expectations together with something called the likelihood, and then renormalizing to give the posterior. The likelihood quantifies the relationship between the unknown and the observed data; the posterior is a distribution that describes the remaining uncertainty about the unknown variable. Adherents of Bayesian principles take decisions by calculating the losses (or, if they are more optimistic than the median statistician, gains) they expect to accrue, based on this posterior distribution. As is well-aired in this volume, Bayesian notions also apply in dynamic domains, in which the unknown quantity and information about it both evolve over time. In this case, it is possible to generate predictive posterior distributions that capture expectations about future states.

Humans can be instructed verbally to perform computationally complex cognitive tasks; their performance then improves relatively slowly over the course of practice. Many skills underlie these abilities; in this paper, we focus on the particular question of a uniform architecture for the instantiation of habitual performance and the storage, recall, and execution of simple rules. Our account builds on models of gated working memory, and involves a bilinear architecture for representing conditional input-output maps and for matching rules to the state of the input and working memory. We demonstrate the performance of our model on two paradigmatic tasks used to investigate prefrontal and basal ganglia function.

The mammalian brain possesses multiple memory systems, including the striatum, the locus of procedural memories underlying habits, the neocortex, the main site for long-term general perceptual and semantic knowledge, and the hippocampus, the area largely responsible for storing and processing specific autobiographical memories [1,2]. These three systems and their interactions have been extensively studied, both empirically [3] and theoretically [4], but their collective roles in guiding optimal behavior have only rarely been addressed [5]. The contribution of episodic memory is particularly mysterious. Here, we develop a normative framework of control in the face of uncertainty, in which each plays a precisely delineated part.

A novel method for spike and other waveforms in the EEG based on independent component analysis (ICA) and a quadratic classifier

Contents: Foreword, with apologies Translating the raindrop A sermon on the violin Baudelaire's Wagner: the indescribable, the untranslatable, the inaudible Keeping the voice of the nightingale alive in the age of mechanical reproduction On the evidence of Mallarme's music How music enables Proust to write paradise lost 'Song must write': Roland Barthes's hallucinations 'Sing me a song to make death tolerable': music in mourning for Derrida Conclusion Bibliography Index.

Reinforcement learning is one of the means by which animals and artificial systems can learn to optimize their behaviour in the face of rewards and punishments. Reinforcement learning algorithms have been developed that are closely related to methods of dynamic programming, which is a general approach to optimal control. Reinforcement learning phenomena have been observed in psychological studies of animal behaviour, and in neurobiological investigations of neuromodulation and addiction. 
 
Keywords: 
 
dynamic programming; 
value function; 
policy; 
actor–critic; 
Q-learning

Despite their epidemiological importance, psychiatric diseases are only poorly understood. Nevertheless, judging by the efficacy of pharmacological treatments, most appear to involve characteristic dysfunctions of the dopaminergic (DA), serotonergic (5HT) and/or noradrenergic neuromodulatory systems that are the foci of intense computational neuroscience studies. We seek to use this tie to provide a link from normative neuromodulatory models to psychiatric dysfunction, here in particular in the context of extensively validated animal models of depression.

Dopamine modulation in the basal ganglia locks the gate to working memory

Many different varieties of modeling coexist in theoretical neuroscience. Here, we consider the positive and negative implications, for theories of schizophrenia, of a crucial distinction between computational and mathematical modeling.

Electroencephalogram is a complex signal which, until now, has required expert human visual analysis to be used as a medical diagnostic test. An efficient method for automated analysis would provide substantial time saving in practice. A new approach for the automatic detection of epileptic activity in the form of spike and sharp waves in EEG recordings is presented. It comprises feature extraction derived from Independent Component Analysis and a quadratic classifier. Optimisation with respect to correction for eyeblinks and occipital alpha rhythm was cross-evaluated on sharp and spike waves from 7 EEG recordings of total duration 123 minutes previously labelled by an expert. With a training set discrimination threshold of 70%, the sensitivity was 64.1% with 36.1 false positives per minute. After correction for eyeblinks and occipital alpha, sensitivity and false positives reduced to 64% and 59% and 29.7 and 16.6 per min, respectively. Optimisation is still in development; planned improvements include consideration of spatial patterning of epileptic activity and correction for other background activity and artefacts.

The Classification of Spikes in EEG Recordings using Features Derived from ICA

malignant evaluation :: reinforcement learning, neuromodulation and depression

Extensive animal studies indicate that the neuromodulator norepinephrine plays an important role in specific aspects of vigilance, attention and learning, putatively serving as a neural interrupt or reset function. The activity of norepinephrine-releasing neurons in the locus coeruleus during attentional tasks is modulated not only by the animal's level of engagement and the sensory inputs, but also by temporally rich aspects of internal decision-making processes. Here, we propose that it is unexpected changes in the world within the context of a task that activate the noradrenergic interrupt signal. We quantify this idea in a Bayesian model of a well-studied visual discrimination task, demonstrating that the model captures a rich repertoire of noradrenergic responses at the sub-second temporal resolution.

Phasic norepinephrine: A neural interrupt signal for unexpected events

Many neural areas, notably, the hippocampus, show structured, dynamical, population behavior such as coordinated oscillations. It has long been observed that such oscillations provide a substrate for representing analog information in the firing phases of neurons relative to the underlying population rhythm. However, it has become increasingly clear that it is essential for neural populations to represent uncertainty about the information they capture, and the substantial recent work on neural codes for uncertainty has omitted any analysis of oscillatory systems. Here, we observe that, since neurons in an oscillatory network need not only fire once in each cycle (or even at all), uncertainty about the analog quantities each neuron represents by its firing phase might naturally be reported through the degree of concentration of the spikes that it fires. We apply this theory to memory in a model of oscillatory associative recall in hippocampal area CA3. Although it is not well treated in the literature, representing and manipulating uncertainty is fundamental to competent memory; our theory enables us to view CA3 as an effective uncertainty-aware, retrieval system.

P04.6 Detection of spikes in EEG recordings using features derived from ICA

Abstract The representation of hierarchically structured knowledge in systems using distributed patterns of activity is an abiding concern for the connectionist solution of cognitively rich problems. Here, we use statistical unsupervised learning to consider semantic aspects of structured knowledge representation. We meld unsupervised learning notions formulated for multilinear models with tensor product ideas for representing rich information. We apply the model to images of faces.

Decisional conflicts abound in sensory processing and perce tual decision-making, and they arise from diverse sources . These conflicts can result directly from conflicting informa tion in the sensory inputs themselves – such as conflicts between modalities in the Stroop task, between spatially ad jacent stimuli in the Eriksen task, or between the eyes in the binocular rivalry task. Another class of conflicts is mor e indirect, as when there are multiple, conflicting interpre tations consistent with the same sensory-evoked neural inp uts. Examples of this latter type include multi-stable visu al displays, and contexts in which the semantical relationshi p among sensory objects are non-stationary over time.

A Bayesian View of Sensory Conflicts in Decision-Making March 3 , 2006 1 Introduction

How motivation influences habitual behavior is unclear, since only motivational decrements have been considered. Here, in two experiments, we investigated the effects of motivational up-shifts and side-shifts on instrumental behavior which was extensively trained using a protocol known to promote habitual responding. In Experiment 1, hungry rats were trained to lever press for sucrose solution. Following a side-shift from foodto water-deprivation, rats showed less lever pressing in extinction compared to non-shifted controls, although a subsequent consumption test found no differences in sucrose consumption between thirsty and hungry groups. In Experiment 2, undeprived rats were trained to lever press for either sucrose solution or sucrose pellets. A post-training up-shift from satiety to water-deprivation did not affect lever pressing in extinction, regardless of outcome identity, although free consumption of sucrose solution, but not of pellets, was enhanced. Together, these results suggest that motivation affects extensively-trained instrumental behavior through a combination of general drive and generalization decrement, but not through determining the value

Gaussian scale mixture models offer a top-down description of signal generation that captures key bottom-up statistical characteristics of filter responses to images. However, the pattern of dependence among the filters for this class of models is prespecified. We propose a novel extension to the gaussian scale mixturemodel that learns the pattern of dependence from observed inputs and thereby induces a hierarchical representation of these inputs. Specifically, we propose that inputs are generated by gaussian variables (modeling local filter structure), multiplied by a mixer variable that is assigned probabilistically to each input from a set of possible mixers. We demonstrate inference of both components of the generative model, for synthesized data and for different classes of natural images, such as a generic ensemble and faces. For natural images, the mixer variable assignments show invariances resembling those of complex cells in visual cortex; the statistics of the gaussian components of the model are in accord with the outputs of divisive normalization models. We also show how our model helps interrelate a wide range of models of image statistics and cortical processing.

Soft Mixer Assignment in a Hierarchical Generative Model of Natural Scene Statistics

The effects of motivation on rates of responding: A reinforcement learning approach

Uncertainty-based competition between prefrontal and striatal systems for behavioural control

Representational pursuit: Population codes for dynamic environments

Cholinergic contribution to attentional effects in v1 neurons of the macaque monkey

Experimental data indicate that norepinephrine is critically involved in aspects of vigilance and attention. Previously, we considered the function of this neuromodulatory system on a time scale of minutes and longer, and suggested that it signals global uncertainty arising from gross changes in environmental contingencies. However, norepinephrine is also known to be activated phasically by familiar stimuli in well-learned tasks. Here, we extend our uncertainty-based treatment of norepinephrine to this phasic mode, proposing that it is involved in the detection and reaction to state uncertainty within a task. This role of norepinephrine can be understood through the metaphor of neural interrupts.

This work is about interactions between facilitation and inhibition of behavioural responses. Generally, rewards elicit approach and are associated with facilitation of responses, whereas punishments elicit avoidance and inhibit behavioural responses other than fight or flight. Dopamine (DA) and serotonine (5HT) have been widely associated with respectively facilitatory and inhibitory regulation of behaviour, or approach and withdrawal. Dopamine facilitates action (drive effect), and reinforces action-outcome, stimulus-outcome and stimulus-response associations (learning effect). Serotonin generally inhibits reward-related responding, but can also facilitate it ; there being at least 14 subtypes of serotonin receptors allows for a vast range of complementary (and sometimes seemingly contradictory) effects. Serotonin and dopamine interact at the level of their numerous shared target areas in the brain, and serotonin also regulate dopamine at the level of cell bodies. The ambiguous influence of serotonin on the dopaminergic system parallels its effects on behaviour ; that is, generally inhibitory but sometimes excitatory. Punishment provides a context of increased interactions between approach and withdrawal, as well as serotonin and dopamine. Therefore, studying what happens during punishment can provide insight on the general meaning of these interactions. Here, we provide a model of behaviour during punishment and propose an interpretation in terms of neuromodulators. The core of the model is the hypothesis that the best way to cope during punishment is to dampen most rewards, while overemphasizing the effect of the spared ones ; coping strategies would thus be better implemented and learnt. Dopamine is attributed its usual facilitatory role on action, and serotonin is pictured as regulating approach and inhibition on a higher hierarchical level by carving dopamine function.

RAPPORT DE STAGE D'OPTION SCIENTIFIQUE Rewards, Punishment and the Brain

Uncertainty-based competition between prefrontal and dorsolateral striatal systems for behavioral control

Attention-deficit/hyperactivity disorder (ADHD) affects up to 10% of school-age children. The impulsivity which is seen as its core feature persists over years, yet experimental measures of impulsivity can be altered in a single session. In this study, we tested the theory that both the persistence and the variability of impulsivity could be the result of abnormalities in learning mechanisms and environment.

METHOD
We extended an existing model of the role of dopamine in operant conditioning to address the delayed response time task, which is one of the standard tests for impulsivity in ADHD. In this task, subjects choose between immediate responding for a small reinforcer and later responding for a larger one. We studied the influence on impulsivity of four key parameters of the model: The learning rate, discount factor, brittleness, and action bias.

RESULTS
The behavior of the model is broadly comparable with electrophysiological (monkey) and behavioral (ADHD and normal) data. Variations in any of the parameters can cause impulsivity. All parameters except the discount factor show inverted U-shaped curves for their effects on impulsivity, suggesting, for example, how either hyper- or hypofunctioning of dopamine can cause impulsivity. The model suggests how decision making can be affected by environmental unpredictability, and thus offers an account of one aspect of the natural history of ADHD.

Some types of ADHD may be caused by specific deficits in reinforcement learning and in the use of learned lessons. Environmental factors can interact with these deficits to delay maturation.

Dopamine, learning, and impulsivity: a biological account of attention-deficit/hyperactivity disorder.

The misjudgement of tilt in images lies at the heart of entertaining visual illusions and rigorous perceptual psychophysics. A wealth of findings has attracted many mechanistic models, but few clear computational principles. We adopt a Bayesian approach to perceptual tilt estimation, showing how a smoothness prior offers a powerful way of addressing much confusing data. In particular, we faithfully model recent results showing that confidence in estimation can be systematically affected by the same aspects of images that affect bias. Confidence is central to Bayesian modeling approaches, and is applicable in many other perceptual domains.

'Waking the face that no one is': A study in the musical context of symbolist poetics.

Reinforcement learning models have long promised to unify computational, psychological and neural accounts of appetitively conditioned behavior. However, the bulk of data on animal conditioning comes from free-operant experiments measuring how fast animals will work for reinforcement. Existing reinforcement learning (RL) models are silent about these tasks, because they lack any notion of vigor. They thus fail to address the simple observation that hungrier animals will work harder for food, as well as stranger facts such as their sometimes greater productivity even when working for irrelevant outcomes such as water. Here, we develop an RL framework for free-operant behavior, suggesting that subjects choose how vigorously to perform selected actions by optimally balancing the costs and benefits of quick responding. Motivational states such as hunger shift these factors, skewing the tradeoff. This accounts normatively for the effects of motivation on response rates, as well as many other classic findings. Finally, we suggest that tonic levels of dopamine may be involved in the computation linking motivational state to optimal responding, thereby explaining the complex vigor-related effects of pharmacological manipulation of dopamine.

Decision making in an uncertain environment poses a conflict between the opposing demands of gathering and exploiting information. In a classic illustration of this " exploration-exploitation " dilemma 1 , a gambler must balance the desire to select what appears the richest option on the basis of accumulated experience, against the desire to choose a less familiar but potentially more advantageous option. Substantial neural, behavioral and computational evidence suggests a dopaminergic/striatal network mediates learning to exploit. However, the neural and computational substrates of exploration, a key and computationally challenging aspect of behavioral flexibility, are less clear. In a human gambling task, we show that subjects' choices can be characterized by an approximate solution to the dilemma that is well studied in the computational literature. Furthermore, by using this computational model to classify decisions as exploratory or exploitative, we show that an area of the frontopolar cortex is differentially active during exploratory decisions. In contrast, striatal and more medial-caudal prefrontal regions exhibit activity characteristic of an involvement in value-based decision making. The results suggest a model of action selection under uncertainty that involves switching between exploratory and exploitative behavioral modes, and indicate a computationally precise regulatory role for frontopolar cortex in exploration. Much is known about exploitative aspects of appetitive choice, particularly in the mammalian brain. A wealth of studies suggest the involvement of two systems: the striatum 2–6 and particularly its dopaminergic innervation 7,8 , which learns the utilities of actions, and expresses habits 9 ; and various regions of prefrontal cortex, which are associated with more reflective planning 10. Substantial reinforcement learning 11 (RL) theory, including the temporal difference algorithm (TD) underpins both the nature 7,8 and the interaction 12 of these systems. However, this knowledge sheds little light on one of the most pervasive characteristics of adaptive behavior, namely a proclivity to explore. Far from representing idle curiosity, exploration is critical for animals to discover how best to harvest resources, such as food or water, in an unknown and dynamic environment. Although well studied both ecologically 13 and theoretically 1 , the neural mechanisms that underpin exploratory action are far from clear. Exploration is an informationally and computationally refined capacity that demands careful regulation. On this basis we can conjecture an involvement of areas that influence and modulate the reflective planning system, notably regions in the anterior prefrontal cortex, including the frontal pole. However, little is so far …

Polar exploration : An anterior prefrontal substrate for exploratory decisions in humans

Matching storage and recall: hippocampal spike timing–dependent plasticity and phase response curves

This article sets out to examine what Debussy wrote about music in the light of the discourse on music, literature, and nature that Debussy knew from contemporary literature. It becomes apparent that Debussy shares with, for example, MallarmŽ a refusal to consider that his work renders natural scenes present. Indeed, he rejects entirely the notion that music can or should represent anything (when it appears to represent, it is, precisely, not music). Debussy accordingly despises programs and critics who look in his music for images or ideas that they expect him to have put there.
Why, then, does he give his pieces programmatic titles? And how is one to understand the relationship between words and music, for example, in PellŽas et MŽlisande? The answer emerges from an analysis of the special relationship that Debussy constructs between music and nature. On the one hand, Debussy tells us that "art is the most beautiful of lies"; accordingly, music never tells us any specific articulated truth about nature. On the other hand, the dynamics of our perception of nature, in which we see through specific features, as poetry might articulate them, to an inexpressible totality, a "mouvement total de la nature," is the best analogue for the process of musical creation, which traverses sense toward an ideal unity beyond the articulation of meaning. Our duty, then, would be to look past the expression of the words associated with Debussy9s music, not to find in the music an extension or repetition of the words9 meaning, but to sense, between as well as beyond them, an echo of that ideal unity.

The basal ganglia are widely believed to be involved in the learned selection of actions. Building on this idea, reinforcement learning (RL) theories of optimal control have had some success in explaining the responses of their key dopaminergic afferents. While these model-free RL theories offer a compelling account of a range of neurophysiological and behavioural data, they offer only an incomplete picture of action control in the brain. Psychologists and behavioural neuroscientists have long appealed to the existence of at least two separate control systems underlying the learned control of behaviour. The habit system is closely identified with the basal ganglia, and we associate it with the model-free RL theories. The other system, more loosely localised in prefrontal regions and without such a detailed theoretical account, is associated with cognitively more sophisticated goal-directed actions. On the critical issue of which system determines the ultimate output when they disagree, there is a wide range of experimental results and sparse theoretical underpinning. Here, we extend the RL account of neural action control by first interpreting goal-directed actions in terms of an alternative model-based strategy for RL. Then, by considering the relative uncertainties of modelfree and model-based controllers, we offer a new and more comprehensive account of the confusing experimental results about how the systems trade off control. Our theory offers a more sharply delineated view of the contributions of the basal ganglia to learned behavioural control.

This article sets out to examine what Debussy wrote about music in the light of the discourse on music, literature, and nature that Debussy knew from contemporary literature. It becomes apparent that Debussy shares with, for example, Mallarmé a refusal to consider that his work renders natural scenes present. Indeed, he rejects entirely the notion that This content downloaded from 129.215.149.97 on Mon, 2 Sep 2013 04:58:37 AM All use subject to JSTOR Terms and Conditions 229 PETER DAYAN Meaning in Debussy’s Writing music can or should represent anything (when it appears to represent, it is, precisely, not music). Debussy accordingly despises programs and critics who look in his music for images or ideas that they expect him to have put there. Why, then, does he give his pieces programmatic titles? And how is one to understand the relationship between words and music, for example, in Pelléas et Mélisande? The answer emerges from an analysis of the special relationship that Debussy constructs between music and nature. On the one hand, Debussy tells us that “art is the most beautiful of lies”; accordingly, music never tells us any specific articulated truth about nature. On the other hand, the dynamics of our perception of nature, in which we see through specific features, as poetry might articulate them, to an inexpressible totality, a “mouvement total de la nature,” is the best analogue for the process of musical creation, which traverses sense toward an ideal unity beyond the articulation of meaning. Our duty, then, would be to look past the expression of the words associated with Debussy’s music, not to find in the music an extension or repetition of the words’ meaning, but to sense, between as well as beyond them, an echo of

Edinburgh Research Explorer Nature, music, and meaning in Debussy's writings

There is something rotten in the state of current reinforcement learning models of conditioning. Most experiments report measures such as the rate of responding given the state of the subject and the configuration of the environment. There is even further sub-structure in the temporal organisation of responses, which includes effects associated with the expected timing of forthcoming rewards[1]. However, current theoretical treatments are largely restricted to choices between discrete actions, and are silent about rates or any other aspect of action at a temporal fine scale. This lacuna is brought into sharp relief by current work on the effects of motivation on reinforcement learning, since 'energizing', one of two main motivational effects, is exactly concerned with modulations in the vigour of prepotent responses, and thus changes in rates. Furthermore, dopamine, the golden-haired neurochemical of reinforcement learning, has been directly implicated in these energizing motivational effects[2]. Here, we use data collected from experiments into both energizing, and motivation's other main effect ('directing' behavior, by altering the structure of subjects' goals) to investigate the influence of motivation on free-operant instrumental behavior in detail, in order to propose a reinforcement learning model of rates of responding.

Motivational effects on behavior: Towards a reinforcement learning model of rates of responding

Matching storage and recall: constructing optimal rate and phase-coded autoassociative memories

Matching storage and recall for rate- and phase-based autoassociative memories

Substantial evidence suggests that the phasic activities of dopaminergic neurons in the primate midbrain represent a temporal difference (TD) error in predictions of future reward, with increases above and decreases below baseline consequent on positive and negative prediction errors, respectively. However, dopamine cells have very low baseline activity, which implies that the representation of these two sorts of error is asymmetric. We explore the implications of this seemingly innocuous asymmetry for the interpretation of dopaminergic firing patterns in experiments with probabilistic rewards which bring about persistent prediction errors. In particular, we show that when averaging the non-stationary prediction errors across trials, a ramping in the activity of the dopamine neurons should be apparent, whose magnitude is dependent on the learning rate. This exact phenomenon was observed in a recent experiment, though being interpreted there in antipodal terms as a within-trial encoding

We study the synthesis of neural coding, selective attention and perceptual decision making. A hierarchical neural architecture is proposed, which implements Bayesian integration of noisy sensory input and top-down attentional priors, leading to sound perceptual discrimination. The model offers an explicit explanation for the experimentally observed modulation that prior information in one stimulus feature (location) can have on an independent feature (orientation). The network's intermediate levels of representation instantiate known physiological properties of visual cortical neurons. The model also illustrates a possible reconciliation of cortical and neuromodulatory representations of uncertainty.

Inference, Attention, and Decision in a Bayesian Neural Architecture

Daubenton’s bats Myotis daubentoni (Chiroptera: Vespertilionidae). J. Zool. 215, 113–132 (1988). 15. Krull, D., Schumm, A., Metzner, W. & Neuweiler, G. Foraging areas and foraging behavior in the notch-eared bat, Myotis emarginatus (Vespertilionidae). Behav. Ecol. Sociobiol. 28, 247–253 (1991). 16. Schumm, A., Krull, D. & Neuweiler, G. Echolocation in the notch-eared bat, Myotis emarginatus. Behav. Ecol. Sociobiol. 28, 255–261 (1991). 17. Britton, A. R. C., Jones, G., Rayner, J. M. V., Boonman, A. M. & Verboom, B. Flight performance, echolocation and foraging behaviour in pond bats, Myotis dasycneme (Chiroptera: Vespertilionidae). J. Zool. 241, 503–522 (1997). 18. Siemers, B. M. & Schnitzler, H.-U. Natterer’s bat (Myotis nattereri Kuhl, 1818) hawks for prey close to vegetation using echolocation signals of very broad bandwidth. Behav. Ecol. Sociobiol. 47, 400–412 (2000). 19. Swift, S. M. & Racey, P. A. Gleaning as a foraging strategy in Natterer’s bat Myotis nattereri. Behav. Ecol. Sociobiol. 52, 408–416 (2002). 20. Fenton, M. B. & Bogdanowicz, W. Relationships between external morphology and foraging behaviour: bats in the genus Myotis. Can. J. Zool. 80, 1004–1013 (2002). 21. Arlettaz, R., Jones, G. & Racey, P. A. Effect of acoustic clutter on prey detection by bats. Nature 414, 742–745 (2001). 22. Siemers, B. M., Stilz, P. & Schnitzler, H.-U. The acoustic advantage of hunting at low heights above water: behavioural experiments on the European ’trawling’ bats Myotis capaccinii, M. dasycneme and M. daubentonii. J. Exp. Biol. 204, 3843–3854 (2001). 23. Harvey, P. H. & Pagel, M. D. The Comparative Method in Evolutionary Biology 138–162 (Oxford Univ. Press, Oxford, 1991). 24. Ruedi, M. & Mayer, F. Molecular systematics of bats of the genus Myotis (Vespertilionidae) suggests deterministic ecomorphological convergences. Mol. Phyl. Evol. 21, 436–448 (2001). 25. Simmons, J. A. & Stein, R. A. Acoustic imaging in bat sonar: Echolocation signals and the evolution of echolocation. J. Comp. Physiol. A 135, 61–84 (1980). 26. von Helversen, O. & von Helversen, D. Acoustic guide in bat pollinated flower. Nature 398, 759–760 (1999). 27. Schmidt, S., Hanke, S. & Pillat, J. The role of echolocation in the hunting of terrestrial prey—new evidence for an underestimated strategy in the gleaning bat, Megaderma lyra. J. Comp. Physiol. A 186, 975–988 (2000). 28. Morse, P. M. & Ingard, K. U. Theoretical Acoustics (Princeton Univ. Press, Princeton, 1986). 29. Kingston, T., Jones, G., Akbar, Z. & Kunz, T. H. Echolocation signal design in Kerivoulinae and Murinae (Chiroptera: Vespertilionidae) from Malaysia. J. Zool. 249, 359–374 (1999). 30. Müller, R. & Kuc, R. Foliage echoes: A probe into the ecological acoustics of bat echolocation. J. Acoust. Soc. Am. 108, 836–845 (2000).

Metabolic network analysis of the causes and evolution of enzyme dispensability in yeast

Instrumental conditioning studies how animals and humans choose actions appropriate to the affective structure of an environment. According to recent reinforcement learning models, two distinct components are involved: a “critic,” which learns to predict future reward, and an “actor,” which maintains information about the rewarding outcomes of actions to enable better ones to be chosen more frequently. We scanned human participants with functional magnetic resonance imaging while they engaged in instrumental conditioning. Our results suggest partly dissociable contributions of the ventral and dorsal striatum, with the former corresponding to the critic and the latter corresponding to the actor.

Dissociable Roles of Ventral and Dorsal Striatum in Instrumental Conditioning

David Arnosti, East Lansing, Mich. Spyros Artavanis-Tsakonas, Charlestown, Mass. Jayanth Banavar, University Park, Tex. Albert-Lázló Barabási, Notre Dame, Ind. Michel Bauer, Gif-sur-Yvette Aviv Bergman, Bronx, N.Y. Denis Bernard, Gif-sur-Yvette Roman Borisyuk, Plymouth Paul Bourgine, Paris Spencer Brown, Gif-sur-Yvette Mark Buchanan, Livarot Georg Casari, Heidelberg Didier Chatenay, Strasbourg Irun R. Cohen, Rehovot Garry Corthals, Genève Christoph Cremer, Heidelberg Peter Dayan, London Paolo De Los Rios, Lausanne Jacques M. Deshusses, Geneva Ken A. Dill, San Francisco, Calif. Jean-Pierre Dupuy, Paris Albert Goldbeter, Brussels François Gros, Paris Rainer Heintzmann, Göttingen Denis F. Hochstrasser, Genève

As animals interact with their environments, they must constantly update estimates about their states. Bayesian models combine prior probabilities, a dynamical model and sensory evidence to update estimates optimally. These models are consistent with the results of many diverse psychophysical studies. However, little is known about the neural representation and manipulation of such Bayesian information, particularly in populations of spiking neurons. We consider this issue, suggesting a model based on standard neural architecture and activations. We illustrate the approach on a simple random walk example, and apply it to a sensorimotor integration task that provides a particularly compelling example of dynamic probabilistic computation.

Expected and unexpected uncertainties control allocation of attention in a novel attentional learning task.

A review of "On Intelligence", a book exploring brain function by entrepreneur Jeff Hawkins and science writer Sandra Blakeslee

The disenchanted lyre: musical instruments and the human voice in 19th century French literature

Rate- and phase-coded autoassociative memories: Bayesian inference

In the analysis of natural images, Gaussian scale mixtures (GSM) have been used to account for the statistics of filter responses, and to inspire hierarchical cortical representational learning schemes. GSMs pose a critical assignment problem, working out which filter responses were generated by a common multiplicative factor. We present a new approach to solving this assignment problem through a probabilistic extension to the basic GSM, and show how to perform inference in the model using Gibbs sampling. We demonstrate the efficacy of the approach on both synthetic and image data.

Areas of the brain involved in various forms of memory exhibit patterns of neural activity quite unlike those in canonical computational models. We show how to use well-founded Bayesian probabilistic autoassociative recall to derive biologically reasonable neuronal dynamics in recurrently coupled models, together with appropriate values for parameters such as the membrane time constant and inhibition. We explicitly treat two cases. One arises from a standard Hebbian learning rule, and involves activity patterns that are coded by graded firing rates. The other arises from a spike timing dependent learning rule, and involves patterns coded by the phase of spike times relative to a coherent local field potential oscillation. Our model offers a new and more complete understanding of how neural dynamics may support autoassociation.

Temporal difference models describe higher-order learning in humans

Off-line replay maintains declarative memories in a model of hippocampal-neocortical interactions

Dopamine Modulation in a Basal Ganglio-Cortical Network of Working Memory

Residual micro-saccades, tremor and fixation errors imply that, on different trials in visual tasks, stimulus arrays are inevitably presented at different positions on the retina. Positional variation is likely to be specially important for tasks involving visual hyperacuity, because of the severe demands that these tasks impose on spatial resolution. In this paper, we show that small positional variations lead to a structural change in the nature of the ideal observer's solution to a hyperacuity-like visual discrimination task such that the optimal discriminator depends quadratically rather than linearly on noisy neural activities. Motivated by recurrent models of early visual processing, we show how a recurrent preprocessor of the noisy activities can produce outputs which, when passed through a linear discriminator, lead to better discrimination even when the positional variations are much larger than the threshold acuity of the task. Since, psychophysically, hyperacuity typically improves greatly over the course of perceptual learning, we discuss our model in the light of results on the speed and nature of learning.

Nonlinear ideal observation and recurrent preprocessing in perceptual learning.

Despite strong implication of the neuromodulators acetylcholine (ACh) and norepinephrine (NE) in cognitive tasks, there is little consensus on their computational functions. We propose that they report uncertainties: ACh signals expected uncertainty, coming from known variability within a context; NE signals unexpected uncertainty, as when the environment is dramatically changed. We apply these ideas to a novel attention task, which allows explicit manipulation of expected and unexpected uncertainties. In our model, ACh and NE interact in a precisely specified and part-opponent, part-synergistic manner. Simulation results replicate existent data, and make experimentally tractable predictions regarding neuronal responses and certain psychophysical measures.

Temporal Difference Models and Reward-Related Learning in the Human Brain

Dopamine exerts two classes of effect on the sustained neural activity in prefrontal cortex that underlies working memory. Direct release in the cortex increases the contrast of prefrontal neurons, enhancing the robustness of storage. Release of dopamine in the striatum is associated with salient stimuli and makes medium spiny neurons bistable; this modulation of the output of spiny neurons affects prefrontal cortex so as to indirectly gate access to working memory and additionally damp sensitivity to noise. Existing models have treated dopamine in one or other structure, or have addressed basal ganglia gating of working memory exclusive of dopamine effects. In this paper we combine these mechanisms and explore their joint effect. We model a memory-guided saccade task to illustrate how dopamine's actions lead to working memory that is selective for salient input and has increased robustness to distraction.

Dopamine Modulation in a Basal Ganglio-cortical Network Implements Saliency-based Gating of Working Memory

In the vertebrate nervous system, sensory stimuli are typically encoded through the concerted activity of large populations of neurons. Classically, these patterns of activity have been treated as encoding the value of the stimulus (e.g., the orientation of a contour), and computation has been formalized in terms of function approximation. More recently, there have been several suggestions that neural computation is akin to a Bayesian inference process, with population activity patterns representing uncertainty about stimuli in the form of probability distributions (e.g., the probability density function over the orientation of a contour). This paper reviews both approaches, with a particular emphasis on the latter, which we see as a very promising framework for future modeling and experimental work.

It is a commonplace in statistics that uncertainty about parameters drives learning. Indeed one of the most influential models of behavioural learning has uncertainty at its heart. However, many popular theoretical models of learning focus exclusively on error, and ignore uncertainty. Here we review the links between learning and uncertainty from three perspectives: statistical theories such as the Kalman filter, psychological models in which differential attention is paid to stimuli with an effect on the speed of learning associated with those stimuli, and neurobiological data on the influence of the neuromodulators acetylcholine and norepinephrine on learning and inference.

Nonlinear ideal observation and recurrent preprocessing in perceptual learning

Acetylcholine and norepinephrine in concert and opposition: a fresh look at spatial attention

Perceptual inference fundamentally involves uncertainty, arising from noise in sensation and the ill-posed nature of many perceptual problems. Accurate perception requires that this uncertainty be correctly represented, manipulated, and learned about. The choicessubjects makein various psychophysical experiments suggest that they do indeed take such uncertainty into account when making perceptual inferences, posing the question as to how uncertainty is represented in the activities of neuronal populations. Most theoretical investigations of population coding have ignored this issue altogether; the few existing proposals that address it do so in such a way that it is fatally conflated with another facet of perceptual problems that also needs correct handling: multiplicity (that is, the simultaneous presence of multiple distinct stimuli). We present and validate a more powerful proposal for the way that population activity may encode uncertainty, both distinctly from and simultaneously with multiplicity.

Doubly Distributional Population Codes: Simultaneous Representation of Uncertainty and Multiplicity

Computational mysteries surround the kernels relating the magnitude and sign of changes in efficacy as a function of the time difference between pre- and post-synaptic activity at a synapse. One important idea34 is that kernels result from filtering, ie an attempt by synapses to eliminate noise corrupting learning. This idea has hitherto been applied to trace learning rules; we apply it to experimentally-defined kernels, using it to reverse-engineer assumed signal statistics. We also extend it to consider the additional goal for filtering of weighting learning according to statistical surprise, as in the Z-score transform. This provides a fresh view of observed kernels and can lead to different, and more natural, signal statistics.

Graphical Models: Foundations of Neural Computation.Computational Neuroscience. Edited byMichael I Jordanand, Terrence J Sejnowski.A Bradford Book. Cambridge (Massachusetts): MIT Press. $32.95 (paper). xxiv + 421 p; ill.; index. ISBN: 0–262–60042–0. 2001.

Inference and adaptation in noisy and changing, rich sensory environments are rife with a variety of specific sorts of variability. Experimental and theoretical studies suggest that these different forms of variability play different behavioral, neural and computational roles, and may be reported by different (notably neuromodulatory) systems. Here, we refine our previous theory of acetylcholine's role in cortical inference in the (oxymoronic) terms of expected uncertainty, and advocate a theory for norepinephrine in terms of unexpected uncertainty. We suggest that norepinephrine reports the radical divergence of bottom-up inputs from prevailing top-down interpretations, to influence inference and plasticity. We illustrate this proposal using an adaptive factor analysis model.

Expected and Unexpected Uncertainty: ACh and NE in the Neocortex

Adaptation is a ubiquitous neural and psychological phenomenon, with a wealth of instantiations and implications. Although a basic form of plasticity, it has, bar some notable exceptions, attracted computational theory of only one main variety. In this paper, we study adaptation from the perspective of factor analysis, a paradigmatic technique of unsupervised learning. We use factor analysis to re-interpret a standard view of adaptation, and apply our new model to some recent data on adaptation in the domain of face discrimination.

Neural systems are analyzed by building multiple levels of descriptive and explanatory mathematical models. Parallel to these are interpretive computational models, showing how information is represented and manipulated. 
 
Keywords: 
 
reductive models; 
computational models; 
quantitative models

A standard view of memory consolidation is that episodes are stored temporarily in the hippocampus, and are transferred to the neocortex through replay. Various recent experimental challenges to the idea of transfer, particularly for human memory, are forcing its re-evaluation. However, although there is independent neurophysiological evidence for replay, short of transfer, there are few theoretical ideas for what it might be doing. We suggest and demonstrate two important computational roles associated with neocortical indices.

brain report errors in the prediction of reward has been a powerful (though not undisputed) organizing force for a wealth of experimental data (see Schultz et al., 1997; Peter Dayan1,3 and Bernard W. Balleine2,3 Gatsby Computational Neuroscience Unit University College London Schultz, 2002 [this issue of Neuron]; Montague and 17 Queen Square Berns, 2002 [this issue of Neuron]). This theory derives London WC1N 3AR from reinforcement learning (Sutton and Barto, 1998), United Kingdom which shows how a particular form of the error (called 2 Department of Psychology and the temporal difference error) can be used to learn prethe Brain Research Institute dictions of reward delivery and also how the predictions University of California, Los Angeles can be used to learn to choose an adaptive course of Box 951563 action in terms of maximizing reward and minimizing Los Angeles, California 90095 punishment (Houk et al., 1995; Suri and Schultz, 1998, 1999). A popular reinforcement learning model called the actor-critic has been used to offer an account of the There is substantial evidence that dopamine is inmain subdivisions of the midbrain dopamine system. In volved in reward learning and appetitive conditioning. one version of this, the dopamine cells in the ventral However, the major reinforcement learning-based thetegmental area (VTA) and the substantia nigra pars comoretical models of classical conditioning (crudely, prepacta (SNc) report the same prediction error, but turn diction learning) are actually based on rules designed it to two different uses. VTA dopamine cells are associto explain instrumental conditioning (action learning). ated with the critic, controlling the learning of values Extensive anatomical, pharmacological, and psychoheld in the basolateral nucleus of the amygdala and the logical data, particularly concerning the impact of moorbitofrontal cortex. SNc dopamine cells are associated tivational manipulations, show that these models are with the actor, controlling the learning of actions in comunreasonable. We review the data and consider the petitive cortico-striato-thalamo-cortical loops (Alexaninvolvement of a rich collection of different neural sysder and Crutcher, 1990). tems in various aspects of these forms of conditioning. Here, we evaluate the actor-critic model of the dopaDopamine plays a pivotal, but complicated, role. mine system from the perspective of the substantial psychological and neurobiological data on motivation, Behavioral psychologists have long made a set of diswhich is key to the modern view of reward learning. The tinctions between classical/Pavlovian conditioning and actor-critic model can be seen as a particular form of instrumental/operant conditioning. Both forms of condione of the better accepted motivational theories, namely tioning concern the ways that animals learn to predict incentive learning theory (Bindra, 1974, 1978; Bolles, and respond to important events in their environments, 1975; Toates 1986, 1994), in which stimuli associated such as the delivery of appetitive and aversive stimuli with positive reinforcers such as food or water (which (food/water and mild electric shocks, respectively). In are known as Pavlovian excitors) are thought to act classical conditioning, the outcomes are provided whatas conditioned incentives for instrumental conditioning. ever the animals do, and so any changes in behavior This is the conditioned reinforcement effect, that if a rat presumably reflect innately specified reactions to preobserves that a particular light always comes on just dictions of the outcomes. Conversely, in instrumental before it receives some food, it will then learn to press conditioning, whether or not an animal gets a reward or a lever in order to get that light, even if in those learning punishment depends on the actions it performs. Instrutrials no food is provided. Despite this solid foundation, mental conditioning is thus closely related to the engithe actor-critic model fails to take into account large neering theory of optimal control and the computer scibodies of work (recently reviewed from a theoretical ence theory of reinforcement learning, which both study perspective in Berridge, 2001; Dickinson and Balleine, how systems of any sort can choose their actions to 2002) on the many psychological differences between maximize rewards or minimize punishments. The operaPavlovian and instrumental conditioning in terms of motional distinction between classical and instrumental tivational processes and action determination and also conditioning may seem like the sort of thing about which on the neural underpinnings of these differences. only dyed-in-the-wool behaviorists could care. HowThese data, together with those arguing against a ever, critical issues turn on it, such as the organization simple conflation of Pavlovian conditioned responses, of goal-directed behavior and motivational control, e.g., goal-directed instrumental actions, and habitual instruthe way that animals head for water if thirsty but food mental actions, force substantial changes to both asif hungry. In this review, we argue that powerful and pects of the actor-critic model. Most critically, the founpredictive theories of the neural basis of appetitive condations of the relationship between Pavlovian and ditioning have failed to respect important aspects of the instrumental conditioning in the existing dopaminergic distinction and point the way toward their improvement. model are decimated by recent data suggesting that The idea that dopamine cells in the vertebrate midthere are at least two independent, largely anatomically distinct, reward processes, only one of which appears to be sensitive to dopaminergic manipulations. Modifi3 Correspondence: dayan@gatsby.ucl.ac.uk (P.D.), balleine@

C. R. Gallistel and J. Gibbon (2000) presented quantitative data on the speed with which animals acquire behavioral responses during autoshaping, together with a statistical model of learning intended to account for them. Although this model captures the form of the dependencies among critical variables, its detailed predictions are substantially at variance with the data. In the present article, further key data on the speed of acquisition are used to motivate an alternative model of learning, in which animals can be interpreted as paying different amounts of attention to stimuli according to estimates of their differential reliabilities as predictors.

Review: While the Music Lasts: The Representation of Music in the Works of George Sand

Introduction for 2002 Special Issue: Computational Models of Neuromodulation

Temporal difference learning model accounts for responses in human ventral striatum

Theoretical analysis and computational modeling are important tools for characterizing what nervous systems do, determining how they function, and understanding why they operate in particular ways. Neuroscience encompasses approaches ranging from molecular and cellular studies to human psychophysics and psychology. Theoretical neuroscience encourages crosstalk among these subdisciplines by constructing compact representations of what has been learned, building bridges between different levels of description, and identifying unifying concepts and principles. In this book, we present the basic methods used for these purposes and discuss examples in which theoretical approaches have yielded insights into nervous system function. (From the preface to Theoretical neuroscience)

Positional variation in perceptual learning: quadratic ideal observation, recurrent pre-processing, and transfer

The design and use of expert systems for medical diagnosis remains an attractive goal. One such system, the Quick Medical Reference, Decision Theoretic (QMR-DT), is based on a Bayesian network. This very large-scale network models the appearance and manifestation of disease and has approximately 600 unobservable nodes and 4000 observable nodes that represent, respectively, the presence and measurable manifestation of disease in a patient. Exact inference of posterior distributions over the disease nodes is extremely intractable using generic algorithms. Inference can be made much more efficient by exploiting the QMR-DT's unique structure. Indeed, tailor-made inference algorithms for the QMR-DT efficiently generate exact disease posterior marginals for some diagnostic problems and accurate approximate posteriors for others. 
In this thesis, I identify a risk with using the QMR-DT disease posteriors for medical diagnosis. Specifically, I show that patients and physicians conspire to preferentially report findings that suggest the presence of disease. Because the QMR-DT does not contain an explicit model of this reporting bias, its disease posteriors may not be useful for diagnosis. Correcting these posteriors requires augmenting the QMR-DT with additional variables and dependencies that model the diagnostic procedure. 
I introduce the diagnostic QMR-DT (dQMR-DT), a Bayesian network containing both the QMR-DT and a simple model of the diagnostic procedure. Using diagnostic problems sampled from the dQMR-DT, I show the danger of doing diagnosis using disease posteriors from the unaugmented QMR-DT. I introduce a new class of approximate inference methods, based on feed-forward neural networks, for both the QMR-DT and the dQMR-DT. I show that these methods, recognition models, generate accurate approximate posteriors on the QMR-DT, on the dQMR-DT, and on a version of the dQMR-DT specified only indirectly through a set of presolved diagnostic problems. (Copies available exclusively from MIT Libraries, Rm. 14-0551, Cambridge, MA 02139-4307. Ph. 617-253-5668; Fax 617-253-1690.)

Acetylcholine (ACh) has been implicated in a wide variety of tasks involving attentional processes and plasticity. Following extensive animal studies, it has previously been suggested that ACh reports on uncertainty and controls hippocampal, cortical and cortico-amygdalar plasticity. We extend this view and consider its effects on cortical representational inference, arguing that ACh controls the balance between bottom-up inference, influenced by input stimuli, and top-down inference, influenced by contextual information. We illustrate our proposal using a hierarchical hidden Markov model.

Theoretical neuroscience provides a quantitative basis for describing what nervous systems do, determining how they function, and uncovering the general principles by which they operate. This text introduces the basic mathematical and computational methods of theoretical neuroscience and presents applications in a variety of areas including vision, sensory-motor integration, development, learning, and memory. The book is divided into three parts. Part I discusses the relationship between sensory stimuli and neural responses, focusing on the representation of information by the spiking activity of neurons. Part II discusses the modeling of neurons and neural circuits on the basis of cellular and synaptic biophysics. Part III analyzes the role of plasticity in development and learning. An appendix covers the mathematical methods used, and exercises are available on the book's Web site.

Theoretical Neuroscience: Computational and Mathematical Modeling of Neural Systems

Learning to evaluate Go positions via temporal difference methods

A familiarity-based learning procedure for the establishment of place fields in area CA3 of the rat hippocampus

The standard reinforcement learning view of the involvement of neuromodulatory systems in instrumental conditioning includes a rather straightforward conception of motivation as prediction of sum future reward. Competition between actions is based on the motivating characteristics of their consequent states in this sense. Substantial, careful, experiments reviewed in Dickinson & Balleine,12,13 into the neurobiology and psychology of motivation shows that this view is incomplete. In many cases, animals are faced with the choice not between many different actions at a given state, but rather whether a single response is worth executing at all. Evidence suggests that the motivational process underlying this choice has different psychological and neural properties from that underlying action choice. We describe and model these motivational systems, and consider the way they interact.

A model of stereo segmentation by contextual influences: popout, disparity capture, transparency, and depth boundary enhancement

Strong constraints on the neural mechanisms underlying the formation of place fields in the rodent hippocampus come from the systematic changes in spatial activity patterns that are consequent on systematic environmental manipulations. We describe an attractor network model of area CA3 in which local, recurrent, excitatory, and inhibitory interactions generate appropriate place cell representations from location- and direction-specific activity in the entorhinal cortex. In the model, familiarity with the environment, as reflected by activity in neuromodulatory systems, influences the efficacy and plasticity of the recurrent and feedforward inputs to CA3. In unfamiliar, novel, environments, mossy fiber inputs impose activity patterns on CA3, and the recurrent collaterals and the perforant path inputs are subject to graded Hebbian plasticity. This sculpts CA3 attractors and associates them with activity patterns in the entorhinal cortex. In familiar environments, place fields are controlled by the way that perforant path inputs select among the attractors. Depending on the training experience provided, the model generates place fields that are either directional or nondirectional and whose changes when the environment undergoes simple geometric transformations are in accordance with experimental data. Representations of multiple environments can be stored and recalled with little interference, and these have the appropriate degrees of similarity in visually similar environments.

The Involvement of Recurrent Connections in Area CA3 in Establishing the Properties of Place Fields: a Model

Review. Stephane Mallarmee: correspondance: complements et supplements. LJ Austin, B Marchal, N Luckhurst [edd]

We discsus Hinton’s (1989) relative payoff procedure (RPP), a static reinforcement learning algorithm whose foundation is not stochastic gradient ascent. We show circumstances under which applying the RPP is guaranteed to increase the mean return, even though it can make large changes in the values of the parameters. The proof is based on a mapping between the RPP and a form of the expectation-maximisation procedure of Dempster, Laird & Rubin (1976).

This paper presents a model of how hippocampal place cells might be used for spatial navigation in two watermaze tasks: the standard reference memory task and a delayed matching‐to‐place task. In the reference memory task, the escape platform occupies a single location and rats gradually learn relatively direct paths to the goal over the course of days, in each of which they perform a fixed number of trials. In the delayed matching‐to‐place task, the escape platform occupies a novel location on each day, and rats gradually acquire one‐trial learning, i.e., direct paths on the second trial of each day. The model uses a local, incremental, and statistically efficient connectionist algorithm called temporal difference learning in two distinct components. The first is a reinforcement‐based “actor‐critic” network that is a general model of classical and instrumental conditioning. In this case, it is applied to navigation, using place cells to provide information about state. By itself, the actor‐critic can learn the reference memory task, but this learning is inflexible to changes to the platform location. We argue that one‐trial learning in the delayed matching‐to‐place task demands a goal‐independent representation of space. This is provided by the second component of the model: a network that uses temporal difference learning and self‐motion information to acquire consistent spatial coordinates in the environment. Each component of the model is necessary at a different stage of the task; the actor‐critic provides a way of transferring control to the component that performs best. The model successfully captures gradual acquisition in both tasks, and, in particular, the ultimate development of one‐trial learning in the delayed matching‐to‐place task. Place cells report a form of stable, allocentric information that is well‐suited to the various kinds of learning in the model. Hippocampus 2000;10:1–16. © 2000 Wiley‐Liss, Inc.

A model of hippocampally dependent navigation, using the temporal difference learning rule

Stimulus arrays are inevitably presented at different positions on the retina in visual tasks, even those that nominally require fixation. In particular, this applies to many perceptual learning tasks. We show that perceptual inference or discrimination in the face of positional variance has a structurally different quality from inference about fixed position stimuli, involving a particular, quadratic, non-linearity rather than a purely linear discrimination. We show the advantage taking this non-linearity into account has for discrimination, and suggest it as a role for recurrent connections in area VI, by demonstrating the superior discrimination performance of a recurrent network. We propose that learning the feedforward and recurrent neural connections for these tasks corresponds to the fast and slow components of learning observed in perceptual learning tasks.

In memory consolidation, declarative memories which initially require the hippocampus for their recall, ultimately become independent of it. Consolidation has been the focus of numerous experimental and qualitative modeling studies, but only little quantitative exploration. We present a consolidation model in which hierarchical connections in the cortex, that initially instantiate purely semantic information acquired through probabilistic unsupervised learning, come to instantiate episodic information as well. The hippocampus is responsible for helping complete partial input patterns before consolidation is complete, while also training the cortex to perform appropriate completion by itself.

Hippocampally-Dependent Consolidation in a Hierarchical Model of Neocortex

I recently heard it stalwartly defended that analytical neurophysiology has reached its apogee in the understanding of the detailed electro-chemical properties of single cells. For instance, powerful genetic, molecular, pharmacological and biophysical techniques have been developed to tease out the channel composition and channel characteristics of identified cells, and there is even a role for modelling in putting together these various pieces to assess their overall interactions. The implicit flipside to these successes is the sparsity of our equivalently detailed understanding of the rich behaviours of these neural elements when combined in circuits, excepting, of course, important examples from various invertebrate systems. It is in this area that this important and cautionary book contributes.

Gaussian distributions lie at the heart of popular tools for capturing structure in high dimensional data. Standard techniques employ as models arbitrary linear transformations of spherical Gaussians. In this paper, we present a simple extension to a class of nonlinear, volume preserving transformations which provides an efficient local description of curvature. The resulting generalized Gaussian models give a simple statistical tool for measuring deviations from multivariate Gaussian distributions. Remarkably, there is a computationally efficient, analytic solution for fitting the parameters of the non-linear models. The power of this approach is demonstrated in a curvature analysis of the Asian foreign exchange market.

Curved Gaussian models with application to modeling foreign exchange rates

Hebbian and competitive Hebbian algorithms are almost ubiquitous in modeling pattern formation in cortical development. We analyse in theoretical detail a particular model (adapted from Piepenbrock & Obermayer, 1999) for the development of Id stripe-like patterns, which places competitive and interactive cortical influences, and free and restricted initial arborisation onto a common footing.

Explaining away has mostly been considered in terms of inference of states in belief networks. We show how it can also arise in a Bayesian context in inference about the weights governing relationships such as those between stimuli and reinforcers in conditioning experiments such as backward blocking. We show how explaining away in weight space can be accounted for using an extension of a Kalman filter model; provide a new approximate way of looking at the Kalman gain matrix as a whitener for the correlation matrix of the observation process; suggest a network implementation of this whitener using an architecture due to Goodall; and show that the resulting model exhibits backward blocking.

Substantial data support a temporal difference (TO) model of dopamine (OA) neuron activity in which the cells provide a global error signal for reinforcement learning. However, in certain circumstances, DA activity seems anomalous under the TD model, responding to non-rewarding stimuli. We address these anomalies by suggesting that DA cells multiplex information about reward bonuses, including Sutton's exploration bonuses and Ng et al's non-distorting shaping bonuses. We interpret this additional role for DA in terms of the unconditional attentional and psychomotor effects of dopamine, having the computational role of guiding exploration.

Opponent interactions between serotonin and dopamine for classical and operant conditioning

We study the impact of correlated neuronal firing rate variability on the accuracy with which an encoded quantity can be extracted from a population of neurons. Contrary to widespread belief, correlations in the variabilities of neuronal firing rates do not, in general, limit the increase in coding accuracy provided by using large populations of encoding neurons. Furthermore, in some cases, but not all, correlations improve the accuracy of a population code.

The Effect of Correlated Variability on the Accuracy of a Population Code

Recurrent network models of area CA3 in the hippocampus capture faithfully many of the properties of place cells. However, they seem ill suited to explaining the substantial experimental data on place cells in environments with particular visual or geometrical similarities. We show that a model in which the activities of CA3 place cells are determined mainly by modifiable recurrent connections (together with global inhibitory feedback) is capable of reproducing the major classes of behavior that are observed. In visually similar environments, the patterns of place cell activities have the appropriate degree of similarity; after geometric transformations to the environment, the model place fields undergo geometric transformations, and also remapping, induced (or uncovered) directionality and disappearance.

Spatial Representations in Related Environments in a Recurrent Model of Area CA3 of the Rat

Physiological investigations into the neural basis of sensory attention have led to puzzling and contradictory results. Attention can seemingly lead to increased, decreased and unchanged neural activities, according to features of attentional experiments that are not well understood. We take one particular case in which activities increase as a result of attention, model its possible statistical underpinning, and relate our model to other attentional suggestions. Increased activities in population codes are associated with increased certainty about the encoded quantities. This increased certainty has to come from somewhere; in our model it emerges from particular changes in the model's processing strategy.

Quantitative data on the speed with which animals acquire behavioral responses during classical conditioning experiments should provide strong constraints on models of learning. However, most models have simply ignored these data; the few that have attempted to address them have failed by at least an order of magnitude. We discuss key data on the speed of acquisition, and show how to account for them using a statistically sound model of learning, in which differential reliabilities of stimuli play a crucial role.

Many recent analysis-by-synthesis density estimation models of cortical learning and processing have made the crucial simplifying assumption that units within a single layer are mutually independent given the states of units in the layer below or the layer above. In this article, we suggest using either a Markov random field or an alternative stochastic sampling architecture to capture explicitly particular forms of dependence within each layer. We develop the architectures in the context of real and binary Helmholtz machines. Recurrent sampling can be used to capture correlations within layers in the generative or the recognition models, and we also show how these can be combined.

Binocular rivalry is the alternating percept that can result when the two eyes see different scenes. Recent psychophysical evidence supports the notion that some aspects of binocular rivalry bear functional similarities to other bistable percepts. We build a model based on the hypothesis (Logothetis & Schall, 1989; Leopold & Logothetis, 1996; Logothetis, Leopold, & Sheinberg, 1996) that alternation can be generated by competition between top-down cortical explanations for the inputs, rather than by direct competition between the inputs. Recent neurophysiological evidence shows that some binocular neurons are modulated with the changing percept; others are not, even if they are selective between the stimuli presented to the eyes. We extend our model to a hierarchy to address these effects.

Review. Studies in Poetic Discourse: Mallarme, Baudelaire, Rimbaud, Holderlin. Translated by W. Whobrey. Frey, Hans-Jost

Hierarchical probabilistic synthesis and analysis models have recently been suggested as architectures for performing density estimation. Strict hierarchies makes it easy to evaluate generative or synthetic probabilities. However, both theoretical and neurobiological considerations weigh in favour of integrating lateral influences within a layer together with top-down and bottom up influences from lower and higher layers. This is known to be computationally tricky. We suggest a new recurrent sampling model and show that has the appropriate structure and behaviour for the analysis model for linear and Gaussian factor analysis. Then we extend this model to the case of binary stochastic units. Finally, we comment on the more general use of this model.

Symmetrically connected recurrent networks have recently been used as models of a host of neural computations. However, biological neural networks have asymmetrical connections, at the very least because of the separation between excitatory and inhibitory neurons in the brain. We study characteristic differences between asymmetrical networks and their symmetrical counterparts in cases for which they act as selective amplifiers for particular classes of input patterns. We show that the dramatically different dynamical behaviours to which they have access, often make the asymmetrical networks computationally superior. We illustrate our results in networks that selectively amplify oriented bars and smooth contours in visual inputs.

Computational Differences between Asymmetrical and Symmetrical Networks

1 INTRODUCTION A cartoon description of the goals of cognitive science and neuroscience might read respectively " how the mind works " and " how the brain works ". In this caricature, there would seem to be little overlap in the vocabularies employed by each domain. The cartoon cognitive scientist could speak at length about decision-making and short-term memory in a relatively self-consistent manner without any need to make reference to the language of neuroscience. Likewise, the cartoon neuroscientist could provide an immense body of physical detail about the function of neurons, synapses and their component parts. She could even build models about how collections of neurons work together or even how they might have developed. In both the cognitive and neural cases, such descriptions are inadequate; some phenomena will appear enduringly complicated, admitting no simple theory at a single level. In the cartoon scenarios, it is possible that many mind-like phenomena are not reducible in any strong way to descriptions enlisting interactions among components in the brain. There are a number of sophisticated arguments suggesting why such a reduction is or is not possible, likely, or fruitful-we do not enter here this debate. Instead, we will illustrate with practical examples the mileage that can be obtained from a kind of 'squeeze' approach to the problem of relating cognitive and neural descriptions. Complexities found by the cognitive scientist find natural explanation in the neural substrate; equivalently the natural theoretical context which is necessary for interpreting the neuroscientist's results, comes from hypothesized purposes. This approach is fairly straightforward: take a consistent description of some behavioral or cog-nitive phenomenon, such as decision-making under simple choice tasks, along with a description of what may be relevant neural constraints and squeeze. The squeeze amounts to building a connection from the vocabulary in one to domain to the vocabulary in the other. To the extent that reality and practicality permit, this seat-of-the-pants heuristic for theory construction pushes 2 top-down and bottom-up constraints toward one another-hence, the title of this chapter. The stated approach clearly exposes our bias: we assume that concepts like attention, reward, memory, decision, etc. will find some mapping onto the descriptions of brain function. The squeeze was first formalised by David Marr using ideas about computational equivalence. He showed how different notions of computation can be used in modeling cognitive and neural phenomena. In his view, cognitive tasks have to be specified …

Most theoretical and empirical studies of population codes make the assumption that underlying neuronal activities is a unique and unambiguous value of an encoded quantity. However, population activities can contain additional information about such things as multiple values of or uncertainty about the quantity. We have previously suggested a method to recover extra information by treating the activities of the population of cells as coding for a complete distribution over the coded quantity rather than just a single value. We now show how this approach bears on psychophysical and neurophysiological studies of population codes for motion direction in tasks involving transparent motion stimuli. We show that, unlike standard approaches, it is able to recover multiple motions from population responses, and also that its output is consistent with both correct and erroneous human performance on psychophysical tasks.

It is well known that for finite-sized networks, onestep retrieval in the autoassociative Willshaw net is a suboptimal way to extract the information stored in the synapses. Iterative retrieval strategies are much better, but have hitherto only had heuristic justification. We show how they emerge naturally from considerations of probabilistic inference under conditions of noisy and partial input and a corrupted weight matrix. We start from the conditional probability distribution over possible patterns for retrieval. This contains all possible information that is available to an observer of the network and the initial input. Since this distribution is over exponentially many patterns, we use it to develop two approximate, but tractable, iterative retrieval methods. One performs maximum likelihood inference to find the single most likely pattern, using the (negative log of the) conditional probability as a Lyapunov function for retrieval. In physics terms, if storage errors are present, then the modified iterative update equations contain an additional antiferromagnetic interaction term and site dependent threshold values. The second method makes a mean field assumption to optimize a tractable estimate of the full conditional probability distribution. This leads to iterative mean field equations which can be interpreted in terms of a network of neurons with sigmoidal responses but with the same interactions and thresholds as in the maximum likelihood update equations. In the absence of storage errors, both models become very similiar to the Willshaw model, where standard retrieval is iterated using a particular form of linear threshold strategy.

Ce texte de Sand pose d'evidents problemes de narratologie. L'A. se penche plus particulierement sur la question de l'identite du narrateur en essayant en particulier d'elucider les relations qui existent entre le narrateur extradiegetique des quatre premieres parties, et le narrateur intradiegetique de la conclusion

The capacity to predict future events permits a creature to detect, model, and manipulate the causal structure of its interactions with its environment. Behavioral experiments suggest that learning is driven by changes in the expectations about future salient events such as rewards and punishments. Physiological work has recently complemented these studies by identifying dopaminergic neurons in the primate whose fluctuating output apparently signals changes or errors in the predictions of future salient and rewarding events. Taken together, these findings can be understood through quantitative theories of adaptive optimizing control.

We describe a linear network that models correlations between real-valued visible variables using one or more real-valued hidden variablesa factor analysis model. This model can be seen as a linear version of the Helmholtz machine, and its parameters can be learned using the wake sleep method, in which learning of the primary generative model is as sisted by a recognition model, whose role is to fill in the values of hidden variables based on the values of visible variables. The generative and recognition models are jointly learned in wake and sleep phases, using just the delta rule. This learning procedure is comparable in simplicity to Hebbian learning, which produces a somewhat different representation of correlations in terms of principal components. We argue that the simplicity of wake-sleep learning makes factor analysis a plausible alternative to Hebbian learning as a model of activity-dependent cortical plasticity.

We study the problem of statistically correct inference in networks whose basic representations are population codes. Population codes are ubiquitous in the brain, and involve the simultaneous activity of many units coding for some low dimensional quantity. A classic example are place cells in the rat hippocampus: these fire when the animal is at a particular place in an environment, so the underlying quantity has two dimensions of spatial location. We show how to interpret the activity as encoding whole probability distributions over the underlying variable rather then just single values, and propose a method of inductively learning mappings between population codes that are computationally tractable and yet offer good approximations to statistically optimal inference. We simulate the method on some simple examples to prove its competence.

We describe the \wake-sleep" algorithm that allows a multilayer, unsupervised, neural network to build a hierarchy of representations of sensory input. The network has bottom-up \recognition" connections that are used to convert sensory input into underlying representations. Unlike most arti cial neural networks, it also has top-down \generative" connections that can be used to reconstruct the sensory input from the representations. In the \wake" phase of the learning algorithm, the network is driven by the bottom-up recognition connections and the top-down generative connections are trained to be better at reconstructing the sensory input from the representation chosen by the recognition process. In the \sleep" phase, the network is driven top-down by the generative connections to produce a fantasized representation and a fantasized sensory input. The recognition connections are then trained to be better at recovering the fantasized representation from the fantasized sensory input. In both phases, the synaptic learning rule is simple and local. The combined e ect of the two phases is to create representations of the sensory input that are e cient in the following sense: On average, it takes more bits to describe each sensory input vector directly than to rst describe the representation of the sensory input chosen by the recognition process and then describe the di erence between the sensory input and its reconstruction from the chosen representation.

Review. Mallarme: La poetique du theatre et l'ecriture. Alcoloumbre, Thierry

We discuss Hinton's (1989) relative payoff procedure (RPP), a static reinforcement learning algorithm whose foundation is not stochastic gradient ascent. We show circumstances under which applying the RPP is guaranteed to increase the mean return, even though it can make large changes in the values of the parameters. The proof is based on a mapping between the RPP and a form of the expectation-maximization procedure of Dempster, Laird, and Rubin (1977).

This paper describes two new methods for modeling the manifolds of digitized images of handwritten digits. The models allow a priori information about the structure of the manifolds to be combined with empirical data. Accurate modeling of the manifolds allows digits to be discriminated using the relative probability densities under the alternative models. One of the methods is grounded in principal components analysis, the other in factor analysis. Both methods are based on locally linear low-dimensional approximations to the underlying data manifold. Links with other methods that model the manifold are discussed.

Conditioning experiments probe the ways that animals make predictions about rewards and punishments and use those predictions to control their behavior. One standard model of conditioning paradigms which involve many conditioned stimuli suggests that individual predictions should be added together. Various key results show that this model fails in some circumstances, and motivate an alternative model, in which there is attentional selection between different available stimuli. The new model is a form of mixture of experts, has a close relationship with some other existing psychological suggestions, and is statistically well-founded.

We provide a model of the standard watermaze task, and of a more challenging task involving novel platform locations, in which rats exhibit one-trial learning after a few days of training. The model uses hippocampal place cells to support reinforcement learning, and also, in an integrated manner, to build and use allocentric coordinates.

Hippocampal Model of Rat Spatial Abilities Using Temporal Difference Learning

Helplessness, a belief that the world is not subject to behavioral control, has long been central to our understanding of depression, and has influenced cognitive theories, animal models and behavioral treatments. However, despite its importance, there is no fully accepted definition of helplessness or behavioral control in psychology or psychiatry, and the formal treatments in engineering appear to capture only limited aspects of the intuitive concepts. Here, we formalize controllability in terms of characteristics of prior distributions over affectively charged environments. We explore the relevance of this notion of control to reinforcement learning methods of optimising behavior in such environments and consider how apparently maladaptive beliefs can result from normative inference processes. These results are discussed with reference to depression and animal models thereof. 2009 Elsevier B.V. All rights reserved.

Author ' s personal copy A Bayesian formulation of behavioral control

Review. Romantic Vision: The Novels of George Sand. Godwin-Jones, Robert

We develop a theoretical framework that shows how mesencephalic dopamine systems could distribute to their targets a signal that represents information about future expectations. In particular, we show how activity in the cerebral cortex can make predictions about future receipt of reward and how fluctuations in the activity levels of neurons in diffuse dopamine systems above and below baseline levels would represent errors in these predictions that are delivered to cortical and subcortical targets. We present a model for how such errors could be constructed in a real brain that is consistent with physiological results for a subset of dopaminergic neurons located in the ventral tegmental area and surrounding dopaminergic neurons. The theory also makes testable predictions about human choice behavior on a simple decision-making task. Furthermore, we show that, through a simple influence on synaptic plasticity, fluctuations in dopamine release can act to change the predictions in an appropriate manner.

A framework for mesencephalic dopamine systems based on predictive Hebbian learning

Review. Le Livre total. Buisine, Alain and Vincent Kaufman (eds)

Analytical Mean Squared Error Curves for Temporal Difference Learning

Binocular rivalry is the alternating percept that can result when the two eyes see different scenes. Recent psychophysical evidence supports an account for one component of binocular rivalry similar to that for other bistable percepts. We test the hypothesis that alternation can be generated by competition between top-down cortical explanations for the inputs, rather than by direct competition between the inputs. Recent neurophysiological evidence shows that some binocular neurons are modulated with the changing percept; others are not, even if they are selective between the stimuli presented to the eyes. We extend our model to a hierarchy to address these effects.

We present a connectionist method for representing images that explicitly addresses their hierarchical nature. It blends data from neuroscience about whole-object viewpoint sensitive cells in inferotemporal cortex and attentional basis-field modulation in V4 with ideas about hierarchical descriptions based on microfeatures. The resulting model makes critical use of bottom-up and top-down pathways for analysis and synthesis. We illustrate the model with a simple example of representing information about faces.

We present a general encoding-decoding framework for interpreting the activity of a population of units. A standard population code interpretation method, the Poisson model, starts from a description as to how a single value of an underlying quantity can generate the activities of each unit in the population. In casting it in the encoding-decoding framework, we find that this model is too restrictive to describe fully the activities of units in population codes in higher processing areas, such as the medial temporal area. Under a more powerful model, the population activity can convey information not only about a single value of some quantity but also about its whole distribution, including its variance, and perhaps even the certainty the system has in the actual presence in the world of the entity generating this quantity. We propose a novel method for forming such probabilistic interpretations of population codes and compare it to the existing method.

Review. Indiana. A new Translation by Sylvia Raphael. Sand, George

We present a connectionist method for representing images that explicitly addresses their hierarchical nature. It blends data from neu-roscience about whole-object viewpoint sensitive cells in inferotem-poral cortex 7 and attentional basis-eld modulation in V4 3 with ideas about hierarchical descriptions based on microfeatures. 4, 10 The resulting model makes critical use of pathways for both analysis and synthesis. 5 We illustrate the model with a simple example of representing information about faces. Substantial recent eeort has been devoted to analysis-by-synthesis models for visual processing. The synthetic or generative models form the map: `object' ! `image' (1) wherèobject' implies the identity of the object (such as a face) and its relevant instantiation parameters (such as whether it is smiling or frowning) andìmage' stands in for the pattern of activity over the input units that is caused by observing the object. The Helmholtz machine 5 (HM) employs unsupervised learning to construct an explicit generative model of this form, using a top-down layered processing structure that is a form of factorial belief network. 9 The activities of the units in the top layer, or possibly all hidden layers, represent the object and the choices of its instantiation parameters. The task for analysis or recognition is to take anìmage' and produce (a probability distribution over) the object that might have generated it, and also the instantiation parameters of that object. The HM uses a bottom-up belief net over the same units to represent the recognition model, and trains top-down and bottom-up models to be mutual inverses.

Functionalism avoids a potentially fatal innnite regress by realising the low level phenomena of mind in mere Turing machines rather than via undischarged homuncull. Adopting a narrow, logical view of such mechanisms has led to two sorts of problems: exponentially intractable models of human inferential competence; and a wide divergence between the supposed competence and observable human performance. These problems have produced a retreat to instrumentalism about folk psychological concepts|a retreat that has long been trumpeted by certain philosophers. We argue that abandoning hope in this way is premature. The problems arise from two quarters: an impoverished notion of competence models that divorce them too far from performance models; and too narrow a view of possible functional mechanisms. We explore the consequences of retaining a traditional view of inference, while adopting a new mechanism for memory. We motivate the latter by developing a seemingly unnatural picture of von Neumann machines, taking their nite memory seriously. Together, the two repairs suuce to make instrumentalism avoidable.

Review. The Miller of Angibault. Translated with an Introduction and Notes by Donna Dickenson. Sand, George

Review. The Master Pipers. Translated with an Introduction and Notes by Rosemary Lloyd. Sand, George

Review. Mallarme: A Throw of the Dice. The Life of Stephane Mallarme. Millan, Gordon

If different causes can interact on any occasion to generate a set of patterns, then systems modeling the generation have to model the interaction too. We discuss a way of combining multiple causes that is based on the Integrated Segmentation and Recognition architecture of Keeler et al. (1991). It is more cooperative than the scheme embodied in the mixture of experts architecture, which insists that just one cause generate each output, and more competitive than the noisy-or combination function, which was recently suggested by Saund (1994a,b). Simulations confirm its efficacy.

Performing policy iteration in dynamic programming should only require knowledge of relative rather than absolute measures of the utility of actions (Werbos, 1991) - what Baird (1993) calls the advantages of actions at states. Nevertheless, most existing methods in dynamic programming (including Baird's) compute some form of absolute utility function. For smooth problems, advantages satisfy two differential consistency conditions (including the requirement that they be free of curl), and we show that enforcing these can lead to appropriate policy improvement solely in terms of advantages.

established from the perspective of psychological experiments, the neural mechanisms that underlie this preA creature presented with an uncertain and diction are less well understood. Prediction, and its apvariable environment needs to anticipate inpropriate use for action, is essentially a computational portant future events or risk diminished chanconcept, but this still leads a wide range of possible theces for survival. These events can include ories to explain existing data. the presence of food, destructive stimuli, and One way for an animal to learn to make predictions is for potential mates. In short, a nervous system it to have a system that reports on its current best guess, must have means to generate guesses about its and to have learning be contingent on err-or-s in this premost likely next state and the most likely next diction: learning only happens if the animal becomes state of the world. Psychologists have studied surprised based on its prediction. This is the underconditions under which animals can learn to lying mechanism behind essentially all adaptation rules predict future reward and punishment. In this in engineering (Kalman, 1960; Widrow & Stearns, 1985) paper, we review the computational theory that may be relevant for understanding this and particular learning rules in psychology (Rescorla & form of learning. Some of the central nlechWagner, 1972; Mackintosh, 1983; Pearce & Hall, 1980). JVe consider below the general requirements for such a anisms required for predictive learning have been discovered in both vertebrate Ljungberg signal in the brain. et al’s (1992) and invertebrate brains (HanlThe construction, delivery and use of an error signal remer, 1994). lated to predictions about future stimuli would require the following: Z) access to a representation of the phenomenon to be Prediction predicted such as the amount of reward or food. t~) accem to the current predictions so that they can be Animals are capable of predicting events aud the cousecolnparecl to the phenonlenon to be predicted. quences of those events on the basis of the sensory inforLIL) capacity to influence plasticity (directly or indirectly) ]U structures responsible for constructing the predication they receive and directing their actions accorcltious. ing to those predictions (see Dickenson, 1980; Mackintosh, 1983; Gallistel, 1990 and Gluck and Thompson, ZU) sufficiently wide broadcast of the error signal so that 1987 for reviews). Although these conclusions are well stimuli in different modalities can be used to make and respond to the predictions. *Howard Hughes Medical Institute, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La These general requirements are met by a number of difJolla, CA 92037, and Department of Biology, University of fusely projecting system of axons that are thought to California, San Diego, La Jolla, CA 92093. report, in part on salient events in the world and within t Department of Brain and Cognitive Science, MIT, Canlthe organism. bridge MA 02139. These axons release neuromodulators t Division of Neuroscience, Baylor College of Medicine, that can influence the effectiveness of synapses in these Houston TX 77030. areas. This anatomical motif is a common feature of many nervous systems and is not unique to vertebrate Permission to make digital/hard copies of all or part of this material withbrains. Invertebrates have analogous sets of neurons out fee is granted provided that the copies are not made or distributed for profit or commercial advantage, the ACM copyright/server with extensive axonal arborizations that deliver neuronotice, the title of the pub Iication and its date appear, and notice is given modulators to widespread target regions (Hawkins and that copyright is by permission of the Association for Computing Machinery, Kandel, 1984; Greenough and Bailey, 1988; Hammer, Inc. (ACM). To copy otherwise, to republish,to post on servers or to 1994). Experiulent al evidence from both behavioral and redistribute to lists, requires specific permission and/or fee. COLT’ ’95 Santa Cruz, CA USA@ 1995 ACM 0-89723-5/95/0007. .$3.50 physiological work suggests that these systems influence

Discovering the structure inherent in a set of patterns is a fundamental aim of statistical inference or learning. One fruitful approach is to build a parameterized stochastic generative model, independent draws from which are likely to produce the patterns. For all but the simplest generative models, each pattern can be generated in exponentially many ways. It is thus intractable to adjust the parameters to maximize the probability of the observed patterns. We describe a way of finessing this combinatorial explosion by maximizing an easily computed lower bound on the probability of the observations. Our method can be viewed as a form of hierarchical self-supervised learning that may relate to the function of bottom-up and top-down cortical processing pathways.

An unsupervised learning algorithm for a multilayer network of stochastic neurons is described. Bottom-up "recognition" connections convert the input into representations in successive hidden layers, and top-down "generative" connections reconstruct the representation in one layer from the representation in the layer above. In the "wake" phase, neurons are driven by recognition connections, and generative connections are adapted to increase the probability that they would reconstruct the correct activity vector in the layer below. In the "sleep" phase, neurons are driven by generative connections, and recognition connections are adapted to increase the probability that they would produce the correct activity vector in the layer above.

The wake-sleep algorithm (Hinton, Dayan, Frey and Neal 1995) is a relatively efficient method of fitting a multilayer stochastic generative model to high-dimensional data. In addition to the top-down connections in the generative model, it makes use of bottom-up connections for approximating the probability distribution over the hidden units given the data, and it trains these bottom-up connections using a simple delta rule. We use a variety of synthetic and real data sets to compare the performance of the wake-sleep algorithm with Monte Carlo and mean field methods for fitting the same generative model and also compare it with other models that are less powerful but easier to fit.

Bee foraging in uncertain environments using predictive hebbian learning

Review. The Poetics of the Occasion: Mallarme and the Poetry of Circumstance. Sugano, Marian Zwerling

Review. Performance in the Texts of Mallarme: The Passage from Art to Ritual. Shaw, Mary Lewis

The methods of temporal differences (Samuel, 1959; Sutton, 1984, 1988) allow an agent to learn accurate predictions of stationary stochastic future outcomes. The learning is effectively stochastic approximation based on samples extracted from the process generating the agent's future. Sutton (1988) proved that for a special case of temporal differences, the expected values of the predictions converge to their correct values, as larger samples are taken, and Dayan (1992) extended his proof to the general case. This article proves the stronger result that the predictions of a slightly modified form of temporal difference learning converge with probability one, and shows how to quantify the rate of convergence. Keywords, reinforcement learning, temporal differences, Q-learning

Utilisant dans cette esthtetique comparee les metaphores de la bestialite et de l'excrement, l'A. met en evidence ce qui oppose l'art baudelairien de l'endiguement et de l'isolement a la pratique sandienne du flux et de l'ecoulement

BAUDELAIRE AT HIS LATRINE: MOTIONS IN THE PETITS POÈMES EN PROSE AND IN GEORGE SAND'S NOVELS

We construct a mixture of locally linear generative models of a collection of pixel-based images of digits, and use them for recognition. Different models of a given digit are used to capture different styles of writing, and new images are classified by evaluating their log-likelihoods under each model. We use an EM-based algorithm in which the M-step is computationally straightforward principal components analysis (PCA). Incorporating tangent-plane information [12] about expected local deformations only requires adding tangent vectors into the sample covariance matrices for the PCA, and it demonstrably improves performance.

Neurons in the visual cortex require correlated binocular activity during a critical period early in life to develop normal response properties. We present a model for how the disparity selectivity of cortical neurons might arise during development. The model is based on Hebbian mechanisms for plasticity at synapses between geniculocortical neurons and cortical cells. The model is driven by correlated activity in retinal ganglion cells within each eye before birth and additionally between eyes after birth. With no correlations present between the eyes, the cortical model developed only monocular cells. Adding a small amount of correlation between eyes at the beginning of development produced cortical neurons that were entirely binocular and tuned to zero disparity. However, if an initial phase of purely same-eye correlations was followed by a second phase of development that included correlations between eyes, the cortical model became populated with both monocular and binocular cells. Moreover, in the two-phase model, binocular cells tended to be selective for zero disparity, whereas the more monocular cells tended to have nonzero disparity. This relationship between ocular dominance and disparity has been observed in the visual cortex of the cat by other workers. Differences in the relative timing of the two developmental phases could account for the higher proportion of monocular cells found in the visual cortices of other animals.

A correlational model for the development of disparity selectivity in visual cortex that depends on prenatal and postnatal phases.

Hebbian synapses lie at the heart of most associative matrix memories (Kohonen 1987; Hinton and Anderson 1981) and are also biologically plausible (Brown et al. 1990; Baudry and Davis 1991). Their analytical and computational tractability make these memories the best understood form of distributed information storage. A variety of Hebbian algorithms for estimating the covariance between input and output patterns has been proposed. This note points out that one class of these involves stochastic estimation of the covariance, shows that the signal-to-noise ratios of the rules are governed by the variances of their estimates, and considers some parallels in reinforcement learning.

The Variance of Covariance Rules for Associative Matrix Memories and Reinforcement Learning

Survival is enhanced by an ability to predict the availability of food, the likelihood of predators, and the presence of mates. We present a concrete model that uses diffuse neurotransmitter systems to implement a predictive version of a Hebb learning rule embedded in a neural architecture based on anatomical and physiological studies on bees. The model captured the strategies seen in the behavior of bees and a number of other animals when foraging in an uncertain environment. The predictive model suggests a unified way in which neuromodulatory influences can be used to bias actions and control synaptic plasticity.

Foraging in an Uncertain Environment Using Predictive Hebbian Learning

The game of Go has a high branching factor that defeats the tree search approach used in computer chess, and long-range spatiotemporal interactions that make position evaluation extremely difficult. Development of conventional Go programs is hampered by their knowledge-intensive nature. We demonstrate a viable alternative by training networks to evaluate Go positions via temporal difference (TD) learning. 
 
Our approach is based on network architectures that reflect the spatial organization of both input and reinforcement signals on the Go board, and training protocols that provide exposure to competent (though unlabelled) play. These techniques yield far better performance than undifferentiated networks trained by selfplay alone. A network with less than 500 weights learned within 3,000 games of 9×9 Go a position evaluation function that enables a primitive one-ply search to defeat a commercial Go program at a low playing level.

Temporal Difference Learning of Position Evaluation in the Game of Go

Estimation of returns over time, the focus of temporal difference (TD) algorithms, imposes particular constraints on good function approximators or representations. Appropriate generalization between states is determined by how similar their successors are, and representations should follow suit. This paper shows how TD machinery can be used to learn such representations, and illustrates, using a navigation task, the appropriately distributed nature of the result.

Improving Generalization for Temporal Difference Learning: The Successor Representation

Book Review:Artificial Intelligence and Human Cognition: A Theoretical Intercomparison of Two Realms of Intellect. Morton Wagman

The elastic net, which has been used to produce accounts of the formation of topology-preserving maps and ocular dominance stripes (OD), embodies a nearest neighbor topology. A Hebbian account of OD is not so restrictedand indeed makes the prediction that the width of the stripes depends on the nature of the (more general) neighborhood relations. Elastic and Hebbian accounts have recently been unified, raising a question mark about their different determiners of stripe widths. This paper considers this issue, and demonstrates theoretically that it is possible to use more general topologies in the elastic net, including those effectively adopted in the Hebbian model.

One way to speed up reinforcement learning is to enable learning to happen simultaneously at multiple resolutions in space and time. This paper shows how to create a Q-learning managerial hierarchy in which high level managers learn how to set tasks to their submanagers who, in turn, learn how to satisfy them. Submanagers need not initially understand their managers' commands. They simply learn to maximise their reinforcement in the context of the current command. 
 
We illustrate the system using a simple maze task. As the system learns how to get around, satisfying commands at the multiple levels, it explores more efficiently than standard, flat, Q-learning and builds a more comprehensive map.

We present a local learning rule in which Hebbian learning is conditional on an incorrect prediction of a reinforcement signal. We propose a biological interpretation of such a framework and display its utility through examples in which the reinforcement signal is cast as the delivery of a neuromodulator to its target. Three examples are presented which illustrate how this framework can be applied to the development of the oculomotor system.

Using Aperiodic Reinforcement for Directed Self-Organization During Development

Review. Mallarme's Text Database. Divagations. I. Text. II. Word Index. Matsumuro, Saburo, Nobuo Takeuchi and Masakatsu Kaneko (eds)

In October 1992, I was awarded funding by the Edinburgh University Enterprise Centre for a ninemonth project entitled ‘The Development of Self-Directed Learning using Computers and Satellite TV’. The aim of the ‘computers’ half of the project was to find ways of getting first-year students to spend more time working by themselves on the quality of their written French.

Expectation learning in the brain using diffuse ascending projections

Review. Mallarme's 'Divagations': A Guide and Commentary. Cohn, Robert Greer

Optimising synaptic learning rules in linear associative memories

Recently Linsker [2] and MacKay and Miller [3,4] have analysed Hebbian correlational rules for synaptic development in the visual system, and Miller [5,8] has studied such rules in the case of two populations of fibres (particularly two eyes). Miller's analysis has so far assumed that each of the two populations has exactly the same correlational structure. Relaxing this constraint by considering the effects of small perturbative correlations within and between eyes permits study of the stability of the solutions. We predict circumstances in which qualitative changes are seen, including the production of binocularly rather than monocularly driven units.

Connectionism's main contribution to cognitive science will prove to be the renewed impetus it has imparted to learning. Learning can be integrated into the existing theoretical foundations of the subject, and the combination, statistical computational theories, provide a framework within which many connectionist mathematical mechanisms naturally fit. Examples from supervised and reinforcement learning demonstrate this. Statistical computational theories already exist for certain associative matrix memories. This work is extended, allowing real valued synapses and arbitrarily biased inputs. It shows that a covariance learning rule optimises the signal/noise ratio, a measure of the potential quality of the memory, and quantifies the performance penalty incurred by other rules. In particular two that have been suggested as occurring naturally are shown to be asymptotically optimal in the limit of sparse coding. The mathematical model is justified in comparison with other treatments whose results differ. Reinforcement comparison is a way of hastening the learning of reinforcement learning systems in statistical environments. Previous theoretical analysis has not distinguished between different comparison terms, even though empirically, a covariance rule has been shown to be better than just a constant one. The workings of reinforcement comparison are investigated by a second order analysis of the expected statistical performance of learning, and an alternative rule is proposed and empirically justified. The existing proof that temporal difference prediction learning converges in the mean is extended from a special case involving adjacent time steps to the general case involving arbitrary ones. The interaction between the statistical mechanism of temporal difference and the linear representation is particularly stark. The performance of the method given a linearly dependent representation is also analysed. The method of planning using temporal difference prediction had previously been applied to solve the navigation task of finding a goal in a grid. This is extended to compare the qualities of alternative representations of the environment and to accomplish simple latent learning when the goal is initially absent. Representations that are coarse-coded are shown to perform particularly well, and latent learning can be used to form them.

Review. Stephane Mallarme: Twentieth-Century Criticism (1972-1979). Morris, D. Hampton

Barto, Sutton and Watkins [2] introduced a grid task as a didactic example of temporal difference planning and asynchronous dynamical programming. This paper considers the effects of changing the coding of the input stimulus, and demonstrates that the self-supervised learning of a particular form of hidden unit representation improves performance.

A recent article (Stanton and Sejnowski 1989) on long-term synaptic depression in the hippocampus has reopened the issue of the computational efficiency of particular synaptic learning rules (Hebb 1949; Palm 1988a; Morris and Willshaw 1989) homosynaptic versus heterosynaptic and monotonic versus nonmonotonic changes in synaptic efficacy. We have addressed these questions by calculating and maximizing the signal-to-noise ratio, a measure of the potential fidelity of recall, in a class of associative matrix memories. Up to a multiplicative constant, there are three optimal rules, each providing for synaptic depression such that positive and negative changes in synaptic efficacy balance out. For one rule, which is found to be the Stent-Singer rule (Stent 1973; Rauschecker and Singer 1979), the depression is purely heterosynaptic; for another (Stanton and Sejnowski 1989), the depression is purely homosynaptic; for the third, which is a generalization of the first two, and has a higher signal-to-noise ratio, it is both heterosynaptic and homosynaptic. The third rule takes the form of a covariance rule (Sejnowski 1977a,b) and includes, as a special case, the prescription due to Hopfield (1982) and others (Willshaw 1971; Kohonen 1972).

Optimal Plasticity from Matrix Memories: What Goes Up Must Come Down

Review. Mallarme's Prose Poems: A Critical Study. Cohn, Robert Greer

Review. Mallarme, or the Poet of Nothingness. Translated and introduced by Ernest Sturm. Sartre, Jean-Paul

Acknowledgements Introduction 1. The Danaides Vessel: on reading Baudelaire's allegories 2. On certain relations: figures of sexuality in Baudelaire 3. Emma's stories: narrative, repetition and desire in Madame Bovary 4. The autobiography of rhetoric: on reading Rimbaud's Une Saison en enfer 5. False confusions: ficitons of masculine desire in Mallarme's 'L'Apres-midi d'un faune' 6. The trials of authority under Louis Bonaparte Notes Index.

The limits of narrative : essays on Baudelaire, Flaubert, Rimbaud, and Mallarmé

It is the reading world's good fortune that Stephane Mallarme's letters survived, allowing later generations an intimate look at the inner life of one of Europe's most important poets. Mallarme (1842-98), often called the father of the Symbolists, has had an immense influence on the development of modern European poetry. It was his ambition to create a poetry pure of quotidian reality autonomous, concentrated, linguistically inventive. His correspondence documents the evolution of this aim, the crafting of a poetics out of a life inescapably "real" in its pains and charms."

Mallarme's reputation as a seminal thinker has steadily grown. Yet, despite the proliferation of references to it, his literary theory has seldom been studied directly; the great theoretical articles of his later years have never been properly elucidated. This book represents the first attempt to examine the later Mallarme's extraordinary and systematic literary idealism through a careful scrutiny of his own pronouncements on it. The book makes selective use of the textual approaches of certain post-structuralist theorists, especially Derrida. Many of their positions turn out to be fascinatingly similar to Mallarme's. But there are also vital differences, which the second part of this study highlights, between Mallarme and the modern theorists, differences which help to explain not only Mallarm e's continuing elusiveness, but also the failure of modern literary theory to face the question which Mallarme always condidered fundamental: what is good poetry?

Mallarmé's "Divine Transposition": Real and Apparent Sources of Literary Value

1 2 Dopamine enhances model-free credit assignment through boosting of retrospective 3 model-based inference 4 5 6

Substantial evidence suggests that phasic activities of midbrain dopaminergic neurons represent reward prediction errors. This interpretation has been challenged by recent experimental results, that show ramps in dopamine activity which are related to reward uncertainty. We show that these ramps result from reward prediction errors alone, given differential scaling of positive and negative errors, thus rendering uncertainty moot. A seminal series of experiments by Wolfram Schultz and his colleagues1 has persuasively suggested that the phasic activities of midbrain dopamine neurons represent a temporal difference (TD) error (written δ(t)) in the predictions of future reward.2–5 This prediction error signal occurs at the time of the delivery of unpredicted rewards, or stimuli predicting future rewards, and can be used to guide prediction learning. TD offers a computationally compelling account of a role for DA in appetitive classical and instrumental conditioning, and a precise and parsimonious computational theory of the generation of DA £ring patterns. Figure 1a shows data from a recent, fascinating, experiment by Fiorillo, Tobler & Schultz (FTS)6 that presents a crucial challenge to TD theory of DA. They studied the consequences of presenting stochastic rewards, and argued that DA activity explicitly represents uncertainty. In the task, presentation of visual stimuli to macaques was associated with the delayed, probabilistic delivery of rewards (drops of juice). Five different stimuli were associated with £ve different reward probabilities (pr = 0, 0.25, 0.5, 0.75, 1). The traces in £gure 1a show the activity of DA cells averaged over trials for each pr, in well-trained monkeys. The £ring patterns in £gure 1a can be separated into three main components, one consistent with the TD account and two at apparent variance with it. The £rst component is the sharp peak just after the time of the predictive stimulus. TD predicts that this response should scale with the probability of reward, and FTS’ is the £rst report that this happens. The second component is the ramp in the responses towards the time of the reward, which is largest for p=0.5. FTS suggested that the ramp represents the uncertainty of the delivery of reward, instead of a prediction error. The ramp is problematic for the TD account of DA activity, because there is no apparent reason for its occurrence (as there is no prediction error in the inter-stimulus interval). Furthermore, since TD learning operates by arranging for DA activity at one time in

Substantial evidence suggests that the phasic activities of dopamine neurons in the midbrain of primates report prediction errors in the delivery of reward. Recent recordings from these neurons in a task involving uncertain reward delivery present a crucial challenge to this hypothesis, and pose questions regarding the effects of both external and representational uncertainty on dopamine activity. Here, we analyse this issue, showing that the apparently anomalous activities are in fact what is expected under a standard prediction error account in light of different scalings of positive and negative prediction errors. We also study the implications of certain forms of representational noise on temporal difference learning.

Taking the posterior distribution over patterns given the input to the network and the synaptic weights between neurons (equation 8 of the main paper) to be the distribution that a network tries to approximate (equation 4 and 5 of the main paper) yields the following update rules for neuronal firing phases, concentrations, and rates:

Uncertainty , phase and oscillatory hippocampal recall supplementary material

A critical question in the neural representations of the sensory world, is how sensory systems can build multi-layer, hierarchical, representations whose semantics are as uniform as possible at every stage. Here, we demonstrate that a statistically normalizing transform on wavelet outputs can license effective hierarchical representations. The figure below outlines our technique in the case of images. (A) shows a classic bowtie dependence between two spatially adjacent wavelet coefficients; and (A: top and left) shows the sparse marginal distributions of the coefficients. We suggest performing the nonlinear marginal transform in (B), giving rise to a standard Gaussian marginal distribution (hence statistically normalized; C: top and left), and a contrast enhanced bowtie (C), with a bimodal conditional distribution of one coefficient given the other. Applying ICA to the non-linearly transformed coefficients, yields higher level units capturing long range structure in the inputs (D; wavelet feedforward weights, black negative; white positive).

Editorial Development happens through the dynamic interaction of biological and physical components at several scales of time and space. These interactions range from the dynamics of gene expression within cells to inter-organ chemical signalling during embryogenesis to the progressive shaping of brain structures through physical and social interaction. What are the adequate levels of abstraction for modelling and understanding such a complex system? This is the topic of the dialog column featured this months, where respond to the dialog initiated by Denis Mareschal. Opinions differ on what should or should not be abstracted. But all converge to a needed shift for 21st century developmental science: " innate " or " learned " are outdated concepts that are not suited for understanding human behaviour and cognition. There are no " start " or " end " , but only continuous processes of change that grow our bodies, our minds and our cultures. After this dialog, a new dialog initiation by John Weng digs into the concept of autonomy for " skull-closed " learning robots, and its implications for socially assistive robotics, echoing the April 2012 dialog column on the interaction between HRI and developmental robotics scientific approaches. In particular he calls for a detailed argumentation of the pros and cons for using emergent representations and skull-closed developmental approaches for assistive robotics applications. Those of you interested in reacting to this dialog initiation are welcome to submit a response (contact pierre-yves.oudeyer@inria.fr) by March 1st, 2013. The length of each response must be between 500 and 700 words (including references). First let me celebrate the success of our IEEE Transactions in Autonomous Mental Development, with the announcement last Summer of its first impact factors: 2.31. This is a very high impact factor when compared with the other well established journals in related computational and robotics disciplines. We all know that impact factors are not the only research quality indicator, but a high impact value adds to the reputational value of our discipline and community. Well done to Zhengyou Zhang, the associate editors, the referees and, of course, the authors. Please keep sending your top quality papers in this top quality journal! We are all geared up for the next IEEE ICDL-EpiRob Conference in San Diego (7-9 November 2012). Following the success in Frankfurt of the integration of the previous IEEE ICDL and the EpiRob conferences, we hope that the San Diego event will …

Chaumont, and Pierre Patte into fruitful dialogue, showing how the reformers’ turn to contemporary experimental physics underscored the theatre as a space of knowledge production. Chapter 5 pursues an investigation into late-eighteenth-century epistemology and optics to analyse changes in perspectival stage decoration, and the study ends with a richly suggestive meditation (by way of Husserl) on the formation of the modern spectatorsubject. The volume features numerous illustrations, and, although Camp’s prose can be somewhat dense at times, his innovative approach and finely marshalled erudition make this sophisticated study of great value to those interested in European theatre history.

La Musique dans la pensée et dans l'œuvre de Stendhal et de Nerval by Anna Opiela (review)

Œuvres complètes, I: Choix des poésies de Ronsard, Du Bellay, Baïf, Belleau, Du Bartas, Chassignet, Desportes, Régnier (review)

the androgyne, and the development of the female artist — are well-worn topics in Sandian criticism. The volume departs from previous approaches through the interpretation of disguise as a psychological and spiritual transformation rather than an erotic category, and through the examination of disguise as a means of developing the character’s identity rather than as an expression of Sand’s personal or authorial androgyny. Nevertheless, it is not entirely clear in what way the culminating finding, namely, that ‘the disguise has highlighted the evolution of the Sandian heroine from a Romantic character suffering from le mal du siècle to an assertive protagonist’ (p. 229), represents a fundamental reassessment of Sand’s work. Although the study intentionally focuses on disguise in Sand’s early novels, it might be interesting to pursue the analysis, which employs some original approaches to Sand, by considering the way in which Sand adapts her strategy in the construction of later heroines, such as the titular protagonists of Jeanne (1844) and Nanon (1872), or the significance of disguise in supernatural settings in Mont-Revêche (1853) and Les Dames vertes (1859).

Nerval et les limbes de l'histoire: lecture des 'Illuminés' (review)

Pas de vérité en art? Quelques pensées de Satie, Braque, Mallarmé et Derrida

Review: La Lyre desenchantee: l'instrument de musique et la voix humaine dans la litterature francaise du XIXe siecle

Dans ses ecrits sur la musique, des l'epoque des Mythologies et jusqu'a la fin de sa vie, Barthes repete le geste symboliste, mallarmeen, qui consiste a definir la litterature (voire l'art en general) a travers les caracteristiques propres a la musique. La musique serait un phenomene sensible, inconcevable en dehors de son rapport au corps, et qui ne peut s'epuiser dans le mouvement de la signification ; de meme la litterature. L'analyse de ce geste aide a voir comment et pourquoi Barthes maintient sa foi en l'existence d'un art haut (par opposition a l'art bourgeois), en la litterature (par opposition au discours non litteraire), en une 'essence' du chant ou de la photographie. Mais si la litterature, chez Barthes, se definit a travers une analogie avec la musique, l'inverse est tout aussi vrai : la musique est dite lettre, texte, prosodie ; Barthes affirme qu'il faut que le chant ecrive. En effet, la critique barthesienne doit evaluer chaque art en fonction de ce qu'il n'est pas ; car 's'il y a une signification des phenomenes sensibles, c'est toujours dans le deplacement, la substitution, bref, en fin de compte, l'absence, qu'elle se manifeste avec le plus d'eclat' ('Le Chant romantique').

Mallarme ou l'obscurite lumineuse. Sous la direction de Bertrand Marchal et Jean-Luc Steinmetz. (Collection Savoir: Lettres). Paris, Hermann, 1999. 384 pp. Pb 240F.

Abstract Baudelaire seems, in his essay on Wagner, to affirm that music (or at least, Wagner's music) can translate positive ideas, and that this can be demonstrated by analysis of the similarities between the reactions of different people to a given musical work. However, he also consistently undermines his own demonstration: the implication is always present that perceived translation into and out of music is never independent of extra-musical suggestion; and it is always also possible, thanks to the constant duplicity of Baudelaire's syntax, to interpret the message apparently conveyed by music, not as a positive and specific one, but as the absolutely general idea of art conceived as a universal. In this way, the relationship between music and letters becomes the indescribable but necessary bridge between the positive and the absolute, or between the real and the ideal; and the Baudelairean doctrine of 'correspondances' may be re-interpreted as the means of maintaining that bridge.

Review. Isidore Ducasse, comte de Lautreamont: Les Chants de Maldoror -- Lettres -- Poesies I et II. Terray, Marie-Louise

Review. Correspondance. Lettres sur la poesie. Edition de Bertrand Marchal. Mallarme, Stephane

Gerard de Nerval ou la devotion a l'imaginaire@@@Nerval et ses peres: Portrait en trois volets avec deux gonds et un cadenas@@@Imagination in Gerard de Nervals Erzahlerischem Werk

Review. Le Desir de la vierge: Herodiade chez Mallarme. Robillard, Monic

Review. 'Les Chants de Maldoror'. Poesies. Lettres. Edition etablie par Patrick Besnier. Lautreamont

Nerval et ses pères : portrait en trois volets avec deux gonds et un cadenas

Review. Ecriture du romantisme II. Les Manuscrits de George Sand. Didier, Beatrice et Jacques Neefs (eds)

Review. Aurelia. Un roman a faire. Les Nuits d'octobre. Petits chateaux de Boheme. Pandora. Promenades et souvenirs. Edition de Jacques Bony. Nerval, Geard de

Review. La Religion de Mallarme: Poesie, mythologie et religion. Marchal, Bertrand

Fever, Absolute Neutrophil Count, Procalcitonin, and the AAP Febrile Infant Guidelines.

We aimed to determine the frequency of bacteremia, septic shock and bacterial meningitis in pediatric liver transplant recipients (pLTRs) in the outpatient setting and to identify clinical factors associated with bacteremia.

METHODS
Multicenter retrospective study of pLTRs evaluated in the emergency department or outpatient clinic between 2010 and 2018 for suspected infection, defined as fever ≥38 °C or a blood culture obtained. We excluded patients with nontransplant immunodeficiency, multiorgan transplants or intestinal failure. The primary outcome was bacteremia; secondary outcomes included fluid-refractory septic shock, bacterial meningitis and antibiotic resistance. The unit of analysis was the encounter.

RESULTS
A total of 151 children had 336 encounters for infection evaluation within 2 years of transplant. Of 307 (91.4%) encounters with blood cultures, 17 (5.5%) had bacteremia, with 10 (58.8%) occurring within 3 months of transplant. Fluid-refractory septic shock and bacterial meningitis occurred in 7 out of 307 (2.8%) and 0 out of 307 encounters, respectively. Factors associated with bacteremia included closer proximity to transplant (<3 months) [odds ratio (OR): 3.6; 95% confidence interval (CI): 1.3-9.8; P = 0.01], shorter duration of illness (OR: 4.3; 95% CI: 1.5-12.0; P < 0.01) and the presence of a central venous catheter (CVC) (OR: 12.7; 95% CI: 4.4-36.6; P < 0.01). However, 5 (29.4%) encounters with bacteremia had none of these factors. Among Gram-positive pathogens, 1 out of 7 (14.2%) isolates were resistant to vancomycin. Among Gram-negative pathogens, 3 out of 13 (23.1%) isolates were resistant to 3rd generation cephalosporins.

Bacteremia was an important cause of infection within 2 years of pLTR. Clinical factors increased the risk of bacteremia. Further, large sample studies should derive multivariable models to identify those at high and low risk of bacteremia to optimize antibiotic use.

Patients with multisystem inflammatory disease in children (MIS-C) are at risk of developing shock. Our objectives were to determine independent predictors associated with development of delayed shock (≥3 hours from emergency department [ED] arrival) in patients with MIS-C and to derive a model predicting those at low risk for delayed shock.

METHODS
We conducted a retrospective cross-sectional study of 22 pediatric EDs in the New York City tri-state area. We included patients meeting World Health Organization criteria for MIS-C and presented April 1 to June 30, 2020. Our main outcomes were to determine the association between clinical and laboratory factors to the development of delayed shock and to derive a laboratory-based prediction model based on identified independent predictors.

RESULTS
Of 248 children with MIS-C, 87 (35%) had shock and 58 (66%) had delayed shock. A C-reactive protein (CRP) level greater than 20 mg/dL (adjusted odds ratio [aOR], 5.3; 95% confidence interval [CI], 2.4-12.1), lymphocyte percent less than 11% (aOR, 3.8; 95% CI, 1.7-8.6), and platelet count less than 220,000/uL (aOR, 4.2; 95% CI, 1.8-9.8) were independently associated with delayed shock. A prediction model including a CRP level less than 6 mg/dL, lymphocyte percent more than 20%, and platelet count more than 260,000/uL, categorized patients with MIS-C at low risk of developing delayed shock (sensitivity 93% [95% CI, 66-100], specificity 38% [95% CI, 22-55]).

Serum CRP, lymphocyte percent, and platelet count differentiated children at higher and lower risk for developing delayed shock. Use of these data can stratify the risk of progression to shock in patients with MIS-C, providing situational awareness and helping guide their level of care.

Predicting Delayed Shock in Multisystem Inflammatory Disease in Children: A Multicenter Analysis From the New York City Tri-State Region.

Accuracy of NGAL As a Biomarker for Urinary Tract Infection in Young Febrile Children: An Individual Patient-Data Meta-Analysis.

Current methods to diagnose bacteremia are limited. In this pilot study of children with cancer presenting with fever, we determined the concordance between a novel high-throughput sequencing platform called BacCapSeq and blood culture. High-throughput sequencing had modest concordance with blood culture. Discordant organisms included those with both unlikely or potential clinical relevance.

High-throughput Sequencing to Identify Bacteremia in Children with Cancer.

Bronchiolitis within the first 3 months of life is a risk factor for more severe illness. We aimed to identify characteristics associated with mild bronchiolitis in infants ≤90 days old presenting to the emergency department (ED).

Abstract Objectives  Clinical decision support (CDS) has promise for the implementation of antimicrobial stewardship programs (ASPs) in the emergency department (ED). We sought to assess the usability of a newly developed automated CDS to improve guideline-adherent antibiotic prescribing for pediatric community-acquired pneumonia (CAP) and urinary tract infection (UTI). Methods  We conducted comparative usability testing between an automated, prototype CDS-enhanced discharge order set and standard order set, for pediatric CAP and UTI antibiotic prescribing. After an extensive user-centered design process, the prototype CDS was integrated into the electronic health record, used passive activation, and embedded locally adapted prescribing guidelines. Participants were randomized to interact with three simulated ED scenarios of children with CAP or UTI, across both systems. Measures included task completion, decision-making and usability errors, clinical actions (order set use and correct antibiotic selection), as well as objective measures of system usability, utility, and workload using the National Aeronautics and Space Administration Task Load Index (NASA-TLX). The prototype CDS was iteratively refined to optimize usability and workflow. Results  Usability testing in 21 ED clinical providers demonstrated that, compared to the standard order sets, providers preferred the prototype CDS, with improvements in domains such as explanations of suggested antibiotic choices ( p  < 0.001) and provision of additional resources on antibiotic prescription ( p  < 0.001). Simulated use of the CDS also led to overall improved guideline-adherent prescribing, with a 31% improvement for CAP. A trend was present toward absolute workload reduction. Using the NASA-TLX, workload scores for the current system were median 26, interquartile ranges (IQR): 11 to 41 versus median 25, and IQR: 10.5 to 39.5 for the CDS system ( p  = 0.117). Conclusion  Our CDS-enhanced discharge order set for ED antibiotic prescribing was strongly preferred by users, improved the accuracy of antibiotic prescribing, and trended toward reduced provider workload. The CDS was optimized for impact on guideline-adherent antibiotic prescribing from the ED and end-user acceptability to support future evaluative trials of ED ASPs.

Evaluation of an Antimicrobial Stewardship Decision Support for Pediatric Infections

There are limited data on examination criteria for diagnosing acute otitis media in young infants. In this 33-site retrospective study of afebrile infants ≤90 days, clinicians typically documented tympanic membrane erythema with ≥1 other otologic abnormalities (64.1%) to diagnose acute otitis media. Notable differences in ear examination findings used for diagnosis existed across age subgroups.

Otologic Examination Findings In Afebrile Young Infants Clinically Diagnosed With Acute Otitis Media

Febrile preterm infants: they are not just small febrile, term infants.

Health care providers (HCPs) in the emergency department (ED) frequently must decide whether to conduct or forego confidential conversations with adolescent patients about sensitive topics, such as those related to mental health, substance use, and sexual and reproductive health. The objective of this multicenter qualitative analysis was to identify factors that influence the conduct of confidential conversations with adolescent patients in the ED.

Factors influencing the conduction of confidential conversations with adolescents in the emergency department: A multicenter, qualitative analysis

Implementation Trials That Change Practice: Evidence Alone Is Never Enough.

Background: Our primary goal was to determine the frequency of bacteremia and urinary tract infections (UTI) in pediatric renal transplant recipients presenting with suspected infection within 2 years of transplant and to identify clinical and laboratory factors associated with bacteremia. Methods: We conducted a retrospective cross-sectional study for all pediatric (<18 years old) renal transplant recipients seen at 3 large children’s hospitals from 2011 to 2018 for suspected infection within 2 years of transplant date, defined as pyrexia (>38°C) or a blood culture being ordered. Patients with primary immunodeficiencies, nontransplant immunosuppression, intestinal failure, and patients who had moved out of the local area were excluded. The primary outcome was bacteremia or UTI; secondary outcomes included pneumonia, bacterial or fungal meningitis, respiratory viral infections, and antibiotic resistance. The unit of analysis was the visit. Results: One hundred fifteen children had 267 visits for infection evaluation within 2 years of transplant. Bacteremia (with or without UTI) was diagnosed in 9/213 (4.2%) and UTIs in 63/189 (33.3%). Tachycardia and hypotension were present in 66.7% and 0% of visits with documented bacteremia, respectively. White blood cell (12,700 cells/mm3 vs. 10,900 cells/mm3; P = 0.43) and absolute neutrophil count (10,700 vs. 8200 cells/mm3; P = 0.24) were no different in bacteremic and nonbacteremic patients. The absolute band count was higher in children with bacteremia (1900 vs. 600 cells/mm3; P = 0.02). Among Gram-negative pathogens, antibiotic resistance was seen to 3rd (14.5%) and 4th (3.6%) generation cephalosporins, 12.7% to semisynthetic penicillins, and 3.6% to carbapenems. Conclusions: Bacteremia or UTIs were diagnosed in one-quarter of all pediatric renal transplant recipients presenting with suspected infection within 2 years of transplant. Evaluations were highly variable, with one-third of visits not having urine cultures obtained. No single demographic, clinical or laboratory variable accurately identified patients with bacteremia, although combinations of findings may identify a high-risk population.

Frequency of Bacteremia and Urinary Tract Infection in Pediatric Renal Transplant Recipients

Objective Adolescent females in the United States continue to have unmet sexual and reproductive healthcare needs. Research shows that interventions incorporating peer support can augment perceived self-efficacy and reinforce healthy behaviors. Yet, few user-centered digital sexual health interventions incorporate peer support, and aim to change perceptions of peer norms and model social skills. The objective of this study was to design and demonstrate the receptivity of adolescent females to illustrated digital social media stories that promote healthy sexual behaviors and peer social support. Methods We conducted a three-phase study approved by our Institutional Review Board. In Phase 1, we presented sexually active adolescent female emergency department patients aged 14–19 with eight sexual health scenarios via a survey study. Participants wrote three text messages addressed to the protagonist of each scenario which motivated and encouraged her to consider the use of contraceptives. Messages were scored based on the construct of peer support (emotional, tangible, informational, and belonging). In Phase 2, we worked with a professional artist and screenwriter to design digital sexual health comics using the gathered messages. In Phase 3, we gathered feedback on the comics from adolescent female emergency department patients. Results Females (n  =  22) provided 352 messages. Using top rated messages, we designed five digital visualizations in a running story called Mari tells it like it is. Each story incorporated 5–12 peer-authored quotes. We inserted the final images into Instagram®. Additional females (n  =  39) found the images “relatable,” “super-realistic,” and “educational.” Conclusion Collecting peer-authored texts from our local adolescent community led to the creation of well-received sexual health visualizations. This novel method of design incorporated adolescent voices to promote peer support and healthy behaviors.

Designing illustrative social media stories to promote adolescent peer support and healthy sexual behaviors

Abstract Exclusion of special populations (older adults; pregnant women, children, and adolescents; individuals of lower socioeconomic status and/or who live in rural communities; people from racial and ethnic minority groups; individuals from sexual or gender minority groups; and individuals with disabilities) in research is a pervasive problem, despite efforts and policy changes by the National Institutes of Health and other organizations. These populations are adversely impacted by social determinants of health (SDOH) that reduce access and ability to participate in biomedical research. In March 2020, the Northwestern University Clinical and Translational Sciences Institute hosted the “Lifespan and Life Course Research: integrating strategies” “Un-Meeting” to discuss barriers and solutions to underrepresentation of special populations in biomedical research. The COVID-19 pandemic highlighted how exclusion of representative populations in research can increase health inequities. We applied findings of this meeting to perform a literature review of barriers and solutions to recruitment and retention of representative populations in research and to discuss how findings are important to research conducted during the ongoing COVID-19 pandemic. We highlight the role of SDOH, review barriers and solutions to underrepresentation, and discuss the importance of a structural competency framework to improve research participation and retention among special populations.

Barriers to and solutions for representative inclusion across the lifespan and in life course research: The need for structural competency highlighted by the COVID-19 pandemic

Lung ultrasound (LUS) may help determine illness severity in children with acute lower respiratory tract infections (LRTI) but limited pediatric studies exist. Our objective was to determine the association between LUS findings and illness severity in children with LRTI.

Lack of Association Between a Quantified Lung Ultrasound Score and Illness Severity in Pediatric Emergency Department Patients With Acute Lower Respiratory Infections

Objective The aim of this study was to validate an adult-derived clinical decision rule for ultrasound identification of methicillin-resistant Staphylococcus aureus (MRSA) skin abscesses in a pediatric cohort. Methods We conducted a retrospective study of skin and soft tissue infections in patients <21 years presenting to the emergency department who had radiology performed ultrasounds completed and wound cultures obtained. Ultrasound scans were reviewed for edge definition, volume, and shape by 2 pediatric emergency physicians with expertise in point-of-care ultrasound, with approximately 25% of scans reviewed by both experts to evaluate interrater reliability. A third, blinded expert weighed in for discrepancies before analysis. Test performance characteristics were calculated for the clinical decision rule in children. Results Two hundred nine patients were enrolled, with mean age of 9.8 (±6.7) years; 87 (42%) were male. Sixty-nine (33%) patients had a wound culture positive for MRSA. The clinical decision rule had a sensitivity of 86% (95% confidence interval [CI], 75%–93%), specificity of 32% (95% CI, 25%–41%), positive predictive value of 38% (95% CI, 35%–42%), negative predictive value of 82% (95% CI, 71%–89%), positive likelihood ratio of 1.26 (95% CI, 1.08–1.46), negative likelihood ratio of 0.45 (95% CI, 0.24–0.84), and an odds ratio of 2.8 (95% CI, 1.31–5.97). Conclusions This clinical decision rule for ultrasound identification of MRSA abscesses had moderately high sensitivity and negative predictive value in pediatric patients, with similar sensitivity compared with the original adult validation group. Ultrasound may help identify MRSA abscesses, allowing for improved antibiotic choices and outcomes for children with MRSA abscesses.

Validation of a Clinical Decision Rule for Ultrasound Identification of MRSA Skin Abscesses in Children

OBJECTIVE
To determine the prevalence of bacteremia and/or bacterial meningitis in febrile infants ≤60 days of age with positive urinalysis (UA) results.

METHODS
Secondary analysis of a prospective observational study of noncritical febrile infants ≤60 days between 2011 and 2019 conducted in the Pediatric Emergency Care Applied Research Network emergency departments. Participants had temperatures ≥38°C and were evaluated with blood cultures and had UAs available for analysis. We report the prevalence of bacteremia and bacterial meningitis in those with and without positive UA results.

RESULTS
Among 7180 infants, 1090 (15.2%) had positive UA results. The risk of bacteremia was higher in those with positive versus negative UA results (63/1090 [5.8%] vs 69/6090 [1.1%], difference 4.7% [3.3% to 6.1%]). There was no difference in the prevalence of bacterial meningitis in infants ≤28 days of age with positive versus negative UA results (∼1% in both groups). However, among 697 infants aged 29 to 60 days with positive UA results, there were no cases of bacterial meningitis in comparison to 9 of 4153 with negative UA results (0.2%, difference -0.2% [-0.4% to -0.1%]). In addition, there were no cases of bacteremia and/or bacterial meningitis in the 148 infants ≤60 days of age with positive UA results who had the Pediatric Emergency Care Applied Research Network low-risk blood thresholds of absolute neutrophil count <4 × 103 cells/mm3 and procalcitonin <0.5 ng/mL.

Among noncritical febrile infants ≤60 days of age with positive UA results, there were no cases of bacterial meningitis in those aged 29 to 60 days and no cases of bacteremia and/or bacterial meningitis in any low-risk infants based on low-risk blood thresholds in both months of life. These findings can guide lumbar puncture use and other clinical decision making.

Serious Bacterial Infections in Young Febrile Infants With Positive Urinalysis Results.

Objectives The aims of the study were to determine the frequency of and factors associated with leftover or expired prescription medication (“leftover medication”) presence in homes with children and to assess caregivers' reported behaviors and knowledge regarding disposal of leftover medications in the home. Methods This study is a planned secondary analysis from a survey of primary caregivers of children aged 1 to 17 years presenting to an emergency department. The survey assessed leftover medications in the home and medication disposal practices, knowledge, and guidance. The survey was developed iteratively and pilot tested. Multivariable logistic regression was used to identify factors associated with leftover medication presence in the home. Results We enrolled 550 primary caregivers; 97 of the 538 analyzed (18.0%; 95% confidence interval [CI], 14.8–21.5) reported having leftover medications in their home, most commonly antibiotics and opioids. Of respondents, 217/536 (40.5%) reported not knowing how to properly dispose of medications and only 88/535 (16.4%) reported receiving guidance regarding medication disposal. Most caregivers reported throwing leftover medications in the trash (55.7%) or flushing them down the toilet (38.5%). Caregivers with private insurance for their child were more likely to have leftover medications (adjusted odds ratio [aOR], 1.99; CI, 1.15–3.44), whereas Hispanic caregivers (aOR, 0.24; CI, 0.14–0.42) and those who received guidance on leftover medications (aOR, 0.30; CI, 0.11–0.81) were less likely to have leftover medications in the home. Conclusions Leftover medications are commonly stored in homes with children and most caregivers do not receive guidance on medication disposal. Improved education and targeted interventions are needed to ensure proper medication disposal practices.

Caregiver Practices and Knowledge Regarding Leftover Prescription Medications in Homes With Children

Urinary Tract Infections in Children: Accuracy of a Novel Dipstick Biomarker Test via Bagged Urine Sampling

Intravenous ketorolac is commonly used for treating migraine headaches in children. However, the prerequisite placement of an intravenous line can be technically challenging, time‐consuming, and associated with pain and distress. Intranasal ketorolac may be an effective alternative that is needle‐free and easier to administer. We aimed to determine whether intranasal ketorolac is non‐inferior to intravenous ketorolac for reducing pain in children with migraine headaches.

Intranasal ketorolac versus intravenous ketorolac for treatment of migraine headaches in children: A randomized clinical trial

Introduction There remain significant knowledge gaps about the management and outcomes of children with anaphylaxis. These gaps have led to practice variation regarding decisions to hospitalise children and length of observation periods following treatment with epinephrine. The objectives of this multicentre study are to (1) determine the prevalence of and risk factors for severe, persistent, refractory and biphasic anaphylaxis, as well as persistent and biphasic non-anaphylactic reactions; (2) derive and validate prediction models for emergency department (ED) discharge; and (3) determine data-driven lengths of ED and inpatient observation prior to discharge to home based on initial reaction severity. Methods and analysis The study is being conducted through the Pediatric Emergency Medicine Collaborative Research Committee (PEMCRC). Children 6 months to less than 18 years of age presenting to 30 participating EDs for anaphylaxis from October 2015 to December 2019 will be eligible. The primary outcomes for each objective are (1) severe, persistent, refractory or biphasic anaphylaxis, as well as persistent or biphasic non-anaphylactic reactions; (2) safe ED discharge, defined as no receipt of acute anaphylaxis medications or hypotension beyond 4 hours from first administered dose of epinephrine; and (3) time from first to last administered dose of epinephrine and vasopressor cessation. Analyses for each objective include (1) descriptive statistics to estimate prevalence and generalised estimating equations that will be used to investigate risk factors for anaphylaxis outcomes, (2) least absolute shrinkage and selection operator regression and binary recursive partitioning to derive and validate prediction models of children who may be candidates for safe ED discharge, and (3) Kaplan-Meier analyses to assess timing from first to last epinephrine doses and vasopressor cessation based on initial reaction severity. Ethics and dissemination All sites will obtain institutional review board approval; results will be published in peer-reviewed journals and disseminated via traditional and social media, blogs and online education platforms.

PEMCRC anaphylaxis study protocol: a multicentre cohort study to derive and validate clinical decision models for the emergency department management of children with anaphylaxis

Upregulation of type 1 conventional dendritic cells implicates antigen cross-presentation in multisystem inflammatory syndrome

Supplemental digital content is available in the text. Objectives Nearly 1 million children visit emergency departments (EDs) annually for mental health crises. Caregivers play a critical role in the outcome of mental illness in their children, yet there is limited research on effective means to engage caregivers in the ED and provide the support they need. Our aim was to determine caregivers' perceptions about mental illness in their children, specifically regarding suicidality and depression, the impact of the children's mental health on the caregiver, and barriers to and facilitators of treatment. Methods Guided by qualitative descriptive methodology, we conducted semistructured, open-ended interviews with a purposive sample of English-speaking primary caregivers of children 6 to 17 years old who presented with suicidal ideations or behaviors to 1 urban pediatric ED. Interviews were recorded and transcribed verbatim, and conventional content analysis was performed. Results The participants (n = 20) were largely single ethnic-racial minority mothers. Content analysis identified 6 categories: caregivers' definitions of mental health, depression, and suicidality; perceived causes of mental illness; difficulty in identification of mental illness; the influence of the mental illness on caregivers; a complex network of communication among involved parties that resulted in the child's ED visit, as well as barriers to and facilitators of treatment. Conclusions We identified several categories that encapsulate caregivers' perceptions of mental health and mental illness in their children and its effect on them. Future research should explore how inner-city EDs might partner with schools and trusted community-based organizations to enhance caregiver knowledge, reduce obstacles to care, increase screening for at-risk youth and implement strategies to optimize outcomes for children with depression and suicidal ideations.

Caregiver Perceptions of Mental Health and Barriers to and Facilitators of Their Child's Treatment

Validation of A Prediction Rule For Serious Bacterial Infections (SBIs) In Febrile Infants < 60 Days In A Multicenter Network

Risk of Traumatic Brain Injuries in Infants Younger than 3 Months With Minor Blunt Head Trauma.

Urinary neutrophil gelatinase‐associated lipocalin (uNGAL) appears highly accurate to identify urinary tract infections (UTIs) when obtained via catheterization. Our primary aim was to determine the agreement in uNGAL levels between paired catheter and bag urine specimens. Our secondary aim was to compare the diagnostic test characteristics of quantitative uNGAL, dipstick uNGAL (a potential point‐of‐care test), and urinalysis (UA).

Urinary tract infections in children: Testing a novel, noninvasive, point‐of‐care diagnostic marker

Decreasing unnecessary cranial computed tomography (CT) use in pediatric head trauma patients remains important for emergency departments (EDs) across the US. Our study evaluated CT use in children with minor blunt head trauma in 21 community EDs within an integrated health-care system.

METHODS
We studied all children younger than 18 years old presenting to 21 community EDs between 2016 through 2018 with acute minor blunt head trauma, defined by an algorithm of ED chief complaints and diagnoses. We excluded patients with traumatic brain injuries diagnosed in the prior year, a CT within 24 hours prior to the ED visit, or an ED Glasgow Coma Scale score of less than 14.

RESULTS
Among 39,792 pediatric minor head trauma ED visits, the aggregate CT use proportion across all EDs was 12.9% [95% confidence interval (CI), 12.6-13.3%; facility-level range, 5.4-21.6%]. The 7 facilities that had previously received a clinical decision support system intervention implementing the Pediatric Emergency Care Applied Research Network rules during 2013 through 2014 had an aggregate mean CT ordering rate of 11.2% (95% CI, 10.7-11.7%; facility-level range, 5.4-14.3%) compared to 14.1% (95% CI, 13.6-14.5%; facility-level range, 7.3-21.6%) for the nonintervention facilities.

CT use for children with minor blunt head trauma in the community EDs of an integrated health-care system was low and stable across facilities from 2016 through 2018. This may be indicative of the safe stewardship of resources in the system, including the absence of financial or medicolegal incentives to scan very low-risk patients as well the availability of resources for close patient follow-up.

Computed Tomography Use in Children With Minor Head Trauma Presenting to 21 Community Emergency Departments Within an Integrated Health-Care System.

BACKGROUND/OBJECTIVE
To characterize the relationship between the presence of enteroviral skin infection, defined as a positive skin polymerase chain reaction (PCR) test, and the nasopharyngeal (NP) respiratory pathogen panel (RPP) PCR test which includes enterovirus/rhinovirus as an analyte.

METHODS
A retrospective chart review was performed on 543 subjects, age 18 years or younger, who had enterovirus (EV) skin swabs performed at an academic medical center in New York City between September 2014 and November 2019. Those patients with positive EV skin PCR were considered to have an enteroviral skin infection, and those with a negative EV skin PCR were considered not to have an enteroviral skin infection. Of those 543 children who had EV skin PCR, 170 also had an NP swab RPP performed. These NP swab RPP results were characterized as positive or negative, and if positive, it was noted if the patient was positive or negative for enterovirus/rhinovirus. The positive predictive value (PPV), negative predictive value (NPV), specificity, and sensitivity of a NP swab RPP for enteroviral skin infection were then calculated.

RESULTS
An enterovirus/rhinovirus NP swab RPP had a NPV of 95%, PPV of 43%, sensitivity of 90%, and specificity of 62% for cutaneous enterovirus infection.

The enteroviral skin PCR test is an assay that was validated at this institution. In clinically suspicious cases of EV, a positive NP swab RPP for enterovirus/rhinovirus is a sensitive test. A negative test is highly predictive of not having EV on the skin. Although further data are needed, given that NP swab RPP is readily available, these data may suggest that an NP swab RPP, when appropriately utilized, can support or exclude a clinical diagnosis of cutaneous enterovirus in the pediatric population.

The use of respiratory pathogen panel nasal polymerase chain reaction testing in predicting cutaneous enteroviral infections in the pediatric population.

Clinical Interpretation of Self-Reported Pain Scores in Children with Acute Pain.

Supplemental digital content is available in the text. Objective Male adolescents frequently present to the emergency department (ED) and many participate in behaviors increasing their risk of sexually transmitted infections and unintended pregnancies. Although the ED visit may represent an intervention opportunity, how best to design and deliver a sexual health intervention matching the preferences of adolescent male users is unclear. Our objective was to explore receptivity to and preferences for sexual health interventions among adolescent male ED patients. Methods In this qualitative study, we asked sexually active male ED patients aged 14 to 21 years about their attitudes toward ED-based sexual health interventions and preferences for intervention modalities. Participants interacted with an early prototype of a digital intervention to gather specific feedback. Enrollment continued until saturation of key themes. Interviews were recorded, transcribed, and coded based on thematic analysis using NVivo. Results Participants (n = 42) were predominantly 18 to 21 years (63%) and Hispanic (79%). Although most (71%) had sex in the prior 3 months, 45% did not use a condom at last intercourse and 17% had impregnated a partner. Participants viewed the ED visit as unused time without distracting influences, suitable for educational sexual health interventions. They considered ED-based digital interventions a reliable and confidential source of information. Engaging interventions allowed user control and provided novel and relatable content. Conclusions Adolescent male ED patients are receptive to ED-based digital sexual health interventions. These identified preferences should be considered when designing future user-informed sexual health interventions for the ED setting.

Adolescent Male Receptivity of and Preferences for Sexual Health Interventions in the Emergency Department

Adolescent females presenting to emergency departments (EDs) inconsistently use contraceptives. We aimed to assess implementation outcomes and potential efficacy of a user‐informed, theory‐based digital health intervention developed to improve sexual and reproductive health for adolescent females in the ED.

A multi‐media digital intervention to improve the sexual and reproductive health of female adolescent emergency department patients

Prevalence of Bacteremia And Meningitis In Febrile Infants ≤ 60 Days With Positive Urinalyses In A Multicenter Network

The Journal of adolescent health : official publication of the Society for Adolescent Medicine

A User-Informed, Theory-Based Pregnancy Prevention Intervention for Adolescents in the Emergency Department: A Prospective Cohort Study.

* Abbreviation:
 COVID-19 — : coronavirus disease 2019

In this issue of Pediatrics , Sisk et al1 used state and territory health department data to describe temporal and geographic trends in coronavirus disease 2019 (COVID-19) among children over a 4-month period. The authors found that in the latter half of the study period, the proportion of cases identified in children increased threefold to fourfold from the start of the study period.

We were struck by several features of this report, which we feel have implications for COVID-19 surveillance. First, there was substantial heterogeneity across the data sources aggregated regarding definitions (including the chronological definition of a child) and the data reported. There was also variation across surveillance methods regarding which tests were used and reported. For example, Texas only reports confirmed cases, defined by polymerase chain reaction, and does not report rapid antigen tests, which define a probable case,2 … 

Address correspondence to Andrea T. Cruz, MD, MPH, Department of Pediatrics, Baylor College of Medicine, 6621 Fannin St, Suite A2210, Houston, TX 77030. E-mail: acruz{at}bcm.edu

Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial

Comparison of Preadministered and Coadministered Lidocaine for Treating Pain and Distress Associated With Intranasal Midazolam Administration in Children: A Randomized Clinical Trial.

Abstract Objective This study was aimed to explore the intersection between organizational environment, workflow, and technology in pediatric emergency departments (EDs) and how these factors impact antibiotic prescribing decisions. Methods Semistructured interviews with 17 providers (1 fellow and 16 attending faculty), and observations of 21 providers (1 physician assistant, 5 residents, 3 fellows, and 12 attendings) were conducted at three EDs in the United States. We analyzed interview transcripts and observation notes using thematic analysis. Results Seven themes relating to antibiotic prescribing decisions emerged as follows: (1) professional judgement, (2) cognition as a critical individual resource, (3) decision support as a critical organizational resource, (4) patient management with imperfect information, (5) information-seeking as a primary task, (6) time management, and (7) broad process boundaries of antibiotic prescribing. Discussion The emerging interrelated themes identified in this study can be used as a blueprint to design, implement, and evaluate clinical decision support (CDS) systems that support antibiotic prescribing in EDs. The process boundaries of antibiotic prescribing are broader than the current boundaries covered by existing CDS systems. Incongruities between process boundaries and CDS can under-support clinicians and lead to suboptimal decisions. We identified two incongruities: (1) the lack of acknowledgment that the process boundaries go beyond the physical boundaries of the ED and (2) the lack of integration of information sources (e.g., accessibility to prior cultures on an individual patient outside of the organization). Conclusion Significant opportunities exist to improve appropriateness of antibiotic prescribing by considering process boundaries in the design, implementation, and evaluation of CDS systems.

Considerations for Designing EHR-Embedded Clinical Decision Support Systems for Antimicrobial Stewardship in Pediatric Emergency Departments

Background 7 Viral infection of the respiratory tract is one of the major causes of hospital visits for young 8 children. In this study, we report the occurrence and co-occurrence of different virus types and 9 subtypes among the patients arriving at the pediatric emergency room of New York Presbyterian 10 Hospital, a major urban hospital. 11 Methods We collected nasal swabs from the patients and their accompanying persons. We also recorded the levels 13 (None, Mild, High, and Severe) of their symptoms (Fever, Chill, Muscle Pain, Watery Eye, Runny Nose, 14 Sneezing, Sore throat and Cough). The collected swabs were tested for the presence of common viruses 15 infecting the respiratory tract. Human Rhinovirus was associated with less severe symptoms. In addition, we observed that Influenza and Respiratory Syncytial Virus were more likely to infect a patient when these viruses also infected the 2 accompanying person. We also found that it was difficult to distinguish among viruses based on the 3 symptoms. The inability to distinguish among different virus types and subtypes is explained by the fact 4 that multiple viruses lead to similar symptoms. The findings of this study provide a better understanding of respiratory viral infections in small children 7 presenting at a pediatric emergency room in New York.

Virome of New York Presbyterian Hospital 1 pediatric emergency 2

Respiratory viral infections are a leading cause of disease worldwide. However, the overall community prevalence of infections has not been properly assessed, as standard surveillance is typically acquired passively among individuals seeking clinical care.

Active surveillance documents rates of clinical care seeking due to respiratory illness

Author response for "Respiratory viruses in pediatric emergency department patients and their family members"

Pain and distress associated with intranasal midazolam administration can be decreased by administering lidocaine before intranasal midazolam (preadministered lidocaine) or combining lidocaine with midazolam in a single solution (coadministered lidocaine). We hypothesized coadministered lidocaine is non‐inferior to preadministered lidocaine for decreasing pain and distress associated with intranasal midazolam administration.

Comparison of preadministered and coadministered lidocaine for treating pain and distress associated with intranasal midazolam administration in children: A randomized clinical trial

Playground equipment-related extremity fractures in children presenting to US emergency departments, 2006–2016

Interobserver Agreement in the Assessment of Clinical Findings in Children with Headaches.

Respiratory viral infections account for a substantial fraction of pediatric emergency department (ED) visits. We examined the epidemiological patterns of seven common respiratory viruses in children presenting to EDs with influenza‐like illness (ILI). Additionally, we examined the co‐occurrence of viral infections in the accompanying adults and risk factors associated with the acquisition of these viruses.

Respiratory viruses in pediatric emergency department patients and their family members

In this case series of 7 febrile infants aged ≤60 days with confirmed SARS-CoV-2 infection, no severe outcomes occurred. In this case series, we describe the clinical course and outcomes of 7 febrile infants aged ≤60 days with confirmed severe acute respiratory syndrome coronavirus 2 infection. No infant had severe outcomes, including the need for mechanical ventilation or ICU level of care. Two infants had concurrent urinary tract infections, which were treated with antibiotics. Although a small sample, our data suggest that febrile infants with severe acute respiratory syndrome coronavirus 2 infection often have mild illness.

Novel Coronavirus Infection in Febrile Infants Aged 60 Days and Younger

Invasive bacterial infections and adverse events are uncommon in afebrile infants with clinician-diagnosed acute otitis media. OBJECTIVES: To determine the prevalence of invasive bacterial infections (IBIs) and adverse events in afebrile infants with acute otitis media (AOM). METHODS: We conducted a 33-site cross-sectional study of afebrile infants ≤90 days of age with AOM seen in emergency departments from 2007 to 2017. Eligible infants were identified using emergency department diagnosis codes and confirmed by chart review. IBIs (bacteremia and meningitis) were determined by the growth of pathogenic bacteria in blood or cerebrospinal fluid (CSF) culture. Adverse events were defined as substantial complications resulting from or potentially associated with AOM. We used generalized linear mixed-effects models to identify factors associated with IBI diagnostic testing, controlling for site-level clustering effect. RESULTS: Of 5270 infants screened, 1637 met study criteria. None of the 278 (0%; 95% confidence interval [CI]: 0%–1.4%) infants with blood cultures had bacteremia; 0 of 102 (0%; 95% CI: 0%–3.6%) with CSF cultures had bacterial meningitis; 2 of 645 (0.3%; 95% CI: 0.1%–1.1%) infants with 30-day follow-up had adverse events, including lymphadenitis (1) and culture-negative sepsis (1). Diagnostic testing for IBI varied across sites and by age; overall, 278 (17.0%) had blood cultures, and 102 (6.2%) had CSF cultures obtained. Compared with infants 0 to 28 days old, older infants were less likely to have blood cultures (P < .001) or CSF cultures (P < .001) obtained. CONCLUSION: Afebrile infants with clinician-diagnosed AOM have a low prevalence of IBIs and adverse events; therefore, outpatient management without diagnostic testing may be reasonable.

Invasive Bacterial Infections in Afebrile Infants Diagnosed With Acute Otitis Media

The clinical course of SARS-CoV-2 infection in young infants is not well understood. In this prospective cohort study, we compared the presence and duration of symptoms in febrile infants ≤60 days with (n = 7) and without (n = 16) SARS-CoV-2 infection. Overall, we observed overlapping symptoms and duration of illness, with longer length of cough and nasal congestion among the SARS-CoV-2-positive infants.

Presence and Duration of Symptoms in Febrile Infants With and Without SARS-CoV-2 Infection.

Background: Viral infection of the respiratory tract is one of the major causes of hospital visits for young children. In this study, we report the occurrence and co-occurrence of different virus types and subtypes among the patients arriving at the pediatric emergency room of New York Presbyterian Hospital, a major urban hospital. Methods: We collected nasal swabs from the patients and their accompanying persons. We also recorded the levels (None, Mild, High, and Severe) of their symptoms (Fever, Chill, Muscle Pain, Watery Eye, Runny Nose, Sneezing, Sore throat and Cough). The collected swabs were tested for the presence of common viruses infecting the respiratory tract. Results: Human Rhinovirus was the most common virus among the patients, followed Influenza and Respiratory Syncytial Virus. Human Rhinovirus was most common in summer, autumn and spring. In contrast, influenza was more common in winter. Further, Influenza A virus was more likely to co-occur with Corona Virus 229E. In comparison, Influenza was less likely to co-occur with Human Rhinovirus. Moreover, Influenza, Parainfluenza and Corona virus were associated with more severe symptoms, while Human Rhinovirus was associated with less severe symptoms. In addition, we observed that Influenza and Respiratory Syncytial Virus were more likely to infect a patient when these viruses also infected the accompanying person. We also found that it was difficult to distinguish among viruses based on the symptoms. The inability to distinguish among different virus types and subtypes is explained by the fact that multiple viruses lead to similar symptoms. Conclusions: The findings of this study provide a better understanding of respiratory viral infections in small children presenting at a pediatric emergency room in New York.

114 Effect of Clinical Decision Support on Head Computed Tomography for Children With Minor Head Trauma

Intranasal hydromorphone for treatment of acute pain in children: A pilot study.

In a multicenter study, adolescents presenting to the ED with SC acute toxicity had significant neuropsychiatric outcomes. BrightcoveDefaultPlayer10.1542/6138652437001PEDS-VA_2018-2690 Video Abstract BACKGROUND AND OBJECTIVES: Adolescents represent the largest age group that presents to emergency departments (ED) for synthetic cannabinoid (SC) toxicity; however, the neurotoxic effects of acute SC exposures in this group are understudied. Our aim was to characterize the neuropsychiatric presentation of adolescents with SC-related exposure in the ED compared with those with traditional cannabis exposure. METHODS: A multicenter registry of clinical information prospectively collected by medical toxicologists (Toxicology Investigators Consortium Case Registry) was reviewed for adolescents presenting to the ED after SC or cannabis exposure from 2010 through 2018. Associations were measured between drug exposures and neuropsychiatric symptoms and/or signs. Exposures were classified into 4 groups: SC-only exposure, SC-polydrug exposures, cannabis-only exposure, and cannabis-polydrug exposures. RESULTS: Adolescents presenting to the ED with SC-only exposure (n = 107) had higher odds of coma and/or central nervous system depression (odds ratio [OR] 3.42; 95% confidence interval [CI] 1.51–7.75) and seizures (OR 3.89; 95% CI 1.39–10.94) than those with cannabis-only exposure (n = 86). SC-only drug exposure was associated with lower odds of agitation than cannabis-only exposure (OR 0.18; 95% CI 0.10–0.34). In contrast, the group with SC-polydrug exposures (n = 38) had higher odds of agitation (OR 3.11; 95% CI 1.56–7.44) and seizures (OR 4.8; 95% CI 1.80–12.74) than the cannabis-polydrug exposures group (n = 117). CONCLUSIONS: In this multisite cohort of US adolescents assessed in the ED, SC exposure was associated with higher odds of neuropsychiatric morbidity than cannabis exposure providing a distinct neurospychiatric profile of acute SC toxicity in adolescents.

Neuropsychiatric Sequelae in Adolescents With Acute Synthetic Cannabinoid Toxicity

Expedited partner therapy (EPT) refers to treating sexual partners of patients with sexually transmitted infections by providing prescriptions or medications to give to their partners. Expedited partner therapy is not routinely prescribed in the emergency department (ED). Our objective was to explore adolescent preferences for EPT use in the ED.

METHODS
We conducted a mixed-methods study using surveys and semistructured interviews in one urban ED. Sexually active patients aged 15 to 19 years completed an anonymous survey eliciting (1) sexual history and risky sexual behaviors, (2) preferences for partner notification when hypothetically testing positive for an STI, and (3) preferences for EPT. A subsample of survey respondents participated in the interviews, which were conducted until no new perspectives emerged. Investigators analyzed interviews using thematic analysis.

RESULTS
A total of 247 participants completed surveys; the majority were female (183/247, 74%), Hispanic (209/243, 86%), and did not use a condom at last intercourse (129/243, 53%). Two thirds of participants (152/236, 64%) did not prefer EPT for partner notification. Preference for EPT was not associated with sex, age, ethnicity, condom use, a steady sexual partner, or STI history. Qualitative data from both surveys and interviews revealed the following reasons for not preferring EPT: concern for partner safety, importance of determining partner STI status, perceived benefit of clinical interaction, and partner accountability. Reasons for preferring EPT included increased treatment accessibility and convenience.

The majority of adolescent patients in a pediatric ED did not prefer EPT. Emergency department practitioners should address common concerns regarding EPT to increase EPT adherence if prescribed.

Preferences for Expedited Partner Therapy Among Adolescents in an Urban Pediatric Emergency Department: A Mixed-Methods Study.

Practice Variation in the Evaluation and Disposition of Febrile Infants ≤60 Days of Age.

Implementation of a Clinical Decision Support System for Children With Minor Blunt Head Trauma Who Are at Nonnegligible Risk for Traumatic Brain Injuries

Early fatherhood is common in the United States (U.S.). The emergency department (ED) plays a disproportionate role in serving patients with unmet reproductive and sexual health needs. With 8 million adolescent males visiting U.S. EDs annually, the ED is a potential site to implement interventions to minimize early fatherhood and unintended teenage pregnancy. Little is known about how adolescent male ED patients perceive and behave in sexual relationships and how they influence contraceptive decision making. The objective of this study was to identify the barriers and enablers affecting contraceptive and condom use among adolescent male ED patients. Semistructured interviews were conducted with males aged 14–19 in one urban ED. Enrollment continued until saturation of key themes. Interviews were recorded, transcribed, and coded based on thematic analysis using NVivo 10. The Social Ecological Model was used to organize and understand themes. Participants (n = 24) were predominantly 18–19 years (63%) and Hispanic (92%). Most (71%) had sex ≤3 months prior but infrequently used a condom at last intercourse (42%). The primary barrier influencing contraceptive use was lack of knowledge of effective contraceptives. Other barriers consisted of perceived gender roles, poor partner communication, and little relationship with a primary provider. Enablers included intention not to get a partner pregnant, school-based sexual health education, normalcy to use condoms, and a trustworthy confidante. The identified barriers and enablers influencing adolescent males’ perspectives toward contraceptives should be addressed if designing future ED-based pregnancy prevention interventions targeting teen males.

A Qualitative Assessment to Understand the Barriers and Enablers Affecting Contraceptive Use Among Adolescent Male Emergency Department Patients

Engaging Adolescents With Sexual Health Messaging: A Qualitative Analysis.

Importance In young febrile infants, serious bacterial infections (SBIs), including urinary tract infections, bacteremia, and meningitis, may lead to dangerous complications. However, lumbar punctures and hospitalizations involve risks and costs. Clinical prediction rules using biomarkers beyond the white blood cell count (WBC) may accurately identify febrile infants at low risk for SBIs. Objective To derive and validate a prediction rule to identify febrile infants 60 days and younger at low risk for SBIs. Design, Setting, and Participants Prospective, observational study between March 2011 and May 2013 at 26 emergency departments. Convenience sample of previously healthy febrile infants 60 days and younger who were evaluated for SBIs. Data were analyzed between April 2014 and April 2018. Exposures Clinical and laboratory data (blood and urine) including patient demographics, fever height and duration, clinical appearance, WBC, absolute neutrophil count (ANC), serum procalcitonin, and urinalysis. We derived and validated a prediction rule based on these variables using binary recursive partitioning analysis. Main Outcomes and Measures Serious bacterial infection, defined as urinary tract infection, bacteremia, or bacterial meningitis. Results We derived the prediction rule on a random sample of 908 infants and validated it on 913 infants (mean age was 36 days, 765 were girls [42%], 781 were white and non-Hispanic [43%], 366 were black [20%], and 535 were Hispanic [29%]). Serious bacterial infections were present in 170 of 1821 infants (9.3%), including 26 (1.4%) with bacteremia, 151 (8.3%) with urinary tract infections, and 10 (0.5%) with bacterial meningitis; 16 (0.9%) had concurrent SBIs. The prediction rule identified infants at low risk of SBI using a negative urinalysis result, an ANC of 4090/µL or less (to convert to ×109 per liter, multiply by 0.001), and serum procalcitonin of 1.71 ng/mL or less. In the validation cohort, the rule sensitivity was 97.7% (95% CI, 91.3-99.6), specificity was 60.0% (95% CI, 56.6-63.3), negative predictive value was 99.6% (95% CI, 98.4-99.9), and negative likelihood ratio was 0.04 (95% CI, 0.01-0.15). One infant with bacteremia and 2 infants with urinary tract infections were misclassified. No patients with bacterial meningitis were missed by the rule. The rule performance was nearly identical when the outcome was restricted to bacteremia and/or bacterial meningitis, missing the same infant with bacteremia. Conclusions and Relevance We derived and validated an accurate prediction rule to identify febrile infants 60 days and younger at low risk for SBIs using the urinalysis, ANC, and procalcitonin levels. Once further validated on an independent cohort, clinical application of the rule has the potential to decrease unnecessary lumbar punctures, antibiotic administration, and hospitalizations.

A Clinical Prediction Rule to Identify Febrile Infants 60 Days and Younger at Low Risk for Serious Bacterial Infections

250. The Development of A Theory-Based, User-Informed, Digital Intervention To Promote Pregnancy Prevention Among Adolescent Female Emergency Department Patients

Objectives Limited literature has investigated caregiver sharing of prescription medications with children. Our primary aim was to determine the frequency of and factors associated with prescription medication sharing within families. Our secondary aim was to determine the source and type of medications shared. Methods We conducted a survey of a convenience sample of caregivers of children 1 to 17 years in a pediatric emergency department. The survey was developed through literature review, iterative feedback, and pilot testing on caregivers. We used logistic regression to identify factors associated with any history of medication sharing with a child in the home (primary outcome). Results We enrolled 550 primary caregivers; 68 of the 535 analyzed (12.7%; 95% confidence interval [CI], 10.0–15.8) reported prescription medication sharing with their child/children. Of those who shared, 50 (73.5%) shared asthma medications and 14 (20.6%) shared antibiotics. Of the caregivers who shared prescription medications, 70.6% shared a medication for one child with another child, whereas 33.8% of caregivers shared their own or another adult's medication with their child. A child in the home with asthma (adjusted odds ratio [aOR], 3.35; CI, 1.82–6.17), a greater number of children in the household (aOR, 1.29; CI, 1.04–1.60), and a caregiver who previously shared medications with other family members and/or friends (aOR, 4.10; CI, 1.84–9.15) were factors independently associated with medication sharing. Conclusions Prescription medication sharing within families is common and most often involves asthma medications. We identified several factors associated with prescription medication sharing that could be used to target caregivers for preventative interventions.

Frequency of and Factors Associated With Prescription Medication Sharing Within Families

Supplemental digital content is available in the text. Objectives The objective of this study was to determine emergency department (ED) physician adherence with the 2011 Pediatric Infectious Diseases Society (PIDS) and Infectious Diseases Society of America (IDSA) guidelines for outpatient management of children with mild-to-moderate community-acquired pneumonia (CAP). Methods A cross-sectional survey of physicians on the American Academy of Pediatrics Section on Emergency Medicine Survey listserv was conducted. We evaluated ED physicians' reported adherence with the PIDS/IDSA guidelines through presentation of 4 clinical vignettes representing mild-to-moderate CAP of presumed viral (preschool-aged child), bacterial (preschool and school-aged child), and atypical bacterial (school-aged child) etiology. Results Of 120 respondents with analyzable data (31.4% response rate), use of chest radiograph (CXR) was nonadherent to the guidelines in greater than 50% of respondents for each of the 4 vignettes. Pediatric emergency medicine fellowship training was independently associated with increased CXR use in all vignettes, except for school-aged children with bacterial CAP. Guideline-recommended amoxicillin was selected to treat bacterial CAP by 91.7% of the respondents for preschool-aged children and by 75.8% for school-aged children. Macrolide monotherapy for atypical CAP was appropriately selected by 88.2% and was associated with obtaining a CXR (adjusted odds ratio, 3.9 [95% confidence interval, 1.4–11.1]). Guideline-adherent antibiotic use for all vignettes was independently associated with congruence between respondent's presumed diagnosis and the vignette's intended etiologic diagnosis. Conclusions Reported ED CXR use in the management of outpatient CAP was often nonadherent to the PIDS/IDSA guidelines. Most respondents were adherent to the guidelines in their use of antibiotics. Strategies to increase diagnostic test accuracy are needed to improve adherence and reduce variation in care.

Guideline Adherence in Diagnostic Testing and Treatment of Community-Acquired Pneumonia in Children

Identifying changes in pain score associated with clinically meaningful outcomes is necessary when using self-report measures to assess pain in children. We aimed to determine the changes in pain score associated with a minimum clinically significant difference (MCSD), ideal clinically significant difference (ICSD), and patient-perceived adequate analgesia (PPAA) and to evaluate for differences based on initial pain intensity and patient characteristics.

METHODS
This was a cross-sectional study of children 6 to 17 and 4 to 17 years old who were assessed using the Verbal Numerical Rating Scale (VNRS) and Faces Pain Scale-Revised (FPS-R), respectively. Children qualitatively described any endorsed change in pain score; those who received an analgesic were asked if they wanted additional analgesics to decrease their pain intensity. We used a receiver operating characteristic curve-based methodology to identify changes in pain score associated with "a little less" and "much less" pain (MCSD and ICSD, respectively) and patients declining additional analgesics because of adequate analgesia (PPAA).

RESULTS
We enrolled 431 children with painful conditions. For the VNRS, raw change and percent reductions in pain scores associated with MCSD, ICSD, and PPAA were 2/10 and 20%, 3/10 and 44%, and 2/10 and 29%, respectively, and for the FPS-R, 2/10 and 33%, 4/10 and 60%, and 4/10 and 40%, respectively. Raw change in pain scores increased with increasing initial pain intensity, but percent reductions remained stable. There were no significant differences based on patient characteristics such as age, sex, and race/ethnicity.

Our findings provide patient-centered outcomes in children that are suitable for designing trials and are generalizable across patient characteristics.

Academic emergency medicine : official journal of the Society for Academic Emergency Medicine

Changes in Pain Score Associated With Clinically Meaningful Outcomes in Children With Acute Pain.

Our purpose was to determine the potential effect of preprocedural ultrasound (US) to increase lumbar puncture (LP) success compared with standard palpation method. Further, we assessed feasibility of and clinician satisfaction with a standardized US protocol.

METHODS
This prospective, two-arm, parallel-group randomized trial was conducted in a single-center pediatric emergency department. We compared preprocedural US versus palpation method on success with infant LPs. Infants less than 3 months of age requiring LP were enrolled. Sixteen pediatric emergency medicine physicians with varied US experience were trained to conduct the USs to mark interspace locations. Primary outcome was successful LP, defined as obtaining a cerebrospinal fluid (CSF) sample on first attempt with < 1,000 red blood cells per high-powered field (clear CSF). Secondary outcomes included clear CSF on any attempt, any CSF on the first attempt, traumatic LP proportion, and LP attempt frequency. Feasibility was assessed by comparing provider number attempting the LP and procedure duration. Clinician satisfaction and sonographer perceptions of US acceptability and impact were assessed.

RESULTS
Eighty-one patients consented and 80 were analyzed (99%): 40 per group. No statistical difference was seen for the primary outcome (p > 0.05) between intervention and control groups (difference 3%; 95% confidence interval = -19% to 24%). There were no statistical differences between intervention and controls groups for secondary outcomes including the rate of traumatic LPs, number of attempts, and the duration of LP procedure. Most sonographers (84%) strongly agreed or agreed that the US protocol was technically easy to perform, well tolerated by the patient (94%), well accepted by the family (100%), and well accepted by the LP procedural clinicians (99%). In the US group, the majority of clinicians who performed the LPs (68.4%) noted that the preprocedural US influenced their behavior, most commonly helping with overall visualization at the selected interspace (28.9%) or prompting a change in interspace (26.3% higher, 5.3% lower). Seventy-seven percent agreed or strongly agreed that they would like to use the technique again for their next LP. The mean US duration was 4.6 minutes.

Preprocedural US by did not improve the rates of first-attempt success when compared with palpation method. Our results suggest that US is feasible and well accepted, with a perceptible impact on care.

Preprocedural Ultrasound for Infant Lumbar Puncture: A Randomized Clinical Trial

Background Clinicians appear to obtain emergent neuroimaging for children with headaches based on the presence of red flag findings. However, little data exists regarding the prevalence of these findings in emergency department populations, and whether the identification of red flag findings is associated with potentially unnecessary emergency department neuroimaging. Objectives We aimed to determine the prevalence of red flag findings and their association with neuroimaging in otherwise healthy children presenting with headaches to the emergency department. Our secondary aim was to determine the prevalence of emergent intracranial abnormalities in this population. Methods A prospective cohort study of otherwise healthy children 2–17 years of age presenting to an urban pediatric emergency department with non-traumatic headaches was undertaken. Emergency department physicians completed a standardized form to document headache descriptors and characteristics, associated symptoms, and physical and neurological exam findings. Children who did not receive emergency department neuroimaging received 4-month telephone follow-up. Outcomes included emergency department neuroimaging and the presence of emergent intracranial abnormalities. Results We enrolled 224 patients; 197 (87.9%) had at least one red flag finding on history. Several red flag findings were reported by more than a third of children, including: Headache waking from sleep (34.8%); headache present with or soon after waking (39.7%); or headaches increasing in frequency, duration and severity (40%, 33.1%, and 46.3%). Thirty-three percent of children received emergency department neuroimaging. The prevalence of emergent intracranial abnormalities was 1% (95% CI 0.1, 3.6). Abnormal neurological exam, extreme pain intensity of presenting headache, vomiting, and positional symptoms were independently associated with emergency department neuroimaging. Conclusions Red flag findings are common in children presenting with headaches to the emergency department. The presence of red flag findings is associated with emergency department neuroimaging, although the risk of emergent intracranial abnormalities is low. Many children with headaches may be receiving unnecessary neuroimaging due to the high prevalence of non-specific red flag findings.

Red flag findings in children with headaches: Prevalence and association with emergency department neuroimaging

Emergency medical services (EMS) providers must be able to identify the most appropriate destination facility when treating children with potentially severe medical illnesses. Currently, no validated tool exists to assist EMS providers in identifying children who need transport to a hospital with higher-level pediatric care. For such a tool to be developed, a criterion standard needs to be defined that identifies children who received higher-level pediatric medical care.

OBJECTIVE
The objective was to develop a consensus-based criterion standard for children with a medical complaint who need a hospital with higher-level pediatric resources.

METHODS
Eleven local and national experts in EMS, emergency medicine (EM), and pediatric EM were recruited. Initial discussions identified themes for potential criteria. These themes were used to develop specific criteria that were included in a modified Delphi survey, which was electronically delivered. The criteria were refined iteratively based on participant responses. To be included, a criterion required at least 80% agreement among participants. If an item had less than 50% agreement, it was removed. A criterion with 50% to 79% agreement was modified based on participant suggestions and included on the next survey, along with any new suggested criteria. Voting continued until no new criteria were suggested and all criteria received at least 80% agreement.

RESULTS
All 11 recruited experts participated in all seven voting rounds. After the seventh vote, there was agreement on each item and no new criteria were suggested. The recommended criterion standard included 13 items that apply to patients 14 years old or younger. They included IV antibiotics for suspicion of sepsis or a seizure treated with two different classes of anticonvulsive medications within 2 hours, airway management, blood product administration, cardiopulmonary resuscitation, electrical therapy, administration of specific IV/IO drugs or respiratory assistance within 4 hours, interventional radiology or surgery within 6 hours, intensive care unit admission, specific comorbid conditions with two or more abnormal vital signs, and technology-assisted children seen for device malfunction.

We developed a 13-item consensus-based criterion standard definition for identifying children with medical complaints who need the resources of a hospital equipped to provide higher-level pediatric services. This criterion standard will allow us to create a tool to improve pediatric patient care by assisting EMS providers in identifying the most appropriate destination facility for ill children.

Consensus‐based Criterion Standard for the Identification of Pediatric Patients Who Need Emergency Medical Services Transport to a Hospital with Higher‐level Pediatric Resources

The risk of early seizure recurrences after first unprovoked seizures in children is largely unknown. We aimed to determine the rate of seizure recurrence within 14 days of first unprovoked seizures in children and identify associated risk factors. Secondarily, we aimed to determine the risk of recurrence at 48 hours and 4 months.

METHODS
We conducted a secondary analysis of a multicenter cohort study of children 29 days to 18 years with first unprovoked seizures. Emergency department (ED) clinicians completed standardized histories and physical examinations. The primary outcome, recurrent seizure at 14 days, and the secondary outcomes, recurrence at 48 hours and 4 months, were assessed by telephone follow-up and medical record review. For each recurrence time point, we excluded those patients for whom no seizure had recurred but chronic antiepileptic drugs had been initiated.

RESULTS
A total of 475 patients were enrolled in the parent study. Of evaluable patients for this secondary analysis, 26 of 392 (6.6%, 95% confidence interval [CI] = 4.4%-9.6%) had recurrences within 48 hours of the incident seizures, 58 of 366 (15.8%, 95% CI = 12.3%-20.0%) had recurrences within 14 days, and 107 of 340 (31.5%, 95% CI = 26.6%-36.7%) had recurrences within 4 months. On logistic regression analysis, age younger than 3 years was independently associated with a higher risk of 14-day recurrence (adjusted odds ratio [OR] = 2.1, 95% CI = 1.2-3.7; p = 0.01). Having had more than one seizure within the 24 hours prior to ED presentation was independently associated with a higher risk of seizure recurrence at 48 hours (adjusted OR = 4.3, 95% CI = 1.9-9.8; p < 0.001).

Risk of seizure recurrence 14 days after first unprovoked seizures in children is substantial, with younger children at higher risk. Prompt completion of an electroencephalogram and evaluation by a neurologist is appropriate for these children.

Abstract Background The overuse of cranial computed tomography (CT) to diagnose potential traumatic brain injuries (TBIs) exposes children with minor blunt head trauma to unnecessary ionizing radiation. The Pediatric Emergency Care Applied Research Network and the Clinical Research on Emergency Services and Treatments Network implemented TBI prediction rules via electronic health record (EHR) clinical decision support (CDS) to decrease use of CTs in children with minor blunt head trauma. Objective This article aims to facilitate implementation and dissemination of a CDS alert into emergency departments around the country. Methods We evaluated the EHR CT CDS tool through a mixed-methods analysis of 38 audio-recorded interviews with health care stakeholders and quantitative data sources, using the Reach, Efficacy, Adoption, Implementation, and Maintenance framework. Results Reach —The demographics of participants enrolled in the clinical trial were consistent with national estimates of TBI prevalence. Efficacy—There was a variable and modest reduction in CT rates for the 8,067 children with minor head trauma whose clinicians received CDS. Adoption —The EHR CT CDS tool was well matched with the organizational mission, values, and priorities of the implementation sites. Implementation— The most important predisposing factors for successful implementation were the presence of an approachable clinical champion at each site and belief that the tool was a relevant, reusable knowledge asset. Enabling factors included an effective integration within the clinical workflow, organizational investment in user training, and ease of use. Maintenance — Reinforcing factors for the EHR CT CDS tool included a close fit with the institutional culture, belief that it was useful for providers and families, and a good educational and informational tool. As such, the EHR CT CDS tool was maintained in clinical practice long after study completion. Conclusion Data from this mixed-methods study complement findings from the efficacy trial and provide critical components for consideration prior to integration and subsequent dissemination of the EHR CT CDS tool. Trial Registration NCT01453621, Registered September 27, 2011

Applying the RE-AIM Framework for the Evaluation of a Clinical Decision Support Tool for Pediatric Head Trauma: A Mixed-Methods Study

Objectives The aims of this study were to quantify the pain and distress associated with the administration of intranasal (IN) midazolam in young children using 4 observational measures and to evaluate the degree of validity of these measures. Methods We conducted a prospective observational pilot study. Children aged 1 to 7 years requiring IN midazolam were enrolled. Children were videotaped, and scores were assigned to baseline and administration phases using the Observational Scale of Behavioral Distress–Revised (OSBD-R), Children's Hospital of Eastern Ontario Pain Scale (CHEOPS), and the Faces-Legs-Activity-Cry-Consolability (FLACC) scale. The cry duration following administration was assessed. Interrater reliability and convergent validity were determined for all 4 measures. Internal consistency and responsivity for the OSBD-R, CHEOPS, and FLACC scales were determined. Results We enrolled 20 children. The mean OSBD-R, CHEOPS, and FLACC scores associated with administration of IN midazolam were 27.1 (SD, 13.5), 11.5 (SD, 1.2), and 8.9 (SD, 2.7), respectively. The mean cry duration was 105.5 (SD, 68.8) seconds. The intraclass correlation coefficients for all measures ranged from 0.82 to 0.99. The Cronbach α's for the OSBD-R, CHEOPS, and FLACC were between 0.71 and 0.97. Pearson correlation coefficients for comparisons between OSBD-R, CHEOPS, and FLACC were between 0.82 and 0.96 but were between 0.32 and 0.51 for comparisons involving cry duration. Conclusions We have identified estimates of pain and distress associated with administration of IN midazolam in young children that can be used to determine desired effect sizes for trials that study interventions to treat this pain and distress. The OSBD-R, CHEOPS, and FLACC scales are suitable choices for outcome measures.

Quantification of Pain and Distress Associated With Intranasal Midazolam Administration in Children and Evaluation of Validity of Four Observational Measures

Introduction Although bronchiolitis is a common reason for infant hospitalization, significant heterogeneity persists in its management. The American Academy of Pediatrics currently recommends that inhaled albuterol not be used in routine care of children with bronchiolitis. Our objective was to identify factors associated with pre-admission (e.g., emergency department or primary care) use of albuterol among infants hospitalized for bronchiolitis. Methods We analyzed data from a 17-center observational study of 1,016 infants (age <1 year) hospitalized with bronchiolitis between 2011–2014. Pre-admission albuterol use was ascertained by chart review, and data were available for 1,008 (99%) infants. We used multivariable logistic regression to identify infant characteristics independently associated with pre-admission albuterol use. Results Half of the infants (n=508) received at least one albuterol treatment before admission. Across the 17 hospitals, pre-admission albuterol use ranged from 23–84%. In adjusted analysis, independent predictors of albuterol use were the following: age ≥2 months (age 2.0–5.9 months [odds ratio (OR) 2.09, 95% confidence interval (CI) {1.45–3.01}] and age 6.0–11.9 months [OR 2.89, 95% CI {1.99–4.19}]); prior use of a bronchodilator (OR 1.89, 95% CI [1.24–2.90]); and presence of wheezing documented in pre-admission chart (OR 3.94, 95% CI [2.61–5.93]). By contrast, albuterol use was less likely among those with ≥7 days since the start of breathing problem (OR 0.66, 95% CI [0.44–1.00]) and parent-reported fever (OR 0.75, 95% CI [0.58–0.96]). Conclusion Variation in pre-admission albuterol use suggests that local practice had a strong influence on use, but that patient characteristics also influenced the decision. While we agree with current guidelines in recommending against albuterol for all infants with bronchiolitis, our understanding of possible subgroups of responders may improve through investigation of infants with the identified characteristics.

Multicenter Study of Albuterol Use Among Infants Hospitalized with Bronchiolitis

Adolescent male receptivity to sexual health interventions in the emergency department

Objectives Emergency department (ED) visits are an opportunity to initiate chronic asthma care. Ideally, this care should be implemented in a fashion that limits utilization of scarce ED resources. We developed, iteratively refined, and pilot tested the feasibility of a computerized asthma kiosk to (1) capture asthma information, (2) deliver asthma education, and (3) facilitate guideline-based chronic asthma management. Methods The following are the 4 phases of this study: (1) developing the content and structure of a computerized asthma kiosk, (2) iterative refinement through heuristic testing by human-computer interface experts, (3) usability testing with ED providers (n = 4) and caregivers of children with asthma (n = 4), and (4) pilot testing the kiosk with caregivers (n = 31) and providers in the ED (n = 18). Outcome measures for the pilot-testing phase were the proportion of ED providers who prescribed long-term controller medication (LTCM) and asthma action plans (AsAPs) and the proportion of children who took LTCMs and attended primary care providers follow-up. Results After kiosk development and refinement, pilot implementation resulted in LTCMs prescribing and AsAP provision for 19 (61%) of 31 and 17 (55%) of 31 patients, respectively. Before kiosk use, the proportion of the 18 ED providers who reported prescribing LTCM was 1 (5%) of 18, and providing AsAPs was 0 (0%) of 18. Eighteen (58%) of the 31 caregivers reported that their children used LTCMs after kiosk use and 13 (42%) of 31 reported following up with the primary care provider within 1 month of the ED visits. Conclusions A rigorously developed asthma kiosk showed promise for initiating chronic asthma care in the ED.

Development and Pilot Testing of a Computerized Asthma Kiosk to Initiate Chronic Asthma Care in a Pediatric Emergency Department

Clinical Judgment and the Pediatric Emergency Care Applied Research Network Head Trauma Prediction Rules.

Traumatic brain injury (TBI) is the leading cause of traumatic death in children. As many children with TBIs have subtle symptoms and missed or delayed diagnoses may result in increased morbidity, emergency department clinicians must frequently determine which children require emergent cranial computed tomographic (CT) scanning even after apparently minor blunt head trauma. Overuse of CT scans, however, has important drawbacks, including radiation-induced malignancies. Two large cohorts have documented the association of cranial CT scanning with cancer in children. This article is protected by copyright. All rights reserved.

Multiple Pediatric Head Injury Decision Rules but What Should the Clinician Use?

OBJECTIVE
The use of computed tomography (CT) and ultrasound (US) in patients with acute abdominal pain has substantial variation across pediatric emergency departments (EDs). This study compares the cost of diagnosing and treating suspected appendicitis across a multicenter network of children's hospitals.

METHODS
This study is a secondary analysis using deidentified data of a prospective, observational study of patients with suspected appendicitis at nine pediatric EDs. The study included patients 3 to 18 years old who presented to the ED with acute abdominal pain of <96 hours' duration.

RESULTS
Our data set contained 2,300 cases across nine sites. There was an appendicitis rate of 31.8% and perforation rate of 25.7%. Sites correctly diagnosed appendicitis in over 95% of cases. The negative appendicitis rate ranged from 2.5% to 4.7% while the missed appendicitis rate ranged from 0.3% to 1.1% with no significant differences in these rates across site. Across sites, we found a strong positive correlation (0.95) between CT rate and total cost per case and a strong negative correlation (-0.71) between US rate and cost. The cost per case at US sites was 5.2% ($367) less than at CT sites (p < 0.001). Similarly, costs per case at mixed sites were 3.4% ($244) less than at CT sites (p < 0.001). Comparing costs among CT sites or among US sites, the cost per case generally increased as the images per case increased among both CT sites and US sites, but the costs were universally higher at CT sites.

Our results provide support for US as the primary imaging modality for appendicitis. Sites that preferentially utilized US had lower costs per case than sites that primarily used CT. Imaging rates across sites varied due to practice patterns and resulted in a significant cost consequence without higher rates for negative appendectomies or missed appendicitis cases.

Economic Analysis of Diagnostic Imaging in Pediatric Patients With Suspected Appendicitis

In this study, we develop and validate a new score that can be used to accurately quantify risk for appendicitis. OBJECTIVES: We sought to develop and validate a clinical calculator that can be used to quantify risk for appendicitis on a continuous scale for patients with acute abdominal pain. METHODS: The pediatric appendicitis risk calculator (pARC) was developed and validated through secondary analyses of 3 distinct cohorts. The derivation sample included visits to 9 pediatric emergency departments between March 2009 and April 2010. The validation sample included visits to a single pediatric emergency department from 2003 to 2004 and 2013 to 2015. Variables evaluated were as follows: age, sex, temperature, nausea and/or vomiting, pain duration, pain location, pain with walking, pain migration, guarding, white blood cell count, and absolute neutrophil count. We used stepwise regression to develop and select the best model. Test performance of the pARC was compared with the Pediatric Appendicitis Score (PAS). RESULTS: The derivation sample included 2423 children, 40% of whom had appendicitis. The validation sample included 1426 children, 35% of whom had appendicitis. The final pARC model included the following variables: sex, age, duration of pain, guarding, pain migration, maximal tenderness in the right-lower quadrant, and absolute neutrophil count. In the validation sample, the pARC exhibited near perfect calibration and a high degree of discrimination (area under the curve: 0.85; 95% confidence interval: 0.83 to 0.87) and outperformed the PAS (area under the curve: 0.77; 95% confidence interval: 0.75 to 0.80). By using the pARC, almost half of patients in the validation cohort could be accurately classified as at <15% risk or ≥85% risk for appendicitis, whereas only 23% would be identified as having a comparable PAS of <3 or >8. CONCLUSIONS: In our validation cohort of patients with acute abdominal pain, the pARC accurately quantified risk for appendicitis.

Development and Validation of a Novel Pediatric Appendicitis Risk Calculator (pARC)

Risk of Bacterial Coinfections in Febrile Infants 60 Days Old and Younger with Documented Viral Infections

This prospective study reveals the accuracy of the urinalysis for diagnosing UTIs in febrile infants 60 days and younger with and without bacteremia. OBJECTIVES: Reports of the test accuracy of the urinalysis for diagnosing urinary tract infections (UTIs) in young febrile infants have been variable. We evaluated the test characteristics of the urinalysis for diagnosing UTIs, with and without associated bacteremia, in young febrile infants. METHODS: We performed a planned secondary analysis of data from a prospective study of febrile infants ≤60 days old at 26 emergency departments in the Pediatric Emergency Care Applied Research Network. We evaluated the test characteristics of the urinalysis for diagnosing UTIs, with and without associated bacteremia, by using 2 definitions of UTI: growth of ≥50 000 or ≥10 000 colony-forming units (CFUs) per mL of a uropathogen. We defined a positive urinalysis by the presence of any leukocyte esterase, nitrite, or pyuria (>5 white blood cells per high-power field). RESULTS: Of 4147 infants analyzed, 289 (7.0%) had UTIs with colony counts ≥50 000 CFUs/mL, including 27 (9.3%) with bacteremia. For these UTIs, a positive urinalysis exhibited sensitivities of 0.94 (95% confidence interval [CI]: 0.91–0.97), regardless of bacteremia; 1.00 (95% CI: 0.87–1.00) with bacteremia; and 0.94 (95% CI: 0.90–0.96) without bacteremia. Specificity was 0.91 (95% CI: 0.90–0.91) in all groups. For UTIs with colony counts ≥10 000 CFUs/mL, the sensitivity of the urinalysis was 0.87 (95% CI: 0.83–0.90), and specificity was 0.91 (95% CI: 0.90–0.92). CONCLUSIONS: The urinalysis is highly sensitive and specific for diagnosing UTIs, especially with ≥50 000 CFUs/mL, in febrile infants ≤60 days old, and particularly for UTIs with associated bacteremia.

Accuracy of the Urinalysis for Urinary Tract Infections in Febrile Infants 60 Days and Younger

Abstract Background Clinical decision support (CDS) embedded into the electronic health record (EHR), is a potentially powerful tool for institution of antimicrobial stewardship programs (ASPs) in emergency departments (EDs). However, design and implementation of CDS systems should be informed by the existing workflow to ensure its congruence with ED practice, which is characterized by erratic workflow, intermittent computer interactions, and variable timing of antibiotic prescription. Objective This article aims to characterize ED workflow for four provider types, to guide future design and implementation of an ED-based ASP using the EHR. Methods Workflow was systematically examined in a single, tertiary-care academic children's hospital ED. Clinicians with four roles (attending, nurse practitioner, physician assistant, resident) were observed over a 3-month period using a tablet computer-based data collection tool. Structural observations were recorded by investigators, and classified using a predetermined set of activities. Clinicians were queried regarding timing of diagnosis and disposition decision points. Results A total of 23 providers were observed for 90 hours. Sixty-four different activities were captured for a total of 6,060 times. Among these activities, nine were conducted at different frequency or time allocation across four roles. Moreover, we identified differences in sequential patterns across roles. Decision points, whereby clinicians then proceeded with treatment, were identified 127 times. The most common decision points identified were: (1) after/during examining or talking to patient or relative; (2) after talking to a specialist; and (3) after diagnostic test/image was resulted and discussed with patient/family. Conclusion The design and implementation of CDS for ASP should support clinicians in various provider roles, despite having different workflow patterns. The clinicians make their decisions about treatment at different points of overall care delivery practice; likewise, the CDS should also support decisions at different points of care.

Examining Workflow in a Pediatric Emergency Department to Develop a Clinical Decision Support for an Antimicrobial Stewardship Program

A Clinical Score to Predict Appendicitis in Older Male Children.

Texting to Increase Contraceptive Initiation Among Adolescents in the Emergency Department.

Development and Validation of a Risk Equation for Appendicitis in Children Presenting With Abdominal Pain

1 Children’s Hospital Colorado, Department of Research Informatics, Aurora, Colorado, United States; 2 University of Colorado, Department of Pediatrics, Section of Emergency Medicine, Aurora, Colorado, United States; 3 Nationwide Children’s Hospital, Columbus, Ohio, United States; 4 Children’s Hospital Medical Center, Cincinnati, Ohio, United States; 5 Kaiser Permanente, San Rafael Medical Center, San Rafael, California, United States; 6Kaiser Permanente, Sacramento Medical Center, Sacramento, California, United States; 7 University of California Davis School of Medicine, Departments of Emergency Medicine and Pediatrics, Sacramento, California, United States; 8 Children’s Hospital Colorado, Department of Clinical Application Services, Aurora, Colorado, United States; 9 Children’s Hospital of Philadelphia and Perelman School of Medicine, Philadelphia, Pennsylvania, United States; 10 Columbia University College of Physicians and Surgeons, Department of Pediatrics, Division of Emergency Medicine, New York, New York, United States

A Multi-Center Study of Clinical Decision Support for Children with Head Trauma

We examine the influence of time from emergency department evaluation until operation on perforation in a prospective, multicenter cohort of children with appendicitis. BACKGROUND AND OBJECTIVES: In patients with appendicitis, the risk of perforation increases with time from onset of symptoms. We sought to determine if time from emergency department (ED) physician evaluation until operative intervention is independently associated with appendiceal perforation (AP) in children. METHODS: We conducted a planned secondary analysis of children aged 3 to 18 years with appendicitis enrolled in a prospective, multicenter, cross-sectional study of patients with abdominal pain (<96 hours). Time of initial physical examination and time of operation were recorded. The presence of AP was determined using operative reports. We analyzed whether duration of time from initial ED physician evaluation to operation impacted the odds of AP using multivariable logistic regression, adjusting for traditionally suggested risk factors that increase the risk of perforation. We also modeled the odds of perforation in a subpopulation of patients without perforation on computed tomography. RESULTS: Of 955 children with appendicitis, 25.9% (n = 247) had AP. The median time from ED physician evaluation to operation was 7.2 hours (interquartile range: 4.8–8.5). Adjusting for variables associated with perforation, duration of time (≤ 24 hours) between initial ED evaluation and operation did not significantly increase the odds of AP (odds ratio = 1.0, 95% confidence interval, 0.96–1.05), even among children without perforation on initial computed tomography (odds ratio = 0.95, 95% confidence interval, 0.89–1.02). CONCLUSIONS: Although duration of abdominal pain is associated with AP, short time delays from ED evaluation to operation did not independently increase the odds of perforation.

Time From Emergency Department Evaluation to Operation and Appendiceal Perforation

Working at the intersection of context, culture, and technology: Provider perspectives on antimicrobial stewardship in the emergency department using electronic health record clinical decision support

Optimal Volume of Administration of Intranasal Midazolam in Children: A Randomized Clinical Trial

Validity and Reliability of the Verbal Numerical Rating Scale for Children Aged 4 to 17 Years With Acute Pain

The urinary biomarker uNGAL displayed substantial accuracy to diagnose UTIs in febrile infants and young children when compared with standard UA. OBJECTIVES: To determine the accuracy of the novel biomarker urinary neutrophil gelatinase–associated lipocalin (uNGAL) to diagnose urinary tract infections (UTIs) in febrile infants and young children. METHODS: Prospective cross-sectional study of febrile infants <3 months ( ≥ 38.0°C) and children 3 to 24 months (≥ 39.0°C) evaluated for UTIs. uNGAL levels, urinalysis, Gram-stain and culture were obtained. UTI was defined by colony counts. RESULTS: Of 260 patients, 35 (13.5%) had UTIs. Median uNGAL levels were 215.1 ng/mL (interquartile range: 100.3–917.8) and 4.4 ng/mL (interquartile range: 1.6–11.8) in the groups diagnosed with and without UTIs, respectively. The area under the receiver-operating characteristic curve for uNGAL was 0.978 (95% confidence interval [CI]: 0.948–1.000). At a threshold uNGAL level of 39.1 ng/mL, sensitivity was 97.1% (95% CI: 83.4–99.9) and specificity was 95.6% (95% CI: 91.7–97.7). uNGAL had higher sensitivity than the combination of leukocyte esterase (in trace or greater amounts) or nitrite (+) (97.1%, 95% CI: 83.4–99.9 vs 74.3%, 95% CI: 56.4–86.9), with similar specificity (95.6%, 95% CI: 91.7–97.7 vs 97.3%, 95% CI: 94.0–98.9). uNGAL had higher sensitivity than Gram-stain (97.1%, 95% CI: 83.4–99.9 vs 74.3%, 95%: CI: 56.4–86.9), with similar specificity (95.6%, 95% CI: 91.7–97.7 vs 100.0%, 95% CI: 97.9–100.0). CONCLUSIONS: uNGAL has substantial accuracy to identify those with and without UTIs in infants and young children. Further studies will need to confirm our findings and determine if uNGAL is a more cost-effective test than standard screening tests.

Urinary Neutrophil Gelatinase–Associated Lipocalin for the Diagnosis of Urinary Tract Infections

Computed tomography (CT) is often used in the emergency department (ED) evaluation of children with posttraumatic seizures (PTS); however, the frequency of traumatic brain injuries (TBIs) and short-term seizure recurrence is lacking. Our main objective was to evaluate the frequency of TBIs on CT and short-term seizure recurrence in children with PTS. We also aimed to determine the associations between the likelihood of TBI on CT with the timing of onset of PTS after the traumatic event and duration of PTS. Finally, we aimed to determine whether patients with normal CT scans and normal neurological examinations are safe for discharge from the ED.

METHODS
This was a planned secondary analysis from a prospective observational cohort study to derive and validate a neuroimaging decision rule for children after blunt head trauma at 25 EDs in the Pediatric Emergency Care Applied Research Network. We evaluated children < 18 years with head trauma and PTS between June 2004 and September 2006. We assessed TBI on CT, neurosurgical interventions, and recurrent seizures within 1 week. Patients discharged from the ED were contacted by telephone 1 week to 3 months later.

RESULTS
Of 42,424 children enrolled, 536 (1.3%, 95% confidence interval [CI] = 1.2%-1.4%) had PTS. A total of 466 of 536 (86.9%, 95% CI = 83.8%-89.7%) underwent CT in the ED. TBIs on CT were identified in 72 (15.5%, 95% CI = 12.3%-19.1%), of whom 20 (27.8%, 95% CI = 17.9%-39.6%) underwent neurosurgical intervention and 15 (20.8%, 95% CI = 12.2%-32.0%) had recurrent seizures. Of the 464 without TBIs on CT (or no CTs performed), 457 had recurrent seizure status known, and five (1.1%, 95 CI = 0.4%-2.5%) had recurrent seizures; four of five presented with Glasgow Coma Scale scores < 15. None of the 464 underwent neurosurgical intervention. We found significant associations between likelihood of TBI on CT with longer time until the PTS after the traumatic event (p = 0.006) and longer duration of PTS (p < 0.001).

Children with PTS have a high likelihood of TBI on CT, and those with TBI on CT frequently require neurosurgical interventions and frequently have recurrent seizures. Those without TBIs on CT, however, are at low risk of short-term recurrent seizures, and none required neurosurgical interventions. Therefore, if CT-negative and neurologically normal, patients with PTS may be safely considered for discharge from the ED.

Prevalence of Brain Injuries and Recurrence of Seizures in Children With Posttraumatic Seizures

The investigators provide data from a multicenter trial regarding whether implementation of prediction rules safely decreases computed tomography use in children with minor head trauma. OBJECTIVES: We determined whether implementing the Pediatric Emergency Care Applied Research Network (PECARN) traumatic brain injury (TBI) prediction rules and providing risks of clinically important TBIs (ciTBIs) with computerized clinical decision support (CDS) reduces computed tomography (CT) use for children with minor head trauma. METHODS: Nonrandomized trial with concurrent controls at 5 pediatric emergency departments (PEDs) and 8 general EDs (GEDs) between November 2011 and June 2014. Patients were <18 years old with minor blunt head trauma. Intervention sites received CDS with CT recommendations and risks of ciTBI, both for patients at very low risk of ciTBI (no Pediatric Emergency Care Applied Research Network rule factors) and those not at very low risk. The primary outcome was the rate of CT, analyzed by site, controlling for time trend. RESULTS: We analyzed 16 635 intervention and 2394 control patients. Adjusted for time trends, CT rates decreased significantly (P < .05) but modestly (2.3%–3.7%) at 2 of 4 intervention PEDs for children at very low risk. The other 2 PEDs had small (0.8%–1.5%) nonsignificant decreases. CT rates did not decrease consistently at the intervention GEDs, with low baseline CT rates (2.1%–4.0%) in those at very low risk. The control PED had little change in CT use in similar children (from 1.6% to 2.9%); the control GED showed a decrease in the CT rate (from 7.1% to 2.6%). For all children with minor head trauma, intervention sites had small decreases in CT rates (1.7%–6.2%). CONCLUSIONS: The implementation of TBI prediction rules and provision of risks of ciTBIs by using CDS was associated with modest, safe, but variable decreases in CT use. However, some secular trends were also noted.

Use of Traumatic Brain Injury Prediction Rules With Clinical Decision Support

BACKGROUND Antimicrobial stewardship programs (ASPs) effectively optimize antibiotic use for inpatients; however, the extent of emergency department (ED) involvement in ASPs has not been described. OBJECTIVE To determine current ED involvement in children’s hospital ASPs and to assess beliefs and preferred methods of implementation for ED-based ASPs. METHODS A cross-sectional survey of 37 children’s hospitals participating in the Sharing Antimicrobial Resistance Practices collaboration was conducted. Surveys were distributed to ASP leaders and ED medical directors at each institution. Items assessed included beliefs regarding ED antibiotic prescribing, ED prescribing resources, ASP methods used in the ED such as clinical decision support and clinical care guidelines, ED participation in ASP activities, and preferred methods for ED-based ASP implementation. RESULTS A total of 36 ASP leaders (97.3%) and 32 ED directors (86.5%) responded; the overall response rate was 91.9%. Most ASP leaders (97.8%) and ED directors (93.7%) agreed that creation of ED-based ASPs was necessary. ED resources for antibiotic prescribing were obtained via the Internet or electronic health records (EHRs) for 29 hospitals (81.3%). The main ASP activities for the ED included production of antibiograms (77.8%) and creation of clinical care guidelines for pneumonia (83.3%). The ED was represented on 3 hospital ASP committees (8.3%). No hospital ASPs actively monitored outpatient ED prescribing. Most ASP leaders (77.8%) and ED directors (81.3%) preferred implementation of ED-based ASPs using clinical decision support integrated into the EHR. CONCLUSIONS Although ED involvement in ASPs is limited, both ASP and ED leaders believe that ED-based ASPs are necessary. Many children’s hospitals have the capability to implement ED-based ASPs via the preferred method: EHR clinical decision support. Infect Control Hosp Epidemiol 2017;38:469–475

Current State of Antimicrobial Stewardship in Children’s Hospital Emergency Departments

Objectives We aimed to determine the prevalence of and adverse outcomes caused by pneumocephali in children with minor blunt head trauma who had no other intracranial injuries (ie, isolated pneumocephali). Methods We conducted a secondary analysis of a public use dataset from a multicenter prospective study of pediatric minor head trauma. We included children younger than 18 years with Glasgow Coma Scale (GCS) scores of 14 or 15 and non-trivial mechanisms of injury who had cranial computed tomographies obtained. Patients with isolated pneumocephali were those without other traumatic brain injuries (TBIs) but could have non-depressed or basilar skull fractures (BSFs). We defined adverse outcomes as death, need for neurosurgery, or intubation more than 24 hours for TBI. Results Pneumocephali occurred in 148 (1.0%; 95% confidence interval, 0.8%–1.2%) of 14,983 patients; 54 (36.5%) of 148 were isolated. Of these 54 patients, 42 (77.8%) had associated BSFs (7 of whom also had linear skull fractures) and 8 (14.8%) had associated linear skull fractures without BSFs; 4 patients (7.4%) had no fractures. Thirty-three patients (61.1%) had both GCS scores of 15 and no other signs of altered mental status. All patients with isolated pneumocephali and available descriptive data (n = 26) had small-sized pneumocephali. There were no deaths, neurosurgical interventions, or intubations for more than 24 hours for TBI (95% confidence interval for any of the outcomes, 0%–7.9%) in the 54 patients with isolated pneumocephali. Conclusions Children with isolated pneumocephali and GCS scores of 14 or 15 after minor blunt head trauma are unlikely to have adverse clinical outcomes.

Acute Outcomes of Isolated Pneumocephali in Children After Minor Blunt Head Trauma

OBJECTIVE
White blood cell (WBC) count and absolute neutrophil count (ANC) are a standard part of the evaluation of suspected appendicitis. Specific threshold values are utilized in clinical pathways, but the discriminatory value of WBC count and ANC may vary by age. The objective of this study was to investigate whether the diagnostic value of WBC count and ANC varies across age groups and whether diagnostic thresholds should be age-adjusted.

METHODS
This is a multicenter prospective observational study of patients aged 3-18 years who were evaluated for appendicitis. Receiver operator characteristic curves were developed to assess overall discriminative power of WBC count and ANC across three age groups: <5, 5-11, and 12-18 years of age. Diagnostic performance of WBC count and ANC was then assessed at specific cut-points.

RESULTS
A total of 2,133 patients with a median age of 10.9 years (interquartile range = 8.0-13.9 years) were studied. Forty-one percent had appendicitis. The area under the curve (AUC) for WBC count was 0.69 (95% confidence interval [CI] = 0.61 to 0.77) for patients < 5 years of age, 0.76 (95% CI = 0.73 to 0.79) for 5-11 years of age, and 0.83 (95% CI = 0.81 to 0.86) for 12-18 years of age. The AUCs for ANC across age groups mirrored WBC performance. At a commonly utilized WBC cut-point of 10,000/mm3 , the sensitivity decreased with increasing age: 95% (<5 years), 91% (5-11 years), and 89% (12-18 years) whereas specificity increased by age: 36% (<5 years), 49% (5-12 years), and 64% (12-18 years).

WBC count and ANC had better diagnostic performance with increasing age. Age-adjusted values of WBC count or ANC should be considered in diagnostic strategies for suspected pediatric appendicitis.

The Influence of Age on the Diagnostic Performance of White Blood Cell Count and Absolute Neutrophil Count in Suspected Pediatric Appendicitis.

Background Over 15 million adolescents use the emergency department (ED) each year in the United States. Adolescent females who use the ED for medical care have been found to be at high risk for unintended pregnancy. Given that adolescents represent the largest users of text messaging and are receptive to receiving text messages related to their sexual health, the ED visit represents an opportunity for intervention. Objective The aim of this qualitative study was to explore interest in and preferences for the content, frequency, and timing of an ED-based text message intervention to prevent pregnancy for adolescent females. Methods We conducted semistructured, open-ended interviews in one urban ED in the United States with adolescent females aged 14-19 years. Eligible subjects were adolescents who were sexually active in the past 3 months, presented to the ED for a reproductive health complaint, owned a mobile phone, and did not use effective contraception. Using an interview guide, enrollment continued until saturation of key themes. The investigators designed sample text messages using the Health Beliefs Model and participants viewed these on a mobile phone. The team recorded, transcribed, and coded interviews based on thematic analysis using the qualitative analysis software NVivo and Excel. Results Participants (n=14) were predominantly Hispanic (13/14; 93%), insured (13/14; 93%), ED users in the past year (12/14; 86%), and frequent text users (10/14; 71% had sent or received >30 texts per day). All were interested in receiving text messages from the ED about pregnancy prevention, favoring messages that were “brief,” “professional,” and “nonaccusatory.” Respondents favored texts with links to websites, repeated information regarding places to receive “confidential” care, and focused information on contraception options and misconceptions. Preferences for text message frequency varied from daily to monthly, with random hours of delivery to maintain “surprise.” No participant feared that text messages would violate her privacy. Conclusions Adolescent female patients at high pregnancy risk are interested in ED-based pregnancy prevention provided by texting. Understanding preferences for the content, frequency, and timing of messages can guide in designing future interventions in the ED.

Adolescent Female Text Messaging Preferences to Prevent Pregnancy After an Emergency Department Visit: A Qualitative Analysis

OBJECTIVE
The objective was to compare the accuracy of the pediatric Glasgow Coma Scale (GCS) score in preverbal children to the standard GCS score in older children for identifying those with traumatic brain injuries (TBIs) after blunt head trauma.

METHODS
This was a planned secondary analysis of a large prospective observational multicenter cohort study of children with blunt head trauma. Clinical data were recorded onto case report forms before computed tomography (CT) results or clinical outcomes were known. The total and component GCS scores were assigned by the physician at initial emergency department evaluation. The pediatric GCS was used for children <2 years old and the standard GCS for those ≥2 years old. Outcomes were TBI visible on CT and clinically important TBI (ciTBI), defined as death from TBI, neurosurgery, intubation for more than 24 hours for the head injury, or hospitalization for 2 or more nights for the head injury in association with TBI on CT. We compared the areas under the receiver operating characteristic (ROC) curves between age cohorts for the association of GCS and the TBI outcomes.

RESULTS
We enrolled 42,041 patients, of whom 10,499 (25.0%) were <2 years old. Among patients <2 years, 313/3,329 (9.4%, 95% confidence interval [CI] = 8.4% to 10.4%) of those imaged had TBIs on CT and 146/10,499 (1.4%, 95% CI = 1.2% to 1.6%) had ciTBIs. In patients ≥2 years, 773/11,977 (6.5%, 95% CI = 6.0% to 6.9%) of those imaged had TBIs on CT and 572/31,542 (1.8%, 95% CI = 1.7% to 2.0%) had ciTBIs. For the pediatric GCS in children <2 years old, the area under the ROC curve was 0.61 (95% CI = 0.59 to 0.64) for TBI on CT and 0.77 (95% CI = 0.73 to 0.81) for ciTBI. For the standard GCS in older children, the area under the ROC curve was 0.71 (95% CI = 0.70 to 0.73) for TBI on CT scan and 0.81 (95% CI = 0.79 to 0.83) for ciTBI.

The pediatric GCS for preverbal children was somewhat less accurate than the standard GCS for older children in identifying those with TBI on CT. However, the pediatric GCS for preverbal children and the standard GCS for older children were equally accurate for identifying ciTBI.

Performance of the Pediatric Glasgow Coma Scale Score in the Evaluation of Children With Blunt Head Trauma.

374EMF Development of an Emergency Department-Based Antimicrobial Stewardship Program Using Clinical Decision Support

Background: Few data exist on the presentations and clinical courses of infants with enterococcal urinary tract infections (UTI). The objective of this study was to compare the clinical presentation, sensitivity of urinalysis (UA) and Gram’s stain, radiological abnormalities and adverse events of febrile infants with enterococcal UTIs to those with Gram-negative UTIs. Methods: Retrospective study of febrile (≥38.0°C) infants 29–60 days of age with UTIs at 20 emergency departments. UTI was defined as growth of (1) ≥50,000 colony forming units (CFUs)/mL of a single pathogen; or (2) either 10,000 to <50,000 CFUs/mL or 10,000–100,000 CFUs/mL (depending on laboratory reporting) with a positive UA or Gram’s stain. Results: Thirty-seven (2.0%) of 1870 infants with febrile UTIs had enterococcal UTIs. On bivariable analysis, infants with enterococcal UTIs more frequently had histories of prematurity, previous hospitalizations, histories of genitourinary abnormalities, previous UTIs and ill-appearance in the emergency department compared with infants with Gram-negative UTIs (all P <0.05). On multivariable analysis, ≥ grade 3 vesicoureteral reflux (adjusted odds ratio 3.2, 95% confidence interval: 1.4, 7.6) and hydronephrosis (adjusted odds ratio 3.3, 95% confidence interval: 1.4, 7.9) were associated with enterococcal UTIs. Both groups had similar low risks of adverse events or severe clinical courses. The urine white blood cell count alone or in combination with leukocyte esterase was more sensitive for Gram-negative than enterococcal UTIs (range 80.4%–93.9% vs. 50.0%–75.9%). Conclusions: Febrile infants with enterococcal UTIs had a low likelihood of adverse events or severe clinical course, similar to those with Gram-negative UTIs. Infants with enterococcal UTIs frequently had underlying hydronephrosis and/or vesicoureteral reflux. The preliminary diagnosis of enterococcal UTIs may be inaccurate if based on UA.

Comparison of Febrile Infants With Enterococcal and Gram-negative Urinary Tract Infections

Use of a remote clinical decision support service for a multicenter trial to implement prediction rules for children with minor blunt head trauma

Summary Introduction For children who present to emergency departments (EDs) due to blunt head trauma, ED clinicians must decide who requires computed tomography (CT) scanning to evaluate for traumatic brain injury (TBI). The Pediatric Emergency Care Applied Research Network (PECARN) derived and validated two age-based prediction rules to identify children at very low risk of clinically-important traumatic brain injuries (ciTBIs) who do not typically require CT scans. In this case report, we describe the strategy used to implement the PECARN TBI prediction rules via electronic health record (EHR) clinical decision support (CDS) as the intervention in a multicenter clinical trial. Methods Thirteen EDs participated in this trial. The 10 sites receiving the CDS intervention used the Epic® EHR. All sites implementing EHR-based CDS built the rules by using the vendor’s CDS engine. Based on a sociotechnical analysis, we designed the CDS so that recommendations could be displayed immediately after any provider entered prediction rule data. One central site developed and tested the intervention package to be exported to other sites. The intervention package included a clinical trial alert, an electronic data collection form, the CDS rules and the format for recommendations. Results The original PECARN head trauma prediction rules were derived from physician documentation while this pragmatic trial led each site to customize their workflows and allow multiple different providers to complete the head trauma assessments. These differences in workflows led to varying completion rates across sites as well as differences in the types of providers completing the electronic data form. Site variation in internal change management processes made it challenging to maintain the same rigor across all sites. This led to downstream effects when data reports were developed. Conclusions The process of a centralized build and export of a CDS system in one commercial EHR system successfully supported a multicenter clinical trial.

Clinical Decision Support for a Multicenter Trial of Pediatric Head Trauma

Clinical Presentations and Outcomes of Children With Basilar Skull Fractures After Blunt Head Trauma.

Objectives The aims of this study were to define the Faces Pain Scale–Revised (FPS-R) and Color Analog Scale (CAS) scores associated with no pain, mild pain, moderate pain, and severe pain in children with acute pain, and to identify differences based on age, sex, and ethnicity. Methods We conducted a prospective observational study in 2 pediatric emergency departments of children aged 4 to 17 years with painful and nonpainful conditions. We assessed their pain intensity using the FPS-R, CAS, and qualitative measures. Pain score cut points that best differentiated adjacent categories of pain were identified using a receiver operating characteristic–based method. Cut points were compared within subgroups based on age, sex, and ethnicity. Results We enrolled 620 patients, of whom 314 had painful conditions. The mean age was 9.2 years; 315 (50.8%) were in the younger age group (aged 4–7 years); 291 (46.8%) were female; and 341 (55%) were Hispanic. The scores best representing categories of pain for the FPS-R were as follows: no pain, 0 and 2; mild pain, 4; moderate pain, 6; and severe pain, 8 and 10. For the CAS, these were 0 to 1, 1.25 to 2.75, 3 to 5.75, and 6 to 10, respectively. Children with no pain frequently reported nonzero pain scores. There was considerable overlap of scores associated with mild and moderate pain. There were no clinically meaningful differences of scores representing each category of pain based on age, ethnicity, and race. Conclusions We defined pain scores for the FPS-R and CAS associated with categories of pain intensity in children with acute pain that are generalizable across subgroups based on patient characteristics. There were minor but potentially important differences in pain scores used to delineate categories of pain intensity compared to prior convention.

Defining No Pain, Mild, Moderate, and Severe Pain Based on the Faces Pain Scale–Revised and Color Analog Scale in Children With Acute Pain

Objective Adolescents are the largest users of mobile technology; yet, there are little data regarding their receptivity to the use of mobile health technology (mHealth) from the emergency department (ED). The objective of this study was to determine adolescents' preferences for receiving ED discharge and follow-up information via mHealth and factors associated with those preferences. Methods We administered an anonymous self-reporting survey to patients aged 14 to 19 years discharged from an urban pediatric ED. We conducted exploratory bivariate analyses to evaluate differences in communication preferences based on patient characteristics. We used multivariable logistic regression to determine whether preference for health information via mHealth is associated with frequent information technology (IT) use, adjusting for age, sex, ethnicity, and insurance status. Results Four hundred thirty-nine adolescents completed the survey. Most were female (n = 279, 64%), 14 to 17 years old (n = 247, 57%), Hispanic (n = 359, 86%), and insured (n = 388, 88%). Adolescents used IT often, texting more than 30 times a day (58%) and emailing more than once a day (61%). Most (n = 335, 78%) were interested in electronic communication from the ED. Teens expressed particular interest in using email for discharge instructions (n = 196, 47%), physician referrals (n = 197, 48%), and test results (n = 201, 48%) and using texting for medication (n = 155, 38%) and appointment reminders (n = 170, 41%). Individuals tended to prefer communication with IT modes that they typically used, although only email was independently associated with preference for this mode (adjusted odds ratio, 2.8; 95% confidence interval, 1.5-5.3). Conclusions Adolescent patients are interested in receiving health information from the ED, mainly via email and texting. Future ED interventions should evaluate the effectiveness of these modalities to communicate with patients after discharge.

Mobile Health Technology to Communicate Discharge and Follow-Up Information to Adolescents From the Emergency Department

Objectives Abscess incision and drainage (I&D) are painful and distressing procedures in children. Intranasal (IN) fentanyl is an effective analgesic for reducing symptomatic pain associated with fractures and burns but has not been studied for reducing procedural pain during abscess I&D. Our objective was to compare the analgesic efficacy of IN fentanyl with intravenous (IV) morphine for abscess I&D in children. Methods We performed a randomized noninferiority trial in children aged 4 to 18 years undergoing abscess I&D in a pediatric emergency department. Patients received IN fentanyl (2 &mgr;g/kg; maximum, 100 &mgr;g) or IV morphine (0.1 mg/kg; maximum, 8 mg). The primary outcome, determined independently by blinded assessors, was the Observational Scale of Behavioral Distress-Revised (OSBD-R). The prestated margin of noninferiority (&Dgr;) was 1.80. Secondary outcomes included self-reported pain, treatment failure, and patient and parental satisfaction. Results We enrolled 20 children (median age, 15.4 years), 10 in each group. The difference between total OSBD-R scores was −13.45 (95% confidence interval, −24.24 to −2.67), favoring IN fentanyl. There was less self-reported pain in patients who received IN fentanyl immediately after the procedure. Four patients (40%) receiving IV morphine had treatment failures and required moderate sedation or had the procedure terminated. More patients who received IN fentanyl were satisfied with the analgesic administered compared with those who received IV morphine. Conclusions In a small sample of children aged 4 to 18 years undergoing abscess I&D, IN fentanyl was noninferior, and potentially superior, to IV morphine for reducing procedural pain and distress.

Randomized Trial of Intranasal Fentanyl Versus Intravenous Morphine for Abscess Incision and Drainage

IMPORTANCE
Young febrile infants are at substantial risk of serious bacterial infections; however, the current culture-based diagnosis has limitations. Analysis of host expression patterns ("RNA biosignatures") in response to infections may provide an alternative diagnostic approach.

OBJECTIVE
To assess whether RNA biosignatures can distinguish febrile infants aged 60 days or younger with and without serious bacterial infections.

DESIGN, SETTING, AND PARTICIPANTS
Prospective observational study involving a convenience sample of febrile infants 60 days or younger evaluated for fever (temperature >38° C) in 22 emergency departments from December 2008 to December 2010 who underwent laboratory evaluations including blood cultures. A random sample of infants with and without bacterial infections was selected for RNA biosignature analysis. Afebrile healthy infants served as controls. Blood samples were collected for cultures and RNA biosignatures. Bioinformatics tools were applied to define RNA biosignatures to classify febrile infants by infection type.

EXPOSURE
RNA biosignatures compared with cultures for discriminating febrile infants with and without bacterial infections and infants with bacteremia from those without bacterial infections.

MAIN OUTCOMES AND MEASURES
Bacterial infection confirmed by culture. Performance of RNA biosignatures was compared with routine laboratory screening tests and Yale Observation Scale (YOS) scores.

RESULTS
Of 1883 febrile infants (median age, 37 days; 55.7% boys), RNA biosignatures were measured in 279 randomly selected infants (89 with bacterial infections-including 32 with bacteremia and 15 with urinary tract infections-and 190 without bacterial infections), and 19 afebrile healthy infants. Sixty-six classifier genes were identified that distinguished infants with and without bacterial infections in the test set with 87% (95% CI, 73%-95%) sensitivity and 89% (95% CI, 81%-93%) specificity. Ten classifier genes distinguished infants with bacteremia from those without bacterial infections in the test set with 94% (95% CI, 70%-100%) sensitivity and 95% (95% CI, 88%-98%) specificity. The incremental C statistic for the RNA biosignatures over the YOS score was 0.37 (95% CI, 0.30-0.43).

CONCLUSIONS AND RELEVANCE
In this preliminary study, RNA biosignatures were defined to distinguish febrile infants aged 60 days or younger with vs without bacterial infections. Further research with larger populations is needed to refine and validate the estimates of test accuracy and to assess the clinical utility of RNA biosignatures in practice.

Association of RNA Biosignatures With Bacterial Infections in Febrile Infants Aged 60 Days or Younger.

OBJECTIVE
Children with minor head trauma frequently present to emergency departments (EDs). Identifying those with traumatic brain injuries (TBIs) can be difficult, and it is unknown whether clinical prediction rules outperform clinician suspicion. Our primary objective was to compare the test characteristics of the Pediatric Emergency Care Applied Research Network (PECARN) TBI prediction rules to clinician suspicion for identifying children with clinically important TBIs (ciTBIs) after minor blunt head trauma. Our secondary objective was to determine the reasons for obtaining computed tomography (CT) scans when clinical suspicion of ciTBI was low.

METHODS
This was a planned secondary analysis of a previously conducted observational cohort study conducted in PECARN to derive and validate clinical prediction rules for ciTBI among children with minor blunt head trauma in 25 PECARN EDs. Clinicians recorded their suspicion of ciTBI before CT as <1, 1-5, 6-10, 11-50, or >50%. We defined ciTBI as 1) death from TBI, 2) neurosurgery, 3) intubation for more than 24 hours for TBI, or 4) hospital admission of 2 nights or more associated with TBI on CT. To avoid overfitting of the prediction rules, we performed comparisons of the prediction rules and clinician suspicion on the validation group only. On the validation group, we compared the test accuracies of clinician suspicion > 1% versus having at least one predictor in the PECARN TBI age-specific prediction rules for identifying children with ciTBIs (one rule for children <2 years [preverbal], the other rule for children >2 years [verbal]).

RESULTS
In the parent study, we enrolled 8,627 children to validate the prediction rules, after enrolling 33,785 children to derive the prediction rules. In the validation group, clinician suspicion of ciTBI was recorded in 8,496/8,627 (98.5%) patients, and 87 (1.0%) had ciTBIs. CT scans were obtained in 2,857 (33.6%) patients in the validation group for whom clinician suspicion of ciTBI was recorded, including 2,099/7,688 (27.3%) of those with clinician suspicion of ciTBI of <1% and 758/808 (93.8%) of those with clinician suspicion >1%. The PECARN prediction rules were significantly more sensitive than clinician suspicion >1% of ciTBI for preverbal (100% [95% confidence interval {CI} = 86.3% to 100%] vs. 60.0% [95% CI = 38.7% to 78.9%]) and verbal children (96.8% [95% CI = 88.8% to 99.6%] vs. 64.5% [95% CI = 51.3% to 76.3%]). Prediction rule specificity, however, was lower than clinician suspicion >1% for preverbal children (53.6% [95% CI = 51.5% to 55.7%] vs. 92.4% [95% CI = 91.2% to 93.5%]) and verbal children (58.2% [95% CI = 56.9% to 59.4%] vs. 90.6% [95% CI = 89.8% to 91.3%]). Of the 7,688 patients in the validation group with clinician suspicion recorded as <1%, CTs were nevertheless obtained in 2,099 (27.3%). Three of 16 (18.8%) patients undergoing neurosurgery had clinician suspicion of ciTBI <1%.

The PECARN TBI prediction rules had substantially greater sensitivity, but lower specificity, than clinician suspicion of ciTBI for children with minor blunt head trauma. Because CT ordering did not follow clinician suspicion of <1%, these prediction rules can augment clinician judgment and help obviate CT ordering for children at very low risk of ciTBI.

Comparison of Prediction Rules and Clinician Suspicion for Identifying Children With Clinically Important Brain Injuries After Blunt Head Trauma.

BACKGROUND AND OBJECTIVE: Children and adolescents with minor blunt head trauma and isolated skull fractures are often admitted to the hospital. The objective of this study was to describe the injury circumstances and frequency of clinically important neurologic complications among children with minor blunt head trauma and isolated linear skull fractures. METHODS: This study was a planned secondary analysis of a large prospective cohort study in children <18 years old with blunt head trauma. Data were collected in 25 emergency departments. We analyzed patients with Glasgow Coma Scale scores of 14 or 15 and isolated linear skull fractures. We ascertained acute neurologic outcomes through clinical information collected during admission or via telephone or mail at least 1 week after the emergency department visit. RESULTS: In the parent study, we enrolled 43 904 children (11 035 [25%] <2 years old). Of those with imaging studies, 350 had isolated linear skull fractures. Falls were the most common injury mechanism, accounting for 70% (81% for ages <2 years old). Of 201 hospitalized children, 42 had computed tomography or MRI repeated; 5 had new findings but none required neurosurgical intervention. Of 149 patients discharged from the hospital, 20 had repeated imaging, and none had new findings. CONCLUSIONS: Children with minor blunt head trauma and isolated linear skull fractures are at very low risk of evolving other traumatic findings noted in subsequent imaging studies or requiring neurosurgical intervention. Hospital admission for neurologically normal children with isolated linear skull fractures after minor blunt head trauma for monitoring is typically unnecessary.

Isolated Linear Skull Fractures in Children With Blunt Head Trauma

BACKGROUND AND OBJECTIVES: Prospective data are lacking to determine which children might benefit from prompt neuroimaging after unprovoked seizures. We aimed to determine the prevalence of, and risk factors for, relevant intracranial abnormalities in children with first, unprovoked seizures. METHODS: We conducted a 6-center prospective study in children aged >28 days to 18 years with seemingly unprovoked seizures. Emergency department (ED) clinicians documented clinical findings on a standardized form. Our main outcome was the presence of a clinically relevant intracranial abnormality on computed tomography (CT) or MRI, defined as those that might change management, either emergently, urgently, or nonurgently. RESULTS: We enrolled 475 of 625 (76%) eligible patients. Of 354 patients for whom cranial MRI or CT scans were obtained in the ED or within 4 months of the ED visit, 40 (11.3%; 95% confidence interval [CI]: 8.0–14.6%) had clinically relevant intracranial abnormalities, with 3 (0.8%; 95% CI: 0.1–1.8%) having emergent/urgent abnormalities. On logistic regression analysis, a high-risk past medical history (adjusted odds ratio: 9.2; 95% CI: 2.4–35.7) and any focal aspect to the seizure (odds ratio: 2.5; 95% CI: 1.2–5.3) were independently associated with clinically relevant abnormalities. CONCLUSIONS: Clinically relevant intracranial abnormalities occur in 11% of children with first, unprovoked seizures. Emergent/urgent abnormalities, however, occur in <1%, suggesting that most children do not require neuroimaging in the ED. Findings on patient history and physical examination identify patients at higher risk of relevant abnormalities.

Prevalence of and Risk Factors for Intracranial Abnormalities in Unprovoked Seizures

The battle against antimicrobial resistance: time for the emergency department to join the fight.

Female adolescents at high pregnancy risk frequently visit the emergency department (ED) and lack primary providers. It is unclear if current methods of ED referral are successful. The objective of this pilot study was to assess the potential effect and feasibility of a standardized, enhanced method of referral of sexually active females from an ED for family planning (FP).

METHODS
We conducted an ED-based intervention study using an enhanced referral process, which included a wallet card advertising a walk-in, adolescent-friendly FP clinic and a standardized ED physician monologue. ED physicians were instructed to disseminate the enhanced process to sexually active females ages 12-19 years (intervention group). Patients receiving the intervention were prospectively enrolled. The control group consisted of patients who, on retrospective review, came to the ED during the enrollment period and were eligible but were not enrolled. We used the electronic medical record (EMR) to identify and randomly select missed eligible patients (control group) and accumulated one control for each case. The primary outcome was FP follow-up within 2 months, measured by EMR review.

RESULTS
The intervention (n=101) and control groups (n=101) were similar in age, prior ED visits (54% versus 56%), and previous FP visits (28% versus 28%). The absolute difference in follow-up to a FP clinic between the enhanced referral group (7%; 7/101) compared with the nonenhanced referral group (5%; 5/101) was only 2% (95% confidence interval -5% to 9%). Feasibility of the intervention was modest, with a best-case scenario of 59/160 (37%) of eligible patients captured.

An enhanced referral initiative relying on physician participation did not substantially increase follow-up rates to a FP clinic and showed modest feasibility. More research is required to identify effective means of ED-based referral for preventive reproductive care.

Enhancing referral of sexually active adolescent females from the emergency department to family planning.

The objective was to determine the minimum and ideal clinically significant differences (MCSD, ICSD) in pain intensity in children for the Faces Pain Scale-Revised (FPS-R) and the Color Analog Scale (CAS) and to identify any differences in these estimates based on patient characteristics.

METHODS
This was a prospective study of children aged 4 to 17 years with acute pain presenting to two urban pediatric emergency departments. Participants self-reported their pain intensity using the FPS-R and CAS and qualitatively described their changes in pain. Changes in pain score reported using the FPS-R and CAS that were associated with "a little less" and "much less" pain (MCSD and ICSD, respectively) were identified using a receiver operating characteristic-based method and expressed as raw change score and percent reductions. Estimates of MCSD and ICSD were determined for each category of initial pain intensity (mild, moderate, and severe) and patient characteristics (age, sex, and ethnicity). Post hoc exploratory analyses evaluated categories of race, primary language, and etiology of pain.

RESULTS
A total of 314 children with acute pain were enrolled; mean (±SD) age was 9.8 (±3.8) years. The FPS-R raw change score and percent reduction MCSD estimates were 2/10 and 25%, with ICSD estimates of 3/10 and 60%. For the CAS, raw change score and percent reduction MCSD estimates were 1/10 and 15%, with ICSD estimates of 2.75/10 and 52%. For both scales, raw change score and percent reduction estimates of the MCSD remained unchanged in children with either moderate or severe pain. For both scales, estimates of ICSD were not stable across categories of initial pain intensity. There was no difference in MCSD or ICSD based on age, sex, ethnicity, race, primary language, or etiology of pain.

The MCSD estimates can be expressed as raw change score and percent reductions for the FPS-R and CAS. These estimates appear stable for children with moderate to severe pain, irrespective of age, sex, and ethnicity. Estimates of ICSD were not stable across different categories of initial pain intensity, therefore limiting their potential generalizability.

Clinically significant differences in acute pain measured on self-report pain scales in children.

Summary Background: Overuse of cranial computed tomography scans in children with blunt head trauma unnecessarily exposes them to radiation. The Pediatric Emergency Care Applied Research Network (PECARN) blunt head trauma prediction rules identify children who do not require a computed tomography scan. Electronic health record (EHR) based clinical decision support (CDS) may effectively implement these rules but must only be provided for appropriate patients in order to minimize excessive alerts. Objective: To develop, implement and evaluate site-specific groupings of chief complaints (CC) that accurately identify children with head trauma, in order to activate data collection in an EHR. Methods: As part of a 13 site clinical trial comparing cranial computed tomography use before and after implementation of CDS, four PECARN sites centrally developed and locally implemented CC groupings to trigger a clinical trial alert (CTA) to facilitate the completion of an emergency department head trauma data collection template. We tested and chose CC groupings to attain high sensitivity while maintaining at least moderate specificity. Results: Due to variability in CCs available, identical groupings across sites were not possible. We noted substantial variability in the sensitivity and specificity of seemingly similar CC groupings between sites. The implemented CC groupings had sensitivities greater than 90% with specificities between 75–89%. During the trial, formal testing and provider feedback led to tailoring of the CC groupings at some sites. Conclusion: CC groupings can be successfully developed and implemented across multiple sites to accurately identify patients who should have a CTA triggered to facilitate EHR data collection. However, CC groupings will necessarily vary in order to attain high sensitivity and moderate-to-high specificity. In future trials, the balance between sensitivity and specificity should be considered based on the nature of the clinical condition, including prevalence and morbidity, in addition to the goals of the intervention being considered. Citation: Deakyne SJ, Bajaj L, Hoffmann J, Alessandrini E, Ballard DW, Norris R, Tzimenatos L, Swietlik M, Tham E, Grundmeier RW, Kuppermann N, Dayan PS. Development, Evaluation and Implementation of Chief Complaint Groupings to Activate Data Collection in a Multi-Center Study of Clinical Decision Support for Children with Head Trauma. Appl Clin Inform 2015; 6: 521–535 http://dx.doi.org/10.4338/ACI-2015-02-RA-0019

Development, Evaluation and Implementation of Chief Complaint Groupings to Activate Data Collection

Objective The objective of the study was to describe the epidemiology, cranial computed tomography (CT) findings, and clinical outcomes of children with blunt head trauma after television tip-over injuries. Methods We performed a secondary analysis of children younger than 18 years prospectively evaluated for blunt head trauma at 25 emergency departments (EDs) in the Pediatric Emergency Care Applied Research Network from June 2004 to September 2006. Children injured from falling televisions were included. Patients were excluded if injuries occurred more than 24 hours before ED evaluation or if neuroimaging was obtained before evaluation. Data collected included age, race, sex, cranial CT findings, and clinical outcomes. Clinically important traumatic brain injuries (ciTBIs) were defined as death from TBI, neurosurgery, intubation for more than 24 hours for the TBI, or hospital admission of 2 nights or more for the head injury, in association with TBI on CT. Results A total of 43,904 children were enrolled into the primary study and 218 (0.5%; 95% confidence interval [CI], 0.4% to 0.6%) were struck by falling televisions. The median (interquartile range) age of the 218 patients was 3.1 (1.9–4.9) years. Seventy-five (34%) of the 218 underwent CT scanning. Ten (13.3%; 95% CI, 6.6% to 23.2%) of the 75 patients with an ED CT had traumatic findings on cranial CT scan. Six patients met the criteria for ciTBI. Three of these patients died. All 6 patients with ciTBIs were younger than 5 years. Conclusions Television tip-overs may cause ciTBIs in children, including death, and the most severe injuries occur in children 5 years or younger. These injuries may be preventable by simple preventive measures such as anchoring television sets with straps.

Researchers have attempted to optimize imaging utilization by describing which clinical variables are more predictive of acute disease and, conversely, what combination of variables can obviate the need for imaging. These results are then used to develop evidence-based clinical pathways, clinical decision instruments, and clinical practice guidelines. Despite the validation of these results in subsequent studies, with some demonstrating improved outcomes, their actual use is often limited. This article outlines a research agenda to promote the dissemination and implementation (also known as knowledge translation) of evidence-based interventions for emergency department (ED) imaging, i.e., clinical pathways, clinical decision instruments, and clinical practice guidelines. We convened a multidisciplinary group of stakeholders and held online and telephone discussions over a 6-month period culminating in an in-person meeting at the 2015 Academic Emergency Medicine consensus conference. We identified the following four overarching research questions: 1) what determinants (barriers and facilitators) influence emergency physicians' use of evidence-based interventions when ordering imaging in the ED; 2) what implementation strategies at the institutional level can improve the use of evidence-based interventions for ED imaging; 3) what interventions at the health care policy level can facilitate the adoption of evidence-based interventions for ED imaging; and 4) how can health information technology, including electronic health records, clinical decision support, and health information exchanges, be used to increase awareness, use, and adherence to evidence-based interventions for ED imaging? Advancing research that addresses these questions will provide valuable information as to how we can use evidence-based interventions to optimize imaging utilization and ultimately improve patient care.

Knowledge Translation and Barriers to Imaging Optimization in the Emergency Department: A Research Agenda.

BACKGROUND Little data exist to guide the management of children with cerebral contusions after minor blunt head trauma. We therefore aimed to determine the risk of acute adverse outcomes in children with minor blunt head trauma who had cerebral contusions and no other traumatic brain injuries on computed tomography (i.e., isolated cerebral contusions). METHODS We conducted a secondary analysis of a public use data set originating from a prospective cohort study performed in 25 PECARN (Pediatric Emergency Care Applied Research Network) emergency departments of children younger than 18 years with blunt head trauma resulting from nontrivial injury mechanisms and with Glasgow Coma Scale (GCS) scores of 14 or 15. In this analysis, we included only children with isolated cerebral contusions. We defined a normal mental status as a GCS score of 15 and no other signs of abnormal mental status. Acute adverse outcomes included intubation longer than 24 hours because of the head trauma, neurosurgery, or death from the head injury. RESULTS Of 14,983 children with GCS scores of 14 or 15 who received cranial computed tomography scans in the parent study, 152 (1.0%; 95% confidence interval, 0.8–1.2%) had cerebral contusions, of which 54 (35.8%) of 151 with available data were isolated. The median age of those with isolated cerebral contusions was 9 years (interquartile range, 1–13); 31 (57.4%) had a normal mental status. Of 36 patients with available data on isolated cerebral contusion size, 34 (94.4%) were described as small. 43 (79.6%) of 54 patients with isolated cerebral contusions were hospitalized, including 16 (29.6%) of 54 to an intensive care unit. No patients with isolated cerebral contusions died, were intubated longer than 24 hours for head trauma, or required neurosurgery (95% confidence interval for all outcomes, 0–6.6%). CONCLUSION Children with small isolated cerebral contusions after minor blunt head trauma are unlikely to require further acute intervention, including neurosurgery, suggesting that neither intensive care unit admission nor prolonged hospitalization is generally required. LEVEL OF EVIDENCE Epidemiologic study, level IV.

Acute outcomes of isolated cerebral contusions in children with Glasgow Coma Scale scores of 14 to 15 after blunt head trauma

Increased use of computed tomography (CT) in children is concerning owing to the cancer risk from ionizing radiation, particularly in children younger than 2 years. A guardian report that a child is acting abnormally is a risk factor for clinically important traumatic brain injury (ciTBI) and may be a driving factor for CT use in the emergency department.

OBJECTIVE
To determine the prevalence of ciTBIs and TBIs in children younger than 2 years with minor blunt head trauma and a guardian report of acting abnormally with (1) no other findings or (2) other concerning findings for TBI.

Secondary analysis of a large, prospective, multicenter cohort study that included 43 399 children younger than 18 years with minor blunt head trauma evaluated in 25 emergency departments. The study was conducted on data obtained between June 2004 and September 2006. Data analysis was performed between August 21, 2014, and March 9, 2015.

EXPOSURES
A guardian report that the child was acting abnormally after minor blunt head trauma.

The prevalence of ciTBI (defined as death, neurosurgery, intubation for >24 hours, or hospitalization for ≥2 nights in association with TBI on CT imaging) and TBI on CT imaging in children with a guardian report of acting abnormally with (1) no other findings and (2) other concerning findings for TBI.

RESULTS
Of 43 399 children in the cohort study, a total of 1297 children had reports of acting abnormally, of whom 411 (31.7%) had this report as their only finding. Reported as percentage (95% CI), 1 of 411 (0.2% [0-1.3%]) had a ciTBI, and 4 TBIs were noted on the CT scans in 185 children who underwent imaging (2.2% [0.6%-5.4%]). In children with reports of acting abnormally and other concerning findings for TBI, 29 of 886 (3.3% [2.2%-4.7%]) had ciTBIs and 66 of 674 (9.8% [7.7%-12.3%]) had TBIs on CT.

Clinically important TBIs are very uncommon, and TBIs noted on CT are uncommon in children younger than 2 years with minor blunt head trauma and guardian reports of the child acting abnormally with no other clinical findings suspicious for TBI. Computed tomographic scans are generally not indicated in these children although observation in the emergency department may be warranted.

Association of a Guardian's Report of a Child Acting Abnormally With Traumatic Brain Injury After Minor Blunt Head Trauma.

OBJECTIVE: To determine the risk of traumatic brain injuries (TBIs) in children with headaches after minor blunt head trauma, particularly when the headaches occur without other findings suggestive of TBIs (ie, isolated headaches). METHODS: This was a secondary analysis of a prospective observational study of children 2 to 18 years with minor blunt head trauma (ie, Glasgow Coma Scale scores of 14–15). Clinicians assessed the history and characteristics of headaches at the time of initial evaluation, and documented findings onto case report forms. Our outcome measures were (1) clinically important TBI (ciTBI) and (2) TBI visible on computed tomography (CT). RESULTS: Of 27 495 eligible patients, 12 675 (46.1%) had headaches. Of the 12 567 patients who had complete data, 2462 (19.6%) had isolated headaches. ciTBIs occurred in 0 of 2462 patients (0%; 95% confidence interval [CI]: 0%–0.1%) in the isolated headache group versus 162 of 10 105 patients (1.6%; 95% CI: 1.4%–1.9%) in the nonisolated headache group (risk difference, 1.6%; 95% CI: 1.3%–1.9%). TBIs on CT occurred in 3 of 456 patients (0.7%; 95% CI: 0.1%–1.9%) in the isolated headache group versus 271 of 6089 patients (4.5%; 95% CI: 3.9%–5.0%) in the nonisolated headache group (risk difference, 3.8%; 95% CI: 2.3%–4.5%). We found no significant independent associations between the risk of ciTBI or TBI on CT with either headache severity or location. CONCLUSIONS: ciTBIs are rare and TBIs on CT are very uncommon in children with minor blunt head trauma when headaches are their only sign or symptom.

152. Exploring Attitudes and Receptivity to Expedited Partner Therapy for Adolescents in an Urban Pediatric Emergency Department: A Mixed-Methods Study

Barriers to and enablers of contraceptive use among adolescent females and their interest in an emergency department based intervention.

Abstract Objective. The objective of this guideline is to recommend evidence-based practices for timely prehospital pediatric seizure cessation while avoiding respiratory depression and seizure recurrence. Methods. A multidisciplinary panel was chosen based on expertise in pediatric emergency medicine, prehospital medicine, and/or evidence-based guideline development. The panel followed the National Prehospital EBG Model using the GRADE methodology to formulate questions, retrieve evidence, appraise the evidence, and formulate recommendations. The panel members initially searched the literature in 2009 and updated their searches in 2012. The panel finalized a draft of a patient care algorithm in 2012 that was presented to stakeholder organizations to gather feedback for necessary revisions. Results. Five strong and ten weak recommendations emerged from the process; all but one was supported by low or very low quality evidence. The panel sought to ensure that the recommendations promoted timely seizure cessation while avoiding respiratory depression and seizure recurrence. The panel recommended that all patients in an active seizure have capillary blood glucose checked and be treated with intravenous (IV) dextrose or intramuscular (IM) glucagon if <60 mg/dL (3 mmol/L). The panel also recommended that non-IV routes (buccal, IM, or intranasal) of benzodiazepines (0.2 mg/kg) be used as first-line therapy for status epilepticus, rather than the rectal route. Conclusions. Using GRADE methodology, we have developed a pediatric seizure guideline that emphasizes the role of capillary blood glucometry and the use of buccal, IM, or intranasal benzodiazepines over IV or rectal routes. Future research is needed to compare the effectiveness and safety of these medication routes.

An Evidence-based Guideline for Pediatric Prehospital Seizure Management Using GRADE Methodology

Abstract Background. The management of acute traumatic pain is a crucial component of prehospital care and yet the assessment and administration of analgesia is highly variable, frequently suboptimal, and often determined by consensus-based regional protocols. Objective. To develop an evidence-based guideline (EBG) for the clinical management of acute traumatic pain in adults and children by advanced life support (ALS) providers in the prehospital setting. Methods. We recruited a multi-stakeholder panel with expertise in acute pain management, guideline development, health informatics, and emergency medical services (EMS) outcomes research. Representatives of the National Highway Traffic Safety Administration (sponsoring agency) and a major children's research center (investigative team) also contributed to the process. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to guide the process of question formulation, evidence retrieval, appraisal/synthesis, and formulation of recommendations. The process also adhered to the National Prehospital Evidence-Based Guideline (EBG) model process approved by the Federal Interagency Council for EMS and the National EMS Advisory Council. Results. Four strong and three weak recommendations emerged from the process; two of the strong recommendations were linked to high- and moderate-quality evidence, respectively. The panel recommended that all patients be considered candidates for analgesia, regardless of transport interval, and that opioid medications should be considered for patients in moderate to severe pain. The panel also recommended that all patients should be reassessed at frequent intervals using a standardized pain scale and that patients should be re-dosed if pain persists. The panel suggested the use of specific age-appropriate pain scales. Conclusion. GRADE methodology was used to develop an evidence-based guideline for prehospital analgesia in trauma. The panel issued four strong recommendations regarding patient assessment and narcotic medication dosing. Future research should define optimal approaches for implementation of the guideline as well as the impact of the protocol on safety and effectiveness metrics.

Emergency department practice variation in computed tomography use for children with minor blunt head trauma.

Objective Controversy exists regarding the disposition of young febrile infants who present to emergency departments (EDs) with urinary tract infections (UTIs). In a large multicenter cohort of such patients, we aimed to determine the variation in patient disposition and clinical factors independently associated with outpatient management. Methods Secondary analysis of a retrospective study of infants 29 to 60 days with fever (≥38.0°C), urinalysis finding, and culture-proven UTIs presenting to 20 North American EDs belonging to the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. We determined independent factors associated with outpatient management. Results Of 1764 infants with UTIs, 132 (7.5%) were discharged home from the ED. The proportion of infants managed as outpatients varied among sites (0%–20.0%). Of the 132 infants, 29 (22.0%) were subsequently hospitalized after culture results were known, including 5 patients with bacteremia. None of the 107 patients initially discharged from the ED for whom outcomes were known had adverse events (0%; 95% CI, 0%–2.7%). On multivariable regression and generalized estimated equations analyses, only clinical site, presence of upper respiratory tract infection symptoms, absence of vomiting, and having fewer than 10 white blood cells per microliter on cerebrospinal fluid examination were independently associated with discharge from the ED. Clinical site was the factor most highly associated with outpatient management (odds ratio, 8.8; 95% confidence interval, 5.2–15.0). Conclusions There is substantial practice variation regarding the disposition of febrile infants 29 to 60 days of age with UTIs. Institutional practice is the strongest predictor of outpatient management. Further evidence is needed to guide the management of non–toxic-appearing young febrile infants with UTIs.

Outpatient Management of Young Febrile Infants With Urinary Tract Infections

Erratum: Identification of children at very low risk of clinically-important brain injuries after head trauma: A prospective cohort study (Lancet (2009) 374 (1160-70))

Abstract Background. The burgeoning literature in prehospital care creates an opportunity to improve care through evidence-based guidelines (EBGs). Previously, an established process for the creation of such guidelines and adoption and implementation at the local level was lacking. This has led to great variability in the content of prehospital protocols in different jurisdictions across the globe. Recently the Federal Interagency Committee on Emergency Medical Services (FICEMS) and the National EMS Advisory Council (NEMSAC) approved a National Prehospital Evidence-based Guideline Model Process for the development, implementation, and evaluation of EBGs. The Model Process recommends the use of established guideline development tools such as Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). Objective. To describe the process of development of three prehospital EBGs using the National Prehospital EBG Model Process (EBG Model Process) and the GRADE EBG development tool. Methods. We conducted three unique iterations of the EBG Model Process utilizing the GRADE EBG development tool. The process involved 6 distinct and essential steps, including 1) assembling the expert panel and providing GRADE training; 2) defining the evidence-based guideline (EBG) content area and establishing the specific clinical questions to address in patient, intervention, comparison, and outcome (PICO) format; 3) prioritizing outcomes to facilitate systematic literature searches; 4) creating GRADE tables, or evidence profiles, for each PICO question; 5) vetting and endorsing GRADE evidence tables and drafting recommendations; and 6) synthesizing recommendations into an EMS protocol and visual algorithm. Feedback and suggestions for improvement were solicited from participants and relevant stakeholders in the process. Results. We successfully used the process to create three separate prehospital evidence-based guidelines, formatted into decision tree algorithms with levels of evidence and graded recommendations assigned to each decision point. However, the process revealed itself to be resource intensive, and most of the suggestions for improvement would require even more resource utilization. Conclusions. The National Prehospital EBG Model Process can be used to create credible, transparent, and usable prehospital evidence-based guidelines. We suggest that a centralized or regionalized approach be used to create and maintain a full set of prehospital EBGs as a means of optimizing resource use.

The Development of Evidence-based Prehospital Guidelines Using a GRADE-based Methodology

BACKGROUND The aim of this study was to evaluate the variability of clinician-performed Focused Assessment with Sonography for Trauma (FAST) examinations and its impact on abdominal computed tomography (AbCT) use in hemodynamically stable children with blunt torso trauma (BTT). The FAST is used with variable frequency in children with BTT. METHODS We performed a planned secondary analysis of children (<18 years) with BTT. Patients with a Glasgow Coma Scale (GCS) score of less than 9, those with hypotension, and those taken directly to the operating suite were excluded. Clinicians documented their suspicion for intra-abdominal injury (IAI) as very low, less than 1%; low, 1% to 5%; moderate, 6% to 10%; high, 11% to 50%; or very high, greater than 50%. We determined the relative risk (RR) for AbCT use based on undergoing a FAST examination in each of these clinical suspicion strata. RESULTS Of 6,468 (median age, 11.8 years; interquartile range, 6.3–15.5 years) children who met eligibility, 887 (13.7%) underwent FAST examination before CT scan. A total of 3,015 (46.6%) underwent AbCT scanning, and 373 (5.8%) were diagnosed with IAI. Use of the FAST increased as clinician suspicion for IAI increased, 11.0% with less than 1% suspicion for IAI, 13.5% with 1% to 5% suspicion, 20.5% with 6% to 10% suspicion, 23.2% with 11% to 50% suspicion, and 30.7% with greater than 50% suspicion. The patients in whom the clinicians had a suspicion of IAI of 1% to 5% or 6% to 10% were significantly less likely to undergo a CT scan if a FAST examination was performed: RR, 0.83 (0.67–1.03); RR, 0.81 (0.72–0.91); RR, 0.85 (0.78–0.94); RR, 0.99 (0.94–1.05); and RR, 0.97 (0.91–1.05) for patients with clinician suspicion of IAI of less than 1%, 1% to 5%, 6% to 10%, 11% to 50%, and greater than 50%, respectively. CONCLUSION The FAST examination is used in a relatively small percentage of children with BTT. Use increases as clinician suspicion for IAI increases. Patients with a low or moderate clinician suspicion of IAI are less likely to undergo AbCT if they receive a FAST examination. A randomized controlled trial is required to more precisely determine the benefits and drawbacks of the FAST examination in the evaluation of children with BTT. LEVEL OF EVIDENCE Prognostic and epidemiologic study, II.

Use of the focused assessment with sonography for trauma (FAST) examination and its impact on abdominal computed tomography use in hemodynamically stable children with blunt torso trauma

Effectiveness of the head CT choice decision aid in parents of children with minor head trauma: study protocol for a multicenter randomized trial

Risk of traumatic brain injuries in children younger than 24 months with isolated scalp hematomas.

Among more than 43,000 children treated in 25 emergency departments for blunt head trauma, traumatic brain injury was identified on CT scan in 7% of the patients. Falls were the most frequent injury mechanism for children under the age of 12 years.

Epidemiology of blunt head trauma in children in U.S. emergency departments.

We present the case of a 3-month-old girl who had unrepaired Tetralogy of Fallot who presented to the emergency department with an acute hypoxic episode. The patient was hyperpneic and cyanotic, with an initial oxygen saturation of 56%. She did not respond to knee-to-chest positioning. A single dose of intranasal fentanyl was administered with subsequent resolution of her symptoms and improvement of her oxygen saturation to 78% within 10 minutes. To our knowledge, this is the first report of the successful treatment of a hypoxic episode of Tetralogy of Fallot using intranasal fentanyl.

Treatment of Tetralogy of Fallot Hypoxic Spell With Intranasal Fentanyl

We compared measles, mumps, rubella (MMR), and influenza vaccination rates of children presenting to a Pediatric Emergency Department (PED) in New York City with rates from national assessments. MMR and influenza vaccination rates in this PED population were generally comparable to community rates, but lower than Healthy People 2020 targets.

Vaccination Rates for Measles, Mumps, Rubella, and Influenza Among Children Presenting to a Pediatric Emergency Department in New York City.

Adolescent females’ preferences for a pregnancy prevention intervention using text messaging

Abstract Objective. To describe pediatric patients transported by the Pediatric Emergency Care Applied Research Network's (PECARN's) affiliated emergency medical service (EMS) agencies and the process of submitting and aggregating data from diverse agencies. Methods. We conducted a retrospective analysis of electronic patient care data from PECARN's partner EMS agencies. Data were collected on all EMS runs for patients less than 19 years old treated between 2004 and 2006. We conducted analyses only for variables with usable data submitted by a majority of participating agencies. The investigators aggregated data between study sites by recoding it into categories and then summarized it using descriptive statistics. Results. Sixteen EMS agencies agreed to participate. Fourteen agencies (88%) across 11 states were able to submit patient data. Two of these agencies were helicopter agencies (HEMS). Mean time to data submission was 378 days (SD 175). For the 12 ground EMS agencies that submitted data, there were 514,880 transports, with a mean patient age of 9.6 years (SD 6.4); 53% were male, and 48% were treated by advanced life support (ALS) providers. Twenty-two variables were aggregated and analyzed, but not all agencies were able to submit all analyzed variables and for most variables there were missing data. Based on the available data, median response time was 6 minutes (IQR: 4–9), scene time 15 minutes (IQR: 11–21), and transport time 9 minutes (IQR: 6–13). The most common chief complaints were traumatic injury (28%), general illness (10%), and respiratory distress (9%). Vascular access was obtained for 14% of patients, 3% received asthma medication, <1% pain medication, <1% assisted ventilation, <1% seizure medication, <1% an advanced airway, and <1% CPR. Respiratory rate, pulse, systolic blood pressure, and GCS were categorized by age and the majority of children were in the normal range except for systolic blood pressure in those under one year old. Conclusions. Despite advances in data definitions and increased use of electronic databases nationally, data aggregation across EMS agencies was challenging, in part due to variable data collection methods and missing data. In our sample, only a small proportion of pediatric EMS patients required prehospital medications or interventions.

Characteristics of the Pediatric Patients Treated by the Pediatric Emergency Care Applied Research Network's Affiliated EMS Agencies

Effect of Hispanic ethnicity and language barriers on appendiceal perforation rates and imaging in children.

Association of traumatic brain injuries with vomiting in children with blunt head trauma.

A history of loss of consciousness (LOC) is frequently a driving factor for computed tomography use in the emergency department evaluation of children with blunt head trauma. Computed tomography carries a nonnegligible risk for lethal radiation-induced malignancy. The Pediatric Emergency Care Applied Research Network (PECARN) derived 2 age-specific prediction rules with 6 variables for clinically important traumatic brain injury (ciTBI), which included LOC as one of the risk factors.

OBJECTIVE
To determine the risk for ciTBIs in children with isolated LOC.

This was a planned secondary analysis of a large prospective multicenter cohort study. The study included 42 ,412 children aged 0 to 18 years with blunt head trauma and Glasgow Coma Scale scores of 14 and 15 evaluated in 25 emergency departments from 2004-2006.

EXPOSURE
A history of LOC after minor blunt head trauma.

The main outcome measures were ciTBIs (resulting in death, neurosurgery, intubation for >24 hours, or hospitalization for ≥2 nights) and a comparison of the rates of ciTBIs in children with no LOC, any LOC, and isolated LOC (ie, with no other PECARN ciTBI predictors).

RESULTS
A total of 42 412 children were enrolled in the parent study, with 40 693 remaining in the current analysis after exclusions. Of these, LOC occurred in 15.4% (6286 children). The prevalence of ciTBI with any history of LOC was 2.5% and for no history of LOC was 0.5% (difference, 2.0%; 95% CI, 1.7-2.5). The ciTBI rate in children with isolated LOC, with no other PECARN predictors, was 0.5% (95% CI, 0.2-0.8; 13 of 2780). When comparing children who have isolated LOC with those who have LOC and other PECARN predictors, the risk ratio for ciTBI in children younger than 2 years was 0.13 (95% CI, 0.005-0.72) and for children 2 years or older was 0.10 (95% CI, 0.06-0.19).

Children with minor blunt head trauma presenting to the emergency department with isolated LOC are at very low risk for ciTBI and do not routinely require computed tomographic evaluation.

Isolated loss of consciousness in children with minor blunt head trauma.

Medical Student Documentation in the Emergency Department in the Era of Electronic Health Records - a National Survey of Emergency Department Directors and Medical Student Representatives

Objective Children evaluated in emergency departments for blunt head trauma (BHT) frequently undergo computed tomography (CT), with some requiring pharmacological sedation. Cranial CT sedation complications are understudied. The objective of this study was to document the frequency, type, and complications of pharmacological sedation for cranial CT in children. Methods We prospectively enrolled children (younger than 18 years) with minor BHT presenting to 25 emergency departments from 2004 to 2006. Data collected included sedation agent and complications. We excluded patients with Glasgow Coma Scale scores of less than 14. Results Of 57,030 eligible patients, 43,904 (77%) were enrolled in the parent study; 15,176 (35%) had CT scans performed or planned, and 527 (3%) received pharmacological sedation for CT. Sedated patients’ characteristics were as follows: median age, 1.7 years (interquartile range, 1.1–2.5 years); male 61%; Glasgow Coma Scale score of 15, 86%; traumatic brain injury on CT, 8%. There were 488 patients (93%) who received 1 sedative. Sedation use (0%–21%) and regimen varied by site. Pentobarbital (n = 164) and chloral hydrate (n = 149) were the most frequently used agents. Sedation complications occurred in 49 patients (9%; 95% confidence interval [CI], 7%–12%): laryngospasm 1 (0.2%; 95% CI, 0%–1.1%), failed sedation 31 (6%; 95% CI, 4%–8%), vomiting 6 (1%; 95% CI, 0.4%–2%), hypotension 13 (4%; 95% CI, 2%–7%), and hypoxia 1 (0.2%; 95% CI, 0%–2%). No cases of apnea, aspiration, or reversal agent use occurred. One patient required intubation. Vomiting and failed sedation were most common with chloral hydrate. Conclusions Pharmacological sedation is infrequently used for children with minor BHT undergoing CT, and complications are uncommon. The variability in sedation medications and frequency suggests a need for evidence-based guidelines.

Pharmacological Sedation for Cranial Computed Tomography in Children After Minor Blunt Head Trauma

BACKGROUND AND OBJECTIVES: The Faces Pain Scale–Revised (FPS-R) and Color Analog Scale (CAS) are self-report pain scales commonly used in children but insufficiently validated in the emergency department setting. Our objectives were to determine the psychometric properties (convergent validity, discriminative validity, responsivity, and reliability) of the FPS-R and CAS, and to determine whether degree of validity varied based on age, sex, and ethnicity. METHODS: We conducted a prospective, observational study of English- and Spanish-speaking children ages 4 to 17 years. Children with painful conditions indicated their pain severity on the FPS-R and CAS before and 30 minutes after analgesia. We assessed convergent validity (Pearson correlations, Bland-Altman method), discriminative validity (comparing pain scores in children with pain against those without pain), responsivity (comparing pain scores pre- and postanalgesia), and reliability (Pearson correlations, repeatability coefficient). RESULTS: Of 620 patients analyzed, mean age was 9.2 ± 3.8 years, 291(46.8%) children were girls, 341(55%) were Hispanic, and 313(50.5%) were in the younger age group (<8 years). Pearson correlation was 0.85, with higher correlation in older children and girls. Lower convergent validity was noted in children <7 years of age. All subgroups based on age, sex, and ethnicity demonstrated discriminative validity and responsivity for both scales. Reliability was acceptable for both the FPS-R and CAS. CONCLUSIONS: The FPS-R and CAS overall demonstrate strong psychometric properties in children ages 4 to 17 years, and between subgroups based on age, sex, and ethnicity. Convergent validity was questionable in children <7 years old.

Computed tomography (CT) with enteric contrast is frequently used to evaluate children with suspected appendicitis. The use of CT with intravenous (IV) contrast alone (CT IV) may be sufficient, however, particularly in patients with adequate intra-abdominal fat (IAF).

The authors aimed 1) to determine the ability of radiologists to visualize the normal (nondiseased) appendix with CT IV in children and to assess whether IAF adequacy affects this ability and 2) to assess the association between IAF adequacy and patient characteristics.

METHODS
This was a retrospective 16-center study using a preexisting database of abdominal CT scans. Children 3 to 18 years who had CT IV scan and measured weights and for whom appendectomy history was known from medical record review were included. The sample was chosen based on age to yield a sample with and without adequate IAF. Radiologists at each center reread their site's CT IV scans to assess appendix visualization and IAF adequacy. IAF was categorized as "adequate" if there was any amount of fat completely surrounding the cecum and "inadequate" if otherwise.

RESULTS
A total of 280 patients were included, with mean age of 10.6 years (range = 3.1 to 17.9 years). All 280 had no history of prior appendectomy; therefore, each patient had a presumed normal appendix. A total of 102 patients (36.4%) had adequate IAF. The proportion of normal appendices visualized with CT IV was 72.9% (95% confidence interval [CI] = 67.2% to 78.0%); the proportions were 89% (95% CI = 81.5% to 94.5%) and 63% (95% CI = 56.0% to 70.6%) in those with and without adequate IAF (95% CI for difference of proportions = 16% to 36%). Greater weight and older age were strongly associated with IAF adequacy (p < 0.001), with weight appearing to be a stronger predictor, particularly in females. Although statistically associated, there was noted overlap in the weights and ages of those with and without adequate IAF.

Protocols using CT with IV contrast alone to visualize the appendix can reasonably include weight, age, or both as considerations for determining when this approach is appropriate. However, although IAF will more frequently be adequate in older, heavier patients, highly accurate prediction of IAF adequacy appears challenging solely based on age and weight.

Computed tomography with intravenous contrast alone: the role of intra-abdominal fat on the ability to visualize the normal appendix in children.

The objective was to investigate clinician knowledge of and attitudes toward clinical decision support (CDS) and its incorporation into the electronic health record (EHR).

METHODS
This was an electronic survey of emergency physicians (EPs) within an integrated health care delivery system that uses a complete EHR. Randomly assigned respondents completed one of two questionnaires, both including a hypothetical vignette and self-reported knowledge of and attitudes about CDS. One vignette version included CDS, and the other did not (NCDS). The vignette described a scenario in which a cranial computed tomography (CCT) is not recommended by validated prediction rules (the Pediatric Emergency Care Applied Research Network [PECARN] rules). In both survey versions, subjects responded first with their likely approach to evaluation and then again after receiving either CDS (the PECARN prediction rules) or no additional support. Descriptive statistics were used for self-reported responses and multivariate logistic regression was used to identify predictors of self-reported knowledge and use of the PECARN rules, as well as use of vignette responses.

RESULTS
There were 339 respondents (68% response rate), with 172 of 339 (51%) randomized to the CDS version. Initially, 25% of respondents to each version indicated they would order CCTs. After CDS, 30 of 43 (70%) of respondents who initially would order CCTs changed their management decisions to no CCT versus two of 41 (5%) with the NCDS version (chi-square, p = 0.003). In response to self-report questions, 81 of 338 respondents (24%) reported having never heard of the PECARN prediction rules, 122 of 338 (36%) were aware of the rules but not their specifics, and 135 of 338 (40%) reported knowing the rules and their specifics. Respondents agreed with favorable statements about CDS (75% to 96% agreement across seven statements) and approaches to its implementation into the EHR (60% to 93% agreement across seven statements). In multivariable analyses, EPs with tenure of 5 to 14 years (odds ratio [AOR] = 0.51, 95% confidence interval [CI] = 0.30 to 0.86) and for 15 years or more (AOR = 0.37, 95% CI = 0.20 to 0.70) were significantly less likely to report knowing the specifics of the PECARN prediction rules compared with EPs who practiced for fewer than 5 years. In addition, in the initial vignette responses (across both versions), physicians with ≥15 years of ED tenure compared to those with fewer than 5 years of experience (AOR = 0.30, 95% CI = 0.13 to 0.69), and those reporting knowing the specifics of the PECARN prediction rules were less likely to order CCTs (AOR = 0.53, 95% CI = 0.30 to 0.92).

EPs incorporated pediatric head trauma CDS via the EHR into their clinical judgment in a hypothetical scenario and reported favorable opinions of CDS in general and their inclusion into the EHR.

Emergency physicians' knowledge and attitudes of clinical decision support in the electronic health record: a survey-based study.

The prevalence of traumatic brain injuries after minor blunt head trauma in children with ventricular shunts.

Variation in resource utilization across a national sample of pediatric emergency departments.

With Bacterial Meningitis Effect of Antibiotic Pretreatment on Cerebrospinal Fluid Profiles of Children

OBJECTIVE: Cranial computed tomography (CT) scans are frequently obtained in the evaluation of blunt head trauma in children. These scans may detect unexpected incidental findings. The objectives of this study were to determine the prevalence and significance of incidental findings on cranial CT scans in children evaluated for blunt head trauma. METHODS: This was a secondary analysis of a multicenter study of pediatric blunt head trauma. Patients <18 years of age with blunt head trauma were eligible, with those undergoing cranial CT scan included in this substudy. Patients with coagulopathies, ventricular shunts, known previous brain surgery or abnormalities were excluded. We abstracted radiology reports for nontraumatic findings. We reviewed and categorized findings by their clinical urgency. RESULTS: Of the 43 904 head-injured children enrolled in the parent study, 15 831 underwent CT scans, and these latter patients serve as the study cohort. On 670 of these scans, nontraumatic findings were identified, with 16 excluded due to previously known abnormalities or surgeries. The remaining 654 represent a 4% prevalence of incidental findings. Of these, 195 (30%), representing 1% of the overall sample, warranted immediate intervention or outpatient follow-up. CONCLUSIONS: A small but important number of children evaluated with CT scans after blunt head trauma had incidental findings. Physicians who order cranial CTs must be prepared to interpret incidental findings, communicate with families, and ensure appropriate follow-up. There are ethical implications and potential health impacts of informing patients about incidental findings.

Incidental Findings in Children With Blunt Head Trauma Evaluated With Cranial CT Scans

Identifying children at very low risk of clinically important blunt abdominal injuries.

Referring sexually active female adolescents from the Emergency Department to family planning clinic: Is a wallet card effective?

Cranial CT Scans Incidental Findings in Children With Blunt Head Trauma Evaluated With

Informing the design of clinical decision support services for evaluation of children with minor blunt head trauma in the emergency department: A sociotechnical analysis

The objectives were to assess the test characteristics of ultrasound (US) in diagnosing appendicitis in children and to evaluate site-related variations based on the frequency of its use. Additionally, the authors assessed the test characteristics of US when the appendix was clearly visualized.

METHODS
This was a secondary analysis of a prospective, 10-center observational study. Children aged 3 to 18 years with acute abdominal pain concerning for appendicitis were enrolled. US was performed at the discretion of the treating physician.

RESULTS
Of 2,625 patients enrolled, 965 (36.8%) underwent abdominal US. US had an overall sensitivity of 72.5% (95% confidence interval [CI] = 58.8% to 86.3%) and specificity 97.0% (95% CI = 96.2% to 97.9%) in diagnosing appendicitis. US sensitivity was 77.7% at the three sites (combined) that used it in 90% of cases, 51.6% at a site that used it in 50% of cases, and 35% at the four remaining sites (combined) that used it in 9% of cases. US retained a high specificity of 96% to 99% at all sites. Of the 469 (48.6%) cases across sites where the appendix was clearly visualized on US, its sensitivity was 97.9% (95% CI = 95.2% to 99.9%), with a specificity of 91.7% (95% CI = 86.7% to 96.7%).

Ultrasound sensitivity and the rate of visualization of the appendix on US varied across sites and appeared to improve with more frequent use. US had universally high sensitivity and specificity when the appendix was clearly identified. Other diagnostic modalities should be considered when the appendix is not definitively visualized by US.

Performance of ultrasound in the diagnosis of appendicitis in children in a multicenter cohort.

OBJECTIVE: The Pediatric Emergency Care Applied Research Network (PECARN) traumatic brain injury (TBI) clinical prediction rules identify children with minor blunt head trauma who are at low risk for clinically important traumatic brain injuries. We measured the agreement between the registered nurse (RN) and physician (MD) assessments. METHODS: We performed a cross-sectional study of all children <18 years of age with minor blunt head trauma who presented to a single emergency department. RNs and MDs independently assessed each child and recorded age-based PECARN predictors. As symptoms can change over time, we included cases only when both evaluations were completed within 60 minutes. We used the κ statistic to measure RN-MD agreement, with the main analysis focusing on the overall PECARN rule agreement. RESULTS: Of the 1624 eligible children, 1191 (73%) had evaluations completed by both RN and ED providers, of which 437 (37%) were in children <2 years of age. The median time between completions of the provider forms was 12 minutes (interquartile range 4–25 minutes). The overall agreement between the RN and MD was higher for the older children (κ 0.55, 95% confidence interval 0.49–0.61 for children 2–18 years versus κ 0.32, 95% confidence interval 0.23–0.41 for children <2 years). CONCLUSIONS: The overall agreement between RN and MD for the PECARN TBI prediction rules was moderate for older children and fair for younger children. Initial RN assessments should be verified by the MD before clinical application, especially for the youngest children.

Nurse and Physician Agreement in the Assessment of Minor Blunt Head Trauma

Objectives To prospectively determine the test characteristics of the 3-view abdominal radiograph to decrease the likelihood of ileocolic intussusception. Methods We conducted a prospective cross-sectional study of children aged 3 months to 3 years suspected of having intussusception at a children’s hospital emergency department. Clinicians obtained supine, prone, and left lateral decubitus radiographs. We determined the presence or absence of intussusception by air enema, ultrasound, operative report, or clinical follow-up. A masked pediatric radiologist reviewed all radiographs. The criteria evaluated were whether air was visualized in the ascending colon on each view and in the transverse colon on the supine view. Results Nineteen (14.8%) of 128 patients had intussusception. Using air in the ascending colon on all 3 views as the diagnostic criteria, the test characteristics of the 3-view radiograph were sensitivity, 100% (95% confidence interval [CI], 79.1–100); specificity, 17.4% (95% CI, 11.1–26.1); negative predictive value, 100% (95% CI, 79.1–100); and likelihood ratio of a negative test, 0. When 2 or more of 3 views had air in the ascending colon, sensitivity decreased to 89.5% (95% CI, 75.7–100) and specificity improved to 45.0% (95% CI, 35.6–54.3). Air in the transverse colon had moderate sensitivity, 84.2% (95% CI, 67.8–100), but further improved specificity, 63.3% (95% CI, 54.2–72.4). Conclusions The presence of air in the ascending colon on the 3-view abdominal radiograph can decrease the likelihood of or exclude intussusception. When clinical suspicion is low, the presence of specific criterion on a 3-view abdominal radiograph series may obviate the need for further studies.

Accuracy of Plain Radiographs to Exclude the Diagnosis of Intussusception

Identifying adolescent females at high risk of pregnancy in a pediatric emergency department.

An Activity Theory Based Analysis of Work Activities in the Emergency Department

OBJECTIVE
To validate and refine a clinical prediction rule to identify which children with acute abdominal pain are at low risk for appendicitis (Low-Risk Appendicitis Rule).

DESIGN
Prospective, multicenter, cross-sectional study.

SETTING
Ten pediatric emergency departments.

Children and adolescents aged 3 to 18 years who presented with suspected appendicitis from March 1, 2009, through April 30, 2010.

The test performance of the Low-Risk Appendicitis Rule.

RESULTS
Among 2625 patients enrolled, 1018 (38.8% [95% CI, 36.9%-40.7%]) had appendicitis. Validation of the rule resulted in a sensitivity of 95.5% (95% CI, 93.9%-96.7%), specificity of 36.3% (33.9%-38.9%), and negative predictive value of 92.7% (90.1%-94.6%). Theoretical application would have identified 573 (24.0%) as being at low risk, misclassifying 42 patients (4.5% [95% CI, 3.4%-6.1%]) with appendicitis. We refined the prediction rule, resulting in a model that identified patients at low risk with (1) an absolute neutrophil count of 6.75 × 103/μL or less and no maximal tenderness in the right lower quadrant or (2) an absolute neutrophil count of 6.75 × 103/μL or less with maximal tenderness in the right lower quadrant but no abdominal pain with walking/jumping or coughing. This refined rule had a sensitivity of 98.1% (95% CI, 97.0%-98.9%), specificity of 23.7% (21.7%-25.9%), and negative predictive value of 95.3% (92.3%-97.0%).

We have validated and refined a simple clinical prediction rule for pediatric appendicitis. For patients identified as being at low risk, clinicians should consider alternative strategies, such as observation or ultrasonographic examination, rather than proceeding to immediate computed tomographic imaging.

Validation and refinement of a prediction rule to identify children at low risk for acute appendicitis.

OBJECTIVE
To determine the prevalence of clinically important traumatic brain injuries (TBIs) with severe injury mechanisms in children with minor blunt head trauma but with no other risk factors from the Pediatric Emergency Care Applied Research Network (PECARN) TBI prediction rules (defined as isolated severe injury mechanisms).

DESIGN
Secondary analysis of a large prospective observational cohort study.

SETTING
Twenty-five emergency departments participating in the PECARN.

PATIENTS
Children with minor blunt head trauma and Glasgow Coma Scale scores of at least 14.

Treating clinicians completed a structured data form that included injury mechanism (severity categories defined a priori).

Clinically important TBIs were defined as intracranial injuries resulting in death, neurosurgical intervention, intubation for more than 24 hours, or hospital admission for at least 2 nights. We investigated the rate of clinically important TBIs in children with either severe injury mechanisms or isolated severe injury mechanisms.

RESULTS
Of the 42,412 patients enrolled in the overall study, 42,099 (99%) had injury mechanisms recorded, and their data were included for analysis. Of all study patients, 5869 (14%) had severe injury mechanisms, and 3302 (8%) had isolated severe injury mechanisms. Overall, 367 children had clinically important TBIs (0.9%; 95% CI, 0.8%-1.0%). Of the 1327 children younger than 2 years with isolated severe injury mechanisms, 4 (0.3%; 95% CI, 0.1%-0.8%) had clinically important TBIs, as did 12 of the 1975 children 2 years or older (0.6%; 95% CI, 0.3%-1.1%).

Children with isolated severe injury mechanisms are at low risk of clinically important TBI, and many do not require emergent neuroimaging.

Prevalence of clinically important traumatic brain injuries in children with minor blunt head trauma and isolated severe injury mechanisms.

Abstract We describe a 4-year-old boy who presents to the emergency department with lethargy, bradycardia, and initial hypertension followed by hypotension due to guanfacine toxicity after ingestion of standard doses of the extended release formulation. This is the first case report to describe the use of naloxone to treat these symptoms and document improvements in level of consciousness, blood pressure, and heart rate associated with this therapy.

Cranial Computed Tomography Use Among Children With Minor Blunt Head Trauma

OBJECTIVE: Our objective was to determine the interrater reliability of clinical history and physical examination findings in children undergoing evaluation for possible appendicitis in a large, multicenter cohort. METHODS: We conducted a prospective, multicenter, cross-sectional study of children aged 3–18 years with possible appendicitis. Two clinicians independently evaluated patients and completed structured case report forms within 60 minutes of each other and without knowing the results of diagnostic imaging. We calculated raw agreement and assessed reliability by using the unweighted Cohen κ statistic with 2-sided 95% confidence intervals. RESULTS: A total of 811 patients had 2 assessments completed, and 599 (74%) had 2 assessments completed within 60 minutes. Seventy-five percent of paired assessments were completed by pediatric emergency physicians. Raw agreement ranged from 64.9% to 92.3% for history variables and 4 of 6 variables had moderate interrater reliability (κ > .4). The highest κ values were noted for duration of pain (κ = .56 [95% confidence intervals .51–.61]) and history of emesis (.84 [.80–.89]). For physical examination variables, raw agreement ranged from 60.9% to 98.7%, with 4 of 8 variables exhibiting moderate reliability. Among physical examination variables, the highest κ values were noted for abdominal pain with walking, jumping, or coughing (.54 [.45–.63]) and presence of any abdominal tenderness on examination (.49 [.19–.80]). CONCLUSIONS: Interrater reliability of patient history and physical examination variables was generally fair to moderate. Those variables with higher interrater reliability are more appropriate for inclusion in clinical prediction rules in children with possible appendicitis.

Interrater Reliability of Clinical Findings in Children With Possible Appendicitis

The effect of abdominal pain duration on the accuracy of diagnostic imaging for pediatric appendicitis.

The objective was to describe the association between two novel biomarkers, calprotectin and leucine-rich alpha glycoprotein-1 (LRG), and appendicitis in children.

METHODS
This was a prospective, cross-sectional study of children 3 to 18 years old presenting to a pediatric emergency department (ED) with possible appendicitis. Blood and urine samples were assayed for calprotectin and LRG via enzyme-linked immunosorbent assay (ELISA). Final diagnosis was determined by histopathology or telephone follow-up. Biomarker levels were compared for subjects with and without appendicitis. Recursive partitioning was used to identify thresholds that predicted appendicitis.

RESULTS
Of 176 subjects, mean (±SD) age was 11.6 (±4.0) years and 52% were male. Fifty-eight patients (34%) were diagnosed with appendicitis. Median plasma calprotectin, serum LRG, and urine LRG levels were higher in appendicitis versus nonappendicitis (p < 0.008). When stratified by perforation status, median plasma calprotectin and serum LRG levels were higher in nonperforated appendicitis versus nonappendicitis (p < 0.01). Median serum LRG, urine LRG, and plasma calprotectin levels were higher in perforated appendicitis compared to nonperforated appendicitis (p < 0.05). Urine calprotectin did not differ among groups. A serum LRG < 40,150 ng/mL, a urine LRG < 42 ng/mL, and a plasma calprotectin < 159 ng/mL, each provided a sensitivity and negative predictive value of 100% to identify children at low risk for appendicitis, but with specificities ranging from 23% to 35%. The standard white blood cell (WBC) count achieved 100% sensitivity at a higher specificity than both novel biomarkers.

Plasma calprotectin and serum/urine LRG are elevated in pediatric appendicitis. No individual marker performed as well as the WBC count.

OBJECTIVE
To determine if patient race/ethnicity is independently associated with cranial computed tomography (CT) use among children with minor blunt head trauma.

DESIGN
Secondary analysis of a prospective cohort study.

SETTING
Pediatric research network of 25 North American emergency departments.

PATIENTS
In total, 42 412 children younger than 18 years were seen within 24 hours of minor blunt head trauma. Of these, 39 717 were of documented white non-Hispanic, black non-Hispanic, or Hispanic race/ethnicity. Using a previously validated clinical prediction rule, we classified each child's risk for clinically important traumatic brain injury to describe injury severity. Because no meaningful differences in cranial CT rates were observed between children of black non-Hispanic race/ethnicity vs Hispanic race/ethnicity, we combined these 2 groups.

Cranial CT use in the emergency department, stratified by race/ethnicity.

RESULTS
In total, 13 793 children (34.7%) underwent cranial CT. The odds of undergoing cranial CT among children with minor blunt head trauma who were at higher risk for clinically important traumatic brain injury did not differ by race/ethnicity. In adjusted analyses, children of black non-Hispanic or Hispanic race/ethnicity had lower odds of undergoing cranial CT among those who were at intermediate risk (odds ratio, 0.86; 95% CI, 0.78-0.96) or lowest risk (odds ratio, 0.72; 95% CI, 0.65-0.80) for clinically important traumatic brain injury. Regardless of risk for clinically important traumatic brain injury, parental anxiety and request was commonly cited by physicians as an important influence for ordering cranial CT in children of white non-Hispanic race/ethnicity.

Disparities may arise from the overuse of cranial CT among patients of nonminority races/ethnicities. Further studies should focus on explaining how medically irrelevant factors, such as patient race/ethnicity, can affect physician decision making, resulting in exposure of children to unnecessary health care risks.

Cranial computed tomography use among children with minor blunt head trauma: association with race/ethnicity.

OBJECTIVE: Children with minor blunt head trauma often are observed in the emergency department before a decision ismade regarding computed tomography use. We studied the impact of this clinical strategy on computed tomography use and outcomes. METHODS: We performed a subanalysis of a prospective multicenter observational study of children with minor blunt head trauma. Clinicians completed case report forms indicating whether the child was observed before making a decision regarding computed tomography. We defined clinically important traumatic brain injury as an intracranial injury resulting in death, neurosurgical intervention, intubation for longer than 24 hours, or hospital admission for 2 nights or longer. To compare computed tomography rates between children observed and those not observed before a decision was made regarding computed tomography use, we used a generalized estimating equation model to control for hospital clustering and patient characteristics. RESULTS: Of 42 412 children enrolled in the study, clinicians noted if the patient was observed before making a decision on computed tomography in 40 113 (95%). Of these, 5433 (14%) children were observed. The computed tomography use rate was lower in those observed than in those not observed (31.1% vs 35.0%; difference: 3.9% [95% confidence interval: 5.3 to 2.6]), but the rate of clinically important traumatic brain injury was similar (0.75% vs 0.87%; difference: 0.1% [95% confidence interval: 0.4 to 0.1]). After adjustment for hospital and patient characteristics, the difference in the computed tomography use rate remained significant (adjusted odds ratio for obtaining a computed tomography in the observed group: 0.53 [95% confidence interval: 0.43–0.66]). CONCLUSIONS: Clinical observation was associated with reduced computed tomography use among childrenwithminor blunt head trauma and may be an effective strategy to reduce computed tomography use. Pediatrics 2011;127:1067–1073 AUTHORS: Lise E. Nigrovic, MD, MPH,a Jeff E. Schunk, MD,b,c Adele Foerster, MSN,d Arthur Cooper, MD,e Michelle Miskin, MS,c Shireen M. Atabaki, MD, MPH,f John Hoyle, MD,g Peter S. Dayan, MD, MSc,h James F. Holmes, MD, MPH,i Nathan Kuppermann, MD, MPH,j and the Traumatic Brain Injury Group for the Pediatric Emergency Care Applied Research Network aDivision of Emergency Medicine, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts; bDepartment of Pediatrics, Primary Children’s Medical Center, Salt Lake City, Utah; cUniversity of Utah School of Medicine, Salt Lake, Utah; dSilver Spring Emergency Physicians, Holy Cross Hospital, Silver Spring, Maryland; eDepartment of Surgery, Harlem Hospital Medical Center and hDepartment of Pediatrics, Morgan Stanley Children’s Hospital of New York–Presbyterian, Columbia University College of Physicians and Surgeons, New York, New York; Departments of fPediatrics and Emergency Medicine, Children’s National Medical Center, George Washington University School of Medicine, Washington, DC; gDivision of Emergency Medicine, Helen DeVos Children’s Hospital, Michigan State University School of Medicine, Grand Rapids, Michigan; and iDepartment of Emergency Medicine and Departments of jEmergency Medicine and Pediatrics, Davis Medical Center, University of California, Davis School of Medicine, Davis, California

Network Kuppermann and the Traumatic Brain Injury Group for the Pediatric Emergency Care

Intracranial hemorrhage after blunt head trauma in children with bleeding disorders.

OBJECTIVES: Variables used in prediction rules and clinical guidelines should show acceptable agreement when assessed by different observers. Our objective was to determine the interobserver agreement of patient history and physical examination variables used to assess children undergoing emergency department (ED) evaluation for a first seizure not provoked by a known precipitant such as fever or trauma (ie, an unprovoked seizure). METHODS: We conducted a prospective cohort study of children aged 28 days to 18 years evaluated for unprovoked seizures at 6 tertiary care EDs. We excluded patients if previously evaluated for a similar event. Two clinicians independently completed a clinical assessment before neuroimaging. We determined agreement for each clinical variable by using the unweighted statistic. RESULTS: A total of 217 paired observations were analyzed; median patient age was 53.5months, and 38%were younger than 2 years. Agreement beyond chance was at least moderate ( 0.41) for 21 of 31 (68%) variables for which could be calculated. was 0.41 for 7 of 11 (64%) general history variables, all 8 seizure-specific history variables (including seizure focality), and 6 of 12 (50%) physical examination variables. Agreement beyond chance was substantial or better ( 0.61) for 2 of 11 (18%) general history variables, for 5 of 8 (63%) seizure-specific history variables, and for 2 of 12 (17%) physical examination variables. CONCLUSIONS: For children with first unprovoked seizures evaluated in the ED, clinicians frequently assess findings from seizure-specific history with substantial agreement beyond chance. Those clinical variables that have been associated with the presence of intracranial abnormalities and show reliability between assessors, such as seizure focality and the presence of any focal neurological finding, may be more useful in the ED assessment of children with first unprovoked seizures. Pediatrics 2011;127: e1266–e1271 AUTHORS: Peter S. Dayan, MD, MSc,a Kathleen Lillis, MD,b Jonathan Bennett, MD,c Gregory Conners, MD, MPH, MBA,d Pam Bailey, MD,e James Callahan, MD,f Cidgem Akman, MD,a Neil Feldstein, MD,a W. Allen Hauser, MD,a,g Nathan Kuppermann, MD, MPH,h and the Pediatric Emergency Department Northeast Team of the Pediatric Emergency Care Applied Research Network (PECARN) aDepartment of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York; bDepartment of Pediatrics, State University of New York at Buffalo, Buffalo, New York; cDepartment of Pediatrics, Alfred I. duPont Hospital for Children, Wilmington, Delaware; dDepartment of Emergency Medicine, University of Rochester, Rochester, New York; eDepartment of Pediatrics, Baylor College of Medicine, Houston, Texas; fDepartments of Emergency Medicine and Pediatrics, Upstate Medical College, Syracuse, New York; gGertrude Sergievsky Center, New York, New York; and hDepartments of Emergency Medicine and Pediatrics, University of California, Davis Medical Center, Davis, California

With First Unprovoked Seizures Interobserver Agreement in the Assessment of Clinical Findings in Children

To determine the prevalence of and to identify risk factors for sterile cerebrospinal fluid (CSF) pleocytosis in a large sample of febrile young infants with urinary tract infections (UTIs) and to describe the clinical courses of those patients.

DESIGN
Secondary analysis of a multicenter retrospective review.

SETTING
Emergency departments of 20 North American hospitals. Patients Infants aged 29 to 60 days with temperatures of 38.0°C or higher and culture-proven UTIs who underwent a nontraumatic lumbar puncture from January 1, 1995, through May 31, 2006.

MAIN EXPOSURE
Febrile UTI.

Presence of sterile CSF pleocytosis defined as CSF white blood cell count of 10/μL or higher in the absence of bacterial meningitis and clinical course and treatment (ie, presence of adverse events, time to defervescence, duration of parenteral antibiotic treatment, and length of hospitalization).

RESULTS
A total of 214 of 1190 infants had sterile CSF pleocytosis (18.0%; 95% confidence interval, 15.9%-20.3%). Only the peripheral white blood cell count was independently associated with sterile CSF pleocytosis, and patients with a peripheral white blood cell count of 15/μL or higher had twice the odds of having sterile CSF pleocytosis (odds ratio, 1.97; 95% confidence interval, 1.32-2.94; P = .001). In the subset of patients at very low risk for adverse events (ie, not clinically ill in the emergency department and without a high-risk medical history), patients with and without sterile CSF pleocytosis had similar clinical courses; however, patients with CSF pleocytosis had longer parenteral antibiotics courses (median length, 4 days [interquartile range, 3-6 days] vs 3 days [interquartile range, 3-5 days]) (P = .04).

Sterile CSF pleocytosis occurs in 18% of young infants with UTIs. Patients with CSF pleocytosis at very low risk for adverse events may not require longer treatment with antibiotics.

Sterile cerebrospinal fluid pleocytosis in young febrile infants with urinary tract infections.

Associates of stigma in an incident epilepsy population from northern Manhattan, New York City

Do children with blunt head trauma and normal cranial computed tomography scan results require hospitalization for neurologic observation?

The objective was to assess the accuracy of novel and traditional biomarkers in patients with suspected appendicitis as a function of duration of symptoms.

METHODS
This was a prospective cohort study, conducted in a tertiary care emergency department (ED). The authors enrolled children 3 to 18 years old with acute abdominal pain of less than 96 hours and measured serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP), white blood cell (WBC) count, and absolute neutrophil count (ANC). Final diagnosis was determined by histopathology or telephone follow-up. Trends in biomarker levels were examined based on duration of abdominal pain. The accuracy of biomarkers was assessed with receiver operating characteristic (ROC) curves. Optimal cut-points and test performance characteristics were calculated for each biomarker.

RESULTS
  Of 280 patients enrolled, the median age was 11.3 years (interquartile range [IQR] = 8.6 to 14.8), 57% were male, and 33% had appendicitis. Median IL-6, median CRP, mean WBC count, and mean ANC differed significantly (p < 0.001) between patients with nonperforated appendicitis and those without appendicitis; median IL-8 levels did not differ between groups. In nonperforated appendicitis, median IL-6, WBC, and ANC levels were maximal at less than 24 hours of pain, while CRP peaked between 24 and 48 hours. In perforated appendicitis, median IL-8 levels were highest by 24 hours, WBC count and IL-6 by 24 to 48 hours, and CRP after 48 hours of pain. The WBC count appeared to be the most useful marker to predict appendicitis in those with fewer than 24 or more than 48 hours of pain, while CRP was the most useful in those with 24 to 48 hours of pain.

In this population, the serum levels and accuracy of novel and traditional biomarkers varies in relation to duration of abdominal pain. IL-6 shows promise as a novel biomarker to identify children with appendicitis.

Discriminative accuracy of novel and traditional biomarkers in children with suspected appendicitis adjusted for duration of abdominal pain.

OBJECTIVES: Variables used in prediction rules and clinical guidelines should show acceptable agreement when assessed by different observers. Our objective was to determine the interobserver agreement of patient history and physical examination variables used to assess children undergoing emergency department (ED) evaluation for a first seizure not provoked by a known precipitant such as fever or trauma (ie, an unprovoked seizure). METHODS: We conducted a prospective cohort study of children aged 28 days to 18 years evaluated for unprovoked seizures at 6 tertiary care EDs. We excluded patients if previously evaluated for a similar event. Two clinicians independently completed a clinical assessment before neuroimaging. We determined agreement for each clinical variable by using the unweighted κ statistic. RESULTS: A total of 217 paired observations were analyzed; median patient age was 53.5 months, and 38% were younger than 2 years. Agreement beyond chance was at least moderate (κ ≥ 0.41) for 21 of 31 (68%) variables for which κ could be calculated. κ was ≥0.41 for 7 of 11 (64%) general history variables, all 8 seizure-specific history variables (including seizure focality), and 6 of 12 (50%) physical examination variables. Agreement beyond chance was substantial or better (κ ≥ 0.61) for 2 of 11 (18%) general history variables, for 5 of 8 (63%) seizure-specific history variables, and for 2 of 12 (17%) physical examination variables. CONCLUSIONS: For children with first unprovoked seizures evaluated in the ED, clinicians frequently assess findings from seizure-specific history with substantial agreement beyond chance. Those clinical variables that have been associated with the presence of intracranial abnormalities and show reliability between assessors, such as seizure focality and the presence of any focal neurological finding, may be more useful in the ED assessment of children with first unprovoked seizures.

Interobserver Agreement in the Assessment of Clinical Findings in Children With First Unprovoked Seizures

14 Cranial CT Use for Minor Head Trauma in Children Is Associated With Race/Ethnicity

OBJECTIVE: Children with minor blunt head trauma often are observed in the emergency department before a decision is made regarding computed tomography use. We studied the impact of this clinical strategy on computed tomography use and outcomes. METHODS: We performed a subanalysis of a prospective multicenter observational study of children with minor blunt head trauma. Clinicians completed case report forms indicating whether the child was observed before making a decision regarding computed tomography. We defined clinically important traumatic brain injury as an intracranial injury resulting in death, neurosurgical intervention, intubation for longer than 24 hours, or hospital admission for 2 nights or longer. To compare computed tomography rates between children observed and those not observed before a decision was made regarding computed tomography use, we used a generalized estimating equation model to control for hospital clustering and patient characteristics. RESULTS: Of 42 412 children enrolled in the study, clinicians noted if the patient was observed before making a decision on computed tomography in 40 113 (95%). Of these, 5433 (14%) children were observed. The computed tomography use rate was lower in those observed than in those not observed (31.1% vs 35.0%; difference: −3.9% [95% confidence interval: −5.3 to −2.6]), but the rate of clinically important traumatic brain injury was similar (0.75% vs 0.87%; difference: −0.1% [95% confidence interval: −0.4 to 0.1]). After adjustment for hospital and patient characteristics, the difference in the computed tomography use rate remained significant (adjusted odds ratio for obtaining a computed tomography in the observed group: 0.53 [95% confidence interval: 0.43–0.66]). CONCLUSIONS: Clinical observation was associated with reduced computed tomography use among children with minor blunt head trauma and may be an effective strategy to reduce computed tomography use.

The Effect of Observation on Cranial Computed Tomography Utilization for Children After Blunt Head Trauma

Identification of children with low-risk brain injuries – Authors' reply

BACKGROUND: There is limited evidence from which to derive guidelines for the management of febrile infants aged 29 to 60 days with urinary tract infections (UTIs). Most such infants are hospitalized for ≥48 hours. Our objective was to derive clinical prediction models to identify febrile infants with UTIs at very low risk of adverse events and bacteremia in a large sample of patients. METHODS: This study was a 20-center retrospective review of infants aged 29 to 60 days with temperatures of ≥38°C and culture-proven UTIs. We defined UTI by growth of ≥50 000 colony-forming units (CFU)/mL of a single pathogen or ≥10 000 CFU/mL in association with positive urinalyses. We defined adverse events as death, shock, bacterial meningitis, ICU admission need for ventilator support, or other substantial complications. We performed binary recursive partitioning analyses to derive prediction models. RESULTS: We analyzed 1895 patients. Adverse events occurred in 51 of 1842 (2.8% [95% confidence interval (CI): 2.1%–3.6%)] and bacteremia in 123 of 1877 (6.5% [95% CI: 5.5%–7.7%]). Patients were at very low risk for adverse events if not clinically ill on emergency department (ED) examination and did not have a high-risk past medical history (prediction model sensitivity: 98.0% [95% CI: 88.2%–99.9%]). Patients were at lower risk for bacteremia if they were not clinically ill on ED examination, did not have a high-risk past medical history, had a peripheral band count of <1250 cells per μL, and had a peripheral absolute neutrophil count of ≥1500 cells per μL (sensitivity 77.2% [95% CI: 68.6%–84.1%]). CONCLUSION: Brief hospitalization or outpatient management with close follow-up may be considered for infants with UTIs at very low risk of adverse events.

Febrile Infants With Urinary Tract Infections at Very Low Risk for Adverse Events and Bacteremia

Up to 3 million US children are cared for by emergency medical services (EMSs) annually. Limited research exists on pediatric prehospital care. The Pediatric Emergency Care Applied Research Network (PECARN) mission is to perform high-quality research for children, including prehospital research. Our objective was to develop a pediatric-specific prehospital research agenda. Methods: Representatives from all 4 PECARN nodes and from EMS agency partners participated in a 3-step process. First, participants ranked potential research priorities and suggested others. Second, participants reranked the list in order of importance and scored each priority using a modified Hanlon method (prevalence, seriousness, and practicality of each research area were assessed). Finally, the revised priority list was presented at a PECARN EMS summit, and consensus was sought. Results: Forty-two representatives participated, including PECARN representatives, EMS agency leaders, and nationally recognized prehospital researchers. Consensus was reached on the priority ranking. The prioritization processes resulted in 2 ranked lists: 15 clinical topics and 5 EMS system topics. The top 10 clinical priorities included (1) airway management, (2) respiratory distress, (3) trauma, (4) asthma, (5) head trauma, (6) shock, (7) pain, (8) seizures, (9) respiratory arrest, and (10) C-spine immobilization. The 5 EMS system topics identify methods to improve prehospital care on the system level. Conclusions: PECARN has identified high-priority EMS research topics for children using a consensus-derived method. These research priorities include novel EMS system topics. The PECARN EMS pediatric research priority list will help focus future pediatric prehospital research both within and outside the network.

Objective: Chest pain is a common presentation in the pediatric emergency department (PED). In the majority of cases, no clear medical cause is found. Among adults with noncardiac chest pain, psychopathology including panic disorder is common. We assessed the likelihood and type of psychopathology as well as the health status of children and adolescents with unexplained chest pain who presented to the PED. Methods: We performed a semistructured diagnostic interview of children 8 to 17 years old who presented to an urban, tertiary-care PED with a primary complaint of chest pain for which no medical cause was found. We used Diagnostic Statistical Manual of Mental Disorders, Fourth Edition criteria to diagnose psychopathology. We also assessed pain severity, extent of other somatic complaints, quality of life, and functional disability using standard, validated instruments. Results: We enrolled 32 children with a mean age of 12.8 (SD, 2.9) years (range, 8-17 years); 47% were female. Twenty-six (81%) were diagnosed with a Diagnostic Statistical Manual of Mental Disorders, Fourth Edition anxiety disorder; 9 (28%) had full-criteria panic disorder. Quality of life was compromised in multiple domains, and children reported a range of functional disabilities due to chest pain. Other somatic symptoms, including other pain complaints, were commonly reported in this sample. Conclusion: Unexplained chest pain in the PED is frequently associated with potentially treatable anxiety disorders. Emergency physicians should consider the possibility of anxiety disorders in patients with medically unexplained chest pain.

Psychopathology and Disability in Children With Unexplained Chest Pain Presenting to the Pediatric Emergency Department

Bacterial Meningitis Cerebrospinal Fluid Pleocytosis at Very Low Risk of Clinical Prediction Rule for Identifying Children

Objective: To describe the patterns of referral and use of resources for patients with psychiatric-related visits presenting to pediatric emergency departments (EDs) in a pediatric research network. Methods: We conducted a retrospective chart review of a random sample of patients (approximately 10 charts per month per site) who presented with psychiatric-related visits in 2002 to 4 pediatric EDs in the Pediatric Emergency Care Applied Research Network. Emergency department resource use variables evaluated included the use of consultation services, restraints, and laboratory tests as well as ED length of stay. Results: We reviewed 462 patient visits with a psychiatric-related ED diagnosis. Mean (SD) age was 12.8 (3.7) years, 52% were male, and 49% were African American. The most common chief complaints were suicidality (47%), aggression/agitation (42%), and anxiety/depression (27%), alone or in combination. Ninety percent of patients (range across sites, 83%-94%) had a mental health consult in the ED, 5% were restrained (range, 3%-9%), and 35% had a laboratory test performed (range, 15%-63%). Mean (SD) ED length of stay was 5.1 (5.4) hours, and 52% were admitted (93% to a psychiatric bed, including transfers to separate psychiatric facilities). Conclusions: Children with psychiatric-related visits seem to require substantial ED resources. Interventions are needed to reduce the burden on the ED by increasing the linkage to mental health services, particularly for suicidal youths.

Referral and Resource Use Patterns for Psychiatric-Related Visits to Pediatric Emergency Departments

This is a commentary on a Cochrane review, published in this issue of EBCH, first published as: Appleton R, Macleod S, Martland T. Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.: CD001905. DOI: 10.1002/14651858.CD001905.pub2. 
 
Further information for this Cochrane review is available in this issue of EBCH in the accompanying Summary article. Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. The Cochrane Collaboration

Commentary on ‘Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children’, with a response from the review authors

We determined underlying cause‐specific mortality for incident unprovoked seizures from Northern Manhattan, New York City. We calculated the case fatality, proportionate mortality, and the underlying cause‐specific standardized mortality ratios (SMRs), with U.S. death rates as the standard. Thirty‐two deaths were observed between 2003 and 2007 among 209 participants. Case fatality was significantly lower for idiopathic/cryptogenic seizures versus symptomatic seizures. About 31.3% of the deaths were attributed to malignant neoplasms, 25.0% to diseases of the heart, 15.6% to influenza and pneumonia, 3.1% to cerebrovascular diseases, and 25.0% to other causes. Significant SMRs were observed for all causes (SMR = 1.6), influenza and pneumonia (SMR = 7.1), and malignant neoplasms (SMR = 2.9). Younger cases (<65 years) had increased SMRs for all causes, malignant neoplasms, and other causes. Older cases (≥65 years) had increased SMRs for influenza and pneumonia. Underlying cause of death paralleled the underlying cause of seizure in patients with symptomatic etiologies.

Underlying cause of death in incident unprovoked seizures in the urban community of Northern Manhattan, New York City

Nathan Kuppermann, James F Holmes, Peter S Dayan, John D Hoyle, Jr, Shireen M Atabaki, Richard Holubkov, Frances M Nadel, David Monroe, Rachel M Stanley, Dominic A Borgialli, Mohamed K Badawy, Je E Schunk, Kimberly S Quayle, Prashant Mahajan, Richard Lichenstein, Kathleen A Lillis, Michael G Tunik, Elizabeth S Jacobs, James M Callahan, Marc H Gorelick, Todd F Glass, Lois K Lee, Michael C Bachman, Arthur Cooper, Elizabeth C Powell, Michael J Gerardi, Kraig A Melville, J Paul Muizelaar, David H Wisner, Sally Jo Zuspan, J Michael Dean, Sandra L Wootton-Gorges, for the Pediatric Emergency Care Applied Research Network (PECARN)*

Identifi cation of children at very low risk of clinically-important brain injuries after head trauma: a prospective cohort study

Identification of children at very low risk of clinically-important brain injuries after head trauma: a prospective cohort study

Do workshops in evidence-based practice equip participants to identify and answer questions requiring consideration of clinical research? A diagnostic skill assessment

OBJECTIVE: We aimed to determine the risk of SBIs in febrile infants with influenza virus infections and compare this risk with that of febrile infants without influenza infections. PATIENTS AND METHODS: We conducted a multicenter, prospective, cross-sectional study during 3 consecutive influenza seasons. All febrile infants ≤60 days of age evaluated at any of 5 participating pediatric EDs between October and March of 1998 through 2001 were eligible. We determined influenza virus status by rapid antigen detection. We evaluated infants with blood, urine, cerebrospinal fluid, and stool cultures. Urinary tract infection (UTI) was defined by single-pathogen growth of either ≥5 × 104 colony-forming units per mL or ≥104 colony-forming units per mL in association with a positive urinalysis. Bacteremia, bacterial meningitis, and bacterial enteritis were defined by growth of a known bacterial pathogen. SBI was defined as any of the 4 above-mentioned bacterial infections. RESULTS: During the 3-year study period, 1091 infants were enrolled. A total of 844 (77.4%) infants were tested for the influenza virus, of whom 123 (14.3%) tested positive. SBI status was determined in 809 (95.9%) of the 844 infants. Overall, 95 (11.7%) of the 809 infants tested for influenza virus had an SBI. Infants with influenza infections had a significantly lower prevalence of SBI (2.5%) and UTI (2.4%) when compared with infants who tested negative for the influenza virus. Although there were no cases of bacteremia, meningitis, or enteritis in the influenza-positive group, the differences between the 2 groups for these individual infections were not statistically significant. CONCLUSIONS: Febrile infants ≤60 days of age with influenza infections are at significantly lower risk of SBIs than febrile infants who are influenza-negative. Nevertheless, the rate of UTI remains appreciable in febrile, influenza-positive infants.

Influenza Virus Infection and the Risk of Serious Bacterial Infections in Young Febrile Infants

Purpose: To estimate the incidence and mortality associated with first unprovoked seizure or newly diagnosed epilepsy in a low‐income, predominantly Hispanic community in Northern Manhattan, New York City.

Estimating the incidence of first unprovoked seizure and newly diagnosed epilepsy in the low‐income urban community of Northern Manhattan, New York City

Objective: Whether magnetic resonance imaging (MRI) is informative in febrile seizures (FS) is unknown. We undertook a study to determine the frequency of MRI‐detected brain abnormalities and to evaluate their association with FS type and with specific features of complex FS.

Are MRI‐detected brain abnormalities associated with febrile seizure type?

OBJECTIVE. The goal of this study was to evaluate the effect of antibiotic administration before lumbar puncture on cerebrospinal fluid profiles in children with bacterial meningitis. METHODS. We reviewed the medical records of all children (1 month to 18 years of age) with bacterial meningitis who presented to 20 pediatric emergency departments between 2001 and 2004. Bacterial meningitis was defined by positive cerebrospinal fluid culture results for a bacterial pathogen or cerebrospinal fluid pleocytosis with positive blood culture and/or cerebrospinal fluid latex agglutination results. Probable bacterial meningitis was defined as positive cerebrospinal fluid Gram stain results with negative results of bacterial cultures of blood and cerebrospinal fluid. Antibiotic pretreatment was defined as any antibiotic administered within 72 hours before the lumbar puncture. RESULTS. We identified 231 patients with bacterial meningitis and another 14 with probable bacterial meningitis. Of those 245 patients, 85 (35%) had received antibiotic pretreatment. After adjustment for patient age, duration and severity of illness at presentation, and bacterial pathogen, longer duration of antibiotic pretreatment was not significantly associated with cerebrospinal fluid white blood cell count, cerebrospinal fluid absolute neutrophil count. However, antibiotic pretreatment was significantly associated with higher cerebrospinal fluid glucose and lower cerebrospinal fluid protein levels. Although these effects became apparent earlier, patients with ≥12 hours of pretreatment, compared with patients who either were not pretreated or were pretreated for <12 hours, had significantly higher median cerebrospinal fluid glucose levels (48 mg/dL vs 29 mg/dL) and lower median cerebrospinal fluid protein levels (121 vs 178 mg/dL). CONCLUSIONS. In patients with bacterial meningitis, antibiotic pretreatment is associated with higher cerebrospinal fluid glucose levels and lower cerebrospinal fluid protein levels, although pretreatment does not modify cerebrospinal fluid white blood cell count or absolute neutrophil count results.

Effect of Antibiotic Pretreatment on Cerebrospinal Fluid Profiles of Children With Bacterial Meningitis

Purpose of review We present data from recently conducted research regarding controversial aspects of the evaluation and management of children with minor blunt head trauma. Recent findings Clinicians frequently but at times indiscriminately perform computed tomography scans for children with minor blunt head trauma resulting in potentially harmful radiation exposure. Recent guidelines recognize the limited but increasing data available to make strong recommendations regarding appropriate neuroimaging decisions. Investigators have derived and validated clinical prediction models to accurately identify patients with substantial traumatic brain injury, though no clear definitive rule exists. Children younger than 2 years appear to have a higher risk of intracranial injury following minor head trauma. These patients can be difficult to assess, with the evidence suggesting the need for a more conservative approach to diagnostic imaging. We present current and accepted definitions of concussion along with risk factors and treatment for postconcussion syndrome. Current return-to-play guidelines suggest that athletes who have sustained concussion should not resume play until symptoms have resolved because of the possibility, though rare, of second impact syndrome. Summary Research in the management of children with minor head trauma is actively evolving. We present a review of recent developments that can influence current clinical practice.

Controversies in the evaluation and management of minor blunt head trauma in children

CONTEXT
Children with cerebrospinal fluid (CSF) pleocytosis are routinely admitted to the hospital and treated with parenteral antibiotics, although few have bacterial meningitis. We previously developed a clinical prediction rule, the Bacterial Meningitis Score, that classifies patients at very low risk of bacterial meningitis if they lack all of the following criteria: positive CSF Gram stain, CSF absolute neutrophil count (ANC) of at least 1000 cells/microL, CSF protein of at least 80 mg/dL, peripheral blood ANC of at least 10,000 cells/microL, and a history of seizure before or at the time of presentation.

OBJECTIVE
To validate the Bacterial Meningitis Score in the era of widespread pneumococcal conjugate vaccination.

DESIGN, SETTING, AND PATIENTS
A multicenter, retrospective cohort study conducted in emergency departments of 20 US academic medical centers through the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. All children aged 29 days to 19 years who presented at participating emergency departments between January 1, 2001, and June 30, 2004, with CSF pleocytosis (CSF white blood cells > or =10 cells/microL) and who had not received antibiotic treatment before lumbar puncture.

The sensitivity and negative predictive value of the Bacterial Meningitis Score.

RESULTS
Among 3295 patients with CSF pleocytosis, 121 (3.7%; 95% confidence interval [CI], 3.1%-4.4%) had bacterial meningitis and 3174 (96.3%; 95% CI, 95.5%-96.9%) had aseptic meningitis. Of the 1714 patients categorized as very low risk for bacterial meningitis by the Bacterial Meningitis Score, only 2 had bacterial meningitis (sensitivity, 98.3%; 95% CI, 94.2%-99.8%; negative predictive value, 99.9%; 95% CI, 99.6%-100%), and both were younger than 2 months old. A total of 2518 patients (80%) with aseptic meningitis were hospitalized.

This large multicenter study validates the Bacterial Meningitis Score prediction rule in the era of conjugate pneumococcal vaccine as an accurate decision support tool. The risk of bacterial meningitis is very low (0.1%) in patients with none of the criteria. The Bacterial Meningitis Score may be helpful to guide clinical decision making for the management of children presenting to emergency departments with CSF pleocytosis.

Clinical prediction rule for identifying children with cerebrospinal fluid pleocytosis at very low risk of bacterial meningitis.

To determine whether peripheral veins can be detected by ultrasound (US) and to determine vein characteristics, as measured by US, that are associated with successful peripheral venous (PV) catheterization in young children.

METHODS
The authors conducted an observational study in the pediatric emergency department (ED), with a convenience sample of children younger than 7 years. They evaluated attempts at PV catheterization in two groups on the basis of the visibility and palpability of the patients' veins: 1) clinically apparent (visible or palpable) and 2) not clinically apparent (nonvisible and nonpalpable). The authors obtained sonographic measurements in a transverse view (vertical diameter, circumference, and area) and in a longitudinal view (maximal uninterrupted length). Practitioners blinded to the US images then attempted to catheterize veins in the usual manner. The proportion of clinically apparent veins and the proportion of veins that were successfully catheterized that were identified by US were assessed, and the association between ultrasonographic vein measurements and success at catheterization, controlling for possible confounders, was determined.

RESULTS
The authors assessed 120 attempts (90 clinically apparent and 30 not clinically apparent) at PV catheterization in 83 patients. US detected all 90 clinically apparent veins, and cannulation success rate was 62/90 (69%). In the not clinically apparent vein group, the rate of success was only 3/30 (10%), and US detected all successfully catheterized veins. In no instance was cannulation successful when the vein was not detected by US. Maximal vein length in longitudinal view was an independent predictor of cannulation success in multivariate analysis.

Ultrasound appears to be capable of detecting peripheral veins in children younger than 7 years of age, with lack of US vein visualization likely leading to unsuccessful PV placement. Greater vein length visualization may be a useful predictor of successful PV catheterization.

A pilot study of ultrasound analysis before pediatric peripheral vein cannulation attempt.

To be useful in development of clinical decision rules, clinical variables must demonstrate acceptable agreement when assessed by different observers. The objective was to determine the interobserver agreement in the assessment of historical and physical examination findings of children undergoing emergency department (ED) evaluation for blunt head trauma.

METHODS
This was a prospective cohort study of children younger than 18 years evaluated for blunt head trauma at one of 25 EDs in the Pediatric Emergency Care Applied Research Network (PECARN). Patients were excluded if injury occurred more than 24 hours prior to evaluation, if neuroimaging was obtained at another hospital prior to evaluation, or if the patient had a clinically trivial mechanism of injury. Two clinicians independently completed a standardized clinical assessment on a templated data form. Assessments were performed within 60 minutes of each other and prior to clinician review of any neuroimaging (if obtained). Agreement between the two observers beyond that expected by chance was calculated for each clinical variable, using the kappa (kappa) statistic for categorical variables and weighted kappa for ordinal variables. Variables with a lower 95% confidence limit (LCL) of kappa > 0.4 were considered to have acceptable agreement,

RESULTS
Fifteen-hundred pairs of observations were obtained. Acceptable agreement was achieved in 27 of the 32 variables studied (84%). Mechanism of injury (low, medium, or high risk) had kappa = 0.83. For subjective symptoms, kappa ranged from 0.47 (dizziness) to 0.93 (frequency of vomiting); all had 95% LCL > 0.4. Of the physical examination findings, kappa ranged from 0.22 (agitated) to 0.89 (Glasgow Coma Scale [GCS] score). The 95% LCL for kappa was < 0.4 for four individual signs of altered mental status and for quality (i.e., boggy or firm) of scalp hematoma if present.

Both subjective and objective clinical variables in children with blunt head trauma can be assessed by different observers with acceptable agreement, making these variables suitable candidates for clinical decision rules.

Interobserver agreement in assessment of clinical variables in children with blunt head trauma.

Objectives: To determine the test characteristics of the 3-view abdominal radiograph series to exclude intussusception in children presenting to the pediatric emergency department. Methods: We performed a single-center retrospective review of children for whom supine, prone, and lateral decubitus abdominal radiographs were performed as part of our standard diagnostic evaluation for intussusception. A pediatric radiologist masked to the patient's clinical data and outcome reviewed all radiographs. The criterion evaluated was whether air was visualized in the ascending colon on each of the 3 radiograph views. We determined the presence or absence of intussusception hierarchically by definitive radiological study report, surgical operative note, or clinical outcome. Results: We analyzed 179 patients, of whom 27 (15.1%) were diagnosed with intussusception. The test characteristics of the 3-view radiograph series in the diagnosis of intussusception when all 3 views had air in the ascending colon were sensitivity of 100% (95% confidence interval [CI] 87-100), specificity of 18.4% (95% CI, 12.3-24.6), likelihood ratio for a negative test of 0 (95% CI, 0.01-1.53), and negative predictive value (NPV) of 100% (lower bound 95% CI, 98%). When at least 2 views had air in the ascending colon, the test characteristics were sensitivity of 96.3% (95% CI, 89.2-100), specificity of 41.4% (95% CI, 33.6-49.3), likelihood ratio for a negative test of 0.09 (0.01-0.62), and NPV of 98.4 (95% CI, 95.2-100). Conclusions: Using specific criteria, the presence of air in the ascending colon on 2 or 3 abdominal radiograph views has the potential to substantially decrease the likelihood of or exclude intussusception.

Test Characteristics of the 3-View Abdominal Radiograph Series in the Diagnosis of Intussusception

Objectives: To compare the clinical efficacy of single-dose intramuscular (IM) dexamethasone phosphate to a 5-day course of oral prednisolone for the treatment of moderate asthma exacerbations in young children discharged from the emergency department (ED). Methods: We performed a prospective, randomized trial in children aged 18 months to less than 7 years with asthma who presented to the ED with a clinical asthma score of 3 to 7 on a 9-point scale. Children were randomized to 1 dose of IM dexamethasone (0.6 mg/kg, maximum 15 mg) or oral prednisolone (2 mg/kg, maximum 50 mg) once daily for 5 days. The primary outcome, measured only for patients discharged from the ED, was change in asthma score from ED presentation to 4-day follow-up examination, as assessed by a physician masked to group assignment. We assessed secondary clinical course outcomes by a structured interview at 4 and 14 days. Results: Eighty-eight patients were appropriately randomized to dexamethasone and 93 to prednisolone. Group characteristics were similar at baseline. Among those discharged from the ED, 62 (90%) of 69 and 64 (90%) of 74 patients in the dexamethasone and prednisolone groups, respectively, were reassessed at 4 days for the primary outcome. The mean change in total asthma score at 4-day follow-up was 3.6 in the dexamethasone group and 3.4 in the prednisolone group (difference, 0.2; 95% confidence interval, −0.4 to 0.7). Of patients initially discharged, 5.9% of dexamethasone patients and 4.1% of prednisolone patients were admitted before the 2-week follow-up (difference, 1.8%; 95% confidence interval, −5.4% to 9.0%). Conclusions: A single dose of IM dexamethasone showed no clinically meaningful difference in outcomes compared with a 5-day course of oral prednisolone for the treatment of moderate acute asthma exacerbations in young children who are discharged from the ED.

Randomized Trial of Single-Dose Intramuscular Dexamethasone Compared With Prednisolone for Children With Acute Asthma

Blunt Head Trauma in the Pediatric Emergency Care Applied Research Network (PECARN)

Clinical question : in children exposed to a single head CT , what are the risks of adverse effects from radiation ?

Knowledge translation (KT) research in emergency medicine (EM) is in its infancy, and few EM investigators have the skills needed to perform KT research. Furthermore, the capacity to perform such KT research is underdeveloped in the field of EM. This consensus group used an iterative process to set forth initial recommendations and suggest methods for the development of EM KT research capacity. We have emphasized the need to form sustainable linkages, particularly between EM researchers and KT scientists, and to educate EM researchers in KT research methods to help create and sustain a culture of KT in our field. EM KT researchers must also engage local and national organizations and stakeholders to fund and promote KT research. Finally, we see the need to further develop and support EM research networks, as these networks will be both the clinical laboratories in which to perform the KT research and the incubators for the development of EM KT research experts.

Development of the capacity necessary to perform and promote knowledge translation research in emergency medicine.

309: Peripheral Vein Detection Using Ultrasound and Sonographic Factors Associated with Successful Peripheral Vein Cannulation in Young Children Presenting to the Pediatric Emergency Department: A Pilot Study

The Pediatric Emergency Care Applied Research Network: Progress and Update

OBJECTIVE. To determine the likelihood of intracranial pathologic conditions requiring emergency neurosurgical or medical intervention among children without meningitis who presented to the pediatric emergency department after a first complex febrile seizure. METHODS. We performed a retrospective review of prospectively collected data for children in neurologically normal condition who presented to a single pediatric emergency department after a first complex febrile seizure (focal, multiple, or prolonged). The complex febrile seizure classification was determined independently by 2 epileptologists. The presence of intracranial pathologic conditions was determined through review of neuroimaging results, telephone interviews, or medical record review. RESULTS. Data for 71 children with first complex febrile seizures were analyzed. Fifty-one (72%) had a single complex feature (20 focal, 22 multiple, and 9 prolonged), and 20 (28%) had multiple complex features. None of the 71 patients (1-sided 95% confidence interval: 4%) had intracranial pathologic conditions that required emergency neurosurgical or medical intervention. CONCLUSIONS. For children with first complex febrile seizures, the risk of intracranial pathologic conditions that require emergency neurosurgical or medical intervention is low, which suggests that routine emergency neuroimaging for this population is unnecessary.

Risk of Intracranial Pathologic Conditions Requiring Emergency Intervention After a First Complex Febrile Seizure Episode Among Children

Purpose of review Rapid sequence intubation is the method of choice for intubation of the emergency department patient. The purpose of the present review is to address several controversies pertaining to emergency department rapid sequence intubation of children. Recent findings The topics covered in this review include the determination of the appropriate clinician to perform emergency department intubation, the use of atropine and lidocaine as premedications, the choice of sedative agents depending upon the clinical scenario, and the choice of neuromuscular blockade agent. Concerning these topics,The literature supports that emergency department physicians, with appropriate training, successfully perform intubation in most patients.Limited data exist to determine the appropriate use of atropine and lidocaine for rapid sequence intubation.Etomidate has clearly become a preferred sedative for rapid sequence intubation with a low risk of cardiovascular side effects. Thiopental and propofol may more readily provide adequate sedation as compared with etomidate but both have the potential to reduce blood pressure.Succinylcholine arguably remains the preferred neuromuscular blockade agent for rapid sequence intubation in most children. The side effects of succinylcholine occur in relatively predictable circumstances. Rocuronium is a commonly used nondepolarizing paralytic agent but its prolonged duration of action must be weighed against the risk of side effects associated with succinylcholine. Summary Though more research is needed, the available data allow for the development of protocols that will result in a rational, scenario-based approach to rapid sequence intubation in children.

Objective. Previous research has identified clinical predictors for urinary tract infection (UTI) to guide urine screening in febrile children <24 months of age. These studies have been limited to single centers, and few have focused on young infants who may be most at risk for complications if a UTI is missed. The objective of this study was to identify clinical and demographic factors associated with UTI in febrile infants who are ≤60 days of age using a prospective multicenter cohort. Methods. We conducted a multicenter, prospective, cross-sectional study during consecutive bronchiolitis seasons. All febrile (≥38°C) infants who were ≤60 days of age and seen at any of 8 pediatric emergency departments from October through March 1999–2001 were eligible. Clinical appearance was evaluated using the Yale Observation Scale. UTI was defined as growth of a known bacterial pathogen from a catheterized specimen at a level of (1) ≥50000 cfu/mL or (2) ≥10000 cfu/mL in association with a positive dipstick test or urinalysis. We used bivariate tests and multiple logistic regression to identify demographic and clinical factors that were associated with the likelihood of UTI. Results. A total of 1025 (67%) of 1513 eligible patients were enrolled; 9.0% of enrolled infants received a diagnosis of UTI. Uncircumcised male infants had a higher rate of UTI (21.3%) compared with female (5.0%) and circumcised male (2.3%) infants. Infants with maximum recorded temperature of ≥39°C had a higher rate of UTI (16.3%) than other infants (7.2%). After multivariable adjustment, UTI was associated with being uncircumcised (odds ratio: 10.4; bias-corrected 95% confidence interval: 4.7–31.4) and maximum temperature (odds ratio: 2.4 per °C; 95% confidence interval: 1.5–3.6). Factors that were reported previously to be associated with risk for UTI in infants and toddlers, such as white race and ill appearance, were not significantly associated with risk for UTI in this cohort of young infants. Conclusions. Being uncircumcised and height of fever were associated with UTI in febrile infants who were ≤60 days of age. Uncircumcised male infants were at particularly high risk and may warrant a different approach to screening and management.

Clinical and Demographic Factors Associated With Urinary Tract Infection in Young Febrile Infants

Young Febrile Infants Clinical and Demographic Factors Associated With Urinary Tract Infection in

Maria Y. Kwok, MD, MPH, Christine M. Walsh-Kelly, MD, Jo Bergholte, MS, Marc H. Gorelick, MD, MSCE, Pediatric Emergency Medicine, Medical College of Wisconsin, Milwaukee, WI. Purpose: Exhaled nitric oxide (eNO) has proven to be a sensitive, noninvasive method to measure the degree of chronic airway inflammation in pediatric and adult asthmatic patients. eNO levels have been used to monitor chronic asthma treatment in outpatient settings, but they have not been evaluated as a measure of acute asthma severity. This study examined the association betwen eNO and the pulmonary index score (PIS), percent peak f low rate (%PFR), and dispostion for acute asthma exacerbations. Methods: This was a prospective study of children younger than 18 years with a physician diagnosis of asthma and treated in an emergency department (ED) for an acute asthma exacerbation. eNO levels were obtained via an online tidal breathing method. Levels were compared with the ED PIS, %PFR, ED dispostion, and other clinical outcomes using Spearman rho correlation and receiver operator characteristic (ROC) curve. Additional information onfactors that might affect eNO levels was collected. Results: Of the 88 subjects, 33 (40%) were categorized as having mild, 41 (49%) moderate, and 8 (10%) severe acute asthma exacerbation based on PIS. Mean eNO levels for the mild, moderate, and severe groups were 10.5 ± 7.6 (SE 1.3), 9.1 ± 7.9 (SE 1.3), and 10.2 ± 7.9 (SE 2.8), respectively. No statistically significant correlation between eNO levels and either the PIS (r = 0.063, P = 0.58) or the %PFR (r = 0.114, P = 0.534) were identified even when adjusted for confounders including inhaled steroid use, cigarette smoking exposure, and baseline chronic asthma severity. eNO levels did not predict hospital admission with area under the ROC curve of 0.609. No significant correlations were observed between eNO levels and outcomes such as number of days missed from school/daycare (r = 0.18, P = 0.27), number of days missed from work (r = 0.167, P = 0.34), or duration of symptoms (r = 0.015, P = 0.92). Conclusions: eNO levels do not correlate with acute asthma severity, ED disposition, or early clinical outcomes in children with acute asthma exacerbation.

American Academy of Pediatrics, Section on Emergency Medicine, Scientific Abstract Presentations, 2004 AAP National Conference and Exhibition

OBJECTIVE
The authors sought to derive maximally sensitive prediction rules for identifying children with significant fractures after acute twisting injuries to the ankle.

METHODS
The authors prospectively enrolled a convenience sample of patients younger than 18 years of age who presented to the pediatric emergency department of an urban, tertiary care center after sustaining acute twisting injuries of the ankle. The ankle was defined in two regions: the malleolar zone and the midfoot zone. Clinical findings were documented on standardized data collection sheets by faculty physicians before completion of ankle and/or foot radiograph series. Significant fracture was defined a priori as any fracture other than an avulsion < or =3 mm. The authors conducted binary recursive partitioning with cross-validation to develop models to predict fracture.

RESULTS
Data from 717 enrolled patients with a median age of 12.9 years were analyzed. Significant malleolar zone and midfoot zone fractures were diagnosed in 81 of 682 (11.9%) and 10 of 173 (5.8%) patients for whom ankle and foot radiographs were obtained. Recursive partitioning identified patients at low risk for malleolar zone fracture if 1) they had no bone tenderness at either malleolus or the region just proximal to the fibula malleolus or 2) they had bone tenderness at either malleolus but were able to walk four steps in the emergency department and had no swelling at either malleolus. The two-part malleolar zone rule had a sensitivity of 100% and specificity of 19.1% on the learning data and 95.1% (95% confidence interval [95% CI] = 87.8% to 98.6%) and 20.0% (95% CI = 16.8% to 23.4%) on the test data. Tenderness either at the proximal fifth metatarsal or cuboid identified midfoot zone fractures with a sensitivity of 100% and specificity of 31.9% on the learning data and 90.0% (95% CI = 55.4% to 99.7%) and 35.0% (95% CI = 27.7% to 42.8%) on the test sample.

A set of sensitive prediction rules was developed to identify children with significant fractures after twisting injuries to the ankle. External validation and refinement of the rules will be needed before recommendation of widespread use.

Derivation of clinical prediction rules to identify children with fractures after twisting injuries of the ankle.

The evaluation of young febrile infants is controversial, in part because it is unclear whether clinical evidence of a viral infection significantly reduces the risk of serious bacterial infections (SBIs). Specifically, it remains unclear whether the risk of SBI is altered in a meaningful way in the presence of respiratory syncytial virus (RSV) infections.

OBJECTIVE
The objective of this study was to determine the risk of SBI in young febrile infants who are infected with RSV compared with those without RSV infections.

METHODS
We conducted a 3-year multicenter, prospective, cross-sectional study. All febrile (> or =38 degrees C) infants who were < or =60 days of age and presented to any of 8 pediatric emergency departments from October through March 1998-2001 were eligible. General clinical appearance was evaluated using the Yale Observational Scale. We determined RSV status by antigen testing of nasopharyngeal secretions. We defined bronchiolitis as either wheezing alone or chest retractions in association with an upper respiratory infection. We evaluated infants with blood, urine, cerebrospinal fluid, and stool cultures. Urinary tract infection (UTI) was defined by single pathogen growth of > or =5 x 10(4) cfu/mL, or > or =10(4) cfu/mL in association with a positive urinalysis in a catheterized specimen, or > or = 10(3) cfu/mL in a suprapubic aspirate. Bacteremia, bacterial meningitis, and bacterial enteritis were defined by growth of a known bacterial pathogen. SBI was defined as any of the above-mentioned 4 bacterial infections.

RESULTS
We enrolled 1248 patients, including 269 (22%) with RSV infections. The overall SBI status could be determined in 1169 (94%) of the 1248 patients, and the rate of SBIs was 11.4% (133 of 1169; 95% confidence interval [CI]: 9.6%-13.3%). The rate of SBIs in the RSV-positive infants was 7.0% (17 of 244; 95% CI: 4.1%-10.9%) compared with 12.5% (116 of 925; 95% CI: 10.5%-14.8%) in the RSV-negative infants (risk difference: 5.5%; 95% CI: 1.7%-9.4%). The rate of UTI in the RSV-positive infants was 5.4% (14 of 261; 95% CI: 3.0%-8.8%) compared with 10.1% (98 of 966; 95% CI: 8.3%-12.2%) in the RSV-negative infants (risk difference: 4.7%; 95% CI: 1.4%-8.1%). The RSV-positive infants had a lower rate of bacteremia than the RSV-negative infants (1.1% vs 2.3%; risk difference: 1.2%; 95% CI: -0.4% to 2.7%). No RSV-positive infant had bacterial meningitis (0 of 251; 95% CI: 0%-1.2%); however, the differences between the 2 groups with regard to bacteremia and bacterial meningitis did not achieve statistical significance.

Febrile infants who are < or =60 days of age and have RSV infections are at significantly lower risk of SBI than febrile infants without RSV infection. Nevertheless, the rate of SBIs, particularly as a result of UTI, remains appreciable in febrile RSV-positive infants.

Risk of serious bacterial infection in young febrile infants with respiratory syncytial virus infections.

Objectives: Although often managed differently than older children, no study has specifically described the clinical course of urinary tract infections (UTIs) in young infants. Our objective was to determine the risk of progression of illness and the pattern of fever resolution in infants younger than 60 days of age with Gram-negative rod UTIs. Methods: We completed a retrospective medical chart review. Patients younger than 60 days of age presenting to an urban, tertiary care pediatric hospital were included if they had single organism growth of Gram-negative rods in any amount from suprapubic aspiration samples or more than 10,000 cfu/mL from catheterized specimens. Significant progression of illness was defined as the need for transfer to an intensive care setting. Fever was defined as a rectal temperature of 38.0°C or higher or an axillary temperature 37.0°C or higher. Temperatures were assigned to blocks of 4 hours. Results: Of 128 patients with available records, none were transferred from the general pediatric ward to the intensive care unit and 2 were transferred to a step-down unit for events potentially unrelated to the UTI. No patient had a positive repeat urine culture. For patients with fever, median time to fever resolution was within the 4 to 8 hour time block. Eighty-five percent of the febrile patients became afebrile within 24 hours and only 3.6% were febrile after 48 hours. Conclusions: Progression of illness in infants with Gram-negative rod UTIs is unlikely. Fever resolution is rapid. If subsequent studies concur with our findings, outpatient therapy or short-stay unit admission may become a viable management strategy.

Clinical Course of Urinary Tract Infections in Infants Younger Than 60 Days of Age

summarize data from recently conducted research regarding controversial aspects of the management of children with bronchiolitis. These data suggest that chronic medical history, gestational age at birth, postnatal age, and physiological variables can identify those children at higher risk for a more severe course of bronchiolitis. Large prospective studies also suggest that the likelihood of significant bacterial illness in febrile infants with bronchiolitis may be lower than in children without bronchiolitis. Nevertheless, urinary tract infections remain relatively common in young febrile children with bronchiolitis. Lastly and unfortunately, the data note a relative lack of effective therapies for children with bronchiolitis, although certain therapies such as systemic corticosteroids show potential efficacy and are in need of further study. The remaining uncertainty surrounding many issues pertaining to bronchiolitis highlight the need for more research aimed to: (1) develop prognostic models to identify patients at risk for a more severe clinical course, (2) develop generalizable diagnostic models to identify febrile infants with bronchiolitis at high and very low risk of significant bacterial illness, and (3) evaluate the effectiveness of promising therapies. Clin Ped Emerg Med 5:41-53. © 2004 Elsevier Inc. All rights reserved. Controversies in the Management of Children with Bronchiolitis

Subgroup of Hospitalized Patients With Congenital Heart Disease , Chronic Lung Disease , or Immunosuppression

Erratum: Can a clinical decision rule identify young febrile infants with serious bacterial infection? (Pediatric Emergency Care (October 2002) (393))

Variation in Diagnosis and Treatment of Children with Ankle Growth Plate Tenderness and Negative Radiography

Objective The utility of the Gram stain for the preliminary diagnosis of urinary tract infections (UTI) in infants ≤ 60 days of age has not been clearly defined. Our purpose was to assess the test characteristics of the Gram stain in febrile infants and compare them to urinalysis (UA) and microscopy. Methods The study was prospective and observational. Urine samples were obtained from a consecutive sample of infants ≤ 60 days of age with a temperature of ≥ 38.0°C presenting to a pediatric emergency department during 2 consecutive winter seasons. Single pathogen growth of ≥ 104 cfu/mL from a catheterized specimen and ≥ 103 cfu/mL from a suprapubic specimen was considered positive. A positive Gram stain was defined as the identification of any organisms. Urinalysis was tested for the presence of nitrites and for leukocyte esterase (LE). Urine microscopy was analyzed for white blood cells per high power field (WBC/hpf). Results Fourteen of 246 patients were excluded; 11 because no Gram stain was completed. Of the remaining 232 patients, Gram stain had a sensitivity of 85.2% (95% CI 71.9–98.6%), a specificity of 99.0% (95% CI 97.7–100%), a likelihood ratio for a positive test of 87.3 (95% CI 21.8–349.9), and a likelihood ratio for a negative test of 0.15 (95% CI 0.06–0.37). There were 193 specimens for which a Gram stain and a complete UA and microscopy were completed and compared. Urine microscopy had a lower sensitivity and specificity than Gram stain for both ≥ 5 WBC/hpf and ≥ 10 WBC/hpf. In addition to the Gram stain, a dipstick negative for nitrites and LE had a low negative likelihood ratio (0.16), useful for decreasing the likelihood of a UTI. Conclusions The Gram stain has excellent test characteristics for the preliminary diagnosis of a UTI in febrile infants. Patient disposition and therapy will likely change if clinical protocols and guidelines use the Gram stain rather than urine microscopy for preliminary diagnosis of UTI in infants.

Test characteristics of the urine Gram stain in infants ≤ 60 days of age with fever

The test characteristics of rapid tests for respiratory syncytial virus (RSV) in infants may differ from older children secondary to a lower likelihood of previous illness with RSV. Our main goal was to establish the test characteristics of the RSV Abbott Testpack (TP) enzyme-linked immunoabsorbent assay (EIA) ® in febrile infants < 60 days of age. Our secondary goal was to determine the likelihood of RSV given a particular clinical syndrome and a negative or positive EIA. A prospective sample of infants with a temperature > 38.00C was evaluated during 2 successive RSV seasons. Conventional tissue and shell vial viral cultures were utilized as the reference standard. The RSV Abbott Testpack EJA® had a sensitivity of 75% (95% CI 60-90%), a specificity of 98% (95% CI 96-100%), a positive predictive value of 89% (95% CI 77-100%), a negative predictive value of 95% (95% CI 91-98%), a likelihood ratio for a positive test of 35.5 (95% CI 11.4-110.7), and a likelihood ratio for a negative test of 0.26 (95% CI 0.14-0.47). Even with a negative EIA, patients with lower and upper respiratory tract illness still had a 22.3% and 5.5% chance of harboring RSV, respectively. The RSV Abbott Testpack® is a useful diagnostic tool in the detection of RSV in febrile infants but has limitations. During months typically associated with RSV disease, a positive RSV TP indicates a high likelihood of illness, but clinicians should be wary of false negatives.

Test Characteristics of the Respiratory Syncytial Virus Enzyme-Linked Immunoabsorbent Assay in Febrile Infants?60 Days of Age

Objective The purpose of this study is to compare the cosmetic outcome of scalp wound closure with staples to traditional skin sutures. Methods A prospective, randomized trial was conducted using a convenience sample of children (aged 1–16 y) with simple scalp lacerations admitted to the pediatric emergency department. After parental consent was obtained, patients were randomly assigned to either a stapling or suturing procedure. A trained attending physician completed the procedure following a standard protocol. Based on previously published data, a sample size of 18 patients per group was calculated to give 85% power to detect a 10% difference on a visual analogue scale (VAS) score (two-sided alpha 0.05). Initial outcome of wound healing at 7 to 10 days and final cosmetic outcome after 6 to 18 months were estimated using a VAS. Cosmetic outcome was assessed by a physician blinded to the procedure. Data were analyzed using SPSS (Version 8.02; SPSS Inc., Chicago, IL). The VAS scores for the two treatment groups were compared using the two-tailed Student t test. Analysis of age, race, mode of injury, time interval, and size of the wound were performed to estimate the strength of the association of VAS score with the treatment, adjusted for the covariates. Results A total of 42 patients were enrolled. Of the 42, 38 (90.5%) finished the initial follow-up and 31 of those 38 (81.6%) finished the final follow-up. There were no significant demographic differences between groups at recruitment and first follow-up. Among those patients who completed the final follow-up, 15 underwent stapling, and 16 underwent suturing. There were no significant demographic or baseline differences between the groups. Procedure time was significantly lower in the stapling group (P = 0.001). Final follow-up evaluations were completed in 12 ± 4 months. The mean VAS scores at first and final follow-up were 78.75 ± 16.16 and 96.31 ± 8.06 for the suturing group and 86.67 ± 9.76 and 97 ± 7.02 for the stapling group (P = 0.17). There remained no significant difference in the final follow-up VAS score between groups when adjusted for covariates. Conclusion Stapling appears to be a fast and cosmetically acceptable alternative to suturing for simple scalp lacerations.

Cosmetic outcome of scalp wound closure with staples in the pediatric emergency department: A prospective, randomized trial

The purpose of this study was to determine the possible causes, clinical findings, and associated complications of pneumomediastinum in children. Medical records fromJanuary 1985 to December 1994 were retrospectively reviewed at Children's Hospital Medical Center of Akron using International Classification of Diseases, ninth revision, codes to identify cases of pneumomediastinum. The medical causes, nontraumatic and noniatrogenic, of pneumomediastinum were studied; intubated or trauma patients and patients having undergone procedures were excluded. Neonates were also excluded. Twenty-nine cases of pneumomediastinum were identified. Two patients (7%) had recurrent pneumomediastinum. Only the first episode of pneumomediastinum was included in the data analysis. Twenty males (69%) and nine females (31%) were affected. The most common medical causes of pneumomediastinum were asthma exacerbations (17/59%) and infections (8/28%). Over the 10-year period, the prevalence of pneumomediastinum in children with asthma exacerbations was 0.2% (21/10,472); 1% (1/126) in children with airway foreign bodies and 0.2% (1/351) in children with esophageal foreign bodies. The most common signs and symptoms were subcutaneous emphysema (22/76%), sore throat or neck pain (11/38%), and Hamman's crunch (3/10%). The most common complication was pneumothorax with small pneumothoraces in 2 patients (7%) and a tension pneumothorax in 1 asthmatic with recurrent pneumomediastinum. Patients without sore throat or neck pain and patients admitted to the intensive care unit had greater hospital lengths of stay. Pneumomediastinum appears to be uncommon in children. The most common medical causes were asthma and infections. The most common signs and symptoms were subcutaneous emphysema, sore throat or neck pain, and Hamman's crunch. The most common complication was pneumothorax. The clinical significance of pneumomediastinum is its cause and association with significant complications.

As well as describing our pediatric BB and pellet gun injuries and the circumstances surrounding these injuries, we also evaluated parental perceptions of the dangers of BB and pellet guns. A convenience sample of three groups of parents and their children presenting to a Midwest, urban, children's hospital emergency department was prospectively enrolled. The three groups of parents included the injured group, which consisted of the parents whose children had been injured by BB or pellet guns; the gun group, which consisted of the parents who allowed their children to possess BB or pellet guns but had not sustained injury from these guns; and the no gun group, which consisted of the parents who did not allow their children to have these guns. All parents completed a survey concerning their attitudes toward BB and pellet guns. Twenty-eight parents completed questionnaires in each of the three groups. Most BB and pellet gun injuries occurred in adolescent males at home without adult supervision and were inflicted by a friend or by themselves. The injured group and the no gun group viewed BB and pellet guns as significantly more dangerous than the gun group. Parents who allow their children to have BB or pellet guns appear to misperceive their potential for injury by allowing their children to use these guns in an unsafe manner. Clinicians must educate parents about the significant potential for injury of nonpowdered guns.

Background To avoid potential contamination, it is recommended that the first few drops of urine be discarded when obtaining a catheterized urine sample from a child being evaluated for a urinary tract infection (UTI). The existing evidence to make such a recommendation is scant. Our goal, therefore, was to determine whether the urinalysis, Gram stain, and culture results were significantly different from the initial and later urine samples collected from catheterized children. Methods A prospective diagnostic discrimination between early and later urine samples was conducted on a convenience sample of pediatric patients being evaluated for a UTI in an urban emergency department. Results of the urinalysis, Gram stain, and quantitative culture were compared between the early and later stream urine samples. Results Data from 86 children were analyzed. Four of 80 patients had a false identification of low colony count bacteruria from the early but not from the later stream. For patients with negative cultures, the early stream was also more likely to falsely identify ≥ 5 wbc/hpf (P< 0.01) or bacteruria (P< 0.05) on urinalysis than the later stream. Conclusions There is a small but potentially meaningful contamination of the early stream urine compared with the later stream in young children catheterized to evaluate for a urinary tract infection.

A comparison of the initial to the later stream urine in children catheterized to evaluate for a urinary tract infection

Likelihood ratios when the results of diagnostic tests are continuous variables.

Objective To examine the presentation, course, and outcome of pneumococcal bacteremia in children Infected with human immunodeficiency virus (HIV). Methods A retrospective series of HTV-infected children less than 18 years of age with Streptococcus pneumoniae bacteremia from four urban, tertiary care hospitals was evaluated. The main outcome measures included persistent bacteremia, the development of a focal infection, and death. Results Seventy-two episodes of pneumococcal bacteremia were identified in 59 patients. Fifty-four first episodes were included; 26/54 were occult. Mean temperature was 39.8°C. In patients with bacteremia, white blood cells (WBCs) ≥ 15,000 and ≥ 10,000 had sensitivities of 40% and 75%, respectively. At the time of bacteremia, age >3 years old was associated with a lower mean WBC count compared with episodes occurring in patients <3 years old (11.2 vs 16.1, P < 0.05). Patients with occult bacteremia who were discharged with antibiotics (12 i.m., 7 p.o.) were less likely than patients without antibiotic treatment to have persistent bacteremia at a return visit within 72 hours (0/19 vs 2/5, P < 0.05). No patient with occult bacteremia died, progressed to clinical meningitis, or had other sequelae. Two of fifty-four patients died as a result of their first episode of invasive pneumococcal disease. Both patients who died had meningitis and appeared ill on initial presentation. Conclusions Neither a WBC count ≥ 15,000 nor ≥ 10,000 is a sensitive indicator of pneumococcal bacteremia in HTV-infected children. Empiric antibiotics are useful to decrease the risk of persistent bacteremia. Children infected with HIV who have occult pneumococcal bacteremia appear to do well with appropriate antibiotics. Patients who are afebrile and well appearing on revaluation may be safely treated as outpatients.

Streptococcus pneumoniae bacteremia in children infected with HIV: Presentation, course, and outcome

DECREASING FALSE POSITIVE URINE RESULTS: THE UTILITY OF A MIDSTREAM CATHETERIZED SPECIMEN

Idiopathic, bilateral pneumothorax: case report in a young child.

PNEUMOCOCCAL BACTEREMIA IN HIV-INFECTED CHILDREN: A FAVORABLE COURSE AND OUTCOME

Three waveguide structures with different properties have been analysed using the effective index method, the finite difference method and a function fitting method. The effective index method is quick and easy to use and gives reasonable accuracy for two of the structures, and good accuracy for the third. Using the finite difference method very good accuracy can be attained for all structures; however, the level of accuracy is a function of mesh size and so of computer time.

A number of different methods of calculating the coupling efficiency between a semiconductor waveguide and an optical fibre have been studied. The limitations to the simplest methods have been identified. Practical designs of waveguide have been analysed, and a structure with a coupling efficiency of 0.6 dB has been discussed.

Semiconductor Waveguides: Analysis Of Coupling Between Rib Waveguides And Optical Fibres

Optical propagation in semiconductor waveguides has been analysed in three ways: the semi-analytic `effective index' method and two numerical methods based on variational techniques. Comparisons have been made using three semiconductor waveguide structures, and some fundamental limitations to accuracy have been identified. The techniques have also been used to calculate the transfer length for directional couplers.

Semiconductor waveguides: analysis of optical propagation in single rib structures and directional couplers

A Monte Carlo type simulation of electron interaction in a shaped electron beam lithography system has been developed. The simulation has been used to model a shaped beam system using Kohler illumination, and shows correct imaging when electron interaction is neglected. The loss of resolution due to interaction is demonstrated, and it is proposed that this technique may be used for the quantitive assessment of the effects on interaction in shaped beam systems.

Monte Carlo modeling of current distribution in shaped electron beams

Disk scrubbing is a background process to fix read errors by reading the disks. However, scrubbing the entire storage array can significantly increase the system load and degrade system performance when there is high incoming IO. Deciding "which disk to scrub" complemented with "when to scrub" can significantly improve the data centre's overall reliability and power saving. We present a solution on an open-source SMART dataset that performs selective scrubbing and designs a scrub frequency based on the scrub cycle. The method leverages an algorithmic randomness framework to quantify the health of the concerned drives and ranks them for selective scrubbing.

Proceedings of the 15th ACM International Conference on Systems and Storage

Substantial data support a temporal difference (TD) model of dopamine (DA) neuron activity in which the cells provide a global error signal for reinforcement learning. However, in certain circumstances, DA activity seems anomalous under the TD model, responding to non-rewarding stimuli. We address these anomalies by suggesting that DA cells multiplex information about reward bonuses, including Sutton's exploration bonuses and Ng et al's non-distorting shaping bonuses. We interpret this additional role for DA in terms of the unconditional attentional and psychomotor effects of dopamine, having the computational role of guiding exploration. Disciplines Applied Statistics | Biostatistics This journal article is available at ScholarlyCommons: http://repository.upenn.edu/statistics_papers/472

– Markov decision problems – Optimization of long term return – Interaction between an agent and its environment Dynamic programming as a formal solution – Policy iteration – Value iteration Temporal difference methods as a practical solution – Actor-critic learning – Q-learning Extensions to temporal difference – Model-based methods – TD and eligibility traces – Representation and neural nets – Gradient-based methods Formalizing learning in the brain Examples – Checkers 1 – Backgammon – Robots – Finance Summary and future directions Processed using L A T E X2e 2 Glossary Markov chain a model for a random process that evolves over time such that the states (like locations in a maze) occupied in the future are independent of the states in the past given the current state. Markov decision problem (MDP) a model for a controlled random process in which an agent's choice of action determines the probabilities of transitions of a Markov chain and lead to rewards (or costs) that need to be maximised (or minimised). policy a deterministic or stochastic scheme for choosing an action at every state or location. reward an immediate, possibly stochastic, payoff that results from performing an action in a state. In an MDP, the immediate reward depends on the current state and action only. The agent's aim is to optimise a sum or average of (possibly discounted) future rewards. value function a function defined over states, which gives an estimate of the total (possibly discounted) reward expected in the future, starting from each state, and following a particular policy. discounting if rewards received in the far future are worth less than rewards received sooner, they are described as being discounted. Humans and animals appear to discount future rewards hyperbolically; exponential discounting is common in engineering and finance. dynamic programming a collection of calculation techniques (notably policy and value iteration) for finding a policy that maximises reward or minimises costs. temporal difference prediction error a measure of the inconsistency between estimates of the value function at two successive states. This prediction error can be used to improve the predictions and also to choose good actions. Reinforcement learning is the study of how animals and artificial systems can learn to optimize their behavior in the face of rewards and punishments. Reinforcement learning algorithms have been developed that are closely related to methods of dynamic programming, which is a general approach to optimal control. Reinforcement learning …

Encyclopedia of Cognitive Science , in press Reinforcement Learning

The formation and modification of connections between nerve cells is of critical importance in understanding the complex and robust computations of the nervous system. Experimental neuroscience provides large quantities of data on the scale of neurons, synapses and molecules as well as on the larger scale of regional brain activity and behaviour. Mathematical models have an important role in formalising the key rules of development and learning that tie together these levels. A wide variety of mathematical and computational formalisms and techniques were discussed. Although the application of the ideas and methods is more general, some particular neurobiological issues formed the context of the modelling, including: • the dynamics of how neurons are assembled from proteins and how they follow very noisy molecular gradients to find their target regions; • the origin of topographic mappings of neurons in one structure (e.g. the retina) to another (e.g. the optic tectum) by molecular gradient matching; • how the brain can maintain stable memories in the face of constantly changing the representations; • how cells come to be laid out in semi-regular mosaics in structures such as the retina; • the role of neuronal activity in self-organisation of neuronal connectivity; and • how the neurotransmitter dopamine affects learning by gating the plasticity of synapses.

Report on ICMSWorkshop on Mathematical models of development and learning in the nervous system Edinburgh 21 & 22 July 2006 Scientific organisers

In real-world statistical inference problems, such as the diagnosis of diseases from the results of medical tests and procedures, there are systematic observation biases as to which test results are available. Ignoring these biases leads to catastrophically poor inference. We have previously shown that pre-trained recognition networks are one of the statistically and computationally best ways of performing inference in the largest scale statistical medical diagnosis belief network (QMRDT). In this paper, we show how to use a gating process to integrate the outputs of a library of recognition networks, each trained on a different observation bias. The resulting network performs accurate inference even for previously unseen biases.

Applications Preference : Oral Observation Biases in Diagnostic Inference

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小鈍的頭部外傷を有する小児のための予測ルールを実装するための多施設試験のための遠隔臨床意思決定支援サービスの利用【Powered by NICT】

One character in Cortazar's novel (Persio) truly believes in cosmic rhythm. This belief is characteristic of a magical view of the universe central to 1960s (proto-‘New Age’) counterculture. The other characters in Los Premios, like the implied narrator, reject Persio's essentialism; they dismiss the notion that there is really any rhythm common to art, humanity, and the universe. However, there are key points in the narrative, inspired by falling in love and by works of art, at which their world does appear patterned by just such a rhythm, a ‘swing cosmico’. The novel itself turns out to depend on the intermittent conviction of this rhythm, not objectively embedded in anything, but always seen, living, and dying in time; the price of art is the acceptance of this rhythmed mortality.

OBJETIVO: Evaluar el efecto de la administración de antibióticos antes de la punción lumbar sobre los perfiles celular y bioquímico de LCR en niños con meningitis bacteriana. MÉTODOS: Revisamos las historias clínicas de todos los niños (un mes a 18 años de edad) con meningitis bacteriana que se presentaron en 20 servicios de urgencias pediátricas entre 2001 y 2004. La meningitis bacteriana se definió por un cultivo positivo de LCR para un patógeno bacteriano o pleocitosis en LCR (recuento de leucocitos en LCR 10 células/ mm3) con un hemocultivo y/o prueba de aglutinación del látex en LCR positivos. Una meningitis bacteriana probable se definió por una tinción de Gram positiva en LCR con hemocultivo y cultivo bacteriano de LCR negativos. El pretratamiento con antibióticos se definió como cualquier antibiótico administrado en un plazo de 72 h de la realización de la punción lumbar. Efectuamos un análisis de regresión lineal multivariable para determinar la relación entre el pretratamiento y los parámetros del LCR. RESULTADOS: Identificamos a 231 pacientes con meningitis bacteriana y a otros 14 con una probable meningitis bacteriana. De estos 245, 85 (35%) habían recibido pretratamiento antibiótico. Después de un ajuste para la edad del paciente, duración y gravedad de la enfermedad en el momento de la presentación, al igual que el patógeno bacteriano, la duración más prolongada del pretratamiento con antibióticos no se asoció significativamente con el recuento de leucocitos, recuento absoluto de neutrófilos (RAN) o tasa de positividad de la tinción de Gram, analizados en LCR. No obstante, el pretratamiento con antibióticos se asoció significativamente con una mayor concentración de glucosa y un nivel más bajo de proteínas en LCR. Aunque estos efectos se hicieron evidentes más temprano, cuando los comparamos con pacientes no pretratados o pretratados durante < 12 h, en aquellos con 12 h de pretratamiento se detectó una concentración mediana significativamente mayor de glucosa (48 mg/dl comparado con 29 mg/dl; p = 0,001) y valores medianos Efecto del pretratamiento con antibióticos sobre el perfil celular y bioquímico del líquido cefalorraquídeo de niños con meningitis bacteriana

Efecto del pretratamiento con antibióticos sobre el perfil celular y bioquímico del líquido cefalorraquídeo de niños con meningitis bacteriana

Riesgo de enfermedad intracraneal con necesidad de intervención urgente después de una primera convulsión febril compleja en el niño

Model-based and model-free reinforcement learning: the experiments

Vigour in the face of fluctuating rates of reward: An experimental test

Approaching avoidance: asymmetries in reward and punishment processing

Temporally distributed information gets optimally combined by change-based information processing

The methods of temporal di erences (Samuel, 1959; Sutton 1984, 1988) allow agents to learn accurate predictions about stationary stochastic future outcomes. The learning is e ectively stochastic approximation based on samples extracted from the process generating the agent's future. Sutton (1988) proved that for a special case of temporal di erences, the expected values of the predictions converge to their correct values, as larger samples are taken, and Dayan (1992) extended his proof to the general case. This paper proves the stronger result that the predictions of a slightly modi ed form of temporal di erence learning converge with probability one, and shows how to quantify the rate of convergence.

Male depression is an attempt to extend the definition of depression to address an atypical cluster of symptoms that have been associated with suicide completion in community-dwelling populations. These include externalizing behaviour, avoidance, emotional suppression, irritability, substance misuse, and risk-seeking behaviour. Temporal discounting is a measure of economic impulsivity and a possible transdiagnostic neurocognitive domain that plays an essential role in everyday decision-making. Previous studies have found mixed results relating economic impulsivity to depression. We hypothesized that this divergence could be attributed to the heterogeneity of depression and contrasted temporal discounting between general ICD-10 depression and the specific, and possibly more impulsive male depression. We administered a temporal discounting task to 170 in-ward psychiatric patients and 176 healthy controls (HC). All patients fulfilled the ICD-10 criteria for moderate to severe depression. The patients were separated into a male-depressed group (MD) and a general major depression group (MDD) using median split of the Male Depression Risk Score (MDRS-22). HC had subthreshold scores for depression and had no neuropsychiatric history. We used the Bayesian information criterion (BIC) to compare 3 models of delay discounting. All models were based on the hyperbolic discounting model Q(R,D,k)=R/(1+k*D) where R =reward, k=discounting rate, and D=delay, comparing the subjective value of the immediate option Qi=Q(Ri,0,k) against the delayed option Qd=Q(Rd,D,k). Models differed in their treatment of noise in generating the probability pi of making the impulsive choice of the immediate option (with σ(z) = 1/(1 + exp(−z))): (1) preference-temperature model (k, β): pi=σ(β(Qi – Qd)) (2) preference-uncertainty model (μ, σ): draw log ks ~N(μ, σ): if Qi > Q(Rd,D, ks), pi=1; otherwise pi=0 (3) trembling-hand model (k, β, lapse): λ = (3/56)* σ(lapse)+1e-4 pi=(1–2λ(σ(β(Qi – Qd))+λ The preference-temperature model yielded the best fit (BIC(1)=3.817, BIC(2)=3.893, BIC(3)=7.001). There was no significant group difference in the model-specific parameters: discount rate k and inverse temperature β. There was a correlation between choosing the immediate reward and MDRS-22 (r=0.234, p<0.001), as well as with Beck’s Depression Inventory (BDI-II) (r=0.191, p<0.001), but no significant group differences (ANOVA: F=0.454, p=0.501). We could not find any model-based differences between the three groups. However, model- agnostic results suggested that male depressiveness, but also ICD-10 depressiveness, were associated with more impulsive choices. A noteworthy limitation was a strong correlation between BDI-II and MDRS-22 in our sample.

Çocuklarda minör künt kafa travmasının değerlendirme ve tedavisinde çelişkiler

To survive, an animal must use sensory events to predict the presence of mates, food, danger, and various other stimuli that are important for its survival and procreation. Although reliable prediction is critical, it is not understood how such prediction is carried out by nervous systems. We present a model which utilizes diffuse neuromodulatory systems to implement a predictive version of a Hebbian rule, and embed this rule in a feasible neural architecture. The predictive model suggests a unified way in which neuromodulatory influences are used to bias actions and control learning. When required to forage in a stochastic environment, the model captures the strategies seen in the behavior of bees and a number of other animals. It further suggests that predictive rules for synaptic plasticity offer a simple framework which is nevertheless more powerful than correlational accounts.

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Les rythmes de vie des sportifs de haut niveau : le défi de la performance face à la contrainte de temps Fabrice Burlot, Fanny Le Mancq, Brice Lefevre, Patrick Mignon, Anne-Claire Macquet, Rémy Richard, Charles-Éric Adam, Mathilde Julla-Marcy

Les rythmes de vie des sportifs de haut niveau : le défi de la performance face à la contrainte de temps

Dans les coulisses des competitions handisports de haut-niveau se deroule une epreuve inaccessible au regard du public : le processus de classification. L’expertise, imperative pour attribuer une classe a chaque sportif se materialise par une serie d’operations effectuees aussi bien par les classificateurs que par les principaux protagonistes : observer, mesurer, quantifier, qualifier, comparer, protester, deliberer… Cette quete d’objectivite s’organise dans plusieurs arenes (vestiaires, Bureau Executif du Comite International Paralympique, Commission de Classification, laboratoires). Mais l’impression de stabilite du dispositif contraste avec les temoignages et les observations visant les protocoles d’examen des corps. Les dirigeants cherchent donc a entretenir l’interet de la competition pour les pratiquants et les spectateurs. La complexite du processus apparait comme un polyptyque evolutif dans lequel les acteurs tentent de mettre de l’ordre et dont le sociologue s’attache a rassembler les pieces eparpillees, tel un commissaire d’exposition.La recherche du langage sociologique le plus approprie permet d’analyser l’adoption, l’entretien, ou l’abandon de la croyance dans l’efficacite du dispositif dont l’enjeu final est la credibilite des Jeux Paralympiques. Comment est rendue possible et acceptable la mise en equivalence de sportifs aux corps uniques ? Comment les acteurs œuvrent a transformer ou a maintenir en l’etat un dispositif qui separe des individus en meme temps qu’il les regroupe? L’enquete permet de comprendre les conditions d’existence du handisport et du sport adapte de competition et contribue a la reflexion sur les frontieres entre les individus.

Le processus de classification en handisport : sociologie d’un polyptyque évolutif

La conducta de las actividades de iniciacion. - El objeto del estudio es describir algunas formas de practicas de iniciacion tales cuales se encuentran actualmente. Los autores desarrollan las concepciones metodo- logicas de este estudio, recuerdan el contenido de los textos oficiales sobre las actividades de iniciacion, y describen algunos ejemplos concretos.

Le soixantième anniversaire du rétablissement de la Faculté de Droit de l'université de Nancy (1864-1924)

Pour la nouvelle année 1915. Aux trois ordres d'enseignement dans les départements lorrains

Functional ultrasound imaging (fUS) is an emerging imaging technique that indirectly measures neural activity via changes in blood volume. To date it has not been used to image chronically during cognitive tasks in freely moving animals. Performing those experiments faces a number of exceptional challenges: performing large durable craniotomies with chronic implants, designing behavioural experiments matching the hemodynamic timescale, stabilizing the ultrasound probe during freely moving behavior, accurately assessing motion artifacts and validating that the animal can perform cognitive tasks at high performance while tethered. In this study, we provide validated solutions for those technical challenges. In addition, we present standardized step-by-step reproducible protocols, procedures and data processing pipelines that open up the opportunity to perform fUS in freely moving rodents performing complex cognitive tasks. Moreover, we present proof-of-concept analysis of brain dynamics during a decision making task. We obtain stable recordings from which we can robustly decode task variables from fUS data over multiple months. Moreover, we find that brain wide imaging through hemodynamic response is nonlinearly related to cognitive variables, such as task difficulty, as compared to sensory responses previously explored.

Chronic brain functional ultrasound imaging in freely moving rodents performing cognitive tasks

While recent advancements in artificial intelligence (AI) language models demonstrate cutting-edge performance when working with English texts, equivalent models do not exist in other languages or do not reach the same performance level. This undesired effect of AI advancements increases the gap between access to new technology from different populations across the world. This unsought bias mainly discriminates against individuals whose English skills are less developed, e.g., non-English speakers children. Following significant advancements in AI research in recent years, OpenAI has recently presented DALL-E: a powerful tool for creating images based on English text prompts. While DALL-E is a promising tool for many applications, its decreased performance when given input in a different language, limits its audience and deepens the gap between populations. An additional limitation of the current DALL-E model is that it only allows for the creation of a few images in response to a given input prompt, rather than a series of consecutive coherent frames that tell a story or describe a process that changes over time. Here, we present an easy-to-use automatic DALL-E storytelling framework that leverages the existing DALL-E model to enable fast and coherent visualizations of non-English songs and stories, pushing the limit of the one-step-at-a-time option DALL-E currently offers. We show that our framework is able to effectively visualize stories from non-English texts and portray the changes in the plot over time. It is also able to create a narrative and maintain interpretable changes in the description across frames. Additionally, our framework offers users the ability to specify constraints on the story elements, such as a specific location or context, and to maintain a consistent style throughout the visualization.

Cross-modality supervised image restoration enables nanoscale tracking of synaptic plasticity in living mice

Learning interpretable representations of neural dynamics at a population level is a crucial first step to understanding how observed neural activity relates to perception and behavior. Models of neural dynamics often focus on either low-dimensional projections of neural activity, or on learning dynamical systems that explicitly relate to the neural state over time. We discuss how these two approaches are interrelated by considering dynamical systems as representative of flows on a low-dimensional manifold. Building on this concept, we propose a new decomposed dynamical system model that represents complex non-stationary and nonlinear dynamics of time series data as a sparse combination of simpler, more interpretable components. Our model is trained through a dictionary learning procedure, where we leverage recent results in tracking sparse vectors over time. The decomposed nature of the dynamics is more expressive than previous switched approaches for a given number of parameters and enables modeling of overlapping and non-stationary dynamics. In both continuous-time and discrete-time instructional examples we demonstrate that our model can well approximate the original system, learn efficient representations, and capture smooth transitions between dynamical modes, focusing on intuitive low-dimensional non-stationary linear and nonlinear systems. Furthermore, we highlight our model's ability to efficiently capture and demix population dynamics generated from multiple independent subnetworks, a task that is computationally impractical for switched models. Finally, we apply our model to neural"full brain"recordings of C. elegans data, illustrating a diversity of dynamics that is obscured when classified into discrete states.

Decomposed Linear Dynamical Systems (dLDS) for learning the latent components of neural dynamics

Sequential and efficient neural-population coding of complex task information.

As acquiring bigger data becomes easier in experimental brain science, computational and statistical brain science must achieve similar advances to fully capitalize on these data. Tackling these problems will benefit from a more explicit and concerted effort to work together. Specifically, brain science can be further democratized by harnessing the power of community-driven tools, which both are built by and benefit from many different people with different backgrounds and expertise. This perspective can be applied across modalities and scales and enables collaborations across previously siloed communities. Expected final online publication date for the Annual Review of Neuroscience, Volume 43 is July 8, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Toward Community-Driven Big Open Brain Science: Open Big Data and Tools for Structure, Function, and Genetics.

Tracking algorithms such as the Kalman filter aim to improve inference performance by leveraging the temporal dynamics in streaming observations. However, the tracking regularizers are often based on the $\ell _p$-norm which cannot account for important geometrical relationships between neighboring signal elements. We propose a practical approach to using the earth mover's distance (EMD) via the earth mover's distance dynamic filtering (EMD-DF) algorithm for causally tracking time-varying sparse signals when there is a natural geometry to the coefficient space that should be respected (e.g., meaningful ordering). Specifically, this letter presents a new Beckmann formulation that dramatically reduces computational complexity, as well as an evaluation of the performance and complexity of the proposed approach in imaging and frequency tracking applications with real and simulated neurophysiology data.

Efficient Tracking of Sparse Signals via an Earth Mover's Distance Dynamics Regularizer

Tracking time-varying signals is an important task for practical systems working with large discretized domains. Under such settings, sparsity-based approaches improve tracking accuracy since typically few targets appear in the scene (i.e. few locations in the discretized space are occupied). Discretization introduces a unique challenge: the traditional $\ell_{p}$ -norm dynamic constraints produce significant errors when there is even a small spatial mismatch between the predicted and true state. To overcome this, we present a tracking algorithm leveraging concepts from optimal transport, namely utilizing the earth-movers distance (EMD) as a dynamic regularizer to the $\ell_{1}$ -regularized inference problem (i.e., LASSO [1], or BPDN [2]). We extend the problem formulation to complex valued signals and modify the optimization program to reduce the computational burden. We demonstrate the efficacy of our approach in imaging and frequency tracking applications.

Sparse Dynamic Filtering via Earth Mover's Distance Regularization

Theoretical understanding of deep learning is one of the most important tasks facing the statistics and machine learning communities. While deep neural networks (DNNs) originated as engineering methods and models of biological networks in neuroscience and psychology, they have quickly become a centerpiece of the machine learning toolbox. Unfortunately, DNN adoption powered by recent successes combined with the open-source nature of the machine learning community, has outpaced our theoretical understanding. We cannot reliably identify when and why DNNs will make mistakes. In some applications like text translation these mistakes may be comical and provide for fun fodder in research talks, a single error can be very costly in tasks like medical imaging. As we utilize DNNs in increasingly sensitive applications, a better understanding of their properties is thus imperative. Recent advances in DNN theory are numerous and include many different sources of intuition, such as learning theory, sparse signal analysis, physics, chemistry, and psychology. An interesting pattern begins to emerge in the breadth of possible interpretations. The seemingly limitless approaches are mostly constrained by the lens with which the mathematical operations are viewed. Ultimately, the interpretation of DNNs appears to mimic a type of Rorschach test --- a psychological test wherein subjects interpret a series of seemingly ambiguous ink-blots. Validation for DNN theory requires a convergence of the literature. We must distinguish between universal results that are invariant to the analysis perspective and those that are specific to a particular network configuration. Simultaneously we must deal with the fact that many standard statistical tools for quantifying generalization or empirically assessing important network features are difficult to apply to DNNs.

Interpreting Deep Learning: The Machine Learning Rorschach Test?

Neural networks have become a ubiquitous as cognitive models in neuroscience and as machine learning systems. Deep neural networks in particular are achieving near-human performance in many applications. More recently, recurrent neural networks (RNNs) are being increasingly utilized, both as standalone structures and as layers of deep networks. RNNs are especially interesting as cortical networks are recurrent, indicating that recurrent connections are important in human-level processing. Despite their growing use, theory on the computational properties of RNNs is sparse. As many applications hinge on RNNs accumulating information dynamically, the ability of RNNs to iteratively compress information into the network is particularly critical. We thus present here non-asymptotic bounds on the network’s short-term memory (STM; the number of inputs that can be compressed into and recovered from a network state). Previous bounds on a random RNN’s STM limit the number of recoverable inputs by the number of network nodes. We show that when the input sequences are sparse in a basis or the matrix inputs is low-rank, the number of network nodes needed to achieve an STM grows as the overall information rate. Thus RNNs can efficiently store information embedded in longer input streams, shedding light on their computational capabilities.

Short-term Sequence Memory: Compressive effects of Recurrent Network Dynamics

An important problem in statistical signal processing is understanding how to exploit signal structure in inference problems. In recent years, sparse signal models have enjoyed great success, achieving state-of-the-art performance in many applications. Some algorithms further improve performance by taking advantage of temporal dynamics for streams of observations. However, often the tracking regularizers used are based on the $\ell_p$-norm which does not take full advantage of the relationship between neighboring signal elements. In this work, we propose the use of the earth mover's distance (EMD) as an alternative tracking regularizer. We introduce the earth mover's distance dynamic filtering (EMD-DF) algorithm which includes two variants: one which uses the traditional EMD as a tracking regularizer in the $\ell_1$ sparse recovery problem for nonnegative signals, and a relaxation which allows for complex valued signals. Through experiments on simulated and real data, we conclude that EMD-DF can outperform current state-of-the-art sparse tracking algorithms.

Earth Mover's Distance as a Dynamics Regularizer for Sparse Signal Tracking

Tracking time-varying signals is an important part of many engineering systems. Recently, signal processing techniques have been developed to improve tracking performance when the signal of interest is known a-priori to be sparse. Leveraging sparsity, however, depends heavily on gridding the space, treating the signal as a collection of active or inactive pixels in an image, rather than traditional methods which track the continuous spatial coordinates. Using the dynamics constraint in this setting is challenging, as a model which approximately predicts target location may result in seemingly large errors, as measured by the ℓp-norm typically used in such algorithms. To take advantage of approximate spatial priors without introducing unnecessary penalties, we present a tracking algorithm using the earth-mover's distance (EMD) as an alternate dynamics regularization term. We note that while requiring a higher computational burden, the EMD can more effectively utilize target location prediction when the space is gridded.

2017 IEEE 7th International Workshop on Computational Advances in Multi-Sensor Adaptive Processing (CAMSAP)

Recursive neural networks (RNNs) are becoming an increasingly important part of the machine learning toolbox [1], [2], [3] in applications such as video [4], audio [5], EEG data [6]. These networks have been used as either stand-alone tools for training classifiers, or as in layers in conventional deep neural networks to expand their use to time-varying data [7], [5], [6]. Mathematically, RNNs are a state of M nodes x ∈ R that evolve as

Compression of multiple input streams into recursive neural networks

Accurate statistical models of neural spike responses can characterize the information carried by neural populations. But the limited samples of spike counts during recording usually result in model overfitting. Besides, current models assume spike counts to be Poisson-distributed, which ignores the fact that many neurons demonstrate over-dispersed spiking behaviour. Although the Negative Binomial Generalized Linear Model (NB-GLM) provides a powerful tool for modeling over-dispersed spike counts, the maximum likelihood-based standard NB-GLM leads to highly variable and inaccurate parameter estimates. Thus, we propose a hierarchical parametric empirical Bayes method to estimate the neural spike responses among neuronal population. Our method integrates both Generalized Linear Models (GLMs) and empirical Bayes theory, which aims to (1) improve the accuracy and reliability of parameter estimation, compared to the maximum likelihood-based method for NB-GLM and Poisson-GLM; (2) effectively capture the over-dispersion nature of spike counts from both simulated data and experimental data; and (3) provide insight into both neural interactions and spiking behaviours of the neuronal populations. We apply our approach to study both simulated data and experimental neural data. The estimation of simulation data indicates that the new framework can accurately predict mean spike counts simulated from different models and recover the connectivity weights among neural populations. The estimation based on retinal neurons demonstrate the proposed method outperforms both NB-GLM and Poisson-GLM in terms of the predictive log-likelihood of held-out data.1

Recurrent neural networks (RNNs) have drawn interest from machine learning researchers because of their effectiveness at preserving past inputs for time-varying data processing tasks. To understand the success and limitations of RNNs, it is critical that we advance our analysis of their fundamental memory properties. We focus on echo state networks (ESNs), which are RNNs with simple memoryless nodes and random connectivity. In most existing analyses, the short-term memory (STM) capacity results conclude that the ESN network size must scale linearly with the input size for unstructured inputs. The main contribution of this paper is to provide general results characterizing the STM capacity for linear ESNs with multidimensional input streams when the inputs have common low-dimensional structure: sparsity in a basis or significant statistical dependence between inputs. In both cases, we show that the number of nodes in the network must scale linearly with the information rate and poly-logarithmically with the ambient input dimension. The analysis relies on advanced applications of random matrix theory and results in explicit non-asymptotic bounds on the recovery error. Taken together, this analysis provides a significant step forward in our understanding of the STM properties in RNNs.

Distributed Sequence Memory of Multidimensional Inputs in Recurrent Networks

Despite the importance of sparsity signal models and the increasing prevalence of high-dimensional streaming data, there are relatively few algorithms for dynamic filtering of timevarying sparse signals. Of the existing algorithms, fewer still provide strong performance guarantees. This paper examines two algorithms for dynamic filtering of sparse signals that are based on efficient ℓ1 optimization methods. We first present an analysis for one simple algorithm (BPDN-DF) that works well when the system dynamics are known exactly. We then introduce a novel second algorithm (RWL1-DF) that is more computationally complex than BPDN-DF but performs better in practice, especially in the case where the system dynamics model is inaccurate. Robustness to model inaccuracy is achieved by using a hierarchical probabilistic data model and propagating higher-order statistics from the previous estimate (akin to Kalman filtering) in the sparse inference process. We demonstrate the properties of these algorithms on both simulated data as well as natural video sequences. Taken together, the algorithms presented in this paper represent the first strong performance analysis of dynamic filtering algorithms for time-varying sparse signals as well as state-of-the-art performance in this emerging application.

Dynamic Filtering of Time-Varying Sparse Signals via $\ell _1$ Minimization

Sparsity-based models have enabled significant advances in many image processing tasks. Hyperspectral imagery (HSI) in particular has benefited from these approaches due to the significant low-dimensional structure in both spatial and spectral dimensions. Specifically, previous work has shown that sparsity models can be used for spectral superresolution, where spectral signatures with HSI-level resolution are recovered from measurements with multispectral-level resolution (i.e., an order of magnitude fewer spectral bands). In this letter, we expand on those results by introducing a new inference approach known as reweighted l1 spatial filtering (RWL1-SF). RWL1-SF incorporates a more sophisticated signal model that allows for variations in the SNR at each pixel as well as spatial dependences between neighboring pixels. The results demonstrate that the proposed approach leverages signal structure beyond simple sparsity to achieve significant improvements in spectral superresolution.

Spectral Superresolution of Hyperspectral Imagery Using Reweighted $\ell_{1}$ Spatial Filtering

Hyperspectral imagery (HSI) is an important imaging modality for remote sensing applications in many fields, including oceanic and atmospheric sciences [1], agriculture [2], defense, and space exploration [3]. Despite the richer potential of HSI sensors for scientific studies and applications, engineering tradeoffs, such as memory and communication bandwidth constraints, typically favor multispectral (MSI) sensor designs. We outline here continuing work which utilizes the statistical structure of HSI in order to extrapolate HSI-resolution spectra from more limited multi-spectral measurements. Accurate spectral super-resolution can substantially extend the utility of current and legacy MSI sensors, as well as open up the engineering design space of future missions. Ideally, both high spatial and high spectral resolution can be obtained with a combination of heritage optical design and sparse signal processing. While previous works on this topic demonstrate success on resolving MSI data simulated by artificially blurring real HSI images [4, 5], we demonstrate the utility of our methods on resolving real MSI data and validating the results by comparing to HSI images of the same scene. Specifically, we take geographically co-located oceanic water-color images taken by the VIIRS MSI imager [6] and the HICO HSI imager [7] and demonstrate that the proposed methodology can extrapolate HICO-resolution spectra from the more limited VIIRS measurements. Our proposed methodology is based on recent advances in sparsity-based signal processing. Sparsity-based techniques seek to describe data via a parsimonious representation in a large ambient space. In particular, given a large dictionary of feature vectors, sparse methods attempt to recover the smallest number of these features which explain the observation. Sparsity-based signal processing has proven invaluable in obtaining state-of-the-art solution to many linear inverse problems [8], and recent work demonstrates the applicability of sparsity based methods to HSI data. In fact both spatial and spectral sparsity has been used in the HSI literature for spectral unmixing [9, 10], classification [11], spectral dictionary learning [12, 4], and spatial super-resolution [13].

Sparsity Based Spectral Super-Resolution and Applications to Ocean Water Color

The short term memory of randomly connected networks has been recently studied in order to better understand the computational and predictive power of such networks. In particular, random, linear, orthogonal networks have been explored extensively in the context a single input stream driving the network. The most recent results state that a stream of length N can be recovered from a network of size O(S log6 (N)) assuming that the input is S-sparse in some basis. Little work, however, addresses more complex networks where multiple input streams feed into the same network. In this paper we extend the results for recovering sparse input streams the multiple input streams feeding into the same network. We find that we can recover L input streams of length N with a network that has O(S log5 (LN)) nodes.

2014 IEEE Global Conference on Signal and Information Processing (GlobalSIP)

Causal inference of dynamically changing signals is a vital task in many applications, including real-time image processing and channel estimation. Over the past few years, many algorithms have been proposed to accomplish this task, but extremely few algorithms have any theoretical guarantees on stability, convergence or performance. In this work we use results from the sparsity-based signal processing literature to demonstrate some basic bounds for one particular algorithm: basis pursuit de-noising with dynamic filtering (BPDN-DF). We show for what parameter ranges the algorithm remains stable for, and provide some guarantees on the steady-state approximation error.

Many modern signal processing applications can be stated in terms of performing inference on sparse signals that have significant dependencies between those signals. Consider the task of recovering signals xn ∈ R from incomplete and noisy linear measurements yn = Φnxn + n, where Φn ∈ RM×N is the potentially timevarying measurement matrix, n is the measurement noise, and n ∈ K is an index (e.g., temporal or spatial). Many methods estimate each xn independently by assuming that xn is sparse in some dictionary (xn = Dan with a sparse). More recent methods have sought to leverage inter-signal dependencies through joint inference. For example, in some applications (e.g. recovery of video sequences or dynamic MRI) n ∈ K ⊂ Z represents a time index and we wish to recover ordered sparse signals with a known dynamics model

When bits meet brains: Locally competitive algorithms for sparse approximation

Cortical networks are hypothesized to rely on transient network activity to support short-term memory (STM). In this letter, we study the capacity of randomly connected recurrent linear networks for performing STM when the input signals are approximately sparse in some basis. We leverage results from compressed sensing to provide rigorous nonasymptotic recovery guarantees, quantifying the impact of the input sparsity level, the input sparsity basis, and the network characteristics on the system capacity. Our analysis demonstrates that network memory capacities can scale superlinearly with the number of nodes and in some situations can achieve STM capacities that are much larger than the network size. We provide perfect recovery guarantees for finite sequences and recovery bounds for infinite sequences. The latter analysis predicts that network STM systems may have an optimal recovery length that balances errors due to omission and recall mistakes. Furthermore, we show that the conditions yielding optimal STM capacity can be embodied in several network topologies, including networks with sparse or dense connectivities.

Short-Term Memory Capacity in Networks via the Restricted Isometry Property

Accurate estimation of undersampled time-varying signals improves as stronger signal models provide more information to aid the estimator. In class Kalman filter-type algorithms, dynamic models of signal evolution are highly leveraged but there is little exploitation of structure within a signal at a given time. In contrast, standard sparse approximation schemes (e.g., L1 minimization) utilize strong structural models for a single signal, but do not admit obvious ways to incorporate dynamic models for data streams. In this work we introduce a causal estimation algorithm to estimate time-varying sparse signals. This algorithm is based on a hierarchical probabilistic model that uses re-weighted L1 minimization as its core computation, and propagates second order statistics through time similar to classic Kalman filtering. The resulting algorithm achieves very good performance, and appears to be particularly robust to errors in the dynamic signal model.

2013 IEEE International Conference on Acoustics, Speech and Signal Processing

The sparse coding hypothesis has generated significant interest in the computational and theoretical neuroscience communities, but there remain open questions about the exact quantitative form of the sparsity penalty and the implementation of such a coding rule in neurally plausible architectures. The main contribution of this work is to show that a wide variety of sparsity-based probabilistic inference problems proposed in the signal processing and statistics literatures can be implemented exactly in the common network architecture known as the locally competitive algorithm (LCA). Among the cost functions we examine are approximate norms (), modified -norms, block- norms, and reweighted algorithms. Of particular interest is that we show significantly increased performance in reweighted algorithms by inferring all parameters jointly in a dynamical system rather than using an iterative approach native to digital computational architectures.

A Common Network Architecture Efficiently Implements a Variety of Sparsity-Based Inference Problems

Recursive estimation of dynamic signals with sparsity models via re-weighted L1 minimization

Adam S. Charles, Han Lun Yap, and Christopher J. Rozell Summary Understanding the memory capacity of neural circuits is vital to understanding the performance of tasks such as working memory. In particular, critical questions recently raised in the literature include the effects of network size, connectivity pattern and natural signal statistics on the ability of a neural circuit to encode a temporal memory in its transient dynamics. Recently, results using the tools of compressive sensing (CS) have indicated that the memory capacity of a linear neural circuit could exceed the number of neurons in the network when the temporal signals are sparse (i.e., having few non-zeros) [White et al., 2004, Ganguli and Sompolinsky, 2010]. In this work we perform a full CS analysis of the memory capacity of a neural circuit for general inputs that are sparse in a known basis (a useful model for many natural signals [Olshausen and Field, 1996]). Using a model similar to that proposed in [Ganguli and Sompolinsky, 2010], our results 1) provide signal recovery guarantees for the exact linear network dynamics with no approximations; 2) provide guarantees for every temporal sequences sparse in any basis (not average performance), where the memory capacity penalty associated with using a specific basis is well defined; and 3) quantify the dependence of the memory capacity on properties of the neural connectivity pattern. Our analyses (based on the restricted isometry property [Candès, 2006]) demonstrate that the memory capacity can far exceed the number of neurons in the circuit, and illustrate the magnitude of this excess in two distinct cases: 1) the perfect recovery of finite-length signals that are within the capacity of the circuit, and 2) the recovery error for signals that are beyond the capacity of the circuit (possibly infinitely long), with an exponential forgetting factor in the circuit. These results point to the existence of an optimal signal length (for a given network) where the joint recovery error due to un-recalled signal and recall errors is minimized. Additional information Figure 1 shows numerical simulations of memory sequence recovery error from neural circuits.

Short-Term Memory Capacity in Recurrent Networks via Compressed Sensing

Signal estimation from incomplete observations improves as more signal structure can be exploited in the inference process. Classic algorithms (e.g., Kalman filtering) have exploited strong dynamic structure for time-varying signals while modern work has often focused on exploiting low-dimensional signal structure (e.g., sparsity in a basis) for static signals. Few algorithms attempt to merge both static and dynamic structure to improve estimation for time-varying sparse signals (e.g., video). In this work we present a re-weighted l_1 dynamic filtering scheme for causal signal estimation that utilizes both sparsity assumptions and dynamic structure. Our algorithm leverages work on hierarchical Laplacian scale mixture models to create a dynamic probabilistic model. The resulting algorithm incorporates both dynamic and sparsity priors in the estimation procedure in a robust and efficient algorithm. We demonstrate the results in simulation using both synthetic and natural data.

Re-Weighted l_1 Dynamic Filtering for Time-Varying Sparse Signal Estimation

Compressed sensing is an important application in signal and image processing which requires solving nonlinear optimization problems. A Hopfield-Network-like analog system is proposed as a solution, using the locally competitive algorithm (LCA) to solve an overcomplete l1 sparse approximation problem. A scalable system architecture using sub-threshold currents is described, including vector matrix multipliers (VMMs) and a nonlinear thresholder. A 4 × 6 nonlinear system is implemented on the RASP 2.9v chip, a field programmable analog array with directly programmable floating gate elements, allowing highly accurate VMMs. The circuit successfully reproduced the outputs of a digital optimization program, converging to within 4.8% rms, and an objective value only 1.3% higher on average. The active circuit consumed 29 μA of current at 2.4 V, and converges on solutions in 240 μs. A smaller 2 × 3 system is also implemented. Extrapolating the scaling trends to a N=1000 node system, the analog LCA compares favorably with state-of-the-art digital solutions, using a small fraction of the power to arrive at solutions ten times faster. Finally, we provide simulations of large scale systems to show the behavior of the system scaled to nontrivial problem sizes.

IEEE Journal on Emerging and Selected Topics in Circuits and Systems

Low Power Sparse Approximation on Reconfigurable Analog Hardware

The ability of networked systems (including artificial or biological neuronal networks) to perform complex data processing tasks relies in part on their ability to encode signals from the recent past in the current network state. Here we use Compressed Sensing tools to study the ability of a particular network architecture (Echo State Networks) to stably store long input sequences. In particular, we show that such networks satisfy the Restricted Isometry Property when the input sequences are compressible in certain bases and when the number of nodes scale linearly with the sparsity of the input sequence and logarithmically with its dimension. Thus, the memory capacity of these networks depends on the input sequence statistics, and can (sometimes greatly) exceed the number of nodes in the network. Furthermore, input sequences can be robustly recovered from the instantaneous network state using a tractable optimization program (also implementable in a network architecture).

The Restricted Isometry Property for Echo State Networks with applications to sequence memory capacity

The spectral features in hyperspectral imagery (HSI) contain significant structure that, if properly characterized, could enable more efficient data acquisition and improved data analysis. Because most pixels contain reflectances of just a few materials, we propose that a sparse coding model is well-matched to HSI data. Sparsity models consider each pixel as a combination of just a few elements from a larger dictionary, and this approach has proven effective in a wide range of applications. Furthermore, previous work has shown that optimal sparse coding dictionaries can be learned from a dataset with no other a priori information (in contrast to many HSI “endmember” discovery algorithms that assume the presence of pure spectra or side information). We modified an existing unsupervised learning approach and applied it to HSI data (with significant ground truth labeling) to learn an optimal sparse coding dictionary. Using this learned dictionary, we demonstrate three main findings: 1) the sparse coding model learns spectral signatures of materials in the scene and locally approximates nonlinear manifolds for individual materials; 2) this learned dictionary can be used to infer HSI-resolution data with very high accuracy from simulated imagery collected at multispectral-level resolution, and 3) this learned dictionary improves the performance of a supervised classification algorithm, both in terms of the classifier complexity and generalization from very small training sets.

In this work we address the problem of state estimation in dynamical systems using recent developments in compressive sensing and sparse approximation. We formulate the traditional Kalman filter as a one-step update optimization procedure which leads us to a more unified framework, useful for incorporating sparsity constraints. We introduce three combinations of two sparsity conditions (sparsity in the state and sparsity in the innovations) and write recursive optimization programs to estimate the state for each model. This paper is meant as an overview of different methods for incorporating sparsity into the dynamic model, a presentation of algorithms that unify the support and coefficient estimation, and a demonstration that these suboptimal schemes can actually show some performance improvements (either in estimation error or convergence time) over standard optimal methods that use an impoverished model.

Recent research has shown that performance in signal processing tasks can often be significantly improved by using signal models based on sparse representations, where a signal is approximated using a small number of elements from a fixed dictionary. Unfortunately, inference in this model involves solving non-smooth optimization problems that are computationally expensive. While significant efforts have focused on developing digital algorithms specifically for this problem, these algorithms are inappropriate for many applications because of the time and power requirements necessary to solve large optimization problems. Based on recent work in computational neuroscience, we explore the potential advantages of continuous time dynamical systems for solving sparse approximation problems if they were implemented in analog VLSI. Specifically, in the simulated task of recovering synthetic and MRI data acquired via compressive sensing techniques, we show that these systems can potentially perform recovery at time scales of 10-20{\mu}s, supporting datarates of 50-100 kHz (orders of magnitude faster that digital algorithms). Furthermore, we show analytically that a wide range of sparse approximation problems can be solved in the same basic architecture, including approximate $\ell^p$ norms, modified $\ell^1$ norms, re-weighted $\ell^1$ and $\ell^2$, the block $\ell^1$ norm and classic Tikhonov regularization.

Analog Sparse Approximation with Applications to Compressed Sensing

Compressive sensing results have allowed accurate reconstruction of highly undersampled signals by leveraging known signal structure [1]. Recently, there has been a push to extend these results into an area of great interest for a large number of fields: the estimation of dynamically changing signals [2]–[5]. If known, or even partially known dynamics are transforming a state, then past observations should be able to be incorporated into the estimation process of a state at any given time in order to increase the accuracy of the estimation. Typically a dynamical state xn ∈ R is assumed to evolve with some approximately known dynamics fn(·) as

A Hierarchical Re-weighted-l1 Approach for Dynamic Sparse Signal Estimation

This paper presents an algorithm for an ℓ1-regularized Kalman filter. Given observations of a discrete-time linear dynamical system with sparse errors in the state evolution, we estimate the state sequence by solving an optimization algorithm that balances fidelity to the measurements (measured by the standard ℓ2 norm) against the sparsity of the innovations (measured using the ℓ1 norm). We also derive an efficient algorithm for updating the estimate as the system evolves. This dynamic updating algorithm uses a homotopy scheme that tracks the solution as new measurements are slowly worked into the system and old measurements are slowly removed. The effective cost of adding new measurements is a number of low-rank updates to the solution of a linear system of equations that is roughly proportional to the joint sparsity of all the innovations in the time interval of interest.

2011 IEEE International Conference on Acoustics, Speech and Signal Processing (ICASSP)

Estimation and dynamic updating of time-varying signals with sparse variations

While current inference methods can decompose audio signals, they require the entire signal upfront and are therefore ill-suited for real-time applications requiring causal processing. We propose a neurally-inspired, causal, sparse inference scheme based on the Locally Competitive Algorithm (LCA) over a temporal-spectral neighborhood. We demonstrate that this causal inference scheme can achieve lower sparsity levels and better signal fidelity than current filter and threshold approaches. Additionally, for some regimes, the sparsity level approaches those of Matching Pursuit while still maintaining signal integrity.

2011 Digital Signal Processing and Signal Processing Education Meeting (DSP/SPE)

A causal Locally Competitive Algorithm for the sparse decomposition of audio signals

The growing use of hyperspectral imagery lead us to seek automated algorithms for extracting useful information about the scene. Recent work in sparse approximation has shown that unsupervised learning techniques can use example data to determine an efficient dictionary with few a priori assumptions. We apply this model to sample hyperspectral data and show that these techniques learn a dictionary that: 1) contains a meaningful spectral decomposition for hyperspectral imagery, 2) admit representations that are useful in determining properties and classifying materials in the scene, and 3) forms local approximations to the nonlinear manifold structure present in the actual data.

2010 Conference Record of the Forty Fourth Asilomar Conference on Signals, Systems and Computers

The Enzonalasporites group of Triassic pollen genera and species: New morphological and ultrastructural data, revised taxonomy and paleobiogeographical aspects

The Triassic pollen genus Camerosporites: New morphological and ultrastructural data, revised taxonomy and paleobiogeographical aspects

Abstract The upper Paleozoic–lower Mesozoic strata in the northeastern Galilee Basin are important for their hydrocarbon and groundwater potential; however, despite numerous previous investigations, the nature of this stratigraphic interval remains enigmatic. This study integrates lithostratigraphy, palynology and U–Pb zircon geochronology of well-exposed Permian and Triassic sedimentary rocks and nearby stratigraphic cores from the Hughenden district to determine their maximum depositional ages and then revises the stratigraphy where necessary. The newly defined Galah Tuff Bed was discovered at the top of the Betts Creek beds in Porcupine Gorge and was dated at 251.9 ± 3 Ma. This provides an important age constraint for the Betts Creek beds and is a tie-point for correlations with coeval units in the adjacent Bowen Basin and the Sydney and Gunnedah basins to the southeast. The Galah Tuff Bed is interpreted to correlate with the Yarrabee Tuff in the Bowen Basin. Unconformably overlying the Betts Creek beds is a newly recognised stratigraphic unit, defined herein as the Porcupine Gorge Formation. Detrital zircon maximum depositional ages and palynology indicate a significant depositional hiatus of up to 20 million years between the Betts Creek beds and Porcupine Gorge Formation. The hiatus indicates that the lower part of the Porcupine Gorge Formation is at least upper Middle Triassic, whereas the upper part of the unit extends into the Late Triassic. This age also constrains the overlying Warang Sandstone, which is considerably younger locally than previously reported and is likely diachronous across the northeastern Galilee Basin. KEY POINTS An integrated lithostratigraphy, palynology and U–Pb detrital zircon geochronology methodology is applied to the Permian–Triassic succession the northeastern Galilee Basin. Two new stratigraphic units were recognised: the upper Permian Galah Tuff Bed (251.9 ± 3 Ma) and the late Middle–Late Triassic Porcupine Gorge Formation (238.7 ± 3 Ma). The Galah Tuff Bed, correlative of the Yarrabee Tuff in the Bowen Basin, is evidence for widespread volcanism in the late Permian. The age of the Porcupine Gorge Formation indicates diachroneity of the Triassic succession in the Galilee Basin, warranting further examination.

A revised Permian–Triassic stratigraphic framework for the northeastern Galilee Basin, Queensland, Australia, and definition of a new Middle–Upper Triassic sedimentary unit

The sedimentological evolution and petroleum potential of a very thick Upper Cretaceous marine mudstone succession from the southern high latitudes—a case study from the Bight Basin, Australia

 Palynofacies analysis was carried out on 92 core samples from the fluvio-deltaic Middle to Upper Triassic Mungaroo Formation, Northern Carnarvon Basin, Western Australia. The analyses demonstrate that each depositional environment (“depofacies”) sampled has a characteristic palynofacies assemblage reflecting the varied origins, transport, sorting, and preservation histories of organic particles in sediments. The sampling covered a wide range of depofacies identified in fluvial channel, floodplain, crevasse splay, distributary channel, and tidal zone paleoenvironments and included laminated to massive mudstones and siltstones, cross-bedded sandstones, immature pedogenically altered paleosols, and coals. Although each depofacies has a characteristic palynofacies association, there is a high degree of variability within and overlap between preparations. Black-opaque particles were the dominant component in active fluvial, crevasse, and distributary channels. In contrast, palynomorphs, brown wood particles, and cuticle were more common in abandoned channels, floodplain lakes, and other lower-energy environments. The composition of palynomorphs also varies greatly between depofacies due to factors including the bioproductivity of the surrounding vegetation source area, water-table levels, preservation potential, and the fluid dynamic properties of organic particles. The depofacies were grouped into five “process regimes” (active channels, abandoned channels, lakes and periodically flooded areas, paleosols and swamps, tidal mudflats) based on their dominant depositional process. Depofacies in the same process regime tended to have similar palynofacies associations. Active channels yielded similar assemblages irrespective of whether they were fluvial, crevasse, or distributary channels because their dominant characteristic is high flow energy, which encourages the bypass of finer-grained particles, enhances the mechanical degradation of plant debris, and may inhibit local vegetation growth. Organic particles found in lower-energy environments (e.g., floodplain lakes) are on average larger, more elongate, and better preserved than particles found in high-energy environments (e.g., active channels). Although this study was restricted to samples from the upper Samaropollenites speciosus and lower Minutosaccus crenulatus biostratigraphic zones in a geographically limited area, its results are not influenced by the specific taxonomic composition of the vegetation but by the physiographic structure of surrounding plant communities; this suggests that palynofacies analysis could be used to distinguish depositional environments in deltaic settings from other stratigraphic intervals.

Depositional settings and palynofacies assemblages of the Upper Triassic fluvio-deltaic Mungaroo Formation, northern Carnarvon Basin, Western Australia

Sedimentological evolution of a thick Upper Cretaceous mudstone succession from the southern high latitudes - insights from IODP Site 1512, Bight Basin, Australia

Summary Kerogen slides were made from 92 core samples selected from the Upper Triassic Mungaroo Formation in four wells in the Gorgon area of the Northern Carnarvon Basin. The slides were examined to investigate relationships between kerogen assemblages and their depositional environments (“depofacies”). Although the assemblages naturally vary and overlap to an extent, each depofacies has a characteristic kerogen assemblage. Moreover, depofacies which are genetically similar tend to have similar assemblages even though they may have been deposited in different parts of the delta. For example, active channels tend to have similar kerogen assemblages (abundant black-opaque particles, few cuticles, sparse palynomorphs) irrespective of whether they are fluvial, crevasse or distributary channels; in this case, it is inferred that the overwhelming factor in the kerogen assemblages is the high energy level of the environment of deposition, and its consequent inhibition of local vegetation and promotion of mechanical degradation of organic particles.

Kerogen associations and paleoenvironmental interpretation of the Upper Triassic Mungaroo Formation in the Gorgon Area, Northern Carnarvon Basin, Western Australia

The North Pacific eastern boundary upwelling system is one of the most ecologically productive, economically relevant, and well-studied systems in the world. Over the last 60 years, a wide range of observations have documented the significant impacts of the El Niño Southern Oscillation (ENSO) on marine ecosystems along the US West Coast. Yet there has been no systematic attempt to use this knowledge to explicitly forecast local marine ecosystem responses to individual ENSO events.

A framework for ENSO predictability of marine ecosystem drivers along the US West Coast

The composition and diversity of dinosporin in species of the Apectodinium complex (Dinoflagellata)

Here we present combined radioisotopic dating (U‐Pb zircon) and cyclostratigraphic analysis of the carbon isotope excursion at the Paleocene‐Eocene (P‐E) boundary in Spitsbergen to determine the numerical age of the boundary. Incorporating the total uncertainty from both radioisotopic and cyclostratigraphic data sets gives an age ranging from 55.728 to 55.964 Ma, within error of a recently proposed astronomical age of ∼55.93 Ma. Combined with the assumption that the Paleocene Epoch spans twenty‐five 405 kyr cycles, our new age for the boundary suggests an age of ∼66 Ma for the Cretaceous‐Paleogene boundary. Furthermore, our P‐E boundary age is consistent with the hypothesis that the onset of the Paleocene‐Eocene thermal maximum at the boundary occurred on the falling limb of a 405 kyr cycle, suggesting the event was initiated by a different mechanism to that which triggered the other early Eocene hyperthermals.

Constraints on the numerical age of the Paleocene‐Eocene boundary

Slow release of fossil carbon during the Palaeocene-Eocene Thermal Maximum

The interaction of the ocean, atmosphere and ice in the Arctic region plays a critical role in modulating global climate. However, recent observations have illustrated the region is changing rapidly in response to anthropogenically-induced warming. Given the uncertainty in climate model predictions, one way to analyse the response of the Arctic to warming is to generate records through transient warm intervals from the geological past. However, the most pronounced warming event of the Cenozoic, known as the Palaeocene/Eocene thermal maximum (PETM), is poorly documented in the Arctic region. Therefore, in order to place further constraints on environmental conditions in the high Arctic during the PETM, this thesis documents results from two new PETM localities in the Spitsbergen Central Basin, the BH9/05 core and the Bergmanfjellet outcrop section. Results from sedimentological, palynofacies and dinoflagellate cyst (dinocyst) analyses have been compared to previous results from the Longyearbyen section (Spitsbergen) and Intergrated Ocean Drilling Project Site 302-4A in order to analyse spatial and temporal changes across the event in this high Arctic setting. Analysis of Fe and Mn XRF time-series from core BH9/05 has been used to construct a cyclostratigraphic age model to constrain temporal changes. Together with radio-isotopic dating of a bentonite layer within the PETM, the cyclostratigraphic age model implies that the onset of the event occurred on a falling limb of the 405 kyr eccentricity cycle (between 55.728 and 55.964 Ma). Given that other early Palaeogene transient warming events (hyperthermals) have consistently been documented at the peak of both 100 and 405 kyr eccentricity cycles, or on the rising limb of such cycles, this suggests the PETM may have been initiated by a different mechanism compared to other hyperthermals. Furthermore, comparison of dinocyst assemblages across the Spitsbergen Central Basin illustrates a pronounced influx of the low salinity tolerant taxon Senegalinium during the PETM, consistent with a regime of enhanced precipitation and runoff. Such conditions led to salinity stratification, which together with elevated productivity and the warming of Arctic waters led to sedimentary anoxia and enhanced burial of marine organic matter. As the mechanisms driving anoxia and elevated productivity seen in the Central Basin would be expected to occur across the Arctic region, it is probable that the enhanced burial of contemporary marine organic matter was a pan-Arctic phenomenon in marginal settings. Given the burial of this type of organic matter sequesters carbon directly from the exogenic system, this suggests that the Arctic would have been a significant carbon sink during the PETM.

Palaeoceanographic change during the Palaeocene/Eocene thermal maximum in Arctic Spitsbergen

' s personal copy Sea-level and salinity fl uctuations during the Paleocene – Eocene thermal maximum in Arctic Spitsbergen

Sea-level and salinity fluctuations during the Paleocene–Eocene thermal maximum in Arctic Spitsbergen

ABSTRACT While the Russian decision to annex Crimea has been widely explored and debated, scholarship has largely overlooked the Ukrainian response. Why did the Ukrainian side refrain from escalating? I address this gap, leveraging recently declassified primary-source materials from Ukraine’s National Security and Defense Council to provide an original explanation for the Ukrainian decision not to fight for the peninsula. I find evidence in favor of realist explanations, while domestic politics was largely absent in decision-makers’ discussions. Additionally, I find prospect theory to offer a compelling account for the Ukrainian decision. This article therefore explains why decision-makers were risk-averse despite the loss of Ukrainian territory.

Why Didn’t Ukraine Fight for Crimea? Evidence from Declassified National Security and Defense Council Proceedings

This article explores developments in center-region relations between the Russian federal government and the Republic of Tatarstan, a federal subject of the Russian Federation. I argue that instrumentalist accounts are unable to satisfactorily explain several key moments in Tatarstan’s relations with the federal center, and that a focus on symbolic politics provides important analytical leverage. I examine three such episodes: aborted plans to introduce a Latin script for the Tatar language in 1999, the expiration of treaty-based relations and the assault on the region’s Tatar-language education policy in 2017, and the institution of the presidency – which exists to this day. In all three cases, interest-based explanations alone fail to account for what actually happened, whereas ideational explanations can help explain and interpret regional leaders’ actions. This has important implications for how we understand regional political dynamics in Russia amidst conditions of centralization.

Office Politics: Tatarstan’s Presidency and the Symbolic Politics of Regionalism

Overall, the volume provides interesting (and also innovative) insights into identity formation in the Central Asian countries. what could have strengthened the book would be the inclusion of more comparative studies within the region, as case contextualisation supports a better understanding of identity-building processes. Most of the studies employ process tracing, investigating a number of Soviet legacies, in order to make sense of the construction of identities today. This leads to both redundancy and generalisation. Soviet legacies on the macro-level apply to all cases under investigation, and identity building seems to be more complex than just responding to the past. Comparison of contemporary identity projects within the region would highlight the unique and diverse aspects of identity-building processes in different Central Asian countries, some of which seem to reflect contemporary rival projects in the political and social spheres rather than responses to the Soviet past. One perspective generally missing is bottom-up research and micro-focus on identity formation. All contributions explore the field top-down from a macroor meso-level analysis.

Democracy in Central Asia. Competing Perspectives and Alternative Strategies

Chapter Five Three Chapters on Consecration from the Oḍiyāna Mahāmudrā Lineage

The Seven Siddhi Texts (Grub pa sde bdun): Remarks on the Corpus and Its Employment in Sa skya-Bka’ brgyud Mahāmudrā Polemical Literature

This essay begins with a brief discussion of the marginalization of demonology in the study of both Indian Buddhist traditions and Āyurvedic medicine. Unlike the study of Buddhist traditions in other geographic regions, there has been relatively little scholarship on the dialogue between Indian Buddhist communities and the localized spirit deity cults with which they have interacted for more than two millennia. The modern study of Āyurverda, with few exceptions, demonstrates a similar trend in the marginalization of bhūtavidyā, or demonology, which has constituted a legitimate branch of Āyurvedic medicine from at least the time that the earliest Āyurvedic compendium, the Carakasaṃhitā, was composed. This essay argues that this lack of proper attention to Indian Buddhist and Āyurvedic medical demonology is symptomatic of a broader, persistent bias in the human sciences. The essay then examines a handful of stories from the Karmaśataka, a collection of Buddhist avadānas, to argue that certain Buddhist communities may have held their own biases against systems of medical demonology, albeit for entirely different reasons. The balance of this essay then concludes with an analysis of The Sūtra of the Seven Buddhas that presents this work as an example of Buddhist medical demonology.

Author(s): Krug, Adam Charles | Advisor(s): Wallace, Vesna A; Cabezon, Jose I | Abstract: This study examines The Seven Siddhi Texts, a short corpus of tantric Buddhist works that the Tibetan tradition identifies as the mahāmudrā transmission from the famed semi-mythical land of Oḍiyāna. Owing to the nature of the corpus itself, this study is best characterized as properly Indo-Tibetan in its scope. The Seven Siddhi Texts are first examined here as independent treatises that reflect the development of Vajrayāna Buddhism in its Indic cultural and historical contexts between the eighth and tenth centuries. They are then approached as a means for examining the formulation of Vajrayāna institutions and their attendant corpora in Nepal. Finally, they provide a case study in the phenomenon of practical canonicity in their employment in mahāmudrā polemical literature in Tibet from the fifteenth to seventeenth centuries. Part I argues for the adoption of a demonological paradigm in the study of South Asian religions. Using data from The Seven Siddhi Texts in dialogue with the Āyurvedic discipline of demonology (bhūtavidyā), it highlights that Vajrayāna Buddhist traditions maintained a dual apotropaic-soteriological goal in their conception of the practice of yoga. Part II addresses the sociological implications of sect and sectarian identity in The Seven Siddhi Texts. It presents the phenomenon of dissimulative asceticism in Vajrayāna Buddhism as a potential social context for the highly Śaiva-Buddhist hybrid forms of ritual that emerged with the Buddhist yoginītantras. It then addresses the issue of inclusivist and exclusivist expressions of sectarian identity from the authors of The Seven Siddhi Texts. Part III discusses the formulation and transmission of The Seven Siddhi Texts as a corpus of mahāmudrā works in light of the broader phenomenon of practical canonicity in Buddhist traditions. It presents philological evidence that The Seven Siddhi Texts were part of a known mahāmudrā practical canon in Nepal prior to their transmission to Tibet. It then discusses historical data and Tibetan historiography on their transmission to Tibet beginning in the eleventh century. It concludes with a discussion of The Seven Siddhi Texts' incorporation into two Kagyu mahāmudrā practical canons in Tibet at the turn of the sixteenth century, and the role that The Seven Siddhi Texts played in a number of mahāmudrā polemical works composed by the subsequent generation of Kagyu authors.

The Seven Siddhi Texts: The Oḍiyāna Mahāmudrā Lineage in its Indic and Tibetan Contexts

Tantric Epistemology and the Problem of Ineffability in the Seven Siddhi Texts

La relation entre Pakpa (’Gro mgon ’Phags pa Blo gros rgyal mtshan ; 1235−1280), patriarche des Sakya (Sa skya), Qubilai Qa’an (1215−1294) et la cour des Yuan occupe une place unique dans les travaux historiques premodernes tibetains et mongols et parmi les erudits modernes de l’histoire politique et religieuse du Tibet, de la Mongolie et de la Chine. Conseils au Prince Jibik Temur : un chapelet joyau contient ce qui est probablement le premier ouvrage litteraire de Pakpa sur le concept des deux systemes (tsul nyi ; Wylie : tshul gnyis), une theorie politico-religieuse qui souligne les dynamiques de la relation tibetaine yoncho (yon mchod), appelee aussi « relation de maitre spirituel a protecteur laic » que les recits historiques tibetains et mongols considerent souvent comme ayant ete officiellement codifiee lorsque Pakpa etait precepteur imperial de Qubilai Qa’an. Cet article commence par fournir des donnees historiques sur Jibik Temur (ne c. 1246) en identifiant sa place dans la lignee ainsi que son role dans les annees de formation de l’empire Yuan. Il se poursuit par une analyse du tsul nyi qui est le theme principal du Conseils au Prince Jibik Temur et par une clarification des usages de ce terme par Pakpa dans son texte. Cette recherche determine plusieurs sources canoniques des vers de Pakpa sur l’ethique du gouvernement et, finalement, appelle a considerer l’importance de ce texte en tant qu’exemple d’ethique appliquee au lieu de le lire comme un ouvrage general sur l’ethique bouddhique normative. Places dans leur contexte historique, plusieurs des vers de Pakpa portant sur les instructions de gouvernance paraissent directement aborder les problemes auxquels le prince etait confronte quand le texte fut compose, pendant l’ete 1266. Cette analyse se conclut sur des considerations plus larges concernant les dynamiques de la relation entre Pakpa et Jibik Temur. Les ecrits de Pakpa adresses a Jibik Temur revelent que le role de Pakpa, en tant que precepteur du prince, etait simultanement religieux, politique et personnel. C’etait a la fois une relation de nature personnelle et religieuse qui fut integree dans une structure politique plus formelle et institutionnalisee.

Pakpa’s Verses on Governance in Advice to Prince Jibik Temür: A Jewel Rosary

Reason and Experience in Tibetan Buddhism: Mabja Jangchub Tsöndrü and the Traditions of the Middle Way

The sustainability movement has established a firm foothold in the Civil Engineering profession. The use of recycled asphalt shingles (RAS) is the latest development in the world of asphalt pavement sustainability. The relative abundance of tear-off shingles and their high asphalt content is driving RAS usage in highway and airfield pavements. However, the ultimate objective of any pavement system is to provide a structural and functional roadway that can allow users to safely travel. Both state highway engineers and the general public need to be assured that the end product will not compromise performance. The performance grade of virgin asphalt binder will likely be altered when RAS is introduced into the asphalt mixture. The resulting Superpave material properties need to be predicted in order to assess that the mixture will perform adequately. In an experimental campaign which sought to investigate this, virgin PG 64-22 and PG 46-34 binders were blended with RAS binder at various percentages. Superpave material properties were measured and the performance grades determined for all binder blends. Prediction of complex shear modulus and flexural creep stiffness were then attempted using Hashin and Shrikman's Arbitrary Phase Model. Use of calibration factors were found to accurately predict high temperature complex shear modulus, however, the model produced unexpected results for low temperature flexural creep stiffness. Micromechanical models that take into account the viscoelastic nature of asphalt would be expected to give an accurate prediction of material properties and should be pursued in further research. Finally, these micromechanical models should be incorporated into a practical system to aid designers in the maximization of recycled materials in asphalt pavements.

Characterization and micromechanical investigation of recycled asphalt shingle binder blends

In general, pavement treatment actions transform pavement segments from one condition state to another. The transformation could be summarized using treatment transition matrices (T2Ms) that indicate the probability that a pavement segment transfers from one condition state to another. This probability is a function of the before treatment pavement condition state and the treatment type. Some State Highway Agencies (SHAs) collect and store pavement condition data along 0.1 mile pavement survey or segment lengths while others use different survey lengths. The data variability makes it difficult to model the pavement conditions of each segment over time and to assess its transition from one condition state to another. It has been suggested that increasing the pavement length over which the conditions are analyzed may decrease the data variability and improve the modeling of pavement conditions over time. Nearly 445 miles of flexible pavements that were subjected to asphalt concrete (AC) overlay and 349 miles of the same subjected to mill and fill were analyzed to determine the effects of the pavement analysis length on the T2Ms. In the analysis, the data of each 0.1 mile pavement segment were used to generate analysis lengths of 0.1, 0.4, 0.7, and 1.0 miles. Results of the analysis are presented and discussed in this paper. It is shown that, for IRI and rut depth data, the T2Ms are independent of the pavement analysis length. However, T2Ms based on cracking data are a function of the pavement analysis length.

Impacts of Pavement Condition Analysis Length on Treatment Transition Matrices and Treatment Benefits

One of the objectives of a comprehensive pavement management system is to deliver to the public cost effective, safe, and conveniently accessible road network. This objective could be accomplished through a series of treatments to maintain, upgrade, and improve the condition and safety of the road network within a given budget constraint. The cost effectiveness of each treatment is a function of the selected treatment types, project boundaries, and time of action. The selection of treatment types must be based on the pavement surface condition and its rate of deterioration prior to treatment, the causes of distresses and the impact of each treatment or treatment strategy on the health of the network. The long term effect of pavement deterioration could be analyzed using Markov Chain Algorithm (MCA) utilizing a pavement network deterioration matrix. In reality such deterioration matrix applies, on a yearly basis, to about 90% of the pavement network having the do-nothing alternative. The problem is that MCA cannot be used when a certain percent of the pavement network is treated on a yearly basis. Thus, MCA modifications needs to be developed to reflect the long-term effects of a given treatment strategy on the pavement network. Such modifications are based on treatment transition matrices expressing the probability of transitioning pavement sections from one condition state before treatment to another state after treatment. This paper presents and discusses the formation of the treatment transition matrices, and a developed algorithm for the modification of the MCA and its advantages and shortcomings.

Strategy Analysis Using Treatment Transition Matrices of In-service Pavement Condition Data

The effectiveness of pavement treatments is a function of several factors, including material quality, design, distribution of pavement condition states (conditions and rates of deterioration) before treatment, and construction quality. Because of these factors, state highway agencies have established estimates of treatment service lives with significantly wide ranges. These wide ranges make the calculation of treatment benefits or effectiveness a difficult task unless the role of each factor that affects service life is well understood. This study analyzed the impacts of the state of the practice of Colorado, Louisiana, and Washington on the effectiveness of thin (< 2.5 in.) hot-mix asphalt (HMA) overlay treatment. This paper reports that analysis of time-series pavement condition and distress data of previously treated pavement sections can be tabulated in a matrix format to demonstrate a snapshot examination of past practice. Such matrices are called treatment transition matrices (T2Ms). The data in the matrices express the probability that a pavement treatment will have certain effectiveness. T2Ms for pavement projects subjected to thin HMA overlays by three state highway agencies are discussed. Differences in treatment effectiveness were related to differences in the state of the practice in the three states. Selection of treatment timing and project boundaries significantly affected treatment effectiveness, and similar states of the practice yielded similar treatment effectiveness.

Impact of Three State Practices on Effectiveness of Hot-Mix Asphalt Overlay

When a pavement section is subjected to preservation or rehabilitation treatments, its surface conditions transfer from one condition state before treatment to another after treatment. This transformation is a function of the condition state before treatment, the treatment type and timing, the project boundaries, and the quality of construction. The pavement surface conditions along a project vary substantially from one point to the next. Hence, a typical pavement project consists of several condition states that will be transferred to another set of condition states due to the treatment. The probability of such transformation of each pavement segment from one condition state to another populates the cells of the treatment transition matrix. In this study, the before and after treatment distributions of 0.1 mile pavement segments along flexible pavement projects in the State of Louisiana that were subjected to asphalt concrete overlay, mill and fill, and single and double chip seals were studied. Treatment transition matrices were formed and analyzed. The results are presented and discussed in this paper. It is shown that treatment transition matrices can be used to study the health of the pavement network, construction quality, the differences in the state-of-the-practice between the various regions within the state, the benefits of the treatments, and to establish the parameters for design-build warranties. It is also shown that the state-of-the-practice for the selection of treatment type is not dependent on the before treatment distribution of the condition states of the 0.1 mile pavement segments.

Pavement Treatment Transition Matrices: Reality Check on Treatment Practices

Black Print Unbound: The Christian Recorder , African American Literature, and Periodical Culture. Eric Gardner.

Eric Gardner’s Black Print Unbound: The Christian Recorder, African American Literature, and Periodical Culture examines African American individuals and communities during the Civil War era that were affiliated with the Christian Recorder, a weekly paper published by the African Methodist Episcopal (AME) Church. Arguing for an approach to early African American literary history “unbound” by the critical attention given to slave narratives, novels, and other bound books by black authors, Gardner builds on the foundational work of Frances Smith Foster, Elizabeth McHenry, and others to demonstrate the centrality of black periodicals—especially religious publications—to nineteenth-century African American literature. Meticulously excavating the lives, thoughts, and actions of the Christian Recorder’s many subscribers, contributors, editors, and publishers, Black Print Unbound recovers the “embodied and imagined” community formed and sustained through this periodical (16). This in-depth case study thus makes a significant contribution to ongoing debates surrounding print cultures and their publics in the United States during the nineteenth century. As a publication “conceived by African Americans, edited by African Americans, written primarily by African Americans, and largely distributed by African Americans to an almost completely African American audience” (4), the Christian Recorder provided a medium for expressing the desires, concerns, and imaginations of a community united through racial and religious identification. The opening chapter serves as an introduction that situates the work at the intersection of African American literary history and print culture studies. Beginning with an 1862 meeting in which the prominent AME bishop Daniel Payne gave Abraham Lincoln issues of the Christian Recorder, Gardner moves from these male leaders to consider the other ways the paper entered the White House. In particular, he offers readers a concise overview of the lives of Elizabeth Keckley and William Slade, African Americans employed by the Lincoln family. Actively involved in the African American community in Washington, DC, Keckley and Slade both subscribed and contributed to the

Black Print Unbound: The Christian Recorder, African American Literature, and Periodical Culture by Eric Gardner (review)

newspaper, John Brown Russwurm occupies a significant place in the history of black periodicals. Russwurm played a pivotal role, according to Timothy Patrick McCarthy, in “the creation of a new print medium designed to galvanize the black community by representing a more unified political voice based on black interests and opinions.”1 As they noted in the paper’s prospectus, Russwurm and his partner Samuel Cornish envisioned Freedom’s Journal as a forum “through which a single voice may be heard, in defence of five hundred thousand free people of colour.”2 In addition to advocating for abolition and promoting black literacy, that collective public voice also spoke out strongly against the efforts of the American Colonization Society (ACS) to resettle free and manumitted black Americans in Liberia. When Russwurm resigned from Freedom’s Journal in 1829 to go to Liberia and began editing the Liberia Herald shortly after settling in the colony, his decision thus struck a dissonant chord for many of his associates in America. Recent work by Winston James and Sandra Sandiford Young points to Russwurm’s earlier plans to emigrate to Haiti, his growing frustration with limited opportunities for free blacks in America, and his transnational framework for thinking about black nationality as factors that influenced his eventual embrace of Liberian colonization.3 However, no historical evidence reveals a specific event that prompted his reversal of opinion about the ACS. What is clear is that once in Liberia, Russwurm sought to use the Herald to persuade black and white readers within and outside the United States that “there is no other home for the man of color . . . than Africa.”4 Yet to Cornish and others associated with Freedom’s Journal, including David Walker, his decision to go to Liberia represented a betrayal and his new publication an obstacle for black communities demanding respect and equality at home in the United States. Indeed, because Russwurm spoke out in the

“A Traitor to His Brethren”?: John Brown Russwurm and the Liberia Herald

In reply to Robert P Crease's article "Feynman's failings" (March p25, http://ow.ly/uKDFS).

Subjectivity in the Twenty-First Century: Radical Subjectivity and the N-Row Wampum

THE CULTURE AND COMMERCE OF THE EARLY AMERICAN NOVEL: READING THE ATLANTIC WORLD-SYSTEM

Naturalizing Empire examines processes of U.S. empire- building through a comparative analysis of U.S. American influence in Liberia, Hawai'i, and Nicaragua in the mid- nineteenth century, focusing on cultural representations of agents of empire assuming or imposing different national identities to gain control of territory and establish networks of trade. I consider how issues of naturalization and sovereignty were bound up within different forms of literary and print culture in order to address the imperial and anti-imperial politics of both canonical and non-canonical literature. This dissertation extends recent scholarship in American literary and cultural studies that examines forms of imperialism beyond the framework of the nation-state, focusing on actions distinct from (and even antagonistic to) the U.S. state and its official representatives. I address the relationship between antebellum culture and different imperial formations that involve selectively disclaiming U.S. national identity as well as controlling a politically independent territory as a means of configuring the U.S. as an exception to (and exceptional) empire. Each chapter addresses particular genres of print culture, including the historical romance, sentimentalism, and cultures of sensation. In chapter one I examine sentimental writings about Liberia by Sarah Hale, Harriet Beecher Stowe, and Helen Knight. In this chapter I also examine critiques of colonization in African American literature, specifically Martin Delany's letters, speeches, and fiction. My second chapter focuses on the Pacific historical romances of James Fenimore Cooper and James Jackson Jarves. In contrast to these texts, I also examine the historiography of Native Hawaiian writers David Malo and Samuel Kamakau that challenged the U.S. presence in the Pacific. Finally, chapter three analyzes sensational stories of filibustering in Nicaragua and representations of the filibuster public sphere in the newspaper El Nicaraguense as well as Frank Leslie's Illustrated Newspaper. Taken as a whole, I suggest literary and other cultural representations of national identities and national boundaries, as well as the development of American literary genres, are in fact transnational formations that both facilitate and contest different forms of U.S. empire

Naturalizing empire : citizenship, sovereignty, and antebellum American literature

Albert Hadley is one of the most brilliant and influential designers America has ever produced. Adam Lewis has drawn together a revealing history from Hadley's warm and informative stories and reminiscences, on subjects ranging from open evaluations of his working philosophy to the most intimate portrayals of his personal life. A child with an unconventional flair for colour and light, Hadley spent his youth exploring aspects of design and yearning to move to New York City, the hub of sophistication and the epicenter of American fine arts.

Albert Hadley: The Story of America's Preeminent Interior Designer

Der Postillon von Lonjumeau : komische Oper in drei Aufzügen nach dem Französischen der von Leuben und Brunsmick

Arien-Album : Sammlung berühmter Arien für Tenor mit Pianofortebegleitung

Ulubione wyiątki do grania na fortepian [z opery:] Pocztylion z Lonjumeau [!] z muzyką Adama

ABSTRACT Sex trafficking is considered a public health emergency, although there is public confusion about the crime. Defendant gender has been demonstrated to affect juror decision-making within crimes of sexual victimisation, but there was no known literature examining the effect of defendant gender on juror decision-making within a sex trafficking case. To address this void in the literature, we investigated the effect of defendant gender on juror decision-making in a mock sex trafficking case. A community sample of jury-eligible individuals (n = 204) were randomly assigned to either a male or female defendant gender condition in which they read a sex trafficking mock trial summary and completed the Juror Decision Scale. The male defendant was found guilty significantly more frequently than the female defendant although the effect size was relatively small. Complainant Believability, Defendant Believability, and Decision Confidence significantly predicted verdict. Implications of these findings for the justice system are discussed. PRACTICE IMPACT STATEMENT The importance of addressing the crime of sex trafficking is paramount; however, there was a void in the juror decision-making literature. Findings from this experimental simulation of juror decision-making in a mock sex trafficking case indicated that defendant gender plays a role in verdict formation. Juror education is recommended to reduce the effects of gender bias in sex trafficking jury trials.

The role of defendant gender on juror decision-making within a mock sex trafficking case among a jury-eligible community sample

Not All Hate Crimes are Created Equal: An Examination of the Roles of Ambiguity and Expectations in Perceptions of Hate Crimes

La presente invention concerne de nouveaux composes, 2, 4,4,4-tetrafluoro-1-butene et (E)- et (Z)-1,1,1,3-tetrafluoro-2 butenes. Cette invention concerne aussi les nouveaux premier et deuxiemes processus suivant de production de 2,4,4,4-tetrafluoro-1-butene, (E)- et (Z)-1,1,1,3-tetrafluoro-2-butenes, et 1,1,3-trifluorobutadiene. Le premier processus est un processus de production de 2,4,4,4-tetrafluoro-1-butene par chauffage de 1,1,1,3,3-pentaflurobutane a une temperature comprise entre environ 200 °C et environ 700 °C. le deuxieme processus est un processus de production de (E)- et de (Z)-1,1,1,3-tetrafluoro-2-butenes par apport de 1,1,1,3,3-pentafluorobutane avec une base. Par ce premier et ce deuxieme processus il est possible d'obtenir des fluorobutenes cible respectifs avec une haute selectivite. Dans les troisieme, quatrieme et cinquieme processus, 2,4,4,4-tetrafluoro-1-butene, (E)- et (Z)-1,1,1,3-tetrafluoro-2-butene, et 1,1,3,-trifluorobutadiene peuvent etre produits par chauffage de 1,1,1,3,3-pentafluorobutane en presence d'un catalyseur. Ce catalyseur peut etre regenere au contact d'un gaz contenant halogene dans le sixieme processus.

Abstract:An overview of the George A. Romero Archival Collection at the University of Pittsburgh that focuses on the newly recovered short film Jacaranda Joe (1994), an early "found footage" film about a bigfoot-like creature who has been caught on tape by a TV crew while shooting in the Everglades. The article traces the ideas from that short back to unmade projects from the 1970s—including The Footage, a proposed feature set to star legendary Pittsburgh Steelers running back Franco Harris—then shows how they were revisited and transformed in other unfilmed projects in the 1990s and early 2000s until ultimately finding cinematic expression in the 2006 feature film Diary of the Dead. This article argues for the importance of unfilmed work to film scholarship, and particularly toward auteurist studies, using the hundreds of drafts of scripts and treatments from the Romero Collection to demonstrate a range of genres, themes, and interests that is not evident in Romero's feature filmography.

In Search of Bigfoot: Recovering George A. Romero's Jacaranda Joe

Extensions of Our Body Moving, Dancing: The American Avant-Garde's Theories of Handheld Subjectivity

‘Minimal symptom expression’ in patients with acetylcholine receptor antibody-positive refractory generalized myasthenia gravis treated with eculizumab

Long-term efficacy and safety of eculizumab in Japanese patients with generalized myasthenia gravis: A subgroup analysis of the REGAIN open-label extension study

Abstract:Alexander Galloway has argued that the subjective camera of first-person shooter (FPS) games marks a distinct break from cinematic traditions. In this article, I suggest that the FPS camera might belong to a longer history of "searching" cameras that begins with another kind of first-person camerawork: handheld cinematography. To understand the meanings of the handheld camera, this article looks to the documentary tradition. The horror genre provides two notable analogues for the FPS camera: the "killer POV" sequences that were an emblem of the slasher era and the faux-documentary handheld cameras of the "found footage" cycle that came to prominence in cinema alongside the rise of the FPS in gaming. Found footage, unlike FPS, is predicated on looking within the film being a fundamentally vulnerable act and on the helplessness of the viewer to intervene in the action on-screen. While the "shooter" in "first-person shooter" indicates a marriage of action and looking, games like Amnesia: The Dark Descent (Frictional Games, 2010) and Layers of Fear (Bloober Team, 2016) have, like found footage films, equated "horror" with a sense of helplessness and vulnerability by removing combat as an option and by minimizing the player's capacity for control. Thus, the contemporary horror genre is being defined across media through an emphasis on the vulnerability and impotence of the searching camera.

The Searching Camera: First-Person Shooters, Found-Footage Horror Films, and the Documentary Tradition

In the 21st century, the horror genre is defined across mediums, with video games, television, and internet-based forms as central to moving-image horror as is the cinema—and, further, the form and style of horror moves between mediums. This chapter establishes the current transmedial nature of moving-image horror by analyzing two recent films, Unfriended (2015) and Unfriended: Dark Web (2018). These films eschew traditional cinematic editing and camerawork in favor of a style and structure consisting of browsing, messaging, and other networked communications taking place on a single laptop screen. This chapter also introduces the book structure that centers around a movement from sensation to narrative—aesthetics of emergence and of absorption or immersion—from works that are almost exclusively shock-based to those whose interest in the genre is firmly entrenched in telling complex absorbing stories about monsters.

It makes us jump. It makes us scream. It haunts our nightmares. So why do we watch horror? Why do we play it? What could possibly be appealing about a genre that tries to terrify us? Why would we subject ourselves to shriek-inducing shocks, or spend dozens of hours watching a television show about grotesque flesh-eating monsters? Horror offers us a connection to fears that are otherwise unspeakable, even inconceivable, so why do we seek it out? Monstrous Forms offers a theory of horror that works through the genre across a broad range of contemporary moving-image media: film, television, videogames, YouTube, gifs, streaming, virtual reality. This book analyzes our experience of and engagement with horror by focusing on its form, paying special attention to the common ground, the styles, and forms that move between mediums. It looks at the ways that moving-image horror addresses its audiences; the ways that it elicits, or demands, responses from its viewers, players, browsers. Camera movement (or “camera” movement), jump scares, offscreen monsters—horror innovates and perfects styles that directly provoke and stimulate the bodies in front of the screen. Analyzing films including Paranormal Activity, It Follows, and Get Out; videogames including Amnesia: The Dark Descent, Layers of Fear, and Until Dawn; and TV shows including The Walking Dead and American Horror Story, Monstrous Forms argues for understanding horror through its sensational address and dissects the forms that make that address so effective.

Chapter 3 refines the discussion of the sensational address and horror spectatorship by analyzing the first-person camerawork that I dub “Killer POV.” Killer POV—a subjective camera without a reverse shot—is at the center of many of the most influential writings on modern horror. However, these discussions often start from the assumption that the camera’s point of view produces identification with the unseen killers or monsters whose perspectives we presume to be represented. This chapter attempts to disengage our understanding of horror spectatorship from such models to provide an alternative reading of Killer POV that engages with the genre’s structures of looking and being looked at while remaining sensitive to what precisely is being communicated to viewers by these shots. Killer POV signals to the viewer the presence of a threat without displaying the killer onscreen. This chapter reads Killer POV through the lens of the sensational address, understanding it in terms of its effects on the spectator. In this reading, Killer POV does not elicit fantasies of mastery and control, but, rather, separates the dominating, sadistic look of the killer from the viewer’s powerless look at Killer POV.

Chapter 5 begins the second part of the book, “Scary Monsters (and Super Creeps).” Whereas the first part focused on the sensational address and direct stimulation of the horror viewer, gamer, and browser, the second half focuses on monsters. This chapter argues for understanding monsters as figures that embody and limit anxieties, and which therefore offer reassuring locations onto which those anxieties can be placed. This argument places the monster-centric “philosophy of horror” of Noel Carroll in dialogue with the explicitly unembodied theory of abjection of Julia Kristeva to understand the importance of this embodiment and limitation to traditional horror: horror is a vehicle for working through anxieties that otherwise are not, or cannot, be articulated. The chapter first establishes the extent to which monstrosity is an essentially formal category—decided by stylistic presentation as much as by biological make-up. It then performs close readings of three recent works that engage with this tradition of monstrous forms to minimize visualization and embodiment and, therefore, the monster function: It Follows (2014), the Paranormal Activity series of films (2007–2015), and the game Amnesia: The Dark Descent (2010).

Chapter 2 looks at jump scares and the fad of “screamers” found across the internet: brief videos or gifs designed to cause an unsuspecting browser to scream and jump. They appeared when jump scares were ascendant within the horror genre thanks to video games; screamers’ online popularity led to importation into the cinema through films such as the Paranormal Activity series. The chapter develops the importance of shock to the horror genre and the similarities between engagement across mediums. Shock is a challenge to viewer/browser/gamer mastery and self-control. Screamers offer the opportunity to reassert one’s own self through repetition and sharing, showing how similar processes are central to the experience of horror film viewing and gameplay. It discusses “elevated horror” and the tendency to disparage sensation in opposition to traditional virtues of narrative cinema. The chapter’s counterpoint for this assumption is with close readings of “elevated” horror films, The Witch (2015) and The Babadook (2014).

Correction to: Eculizumab improves fatigue in refractory generalized myasthenia gravis

This chapter focuses on horror that prioritizes narrative over sensation to work through why the themes of horror hold fascination for viewers and gamers when not paired with visceral affective goals. The chapter theorizes this mode as “integrated horror”—works that incorporate horror tropes into existing narrative forms and structures—with recent television at the forefront of this trend. Integrated horror allows for exploration of, and familiarization with, monsters and monstrosity, of death and abjection. This mode allows viewers and gamers to conceive of and, in some sense, work through, the inconceivable fears that define horror. This chapter discusses the uses of monsters and why we embrace them over the course of the dozens or hundreds of hours that make up a television show like The Walking Dead (2010–) and American Horror Story (2011–).

This chapter offers a theory of moving-image horror based in the “sensational address,” the construction of mise-en-scène around the provocation of the viewer/gamer. It builds off of the tradition of theorizing horror film spectatorship to show the commonalities between horror film viewing and playing horror games—using trailers depicting audience reactions to Paranormal Activity (2007–2009) and Saw 3D: The Final Chapter (2010) as well as reaction videos made about horror games—to analyze the effects of a sensational, physical engagement with the screen. It argues for a fundamentally ludic understanding of horror film spectatorship that places the viewing activity of the horror film spectator and the active “entanglement” of the horror gamer on a spectrum of interactivity. This chapter proposes an understanding of horror as an engagement with the inconceivable, with things we fear but cannot fully comprehend. Sensational horror translates that feeling of inconceivable horror into visceral, physical experience.

This final chapter continues the discussion of monsters by engaging with the writings of Robin Wood, who theorized monsters as fundamentally ambivalent figures who allow us to envision alternatives to the restrictive social order. It then realigns Wood’s terms to show how the recent horror genre has been structured around questions not simply of monstrosity, but of asserting or maintaining humanity—and recognizing the humanity of others—in the face of monstrosity and other inconceivable horrors. This is the explicit theme of The Walking Dead TV series, as is emphasized in its first video game adaptation, The Walking Dead: The Game (2012), but is there at the beginnings of the modern genre in the 1960s with a film like Night of the Living Dead (1968). The chapter concludes with a discussion of how understandings of “monstrosity” and “humanity” are redefined around questions of morality with two high-profile, integrated horror films, Get Out (2017) and The Shape of Water (2017).

Eculizumab improves fatigue in refractory generalized myasthenia gravis

The epilogue takes stock of the current genre by continuing the look at Get Out and The Shape of Water and fellow 2017 horror film blockbuster It. Focusing on the emblematic images of each film’s marketing campaign, the epilogue analyses the different valences and emphases of each: on the visceral provocations of the sensational address (It), on the depiction and exploration of fear and abjection (Get Out), and on the appeal of monsters and monstrosity (The Shape of Water). This allows for the epilogue to chart out the primary forms of horror in a contemporary genre that has been shaped in equal parts by film, television, and video games, with increasing contributions from new media and internet-based forms. The book has focused on convergence of the genre across mediums, and it closes with a suggestion that the future of the genre lies in a convergence of these forms. that, although the marketing for each of these films suggests an emphasis on sensation or a specific aspect of narrative, the films themselves suggest an increasing comfort with balance these different approaches that had once been thought of as mutually exclusive. In the digital era, new mediums increasingly balance direct, often sensational, aims with narrative depth, and so a medium like virtual reality may find horror to be an ideal model.

| The giallo, an Italian genre of horror film that peaked in the 1970s, is infamous for peddling shock and slaughter. Under the graphic sex and violence, however, the giallo expresses popular anxiety surrounding the transgression of social and sexual norms in modern Italy. Superficially, the giallo seems to suggest that social and cultural turmoil necessarily produces death. Yet the giallo foregrounds the obvious excitement and attraction of transgression, allowing that transgression could in fact be generative of positive, invigorating difference. Résumé | Le giallo, un genre de film d’horreur italien qui a connu son heure de gloire dans les années 70, a la réputation de mélanger choc et massacre. Sous l’aspect pornographique et violent, toutefois, le giallo exrime l’anxiété populaire qui entoure la transgression des normes sociales et sexuelles dans l’Italie moderne. En surface, le giallo semble suggérer que l’agitation sociale et culturelle conduit nécessairement à la mort. Cependant en mettant en avant l’excitation et l’attrait évidents de la transgression, le giallo permet à cette transgression d’être porteuse de différences positives et tonifiantes. Mots-clé: giallo, transgression, mondernité, violence contre les femmes, cinéma d’horreur. The giallo was a particularly fleshy style of horror film from Italy that began in the early 1960s and flourished during the 1970s: a blood-soaked spectacle identified with cheap thrills and frequently low production values. Despite this, the giallo was shrewdly perceptive in its projections of social anxieties during the most violent decade of Italy’s postwar history. In transgression, the giallo saw thrilling possibility and dangerous disorder, and in hegemony, stability and suffocation. These films largely regarded the upheaval of modernity with ambivalence while nevertheless generating much of its diegetic tensions from the instability of social norms—particularly those surrounding gender. Trafficking in sleaze, shock, and slaughter, the giallo appeared to argue that the volatility of modern life necessarily produces death. However, this impression is but a first glance. A more incisive examination of how the giallo presents transgression as a production of difference reveals a different understanding of social turmoil: as a generative force to be embraced.

Killer POV—a subjective camera without a reverse shot—is at the center of many of the most influential critical writings on modern horror. However, these discussions often start from the assumption that the camera’s point of view produces identification. This essay attempts to disengage our understanding of horror spectatorship from such models and to provide an alternative reading of killer POV that engages with the genre’s structures of looking/being looked at while remaining sensitive to what precisely is being communicated to viewers by these shots. Killer POV signals to the viewer the presence of a threat without displaying the monster/killer/bearer of the look onscreen. In addition to keeping the threat un-embodied (or only vaguely embodied) and unplaced, killer POV alerts the viewer to the films’ withholding of crucial diegetic information, both of which are essential to understanding the unique mode of spectatorship provoked by modern horror films.

Imaginations: Journal of Cross-Cultural Image Studies/revue d'études interculturelle de l'image

Killer POV: First-Person Camera and Sympathetic Identification in Modern Horror

Abstract:This essay argues that Hammer Film Productions' Gothic revival films need to be understood not as the last gasp of an older form of horror, but as the genre's first steps in a new direction. Hammer relocated monstrosity within the psyche, but did so alongside traditional creatures, in old-world Gothic settings. The Gothic signifiers enabled a subtler generic transformation, but also anchor so-called New Horror in the much older thematic concerns of the Gothic.

Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study

Abstract The art film Naked Lunch (1991) may have marked a turn away from the horror genre for David Cronenberg, but it also features both monsters and monstrosity. Protagonist Bill Lee wanders passively through a surreal landscape populated with fantastical creatures feeding him orders that correspond to the impulses he does not recognize within himself. By Cronenberg’s own description, these monsters are projections, excusing and externalizing Lee’s internal, unacknowledged anxieties. Since these monsters are embodied outside himself, Lee never has to confront his internal conflicts as such. Engaging with writings on horror and monsters by Julia Kristeva, Noël Carroll, and Jeffrey Jerome Cohen, this essay uses Naked Lunch to develop a Cronenbergian theory of monstrosity. Monsters objectify the abject, but in doing so evade the sources of abjection. Cronenberg, a filmmaker constantly exploring abjection and monstrosity, for the first time in his filmography articulates this problematic relationship between them explicitly in Naked Lunch.

I, Mugwump: projection, abjection, and Cronenbergian monstrosity in Naked Lunch

While numerous contemporary composers have explored the endless possibilities afforded by microtonal tuning systems, Western popular music has hitherto rarely ventured from the harmonic comfort zone of 12-tone equal temperament. This article highlights an unlikely exception to this trend in the emergence of a community of microtonal electronic dance musicians, and examines how changes in technology, culture, and distribution might have led to its development.

Microtonal Tunings in Electronic Dance Music: A Survey of Precedent and Potential

A cinema of wounded bodies: Sensational abjection and the spaces of modern horror

Le toréador, ou, L'accord parfait : opéra bouffon en deux actes = Der Toreador, oder, Der vollkommene Dreiklang : burleske Oper in zwei Akten : burlesque opera in two acts

Albert Wolff conducts Massenet : Orchestral suites nos. 4 & 7, etc

Christmas joy : instrumental solos for the holiday season : flute

Giselle : (a ballet in two acts) . Graduation Ball . Gaîté Parisienne

O holy night : for full chorus of mixed voices and solo soprano or tenor with piano accompaniment

O holy night! : cantique de Nöel : Christmas song : for voice and piano

Le Chalet. Opéra comique en un acte. Paroles de Mill. Scribe and Melesville. Partition Piano et Chant. Vol. 1.

Musique pour le ballet en 3 actes de meme titre. - 1re representation : Londres, Drury Lane theatre, 27 septembre 1845

20 Effect of speed humps on injuries consequences on highways transversing through towns

This study focused on the examining the increased attention to water in decentralization which is an issue that needs immediate action because without water there is no life. One way to improve performance of water service delivery is to fully decentralize this service and allow the decisions relating to water service delivery to be locally made for the local development. This study examined the impact of decentralization on water service delivery in Ukonga ward, Ilala District of Dar Es salaam, Tanzania. Existence of few empirical studies on the impact of decentralization on water service delivery is the motivation for this study. The study adopted a descriptive cross-sectional survey design that involved the use of questionnaires and interviews in collecting data from a sample of 375 respondents randomly selected from a population of 19,290 households of Ukonga ward. The study recommends that all the government through its agents responsible for water service delivery such as DAWASCO (Dar es salaam Water and Sewerage Corporation) and other agents in the local government level needs to use more resources and take a proactive approach in order to solve these problems such as; the price of piped water, the cost of water connection, cost of water maintenance, accessibility of water from DAWASCO well and access of piped water from DAWASCO. Finally the government should fully implement its policy of decentralization by devolution so that services such as water can be realistically closer to the people.

This study focused on the examining the impacts of prolonging conflicts and political instability on service delivery in Tanzania and Tarime cited as a case study. The research took place in Tarime district of Mara region where the researcher conducted his practical training as well as making an investigation on prolonging conflicts and political instability on service delivery using Tarime as one among of the major places found in Tanzania with persisting conflicts. Relevant literature readings necessary for accomplishing the study were done, the researcher tried to look on how other authors tried to explain about prolonging conflicts, also the researcher tried to look how other authors says on the impacts of prolonging conflicts and political instability on service delivery. The researchers used interview and questionnaire as a primary source of data collection from respondents, where other methods of data collection were not successful. The researcher administered face to face interview through continuous interaction with the targeted population who are Kurya elders, Tarime indigenous and government officials. Secondary source of data included reports from Tarime central police, Nyamwaga police station. The researcher comes out with findings that revealed the major causes and impacts prolonging conflicts and political instability on service delivery as well as the strategies used by the government to solve the given conflict. Conclusion and recommendation have been drawn, where the research has found out that the government measures are all ineffective and therefore the study recommends the government to work with the local community and come up with better short term and long term solutions to eradicate the problem of prolonged conflicts and political instability in Tarime

Mapping and Internet Based Public Transportation Journey Planning and Information Systems

An Overview of Corona Charged Aerosol Detection in Pharmaceutical Analysis

Development and validation of a high performance liquid chromatography-diode array detection method for the determination of aging markers in tequila.

The reduction of vapor-phase cis-1,2-dichloroethylene (cis-DCE) by zero-valent iron [Fe(0)] and nickel-plated iron (Ni/Fe) was assessed as a possible treatment strategy for organohalides in landfill gas and soil vapor extraction system offgas. The rate of cis-DCE removal and the consequent formation of ethylene, ethane, and vinyl chloride were measured in both batch and column reactors. Auger Electron Spectroscopy was used to determine nickel surface loading before and a fter reaction. In batch experiments, nickel surface loadings greater than 30% increased the pseudo-first-order rate constant for cis-DCE reduction by a factor of 10–20 over that of unamended Fe(0). In column studies using Ni/Fe particles (40% nickel surface loading), 100% removal of gaseous cis-DCE was initially achieved from both anaerobic and aerobic gas streams, compared to only partial removal of cis-DCE in columns containing Fe(0). The enhanced reactivity of Ni/Fe r eductants relative to Fe(0) diminished, however, over time in both a...

Treatment of Vapor-Phase Organohalides with Zero-Valent Iron and Ni/Fe Reductants

Applications of surface analysis in the environmental sciences: dehalogenation of chlorocarbons with zero-valent iron and iron-containing mineral surfaces

View of the political state of Scotland in the last century; A confidential report on the political opinions, family connections, or personal circumstances of the 2662 county voters in 1788

In study planning for large-scale epidemiological studies with multi-type examinations, important resource questions have to be answered, e.g. study horizons, personnel and other resources and cost estimates are needed. A simulation approach for scheduling that uses relevant parameters to simulate examination times gives simulation distributions that can be utilised to answer planning questions.

A simulation approach to study planning for large-scale epidemiological surveys.

Rising water scarcity in agriculture has been a major concern worldwide. As resource managers seek to address this issue, Integrated Water Resources Management (IWRM) has become a widely accepted sustainability paradigm. The purpose of this study is to evaluate restoration alternatives of irrigation tanks by applying multi-criteria and probabilistic benefit–cost analysis for a rural watershed in India. We incorporate the principles of local-IWRM, namely, hydrological balance, efficiency, equity, stakeholders’ involvement, and uncertainty. We use the mixed-method approach of data collection, including remotely sensed hydro-ecological data, walk-through field observations, focus groups, and household surveys. The study region produces a large percent of runoff water (i.e., about 67% of the total precipitation) which can be partially captured to sustain irrigation tanks. The majority of the tanks in the study area do possess moderate to high irrigation potential yet remain in poor conditions. A proposed lift irrigation scheme with a 75% or more increase in water availability could return from ₹ 1.23 to ₹ 1.73 on every Indian rupee (₹) invested, in addition to other socio-ecological benefits. The increase in water availability could lead to future crop area expansion, which comes with a high price tag. Therefore, using additional water on the existing crop area can be just as economically viable as water-induced crop expansion. A coordinated effort on the part of local agencies and water users is necessary for efficient and equitable use of incremental water that comes from any restoration efforts in the study area or elsewhere.

Multi-Criteria Hydro-Economic Decision Tool for Rejuvenating Community Irrigation Tanks in Rural India

Assessment of Watersheds for Sustainable Agriculture in Karnataka, India

Enhanced oxygen delignification of softwood pulp samples (taken upstream and downstream of a commercial oxygen delignification unit) improved the initial rate of enzymatic saccharification and overall yield of monomeric sugars by 62–82% and 76–80%, respectively. Laboratory‐scale experiments were used to examine the effect of a broad range of operating parameters (temperature, time, caustic concentration, and oxygen partial pressure) on the effectiveness of oxygen delignification. Using empirical models, kappa number (residual lignin content) was found to effectively predict final conversion to monomeric sugars. Application of oxygen delignification to sulfite mill knots resulted in smaller (20–25%) reduction in lignin content. However, using a combination of oxygen delignification and particle size reduction, up to 80% of the carbohydrate in the reject knots could be converted to fermentable sugars.

Effect of Oxygen Delignification Operating Parameters on Downstream Enzymatic Hydrolysis of Softwood Substrates

Oxygen delignification as a pretreatment for the enzymatic hydrolysis of lignocellulosic material

We reflect on the proceedings of a symposium at a conference of the Centers for Disease Control and Prevention National Center on Birth Defects and Developmental Disabilities. We present examples of bridging the gap between science and policy to achieve improvements in children's health through case studies in early hearing detection and intervention, folic acid fortification to prevent birth defects, sleep positioning recommendations to reduce infant mortality, and workplace lactation support programs. We discuss case studies that present different policy strategies (public health law and voluntary practices) for improving public health. These case studies demonstrate both the power of policy as a tool for improving children's health and the challenges of communicating public health research to policy decisionmakers.

Meeting the challenge: using policy to improve children's health.

EVALUATIONS, A TALE OF LOVE AND HATE STRATEGIC MANAGEMENT OF CHANGE

Research Park Development from a University Relationship Perspective: A Proposed Framework for Planning.

Variation and consistency in the performance-satisfaction relationship in industrial organizations

From esses to aitches: identifying pathways of diachronic change

Cell migration plays an essential role in the immune response and is tightly regulated by both chemical and mechanical cues. After exiting circulation, immune cells navigate through tissues while mechanically confined by extracellular matrix components and tissue-resident cells. Common in vitro systems enable modeling of leukocyte migration through collagen-based hydrogels (individual fiber stiffness ∼ 300 MPa) or in confined polymer-based microchannels (stiffness > MPa), however these existing systems fail to replicate the bidirectional mechanical interactions between migrating leukocytes and resident cells that typically exhibit a stiffness between 200-3000 Pa. Here, we utilize live-imaging of a dual-transgenic zebrafish to capture mechanical deformations of epidermal keratinocytes induced by interaction with migrating neutrophils. Subsequently, we engineer in vitro migration channels bound by a deformable liquid-liquid interface with tunable mechanical properties that replicate single cell keratinocyte deformations during neutrophil migration in vivo. We find that controlling the mechanical properties of the interface modulates neutrophil motility. This work introduces an in vitro controlled material interface that closely mimics the mechanical interactions between neutrophils and surrounding cells in vivo to provide a biologically relevant platform for exploring the influence of mechanical forces on cell migration.

Liquid-liquid interface microchannels with tunable mechanical properties mimic tissue deformations during neutrophil interstitial migration in vivo

A LOW COST INFLATABLE CUBESAT DRAG BRAKE UTILIZING SUBLIMATION Adam Horn Old Dominion University, 2017 Director: Dr. Robert L. Ash The United Nations Inter-Agency Debris Coordination Committee has adopted a 25-year post-mission lifetime requirement for any satellite orbiting below 2000 km in order to mitigate the growing orbital debris threat. Low-cost CubeSats have become important satellite platforms with startling capabilities, but this guideline restricts them to altitudes below 600 km because they remain in orbit too long. In order to enable CubeSat deployments at higher release altitudes, a low-cost, ultra-reliable deorbit device is needed. This thesis reports on efforts to develop a deployable and passively inflatable drag brake that can deorbit from higher orbital altitudes, thereby complying with the 25-year orbital lifetime guideline. On the basis of concepts first implemented during the NASA Echo Satellite Project, this study investigated the design of an inflatable CubeSat drag device that utilizes sublimating benzoic acid powder as the inflation propellant. Testing has focused on demonstrating the functionality of charging a Mylar drag brake bladder with appropriate quantities of benzoic acid powder, and the exposure to a controlled-temperature vacuum chamber causing the bladder to inflate. Although results show a measureable increase in internal pressure when introduced to anticipated orbital temperatures, a significant air-derived expansion prior to sublimation was encountered due to the undetectable volume of ambient residual air in the fabricated membrane bladders. These tests have demonstrated the feasibility of this approach, thereby demonstrating that this concept can create a potentially smaller and less expensive drag device, eliminating inflation gas tanks and valves. In that way, this system can provide a low-cost, miniaturized system that reduces a CubeSat’s orbital lifetime to less than 25 years, when placed at higher orbital altitude.

This thesis was conducted to determine the awareness of the Human Immunodeficiency Virus (HIV) in Russia. A perception model by David L. Rousseau and Rocio GarciaRetamero was used as a theoretical basis for this analysis. The perception model was adapted to analyze Russian-HIV research done between 1988 and 2013, and then compare the results to another analysis of research done from 2014 to the present. The results indicate that Russia’s awareness to the virus declined between 1988 and 2013 and remains in this general position due to stigmatization that has been documented between 2014 and the present. Russia faces an HIV epidemic and unless a more in-depth analysis of how Russians perceive the HIV situation is understood, Russia will be hard-pressed to eliminate the disease from within its borders.

Investigating Russian Awareness of HIV Using a Perception Model: An Analysis of Russia's Socio-Cultural Infrastructure

As automated tools for grading programming assignments become more widely used, it is imperative that we better understand how students are utilizing them. Other researchers have provided helpful data on the role automated assessment tools (AATs) have played in the classroom. In order to investigate improved practices in using AATs for student learning, we sought to better understand how students iteratively modify their programs toward a solution by analyzing more than 45,000 student submissions over 7 semesters in an introductory (CS1) programming course. The resulting metrics allowed us to study what steps students took toward solutions for programming assignments. This paper considers the incremental changes students make and the correlating score between sequential submissions, measured by metrics including source lines of code, cyclomatic (McCabe) complexity, state space, and the 6 Halstead measures of complexity of the program. We demonstrate the value of throttling and show that generating software metrics for analysis can serve to help instructors better guide student learning.

Proceedings of the 46th ACM Technical Symposium on Computer Science Education

An Empirical Study of Iterative Improvement in Programming Assignments

Functional Anatomy of the Forelimb Muscles of the Ocelot (Leopardus pardalis)

Giselle : ballet en deux actes sur un argument de Théophile Gautier et Jules-Henri Vernoy de Saint-Georges d'après Heinrich Heine

24 petits Noëls tres faciles pour piano ou harmonium = Easy Christmas carols = Leichte Weihnachtslieder

Giselle, ou, Les Wilis : ballet-pantomime en deux actes de Théophile Gautier et Saint-Georges

Table of content . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 About the content . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Is part of . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Editions of this work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 partitions (1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 spectacles (1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Pages in data.bnf.fr . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Related authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 This page in data.bnf.fr lab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Sources and references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Link to the main catalogue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Variant of the title

Opera-comique en 3 actes. - Dates de composition : novembre 1835-avril 1836. - 1re representation : Paris, Opera-Comique (salle de la Bourse), le 13 octobre 1836

Opera en 3 actes. - 1re representation : Paris, Theâtre-Lyrique, 6 octobre 1853. - 1re ed. (version chant et piano) : ca 1854

Table of content . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 About the content . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Is part of . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Editions of this work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 spectacles (1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 partitions (1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Pages in data.bnf.fr . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Related authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 This page in data.bnf.fr lab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Sources and references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Link to the main catalogue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Sources

Opera en 2 actes. - 1re representation : Paris, Opera-Comique (Salle Favart), 17 octobre 1855. - 1re ed. (version chant et piano) : Paris, 1855

Musique pour le ballet en 1 prologue et 3 actes de meme titre. - Compose avec la collaboration d'Alfred de Clemenceau de Saint-Julien. - 1re representation : Paris, Opera, 8 octobre 1849

There is a growing need for the integrated investigation of propulsion and thermal management system performance during the design of the gas turbine engine cycle. Previously, studies have focused on the development of transient, thermodynamic models of the energy conservation between the various subsystems to carry out these investigations. The current work builds on these previous studies by directly considering the exergy destruction throughout the integrated system. Physics-based formulations involving the concurrent usage of the first and second laws of thermodynamics are incorporated into an integrated propulsion and thermal management systems model. The inclusion of this information leads to the direct thermodynamic prediction of the system losses. The characterization of the thermodynamic irreversibility distribution helps give the propulsion systems designer an absolute and consistent view of the tradeoffs associated with the design of the entire integrated system.

Characterization of Thermodynamic Irreversibility for Integrated Propulsion and Thermal Management Systems Design

Optimal allocation of thermodynamic irreversibility for the integrated design of propulsion and thermal management systems

A methodology is presented for optimization of transient thermal responses of an “Energy Optimized Aircraft” modeling and simulation environment. The increasing challenges of aircraft thermal management and complex systems integration require knowledge about transient thermal loads early in the design cycle. A previously developed “Tip-to-Tail” aircraft thermal model provides this capability, but it is difficult to efficiently optimize the aircraft design directly. A surrogate modeling approach is chosen based on its ability to rapidly predict subsystem temperatures over a mission. The aircraft thermal management system is then designed to minimize exceedance of the temperature limit. Nomenclature limit1 MSE = mean squared error of liquid-cooled avionics temperatures greater than or equal to the limit limit2 MSE = mean squared error of liquid-cooled avionics temperatures greater than the limit sp MSE = mean squared error of liquid-cooled avionics temperatures from the setpoint i T

INVENT Surrogate Modeling and Optimization of Transient Thermal Responses

A system-level thermal management aircraft model has been developed in a multidisciplinary modeling and simulation environment. Individual subsystem models developed exclusively in MATLAB/Simulink, representing the vehicle dynamics, the propulsion, electrical power, and thermal systems, and their associated controllers, are combined to investigate the thermal management issues of a typical long range strike platform. A thermal tip-to-tail model allows conceptual design trade studies of various subsystems and can quantify performance gains across the aircraft. The final result is an aircraft that is thermally optimized at the system-level, rather than at the subsystemlevel. In addition, the model has been built without the aid of proprietary data, thereby allowing the distribution of the tool to a variety of conceptual design groups and researchers. Special attention has been paid to the development of transient component models within the thermal management systems, including the Integrated Power Package, heat exchangers, fuel and oil pumps, and the engine oil heat rejection. As a result, the thermal and power challenges that face modern aircraft can be addressed, potentially increasing the performance capabilities of future aircraft. Preliminary simulation results are discussed with a specific focus on the thermal challenges encountered during reduced engine power mission segments.

Facilitating the Energy Optimization of Aircraft Propulsion and Thermal Management Systems through Integrated Modeling and Simulation

The investigation of the thermal management requirements of gas turbine integrated power systems is becoming increasingly important during the conceptual design phase of advanced commercial and military aircraft engines. Much of this emphasis is due to the escalating thermal loads and the increasing interac tions between the various subsystems in today’s high-power applications. As a result, dy namic modeling and simulation of thermal management systems (TMS) in an integrated fashion is now of prime importance. The Numerical Propulsion System Simulation (NPSS) software has previously shown promise in the area of steady-stat e thermal modeling. The transient simulation capabilities and integrated modeling env ironment of this software are leveraged here to simulate the transient thermal re sponse within an integrated highpower concept. A proof of concept model has been created of a typical more-electric system that highlights the capability of the improv ed modeling method. For this model, the propulsion system and TMS have both been simulated in NPSS and linked to an electrical model created in Simulink. The results o f this integrated power system model are then presented. Nomenclature h = enthalpy m& = mass flowrate q& = heat transfer rate p = pressure t = time V = volume ρ = density

Thermal Management Modeling for Integrated Power Systems in a Transient, Multidisciplinary Environment

Today, operators of classic aircraft are seeking the addition of new technologies, such as the integration of GPS/FMS, and even complete Electronic Information Systems (EIS), in order to meet the demands of a rapidly changing operational environment. The addition of such items to an already crowded flight deck poses problems that the original manufacturer never had to consider. The most obvious is the lack of adequate and appropriate space ("real estate") in which to install such updates. Unfortunately, such additions in an already limited area, can lead to very different and quite unique crew interfaces due to the location chosen for the new display/control box (or boxes). This lack of space can also lead to the complex redesign, combining, and miniaturization of current systems simply to provide sufficient "real estate" to install the new box(es). This, in itself, may very well lead to increased crew workload which may not be immediately apparent to design engineers. This paper examines the human factors issues involved with the integration of modern electronic information systems into the flight deck of classic air transport category aircraft through the Supplemental Type Certificate process.

17th DASC. AIAA/IEEE/SAE. Digital Avionics Systems Conference. Proceedings (Cat. No.98CH36267)

The aftermarket integration of modern electronic information systems in classic aircraft-human factors design considerations

Recent changes in DoD procurement directives have encouraged the purchase of civilian products for use in certain military applications. One such application is the upgrade of avionics suites with the Global Positioning System (GPS) in military air transport aircraft to meet joint civil-military operational requirements. This paper reviews the Commercial Off-the-Shelf (COTS) concept and the proper use of TSOs, ACs, and FARs in both the design and integration process. It further describes the importance and methodology of using the FAA and qualified FAA Designated Engineering Representative (DER) pilots throughout the design and certification process to evaluate component functionality, pilot-device interface, cockpit integration issues, plus compatibility with current and projected airspace operational requirements. Emphasis is placed upon the creation and use of agreements and a detailed Certification Plan between the FAA, the applicant, and the user community which include both technical and human factors compliance methods.

Civil Certification of Avionics Modifications in Military Transport Category Aircraft

A ground-based simulator experiment was conducted to investigate the influence of simulator cue variations on helicopter autorotation landing-task performance. Using the NASA Ames Research Center Vertical Motion Simulator (VMS), variations were made in motion-system performance and selection of either longitudinal or lateral linear acceleration cues. Analysis of landing performance statistics and pilot commentary revealed that task performance changed with degraded motion cues. However, fixed base (no motion) could provide acceptable landing performance if adequate visual cues were present. Lontitudinal linear-acceleration cues assisted one pilot's control of the landing forward speed, while lateral linear-acceleration cues assisted in control of lateral drift or sideslip. Variations were also made in the content and details of visual landing scenes. Pilot commentary collected on the use of three landing scenes stressed the importance of receiving consistent, easily recognized, position, attitude, and speed cues from the visual scene. The importance of subtle aural cues to pilot acceptance of the simulation was also noted.

Abstract : Environmental testing of the YAH-64 helicopter was conducted in the McKinley Climatic Laboratory, Eglin Air Force Base, Florida. The US Army Aviation Engineering Flight Activity was responsible for the evaluation of aircraft systems and the US Army Aviation Development Test Activity was responsible for the mission equipment evaluation. The test consisted of 14.4 hours of aircraft operating time between 2 November and 16 December 1981. Testing was accomplished at 125, 70, -25, and -50 F with the aircraft attached to the hangar floor. At each temperature, testing consisted of preflight inspections, APU and engine starts, simulated mission profiles, engine shut down, and maintenance inspections. Nine deficiencies were found which would preclude mission accomplishment: (1) the fire control computer was unreliable, (2) the symbol generator required an excessive warm-up time at cold temperatures, (3) the heading and attitude reference system was unreliable, (4) the environmental control unit failed to provide adequate heating or cooling to the cockpit and avionics bays at -25 F, -50 F, and 125 F, (5) the TADS/PNVS and weapons systems did not function adequately at 125 F, (6) the APU aborted its start sequence because it could not accelerate the accessory gearbox to operating speed at -25 F and -50 F, (7) the hydraulic hand pump was ineffective at -25 F and -50 F, (8) the utility hydraulic manifold allowed the accumulator to bleed off at -25 F and -50 F, and (9) failure of the hydraulic flex lines at cold ambient temperatures.

Abstract : The United States Army Aviation Engineering Flight Activity conducted a climatic laboratory evaluation of the Boeing Vertol YCH-47D helicopter. Approximately 17-1/2 hours of aircraft operating time and 22 test runs were required to complete the test. The YCH-47D systems, subsystems and components were evaluated at stabilized temperatures ranging from -65 F to +125 F. In some cases, inconclusive results were obtained at the colder temperatures because the test was conducted without rotor blades. The foremost of which are the apparent inability of the flight control hydraulic fluid to warm sufficiently for flight and the pilot's inability to neutralize the flight controls prior to engine start. The YCH-47D performed acceptably from -25 F to 125 F and exhibited potential for operation at a temperature of -50 F. Two deficiencies were identified: (1) failure of the engine control lever to control the engine during start because of excess moisture in the cockpit; and (2) the erratic operation of the hydraulic power transfer units at -50 F. A total of 14 shortcomings were also identified. Further engineering testing below -25 F with rotor blades installed is recommended to determine if the hydraulic fluid temperature can be increased and maintained in flight at a level that would provide satisfactory flight control response and to evaluate the use of MIL-H-5606 hydraulic fluid at the lower temperatures. The operator's manual should specify a minimum temperature for aircraft operation. (Author)

Abstract : The YCH-47D helicopter icing test was conducted between 4 February and 28 March 1980. Twenty flights were conducted, seven in the artificial environment, eleven in natural icing and two flights in heavy snow. A total of 35 hours were flown with 17.4 hours in the icing environment. Testing was conducted at St. Paul, Minnesota, in two phases: (1) protected (the deice system operated automatically) in the artificial environment and (2) unprotected (the deice system in a standby status), both in the artificial and natural environment. The YCH-47D was evaluated at conditions varying from 0.1 to 1.5 gm/m cube liquid water content (LWC) and temperatures varying from -2 degrees C to -20 degrees C. Maximum time for an individual flight in the natural environment was 95 minutes at an average LWC of 0.2 gm/m cube and -10 degrees C.

Abstract : The Preliminary Airworthiness Evaluation of the YCH-47D helicopter was conducted between 11 September and 6 December 1979. Seventeen flights were required for a total of 41.4 hours, of which 32.8 hours were productive. Testing was conducted at the Boeing Flight Test Facility at Wilmington, Delaware. The YCH-47D exhibits improved lift capability at a hover (both in and out of ground effect) when compared to the CH-47C with fiberglass rotor blades and T55-L-712 engines. Higher airspeeds are also possible at high gross weights. The AFCS was found to be an enhancing characteristic. Twenty shortcomings and one deficiency were also documented during the test. The deficiency of delay in power steering activation should be corrected prior to operational deployment. The noise level in the cockpit and cabin showed no apparent improvement over previous models and was of sufficient magnitude to induce temporary hearing loss without adequate protection. The vibration levels became excessive above 145 KIAS, increasing to unacceptable prior to V sub H, with 6 per rev vibrations being predominent.

Preliminary Airworthiness Evaluation (PAE 1) of the YCH-47D Helicopter

Anecdotally, it is believed that the deadlift exercise brings about greater levels of central fatigue than other exercises; however no empirical evidence exists to support this view. Additionally, little is known about the acute endocrine response to heavy deadlift exercise and how this may differ to other similar compound exercises. Therefore, the aim of this study was to identify and compare the acute, neuromuscular and endocrine responses to squat and deadlift exercise. Ten resistance trained males completed 8 sets of 2 repetitions at 95 % of one repetition maximum. Maximum voluntary isometric knee extensor force (MVIC), along with measures of central (voluntary activation (VA) and surface electromyography (EMG)) and peripheral (electrically evoked control stimulus) fatigue were made prior to and 5 and 30 min post-exercise. Additionally, salivary testosterone and cortisol were measured at these same time points. MVIC was reduced after the completion of both exercises (p = 0.007) however no difference between exercises was evident. Similarly, although VA changed over time (p = 0.0001) no difference was observed between exercises. As a measure of peripheral fatigue, force from the control stimulus changed over time (p = 0.003) with a greater decrease evident after the squat (p = 0.034). EMG was reduced over time (p = 0.048) but no difference was seen between exercises. No change was seen in testosterone and cortisol. Even though a greater absolute load and larger volume-load was completed for the deadlift, no difference in central fatigue was evident between the two compound exercises. The greater peripheral fatigue observed after squat exercise may be due to the greater work completed by the quadriceps with this exercise. These results suggest that separate periodization, tapering and programming considerations may be unnecessary when using the squat and deadlift to develop muscular strength.

Acute neuromuscular and endocrine responses to two different compound exercises: squat versus deadlift.

Assessment of Alternate Viscoelastic Contact Models for a Bearing Interface between an Axial Piston Pump Swash Plate and Housing

Investigation of Off-axis Excitation due to Component Asymmetry with a Non-Resonant Dynamic Stiffness Test Method

An Upper Extremity Biomechanical Model: Application to the Bicep Curl

High‐Impact Practices, Student Agency, and Equity in Course Design and Assessment

Asking the Right Questions: Reflective Preparation for a Program Review

This study analyzes the debate between Kant and Schiller about the role of feelings in the moral sphere based on the concept of obligation ( Verbindlichkeit ) and the concept of chimerical ethics. The concept of obligation is a central concept in all development of ethics of Kant from the Prize Essay (1763) on. The notion of obligation plays an important role in the debate between Kant and Schiller, since Kant said the concept of duty and the concept of grace could not be harmonized as Schiller thought with the figure of the beautiful soul in Grace and Dignity (1793).  Kant discusses the notion of the chimerical ethics in the Lectures on Ethics based on the Baumgarten and Meier. One main characteristic of a chimerical ethical is imposed to human beings to perform an obligation that exceeds the human capacity. One could say that the concept of chimeric ethics influences the conception of moral fanaticism of the Critique of Practical Reason of Kant and the refusal of the ideal of perfection of Stoic ethics. In the debate between Kant and Schiller, the main point of divergence between them is about the possibility of realizing the ideal of moral perfection contained in the concept of the beautiful soul.

The ethics of Kant is often referred to as a deontological ethics, as one ethical conception, whose fundamental concept is moral obligation in contrast to the teleological ethics, whose fundamental concept is end. This dichotomy does not naturally capture the complexity of the ethical conception of Kant in relation to other ethical views as utilitarianism, ethical virtues, among others. The ethics of Kant also operates with the concept of end in the second part of The Metaphysics of Morals, the Doctrine of Virtue. Kant said that there are two ends which are both duties (MS, AA 06 382-3), namely, a "categorical imperative of pure practical reason (...)the concept of duty will lead to ends and will have to establish maxims with respect to ends we ought to set ourselves". These ends are our own perfection (eigeneVollkommenheit) and the happiness of others (fremdeGluckseligkeit). However, as claimed by Oliver Sensen (2015, p. 139), even if the concept of obligation (Verbindlichkeit, Verpflichtung, obligatio) is not that concept which routinely is used to summarize the ethical thinking of Kant, "obligation is at the heart of moral philosophy of Kant, and the bond behind many of the other concepts. " That is the case mainly when discussing the development of ethical thinking of Kant, especially the precritical ethical thinking, namely, what Kant thought about ethics before publication of The Groundwork of Metaphysics of Morals in 1785. The first book where Kant deals with moral philosophy is the Enquiry into the Distinctness of the Principles of Natural Theology and Morals or what is normally called the Prize Essay in 1763. The central concept here is the notion of the primary obligation and the precarious condition of the moral philosophy in this moment (A. A, II, 298). The concept of obligation here is not

This study deals with the debate between Kant and Schiller about the role of the inclinations and the duty in morality. Based on an epigram of Schiller many critics of the ethics of Kant said that Kant offers no place to feelings in ethics. However, this scenario has changed in recent years with several members of the Kant-Forschung highlighting the role that Kant gives virtue and feelings in his later works. Now it is a commomplace to identify the position of Schiller regarding the ethics of Kant with what Schiller said in his work Uber Anmut und Wurde. Therefore, this study seeks to show how duty and inclination plays an important role in the ethical conceptions of Schiller and Kant. Moreover, Schiller raises some objections against the ethics of Kant and this study aims to outline some answers from Kant to these objections in works such as The Metaphysics of Morals, Vorarbeiten zur Religion and Vorlesungen zur Moralphilosophie.

A lthough the National Survey of Student Engagement (NSSE) collects responses from hundreds of participating colleges and universities every year, its ultimate goal is not to collect data but to catalyze improvement in undergraduate education. Launched in 2000 by the Pew Charitable Trusts in response to growing national and local pressures for higher education to focus on measures of education quality and for colleges and universities to engage in meaningful improvement, the NSSE has become a leader in a campaign to focus attention on a number of relatively clear characteristics of effective environments for teaching and learning. The NSSE’s process indicators related to good practices in undergraduate education provide diagnostic information about concrete activities that can guide interventions to promote improvement. By 2014, more than 1,500 institutions had participated in the NSSE, and over 4.5 million students had completed the questionnaire. In addition, the launch of two complementary instruments, the Faculty Survey of Student Engagement (FSSE) and the Beginning College Survey of Student Engagement (BCSSE), have furthered efforts to encourage the use of data for improvement by equipping institutions with information about faculty perceptions and entering students’ expectations for engagement. Given these noble goals and all the student engagement data, what impact has the NSSE had on the use of data for improvement on campuses? And what lessons does this work suggest for the improvement agenda in higher education?

Using Mini‐Grants to Create Sustained Faculty Buy‐In for Student‐Centered Pedagogy and Assessment in STEM Foundation Courses

This study reconstructs some of the major criticisms of the ethics of virtue to the ethics of Kant and examines such criticism in the light of the debate between Kant and Schiller as to the role of duty and inclinations in moral actions. Proponents of the ethics of virtue criticize the dominance of ethics based on principles (Kantianism and utilitarianism) in contemporary moral thought. However, it is not always clear exactly which ethical conception these criticisms are addressed to and if, instead of a critique of the ethics of Kant, these criticisms are first aimed at the status quo of contemporary moral philosophy. The main criticism of the ethics of Kant considers the absence of a role to feelings and emotions in actions endowed with moral value. However, as will be shown, feelings and emotions are relevant to Kant’s moral philosophy, and therefore these criticisms are not directed to the ethics of Kant, but rather to a caricature of it.

Enterprise computing services play a critical role in universities enabling faculty, students, and staff to complete meaningful work and further goals of the institution. These services require physical server computers with processors, disk space, and memory. Physical servers take up data center space and consume power; they are designed for performance with little detail paid to ecological design. In an effort to reduce hardware and maintenance costs, a trend to virtualize these servers exists, which would also free up physical space and save energy. This exploratory case study explored the current sustainable computing trends at a large university in the Midwest as well as whether practices of virtualizing enterprise server computers were economically, socially, and ecologically sustainable. Finally, this study investigated how these practices were planned, monitored, and evaluated. Findings indicate virtualizing enterprise servers in the Intelligent Infrastructure is economically, socially, and environmentally sustainability. Recommendations for university leadership were developed as a result of data gathering and analysis from participant interviews, correspondence, observations and artifacts. Maximizing utility and outreach were the two dominant related themes present in the data sources.

Proceedings of PICMET '14 Conference: Portland International Center for Management of Engineering and Technology; Infrastructure and Service Integration

Exploring the sustainability life cycle of enterprise computers in higher education

Este artigo busca apontar semelhancas possiveis entre criticas de Schopenhauer a moral de Kant e as criticas contemporâneas de defensores de uma etica de virtude contra eticas de principios. Para tanto ele, primeiramente, reconstroi a critica de Schopenhauer. Em seguida, apresenta as criticas de Anscombe e MacIntyre as eticas de principios. Conclui apontando que, embora existam certamente diferencas, ambas coincidem em diversos aspectos. Palavras-chave: Kant. Schopenhauer. Etica de virtudes. Etica de principios. G.E.M. Anscombe. Alasdair MacIntyre.

Section 28(2) of the Constitution states that a child's best interest is of paramount importance in every matter concerning the child. Section 9 further provides that every person is considered equal before the law and has the right to equal protection and benefit of the law. Several grounds are listed relating to the unfair discrimination of persons, including their sexual orientation. The concept of care is incorporated in the Children's Act, and it entails a comprehensive description of parents' daily life regarding children and the powers and duties expected to ensure the general protection, well-being and best interests of the child.The aim of this contribution is to discuss the sexual orientation of a parent as a factor when considering care and the extent to which courts may give consideration to such a factor. The article will also address the question of whether or not the role of a parent's sexual orientation in determining the best interests of the child has changed since the common law concept of custody was replaced by the concept of care in the Children's Act. In this article, care and the best interests of the child will be discussed first. International law will be considered thereafter, followed by a discussion on the approach of our courts, pre- and post-1994, in order to come to a conclusion and make recommendations.

The Sexual Orientation of a Parent as a Factor When Considering Care

Esse artigo reconstroi as principais criticas de Hilary Putnam contra aqueles que tentam desqualificar a filosofia moral baseando-se em consideracoes ontologicas e epistemicas. Os que desqualificam a filosofia moral o fazem dentre outras razoes, por que os juizos morais careceriam de cientificidade, na medida em que nao haveria objetos correspondentes e, consequentemente, nao haveria condicoes de verdade. Por isso, os juizos morais seriam reduzidos a enunciados meramente emotivos. Em seguida, esse artigo reconstroi os tracos gerais do expressivismo de normas de Allan Gibbard a luz das criticas de Putnam. Finalmente, reconstroi algumas das principais criticas de Habermas ao expressivismo de normas de Gibbard.

Darling-Hammond, L., & Lieberman, A. (Eds.). (2012). Teacher education around the world: Changing policies and practices. New York, NY: Routledge.Exploring Different Nations' Approach to Teacher EducationTeacher quality is a key component of the educational policy discourse in countries around the world, with teacher preparation being at the center of many of those discussions. Teacher Education Around the World: Changing Policies and Practices (Darling-Hammond & Lieberman, 2012) considers how a variety of countries in different parts of the world endeavor to improve teacher education-from the preparation of prospective teachers to providing practicing teachers the support and resources needed to improve their teaching. Each chapter, except the last, in this edited book selects a country that traditionally scores highly on international education assessments and examines the teacher education policies in place in that country, the educational discourse around those policies, and the cultural zeitgeist that inform those policies and discourses. The final chapter, written by the book's editors, seeks to find common themes emerging from the earlier chapters that they believe can be transferred to other teacher education programs. Hammond and Lieberman (2012) use international educational assessments to select what they believe are exemplary teacher education programs, with the logical assumptions that if students perform well on these assessments then they are being taught well by good teachers, and thus teachers are being taught well in teacher-preparation programs, being given effective opportunities for professional development, or both.Teacher Education examines policies and practices in several countries in Asia, Europe, and North America that traditionally score highly on international educational evaluations. However, each chapter takes a different approach as each chapter's author or authors examine different aspects of their country's teacher education model. Some chapters endeavor to broadly describe teacher education in the country in its totality, while others focus more on current policies that directly influence teacher education in that county. For example, the particularly strong chapter on Finland's teacher education provides a thorough but concise description of the teacher education process, from training prospective teachers to the continuing education of practicing teachers, as well as addressing the cultural nuances that affect teacher education in the country. At the same time, another strong chapter focused on Canadian teacher education by thoroughly detailing Ontario's initiatives to improve K12 education that began in 2003, and what role in-service teacher training played in those initiatives. Other countries studied in the book include The Netherlands, The United Kingdom, Singapore, Hong Kong, Australia, and The United States. Each of these individual chapters takes a slightly different approach in balancing policy and procedures with the historical and cultural context informing those policies and procedures.The volume is at its strongest when it focuses less on the individual programs and instead chooses to examine the historical and cultural influences underpinning those decisions and debates. Chapter 1 (Finland), Chapter 5 (Hong Kong), and Chapter 6 (Ontario, Canada) do an excellent job of conveying the culture of the region as it related to education, how teacher education fit into that culture, and how the culture of education informed the policies, discourse, and decisions enacted affecting teacher education. For example, Chapter 1 describes how the Finnish people view education as "an integral part of the Finnish culture and society" (Salhberg, 2012, p. 4) and that teachers are held in high-esteem by the Finnish people. This contrasts to Ontario's view of education and view of teachers after a contentious and divisive political campaign targeting K-12 teachers. …

Dr. Feldhaus is an Associate Professor of Organizational Leadership with the Purdue School of Engineering and Technology at Indiana University Purdue University Indianapolis. He also serves as Chair of Gradaute Technology programs and recently developed the STEM Education track for the MS in Technology degree program. This partnership with the Indiana University School of Education allows students to receive the Indiana Teaching License in Engineering Technology Education and/or Computer Education as part of the MS in Technology degree.

AC 2011-2597: FACTORS THAT INFLUENCE THE USE OF SUSTAIN- ABLE TECHNOLOGY IN STRUCTURAL DESIGN

Este trabalho busca reconstruir, analisar e contrastar a concepcao de liberdade desenvolvida por Habermas em seus escritos a respeito de bioetica com a concepcao de liberdade na obra de Kant. Alem disso, embora Habermas seja herdeiro do kantismo (ao menos ele se intitula um herdeiro de Kant), e possivel tracar semelhancas e diferencas entre a posicao normativa habermasiana em Die Zukunft der menschlichen Natur e a posicao de Kant na Grundlegung e na Metaphysik der Sitten.

O filosofo e sociologo alemao Jurgen Habermas, sem soma de duvida, participou de 
grande parte dos debates contemporâneos a respeito de questoes fundamentais da 
filosofia como a disputa a respeito do estatuto de cientificidade das ciencias humanas e 
sociais, a respeito da legitimidade das normas juridicas em sociedades capitalistas 
avancadas, a respeito das implicacoes normativas dos recentes e futuros avancos no 
campo da engenharia genetica aplica a medicina reprodutiva, a respeito do papel da 
religiao na esfera publica, a respeito da plausibilidade de continuar o projeto kantiano de 
uma ordem mundial cosmopolita a luz de eventos historicos recentes, entre outras 
coisas. Na maioria das oportunidades em que se manifestou a respeito de tais temas, 
Habermas confrontou sua posicao com a de grandes pensadores do passado ou do 
presente como Kant, Hobbes, Rousseau, Foucault, Nietzsche, Hart, Dworkin, Weber, 
entre outros. 
Os estudos que compoem o presente volume foram apresentados em outubro de 
2011, durante o VII Coloquio Habermas: Habermas e Interlocucoes e II Simposio 
Nacional de Filosofia: Etica, Filosofia Politica e Linguagem em Londrina, no 
Anfiteatro Maior do Centro de Letras e Ciencias Humanas da Universidade Estadual de 
Londrina. 
A primeira parte do volume contem os resumos expandidos dos conferencistas e 
palestrantes convidados. A segunda parte contem os resumos expandidos das 
comunicacoes daqueles que submeterem seus trabalhos apenas nessa modalidade. A 
parte final, e mais extensa, contem os textos completos da comunicacoes daqueles que 
submeteram seus trabalhos na modalidade texto completo. 
Agradeco ao Dr. Delamar Jose Volpato Dutra pelo incentivo e apoio a realizacao 
do evento em Londrina. 
Agradeco a todos os professores do departamento de filosofia da Universidade 
Estadual de Londrina que de alguma maneira contribuiram para a realizacao do evento. 
Agradeco a todos os alunos da graduacao (em filosofia e direito) e posgraduacao 
em filosofia da Universidade Estadual de Londrina que de alguma maneira 
contribuiram com o bom andamento dos trabalhos, durante a realizacao do evento e ate 
mesmo antes dele, auxiliando na confeccao do material de divulgacao e na propria 
divulgacao do evento. 
Agradeco a CAPES e a Fundacao Araucaria pelo apoio financeiro ao Evento

Factors that Influence the Use of Sustainable Technology in Structural Design

Students Reflections on Learning in an Inquiry-based Number Theory Course

Este trabalho busca reconstruir a estrategia argumentativa habermasiana a respeito da eugenia liberal, clonagem humana, pesquisa com embrioes e diagnostico genetico de pre-implantacao assim como as principais criticas suscitadas a essa estrategia.

In the U.S., career/technical education (CTE) prepares high school students for the workplace, higher education, and civic involvement. In many instances, however, CTE's value to current and prospective students, parents, employers, and others is ambiguous or ill-informed. This paper outlines the evolution of CTE; identifies key changes and challenges to CTE in recent years; presents results of a recent study of the perceptions held by CTE graduates in engineering/science/technology and other related fields; and identifies the implications CTE has on lifelong learning, workforce readiness, and economic development activities. Considerations for college and university faculty and administrators, employers, and policymakers, among other stakeholders, will be discussed, and recommendations for policy, practice, and future research will be identified

2006 Technology Management for the Global Future - PICMET 2006 Conference

Career/Technical Education and Workforce Readiness: Perceptions, Implications, and Considerations

Clearly, all levels of education are moving towards a standards based form of assessment of student learning. At the K-12 level, State Departments of Education are leading the way by creating specific standards and using norm and criterion referenced standardized tests to ensure that minimum standards are met. At the university level, accrediting bodies, including the Accreditation Board for Engineering and Technology (ABET), have revised the criteria for accrediting programs. The new approach shifts emphasis away from what is being taught to what is being learned and is less proscriptive of required coursework [1]. Learning outcomes are now based on what students should know and be able to do in order to prove they are competent in both university and professional standards. But many questions remain regarding the best way to assess standards based student learning and aligning the numerous standards set forth by university, professional and regional accrediting bodies.

In volume 30, issue 4 of Art Therapy: Journal of the American Art Therapy Association, the name of an art therapist was incorrectly identified in “BroadeningHistory, Expanding Possibilities: Contributions ofWayne Ramirez to Art Therapy,” by Jordan Potash and Wayne Ramirez, pp. 169–176, DOI:10.1080/07421656.2014.847084. On p. 171, the name of the art therapist should appear as Herschel Stroyman, and not Herschel Strogman. The authors apologize for the error.

Abstract This pilot study examines an aspect of construct validity of the Draw-a-Person-in-the-Rain (DAPR) assessment utilizing a sample (N = 58) of third-grade public school children from three geographic regions of the United States (Great Plains, Rocky Mountain, and Pacific Northwest) that differ in climate and frequency of precipitation. A scoring system was used to indicate the presence or absence of environmental elements depicted in the drawings. Results indicate a significant difference between the scores on drawings from the Great Plains and those from the Pacific Northwest sites, suggesting that the typical precipitation pattern of a given region may influence how a person responds to the DAPR task. Although findings are preliminary, they suggest that further examination of the validity of the DAPR is needed.

Art Psychotherapy, 2nd edition, H. Wadeson. John Wiley & Sons, Inc., Hoboken, NJ (2010)

Investigating Resource Structure and Human Mobility: An Example from Folsom-Aged Bison Kill Sites on the U.S. Southern Great Plains

In this thesis I seek to demonstrate that the legal and
 customary norms defining the permissible use of lethal force by
 police are more restrictive than those defining the permissible
 use of lethal force by military personnel. I argue that in many
 cases this asymmetry can rest on a foundation provided by the
 moral norms of individual self- defense, but that the strength of
 this foundation is contingent on the context in which lethal
 force is used. Provided that three contextual asymmetries between
 police and military operations hold, we can morally justify the
 asymmetric legal and customary permissions granted to these two
 institutions on the basis of threat, liability, necessity, and
 proportionality. However, there are limits to the moral grounds
 these norms can provide. In cases where the three contextual
 asymmetries begin to break down, the moral foundation offered by
 the moral norms of individual self-defense weakens. In cases of
 contextual equivalence, we are forced to adopt one of two
 conclusions. Either we accept that our legal and customary norms
 are without moral foundation in such cases, or we must find
 alternative moral reasons to morally justify the asymmetry. In
 the final section I briefly draw out the strengths and weaknesses
 of both positions and offer some discussion of what other moral
 reasons we might use to shore-up the moral foundation for the
 asymmetry in the legal and customary norms regulating the
 permissible use by military and police institutions.

A Problem of Paradigms: Grounding Asymmetric Institutional Permissions for the Use of Lethal Force

This edited collection examines the ethical trade-offs involved in cybersecurity: between security and privacy; individual rights and the good of a society; and between the types of burdens placed on particular groups in order to protect others. Foreword Governments and society are increasingly reliant on cyber systems. Yet the more reliant we are upon cyber systems, the more vulnerable we are to serious harm should these systems be attacked or used in an attack. This problem of reliance and vulnerability is driving a concern with securing cyberspace. For example, a ‘cybersecurity’ team now forms part of the US Secret Service. Its job is to respond to cyber-attacks in specific environments such as elevators in a building that hosts politically vulnerable individuals, for example, state representatives. Cybersecurity aims to protect cyberinfrastructure from cyber-attacks; the concerning aspect of the threat from cyber-attack is the potential for serious harm that damage to cyber-infrastructure presents to resources and people. These types of threats to cybersecurity might simply target information and communication systems: a distributed denial of service (DDoS) attack on a government website does not harm a website in any direct way, but prevents its normal use by stifling the ability of users to connect to the site. Alternatively, cyber-attacks might disrupt physical devices or resources, such as the Stuxnet virus, which caused the malfunction and destruction of Iranian nuclear centrifuges. Cyber-attacks might also enhance activities that are enabled through cyberspace, such as the use of online media by extremists to recruit members and promote radicalisation. Cyber-attacks are diverse: as a result, cybersecurity requires a comparable diversity of approaches. Cyber-attacks can have powerful impacts on people’s lives, and so—in liberal democratic societies at least—governments have a duty to ensure cybersecurity in order to protect the inhabitants within their own jurisdiction and, arguably, the people of other nations. But, as recent events following the revelations of Edward Snowden have demonstrated, there is a risk that the governmental pursuit of cybersecurity might overstep the mark and subvert fundamental privacy rights. Popular comment on these episodes advocates transparency of government processes, yet given that cybersecurity risks represent major challenges to national security, it is unlikely that simple transparency will suffice. Managing the risks of cybersecurity involves trade-offs: between security and privacy; individual rights and the good of a society; and types of burdens placed on particular groups in order to protect others. These trade-offs are often ethical trade-offs, involving questions of how we act, what values we should aim to promote, and what means of anticipating and responding to the risks are reasonably—and publicly—justifiable. This Occasional Paper (prepared for the National Security College) provides a brief conceptual analysis of cybersecurity, demonstrates the relevance of ethics to cybersecurity and outlines various ways in which to approach ethical decision-making when responding to cyber-attacks.

Des aspects de la presente invention concernent des systemes, des procedes, des produits programmes d'ordinateur et analogues pour etablir une conference collaborative avec de multiples participants sur un reseau de communication, et plus specifiquement pour un dispositif de commande de conference dans le reseau concu pour commander certains aspects de l'etablissement d'une conference collaborative Dans un mode de realisation particulier, l'utilisateur du reseau peut acceder a l'application de systeme de commande afin de fournir un ou plusieurs parametres ou reglages de conference dont l'utilisateur souhaite disposer pendant une session de conference collaborative. Les parametres peuvent ensuite etre etablis par le systeme de commande et associes a la session de conference impliquant l'utilisateur. Dans un mode de realisation, de telles informations peuvent etre associees au jeton d'identification. Dans un autre mode de realisation, un utilisateur du systeme de commande de conference collaborative peut s'abonner pour recevoir une notification lorsqu'un autre utilisateur du systeme accede a une partie d'une conference collaborative du systeme.

Jeton d'identification dans un système de conférence collaborative

Systeme et procede d'integration de client voip pour une audioconference

Experimental Analysis of the Effects of the Variation of Drawbar Pull Test Parameters for Exploration Vehicles on GRC-1 Lunar Soil Simulant

With 1,500 companies now estimated to have set net zero targets, corporate engagement with carbon dioxide removal (CDR) has gained substantial momentum. Yet despite the corporate sector becoming a key domain of CDR decision-making, corporates have not received research attention as influential actors in the governance of CDR. This paper provides a perspective on how corporates influence and enact de facto governance of CDR. We collate a preliminary evidence base regarding possible modes of CDR governance by corporates. Focusing on voluntary corporate engagement with CDR, we examine how and why firm-level decision-making takes place, and interrogate the implications of such activity. We find that the current literature focuses on techno-economic attributes of CDR solutions as drivers of corporate engagement; however, the ability for corporates to formulate a (business) case for engaging with CDR is potentially shaped by a broader array of financial and non-financial factors that are currently overlooked. This gives corporates the influence to define what and how to govern, an inherently “political act.” We finally highlight possible lenses for future research, noting lessons to be drawn from climate justice, anticipatory governance, responsible innovation, and futures literatures. These could provide a deepened understanding of the dynamics and implications of current de facto CDR governance, and allow this to be challenged where appropriate. Ultimately, without awareness and oversight of how CDR is being governed in the real world, policy and governance research may not be successful in driving us toward desired net zero futures.

The Role of Corporates in Governing Carbon Dioxide Removal: Outlining a Research Agenda

User-Constrained Algorithms for Aggregate Residential Demand Response Programs with Limited Feedback.

The increasing pervasion of information and com- munication technology (ICT) in the power grid motivates innova- tive research towards intelligent system control. Especially against the background of the growing share of renewable generation, novel approaches that mitigate e. g. grid expansion costs are of great interest. In this paper, the self-organized and thus completely distributed control concept COHDA for the online scheduling of responsive loads is employed as an alternative to the traditional centralized control. By distributing the decision mak- ing process, no global state information about the participating devices has to be gathered beforehand. The proposed approach is applied to the mitigation of wind power fluctuations on a minute basis by controllable heat pumps. Simulation results indicate that even in the presence of moderate time delays between wind power measurements and the resulting control action from the responsive population (i. e. including the distributed scheduling process), a significant reduction of fluctuations can be achieved.

Self-Organizing Demand Response with Comfort-Constrained Heat Pumps

An appliance that is powered from alternating current and has two or more loads M1, M2 comprises a voltage regulator 820 a zero cross detector 830 and a microprocessor 810 that controls the voltage to each load M1, M2 so that the total current consumed does not exceed a predetermined level. Loads M1 and M2 may comprise motors for an agitator and a fan respectively, in a floor care appliance or vacuum cleaner (fig 1, 10). Microprocessor 810 may use internal timers to control the turn-on time and hence the average voltage supplied by triac units MOC1, MOC2. A current sensor 870 comprising a resistor or a Hall effect sensor detects the current consumed by a load. The microprocessor 810 may adjust the voltage according to either a table of values or a mathematical relationship and may be used to collect performance data for maintenance purposes.

Method of floor cleaning using apparatus with a removable suction nozzle

A floor cleaning device comprises a base portion 916 for movement along a surface, a handle pivotally connected to the base portion, a suction nozzle 918 connected to the base portion and movable between a first position away from the surface and a second position close to the surface, a pair of arms 928, 930 attached to the suction nozzle and extending rearwardly from the suction nozzle, the arms being pivotally connected to the base portion, and a recovery container removably mounted on the handle in fluid communication with the suction nozzle for holding dirt transported by the nozzle. A brush assembly 926 may be placed adjacent the nozzle. A liquid distribution system may also be provided. A squeegee may be connected to the nozzle.

A sol.Elle cleaning device refers to a device which comprises a base (44) for movement on a surface, a channel formed in the base (44), and a nozzle assembly (62) removably attached to the base (44), the nozzle assembly (62) comprising a sliding bolt, the sliding latch slidably engaging the base channel (44) for securing the nozzle assembly ( 62) to the base (44). The sliding latch includes a hook portion which cooperates with the rib for securing the nozzle assembly (62) to the base (44) when the sliding latch slides translational movement over a predetermined distance. The sliding bolt has a camming against a cam member for guiding the nozzle assembly (62) against the base (44) .Use cleaning hard floors.

Neural-Matrix style, high-density electrode arrays for brain-machine interfaces (BMIs) and neuroscientific research require the use of multiplexing: Each recording channel can be routed to one of several electrode sites on the array. This capability allows the user to flexibly distribute recording channels to the locations where the most desirable neural signals can be resolved. For example, in the Neuropixel probe, 960 electrodes can be addressed by 384 recording channels. However, currently no adaptive methods exist to use recorded neural data to optimize/customize the electrode selections per recording context. Here, we present an algorithm called classification-based selection (CBS) that optimizes the joint electrode selections for all recording channels so as to maximize isolation quality of detected neurons. We show, in experiments using Neuropixels in non-human primates, that this algorithm yields a similar number of isolated neurons as would be obtained if all electrodes were recorded simultaneously. Neuron counts were 41-85% improved over previously published electrode selection strategies. The neurons isolated from electrodes selected by CBS were a 73% match, by spike timing, to the complete set of recordable neurons around the probe. The electrodes selected by CBS exhibited higher average per-recording-channel signal-to-noise ratio. CBS, and selection optimization in general, could play an important role in development of neurotechnologies for BMI, as signal bandwidth becomes an increasingly limiting factor. Code and experimental data have been made available1.

Optimal Adaptive Electrode Selection to Maximize Simultaneously Recorded Neuron Yield

Multivariate analysis of fMRI data has benefited substantially from advances in machine learning. Most recently, a range of probabilistic latent variable models applied to fMRI data have been successful in a variety of tasks, including identifying similarity patterns in neural data (Representational Similarity Analysis and its empirical Bayes variant, RSA and BRSA; Intersubject Functional Connectivity, ISFC), combining multi-subject datasets (Shared Response Mapping; SRM), and mapping between brain and behavior (Joint Modeling). Although these methods share some underpinnings, they have been developed as distinct methods, with distinct algorithms and software tools. We show how the matrix-variate normal (MN) formalism can unify some of these methods into a single framework. In doing so, we gain the ability to reuse noise modeling assumptions, algorithms, and code across models. Our primary theoretical contribution shows how some of these methods can be written as instantiations of the same model, allowing us to generalize them to flexibly modeling structured noise covariances. Our formalism permits novel model variants and improved estimation strategies: in contrast to SRM, the number of parameters for MN-SRM does not scale with the number of voxels or subjects; in contrast to BRSA, the number of parameters for MN-RSA scales additively rather than multiplicatively in the number of voxels. We empirically demonstrate advantages of two new methods derived in the formalism: for MN-RSA, we show up to 10x improvement in runtime, up to 6x improvement in RMSE, and more conservative behavior under the null. For MN-SRM, our method grants a modest improvement to out-of-sample reconstruction while relaxing an orthonormality constraint of SRM. We also provide a software prototyping tool for MN models that can flexibly reuse noise covariance assumptions and algorithms across models.

Recommendation systems are becoming increasingly important, as evidenced by the popularity of the Netflix prize and the sophistication of various online shopping systems. With this increase in interest, a new problem of nefarious or false rankings that compromise a recommendation system's integrity has surfaced. We consider such purposefully erroneous rankings to be a form of “toxic waste,” corrupting the performance of the underlying algorithm. In this paper, we propose an adaptive reweighted algorithm as a possible approach towards correcting this problem. Our algorithm relies on finding a low-rank-plus-sparse decomposition of the recommendation matrix, where the adaptation of the weights aids in rejecting the malicious contributions. Simulations suggest that our algorithm converges fairly rapidly and produces accurate results.

Cleaning up toxic waste: Removing nefarious contributions to recommendation systems

We have developed an algorithm, called multi–motor unit action potential analysis (MMA), to aid quantification in routine needle EMG examination. In only 5–8 min, it was possible to extract, analyze, and validate 20 motor unit action potentials (MUAPs). In the biceps muscle of normal subjects, the MUAP measurements are compared with measurements using manual, triggered averaging, automatic decomposition, and other MMA algorithms described in the literature. The mean values of MUAP features by MMA fell between the extreme limits obtained from the amplitude‐triggered method and the manual method described in the literature. In patients, the results are consistent with routine EMG and similar to those results described in the literature. Fast acquisition and analysis of MUAPs as well as interference pattern (IP) analysis make this technique useful to document EMG abnormalities in routine needle examination.© 1995 John Wiley & Sons, Inc.

Differences in Long-Term Outcomes in End-Stage Kidney Disease Patients with Chronic Limb-Threatening Ischemia.

Investigating the Effects of a Lower Extremity Bypass Enhanced Recovery Pathway on Postoperative Opioid Use and Patient Pain Scores

Investigating Glycemic Control in Patients Undergoing Lower Extremity Bypass within an Enhanced Recovery Pathway at a Single Institution.

Accidental Central Venous Catheter Cannulation into Aberrant Arterial Anatomy Requiring Endovascular Intervention

Readmissions Following Endovascular Thoracoabdominal Aortic Repairs in the Vascular Implant Surveillance and Interventional Outcomes Network

Intravascular Ultrasound for the Evaluation and Management of Retroperitoneal, Genitourinary Malignancies

Aortic Visceral Segment Instability is evident following Thoracic Endovascular Aortic Repair for Acute and Subacute Type B Aortic Dissection.

Aortic Visceral Segment Instability Is Evident After Thoracic Endovascular Aortic Repair for Acute Type B Aortic Dissections

Concomitant paravisceral and thoracic mycotic aortic aneurysms in a cirrhotic patient

ANTI-PIG ANTIBODY IN INFANTS: CAN A GENETICALLY-ENGINEERED PIG HEART BRIDGE TO ALLOTRANSPLANTATION?

It has been speculated that the immunomodulation associated with pregnancy, e.g., decreasing pro-inflammatory cytokines, increasing anti-inflammatory cytokines, upregulation of T regulatory cells (Tregs), is in part due to the effect of human chorionic gonadotropin (hCG). In this study, we tested the effect of hCG on proliferation of human peripheral blood mononuclear cells (PBMCs) stimulated by irradiated pig PBMCs. Mixed lymphocyte reaction (MLR) was carried out with human PBMCs as responders and irradiated wild-type pig PBMCs as stimulators, with or without hCG. The spontaneous mean proliferation of CD3+T cells was 7% and, when stimulated by phytohemagglutinin (PHA) was 43%. When stimulated with irradiated wild-type pig PBMCs, CD3+T cell proliferation was 18%. When hCG (at concentrations of 100 IU/ml, 500 IU/ml, and 1,000 IU/ml) was added to the MLR, the proliferation of CD3+T lymphocytes was 20%, 20%, and 18%, respectively. hCG also had no effect on the proliferation of CD4+T and CD8+T cells. hCG does not suppress human lymphocyte proliferation stimulated by wild-type pig PBMCs in MLR (unless this is related to an increased number of Tregs, which was not tested in this study).

Lack of Effect of Human Chorionic Gonadotropin in Mixed Lymphocyte Reaction in Xenotransplantation

The Case for Pig Heart Xenotransplantation in Infants with Complex Congenital Heart Disease

The “Baby Fae” baboon heart transplant—Potential cause of rejection

There is a continuing need for donor hearts for infants with complex congenital heart defects. The transplantation of hearts from neonatal pigs would be an alternative to human organs, particularly if donor‐specific immunological tolerance could be achieved. The great majority of infant humans do not make natural (preformed) antibodies against triple‐knockout (TKO) pigs (that do not express any of the three known pig antigens against which humans have natural anti‐pig antibodies). The transplantation of a heart from a TKO pig into an infant would therefore minimize any risk of early antibody‐mediated rejection, and, with adequate immunosuppressive therapy, prolonged graft survival may well be achieved. Total host thymectomy (commonly carried out at the time of orthotopic heart transplantation in this age group) ± residual T‐cell depletion and donor‐specific pig thymus tissue transplantation might induce T‐cell tolerance and allow immunosuppressive therapy to be discontinued (if there is in vitro evidence of T‐cell and B‐cell nonresponsiveness to donor‐specific pig cells). Even if tolerance were not achieved, with continuing immunosuppressive therapy, the graft would likely “bridge” the patient until a suitable allograft became available or be associated with prolonged xenograft function.

An approach to induction of tolerance to pig cardiac xenografts in neonates

P03. Axillary tumour burden in low-risk breast cancer patients with an abnormal pre-operative axillary ultrasound: Are some patients being fast-tracked to a clearance?

A protein structure-guided drug design approach was employed to develop small molecule inhibitors of the BET family of bromodomains that were distinct from the known (+)-JQ1 scaffold class. These efforts led to the identification of a series of substituted benzopiperazines with structural features that enable interactions with many of the affinity-driving regions of the bromodomain binding site. Lipophilic efficiency was a guiding principle in improving binding affinity alongside drug-like physicochemical properties that are commensurate with oral bioavailability. Derived from this series was tool compound FT001, which displayed potent biochemical and cellular activity, translating to excellent in vivo activity in a mouse xenograft model (MV-4-11).

Design and Optimization of Benzopiperazines as Potent Inhibitors of BET Bromodomains.

Molecular basis of USP7 inhibition by selective small-molecule inhibitors

The invention relates to pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one and imidazo[5,1-f][1,2,4]triazin-4(3H)-one derivatives as inhibitors of the ubiquitin-specific protease 7 (USP7) useful in the treatment of cancers, neurodegenerative diseases, immunological disorders, inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, and bacterial infections and diseases, having the Formula (I) where R l , R 2 , R 3 , R 4 , R s , R s' , R 6 , X l , X 2 , m, and n are described herein.

PYRROLOTRIAZINONE AND IMIDASOTRIAZINONE DERIVATIVES AS OBIQUITIN-SPECIFIC PROTEASE 7 CUSP? ) INHIBITORS FOR THE TREATMENT OF CANCER AND OTHER USP7 MEDIATED DISEASES

Members of the Bromodomain and Extra-Terminal (BET) family of bromodomain-containing proteins (BRD2, BRD3, BRD4, and BRDT) bind to acetylated lysine residues on histone tails and act as epigenetic readers to regulate chromatin structure and gene expression. In particular, BET family member BRD4 has been shown to positively regulate the expression of MYC and other critical cancer-associated genes through the localization of BRD4 to super-enhancer regulatory elements. Results from preclinical studies conducted using the small molecule tool BET inhibitor (+)-JQ1, and emerging data from clinical trials of BET inhibitors in leukemia and lymphoma patients, have provided support for the therapeutic potential of BET inhibitors in hematologic malignancies.

A protein structure-guided drug design approach was employed to explore small molecule acetyl lysine mimetics and led to the identification of the BET inhibitor FT-1101, which is structurally unrelated to reported clinical-stage BET inhibitors in the (+)-JQ1 class. In biochemical binding assays, FT-1101 displayed equipotent inhibition of binding of both bromodomains in all four BET family members to a known bromodomain ligand (Kd ≤ 20 nM). In vitro , FT-1101 displayed potent anti-proliferative activity across a broad panel of human leukemia, lymphoma, and multiple myeloma cell lines, with 66 out of 123 cell lines having IC50 values < 500 nM. For the MV-4-11 acute myeloid leukemia cell line, the anti-proliferative activity of FT-1101 (IC50 = 40 nM) correlated with down-regulation of MYC gene and protein expression, suggesting that its anti-proliferative activity was at least in part due to suppression of MYC . Additionally, genome-wide mapping of BRD4 super-enhancer binding sites in MV-4-11 cells by ChIP-sequencing identified several potential pharmacodynamic biomarkers outside of the MYC signaling network.

In vivo , in the MV-4-11 xenograft model, oral treatment with FT-1101 at its maximum tolerated dose resulted in significant tumor growth inhibition, including tumor regressions, on schedules ranging from once daily to once weekly, and similar activity was also observed in the THP-1 AML xenograft model. Superior in vivo efficacy in the MV-4-11 model was observed for FT-1101 relative to BET inhibitors of the (+)-JQ1 class. In vivo efficacy was associated with prolonged drug exposure and a >75% decrease in MYC gene expression in tumors that was sustained for at least 12 hours. FT-1101 also crossed the blood-brain barrier in mice, achieving a pharmacologically relevant free drug concentration in the brain.

The promising preclinical profile of FT-1101 warranted its rapid progression into human clinical trials, and a Phase 1 study in patients with relapsed refractory acute leukemia or high-risk myelodysplastic syndrome is currently underway.

Disclosures No relevant conflicts of interest to declare.

FT-1101: A Structurally Distinct Pan-BET Bromodomain Inhibitor with Activity in Preclinical Models of Hematologic Malignancies

Two strategies toward the total synthesis of maoecrystal V (1) culminating in the construction of core structures 2 and 3 are described.

This work describes the preparation of approximately 13,000 compounds for rapid identification of hits in high‐throughput screening (HTS). These compounds were designed as potential serine/threonine or tyrosine kinase inhibitors. The library consists of various scaffolds, e.g., purines, oxindoles, and imidazoles, whereby each core scaffold generally includes the hydrogen bond acceptor/donor properties known to be important for kinase binding. Several of these are based upon literature kinase templates, or adaptations of them to provide novelty. The routes to their preparation are outlined. A variety of automation techniques were used to prepare >500 compounds per scaffold. Where applicable, scavenger resins were employed to remove excess reagents and when necessary, preparative high performance liquid chromatography (HPLC) was used for purification. These compounds were screened against an ‘in‐house’ kinase panel. The success rate in HTS was significantly higher than the corporate compound collection. © 2004 Wiley Periodicals, Inc.

Preparation of kinase‐biased compounds in the search for lead inhibitors of kinase targets

Total synthesis of spongistatin 1: a synthetic strategy exploiting its latent pseudo-symmetry.

High Affinity, Bioavailable 3‐Amino‐1,4‐benzodiazepine‐Based γ‐Secretase Inhibitors.

A new approach to the synthesis of 1,4-benzodiazepines and 3-amino-1,4-benzodiazepines, which employs the Pd-catalyzed cross-coupling reaction of an imidoyl chloride with an organometallic reagent as the key step, is described. A five-step synthesis of a key intermediate is described and it is shown that in only four further steps (three couplings and a TFA-mediated BOC-deprotection) a wide variety of N1-, C3-amino-, C5-carbon-, or nitrogen-substituted 1,4-benzodiazepines can be synthesized.

New Synthesis of 1,3-Dihydro-1,4-benzodiazepin-2(2 H )-ones and 3-Amino-1,3-dihydro-1,4-benzodiazepin-2(2 H )-ones: Pd-Catalyzed Cross-Coupling of Imidoyl Chlorides with Organoboronic Acids

New synthesis of 1,3-dihydro-1,4-benzodiazepin-2(2H)-ones and 3-amino-1,3-dihydro-1,4-benzodiazepin-2(2H)-ones: Pd-catalyzed cross-coupling of imidoyl chlorides with organoboronic acids.

In this paper, we describe the development of a novel series of high affinity, orally bioavailable 3-amino-1,4 benzodiazepine-based gamma-secretase inhibitors for the potential treatment of Alzheimer's disease. We disclose structure-activity relationships based around the 1, 3 and 5 positions of the benzodiazepine core structure.

High affinity, bioavailable 3-amino-1,4-benzodiazepine-based gamma-secretase inhibitors.

High affinity, bioavailable 3-Amino-1,4-benzodiazepine-Based γ-Secretase inhibitors

In this issue of the journal, Bowring et al.(1) examine the impact of splitliver (SL) offer acceptance on liver transplant candidate mortality. SL transplantation was developed to increase access to sizeappropriate deceased donor liver allografts for young children who are at particularly high risk of waitlist mortality.(2,3) It is a technically challenging procedure in which a whole liver (WL) is meticulously divided into 2 transplantable partial allografts. The leftsided allograft is most often allocated to a child, whereas the larger rightsided allograft is commonly allocated to an adult. When successfully performed, SL transplantation doubles the number of liver transplantations performed from a single donor and helps mitigate the organ shortage. The techniques for implantation and complications associated with SL transplantation pose unique challenges compared with WL transplantation. In SL transplantation, a microvascular arterial reconstruction must be performed in the recipient of the graft allocated without the common hepatic artery. The need for a hilar dissection/ hepatic duct transection and the presence of a parenchymal cut surface increases the risk for biliary complications. In addition, the reduced liver mass of the SL requires more careful recipient selection to minimize the risk of early postoperative hepatic insufficiency (smallforsize syndrome) or primary graft nonfunction.(4) These challenges, in conjunction with historical data suggesting inferior graft survival, explain the overall hesitancy of many centers to use SL for adult recipients.(5,6) As a result, half of all adult SL offers are accepted below candidate sequence number 12, and SL comprise only 1.5% of all liver transplantations performed in the United States.(7) SL use is also concentrated at certain centers with expertise in the procedure, with only 10 centers performing nearly 50% of all SL transplants in the United States.(7) In their groundbreaking article, “Survival Benefit of SplitLiver Transplantation for Pediatric and Adult Candidates,” Bowring et al.(1) examine mortality in adult and pediatric candidates who accepted an SL offer compared with mortality in candidates who declined an SL offer and remained on the transplant waiting list. Their findings call into question the practice of declining an SL offer in the hope of finding a “better” offer in the future. The authors used a case control study design to analyze Scientific Registry of Transplant Recipients data on candidates who were ever offered an SL graft. The primary endpoint was mortality after adjustment for individual patient factors. The results demonstrated a 43% reduction in mortality for small pediatric candidates (≤7 kg) and a 63% reduction in mortality for adult candidates who accepted an SL offer compared with those who declined an SL offer. The authors conclude that the benefit of using the SL allograft greatly exceeds the combined risk of mortality from waiting for a different offer and posttransplant mortality from using a different allograft of unknown quality. Given these findings, it stands to reason that a concerted effort should be made to prioritize SL transplantation in the United States. However, current local and regional variances attempting to increase the number of SL transplants by having an often high Model for EndStage Liver Disease adult candidate offered a WL voluntarily agree to an SL have been largely unsuccessful. Conversely, a mandatory splitting policy modeled after the Italian experience, which resulted in an increase in SL transplants with a decrease in both pediatric and adult waitlist mortality, could be successful but likely contentious.(8) An alternative third option would be to confer some additional prioritization to adult candidates willing to accept an SL allograft within the framework of a continuous distribution model.(9) In this model, Abbreviations: SL, split liver; WL, whole liver.

The Coronavirus Disease 2019 (COVID‐19) pandemic has substantially impacted solid organ transplantation, including temporary inactivation of waitlist candidates with COVID‐19 infection. We report two cases of liver transplantation (LT) in individuals with asymptomatic COVID‐19 infection. The first patient is a 68‐year‐old female with decompensated cirrhosis complicated by worsening frailty and sarcopenia. The second patient is a 22‐year‐old female with acute liver failure likely secondary to drug/toxin exposure. Both patients were treated with COVID‐19‐directed therapies and neither patient developed symptomatic disease. These cases demonstrate that LT can be safely performed in select patients with asymptomatic COVID‐19 infection at the time of transplant.

Successful liver transplantation in patients with active SARS-CoV-2 infection

OBJECTIVE Recent data have suggested that persistent opioid use is prevalent following trauma. The effect of type of injury and total injury burden is not known. We sought to characterize the relationship between injury location and severity and risk of persistent opioid use. METHODS We investigated postdischarge opioid utilization among patients who were admitted for trauma between January 2010 and June 2017 using the Optum Clinformatics Database. New persistent opioid use (NPOU) was defined as one of the following scenarios: (1) two separate opioid prescription fills between 0 and 14 days postdischarge and having 1+ fills in the 91 to 180 days following discharge or (2) filling a prescription in the 15 to 90 days following discharge in addition to a filling in the 91 to 180 day postdischarge period. Multivariable logistic regression was used to assess the relationship between injury type and severity with new persistent opioid use development. RESULTS A total of 26,437 opioid-naive patients were included in the analysis. Overall, 2,277 patients (8.6%) met the criteria for NPOU. After adjustment for confounding, NPOU was significantly more common for patients with injury to the extremities (adjusted odds ratio [aOR], 1.75; 95% confidence interval [CI], 1.57–1.94) or abdomen (adjusted odds ratio [aOR], 1.42; 95% CI, 1.22–1.64). Importantly, patients with maximum Abbreviated Injury Scale score of ≥2 for any body region had 1.49-fold odds of NPOU compared with patients with score of 1 (95% CI, 1.28–1.73), while no difference was seen across groupings of total injury burden based on Injury Severity Score. CONCLUSION New persistent opioid use is common among patients suffering from trauma. In addition, patients suffering from extremity and abdominal injuries are at highest risk. Maximum individual region injury severity predicts development of new persistent use, whereas total injury severity does not. LEVEL OF EVIDENCE Prognostic and epidemiological, level III.

Effect of injury location and severity on opioid use after trauma

Sleep Patterns and Quality Among Inpatients Recovering From Elective Surgery: A Mixed-Method Study.

Why do these issues exist? Is there a deficit in providers knowledge or skill or healthcare system process or outcomes? Please explain. Evaluating the effectiveness of laws is difficult because of the confounding variable that change over time. Pooled time series allow for other states to control for these variables and allow the impact of changes in laws to be measured over long periods of time.

Supplemental digital content is available in the text. OBJECTIVE The American Association for the Surgery of Trauma (AAST) developed an anatomic grading system to assess disease severity through increasing grades of inflammation. Severity grading can then be utilized in risk-adjustment and stratification of patient outcomes for clinical benchmarking. We sought to validate the AAST appendicitis grading system by examining the ability of AAST grade to predict clinical outcomes used for clinical benchmarking. METHODS Surgical quality program data were prospectively collected on all adult patients undergoing appendectomy for acute appendicitis at our institution between December 2013 and May 2018. The AAST acute appendicitis grade from 1 to 5 was assigned for all patients undergoing open or laparoscopic appendectomy. Primary outcomes were occurrence of major complications, any complications, and index hospitalization length of stay. Multivariable models were constructed for each outcome without and with inclusion of the AAST grade as an ordinal variable. We also developed models using International Classification of Diseases, 9th or 10th Rev.—Clinical Modification codes to determine presence of perforation for comparison. RESULTS A total of 734 patients underwent appendectomy for acute appendicitis. The AAST score distribution included 561 (76%) in grade 1, 49 (6.7%) in grade 2, 79 (10.8%) in grade 3, 33 (4.5%) in grade 4, and 12 (1.6%) in grade 5. The mean age was 35.3 ± 14.7 years, 47% were female, 20% were nonwhite, and 69% had private insurance. Major complications, any complications, and hospital length of stay were all positively associated with AAST grade (p < 0.05). Risk-adjustment model fit improved after including AAST grade in the major complications, any complications, and length of stay multivariable regression models. The AAST grade was a better predictor than perforation status derived from diagnosis codes for all primary outcomes studied. CONCLUSION Increasing AAST grade is associated with higher complication rates and longer length of stay in patients with acute appendicitis. The AAST grade can be prospectively collected and improves risk-adjusted modeling of appendicitis outcomes. LEVEL OF EVIDENCE Prospective/Epidemiologic, Level III.

Validation of the American Association for the Surgery of Trauma grading system for acute appendicitis severity

Validation of the AAST Grading System for Acute Cholecystitis Severity

Statewide Prehabilitation Program and Episode Payment in Medicare Beneficiaries.

Pilot of an Asynchronous Web-based Video Curriculum to Improve Firearm Safety Counseling by Pediatric Residents.

A scoping review of patterns, motives, and risk and protective factors for adolescent firearm carriage

Rates and correlates of risky firearm behaviors among adolescents and young adults treated in an urban emergency department.

Timely treatment is essential for optimal outcomes after burn injury, but the method of resource distribution to ensure access to proper care in developing countries remains unclear. We therefore sought to examine access to burn care and the presence/absence of resources for burn care in India.

METHODS
We surveyed all eligible burn centers (n=67) in India to evaluate burn care resources at each facility. We then performed a cross-sectional geospatial analysis using geocoding software (ArcGIS 10.3) and publicly available hospital-level data (WorldStreetMap, WorldPop database) to predict the time required to access care at the nearest burn center. Our primary outcome was time required to reach a burn facility within India. Descriptive statistics were used to present our results.

RESULTS
Of the 67 burn centers that completed the survey, 45% were government funded. Over one billion (75.1%) Indian citizens live within two hours of a burn center, but only 221.9 million (15.9%) live within two hours of a burn center with both an intensive care unit (ICU) and a skin bank. Burn units are staffed primarily by plastic surgeons (n=62, 93%) with an average of 5.8 physicians per unit. Most burn units (n=53, 79%) have access to hemodialysis.

While many Indian citizens live within two hours of a burn center, most centers do not offer ICU and skin bank services that are essential for modern burn care. Reallocation of resources to improve transportation and availability of ICU and skin bank resources is necessary to improve burn care in India.

Journal of burn care & research : official publication of the American Burn Association

"Geospatial Mapping as a Guide for Resource Allocation Among Burn Centers in India".

Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery

Comment on: medium to long-term outcomes of bariatric surgery in older adults with super obesity.

The quality of surgical care in safety net hospitals: a systematic review.

Background: The incidence of esophageal cancer (EC) in Michigan (MI) is among the highest in the nation. Moreover, even higher rates are observed among the state's most vulnerable minority populations. The purpose of this study was to quantify the utilization of resources by African-American (AA) EC patients at the University of Michigan Medical Center (UMMC), a state sponsored hospital tasked with providing cancer care for all MI residents.

Methods: All patients presenting with a diagnosis of stage I-III EC from April 2007 to April 2012 were identified using the UMMC information technology department. A retrospective chart review was performed eliciting information on demographics, comorbid conditions and treatments received. We used multivariable logistic regression to examine patient demographics, comorbid conditions and tumor specific characteristics as predictors of receipt of neoadjuvant chemoradiation and esophagectomy. Patients with cervical esophageal cancers and stage IV disease were excluded.

Results: A total of 718 patient charts (95.1% white, 2.26% AA, 2.64% asian/hispanic/other) were reviewed. Overall, only 14 of the 16 AA patients were MI residents. White patients were more likely to travel greater distances compared with AA patients (median distance in miles 242.1 vs. 81.0, respectively, p<0.001). Although UMMC is approximately 30 miles from Metro Detroit, only 5 AA patients from this area sought care at UMMC. AA patients were more likely to report current tobacco use (56.3% vs. 23.4%, p<0.01) at the time of diagnosis, have squamous cell histology (62.5% vs. 7.82%, p<0.001) and have tumors located in the mid-esophagus (43.8% vs. 6.1%, p<0.001), compared with white patients. AA and white patients were largely indistinguishable in terms of age at the time of diagnosis, the number of comorbid conditions, insurance status and stage at diagnosis. After adjusting for patient factors, comorbid conditions and tumor characteristics, AA patients (OR 0.12, 95%CI 0.02-0.55), patients with congestive heart failure (OR 0.21, 95%CI 0.08-0.60) and pulmonary disease (OR 0.45, 95%CI 0.23-0.91) were significantly less likely to undergo esophagectomy. There were no race-related differences in the use of neoadjuvant chemoradiation.

Conclusions: Racial disparities in the treatment of EC are widely recognized and considered an important public health and policy concern. UMMC provides care for more than 50% of all EC patients in MI. However, relatively few AA patients seek care at UMMC, a high volume regional center. Our ability to estimate racial differences in care within UMMC was limited by sample size constraints among the AA population. Efforts to reduce racial disparities in treatment and ultimately improve EC outcomes will require providers to assure that patients are referred for the appropriate treatments and have assistance navigating the cancer care system. 

Citation Format: Sha'Shonda L. Revels, Charles A. Mouch, Rishindra M. Reddy. Limited esophageal cancer care access among African American patients in Michigan. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B58.

Abstract B58: Limited esophageal cancer care access among African American patients in Michigan.

We present 3 cases of a 12-year-old boy, an 8-year-old girl, and a 9-year-old boy with progressive paresis of the peroneal nerve. Peroneal intraneural ganglia are a rare cause of paralysis of the lower limb in children; more often these symptoms occur because of exostosis. Ultrasound imaging in both patients showed a cystic mass near the fibular neck. Magnetic resonance imaging examination revealed that the ganglion is communicating with the proximal tibiofibular joint. Surgical exploration in these patients confirmed a cystic formation involving the common peroneal nerve. The ganglion originates from the articular nerve branch to the proximal tibiofibular joint. Total recovery of nerve function was seen 2 years later for the first patient, whereas the other 2 showed immediate postoperative improvement of peroneal nerve function and complete recovery within 6 to 8 weeks. On the other hand, patients with exostosis showed varying outcomes. In children with symptoms suspicious of nerve compression, fast diagnosis and immediate treatment are necessary to ensure the best possible recovery.

An Unusual Cause of Paralysis of the Peroneal Nerve: A Report of 3 Cases

BOARD OF LIGHTS AND WATER SPECIAL MEETING City of Marietta Meeting Agenda

Social networks and college performance: Evidence from dining data

Contesting student identities : making sense of students’ positioning in higher education policy.

Although numerous studies have examined if students of color benefit from having a teacher of the same race/ethnicity, all attention has been paid to students without disabilities. We examine whether the same benefits hold for students with disabilities (SWDs). Using a nationally representative data set of kindergartners, we explored whether SWDs of color had different academic and social–emotional outcomes when with a teacher of the same race/ethnicity. We compared students of color with and without disabilities in the same classroom with regard to a same-race teacher match. Unlike students without disabilities, we do not find evidence in the data set that SWDs of color benefit from a same-race teacher match in terms of achievement and social–emotional development. Implications with regard to educational equity are discussed.

Same-Race Student–Teacher: Comparing Outcomes for Kindergartners With and Without Disabilities

Our nation’s classrooms have become increasingly racially and ethnically diverse. Given these demographic changes, many policymakers and practitioners have expressed the need for increased attention to how teacher diversity might be linked to reducing racial/ethnic differences in teachers’ ratings of social-emotional skills for students of color. Using the most recent nationally representative data, we investigated whether kindergarteners have different social-emotional ratings when they had a teacher whose racial/ethnic group was the same as their own. We found that having a teacher of the same race was unrelated to teachers’ ratings of children’s internalizing problem behaviors, interpersonal skills, approaches to learning, and self-control. However, students whose teachers’ race/ethnicity matched their own had more favorable ratings of externalizing behaviors. Results are discussed in terms of implications for school disciplinary policies.

Author(s): Wright, Adam C. | Advisor(s): Startz, Richard | Abstract: This dissertation consists of three essays in applied microeconomics that investigate how teacher and student interactions affect human capital and skill accumulation. The first essay addresses the topic of how race and ethnicity affect teachers’ perceptions students’ behavior. African-American students are considerably more likely than their white peers to be rated as disruptive by their teacher and experience school discipline, but are also much less likely to have a teacher of the same race. This paper explores whether the racial or ethnic congruence of teachers and students affects teachers’ perceptions of students’ disruptive behavior and has larger consequences for student suspension rates. To identify the effect of racial interactions on teacher assessments, I estimate models that include both classroom and student fixed effects. I find that African-American students are rated as less disruptive when they have an African-American teacher, whereas perceptions of white and Hispanic students’ disruptiveness are unaffected by having a teacher of the same race or ethnicity. I also find that African-American students with more African-American teachers are suspended less often, suggesting the underrepresentation of African-American teachers has important implications for black-white gaps in school discipline.The second essay, coauthored with Michael Gottfried and Vi-Nhuan Le, examines whether gaps in social-emotional skills between students of color and white students is smaller in classrooms with teachers of color. Our nation’s classrooms have become increasingly racially and ethnically diverse. Given these demographic changes, many policymakers and practitioners have expressed the need for increased attention to how teacher diversity might be linked to reducing racial/ethnic differences in teachers’ ratings of social-emotional skills for students of color. Using the most recent nationally representative data, we investigated whether kindergartners have different social-emotional ratings when they had a teacher whose racial/ethnic group was the same as their own. We found that having a teacher of the same race was unrelated to teachers’ ratings of children’s internalizing problem behaviors, interpersonal skills, approaches to learning, and self-control. However, students whose teachers’ race/ethnicity matched their own had more favorable ratings of externalizing behaviors. Results are discussed in terms of implications for school disciplinary policies.In the third essay, I estimate spillovers of teachers from a selective alternative teacher certification program. The growing prevalence of teachers from selective alternative teacher certification programs has prompted research into how these teachers affect their own students’ performance. Little is known, however, about how the presence of this type of teacher might affect the performance of other teachers. This paper explores the extent to which the presence of teachers from a selective alternative certification program, Teach For America, affects grade-level student achievement in nearby grades. Using data from California elementary schools, I find that grades adjacent to Teach For America grades improve in both math and English as Teach For America presence increases.

Marksizm byl i wciąz zdaje sie byc dominującą perspektywą teoretyczną w obrebie krytycznej analizy polityki edukacyjnej. Autor opisuje zroznicowane „obrazy” szkoly obecne w teorii marksistowskiej, a krytykowane za determinizm ekonomiczny i redukcjonizm klasowy. Odwolując sie do prac Ernesto Laclaua, prezentuje alternatywne dla marksizmu ramy teoretyczne, ktore mozna wykorzystac w krytycznych badaniach produkcji i implementacji polityki edukacyjnej. Z tej perspektywy, szkola oraz polityka edukacyjna postrzegane są jako przestrzenie politycznej kontestacji i walki o hegemonie.

The school as an arena of political contestation: education policy from a post-Marxist perspective

Presidential Succession: The Role of the President in Succession Planning at Baptist Colleges and Universities.

The hierarchical nature of higher education, in which schools compete in small enclaves for the best students, and competition for higher rankings among private, non-profit liberal arts colleges has prompted some schools to drastically increase their tuition in order to correspond with the price changes of rival institutions. Since top liberal arts schools operate with sizable excess demand for enrollment spots, significant tuition alterations generally do not affect the quantity of enrolled students at these schools. However, the extent to which increases in tuition affect the quality of enrolled students has not been thoroughly examined. This study directly analyzes the sensitivity of student quality to a change in tuition. This analysis includes the development of a theoretical model that relates student quality to price by maximizing the educational reputation of a non-profit, liberal arts college subject to its tuition revenue minus its cost of operation. This model is used to derive an equation for the price elasticity of student quality and then is tested empirically by measuring the effect of tuition changes on student quality. The results show a more significant negative relationship between full tuition and student quality for lower ranked schools.

An analysis of tuition and enrollment in higher education : measuring price elasticity

Abstract Quantitative analysis of multicellular organization, cell–cell junction integrity, and substrate properties is essential to understand the mechanisms underlying collective cell migration. However, spatially and temporally defining these properties is difficult within collectively migrating cell groups due to challenges in accurate cell segmentation within the monolayer. In this paper, we present Matlab®-based algorithms to spatially quantify multicellular organization (migration distance, interface roughness, and cell alignment, area, and morphology), cell–cell junction integrity, and substrate features in confocal microscopy images of two-dimensional collectively migrating endothelial monolayers. We used novel techniques, including measuring the migrating front roughness using a parametric curve formulation, automatically binning cells to obtain data as a function of distance from the migrating front, using iterative morphological closings to fully define cell boundaries, quantifying β-catenin localization as a measure of cell–cell junction integrity, and skeletonizing fibronectin to determine fiber length and orientation. These algorithms are widely accessible, as they use common fluorescent markers and Matlab® functions, and provide high-throughput critical feature quantification within collectively migrating cell groups. These image analysis algorithms can help standardize feature quantification among different experimental techniques, cell types, and research groups studying collective cell migration.

Quantification of Multicellular Organization, Junction Integrity, and Substrate Features in Collective Cell Migration

Endothelial directed collective migration depends on substrate stiffness via localized myosin contractility and cell-matrix interactions.

Overview of Microsystems for Studying Cell Behavior Under Culture

Mechanotransduction of Substrate Stiffness in Endothelial Cell Collective Migration

Angioneural Crosstalk in Scaffolds with Oriented Microchannels for Regenerative Spinal Cord Injury Repair

Pupillometry is used clinically to evaluate retinal and optic nerve health by measuring pupillary function in response to light stimuli. We have developed an algorithm using murine pupillometric measurements to automate the analysis of pupillometric data. The raw data is filtered and thresholding is used to remove data caused by eye blinking, loss of pupil tracking, and/or head movement. Twelve physiologically relevant parameters are extracted from the collected data. Algorithm derived values do not deviate significantly from the manually calculated parameters (p ≥ 0.05). This algorithm can be used to establish normative values of pupillary light responses for humans, as well as wild-type and transgenic mouse strains, which can subsequently be used as reference metrics for characterizing the retinal phenotype of retinal disease. Furthermore, it will be instrumental in the assessment of functional visual recovery in humans and pre-clinical models of retinal degeneration and optic nerve disease following pharmacological or gene-based therapies.

Proceedings of the 2010 IEEE 36th Annual Northeast Bioengineering Conference (NEBEC)

Impairment of Pupillary Light Responses in Murine Models of Retinal Degeneration

Matrix biology : journal of the International Society for Matrix Biology

Chondroitin sulfate based niches for chondrogenic differentiation of mesenchymal stem cells.

Response of zonal chondrocytes to extracellular matrix‐hydrogels

Human embryonic germ (hEG) cells have the potential to self-renew over long periods of time and differentiate into various lineages. Cells derived from embryoid bodies of hEG cells express a broad spectrum of gene markers and have been induced towards cells of ecto-dermal and recently endo-dermal and mesenchymal lineages. LVEC cells express a number of surface marker proteins characteristic of mesenchymal stem cells (MSCs), indicating the potential of these cells to differentiate into mesenchymal tissues. Here we demonstrate the homogenous differentiation of LVEC cells into hyaline cartilage. Three dimensional tissue formation is achieved by encapsulating cells in synthetic hydrogels followed by incubation in chondrocyte-conditioned culture medium. Homogenous hyaline cartilage was produced, even after 63 population doublings (13 passages). The high proliferative capacity of these cells without teratoma formation, homogenous differentiation, and three-dimensional cartilage tissue formation suggests the significant potential of LVEC cells for cartilage tissue engineering applications

Chondrogenic differentiation of human embryonic germ cell derived cells in hydrogels

Enhanced chondrogenic differentiation of murine embryonic stem cells in hydrogels with glucosamine.

Histamine H1 and H2 receptor-mediated vasoreactivity of human internal thoracic and radial arteries.

Cette invention porte sur un procede d'administration transdermique d'un agent actif volatile, de preference choisi parmi la Nicotine et la Selegiline. Ce procede comprend l'application a une zone de la peau d'une solution, de preference sous forme de pulverisation, contenant l'agent actif volatile dissous dans un solvant volatile dont la concentration se situe dans la plage de 0,5 a 25% en poids sans occlusion de la solution appliquee.

Procédé et système pour l'administration transdermique d'un agent actif volatil

Cette invention concerne un systeme d'administration transdermique comprenant une composition qui contient un agent pharmacologique et un activateur de penetration, lequel activateur comprend du polyethylene glycol (PEG) presentant un poids moleculaire moyen egal ou inferieur a 300.

Système d'administration transdermique pour hormones et stéroïdes

La presente invention concerne un instrument (1) concu pour appliquer un volume de liquide sur une surface a traiter. Cet instrument comprend un moyen de support (3) sur lequel est monte un receptacle (2) qui definit un espace de reservoir (4) concu pour recevoir le liquide. Le receptacle presente une paroi (6) qui comporte une surface active utilisee pour etaler le liquide sur la surface a traiter. La paroi (6) peut etre deformee de facon resiliente, de maniere que, en service, la surface active reste en contact avec la surface a traiter lors de l'etalement du liquide. L'instrument selon cette invention s'utilise de facon specifique pour appliquer une lotion transdermique au niveau de la region axillaire de l'utilisateur. Cette invention concerne aussi un systeme d'administration transdermique d'un agent actif physiologique d'une composition liquide, ainsi qu'un procede permettant de mettre en oeuvre ce systeme.

Les pansements adhesifs decrits presentent un adhesif comprenant un copolymere sequence reticule et un plastifiant. Ce copolymere sequence comprend des segments durs et souples, un reticulation chimique existant entre les segments souples, et le plastifiant etant present en une quantite d'au moins 10 % en poids de l'adhesif. Le plastifiant est un ester huileux a poids moleculaire eleve. Les segments sont en mesure de transporter et d'administrer des doses accrues d'antagonistes 5-HT3, notamment d'ondansetron et de granisetron.

Annales de medecine legale, criminologie, police scientifique et toxicologie

Extending contingency management to the treatment of homeless youth

Affective, Behavioral, and Social-Cognitive Dysregulation as Mechanisms for Sexual Abuse Revictimization

Misinformation, traumatic memory, and memory assessment / by Adam Reichle.

Although Essential Tremor is one of the most common movement disorders, current treatment options are relatively limited. Peripheral tremor suppression methods have shown potential, but we do not currently know which muscles are most responsible for patients' tremor, making it difficult to optimize suppression methods. The purpose of this study was to quantify the relationships between the tremorogenic activity in muscles throughout the upper limb. Muscle activity was recorded from the 15 major superficial upper-limb muscles in 24 subjects with Essential Tremor while they held various postures or made upper-limb movements. We calculated the coherence in the tremor band (4-12 Hz) between the activity of all muscle pairs and the time-varying phase difference between sufficiently coherent muscle pairs. Overall, the observed pattern somewhat mirrored functional relationships: agonistic muscle pairs were most coherent and in phase, whereas antagonist and unrelated muscle pairs exhibited less coherence and were either consistently in phase, consistently antiphase, consistently out of phase (unrelated pairs only), or else inconsistent. Patients exhibited significantly more coherence than control subjects (p<0.001) in the vast majority of muscle pairs (95 out of 105). Furthermore, differences between patients and controls were most pronounced among agonists; thus, the coherence pattern existing in control subjects was accentuated in patients with ET. We conclude that tremor-band activity is broadly distributed among the muscles of the upper limb, challenging efforts to determine which muscles are most responsible for a patient's tremor.

Essential Tremor accentuates the pattern of tremor-band coherence between upper-limb muscles.

Distribution of tremorogenic activity among the major superficial muscles of the upper limb in persons with Essential tremor

Distribution of tremor among the major degrees of freedom of the upper limb in subjects with Essential Tremor

Distribution of Essential Tremor in the Degrees of Freedom of the Upper Limb Adam Charles Pigg Department of Mechanical Engineering, BYU Master of Science This study seeks to understand upper limb tremor in subjects with essential tremor (ET). A thorough understanding of tremor distribution will allow for the more effective development of tremor suppression devices, which offer an alternative to current treatments. Previous studies primarily focused on tremor in the hand only. This study seeks to characterize the distribution of tremor throughout the upper limb. We measured tremor in 25 subjects diagnosed with ET using motion capture, which provided displacement information of the limb during multiple postural and kinetic tasks. Inverse kinematics allowed us to analyze the motion capture data in the 7 major degrees of freedom (DOF) of the upper limb. The power spectral density estimate was used to determine: relative tremor magnitude throughout the DOFs, tremor variation between tasks, variation between subjects, and frequency variations between DOFs. Data analysis revealed that tremor increase is roughly proximal to distal. We also show that tremor magnitude in kinetic tasks is significantly higher than in postural tasks. Although we found some variation in tremor distribution between subjects, the roughly proximal to distal increase in tremor severity holds for several subsets of the study population. Finally, we found that tremor frequency doesn’t vary significantly (< 1 Hz) between DOFs, in subjects with severe tremor. Our study shows that tremor distribution is quite stereotyped between subjects with ET. Furthermore, we have shown that tremor is greatest in the distal DOFs. This provides a compelling starting point for the development of future tremor suppression devices.

Distribution of Essential Tremor in the Degrees of Freedom of the Upper Limb

Tremor is the most common movement deficit and manifests in a variety of disorders, including Essential Tremor, Parkinson's Disease, Dystonia, and Cerebellar Ataxia. Although medication and surgical interventions have significantly reduced patient suffering, they are only partially effective and can carry undesired side effects, leaving many patients without satisfactory treatment options. Wearable tremor-suppressing devices could provide an alternative to medication and surgery. Multiple research groups have developed orthotic prototypes to low-pass filter tremor, but these devices have not yet been optimized for in-vivo use. Optimizing non-invasive tremor suppression requires an understanding of where the tremor originates mechanically (which muscles) and how it propagates to the hand (where it matters most). Here we present on the beginnings of our multi-pronged work to determine the origin, propagation, and distribution of Essential Tremor, and we provide preliminary results.

2017 International Conference on Rehabilitation Robotics (ICORR)

Toward quantitative characterization of essential tremor for future tremor suppression

Introduction: Essential Tremor (ET) is the most common type of tremor and one of the most common movement disorders. It manifests as low-frequency (4-12 Hz) postural and kinetic tremor and is exacerbated by emotion, exercise, and fatigue. In most patients, ET produces a tremor in the upper limbs, making activities of daily living difficult or impossible. Despite its devastating effect on upper limb function, we do not know how ET is distributed throughout the upper limb. Most studies have focused on either a single degree of freedom (DOF) or endpoint tremor. While these methods are useful for reducing the complexity of the problem and focusing on the neurophysiology of ET, they are insufficient for developing optimal treatment options. Using motion capture sensors and surface electromyography (EMG), we are characterizing the severity and frequency of tremor in the major DOFs of the upper limb of patients with ET.

Characterization of essential tremor in the major degrees of freedom of the upper limb

Adaptation of Micro Vibration Motors from Cell Phones to Corneal Incisions

 Different simulated injection scenarios can significantly cool carbon capture utilization and storage (CCUS)wells. Cases representing different scenarios were modeled to help determine appropriate temperature specifications for completions equipment in CCUS wells.
 Depleted reservoirs, in particular gas reservoirs, will not support a static column of liquid or dense-phase CO2 to surface at the initial reservoir pressure. During injection, unless there is significant friction or backpressure, the upper part of the well will be at low pressure, with CO2 in the gas phase. Injected, liquid CO2 will depressurize across the wellhead choke, or the upper tubing, resulting in significant cooling as the saturation curve is reached and the CO2 starts flashing. For steady-state injection across a narrow range of rates, a tapered or narrow completion string can be designed that provides sufficient friction pressure to keep the CO2 in the liquid phase. A portfolio or set of wells, potentially with different tubing sizes, will give more flexibility for managing injection rates.
 Transient scenarios such as injection startup or shutdown cause rapid changes in rate and can consequently induce severe thermal shocks. These cannot be completely prevented using only friction or passive downhole devices. Many completion options have been proposed to provide flexibility for injection rate changes and/or reservoir pressure increases. These include concentric or dual strings providing multiple flow paths with different flow areas and hence friction, downhole passive chokes, backpressure control valves, surface-operated downhole flow control valves, and various combinations of these and other technologies. Currently, the only methods to eliminate all the scenarios consideredmay be (active) backpressure control and surface-controlled downhole flow control valves. Whereas the transient effects are most severe in depleted reservoirs, they are also shown to occur in reservoirs approaching hydrostatic pressure.
 The most important component in the completion string is arguably the subsurface safety valve (SSSV). API 14B specifies a maximum leak rate for the closed SSSV. Following a blowout or depressurization event, a leak of high-pressure, liquid CO2 from below the SSSV to low-pressure, gas-phase CO2 above will cause localized cooling at the SSSV, in addition to that caused by the initial depressurization condition. Modeling included simulations of blowout and subsequent SSSV leakage phases for different periods of injection and hence reservoir cooldown.
 To quantify these effects, the work considered temperatures in the different radial sections of the well versus time and depth. Sensitivities on annulus fluid, reservoir properties including pressure and permeability, the rate of mass transfer between phases, and other variables were also investigated. Modeling was performed using a commercial dynamic multiphase flow simulator.

Temperature Specifications for CCUS Completions Equipment: Steady-State and Transient Thermal Simulations

 Horizontal wells increase the reservoir-wellbore contact area, allowing the wells to produce at higher flow rates with smaller drawdowns which is especially important in oil reservoirs with a large gas cap or aquifer. Long wellbore lengths can lead to production challenges such as water or gas coning and cusping, an unwanted fluid breakthrough from high-permeability zones, and uneven inflow along the wellbore and nonuniform reservoir sweep.
 Inflow control devices (ICDs), based on well-established technology, have been used in hundreds of wells worldwide. Different ICD types and design methods are available and can be applied to mitigate some of the production challenges. The ICDs are installed as an integral part of the sand screens in the well completion hardware. They can be passive, where the ICD size and configuration does not change after it is run in the hole, or autonomous, where the ICD adapts to changes in downhole fluid-flow properties. However, the decision regarding the use of ICDs as well as the design criteria and selection has to be made prior to the well completion operation.
 This paper presents a feasibility study on an ICD application in an offshore Nigeria delta oil field with multiple hydrocarbon-bearing reservoirs. Most of the development wells in the field have horizontal openhole 1,000 to 3,000 ft drain sections completed with standalone screens. Strong aquifer and reservoir heterogeneity create production challenges associated with early water breakthrough and suboptimal reservoir sweep. This paper presents a detailed approach to ICD design, sensitivity analysis, and completion optimization, which is based on the coupling of a 3D reservoir model, segmented wellbore model, and ICD models. The proposed ICD completion design is evaluated and sensitized to subsurface reservoir uncertainties using volumetrics. The final decision process is presented to guide the selection and feasibility of an ICD application for two reservoirs.

Feasibility Study and Selection Process for ICD Applications in an Offshore Niger Delta Field

Efficient Optimization Strategies for Developing Intelligent Well Business Cases

Optimized Modeling Workflows for Designing Passive Flow Control Devices in Horizontal Wells

Implementation of Customized Algorithms Extends Downhole Flowmeter Application in Two-Phase Oil/Gas Flow: A Subsea North Sea Case Study

Hydroxyl Radical-Driven Transformations of Bisphenol a and 2,4 Dinitroanisole: Experimental and Computational Analysis

This study investigated the kinetics and reaction mechanisms associated with advanced oxidation of 2,4‐dinitroanisole (DNAN) with light emitting diodes (LEDs) in the UV/H2O2 process. The pseudo first‐order reaction rate constants for DNAN oxidation depended on the H2O2/DNAN molar ratio and were between 0.017 and 0.026 min−1. Hydroxyl radical scavenging was strongly implicated by the experimental results. High mass spectrophotometric chromatograms showed the presence of several by‐products, including three with ecotoxicity that is greater than that of DNAN. Transformation pathways were analysed using Density Functional Theory (DFT), which helped to predict the presence of experimentally detected DNAN by‐products by considering Mulliken charges. This study is the first to elucidate DNAN transformation mechanisms using both experimental studies and computational chemistry.

2,4‐dinitroanisole transformation during advanced oxidation with ultraviolet light emitting diodes and hydrogen peroxide

The persistence of high consequence public health pathogens in a wastewater treatment system can significantly impact worker safety, as well as the public and downstream water bodies, particularly if the system is forced to shut down the treatment processes. This study utilizes organism viability to compare the persistence of three pathogen surrogates in wastewater using a pilot-scale activated sludge treatment (AST) system, operated to mimic treatment processes of large-scale plants. Bacillus globigii spores, surrogate for Bacillus anthracis, persisted in the AST system for at least a 50-day observation period leading to a possible steady condition far beyond the solid retention time for sludge particles. MS2 bacteriophage, surrogate for Poliovirus and other non-enveloped enteric viruses, was observed for up to 35 days after introduction, which largely and expectedly correlated to the measured solid retention time. Phi-6 bacteriophage, a surrogate for Ebola virus and other enveloped viruses, was detected for no more than 4 days after introduction, even though the AST system was operated to provide three times slower solids removal than for the other surrogates. This suggests Phi-6 is subject to inactivation under AST conditions rather than physical removal. These results may suggest similar persistence for the surrogated pathogens, leading to appropriate consequence management actions.

Persistence of surrogates for high consequence viral and bacterial pathogens in a pilot-scale activated sludge treatment system

Bioaerosol emission is correlated to quantitative descriptors across different scales.

The effect of mixing and free-floating carrier media on bioaerosol release from wastewater: a multiscale investigation with Bacillus globigii

Bioaerosol emissions from activated sludge basins: Characterization, release, and attenuation

The removal of chlorinated hydrocarbons by mineral phases is important in areas where biologically mediated natural attenuation might not remove recalcitrant pollutants. Most investigations into mineral phases include ferric iron oxides or hydroxides that need a source of ferrous iron to facilitate pollutant reduction. Mixed phase iron oxides were shown to be much stronger at reducing chlorinated hydrocarbons. This work expands on other studies with mixed phase iron oxides by examining them at high pH and without buffer. This work also examined the effect of Fe(II) species that form at higher pH both by themselves and in association with magnetite nanoparticles on reaction potency and product distribution of chlorinated pollutants. Results show that Fe(II) alone produces species that may react better than magnetite alone and the combination of magnetite and Fe(II) species had a synergistic effect on pollutant removal at pH 10 or more.

Abiotic Reduction Transformations of Recalcitrant Chlorinated Methanes, Chlorinated Ethanes, and 2,4-Dinitroanisole By Reduced Iron Oxides at Bench-Scale

Abiotic Reduction of Nitrite and Nitrate by Nanoscale Chemogenic Magnetite: Pathways for Significant Greenhouse Gas Production

ABIOTIC REDUCTION OF NITRITE AND NITRATE BY CHEMOGENIC MAGNETITE NANOPARTICLES: IMPLICATIONS IN NITROGEN CYCLING AND GREENHOUSE GAS PRODUCTION

This paper discussed why making sense of maths is important for Scottish children. It was presented at the Contemporary Childhood Conference, September 2014.

Innovative practices: why making sense of maths is important for Scottish children

Black's Guide to Liverpool and Birkenhead; With Environs Including New Brighton and Southport

Covering television, film, radio and theatre, the Dictionary of Media Studies includes thousands of words and expressions used in the media and entertainment industries. Whether someone wants to find out the definition of cinema verite or the components of a storyboard, this dictionary has all the answers. Handy supplements include details of media law in the UK, contact and circulation details for major magazines and newspapers, and a list of key media resources on the Web. "Ideal for the 100,000 students of media studies at GCSE and above." Publishing News

Adam & Charles Black, 1807-1957 : some chadters in the history of a publishing house

Black's guide to West Kent : Tunbridge Wells, Maidstone, Rochester, etc.

Black's general atlas of the world : containing the latest discoveries, new boundaries, and introductory description

Outlines of comparative anatomy intended principally for the use of students

Foreword by Rachel Joyce The annual edition of the best-selling guide to all aspects of the media and how to write and get published, the Writers' & Artists' Yearbook is now in its 109th edition. Acknowledged by the publishing industry, authors and would-be writers as the indispensable companion to navigating the world of publishing. The 80+ articles provide inspirational and how-to guidance on writing for newspapers, magazines, scripts for film, radio and TV; advice on writing and submitting plays, poetry, non-fiction and fiction of all genres - from fantasy to thrillers to romance; how to contact publishers and agents; managing finances as a writer; negotiating legal issues, such as copyright; understanding the editing process; self-publishing and conventional routes; digital and print. NEW articles in the 2016 edition include: Alison Weir Historical fiction Ben Schott On writing Rose Prince Writing about food Sara Wheeler Travel Writing Danny Hahn Literary translation Nick Spalding Being a hybrid author Mel Sherratt Successful self-publishing Mike Poulton Adapting works for the stage Julia Copus Being a published poet and pieces on: Writing theatre reviews, Graphic novels, Getting poetry published, Literary festivals, Greetings cards Every one of over 4,500 listings of who to contact, where and for which disciplines across the media, are reviewed and most updated, with new listings added every year. The combination of up-to-date listings information and expert advice, make the Yearbook a topical and reliable resource; the perfect gift for every writer every year.

the pursuit of this interesting and important study, which has been too mllC neglected in this country?one reason, probably, why physiology, as taug1'1' in many of our schools, remains disfigured by many crude theories and spe' culations, which have long since disappeared on the Continent; tested, a_3 they have been there, by the rigid laws deduced from the successful pursu1' of comparative anatomy, embryogeny or organogenesy, and teratology* ?{ the science of monstrosities. The co-ordinate pursuit of these department of science has given birth to the doctrine of morphology, or the unity of ?f' g-anic elements, which, under the various forms which they assume in d''' ferent classes and genera of animals, is the very foundation of the Frenc.

The Psychological Science Accelerator’s COVID-19 rapid-response dataset

A large interdisciplinary body of research on human judgment and decision making documents systematic deviations between prescriptive decision models (i.e., how individuals should behave) and descriptive decision models (i.e., how individuals actually behave). One canonical example is the loss-gain framing effect on risk preferences: the robust tendency for risk preferences to shift depending on whether outcomes are described as losses or gains. Traditionally, researchers argue that decision makers should always be immune to loss-gain framing effects. We present three preregistered experiments (N = 1,954) that qualify this prescription. We predict and find that while third-party observers penalize decision makers who make risk-averse (vs. risk-seeking) choices when choice outcomes are framed as losses, this result reverses when outcomes are framed as gains. This reversal holds across five social perceptions, three decision contexts, two sample populations of United States adults, and with financial stakes. This pattern is driven by the fact that observers themselves fall victim to framing effects and socially derogate (and financially punish) decision makers who disagree. Given that individuals often care deeply about their reputation, our results challenge the long-standing prescription that they should always be immune to framing effects. The results extend understanding not only for decision making under risk, but also for a range of behavioral tendencies long considered irrational biases. Such understanding may ultimately reveal not only why such biases are so persistent but also novel interventions: our results suggest a necessary focus on social and organizational norms. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Observers penalize decision makers whose risk preferences are unaffected by loss-gain framing.

Author Correction: A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic

Why is exposure to opposing views aversive? Reconciling three theoretical perspectives.

Abstract To assess whether behaviors like framing effects are rational, researchers need to consider decision makers' goals. I argue that researchers should broaden the scope of analysis to include impression management goals. Under predictable conditions, behaviors traditionally considered irrational (e.g., loss–gain framing effects on risk preferences) can be reputationally rewarding, casting doubt on strict claims of irrationality.

You can’t handle the truth! Conflict counterparts over-estimate each other’s feelings of self-threat

In COVID-19 Health Messaging, Loss Framing Increases Anxiety with Little-to-No Concomitant Benefits: Experimental Evidence from 84 Countries

Attitude conflict — interpersonal disagreement on deeply-held, identity relevant issues — is common in personal, professional, and policy settings. Understanding one ’ s counterpart is critical to success in such contexts. Although prior literature focuses on misperceptions of counterpart cognitions , people often rely on affect to explain others ’ behavior. Here, we examine the accuracy of individuals ’ assessments of others ’ affective states during attitude conflict. Specifically, we examine one affective state that has been theorized to play a central role in such situations: self-threat (i.e., threat to the integrity of an individual ’ s self-concept). In four pre-registered studies (N = 1,707), individuals systematically over-estimated the levels of threat reported by conflict counterparts, which in turn increased confidence in persuasion. The effect was mediated by “ naïve realism, ” an excessive faith in the objectivity of one ’ s views. The present studies document a novel barrier to effective communication and extend our understanding of how affect drives behavior during attitude conflict.

You can ’ t handle the truth! Conflict counterparts over-estimate each other ’ s feelings of self-threat ☆ Organizational Behavior and Human Decision Processes

Given the many contexts in which people have difficulty engaging with views that disagree with their own—from political discussions to workplace conflicts—it is critical to understand how conflictual conversations can be improved. Whereas previous work has focused on strategies to change individual-level mindsets (e.g., encouraging open-mindedness), the present study investigated the role of partners’ beliefs about their counterparts. Across seven preregistered studies (N = 2,614 adults), people consistently underestimated how willing disagreeing counterparts were to learn about opposing views (compared with how willing participants were themselves and how willing they believed agreeing others would be). Further, this belief strongly predicted greater derogation of attitude opponents and more negative expectations for conflictual conversations. Critically, in both American partisan politics and the Israeli-Palestinian conflict, a short informational intervention that increased beliefs that disagreeing counterparts were willing to learn about one’s views decreased derogation and increased willingness to engage in the future. We built on research recognizing the power of the situation to highlight a fruitful new focus for conflict research.

Underestimating Counterparts’ Learning Goals Impairs Conflictual Conversations

Given the rise of affective polarization, it is critical to understand barriers to effective conversations between partisans and how such conversations can be improved. While previous work has focused on strategies to change individual-level mindsets (e.g., encouraging openmindedness), we investigated the unique role of partisans’ beliefs about their counterparts. Across seven pre-registered studies (N=2,614), partisans consistently under-estimated how willing disagreeing counterparts were to learn about their views (compared to themselves and to agreeing others). Further, this belief strongly predicted greater derogation of attitude opponents and more negative expectations for conflictual conversations. Critically, in both American partisan politics and the Israeli-Palestinian conflict, a short informational intervention that increased beliefs that counterparts were willing to learn about one’s views decreased derogation and increased willingness to engage in the future. We build on the research tradition of recognizing the power of the situation to highlight a fruitful new research focus for conflict research.

Running head : LEARNING GOALS IN ATTITUDE CONFLICT 1 Learning Goals in Attitude Conflict

The Role of Social Signaling in Selective Exposure to Information

A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic

Escalation of commitment-the tendency to remain committed to a course of action, often despite negative prospects-is common. Why does it persist? Across three preregistered experiments (N = 3,888), we tested the hypothesis that escalating commitment signals trustworthiness. Experiments 1-2, respectively, revealed that decision makers who escalated commitment were perceived as more trustworthy and entrusted with 29% more money by third-party observers. Experiment 3 revealed that decision makers who escalated commitment subsequently made more trustworthy choices, returning 15% more money than those who de-escalated. Decision makers were equally likely to escalate commitment in public versus in private, possibly because they previously internalized how others would evaluate them. Complementing research examining cognitive factors driving escalation of commitment, the present work reveals that accounting for the reputational causes and consequences of decisions to escalate enhances understanding of why escalation is so common and suggests how organizations might reduce it. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Staying the course: Decision makers who escalate commitment are trusted and trustworthy.

P002/Romania: A global test of brief reappraisal interventions on emotions during the COVID-19 pandemic

P002/UK: A global test of brief reappraisal interventions on emotions during the COVID-19 pandemic

P002/USA: A global test of brief reappraisal interventions on emotions during the COVID-19 pandemic

P002/Sweden: A global test of brief reappraisal interventions on emotions during the COVID-19 pandemic

P002/Russia: A global test of brief reappraisal interventions on emotions during the COVID-19 pandemic

Disagreement is an unavoidable part of social life. Because no two people hold identical beliefs, knowledge, values, or goals, opposing viewpoints are bound to arise at some point in the pursuit of...

The Art and Science of Disagreeing: How to Create More Effective Conversations About Opposing Views

P002/Nigeria: A global test of brief reappraisal interventions on emotions during the COVID-19 pandemic

P002/Austria: A global test of brief reappraisal interventions on emotions during the COVID-19 pandemic

The COVID-19 pandemic presents a critical need to identify best practices for communicating health information to the global public. It also provides an opportunity to test theories about risk communication. As part of a larger Psychological Science Accelerator COVID-19 Rapid Project, a global consortium of researchers will experimentally test competing hypotheses regarding the effects of framing messages in terms of losses versus gains. We will examine effects on three primary outcomes: intentions to adhere to policies designed to prevent the spread of COVID-19, opinions about such policies, and the likelihood that participants seek additional policy information. Whereas research on negativity bias and loss aversion predicts that loss-framing will have greater impact, research on encouraging the adoption of protective health behaviour suggests the opposite (i.e., gain-framing will be more persuasive). We will also assess effects on experienced anxiety. Given the potentially low cost and the scalable nature of framing interventions, results could be valuable to health organizations, policymakers, and news sources globally.

A global test of message framing on behavioural intentions, policy support, information seeking, and experienced anxiety during the COVID-19 pandemic

P002/Egypt: A global test of brief reappraisal interventions on emotions during the COVID-19 pandemic

P002/South Korea: A global test of brief reappraisal interventions on emotions during the COVID-19 pandemic

P002/South Africa: A global test of brief reappraisal interventions on emotions during the COVID-19 pandemic

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion regulation strategy which modifies how one thinks about a situation. Participants from 87 countries/regions (N = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vs. both control conditions) had consistent effects in reducing negative emotions and increasing positive emotions across different measures. Reconstrual and repurposing had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world to build resilience during the pandemic and beyond.

A global test of brief reappraisal interventions on emotions during the COVID-19 pandemic

P002/Mexico: A global test of brief reappraisal interventions on emotions during the COVID-19 pandemic

P002/Japan: A global test of brief reappraisal interventions on emotions during the COVID-19 pandemic

P002/China: A global test of brief reappraisal interventions on emotions during the COVID-19 pandemic

P002/Switzerland: A global test of brief reappraisal interventions on emotions during the COVID-19 pandemic

P002/Kenya: A global test of brief reappraisal interventions on emotions during the COVID-19 pandemic

Significance The epidemic of deaths attributable to addictive substances, including tobacco, highlights the need to better understand ways in which emotions drive substance craving and consumption. In a test of alternative theories of emotion and decision making, we found that sadness, specifically, rather than negative mood, generally, increased addictive substance use. In a nationally representative, longitudinal sample, sadness—but not other negative emotions—reliably predicted current smoking and relapse 20 y later. In laboratory experiments with real smokers, sadness increased both impatience for cigarette puffs and actual volume of puffs taken. Results provide not only theoretical implications but also policy implications for the design of antismoking public service announcements, which could unintentionally increase cigarette cravings among smokers if they trigger sadness. Do negative feelings in general trigger addictive behavior, or do specific emotions play a stronger role? Testing these alternative accounts of emotion and decision making, we drew on the Appraisal Tendency Framework to predict that sadness, specifically, rather than negative mood, generally, would 1) increase craving, impatience, and actual addictive substance use and 2) do so through mechanisms selectively heightened by sadness. Using a nationally representative, longitudinal survey, study 1 (n = 10,685) revealed that sadness, but not other negative emotions (i.e., fear, anger, shame), reliably predicted current smoking as well as relapsing 20 years later. Study 2 (n = 425) used an experimental design, and found further support for emotion specificity: Sadness, but not disgust, increased self-reported craving relative to a neutral state. Studies 3 and 4 (n = 918) introduced choice behavior as outcome variables, revealing that sadness causally increased impatience for cigarette puffs. Moreover, study 4 revealed that the effect of sadness on impatience was more fully explained by concomitant appraisals of self-focus, which are specific to sadness, than by concomitant appraisals of negative valence, which are general to all negative emotions. Importantly, study 4 also examined the topography of actual smoking behavior, finding that experimentally induced sadness (as compared to neutral emotion) causally increased the volume and duration of cigarette puffs inhaled. Together, the present studies provide support for a more nuanced model regarding the effects of emotion on tobacco use, in particular, as well as on addictive behavior, in general.

Sadness, but not all negative emotions, heightens addictive substance use

Conflict arises when people have different goals or interests. People often expect conflict to arise in social interactions, and may use various tactics to avoid conflict or manage it once it emerg...

In a Conflict State of Mind: How Do People Act Upon Their Expectations of Conflict?

Emotional Underpinnings of Rally Effects: The Mediating Role of Perceived Hawkishness

Nine-component seismic amplitude inversion : a case study in the Eagle Ford shale

Defined as the smarter, greener and more efficient movement of people and goods around the world, Intelligent Mobility is a sector of the wider transport industry which is predicted to be worth around £900 billion a year by 2025. In order to play a leading role in this sector, however, the UK will have to address a number of issues in regards to data access, data handling and data skills n with data having been identified as la new form of oilr for future transport systems. The key findings of this report can be summarised as follows: 1. The transport industry will be confronted with ever vaster amounts of data in the coming years as developments such as the Internet of Things rapidly expand the volume, velocity and variety of data related to transport and mobility; 2. This report has identified 11 obvious transport-related data gaps n in some cases referring to datasets which do not yet exist at all in the UK, in other cases to datasets which exist only in lsilosr or which are not yet open or freely available; 3. Standardisation of data remains an issue, with few private sector providers currently adhering to globally common data formats, and some forms of real-time data standards still to be defined; 4. More has to be done to address public concerns over personal data privacy n identified as one of the key long-term threats to creating successful crowd-sourced products and services; 5. UK investment is urgently needed to ensure sufficient levels of skilled technical talent, organisational capability and technology in the transport sector to handle the imminent surge in transport-related data.

The transport data revolution: investigation into the data required to support and drive intelligent mobility

Risk of Readmission After Uncomplicated Hospitalization After Radical Cystectomy

External validation of the Mayo Clinic Stage, Size, Grade, and Necrosis score in patients with renal cell carcinoma and venous tumor thrombus

521Background: Circulating tumor DNA (ctDNA) displays characteristics of an ideal serum biomarker. We sought to develop whole-exome sequencing of ctDNA to interrogate commonly mutated genes in renal cell carcinoma (RCC) for early tumor detection through a single blood sample. Methods: Patients with solid renal tumors and healthy controls provided 40 mL blood from which purified plasma cell-free DNA was prepared. A multiplex bar-coded polymerase chain reaction amplification using the Fluidigm Access Array was performed to prepare sequencing libraries for the Illumina HiSeq platform. Galaxy workflow was then utilized to identify mutations within the plasma cell-free DNA samples and results were compared to buffy coat sequencing containing control DNA for each individual’s sample. The following genes were queried: VHL, PBRM1, SETD2, BAP1, KDM5C, KIT, NFE2L2, MET, TP53, CDKN2A, FGFR3, PIK3CA, BRAF, and MUC4. Criteria for calling mutations included adequate frequency by overall count and percentage of reads, i...

Sepsis-induced intestinal hyperpermeability is mediated by disruption of the epithelial tight junction, which is closely associated with the perijunctional actin-myosin ring. Myosin light chain kinase (MLCK) phosphorylates the myosin regulatory light chain, resulting in increased permeability. The purpose of this study was to determine whether genetic deletion of MLCK would alter gut barrier function and survival from sepsis. MLCK−/− and wild-type (WT) mice were subjected to cecal ligation and puncture and assayed for both survival and mechanistic studies. Survival was significantly increased in MLCK−/− mice (95% versus 24%, p < 0.0001). Intestinal permeability increased in septic WT mice compared with unmanipulated mice. In contrast, permeability in septic MLCK−/− mice was similar to that seen in unmanipulated animals. Improved gut barrier function in MLCK−/− mice was associated with increases in the tight junction mediators ZO-1 and claudin 15 without alterations in claudin 1, 2, 3, 4, 5, 7, 8 and 13, occludin or JAM-A. Other components of intestinal integrity (apoptosis, proliferation and villus length) were unaffected by MLCK deletion, as were local peritoneal inflammation and distant lung injury. Systemic IL-10 was decreased greater than 10-fold in MLCK−/− mice; however, survival was similar between septic MLCK−/− mice given exogenous IL-10 or vehicle. These data demonstrate that deletion of MLCK improves survival following sepsis, associated with normalization of intestinal permeability and selected tight junction proteins.

Myosin Light Chain Kinase Knockout Improves Gut Barrier Function and Confers a Survival Advantage in Polymicrobial Sepsis

PD41-02 NOMOGRAM TO PREDICT RECURRENCE IN NON-METASTATIC RCC WITH THROMBUS USING A MULTI-CENTER CONTEMPORARY SERIES

Implementation of a Tele-urology Program for Outpatient Hematuria Referrals: Initial Results and Patient Satisfaction.

Impact of synchronous metastasis distribution on cancer specific survival in renal cell carcinoma after radical nephrectomy with tumor thrombectomy.

PD35-05 MULTICENTER VALIDATION OF PREDICTIVE MODEL FOR POSTSURGICAL RECURRENCE IN NON-METASTATIC RCC WITH THROMBUS

Impact of histologic subtype on cancer-specific survival in patients with renal cell carcinoma and tumor thrombus.

Inherent Difficulties of Measuring the Burden of Surgical Disease in Resource-Poor Settings

Utility of preoperative inflammatory markers for prognosis in patients with renal cell carcinoma and vena cava tumor thrombus

Predicting Length of Stay Following Radical Nephrectomy Using the National Surgical Quality Improvement Program Database.

North Carolina Journal of International Law and Commercial Regulation

In Deepwater: Cuba, Offshore Drilling, and Political Brinkmanship

Alcoholism is a costly disease that is responsible for a significant portion of the global disease burden, yet there is much is left to know about how this disease develops. Tolerance plays a critical role in predisposing an individual to alcohol abuse. Recently, the active zone of presynaptic neurons has been implicated as an ethanol effector. In this study, we examined the role that a presynaptic active zone protein, Dunc13, plays in the formation of tolerance to alcohol. Dunc13 is an ortholog of mammalian Unc13-1, and through the use of Drosophila as a model system, we show that genetic reduction of this protein creates ethanol resistance in naive flies. This genetic reduction is also used as a tool to examine the transcriptome that results from alcohol exposure. mRNA samples were sequenced from haploinsufficient Dunc13 flies, as well as wildtype Canton-S flies. These sequences were used to identify genes that are differentially expressed between these two genotypes without exposure to ethanol and four hours after a sedating dose of ethanol. Naive and ethanol exposed haploinsufficient Dunc13 flies did not have any genes with significantly different levels of expression. This indicates Dunc13 flies are transcriptionally resistant to ethanol treatment. The genetic manipulation creates a neurophysiological state that does not have a differential response to rapid ethanol tolerance, highlighting the importance of this protein in the acquisition of tolerance. Further, the genes identified in this study contribute to the platform with which alcohol tolerance can be studied.

Analysis of Dunc-13 and its Role in the Formation of Ethanol Tolerance in Drosophila Melanogaster

Registration of Arkot 0611, Arkot 0617, and Arkot 0712 Cotton Germplasm Lines

ABSTRACT Gravity is a fundamental stimulus that affects plant growth and development. The gravity persistent signal (GPS) treatment uses a cold treatment to isolate the events of signal transduction. Plants are reoriented horizontally in the dark at 4°C for 1 hour and then returned to vertical at room temperature. A gene expression microarray was designed to identify genes that are regulated during the GPS treatment. Arabidopsis thaliana var. Columbia was grown to maturity with inflorescence stems of 8-10 cm. Total mRNA was collected from inflorescence stems at 2, 4, 10, and 30 min after reorientation in the cold. cDNA was synthesized from the mRNA and then probed against an Arabidopsis gene expression array with 4 replicates per time point. Analyses presented here focus on transcription factors because of their regulatory functions in response pathways. Five transcription factors (AtAIB, WRKY18, WRKY26, WRKY33, and BT2) were selected for further study based on their expression at 4 min. Quantitative real-time polymerase chain reaction ((PCR) RT-qPCR) was performed to confirm expression seen in the microarray data. Seeds of Arabidopsis lines containing T-DNA insertions in the genes were obtained, plants bred to homozygosity, and the mutants analyzed for GPS phenotype. Mutant analysis shows significant differences in curvature of inflorescence stems between mutants and wild type.

Microarray Identifies Transcription Factors Potentially Involved in Gravitropic Signal Transduction in Arabidopsis

Within the framework of the relativistic distorted wave impulse approximation (DWIA), we investigate the sensitivity of the analyzing power - for exclusive proton knockout from the 3s$_{1/2}$, 2d$_{3/2}$ and 2d$_{5/2}$ states in $^{208}$Pb, at an incident laboratory kinetic energy of 202 MeV, and for coincident coplanar scattering angles ($28.0^{\circ}$, $-54.6^{\circ}$) - to different distorting optical potentials, finite-range (FR) versus zero-range (ZR) approximations to the DWIA, as well as medium-modified coupling constants and meson masses. Results are also compared to the nonrelativistic DWIA predictions based on the Schr\"{o}dinger equation. Whereas the nonrelativistic model fails severely, both ZR and FR relativistic DWIA models provide an excellent description of the data. For the FR predictions, it is necessary to invoke a 20% reduction of sigma-nucleon and omega-nucleon coupling constants as well as for $\sigma$-, $\rho$- and $\omega$-meson masses, by the nuclear medium. On the other hand, the ZR predictions suggest that the strong interaction in the nuclear medium is adequately represented by the free nucleon-nucleon interaction associated with the impulse approximation. We also demonstrate that, although the analyzing power is relatively insensitive to the use different relativistic global optical potential parameter sets, the prominent oscillatory behavior of this observable is largely attributed to distortion of the scattering wave functions relative to their plane wave values.

Relativistic predictions of exclusive 208Pb(p →,2p)207Tl analyzing powers at an incident energy of 202 MeV

A study of the photolysis of dimethyl diazo malonate in cyclohexene.

Survey, Shovel Probes, and Population Estimates: Studying Regional Demography in the Intermediate Area Using Subsurface Sherd Deposits

Archaeological research has by now revealed a great deal of variation in the way early complex societies, or chiefdoms, developed. This variation is widely recognized, but our understanding of the forces that produced it remains relatively undeveloped. This paper takes aim at such understanding by exploring variation in the local economies of six early chiefdoms; it considers what implications this variation had for trajectories of chiefdom development, as well as the source of that variation. Economic exchange is a primary form of local interaction in all societies. Because of distance-interaction principles, closer household spacing within local communities facilitated more frequent interaction and thus encouraged productive differentiation, economic interdependence, and the development of well-integrated local economies. Well-integrated local economies, in turn, provided ready opportunities for aspiring leaders to accumulate wealth and fund political economies, and pursuit of these opportunities led to societies with leaders whose power had a direct economic base. Wider household spacing, on the other hand, impeded interaction and the development of well-integrated local economies. In such contexts, aspiring leaders were able to turn to ritual and religion as a base of social power. Even when well-integrated local economies offered opportunities for wealth accumulation and a ready source of funding for political economies, these opportunities were not always taken advantage of. That variation in the shapes of early chiefdoms can be traced back to patterns of household spacing highlights the importance of settlement and interaction in explaining not just chiefdom development, but societal change more generally.

Local economies and household spacing in early chiefdom communities

Environmental risk buffering in Chinese Neolithic villages: Impacts on community structure in the Central Plains and the Western Liao Valley

Making absolute population estimates in the Intermediate Area using the area and density of ceramic sherd scatters: An application of regression analysis

Inequality, demography, and variability among early complex societies in Central Pacific Panama

Interregional Exchange and the Rise of Inequality in the Intermediate Area

This research explores the development of organizational variation among early complex societies in Central Pacific Panama. Beginning around the onset of the Late Ceramic II period (AD 700-1522) strongly hierarchal societies emerged in multiple parts of this macroregion, such as the Rio Parita valley, and continued to develop until the sixteenth century. Social power within these societies was drawn from a wide range of different activities, but there is strong evidence to suggest that such power was drawn from the same general suite of activities in different regions, and at different points in time. Despite these similarities, however, there were other parts of Central Panama, such as the Rio Tonosi valley, where early complex societies also evolved, but that did not develop the strong levels of social hierarchy or engage in the same sorts of aggrandizing behavior that is documented in other regions. These societies interacted with and shared many important sociocultural characteristics with those that were more hierarchical, but for some reason seem do not seem to have developed systems of strong hierarchical organization. 
 
This research set out to explore the factors that led to such variation by conducting a systematic, full-coverage regional-scale survey of the Rio Tonosi valley, so as to compare the settlement and demographic patterns that played out in this region to those of the Rio Parita valley, where regional survey has already been carried out. These results suggest that, despite exhibiting many strong similarities in demographic and social organization between AD 200 and 500, the trajectories of these two regions began to diverge sometime between AD 500 and 1000. This divergence seems to have been sparked by differential levels of regional demographic growth, coupled with differential levels of environmental risk that existed in these regions. These differences prompted early complex societies to organize their interaction in substantially different ways across the landscape, facilitating different sorts of activities and forms of social behavior, ultimately leading to the organizational variation that can be observed in the Late Ceramic II period.

Organization and Growth among Early Complex Societies in Central Pacific Panama

In this paper, we present a molecular network that bacteria use to talk to each other (i.e. communicate), this network calculates the dynamics of some primary components of the quorum sensing (QS) system that will develop a model with more working compounds. This QS system is acting when bacteria are growing. This action gives the bacteria new conditions to grow as response to form shapes or collective motions.

A zirconium oxide film self-assembled at the air–water interface

ABSTRACT This is the first review to provide both a systematic and meta-analytic approach to characterizing motor planning deficits in children with Developmental Coordination Disorder (DCD). Task complexity appears to be a key factor affecting motor planning in children with DCD. However, the different task-related factors and how they affect motor planning ability has not been examined. By systematically reviewing ten studies examining motor planning in children aged 4- to 14 years with and without DCD using grip selection tasks, task complexity was determined according to grip choices, level of precision, number of action steps and degree of rotation. A meta-analysis (N = 607; DCD = 255) revealed that, overall, those with DCD were 6.8% less likely to plan motor actions comfortably than typically developing children. This ability was moderated by task complexity (I2 = 66.7%), with performance differences ranging from 2.33% for low (g = 0.21) to 13.77% (g = 0.79) for high complexity. The results confirmed that children with DCD are able to plan for comfortable end states for tasks with simple and medium complexity level. When task complexity increased, compared to typically developing children, the motor planning ability of those with DCD was affected to a significantly greater extent. These findings provide important implications for both behavioral and neurological interventions.

Examining complexity in grip selection tasks and consequent effects on planning for end-state-comfort in children with developmental coordination disorder: A systematic review and meta-analysis

International validation of the EORTC QLQ-PRT20 module for assessment of quality of life symptoms relating to radiation proctitis: a phase IV study

Patterns in Participation: Factors Influencing Parent Attendance at Two, Centre-Based Early Childhood Interventions

Rationale Phonological awareness, letter knowledge, oral language (including sentence recall) and rapid automatised naming are acknowledged within-child predictors of literacy development. Separate research has identified family factors including socio-economic status, parents’ level of education and family history. However, both approaches have left unexplained significant amounts of variance in literacy outcomes. This longitudinal study sought to improve prospective classification accuracy for young children at risk of literacy failure by adding two new family measures (parents’ phonological awareness and parents’ perceived self-efficacy), and then combining the within-child and family factors. Method Pre-literacy skills were measured in 102 four year olds (46 girls and 56 boys) at the beginning of Preschool, and then at the beginning and end of Kindergarten, when rapid automatised naming was also measured. Family factors data were collected at the beginning of Preschool, and children’s literacy outcomes were measured at the end of Year 1 (age 6–7 years). Results Children from high-risk backgrounds showed poorer literacy outcomes than low-risk students, though three family factors (school socio-economic status, parents’ phonological awareness, and family history) typically accounted for less Year 1 variance than the within-child factors. Combining these family factors with the end of Kindergarten within-child factors provided the most accurate classification (i.e., sensitivity = .85; specificity = .90; overall correct = .88). Implications Our approach would identify at-risk children for intervention before they began to fail. Moreover, it would be cost-effective because although few at-risk children would be missed, allocation of unnecessary educational resources would be minimised.

A Spotlight on Preschool: The Influence of Family Factors on Children’s Early Literacy Skills

It is generally agreed that efficiency in processing basic speech sounds is a strong indicator of literacy outcomes. However, there is some debate about the extent to which this capacity is encapsulated within the language system. We report results based on pretest data obtained in an early music training study investigating the relationship between a motor‐rhythmic measure of ability (synchronous tapping) and the purported purely linguistically based processing measures, Rapid Automatized Naming (RAN) and Phonological Awareness (PA). Results suggest that RAN ability relies to some extent on nonlinguistic temporal processing skills.

Motor Timing and Precursor Literacy Skills in Very Young Children

Risk of within-hotel transmission of SARS-CoV-2 during on-arrival quarantine in Hong Kong: an epidemiological and phylogenomic investigation

Hong Kong experienced a surge of Omicron BA.2 infections in early 2022, resulting in one of the highest per-capita death rates of COVID-19. The outbreak occurred in a dense population with low immunity towards natural SARS-CoV-2 infection, high vaccine hesitancy in vulnerable populations, comprehensive disease surveillance and the capacity for stringent public health and social measures (PHSMs). By analyzing genome sequences and epidemiological data, we reconstructed the epidemic trajectory of BA.2 wave and found that the initial BA.2 community transmission emerged from cross-infection within hotel quarantine. The rapid implementation of PHSMs suppressed early epidemic growth but the effective reproduction number ( R _ e ) increased again during the Spring festival in early February and remained around 1 until early April. Independent estimates of point prevalence and incidence using phylodynamics also showed extensive superspreading at this time, which likely contributed to the rapid expansion of the epidemic. Discordant inferences based on genomic and epidemiological data underscore the need for research to improve near real-time epidemic growth estimates by combining multiple disparate data sources to better inform outbreak response policy. Hong Kong experienced a large wave of COVID-19 in early 2022 driven by Omicron BA.2. Here, the authors describe the epidemiological dynamics of this wave and show discordant inferences based on genomic and epidemiological data that underscore the need to improve near real-time epidemic growth estimates.

Resurgence of Omicron BA.2 in SARS-CoV-2 infection-naive Hong Kong

Genomic epidemiology of SARS-CoV-2 under an elimination strategy in Hong Kong

Background: The time-varying reproduction number, Rt, is commonly used to monitor the transmissibility of an infectious disease during an epidemic, but standard methods for estimating Rt seldom account for the impact of overdispersion on transmission. Methods: We developed a negative binomial framework to estimate Rt and a time-varying dispersion parameter (kt). We applied the framework to COVID-19 incidence data in Hong Kong in 2020 and 2021. We conducted a simulation study to compare the performance of our model with the conventional Poisson-based approach. Results: Our framework estimated an Rt peaking around 4 (95% credible interval = 3.13, 4.30), similar to that from the Poisson approach but with a better model fit. Our approach further estimated kt <0.5 at the start of both waves, indicating appreciable heterogeneity in transmission. We also found that kt decreased sharply to around 0.4 when a large cluster of infections occurred. Conclusions: Our proposed approach can contribute to the estimation of Rt and monitoring of the time-varying dispersion parameters to quantify the role of superspreading.

Accounting for the Potential of Overdispersion in Estimation of the Time-varying Reproduction Number

Ruopeng Xie The University of Hong Kong Dillon Adam The University of Hong Kong Kimberly Edwards The University of Hong Kong https://orcid.org/0000-0003-0944-3118 Shreya Gurung The University of Hong Kong Xiaoman Wei The University of Hong Kong Benjamin Cowling University of Hong Kong https://orcid.org/0000-0002-6297-7154 Vijaykrishna Dhanasekaran (  veej@hku.hk ) The University of Hong Kong https://orcid.org/0000-0003-3293-6279

Genomic epidemiology of in uenza B circulation in China during prolonged border closure from 2020 to 2021

Background: Hong Kong has enforced stringent travel restrictions particularly for inbound travellers since the emergence of SARS-CoV-2. Understanding the characteristics of imported COVID-19 cases is important for establishing evidence-based control measures. Methods: We conducted a retrospective cohort study to summarise the characteristics of cases classified as imported cases that were detected on or soon after arrival into Hong Kong from 13 November 2020 through to 31 January 2022, when all arriving persons were required to quarantine in a hotel or a designated quarantine facility. We analysed individual demographics, and clinical information including symptoms and disease severity, virus variants, and Ct values. Results: There were 2269 imported COVID-19 cases aged 0-85 years identified in Hong Kong. Almost half (48.6%) of the imported cases were detected on arrival. A shorter median delay from arrival to isolation was observed in Delta and Omicron cases (3 days) than cases infected with the ancestral strain and other variants (12 days; p<0.001) while lower Ct values at isolation were observed in cases infected with Omicron than the ancestral strain or other variants. No Omicron cases were detected beyond 14 days after arrival, and the cases (n=58, 2.6%) detected after 14 days of quarantine more frequently presented without symptoms at isolation and had a higher RT-PCR Ct-value during isolation. At least some of these cases were post-arrival infections. Conclusions: Testing inbound travellers at arrival and during on-arrival quarantine can detect imported cases early although it may not be sufficient to prevent all introductions of COVID-19 into the community. Public health measures should be adjusted in responses to the emergence of new variants of SARS-CoV-2 based on the epidemiologic evidence from continuous surveillance.

An observational study on imported COVID-19 cases in Hong Kong during mandatory on-arrival hotel quarantine

The serial interval distribution is used to approximate the generation time distribution, an essential parameter to predict the effective reproductive number "R_t", a measure of transmissibility. However, serial interval distributions may change as an epidemic progresses rather than remaining constant. Here we show that serial intervals in Hong Kong varied over time, closely associated with the temporal variation in COVID-19 case profiles and public health and social measures that were implemented in response to surges in community transmission. Quantification of the variation over time in serial intervals led to improved estimation of R_t, and provided additional insights into the impact of public health measures on transmission of infections.

Insights into COVID-19 epidemiology and control from temporal changes in serial interval distributions in Hong Kong

COVID-19 remains a persistent threat, especially with the predominant Omicron variant emerging in early 2022, presenting with high transmissibility, immune escape, and waning. There is a need to rapidly ramp up global vaccine coverage while enhancing public health and social measures. Timely and reliable estimation of the reproduction number throughout a pandemic is critical for assessing the impact of mitigation efforts and the potential need to adjust for control measures. We conducted a systematic review on the reproduction numbers of the Omicron variant and gave the pooled estimates. We identified six studies by searching PubMed, Embase, Web of Science, and Google Scholar for articles published between 1 January 2020 and 6 March 2022. We estimate that the effective reproduction number ranges from 2.43 to 5.11, with a pooled estimate of 4.20 (95% CI: 2.05, 6.35). The Omicron variant has an effective reproduction number which is triple (2.71 (95% CI: 1.86, 3.56)) that of the Delta variant.

Reproduction Number of the Omicron Variant Triples That of the Delta Variant

Abstract China experienced a resurgence of seasonal influenza activity throughout 2021 despite intermittent control measures and prolonged international border closure. We show genomic evidence for multiple A(H3N2), A(H1N1), and B/Victoria transmission lineages circulating over 3 years, with the 2021 resurgence mainly driven by two B/Victoria clades. Phylodynamic analysis revealed unsampled ancestry prior to widespread outbreaks in December 2020, showing that influenza lineages can circulate cryptically under non-pharmaceutical interventions enacted against COVID-19. Novel haemagglutinin gene mutations and altered age profiles of infected individuals were observed, and Jiangxi province was identified as a major source for nationwide outbreaks. Following major holiday periods, fluctuations in the effective reproduction number were observed, underscoring the importance of influenza vaccination prior to holiday periods or travel. Extensive heterogeneity in seasonal influenza circulation patterns in China determined by historical strain circulation indicates that a better understanding of demographic patterns is needed for improving effective controls.

Genomic epidemiology of seasonal influenza circulation in China during prolonged border closure from 2020 to 2021

Abstract Superspreading, or overdispersion in transmission, is a feature of SARS‐CoV‐2 transmission which results in surging epidemics and large clusters of infection. The dispersion parameter is a statistical parameter used to characterize and quantify heterogeneity. In the context of measuring transmissibility, it is analogous to measures of superspreading potential among populations by assuming that collective offspring distribution follows a negative‐binomial distribution. We conducted a systematic review and meta‐analysis on globally reported dispersion parameters of SARS‐CoV‐2 infection. All searches were carried out on 10 September 2021 in PubMed for articles published from 1 January 2020 to 10 September 2021. Multiple estimates of the dispersion parameter have been published for 17 studies, which could be related to where and when the data were obtained, in 8 countries (e.g. China, the United States, India, Indonesia, Israel, Japan, New Zealand and Singapore). High heterogeneity was reported among the included studies. The mean estimates of dispersion parameters range from 0.06 to 2.97 over eight countries, the pooled estimate was 0.55 (95% CI: 0.30, 0.79), with changing means over countries and decreasing slightly with the increasing reproduction number. The expected proportion of cases accounting for 80% of all transmissions is 19% (95% CrI: 7, 34) globally. The study location and method were found to be important drivers for diversity in estimates of dispersion parameters. While under high potential of superspreading, larger outbreaks could still occur with the import of the COVID‐19 virus by traveling even when an epidemic seems to be under control.

Systematic review and meta‐analyses of superspreading of SARS‐CoV‐2 infections

Incorporating temporal distribution of population-level viral load enables real-time estimation of COVID-19 transmission

Background: Despite relatively few reports of residential case clusters of COVID-19, building-wide compulsory testing notices on residential apartment blocks are frequently applied in Hong Kong with the aim of identifying cases and reducing transmission. Methods: We aimed to describe the frequency of residential case clusters and the efficiency of compulsory testing notices in identifying cases. The residences of locally infected COVID-19 cases in Hong Kong were grouped to quantify the number of cases per residence. Buildings targeted in compulsory testing notices were matched with the residence of cases to estimate the number of cases identified. Results: We found that most of the residential buildings (4246/7688, 55.2%) with a confirmed COVID-19 case had only one reported case. In the fourth and the fifth epidemic wave in Hong Kong, we estimated that compulsory testing notices detected 29 cases (95% confidence interval: 26, 32) and 46 cases (44, 48) from every 100 buildings tested (each with hundreds of residents), respectively. Approximately 13% of the daily reported cases were identified through compulsory testing notices. Conclusions: Compulsory testing notices can be an essential method when attempting to maintain local elimination (zero covid) and most impactful early in an epidemic when the benefit remains of stemming a new wave. Compulsory testing therefore appears to be a relatively inefficient control measure in response to sustained community transmission in the community.

Residential clustering of COVID-19 cases and efficiency of building-wide compulsory testing notices as a transmission control measure in Hong Kong

Superspreading in transmission is a feature of SARS-CoV-2 transmission. We conducted a systematic review and meta-analysis on globally reported dispersion parameters of SARS-CoV-2. The pooled estimate was 0.55 (95% CI: 0.30, 0.79). The study location and method were found to be important drivers for its diversity.

Superspreading of SARS-CoV-2 infections: A Systematic Review and Meta-analysis

Disparities were marked in previous pandemics, usually with higher attack rates reported for those in lower socioeconomic positions and for ethnic minorities.

METHODS
We examined characteristics of laboratory-confirmed COVID-19 cases in Hong Kong, assessed associations between incidence and population-level characteristics at the level of small geographic areas, and evaluated relations between socioeconomics and work-from-home (WFH) arrangements.

RESULTS
The largest source of COVID-19 importations switched from students studying overseas in the second wave to foreign domestic helpers in the third. The local cases were mostly individuals not in formal employment (retirees and homemakers) and production workers who were unable to WFH. For every 10% increase in the proportion of population employed as executives or professionals in a given geographic region, there was an 84% (95% confidence interval (CI): 1% to 97%) reduction in the incidence of COVID-19 during the third wave. In contrast, in the first two waves, the same was associated with 3.69 times (95% CI: 1.02 to 13.33) higher incidence. Executives and professionals were more likely to implement WFH and experienced frequent changes in WFH practice, compared to production workers.

Consistent findings on the reversed socioeconomic patterning of COVID-19 burden between infection waves in Hong Kong at both individual and population level analyses indicated that risks of infections may be related to occupations involving high exposure frequency and WFH flexibility. Contextual determinants should be taken into account in policy planning aiming at mitigating such disparities.

Changing disparities in COVID-19 burden in the ethnically homogeneous population of Hong Kong through pandemic waves: an observational study.

Background. A large cluster of 59 cases were linked to a single flight with 146 passengers from New Delhi to Hong Kong in April 2021. This outbreak coincided with early reports of exponential pandemic growth in New Delhi, which reached a peak of >400,000 newly confirmed cases on 7 May 2021. Methods. Epidemiological information including date of symptom onset, date of positive-sample detection, and travel and contact history for individual cases from this flight were collected. Whole genome sequencing was performed, and sequences were classified based on the dynamic Pango nomenclature system. Maximum-likelihood phylogenetic analysis compared sequences from this flight alongside other cases imported from India to Hong Kong on 26 flights between June 2020 and April 2021, as well as sequences from India or associated with India-related travel from February to April 2021, and 1,217 reference sequences. Results. Sequence analysis identified six lineages of SARS-CoV-2 belonging to two variants of concern (Alpha and Delta) and one variant of public health interest (Kappa) involved in this outbreak. Phylogenetic analysis confirmed at least three independent sub-lineages of Alpha with limited onward transmission, a superspreading event comprising 37 cases of Kappa, and transmission of Delta to only one passenger. Additional analysis of another 26 flights from India to Hong Kong confirmed widespread circulation of all three variants in India since early March 2021. Conclusions. The broad spectrum of disease severity and long incubation period of SARS-CoV-2 pose a challenge for surveillance and control. As illustrated by this particular outbreak, opportunistic infections of SARS-CoV-2 can occur irrespective of variant lineage, and requiring a nucleic acid test within 72 hours of departure may be insufficient to prevent importation or in-flight transmission.

Pacific Eclipse - A tabletop exercise on smallpox pandemic response.

Testing of an entire community has been used as an approach to control COVID-19. In Hong Kong, a universal community testing programme (UCTP) was implemented at the fadeout phase of a community epidemic in July to September 2020. We described the utility of the UCTP in finding unrecognised infections, and analysed data from the UCTP and other sources to characterise transmission dynamics.

METHODS
We described the characteristics of people participating in the UCTP and compared the clinical and epidemiological characteristics of COVID-19 cases detected by the UCTP versus those detected by clinical diagnosis and public health surveillance (CDPHS). We developed a Bayesian model to estimate the age-specific incidence of infection and the proportion of cases detected by CDPHS.

RESULTS
1.77 million people, 24% of the Hong Kong population, participated in the UCTP from 1 to 14 September 2020. The UCTP identified 32 new infections (1.8 per 100,000 samples tested), consisting of 29% of all local cases reported during the two-week UCTP period. Compared with the CDPHS, the UCTP detected a higher proportion of sporadic cases (62% versus 27%, p <0.01) and identified 6 (out of 18) additional clusters during that period. We estimated that 27% (95% credible interval: 22%, 34%) of all infections were detected by the CDPHS in the third wave.

We reported empirical evidence of the utility of population-wide COVID-19 testing in detecting unrecognised infections and clusters. Around three quarters of infections have not been identified through existing surveillance approaches including contact tracing.

Universal community nucleic acid testing for COVID-19 in Hong Kong reveals insights into transmission dynamics: a cross-sectional and modelling study.

The global epidemiology of Hepatitis A outbreaks 2016-2018 and the utility of EpiWATCH as a rapid epidemic intelligence service

Over the last two decades, Australia has experienced four severe influenza seasons caused by a predominance of influenza A (A/H3N2): 2003, 2007, 2012, and 2017.

Comparative epidemiology, phylogenetics, and transmission patterns of severe influenza A/H3N2 in Australia from 2003 to 2017

Objectives In this study, we aimed to measure the awareness, acceptability and perceptions of current issues in biosecurity posed by infectious diseases dual-use research of concern (DURC) in the community. DURC is conducted today in many locations around the world for the benefit of humanity but may also cause harm through either a laboratory accident or deliberate misuse. Most DURC is approved by animal ethics committees, which do not typically consider harm to humans. Given the unique characteristics of contagion and the potential for epidemics and pandemics, the community is an important stakeholder in DURC. Design Self-administered web-based cross-sectional survey. Participants Participants over the age of 18 in Australia and 21 in the USA were included in the survey. A total of 604 participants completed the study. The results of 52 participants were excluded due to potential biases about DURC stemming from their employment as medical researchers, infectious diseases researchers or law enforcement professionals, leaving 552 participants. Of those, 274 respondents resided in Australia and 278 in the USA. Outcomes Baseline awareness, acceptability and perceptions of current issues surrounding DURC. Changes in perception from baseline were measured after provision of information about DURC. Results Presurvey, 77% of respondents were unaware of DURC and 64% found it unacceptable or were unsure. Two-thirds of respondents did not change their views. The baseline perception of high risk for laboratory accidents (29%) and deliberate bioterrorism (34%) was low but increased with increasing provision of information (42% and 44% respectively, p<0.001), with men more accepting of DURC (OR=1.79, 95% CI 1.25 to 2.57, p=0.002). Postsurvey, higher education predicted lower risk perception of laboratory accidents (OR=0.56, 95% CI 0.34 to 0.93, p=0.02) and bioterrorism (OR=0.48, 95% CI 0.29 to 0.80, p=0.004). Conclusion The community is an important stakeholder in infectious diseases DURC but has a low awareness of this kind of research. Only a minority support DURC, and this proportion decreased with increasing provision of knowledge. There were differences of opinion between age groups, gender and education levels. The community should be informed and engaged in decisions about DURC.

Public awareness, acceptability and risk perception about infectious diseases dual-use research of concern: a cross-sectional survey

To compare the clinical features of Middle East respiratory syndrome coronavirus (MERS‐CoV) infection between paediatric and adult cases.

Epidemiology of paediatric Middle East respiratory syndrome coronavirus and implications for the control of coronavirus virus disease 2019

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases

The Molecular Epidemiology and Clinical Phylogenetics of Rhinoviruses Among Paediatric Cases in Sydney, Australia

Clustering and superspreading potential of SARS-CoV-2 infections in Hong Kong

This study compared the phylogeography of MERS-CoV between hospital outbreak-associated cases and sporadic cases in Saudi Arabia. We collected complete genome sequences from human samples in Saudi Arabia and data on the multiple risk factors of human MERS-CoV in Saudi Arabia reported from 2012 to 2018. By matching each sequence to human cases, we identified isolates as hospital outbreak-associated cases or sporadic cases. We used Bayesian phylogenetic methods including temporal, discrete trait analysis and phylogeography to uncover transmission routes of MERS-CoV isolates between hospital outbreaks and sporadic cases. Of the 120 sequences collected between 19 June 2012 and 23 January 2017, there were 64 isolates from hospital outbreak-associated cases and 56 from sporadic cases. Overall, MERS-CoV is fast evolving at 7.43 × 10−4 substitutions per site per year. Isolates from hospital outbreaks showed unusually fast evolutionary speed in a shorter time-frame than sporadic cases. Multiple introductions of different MERS-CoV strains occurred in three separate hospital outbreaks. MERS-CoV appears to be mutating in humans. The impact of mutations on viruses transmissibility in humans is unknown.

The Phylogeography of MERS-CoV in Hospital Outbreak-Associated Cases Compared to Sporadic Cases in Saudi Arabia

Epidemics are influenced by both disease and societal factors and can grow exponentially over short time periods. Epidemic risk analysis can help in rapidly predicting potentially serious outcomes and flagging the need for rapid response. We developed a multifactorial risk analysis tool ‘EpiRisk’ to provide rapid insight into the potential severity of emerging epidemics by combining disease-related parameters and country-related risk parameters. An initial set of 18 disease and country-related risk parameters was reduced to 14 following qualitative discussions and the removal of highly correlated parameters by a correlation and clustering analysis. Of the remaining parameters, three risk levels were assigned ranging from low (1) moderate (2) and high (3). The total risk score for an outbreak of a given disease in a particular country is calculated by summing these 14 risk scores, and this sum is subsequently classified into one of four risk categories: low risk (<21), moderate risk (21–29), high risk (30–37) and extreme risk (>37). Total risk scores were calculated for nine retrospective outbreaks demonstrating an association with the actual impact of those outbreaks. We also evaluated to what extent the risk scores correlate with the number of cases and deaths in 61 additional outbreaks between 2002 and 2018, demonstrating positive associations with outbreak severity as measured by the number of deaths. Using EpiRisk, timely intervention can be implemented by predicting the risk of emerging outbreaks in real time, which may help government and public health professionals prevent catastrophic epidemic outcomes.

A rapid risk analysis tool to prioritise response to infectious disease outbreaks

 Superspreading events have characterised previous epidemics of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) infections. Using contact tracing data, we identified and characterized SARS-CoV-2 clusters in Hong Kong. Given a superspreading threshold of 6-8 secondary cases, we identified 5-7 probable superspreading events and evidence of substantial overdispersion in transmissibility, and estimated that 20% of cases were responsible for 80% of local transmission. Among terminal cluster cases, 27% (45/167) ended in quarantine. Social exposures produced a greater number of secondary cases compared to family or work exposures (p<0.001) while delays between symptom onset and isolation did not reliably predict the number of individual secondary cases or resulting cluster sizes. Public health authorities should focus on rapid tracing and quarantine of contacts, along with physical distancing to prevent superspreading events in high-risk social environments.

Clustering and superspreading potential of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in Hong Kong

The clinical severity and observed case fatality ratio of influenza A/H1N1pdm09 in India, particularly in 2015 and 2017 far exceeds current global estimates. Reasons for these frequent and severe epidemic waves remain unclear. We used Bayesian phylodynamic methods to uncover possible genetic explanations for this, while also identifying the transmission dynamics of A/H1N1pdm09 between 2009 and 2017 to inform future public health interventions. We reveal a disproportionate selection at haemagglutinin residue positions associated with increased morbidity and mortality in India such as position 222 and clade 6B characteristic residues, relative to equivalent isolates circulating globally. We also identify for the first time, increased selection at position 186 as potentially explaining the severity of recent A/H1N1pdm09 epidemics in India. We reveal national routes of A/H1N1pdm09 transmission, identifying Maharashtra as the most important state for the spread throughout India, while quantifying climactic, ecological, and transport factors as drivers of within-country transmission. Together these results have important implications for future A/H1N1pdm09 surveillance and control within India, but also for epidemic and pandemic risk prediction around the world.

Phylodynamics of Influenza A/H1N1pdm09 in India Reveals Circulation Patterns and Increased Selection for Clade 6b Residues and Other High Mortality Mutants

An increase in the number of Acute Flaccid Myelitis (AFM) cases reported in the USA was detected in August 2018. The CDC has confirmed 186 cases of AFM in 2018 making this the largest outbreak of AFM reported in the USA. The cause however remains unknown. In this watching brief we review key features of the current outbreak in context, describe what is known about AFM, and consider probable causes. A two-year epidemic cycle of AFM appears to be emerging, and most current evidence implicates both EV-A71 and EV-D68 as the probable cause of the current outbreak yet key questions remain.

Bioterrorism and pandemics pose great risk to the health and safety of our modern world. Pandemic scenario exercises commonly use diseases that are most likely to cause moderate harm in an epidemic scenario such as influenza. Despite the generalisable nature of most pandemic responses, exercises often fail to take account of the broader impacts of a pandemic scenario. In August 2018, The Exercise Mataika pandemic workshop was conducted by the NHMRC Centre for Research Excellence Integrated Systems for Epidemic Response at the University of New South Wales, Australia. By utilising a high risk, worst case scenario – the deliberate release of Smallpox in Fiji and a much larger Asian country – impacts not often considered in pandemic planning, such as the resiliency of the health system, absenteeism, social cohesion, and broader impacts on society were considered, and compared, across geographic and social groupings. This study aimed to collect and analyse participant perceptions and evaluation of Exercise Mataika. A mixed methods study collecting participants ratings of experience, value and utility aspects of the scenario coupled with a thematic analysis of qualitative responses was conducted. Quantitative ratings for the activity were overwhelmingly positive, with respondents highlighting that the activity was useful, different in format, identified issues not often explored in pandemic exercises, and was a valuable educational and networking opportunity. Qualitative analysis and combined mixed-methods analysis revealed more nuanced findings. While respondents remained positive about the exercise format, subgroups highlighted potential missed opportunities and areas within the scenario where greater focus could have been directed. Overall the findings highlighted the value of including a wide range of exercise attendees both across sectors and nationalities, and addressing a far broader set of considerations across multiple domains. These findings will guide future development of pandemic response exercises and education.

Themes and correlations of participant experience and evaluation of an interactive bioterrorism release exercise – a mixed methods study

It appears inter‐seasonal influenza notifications have been increasing in summer months in Australia. This study aims to determine changes in inter‐seasonal influenza activity in Australia over time.

Adherence to anti-vectorial prevention measures among travellers with chikungunya and malaria returning to Australia: comparative epidemiology

Highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype are a major concern to human and animal health in Indonesia. This study aimed to characterize transmission dynamics of H5N1 over time using novel Bayesian phylogeography methods to identify factors which have influenced the spread of H5N1 in Indonesia. We used publicly available hemagglutinin sequence data sampled between 2003 and 2016 to model ancestral state reconstruction of HPAI H5N1 evolution. We found strong support for H5N1 transmission routes between provinces in Java Island and inter-island transmissions, such as between Nusa Tenggara and Kalimantan Islands, not previously described. The spread is consistent with wild bird flyways and poultry trading routes. H5N1 migration was associated with the regions of high chicken densities and low human development indices. These results can be used to inform more targeted planning of H5N1 control and prevention activities in Indonesia.

Abstract Variola virus is at risk of re-emergence either through accidental release, bioterrorism, or synthetic biology. The use of phylogenetics and phylogeography to support epidemic field response is expected to grow as sequencing technology becomes miniaturized, cheap, and ubiquitous. In this study, we aimed to explore the use of common VARV diagnostic targets hemagglutinin (HA), cytokine response modifier B (CrmB), and A-type inclusion protein (ATI) for phylogenetic characterization as well as the representativeness of modelling strategies in phylogeography to support epidemic response should smallpox re-emerge. We used Bayesian discrete-trait phylogeography using the most complete data set currently available of whole genome (n = 51) and partially sequenced (n = 20) VARV isolates. We show that multilocus models combining HA, ATI, and CrmB genes may represent a useful heuristic to differentiate between VARV Major and subclades of VARV Minor which have been associated with variable case-fatality rates. Where whole genome sequencing is unavailable, phylogeography models of HA, ATI, and CrmB may provide preliminary but uncertain estimates of transmission, while supplementing whole genome models with additional isolates sequenced only for HA can improve sample representativeness, maintaining similar support for transmission relative to whole genome models. We have also provided empirical evidence delineating historic international VARV transmission using phylogeography. Due to the persistent threat of re-emergence, our results provide important research for smallpox epidemic preparedness in the posteradication era as recommended by the World Health Organisation.

Bayesian Phylogeography and Pathogenic Characterization of Smallpox Based on HA, ATI, and CrmB Genes

Characterising routes of H5N1 and H7N9 spread in China using Bayesian phylogeographical analysis

Amalie Dyda1, Sacha Stelzer-Braid2,3, Dillon Adam1, Abrar A Chughtai1, C Raina MacIntyre1,4 1. School of Public Health and Community Medicine, University of New South Wales (UNSW), Sydney, New South Wales (NSW), Australia 2. School of Medical Sciences, University of New South Wales (UNSW), Sydney, New South Wales (NSW), Australia 3. Division of Serology and Virology, South Eastern Area Laboratory Services, Prince of Wales Hospital, Sydney, Australia 4. College of Public Service and Community Solutions and College of Health Solutions, Arizona State University, Tempe, Arizona, United States

The association between acute flaccid myelitis ( AFM ) and Enterovirus D 68 ( EVD 68 ) – what is the evidence for causation ?

Background Enterovirus D68 (EV-D68) has historically been a sporadic disease, causing occasional small outbreaks of generally mild infection. In recent years, there has been evidence of an increase in EV-D68 infections globally. Large outbreaks of EV-D68, with thousands of cases, occurred in the United States, Canada and Europe in 2014. The outbreaks were associated temporally and geographically with an increase in clusters of acute flaccid myelitis (AFM). Aims: We aimed to evaluate a causal association between EV-D68 and AFM.  Methods: Using data from the published and grey literature, we applied the Bradford Hill criteria, a set of nine principles applied to examine causality, to evaluate the relationship between EV-D68 and AFM. Based on available evidence, we defined the Bradford Hill Criteria as being not met, or met minimally, partially or fully.  Results: Available evidence applied to EV-D68 and AFM showed that six of the Bradford Hill criteria were fully met and two were partially met. The criterion of biological gradient was minimally met. The incidence of EV-D68 infections is increasing world-wide. Phylogenetic epidemiology showed diversification from the original Fermon and Rhyne strains since the year 2000, with evolution of a genetically distinct outbreak strain, clade B1. Clade B1, but not older strains, is associated with AFM and is neuropathic in animal models.  Conclusion: While more research is needed on dose–response relationship, application of the Bradford Hill criteria supported a causal relationship between EV-D68 and AFM.

The association between acute flaccid myelitis (AFM) and Enterovirus D68 (EV-D68) – what is the evidence for causation?

The risk and benefits of gain‐of‐function studies on influenza A have been widely debated since 2012 when the methods to create two respiratory transmissible H5N1 mutant isolates were published. Opponents of gain‐of‐function studies argue the biosecurity risk is unacceptable, while proponents cite potential uses for pandemic surveillance, preparedness and mitigation. In this commentary, we provide an overview of the background and applications of gain‐of‐function research and argue that the anticipated benefits have yet to materialize while the significant risks remain.

Does influenza pandemic preparedness and mitigation require gain‐of‐function research?

Effective response to infectious diseases outbreaks relies on the rapid and early detection of those outbreaks. Invalidated, yet timely and openly available digital information can be used for the early detection of outbreaks. Public health surveillance authorities can exploit these early warnings to plan and co-ordinate rapid surveillance and emergency response programs. In 2016, a digital disease detection competition named ZikaHack was launched. The objective of the competition was for multidisciplinary teams to design, develop and demonstrate innovative digital disease detection solutions to retrospectively detect the 2015-16 Brazilian Zika virus outbreak earlier than traditional surveillance methods. In this paper, an overview of the ZikaHack competition is provided. The challenges and lessons learned in organizing this competition are also discussed for use by other researchers interested in organizing similar competitions.

An overview of the epidemiology and emergence of influenza A infection in humans over time

Objectives We examined the combined effects of behavioural inhibition and behavioural activation, on one hand, and locus of control, on the other hand, on different categories of smoking behaviour (non-smoking, ex-smoking, occasional smoking, daily smoking). Design This study adopted a cross-sectional design. Participants completed questionnaires regarding demographics, smoking patterns, behavioural inhibition/behavioural activation systems and locus of control. Setting The study was conducted across four companies from the transportation, cooling plant and education sectors in Singapore. Participants Three hundred sixty-nine male working adults were included in the final sample. Results Corroborating previous research, a logistic regression model examining behavioural inhibition/behavioural activation systems revealed that the fun-seeking aspect of behavioural activation was a unique predictor in distinguishing non-smokers from daily smokers (OR=1.24, p=0.012). By contrast, in a separate model examining locus of control, external locus of control was found to be a unique predictor in distinguishing non-smokers from daily smokers (OR=1.13, p<0.001). In addition, a third model combining both behavioural inhibition/behavioural activation systems and locus of control found that only external locus of control remained a significant predictor (OR=1.12, p<0.001). Further analyses revealed a mediating effect of external locus of control on the relationship between fun-seeking and smoking behaviour. That is, the increase in the odds of daily smoking due to fun-seeking was explained by external locus of control (direct pathway OR=1.20, p=0.058; indirect pathway OR=1.04, p<0.050). Conclusions Overall, fun-seeking through its influence on external locus of control indirectly affects daily smoking behaviour, suggesting a more complex relationship than shown in previous research.

Effects of fun-seeking and external locus of control on smoking behaviour: a cross-sectional analysis on a cohort of working men in Singapore

Community water fluoridation has been named one of the 10 greatest public health achievements of the 20th century for its role in improving dental health. I leverage county level variation in the timing of fluoride adoption, combined with restricted U.S. Census data that link over 29 million individuals to their county of birth, to estimate the causal effects of childhood fluoride exposure. Children exposed to community water fluoridation from age zero to five are worse off as adults on indices of economic selfsufficiency (-1.9% of a SD) and physical ability and health (-1.2% of a SD). They are also significantly less likely to graduate high school or serve in the military and more likely to be incarcerated as adults. These findings overturn existing conclusions about safe levels of fluoride exposure and its impact on adult labor market outcomes.

What’s in the Water? Long-Run Effects of Fluoridation on Health and Economic Self-Sufficiency

Space is a resource that is constantly being depleted, especially in mega-cities. Underground workspaces (UGS) are increasingly being included in urban plans and have emerged as an essential component of vertical cities. While progress had been made on the engineering aspects associated with the development of high-quality UGS, public attitudes toward UGS as work environments (ie, the public's design concerns with UGS) are relatively unknown. Here, we present the first large-scale study examining preferences and attitudes toward UGS, surveying close to 2000 participants from four cities in three continents (Singapore, Shanghai, London, and Montreal). Contrary to previous beliefs, air quality (and not lack of windows) is the major concern of prospective occupants. Windows, temperature, and lighting emerged as additional important building performance aspects for UGS. Early adopters (ie, individuals more willing to accept UGS and thus more likely to be the first occupants) across all cities prioritized air quality. Present results suggest that (perceived) air quality is a key building performance aspect for UGS that needs to be communicated to prospective occupants as this will improve their attitudes and views toward UGS. This study highlights the importance of indoor air quality for the public.

The importance of air quality for underground spaces: An international survey of public attitudes.

White- and Blue- collar workers responses’ towards underground workspaces

Abstract Underground workplaces (UWS) are increasingly being recognised as a sustainable solution to concerns regarding lack of space facing megacities. UWS can multiply available space by reducing urban sprawl thereby improving quality of life in cities. However, developing workplaces that respond to the needs and preferences of occupants will be a crucial factor in determining the success of this concept. We examine the experiences of existing full-time employees of a large underground facility in North America and analyse how these are related to company policies and other organisational factors. From in-depth interviews of 73 participants, three predominant themes emerged from the analyses: environmental effects (e.g. lack of sunlight), design (e.g. the unique working environment), and organisational factors and social dynamics (e.g. policies regarding breaks). We discuss these themes in relation with interventions that may improve employee comfort and retention and suggest that many factors are within organisational control. Practitioner Summary: Underground workplaces are a sustainable solution to lack of urban space. However, developing effective workplaces is crucial to their success. We examine the experiences of existing employees of an underground facility in North America. We suggest that most negative attitudes towards underground spaces can be mitigated through simple organisational interventions. Abbreviations: UWS: underground workplaces; IRB: institutional review board

Employee experiences in underground workplaces: a qualitative investigation

Background We aimed to examine the association between shift work and sleep quality in a diverse occupational type. Methods This was a cross-sectional study of self-reported sleep quality in 424 workers aged ≥21 using the Pittsburgh Sleep Quality Index (PSQI). We divided workers into two categories based on their PSQI score: (a) ≤5 (good sleep quality) and (b) >5 (poor sleep quality). We used multiple logistic regressions to assess the association between shift work and sleep quality adjusted for potential confounders. Results The mean age was 39.2 (SD = 11.3) years, with shift workers being older than their counterparts. Most workers were of Chinese ethnicity (63.9%). Males were significantly more likely to undertake shift work than females (89% v 11%, p-value<0.001), but it should be noted that the majority of workers was male (78.8%) in this sample of workers. Shift workers had a 198% increased odds of poor sleep quality compared to non-shift workers (OR = 2.98; 95% CI:1.53–5.81). Conclusion Shift work was significantly and independently associated with increased odds of poor sleep quality in this sample of workers. The present findings may inform employment guidelines and help develop workplace health promotion interventions aimed at improving sleep quality among workers and ultimately lead to a healthier workforce.

Association between shift work and poor sleep quality in an Asian multi-ethnic working population: A cross-sectional study

Greater adoption of wearable devices with multiple sensors may enhance personalized health monitoring, facilitate early detection of some diseases, and further scale up population health screening. However, few studies have explored the utility of data from wearable fitness trackers in cardiovascular and metabolic disease risk prediction.

OBJECTIVE
This study aimed to investigate the associations between a range of activity metrics derived from a wearable consumer-grade fitness tracker and major modifiable biomarkers of cardiometabolic disease in a working-age population.

METHODS
This was a cross-sectional study of 83 working adults. Participants wore Fitbit Charge 2 for 21 consecutive days and went through a health assessment, including fasting blood tests. The following clinical biomarkers were collected: BMI, waist circumference, waist-to-hip ratio, blood pressure, triglycerides (TGs), high-density lipoprotein (HDL) and low-density lipoprotein cholesterol, and blood glucose. We used a range of wearable-derived metrics based on steps, heart rate (HR), and energy expenditure, including measures of stability of circadian activity rhythms, sedentary time, and time spent at various intensities of physical activity. Spearman rank correlation was used for preliminary analysis. Multiple linear regression adjusted for potential confounders was used to determine the extent to which each metric of activity was associated with continuous clinical biomarkers. In addition, pairwise multiple regression was used to investigate the significance and mutual dependence of activity metrics when two or more of them had significant association with the same outcome from the previous step of the analysis.

RESULTS
The participants were predominantly middle aged (mean age 44.3 years, SD 12), Chinese (62/83, 75%), and male (64/83, 77%). Blood biomarkers of cardiometabolic disease (HDL cholesterol and TGs) were significantly associated with steps-based activity metrics independent of age, gender, ethnicity, education, and shift work, whereas body composition biomarkers (BMI, waist circumference, and waist-to-hip ratio) were significantly associated with energy expenditure-based and HR-based metrics when adjusted for the same confounders. Steps-based interdaily stability of circadian activity rhythm was strongly associated with HDL (beta=5.4 per 10% change; 95% CI 1.8 to 9.0; P=.005) and TG (beta=-27.7 per 10% change; 95% CI -48.4 to -7.0; P=.01). Average daily steps were negatively associated with TG (beta=-6.8 per 1000 steps; 95% CI -13.0 to -0.6; P=.04). The difference between average HR and resting HR was significantly associated with BMI (beta=-.5; 95% CI -1.0 to -0.1; P=.01) and waist circumference (beta=-1.3; 95% CI -2.4 to -0.2; P=.03).

Wearable consumer-grade fitness trackers can provide acceptably accurate and meaningful information, which might be used in the risk prediction of cardiometabolic disease. Our results showed the beneficial effects of stable daily patterns of locomotor activity for cardiometabolic health. Study findings should be further replicated with larger population studies.

Activity Tracker–Based Metrics as Digital Markers of Cardiometabolic Health in Working Adults: Cross-Sectional Study

Indoor environmental quality (IEQ) is a general indicator of the quality of conditions inside a building. We investigated associations of perceived IEQ including air quality, thermal comfort, noise, and light quality with stress at work and the extent to which workplace location modifies these associations. We recruited 464 full-time workers from four companies in Singapore. Data on socio-demographic characteristics, lifestyle/health-related factors, and workplace factors were collected through self-administered questionnaires. Perceived IEQ satisfaction scores of all four factors were collected using the validated OFFICAIR questionnaire. We fitted a logistic regression model to assess associations between each perceived IEQ score and stress at work, adjusting for potential confounders. The odds ratio for stress at work associated with a 1-unit increase in perceived air quality score was 0.88 (0.82-0.94), 0.89 (0.82-0.97) for thermal comfort, 0.93 (0.87-0.98) for noise, and 0.88 (0.82-0.94) for light quality. Significant associations were found in office and control rooms for all four perceived IEQ, except for thermal comfort in office rooms. Higher satisfaction levels of perceived air quality, thermal comfort, noise, and lighting, were significantly associated with a reduction in stress at work. Our findings could potentially provide a useful tool for environmental health impact assessment for buildings.

Associations of perceived indoor environmental quality with stress in the workplace.

Elderly populations in Asian countries are expected to increase rapidly in the next few decades. Older adults, particularly in high-density cities, spend a considerable amount of time in urban green spaces (UGSs). The World Health Organization noted that UGSs are key to improving the age-friendliness of neighborhoods. Thus, it is necessary to design UGSs for the promotion of healthy ageing to enhance preventive healthcare and relieve medical burdens. This study conducted interviews using a questionnaire with a sample size of 326 participants in the cities of Hong Kong (China) and Tainan (Taiwan region). The inter-relationships among the design of UGSs (e.g., spatial distribution and accessibility, characteristics of plants and UGSs), older adults’ perceptions on safety and aesthetics quality of UGSs, and their self-reported health conditions (assessed by the self-reported SF-12v2 Health Survey) were investigated with bivariate Spearman rank correlation tests. The results indicate that the duration of visits to UGSs was positively associated with mental health and social functioning, two subscales evaluating health-related quality of life in SF 12v2. The statistical model (moderation analysis) showed that such a correlation was especially significant in women and those with low social support and social capital. A positive relationship was found between the physical health subscale and perceived safety in UGSs. This relationship was stronger among older adults living alone (moderation analysis). Furthermore, the color of plants and maintenance condition of UGSs were significant aspects affecting the subjective assessment of aesthetic quality. This study provides useful information regarding how to plan and design urban green spaces with certain characteristics that could improve the accessibility and aesthetic quality, which are preferred by older adults.

International Journal of Environmental Research and Public Health

The development of underground workspaces is a strategic effort towards healthy urban growth in cities with ever-increasing land scarcity. Despite the growth in underground workspaces, there is limited information regarding the impact of this environment on workers’ health. The Health Effects of Underground Workspaces (HEUW) study is a cohort study that was set up to examine the health effects of working in underground workspaces. In this paper, we describe the rationale for the study, study design, data collection, and baseline characteristics of participants. The HEUW study recruited 464 participants at baseline, of whom 424 (91.4%) were followed-up at 3 months and 334 (72.0%) at 12 months from baseline. We used standardized and validated questionnaires to collect information on socio-demographic and lifestyle characteristics, medical history, family history of chronic diseases, sleep quality, health-related quality of life, chronotype, psychological distress, occupational factors, and comfort levels with indoor environmental quality parameters. Clinical and anthropometric parameters including blood pressure, spirometry, height, weight, and waist and hip circumference were also measured. Biochemical tests of participants’ blood and urine samples were conducted to measure levels of glucose, lipids, and melatonin. We also conducted objective measurements of individuals’ workplace environment, assessing air quality, light intensity, temperature, thermal comfort, and bacterial and fungal counts. The findings this study will help to identify modifiable lifestyle and environmental parameters that are negatively affecting workers’ health. The findings may be used to guide the development of more health-promoting workspaces that attempt to negate any potential deleterious health effects from working in underground workspaces.

Health Effects of Underground Workspaces cohort: study design and baseline characteristics

Prevalence of sick building syndrome and its association with perceived indoor environmental quality in an Asian multi-ethnic working population

The Star Excursion Balance Test (SEBT) is a common assessment used across clinical and research settings to test dynamic standing balance. The primary measure of this test is maximal reaching distance performed by the non-stance limb. Response time (RT) is a critical cognitive component of dynamic balance control and the faster the RT, the better the postural control and recovery from a postural perturbation. However, the measure of RT has not been done in conjunction with SEBT, especially with musculoskeletal fatigue. The purpose of this study is to examine RT during a SEBT, creating a modified SEBT (mSEBT), with a secondary goal to examine the effects of muscular fatigue on RT during SEBT. Sixteen healthy young male and female adults [age: 20 ± 1 years; height: 169.48 ± 8.2 cm; weight: 67.93 ± 12.7 kg] performed the mSEBT in five directions for three trials, after which the same was repeated with a response time task using Blazepod™ with a random stimulus. Participants then performed a low-intensity musculoskeletal fatigue task and completed the above measures again. A 2 × 2 × 3 repeated measures ANOVA was performed to test for differences in mean response time across trials, fatigue states, and leg reach as within-subjects factors. All statistical analyses were conducted in JASP at an alpha level of 0.05. RT was significantly faster over the course of testing regardless of reach leg or fatigue state (p = 0.023). Trial 3 demonstrated significantly lower RT compared to Trial 1 (p = 0.021). No significant differences were found between fatigue states or leg reach. These results indicate that response times during the mSEBT with RT is a learned skill that can improve over time. Future research should include an extended familiarization period to remove learning effects and a greater fatigue state to test for differences in RT during the mSEBT.

Quick on Your Feet: Modifying the Star Excursion Balance Test with a Cognitive Motor Response Time Task

Abstract The development of wearable technology, which enables motion tracking analysis for human movement outside the laboratory, can improve awareness of personal health and performance. This study used a wearable smart sock prototype to track foot–ankle kinematics during gait movement. Multivariable linear regression and two deep learning models, including long short-term memory (LSTM) and convolutional neural networks, were trained to estimate the joint angles in sagittal and frontal planes measured by an optical motion capture system. Participant-specific models were established for ten healthy subjects walking on a treadmill. The prototype was tested at various walking speeds to assess its ability to track movements for multiple speeds and generalize models for estimating joint angles in sagittal and frontal planes. LSTM outperformed other models with lower mean absolute error (MAE), lower root mean squared error, and higher R-squared values. The average MAE score was less than 1.138° and 0.939° in sagittal and frontal planes, respectively, when training models for each speed and 2.15° and 1.14° when trained and evaluated for all speeds. These results indicate wearable smart socks to generalize foot–ankle kinematics over various walking speeds with relatively low error and could consequently be used to measure gait parameters without the need for a lab-constricted motion capture system.

Closing the Wearable Gap: Foot–ankle kinematic modeling via deep learning models based on a smart sock wearable

This single-subject case study compared a golfer's swing kinematics and kinetics on a driving range and golf course using a pair of pressure sensor socks and a markerless motion capture solution. Results indicated a significant difference in the right and left plantar pressure percentages in wedge swings and 7-iron chest sway (p<0.05). Findings suggest that wearable and mobile technology can measure discrete and longitudinal training and gameplay to enhance a golfer's performance.

2023 IEEE Conference on Virtual Reality and 3D User Interfaces Abstracts and Workshops (VRW)

The Opportunity to Collect Kinetic Forces During a Round of Golf Using Wearable Devices: Single-Subject Case Study – The Full Swings

Cognitive performance is negatively affected by the presence of noise, which is seen as a distractor and a stressor, especially in hazardous occupational environments. The addition of musculoskeletal fatigue that commonly accompanies occupational work due to noise interruption can further elevate risk and compromise safety. The purpose of the study was to investigate the impact of both individual and a combination of noise interference and physical workload on simple and choice response time tasks. Sixteen healthy male and female participants (age: 20 ± 1 years; height: 169.48 ± 8.2 cm; weight: 67.93 ± 12.7 kg) performed a simple (SRT) and choice response task (CRT) with three Blazepod™ light response time systems by striking with the dominant lower extremity from a seated position while listening to noises from a construction site (65–85dB) through headphones. Participants then performed a low-intensity musculoskeletal fatigue task and completed the above measures again. Response times (RT) (ms) from three trials of SRT and CRT, both without and with noise interference, before (PRE) and after the workload (POST), were averaged, and a 2 (Noise) × 2 (workload) × 2 (task) repeated measure ANOVA and a 2 (Noise) × 2 (workload) repeated measure ANOVA were performed for SRT and CRT, respectively, using JASP at an alpha level of 0.05. Results revealed a significant interaction between workload task (p = 0.041), as well as a main effect significance for the workload (p = 0.007) and noise (p = 0.044). The main effect significance also existed for workload in SRT (p = 0.009) and for noise in CRT (p = 0.002). In SRT, RT was significantly faster during the POST fatigue measure, suggesting a possible cognitive arousal and a learning effect improvement rather than a negative fatigue effect. In both SRT and CRT, as well as individually in CRT, RT was significantly slower due to noise interruption, negatively impacting performance, especially in the more challenging CRT compared to SRT. Thus, findings from the current study suggest that the impact of noise interruption is significant when the complexity of the response task is greater, and the potential cognitive arousal due to the workload and potential learning effects may influence response time performances. Finally, a lower extremity cognitive–motor task demonstrates response time behavior similar to such upper extremity cognitive–motor tasks.

Noise Interference Impacts Simple and Choice Response Times during a Lower Extremity Cognitive–Motor Task

The utilization of commercially available virtual reality (VR) environments has increased over the last decade. Motion sickness that is commonly reported while using VR devices is still prevalent and reported at a higher than acceptable rate. The virtual reality induced symptoms and effects (VRISE) are considered the largest barrier to widespread usage. Current measurement methods have uniform use across studies but are subjective and are not designed for VR. VRISE and other motion sickness symptom profiles are similar but not exactly the same. Common objective physiological and biomechanical as well as subjective perception measures correlated with VRISE should be used instead. Many physiological biomechanical and subjective changes evoked by VRISE have been identified. There is a great difficulty in claiming that these changes are directly caused by VRISE due to numerous other factors that are known to alter these variables resting states. Several theories exist regarding the causation of VRISE. Among these is the sensory conflict theory resulting from differences in expected and actual sensory input. Reducing these conflicts has been shown to decrease VRISE. User characteristics contributing to VRISE severity have shown inconsistent results. Guidelines of field of view (FOV), resolution, and frame rate have been developed to prevent VRISE. Motion-to-photons latency movement also contributes to these symptoms and effects. Intensity of content is positively correlated to VRISE, as is the speed of navigation and oscillatory displays. Duration of immersion shows greater VRISE, though adaptation has been shown to occur from multiple immersions. The duration of post immersion VRISE is related to user history of motion sickness and speed of onset. Cognitive changes from VRISE include decreased reaction time and eye hand coordination. Methods to lower VRISE have shown some success. Postural control presents a potential objective variable for predicting and monitoring VRISE intensity. Further research is needed to lower the rate of VRISE symptom occurrence as a limitation of use.

Virtual Reality Induced Symptoms and Effects: Concerns, Causes, Assessment & Mitigation

While design modifications present on work boots improve safety, they may not always provide optimal human performance during work tasks. Understanding the impact of these different design features on biomechanical and physiological postural control and locomotion variables can aid in better design modifications that can provide a safe and efficient human performance. This brief review focuses on a series of studies conducted by the current research team, that have tested three different work boots (SB: high-top steel-toed work boots; TB: high-top tactical work boots; SR: low-top slip-resistant work boots). The series of studies included testing of these work boots or combinations of them under acute and chronic simulated occupational workloads, assessing biomechanical variable such as postural stability, gait, slips, and muscle activity, as well as physiological variables such as heart rate, energy expenditure, oxygen consumption, and pain perception. The impact of each of the work boots and their design feature on postural control and locomotion are summarized from these studies’ previously published literature. Finally, work boot design suggestions for optimal human performance are provided for better work boot selection, modification, and design.

Occupational Footwear Design Influences Biomechanics and Physiology of Human Postural Control and Fall Risk

This study aims to quantify wearers’ perceived sensory/tactile comfort responses to clinical and sub-clinical compression socks before, during, and after several activities (postural stability tasks, donning, and doffing). Through purposive sampling, the researchers recruited 20 participants (11 male and 9 female) aged 21.5 ± 2 years. Among all participants, 40% had chronic ankle instability, 30% were copers, and 30% were healthy control groups. Sensory/tactile and movement comfort were assessed using a comfort 8-item questionnaire in a wear trial. The findings exhibit that the tested clinical socks are more comfortable than subclinical socks regardless of the participant types. The strongest positive correlation was between material appearance and hand feel (r = 0.84, ** p < 0.01) and between ‘no red marks’ and non-itchiness (r = 0.72, ** p < 0.01). Additionally, no statistically significant differences in comparisons of comfort assessment measures were reported. However, due to the consistency of the trends in differences, the researchers suggest that these findings warrant additional research using a more robust sampling technique. According to the findings of this study, a higher-pressure level compression sock may be preferable for patients with ankle stability issues, as there is no significant evidence for a comforting outcome.

Sensory and Tactile Comfort Assessment of Sub-Clinical and Clinical Compression Socks on Individuals with Ankle Instability

Background: Changes in the visual environment and thereby, the spatial orientation, can induce postural instability leading to falls. Virtual reality (VR) has been used to expose individuals to virtual environments (VE) that increase postural threats. Claustrophobia is an anxiety disorder categorized under situational phobias and can induce such postural threats in a VE. Purpose: The purpose of the study was to investigate if VR-generated claustrophobic simulation has any impact on postural threats that might lead to postural instability. Methods: Thirty healthy men and women (age: 20.7 ± 1.2 years; height: 166.5 ± 7.3 cm; mass: 71.7 ± 16.2 kg) were tested for postural stability while standing on a force platform, upon exposure to five different testing trials, including a normal stance (NoVR), in stationary VE (VR), and three consecutive, randomly initiated, unexpected claustrophobia trials (VR CP1, VR CP2, VR CP3). The claustrophobia trials involved all four walls closing in towards the center of the room. Center of pressure (COP)-derived postural sway variables were analyzed with a one-way repeated measures analysis of variance at an alpha level of 0.05. Results: Significant main effect differences existed in all but one dependent COP-derived postural sway variables, at p < 0.05. Post-hoc pairwise comparisons with a Bonferroni correction revealed that, predominantly, postural sway excursions were significantly lower in claustrophobia trials compared to NoVR and VR, but only accomplished with significantly increased sway velocity. Conclusion: The VR CP trials induced lower postural sway magnitude, but with increased velocity, suggesting a bracing and co-contraction strategy when exposed to virtual claustrophobic postural threats. Additionally, postural sway decreased with subsequent claustrophobia trials, suggesting potential motor learning effects. Findings from the study offer insights to postural control behavior under virtual claustrophobic simulations and can aid in VR exposure therapy for claustrophobia.

The Walls Are Closing in: Postural Responses to a Virtual Reality Claustrophobic Simulation

Compression socks are used by a very diverse group of individuals and may potentially have a greater impact on physically diminished or impaired individuals as opposed to healthy individuals. The purpose of this study was to compare the effects of sub-clinical (SC) and clinical (CL) compression socks among healthy (CON), copers (COP), and individuals with chronic ankle instability (CAI). Postural stability was evaluated in 20 participants (11 males and 9 females) using Balance Tracking System Balance platform (BTrackS™) during the modified clinical test of sensory integration in balance (mCTSIB) and limits of stability (LOS) tests. Postural sway parameters were analyzed using a mixed model repeated measures analysis of variance 3 (group: CON, COP, and CAI) by 3 (compression condition: BF, SC, and CL) × 4 (balance condition: EO, EC, EOF, and ECF) for mCTSIB and a 3 (group: CON, COP, and CAI) by 3 (compression condition: BF, SC, CL) × 4 (balance condition: FL, BL, BR, FR) for LOS. Results revealed significantly greater postural stability with both SC and CL compression socks when compared to barefoot conditions. However, no significant differences were observed among groups for compression socks grades. Both SC and CL compression socks may be effective in increasing postural stability.

Impact of Sub-Clinical and Clinical Compression Socks on Postural Stability Tasks among Individuals with Ankle Instability

Muscle activity from the slipping leg have been previously used to analyze slip induced falls. However, the impact of casual alternative footwear on slipping leg muscle activity when exposed to slippery environments is still unknown. The purpose of the study was to analyze the impact of alternative footwear (crocs (CC) and flip-flops (FF)) compared to slip-resistant footwear (LT) on lower extremity muscle activity when exposed to dry gait (NG), unexpected (US), alert (AS), and expected slips (ES). Eighteen healthy males (age: 22.3 ± 2.2 years; height: 177.7 ± 6.9 cm; weight: 79.3 ± 7.6 kg) completed the study in a repeated measures design in three footwear sessions separated by 48 h. Electromyography (EMG) muscle activity from four muscles of the lead/slipping leg was measured during the stance phase of the gait-slip trials. A 3 (footwear) × 4 (gait-slip trials) repeated measures analysis of variance was used to analyze EMG dependent variables mean, peak, and percent of maximal voluntary contraction. Greater lower extremity muscle activation during the stance phase was seen in US and AS conditions compared to NG and ES. In addition, footwear differences were seen for the alternative footwear (CC and FF) during US and AS, while the low top slip resistant shoe had no differences across all gait trials, suggesting it as the most efficient footwear of choice, especially when maneuvering slippery flooring conditions, either with or without the knowledge of an impending slip.

Lower Extremity Muscle Activation in Alternative Footwear during Stance Phase of Slip Events

Soft robotic sensors, a class of pliable, embeddable sensors, are well-suited for applications in wearable technology because of their ease of integration with common clothing articles. The suitability of soft robotic sensors for estimation of human joint angles has been proven; this research represents another step towards development of a reliable laboratory data collection platform for the human ankle joint complex. In this research, the accuracy and repeatability of a newly-developed wearable prototype are evaluated as a potential replacement for camera-based motion capture by measuring differences between simultaneously collected motion capture and stretch sensor data. The accuracy of these measurements is compared to measurements collected using a previous prototype for validation. Results show that the newly-developed prototype is capable of joint angle estimation within 1.86° mean-absolute-error during complex, dynamic movements and that wearing shoes over the sock prototype does not significantly degrade performance.

Closing the Wearable Gap–Part IX: Validation of an Improved Ankle Motion Capture Wearable

Textile and electronic components are critical elements of most wearable technologies (wearables); both components deteriorate at different rates depending on factors of use, care, and user handling. The differences in mechanical performance characteristics (MPC) (i.e., abrasion, elongation, and bursting strength) of these components create a challenge for researchers and product designers to develop user-centric and economical wearables. For example, athletic wearables made of nylon/spandex knit blends exhibit drastically different MPC from minimal fiber content changes (1- 10%). However, the wearable's end-use remains constant. This article presents ideas and methods for testing MPC and how to evaluate results for different end-use cases. Designing for end-user activities also highlights these performance differences because specific, end-uses drive textiles design, which may or may not be the wearable design's end-use. Three American Society for Testing and Materials (ASTM) test methods were used to test MPC of athletic fabrics and soft robotic sensors (SRS) to determine the abrasion resistance, elongation, and bursting strength of these components and two-tail ttest comparisons were performed on the results. The SRS's durability is less than the textiles they are integrated into, and with no standards for MPC testing on SRS, it can be unclear how long a sensor will last. Such methods need to be developed so product developers can find efficient combinations of fibers and electronic components to ensure user-centric functionality, wearer comfort, extended product longevity, and overall consumer satisfaction.

Deterioration of textile vs. electronic components over time in athletic wearable devices

Background: Occupational footwear and a prolonged duration of walking have been previously reported to play a role in maintaining postural stability. The purpose of this paper was to analyze the impact of three types of occupational footwear: the steel-toed work boot (ST), the tactical work boot (TB), and the low-top work shoe (LT) on previously unreported lower extremity muscle activity during postural stability tasks. Methods: Electromyography (EMG) muscle activity was measured from four lower extremity muscles (vastus medialis (VM), medial hamstrings (MH), tibialis anterior (TA), and medial gastrocnemius (MG) during maximal voluntary isometric contractions (MVIC) and during a sensory organization test (SOT) every 30 min over a 4 h simulated workload while wearing ST, TB, and LT footwear. The mean MVIC and the mean and percentage MVIC during each SOT condition from each muscle was analyzed individually using a repeated measures ANOVA at an alpha level of 0.05. Results: Significant differences (p < 0.05) were found for maximal exertions, but this was limited to only the time main effect. No significant differences existed for EMG measures during the SOT. Conclusion: The findings suggest that occupational footwear type does not influence lower extremity muscle activity during both MVIC and SOT. Significantly lower muscle activity during maximal exertions over the course of the 4 h workload was evident, which can be attributed to localized muscular fatigue, but this was not sufficient to impact muscle activity during postural stability tasks.

Role of Occupational Footwear and Prolonged Walking on Lower Extremity Muscle Activation during Maximal Exertions and Postural Stability Tasks

Falls are extremely common in occupational settings. Intrinsic factors such as overexertion and extrinsic factors such as the supporting surface are causative factors of falls. The impact of prolonged exposure to a slippery surface on postural stability has not been previously studied. The purpose of the study was to analyze the effect of extended exposure to a dry and a slippery surface on postural stability. Eighteen males (age: 21.17 ± 3.38 years; height: 1.77 ± 0.08 m; mass: 89.81 ± 14.23 kg) were recruited and subjected to one-hour walking on a dry surface and a slippery surface on two different days. Participants’ balance was assessed using a force platform in stable and unstable conditions at 0, 30, and 60 min. Postural sway variables were analyzed using a 2 (surface) × 3 (time) repeated-measures ANOVA. Significant time main effects were observed in the stable condition with greater balance decrements at 30 and 60 min. Greater balance decrements were observed on the slippery surface compared to the dry surface in the unstable condition. The balance decrements can be attributed to overexertion due to the physiological workload of prolonged walking and to the potential gait modifications due to walking on the slippery surface.

Impact of Prolonged Exposure to a Slippery Surface on Postural Stability

Background: Wearable technology is used by clinicians and researchers and play a critical role in biomechanical assessments and rehabilitation. Objective: The purpose of this research is to validate a soft robotic stretch (SRS) sensor embedded in a compression knee brace (smart knee brace) against a motion capture system focusing on knee joint kinematics. Methods: Sixteen participants donned the smart knee brace and completed three separate tasks: non-weight bearing knee flexion/extension, bodyweight air squats, and gait trials. Adjusted R2 for goodness of fit (R2), root mean square error (RMSE), and mean absolute error (MAE) between the SRS sensor and motion capture kinematic data for all three tasks were assessed. Results: For knee flexion/extension: R2 = 0.799, RMSE = 5.470, MAE = 4.560; for bodyweight air squats: R2 = 0.957, RMSE = 8.127, MAE = 6.870; and for gait trials: R2 = 0.565, RMSE = 9.190, MAE = 7.530 were observed. Conclusions: The smart knee brace demonstrated a higher goodness of fit and accuracy during weight-bearing air squats followed by non-weight bearing knee flexion/extension and a lower goodness of fit and accuracy during gait, which can be attributed to the SRS sensor position and orientation, rather than range of motion achieved in each task.

Closing the Wearable Gap—Part VIII: A Validation Study for a Smart Knee Brace to Capture Knee Joint Kinematics

Abstract Due to the limited capacity of the brain, prolonged mental tasks placed on an individual could cause cognitive fatigue (CF). CF is known to cause attention deficits, leading to poor situational awareness and vigilance. Depending on the circumstances, such attention deficits may cause catastrophic outcomes, causing harm to many individuals. Hence, early identification of CF is mandatory. Wearable technology seems to provide a promising solution in detecting CF by monitoring the alterations of physiological parameters, eye movements, speech, or brain activity. Further, some recently developed wearable devices are shown to have the potential to alert the user regarding an impending CF and activate safety measurements. However, other coinciding factors, such as emotions or exercise, could alter the aforementioned factors used in the detection of CF. Thus, the accuracy and validity of recognizing CF using wearables are lower than detecting physical fatigue. However, with the advancements of technology, these devices continue to demonstrate excellent improvements. This article provides a condensed summary of the use of wearable devices in detecting CF in the recent literature and their possible developments in the future. Concepts discussed in the article will interest the ergonomists, health and safety engineers, human factors engineers, and health care professionals.

The use of wearable devices in cognitive fatigue: current trends and future intentions

Background: Postural strategies such as ankle, hip, or combined ankle-hip strategies are used to maintain optimal postural stability, which can be influenced by the footwear type and physiological workload. Purpose: This paper reports previously unreported postural strategy scores during the six conditions of the sensory organization test (SOT). Methods: Fourteen healthy males (age: 23.6 ± 1.2 years; height: 181 ± 5.3 cm; mass: 89.2 ± 14.6 kg) were tested for postural strategy adopted during SOT in three types of occupational footwear (steel-toed work boot, tactical work boot, low-top work shoe) every 30 min during a 4-h simulated occupational workload. Postural strategy scores were analyzed using repeated measures analysis of variance at 0.05 alpha level. Results: Significant differences among postural strategy scores were only evident between SOT conditions, and but not between footwear type or the workload. Conclusions: Findings indicate that occupational footwear and occupational workload did not cause a significant change in reliance on postural strategies. The significant changes in postural strategy scores were due to the availability of accurate and/or conflicting sensory feedback during SOT conditions. In SOT conditions where all three types of sensory feedback was available, the ankle strategy was predominantly adopted, while more reliance on hip strategy occurred in conditions with absent or conflicting sensory feedback.

Sensory Organization Test Conditions Influence Postural Strategy Rather than Footwear or Workload

Abstract Footwear and physiological workload have been reported to impact postural stability. Analyses of postural strategies during sensory organisation test (SOT) can aid better understanding of postural control behaviour. The paper reports previously unreported postural strategy scores from each SOT condition, in various types of footwear when exposed to different workloads from two different completed studies. Study 1 analysed postural strategies in alternative footwear [Crocs (CC), flip-flops (FF) and Vibram five-finger (VIB)] before and after a low-intensity workload (n = 18; age: 22.9 ± 2.8 years; height: 179 ± 6.0 cm; mass: 81.3 ± 8.8 kg) and study 2 in military footwear [standard tactical boot (STD) and minimalist tactical boot (MIN)] before and after a high-intensity workload (n = 16; age: 26.63 ± 3.93 years; height: 178.04 ± 6.2 cm; mass: 87 ± 12.4 kg). Findings from the current analyses revealed significant differences in footwear type, workload, and SOT conditions. Design characteristics on alternative footwear and the low intensity workload were not sufficient to cause a significant shift from a predominant ankle to hip strategy. However, design characteristics of STD and the high-intensity workload did cause a shift from an ankle to hip strategy. During SOT conditions where all three types of feedback was readily available (visual, vestibular and somatosensory), an ankle strategy was used to maintain postural stability, while more reliance on hip strategy existed when sensory feedback was absent or in conflict.

An analysis of postural control strategies in various types of footwear with varying workloads

ABSTRACT This study examined lower extremity joint kinematics in individuals with chronic ankle instability (CAI) and controls during unanticipated and anticipated single-leg drop landings onto a laterally inclined platform. Physically active adults with CAI 15 (n = 15) and controls (n = 15) performed an unanticipated and anticipated 30 cm single-leg drop landing onto a 20° laterally inclined platform. Three-dimensional ankle, knee and hip-joint kinematics were recorded 200 ms pre- to 200 post-landing and analysed with a 2 (group) × 2 (landing condition) SPM ANOVA (p < 0.05). Results revealed individuals with CAI displayed significantly greater ankle internal rotation post-landing across both landing conditions. Anticipated landings elicited significantly greater pre-landing ankle inversion and external rotation, knee abduction and hip adduction. Additionally, significantly less ankle inversion, knee and hip flexion, and knee adduction and hip abduction were present during post-landing of the anticipated landing. Greater ankle internal rotation during landing may contribute to the ankle ‘giving way’ in individuals with CAI. However, preparatory and reactive proximal-joint kinematics were similar in both groups during landing. This highlights the possible role of the knee and hip joints in assisting with ankle-joint stability during anticipated inversion perturbations.

Lower extremity joint kinematics of a simulated lateral ankle sprain after drop landings in participants with chronic ankle instability

Dielectric elastomers have emerged in recent years as a smart material capable of acting as an actuator, a sensor, or a generator. When used as a sensor, this soft, flexible material exhibits a change in capacitance as it is deformed in both compression and tension. This has led to the adaptation of dielectric elastomer sensors in the wearable technology space, where careful sensor placement can enable the measurement of biomechanical movement. However, these sensors may not be measured using traditional capacitance measurement techniques due to their increased electrode resistance. Thus, a low frequency, low voltage capacitive measurement methodology needs to be derived for these sensors to thrive in wearable applications. In this work, we propose such a methodology which utilizes phase detection with the Goertzel algorithm. Traditionally used for tone detection, the Goertzel algorithm provides an efficient method for recovering individual terms of the DFT. Our sensing methodology is integrated into a low-cost microcontroller and integrated with a wireless microcontroller to enable remote measurement of the dielectric elastomers. The open sourcing of this device may jump-start the widespread adoption of dielectric elastomers as biomechanical sensors.

Low-voltage capacitive measurement methodology for dielectric elastomers

Computational approaches, especially Finite Element Analysis (FEA), have been rapidly growing in both academia and industry during the last few decades. FEA serves as a powerful and efficient approach for simulating real-life experiments, including industrial product development, machine design, and biomedical research, particularly in biomechanics and biomaterials. Accordingly, FEA has been a "go-to" high biofidelic software tool to simulate and quantify the biomechanics of the foot-ankle complex, as well as to predict the risk of foot and ankle injuries, which are one of the most common musculoskeletal injuries among physically active individuals. This paper provides a review of the in silico FEA of the foot-ankle complex. First, a brief history of computational modeling methods and Finite Element (FE) simulations for foot-ankle models is introduced. Second, a general approach to build a FE foot and ankle model is presented, including a detailed procedure to accurately construct, calibrate, verify, and validate a FE model in its appropriate simulation environment. Third, current applications, as well as future improvements of the foot and ankle FE models, especially in the biomedical field, are discussed. Lastly, a conclusion is made on the efficiency and development of FEA as a computational approach in investigating the biomechanics of the foot-ankle complex. Overall, this review integrates insightful information for biomedical engineers, medical professionals, and researchers to conduct more accurate research on the foot-ankle FE models in the future.

In Silico Finite Element Analysis of the Foot Ankle Complex Biomechanics: A Literature Review.

Background: Bat velocity, attack angle, and vertical angle are common variables that coaches and players want to evaluate during their baseball or softball swing. Objective: The purpose of this study was to investigate and validate a baseball bat handle sensor against motion capture using recreational baseball and softball athletes for bat velocity, attack angle, and vertical angle. Methods: This single visit cross-sectional experimental design study utilized eighteen recreational baseball and softball players (ten males and eight females, age: 20.70 ± 1.69 years, height: 170.74 ± 5.69 cm, weight: 77.97 ± 12.30 kg) were recruited. Bat velocity, attack angle, and vertical angle from the bat handle sensor and 12-camera motion capture system were collected and compared using a two-tailed paired t-test. Results: Differences were statistically significant, showing that 95% of the time, the bat handle sensor overestimated the bat velocity by 1.92 to 2.77 m/s, underestimated the attack angle by -3.46 to -1.96o, and overestimated the vertical angle by 1.64 to 3.21o, compared to the motion capture system. Conclusion: The bat velocity and vertical angle were overestimated, while the attack angle was underestimated by the bat sensor. The information presented in this study can be viable information for coaches and players when utilizing the baseball bat handle sensor technology for training, practice, or in-game situations.

Validation of a Bat Handle Sensor for Measuring Bat Velocity, Attack Angle, and Vertical Angle

Trip-induced falls are extremely common in ergonomic settings. Such situations can lead to fatal or non-fatal injuries, affecting the workers’ quality of life and earning capacity. Dual tasking (DT) is a leading cause of trips and ineffective obstacle clearance among workers. DT increases their attentional demand, challenging both postural control and concurrent secondary tasks. As the human brain has limited attentional processing capacity, even young, healthy adults need to prioritize duties during DT. This article aimed to analyze these secondary task types and their applications in recent trip-related studies conducted on young, healthy adults. An extensive review of the recent trip-related literature was performed to provide a condensed summary of the dual tasks used. In previous trip-related literature, distinct types of secondary tasks were used. The choice of the concurrent task must be made vigilantly depending on the occupation, environmental context, available resources, and feasibility. DT can be used as a tool to train workers on selective attention, which is a lifesaving skill in ergonomic settings, especially in the occupations of roofers, construction workers, or truck drivers. Such training can result in successful obstacle clearance and trip recovery skills, which eventually minimizes the number of falls at the workplace.

Dual Tasking during Trip Recovery and Obstacle Clearance among Young, Healthy Adults in Human Factors Research

A novel wearable solution using soft robotic sensors (SRS) has been investigated to model foot-ankle kinematics during gait cycles. The capacitance of SRS related to foot-ankle basic movements was quantified during the gait movements of 20 participants on a flat surface as well as a cross-sloped surface. In order to evaluate the power of SRS in modeling foot-ankle kinematics, three-dimensional (3D) motion capture data was also collected for analyzing gait movement. Three different approaches were employed to quantify the relationship between the SRS and the 3D motion capture system, including multivariable linear regression, an artificial neural network (ANN), and a time-series long short-term memory (LSTM) network. Models were compared based on the root mean squared error (RMSE) of the prediction of the joint angle of the foot in the sagittal and frontal plane, collected from the motion capture system. There was not a significant difference between the error rates of the three different models. The ANN resulted in an average RMSE of 3.63, being slightly more successful in comparison to the average RMSE values of 3.94 and 3.98 resulting from multivariable linear regression and LSTM, respectively. The low error rate of the models revealed the high performance of SRS in capturing foot-ankle kinematics during the human gait cycle.

Closing the Wearable Gap—Part VI: Human Gait Recognition Using Deep Learning Methodologies

Background: Postural stability and cognitive performance are challenged in firefighters. The purpose of this investigation was to examine the impact of 7-day ketone supplementation on postural stability, cognitive performance, and muscular activation before and after a physiological workload. Methods: Nine professional firefighters completed two experimental sessions (preand post-workload) in a counterbalanced, double-blind design. Participants ingested either a ketone salt (KS) or placebo (PLA) daily for seven days, and had an eighth ingestion 30 min prior to testing. Each experimental testing consisted of maximal voluntary contractions (MVIC) for four muscles (knee flexors—BF, extensor—VM, ankle dorsiflexors—TA, and plantar flexors—MG) using electromyography and postural stability testing (eyes open (EO), eyes closed (EC), and eyes open-dual-task using a FitLightTM system (EOT)), before (pre-workload) and after (post-workload) a simulated physiological workload. The workload consisted of 35 min steady state exercise at 60% of peak oxygen consumption wearing firefighter personal protective equipment (PPE). Results: Significant differences were limited to time effects (pre-workload vs. post-workload), with no differences between groups (KS vs. PLA). Significantly lower muscle activity in VM, TA, and MG during MVIC, greater postural sway and muscle activity in BF during EC and EOT, and slower response time during EOT were evident post-workload. Conclusions: A 7-day ketone supplementation does not impact postural stability, muscle activity, and cognitive tasks, but a fatiguing workload causes significant performance reduction.

Effects of Ketone Ingestion on Single and Dual-Task Postural Stability and Muscular Exertion in Firefighters

Impact of military footwear type and a load carriage workload on slip initiation biomechanics

Maintaining upright standing balance is critical for military personal. The impact of military footwear and occupation-related fatigue on muscle activity during balance performance has been previously documented. However, the current literature has not provided a muscle activation profile of the lower extremity during challenging conditions such as unilateral balance trials. Twenty-two recreationally active male participants (age: 22.2 ± 2.7 years; height: 177 ± 6.8 cm; mass: 79.8 ± 9.7 kg) donned two styles of military footwear (minimalist and standard) and performed a military style workload. Unilateral static balance was accessed before (PRE) and after (POST) the workload as surface electromyography was recorded on the right lower extremity. This study found that the minimalist footwear increased muscle activation prior to the workload compared to the standard footwear (co-contraction index mean difference: 0.149), whereas the standard footwear increased muscle activity after the workload (co-contraction index mean difference: 0.097). These findings suggest that footwear design characteristics affect lower extremity muscle activity differently depending on the workload condition. These findings intend to aid in the design of military footwear to maximize balance performance in a military population.

Military-Type Workload and Footwear Alter Lower Extremity Muscle Activity during Unilateral Static Balance: Implications for Tactical Athletic Footwear Design

CONTEXT
Individuals with chronic ankle instability (CAI) demonstrate altered lower limb movement dynamics during jump landings, which can contribute to recurrent injury. However, the literature examining lower limb movement dynamics during a side-cutting task in individuals with CAI is limited.

OBJECTIVE
To assess lower limb joint kinetics and sagittal-plane joint stiffness during the stance phase of a side-cutting task in individuals with or without CAI.

DESIGN
Cohort study.

SETTING
Motion-capture laboratory.

Fifteen physically active, young adults with CAI (7 men, 8 women; age = 21.3 ± 1.6 years, height = 171.0 ± 11.2 cm, mass = 73.4 ± 15.2 kg) and 15 healthy matched controls (7 men, 8 women; age = 21.5 ± 1.5 years, height = 169.9 ± 10.6 cm, mass = 75.5 ± 13.0 kg).

INTERVENTION(S)
Lower limb 3-dimensional kinematic and ground reaction force data were recorded while participants completed 3 successful trials of a side-cutting task. Net internal joint moments, in addition to sagittal-plane ankle-, knee-, and hip-joint stiffness, were computed from 3-dimensional kinematic and ground reaction force data during the stance phase of the side-cutting task and analyzed.

MAIN OUTCOME MEASURE(S)
Data from each participant's stance phase were normalized to 100% from initial foot contact (0%) to toe-off (100%) to compute means, standard deviations, and Cohen d effect sizes for all dependent variables.

RESULTS
The CAI group exhibited a reduced ankle-eversion moment (39%-81% of stance phase) and knee-abduction moment (52%-75% of stance phase) and a greater ankle plantar-flexion moment (3%-16% of stance phase) than the control group (P range = .009-.049). Sagittal-plane hip-joint stiffness was greater in the CAI than in the control group (t28 = 1.978, P = .03).

Our findings suggest that altered ankle-joint kinetics and increased hip-joint stiffness were associated when individuals with CAI performed a side-cutting task. These lower limb kinetic changes may contribute to an increased risk of recurrent lateral ankle sprains in people with CAI. Clinicians and practitioners can use these findings to develop rehabilitation programs for improving maladaptive movement mechanics in individuals with CAI.

Lower Limb Joint Kinetics During a Side-Cutting Task in Participants With or Without Chronic Ankle Instability.

Journal of electromyography and kinesiology : official journal of the International Society of Electrophysiological Kinesiology

Ankle kinematics, center of pressure progression, and lower extremity muscle activity during a side-cutting task in participants with and without chronic ankle instability.

Abstract Falls and fall-related injuries are remarkably common in occupational settings. In 2017, 227,760 workers sustained fall-related injuries leading to a loss of working days and 887 workers sustained lethal falls. Causation of falls could be multifactorial with the contribution of extrinsic and intrinsic factors. The outcome of such falls could vary from simple contusions to fatal injuries. Occupational falls not only affect employees’ health and quality of life but also decrease workplace productivity due to loss of working days and worker performance insufficiency as a result of sustained injuries. Furthermore, health costs, worker compensations, and replacement workers add to the economic burden of the workplace. Thus, fall detection and prevention in the workplace is mandatory. There are distinct traditional and contemporary methods of fall prevention established in the human factors and ergonomics field with unique advantages and disadvantages. Selection of an appropriate method should be done vigilantly considering feasibility, availability of facilities, and affordability by the administration. This article summarises and expands on previous literature suggested for early detection and prevention of occupational falls. Concepts discussed in the paper will benefit human factors engineers, ergonomists, health and safety engineers, occupational therapists, and other health care professionals. Relevance to human factors / ergonomics theory Falls are unavoidable in the ergonomic settings but could be minimized. This article provides the currently available fall prevention and detection methods along with the strengths and weaknesses of each method. The article will provide an overview of such methods to the employers in order to select and implement the most applicable methods to their workplace.

Occupational falls: interventions for fall detection, prevention and safety promotion

Abstract Intrinsic factors such as foot arch type and extrinsic factors such as footwear are among the main contributors for a higher lower extremity injury incidence due to their impact on postural stability. The purpose of this study was to investigate the impact of foot type and two types of Vibram™ five fingers footwear on static postural stability. Twenty-four healthy males (age 21.38 ± 2.50 years, height 1.74 ± 0.06 m, mass 71.24 ± 10.37 kg) were recruited and categorized into neutral, pronated and supinated categories according to the foot posture index 6. Participants were tested on the barefoot condition first, followed by two types of minimalist Vibram™ footwear [Vibram™ Bikila (VB) and Vibram™ Trek ascent (VT)] in a counterbalanced manner. Static balance was tested on a stable and unstable surface under the following conditions: bilateral eyes open (BL EO), bilateral eyes closed (BL EC), unilateral eyes open (UL EO) and unilateral eyes closed (UL EC)]. The results revealed a significant footwear main effect for the stable BL EO, stable UL EC, and unstable UL EC conditions with greater balance performance in the barefoot condition compared to shod conditions. In the unstable UL EO condition, shod conditions elicited greater balance performance compared to bare feet. Overall, VT had greater balance performance compared to VB. Foot type did not demonstrate a significant impact on static balance. In conclusion, the barefoot condition elicited greater static balance performance in all conditions except during extremely challenging sensory conditions where VT was found to be the footwear of choice, which can be attributed to its design characteristics.

Impact of foot arch type and minimalist footwear on static postural stability

In order to successfully hit a baseball, hitters must utilize a series of preparatory movements (swing phases) which include shifting their body weight, stepping, landing, and swinging. The purpose of this study was to examine the differences between start times for swing phases (shifting, stepping, landing, and swinging)for currently active baseball players. Participants (n = 12) were all current collegiate baseball athletes. Retroreflective markers, surface electromyography (EMG) and two force platforms were utilized to complete a swing analysis. Each participant completed five swinging trials off a tee. All dependent variables were compared using a repeated measures 1×4 ANOVA with LSD post hoc comparison (p < 0.05) if necessary. The results demonstrated that the participants started the swing phases in a statistically significant sequence of shifting, stepping, landing, and swinging. The ability of the athletes to start the swing phases in this sequential order may be advantageous to regulate spatial parameters of their swing and provide more time to generate power. These results allow for coaches to better understand how to instruct their athletes to be successful at the plate.

Decrements to postural control manifest as an increase in muscle activity, indicating continuous attempts to maintain body equilibrium and postural stability. Extrinsic factors such as footwear, and intrinsic factors such as muscle fatigue, can affect postural stability. The purpose of this study was to analyze the impact of two types of military footwear and a military-type load-carrying task on lower extremity muscle activity during various postural stability tasks. Sixteen males’ (age: 26.63 ± 3.93 years; mass: 87 ± 12.4 kg; height: 178.04 ± 6.2 cm) muscle activity from knee flexors, extensors, ankle dorsiflexors, and plantar flexors were measured using electromyography in standard (STD) and minimalist (MIN) military footwear, before (PRE) and after (POST) a simulated workload during sensory organization and motor control tests on the Neurocom EquitestTM. Mean muscle activity was analyzed using 2 (footwear) × 2 (time) repeated measures ANOVA with an alpha level of 0.05. Results revealed a requirement of significantly greater muscle activity in POST and STD. MIN demonstrated lesser balance decrements POST workload, which could be attributed to its design characteristics. Results will help in suggesting footwear design characteristics to minimize muscular exertion while eliciting better postural control, and to prevent postural instability due to overexertion in military personnel.

Muscle Activity during Postural Stability Tasks: Role of Military Footwear and Load Carriage

PURPOSE
Wearing a weighted vest (WV) during daily living and training can enhance jump and sprint performance, however, studies examining the efficacy of this method in female populations is limited. This study examined the effect of wearing a WV during daily living and training on countermovement jump (CMJ), change-of-direction (CoD), and sprint performance.

METHODS
Trained females were separated into intervention (n=9) and control (n=10) groups. The intervention group wore WVs of ~8% body mass 4 d/wk, 8 h/day (32 h/wk total), and 3 training sessions per week for the first 3 weeks. Subsequently, 3 weeks of regular training without WV stimulus was completed. The control group received no intervention and continued normal training for 6 weeks. Average and best performance was assessed on the single CMJ, four continuous CMJ (4CMJ), t-test CoD drill, and a 25 m sprint at baseline, week 3, and week 6.

RESULTS
No significant interactions or group effects were found. However, significant time main effects revealed increases in average rate of force development during the CMJ from baseline to week 3 (P=.048) and week 6 (P=.013), while peak vertical ground reaction force increased during 4CMJ from baseline to week 3 (P=.048) and week 6 (P=.025) for both groups.

The lower relative WV load used in this study failed to elicit significant improvements in jump and sprint performance in comparison to routine training, or that have been found in past investigations with elite male athletes completing high intensity performance tasks with greater WV loads.

Effects of Weighted Vest Loading during Daily Living Activities on Countermovement Jump and Sprint Performance.

Background Falls due to postural instability are common in construction environments especially from a height. The purpose of the study was to investigate the impact of virtual reality (VR)-generated environments at different virtual heights on postural stability. Methods Nineteen adults were analyzed for postural stability, tested in real (No VR) environment and in three VR environments, randomly assigned, at virtual heights of 0 ft. (VR0), 40 ft. (VR40), and 120 ft. (VR120). Postural stability was quantified using center of pressure postural sway variables and analyzed using a repeated measures analysis of variance (ANOVA). Participants also completed a simulation sickness questionnaire (SSQ) before and after VR exposure and a presence questionnaire (PQ) after VR exposure. Findings Significant postural instability (p < .05) was identified between VR and No VR, in which increased postural instability was evident in all VR conditions compared with No VR. Scores from SSQ were within a pre–post score difference of five and the PQ score was (104.21 ± 14.03). Conclusion/Application to Practice Findings suggest that VR environments, regardless of virtual height, induced increased postural instability, which can be attributed to visual sensory conflicts to the postural control system created by VR exposure. Participants’ subjective responses on SSQ and PQ confirmed the feasibility of using VR to represent realistic immersions in virtual heights. However, objectively, VR could potentially lead to postural instability, stressing caution. VR can be a potential tool for providing virtual high-altitude environment exposure for fall prevention training, however, more research is needed on postural adaptation with acute and chronic exposure to VR.

Impact of Virtual Reality–Generated Construction Environments at Different Heights on Postural Stability and Fall Risk

Postural control is a complex process requiring both sensory and motor responses. Perturbation-based balance training has emerged as an effective fall prevention intervention, which provides physical postural perturbations for postural control training and adaptation. With the advent of technology, virtual reality (VR) has also been used for fall prevention training by providing visual postural perturbations. This article addresses such VR studies, including a recent experiment which involved recreating the classical “moving room” paradigm into a “virtual moving room-wall paradigm” to assess the impact of VR-induced visual postural perturbations on postural stability and control. Evidence of both compensatory and anticipatory postural responses during unexpected and expected visual postural perturbations is presented. The future scope, required virtual environment set-up variations, limitations, and significance of a “virtual moving wall” paradigm in the learning and adaptation of postural control behavior are also discussed.

Is it me or the room moving? Recreating the classical “moving room” experiment with virtual reality for postural control adaptation

Background: High-intensity interval training (HIIT) has grown in popularity, with studies demonstrating improvements in aerobic and anaerobic performances within Sedentary and Recreationally active adults. Little research has been comprised on collegiate, middle-distance runners (800m/1500m). Objective: This research study aimed to investigate the impact of four-weeks HIIT cycling training on collegiate 800/1500m runners performance, and determine whether HIIT can be used as an alternative training method for student athletes. Methods: Twelve middle-distance runners were recruited, with six athletes completing the intervention. Athletes completed pre-testing, which included a 1500m time trial, a GXT, stride length and frequency measurements, and MVIC, using Biopac electromyography (EMG). After pre-testing, athletes completed four weeks of HIIT twice per week. The HIIT consisted of four 20-second bouts with 4 minutes recovery. Following the completion of the training intervention, post-testing was performed for all measures. A paired t-test was used to determine differences between pre- and post-performance tests. An ANOVA was used to determine changes in heart rate and RPE during the GXT. Results: Significant changes were demonstrated between the pre- and post-muscle activation tests of the quadriceps (p=0.05). Significant changes were seen with both HR (p<0.05) and RPE (p<0.05) throughout the GXT. No other significant differences were demonstrated between pre- and post-performance tests, concluding four-weeks HIIT does not alter 800/1500m performance. Conclusion: From the results of this study, HIIT could be used as an alternate method for training for 800/1500m runners. Further reasearch should be conducted toto further understand the impacts of HIIT on middle distance athletes.

High-Intensity Interval Training in Middle-Distance NCAA Division I 800/1500m Collegiate Athletes

The National Science Foundation (NSF) Innovation Corps (I-Corps) teams program was designed to provide learning environments and entrepreneurship training for graduate students and researchers to translate and commercialise their fundamental research results through customer discovery and starting new companies. A Mississippi State University (MSU) team participated in this program with their preliminary design of metal-based arch wedge supports (AWSs) produced using additive manufacturing (AM) methods and the results obtained from the team's NSF I-Corps site program. During the seven-week I-Corps program, 102 interviews were conducted and the team gained a deep understanding of customers, partners, and markets. Based on the intensive interviews with potential customers and partners, the team has formed a business canvas model and decided to pursue the commercialisation of applying AM methods to produce custom and semi-customised foot orthotics with high durability at low cost. A PhD student, who is also the entrepreneur lead of this team, has gained substantial entrepreneurship skills through the I-Corps training program.

International Journal of Technology Transfer and Commercialisation

Additively manufactured metal foot orthotics and educating tomorrow's engineering entrepreneur: lessons learned from NSF I-Corps

Wearable sensors are beneficial for continuous health monitoring, movement analysis, rehabilitation, evaluation of human performance, and for fall detection. Wearable stretch sensors are increasingly being used for human movement monitoring. Additionally, falls are one of the leading causes of both fatal and nonfatal injuries in the workplace. The use of wearable technology in the workplace could be a successful solution for human movement monitoring and fall detection, especially for high fall-risk occupations. This paper provides an in-depth review of different wearable stretch sensors and summarizes the need for wearable technology in the field of ergonomics and the current wearable devices used for fall detection. Additionally, the paper proposes the use of soft-robotic-stretch (SRS) sensors for human movement monitoring and fall detection. This paper also recapitulates the findings of a series of five published manuscripts from ongoing research that are published as Parts I to V of “Closing the Wearable Gap” journal articles that discuss the design and development of a foot and ankle wearable device using SRS sensors that can be used for fall detection. The use of SRS sensors in fall detection, its current limitations, and challenges for adoption in human factors and ergonomics are also discussed.

Wearable Stretch Sensors for Human Movement Monitoring and Fall Detection in Ergonomics

This paper presents a retrospective of the benchmark testing methodologies developed and accumulated into the stretch sensor tool kit (SSTK) by the research team during the Closing the Wearable Gap series of studies. The techniques developed to validate stretchable soft robotic sensors (SRS) as a means for collecting human kinetic and kinematic data at the foot-ankle complex and at the wrist are reviewed. Lessons learned from past experiments are addressed, as well as what comprises the current SSTK based on what the researchers learned over the course of multiple studies. Three core components of the SSTK are featured: (a) material testing tools, (b) data analysis software, and (c) data collection devices. Results collected indicate that the stretch sensors are a viable means for predicting kinematic data based on the most recent gait analysis study conducted by the researchers (average root mean squared error or RMSE = 3.63°). With the aid of SSTK defined in this study summary and shared with the academic community on GitHub, researchers will be able to undergo more rigorous validation methodologies of SRS validation. A summary of the current state of the SSTK is detailed and includes insight into upcoming experiments that will utilize more sophisticated techniques for fatigue testing and gait analysis, utilizing SRS as the data collection solution.

Closing the Wearable Gap-Part VII: A Retrospective of Stretch Sensor Tool Kit Development for Benchmark Testing

Krings, BM, Shepherd, BD, Swain, JC, Turner, AJ, Chander, H, Waldman, HS, McAllister, MJ, Knight, AC, and Smith, JW. Impact of fat grip attachments on muscular strength and neuromuscular activation during resistance exercise. J Strength Cond Res XX(X): 000-000, 2018-The purpose of this study was to examine the acute effects of Fat Gripz (FG) on muscular activation and strength. Resistance trained men (n = 15; age = 22.4 ± 2.3 years; mass = 83.2 ± 11.1 kg) performed 2 experimental trials in a randomized order. Subjects completed 1 repetition maximum (1RM) testing with an Olympic barbell (OB) and with FG attached to an OB during the exercises of deadlift, bent-over row, upright row, concentration curl, and completed maximum repetitions of pull-ups until failure. Surface electromyography (EMG) was used to measure muscle activity from 8 upper extremity muscles (trapezius, medial deltoid, biceps brachii, triceps brachii, flexor carpi radialis, flexor carpi ulnaris, extensor carpi radialis, and extensor carpi ulnaris), while performing maximal voluntary isometric contractions during 1RM trials and while performing maximum number of pull-ups. When using the FG, 1RM strength was significantly decreased for each exercise, and the maximal number of pull-ups completed was significantly lower. Electromyography muscle activity was significantly increased in the forearm and shoulder muscles, but significantly decreased in the upper arm muscles with the use of FG during deadlift, bent-over row, and pull-ups. However, there were no differences for EMG activity for upright row and concentration curl. Differences in maximal strength, pull-up performance, and EMG activity with FG use may be due to the different muscle length positions. Although FG training may increase neuromuscular activation, decrements in muscular strength may result in prescribing low training loads that may not be ideal for building muscular strength.

Impact of Fat Grip Attachments on Muscular Strength and Neuromuscular Activation During Resistance Exercise.

Neuromuscular control in individuals with chronic ankle instability: A comparison of unexpected and expected ankle inversion perturbations during a single leg drop-landing.

The purpose of the article is to identify if novel footwear design could aid in postural stability and fall prevention in workplace. Footwear design has been reported to aid the task of maintaining postural stability or balancing in an erect stance while minimizing risk of falls. Minimalistic footwear that has design features such as low mass, lower heel height, and thin midsole can positively influence postural stability. Minimalistic military footwear has been shown to lower incidences of falls with efficient muscular effort. Occupational footwear that abides by safety standards with minimalistic features can help maintain postural stability and reduce falls.

Ergonomics in Design: The Quarterly of Human Factors Applications

Does Minimalist Footwear Design Aid in Postural Stability and Fall Prevention in Ergonomics?

HITT is a common training method incorporated for all fitness levels and been shown to improve athlete performance. However, these results were shown in sedentary and recreationally active populations and little research has been done with the Division I collegiate athlete population. PURPOSE: This study questioned whether HIIT could increase performance within this level of athletes, specifically middle distance runners (800/1500 m). METHODS: A total of six Division I Collegiate level (800/1500 m) runners completed the study (three males, three female). The participant completed four weeks of HIIT, consisting on two HIIT workouts per week. The HIIT consisted of four 20-s Wingate tests with 4-min recovery between each. Both preand postperformance tests were completed, consisting of a run to volitional exhaustion, RPE, HR, which were collected on a treadmill. Stride length and stride frequency, were also measure during a 1500 m time trial on the track. RESULTS: Significant differences were not found for performance preand posttraining intervention, with respect to time to completion of the 1500 m time trial (pre-intervention: 5.0 ± 0.7 min; post-intervention: 4.8 ± 0.5 min; p = 0.23), and time to volitional exhaustion (pre-intervention: 20.1 ± 1.2 min; post-intervention: 19.7 ± 1.3 min; p = 0.14). RPE (p = 0.64), HR (p = 0.09), stride length (p = 0.09), and stride frequency (p = 0.78), showed no significant changes preand post-intervention. CONCLUSIONS: HIIT did not impact 800/1500 m middle distance runner’s performance, suggesting it can maintain performance, providing alternative training methods.

Can High Intensity Interval Training Effect Division I College 800/1500m Runner’s Performance

The impact of occupational footwear and workload on postural stability has been studied previously to prevent fall-related workplace injuries.

OBJECTIVE
The purpose of this study was to assess the impact of two types of occupational footwear [steel-toed (SB) and tactical (TB) work boots] on human balance, when exposed to physical workload.

METHODS
Postural stability was evaluated in eighteen male participants in the following conditions: eyes open (EO), eyes closed (EC), eyes open unstable surface (EOU) and eyes closed unstable surface (ECU). Postural sway parameters were analyzed using a 2×3 repeated measures analysis of variance design [prior to (PRE) and twice post-workload (POST1 & POST2) separated by 10 minutes of rest].

RESULTS
Findings revealed that the use of SB resulted in greater postural stability, which could be attributed to the design characteristics of these footwear and that postural stability was negatively impacted immediately after the workload which could be attributed to the physical exertions during the workload. However, significant differences were limited to ECU with no visual and altered somatosensory feedback.

Design features on occupational footwear can aid postural stability while physical exertional tasks can be detrimental. Findings can offer design and work-rest scheduling suggestions to improve work safety.

Impact of Occupational Footwear and Workload on Postural Stability in Work Safety.

Background: Virtual reality (VR) is becoming a widespread tool in rehabilitation, especially for postural stability. However, the impact of using VR in a “moving wall paradigm” (visual perturbation), specifically without and with anticipation of the perturbation, is unknown. Methods: Nineteen healthy subjects performed three trials of static balance testing on a force plate under three different conditions: baseline (no perturbation), unexpected VR perturbation, and expected VR perturbation. The statistical analysis consisted of a 1 × 3 repeated-measures ANOVA to test for differences in the center of pressure (COP) displacement, 95% ellipsoid area, and COP sway velocity. Results: The expected perturbation rendered significantly lower (p < 0.05) COP displacements and 95% ellipsoid area compared to the unexpected condition. A significantly higher (p < 0.05) sway velocity was also observed in the expected condition compared to the unexpected condition. Conclusions: Postural stability was lowered during unexpected visual perturbations compared to both during baseline and during expected visual perturbations, suggesting that conflicting visual feedback induced postural instability due to compensatory postural responses. However, during expected visual perturbations, significantly lowered postural sway displacement and area were achieved by increasing the sway velocity, suggesting the occurrence of postural behavior due to anticipatory postural responses. Finally, the study also concluded that VR could be used to induce different postural responses by providing visual perturbations to the postural control system, which can subsequently be used as an effective and low-cost tool for postural stability training and rehabilitation.

Virtual-Reality-Induced Visual Perturbations Impact Postural Control System Behavior

Individuals with chronic ankle instability exhibit dynamic postural stability deficits and altered unilateral landing biomechanics: A systematic review.

Anticipating ankle inversion perturbations during a single-leg drop landing alters ankle joint and impact kinetics.

The Interaction of Cognitive Interference, Standing Surface, and Fatigue on Lower Extremity Muscle Activity

The linearity of soft robotic sensors (SRS) was recently validated for movement angle assessment using a rigid body structure that accurately depicted critical movements of the foot–ankle complex. The purpose of this study was to continue the validation of SRS for joint angle movement capture on 10 participants (five male and five female) performing ankle movements in a non-weight bearing, high-seated, sitting position. The four basic ankle movements—plantar flexion (PF), dorsiflexion (DF), inversion (INV), and eversion (EVR)—were assessed individually in order to select good placement and orientation configurations (POCs) for four SRS positioned to capture each movement type. PF, INV, and EVR each had three POCs identified based on bony landmarks of the foot and ankle while the DF location was only tested for one POC. Each participant wore a specialized compression sock where the SRS could be consistently tested from all POCs for each participant. The movement data collected from each sensor was then compared against 3D motion capture data. R-squared and root-mean-squared error averages were used to assess relative and absolute measures of fit to motion capture output. Participant robustness, opposing movements, and gender were also used to identify good SRS POC placement for foot–ankle movement capture.

Closing the Wearable Gap—Part II: Sensor Orientation and Placement for Foot and Ankle Joint Kinematic Measurements

CONTEXT
Lateral ankle sprains are a common injury in which the mechanics of injury have been extensively studied. However, the anticipatory mechanisms to ankle inversion perturbations are not well understood.

OBJECTIVE
To examine lower-extremity kinematics, including spatial and temporal variables of maximum inversion displacement and maximum inversion velocity, during landings on a tilted surface using a new experimental protocol to replicate a lateral ankle sprain.

SETTING
Three-dimensional motion analysis laboratory.

A total of 23 healthy adults.

Participants completed unexpected (UE) and expected (EXP) unilateral landings onto a tilted surface rotated 25° in the frontal plane from a height of 30 cm.

Ankle, knee, and hip kinematics at each discrete time point from 150 ms pre-initial contact (IC) to 150 ms post-IC, in addition to maximum ankle inversion and maximum inversion velocity, were compared between UE and EXP landings.

RESULTS
The UE landing produced significantly greater maximum inversion displacement (P < .01) and maximum inversion velocity (P = .02) than the EXP landing. Significantly less ankle inversion and internal rotation were found during pre-IC, whereas during post-IC, significantly greater ankle inversion, ankle internal rotation, knee flexion, and knee abduction were observed for the UE landing (P < .05). In addition, significantly less hip flexion and hip adduction were observed for the UE landing during pre-IC and post-IC (P < .05).

Differences in the UE and EXP landings indicate the experimental protocol presented a UE inversion perturbation that approximates the mechanism of a lateral ankle sprain. Furthermore, knowledge of the inversion perturbation elicited a hip-dominant strategy, which may be utilized to assist with ankle joint stabilization during landing to further protect the lateral ankle from injury.

Lower-Extremity Kinematics During Ankle Inversion Perturbations: A Novel Experimental Protocol That Simulates an Unexpected Lateral Ankle Sprain Mechanism.

Flatfeet: Biomechanical implications, assessment and management.

disorder. This individual was detected using the SCOFF tool and was not detected using the PPE questions. An analysis of the component questions identified the single question “Do you worry that you have lost control over how much you eat?” from the SCOFF tool to be the most sensitive and specific (70%, 100%) to detect disordered eating in collegiate athletes. CONCLUSIONS: Our results suggest that the current consensus PPE screening questions are neither sensitive nor specific to detect eating disorders in collegiate athletes. Further studies are needed to determine the appropriate questions for screening in the collegiate athlete population.

Quantification of Ground Reaction Forces for Skilled Versus Recreational Baseball Hitting

The purpose of this study was to use 3D motion capture and stretchable soft robotic sensors (SRS) to collect foot-ankle movement on participants performing walking gait cycles on flat and sloped surfaces. The primary aim was to assess differences between 3D motion capture and a new SRS-based wearable solution. Given the complex nature of using a linear solution to accurately quantify the movement of triaxial joints during a dynamic gait movement, 20 participants performing multiple walking trials were measured. The participant gait data was then upscaled (for the SRS), time-aligned (based on right heel strikes), and smoothed using filtering methods. A multivariate linear model was developed to assess goodness-of-fit based on mean absolute error (MAE; 1.54), root mean square error (RMSE; 1.96), and absolute R2 (R2; 0.854). Two and three SRS combinations were evaluated to determine if similar fit scores could be achieved using fewer sensors. Inversion (based on MAE and RMSE) and plantar flexion (based on R2) sensor removal provided second-best fit scores. Given that the scores indicate a high level of fit, with further development, an SRS-based wearable solution has the potential to measure motion during gait- based tasks with the accuracy of a 3D motion capture system.

Closing the Wearable Gap—Part IV: 3D Motion Capture Cameras Versus Soft Robotic Sensors Comparison of Gait Movement Assessment

Background: An induced loss of balance resulting from a postural perturbation has been reported as the primary source for postural instability leading to falls. Hence; early detection of postural instability with novel wearable sensor-based measures may aid in reducing falls and fall-related injuries. The purpose of the study was to validate the use of a stretchable soft robotic sensor (SRS) to detect ankle joint kinematics during both unexpected and expected slip and trip perturbations. Methods: Ten participants (age: 23.7 ± 3.13 years; height: 170.47 ± 8.21 cm; mass: 82.86 ± 23.4 kg) experienced a counterbalanced exposure of an unexpected slip, an unexpected trip, an expected slip, and an expected trip using treadmill perturbations. Ankle joint kinematics for dorsiflexion and plantarflexion were quantified using three-dimensional (3D) motion capture through changes in ankle joint range of motion and using the SRS through changes in capacitance when stretched due to ankle movements during the perturbations. Results: A greater R-squared and lower root mean square error in the linear regression model was observed in comparing ankle joint kinematics data from motion capture with stretch sensors. Conclusions: Results from the study demonstrated that 71.25% of the trials exhibited a minimal error of less than 4.0 degrees difference from the motion capture system and a greater than 0.60 R-squared value in the linear model; suggesting a moderate to high accuracy and minimal errors in comparing SRS to a motion capture system. Findings indicate that the stretch sensors could be a feasible option in detecting ankle joint kinematics during slips and trips.

Closing the Wearable Gap—Part III: Use of Stretch Sensors in Detecting Ankle Joint Kinematics During Unexpected and Expected Slip and Trip Perturbations

Bilateral spatiotemporal postural control impairments are present in participants with chronic ankle instability.

Background: Postural stability and cognitive performance are challenged in firefighters. The purpose of this investigation was to examine the impact of 7-day ketone supplementation on postural stability, cognitive performance, and muscular activation before and after a physiological workload. Methods: Nine professional firefighters completed two experimental sessions (pre- and post-workload) in a counterbalanced, double-blind design. Participants ingested either a ketone salt (KS) or placebo (PLA) daily for seven days, and had an eighth ingestion 30 min prior to testing. Each experimental testing consisted of maximal voluntary contractions (MVIC) for four muscles (knee flexors—BF, extensor—VM, ankle dorsiflexors—TA, and plantar flexors—MG) using electromyography and postural stability testing (eyes open (EO), eyes closed (EC), and eyes open-dual-task using a FitLight™ system (EOT)), before (pre-workload) and after (post-workload) a simulated physiological workload. The workload consisted of 35 min steady state exercise at 60% of peak oxygen consumption wearing firefighter personal protective equipment (PPE). Results: Significant differences were limited to time effects (pre-workload vs. post-workload), with no differences between groups (KS vs. PLA). Significantly lower muscle activity in VM, TA, and MG during MVIC, greater postural sway and muscle activity in BF during EC and EOT, and slower response time during EOT were evident post-workload. Conclusions: A 7-day ketone supplementation does not impact postural stability, muscle activity, and cognitive tasks, but a fatiguing workload causes significant performance reduction.

Effects of 7-Day Ketone Ingestion and a Physiological Workload on Postural Stability, Cognitive, and Muscular Exertion Measures in Professional Firefighters

Mean muscle activation comparison between fastballs and curveballs with respect to the upper and lower extremity.

The purpose of this study was to evaluate the use of compressible soft robotic sensors (C-SRS) in determining plantar pressure to infer vertical and shear forces in wearable technology: A ground reaction pressure sock (GRPS). To assess pressure relationships between C-SRS, pressure cells on a BodiTrakTM Vector Plate, and KistlerTM Force Plates, thirteen volunteers performed three repetitions of three different movements: squats, shifting center-of-pressure right to left foot, and shifting toes to heels with C-SRS in both anterior–posterior (A/P) and medial–lateral (M/L) sensor orientations. Pearson correlation coefficient of C-SRS to BodiTrakTM Vector Plate resulted in an average R-value greater than 0.70 in 618/780 (79%) of sensor to cell comparisons. An average R-value greater than 0.90 was seen in C-SRS comparison to KistlerTM Force Plates during shifting right to left. An autoregressive integrated moving average (ARIMA) was conducted to identify and estimate future C-SRS data. No significant differences were seen in sensor orientation. Sensors in the A/P orientation reported a mean R2 value of 0.952 and 0.945 in the M/L sensor orientation, reducing the effectiveness to infer shear forces. Given the high R values, the use of C-SRSs to infer normal pressures appears to make the development of the GRPS feasible.

Closing the Wearable Gap—Part V: Development of a Pressure-Sensitive Sock Utilizing Soft Sensors

Impact of military type footwear and workload on heel contact dynamics during slip events

A nitinol-based arch wedge support (AWS) was designed using computational approach. Finite element analysis (FEA) was performed to on this design to assess the influence of loading, boundary conditions, and thickness on the mechanical response of the computer-aid design (CAD) model. Five loading conditions caused by different human movements, two boundary conditions, and three thicknesses are involved in this computational study. FEA results showed that the presented AWS design can resist forces caused by different human motions without generating any permanent deformation. The study features the first time to design and evaluate a thin-walled nitinol AWS model. The results of this study form the background of prototyping and experimental testing of the design in the next phase.

Computational Design and Analysis of Nitinol-Based Arch Wedge Support

Influence of military workload and footwear on static and dynamic balance performance

Falls and fall-related injuries are a serious health concern in geriatric populations, especially with age-related deficits in postural control and during postural control challenging dual-task situations. Balance training has been reported to be beneficial in reducing falls. However, some of these exercises have their inherent physical challenges that prevent the elderly population from performing them effectively. Other concomitant age-related illness in the elderly pose further challenges in performing these exercises. Hence, the topic of finding alternative types of balance training that are effective and are performed in a safer environment is constantly researched. One such alternative is hydrotherapy that focuses on balance and postural perturbation-based exercises in water-based environments such as aquatic swimming pools or in dedicated hydrotherapy pools. Hydrotherapy for geriatric populations has been reported to be beneficial in improving balance, motor and cognitive tasks with improved motivation and positive attitude towards exercises. Additionally, hydrotherapy also has properties of buoyancy, resistance and temperature, which benefit biomechanical and physiological wellness and offers a safe environment to perform balance training. Hydrotherapy balance training need to be scaled and prescribed according to individual needs and can serve as an effective training and rehabilitation protocol in reducing falls in geriatric population.

Falls in Geriatric Populations and Hydrotherapy as an Intervention: A Brief Review

Interviews from strength and conditioning coaches across all levels of athletic competition identified their two biggest concerns with the current state of wearable technology: (a) the lack of solutions that accurately capture data “from the ground up” and (b) the lack of trust due to inconsistent measurements. The purpose of this research is to investigate the use of liquid metal sensors, specifically Liquid Wire sensors, as a potential solution for accurately capturing ankle complex movements such as plantar flexion, dorsiflexion, inversion, and eversion. Sensor stretch linearity was validated using a Micro-Ohm Meter and a Wheatstone bridge circuit. Sensors made from different substrates were also tested and discovered to be linear at multiple temperatures. An ankle complex model and computing unit for measuring resistance values were developed to determine sensor output based on simulated plantar flexion movement. The sensors were found to have a significant relationship between the positional change and the resistance values for plantar flexion movement. The results of the study ultimately confirm the researchers’ hypothesis that liquid metal sensors, and Liquid Wire sensors specifically, can serve as a mitigating substitute for inertial measurement unit (IMU) based solutions that attempt to capture specific joint angles and movements.

Closing the Wearable Gap: Mobile Systems for Kinematic Signal Monitoring of the Foot and Ankle

Abstract Postural stability has been shown to be impacted by footwear and task performed. This study analysed the impact of two military footwear, standard boot (STB) and minimalist boot (MTB) on postural stability, before (PRE) and after (POST) a load carriage task. Sixteen participants were tested for postural stability using sensory organisation and motor control tests on Neurocom Equitest™. Postural sway, equilibrium scores and postural latencies were analysed using a two-factor repeated measures ANOVA: boot type (STB-MTB) × time (PRE-POST) load carriage task. Significantly greater postural sway variables, lower balance scores and slower postural latencies were seen in STB and POST load carriage conditions (p < .05). The results suggest that MTB exhibited greater balance compared to STB in balance conditions that rely on somatosensory feedback and that balance is lowered after a load carriage task. Decrements in postural stability could be attributed to boot design characteristics and muscular exertion due to the load carriage task. Practitioner Summary: Maintaining optimal postural stability is crucial in military. Impact of military footwear types and load carriage task on postural stability are addressed. Findings provide footwear design and physical exertion implications on postural stability leading to potential interventions that reduce postural stability decrements; thereby, reducing potential falls and fall related injuries.

Impact of military type footwear and load carrying workload on postural stability

Abstract A computational investigation was performed in this study to evaluate the force bearing and deflection performance of a nitinol-based arch wedge support (AWS) design. Effects of force, boundary condition, and thickness on the mechanical behavior of the AWS design are discussed based on the obtained numerical results. Various force conditions corresponding to five typical human movements are calculated and considered for the finite element analysis (FEA) simulations. Two extreme boundary conditions are evaluated, a fully constrained case in which the AWS model cannot move, and a less constrained case to simulate the scenario that an AWS moves along the inner surface in the rear of shoe while its bottom stays in contact with the bottom inside surface of the shoe. The two selected boundary conditions represent scenarios where most and least degrees of freedom of the AWS model are constrained, respectively. Any real boundary conditions that an AWS may be subject within the shoe can be modeled as a combination of the two motions. Three thicknesses, 1 mm, 2.5 mm, and 5 mm, are evaluated in this study to determine the thickness effects. The results confirm that the proposed thin-walled nitinol AWS design is capable of resisting various forces and motions without any permanent deformation. Since this is the first time that a thin-walled nitinol AWS design is proposed and there is no previous experimental data, mesh refinement and numerical sensitivity analysis are also conducted to make sure that the FEA results would correctly reflect the real world results. Based on the results obtained from this study, a prototype of the AWS will be developed using additive manufacturing technologies for further human factors and material testing.

International Journal for Computational Methods in Engineering Science and Mechanics

Assessment of performance of Nitinol-based arch wedge supports in bearing forces and stresses due to human movement using FEA

Ground reaction forces during a drop vertical jump: Impact of external load training.

Limited research exists on the physiological demands of occupational footwear. Therefore, the purpose of this investigation was to examine the impact of tactical boots (TB) (0.5 kg) and steel-toed work boots (WB) (0.9 kg) on oxygen consumption (V̇O2) and cardiorespiratory responses during simulated walking protocols. Seventeen healthy male (age: 21.9 ± 2.0 years; height: 177.6 ± 4.8 cm; mass: 80.0 ± 9.4 kg) participants completed a total of four 20-min experimental walking trials: (1) WB horizontal protocol, (2) WB graded protocol, (3) TB horizontal protocol, and (4) TB graded protocol, following a randomized repeated measures design. On average, across each protocol, the larger mass of the WB increased absolute V̇O2 by 6.2% and 7.1% for the horizontal and graded protocols, respectively. The WB also caused a significant increase in absolute V̇O2 compared to TB during the horizontal protocol while walking at speeds of 4.0, 5.2, and 6.4 km/h (p < 0.05). No significant differences were observed for heart rate, breathing rate, or ratings of perceived exertion (p > 0.05). The results of this study indicate that wearing occupational footwear with a larger mass can significantly increase energy expenditure compared to footwear of lighter mass. However, energy expenditure increased without changes in physiological measures of energy expenditure. Footwear manufacturers may want to improve footwear design characteristics to maintain required safety guidelines while minimizing footwear mass.

Impact of occupational footwear during simulated workloads on energy expenditure

The role of military footwear and workload on ground reaction forces during a simulated lateral ankle sprain mechanism.

This study examined the effects of a d-β-hydroxybutyrate (βHB) containing beverage on cognitive and performance measures during a bout of repeated Wingates. Fifteen healthy, college-aged males (mean ± SD; age: 23.1 ± 2.4 years, height: 165.4 ± 2.0 cm, mass: 81.4 ± 9.2 kg) volunteered for the present study. Trial 1 consisted of baseline measures and familiarization for the protocol. During trials 2 and 3, subjects reported to the laboratory, after a 10-h fast, and ingested 11.38 g of βHB or a placebo (PLA) beverage 30 min before exercise. Participants then completed a cognitive challenge (CC), consisting of a 5-min FitLight response task while cycling. At the cessation of the test, participants then completed four 15-s repeated Wingates with 4 min of rest between, followed by another 5-min CC response task. Blood ketones, glucose, and lactate were measured pre-CC and post-Wingates. βHB levels were significantly higher compared with PLA (0.53 vs. 0.21 mmol/L), respectively. A significant order effect was observed across trials 2 and 3 for total FitLight misses and hits, regardless of treatment. Further, there were no significant differences among Wingate power output between treatments, although fatigue index was higher in the βHB group compared with PLA (32.3 vs. 29.4 W/s), respectively. In conclusion, βHB did not improve high-intensity cycling or cognitive performance measures; however, these findings might be partially explained by the absolute dosing protocol used for βHB in the present study as opposed to a relative (g/kg) dosing protocol used in previous research.

Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme

Exogenous ketone salts do not improve cognitive responses after a high-intensity exercise protocol in healthy college-aged males.

Abstract This study investigated the influence of external load training (ELT) on static and dynamic balance. Nineteen females stratified into two groups (ELT = 9, control = 10) completed three testing sessions over 6 weeks. The ELT group wore weighted vests (WV) of ~8% body mass for 32 h/week during daily living and three training sessions/week for 3 weeks. Following completion of ELT, a 3 week detraining (DET) phase was completed. Bilateral and unilateral static balance were assessed with eyes open and closed. Dynamic balance was assessed using the star excursion balance test (SEBT). Static and dynamic balance variables were analysed using a 2 (group) x 3 (time) between participants repeated measures ANOVA (p < 0.05). Results revealed significant reductions in average centre of pressure (COP) velocity in the control group on the non-dominant limb with eyes closed, and significantly greater reach distances in the ELT group on the SEBT for the posteromedial and medial directions on the dominant limb (p < 0.05). These findings suggest the ELT group did not significantly improve their balance in comparison to the control group. However, future research should further examine this unique, supplemental training method and the impact on balance performance.

External load training does not alter balance performance in well-trained women

International Journal of Exercise Science 11(1): 331-341, 2018. Footwear worn and workload performed can influence muscular exertion, which is critical in occupational environments. The purpose of the study was to assess the impact of two occupational footwear, steel-toed (SWB) and tactical (TWB) work boots, on muscular exertion when exposed to a physical workload. Eighteen healthy male participants (age: 21.27 ± 1.7 years; height: 177.67 ± 6.0 cm; mass: 87.95 ± 13.8 kg) were tested for maximal voluntary isometric contraction (MVIC) using electromyography (EMG) and pressure pain threshold (PPT) using an algometer for four lower extremity muscles prior to (pre-test) and two times after a physical treadmill workload (post-test 1 & post-test 2). Additionally, heart rate (HR), ratings of perceived exertion (RPE) at the end of the workload, and recovery were recorded along with the time spent on treadmill (TT). Results from the study revealed that PPT was significantly lowered in ankle dorsiflexors immediately following the workload and EMG mean and peak muscle activity were significantly lowered in post-test 2 session in knee extensors. No significant differences were found between footwear types in all measures. The findings could be attributed to the acute muscle soreness as a result of muscular exertion from the workload. The footwear design and mass did not impact PPT, MVIC, HR, RPE, and TT with the workload administered in the study.

Impact of Occupational Footwear and Workload on Lower Extremity Muscular Exertion

Abstract Lower extremity muscular exertion and footwear design characteristics during a physiological workload have been shown to influence muscle activity. However, a dearth in the literature remains on muscular activation and exertion influenced by different military footwear when exposed to a military-type workload during static standing. The purpose of the study was to assess lower extremity muscular activity during erect standing, before (PRE) and after (POST) a military workload, in two military footwear [standard tactical (STD), minimalist (MIN)]. Twenty-two recreationally trained males (age: 22.1 § 2.1 years; height: 176.6 § 6.8 cm; mass: 79.8 § 9.7 kg) were tested, following a repeated measures counterbalanced footwear assignment. Participants performed maximal voluntary isometric contractions (MVICs) and bilateral static balance assessments before and after a 16-kg load-carrying treadmill workload. Electromyography (EMG) muscle activity was collected during the postural control tasks on ankle dorsiflexors, plantar flexors, inverters and everters in pre-workload and post-workload conditions. Dependent EMG variables of mean, peak, root-mean square, percent MVIC and co-contraction index were calculated and analyzed with a 2 £ 2 within-subjects repeated measures analysis of variance with the alpha level set p < 0.05. Pre-workload muscle activity did not differ between footwear. However, MIN demonstrated lower muscle activity during post-workload static standing. Additionally, a shorter workload time was recorded while donning STD compared to MIN. In acute conditions, lower extremity muscle activity does not differ between the military footwear. However, after undergoing an occupation-related workload, standard tactical footwear increases muscle exertion, thus suggesting a diminished effect on lower extremity muscle activity.

Influence of military-type workload and footwear on muscle exertion during static standing

Slips occur as a result of failure of normal locomotion. The purpose of this study is to analyze the impact of alternative footwear (Crocs™, flip-flops) and an industry standard low-top slip-resistant shoe (SRS) under multiple gait trials (normal dry, unexpected slip, alert slip and expected slip) on lower extremity joint kinematics, kinetics and muscle activity. Eighteen healthy male participants (age: 22.28 ± 2.2 years; height: 177.66 ± 6.9 cm; mass: 79.27 ± 7.6 kg) completed the study. Kinematic, kinetic and muscle activity variables were analyzed using a 3(footwear) × 4(gait trials) repeated-measures analysis of variance at p = 0.05. Greater plantar flexion angles, lower ground reaction forces and greater muscle activity were seen on slip trials with the alternative footwear. During slip events, SRS closely resembled normal dry biomechanics, suggesting it to be a safer footwear choice compared with alternative footwear.

Maintaining postural stability is crucial, especially in hazardous occupational environments. The purpose of the study was to assess the role of three occupational footwear (low top shoe (LT); tactical work boot (TB) and steel-toed work boot (WB)) on postural stability when exposed to an occupational workload (4-h) involving standing/walking using the sensory organization test (SOT) equilibrium (EQ) scores and comparing current results with previously published postural sway variables from the same study. Fourteen male adults were tested on three separate days wearing a randomized occupational footwear, at the beginning (pre) and every 30 min of the 4-h workload until 240th min. SOT EQ scores were analyzed using a 3 × 9 repeated measures analysis of variance at an alpha level of 0.05. Significant differences between footwear was found in eyes open (p = 0.03) and eyes closed (p = 0.001) conditions. Pairwise comparisons revealed that LT had significantly lower postural stability compared to TB and WB. No other significant differences were found between footwear and over time. Significant differences between footwear can be attributed to design characteristics of footwear. Lack of significant differences over time suggests that, even though the average EQ scores decreased during the workload implying less postural stability, SOT EQ scores alone may not be sufficient to detect postural stability changes over the 4-h workload.

Postural Control in Workplace Safety: Role of Occupational Footwear and Workload

Abstract Track and field events place different demands on athletes and may have an effect on balance. This study investigated the effects of event specialty, gender, and leg dominance on balance among adolescent track and field athletes. Forty healthy adolescent track and field athletes (male = 23, female = 17) categorised into three different groups (sprinter = 20, distance runners = 13, throwers = 7) had their single leg static balance measured with the eyes open and the eyes closed using an AMTI force platform. Dependent variables included average displacement (cm) of the centre of pressure (COP) in the anterior/posterior direction and medial/lateral directions, the average velocity of the COP (cm/s) and the 95% ellipse area (cm2). Variables were analysed using a 3 (event specialty) × 2 (gender) × 2 (leg) ANOVA with repeated measures on the leg variable (p < 0.05). There was a significant difference (p < 0.05) in the average displacement of the COP in the medial/lateral direction for both the eyes open and closed condition, with the non-dominant leg demonstrating greater displacement than the dominant leg. This might increase the risk of injury for the non-dominant leg, but additional data should be collected and analysed on both dynamic balance and performance.

The purpose of this study was to examine the effects of participation in equine-assisted therapy for an individual with a spinal cord injury.  This study examined one male participant (age = 33 years) with an incomplete level C3-C4 spinal cord injury and spastic paresis. The participant completed two therapeutic horseback riding programs, each lasting 6 weeks, with an approximately 5-month break between the programs. His walking gait was analyzed before and after each of two riding sessions, which occurred on a weekly basis during the riding programs. Walking gait was analyzed using Dartfish TM video software before and after each of two separate riding sessions. The variables measured included stride length and width (meters), ankle, knee, and hip angles (degrees) at heel strike and toe-off.  All joint angle were measured in the sagittal plane. The results revealed improvements in range of motion for both the left and right ankle angle (15° changes or greater).  There was a slight decrease in right hip angle at heel strike (7°) across riding programs, and a decrease in stride length (0.2 m). Based on these results for the current participant, equine-assisted therapy may be used as an effective treatment to maintain mobility and walking gait for some individuals with spinal cord injury.

The Effect of Equine-Assisted Therapy on Gait for an Individual with a Spinal Cord Injury

The purpose of this study was to examine the effects of equine assisted therapy on selected gait parameters in a person with Down syndrome. One female participant with Down syndrome completed two therapeutic horseback riding programs, each consisting of six riding sessions. Specific gait characteristics were analyzed with a trend analysis of the data by examining the means of the different variables. The trend analysis revealed a difference in stride length as well as hip and knee angle. These results indicate that over the course of the two therapeutic horseback riding programs, changes in gait occurred. Therefore, therapeutic horseback riding may have the potential to benefit gait characteristics and stability in young adult females with Down syndrome; however, further research is warranted.

Equine Assisted Therapy and Changes in Gait for a Young Adult Female with Down Syndrome

Human balance has been shown to be invariably affected by footwear that acts as an interface between the body and the ground. However, the impact of more commonly used alternative footwear combined with transient low level muscular workloads under external perturbations is still unknown. PURPOSE: The purpose of the investigation was to determine the effect of three types of alternative footwear [clog style molded plastic shoes (CC), flip-flops (FF), minimalist toe-shoes (MIN)], on balance recovery during external perturbations prior to and after a transient physiological workload. METHODS: Eighteen healthy male adults (age: 22.94 ± 2.9 years; height: 179 ± 6.0 cm; mass: 81.3 ± 8.8 kg) completed the study following a repeated measures design and a counter balanced footwear assignment. Following an initial familiarization day, participants were tested for postural response latencies (milliseconds) using the medium and large forward/ backward perturbations [Motor Control Test (MCT)] on the NeuroCom Equitest, both prior to and after, walking a mile on a treadmill at a normal self-selected pace. The response latencies were analyzed using a 3x2 [3 (Footwear) x 2 (Pre-Post Workload)] repeated measures ANOVA individually for the perturbations at an alpha level of 0.05. RESULTS: The results revealed no significant main effect differences or interaction for footwear and pre-post workload differences in postural response latencies at p = 0.05. CONCLUSION: Previous literature has demonstrated delayed postural response latencies with flip-flops and faster response latencies in barefoot conditions, which were attributed to the design and material characteristics of the worn footwear. However, these results suggest that the design features on the alternative footwear and/or the transient physiological workload was not sufficient to cause changes in the postural response latencies during external balance perturbations in college aged healthy male adults.

Impact Of Low Intensity Workload On Muscle Exertion In Alternative Footwear: 908 Board #304 May 27, 2

METHODS: 5 healthy male runners (age 33.7 ± 13.6), who run a minimum of 10 mpw in TR running shoes, have been recruited in this ongoing study. All subjects underwent an instrumented treadmill analysis, first with a neutral, TR shoe and then with a HC shoe. Subjects ran at a self-selected speed (range 2.46 2.91 m/s), which remained constant across conditions. Variables associated with impact were assessed to include, vertical impact peak (VIP), instantaneous (VILR) and average (VALR) load rate, peak lateral force (PLF) and peak medial force (PMF). Additionally, peak vertical force (PVF) was assessed. All force values were normalized to body weight. Mean and percent differences were calculated. A statistical analysis will be performed when all subjects have been recruited and tested.

The Effect Of Commonly Used Alternative Footwear On Balance: 1161 Board #6 May 28, 8

The driver is the club which receives the greatest scrutiny by golfers and the most marketing efforts by manufacturers. One characteristic often indicated and believed to effect driver performance is the degree of loft on the clubface. The purpose of the current study was to investigate the effect that the loft of a driver and gender has on golf ball launch variables and distance. The variables that were examined included club head speed, ball speed, launch angle, descent (impact) angle, total spin, carry, and total distance. Fifteen participants (12 male, 3 female) with a handicap of eight or lower were used to test three different degree drivers (9.5°, 10.5°, and 13°) on the variables listed above. Participants performed ten tested swings for each driver and the variables were measured. The data were analyzed with a two (gender) by three (club face loft) repeated-measures ANOVA. There were significant differences (p < .05) in total spin rate, descent angle, and total distance between the clubs. The male...

The Effect of Static Club Head Loft of a Driver on Golf Ball Launch Variables and Distance

CONTEXT
The dominant and nondominant legs respond asymmetrically during landing tasks, and this difference may occur during an inversion perturbation and provide insight into the role of ankle-evertor and -invertor muscle activity.

OBJECTIVE
To determine if there is a difference in the ratio of evertor to invertor activity between the dominant and nondominant legs and outer-sole conditions when the ankle is forced into inversion.

DESIGN
Repeated-measures single-group design.

SETTING
University laboratory.

15 physically active healthy volunteers with no previous history of an ankle sprain or lower extremity surgery or fracture.

An outer sole with fulcrum was used to cause 25° of inversion at the subtalar joint after landing from a 27-cm step-down task. Participants performed 10 fulcrum trials on both the dominant and nondominant leg.

The ratio of evertor to invertor muscle activity 200 ms before and 200 ms after the inversion perturbation was measured using electromyography. This ratio was the dependent variable. Independent variables included outer-sole condition (fulcrum, flat), leg (dominant, nondominant), and time (prelanding, postlanding). The data were analyzed with separate 2-way repeated-measures ANOVA, 1 for the prelanding ratios and 1 for the postlanding ratios.

RESULTS
For the postlanding ratios, the fulcrum outer sole had a significantly greater (P < .05) ratio than the flat outer sole, and the nondominant leg had a significantly greater (P < .05) ratio than the dominant leg.

These results indicate that a greater evertor response is produced when the ankle is forced into inversion, and a greater response is produced for the nondominant leg, which may function better during a postural-stabilizing task than the dominant leg.

Difference in ratio of evertor to invertor activity between the dominant and nondominant legs during simulated lateral ankle sprain.

The purpose of the study was to evaluate the effects of six weeks of strength/functional training on muscular strength and golf performance, measured by club-head speed. Ten participants (age = 21.4 ± 2.3 yrs) were randomly assigned to an experimental group performing 6 weeks of strength/functional training or a control group that followed their regular activity/golf routine. Club-head speed was measured as an indicator of golf performance. A 2 × 2 ANOVA with repeated measures on swing speed revealed significant (p .05) differences were noted for vertical jump or sit-and-reach. Participants realized improvements in strength during their participation but these did not translate to...

Effectiveness of a Six-Week Strength and Functional Training Program on Golf Performance

When the ankle is forced into inversion, the speed at which this movement occurs may affect the extent of injury. The purpose of this investigation was to develop a fulcrum device to mimic the mechanism of a lateral ankle sprain and to determine the reliability and validity of the temporal variables produced by this device. Additionally, this device was used to determine if a single previous lateral ankle sprain or ankle taping effected the time to maximum inversion and/or mean inversion speed. Twenty-six participants (13 with history of a single lateral ankle sprain and 13 with no history of injury) completed the testing. The participants completed testing on three separate days, performing 10 trials with the fulcrum per leg on each testing day, and tape was applied to both ankles on one testing day. No significant interactions or main effects were found for either previous injury or ankle taping, but good reliability was found for time to maximum inversion (ICC = .81) and mean inversion speed (ICC = .79). The findings suggest that although neither variable was influenced by the history of a single previous lateral ankle sprain or ankle taping, both variables demonstrated good reliability and construct validity, but not discriminative validity.

Development of a fulcrum methodology to replicate the lateral ankle sprain mechanism and measure dynamic inversion speed

This study examined potential benefits from participation in therapeutic horseback riding for an individual with Friedreich’s Ataxia (FA). FA is an autosomal recessive neurological disorder with a side effect being gait ataxia. The participant’s gait was analyzed using Dartfish™ video software before and after two separate 6-week riding sessions, separated by a five-month lay-off. A significant difference in stride length (p < 0.05) was found, with a decrease occurring in the second riding session (0.99 ± 0.10 m to 0.74 ± 0.19 m). Analysis of the other variables revealed no significant differences in gait before and after each individual riding session, nor were they observed from the first day to the last day of each six week session, or intersession observations. The decrease in stride length may indicate a decrement in stability as the disease progresses, but the lack of significant differences in joint angles may indicate therapeutic horseback riding helped prevent some of the decrements caused by FA.

Friedreich's Ataxia and Gait Changes through Participation in Therapeutic Horseback Riding

The latency of the peroneus longus may be a key factor in the prevention of lateral ankle sprains (LASs). In addition, ankle taping is often applied to help prevent LASs. The purpose of this study was to determine the effects of a previous LAS and ankle taping on the latency of the peroneus longus after an inversion perturbation. Twenty-six participants, including 13 participants with no previous history of a LAS and 13 participants with a history of a single LAS completed the testing. Ankle taping was applied in a closed basket weave technique on one of the two testing days. The latency of the peroneus longus was determined by the onset of muscle activity exceeding 10 SD from baseline activity, after initiation of the 25° inversion perturbation. A significant main effect (p < 0.05) was present for the ankle support condition, with ankle taping causing a significant reduction in latency of the peroneus longus (65.04 ± 10.81 to 57.70 ± 9.39 ms). There was no difference (p>0.05) in latency between the injury groups. Ankle taping, immediately after application, reduces the latency of the peroneus longus among participants with and without a history of a LAS.

Effects of previous lateral ankle sprain and taping on the latency of the peroneus longus

Influence Of Therapeutic Horseback Riding On Gait For A Participant With Friedreich's Ataxia: 1395

The purpose of this investigation was to determine the effect of different types of ankle sprains on the response latency of the peroneus longus and peroneus brevis to an inversion perturbation, as well as the time to complete the perturbation (time to maximum inversion). To create a forced inversion moment of the ankle, an outer sole with fulcrum was used to cause 25 degrees of inversion at the ankle upon landing from a 27 cm step-down task. Forty participants completed the study: 15 participants had no history of any ankle sprain, 15 participants had a history of a lateral ankle sprain, and 10 participants had a history of a high ankle sprain. There was not a significant difference between the injury groups for the latency measurements or the time to maximum inversion. These findings indicate that a previous lateral ankle sprain or high ankle sprain does not affect the latency of the peroneal muscles or the time to complete the inversion range of motion.

Effects of inversion perturbation after step down on the latency of the peroneus longus and peroneus brevis.

CONTEXT
The latency of the peroneus longus in response to an inversion perturbation is a key component in the prevention of lateral ankle sprains. In addition, the dominant ankle is sprained more frequently than the nondominant ankle, but the cause of this has not been examined.

OBJECTIVE
To investigate the combination of these 2 research-supported statements, the purpose of this study was to use an inversion perturbation that replicates the mechanism of a lateral ankle sprain to determine whether there is a difference in the latency of the peroneus longus between the dominant and nondominant legs.

DESIGN

SETTING

Outer sole with fulcrum was used to cause 25° of inversion at the subtalar joint on landing from a 27-cm step-down task. Participants performed 10 trials on both the dominant and nondominant leg.

2 latency measures of the peroneus longus of both the dominant and nondominant leg, calculated as the amount of time from the moment of touchdown of the fulcrum until muscle activity exceeded 5 and 10 SD above baseline muscle activity.

RESULTS
The latency of the peroneus longus of the nondominant leg was significantly shorter when using both 5 SD (F1,14= 9.34, P = .009, d = .895) and 10 SD (F1,14= 18.56, P = .001, d = .920) above baseline muscle activity.

This difference in latency may be a result of the different demands placed on the dominant and nondominant legs during activity and may predispose the dominant ankle to a greater number of ankle sprains than the nondominant ankle.

Difference in response latency of the peroneus longus between the dominant and nondominant legs.

Effects of Ankle Taping on Single and Double Leg Balance Ankle sprains are a common injury and athletic tape is often applied to help prevent this injury, however, the effects of ankle taping on balance are relatively unclear. Additionally, the dominant and non-dominant legs often have different demands placed upon them and may yield different balance scores. Twenty five healthy participants (18 female, 7 male; age=20.5±1.19 years; mass=69.24±12.72 kg; height=1.69±.087 m) completed double and single leg balance assessments with the eyes open and eyes closed under three ankle support conditions: no ankle tape, PowerTape™, and Coach™ Tape, on the Neurocom Basic BalanceMaster™. Balance assessments were completed before ankle taping (pre-test), immediately after ankle taping (acute-test), and after 20 minutes of walking (post-test). The sway velocity of the participants' center of gravity (deg/s) was the dependent variable. A significant three way interaction was found for the single leg, eyes closed assessment (P = .037), with increased sway velocity for the PowerTape™ and Coach™ tape condition. The non-dominant leg had significantly less sway velocity than the dominant leg for the eyes open condition (P < .001). These results indicate differing affects on balance for different types of athletic tape, and balance differences between the dominant and non-dominant leg, with the non-dominant leg presenting lower sway velocities.

Effects of Inversion Perturbation After Drop Landing on the Latency of the Ankle Musculature

Neurological Insufficiency: The Biceps Brachii Potential In Pronated Elbow Flexion: 2279

Influence Of Ankle Taping On The Kinetics Of A Lateral Jump: 2573

Influence of Sneakers versus Flip-flops on Attack Angle and Peak Vertical Force at Heel Contact: 1920

The Influence of Mechanical Nerve Stimulation on Center of Gravity: 1969

Comparison of Glenohumeral Range of Motion in Throwing Athletes versus Non-Throwing Athletes: 2535

Heritage learners are more sensitive to effects of script: Evidence from Korean

Abstract Because of their ex utero development, relatively simple nervous system, translucency, and availability of tools to investigate neural function, larval zebrafish are an exceptional model for understanding neurodevelopmental disorders and the consequences of environmental toxins. Furthermore, early in development, zebrafish larvae easily absorb chemicals from water, a significant advantage over methods required to expose developing organisms to chemical agents in utero. Bisphenol A (BPA) and BPA analogs are ubiquitous environmental toxins with known molecular consequences. All humans have measurable quantities of BPA in their bodies. Most concerning, the level of BPA exposure is correlated with neurodevelopmental difficulties in people. Given the importance of understanding the health-related effects of this common toxin, we have exploited the experimental advantages of the larval zebrafish model system to investigate the behavioral and anatomic effects of BPA exposure. We discovered that BPA exposure early in development leads to deficits in the processing of sensory information, as indicated by BPA’s effects on prepulse inhibition (PPI) and short-term habituation (STH) of the C-start reflex. We observed no changes in locomotion, thigmotaxis, and repetitive behaviors (circling). Despite changes in sensory processing, we detected no regional or whole-brain volume changes. Our results show that early BPA exposure can induce sensory processing deficits, as revealed by alterations in simple behaviors that are mediated by a well-defined neural circuit.

Bisphenol A Exposure Induces Sensory Processing Deficits in Larval Zebrafish during Neurodevelopment

Abstract Alzheimer’s disease (AD) is characterized by progressive cognitive impairment associated with synaptic dysfunction and dendritic spine loss and the pathologic hallmarks of β-amyloid (Aβ) plaques and hyperphosphorylated tau tangles. 14-3-3 proteins are a highly conserved family of proteins whose functions include regulation of protein folding, neuronal architecture, and synaptic function. Additionally, 14-3-3s interact with both Aβ and tau, and reduced levels of 14-3-3s have been shown in the brains of AD patients and in AD mouse models. Here, we examine the neuroprotective potential of the 14-3-3θ isoform in AD models. We demonstrate that 14-3-3θ overexpression is protective and 14-3-3θ inhibition is detrimental against oligomeric Aβ-induced neuronal death in primary cortical cultures. Overexpression of 14-3-3θ using an adeno-associated viral (AAV) vector failed to improve performance on behavioral tests, improve Aβ pathology, or affect synaptic density in the J20 AD mouse model. Similarly, crossing a second AD mouse model, the AppNL-G-F knock-in (APP KI) mouse, with 14-3-3θ transgenic mice failed to rescue behavioral deficits, reduce Aβ pathology, or impact synaptic density in the APP KI mouse model. 14-3-3θ is likely partially insolubilized in the APP models, as demonstrated by proteinase K digestion. These findings do not support increasing 14-3-3θ expression as a therapeutic approach for AD.

14-3-3θ Does Not Protect against Behavioral or Pathological Deficits in Alzheimer’s Disease Mouse Models

Abstract This paper focuses on the question of the representation of nasality as well as speakers’ awareness and perceptual use of phonetic nasalisation by examining surface nasalisation in two types of vowels in Bengali: underlying nasal vowels (CṼC) and nasalised vowels before a nasal consonant (CVN). A series of three cross-modal forced-choice experiments was used to investigate the hypothesis that only unpredictable nasalisation is stored and that this sparse representation governs how listeners interpret vowel nasality. Visual full-word targets were preceded by auditory primes consisting of CV segments of CVC words with nasal vowels ([tʃɑ̃] for [tʃɑ̃d] ‘moon’), oral vowels ([tʃɑ] for [tʃɑl] ‘unboiled rice’) or nasalised oral vowels ([tʃɑ̃(n)] for [tʃɑ̃n] ‘bath’) and reaction times and errors were measured. Some targets fully matched the prime while some matched surface or underlying representation only. Faster reaction times and fewer errors were observed after CṼC primes compared to both CVC and CVN primes. Furthermore, any surface nasality was most frequently matched to a CṼC target unless no such target was available. Both reaction times and error data indicate that nasal vowels are specified for nasality leading to faster recognition compared to underspecified oral vowels, which cannot be perfectly matched with incoming signals.

Bengali nasal vowels: lexical representation and listener perception

Bilingual children’s visual attention while reading digital picture books and story retelling

Transitional areas affect perception of workspaces and employee well-being: A study of underground and above-ground workspaces

Abstract Larval zebrafish possess a number of molecular and genetic advantages for rigorous biological analyses of learning and memory. These advantages have motivated the search for novel forms of memory in these animals that can be exploited for understanding the cellular and molecular bases of vertebrate memory formation and consolidation. Here, we report a new form of behavioral sensitization in zebrafish larvae that is elicited by an aversive chemical stimulus [allyl isothiocyanate (AITC)] and that persists for ≥30 min. This form of sensitization is expressed as enhanced locomotion and thigmotaxis, as well as elevated heart rate. To characterize the neural basis of this nonassociative memory, we used transgenic zebrafish expressing the fluorescent calcium indicator GCaMP6 (Chen et al., 2013); because of the transparency of larval zebrafish, we could optically monitor neural activity in the brain of intact transgenic zebrafish before and after the induction of sensitization. We found a distinct brain area, previously linked to locomotion, that exhibited persistently enhanced neural activity following washout of AITC; this enhanced neural activity correlated with the behavioral sensitization. These results establish a novel form of memory in larval zebrafish and begin to unravel the neural basis of this memory.

Induction of Short-Term Sensitization by an Aversive Chemical Stimulus in Zebrafish Larvae

The cubicle deconstructed: Simple visual enclosure improves perseverance

The underground workspaces questionnaire (UWSQ): Investigating public attitudes toward working in underground spaces

Virtual reality (VR) is rapidly becoming an inexpensive, mainstream technology. VR technology is superambulatory as it allows participants to be examined under standardized environments and tests anywhere. In addition, it can test participants in different virtual spaces, including environments that are unsafe, inaccessible, costly or difficult to set up, or even nonexistent. We summarize the benefits and potential problems of VR technology, but we also move beyond theoretical approaches and present a customizable, open-source VR system (PSY-VR) that allows scalable psychological testing in modifiable VR environments. This system allows users to modify the environment using a simple graphical interface, without programming expertise. Moreover, as a proof-of-concept, we compare responses in a typical Flanker task between a real laboratory and a painstakingly matched virtual laboratory. Results indicate that the VR responses are comparable to real life testing, demonstrating the utility of VR for psychological assessment studies. The predicted rapid advancement of VR immersive technologies, as well the ease of their integration with physiological metrics ensures that VR-based assessment will be the modus operandi of psychological assessment in the future. This will allow controllable, low-cost assessment on a global scale.

Assessing the Suitability of Virtual Reality for Psychological Testing

Comment on “Using functional Magnetic Resonance Imaging (fMRI) to analyze brain region activity when viewing landscapes”

ABSTRACT Although outdoor thermal comfort has gained increasing research attention, meteorological conditions and thermal sensation in different urban settings in high-density cities have not been systematically studied from the perspective of urban planning and design. Considering the potential relationship between environmental quality and thermal sensation in outdoor spaces— an emerging topic in perceived comfort, this study offers a new approach for planning and design for climate resilience in cities. This paper presents the results of an outdoor thermal comfort survey conducted on hot summer days in Hong Kong. Diverse patterns of PET-comfort ratings relationships were found in different urban settings. The study revealed that air temperature, subjective assessments of solar radiation and wind environment were strong determinants of thermal sensation and evaluation. In our analysis, wind condition showed a significant indirect effect on comfort through subjective perception. Statistical modelling showed that subjective perceptions on microclimate condition and comfort are moderated by various aspects of environmental quality. The findings of this study help inform future design for climate resilience in outdoor urban spaces in hot-humid subtropical cities.

Design for climate resilience: influence of environmental conditions on thermal sensation in subtropical high-density cities

Digging Deep: The Effect of Design on the Social Behavior and Attitudes of People Working in Underground Workplaces in Europe

The Influence of Room Size on Error Monitoring: Evidence from Event-Related Potential Responses

Working in underground spaces: Architectural parameters, perceptions and thermal comfort measurements

With a growing need for usable land in urban areas, subterranean development has been gaining attention. While construction of large underground complexes is not a new concept, our understanding of various socio-cultural aspects of staying underground is still at a premature stage. With projected emergence of underground built environments, future populations may spend much more of their working, transit, and recreational time in underground spaces. Therefore, it is essential to understand the challenges and advantages that such environments have to improve the future welfare of users of underground spaces. The current paper discusses various psycho-social aspects of underground spaces, the impact they can have on the culture shared among the occupants, and possible solutions to overcome some of these challenges.

Nonlinear saddle point spectroscopy and electron-phonon interaction in graphene

Psycho-biological factors associated with underground spaces: What can the new era of cognitive neuroscience offer to their study?

Six cross-modal lexical decision tasks with priming probed listeners’ processing of the geminate–singleton contrast in Bengali, where duration alone leads to phonemic contrast ([pata] ‘leaf’ vs. [pat:a] ‘whereabouts’), in order to investigate the phonological representation of consonantal duration in the lexicon. Four form-priming experiments (auditory fragment primes and visual targets) were designed to investigate listeners’ sensitivity to segments of conflicting duration. Each prime derived from a real word ([kʰɔm]/[gʰenː]) was matched with a mispronunciation of the opposite duration (*[kʰɔmː]/*[gʰen]) and both were used to prime the full words [kʰɔma] (‘forgiveness’) and [gʰenːa] (‘disgust’) respectively. Although all fragments led to priming, the results showed an asymmetric pattern. The fragments of words with singletons mispronounced as geminates led to equal priming, while those with geminates mispronounced as singletons showed a difference. The priming effect of the real-word geminate fragment was significantly greater than that of its corresponding nonword singleton fragment. In two subsequent semantic priming tasks with full-word primes a stronger asymmetry was found: nonword geminates (*[kʰɔmːa]) primed semantically related words ([marjona] ‘forgiveness’) but singleton nonword primes (*[gʰena]) did not show priming. This overall asymmetry in the tolerance of geminate nonwords in place of singleton words is attributed to a representational mismatch and points towards a moraic representation of duration. While geminates require a mora which cannot be derived from singleton input, the additional information in geminate nonwords does not create a similar mismatch.

Processing of Phonemic Consonant Length: Semantic and Fragment Priming Evidence from Bengali

This paper proposes a new framework for the on-line monitoring and adaptive control of automation in complex and safety-critical human-machine (HM) systems using psychophysiological markers relating to humans under mental stress. The starting point of this framework relates to the assessment of the so-called operator functional state (OFS) using psychophysiological measures. An adaptive fuzzy model linking Heart-Rate Variability (HRV) and Task Load Index (TLI) with the subjects' optimal performance has been elicited and validated off-line via a series of experiments involving process control tasks simulated on an automationenhanced Cabin Air Management System (aCAMS). The elicited model has been used as the basis for an on-line control system via the predictions of the system performance indicators corresponding to the operator stressful state. These indicators have been used by a fuzzy decisionmaker to modify the level of automation under which the system may operate. A real-time architecture has been developed as a platform for this approach. It has been validated in a series of human volunteer studies with promising improvement in performance.

Real-time adaptive automation system based on identification of operator functional state ( OFS ) in simulated process c ontrol operations

Asymmetric processing of durational differences – Electrophysiological investigations in Bengali

Many models have been proposed to account for the role that the mental lexicon plays in the initial stages of speech perception. One fundamental disparity between these models is how speech is phonologically represented in the mental lexicon. Theories range from full specification and representation of all phonological information to sparse specification. We report on two perception experiments using context independent mispronunciations (i.e. mispronunciations not governed by phonological rules) to test the predictions of the two most divergent models. Models assuming full specification and storage of all phonological information (e.g. exemplar models) predict symmetric acceptance or rejection of mispronunciations that only differ from real words in place of articulation of the medial consonant (*temor-tenor, *inage-image). Models assuming that only contrasting phonological information is stored (as in FUL) predict asymmetric patterns of acceptance, i.e. mispronunciations with medial coronal consonants will be better tolerated (*temor) than mispronunciations with medial labial or velar consonants. Results of two experiments using lexical decision with semantic priming in British English reveal an asymmetry in the acceptance of mispronunciations for coronal vs. noncoronal consonants. Both reaction time latencies as well as N400 amplitudes exhibit asymmetries, supporting the notion of abstract asymmetric lexical representation.

Aligning mispronounced words to meaning: Evidence from ERP and reaction time studies

This paper proposes a new framework for the online monitoring and adaptive control of automation in complex and safety-critical human-machine systems using psychophysiological markers relating to humans under mental stress. The starting point of this framework relates to the assessment of the so-called operator functional state using psychophysiological measures. An adaptive fuzzy model linking heart-rate variability and task load index with the subjects' optimal performance has been elicited and validated offline via a series of experiments involving process control tasks simulated on an automation-enhanced Cabin Air Management System. The elicited model has been used as the basis for an online control system via the predictions of the system performance indicators corresponding to the operator stressful state. These indicators have been used by a fuzzy decision maker to modify the level of automation under which the system may operate. A real-time architecture has been developed as a platform for this approach. It has been validated in a series of human volunteer studies with promising improvement in performance.

IEEE Transactions on Systems, Man, and Cybernetics - Part A: Systems and Humans

Real-Time Adaptive Automation System Based on Identification of Operator Functional State in Simulated Process Control Operations

Sensitivity of candidate markers of psychophysiological strain to cyclical changes in manual control load during simulated process control.

The Assessment of Heart Rate Variability (HRV) and Task Load Index (TLI) as Physiological Markers for Physical Stress

This paper proposes a new framework for the on-line monitoring and adaptive control of psychophysiological markers relating to humans under stress. The starting point of this framework relates to the assessment of the so-called operator functional state (OFS) using physical as well as psychological measures. An adaptive neural-fuzzy model linking Heart-Rate Variability (HRV) and Task Load Index (TLI) with the subjects’ optimal performance has been elicited and validated via a series of real-life experiments involving process control tasks simulated on an Automation-Enhanced Cabin Air Management System (aCAMS). The elicited model has been used as the basis for an on-line control system, whereby the model predictions which indicate whether the actual system is in error or not, have been used to modify the level of automation which the system may operates under.

A New Framework for Real-Time Adaptive Fuzzy Monitoring and Control for Humans Under Psychophysiological Stress

Prediction of operator breakdown in complex systems depends on detecting states of extreme strain resulting from sustained compensator y activity, associated with fatigue and loss of control. This research is aimed at identifying the underlying state(s) that correspond to this limit in terms of key psychophysiological markers. To address these issues the study used a new ‘cyclic l oading’ method, based on strain testing methods in mechanical engineering. Manual c ontrol load on a process control task is increased until compensatory control limits are breached and primary performance begins to fail; then reduced until perf ormance recovers to within normal limits. The cyclic loading method is shown to be a valuable tool for exploring the dynamics of operator/task interactions under high d emand. Principal component analysis of correlations between hysteresis functio s for relevant markers of strain (differences between loading and unloading response ) showed evidence of two distinctive psychophysiological patterns, correspon ding to fatigue/control and effort management processes. These findings suggest that p rediction of operator risk will need to consider both early onset of fatigue effect s, leading to loss of task control, and differences in effort management strategies emp loyed by operators to maintain performance goals.

Development of a cyclic loading method for the study of patterns of breakdown in complex performance under high load

This paper assesses the operator functional state (OFS) based on a collection of psychophysiological (i.e., cardiovascular and EEG) and performance measures. Two types of adaptive fuzzy model, namely ANFIS (adaptive-network-based fuzzy inference system) and GA (genetic algorithm) based Mamdani fuzzy model, are employed to estimate the OFSs under a set of simulated process control tasks involved in an automation-enhanced cabin air management system (aCAMS). The fuzzy modelling procedures are described in detail. The adaptive fuzzy models are validated using real-life data measured from two well-trained collegiate participants. The preliminary simulation results implied that the overall performance of human-machine system may be improved by identifying and predicting OFSs via the proposed fuzzy models.

Adaptive fuzzy model of operator functional state in human-machine system: a preliminary study

Abstract In the first part of this paper we propose to revisit the closed-loop physiological model relating to human volunteers who are subjected to physical workload (stress), first proposed by Luczak and his research team in 1970s. The original model is further investigated and its parameters optimised via Genetic Algorithms using real data. The second part of this paper relates to the possible extensions of the model to model the effect of mental workload (psychological stress) on the cardiovascular system, namely heart rate variability. The autoregressive modelling based spectral analysis method is described and its application to spectral analysis of heart rate variability is evaluated. The assessment of heart rate spectra aimed at providing a meaningful measure of mental workload is also discussed.

MODELLING AND ANALYSIS OF HRV UNDER PHYSICAL AND MENTAL WORKLOADS

A platform support comprises a support body (11) securable to a platform and a locking arm (19) pivotally connected at one end to the body, and securable at its other end to a step ladder. The locking arm has projections (29) which, in use, releasably engage apertures (26) on the body so that the arm is secured in place when the platform is in a horizontal 'in use' position (see figures 7 and 8).

Head Impact Exposure and Biomechanics in University Varsity Women’s Soccer

including team sports, general fitness, and social (e.g. dance). Yet, how much overall PA and MVPA occurs over these differing PE class modules remains unclear. The System for Observing Fitness Instruction Time (SOFIT) is a simple observational tool that PE instructors can use to calculate PA. PURPOSE: To observe student PA levels across multiple PE modules using SOFIT. METHODS: A modified SOFIT was used to assess PA over 15, 90-minute PE classes (N = 124) across 3 modules: team sports (8 sessions), general fitness (3 sessions), and dance (4 sessions) in a single middle school. PA was coded from 1-5 corresponding to lying down, sitting, standing, walking, and vigorous, respectively. The same observer recorded PA in the last minute of a 5minute interval based on activity in the prior 4 minutes. Separate 1-way ANOVA examined differences in MVPA (i.e. scores  4) and overall PA across modules with Tukey-Kramer post hoc analyses as appropriate. RESULTS: Overall PA differed significantly across modules (p = .02), with team sports producing higher PA (3.80±.36) than dance (3.19 ± .39; p = .04). MVPA was similar across all modules (team sports: 4.29 ± .43, general fitness: 4.06 ± .28, dance: 3.70 ± .41; F2,12 = 2.83; p = .09). CONCLUSION: Although team sports produced greater overall PA, all modules (team sports, fitness, and dance) produced similar MVPA. As MVPA is suggested to be the preferred component of overall PA for improving overall health, all these modules are viable options for producing MVPA during PE classes in this population. To improve adherence to these different activities, future researchers should compare enjoyment levels for students across these activities. Overall, as PE classes are the greatest contribution to in-school PA for students, PE instructors and school health administrators can use our findings to choose appropriate modules to teach children PE and, concurrently, positively address the childhood obesity epidemic.

Differences In Foot Kinematics Between Forefoot Strikers In Minimalist And Conventional Running Shoes

ABSTRACT The objective of this study was to investigate how the inclusion of a cushioning underlay in a third-generation artificial turf (3G) affects player biomechanics during soccer-specific tasks. Twelve soccer players (9 males/3 females; 22.6 ± 2.3 y) participated in this study. Mechanical impact testing of each 3G surface; without (3G-NCU) and with cushioning underlay (3G-CU) were conducted. Impact force characteristics, joint kinematics and joint kinetics variables were calculated on each surface condition during a sprint 90° cut (90CUT), a sprint 180° cut (180CUT), a drop jump (DROP) and a sprint with quick deceleration (STOP). For all tasks, greater peak resultant force, peak knee extensor moment and peak ankle dorsi-flexion moment were found in 3G-NCU than 3G-CU (p < 0.05). During 90CUT and STOP, loading rates were higher in 3G-NCU than 3G-CU (p < 0.05). During 180CUT, higher hip, knee and ankle ranges of motion were found in 3G-NCU (p < 0.05). These findings showed that the inclusion of cushioning underlay in 3G reduces impact loading forces and lower limb joint loading in soccer players across game-specific tasks. Overall, players were not attempting to reduce higher lower limb impact loading associated with a lack of surface cushioning underlay.

Lack of impact moderating movement adaptation when soccer players perform game specific tasks on a third-generation artificial surface without a cushioning underlay

It remains to be determined whether running training influences the amplitude of lower limb muscle activations before and during the first half of stance and whether such changes are associated with joint stiffness regulation and usage of stored energy from tendons. Therefore, the aim of this study was to investigate neuromuscular and movement adaptations before and during landing in response to running training across a range of speeds. Two groups of high mileage (HM; >45 km/wk, n = 13) and low mileage (LM; <15 km/wk, n = 13) runners ran at four speeds (2.5-5.5 m/s) while lower limb mechanics and electromyography of the thigh muscles were collected. There were few differences in prelanding activation levels, but HM runners displayed lower activations of the rectus femoris, vastus medialis, and semitendinosus muscles postlanding, and these differences increased with running speed. HM runners also demonstrated higher initial knee stiffness during the impact phase compared with LM runners, which was associated with an earlier peak knee flexion velocity, and both were relatively unchanged by running speed. In contrast, LM runners had higher knee stiffness during the slightly later weight acceptance phase and the disparity was amplified with increases in speed. It was concluded that initial knee joint stiffness might predominantly be governed by tendon stiffness rather than muscular activations before landing. Estimated elastic work about the ankle was found to be higher in the HM runners, which might play a role in reducing weight acceptance phase muscle activation levels and improve muscle activation efficiency with running training.NEW & NOTEWORTHY Although neuromuscular factors play a key role during running, the influence of high mileage training on neuromuscular function has been poorly studied, especially in relation to running speed. This study is the first to demonstrate changes in neuromuscular conditioning with high mileage training, mainly characterized by lower thigh muscle activation after touch down, higher initial knee stiffness, and greater estimates of energy return, with adaptations being increasingly evident at faster running speeds.

Adjustments with running speed reveal neuromuscular adaptations during landing associated with high mileage running training.

The purpose of this study was to investigate the effects of prolonged high-intensity running on impact accelerations in trained runners. Thirteen male distance runners completed two 20-minute treadmill runs at speeds corresponding to 95% of onset of blood lactate accumulation. Leg and head accelerations were collected for 20 s every fourth minute. Rating of perceived exertion (RPE) scores were recorded during the third and last minute of each run. RPE responses increased (P < .001) from the start (11.8 ± 0.9, moderate intensity) of the first run to the end (17.7 ± 1.5, very hard) of the second run. Runners maintained their leg impact acceleration, impact attenuation, stride length, and stride frequency characteristics with prolonged run duration. However, a small (0.11-0.14g) but significant increase (P < .001) in head impact accelerations were observed at the end of both first and second runs. It was concluded that trained runners are able to control leg impact accelerations during sustained high-intensity running. Alongside the substantial increases in perceived exertion levels, running mechanics and frequency domain impact attenuation levels remained constant. This suggests that the present trained runners are able to cope from a mechanical perspective despite an increased physiological demand.

Can Trained Runners Effectively Attenuate Impact Acceleration During Repeated High-Intensity Running Bouts?

This study examined the influence of modeling approaches on lower limb on transient knee joint moments during single leg landings. A typical GDoF joint model was compared to a constrained 3DoF model. For peak moments and rates of moment increases there was no difference between joint models. Earlier, and greater moments were obtained using data from a 3D-printed plate moulded to each individual's tibia. Maintaining high frequencies in the dataset using the 3D-printed plate was important for determining initial joint loading and associated risk factors for sports injuries.

DETERMINING INITIAL KNEE JOlNT LOADiNG DURING A SINGLE LIMB DROP LANDING: REDUCING SOFT TISSUE ERRORS

High levels of gait asymmetry are associated with many pathologies. Our long-term goal is to improve gait symmetry through real-time biofeedback of a symmetry index. Symmetry is often reported as a single metric or a collective signature of multiple discrete measures. While this is useful for assessment, incorporating multiple feedback metrics presents too much information for most subjects to use as visual feedback for gait retraining. The aim of this article was to develop a global gait asymmetry (GGA) score that could be used as a biofeedback metric for gait retraining and to test the effectiveness of the GGA for classifying artificially-induced asymmetry. Eighteen participants (11 males; age 26.9 y [SD = 7.7]; height 1.8 m [SD = 0.1]; body mass 72.7 kg [SD = 8.9]) walked on a treadmill in 3 symmetry conditions, induced by wearing custom-made sandals: a symmetric condition (identical sandals) and 2 asymmetric conditions (different sandals). The GGA score was calculated, based on several joint angles, and compared between conditions. Significant differences were found among all conditions (P < .001), meaning that the GGA score is sensitive to different levels of asymmetry, and may be useful for rehabilitation and assessment.

PURPOSE
The purpose of this study was to determine whether real-time feedback (RTF) training would reduce impact loading variables previously linked with tibial stress fracture risk and whether these adaptations would influence running economy.

METHODS
Twenty-two male runners were randomly assigned to RTF (n = 12) and control (n = 10) groups. The RTF group received feedback based on their peak tibial axial accelerations (PTA) during six 20-min treadmill runs for 3 wk, whereas the control group adhered to the same training but without feedback. Unilateral three-dimensional kinematic and kinetic analysis and running economy measurements were conducted before, after, and at 1 month posttraining.

RESULTS
The RTF group had significant reductions (P < 0.01) in PTA and average and instantaneous vertical force loading rates after training as compared with no changes in the control group. These modifications in impact loads were only maintained in PTA 1 month after the training. A significant increase (P = 0.0033) in ankle plantarflexion at initial contact and a significant change (P = 0.030) in foot strike pattern from a rearfoot to midfoot strike pattern and a significant decrease (P = 0.008) in heel vertical velocity at initial contact appeared to be the primary mechanical strategies adopted by runners to reduce impact loading after RTF training. Despite these gait adaptations, running economy was unaffected.

The results of this study suggest that gait retraining using RTF is an effective means of eliciting reductions in impact loading without negatively affecting running economy. However, with loading rate reductions not being maintained 1 month posttraining, further research is required to determine how these reductions in impact severity can be retained long term.

Influence of tibial shock feedback training on impact loading and running economy.

PURPOSE
The purpose of this study was to investigate the acute effects of progressive fatigue on the parameters of running mechanics previously associated with tibial stress fracture risk.

METHODS
Twenty-one trained male distance runners performed three sets (Pre, Mid, and Post) of six overground running trials at 4.5 m.s(-1) (± 5%). Kinematic and kinetic data were collected during each trial using a 12-camera motion capture system, force platform, and head and leg accelerometers. Between tests, each runner ran on a treadmill for 20 min at their corresponding lactate threshold (LT) speed. Perceived exertion levels (RPE) were recorded at the third and last minute of each treadmill run.

RESULTS
RPE scores increased from 11.8 ± 1.3 to 14.4 ± 1.5 at the end of the first LT run and then further to 17.4 ± 1.6 by the end of the second LT run. Peak rearfoot eversion, peak axial head acceleration, peak free moment and vertical force loading rates were shown to increase (P < 0.05) with moderate-large effect sizes during the progression from Pre to Post tests, although vertical impact peak and peak axial tibial acceleration were not significantly affected by the high-intensity running bouts.

Previously identified risk factors for impact-related injuries (such as tibial stress fracture) are modified with fatigue. Because fatigue is associated with a reduced tolerance for impact, these findings lend support to the importance of those measures to identify individuals at risk of injury from lower limb impact loading during running.

Effects of fatigue on running mechanics associated with tibial stress fracture risk.

The aim of this study was to investigate the effects of high-intensity fatiguing running on tibial acceleration and shock attenuation. Fourteen highly-trained male runners volunteered and completed an incremental treadmill-based lactate threshold test. On a subsequent test day, tibial acceleration and head acceleration values were recorded in all runners during two 20-minute treadmill running bouts at each subject’s lactate threshold (3.5mM) speed. Results indicated no significant change in tibial acceleration during the running bouts, however head acceleration did significantly increase (38%) over time. This resulted in an overall decrease in shock attenuation due to the fatiguing running. The results indicate that these highly-trained runners may show improved movement strategies that allow them to maintain tibial acceleration rates even in a fatigued state.

THE INFLUENCE OF HIGH-INTENSITY RUN DURATION ON TIBIAL ACCELERATION AND SHOCK ATTENUTION

Humans naturally perform a countermovement (CM) action in order to attain a certain height or distance in jumping. This CM action initiates many movement coordination principles such as increasing lower limb joint range of motion (ROM) to allow the performer to be in a more effective position for jumping. In a study where the knee joint ROM was experimentally controlled Moran and Wallace (2007) reported a 17% increase in jump height with a 20° increase in knee joint flexion. Although Moran and Wallace (2007) experimentally controlled two knee flexion ranges, their results revealed a natural increase in hip joint ROM with subsequent increased knee flexion. No study, to the author’s knowledge, has managed to identify the possible relationship between knee and hip joint ROM during a CM jump. The aim of this study is to examine the relationship between hip and knee joint ROM during CM vertical jumping and to determine if there are optimum joint flexion ranges at the hip and knee for jump height.

CHANGES IN LOWER LIMB JOINT RANGE OF MOTION ON COUNTERMOVEMENT VERTICAL JUMPING

A decreased kinematic variability was found in runners with patellofemoral pain compared with uninjured runners (Hamill et al., 1999: Clinical Biomechanics, 14, 297 – 308). Therefore, the aim of this study was to investigate the kinematic, kinetic, and EMG activity variability in runners with Achilles tendinopathy. 
Thirty-four uninjured runners (body mass 67.8±10.5 kg; height 1.71±0.09 m; age 37.0±9.2 years) and 25 runners diagnosed with Achilles tendinopathy (body mass 77.6±12.6 kg; height 1.78±0.07 m; age 41.8±9.7 years) were recruited. After receiving institutional ethics approval, the participants performed 10 trials at a self-selected running ...

Annual conference of the british association of sport and exercise sciences

Syndepositional diagenesis is a complicating factor when interpreting geochemical proxies in carbonate sedimentary environments. Previous studies have suggested that carbonate deposits may preserve the geochemical and isotopic signatures of seawater that can be used for paleo-redox reconstructions. However, more work is necessary to understand how these trace metals are preserved. The present study examines shallow marine carbonate sediments from the Bahamas to better understand diagenetic effects on trace metal uptake and sequestration. Analysis of diagenetic effects and trace metal uptake follows a multi-method approach, combining sequential extraction, stable isotope analyses, and rare earth elemental analysis. Stable isotopes track bacterial sulfate reduction, denitrification, and organic matter source and provide insight into thresholds and processes for the authigenic trace metal uptake. Importantly, exchangeable phases exhibit authigenic accumulation of molybdenum, uranium and vanadium, and intensified bacterial sulfate reduction is evidenced by most depleted sulfur isotope signatures. In addition, rare earth element values are very indicative proxies that suggest altered primary seawater trace element in carbonates (no cerium or lanthanum anomaly, moderate heavy rare earth element enrichment, decreased y/ho ratios and positive correlations between aluminum, manganese, and iron). Taken together, these results allow the development of a framework to better understand how to apply sedimentary geochemistry of carbonate rocks to paleo-environments as this study shows significant authigenic accumulation of redox-sensitive trace metals by exchangeable phases.

Syndepositional Uptake of Uranium, Molybdenum and Vanadium into Modern Bahamian Carbonate Sediments during Early Diagenesis

Abstract Ecosystem services (ES) have been well studied in most biomes, but the Arctic tundra has received little attention, despite covering over 10% of terrestrial Earth. Using established ES methodologies, we calculated values (in 2016 USD) for the United States Arctic National Wildlife Refuge, a region virtually undisturbed by humans, but slated for future oil and gas drilling. We estimated the Refuge is worth about 1957 USD/hectare/year, equal to over 15 billion USD annually. Globally important services, such as climate regulation (e.g., carbon storage) and non-use services (e.g., aesthetic information), contributed the most value and were similar to valuations from more productive ecosystems. Local services made smaller contributions to the total, but they remain vitally important to local indigenous cultures. Strikingly, a contingent valuation survey of US residents found that, after neutral educational information, willingness-to-pay to maintain the Refuge in its current state exceeded estimated values of the oil and gas deposits. Our study shows that citizens may value Arctic habitats beyond their traditional economic development potential. Our comprehensive ecosystem services valuation suggests that maintaining the Refuge in its current condition (i.e., de facto wilderness) with its full range of ES is more valuable to humanity compared to development for oil and gas.

Comprehensive Valuation of the Ecosystem Services of the Arctic National Wildlife Refuge

Effects of Lespedeza cuneata invasion on tallgrass prairie plant and arthropod communities

The Complementary Relationship of Bison Grazing and Arthropod Herbivory in Structuring a Tallgrass Prairie Community☆

Circulation patterns in the Late Pennsylvanian North American Midcontinent Sea inferred from spatial gradients in sediment chemistry and mineralogy

Investigating Trace Metal Sequestration of Reducing Environments in Modern and Ancient Settings

INVESTIGATING REDOX SENSITIVE TRACE METAL UPTAKE IN THE HEEBNER SHALE OF THE LATE PENNSYLVANIAN MIDCONTINENT SEA TO TEST A SUPERESTUARINE DEPOSITIONAL MODEL

Abstract Saflufenacil, a pyrimidinedione herbicide, is used for contact and residual broadleaf weed control in various crops. Bioactivity of saflufenacil in soil was tested in greenhouse and laboratory studies on 29 soils representing a wide range of soil properties and geographic areas across the United States. A greenhouse bioassay method was developed using various concentrations of saflufenacil applied PPI to each soil. Whole canola plants were harvested 14 d after treatment, and fresh and dry weights were recorded. Nonlinear regression analysis was used to determine the effective saflufenacil doses for 50% (ED50,), 80% (ED80), and 90% (ED90) inhibition of total plant fresh weight. Bioactivity of saflufenacil in soil was strongly correlated to soil organic (R  =  0.85) and humic matter (R  =  0.81), and less correlated to cation exchange capacity (R  =  0.49) and sand content (R  =  −0.32). Stepwise regression analysis indicated that organic matter was the major soil constituent controlling bioactivity in soil and could be used to predict the bioactivity of saflufenacil. Saflufenacil phytotoxicity was found to be dependent on soil property; therefore, efficacy and crop tolerance from PRE and PPI applications may vary based on soil organic matter content and texture classification. Nomenclature: Saflufenacil; canola, Brassica napus L.

Abstract Pesticide sorption by soil is among the most sensitive input parameters in many pesticide-leaching models. For many pesticides, organic matter is the most important soil constituent influencing pesticide sorption. Increased fertility, irrigation, and mowing associated with highly maintained turfgrass areas result in constant deposition of organic material, creating a soil system that can change drastically with time. Changes in soil characteristics could affect the environmental fate of pesticides applied to turfgrass systems of varying ages. Sorption characteristics of simazine and S-metolachlor were determined on five soils from bermudagrass systems of increasing ages (1, 4, 10, 21, and 99 yr) and compared to adjacent native pine and bare-ground areas. Surface soil (0 to 5 cm) and subsurface soil (5 to 15 cm) from all sites were air-dried and passed through a 4-mm sieve for separation from plant material. Using a batch-equilibrium method, sorption isotherms were determined for each soil. Data were fit to the Freundlich equation, and Kd (soil sorption coefficient) and Koc (organic carbon sorption coefficient) values were determined. Sorption and soil system age were directly related to organic matter content in the soil. Sorption of both herbicides increased with age of the soil system and was greatest on the surface soil from the oldest bermudagrass soil system. Herbicide sorption decreased at greater soil depths with lower organic matter. Greater amount of 14C–simazine sorbed to subsurface soil of the oldest turfgrass system compared to 14C–S-metolachlor. Results indicate that as bermudagrass systems age and accumulate higher organic matter levels increased herbicide sorption may decrease the leaching potential and bioavailability of simazine and S-metolachlor. Nomenclature: Simazine; S-metolachlor; bermudagrass; Cynodon dactylon [(L.) Pers.].

Sorption of Simazine and S-Metolachlor to Soils from a Chronosequence of Turfgrass Systems

Concern about pesticide losses from maintained turfgrass areas led us to examine the fate of the triazine herbicide simazine in turfgrass systems and, specifically, interactions between simazine binding to soil organic matter and biodegradation. Soil samples were removed from turfgrass systems of different ages, placed in microcosms, conditioned as sterile or nonsterile, and exposed to 14 C-simazine. At seven sampling intervals, the soil was extracted and 14 C was separated into three pools; bound, extractable, and CO 2 . With sterilized surface soil (0-5 cm), 52, 70, and 71% of applied 14 C-simazine was bound to soil from the 4-, 21-, and 99-yr-old turfgrass systems, respectively, after 16 wk. With nonsterile conditions, biodegradation became dominant, as 60 to 80% of the 14 C was recovered in the CO 2 fraction and binding was held at -20%. Among all soils evaluated, bound 14 C and 14 CO 2 production was lower in subsurface soil (5-15 cm) from the 4- and 21-yr-old turfgrass systems. 14 C-simazine disappearance time (DT 50 ) values under nonsterile conditions ranged from 0.9 to 5.8 wk. Results indicate that turfgrass systems have a relatively low amount of simazine available for leaching as the systems age due to a large capacity for biodegradation and binding to organic matter.

Soil Organic Matter Changes in Turfgrass Systems Affect Binding and Biodegradation of Simazine

Soil properties affect simazine and saflufenacil fate, behavior, and performance

Field research was conducted to evaluate plant growth-regulator efficacy for tall fescue growth and seedhead suppression applied using application placement equipment. Specially designed equipment outfitted with fluid application systems applies low-volume plant growth regulator directly on plant foliage, reducing opportunity for drift and visible application. Wet-blade mowers are equipped to apply plant growth regulators and mow in a single pass, whereas rotary-wick applicators simply wipe chemicals directly on uncut vegetation. Therefore, a wet-blade, rotary-wick, and broadcast sprayer system were chosen to apply imazapic at three rates (9, 35, and 53 g ai/ha), and a mefluidide + chlorsulfuron tank mix at 7 + 140 g ai/ha to tall fescue roadsides for vegetative growth and seedhead suppression. Experiments were conducted during the spring and summer of 2004 in central and western North Carolina. Tall fescue was slightly injured and discolored by all treatments but fully recovered by 2 mo after treatment. Imazapic suppressed new vegetative growth 3 mo after treatment compared with the nonmowed–nontreated control (16.1 cm of growth) and the mowed–nontreated control (21.1 cm) when applied with the rotary-wick applicator (8.5 cm) and broadcast sprayer (6.2 cm). However, differences in vegetative height primarily occurred when application placement equipment treatments were compared with nontreated vegetation as opposed to mowed–nontreated plants. Although mowed–nontreated and wet-blade–treated plots had more new vegetative growth, nonmowed–nontreated plots still consistently had the greatest vegetative height. Seedhead suppression ranged from 87 to 100% when compared with the nonmowed–nontreated control, with wet-blade treatments consistently providing the least-effective seedhead suppression. Overall, application placement equipment did not improve plant growth-regulator efficacy when compared with the foliar broadcast spray. Nomenclature: Chlorsulfuron; imazapic; mefluidide; tall fescue, Lolium arundinaceum (Schreb.) S.J. Darbyshire, ‘Kentucky 31’

Efficacy of Application Placement Equipment for Tall Fescue (Lolium Arundinaceum) Growth and Seedhead Suppression

Seashore paspalum (Paspalum vaginatum) has great potential for use in salt-affected turfgrass sites. Use of this grass on golf courses, athletic fields, and lawns in subtropical coastal areas may aid in conservation of freshwater resources. Belonolaimus longicaudatus and Hoplolaimus galeatus are considered among the most damaging root pathogens of turfgrasses in Florida. Glasshouse experiments were performed in 2002 and 2003 to examine the effects of increasing levels of irrigation salinity on B. longicaudatus and H. galeatus. Irrigation treatments were formulated by concentrating deionized water to six salinity levels (0, 5, 10, 15, 20, and 25 dS/m). Final population densities of H. galeatus followed a negative linear regression (r(2) = 0.92 and 0.83; P <= 0.01) with increasing salinity levels. Final population densities of B. longicaudatus were quadratically (r(2) = 0.72 and 0.78; P <= 0.01) related to increasing salinity levels from 0 to 25 dS/m. An increase in population densities of B. longicaudatus was observed at moderate salinity levels (10 and 15 dS/m) compared to 0 dS/m. Root-length comparisons revealed that B. longicaudatus caused root stunting at low salinity levels, 0 to 10 dS/m, but roots were not affected at 15 to 25 dS/m. These results indicate that the ability of B. longicaudatus to feed and stunt root growth was negatively affected at salinity levels of 15 dS/m and above.

Saline Irrigation Affects Belonolaimus longicaudatus and Hoplolaimus galeatus on Seashore Paspalum.

Seashore paspalum (Paspalum vaginatum Swartz) is a warm-season grass capable of growing in the saline environments present in coastal areas of Florida (2). A major limitation of cultivating turfgrasses in the sandy soils of Florida is the destruction of roots by plant-parasitic nematodes (3). A survey was performed to determine the plant-parasitic nematodes associated with seashore paspalum. Sampling locations ranged from Daytona Beach to Miami Beach on the eastern coast and from Tampa to Naples on the western coast. Soil samples were taken during the spring and summer months of 2002 and 2003 from different golf courses and home lawns. In 2002, soil samples were taken from five golf courses (37 samples) and seven home lawns (17 samples). In the next year, three golf courses (23 samples) and 13 home lawns (34 samples) were sampled. Nematodes were extracted from 100 cm3 soil samples using a modified centrifugal-sugar flotation technique (1). Ten genera of plant-parasitic nematodes were present from the samples obtained from golf courses. In addition, two more plant-parasitic nematode genera were present in samples from home lawns. The genera most frequently detected were Hoplolaimus, Mesocriconema, Hemicriconemoides, and Helicotylenchus, which were found at 100, 100, 88, and 88% of the golf courses surveyed and at 75, 95, 70, and 85% of the home lawns sampled, respectively. Genera Xiphinema, Pratylenchus, and Tylenchorhynchus, were found in less than 30% of the golf courses and less than 45% of the home lawns sampled. Genera Peltamigratus and Hemicycliophora were associated with a low percentage of the home lawns. A moderately high frequency of the genus Belonolaimus present in soil samples from golf courses (50%) and home lawns (40%) was consistent for other grasses grown in sandy soils associated with coastal areas in Florida (4). Populations of the genera Belonolaimus, Hoplolaimus, Helicotylenchus, Trichodorus, Hemicriconemoides, and Mesocriconema were above the action threshold levels for bermudagrass used by the University of Florida Nematode Assay Laboratory. Genera Hoplolaimus, Belonolaimus, and Trichodorus were associated with irregular-shaped yellowing and declining turfgrass areas sampled in this survey. Large populations of Helicotylenchus spp. (>500 nematodes per 100 cm3 of soil) were often found associated with seashore paspalum. To our knowledge, this is the first report of plant-parasitic nematodes associated with seashore paspalum in Florida. References: (1) W. R. Jenkins. Plant Dis. Rep. 48:692, 1964. (2) J. Morton. Proc. Fla. State Hortic. Soc. 86:482, 1973. (3) V. G. Perry and H. Rhoades. Pages 144-149 in: Nematology in the Southern Region of the United States. Southern Cooperative Series Bull. 276, University of Arkansas Agric. Pub., Fayetteville, 1982. (4) R. T. Robbins and K. R. Barker. J. Nematol. 6:1, 1974.

First Report of Plant-Parasitic Nematodes on Seashore Paspalum (Paspalum vaginatum) in Florida.

Belonolaimus longicaudatus and Hoplolaimus galeatus are considered among the most damaging pathogens of turfgrasses in Florida. However, the host status of seashore paspalum (Paspalum vaginatum) is unknown. Glasshouse experiments were performed in 2002 and 2003 to determine the tolerance of 'SeaIsle 1' seashore paspalum to a population of B. longicaudatus and a population of H. galeatus, and to compare to 'Tifdwarf' bermudagrass for differences. Both nematode species reproduced well on either grass, but only B. longicaudatus consistently reduced root growth as measured by root length. Belonolaimus longicaudatus reduced root growth (P </= 0.05) by 35% to 45% at 120 days after inoculation on both grasses. In 2003, higher inoculum levels of H. galeatus reduced root growth (P </= 0.05) by 19.4% in seashore paspalum and by 14% in bermudagrass after 60 and 120 days of exposure, respectively. Percentage reductions in root length caused by H. galeatus and B. longicaudatus indicated no differences between grass species, although Tifdwarf bermudagrass supported higher soil population densities of both nematodes than SeaIsle 1 seashore paspalum.

Host Status of 'SeaIsle 1' Seashore Paspalum (Paspalum vaginatum) to Belonolaimus longicaudatus and Hoplolaimus galeatus.

Belonolaimus longicaudatus AND Hoplolaimus galeatus ON SEASHORE PASPALUM (Paspalum vaginatum)

Latest Developments in Using Combustion Chemical Vapor Deposition to Fabricate Coated Conductors

Silicon-on-insulator (SOI) has proven to be a viable alternative to traditional bulk silicon for fabrication of complementary metal–oxide–semiconductor devices. However, a number of unusual phenomena with regards to diffusion and segregation of dopants in SOI have yet to be explained. In the present study, SOITEC wafers were thinned to 700 and 1600 A using oxidation and etching. Ion implantation was performed into SOI and bulk silicon wafers using 11B+ ions at 6.5 and 19 keV with a dose of 3×1014 cm−2. Thermal processing occurred in a furnace at 750 °C for times ranging from 5 min to 8 h under an inert ambient. Using quantitative transmission electron microscopy it was observed that the concentration of trapped interstitials and density of {311} defects was significantly reduced in SOI compared to the bulk. Hall effect was used to monitor the activation process of boron in SOI and bulk silicon. Significantly less activation was observed in SOI compared to the bulk and was dependent on the surface silicon ...

Secondary defect formation in bonded silicon-on-insulator after boron implantation

Combustion Chemical Vapor Deposition (CCVD) is a nonvacuum technique being investigated, in conjunction with the Rolling Assisted Biaxially Textured Substrates (RABiTS/spl trade/) process, as a method to fabricate low-cost, long-length Yttrium Barium Copper Oxide (YBCO) coated conductor tapes. This technique has been scaled to produce meter + lengths of buffer material with excellent epitaxial and microstructural uniformity along the length. Additional efforts focus on depositing YBCO on these lengths using several deposition techniques including CCVD. Pulsed laser deposition (PLD) YBCO with critical current densities >1 MA/cm/sup 2/ have been achieved on short coupons taken from meter lengths of CeO/sub 2//STO/Ni architectures. CCVD buffer layers on Ni-W are still being optimized as YBCO critical current densities are less than 50,000 A/cm/sup 2/. The critical current densities of coupons of YBCO deposited by CCVD onto CCVD buffered substrates is increasing up to 100,000 A/cm/sup 2/, but further optimization is needed to yield high performance samples.

The progress made using the combustion chemical vapor deposition (CCVD) technique to fabricate YBa/sub 2/Cu/sub 3/O/sub 7-x/ coated conductors

The defect evolution upon annealing of low energy, amorphizing germanium implants into silicon was studied using plan-view transmission electron microscopy. Implants with energies of 5–30 keV at an amorphizing dose of 1×1015 Ge+ cm−2 were annealed at 750 °C from 10 s to 360 min. For the implant energies of 10 and 30 keV, the defects form clusters which evolve to {311} defects that subsequently dissolve or form stable dislocation loops. However, as implant energy drops to 5 keV, the interstitials evolve from clusters to small, unstable loops which dissolve within a small time window and do not form {311}’s. To determine the effect of the free surface as an interstitial recombination sink for 5 keV implants, the amorphous layer of a 10 keV implant was lapped to less than the thickness of a 5 keV amorphous layer and then annealed. We found that the defect dissolution observed for the 5 keV implant energy was dependent on the implant energy and not the proximity of the end-of-range damage to the surface. The ...

Defect evolution of low energy, amorphizing germanium implants in silicon

The innovative Combustion Chemical Vapor Deposition (CCVD) process is a non-vacuum technique that is being investigated to enable next generation products in several application areas including high-temperature superconductors (HTS). In combination with the Rolling Assisted Biaxially Textured Substrate (RABiTS) technology, the CCVD process has significant promise to provide low-cost, high-quality lengths of YBCO coated conductor. Over 100 meter lengths of both Ni and Ni-W (3 at. Wt.%) substrates with a surface roughness of 12-18 nm were produced. The CCVD technology has been used to deposit both buffer layer coatings as well as YBCO superconducting layers. Buffer layer architecture of strontium titanate (SrTiO{sub 3}) and ceria (CeO{sub 2}) have been deposited by CCVD on textured nickel substrates and optimized to appropriate thicknesses and microstructures to provide templates for growing PLD YBCO with a J{sub c} of 1.1 MA/cm{sup 2} at 77 K and self-field. The CCVD buffer layers have been scaled to meter plus lengths with good epitaxial uniformity along the length. A short sample cut from one of the lengths enabled high critical current density PLD YBCO. Films of CCVD YBCO superconductors have been grown on single crystal substrates with critical current densities over 1 MA/cm{sup 2}. In addition, superconductingmore » YBCO films with an I{sub c} of 60 A/cm-width (J{sub c} = 1.5 MA/cm{sup 2}) were grown on ORNL RABiTS (CeO{sub 2}/YSZ/Y{sub 2}O{sub 3}/Ni/Ni-3W) using CCVD process.« less

The Progress on Low-Cost, High-Quality, High-Temperature Superconducting Tapes Deposited by the Combustion Chemical Vapor Deposition Process

The enormous technological potential of high-temperature superconductors (HTS) was realized immediately following their discovery in 1986, yet these materials largely remain laboratory curiosities as scientists struggle to scale from coupons to long lengths of practical coated conductor. Although both vacuum and non-vacuum processes are being investigated for commercial production, low-throughput vacuum techniques were the first to succeed in producing the buffer and superconducting layers necessary for superconducting tape with high critical currents. However, vacuum processes are not only expensive but impractical when addressing the needs for rapid production of kilometer lengths of wire. The innovative Combustion Chemical Vapor Deposition (CCVD) method used with the Rolling Assisted Biaxially Textured Substrates (RABiTS™) technology has shown significant promise in fabricating the multi-layer structures necessary for successful HTS tape while overcoming many of the shortcomings of traditional vacuum techniques. The key advantage of the CCVD technology is its ability to deposit high quality thin films in the open atmosphere using inexpensive precursor chemicals in solution. As a result, continuous, production-line manufacturing is possible with significantly reduced capital requirements and operating costs when compared to competing vacuum-based technologies. The current status of development for production of long lengths of high-temperature superconductors using CCVD will be discussed.

High-Temperature Superconducting Tapes Deposited by the Non-Vacuum, Low-Cost Combustion Chemical Vapor Deposition Technique

Photo-patternable precursors to oxide electrodes for ferroelectric memory devices

Synthesis, coordination chemistry and crystal structures of [2+2] macrocycles incorporating 2,6-bis(thiomethyl)pyridine sub-units

Rhodium complexes of some functionalised pyridine ligands incorporating nitrogen and sulphur donor sets

The first structurally characterised example of a manganese(II) complex with monodentate thione ligands; the crystal and molecular structure of trans-dichloro{tetrakis(2(1H)-pyridinethione-S)}manganese(II)

The reactivity of rhodium(II) metal-metal bonded systems with nitrogen and sulfur donor ligands

Abstract An efficient structure for single-bit bandpass bit-stream filtering is presented. This structure contains only one multiplication arithmetic found in traditional filtering operations, whilst producing a filtered single-bit output. This work is built on a previous work by the authors where a low-pass ternary filter has been designed; the filter contains an efficient ternary filter cascaded with a recursive sigma-delta filter. The theme of these works has been to efficiently and simply filter signals using single-bit signal processing techniques. Keeping with this theme we propose in this work a bandpass single-bit filter that consists of a ternary finite-impulse-response (FIR) filter and a sigma-delta modulator, both designed to operate in the bandpass mode. As the ternary filter produces a multi-bit output, a sigma-delta modulator is necessary to remodulate the filtered signal back into the single-bit format.

Recently, we have presented efficient structures for filters that produce an output with a single-bit resolution. As an application and extension of these works a base-band digital single-bit non-coherent binary frequency shift keying (BFSK) demodulator is proposed. This new structure contains no multi-bit multiplications unlike traditional methods of digital BFSK demodulation. The single-bit BFSK demodulator is then simulated using an additive white Gaussian noise channel. As a benchmark the single-bit BFSK demodulator and the theoretical non-coherent BFSK demodulator bit errors are calculated and compared.

Efficient filtering of sigma-delta bit-streams using a finite-impulse response (FIR)-like digital filter is presented. The filter combines a lowpass sigma-delta modulator system and a ternary FIR filter. Unlike conventional FIR filters, the combination of the two components allows a bit stream to be filtered, with the output being retained in single-bit format. Index Terms—Digital filtering, finite-impulse response (FIR), in- finite impulse response (IIR), modulation, sigma-delta, single-bit, ternary filter.

An all-digital single-bit resonator is presented. The resonator input can be either a single-bit or multi-bit signal and the resonator output is in single-bit format. This resonator structure contains no multi-bit multiplication operations, making the resonator efficient for implementation.

Efficient filtering of sigma-delta bit-streams using a finite-impulse response (FIR)-like digital filter is presented. The filter combines a lowpass sigma-delta modulator system and a ternary FIR filter. Unlike conventional FIR filters, the combination of the two components allows a bit stream to be filtered, with the output being retained in single-bit format.

Efficient single-bit ternary digital filtering using sigma-delta modulator

Recently we have proposed a new structure for efficient single-bit filtering. The system consists of a ternary finite impulse response filter and a remodulating low-pass infinite 
impulse response filter. Embedded within the remodulating filter is a sigma-delta modulator. In this work we examine several interpolation methods for generating the ternary taps, along with their effect on the system frequency response.

Recently we have proposed a structure for single-bit filtering. This structure contains a ternary finite-impulse-response filter cascaded with a first-order infinite-impulse-response (IIR) filter. The recursive IIR filter contains a sigma-delta modulator embedded within the loop. This structure filters input signals and produces a single-bit output signal. The stability of such a system has yet to be analyzed. In this paper we use a new mean-square-error correlation-based method to determine the stability of sigma-delta based IIR filters. The approach is applied to test the stability of the above single-bit filtering system.

A correlative criterion for the stability of sigma-delta based IIR filter: application to an FIR-like bit-stream filter

An all-digital single-bit resonator is presented. The resonator input can be either a single-bit or multi-bit signal and the resonator output is in single-bit format. This resonator structure contains no multi- bit multiplication operations, making the resonator efﬁcient for implementation. Conclusion: A digital single-bit resonator is proposed. This resonator can accept either multi-bit or single-bit input words and produces a single-bit output. The system is implementation efﬁcient as it contains no multi-bit multiplications. It consists only of a multiplexer and a bandpass S D M. Simulations showed that the feedback gain has some control over the resonator’s stopband attenuation and the 3 dB bandwidth.

ABSTRACT Surveillance technologies – particularly digital surveillance technologies – have proliferated and become increasingly powerful in recent years. This article discusses recent and emerging legal and policy developments in Australia with respect to facial recognition and related technologies in particular. It analyses these developments from the perspective of international human rights law, focussing on privacy and related rights. The article contends that greater attention needs to be paid in Australia to the risks to human rights posed by these technologies, both in the development of policy and legislation, and on the part of a citizenry which stands to have its freedom significantly restricted in the coming years.

Government surveillance and facial recognition in Australia: a human rights analysis of recent developments

In 2010 the Australian Government decided that it would not propose a Human Rights Act, despite the relevant recommendation of the 2008-09 National Human Rights Consultation. Instead, it introduced a Human Rights Framework comprising several measures to enhance human rights protection, including theHuman Rights (Parliamentary Scrutiny) Act 2011. The scrutiny regime under that Act was designed to ensure rights would be given due consideration before Commonwealth legislation was passed. The Act created a unique 'bipartite dialogue' system, involving a formal interchange on rights compatibility between the executive and Parliament, while excluding the courts. This set the Commonwealth apart from jurisdictions such as the ACT, Victoria, New Zealand and the UK, which have statutory rights instruments administered by their courts. The book presents a detailed study of all aspects of the scrutiny regime, and compares the regime with its closest counterparts overseas. In assessing the regime's impact, it argues that a system in which the executive and Parliament are responsible both for protecting rights and for remedying rights breaches is neither more legitimate nor more effective than one involving all three branches of government. Accordingly, it calls for strengthening reforms.

Two recent cases have shed considerable light on what administrative decision-makers must do to comply with their human rights obligations under Victoria's Charter of Human Rights and Responsibilities Act 2006 (Vic). This clarity is long overdue and much needed both for those who believe their rights have been unlawfully impinged and for public authorities themselves, who need to understand the precise scope of the powers they exercise. However, we argue that these developments also serve to highlight the lack of effective, appropriate, affordable and independent oversight of public authorities' compliance with their Charter obligations.

Submission on the Migration Amendment (Regaining Control over Australia’s Protection Obligations) Bill 2013

The Optional Protocol to the Convention against Torture ('OPCAT') is a unique, action‑based treaty which is designed to protect people everywhere who have been deprived of their liberty. Detention puts individuals in a very vulnerable position, as they are at the mercy of the State and rely on the authorities for even their most basic needs. This raises a very real risk of human rights abuses - a risk which can only be mitigated by strong oversight mechanisms. The OPCAT provides a framework for such mechanisms, and is currently being considered for ratification by Australia. This article sets out some of the issues associated with ratification, including the potential costs, the places of detention it is likely to cover and which bodies are likely to be involved in implementation. It also explains that the OPCAT is highly relevant to Australia because it is about much more than just torture.

Submission to Senate Legal and Constitutional Affairs Committee on Migration Amendment (Unauthorised Maritime Arrivals and Other Measures) Bill 2012

SUMMARY A computer-based analysis of large combination vehicles was conducted to examine the likely dynamic response of such systems when exposed to sudden crosswind gusts. The results indicate that relatively large crosswind-related offtracking and roll responses are possible for the so-called “western” triple combination vehicle (27-ft trailers) while travelling at highway speeds under empty and certain partially-loaded conditions. Strong sensitivities of the basic system response were observed for variations in vehicle operating speed, loading configuration, and crosswind magnitude. Additional calculations were also conducted for low speed operations under very high crosswind conditions where “blow-over” of the full-trailers is possible.

THE CROSSWIND SENSITIVITY OF UNLADEN DOUBLES AND TRIPLES COMBINATIONS AND THEIR SUSCEPTIBILITY TO WIND-INDUCED OFFTRACKING AND ROLLOVER

The relationship of the steering controllability characteristics of domestically-produced subcompact, compact, and intermediate size automobiles to specifications on yaw-rate gain and response time as developed in NHTSA research programs is examined through (1) an analytical survey of the yaw response of 1977 vehicles and (2) open- and closed-loop testing of 3 selected vehicles in modified and unmodified conditions. It is found that, with the exception of some vehicle models equipped with manual steering, the directional performance characteristics of currently produced subcompact, compact, and intermediate size cars lie within the 'optimum' region that has been defined through NHTSA research. It is recommended that further effort in defining safety-related handling requirements is needed before implementing vehicle performance specifications.

Telemedicine Program in Rural Australia A telemedicine program was established in two rural areas of Australia to provide remote guidance for exercise stress testing and Holter monitoring. The prog...

Addition of Supervised Exercise Training to a Post-Hospital Disease Management Program for Patients Recently Hospitalized With Acute Heart Failure: The EJECTION-HF Randomized Phase 4 Trial.

To evaluate the impact of exercise physiology (EP) care on current or former Defence and First Responder participants with self-reported post-traumatic stress disorder (PTSD) attending the Queensland University of Technology (QUT) teaching clinic.

Exercise physiology services improve symptoms of PTSD in people attending a university teaching clinic

Background: Exercise stress testing (EST) is a noninvasive procedure that aids the diagnosis and prognosis of a range of cardiac pathologies. Reduced access is recognized as a limiting factor in enabling early access to treatment or safe and appropriate discharge. Increased accessibility can be achieved by utilizing nonphysician health practitioners to supervise tests. To implement nonphysician-led EST in clinical environments, there is a need for the development and administration of feasible and effective models. Objective: Via inpatient and outpatient referral, this article aims to present 2 standardized models of care for patients requiring EST for diagnostic and prognostic evaluation of numerous pathologies. Method: An inpatient and outpatient model was implemented at the Royal Brisbane and Women’s Hospital and Logan Hospital in Queensland, Australia between July 2013 and December 2015. Tests were performed by 2 cardiac scientists employed by each hospital. All tests were immediately reported by a cardiology advanced trainee registrar or consultant cardiologist. Results: A total of 2095 tests were performed via the 2 models. Overall, 73 had a positive result (3.5%), 120 equivocal (5.7%), 129 inconclusive/submaximal (6.2%), and 1773 negative (85.2%). After further testing, 38 of the patients with positive and equivocal results were diagnosed with flow-limiting coronary artery disease. The remaining patients were resolved as negative through further diagnostic testing or lost to follow up. Conclusions: After implementation of the 2 models, patient flow was improved for earlier discharge, reduced waiting times, or timely identification of possible cardiac pathologies, thereby optimizing patient care.

Two Models to Conduct Nonphysician-led Exercise Stress Testing in Low to Intermediate Risk Patients

A Clinical Decision Rule to Identify Emergency Department Patients at Low Risk for Acute Coronary Syndrome Who Do Not Need Objective Coronary Artery Disease Testing: The No Objective Testing Rule.

Tele-Super-Educating Our Rural Partners to Ensure Diagnostic Quality Exercise Stress Testing

Background: Sleep disturbances, including insomnia and sleep-disordered breathing, are a common complaint in people with heart failure and impair well-being. Exercise training (ET) improves quality of life in stable heart failure patients. ET also improves sleep quality in healthy older patients, but there are no previous intervention studies in heart failure patients. Aim: The aim of this study was to examine the impact of ET on sleep quality in patients recently discharged from hospital with heart failure. Methods: This was a sub-study of a multisite randomised controlled trial. Participants with a heart failure hospitalisation were randomised within six weeks of discharge to a 12-week disease management programme including exercise advice (n=52) or to the same programme with twice weekly structured ET (n=54). ET consisted of two one-hour supervised aerobic and resistance training sessions, prescribed and advanced by an exercise specialist. The primary outcome was change in Pittsburgh Sleep Quality Index (PSQI) between randomisation and week 12. Results: At randomisation, 45% of participants reported poor sleep (PSQI≥5). PSQI global score improved significantly more in the ET group than the control group (–1.5±3.7 vs 0.4±3.8, p=0.03). Improved sleep quality correlated with improved exercise capacity and reduced depressive symptoms, but not with changes in body mass index or resting heart rate. Conclusion: Twelve weeks of twice-weekly supervised ET improved sleep quality in patients recently discharged from hospital with heart failure.

The effect of a supervised exercise training programme on sleep quality in recently discharged heart failure patients

Utility of Routine Exercise Stress Testing among Intermediate Risk Chest Pain Patients Attending an Emergency Department.

Implementation of “Non-physician led exercise stress testing” is effective to create access and optimise patient flow in tertiary, regional and rural hospitals

National guidelines for management of intermediate risk patients with suspected acute coronary syndrome, in whom AMI has been excluded, advocate provocative testing to final risk stratify these patients into low risk (negative testing) or high risk (positive testing suggestive of unstable angina). Adults less than 40 years have a low pretest probability of acute coronary syndrome. The utility of exercise stress testing in young adults with chest pain suspected of acute coronary syndrome who have National Heart Foundation intermediate risk features was evaluated.

Limited utility of exercise stress testing in the evaluation of suspected acute coronary syndrome in patients aged less than 40 years with intermediate risk features

OBJECTIVE
Chest pain is one of the most common complaints in patients presenting to an emergency department. Delays in management due to a lack of readily available objective tests to risk stratify patients with possible acute coronary syndromes can lead to an unnecessarily lengthy admission placing pressure on hospital beds or inappropriate discharge. The need for a co-ordinated system of clinical management based on enhanced communication between departments, timely and appropriate triage, clinical investigation, diagnosis, and treatment was identified.

METHODS
An evidence-based Chest Pain Management Service and clinical pathway were developed and implemented, including the introduction of after-hours exercise stress testing.

RESULTS
Between November 2005 and March 2013, 5662 patients were managed according to a Chest Pain Management pathway resulting in a reduction of 5181 admission nights by more timely identification of patients at low risk who could then be discharged. In addition, 1360 days were avoided in high-risk patients who received earlier diagnosis and treatment.

The creation of a Chest Pain Management pathway and the extended exercise stress testing service resulted in earlier discharge for low-risk patients; and timely treatment for patients with positive and equivocal exercise stress test results. This service demonstrated a significant saving in overnight admissions.

Implementation of a chest pain management service improves patient care and reduces length of stay.

PM489 Non-physician led exercise stress testing is a feasible and effective practice in low to intermediate risk patients with chest pain

Exercise stress testing is a non-invasive procedure that provides diagnostic and prognostic information for the evaluation of several pathologies, including arrhythmia provocation, assessment of exercise capacity, and coronary heart disease. Historically, exercise tests were directly supervised by physicians; however, cost-containment issues and time constraints on physicians have encouraged the use of health professionals with specific training and experience to supervise selected exercise stress tests. Evidence suggests that non-physician-led exercise stress testing is a safe and effective practice with similar morbidity and mortality rates as those performed or supervised by a physician.

Non-physician-led exercise stress testing is a safe and effective practice.

Purpose 
The primary objective of this study was to examine the effect of exercise on subjective sleep quality in heart failure patients. 
 
Methods 
This study used a randomised, controlled trial design with blinded end-point analysis. Participants were randomly assigned to a 12-week programme of education and self-management support (control) or to the same programme with the addition of a tailored physical activity programme designed and supervised by an exercise specialist (intervention). The intervention consisted of 1 hour of aerobic and resistance exercise twice a week. 
 
Participants included 108 patients referred to three hospital heart failure services in Queensland, Australia. 
 
Results 
Patients who participated in supervised exercise classes showed significant improvement in subjective sleep quality, sleep latency, sleep disturbance and global sleep quality scores after 12 weeks of supervised hospital based exercise. Secondary analysis showed that improvements in sleep quality were correlated with improvements in geriatric depression score (p=0.00) and exercise performance (p=0.03). General linear models were used to examine whether the changes in sleep quality following intervention occurred independently of changes in depression, exercise performance and weight. Separate models adjusting for each covariate were performed. Results suggest that exercise significantly improved sleep quality independent of changes in depression, exercise performance and weight. 
 
Conclusion 
This study supports the hypothesis that a 12 week program of aerobic and resistance exercise improves subjective sleep quality in patients with heart failure. This is the first randomised controlled trial to examine the role of exercise in the improvement of sleep quality for patients with this disease. While this study establishes exercise as a therapy for poor sleep quality, further research is needed to investigate exercise as a treatment for other parameters of sleep in this population. Study investigators plan to undertake a more in-depth examination within the next 12 months

The Utility of Exercise Stress Test in the Risk Stratification of Women Aged 40–54 Years with Suspected Intermediate Risk Acute Coronary Syndrome

Conclusion: Our results demonstrate that lesion eccen- tricity in human coronary arteries affects mechanical forces throughout cardiac cycle.

Limited Utility of Exercise Stress Test in the Evaluation of Suspected Acute Coronary Syndrome in Patients Aged Less Than 40 Years with Intermediate Risk Features

The Exercise Joins Education: Combined Therapy to Improve Outcomes in Newly‐discharged Heart Failure (EJECTION‐HF) study will evaluate the impact of a supervised exercise training programme (ETP) on clinical outcomes in recently hospitalized heart failure patients attending a disease management programme (DMP).

Exercise training in recently hospitalized heart failure patients enrolled in a disease management programme: design of the EJECTION‐HF randomized controlled trial

EJECTION-HF: Exercise joins education: Combined therapy to improve outcomes in newly-discharged heart failure patients

Patients presenting to the emergency department with chest pain require prompt identification and referral, as early treatment of patients with an acute coronary syndrome (ACS) is crucial to decrease morbidity and mortality (Steurer et al, Emerg Med J. 2010;27:896-902). Although rule-in ACS is critical and time dependant, other difficulties arise during the rule-out ACS process (Steurer et al, Emerg Med J. 2010;27:896-902). Inappropriate discharge of patients with misdiagnosed acute myocardial infarction is associated with significant morbidity and mortality. Concerns relating to inappropriate discharge result in readmission with resultant lengthy hospital stays, high costs, and contribute to overcrowding and bed block (Amsterdam et al, J Am Coll Cardiol. 2002;40:251-256; Cardiol Clin. 2005;23:503-516; Furtado et al, Emerg Med. In press; Karlson, Am J Cardiol. 1991;68:171-175; Ng et al, Am J Cardiol. 2001;88:611-617; Ramakrishna et al, Mayo Clin Proc. 2005;80:322-329; Stowers, Crit Pathw Cardiol. 2003;2:88-94). The challenge of chest pain diagnosis has led to a number of associated problems within the health care system. The growing need for improvements in consistency of patient care, resource efficiency, and quality of patient healthcare has led to the development of chest pain pathways (Erhardt et al, Eur Heart J. 2002;23:1153-1176). The development and implementation of chest pain pathways is not without difficulties. These may arise from differences in the management approaches of health practitioners, poor adherence to guidelines, and concerns for costs. New procedures such as new cardiac injury markers, stress testing, and specialized chest pain units have led to a reduction in admission rates and length of stay, reduced costs, and a reduction of inappropriate discharge of patients with ischemic heart disease.

Implementation of a chest pain management service improves patient care and reduces costs

Increased mechanoreceptor/metaboreceptor stimulation explains the exaggerated exercise pressor reflex seen in heart failure.

Feasibility and safety of cardiopulmonary exercise testing in Fabry disease

Exercise hyperventilation in chronic heart failure is not caused by systemic lactic acidosis

Putative contribution of prostaglandin and bradykinin to muscle reflex hyperactivity in patients on Ace-inhibitor therapy for chronic heart failure.

Differential contribution of dead space ventilation and low arterial pCO2 to exercise hyperpnea in patients with chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

Background—An important role of the increased stimulation of skeletal muscle ergoreceptors (intramuscular afferents sensitive to products of muscle work) in the genesis of symptoms of exertion intolerance in chronic heart failure (CHF) has been proposed. With the use of selective infusions and dietary manipulation methods, we sought to identify the role of H+, K+, lactate, and peripheral hemodynamics on ergoreflex overactivation. Methods and Results—Ten stable CHF patients (aged 67.9±2.5 years, peak oxygen uptake 16.3±1.2 mL · kg−1 · min−1) and 10 age-matched and sex-matched healthy subjects were studied. The ergoreflex contribution to ventilation was assessed by post-handgrip regional circulatory occlusion (PH-RCO) and computed as the difference in ventilation between PH-RCO and a control run without PH-RCO. This test was performed on 6 separate occasions. On each occasion a different chemical was infused (insulin, sodium nitroprusside, sodium bicarbonate, dopamine, or saline) or a 36-hour glucose-free diet was undertaken before the test. During all stages of the protocol, the local muscular blood effluent concentrations of H+, K+, glucose, and lactate were assessed. An ergoreflex effect on the ventilatory response was seen in patients (versus control subjects) during the saline infusions (6.7±2.3 L/min versus −0.1±0.5 L/min, P <0.01). The only intervention to significantly lower the ergoreflex was sodium bicarbonate (0.4±0.3 L/min versus −0.2±0.4 L/min in control subjects, P =NS; versus saline P <0.05), which also reduced H+ concentration during exercise (47.4±1.3 versus 50.0±1.4 nmol/L on saline, P <0.05). Conclusion—A reduction of the H+ concentration by infusion of sodium bicarbonate abolishes the increased ergoreceptor activity in CHF, suggesting a role of H+ in ergoreflex activation, either directly or indirectly.

Skeletal Muscle Reflex in Heart Failure Patients: Role of Hydrogen

Skeletal Muscle Hypothesis in Heart Failure: Potential Triggers of Ergoreflex Stimulation

Reproducibility of the measurement of the muscle ergoreflex activity in chronic heart failure

PURPOSE
Accumulation of by-products of metabolism within skeletal muscle may stimulate sensory nerves, thus evoking a pressor response named muscle metaboreflex. The aim of this study was to evaluate changes in central hemodynamics occurring during the metaboreflex activation.

METHODS
In seven healthy subjects, the metaboreflex was studied by postexercise regional circulatory occlusion at the start of the recovery from a mild rhythmic forearm exercise. Central hemodynamics was evaluated by means of impedance cardiography.

RESULTS
The main findings of this study were that, with respect to rest, the metaboreflex: 1) raised mean blood pressure (+13%; P < 0.01); 2) enhanced myocardial contractility (-12% in preejection period/left ventricular ejection time ratio; P < 0.01); 3) prolonged diastolic time (+11%; P < 0.01); 4) increased stroke volume (+ 10%; P < 0.05); and 5) increased cardiac output (+6%; P < 0.05). These responses were present neither during recovery without circulatory occlusion nor during circulatory occlusion without prior exercise. Moreover, the metaboreflex did not affect systemic vascular resistance and induced bradycardia with respect to recovery without circulatory occlusion.

These results suggest that the blood pressure response during metaboreflex activation after mild rhythmic exercise is strongly dependent on the capacity to increase cardiac output rather than due to increased vascular resistance.

Chemical Mediators of the Muscle Ergoreflex in Chronic Heart Failure: A Putative Role for Prostaglandins in Reflex Ventilatory Control

Background— The overactivity of ergoreceptors (intramuscular afferents sensitive to products of skeletal muscle work) may be responsible for the abnormal responses to exercise and symptoms of exercise intolerance in chronic heart failure (CHF); however, little is known of the chemical nature of the stimuli involved. We investigated biochemical factors (H+, Vco2, Vo2, Hco3, K+, phosphate, lactate, PGE2, PGF1α, and bradykinin) potentially involved in ergoreceptor activation. Methods and Results— Sixteen stable patients with CHF (64.9±2.7 years, peak Vo2 15.8±0.7 mL/kg per min) and 10 age-matched controls were studied. The ergoreceptor test involved two 5-minute handgrip exercises. On one occasion, the subjects recovered normally (control recovery), whereas on the other a posthandgrip regional circulatory occlusion was induced in the exercising arm, isolating the stimulation of the ergoreceptor after exercise. The ergoreflex was quantified as the difference in ventilation between the posthandgrip regional...

Chemical Mediators of the Muscle Ergoreflex in Chronic Heart Failure A Putative Role for Prostaglandins in Reflex Ventilatory Control

Increased activity of muscle metaboreceptors (afferents sensitive to muscle contraction that are responsible for the ventilatory responses to exercise) has been proposed in patients with chronic heart failure (CHF) to constitute a missing link between muscle metabolic abnormalities and exercise overventilation. We looked at this reflex overactivation to determine if it is systemic or limited to a single muscle region in the same human subject. This was done by comparing the metaboreflex response of ventilatory control in the lower and upper limbs in CHF patients and healthy controls. Groups of 15 stable CHF patients (63.7+/-2.7 years) and eight control subjects (69.8+/-1.8 years) performed both leg and arm metaboreflex tests. These metaboreflex tests involved two 5 min episodes of bicycle or handgrip exercise: on one occasion after the exercise the subjects recovered normally, while on the other occasion tourniquet cuffs were inflated around the exercising limb to supra-systolic pressure at the onset of recovery to obtain a regional circulatory occlusion, which isolates and maintains the stimulation of the metaboreflex after exercise. The contribution of the metaboreflex to exercise ventilation was computed as the absolute increment of peak ventilation that was maintained by regional circulatory occlusion. The metaboreceptor contribution to the ventilatory response to both leg exercise (patients, 5.3+/-1.6 litres/min; controls, 0.2+/-0.7 litres/min) and arm exercise (patients, 3.7+/-1.0 litres/min; controls, 0.02+/-0.4 litres/min) was significantly higher in CHF patients (P<0.05). A significant correlation was present between metaboreflex responses to arm and leg exercises (r=0.4, P<0.05). Metaboreflex responses during both types of exercise were inversely correlated with peak oxygen uptake (leg, r=-0.43, P<0.05; arm, r=-0.633, P=0.0009), but only the reflex during arm exercise was correlated with the .V(E) (ventilation)/.V(CO)(2) (CO(2) production) slope (r=0.576, P<0.005). Thus the metaboreflex system is systemically overactive and may potentially contribute to exercise intolerance during both lower- and upper-limb efforts in CHF. This suggests a unique mechanism responsible for overactivation of this system in the skeletal muscle of heart failure patients.

Relationship of skeletal muscle metaboreceptors in the upper and lower limbs with the respiratory control in patients with heart failure.

Abnormal temporal dynamics of blood pressure and RR interval regulation in patients with chronic heart failure: relationship to baroreflex sensitivity.

Validation of a treadmill exercise test protocol with improved metabolic plateau formation in patients with chronic congestive heart failure.

Patients with heart failure are limited in their ability to tolerate exercise. Recent research has suggested that this limitation cannot be entirely attributed to cardiac or lung impairment but rather that changes in peripheral muscles may play an important role. There are objective similarities between heart failure and muscular deconditioning. Deficiencies in peripheral blood flow and skeletal muscle function, morphology, metabolism and function are present in both conditions. Moreover, an exaggerated activity of the receptors sensitive to exercise-derived metabolic signals (muscle ergoreceptors and peripheral and central chemoreceptors) leads to early and profound exercise-induced fatigue and dyspnoea. These muscle afferents contribute to the ventilatory, haemodynamic and autonomic responses to exercise both in physiological and pathological conditions, including chronic heart failure. Against this background, a skeletal muscle origin of symptoms in heart failure has been proposed. The protective effects of physical training have been described in many recent studies: training improves ventilatory control, skeletal muscle metabolism and autonomic nervous system activity. The exercise training appears to induce its beneficial effects on skeletal muscle both directly (on muscle function, histological and biochemical features) and indirectly (by reducing the activation of the muscle afferents). The metabolic mediators of these muscle afferents may become a potential target in the future therapy of heart failure symptoms.

OBJECTIVE To assess the value of cardiopulmonary exercise testing in predicting prognosis in a cohort of elderly patients with chronic heart failure (CHF). DESIGN A retrospective cohort study of all patients with CHF over the age of 70 years assessed between January 1992 and May 1997. SETTING Tertiary centre. PATIENTS 50 patients (mean (SD) age 75.9 (4.5) years, 8 women) with CHF New York Heart Association (NYHA) class I (3 patients), II (25 patients), III (20 patients), and IV (2 patients). Follow up was complete for two years in all patients. RESULTS The patients underwent cardiopulmonary exercise testing (peak oxygen consumption 15.2 (4.5) ml/kg/min, minute ventilation/carbon dioxide production (VE/Vco 2) slope 38.7 (11.8)); radionucleide ventriculography (left ventricular ejection fraction 32.8 (14.3)%); serum sodium measurement (139 (2.8) mmol/l); and echocardiography (left ventricular end diastolic dimension 6.1 (1.1) cm, left ventricular end systolic dimension 4.7 (1.5) cm). At the end of follow up in May 1999, 26 patients had died. The median follow up of the survivors was 47.7 months (interquartile range 31.5–53.5 months). On univariate analysis VE/Vco 2 slope (p < 0.0001), NYHA class (p < 0.001), peak oxygen uptake (Vo 2) (p < 0.01), left ventricular end systolic dimension (p < 0.05), and serum sodium concentration (p < 0.05) had significant predictive power. Stepwise multivariate analysis identified only VE/Vco 2 slope (p < 0.01), NYHA class (p < 0.05), and peak Vo 2 (p< 0.05) as conveying significant independent prognostic information. CONCLUSION Elderly patients with CHF have a high mortality, with the majority dead within two years. Cardiopulmonary exercise testing provides important information for risk stratification within this group and its use should not be neglected.

Chronic heart failure in the elderly: value of cardiopulmonary exercise testing in risk stratification

 The use of intraoperative ultrasound (iUS) has been associated with prolonged survival in patients with high grade glioma. However, iUS remains an under-utilised surgical adjunct in many neurosurgical units due to greater familiarity with CT and MR imaging. Navigated intraoperative ultrasound (NiUS) facilitates co-registration of pre-operative MR imaging with iUS, offering a number of advantages over standard neuronavigation. The aim of this study was to describe our initial experiences with NiUS for brain tumour resection in adults.
 
 We prospectively collected data on patient demographics, tumour location and histology, extent of resection and early post-operative outcome in 9 consecutive patients. Brainlab neuronavigation (BrainLab, Germany) and the BK5000 cranial ultrasound probe (BK Medical, Denmark) were used in all cases. We also collected data on surgical intent and the use of surgical adjuncts including neurophysiology monitoring, DTI and 5ALA.
 
 NiUS was used in 9 patients (6 male, 3 female). iUS scans were successfully co-registered in all cases. Histological diagnoses were GBM (7 patients), melanoma (1 patient) and oligodendroglioma (1 patient). NiUS was used in conjunction with the following techniques and adjuncts – awake craniotomy (2), DTI (all cases), neurophysiology monitoring (4 cases) and 5ALA (7 cases). Gross total resection was achieved in 8 patients. The mean operative time was 4 hours and 7 minutes, which is significantly lower than that reported in a recently published series involving intra-operative MRI. No patients suffered any deterioration in neurological status in the early post-operative period.
 
 NiUS was rapidly assimilated into our surgical workflow with successful co-registration in all cases. NiUS was used successfully in conjunction with awake craniotomy, neurophysiology monitoring, DTI and 5ALA for both enhancing and non-enhancing tumours. Based on our early experience we offer learning points on patient positioning, set up of equipment and interpretation of iUS. Further studies are required to determine the impact of NiUS on patient outcome.

Initial experience with navigated intraoperative ultrasound for brain tumour surgery

Abstract Background When appropriately selected, a high proportion of patients with suspected idiopathic normal pressure hydrocephalus (iNPH) will respond to cerebrospinal fluid diversion with a shunt. Extended lumbar drainage (ELD) is regarded as the most accurate test for this condition, however, varying estimates of its accuracy are found in the current literature. Here, we review the literature in order to provide summary estimates of sensitivity, specificity, positive- and negative predictive value for this test through meta-analysis of suitably rigorous studies. Methods Studies involving a population of NPH patients with predominantly idiopathic aetiology (>80%) in which the intention of the study was to shunt patients regardless of the outcome of ELD were included in the review. Various literature databases were searched to identify diagnostic test accuracy studies addressing ELD in the diagnosis of iNPH. Those studies passing screening and eligibility were assessed using the QUADAS-2 tool and data extracted for bivariate random effects meta-analysis. Results Four small studies were identified. They showed disparate results concerning diagnostic test accuracy. The summary estimates for sensitivity and specificity were 94% (CI 41–100%) and 85% (CI 33–100%), respectively. The summary estimates of positive and negative predictive value were both 90% (CIs 65–100% and 48–100%, respectively). Conclusion Large, rigorous studies addressing the diagnostic accuracy of ELD are lacking, and little robust evidence exists to support the use of ELD in diagnostic algorithms for iNPH. Therefore, a large cohort study, or ideally an RCT, is needed to determine best practice in selecting patients for shunt surgery.

Extended lumbar drainage in idiopathic normal pressure hydrocephalus: a systematic review and meta-analysis of diagnostic test accuracy

PROGNOSTIC INDICES FOR BRAIN METASTASES – WHICH BEST REFLECTS A UK COHORT, AND WHAT IS THE PROGNOSIS OF OUR METASTASIS PATIENTS?

A 16 year old girl presented with sudden onset severe central abdominal and left shoulder pain. She had a history of intermittent generalised abdominal pain associated with early satiety and nausea after eating over the preceding year. On assessment, she was tachycardic at 120 beats/min and had a firm, tender mass in the epigastrium. Blood tests revealed a normocytic anaemia (haemoglobin 84 g/L, normal range 12-16) and a neutrophil count of 15×109 /L (normal range 1.8-8). A plain chest radiograph showed substantial air under the diaphragm, and computed tomography (CT) imaging identified the presence of a large hypodense, heterogeneous mass that almost completely filled the stomach, with leakage of oral contrast into the intra-abdominal space (fig 1⇓). On direct questioning, the patient admitted to a tendency to chew her hair, but claimed she had refrained from this for nearly a year preceding her current presentation.

Fig 1  (A) Erect chest radiograph. (B) Computed tomography image (coronal view) of abdomen and pelvis with oral contrast

### 1. What is the cause of this patient’s presentation?

#### Short answer

Perforation of the stomach secondary to a giant trichobezoar (fig 2⇓).

Fig 2  (A) Erect chest radiograph. (1) Free air under diaphragm. (B) CT coronal view of abdomen and pelvis with oral contrast. (2) Oral contrast seen outside stomach (indicating perforation); (3) Locules of free air …

Laryngotracheal stenosis (LTS) is a rare condition that occurs most commonly as a result of instrumentation of the airway but may also occur as a result of inflammatory conditions or idiopathically. Here, we present the case of a patient who developed LTS as a complication of granulomatosis with polyangiitis (GPA), which was misdiagnosed as asthma for 6 years. After an admission with respiratory symptoms that worsened to the extent that she required intubation, a previously well 14-year-old girl was diagnosed with GPA. Following immunosuppressive therapy, she made a good recovery and was discharged after 22 days. Over subsequent years, she developed dyspnoea and “wheeze” and a diagnosis of asthma was made. When she became pregnant, she was admitted to hospital with worsening respiratory symptoms, whereupon her “wheeze” was correctly identified as “stridor,” and subsequent investigations revealed a significant subglottic stenosis. The delay in diagnosis precluded the use of minimally invasive therapies, with the result that intermittent laser resection and open laryngotracheal reconstructive surgery were the only available treatment options. There were numerous points at which the correct diagnosis might have been made, either by proper interpretation of flow-volume loops or by calculation of the Empey or Expiratory Disproportion Indices from spirometry data.

Not Always Asthma: Clinical and Legal Consequences of Delayed Diagnosis of Laryngotracheal Stenosis

Dupuytren's disease is a fibroproliferative condition of the palm, with a predilection for men, which has affected Northern Europeans since the Viking conquests. Although strongly heritable, clear evidence exists for environmental factors that modify the underlying genetic risk, such as diabetes, heavy drinking, and smoking. Evidence also exists for epilepsy (probably due to treatment with certain anti-epileptic drugs), and Human Immunodeficiency Virus infection. Recent large studies have shown no relationship with manual labour or vibrating tools. Two theories have emerged regarding the pathogenic mechanism: the first attributes the aberrant healing process that characterises Dupuytren's to free radicals, generated as a result of microangiopathy, whereas the second cites a genetic tendency toward apoptosis-resistant myofibroblasts. Despite only one study demonstrating linkage, emerging data from genome-wide association studies highlight a series of single nucleotide polymorphisms near members of the Wnt signalling pathway, and transcriptional profiling studies have consistently identified certain components of the extracellular matrix.

Hand surgery : an international journal devoted to hand and upper limb surgery and related research : journal of the Asia-Pacific Federation of Societies for Surgery of the Hand

Dupuytren's contracture: emerging insight into a Viking disease.

Recent evidence has shown that SOX9 is required for the proliferation and multipotentiality of neural progenitors in the developing CNS. Notably, these findings suggest that in contrast to previous studies, SOX9 is important for differentiation along the neuronal lineage, both in the adult and embryonic CNS. Here, a phenotypic analysis of the CNS-specific Sox9-null forebrain, including detailed analysis of cortical lamination, shows that neurons of the appropriate layer-identity are born and migrate to their destined layers. All other parameters in this analysis were normal, with the exception of the formation of glia from the ventral and dorsal telencephalons, and midline glial structures, which were absent in the mutant. Since Sox9 is expressed long before the onset of gliogenesis in these brain regions, the possibility that Sox9 may ‘prime’ the progenitors of the ventricular zone to respond to a gliogenic signal arose. To investigate this, populations of Sox9-deficient and wild-type dorsal telencephalon cells were enriched for progenitors and subjected to transcriptional profiling. Bioinformatic analysis revealed that ‘vascular endothelial growth factor’ receptors, which are important for gliogenesis, were down-regulated, in addition to two transcription factors. Previously, Sox9-deficient neural progenitors have been shown to generate neurospheres poorly, and so the dataset of potential targets was used to identify candidates that might mediate this reduced neurosphere-forming ability. Thirteen down-regulated targets were confirmed by qPCR, six of which were expressed in the same distribution as Sox9 in the embryonic telencephalon; three were also expressed in neurosphere cultures. Of these, one encoded a K+ channel (Kir4.1), and the other a modulator of the GABAA channel (DBI). In order to show that reduced expression of one of these might contribute to the Sox9-deficient neurosphere phenotype, pharmacological modulators were used and showed that blockade of Kir4.1 or enhancement of GABAA channels mimicked the effect of Sox9 loss, leaving open the possibility that Kir4.1 or DBI expression might mediate this effect.

Detection of coeliac patients at risk of an osteoporotic fracture: a two-cycle clinical audit

Applying the Asymmetric Information Management (
 AIM
 ) technique to virtual interviewing

 AIM
 ) technique to insurance claims

Sexual offending and barriers to employability: public perceptions of who to hire

Amplifying recall after delays via initial interviewing: Inoculating truth-tellers' memory as a function of encoding quality.

Lie-detection by Strategy Manipulation: Developing an Asymmetric Information Management (AIM) Technique

Amplifying deceivers' flawed metacognition: Encouraging disclosures after delays with a model statement.

The Verifiability Approach (VA) is a lie detection tool that examines reported checkable details. Across two studies, we attempt to exploit liar’s preferred strategy of repeating information by examining the effect of questioning adult interviewees before the VA. In Study 1, truth tellers (n=34) and liars (n=33) were randomly assigned to either an initial open or closed questioning condition. After initial questioning, participants were interviewed using the VA. In Study 2, truth tellers (n=48) and liars (n=48) were interviewed twice, with half of each veracity group randomly assigned to either the Information Protocol (an instruction describing the importance of reporting verifiable details) or control condition. Only truth tellers revised their initial statement and to include verifiable detail. This pattern was most pronounced when initial questioning was open (Study 1) and when the information protocol was used between recall attempts (Study 2). Thus, liar’s preferred strategy of maintaining consistency between statements appears exploitable using the VA. RUNNING HEAD: The effect of initial questioning on the VA 2 General Audience Summary: Across two studies we explored if the Verifiability Approach – a technique for distinguishing liars from truth tellers using the quantity of verifiable detail reported in interviewees’ statements – can be adapted to elicit consistency-based cues to deception by asking questions before administering the full VA procedure..Truth tellers appeared willing to revise their initial statement and, when prompted, reported previously undisclosed verifiable detail. Conversely, liars appeared unwilling to revise their initial statement to include new verifiable detail.

Extending the verifiability approach framework: The effect of initial questioning

Method. In the experiment, 53 participants were interviewed. Truth tellers (n = 27) discussed a trip they had made during the last twelve months; liars (n = 26) fabricated a story about such a trip. The interview consisted of an initial recall followed by a model statement (a detailed account of an experience unrelated to the topic of investigation) followed by a post-model statement recall. The key dependent variables were the amount of information provided and the proportion of all statements that were complications.

Within‐subjects verbal lie detection measures: A comparison between total detail and proportion of complications

Background. ‘Interviewing to detect deception’ research is sparse across different Ethnic Groups. In the present experiment, we interviewed truth tellers and liars from British, Chinese, and Arab origins. British interviewees belong to a low-context culture (using a communication style that relies heavily on explicit and direct language), whereas Chinese and Arab interviewees belong to high-context cultures (communicate in ways that are implicit and rely heavily on context).

Deception and decay: Verbal lie detection as a function of delay and encoding quality.

Deception and Decay: Verbal Lie Detection as a Function of Delay and Encoding Quality

Insurance based lie detection: Enhancing the verifiability approach with a model statement component.

Research examining how truth tellers’ and liars’ verbal behavior is attenuated as a function of delay is largely absent from the literature, despite its important applied value. We examined this factor across 2 studies in which we examined the effects of a hypothetical delay (Experiment 1) or actual delay (Experiment 2) on liars’ accounts. In Experiment 1—an insurance claim interview setting—claimants either genuinely experienced a (staged) loss of a tablet device (n = 40) or pretended to have experienced the same loss (n = 40). Truth tellers were interviewed either immediately after the loss (n = 20) or 3 weeks after the loss (n = 20), whereas liars had to either pretend the loss occurred either immediately before (n = 20) or 3 weeks before (n = 20) the interview (i.e., hypothetical delay for liars). In Experiment 2—a Human Intelligence gathering setting—sources had to either lie (n = 50) or tell the truth (n = 50) about a secret video they had seen concerning the placing of a spy device. Half of the truth tellers and liars where interviewed immediately after watching the video (n = 50), and half where interviewed 3-weeks later (n = 50; i.e., real delay for liars). Across both experiments, truth tellers interviewed after a delay reported fewer details than truth tellers interviewed immediately after the to-be-remembered event. In both studies, liars failed to simulate this pattern of forgetting and reported similar amounts of detail when interviewed without or after a delay, demonstrating a stability bias in reporting.

Purpose 
 
Lie detection in insurance claim settings is difficult as liars can easily incorporate deceptive statements within descriptions of otherwise truthful events. We examined whether the Verifiability Approach (VA) could be used effectively in insurance settings. According to the VA, liars avoid disclosing details that they think can be easily checked, whereas truth tellers are forthcoming with verifiable details. 
 
Method 
 
The study experimentally manipulated notifying claimants about the interviewer's intention to check their statements for verifiable details (the ‘Information Protocol’). It was hypothesized that such an instruction would (1) encourage truth tellers to provide more verifiable details than liars and to report identifiable witnesses who had witnessed the event within their statements, and (2) would enhance the diagnostic accuracy of the VA. Participants reported 40 genuine and 40 fabricated insurance claim statements, in which half the liars and truth tellers were notified about the interviewer's intention to check their statements for verifiable details. 
 
Results 
 
Both hypotheses were supported. In terms of accuracy, notifying claimants about the interviewer's intention to check their statements for verifiable details increased accuracy rates from around chance level to around 80%. 
 
The VA, including the information protocol, can be used in insurance settings.

Applying the Verifiability Approach to insurance claims settings: Exploring the effect of the information protocol

A metacognitive model of memory regulation was applied to information-gathering interviews with deceptive and truth-telling participants. Theoretically, differential strategies of the liars and truth-tellers would direct specific metacognitive processes and elicit veracity cues. 
60 participants (40 female, 20 male) were interviewed and asked to lie or tell the truth about an event. Half the liars and half the truth-tellers were given 5 minutes preparation. 
It was found that, despite a majority of liars reported adopting an ‘embedding’ strategy (whereby lies are concealed within really experienced events), significantly more fine-grain precise details (e.g. ‘he was 6’ 3” tall’, ‘the chair was red’) were reported by truth-tellers than liars. 
Additionally, truth-tellers reports contained significantly more reminiscence (recalling details in follow up questions not originally remembered) than liars. This provides the first evidence suggesting that embedding is not an effective counter-strategy to reminiscence based veracity tools. However, no evidence was found for increased verbal-decline for liars. 
Furthermore, no effect of preparation was found for fine-grain details, reminiscence, or verbal-decline. 
It is concluded that although the current results with respect to reminiscence are encouraging, the boundary conditions associated with fine-grain detail reporting should be established before such models are integrated into cognitive based lie-detectors.

Lie to me: investigating the strategic regulation of fine-grain details in truth-tellers and liars

The emergence of collective behavior on social and biological networks

Bistability and the Emergence of Oscillations in Repressilator Models with Quorum Sensing

The transient dynamics of dilation waves in granular phase transitions during silo discharge

Experimental investigations of granular matter flow regimes leading to insight into lahar flow dynamics : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Earth Science at Massey University, Manawatū, New Zealand

Giant dike swarms are present on Venus, Earth, and Mars [1]. On Mars, sets of graben radiating from centres in the Tharsis volcanic region are taken as evidence for the presence of giant dike swarms [2]. The Mangala Fossa graben system and the related Mangala Valles flood valley probably have had their origins in crustal fracturing caused by the intrusion of one of these dikes [3, 4], which we call the Arsia-Mangala dike. The graben segments formed when the combination of regional extensional tectonic forces and local stresses due to dike injection caused surface subsidence along pairs of inward-facing faults [5]. In the longest graben segment, subsurface aquifer water exploited the graben faults to reach the surface, flood the graben interior, and overflow to erode the Mangala Valles flood channels [4]. Here we propose that 3 other groups of surface features are related to the emplacement of the Arsia-Mangala dike. Specifically, we infer that they are due to asymmetric changes in surface topography in the propagation direction, which the upper edge of the laterally propagating dike was unable to track vertically as the dike was being emplaced, thus leading to the dike top dynamically approaching unusually close to the surface.

The surface expression of the Arsia-Mangala Dike, Mars, is controlled by the "Sawtooth" profile of surface topography.:42nd Lunar and Planetary Science Conference (2011)

Mangala Valles is one of many sites on Mars probably formed by massive catastrophic release of water onto the surface [1-3]. The water was released after a dike intruded into the area from the near-by Tharsis region, causing formation of a graben, Mangala Fossa [4]. Water was forced to the surface up the graben boundary faults by topographic pressure gradients and buoyancy. Proximal to the eastern arm of the Mangala Fossa graben two types of deposit are present. (Figure 1). The dune-like features that are found at the far eastern end of the graben (C) are proposed to be of phreatomagmatic origin [5]. We suggest that the other type of deposit, seen along the strike of the eastern arm (A and B), are mud deposits, ejected by CO2-driven water fountains. The mechanism is similar to that seen in the Lake Nyos and Monoun (both in Cameroon) degassing events [6].

The Current Population Survey Annual Social and Economic Supplement (CPS ASEC) is the source of the nation’s official household income and poverty statistics. In 2012, the CPS ASEC showed that median household income was $33,800 for householders aged 65 and over and the poverty rate was 9.1 percent for persons aged 65 and over. When we instead use an extensive array of administrative income records linked to the same CPS ASEC sample, we find that median household income was $44,400 (30 percent higher) and the poverty rate was just 6.9 percent. We demonstrate that large differences between survey and administrative record estimates are present within most demographic subgroups and are not easily explained by survey design features or processes such as imputation. Further, we show that the discrepancy is mainly attributable to underreporting of retirement income from defined benefit pensions and retirement account withdrawals. Using archived survey and administrative record data, we extend our analysis back to 1990 and provide evidence of underreporting from an earlier period. We also document a growing divergence over time between the two measures of median income which is in turn driven by the growth in retirement income underreporting. Turning to synthetic cohort analysis, we show that in recent years, most households do not experience substantial declines in total incomes upon retirement or any increases in poverty rates. Our results have important implications for assessing the relative value of different sources of income available to older Americans, including income from the nation’s largest retirement program, Social Security. We caution, however, that our findings apply to the population aged 65 and over in 2012 and cannot easily be extrapolated to future retirees.

Declining response rates to surveys is a widespread and troubling problem. Unit non-response (when a household is not interviewed at all) has been rising in most surveys. For example, unit non-response rates rose by 3-12 percentage points over the 1990s for six U.S. Census Bureau surveys (Atrostic et al. 2001). Many recent papers have raised the concern that this increased non-response has led to bias in key statistics. In light of this concern, we propose a new method to evaluate and correct bias from unit non-response. We apply this method to the Current Population Survey (CPS), the most used economic survey and the source of official employment, income, poverty, inequality and health insurance coverage information. Specifically, we use addresses to link the 2011 CPS Annual Social and Economic Supplement (CPS ASEC) to IRS Form 1040 records. This link allows us to compare several characteristics of respondents and non-respondents, including income and some of its components, self-employment status, marital status, number of children, and the receipt of social security. We find little evidence of differences between the percentiles of the income distribution of the linked respondents and nonrespondents. We also find little difference between the respondent distribution, conventionally adjusted for non-response, and the combined respondent and non-respondent distributions. Significant differences between respondent and non-respondents are found for the number of children, and some other characteristics. We then compare our new method of assessing unitnonresponse bias to prior methods. JEL CODES: C81, D31, I32

Bias from Unit Non-Response in the Measurement of Income in Household Surveys

In the past several decades, individuals 65 and over have experienced remarkable declines in their official poverty rate, from 35.2 percent in 1959 to 9.1 percent in 2012. These poverty rates, however, are based on self-reported income data from the Current Population Survey Annual Social and Economic Supplement (CPS ASEC), also known as the March Supplement. Retirement income (other than Social Security or Veteran’s benefits) is a significant portion of income reported by the elderly, but some analysts have suggested that the shift from pensions to individual retirement accounts may cause surveys like the CPS ASEC to mismeasure retirement income. In this paper I evaluate the quality of the retirement income data in the 2010 CPS ASEC by individually matching respondents to IRS 1099-R forms filed with tax returns for the 2009 tax year. I find that recipiency of retirement income may be underreported on the CPS ASEC, as only a third of individuals with matched 1099-R forms reported receiving any retirement income. Much of this discrepancy, however, may be due to differences in scope, as the 1099-R covers a wider set of payments than is intended to be captured in the CPS ASEC retirement income items. In cases where positive amounts are reported on the CPS ASEC, however, those amounts appear to be quite accurate. Among cases with positive reported income, the correlation between CPS ASEC and 1099-R log amounts is 0.769. Upon modeling 1099-R recipiency as a function of age with discontinuities at various policy-relevant age cutoffs, I find a 14.0 percentage-point jump in recipiency at age 59½, the age at which IRA withdrawals are allowed without penalty. Taken together, these results provide suggestive evidence that retirement income may represent an underestimated contribution to the material well-being of the elderly.

An Evaluation of Retirement Income in the CPS ASEC Using Form 1099-R Microdata *

SUMMARY 1. Freshwater resource managers are increasingly obligated to consider the impacts of large river engineering projects on ecosystem services. We evaluated the effect of altered water regime from the operation of a large dam on the production of the downstream tropical floodplain fishery of the Kafue River, Zambia. We compared the benefits of increased hydropower relative to potentially lost fishery production. 2. We compiled a long-term data set consisting of experimental gillnet catches, artisanal harvesting effort and monthly river flows for 25 years prior to and 29 years after the 1977 completion of the upstream Itezhi-Tezhi Dam. As a metric of the flood regime, we calculated a canonical correlation score for each hydrological year before and after dam closure. For the period following dam construction, we used the Muskingum method of flood routing to estimate ‘no-dam’ flows through the fishery area and downstream hydroelectric turbines at the Kafue Gorge Dam. 3. We compared 16 alternative models of catch per unit effort (CPUE) with and without an effect of water regime on fish population growth rate. Using the two best fitting models, we estimated the total observed fishery harvest and simulated ‘no-dam’ fisheries harvest and found no significant effect of altered water regime on fishery production. 4. We estimate that the large upstream dam increases downstream hydropower production by about $18 million USD per annum. The reduction in fishery production caused by the altered water regime is not significantly different than zero, although the average reduction amounts to about $2.3 million annually. The total estimated value of harvest ranges from $1.3 million to $56 million annually. 5. Large observed declines in fish abundance over the 54-year study period are attributed primarily with similarly large increases in total fishing effort in this mostly open-access artisanal fishery. 6. These results contrast with other examples of the effects of flow alteration on fish, probably because levels of fisheries exploitation on the Kafue River are very high relative to better studied regions on other continents; our focus on the whole fish community; and the unprecedented length of the time series we considered. If the goal is to sustain fishery production, investments in altering flow regime are likely to be less effective than investments to decrease fishing effort.

The potential trade‐off between artisanal fisheries production and hydroelectricity generation on the Kafue River, Zambia

Various economic theories suggest that one reason for low rates of employment among low-skill, inner-city residents is that they are spatially separated from jobs that have moved out to the suburbs. This implies that if more low-skill urban dwellers owned cars, gaps in employment rates would shrink. I exploit variation in state ―prior approval‖ insurance rate regulation which has been shown to suppress auto insurance prices, thereby decreasing the cost of owning a car. I find that prior approval laws increase the proportion of multi-car households among married couples with children. In those households, I find that the additional car in the household encourages mothers to decrease their labor supply while their husbands increase their labor supply. One possible explanation of this result is that cars are stronger complements to time spent in home production (and especially childrearing) than they are to time spent in the labor market. JEL Classifications: R23, R41, R49, J61, J64, J68

The Effect of Car Ownership on Employment : Evidence from State Insurance Rate Regulation [ Job Market Paper – Preliminary and Incomplete ]

Summary Simple, inexpensive techniques were used to analyse the mtDNA of nine chromosomally distinct populations of Petrogale. Eight of these populations occur in sequence along the Great Dividing Range of eastern Australia; six have been described as species. Diagnostic mtDNA morphs were found throughout the latitudinal ranges of four of the described species. A fifth morph spanned the ranges of two described species and three additional taxa which have been designated chromosome races. These five mtDNA morphs, and others with local distributions, were used to assess interactions between the taxa. Limited introgression was indicated across the chromosomal boundaries of P. penicillata/P. herberti and P. inornata/P. assimilis; atypical mtDNA morphs were found within the P. herberti and P. inornata chromosomal distributions. No introgression was detected between P. herberti and P. inornata, whose distributions are separated by the Fitzroy River. Nor was there evidence of recent contact between P. assimilis, P. herberti and P. purpureicollis, despite the late occupancy of parts of the intervening area by unidentified Petrogale. These data, considered in the light of information obtained from previous studies on chromosomes, allozymes and parasites, have contributed to the decision to consider all the eastern representatives of the lateralis-penicillata group of Petrogale as being specifically distinct from each other.

Mitochondrial DNA analysis of introgression between adjacent taxa of rock-wallabies, Petrogale species (Marsupialia: Macropodidae)

Simple, inexpensive techniques were used to analyse the mtDNA of nine chromosomally distinct populations of Petrogale. Eight of these populations occur in sequence along the Great Dividing Range of eastern Australia; six have been described as species. Diagnostic mtDNA morphs were found throughout the latitudinal ranges of four of the described species. A fifth morph spanned the ranges of two described species and three additional taxa which have been designated chromosome races. These five mtDNA morphs, and others with local distributions, were used to assess interactions between the taxa. Limited introgression was indicated across the chromosomal boundaries of P. penicillata/P. herberti and P. inornata/P. assimilis; atypical mtDNA morphs were found within the P. herberti and P. inornata chromosomal distributions. No introgression was detected between P. herberti and P. inornata, whose distributions are separated by the Fitzroy River. Nor was there evidence of recent contact between P. assimilis, P. herberti and P. purpureicollis, despite the late occupancy of parts of the intervening area by unidentified Petrogale. These data, considered in the light of information obtained from previous studies on chromosomes, allozymes and parasites, have contributed to the decision to consider all the eastern representatives of the lateralis-penicillata group of Petrogale as being specifically distinct from each other.

Mitochondrial DNA analysis of introgression between adjacent taxa of rock-wallabies , Petrogale species ( Marsupialia : Macropodidae )

Improving the rate of production of sheep embryos using in vitro maturation and fertilization

The use of a sugarcane "test plant" as a means of detecting the presence of ratoon stunting disease in sugarcane.

The occurrence of a morbid condition of sweet orange trees on sour orange rootstocks that resulted in the loss of many previously profitable citrus trees was observed in the citrus area of Louisiana in 1950# Although sweet orange scions were present on several different rootstocks, only those on sour orange appeared to be affected* Gross symptoms and a positive reaction to the starch test, although not specific diagnostic characters, indicated that a very•t destructive disease known as "trlsteza" in Brasil or quick decline0 in California perhaps had spread to Louisiana* Budwood from Infected trees inoculated into healthy sour orange rootstocks resulted in the production of stunted trees, but no symptoms by which the disease could be posi­ tively identified were observed* The use of the bottlegrafting technique, using West Indian lime seedlings as indicator plants, resulted in the production of veinclearing, leaf-cupping and stem-pitting symptoms which proved to be specific and in exact agreement with results of other investigators of the tttrist©zaw disease* Further evidence that the disease in Louisiana was "tristeza" or "quick decline" was gathered by a study of the pathological anatomy of the diseased trees In the immediate area of the bud union* The necrotic deterioration of the phloem sieve tubes was observed and appeared to be identical with obser­ vations on the "tristeza" and "quick decline" disease Transmission of the causal agent from trees In the

Studies on the Cause and Transmission of a Louisiana Citrus Disease Similar to Tristeza.

A bioinspired synthesis of Pinoxaden metabolites 2-5 is described herein. A site-selective C-H oxidation strategy validated by density functional theory (DFT) calculations was devised for preparing metabolites 2-4. Oxidation of the benzylic C-H bond in tertiary alcohol 7 using K2S2O8 and catalytic AgNO3 formed the desired metabolite 2 that enabled access to metabolites 3 and 4 in a single step. Unlike most metal/persulfate-catalyzed transformations reported for the C-C and C-O bond formation reactions wherein the metal acts as a catalyst, we propose that Ag(I)/K2S2O8 plays the role of an initiator in the oxidation of intermediate 7 to 2. Metabolite 2 was subjected to a ruthenium tetroxide-mediated C-H oxidation to form metabolites 3 and 4 as a mixture that were purified to isolate pure standards of these metabolites. Metabolite 5 was synthesized from readily available advanced intermediate 9 via a House-Meinwald-type rearrangement in one step using a base.

Bioinspired Synthesis of Pinoxaden Metabolites Using a Site-Selective C-H Oxidation Strategy.

A plenty of azacycles is obtained by a cascade sequence of carbopalladation followed by cross-coupling/electrocyclization, or reduction processes.

Ynamide Carbopalladation: A Flexible Route to Mono‐, Bi‐ and Tricyclic Azacycles.

Bromoenynamides represent precursors to a diversity of azacycles by a cascade sequence of carbopalladation followed by cross-coupling/electrocyclization, or reduction processes. Full details of our investigations into intramolecular ynamide carbopalladation are disclosed, which include the first examples of carbopalladation/cross-coupling reactions using potassium organotrifluoroborate salts; and an understanding of factors influencing the success of these processes, including ring size, and the nature of the coupling partner. Additional mechanistic observations are reported, such as the isolation of triene intermediates for electrocyclization. A variety of hetero-Diels–Alder reactions using the product heterocycles are also described, which provide insight into Diels–Alder regioselectivity.

Ynamide Carbopalladation: A Flexible Route to Mono-, Bi- and Tricyclic Azacycles

Bromoenynamides can serve as substrates for the synthesis of a diverse range of bicyclic aminodienes using a palladium cascade cyclization.

Palladium‐Catalyzed Cascade Cyclization of Ynamides to Azabicycles.

Cascade reactions: A modular assembly of azabicycles by using a cascade cyclization/Suzuki coupling/6π-electrocyclization of bromoenynamides is reported. The reaction offers a wide substituent scope on the bicyclic aminodiene products, which can be selectively oxidized as a general approach to aromatic azabicycles.

Palladium-catalyzed cascade cyclization of ynamides to azabicycles.

LIVING RING-OPENING POLYMERIZATION OF CYCLIC ESTERS WITH PHOSPHAZENE ORGANOCATALYSTS

The intramolecular insertion of rhodium carbenoids into the alpha-C-H bonds of allylic ethers to give 3(2H)-furanones has been explored. Cyclopropanation is favored irrespective of the complex used for carbenoid generation or the substitution pattern of the allylic ether, unless a substituent is placed on the tether connecting the ether to the alpha-diazo ketone. Unusual acetal products resulting from an anomalous C-H insertion process are obtained in addition to the expected 3(2H)-furanones formed by conventional carbenoid C-H insertion. These acetals are the favored C-H insertion products in certain circumstances and particularly in cases where carbenoid generation is effected using an electron-deficient rhodium complex. Experiments with simple deuterium labeled substrates reveal that anomalous C-H insertion products arise by a mechanism that is distinct from that leading to the formation of conventional C-H insertion products. The formation of acetal products and the outcome of reactions performed using deuterium-labeled substrates suggest that a mechanism involving hydride migration to the rhodium center of the carbenoid is operative.

Anomalous intramolecular C-H insertion reactions of rhodium carbenoids: factors influencing the reaction course and mechanistic implications.

Observations on the Regio‐ and Stereoselective Trapping of Organozinc Carbenoids by Acetoxybutadienes: A Useful Route to Functionalized Vinylcyclopropanes.

Observations on the regio- and stereoselective trapping of organozinc carbenoids by acetoxybutadienes: a useful route to functionalised vinylcyclopropanes

Attempts to develop a ring-opening polymerization (ROP) approach to polymeric zirconocene complexes are reported. A new silicon-bridged [1][1]zirconocenophane, (SiMe2)2(η5-C5H3)2Zr(NEt2)2 (3a), was synthesized by reaction of Zr(NEt2)4 with (C5H4)2(SiMe2)2 (4). Single-crystal X-ray diffraction revealed a highly tilted structure with an angle of 73.1(4)°, a significant increase over the untethered compound (η5-MeC5H4)2ZrCl2 (2), which possesses a tilt angle of 54.2°. This and the related compounds (SiMe2)(η5-C5H4)2MCl2 (1a, M = Ti; 1b, M = Zr) and (SiMe2)2(η5-C5H3)2ZrCl2 (3b) were tested for transition-metal catalyzed ROP behavior in the presence of Pt(0) catalysts but were found to be inactive. The novel spirocyclic silacyclobutane-bridged monomer (CH2)3Si(η5-C5H4)2ZrCl2 (7b) was prepared via a “fly trap” amine elimination reaction between cyclotrimethylenedicyclopentadienylsilane (8) and Zr(NMe2)4; this initially yielded (CH2)3Si(η5-C5H4)2Zr(NMe2)2 (7a), which was converted to 7b by reaction with a slight...

Ring-Opening Polymerization Behavior of ansa- and Spirocyclic ansa-Zirconocene Complexes

Anomalous Products from Intramolecular Insertion Reactions of Rhodium Carbenoids into the α-C-H Bonds of Ethers.

Synthesis of Aryl‐Substituted Allylic Amines via Palladium‐Catalyzed Coupling of Aryl Iodides, Nonconjugated Dienes, and Amines.

SYNTHESIS OF ARYL-SUBSTITUTED ALLYLIC AMINES VIA PALLADIUM-CATALYZED COUPLING OF ARYL IODIDES, NONCONJUGATED DIENES, AND AMINES

The reaction of 4-methylquinoline with organolithium reagents followed by ethyl chloroformate leads to N-ethoxycarbonyl-1,2-dihydroquinolines, and not the 1,4-analogues as recently postulated.

1,2-or 1,4-Addition in the interaction of quinolines and organolithium compounds

Certain quinolines react with the anion (Ph2COLi)– derived from benzophenone and excess of lithium to give high yields of 1,2,4,5-tetrahydro-4,4-diphenyl-2,5-methano-3,1 -benzoxazepines (I). These may be smoothly converted by 70% sulphuric acid into 4-(diphenylmethyl) quinolines (VIII).

Organolithium chemistry of N-heterocycles. Part IV. Formation of 1,2,4,5-tetrahydro-4,4-diphenyl-2,5-methano-3,1-benzoxazepines from quinolines

The reactions of quinoline and 4-methylquinoline with organolithium reagents lead to the corresponding 2-sub-stituted 1,2-dihydro-1-lithioquinolines (IV), which upon hydrolysis provide the 2-substituted quinolines (V). Addition of ethyl chloroformate to the reaction mixture prior to hydrolysis gives the ethyl 1,2-dihydroquinoline-1-carboxylates (VI) and not the 1,4-dihydroquinoline analogues (III) as was recently postulated.

The question of 1,2- or 1,4-addition of organolithium compounds to quinolines

Treatment of 2-methylquinoline with lithium in tetrahydrofuran at 0° gives a dimeric product (IV). From this several reduced dimers have been obtained [(II), (III) and (V)]. The reduction of 2,6-dimethylquinoline proceeds in a similar manner.

Organolithium chemistry of N-heterocycles. Part III. Reduction of 2-methylquinoline by lithium in tetrahydrofuran

Treatment of pyridines and benzopyridines with benzophenone and lithium in ether affords a convenient route to the alcohols (I) and (with some quinolines) leads to the formation of the 4,4-diphenyl-1,2,4,5-tetrahydro-2,5-methano-3,1-benzoxazepines (II).

Reaction of phenyl-lithium and 2-methylquinoline in diethyl ether gives, to the exclusion of azomethine addition, 90% side-chain metallation. Analogous compounds containing activated 2-methyl groups react similarly, except that 2,4-lutidine produced 2,4-dimethyl-6-phenylpyridine.

Organolithium chemistry of N-heterocycles. Part I. Action of phenyllithium on 2-methylpyridines and 2-methylquinolines

Metallated pyridines and quinolines (RCH2Li) react with molecular oxygen to give ethanes (RCH2·CH2R); methanols (RCH2·OH) are also formed from the pyridines.

Organolithium chemistry of N-heterocycles. Part II. Oxidation of 2-quinolylmethyl-lithium and related compounds by molecular oxygen

Ready for Prime Time? Chief Resident Autonomy and Performance in Emergency General Surgery Using Case Evaluation Data from the System for Improving and Measuring Procedural Learning

LBA3 Expectations and acceptance of nurse practitioners regarding a health-recording digital platform. Semi-quantitative survey

Prestressed concrete panels have been used by the bridge construction industry in the state of Texas for many years to increase construction speed and improve safety and economy. At expansion joints, cast-in-place concrete is used and requires temporary formwork and slows construction. In a previous Texas Department of Transportation (TxDOT) project (0-4418), a full-scale bridge deck was constructed that included precast panels at a 0 deg skew. The results indicated that the precast panel system provided adequate strength and reduced construction costs compared with the traditional cast-in-place details at the expansion joint. In this investigation (TxDOT Project 0-5367) two areas not covered in Project 0-4418 were studied: fatigue performance of bridge decks using precast panels at the expansion joints and the use of precast panels at skewed expansion joints. Fatigue response of precast panels under loading at the expansion joint in 0 deg skew bridges was excellent. Skewed precast panels at expansion joints were tested under static and fatigue loads. Two skew angles were tested: 30 deg and 45 deg. Six specimens were constructed and subjected to a total of eleven tests. Loads were applied at midspan of the skewed end of each specimen, and some specimens were also loaded at the joint between trapezoidal (skewed) panels and an adjacent rectangular panel. The skewed panels performed well. Design recommendations for implementation of skewed panels were developed.

Recommendations for the Use of Precast Deck Panels at Expansion Joints

Executive Session It was the consensus of the City Council that the City Council meet in closed session at 5:36 p.m. to:

There has been a great deal of concern by county engineers and supervisors over constrained budgets, lack of resources and a deteriorating infrastructure, as they affect the secondary road system in Iowa. In addition, public input and/or political pressure have been increasing over the years. This study was initiated to determine the most important issues facing counties and document the way in which various Iowa counties have been addressing those issues. The list of issues was developed through meetings of county engineers and supervisors in each of the Iowa Department of Transportation (DOT) regions around the state. Questionnaires were sent to all engineers and supervisors statewide asking them how the various issues (e.g. snow and ice removal policies, Level "B" roads, and so on) were handled in their respective counties. The responses were then compiled into this document. The subjects selected and used include: county policies, ordinances, resolutions; snow and ice removal policy; dust control; Level "B" roads; vacating roads; rural development; private entrance construction and maintenance; roadside management practices; right of way encroachments and easements; personnel matters, staff and organization; communicating information to citizens; supervisor/ engineer relations; and county leasing/purchasing practices.

Summary. A workshop to introduce medical teachers to the use of microcomputers is described. Details are given of the programs demonstrated, which include interactive programs to interview patients, clinical management simulations, educational games and diagnostic simulations and aids. The plenary discussion is reported as an explanation of computer terms and advice for setting up microcomputers as teaching aids.

During the past five years, Pinellas County, Florida, home to Clearwater and St Petersburg beaches, located in the Tampa Bay region, has operated and maintained two U.S. Department of Transportation (USDOT) funded and supported adaptive signal systems. Throughout this period, Pinellas County and the Florida Department of Transportation (FDOT) performed before/after studies, established the costs versus benefit ratios, and ultimately summarized the lessons learned from the first stages of the Real-time Traffic Adaptive Signal Control System (RT-TRACS) deployment. These reports and findings helped determine ways that the adaptive systems could be improved. In the past few years, many changes have been made to not only save money for deployment, but to improve the adaptive algorithms and overall efficiency in the operation and maintenance of the systems. This paper will delve into those improvements and compare the new deployment costs against today’s similar adaptive signal systems.

Long before Hurricane Katrina and the active hurricane seasons of 2004 and 2005, there was Hurricane Andrew. In 1992, Category 5 Hurricane Andrew devastated the south Florida region, packing 165 mph winds and causing $30 billion in damage. With that hurricane, many state and local agencies were enlightened on what a major hurricane could do to local inhabitants and the surrounding infrastructure. This single hurricane rewrote building design standards and redefined emergency response plans. State and local officials began reviewing their current facilities and were surprised to find out that most buildings could not even withstand a Category 3 hurricane impact. Many first responders’ warehouses and facilities may not even withstand a strong Category 1. With that review, Pinellas County embarked on a program to hardening facilities in the mid 90’s and came to a realization there was a dramatic need to establish an emergency responder’s facility that could house workers and equipment throughout the strongest of hurricanes, and be able to be the first out the door to start the cleanup effort. This paper will summarize the characteristics and abilities of the new Pinellas County Emergency Responders Building and traffic control center.

Pinellas County Public Works Emergency Responders Building and Traffic Control Center

Pinellas County, Florida, home to Clearwater and St Petersburg beaches, located in the Tampa Bay region, continues to battle congestion on its signalized arterial transportation system by exploring non-intrusive and cost effective solutions. A joint-agency Countywide ITS committee was formed to decide on technologies that would increase capacity along these arterial corridors. The committee chose to implement two FHWA-supported RTTRACS adaptive signal packages, RHODES, researched and distributed by ATLAS Research Center, University of Arizona, and Telvent-Farradyne’s OPAC. This discussion will focus on the deployment, operation and maintenance of deploying these systems, along with an overview of lessons learned on their deployment thus far.

RT-TRACS Adaptive Signal Operations, Maintenance and Lessons Learned

From Los AngelestoKiev:Paperson the Occasion of the Ninth International Congress of Slavists,Kiev,September, 1983. Edited by Vladimir Markov and Dean Worth. Columbus, OH: Slavica Publishers, Inc., 1983. 250 pp. $17.95.

From the Fair Labor Standards Act to Individual State Minimum Wages: Measuring State Minimum Wages and Economic Performance

Comfort with varying levels of human supervision in self-driving cars: determining factors in Europe

This study examined the role of the “animated eBook advantage” in child bilingual’s Mandarin learning, which has tended to be examined in the acquisition of Germanic languages. With this aim, 102 4- to 5-year-old preschoolers in Singapore were assigned to one of four conditions: (a) animated eBooks (+sound+motion), (b) static eBooks with sound, (c) static eBooks only, and (d) a control condition where children played a math game on an iPad. Three stories were displayed to children each for four times over 2 weeks, while visual attention was traced with an eye tracker. Children’s target words and story comprehension were assessed for the effects of the intervention conditions. The results revealed that children in the animated condition outperform their counterparts in total fixation duration, target word production, and storytelling of one of the stories (Cycling With Grandpa). There were no consistent differences between the two static conditions. Our results indicate the importance of motion in animated eBook design, in line with previous findings.

Motion and Sound in Animated Storybooks for Preschoolers’ Visual Attention and Mandarin Language Learning: An Eye-Tracking Study With Bilingual Children

Ballet de la Ópera Municipal de Marsella ; Ballet-Theatre Contemporain ; Ballet Nacional de Cuba

Sinfonía en do ; El mandarín maravilloso ; Giselle ; El príncipe Igor

La Llama de París ; Melodía ; La Ninfa ; El cazador y el pájaro ; Los muñecos ; El Corsario ; Giselle ; La Muerte del cisne ; Don Quijote ; La fuente de Bakhtchiserail

Festival del Ballet Europeo con la participación de las importantes compañías Antonio Ballet Español y Ballet Nacional Holandés con eminentes artistas invitados

Sadler's Wells Theatre Ballet actualmente Royal Ballet, bajo la direccion artistica de Dame Ninette de Valois

Representaciones extraordinarias de ballets por el Cuerpo de Baile del Teatro Nacional de la Ópera de París

DISPOSITIF ET PROCÉDÉS DE PARTAGE DE CHARGE D'IMPLANT MYOCARDIQUE POUR FAVORISER UNE FONCTION LV

L'invention porte sur des dispositifs, des procedes et des kits destines a evaluer et/ou a ameliorer l'accessibilite d'un espace sous-valvulaire cardiaque, a acceder a l'espace sous-valvulaire cardiaque (par exemple, pour fournir un acces a un ou plusieurs autres dispositifs) et/ou positionner un ou plusieurs dispositifs dans l'espace sous-valvulaire cardiaque. Les dispositifs decrits dans la description peuvent par exemple inclure des catheters pouvant etre utilises pour manipuler un ou plusieurs cordages tendineux, des catheters de diagnostic presentant differentes dimensions et/ou formes (par exemple, differentes courbures), des catheters de guidage presentant differentes dimensions et/ou formes (par exemple, differentes courbures) et des catheters de visualisation. Dans certaines variantes, les dispositifs, procedes et/ou kits peuvent etre utilises pour visualiser un site cible, tel qu'une rainure sous-annulaire d'une valvule cardiaque. Dans certaines variantes, les dispositifs, procedes et/ou kits peuvent etre utilises pour manipuler des cordages tendineux afin d'obtenir un espace supplementaire dans un ventricule cardiaque (par exemple, pour ameliorer l'accessibilite audit ventricule).

Cathéters de diagnostic, cathéters de guidage, dispositifs de visualisation et dispositifs de manipulation de cordages, kits et procédés apparentés

L'invention concerne un dispositif medical de ligature et de coupe endoscopique d'un vaisseau du corps. Le dispositif peut etre insere par voie percutanee dans un patient afin d'executer plusieurs actes possibles. Les ameliorations apportees au dispositif comprennent une mâchoire articulee capable de saisir et de sertir des vaisseaux du corps. Un systeme ameliore d'apport de clip et un clip ameliore ligaturant les vaisseaux du corps sont egalement decrits. L'instrument comprend un element coupant rotatif constituant un moyen de coupe de vaisseaux corporels plus efficace. De plus, tout le systeme permet un mode de fonctionnement simplifie et plus efficace.

Systeme et methode utiles pour la ligature et la coupe de tissus

Folk Song in the Wind Band Music of Haydn Wood: Mannin Veen and a New Performing Edition of the Seafarer

This study was carried out to assess the effects of LGAs in promoting citizen involvement in decision making process in Ilala municipality. The objective of the study was to find out if there is citizen involvement in local government authorities. The study used a case study research design with a sample of 175 respondents selected through convenience and purposive sampling techniques. Data were collected by using questionnaires and interviews. They were analyzed by using SPSS Version 21 and Microsoft Word for text processing. Findings revealed there was a policy or regulation which advocated citizen involvement but few employees and public servants were not aware of the policy. The public was involved in LGA meeting and activities more than three times. The way of involving the public was not constant. The public was involved satisfactorily in different activities other than financial. The study recommended that new employees be made aware of the policy/Transparency in financial transactions, that public servants are held, communication be improved, corruption be fought and that further studies be conducted.

Citizen Involvement in Decision Making Process in Ilala Municipality, Dar es Salaam – Tanzania

The purpose of the study was to establish the effect of job satisfaction on organizational citizenship behavior. Cross sectional survey design was employed with a sample of 436 employees from three multinational telecommunication corporations. Simple random sampling was employed to select the respondents. Regression analysis was used to establish the effect of job satisfaction on organizational citizenship behavior. Findings indicate significant relationship between job satisfaction and organizational citizenship behavior. We therefore conclude that when employees are satisfied with their jobs they get committed to develop citizenship behavior in organizations.

Job Satisfaction and Organizational Citizenship Behavior (OCB) in Multinational Telecommunication in Uganda

This study set out to establish whether cultural norms and beliefs affect the use of e-commerce among traders in Kampala. A sample of 84 businesses was used in the study. Businesses were clustered and simple random sampling was employed. Cross-sectional survey design was adopted. The findings indicated a positive significant correlation between cultural norms, beliefs and e-commerce use among traders in Kampala.  This led to a conclusion that cultural norms, beliefs and influence e-commerce adoption and use among traders in Kampala. This implies that both cultural norms and beliefs have a direct bearing on adoption of electronic commerce. It is therefore recommended that to promote the use of e-commerce, business people should change their norms and beliefs positively towards use of the internet to enhance their businesses.

Cultural norms, beliefs and use of e-commerce among traders in Kampala, Uganda

Decentralization by devolution (D by D) is a driving force for service delivery, so if all elements of D by D complement each other the delivery of water service can be realized. This study examined decentralization by devolution in Tanzania: Reflections on water service delivery in selected wards of Ilala municipality. The objective of the study was to examine the influence of D by D on water service delivery. The focus of the study was the variations between urban and peri-urban areas of Ilala Municipality. Existence of few empirical studies on the impact of D by D on water service delivery is the motivation for this study. The study adopted a descriptive comparative cross-sectional survey design that involved the use of questionnaires and interviews in collecting data from a sample of 384 respondents selected from a population of 64,579. The study also involved 9 key informants purposively selected from among the household and 5 purposively selected from local government officials and 3 purposively selected from central government officials so that to provide qualitative data to supplement the quantitative data obtained from questionnaires. Data was analyzed using frequencies, means, and standard deviation. The study revealed that the one aspect of D by D (fiscal aspect) has no influence on water service delivery and also coefficients revealed that by comparison, out of the three elements of decentralization by devolution, political decentralization explains a higher variance in water service delivery, followed by administrative decentralization. The study recommends that since D by D among other things aims at bringing services closer to the people, local officials should involve citizens in deciding matters affecting their livelihoods including planning and setting their priorities especially in water service delivery and there is need for water policy to state clearly how D by D works especially on water service delivery.

Decentralization by Devolution in Tanzania: Reflections on Water Service Delivery in the Selected Wards of Ilala Municipality, Dar es Salaam

Documentació sobre les funcions extraordinàries en benefici dels empleats permanents, porters i acomodadors del G.T. del Liceu celebrades el 1957

Measuring Investments in Active Transportation When Accomplished as Part of Other Projects

In recent years, newly developed methods to train spiking neural networks (SNNs) have rendered them as a plausible alternative to Artificial Neural Networks (ANNs) in terms of accuracy, while at the same time being much more energy efficient at inference and potentially at training time. However, it is still unclear what constitutes a good initialisation for an SNN. We often use initialisation schemes developed for ANN training which are often inadequate and require manual tuning. In this paper, we attempt to tackle this issue by using techniques from the ANN initialisation literature as well as computational neuroscience results. We show that the problem of weight initialisation for ANNs is a more nuanced problem than it is for ANNs due to the spike-and-reset non-linearity of SNNs and the firing rate collapse problem. We firstly identify and propose several solutions to the firing rate collapse problem under different sets of assumptions which successfully solve the issue by leveraging classical random walk and Wiener processes results. Secondly, we devise a general strategy for SNN initialisation which combines variance propagation techniques from ANNs and different methods to obtain the expected firing rate and membrane potential distribution based on diffusion and shot-noise approximations. Altogether, we obtain theoretical results to solve the SNN initialisation which consider the membrane potential distribution in the presence of a threshold. Yet, to what extent can these methods be successfully applied to SNNs on real datasets remains an open question.

Binaural rendering of Ambisonics signals is a common way to reproduce spatial audio content. Processing Ambisonics signals at low spatial orders is desirable in order to reduce complexity, although it may degrade the perceived quality, in part due to the mismatch that occurs when a low-order Ambisonics signal is paired with a spatially dense head-related transfer function (HRTF). In order to alleviate this issue, the HRTF may be preprocessed so its spatial order is reduced. Several preprocessing methods have been proposed, but they have not been thoroughly compared yet. In this study, nine HRTF preprocessing methods were used to render anechoic binaural signals from Ambisonics representations of orders 1 to 44, and these were compared through perceptual hearing models in terms of localisation performance, externalisation and speech reception. This assessment was supported by numerical analyses of HRTF interpolation errors, interaural differences, perceptually-relevant spectral differences, and loudness stability. Models predicted that the binaural renderings’ accuracy increased with spatial order, as expected. A notable effect of the preprocessing method was observed: whereas all methods performed similarly at the highest spatial orders, some were considerably better at lower orders. A newly proposed method, BiMagLS, displayed the best performance overall and is recommended for the rendering of bilateral Ambisonics signals. The results, which were in line with previous literature, indirectly validate the perceptual models’ ability to predict listeners’ responses in a consistent and explicable manner.

Assessing HRTF preprocessing methods for Ambisonics rendering through perceptual models

Rate and Temporal Coding of Regular and Irregular Pulse Trains in Auditory Midbrain of Normal-Hearing and Cochlear-Implanted Rabbits

Modularity of neural networks – both biological and artificial – can be thought of either structurally or functionally, and the relationship between these is an open question. We show that enforcing structural modularity via sparse connectivity between two dense sub-networks which need to communicate to solve the task leads to functional specialization of the sub-networks, but only at extreme levels of sparsity. With even a moderate number of interconnections, the sub-networks become functionally entangled. Defining functional specialization is in itself a challenging problem without a universally agreed solution. To address this, we designed three different measures of specialization (based on weight masks, retraining and correlation) and found them to qualitatively agree. Our results have implications in both neuroscience and machine learning. For neuroscience, it shows that we cannot conclude that there is functional modularity simply by observing moderate levels of structural modularity: knowing the brain’s connectome is not sufficient for understanding how it breaks down into functional modules. For machine learning, using structure to promote functional modularity – which may be important for robustness and generalization – may require extremely narrow bottlenecks between modules.

Visualizing a joint future of neuroscience and neuromorphic engineering

There is an increasing interest in emulating Spiking Neural Networks (SNNs) on neuromorphic computing devices due to their low energy consumption. Recent advances have allowed training SNNs to a point where they start to compete with traditional Artificial Neural Networks (ANNs) in terms of accuracy, while at the same time being energy efficient when run on neuromorphic hardware. However, the process of training SNNs is still based on dense tensor operations originally developed for ANNs which do not leverage the spatiotemporally sparse nature of SNNs. We present here the first sparse SNN backpropagation algorithm which achieves the same or better accuracy as current state of the art methods while being significantly faster and more memory efficient. We show the effectiveness of our method on real datasets of varying complexity (Fashion-MNIST, Neuromophic-MNIST and Spiking Heidelberg Digits) achieving a speedup in the backward pass of up to 150 x, and 85% more memory efficient, without losing accuracy.

Deep neural networks have had considerable success in neuroscience as models of the visual system, and recent work has suggested this may also extend to the auditory system. We tested the behaviour of a range of state of the art deep learning-based automatic speech recognition systems on a wide collection of manipulated sounds used in standard human psychometric experiments. While some systems showed qualitative agreement with humans in certain tests, in others all tested systems diverged markedly from humans. In particular, all systems used spectral invariance, temporal fine structure and speech periodicity differently from humans. We conclude that despite some promising results, none of the tested automatic speech recognition systems can yet act as a strong proxy for human speech recognition. However, we note that the more recent systems with better performance also tend to better match human results, suggesting that continued cross-fertilisation of ideas between human and automatic speech recognition may be fruitful. Our open source toolbox allows researchers to assess future automatic speech recognition systems or add additional psychoacoustic measures.

Brian2GeNN: accelerating spiking neural network simulations with graphics hardware

An accurate auditory space map can be learned from auditory experience, for example during development or in response to altered auditory cues such as a modified pinna. We studied neural network models that learn to localise a single sound source in the horizontal plane using binaural cues based on limited supervisions. These supervisions can be unreliable or sparse in real life. First, a simple model that has unreliable estimation of the sound source location is built, in order to simulate the unreliable auditory orienting response of newborns. It is used as a Teacher that acts as a source of unreliable supervisions. Then we show that it is possible to learn a continuous auditory space map based only on noisy left or right feedbacks from the Teacher. Furthermore, reinforcement rewards from the environment are used as a source of sparse supervision. By combining the unreliable innate response and the sparse reinforcement rewards, an accurate auditory space map, which is hard to be achieved by either one of these two kind of supervisions, can eventually be learned. Our results show that the auditory space mapping can be calibrated even without explicit supervision. Moreover, this study implies a possibly more general neural mechanism where multiple sub-modules can be coordinated to facilitate each other's learning process under limited supervisions.

Learning Absolute Sound Source Localisation With Limited Supervisions

Sound localization in reverberant environments is a difficult task that human listeners perform effortlessly. Many neural mechanisms have been proposed to account for this behavior. Generally they rely on emphasizing localization information at the onset of the incoming sound while discarding localization cues that arrive later. We modelled several of these mechanisms using neural circuits commonly found in the brain and tested their performance in the context of experiments showing that, in the dominant frequency region for sound localisation, we have a preference for auditory cues arriving during the rising slope of the sound energy (Dietz et al., 2013). We found that both single cell mechanisms (onset and adaptation) and population mechanisms (lateral inhibition) were easily able to reproduce the results across a very wide range of parameter settings. This suggests that sound localization in reverberant environments may not require specialised mechanisms specific to perform that task, but could instead rely on common neural circuits in the brain. This would allow for the possibility of individual differences in learnt strategies or neuronal parameters. This research is fully reproducible, and we made our code available to edit and run online via interactive live notebooks.

General neural mechanisms can account for rising slope preference in localization of ambiguous sounds

Sound localization in reverberant environments is a difficult task that human listeners perform effortlessly. Many neural mechanisms have been proposed to account for this behavior. Generally they rely on emphasizing localization information at the onset of the incoming sound while discarding localization cues that arrive later. We modelled several of these mechanisms using neural circuits commonly found in the brain and tested their performance in the context of experiments showing that, in the dominant frequency region for sound localisation, we have a preference for auditory cues arriving during the rising slope of the sound energy (Dietz et al. 2013). We found that both single cell mechanisms (onset and adaptation) and population mechanisms (lateral inhibition) were easily able to reproduce the results across a very wide range of parameter settings. This suggests that sound localization in reverberant environments may not require specialised mechanisms specific to that task, but may instead rely on common neural circuits in the brain. This is in line with the theory that the brain consists of functionally overlapping general purpose mechanisms rather than a collection of mechanisms each highly specialised to specific tasks. This research is fully reproducible, and we made our code available to edit and run online via interactive live notebooks.

Canonical brain computations account for perceived sound source location

Author response: Brian 2, an intuitive and efficient neural simulator

Brian 2 allows scientists to simply and efficiently simulate spiking neural network models. These models can feature novel dynamical equations, their interactions with the environment, and experimental protocols. To preserve high performance when defining new models, most simulators offer two options: low-level programming or description languages. The first option requires expertise, is prone to errors, and is problematic for reproducibility. The second option cannot describe all aspects of a computational experiment, such as the potentially complex logic of a stimulation protocol. Brian addresses these issues using runtime code generation. Scientists write code with simple and concise high-level descriptions, and Brian transforms them into efficient low-level code that can run interleaved with their code. We illustrate this with several challenging examples: a plastic model of the pyloric network, a closed-loop sensorimotor model, a programmatic exploration of a neuron model, and an auditory model with real-time input.

Decision letter: State-dependent geometry of population activity in rat auditory cortex

Short-term effects of sound localization training in virtual reality

The Effect of Auditory Anchors on Sound Localization: A Preliminary Study

Our understanding of hearing and speech recognition rests on controlled experiments requiring simple stimuli. However, these stimuli often lack the characteristics of complex sounds such as speech. We propose an approach that combines neural modelling with machine learning to determine relevant low-level auditory features. Our approach bridges the gap between detailed neuronal models that capture specific auditory responses, and research on the statistics of real-world speech data and speech recognition. First, we introduce a feature detection model with a modest number of parameters that is compatible with auditory physiology. In order to objectively determine relevant feature detectors within the model parameter space, the model is tested in a speech classification task, using a simple classifier that approximates the information bottleneck. This framework allows us to determine the best model parameters and their neurophysiological and psychoacoustic implications. We show that our model can capture a variety of well-studied features (such as amplitude modulations and onsets) and allows us to unify concepts from different areas of hearing research. Our approach has various potential applications. Firstly, it could lead to new, testable experimental hypotheses for understanding hearing. Moreover, promising features could be directly applied as a new acoustic front-end for speech recognition systems.

A Unifying Framework for Neuro-Inspired, Data-Driven Detection of Low-Level Auditory Features

It is very common in studies of the learning capabilities of spiking neural networks (SNNs) to use homogeneous neural and synaptic parameters (time constants, thresholds, etc.). Even in studies in which these parameters are distributed heterogeneously, the advantages or disadvantages of the heterogeneity have rarely been studied in depth. By contrast, in the brain, neurons and synapses are highly diverse, leading naturally to the hypothesis that this heterogeneity may be advantageous for learning. Starting from two state-of-the-art methods for training spiking neural networks (Nicola & Clopath, 2017; Shrestha & Orchard, 2018), we found that adding parameter heterogeneity reduced errors when the network had to learn more complex patterns, increased robustness to hyperparameter mistuning, and reduced the number of training iterations required. We propose that neural heterogeneity may be an important principle for brains to learn robustly in real world environments with highly complex structure, and where task-specific hyperparameter tuning may be impossible. Consequently, heterogeneity may also be a good candidate design principle for artificial neural networks, to reduce the need for expensive hyperparameter tuning as well as for reducing training time.

Advantages of heterogeneity of parameters in spiking neural network training

We introduce neural topic modelling an unsupervised, scalable and interpretable neural data analysis tool which can be applied across different spatial and temporal scales. The aim is an approach that can handle the everincreasing number of neurons recorded by high channel count multi-electrode arrays. Neural topic modelling is based on latent Dirichlet allocation, a method routinely used in text mining to find latent topics in texts. The spike trains are converted into “neural words” the presence or absence of discrete events (e.g. neuron 1 has a higher firing rate than usual). Neural topic modelling results in a number of topics (probability distributions over words) which best explain the given co-occurrences of neural words over time. Applied to an electrophysiological dataset of mouse visual cortex, hippocampus and thalamus neurons, neural topic modelling groups neural words into topics which exhibit common attributes such as overlapping receptive fields or proximity on the recording electrode. It recovers these relationships despite receiving no knowledge about the cortex topography or about the spatial structure of the stimuli. Choosing neural activity patterns as neural words that are relevant to the brain makes the topics interpretable by both the brain and researchers, setting neural topic modelling apart from other machine learning approaches.

To be maximally useful for neuroscience research, neural simulators must make it possible to define original models. This is especially important because a computational experiment might not only need descriptions of neurons and synapses, but also models of interactions with the environment (e.g. muscles), or the environment itself. To preserve high performance when defining new models, current simulators offer two options: low-level programming, or mark-up languages (and other domain specific languages). The first option requires time and expertise, is prone to errors, and contributes to problems with reproducibility and replicability. The second option has limited scope, since it can only describe the range of neural models covered by the ontology. Other aspects of a computational experiment, such as the stimulation protocol, cannot be expressed within this framework. “Brian” 2 is a complete rewrite of Brian that addresses this issue by using runtime code generation with a procedural equation-oriented approach. Brian 2 enables scientists to write code that is particularly simple and concise, closely matching the way they conceptualise their models, while the technique of runtime code generation automatically transforms high level descriptions of models into efficient low level code tailored to different hardware (e.g. CPU or GPU). We illustrate it with several challenging examples: a plastic model of the pyloric network of crustaceans, a closed-loop sensorimotor model, programmatic exploration of a neuron model, and an auditory model with real-time input from a microphone.

”Listen to the cello in this symphony!” How can we direct selective attention according to different goals, even in distracting environments which we haven’t experienced before? It is an essential cognitive ability of the brain, but remains challenging for machines. We developed a computational model that can identify individual digits in images containing multiple overlapping digits, without ever having seen overlapping digits during training. The goal-driven attentional selection is modelled as inferring the posterior distribution of latent variables (the attended target) in a generative model, conditioned on both sensory input and different semantic goals. A neural network model has been build to efficiently carry out the the inference process by predicting the most likely results, instead of using classic per-sample based iterative optimization methods which may not naturally map onto neural structures. Our model also help to understand how top-down and bottom-up attention are combined during perception in the brain.

An Inference Network Model for Goal-directed Attentional Selection

“Brian” is a popular Python-based simulator for spiking neural networks, commonly used in computational neuroscience. GeNN is a C++-based meta-compiler for accelerating spiking neural network simulations using consumer or high performance grade graphics processing units (GPUs). Here we introduce a new software package, Brian2GeNN, that connects the two systems so that users can make use of GeNN GPU acceleration when developing their models in Brian, without requiring any technical knowledge about GPUs, C++ or GeNN. The new Brian2GeNN software uses a pipeline of code generation to translate Brian scripts into C++ code that can be used as input to GeNN, and subsequently can be run on suitable NVIDIA GPU accelerators. From the user’s perspective, the entire pipeline is invoked by adding two simple lines to their Brian scripts. We have shown that using Brian2GeNN, typical models can run tens to hundreds of times faster than on CPU.

Brian2GeNN: a system for accelerating a large variety of spiking neural networks with graphics hardware

A VR-Based Mobile Platform for Training to Non-Individualized Binaural 3D Audio

Advances in experimental techniques and computational power allowing researchers to gather anatomical and electrophysiological data at unprecedented levels of detail have fostered the development of increasingly complex models in computational neuroscience. Large-scale, biophysically detailed cell models pose a particular set of computational challenges, and this has led to the development of a number of domain-specific simulators. At the other level of detail, the ever growing variety of point neuron models increases the implementation barrier even for those based on the relatively simple integrate-and-fire neuron model. Independently of the model complexity, all modeling methods crucially depend on an efficient and accurate transformation of mathematical model descriptions into efficiently executable code. Neuroscientists usually publish model descriptions in terms of the mathematical equations underlying them. However, actually simulating them requires they be translated into code. This can cause problems because errors may be introduced if this process is carried out by hand, and code written by neuroscientists may not be very computationally efficient. Furthermore, the translated code might be generated for different hardware platforms, operating system variants or even written in different languages and thus cannot easily be combined or even compared. Two main approaches to addressing this issues have been followed. The first is to limit users to a fixed set of optimized models, which limits flexibility. The second is to allow model definitions in a high level interpreted language, although this may limit performance. Recently, a third approach has become increasingly popular: using code generation to automatically translate high level descriptions into efficient low level code to combine the best of previous approaches. This approach also greatly enriches efforts to standardize simulator-independent model description languages. In the past few years, a number of code generation pipelines have been developed in the computational neuroscience community, which differ considerably in aim, scope and functionality. This article provides an overview of existing pipelines currently used within the community and contrasts their capabilities and the technologies and concepts behind them.

Code Generation in Computational Neuroscience: A Review of Tools and Techniques

Bach et al. [1] recently presented an algorithm for constructing confluent drawings, by leveraging power graph decomposition to generate an auxiliary routing graph. We identify two issues with their method which we call the node split and short-circuit problems, and solve both by modifying the routing graph to retain the hierarchical structure of power groups. We also classify the exact type of confluent drawings that the algorithm can produce as ‘power-confluent’, and prove that it is a subclass of the previously studied ‘strict confluent’ drawing. A description and source code of our implementation is also provided, which additionally includes an improved method for power graph construction.

Further Towards Unambiguous Edge Bundling: Investigating Power-Confluent Drawings for Network Visualization

Bach et al. [1] recently presented an algorithm for constructing general confluent drawings, by leveraging power graph decomposition to generate an auxiliary routing graph. We show that the resulting drawings are not strictly guaranteed to be confluent due to potential corner cases that do not satisfy the original definition. We then reframe their work within the context of previous literature on using auxiliary graphs for bundling, which will help to guide future research in this area.

Comments on "Towards Unambiguous Edge Bundling: Investigating Confluent Drawings for Network Visualization"

Modelling firing regularity in the ventral cochlear nucleus: Mechanisms, and effects of stimulus level and synaptopathy

Headphone-based virtual audio systems typically use non-individualized head-related transfer functions (HRTFs) to create the illusion of spatialized sound. Listeners are therefore provided with unfamiliar spatial cues leading to poor sound localization. In this study, a smartphone-based system was developed to investigate the effects of short-term training on virtual sound localization accuracy. Participants underwent multiple training sessions in which visual positional feedback was provided in a virtual environment, interleaved with localization accuracy evaluation sessions. Different versions of the training software were developed to investigate the effects of introducing game-design elements ("gamification") and relative sound source motion using head tracking ("active listening") on improvements in localization accuracy. The results demonstrate that adaptation to a non-individualized HRTF can be facilitated using a small number of short (12 minute) training sessions, and is retained across multiple days. This adaptation is not HRTF-specific, as the learning effect generalizes to a second HRTF not used in the training, regardless of the training paradigm used. The introduction of game-design elements and the use of active listening had no significant effect on the efficacy of localization training.

Effects of gamification and active listening on short-term sound localization training in virtual reality

There are a number of detailed models of auditory neurons that are able to reproduce a wide range of phenomena. However, using these models to test hypotheses can be challenging, as they have many parameters and complex interacting subsystems. This makes it difficult to investigate the function of a mechanism by varying just one parameter in isolation, or to assess the robustness of a model by systematically varying many parameters. In some cases, by limiting the scope of a model to testing a specific hypothesis using a particular set of stimuli, it is possible to create a reduced mathematical model with relatively few, independent parameters. This has considerable advantages with respect to the problems above. In particular, if a certain behavior is robust and does not depend on finely tuned parameters, then different implementations are more likely to produce the same results—a key property for reproducible research. In addition, the code for these models is typically simpler and therefore more readable...

On the use of hypothesis-driven reduced models in auditory neuroscience

26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3

Despite compelling evidence that glial cells could crucially regulate neural network activity, the vast majority of available neural simulators ignores the possible contribution of glia to neuronal physiology. Here, we show how to model glial physiology and neuron-glia interactions in the Brian 2 simulator. Brian 2 offers facilities to explicitly describe any model in mathematical terms with limited and simple simulator-specific syntax, automatically generating high-performance code from the user-provided descriptions. The flexibility of this approach allows us to model not only networks of neurons, but also individual glial cells, electrical coupling of glial cells, and the interaction between glial cells and synapses. We therefore conclude that Brian 2 provides an ideal platform to efficiently simulate glial physiology, and specifically, the influence of astrocytes on neural activity.

A popular method of force-directed graph drawing is multidimensional scaling using graph-theoretic distances as input. We present an algorithm to minimize its energy function, known as stress, by using a relaxation method that considers a single pair of vertices at a time. Our results show that relaxation can reach lower stress levels faster and more consistently than majorization, without needing help from a good initialization. We then present various real-world applications to show how the unique properties of relaxation make it easier to produce constrained layouts than previous approaches. We also show how relaxation can be directly applied within the sparse stress approximation of Ortmann et al. [1], making the algorithm scalable up to large graphs.

The auditory system processes temporal information at multiple scales, and disruptions to this temporal processing may lead to deficits in auditory tasks such as detecting and discriminating sounds in a noisy environment. Here, a modelling approach is used to study the temporal regularity of firing by chopper cells in the ventral cochlear nucleus, in both the normal and impaired auditory system. Chopper cells, which have a strikingly regular firing response, divide into two classes, sustained and transient, based on the time course of this regularity. Several hypotheses have been proposed to explain the behaviour of chopper cells, and the difference between sustained and transient cells in particular. However, there is no conclusive evidence so far. Here, a reduced mathematical model is developed and used to compare and test a wide range of hypotheses with a limited number of parameters. In line with recent work suggesting that there is no clear classification into discrete classes, simulations results show a continuum of cell types and behaviours: chopper-like behaviour arises for a wide range of parameters, suggesting that multiple mechanisms may underlie this behaviour. Finally, the model is used to predict the effects of a reduction in the number of auditory nerve fibres (deafferentation due to, for example, cochlear synaptopathy). We have made an online interactive version of this paper in which all the model parameters can be changed.

Changes In Firing Regularity In The Normal And Impaired Auditory System

The computation of binaural cues such as the Interaural Time Difference (ITD) and Interaural Level Difference (ILD) by the auditory system is known to play an important role in spatial hearing. It is not yet understood how such computations are performed in realistic acoustic environments where noise and reverberations are present. It has been hypothesized that robust sound localization is achieved through the extraction of the ITD information in the rising part of amplitude modulated (AM) sounds. Dietz et al. (2013) tested this hypothesis using psychoacoustics and MEG experiments. They presented AM sounds with ITDs varying during the course of one AM cycle. Their results showed that participants preferentially extracted the ITD information in the rising portion of the AM cycle. We designed a computational model of the auditory pathway to investigate the neural mechanisms involved in this process. Two mechanisms were tested. The first one corresponds to the adaptation in the auditory nerve fibers. The sec...

The roles of inhibition and adaptation for spatial hearing in difficult listening conditions

A framework aimed at improving the testability and comparability of binaural models will be presented. The framework consists of two key elements: (1) a repository of testing software that evaluates the models against published data and (2) a model repository. While the framework is also intended for physiological data, the planned initial contribution will be psychoacoustical data together with their psychoacoustical testing protocols, as well as existing binaural models from available auditory toolboxes. Researchers will be invited to provide their established as well as newly developed models in whatever programming language they prefer, given the models are compatibility with the proposed interface to the testing software. This entails that the models act as artificial observers, testable with exactly the same procedure as the human subjects. A simple communication protocol based on wav and txt-files is proposed because these are supported by every programming environment, and are able connect models ...

An initiative for testability and comparability of binaural models

A popular method of force-directed graph drawing is multidimensional scaling using graph-theoretic distances as input. We present an algorithm to minimize its energy function, known as stress, by using stochastic gradient descent (SGD) to move a single pair of vertices at a time. Our results show that SGD can reach lower stress levels faster and more consistently than majorization, without needing help from a good initialization. We then show how the unique properties of SGD make it easier to produce constrained layouts than previous approaches. We also show how SGD can be directly applied within the sparse stress approximation of Ortmann et al. [1], making the algorithm scalable up to large graphs.

Many computational models of the auditory system exist, most of which can predict a variety of psychoacoustical, physiological, or other experimental data. However, it is often challenging to apply existing third party models to own experimental paradigms, even if the model code is available. It will be demonstrated that model applicability is increased by providing a framework where the model acts as artificial observer performing exactly the same task as the subject (e.g., adaptive staircase procedure). A possible separation of the actual auditory processing of the model from the decision making stage will be discussed, which allows for testing the auditory processing of one model in a variety of experimental paradigms. The framework will consist of a citable data repository providing the required data for the models as well as toolboxes implementing both the auditory models and a variety of experimental paradigms. The model framework will be demonstrated with exemplary binaural models applied to the th...

Developments in microfabrication technology have enabled the production of neural electrode arrays with hundreds of closely spaced recording sites, and electrodes with thousands of sites are under development. These probes in principle allow the simultaneous recording of very large numbers of neurons. However, use of this technology requires the development of techniques for decoding the spike times of the recorded neurons from the raw data captured from the probes. Here we present a set of tools to solve this problem, implemented in a suite of practical, user-friendly, open-source software. We validate these methods on data from the cortex, hippocampus and thalamus of rat, mouse, macaque and marmoset, demonstrating error rates as low as 5%.

Neuron Classes Within Layer 4 of Rat Barrel Cortex Angular Tuning and Velocity Sensitivity in Different

superior olive and synaptic inputs to mature neurons of the medial Functional localization of neurotransmitter receptors

Downstream changes in firing regularity following damage to the early auditory system

SpineML and Brian 2.0 interfaces for using GPU enhanced Neuronal Networks (GeNN)

Brian 2: neural simulations on a variety of computational hardware

Author response: Decoding neural responses to temporal cues for sound localization

Brian 2 - the second coming: spiking neural network simulation in Python with code generation

The activity of sensory neural populations carries information about the environment. This may be extracted from neural activity using different strategies. In the auditory brainstem, a recent theory proposes that sound location in the horizontal plane is decoded from the relative summed activity of two populations in each hemisphere, whereas earlier theories hypothesized that the location was decoded from the identity of the most active cells. We tested the performance of various decoders of neural responses in increasingly complex acoustical situations, including spectrum variations, noise, and sound diffraction. We demonstrate that there is insufficient information in the pooled activity of each hemisphere to estimate sound direction in a reliable way consistent with behavior, whereas robust estimates can be obtained from neural activity by taking into account the heterogeneous tuning of cells. These estimates can still be obtained when only contralateral neural responses are used, consistently with unilateral lesion studies. DOI: http://dx.doi.org/10.7554/eLife.01312.001

Decoding neural responses to temporal cues for sound localization

Abstract Cluster analysis faces two problems in high dimensions: the “curse of dimensionality” that can lead to overfitting and poor generalization performance and the sheer time taken for conventional algorithms to process large amounts of high-dimensional data. We describe a solution to these problems, designed for the application of spike sorting for next-generation, high-channel-count neural probes. In this problem, only a small subset of features provides information about the cluster membership of any one data vector, but this informative feature subset is not the same for all data points, rendering classical feature selection ineffective. We introduce a “masked EM” algorithm that allows accurate and time-efficient clustering of up to millions of points in thousands of dimensions. We demonstrate its applicability to synthetic data and to real-world high-channel-count spike sorting data.

Simulating biological neuronal networks is a core method of research in computational neuroscience. A full specification of such a network model includes a description of the dynamics and state changes of neurons and synapses, as well as the synaptic connectivity patterns and the initial values of all parameters. A standard approach in neuronal modeling software is to build network models based on a library of pre-defined components and mechanisms; if a model component does not yet exist, it has to be defined in a special-purpose or general low-level language and potentially be compiled and linked with the simulator. Here we propose an alternative approach that allows flexible definition of models by writing textual descriptions based on mathematical notation. We demonstrate that this approach allows the definition of a wide range of models with minimal syntax. Furthermore, such explicit model descriptions allow the generation of executable code for various target languages and devices, since the description is not tied to an implementation. Finally, this approach also has advantages for readability and reproducibility, because the model description is fully explicit, and because it can be automatically parsed and transformed into formatted descriptions. The presented approach has been implemented in the Brian2 simulator.

Equation-oriented specification of neural models for simulations

Playdoh: A lightweight Python library for distributed computing and optimisation

Modern graphics cards contain hundreds of cores that can be programmed for intensive calculations. They are beginning to be used for spiking neural network simulations. The goal is to make parallel simulation of spiking neural networks available to a large audience, without the requirements of a cluster. We review the ongoing efforts towards this goal, and we outline the main difficulties.

Online auditory filter processing using vectorization along channels

High-level languages (Matlab, Python) are popular in neuroscience because they are flexible and accelerate development. However, for simulating spiking neural networks, the cost of interpretation is a bottleneck. We describe a set of algorithms to simulate large spiking neural networks efficiently with high-level languages using vector-based operations. These algorithms constitute the core of Brian, a spiking neural network simulator written in the Python language. Vectorized simulation makes it possible to combine the flexibility of high-level languages with the computational efficiency usually associated with compiled languages.

The human cochlea includes about 3000 inner hair cells which filter sounds at frequencies between 20 Hz and 20 kHz. This massively parallel frequency analysis is reflected in models of auditory processing, which are often based on banks of filters. However, existing implementations do not exploit this parallelism. Here we propose algorithms to simulate these models by vectorizing computation over frequency channels, which are implemented in “Brian Hears,” a library for the spiking neural network simulator package “Brian.” This approach allows us to use high-level programming languages such as Python, because with vectorized operations, the computational cost of interpretation represents a small fraction of the total cost. This makes it possible to define and simulate complex models in a simple way, while all previous implementations were model-specific. In addition, we show that these algorithms can be naturally parallelized using graphics processing units, yielding substantial speed improvements. We demonstrate these algorithms with several state-of-the-art cochlear models, and show that they compare favorably with existing, less flexible, implementations.

Brian Hears: Online Auditory Processing Using Vectorization Over Channels

Graphs are called navigable one can find short paths through them using only local knowledge [2]. This requires a very precise link distribution, and yet many important real-world networks are navigable [1]. How does such a link distribution arise? Oskar Sandberg proposed a model of network formation in an attempt to explain how navigability arises [2]. The model takes a geographic nearest-neighbor network and adds links based on a model of intrinsic similarity between nodes. The model produces the right link distribution in special theoretical cases and simulations, but it’s full theoretical consequences are unknown. Sandberg conjectures that the model in general behaves as it does in his special case. The main difficulty in the proof is that links are not created independently, so it is not easy to prove statements about an entire greedy path. In this project, I attempted to solve this difficulty for a special case. I did not succeed, but present theoretical and computational evidence in favor of this conjecture.

CS 224 W Project Writeup : On Navigability in Small-World Networks

Computational modeling is increasingly used to understand the function of neural circuits in systems neuroscience. These studies require models of individual neurons with realistic input–output properties. Recently, it was found that spiking models can accurately predict the precisely timed spike trains produced by cortical neurons in response to somatically injected currents, if properly fitted. This requires fitting techniques that are efficient and flexible enough to easily test different candidate models. We present a generic solution, based on the Brian simulator (a neural network simulator in Python), which allows the user to define and fit arbitrary neuron models to electrophysiological recordings. It relies on vectorization and parallel computing techniques to achieve efficiency. We demonstrate its use on neural recordings in the barrel cortex and in the auditory brainstem, and confirm that simple adaptive spiking models can accurately predict the response of cortical neurons. Finally, we show how a complex multicompartmental model can be reduced to a simple effective spiking model.

In the neocortex, neuronal selectivities for multiple sensorimotor modalities are often distributed in topographical maps thought to emerge during a restricted period in early postnatal development. Rodent barrel cortex contains a somatotopic map for vibrissa identity, but the existence of maps representing other tactile features has not been clearly demonstrated. We addressed the issue of the existence in the rat cortex of an intrabarrel map for vibrissa movement direction using in vivo two-photon imaging. We discovered that the emergence of a direction map in rat barrel cortex occurs long after all known critical periods in the somatosensory system. This map is remarkably specific, taking a pinwheel-like form centered near the barrel center and aligned to the barrel cortex somatotopy. We suggest that this map may arise from intracortical mechanisms and demonstrate by simulation that the combination of spike-timing-dependent plasticity at synapses between layer 4 and layer 2/3 and realistic pad stimulation is sufficient to produce such a map. Its late emergence long after other classical maps suggests that experience-dependent map formation and refinement continue throughout adult life.

Late Emergence of the Vibrissa Direction Selectivity Map in the Rat Barrel Cortex

Complex dynamics deals with the iteration of holomorphic functions. As is well known, the first functions to be studied which gave non-trivial dynamics were quadratic polynomials, which produced beautiful computer generated pictures of Julia sets and the Mandelbrot set. In the same spirit, this article aims to study the dynamics of the simplest non-trivial quasiregular mappings. These are mappings in R2 which are a composition of a quadratic polynomial and an affine stretch.

To localise the source of a sound, we use location-specific properties of the signals received at the two ears caused by the asymmetric filtering of the original sound by our head and pinnae, the head-related transfer functions (HRTFs). These HRTFs change throughout an organism's lifetime, during development for example, and so the required neural circuitry cannot be entirely hardwired. Since HRTFs are not directly accessible from perceptual experience, they can only be inferred from filtered sounds. We present a spiking neural network model of sound localisation based on extracting location-specific synchrony patterns, and a simple supervised algorithm to learn the mapping between synchrony patterns and locations from a set of example sounds, with no previous knowledge of HRTFs. After learning, our model was able to accurately localise new sounds in both azimuth and elevation, including the difficult task of distinguishing sounds coming from the front and back.

Spike timing is precise in the auditory system and it has been argued that it conveys information about auditory stimuli, in particular about the location of a sound source. However, beyond simple time differences, the way in which neurons might extract this information is unclear and the potential computational advantages are unknown. The computational difficulty of this task for an animal is to locate the source of an unexpected sound from two monaural signals that are highly dependent on the unknown source signal. In neuron models consisting of spectro-temporal filtering and spiking nonlinearity, we found that the binaural structure induced by spatialized sounds is mapped to synchrony patterns that depend on source location rather than on source signal. Location-specific synchrony patterns would then result in the activation of location-specific assemblies of postsynaptic neurons. We designed a spiking neuron model which exploited this principle to locate a variety of sound sources in a virtual acoustic environment using measured human head-related transfer functions. The model was able to accurately estimate the location of previously unknown sounds in both azimuth and elevation (including front/back discrimination) in a known acoustic environment. We found that multiple representations of different acoustic environments could coexist as sets of overlapping neural assemblies which could be associated with spatial locations by Hebbian learning. The model demonstrates the computational relevance of relative spike timing to extract spatial information about sources independently of the source signal.

Complex dynamics deals with the iteration of holomorphic functions. As is well known, the first functions to be studied which gave non-trivial dynamics were quadratic polynomials, which produced beautiful computer generated pictures of Julia sets and the Mandelbrot set. In the same spirit, this article aims to study the dynamics of the simplest non-trivial quasiregular mappings. These are mappings in 

 R
 
 2
 
 \mathbb {R}^{2}
 
 which are a composition of a quadratic polynomial and an affine stretch.

Conformal Geometry and Dynamics of the American Mathematical Society

Spiking models can accurately predict the spike trains produced by cortical neurons in response to somatically injected currents. Since the specific characteristics of the model depend on the neuron, a computational method is required to fit models to electrophysiological recordings. The fitting procedure can be very time consuming both in terms of computer simulations and in terms of code writing. We present algorithms to fit spiking models to electrophysiological data (time-varying input and spike trains) that can run in parallel on graphics processing units (GPUs). The model fitting library is interfaced with Brian, a neural network simulator in Python. If a GPU is present it uses just-in-time compilation to translate model equations into optimized code. Arbitrary models can then be defined at script level and run on the graphics card. This tool can be used to obtain empirically validated spiking models of neurons in various systems. We demonstrate its use on public data from the INCF Quantitative Single-Neuron Modeling 2009 competition by comparing the performance of a number of neuron spiking models.

Automatic Fitting of Spiking Neuron Models to Electrophysiological Recordings

“Brian” is a simulator for spiking neural networks (http://www.briansimulator.org). The focus is on making the writing of simulation code as quick and easy as possible for the user, and on flexibility: new and non-standard models are no more difficult to define than standard ones. This allows scientists to spend more time on the details of their models, and less on their implementation. Neuron models are defined by writing differential equations in standard mathematical notation, facilitating scientific communication. Brian is written in the Python programming language, and uses vector-based computation to allow for efficient simulations. It is particularly useful for neuroscientific modelling at the systems level, and for teaching computational neuroscience.

Contracts and Grants with Industry - VISIONTRAIN : Computational and Cognitive Vision Systems: A Training European Network

We prove that the Bers and Maskit slices of the quasi-Fuchsian space of a once-punctured torus have a dense, uncountable set of points in their boundaries about which the boundary spirals infinitely.

Conformal Geometry and Dynamics of The American Mathematical Society

The Maskit slice of quasifuchsian space can be embedded as a simply connected subset of C bounded by a simple closed curve. At almost every point in the boundary of such a set, the boundary is twisting – spiralling infinitely in both directions – or conformal – roughly speaking, with well defined tangents. The numerical evidence presented in this paper suggests that in the case of the Maskit slice it is twisting at almost every point in its boundary. We also suggest an approach to proving this conjecture, and present an argument that suggests the Hausdorff dimension of the Maskit slice should be less than 1.25.

Humans Sensitivity Distribution in Perceptual Space by a Wearable Haptic Sleeve

This thesis describes the design and construction of pressure sensing matrices for capturing human location and activity data from large surfaces in a space such as the floors, walls, tabletops, countertops, and furniture. With the ability to operate either alone or connected to others in an assembly, each sensor module is 0.3m x 2m, contains 512 force sensitive resistors, and has a refresh rate of about 8Hz. Each module was made with conductive inkjet printing and PCB fabrication, creating a low-profile sensing surface with robust signal-collecting circuitry. Several experiments were conducted on an assemblage of three modules to assess parameters such as response time, sensitivity, measurement repeatability, spatial and pressure resolution, and accuracy in analyzing walking data as compared to a camera. Applications that could employ such a system are explored and two visualizations were prototyped that could ambiently provide data and trends to a user. Thesis Supervisor: Kent Larson Title: Principal Research Scientist, Changing Places Group, MIT Media Lab

Aware surfaces : large-scale, surface-based sensing for new modes of data collection, analysis, and human interaction

Light consists of frequency (color) and brightness (tone). The human eye consists of two types of light receptors: cones and rods. Cones are sensitive to frequency (color) and rods are sensitive to brightness (tone). In the human eye color from the cones gets grayed [coined term]; that is, toned by the rods. The Munsell Color System model graphically shows how this is done. Conclusion: The result is that light that seen is actually color that is grayed [toned].

Abstract : Automatic cuers and recognizers have been included in many recent weapons systems designs. In systems such as the Comanche helicopter a successful cuer/recognizer will significantly reduce crew workloads and will shorten acquisition timelines considerably. Focal plane array development has matured to the point where a new generation of common detector modules are being built under the IRFPA program. In the initial phases of the program it became important to take a look at different proposed array configurations, and to try to draw conclusions about the resulting image quality and impact that would have on future automatic target recognizer performance. The focus of this investigation has been the impact of several key FPA parameters on ATh performance. The experimental design was chosen to be independent of specific ATh algorithms and focused on the amount of image degradation and information loss attributable to a particular FPA design change. Sensor parameters studied included detector size, detector geometry, noise, detector response nonuniformity, and array sampling effects. Range dependence of the image quality degradation due to each of the sensor parameters is presented. (KAR) P. 3

The Influence of Focal Plane Array Design Parameters on Future Automatic Target Recognizer Performance.

L'invention concerne un procede et un systeme qui permettent de recuperer des taxes remboursables. Un procede pour traiter une transaction de paiement associee a un achat et pour rembourser une taxe payee sur l'achat consiste (i) a recevoir sur un reseau, a partir d'un appareil de commercant, des donnees relatives a une transaction de paiement associee a une carte de paiement electronique, et a stocker lesdites donnees dans un enregistrement de transaction de paiement dans une memoire de donnees, (ii) a analyser l'enregistrement de transaction de paiement pour determiner si la transaction de paiement peut donner droit ou non a un remboursement de taxe ; (iii) a determiner une valeur de remboursement de taxe associee a la transaction de paiement ; e iv) a coordonner un emetteur associe a la carte de paiement et une administration fiscale de facon a crediter un compte associe a la carte de paiement electronique de la valeur de remboursement de taxe. L'invention fournit ainsi une technique au moyen de laquelle un titulaire de carte 'outre-mer' peut se voir fournir un remboursement de la taxe payee sur des achats pouvant donner droit a un remboursement d'une maniere qui est conviviale et transparente pour le titulaire de carte, ce qui a ete, jusqu'a present, effectue dans un environnement de transaction en grande partie a base de papier. L'invention concerne egalement un systeme dans lequel le procede peut etre mis en œuvre.

L'invention concerne des dispositifs, des systemes et des procedes qui facilitent la mise en œuvre de plans sensoriels personnalises. Grâce a l'utilisation de divers modes de realisation de la presente invention, un ou plusieurs etats sensoriels indesirables peuvent etre attenues.

Dispositifs pour faciliter l'administration d'une expérience sensorielle personnalisée et leurs systèmes et procédés d'utilisation

The project developed statistical tools for the application of decision theory and operations research methods, including cost-benefit analysis, to the DQO process for environmental clean up. A pilot study was conducted, using these methods at the Hanford site, to estimate vadose zone contamination plumes under the SX tank farm, and to help plan further sampling.

Extension and Enhancement Methods for Setting Data Quality Objectives

The costs of characterization can comprise a sizeable fraction of a remediation program budget. The DQO Process has been instituted at DOE to ensure that the investment in characterization adds net value to each remediation project. Thoughtful characterization can be very important to minimizing the total cost of a remediation. Strategic information gained by characterization can reduce the remediation costs by reducing the unproductive investment in unnecessary remediation of portions of a site that really don`t need to be remediated, and strategic information can reduce remediation costs by reducing the frequency of expensive rework or emergency action that result when remediation has not been pursued to the extent that really is needed.

Statistical and cost-benefit enhancements to the DQO process for characterization decisions

Risk-based decision making: an integrated approach for efficient site cleanup

Risk-based decision making case study: application at a Superfund cleanup

We describe a case study near Times Beach, Montana, where the application of an integrated approach described led to significant savings in time and money

Two recent developments at EPA, the Superfund Accelerated Cleanup Model and the guidelines for setting data quality objectives, offer real promise for using risk standards to clean up sites efficiently. The authors describe the key elements of the new approaches and how they can save time and money

This paper presents a prototype model for a microcomputer generated integrated planning, budgeting, reporting, and management information system suitable for agricultural research organizations in developing countries.

A microcomputer based planning and budgeting system for agricultural research programs

Learning the iOS 4 SDK for JavaScript Programmers - Create Native Apps with Objective-C and Xcode: Covers iOS SDK 4.2

In today's Web 2.0 world, JavaScript and Dynamic HTML are at the center of the hot new approach to designing highly interactive pages on the client side. With this environment in mind, the new edition of this book offers bite-sized solutions to very specific scripting problems that web developers commonly face. Each recipe includes a focused piece of code that you can insert right into your application. Why is JavaScript & DHTML Cookbook so popular? After reading thousands of forum threads over the years, author and scripting pioneer Danny Goodman has compiled a list of problems that frequently vex scripters of various experience levels. For every problem he addresses, Goodman not only offers code, but a discussion of how and why the solution works. Recipes range from simple tasks, such as manipulating strings and validating dates in JavaScript, to entire libraries that demonstrate complex tasks, such as cross-browser positioning of HTML elements, sorting tables, and implementing Ajax features on the client. Ideal for novices as well as experienced scripters, this book contains more than 150 recipes for: Working with interactive forms and style sheetsPresenting user-friendly page navigationCreating dynamic content via Document Object Model scriptingProducing visual effects for stationary contentPositioning HTML elementsWorking with XML data in the browser Recipes in this Cookbook are compatible with the latest W3C standards and browsers, including Internet Explorer 7, Firefox 2, Safari, and Opera 9. Several new recipes provide client-side Ajax solutions, and many recipes from the previous edition have been revised to help you build extensible user interfaces for Web 2.0 applications. If you want to write your own scripts and understand how they work, rather than rely on a commercial web development framework, the JavaScript & DHTML Cookbook is a must.

Make your Web pages stand out above the noise with JavaScript and the expert instruction in this much-anticipated update to the bestselling JavaScript Bible. With renowned JavaScript expert Danny Goodman at your side, you'll get a thorough grounding in JavaScript basics, see how it fits with current Web browsers, and find all the soup-to-nuts detail you'll need. Whether you're a veteran programmer or just starting out, this is the JavaScript book Web developers turn to again and again. Note: CD-ROM/DVD and other supplementary materials are not included as part of eBook file.

Packed with information on the latest web specifications and browser features, this new edition is your ultimate one-stop resource for HTML, XHTML, CSS, Document Object Model (DOM), and JavaScript development. Here is the comprehensive reference for designers of Rich Internet Applications who need to operate in all modern browsers, including Internet Explorer 7, Firefox 2, Safari, and Opera. With this book, you can instantly see browser support for the latest standards-based technologies, including CSS Level 3, DOM Level 3, Web Forms 2.0, XMLHttpRequest for AJAX applications, JavaScript 1.7, and many more. This new edition:Provides at-a-glance references for the tags, attributes, objects, properties, methods, and events of HTML, XHTML, CSS, DOM, and core JavaScript. You can quickly look up a particular feature or language term to see if it is available in desired browser brands and versions.Includes handy cross referencing that lets you look up an attribute (or object property, method, or event type) to find all the items that recognize it, including interrelated HTML tags, style properties, and document object model methods, properties, and events.Offers appendices where you can quickly locate values useful in HTML authoring and scripting. You'll find coverage of commands used across three browsers for user-editable content.Includes a glossary that gives you quick explanations of some of the new and potentially confusing terminology of DHTML.Dynamic HTML: The Definitive Reference speeds the way to adding sophisticated features to your web pages. Indispensable, complete, and succinct, this bestselling guide is the must-have compendium for all web developers involved in creating dynamic web content.

JavaScript and DHTML cookbook - solutions and examples for web programmers (2. ed.)

Dynamic HTML - the definitive reference: a comprehensive resource for HTML, CSS, DOM and JavaScript (2. ed.)

From the Publisher: 
This book will cover the new powerful functionality JavaScript will gain with the release of fifth generation revisions of Internet Esxplorer and Netscape Communicator. The Gold Bible, will feature essential new JavaScript information, additional ready-to-use JavaScript applications and scores of additional JavaScript and Web page routines. This book will bring programmmers and non-technical professionals, including casual programmmers and scripters, painlessly up to speed on all aspects of mastering JavaScript. Key topics include programming fundamentals, JavaScript language elements and how to use them effectively, plus how to easily and efficiently add powerful new functionality to HTML documents and Java applets.

Even the giant 4th Edition and massive Gold Edition of the JavaScript Bible couldn't hold all the superior knowledge and experience of scripting guru Danny Goodman. Examples sections from reference Parts III and IV appeared only on the CD-ROMs of those two books. Now, in this JavaScript Examples Bible, we bring you the Document Object Model (DOM) and core JavaScript language examples sections in their entirety in convenient form - plus new introductory sections by Danny to guide you to the most important concepts and examples in each chapter.

Thank you for downloading danny goodmans applescript handbook. As you may know, people have search numerous times for their favorite novels like this danny goodmans applescript handbook, but end up in infectious downloads. Rather than enjoying a good book with a cup of tea in the afternoon, instead they cope with some malicious bugs inside their desktop computer. danny goodmans applescript handbook is available in our digital library an online access to it is set as public so you can download it instantly. Our digital library saves in multiple locations, allowing you to get the most less latency time to download any of our books like this one. Merely said, the danny goodmans applescript handbook is universally compatible with any devices to read.

Dynamic HTML: The Definitive Reference is an indispensable compendium for Web content developers. It contains complete reference material for all of the HTML tags, CSS style attributes, browser document objects, and JavaScript objects supported by the various standards and the latest versions of Netscape Navigator and Microsoft Internet Explorer.

Create Web Pages That Think! Whether you're a novice Web author wondering what JavaScript can do for you or a seasoned HTML scripter anxious to exploit JavaScript's evolving functionality, this authoritative, all-in-one resource -- by the most experienced computer scripting author in the industry -- lets you create pages so inviting, users will spend more time at your Web site and come back for more! For Cool Web Pages, Master Today's Hottest Scripting Language! 
Get up to speed FAST with "crash courses" on programming fundamentals and object-oriented basics Key into the lessons you need with clearly labeled beginning, intermediate, and advanced terminology Implement JavaScript into your site with step-by-step how-to's Learn from ready-to-run JavaScript and HTML examples Apply expert script debugging and design tips Get ongoing support at IDG Books Worldwide and Danny Goodman's Web sites

Apple Guide is the sophisticated, interactive online help system provided with Macintosh System 7.5. Danny Goodman's Apple Guide Starter Kit provides you with an automated tool and quick, hands-on instructions for creating your own Apple Guide databases for any task or procedure with the Macintosh. 
The Starter Kit includes everything you need to write and compile simple, effective Guides. Using the Apple Guide Starter program included on this disk, you can make Guides quickly and easily, without having to learn a scripting language or write coded files (which is what you have to do without the program). The authors provide expert advice on how to design a good Guide, from planning and creation through testing, revising, and indexing. And you'll get tips on how to enhance your Guides by adding graphics, decision panels, context checks, and more. 
For novice and experienced users alike, Danny Goodman's Apple Guide Starter Kit provides an all-in-one, easy-to-use package for creating interactive instruction.

HyperCard for browsers - making tracks through stacks The dynamic file cabinet - information storage and retrieval Stacks from scratch - building with buttons HyperCard's Hidden Layers - backgrounds and backtracking Behind the buttons - introducing HyperTalk Creating hypertext - nonlinear writing Multimedia in minutes.

A Tutorial to Accompany Danny Goodman's Computer Concepts Using the MacIntosh

Living at Light Speed:: Your Survival Guide to Life on the Information Superhighway

Designed to put first-time users at ease with technology, this book is written for the novice who is intimidated by the concept of operating a computer.

Danny Goodman's Hypercard developer's guide: the ultimate guide to Hypercard stack development

Shows users how to build working HyperCard applications. How to create more sophisticated applications by means of the HyperTalk scripting language. Incorporates new multimedia capabilities.

Abstract The place of interfaith dialogue in Orthodox Judaism has been the subject of extensive discussion. This article offers a reading of Rabbi Joseph Soloveitchik's and Rabbi Irving Greenberg's stances on interfaith dialogue that situates them in a Jewish philosophical context. Some scholars have argued that Soloveitchik's refusal to engage in Jewish-Christian theological dialogue must be understood historically; others have argued that his opposition to such dialogue must be understood halakhically. This article, building upon the view articulated by Daniel Rynhold in his 2003 article that Soloveitchik's stance on interfaith dialogue must be understood philosophically, posits that in order for Soloveitchik's stance on interfaith dialogue to be fully understood, it should be studied bearing in mind the influence of Hermann Cohen upon Soloveitchik's religious philosophy. This article, which demonstrates the direct influence of Franz Rosenzweig upon aspects of Greenberg's thought, further argues that in order for Greenberg's stance on interfaith dialogue—as well as his interfaith theology—to be completely grasped, his positions upon these theological matters must be studied with the awareness of Franz Rosenzweig's influence upon his thought. The reading offered in this article of Cohen and Soloveitchik and of Rosenzweig and Greenberg does not purport to minimize the irreconcilable differences between these thinkers; nonetheless, it believes that the substantial resemblances—and, in the case of Rosenzweig and Greenberg, the direct influence—between the views of Christianity held by these pairs of figures are significant and suggest a reconsideration of the role of philosophy in the story of American Jewish theology.

From Confrontation to Cooperation: The Philosophical Foundations of the Joseph B. Soloveitchik-Irving Greenberg Schism on Jewish-Christian Dialogue

ABSTRACT:Philip Roth's engagement with William Shakespeare has been a steady and intense career-long affair. Hermione Lee, in remarks delivered on the occasion of Roth's eightieth birthday, observed that Roth's use of Shakespeare extends at least as far back as Portnoy's Complaint (1969). "Roth has Shakespeare deep in his head," Lee averred, and of this there can be no doubt. What can be questioned, however, is the upward-charting trajectory of Roth's use of Shakespeare. Even a cursory reading of Roth reveals that the more he aged, and the more his career progressed, the more he invoked Shakespeare, demonstrated in the series of novels beginning with Operation Shylock (1993), crescendoing in Sabbath's Theater (1995), and culminating in Exit Ghost (2007) and The Humbling (2009). Roth's greater use of Shakespeare in the later stages of his career—greater in the dual senses of frequency and engagement—can be ascribed, this article argues, to Roth's growing involvement with Jewish identity and human mortality.

"The Uncontrollability of Real Things": Operation Shylock, Sabbath's Theater, and Philip Roth's Falstaffian Theology of Judaism

Scientists offer personal accounts of the challenges, struggles, successes, U-turns, and satisfactions encountered in their careers in industry, academia, and government. 
 
 This insightful book offers essential life and career lessons for newly minted STEM graduates and those seeking a career change. Thirty-six leading scientists and engineers (including two Nobel Prize winners) describe the challenges, struggles, successes, satisfactions, and U-turns encountered as they established their careers. Readers learn that there are professional possibilities beyond academia, as contributors describe the paths that took them into private industry and government as well as to college and university campuses. They discuss their varying preferences for solitary research or collaborative teamwork; their attempts to achieve work-life balance; and unplanned changes in direction that resulted in a more satisfying career. Women describe confronting overt sexism and institutional gender bias; scientists of color describe the experience of being outsiders in their field. 
 
 One scientist moves from startup to startup, enjoying a career of serial challenges; another spends decades at one university; another has worked in academia, industry, and government. Some followed in the footsteps of parents; others were the first in their family to go to college. Many have changed fields, switched subjects, or left established organizations for something new. Taken together, these essays make it clear that there is not one path to a profession in science, but many. 
 
 Contributors 
 Stephon Alexander, Norman Augustine, Wanda Austin, Kimberly Budil, Wendy Cieslak, Jay Davis, Tamara Doering, Stephen D. Fantone, Kathleen Fisher, David Galas, Kathy Gisser, Sandra Glucksmann, Daniel Goodman, Renee Horton, Richard Lethin, Christopher Loose, John Mather, Richard Miles, Paul Nielsen, Michael O'Hanlon, Deirdre Olynick, Jennifer Park, Ellen Pawlikowski, Ethan Perlstein, Richard Post, William Press, Beth Reid, Jennifer Roberts, Jessica Seeliger, David Spergel, Ellen Stofan, Daniel Theobald, Shirley Tilghman, Jami Valentine, Z. Jane Wang, Rainer Weiss

Find Your Path: Unconventional Lessons from 36 Leading Scientists and Engineers

Narrating the Law: A Poetics of Talmudic Legal Stories. By Barry Scott Wimpfheimer. Philadelphia: University of Pennsylvania Press, 2011. Pp. 239. $59.95.

Stories of the Law: Narrative Discourse and the Construction of Authority in the Mishnah. By Moshe Simon‐Shoshan. New York: Oxford University Press, 2012. Pp. xv + 287. $74.00.

Monotheism and Ethics: Historical and Contemporary Intersections Among Judaism, Christianity and Islam. Edited by Y. Tzvi Langermann . Studies on the Children of Abraham. Leiden: Brill, 2012. Pp. 289. $144.00.

Believing and Its Tensions: A Personal Conversation about God, Torah, Suffering and Death in Jewish Thought. By Neil Gillman. Woodstock, VT: Jewish Lights, 2013. Pp. xviii + 113. $19.99.

The poster will present the results of an Action Research Plan of teaching grammar in context to a fifth-grade Reading/Language Arts class. By teaching grammar in context teachers have opportunities to extend concepts and include students in the lesson. Students become active participants in their learning. Statement of the Problem The incoming fifth grade students spend more than half of their fourth grade year working on writing. Unfortunately they spend almost no time learning grammar. By the time they come to my 5 th grade class the students know how to write a proper grabber, a catchy topic sentence, but they cannot write using proper grammar. Most Language Arts teachers say that there is just not enough time in the day to include grammar in their daily lesson. However, time does not seem to be the only issue. Teachers also say that students do not have a good foundation so they need to reteach, or that they just neglect teaching grammar altogether. Lessons that teach grammar in isolation do not allow students to make connections between the grammar principle being taught and how to incorporate it into their own writing. By teaching grammar in context teachers have opportunities to extend concepts and include students in the lesson. Students become active participants in their learning. Once the students get used to this new learning style it becomes second nature and hopefully their grammar and writing will have improved. Purpose and/or Research Question The purpose of this study is to find out if teaching grammar in context, will allow my students’ grammar to improve, specifically commas. I will focus on three types of commas; commas in a series, combined sentences with a coordinating conjunction, and sentences that begin with a subordinating conjunction. Literature Review Most teachers feel at ease when it comes to the conventional rules of grammar. Teachers certainly feel comfortable correcting their students’ grammar mistakes. However, many teachers do not feel comfortable teaching grammar, usage, and mechanics. While grammar textbooks are filled with rules, they do not teach students how to transfer these rules to their writing. Even for the most skilled teacher taking the time to teach grammar, explain the rules in depth, provide examples, and allow students to apply what they have learned can be a daunting task. Dean (2011) notes that teachers are comfortable with that perspective of grammar, it is the way grammar has always been taught. “The challenge, then, is to create opportunities for grammar study that are both rigorous and relevant, that prompts students to systematically explore the language in texts that are meaningful to them-both as readers and as writers” (Zuidema, 2012, p 64). Jeff Anderson’s grammar lessons involve transferring focus between reading or writing and explicit grammar problems that his students come across. Lessons on a particularly troubling grammar topic are then applied to a larger context so that students see “the story of grammar’s power to communicate meaning and beauty” (Anderson, 2006 p 28). Ediger (2011) writes that teachers should make grammar instruction interesting and relevant to their students. Providing activities that are both stimulating and motivating can alleviate lessons that are boring and uninspiring. Teachers need to get creative with the way they teach grammar especially in today’s society of texting. Research Methodology I will be implementing my action research plan in a fifth grade Reading/Language Arts classroom. These classes comprise of a mixed population; a few FCAT level 1’s, but mostly level 2’s and 3’s. There are also a number of ESOL students in each of the classes. Three times a week I will instruct the whole class using a power point presentation on the three different types of commas (commas in a series, sentences with a coordinating conjunction, and sentences with a subordinating conjunction). Before implementing my intervention (teaching grammar in context –commas), I will give the students a pre-test on commas. When the 8 weeks are up I will give the students a post-test on commas. The pre and post-test will help me determine whether the intervention, teaching grammar in context, was successful. I will compare the test scores to see if the intervention did in fact improve my students’ grammar usage. After completing each lesson, which should take about two weeks for each comma type, I will give the students various assignments and check for correct and incorrect comma usage. Frequency of correct/incorrect answers will be recorded using tally marks. This will help the students monitor their own learning. Findings After I complete my action research project I hope to find that my students grammar will improve, specifically commas. The intervention, teaching grammar in context, is a completely new concept for these students. Although teaching grammar in context is a new concept for my students I hope that they are able to grasp the concept and ultimately become more active learners. If the intervention is successful I hope to teach other grammar principles as well. Implications for the Field I hope to share these lessons and the idea of teaching grammar as principles not as a set of rules with other Language Arts teachers in my grade level as well as other grade levels. I would like to meet with other teachers and come up with new ideas for how we can incorporate ten-minute grammar lessons into our daily lessons. I know that in high school and college academic style writing is mandatory and that students are struggling with this writing style probably because we have neglected to teach it to them. References: Anderson, J. (2006). Zooming in and zooming out: Putting grammar in context into context. English Journal, 95 (5), 28-34. Dean, D. (2011). Shifting perspectives about grammar: Changing what and how we Teach. English Journal, 100 (4), 20-26. Ediger, M. (2012). Studying Grammar in the Technological Age. Reading Improvement, 49 (2), 35-37. Zuidema, L. (2012). The grammar workshop: Systematic language study in reading and writing contexts. English Journal 101 (5). 63-71.

From Defender to Critic: The Search For A New Jewish Self. By David Hartman. Woodstock, VT: Jewish Lights, 2012. Pp. xix + 303. $35.00.

Radical Responsibility: Celebrating the Thought of Chief Rabbi Lord Jonathan Sacks. Edited by Michael J. Harris , Daniel Rynhold , and Tamra Wright . New Milford, CT: Maggid Books, 2012. Pp. xxxi + 264. $29.95.

"One who loves money is not satisfied with money," states the Bible in Ecclesiastes 5:10. When the rabbis of antiquity expanded upon this apothegm and wrote, "envy, desire and greed remove a man from the world" (Mishnah, Ethics of the Fathers 4:21), this may as well have been a Delphic utterance about Jordan Belfort. Martin Scorsese's latest masterpiece, The Wolf of Wall Street, is at once a brilliant display of virtuoso filmmaking at its finest, as well as a cautionary tale that illustrates the biblical and religio-ethical warning concerning the perils of unchecked greed, envy and desire.Jordan Belfort was clearly one for whom the admonition "don't be greedy, for a greedy person is an idolater, worshipping the things of this world" (Colossians 3:5) was not a living value. In real life, Belfort was one of the most notorious white-collar criminals of the past thirty years, and was the King (or "Wolf") of Wall Street until a long-simmering FBI investigation finally dethroned him and put him behind bars. The fraud prince of penny stocks penned The Wolf of Wall Street, an eponymously titled memoir about his avaricious exploits, while stewing for several months in federal prison. After a similarly long-simmering production process, Leonardo DiCaprio, writer Terence Winter, and director Martin Scorsese finally brought a film about this devilishly duplicitous yet irresistibly charismatic figure into the light of day and onto the light of cinema screens.DiCaprio dramatizes Belfort's deviousness so effectively, so mercilessly, and so dynamically, that DiCaprio's Belfort takes on mythic hues. DiCaprio's Belfort is greedier than Michael Douglas's Gordan Gecko (Wall Street, 1987), more animalistically lustful than Marlon Brando's Paul (Last Tango in Paris, 1972-or Brando's Stanley Kowalski [A Streetcar Named Desire, 1951]), and more incorrigibly covetous than Cain (Genesis 4) and Kane (Citizen Kane, 1941, from Orson Welles).Like Charles Foster Kane, Jordan Belfort could have led a simple life with a modest income and a happy wife, and like Kane, Belfort was a man of outsized ambitions but without the ethical scruples of a moral tradition or a religious discipline that could have helped him harness his hubris. Belfort, as portrayed by DiCaprio, does not possess the patience to toil away in the back alleys of Wall Street finance firms, and when the company for which he was working suffers through the Black Monday stock market crash of 1987 and lays off much of its workforce-including him-Belfort is fortuitously yet unfortunately provided with an opening to indulge his amoral ambitions.While job-hunting for stock-trading jobs, he chances upon a shabby stock-trading shop in Long Island. What it lacks in glamor and glory, it makes up for in entrepreneurial opportunity. Belfort is at first surprised to become appraised of what the firm does- selling artificially inflated penny-stocks to easily manipulable men and women-and that it may not be so, well, legal. But he becomes intrigued when he is informed that a trader can net a seemingly infinitely greater commission on selling penny-stocks compared to the infinitesimal commission he had been earning as an honest salesman of solid stocks on Wall Street.'Let me give it a shot,' he asks the penny-stock traders. He picks up the office phone, makes a few calls, and within minutes he has miraculously sold a small-fortune of penny-stocks. The other traders are so awestruck by his overwhelming penny-stock- selling performance that they are rendered dumbstruck. It's as if they're the baseball scouts watching a young Roy Hobbs (Robert Redford) throw fastballs across a tawny Midwestern cornfield, or a comedy-club audience watching a young pre-Seinfeld Jerry Seinfeld perform a stand-up set. Belfort is not just a natural; he could be the greatest salesman of all time. If a salesman is only out there "on a smile and a shoeshine," as Willy Loman would have it, DiCaprio's young Belfort is out there on a smile as scintillating as the light of a thousand suns, and with a shoeshine that could make the grimiest coal-miner's loafers glow like green-and-white gold. …

The God Who Hates Lies: Confronting & Rethinking Jewish Tradition by David Hartman, with Charlie Buckholtz. Woodstock, VT: Jewish Lights, 2011. Pp. vii + 192. $24.99.

Paul Tillich and the Possibility of Revelation Through Film. By Jonathan Brant. New York: Oxford University Press, 2012. Pp. viii + 270. $68.00.

Our Religious Brains: What Cognitive Science Reveals about Belief, Morality, Community and our Relationship with God. By Ralph D. Mecklenburger. Woodstock, VT: Jewish Lights, 2012. Pp. xxv + 192. $24.99.

This paper lists some of the major international political issues related to Japan’s whaling, describes the position of anti-whaling members of the International Whaling Commission (IWC) and that of those members supporting the sustainable use of all marine resources, including whales. This provides a context for examining the role of anti-whaling NGOs in a failed process that was aimed at resolving the bipolar and dysfunctional nature of the IWC. The process, called “The Future of the IWC”, was intended to elicit compromises from both sides that would produce a fair and balanced interim arrangement, put aside the irreconcilable positions, remove the ill-will and acrimony from the institutional discourse, build trust, and, during the interim period, address the major issues faced by the Commission. During the negotiations Japan had offered substantial compromises, including a more than 50% reduction of its Antarctic whaling. However, because of pressure from NGOs, no compromises were offered by anti-whaling members of the IWC, so no consensus was possible. This is because a successful outcome, which would have brought all whaling under the Commission’s authority with substantially reduced catches, particularly in the southern ocean would have undermined the fund-raising objectives and economic interests of the anti-whaling NGOs. The unsuccessful end to the “Future of the IWC” process, brought about by the influence of anti-whaling NGOs on member governments, means that whaling other than

Sacred Scriptures, Secular Interpretations: The Bible as an Anthology of Philosophy, Psychology, Literature, and Religion

Torah From Heaven: The Reconstruction of Faith. By Norman Solomon. Oxford: The Littman Library of Jewish Civilization, 2012. Pp. xv + 395. $39.95.

Jewish Theology and World Religion. Edited by Alon Goshen-Gottstein and Eugene Korn . Oxford: The Littman Library of Jewish Civilization, 2012. Pp. xiv + 344. $64.50.

In the case of Coury v. Prot, Circuit Judge Dennis concludes that the word 'resides' as used in the Section 1, Clause 1 of the Fourteenth Amendment means 'domiciled' in a State. This is shown to be wrong. In the Slaughterhouse Cases, the Supreme Court states that 'resides' means a 'bona fide residence' in a State. Also, Judge Dennis conveys that there is only one state citizen for purposes of diversity of citizenship. This is also shown to be incorrect. There are two distinct state citizens for purposes of diversity of citizenship. Comments are made on averments on citizenship for purposes of diversity of citizenship jurisdiction for a citizen of the United States, under Section 1, Clause 1 of the Fourteenth Amendment, and for a citizen of a State who is not a citizen of the United States, under Article IV, Section 2, Clause 1 of the Constitution of the United States of America.

Comment on Case: Coury v. Prot, 85 F. 3d 244, 1996 (Diversity of Citizenship)

In any State of the Union, since the adoption of the Fourteenth Amendment and the Slaughterhouse Cases, there are now two distinct state citizens. The first is recognized at Article IV, Section 2, Clause 1 of the Constitution. The next is recognized at Section 1, Clause 1 of the Fourteenth Amendment. A citizen of a State, under Article IV, Section 2, Clause 1 of the Constitution is a citizen of the several States. A citizen of a State, under Section 1, Clause 1 of the Fourteenth Amendment, is a citizen of the United States. Privileges and immunities of a citizen of the United States are not the same as privileges and immunities of a citizen of the several States. Slaughterhouse Cases (83 U.S. (16 Wall.) 36, at 74, 1873). Therefore, there are two distinct state citizens. Chadwick v. Kelley (187 U.S. 540, at 546, 1903). Article III, Section 2 of the Constitution of the United States of America provides that “[t]he judicial Power shall extend to controversies between Citizens of different States.” Jurisdiction then of the courts of the United States is declared to extend to controversies between “citizens of different States.” A citizen of a State, under Article IV, Section 2, Clause 1 of the Constitution, only has to aver that he or she is a citizen of a State of the Union. Brown v. Keene (33 U.S. (Peters 8) 112, at 115 thru 116, 1834). A citizen of a State, under Section 1, Clause 1 of the Fourteenth Amendment, is to aver that he or she is a citizen of the United States AND a citizen of a State of the Union. Steigleder v. McQuesten (198 U.S. 141, 141 and 142, 1905). See also Sun Printing & Publishing Association v. Edwards (194 U.S. 377, 383, 1904). A citizen of a State, under Article IV, Section 2, Clause 1 of the Constitution, can pursue a cause of action against another citizen of a State, under Article IV, Section 2, Clause 1 of the Constitution. Brown v. Flectcher (235 U.S. 589, at 594, 1914). Thus, there are two distinct state citizens for purposes of diversity of citizenship.

Two Distinct State Citizens for Purposes of Diversity of Citizenship

Discover that since the adoption of the Fourteenth Amendment and the Slaughterhouse Cases, there is a citizen of the United States, who is not a citizen of the several States (united) and a citizen of the several States (united) who is not a citizen of the United States. See that a citizen of a State, under Article IV, Section 2, Clause 1 of the Constitution, is a citizen of the several States (united), and owes allegiance to the several States united; that is, to the United States, as expressed in plural form. Also, find out that a citizen of a State who is a citizen of the several States (united), is a nationality of the nation of the United States. Thus, there are two nationalities for the nation of the United States; a citizen of the United States, under Section 1 of the Fourteenth Amendment, and a citizen of the several States (united), under Article IV, Section 2, Clause 1 of the Constitution.

Discover that before the Fourteenth Amendment, both jus soli and jus sanguinis were followed in the United State of America. However, with the ratification of the Fourteenth Amendment, the United States of America adopted the principle of jus sanguinis for determining the citizenship of one born in the United States and overseas. For the several States, nothing changed, they still follow both jus soli and jus sanguinis.

Jus Sanguinis is the Rule for the United States; Jus Soli or Jus Sanguinis, or both, for the Several States

The seventh in a series on blunders made by the Supreme Court of the United States. In this article the case of the Slaughterhouse Cases (83 U.S. (Wall. 16) 36, 1873) is reviewed. The blunder made is that one born or naturalized in the United States, under Section 1 of the Fourteenth Amendment, is a citizen of the Union. However, it is shown that the terms "United States" and "Union" are used in different senses in the Constitution of the United States of America. That they do not have the same meanings. Thus, one who is born or naturalized in the United States, under Section 1 of the Fourteenth Amendment, is a citizen of the United States and not a citizen of the Union.

William Bennett Munro, Professor of Municipal Government at Harvard University, in his work "The Government of the United States: National, State, and Local" (1919) writes at page 73: “So far as the rules of international law are concerned, only one citizenship is recognized [from the United States], namely, citizenship of the United States.”This is incorrect. This paper shows that there are two citizens, not one, in the country of the United States, under the Constitution of the United States of America. Legal authority quoted, cited and linked.

For Purposes of International Law, There are Two Citizens in the Country of the United States

Discover what a diversity of citizenship case is; that in a diversity of citizenship case the proper citizenship must exist both when the action is commenced at the state level and when the petition for removal is filed at the federal level. See that a corporation, partnership, limited liability company, alien, citizen of the United States, and a citizen of a State who is not a citizen of the United States, can be a party to such an action. Legal authority quoted, cited, and linked. Also links to more detailed information on diversity of citizenship included.

A natural (native) born citizen is one who is born with the territory of a government (country) and subject to its jurisdiction. A natural (native) born citizen under Article II, Section 1, Clause 5, before the adoption of the Fourteenth Amendment, was a person born in the United States of America, in an individual State. Did the Fourteenth Amendment change this? Discover that the Fourteenth Amendment did not change this. A natural (native) born citizen under Article II, Section 1, Clause 5 is still one who is born in the United States of America, in an individual State. However, it is a citizen of a State who is not a citizen of the United States, under Article IV, Section 2, Clause 1 of the Constitution of the United States of America, that can be President of the United States of America, not a citizen of the United States, under Section 1, Clause 1 of the Fourteenth Amendment.

A citizen of a State who is not a citizen of the United States, is a citizen of the several States when abroad. This can be seen in the case of Hilton v. Guyot (159 U.S. 113, 1895). In this case defendants are citizens of the State of New York excising their commercial privileges as citizens of the several States. They have a principal place of business in the city of New York and have a storehouse and an agent in Paris, France. According to the Supreme Court of the United States they appeared and carried on litigation in the courts of France.

A Citizen of a State is a Citizen of the Several States when Abroad

In my work “Diversity of Citizenship and a Citizen of a State who is not a Citizen of the United States”, I showed in the cases of Bondurant v. Watson (103 U.S. 281, 1880) and Sun Printing & Publishing Association v. Edwards (194 U.S. 377, 1904) that one who is a citizen of the United States and a citizen of a State (Fourteenth Amendment), as well as one who is a citizen of a State who is not a citizen of the United States (Article IV, Section 2, Clause 1 of the Constitution), has the requisite citizenship to give a circuit court of the United States jurisdiction in a diversity of citizenship suit. In my work “Diversity of Citizenship includes a Citizen of a State who is not a Citizen of the United States”, I made the following statement: “A citizen of the United States is to identified his citizenship in a federal court by averring that he or she is a citizen of the United States AND a citizen of a State of the Union. . . . The reason for this is that a citizen of the United States can be a citizen of the United States without being a citizen of a State, as in the case of living overseas (aboard)." In this work I show that unless one who is a citizen of the United States does not aver in a diversity of citizenship suit that he or she is a citizen of the United States that he or she will be presumed to be a citizen of a State; Brown v. Keene (33 U.S. (Peters 8) 112, 1834), and that if one is a citizen of the United States, he or she still must aver that he or she is a citizen of the United States AND a citizen of a State of the Union in a diversity of citizenship suit; that the Fourteenth Amendment did not change this requirement; Wood v. Wagon (6 U.S. (2 Cranch) 1, 1804), Robertson v. Cease (97 U.S. 646, 1878), Steigleder v. McQuesten (198 U.S. 141, 1905).

In my work “Diversity of Citizenship includes a Citizen of a State who is not a Citizen of the United States”, I showed in the case of Bible Society v. Grove (101 U.S. 610, 1879); cited in Young v. Parker’s Administrator (132 U.S. 267, 1889), that since the adoption of the Fourteenth Amendment and the Slaughterhouse Cases, a citizen of a State (who is not a citizen of the United States) under Article IV, Section 2, Clause 1 of the Constitution of the United States of America, is still recognized in diversity of citizenship suits, in particular in cases which are removed from the state level to the federal level. In this work I show that one who is a citizen of the United States and a citizen of a State (Fourteenth Amendment), as well as one who is a citizen of a State who is not a citizen of the United States (Article IV, Section 2, Clause 1 of the Constitution), has the requisite citizenship to give a circuit court of the United States jurisdiction in a diversity of citizenship suit. The cases of Bondurant v. Watson (103 U.S. 281, 1880) and Sun Printing & Publishing Association v. Edwards (194 U.S. 33, 1904) are provided for this purpose.

Diversity of Citizenship Includes a Citizen of a State Who is Not a Citizen of the United States

The eighth in a series on blunders made by the Supreme Court of the United States. In this article the case of Cramer v. United States (325 U.S. 1, 1945) is reviewed. The blunder made is that the United States Supreme Court applied this section to a citizen of the United States, under the Fourteenth Amendment, when this section relates to a citizen of a State who is a citizen of the several States (united), under Article IV, Section 2, Clause 1 of the Constitution of the United States of America.

In the case of Ceglia v. Zuckerberg and Facebook Inc., the plaintiff, Paul D. Ceglia avers that he is a resident of the State of New York and that Mark Elliot Zuckerberg, CEO of Facebook, Incorporated, is a resident of the State of California. See that these averments are fatal to proceeding in the United States circuit court on grounds of diversity of citizenship. Legal authority quoted, cited and linked.

Comment On Case: Ceglia v. Zuckerberg and Facebook, Inc. (Diversity of Citizenship)

The sixth in a series on blunders made by the Supreme Court of the United States. In this article the case of Chirac v. Lessee of A. F. Chirac et. al. (15 U.S. (Wheat. 2) 259, 1817) is selected. The blunder made is that Congress, according to the Supreme Court of the United States, has been given the power of naturalization under the Constitution. However, it is shown that the Constitution of the United States of America only gives to Congress the power to prescribe the rule of naturalization for the several States. Such a rule relates to residency within a State of the Union.

The second in a series of two articles on blunders made by the Supreme Court of the United States. In this article the case of McCulloch v. State of Maryland (17 U.S. 316, 1819) is examined. The blunder made is that Congress under the 'necessary and proper' clause has implied powers. Reference to The Federalist Papers is made to show that Congress does not have implied powers under this provision, however, that the provision only authorizes Congress to pass necessary and proper laws for executing the powers granted to it under the Constitution.

The first in a series of two articles on blunders made by the Supreme Court of the United States. In this article the case of United States v. Curtiss-Wright Export Corporation (299 U.S. 304, 1936) is analyzed. The blunder made is that sovereignty passed from Great Britain to the United Colonies when the Declaration of Independence was passed. However, it is shown that sovereignty passed from Great Britain upon the treaty of September 23, 1783, and not the Declaration of Independence, and that sovereignty passed to the States (Independent States) and not the United Colonies.

There are two state citizens under the Constitution of the United States of America. One is at Article IV, Section 2, Clause 1 of the Constitution. The other is at Section 1, Clause 1 of the Fourteenth Amendment. Legal authority quoted, cited, and linked.

Two State Citizens Under the Constitution of the United States of America

Article IV, Section 2, Clause 1 has been defined to have both fundamental privileges and immunities as well as common privileges and immunities. After the adoption of the Constitution of the United States of America, there were two trains of thought regarding the privileges and immunities protected under Article IV, Section 2, Clause 1 of the Constitution. The first was that the privileges and immunities protected were fundamental privileges and immunities. The second was that Article IV, Section 2, Clause 1 granted common privileges and immunities to the citizens of sister States when they were in another State.The Supreme Court of the United States eventually took up the task of defining the privileges and immunities contained in Article IV, Section 2, Clause 1. In Paul v. State of Virginia, the Supreme Court stated that Article IV, Section 2, Clause 1 of the Constitution protected common privileges and immunities. However, in Ward v. State of Maryland, the Supreme Court of the United States, took the position that Article IV, Section 2, Clause 1 described fundamental privileges and immunities. It was in the Slaughterhouse Cases, where the Supreme Court of the United States finally defined the privileges and immunities in Article IV, Section 2, Clause 1 of the Constitution. The Slaughterhouse Court defined privileges and immunities under Article IV, Section 2, Clause 1 of the Constitution of the United States of America to include fundamental privileges and immunities AS WELL AS common privileges and immunities.

Article IV, Section 2, Clause 1 is Defined to have both Fundamental and Common Privileges and Immunities

The fourth in a series on blunders made by the Supreme Court of the United States. In this article the case of Hague v. Committee for Industrial Organization et. al. (307 U.S. 496, 1939) is reviewed. The blunder made is that Article IV, Section 2, Clause 1 of the Constitution of the United States has only common privileges and immunities. It is shown that Article IV, Section 2, Clause 1 has both common privileges and immunities as well as fundamental privileges and immunities.

The IWC moratorium on commercial whaling was not a value judgment and was not intended as a permanent prohibition

Discover that before the Fourteenth Amendment, a citizen of a State was recognized under international law with the nationality of a citizen of the United States. A citizen of the United States was also a citizen of the several States (united). However, the Fourteenth Amendment changed that. In the Slaughterhouse Cases, the Supreme Court split the two equivalent terms. Thereafter, there was a citizen of the United States and a citizen of the several States (united), under the Constitution of the United States of America.See that a citizen of a State, under Article IV, Section 2, Clause 1 of the Constitution is now a citizen of the several States (united) under the Constitution and is to be recognized under international law with the nationality of a citizen of the several States (united). Find out that a citizen of the United States, under Section 1 of the Fourteenth Amendment is also recognized under international law with the nationality of a citizen of the United States. Examine applications for passports filed by citizen(s) of a State both before and after the adoption of the Fourteenth Amendment.

A Citizen of a State, under Article IV, Section 2, Clause 1 of the Constitution, Can Get a Passport

The “Future of the IWC”: Why the Initiative to Save the International Whaling Commission Failed

The third in a series on blunders made by the Supreme Court of the United States. In this article the case of United States v. Wong Kim Ark (169 U.S. 649, 1898) is critiqued. The blunder made is that one born of resident aliens in the State of California is a citizen of the United States, when such a person is a citizen of the State of California. It is shown that the political jurisdiction of the United States extends only to the District of Columbia, its territories and possessions, and federal enclaves within the several States of the Union. And that a person born in a State of the Union is not subject to the political jurisdiction of the United States, but rather, to the political jurisdiction of a particular State.

The fifth in a series on blunders made by the Supreme Court of the United States. In this article the case of Colgate v. Harvey (296 U.S. 404, 1935) is presented. The blunder made is that a citizen of the United States is a citizen of a State under Article IV, Section 2, Clause 1 of the Constitution. However, it is shown that a citizen of the United States is a citizen of a State under Section 1, Clause 1 of the Fourteenth Amendment, not Article IV, Section 2, Clause 1 of the Constitution of the United States of America. Legal authority quoted, cited, and linked.

The Fourteenth Amendment was adopted on July 28, 1868. The Fourteenth Amendment according to the Supreme Court of the United States, in the Slaughterhouse Cases, changed citizenship under the Constitution. Citizenship of a State was now to be considered as separate and distinct from citizenship of the United States. A citizen of a State was to be considered as separate and distinct from a citizen of the United States.A citizen of the United States is located at Section 1 of the Fourteenth Amendment. A citizen of a State is to be found at Article IV, Section 2, Clause 1 of the Constitution of the United States of America.A citizen of the United States is to identified his citizenship in a federal court by averring that he or she is a citizen of the United States AND a citizen of a State of the Union. A citizen of a State is to aver that he or she is a citizen of a State of the Union.A citizen of a State can be a party to a suit based on diversity of citizenship, and also under Article III, Section 2 of the Constitution of the United States of America.

Citizen of a State Under Article IV, Section 2, Clause 1 Can be a Litigant in Federal Court

At the time of the decision of the Supreme Court of the United States in Dred Scott v. Sanford, in the year of 1856, there were black citizens as well as black slaves. Black citizens were descendants of blacks who were citizens at the time of the adoption of the Constitution. Black slaves were descendants of blacks who were slaves at the time of the adoption of the Constitution. There were also free persons of color; that is, black slaves emancipated, before the adoption of the Constitution of the United States of America as well as after the adoption of the Constitution.The case of Dred Scott v. Sanford dealt with free persons of color; that is, with black slaves emancipated, after the adoption of the Constitution of the United States of America. Therefore, the case of Dred Scott v. Sanford, had nothing to do with black citizens.Thus, a black slave, set free after the adoption of the Constitution of the United States of America, cannot, UNFORTUNATELY, be a citizen of a State, as well as a citizen of the United States because, although a free person, he or she is not a citizen required by Article IV, Section 2, Clause 1 of the Constitution.In addition, a black slave made a citizen of a State, by a State, after the adoption of the Constitution could not be a citizen of a State under Article IV, Section 2, Clause 1 because such a person; that is, the black slave, had to be a citizen of a State under Article IV, Section 2, Clause 1 of the Constitution.From Dred Scott v. Sanford: “It is true, every person, and every class and description of persons, who were at the time of the adoption of the Constitution recognized as citizens in the several States, became also citizens of this new political body; BUT NONE OTHER; it was formed by them, and for them and their posterity, but for no one else."

Section 1, Clause 1 of the Fourteenth Amendment to the Constitution of the United States of America states: ”All persons born or naturalized in the United States, and subject to the jurisdiction thereof, are citizens of the United States and of the State wherein they reside.” By force of Section 1, Clause 1 of the Fourteenth Amendment, a citizen of the United States can become also a citizen of a State. As such, a citizen of the United States would be, in this case, a citizen of the United States AND a citizen of a State. Or, in other words, a citizen of the United States resident in a State. Citizenship in a particular State, therefore, is based on residence.

Section 1, Clause 1 of the Fourteenth Amendment: Citizenship in a State Based on Residence

Article III, Section 2 of the Constitution of the United States (of America) provides that [t]he judicial Power shall extend to controversies between “Citizens of different States” as well as to controversies between citizens of a State and “foreign States, citizens or subjects.” Jurisdiction then of the courts of the United States is declared to extend to controversies between “citizens of different States” as well as to controversies between citizens of a State and “foreign States, citizens or subjects.”The Fourteenth Amendment was adopted on July 28, 1868. Did the amendment affect or modify Article III, Section 2 of the Constitution of the United States (of America). The answer is no. Robertson v. Cease: 97 U.S. 646 (1878). A citizen of the United States, therefore, is to aver that he or she is a citizen of the United States and a citizen of a State in a legal proceeding in a federal court. Steigleider v. McQuesten: 198 U.S. 141 (1905). While a citizen of a State is to aver that he or she is a citizen of a State. Steigleider v. McQuesten, supra. A citizen of a State is to aver also that he or she is a citizen of the several States. See Footnote 6 of the article for legal authority.

Citizenship and the Federal Courts after the Fourteenth Amendment

In the brief filed with the Supreme Court of the United States, Petitioners argue to overturn the Slaughterhouse Cases in reference to the Privileges or Immunities Clause of the Fourteenth Amendment. What Petitioners failed to see in their references to the Slaughterhouse Cases was that there were two citizens the Court was referring to, and not one. The Petitioners also failed to see that Section 1, Clause 1 and Section 1, Clause 2 of the Fourteenth Amendment were treated differently by the Slaughterhouse court. The purported quote of Article IV, Section 2, Clause 1 (OF) was nothing unusual in Slaughterhouse. And, the Petitioners also make the erroneous conclusion about a citizen of a State being the same as a citizen of the several States.

There is a desire to overturn the Slaughterhouse Cases using the case McDonald v. City of Chicago. The reason centers on the Privileges or Immunities Clause of the Fourteenth Amendment. The Supreme Court does not have to restore the Privileges or Immunities Clause of the Fourteenth Amendment. People need to understand that there are now two citizens under the Constitution, each with a different set of privileges and immunities.

Restore the Privileges or Immunities Clause? Overturn Slaughterhouse?

Before the Fourteenth Amendment, there was only a citizen of a State and a citizen of the United States. One born in a State of the Union, was, in general, a citizen of that particular State. As such he or she was entitled to the special privileges and immunities of that particular State, and was entitled to the common privileges and immunities of citizens of another State in which he or she was in, and had fundamental privileges and immunities recognized under Article IV, Section 2, Clause 1. A citizen of a State, under Article IV, Section 2, Clause 1 of the Constitution, before the Fourteenth Amendment, was recognized as a citizen of the United States, under international law. However, the Fourteenth Amendment transferred a citizen of the United States (with its common privileges and immunities) from Article IV, Section 2, Clause 1 of the Constitution to Section 1, Clause 2 of the Fourteenth Amendment. A citizen of the United States is still recognized as such, under international law. A citizen of a State is not. The solution was to create another citizen under the Constitution, which would be recognized under international law as such. The Supreme Court, in the Slaughterhouse Cases, decided to modified Article IV, Section 2, Clause 1 of the Constitution, to give effect to the Fourteenth Amendment. One word was changed. In Article IV, Section 2, Clause 1 “citizens in the several States” was changed to “citizens of the several States.” Thus, there are now privileges and immunities of citizens of the several States at Article IV, Section 2, Clause 1 of the Constitution. Privileges and immunities of a citizen of a State are to be found in the constitution and laws of a particular State. While privileges and immunities of a citizen of the United States are located at Section 1, Clause 2 of the Fourteenth Amendment. Therefore, there is now a citizen of the United States and also a citizen of the several States.

The Fourteenth Amendment's Effect on Article IV, Section 2, Clause 1 of the Constitution of the United States of America

Before the adoption of the Fourteenth Amendment to the Constitution of the United States, one was considered a citizen of a State as well as a citizen of the United States. As such, one owe allegiance to both the individual State government as well as the United States government. After the ratification of the Fourteenth Amendment; in the Slaughterhouse Cases, it was held that citizenship of a State was separate and distinct from citizenship of the United States. That a citizen of a State was separate and distinct from a citizen of the United States. Now a citizen of a State owes allegiance to the individual State government while a citizen of the United States owes allegiance to the United States government. A citizen of the United States, in addition, as a citizen of the United States and a citizen of a State, owes allegiance to the individual State government and the United States government. Quotes and cites to cases of the Supreme Court of the United States included.

Citizenship and Allegiance: Before and After the Fourteenth Amendment

Since the adoption of the Fourteenth Amendment, there are three sets of privileges and immunities. Privileges and immunities of citizens of the United States are located at Section 1, Clause 2 of the Fourteenth Amendment. Privileges and immunities of citizens of a State are to be found in the constitution and laws of the individual State (McKane v. Durston, 153 U.S. 684, at 687 1894). Privileges and immunities of citizens of the several States are designated at Article IV, Section 2, Clause 1 of the Constitution (Hodges v. United States, 203 U.S. 1, at 15 1906).Privileges and immunities of a citizen of the United States arise "out of the nature and essential character of the Federal government, and granted or secured by the Constitution." (Duncan v. Missouri, 152 U.S. 377, 382 1894). Privileges and immunities of a citizen of a State are to be found with the individual State's constitution and laws. (McKane v. Durston, supra). Privileges and immunities of a citizen of the several States are those described in Corfield v. Coryell by Mr. Justice Washington. (Hodges v. United States, supra).A citizen of the United States is entitled to privileges and immunities of a citizen of a State under Section 1, Clause 1 of the Fourteenth Amendment. A citizen of a State is entitled to privileges and immunities of a citizen of the several States under Article IV, Section 2, Clause 1 of the Constitution (Harris v. Balk, 198 U.S. 215, at 223 1905).A citizen of the United States is not entitled to privileges and immunities of a citizen of the several States, and a citizen of the several States is not entitled to privileges and immunities of a citizen of the United States. Therefore, there is now a citizen of the United States AND a citizen of a State under Section 1, Clause 1 of the Fourteenth Amendment; and also a citizen of a State AS WELL AS a citizen of the several States under Article IV, Section 2, Clause 1 of the Constitution.

An Overview of Citizenship in the United States since the Adoption of the Fourteenth Amendment

Article IV, Section 2, Clause 1 of Constitution was modified by the Fourteenth Amendment, in particular, Section 1, Clause 2. This was determined by the Supreme Court of the United States, in the Slaughterhouse Cases. A citizen of a State, under Article IV, Section 2, Clause 1 of the Constitution, is entitled to privileges and immunities of citizens in the several States AND entitled to privileges and immunities of citizens of the several States. Privileges and immunities of citizens in the several States are still common privileges and immunities. Privileges and immunities of citizens of the several States are fundamental privileges and immunities. Article IV, Section 2, Clause 1 of the Constitution of the United States of America should read: "The Citizens of each State shall be entitled to all the Privileges and Immunities of Citizens IN and OF the several States." Cites and quotes to cases from the Supreme Court of the United States included.

Shall Be Entitled to All Privileges and Immunities of Citizens IN and OF the Several States

Before the Fourteenth Amendment, there was only a citizen of a State, under Article IV, Section 2, Clause 1 of the Constitution of the United States of America. Such a citizen was also a citizen of the United States, under the law of nations (international law).However, in the Slaughterhouse Cases (1873), the Supreme Court decided that because of the Fourteenth Amendment, citizenship of a State was to be separate and distinct from citizenship of the United States. A citizen of a State was to be considered as separate and distinct from a citizen of the United States.One can be a citizen of the United States and not a citizen of a State. And, one can be a citizen of a State and not a citizen of the United States.So, there is a citizen of a State and also a citizen of the United States. In addition, there are now two citizens, a citizen of a State, under Article IV, Section 2, Clause 1 of the Constitution of the United States of America and also a citizen of the United States, under Section 1 of the Fourteenth Amendment. A citizen of the United States can become also a citizen of a State, under Section 1, Clause 1 of the Fourteenth Amendment. In such case then there would be a citizen of a State, under Article IV, Section 2, Clause 1 of the Constitution and also a citizen of the United States and a citizen of a State, under Section 1 of the Fourteenth Amendment.Therefore, in any State of the Union, there are two State citizens, a citizen of a State, under Article IV, Section 2, Clause 1 of the Constitution, and also a citizen of a State (and a citizen of the United States), under Section 1, Clause 1 of the Fourteenth Amendment. The only difference between them is that a citizen of a State, under Article IV, Section 2, Clause 1 of the Constitution, is one born in a State of the Union; that is a native born citizen whereas a citizen of a State, under Section 1, Clause 1 of the Fourteenth Amendment, is also a citizen of the United States residing in a particular State.

With the ratification of the Fourteenth Amendment on July 28 1868, there are now two state citizens under the Constitution of the United States (of America). One state citizen is, under Section 1, Clause 1 of the Fourteenth Amendment, a citizen of the United States. The other state citizen is, under Article IV, Section 2, Clause 1 of the Constitution, a citizen of the several States. In addition, there is a state citizen, with privileges and immunities of a citizen of the several States; under Article IV, Section 2, Clause 1 of the Constitution and there is a state citizen, with privileges and immunities of a citizen of the United States; under Section 1, Clause 2 of the Fourteenth Amendment (Chadwick v. Kelley: 187 U.S. 540).

This article is a critique of two reports of “independent legal experts” sponsored by the International Fund for Animal Welfare (IFAW); the “Paris Panel” and the “London Panel.” The article shows that the Paris Panel's conclusion that Japan's research whaling in the Antarctic is unlawful and an abuse of rights under the International Convention for the Regulation of Whaling (ICRW) is based on misuse of evidence and failure to properly interpret Article VIII of the Convention and the legal status of recommendatory non-binding resolutions. It also shows that the London Panel's conclusion that the import of humpback whales from Japan's research program in the Antarctic and sei whales from its research program in the North Pacific are a violation of trade rules under the Convention on International Trade in Endangered Species of Wild Fauna and Flora is based on incorrect interpretation of that Convention's trade rules. It is concluded that the two independent legal experts panel reports are, from a legal pers...

Japan's Research Whaling Is Not Unlawful and Does Not Violate CITES Trade Rules

Before the Fourteenth Amendment, the governments of the several States were considered separate and distinct sovereignties from each other as well as from the government of the United States. After the Fourteenth Amendment, the governments of the several states are still considered separate and distinct sovereignties from each other as well as from the government of the United States. Before the Fourteenth Amendment, a native born citizen was a citizen of a State, and a native born citizen of the United States, when aboard. Before the Fourteenth Amendment, an alien or foreigner could become a naturalized citizen of the United States or a naturalized citizen of a State. A naturalized citizen of the United States domiciled in a State, became a citizen of that State; that is, a citizen of the United States AS WELL AS a citizen of a State. A naturalized citizen of a State became also a citizen of the United States; that is, a citizen of a State AS WELL AS a citizen of the United States. Before the Fourteenth Amendment, a naturalized citizen of the United States and a naturalized citizen of a State were also a naturalized citizen of the United States, when aboard. Citizenship of the United States was established by the Supreme Court in the case of Dred Scott. Instead of distinguishing between a citizen of a State, under the constitution and laws of the individual State, and a citizen of a State, under the Constitution and laws of the United States, Chief Justice Tanney, in this case, made a distinction between a citizen of a State, under the constitution and laws of the individual State and a citizen of the United States under the Constitution and laws of the United States. Because of this, citizenship of the United States, became a constitutional reality, instead of being an international status. After the Fourteenth Amendment, citizenship of a State and citizenship of the United States were held to be separate and distinct by the Supreme Court in the Slaughterhouse Cases. That a citizen of a State was separate and distinct from a citizen of a United States. After the Fourteenth Amendment, a native born citizen is a citizen of a State, and a native born citizen of the several States, when aboard. After the Fourteenth Amendment, an alien or foreigner could become a naturalized citizen of the United States or a naturalized citizen of a State. A naturalized citizen of the United States residing in a State, becomes a citizen of that State; that is, a citizen of the United States AND a citizen of a State. A naturalized citizen of a State becomes also a citizen of the several States; that is, a citizen of a State AS WELL AS a citizen of the several States. After the Fourteenth Amendment, a naturalized citizen of the United States is a naturalized citizen of the United States, when aboard. After the Fourteenth Amendment, a naturalized citizen of a State is a naturalized citizen of the several States, when aboard. After the Fourteenth Amendment, a citizen of the United States is one who is born in the United States and not a State. And naturalized in the United States and not naturalized in a State. Regarding a foreign corporation, it is neither a citizen of the several States under Article IV, Section 2, Clause 1 of the Constitution of the United States (of America) nor a citizen of the United States under Section 1 of the Fourteenth Amendment. A corporation, before the Fourteenth Amendment, was not considered a citizen of a State, under the Constitution. After the Fourteenth Amendment, a corporation is neither considered a citizen of the several States, under Article IV, Section 2, Clause 1 of the Constitution of the United States (of America) nor a citizen of the United States under Section 1 of the Fourteenth Amendment.

Natural (Native) Born Citizen Defined: Before and After the Fourteenth Amendment

A citizen of a State, under Article IV, Section 2, Clause 1 of the Constitution, before the adoption of the Fourteenth Amendment, was entitled to privileges and immunities of a citizen of the United States. However, with the adoption of the Fourteenth Amendment, privileges and immunities of a citizen of the United States were transferred from Article IV, Section 2, Clause 1 of the Constitution to Section 1, Clause 2 of the Fourteenth Amendment. Thus, Article IV, Section 2, Clause 1 was modified with the adoption of the Fourteenth Amendment. Article IV, Section 2, Clause 1 of the Constitution no longer applies to a citizen of the United States. Section 1 of the Fourteenth Amendment does. Now Article IV, Section 2, Clause 1 of the Constitution applies to privileges and immunities of a citizen of the several States; that is, a citizen of all the several States, generally. A citizen of the several States has both fundamental privileges and immunities, and, as a citizen of a State, has common privileges and immunities with those citizens of a particular State he or she is in.

Section 1, Clause 2 of the Fourteenth Amendment Modified Article IV, Section 2, Clause 1 of the Constitution of the United State of America - Part 1

A citizen of a State, under Article IV, Section 2, Clause 1 of the Constitution of the United States of America, is now also a citizen of the several States. Such citizen is recognized under international law as a citizen of the several States.A citizen of a State, under Article IV, Section 2, Clause 1 of the Constitution of the United States of America, is a citizen of a particular State as well as a citizen of all the several States; that is, a citizen of the several States, generally. A citizen of the United States, however, is a citizen of the territories and possessions of the United States, including the District of Columbia and the federal enclaves in the several States of the Union. Therefore, in the country of the United States, since the adoption of the Fourteenth Amendment and the Slaughterhouse Cases, there are two citizens, a citizen of the several States, and a citizen of the United States.

Section 1, Clause 2 of the Fourteenth Amendment Modified Article IV, Section 2, Clause 1 of the Constitution of the United State of America – Part 2

The Fourteenth Amendment created not one, but two citizens under the Constitution of the United States (of America): "Consequently, one who is created a citizen of the United States, is certainly not made a citizen of any particular State. It follows, that as it is only the citizens of the State who are entitled to all privileges and immunities of citizens of the several States, then a distinction both in name and privileges is made to exist between citizens of the United States, ex vi termini, and citizens of the respective (several) States." Ex parte Frank Knowles: 5 Cal. 300, at page 304 (1855). This article shows the legal reasoning to this conclusion.

The Fourteenth Amendment Created Two Citizens: A Concise Explanation

The Constitution of the United States of America is a document “ordained and established” by the people, for the United States of America, in which the government; that is, the Congress is given “delegated, limited and enumerated powers.” In addition, some exceptions, limitations, or restrictions were placed on some of these powers. And, additional powers, or restrictions to powers granted, to Congress can be granted, or imposed, through an amendment to the Constitution. “. . . It is no longer open to question that by the Constitution a nation was brought into being, and that that instrument was not merely operative to establish a closer union or league of States. Whatever powers of government were granted to the Nation or reserved to the States (and for the description and limitation of those powers we must always accept the Constitution as alone and absolutely controlling), there was created a Nation, to be known as the United States of America, and as such then assumed its place among the nations of the world.” State of Kansas v. State of Colorado: 206 U.S. 46, 80 (1907).

Justice Bushrod Washington's determination of the Privileges and Immunities clause of Article IV, Section 2, Clause 1 of the Constitution of the United States is still the first, and leading opinion, on this clause of the Constitution. Corfield before and after the Fourteenth Amendment relates to Article IV, Section 2, Clause 1 of the Constitution of the United States, but now it describes the privileges and immunities of a citizen of the several States, whereas before the Fourteenth Amendment, it described the privileges and immunities a citizen of one state had in another State.

A natural (native) born citizen is one who is born with the territory of a government (country) and subject to its jurisdiction. Under the Constitution of the United States; at Article II, Section 5, Clause 1; a natural born citizen is a person born in the United States of America; in a different state, before the adoption of the Constitution of the United States and under the Articles of Confederation or a person born in the United States of America, in an individual State, under the Constitution of the United States. The Fourteenth Amendment created two citizens under the Constitution of the United States; a citizen of the several States, under Article IV, Section 2, Clause 1 and a citizen of the United States, under the first section of the Fourteenth Amendment. The proper question to be asked is if a citizen of the United States, after the adoption of the Fourteenth Amendment, can be considered a native born citizen (natural born citizen), under the Constitution of the United States, eligible to be President of the United States of America?

The Fourteenth Amendment was passed by the 39th Congress on June 13, 1866. Known as the "Reconstruction Amendment(s)" (one of three, the other two being the Thirteenth and Fifteenth Amendments) it contains five sections. Its main purpose was to make black slaves, freed under the Thirteenth Amendment, citizens under the Constitution of the United States. Section 2 of the Fourteenth Amendment modified Article I, Section 2 of the Constitution of the United States. In addition, Section 1, Clause 2 changed the wording in Article IV, Section 2, Clause 1 of the Constitution of the United States.

The Effects of the Fourteenth Amendment on the Constitution of the United States: More

Previous articles of mine have analyzed the Slaughterhouse Cases, primarily, in showing that there are indeed two citizens under the Constitution of the United States since the adoption of the Fourteenth Amendment and the decision of the Supreme Court in the Slaughterhouse Cases. This article will show that since the Slaughterhouse Cases, there are two citizens under the Constitution of the United States.

This article will show that since the adoption of the Fourteenth Amendment, the Supreme Court has made clear that there are two citizens under the Constitution of the United States, a citizen of the United States and a citizen of the several States.

There appears to be a misunderstanding by some in reading the Slaughterhouse Cases between a citizen of a state and a citizen of the several states. This is understandable since you have to read more than the opinion of the court. They are not, however, the same. Privileges and immunities of state citizenship, in general, are to be found in the constitution and laws of the individual state. On the other hand, privileges and immunities of citizenship of the several States are designated in Article IV, Section 2, Clause 1 of the Constitution of the United States.

Under the Constitution of the United States, there are two citizens. They are a citizen of the United States and a citizen of the several States. The Supreme court, in the Slaughterhouse Cases, decided that they were separate and distinct with the adoption of the Fourteenth Amendment. Privileges and immunities of a citizen of the United States are in the Fourteenth Amendment. For a citizen of the several States, they are located at Article IV, Section 2 of the Constitution. Privileges and immunities of a citizen of the several States are composed of fundamental, common, and special, privileges and immunities.

Much has been written on the Slaughterhouse Cases. Decided in 1873, this case is still controversial today as when it was made public on April 14 1873. What may not be known is that the Supreme Court also decided that because of the Fourteenth Amendment there were now two citizens under the Constitution of the United States; a citizen of the United States and a citizen of the several States.

Citizenship under the Constitution was changed by the Fourteenth Amendment. Before the Fourteenth Amendment there was only one class of citizens under the Constitution of the United States. After the adoption of the Fourteenth Amendment, the Supreme Court, in the Slaughterhouse Cases, decided that there were two citizens under the Constitution of the United States. However, the legal authority stemming from this decision is divided; with one being correct, the other incorrect. This cannot exist. Lex uno ore omnes alloquitur. Under the correct line of legal authority The United States of America is a Republic. Its citizens hold a dual citizenship. They are a citizen of the State in which they reside, and a citizen of the several States, or, of the United States.

Is There More than One Citizen Under the U. S. Constitution? - Slaughterhouse Revisited

It is a popular misconception today that because of the Fourteenth Amendment and the Slaughterhouse Cases, that there is only one citizen, a citizen of the United States. Such is not the case. The Supreme Court, in the Slaughterhouse Cases, decided that because of the Fourteenth Amendment, there were now two separate and distinct citizens under the Constitution of the United States (and not the Fourteenth Amendment) a citizen of the United States and a citizen of the several States. This paper is a revision to Two Citizens Under The Constitution. The author has discovered more materials, including a Supreme Court case, which supports the conclusion that there are two separate and distinct citizens under the Constitution.

A memorandum decision has been given two roles in our legal system. The first role is that it is used in a dispositive manner to a case which has mainly factual issues which is to be unpublished. The last role is that it is employed in an non-dispositive manner to a case which has primarily legal issues which is to be published. As it stands now, there is the possibility of a memorandum decision being used in a case with legal issues which is to be published, in a dispositive manner. Such a use would be a violation of due process since the decision would lack the reasons, that is; the legal authority justifying the ruling. It would be an arbitrary and capricious action.

The deep philosophical and political divisions between the International Whaling Commission (IWC) member countries that support managed whaling activities and those opposed to any harvesting of whales has caused a seriously dysfunctional situation at the IWC. The IWC Scientific Committee, reflecting the division of the whole organization, has been failing to provide consensus scientific advice on important whale conservation and management issues. Strong personal positions on the issues related to whaling, the influence of national government positions on scientists and advocacy have polarized the debates within the Scientific Committee. Scientific uncertainty and the precautionary approach have often been misused to promote anti-whaling positions. Furthermore, considerable effort and energy have been spent collecting as many names as possible on working papers to demonstrate that many share a certain view with the original author. This voting-like practice gives a false impression that a larger number of co-authors means a greater plausibility of the views expressed. This dysfunctional situation not only prevents proper conservation and sustainable utilization of whale stocks but also sets a bad precedent for other natural resource management issues. The Scientific Committee and its advice are becoming increasingly irrelevant to decisions regarding the management of whales and it is legitimate to ask whether under current circumstances it is even needed. However, science has never been the real issue behind the dispute. Unless the Commission and its member governments change their institutionalized dysfunctional discourse and procedures, it is naive to expect outputs from the Scientific Committee that are useful for the sustainable use and management of whale resources in accordance with the objectives of the ICRW.

Role and Problems of the Scientific Committee of the International Whaling Commission in terms of Conservation and Sustainable Utilization of Whale Stocks

Responses to Aron, Burke, and Freeman’s Forum article,“Scientists versus Whaling: Science, Advocacy, and Errors of Judgment” (BioScience 52: 1137–1140), by Clapham and colleagues, Orians and colleagues, and Holt in the March 2003 issue of BioScience mischaracterize Japan’s whale research programs. Clapham and colleagues state that Japan’s research program in the North Pacific “presumes, on an almost a priori basis, that whales (not humans) are primarily responsible for worldwide declines in fish stocks.” To the contrary, the overall aim of JARPN II is to contribute to the development of an ecological management approach. Clapham and colleagues ignore the fact that the International Whaling Commission (IWC) unanimously adopted a resolution making the study of interactions between whales and fisheries a matter of priority and that the FAO’s Committee on Fisheries and the Johannesburg Plan adopted at the 2002 World Summit on Sustainable Development have urged the development and implementation of ecosystem approaches to fisheries management. Other statements made by Clapham and colleagues accuse Japan of being “obstructive.”There is more than a little irony in the fact that these scientists criticize the research and its methods and data at the same time they seek to deny Japanese scientists the normal first right of data publication. Orians and colleagues claim that the research “results in the needless deaths of hundreds of whales each year, despite a global moratorium to which Japan is legally bound.”This and other statements of theirs appear to be political advocacy rather than science. Holt omits the critical point that much of the rationale for support of the International Convention for the Regulation of Whaling (ICRW) moratorium was related to the uncertainty of the science and management of whale stocks. Research was initiated in response to the rationale for the moratorium. The ICRW, which was adopted in 1946 and which established the IWC, has as its objective to provide for the conservation of whales for the benefit of the whaling industry and its consumers. Notwithstanding this, the now institutionalized discourse within the IWC reflects a strong difference of views between members who wish to sustainably utilize abundant species of whales for food and those who wish to protect all whales. Rather than adopting regulations to ensure that whaling is sustainable, regulations adopted since 1982, namely the moratorium on commercial whaling and the sanctuary in the Antarctic, are counter to the purpose of the ICRW and without scientific foundation.

The General Medical Council has stated that medical ethics and law should constitute one of the core components of the medical curriculum.' The practice of good medicine inevitably raises both ethical and legal issues and demands an understanding of both. In this document, teachers of medical ethics and law in medical schools throughout the UK now offer their own consensus statement about the issues, concepts, arguments, skills and attitudes that all medical students should understand and know how to apply in practice by the time they qualify. This consensus proposes a minimal core undergraduate programme ofwork which we believe to be consistent with the stated objective of the General Medical Council that students should acquire a knowledge and understanding of "ethical and legal issues relevant to the practice of medicine" and an "ability to understand and analyse ethical problems so as to enable patients, their families, society and the doctor to have proper regard to such problems in reaching decisions".' Some organisational principles are also summarised which we believe to be crucial for the successful implementation of our proposed undergraduate programme.

Teaching medical ethics and law within medical education: a model for the UK core curriculum.

Teaching medical ethics and law within medical education: a model for the UK core curriculum. Consensus statement by teachers of medical ethics and law in UK medical schools

Nursing staff development programs must be responsive to current changes in healthcare. New nursing staff must be prepared to manage continuous change and to function competently in clinical practice.

METHOD
The orientation pathway, based on a case management model, is used as a structure for the orientation phase of staff development. The integrated case is incorporated as a teaching strategy in orientation. The integrated case method is based on discussion and analysis of patient situations with emphasis on role modeling and integration of theory and skill.

RESULTS
The orientation pathway and integrated case teaching method provide a useful framework for orientation of new staff. Educators, preceptors and orientees find the structure provided by the orientation pathway very useful.

Orientation that is developed, implemented and evaluated based on a case management model with the use of an orientation pathway and incorporation of an integrated case teaching method provides a standardized structure for orientation of new staff. This approach is designed for the adult learner, promotes conceptual reasoning, and encourages the social and contextual basis for continued learning.

Application of the critical pathway and integrated case teaching method to nursing orientation.

The international politics of whaling: Peter J Stoett UBC Press, 1997, 228 pp. $65.00. ISBN 0-7748-0605-2

We took as our working hypothesis the premise that there could be a single locus of major effect underlying a subset of cases in the simulated Problem 2 data set, and took as our primary goal the task of mapping that locus. Treating the disease as dichotomous and using discriminant function analysis, we were able to separate affected individuals into two disease categories: Disease Type I (DT‐I) cases, whose disease was by hypothesis caused by the major locus; and Disease Type II (DT‐II) cases, whose disease was by hypothesis produced by other causes. Segregation analysis showed evidence of simple recessive inheritance among the DT‐I individuals. Linkage analysis under the best‐fitting recessive model gave clear evidence of linkage to D1G2. In the generating model, this marker is linked to a major gene for disease with recombination fraction θ = 0, and the mode of inheritance at that locus is recessive (when the trait is considered as a dichotomy). We conclude that when the true model is complex, focussing on subtypes of disease that show evidence of simple Mendelian inheritance may be a useful first step in determining the underlying model and mapping major genes. © 1995 Wiley‐Liss, Inc.

On March 17, 2020, the province of Alberta declared a state of emergency in the wake of the coronavirus pandemic that was sweeping the world, sending people into lockdown and shuttering economic activity. Alberta was particularly hard hit by this crisis. The Alberta economy, which relies heavily on the energy sector, was reeling from a global drop in energy demand and oversupply of oil that sent prices into negative territory. Politically, Premier Jason Kenney and the UCP government rose to power on the promise of creating jobs and fixing Alberta’s economy. COVID-19 upended these plans and has led to a growing deficit, tens of thousands of additional lost jobs, a downgrading of the province’s credit rating, and a net out-migration as people seek opportunities elsewhere. It is a grim economic picture and with the coronavirus pandemic far from over, stark tradeoffs persist in the potentially conflicting goals of safeguarding public health and economic well being.

Health and Politics: Analyzing the Government of Alberta’s COVID-19 Communications

Objectives
This study aimed to determine the effects of the soft tissue and bone widths of the patient's hip and shoulder region on the patient's position and postoperative acetabular inclination angles in the lateral decubitus position during hip replacement procedures.
Materials and Methods
Seventy-three patients with primary coxarthrosis who underwent primary hip arthroplasty by a single experienced surgeon using a water gauge assisted inclinometer in lateral decubitus position were retrospectively studied.
Soft tissue and bone widths of the shoulder, ASIS (Anterior superior iliac spine), and trochanter levels measured from the preoperative radiographs of the patients and shoulder/hip (ASIS-trochanter) ratios were calculated and made statistical comparisons with postoperative acetabular inclination angle.
Results
Postoperative inclination angle had a strong negative correlation with trochanter/shoulder soft tissue ratio, a moderate negative correlation with ASIS/shoulder soft tissue ratio, and a weak negative correlation with trochanter and ASIS/shoulder bone ratios.
When patients are grouped by trochanter/shoulder ratio, the postoperative inclination value is 43.04 (38-47) degrees in the group with the ratio < 0.85, the postoperative inclination value is 38.67 (33-45) degrees in the group with the ratio of 0.85-1, and the mean postoperative inclination value in the group with the ratio > 1 was found to be 35.60 (30-38) degrees. (p < 0.001)
As for the postoperative inclination values, the mean trochanter/shoulder and ASIS/shoulder values in the group with ≤ 40 degrees were 0.99 and 0.94, respectively, while these values in the group with > 40 degrees were 0.83 and 0.79, respectively. (p < 0.001).
Soft tissue widths in the shoulder and hip regions may affect the surgical position and postoperative acetabular inclination angle. Knowing the relationship between the patient's preoperative hip and shoulder distance can influence the expected clinical outcome after hip arthroplasty. Therefore, surgeons should consider these effects when planning hip arthroplasty surgery.

The effects of shoulder and hip widths on the acetabular angle in hip arthroplasty performed in the lateral decubitus position.

Trochanter/shoulder ratio effect on postop inclination

Management of Columbia River Salmon Under the Endangered Species Act: Environmental Engineering for a Dysfunctional Ecosystem

It is often asserted that more information on the battlefield leads to greater situational awareness (SA) which, in turn, translates to enhanced mission performance and outcomes.  However, the volume of available information on the modern networked battlefield is extensive and growing, which induces risk of indecision due to cognitive overload.  The potential overload highlights the need to streamline the flow of information to those critical streams that provide the most value to a tactical leader’s decision process at particular points in time. The purpose of this study is to identify critical information streams required by tactical leaders within the various phases of a dismounted search and attack/react to contact scenario.  Domain Mapping Matrix methodology (DMM) is utilized to quantify the value of various information streams relative to the sub -phases within the scenario using a constructed nominal scale. The significance of the highlighted interactions is validated through the use of statistical analysis, with combat veterans serving as test cases. The findings of this study will facilitate the development of decision models that will eventually enable more accurate and realistic simulation of the leader’s decision processes that increased SA purportedly enhances.

Identifying and Quantifying Critical Information Streams for Tactical Combat Decision Modeling

The federal-aid highway program has evolved, especially in the design arena. Engineers need to consider standard roadway characteristics while accounting for economic, environmental and social impacts. In response to the need for greater flexibility in the design process, the Federal Highway Administration (FHWA) recently proposed revising the controlling criteria in its highway design policy. FHWA has proposed retaining only two controlling criteria for National Highway System roadways with a design speed of less than 50 miles per hour: design speed and design loading structural capacity. This will allow engineers working on multimodal projects to develop unique solutions that address the specific circumstances of each project.

This paper highlights the methodology and results of a safety data analysis undertaken as part of the study process for the Federal Highway Administration’s (FHWA) Separated Bike Lane Planning and Design Guide. It outlines challenges and recommends a data collection framework that will lead to a better understanding of the full volume and safety picture for separated bike lanes. This study evaluated 18 sites before and after the installation of separated bike lanes. Of the 18 sites, 14 locations had data on both total crashes and bicycle crashes. Eight of these locations saw a decrease in total crashes and five sites saw a decrease in bicycle crashes. This translates to nine of 14 sites demonstrating a decrease in crashes of some sort. Four of the 14 sites saw decreases in both bicycle and total crashes. Similar trends are seen when considering bicycle exposure at sites with at least four average annual bicycle crashes. Five of the 10 sites saw decreases in average annual bicycle crashes per average hourly bicycle volume. It appears that the introduction of separated bike lanes may result in increased challenges at intersections. All six of the sites where the analysis included consideration of intersection vs. midblock crashes saw an increase in the percentage of crashes that occurred at an intersection. This was true for bicycle crashes as well as those not involving a bicycle. However, these comparisons did not control for changes in bicycle volumes between the before and after periods. There are significant data limitations to this study. In particular, challenges associated with obtaining bicycle volume data (both before and after) make it difficult to understand the true impacts on safety of separated bike lanes. Also, the small number of bicycle crashes occurring at these locations yield analysis results with very large percentage changes (increases or decreases) since a change of one or two crashes can effectively double or triple the crash count for that site. It is critical that this data is collected so that future studies may evaluate the safety of separated bike lanes under different conditions and designs in greater detail. For this reason, a recommended minimum data collection approach is presented in this paper to, over time, improve the quantity and quality of data on separated bike lanes.

The purpose of this study is to determine whether highway infrastructure in Montana is adequate to support future expected growth in traffic resulting from economic development in Canada, and a number of potential changes in border operations, industry structure and freight-related policy. Historical data on cross-border traffic, empirical findings from existing research, interviews with selected industry representatives and subject matter experts, as well as professional judgment, were used to: i) provide an overview of the regional economy, highlighting threats and opportunities for future economic development and growth in international trade; ii) develop forecasts of cross-border commodity flows and commercial traffic under alternative scenarios and economic growth assumptions; iii) document existing conditions along two highway corridors connecting US 2 with the Canadian border, namely the S-232 corridor between US 2 and Wild Horse, and the US 191 corridor between US 2 and Morgan; and iv) assess whether existing highway infrastructure along these corridors was adequate to accommodate future expected traffic levels. A number of conclusions could be reached. First, it is anticipated that existing highway infrastructure in Montana will be adequate to handle the potential increase in overall traffic, as well as the potential increase of truck traffic for both corridors of interest. Second, should the existing pavement and geometric conditions be maintained, the expected increase in annual average daily traffic (AADT) and truck percentages should not degrade the weighted traffic operations below free-flow conditions (LOS A); although individual locations within the corridor may experience higher degradation in operations than the overall weighted average operations. Third, traffic operations along the highway segments immediately adjacent to the ports are expected to remain below free-flow conditions through 2032. Only under the most aggressive growth scenario would traffic conditions south of Wild Horse deteriorate below LOS A in the busiest hour, in 2028.

Impact of Canadian Economic Development on Northern Montana Highways Phase II, Ports of Wild Horse and Morgan Highway Corridors

The goal of this project is to upgrade existing building facilities owned by Nunamiut Corporation in Anaktuvuk Pass, AK. The upgrades mentioned will include lighting, heating system, insulation and smart control units designed to increase the energy efficiency of Village Corporation owned buildings.

Introductions or invasions of nonnative organisms can mediate major changes in the trophic structure of aquatic ecosystems. Here we document multitrophic level impacts in a spatially extensive system that played out over more than a century. Positive interactions among exotic vertebrate and invertebrate predators caused a substantial and abrupt shift in community composition resulting in a trophic cascade that extended to primary producers and to a nonaquatic species, the bald eagle. The opossum shrimp, Mysis diluviana, invaded Flathead Lake, Montana, the largest freshwater lake in the western United States. Lake trout had been introduced 80 y prior but remained at low densities until nonnative Mysis became established. The bottom-dwelling mysids eliminated a recruitment bottleneck for lake trout by providing a deep water source of food where little was available previously. Lake trout subsequently flourished on mysids and this voracious piscivore now dominates the lake fishery; formerly abundant kokanee were extirpated, and native bull and westslope cutthroat trout are imperiled. Predation by Mysis shifted zooplankton and phytoplankton community size structure. Bayesian change point analysis of primary productivity (27-y time series) showed a significant step increase of 55 mg C m−2 d−1 (i.e., 21% rise) concurrent with the mysid invasion, but little trend before or after despite increasing nutrient loading. Mysis facilitated predation by lake trout and indirectly caused the collapse of kokanee, redirecting energy flow through the ecosystem that would otherwise have been available to other top predators (bald eagles).

Long-term effects of a trophic cascade in a large lake ecosystem

Salmon populations are highly variable in both space and time. Accurate forecasting of the productivity of salmon stocks makes effective management and conservation of the resource extremely challenging. Furthermore, widespread and consistent data on the productivity of species‐specific and total salmon stocks in a river are almost nonexistent. Ranking rivers based on physical complexity derived from remote sensing allows rivers to be objectively compared. Our approach considered rivers with great geomorphic complexity (e.g. having expansive, multichanneled floodplains and/or on‐channel lakes) as likely to have greater productivity of salmon than rivers flowing in constrained or canyon‐bound channels. Our objective was to develop a database of landscape metrics that could be used to rank the rivers in relation to potential salmon productivity. We then examined the rankings in relation to existing empirical (monitoring) data describing productivity of salmon stocks. To extract the metrics for each river basin we used a digital elevation model and multispectral satellite imagery. We developed procedures to extract channel networks, floodplains, on‐channel lakes and other catchment features; variables such as catchment area, channel elevation, main channel length, floodplain area, and density of hydrojunctions (nodes) were measured. We processed 1509 catchments in the North Pacific Rim including the Kamchatka Peninsula in Russia and western North America. Overall, catchments were most physically complex in western Kamchatka and western Alaska, and particularly on the Arctic North Slope of Alaska. We could not directly examine coherence between potential and measured productivity except for a few rivers, but the expected relationship generally held. The resulting database and systematic ranking are objective tools that can be used to address questions about landscape structure and biological productivity at regional to continental extents, and provide a way to begin to efficiently prioritize the allocation of funding and resources towards salmon management and conservation. Copyright © 2010 John Wiley & Sons, Ltd.

Remote sensing analysis of physical complexity of North Pacific Rim rivers to assist wild salmon conservation

Although many communities are interested in improving their multimodal transportation facilities, setting priorities can be difficult due to the lack of detailed data. This article discusses several approaches to setting priorities for pedestrian-oriented projects. The first approach involves evaluating pedestrian infrastructure needs, which focuses on existing conditions and the quality of the physical environment to gain knowledge of how comfortable and safe pedestrians feel when they walk along and across streets. A second type of assessment focuses on pedestrian crashes. This method evaluates places where pedestrians are being struck by motor vehicles, and prioritizes locations with many crashes. The third approach is a demand-based assessment that highlights where people need and want to walk, both currently and in the future. Demand can be assessed by evaluating the location of pedestrian trip generators or by estimating actual pedestrian volumes. Together these approaches form a toolbox of strategies that are especially useful in large networks where system-wide measures are needed.

The Future of Fisheries Science: Merging Stock Assessment with Risk Assessment, for Better Fisheries Management

The escapement goals and management strategies for salmon stocks in the AYK region have been the subject of considerable controversy yet are critical in the management of these resources. It is widely recognized that there are limitations to the existing methods of creating brood tables and fitting Ricker or other stock-recruitment curves to these data, given the limited information for many AYK systems. In recent years there have been a number of new initiatives for evaluation of escapement goals, including methods that formally incorporate uncertainty and risk, habitat conditions, explicit analysis of life histories, use of data other than brood tables, understanding of stock structure and biocomplexity within watersheds, and evaluation of objectives other than maximum sustained yield. This project brought together a range of experts to evaluate the utility of these new methods for determining escapement goals for AYK stocks, assemble existing data relevant to calculation of AYK escapement goals, and to try to apply the new tools to several AYK systems. In this report, we present results from six activities. First, we provide a summary of existing data potentially useful for traditional escapement goal analyses, and a listing of all the technical reports in support of those data. In addition, CDs of the actual data are being supplied to AYK SSI staff. Second, we present a preliminary approach for assigning a metric to data quality so that data quality might be incorporated into future models. Third, we report on the reanalysis of productivity changes in three AYK salmon stocks, including three additional years of brood-year catch and escapement data. The reanalysis reinforced the conclusions from the 2004 analysis: all three stocks exhibit a strong downward, long-term trend in density-corrected recruits per spawner; and the strong year effects after correcting for both the trend and density show strong driving by some regional factor that affects all three stocks more or less synchronously. Fourth, we present a brief discussion of the potential effects of marine-derived nutrients on escapement goals. Fifth, we compare a new method of life-history-based modeling to outcomes of traditional spawner-recruit models. We find that escapement goals as determined by a life history approach are lower than escapement goals using a traditional Ricker analysis. Last, we present a preliminary overview of the kind of analysis that could eventually be useful for habitat-based estimates of spawning goals, by linking the total estimated rearing area of different types to the production rates for each habitat type.

2007 Arctic Yukon Kuskokwim Sustainable Salmon Initiative Project Final Product Alternative methods for setting escapement goals in AYK 1

Abstract The year 2006 marked two milestones in the Columbia River Basin and the Pacific Northwest region's efforts to rebuild its once great salmon and steelhead runs—the 25th anniversary of the creation of the Northwest Power and Conservation Council and the 10th anniversary of an amendment to the Northwest Power Act that formalized scientific peer review of the council's Fish and Wildlife Program and its varied individual projects. The authors of this article served as peer reviewers in the last decade. Restoration efforts in the Columbia River constitute a massive long-term attempt at fisheries and ecosystem restoration. In this article we examine some of the lessons we learned in reviewing the research, monitoring, and evaluation efforts of projects and their effects on advancing knowledge (i.e., adaptive management) in the Columbia River Basin Fish and Wildlife Program, one of the most ambitious and expensive long-term ecological restoration programs in the United States.

Research, Monitoring, and Evaluation of Fish and Wildlife Restoration Projects in the Columbia River Basin: Lessons Learned and Suggestions for Large-Scale Monitoring Programs

Research, Monitoring and Evaluation of Fish and Wildlife Restoration Projects in the Columbia River Basin:

Globally, there is increased scientific and public interest in the concept of ecosystem-based fisheries management (EBFM). This trend is fueled by a widespread perception that large-scale fishing operations are powerful forces altering the structure and function of marine ecosystems. It is acknowledged that management needs to better account for variations in ocean productivity, stock structure, and changing social values. Many countries are contemplating how to improve ocean fishery management. In the United States, fishery management bodies are experiencing pressure to undertake the daunting task of moving from their current single-species management plans to EBFM. Impediments include lack of a clear definition of EBFM, what it entails, or how to proceed. In this paper, characteristics of fishery management that are unique to EBFM are identified. The transition to EBFM needs to be evolutionary rather than revolutionary. A course of action is outlined that can be used to guide this transition. Modeling a...

Ecosystem-based fisheries management: some practical suggestions

12 – Federal and State Approaches to Salmon Recovery at the Millennium

Some salmon hatchery programs intentionally integrate the wild and hatchery population by taking naturally spawned fish as some fraction of the broodstock and allowing hatchery progeny to constitute some fraction of the adults spawning in the wild. This circumvents some ecological concerns about the effects of hatchery fish on the "wild" population while still reaping some of the benefits of increased potential for harvest, but it increases some genetic concerns. Here, we model phenotypic evolution in the integrated population to investigate the effects on natural spawning fitness at the joint selection and demographic equilibrium. We find a potential, but not a certainty, depending on quantitative aspects of the management interacting with biological characteristics of the stock, for substantial erosion of natural spawning fitness, compared with the original wild population, including the possibility of runaway selection driving natural spawning fitness effectively to zero. The vulnerability to such evolutionary deterioration increases with the magnitude of the contribution of hatchery breeding to the total production and increases with harvest. The response of the selection equilibrium to increasing contribution of hatchery progeny to the broodstock can exhibit a catastrophic discontinuity.

Some salmon hatchery programs intentionally integrate the wild and hatchery population by taking naturally spawned fish as some fraction of the broodstock and allowing hatchery progeny to constitute some fraction of the adults spawning in the wild. This circumvents some ecological concerns about the effects of hatchery fish on the "wild" population while still reaping some of the benefits of increased potential for harvest, but it increases some genetic concerns. Here, we model phenotypic evolution in the integrated population to investigate the effects on natural spawning fitness at the joint selection and demographic equilibrium. We find a potential, but not a certainty, depending on quantitative aspects of the management interacting with biological characteristics of the stock, for substantial erosion of natural spawning fitness, compared with the original wild population, including the possibility of runaway selection driving natural spawning fitness effectively to zero. The vulnerability to such evol...

Selection equilibrium for hatchery and wild spawning fitness in integrated breeding programs

Use of best science, by today’s standards, for managing salmon harvest, should mean employing a harvest control rule whose performance has been demonstrated to be at least as good as other practical alternative control rules in the context of a management strategy evaluation. Management strategy evaluation simulates performance of the candidate control rule in an operating model of the system consisting of the fishery, the fish stock, and its environment. Ideally, the operating model will be parametrized using all available data, weighted appropriately for the data quality, and analyzed by up-to-date statistical methods which quantify all relevant uncertainties as well as providing parameter estimates. This program of analysis is well recognized, in principle, within fisheries science, and was clearly defined and recommended by Hilborn and Walters (1992). A recent sophisticated and comprehensive theoretical treatment is given by Schnute et al. (2000).

UNCERTAINTY ANALYSIS OF STOCK RECRUITMENT RELATIONSHIPS FOR SELECTEDWESTERN ALASKA

Taking the Prior Seriously: Bayesian Analysis without Subjective Probability

Critical conservation decisions often hinge on estimates of population size, population growth rate, and survival rates, but as a practical matter it is difficult to obtain enough data to provide precise estimates. Here we discuss Bayesian methods for simultaneously drawing on the information content from multiple sorts of data to get as much precision as possible for the estimates. The basic idea is that an underlying population model can connect the various sorts of observations, so this can be elaborated into a joint likelihood function for joint estimation of the respective parameters. The potential for improved estimates derives from the potentially greater effective sample size of the aggregate of data, even though some of the data types may only bear directly on a subset of the parameters. The achieved improvement depends on specifics of the interactions among parameters in the underlying model, and on the actual content of the data. Assuming the respective data sets are unbiased, notwithstanding the fact that they may be noisy, we may gauge the average improvement in the estimates of the parameters of interest from the reduction, if any, in the standard deviations of their posterior marginal distributions. Prospective designs may be evaluated from analysis of simulated data. Here this approach is illustrated with an assessment of the potential value in various ways of merging mark-resight and carcass-survey data for the Florida manatee, as could be made possible by various modifications in the data collection protocols in both programs.

METHODS FOR JOINT INFERENCE FROM MULTIPLE DATA SOURCES FOR IMPROVED ESTIMATES OF POPULATION SIZE AND SURVIVAL RATES

The regional impacts of economic development incentives are studied in the context of a computable general equilibrium (CGE) model. The object is to evaluate the effectiveness of several incentives used to attract new businesses in the city of Pueblo, Colorado. The results show that the regional benefits of these incentives are relatively small, and the net benefits to the local population when all impacts are accounted for are likely to be negative. Instead, the benefits are largely transferred to new businesses and employees who migrate to the region in response to the incentives. Contrary to perceptions about the multiplier impacts of economic development, the net impact on the local manufacturing sector is negative as well. The incentives cause a substitution effect, as investment is shifted toward export-oriented manufacturing sectors that are favored for economic development. These results address the seeming paradox that economic development can attract new businesses and jobs, yet be unpopular enough among local residents for them to vote against continuing it.

Are Economic Development Incentives Worth it? A Computable General Equilibirum Analysis of Pueblo, Colorado's Efforts to Attract Business

ISAB Comments on Draft NOAA Technical Recovery Team Documents Identifying Independent Salmonid Populations Within Evolutionarily Significant Units (Review of Interior Columbia TRT Draft Document)

Development of a yield prediction model for site-specific management of herbicide and fertilizer.

Scientific Review of the Harvest Strategy Currently Used in the BSAI and GOA Groundfish Fishery Management Plans

Risk assessments inevitably extrapolate from the known to the unknown. The resulting calculation of risk involves two fundamental kinds of uncertainty: uncertainty owing to intrinsically unpredictable (random) components of the future events, and uncertainty owing to imperfect prediction formulas (parameter uncertainty and error in model structure) that are used to predict the component that we think is predictable. Both types of uncertainty weigh heavily both in health and ecological risk assessments. Our first responsibility in conducting risk assessments is to ensure that the reported risks correctly reflect our actual level of uncertainty (of both types). The statistical methods that lend themselves to correct quantification of the uncertainty are also effective for combining different sources of information. One way to reduce uncertainty is to use all the available data. To further sharpen future risk assessments, it is useful to partition the uncertainty between the random component and the component due to parameter uncertainty, so that we can quantify the expected reduction in uncertainty that can be achieved by investing in a given amount of future data. An example is developed to illustrate the potential for use of comparative data, from toxicity testing on other species or other chemicals, to improve the estimates of low-effect concentration in a particular case with sparse case-specific data.

Extrapolation in Risk Assessment: Improving the Quantification of Uncertainty, and Improving Information to Reduce the Uncertainty

-A Bayesian time series analysis technique, the dynamic linear model, was used to analyze counts of Trumpeter Swans (Cygnus buccinator) summering in Idaho, Montana, and Wyoming from 1931 to 2000. For the Yellowstone National Park segment of white birds (sub-adults and adults combined) the estimated probability of a positive growth rate is 0.01. The estimated probability of achieving the Subcommittee on Rocky Mountain Trumpeter Swans 2002 population goal of 40 white birds for the Yellowstone segment is less than 0.01. Outside of Yellowstone National Park, Wyoming white birds are estimated to have a 0.79 probability of a positive growth rate with a 0.05 probability of achieving the 2002 objective of 120 white birds. In the Centennial Valley in southwest Montana, results indicate a probability of 0.87 that the white bird population is growing at a positive rate with considerable uncertainty. The estimated probability of achieving the 2002 Centennial Valley objective of 160 white birds is 0.14 but under an alternative model falls to 0.04. The estimated probability that the Targhee National Forest segment of white birds has a positive growth rate is 0.03. In Idaho outside of the Targhee National Forest, white birds are estimated to have a 0.97 probability of a positive growth rate with a 0.18 probability of attaining the 2002 goal of 150 white birds.

Bayesian time series analysis of segments of the Rocky Mountain trumpeter swan population

Abstract Chinook salmon (Oncorhynchus tshawytscha), hatchery-reared as juveniles, returned to the upper Columbia River Basin in numbers exceeding broodstock and fishery needs during the spring of 2000. Plans to euthanize these adults were opposed by some regional stakeholders, who preferred letting them spawn naturally in streams also used by endangered spring-run chinook salmon. The National Marine Fisheries Service requested that the Independent Scientific Advisory Board review the scientific literature and conclude whether it was biologically sound to permit hatchery-origin adult salmon to spawn in the wild in large numbers. Substantial experimental evidence demonstrates that domestication selection can genetically alter hatchery populations in a few generations and that hatchery-origin adults returning from the ocean and spawning in the wild produce fewer progeny than adults of wild origin spawning in the wild. More limited evidence suggests that interbreeding between hatchery-origin adults and wild f...

Abstract The adoption of precision technologies that spatially register measurements using global positioning systems (GPS) greatly facilitates conducting large-scale on-farm research by farmers. On-farm experiments that utilize producer equipment include variations in agronomic practices that occur in situations where we want to predict the effect of inputs on yield. The domain of inference for such on-farm studies therefore more closely matches that desired by researchers. To investigate the feasibility of on-farm research using GPS, a study was conducted to evaluate the potential benefit of site-specific weed management. The study utilized producer-maintained field-scale equipment on four Montana farms in dryland spring wheat production. Paired site-specific and whole-field herbicide treatment areas were established in 0.9 to 1.9-ha blocks using consultant weed maps and a geographic information system (GIS). Yield was unaffected by herbicide treatment strategy (site-specific or broadcast). Minimal detectable yield differences were evaluated for the experimental design (0.2 T ha−1). Net returns increased when the percentage of field infested by wild oat decreased. Visual ratings of wild oat density taken at harvest indicated no difference in wild oat control between treatments in two of four site-years. This research suggests that producer-owned equipment can be used to compare treatments, but the accuracy and subsequent power of such comparisons are likely to be low. Nomenclature: Fenoxaprop; imazamethabenz; tralkoxydim; kochia, Kochia scoparia L. KCHSC; Russian thistle, Salsola iberica Sennen and Pau SASKR; spring wheat, Triticum aestivum L; wild oat, Avena fatua L. AVEFA.

Implementing and conducting on-farm weed research with the use of GPS

Model Synthesis Report An Analysis of Decision Support Tools Used in Columbia River Basin Salmon Management

The November 30, 2000 Biological Opinion (Nov2000BiOp) prepared by the National Marine Fisheries Service (NMFS) resulted in a finding of jeopardy to the Endangered western stock of Steller sea lions (SSL; Eumetopias jubatus) relative to fisheries for pollock, Atka mackerel, and Pacific cod under management jurisdiction of the North Pacific Fisheries Management Council (Council). The Nov2000BiOp set forth a set of management measures (termed reasonable and prudent alternatives or RPAs) intended to alleviate jeopardy if implemented in the 2001 fishing season. There is continuing scientific debate about the evidence regarding food competition between SSL and these commercial fisheries, and the role of other factors that might be limiting the recovery of SSL, and the implications of this evidence for the conclusions of the Nov2000BiOp. The Council initially tasked this team to review the Nov2000BiOp with particular focus on the following three tasks: 1) determine the types of information that should be collected and analyses necessary to demonstrate an unequivocal adverse affect of commercial groundfish fisheries on SSL mortality, 2) recommend an appropriate experimental design to improve our understanding of the interactions between fisheries and SSL, and the efficacy of imposed management measures to promote recovery of the SSL population, and 3) review reports of stressed pinniped populations worldwide. Subsequent to the team's interim report to the Council, NMFS released a new draft Biological Opinion in August 2001 (Aug2001BiOp) as Appendix A to a Supplemental Environmental Impact Statement. The team was asked to review both the new biological information on SSL and the analyses used in the development of the new RPAs. We refer to this as Task 4. The overall conclusion of the Nov2000BiOp is that there is great uncertainty about the effects of the groundfish fisheries on SSL, but it is possible that these effects could be negative. However, the evidence presented in the Nov2000BiOp is almost entirely circumstantial. With respect to many of the key hypotheses (e.g., local depletion of prey by fishing, effects of local depletion on SSL) there are essentially no direct data bearing on the specific mechanisms for the effects of fishing on SSL. For the most part, the arguments in the Nov2000BiOp are constructed on the basis that such effects are possible, biologically imaginable, and are not contradicted by the available data. 3 There is no question that the number of SSL in the western stock has declined dramatically since the 1970s. However, there …

Statement with Respect to the Western Stock of the Steller Seal Lion , with Comments on the Draft August 2001 Biological Opinion

Review of the November 2000 Biological Opinion and Incidental Take Statement with respect to the Western Stock of the Steller seal lion

Parameterizing weed interference models with site specific data.

Richard Alldredge, Washington State UniversityPeter Bisson, ISRP member through FY1999 Review; United States Forest ServiceDaniel Bottom, Oregon Department of Fish and WildlifeGlen Cada, Oak Ridge National Laboratories, Environmental Sciences DivisionDouglas Crowe, Wildlife Consultant, WyomingKen Currens, Northwest Indian Fisheries CommissionPeter Delaney, Department of Fisheries and Ocean, Vancouver, BCRobert Gresswell, Northwest Biological Science Center, USGSJack Griffith, Idaho State UniversityJames Hall, Oregon State UniversityDavid Hankin, Humboldt State UniversityBrent Hargreaves, Pacific Biological Station, Nanaimo, B.C.Robb Leary, University of MontanaHiram Li, Oregon State UniversityJack McIntyre, Fisheries ConsultantPhillip Mundy, Fisheries and Aquatic Sciences, ConsultantDavid Philipp, Illinois Natural History SurveyDaniel Pletscher, University of MontanaThomas Quinn, University of WashingtonAndrew Sheldon, University of MontanaSi Simenstead, University of WashingtonAlan Springer, University of AlaskaGilbert Sylvia, Hatfield Marine Science Center, Oregon State UniversityBruce Ward, University of British ColumbiaRay White, Trout Habitat Specialists, ConsultantRobert White, Montana State UniversityJack Williams, United States Forest Service, Boise National Forest

Volume II: Review and Recommendations of Individual FY2000 Project Proposals

A computable general equilibrium model of the southeastern Colorado economy is used to compare the economic impacts of a proposed increase in reservoir storage to an alternative: temporary water transfers. While both provide municipalities with reliable water supply during droughts and are shown to benefit both rural and urban communities, temporary transfers are accomplished at a much lower economic and environmental cost. This analysis illustrates how computable general equilibrium models provide a more realistic portrayal of the impact of policy changes than input-output analysis by allowing substitution in response to economic conditions.

MORE RESERVOIRS OR TRANSFERS? A COMPUTABLE GENERAL EQUILIBRIUM ANALYSIS OF PROJECTED WATER SHORTAGES IN THE ARKANSAS RIVER BASIN

The Northwest Power Planning Council (Council) requested the Independent Scientific Advisory Board (ISAB) to undertake a review of the impacts of estuarine conditions on the Council's mission to " protect, mitigate and enhance " fish and wildlife in the Columbia River as affected by development and operation of the hydroelectric system. The ISAB agreed to undertake the review but cautioned that it was unlikely that it could quantify the impact of changes in the estuary relative to specific program or management actions taken in the upper river. The ISAB could, however, provide a historical perspective and qualitative assessment of impacts, identify potentially useful collaborations, and provide recommendations concerning future efforts needed to more quantitatively address this issue (letter to Council, Jan. 26, 2000). While conducting this review the ISAB became aware that there was extensive overlap between a study by the National Marine Fisheries Service (NMFS) and this ISAB assignment. The ISAB expects the NMFS study will add significantly to an informed response to the Council. Consequently, this report has been prepared as a preliminary reply, with additional detail possible following publication of the NMFS study. Before human influence, the Columbia River estuary was a high-energy environment dominated by physical forces, with extensive sand-beds and highly variable river flows. Several authors have suggested that the biological processes in this environment may have been unique on the Pacific coast. The estuary of today, however, has been extensively modified in terms of physical and biological processes. The development and operation of the hydroelectric system have contributed significantly to these changes. Direct effects have been through changes in seasonal flow rates, reduced sediment discharge, and resultant changes in the estuary's energy balance. There is extensive documentation about changes in the estuary over the past century. The major changes resulting from development of peripheral wetlands and their isolation from the estuary, development and deepening of the Federal Navigation Channel, and regulation of upper Columbia River flows for hydrosystem needs and flood control. The effects of these changes do not function discretely. The estuary is a complex interaction of physical features (predominated by the energy balance between river flow and tidal forces), resultant changes in circulation, salinity intrusion, sediment processes, and ultimately the biological consequences of these changes. Superimposed on this dynamic environment have been changes in water quality, introduction of exotic species, and the enormous investment in hatchery production of salmonids to mitigate for …

The Columbia River Estuary and the Columbia River Basin Fish and Wildlife Program

Land Claim Agreements and the Management of Whaling in the Canadian Arctic (第11回北方民族文化シンポジウム「開発と北方諸民族」)

Apparatus and method for bypassing eject gas around an annular seal disposed between the trailing end of a missile and a launch tube only in an area where the trailing end of the missile is close to the launch tube in order to provide a centering force on the trailing end of the missile to stabilize the in-tube trajectory of the missile during ejection.

Review of the Columbia River Basin Fish and Wildlife Program as directed by the 1996 amendment to the Power Act

A qualitative determination of whether a population is above or below its MNPL can be carried out under circumstances where the value of the MNPL itself, and other details of the production curve, cannot be estimated. This qualitative assessment may often be sufficient for management decisions. The method proceeds by locally approximating the production curve, in the neighborhood of the present population density, from data on population sizes and harvests, and then determining whether this represents the ascending or descending arm of the curve. When the harvests are small, or when the harvests are a constant fraction of the production, the population-size data need only be relative. With adequate quantities of data, this assessment method can accommodate random measurement error and random perturbations in the dynamics of the population system.

DYNAMIC RESPONSE ANALYSIS. I. QUALITATIVE ESTIMATION OF STOCKSTATUS RELATIVE TO MAXIMUM NETPRODUCTIVITY LEVEL FROMOBSERVED DYNAMICS

: Recent reformulation of the birth-and-death process model to include the effects of environmental variation on stochastic demography presents a pessimistic view of the prospects for persistence of small populations. The models indicate that modest increases in population size, or in the mean (positive) growth rate of the population, do not dramatically increase the mean persistence time. The key to long-term persistence seems to lie in reducing the variance in the population growth rate. 
 
Natural populations, of those species that are not numerous, achieve their persistence through a variety of variance-reduction mechanisms. These notably include: I) risk-averaging by wide geographic distribution over areas that experience mutually independent environmental variation, and 2) reliance on restricted “hot spots” of especially favorable habitat where the local population growth rate is almost invariably strongly positive when the population is not crowded. 
 
These natural mechanisms depend on a spatial scale, and on species-specific richness of habitat, which is not readily attained for many species on biological reserves with a “hamis-off” management policy. However, these mechanisms can be mimicked by management intervention strategies-particularly by reintroduction programs in an “archipelago” of geographically dispersed reserves that are otherwise mutually isolated and by resource augmentation, predator and disease control, and other survival-and-reproduction enhancement programs implemented specifcally at times when the population is at a low ebb. 
 
Resumen: La reciente reformulacion del modelo de proceso nacimiento-muerte, que incluye los efectos de cambios—ambientales sobre demografia estocastica, presenta una version pesimista para con las perspectivas de persistencia de poblaciones pequenas. Los modelos indican que un incremento modesto en el tamano de la poblacion o en la media de su tasa de incremento (positivo), no aumenta dramati-camente la medida del tiempo de persistencia de la poblacion. La clave, para la persistencia de poblaciones en el largo plazo, pareciera encontrarse en la reduccion de la variaciones de la tasa de incremento poblacional. 
 
Las poblaciones naturales, de aquellas especies que no son numerosas, consiguen persistir mediante una variedad de mecanismos de reduccion de la varianza en la tasa de su incremento poblacional. Estos incluyen notablemente a 1) promediacion del riesgo a traves de una amplia distribucion geografica sobre areas que experimentan variaciones am-bientales en forma independiente mutuamente, y 2) ocupacion de “sitios especiales” donde el region es especialmente favorable, lo cual permite que la tasa de incremento poblacional sea fuertementepositiva e invariable siemprey cuando no exista una diversidad excesiva. 
 
Estos mecanismos naturales dependen de una escala especial y riqueza de regiones especificas para una especie dada, que no se consigue facilmente para rnuchas especies en aquellas reservas biologicas que no tengan un manejo intensivo. Sin embargo, estos mecanismos naturales pueden ser reproducidos mediante estrategias de intervenciones de manejo. Ello, particularmente, por medio de programas de re-introducion en un “archipielago” de resmas geograficamente dispersas que de otra forma estarian aisladas entre ellas. Asi mismo, se puede lograr lo senalado mediante el aumento de los recursos ambientales requeridos por una especie dada, por el control de predatores y enfmedades y por medio de otros programas que incrementen la supervi-venciay reproduccion de poblaciones, especialmente cuando se implementan en los momentos cuando las poblaciones se encuentran en condiciones pauperrimas.

CONSIDERATION OF STOCHASTIC DEMOGRAPHY IN THE DESIGN AND MANAGEMENT OF BIOLOGICAL RESERVES

Viable Populations for Conservation: The demography of chance extinction

Risk spreading as an adaptive strategy in iteroparous life histories.

Reproductive value is the central construct in life history optimization. In the optimal life history, the reproductive value at every age represents the solution to a constrained maximization problem. This holds true regardless of trade-offs across age classes. The recent literature arguing to the contrary has misunderstood the principle and has neglected the constraints in the maximization. In reviewing the matter, this paper considers maximization over segments of the life history, maximization over segments taken in reverse sequence, maximization of terms of a decomposition into instantaneous contributions at a given age, and maximization of reproductive value over alternative states such as the sexes. To clarify the relation between the maximization procedure and the constraints, a simple iterative approach to achieving maximization and simultaneously satisfying the constraints is described. To arrive at the instantaneous decomposition, it is shown that reproductive value arises as an adjoint variable in an optimal control formulation, where effects across age classes are explicitly incorporated in a variable representing physiological state. In considering alternative states, this paper defines a male reproductive value and concludes that at equilibrium sex composition, the reproductive values of each sex will be equal at any age where a sex change is possible. Coincidentally, some common errors in the discrete time formulation of reproductive value and Lotka's equation are corrected.

Optimal Life Histories, Optimal Notation, and the Value of Reproductive Value

The maximum yield problem: Distortion in the yield curve due to age structure

We model the effects of environmental fluctuation on population growth as acting through an interaction between microhabitat heterogeneity and fluctuations in a regional environmental variable. The results are richer in biologically important detail than are the results of introducing a simple noise term to modify a variable in a model, such as the logistic. In particular, we find that the value of a parameter describing the mean value of a random environmental variable affects both the variance and the skew of the frequency distribution of regional carrying capacity for the species, which in turn will contribute to determining the species' manner of population fluctuation. We broadly classify the patterns of fluctuating carrying capacity according to the skew. Three basic patterns emerge, and we name these and relate them to the selective circumstances that they will engender. They involve, respectively, survival in a predominantly unfavorable environment (adversity selection), utilization of an unpredictable and intermittently favorable environment (exploitation selection), and competition in a predominantly favorable and fully occupied environment (saturation selection). Using these patterns of fluctuation in conjunction with two models of population growth, we obtain population simulations which suggest demographic strategies appropriate in each context. The regimes are not readily categorizable as to the intensity of r-selection versus K-selection, which suggests that the r-K classification is oversimplified. The nature of the fluctuations in growth parameters experienced by a given species are sufficiently sensitive to properties of the species itself that many different adaptive demographies may be represented in a community occupying a single environment.

Classifying Species According to Their Demographic Strategy. I. Population Fluctuations and Environmental Heterogeneity

Using the ratio of effective reproduction to survival rate, with time scaled in units of time till independence, as an index to age specific reproductive effort, we ask how optimal reproductive effort should vary when environmental conditions change. With an idealized portrayal of the effects of environmental change introduced to a fitness set analysis of the trade-off between reproduction and survival, we find that the optimal reproductive effort is indifferent to environmental change. Deviations from this null case are obtained in a more general model, where we find that a pattern of increasing reproductive effort with environmental amelioration and decreasing reproductive effort with environmental deterioration is predicted when older breeding age classes are less affected by environmental change that are younger age classes, or when the potential adult survival rates are less affected by environmental change than are the potential survival rates of dependent young or the potential natality rates. Where the converse of these conditions obtains, the reverse pattern of change of reproductive effort will be favored. The assumptions of the null-case model provide precise definitions of the threshold conditions at which the pattern of reproductive effort will switch from one type to the other. The circumstances under which regulation of reproductive effort is predicted to be expressed as an increase in reproductive effort in more favorable times and a decrease in less favorable times are commonly met, especially in the life histories of many long-lived vertebrates. Thus the analysis of optimal life histories offers a competing explanation for some patterns of reproductive behavior that are otherwise described as social adaptations that evolved in response to the selective advantage of population regulation.

If competition within some guild were always for the same resource, and pursued in the same way, it would be a simple matter to rank species unambiguously on the basis of their competitive abilities. Competitive rank could be assigned according to how effectively any species preempted that resource in that way. As it happens, surprisingly simple systems may defy this sort of analysis. For example, F. E. Smith (unpubl.) investigated patterns of sapling distribution in a beech-maple woodland, where robust maple saplings were found predominantly under beech canopy trees, and robust beeches under maple. As both trees are well represented dominants in the climax forest it is not immediately clear how they should be ranked competitively, especially since we cannot simply say that one or the other species is superior in its primary struggle (competitive sapling growth) for a fundamental resource (space). The reason is that, contrary to what we might have first expected, the saplings perceive two fundamental resources (space under a beech canopy tree, and space under a maple) and one species is the superior competitor for one resource, while the second is superior at the other resource. That competing species may partition a resource is a classic observation (Gause, 1936), well integrated in modern ecological analysis (e.g., Schoener, 1968); what is novel in the present example is that the essence of the partitioning is entirely contingent upon the presence or absence of the respective competitor species, rather than somehow being an intrinsic subdivision of their common "environment." As the multiplicity of objects of competition of this sort can increase in proportion to the total number of competing species, one implication is that competitive ranking may be ambiguous. If species A outcompetes B and B outcompetes C, the object (or manner) of competition may be different for the two pairs, in which case we have no a priori way of predicting the outcome of, say, A competing against C. For this third pairwise interaction, the critical resource might be either of the resources which respectively determined the interaction of the other two pairs, or it might even be a third. So it may be quite consistent biologically that species A outcompetes B, B outcompetes C, and C outcompetes A. In this situation we would judge the competitive relation between the three species to be intransitive; and, in the context of a competitive ranking of the three species in some single dimension, their pairwise competitive relations are mathematically inconsistent. The degree of intransitivity of competitive relations can serve as an indirect measure of the dimensionality of the resource space the competitors perceive. The number of effective resources available to a competition community will determine the maximal number of species that can persist in a stationary state (Levin, 1970). Intransitivities may permit continued coexistence of competitors with stable oscillation of numbers (Gilpin, 1975). Thus it is of interest to know what is the extent of intransitivity in pairwise interactions between competitors. In this paper, I report the results of an attempt to assay these properties in a suite of Drosophila species in laboratory culture.

About twenty years ago, the belief, traditional among ecologists, that complex natural communities are more stable than simple ones was given formal expression in a way that seemed to offer promise of both precise empirical tests and further theoretical development. The elaboration of theoretical models at first yielded gratifying results suggesting reasons why complex ecological systems should indeed be more stable, but these models suffered from questionable analogies and the use of peculiar and unrealistic mathematical representations. The broad scope of the diversity-stability hypothesis, and its particular implications, elevated it to a position importance in practical debates concerning resource management, pest control, and preservation of natural areas. Observational confirmation of the diversity-stability hypothesis never materialized. In this paper we review the development of the diversity-stability hypothesis, evaluate attempts to support or refute it, and suggest an alternate perspective for interpreting population stability. We conclude that there is no simple relationship between diversity and stability in ecological systems.

Where reproductive effort subjects the parent to a risk, the benefit of some breeding activity's contribution to present fitness must be weighed against the loss to future fitness. With risk and benefit defined in terms of life-table parameters, a simple model for a long-lived iteroparous organism permits calculation of the quantitative relation between risk and benefit necessary if an increase in reproductive effort is to be selected for. Constraints on the maximal real benefit establish a corresponding risk ceiling which represents that lowest increment to reproductive cost which can not be compensated by any realizable cost-benefit ratio. Application of this model to data for some offshore-feeding seabirds indicates that an increased reproductive effort will be selected for in these organisms only if the fractional amount by which fledging success increases is at least 19 times greater than the fractional amount by which parental survivorship is decreased. The calculated margin of possibly compensable mortality increment is .28 deaths per capita. These rather stringent conditions on reproductive effort help account for some otherwise puzzling features of the reproductive strategy of oceanic seabirds: namely, deferred maturity, delayed resumption of breeding after a failed attempt, and nest desertion and abondonment of courtship and nest building during periods of stress. While the model only considers Darwinian fitness at the level of the individual, the demographic properties selected for in this particular instance may significantly stabilize the population and create a misleading impression of selection for stability and reproductive restraint.

The paleoecology of the Tower Island bird colony : a critical examination of complexity-stability theory /

A 4-m drill core of undisturbed sedimentary rock from the crater lake on Isla Genovesa (Tower) has well-defined banding, revealing a complex depositional End_Page 333------------------------------ history spanning at least 5,000 years. Amidst the bands are intervals of translucent green gel, with white granular inclusions in places. One section of gel occupies an interval of nearly 10 cm, and the uppermost is within 20 cm of the rock/water interface. Three hypotheses describing the structure of the gel seemed plausible: that it was a proteinaceous gel, a polysaccharide gel, or a silica gel. Infrared spectroscopy of a sample which had separated during storage revealed no absorption at 6 µ, precluding the presence of peptide bonds. There was little in the spectra to suggest that saccharides were present, but strong absorption between 9 and 10 µ suggested abundant silicon. X-ray diffraction of samples soaked in distilled water gave strong indications of halite, which wou d mask the presence of silicon. D.C. arc emission spectroscopy showed the sample to be rich in silicon, sodium, calcium, and magnesium, and to contain trace amounts of other elements normally present in seawater. We conclude that the sample is a silica gel, hydrated with seawater and containing microcrystals of sodium and magnesium salts. The gels formed on the bottom of a lake which is now 30 m deep and with a salinity of 52 ^pmil, or half again as salty as seawater. The lake is highly productive so that reducing conditions with free sulfides prevail at the bottom. This fertile condition is apparently maintained by a large input of guano from the immense colonies of seabirds which inhabit the island. Study of diatoms and other fossils incorporated in the gels, and of the pigments preserved in them, is enabling us to reconstruct the environment in which a silica gel forms under the waters of this crater lake. These conclusions may prove useful when seeking to explain the origin of cherts. End_of_Article - Last_Page 334------------

Recent Silica Gel from Saline Lake in Galapagos Islands: ABSTRACT

Madness of this magnitude is a uniquely contemporary phenomenon. The capacity to wreak global havoc and the ability to predict that we are going to exercise this demonic capacity in an increasingly destructive fashion are both very recent additions to our cultural repertoire. Scarcely 10 years ago, members of the scientific community could, with only scattered misgivings, believe that our society was pursuing a sane and fruitful course. It was an honest mistake then. Today, that sort of faith can only be the product of perverse selfdeception in the face of painfully discouraging environmental inventories (NAS, 1969), and well-documented indictments of the technological quickfix (Ehrlich and Holdren, 1969). If men of goodwill and understanding are obliged by reason to admit the error of their culture's ways, will not those errors be automatically corrected? Is it not fundamentally impossible for an entire civilization to apply its efforts toward goals it does not want? The burden of this paper shall be to suggest that the most appropriate answer to both these questions is "No." I shall further attempt to show that the very expectation of automatic social regulation and self-correcting policy formation is, in fact, a major contributor to ecological irrationality. It is difficult for those of us steeped in the lore of systems analysis to conceptualize the awesome discrepancies between the acknowledged goals of a society and the actual effects of a society directing its activities toward a realization of those goals as perceived. To gain any understanding of the situation we first must remind ourselves

OBJECTIVE
To report the results of penetrating keratoplasty performed by residents.

METHOD
A retrospective medical record review of all patients undergoing penetrating keratoplasty performed by residents at our institution from April 1998 to April 2002.

RESULTS
Forty penetrating keratoplasty procedures were performed by 8 residents. The most common indication was keratoconus (17 eyes [43%]), followed by corneal scarring (14 eyes [35%]). Mean preoperative best-corrected visual acuity was 20/250. No intraoperative complications were reported. Mean follow-up time was 15 months. Postoperatively, mean best-corrected visual acuity was 20/40, mean postoperative astigmatism was 3.4 +/- 2.1 diopters, and graft survival was 92.5%. Postoperative complications included elevated intraocular pressure, wound dehiscence, and endophthalmitis.

Best-corrected visual acuity, postoperative astigmatism, graft survival, and intraoperative and postoperative complications.

Residents can be introduced to penetrating keratoplasty and achieve surgical success with intraoperative and postoperative complication rates similar to those previously published.

Clinical and ultrastructural features of a novel hereditary anterior segment dysgenesis.

PURPOSE
The development of bacterial keratitis after laser in situ keratomileusis (LASIK) has been described in only a few isolated cases. We report the development of bacterial keratitis as a postoperative complication of LASIK in three subjects.

DESIGN
A retrospective interventional small case series.

Three patients who underwent LASIK for correction of myopia during July and August 1998 and had bacterial keratitis develop after surgery.

METHODS
Bacterial keratitis was encountered in the operated eyes between 1 and 22 days after surgery. Topical antibiotic therapy was administered. In one eye, which had significant opacification and irregularity of the flap was developed, lamellar keratoplasty was performed.

Postoperative inflammation was followed clinically and photographically until it resolved. Visual acuity was measured at intervals throughout the follow-up period.

RESULTS
Keratitis resolved within 3 to 16 days of starting antibiotic therapy. The final best-corrected visual acuities were 20/30, 20/15, and 20/25.

Although infectious keratitis after LASIK is an infrequently reported event, it should be discussed preoperatively with patients as a possible complication.

Bacterial keratitis after [correction of following] laser in situ keratomileusis.

Simplifying Phacoemulsification. Safe and Efficient Methods for Cataract Surgery, Fifth edition, Paul S. Koch. SLACK, Inc, Thorofare, New Jersey (1997), 240, index, illustrated. $65

PURPOSE
To purify and characterize a cornea-associated antigen (CO-Ag) and to determine antibody levels to CO-Ag in patients with Mooren's ulcer.

METHOD
Standard ion exchange and gel filtration chromatographies were used to isolate and purify CO-Ag from crude bovine stromal extracts. The serum of a patient with Mooren's ulcer, containing a high level of antibodies directed against CO-Ag, was used to monitor isolation procedures. Using this newly purified CO-Ag, an enzyme-linked immunoabsorbent assay was used to detect the presence of antibodies to CO-Ag in the sera of other patients with Mooren's ulcer.

RESULTS
CO-Ag was purified to apparent homogeneity from bovine corneal stromal extracts by a series of ion exchange chromatographies and gel filtration. Polyacrylamide gel electrophoresis showed that CO-Ag was a tetramer with a molecular weight of 30,000 d that may dissociate under denaturing conditions into a monomer of 7000 d. Strong indirect immunofluorescent staining was demonstrated of the stroma by guinea pig anti-CO-Ag antibody. A statistically significant difference in the level of specific antibodies to CO-Ag between patients with Mooren's ulcer and controls was found (P < 0.001). The antibody level was elevated in patients with Mooren's ulcer (mean antibody level, 0.58 +/- 0.13) compared with the controls (mean antibody level, 0.22 +/- 0.04).

These results suggest that an autoantigen exists in the corneal stroma that reacts with serum antibodies from patients with Mooren's ulcer. The availability of a purified corneal antigen could facilitate the diagnosis and define the pathogenetic mechanisms in Mooren's ulcer.

Autoimmunity to a cornea-associated stromal antigen in patients with Mooren's ulcer.

It has been known for almost a century that radial keratotomy (RK) will flatten the cornea and reduce myopia. Since the introduction of radial keratotomy (RK) in the United States by Bores in 1978, there have been many published studies documenting the effects of this procedure. The questions. about radial keratotomy today are not only quantitative but also qualitative in nature. We know this technique can flatten the cornea, but how reliably can the results be predicted? Does the patient benefit suffic...

Intraocular lens implantation after cataract extraction has become a common practice in the United States. However, unwanted optical images can correct an otherwise successful surgery into one that causes patient dissatisfaction. Refinements in manufacturing design and finishing have greatly improved the quality of present day intraocular lenses, but there is continued interest in simulating the optics of the human crystalline lens. We will discuss the optical requirements of intraocular lenses and how these are influenced by optic design and dimension, and spectral transmission characteristics.

Because of the high incidence and great variety of complications associated with anterior chamber intraocular lenses, we have developed a technique for the implantation of a posterior chamber intraocular lens in the absence of posterior capsular support. The posterior chamber IOL is placed in the ciliary sulcus by suturing the superior haptic to the iris and the inferior haptic to the sclera at the ciliary sulcus. We have used this technique successfully in both complicated extracapsular surgery and secondary intraocular lens implantation.

Posterior chamber intraocular lens implantation in the absence of posterior capsular support.

Although epikeratoplasty (epikeratophakia) for aphakia in children has achieved a high degree of success, there remains a significant incidence of complications, some of which may result in removal of the lenticule. We report a 2-year-old child in whom epikeratoplasty was followed by an acute suppurative keratitis, necessitating removal of the epikeratoplasty lenticule. The recipient bed remained scarred following removal of the lenticule with anterior stomal fibrosis, which precluded good vision. We were able to avoid a penetrating keratoplasty by performing a superficial lamellar keratoplasty with a repeat epikeratoplasty that has remained clear.

Lamellar keratectomy and repeat epikeratoplasty following failed epikeratoplasty. A clinicopathologic report.

To avoid the complications associated with anterior chamber intraocular lenses (IOLs), we have developed a technique for the implantation of a posterior chamber IOL in the absence of capsular support. The IOL is secured in the ciliary sulcus by suturing the haptics to the sclera at the ciliary sulcus inferiorly and to the sclera or iris superiorly. We have used this technique for secondary IOL implantation in 16 contact lens-intolerant patients with aphakia with a mean follow-up of 9 months (range, 5 to 20 months) and in eight eyes at the time of IOL removal. All eyes with secondary implants had equal or improved vision postoperatively; none developed persistent angiographic cystoid macular edema. In the 8 patients with IOL exchange, visual acuity improved in five eyes, remained the same in two, and decreased two lines in one. Suturing of an IOL in the ciliary sulcus has enabled us to use a posterior chamber IOL in eyes without a posterior capsule when secondary IOL implantation or IOL exchange is indicated. Secondary posterior chamber IOL implantation is recommended only when satisfactory vision cannot be achieved with glasses or contact lenses, and further follow-up is needed before this procedure can be widely recommended.

Posterior chamber intraocular lens implantation in the absence of capsular support.

Due to continued improvement in lens design, lens manufacturing, and surgical technique, the incidence of complications of cataract surgery with intraocular lens (IOL) implantation have decreased in recent years. Complications may be categorized into operative and postoperative, both early and late onset. Operative complications include posterior capsule rupture with or without vitreous loss, loss of all or part of the lens nucleus, iris damage, and stripping of Descemet's membrane. Early postoperative complications include pupillary block, hyphema, elevation of the intraocular pressure associated with the use of viscoelastic substances, persistent uveitis with or without hypopyon, and endophthalmitis. Late postoperative complications include IOL malposition, secondary glaucoma, cystoid macular edema, retinal detachment, and pseudophakic bullous keratopathy.

Complications of cataract extraction with intraocular lens implantation.

We examined seven patients who had a syndrome of symptomatic monocular blind spot enlargement without optic disc edema. Two patients had previous blind spot enlargement that resolved over several months. The scotoma in each patients was absolute, measured 15 degrees to 20 degrees in diameter, had steep geographic margins, and extended to within 5 degrees to 10 degrees of fixation. Typically, patients had normal visual acuity, color vision, pupillary responses, and ophthalmoscopic findings. Photostress recovery, tested in two patients, was prolonged in the affected eye. Fluorescein angiography showed no abnormalities corresponding to the scotoma. Orbital computed tomographic scans in three patients and visual evoked responses in one patient were normal. Multifocal electroretinography, performed in two patients, showed loss of retinal waveforms in a large region surrounding the optic disc. Our findings suggest that retinal dysfunction produces this big blind spot syndrome, but we do not know its cause.

Acute idiopathic blind spot enlargement. A big blind spot syndrome without optic disc edema.

To the Editor. —Chronic blepharitis is one of the most common ocular disorders in humans. 1 It often can be a very annoying and difficult condition to treat. Whereas some patients complain only of red and itchy eyes, blepharitis can also make the adaptation to contact lenses extremely difficult, aggravate or slow the treatment of keratitis sicca, endanger intraocular surgery, or lead to corneal complications, such as toxic epithelial keratitis, catarrhal ulceration, or phlyctenulosis. 2 There is no definitive and precise treatment for this condition. However, it is well accepted that lid scrubs may improve the condition for long periods. Baby shampoo has been the usual medication for lid scrubs in chronic blepharitis. However, a number of patients complain of irritation when using this shampoo if it spills onto the conjunctival surface. Recently, we tried a new detergent called I-Scrub (Spectra Pharmaceutical Services Inc, Hanover, Mass), which we have found

Experience with a new detergent lid scrub in the management of chronic blepharitis.

Staphylococcus epidermidis accounts for nearly one third of all cases of bacterial keratitis in certain geographic areas. Recently, the sensitivity of this organism has changed dramatically so that nearly half of nosocomially acquired systemic S epidermidis infections are resistant to methicillin sodium, cephalosporins, and aminoglycosides. Methicillin-resistant and gentamicin sulfate-resistant S epidermidis causing infectious blepharoconjunctivitis and endophthalmitis has previously been reported. Two cases of methicillin- and gentamicin-resistant S epidermidis keratitis occurred that were treated successfully with topical vancomycin hydrochloride.

Methicillin-resistant Staphylococcus epidermidis keratitis treated with vancomycin.

Aneurysms of the intracavernous portion of the internal carotid artery may become very large, but they very rarely rupture. A case is described in which rupture of such a lesion resulted in a lethal massive subdural hematoma with transtentorial herniation. This is the second reported case of substantiated intracranial rupture from a wholly intracavernous carotid artery aneurysm.

Rupture of cavernous carotid artery aneurysm causing subdural hematoma and death. Case report.

To the Editor. —PostoperativeCandida parapsilosisendophthalmitis occurred in a group of patients secondary to the administration of a contaminated lot of intraocular irrigating solution. All patients underwent subsequent therapeutic vitrectomy combined with intravitreal amphotericin B, intravenous intraocular amphotericin B, and oral flucytosine therapy; this group of 15 patients has previously been described.1We recently treated an additional patient who was exposed to the same lot of contaminated irrigating solution and had a prolonged delay in the presentation of postoperativeC parapsilosisendophthalmitis. Report of a Case. —An 89-year-old healthy man underwent extracapsular cataract extraction with implantation of an anterior chamber intraocular lens in the right eye in July 1983. Postoperatively, he had a mild persistent iridocyclitis that was treated intermittently with a topical corticosteroid over the ensuing two years. Two months before our examination, the patient noted a mild increase in redness in the eye that had been

Oral ketoconazole and intraocular amphotericin B for treatment of postoperative Candida parapsilosis endophthalmitis.

The nutritional supply of corneal regions in experimental animals. III. Further studies on the corneal transport of inorganic ions.

The Federal Highway Administration (FHWA) is working to encourage walking and biking as forms of transportation while also improving pedestrian and bicyclist safety. Bicycle infrastructure, including bike lanes separated from automobiles, can make cycling safer and make cyclists feel more comfortable on the road. FHWA has released a new publication, Separated Bike Lane Planning and Design Guide to help develop bicycle infrastructure. The document uses case studies and lessons learned to demonstrate the design and usage of separated bike lanes. Introducing separated bike lanes will help increase bicycle ridership.

In this issue of JCP, Zhou and colleagues review and integrate placebo-controlled efficacy trials of medications for treatment-resistant depression (TRD) to compare efficacy in a meta-analysis. They conclude that, among 11 augmentation options for TRD, aripiprazole and quetiapine have the most robust evidence for efficacy, with the caveats that these treatments carry substantial risks of adverse events and no long-term data are available. In the absence of direct comparisons, this exercise highlights the formidable challenges that clinicians face when making decisions.

Improving the care of patients who have treatment-resistant depression: the promise of the PCORnet Mood Network.

ANALOGS OF OMEGA-3 PUFAs DERIVED LIPID MEDIATORS AND METHOD OF USE

Use of a compound in the preparation of a medicament for the treatment of ADHD in humans, the compound having the formula ** (See formula) ** in which - R1 is hydrogen, alkyl, cycloalkyl, optionally esterified hydroxyalkyl, alkoxyalkyl, or heteroaryl optionally substituted phenyl, alkoxy, aryloxy, alkylthio, arylthio, alkoxycarbonyl, aminocarbonyl, alkyl- or dialkyl-aminocarbonyl, nitro, amino, alkyl- or dialkylamino, alkylsulfonylamino, arylamino, cyano, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl optionally esterified, alkyl- or aminosulphonyl or alkylsulfinyl, alkyl- or dialkyl-aminosulphonyl or alkylsulfinyl, p has the value 0-3; - R 2 and R''2 are independently hydrogen or an alkyl group ynyq have the value 0 or 1; - R3 can have the same meaning as R1, or is alkylidene, an oxo or thioxo group, and m has the value 0-2; - A forms, with the two carbon atoms of the phenyl group, an optionally partially or fully unsaturated cyclic group having six ring atoms comprising 1 to 3 heteroatoms selected from the group consisting of O, S and N, with provided that the sum of the number of oxygen atoms and a maximum sulfur 2; wherein - the compound may be a racemate or a single diastereomer or enantiomer; - an acid or a pharmaceutically acceptable salt thereof.

Treatment for hyperactivity disorder attention deficit disorder.

Journal of chromatography. B, Biomedical sciences and applications

Determination of trans-resveratrol in human plasma by high-performance liquid chromatography.

We performed simple segregation analyses of panic disorder using 126 families of probands with DSM-III-R panic disorder who were ascertained for a family study of anxiety disorders at an anxiety disorders research clinic. We present parameter estimates for dominant, recessive, and arbitrary single major locus models without sex effects, as well as for a nongenetic transmission model, and compare these models to each other and to models obtained by other investigators. We rejected the nongenetic transmission model when comparing it to the recessive model. Consistent with some previous reports, we find comparable support for dominant and recessive models, and in both cases estimate nonzero phenocopy rates. The effect of restricting the analysis to families of probands without any lifetime history of comorbid major depression (MDD) was also examined. No notable differences in parameter estimates were found in that subsample, although the power of that analysis was low. Consistency between the findings in our sample and in another independently collected sample suggests the possibility of pooling such samples in the future in order to achieve the necessary power for more complex analyses.

Although there is high comorbidity between major depression (MDD) and dysthymia, the nature of this relationship is unclear. An ongoing family study provided an opportunity to examine this relationship. Data are presented on 435 directly interviewed adult first degree relatives of 45 screened normal control probands and 148 probands in three clinical diagnostic groups: panic disorder only, panic disorder plus MDD, and early onset MDD without panic. Many of the psychiatrically ill probands also had comorbid dysthymia. Best estimate diagnoses on all relatives were made blind to proband diagnostic status using direct information obtained with the SADS-LA and/or family history information from multiple informants obtained using a modified version of the FH-RDC. We sought to determine the relationship between DSM-III-R dysthymia and panic disorder and/or MDD and to assess whether or not dysthymia is specifically transmitted within families. Controlling for comorbidity in probands, we found no familial association between panic disorder and dysthymia but we did find an increased risk of dysthymia in relatives of probands with early onset MDD. Additionally we found specific transmission of dysthymia to relatives independent of presence of comorbid panic disorder and/or MDD in probands. These findings support the validity of dysthymia as a specific disorder and suggest as well that dysthymia may be on the spectrum of early onset MDD. Depression 2:252–258 (1994/1995). © 1995 Wley-Liss, Inc.

Relationship between dysthymia and major depression: an analysis of family study data

The guidelines developed by the Adult Treatment Panel of the National Cholesterol Education Program identified low density lipoprotein (LDL) as the major atherogenic lipoprotein, and high levels of LDL-cholesterol as the primary target for cholesterol-lowering therapy. Low levels of high density lipoprotein (HDL)-cholesterol were recognized as a major risk factor for coronary heart disease. This report reexamines in depth the recommendations of the Adult Treatment Panel on HDL-cholesterol. Two major questions are discussed: (1) Should HDL-cholesterol levels be measured in all adults, as recommended for total cholesterol? (2) Should patients found to have a low serum HDL [corrected]-cholesterol level (less than 35 mg/dL [less than 0.91 mmol/L]) enter medical therapy to raise the level? The guidelines of the Adult Treatment Panel are reaffirmed as appropriate from the current perspective. These guidelines recommend that HDL-cholesterol levels be determined in patients deemed to be at high risk for coronary heart disease and suggest that HDL measurement is optional for individuals with borderline-high total levels. The guidelines of the Adult Treatment Panel recommend that low HDL-cholesterol levels be raised mainly by hygienic means (ie, smoking cessation, weight loss, aerobic exercise). When drug therapy is required for high LDL-cholesterol levels in the presence of low HDL levels, cholesterol-lowering drugs that concomitantly raise HDL should be given first priority.

The place of HDL in cholesterol management. A perspective from the National Cholesterol Educational Program.

Vitamin A is normally transported in plasma as retinol bound to a specific protein, retinol-binding protein (RBP). Detailed studies were conducted to examine the effects of excess vitamin A on the plasma concentration and metabolism of RBP, and to obtain information about vitamin A transport in the hypervitaminotic state. Two separate experiments were conducted. In the first (Study I, 99 days), plasma RBP and vitamin A levels were compared in three groups of rats fed 0.14 mg (control), 7.3 mg (group 2), or 41 mg (group 3) of vitamin A per day. After day 50 of the study, the administration of excess vitamin A to hypervitaminotic rats (groups 2 and 3) was discontinued and the rats were allowed to recover from vitamin A toxicity. In the second, shorter experiment (Study II), serum vitamin A and RBP levels were compared in control and hypervitaminotic (34 mg of retinyl acetate per day) rats. The rats in this study were also given [3-H]retinyl acetate daily to determine the distribution of retinyl esters and retinol between the lipoprotein and nonlipoprotein protein fractions of plasma. In both studies, administration of large, excessive doses of vitamin A resulted in substantial and significant decreases in the levels of serum RBP. Excessive doses of vitamin A produced fatty liver in the rats, in association with a normal (group 2, Study I) or with a decreased (group 3, Study I) level of RBP in the liver. It is possible that excess vitamin A leads to decreased rates of RBP synthesis in, and of RBP secretion from, the liver. Administration of excessive doses of vitamin A also resulted in elevations of serum vitamin A levels, which were mainly due to large increases in the circulating levels of retinyl esters. In the hypervitaminotic rats, most of the serum vitamin A, and virtually all of the retinyl esters, was found in association with the serum lipoproteins of hydrated density less than 1.21. These results demonstrate that the serum lipoproteins play an important role in the transport of the vitamin A that accumulates in serum in hypervitaminosis A. We suggest that the toxic manifestations of hypervitaminosis A occur when vitamin A circulates in plasma and is presented to membranes in a form other than bound to RBP. Plasma lipoproteins may nonspecificially deliver vitamin A to biological membranes and hence lead to vitamin A toxicity.

Metabolism of retinol-binding protein and vitamin A during hypervitaminosis A in the rat.

SUMMARY Chylomicrons containing newly absorbed labeled vitamin A were injected intravenously into normal intact rats, and the tissue distribution of radioactivity was observed for several days. Chylomicrons were used so that the vitamin could be administered physiologically, in the form in which it is normally absorbed. ‘The total recovery of lipid-soluble radioactivity in the entire animal varied from 92% after 17 min to 63% after 24 hr to 56% after 6 days. At all times approximately two-thirds of the recovered radioactivity was found in the liver. Substantial amounts of radioactivity were also found in the kidneys and in the total depot fat, and small but significant amounts of labeled vitamin A were found in the plasma, small intestine, lungs, and adrenals. After 8 hr, labeled retinyl esters predominated in all tissues except plasma, with small aniounts of labeled retinol also being present. Quantitatively significant amounts of labeled retinal or retinoic acid were not observed. The composition of labeled retinyl esters was remarkable in showing a consistent predominance of saturated esters in all tissues. Marked differences were, however, seen in the relative amounts of labeled retinyl palmitate and stearate in different tissues. During the first 24 hr 3.7% of the injected radioactivity was excreted as expired COS, 3.5% was excreted as water-soluble compounds in the urine, and 8.7y0 was excreted in the bile. The biliary metabolites apparently consisted of a heterogeneous mixture of polar compounds, some of which were present as glucuronic acid conjugates.

TISSUE DISTRIBUTION AND METABOLISM OF NEWLY ABSORBED VITAMIN A IN THE RAT.

THE TURNOVER OF INDIVIDUAL CHOLESTEROL ESTERS IN HUMAN AND RAT PLASMA.

This article is a critique of two reports of “independent legal experts” sponsored by the International Fund for Animal Welfare (IFAW); the “Paris Panel” and the “London Panel.” The article shows that the Paris Panel's conclusion that Japan's research whaling in the Antarctic is unlawful and an abuse of rights under the International Convention for the Regulation of Whaling (ICRW) is based on misuse of evidence and failure to properly interpret Article VIII of the Convention and the legal status of recommendatory non-binding resolutions. It also shows that the London Panel's conclusion that the import of humpback whales from Japan's research program in the Antarctic and sei whales from its research program in the North Pacific are a violation of trade rules under the Convention on International Trade in Endangered Species of Wild Fauna and Flora is based on incorrect interpretation of that Convention's trade rules. It is concluded that the two independent legal experts panel reports are, from a legal perspective, seriously flawed, rendering their conclusions invalid and relegating the reports to the status of IFAW propaganda.

Why are some individuals better at recognising faces? Uncovering the neural mechanisms supporting face recognition ability has proven elusive. To tackle this challenge, we used a multi-modal data-driven approach combining neuroimaging, computational modelling, and behavioural tests. We recorded the high-density electroencephalographic brain activity of individuals with extraordinary face recognition abilities—super-recognisers—and typical recognisers in response to diverse visual stimuli. Using multivariate pattern analyses, we decoded face recognition abilities from 1 second of brain activity with up to 80% accuracy. To better understand the mechanisms subtending this decoding, we compared computations in the brains of our participants with those in artificial neural network models of vision and semantics, as well as with those involved in human judgments of shape and meaning similarity. Compared to typical recognisers, we found stronger associations between early brain computations of super-recognisers and mid-level computations of vision models as well as shape similarity judgments. Moreover, we found stronger associations between late brain representations of super-recognisers and computations of the artificial semantic model as well as meaning similarity judgments. Overall, these results indicate that important individual variations in brain processing, including neural computations extending beyond purely visual processes, support differences in face recognition abilities. They provide the first empirical evidence for an association between semantic computations and face recognition abilities. We believe that such multi-modal data-driven approaches will likely play a critical role in further revealing the complex nature of idiosyncratic face recognition in the human brain. Significance The ability to robustly recognise faces is crucial to our success as social beings. Yet, we still know little about the brain mechanisms allowing some individuals to excel at face recognition. This study builds on a sizeable neural dataset measuring the brain activity of individuals with extraordinary face recognition abilities—super-recognisers—to tackle this challenge. Using state-of-the-art computational methods, we show robust prediction of face recognition abilities in single individuals from a mere second of brain activity, and revealed specific brain computations supporting individual differences in face recognition ability. Doing so, we provide direct empirical evidence for an association between semantic computations and face recognition abilities in the human brain—a key component of prominent face recognition models.

Revealing feature spaces underlying similarity judgments of natural scenes in individual participants

Target similarity effects in Lag 1 Sparing of the Attentional Blink

Revealing the Feature Dimensions Driving Similarity Judgements of Natural Scenes

Our understanding of how information unfolds when we recall events from memory remains limited. In this study, we investigate whether the reconstruction of visual object memories follows a backward trajectory along the ventral visual stream with respect to perception, such that their neural feature representations are gradually reinstated from late areas close to the hippocampus backwards to lower-level sensory areas. We use multivariate analyses of fMRI activation patterns to map the constituent features of the object memories onto the brain during retrieval, and EEG-fMRI fusion to track the temporal evolution of the reactivated patterns. Participants studied new associations between verbs and randomly paired object images in an encoding phase, and subsequently recalled the objects when presented with the corresponding verb cue. Decoding reactivated memory features from fMRI activity revealed that retrieval patterns were dominated by conceptual features, represented in comparatively late visual and parietal areas. Representational-similarity-based fusion then allowed us to map the EEG patterns that emerged at each given time point of a trial onto the spatially resolved fMRI patterns. This fusion suggests that memory reconstruction proceeds backwards along the ventral visual stream from anterior fronto-temporal to posterior occipital and parietal regions, in line with a semantic-to-perceptual gradient. A linear regression on the peak time points of reactivated brain regions statistically confirms that the temporal progression is reversed with respect to encoding. Together, the results shed light onto the spatio-temporal trajectories along which memories are reconstructed during associative retrieval, and which features of an image are reconstructed when in time and where in the brain.

Reconstructing Spatio-Temporal Trajectories of Visual Object Memories in the Human Brain

Advances in artificial intelligence have inspired a paradigm shift in human neuroscience, yielding large-scale functional magnetic resonance imaging (fMRI) datasets that provide high-resolution brain responses to thousands of naturalistic visual stimuli. Because such experiments necessarily involve brief stimulus durations and few repetitions of each stimulus, achieving sufficient signal-to-noise ratio can be a major challenge. We address this challenge by introducing GLMsingle, a scalable, user-friendly toolbox available in MATLAB and Python that enables accurate estimation of single-trial fMRI responses (glmsingle.org). Requiring only fMRI time-series data and a design matrix as inputs, GLMsingle integrates three techniques for improving the accuracy of trial-wise general linear model (GLM) beta estimates. First, for each voxel, a custom hemodynamic response function (HRF) is identified from a library of candidate functions. Second, cross-validation is used to derive a set of noise regressors from voxels unrelated to the experiment. Third, to improve the stability of beta estimates for closely spaced trials, betas are regularized on a voxel-wise basis using ridge regression. Applying GLMsingle to the Natural Scenes Dataset and BOLD5000, we find that GLMsingle substantially improves the reliability of beta estimates across visually-responsive cortex in all subjects. Comparable improvements in reliability are also observed in a smaller-scale auditory dataset from the StudyForrest experiment. These improvements translate into tangible benefits for higher-level analyses relevant to systems and cognitive neuroscience. We demonstrate that GLMsingle: (i) helps decorrelate response estimates between trials nearby in time; (ii) enhances representational similarity between subjects within and across datasets; and (iii) boosts one-versus-many decoding of visual stimuli. GLMsingle is a publicly available tool that can significantly improve the quality of past, present, and future neuroimaging datasets sampling brain activity across many experimental conditions.

Improving the accuracy of single-trial fMRI response estimates using GLMsingle

Interpreting the meaning of a visual scene requires not only identification of its constituent objects, but also a rich semantic characterization of object interrelations. Here, we study the neural mechanisms underlying visuo-semantic transformations by applying modern computational techniques to a large-scale 7T fMRI dataset of human brain responses elicited by complex natural scenes. Using semantic embeddings obtained by applying linguistic deep learning models to human-generated scene descriptions, we identify a widely distributed network of brain regions that encode semantic scene descriptions. Importantly, these semantic embeddings better explain activity in these regions than traditional object category labels. In addition, they are effective predictors of activity despite the fact that the participants did not actively engage in a semantic task, suggesting that visuo-semantic transformations are a default mode of vision. In support of this view, we then show that highly accurate reconstructions of scene captions can be directly linearly decoded from patterns of brain activity. Finally, a recurrent convolutional neural network trained on semantic embeddings further outperforms semantic embeddings in predicting brain activity, providing a mechanistic model of the brain’s visuo-semantic transformations. Together, these experimental and computational results suggest that transforming visual input into rich semantic scene descriptions may be a central objective of the visual system, and that focusing efforts on this new objective may lead to improved models of visual information processing in the human brain.

Converging, cross-species evidence indicates that memory for time is supported by hippocampal area CA1 and entorhinal cortex. However, limited evidence characterizes how these regions preserve temporal memories over long timescales (e.g., months). At long timescales, memoranda may be encountered in multiple temporal contexts, potentially creating interference. Here, using 7T fMRI, we measured CA1 and entorhinal activity patterns as human participants viewed thousands of natural scene images distributed, and repeated, across many months. We show that memory for an image’s original temporal context was predicted by the degree to which CA1/entorhinal activity patterns from the first encounter with an image were re-expressed during re-encounters occurring minutes to months later. Critically, temporal memory signals were dissociable from predictors of recognition confidence, which were carried by distinct medial temporal lobe expressions. These findings suggest that CA1 and entorhinal cortex preserve temporal memories across long timescales by coding for and reinstating temporal context information.

Re-expression of CA1 and entorhinal activity patterns preserves temporal context memory at long timescales

We aimed to identify neural computations underlying the loss of face identification ability by modelling the brain activity of brain-lesioned patient PS, a well-documented case of acquired pure prosopagnosia. We collected a large dataset of high-density electrophysiological (EEG) recordings from PS and neurotypicals while they completed a one-back task on a stream of face, object, animal and scene images. We found reduced neural decoding of face identity around the N170 window in PS, and conjointly revealed normal non-face identification in this patient. We used Representational Similarity Analysis (RSA) to correlate human EEG representations with those of deep neural network (DNN) models of vision and caption-level semantics, offering a window into the neural computations at play in patient PS’s deficits. Brain representational dissimilarity matrices (RDMs) were computed for each participant at 4 ms steps using cross-validated classifiers. PS’s brain RDMs showed significant reliability across sessions, indicating meaningful measurements of brain representations with RSA even in the presence of significant lesions. Crucially, computational analyses were able to reveal PS’s representational deficits in high-level visual and semantic brain computations. Such multi-modal data-driven characterisations of prosopagnosia highlight the complex nature of processes contributing to face recognition in the human brain. Highlights We assess the neural computations in the prosopagnosic patient PS using EEG, RSA, and deep neural networks Neural dynamics of brain-lesioned PS are reliably captured using RSA Neural decoding shows normal evidence for non-face individuation in PS Neural decoding shows abnormal neural evidence for face individuation in PS PS shows impaired high-level visual and semantic neural computations

Advances in modern artificial intelligence (AI) have inspired a paradigm shift in human neuroscience, yielding large-scale functional magnetic resonance imaging (fMRI) datasets that provide high-resolution brain responses to tens of thousands of naturalistic visual stimuli. Because such experiments necessarily involve brief stimulus durations and few repetitions of each stimulus, achieving sufficient signal-to-noise ratio can be a major challenge. We address this challenge by introducing GLMsingle, a scalable, user-friendly toolbox available in MATLAB and Python that enables accurate estimation of single-trial fMRI responses (glmsingle.org). Requiring only fMRI time-series data and a design matrix as inputs, GLMsingle integrates three techniques for improving the accuracy of trial-wise general linear model (GLM) beta estimates. First, for each voxel, a custom hemodynamic response function (HRF) is identified from a library of candidate functions. Second, cross-validation is used to derive a set of noise regressors from voxels unrelated to the experimental paradigm. Third, to improve the stability of beta estimates for closely spaced trials, betas are regularized on a voxel-wise basis using ridge regression. Applying GLMsingle to the Natural Scenes Dataset and BOLD5000, we find that GLMsingle substantially improves the reliability of beta estimates across visually-responsive cortex in all subjects. Furthermore, these improvements translate into tangible benefits for higher-level analyses relevant to systems and cognitive neuroscience. Specifically, we demonstrate that GLMsingle: (i) improves the decorrelation of response estimates between trials that are nearby in time; (ii) enhances representational similarity between subjects both within and across datasets; and (iii) boosts one-versus-many decoding of visual stimuli. GLMsingle is a publicly available tool that can significantly improve the quality of past, present, and future neuroimaging datasets that sample brain activity across many experimental conditions.

GLMsingle: a toolbox for improving single-trial fMRI response estimates

ABSTRACT How does the auditory system categorize natural sounds? Here we apply multimodal neuroimaging to illustrate the progression from acoustic to semantically dominated representations. Combining magnetoencephalographic (MEG) and functional magnetic resonance imaging (fMRI) scans of observers listening to naturalistic sounds, we found superior temporal responses beginning ∼55 ms post-stimulus onset, spreading to extratemporal cortices by ∼100 ms. Early regions were distinguished less by onset/peak latency than by functional properties and overall temporal response profiles. Early acoustically-dominated representations trended systematically toward category dominance over time (after ∼200 ms) and space (beyond primary cortex). Semantic category representation was spatially specific: Vocalizations were preferentially distinguished in frontotemporal voice-selective regions and the fusiform; scenes and objects were distinguished in parahippocampal and medial place areas. Our results are consistent with real-world events coded via an extended auditory processing hierarchy, in which acoustic representations rapidly enter multiple streams specialized by category, including areas typically considered visual cortex. Video Abstract Read the transcript Watch the video on Vimeo © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group

Cochlea to categories: The spatiotemporal dynamics of semantic auditory representations

A massive 7T fMRI dataset to bridge cognitive neuroscience and artificial intelligence

Disentangling five dimensions of animacy in human brain and behaviour

Knowing how humans differentiate children from adults has useful implications in many areas of both forensic and cognitive psychology. Yet, how we extract age from faces has been surprisingly underexplored in both disciplines. Here, we used a novel data-driven experimental technique to objectively measure the facial features human observers use to categorise child and adult faces. Relying on more than 35,000 trials, we used a reverse correlation technique that enabled us to reveal how specific features which are known to be important in face-perception––position, spatial-frequency (granularity), and orientation––are associated with accurate child and adult discrimination. This showed that human observers relied on evidence in the nasal bone and eyebrow area for accurate adult categorisation, while they relied on the eye and jawline area to accurately categorise child faces. For orientation structure, only facial information of vertical orientation was linked to face-adult categorisation, while features of horizontal and, to a lesser extent oblique orientations, were more diagnostic of a child face. Finally, we found that spatial-frequency (SF) diagnosticity showed a U-shaped pattern for face-age categorisation, with facial information in low and high spatial frequencies being diagnostic of child faces, and mid spatial frequencies being diagnostic of adult faces. Through this first characterisation of the facial features of face-age categorisation, we show that important face information found in psychophysical studies of face-perception in general (i.e. the eye area, the horizontals, and mid-level SFs) are crucial to the practical context of face-age categorisation, and present data-driven procedures through which face-age classification training could be implemented for real world challenges.

Diagnostic Features for Human Categorisation of Adult vs. Child Faces

Knowing how humans differentiate children from adults has useful implications in many areas of both forensic and cognitive psychology. Yet, how we extract age from faces has been surprisingly underexplored in both disciplines. Here, we used a novel data-driven experimental technique to objectively measure the facial features human observers use to categorise child and adult faces. Relying on more than 35,000 trials, we used a reverse correlation technique that enabled us to reveal how specific features which are known to be important in face-perception – position, spatial-frequency (SF), and orientation – are associated with accurate child and adult discrimination. This showed that human observers relied on evidence in the nasal bone and eyebrow area for accurate adult categorisation, while they relied on the eye and jawline area to accurately categorise child faces. For orientation structure, only facial information of vertical orientation was linked to face-adult categorisation, while features of horizontal and, to a lesser extent oblique orientations, were more diagnostic of a child face. Finally, we found that SF diagnosticity showed a U-shaped pattern for face-age categorisation, with information in low and high SFs being diagnostic of child faces, and mid SFs being diagnostic of adult faces. Through this first characterisation of the facial features of face-age categorisation, we show that important information found in psychophysical studies of face-perception in general (i.e., the eye area, horizontals, and mid-level SFs) is crucial to the practical context of face-age categorisation, and present data-driven procedures through which face-age classification training could be implemented for real-world challenges.

Diagnostic Features for Human Categorisation of Adult and Child Faces

Decoding real-world visual recognition abilities in the human brain

The target similarity conundrum in rapid serial visual presentation

Extensive sampling of neural activity during rich cognitive phenomena is critical for robust understanding of brain function. We present the Natural Scenes Dataset (NSD), in which high-resolution fMRI responses to tens of thousands of richly annotated natural scenes are measured while participants perform a continuous recognition task. To optimize data quality, we develop and apply novel estimation and denoising techniques. Simple visual inspections of the NSD data reveal clear representational transformations along the ventral visual pathway. Further exemplifying the inferential power of the dataset, we use NSD to build and train deep neural network models that predict brain activity more accurately than state-of-the-art models from computer vision. NSD also includes substantial resting-state and diffusion data, enabling network neuroscience perspectives to constrain and enhance models of perception and memory. Given its unprecedented scale, quality, and breadth, NSD opens new avenues of inquiry in cognitive and computational neuroscience.

A massive 7T fMRI dataset to bridge cognitive and computational neuroscience

In pure coordination games players seek to coordinate responses with one another without communicating. Without a logically correct response, success depends upon players intuiting a response that is mutually obvious. Previous work suggests that such coordination requires a distinctive form of “group” thinking and sufficient mutual knowledge, but reveals little about the basis for the intuitive judgements themselves. Here, that question was addressed for the first time by examining the basis of coordination performance of groups whose intuitions might plausibly differ: children versus adults. Twenty-five 5-year-olds, 30 7-year-olds, and 25 adults undertook four types of coordination game, and novel metrics allowed “intuitive alignment” in responses to be evaluated within- and between-groups. All groups performed above chance, and adults showed higher levels of alignment than children, but adults and children showed different patterns in their intuitions. Implications for intergenerational understanding and mis-understanding are discussed.

Meeting and Missing Minds: Children and Adults Use Alignment of Intuitions to Solve Pure Coordination Games

Sleep spindles track cortical learning patterns for memory consolidation

Multivariate pattern analysis reveals domain-general enhancement of visual representations in individuals with “super-recognition” of faces

Significance How do we adaptively switch from perceiving the external world to retrieving goal-relevant internal memories? To tackle this question, we used—in a cued-recall paradigm—direct intracranial recordings from the human hippocampus complemented by high-density scalp electroencephalography (EEG). We found that a hippocampal signal ∼500 ms after a perceptual cue marks the conversion from external (perceptual) to internal (mnemonic) representations. This sets in motion a recall cascade involving posterior parietal and medial prefrontal cortex, revealed via source-localized and time-resolved EEG alpha power. Together, these results unveil the hippocampal–cortical dynamics supporting rapid and flexible memory recall. Adaptive memory recall requires a rapid and flexible switch from external perceptual reminders to internal mnemonic representations. However, owing to the limited temporal or spatial resolution of brain imaging modalities used in isolation, the hippocampal–cortical dynamics supporting this process remain unknown. We thus employed an object-scene cued recall paradigm across two studies, including intracranial electroencephalography (iEEG) and high-density scalp EEG. First, a sustained increase in hippocampal high gamma power (55 to 110 Hz) emerged 500 ms after cue onset and distinguished successful vs. unsuccessful recall. This increase in gamma power for successful recall was followed by a decrease in hippocampal alpha power (8 to 12 Hz). Intriguingly, the hippocampal gamma power increase marked the moment at which extrahippocampal activation patterns shifted from perceptual cue toward mnemonic target representations. In parallel, source-localized EEG alpha power revealed that the recall signal progresses from hippocampus to posterior parietal cortex and then to medial prefrontal cortex. Together, these results identify the hippocampus as the switchboard between perception and memory and elucidate the ensuing hippocampal–cortical dynamics supporting the recall process.

The hippocampus as the switchboard between perception and memory

As the human brain transforms incoming sounds, it remains unclear whether semantic meaning is assigned via distributed, domain-general architectures or specialized hierarchical streams. Here we show that the spatiotemporal progression from acoustic to semantically dominated representations is consistent with a hierarchical processing scheme. Combining magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) patterns, we found superior temporal responses beginning ~80 ms post-stimulus onset, spreading to extratemporal cortices by ~130 ms. Early acoustically-dominated representations trended systematically toward semantic category dominance over time (after ~200 ms) and space (beyond primary cortex). Semantic category representation was spatially specific: vocalizations were preferentially distinguished in temporal and frontal voice-selective regions and the fusiform face area; scene and object sounds were distinguished in parahippocampal and medial place areas. Our results are consistent with an extended auditory processing hierarchy in which acoustic representations give rise to multiple streams specialized by category, including areas typically considered visual cortex.

Spatiotemporal Dynamics of Sound Representations reveal a Hierarchical Progression of Category Selectivity

Clinically relevant autistic traits predict greater reliance on detail for image recognition

Perceptual and conceptual representations of objects in the human brain

Sleep stabilizes newly acquired memories, a process referred to as memory consolidation. According to recent studies, sleep-dependent consolidation processes might be deployed to different extents for different types of memories. In particular, weaker memories might beneﬁt greater from post-learning sleep than stronger memories. However, under standard testing conditions, sleep-dependent consolidation effects for stronger memories might be obscured by ceiling effects. To test this possibility, we devised a new memory paradigm (Memory Arena) in which participants learned temporospatial arrangements of objects. Prior to a delay period spent either awake or asleep, training thresholds were controlled to yield relatively weak or relatively strong memories. After the delay period, retrieval difﬁculty was controlled via the presence or absence of a retroactive interference task. Under standard testing conditions (no interference), a sleep-dependent consolidation effect was indeed observed for weaker memories only. Critically though, with increased retrieval demands, sleep-dependent consolidation effects were seen for both weaker and stronger memories. These results suggest that all memories are consolidated during sleep, but that memories of different strengths require different testing conditions to unveil their beneﬁt from post-learning sleep.

University of Birmingham Does sleep-dependent consolidation favour weak memories?

Precise identification of semantic representations in the human brain

The spatiotemporal neural dynamics underlying perceived similarity for real-world objects

Retrieval aids the creation of a generalised memory trace and strengthens episode-unique information

Deep feedforward neural network models of vision dominate in both computational neuroscience and engineering. The primate visual system, by contrast, contains abundant recurrent connections. Recurrent signal flow enables recycling of limited computational resources over time, and so might boost the performance of a physically finite brain or model. Here we show: (1) Recurrent convolutional neural network models outperform feedforward convolutional models matched in their number of parameters in large-scale visual recognition tasks on natural images. (2) Setting a confidence threshold, at which recurrent computations terminate and a decision is made, enables flexible trading of speed for accuracy. At a given confidence threshold, the model expends more time and energy on images that are harder to recognise, without requiring additional parameters for deeper computations. (3) The recurrent model’s reaction time for an image predicts the human reaction time for the same image better than several parameter-matched and state-of-the-art feedforward models. (4) Across confidence thresholds, the recurrent model emulates the behaviour of feedforward control models in that it achieves the same accuracy at approximately the same computational cost (mean number of floating-point operations). However, the recurrent model can be run longer (higher confidence threshold) and then outperforms parameter-matched feedforward comparison models. These results suggest that recurrent connectivity, a hallmark of biological visual systems, may be essential for understanding the accuracy, flexibility, and dynamics of human visual recognition. Author summary Deep neural networks provide the best current models of biological vision and achieve the highest performance in computer vision. Inspired by the primate brain, these models transform the image signals through a sequence of stages, leading to recognition. Unlike brains in which outputs of a given computation are fed back into the same computation, these models do not process signals recurrently. The ability to recycle limited neural resources by processing information recurrently could explain the accuracy and flexibility of biological visual systems, which computer vision systems cannot yet match. Here we report that recurrent processing can improve recognition performance compared to similarly complex feedforward networks. Recurrent processing also enabled models to behave more flexibly and trade off speed for accuracy. Like humans, the recurrent network models can compute longer when an object is hard to recognise, which boosts their accuracy. The model’s recognition times predicted human recognition times for the same images. The performance and flexibility of recurrent neural network models illustrates that modeling biological vision can help us improve computer vision.

Recurrent neural networks can explain flexible trading of speed and accuracy in biological vision

In this project, we use multivariate analysis techniques on simultaneously acquired EEG and fMRI data to investigate the spatio-temporal dynamics of memory retrieval. We specifically explore how the neural representations of a retrieved object differ from the representations of the originally perceived object. Participants studied novel associations between objects and verbs in an encoding phase, and subsequently recalled the objects upon presentation of the corresponding verb cue. Multivariate pattern classifiers were first used to decode perceptual and conceptual processing from EEG and fMRI brain activation patterns separately. At the hemodynamic level, we found that conceptual features were generally dominant during memory retrieval, and represented at later processing stages than perceptual features. At the electrophysiological level, the conceptual dominance was reflected in an earlier representation of conceptual than perceptual information during recall, showing a reversed order relative to initial encoding (perception). Finally, representational similarity analyses allowed us to map the EEG time courses onto spatial fMRI patterns, demonstrating again that it is primarily the later stages of visual processing that are recapitulated during memory recall. Together, the results shed light onto the nature of mental representations during the reconstruction of visual objects from memory.

Representational similarity analyses in simultaneous EEG-fMRI measurements reveal the spatio-temporal trajectories of reconstructed episodic memories

Conscious perception of natural images is constrained by category-related visual features

High-level interference and low-level priming in the Attentional Blink

The two-faces of recognition ability: better face recognizers extract different physical content from left and right sides of face stimuli

Spatiotemporal neural representations in high-level visual cortex evoked from sounds

Massed synchronised neuronal firing is detrimental to information processing. When networks of task-irrelevant neurons fire in unison, they mask the signal generated by task-critical neurons. On a macroscopic level, mass synchronisation of these neurons can contribute to the ubiquitous alpha/beta (8-30Hz) oscillations. Reductions in the amplitude of these oscillations, therefore, may reflect a boost in the processing of high-fidelity information within the cortex. Here, we test this hypothesis. Twenty-one participants completed an associative memory task while undergoing simultaneous EEG-fMRI recordings. Using representational similarity analysis, we quantified the amount of stimulus-specific information represented within the BOLD signal on every trial. When correlating this metric with concurrently-recorded alpha/beta power, we found a significant negative correlation which indicated that as alpha/beta power decreased, our metric of stimulus-specific information increased. This effect generalised across cognitive tasks, as the negative relationship could be observed during visual perception and episodic memory retrieval. Further analysis revealed that this effect could be better explained by alpha/beta power decreases providing favourable conditions for information processing, rather than directly representing stimulus-specific information. Together, these results indicate that alpha/beta power decreases parametrically track the fidelity of both externally-presented and internally-generated stimulus-specific information represented within the cortex.

Alpha/beta power decreases track the fidelity of stimulus-specific information

Over recent years, multivariate pattern analysis (“decoding”) approaches have become increasingly used to investigate “when” and “where” our brains conduct meaningful processes about their visual environments. Studies using time-resolved decoding of M/EEG patterns have described numerous processes such as object/face familiarity and the emergence of basic-to-abstract category information. Surprisingly, no study has, to our knowledge, revealed “what” (i.e. the actual visual information that) our brain uses while these computations are examined by decoding algorithms. Here, we revealed the time course at which our brain extracts realistic category-specific information about visual objects (i.e. emotion-type & gender information from faces) with time-resolved decoding of high-density EEG patterns, as well as carefully controlled tasks and visual stimulation. Then, we derived temporal generalization matrices and showed that category-specific information is 1) first diffused across brain areas (250 to 350 ms) and 2) encoded under a stable neural pattern that suggests evidence accumulation (350 to 650 ms after face onset). Finally, we bridged time-resolved decoding with psychophysics and revealed the specific visual information (spatial frequency, feature position & orientation information) that support these brain computations. Doing so, we uncovered interconnected dynamics between visual features, and the accumulation and diffusion of category-specific information in the brain.

Visual representations supporting category-specific information about visual objects in the brain

When two targets (T1 and T2) are presented in a rapidly sequentially-presented stream of distractors, subjects often show a clear deficiency to report T2 when presented 200-500 ms after T1. This effect is known as the Attentional Blink (AB). Using the AB as a method to quantify the probability of conscious access, we investigate why some images seem to rise to consciousness more readily. By defining the representational relationships between images using fMRI and CNNs, we show that images that are distinct in high-level representations are more resilient to the AB effect, while low-level similarity to other images increase the probability of conscious access. These results were replicated using representational geometries derived from both functional Magnetic Resonance Imaging (fMRI) and Convolutional Neural Network (CNN). This provides additional parallels between the hierarchical complexity of CNNs trained on object classification and the human visual ventral stream, with CNN and brain representations predicting behaviour in a similar way.

Brain and DCNN representational geometries predict variability in conscious access

The testing-effect, or retrieval-mediated learning, is one of the most robust effects in memory research. It shows that actively and repeatedly retrieving information, compared to merely restudying it, improves long-term retention. Surprisingly, little is known about the neurocognitive mechanisms underlying this phenomenon. Attempting to fill this gap, a recent framework proposed that retrieval acts as a fast memory consolidation mechanism, stabilizing memories through online reactivation, similar to memory replay during offline (e.g. sleep) consolidation. In this fMRI study, we empirically tested the predictions derived from this framework. We predicted that reactivation during retrieval allows memories to become embedded in neocortex, creating an additional route to access the memory trace and rendering it less hippocampus-dependent. Participants encoded scene-object pairs and either retrieved or restudied the objects over two sessions, two days apart. We analysed univariate and multivariate changes in brain activity specific to retrieval but not restudy, and tested whether the predicted changes occur rapidly within a session, or evolve slowly, across the two days. Results showed that medial prefrontal cortex activation increased across retrieval trials within one session, consistent with a fast consolidation account. Hippocampal activity decreased across sessions, suggesting a slower mechanism. Moreover, Representational Similarity Analyses (RSA) showed that consecutive retrieval attempts strengthen both higher-level semantic and episode-specific information in parietal areas, both across but not within sessions. Our findings suggest that retrieval supports the online creation of a neocortical trace, which becomes increasingly relevant at long delays when hippocampus-dependent episodic details would otherwise have faded. Significance statement Repeated remembering strengthens memories much more so than repeated learning. The aim of this study was to shed light onto the poorly understood neurocognitive underpinnings of retrieval-mediated learning. We tested a novel framework proposing that a memory’s stabilization via retrieval relies on mechanisms akin to those involved in offline systems consolidation. Observing the retrieval-induced neural pattern changes across different timescales, we find that retrieval stabilizes semantic and episodic aspects of the original memories, and produces increases in prefrontal activity and decreases in hippocampal activity that are consistent with the consolidation view, but not necessarily with a fast acting mechanism. Our findings inform cognitive theories of the testing effect, suggesting that retrieval produces its benefits by interacting with hippocampal-neocortical consolidation mechanisms.

Testing the fast consolidation hypothesis of retrieval-mediated learning

Author Correction: Retrieval induces adaptive forgetting of competing memories via cortical pattern suppression

Preferential use of local visual information in individuals with many autistic traits

: The distinction between animate and inanimate objects plays an important role in object recognition. The following 5 dimensions were shown in previous studies to be important for animacy perception independently: “being alive”, “looking like an animal”, “having mobility”, “having agency” and “being unpredictable”. However, it is not known how these dimensions in combination determine how we perceive animacy. To investigate, we created a stimulus set (M = 300) with almost all dimension combinations for which we acquired behavioural ratings on the 5 dimensions. We show that subjects (N = 26) are consistent in animacy ratings (r = 0.6) and that “being alive” and “having agency” dimensions are highly correlated (r = 0.62). To design a stimulus sub-set that is decorrelated on animacy dimensions for future fMRI and EGG experiments we used a genetic algorithm. Our approach proved to be successful in stimuli selection (max r = 0.35, compared to max r = 0.59 when using a random search). In summary, our study systematically investigates animacy dimensions, provides new insights in animacy perception, and presents an approach for decorrelating stimuli dimensions that can be useful for other studies.

Animacy Dimensions Ratings and Approach for Decorrelating Stimuli Dimensions

Individuals with an autism spectrum disorder (ASD) diagnosis are often described as having an ‘eye for detail’1. This observation, and the finding that individuals with ASD tend to ‘see the trees before the forest’ when performing the Navon task2, has led to the proposal that ASD is characterized by a bias towards processing local image details3. However, it remains to be shown that natural image recognition in individuals with autism depends more on fine image detail. Here, we resolve this issue by showing that natural image recognition relies more on details in individuals with an above-median number of autistic traits. Furthermore, we found that reliance on details was best predicted by the presence of the most clinically relevant autistic traits. Therefore, our findings raise the possibility that a wide range of real-life abilities and difficulties associated with ASD are related to an enhanced reliance on visual details.

Individuals with clinically relevant autistic traits tend to have an eye for detail

Task-Dependent Information Compression in Face, Object and Scene Categorization

The ability to orient and respond swiftly to our surroundings requires the detection and identification of sounds within moments. Broad descriptors of sounds, such as living and non-living objects, can be discriminated from neural activity starting within the first 100ms of perception, yet when are distinct sound categories (e.g., animals) and individual sounds (e.g., goat) represented and distinguished within the brain across time? To investigate this question, we use magnetoencephalography (MEG) and multivariate analyses of neural activity to examine the time course of audition across individual sounds (e.g., goat) and sound categories (animals, objects, people, spaces). Our results reveal a striking early signal for sound selectivity starting within 80ms after stimulus onset for both individual sounds and sound categories. Sound categories showed a more diffuse generalization across time. Notably, human voices were especially pronounced and distinctive compared with other sound categories. These results illuminate the rapid and parallel emergence of sound identity and category information in the brain, and provide critical evidence that these representations dynamically evolve across time in distinct ways.

Temporal dynamics underlying sound discrimination in the human brain

Episodic simulations reveal the structure of affective representations in the ventromedial prefrontal cortex

While the perception of time plays a crucial role in our day-to-day functioning, the underlying neural mechanism of time processing on short time scales (~1s) remains to be elucidated. Recently, the power of beta oscillations (~20 Hz) has been suggested to play an important role in temporal processing. However, the paradigms supporting this view have often had confounds of working memory, as well as motor preparation. In the current EEG study, we set out to investigate if power of oscillatory activity would be involved in time perception without an explicit working memory component or confound of a motor response. Participants indicated through a button press whether the time between a tone and a visual stimulus was 1 or 1.5s.Critically, we focused on the differences in oscillatory activity in the alpha (~10 Hz) and beta (~20 Hz) ranges preceding correct versus incorrect temporal judgments. Behaviourally, we found participants made more errors on the long (1.5s) than on the short (1s) interval. In addition, we found that participants were fastest to correctly respond to a long interval. The onset of the tone induced a suppression of alpha and beta activity over occipital and parietal electrodes. In the long estimation intervals, this suppression was greater for correct than incorrect estimations. Interestingly, alpha and beta suppression allowed us to predict whether participants would judge the long interval correctly. For the short interval trials we did not find a significant difference in alpha or beta band activity for the correct and incorrect judgments. Taken together, our behavioural and EEG results suggest a multifaceted role of alpha and beta activity in the temporal estimation of sub- and supra-second intervals, where power increases seem to lead to temporal compression. Higher alpha and beta power resulted in shorter temporal judgments for sub-second intervals. Highlights Temporal judgments without motor confounds were studied with EEG. Alpha/beta activity differences for correct and incorrect temporal judgments. Sub-second intervals were judged as short when alpha/beta power was higher.

Alpha/beta power compresses time in sub-second temporal judgments

Vision involves complex neuronal dynamics that link the sensory stream to behaviour. To capture the richness and complexity of the visual world and the behaviour it entails, we used an ecologically valid task with a rich set of real-world object images. We investigated how human brain activity, resolved in space with functional MRI and in time with magnetoencephalography, links the sensory stream to behavioural responses. We found that behaviour-related brain activity emerged rapidly in the ventral visual pathway within 200ms of stimulus onset. The link between stimuli, brain activity, and behaviour could not be accounted for by either category membership or visual features (as provided by an artificial deep neural network model). Our results identify behaviourally-relevant brain activity during object vision, and suggest that object representations guiding behaviour are complex and can neither be explained by visual features or semantic categories alone. Our findings support the view that visual representations in the ventral visual stream need to be understood in terms of their relevance to behaviour, and highlight the importance of complex behavioural assessment for human brain mapping.

Neural dynamics of real-world object vision that guide behaviour

Characterizing the spatio-temporal dynamics of behavior-related neural activity during human visual object perception

Categorical differences in the conscious access to visual objects

Revealing the temporal dynamics of individually unique object representations

Retrieval Induces Adaptive Forgetting of Competing Memories via Cortical Pattern Suppression

The human voice areas: Spatial organization and inter-individual variability in temporal and extra-temporal cortices

In the early days of neuroimaging, brain function was investigated by averaging across voxels within a region, stimuli within a category and individuals within a group. These three forms of averaging discard important neuroscientific information. Recent studies have explored analyses that combine the evidence in better-motivated ways. Multivariate pattern analyses enable researchers to reveal representations in distributed population codes, honouring the unique information contributed by different voxels (or neurons). Condition-rich designs more richly sample the stimulus space and can treat each stimulus as a unique entity. Finally, each individual’s brain is unique and recent studies have found ways to model and analyse the interindividual representational variability. Here we review our field’s journey towards more sophisticated analyses that honour these important idiosyncrasies of brain representations. We describe an emerging framework for investigating individually unique pattern representations of particular stimuli in the brain. The framework models stimuli, responses and individuals multivariately and relates representations by means of representational dissimilarity matrices. Important components are computational models and multivariate descriptions of brain and behavioural responses. These recent developments promise a new paradigm for studying the individually unique brain at unprecedented levels of representational detail.

The brain of the beholder: honouring individual representational idiosyncrasies

Significance Everyone is different. Understanding the unique way an individual perceives the world is a fundamental goal of psychology and brain science. Using novel methods for analyzing functional MRI (fMRI) data, we show that each person viewing a set of objects represents the objects uniquely in his or her brain. Moreover, given an individual’s measured brain-activity patterns, idiosyncrasies in his or her perception of the similarities among the objects can be predicted. Prediction accuracy is modest using current technology. However, our results demonstrate that fMRI has the power to reveal individually unique representations of particular objects in the human brain. The novel method might help us understand the biological substrate of individual experience in mental health and disease. The unique way in which each of us perceives the world must arise from our brain representations. If brain imaging could reveal an individual’s unique mental representation, it could help us understand the biological substrate of our individual experiential worlds in mental health and disease. However, imaging studies of object vision have focused on commonalities between individuals rather than individual differences and on category averages rather than representations of particular objects. Here we investigate the individually unique component of brain representations of particular objects with functional MRI (fMRI). Subjects were presented with unfamiliar and personally meaningful object images while we measured their brain activity on two separate days. We characterized the representational geometry by the dissimilarity matrix of activity patterns elicited by particular object images. The representational geometry remained stable across scanning days and was unique in each individual in early visual cortex and human inferior temporal cortex (hIT). The hIT representation predicted perceived similarity as reflected in dissimilarity judgments. Importantly, hIT predicted the individually unique component of the judgments when the objects were personally meaningful. Our results suggest that hIT brain representational idiosyncrasies accessible to fMRI are expressed in an individual's perceptual judgments. The unique way each of us perceives the world thus might reflect the individually unique representation in high-level visual areas.

Unique semantic space in the brain of each beholder predicts perceived similarity

INTRODUCTION: Binge drinking is now considered a central public health issue and is associated with emotional and interpersonal problems, but the neural implications of these deficits remain unexplored. The present study aimed at offering the first insights into the effects of binge drinking on the neural processing of vocal affect. METHOD: On the basis of an alcohol-consumption screening phase (204 students), 24 young adults (12 binge drinkers and 12 matched controls) were selected and performed an emotional categorization task on morphed vocal stimuli (drawn from a morphed fear-anger continuum) during fMRI scanning. RESULT: In comparison to controls, binge drinkers presented (1) worse behavioural performance in emotional affect categorization; (2) reduced activation of bilateral superior temporal gyrus; and (3) increased activation of right middle frontal gyrus. CONCLUSION: These results constitute the first evidence of altered cerebral processing of emotional stimuli in binge drinking and confirm that binge drinking leads to marked cerebral changes, which has important implications for research and clinical practice. Language: en

OR02-2BINGE DRINKING INFLUENCES THE CEREBRAL PROCESSING OF AFFECTIVE VOICES IN YOUNG ADULTS

Representational geometry measures predict categorisation speed for particular visual objects

Cortex; a Journal Devoted to the Study of the Nervous System and Behavior

People-selectivity, audiovisual integration and heteromodality in the superior temporal sulcus

Automatic domain-general processing of sound source identity in the left posterior middle frontal gyrus

Audiovisual Integration of Face–Voice Gender Studied Using “Morphed Videos”

Binge drinking influences the cerebral processing of vocal affective bursts in young adults☆

Normal listeners effortlessly determine a person's gender by voice, but the cerebral mechanisms underlying this ability remain unclear. Here, we demonstrate 2 stages of cerebral processing during voice gender categorization. Using voice morphing along with an adaptation-optimized functional magnetic resonance imaging design, we found that secondary auditory cortex including the anterior part of the temporal voice areas in the right hemisphere responded primarily to acoustical distance with the previously heard stimulus. In contrast, a network of bilateral regions involving inferior prefrontal and anterior and posterior cingulate cortex reflected perceived stimulus ambiguity. These findings suggest that voice gender recognition involves neuronal populations along the auditory ventral stream responsible for auditory feature extraction, functioning in pair with the prefrontal cortex in voice gender perception.

Cerebral Processing of Voice Gender Studied Using a Continuous Carryover fMRI Design

The most important sound in our auditory environment is the human voice. Voice professionals, whether they are teachers, radio hosts, sport coaches, 
use their voice on a everyday basis to earn their living and communicate information and knowledge. We grow up spending most of our time everyday listening to voices in school, at the sports club, on t.v., etc. So much that by the time we are adults, voice plays a major role in our everyday social interactions. Yet, while extensive research has been conducted on speech perception voice alone has only just started generating more and more interest in the cognitive neuroscience research community. Voice is not "just" a speech carrier, it conveys rich paralinguistic information such as gender, age, identity or affective state. A theoretical model which emphasises the similarities between face and voice processing was recently introduced, suggesting a serial and parallel processing pathway of voice information leading to high level cognitive processes like person identification. Globally this model of voice processing suggests an extraction of low-level acoustic features, followed by a voice structural encoding leading to parallel pathways for the recognition of speech, affect and identity related information. Furthermore, this model suggested potential interactions with face perception pathways. In this thesis, I investigated two different stages of this voice perception model. 

First, little is known about the speed at which the distinction between vocal and non-vocal sounds is performed, i.e. is there a time-frame where the "voice structural analysis" would occur. Using electroencephalography, we conducted an experiment in order to delineate this voice vs. non-voice perception time-frame. I observed an early electro-physiological response preferential to voice stimuli, emerging around 164 ms on fronto-temporal electrodes FC5 and FC6 which was termed the "fronto-temporal positivity to voice". 

Second, little is known about the neural basis behind the perception of paralinguistic information such as identity, gender or affective state contained in the human voice. I used voice gender as a tool to investigated the "voice recognition units" stage of the voice perception model. The cognitive processes behind voice gender perception are still under debate, and more precisely, the nature of the representation of voice gender, whether it is organised around low level acoustical discriminants, or relies on high level categorical representations still remains unclear. Voice gender continua can be created in order to parametrically control the degree of gender contained in voice. 

I investigated the importance of low level acoustic features using the recently developed auditory morphing algorithms. I averaged 32 male and 32 female voices in order to "approximate" a prototypical voice for each gender. From those prototypes, I generated caricatures by exaggerating the acoustical properties of the male prototype in reference to the female prototype. Those voice composites were included along with 3 pairs of male and female voice exemplars in a voice gender adaptation experiment. I observed significantly stronger perceptual after-effects caused by adaptation from the voice gender caricatures. This result provides evidence for a determinant role of the low level acoustical features in our ability to perceive the gender of a voice. 

Finally, using functional magnetic resonance imaging (fMRI), I investigated whether brain regions of the 
auditory cortex are sensitive to voice gender, voice gender adaptation, and whether a dissociation between extraction of acoustical features and higher level, perceptual representations could be achieved. I used voice gender continua and an event-related fMRI design called the continuous carry-over design to assess these working hypotheses. I observed a covariation between BOLD signal and the degree of acoustical differences in consecutive voices in the anterior part of the right superior temporal sulcus, where the extraction of voice gender related acoustical features occurs. Furthermore, I observed a higher level network involving the bilateral inferior frontal gyrus, the insula and the anterior cingulate cortex where a summary of acoustical features would be input from auditory areas enabling a voice gender categorisation.

Adaptive cognition is fostered by knowledge about the structure and value of our environment. Here, we hypothesize that these two kinds of information are inherently intertwined as affective schemas in the medial prefrontal cortex (mPFC). Schemas (e.g., of a social network) emerge by extracting commonalities across experiences and can be understood as graphs comprising nodes (e.g., people) and edges (e.g., their relationships). We sampled information about unique real-life environments (i.e., about personally familiar people and places) and probed their neural representations with fMRI. Using representational similarity analysis, we show that the mPFC encodes both, the nodes and the edges of the schema. Critically, the strength of the edges is not only determined by experience and centrality of a given node but also by its affective value. We thus account for the involvement of the mPFC in seemingly disparate functions and suggest that valuation emerges naturally from encoded memory representations.

Revealing the structure of affective schematic representations in the medial prefrontal cortex

AIMS
Emotional facial expression (EFE) decoding impairment has been repeatedly reported in alcoholism (e.g. Philippot et al., 1999). Nevertheless, several questions are still under debate concerning this alteration, notably its generalization to other emotional stimuli and its variation according to the emotional valence of stimuli.

METHODS
Eighteen recently detoxified alcoholic subjects and 18 matched controls performed a decoding test consisting in emotional intensity ratings on various stimuli (faces, voices, body postures and written scenarios) depicting different emotions (anger, fear, happiness, neutral, sadness). Perceived threat and difficulty were also assessed for each stimulus.

RESULTS
Alcoholic individuals had a preserved decoding performance for happiness stimuli, but alcoholism was associated with an underestimation of sadness and fear, and with a general overestimation of anger. More importantly, these decoding impairments were observed for faces, voices and postures but not for written scenarios.

We observed for the first time a generalized emotional decoding impairment in alcoholism, as this impairment is present not only for faces but also for other visual (i.e. body postures) and auditory stimuli. Moreover, we report that this alteration (1) is mainly indexed by an overestimation of anger and (2) cannot be explained by an 'affect labelling' impairment, as the semantic comprehension of written emotional scenarios is preserved. Fundamental and clinical implications are discussed.

Impaired emotional facial expression decoding in alcoholism is also present for emotional prosody and body postures.

Anatomical connectivity between face- and voice-selective cortex

Auditory response of the Temporal Voice Areas (TVA) predicts memory performance for voices, but not bells.

Electrophysiological evidence for an early processing of human voices

Investigating the representation of voice gender using a continuous carry-over fMRI design

Multivariate pattern analyses of functional MR imaging of the voice neural network

It is presently unknown whether our response to affective vocalizations is specific to those generated by humans or more universal, triggered by emotionally matched vocalizations generated by other species. Here, we used functional magnetic resonance imaging in normal participants to measure cerebral activity during auditory stimulation with affectively valenced animal vocalizations, some familiar (cats) and others not (rhesus monkeys). Positively versus negatively valenced vocalizations from cats and monkeys elicited different cerebral responses despite the participants' inability to differentiate the valence of these animal vocalizations by overt behavioural responses. Moreover, the comparison with human non-speech affective vocalizations revealed a common response to the valence in orbitofrontal cortex, a key component on the limbic system. These findings suggest that the neural mechanisms involved in processing human affective vocalizations may be recruited by heterospecific affective vocalizations at an unconscious level, supporting claims of shared emotional systems across species.

The goal of this study was to determine whether aging brings modifications to the role played by different sources of afferent information for movement control. Older and younger subjects practiced an aiming task for either 40 or 200 trials while different sources of afferent information were available. Following the practice phase, all subjects were submitted to transfer tests in which the afferent information was either maintained or modified. Results indicate that modifying the sources of afferent information available for motor control from acquisition to transfer minimal effects for the older subjects but caused large increase in error for the younger subjects. These results suggest that learning is specific to the sources of afferent information available while practicing the task for the younger subjects, whereas older subjects show more flexibility in their utilization of afferent information for motor control.

Differential roles with aging of visual and proprioceptive afferent information for fine motor control.

We this question by characterising the brain computations of individuals with extraordinary recognition abilities using high-density electroencephalographic signals and a combination of behavioural tests, artificial neural network models, and machine learning analyses. We found that individual face recognition ability can be decoded from brain activity in an extended temporal interval for face and non-face objects. We show that both visual and semantic brain computations contribute to these individual differences. we computed the pairwise similarity between unit activation patterns for each image independently in each CNN layer. The caption-level RDMs were derived from human caption descriptions of the images transformed into sentence embeddings. Brain RDMs were computed using cross-validated decoding performance between the EEG topographies from each pair of stimuli at every 4 ms time-point. Mutual information (Ince et al., 2017) between the model RDMs and the brain RDMs was assessed, for every participant, at each 4 ms step from stimulus onset.

Researcher perspectives on ethics considerations in epigenetics: an international survey

Moving effectively is essential for any animal. That’s why many different kinds of brain processes likely contribute to learning and adapting movement. How these contributions are combined to shape behavior is unknown. Nevertheless, the field of motor adaptation has been working under the assumption that measures of explicit and implicit motor adaptation can simply be added in total adaptation – without testing this assumption. Here we put this additivity assumption to the test in various ways, but we find that measures of implicit and explicit adaptation are not additive. This means that future studies should measure both implicit and explicit adaptation directly. It also challenges us to disentangle how various motor adaptation processes combine when producing movements, and may have implications for our understanding of other kinds of learning as well.(data and code: https://osf.io/kr5eh)

Measures of Implicit and Explicit Adaptation Do Not Linearly Add

People continuously adapt their movements to ever-changing circumstances, and particularly in skills training and rehabilitation, it is crucial that we understand how to optimize implicit adaptation in order for these processes to require as little conscious effort as possible. Although it is generally assumed that the way to do this is by introducing perturbations gradually, the literature is ambivalent on the effectiveness of this approach. Here we test whether there are differences in motor performance when adapting to an abrupt compared to a ramped visuomotor rotation. Using a within-subjects design, we test this question under 3 different rotation sizes: 30°, 45°, and 60°, as well as in 3 different populations: younger adults, older adults, and patients with mild cerebellar ataxia. We find no significant differences in either the behavioural outcomes, or model fits, between abrupt and gradual learning across any of the different conditions. Neither age, nor cerebellar ataxia had any significant effect on motor adaptation either. These findings together indicate that motor adaptation is not modulated by introducing a perturbation abruptly compared to gradually, and is also unaffected by age or mild cerebellar ataxia.

Motor adaptation does not differ when a perturbation is introduced abruptly or gradually

Probes flashed within a moving frame are dramatically displaced (Özkan et al, 2021; Wong &Mack, 1981). The effect is much larger than that seen on static or moving probes (induced motion, Duncker, 1929; Wallach et al, 1978). These flashed probes are often perceived with the separation they have in frame coordinates — a 100% effect. Here we explore this frame effect on flashed tests with several versions of the standard stimulus. We find that the frame effect holds for smoothly or abruptly displacing frames, even when the frame changed shape or orientation between the endpoints of its travel. The path could be non-linear, even circular. The effect was driven by perceived not physical motion. When there were competing overlapping frames, the effect was determined by which frame was attended. There were a number of constraints that limited the effect. A static anchor near the flashes suppressed the effect but an extended static texture did not. If the probes were continuous rather than flashed, the effect was abolished. The observational reports of 30 online participants suggest that the frame effect is robust to many variations in its shape and path and leads to a perception of flashed tests in their locations relative to the frame as if the frame were stationary. Our results highlight the role of frame continuity and of the grouping of the flashes with the frame in generating the frame effect.

Adapting to visuomotor rotations in stepped increments increases implicit motor learning

If a gabor pattern drifts in one direction while its internal texture drifts in the orthogonal direction, its perceived position deviates further and further away from its true path. We first evaluated the illusion using manual tracking. Participants followed the gabor with a stylus on a drawing tablet that coincided optically with the horizontal monitor surface. Their hand and the stylus were not visible during the tracking. The magnitude of the tracking illusion corresponded closely to previous perceptual and pointing measures indicating that manual tracking is a valid measure for the illusion. This allowed us to use it in a second experiment to capture the behavior of the illusion as it eventually degrades and breaks down in single trials. Specifically, the deviation of the gabor stops accumulating at some point and either stays at a fixed offset or resets toward the veridical position. To report the perceived trajectory of the gabor, participants drew it after the gabor was removed from the monitor. Resets were detected and analyzed and their distribution matches neither a temporal nor a spatial limit, but rather a broad gamma distribution over time. This suggests that resets are triggered randomly, about once per 1.3 s, possible by extraneous distractions or eye movements.

Measuring the double-drift illusion and its resets with hand trajectories

The wall orientation is consistent with the perturbation The wall orientation is inconsistent with the perturbation Most studies have focused on how we adapt to perturbations applied to our moving hand. But less is known about motor adaptation to perturbations applied to moving objects we interact with. We therefore designed a web-browser Pong game to investigate: Whether participants adapt to bounce ball perturbations Whether visual cues about the tilt of the bouncing wall improve adaptation Bounce perturbations decrease interception succcess rates

Adaptation to Pong bounce perturbations is quick and independent from wall tilt

Motor adaptation describes the ability of the motor system to counteract repeated perturbations in order to reduce movement errors. Most research in the field investigated adaptation in response to perturbations affecting the moving hand. Fewer studies looked at the effect of a perturbation applied to the movement target, however they used simplistic visual stimuli. In this study, we examined motor adaptation to perturbations affecting the motion of dynamic targets. In addition, we asked whether external visual cues in the environment could facilitate this process. To do so, participants were asked to play an online version of the Pong game in which they intercepted a ball bouncing off a wall using a paddle. A perturbation was applied to alter the post-bounce trajectory of the ball and the wall orientation was manipulated to be consistent or not with the ball trajectory. The “trained tilt” group (n = 34) adapted to the consistent condition and the “trained horizontal” group (n = 36) adapted to the inconsistent condition. In case participants optimally integrate external visual cues, the “trained tilt” group is expected to exhibit faster and/or more complete adaptation than the “trained horizontal” group. We found that the perturbation reduced interception accuracy. Participants showed large interception errors when the perturbation was introduced, followed by rapid error decrease and aftereffects (errors in the opposite direction) once the perturbation was removed. Although both experimental groups showed these typical markers of motor adaptation, we did not find differences in interception success rates or errors between the “trained tilt” and “trained horizontal” groups. Our results demonstrate that participants quickly adapted to the dynamics of the pong ball. However, the visual tilt of the bouncing surface did not enhance their performance. The present study highlights the ability of the motor system to adapt to external perturbations applied to a moving target in a more dynamical environment and in online settings. These findings underline the prospects of further research on sensorimotor adaptation to unexpected changes in the environment using more naturalistic and complex real-world or virtual reality tasks as well as gamified paradigms.

Rapid motor adaptation to bounce perturbations in online Pong game is independent from the visual tilt of the bouncing surface

The effects of visual cues in an immersive virtual reality environment on adaptation to internal and external errors

Purpose To explore the effect of joint hypermobility on acuity, and plasticity, of hand proprioception. Materials and Methods We compared proprioceptive acuity between EDS patients and controls. We then measured any changes in their estimate of hand position after participants adapted their reaches in response to altered visual feedback of their hand. The Beighton Scale was used to quantify the magnitude of joint hypermobility. Results There were no differences between the groups in the accuracy of estimates of hand location, nor in the visually-induced changes in hand location. However, EDS patients’ estimates were less precise when based purely on proprioception and could be partially predicted by Beighton score. Conclusions EDS patients are less precise at estimating their hand’s location when only afferent information is available, but the presence of efferent signalling may reduce this imprecision. Those who are more hypermobile are more likely to be imprecise.

Significance Every eye movement drags the visual scene over our retinas and yet nothing appears to move. We now report a small-scale version of this visual stability with a square frame moving on a monitor in a well-lit room. Probes flashed before and after the frame’s motion are also stabilized in the frame’s coordinates—as if the frame were stationary—shifting perceived locations by up to half the screen’s width from their physical locations. Paradoxically, with these small frames, this ∼100% stabilization occurs despite visible frame motion. Unlike motion-induced position shifts, frame-induced shifts are independent of speed and depend instead on the distance the frame travels. This powerful discounting of motion may reveal a critical component of visual stability. To capture where things are and what they are doing, the visual system may extract the position and motion of each object relative to its surrounding frame of reference [K. Duncker, Routledge and Kegan Paul, London 161–172 (1929) and G. Johansson, Acta Psychol (Amst.) 7, 25–79 (1950)]. Here we report a particularly powerful example where a paradoxical stabilization is produced by a moving frame. We first take a frame that moves left and right and we flash its right edge before, and its left edge after, the frame’s motion. For all frame displacements tested, the two edges are perceived as stabilized, with the left edge on the left and right edge on the right, separated by the frame’s width as if the frame were not moving. This stabilization is paradoxical because the motion of the frame itself remains visible, albeit much reduced. A second experiment demonstrated that unlike other motion-induced position shifts (e.g., flash lag, flash grab, flash drag, or Fröhlich), the illusory shift here is independent of speed and is set instead by the distance of the frame’s travel. In this experiment, two probes are flashed inside the frame at the same physical location before and after the frame moves. Despite being physically superimposed, the probes are perceived widely separated, again as if they were seen in the frame’s coordinates and the frame were stationary. This paradoxical stabilization suggests a link to visual stability across eye movements where the displacement of the entire visual scene may act as a frame to stabilize the perception of relative locations.

Publisher Correction: Implicit motor learning within three trials

If a gabor pattern drifts in one direction while its internal texture drifts in the orthogonal direction, its perceived position deviates further and further away from its true path. We first evaluated the illusion using manual tracking. Participants followed the gabor with a stylus on a drawing tablet that coincided optically with the horizontal monitor surface. Their hand and the stylus were not visible during the tracking. The magnitude of the tracking illusion corresponded closely to previous perceptual and pointing measures indicating that manual tracking is a valid measure for the illusion. This allowed us to use it in a second experiment to capture the behavior of the illusion as it eventually degrades and breaks down in single trials. Specifically, the deviation of the gabor stops accumulating at some point and either stays at a fixed offset or resets toward the veridical position. To report the perceived trajectory of the gabor, participants drew it after the gabor was removed from the monitor. Resets were detected and analyzed and they suggest that there is a spatial limit beyond which the illusion saturates or resets.

Modeling inter-trial variability of pointing movements during visuomotor adaptation

External error attribution dampens efferent-based predictions but not proprioceptive changes in hand localization

Knowing where our limbs are in space is essential for moving and for adapting movements to various changes in our environments and bodies. The ability to adapt movements declines with age, and age-related cognitive decline can explain a decreased ability to adopt and deploy explicit, cognitive strategies in motor learning. Age-related sensory decline could also lead to a reduced fidelity of sensory position signals and error signals, each of which can affect implicit motor adaptation. Here we investigate two estimates of limb position; one based on proprioception, the other on predicted sensory consequences of movements. Each is considered a measure of an implicit adaptation process and may be affected by both age and cognitive strategies. Both older (n = 38) and younger (n = 42) adults adapted to a 30° visuomotor rotation in a centre-out reaching task. We make an explicit, cognitive strategy available to half of participants in each age group with a detailed instruction. After training, we first quantify the explicit learning elicited by instruction. Instructed older adults initially use the provided strategy slightly less than younger adults but show a similar ability to evoke it after training. This indicates that cognitive explanations for age-related decline in motor learning are limited. In contrast, training induced much larger shifts of state estimates of hand location in older adults compared to younger adults. This is not modulated by strategy instructions, and appears driven by recalibrated proprioception, which is almost twice as large in older adults, while predictions might not be updated in older adults. This means that in healthy aging, some implicit processes may be compensating for other changes to maintain motor capabilities, while others also show age-related decline (data: https://osf.io/qzhmy).

Explicit awareness of a task is often evoked during rehabilitation and sports training with the intention of accelerating learning and improving performance. However, the effects of awareness of perturbations on the resulting sensory and motor changes produced during motor learning are not well understood. Here, we use explicit instructions as well as large rotation sizes to generate awareness of the perturbation during a visuomotor rotation task and test the resulting changes in both perceived and predicted sensory consequences as well as implicit motor changes. We split participants into 4 groups which differ in both magnitude of the rotation (either 30° or 60°) during adaptation, and whether they receive a strategy to counter the rotation or not prior to adaptation. Performance benefits of explicit instruction are largest during early adaptation but continued to lead to improved performance through 90 trials of training. We show that with either instruction, or with large perturbations, participants become aware of countering the rotation. However, we find a base amount of implicit learning, with equal magnitudes, across all groups, even when asked to exclude any strategies while reaching with no visual feedback of the hand. Participants also estimate the location of the unseen hand when it is moved by the robot (passive localization) and when they generate their own movement (active localization) following adaptation. These learning-induced shifts in estimates of hand position reflect both proprioceptive recalibration and updates in the predicted consequences of movements. We find that these estimates of felt hand position, which reflect updates in both proprioception and efference based estimates of hand position, shift significantly for all groups and were not modulated by either instruction or perturbation size. Our results indicate that not all processes of motor learning benefit from an explicit awareness of the task. Particularly, proprioceptive recalibration and the updating of predicted sensory consequences are largely implicit processes.

The effects of awareness of the perturbation during motor adaptation on hand localization

Adapting reaches to altered visual feedback not only leads to motor changes, but also to shifts in perceived hand location; “proprioceptive recalibration”. These changes are robust to many task variations and can occur quite rapidly. For instance, our previous study found both motor and sensory shifts arise in as few as 6 rotated-cursor training trials. The aim of this study is to investigate one of the training signals that contribute to these rapid sensory and motor changes. We do this by removing the visuomotor error signals associated with classic visuomotor rotation training; and provide only experience with a visual-proprioceptive discrepancy for training. While a force channel constrains reach direction 30o away from the target, the cursor representing the hand unerringly moves straight to the target. The resulting visual-proprioceptive discrepancy drives significant and rapid changes in no-cursor reaches and felt hand position, again within only 6 training trials. The extent of the sensory change is unexpectedly larger following the visual-proprioceptive discrepancy training. Not surprisingly the size of the reach aftereffects is substantially smaller than following classic visuomotor rotation training. However, the time course by which both changes emerge is similar in the two training types. These results suggest that even the mere exposure to a discrepancy between felt and seen hand location is a sufficient training signal to drive robust motor and sensory plasticity.

The fast contribution of visual-proprioceptive discrepancy to reach aftereffects and proprioceptive recalibration

During motor adaptation the discrepancy between predicted and actually perceived sensory feedback is thought to be minimized, but it can be difficult to measure predictions of the sensory consequences of actions. Studies attempting to do so have found that self-directed, unseen hand position is mislocalized in the direction of altered visual feedback. However, our lab has shown that motor adaptation also leads to changes in perceptual estimates of hand position, even when the target hand is passively displaced. We attribute these changes to a recalibration of hand proprioception, since in the absence of a volitional movement, efferent or predictive signals are likely not involved. The goal here is to quantify the extent to which changes in hand localization reflect a change in the predicted sensory (visual) consequences or a change in the perceived (proprioceptive) consequences. We did this by comparing changes in localization produced when the hand movement was self-generated (‘active localization’) versus robot-generated (‘passive localization’) to the same locations following visuomotor adaptation to a rotated cursor. In this passive version, there should be no predicted consequences of these robot-generated hand movements. We found that although changes in localization were somewhat larger in active localization, the passive localization task also elicited substantial changes. Our results suggest that the change in hand localization following visuomotor adaptation may not be based entirely on updating predicted sensory consequences, but may largely reflect changes in our proprioceptive state estimate.

Separating Predicted and Perceived Sensory Consequences of Motor Learning

Correction: Separating Predicted and Perceived Sensory Consequences of Motor Learning

Training to reach with rotated visual feedback results in adaptation of hand movements, which persist when the perturbation is removed (reach aftereffects). Training also leads to changes in felt hand position, which we refer to as proprioceptive recalibration. The rate at which motor and proprioceptive changes develop throughout training is unknown. Here, we aim to determine the timescale of these changes in order to gain insight into the processes that may be involved in motor learning. Following six rotated reach training trials (30° rotation), at three radially located targets, we measured reach aftereffects and perceived hand position (proprioceptive guided reaches). Participants trained with opposing rotations one week apart to determine if the original training led to any retention or interference. Results suggest that both motor and proprioceptive recalibration occurred in as few as six rotated-cursor training trials (7.57° & 3.88° respectively), with no retention or interference present one week after training. Despite the rapid speed of both motor and sensory changes, these shifts do not saturate to the same degree. Thus, different processes may drive these changes and they may not constitute a single implicit process.

Time Course of Reach Adaptation and Proprioceptive Recalibration during Visuomotor Learning

Concurrent adaptation to opposing visuomotor rotations by varying hand and body postures

Background: People with color vision deficiencies report numerous limitations in daily life, restricting, for example, their access to some professions. However, they use basic color terms systematically and in a similar manner as people with normal color vision. We hypothesize that a possible explanation for this discrepancy between color perception and behavioral consequences might be found in the gaze behavior of people with color vision deficiency. Methods: A group of participants with color vision deficiencies and a control group performed several search tasks in a naturalistic setting on a lawn. All participants wore a mobile eye-tracking-driven camera with a high foveal image resolution (EyeSeeCam). Search performance as well as fixations of objects of different colors were examined. Results: Search performance was similar in both groups in a color-unrelated search task as well as in a search for yellow targets. While searching for red targets, participants with color vision deficiencies exhibited a strongly degraded performance. This was closely matched by the number of fixations on red objects shown by the two groups. Importantly, once they fixated a target, participants with color vision deficiencies exhibited only few identification errors. Conclusions: In contrast to controls, participants with color vision deficiencies are not able to enhance their search for red targets on a (green) lawn by an efficient guiding mechanism. The data indicate that the impaired guiding is the main influence on search performance, while foveal identification (verification) is largely unaffected by the color vision deficiency.

Visual Search in the Real World: Color Vision Deficiency Affects Peripheral Guidance, but Leaves Foveal Verification Largely Unaffected

Visual search can be accelerated when properties of the target are known. Such knowledge allows the searcher to direct attention to items sharing these properties. Recent work indicates that information about properties of non-targets (i.e., negative cues) can also guide search. In the present study, we examine whether negative cues lead to different search behavior compared to positive cues. We asked observers to search for a target defined by a certain shape singleton (broken line among solid lines). Each line was embedded in a colored disk. In “positive cue” blocks, participants were informed about possible colors of the target item. In “negative cue” blocks, the participants were informed about colors that could not contain the target. Search displays were designed such that with both the positive and negative cues, the same number of items could potentially contain the broken line (“relevant items”). Thus, both cues were equally informative. We measured response times and eye movements. Participants exhibited longer response times when provided with negative cues compared to positive cues. Although negative cues did guide the eyes to relevant items, there were marked differences in eye movements. Negative cues resulted in smaller proportions of fixations on relevant items, longer duration of fixations and in higher rates of fixations per item as compared to positive cues. The effectiveness of both cue types, as measured by fixations on relevant items, increased over the course of each search. In sum, a negative color cue can guide attention to relevant items, but it is less efficient than a positive cue of the same informational value.

Gaze in Visual Search Is Guided More Efficiently by Positive Cues than by Negative Cues

The relation of selective attention to understanding of natural scenes has been subject to intense behavioral research and computational modeling, and gaze is often used as a proxy for such attention. The probability of an image region to be fixated typically correlates with its contrast. However, this relation does not imply a causal role of contrast. Rather, contrast may relate to an object's “importance” for a scene, which in turn drives attention. Here we operationalize importance by the probability that an observer names the object as characteristic for a scene. We modify luminance contrast of either a frequently named (“common”/“important”) or a rarely named (“rare”/“unimportant”) object, track the observers' eye movements during scene viewing and ask them to provide keywords describing the scene immediately after. When no object is modified relative to the background, important objects draw more fixations than unimportant ones. Increases of contrast make an object more likely to be fixated, irrespective of whether it was important for the original scene, while decreases in contrast have little effect on fixations. Any contrast modification makes originally unimportant objects more important for the scene. Finally, important objects are fixated more centrally than unimportant objects, irrespective of contrast. Our data suggest a dissociation between object importance (relevance for the scene) and salience (relevance for attention). If an object obeys natural scene statistics, important objects are also salient. However, when natural scene statistics are violated, importance and salience are differentially affected. Object salience is modulated by the expectation about object properties (e.g., formed by context or gist), and importance by the violation of such expectations. In addition, the dependence of fixated locations within an object on the object's importance suggests an analogy to the effects of word frequency on landing positions in reading.

Fixations on objects in natural scenes: dissociating importance from salience

For natural scenes, attention is frequently quantified either by performance during rapid presentation or by gaze allocation during prolonged viewing. Both paradigms operate on different time scales, and tap into covert and overt attention, respectively. To compare these, we ask some observers to detect targets (animals/vehicles) in rapid sequences, and others to freely view the same target images for 3 s, while their gaze is tracked. In some stimuli, the target's contrast is modified (increased/decreased) and its background modified either in the same or in the opposite way. We find that increasing target contrast relative to the background increases fixations and detection alike, whereas decreasing target contrast and simultaneously increasing background contrast has little effect. Contrast increase for the whole image (target + background) improves detection, decrease worsens detection, whereas fixation probability remains unaffected by whole-image modifications. Object-unrelated local increase or decrease of contrast attracts gaze, but less than actual objects, supporting a precedence of objects over low-level features. Detection and fixation probability are correlated: the more likely a target is detected in one paradigm, the more likely it is fixated in the other. Hence, the link between overt and covert attention, which has been established in simple stimuli, transfers to more naturalistic scenarios.

Attention in natural scenes: contrast affects rapid visual processing and fixations alike

Mind the step: complementary effects of an implicit task on eye and head movements in real-life gaze allocation

Our decisions are guided by the rewards we expect. These expectations are often based on incomplete knowledge and are thus subject to uncertainty. While the neurophysiology of expected rewards is well understood, less is known about the physiology of uncertainty. We hypothesize that uncertainty, or more specifically errors in judging uncertainty, are reflected in pupil dilation, a marker that has frequently been associated with decision making, but so far has remained largely elusive to quantitative models. To test this hypothesis, we measure pupil dilation while observers perform an auditory gambling task. This task dissociates two key decision variables – uncertainty and reward – and their errors from each other and from the act of the decision itself. We first demonstrate that the pupil does not signal expected reward or uncertainty per se, but instead signals surprise, that is, errors in judging uncertainty. While this general finding is independent of the precise quantification of these decision variables, we then analyze this effect with respect to a specific mathematical model of uncertainty and surprise, namely risk and risk prediction error. Using this quantification, we find that pupil dilation and risk prediction error are indeed highly correlated. Under the assumption of a tight link between noradrenaline (NA) and pupil size under constant illumination, our data may be interpreted as empirical evidence for the hypothesis that NA plays a similar role for uncertainty as dopamine does for reward, namely the encoding of error signals.

Pupil Dilation Signals Surprise: Evidence for Noradrenaline’s Role in Decision Making

The human visual system seems to be particularly efficient at detecting faces. This efficiency sometimes comes at the cost of wrongfully seeing faces in arbitrary patterns, including famous examples such as a rock configuration on Mars or a toast's roast patterns. In machine vision, face detection has made considerable progress and has become a standard feature of many digital cameras. The arguably most wide-spread algorithm for such applications (“Viola-Jones” algorithm) achieves high detection rates at high computational efficiency. To what extent do the patterns that the algorithm mistakenly classifies as faces also fool humans? We selected three kinds of stimuli from real-life, first-person perspective movies based on the algorithm's output: correct detections (“real faces”), false positives (“illusory faces”) and correctly rejected locations (“non faces”). Observers were shown pairs of these for 20 ms and had to direct their gaze to the location of the face. We found that illusory faces were mistaken for faces more frequently than non faces. In addition, rotation of the real face yielded more errors, while rotation of the illusory face yielded fewer errors. Using colored stimuli increases overall performance, but does not change the pattern of results. When replacing the eye movement by a manual response, however, the preference for illusory faces over non faces disappeared. Taken together, our data show that humans make similar face-detection errors as the Viola-Jones algorithm, when directing their gaze to briefly presented stimuli. In particular, the relative spatial arrangement of oriented filters seems of relevance. This suggests that efficient face detection in humans is likely to be pre-attentive and based on rather simple features as those encoded in the early visual system.

Faces in Places: Humans and Machines Make Similar Face Detection Errors

Farb- und formbasierte visuelle Suche bei unterschiedlichen Farbsehfähigkeiten in natürlicher Umgebung

Die Oberjura- und Unterkreide-Sedimentation in den nördlichen und östlichen Niederlanden

The Psychology of Thought[Tatsachen und Probleme zu einer Psychologie der Denkvorgänge, I. Ueber Gedanken]. Karl Bühler. Leipzig: Wilhelm Engelmann, 1907

The Action of Adalin in the Neuroses and Psychoses [Ueber Adalinwirkung bei Neurosen und Psychosen]. (Zeit. Neurol. u. Psychiat., Bd. iv, H. 4, 1911.) Hennes, H.

The New Sedative and Hypnotic, “Adalin” [Ueber das neue Sedativum und Hypnoticum “Adalin”]. (Zeitschr. Neurol. u. Psychiat., Bd. iv, H. 4, 1911.) Pelz

Psycho-therapy [Zur Psychologie und Therapie Neurotischer Symptome]

Hysteria and Psycho-Analysis [Hysterie und Moderne Psycho-Analyse]. (Psychol. Neurol. Wochenschr., Nr. 45–50, 1910.) Friedländer, A.

The Psychology of Dementia Praecox [Uber die Psychologie der Dementia Praecox]: By C. G. Jung. Halle: Carl Marhold, 1907

Stereotypy and other Katatonic Phenomena in Idiots [Ueber Stereotypien und sonstige katatonische Erscheinungen bei Idioten]. (Zeitschr. f. d. gesamt. Neurol. u. Psychiat., H. 3, Bd. iv, 1911.) Plaskuda, W.

Hysterical Pyrexia [Ueber hysterisches Fieber]. (Zeitschr. f. Neurol. u. Psychiat., Bd. v, H. 5, 1911.) Kauffmann, M.

Introducing altered visual feedback of the hand results in quick adaptation of reaching movements. And while this may be partly due to explicit strategies, our lab has shown that implicit changes like reach aftereffects and shift in estimates of the unseen hand, can also emerge and even saturate within a few training trials. The goal of the current study is to determine whether these rapid changes in unseen hand position that occur during classical visuomotor adaptation are diminished or slowed when feedback during training is reduced. We reduced feedback by either providing visual feedback only at the end of the reach (terminal feedback) or constraining hand movements to reduce efferent contribution (exposure). We measured changes as participants completed reaches with a 30° rotation, a −30° rotation and clamped visual feedback, with these two “impoverished” training conditions, along with classical visuomotor adaptation training, while continuously estimating their felt hand position. Classic continuous-cursor training produced exemplary learning curves and rapid and robust shifts in felt hand position. Training with terminal feedback slightly reduced the initial rate of change in overall adaptation and but not the magnitude of shifts in felt hand position. Finally using a robot to constrain and deviate hand movement direction, called exposure training, only delayed saturation of proprioceptive changes by a single trial and these changes were slightly smaller than those during classical training. Taken together, adaptation and shifts in felt hand position are a rapid and robust responses to sensory mismatches and are only slightly modulated when feedback is reduced. This means that, given a visuo-proprioceptive mismatch, the resulting shift in sense of limb position can contribute to movements from the start of adaptation.

Perceived position stabilization depends on the moving frame’s displacement: an online study

Purpose: To explore the effect of joint hypermobility on acuity, and plasticity, of hand proprioception. Materials and Methods: We compared proprioceptive acuity between EDS patients and controls. We then measured any changes in their estimate of hand position after participants adapted their reaches in response to altered visual feedback of their hand. The Beighton Scale was used to quantify the magnitude of joint hypermobility. Results: There were no differences between the groups in the accuracy of estimates of hand location, nor in the visually-induced changes in hand location. However, EDS patients’ estimates were less precise when based purely on proprioception and could be moderately predicted by Beighton score. Conclusions: EDS patients are less precise at estimating their hand’s location when only afferent information is available, but the presence of efferent signalling may reduce this imprecision. Those who are more hypermobile are more likely to be imprecise. This deficit likely has peripheral origins since we found no differences in the extent of sensorimotor plasticity.

Proprioceptive imprecision in Ehlers-Danlos Syndrome does not affect the extent of sensorimotor plasticity

In motor learning, the slow development of implicit learning, following explicit components of learning is well established. While much is known about behaviour during adaptation to a perturbation in reaches, saccades and locomotion, little is known about implicit processes during adaptation. Implicit learning is characterized by both changes in internal models and state estimates of limb position, which we measure as reach aftereffects and shifts in hand localization, after every training trial. This allows trial-by-trial mapping of implicit learning. Participants reached to targets with aligned, then 30° rotated, counter-rotated and finally error-clamped cursor feedback. This paradigm allows fitting a common state space model to the reach performance. The slow process of the model did not match the time course of either of our implicit measures. The observed implicit changes were near asymptote after only one perturbed training trial and thus occur much faster than conventionally believed.

An accurate estimate of limb position is necessary for movement planning. Where we localize our unseen hand after a reach depends on felt hand position, or proprioception, but this is usually neglected in favour of predicted sensory consequences based on efference copies of motor commands. Both sources of information should contribute, so here we set out to further investigate how much of hand localization depends on proprioception and how much on predicted sensory consequences. We use a passive training paradigm with rotated visual feedback that eliminates the possibility to update predicted sensory consequences, but still recalibrates proprioception. After this training we measure participants’ hand location estimates based on both efference-based predictions and afferent proprioceptive signals with self-generated hand movements as well as based on proprioception only with robot-generated movements. We find indistinguishable shifts in hand localization after robot- and self-generated hand movements, and changes in open-loop reaches. Both motor and proprioceptive changes are only slightly smaller as those after training with self-generated movements, confirming that proprioception plays a large role in estimating limb position and in planning movements. (data: https://doi.org/10.17605/osf.io/zfdth, preprint: https://doi.org/10.1101/384941)

Motor learning without moving: Proprioceptive and predictive hand localization after passive visuoproprioceptive discrepancy training

The ability to make goal-directed movements relies on estimates of limb position, based on vision, proprioception, as well as efference-based predictions. We measure the plasticity of proprioceptive and efferent-based estimates of the hand using a series of visuomotor adaptation experiments, which involve reaching with a rotated cursor. This rotated cursor training leads to changes in movements, proprioception and prediction. We measure the speed of these changes as well as fit them to the multi-rate model (Smith et al., 2006) which consists of a fast and slow process. We used a multiphase experiment which alternated between one rotated training trial and then one of 3 intervening tasks. To measure changes in hand localization, participants estimated the location of the unseen hand when it is moved by the robot (passive localization) or when they generated their own movement (active localization). By comparing the differences between these hand estimates after passive (only proprioception) or active (both proprioception and efferent-based prediction) movements, we are able to measure predicted sensory consequences of movement. The 3rd intervening task type was a no-cursor reach where no visual feedback of hand position or trial success was given. The trial-by-trial data suggest that proprioception recalibrates extremely fast, and is simply proportional to the visual-proprioceptive discrepancy, and does not reflect either model process. Prediction and and no-cursor reaches do not reflect either process fitted to training, but appear to be best explained by their own set of dual processes. Thus, these changes seem to reflect separate adaptation mechanisms.

Modeling the time course of change following visuomotor adaptation in movement, proprioception and prediction

People are incredibly good at adapting their movements to altered circumstances, likely engaging multiple learning processes. How multi-process motor learning dynamics depend on the task or change with age is still unclear. In several experiments we investigate how well a two-rate model with a fast and slow process (Smith et al., 2006) can account for changes in task demands, and how age affects two-rate adaptation. Each participant separately learns two rotations in counterbalanced order and separate parts of the workspace. This way we can compare model fits on data from two tasks within each participant. We tested if two-rate model fits are affected by providing continuous or terminal feedback. Terminal feedback disambiguates error size, which would benefit error-based models of motor learning. However, adaptation with terminal feedback could be explained with a single-rate process, so that continuous feedback seems better suited for studying multi-rate motor learning. Second, we tested how older and younger adults learn either an abruptly or gradually introduced rotation. We found no effect of age, but this may be due to our choice of paradigm, in particular the final part of the task that's meant to separate the two model processes. We test this in a third experiment. Each participant does two of four different paradigms, with identical initial learning. The final parts of the task differ, affecting the model fits' fast and slow contributions to initial learning. Our results guide experimental design for two-rate model studies, and show that within-participant paradigms are both possible and useful.Acknowledgments: NSERC; DFG EG 145/1-1

Fast and slow processes in visuomotor adaptation: Task design and aging

Knowing where your limbs are is important for moving. This is informed by vision, proprioception, and prediction of sensory consequences based on efference copies. When visual feedback of hand is rotated during training, proprioception and prediction are adjusted towards the visual feedback. Here we test whether these changes are mainly implicit, hence decreasing with increased explicit information. All participants trained with a 30-degree rotated hand-cursor, and we manipulated explicit learning in three groups: 1) an "instructed" group given a strategy to counter the rotation, 2) a "cursor-jump" group that saw the cursor jump from 0-degree to 30-degree rotation on every trial, 3) an "implicit" control group, that received neither instructions nor different stimuli. During training, the instructed group countered the rotation immediately, while the other groups took longer (within 15-20 trials) to compensate for the cursor-rotation. Moreover, when including or excluding the strategy learned to counter the rotation, only the implicit group could not switch their strategy on or off at will, suggesting unawareness of their learning. Participants also localized their hand before and after training. They either moved their own hand, allowing hand localization with proprioception and efference-based predictions, or the robot moved their hand, providing only proprioceptive hand position. We found no differences between groups in either recalibrated proprioception or updated predictions. Since manipulating explicit learning clearly worked, our localization data suggests that neither proprioceptive recalibration nor updating of predictions fall on one side of the implicit-explicit learning divide, but are separate processes.

Proprioceptive recalibration and uPDating predicted sensory consequences are neither exclusively implicit nor explicit

An accurate estimate of limb position is necessary for movement. Where we localize our unseen hand after a reach depends on felt hand position, or proprioception, but often only predicted sensory consequences based on efference copies of motor commands are considered. Both signals should contribute, so here we use passive training with rotated visual feedback of hand position to prevent updates of predicted sensory consequences, but still recalibrate proprioception. After this training we measure participants' hand location estimates based on both efference-based predictions and afferent proprioceptive signals with self-generated hand movements as well as based on proprioception only with robot-generated movements. The changes in hand localization are equally large after training with robot- and self-generated hand movements. Both motor and proprioceptive changes are only slightly smaller as those after training with self-generated movements, confirming that recalibrated proprioception contributes to motor learning.

Motor Learning Without Moving: Hand Localization after Passive Training

Data and documentation for the effect of negative cues on eye movements in search

Recently there has been renewed interest in understanding the different contributions of explicit and implicit learning to motor learning, such as visuomotor rotation adaptation. Visuomotor rotation adaptation also evokes proprioceptive recalibration, but the contribution of explicit and implicit learning to proprioceptive recalibration is unknown. To investigate this, we instructed one group of participants with an explicit strategy to counter the rotation and another group received no such instruction (see Werner et al., 2015). Learning in the explicitly instructed group is almost instantaneous, but settles more slowly in the implicit group. When asked not to apply the learned strategy, the implicit group is not able to do so, whereas the explicit group can. These results both show a typical difference in learning explained by the explicit and implicit instructions. We also recorded estimates of hand position before and after training in each group. Crucially, participants either moved their own hand, enabling them to use (updated) predicted sensory consequences in estimating their hand position, or the apparatus moved their hand, so that only proprioception was available. Active localization leads to larger shifts in localization than passive movements, but the shifts in localization are identical for the implicitly and explicitly instructed groups. The availability of prediction also doesn't interact with instruction. This is clear evidence that proprioceptive recalibration is an exclusively implicit process that does not rely on motor errors, or instructions on how to counter them, but rather on the discrepancy between visual and proprioceptive feedback.Acknowledgments: Supported by DFG HA 6861/2-1 to BMtH; NSERC to DYPH

In visuomotor adaptation, when subjects first make a reach there is a mismatch between actual and predicted sensory feedback. Subsequently they adapt to accurately reach the target, and update their predictions about sensory feedback which informs changes in hand localization. Additionally, our lab and others have shown that hand proprioception recalilbrates to visual feedback ("proprioceptive recalibration"). Here we quantify the contributions of updated predicted sensory consequences and recalibrated proprioception to hand localization. Ifthere is no discrepancy between predicted and actual visual feedback of the hand during reach training, then any changes in hand localization are due to proprioceptive recalibration. In experiment 1, our subjects trained to actively reach to a target with a 30° rotation. In experiment 2, they were exposed to visual and proprioceptive discrepancy only (cross-sensory error signal; Cressman & Henriques, 2010), but since the apparatus moved the participants' hands there was no prediction about visual consequences to update. Then we measured changes in hand localization, also with both active and passive placement of the adapted hand; i.e. with and without predictions. Hand localization changed substantially in all conditions. With active training, the change for passive placement accounted for two thirds of the change for active placement. As expected, passive training did not lead to a difference between active and passive localization, suggesting both reflect proprioceptive recalibration only. This shows that cross-sensory error signals affect motor performance and lead to proprioceptive recalibration, and thus seem to be an unappreciated aspect of motor learning.

Sensory consequences of hand movement following exposure to visual-proprioceptive discrepancy

Dataset for the predicted and perceived sensory consequences of movement

Reach parameters and touch screen responses for the predicted and perceived sensory consequences of movement

Introduction: In both unisensory and multisensory tasks, human observers have repeatedly been shown to be optimal or near-optimal in their integration of multiple cues (Ernst & Banks, 2002; Körding et al., 2007). Most of the research on cue integration has assumed that the noise in each cue follows a normal distribution, and thus that (a) the variance of the noise is a perfect indicator of the reliability of the cue, and (b) optimal integration is therefore achieved via a linear combination of the cues. However, little is known about how humans might integrate other noise distributions, e.g., those that may not be symmetric or unimodal, or which may require nonlinear cue combination. Here we ask if human observers are able to learn both lower-order and higher-order statistics (e.g., skewness) of non-normal distributions, and whether and how the acquired statistical features of such distributions affect cue integration.

Optimality under fire: Dissociating learning from Bayesian integration

The role of low-level features for rapid object detection and guidance of gaze in natural scenes

Does an object's contrast affect attention and detection equally?

Discomfort glare, among different aspects of visual discomfort is a phenomenon which is little understood and hard to quantify. As this phenomenon is dependent on the building occupant’s view direction and on the relative position of the glare source, a deeper knowledge of one’s visual behavior within a space could provide pertinent insights into better understanding glare. To address this need, we set up an experiment to investigate dependencies of view direction distribution to a selected range of brightness and contrast distributions in a standard office scenario. The participants were asked to perform a series of tasks including reading, thinking, filling in a questionnaire and waiting. The direction of their view was monitored by recording participants’ eye movements using eye-tracking methods. Preliminary results show that different facade configurations have different effects on the eye movement patterns, with a strong dependency on the performed task. This pilot study will serve as a first step to integrate eye-tracking methods into visual comfort assessments and lead to a better understanding of the impact of discomfort glare on visual behavior.

Integration of Eye-tracking Methods in Visual Comfort Assessments

Real-world search strategies with normal and deficient colour-vision

Online action-to-perception transfer: Only percept-dependent action affects perception

Saliency on a natural scene background: Effects of color and luminance contrast add linearly

Movement-related EEG indices of preparation in task switching and motor control

Data and documentation for the paper: Gaze in visual search is guided more efficiently by positive cues than by negative cues

“Natural” gaze is typically measured by tracking eye positions during scene presentation in laboratory settings. How informative are such investigations for real-world conditions? Using a mobile eyetracking setup (“EyeSeeCam”), we measure gaze during free exploration of various in- and outdoor environments, while simultaneously recording head-centred videos. Here, we replay these videos in a laboratory setup. Half of the laboratory observers view the movies continuously, half as sequences of static 1-second frames. We find a bias of eye position to the stimulus centre, which is strongest in the 1 s frame replay condition. As a consequence, interobserver consistency is highest in this condition, though not fully explained by spatial bias alone. This leaves room for image specific bottom-up models to predict gaze beyond generic biases. Indeed, the “saliency map” predicts eye position in all conditions, and best for continuous replay. Continuous replay predicts real-world gaze better than 1 s frame replay does. In conclusion, experiments and models benefit from preserving the spatial statistics and temporal continuity of natural stimuli to improve their validity for real-world gaze behaviour.

Gaze allocation in natural stimuli: Comparing free exploration to head-fixed viewing conditions

Proportion of fixations on relevant items for the first five fixations in each trial for experiment 1.

Gaze change can misalign spatial reference frames encoding visual and vestibular signals in cortex, which may affect the heading discrimination. Here, by systematically manipulating the eye-in-head and head-on-body positions to change the gaze direction of subjects, the performance of heading discrimination was tested with visual, vestibular, and combined stimuli in a reaction-time task in which the reaction time is under the control of subjects. We found the gaze change induced substantial biases in perceived heading, increased the threshold of discrimination and reaction time of subjects in all stimulus conditions. For the visual stimulus, the gaze effects were induced by changing the eye-in-world position, and the perceived heading was biased in the opposite direction of gaze. In contrast, the vestibular gaze effects were induced by changing the eye-in-head position, and the perceived heading was biased in the same direction of gaze. Although the bias was reduced when the visual and vestibular stimuli were combined, integration of the 2 signals substantially deviated from predictions of an extended diffusion model that accumulates evidence optimally over time and across sensory modalities. These findings reveal diverse gaze effects on the heading discrimination and emphasize that the transformation of spatial reference frames may underlie the effects.

Diverse effects of gaze direction on heading perception in humans.

How mechanical allodynia following nerve injury is encoded in patterns of neural activity in the spinal cord dorsal horn (DH) is not known. We addressed this using the spared nerve injury model of neuropathic pain and in vivo electrophysiological recordings. Surprisingly, despite dramatic behavioral over-reactivity to mechanical stimuli following nerve injury, an overall increase in sensitivity or reactivity of DH neurons was not observed. We did, however, observe a marked decrease in correlated neural firing patterns, including the synchrony of mechanical stimulus-evoked firing, across the DH. Alterations in DH temporal firing patterns were recapitulated by silencing DH parvalbumin+ (PV+) inhibitory interneurons, previously implicated in mechanical allodynia, as were allodynic pain-like behaviors in mice. These findings reveal decorrelated DH network activity, driven by alterations in PV+ interneurons, as a prominent feature of neuropathic pain, and suggest that restoration of proper temporal activity is a potential treatment for chronic neuropathic pain.

Nerve injury disrupts temporal processing in the spinal cord dorsal horn through alterations in PV+ interneurons

A key computation in building adaptive internal models of the external world is to ascribe sensory signals to their likely cause(s), a process of Bayesian Causal Inference (CI). CI is well studied within the framework of two-alternative forced-choice tasks, but less well understood within the cadre of naturalistic action-perception loops. Here, we examine the process of disambiguating retinal motion caused by self- and/or object-motion during closed-loop navigation. First, we derive a normative account specifying how observers ought to intercept hidden and moving targets given their belief over (i) whether retinal motion was caused by the target moving, and (ii) if so, with what velocity. Next, in line with the modeling results, we show that humans report targets as stationary and steer toward their initial rather than final position more often when they are themselves moving, suggesting a misattribution of object-motion to the self. Further, we predict that observers should misattribute retinal motion more often: (i) during passive rather than active self-motion (given the lack of an efference copy informing self-motion estimates in the former), and (ii) when targets are presented eccentrically rather than centrally (given that lateral self-motion flow vectors are larger at eccentric locations during forward self-motion). Results confirm both of these predictions. Lastly, analysis of eye-movements show that, while initial saccades toward targets are largely accurate regardless of the self-motion condition, subsequent gaze pursuit was modulated by target velocity during object-only motion, but not during concurrent object- and self-motion. These results demonstrate CI within action-perception loops, and suggest a protracted temporal unfolding of the computations characterizing CI.

Causal inference during closed-loop navigation: parsing of self- and object-motion

Working memories are thought to be held in attractor networks in the brain. These attractors should keep track of the uncertainty associated with each memory, so as to weigh it properly against conflicting new evidence. However, conventional attractors do not represent uncertainty. Here we show how uncertainty could be incorporated into an attractor, specifically a ring attractor that encodes head direction. First, we introduce the first rigorous normative framework (the circular Kalman filter) for benchmarking the performance of a ring attractor under conditions of uncertainty. Next we show that the recurrent connections within a conventional ring attractor can be re-tuned to match this benchmark. This allows the amplitude of network activity to grow in response to confirmatory evidence, while shrinking in response to poor-quality or strongly conflicting evidence. This “Bayesian ring attractor” performs near-optimal angular path integration and evidence accumulation. Indeed, we show that a Bayesian ring attractor is consistently more accurate than a conventional ring attractor. Moreover, near-optimal performance can be achieved without exact tuning of the network connections. Finally, we use large-scale connectome data to show that the network can achieve near-optimal performance even after we incorporate biological constraints. Our work demonstrates how attractors can implement a dynamic Bayesian inference algorithm in a biologically plausible manner, and it makes testable predictions with direct relevance to the head direction system, as well as any neural system that tracks direction, orientation, or periodic rhythms. Significance Statement Data from human subjects as well as animals shows that working memories are associated with a sense of uncertainty. Indeed, a sense of uncertainty is what allows an observer to properly weigh new evidence against their current memory. However, we do not understand how the brain tracks uncertainty. Here we describe a simple and biologically plausible network model that can track the uncertainty associated with a working memory. The representation of uncertainty in this model improves the accuracy of its working memory, as compared to conventional models, because it assigns the proper weight to new conflicting evidence. Our model provides a new interpretation for observed fluctuations in brain activity, and it makes testable new predictions.

Statistical inference is the optimal process for forming and maintaining accurate beliefs about uncertain environments. However, human inference comes with costs due to its associated biases and limited precision. Indeed, biased or imprecise inference can trigger variable beliefs and unwarranted changes in behavior. Here, by studying decisions in a sequential categorization task based on noisy visual stimuli, we obtained converging evidence that humans reduce the variability of their beliefs by updating them only when the reliability of incoming sensory information is judged as sufficiently strong. Instead of integrating the evidence provided by all stimuli, participants actively discarded as much as a third of stimuli. This conditional belief updating strategy shows good test-retest reliability, correlates with perceptual confidence, and explains human behavior better than previously described strategies. This seemingly suboptimal strategy not only reduces the costs of imprecise computations, but counter-intuitively increases the accuracy of resulting decisions.

Efficient stabilization of imprecise statistical inference through conditional belief updating

In uncertain environments, seeking information about alternative choice options is essential for adaptive learning and decision-making. However, information seeking is usually confounded with changes-of-mind about the reliability of the preferred option. Here, we exploited the fact that information seeking requires control over which option to sample to isolate its behavioral and neurophysiological signatures. We found that changes-of-mind occurring with control require more evidence against the current option, are associated with reduced confidence, but are nevertheless more likely to be confirmed on the next decision. Multimodal neurophysiological recordings showed that these changes-of-mind are preceded by stronger activation of the dorsal attention network in magnetoencephalography (MEG), and followed by increased pupil-linked arousal during the presentation of decision outcomes. Together, these findings indicate that information seeking increases the saliency of evidence perceived as the direct consequence of one’s own actions. Highlights Exploration-exploitation dilemmas confound information seeking with changes-of-mind. Unlike changes-of-mind, information seeking requires control over information sampling. Information seeking is associated with reduced confidence and active hypothesis testing. Stronger neurophysiological correlates of attention and arousal during information seeking.

Controllability boosts neural and cognitive signatures of changes-of-mind in uncertain environments

Working memories are thought to be held in attractor networks in the brain. Because working 9 memories are often based on uncertain information, memories should ideally come with a 10 representation of this uncertainty for strategic use in behavior. However, the attractor states that 11 hold these memories in attractor networks commonly do not represent such uncertainty. Focusing 12 here on ring attractor networks for encoding head direction, we show that these networks in fact 13 feature all the motifs required to represent uncertainty in head direction estimates. Specifically, 14 they could do so by transiently modulating their overall activity by uncertainty, in line with a circular 15 Kalman filter that performs near-optimal statistical circular estimation. More generally, we show 16 that ring attractors can perform near-optimal Bayesian computation if they can flexibly deviate 17 from their attractor states. Finally, we show that the basic network motifs sufficient for such 18 statistical inference are already known to be present in the brain. Overall, our work demonstrates 19 that ring attractors can in principle implement a dynamic Bayesian inference algorithm in a 20 biologically plausible manner.

Bayesian inference of circular variables 1 in ring attractor networks 2

Statistical inference is the optimal process for forming and maintaining accurate beliefs about the structure of one’s uncertain environment. However, human inference comes with costs due to its associated biases and limited precision. Indeed, biased or imprecise inference can trigger variable beliefs and unwarranted changes in behavior. Here, by studying decisions in a sequential categorization task based on noisy visual stimuli, we obtained converging evidence that humans mitigate the variability of their beliefs about stimulus category by updating them only when the reliability of incoming sensory information is judged as sufficiently strong, effectively discarding as much as a third of available stimuli. This metacognitive control of inference shows good test-retest reliability, correlates with perceptual confidence measured in a separate task, and better explains behavior than previously described strategies. This conditional belief updating strategy not only reduces the costs of imprecise computations, but also counter-intuitively increases the accuracy of resulting decisions.

Efficient metacognitive control of imprecise statistical inference

Angular path integration is the ability of a system to estimate its own heading direction from potentially noisy angular velocity (or increment) observations. Non-probabilistic algorithms for angular path integration, which rely on a summation of these noisy increments, do not appropriately take into account the reliability of such observations, which is essential for appropriately weighing one’s current heading direction estimate against incoming information. In a probabilistic setting, angular path integration can be formulated as a continuous-time nonlinear filtering problem (circular filtering) with observed state increments. The circular symmetry of heading direction makes this inference task inherently nonlinear, thereby precluding the use of popular inference algorithms such as Kalman filters, rendering the problem analytically inaccessible. Here, we derive an approximate solution to circular continuous-time filtering, which integrates state increment observations while maintaining a fixed representation through both state propagation and observational updates. Specifically, we extend the established projection-filtering method to account for observed state increments and apply this framework to the circular filtering problem. We further propose a generative model for continuous-time angular-valued direct observations of the hidden state, which we integrate seamlessly into the projection filter. Applying the resulting scheme to a model of probabilistic angular path integration, we derive an algorithm for circular filtering, which we term the circular Kalman filter. Importantly, this algorithm is analytically accessible, interpretable, and outperforms an alternative filter based on a Gaussian approximation.

Projection Filtering With Observed State Increments With Applications in Continuous-Time Circular Filtering

Efficient navigation requires animals to track their position, velocity and heading direction (HD). Bayesian inference provides a principled framework for estimating these quantities from unreliable sensory observations, yet little is known about how and where Bayesian algorithms could be implemented in the brain's neural networks. Here, we propose a class of recurrent neural networks that track both a dynamic HD estimate and its associated uncertainty. They do so according to a circular Kalman filter, a statistically optimal algorithm for circular estimation. Our network generalizes standard ring attractor models by encoding uncertainty in the amplitude of a bump of neural activity. More generally, we show that near-Bayesian integration is inherent in ring attractor networks, as long as their connectivity strength allows them to sufficiently deviate from the attractor state. Furthermore, we identified the basic network motifs that are required to implement Bayesian inference, and show that these motifs are present in the Drosophila HD system connectome. Overall, our work demonstrates that the Drosophila HD system can in principle implement a dynamic Bayesian inference algorithm in a biologically plausible manner, consistent with recent findings that suggest ring-attractor dynamics underlie the Drosophila HD system.

A Bayesian perspective on the ring attractor for heading-direction tracking in the Drosophila central complex

Scaling of sensory information in large neural populations shows signatures of information-limiting correlations

During periods of rest, hippocampal place cells feature bursts of activity called sharp-wave ripples (SWRs). Heuristic approaches to their analysis have revealed that a small fraction of SWRs appear to “simulate” trajectories through the environment—called awake hippocampal replay—while the functional role of a majority of these SWRs remains unclear. Applying a novel probabilistic approach to characterize the spatio-temporal dynamics embedded in SWRs, we instead show that almost all SWRs of foraging rodents simulate such trajectories through the environment. Furthermore, these trajectories feature momentum, that is, inertia in their velocities, that mirrors the animals’ natural movement. This stands in contrast to replay events during sleep which seem to follow Brownian motion without such momentum. Lastly, interpreting the replay trajectories in the context of navigational planning revealed that similar past analyses were biased by the heuristic SWR sub-selection. Overall, our approach provides a more complete characterization of the spatio-temporal dynamics within SWRs, highlights qualitative differences between sleep and awake replay, and ought to support future, more detailed, and less biased analysis of the role of awake replay in navigational planning.

A large majority of awake hippocampal sharp-wave ripples feature spatial trajectories with momentum

In uncertain environments, seeking information about the accuracy of alternative strategies is essential for adapting behavior to changes in task contingencies. However, information seeking often co-occurs with changes-of-mind about the perceived accuracy of the current strategy, making it difficult to isolate its specific mechanisms. Here we leveraged the fact that genuine information seeking requires instrumental control to study its cognitive signatures in an adaptive decision-making task tested with and without control. We found that changes-of-mind occurring in controllable environments require more evidence against the current strategy, are associated with reduced confidence, but are nevertheless more likely to be confirmed on the next decision. Computational modelling explained these effects of information seeking through a decrease in the perceived volatility of controllable environments, resulting in stronger and more prolonged effects of changes-of-mind on cognition and behavior. Together, these findings explain the high degree of subjective uncertainty associated with information seeking.

Specific cognitive signatures of information seeking in controllable environments

Controllability reveals defining features of information seeking

Identifying the structure of motion relations in the environment is critical for navigation, tracking, prediction, and pursuit. Yet, little is known about the mental and neural computations that allow the visual system to infer this structure online from a volatile stream of visual information. We propose online hierarchical Bayesian inference as a principled solution for how the brain might solve this complex perceptual task. We derive an online Expectation-Maximization algorithm that explains human percepts qualitatively and quantitatively for a diverse set of stimuli, covering classical psychophysics experiments, ambiguous motion scenes, and illusory motion displays. We thereby identify normative explanations for the origin of human motion structure perception and make testable predictions for new psychophysics experiments. The proposed online hierarchical inference model furthermore affords a neural network implementation which shares properties with motion-sensitive cortical areas and motivates a novel class of experiments to reveal the neural representations of latent structure.

Structure in motion: visual motion perception as online hierarchical inference

Angular path integration is the ability of a system to estimate its own heading direction from potentially noisy angular velocity (or increment) observations. Despite its importance for robot and animal navigation, current algorithms for angular path integration lack probabilistic descriptions that take into account the reliability of such observations, which is essential for appropriately weighing one’s current heading direction estimate against incoming information. In a probabilistic setting, angular path integration can be formulated as a continuous-time nonlinear filtering problem (circular filtering) with increment observations. The circular symmetry of heading direction makes this inference task inherently nonlinear, thereby precluding the use of popular inference algorithms such as Kalman filters and rendering the problem analytically inaccessible. Here, we derive an approximate solution to circular continuous-time filtering, which integrates increment observations while maintaining a fixed representation through both state propagation and observational updates. Specifically, we extend the established projectionfiltering method to account for increment observations and apply this framework to the circular filtering problem. We further propose a generative model for continuous-time angular-valued direct observations of the hidden state, which we integrate seamlessly into the projection filter. Applying the resulting scheme to a model of probabilistic angular path integration, we derive an algorithm for circular filtering, which we term the circular Kalman filter. Importantly, this algorithm is analytically accessible, interpretable, and outperforms an alternative filter based on a Gaussian approximation.

Angular Path Integration by Projection Filtering with Increment Observations

The adaptation of neural codes to the statistics of their environment is well captured by efficient coding approaches. Here we solve an inverse problem: characterizing the objective and constraint functions that efficient codes appear to be optimal for, on the basis of how they adapt to different stimulus distributions. We formulate a general efficient coding problem, with flexible objective and constraint functions and minimal parametric assumptions. Solving special cases of this model, we provide solutions to broad classes of Fisher information-based efficient coding problems, generalizing a wide range of previous results. We show that different objective function types impose qualitatively different adaptation behaviors, while constraints enforce characteristic deviations from classic efficient coding signatures. Despite interaction between these effects, clear signatures emerge for both unconstrained optimization problems and information-maximizing objective functions. Asking for a fixed-point of the neural code adaptation, we find an objective-independent characterization of constraints on the neural code. We use this result to propose an experimental paradigm that can characterize both the objective and constraint functions that an observed code appears to be optimized for.

Adaptation Properties Allow Identification of Optimized Neural Codes

Traditional accumulation-to-bound decision-making models assume that all choice options are processed simultaneously with equal attention. In real life decisions, however, humans tend to alternate their visual fixation between individual items in order to efficiently gather relevant information [46, 23, 21, 12, 15]. These fixations also causally affect one’s choices, biasing them toward the longer-fixated item [38, 2, 25]. We derive a normative decision-making model in which fixating a choice item boosts information about that item. In contrast to previous models [25, 39], we assume that attention enhances the reliability of information rather than its magnitude, consistent with neurophysiological findings [3, 13, 29, 45]. Furthermore, our model actively controls fixation changes to optimize information gathering. We show that the optimal model reproduces fixation patterns and fixation-related choice biases seen in human decision-makers, and provides a Bayesian computational rationale for the fixation bias. This insight led to additional behavioral predictions that we confirmed in human behavioral data. Finally, we explore the consequences of changing the relative allocation of cognitive resources to the attended versus the unattended item, and show that decision performance is benefited by a more balanced spread of cognitive resources.

Optimal policy for attention-modulated decisions explains human fixation behavior

The impact of learning on perceptual decisions and its implication for speed-accuracy tradeoffs

Decision-makers are often faced with limited information about the outcomes of their choices. Current formalizations of uncertain choice, such as the explore-exploit dilemma, do not apply well to decisions in which search capacity can be allocated to each option in variable amounts. Such choices confront decision-makers with the need to tradeoff between breadth - allocating a small amount of capacity to each of many options – and depth - focusing capacity on a few options. We formalize the breadth-depth dilemma through a finite sample capacity model. We find that, if capacity is smaller than 4-7 samples, it is optimal to draw one sample per alternative, favoring breadth. However, for larger capacities, a sharp transition is observed, and it becomes best to deeply sample a very small fraction of alternatives, that decreases with the square root of capacity. Thus, ignoring most options, even when capacity is large enough to shallowly sample all of them, reflects a signature of optimal behavior. Our results also provide a rich casuistic for metareasoning in multi-alternative decisions with bounded capacity.

The breadth-depth dilemma in a finite capacity model of decision-making

DrugowitschLab/SensoryInformationScaling: Code as used in manuscript

Control of Synaptic Specificity by Establishing a Relative Preference for Synaptic Partners

How is information distributed across large neuronal populations within a given brain area? One possibility is that information is distributed roughly evenly across neurons, so that total information scales linearly with the number of recorded neurons. Alternatively, the neural code might be highly redundant, meaning that total information saturates. Here we investigated how information about the direction of a moving visual stimulus is distributed across hundreds of simultaneously recorded neurons in mouse primary visual cortex (V1). We found that information scales sublinearly, due to the presence of correlated noise in these populations. Using recent theoretical advances, we compartmentalized noise correlations into information-limiting and nonlimiting components, and then extrapolated to predict how information grows when neural populations are even larger. We predict that tens of thousands of neurons are required to encode 95% of the information about visual stimulus direction, a number much smaller than the number of neurons in V1. Overall, these findings suggest that the brain uses a widely distributed, but nonetheless redundant code that supports recovering most information from smaller subpopulations.

Scaling of information in large neural populations reveals signatures of information-limiting correlations

Secrets of Meissner corpuscles The Meissner corpuscle, a mechanosensory end organ, was discovered more than 165 years ago and has since been found in the glabrous skin of all mammals, including that on human fingertips. Although prominently featured in textbooks, the function of the Meissner corpuscle is unknown. Neubarth et al. generated adult mice without Meissner corpuscles and used them to show that these corpuscles alone mediate behavioral responses to, and perception of, gentle forces (see the Perspective by Marshall and Patapoutian). Each Meissner corpuscle is innervated by two molecularly distinct, yet physiologically similar, mechanosensory neurons. These two neuronal subtypes are developmentally interdependent and their endings are intertwined within the corpuscle. Both Meissner mechanosensory neuron subtypes are homotypically tiled, ensuring uniform and complete coverage of the skin, yet their receptive fields are overlapping and offset with respect to each other. Science, this issue p. eabb2751; see also p. 1311 Light touch perception and fine sensorimotor control arise from spatially overlapping mechanoreceptors of the Meissner corpuscle. INTRODUCTION Meissner corpuscles are mechanosensory end organs that densely occupy mammalian glabrous skin. The basic anatomy of the Meissner corpuscle and the Aβ (large soma diameter and fast action potential conducting) mechanosensory neurons that innervate it have been widely described. However, little is known about the requirement for the Meissner corpuscle and its innervating Aβ mechanosensory neurons for touch-related behaviors, sensorimotor capabilities, and tactile perception. RATIONALE Mice lacking either brain-derived neurotrophic factor (BDNF) or its receptor TrkB have a range of developmental deficits, including an absence of Meissner corpuscles. We reasoned that confining TrkB manipulations to sensory neurons in conjunction with selective genetic labeling approaches would allow us to investigate the developmental assembly of Meissner corpuscles and their functions in somatosensation. While examining Meissner corpuscle development, we found that two Aβ mechanosensory neuron types innervate the corpuscle. Here, we assessed the requirement of Meissner corpuscles for touch sensitivity and fine sensorimotor control and the anatomical, physiological, and ultrastructural properties of the two Aβ sensory neurons that innervate this mechanosensory end organ. RESULTS Sensory neuron–specific knockout of TrkB resulted in complete loss of Meissner corpuscles without affecting other mechanosensory end organs in mouse glabrous (nonhairy) skin, including Aβ mechanosensory neuron–Merkel cell complexes and Pacinian corpuscles. Behavioral measurements showed that mice lacking Meissner corpuscles were deficient in perceiving and reacting to the gentlest detectable forces acting on glabrous skin and in fine sensorimotor control. Genetic labeling experiments revealed that Meissner corpuscles are innervated by two molecularly distinct Aβ sensory neuron types, one that expresses TrkB and the other that expresses the tyrosine kinase Ret. Despite innervating the same end organ, the responses of these two Aβ neuron types to tactile stimuli differed: The TrkB-positive (TrkB+) Meissner afferent was more sensitive and responded at both the onset and the offset of step indentations of glabrous skin, whereas the Ret+ Meissner afferent was less sensitive and rarely responded at step offset. Some Ret+ neurons even had sustained responses during a static indentation stimulus. In addition, the axonal endings of these two Aβ mechanosensory neuron types were found to be homotypically tiled but heterotypically offset. Computational modeling suggested that this anatomical arrangement maximizes information available for encoding acuity while ensuring complete coverage of the skin using a limited number of neurons. Finally, ultrastructural analysis using electron microscopy revealed that the axon terminals of the more sensitive TrkB+ Meissner afferents had greater numbers of lamellar cell wrappings than the terminals of the less sensitive Ret+ Meissner afferents. CONCLUSION We conclude that two homotypically tiled but heterotypically offset Aβ mechanosensory neurons with distinct molecular, physiological, and ultrastructural properties innervate Meissner corpuscles, which underlie the perception of, and behavioral responses to, the gentlest detectable forces acting on glabrous skin. Anatomy and physiology of Meissner corpuscles required for tactile behavior. (A to C) Meissner corpuscles and their Aβ afferents (A) were required for normal tactile sensitivity (B) and fine sensorimotor control (C). (D) TrkB+ and Ret+ Aβ neurons both innervated Meissner corpuscles. (E and F) TrkB+ Meissner afferents were more sensitive (E) and had more lamellar cell wrappings [(F), arrows indicate axons wrapped with lamellar processes] compared with Ret+ Meissner afferents. In (A), S100 and NFH are antibodies used to visualize Meissner corpuscles and their afferents, respectively. In (B) and (C), error bars represent SEM, and *p < 0.05, **p < 0.01, and ***p < 0.001. Meissner corpuscles are mechanosensory end organs that densely occupy mammalian glabrous skin. We generated mice that selectively lacked Meissner corpuscles and found them to be deficient in both perceiving the gentlest detectable forces acting on glabrous skin and fine sensorimotor control. We found that Meissner corpuscles are innervated by two mechanoreceptor subtypes that exhibit distinct responses to tactile stimuli. The anatomical receptive fields of these two mechanoreceptor subtypes homotypically tile glabrous skin in a manner that is offset with respect to one another. Electron microscopic analysis of the two Meissner afferents within the corpuscle supports a model in which the extent of lamellar cell wrappings of mechanoreceptor endings determines their force sensitivity thresholds and kinetic properties.

Meissner corpuscles and their spatially intermingled afferents underlie gentle touch perception

Human visual motion perception shows hallmarks of Bayesian structural inference

Significance From choosing among the many courses offered in graduate school to dividing budget into research programs, the breadth–depth is a commonplace dilemma that arises when finite resources (e.g., time, money, cognitive capabilities) need to be allocated among a large range of alternatives. For such problems, decision makers need to trade off breadth—allocating little capacity to each of many alternatives—and depth—focusing capacity on a few options. We found that little available capacity (less than 10 samples for search) promotes allocating resources broadly, and thus breadth search is favored. Increased capacity results in an abrupt transition toward favoring a balance between breadth and depth. We finally describe a rich casuistic and heuristics for metareasoning with finite resources. In multialternative risky choice, we are often faced with the opportunity to allocate our limited information-gathering capacity between several options before receiving feedback. In such cases, we face a natural trade-off between breadth—spreading our capacity across many options—and depth—gaining more information about a smaller number of options. Despite its broad relevance to daily life, including in many naturalistic foraging situations, the optimal strategy in the breadth–depth trade-off has not been delineated. Here, we formalize the breadth–depth dilemma through a finite-sample capacity model. We find that, if capacity is small (∼10 samples), it is optimal to draw one sample per alternative, favoring breadth. However, for larger capacities, a sharp transition is observed, and it becomes best to deeply sample a very small fraction of alternatives, which roughly decreases with the square root of capacity. Thus, ignoring most options, even when capacity is large enough to shallowly sample all of them, is a signature of optimal behavior. Our results also provide a rich casuistic for metareasoning in multialternative decisions with bounded capacity using close-to-optimal heuristics.

Hierarchical motion structure is employed by humans during visual perception

Prefrontal mechanisms combining rewards and beliefs in human decision-making

Diffusion processes with boundaries are models of transport phenomena with wide applicability across many fields. These processes are described by their probability density functions (PDFs), which often obey Fokker-Planck equations (FPEs). While obtaining analytical solutions is often possible in the absence of boundaries, obtaining closed-form solutions to the FPE is more challenging once absorbing boundaries are present. As a result, analyses of these processes have largely relied on approximations or direct simulations. In this paper, we studied two-dimensional, time-homogeneous, spatially correlated diffusion with linear, axis-aligned, absorbing boundaries. Our main result is the explicit construction of a full family of closed-form solutions for their PDFs using the method of images. We found that such solutions can be built if and only if the correlation coefficient ρ between the two diffusing processes takes one of a numerable set of values. Using a geometric argument, we derived the complete set of ρ's where such solutions can be found. Solvable ρ's are given by ρ=-cos(π/k), where k∈Z^{+}∪{+∞}. Solutions were validated in simulations. Qualitative behaviors of the process appear to vary smoothly over ρ, allowing extrapolation from our solutions to cases with unsolvable ρ's.

Family of closed-form solutions for two-dimensional correlated diffusion processes.

Interacting with volatile environments stabilizes hidden-state inference and its brain signatures

Linear and logistic regression are essential workhorses of statistical analysis, whose Bayesian treatment has received much recent attention (Bishop, 2006; Gelman et al., 2013; Hastie, Tibishirani, & Friedman, 2011; Murphy, 2012). Using Bayesian statistics for linear and logistic regression allows specifying prior beliefs over certain model parameters, which makes it particularly useful for small and/or high-dimensional datasets. Bayesian regression furthermore provides an estimate of the uncertainty about estimated regression coefficients, as well as uncertainty about predictions arising from the regression. Both are again particularly important for small and/or high-dimensional datasets, as the use of such data might result in highly uncertain predictions, and allow the user to be explicit about this uncertainty.

Significance The structured organization of motion in visual scenes is highly informative for our everyday perception: We recognize people by the way they walk, track objects through occlusion, or predict hazardous situations from the traffic flow. It is, however, unclear how our minds tame the overwhelmingly complex stream of dynamic information received by the retina to form such stable percepts. We argue that an observer can exploit a “divide-and-conquer” strategy where complex motion relations are broken down into compositions of simpler motions. Evidence for hierarchical decomposition comes from multiple object tracking and prediction experiments in which humans are able to exploit motion structure knowledge to improve performance. Our results can guide neuroscience experiments on the neural representation of structure. In the real world, complex dynamic scenes often arise from the composition of simpler parts. The visual system exploits this structure by hierarchically decomposing dynamic scenes: When we see a person walking on a train or an animal running in a herd, we recognize the individual’s movement as nested within a reference frame that is, itself, moving. Despite its ubiquity, surprisingly little is understood about the computations underlying hierarchical motion perception. To address this gap, we developed a class of stimuli that grant tight control over statistical relations among object velocities in dynamic scenes. We first demonstrate that structured motion stimuli benefit human multiple object tracking performance. Computational analysis revealed that the performance gain is best explained by human participants making use of motion relations during tracking. A second experiment, using a motion prediction task, reinforced this conclusion and provided fine-grained information about how the visual system flexibly exploits motion structure.

Hierarchical structure is employed by humans during visual motion perception

Significance Popular models for the trade-off between speed and accuracy of everyday decisions usually assume fixed, low-dimensional sensory inputs. In contrast, in the brain, these inputs are distributed across larger populations of neurons, and their interpretation needs to be learned from feedback. We ask how such learning could occur and demonstrate that efficient learning is significantly modulated by decision confidence. This modulation predicts a particular dependency pattern between consecutive choices and provides insight into how a priori biases for particular choices modulate the mechanisms leading to efficient decisions in these models. Diffusion decision models (DDMs) are immensely successful models for decision making under uncertainty and time pressure. In the context of perceptual decision making, these models typically start with two input units, organized in a neuron–antineuron pair. In contrast, in the brain, sensory inputs are encoded through the activity of large neuronal populations. Moreover, while DDMs are wired by hand, the nervous system must learn the weights of the network through trial and error. There is currently no normative theory of learning in DDMs and therefore no theory of how decision makers could learn to make optimal decisions in this context. Here, we derive such a rule for learning a near-optimal linear combination of DDM inputs based on trial-by-trial feedback. The rule is Bayesian in the sense that it learns not only the mean of the weights but also the uncertainty around this mean in the form of a covariance matrix. In this rule, the rate of learning is proportional (respectively, inversely proportional) to confidence for incorrect (respectively, correct) decisions. Furthermore, we show that, in volatile environments, the rule predicts a bias toward repeating the same choice after correct decisions, with a bias strength that is modulated by the previous choice’s difficulty. Finally, we extend our learning rule to cases for which one of the choices is more likely a priori, which provides insights into how such biases modulate the mechanisms leading to optimal decisions in diffusion models.

Lateral orbitofrontal cortex anticipates choices and integrates prior with current information

Humans and animals can integrate sensory evidence from various sources to make decisions in a statistically near-optimal manner, provided that the stimulus presentation time is fixed across trials. Little is known about whether optimality is preserved when subjects can choose when to make a decision (reaction-time task), nor when sensory inputs have time-varying reliability. Using a reaction-time version of a visual/vestibular heading discrimination task, we show that behavior is clearly sub-optimal when quantified with traditional optimality metrics that ignore reaction times. We created a computational model that accumulates evidence optimally across both cues and time, and trades off accuracy with decision speed. This model quantitatively explains subjects' choices and reaction times, supporting the hypothesis that subjects do, in fact, accumulate evidence optimally over time and across sensory modalities, even when the reaction time is under the subject's control. DRUGOWITSCH, Jan, et al. Optimal multisensory decision-making in a reaction-time task. eLife, 2014, vol. n/a, p. e03005 DOI : 10.7554/eLife.03005

Optimal multisensory decision-making 1 in a reaction-time task 2 3 Running title : Multisensory decision-making in reaction-time task 4 5

Confidence and certainty: distinct probabilistic quantities for different goals

Computational Precision o f Mental Inference as Critical Source of Human Choice Suboptimality Highlights

Fast and accurate Monte Carlo sampling of first-passage times from Wiener diffusion models

Computational Precision of Mental Inference as Critical Source of Human Choice Suboptimality

Multiplicative and Additive Modulation of Neuronal Tuning with Population Activity Affects Encoded Information

Becoming Confident in the Statistical Nature of Human Confidence Judgments

Predictive coding appears to be one of the fundamental working principles of brain processing. Amongst other aspects, brains often predict the sensory consequences of their own actions. Predictive coding resembles Kalman filtering, where incoming sensory information is filtered to produce prediction errors for subsequent adaptation and learning. However, to generate prediction errors given motor commands, a suitable temporal forward model is required to generate predictions. While in engineering applications, it is usually assumed that this forward model is known, the brain has to learn it. When filtering sensory input and learning from the residual signal in parallel, a fundamental problem arises: the system can enter a delusional loop when filtering the sensory information using an overly trusted forward model. In this case, learning stalls before accurate convergence because uncertainty about the forward model is not properly accommodated. We present a Bayes-optimal solution to this generic and pernicious problem for the case of linear forward models, which we call Predictive Inference and Adaptive Filtering (PIAF). PIAF filters incoming sensory information and learns the forward model simultaneously. We show that PIAF is formally related to Kalman filtering and to the Recursive Least Squares linear approximation method, but combines these procedures in a Bayes optimal fashion. Numerical evaluations confirm that the delusional loop is precluded and that the learning of the forward model is more than 10-times faster when compared to a naive combination of Kalman filtering and Recursive Least Squares.

Simultaneous learning and filtering without delusions: a Bayes-optimal combination of Predictive Inference and Adaptive Filtering

These notes contain a brief introduction to finding normative solutions to the speed-accuracy trade-off in perceptual decision-making. They were written for the FENS-Hertie Winter School 2015 ”The neuroscience of decision making”. The presented approach is based on Drugowitsch et al. (2012), Drugowitsch et al. (2014a), and Drugowitsch et al. (2014b). The code for all figures is available on my Github page, https://github.com/jdrugo/FENS2015.

NOTES ON NORMATIVE SOLUTIONS TO THE SPEED-ACCURACY TRADE-OFF IN PERCEPTUAL DECISION-MAKING

For decisions made under time pressure, effective decision making based on uncertain or ambiguous evidence requires efficient accumulation of evidence over time, as well as appropriately balancing speed and accuracy, known as the speed/accuracy trade-off. For simple unimodal stimuli, previous studies have shown that human subjects set their speed/accuracy trade-off to maximize reward rate. We extend this analysis to situations in which information is provided by multiple sensory modalities. Analyzing previously collected data (Drugowitsch et al., 2014), we show that human subjects adjust their speed/accuracy trade-off to produce near-optimal reward rates. This trade-off can change rapidly across trials according to the sensory modalities involved, suggesting that it is represented by neural population codes rather than implemented by slow neuronal mechanisms such as gradual changes in synaptic weights. Furthermore, we show that deviations from the optimal speed/accuracy trade-off can be explained by assuming an incomplete gradient-based learning of these trade-offs. DOI: http://dx.doi.org/10.7554/eLife.06678.001

Tuning the speed-accuracy trade-off to maximize reward rate in multisensory decision-making

Humans and animals can integrate sensory evidence from various sources to make decisions in a statistically near-optimal manner, provided that the stimulus presentation time is fixed across trials. Little is known about whether optimality is preserved when subjects can choose when to make a decision (reaction-time task), nor when sensory inputs have time-varying reliability. Using a reaction-time version of a visual/vestibular heading discrimination task, we show that behavior is clearly sub-optimal when quantified with traditional optimality metrics that ignore reaction times. We created a computational model that accumulates evidence optimally across both cues and time, and trades off accuracy with decision speed. This model quantitatively explains subjects's choices and reaction times, supporting the hypothesis that subjects do, in fact, accumulate evidence optimally over time and across sensory modalities, even when the reaction time is under the subject's control. DOI: http://dx.doi.org/10.7554/eLife.03005.001

In an uncertain and ambiguous world, effective decision making requires that subjects form and maintain a belief about the correctness of their choices, a process called meta-cognition. Prediction of future outcomes and self-monitoring are only effective if belief closely matches behavioral performance. Equality between belief and performance is also critical for experimentalists to gain insight into the subjects' belief by simply measuring their performance. Assuming that the decision maker holds the correct model of the world, one might indeed expect that belief and performance should go hand in hand. Unfortunately, we show here that this is rarely the case when performance is defined as the percentage of correct responses for a fixed stimulus, a standard definition in psychophysics. In this case, belief equals performance only for a very narrow family of tasks, whereas in others they will only be very weakly correlated. As we will see it is possible to restore this equality in specific circumstances but this remedy is only effective for a decision-maker, not for an experimenter. We furthermore show that belief and performance do not match when conditioned on task difficulty – as is common practice when plotting the psychometric curve – highlighting common pitfalls in previous neuroscience work. Finally, we demonstrate that miscalibration and the hard-easy effect observed in humans' and other animals' certainty judgments could be explained by a mismatch between the experimenter's and decision maker's expected distribution of task difficulties. These results have important implications for experimental design and are of relevance for theories that aim to unravel the nature of meta-cognition.

Relation between Belief and Performance in Perceptual Decision Making

Previous theoretical and experimental work on optimal decision-making was restricted to the artificial setting of a reliability of the momentary sensory evidence that remained constant within single trials. The work presented here describes the computation and characterization of optimal decision-making in the more realistic case of an evidence reliability that varies across time even within a trial. It shows that, in this case, the optimal behavior is determined by a bound in the decision maker's belief that depends only on the current, but not the past, reliability. We furthermore demonstrate that simpler heuristics fail to match the optimal performance for certain characteristics of the process that determines the time-course of this reliability, causing a drop in reward rate by more than 50%.

It has been shown previously that the control of a robot arm can be efficiently learned using the XCSF learning classifier system, which is a nonlinear regression system based on evolutionary computation. So far, however, the predictive knowledge about how actual motor activity changes the state of the arm system has not been exploited. In this paper, we utilize the forward velocity kinematics knowledge of XCSF to alleviate the negative effect of noisy sensors for successful learning and control. We incorporate Kalman filtering for estimating successive arm positions, iteratively combining sensory readings with XCSF-based predictions of hand position changes over time. The filtered arm position is used to improve both trajectory planning and further learning of the forward velocity kinematics. We test the approach on a simulated kinematic robot arm model. The results show that the combination can improve learning and control performance significantly. However, it also shows that variance estimates of XCSF prediction may be underestimated, in which case self-delusional spiraling effects can hinder effective learning. Thus, we introduce a heuristic parameter, which can be motivated by theory, and which limits the influence of XCSF's predictions on its own further learning input. As a result, we obtain drastic improvements in noise tolerance, allowing the system to cope with more than 10 times higher noise levels.

Filtering Sensory Information with XCSF: Improving Learning Robustness and Robot Arm Control Performance

Author response: Optimal multisensory decision-making in a reaction-time task

Trial by trial decoding of decisions in monkey MT cortex from small neuronal populations

Spontaneous population activity fluctuations boost sensory tuning curves and gate information processing

The article describe the model, derivation, and implementation of variational Bayesian inference for linear and logistic regression, both with and without automatic relevance determination. It has the dual function of acting as a tutorial for the derivation of variational Bayesian inference for simple models, as well as documenting, and providing brief examples for the MATLAB/Octave functions that implement this inference. These functions are freely available online.

Variational Bayesian inference for linear and logistic regression

Decision making often involves the accumulation of information over time, but acquiring information typically comes at a cost. Little is known about the cost incurred by animals and humans for acquiring additional information from sensory variables due, for instance, to attentional efforts. Through a novel integration of diffusion models and dynamic programming, we were able to estimate the cost of making additional observations per unit of time from two monkeys and six humans in a reaction time (RT) random-dot motion discrimination task. Surprisingly, we find that the cost is neither zero nor constant over time, but for the animals and humans features a brief period in which it is constant but increases thereafter. In addition, we show that our theory accurately matches the observed reaction time distributions for each stimulus condition, the time-dependent choice accuracy both conditional on stimulus strength and independent of it, and choice accuracy and mean reaction times as a function of stimulus strength. The theory also correctly predicts that urgency signals in the brain should be independent of the difficulty, or stimulus strength, at each trial.

It was previously shown that the control of a robot arm can be efficiently learned using the XCSF classifier system. So far, however, the predictive knowledge about how actual motor activity changes the state of the arm system has not been exploited. In this paper, we exploit the forward velocity kinematics knowledge of XCSF to alleviate the negative effect of noisy sensors for successful learning and control. We incorporate Kalman filtering for estimating successive arm positions iteratively combining sensory readings with XCSF-based predictions of hand position changes over time. The filtered arm position is used to improve both trajectory planning and further learning of the forward velocity kinematics. We test the approach on a simulated, kinematic robot arm model. The results show that the combination can improve learning and control performance significantly. However, it also shows that variance estimates of XCSF predictions maybe underestimated, in which case self-delusional spiraling effects hinder effective learning. Thus, we introduce a heuristic parameter, which limits the influence of XCSF's predictions on its own further learning input. As a result, we obtain drastic improvements in noise tolerance coping with more than ten times higher noise levels.

Filtering sensory information with XCSF: improving learning robustness and control performance

Probabilistic vs. non-probabilistic approaches to the neurobiology of perceptual decision-making

This book constitutes the thoroughly refereed joint post-conference proceedings of two consecutive International Workshops on Learning Classifier Systems that took place in Atlanta, GA, USA in July 2008, and in Montreal, Canada, in July 2009 - all hosted by the Genetic and Evolutionary Computation Conference, GECCO. The 12 revised full papers presented were carefully reviewed and selected from the workshop contributions. The papers are organized in topical sections on LCS in general, function approximation, LCS in complex domains, and applications.

Learning Classifier Systems: 11th International Workshop, IWLCS 2008, Atlanta, GA, USA, July 13, 2008, and 12th International Workshop, IWLCS 2009, ... / Lecture Notes in Artificial Intelligence)

Optimal decision bounds for probabilistic population codes and time varying evidence

This book provides a comprehensive introduction to the design and analysis of Learning Classifier Systems (LCS) from the perspective of machine learning. LCS are a family of methods for handling unsupervised learning, supervised learning and sequential decision tasks by decomposing larger problem spaces into easy-to-handle subproblems. Contrary to commonly approaching their design and analysis from the viewpoint of evolutionary computation, this book instead promotes a probabilistic model-based approach, based on their defining question "What is an LCS supposed to learn?". Systematically following this approach, it is shown how generic machine learning methods can be applied to design LCS algorithms from the first principles of their underlying probabilistic model, which is in this book for illustrative purposes closely related to the currently prominent XCS classifier system. The approach is holistic in the sense that the uniform goal-driven design metaphor essentially covers all aspects of LCS and puts them on a solid foundation, in addition to enabling the transfer of the theoretical foundation of the various applied machine learning methods onto LCS. Thus, it does not only advance the analysis of existing LCS but also puts forward the design of new LCS within that same framework.

Design and Analysis of Learning Classifier Systems: A Probabilistic Approach (Studies in Computational Intelligence)

Design and Analysis of Learning Classifier Systems - A Probabilistic Approach

Analysis and Improvements of the Classifier Error Estimate in XCSF

Learning Classifier Systems (LCS) are a family of rule-based machine learn­ ing methods. They aim at the autonomous production of potentially humanreadable results that are the most compact generalised representation whilst also maintaining high predictive accuracy, with a wide range of application areas, such as autonomous robotics, economics, and multi-agent systems. Their design is mainly approached heuristically and, even though their perfor­ mance is competitive in regression and classification tasks, they do not meet their expected performance in sequential decision tasks despite being initially designed for such tasks. It is out contention that improvement is hindered by a lack of theoretical understanding of their underlying mechanisms and dy­ namics. To improve this understanding, our work proposes a new methodology for their design that centres on the model they use to represent the problem struc­ ture, and subsequently applies standard machine learning methods to train this model. The LCS structure is commonly a set of rules, resulting in a para­ metric model that combines a set of localised models, each representing one rule. This leads to a general definition of the optimal set of rules as being the one whose model represents the data best and at a minimum complexity, and hence an increased theoretical understanding of LCS. Consequently, LCS training reduces to searching and evaluating this set of rules, for which we introduce and apply several standard methods that are shown to be closely related to current LCS implementations. The benefit of taking this approach is not only a new view on LCS, and the transfer of the formal basis of the applied methods to the analysis of LCS, but also the first general definition for what it means for a set of rules to be optimal. The work promises advances in several areas, such as developing new LCS implementations with performance guarantees, to improve their performance, and foremost their theoretical understanding.

Learning classifier systems from first principles : a probabilistic reformulation of learning classifier systems from the perspective of machine learning

We study the current definition of classifier error in XCSF and we discuss the limitations of the algorithm that is currently used to compute classifier error from online experience. We introduce a new definition of classifier error and study the performance of two novel estimation algorithms based on this definition. Our results suggest that the new estimation algorithms can be more robust and improve system generalization.

In this study we deal with the mixing problem, which concerns combining the prediction of independently trained local models to form a global prediction. We deal with it from the perspective of Learning Classifier Systems where a set of classifiers provide the local models. Firstly, we formalise the mixing problem and provide both analytical and heuristic approaches to solving it. The analytical approaches are shown to not scale well with the number of local models, but are nevertheless compared to heuristic models in a set of function approximation tasks. These experiments show that we can design heuristics that exceed the performance of the current state-of-the-art Learning Classifier System XCS, and are competitive when compared to analytical solutions. Additionally, we provide an upper bound on the prediction errors for the heuristic mixing approaches.

In this paper we explicitly identify the probabilistic model underlying LCS by linking it to a generalisation of the common Mixture-of-Experts model. Having an explicit representation of the model not only puts LCS on a strong statistical foundation and identifies the assumptions that the model makes about the data, but also allows us to use off-the-shelf training methods to train it. We show how to exploit this advantage by embedding the LCS model into a fully Bayesian framework that results in an objective function for a set of classifiers, effectively turning the LCS training into a principled optimisation task. A set of preliminary experiments demonstrate the feasibility of this approach.

We present a generalisation to the Mixtures of Experts model that introduces prior localisation of the experts as part of the model structure, and as such relates them strongly to the evolutionary computation ML method known as Learning Classifier Systems. While the introduced generalisa-tion allows specification of more complex localisation patterns, identifying good models becomes more difficult. We approach this tradeoff by introducing a new training schema that makes fitting a single model computationally less demanding and shifts the importance to searching the space of possible model structures, guided by approximate variational Bayesian inference to fit the model and find the model evidence. We demonstrate model search for simple non-linear curve fitting tasks by sampling from the model posterior, as a proof-of-concept alternative to the genetic algorithm used in Learning Classifier Systems for that purpose.

Generalised mixtures of experts, independent expert training, and learning classifier systems

A formal framework and extensions for function approximation in learning classifier systems

To fully understand the properties of Accuracy-based Learning Classifier Systems, we need a formal framework that captures all components of classifier systems, that is, function approximation, reinforcement learning, and classifier replacement, and permits the modelling of them separately and in their interaction. In this paper we extend our previous work on function approximation [22] to reinforcement learning and its interaction between reinforcement learning and function approximation. After giving an overview and derivations for common reinforcement learning methods from first principles, we show how they apply to Learning Classifier Systems. At the same time, we present a new algorithm that is expected to outperform all current methods, discuss the use of XCS with gradient descent and TD(λ), and given an in-depth discussion on how to study the convergence of Learning Classifier Systems with a time-invariant population.

A formal framework for reinforcement learning with function approximation in learning classifier systems

In this paper we are extending our previous work on analysing Learning Classifier Systems (LCS) in the reinforcement learning framework [4] to deepen the theoretical analysis of Value Iteration with LCS function approximation. After introducing our formal framework and some mathematical preliminaries we demonstrate convergence of the algorithm for fixed classifier mixing weights, and show that if the weights are not fixed, the choice of the mixing function is significant. Furthermore, we discuss accuracy-based mixing and outline a proof that shows convergence of LCS Value Iteration with an accuracy-based classifier mixing. This work is a significant step towards convergence of accuracy-based LCS that use Q-Learning as the reinforcement learning component.

Towards convergence of learning classifier systems value iteration

Standardised simulation platforms such as RePast, Swarm, MASON and NetLogo are making Agent-Based Modelling accessible to ever-widening audiences. Some proportion of these modellers have good reason to want their agents to express relatively complex behaviour, or they may wish to describe their agents’ actions in terms of real time. Agents of increasing complexity may often be better (more simply) described using hierarchical constructs which express the priorities and goals of their actions, and the contexts in which sets of actions may be applicable (Bryson, 2003a). Describing an agent’s behaviour clearly and succinctly in this way might seem at odds with the iterative, cycle-based nature of most simulation platforms. Because each agent is known to act in lock-step synchrony with the others, describing the individual’s behaviour in terms of fluid, coherent long-term plans may seem difficult. In this paper we describe how an action-selection system designed for more conventionallyhumanoid AI such as robotics and virtual reality can be incorporated into a cycle-based ABM simulation platform. We integrate a Python-language version of the action selection for Bryson’s Behavior Oriented Design (BOD) into a fairly standard cycle-based simulation platform, MASON (Luke et al., 2003). The resulting system is currently being used as a research platform in our group, and has been used for laboratories in the European Agent Systems Summer School.

Integrating Life-Like Action Selection into Cycle-Based Agent Simulation Environments

The development of the XCS Learning Classifier System has produced a robust and stable implementation that performs competitively in direct-reward environments. Although investigations in delayed-reward (i.e. multi-step) environments have shown promise, XCS still struggles to efficiently find optimal solutions in environments with long action-chains. This paper highlights the strong relation of XCS to reinforcement learning and identifies some of the major differences. This makes it possible to add Eligibility Traces to XCS, a method taken from reinforcement learning to update the prediction of the whole action-chain on each step, which should cause prediction update to be faster and more accurate. However, it is shown that the discrete nature of the condition representation of a classifier and the operation of the genetic algorithm cause traces to propagate back incorrect prediction values and in some cases results in a decrease of system performance. As a result further investigation of the existing approach to generalisation is proposed.

VBLinLogit libary for variational Bayesian linear and logistic regression for MATLAB/Octave

Many everyday life decisions require allocating finite resources, such as attention or time, to examine multiple available options, like choosing an online food supplier. In these cases, our search resources can be spread across many options (breadth) or focused on a few of them (depth). Whilst theoretical work has described how finite resources should be allocated to maximise utility in these problems, evidence about how humans balance breadth and depth is lacking. We introduce a novel experimental paradigm where humans make a many-alternative decision under finite resources. In an imaginary scenario, participants allocate a finite budget to sample amongst multiple apricot suppliers in order to estimate the quality of their fruits, and ultimately choose the best one. We found that at low budget capacity participants sample as many suppliers as possible, and thus prefer breadth, whereas at high capacities participants sample just a few chosen alternatives in depth, and intentionally ignore the rest. The number of alternatives sampled increases with capacity following a power law with an exponent close to 0.75. In richer environments, where good outcomes are more likely, humans further favour depth. Participants deviate from optimality and tend to allocate capacity amongst the selected alternatives more homogeneously than it would be optimal, but the impact on the outcome is small. Overall, our results undercover a rich phenomenology of close-to-optimal behaviour and biases in complex choices.

Humans balance breadth and depth: Near-optimal performance in many-alternative decision making

Emotional states are an important ingredient of decision-making. Human beings are immersed into a sea of emotions where episodes of high mood alternate with episodes of low mood. While changes in mood are well characterized, little is known about how these fluctuations interact with metacognition, and in particular with our perception of having made the right choice. Here, we evaluate how implicit measurements of confidence are related with the emotional states of human participants through two online longitudinal experiments involving mood self-reports and visual discrimination decision-making tasks. Self-confidence was assessed on each session by monitoring the proportion of opt-out trials when an opt-out option was available, as well as the mean reaction times on standard correct trials. We first report a strong coupling between the mood, stress, food enjoyment and quality of sleep reported by participants in the same session. Second, we confirmed that the proportion of opt-out responses as well as reaction times in non-opt-out trials provided reliable indices of self-confidence in each session. We introduce a normative measure of overconfidence based on the pattern of opt-out selection and the signal-detection-theory framework. Finally and crucially, we found that mood, sleep quality, food enjoyment and stress level are not coupled with self-confidence, but rather they fluctuate at different time scales: emotional states expose faster fluctuations (over one day or half-a-day) than self-confidence level (two-and-a-half days). Therefore, our findings suggest that emotional states and confidence in decision making spontaneously fluctuate in an independent manner in the healthy adult population.

Emotional states and self-confidence independently fluctuate at different time scales

Review for "Neural networks of different species, brain areas and states can be characterized by the probability polling state"

Abstract Pointing to similarities between challenges encountered in today's neural coding and twentieth-century behaviorism, we draw attention to lessons learned from resolving the latter. In particular, Perceptual Control Theory posits behavior as a closed-loop control process with immediate and teleological causes. With two examples, we illustrate how these ideas may also address challenges facing current neural coding paradigms.

Las neuronas del cortex cerebral de los mamiferos reciben la actividad generada por miles de otras neuronas pertenecientes a la misma red local. Entender las propiedades de la respuesta de estas neuronas en funcion de las propiedades de la senal generada por la red local es crucial. Tradicionalmente, esta senal ha sido estudiada usando grandes simplificaciones. En particular, la senal carecia las escalas de tiempo que describen la sincronia entre las neuronas o la constante de tiempo de las sinapsis. En mi Tesis, abordo el problema de entender la respuesta de una neurona que integra una senal caracterizada por escalas de tiempo de sincronizacion o sinapticas. Utilizo el formalismo de la ecuacion de Fokker-Planck para describir el estado de una neurona que recibe una senal estocastica descrita por estas escalas de tiempo. Resolviendo esta ecuacion en muchos limites interesantes, soy capaz de dar una respuesta general a la pregunta de cuales son las propiedades de disparo de neuronas corticales que reciben senales realistas. Este estudio esta acompanado profusamente de muchos ejemplos relevantes (nucleos cerebelares profundos, receptores NMDA, corteza auditiva primaria...), donde los resultados anteriores son utilizados. Mi Tesis es, pues, relevantes para estudiosos de la descripcion de las propiedades de respuesta de las neuronas en la corteza.

Effects of synchronization and synaptic time scales on the neuronal response

Many sensory systems have evolved to optimally combine signals from multiple sensory modalities to improve perception. While theories have been proposed to explain how this process is accomplished through probabilistic inference using large neural populations in vertebrates, how animals with dramatically smaller nervous systems such as the Drosophila melanogaster larva achieve multisensory combination remains elusive. Here, we systematically characterize larval navigation in different configurations of odor and temperature gradients with optogenetically-controlled noise. Using a data-driven agent-based model, we find that larvae adapt to the reliability of individual sensory signals, and in some cases minimize the variance of the combined signal. Besides firmly establishing that probabilistic inference directs natural orientation behaviors in the Drosophila larva, our results indicate that the exact mechanism underlying the combination of sensory information may be modality-dependent. By underscoring that probabilistic inference is inherent to insect nervous systems, our work opens the way for studying its neural implementation.

Computational principles of adaptive multisensory combination in the Drosophila larva

Learning to make adaptive decisions depends on exploring options, experiencing their consequence, and reassessing one’s strategy for the future. Although several studies have analyzed various aspects of value-based decision-making, most of them have focused on decisions in which gratification is cued and immediate. By contrast, how the brain gauges delayed consequence for decision-making remains poorly understood. To investigate this, we designed a novel decision-making task in which each decision altered future options to decide upon. The task was organized in groups of inter-dependent trials, and the participants were instructed to maximize cumulative reward value within each group. In the absence of any explicit performance feedback, the participants had to test and internally assess specific criteria to make decisions. The absence of explicit feedback was key to specifically study how the assessment of consequence forms and influences decisions as learning progresses. We formalized this operation mathematically by means of a multi-layered decision-making model. It uses a mean-field approximation to describe the dynamics of two populations of neurons which characterize the binary decision-making process. The resulting decision-making policy is dynamically modulated by an internal oversight mechanism based on the prediction of consequence. This policy is reinforced by rewarding outcomes. The model was validated by fitting each individual participants’ behavior. It faithfully predicted non-trivial patterns of decision-making, regardless of performance level. These findings provide an explanation to how delayed consequence may be computed and incorporated into the neural dynamics of decision-making, and to how adaptation occurs in the absence of explicit feedback. AUTHOR SUMMARY Decision-making often entails anticipating the consequences of one’s choices over time. However, real-world choice outcomes are not always immediate, adding significant challenges to determining their long-term implications for behavior. Most previous studies on reward-driven decision-making focus on task paradigms in which the decision outcomes are immediate and explicitly cued. However, the cognitive and neurobiological mechanisms by which the brain learns about and incorporates delayed and uncertain consequences remain unclear. Consequently, the primary aim of our study was twofold. First, we designed an experimental task in which participants were instructed to maximize the reward value across sequences of trials in which some of the stimuli offers were dependent on previous choices. Crucially, participants had to learn the decision-making strategy by making exploratory decisions in the absence of any explicit feedback. We analyzed the resulting behavior to characterize individual differences in decision strategy and learning rates. Secondly, we built a model of the underlying cognitive processes involved in strategy learning and consequence-based decision-making. We formalized this by using a three-layer model which accurately reproduced the behavior of individual participants. The resulting model provides a discrete computational account of consequence-based decision-making.

A Theoretical Formalization of Consequence-Based Decision-Making

We present a new AdEx mean-field framework to model two networks of excitatory and inhibitory neurons, representing two cortical columns, and interconnected with excitatory connections contacting both Regularly Spiking (excitatory) and Fast Spiking (inhibitory) cells. This connection scheme is biophysically plausible since it is based on intercolumnar excitation and intracolumnar excitation-inhibition. This configuration introduces bicolumnar competition, sufficient for choosing between two alternatives. Each column represents a pool of neurons voting for one of two choices indicated by two stimuli presented on a monitor in human and macaque experiments. The task also requires maximizing the cumulative reward over each episode, which consists of a certain number of trials. The cumulative reward depends on the coherency between choices of the participant/model and preset strategy in the experiment. We endow the model with a reward-driven learning mechanism allowing to capture the implemented strategy, as well as to model individual exploratory behavior. We compare the simulation results to the behavioral data obtained from the human and macaque experiments in terms of performance and reaction time. This model provides a biophysical ground for simpler phenomenological models proposed for similar decision-making tasks and can be applied to neurophysiological data obtained from the macaque brain. Finally, it can be embedded in whole-brain simulators, such as The Virtual Brain (TVB), to study decision-making in terms of large scale brain dynamics.

A biologically plausible decision-making model based on interacting cortical columns

Previous work has separately addressed different forms of action, state and action-state entropy regularization, pure exploration and space occupation. These problems have become extremely relevant for regularization, generalization, speeding up learning and providing robust solutions at unprecedented levels. However, solutions of those problems are hectic, ranging from convex and non-convex optimization, and unconstrained optimization to constrained optimization. Here we provide a general dual function formalism that transforms the constrained optimization problem into an unconstrained convex one for any mixture of action and state entropies. The cases with pure action entropy and pure state entropy are understood as limits of the mixture.

A general Markov decision process formalism for action-state entropy-regularized reward maximization

During economic choice, we often consider options in alternation, until we commit to one. Nonetheless, neuroeconomics typically ignores the dynamic aspects of deliberation. We trained macaques to perform a value-based decision-making task where two risky offers were presented in sequence at different locations of the visual field, each followed by a delay epoch where offers were invisible. Subjects looked at the offers in sequence, as expected. Surprisingly, during the delay epochs, we found that subjects still tend to look at empty locations where the visual offers were formerly presented; and, moreover, longer fixation to given empty location increases the probability of choosing the associated offer, even after controlling for the offer values. We show that activity in orbitofrontal cortex (OFC) reflects the value of the gazed offer, but also the value of the offer associated to the gazed spatial location, even if it is not the most recently viewed. This reactivation reflects a reevaluation process, as fluctuations in neural spiking during offer stimuli presentation and delays correlate with upcoming choice. Our results suggest that look-at-nothing gazing triggers the reactivation of a previously seen offer for further reevaluation, revealing novel aspects of deliberation.

Gaze-centered gating and reactivation of value encoding in orbitofrontal cortex

Mood and implicit confidence independently fluctuate at different time scales

Intrinsic motivation generates behaviors that do not necessarily lead to immediate reward, but help exploration and learning. Here we show that agents having the sole goal of maximizing occupancy of future actions and states, that is, moving and exploring on the long term, are capable of complex behavior without any reference to external rewards. We ﬁnd that action-state path entropy is the only measure consistent with additivity and other intuitive properties of expected future action-state path occupancy. We provide analytical expressions that relate the optimal policy with the optimal state-value function, from where we prove uniqueness of the solution of the associated Bellman equation and convergence of our algorithm to the optimal state-value function. Using discrete and continuous state tasks, we show that ‘dancing’, hide-and-seek and a basic form of altruistic behavior naturally result from entropy seeking without external rewards. Intrinsically motivated agents can objectively determine what states constitute rewards, exploiting them to ultimately maximize action-state path entropy.

Seeking entropy: complex behavior from intrinsic motivation to occupy action-state path space

Simple Summary During the deep phases of sleep we do not normally wake up by a thunder, but we nevertheless notice it when awake. The exact same sound gets to our ears and cortex through the thalamus and still, it triggers two very different responses. There is growing experimental evidence that these two states of the brain—sleep and wakefulness—distribute sensory information in different ways across the cortex. In particular, during sleep, neuronal responses remain local and do not spread out across distant synaptically connected regions. On the contrary, during wakefulness, stimuli are able to elicit a wider spatial response. We have used a computational model of coupled cortical columns to study how these two propagation modes arise. Moreover, the transition from sleep-like to waking-like dynamics occurs in agreement with the synaptic homeostasis hypothesis and only requires the increase of excitatory conductances. We have found that, in order to reproduce the aforementioned observations, this parameter change has to be selectively applied: synaptic conductances between distinct columns have to be potentiated over local ones. Abstract Non-threatening familiar sounds can go unnoticed during sleep despite the fact that they enter our brain by exciting the auditory nerves. Extracellular cortical recordings in the primary auditory cortex of rodents show that an increase in firing rate in response to pure tones during deep phases of sleep is comparable to those evoked during wakefulness. This result challenges the hypothesis that during sleep cortical responses are weakened through thalamic gating. An alternative explanation comes from the observation that the spatiotemporal spread of the evoked activity by transcranial magnetic stimulation in humans is reduced during non-rapid eye movement (NREM) sleep as compared to the wider propagation to other cortical regions during wakefulness. Thus, cortical responses during NREM sleep remain local and the stimulus only reaches nearby neuronal populations. We aim at understanding how this behavior emerges in the brain as it spontaneously shifts between NREM sleep and wakefulness. To do so, we have used a computational neural-mass model to reproduce the dynamics of the sensory auditory cortex and corresponding local field potentials in these two brain states. Following the synaptic homeostasis hypothesis, an increase in a single parameter, namely the excitatory conductance g¯AMPA, allows us to place the model from NREM sleep into wakefulness. In agreement with the experimental results, the endogenous dynamics during NREM sleep produces a comparable, even higher, response to excitatory inputs to the ones during wakefulness. We have extended the model to two bidirectionally connected cortical columns and have quantified the propagation of an excitatory input as a function of their coupling. We have found that the general increase in all conductances of the cortical excitatory synapses that drive the system from NREM sleep to wakefulness does not boost the effective connectivity between cortical columns. Instead, it is the inter-/intra-conductance ratio of cortical excitatory synapses that should raise to facilitate information propagation across the brain.

Computational Modeling of Information Propagation during the Sleep–Waking Cycle

The dynamics of decision-making and action during active sampling

Deep imagination is a close to optimal policy for planning in large decision trees under limited resources

Ketamine disrupts naturalistic coding of working memory in primate lateral prefrontal cortex networks

A substantial body of research in the past few decades has converged on the idea that the so-called “sense of agency”, the feeling of being in control of our own actions, arises from the integration of multiple sources of information at different levels. In this study, we investigated whether a measurable sense of agency can be detected for mental actions, without the contribution of motor components. We used a fake action-effect paradigm, where participants were led to think that a motor action or a particular thought could trigger a sound. Results showed that the high-level sense of agency, measured through explicit reports, was of comparable strength for motor and mental actions. The ‘intentional binding’ effect, a phenomenon typically associated with the experience of agency, was also observed for both motor and mental actions, with the only exception of short action-effect delays. Furthermore, a consistent relationship between explicit reports of agency and intentional binding was found. Taken together, our results provide novel insights into the specific role of intentional cues in instantiating a sense of agency, even in the absence of motor signals. These results may have important implications for future brain-computer interfaces as well as for the study of pathological disruptions of agency.

Sense of agency for mental actions: Insights from a belief-based action-effect paradigm

Correction: Representation of foreseeable choice outcomes in orbitofrontal cortex triplet-wise interactions

Abstract When facing many options, we narrow down our focus to very few of them. Although behaviors like this can be a sign of heuristics, they can actually be optimal under limited cognitive resources. Here, we study the problem of how to optimally allocate limited sampling time to multiple options, modeled as accumulators of noisy evidence, to determine the most profitable one. We show that the effective sampling capacity of an agent increases with both available time and the discriminability of the options, and optimal policies undergo a sharp transition as a function of it. For small capacity, it is best to allocate time evenly to exactly five options and to ignore all the others, regardless of the prior distribution of rewards. For large capacities, the optimal number of sampled accumulators grows sublinearly, closely following a power law as a function of capacity for a wide variety of priors. We find that allocating equal times to the sampled accumulators is better than using uneven time allocations. Our work highlights that multialternative decisions are endowed with breadth–depth tradeoffs, demonstrates how their optimal solutions depend on the amount of limited resources and the variability of the environment, and shows that narrowing down to a handful of options is always optimal for small capacities.

Optimal Allocation of Finite Sampling Capacity in Accumulator Models of Multialternative Decision Making

In biological neuronal networks, information representation and processing are achieved through plasticity learning rules that have been empirically characterized as sensitive to second and higher-order statistics in spike trains. However, most models in both computational neuroscience and machine learning aim to convert diverse statistical properties in inputs into first-order statistics in outputs, like in modern deep learning networks. In the context of classification, such schemes have merit for inputs like static images, but they are not well suited to capture the temporal structure in time series. In contrast, the recently developed covariance perceptron uses second-order statistics by mapping input covariances to output covariances in a consistent fashion. Here, we explore the applicability of covariance-based perceptron readouts in reservoir computing networks to classify synthetic multivariate time series structured at different statistical orders (first and second). We show that the second-order framework outperforms or matches the classical mean paradigm in terms of accuracy. Our results highlight a nontrivial relationship between input and reservoir properties in generating the output reservoir activity, which suggests an important role for recurrent connectivity in transforming information representations in biologically inspired architectures. Finally, we solve a speech recognition task for the classification of spoken digits to further demonstrate the potential of covariance-based decoding for real data.

Covariance-based information processing in reservoir computing systems

Shared neuronal variability has been shown to modulate cognitive processing. However, the relationship between shared variability and behavioral performance is heterogeneous and complex in frontal areas such as the orbitofrontal cortex (OFC). Mounting evidence shows that single-units in OFC encode a detailed cognitive map of task-space events, but the existence of a robust neuronal ensemble coding for the predictability of choice outcome is less established. Here, we hypothesize that the coding of foreseeable outcomes is potentially unclear from the analysis of units activity and their pairwise correlations. However, this code might be established more conclusively when higher-order neuronal interactions are mapped to the choice outcome. As a case study, we investigated the trial-to-trial shared variability of neuronal ensemble activity during a two-choice interval-discrimination task in rodent OFC, specifically designed such that a lose-switch strategy is optimal by repeating the rewarded stimulus in the upcoming trial. Results show that correlations among triplets are higher during correct choices with respect to incorrect ones, and that this is sustained during the entire trial. This effect is not observed for pairwise nor for higher than third-order correlations. This scenario is compatible with constellations of up to three interacting units assembled during trials in which the task is performed correctly. More interestingly, a state-space spanned by such constellations shows that only correct outcome states that can be successfully predicted are robust over 100 trials of the task, and thus they can be accurately decoded. However, both incorrect and unpredictable outcome representations were unstable and thus non-decodeable, due to spurious negative correlations. Our results suggest that predictability of successful outcomes, and hence the optimal behavioral strategy, can be mapped out in OFC ensemble states reliable over trials of the task, and revealed by sufficiency complex neuronal interactions.

Representation of foreseeable choice outcomes in orbitofrontal cortex triplet-wise interactions

Systems neuroscience is still mainly a neuronal field, despite the plethora of evidence supporting the fact that astrocytes modulate local neural circuits, networks, and complex behaviors. In this article, we sought to identify which types of studies are necessary to establish whether astrocytes, beyond their well‐documented homeostatic and metabolic functions, perform computations implementing mathematical algorithms that sub‐serve coding and higher‐brain functions. First, we reviewed Systems‐like studies that include astrocytes in order to identify computational operations that these cells may perform, using Ca2+ transients as their encoding language. The analysis suggests that astrocytes may carry out canonical computations in a time scale of subseconds to seconds in sensory processing, neuromodulation, brain state, memory formation, fear, and complex homeostatic reflexes. Next, we propose a list of actions to gain insight into the outstanding question of which variables are encoded by such computations. The application of statistical analyses based on machine learning, such as dimensionality reduction and decoding in the context of complex behaviors, combined with connectomics of astrocyte–neuronal circuits, is, in our view, fundamental undertakings. We also discuss technical and analytical approaches to study neuronal and astrocytic populations simultaneously, and the inclusion of astrocytes in advanced modeling of neural circuits, as well as in theories currently under exploration such as predictive coding and energy‐efficient coding. Clarifying the relationship between astrocytic Ca2+ and brain coding may represent a leap forward toward novel approaches in the study of astrocytes in health and disease.

The primate lateral prefrontal cortex (LPFC) is considered fundamental for temporarily maintaining and manipulating mental representations that serve behavior, a cognitive function known as working memory1. Studies in non-human primates have shown that LPFC lesions impair working memory2 and that LPFC neuronal activity encodes working memory representations3. However, such studies have used simple displays and constrained gaze while subjects held information in working memory3, which put into question their ethological validity4,5. Currently, it remains unclear whether LPFC microcircuits can support working memory function during natural behavior. We tested macaque monkeys in a working memory navigation task in a life-like virtual environment while their gaze was unconstrained. We show that LPFC neuronal populations robustly encode working memory representations in these conditions. Furthermore, low doses of the NMDA receptor antagonist, ketamine, impaired working memory performance while sparing perceptual and motor skills. Ketamine decreased the firing of narrow spiking inhibitory interneurons and increased the firing of broad spiking cells reducing population decoding accuracy for remembered locations. Our results show that primate LPFC generates robust neural codes for working memory in naturalistic settings and that such codes rely upon a fine balance between the activation of excitatory and inhibitory neurons.

Naturalistic coding of working memory in primate prefrontal cortex

Identifying the features of population responses that are relevant to the amount of information encoded by neuronal populations is a crucial step toward understanding the neural code. Statistical features such as tuning properties, individual and shared response variability, and global activity modulations could all affect the amount of information encoded and modulate behavioral performance. We show that two features in particular affect information: the modulation of population responses across conditions and the projection of the inverse population variability along the modulation axis. We demonstrate that fluctuations of these two quantities are correlated with fluctuations of behavioral performance in various tasks and brain regions. In contrast, fluctuations in mean correlations among neurons and global activity have negligible or inconsistent effects on the amount of information encoded and behavioral performance. Our results are consistent with predictions of a model that optimally decodes population responses, which suggests that in our behavioral tasks the readout of information is near-optimal.

Identifying the most influential features of neural population responses for information encoding and behavior

Learning in neuronal networks has developed in many directions, in particular to reproduce cognitive tasks like image recognition and speech processing. Implementations have been inspired by stereotypical neuronal responses like tuning curves in the visual system, where, for example, ON/OFF cells fire or not depending on the contrast in their receptive fields. Classical models of neuronal networks therefore map a set of input signals to a set of activity levels in the output of the network. Each category of inputs is thereby predominantly characterized by its mean. In the case of time series, fluctuations around this mean constitute noise in this view. For this paradigm, the high variability exhibited by the cortical activity may thus imply limitations or constraints, which have been discussed for many years. For example, the need for averaging neuronal activity over long periods or large groups of cells to assess a robust mean and to diminish the effect of noise correlations. To reconcile robust computations with variable neuronal activity, we here propose a conceptual change of perspective by employing variability of activity as the basis for stimulus-related information to be learned by neurons, rather than merely being the noise that corrupts the mean signal. In this new paradigm both afferent and recurrent weights in a network are tuned to shape the input-output mapping for covariances, the second-order statistics of the fluctuating activity. When including time lags, covariance patterns define a natural metric for time series that capture their propagating nature. We develop the theory for classification of time series based on their spatio-temporal covariances, which reflect dynamical properties. We demonstrate that recurrent connectivity is able to transform information contained in the temporal structure of the signal into spatial covariances. Finally, we use the MNIST database to show how the covariance perceptron can capture specific second-order statistical patterns generated by moving digits. Author summary The dynamics in cortex is characterized by highly fluctuating activity: Even under the very same experimental conditions the activity typically does not reproduce on the level of individual spikes. Given this variability, how then does the brain realize its quasi-deterministic function? One obvious solution is to compute averages over many cells, assuming that the mean activity, or rate, is actually the decisive signal. Variability across trials of an experiment is thus considered noise. We here explore the opposite view: Can fluctuations be used to actually represent information? And if yes, is there a benefit over a representation using the mean rate? We find that a fluctuation-based scheme is not only powerful in distinguishing signals into several classes, but also that networks can efficiently be trained in the new paradigm. Moreover, we argue why such a scheme of representation is more consistent with known forms of synaptic plasticity than rate-based network dynamics.

The covariance perceptron: A new paradigm for classification and processing of time series in recurrent neuronal networks

Identifying the features of population responses that are relevant to the amount of information encoded by neuronal populations is a crucial step toward understanding population coding. Statistical features, such as tuning properties, individual and shared response variability, and global activity modulations, could all affect the amount of information encoded and modulate behavioral performance. We show that two features in particular affect information: the modulation of population responses across conditions (population signal) and the inverse population covariability along the modulation axis (projected precision). We demonstrate that fluctuations of these two quantities are correlated with fluctuations of behavioral performance in various tasks and brain regions consistently across 4 monkeys (1 female and 1 male Macaca mulatta; and 2 male Macaca fascicularis). In contrast, fluctuations in mean correlations among neurons and global activity have negligible or inconsistent effects on the amount of information encoded and behavioral performance. We also show that differential correlations reduce the amount of information encoded in finite populations by reducing projected precision. Our results are consistent with predictions of a model that optimally decodes population responses to produce behavior. SIGNIFICANCE STATEMENT The last two or three decades of research have seen hot debates about what features of population tuning and trial-by-trial variability influence the information carried by a population of neurons, with some camps arguing, for instance, that mean pairwise correlations or global fluctuations are important while other camps report opposite results. In this study, we identify the most important features of neural population responses that determine the amount of encoded information and behavioral performance by combining analytic calculations with a novel nonparametric method that allows us to isolate the effects of different statistical features. We tested our hypothesis on 4 macaques, three decision-making tasks, and two brain areas. The predictions of our theory were in agreement with the experimental data.

The Effects of Population Tuning and Trial-by-Trial Variability on Information Encoding and Behavior

Department of Computing and Informatics, Faculty of Science and Technology, Bournemouth University, Poole, United Kingdom, 2 Bernstein Center for Computational Neuroscience Heidelberg-Mannheim, Mannheim, Germany, Center for Brain and Cognition and Department of Information and Communications Technologies, Pompeu Fabra University, Research Unit, Parc Sanitari Sant Joan de Déu, Barcelona, Spain, Center for Brain and Cognition, Computational Neuroscience Group, Department of Information and Communication Technologies, Universitat Pompeu Fabra, Barcelona, Spain, 5 Institució Catalana de la Recerca i Estudis Avançats (ICREA), Barcelona, Spain, Department of Neuropsychology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany, 7 School of Psychological Sciences, Monash University, Melbourne, VIC, Australia, Department of Theoretical Neuroscience, Bernstein Center for Computational Neuroscience Heidelberg-Mannheim, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

This document contains the outcome of the first Human behaviour and machine intelligence (HUMAINT) workshop that took place 5-6 March 2018 in Barcelona, Spain. The workshop was organized in the context of a new research programme at the Centre for Advanced Studies, Joint Research Centre of the European Commission, which focuses on studying the potential impact of artificial intelligence on human behaviour. The workshop gathered an interdisciplinary group of experts to establish the state of the art research in the field and a list of future research challenges to be addressed on the topic of human and machine intelligence, algorithm's potential impact on human cognitive capabilities and decision making, and evaluation and regulation needs. The document is made of short position statements and identification of challenges provided by each expert, and incorporates the result of the discussions carried out during the workshop. In the conclusion section, we provide a list of emerging research topics and strategies to be addressed in the near future.

Assessing the impact of machine intelligence on human behaviour: an interdisciplinary endeavour

Human confidence judgments reflect reliability-based hierarchical integration of contextual information

While previous studies have shown that human behavior adjusts in response to uncertainty, it is still not well understood how uncertainty is estimated and represented. As probability distributions are high dimensional objects, only constrained families of distributions with a low number of parameters can be specified from finite data. However, it is unknown what the structural assumptions are that the brain uses to estimate them. We introduce a novel paradigm that requires human participants of either sex to explicitly estimate the dispersion of a distribution over future observations. Judgments are based on a very small sample from a centered, normally distributed random variable that was suggested by the framing of the task. This probability density estimation task could optimally be solved by inferring the dispersion parameter of a normal distribution. We find that although behavior closely tracks uncertainty on a trial-by-trial basis and resists an explanation with simple heuristics, it is hardly consistent with parametric inference of a normal distribution. Despite the transparency of the simple generating process, participants estimate a distribution biased towards the observed instances while still strongly generalizing beyond the sample. The inferred internal distributions can be well approximated by a nonparametric mixture of spatially extended basis distributions. Thus, our results suggest that fluctuations have an excessive effect on human uncertainty judgments because of representations that can adapt overly flexibly to the sample. This might be of greater utility in more general conditions in structurally uncertain environments.

Instance-based generalization for human judgments about uncertainty

The brain uses a mixture of distributed and modular organization to perform computations and generate appropriate actions. While the principles under which the brain might perform computations using modular systems have been more amenable to modeling, the principles by which the brain might make choices using distributed principles have not been explored. Our goal in this perspective is to delineate some of those distributed principles using a neural network method and use its results as a lens through which to reconsider some previously published neurophysiological data. To allow for direct comparison with our own data, we trained the neural network to perform binary risky choices. We find that value correlates are ubiquitous and are always accompanied by non-value information, including spatial information (i.e., no pure value signals). Evaluation, comparison, and selection were not distinct processes; indeed, value signals even in the earliest stages contributed directly, albeit weakly, to action selection. There was no place, other than at the level of action selection, at which dimensions were fully integrated. No units were specialized for specific offers; rather, all units encoded the values of both offers in an anti-correlated format, thus contributing to comparison. Individual network layers corresponded to stages in a continuous rotation from input to output space rather than to functionally distinct modules. While our network is likely to not be a direct reflection of brain processes, we propose that these principles should serve as hypotheses to be tested and evaluated for future studies.

Using a Simple Neural Network to Delineate Some Principles of Distributed Economic Choice

Possible options in a decision often organize as a hierarchy of subdecisions. A recent study concluded that perceptual processes in primates mimic this hierarchical structure and perform subdecisions in parallel. We argue that a flat model that directly selects between final choices accounts more parsimoniously for the reported behavioral and neural data. Critically, a flat model is characterized by decision signals integrating evidence at different hierarchical levels, in agreement with neural recordings showing this integration in localized neural populations. Our results point to the role of experience for building integrated perceptual categories where sensory evidence is merged prior to decision. DOI: http://dx.doi.org/10.7554/eLife.16650.001

Results of recent studies point towards a new framework for the neural bases of economic choice. The principles of this framework include the idea that evaluation is limited to a single option within the focus of attention and that we accept or reject that option relative to the entire set of alternatives. Rejection leads attention to a new option, although it can later switch back to a previously rejected one. The option to which a neuron’s firing rate refers is determined dynamically by attention and not stably by labelled lines. Value is always computed relative to the value of rejection. Comparison results not from explicit competition between discrete populations of neurons, but indirectly, as in a horse race, from the fact that the first option whose value crosses a threshold is selected. Consequently, comparison can occur within a single pool of neurons rather than by competition between two or more neuronal populations. The computations that constitute comparison thus occur at multiple levels, including premotor levels, simultaneously (i.e. the brain uses a distributed consensus), and not in discrete stages. This framework suggests a solution to a set of otherwise unresolved neuronal binding problems that result from the need to link options to values, comparisons to actions, and choices to outcomes.

Inactivation of lateral prefrontal cortex increases activity of MT neurons during memory-guided comparisons of visual motion

The brain exhibits complex spatio-temporal patterns of activity. This phenomenon is governed by an interplay between the internal neural dynamics of cortical areas and their connectivity. Uncovering this complex relationship has raised much interest, both for theory and the interpretation of experimental data (e.g., fMRI recordings) using dynamical models. Here we focus on the so-called inverse problem: the inference of network parameters in a cortical model to reproduce empirically observed activity. Although it has received a lot of interest, recovering directed connectivity for large networks has been rather unsuccessful so far. The present study specifically addresses this point for a noise-diffusion network model. We develop a Lyapunov optimization that iteratively tunes the network connectivity in order to reproduce second-order moments of the node activity, or functional connectivity. We show theoretically and numerically that the use of covariances with both zero and non-zero time shifts is the key to infer directed connectivity. The first main theoretical finding is that an accurate estimation of the underlying network connectivity requires that the time shift for covariances is matched with the time constant of the dynamical system. In addition to the network connectivity, we also adjust the intrinsic noise received by each network node. The framework is applied to experimental fMRI data recorded for subjects at rest. Diffusion-weighted MRI data provide an estimate of anatomical connections, which is incorporated to constrain the cortical model. The empirical covariance structure is reproduced faithfully, especially its temporal component (i.e., time-shifted covariances) in addition to the spatial component that is usually the focus of studies. We find that the cortical interactions, referred to as effective connectivity, in the tuned model are not reciprocal. In particular, hubs are either receptors or feeders: they do not exhibit both strong incoming and outgoing connections. Our results sets a quantitative ground to explore the propagation of activity in the cortex.

Estimation of Directed Effective Connectivity from fMRI Functional Connectivity Hints at Asymmetries of Cortical Connectome

Author response: Breaking down hierarchies of decision-making in primates

Dynamic model of whole cortex reveals disassortative hub structure in the intracortical connectome

the Nucleus Tractus Solitarius From Rat Excitatory Synaptic Transmission to Interneurons in Rapidly Deactivating AMPA Receptors Determine

Neuronal activity in cortex is variable both spontaneously and during stimulation, and it has the remarkable property that it is Poisson-like over broad ranges of firing rates covering from virtually zero to hundreds of spikes per second. The mechanisms underlying cortical-like spiking variability over such a broad continuum of rates are currently unknown. We show that neuronal networks endowed with probabilistic synaptic transmission, a well-documented source of variability in cortex, robustly generate Poisson-like variability over several orders of magnitude in their firing rate without fine-tuning of the network parameters. Other sources of variability, such as random synaptic delays or spike generation jittering, do not lead to Poisson-like variability at high rates because they cannot be sufficiently amplified by recurrent neuronal networks. We also show that probabilistic synapses predict Fano factor constancy of synaptic conductances. Our results suggest that synaptic noise is a robust and sufficient mechanism for the type of variability found in cortex.

Correlated and synchronous activity in populations of neurons has been observed in many brain regions and has been shown to play a crucial role in cortical coding, attention, and network dynamics (Singer and Gray, 1995; Salinas and Sejnowski, 2001). However, we still lack a detailed knowledge of the origin and function, if any, of neuronal correlations. In this Research Topic, new ideas about these long standing questions are put forward. One group of studies in this Research Topic investigates the interaction of neuronal correlations with cellular and circuit mechanisms at the level of single neurons and cell pairs. Bolhasani et al. (2013) study the interaction between direct synaptic coupling between two neurons with correlated stochastic input to the neurons. They find that excitatory synaptic coupling can alter the transfer of pairwise correlations from current input to spike output. Interestingly, there is an optimal value of synaptic coupling strength for which the sensitivity of output correlations to input correlations is maximized. 
 
Bird and Richardson (2014) study the interaction between long term plasticity, synaptic vesicle depletion at multiple release sites and presynaptic spiking correlations. They find that there is an optimal number of release sites for driving postsynaptic spiking when synchrony is present in the presynaptic spike trains. Schwalger and Lindner (2013) investigated correlations between the interspike intervals of oscillator model neurons with adaptation. They reveal a fundamental connection between interval correlations and the phase response curve of the neuron model. They also show that when firing rates are high, negative interval correlations cause long-timescale variability of a model neuron's activity to be small. 
 
A second group of studies in this Research Topic investigates neuronal correlations on the level of networks. The key questions that these studies addressing are: (1) How are pairwise and higher order correlations generated in networks and which of them are important for a given network? and (2) How should we uncover and interpret spike train correlations in a given dataset? 
 
Four studies Zhou et al. (2013), Grytskyy et al. (2013), Barreiro et al. (2014), and Jahnke et al. (2013) have focused on the first question. 
 
Zhou et al. (2013) investigated coupled pairs of neurons receiving temporally correlated input currents. They show that pairs of neurons may be more synchronized if they have some degree of heterogeneity in their intrinsic properties. Temporal correlations in the noise that these neurons receive may also promote synchrony. 
 
Grytskyy et al. (2013) have addressed how recurrent neural networks can support the generation of pairwise correlations. The authors put forward a unified framework for the generation of pairwise correlations in recurrent networks and hypothesize that many different single model neurons, when coupled to a network, may generate the same pairwise correlation structures. Interestingly, the authors could show the equivalence of different single neuron models in a linear approximation to a model with fluctuating continuous variables. This could be a useful tool for assessing correlations across models and experiments. 
 
In a complementary study, Barreiro et al. (2014) have focused on the emergence of pairwise and higher order correlations in retina models. The authors find that maximum entropy pairwise models capture surprisingly well the network spiking dynamics. What is surprising about these results is that higher-order correlations in this type of models can be constrained to be far lower than the statistically possible limits and that their strength depends more on the structure of the common input than on the synaptic connectivity profile. 
 
Jahnke et al. (2013) focused on spike patterns rather than correlations and proposed a mechanism for precise spike time pattern generation and replay in neural networks that lack strong densely connected feed-forward structures. The authors put forward the hypothesis that a non-linearity in synaptic summation rules may explain the lack of observed strong feed-forward structures in live networks. 
 
A team lead by Sonja Grun has tackled the second question, how spike correlations may be detected in a given data set. Torre et al. (2013) have extended our methodical toolbox and proposed a new method for the extraction of statistically overrepresented spike patterns that may be the functionally significant “cell assemblies” proposed by Abeles (1982). The challenge this study has taken on is to extract from large number of simultaneously recorded neurons candidate assemblies that are systematically co-activated. This search algorithm may help to reveal how precise multi-neuron synchronization patterns that go beyond the standard pairwise analysis may relate to behavior. 
 
In an opinion article, Zanin and Papo (2013) also address the second question. They suggest that one has to be cautious about interpreting neuronal correlations between neurons or brain areas, because typical measurements of effective connectivity might lead to false positives even when the neurons or the brain areas are indeed performing independent computations. 
 
A third group of studies in this Research Topic addresses the computational advantages of neuronal correlations in the brain. Kilpatrick (2013) studied neuronal networks that sustain bump attractors, a well-established model for the maintenance of spatial cues in working memory tasks (Funahashi et al., 1989; Wimmer et al., 2014). In these models, the position of the bump undergoes a diffusion process, implying that the encoded memory degrades as the time progresses. Notably, Kilpatrick found that connecting several areas with similar bump attractors resulted in an increased stability of the stored memories because the variability within the areas could be averaged out. However, if the variability across areas was correlated, the diffusion of the bump attractor underwent larger variability. This study, therefore, suggests that correlated noise across neuronal areas can impoverish the precision of the encoding of spatial cues in working memory task. 
 
In another study, Dipoppa and Gutkin (2013) found that correlations might have a positive role in working memory tasks by a mechanism that they named “correlation-induced gating.” These authors and others have previously showed that correlations tend to destabilize the memory trace of an item stored in working memory. This result might suggest that correlations are deleterious for working memory, but Dipoppa and Gutkin argue that this is not the case: correlations in working memory circuits can be strongly beneficial to suppress the harmful interference of distractors, irrelevant items that do not need to be stored in memory to solve the ongoing task. This study, therefore, shows in an elegant way how changing correlations within specific neuronal population can allow for flexible gating of sensory information into working memory circuits. 
 
Previous works have showed that synchronization between neuronal ensembles might play an important role in the binding of features belonging to a same object (Engel and Singer, 2001). In a theoretical work presented in this Research Topic, Finger and Koenig (2014) took an important step forward by showing that binding of features in natural images can be mediated by phase synchronization in a network of neural oscillators. The authors also found that the network, trained with natural images, developed small-world properties, and even allowed binding of features over long distances. This study strongly supports the idea that neuronal correlations in the brain might play an important computational role. 
 
In a study where the LFP and single-cell activity were recorded in the hippocampal formation of epileptic patients, Alvarado-Rojas et al. (2013) found that activity of a sizable fraction of neurons preceded interictal epileptiform discharges, as measured by LFP activity. 
 
These studies give conspicuous examples for the ambivalent nature of neuronal correlations: in some conditions correlations might be a signature of dynamic instability of the network, but in other conditions correlations might be used to perform complex and flexible computations, such as binding or information gating. Although these works have provided new clues about the role of neuronal correlations, there are yet many unsolved questions, such as how neuronal correlations are generated and propagated (Moreno et al., 2002; Moreno-Bote and Parga, 2006; de la Rocha et al., 2007; Ostojic et al., 2009; Renart et al., 2010; Rosenbaum et al., 2010, 2011; Tchumatchenko et al., 2010; Cohen and Kohn, 2011; Tchumatchenko and Wolf, 2011; Helias et al., 2014) and how correlations are shaped by limited information in sensory inputs and by neuronal computations. It is clear that the study of the impact of neuronal correlations on information transmission and brain computation, and vice versa, is still an arena for exciting new discoveries.

Correlated neuronal activity and its relationship to coding, dynamics and network architecture

A theory of decision-making using diffusion-to-bound models: choice, reaction-time and confidence

Fano factor constancy and scale-invariant sampling in recurrent networks with probabilistic synapses

Decoding in the dark: extracting information from spontaneous activity in primary visual cortex

It is well-established that some aspects of perception and action can be understood as probabilistic inferences over underlying probability distributions. In some situations, it would be advantageous for the nervous system to sample interpretations from a probability distribution rather than commit to a particular interpretation. In this study, we asked whether visual percepts correspond to samples from the probability distribution over image interpretations, a form of sampling that we refer to as Bayesian sampling. To test this idea, we manipulated pairs of sensory cues in a bistable display consisting of two superimposed moving drifting gratings, and we asked subjects to report their perceived changes in depth ordering. We report that the fractions of dominance of each percept follow the multiplicative rule predicted by Bayesian sampling. Furthermore, we show that attractor neural networks can sample probability distributions if input currents add linearly and encode probability distributions with probabilistic population codes.

Probabilities of perceptual depth ordering in transparent motion and the relative effect of different depth cues

Delivery of neurotransmitter produces on a synapse a current that flows through the membrane and gets transmitted into the soma of the neuron, where it is integrated. The decay time of the current depends on the synaptic receptor's type and ranges from a few (e.g., AMPA receptors) to a few hundred milliseconds (e.g., NMDA receptors). The role of the variety of synaptic timescales, several of them coexisting in the same neuron, is at present not understood. A prime question to answer is which is the effect of temporal filtering at different timescales of the incoming spike trains on the neuron's response. Here, based on our previous work on linear synaptic filtering, we build a general theory for the stationary firing response of integrate-and-fire (IF) neurons receiving stochastic inputs filtered by one, two, or multiple synaptic channels, each characterized by an arbitrary timescale. The formalism applies to arbitrary IF model neurons and arbitrary forms of input noise (i.e., not required to be gaussian or to have small amplitude), as well as to any form of synaptic filtering (linear or nonlinear). The theory determines with exact analytical expressions the firing rate of an IF neuron for long synaptic time constants using the adiabatic approach. The correlated spiking (cross-correlations function) of two neurons receiving common as well as independent sources of noise is also described. The theory is illustrated using leaky, quadratic, and noise-thresholded IF neurons. Although the adiabatic approach is exact when at least one of the synaptic timescales is long, it provides a good prediction of the firing rate even when the timescales of the synapses are comparable to that of the leak of the neuron; it is not required that the synaptic time constants are longer than the mean interspike intervals or that the noise has small variance. The distribution of the potential for general IF neurons is also characterized. Our results provide powerful analytical tools that can allow a quantitative description of the dynamics of neuronal networks with realistic synaptic dynamics.

Response of integrate-and-fire neurons to noisy inputs filtered by synapses with arbitrary timescales: firing rate and correlations.

Noise vs. adaptation: which is responsible for perceptual switches?

Diffusion models have become essential for describing the performance and statistics of reaction times in human decision making. Despite their success, it is not known how to evaluate decision confidence from them. I introduce a broader class of models consisting of two partially correlated neuronal integrators with arbitrarily time-varying decision boundaries that allow a natural description of confidence. The dependence of decision confidence on the state of the losing integrator, decision time, time-varying boundaries, and correlations is analytically described. The marginal confidence is computed for the half-anticorrelated case using the exact solution of the diffusion process with constant boundaries and compared to that of the independent and completely anticorrelated cases.

Decision Confidence and Uncertainty in Diffusion Models with Partially Correlated Neuronal Integrators

When an ambiguous stimulus is viewed for a prolonged time, perception alternates between the different possible interpretations of the stimulus. The alternations seem haphazard, but closer inspection of their dynamics reveals systematic properties in many bistable phenomena. Parametric manipulations result in gradual changes in the fraction of time a given interpretation dominates perception, often over the entire possible range of zero to one. The mean dominance durations of the competing interpretations can also vary over wide ranges (from less than a second to dozens of seconds or more), but finding systematic relations in how they vary has proven difficult. Following the pioneering work of W. J. M. Levelt (1968) in binocular rivalry, previous studies have sought to formulate a relation in terms of the effect of physical parameters of the stimulus, such as image contrast in binocular rivalry. However, the link between external parameters and "stimulus strength" is not as obvious for other bistable phenomena. Here we show that systematic relations readily emerge when the mean dominance durations are examined instead as a function of "percept strength," as measured by the fraction of dominance time, and provide theoretical rationale for this observation. For three different bistable phenomena, plotting the mean dominance durations of the two percepts against the fraction of dominance time resulted in complementary curves with near-perfect symmetry around equi-dominance (the point where each percept dominates half the time). As a consequence, the alternation rate reaches a maximum at equi-dominance. We next show that the observed behavior arises naturally in simple double-well energy models and in neural competition models with cross-inhibition and input normalization. Finally, we discuss the possibility that bistable perceptual switches reflect a perceptual "exploratory" strategy, akin to foraging behavior, which leads naturally to maximal alternation rate at equi-dominance if perceptual switches come with a cost.

Alternation rate in perceptual bistability is maximal at and symmetric around equi-dominance.

Balance between noise and adaptation in competition models of perceptual bistability

Response of integrate-and-fire neurons to noisy inputs filtered by synapses with arbitrary timescales: firing rate and correlations

Ambiguous stimuli with two distinct interpretations give rise to perceptual alternations between them. During prolonged viewing of transparently moving gratings, observers report periods of perceiving one grating in front of the other, alternating with periods of the reverse depth ordering. We measured the percepts' dominance times to study the effect of depth cues (wavelength, duty cycle, and speed) on the perceived depth ordering. The grating with shorter wavelength, lower duty cycle, or higher speed was perceived as being behind the other for a fraction of time larger than one half. The fraction of time spent perceiving each grating as behind changed gradually as a function of the parameters. The fraction of dominance depended on the ratio between the gratings' wavelengths, not on their absolute sizes. The wavelength ratio had a stronger effect on perceived depth than that of duty cycle or speed and could override stereoscopic disparity cues. Similar results were obtained with superimposed moving surfaces of random dots. The findings are interpreted in terms of their relation to statistical properties of natural surfaces and provide evidence that the fraction of dominance of each percept represents the likelihood that it corresponds to the true interpretation of the underlying scene.

Spike correlations between neurons are ubiquitous in the cortex, but their role is not understood. Here we describe the firing response of a leaky integrate-and-fire neuron (LIF) when it receives a temporarily correlated input generated by presynaptic correlated neuronal populations. Input correlations are characterized in terms of the firing rates, Fano factors, correlation coefficients, and correlation timescale of the neurons driving the target neuron. We show that the sum of the presynaptic spike trains cannot be well described by a Poisson process. In fact, the total input current has a nontrivial two-point correlation function described by two main parameters: the correlation timescale (how precise the input correlations are in time) and the correlation magnitude (how strong they are). Therefore, the total current generated by the input spike trains is not well described by a white noise gaussian process. Instead, we model the total current as a colored gaussian process with the same mean and two-point correlation function, leading to the formulation of the problem in terms of a Fokker-Planck equation. Solutions of the output firing rate are found in the limit of short and long correlation timescales. The solutions described here expand and improve on our previous results (Moreno, de la Rocha, Renart, & Parga, 2002) by presenting new analytical expressions for the output firing rate for general IF neurons, extending the validity of the results for arbitrarily large correlation magnitude, and by describing the differential effect of correlations on the mean-driven or noise-dominated firing regimes. Also the details of this novel formalism are given here for the first time. We employ numerical simulations to confirm the analytical solutions and study the firing response to sudden changes in the input correlations. We expect this formalism to be useful for the study of correlations in neuronal networks and their role in neural processing and information transmission.

Theory of Input Spike Auto- and Cross-Correlations and Their Effect on the Response of Spiking Neurons

Maximum alternation rate in bi-stable perception occurs at equidominance: experiments and modeling

When a stimulus supports two distinct interpretations, perception alternates in an irregular manner between them. What causes the bistable perceptual switches remains an open question. Most existing models assume that switches arise from a slow fatiguing process, such as adaptation or synaptic depression. We develop a new, attractor-based framework in which alternations are induced by noise and are absent without it. Our model goes beyond previous energy-based conceptualizations of perceptual bistability by constructing a neurally plausible attractor model that is implemented in both firing rate mean-field and spiking cell-based networks. The model accounts for known properties of bistable perceptual phenomena, most notably the increase in alternation rate with stimulation strength observed in binocular rivalry. Furthermore, it makes a novel prediction about the effect of changing stimulus strength on the activity levels of the dominant and suppressed neural populations, a prediction that could be tested with functional MRI or electrophysiological recordings. The neural architecture derived from the energy-based model readily generalizes to several competing populations, providing a natural extension for multistability phenomena.

Noise-induced alternations in an attractor network model of perceptual bistability.

Spike trains from cortical neurons show a high degree of irregularity, with coefficients of variation (CV) of their interspike interval (ISI) distribution close to or higher than one. It has been suggested that this irregularity might be a reflection of a particular dynamical state of the local cortical circuit in which excitation and inhibition balance each other. In this balanced state, the mean current to the neurons is below threshold, and firing is driven by current fluctuations, resulting in irregular Poisson-like spike trains. Recent data show that the degree of irregularity in neuronal spike trains recorded during the delay period of working memory experiments is the same for both low-activity states of a few Hz and for elevated, persistent activity states of a few tens of Hz. Since the difference between these persistent activity states cannot be due to external factors coming from sensory inputs, this suggests that the underlying network dynamics might support coexisting balanced states at different firing rates. We use mean field techniques to study the possible existence of multiple balanced steady states in recurrent networks of current-based leaky integrate-and-fire (LIF) neurons. To assess the degree of balance of a steady state, we extend existing mean-field theories so that not only the firing rate, but also the coefficient of variation of the interspike interval distribution of the neurons, are determined self-consistently. Depending on the connectivity parameters of the network, we find bistable solutions of different types. If the local recurrent connectivity is mainly excitatory, the two stable steady states differ mainly in the mean current to the neurons. In this case, the mean drive in the elevated persistent activity state is suprathreshold and typically characterized by low spiking irregularity. If the local recurrent excitatory and inhibitory drives are both large and nearly balanced, or even dominated by inhibition, two stable states coexist, both with subthreshold current drive. In this case, the spiking variability in both the resting state and the mnemonic persistent state is large, but the balance condition implies parameter fine-tuning. Since the degree of required fine-tuning increases with network size and, on the other hand, the size of the fluctuations in the afferent current to the cells increases for small networks, overall we find that fluctuation-driven persistent activity in the very simplified type of models we analyze is not a robust phenomenon. Possible implications of considering more realistic models are discussed.

Mean-Driven and Fluctuation-Driven Persistent Activity in Recurrent Networks

Theory of spike correlations: a formal description of input and output correlations in spiking neurons

An analytical description of the response properties of simple but realistic neuron models in the presence of noise is still lacking. We determine completely up to the second order the firing statistics of a single and a pair of leaky integrate-and-fire neurons receiving some common slowly filtered white noise. In particular, the auto- and cross-correlation functions of the output spike trains of pairs of cells are obtained from an improvement of the adiabatic approximation introduced previously by Moreno-Bote and Parga [Phys. Rev. Lett. 92, 028102 (2004)10.1103/PhysRevLett.92.028102]. These two functions define the firing variability and firing synchronization between neurons, and are of much importance for understanding neuron communication.

Auto- and crosscorrelograms for the spike response of leaky integrate-and-fire neurons with slow synapses.

Because of intense synaptic activity, cortical neurons are in a high conductance state. We show that this state has important consequences on the properties of a population of independent model neurons with conductance-based synapses. Using an adiabaticlike approximation we study both the membrane potential and the firing probability distributions across the population. We find that the latter is bimodal in such a way that at any particular moment some neurons are inactive while others are active. The population rate and the response variability are also characterized.

Membrane potential and response properties of populations of cortical neurons in the high conductance state.

Simple model neurons with AMPA and NMDA filters: role of synaptic time scales

During active states of the brain neurons process their afferent currents with an effective membrane time constant much shorter than its value at rest. This fact, together with the existence of several synaptic time scales, determines to which aspects of the input the neuron responds best. Here we present a solution to the response of a leaky integrate-and-fire neuron with synaptic filters when long synaptic times are present, and predict the firing rate for all values of the synaptic time constant. We also discuss under which conditions this neuron becomes a coincidence detector.

Role of synaptic filtering on the firing response of simple model neurons.

Many everyday life decisions require allocating finite resources, such as attention or time, to examine multiple available options, like choosing a food supplier online. In cases like these, resources can be spread across many options (breadth) or focused on a few of them (depth). Whilst theoretical work has described how finite resources should be allocated to maximize utility in these problems, evidence about how humans balance breadth and depth is currently lacking. We introduce a novel experimental paradigm where humans make a many-alternative decision under finite resources. In an imaginary scenario, participants allocate a finite budget to sample amongst multiple apricot suppliers in order to estimate the quality of their fruits, and ultimately choose the best one. We found that at low budget capacity participants sample as many suppliers as possible, and thus prefer breadth, whereas at high capacities participants sample just a few chosen alternatives in depth, and intentionally ignore the rest. The number of alternatives sampled increases with capacity following a power law with an exponent close to 3/4. In richer environments, where good outcomes are more likely, humans further favour depth. Participants deviate from optimality and tend to allocate capacity amongst the selected alternatives more homogeneously than it would be optimal, but the impact on the outcome is small. Overall, our results undercover a rich phenomenology of close-to-optimal behaviour and biases in complex choices.

Balance between breadth and depth in human many-alternative decisions

Background: As artificial intelligence (AI) continues to advance with breakthroughs in natural language processing (NLP) and machine learning (ML), such as the development of models like OpenAI's ChatGPT, new opportunities are emerging for efficient curation of electronic health records (EHR) into real-world data (RWD) for evidence generation in oncology. Our objective is to describe the research and development of industry methods to promote transparency and explainability. Methods: We applied NLP with ML techniques to train, validate, and test the extraction of information from unstructured documents (eg, clinician notes, radiology reports, lab reports, etc.) to output a set of structured variables required for RWD analysis. This research used a nationwide electronic health record (EHR)-derived database. Models were selected based on performance. Variables curated with an approach using ML extraction are those where the value is determined solely based on an ML model (ie, not confirmed by abstraction), which identifies key information from visit notes and documents. These models do not predict future events or infer missing information. Results: We developed an approach using NLP and ML for extraction of clinically meaningful information from unstructured EHR documents and found high performance of output variables compared with variables curated by manually abstracted data. These extraction methods resulted in research-ready variables including initial cancer diagnosis with date, advanced/metastatic diagnosis with date, disease stage, histology, smoking status, surgery status with date, biomarker test results with dates, and oral treatments with dates. Conclusions: NLP and ML enable the extraction of retrospective clinical data in EHR with speed and scalability to help researchers learn from the experience of every person with cancer.

Approach to Machine Learning for Extraction of Real-World Data Variables from Electronic Health Records

Objective: Machine learning has the potential to increase the scale of real-world data curated from electronic health records, but maintaining a high standard of data quality is important to avoid biasing downstream analyses. To increase scale without compromising quality, we propose a hybrid data curation methodology that employs both manual abstraction by clinical experts and automated extraction by machine learning models. Materials and Methods: Our methodology makes the determination about when to employ manual abstraction using a confidence score associated with each model output. We describe a process for selecting confidence thresholds based on simulations validated against a reference-standard labeled dataset. To establish the fitness of our methodology for retrospective research, we apply it to a multi-variable cohort selection task on a large real-world oncology database. Results: Only small amounts of manual abstraction are required for hybrid curation to achieve expert-level error rates. In fact, the hybrid methodology can even reduce error rates relative to manual abstraction in some cases. We further demonstrate that demographic characteristics of a research cohort defined using hybrid variables are comparable to one curated with conventional methods. Discussion Our methodology is general and makes few assumptions about the clinical variable or machine learning model. A key requirement is the availability of reference standard labels for calibrating the tradeoff between abstraction effort and data quality. Conclusion: Incorporating machine learning into real-world data curation using hybrid methodology holds the promise to scale practicable cohort sizes while maintaining fit for research purposes.

A hybrid approach to scalable real-world data curation by machine learning and human experts

seaborn is a library for making statistical graphics in Python. It provides a high-level interface to matplotlib and integrates closely with pandas data structures. Functions in the seaborn library expose a declarative, dataset-oriented API that makes it easy to translate questions about data into graphics that can answer them. When given a dataset and a specification of the plot to make, seaborn automatically maps the data values to visual attributes such as color, size, or style, internally computes statistical transformations, and decorates the plot with informative axis labels and a legend. Many seaborn functions can generate figures with multiple panels that elicit comparisons between conditional subsets of data or across different pairings of variables in a dataset. seaborn is designed to be useful throughout the lifecycle of a scientific project. By producing complete graphics from a single function call with minimal arguments, seaborn facilitates rapid prototyping and exploratory data analysis. And by offering extensive options for customization, along with exposing the underlying matplotlib objects, it can be used to create polished, publication-quality figures.

Despite decades of science investigating the neural underpinnings of episodic memory retrieval, a critical question remains: how does stress influence remembering and the neural mechanisms of recollection in humans? Here, we used functional magnetic resonance imaging and multivariate pattern analyses to examine the effects of acute stress during retrieval. We report that stress reduced the probability of recollecting the details of past experience, and that this impairment was driven, in part, by a disruption of the relationship between hippocampal activation, cortical reinstatement, and memory performance. Moreover, even memories expressed with high confidence were less accurate under stress, and this stress-induced decline in accuracy was explained by reduced posterior hippocampal engagement despite similar levels of category-level cortical reinstatement. Finally, stress degraded the relationship between the engagement of frontoparietal control networks and retrieval decision uncertainty. Collectively, these findings demonstrate the widespread consequences of acute stress on the neural systems of remembering.

Stress Impairs Episodic Retrieval by Disrupting Hippocampal and Cortical Mechanisms of Remembering.

Working memory is central to human cognition, and intensive cognitive training has been shown to expand working memory capacity in a given domain. It remains unknown, however, how the neural systems that support working memory are altered through intensive training to enable the expansion of working memory capacity. We used fMRI to measure plasticity in activations associated with complex working memory before and after 20 days of training. Healthy young adults were randomly assigned to train on either a dual n-back working memory task or a demanding visuospatial attention task. Training resulted in substantial and task-specific expansion of dual n-back abilities accompanied by changes in the relationship between working memory load and activation. Training differentially affected activations in two large-scale frontoparietal networks thought to underlie working memory: the executive control network and the dorsal attention network. Activations in both networks linearly scaled with working memory load before training, but training dissociated the role of the two networks and eliminated this relationship in the executive control network. Load-dependent functional connectivity both within and between these two networks increased following training, and the magnitudes of increased connectivity were positively correlated with improvements in task performance. These results provide insight into the adaptive neural systems that underlie large gains in working memory capacity through training.

Intensive Working Memory Training Produces Functional Changes in Large-scale Frontoparietal Networks

Abstract Many decisions require a context‐dependent mapping from sensory evidence to action. The capacity for flexible information processing of this sort is thought to depend on a cognitive control system in frontoparietal cortex, but the costs and limitations of control entail that its engagement should be minimized. Here, we show that humans reduce demands on control by exploiting statistical structure in their environment. Using a context‐dependent perceptual discrimination task and model‐based analyses of behavioral and neuroimaging data, we found that predictions about task context facilitated decision making and that a quantitative measure of context prediction error accounted for graded engagement of the frontoparietal control network. Within this network, multivariate analyses further showed that context prediction error enhanced the representation of task context. These results indicate that decision making is adaptively tuned by experience to minimize costs while maintaining flexibility.

Adaptive Engagement of Cognitive Control in Context‐Dependent Decision Making

Significance Information is represented in the brain by distributed patterns of cortical activity. In sensory cortex, these patterns are expressed across circuits with an intrinsic functional architecture that is organized along relevant stimulus dimensions. However, it is unknown whether similar organizational principles underlie distributed representations of more abstract information, such as rules or goals. We analyzed correlations in spontaneous activity to identify fine-scaled subnetworks in human prefrontal cortex. These subnetworks were differentially engaged when subjects followed rules in a complex decision-making task. Our results show how the abstract representations that support goal-directed cognition are constrained by an intrinsic functional architecture and prompt new models of information representation in association cortex. Human prefrontal cortex supports goal-directed behavior by representing abstract information about task context. The organizational basis of these context representations, and of representations underlying other higher-order processes, is unknown. Here, we use multivariate decoding and analyses of spontaneous correlations to show that context representations are distributed across subnetworks within prefrontal cortex. Examining targeted prefrontal regions, we found that pairs of voxels with similar context preferences exhibited spontaneous correlations that were approximately twice as large as those between pairs with opposite context preferences. This subnetwork organization was stable across task-engaged and resting states, suggesting that abstract context representations are constrained by an intrinsic functional architecture. These results reveal a principle of fine-scaled functional organization in association cortex.

Distributed representation of context by intrinsic subnetworks in prefrontal cortex

Illness Progression, Recent Stress, and Morphometry of Hippocampal Subfields and Medial Prefrontal Cortex in Major Depression

Cognitive control allows stimulus-response processing to be aligned with internal goals and is thus central to intelligent, purposeful behavior. Control is thought to depend in part on the active representation of task information in prefrontal cortex (PFC), which provides a source of contextual bias on perception, decision making, and action. In the present study, we investigated the organization, influences, and consequences of context representation as human subjects performed a cued sorting task that required them to flexibly judge the relationship between pairs of multivalent stimuli. Using a connectivity-based parcellation of PFC and multivariate decoding analyses, we determined that context is specifically and transiently represented in a region spanning the inferior frontal sulcus during context-dependent decision making. We also found strong evidence that decision context is represented within the intraparietal sulcus, an area previously shown to be functionally networked with the inferior frontal sulcus at rest and during task performance. Rule-guided allocation of attention to different stimulus dimensions produced discriminable patterns of activation in visual cortex, providing a signature of top-down bias over perception. Furthermore, demands on cognitive control arising from the task structure modulated context representation, which was found to be strongest after a shift in task rules. When context representation in frontoparietal areas increased in strength, as measured by the discriminability of high-dimensional activation patterns, the bias on attended stimulus features was enhanced. These results provide novel evidence that illuminates the mechanisms by which humans flexibly guide behavior in complex environments.

Frontoparietal Representations of Task Context Support the Flexible Control of Goal-Directed Cognition

Fluid intelligence is important for successful functioning in the modern world, but much evidence suggests that fluid intelligence is largely immutable after childhood. Recently, however, researchers have reported gains in fluid intelligence after multiple sessions of adaptive working memory training in adults. The current study attempted to replicate and expand those results by administering a broad assessment of cognitive abilities and personality traits to young adults who underwent 20 sessions of an adaptive dual n-back working memory training program and comparing their post-training performance on those tests to a matched set of young adults who underwent 20 sessions of an adaptive attentional tracking program. Pre- and post-training measurements of fluid intelligence, standardized intelligence tests, speed of processing, reading skills, and other tests of working memory were assessed. Both training groups exhibited substantial and specific improvements on the trained tasks that persisted for at least 6 months post-training, but no transfer of improvement was observed to any of the non-trained measurements when compared to a third untrained group serving as a passive control. These findings fail to support the idea that adaptive working memory training in healthy young adults enhances working memory capacity in non-trained tasks, fluid intelligence, or other measures of cognitive abilities.

Failure of Working Memory Training to Enhance Cognition or Intelligence

Nipype 2012: More packages, reusable workflows and reproducible science

Current neuroimaging software offer users an incredible opportunity to analyze their data in different ways, with different underlying assumptions. Several sophisticated software packages (e.g., AFNI, BrainVoyager, FSL, FreeSurfer, Nipy, R, SPM) are used to process and analyze large and often diverse (highly multi-dimensional) data. However, this heterogeneous collection of specialized applications creates several issues that hinder replicable, efficient, and optimal use of neuroimaging analysis approaches: (1) No uniform access to neuroimaging analysis software and usage information; (2) No framework for comparative algorithm development and dissemination; (3) Personnel turnover in laboratories often limits methodological continuity and training new personnel takes time; (4) Neuroimaging software packages do not address computational efficiency; and (5) Methods sections in journal articles are inadequate for reproducing results. To address these issues, we present Nipype (Neuroimaging in Python: Pipelines and Interfaces; http://nipy.org/nipype), an open-source, community-developed, software package, and scriptable library. Nipype solves the issues by providing Interfaces to existing neuroimaging software with uniform usage semantics and by facilitating interaction between these packages using Workflows. Nipype provides an environment that encourages interactive exploration of algorithms, eases the design of Workflows within and between packages, allows rapid comparative development of algorithms and reduces the learning curve necessary to use different packages. Nipype supports both local and remote execution on multi-core machines and clusters, without additional scripting. Nipype is Berkeley Software Distribution licensed, allowing anyone unrestricted usage. An open, community-driven development philosophy allows the software to quickly adapt and address the varied needs of the evolving neuroimaging community, especially in the context of increasing demand for reproducible research.

Nipype: A Flexible, Lightweight and Extensible Neuroimaging Data Processing Framework in Python

The University of Colorado implemented a blended methods curriculum to improve third-year medical student electrocardiography acquisition skills. The authors evaluated this program using a validated 17-item pretest and posttest. The blended methods curriculum yielded a significant effect size and impact on student learning. These results support the need for educational methods that include active in-person learning and including multiple methods of instruction to maximally improve student electrocardiography interpretation skills. Objectives The ability to interpret a 12-lead electrocardiogram (ECG) is an essential skill in inpatient and outpatient settings. In medical school, this skill is generally taught during the Internal Medicine clerkship. Blended learning is a pedagogical tool that combines different modes of information delivery, models of teaching, and learning styles combining face-to-face learning sessions with online learning. The objectives of this study were to develop a curriculum using a blended educational model including lecture, focused educational videos, flipped classroom, and team-based learning to teach a systematic approach to ECG interpretation and enhance the ability of students to identify common and life-threatening electrocardiographic abnormalities. Methods Between 2016 and 2019, 349 medical students from the University of Colorado School of Medicine received the blended learning curriculum, which included an introductory lecture followed by five 30-minute sessions. These sessions encompassed preclass videos and team-based learning in a flipped-classroom design covering critical concepts in electrocardiography. A sample of 64 students completed a survey evaluating confidence in ECG interpretation skills before and after the curriculum. All of the students completed a 17-item pretest and posttest. Results The new curriculum improved learner confidence in ECG interpretation (Wilcoxon signed rank-sum test, P < 0.001). Postcurriculum test scores showed statistically significant improvement in all of the diagnoses tested (paired Student t test, P < 0.01), the most significant gains occurring in the life-threatening tracings of ventricular fibrillation and in ventricular tachycardia. Conclusions Using a blended learning model with multiple educational modalities resulted in significant improvement in learners’ performance and confidence in ECG interpretation.

Evaluating a Blended Learning Model for Medical Student ECG Teaching

Medical students have re-entered their clinical training in a milieu that is vastly different from the one familiar to us. The coronavirus disease 2019 (COVID-19) pandemic shifted vital curriculum into the virtual setting; however, some aspects of clinical education are immobile because they are rooted to one thing: bedside teaching. Physical examination (PE) is one such example. The atrophy of PE skills leads to the increased cost of care and diagnostic error, making the teaching of these skills indispensable. The need to conserve personal protective equipment and limitations on student–patient interactions decrease learner time at the bedside. The pandemic also placed limitations on radiographic test ordering because of the increased time required to sterilize equipment and rooms. As such, teaching methods that encourage students to rely on PE as part of their diagnostic reasoning are needed. This education must be flexible, balancing the need for time at the bedside with methods that allow some of the teaching to occur away from the patient to reduce potential viral exposure. Medical students are frequently taught the “head-to-toe” (HTT) examination before clerkships, but clinical teachers lack the time to teach and provide feedback on this method. Experienced clinicians tailor the PE for a specific patient based on their history and clinical presentation. The hypothesis-driven physical examination (HDPE) is a framework that applies the PE in a context-specific, directed approach based on the likelihood of a suspected diagnosis. This approach places PE teaching within the framework of clinical reasoning, more closely reflecting the PEs performed by practicing physicians. A survey of 106 Liaison Committee on Medical Education–accredited medical schools revealed that 56% of medical schools taught a combination of a comprehensive (HTT) approach combined with a clinical

Recovering Critical Curriculum: Hypothesis-Driven Physical Examination as a Method to Increase Clinical Skills Teaching When Bedside Teaching Remains Limited

Ethics and law: Teaching and assessing ethics and law in the dental curriculum

We aim to delineate whether there is increased blood loss with the use of cannulated pedicle screws compared to solid pedicle screws in patients undergoing posterior spinal fusion. A single-centre retrospective case-control study was undertaken on patients undergoing PSF for spinal fractures. Cannulated screw fixation was compared with solid screw fixation. Intraoperative blood loss was estimated using pre and postoperative haemoglobin levels, recorded estimated blood loss and cell saver reports. Anticoagulation, blood product administration, operative time and number of levels fused were assessed. A total of 64 cases, 32 in each cohort, were included in the analysis. Overall mean haemoglobin reduction from pre- to post-operative was 2.82 ± 1.85 g/L per screw inserted in the cannulated group, compared to a haemoglobin decrease of 2.81 ± 1.521 g/L per screw inserted in the solid screw group (p = 0.971). Total estimated intraoperative blood loss was 616.3 + 355.4 mL in the cannulated group, compared to 713.6 + 473.5 mL in the solid screw group (p = 0.456). Patients with preoperative thrombocytopenia had a transfusion rate of 0.5 ± 0.71 units/patient compared to 0.04 ± 0.19 units/patient in patients with normal platelet levels (p < 0.005). The differences in blood loss observed between cannulated and solid pedicle screws are non-significant overall. The largest predictor for need of transfusion was pre-operative thrombocytopenia, regardless of the type of screw used.

Blood Loss Following Open Posterior Spinal Fusion in Fractures: Cannulated vs. Solid Pedicle Screws

European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society

Study Design: Case report and literature review. Objection: Aim of this study was to summarize the current evidence base behind subacute posttraumatic ascending myelopathy (SPAM) including the epidemiology, presentation, diagnosis, prognosis, and etiology. Summary of Background Data: SPAM is a rare, potentially fatal disorder which is not attributable to ongoing mechanical instability, syrinx formation, or iatrogenic causes. Methods: A systematic literature search on SPAM was performed on Medline, Ovid, Cochrane, Embase, and PubMed databases between 1969 and 2021. Cases were reviewed and the findings summarized. Further evidence was reviewed to support the hypothesis that disruption of cerebrospinal fluid (CSF) circulation is the underlying etiology of the condition. Results: It is estimated to occur in 0.4%–0.7% of spinal cord injuries and may have a mortality of up to 10%. The most likely etiology disruption of CSF circulation leading to further damage to the spinal cord presumably through pressure mediated effects such as a reduction in cellular perfusion. Conclusion: There is effectively no treatment of this condition, however, with interest developing in monitoring of CSF pressures during spinal cord injury this may help confirm the etiology, and allow the suggestion of therapies such as drains or expansion duraplasty to reduce spinal cord pressures. Level of Evidence: Level II—case report and systematic review.

Cervical immobilization in trauma patients: soft collars better than rigid collars? A systematic review and meta-analysis.

P158. SPAM: subacute posttraumatic ascending myelopathy is a rare but devastating disorder: what do we know?

Correction of the pelvic incidence using a bilateral extending pelvic osteotomy: a proof of concept study

A systematic review of economic evaluations of preoperative smoking cessation for preventing surgical complications.

Background: Vaccine pharmacovigilance is at the forefront of the public eye. Shoulder Injuries Related to Vaccine Administration (SIRVA) is a poorly understood Adverse Event Following Immunisation, with iatrogenic origins. Criteria for medicolegal diagnosis of SIRVA is conflicting, current literature and educational materials are lacking, and healthcare practitioner knowledge of the condition is unknown. Methods: A cross-sectional, convenience sampled survey, utilising a validated online questionnaire assessed practitioner knowledge of SIRVA, safe injecting, and upper limb anatomy, and preferred definition for SIRVA. Results: Mean scores were moderate for safe injecting knowledge (69%), and poor for knowledge of anatomy (42%) and SIRVA (55%). Non-immunising healthcare practitioners scored significantly (p = 0.01, and < 0.05, respectively) higher than immunising practitioners for anatomy (2.213 ± 1.52 vs. 3.12 ± 1.50), and safe injecting knowledge (6.70 ± 1.34 vs. 7.14 ± 1.27). Only 52% of authorised vaccinators accurately selected a 40 × 20 mm area recommended for safe injecting. Majority (91.7%) of respondents thought nerve injuries should be included in the diagnostic criteria for SIRVA. Discussion and conclusions: Greater education and awareness of SIRVA is needed in all healthcare disciplines. Consensus regarding SIRVA definition is paramount for accurate reporting and improved future understanding of all aspects of SIRVA.

Healthcare Practitioners Knowledge of Shoulder Injury Related to Vaccine Administration (SIRVA)

Objectives To report on the design, implementation and evaluation of the safety and effectiveness of the Back pain Assessment Clinic (BAC) model. Design BAC is a new, community-based specialist service for assessing and managing neck and low back pain (LBP). The BAC pilot was supported by a Victorian Department of Health and Human Services grant and was evaluated using the Victorian Innovation Reform Impact Assessment Framework (VIRIAF). Data were obtained by auditing BAC activity (22 July 2014 to 30 June 2015) and conducting surveys and interviews of patients, stakeholders and referrers. Setting Tertiary and primary care. Participants Adult patients with neck and LBP referred for outpatient surgical consultation. Main outcome measures VIRIAF outcomes: (1) access to care; (2) appropriate and safe care; (3) workforce optimisation and integration; and (4) efficiency and sustainability. Results A total of 522 patients were seen during the pilot. Most were referred to hospital services by general practitioners (87%) for LBP (63%) and neck pain (24%). All patients were seen within 10 weeks of referral and commenced community-based allied health intervention within 2–4 weeks of assessment in BAC. Of patients seen, 34% had medications adjusted, 57% were referred for physiotherapy, 3.2% to pain services, 1.1% to rheumatology and 1.8% for surgical review. Less MRI scans were ordered in BAC (6.4%) compared with traditional spinal surgical clinics (89.8%), which translated to a cost-saving of $52 560 over 12 months. Patient and staff satisfaction was high. There have been no patient complaints or adverse incidents. Conclusion Evaluation of the BAC pilot suggests it is a potentially safe and cost-saving alternative model of care. Results of the BAC pilot merit further evaluation to determine the potential cost-effectiveness, longer term and broader societal impact of implementing BAC more widely.

Is establishing a specialist back pain assessment and management service in primary care a safe and effective model? Twelve-month results from the Back pain Assessment Clinic (BAC) prospective cohort pilot study

Back pain is the leading international cause of life years lived with disability, and in Australia in 2008–2009 $1.2 billion of healthcare expenditure was attributed to back disorders, with $560 million being for admitted patient costs. However the overall value of these procedures on clinical outcomes and quality of life for Australian patients is not well documented. Furthermore, variation in procedure rates for lumbar spine surgery has recently been noted by the Australian Commission on Safety and Quality in Health Care (ACSQHC) where rates of lumbar decompression procedures across Australia had a fivefold variance, and rates of lumbar fusion procedures had a nearly sevenfold variance. While this variation is likely multifactorial comprising patient related factors, service access and clinician practice, it was also considered that some was potentially clinically unwarranted. As a result, the ACSQHC recommended that a national registry for all patients undergoing lumbar spinal fusion operations be established. Concurrently, musculoskeletal conditions have been listed as a priority domain for the development of clinical quality registries (CQRs) in Australia by the ACSQHC. CQRs collect standardized clinical information regarding a particular condition or disease from multiple institutions for the primary purpose of quality improvement. CQRs differ from registries based on claims data or other proxies of outcome. While these may offer valuable insights, they are not likely to provide the granular data needed to drive clinician-led quality improvement. There are at least 25 prospective spine surgery registries currently operating throughout Europe, North America and the United Kingdom. While some Australian surgeons have participated in the Spine Society of Europe’s Spine Tango Registry, Australia has not had a nationally led spine surgery outcomes registry until now. Sponsored by the Spine Society of Australia (SSA), funded by industry and managed in conjunction with Monash University, the Australian Spine Registry (ASR) pilot was established in 2017 following a clinician expression of interest process, and commenced data collection in January 2018. The pilot aims to assess the feasibility and methodology of establishing a clinical quality spine registry in Australia. The ASR Steering Committee is comprised of SSA membership, surgeons participating in the pilot, Monash University and with funders potentially as non-voting members. Using customized commercial software, the registry will initially collect information from participating orthopaedic surgeons and neurosurgeons across 10 public and private settings in multiple states. The registry data is owned by the SSA, and all external requests for data (beyond the initial pilot) will be in accordance with the ASR Data Request Policy, which is aligned with other Monash clinical registries and the ACSQHC’s Operating Principles (2008). The ultimate aim of the ASR is to enhance the quality of care for spine surgery patients via: • Monitoring of individual patient’s postoperative progress. • Providing a tool for individual surgeons to complete audits of their surgery. • Obtaining data for implant and prosthesis surveillance. • Monitoring trends in surgical approach and outcomes for spine surgery. • Providing an infrastructure to assist specific research and targeted studies. • Determining the results and functional effectiveness of specific spine surgeries in a ‘real world’ setting. The ASR collects patient demographic, clinical and comorbidity data; surgical details and complications; and patient reported outcome measures (PROMs). PROMs are collected prior to surgery and at 6, 12 and 24 months post-operatively using the same collection tools as the major international registries (the EuroQol five dimensions, the Oswestry Disability Index (ODI), and the Neck Disability Index). Data collection is via multiple methods, a strategy that is recommended internationally to optimize data capture, including web-based direct-entry by clinicians and their affiliated staff, email and paper-based forms for patients. The dataset of the ASR has been mapped to the International Consortium of Health Outcomes Measurement’s Low Back Pain Standard Set 2015, to facilitate international harmonization and benchmarking of data. Similar to the British Spine Registry, the ASR proposes to initially define quality measures for only a few specific procedures – discectomies, primary anterior cervical discectomy with fusion and L4-5 degenerative spondylolysthesis. Outcome measurement for the ASR is based on that defined by spine registries internationally for lumbar surgery, with the primary endpoint being a minimum clinically important difference in the ODI. Spine registries internationally have also developed predictive models of patient factors that determine successful surgical outcomes and medical complications reflecting the importance of patient factors in surgery success. The establishment of the ASR presents challenges and opportunities. For example, adjusting for patient and disease factors is important, and a locally applicable model for this needs to be determined to support benchmarking of outcomes. Quality assurance of data will initially be undertaken via practice/medical record audits of participating surgeons, however in the longer term periodic audits of hospital health information system reports will need to be

Monitoring outcomes in spine surgery: rationale behind the Australian Spine Registry

Locking stand-alone cages versus anterior plate constructs in single-level fusion for degenerative cervical disease: a systematic review and meta-analysis

Introduction Upper trunk brachial plexus palsy can result from high-energy trauma and has never been reported following spinal manipulation. Background The case is presented of a patient who developed an acute brachial plexus upper trunk palsy following spinal manipulative therapy. Discussion Discussion is made on the incidence of complications following manipulation and recommendations to prospectively capture all serious complications. Concluding remarks Risks exist with spinal manipulative therapy. Neurological injury can occur. Risk assessment and re-examination should occur at every visit. Large rigorous prospective studies are required to identify the true incidence of serious complications resulting from manipulative therapy and the benefit:risk ratio.

Upper Trunk Brachial Plexus Palsy Following Chiropractic Manipulation

Study Design. Prospective cohort study and systematic literature review. Objective. To compare the functional outcomes for lumbar spinal fusion in both compensation and noncompensation patients in an environment of universal no fault compensation and then to compare these outcomes with those in worker's compensation and nonworkers compensation cohorts from other countries. Summary of Background Data. Compensation has an adverse effect on outcomes in spine fusion possibly based on adversarial environment, delayed resolution of claims and care, and increased compensation associated with prolonged disability. It is unclear whether a universal no fault compensation system would provide different outcomes for these patients. New Zealand's Accident Compensation Corporation (ACC) provides universal no fault compensation for personal injury secondary to accident and offers an opportunity to compare results with differing provision of compensation. Methods. A total of 169 patients undergoing lumbar spinal fusion were assessed preoperatively, at 1 year, and at long-term follow-up out to 14 years, using functional outcome measures and health-related quality-of-life measures. Comparison was made between those covered and not covered by ACC for 3 distinct diagnostic categories. A systematic literature review comparing outcomes in Worker's Compensation and non-Compensation cohorts was also performed. Results. The functional outcomes for both ACC and non-ACC cohorts were similar, with significant and comparable improvements over the first year that were then sustained out to long-term follow-up for both cohorts. At long-term follow-up, the health-related quality-of-life measures were the same between the 2 cohorts. The literature review revealed a marked difference in outcomes between worker's compensation and non–worker's compensation cohorts with a near universal inferior outcome for the compensation group. Conclusion. The similarities in outcomes of patients undergoing lumbar spine fusion under New Zealand's universal no fault compensation system, when compared with the dramatically inferior outcomes for these patients under other worker's compensation systems, suggest that the system of compensation has a major influence on patient outcomes, and that change of compensation to a universal no fault system is beneficial for patients undergoing lumbar fusion surgery. Level of Evidence: 2

The Influence of No Fault Compensation on Functional Outcomes After Lumbar Spine Fusion

TO THE EDITOR: We congratulate Delitto and colleagues (1) for conducting a randomized, controlled trial comparing surgery with PT for the treatment of lumbar spinal stenosis (LSS). However, we have serious concerns about their methods, particularly their interpretation of the results. We do not agree that the study shows that surgical decompression yielded similar effects to a PT regimen among patients with LSS who were surgical candidates. We believe that adherence to intention-to-treat analysis severely distorts the results and leads to erroneous conclusions. Figure 1 indicates that almost two thirds of suitable patients (312 of 481) declined to participate and to be randomly assigned. No information on these patients was presented, but, on the basis of previous, larger, similar studies, these nonparticipants probably experienced greater disability than those who volunteered for randomization (2, 3). This factor raises doubts about this study's external validity. Of the patients allocated to PT, 57% crossed over to surgery after receiving an average of 7.8 PT sessions. In the real world, crossover equates to treatment failure, yet the authors do not seem to acknowledge this when analyzing PT success. As treated, only 15 of 73 PT patients (21%) had a successful outcome. Two patients crossed over from surgery to PT, presumably doing so before surgery took place. This circumstance delineates the near impossibility of performing a randomized, controlled trial between surgical and nonsurgical care options and represents temporal inequality. The value of intention-to-treat analysis in maintaining the benefits of randomization is clear when crossover rates are low and study groups compare equivalent medical treatments. However, this method is inappropriate when comparing surgical versus nonsurgical treatments when crossover is high in 1 study group. Such trials tend to select a cohort of mildly severe cases of the study condition and have prolonged delays in recruitment, as did this one. In clinical practice, many patients have had unsuccessful experiences with nonsurgical care, including PT, before considering surgery for a degenerative disorder, such as LSS. As Delitto and colleagues' study shows, some will experience satisfactory improvement with PT. However, this study also shows that many persons with substantial disability will opt out of PT and instead choose surgical decompression. Including these patients as PT successes is therefore inappropriate. To suggest that this study's findings show equivalence of PT and surgery represents a failure of the study's methods and analysis. Comparing surgical versus nonsurgical therapies with high crossover remains a challenge for methods of evidence-based medicine.

Study Design. Retrospective cohort study and systematic literature review. Objective. To examine the influence of “universal no-fault compensation” upon return-to-work rates in patients undergoing lumbar spinal fusion, and then to make comparison with workers' compensation (WC) and non-workers' compensation (non-WC) claimants. Summary of Background Data. Compensation has an adverse influence upon outcomes and return to work in lumbar spinal fusion. It is unclear whether this is due to the compensation per se, or due to the features of WC including its adversarial environment, delayed resolution of claims, and need for disability enhancement to promote compensation. The New Zealand Accident Compensation Corporation (ACC) is a universal no-fault system offering early treatment and salary reimbursement. Given the differing features of these compensation systems, comparison of return-to-work rates may give insight into the differing outcomes for the two compensation systems. Methods. From a cohort of 428 patients undergoing lumbar spinal fusion, 178 patients covered by ACC system underwent a structured interview to determine pre-injury, pre-surgical, and post-surgical work status. A systematic literature review was performed relating to lumbar spine fusion, return to work, and WC. Results. The return-to-work rate for the ACC patients in work at the time of their injury was 81%. The systematic review of 21 studies including 2519 subjects revealed a return-to-work rate of 40% for WC patients, and 74% for non-WC patients (P < 0.001). There was a significantly greater return-to-work rate for ACC patients than WC patients (P < 0.001), but no difference between ACC and non-WC patients. Conclusion. The return-to-work rates for a universal no-fault compensation system are higher than those under WC cover, and are compatible with non-WC cases. This suggests that the features of WC may contribute to the inferior return-to-work rates. Level of Evidence: 3

Universal No-fault Compensation is Associated With Improved Return to Work Rates in Spine Fusion

TO THE EDITOR: Following media reports of a complaint to the Australian Health Practitioner Regulation Agency regarding a 4-month-old baby’s neck fracture following chiropractic treatment for apparent torticollis,1 the president of the Chiropractors’ Association of Australia stated that “not a single serious adverse event has been recorded in the literature (worldwide) involving a qualified chiropractor treating a child since 1992”.2 However, an examination of the medical literature on adverse events related to chiropractic reveals an interesting story. A PubMed search for “chiropractic adverse event(s)” identifies 18 primary research papers since 1992 that could be classified as examining adverse events, none of which were Australian. Why are there no Australian reports of adverse events associated with chiropractic manipulation? The answer is strikingly simple — there is currently no adverse events reporting system for chiropractic in Australia. This lack of local data means we have to look internationally to gauge the likelihood of chiropractic adverse events. A 2002 Canadian study3 describes 23 cases of vertebral artery dissection associated with chiropractic manipulation over a 10-year period, suggesting a real risk associated with these techniques. Adverse event reporting systems are crucial for maintaining quality and safety in health care. Such systems ensure that adverse events are reviewed, thus identifying root causes of error, minimising risk of recurrence, ensuring professional accountability and improving patient care.4 Recognition of adverse events is a fundamental principle of open disclosure, as highlighted by the Australian Commission on Safety and Quality in Health Care.5 Open recognition and analysis of adverse events fosters public trust in health organisations and individual health care providers. Mitigating risk through quality improvement has long been recognised by industries as distinct as aviation, construction and medicine. The chiropractic profession is no more immune to error than any other. A chiropractic adverse events reporting system would bring chiropractors in line with other Australian health professionals and fulfil public entitlement to safe, high-quality care.

The need for a chiropractic adverse events reporting system in Australia

Study Design: Long-term prospective observational cohort study. Objective: The objective of the study was to compare the long-term functional outcomes of posterolateral fusion (PLF) and posterior lumbar interbody fusion (PLIF) for the treatment of adult isthmic spondylolisthesis (IS). Summary of Background Data: PLIF has the theoretical advantage of improving sagittal alignment and providing a larger, more consistent fusion mass in patients with IS compared with PLF. Studies to date though have not shown a clinical difference, with follow-up of 2 years. Methods: An prospective cohort study was performed of a single surgeon’s patients with IS treated surgically over a 10-year period. Average follow-up was 7 years and 10 months. Preoperative patient characteristics between the 2 groups were not significantly different. The return rate of the long-term questionnaires was 83%. Outcome measures were the Roland Morris Disability Questionnaire (RMDQ), Low Back Outcome Score (LBOS), Short Form (SF)-12v2, and SF-6D R2. Results: PLIF provided better short-term and long-term results than PLF. The PLIF group had significantly better LBOS scores in the long term, and nonsignificantly better RMDQ scores. As measured by the RMDQ Minimal Clinically Important Difference set at 4 and 8, the LBOS Minimal Clinically Important Difference set at 7.5 points and by SF-12v2 Physical Component Score, PLIF patients performed better than PLF patients. When analyzing single-level fusions alone, the difference is more pronounced, with Physical Component Score, Mental Component Scores, and SF-6D R2 all being significantly better in the PLIF group rather than the PLF group. Conclusions: This study strongly supports the use of PLIF to obtain equivalent or superior clinical outcomes compared with PLF for spinal fusion for lumbar IS. Although there are considerable issues when commenting on the results of observational studies, the results of this study are the first to report long-term follow-up beyond 2 years, and further larger long-term randomized studies are suggested.

What is the Optimum Fusion Technique for Adult Isthmic Spondylolisthesis—PLIF or PLF? A Long-Term Prospective Cohort Comparison Study

Posterior lumber interbody fusion (PLIF) has the theoretical advantage of optimising foraminal decompression, improving sagittal alignment and providing a more consistent fusion mass in adult patients with isthmic spondylolisthesis (IS) compared to posterolateral fusion (PLF). Previous studies with only short-term follow-up have not shown a difference between fusion techniques. An observational cohort study was performed of a single surgeon9s patients treating IS over a ten year period (52 patients), using either PLF (21 pts) or PLIF (31pts). Preoperative and 12-month data were collected prospectively, and long-term follow-up was by mailed questionnaire. Preoperative patient characteristics between the two groups were not significantly different. Average follow-up was 7 years, 10 months, and 81% of questionnaires were returned. Outcome measures were Roland Morris Disability Questionnaire (RMDQ), Low Back Outcome Score (LBOS), SF-12v2 and SF-6D R2. The SF-6D R2 is a “whole of health” measure. PLIF provided better short- and long-term results than PLF. The PLIF group had significantly better LBOS scores in the long term, and non-significantly better RMDQ scores in the long term. As measured by RMDQ Minimum Clinically Important Difference (MCID) short term set at 4, RMDQ MCID set at 8, the LBOS MCID set at 7.5 points and by SF-12v2 physical component score (PCS), PLIF patients performed better than PLF patients. When analysing single level fusions alone, the difference is more pronounced, with PCS, mental component scores and SF-6D R2 all being significantly better in the PLIF group rather than the PLF group. This paper strongly supports the use of PLIF to obtain equivalent or superior clinical outcomes when compared to PLF for spinal fusion for lumbar isthmic spondylolisthesis. The results of this study are the first to report to such long-term follow-up comparing these two procedures.

LONG-TERM OUTCOMES FOLLOWING LUMBAR SPINE FUSION FOR ADULT ISTHMIC SPONDYLOLISTHESIS: A COMPARISON OF POSTERIOR LUMBAR INTERBODY FUSION WITH POSTEROLATERAL FUSION

The parachute is a device that is in widespread use by pilots, soldiers, performance artists and recreational skydivers, in order to control the vertical velocity of their fall to earth. The mechanism of action of the parachute is to provide increased drag, countering the force of gravity. This lowers the terminal velocity and allows the descent to be finally stopped by a physiologically acceptable vertical deceleration. Although this mechanism is well accepted by experts in the area, there is only level 5 evidence supporting its use. The practice of evidence-based medicine demands, however, that before a treatment can be recommended for widespread use, satisfactory levels of evidence must exist, proving its efficacy. The landmark paper by Smith and Pell pointed out that, as far as parachute use is concerned, there do not appear to be any good quality, doubleblinded randomized controlled trials supporting its use. Intention-to-treat (ITT) analysis is an epidemiological methodology whereby a subject’s outcome is related only to their initial randomization group, rather than how they were eventually treated. The latter is known as ‘as-treated (AT) analysis’. ITT analysis examines the effects of instituting a population-wide therapy decision in real life, while AT analysis examines the treatment effects on an individual basis. Both analyses, therefore, are applicable under different circumstances, depending on what the question is, and this distinction often leads to misinterpretation and misapplication of study results. While popular in trials of pharmaceuticals, the application of ITT analysis to surgical research has often been met with significant resistance, and led to great inconsistency in the interpretation of even well-conducted trials. In this paper, we wish to extend the experimental model of Smith et al., and assess the effectiveness of parachutes through the use of a hypothetical study, performed using virtual subjects. ITT and AT analysis will both be reported, and difficulties in using these analyses will be discussed.

Long-Term Outcomes Following Lumbar Spine Fusion for Adult Isthmic Spondylolisthesis: A Comparison of PLIF Versus PLF

Background Deep venous thrombosis (DVT) and pulmonary embolus (PE) remain common surgical complications, often affecting patients without any prior warning. Postoperative spinal epidural hematomas (SEH) may have a devastating impact on a patient's recovery from a routine procedure. The effect of preoperative DVT prophylaxis administration on elective spinal patients has not previously been studied. Study Design Retrospective cohort analysis. Objective To correlate the incidence of preoperative DVT prophylaxis administration and the rate of postoperative DVT, PE, and SEH after elective spinal surgery. Summary of Background Data Earlier studies have shown a postoperative DVT rate in elective spinal patients of between 0.3% and 31%, a PE rate of 0.2% to 0.9%, and a SEH rate of approximately 0.1%. Methods About 3870 patient notes, from 2004 to 2008 elective spinal procedures, were reviewed. DVT, PE, and SEH rates were compared between those patients receiving and not receiving preoperative DVT prophylaxis. Results The 36.9% of patients received preoperative DVT prophylaxis, and 19 patients suffered and DVT and/or PE. Nine of these had received preoperative prophylaxis, giving an odds ratio of 0.91. Sixteen patients suffered a SEH, and this gave an odds ratio of 1.33. The SEH's presented with a median postoperative time of 4 days. Conclusions Preoperative DVT prophylaxis does not influence the rate of postoperative DVT or PE among elective spinal patients. It probably does not influence SEH rate, and it is noted that SEH may present quite late, in contrast to currently accepted time courses.

Does Preoperative DVT Chemoprophylaxis in Spinal Surgery Affect the Incidence of Thromboembolic Complications and Spinal Epidural Hematomas?

Water use in the surgical scrub: isn't it time to stop using water at all?

Peripheral hyperalgesia in experimental neuropathy: mediation by α2-adrenoreceptors on post-ganglionic sympathetic terminals

The role of the saphenous nerve in experimental sciatic nerve mononeuropathy produced by loose ligatures: Comment

ABSTRACT:First staged in Dublin in 1663, Katherine Philips's Pompey, a translation of Corneille's Pompée, was the first play by a woman to be performed on the British stage. It was also pathbreaking in its dramatic incorporation of entr'acte songs, which Philips newly added. This essay explores the complex afterlife of one song from the play, Pompey's Ghost. It was her most widely disseminated text, though it largely circulated anonymously or attributed to other authors. Between 1663 and 1806 the song was set to music at least five times. One late seventeenth-century setting became popular in New England and was known there into the nineteenth century. By the late eighteenth century, through another setting, the song became identified as Scottish in origin. The tune to which Pompey's Ghost was sung in Scotland had been thought lost but can now be identified, restoring more of the song's complex reception history and significance.

This chapter analyses the main collections centred on Shakespearean music published in the nineteenth century with a view to determining the underlying cultural processes that led to their creation. Largely through the frequent revivals of the plays, by the early nineteenth century there developed a significant number of settings of the songs, several of which had held the stage since the early eighteenth century. William Linley was first to anthologize the plays’ songs, thus presenting them as a coherent body deserving of prominence in the cultural imagination. By the end of the century, the repertoire had become vast enough to warrant catalogues of musical references and musical settings. The central argument offered is that this emergence of ‘Shakespearean song’ as a sub-plot within bardolatory was an expression of cultural nationalism, in which the idea of Shakespeare as inherently musical dramatist filled the cultural void created by the perceived failure of English music.

Working in Cork: Everyday Life in Irish Steel, Sunbeam Wolsey, and the Ford Marina Plant, 1917–2001 by Liam Cullinane (review)

Music for St Cecilia's Day: From Purcell to Handel. By BryanWhite. Woodbridge: Boydell & Brewer. 2019. xx + 377 p. 15 b. and w. illus. £45 (hb). ISBN 978‐1‐78327‐347‐8.

Oskar Cox Jensen, David Kennerley, and Ian Newmann (eds). Charles Dibdin and Late Georgian Culture

The two best accounts of the morality play Everyman are by Lawrence V. Ryanl and Thomas F. Van Laan.2 Both discuss the structure of the play, with Ryan elucidating the dramatic and emotional patterns and Van Laan describing the "two-part structure" of the action, which first descends and then ascends. Both show the way that Christian doctrine receives embodiment in the art of the play, and both examine the structure of theme, action, and character. I propose here to extend their discussions by offering the term "comedy" as the term proper for the rhythm of the action and by analyzing this comic pattern in the principal metaphors of the play. I shall also suggest the play's close connection to the rites of the Church: (1) O. B. Hardison indicates that the morality play "depends on the sacraments" and that the characters act as they do "because a sacramental psychology requires them" so to act;3 and Everyman brings most if not all of the seven sacraments into its structure. (2) Everyman participates in the same pattern of comic restoration which the Mass enacts. Futhermore, (3) the structure of the principal metaphors of the play is the same as that of one specific feature of the liturgy namely, the priest's prayers of preparation offered prior to saying Mass. Therefore, I shall suggest that Everyman is like much medieval drama in taking its origins (at least in part) in the liturgy. Ryan presents a fine summary of the theological concepts of the play, and I shall assume the perspective of these ideas as I write. Both Ryan and Van Laan limit their remarks to the English play; and so, too, shall I.

This collection of essays has its origins in two conferences held in 2011 celebrating the 450th anniversary of the birth of Peter Philips (d. 1628). A stubborn Catholic born in England, he spent much of his career in the Spanish Netherlands. Philips was a distinguished and able composer, steeped in the English tradition but also fully conversant with Italian style. His music was disseminated widely in manuscript and print and his Continental career makes him an obvious figure through which to investigate networks of culture in early modern Europe. The book comprises fourteen essays by emerging and established scholars. The first is an introductory overview by David J. Smith. In chapter 2, Smith uses Philips’s keyboard music to foreground the ways in which early modern music (and musicians) operated in an often complex network of patronage. He begins by reassessing the evidence for Philips’s 1593 journey to Amsterdam, during which he was accused of planning to sail from Middelburg to England to make an assault on Queen Elizabeth, which led to an interrogation in The Hague. Smith goes on to discuss the various stylistic and personal interconnections between Philips and Sweelinck, Byrd, Morley, and Thomas Tomkins. The interconnections are part of ‘a continuum from ‘‘real’’ networks . . . to ‘‘virtual ones’’’ (p. 30): the former involves direct contact between the characters; the latter indirect contact, even across generations. Smith convincingly suggests that Byrd was the figure at the centre of this ‘web of networks’. In the following chapter E¤ milie Corswarem focuses on musical relations between Lie' ge and Brussels through the prism of the so-called Liber fratrum cruciferorum Leodiensium, an organ manuscript compiled in the early seventeenth century. The manuscript is interesting in its inclusion of (to us) lesser-known composers alongside works by Merulo, Gabrieli, and Sweelinck. As Corswarem points out, the works are indicative of an essentially forward-looking repertory that also takes into account the way in which the approach to organ-building and playing was changing at the turn of the century. While Philips himself does not appear to have visited Lie' ge, there were evidently a good number of musicians from there who were active in Brussels. The chapter demonstrates how interconnections and networks of musicians, sources, and organ-builders in Lie' ge ‘gave rise to a distinctive and progressive organ repertoire’ in the city (p. 47). Next, Anne Lyman re-examines Philips’s three collections of few-voiced motets (1613, 1616, 1628) in the light of newly discovered archival evidence relating to the Confraternity of Our Lady of the Assumption at the Church of Sint-Goedele in Brussels. The confraternity was founded by Archduchess Isabella in 1623, and Philips was a member. The evidence is thin on the identity of the music heard at the confraternity, but Lynan convincingly suggests that Philips’s few-voice motets were among the repertory. In chapter 5 Naomi J. Barker examines ‘The Musical Legacy of the Accademia dei Lincei’. Her objective is stated clearly in the opening sentence: the chapter seeks to ‘argue that references to distant Greek and Roman antiquity provided an anchor of authority through seismic cultural shifts in early seventeenth-century Rome’ (p. 59). The musical examples are taken from Frescobaldi’s printed keyboard works, and one recurring idea in particularçthe gapped chromatic fourth (e.g. a, f , f, e). Barker argues that this motive, which recurs in various guises in a number of his works, is ‘described by Vicentino, Giovanni Battista Doni and others as indicative of the chromatic genus of ancient Greek music’ (p. 62). Thus she situates it not within an emerging sense of tonality but within this locus of authority rooted in academic discourse on ancient Greece, and it may represent an attempt by the composer to ‘tap into the intellectual trends’of his patrons (p. 63). Barker offers an interesting perspective on the interconnection between theory and practice; although the evidence is far from overwhelming, one suspects that there must be something to the idea of communication between patron and composer, even if the nature of that discourse is arcane. Rachelle Taylor and Frauke Ju« rgensen return to the English context with ‘A Discussion of Networks Involving Byrd and his Disciples’. The essay follows on from Smith’s earlier contextual narrative by examining Byrd’s networks of influence. As the authors observe, there is no firm evidence that Byrd actually taught any of the professional musicians whose style is clearly indebted to his. But whether or not there was an actual teacher^student relationship, it is clear that Byrd provided an authoritative model; this particularly resonates

Networks of Music and Culture in the Late Sixteenth and Early Seventeenth Centuries: A Collection of Essays in Celebration of Peter Philips’s 450th Anniversary ed. by David J. Smith and Rachelle Taylor (review)

Stephen Hough and I collided for the first time when we were research fellows in the USA. That encounter in 1980 sowed in me the seed that was to become one of my closest friendships, although at the very beginning I had my doubts. Stephen had hit St Louis about a year before I did and we were to share an office. The potential difficulty lay in putting a slightly 'left of centre' Brit in with a South African, and an Afrikaans one at that. This was 1980.

South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde

Leonard Bernstein’s advocacy of Gustav Mahler’s music has been viewed primarily as a consequence of his position in a lineage of prominent conductors who preceded him as Mahler proponents. But treating Bernstein’s conducting as divorced from another crucial aspect of his musical life—his composing—has limited our understanding of how ideas about music circulated in the twentieth century. This study argues that Bernstein’s relationship with Aaron Copland, his mentor as a composer, played a central role in his engagement with Mahler’s music. Correspondence suggests that from the 1930s, Copland discussed Mahler’s compositions with Bernstein and supported his interest in performing them, particularly the Second Symphony. A script for a lecture from the New York Philharmonic Mahler festival in 1960 shows that Bernstein borrowed content and phraseology from Copland’s 1941 book Our New Music in an attempt to define Mahler as a forerunner of twentieth-century tonal composition.

Sonic Multiplicities: Hong Kong Pop and the Global Circulation of Sound and Image by Yiu Fai Chow and Jeroen de Kloet (review)

Make no mistake, a full-length monograph dedicated to Thomas Augustine Arne is long overdue. His popular reputation may rest in large part on Rule Britannia (David Cameron is perhaps the egregious exception that proves the rule), but Arne was in fact the finest and most significant English composer of theatre music in eighteenth-century London. A Catholic, the usual channels of official patronage were closed to him; by necessity and (one suspects predominantly) by inclination, Arne was essentially a theatre composer for his entire career, which lasted over half a century to his death in 1778. Moreover, Arne was a prolific, if uneven, composer. Many of his works are, however, lost (including the late setting of Mason’s Caractacus, which according to Samuel Arnold contained ‘some of the brightest and most vigorous emanations of Dr Arne’s genius’). Thus, the title of Gilman’s book is more ambitious than it might first seem. In the preface, Gilman sets out his threefold purpose: to provide ‘a comprehensive biography and account of the performance and publication of Arne’s works during his lifetime’ (p. 1); to consider ‘Arne’s social context’ (p. 2); and to offer ‘description and analysis of numerous representative musical illustrations drawn from vocal works for the theatre spanning Arne’s career’ (p. 3). After a ‘Polemical Introduction’, the book is arranged chronologically in fourteen chapters, the first of which is a substantial biographical account. Also included are two useful appendices: transcriptions of correspondence between Arne and David Garrick, and a transcription of Arne’s will. The bibliography could have benefitted from division into primary and secondary sources; it is substantial, although there are some surprising omissions: most glaring is Irena Cholij’s 1995 Ph.D. thesis ‘Music in Eighteenth-Century London Shakespeare Productions’, which offers a tremendous wealth of information concerning Arne’s Shakespearean settings. The ‘Polemical Introduction’ is a reprint of a 2009 article published in Eighteenth-Century Studies, ‘Arne, Handel, the Beautiful, and the Sublime’. Here Gilman rightly points out that theatre music needs to be understood in its original context, something that is often not possible in commercial sound recordings and detrimental to composers such as Arne (p. 3). I feel he is on less sure ground, however, when proposing that the neglect of Arne’s music in the nineteenth century was largely to do with contemporary ‘critical aesthetics of the distinction between the beautiful and the sublime’ (p. 4); in short, Arne’s music was regarded as ‘the musically beautiful’ while Handel’s was ‘sublime’, and this perceived superficiality of Arne’s music led to his neglect. But regardless of the distance at which they are viewed, not every star shines with equal luminosity. Arne was capable of writing some truly excellent music, but he had a remarkable capacity at the other end of the quality scale too. One also has to contend with the incomplete state of many of the works (i.e. surviving only in vocal scores, lacking recitatives and choruses, etc.), not to mention those lost to theatre fires as well as Michael Arne’s feckless handling of his father’s manuscripts post mortem. The result is a frustratingly incomplete picture that has surely been most detrimental to Arne’s later reception. But regardless of whether one is swayed by Gilman’s arguments, it is striking to find absolutely no attempt made to pursue this line of enquiry. There is certainly ample material for a monograph without this introduction; indeed, the space could easily have been put to better use (e.g. works list, discography, list of sources). Its inclusion is representative of the somewhat ‘kitchen sink’ approach taken throughout the book, which is perhaps best exemplified by the music examples. Gilman makes the point that much of Arne’s music is not available in recordings: either works haven’t been recorded or they are hard to come by. While it is true that there is a lamentable lack of recordings (particularly of complete works), a good number are widely available and a discography would have been useful. (One may access a comprehensive discography online, at 5http://www.allmusic. com/artist/thomas-arne-mn0001161497/composi tions4: this site gives details of dozens of

Polish Film and the Holocaust displays the same virtues as Marek Haltof’s Polish National Cinema, from the same publisher, to which the new book forms in a sense a companion piece. Here too one has a judicious and well-organized chronological survey (the three central periods being 1955–1965, 1965–1980 and 1981 to the present), the result of a good deal of compilation, research and effective synthesis. The work is highly economical, packing discussion of a large number of films (almost all of the 46 features listed in the extensive filmography receive at least a paragraph, many a page or two, and a select few a chapter or large chapter-portion, though inevitably less attention can be paid to the 68 documentaries, shorts and television films that constitute part two of the filmography) into 229 pages of discursive text. The book also includes a fourteen-page ‘Select bibliography’. One of the encomia on its cover describes the subject as ‘significant and little examined’, thus raising the question of the causes of its previous neglect. Part of the answer lies in its frequent dissolution into larger studies of Holocaust representation, which can only sample the Polish contribution to it,

Song, dance, muSic and revolution in JancSó-land, Még Kér A Nép/red psAlM, miklóS JancSó ([1971] 2012) Hungary: Mafilm/Mokep UK: Second Run, with special features: A kövek üzenete – Hegyalja/Message of the Stones; New essay by Peter Hames. Length: Main feature 82 mins., Special feature 54 mins., Colour, Aspect Ratio: 1.85:1/16:9 anamorphic, Sound: Original mono (restored), PAL, Language: Hungarian, Subtitles: English, Second Run DVD 061, Region 0, RPP: £12.99.

Song, Dance, Music and Revolution in Jancsó-Land, Még kér a Nép/Red Psalm, Miklós Jancsó ([1971] 2012)

From Room to Room: The Poetry of Eli Mandel, ed. Peter Webb, afterword by Andrew Stubbs; Plans Deranged by Time: The Poetry of George Fetherling, ed. A.F. Moritz, afterword by George Fetherling

Literatura faktů: the literature of facts. This was the common term to denote nonfiction in the former Czechoslovakia, and it is still widely used today in both Czech and Slovak (derived from the German FaktLiteratur). This monograph is such a book of facts on the Slovak ‘New Wave’ director Ján Kadár. There is, however, a distinct tradition among a certain generation of Czech and Slovak scholars where facts are researched and gathered but no attempt at a selection, let alone an interpretation, is made. The present monograph, unfortunately, conforms to this tradition, so the reader will find here

The last round-up…: 42nd Hungarian Film Week, Budapest, 5–8 May 2011

ABSTRACT This article presents a detailed account (provenance, codicology and contents) of Surrey History Centre, Woking, MS LM/1 083191/35, a late Restoration manuscript of lyra-viol and keyboard music. Originally from the papers of the More-Molyneux family of Loseley Park, LM/1083191135 is a source of otherwise unknown music by John Moss and Gerhard Diesineer. Two of the lyra-viol pieces in particular demonstrate that the Waking manuscript dates to at least 1687 or 1688, making it the latest known English source of viol music in tablature. The primary purpose of the manuscript seems to have been didactic. It was copied by a single scribe, who was evidently a musician actively engaged with the popular music and current political events of mid- to late-1680s London. LM/1083191/35 allows us a rare glimpse into the amateur musical world of 1680s London.

A LITTLE-KNOWN SOURCE OF RESTORATION LYRA-VIOL AND KEYBOARD MUSIC: SURREY HISTORY CENTRE, WOKING, LM/1083/91/35

Musical Other’, that reveals the most about the composer. The composer’s admiration for and fascination with musicians of different classes of society, or foreigners playing unusual instruments, is shown to be a genuinely enlightened response to the ‘Musical Other’. Whilst contemporaries might have employed exotic musical vocabularies in their galanteries, none held the style polonais in the same esteem, and none was as successful as Telemann in integrating its elements into his personal idiom. This magnum opus concludes with an Afterword in which Telemann’s legacy as a composer of instrumental music is considered. It is difficult to fault Zohn’s eloquent and elegantly written examination of Telemann’s instrumental music. Those who support the wish of the author that ‘the study of [Telemann’s] works ought to be recognized first and foremost as its own rich reward’ (507) will welcome this volume as an important addition to the literature about a composer whose music continues to amuse, amaze and delight musicians and their audiences around the world. janice b. stockigt

Review of Charles Dibdin: The Sadler’s Wells Dialogues, ed. Peter Holman

One of the original TISH poets, Fred Wah has achieved iconic status in the world of Canadian poetry. It’s about time, then, that someone came along to write a book such as this. And it’s a pleasure to see it as part of the Laurier Poetry Series, which has achieved a standard of excellence that other institutions should be admiring and emulating. The book begins with an excellent biography of Wah, followed by Cabri’s introduction. Cabri begins his explication of Wah’s poetics by referencing a 2007 speech by Wah: “Wah approaches his topic by outlining paradigms for modern lyric and epic, ‘paradigm’ meaning model, pattern, or example of poetic form. His exemplary paradigm for modern lyric is William Carlos Williams’s 1954 poem ‘The Desert Music,’ and for modern epic, a technique, collage – the juxtaposing of texts, images, materials from different times and places and media.” (ix) Although Wah learned this technique from Robert Duncan, Duncan “wanted ‘a poetry of all poetries, grand collage . . . epic in dimensions, that can let – hauntingly so – ‘all of the old stories / whisper once more,’ as he puts it in one poem . . . . By ‘old stories,’ Duncan mostly means ancient Greek, Hebrew, Egyptian, and Christian myths.” (x) Wah diverged from Duncan on this: “Wah’s poetry disentangles itself from modernist ambitions or representing ‘grand collage’ of ‘old stories’ based on a cultures-of-the-world unity.” Instead, Wah draws on Aboriginal culture, including petroglyphs, for his motifs. Cabri concludes this section of his introduction with

The False Laws of Narrative: The Poetry of Fred Wah, selected and with an introduction by Louis Cabri

CINEMA ALL THE TIME: AN ANTHOLOGY OF CZECH FILM THEORY AND CRITICISM, 1908–1939, JAROSLAV ANDĚL AND PETR SZCZEPANIK (EDS.) (2008) trans. Kevin B. Johnson, Prague: National Film Archive, distributed by Michigan Slavic Publications (Michigan Slavic Materials, volume 58), Ann Arbor: University of Michigan, 315pp., 978-0-9-30042-99-8 (Michigan Slavic Publications), 978-80-7004-137-6 (Prague: National Film Archive), paperback, $28.00 USD

'Irish harpers are excellent, and their solemn music is much liked of strangers': The Irish Harp in Non-Irish Contexts in the Seventeenth Century

Lyra-viol Ecclesiastica: A neglected manuscript source in Archbishop Marsh’s Library, Dublin

Although British filmmaking has often been, both literally and metaphorically, on the margins of the European avant-garde, the late 1920s and the1930s, saw a burst of filmmaking which demonstrated a keen engagement with trends more often associated with Continental Europe. Filmmakers such as the New Zealander Len Lye, Brazilian-born Alberto Cavalcanti, refugees from Nazi Germany, as well as home-grown talent such as Humphrey Jennings and Norman McLaren contributed to a small corpus of films which, although not significantly influential on the course of British film, enriched a period in film history primarily noted for the emergence of the documentary movement. However, it seems questionable if a viable, meaningful avant-garde film movement existed in Britain in the 1930s. As Deke Dusinberre (1980) and Michael O’Pray (2003) have both suggested it was more a case of an avantgarde attitude and there were actually very few purely avant-garde films made.1 The (limited) successes and problems encountered by avant-garde filmmakers are of interest not just for the films themselves but also for the complex interactions between these highly idiosyncratic artists and the milieu within which they tried to work, one of private sponsorship, company sponsorship and the semi-governmental remit of bodies such as the Empire Marketing Board (EMB) and the main focus of this study – the General Post Office (GPO) Film Unit. The history of the GPO Film Unit and its problematic relationship with the avant-garde is instructive in that it illustrates many of the problems associated with the attempts by avant-garde artists to work within broader institutional structures. Although the particular situation in Britain in the 1930s is unique, the problems encountered by the avant-garde in relation to finding a niche and a voice in a wider milieu are certainly not.

The avant-garde, the GPO Film Unit, and Britishdocumentary in the 1930s

Here at last is a thorough guide of the most collected dinnerware. In one volume this book provides an excellent survey of the best companies and their most popular lines. The important California companies, including the Wallace China Company, Catalina Pottery, B.J. Brock & Co., and Gladding, McBean & Co. along with other companies nationwide including the Crooksville Art Pottery Co., Frankoma, and the Hall China Company, are among the many potteries represented. The contributions of famous designers such as Ben Seibel, Russel Wright, Eva Zeisel, and Sascha Brastoff are explored. Extensive research has uncovered new information on many of the companies and designers. Over 300 clear photos, extracts from catalogs and advertisements, historical photos, and a well-documented text will help to identify dinnerware, to trace changing technological and design trends, and to showcase an industry in its heyday. As the journey to uncover and identify all the American produced dinnerware from the twentieth century continues, this book serves as an important milestone and an important reference.

ter," was much of a musician because his work is more melodious than forbidding. Or maybe they think it is a simple matter for a novelist to re-create in nontechnical language?in ways that a layman can under stand?the processes by which a composer reaches the crucial sections of symphonies and concertos. One hopes they know enough about the history of American music to appreciate the extent of Skvorecky's knowl edge of the careers of the black musicians Dvorak knew and worked with in New York, Harry T. Burleigh, Sissieretta Jones, and, especially Will Marion Cook (who was a major influence on one generation of New York jazz pianists, Luckey Roberts, James P. Johnson, and Willie "The Lion" Smith, and through them on the next generation, Fats Waller, Count Basie, and Duke Ellington). But maybe they take his historical knowledge for granted and think it is a simple matter to write a novel mostly about real people that will not do violence to what we know about them yet will render them as vividly, as freshly as char acters in novels bearing the customary disclaimer about any resem blance to people living or dead being accidental. I don't know. The whole business of critical receptions and reputations baffles me. I think that Dvorak in Love is a lovely book, silly as it may sound to say so. I do wish, though, that Skvorecky had learned something from one of his minor characters, Zdenka Drbohlavova. Americans couldn't say Zdenka properly?it came out as Stinky?and couldn't pronounce Drbohlavova at all. So she changed her name to Denise Derby. Skvo recky didn't have to go that far?Joe Score would have done nicely. That would have made it a lot easier to tout people onto his novels, which certainly look like winners to me.

1621). His starting point was the notion that Christ would undoubtedly have provided his Church with the best and most suitable form of government available since it was within his power to do so. His next step was to examine the available forms of government: monarchy, aristocracy and democracy, with a view to determining which of these was the best and the most suitable. The conclusion he arrived at was that the best form of government available is a combination of all three. His concept of a monarchy tempered with elements of aristocracy and democracy requires some clarification. It envisages a society in which the supreme rule is in the hands of one man who is superior to all and subject to none. However, the individual parts or provinces of the society are not ruled by vicars of the supreme ruler, but by true princes who are subject to the supreme ruler yet rule their provinces as their own. In this way a society can be truly said to be ruled by a monarchy and an aristocracy. Further, if in this society the supreme ruler and the lesser princes do not acquire their dignity by hereditary succession, but are chosen on merit from the body of the people, then, as a society, it can be truly said to contain an element of democracy. In all this, of course, Bellarmine was describing the Church as he saw it.1 The monarchy, aristocracy and democracy being, respectively, the pope, the bishops and the faithful, and he went on to prove that in fact the Church founded by Christ was of precisely this nature, namely a composite of monarchy, aristocracy and democracy. The Catholic view of the Church, as presented by Bellarmine, saw the Church as essentially a visible society in which all the conditions of membership can be verified externally. ' Nostra autem sententia est, Ecclesiam unam tantum esse,

Cultural competence practices implemented in hospitals and health systems by minority executives on the top management team

LEAD OFFICER, CABINET SUPPORT On behalf of Alison Ward CBE, Chief Executive

Nurses are increasingly being asked to extend or expand their traditional roles, often for reasons other than their own professional development. This study, across three specialties in one hospital, examines whether or not nurses view such change in a positive light.

Nursing standard (Royal College of Nursing (Great Britain) : 1987)

Nurses' attitudes to the extension and expansion of their clinical roles.

EDITOR,—Aneez Esmail and colleagues state that the selection of applicants for entry to medical schools in the United Kingdom is subject to ethnic bias and imply that the medical school of the London Hospital Medical College is one of the nation's worst offenders in this regard.1 People from ethnic minority groups made up 29% of this institution's intake for 1992, and our audit of admissions, conducted annually, indicates that almost certainly no selection …

This study reports results from the first International Body Project (IBP-I), which surveyed 7,434 individuals in 10 major world regions about body weight ideals and body dissatisfaction. Participants completed the female Contour Drawing Figure Rating Scale (CDFRS) and self-reported their exposure to Western and local media. Results indicated there were significant cross-regional differences in the ideal female figure and body dissatisfaction, but effect sizes were small across high-socioeconomic-status (SES) sites. Within cultures, heavier bodies were preferred in low-SES sites compared to high-SES sites in Malaysia and South Africa (ds = 1.94-2.49) but not in Austria. Participant age, body mass index (BMI), and Western media exposure predicted body weight ideals. BMI and Western media exposure predicted body dissatisfaction among women. Our results show that body dissatisfaction and desire for thinness is commonplace in high-SES settings across world regions, highlighting the need for international attention to this problem.

The Attractive Female Body Weight and Female Body Dissatisfaction in 26 Countries Across 10 World Regions: Results of the International Body Project I

Regions: Results of the International Body Project I The Attractive Female Body Weight and Female Body Dissatisfaction in 26 Countries Across 10 World

Design of a Robotic Control Vehicle for Landmine and IED Detection and Marking

Switched reluctance motor drive circuit evaluation criteria for vehicle efficiency responsiveness

In this paper, we describe a novel approach to track the progress of suspected terrorist operations and to optimize courses of action to delay or disrupt these operations. The approach uses Monte Carlo sampling and Bayesian, nonlinear particle filtering to estimate the state (schedule) of a terrorist operation. The operation is specified in the form of a project management model (such as a Program Evaluation and Review Technique (PERT) model) with uncertain task durations. We describe the underlying algorithms for performing the estimation given a set of observables of variable quality, and evaluate the effectiveness of the techniques through a series of numerical experiments that include a wide range of data characteristics.

A Bayesian, Nonlinear Particle Filtering Approach for Tracking the State of Terrorist Operations

As the size of unmanned aerial vehicle (UAV) fleets increases in the future, so will the need to coordinate these fleets effectively. In this paper, we define several negotiation mechanisms for autonomous, distributed coordination of surveillance tasks. These mechanisms are based on dynamic target swapping between UAVs, where the criterion for swapping can be greedy or cooperative and where the amount of information shared by UAVs can be relatively high or low. The results show that high-quality system solutions can be obtained through local optimization by individual UAVs. In addition, we show how the rate of convergence to good system solutions can improve given cooperative UAV behavior (adherence to system goals rather than strictly local goals) and greater information sharing.

International Conference on Integration of Knowledge Intensive Multi-Agent Systems, 2005.

Negotiation mechanisms for coordinated unmanned aerial vehicle surveillance

A 62-year-old woman with autoimmune overlap syndrome and polymyositis presented to this hospital with anemia, thrombocytopenia, and acute renal failure. Four days before admission, she was found on the floor of her home, confused and minimally conversant.

L'invention concerne un moyen pour empecher des souillures TCA de contaminer des boissons et des aliments liquides comprenant l'incorporation de tamis moleculaires dans le processus de fabrication et/ou les materiaux d'emballage afin d'adsorber selectivement les molecules de souillure tout en preservant les profils d'aromes et de saveurs de la boisson ou de l'aliment. L'invention concerne egalement des procedes et des dispositifs pour remedier a des souillures TCA presentes dans des boissons et des aliments liquides d'un consommateur.

Confinement moléculaire très sélectif pour empêcher et enlever des souillures dans des aliments et des boissons

Pancytopénie périphérique et vascularite à ANCA :bonne réponse du traitement immunosuppresseur

L'invention concerne une interface et un procede d'affichage convenant pour un ordinateur personnel, un poste de travail ou un systeme integre individuel comprenant une ou plusieurs interfaces ecran, une videotheque, et un procede permettant d'activer un affichage video quelconque faisant partie d'une pluralite d'affichages video de plusieurs types differents connectes a une ou plusieurs interfaces ecran, a partir de la sortie de la videotheque. OpenGl est une des interfaces API preferes. L'invention concerne egalement un procede permettant d'activer des affichages hybrides ainsi que des affichages a base de segments elementaires utilisant des formats concus pour des images tramees (p. ex. VAPS). L'invention concerne en outre un procede de commutation en temps reel entre les affichages.

New Australian guidelines for the treatment of alcohol problems: an overview of recommendations

Alberta Gambling Research Institute Conference 2019: Blurred Lines in Gambling Research

Introduction The prevalence of disordered gambling worldwide has been estimated at 2.3%. Only a small minority of disordered gamblers seek specialist face-to-face treatment, and so a need for alternative treatment delivery models that capitalise on advances in communication technology, and use self-directed activity that can complement existing services has been identified. As such, the primary aim of this study is to evaluate an online self-directed cognitive–behavioural programme for disordered gambling (GamblingLess: For Life). Methods and analysis The study will be a 2-arm, parallel group, pragmatic randomised trial. Participants will be randomly allocated to a pure self-directed (PSD) or guided self-directed (GSD) intervention. Participants in both groups will be asked to work through the 4 modules of the GamblingLess programme over 8 weeks. Participants in the GSD intervention will also receive weekly emails of guidance and support from a gambling counsellor. A total of 200 participants will be recruited. Participants will be eligible if they reside in Australia, are aged 18 years and over, have access to the internet, have adequate knowledge of the English language, are seeking help for their own gambling problems and are willing to take part in the intervention and associated assessments. Assessments will be conducted at preintervention, and at 2, 3 and 12 months from preintervention. The primary outcome is gambling severity, assessed using the Gambling Symptom Assessment Scale. Secondary outcomes include gambling frequency, gambling expenditure, psychological distress, quality of life and additional help-seeking. Qualitative interviews will also be conducted with a subsample of participants and the Guides (counsellors). Ethics and dissemination The study has been approved by the Deakin University Human Research and Eastern Health Human Research Ethics Committees. Findings will be disseminated via report, peer-reviewed publications and conference presentations. Trial registration number ACTRN12615000864527; results.

GAMBLINGLESS: FOR LIFE study protocol: a pragmatic randomised trial of an online cognitive–behavioural programme for disordered gambling

Understanding Gambling: Mechanisms and Predictors: Alberta Gambling Research Institute's 15th Annual Conference

Research to Practice in Gambling Disorders: Alberta Gambling Research Institute's 12th Annual Conference

Behavioral genetics and population health interventions for alcohol problems: at odds or oddly in agreement?

Clinical practice is busy. People arrive with all manner of health problems and the basic requirement of the role is to help. There are increasing pressures to address a variety of different public health concerns within an already hectic schedule. And now, another suggestion to add to this workload — gambling.1–4 What has gambling got to do with health? 
 
Concerns have been raised that the prevalence of gambling problems has increased as access has been made easier. Gambling gives rise to clear social costs and there is an obvious need to protect children and young people. The involvement of large scale criminal organisations cannot be tolerated.5 The consumer protection and financial implications for individuals and their families operating in unregulated markets merit concern. Policy makers have been slow to respond, but the results of recent action taken are not yet known.4 Allowing the promotion of an activity that causes societal harm will probably be balanced with the potential for revenue generation by politicians. 
 
Despite these valid social concerns, what does gambling have to do with health? Pathological gambling is a known diagnostic category.5 Problem gambling is enmeshed in other addictive behaviours, most notably drinking and smoking.3,6 There are a variety of other mental health concerns of varying severity, from stress and depression through to increased risk of suicide among people with more serious gambling concerns.3,6 The financial difficulties associated with gambling can have direct and indirect health consequences, including the triggering of depressive episodes and creating barriers to accessing healthcare services. The impact is more likely to be most profound among poor and otherwise vulnerable populations. Thus, gambling problems are likely to be implicated in a range of existing clinical presentations,6 and it would appear that the numbers are increasing. 
 
Although encouraging initiatives exist, the extent of gambling problems is likely to overwhelm capacity. The British Medical Association recently recommended that dedicated NHS provisions should be expanded nationally.4 Services for problem gamblers are currently at an early stage of development, so a large need remains unmet. Can, or should, GPs fill this gap? There are possibilities for screening and brief interventions, however, time and wider resource constraints make the widespread adoption of new activities unlikely. The larger question is whether addressing gambling problems fits within the role of the GP. It is conceivable that GPs with special interests may choose to become involved in areas such as this, but should the profession as a whole accept this responsibility? Where should the line be drawn between health care and social problems? 
 
As researchers interested in the secondary prevention of addictions and not GPs, we do not have a particular view on this issue. Gambling problems are very topical and as concerns have escalated the possible role of GPs has been reconsidered.3 For other addictive behaviours, such as smoking and drinking, the generally agreed practice is to screen to identify the occurrence and severity of any problems. For those that are less severe there is the option of providing brief interventions directly within general practice, perhaps involving other healthcare professionals (for example, practice nurses). For those with more severe problems, referral to specialist care is merited. 
 
Given the likelihood that similar recommendations will be made for gambling, GPs will be faced with this issue. We do not yet know to what extent gambling problems are contributory factors to current levels of presentations within general practice in the UK, although data from other countries suggests that this will not be trivial.1–3 As a result, it is not clear what priority, if any, should be given to this problem. Evidence that problem gamblers have poorer health indicates that vigilance for gambling issues may be good clinical practice. Before doing so, however, it is important to recognise that these issues take the role of the GP into new territory, which although may be enthusiastically embraced by a minority, may well be uncomfortable for the majority.

Against the odds: should GPs have any involvement with gambling problems?

Etude sur l'efficacite du pot d'echappement catalytique muni d'un filtre dont est equipe le bus RTS2 circulant dans le centre-ville de Philadelphie

Revenue Service Evaluation of CTO Performance on an RTS2 Bus in Center City Philadelphia

The influence of maritime policy on the performance and progress of the United States merchant marine

A deterministic model of recurrent epidemics is constructed using a non linear relationship between infection rate and number of contacts. Epidemic waves which are not damped are predicted and a relationship between community size and the period of recurrence is established. A possible explanation of measles outbreaks is suggested.

The Quantity Theory of Disaggregated Credit: Do bank credit flows to the real economy cause economic growth?

Under the US Army (Aviation Missile Research, Development & Engineering Center) AMRDEC’s Science & Technology (S&T) Joint Multi Role (JMR) Program, the Joint Common Architecture (JCA) Demonstration (aka, JCA Demo) project was established to exercise the Future Airborne Capability Environment (FACE TM ) Standard and Modeling Tools, validate the JCA concept and reduce risk for follow-on efforts. This was achieved by procuring a software component called the Data Correlation and Fusion Manager (DCFM) along with a Reusable Verification Component (RVC) from multiple vendors, built to the same specification and integrated on multiple undisclosed operating environments (OEs) designed to host FACE conformant Units of Portability (UoPs). Interaction between the software developers and the system integrator was tightly controlled to evaluate whether the information provided was sufficient to define a component that is modular, portable, and interchangeable. A representative acquisition approach was used whereby the interface requirements were provided in the form of a data model. This paper will discuss the experience, significant issues, and lessons learned.

Joint Common Architecture Demonstration Lessons Learned - Honeywell Perspective

Abstract : This paper reports the successful development and performance of a multipurpose warhead for the Hellfire missile. This blast-frag warhead was designed to perforate a target wall and detonate inside the compartment. The new warhead extends Hellfire's defeat capability to patrol boats and MOUT targets. The paper presents performance requirements, hydrocode and analytical analyses, and test results of the explosive load and warhead body. Test results include: (1) Half scale gun tests - that evaluated perforation and ricochet performance of two nose shapes against RHA, mild steel, and fiberglass targets; (2) Full scale dynamic sled tests - that demonstrated successful perforation of steel and brick targets with a missile guidance section; and (3) Static arena tests - that demonstrated two different fragment shapes plus a safe-separation test to prove that the launch platform is safe from aft fragments.

A Blast Frag Warhead for the Hellfire Missile to Defeat Ships and Bunkers

When President Reagan first came into office he considered that U.S. Security would be best served by returning to a policy of protecting America, its people and its allies from the growing Soviet Strategic missile threat rather than merely to merely maintain a credible capability to revenge any nuclear missile attacks. To do this the new President proposed that the U.S. exploit it's technological superiority in order to build and deploy a highly effective missile defense capability on the theory that "who cares how many ICBM's an enemy has if they cannot penetrate to their targets". This plan was subsequently known as The Strategic Defense Initiative (SDI). In his March 1983 speech announcing SDI President Ronald Reagan said: "Wouldn't it be better to save lives than to avenge them?" Before announcing SDI as the most cost-effective way of coping with the growing Soviet missile threat, the new President obviously had to ascertain that proposing such a major change in U.S. National Security policy was logical, feasible, affordable, and politically acceptable. A non-government organization named High Frontier was established in 1981 by supporters and advisors of President Reagan to do this. Its initial mission was "to evaluate SDI's technical feasibility, military soundness, economic viability, and political acceptability". When Reagan came into office the strategic balance was shifting in favor of the USSR. Upon taking office the new President had a mandate to reverse this trend and there were only two ways of going about doing it under the then and still prevalent policy of Mutual Assured Destruction (MAD). Either he had to match the Soviet build-up with massive new U.S. offensive missile programs or with multi-billion dollar passive missile survival concepts such as road mobility and/or deep silos in the Rocky Mountains. Under MAD, and its handmaiden the ABM Treaty, cost-effective active defenses such as proposed in Reagan's SDI programs could not be implemented even though these were obviously the cheapest and most effective way of countering the Soviet build-up. Running an open-ended arms race in ballistic missiles with the Soviets, to maintain a credible capability to retaliate under the MAD policy, would have been far more costly than building effective defenses. Furthermore basing national security on the ability to revenge aggression rather than defeat it made no military sense. All citizens of any country defend their families, their property and their homes against local threats and expect their government to defend and protect them against foreign threats. Common sense suggests that people are not interested in being revenged after they are dead; they would rather be protected. Therefore if protection were technologically feasible and affordable, as it has been for over a decade, this was obviously the politically desirable route to take. The Situation at the End of 1996 In March 1983, Reagan announced his intention of building costeffective missile defenses. More than ten years of study have made it eminently clear that such defenses are affordable and feasible. Meanwhile the worldwide environment has changed. While the Cold War threat of massive missile attacks by the USSR has decreased, the likelihood of strikes by missiles armed with warheads of mass destruction has if anything increased. Proliferation of both weapons and missile technology on a worldwide basis is rapidly placing these capabilities in the hand of an increasing number of irresponsible and often terrorist governments. Unfortunately, as of today the U.S. has no, repeat no, deployed capability to shoot down any ballistic missile fired at America. This is not due to technical or financial constraints but solely to politics. And this situation exists notwithstanding the fact that Third World leaders such as Saddam Hussein said over 6 years ago, in 1990, that: "Our missiles cannot reach Washington, but if they could we would hit there" Although the Clinton administration that was recently reelected, clearly understands that America is totally defenseless against missile attack, President Clinton vetoed the 1996 Defense Authorization Act largely because it directed that all 50 states be defended by early in the next decade. …

Interoperability between systems is increasingly important within the military community. Traditionally, many tactical systems have been implemented as self-contained entities, incapable or minimally capable of interoperation with systems of different versions, vendors, and military branches. This has certainly been true of remoted signals intelligence (SIGINT) systems. Custom protocols and architectures, unique to each system, have frequently been justified as necessary to meet operations requirements. The real-time sharing of resources or data between systems has not been feasible. This approach is costly and inflexible. This paper describes the approach taken by SRI International (SRI) to address this problem. Our goal was to define an interoperability architecture for remoted SIGINT systems; this architecture must be open and based on international standards and commercially available products. Key to our architecture is the use at the application layer of the ISO 9506 Manufacturing Message Specification (MMS) protocol standard for the control of remote devices. We validated our approach by implementing a demonstration system consisting primarily of commercial off-the-shelf (COTS) hardware and software products, within a testbed environment. The results of this effort have shown that open, interoperable systems can be developed with commercial technology, thereby reducing implementation effort and cost. The structure of this paper is as follows. First, we present an example of the problem of interoperability in tactical remoted systems, and specifically within tactical airborne SIGINT systems; we then present our method for solving this problem through the use of open COTS technology; and finally, we summarize the lessons learned from taking this approach.<<ETX>>

Achieving open interoperability in tactical remoted systems with COTS technology

With the world community focused on North Korea's nuclear program, the proliferation of weapons of mass destruction and ballistic missiles to the Third World has become a major concern. The proliferation threat is real and it is growing. Over the last twenty years the nuclear "club" has more than doubled, from six nations to thirteen. Nearly thirty nations possess ballistic missiles of varying ranges, and twenty five have chemical and/or biological weapons programs.Contrary to what the world might wish, the end of the Cold War has actually served to spur proliferation efforts rather than dampen them. More and more nations are acquiring mass destruction and ballistic missile technology, spurred by regional rivalries and heightened senses of nationalism. Other nations may desire the prestige accorded ballistic missiles and nuclear capable nations, or feel that such weapons may be a way to buy security on the cheap. India, for example, has declared that its own nuclear program is its only means of staving off "American hegemonism."The collapse of the Soviet Union has lead to a dangerous "brain drain" of highly skilled scientists and technicians from the Former Soviet States to the Third World. Nations such as Iran, North Korea and Libya have been using the promise of high wages in attempts to lure ex-Soviet scientists away from the FSU to work on their own weapons programs. Russian law enforcement agencies recently stopped 60 Russian ballistic missile scientists and technicians at Moscow's Shermyetovo-2 airport as they prepared to fly off to North Korea. Over the last few years dozens of other scientists and technicians have been prevented from seeking employment in Third World weapons programs, but dozens more have managed to leave Russia.The January 1993 Arms Control Today reported that several scientists have contracted to work in Algeria, four have left Russia to take service in India, 50 missile and weapons specialists remain in Iraq, 14 nuclear scientists are working in Iran, and "many" Russian scientists are participating in projects in Libya. The Russian Security Ministry admits that it cannot keep tabs on every scientist with nuclear secrets and that this may represent only a fraction of the FSU scientists and technicians who have taken service abroad.The "brain drain" is not the only proliferation factor added into the equation from the collapse of the USSR. The Russian Mafia has been increasingly active in trying to steal and sell nuclear technology on the black market. The problem has become so serious that the U.S. Federal Bureau of Investigation has opened a branch office in Moscow to help Russian law enforcement agencies stop black market nuclear sales. The going price for a kilogram of enriched Uranium on the black market is $2.2 million--a hefty incentive for nuclear smuggling. But the Russian Mafia may not content itself with selling bits and pieces of nuclear material, and the danger of nuclear weapons theft is also on the rise. U.S. FBI Director Louis Freeh has said he is worried of "the dreadful possibilities" that Russian organized crime organizations may steal nuclear weapons and sell them to terrorist organizations.While Mr. Freeh believes the U.S. has been lucky that no illegal diversions of nuclear weapons have occurred, the sad reality is that a number of Russian nuclear weapons may already have found their way to the Third World. Two years ago Russian General Victor Samoilov told U.S. military visitors that they discovered that "three more nuclear warheads were missing." When pressed by the U.S. delegation, headed by Air Force General John Piotrowski, General Samoilov admitted that they had had at least three tactical nuclear weapons disappear from storage sites and as many as six altogether. As many as 23 nuclear warheads have vanished out of the Komsomolsk-on-Amur nuclear weapons depot near Khabarovsk, believed to be Submarine Launched Ballistic Missile and SS-20 warheads. …

Najwazniejsze wyniki europejskiego sondazu praktyk badawczych oraz potrzeb cyfrowych w humanistyce i naukach o sztuce, przeprowadzonego przez grupe roboczą DARIAH Digital Methods and Practices Observatory (DiMPO). Badanie jest efektem wspolpracy europejskich badaczy z roznych krajow w ramach Grupy Roboczej DiMPO. Badanie zostalo pomyślana jako ponadregionalny sondaz podluzny, przeprowadzany co kilka lat online w krajach europejskich. Jego celem jest dostarczenie opartego na danych przeglądu praktyk badawczych, potrzeb i postaw europejskich badaczy z nauk humanistycznych wobec zasobow cyfrowych, metod i narzedzi, w perspektywie przestrzennej i czasowej. Wyniki pierwszego sondazu (zakonczonego w marcu 2015) zostaną zaprezentowane w wieloautorskim raporcie, ktory zawiera analizy zbiorcze i porownawcze oraz piec raportow narodowych. Kolejne badanie planowane jest na 2017-2018. Wiecej informacji: bit.ly/scholarlypractices
Przeklad na polski: Maciej Maryl (Centrum Humanistyki Cyfrowej Instytutu Badan Literackich PAN)

Europejski sondaż praktyk cyfrowych w humanistyce i naukach o sztuce. Najważniejsze wyniki

Skutecznosc preparatu Advantage [Imidakloprid] w zwalczaniu pchel u duzych psow

Wplyw wody oraz kapieli z uzyciem szamponu na skutecznosc dzialania preparatu Advantage [Bayer] u psow

Ce rapport resume l'analyse statistique des resultats d'une enquete en ligne, conduite par l'Observatoire des Pratiques et Methodes Numeriques (DiMPO), un groupe de travail du VCC2 de l'infrastructure de recherche DARIAH (Digital Research Infrastructure for the Arts and Humanities).

Afin de fournir un tableau base sur des faits, mis a jour et signifiant, des pratiques, besoins et reflexes des chercheurs en sciences humaines au sein d'un monde academique numerique et europeen en pleine evolution, l'enquete en ligne a implique une equipe trans-nationale de chercheurs de plus d'une douzaine de pays, et s'est interessees aux pratiques, reflexes et demandes de la recherche numerique dans toutes les regions de l'Europe, et a travers differents contextes et disciplines en sciences humaines.

Enquête européenne sur les pratiques académiques et les besoins numériques en sciences humaines. Résultats principaux de l'enquête FR DiMPO 2016

La presente invention concerne des systemes de silo transportables innovants pour le stockage de materiaux. L'invention concerne des systemes de stockage par silo auto-erigeables a utiliser dans les secteurs du forage et de l'exploitation du petrole et du gaz naturel. Les systemes de stockage par silo des modes de realisation de la presente invention sont concus de facon unique pour ameliorer les capacites de stockage et la mobilite tout en reduisant l'espace necessaire sur le site de forage.

Système de silo de sable de fracture et méthodes de déploiement et de rétraction de celui-ci

Procédés et appareil de contrôle de la vitesse rotative d'un rotor

On ajoute une source de nutriments a liberation regulee, a faible niveau, a un environnement de biotraitement afin d'augmenter la croissance et l'activite de micro-organismes, et afin de stimuler l'efficacite du biotraitement dans l'elimination de contaminants de l'environnement.

Nutriments a liberation regulee pour microbes et procede de biotraitement

Beginning in the mid-20th Century, 103 Roman Catholic priests from Ireland served in Arizona. Their ministry began with Mexican people with whom they shared something of a common consciousness, resulting from similar histories, worldviews, and cultural values. In the main they were sympathetic to folk traditions and experienced a synergy with Mexicans which enabled them to adapt and learn from Hispanic communities. This was not the case with other clergy. Paradoxically, the Irish priests who accepted Mexican people also accepted the racist structures which marginalized them. In reconstructing this history salient themes engage us: ethnicity, religion (official/popular), prejudice/discrimination, power relations, and the discovery of common ground amid differences. This matrix gives rise to a complex crisscrossing of trajectories of Catholics and Protestants (in society), Irish and Mexican Catholics (in the church), priest and parishioners (in the parish). We won't see anything like this historic encounter again, for the well of Irish vocations has dried up and the once solidly Catholic Mexicans have in growing numbers embraced other faiths. This passing of an era holds lessons.

Irish Priests and Mexicans in Arizona: The Diocese of Tucson 1945-1970

by Steve Fanning The 1970-71 Providence College Student Congress held its final meeting on Monday evening, A p r i l 26. In addition to the swearing-in of new officers and congressmen, the main order of business centered around the Congress' selection of its annual M a n of the Y e a r , N o n Congressman of the Year, and Congressman of the Year. The Rev. John F. Cunningham, O.P. , was chosen, from a field of outstanding nominees, as this year"s recipient of the Man of the Y e a r A w a r d . V a r i o u s c o n g r e s s m e n p a r t i c u l a r l y emphasized, among his many attributes, F r . Cunningham's honesty and his sincere devotion to the students of Providence College. Further, as a member of the college disciplinary board, he has "demonstrated a very real sensitivity to the delicate problem of campus justice." The Congress was in complete agreement that Fr. Cunningham, whether acting officially or unofficially, has been unfailing in his desire to be of service to the student body. The Congress' decision was indeed a difficult one. Included in the list of nominees were the Rev. T. Dominic Rover, the Very Rev. Wil l iam P. Haas, Dr. Richard Lambe, Miss Arlene Jacquette, M r . Ralph Caruso, M r . Richard Grace, Dr. Roger Pearson, the Rev. Wil l iam Quigley, and the Rev. Walter Heath.

Hadlock , Distressed but Hopeful Curriculum Committee Initiates Reforms

Commencement address given by John Ferguson Cunningham, Dean of the College of Agriculture, to the Winter 1939 graduating class of The Ohio State University, University Hall Auditorium, Columbus, Ohio, March 17, 1939.

The Ohio State University Commencement Address by John Ferguson Cunningham, Winter 1939

The poems of Hammond, Shaw, Lovibond, Penrose . The poems of Cunningham and Goldsmith

Variational autoencoders model high-dimensional data by positing low-dimensional latent variables that are mapped through a ﬂexible distribution parametrized by a neural network. Unfortunately, variational autoencoders often suffer from posterior collapse: the posterior of the latent variables is equal to its prior, rendering the variational autoencoder useless as a means to produce meaningful representations. Existing approaches to posterior collapse often attribute it to the use of neural networks or optimization issues due to variational approximation. In this paper, we consider posterior collapse as a problem of latent variable non-identiﬁability. We prove that the posterior collapses if and only if the latent variables are non-identiﬁable in the generative model. This fact implies that posterior collapse is not a phenomenon speciﬁc to the use of ﬂexible distributions or approximate inference. Rather, it can occur in classical probabilistic models even with exact inference, which we also demonstrate. Based on these results, we propose a class of latent-identiﬁable variational autoencoders, deep generative models which enforce identiﬁability without sacriﬁcing ﬂexibility. This model class resolves the problem of latent variable non-identiﬁability by leveraging bijective Brenier maps and parameterizing them with input convex neural networks, without special variational inference objectives or optimization tricks. Across synthetic and real datasets, latent-identiﬁable variational autoencoders outperform existing methods in mitigating posterior collapse and providing meaningful representations of the data.

Summary Recent advances in probabilistic machine learning have given rise to a new family of distributions on the simplex. This distribution, termed the continuous categorical , bears similarities with the Dirichlet in that it deﬁnes an exponential family with a particularly simple closed-form density. However, unlike the Dirichlet (or any log-ratio based method), the continuous categorical log-likelihood function is well deﬁned even in the presence of zero-valued components, making this distribution a valid likelihood model for zero-laden compositional data without requiring imputation of the zeros. In this abstract, we review the key properties of our novel distribution and we present an application where it can be used for dimensionality reduction of compositional data. We also highlight some underexplored connections between the ﬁelds of machine learning and compositional data analysis, to which our novel distribution is closely related.

On a novel probability distribution for zero-laden compositional data

Ensembling neural networks is an effective way to increase accuracy, and can often match the performance of individual larger models. This observation poses a natural question: given the choice between a deep ensemble and a single neural network with similar accuracy, is one preferable over the other? Recent work suggests that deep ensembles may offer distinct benefits beyond predictive power: namely, uncertainty quantification and robustness to dataset shift. In this work, we demonstrate limitations to these purported benefits, and show that a single (but larger) neural network can replicate these qualities. First, we show that ensemble diversity, by any metric, does not meaningfully contribute to an ensemble's uncertainty quantification on out-of-distribution (OOD) data, but is instead highly correlated with the relative improvement of a single larger model. Second, we show that the OOD performance afforded by ensembles is strongly determined by their in-distribution (InD) performance, and -- in this sense -- is not indicative of any"effective robustness". While deep ensembles are a practical way to achieve improvements to predictive power, uncertainty quantification, and robustness, our results show that these improvements can be replicated by a (larger) single model.

Gaussian processes scale prohibitively with the size of the dataset. In response, many approximation methods have been developed, which inevitably introduce approximation error. This additional source of uncertainty, due to limited computation, is entirely ignored when using the approximate posterior. Therefore in practice, GP models are often as much about the approximation method as they are about the data. Here, we develop a new class of methods that provides consistent estimation of the combined uncertainty arising from both the finite number of data observed and the finite amount of computation expended. The most common GP approximations map to an instance in this class, such as methods based on the Cholesky factorization, conjugate gradients, and inducing points. For any method in this class, we prove (i) convergence of its posterior mean in the associated RKHS, (ii) decomposability of its combined posterior covariance into mathematical and computational covariances, and (iii) that the combined variance is a tight worst-case bound for the squared error between the method's posterior mean and the latent function. Finally, we empirically demonstrate the consequences of ignoring computational uncertainty and show how implicitly modeling it improves generalization performance on benchmark datasets.

Variational approximations to Gaussian processes (GPs) typically use a small set of inducing points to form a low-rank approximation to the covariance matrix. In this work, we instead ex-ploit a sparse approximation of the precision matrix. We propose variational nearest neighbor Gaussian process (VNNGP), which introduces a prior that only retains correlations within K nearest-neighboring observations, thereby inducing sparse precision structure. Using the variational framework, VNNGP’s objective can be factorized over both observations and inducing points, enabling stochastic optimization with a time complexity of O ( K 3 ) . Hence, we can arbi-trarily scale the inducing point size, even to the point of putting inducing points at every observed location. We compare VNNGP to other scalable GPs through various experiments, and demonstrate that VNNGP (1) can dramatically outper-form low-rank methods, and (2) is less prone to overfitting than other nearest neighbor methods.

Variational approximations to Gaussian processes (GPs) typically use a small set of inducing points to form a low-rank approximation to the covariance matrix. In this work, we instead ex-ploit a sparse approximation of the precision matrix. We propose variational nearest neighbor Gaussian process (VNNGP), which introduces a prior that only retains correlations within K nearest-neighboring observations, thereby inducing sparse precision structure. Using the variational framework, VNNGP’s objective can be factorized over both observations and inducing points, enabling stochastic optimization with a time complexity of O ( K 3 ) . Hence, we can arbi-trarily scale the inducing point size, even to the point of putting inducing points at every observed location. We compare VNNGP to other scalable GPs through various experiments, and demonstrate that VNNGP (1) can dramatically outper-form low-rank methods, and (2) is less prone to overﬁtting than other nearest neighbor methods.

Probability distributions supported on the simplex enjoy a wide range of applications across statistics and machine learning. Recently, a novel family of such distributions has been discovered: the continuous categorical . This family enjoys remarkable mathematical simplicity; its density function resembles that of the Dirichlet distribution, but with a normalizing constant that can be written in closed form using elementary functions only. In spite of this mathematical simplicity, our understanding of the normalizing constant remains far from complete. In this work, we characterize the numerical behavior of the normalizing constant and we present theoretical and methodological advances that can, in turn, help to enable broader applications of the continuous categorical distribution. Our code is available at https://github.com/cunningham-lab/cb_and_cc/ .

On the Normalizing Constant of the Continuous Categorical Distribution

Likelihood-based deep generative models have recently been shown to exhibit pathological behaviour under the manifold hypothesis as a consequence of using high-dimensional densities to model data with low-dimensional structure. In this paper we propose two methodologies aimed at addressing this problem. Both are based on adding Gaussian noise to the data to remove the dimensionality mismatch during training, and both provide a denoising mechanism whose goal is to sample from the model as though no noise had been added to the data. Our first approach is based on Tweedie's formula, and the second on models which take the variance of added noise as a conditional input. We show that surprisingly, while well motivated, these approaches only sporadically improve performance over not adding noise, and that other methods of addressing the dimensionality mismatch are more empirically adequate.

Data augmentation plays a key role in modern machine learning pipelines. While numerous augmentation strategies have been studied in the context of computer vision and natural language processing, less is known for other data modalities. Our work extends the success of data augmentation to compositional data, i.e., simplex-valued data, which is of particular interest in the context of the human microbiome. Drawing on key principles from compositional data analysis, such as the Aitchison geometry of the simplex and subcompositions, we define novel augmentation strategies for this data modality. Incorporating our data augmentations into standard supervised learning pipelines results in consistent performance gains across a wide range of standard benchmark datasets. In particular, we set a new state-of-the-art for key disease prediction tasks including colorectal cancer, type 2 diabetes, and Crohn's disease. In addition, our data augmentations enable us to define a novel contrastive learning model, which improves on previous representation learning approaches for microbiome compositional data. Our code is available at https://github.com/cunningham-lab/AugCoDa.

Data Augmentation for Compositional Data: Advancing Predictive Models of the Microbiome

Interstellar dust corrupts nearly every stellar observation, and accounting for it is crucial to measuring physical properties of stars. We model the dust distribution as a spatially varying latent field with a Gaussian process (GP) and develop a likelihood model and inference method that scales to millions of astronomical observations. Modeling interstellar dust is complicated by two factors. The first is integrated observations. The data come from a vantage point on Earth and each observation is an integral of the unobserved function along our line of sight, resulting in a complex likelihood and a more difficult inference problem than in classical GP inference. The second complication is scale; stellar catalogs have millions of observations. To address these challenges we develop ziggy, a scalable approach to GP inference with integrated observations based on stochastic variational inference. We study ziggy on synthetic data and the Ananke dataset, a high-fidelity mechanistic model of the Milky Way with millions of stars. ziggy reliably infers the spatial dust map with well-calibrated posterior uncertainties.

The automatic discovery of sparse biomarkers that are associated with an outcome of interest is a central goal of bioinformatics. In the context of high-throughput sequencing (HTS) data, and compositional data (CoDa) more generally, an important class of biomarkers are the log-ratios between the input variables. However, identifying predictive log-ratio biomarkers from HTS data is a combinatorial optimization problem, which is computationally challenging. Existing methods are slow to run and scale poorly with the dimension of the input, which has limited their application to low- and moderate-dimensional metagenomic datasets. Building on recent advances from the field of deep learning, we present CoDaCoRe, a novel learning algorithm that identifies sparse, interpretable, and predictive log-ratio biomarkers. Our algorithm exploits a continuous relaxation to approximate the underlying combinatorial optimization problem. This relaxation can then be optimized efficiently using the modern ML toolbox, in particular, gradient descent. As a result, CoDaCoRe runs several orders of magnitude faster than competing methods, all while achieving state-of-the-art performance in terms of predictive accuracy and sparsity. We verify the outperformance of CoDaCoRe across a wide range of microbiome, metabolite, and microRNA benchmark datasets, as well as a particularly high-dimensional dataset that is outright computationally intractable for existing sparse log-ratio selection methods.1

Scalable Gaussian Process methods are computationally attractive, yet introduce modeling biases that require rigorous study. This paper analyzes two common techniques: early truncated conjugate gradients (CG) and random Fourier features (RFF). We find that both methods introduce a systematic bias on the learned hyperparameters: CG tends to underfit while RFF tends to overfit. We address these issues using randomized truncation estimators that eliminate bias in exchange for increased variance. In the case of RFF, we show that the bias-to-variance conversion is indeed a trade-off: the additional variance proves detrimental to optimization. However, in the case of CG, our unbiased learning procedure meaningfully outperforms its biased counterpart with minimal additional computation. Our code is available at https://github.com/ cunningham-lab/RTGPS.

Bias-Free Scalable Gaussian Processes via Randomized Truncations

We examine the general problem of interdomain Gaussian Processes (GPs): problems where the GP realization and the noisy observations of that realization lie on different domains. When the mapping between those domains is linear, such as integration or differentiation, inference is still closed form. However, many of the scaling and approximation techniques that our community has developed do not apply to this setting. In this work, we introduce the hierarchical inducing point GP (HIP-GP), a scalable interdomain GP inference method that enables us to improve the approximation accuracy by increasing the number of inducing points to the millions. HIP-GP, which relies on inducing points with grid structure and a stationary kernel assumption, is suitable for lowdimensional problems. In developing HIPGP, we introduce (1) a fast whitening strategy, and (2) a novel preconditioner for conjugate gradients which can be helpful in general GP settings.

Hierarchical Inducing Point Gaussian Process for Inter-domain Observations

Gaussian processes remain popular as a flexible and expressive model class, but the computational cost of kernel hyperparameter optimization stands as a major limiting factor to their scaling and broader adoption. Recent work has made great strides combining stochastic estimation with iterative numerical techniques, essentially boiling down GP inference to the cost of (many) matrix-vector multiplies. Preconditioning – a highly effective step for any iterative method involving matrixvector multiplication – can be used to accelerate convergence and thus reduce bias in hyperparameter optimization. Here, we prove that preconditioning has an additional benefit that has been previously unexplored. It not only reduces the bias of the log-marginal likelihood estimator and its derivatives, but it also simultaneously can reduce variance at essentially negligible cost. We leverage this result to derive sample-efficient algorithms for GP hyperparameter optimization requiring as few as O(log ( ε−1 ) ) instead of O(ε−2) samples to achieve error ε. Our theoretical results enable provably efficient and scalable optimization of kernel hyperparameters, which we validate empirically on a set of large-scale benchmark problems. There, variance reduction via preconditioning results in an order of magnitude speedup in hyperparameter optimization of exact GPs.

Reducing the Variance of Gaussian Process Hyperparameter Optimization with Preconditioning

Normalizing flows allow for tractable maximum likelihood estimation of their parameters but are incapable of modelling low-dimensional manifold structure in observed data. Flows which injectively map from lowto high-dimensional space provide promise for fixing this issue, but the resulting likelihood-based objective becomes more challenging to evaluate. Current approaches avoid computing the entire objective – which may induce pathological behaviour – or assume the manifold structure is known beforehand and thus are not widely applicable. Instead, we propose two methods relying on tricks from automatic differentiation and numerical linear algebra to either evaluate or approximate the full likelihood objective, performing end-to-end manifold learning and density estimation. We study the trade-offs between our methods, demonstrate improved results over previous injective flows, and show promising results on out-of-distribution detection.

Gaussian process hyperparameter optimization requires linear solves with, and log -determinants of, large kernel matrices. Iterative numerical tech-niques are becoming popular to scale to larger datasets, relying on the conjugate gradient method (CG) for the linear solves and stochastic trace estimation for the log -determinant. This work introduces new algorithmic and theoretical in-sights for preconditioning these computations. While preconditioning is well understood in the context of CG, we demonstrate that it can also accelerate convergence and reduce variance of the estimates for the log -determinant and its derivative. We prove general probabilistic error bounds for the preconditioned computation of the log -determinant, log -marginal likelihood and its derivatives. Additionally, we derive speciﬁc rates for a range of kernel-preconditioner combinations, showing that up to exponential convergence can be achieved. Our theoretical results enable prov-ably efﬁcient optimization of kernel hyperparameters, which we validate empirically on large-scale benchmark problems. There our approach accelerates training by up to an order of magnitude.

Preconditioning for Scalable Gaussian Process Hyperparameter Optimization

Bayesian model criticism is an important part of the practice of Bayesian statistics. Traditionally, model criticism methods have been based on the predictive check, an adaptation of goodness-of-fit testing to Bayesian modeling and an effective method to understand how well a model captures the distribution of the data. In modern practice, however, researchers iteratively build and develop many models, exploring a space of models to help solve the problem at hand. While classical predictive checks can help assess each one, they cannot help the researcher understand how the models relate to each other. This paper introduces the posterior predictive null check (PPN), a method for Bayesian model criticism that helps characterize the relationships between models. The idea behind the PPN is to check whether data from one model’s predictive distribution can pass a predictive check designed for another model. This form of criticism complements the classical predictive check by providing a comparative tool. A collection of PPNs, which we call a PPN study, can help us understand which models are equivalent and which models provide different perspectives on the data. With mixture models, we demonstrate how a PPN study, along with traditional predictive checks, can help select the number of components by the principle of parsimony. With probabilistic factor models, we demonstrate how a PPN study can help understand relationships between different classes of models, such as linear models and models based on neural networks. Finally, we analyze data from the literature on predictive checks to show how a PPN study can improve the practice of Bayesian model criticism. Code to replicate the results in this paper is available at https://github.com/gemoran/ppn-code.

Large width limits have been a recent focus of deep learning research: modulo computational practicalities, do wider networks outperform narrower ones? Answering this question has been challenging, as conventional networks gain representational power with width, potentially masking any negative effects. Our analysis in this paper decouples capacity and width via the generalization of neural networks to Deep Gaussian Processes (Deep GP), a class of nonparametric hierarchical models that subsume neural nets. In doing so, we aim to understand how width affects (standard) neural networks once they have sufficient capacity for a given modeling task. Our theoretical and empirical results on Deep GP suggest that large width can be detrimental to hierarchical models. Surprisingly, we prove that even nonparametric Deep GP converge to Gaussian processes, effectively becoming shallower without any increase in representational power. The posterior, which corresponds to a mixture of data-adaptable basis functions, becomes less data-dependent with width. Our tail analysis demonstrates that width and depth have opposite effects: depth accentuates a model's non-Gaussianity, while width makes models increasingly Gaussian. We find there is a"sweet spot"that maximizes test performance before the limiting GP behavior prevents adaptability, occurring at width = 1 or width = 2 for nonparametric Deep GP. These results make strong predictions about the same phenomenon in conventional neural networks trained with L2 regularization (analogous to a Gaussian prior on parameters): we show that such neural networks may need up to 500 - 1000 hidden units for sufficient capacity - depending on the dataset - but further width degrades performance.

The Limitations of Large Width in Neural Networks: A Deep Gaussian Process Perspective

Designing clinically translatable artificial intelligence systems for high-dimensional medical imaging

Predicting post-operative right ventricular failure using video-based deep learning

. Bayesian model criticism is an important part of the practice of Bayesian statistics. Traditionally, model criticism methods have been based on the predictive check, an adaptation of goodness-of-ﬁt testing to Bayesian modeling and an eﬀective method to understand how well a model captures the distribution of the data. In modern practice, however, researchers iteratively build and develop many models, exploring a space of models to help solve the problem at hand. While classical predictive checks can help assess each one, they cannot help the researcher understand how the models relate to each other. This paper introduces the posterior predictive null check (PPN), a method for Bayesian model criticism that helps characterize the relationships between models. The idea behind the PPN is to check whether data from one model’s predictive distribution can pass a predictive check designed for another model. This form of criticism complements the classical predictive check by providing a comparative tool. A collection of PPNs, which we call a PPN study, can help us understand which models are equivalent and which models provide diﬀerent perspectives on the data. With mixture models, we demonstrate how a PPN study, along with traditional predictive checks, can help select the number of components by the principle of parsimony. With probabilistic factor models, we demonstrate how a PPN study can help understand relationships between diﬀerent classes of models, such as linear models and models based on neural networks. Finally, we analyze data from the literature on predictive checks to show how a PPN study can improve the practice of Bayesian model criticism. Code to replicate the results in this paper is available at https://github.com/gemoran/ppn-code .

Learned movements can be skillfully performed at different paces. What neural strategies produce this flexibility? Can they be predicted and understood by network modeling? We trained monkeys to perform a cycling task at different speeds, and trained artificial recurrent networks to generate the empirical muscle-activity patterns. Network solutions reflected the principle that smooth well-behaved dynamics require low trajectory tangling. Network solutions had a consistent form, which yielded quantitative and qualitative predictions. To evaluate predictions, we analyzed motor cortex activity recorded during the same task. Responses supported the hypothesis that the dominant neural signals reflect not muscle activity, but network-level strategies for generating muscle activity. Single-neuron responses were better accounted for by network activity than by muscle activity. Similarly, neural population trajectories shared their organization not with muscle trajectories, but with network solutions. Thus, cortical activity could be understood based on the need to generate muscle activity via dynamics that allow smooth, robust control over movement speed.

Motor cortex activity across movement speeds is predicted by network-level strategies for generating muscle activity

A cornerstone of theoretical neuroscience is the circuit model: a system of equations that captures a hypothesized neural mechanism. Such models are valuable when they give rise to an experimentally observed phenomenon -- whether behavioral or a pattern of neural activity -- and thus can offer insights into neural computation. The operation of these circuits, like all models, critically depends on the choice of model parameters. A key step is then to identify the model parameters consistent with observed phenomena: to solve the inverse problem. In this work, we present a novel technique, emergent property inference (EPI), that brings the modern probabilistic modeling toolkit to theoretical neuroscience. When theorizing circuit models, theoreticians predominantly focus on reproducing computational properties rather than a particular dataset. Our method uses deep neural networks to learn parameter distributions with these computational properties. This methodology is introduced through a motivational example of parameter inference in the stomatogastric ganglion. EPI is then shown to allow precise control over the behavior of inferred parameters and to scale in parameter dimension better than alternative techniques. In the remainder of this work, we present novel theoretical findings in models of primary visual cortex and superior colliculus, which were gained through the examination of complex parametric structure captured by EPI. Beyond its scientific contribution, this work illustrates the variety of analyses possible once deep learning is harnessed towards solving theoretical inverse problems.

Interrogating theoretical models of neural computation with emergent property inference

Integrating methods for time-to-event prediction with diagnostic imaging modalities is of considerable interest, as accurate estimates of survival requires accounting for censoring of individuals within the observation period. New methods for time-to-event prediction have been developed by extending the cox-proportional hazards model with neural networks. In this paper, to explore the feasibility of these methods when applied to deep learning with echocardiography videos, we utilize the Stanford EchoNet-Dynamic dataset with over 10,000 echocardiograms, and generate simulated survival datasets based on the expert annotated ejection fraction readings. By training on just the simulated survival outcomes, we show that spatiotemporal convolutional neural networks yield accurate survival estimates. Introduction Recent advances in diagnostic echocardiography AI systems have shown that not only is it possible to automate standard measures of cardiac function (ejection fraction), but even measure common biomarkers that are typically never measured via echocardiography scans (Hemoglobin, blood urea nitrogen).1–3 Our group has shown that predicting post-operative right ventricular failure in the setting of left ventricular assist device implantation is feasible by analyzing the full spatiotemporal density of information within each pre-operative echocardiogram.4 Others have now shown that predicting 1-year mortality is possible using just baseline echocardiography.5 Though this was developed using one of the largest echocardiographic datasets, the work was limited by the use of potentially under-parameterized neural networks, and treatment of right censored survival data as a binary event. Time-to-event predictions rather than simple binary predictions will find more relevance in the clinical setting when working with ‘prognostic’ rather than ‘diagnostic’ AI systems.6 Time-to-event analyses are characterized by the ability to predict event probabilities as a function of time, whereas binary classifiers can only provide predictions for one predetermined duration. One of the advantages of this is that it accounts for censoring of individuals within the observation period.7 This more accurately represents the clinical ground truth where individuals may be either lost to follow up, or have yet to develop an event of interest. Baseline Echocardiogram Numpy Pixel Array) VideoTensor Input (32,3,112,112) 0 5 10 1.905 1.910 1.915 1.920 0 5 10 1.905 1.910 1.915 1.920 0.1240 0.1245 0.1250 0.1255 0.1260 0.1265 mod el-1 mod elmod el-3 ++++++++++++++++++++++++++++ +++ +++++++ + + + 0.00 0.25 0.50 0.75 1.00 0 200 400 600 800 Time 7 x 7 x 7 2x c on v2 _x b lo ck s 2x c on v3 _x b lo ck s 2x c on v4 _x b lo ck s 2x c on v5 _x b lo ck s Av er ag e Po ol in g

Simulating time to event prediction with spatiotemporal echocardiography deep learning

Paraphrase generation is a longstanding important problem in natural language processing. Recent progress in deep generative models has shown promising results on discrete latent variables for text generation. Inspired by variational autoencoders with discrete latent structures, in this work, we propose a latent bag of words (BOW) model for paraphrase generation. We ground the semantics of a discrete latent variable by the target BOW. We use this latent variable to build a fully differentiable content planning and surface realization pipeline. Specifically, we use source words to predict their neighbors and model the target BOW with a mixture of softmax. We use gumbel top-k reparameterization to perform differentiable subset sampling from the predicted BOW distribution. We retrieve the sampled word embeddings and use them to augment the decoder and guide its generation search space. Our latent BOW model not only enhances the decoder, but also exhibits clear interpretability. We show the model interpretability with regard to (1). unsupervised learning of word neighbors (2). the step-by-step generation procedure. Extensive experiments demonstrate the model's transparent and effective generation process.

Simplex-valued data appear throughout statistics and machine learning, for example in the context of transfer learning and compression of deep networks. Existing models for this class of data rely on the Dirichlet distribution or other related loss functions; here we show these standard choices suffer systematically from a number of limitations, including bias and numerical issues that frustrate the use of flexible network models upstream of these distributions. We resolve these limitations by introducing a novel exponential family of distributions for modeling simplex-valued data - the continuous categorical, which arises as a nontrivial multivariate generalization of the recently discovered continuous Bernoulli. Unlike the Dirichlet and other typical choices, the continuous categorical results in a well-behaved probabilistic loss function that produces unbiased estimators, while preserving the mathematical simplicity of the Dirichlet. As well as exploring its theoretical properties, we introduce sampling methods for this distribution that are amenable to the reparameterization trick, and evaluate their performance. Lastly, we demonstrate that the continuous categorical outperforms standard choices empirically, across a simulation study, an applied example on multi-party elections, and a neural network compression task.

The continuous categorical: a novel simplex-valued exponential family

Value and choice as separable and stable representations in orbitofrontal cortex

We revisit expectation propagation (EP) as a prototype for scalable algorithms that partition big datasets into many parts and analyze each part in parallel to perform inference of shared parameters. The algorithm should be particularly efficient for hierarchical models, for which the EP algorithm works on the shared parameters (hyperparameters) of the model. 
The central idea of EP is to work at each step with a "tilted distribution" that combines the likelihood for a part of the data with the "cavity distribution," which is the approximate model for the prior and all other parts of the data. EP iteratively approximates the moments of the tilted distributions and incorporates those approximations into a global posterior approximation. As such, EP can be used to divide the computation for large models into manageable sizes. The computation for each partition can be made parallel with occasional exchanging of information between processes through the global posterior approximation. Moments of multivariate tilted distributions can be approximated in various ways, including, MCMC, Laplace approximations, and importance sampling.

Modern deep learning is primarily an experimental science, in which empirical advances occasionally come at the expense of probabilistic rigor. Here we focus on one such example; namely the use of the categorical cross-entropy loss to model data that is not strictly categorical, but rather takes values on the simplex. This practice is standard in neural network architectures with label smoothing and actor-mimic reinforcement learning, amongst others. Drawing on the recently discovered continuous-categorical distribution, we propose probabilistically-inspired alternatives to these models, providing an approach that is more principled and theoretically appealing. Through careful experimentation, including an ablation study, we identify the potential for outperformance in these models, thereby highlighting the importance of a proper probabilistic treatment, as well as illustrating some of the failure modes thereof.

Uses and Abuses of the Cross-Entropy Loss: Case Studies in Modern Deep Learning

Convolutional neural networks for pose estimation are continuously improving in identifying joints of moving agents from video. However, state-of-the-art algorithms offer no insight into the underlying mechanics of articulated limbs. "Seeing" the mechanics of movement is of major importance for fields like neuroscience, studying how the brain controls movement, and engineering, e.g., using vision to correct for errors in the action of a robotic manipulator. In the pipeline proposed here, we use a convolutional network to track joint positions, and embed these as the joints of a linked robotic manipulator. We develop a probabilistic physical model whose states specify second-order rigid-body dynamics and the torques applied to each actuator. Observations are generated by mapping the joint angles through the forward kinematics function to Cartesian coordinates. For nonlinear state estimation and parameter learning, we build on variational Sequential Monte Carlo (SMC), a differentiable variant of the classical SMC method leveraging variational inference. We extend with a distributed nested SMC algorithm, which, at inference time, wraps multiple independent SMC samplers within an outer-level importance sampler. We extract mechanical quantities from simulated data and newly acquired videos of mice and humans, offering a novel tool for studying e.g. biological motor control.

Inverse articulated-body dynamics from video via variational sequential Monte Carlo

Gaussian processes are the leading class of distributions on random functions, but they suffer from well known issues including difficulty scaling and inflexibility with respect to certain shape constraints (such as nonnegativity). Here we propose Deep Random Splines, a flexible class of random functions obtained by transforming Gaussian noise through a deep neural network whose output are the parameters of a spline. Unlike Gaussian processes, Deep Random Splines allow us to readily enforce shape constraints while inheriting the richness and tractability of deep generative models. We also present an observational model for point process data which uses Deep Random Splines to model the intensity function of each point process and apply it to neural population data to obtain a low-dimensional representation of spiking activity. Inference is performed via a variational autoencoder that uses a novel recurrent encoder architecture that can handle multiple point processes as input. We use a newly collected dataset where a primate completes a pedaling task, and observe better dimensionality reduction with our model than with competing alternatives.

A fundamental goal of visual systems is to condense images into compact representations of the relevant information they contain. Ideally, these representations would consist of the independent “generative factors” that fully determine, on a semantic level, the visual input. Such a “disentangled” representation could consist of the identity of a background scene, and the identity, position, pose, and size of an object. Recent research in deep neural networks (DNNs) has focused on achieving disentangled representations, through unsupervised learning, of single objects or faces in isolation. We trained and analyzed a popular DNN model of disentanglement, the β-variational autoencoder (β-VAE) on a new dataset, containing a “foreground” white circle and “background” isotropic Gaussian. We show that the neural network autoencoder architecture we use can achieve a perfectly disentangled latent representation with supervised learning, but only achieves partial disentanglement when using the unsupervised β-VAE loss function. On our dataset, higher β values result in higher reconstruction loss and greater entanglement. We propose that further inductive bias is needed to achieve better disentanglement, such as a representation which factorizes static properties and their dynamics.

Analyzing disentanglement of visual objects in semi-supervised neural networks

Variational autoencoders (VAE) have quickly become a central tool in machine learning, applicable to a broad range of data types and latent variable models. By far the most common first step, taken by seminal papers and by core software libraries alike, is to model MNIST data using a deep network parameterizing a Bernoulli likelihood. This practice contains what appears to be and what is often set aside as a minor inconvenience: the pixel data is [0,1] valued, not {0,1} as supported by the Bernoulli likelihood. Here we show that, far from being a triviality or nuisance that is convenient to ignore, this error has profound importance to VAE, both qualitative and quantitative. We introduce and fully characterize a new [0,1]-supported, single parameter distribution: the continuous Bernoulli, which patches this pervasive bug in VAE. This distribution is not nitpicking; it produces meaningful performance improvements across a range of metrics and datasets, including sharper image samples, and suggests a broader class of performant VAE.

The continuous Bernoulli: fixing a pervasive error in variational autoencoders

The Gumbel-Softmax is a continuous distribution over the simplex that is often used as a relaxation of discrete distributions. Because it can be readily interpreted and easily reparameterized, it enjoys widespread use. We propose a conceptually simpler and more flexible alternative family of reparameterizable distributions where Gaussian noise is transformed into a one-hot approximation through an invertible function. This invertible function is composed of a modified softmax and can incorporate diverse transformations that serve different specific purposes. For example, the stick-breaking procedure allows us to extend the reparameterization trick to distributions with countably infinite support, or normalizing flows let us increase the flexibility of the distribution. Our construction enjoys theoretical advantages over the Gumbel-Softmax, such as closed form KL, and significantly outperforms it in a variety of experiments.

Invertible Gaussian Reparameterization: Revisiting the Gumbel-Softmax

Spike sorting is a standard preprocessing step to obtain ensembles of single unit data from multiunit, multichannel recordings in neuroscience. However, more recently, some researchers have started doing analyses directly on the unsorted data. Here we present a new computational model that is an extension of the standard (unsupervised) switching Poisson hidden Markov model (where observations are time-binned spike counts from each of N neurons), to a clusterless approximation in which we observe only a d-dimensional mark for each spike. Such an unsupervised yet clusterless approach has the potential to incorporate more information than is typically available from spike-sorted approaches, and to uncover temporal structure in neural data without access to behavioral correlates. We show that our approach can recover model parameters from simulated data, and that it can uncover task-relevant structure from real neural data.

Unsupervised Clusterless Decoding using a Switching Poisson Hidden Markov Model

Generative models often use latent variables to represent structured variation in high-dimensional data, such as images and medical waveforms. However, these latent variables may ignore subtle, yet meaningful features in the data. Some features may predict an outcome of interest (e.g. heart attack) but account for only a small fraction of variation in the data. We propose a generative model training objective that uses a black-box discriminative model as a regularizer to learn representations that preserve this predictive variation. With these discriminatively regularized latent variable models, we visualize and measure variation in the data that influence a black-box predictive model, enabling an expert to better understand each prediction. With this technique, we study models that use electrocardiograms to predict outcomes of clinical interest. We measure our approach on synthetic and real data with statistical summaries and an experiment carried out by a physician.

Discriminative Regularization for Latent Variable Models with Applications to Electrocardiography

Recently much attention has been paid to deep generative models, since they have been used to great success for variational inference, generation of complex data types, and more. In most all of these settings, the goal has been to find a particular member of that model family: optimized parameters index a distribution that is close (via a divergence or classification metric) to a target distribution. Much less attention, however, has been paid to the problem of learning a model itself. Here we introduce a two-network architecture and optimization procedure for learning intractable exponential family models (not a single distribution from those models). These exponential families are learned accurately, allowing operations like posterior inference to be executed directly and generically with an input choice of natural parameters, rather than performing inference via optimization for each particular distribution within that model.

Approximating exponential family models (not single distributions) with a two-network architecture

A cornerstone of theoretical neuroscience is the circuit model: a system of equations that captures a hypothesized neural mechanism. Such models are valuable when they give rise to an experimentally observed phenomenon – whether behavioral or in terms of neural activity – and thus can offer insights into neural computation. The operation of these circuits, like all models, critically depends on the choices of model parameters. Historically, the gold standard has been to analytically derive the relationship between model parameters and computational properties. However, this enterprise quickly becomes infeasible as biologically realistic constraints are included into the model increasing its complexity, often resulting in ad hoc approaches to understanding the relationship between model and computation. We bring recent machine learning techniques – the use of deep generative models for probabilistic inference – to bear on this problem, learning distributions of parameters that produce the specified properties of computation. Importantly, the techniques we introduce offer a principled means to understand the implications of model parameter choices on computational properties of interest. We motivate this methodology with a worked example analyzing sensitivity in the stomatogastric ganglion. We then use it to go beyond linear theory of neuron-type input-responsivity in a model of primary visual cortex, gain a mechanistic understanding of rapid task switching in superior colliculus models, and attribute error to connectivity properties in recurrent neural networks solving a simple mathematical task. More generally, this work suggests a departure from realism vs tractability considerations, towards the use of modern machine learning for sophisticated interrogation of biologically relevant models.

Interrogating theoretical models of neural computation with deep inference

The supplementary motor area (SMA) is believed to contribute to higher-order aspects of motor control. To examine this contribution, we employed a novel cycling task and leveraged an emerging strategy: testing whether population trajectories possess properties necessary for a hypothesized class of computations. We found that, at the single-neuron level, SMA exhibited multiple response features absent in M1. We hypothesized that these diverse features might contribute, at the population level, to avoidance of ‘population trajectory divergence’ – ensuring that two trajectories never followed the same path before separating. Trajectory divergence was indeed avoided in SMA but not in M1. Network simulations confirmed that low trajectory divergence is necessary when guidance of future action depends upon internally tracking contextual factors. Furthermore, the empirical trajectory geometry – helical in SMA versus elliptical in M1 – was naturally reproduced by networks that did, versus did not, internally track context.

Neural Trajectories in the Supplementary Motor Area and Motor Cortex Exhibit Distinct Geometries, Compatible with Different Classes of Computation

Estimation of reliable whole-brain connectivity is a crucial step towards the use of connectivity information in quantitative approaches to the study of neuropsychiatric disorders. When estimating brain connectivity a challenge is imposed by the paucity of time samples and the large dimensionality of the measurements. Bayesian estimation methods for network models offer a number of advantages in this context but are not commonly employed. Here we compare three different estimation methods for the multivariate Ornstein-Uhlenbeck model, that has recently gained some popularity for characterizing whole-brain connectivity. We first show that a Bayesian estimation of model parameters assuming uniform priors is equivalent to an application of the method of moments. Then, using synthetic data, we show that the Bayesian estimate scales poorly with number of nodes in the network as compared to an iterative Lyapunov optimization. In particular when the network size is in the order of that used for whole-brain studies (about 100 nodes) the Bayesian method needs about eight times more time samples than Lyapunov method in order to achieve similar estimation accuracy. We also show that the higher estimation accuracy of Lyapunov method is reflected in a much better classification of individuals based on the estimated connectivity from a real dataset of BOLD fMRI. Finally we show that the poor accuracy of Bayesian method is due to numerical errors, when the imaginary part of the connectivity estimate gets large compared to its real part.

Bayesian estimation for large scale multivariate Ornstein-Uhlenbeck model of brain connectivity

An electrocardiogram (EKG) is a common, non-invasive test that measures the electrical activity of a patient's heart. EKGs contain useful diagnostic information about patient health that may be absent from other electronic health record (EHR) data. As multi-dimensional waveforms, they could be modeled using generic machine learning tools, such as a linear factor model or a variational autoencoder. We take a different approach:~we specify a model that directly represents the underlying electrophysiology of the heart and the EKG measurement process. We apply our model to two datasets, including a sample of emergency department EKG reports with missing data. We show that our model can more accurately reconstruct missing data (measured by test reconstruction error) than a standard baseline when there is significant missing data. More broadly, this physiological representation of heart function may be useful in a variety of settings, including prediction, causal analysis, and discovery.

A Probabilistic Model of Cardiac Physiology and Electrocardiograms

Different population dynamics in the supplementary motor area and motor cortex during reaching

A time-consuming preparatory stage is hypothesized to precede voluntary movement. A putative neural substrate of motor preparation occurs when a delay separates instruction and execution cues. When readiness is sustained during the delay, sustained neural activity is observed in motor and premotor areas. Yet whether delay-period activity reflects an essential preparatory stage is controversial. In particular, it has remained ambiguous whether delay-period-like activity appears before non-delayed movements. To overcome that ambiguity, we leveraged a recently developed analysis method that parses population responses into putatively preparatory and movement-related components. We examined cortical responses when reaches were initiated after an imposed delay, at a self-chosen time, or reactively with low latency and no delay. Putatively preparatory events were conserved across all contexts. Our findings support the hypothesis that an appropriate preparatory state is consistently achieved before movement onset. However, our results reveal that this process can consume surprisingly little time.

Conservation of preparatory neural events in monkey motor cortex regardless of how movement is initiated

Decisions are driven by the coordinated activity of diverse neural populations. Inhibitory neurons play a critical role in decision-making models, but technical challenges have left untested their role in vivo, both in novice and expert decision-makers. To understand the contribution of excitatory and inhibitory neurons to decision-making, we simultaneously measured their activity in mice judging the repetition rate of multisensory pulses. Individual inhibitory neurons were slightly more selective and more strongly correlated than excitatory neurons. Further, inhibitory ensemble activity could be decoded to predict trial-by-trial choice with similar accuracy as excitatory ensembles. Finally, population activity in both cell types changed in parallel as mice transitioned from novice to expert decision-makers: population activity gradually became more choice-selective and prompt. The observations advocate for models in which excitatory and inhibitory connectivity (1) preserves choice selectivity in both populations and (2) is fine-tuned with experience to support expert decision-making.

Inhibitory and excitatory populations in parietal cortex are equally selective for decision outcome in both novices and experts

Motor Cortex Embeds Mus cle-like Commands in an Untangled Population Response Highlights d Motor cortex displays a signature of a smooth dynamical system : low tangling

Motor Cortex Embeds Muscle-like Commands in an Untangled Population Response

Inhibitory neurons play a critical role in decision-making models and are often simplified as a single pool of non-selective neurons lacking connection specificity. This assumption is in keeping with observations in primary visual cortex: inhibitory neurons are broadly tuned in vivo, and show non-specific connectivity in slice. Selectivity of excitatory and inhibitory neurons within decision circuits is not known. We simultaneously measured their activity in the posterior parietal cortex of mice making multisensory decisions. Surprisingly, excitatory and inhibitory neurons were equally selective for the animal’s choice, both at the single cell and population level. Further, excitatory and inhibitory populations exhibited similar changes in selectivity and temporal dynamics during the transition from novice to expert decision-making, paralleling behavioral improvements. These observations, combined with simulations, argue against models assuming non-selective inhibitory neurons. Instead, they argue for selective subnetworks of inhibitory and excitatory neurons that are shaped by experience to support expert decisionmaking.

Excitatory and Inhibitory Subnetworks Are Equally Selective during Decision-Making and Emerge Simultaneously during Learning

The wide adoption of Convolutional Neural Networks (CNNs) in applications where decision-making under uncertainty is fundamental, has brought a great deal of attention to the ability of these models to accurately quantify the uncertainty in their predictions. Previous work on combining CNNs with Gaussian processes (GPs) has been developed under the assumption that the predictive probabilities of these models are well-calibrated. In this paper we show that, in fact, current combinations of CNNs and GPs are miscalibrated. We proposes a novel combination that considerably outperforms previous approaches on this aspect, while achieving state-of-the-art performance on image classification tasks.

Behaviorally Selective Engagement of Short-Latency Effector Pathways by Motor Cortex

Voluntary movement is believed to be preceded by a preparatory stage. Evidence arises from experiments where a delay separates instruction and execution cues. While this sequence emulates some real-world situations (e.g., swatting a fly upon landing) movements are commonly made at a moment of one’s choosing (reaching for a coffee cup) or are made reactively (intercepting a falling cup). To ascertain whether neural events are conserved across such contexts, we examined motor cortex population-level responses in monkeys when reaches were initiated either after an imposed delay, at a self-chosen time, or reactively with very low latency. We found that the same preparatory and movement-related events were conserved. However, preparation was temporally flexible and could be remarkably brief. Our findings support the existing hypothesis that preparation is an obligatory stage that achieves a consistent state prior to movement. Yet our results reveal that preparation can unfold more rapidly than previously supposed.

Conservation of preparatory neural events regardless of how movement is initiated

Structure in neural population recordings: an expected byproduct of simpler phenomena?

Maximum entropy modeling is a flexible and popular framework for formulating statistical models given partial knowledge. In this paper, rather than the traditional method of optimizing over the continuous density directly, we learn a smooth and invertible transformation that maps a simple distribution to the desired maximum entropy distribution. Doing so is nontrivial in that the objective being maximized (entropy) is a function of the density itself. By exploiting recent developments in normalizing flow networks, we cast the maximum entropy problem into a finite-dimensional constrained optimization, and solve the problem by combining stochastic optimization with the augmented Lagrangian method. Simulation results demonstrate the effectiveness of our method, and applications to finance and computer vision show the flexibility and accuracy of using maximum entropy flow networks.

The exponentially large sample space of general binary probabilistic models renders intractable standard operations such as exact marginalization, inference, and normalization. Typically, researchers deal with these distributions via deterministic approximations, the class of belief propagation methods being a prominent example. Comparatively, Markov Chain Monte Carlo methods have been significantly less used in this domain. In this work, we introduce an auxiliary variable MCMC scheme that samples from an annular augmented space, translating to a great circle path around the hypercube of the binary sample space. This annular augmentation sampler explores the sample space more effectively than coordinate-wise samplers and has no tunable parameters, leading to substantial performance gains in estimating quantities of interest in large binary models. We extend the method to incorporate into the sampler any existing mean-field approximation (such as from belief propagation), leading to further performance improvements. Empirically, we consider a range of large Ising models and an application to risk factors for heart disease.

Kernel methods are one of the mainstays of machine learning, but the problem of kernel learning remains challenging, with only a few heuristics and very little theory. This is of particular importance in methods based on estimation of kernel mean embeddings of probability measures. For characteristic kernels, which include most commonly used ones, the kernel mean embedding uniquely determines its probability measure, so it can be used to design a powerful statistical testing framework, which includes nonparametric two-sample and independence tests. In practice, however, the performance of these tests can be very sensitive to the choice of kernel and its lengthscale parameters. To address this central issue, we propose a new probabilistic model for kernel mean embeddings, the Bayesian Kernel Embedding model, combining a Gaussian process prior over the Reproducing Kernel Hilbert Space containing the mean embedding with a conjugate likelihood function, thus yielding a closed form posterior over the mean embedding. The posterior mean of our model is closely related to recently proposed shrinkage estimators for kernel mean embeddings, while the posterior uncertainty is a new, interesting feature with various possible applications. Critically for the purposes of kernel learning, our model gives a simple, closed form marginal pseudolikelihood of the observed data given the kernel hyperparameters. This marginal pseudolikelihood can either be optimized to inform the hyperparameter choice or fully Bayesian inference can be used.

Cortical firing rates frequently display elaborate and heterogeneous temporal structure. One often wishes to compute quantitative summaries of such structure—a basic example is the frequency spectrum—and compare with model-based predictions. The advent of large-scale population recordings affords the opportunity to do so in new ways, with the hope of distinguishing between potential explanations for why responses vary with time. We introduce a method that assesses a basic but previously unexplored form of population-level structure: when data contain responses across multiple neurons, conditions, and times, they are naturally expressed as a third-order tensor. We examined tensor structure for multiple datasets from primary visual cortex (V1) and primary motor cortex (M1). All V1 datasets were ‘simplest’ (there were relatively few degrees of freedom) along the neuron mode, while all M1 datasets were simplest along the condition mode. These differences could not be inferred from surface-level response features. Formal considerations suggest why tensor structure might differ across modes. For idealized linear models, structure is simplest across the neuron mode when responses reflect external variables, and simplest across the condition mode when responses reflect population dynamics. This same pattern was present for existing models that seek to explain motor cortex responses. Critically, only dynamical models displayed tensor structure that agreed with the empirical M1 data. These results illustrate that tensor structure is a basic feature of the data. For M1 the tensor structure was compatible with only a subset of existing models.

Tensor Analysis Reveals Distinct Population Structure that Parallels the Different Computational Roles of Areas M1 and V1

The computational and storage complexity of kernel machines presents the primary barrier to their scaling to large, modern, datasets. A common way to tackle the scalability issue is to use the conjugate gradient algorithm, which relieves the constraints on both storage (the kernel matrix need not be stored) and computation (both stochastic gradients and parallelization can be used). Even so, conjugate gradient is not without its own issues: the conditioning of kernel matrices is often such that conjugate gradients will have poor convergence in practice. Preconditioning is a common approach to alleviating this issue. Here we propose preconditioned conjugate gradients for kernel machines, and develop a broad range of preconditioners particularly useful for kernel matrices. We describe a scalable approach to both solving kernel machines and learning their hyperparameters. We show this approach is exact in the limit of iterations and outperforms state-of-the-art approximations for a given computational budget.

Reorganization between preparatory and movement population responses in motor cortex

Markov Chain Monte Carlo techniques remain the gold standard for approximate Bayesian inference, but their practical issues — including onerous runtime and sensitivity to tuning parameters — often lead researchers to use faster but typically less accurate deterministic approximations. Here we couple the fast but biased deterministic approximation offered by expectation propagation with elliptical slice sampling, a state-of-the-art MCMC method. We extend our hybrid deterministic-MCMC method to include recycled samples and analytical slices, and we rigorously prove the validity of each enhancement. Taken together, we show that these advances provide an order of magnitude gain in efficiency beyond existing state-of-the-art sampling techniques in Bayesian classification and multivariate gaussian quadrature problems.

Hamiltonian Monte Carlo and slice sampling are amongst the most widely used and studied classes of Markov Chain Monte Carlo samplers. We connect these two methods and present Hamiltonian slice sampling, which allows slice sampling to be carried out along Hamiltonian trajectories, or transformations thereof. Hamiltonian slice sampling clarifies a class of model priors that induce closed-form slice samplers. More pragmatically, inheriting properties of slice samplers, it offers advantages over Hamiltonian Monte Carlo, in that it has fewer tunable hyperparameters and does not require gradient information. We demonstrate the utility of Hamiltonian slice sampling out of the box on problems ranging from Gaussian process regression to Pitman-Yor based mixture models.

Among the goals of statistical genetics is to find associations between genetic data and binary phenotypes, such as heritable diseases. Often, the data are obfuscated by confounders such as age, ethnicity, or population structure. Linear mixed models are linear regression models that correct for confounding by means of correlated label noise; they are widely appreciated in the field of statistical genetics. We generalize this modeling paradigm to binary classification, where we face the problem that marginalizing over the noise leads to an intractable, high-dimensional integral. We present a scalable, approximate inference algorithm that lets us fit the model to high-dimensional data sets. The algorithm selects features based on an $\ell_1$ norm regularizer which are up to 40% less confounded compared to the outcomes of uncorrected feature selection, as we show. The proposed method also outperforms Gaussian process classification and uncorrelated probit regression in terms of prediction performance.

Single-trial dynamics of motor cortex and their applications to brain-machine interfaces

role of feedback control in brain-machine interfaces A closed-loop human simulator for investigating the

A typical task in statistical genetics is to find a sparse linear relation between genotypes with phenotypes, but often the data are confounded by age, ethnicity or population structure. We generalize the linear mixed model (LMM) Lasso approach for feature selection under confounding to the case of binary labels. This case is much more involved, as marginalization over the correlated noise leads to an intractable integral. We can overcome this problem with approximate inference techniques. We demonstrate on synthetic and real-world data that the sparse features that our method finds are less correlated with the top confounders. Introduction Genetic association studies have emerged as an important field of statistical genetics [1, 2]. In this class of problems, we associate high dimensional vectors of genotypes, such as SNPs or gene expression levels, with observable outcomes or phenotypes. These outcomes may be binary, such as the risk of getting a certain disease. For various diseases such as type 2 diabetes [3], the sparse linear effects that relate genotypes and phenotypes are largely undetected, which is why these missing associations have been entitled the The Dark Matter of Genomic Associations [4]. The problem is that these sparse signals can be spurious due to confounders that induce spurious non-causal correlations between genotypes and phenotypes. Confounding can stem from varying experimental conditions and demographics such as age, ethnicity or gender [5]. The perhaps most important type of confounding in statistical genetics arises due to population structure [6], which is due to the relatedness between the samples [7, 5, 8]. Ignoring such confounders can often lead to spurious false positive findings that cannot be replicated on independent data [9]. Correcting for such confounding dependencies is considered to be one of the greatest challenges in statistical genetics [10]. In this paper, we propose an algorithm for feature selection in binary classification in the presence of confounding. Our goal is to eliminate the confounder as well as possible and find a sparse weight vector that best captures causal relations. Model Our model builds on the LMM-Lasso [11], an important method of statistical genetics to limit the impact of confounding. While the LMM-lasso relies on linear regression, we generalize this approach to the much more involved classification setup, where the target values are binary. Let X ∈ Rd×n be the matrix of n observed data points. The corresponding labels y ∈ {−1,+1} are assumed to be realized according to the following model, y = sign(X>w + ), ∼ N (0,Σ), (1) where Σ ∈ Rn×n is a fixed covariance matrix and the model parameter w ∈ R is unknown. As in the LMM-lasso, the noise covariance Σ captures similarities between the samples that offer an alternative explanation of the observed labels. This way, the sparse weight vector w focuses on strong sparse signals that can not be well explained in terms of correlated noise. We choose Σ = λ1I + λ2X >X + λ3Σside, where Σside is constructed from side information such as age and geographical location. The weights λi are cross-validated. In order to train the model we aim to maximize the marginal likelihood in the presence of a `1-norm regularizer (Lasso). This leads to the objective function

Finding Sparse Features in Strongly Confounded Medical Binary Data

Psychophysical detection tests are ubiquitous in the study of human sensation and the diagnosis and treatment of virtually all sensory impairments. In many of these settings, the goal is to recover, from a series of binary observations from a human subject, the latent function that describes the discriminability of a sensory stimulus over some relevant domain. The auditory detection test, for example, seeks to understand a subject's likelihood of hearing sounds as a function of frequency and amplitude. Conventional methods for performing these tests involve testing stimuli on a pre-determined grid. This approach not only samples at very uninformative locations, but also fails to learn critical features of a subject's latent discriminability function. Here we advance active learning with Gaussian processes to the setting of psychophysical testing. We develop a model that incorporates strong prior knowledge about the class of stimuli, we derive a sensible method for choosing sample points, and we demonstrate how to evaluate this model efficiently. Finally, we develop a novel likelihood that enables testing of multiple stimuli simultaneously. We evaluate our method in both simulated and real auditory detection tests, demonstrating the merit of our approach.

Latent factor models have been widely used to analyze simultaneous recordings of spike trains from large, heterogeneous neural populations. These models assume the signal of interest in the population is a low-dimensional latent intensity that evolves over time, which is observed in high dimension via noisy point-process observations. These techniques have been well used to capture neural correlations across a population and to provide a smooth, denoised, and concise representation of high-dimensional spiking data. One limitation of many current models is that the observation model is assumed to be Poisson, which lacks the flexibility to capture under- and over-dispersion that is common in recorded neural data, thereby introducing bias into estimates of covariance. Here we develop the generalized count linear dynamical system, which relaxes the Poisson assumption by using a more general exponential family for count data. In addition to containing Poisson, Bernoulli, negative binomial, and other common count distributions as special cases, we show that this model can be tractably learned by extending recent advances in variational inference techniques. We apply our model to data from primate motor cortex and demonstrate performance improvements over state-of-the-art methods, both in capturing the variance structure of the data and in held-out prediction.

High-dimensional neural spike train analysis with generalized count linear dynamical systems

We introduce a novel information-theoretic approach for active model selection and demonstrate its effectiveness in a real-world application. Although our method can work with arbitrary models, we focus on actively learning the appropriate structure for Gaussian process (GP) models with arbitrary observation likelihoods. We then apply this framework to rapid screening for noise-induced hearing loss (NIHL), a widespread and preventible disability, if diagnosed early. We construct a GP model for pure-tone audiometric responses of patients with NIHL. Using this and a previously published model for healthy responses, the proposed method is shown to be capable of diagnosing the presence or absence of NIHL with drastically fewer samples than existing approaches. Further, the method is extremely fast and enables the diagnosis to be performed in real time.

Bayesian Active Model Selection with an Application to Automated Audiometry

Linear dimensionality reduction methods are a cornerstone of analyzing high dimensional data, due to their simple geometric interpretations and typically attractive computational properties. These methods capture many data features of interest, such as covariance, dynamical structure, correlation between data sets, input-output relationships, and margin between data classes. Methods have been developed with a variety of names and motivations in many fields, and perhaps as a result the connections between all these methods have not been highlighted. Here we survey methods from this disparate literature as optimization programs over matrix manifolds. We discuss principal component analysis, factor analysis, linear multidimensional scaling, Fisher's linear discriminant analysis, canonical correlations analysis, maximum autocorrelation factors, slow feature analysis, sufficient dimensionality reduction, undercomplete independent component analysis, linear regression, distance metric learning, and more. This optimization framework gives insight to some rarely discussed shortcomings of well-known methods, such as the suboptimality of certain eigenvector solutions. Modern techniques for optimization over matrix manifolds enable a generic linear dimensionality reduction solver, which accepts as input data and an objective to be optimized, and returns, as output, an optimal low-dimensional projection of the data. This simple optimization framework further allows straightforward generalizations and novel variants of classical methods, which we demonstrate here by creating an orthogonal-projection canonical correlations analysis. More broadly, this survey and generic solver suggest that linear dimensionality reduction can move toward becoming a blackbox, objective-agnostic numerical technology.

Linear dimensionality reduction: survey, insights, and generalizations

Bayesian optimization is a powerful framework for minimizing expensive objective functions while using very few function evaluations. It has been successfully applied to a variety of problems, including hyperparameter tuning and experimental design. However, this framework has not been extended to the inequality-constrained optimization setting, particularly the setting in which evaluating feasibility is just as expensive as evaluating the objective. Here we present constrained Bayesian optimization, which places a prior distribution on both the objective and the constraint functions. We evaluate our method on simulated and real data, demonstrating that constrained Bayesian optimization can quickly find optimal and feasible points, even when small feasible regions cause standard methods to fail.

Image interpolation and denoising are important techniques in image processing. Recently, there has been a growing interest in the use of Gaussian processes (GP) regression for interpolation and denoising of image data. However, exact GP regression suffers from 0 (N3) runtime for data size N, making it intractable for image data. Our GP-grid algorithm reduces the runtime complexity of GP from 0 (N3) to 0 (N312). We provide comprehensive mathematical model as well as experimental results of the GP interpolation performance for division of focal plane polarimeter. The GP interpolation method outperforms the commonly used bilinear interpolation method for polarimeters.

GP-grid image interpolation and denoising for division of focal plane sensors

Image interpolation and denoising for division of focal plane sensors using Gaussian processes.

The ability to automatically discover patterns and perform extrapolation is an essential quality of intelligent systems. Kernel methods, such as Gaussian processes, have great potential for pattern extrapolation, since the kernel flexibly and interpretably controls the generalisation properties of these methods. However, automatically extrapolating large scale multidimensional patterns is in general difficult, and developing Gaussian process models for this purpose involves several challenges. A vast majority of kernels, and kernel learning methods, currently only succeed in smoothing and interpolation. This difficulty is compounded by the fact that Gaussian processes are typically only tractable for small datasets, and scaling an expressive kernel learning approach poses different challenges than scaling a standard Gaussian process model. One faces additional computational constraints, and the need to retain significant model structure for expressing the rich information available in a large dataset. In this paper, we propose a Gaussian process approach for large scale multidimensional pattern extrapolation. We recover sophisticated out of class kernels, perform texture extrapolation, inpainting, and video extrapolation, and long range forecasting of land surface temperatures, all on large multidimensional datasets, including a problem with 383,400 training points. The proposed method significantly outperforms alternative scalable and flexible Gaussian process methods, in speed and accuracy. Moreover, we show that a distinct combination of expressive kernels, a fully non-parametric representation, and scalable inference which exploits existing model structure, are critical for large scale multidimensional pattern extrapolation.

Linear dimensionality reduction methods are a cornerstone of analyzing high dimensional data, due to their simple geometric interpretations and typically attractive computational properties. These methods capture many data features of interest, such as covariance, dynamical structure, correlation between data sets, input-output relationships, and margin between data classes. Methods have been developed with a variety of names and motivations in many fields, and perhaps as a result the deeper connections between all these methods have not been understood. Here we unify methods from this disparate literature as optimization programs over matrix manifolds. We discuss principal component analysis, factor analysis, linear multidimensional scaling, Fisher's linear discriminant analysis, canonical correlations analysis, maximum autocorrelation factors, slow feature analysis, undercomplete independent component analysis, linear regression, and more. This optimization framework helps elucidate some rarely discussed shortcomings of well-known methods, such as the suboptimality of certain eigenvector solutions. Modern techniques for optimization over matrix manifolds enable a generic linear dimensionality reduction solver, which accepts as input data and an objective to be optimized, and returns, as output, an optimal low-dimensional projection of the data. This optimization framework further allows rapid development of novel variants of classical methods, which we demonstrate here by creating an orthogonal-projection canonical correlations analysis. More broadly, we suggest that our generic linear dimensionality reduction solver can move linear dimensionality reduction toward becoming a blackbox, objective-agnostic numerical technology.

A common approach for Bayesian computation with big data is to partition the data into smaller pieces, perform local inference for each piece separately, and finally combine the results to obtain an approximation to the global posterior. Looking at this from the bottom up, one can perform separate analyses on individual sources of data and then combine these in a larger Bayesian model. In either case, the idea of distributed modeling and inference has both conceptual and computational appeal, but from the Bayesian perspective there is no general way of handling the prior distribution: if the prior is included in each separate inference, it will be multiply-counted when the inferences are combined; but if the prior is itself divided into pieces, it may not provide enough regularization for each separate computation, thus eliminating one of the key advantages of Bayesian methods. To resolve this dilemma, we propose expectation propagation (EP) as a general prototype for distributed Bayesian inference. The central idea is to factor the likelihood according to the data partitions, and to iteratively combine each factor with an approximate model of the prior and all other parts of the data, thus producing an overall approximation to the global posterior at convergence. In this paper, we give an introduction to EP and an overview of some recent developments of the method, with particular emphasis on its use in combining inferences from partitioned data. In addition to distributed modeling of large datasets, our unified treatment also includes hierarchical modeling of data with a naturally partitioned structure. The paper describes a general algorithmic framework, rather than a specific algorithm, and presents an example implementation for it.

Expectation Propagation as a Way of Life: A Framework for Bayesian Inference on Partitioned Data

The motor cortex was the one of the first cortical areas to be explored electrophysiologically, yet little agreement has emerged regarding its basic response properties. Often it is assumed that single-neuron responses reflect a preference for a particular movement or movement variable. It may be further assumed that movement is generated by (or at least accompanied by) a growing population-level preference for the relevant movement. This view has been attractive because it provides a canonical form for the single neuron, a link between preparatory and movement activity, a way of interpreting the population response, and a platform for designing analyses and couching hypotheses. However, this traditional view yields predictions that are at odds with basic features of the data. We discuss an alternative simplified model, in which outgoing commands are produced by dynamics that generate different output patterns as a function of the initial preparatory state. For reaching tasks, we hypothesized simple quasioscillatory dynamics because they provide a natural basis set for the empirical patterns of muscle activity. The predictions of the dynamical model match the data well at both the single-neuron and population levels, and the quasioscillatory patterns explain many of the otherwise odd features of the neural responses.

The stretched exponential function has many applications in modeling numerous types of experimental relaxation data. However, problems arise when using standard algorithms to fit this function: we have observed that different initializations result in distinct fitted parameters. To avoid this problem, we developed a novel algorithm for fitting the stretched exponential model to relaxation data. This method is advantageous both because it requires only a single adjustable parameter and because it does not require initialization in the solution space. We tested this method on simulated data and experimental stress-relaxation data from bone and cartilage and found favorable results compared to a commonly-used Quasi-Newton method. For the simulated data, strong correlations were found between the simulated and fitted parameters suggesting that this method can accurately determine stretched exponential parameters. When this method was tested on experimental data, high quality fits were observed for both bone and cartilage stress-relaxation data that were significantly better than those determined with the Quasi-Newton algorithm.

A Novel Method for Curvefitting the Stretched Exponential Function to Experimental Data.

Gaussian processes are typically used for smoothing and interpolation on small datasets. We introduce a new Bayesian nonparametric framework -- GPatt -- enabling automatic pattern extrapolation with Gaussian processes on large multidimensional datasets. GPatt unifies and extends highly expressive kernels and fast exact inference techniques. Without human intervention -- no hand crafting of kernel features, and no sophisticated initialisation procedures -- we show that GPatt can solve large scale pattern extrapolation, inpainting, and kernel discovery problems, including a problem with 383400 training points. We find that GPatt significantly outperforms popular alternative scalable Gaussian process methods in speed and accuracy. Moreover, we discover profound differences between each of these methods, suggesting expressive kernels, nonparametric representations, and exact inference are useful for modelling large scale multidimensional patterns.

GPatt: Fast Multidimensional Pattern Extrapolation with Gaussian Processes

Exact Gaussian process (GP) regression has O(N^3) runtime for data size N, making it intractable for large N. Many algorithms for improving GP scaling approximate the covariance with lower rank matrices. Other work has exploited structure inherent in particular covariance functions, including GPs with implied Markov structure, and inputs on a lattice (both enable O(N) or O(N log N) runtime). However, these GP advances have not been well extended to the multidimensional input setting, despite the preponderance of multidimensional applications. This paper introduces and tests three novel extensions of structured GPs to multidimensional inputs, for models with additive and multiplicative kernels. First we present a new method for inference in additive GPs, showing a novel connection between the classic backfitting method and the Bayesian framework. We extend this model using two advances: a variant of projection pursuit regression, and a Laplace approximation for non-Gaussian observations. Lastly, for multiplicative kernel structure, we present a novel method for GPs with inputs on a multidimensional grid. We illustrate the power of these three advances on several datasets, achieving performance equal to or very close to the naive GP at orders of magnitude less cost.

Scaling Multidimensional Inference for Structured Gaussian Processes.

Exact Gaussian Process (GP) regression has O(N3) runtime for data size N, making it intractable for large N. Advances in GP scaling have not been extended to the multidimensional input setting, despite the preponderance of multidimensional applications. This paper introduces and tests a novel method of projected additive approximation to multidimensional GPs. We illustrate the power of this method on several datasets, achieving performance close to the naive Full GP at orders of magnitude less cost.

Scaling Multidimensional Gaussian Processes using Projected Additive Approximations

Exact Gaussian process (GP) regression has <formula formulatype="inline"><tex Notation="TeX">${\cal O}(N^{3})$</tex> <mathgraphic graphicformat="GIF" fileref="gilboa-ieq1-192.gif"/></formula> runtime for data size <formula formulatype="inline"><tex Notation="TeX">$N$</tex><mathgraphic graphicformat="GIF" fileref="gilboa-ieq2-192.gif"/></formula>, making it intractable for large <formula formulatype="inline"><tex Notation="TeX">$N$</tex> <mathgraphic graphicformat="GIF" fileref="gilboa-ieq3-192.gif"/></formula>. Many algorithms for improving GP scaling approximate the covariance with lower rank matrices. Other work has exploited structure inherent in particular covariance functions, including GPs with implied Markov structure, and inputs on a lattice (both enable <formula formulatype="inline"><tex Notation="TeX">${\cal O}(N)$</tex><mathgraphic graphicformat="GIF" fileref="gilboa-ieq4-192.gif"/> </formula> or <formula formulatype="inline"><tex Notation="TeX">${\cal O}(N\; \log\; N)$</tex> <mathgraphic graphicformat="GIF" fileref="gilboa-ieq5-192.gif"/></formula> runtime). However, these GP advances have not been well extended to the multidimensional input setting, despite the preponderance of multidimensional applications. This paper introduces and tests three novel extensions of structured GPs to multidimensional inputs, for models with additive and multiplicative kernels. First we present a new method for inference in additive GPs, showing a novel connection between the classic backfitting method and the Bayesian framework. We extend this model using two advances: a variant of projection pursuit regression, and a Laplace approximation for non-Gaussian observations. Lastly, for multiplicative kernel structure, we present a novel method for GPs with inputs on a multidimensional grid. We illustrate the power of these three advances on several data sets, achieving performance equal to or very close to the naive GP at orders of magnitude less cost.

Scaling Multidimensional Inference for Structured Gaussian Processes

In many settings, data is collected as multiple time series, where each recorded time series is an observation of some underlying dynamical process of interest. These observations are often time-marked with known event times, and one desires to do a range of standard analyses. When there is only one time marker, one simply aligns the observations temporally on that marker. When multiple time-markers are present and are at dierent times on dierent time series observations, these analyses are more dicult. We describe a Gaussian Process model for analyzing multiple time series with multiple time markings, and we test it on a variety of data.

Cells in V4 and IT respond selectively to a wide variety of moderately complex object features [1], [2], perhaps numbering in the hundreds or thousands or more. Given that object recognition is location-invariant, it follows that, (1) every location in the visual field is analyzed in parallel by a large number of different feature types, which implies that (2) every feature type forms its own retinotopic map coarsely tiling the visual field. The physical interdigitation of neurons participating in a potentially large number of distinct feature maps covering the visual field, each of which must develop separately and unsupervised, presents a significant challenge for conventional map-formation algorithms. In particular, within such a “multimap”, a neuron is surrounded by other neurons coding many feature types different from its own and from each other (see [4] [5] and [3] for data suggestive of this), preventing neurons from co-training, i.e. sharing sensory data, within cohorts defined by a purely spatial criterion. Co-training during development must therefore depend both on the spatial proximity of two neurons as well as their functional similarity. In this work, we have developed a new self-organizing map formation algorithm derived from a Kohonen-style SOM but that uses a hybrid spatial-functional similarity criteria for determining which neurons wire and learn together. Preliminary results show that pure spatial algorithms confronted with multi-feature-type data tend to produce a patchwork of relatively large regions of tissue containing neurons of a single feature type (Figure panel A), whereas the hybrid learning rule produces multiple, finely interdigitated smooth feature maps in which neurons are in general surrounded by cells of other types (Figure panel B). Multimap learning algorithms also have the potential to help explain species-specific differences in the fine-scale smoothness vs. roughness of feature maps in primary sensory areas [4].

Neural prosthetic systems seek to improve the lives of severely disabled people by decoding neural activity into useful behavioral commands. These systems and their decoding algorithms are typically developed "offline," using neural activity previously gathered from a healthy animal, and the decoded movement is then compared with the true movement that accompanied the recorded neural activity. However, this offline design and testing may neglect important features of a real prosthesis, most notably the critical role of feedback control, which enables the user to adjust neural activity while using the prosthesis. We hypothesize that understanding and optimally designing high-performance decoders require an experimental platform where humans are in closed-loop with the various candidate decode systems and algorithms. It remains unexplored the extent to which the subject can, for a particular decode system, algorithm, or parameter, engage feedback and other strategies to improve decode performance. Closed-loop testing may suggest different choices than offline analyses. Here we ask if a healthy human subject, using a closed-loop neural prosthesis driven by synthetic neural activity, can inform system design. We use this online prosthesis simulator (OPS) to optimize "online" decode performance based on a key parameter of a current state-of-the-art decode algorithm, the bin width of a Kalman filter. First, we show that offline and online analyses indeed suggest different parameter choices. Previous literature and our offline analyses agree that neural activity should be analyzed in bins of 100- to 300-ms width. OPS analysis, which incorporates feedback control, suggests that much shorter bin widths (25-50 ms) yield higher decode performance. Second, we confirm this surprising finding using a closed-loop rhesus monkey prosthetic system. These findings illustrate the type of discovery made possible by the OPS, and so we hypothesize that this novel testing approach will help in the design of prosthetic systems that will translate well to human patients.

A closed-loop human simulator for investigating the role of feedback control in brain-machine interfaces.

An L1-regularized logistic model for detecting short-term neuronal interactions

While Gaussian probability densities are omnipresent in applied mathematics, Gaussian cumulative probabilities are hard to calculate in any but the univariate case. We offer here an empirical study of the utility of Expectation Propagation (EP) as an approximate integration method for this problem. For rectangular integration regions, the approximation is highly accurate. We also extend the derivations to the more general case of polyhedral integration regions. However, we find that in this polyhedral case, EP's answer, though often accurate, can be almost arbitrarily wrong. These unexpected results elucidate an interesting and non-obvious feature of EP not yet studied in detail, both for the problem of Gaussian probabilities and for EP more generally.

brain based on the dynamics within the speaker’s brain and we find extensive speaker-listener coupling, extending well-beyond auditory cortex. This coupling vanishes when participants fail to communicate. Moreover, while on average the listeners’ brain activity mirrors the speaker’s activity with a delay, we also identify areas that exhibit predictive anticipatory responses. We connect the extent of neural coupling to a quantitative measure of story comprehension and show that the greater the coupling, the greater the understanding, with anticipatory couplings capturing over 50% of the behavioral variance. We argue that the observed alignment of productionand comprehension-based processes serves as a mechanism by which brains convey information.

III-32. Firing rate oscillations underlie motor cortex responses during reach- ing in monkey

Cortically-controlled prosthetic systems aim to help disabled patients by translating neural signals from the brain into control signals for guiding prosthetic devices. Recent reports have demonstrated reasonably high levels of performance and control of computer cursors and prosthetic limbs, but to achieve true clinical viability, the long-term operation of these systems must be better understood. In particular, the quality and stability of the electrically-recorded neural signals require further characterization. Here, we quantify action potential changes and offline neural decoder performance over 382 days of recording from four intracortical arrays in three animals. Action potential amplitude decreased by 2.4% per month on average over the course of 9.4, 10.4, and 31.7 months in three animals. During most time periods, decoder performance was not well correlated with action potential amplitude (p > 0.05 for three of four arrays). In two arrays from one animal, action potential amplitude declined by an average of 37% over the first 2 months after implant. However, when using simple threshold-crossing events rather than well-isolated action potentials, no corresponding performance loss was observed during this time using an offline decoder. One of these arrays was effectively used for online prosthetic experiments over the following year. Substantial short-term variations in waveforms were quantified using a wireless system for contiguous recording in one animal, and compared within and between days for all three animals. Overall, this study suggests that action potential amplitude declines more slowly than previously supposed, and performance can be maintained over the course of multiple years when decoding from threshold-crossing events rather than isolated action potentials. This suggests that neural prosthetic systems may provide high performance over multiple years in human clinical trials.

Long-term stability of neural prosthetic control signals from silicon cortical arrays in rhesus macaque motor cortex

While Gaussian probability densities are omnipresent in applied mathematics, Gaussian cumulative probabilities are hard to calculate in any but the univariate case. We study the utility of Expectation Propagation (EP) as an approximate integration method for this problem. For rectangular integration regions, the approximation is highly accurate. We also extend the derivations to the more general case of polyhedral integration regions. However, we find that in this polyhedral case, EP's answer, though often accurate, can be almost arbitrarily wrong. We consider these unexpected results empirically and theoretically, both for the problem of Gaussian probabilities and for EP more generally. These results elucidate an interesting and non-obvious feature of EP not yet studied in detail.

Cortical Preparatory Activity: Representation of Movement or First Cog in a Dynamical Machine?

Methods for estimating neural firing rates, and their application to brain-machine interfaces

By decoding neural activity into useful behavioral commands, neural prosthetic systems seek to improve the lives of severely disabled human patients. Motor decoding algorithms, which map neural spiking data to control parameters of a device such as a prosthetic arm, have received particular attention in the literature. Here, we highlight several outstanding problems that exist in most current approaches to decode algorithm design. These include two problems that we argue will unlikely result in further dramatic increases in performance, specifically spike sorting and spiking models. We also discuss three issues that have been less examined in the literature, and we argue that addressing these issues may result in dramatic future increases in performance. These include: non-stationarity of recorded waveforms, limitations of a linear mappings between neural activity and movement kinematics, and the low signal to noise ratio of the neural data. We demonstrate these problems with data from 39 experimental sessions with a non-human primate performing reaches and with recent literature. In all, this study suggests that research in cortically-controlled prosthetic systems may require reprioritization to achieve performance that is acceptable for a clinically viable human system.

Neural prosthetic systems: Current problems and future directions

Our seemingly effortless ability to make coordinated movements belies the sophisticated computational machinery at work in our nervous system. Much has been learned about motor cortical processing with classic systems neuroscience approaches. In recent years, the field has been dramatically expanding the complexity of its data, recording technologies, and experiments. This shift seeks to deliver a much deeper understanding of cortical processing and a much improved ability to control neural prosthetic devices (also called brain-machine interfaces). Realizing this payoff, however, requires analytical and computational methods that can exploit this changing paradigm. This dissertation describes algorithmic developments for understanding cortical processing and for prosthetic systems. The first part focuses on our signal processing efforts to extract useful signals underlying noisy neural activity in the motor system of the primate brain, both for single neurons and for populations of simultaneously recorded neurons. Specifically, I discuss analyzing single neurons using machine learning techniques (Gaussian Processes) in a point process framework, and I describe an approach to mitigate the significant optimization challenges of this method. I then discuss extending this idea across many simultaneously recorded neurons (with a factor analysis-like algorithm) to extract population-level signatures of neural activity. This part also points to broader implications of this work for engineering and statistics. The second part focuses on algorithmic challenges in neural prosthetic systems, first describing performance improvements available via algorithmic optimization of a prosthetic interface. I then discuss other algorithmic areas of prosthetic design, reviewing a number of areas for improvement and pointing to future work to address these current problems. As a whole, this dissertation offers analytical methods that push forward advanced research into the brain's motor system and our ability to meaningfully interface with it.

Algorithms for understanding motor cortical processing and neural prosthetic systems

Influence of heart rate on the BOLD signal: The cardiac response function

Point processes are difficult to analyze because they provide only a sparse and noisy observation of the intensity function driving the process. Gaussian Processes offer an attractive framework within which to infer underlying intensity functions. The result of this inference is a continuous function defined across time that is typically more amenable to analytical efforts. However, a naive implementation will become computationally infeasible in any problem of reasonable size, both in memory and run time requirements. We demonstrate problem specific methods for a class of renewal processes that eliminate the memory burden and reduce the solve time by orders of magnitude.

Fast Gaussian process methods for point process intensity estimation

Juvenile muscular atrophy of the distal upper extremity (Hirayama syndrome): a systematic review

Establishing an attributional style for the 2004 Philadelphia Phillies utilizing the Content Analysis of Verbatim Explanation (CAVE) technique

We describe a study which examined the relationship between certain textual/discursive cues during computer mediated dialogues and correlations of these cues with two measures of impression formation: 1) a global positivity of impressions questionnaire; and 2) perceptions of six personality dimensions. The study also examined discourse phenomena emergent in the conversations. Undergraduates participated in same and mixed sex dyadic, forced turn, computer mediated dialogues and were asked to report impressions of their conversational partners. Results indicated that relative amounts of words per turn, negative disclosure, and evaluative disclosure have significant effects on impression formation. Results also suggest that number of words per turn, number of questions, and evaluative disclosure are emergent in the discourse, and naturally equalize between partners. No gender differences were detected. These findings suggest a new methodology for examining online interaction and concomitant impression formation. Suggestions are made for how this new methodology might be incorporated into autonomous conversational systems.

Proceedings Second International Conference on Cognitive Technology Humanizing the Information Age

Action and reaction: computer-mediated dialogues as a model for natural interfaces

Not all Bloom and gloom: assessing constructive alignment, higher order cognitive skills, and their influence on students’ perceived learning within the practical components of an undergraduate biology course

The use of photogrammetric fossil models in palaeontology education

Data from Rücklin et al. 2021. Acanthodian dental development and the origin of gnathostome dentitions. Nature Ecology & Evolution

Acanthodian dental development and the origin of gnathostome dentitions

Taphonomy experiments reveal the potential for a fossil record of the origin of complex life. The timing of origin of eukaryotes and the sequence of eukaryogenesis are poorly constrained because their fossil record is difficult to interpret. Claims of fossilized organelles have been discounted on the unsubstantiated perception that they decay too quickly for fossilization. We experimentally characterized the pattern and time scale of decay of nuclei, chloroplasts, and pyrenoids in red and green algae, demonstrating that they persist for many weeks postmortem as physical substrates available for preservation, a time scale consistent with known mechanisms of fossilization. Chloroplasts exhibit greater decay resistance than nuclei; pyrenoids are unlikely to be preserved, but their presence could be inferred from spaces within fossil chloroplasts. Our results are compatible with differential organelle preservation in seed plants. Claims of fossilized organelles in Proterozoic fossils can no longer be dismissed on grounds of plausibility, prompting reinterpretation of the early eukaryotic fossil record and the prospect of a fossil record of eukaryogenesis.

Experimental taphonomy of organelles and the fossil record of early eukaryote evolution

The challenge of identifying fossilized organelles has long hampered attempts to interpret the fossil record of early eukaryote evolution. We explore this challenge through experimental taphonomy of nuclei in a living eukaryote and microscale physical and chemical characterization of putative nuclei in embryo-like fossils from the early Ediacaran Weng'an Biota. The fossil nuclei exhibit diverse preservational modes that differ in shape, presence or absence of an inner body and the chemistry of the associated mineralization. The nuclei are not directly fossilized; rather, they manifest as external moulds. Experimental taphonomy of epidermal cells from the common onion (Allium cepa) demonstrates that nuclei are more decay resistant than their host cells, generally maintaining their physical dimensions for weeks to months post-mortem, though under some experimental conditions they exhibit shrinkage and/or become shrouded in microbial biofilms. The fossil and experimental evidence may be rationalized in a single taphonomic pathway of selective mineralization of the cell cytoplasm, preserving an external mould of the nucleus that is itself resistant to both decay and mineral replication. Combined, our results provide both a secure identification of the Weng'an nuclei as well as the potential of a fossil record of organelles that might help arbitrate in long-standing debates over the relative and absolute timing of the evolutionary assembly of eukaryote-grade cells.

Nucleus preservation in early Ediacaran Weng'an embryo-like fossils, experimental taphonomy of nuclei and implications for reading the eukaryote fossil record

Data from Yin et al. (2019) The early Ediacaran Caveasphaera foreshadows the evolutionary origin of animal-like embryology. Current Biology

The Early Ediacaran Caveasphaera Foreshadows the Evolutionary Origin of Animal-like Embryology

Data from Huang et al. (2018) Middle Triassic conodont apparatus architecture revealed by synchrotron X-ray microtomography. Palaeoworld

The Weng'an Biota is a fossil Konservat-Lagerstätte in South China that is c. 570 – 609 myr old and provides an unparalleled snapshot of marine life during the interval in which molecular clocks estimate that animal clades were diversifying. It yields fossils that are three-dimensionally preserved in calcium phosphate with cellular and sometimes subcellular fidelity. The biota includes candidates for the oldest animals in the fossil record, including embryonic, larval and adult forms. We argue that, although the Weng'an Biota includes forms that could be animals, none can currently be assigned to this group with confidence. Nonetheless, the biota offers a rare and valuable window on the evolution of multicellular and soft-bodied organisms in the prelude to the Cambrian radiation.

The Weng'an Biota (Doushantuo Formation): an Ediacaran window on soft-bodied and multicellular microorganisms

Citation for published version (Harvard): Davies, TGD, Lautenschlager, S, Rahman, I, Cunningham, J, Asher, R, Barrett, P, Bates, K, Bengtson, S, Benson, R, Boyer, D, Braga, J, Bright, J, Claessons, L, Cox, P, Dong, X-P, Evans, A, Falkingham, P, Friedman, M, Garwood, R, Goswami, A, Hutchinson, JO, Jeffrey, N, Johanson, Z, Lebrun, R, Martínez-Pérez, CM-P, Marugán-Lobón, JM-L, O'Higgins, P, Metscher, B, Orliac, MO, Rowe, T, Rücklin, MR, Sánchez-Villagra, MRS-V, Shubin, N, Smith, S, Starck, MS, Stringer, C, Summers, AS, Sutton, M, Walsh, S, Weisbecker, VW, Witmer, L, Wroe, S, Yin, ZY, Rayfield, E & Donoghue, PD 2017, 'Open data and digital morphology', Royal Society of London. Proceedings B. Biological Sciences. https://doi.org/10.1098/rspb.2017.0194

Early Cambrian Pseudooides prima has been described from embryonic and post-embryonic stages of development, exhibiting long germ-band development. There has been some debate about the pattern of segmentation, but this interpretation, as among the earliest records of ecdysozoans, has been generally accepted. Here, we show that the ‘germ band’ of P. prima embryos separates along its mid axis during development, with the transverse furrows between the ‘somites’ unfolding into the polar aperture of the ten-sided theca of Hexaconularia sichuanensis, conventionally interpreted as a scyphozoan cnidarian; co-occurring post-embryonic remains of ecdysozoans are unrelated. We recognize H. sichuanensis as a junior synonym of P. prima as a consequence of identifying these two form-taxa as distinct developmental stages of the same organism. Direct development in P. prima parallels the co-occuring olivooids Olivooides, and Quadrapyrgites and Bayesian phylogenetic analysis of a novel phenotype dataset indicates that, despite differences in their tetra-, penta- and pseudo-hexa-radial symmetry, these hexangulaconulariids comprise a clade of scyphozoan medusozoans, with Arthrochites and conulariids, that all exhibit direct development from embryo to thecate polyp. The affinity of hexangulaconulariids and olivooids to extant scyphozoan medusozoans indicates that the prevalence of tetraradial symmetry and indirect development are a vestige of a broader spectrum of body-plan symmetries and developmental modes that was manifest in their early Phanerozoic counterparts.

The early Cambrian fossil embryo Pseudooides is a direct-developing cnidarian, not an early ecdysozoan

Nuclei and nucleoli in embryo-like fossils from the Ediacaran Weng’an Biota

Over the past two decades, the development of methods for visualizing and analysing specimens digitally, in three and even four dimensions, has transformed the study of living and fossil organisms. However, the initial promise that the widespread application of such methods would facilitate access to the underlying digital data has not been fully achieved. The underlying datasets for many published studies are not readily or freely available, introducing a barrier to verification and reproducibility, and the reuse of data. There is no current agreement or policy on the amount and type of data that should be made available alongside studies that use, and in some cases are wholly reliant on, digital morphology. Here, we propose a set of recommendations for minimum standards and additional best practice for three-dimensional digital data publication, and review the issues around data storage, management and accessibility.

The evolutionary emergence of animals is one of the most significant episodes in the history of life, but its timing remains poorly constrained. Molecular clocks estimate that animals originated and began diversifying over 100 million years before the first definitive metazoan fossil evidence in the Cambrian. However, closer inspection reveals that clock estimates and the fossil record are less divergent than is often claimed. Modern clock analyses do not predict the presence of the crown‐representatives of most animal phyla in the Neoproterozoic. Furthermore, despite challenges provided by incomplete preservation, a paucity of phylogenetically informative characters, and uncertain expectations of the anatomy of early animals, a number of Neoproterozoic fossils can reasonably be interpreted as metazoans. A considerable discrepancy remains, but much of this can be explained by the limited preservation potential of early metazoans and the difficulties associated with their identification in the fossil record. Critical assessment of both records may permit better resolution of the tempo and mode of early animal evolution.

The origin of animals: Can molecular clocks and the fossil record be reconciled?

Fossilized embryos afford direct insight into the pattern of development in extinct organisms, providing unique tests of hypotheses of developmental evolution based in comparative embryology. However, these fossils can only be effective in this role if their embryology and phylogenetic affinities are well constrained. We elucidate and interpret the development of Olivooides from embryonic and adult stages and use these data to discriminate among competing interpretations of their anatomy and affinity. The embryology of Olivooides is principally characterized by the development of an ornamented periderm that initially forms externally and is subsequently formed internally, released at the aperture, facilitating the direct development of the embryo into an adult theca. Internal anatomy is known only from embryonic stages, revealing two internal tissue layers, the innermost of which is developed into three transversally arranged walls that partly divide the lumen into an abapertural region, interpreted as the gut of a polyp, and an adapertural region that includes structures that resemble the peridermal teeth of coronate scyphozoans. The anatomy and pattern of development exhibited by Olivooides appears common to the other known genus of olivooid, Quadrapyrgites, which differs in its tetraradial, as opposed to pentaradial symmetry. We reject previous interpretations of the olivooids as cycloneuralians, principally on the grounds that they lack a through gut and introvert, in embryo and adult. Instead we consider the affinities of the olivooids among medusozoan cnidarians; our phylogenetic analysis supports their classification as total‐group Coronata, within crown‐Scyphozoa. Olivooides and Quadrapyrgites evidence a broader range of life history strategies and bodyplan symmetry than is otherwise commonly represented in extant Scyphozoa specifically, and Cnidaria more generally.

Developmental biology of the early Cambrian cnidarian Olivooides

Three‐dimensional analyses of the early Ediacaran microfossils from the Weng'an biota (Doushantuo Formation) have focused predominantly on multicellular forms that have been interpreted as embryos, and yet they have defied phylogenetic interpretation principally because of absence of evidence from other stages in their life cycle. It is therefore unfortunate that the affinities of the various other Doushantuo microfossils have been neglected. A new conical fossil that is preserved at a cellular level is described here. The fossil contains distinct cell clusters that are characterized and analysed in three dimensions. These clusters are often exposed at the specimen surface, and the fossil preserves many hemispherical craters that are interpreted as positions where clusters have left the organism. The cell clusters may be either reproductive propagules or infesting organisms. Similar clusters are found in a variety of Doushantuo organisms including putative animal embryos and algae.

A multicellular organism with embedded cell clusters from the Ediacaran Weng'an biota (Doushantuo Formation, South China)

Tomographic data of tubular fossils from the Ediacaran Weng'an Doushantuo biota

Molecular clock analyses estimate that crown-group animals began diversifying hundreds of millions of years before the start of the Cambrian period. However, the fossil record has not yielded unequivocal evidence for animals during this interval. Some of the most promising candidates for Precambrian animals occur in the Weng'an biota of South China, including a suite of tubular fossils assigned to Sinocyclocyclicus, Ramitubus, Crassitubus and Quadratitubus, that have been interpreted as soft-bodied eumetazoans comparable to tabulate corals. Here, we present new insights into the anatomy, original composition and phylogenetic affinities of these taxa based on data from synchrotron radiation X-ray tomographic microscopy, ptychographic nanotomography, scanning electron microscopy and electron probe microanalysis. The patterns of deformation observed suggest that the cross walls of Sinocyclocyclicus and Quadratitubus were more rigid than those of Ramitubus and Crassitubus. Ramitubus and Crassitubus specimens preserve enigmatic cellular clusters at terminal positions in the tubes. Specimens of Sinocyclocyclicus and Ramitubus have biological features that might be cellular tissue or subcellular structures filling the spaces between the cross walls. These observations are incompatible with a cnidarian interpretation, in which the spaces between cross walls are abandoned parts of the former living positions of the polyp. The affinity of the Weng'an tubular fossils may lie within the algae.

Critical appraisal of tubular putative eumetazoans from the Ediacaran Weng'an Doushantuo biota

Exceptionally preserved fossils provide major insights into the evolutionary history of life. Microbial activity is thought to play a pivotal role in both the decay of organisms and the preservation of soft tissue in the fossil record, though this has been the subject of very little experimental investigation. To remedy this, we undertook an experimental study of the decay of the brine shrimp Artemia, examining the roles of autolysis, microbial activity, oxygen diffusion and reducing conditions. Our findings indicate that endogenous gut bacteria are the main factor controlling decay. Following gut wall rupture, but prior to cuticle failure, gut-derived microbes spread into the body cavity, consuming tissues and forming biofilms capable of mediating authigenic mineralization, that pseudomorph tissues and structures such as limbs and the haemocoel. These observations explain patterns observed in exceptionally preserved fossil arthropods. For example, guts are preserved relatively frequently, while preservation of other internal anatomy is rare. They also suggest that gut-derived microbes play a key role in the preservation of internal anatomy and that differential preservation between exceptional deposits might be because of factors that control autolysis and microbial activity. The findings also suggest that the evolution of a through gut and its bacterial microflora increased the potential for exceptional fossil preservation in bilaterians, providing one explanation for the extreme rarity of internal preservation in those animals that lack a through gut.

Experimental taphonomy of Artemia reveals the role of endogenous microbes in mediating decay and fossilization

Abstract Studies of the development of organisms can reveal crucial information on homology of structures. Developmental data are not peculiar to living organisms, and they are routinely preserved in the mineralized tissues that comprise the vertebrate skeleton, allowing us to obtain direct insight into the developmental evolution of this most formative of vertebrate innovations. The pattern of developmental processes is recorded in fossils as successive stages inferred from the gross morphology of multiple specimens and, more reliably and routinely, through the ontogenetic stages of development seen in the skeletal histology of individuals. Traditional techniques are destructive and restricted to a 2-D plane with the third dimension inferred. Effective non-invasive methods of visualizing paleohistology to reconstruct developmental stages of the skeleton are necessary. In a brief survey of paleohistological techniques we discuss the pros and cons of these methods. The use of tomographic methods to reconstruct development of organs is exemplified by the study of the placoderm dentition. Testing evidence for the presence of teeth in placoderms, the first jawed vertebrates, we compare the methods that have been used. These include inferring development from morphology, and using serial sectioning, microCT or synchrotron X-ray tomographic microscopy (SRXTM), to reconstruct growth stages and directions of growth. The ensuing developmental interpretations are biased by the methods and degree of inference. The most direct and reliable method is using SRXTM data to trace sclerochronology. The resulting developmental data can be used to resolve homology and test hypotheses on the origin of evolutionary novelties.

Knowledge of evolutionary history is based extensively on relatively rare fossils that preserve soft tissues. These fossils record a much greater proportion of anatomy than would be known solely from mineralized remains and provide key data for testing evolutionary hypotheses in deep time. Ironically, however, exceptionally preserved fossils are often among the most contentious because they are difficult to interpret. This is because their morphology has invariably been affected by the processes of decay and diagenesis, meaning that it is often difficult to distinguish preserved biology from artifacts introduced by these processes. Here we describe how a range of analytical techniques can be used to tease apart mineralization that preserves biological structures from unrelated geological mineralization phases. This approach involves using a series of X-ray, ion, electron and laser beam techniques to characterize the texture and chemistry of the different phases so that they can be differentiated in material that is difficult to interpret. This approach is demonstrated using a case study of its application to the study of fossils from the Ediacaran Doushantuo Biota.

Distinguishing biology from geology in soft-tissue preservation.

The origin and evolution of Lophotrochozoa can be traced to the plethora of lower Cambrian scleritome taxa. We aim to determine the character suites linking these stem-Lophotrochozoa to their extant crown relatives, in particular the small shelly tommotiids and the stem-group brachiopods. Tracing the origin of morphological characters from these fossils informs the evolution and construction of lophotrochozoan body plans associated with the Cambrian Explosion. This is achieved by comparing records of exceptional preservation, most conspicuously Burgess Shale type Lagerstatten with more widespread Cambrian stem-brachiopods and small shelly fossils with their purported extant relatives, for example. Determining morphological character homologies is crucial to reconstructing the brachiopod stem-group and in polarising character changes associated with the putative transition from scleritome organisms to crown-group brachiopods. In this thesis arguments for a common origin of specific shell structures and exceptionally preserved soft-tissues are investigated. New records of enigmatic stem-group lophotrochozoans are described from two localities, the Indian Springs and Chengjiang Lagerstatte. Comprising the stem-brachiopod Mickwitzia cf. occidens, a putative stem-group entoproct Cotyledion tylodes and an enigmatic agglutinated tubular lophophorate possessing an unusual combination of phoronid, brachiopod and tommotiid characters, Yuganotheca elegans gen. et sp. nov. The interplay of bauplan, microbial activity and environmental factors resulting in such incidences of exceptional soft tissue preservation is also examined critically. Consequently, the evolution of through-gut bearing bilaterians is suggested as the reason for why the Cambrian hosts such a plethora of Lagerstatten. The closure of this taphonomic window is then associated with increased bioturbation following the Cambrian substrate revolution.

The role of microbes in decay and preservation: a Cambrian Explosion of animals and Lagerstätten.

The chemical construction of complex colloidosomes consisting of a molecularly crowded polyelectrolyte-enriched interior surrounded by a continuous shell of closely packed silica nanoparticles is studied using optical and fluorescence microscopy, high-resolution X-ray microcomputed tomography, and synchrotron radiation X-ray tomographic microscopy. The colloidosomes are prepared by addition of partially hydrophobic silica nanoparticles to dodecane dispersions of positively or negatively charged coacervate microdroplets consisting of aqueous mixtures of poly(diallyldimethylammonium chloride) (PDDA) and adenosine 5'-triphosphate (ATP) or PDDA and poly(acrylic acid) (PAA), respectively. Interfacial assembly of the nanoparticles produces a polydisperse population of well-defined PDDA/PAA droplets with diameters ranging from 50 to 950 μm. In contrast, reconstruction of the PDDA/ATP coacervate interior occurs on addition of the silica nanoparticles to produce a nanoparticle-stabilized oil-in-coacervate-in-oil multiphase emulsion. Transfer of the coacervate-containing colloidosomes into water and replication of their internal structure are achieved by addition of tetramethoxysilane, which serves as both a cross-linking and silicification agent to produce mineralized PDDA/PAA or PDDA/ATP microstructures with a uniform solidified texture or multichambered interior, respectively. The integration of colloidosome and coacervate technologies offers a route to a new type of multifunctional microcompartmentalized system based on the membrane-mediated incarceration of molecularly crowded chemical environments.

Nanoparticle-based membrane assembly and silicification in coacervate microdroplets as a route to complex colloidosomes.

The Early Cambrian organism Olivooides is known from both embryonic and post-embryonic stages and, consequently, it has the potential to yield vital insights into developmental evolution at the time that animal body plans were established. However, this potential can only be realized if the phylogenetic relationships of Olivooides can be constrained. The affinities of Olivooides have proved controversial because of the lack of knowledge of the internal anatomy and the limited range of developmental stages known. Here, we describe rare embryonic specimens in which internal anatomical features are preserved. We also present a fuller sequence of fossilized developmental stages of Olivooides, including associated specimens that we interpret as budding ephyrae (juvenile medusae), all of which display a clear pentaradial symmetry. Within the framework of a cnidarian interpretation, the new data serve to pinpoint the phylogenetic position of Olivooides to the scyphozoan stem group. Hypotheses about scalidophoran or echinoderm affinities of Olivooides can be rejected.

Embryos, polyps and medusae of the Early Cambrian scyphozoan Olivooides

Fossils described as Vernanimalcula guizhouena, from the nearly 600 million‐year‐old Doushantuo Formation in South China, have been interpreted as the remains of bilaterian animals. As such they would represent the oldest putative record of bilaterian animals in Earth history, and they have been invoked in debate over this formative episode of early animal evolution. However, this interpretation is fallacious. We review the evidential basis of the biological interpretation of Vernanimalcula, concluding that the structures key to animal identity are effects of mineralization that do not represent biological tissues, and, furthermore, that it is not possible to derive its anatomical reconstruction on the basis of the available evidence. There is no evidential basis for interpreting Vernanimalcula as an animal, let alone a bilaterian. The conclusions of evolutionary studies that have relied upon the bilaterian interpretation of Vernanimalcula must be called into question.

The Ediacaran Doushantuo biota has yielded fossils interpreted as eukaryotic organisms, either animal embryos or eukaryotes basal or distantly related to Metazoa. However, the fossils have been interpreted alternatively as giant sulphur bacteria similar to the extant Thiomargarita. To test this hypothesis, living and decayed Thiomargarita were compared with Doushantuo fossils and experimental taphonomic pathways were compared with modern embryos. In the fossils, as in eukaryotic cells, subcellular structures are distributed throughout cell volume; in Thiomargarita, a central vacuole encompasses approximately 98 per cent cell volume. Key features of the fossils, including putative lipid vesicles and nuclei, complex envelope ornament, and ornate outer vesicles are incompatible with living and decay morphologies observed in Thiomargarita. Microbial taphonomy of Thiomargarita also differed from that of embryos. Embryo tissues can be consumed and replaced by bacteria, forming a replica composed of a three-dimensional biofilm, a stable fabric for potential fossilization. Vacuolated Thiomargarita cells collapse easily and do not provide an internal substrate for bacteria. The findings do not support the hypothesis that giant sulphur bacteria are an appropriate interpretative model for the embryo-like Doushantuo fossils. However, sulphur bacteria may have mediated fossil mineralization and may provide a potential bacterial analogue for other macroscopic Precambrian remains.

Experimental taphonomy of giant sulphur bacteria: implications for the interpretation of the embryo-like Ediacaran Doushantuo fossils

The Ediacaran Doushantuo biota has yielded fossils that include the oldest widely accepted record of the animal evolutionary lineage, as well as specimens with alleged bilaterian affinity. However, these systematic interpretations are contingent on the presence of key biological structures that have been reinterpreted by some workers as artefacts of diagenetic mineralization. On the basis of chemistry and crystallographic fabric, we characterize and discriminate phases of mineralization that reflect: (i) replication of original biological structure, and (ii) void-filling diagenetic mineralization. The results indicate that all fossils from the Doushantuo assemblage preserve a complex mélange of mineral phases, even where subcellular anatomy appears to be preserved. The findings allow these phases to be distinguished in more controversial fossils, facilitating a critical re-evaluation of the Doushantuo fossil assemblage and its implications as an archive of Ediacaran animal diversity. We find that putative subcellular structures exhibit fabrics consistent with preservation of original morphology. Cells in later developmental stages are not in original configuration and are therefore uninformative concerning gastrulation. Key structures used to identify Doushantuo bilaterians can be dismissed as late diagenetic artefacts. Therefore, when diagenetic mineralization is considered, there is no convincing evidence for bilaterians in the Doushantuo assemblage.

Distinguishing geology from biology in the Ediacaran Doushantuo biota relaxes constraints on the timing of the origin of bilaterians

Theories on the development and evolution of teeth have long been biased by the fallacy that chondrichthyans reflect the ancestral condition for jawed vertebrates. However, correctly resolving the nature of the primitive vertebrate dentition is challenged by a dearth of evidence on dental development in primitive osteichthyans. Jaw elements from the Silurian–Devonian stem-osteichthyans Lophosteus and Andreolepis have been described to bear a dentition arranged in longitudinal rows and vertical files, reminiscent of a pattern of successional development. We tested this inference, using synchrotron radiation X-ray tomographic microscopy (SRXTM) to reveal the pattern of skeletal development preserved in the sclerochronology of the mineralized tissues. The tooth-like tubercles represent focal elaborations of dentine within otherwise continuous sheets of the dermal skeleton, present in at least three stacked generations. Thus, the tubercles are not discrete modular teeth and their arrangement into rows and files is a feature of the dermal ornamentation that does not reflect a polarity of development or linear succession. These fossil remains have no bearing on the nature of the dentition in osteichthyans and, indeed, our results raise questions concerning the homologies of these bones and the phylogenetic classification of Andreolepis and Lophosteus.

Testing models of dental development in the earliest bony vertebrates, Andreolepis and Lophosteus

The objections of Xiao et al. to our reinterpretation are based on incorrect assumptions. The lack of nanocrystals lining the nuclear membrane is consistent with membrane fossilization, and nucleus volume through development is correlated to cytoplasm volume and fully consistent with sizes of eukaryote nuclei. Identical envelope structure unites the developmental stages of the fossils, and 2n cleavage and Y-shaped junctions are holozoan symplesiomorphies.

Response to Comment on “Fossilized Nuclei and Germination Structures Identify Ediacaran ‘Animal Embryos’ as Encysting Protists”

High-resolution imaging of 570-million-year-old fossils suggests that they were not remnants of early animals. Globular fossils showing palintomic cell cleavage in the Ediacaran Doushantuo Formation, China, are widely regarded as embryos of early metazoans, although metazoan synapomorphies, tissue differentiation, and associated juveniles or adults are lacking. We demonstrate using synchrotron-based x-ray tomographic microscopy that the fossils have features incompatible with multicellular metazoan embryos. The developmental pattern is comparable with nonmetazoan holozoans, including germination stages that preclude postcleavage embryology characteristic of metazoans. We conclude that these fossils are neither animals nor embryos. They belong outside crown-group Metazoa, within total-group Holozoa (the sister clade to Fungi that includes Metazoa, Choanoflagellata, and Mesomycetozoea) or perhaps on even more distant branches in the eukaryote tree. They represent an evolutionary grade in which palintomic cleavage served the function of producing propagules for dispersion.

Fossilized Nuclei and Germination Structures Identify Ediacaran “Animal Embryos” as Encysting Protists

Abstract:  Markuelia is a vermiform, annulated introvertan animal known as embryonic fossils from the Lower Cambrian to Lower Ordovician. Analysis of an expanded and revised dataset for Introverta shows that the precise position of Markuelia within this clade is dependent on the taxa included. As a result, Markuelia is assigned to the scalidophoran total group to reflect uncertainty as to whether it is a stem‐scalidophoran or a stem‐priapulid. The taxonomy of the genus is revised to provide an improved taxonomic framework for material assigned to Markuelia. Five species are recognized: M. secunda Val’kov, M. hunanensis Dong and Donoghue, M. lauriei Haug et al., M. spinulifera sp. nov. and M. waloszeki sp. nov. Finally, the preservation of Markuelia is evaluated in the light of both the taphonomy of the fossil embryos themselves and the experimental taphonomy of the priapulid Priapulus caudatus, which has been proposed as both a close relative and an anatomical analogue of Markuelia.

The anatomy, taphonomy, taxonomy and systematic affinity of Markuelia: Early Cambrian to Early Ordovician scalidophorans

Despite widespread interest in the interplay between evolutionary and developmental processes, we still know relatively little about the evolutionary history of larval development. Many clades exhibit multiple shifts from planktotrophic (feeding) to non-planktotrophic (non-feeding) larval development. An important question is whether these switches are scattered randomly through geological history or are concentrated in particular intervals of time. This issue is addressed using the Cretaceous spatangoid sea urchins, which are unusual in that larval strategy can be determined unambiguously from abundantly fossilized adult tests. Using a genus-level phylogeny, we identify five clades of non-planktotrophic taxa, each of which first appears in the fossil record in the Campanian or Maastrichtian (the final two Cretaceous stages). No examples of non-planktotrophy have been identified in any of the earlier stages of the Cretaceous. This strongly suggests that shifts to non-planktotrophic development are clustered in certain episodes of geological history, and this, in turn, implies that extrinsic factors operating at these times are responsible for driving shifts in developmental strategy.

Coordinated shifts to non-planktotrophic development in spatangoid echinoids during the Late Cretaceous

spatangoid echinoids during the Late Cretaceous Coordinated shifts to non-planktotrophic development in

Stomatopods, or mantis shrimps, are malacostracan crustaceans. Known as “lean, mean, killing machines” (Watling et al., 2000, p. 1), modern stomatopods are obligate carnivores, feeding exclusively on live prey (Schram, 1986). Characteristically, their second thoracic appendages are enlarged to form powerful, raptorial claws. Modern stomatopods are divided into two broad functional groups based on the shape and usage of their raptorial claws: ‘spearing’ and ‘smashing’ stomatopods (Caldwell and Dingle, 1976).

Spearing stomatopods are found in each of the seven stomatopod superfamilies (see Ahyong and Harling, 2000; Ahyong, 2001) and spear their prey, which is usually soft-bodied, with the spined terminal forelimb segment (dactyl) of the raptorial claw. Smashing forms are found within four families of the superfamily Gonodactyloidea (although the family Coronodidae within the superfamily Lysiosquilloidea has adaptations for both spearing and smashing). These stomatopods feed mainly on armoured prey such as crabs and gastropods.

There has been a large body of work on the taxonomy, functional morphology and behavior of extant stomatopods. At least 450 extant species have been described (Ahyong, 2001), but the fossil record of the group is poor; less than 30 fossil species from the Mesozoic through the Tertiary, and only four from the Paleozoic have been described (Hof and Briggs, 1997; Jenner et al., 1998). The occurrence of any new fossil material is therefore significant as it contributes important new data to help understand the evolutionary history of the group. In particular, important information can be gained regarding the evolution of spearing and smashing raptorial claws. It should be noted that, in spite of the general paucity of fossil stomatopods, the Miocene of California has previously yielded seven stomatopod specimens. Hof and Schram (1998) have suggested that this abundance, coupled with the demonstration by Hof and Briggs (1997) that stomatopods have …

Lenisquilla Californiensis, A New Species of Stomatopod Crustacean

Sea urchins, like many marine invertebrates, have two major strategies for larval development. Some species have planktotrophic (feeding) larvae, which feed in the water column for a period of weeks to months prior to metamorphosis into a juvenile sea urchin. Other species have nonplanktotrophic (non-feeding) larvae, which are produced in much smaller numbers and do not feed but are instead supplied with nourishment in the form of an egg for the much shorter period they spend prior to metamorphosis. This thesis aims to understand the evolution of these larval modes by focusing on the Cretaceous spatangoid echinoids, where larval mode can be inferred from adult tests, which have an abundant fossil record. The taxonomy of the group was revised in order to ensure that species used in the subsequent analyses are biologically meaningful. Phylogenetic analyses of the species considered valid were then undertaken to provide hypotheses of evolutionary relationships that form the basis of analyses of the evolution of larval strategy. Larval modes were determined for a large number of species. When these data were mapped onto spatangoid phylogeny, non-planktotrophy was shown to have evolved independently on five occasions. The first occurrence of each of the five non-planktotrophic clades is in either the Campanian or Maastrichtian (the final two Cretaceous stages) with no instances of non-planktotrophy prior to the Campanian. There is no support for the hypothesis that non-planktotrophic groups originate preferentially at high latitudes, despite the fact that nonplanktotrophic species are unusually abundant at these latitudes today. Analysis of raw data showed that there is a significant association between non-planktotrophic larval development and both increased speciation rates and reduced species longevity. However, when phylogeny was considered, it was not possible to discount the possibility that significant associations result simply from shared ancestry. No significant associations were identified between larval mode and geographical range, latitude or depth.

The evolution of developmental strategy in Cretaceous spatangoid sea urchins

Embryos from the Ediacaran Doushantuo Formation are among the most astonishing examples of exceptional fossilization. However, the mechanism of fossilization ispoorly understood, leading directly to debate over the interpretation of the fossils, someauthors even questioning their interpretation as embryos. It has been hypothesized thatmicrobial processes are responsible for preservation and mineralization of organic tissues.However, the actions of microbes in preservation of embryos have not been demonstratedexperimentally. We show that bacterial biofilms assemble rapidly in marine embryos,forming detailed pseudomorphs of cellular organization and structure. We define threeessential steps in embryo preservation: 1) blockage of autolysis by reducing or anaerobic conditions; 2) rapid formation of microbial biofilms that consume the embryo butform a replica that retains cell organization and morphology; 3) bacterially-catalyzedmineralization. We identified major bacterial taxa in embryo decay biofilms using16S rDNA sequencing. Decay processes were similar in different taphonomic conditions,but bacterial populations depended on specific conditions. Experimental taphonomyresembles preservation states of fossils. Our data show how fossilization of soft tissues insediments is mediated by bacterial replacement and mineralization, providing a foundationfor experimentally creating biofilms from defined microbial species to model fossilization asa biological process.

Doushantuo fossils are not giant bacteria, but bacterial pseudomorphs of animal embryos

SUMMARY We report new discoveries of embryos and egg capsules from the Lower Cambrian of Siberia, Middle Cambrian of Australia and Lower Ordovician of North America. Together with existing records, embryos have now been recorded from four of the seven continents. However, the new discoveries highlight secular and systematic biases in the fossil record of embryonic stages. The temporal window within which the embryos and egg capsules are found is of relatively short duration; it ends in the Early Ordovician and is roughly coincident with that of typical “Orsten”‐type faunas. The reduced occurrence of such fossils has been attributed to reducing levels of phosphate in marine waters during the early Paleozoic, but may also be owing to the increasing depth of sediment mixing by infaunal metazoans. Furthermore, most records younger than the earliest Cambrian are of a single kind—large eggs and embryos of the priapulid‐like scalidophoran Markuelia. We explore alternative explanations for the low taxonomic diversity of embryos recovered thus far, including sampling, size, anatomy, ecology, and environment, concluding that the preponderance of Markuelia embryos is due to its precocious development of cuticle at an embryonic stage, predisposing it to preservation through action as a substrate on which microbially mediated precipitation of authigenic calcium phosphate may occur. The fossil record of embryos may be limited to a late Neoproterozoic to early Ordovician snapshot that is subject to dramatic systematic bias. Together, these biases must be considered seriously in attempts to use the fossil record to arbitrate between hypotheses of developmental and life history evolution implicated in the origin of metazoan clades.

Fossilized embryos are widespread but the record is temporally and taxonomically biased

Synchrotron X-ray tomographic microscopy of fossil embryos. Nature

Summary The fossil record provides a paucity of data on the development of extinct organisms, particularly for their embryology. The recovery of fossilized embryos heralds new insight into the evolution of development but advances are limited by an almost complete absence of phylogenetic constraint. Markuelia is an exception to this, known from cleavage and pre‐hatchling stages as a vermiform and profusely annulated direct‐developing bilaterian with terminal circumoral and posterior radial arrays of spines. Phylogenetic analyses have hitherto suggested assignment to stem‐Scalidophora (phyla Kinorhyncha, Loricifera, Priapulida). We test this assumption with additional data and through the inclusion of additional taxa. The available evidence supports stem‐Scalidophora affinity, leading to the conclusion that scalidophorans, cyclonerualians, and ecdysozoans are primitive direct developers, and the likelihood that scalidophorans are primitively metameric.

The anatomy, affinity, and phylogenetic significance of Markuelia

The West River bordering New Haven and West Haven, Connecticut, is under evaluation for potential restoration of a former salt marsh. As part of a larger survey of biota associated with this river, the fish fauna was examined in the estuary and adjacent freshwaters. The results provide baseline data for monitoring restoration efforts and indicate the environmental health of the river. The fish communities lacked intolerant species, included significant numbers of individuals of non-native fishes, and showed low abundance and diversity of the native species, all indicating that this stretch of the river represents poor fish habitat with significant ecological disturbances. Some sites contained individuals with excessive parasites, tumors, ulcers, and fin erosion, which suggests physiological stress and potential human health hazards. These problems are localized in the vicinity of combined sewage outflows and/or storm sewer runoff from streets. They are exacerbated by periodic low flow or stagnant waters caused by the tide gates. Salt marsh restoration with tide-gate modification could improve habitat for species with commercial and recreational value and improve movement of diadromous fishes.

Fish Communities as Indicators of Environmental Quality in the West River Watershed

Bone Biopsy (BB) with histomorphometric analysis still represents the gold standard for the diagnosis and classification of different forms of renal osteodystrophy. Bone biopsy is the only technique able to provide comprehensive information on all bone parameters, measuring static and dynamic parameters of turnover, cortical and trabecular microarchitecture, and mineralization defects. In nephrological practice, bone biopsy yields relevant indications to support therapeutic choices in CKD, heavily impacting the management and prognosis of uremic patients. Unfortunately, the use of bone biopsy has decreased; a lack of expertise in performing and interpreting, perceived procedure invasiveness and pain, and reimbursement issues have all contributed to this decline. Nevertheless, both bone biomarkers and instrumental images cannot be considered reliable surrogates for histological findings, being insufficiently accurate to properly evaluate underlying mineral and bone disorders. This is a multidisciplinary position paper from the Nephrology and Osteoporosis Italian Scientific Societies with the purpose of restating the role of bone biopsy in CKD patient management and of providing strong solutions to allow diffusion of this technique in Italy, but potentially also in other countries. The Italian approach through the optimization and standardization of bone biopsy procedure, the construction of the Italian Hub and Spoke network, and a request for adjustment and national homogenization of reimbursement to the Italian Health Ministry has led the way to implement bone biopsy and to improve CKD patient management and prognosis.

Time for Revival of Bone Biopsy with Histomorphometric Analysis in Chronic Kidney Disease (CKD): Moving from Skepticism to Pragmatism

A single-oral bolus of 100,000 IU of cholecalciferol at hospital admission did not improve outcomes in the COVID-19 disease: the COVID-VIT-D—a randomised multicentre international clinical trial

Diagnosis and management of osteoporosis in chronic kidney disease stages 4 to 5D: a call for a shift from nihilism to pragmatism

Is there a role for bisphosphonates in vascular calcification in chronic kidney disease?

Vitamin K2 is a key regulator of clinically relevant molecular processes

Controlling the excessive fracture burden in patients with chronic kidney disease (CKD) Stages G4-G5D remains an impressive challenge. The reasons are 2-fold. First, the pathophysiology of bone fragility in patients with CKD G4-G5D is complex and multifaceted, comprising a mixture of age-related (primary male/postmenopausal), drug-induced and CKD-related bone abnormalities. Second, our current armamentarium of osteoporosis medications has not been developed for, or adequately studied in patients with CKD G4-G5D, partly related to difficulties in diagnosing osteoporosis in this specific setting and fear of complications. Doubts about the optimal diagnostic and therapeutic approach fuel inertia in daily clinical practice. The scope of the present consensus paper is to review and update the assessment and diagnosis of osteoporosis in patients with CKD G4-G5D and to discuss the therapeutic interventions available and the manner in which these can be used to develop management strategies for the prevention of fragility fracture. As such, it aims to stimulate a cohesive approach to the management of osteoporosis in patients with CKD G4-G5D to replace current variations in care and treatment nihilism.

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

European Consensus Statement on the diagnosis and management of osteoporosis in chronic kidney disease stages G4-G5D.

Hyperphosphatemia is a risk factor for vascular calcifications (VCs), which are part of the chronic kidney disease‐mineral and bone disorders (CKD‐MBD). Vitamin K‐dependent proteins such as matrix Gla protein (MGP) and bone Gla proteins (BGP, or osteocalcin) can inhibit VCs and regulate bone mineralization. In this analysis of the Vitamin K Italian (VIKI) study, the relationship between vitamin K status, vertebral fractures (VFs) and VCs in 387 hemodialysis (HD) patients with (N = 163; 42.1%) or without N = 224; 57.9%) sevelamer was evaluated. Levels of vitamin K vitamers K1 and K2 or menaquinones (MK; MK4–7), total and undercarboxylated (uc) forms for both BGP and MGP were determined. Although no differences in clinical characteristics were noted, lower levels of MK4 (0.45 versus 0.6 ng/mL, p = .01) and a greater MK4 deficiency was observed in sevelamer‐treated patients (13.5% versus 5.4%, p = .005). Multivariate logistic regression revealed that MK4 deficiency was associated with sevelamer use (odds ratio [OR] = 2.64, 95% confidence interval [CI] 1.25–5.58, p = .011) and aortic calcification (OR = 8.04, 95% CI 1.07–60.26, p = .04). In the same logistic model, sevelamer amplified the effect of total BGP levels on the odds of VFs in patients with total BGP <150 μg/L compared with those with total BGP ≥150 μg/L (OR = 3.15, 95% CI 1.46–6.76, p = .003). In contrast, there was no such effect in those untreated (total BGP <150 μg/L versus total BGP ≥150 μg/L: OR = 1.21, 95% CI 0.66–2.23, p = .54]; p = .049 for effect modification by sevelamer). Sevelamer may interfere with MK4 levels in HD patients and interact with low BGP levels to increase bone fractures in CKD patients. © 2020 American Society for Bone and Mineral Research (ASBMR).

Sevelamer Use, Vitamin K Levels, Vascular Calcifications, and Vertebral Fractures in Hemodialysis Patients: Results from the VIKI Study

Etelcalcetide Is Effective at All Levels of Severity of Secondary Hyperparathyroidism in Hemodialysis Patients

This article explores the effects of CKD and end-stage kidney disease on magnesium balance. In CKD, there is decreased glomerular filtration of magnesium. Decreased tubular reabsorption can compensate to a degree, but once CKD stage 4 is reached there is a tendency toward hypermagnesemia. In dialysis, magnesium balance is dependent on the constituents of the dialysate that the blood is exposed to. The concentration of dialysate magnesium is just one of the factors that need to be considered. During transplantation, there are particular effects of immunosuppressants that can affect the magnesium balance and need to be considered by the clinician.

The 10th Biennial Hatter Cardiovascular Institute workshop: cellular protection—evaluating new directions in the setting of myocardial infarction, ischaemic stroke, and cardio-oncology

increased mortality and multiple complications including multi-organ failure, shock and fistulization with massive GI bleed. A 60-year-old AAM with a mechanical aortic valve on chronic anticoagulation and a history of alcohol abuse initially presented 2 months prior with acute necrotizing pancreatitis secondary to alcohol abuse. He was treated conservatively with aggressive hydration, pain control and antibiotics and had an uneventful hospitalization. He represented with the acute onset of shortness of breath, nausea, emesis and epigastric pain. Routine labs on admission were notable for an elevated lipase of 417, wbc of 10.7, ALT of 20, AST of 27 and hemoglobin 13.7 g/dL. Hypoxia developed requiring mechanical ventilation along with atrial fibrillation with rapid ventricular response necessitating ICU transfer. He was hemodynamically stabilized and treated aggressive for acute pancreatitis with IVF and narcotic pain medications. Upon transfer from the ICU, he developed worsening epigastric and RUQ pain and melena with a notable decrease in hemoglobin to 6.7 g/dL in the setting of a supratherpeutic INR. A CT pancreas protocol was performed which demonstrated a large pseudocyst measuring 7.3 x 11.4 cm with a large hemorrhagic component, mass effect on the gastric antrum and air present in the head of pancreas without evidence of pseudoaneurysm. His underlying coagulopathy was corrected and an upper endoscopy was performed which found hematin through the stomach and a large fistula in the duodenal bulb with blood/mucin exuding through the tract. A pancreaticoduodenal fistula with associated massive hemorrhage was suspected as the source to his GI bleed. Gastroenterology and pancreaticobiliary surgery were consulted and conservative management was recommended. Pancreaticoduodenal fistula is a rare complication of necrotizing pancreatitis and is associated with massive GI bleeding in 30% of cases. Pancreatic fistulas tend to develop late in the clinical course of severe pancreatitis either from decompression of a pseudocyst or as a complication of phlegmonous pancreatitis. Fistulous communication allows bowel enterokinases to activate pancreatic trypsinogen. Trypsin and other pancreatic enzymes may ultimately result in erosion into nearby vasculature resulting in massive hemorrhage. Treatment is usually conservative. Pancreaticoduodenal fistula should be considered in all patients with recent severe/necrotizing pancreatitis and upper GI bleed.

Clostridium perfringens Bacteremia Caused by Choledocholithiasis

Importance Secondary hyperparathyroidism contributes to extraskeletal calcification and is associated with all-cause and cardiovascular mortality. Control is suboptimal in the majority of patients receiving hemodialysis. An intravenously (IV) administered calcimimetic could improve adherence and reduce adverse gastrointestinal effects. Objective To evaluate the relative efficacy and safety of the IV calcimimetic etelcalcetide and the oral calcimimetic cinacalcet. Design, Setting, and Participants A randomized, double-blind, double-dummy active clinical trial was conducted comparing IV etelcalcetide vs oral placebo and oral cinacalcet vs IV placebo in 683 patients receiving hemodialysis with serum parathyroid hormone (PTH) concentrations higher than 500 pg/mL on active therapy at 164 sites in the United States, Canada, Europe, Russia, and New Zealand. Patients were enrolled from August 2013 to May 2014, with end of follow-up in January 2015. Interventions Etelcalcetide intravenously and oral placebo (n = 340) or oral cinacalcet and IV placebo (n = 343) for 26 weeks. The IV study drug was administered 3 times weekly with hemodialysis; the oral study drug was administered daily. Main Outcomes and Measures The primary efficacy end point was noninferiority of etelcalcetide at achieving more than a 30% reduction from baseline in mean predialysis PTH concentrations during weeks 20-27 (noninferiority margin, 12.0%). Secondary end points included superiority in achieving biochemical end points (>50% and >30% reduction in PTH) and self-reported nausea or vomiting. Results The mean (SD) age of the trial participants was 54.7 (14.1) years and 56.2% were men. Etelcalcetide was noninferior to cinacalcet on the primary end point. The estimated difference in proportions of patients achieving reduction in PTH concentrations of more than 30% between the 198 of 343 patients (57.7%) randomized to receive cinacalcet and the 232 of 340 patients (68.2%) randomized to receive etelcalcetide was −10.5% (95% CI, −17.5% to −3.5%, P for noninferiority, <.001; P for superiority, .004). One hundred seventy-eight patients (52.4%) randomized to etelcalcetide achieved more than 50% reduction in PTH concentrations compared with 138 patients (40.2%) randomized to cinacalcet (P = .001; difference in proportions, 12.2%; 95% CI, 4.7% to 19.5%). The most common adverse effect was decreased blood calcium (68.9% vs 59.8%). Conclusions and Relevance Among patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism, the use of etelcalcetide was not inferior to cinacalcet in reducing serum PTH concentrations over 26 weeks; it also met superiority criteria. Further studies are needed to assess clinical outcomes as well as longer-term efficacy and safety. Trial Registration clinicaltrials.gov Identifier: NCT1896232

Effect of Etelcalcetide vs Cinacalcet on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: A Randomized Clinical Trial

Importance Secondary hyperparathyroidism contributes to extraskeletal complications in chronic kidney disease. Objective To evaluate the effect of the intravenous calcimimetic etelcalcetide on serum parathyroid hormone (PTH) concentrations in patients receiving hemodialysis. Design, Setting, and Participants Two parallel, phase 3, randomized, placebo-controlled treatment trials were conducted in 1023 patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism. Trial A was conducted in 508 patients at 111 sites in the United States, Canada, Europe, Israel, Russia, and Australia from March 12, 2013, to June 12, 2014; trial B was conducted in 515 patients at 97 sites in the same countries from March 12, 2013, to May 12, 2014. Interventions Intravenous administration of etelcalcetide (n = 503) or placebo (n = 513) after each hemodialysis session for 26 weeks. Main Outcomes and Measures The primary efficacy end point was the proportion of patients achieving greater than 30% reduction from baseline in mean PTH during weeks 20-27. A secondary efficacy end point was the proportion of patients achieving mean PTH of 300 pg/mL or lower. Results The mean age of the 1023 patients was 58.2 (SD, 14.4) years and 60.4% were men. Mean PTH concentrations at baseline and during weeks 20-27 were 849 and 384 pg/mL vs 820 and 897 pg/mL in the etelcalcetide and placebo groups, respectively, in trial A; corresponding values were 845 and 363 pg/mL vs 852 and 960 pg/mL in trial B. Patients randomized to etelcalcetide were significantly more likely to achieve the primary efficacy end point: in trial A, 188 of 254 (74.0%) vs 21 of 254 (8.3%; P < .001), for a difference in proportions of 65.7% (95% CI, 59.4%-72.1%) and in trial B, 192 of 255 (75.3%) vs 25 of 260 (9.6%; P < .001), for a difference in proportions of 65.7% (95% CI, 59.3%-72.1%). Patients randomized to etelcalcetide were significantly more likely to achieve a PTH level of 300 pg/mL or lower: in trial A, 126 of 254 (49.6%) vs 13 of 254 (5.1%; P < .001), for a difference in proportions of 44.5% (95% CI, 37.8%-51.2%) and in trial B, 136 of 255 (53.3%) vs 12 of 260 (4.6%; P < .001), for a difference in proportions of 48.7% (95% CI, 42.1%-55.4%). In trials A and B, respectively, patients receiving etelcalcetide had more muscle spasms (12.0% and 11.1% vs 7.1% and 6.2% with placebo), nausea (12.4% and 9.1% vs 5.1% and 7.3%), and vomiting (10.4% and 7.5% vs 7.1% and 3.1%). Conclusions and Relevance Among patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism, use of etelcalcetide compared with placebo resulted in greater reduction in serum PTH over 26 weeks. Further studies are needed to assess clinical outcomes as well as longer-term efficacy and safety. Trial Registration clinicaltrials.gov Identifiers: NCT01788046

Effect of Etelcalcetide vs Placebo on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: Two Randomized Clinical Trials

Pauci Immune crescentic glomerulonephritis in a patient with T-cell lymphoma and argyria

Until the discovery of calcimimetics, the management of secondary hyperparathyroidism (SHPT) relied exclusively on treatment with phosphate binders, vitamin D derivatives or surgical parathyroidectomy with limited success. The therapeutic use of calcimimetic agents, together with a better understanding of the pivotal role of the calcium‐sensing receptor (CaSR) in the physiological regulation of parathyroid gland function, substantially advanced the management of hyperparathyroidism in dialysis practice. Calcimimetics bind selectively to the CaSR receptor in parathyroid tissue and enhance the inhibitory effect of extracellular calcium ions on parathyroid hormone (PTH) secretion, thereby reducing PTH levels even when serum calcium concentrations are normal or low. The availability of calcimimetic agents for clinical use has opened a new era in the management of patients with SHPT. Indeed, calcimimetic compounds have been shown to reduce PTH levels and to lower serum calcium concentrations in all forms of hyperparathyroidism, including primary hyperparathyroidism (PHPT) and parathyroid carcinoma. Such findings underscore the critical importance of the CaSR as a therapeutic target in this family of clinical disorders. New calcimimetic agents are being developed that have the potential to offer improved efficacy and safety compared with currently available calcimimetic compounds.

The Use of Calcimimetics for the Treatment of Secondary Hyperparathyroidism: A 10 Year Evidence Review

Review for "Non‐Additive Effects of combined NOX1 /4 inhibition and calcimimetic treatment on a rat model of chronic kidney disease‐mineral and bone disorder ( CKD‐MBD )"

Effect of remote ischaemic conditioning on contrast-induced nephropathy in patients undergoing elective coronary angiography (ERICCIN): rationale and study design of a randomised single-centre, double-blind placebo-controlled trial

The discovery of fibroblast growth factor-23 (FGF-23) as a key regulator of phosphate and vitamin D metabolism has forced a rethink about the mineral and bone disorder of chronic kidney disease (CKD). FGF-23 powerfully predicts adverse cardiovascular outcomes in patients with CKD and an important question is whether treatment regimens should now be tailored to address FGF-23 levels in addition to those of calcium, phosphate, parathyroid hormone and vitamin D. Nevertheless, despite the known action of active vitamin D therapies to increase FGF-23, this should probably still form an important part of the management of patients with hyperparathyroidism and perhaps at low doses of essentially all patients with advanced renal disease.

The kidney has a vital role in magnesium homeostasis and, although the renal handling of magnesium is highly adaptable, this ability deteriorates when renal function declines significantly. In moderate chronic kidney disease (CKD), increases in the fractional excretion of magnesium largely compensate for the loss of glomerular filtration rate to maintain normal serum magnesium levels. However, in more advanced CKD (as creatinine clearance falls <30 mL/min), this compensatory mechanism becomes inadequate such that overt hypermagnesaemia develops frequently in patients with creatinine clearances <10 mL/min. Dietary calcium and magnesium may affect the intestinal uptake of each other, though results are conflicting, and likewise the role of vitamin D on intestinal magnesium absorption is somewhat uncertain. In patients undergoing dialysis, the effect of various magnesium and calcium dialysate concentrations has been investigated in haemodialysis (HD) and peritoneal dialysis (PD). Results generally show that dialysate magnesium, at 0.75 mmol/L, is likely to cause mild hypermagnesaemia, results for a magnesium dialysate concentration of 0.5 mmol/L were less consistent, whereas serum magnesium levels were mostly normal to hypomagnesaemic when 0.2 and 0.25 mmol/L were used. While dialysate magnesium concentration is a major determinant of HD or PD patients’ magnesium balance, other factors such as nutrition and medications (e.g. laxatives or antacids) also play an important role. Also examined in this review is the role of magnesium on parathyroid hormone (PTH) levels in dialysis patients. Although various studies have shown that patients with higher serum magnesium tend to have lower PTH levels, many of these suffer from methodological limitations. Finally, we examine the complex and often conflicting results concerning the interplay between magnesium and bone in uraemic patients. Although the exact role of magnesium in bone metabolism is unclear, it may have both positive and negative effects, and it is uncertain what the optimal magnesium levels are in uraemic patients.

Magnesium in chronic kidney disease Stages 3 and 4 and in dialysis patients

Mineral metabolism and vitamin D in chronic kidney disease—more questions than answers

Secondary hyperparathyroidism (SHPT) is a challenge frequently encountered in the management of patients with chronic kidney disease (CKD). Downregulation of the parathyroid vitamin D and calcium-sensing receptors represent critical steps that lead to abnormalities in mineral metabolism: high phosphate, low calcium, and vitamin D deficiency. These imbalances result in parathyroid hyperplasia and contribute to vascular calcification. New studies have established a central role for fibroblast growth factor 23 (FGF-23) in the regulation of phosphate-vitamin D homeostasis. FGF-23 concentration increases in CKD and contributes to SHPT. Achieving current targets for the key mineral parameters in the management of SHPT set by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines can be challenging. This review summarizes the current understanding and evidence supporting strategies for SHPT treatment in CKD patients. Treatment should include a combination of dietary phosphorus restriction, phosphate binders, vitamin D sterols, and calcimimetics. Parathyroidectomy is effective in suitable candidates refractory to medical therapy and the standard against which new approaches should be measured. Future strategies may focus on the stimulation of apoptotic activity of hyperplastic parathyroid cells.

Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options.

Dr. Kyle Staller (Medicine): A 62-year-old woman was admitted to this hospital because of renal failure. The patient had an autoimmune overlap syndrome with polymyositis, treated with prednisone and mycophenolate mofetil, but had been in her usual health until 6 weeks before admission, when she noted increasing skin tightness around her mouth, dry mouth, difficulty swallowing, worsening gastroesophageal reflux, hair loss, and discoloration of her fingers, which were ash-colored, painful, and cool. Prednisone was increased from 10 to 20 mg daily, without improvement. Four days before admission, the patient was found on the floor of her bathroom, confused and minimally conversant, and was taken to another hospital. The day before admission to the other hospital, the patient had reported some weakness and no other symptoms. On examination, the temperature was 35.9°C, the blood pressure 175/99 mm Hg, the pulse 84 beats per minute, and the respiratory rate 17 breaths per minute. The patient was awake, with slow responses, and oriented to person only. The skin around the mouth and on the fingers was tight, and there was muscle wasting of the neck. On neurologic examination, she followed simple commands inconsistently, with psychomotor slowing, a decreased ability to name objects, and an inability to read or to repeat words spoken to her. Her face was symmetric, with possible mild weakness on the right side. Muscle strength was 4 out of 5 or better (with 5 indicating normal strength), with mild asterixis bilaterally. Levels of vitamin B12, folate, and glycated hemoglobin were normal, as were tests of coagulation and thyroid function; other laboratory-test results are shown in Table 1. Urinalysis revealed yellow, cloudy urine with a pH of 5.5 and a specific gravity of 1.016; a screening dipstick test showed a large amount of blood, 15 mg of ketones per deciliter, 300 mg of protein per deciliter, and 0.2 mg of urobilinogen per deciliter. Microscopical examination of the urine revealed 1 to 2 hyaline casts per lowpower field, as well as 37 white cells and no red cells per high-power field. A chest radiograph reportedly showed basilar consolidation in the right lung, a small pleural effusion on the right side, and increased interstitial markings bilaterally, which were thought to be chronic. Computed tomography (CT) of the head without the administration of contrast material revealed hyperdensities adjacent Case 30-2011: A 62-Year-Old Woman with Renal Failure

Case records of the Massachusetts General Hospital. Case 30-2011. A 62-year-old woman with renal failure.

Chronic kidney disease-bone and mineral disorder (CKD-MBD) signifies the complex pathophysiological interactions between calcium, phosphorus and regulatory hormones which are associated, sometimes causally, with impaired bone mineralisation and increased fracture risk in patients with CKD. It also signifies a predisposition to vascular calcification (VC), the emergence of which as a likely side effect of some of the current therapies poses a difficult problem for physicians aiming to treat patients with CKD. This complex disorder has seen several important advances in relation to understanding of the pathophysiology and, it is hoped, refinement of therapeutic approaches.

Vitamin D therapies used in the management of dialysis patients may be given either as native vitamin D or as one of several different active vitamin D compounds. Throughout this article a clear distinction will bemade between these different therapies. Many dialysis patients are deficient in native vitamin D and all have complete or relative deficiency of the active hormonal form of vitaminD, namely calcitriol. In dialysis patients there is, therefore, a high probability that at least one, and in many cases two, vitamin D compounds will be needed if deficiency is to be avoided. Contraindications to the use of these compounds are usually relative rather than absolute and, as with any therapeutic intervention, need to be set against the perceived benefits of the proposed therapy.

Opinion: When is Vitamin D Contraindicated in Dialysis Patients?

Transplantation: Supplemental vitamin D: will do no harm and might do good

Management of mineral and bone disorders in chronic kidney disease.

Abstract: Pancreas graft thrombosis is one of the commonest non‐immunological causes for early graft loss after transplantation. This case report describes a patient who developed graft thrombosis after intravenous immunoglobulin administration to treat acute parvovirus B19 infection. The potential role of hypercoagulability in graft thrombosis and the implications for immunoglobulin therapy in transplant patients with hypercoagulable states is discussed.

Pancreas allograft thrombosis following intravenous immunoglobulin administration to treat parvovirus B19 infection

This issue of the journal contains the first of a series of articles that will review the accuracy and utility of various key sets of clinical guidelines in nephrology. These reviews will not constitute guidelines in their own right and will certainly not aim to provide an overview of the topic in question. Instead, they will provide critical reviews of guidelines that are already in the public domain. The reviews will be written taking account of the perspective of the user of clinical guidelines and inevitably this will in some instances result in a degree of detachment from the vantage point of, and disagreement with, those colleagues involved in writing guidelines. Authors have been encouraged not to hold back from explicit criticism, provided that the criticism can be justified by the literature or, where the literature is inadequate, by sensible opinion. Conversely, the reviews will also emphasise the credibility of existing guidelines where appropriate. The initial subjects to be covered are: detection of CKD, anaemia, blood pressure, lipids, and finally mineral and bone disease. All the articles will provide information as to the nature of the guidelines already available and how they can be accessed. Guidelines will be summarised briefly, but not exhaustively. The heart of these reviews will be the critique of guidelines with emphasis on their general usefulness, or lack thereof, to the practicing physician confronting clinical problems. Authors of the reviews have been asked to highlight areas of conspicuous shortfall and to emphasise the need for remedial work or relevant new studies. Guideline development is a very important area of our specialty, powerfully influencing practice and, where well done, providing a major force for good. The converse is also true – poorly drafted, misleading guidelines can be counterproductive with considerable potential to retard or misdirect the evolution of clinical practice. We hope that this series of critiques will facilitate the effort. Published online: October 16, 2008

Cinacalcet, a type II calcimimetic agent that interacts with the calcium-sensing receptor on the parathyroid gland and increases its sensitivity to calcium, has proved an effective therapy for the treatment of the biochemical derangements that comprise uraemic secondary hyperparathyroidism. These patients experience high cardiovascular attrition with evidence that this is associated with vascular calcification, arterial stiffening and increased pulse wave velocity, and with some of the disturbances of bone and mineral metabolism in uraemia. Thus, it is possible that improved biochemical control in calcimimetic-treated patients might lead to better clinical outcomes. This hypothesis was investigated by retrospective analyses of randomized placebo-controlled phase 3 studies. The addition of cinacalcet to standard therapy with active vitamin D and phosphate binders was found to result in a 93% reduction in the rate of parathyroidectomy, a 54% reduction in fracture rate and 39% reduction in the rate of cardiovascular hospitalization, as well as improvements in some measures of quality of life. These encouraging results point to the need for a more robust assessment of the impact of cinacalcet on cardiovascular and skeletal outcomes.

Clinical Outcomes in Secondary Hyperparathyroidism and the Potential Role of Calcimimetics

Chapter 28. Vitamin D: Production, Metabolism, Mechanism of Action, and Clinical Requirements

OBJECTIVE
To evaluate the effectiveness of a protocol designed to optimize serum phosphate levels in patients undergoing regular hemodialysis (HD).

DESIGN
Randomized, controlled trial.

SETTING
Hemodialysis units at Barts and the London NHS Trust and satellite units.

PATIENTS
Thirty-four clinically stable adults undergoing regular HD with a serum phosphate level >1.8 mmol/L on at least one occasion within 4 months of starting the study.

Management of serum phosphate using a specially designed phosphate management protocol during a 4-month study period implemented by a renal dietitian and renal pharmacist compared with standard practice.

Change in serum phosphate levels in both groups after 4 months.

RESULTS
Patients managed using the phosphate management protocol had a significantly greater reduction in serum phosphate levels compared with patients receiving standard practice (-0.22 +/- 0.67 mmol/L vs. +0.19 +/- 0.32 mmol/L, P = 0.03).

The phosphate management protocol was effective, and its implementation was associated with significantly better serum phosphate control in patients undergoing regular HD.

Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation

Evaluation of a phosphate management protocol to achieve optimum serum phosphate levels in hemodialysis patients.

Nephrogenic systemic fibrosis (NSF) was recently linked to gadolinium‐based contrast (GBC) exposure in patients with renal failure. As result, the U.S. Food and Drug Administration (FDA), the UK Commission on Human Medicines (CHM) and the European Pharmacovigilance Working Party Committee for Medicinal Products for Human Use (CHMP) recommended that GBC should be avoided in patients with advanced renal failure (GFR < 30 ml/minute/1.73 m2). Ones initial reaction is to advise avoidance of GBC exposure in patients with any level of kidney disease to prevent this awful complication. However, this approach is not based on data nor is it practical for patients who would benefit from this diagnostic modality. Thus, while complete avoidance cannot currently be advocated, GBC‐enhanced MRI in renal impairment should be reserved for neurological and vascular cases where the quality of information gained is sufficient to justify the risk of potential devastating adverse effects of NSF.

NSF: WHAT WE KNOW AND WHAT WE NEED TO KNOW: Nephrogenic Systemic Fibrosis: A Sufficient Reason to Avoid Gadolinium‐Based Contrast in All Patients with Renal Impairment?

The parathyroid-calcium (Ca(2+)-PTH) curve expresses modulation of parathyroid hormone (PTH) secretion by the parathyroid gland as a function of changing extracellular Ca(2+) concentration. Patients with hyperparathyroidism (HPT) show a rightward shift of the curve compared with controls, suggesting a reduced sensitivity of parathyroid cells to Ca(2+). Increasing the sensitivity of the parathyroid gland to extracellular Ca(2+) by manipulation of the Ca(2+)-sensing receptor (CaR) may have therapeutic potential. Calcimimetics allosterically modify CaR and render it more sensitive to extracellular Ca(2+), accounting for the simultaneous reduction of Ca(2+) and PTH seen in most patients.

METHODS
The Ca(2+)-PTH curve was evaluated in 10 haemodialysis patients, with baseline intact PTH levels >300 pg/ml in two haemodialysis sessions, one before and the other after (range, 9-22 weeks) cinacalcet treatment. In each session a 2-h low-dialysate Ca(2+) concentration was used to induce hypocalcaemia and maximally stimulate PTH secretion, followed immediately by a 2-h high-dialysate Ca(2+) concentration to induce hypercalcaemia and maximally inhibit PTH secretion.

RESULTS
Significant decreases in ionized Ca(2+) and intact PTH were observed following cinacalcet treatment. Cinacalcet treatment also led to a decrease in the set point for Ca(2+) and to a leftward shift of the Ca(2+)-PTH curve. Significant differences were present in all segments of the Ca(2+)-PTH curves.

The pathological rightward shift of the Ca(2+)-PTH curve seen in many HPT patients may be reversed by cinacalcet treatment.

Calcium-mediated parathyroid hormone release changes in patients treated with the calcimimetic agent cinacalcet.

Vitamin D status and bone mass in UK South Asian women references

many questions that require further study. For example, would patients with residual kidney function on dialysis benefit from ergocalciferol ‘‘loading,’’ much as we do with iron? Would this then make 1,25(OH)2 vitamin D levels rise, and result in a fall in PTH levels?Would dialysis patients’ muscular function benefit from replacing 25(OH) vitamin D? This would need to be studied in a double-blinded randomized controlled trial and should include an objective measure of strength such as hand grip. Would replacement of 25(OH) vitamin D deficiency in dialysis patients result in better immunologic functioning resulting in lower risk of infection or development of cancer? Would correction of vitamin D deficiency in dialysis patients have a beneficial effect on vascular calcification? These latter questions would require a very large number of patients to study. To summarize, there are insufficient studies on replacing 25(OH) vitamin D deficiency in dialysis patients. Deficiency is common, especially in peritoneal dialysis patients, and correction is safely achieved with ergocalciferol 50,000 IU/week for 4 weeks or longer. However, the impact of this on muscle strength, bone abnormalities, immune functioning, and vascular calcification require further study. It is time for a placebo-controlled double-blinded study to assess the safety, efficacy, and utility of treating 25(OH) vitaminDdeficiency in dialysis patients. What should we do until such studies are available? Each of us will have to make that decision – ours is to monitor 25(OH) vitamin D levels and replete as necessary.

Opinion: Which of the K/DOQI Guidelines for Bone Disease in Dialysis Patients Should Be Changed?

The coexistence of kidney disease with a need for immunosuppressive therapy leads to the convergence of several threats to bone. These comprise general effects of the primary disease, e.g., inflammatory state, more specific effects of acute renal failure or chronic kidney disease, and effects of therapies. Multisystem inflammatory disease that requires immunosuppression is associated frequently with kidney damage, and any reduction of kidney function that takes the patient into or beyond chronic kidney disease stage 2 for more than a short time is likely to have a negative impact on bone health. Bone mineral density frequently is low and fracture rates are high, although correlations often are poor. Chronic inflammation leads to local and systemic imbalance between bone formation and resorption. Upregulation of NF-kappabeta ligand (RANKL) and variable downregulation of osteoprotegerin are implicated, and bone health may improve in response to treatment of the inflammatory state. Certain immunosuppressive agents, especially glucocorticoids and calcineurin inhibitors, contribute further to bone loss. Antiresorptive agents such as bisphosphonates are used widely and, although able to prevent loss of bone mineral density, have uncertain effects on fracture rates. Augmentation of anabolic activity is desirable but elusive. Synthetic parathyroid hormone is untested but has potential. Manipulation of the RANKL/osteoprotegerin system now is feasible using antibodies to RANKL or synthetic osteoprotegerin. In the future, manipulation of the calcium-sensing receptor using calcimimetic or calcilytic agents may allow the anabolic effects of parathyroid hormone to be harnessed to good effect. With all of these therapies, it will be important to assess response in relation to important clinical end points such as fracture.

Pathogenesis and prevention of bone loss in patients who have kidney disease and receive long-term immunosuppression.

Report of the clinical protocol committee: development of randomized trials for malignant bowel obstruction.

Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO).

REDUCING BLOOD TRANSFUSION IN DIALYSIS UNIT Ruth Yang, John Cunningham, John Connolly & Colley Crawford London UK Blood transfusions are generally detrimental to dialysis patients and should be avoided when possible (Daugirdas J 1994). The risks for patients, including: ABO incompatibility; anaphylactic reaction; transmission of virus infection such as hepatitis B,C or HIV; jeopardy of a prospect for renal transplantation. The dialysis unit has 110 patients. In 2002, 386 blood transfusion units were used. In 2003,we introduced a blood transfusion recording system aiming to monitor and reduce blood transfusion for the dialysis patients. It includes: 1) Introduction of Blood Transfusion Request form filled by doctors. It indicates the reason to prescribe. 2) Introduction of Blood Transfusion Record form filled by nurse for each transfusion. It includes date, patients name, HB, blood units and name of the doctor who prescribes. 3) Introduction of Blood Transfusion Folder. Both forms above are kept in it. The Anaemia co-ordinator produces an on going monthly audit of blood transfusion according to the data. A monthly anaemia review meeting is held between the nephrologists consultants, dialysis unit registrar and anaemia coordinator by using 1) a chart of all dialysis patients’ current Epo dose, monthly HB, MCV, HCT, reticulocyte count, fe, IBS, ferritin and CRP; 2) a trend record of HB and Epo dose for every patient on a monthly basis; 3) a chart with a graph indicating continuing Hb results according to the UK Renal Association, European Best Practice Guide and K/DOQI standards; 4) a chart with a graph indicating a correlation between average HB, average Epo dosage and blood transfusion each month. The result appeared encouraging. Blood transfusion has reduced by 62% in two yeas. Time Blood Transfusion units % 0 0 1 4 8 3 2 0 0 2 % 8 5 5 2 2 3 0 0 2 % 8 3 6 4 1 4 0 0 2 2005 140 36%

Medical management of secondary hyperparathyroidism lessons from renal disease

Camelford water incident aluminium sulphate: retrospective study of the exposed to drinking water contaminated with Disturbance of cerebral function in people

Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy

Early use of cinacalcet (MIMPARA (R)/SENSIPAR (R)) in dialysis patients enables greatest achievement of NKF-KDOQI (TM) treatment targets for bone metabolism

Secondary hyperparathyroidism (HPT) and abnormal mineral metabolism are thought to play an important role in bone and cardiovascular disease in patients with chronic kidney disease. Cinacalcet, a calcimimetic that modulates the calcium-sensing receptor, reduces parathyroid hormone (PTH) secretion and lowers serum calcium and phosphorus concentrations in patients with end-stage renal disease (ESRD) and secondary HPT.

METHODS
We undertook a combined analysis of safety data (parathyroidectomy, fracture, hospitalizations, and mortality) from 4 similarly designed randomized, double-blind, placebo-controlled clinical trials enrolling 1184 subjects (697 cinacalcet, 487 control) with ESRD and uncontrolled secondary HPT (intact PTH > or =300 pg/mL). Cinacalcet or placebo was administered to subjects receiving standard care for hyperphosphatemia and secondary HPT (phosphate binders and vitamin D). Relative risks (RR) and 95% CI were calculated using proportional hazards regression with follow-up times from 6 to 12 months. Health-related quality-of-life (HRQOL) data were obtained from the Medical Outcomes Study Short Form-36 (SF-36), and the Cognitive Functioning scale from the Kidney Disease Quality of Life instrument (KDQOL-CF).

RESULTS
Randomization to cinacalcet resulted in significant reductions in the risk of parathyroidectomy (RR 0.07, 95% CI 0.01-0.55), fracture (RR 0.46, 95% CI 0.22-0.95), and cardiovascular hospitalization (RR 0.61, 95% CI 0.43-0.86) compared with placebo. Changes in HRQOL favored cinacalcet, with significant changes observed for the SF-36 Physical Component Summary score and the specific domains of Bodily Pain and General Health Perception.

Combining results from 4 clinical trials, randomization to cinacalcet led to significant reductions in the risk of parathyroidectomy, fracture, and cardiovascular hospitalization, along with improvements in self-reported physical function and diminished pain. These data suggest that, in addition to its effects on PTH and mineral metabolism, cinacalcet had favorable effects on important clinical outcomes.

Effects of the calcimimetic cinacalcet HCl on cardiovascular disease, fracture, and health-related quality of life in secondary hyperparathyroidism.

[Present status and problems in vitamin D and sevelamer therapy (discussion)].

The last decade has been a remarkably productive one in the field of bone biology. New insights into the maintenance of a normal bone microenvironment have led to significant advances in our understanding of many important skeletal disorders, including renal osteodystrophy. Novel targets for therapeutic manipulation have been exposed and encouraging progress made towards new treatments. In addition, just as clinical studies have alerted us to the potential hazards of vascular calcification, basic science has unearthed the intimate nature of the relationship between the previously separate disciplines of bone and vascular biology. The clinical nephrologist, however, may be forgiven a little cynicism at this point. If such progress has been made, why do the same proverbial difficulties confront us in day-to-day practice? Control of phosphate remains inadequate, despite a literature which constantly reaffirms its crucial importance, and parathyroid hyperplasia seems inevitable in many patients. Furthermore, even the satisfaction of successful control of serum parathyroid hormone concentration must now be tempered by disquiet regarding the skeletal and cardiovascular consequences of oversuppression. This review aims to provide an update of the latest developments in relevant skeletal research and to assess how recently acquired knowledge may improve clinical nephrological practice over the next five years.

Patients with secondary hyperparathyroidism often require therapy that provides long-term control of parathyroid hormone concentrations without increasing calcium and phosphorus concentrations. Cinacalcet modulates the calcium-sensing receptor on the parathyroid gland to reduce secretion of parathyroid hormone and lower serum calcium, phosphorus and calcium-phosphorus product in haemodialysis patients.

METHODS
Dialysis patients with secondary hyperparathyroidism [parathyroid hormone (PTH) level > or =300 pg/ml] who were enrolled in one of four phase 2 placebo-controlled studies were eligible to enroll in an open-label extension study in which all patients received cinacalcet. For this extension study, cinacalcet was initiated at 30 mg in all patients and the dose was escalated to a maximum of 180 mg once daily if PTH concentrations were >250 pg/ml. Use of concomitant vitamin D sterols and phosphate binders was not restricted.

RESULTS
The analysis of all patients (n = 59) completing 100 weeks of cinacalcet treatment showed long-term control of PTH and calcium-phosphorus product. Approximately 55% achieved a PTH concentration < or =300 pg/ml at the week-100 study visit, and approximately 60% had at least a 30% reduction in PTH from baseline. Serum calcium, phosphorus and the calcium-phosphorus product did not increase during the study. Concomitant vitamin D sterol and phosphate binder therapy remained stable. Cinacalcet was safe and generally well tolerated at doses up to 180 mg/day.

In this long-term study, cinacalcet effectively sustained reductions in PTH for up to 3 years without increasing concentrations of serum calcium, phosphorus or calcium-phosphorus product.

Long-term treatment of secondary hyperparathyroidism with the calcimimetic cinacalcet HCl.

Transplanted patients experience rapid loss of bone, high fracture rates, and increases in morbidity and mortality as a consequence of a posttransplant scenario that is highly deleterious to the skeleton. Immune suppressive drugs, especially glucocorticoids, are toxic to bone, often acting on a background of preexisting osteodystrophy resulting from long-standing renal, hepatic, cardiac, or pulmonary disease. Cyclosporin and tacrolimus lead to a severe osteopenic state in rats, but the skeletal toxicity of the calcineurin inhibitors in the clinical environment is less clear. Nor is it clear whether cyclosporin and tacrolimus differ in their skeletal actions. Mycophenolate mofetil and sirolimus do not appear to have important skeletal toxicity. Preventative strategies include minimizing glucocorticoid exposure and implementing therapies to counter the increase in bone resorption and decrease in bone formation that follows transplantation. Antiresorptive agents, especially bisphosphonates, appear capable of retarding or halting the early bone loss and possibly reduce fracture rates also. Vitamin D and calcium are ineffective, but calcitriol has utility in some reports. Bone anabolic agents, such as synthetic parathyroid hormone and growth hormone, have potential, but data are lacking.

Abstract:  Secondary hyperparathyroidism (SHPT) remains an inevitable consequence of untreated chronic uremia. It is the result of a combination of phosphate (P) retention, failure of calcitriol synthesis, and hypocalcemia. Therapies used to correct these abnormalities, namely active vitamin D replacement, calcium (Ca) supplementation, and phosphate (P) restriction, have moderate efficacy but are prone to unacceptable side‐effects. However, there have been new developments in the control of P, vitamin D replacement and modulation of the Ca sensing receptor (CaSR) using calcimimetics. Sevelamer, and in the near future lanthanum, are offering a reasonable level of P control without the toxicities inherent with either aluminum‐ or Ca‐based phosphate binders, and other phosphate binders are in development. ‘Non calcemic’ vitamin D metabolites include 22‐oxacalcitriol, paricalcitol, and doxercalciferol. In various experimental models 22‐oxacalcitriol, in particular, exhibits impressive suppression of parathyroid hormone (PTH) with minimal calcemia, although it has been less impressive when compared with calcitriol in controlled studies in hemodialysis (HD) patients. The advantages of these agents over conventional treatment with calcitriol or alfacalcidol remain uncertain. Cinacalcet, a calcimimetic agent that up‐regulates the sensitivity of the CaSR in parathyroid and other cells, is a new type of therapy for SHPT that simultaneously reduces the concentrations of PTH, Ca, and P in HD patients, enabling a significant number to achieve K/DOQI or other national guidelines. The extent to which this new therapy will improve clinical outcomes remains uncertain. In conclusion, with the advent of new therapies the emphasis in the management of SHPT has evolved to incorporate reduction of Ca loading, control of PTH within specific target ranges, and avoidance of hypercalcemia, hyperphosphatemia and elevation of the calcium phosphorus product.

Benzene increases protein-bound 3-nitrotyrosine in bone marrow of B6C3F1 mice.

The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF-K/DOQItrade mark) has established guidelines for treatment of secondary hyperparathyroidism (HPT). The ability of cinacalcet HCl (Sensipartrade mark) treatment to improve achievement of target levels of parathyroid hormone (PTH), calcium, phosphorus, and calcium-phosphorus product (Ca x P) was investigated in subjects on dialysis with secondary HPT.

METHODS
Data were combined from three placebo-controlled, double-blind, 26-week studies with similar design that randomized 1136 subjects on dialysis to receive traditional therapy plus cinacalcet or placebo. Oral cinacalcet was titrated from 30 to 180 mg/day. Achievement of K/DOQI goals was determined for each treatment group overall and for subgroups defined by baseline intact PTH (iPTH) and Ca x P levels.

RESULTS
Cinacalcet-treated subjects were more likely to achieve a mean iPTH </=300 pg/mL (31.8 pmol/L) than were control subjects on traditional therapy (56% vs. 10%, P < 0.001). Cinacalcet-treated subjects were more likely to achieve concentrations of serum calcium within 8.4 to 9.5 mg/dL (2.10-2.37 mmol/L) and serum phosphorus within 3.5 to 5.5 mg/dL (1.13-1.78 mmol/L) than were control subjects (49% vs. 24% and 46% vs. 33%, P < 0.001 for each). Cinacalcet also improved achievement of Ca x P < 55 mg(2)/dL(2) (4.44 mmol(2)/L(2)) and concurrent achievement of Ca x P < 55 mg(2)/dL(2) (4.44 mmol(2)/L(2)) and iPTH </=300 pg/mL (31.8 pmol/L) (65% vs. 36% and 41% vs. 6%, P < 0.001 for each).

In subjects on dialysis with secondary HPT, cinacalcet facilitates achievement of the K/DOQI-recommended targets for PTH, calcium, phosphorus, and Ca x P.

Achieving NKF-K/DOQI bone metabolism and disease treatment goals with cinacalcet HCl.

Benzene, a constituent of cigarette smoke, is a human leukemogen and induces bone marrow toxicity. The mechanism of benzene-induced toxicity is not well-established. We hypothesized that relatively high levels of nitric oxide formed in bone marrow can react with oxygen and/or superoxide anion that is generated during redox cycling of ring-hydroxylated benzene metabolites to yield peroxynitrite as well as other NO-derived intermediates. Peroxynitrite can either directly damage cellular macromolecules or form nitrated toxic metabolites. Toward this end, we investigated whether nitro derivatives of benzene are formed in bone marrow of mice treated with benzene. First, we have characterized products formed during activation of benzene in Fenton's system in the absence or presence of NO-releasing compound in vitro by GC/MS. The result of above experiment prompted us to determine whether similar products can be formed in vivo. Groups of B6C3F1 male mice, eight weeks of age, were given a single intraperitoneal dose of [14C]benzene (400 mg/kg body wt, 9.7 mCi/mmol) or an equal dose of unlabeled benzene in corn oil, and the mice were killed 0.5 or 1 h posttreatment. The control group received only vehicle injections. Organic solvent extractable metabolites from bone marrow, liver, lungs, and blood of mice treated with [14C]benzene were identified by comparison of their respective retention times under two different HPLC conditions with authentic standard samples. These metabolites were further characterized by comparison of their GC/MS properties to those of reference standards. Nitro metabolites, namely, nitrobenzene, nitrobiphenyl, and nitrophenol isomers, were detected in the bone marrow of the mice 1 h after benzene treatment. Formation of nitro derivatives in other tissues was either not observed or was significantly less than that formed in bone marrow. This study clearly demonstrates that nitric oxide is a contributor to benzene metabolism and can form nitrated derivatives that may, in part, account for bone marrow toxicity.

Detection of nitrated benzene metabolites in bone marrow of B6C3F1 mice treated with benzene.

Treatment of secondary hyperparathyroidism with vitamin D and calcium in patients receiving dialysis is often complicated by hypercalcemia and hyperphosphatemia, which may contribute to cardiovascular disease and adverse clinical outcomes. Calcimimetics target the calcium-sensing receptor and lower parathyroid hormone levels without increasing calcium and phosphorus levels. We report the results of two identical randomized, double-blind, placebo-controlled trials evaluating the safety and effectiveness of the calcimimetic agent cinacalcet hydrochloride.

METHODS
Patients who were receiving hemodialysis and who had inadequately controlled secondary hyperparathyroidism despite standard treatment were randomly assigned to receive cinacalcet (371 patients) or placebo (370 patients) for 26 weeks. Once-daily doses were increased from 30 mg to 180 mg to achieve intact parathyroid hormone levels of 250 pg per milliliter or less. The primary end point was the percentage of patients with values in this range during a 14-week efficacy-assessment phase.

RESULTS
Forty-three percent of the cinacalcet group reached the primary end point, as compared with 5 percent of the placebo group (P<0.001). Overall, mean parathyroid hormone values decreased 43 percent in those receiving cinacalcet but increased 9 percent in the placebo group (P<0.001). The serum calcium-phosphorus product declined by 15 percent in the cinacalcet group and remained unchanged in the placebo group (P<0.001). Cinacalcet effectively reduced parathyroid hormone levels independently of disease severity or changes in vitamin D sterol dose.

Cinacalcet lowers parathyroid hormone levels and improves calcium-phosphorus homeostasis in patients receiving hemodialysis who have uncontrolled secondary hyperparathyroidism.

Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.

Osteoblast-derived interleukin-6 (IL-6) affects bone metabolism and is linked with a number of pathological states characterized by increased bone resorption, including osteoporosis and renal osteodystrophy. To examine the possibility that uraemia directly influences the release of this cytokine in bone, we have investigated the effect of human uraemic serum on the release of IL-6 from human osteoblast-like cells.

METHODS
Individual serum samples collected from healthy male volunteers or male haemodialysis patients prior to and during a dialysis treatment were assayed for IL-6, interleukin-1beta (IL-1beta) and soluble IL-6 receptor (sIL-6R) using specific enzyme-linked immunosorbent assays. MG-63 and SaOS-2 cells were cultured in media containing pooled sera from both groups and alongside matching charcoal-stripped sera. IL-6 concentrations were determined in harvested cell supernatants after 24 h. In further experiments, media containing individual sera obtained from five patients at regular intervals during their haemodialysis treatment were incubated with MG-63 cells to determine the effects of the dialysis process on IL-6 secretion.

RESULTS
Haemodialysis patients had significantly higher (n = 10, P < 0.001) circulating concentrations of IL-6 (7.0 +/- 1.6 pg/ml) than normal subjects (0.4 +/- 0.1 pg/ml), but there were no significant differences in the concentrations of either IL-1beta or sIL-6R. These serum concentrations did not change significantly during 80 min of dialysis. IL-6 release by MG-63 cells incubated with charcoal-stripped serum from normal or from uraemic subjects was similar. Incubation with untreated sera from normal subjects increased IL-6 release by approximately 6-fold above the charcoal-stripped control, whereas sera from uraemic subjects increased IL-6 release by only approximately 2- to 3-fold (normal vs uraemic of 6878 +/- 595 and 2579 +/- 169 pg/ml, respectively, P < 0.001). Similar results were seen with SaOS-2 cells. Haemodialysis did not restore the capacity of uraemic serum to augment IL-6 release to the same degree as normal serum.

These data show that the augmentation of IL-6 release from human osteoblastic cells after incubation with normal serum is greater than after uraemic serum. This may indicate the presence of an inhibitor of IL-6 release in uraemic serum that is involved in the deranged bone turnover of uraemic patients.

Impaired release of interleukin-6 from human osteoblastic cells in the uraemic milieu.

Disturbances in the control of extracellular ionized calcium and phosphorus concentrations, and vitamin D metabolism, in patients with chronic kidney disease (CKD) are associated with prolonged stimulation of the parathyroid glands. This results in increased synthesis and release of parathyroid hormone (PTH) and parathyroid hyperplasia-secondary hyperparathyroidism (SHPT). SHPT is in turn a major driver of the skeletal disturbance that characterizes renal osteodystrophy and is associated with vascular and other soft tissue calcification. Current therapeutic strategies based on vitamin D compounds and calcium-containing phosphate binders are difficult to implement effectively because both agents are associated with substantial, and often dose-limiting, calcaemic actions that prevent the attainment of treatment targets. Calcimimetics are novel agents that increase the sensitivity of calcium-sensing receptors in the parathyroid glands. Consequently, they allow simultaneous reduction of both PTH and extracellular calcium concentrations, thus differing from currently available vitamin D therapies. Reduction of the calcium-phosphorus product (Ca x P) is a consistent feature of calcimimetic therapy and may facilitate the achievement of SHPT treatment targets.

Achieving therapeutic targets in the treatment of secondary hyperparathyroidism.

i m w m t s T c p S a a g UR UNDERSTANDING of the pathogenesis of bone disorders has progressed coniderably over the past 20 years. In individuals ith normal kidney function, the focus has preominantly been on osteoporosis, whereas in ndividuals with impaired kidney function, the ocus has been on the condition referred to as enal osteodystrophy. This pathologic understandng has led to significant advances in the therapy f bone disease as it affects these patient populaions. Although these advances have tended to ccur in parallel, there has been relatively little ntegration between the two. The work group on Osteoporosis in Chronic idney Disease attempted to deal with the interace between osteoporosis and renal osteodystrohy. We recognized a major problematic issue of efining osteoporosis in relationship to the bone isease observed in the chronic kidney disease CKD) patient. The National Institutes of Health NIH) consensus statement on osteoporosis conains minimal reference to CKD as a cause of econdary osteoporosis. This lack of integration s important for several reasons. First, both fields ikely can learn from advances made in the other; nd second, assessment and management strateies may exhibit exploitable areas of overlap. In he clinical arena in particular, the increasing vailability of dual x-ray absorptiometry (DEXA) nd quantitative computed tomography (qCT) acilities for the measurement of bone mineral ensity (BMD) in both the CKD and non-CKD opulations leads to the frequent identification of

American journal of kidney diseases : the official journal of the National Kidney Foundation

Coronary artery calcification measured by electron-beam computerized tomography (EBCT) correlates with plaque burden and vessel stenosis and is predictive of future cardiac events in the general population. Uremic vascular calcification is common and widespread, tends to be medial as well as intimal, and may not relate solely to atherosclerotic lesions. Despite this difference and in the absence of any direct evidence in uremic patients, it is generally implied that coronary artery calcification equates to occlusive atherosclerosis.

METHODS
We set out to compare the predictive value of coronary artery calcification assessed by EBCT with contemporaneous coronary angiography. We studied 18 patients with end-stage renal disease undergoing maintenance dialysis. Seventy-two coronary vessels were analyzed for angiographic evidence of stenotic disease and correlated with individual vessel calcification score.

RESULTS
There was no significant correlation between degree of vessel stenosis and calcification score for individual vessels in patients with a positive calcium scan. Specificity was 48% and the positive predictive value was 53%. However, a calcification score <20 strongly correlated with the absence of significant luminal narrowing, and a 0 calcification score had a negative predictive value of 87.5%.

Coronary artery calcification measured by EBCT is not an accurate marker of the degree of vessel stenosis in coronary artery disease in uremic patients and should not be used as a single screening test for atherosclerotic coronary disease.

Coronary artery calcification measured with electron-beam computerized tomography correlates poorly with coronary artery angiography in dialysis patients.

New vitamin D analogues for osteodystrophy in chronic kidney disease

Renal function and risk stratification in acute coronary syndromes.

Fracture rate after renal transplantation is substantially increased, is a source of morbidity and mortality, and correlates with osteopenia. The rate of bone loss after transplantation is time dependent. While we recorded marked bone loss during the first year after renal transplantation, bone loss in long-term recipients (>24 months) was found to be similar to expected age-related decline. We have previously shown that treatment with pamidronate at the time of transplantation protected the skeleton over a 1-year study period.

METHODS
We have reexamined patients who participated in our original study, all of whom had been randomized to receive either placebo or pamidronate (0.5 mg/kg) at the time of transplantation and 1 month later. We now report 4-year data from 17 of the 26 original cohort. All patients received immunosuppression, comprising prednisolone, cyclosporine, and azathioprine.

RESULTS
We found that without prophylaxis bone loss at 4 years was substantial and significant at the femoral neck (mean loss was -12.3%) but was not significant at the lumbar spine (mean loss was -4.64%). Patients who received two doses of pamidronate experienced no statistically significant bone loss at either the femoral neck or the lumbar spine. Patient characteristics of the placebo and treatment groups were similar with the exception of serum parathyroid hormone concentrations, which remained higher at 4 years in the pamidronate-treated patients (15.8 +/- 3.7 pmol/L vs. 9.8 +/- 1.8 pmol/L, P < 0.05).

Without prophylaxis, most patients who continue to receive low dose glucocorticoids as part of maintenance immunosuppression manifest a substantial deficit in bone mineral density (BMD) at the femoral neck. In contrast, two doses of pamidronate given at the time of transplantation and 1 month later protected the skeleton from significant bone loss over the 4 years after transplantation.

Long-term effects on bone mineral density of pamidronate given at the time of renal transplantation.

Oral cinacalcet HCI (AMG 073) for the treatment of hemodialysis patients with secondary hyperparathyroidism (HPT): Results of a European/Australian-Phase 3 study

Background: New ‘non-calcaemic’ analogues of 1,25-dihydroxyvitamin D<sub>3</sub> (1,25(OH)<sub>2</sub>D<sub>3</sub>) are entering the clinical arena and some of them have been shown to have differential effects in bone. This may have a bearing on the evolution of bone lesions in uraemic patients receiving vitamin D therapies. A potential mechanism for differential effects of analogues lies in their target cell inactivation. Methods: Using a human osteoblastic cell line, MG-63, three analogues, 22-oxacalcitriol (OCT), 19-nor-1,25-dihydroxyvitamin D<sub>2</sub> (paricalcitol) and 1α,25-dihydroxydihydrotachysterol<sub>2</sub> (1,25(OH)<sub>2</sub>DHT<sub>2</sub>), were compared with 1,25(OH)<sub>2</sub>D<sub>3</sub> for (1) their affinity for the vitamin D receptor (VDR) by competitive displacement of tritiated 1,25(OH)<sub>2</sub>D<sub>3</sub> from calf thymus VDR; (2) effects on 24-hydroxylase mRNA expression using comparative RT-PCR, and (3) rates of metabolism, using high performance liquid chromatography, over a 24-hour time course. Results: Relative VDR-binding affinities (IC<sub>50</sub>) were 1,25(OH)<sub>2</sub>D<sub>3</sub> (100%), OCT (25%), paricalcitol (14%) and 1,25(OH)<sub>2</sub>DHT<sub>2</sub> (0.3%). A ≧3-fold increase in 24-hydroxylase mRNA expression was observed for all compounds at 2 h peaking at 7- to 8-fold above control levels by 12 h, with no significant difference between the analogues and 1,25(OH)<sub>2</sub>D<sub>3</sub>. Differences in their rates of metabolism were observed [calculated t½ values = OCT (1.2 h) > paricalcitol (2.3 h) > 1,25(OH)<sub>2</sub>D<sub>3</sub> (2.6 h) > 1,25(OH)<sub>2</sub>DHT<sub>2</sub> (3.4 h)], with OCT having a significantly shorter half-life. Conclusion: In MG-63 cells these analogues up-regulate 24-hydroxylase mRNA expression with similar potency, in each case accelerating ligand inactivation, despite significant differences in VDR affinity. VDR affinity did not correspond to either 24-hydroxylase mRNA expression or the rates of ligand disappearance, suggesting cellular metabolism is one of several factors that determine the analogue specificity of these agents in bone.

Effects of ‘Non-Calcaemic’ Vitamin D Analogues on 24-Hydroxylase Expression in MG-63 Osteoblast-Like Cells

Achievement of proposed NKF-K/DOQI Bone Metabolism and Disease targets Treatment with cinacalcet HCl in dialysis patients with uncontrolled secondary hyperparathyroidism

SUMMARY: Delayed referral of patients with end‐stage renal disease (ESRD) to a nephrologist is associated with considerable early morbidity and increased mortality. The Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) has collected data regarding the timing of referral to a nephrologist for all patients beginning renal replacement therapy (RRT) since 1 April 1995. We examined survival and likelihood of transplantation for patients who started RRT between 1 April 1995 and 31 December 1998, with follow‐up until 31 March 2000 (up to 5 years follow‐up). Of 4886 patients starting RRT, 1277 (26.1%) were in the late referral (LR) group and 3609 (73.9%) were not (NLR). In a multivariate analysis, predictors of LR were age 0–44 years and the presence of two or more comorbidities. Ninety days after referral, 60% of patients in the LR group were on haemodialysis compared with 55% of patients in the NLR group; 40% of patients in each group were receiving peritoneal dialysis at this time. Patients in the LR group were significantly less likely to receive a transplant in the first year after referral and throughout the duration of the study compared with the NLR group. Mortality rates were 19 and 13 persons per 100 patient years in the LR and NLR groups, respectively. In conclusion, delayed referral to a nephrologist was associated with increased mortality which continued for up to 5 years, even after adjustment for known predictors of mortality including age, sex, comorbidities and primary renal disease.

Timing of nephrology referral: a study of its effects on the likelihood of transplantation and impact on mortality

The development of vitamin D analogues capable of effective parathyroid suppression whilst avoiding undesirable low bone turnover, hypercalcaemia and hyperphosphataemia has received considerable attention over the last decade w1x. Much in vitro and animal work has been undertaken with frustrating disparity emerging between therapeutic potential in the experimental setting and performance in available clinical trials. The biology and, in particular, gene regulatory properties of vitamin D are now more fully understood w2x and provide useful insights into the mechanisms underpinning the selective properties encountered experimentally. The formulation of ‘designer’ compounds possessing distinct physiological characteristics that will afford them an advantage in the clinical arena remains an enticing prospect.

Vitamin D analogues: how do they differ and what is their clinical role?

The present review considers the role that bisphosphonates might have in patients with renal failure. Although bisphosphonates are widely used to reduce fracture risk in patients with osteoporosis, few studies have documented their effect in patients with renal osteodystrophy. The pathogenesis of bone loss after renal transplantation and the role of the recently identified osteoprotegerin/receptor activating nuclear factor-κB system is described. Inhibition of bone resorption may prove beneficial when high bone turnover is present, but there are potential drawbacks to widespread use of bisphosphonates. These issues are discussed, with emphasis placed on reports published within the past 18 months.

Very rapid bone loss, osteopenia and skeletal morbidity after renal transplantation have been well documented and found to occur in a sex dependent fashion. Glucocorticoids, cyclosporine and pre-existing uremic osteodystrophy have been implicated in the pathogenesis of the skeletal lesions. Glucocorticoid induced osteopenia is also a serious clinical problem in patients with various nonrenal diseases and can be prevented, or at least attenuated, by pamidronate and other bisphosphonates.

METHOD
We prospectively studied 26 male patients undergoing renal transplantation, and randomized them to receive either placebo or intravenous pamidronate (0.5 mg/kg) at the time of transplantation and again one month later. All patients received immunosuppression comprising prednisolone, cyclosporine and azathioprine. The bone mineral density (BMD) of the second, third and fourth lumbar vertebrae and of the femoral neck was measured at the time of transplantation and at three months and 12 months after transplantation using dual energy X-ray absorptiometry (DXA).

RESULTS
Twelve months after transplantation, the mean (+/- SEM) BMD of the lumbar vertebrae in patients who received placebo had decreased 6.4% (P < 0.05). In contrast, patients who received pamidronate experienced no significant reduction of BMD at the lumbar vertebrae. At the femoral neck, placebo-treated patients showed a reduction of BMD of 9% (P < 0.005), whereas there was no significant change in the pamidronate treated group. The two study groups had similar patient profiles, serum parathyroid hormone (PTH) and aluminium concentrations. After transplantation, comparable falls in the serum creatinine and PTH concentration were found in the two groups. Apart from transient hypocalcemia in two patients, no significant adverse effects of pamidronate were noted.

This study has shown that the early rapid bone loss that occurs in men during the first 12 months after renal transplantation can be prevented by two intravenous doses of pamidronate given at transplantation and one month later. The regimen was simple to administer, well tolerated and potentially applicable to other clinical groups of glucocorticoid treatment patients.

Pamidronate therapy as prevention of bone loss following renal transplantation.

Dihydrotachysterol(2), a licensed pharmaceutical, is hydroxylated to 25-hydroxydihydrotachysterol(2) (25(OH)DHT(2)) and 1 alpha,25-dihydroxydihydrotachysterol(2) (1 alpha,25(OH)(2)DHT(2)) in man. We have compared the biological activity of these metabolites with calcitriol and the 'non-calcaemic' analogue, 22-oxacalcitriol (OCT) in bovine parathyroid cell cultures and in rats.

METHODS
The effect of each sterol on parathyroid hormone (PTH) secreted by primary bovine parathyroid cells was measured. High-performance liquid chromotography and gas chromotography-mass spectrometry were used to investigate in vitro 25(OH)DHT(2) metabolism. Rats were given a single intraperitoneal injection or five daily injections of each sterol, and changes in ionized calcium and PTH were measured.

RESULTS
In vitro, all sterols suppressed PTH significantly. Calcitriol and OCT were of similar potency, but 1 alpha, 25(OH)(2)DHT(2) and 25(OH)DHT(2) required higher concentrations to suppress PTH equally. We were unable to detect metabolism of 25(OH)DHT(2) to 1 alpha,25(OH)(2)DHT(2) in vitro. In rats, a single dose of 0.5 microg/rat of calcitriol increased ionized calcium at 30 and 40 h (statistically significant at 48 h). 50 microg of OCT and 1 alpha,25(OH)(2)DHT(2) did not cause significant hypercalcaemia at 48 h, although 1 alpha,25(OH)(2)DHT(2) caused hypercalcaemia at 30 h. In contrast, 50 microg of 25(OH)DHT(2) caused hypercalcaemia at 48 h but not at 30 h. Five daily doses of 0.001 microg/rat of calcitriol caused a significant rise in calcium and a 50% fall in PTH. OCT and 1 alpha,25(OH)(2)DHT(2) at 0.025 and 0.5 microg/rat respectively caused similar suppression of PTH but without hypercalcaemia.

1 alpha,25(OH)(2)DHT(2) and 25(OH)DHT(2) are potent suppressors of PTH in vitro and in vivo. 25(OH)DHT(2) may be active by virtue of its pseudo-1 alpha-hydroxyl group. Hypercalcaemia caused by a single dose of 1 alpha,25(OH)(2)DHT(2) appeared to be more transient than calcitriol. Five daily doses of 1 alpha, 25(OH)(2)DHT(2) and OCT could achieve 50% suppression of PTH without significant increments in ionized calcium. In contrast, suppression of PTH by calcitriol was associated with significant increments in ionized calcium. These data suggest that like OCT, 1 alpha, 25(OH)(2)DHT(2) can dissociate calcaemic actions from parathyroid-suppressing actions in a manner that may be therapeutically useful.

Potent suppression of the parathyroid glands by hydroxylated metabolites of dihydrotachysterol(2).

The parathyroid glands synthesize and secrete parathyroid hormone (PTH ) in response to low calcium, low 1,25-dihydroxyvitamin D 3 (calcitriol ), and high phosphate concentrations. The interplay between these The vitamin D receptor elements is complex, operating through several feedback mechanisms. Both PTH and calcitriol regulate Calcitriol mediates its genomic eVects through the circulating calcium and phosphate concentrations vitamin D receptor ( VDR), which is a member of the through their action on target organs, namely the steroid/thyroid superfamily of nuclear receptors. kidney, bone, and intestine. PTH and calcitriol regulate Calcitriol binding to VDR results in changes in tranone another’s production, and additionally are both scription rates for those genes that contain vitamin D regulated separately by extracellular calcium and phos- responsive elements ( VDREs). There are many other

EDITOR—Many of the comments of David, Esmonde, McMillan, and Murray et al are incorrect and overlap.1 Owing to space constraints we have addressed points of fact below and opinion based comments in bmj.com (bmj.com/cgi/eletters/320/7245/1337#EL1) or in the printed 2 and longer web versions of our paper (bmj.com/cgi/content/full/319/7213/807/DC1).

Few normative data are published on large series of flash or pattern stimulated visual evoked potentials or the difference in timing between them. In a given subject the flash-pattern difference might be large because of a quicker (shorter) pattern latency than normal, but, to our knowledge, pathologically short pattern evoked responses have not been reported in …

The uremic milieu generates chronic stimulatory input to the parathyroid glands, which is mediated principally by low calcium, high phosphate and low calcitriol, and results in increased parathyroid hormone (PTH) synthesis and release and an increase in parathyroid mitotic activity with the development of monoclonal areas of nodular hyperplasia. Such glands do not fully express the machinery required to mediate the suppressive inputs to the parathyroids; the extracellular calcium receptor (CaR) and the vitamin D receptor (VDR) are both downregulated. In most of these patients ablation, by parathyroidectomy or ethanol injection, provides the only means of correcting the hyperparathyroidism; apoptosis in parathyroid cells is negligible and clinically irrelevant. In practice, surgery is often delayed by a doomed and ultimately futile attempt to effect control by medical means. Better predictors of the likely success or failure of optimal non surgical management are needed. Gland size exceeding 1 cm3 and elevated PTH despite hypercalcemia (implying loss of suppressibility by calcium), in the presence of good phosphate control and adequate calcitriol provision point strongly to eventual failure of medical treatment and the need for parathyroid ablation. Parathyroidectomy, usually subtotal, remains the standard management, with ultrasound guided injection of ethanol or calcitriol showing promise in some centers. The above scenario is unlikely to be changed greatly by the new emerging vitamin D metabolites, but calcimimetic agents may well increase the scope of non surgical management.

Are Parathyroidectomies Still Appropriate in Chronic Dialysis Patients?

The use of calcitriol in the treatment of uremic hyperparathyroidism and renal osteodystrophy is limited in many patients by hypercalcemic side-effects. New less calcemic analogues of calcitriol are being developed, and some are under clinical evaluation. To investigate whether these compounds possess important differences in their action on bone cells, we have studied their effects [with and without parathyroid hormone (PTH)] on the release and synthesis of the resorptive osteotropic cytokine, interleukin-6 (IL-6).

METHODS
MG 63 and SaOS-2 human osteoblastic cell lines were cultured for 6 or 24 hours in media containing calcitriol, the sterols of interest, or 1-34 synthetic PTH. IL-6 release was assayed by commercially available enzyme-linked immunosorbent assay. IL-6 mRNA levels were assessed by reverse transcriptase-polymerase chain reaction.

RESULTS
We found that calcitriol and paricalcitol behaved in a similar fashion, resulting in increased IL-6 release only at higher concentrations (10(-7) to 10(-9) M). In contrast, 22-oxacalcitriol and 1,25-dihydroxydihydrotachysterol2 stimulated release to a similar extent but at concentrations three to four orders of magnitude lower (10(-11) to 10(-13) M), despite being less potent as suppressers of parathyroid function than calcitriol. Studies of IL-6 mRNA showed a similar pattern of concentration and cell line-dependent transcription.

Compounds stimulating IL-6 release at concentrations achievable during the treatment of uremic hyperparathyroidism might favor continuing linked bone formation and resorption and thereby avoid adynamic bone disease while still allowing profound suppression of PTH.

Effects of new analogues of vitamin D on bone cells: implications for treatment of uremic bone disease.

Abstract Objective: To establish whether people exposed to drinking water contaminated with 20 tonnes of aluminium sulphate in the Camelford area of Cornwall in the south west of England in July 1988 had suffered organic brain damage as opposed to psychological trauma only. Design: Retrospective study of affected people. Participants: 55 affected people and 15 siblings nearest in age to one of the group but who had not been exposed to the contaminated water were studied. Main outcome measures: Various clinical and psychological tests to determine medical condition and anxiety levels in affected people. Assessment of premorbid IQ (pFSIQ) with the national adult reading test, a computerised battery of psychomotor testing, and measurement of the difference in latencies between the flash and pattern visual evoked potentials in all participants. Results: The mean (SE) pFSIQ was above average at 114.4 (1.1). The most sensitive of the psychomotor tests for organic brain disease was the symbol digit coding (SDC) test (normal score 100, abnormal <85). Participants performed less well on this test (54.5 (6.0)) than expected from their pFSIQ (P<0.0001) and a little less poorly on the averaged less discriminating tests within the battery (86.1 (2.5), P<0.0001). In a comparison with the 15 sibling pairs (affected people's age 41.0 (3.3) years v sibling age of 42.7 (3.1) years (P=0.36) the exposed people had similar pFSIQ (114.7 (2.1)) to their siblings (116.3 (2.1), (P=0.59) but performed badly on the symbol digit coding test (51.8 (16.6)) v (87.5 (4.9) for siblings, P=0.03). The flash-pattern differences in exposed people were greater than in 42 unrelated control subjects of similar age (27.33 (1.64) ms v 18.57 (1.47) ms, P=0.0002). The 15 unexposed siblings had significantly better flash-pattern differences than their affected siblings (13.4 (2.4) ms v 29.6 (2.9) ms, P=0.0002). No effect of anxiety could be shown on these measurements from the analysis of the anxiety scores of exposed people. Conclusion: People who were exposed to the contaminated water at Camelford suffered considerable damage to cerebral function, which was not related to anxiety. Follow up studies would be required to determine the longer term prognosis for affected individuals. Key messages Aluminium is a well established neurotoxin Accidental contamination of drinking water in Camelford by aluminium sulphate led to symptoms of loss of concentration and short term memory that were initially attributed to anxiety In residents exposed to the contaminated water psychomotor performance was poorer than predicted from premorbid IQ and the difference between flash-pattern visual evoked potentials was greater than normal Anxiety did not influence either of these measures of cerebral function Aluminium sulphate poisoning probably led to long term cerebral impairment in some people in Camelford

Disturbance of cerebral function in people exposed to drinking water contaminated with aluminium sulphate: retrospective study of the Camelford water incident

The past 30 years have seen substantial advances in our understanding of the pathogenesis of the mineral, hormonal and skeletal disorders that comprise renal osteodystrophy. The introduction of calcitriol and alfacalcidol as treatments for this disorder in the early 1970s represented an enormous step forward in clinical practice, but unfortunately, the subsequent refinement of these therapies still leaves us well short of the ideal: hyperphosphatemia and hypercalcemia induced by the vitamin D metabolites, and failure to control parathyroid hyperplasia, all remain problematic. Novel pulsed regimens using alfacalcidol and calcitriol, while clearly effective, have not fulfilled initial high expectations of superiority in the context of comparative studies. New vitamin D metabolites, some of which have exhibited desirable selectivity in experimental settings with reduced tendency to raise phosphate and/or calcium while maintaining good control of the parathyroid glands, are now being evaluated. Of these, 22-oxacalcitriol, paricalcitol (19 nor-1,25 dihydroxyvitamin D2) and doxercalciferol (1 alpha-hydroxyvitamin D2) have all shown high efficacy when compared with placebo, but so also did alfacalcidol and calcitriol in similar studies in the 1970s and 1980s. The results of randomized studies comparing the new vitamin D metabolites with current standard therapy (alfacalcidol or calcitriol) are either not yet available or show uncertain benefits in relation to hypercalcemia, hyperphosphatemia and hyperparathyroidism. The impact of these new metabolites on the increasing prevalence of low turnover bone disease is unknown, although experimentally there is evidence of potentially important differences at the level of the skeleton.

Unless treated with high doses of oral calcium or vitamin D metabolites, the patient with end-stage renal disease (ESRD) undergoing dialysis is usually in a state of negative net calcium balance at the level of the intestine and has negligible urinary calcium losses. The negative net calcium flux across the intestine can be reduced or even made positive by the administration of large doses of calcium supplements (as used in calcium-based phosphate binders), or of 1&alpha;-hydroxylated metabolites of vitamin D, or both. At the level of the peritoneum, calcium mass transfer can also be rendered positive or negative, in this case, by adjustments to the calcium concentration of the peritoneal dialysate. Historically, it was usual to set dialysate calcium concentration at 1.75 mmol/L, this concentration being substantially above the concentration of diffusible calcium in plasma and extracellular fluid. As a result, the dialytic process was

AIM
To determine the number and rates of hospital-acquired blood stream infections in New Zealand public hospitals.

METHOD
From October 1994 to December 1996 each of the 23 Crown Health Enterprises (CHEs) provided the Crown Company Monitoring Advisory Unit with data on the number of episodes of hospital-acquired blood stream infection (HA-BSI) and the number of inpatient admissions.

RESULTS
During the 27 month study period, 3049 episodes of HA-BSI occurred in an inpatient population of 1 300 892 giving a national average rate of 0.23%. HA-BSI rates were highest for the six tertiary level, metropolitan CHEs (range 0.19% - 0.56%) in which 79% of all HA-BSIs occurred.

The HA-BSI rate for New Zealand is within the range that would be expected for a developed country with a comprehensive health service. The variability between CHEs in terms of the clinical services provided and case mix differences invalidates direct comparison of HA-BSI rates. Surveillance for HA-BSI should continue with the collection of data which would allow meaningful comparison of similar tertiary level services.

It’s generally assumed that treating dialysis patients with calcitriol(l,2S-dihydroxy vitamin D) eliminates any concern about vitamin D deficiency. What about the normal precursor to calcitriol, 25-hydroxy vitamin D? If 25-hydroxy vitamin D has unique actions and dialysis patients are deficient in it (dietary factors, little sun exposure) mighm ’t patients benefit from some “regular” vitamin D now omitted from those special dialysis patient vitamins?

Should Vitamin D be Added to Multivitamins for Dialysis Patients?

Immunosuppression and risk of non-melanoma skin cancer in renal transplant recipients

The increasing use of 'reduced calcium' dialysate in CAPD patients treated with calcium-based phosphate binders has raised concerns that this could lead to negative calcium balance, worsening hyperparathyroidism, and osteopenia.

METHODS
The present study was conducted to examine the possibilities (a) that 1.25 mM calcium dialysate leads to negative calcium balance and worsening hyperparathyroidism, and (b) that conversely 1.25 mM calcium dialysate is still too high for some patients. We studied 22 patients who, after a 2-month run in using 1.75 mM calcium dialysate and aluminium hydroxide binders, entered a 3-month phase of 1.25 mM calcium dialysate with continuation of aluminium hydroxide as the sole phosphate binder. The patients then entered a final 9-month phase in which dialysate calcium remained at 1.25 mM and calcium carbonate was substituted for aluminium hydroxide and progressively titrated to achieve optimum phosphate control.

RESULTS
During the initial 3-month period, parathyroid hormone increased from 259, range 11-1149 to 405, range 16-1318 pg/ml (P = 0.0001) and ionized calcium decreased from 1.17 +/- 0.06 to 1.11 +/- 0.08 mM (P = 0.0004). The subsequent 9-month phase was associated with return of parathyroid hormone to baseline levels. Further dialysate calcium reduction to 0.6 mM was implemented in the four patients who became hypercalcaemic.

This study has clearly shown that reduction of dialysate calcium to 1.25 mM can be harmful to CAPD patients if oral calcium availability is inadequate. It has also shown that dialysate calcium at 1.25 mM is a compromise, with increased risk of hyperparathyroidism if calcium intake is too low and, conversely, risk of hypercalcaemia and unacceptable increases of the Ca x Pi product in a minority of patients. At these extremes there is a need for a high-calcium dialysate (1.75 mM) and a very low-calcium dialysate (0.6 mM or less), to optimize management.

Reduced calcium dialysate in CAPD patients: efficacy and limitations.

Human papillomavirus (HPV) carriage in renal transplant recipients (RTRS) at high risk of developing non-melanoma skin cancers (NMSC).

Hyperparathyroidism is a frequent and sometimes disabling complication of uraemia. Chronicity of uraemia is a major determinant of the likelihood of hyperparathyroidism which is seen in large numbers of dialysis patients, regardless of treatment modality, as well as in a significant proportion of non-dialysed patients with chronic renal insufficiency [1]. Hyperparathyroidism also spills over into renal transplantation—while rarely developing de novo following successful transplantation, longstanding parathyroid overactivity and hyperplasia as a result of previous dialysis often leads to significant morbidity following successful transplantation [2].

A 74-year-old man presented with a 1-day history of abdominal pain and cloudy dialysis fluid. Fifty years previously he had had a left orchidectomy and an inguinal hernia repair had been performed because of an undescended testis. Five years later he was found to have a left hydronephrosis requiring nephrectomy. He had psoriasis and a mild polyarthropathy. Fifteen years before this presentation he was noted to have impaired renal function, which declined until he required haemodialysis. Two years prior to admission a Tenckhoff catheter had been inserted and CAPD begun. Two episodes of peritonitis due to coliform organisms had responded to intraperitoneal antibiotics. At presentation his only medication was aluminium hydroxide.

Rhodococcus equi in CAPD-associated peritonitis treated with azithromycin.

Suppression of PTH secretion by 1α,25-dihydroxy-dihydotachysterol in isolated bovine parathyroid cells in tissue culture

GH deficiency is associated with increased cardiovascular morbidity, which may be determined by alterations in vascular risk factors. We report the effect of partially treated hypopituitarism and subsequent GH replacement (mean dose, 0.2 IU/kg.week) on putative cardiovascular risk factors in 22 nondiabetic hypopituitary subjects in a 6-month, double blind, controlled study (active/placebo ratio, 11:11). All patients were subsequently treated with GH for a further 6 months. Total fat, percent body fat, and central fat were measured by dual energy x-ray absorptiometry. The hypopituitary patients had increased percent fat (P = 0.03) and central fat (P < 0.01) compared with body mass index-matched controls. Before GH treatment, fasting (total) and specific insulin positively correlated with body mass index (P = 0.02 and P < 0.001, respectively), waist/hip ratio (P = 0.05 and P = 0.01), and central fat (P = 0.03 and P = 0.003). Specific insulin and insulin sensitivity (IS), calculated by homeostatic model of assessment, were related to total fat (P < 0.001 and P = 0.02). GH treatment for 6 months led to a reduction in total fat (P < 0.02), percent fat (P = 0.002), central fat (P = 0.012), waist/hip ratio (P < 0.05), total cholesterol (P = 0.03), and apolipoprotein-B (P = 00001), as well as a decrease in the IS from 36.9% (range, 12-100%) to 25% (range, 2.5-55%; P = 0.0002). This was paralleled by a rise in fasting (total) and specific insulin (P = 0.016 and P = 0.002). The degree of correlation among indices of IS, body composition, and fat distribution increased after GH treatment. Fasting plasma glucose rose significantly, but was within the reference range. During 12 months of GH therapy, a significant increase in serum lipoprotein-(a) was observed (P < 0.05). Although GH has beneficial effects on central adiposity and lipid fractions, it is also associated with a decrease in IS; these effects may vary between individuals.

The effect of low dose recombinant human growth hormone replacement on regional fat distribution, insulin sensitivity, and cardiovascular risk factors in hypopituitary adults.

Pamidronate [(3-amino-1-hydroxypropylidene)-1,1-bisphosphonate] prevents bone calcium loss during the first 3 months after renal transplantation

The response to erythropoietin (Epo) is dose dependent but, for various poorly understood reasons, variable. In a cross-sectional study we determined the Epo requirement of 60 patients in a dialysis population to identify those patients requiring a high dose of Epo, and ascertained the reasons for higher requirements, paying particular attention to the effect of previous transplantation. All 289 patients attending a single centre were surveyed. Of these, 164 were receiving renal replacement therapy by continuous ambulatory peritoneal dialysis (CAPD) and 125 were on haemodialysis (HD). Patients on HD needed more Epo than those on CAPD (129.0 +/- 14.9 U/kg/week versus 86.9 +/- 10.7 U/kg/week, P < 0.05). However, this difference was accounted for by a subgroup of patients who had a previously failed transplant. The Epo requirement in those patients on HD with a failed transplant was significantly greater than those on HD who had never been transplanted (164.0 +/- 24.5 U/kg/week versus 96.6 +/- 11.9 U/kg/week, P < 0.05). The seven patients who retain their transplanted kidney had the highest Epo requirement of all (213.4 +/- 46.6 U/kg/week). These studies have shown that previous transplantation is a significant determinant of Epo requirement upon return to dialysis. They also show that it is necessary to 'correct' for the effect of previous transplantation when investigating generally accepted determinants of Epo need. Interpretation of previously published studies needs to take account of this.

Increased erythropoietin requirements in patients with failed renal transplants returning to a dialysis programme.

It has recently been shown that in the rat, dihydrotachysterol (DHT) is extensively metabolized in the side-chain in vivo along pathways similar to those of vitamin D. In addition 25-hydroxy-DHT2 [25OHDHT2] is hydroxylated at C1, producing both 1 alpha- and 1 beta- hydroxy compounds. An in vivo study in 1988 demonstrated that in normal adult subjects receiving oral DHT2, plasma 1 alpha,25-dihydroxyvitamin D [1,25-(OH)2D] concentrations fell, but with unchanged plasma PTH levels. Down-regulation of 1,25-(OH)2D3 production by 25-(OH)DHT2 or some other unknown metabolite was also suggested as an explanation for these observations. To investigate whether either of the newly characterized 1 alpha,25- or 1 beta,25-(OH)2DHT2 was formed in vivo in normal man, DHT2 (approximately 1 mg/day, orally) was administered to healthy volunteers (three males and one female). Plasma was analyzed by high performance liquid chromatography and gas chromatography-mass spectrometry, demonstrating the formation of both 1 alpha,25- and 1 beta,25-(OH)2DHT2 in vivo in normal human subjects. Plasma levels of 1,25-(OH)2D3, PTH, ionized and total calcium, inorganic phosphate, and alkaline phosphatase were monitored. The plasma concentrations of DHT2, 25OHDHT2, and 1 alpha,25- and 1 beta,25-(OH)2DHT2 were measured by gas chromatography-mass spectrometry. In all volunteers, plasma ionized calcium increased slightly during DHT2 administration; 1,25-(OH)2D3 and PTH concentrations fell. Plasma levels of DHT2 and its metabolites rose over the same period. The average fall in the level of plasma 1,25-(OH)2D (60-70 pmol/L) was mirrored by a rise in the concentration of 1 alpha,25-(OH)2DHT2 (550 pmol/L). This ratio is appropriate, because it has previously been shown that in a reconstituted COS cell, 1 alpha,25-(OH)2DHT3 has roughly one tenth the potency of 1,25-(OH)2D3. At maximum concentration, the ratios of DHT2/25OHDHT2/1 beta,25-(OH)2DHT2/1 alpha,25-(OH)2DHT2 were approximately 10:1:2:0.1. The concentration of 1 beta,25-(OH)2DHT2 was greater than that of 25OHDHT2, and the ratio of 1 alpha,25- to 1 beta,25-(OH)2DHT2 (1:20) was substantially lower than that in rat plasma (3:10). The data presented here suggest that the active DHT2 metabolite in man is 1 alpha,25-(OH)2DHT2 and that the fall in plasma 1,25-(OH)2D seen during DHT therapy may be partly the result of suppressed PTH secretion.

In vivo dihydrotachysterol2 metabolism in normal man: 1 alpha- and 1 beta-hydroxylation of 25-hydroxydihydrotachysterol2 and effects on plasma parathyroid hormone and 1 alpha,25-dihydroxyvitamin D3 concentrations.

A high incidence of osteopenia is likely in renal transplant recipients in whom pre-existing uraemic osteodystrophy, persisting hyperparathyroidism and glucocorticoids constitute a formidable array of risk factors. The correction of some biochemical and hormonal abnormalities, an increase in body weight and an increase in physical activity following transplantation could favour improvements in skeletal integrity. Using dual energy X-ray absorptiometry (DEXA), we studied prospectively the regional bone mineral density (BMD) of 34 consecutive cadaveric renal allograft recipients who were already established on dialysis. BMD of these patients was measured at the time of transplantation and was repeated at 3, 6 and 12 months following the transplantation. Immunosuppression was achieved using triple therapy: azathioprine, cyclosporin-A and prednisolone. At baseline, total BMD and BMD at the lumbar spine and femoral neck did not differ from age- and sex-matched controls. Females experienced marked and progressive bone loss at the lumbar spine, with less marked changes at the femoral neck. Males, in contrast, experienced substantial reduction of BMD at the femoral neck at 6 months and a recovery at 12 months without significant change at the lumbar spine. Whole body bone mineral content fell transiently in males, with partial recovery by 6 months. No significant correlation was found with the cumulative doses of either corticosteroids or cyclosporin-A, the duration of hospitalisation, the function of the transplant, patient age or menopausal status.(ABSTRACT TRUNCATED AT 250 WORDS)

Loss of regional bone mineral density in the first 12 months following renal transplantation.

Traditional methods for estimating total body fat rely on the assumption that body fat distribution and bone mineral content are constant. However, in patients undergoing renal transplantation rapid changes in body composition occur, with variations in fat distribution and bone mineral content. In order to determine the reliability of skinfold measurement (SFM) in these patients, we compared it with dual energy X-ray absorptiometry (DEXA), which estimates body composition without reliance on assumptions of constant fat distribution and bone mineral content. Thirty-four adult renal transplant recipients were studied at the time of transplantation and again after 3 and 6 months. The correlation coefficients of DEXA vs SFM at the three time points were 0.84, 0.78, 0.85, respectively (P = 0.0001). In 34 healthy adults serving as controls, the correlation coefficient was 0.95 (P = 0.0001). Total body fat increased progressively following renal transplantation (P < 0.03 by 6 months) with SFM showing considerable disagreement with DEXA measurements of percentage total body fat. Thus skinfold measurements underestimated changes in total body fat following renal transplantation, especially in those gaining substantial amounts of body fat, and DEXA appeared to be a more appropriate technique.

Dual energy X-ray absorptiometry versus skinfold measurements in the assessment of total body fat in renal transplant recipients.

Parathyroid sensing of the direction of change of calcium in uremia.

It has become increasingly evident that clear-cut disturbances of bone and mineral metabolism develop early in renal failure. Among these disturbances, hyperparathyroidism is well documented and is usually asymptomatic at that early stage. It is now accepted that early therapy using phosphate restriction, through diet and calcium-containing phosphate binders, and 1 alpha-hydroxylated vitamin D analogues is an effective means of preventing or even reversing hyperparathyroidism in early renal failure. The response to these therapies is both functional (reduced parathyroid hormone secretion) and structural (prevention of parathyroid gland hyperplasia). Parathyroid hyperplasia is largely irreversible; prevention is therefore important and can be achieved initially by a combination of diet and calcium-containing phosphate binders, with later addition of calcitriol or alfacalcidol if parathyroid hormone control cannot be achieved or sustained.

The use of oral calcium carbonate as a phosphate binder is often complicated by hypercalcaemia, particularly with concomitant use of vitamin D analogues. We previously found that stepwise reduction of dialysate calcium effectively countered this complication in haemodialysis patients, and have now assessed the strategy in CAPD patients. Seventeen patients underwent conversion from aluminium hydroxide to calcium carbonate and were followed for 5 months, with subsequent addition of alfacalcidol for a further 5 months. Standard CAPD dialysate (1.75 mM calcium) was used, reducing to 1.45 mM and, if necessary, to 1.00 mM in patients who became hypercalcaemic. While receiving calcium carbonate alone, 12 of the 17 patients became hypercalcaemic, this responding in four to dialysate calcium reduction to 1.45 mM. In the remaining eight patients, further reduction to 1.00 mM was required and in two patients even this failed to control hypercalcaemia adequately, necessitating reversion to aluminium hydroxide. Phosphate control remained unchanged, as did calcium x phosphorus product. There were transient increases of blood ionised calcium, and decreases of parathyroid hormone, with progressive reduction of serum aluminium and alkaline phosphatase. The addition of alfacalcidol (0.25 microgram/day) led to hypercalcaemia in six subjects, successfully countered by dialysate calcium reduction in four. The results show that standard CAPD dialysate calcium at 1.75 mM is too high for the majority of calcium carbonate treated patients and that substantial reductions of the dialysate calcium concentration are required if calcium carbonate is to be used effectively.

Dialysate calcium reduction in CAPD patients treated with calcium carbonate and alfacalcidol.

Skeletal changes following renal transplantation: Rapid early bone loss without subsequent recovery

06 mM Calcium dialysate in CAPD Effective strategy for treating persistent hypercalcaemia in patients receiving calcium carbonate

EBV-genome positive monoclonal B cell cerebral lymphoma in a renal allograft recipient following OKT3 therapy.

We performed dynamic parathyroid function tests, with generation of parathyroid hormone/ionized calcium (PTH/iCa) response curves, obtained during sequential hypercalcaemic and hypocalcaemic dialysis, on six haemodialysis patients before and after 4-weekly 'pulse' doses of oral calcitriol. There were no significant changes in the pretreatment, 2-week and 4-week values of blood ionized calcium, serum total calcium, phosphate, and alkaline phosphatase. PTH decreased significantly after 4 weeks of treatment with calcitriol (P less than 0.03), and the post-treatment PTH/iCa curves were all displaced leftwards and downwards, indicating a marked inhibitory effect of calcitriol on parathyroid responsiveness across and beyond the physiological range of calcaemia. The mean shift of the PTH/iCa relationship was equivalent to a reduction of iCa of 0.2 mM for any given concentration of PTH, and conversely to a 70% reduction of PTH for any given blood iCa. The results suggest that wide spacing of oral 'pulse' doses of calcitriol can achieve favourable modification of the PTH/iCa relationship, and that dosing interval and dose size, rather than route of administration, may be the major determinants of the previously reported superiority of intravenous over daily oral calcitriol regimens.

'Pulse' oral calcitriol in uraemic patients: rapid modification of parathyroid response to calcium.

Plasma endothelin-1 (ET-1)-like immunoreactivity was measured by radioimmune assay in predialysis plasma samples from 16 chronic haemodialysis patients (7 dialysing through arteriovenous (AV) fistulae and 9 using central venous cannulae for access), from 10 patients with functioning renal transplants (5 with AV fistulae and 5 without), and from 6 healthy subjects as controls. Among dialysis patients, ET-1 was greater in those with AV fistulae than in those using cannulae for dialysis (median (range), 5.5 (3.1) pM versus 3.7 (2.0) pM, P = 0.02), and in all haemodialysis patients ET-1 values were substantially greater than in normal controls (3.9 (3.2) pM versus 0.5 (0.1) pM; P = 0.001). In patients with functioning AV fistulae, ET-1 concentrations obtained directly from the AV anastomosis of the fistula (4.4 (3.0) pM) were less than those taken simultaneously from the contralateral arm (5.5 (3.1) pM; P = 0.04), while samples drawn from the venous side of the fistula were intermediate (4.6 (3.4) pM). In renal transplant recipients, ET-1 values did not differ significantly from those in control subjects (0.7 (1.9) pM versus 0.5 (0.1) pM, n.s.), but in these patients there was a significant difference between peripheral venous ET-1 in transplant patients with and without AV fistulae (0.8 (1.9) pM versus 0.6 (1.1) pM respectively, P = 0.04). The results suggest that the increased blood flow rate through the arterialized venous circulation in the fistula arm stimulates increased ET-1 release in these patients, and that this accounts, at least in part, for the increased ET-1 found in the patients with functioning AV fistulae.

Does the arteriovenous fistula in chronic haemodialysis patients stimulate endothelin-1 release?

We performed serial measurements of total body bone mineral content (BMC) and bone mineral density (BMD), and of regional BMD at the lumbar spine and femoral neck using dual energy X-ray absorptiometry. Twenty-six patients (15 females and 11 males) were studied at the time of transplantation, and 3 and 6 months post-transplant. At baseline, the total body BMC and regional BMD values of the patients did not differ significantly from age- and sex-matched controls. Total body BMC had fallen progressively at 3 months, followed by partial recovery at 6 months. Significant decreases of BMD were seen in the lumbar spine and femoral neck at 3 months with no evidence of recovery at 6 months. The changes in these indices correlated well with the duration of hospital stay in the first 3 post-transplant months. This preliminary study demonstrated rapid deterioration of skeletal integrity following renal transplantation and that this might be progressive. Preventative strategies to avoid this early bone loss may need to be investigated.

Changes in total body bone mineral content and regional bone mineral density in renal patients following renal transplantation.

Mycobacterial infection is an important infective complication in British Asian dialysis patients.

The pharmacokinetics of aztreonam and vancomycin were studied in six adult patients who developed peritonitis during Continuous Ambulatory Peritoneal Dialysis. Aztreonam 3 g was added to the first exchange in each 24 h period with vancomycin 500 mg on the first day and 250 mg on each subsequent day (provided the pre-dose serum vancomycin concentration was less than 10 mg/l) for a total of ten days. Aztreonam and vancomycin concentrations were measured in the serum and dialysate at 1, 2, 6, 12, 18 and 24 h after the initial dose and pre-dose on days 5 and 10. By the end of the ten day study all patients had recovered clinically and had a normal dialysate. For aztreonam, the mean peak serum concentration was 84.3 mg/l (range 59.6-102.8), the mean 24 h pre-dose serum concentration was 23.0 mg/l (range 8.6-39.2) and the mean 24 h pre-dose dialysate concentration was 15.5 mg/l (range 5.0-32.0). For vancomycin, the mean peak serum concentration was 10.2 mg/l (range 8.1-12.6), the mean 24 h pre-dose concentration was 5.5 mg/l (range 3.6-6.4), and the mean 24 h pre-dose dialysate concentration was 3.4 mg/l (range 2.4-4.6). In the treatment of CAPD peritonitis, once daily intra-peritoneal administration of aztreonam 3 g with vancomycin 500 mg initially and 250 mg on subsequent days (serum concentrations permitting) provides concentrations of antibiotic in both the serum and dialysate throughout the 24 h period in excess of the inhibitory concentrations of those organisms most frequently encountered in this condition.

Pharmacokinetics of once daily intra-peritoneal aztreonam and vancomycin in the treatment of CAPD peritonitis.

Immunoglobulin heavy chain switch region gene polymorphisms in glomerulonephritis.

Previous studies have suggested that both plasma 24,25‐dihydroxyvitamin D [24,25‐(OH)2D] concentrations and renal 25‐hydroxyvitamin D‐24‐hydroxylase activity are increased in mice with X‐linked hypophosphatemia (Hyp mice). However, because the plasma levels of 24,25‐(OH)2D seemed surprisingly high, we repeated these assays using two different techniques. Mass fragmentographic and radioreceptor assays were employed to compare the plasma concentrations of 25‐hydroxyvitamin D (25‐OHD) and 24,25‐(OH)2D in normal mice with those in Hyp mice. These assays yielded 24,25‐(OH)2D concentrations much lower than previously reported in mice (both normal and Hyp). The concentrations of 25‐OHD3, and 24,25‐(OH)2D3, determined by mass fragmentography, were lower in Hyp mice than in controls [25‐OHD3, 9.7 ± 0.4 versus 14.6 ± 0.6 ng/ml, p < 0.01; 24,25‐(OH)2D3, 7.1 ± 0.3 versus 10.4 ± 0.4 ng/ml, p < 0.01]. Plasma 25‐OHD concentration was the main determinant of plasma 24,25‐(OH)2D, and the ratio of 25‐OHD3 to 24,25‐(OH)2D3 obtained from mass fragmentographic measurements did not differ between the two groups (1.40 ± 0.05 versus 1.36 ± 0.03 ng/ml, NS in normal and Hyp groups, respectively). Separate measurement of plasma 25‐OHD, 24,25‐(OH)2D, and 25‐OHD3‐26,23‐lactone by radioreceptor assay showed no difference between either plasma 24,25‐(OH)2D, or the ratio of 25‐OHD concentration to 24,25‐(OH)2D concentration among Hyp and control animals. In neither study was plasma phosphate concentration related to the 25‐OHD3: 24,25‐(OH)2D3 ratio. We conclude that previous estimations of plasma 24,25‐(OH)2D3 concentrations in mice were erroneously high and, further, that in fact this metabolite is not present in increased concentration in Hyp mice

Plasma 24,25‐dihydroxyvitamin D3 concentrations in x‐linked hypophosphatemic mice: Studies using mass fragmentographic and radioreceptor assays

We have studied the control of amino-terminal parathyroid hormone (PTH) secretion in haemodialysis patients in response to slow or fast calcium infusion and during acute hypocalcaemia. In nine patients, fast calcium infusion (0.4 mmol/kg bodyweight per hour) for 15 min increased ionised calcium and reduced PTH, with an initial t 1/2 of 12.8 min. After the infusion had ceased, calcium decreased steadily, and PTH increased, mean PTH reaching baseline values when calcium was still significantly greater than pre-infusion values. During slow calcium infusion for 2.5 h (0.1 mmol/kg bodyweight per hour), parathyroid suppression was evident at 15 min, when the calcium increment was only 0.03 mM. After 60 min, PTH did not decrease further despite progressive hypercalcaemia. Hypocalcaemic haemodialysis led to rapid increases in PTH. After 15 min, the mean calcium decrement was 0.09 mM (P less than 0.01) and the mean PTH increment was 283 pg/ml (P less than 0.01). The parathyroid response was maximal at 30 min, and did not increase subsequently, despite progressive hypocalcaemia for a further 90 min. During recovery from hypocalcaemia, PTH reduced and, despite comparable hypocalcaemia, PTH during periods of increasing calcium was always lower at a given calcium concentration than while calcium was decreasing. This influence of the direction of change of calcium was not seen during hypocalcaemia. The results showed that even in-advanced renal disease, the parathyroid glands are highly responsive to small initial increments (0.03 mM) and decrements (0.09 mM) in blood calcium, though less so to further perturbation of blood calcium.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of direction and rate of change of calcium on parathyroid hormone secretion in uraemia.

Long-Term Effect of Low Calcium Dialysate on Parathyroid Activity in Dialysis Patients Treated with Calcium Carbonate as a Phosphate Binder

DISTURBANCE OF CEREBRAL FUNCTION BY ALUMINIUM IN HAEMODIALYSIS PATIENTS WITHOUT OVERT ALUMINIUM TOXICITY

To reduce potentially toxic aluminium exposure, the phosphate binding agent aluminium hydroxide was replaced by high-dose oral calcium carbonate in 15 haemodialysis patients. Stepwise reduction in dialysate calcium concentration (from 1.75 to 1.35 mmol/l and then to 1.05 mmol/l) was made when necessitated by hypercalcaemia. After 6 months, the mean daily dose of calcium carbonate was 62 mmol (range 25-150 mmol). This dose maintained good control of plasma phosphate (baseline, 1.34 +/- 0.32 mmol/l (mean +/- SD); 12 weeks, 1.30 +/- 0.22 mmol/l; 24 weeks, 1.51 +/- 0.31 mmol/l). Calcium x phosphate product did not rise significantly (baseline, 3.41; 12 weeks, 3.44; 24 weeks, 4.02). Apart from a transient early increase, ionised calcium did not change significantly (baseline, 1.23 +/- 0.10 mmol/l; 12 weeks, 1.24 +/- 0.10 mmol/l). Intact (1-84) parathyroid hormone concentration decreased from 241 pg/ml to 116 pg/ml (median values, P less than 0.05) after 12 weeks. This simple and well-tolerated regimen almost completely eliminated oral aluminium exposure, effectively controlled plasma phosphate and calcium concentrations, and reduced hyperparathyroidism.

High-dose calcium carbonate with stepwise reduction in dialysate calcium concentration: effective phosphate control and aluminium avoidance in haemodialysis patients.

Summary Patients undertaking maintenance haemodialysis may develop a variety of neurological disorders, the most serious of which is aluminium induced encephalopathy. Abnormally raised serum concentrations of pterins are found in dialysis patients, and neonates with tetrahydrobiopterin deficiency develop mental dysfunction. Dihydropteridine reductase, essential for maintenance of normal levels of tetrahydrobiopterin, is inhibited when aluminium is added to brain homogenate at similar concentrations to those found in aluminium encephalopathy. We have previously shown that erythrocyte dihydropteridine reductase activity was reduced in non-encephalopathic dialysis patients and inversely related to serum aluminium concentration. Concentrations of serum biopterin derivatives were raised but not related to either aluminium or dihydropteridine reductase. In this study of 17 haemodialysis patients, serum biopterin (13.6 ± 1.3 μg/l) and neopterin (66.2 ± 7.4 μg/l) concentrations were raised compared with normal subjects' biopterin (2.4 ± 0.4 g/l) and neopterin (2.8 ± 0.4 μg/l) values (p = 0.0001). When neopterin and biopterin concentrations were corrected for predialysis serum creatinine a weak relationship appeared between them (r = 0.49, P = 0.04). Erythrocyte dihydropteridine reductase was not related to the creatinine corrected neopterin (r = -0.5, p = 0.2), but there was a significant relationship between DHPR and corrected biopterin (r = 0.986, p = 0.0001) and between corrected biopterin and bone aluminium content (r = 0.68, P = 0.03). Our results support the possibility that aluminium causes changes in pterin metabolism which are analogous to those found in Type II hyperphenylalaninaemia. Serum biopterin concentration, corrected for pre-dialysis serum creatinine, can be used satisfactorily to study tetrahydrobiopterin metabolism in haemodialysis patients. However neopterin/biopterin ratios are unpredictably disturbed and cannot be so used. Serum neopterin concentrations are raised more than anticipated from the biopterin concentrations, and this may be due to neopterin release from macrophages activated by dialysis membranes and/or reduced conversion of dihydroneopterin triphosphate to tetrahydrobiopterin.

The in vivo metabolism of dihydrotachysterol3, an analogue of vitamin D3 and a potent calcemic factor, has been studied in the rat. This in vivo metabolism is compared to the in vitro metabolism of 25-hydroxydihydrotachysterol3 in the perfused rat kidney. Using mass spectrometry and ultraviolet spectroscopy, we have identified seven novel metabolites derived from 25-hydroxydihydrotachysterol3. The seven compounds represent intermediates on two renal pathways (24-oxidation and 26,23-lactone formation) also observed for 25-hydroxyvitamin D3. No evidence was found for the renal synthesis of a 1-hydroxylated metabolite of 25-hydroxydihydrotachysterol3 analogous to the hormone 1,25-dihydroxyvitamin D3. Two of the compounds formed in vitro, 24,25-dihydroxydihydrotachysterol3 and 25-hydroxydihydrotachysterol 26,23-lactone, were also formed in vivo. In vivo studies also revealed the formation of two other unidentified metabolites which are presumed to be formed nonrenally and may be calcemic factors. This work shows that dihydrotachysterol3 metabolism is complex and probably utilizes the same side-chain enzymes as vitamin D3. In addition, our work also confirms that intermediates postulated to lie on pathways to 26,23-lactone in the vitamin D3 series are also formed for the side chain in dihydrotachysterol3.

Isolation and identification of seven metabolites of 25-hydroxydihydrotachysterol3 formed in the isolated perfused rat kidney: a model for the study of side-chain metabolism of vitamin D.

ALUMINIUM CHELATION THERAPY IN DIALYSIS PATIENTS: EVIDENCE FOR INHIBITION OF HAEMOGLOBIN SYNTHESIS BY LOW LEVELS OF ALUMINIUM

The metabolism of dihydrotachysterol3 (DHT3), a vitamin D analogue, has been investigated in vivo in the rat after intraperitoneal injection, and the metabolism of the 25-hydroxylated metabolite of DHT3 was studied in vitro in the isolated perfused rat kidney. A large number of metabolites have been obtained and some have been identified. The rat plasma or kidney perfusate were extracted and the metabolites separated by high-performance liquid chromatography (HPLC) in straight- and reverse-phase systems and using cyano columns. Metabolites were identified, using a photodiode array assembly which monitored the HPLC eluate, by the characteristic ultraviolet spectrum of DHT compounds. Tentative structures were assigned to some of the metabolites obtained on the basis of their mobility in the various HPLC systems used in comparison to that of known metabolites of vitamin D. Gas chromatography/mass spectrometry (GC/MS) and direct probe mass spectrometry have been used to confirm the identity of seven metabolites formed in vitro, of which only two have been definitely shown also to be formed in vivo. GC/MS was carried out after derivatization forming trimethylsilyl ethers, n-butyl boronate cyclic esters, and N-O-methyl oximes before and after oxidation with sodium periodate and/or reduction with sodium borohydride. Molecular ions of these compounds are usually of low abundance and characteristic mass fragments at m/z 273, 255 and 121 are always seen with metabolites of DHT.

Use of mass spectrometry in the identification of in vivo and in vitro metabolites of dihydrotachysterol3 in the rat.

Amino-terminal parathyroid hormone (N-PTH) responses during calcium infusion and induced hypocalcaemia in uremic subjects

Silicone spallation from the roller-pump insert in dialysis blood lines leads to the accumulation of silicone in haemodialysis patients, which in turn leads to a foreign-body reaction with granuloma formation. We have studied two patients in whom documented silicone accumulation has been associated with both granuloma formation and significant, persistent hypercalcaemia. In both patients plasma levels of immunoreactive parathyroid hormone and 1,25-dihydroxyvitamin D were low or undetectable. In one patient, hypercalcaemia responded only partially to corticosteroids, but completely to naproxen. Both patients were changed to silicone-free blood lines and their hypercalcaemia subsequently resolved. The results indicate that in some haemodialysis patients, silicone accumulation and granuloma formation may lead to hypercalcaemia that is independent of 1,25-dihydroxyvitamin D, and that may instead reflect altered prostaglandin metabolism.

Aluminum intoxication due to aluminum-containing antacids or dialysate can cause encephalopathy in patients undergoing hemodialysis, but the biochemical mechanism has not been defined. The enzyme dihydropteridine reductase (DHPR) is essential for the maintenance of normal brain concentrations of tetrahydrobiopterin, which is itself required for the synthesis of specific neurotransmitters. This enzyme is also present in erythrocytes. We measured erythrocyte DHPR activity and concentrations of the biopterin derivatives of its substrate and of aluminum in 38 patients on hemodialysis who had no clinical evidence of encephalopathy. Serum aluminum levels ranged from 15 to 190 micrograms per liter (mean, 67.6 +/- 7.7) as compared with 4.9 +/- 0.99 micrograms per liter in normal subjects. DHPR activity was inversely related to the serum aluminum concentration (r = -0.61, P less than 0.001) and was less than the activity predicted from the hemoglobin concentration in these patients. Serum concentrations of biopterin derivatives were markedly elevated. Eighteen patients were given the aluminum-chelating agent deferoxamine in a single dose, after which DHPR activity doubled. These studies suggest that aluminum inhibits DHPR activity in erythrocytes and that aluminum chelation reverses this effect. Although we did not directly measure DHPR activity in the brains of dialysis patients without encephalopathy, we propose that the reduction in activity in erythrocytes may reflect a similar reduction in the brain. Our findings could help to explain the encephalopathy associated with aluminum intoxication.

Serum aluminum levels and erythrocyte dihydropteridine reductase activity in patients on hemodialysis.

Simulated acidosis does not impair 1,25-dihydroxyvitamin D3 production by cultured kidney cells

Studies of the effects of acidosis and dietary calcium on 25‐hydroxyvitamin D3 (25OHD3) metabolism were conducted utilizing assays of mitochondrial 1‐hydroxylase and 24‐hydroxylase activity following 96 hours of acid loading. The results showed decreased 1‐hydroxylase (206 ± 6 vs. 132 ± 22 fmol min−1 mg/mitochondrial protein−1, p < 0.01), augmented 24‐hydroxylase (48 ± 14 vs. 180 ± 30 fmol min−1 mg−1, p < 0.001) and increments in plasma calcium and phosphate following acidosis. High calcium diet also increased 24‐hydroxylase activity (48 ± 14 vs. 160 ± 24 fmol min−1 mg−1, p < 0.001) and plasma calcium, but decreased plasma phosphate. The extramitochondrial concentrations of calcium, potassium, and phosphate which maximally stimulated the hydroxylases in vitro were not altered by the in vivo dietary perturbations. The increments in 1‐hydroxylase and 24‐hydroxylase resulting from the presence of calcium, potassium, or phosphate in optimal concentrations (10−5 M, 100 mM, and 100 mM, respectively) were changed by both acid loading and high calcium diet, decreasing in the case of 1‐hydroxylase and increasing in that of 24‐hydroxylase. The data indicate that the suppression of 1‐hydroxylase and augmentation of 24‐hydroxylase following these dietary perturbations may depend on both changed total enzyme capacity and altered enzyme sensitivity to extramitochondrial ions and are consistent with mediation by calcium of the effects of acidosis.

Effect of dietary acid and calcium on 25‐hydroxyvitamin D metabolism by chick kidney

Residual renal function in hemodialysis patients may protect against hyperaluminemia.

Abnormalities of extracellular fluid (ECF) calcium concentration may lead to marked changes in a variety of cellular and organ functions. These include plasma membrane excitability, with consequent changes in neuromuscular, cardiac, endocrine and exocrine functions, transport function of epithelia and bone metabolism. ECF calcium concentration depends on the balance between calcium entry from gut and bone, and its egress via the kidneys and to bone. The bidirectional movement of calcium in and out of bone is coupled and usually nearly equal, resulting in a net flux that in health is close to zero. These processes are under the control of the calcium regulating hormones, amongst which parathyroid hormone and 1,25dihydroxyvitamin D, the active hormonal form of vitamin D, are dominant. Elevation ofplasma calcium concentration reflects imbalance of these processes (see Table I). Effective management of severe acute hypercalcaemia is of paramount importance because although many of these patients may have advanced malignant disease, this is by no means always the case (see the report by Keeling et al.1) and the penalties for failing to identify and treat severe hypercalcaemia may be grave. Such patients may present with polyuria, polydypsia, vomiting, constipation, salt and water depletion, renal impairment, mental changes and coma. In severe cases treatment must be initiated immediately, with the search for underlying cause(s) proceeding in parallel. Management should be directed towards correction or amelioration of the hypercalcaemia itself, the treatment of complications of the hypercalcaemia, and finally attention should be given to the underlying cause of the hypercalcaemia and its correction. The deleterious effect of hypercalcaemia on renal function is of particular importance as this in itself may exacerbate the problem. Hypercalcaemia reduces both glomerular filtration rate and renal tubular reabsorption of water. Urinary concentrating ability is, therefore, impaired at a time when the patient may already be saline depleted due to vomiting, and thus additional losses occur as a result of the hypercalcaemia-induced polyuria. In turn, salt and water depletion further lowers the glomerular filtration rate, decreasing urinary calcium excretion and exacerbating the hypercalcaemia. Successful treatment depends on halting this downward spiral which, if untreated, will progress at an alarming rate.

Effect of Dialysate Buffer on Potassium (K) Removal During Haemodialysis (HD)

Effect of heavy exercise on mineral metabolism and calcium regulating hormone in humans

There is a linear relationship between potassium removal during haemodialysis and plasma potassium (Kp). Kp falls rapidly during the first hour of dialysis but very little during the last two hours of a five hour dialysis. There is a fairly constant movement of potassium from the intracellular to extracellular space throughout dialysis. Total potassium removal is best predicted by pre-dialysis Kp, but change in Kp is related to the impact of dialysis on acid-base status. The choice of acetate or bicarbonate buffered dialysate does not effect potassium removal during dialysis.

Proceedings of the European Dialysis and Transplant Association - European Renal Association. European Dialysis and Transplant Association - European Renal Association. Congress

Effect of dialysate buffer on potassium removal during haemodialysis.

Acute, but not chronic, metabolic acidosis disturbs 25-hydroxyvitamin D3 metabolism.

The effect of extracellular phosphate on the control of 25-hydroxyvitamin D3 24-hydroxylase was studied in normal mice and littermates with X-linked hypophosphatemic rickets (Hyp). 24-Hydroxylase activity and plasma concentrations of 24,25-dihydroxyvitamin D3 were significantly higher in Hyp mice than in normal mice when both groups were fed a normal diet containing 1.22% calcium (Ca) and 0.8% phosphorus (Pi). The differential in 24-hydroxylase activity was exaggerated when serum phosphate was reduced in normal mice by means of a low Pi diet or increased in Hyp mice by means of a high Pi diet. Differences in 24-hydroxylase activity between the two groups of mice were also demonstrated in the presence of varying Pi concentrations in vitro. Thus, in both Hyp and normal mice, 24-hydroxylase activity is influenced in a qualitatively similar manner by serum Pi. Plasma concentrations of 1,25-dihydroxyvitamin D3 were the same in normal and Hyp mice. The data are consistent with the hypothesis that control the renal metabolism of 25-hydroxyvitamin D3 in Hyp mice is reset such tht 24-hydroxylase activity is inappropriate high for the prevailing serum phosphate over a wide range of concentrations.

Abnormal 24-hydroxylation of 25-hydroxyvitamin D in the X-linked hypophosphatemic mouse.

Patterns of female sexual arousal during sleep and waking: Vaginal thermo-conductance studies

Chronic acidosis with metabolic bone disease. Effect of alkali on bone morphology and vitamin D metabolism.

Effect of Acidosis on the Hepatic and Renal Bioactivation of Vitamin D in the Rat

From our previous work we knew that the epidemic of tonsillitis we described was not controlled by the treatment of cases and carriers alone and that full penicillin prophylaxis to all boys on entry was essential. This regimen entailed giving penicillin four times a day; this was difficult to administer and was stopped in 1978, when the epidemic seemed to be under control. Though these measures appeared to be effective, we were unable to claim with certainty that the improvement was ;anything more than fortuitous. A further epidemic began within eight weeks of stopping the prophylaxis (March 1978), which made it more likely that the control we had reported had resulted from penicillin prophylaxis. This new epidemic presented an opportunity to try to determine the minimum amount of prophylactic penicillin required for control. From our results 0 5 g oral phenoxymethylpenicillin given daily to all boys for 10 days after entry seemed effective; when administered at breakfast and before dispersal to their various activities this was not unduly disruptive. Four cases of rheumatic fever occurred in our first survey and there were two further cases during this epidemic. Since the incidence of rheumatic fever in the United Kingdom is now believed to be very low, these attacks highlight the need to control epidemics of tonsillitis in closed communities. Once again we found a sluggish response to prophylaxis. From our previous experience, perhaps we should have foreseen that it would take time to bring the epidemic under control. We do not know whether we could have achieved a quicker response by treating all boys who were in the centre at the height of the epidemic with oral penicillin, but this would seem likely. There may well be a difference between controlling epidemics in closed communities, such as detention centres, which have a changing population, and semi-closed communities, such as boarding schools, which have a more fixed population. Gastanaduy et al2 recently reported an epidemic in a semi-closed community of 300 people that was brought under control in three -or four months by the administration of intramuscular penicillin or oral antibiotics (phenoxymethylpenicillin or erythromycin) to cases and carriers. We have already suggested that adolescent boys may be particularly prone to Streptococcus pyogenes infections. Bringing together boys of this age group into closed communities will compound the problem, especially if the population is always changing. We do not have figures from other detention centres, but we are told that sore throats are very common. We suspect that our experience at Kirklevington is not unique and in the relatively socially deprived group of boys in detention centres the risk of developing rheumatic fever may well be higher than in the general population.

Do patients receiving regular haemodialysis need folic acid supplements?

Loss of folic acid during a seven-hour dialysis was measured in 15 patients, none of whom were taking supplementary folic acid. A single pass system with a 1.0 m2 Meltec Multipoint dialyser and 11-5 ,Lm thickness Cuprophan membranes was used, blood and dialysate flow rates being 220 and 500 ml/ min respectively. Blood samples were taken from the afferent ("arterial") and efferent ("venous") dialyser lines after 30 minutes' dialysis and again after six and a half hours. The means of the two arterial and two venous serum folate concentrations were used to calculate the total loss for each patient. Serum folate concentration was measured in quintuplicate, using a competitive binding assay (Becton Dickinson Folate Radioassay kit; intraassay coefficient of variation 5-9 %). The mean afferent dialyser line ("arterial") serum folate concentration fell significantly from 431 ±SEM 047 to 349±038 jug/l during the six hours' dialysis (p<001). The median loss of folate into the dialyser was 37-3 Htg (range 3-6-91-5 ag).

Do patients receiving haemodialysis need folic acid supplements?

Inevitably, reading is one of the requirements to be undergone. To improve the performance and quality, someone needs to have something new every day. It will suggest you to have more inspirations, then. However, the needs of inspirations will make you searching for some sources. Even from the other people experience, internet, and many books. Books and internet are the recommended media to help you improving your quality and performance.

Results of biochemical investigations were normal except for plasma bilirubin concentration 41 jAmol/l (2-4 mg/100 ml; conjugated bilirubin 20 itmol/l, 1-2 mg/100 ml), serum alanine aminotransferase 279 U/i, serum yglutamyltranspeptidase 339 U/1, serum alkaline phosphatase 1329 U/l, and serum 5'-nucleotidase 31 U/I. Concentrations of (x-fetoprotein and immunoglobulins G, A, and M were normal. Autoantibody screen and hepatitis B surface antigen were negative. An electrocardiogram was normal. Haemoglobin concentration was 10-3 g/dl, white blood cell count 6-4 x 109/1 (6400/mm3; leucoerythroblastic picture), pla-telet count 18 x 109/1 (18000/mm3), reticulocytes 3 %, erythrocyte sedimentation rate 12 mm in first h, plasma viscosity 1-54 mPa s(cp), and leucocyte alkaline phosphatase score 174; serum vitamin B12, folate, and iron concentrations, and serum total iron-binding capacity, were normal. Ham's test and direct Coombs test were negative; kaolin-cephalin clotting time was 37 s, prothrombin time British ratio 1-42, and serum fibrinogen concentration 2-8 g/l. Bone-marrow aspirate taken on three occasions from different sites (sternum and both posterior iliac crests) showed classical changes of bone-marrow necrosis (figure). Examination of core biopsy specimen confirmed this, and no malig-

Spinal fractures in fused spines: nonoperative treatment is a reliable alternative.

D102. HIGHLIGHTS OF EPIDEMIOLOGIC AND CLINICAL RESEARCH IN BEHAVIORAL SCIENCES

The Role of Biologics in Decreasing Asthma Exacerbation Rate: A Systematic Review and Meta-analysis

Introduction Late atrial arrhythmias after catheter ablation for atrial fibrillation occur in up to 30% of post-ablation patients and are increasingly encountered by emergency physicians. However, diagnosing the exact mechanism of the arrhythmia on the surface electrocardiogram (ECG) remains challenging due to atrial scarring leading to heterogeneous P-wave morphology. Case Report A 74-year-old male with a history of prior catheter ablation for atrial fibrillation presented with palpitations and subacute symptoms of heart failure. The patient’s ECG revealed narrow complex tachycardia with more P waves than QRS complexes. The differential diagnosis included typical flutter, atypical flutter, and focal atrial tachycardias with 2:1 conduction block. P waves were positive in V1 and across all precordial leads (absent precordial transition). This favors atypical flutter originating from the left atrium over typical cavotricuspid isthmus-dependent right atrial flutter. Transthoracic echocardiogram showed a reduced ejection fraction due to tachycardia-mediated cardiomyopathy. The patient underwent a repeat electrophysiology study and ablation, which confirmed the presence of an atypical flutter circuit using the mitral annulus, known as perimitral flutter. Repeat catheter ablation resulted in maintenance of sinus rhythm. At follow-up, his ejection fraction recovered. Conclusion Recognizing ECG findings suggestive of atypical flutter impacts initial emergency department decisions and triage as atypical flutter post-atrial fibrillation ablation is frequently resistant to rate-controlling medications and often requires cardiology and/or electrophysiology consultation if available.

Diagnosing Atypical Flutter in the Post-atrial Fibrillation Ablation Patient: A Case Report

Reply to Letter to the Editor: Spinopelvic Dissociation: A Systematic Review and Meta-analysis.

Objective: Exertional rhabdomyolysis results from a breakdown of skeletal muscle cells after intense exercise in otherwise healthy patients, causing increased levels of creatine kinase (CK) or myoglobin, as well as urine dipstick positive for blood, and may result in kidney insufficiency. The aim of this study was to outline the current perspectives of exertional rhabdomyolysis in athletes and subsequent treatment based on the current literature. Data Sources: We searched the MEDLINE/PubMed and Google databases for ([exercise] OR [exertional]) AND rhabdomyolysis following the PRISMA guidelines. All abstracts were reviewed by 2 independent examiners. Inclusion criteria consisted of original articles presenting studies on exertional rhabdomyolysis or exercise-induced rhabdomyolysis with 7 or more cases. All case reports, case series, or editorials were excluded. Main Results: A total of 1541-abstracts were screened, leaving 25 studies for final inclusion and analysing 772patients. Especially, young male patients were affected at a mean age of 28.7 years (range 15.8-46.6 years). Most of the athletes performed running, including marathons in 54.3% of cases (n = 419/772), followed by weightlifting in 14.8% (n = 114/772). At the time of presentation, the mean creatine kinase was 31 481 IU/L (range 164-106,488 IU/L). Seventeen studies reported the highest level of CK, which was 38 552 IU/L (range 450-88,496 IU/L). For treatment, hydration was the most common method of choice reported by 8 studies. Conclusions: Exertional rhabdomyolysis seems to be underestimated, and it is essential to screen patients who present with muscle soreness/cramps and/or dark urine after heavy endurance events to avoid any further complications. Level of Evidence: II; systematic review.

Exertional Rhabdomyolysis in Athletes: Systematic Review and Current Perspectives

Smartphones and their associated applications are used frequently by patients and clinicians alike. Despite the technology being widely accessible, their use to aid in rehabilitation is yet to be adopted. The SARS CoV-2 pandemic has presented an opportunity to expedite their integration given the difficulty patients currently have in accessing healthcare. The aim of this study was to perform a systematic literature review on the use of smartphone rehabilitation applications compared to standard physiotherapy for back pain. We conducted a search of Medline/Pubmed and google databases using the search terms [APP] AND [[Orthopaedic] OR [Neurosurgery]], following the PRISMA guidelines. All prospective studies investigating rehabilitation applications for back pain or following spine surgery were included. A total of nine studies met the inclusion criteria which investigated 7636 patients, of which 92.4% were allocated to the interventional group (n = 7055/7636) with a follow up of 4 weeks to 6 months. All except one study reported on patients experiencing back pain on average for 19.6 ± 11.6 months. The VAS-pain score was presented in all studies without significance between the interventional and control group (p = 0.399 before and p = 0.277 after intervention). Only one research group found significantly higher improvement in PROMs for the application group, whereas the remaining showed similar results compared to the control group. Using application-based rehabilitation programs provides an easily accessible alternative or substitute to traditional physiotherapy for patients with back pain. Given that smartphones are so prevalent in activities in our daily lives, this will enhance and improve rehabilitation if patients are self-dedicated and compliant.

Concussive symptoms in emergency department patients diagnosed with minor head injury.

Radiation Damage of Silicon and Diamond by High Energy Neutrons, Protons and α Particles

Spend your time even for only few minutes to read a book. Reading a book will never reduce and waste your time to be useless. Reading, for some people become a need that is to do every day such as spending time for eating. Now, what about you? Do you like to read a book? Now, we will show you a new book enPDFd solutions to selected problems from the physics of radiology that can be a new way to explore the knowledge. When reading this book, you can get one thing to always remember in every reading time, even step by step.

A Measurement of the Lifetimes of $D^+_s$ and $D^+$ Mesons in High-Energy Photoproduction

DIAGRAM TECHNIQUES AND CLASSIFICATION PROBLEMS IN HIGH ENERGY PHYSICS.

The representation method of obtaining first and second type Landau curves from the Landau criteria is described. The Plucker characteristic analysis of singular curves is outlined and its relationship with the theory of automorphic functions indicated. A differential approach to singularity classification is discussed and a possible extension of the method to obtain asymptotic behaviour is conjectured. 
 
A preliminary form of some of the material here presented was the basis of a lecture given by the author at the University of Wales Colloquium in Applied Mathematics, Gregynog, 1969.

A differential approach to high energy behaviour of feynman amplitudes

Complex singularities in the ",+N --? "'+ ",+N amplitude corresponding to vertex contractions of the single-loop Feynman diagram exist on the physical sheet of the amplitude irrespective of whether the theory is formulated in terms of timeordered or retarded products_

Let us denote by Pi> i = 1, 2, ... , 5, the four-momenta of the internal lines of the five-point single-loop graph (p~ = fLi). Each vertex may then be labeled by two suffices and we shall denote the four-momenta of the external particles (measured formally as incoming) by P12 = PI' P23 = P2, ... ,P51 = P5 (P~ = M~). Scalar product variables may be constructed as follows

A formula for the number of independent variables describing the scattering of n-particles (neutral scalar bosons) is presented. (C.E.S.)

Modes of analytic continuation of scattering amplitudes are studied. Some features of paths, connecting regions where the amplitudes are mathematically well defined to ones of physical interest, and which lie on the Landau curves, are described.

THE ANALYTIC STRUCTURE OF FUNCTIONS DEFINED BY MULTIPLE INTEGRALS

A perturbation theoretic approach to the analytic properties of collision amplitudes

Sensitive and specific biomarkers for pancreatic cancer are currently unavailable. The high mortality associated with adenocarcinoma of the pancreatic epithelium justifies the broadest possible search for new biomarkers that can facilitate early detection or monitor treatment efficacy. Protein glycosylation is altered in many cancers, leading many to propose that glycoproteomic changes may provide suitable biomarkers. In order to assess this possibility for pancreatic cancer, we have performed an in-depth LC-MS/MS analysis of the proteome and MS(n)-based characterization of the N-linked glycome of a small set of pancreatic ductal fluid obtained from normal, pancreatitis, intraductal papillary mucinous neoplasm (IPMN), and pancreatic adenocarcinoma patients. Our results identify a set of seven proteins that were consistently increased in cancer ductal fluid compared to normal (AMYP, PRSS1, GP2-1, CCDC132, REG1A, REG1B, and REG3A) and one protein that was consistently decreased (LIPR2). These proteins are all directly or indirectly associated with the secretory pathway in normal pancreatic cells. Validation of these changes in abundance by Western blotting revealed increased REG protein glycoform diversity in cancer. Characterization of the total N-linked glycome of normal, IPMN, and adenocarcinoma ductal fluid clustered samples into three discrete groups based on the prevalence of six dominant glycans. Within each group, the profiles of less prevalent glycans were able to distinguish normal from cancer on this small set of samples. Our results emphasize that individual variation in protein glycosylation must be considered when assessing the value of a glycoproteomic marker, but also indicate that glycosylation diversity across human subjects can be reduced to simpler clusters of individuals whose N-linked glycans share structural features.

Discrimination between adenocarcinoma and normal pancreatic ductal fluid by proteomic and glycomic analysis.

Specific protein glycoforms may be uniquely informative about the pathological state of a cyst and may serve as accurate biomarkers. Here we tested that hypothesis using antibody-lectin sandwich arrays in broad screens of protein glycoforms and in targeted studies of candidate markers. We profiled 16 different glycoforms of proteins captured by 72 different antibodies in cyst fluid from mucinous and nonmucinous cysts (n = 22), and we then tested a three-marker panel in 22 addition samples and 22 blinded samples. Glycan alterations were not widespread among the proteins and were mainly confined to MUC5AC and endorepellin. Specific glycoforms of these proteins, defined by reactivity with wheat germ agglutinin and a blood group H antibody, were significantly elevated in mucinous cysts, whereas the core protein levels were not significantly elevated. A three-marker panel based on these glycoforms distinguished mucinous from nonmucinous cysts with 93% accuracy (89% sensitivity, 100% specificity) in a prevalidation sample set (n = 44) and with 91% accuracy (87% sensitivity, 100% specificity) in independent, blinded samples (n = 22). Targeted lectin measurements and mass spectrometry analyses indicated that the higher wheat germ agglutinin and blood group H reactivity was due to oligosaccharides terminating in GlcNAc or N-acetyl-lactosamine with occasional α1,2-linked fucose. The results show that MUC5AC and endorepellin glycoforms may be highly specific and sensitive biomarkers for the differentiation of mucinous from nonmucinous pancreatic cysts.

Specific Glycoforms of MUC5AC and Endorepellin Accurately Distinguish Mucinous from Nonmucinous Pancreatic Cysts*

Interobserver agreement for EUS findings in familial pancreatic-cancer kindreds.

The Victorian Speed Management Policy Committee requested that a study beundertaken to gain a better understanding of actual speeds through strip shopping centres, with a view to developing guidelines for the use of time-based speed limits should they be warranted. Speed surveys were undertaken in ten typical strip shopping centres to produce a graphical and tabular illustration of speed profiles through each of the shopping centres overa 24 hour period for three days. This paper reports on the findings of these surveys. The paper concludes that there is not a significant speeding problem through strip shopping centres during shopping hours, with respect to the current legal limit of 60 km/h. In an environment where significant numbers of vehicles are already constrained to travelling at or below40 km/h, the use of part-time speed limits is considered to be unnecessary and is likely to raise a number of administrative and practical problems. (a) For the covering abstract of this conference see IRRD abstract no. 861222.

SUBTITLE: AMTRAK'S PETER CANNITO, VICE PRESIDENT OF ENGINEERING AND MECHANICAL, AND JOHN CUNNINGHAM, ASSISTANT CHIEF ENGINEER OF M/W AND STRUCTURES, ADDRESS AMTRAK'S UNIQUE ENGINEERING CHALLENGES.

A methodology for processing measurements of rail geometry to help assess the ability of the track to satisfy its present and future requirements is advanced. The emphasis is on Amtrak's passenger service in the Northeast Corridor. The technology described is amenable to other situations where guideway geometry-vehicle dynamic interactions are an issue, and where unsatisfactory responses of track and vehicles can be expressed in an object manner. The method of assessment consists of processing surface and line parameters into 1/3-octave components. This approach is appropriate for treating vehicle resonances whose widths are 1/3-octave or broader. It is also in accordance with evaluating human responses to vibration exposure as specified in standard ISO/DIS 2631.<<ETX>>

A Robotic Controlled Backhoe Loader to Provide Support for Wounded Soldiers to Return to the Civilian Construction Industry

The current-carrying capacity of overhead lines is dependent on weather conditions. Overhead lines can safely carry more than their rated capacity during periods of low ambient temperature or high wind speeds due to cooling effects. Dynamic line rating involves quantifying this additional capacity in real time as local weather conditions change. Increases in line rating due to high wind speeds are anticipated to coincide with moments when increased capacity is required due to wind generation. This paper provides details on the monitoring equipment used and the various rating algorithms and issues with determining the current-limiting section of the line. Building upon earlier work [1], this paper describes the learning gained using the monitoring system and suggests areas of improvement. Preliminary results and an assessment of the increase in capacity provided by dynamic line rating are presented.

2009 44th International Universities Power Engineering Conference (UPEC)

Methodology for applying real-time ratings to wood pole supported overhead lines

In mid 2008 and early 2009 Deutsche Bank and The Boston Consulting Group each released separate reports detailing projected Battery Electric Vehicle production through 2020. These reports both outlined scenarios in which BEVs gained significant market share (1-2%) by the end of the decade. To analyze the magnitude of the annual growth rates needed to obtain these sales figures, similar case studies were identified and evaluated. The transition from gasoline to diesel power in France between 1970 and 2005 (11% average annual growth) as well as the introduction of Hybrid Gasoline-Electric vehicles to the US (46% average annual growth) were selected as relevant points of comparison. Through a review of all major automotive manufacturers, as well as BEV-focused startups, press releases best case and worst case estimates for total BEV production in 2010 and 2011 were obtained. Using these figures it was determined that in a best case, near term production scenario annual production rates would need to average 35 to 40% annual growth over the next 10 years, and in a worst case near term production scenario would need to average in excess of 45% annual growth to reach production estimates. Thesis Supervisor: John B. Heywood Title: San Jae Professor of Mechanical Engineering Director, Sloan Automotive Lab

This article describes the design and potential use in the UK of the Parry People Movers railcar, an electric single-coach vehicle operating on railway track. A vehicle is currently in use to provide a Sunday service along a branch line in the English Midlands. The innovative propulsion system stores kinetic energy using a spinning flywheel, which can power the vehicle for up to two and a half miles. An onboard combustion engine (currently running on liquefied petroleum gas) or an external intermittent electrical charge (IEC) is used to spin the flywheel initially. Use of an IEC involves an outboard arm making contact with an energised rail under the platform at a station. Regenerative braking also re-energises the flywheel. It is hoped that this vehicle, cheap and efficient to operate, will help to keep little-used branch railway lines in use.

Steel-maker Corus of Corby, UK, which manufactures crash barriers, has collaborated with DAF Trucks on crash simulations involving heavy goods vehicles. Using simulation and engineering data supplied by DAF and in tandem with DAF engineers, Corus produced crash software that analysed lorry impacts with crash barriers. This led to improvements in barrier performance and reliability and reduced costs. The software helped in the design of the Vetex untensioned barrier systems, which are faster and simpler to install and easier to maintain than traditional systems. The collaboration gave DAF engineers simulation data on crash barriers that could be used in truck design. DAF can assess the interactions between barrier and impacting truck and optimise truck crash absorption systems, minimising risks to drivers and other vehicle users. The collaboration has cut development times and costs to both companies.

This article looks at the design and use of computer software in engine control. The accelerator pedal is effectively a potentiometer used to measure throttle position and has no direct mechanical link to the engine. When there is a throttle demand, thousands of calculations are done to take into account information from various sensors around the vehicle and then to select an appropriate fuel setting. Programmers and engineers work closely together to achieve the design aims. Software designers check the programming code to avoid the risk of computer failure while the engine is running, and most of the systems have back-up provision. Special characteristics are built in to the control system for off-road vehicles which suffer extra vibration from the driver's foot on the pedal.

Kuwait Oil Company (KOC) has installed and operated gas turbines since 1957. There are currently 79 Gas Turbines ranging in size from 700 to 33,000 H.P. of various types, from industrial to aero-derivative.Gas turbines provide more than half a million in horsepower, which is more than 80% of the power, for machinery and power generation at KOC.This paper covers the introduction and the rappid growth of gas turbine power at KOC. Operational sites at KOC are subject to severe heat, dust and humidity. The experience in the operation and maintenance in the early years of the gas turbines at KOC are described.Gas turbines have played a major role in the success of the Company.Copyright © 1988 by ASME

Gas Turbine Application Over Thirty Years in a Middle East Oil Production Facility

We have tested a large superconducting linear synchronous motor designed for high-speed magnetically levitated vehicles. A single superconducting magnet, from the array of 45 carried by the proposed vehicle, interacts with guideway windings mounted on the rim of a 7.6 m diameter rotating wheel. The split 3-phase "stator" windings are energized from a variable-frequency 40 kVA current-source inverter power supply. All forces and torques developed on the magnet have been monitored over the complete 360° cycle of force angle for a range of suspension heights, lateral displacements, and pitch, roll and yaw angles, at speeds up to 100 km/h. Controlled starting, stopping and section entry have been demonstrated. The results are in excellent agreement with analysis based on mutual inductance computations and on a coupled circuit model of the machine. Highlights of the results are discussed.

A linear synchronous motor has been designed to propel a 480 km/h magnetically levitated passenger vehicle. The paper describes the motor and presents results of tests which have been performed on essentially full-scale components of the motor using a 7.6 m-diameter test-wheel facility. Controlled starting, acceleration, cruising, deceleration and transient operation have been demonstrated. A 6-component force balance has been used to measure the three forces and three moments acting on a single stationary superconducting magnet due to its interaction with the split 3-phase windings mounted on the rim of the test wheel and energized by a variable-frequency current-controlled inverter power supply. Measured forces and terminal characteristics over complete cycles of force angle are claimed to be in agreement with analysis based on a coupled circuit model of the machine and mutual inductance computations. Moments were measured to be small under all operating conditions. Two modes of control have been demonstrated. The alpha -scheme, proposed for a full-scale system, maintains the angle between induced voltage and phase current at a value which optimizes the motor characteristics, i.e. inverter Mva rating, etc. beta- control, which may be required for starting, uses vehicle position detectors to fire the inverter thyristors at appropriate times.

DESIGN, ANALYSIS AND TEST RESULTS FOR A SUPERCONDUCTING LINEAR SYNCHRONOUS MOTOR

Background Despite considerable efforts devoted to the development of prevention interventions aiming at reducing unhealthy alcohol use in tertiary students, their delivery remains often challenging. Interventions including information technology are promising given their potential to reach large parts of the population. Objective This study aims to develop a secondary prevention smartphone app with an iterative qualitative design involving the target population. Methods The app development process included testing a first prototype and a second prototype, developed based on the results of 2 consecutive qualitative assessments. Participants (aged ≥18 years, screened positive for unhealthy alcohol use) were students from 4 tertiary education institutions in the French-speaking part of Switzerland. Participants tested prototype 1 or prototype 2 or both and provided feedback in 1-to-1 semistructured interviews after 2-3 weeks of testing. Results The mean age of the participants was 23.3 years. A total of 9 students (4/9 female) tested prototype 1 and participated in qualitative interviews. A total of 11 students (6/11 female) tested prototype 2 (6 who tested prototype 1 and 5 new) and participated in semistructured interviews. Content analysis identified 6 main themes: “General Acceptance of the App,” “Importance of the Targeted and Relevant App Content,” “Importance of Credibility,” “Importance of the App Usability,” “Importance of a Simple and Attractive Design,” “Importance of Notifications to Ensure App Use over Time.” Besides a general acceptance of the app, these themes reflected participants’ recommendations toward increased usability; to improve the design; to include useful and rewarding contents; to make the app look serious and credible; and to add notifications to ensure its use over time. A total of 11 students tested prototype 2 (6 who tested prototype 1 and 5 new) and participated in semistructured interviews. The 6 same themes emerged from the analysis. Participants from phase 1 generally found the design and content of the app improved. Conclusions Students recommend prevention smartphone apps to be easy to use, useful, rewarding, serious, and credible. These findings may be important to consider when developing prevention smartphone apps to increase the likelihood of app use over time. Trial Registration ISRCTN registry 10007691; https://www.isrctn.com/ISRCTN10007691 International Registered Report Identifier (IRRID) RR2-10.1186/s13063-020-4145-2

Development of a Secondary Prevention Smartphone App for Students With Unhealthy Alcohol Use: Results From a Qualitative Assessment

Introduction: This study examines normative misperceptions in a sample of participants recruited for a brief intervention trial targeting risky cannabis use. Methods: Participants who were concerned about their own risky cannabis use were recruited to help develop and evaluate intervention materials. At baseline, participants reported on their own cannabis use and provided estimates of how often others their gender and age used cannabis in the past 3 months. Comparisons were made between participants estimates of others cannabis use with reports of cannabis use obtained from a general population survey conducted during a similar time period. Results: Participants (N = 744, mean age = 35.8, 56.2% identified as female) largely reported daily or almost daily cannabis use (82.4%). Roughly half (55.3%) of participants estimated that others their age and gender used cannabis weekly or more often in the past 3 months, whereas the majority of people in the general population reported not using cannabis at all. Conclusions: Normative misperceptions about cannabis use were common in this sample of people with risky cannabis use. Limitations and possible future directions of this research are discussed, as well as the potential for targeting these misperceptions in interventions designed to motivate reductions in cannabis use. ClinicalTrials.org number: NCT04060602

Normative Misperceptions About Cannabis Use in a Sample of Risky Cannabis Users

Applying the Canadian Low-Risk Gambling Guidelines to Gambling Harm Reduction in England

Disentangling Medicinal and Recreational cannabis Use Among People Living with HIV: An Ecological Momentary Assessment Study

Examining the influence of rurality on frequency of cannabis use and severity of consequences as moderated by age and gender.

Using a consistency check during data collection to identify invalid responding in an online cannabis screening survey

Primary, secondary, and tertiary reinforcement contribute to the maintenance of smoking behaviour and may influence the efficacy of different cessation treatments. This analysis examined these relationships in a large general population sample and investigated how previous experiences of the different reinforcement mechanisms impacted future quit attempts. Random digit telephone dialing was used to recruit a sample of Canadian adults who smoked and were interested in being part of a hypothetical program that would provide nicotine replacement therapy (NRT) patches free by mail and half of the eligible participants were randomized to actually receive a five-week supply of NRT patches. During the interviews, reasons for relapse to smoking during previous quit attempts were collected and coded by two reviewers (disagreements were settled by a third reviewer). Binary logistic regression was used to determine if type of reinforcer moderated the intervention effect of the patches. Participants who made cessation attempts in the past year were more likely to report negative (p = .039), secondary (p = .041), and tertiary (p = .010) reinforcers and less likely to report positive reinforcers (p = .016) compared to those who did not attempt to quit. Logistic regressions revealed no significant conditional effects of the intervention on the relationship between reinforcer type and quit attempts or 30-day smoking abstinence. Analysis including all three reinforcers showed negative reinforcers decreased but tertiary reinforcers increased the odds participants reported a cessation attempt before the baseline interview and between baseline and 8-weeks. Understanding the different ways nicotine reinforces smoking behaviour could help guide individuals to more effective treatment options.

Learning to quit: can reinforcement theories predict the success of smoking cessation attempts using nicotine replacement therapy patches in a general population sample of smokers at 8-weeks and 6-months follow-up?

Concentrated Distribution of Nicotine Patches to a Town With High Smoking Rates—Any Evidence of Large Impacts on Tobacco Cessation?

Recruitment methods may influence prevalence estimates of people identifying as being in recovery from hazardous alcohol use.

Augmenting an online self-directed intervention for gambling disorder with a single motivational interview: study protocol for a randomized controlled trial

Abstract Purpose: The general public’s attitudes toward former heavy drinkers can impact on the wellbeing of these individuals. The current study sought to determine if describing a former heavy drinker as ‘in recovery,’ and varying the amount they drank, impacts the general public’s perceptions of how the person is functioning (both personally and as a member of society), their need for treatment, and the possibility of a moderate drinking recovery. Materials and methods: An online panel survey (n = 4450; adults from multiple countries) asked participants to read a brief vignette describing a former heavy drinker (i.e. John). Participants were randomized to receive a vignette in which John was described as ‘in recovery’ (vs. no mention of recovery) and as having consumed heavy (vs. very heavy) amounts of alcohol prior to seeking help. Participants were then asked to rate John on how he is functioning, and to also rate the possibility of his recovery with or without treatment and as abstinent or a current moderate drinker. Results and Conclusions: Participants who read the vignette in which John was described as being in recovery rated him as being more likely to be functioning well compared to those where no mention of ‘recovery’ was made. However, this manipulation did not impact ratings regarding the likelihood of untreated and moderate drinking recoveries. Varying the amount of drinking described did not impact ratings of how John was functioning but very heavy (compared to heavy) drinking reduced ratings of the likelihood of untreated and moderate drinking recoveries.

The impact of describing someone as being in recovery from alcohol problems on the general public’s beliefs about their life, use of treatment, and drinking status

Abstract Background The objective of this project is to determine the effectiveness of targeting a community with a high smoking rate with the distribution of free-of-charge nicotine patches in order to promote tobacco cessation. Methods/Design One small community with an elevated smoking rate (compared to national and provincial averages) has been identified. All households in the community will be sent a letter offering one smoker (18 years or older; 10 or more cigarettes per day) in the household a free-of-charge mailed five-week supply of nicotine patches (up to a total of 800 five-week kits will be available for distribution). Participants receiving nicotine patches will be asked to complete a six-month follow-up survey assessing tobacco cessation defined as 30-day point prevalence abstinence. In addition, attempts will be made to employ ongoing national population surveys containing cigarette smoking variables to compare changes in smoking prevalence in the target community to other communities with similar characteristics. Discussion We will examine whether the concentrated distribution of mailed nicotine patches will result in a measurable reduction in smoking rates in the target community. If demonstrated, this would provide support for the targeted population-level distribution of an effective individual-level public health intervention. Clinical Trials registration NCT04534231

Offering nicotine patches to all households in a community with high smoking rates: Pilot test of a population-based approach to promote tobacco cessation

Despite a strong link between suicide risk and depression, a recent literature review found that many effectiveness studies for online depression interventions exclude individuals at risk of suicide. This study scrutinizes how different suicide risk exclusion criteria impact recruitment rates and final sample characteristics.

Two recruitment periods for an online depression intervention trial utilized different suicide risk cutoff exclusion criteria, a one-point difference on the last item of the Personal Health Questionnaire (i.e., more than 0 (Not at all) vs. more than 1 (Several Days)). Bivariate statistics were used to assess differences in recruitment rates and sample characteristics between these two recruitment periods, while all other eligibility criteria and recruitment strategies remained consistent.

RESULTS
The recruitment period using the least restrictive suicide risk exclusion criteria yielded twice as many participants; however, recruited sample characteristics did not significantly differ among demographic or clinical characteristics, despite observable trends.

Researchers should carefully select suicide risk exclusion criteria that balance recruitment rates, study budgets, and sample selection biases, while minimizing participant harm. Moreover, researchers are urged to report suicide risk exclusion rates and consider these exclusions when interpreting results. Limitations of the results are also discussed.

Falling between the cracks: The effect of using different levels of suicide risk exclusion criteria on sample characteristics when recruiting for an online intervention for depression.

Online personalized feedback intervention to reduce risky cannabis use. Randomized controlled trial

There is little evidence relating to the effects of adding guidance to internet-based gambling interventions. The primary aim was to compare the effectiveness of an online self-directed cognitive-behavioural gambling program (GamblingLess) with and without therapist-delivered guidance. It was hypothesised that, compared to the unguided intervention, the guided intervention would result in superior improvements in gambling symptom severity, urges, frequency, expenditure, psychological distress, quality of life and help-seeking. A two-arm, parallel-group, randomised trial with pragmatic features and three post-baseline evaluations (8 weeks, 12 weeks, 24 months) was conducted with 206 gamblers (106 unguided; 101 guided). Participants in both conditions reported significant improvements in gambling symptom severity, urges, frequency, expenditure, and psychological distress across the evaluation period, even after using intention-to-treat analyses and controlling for other low- and high-intensity help-seeking, as well as clinically significant changes in gambling symptom severity (69% recovered/improved). The guided intervention resulted in additional improvements to urges and frequency, within-group change in quality of life, and somewhat higher rates of clinically significant change (77% cf. 61%). These findings, which support the delivery of this intervention, suggest that guidance may offer some advantages but further research is required to establish when and for whom human support adds value.

GamblingLess: A Randomised Trial Comparing Guided and Unguided Internet-Based Gambling Interventions

Are former heavy drinkers in the UK less likely to identify as being in recovery compared to those in the USA? A pilot test

Use of additional nicotine replacement therapy by participants in a five-year follow-up of a tobacco cessation trial.

Randomized controlled trial of online interventions for co-occurring depression and hazardous alcohol consumption: Primary outcome results

Stigmatisation of alcohol and other drug (AOD) use disorders poses a significant barrier to treatment access. A review by the World Health Organization concluded that addictive disorders were the most stigmatised health condition. Few studies have examined whether different etiological models of addiction (MOA) have implications for public stigma toward AOD disorders. The current study examined whether beliefs representative of five MOA predict public stigma levels and whether stigma differs for AOD use disorders relative to other health conditions.

METHODS
Survey data were collected from Canada, the USA and Australia using an online data collection platform. Participants were randomised to one of four vignette manipulations describing an individual with an alcohol use disorder and/or other disorder. Participants' stigma toward the vignette character and beliefs related to five MOA (disease, moral, psychological, sociological, nature) were measured.

RESULTS
Stigma ratings were significantly higher in the alcohol use disorder condition compared to other conditions. Two MOA accounted for significant variance in stigma ratings, where greater beliefs in the nature and psychological MOA predicted significantly lower levels of stigma toward alcohol use disorder. Contrary to predictions, beliefs in the disease MOA did not relate to lower stigma. Lastly, beliefs in the moral MOA partly accounted for geographical region differences (the USA vs. Canada) in public stigma.

DISCUSSION AND CONCLUSIONS
The current study provides further experimental support that AOD disorders are more stigmatised than others. Additionally, the findings suggest that MOA may relate differentially to perceived stigma, and that regional variability in such beliefs exists.

Implications of addiction diagnosis and addiction beliefs for public stigma: A cross-national experimental study.

Information technology and addiction science: promises and challenges

Online interventions for problem gamblers with and without co-occurring unhealthy alcohol use: Randomized controlled trial

Commentary on Mellis & Bickel (2020): The particular case of conducting addiction intervention research on Mechanical Turk.

Abstract Background Some research suggests that internet interventions aimed at people with problematic alcohol use are more effective when provided with guidance from a therapist or coach. Purpose/Objectives: This trial intended to compare the effects of a previously evaluated internet intervention for people with problematic alcohol use when delivered with or without brief email guidance. Methods: Using online advertising, 238 participants, 18 years or older, were recruited and randomized to receive access to the Internet intervention Alcohol Help Center with or without brief email guidance from a health educator. The guidance consisted of at least four structured, slightly individualized emails delivered during the first two weeks after randomization. Participants were followed up at 3 and 6 months. Results: Number of log-ins did not differ significantly between groups throughout the follow-up period. The follow-up rate at 6 months was 47.0%. Generalized estimating equations run on the primary (standard drinks in preceding week/heavy drinking days in preceding week) and secondary outcome variables (AUDIT, AUDIT-C, quality of life) revealed no significant differences between the interventions on any of the outcomes. Conclusions/Importance: The study does not provide support for any added benefits of providing brief guidance via email in an internet intervention for problem drinkers.

Can Brief Email Guidance Enhance the Effects of an Internet Intervention for People with Problematic Alcohol Use? A Randomized Controlled Trial

Can the AUDIT consumption items distinguish lower severity from high severity patients seeking treatment for alcohol use disorder?

Examining Change in Self-Reported Gambling Measures Over Time as Related to Socially Desirable Responding Bias

Smartphone-based secondary prevention intervention for university students with unhealthy alcohol use identified by screening: study protocol of a parallel group randomized controlled trial

Five-Year Follow-up of a Randomized Clinical Trial Testing Mailed Nicotine Patches to Promote Tobacco Cessation Our previous randomized clinical trial1 demonstrated that smokers receiving nicotine patches by mail (5 weeks of nicotine patches) were more likely to report 30-day point prevalence abstinence at 6 months compared with smokers not mailed nicotine patches. The current project extends this research by recontacting participants after 5 years.

Five-Year Follow-up of a Randomized Clinical Trial Testing Mailed Nicotine Patches to Promote Tobacco Cessation.

Background Due to a conscious or unconscious desire to be perceived favorably by others, some participants may under or overexaggerate when reporting sensitive behaviors or attitudes, including those related to addictions. This socially desirable responding bias should be considered when using self-reports in predictive models since it introduces error. Methods A total of 1711 participants were recruited using Amazon's Mechanical Turk crowdsourcing platform for two randomized controlled trials investigating the effectiveness of brief online interventions for hazardous alcohol use. At baseline, participants completed the Balanced Inventory of Desirable Responding (BIDR). Four measures of alcohol use were collected at baseline and follow-up: number of drinks consumed in a typical week, on one occasion, consequences experienced, and amount of perceived risk of injury or illness from alcohol use. Results As expected, individuals scoring high on the BIDR subscales reported less alcohol use and related behaviors (p < 0.05); however, repeating the analyses for each gender showed no difference for females asked direct questions about the frequency of their alcohol use. Mixed-effects models investigating the interaction of socially desirable responding bias over time on alcohol-related measures showed some significant differences in the amount of change reported depending on BIDR scores. Participants with higher self-deceptive enhancement scores reported less change over time in their ratings of risk of illness or injury (p = 0.001) compared to lower-scoring participants. Likewise, high-scoring participants reported less change in the number of consequences experienced due to alcohol use over time on both BIDR subscales. Neither direct measure of alcohol use seemed affected by BIDR scores over time. A different pattern was found in males and females analyzed separately. Conclusions These findings suggest that researchers should consider including measures of socially desirable responding bias in longitudinal studies involving self-reported alcohol use, particularly when modeling alcohol-related measures using rating scales across time. In addition, separate gender analyses may be appropriate. Trial registration: ClinicalTrials.gov NCT03008928. Registered 30 December 2016; ClinicalTrials.gov NCT03060135. Registered 17 February 2017

To Thine Own Self, be True: Examining Change in Self-Reported Alcohol Measures over Time as Related to Socially Desirable Responding Bias among People with Unhealthy Alcohol Use

Targeting mailed nicotine patch distribution interventions to rural regions of Canada: protocol for a randomized controlled trial

Beliefs about cannabis at the time of legalization in Canada: results from a general population survey

Background: In primary care, electronic self-administered screening and brief interventions for unhealthy alcohol may overcome some of the implementation barriers of face-to-face intervention. We developed an anonymous electronic self-administered screening brief intervention device for unhealthy alcohol use and assessed its feasibility and acceptability in primary care practice waiting rooms. Two modes of delivery were compared: with or without the presence of a research assistant (RA) to make patients aware of the device's presence and help users. Using the device was optional. Methods: The devices were placed in 10 participating primary care practices waiting rooms for 6 weeks, and were accessible on a voluntary basis. Number of appointments by each practice during the course of the study was recorded. Access to the electronic brief intervention was voluntary among those who screened positive. Screening and brief intervention rates and characteristics of users were compared across the modes of delivery. Results: During the study, there were 7270 appointments and 1511 individuals used the device (20.8%). Mean age of users was 45.3 (19.5), and 57.9% screened positive for unhealthy alcohol use. Of them, 53.8% accessed the brief intervention content. The presence of the RA had a major impact on the device's usage (59.6% vs 17.4% when absent). When the RA was present, participants were less likely to screen positive (49.4% vs 60.7%, P = 0.0003) but more likely to access the intervention (62.7% vs 51.4%, P = 0.009). Results from the satisfaction survey indicated that users found the device easy to use (93.5%), questions useful (89–95%) and 77.2% reported that their friends would be willing to use it. Conclusions: This pilot project indicates that the implementation of an electronic screening and brief intervention device for unhealthy alcohol is feasible and acceptable in primary care practices but that, without human support, its use is rather limited.

Electronic Screening and Brief Intervention for Unhealthy Alcohol use in Primary Care Waiting Rooms – a Pilot Project

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The last 10 years: any changes in perceptions of the seriousness of alcohol, cannabis, and substance use in Canada?

How one small text change in a study document can impact recruitment rates and follow-up completions

While the Internet has become a popular and effective strategy for recruiting substance users into research, there is a large risk of recruiting duplicate individuals and Internet bots that pose as humans. Strategies to mitigate these issues are outlined and categorized into two groups: (1) automatic techniques which are often embedded into surveys and (2) ongoing manual techniques implemented during recruitment. Potential limitations of these strategies are discussed, and an example of the prevalence of duplicate data within a substance using sample is provided. Overall, it is recommended that researchers consider the use of routine strategies to mitigate the risks associated with recruiting online samples such as: verifying participant contact information, IP address checks, and ongoing cross-checking of participant information for duplicates, similarities and inconsistencies.

Out Damn Bot, Out: Recruiting Real People into Substance Use Studies on the Internet

Pilot study of a repeated random sampling method for surveys focusing on date-specific differences in alcohol consumption among university students

Outcomes of two randomized controlled trials, employing participants recruited through Mechanical Turk, of Internet interventions targeting unhealthy alcohol use

Online Self-Directed Interventions for Gambling Disorder: Randomized Controlled Trial

Smartphone application for unhealthy alcohol use: Pilot randomized controlled trial in the general population.

Pilot randomized controlled trial of an online intervention for problem gamblers

Randomized controlled trial of an Internet intervention for problem gambling provided with or without access to an Internet intervention for co-occurring mental health distress

A randomized trial of brief web-based prevention of unhealthy alcohol use: Participant self-selection compared to a male young adult source population

Background Face-to-face brief interventions for problem drinking are effective, but they have found limited implementation in routine care and the community. Internet-based interventions could overcome this treatment gap. We investigated effectiveness and moderators of treatment outcomes in internet-based interventions for adult problem drinking (iAIs). Methods and findings Systematic searches were performed in medical and psychological databases to 31 December 2016. A one-stage individual patient data meta-analysis (IPDMA) was conducted with a linear mixed model complete-case approach, using baseline and first follow-up data. The primary outcome measure was mean weekly alcohol consumption in standard units (SUs, 10 grams of ethanol). Secondary outcome was treatment response (TR), defined as less than 14/21 SUs for women/men weekly. Putative participant, intervention, and study moderators were included. Robustness was verified in three sensitivity analyses: a two-stage IPDMA, a one-stage IPDMA using multiple imputation, and a missing-not-at-random (MNAR) analysis. We obtained baseline data for 14,198 adult participants (19 randomised controlled trials [RCTs], mean age 40.7 [SD = 13.2], 47.6% women). Their baseline mean weekly alcohol consumption was 38.1 SUs (SD = 26.9). Most were regular problem drinkers (80.1%, SUs 44.7, SD = 26.4) and 19.9% (SUs 11.9, SD = 4.1) were binge-only drinkers. About one third were heavy drinkers, meaning that women/men consumed, respectively, more than 35/50 SUs of alcohol at baseline (34.2%, SUs 65.9, SD = 27.1). Post-intervention data were available for 8,095 participants. Compared with controls, iAI participants showed a greater mean weekly decrease at follow-up of 5.02 SUs (95% CI −7.57 to −2.48, p < 0.001) and a higher rate of TR (odds ratio [OR] 2.20, 95% CI 1.63–2.95, p < 0.001, number needed to treat [NNT] = 4.15, 95% CI 3.06–6.62). Persons above age 55 showed higher TR than their younger counterparts (OR = 1.66, 95% CI 1.21–2.27, p = 0.002). Drinking profiles were not significantly associated with treatment outcomes. Human-supported interventions were superior to fully automated ones on both outcome measures (comparative reduction: −6.78 SUs, 95% CI −12.11 to −1.45, p = 0.013; TR: OR = 2.23, 95% CI 1.22–4.08, p = 0.009). Participants treated in iAIs based on personalised normative feedback (PNF) alone were significantly less likely to sustain low-risk drinking at follow-up than those in iAIs based on integrated therapeutic principles (OR = 0.52, 95% CI 0.29–0.93, p = 0.029). The use of waitlist control in RCTs was associated with significantly better treatment outcomes than the use of other types of control (comparative reduction: −9.27 SUs, 95% CI −13.97 to −4.57, p < 0.001; TR: OR = 3.74, 95% CI 2.13–6.53, p < 0.001). The overall quality of the RCTs was high; a major limitation included high study dropout (43%). Sensitivity analyses confirmed the robustness of our primary analyses. Conclusion To our knowledge, this is the first IPDMA on internet-based interventions that has shown them to be effective in curbing various patterns of adult problem drinking in both community and healthcare settings. Waitlist control may be conducive to inflation of treatment outcomes.

Effectiveness and treatment moderators of internet interventions for adult problem drinking: An individual patient data meta-analysis of 19 randomised controlled trials

Introduction Hazardous alcohol consumption is common among people experiencing depression, often acting to exacerbate depressive symptoms. While many people with these co-occurring disorders do not seek face-to-face treatment, they do seek help online. There are effective internet interventions that target hazardous alcohol consumption or depression separately but none that combine these online interventions without the involvement of a therapist. In order to realise the potential of internet interventions, we need to develop an evidence base supporting the efficacy of internet interventions for co-occurring depression and hazardous alcohol use without any therapist involvement. This study aims to evaluate the effects on drinking, and on depressive symptoms, of combining an internet intervention targeting hazardous alcohol consumption with one for depression. Methods and analysis A double blinded, parallel group randomised controlled trial will be used. Participants with current depression who also drink in a hazardous fashion (n=986) will be recruited for a study to ‘help improve an online intervention for depression’. Participants will be randomised either to receive an established online intervention for depression (MoodGYM) or to receive MoodGYM plus a brief internet intervention for hazardous alcohol consumption (Check Your Drinking; CYD). Participants will be contacted 3 and 6 months after receiving the interventions to assess changes in drinking and depression symptoms. It is predicted that participants receiving the CYD intervention in addition to MoodGYM will report greater postintervention reductions in alcohol consumption and depressive symptoms compared with those who received MoodGYM only. Hypothesised mediation and moderation effects will also be investigated. Using an intention-to-treat basis for the analyses, the hypotheses will be tested using a generalised linear hypothesis framework, and longitudinal analyses will use either generalised linear mixed modelling or generalised estimating equation approach where appropriate. Ethics and dissemination This research comprises the crucial first steps in developing lower-cost and efficacious internet interventions for people suffering from depression who also drink in a hazardous fashion—promoting the widespread availability of care for those in need. This study has been approved by the standing ethics review committee of the Centre for Addiction and Mental Health, and findings will be disseminated in the form of at least one peer-reviewed article and presentations at conferences. Trial registration number NCT03421080; Pre-results.

Does providing a brief internet intervention for hazardous alcohol use to people seeking online help for depression reduce both alcohol use and depression symptoms among participants with these co-occurring disorders? Study protocol for a randomised controlled trial

Correction to: Self-Directed Gambling Changes: Trajectory of Problem Gambling Severity in Absence of Treatment

To send or not to send: weighing the costs and benefits of mailing an advance letter to participants before a telephone survey

Background: To assess whether there has been an increase over time in the proportion of people who drink in a risky fashion, who receive expressions of concern about their drinking or advice to cut down. Methods: Secondary analysis of the Centre for Addiction and Mental Health (CAMH) Monitor population survey, conducted annually in Ontario (participants: 18 or older) and with relevant data available from 1998 to 2015 (N = 48,124). The proportions of participants who drank above weekly low-risk drinking levels (approximated as 15 or more drinks for males and 11 or more for females) who reported receiving expressions of concern about their drinking or advice to cut down were compared between the time periods 1998–2004, 2005–2010, and 2011–2015. Further, proportions were broken down by age group and participant sex. Results: Overall, there were low rates of participants who reported receiving advice about their drinking (16.8% of those drinking above weekly drinking levels) and no evidence of an increase across time, except among males, 34 years and under. Females drinking beyond recommended weekly guidelines were less likely than males to receive advice (11.7% versus 19.3%, respectively; P < .001). Further, older participants drinking beyond weekly guidelines were less likely than younger participants to receive advice (18–34: 16.9%; 35–54: 20.3%; 55 or older: 12.9%; P = .012). Conclusions: Given that heavy alcohol consumption is a significant contributor to the preventable burden of disease, increased emphasis is merited on finding ways to increase the frequency with which people who drink in a risky fashion receive advice to cut down.

Has There Been an Increase in the Frequency with which People who Drink in a Risky Fashion Receive Advice to Cut down on their Drinking from 1998 to 2015?

Betting on Life: Associations Between Significant Life Events and Gambling Trajectories Among Gamblers with the Intent to Quit

Self-Directed Gambling Changes: Trajectory of Problem Gambling Severity in Absence of Treatment

Online interventions for problem gamblers with and without co-occurring problem drinking: study protocol of a randomized controlled trial

AIM
To estimate the long-term efficacy of an internet-based brief intervention (IBI) in decreasing alcohol use among men on (1) number of drinks/week and (2) monthly or more binge drinking prevalence. In addition, overall changes in alcohol use were assessed.

DESIGN
Participants in a cohort study were recruited in a two parallel-group randomized controlled trial of an IBI versus no-intervention control condition, showing a positive intervention effect at 6 months. As part of the regular cohort assessments, participants were re-assessed 47 months after the initial trial, offering an opportunity to determine long-term efficacy.

SETTING
Young Swiss men from the general population.

Of 737 randomized trial participants with unhealthy alcohol use (> 14 drinks/week or ≥ 6 drinks/occasion at least monthly, or Alcohol Use Disorders Identification Test (AUDIT) ≥ 8), 626 completed a cohort assessment at mean ± standard deviation (SD) = 47.4 ± 2.6) months after their randomized trial baseline assessment.

IBI included normative and personalized feedback on alcohol use, risk indicators, information about alcohol and health and recommendations; controls: assessment only.

MEASUREMENTS
Self-reported number of drinks/week and monthly or more binge drinking prevalence.

FINDINGS
Comparisons at follow-up were adjusted for baseline drinking. Missing values were replaced with the last observation carried forward. There was no evidence of differences between the IBI and control group on either the number of drinks/week [IBI: 10.8 (14.2); control: 10.7 (14.1), P = 0.8] or monthly or more binge drinking prevalence (IBI: 65.1%; control: 63.5%, P = 0.5). Although there was no evidence of overall change from baseline in number of drinks/week [9.8 (7.9) at baseline, 10.8 (14.1) at 47 months, P = 0.051], there was evidence that monthly or more binge drinking prevalence had decreased during the follow-up time (84.9% at baseline, 64.3% at 47 months, P < 0.001).

An internet-based brief intervention directed at unhealthy alcohol use among young men does not appear to reduce drinking over the long-term.

Four‐year follow‐up of an internet‐based brief intervention for unhealthy alcohol use in young men

1Centre for Addiction and Mental Health, Toronto, Ontario, Canada; 2Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; 3Research School of Population Health, the Australian National University, Canberra, Australia; 4Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada; 5Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada; 6Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada; 7Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; 8School of Public Health and Health Systems, University of Waterloo, Waterloo, Canada

Beyond Quitting: Any Additional Impact of Mailing Free Nicotine Patches to Current Smokers?

Investigating Patterns of Participation in an Online Support Group for Problem Drinking: a Social Network Analysis

What does it mean when people say that they have received expressions of concern about their drinking or advice to cut down on the AUDIT scale?

A frequent comment from grant and journal article reviewers is that researchers should employ different cut-offs for males and females when recruiting for intervention trials targeting hazardous alcohol consumption. A common example is that when using the Alcohol Use Disorders Identification Test (AUDIT) [1] as part of the inclusion criterion, eligible males can be defined as at risk with a score of 8 or more on the AUDIT and eligible females can be identified based on a score of 6 or more (or 7 or more). Similarly, if using a definition based on alcohol consumption, the criterion of 15 or more drinks per week should be used for males, while 11 per week (or 7, or some other value for either sex) should be used for females. These differential cut-off levels have their origins in epidemiological and public health research, where it has been found that women are at risk of experiencing consequences associated with drinking while consuming at lower levels than males [2]. Low-risk drinking guidelines have been produced based on these findings, with different safe drinking recommendations being made for males and females. These recommendations have presumably then been generalized to justify different inclusion criteria for males and females in intervention trials. There may, however, be an unintended impact of using different eligibility cut-offs for males and females. In order to demonstrate the efficacy of an intervention, participants assigned to receive the intervention must demonstrate statistically significant lower drinking levels at follow-up compared to participants who were assigned randomly to a control group. In order to demonstrate such an impact on drinking, the participants need to be drinking enough at baseline in order for there to be room for reductions in drinking levels at follow-up. Further, outcome analyses often include comparisons to evaluate whether the intervention has an impact among males and females separately. If there are sufficient females who are drinking at relatively low levels at baseline (but nevertheless meet the inclusion criterion for the trial), then it is possible that the intervention might be judged as having no evidence for efficacy in females but efficacy in males, solely because the female participants were drinking less at baseline than the male participants in the trial. As a hypothetical example based on Canadian (Ontario, aged 18 years and older) general population prevalence data [3], a sample of females with an AUDIT score of 6 or more will drink an average [standard deviation (SD)] of 7.2 (6.4) drinks per week, while a sample of males from the same population with an AUDIT score of 8 or more will average 13.2 (11.0) drinks per week. For this sample, 54% of the female population are reporting drinking five or fewer drinks per week while only 25% of the males report drinking this amount. If the primary outcome of the trial is to measure reductions in weekly drinking from baseline to follow-up, then it will be harder to demonstrate a significant change for females than for males. One option might be to incorporate details regarding differential trial inclusion cut-offs (and their concomitant differential patterns of consumption resulting from these cut-offs) for males and females into the power analysis calculations for the study. However, this could lead to untenable increases in the sample size needed. Another would be to target samples where, while the cut-off criterion is lower for females than for males, the actual participants recruited all (or almost all) drink at much higher levels than the lower level of the inclusion criterion. However, it could be argued for this sort of situation that the differential cut-offs for males and females are misleading to the reader, as they do not reflect the actual sample included in the study. If the intent of the trial is to demonstrate the efficacy of an intervention targeting hazardous drinking, then I argue that it is of primary importance to employ a participant sample that is drinking enough at baseline to allow for reductions in alcohol consumption resulting from receiving the intervention. A separate question, and one that merits attention once the efficacy of an intervention has been demonstrated, is whether there is any evidence of impact when the intervention is administered to people who are drinking just above levels of risk [4], whether or not level of risk is differentiated for males and females. However, combining these two objectives (evidence of efficacy and evidence of effectiveness at minimal levels of risk) can have unintended consequences and could lead to false assumptions of sex differences in intervention trials that are an artefact of differential inclusion criteria for males and females.

Unintended impact of using different inclusion cut-offs for males and females in intervention trials for hazardous drinking.

Impact of large-scale distribution and subsequent use of free nicotine patches on primary care physician interaction

Using Mechanical Turk to recruit participants for internet intervention research: experience from recruitment for four trials targeting hazardous alcohol consumption

Mailed distribution of free nicotine patches without behavioral support: Predictors of use and cessation.

Background Technology-delivered interventions are useful tools for addressing unhealthy alcohol use. Smartphones in particular offer opportunities to deliver interventions at the user's convenience. A smartphone application with 5 modules (personal feedback, self-monitoring of drinking, designated driver tool, blood alcohol content [BAC] calculator, information) was developed. Its acceptability and associations between use and drinking outcomes were assessed. Methods One hundred thirty adults with unhealthy alcohol use (>14 [men]/>7 [women] drinks/week or ≥1 episode/month with 6 or more drinks) recruited in Switzerland (n = 70) and Canada (n = 60) were offered to use the application. Follow-up occurred after 3 months. Appreciation, usefulness, and self-reported frequency of use of the modules, and drinking outcomes (drinks/week, binge drinking) were assessed. Associations between application use and drinking at 3 months were evaluated with negative binomial and logistic regression models, adjusted for baseline values and gender. Results Of the participants, 48% were women, mean (SD) age: 32.8 (10.0). Follow-up rate: 86.2%. There were changes from baseline (BL) to follow-up (FU) in number of drinks/week, BL: 15.0 (16.5); FU: 10.9 (10.5), P = .01, and binge drinking, BL: 95.4%; FU: 64.3%, P < .0001. All modules had median ratings between 6 and 8 (scale of 1–10). Among the participants, 77% used the application, 76% used the personal feedback module, 41% the self-monitoring of drinking, 22% the designated driver tool, 53% the BAC calculator, and 31% the information module. Participants using the application more than once reported significantly fewer drinks/week at follow-up: Incidence Rate Ratio (IRR), number of drinks per week = 0.70 (0.51; 0.96). Conclusions A smartphone application for unhealthy alcohol use appears acceptable and useful (although there is room for improvement). Without prompting, its use is infrequent. Those who used the application more than once reported less weekly drinking than those who did not. Efficacy of the application should be tested in a randomized trial with strategies to increase frequency of its use.

Can Amazon's Mechanical Turk be used to recruit participants for internet intervention trials? A pilot study involving a randomized controlled trial of a brief online intervention for hazardous alcohol use

Long-term effectiveness of mailed nicotine replacement therapy: study protocol of a randomized controlled trial 5-year follow-up

Abstract Aim: Given the ubiquitous nature of hangover experience among drinkers, this study aimed to profile hangover experience in terms of the number and patterns of past year symptoms. Methods: Current drinkers in Canada (n = 565) recruited through zoompanel were asked about 13 past year hangover symptoms. These were explored through correlation with alcohol consumption, problems, treatment and other factors. Findings: Increased number of symptoms were associated with higher Alcohol Use Disorders Identification Test (AUDIT) problem score, perceived harm from drinking, younger age and flushing/blushing when drinking (Mean = 3.3 symptoms). Four patterns were found from latent class analysis; class 4 (43%) no symptoms; class 3 (13%) thirst, tiredness, headache, nausea and vomiting; class 2 (22%) thirst, tiredness and headache; and class 1 (21%) wide range. Class 1 was characterised by blushing when drinking, higher perceived harm and attempts to reduce drinking due to hangovers. Classes 1–3 were associated with heavier consumption; only class 3 compared with class 4 had lower drinking refusal self-efficacy. Conclusions: higher alcohol consumption and lower drinking refusal self-efficacy relate to more symptoms; however, a group with variable alcohol consumption did not experience hangovers. The link between problems, treatment and hangover was not clear from patterns of symptoms; symptom severity may be worth further investigation.

Understanding the hangover experience in Canadian adults: A latent class analysis of hangover symptom patterns and their alcohol-related correlates

Background Large-scale public health initiatives providing free nicotine replacement therapy have been shown to increase smoking cessation rates; however, their effectiveness among the highly prevalent population of smokers with depression and anxiety disorders has not been explored. The aim of this study was to investigate the influence of lifetime history of depression or anxiety on smoking cessation success following the free distribution of nicotine patches. Method In the context of a randomised controlled trial, a secondary analysis was conducted on 1000 adult regular smokers randomised to be mailed a 5-week supply of nicotine patches or to a no intervention control group. Participants were divided into subgroups based on the presence of self-reported lifetime diagnosis of depression and anxiety. Results Irrespective of self-reported lifetime history of depression or anxiety, odds of self-reported cessation at 6 months were significantly greater among groups receiving nicotine patches compared to no intervention control (no history of depression or anxiety: OR 2.20; 95% CI 1.05 to 4.63; history of depression or anxiety present: OR 3.90; 95% CI 1.28 to 11.88). Among nicotine patch recipients only, quit outcomes did not differ between those with and without self-reported lifetime depression or anxiety in models unadjusted and adjusted for differences in demographic and smoking characteristics. Conclusions The mass distribution of free nicotine patches (without behavioural support) is effective among smokers with or without lifetime history of depression or anxiety alike, providing further support for the adoption of similar initiatives as a means of promoting tobacco cessation on a population level. Trial registration number NCT01429129, Post-results.

Impact of self-reported lifetime depression or anxiety on effectiveness of mass distribution of nicotine patches

Are young men who overestimate drinking by others more likely to respond to an electronic normative feedback brief intervention for unhealthy alcohol use?

Keywords: 
 
Careless responding; 
data cleaning; 
data integrity; 
invalid responding; 
online survey; 
research outcome quality

Unfaithful findings: identifying careless responding in addictions research.

Background Little is known about the community structure of mental health Internet support groups, quantitatively. A greater understanding of the factors, which lead to user interaction, is needed to explain the design information of these services and future research concerning their utility. Objective A study was conducted to determine the characteristics of users associated with the subgroup community structure of an Internet support group for mental health issues. Methods A social network analysis of the Internet support group BlueBoard (blueboard.anu.edu.au) was performed to determine the modularity of the community using the Louvain method. Demographic characteristics age, gender, residential location, type of user (consumer, carer, or other), registration date, and posting frequency in subforums (depression, generalized anxiety, social anxiety, panic disorder, bipolar disorder, obsessive compulsive disorder, borderline personality disorder, eating disorders, carers, general (eg, “chit chat”), and suggestions box) of the BlueBoard users were assessed as potential predictors of the resulting subgroup structure. Results The analysis of modularity identified five main subgroups in the BlueBoard community. Registration date was found to be the largest contributor to the modularity outcome as observed by multinomial logistic regression. The addition of this variable to the final model containing all other factors improved its classification accuracy by 46.3%, that is, from 37.9% to 84.2%. Further investigation of this variable revealed that the most active and central users registered significantly earlier than the median registration time in each group. Conclusions The five subgroups resembled five generations of BlueBoard in distinct eras that transcended discussion about different mental health issues. This finding may be due to the activity of highly engaged and central users who communicate with many other users. Future research should seek to determine the generalizability of this finding and investigate the role that highly active and central users may play in the formation of this phenomenon.

Community Structure of a Mental Health Internet Support Group: Modularity in User Thread Participation

The efficacy of nicotine replacement therapy (NRT) is well demonstrated in clinical trials in which NRT is accompanied by behavioral support. Epidemiologic data, however, indicate that people using NRT are no more likely to successfully quit smoking than those who do not use NRT.

OBJECTIVE
To evaluate the effect of mailing nicotine patches to smokers without behavioral support on quit success rates.

A single-blinded, 2-group randomized clinical trial of adult smokers recruited across Canada by random-digit dialing of home and cell telephone numbers from June 4, 2012, through June 26, 2014. Follow-up was completed on January 5, 2015, and data were analyzed from May 24, 2015, through July 6, 2015. A total of 2093 individuals who smoked more than 10 cigarettes per day were interviewed at baseline and asked if they would be hypothetically interested in receiving nicotine patches by mail to quit smoking. Those who were interested and deemed eligible to participate (no contraindications to NRT) were randomized to the experimental group to be mailed a 5-week supply of nicotine patches or to a control group. Telephone follow-ups were conducted at 8 weeks and 6 months.

Participants in the experimental group were sent a 5-week course of nicotine patches by expedited postal mail (3 weeks of step 1 [21 mg of nicotine], 1 week of step 2 [14 mg of nicotine], 1 week of step 3 [7 mg of nicotine], no behavioral support provided). Participants randomized to the control group were not offered the nicotine patches or any other intervention.

The primary outcome was 30-day smoking abstinence at 6 months.

RESULTS
Of the 2093 participants who were interviewed as part of the baseline survey (76.5% response rate), 1000 were found eligible for the trial and randomized to a group. Analyses were conducted on 500 participants in the experimental group (mean [SD] age, 48.0 [12.8] years; 255 female [51.0%]) and 499 in the control group (mean [SD] age, 49.7 [12.7] years; 256 female [51.3%]). Self-reported abstinence rates were significantly higher among participants who were sent nicotine patches compared with the control group (30-day abstinence: 38 [7.6%] of 500 vs 15 [3.0%] of 499; odds ratio, 2.65; 95% CI, 1.44-4.89; P = .002). Usable saliva samples were returned by only 50.9% of the participants. Biochemically validated abstinence at 6 months was found in 14 (2.8%) of 500 participants in the experimental group vs 5 (1.0%) of 499 in the control group (odds ratio, 2.85; 95% CI, 1.02-7.96; P = .046).

The trial provides evidence of the effectiveness of mailed nicotine patches without behavioral support to promote tobacco cessation. The strength of these findings is tempered by the lack of biochemical validation for all participants.

TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT01429129.

Effect of Mailing Nicotine Patches on Tobacco Cessation Among Adult Smokers: A Randomized Clinical Trial.

Randomized Controlled Trial of a Brief Versus Extended Internet Intervention for Problem Drinkers

Gender Differences in Self-Conscious Emotions and Motivation to Quit Gambling

Smoking rates are higher in rural than in urban settings.1 Further, access to healthcare and tobacco cessation programmes is challenging in rural areas because of lower population density and large geographic distances.2 Thus, tobacco cessation initiatives that overcome these barriers are needed to address the disparity in healthcare provision in rural settings.3 ,4 One such option is the distribution of nicotine patches by postal mail. However, is there evidence to suggest that such programmes might be effective in rural settings?

Secondary analyses were conducted of …

Effectiveness of mass distribution of nicotine patches to promote tobacco control in rural versus urban settings

Stage of change questions are often included on general population surveys to assess the proportion of current smokers intending to quit. The current study reported on a methodological experiment to establish whether participant's self-reported stage of change can be influenced by asking about interest in free nicotine patches immediately prior to asking about intent to change.

METHODS
As part of an ongoing random digit dialing survey, a randomized half of participants were asked if they would be interested in receiving nicotine patches to help them quit smoking prior to being asked whether they intended to quit smoking in the next 6 months and 30 days.

RESULTS
Participants who were first asked about interest in free nicotine patches were more likely to rate themselves as in preparation for change (asked first = 33%; not asked first = 19%), and less likely to rate themselves as in the precontemplation stage of change (asked first = 34%; not asked first = 47%), compared with participants who were not asked about their interest in free nicotine patches prior to being asked about their stage of change (P < .001).

There are several possible explanations of the results. It is possible that offers of free nicotine patches increases smokers intentions to quit, at least temporarily. Alternatively, smokers being asked about interest in free nicotine patches may expect that the researchers would like to hear about people intending to quit, and respond accordingly.

The Impact of Asking About Interest in Free Nicotine Patches on Smoker's Stated Intent to Change: Real Effect or Artefact of Question Ordering?

Keywords: 
 
Ecological momentary assessment; 
eHealth; 
internet intervention; 
randomized controlled trials; 
review

Keywords: 
 
Alcohol; 
brief intervention; 
clinical trials; 
follow-up rate; 
incentives; 
internet; 
young men

You need to see the world in order to measure it: The importance of a high follow-up rate.

Online interventions for problem gamblers with and without co-occurring mental health symptoms: Protocol for a randomized controlled trial

ABSTRACT Motivation for change and recovery from addiction has been commonly assessed using the Transtheoretical Model's stages of change. Analogous to readiness for change, this measure of motivation may not recognize other elements of motivation relevant to successful change. The aim of this study was to examine the relationship between stages of change and reasons for change according to the Self-Determination Theory among problem gamblers motivated to quit. Motivations for change were examined for 200 adult problem gamblers with intent to quit in the next 6 months (contemplation stage) or 30 days (preparation stage). Analyses revealed that higher autonomous motivation for quitting gambling predicted greater likelihood of being in the preparation stage, whereas those with higher external motivation for change were less likely to be farther along the stage of change continuum. The findings suggest that autonomous motivations relate to readiness for quitting gambling, and may predict successful resolution from problem gambling.

Motivation to quit or reduce gambling: Associations between Self-Determination Theory and the Transtheoretical Model of Change

Questioning Nicotine Replacement Therapy Without Behavioral Support-Reply.

Background Understanding how people participate in and contribute to online health communities (OHCs) is useful knowledge in multiple domains. It is helpful for community managers in developing strategies for building community, for organizations in disseminating information about health interventions, and for researchers in understanding the social dynamics of peer support. Objective We sought to determine if any patterns were apparent in the nature of user participation across online health communities. Methods The current study involved a systematic review of all studies that have investigated the nature of participation in an online health community and have provided a quantifiable method for categorizing a person based on their participation style. A systematic search yielded 20 papers. Results Participatory styles were classified as either multidimensional (based on multiple metrics) or unidimensional (based on one metric). With respect to the multidimensional category, a total of 41 different participation styles were identified ranging from Influential Users who were leaders on the board to Topic-Focused Responders who focused on a specific topic and tended to respond to rather than initiate posts. However, there was little overlap in participation styles identified both across OHCs for different health conditions and within OHCs for specific health conditions. Five of the 41 styles emerged in more than one study (Hubs, Authorities, Facilitators, Prime Givers, and Discussants), but the remainder were reported in only one study. The focus of the unidimensional studies was on level of engagement and particularly on high-engaged users. Eight different metrics were used to evaluate level of engagement with the greatest focus on frequency of posts. Conclusions With the exception of high-engaged users based on high post frequency, the current review found little evidence for consistent participatory styles across different health communities. However, this area of research is in its infancy, with most of the studies included in the review being published in the last 2 years. Nevertheless, the review delivers a nomenclature for OHC participation styles and metrics and discusses important methodological issues that will provide a basis for future comparative research in the area. Further studies are required to systematically investigate a range of participatory styles, to investigate their association with different types of online health communities and to determine the contribution of different participatory styles within and across online health communities.

From Help-Seekers to Influential Users: A Systematic Review of Participation Styles in Online Health Communities

Background Research into e-mental health technologies has developed rapidly in the last 15 years. Applications such as Internet-delivered cognitive behavioral therapy interventions have accumulated considerable evidence of efficacy and some evidence of effectiveness. These programs have achieved similar outcomes to face-to-face therapy, while requiring much less clinician time. There is now burgeoning interest in integrating e-mental health resources with the broader mental health delivery system, particularly in primary care. The Australian government has supported the development and deployment of e-mental health resources, including websites that provide information, peer-to-peer support, automated self-help, and guided interventions. An ambitious national project has been commissioned to promote key resources to clinicians, to provide training in their use, and to evaluate the impact of promotion and training upon clinical practice. Previous initiatives have trained clinicians to use a single e-mental health program or a suite of related programs. In contrast, the current initiative will support community-based service providers to access a diverse array of resources developed and provided by many different groups. Objective The objective of this paper was to develop a conceptual framework to support the use of e-mental health resources in routine primary health care. In particular, models of clinical practice are required to guide the use of the resources by diverse service providers and to inform professional training, promotional, and evaluation activities. Methods Information about service providers’ use of e-mental health resources was synthesized from a nonsystematic overview of published literature and the authors’ experience of training primary care service providers. Results Five emerging clinical practice models are proposed: (1) promotion; (2) case management; (3) coaching; (4) symptom-focused treatment; and (5) comprehensive therapy. We also consider the service provider skills required for each model and the ways that e-mental health resources might be used by general practice doctors and nurses, pharmacists, psychologists, social workers, occupational therapists, counselors, and peer workers Conclusions The models proposed in the current paper provide a conceptual framework for policy-makers, researchers and clinicians interested in integrating e-mental health resources into primary care. Research is needed to establish the safety and effectiveness of the models in routine care and the best ways to support their implementation.

Clinical Practice Models for the Use of E-Mental Health Resources in Primary Health Care by Health Professionals and Peer Workers: A Conceptual Framework

Introduction Alcohol use is one of the leading modifiable morbidity and mortality risk factors among young adults. Study Design 2 parallel-group randomized controlled trial with follow-up at 1 and 6 months. Setting/Participants Internet based study in a general population sample of young men with low-risk drinking, recruited between June 2012 and February 2013. Intervention: Internet-based brief alcohol primary prevention intervention (IBI). The IBI aims at preventing an increase in alcohol use: it consists of normative feedback, feedback on consequences, calorific value alcohol, computed blood alcohol concentration, indication that the reported alcohol use is associated with no or limited risks for health. Intervention group participants received the IBI. Control group (CG) participants completed only an assessment. Main Outcome Measures Alcohol use (number of drinks per week), binge drinking prevalence. Analyses were conducted in 2014–2015. Results Of 4365 men invited to participate, 1633 did so; 896 reported low-risk drinking and were randomized (IBI: n = 451; CG: n = 445). At baseline, 1 and 6 months, the mean (SD) number of drinks/week was 2.4(2.2), 2.3(2.6), 2.5(3.0) for IBI, and 2.4(2.3), 2.8(3.7), 2.7(3.9) for CG. Binge drinking, absent at baseline, was reported by 14.4% (IBI) and 19.0% (CG) at 1 month and by 13.3% (IBI) and 13.0% (CG) at 6 months. At 1 month, beneficial intervention effects were observed on the number of drinks/week (p = 0.05). No significant differences were observed at 6 months. Conclusion We found protective short term effects of a primary prevention IBI. Trial Registration Controlled-Trials.com ISRCTN55991918

Internet-Based Brief Intervention to Prevent Unhealthy Alcohol Use among Young Men: A Randomized Controlled Trial

AIM
To test the efficacy of an internet-based brief intervention (IBI) in decreasing alcohol use among young Swiss men aged 21 years on average.

DESIGN
Two parallel-group randomized controlled trial with a 1 : 1 allocation ratio containing follow-up assessments at 1 and 6 months post-randomization

SETTING
Internet-based study in a general population sample.

Twenty-one-year-old men from Switzerland with unhealthy alcohol use (> 14 drinks/week or ≥ 6 drinks/occasion at least monthly or Alcohol Use Disorders Identification Test (AUDIT) scores ≥ 8) INTERVENTION: IBI consisting of (1) normative feedback, (2) feedback on consequences of alcohol use, (3) calorific value of reported consumption, (4) computed blood alcohol concentration for reported consumption, (5) indication of risk, (6) information on alcohol and health and (7) recommendations indicating low-risk drinking limits. Control condition: no intervention (assessment only).

At 1 and 6 months: quantity/frequency questions on alcohol use (primary outcome: number of drinks/week) and binge drinking prevalence; at 6 months: AUDIT score, consequences of drinking (range = 0-12).

FINDINGS
Follow-up rates were 92% at 1 month and 91% at 6 months. At 6 months, participants in the intervention group (n = 367) reported greater reductions in the number of drinks/week than participants in the control group (n = 370) [treatment × time interaction, incidence rate ratio (RR) = 0.86, 95% confidence interval (CI) = 0.78; 0.96], but no significant differences were observed on binge drinking prevalence. There was a favourable intervention effect on AUDIT scores (IRR = 0.93, 95% CI = 0.88; 0.98), but not on the number of consequences (IRR = 0.93, 95% CI = 0.84; 1.03).

An internet-based brief intervention directed at harmful alcohol use among young men led to a reduction in self-reported alcohol consumption and AUDIT scores compared with a no-intervention control condition (assessment only).

Internet-based brief intervention for young men with unhealthy alcohol use: a randomized controlled trial in a general population sample.

Assessing effective smoking cessation intervention in primary care

Gambler Self-Help Strategies: A Comprehensive Assessment of Strategies and Actions.

Randomized controlled trial of a minimal versus extended Internet-based intervention for problem drinkers: study protocol

Background Alcohol misuse ranks within the top ten health conditions with the highest global burden of disease. Low-intensity, Internet interventions for curbing adult alcohol misuse have been shown effective. Few meta-analyses have been carried out, however, and they have involved small numbers of studies, lacked indicators of drinking within low risk guidelines, and examined the effectiveness of unguided self-help only. We therefore conducted a more thorough meta-analysis that included both guided and unguided interventions. Methods Systematic literature searches were performed up to September 2013. Primary outcome was the mean level of alcohol consumption and drinking within low risk guidelines for alcohol consumption at post-treatment. Findings We selected 16 randomised controlled trials (with 23 comparisons and 5,612 participants) for inclusion. Results, showed a small but significant overall effect size in favour of Internet interventions (g = 0.20, 95% CI: 0.13–0.27, p<.001). Participants in Internet interventions drunk on average 22 grams of ethanol less than controls and were significantly more likely to be adhering to low-risk drinking guidelines at post-treatment (RD 0.13, 95% CI: 0.09–0.17, p<.001). Subgroup analyses revealed no significant differences in potential moderators for the outcome of alcohol consumption, although there was a near-significant difference between comparisons with waitlist control and those with assessment-only or alcohol information control conditions (p = .056). Conclusions Internet interventions are effective in reducing adult alcohol consumption and inducing alcohol users to adhere to guidelines for low-risk drinking. This effect is small but from a public health point of view this may warrant large scale implementation at low cost of Internet interventions for adult alcohol misuse. Moderator analyses with sufficient power are, however, needed in order to assess the robustness of these overall results and to assess whether these interventions may impact on subgroups with different levels of success.

Effectiveness of Guided and Unguided Low-Intensity Internet Interventions for Adult Alcohol Misuse: A Meta-Analysis

Aims This study explores the early development of brief interventions for alcohol using a history of ideas approach with a particular focus on intervention content. Methods The source publications of the key primary studies published from approximately 1962 to 1992 were examined, followed by a brief review of the earliest reviews in this field. These studies were placed in the context of developments in alcohol research and in public health. Results After early pioneering work on brief interventions, further advances were not made until thinking about alcohol problems and their treatment, most notably on controlled drinking, along with wider changes in public health, created new conditions for progress. There was then a golden era of rapid advance in the late 1980s and early 1990s, when preventing the development of problem drinking became important for public health reasons, in addition to helping already problematic drinkers. Many research challenges identified at that time remain to be met. The content of brief interventions changed over the period of study, although not in ways well informed by research advances, and there were also obvious continuities, with a renewed emphasis on the facilitation of self-change being one important consequence of the development of internet applications. Conclusions Ideas about brief interventions have changed in important ways. Brief interventions have been studied with different populations of drinkers, with aims embracing both individual and population-level perspectives, and without well-specified contents. The brief intervention field is an appropriate target for further historical investigations, which may help thinking about addressing alcohol and other problems.

Describing the distribution of engagement in an Internet support group by post frequency: A comparison of the 90-9-1 Principle and Zipf's Law

Purpose – Although the way in which, for example, substance use problems are conceived and reacted to (by experts and treatment professionals but also by the environment), can have vast consequence ...

How should substance use problems be handled? Popular views in Sweden, Finland, and Canada

The current study explored the relationship in a general population sample between problem gambling severity and cognitive distortions about gambling. A representative sample of problem gamblers (N = 766) was asked about cognitive distortions related to gambling. A positive association between gambling severity and cognitive distortions emerged, even when the variables associated with participants' demographic characteristics were accounted for. The current study demonstrates that the relationship between problem gambling severity and cognitive distortions does exist in the general population of problem gamblers. This finding emphasizes the key role that cognitive distortions may play in the development and maintenance of pathological gambling.

Relating severity of gambling to cognitive distortions in a representative sample of problem gamblers

Treatment dismantling pilot study to identify the active ingredients in personalized feedback interventions for hazardous alcohol use: randomized controlled trial

OBJECTIVE
It has been well established that college students engage in heavy drinking during specific social events; however, within the general population, evidence of event-specific drinking has been largely indirect. The present study therefore aimed to investigate the temporal variability in daily alcohol consumption in the winter holiday months among residents of a large metropolitan area.

METHOD
A random-digit-dialing telephone survey was conducted of residents who drank alcohol at least once per month. During a 5-week period beginning December 1, 2009, the number of drinks consumed on each day within the past week was collected for 578 participants.

RESULTS
Weekly variation in alcohol consumption peaked on Fridays and Saturdays and was particularly high on Christmas and New Year's Eve. Mean drink consumption was significantly higher on Christmas and New Year's Eve compared with most weekends within the sampling period.

The present findings provide the first direct evidence, with temporal specificity, that alcohol consumption within the general population is highly event specific. Targeted intervention strategies similar to those used within college student samples may be appropriate for reducing or preventing alcohol-related harmful events on a population level.

Unhealthy alcohol use is a leading contributor to the global burden of disease, particularly among young people. Systematic reviews suggest efficacy of web-based alcohol screening and brief intervention and call for effectiveness trials in settings where it could be sustainably delivered.

OBJECTIVE
To evaluate a national web-based alcohol screening and brief intervention program.

A multisite, double-blind, parallel-group, individually randomized trial was conducted at 7 New Zealand universities. In April and May of 2010, invitations containing hyperlinks to the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) screening test were e-mailed to 14,991 students aged 17 to 24 years.

Participants who screened positive (AUDIT-C score ≥4) were randomized to undergo screening alone or to 10 minutes of assessment and feedback (including comparisons with medical guidelines and peer norms) on alcohol expenditure, peak blood alcohol concentration, alcohol dependence, and access to help and information.

A fully automated 5-month follow-up assessment was conducted that measured 6 primary outcomes: consumption per typical occasion, drinking frequency, volume of alcohol consumed, an academic problems score, and whether participants exceeded medical guidelines for acute harm (binge drinking) and chronic harm (heavy drinking). A Bonferroni-corrected significance threshold of .0083 was used to account for the 6 comparisons and a sensitivity analysis was used to assess possible attrition bias.

RESULTS
Of 5135 students screened, 3422 scored 4 or greater and were randomized, and 83% were followed up. There was a significant effect on 1 of the 6 prespecified outcomes. Relative to control participants, those who received intervention consumed less alcohol per typical drinking occasion (median 4 drinks [interquartile range {IQR}, 2-8] vs 5 drinks [IQR 2-8]; rate ratio [RR], 0.93 [99.17% CI, 0.86-1.00]; P = .005) but not less often (RR, 0.95 [99.17% CI, 0.88-1.03]; P = .08) or less overall (RR, 0.95 [99.17% CI, 0.81-1.10]; P = .33). Academic problem scores were not lower (RR, 0.91 [99.17% CI, 0.76-1.08]; P = .14) and effects on the risks of binge drinking (odds ratio [OR], 0.84 [99.17% CI, 0.67-1.05]; P = .04) and heavy drinking (OR, 0.77 [99.17% CI, 0.56-1.05]; P = .03) were not significantly significant. In a sensitivity analysis accounting for attrition, the effect on alcohol per typical drinking occasion was no longer statistically significant.

A national web-based alcohol screening and brief intervention program produced no significant reductions in the frequency or overall volume of drinking or academic problems. There remains a possibility of a small reduction in the amount of alcohol consumed per typical drinking occasion.

anzctr.org.au Identifier: ACTRN12610000279022.

Web-based alcohol screening and brief intervention for university students: a randomized trial.

Internet-based alcohol brief intervention for young men in the general population

Abstract Over the last several years, there has been a sub-stantial increase in the number of publications reporting onInternet interventions for mental health and addictions. Thispaper provides a summary of the recent research on Internetinterventions for the most common mental health and addic-tions concerns—depression, anxiety, alcohol and smoking.There is considerable evidence for the effectiveness ofInternet-based interventions targeting depression, anxiety dis-orders, alcohol use and smoking. Small to moderate effectsizes have been reported for interventions targeting depres-sion,anxietyandalcoholuse,andsmokinginterventionshaveshownlargeeffects.Theadditionofhumansupporttodepres-sion and anxiety interventions has generally resulted in largertreatmentseffects,butthistrendhasnotbeenobservedintrialsofinterventionstargetingalcoholuse.Thereissomeevidencethat online interventions can be as effective as face-to-facetherapies,atleastforanxietydisorders.Despiteaproliferationof research activity in this area, gaps in knowledge remain.Future research should focus on the development and evalu-ation of interventions for different platforms (e.g. smartphoneapplications),examining the long-term impacts of these inter-ventions, determining active intervention components andidentifying methods for enhancing tailoring and engagement.Careful consideration should be given to the ongoing techni-cal and clinical expertise required to ensure that Internetinterventions are delivered safely and professionally in arapidly changing technology environment.Keywords Internetinterventions .Review .Depression .Anxiety .Alcohol .TobaccoIntroductionInternet interventions for common mental health problemsincluding addiction are beginning to enter the mainstream.Earlyexamplesofinterventionwebsitesappearedapproximate-ly20yearsagoandwerefirstpublishedoninthelate1990sandearly 2000s [1–3]. Thus, it appears that Internet interventions,as with most other health-care innovations, have followed theknowledge translation path that it takes about 17 years for aninnovation to achieve widespread acceptance [ 4, 5]. Evidenceofthisadoptioncanbeseenthroughtheavailabilityofdifferentnumerouswebsitesprovidinginterventionsandtheexistenceofcompendiums (online and others) that review and rate thequalityofthesewebsites(e.g.,Beacon.anu.edu.au)andthroughevidence that consumers endorse the Internet as a commonmeans of accessing health-care information [ 6–8].Further evidence of the increased acceptance of Internetinterventionsistheexplosionofresearchontheirefficacy.Thegoal of this paper is to summarise some of these more recentfindings for common mental health problems and addiction(depression, anxiety, alcohol and smoking).DepressionSeveral reviews conducted within the last 5 years haveamassed considerable evidence for the effectiveness of Inter-net interventions for depression in adults. Five meta-analyses[9, 10, 11†, 12, 13] and two systematic reviews [14, 15]have

InternetInterventionsfor Mental Health andAddictions:Current Findings and Future Directions

Patterns of past year hangover symptomatology in Canadian Adults and relationship with hangover ‘cure’ or ‘prevention’ strategies.

Recruitment and retention in randomised control trials of online alcohol interventions.

Internet Interventions for Mental Health and Addictions: Current Findings and Future Directions

Two challenging issues in Internet intervention research, as well as in other behavioral intervention trials, are ensuring that participants receive the intervention (adherence) and that their outcomes are captured at follow-up (retention) [1]. The interesting analysis presented by Murray et al [2] demonstrated that, at least in their study sample, the participant adherence and retention were positively related. 
 
One issue to consider is whether this finding can be replicated in other study samples. It is possible that research involving, for example, different recruitment methods or with higher (or lower) retention rates, might not display this same positive relationship. To that purpose, results were examined from an Internet intervention trial that employed a proactive telephone recruitment method and obtained complete follow-up data for 86% of participants [3-5]. As with the Murray et al study [2], adherence (measured by the number of intervention participants logging onto a brief alcohol intervention, where N=92; 57 participants logged onto the intervention and 35 participants did not log on) and retention were strongly positively related (retention at 3-months: logged onto intervention=100%, did not log on=80%, P<.001; retention at 6-months: logged onto intervention=100%; did not log on=80%, P<.001; retention at 12-months: logged onto intervention=96%; did not log on=74.3%, P=.002; Fisher’s Exact Tests). 
 
Given that the positive relationship between adherence and retention can be replicated, what are the implications of this finding? From one perspective, the fact that these two key issues are related could underline the increased importance of obtaining a good retention rate. This is because the positive relationship of adherence to retention implies that a confound in the interpretation of the results is more likely as loss to follow-up (or reduced adherence to the intervention) increases. Alternatively, it could be argued that this positive relationship might reduce the importance of obtaining a good retention rate. This is because traditional intent-to-treat analysis assumes that participants who are lost to follow-up do not make any change in their behavior from baseline to follow-up (and are included as imputed values in the analysis based on this assumption). If it is then assumed that only those participants who accessed the intervention will actually make a change in their behavior, then the fact that participants who adhere to the intervention are more likely to follow-up can only increase the likelihood that participants who are lost to follow-up are less likely to have made a change in their behavior (thus validating the intent-to-treat analysis assumption). Determining which of these implications is correct is important, particularly in a field where low retention rates are an unfortunate reality in many research trials [1].

Intervention Adherence is Related to Participant Retention: Implications for Research

McCambridge and colleagues review ethical considerations about the use of deception in online alcohol intervention trials (McCambridge et al. 2013). At issue in particular is the idea of exposing participants to alcohol assessments and experimental manipulations while withholding or altering information, so as to limit participants’ awareness of the study and/or its aims. These approaches can enable relatively more rigorous designs and clearer inferences about intervention effects, but conflict with ethical principles related to autonomy and respect. In the absence of clear guidelines from the public health field they present a thorough discussion of their own experiences, consulting broader ethics frameworks as applicable. Their conclusion (with which we agree) is that, considering the potential benefits and harms, deception is often justified as a means of facilitating accurate inferences about intervention efficacy and processes of behavior change.

Deception in Human Experimental and Public Health Research on Alcohol Problems

Association between tobacco industry denormalization beliefs, tobacco control community discontent and smokers' level of nicotine dependence.

Background Only a small percentage of gamblers ever seek treatment, often due to stigma, embarrassment, or a desire to handle their problems on their own. While the majority of pathological gamblers who achieve remittance do so without accessing formal treatment, factors related to successful resolution have not been thoroughly explored. Objective Employing a prospective natural history design, the study will therefore undertake an investigation to explore life events, motivating factors, and strategies used by problem gamblers to quit or reduce their gambling without formal treatment. Methods Prospective participants (19 years or older) currently gambling at problematic levels with strong intentions toward quitting gambling will be directed to fill out a Web-based survey. Eligible participants will subsequently complete a survey that will assess: (1) types, frequency, and amount of money spent on gambling, (2) life events experienced in the past 12 months, (3) level of autonomous motivation for change, and (4) use of treatment services. Every 3 months for the duration of one year following the completion of their baseline survey, participants will be sent an email notification requesting them to complete a follow-up survey similar in content to the baseline survey. The four surveys will assess whether participants have experienced changes in their gambling behaviors along with positive or negative life events and motivations for change since the last survey. Individuals who are in the action and maintenance stages of quitting gambling at follow-up will be also asked about their techniques and strategies used to quit or reduce gambling. At 18 months post baseline, participants will be asked to complete a fifth and final follow-up survey that will also assess whether participants have experienced any barriers to change and whether they resolved their gambling to low risk levels. Results The study has commenced in May 2013 and is currently in the recruitment stage. The study is scheduled to conclude in 2016. Conclusions As this study will examine the active ingredients in natural recovery from gambling problems, the results will inform ways of promoting change among the large number of problem gamblers who do not seek treatment as well as improve treatment for those who do seek help. The information gained will also be useful in identifying effective self-help strategies for those who face challenges in accessing treatment, may be incorporated in standard treatment, provide brief intervention techniques, as well as inform relapse prevention strategies.

A Prospective Natural History Study of Quitting or Reducing Gambling With or Without Treatment: Protocol

Use of mobile devices to answer online surveys: implications for research

The strength of randomized controlled trials is that they allow causal statements to be made about the efficacy of an intervention. This is because the randomization of participants to experimental condition distributes participants with different characteristics to each experimental condition by chance, including variations in the outcome variables of interest. Such randomization allows the use of statistical tests incorporating probability statements regarding the chance that the difference observed between conditions is due to chance (eg, 1 in 20 chance; P<.05). 
 
Any systematic removal of participants post-randomization interferes with the assumption of the randomness of participant allocation to experimental condition. This can introduce a potential confound or alternative explanation of the results. The recently published study by Rooke et al [1] removed participants from the analysis who reported other treatment use during the study (n=5). The removal of participants was done post-randomization and in a systematic fashion (ie, anyone who reported using other treatment was not included in the analysis). All participants who reported receiving other treatment were in the control condition and were allocated to receive the Web address of an education only website. Even if some participants in the intervention condition had also accessed other treatment, this would still be a systematic, post-randomization removal of participants. However, it is easier to develop alternate explanations of the findings of this trial because all participants using other treatment were from the control condition. 
 
From one perspective, it is possible that the excluded participants were those who were experiencing the most serious problems with their Cannabis use. If this is the case, it could make it less likely that significant differences would be observed between experimental condition by reducing the variance between participants. Alternatively, perhaps these were the five participants in the control condition who were the most motivated to reduce their Cannabis use. This could mean that participants in the control condition were less motivated, on average, than those in the intervention condition, to do something about their Cannabis use. This could serve as an alternate explanation of the findings in this study. 
 
Given that only five participants were removed out of 225 (or 230 if control and intervention group participant totals are added?) randomized at baseline, it is quite possible that this alternate explanation is untrue. However, the authors do expose themselves to alternate explanations of the findings by the removal of these participants. If the systematic removal of participants post-randomization is deemed necessary, one possible solution would be to run (and report on) the analysis with and without these participants included. Such sensitivity analyses would go a long way towards addressing any possible confounds that may have been introduced.

The Systematic Removal of Participants Post-Randomization Can Lead to Alternate Explanations of the Results

Exploratory randomized controlled trial evaluating the impact of a waiting list control design

Internet-based interventions for disordered gamblers: study protocol for a randomized controlled trial of online self-directed cognitive-behavioural motivational therapy

Patterns of last year hangover symptomatology in Canadian Adults and relationship with hangover cures

Assessing the immediate impact of normative drinking information using an immediate post-test randomized controlled design: implications for normative feedback interventions?

1. Tucker J. A. Commentary on Gates et al. (2012): Telehealth services to extend the reach of care involve more than using a telephone for intervention delivery. Addiction 2012; 107: 2159–60. 2. Gates P. J., Norberg M. M., Copeland J., Digiusto E. Randomized controlled trial of a novel cannabis use intervention delivered by telephone. Addiction 2012; 107: 2149–59. 3. Vendetti J., McRee B., Miller M., Christiansen K., Herrell J. The Marijuana Treatment Project Research Group. Correlates of pre-treatment dropout among persons with marijuana dependence. Addiction 2002; 97: 125–34. 4. Okuda M., Hasin D. S., Olfson M., Khan S. S., Nunes E. V., Montoya I. et al. Generalizability of clinical trials for cannabis dependence to community samples. Drug Alcohol Depend 2010; 111: 177–81. 5. Nathan P. E., Gorman J. M. Efficacy, effectiveness, and the clinical utility of psychotherapy research. In: Nathan P. E., Gorman J. M., editors. A Guide to Treatments That Work, 2nd edn. New York: Oxford University Press; 2002, p. 642– 54. 6. Jungerman F. S., Andreoni S., Laranjeira R. Short term impact of same intensity but different duration interventions for cannabis users. Drug Alcohol Depend 2007; 90: 120–7. 7. Fernandes S., Ferigolo M., Benchaya M. C., Moreira T. C., Pierozan P. S., Mazoni C. G. et al. Brief motivational intervention and telemedicine: a new perspective of treatment to marijuana users. Addict Behav 2010; 35: 750–5.

Could the use of biochemical validation of smoking abstinence introduce a confound into the interpretation of randomized controlled trials of tobacco cessation?

Self-selection in a randomized trial of web-based primary and secondary prevention alcohol brief intervention

One of the challenging issues facing the randomized controlled trial (RCT) researcher is how to interpret the results of studies where there are improvements in the behaviour under study but where the degree of improvement does not differ between the experimental conditions [1]. This is especially a challenge when the RCT involves the comparison of two or more interventions rather than an intervention compared to some form of no-intervention control group. 
 
One possible cause of the observed improvement in such trials is that both interventions were “active” - that both interventions were effective in facilitating or causing a change among participants. Unfortunately, there is no way to determine if this claim is definitely true from the results of a negative RCT. Other interpretations of the results include: 1) that the change over time is due to regression to the mean [2, 3]; 2) due to natural history maturation (meaning that participants were in a period in their lives where, on average, a downward trend in quantity of drinking could be expected); or 3) the trial recruited participants who were already motivated to change and who would have done so anyway without exposure to the interventions under study [4]. 
 
Any of these alternate explanations could apply to the recent trial by Hester and colleagues [1]. Further, there is a well-established finding in the alcohol research field that participants in the no intervention control condition of intervention trials show improvements in their drinking from baseline to follow-up [5]. This may be particularly the case in trials recruiting participants from the community rather than from treatment settings where intractable alcohol problems are more common [6]. Essentially, the assumption that any changes over time are due to the intervention in a negative trial is predicated on the assumption that the participants would show no improvement without receiving some type of intervention. There may be some behaviours where this is the case. However, alcohol abuse is demonstrably not one of them. Thus, it is unwise to favour an intervention effect explanation over other causes when faced with the results of an RCT where participants show improvement over time but that there are no significant statistical differences between intervention conditions. [J Med Internet Res 2013;15(8):e179]

Claiming Positive Results From Negative Trials: A Cause for Concern in Randomized Controlled Trial Research

Motivators for Seeking Gambling-Related Treatment Among Ontario Problem Gamblers

Pragmatic randomized controlled trial of providing access to a brief personalized alcohol feedback intervention in university students

To the Editor: Twitter has recently been shown to identify patterns in behaviors and emotions in the general population (eg, changes in mood throughout the day). This may be useful because many psychosocial activities have temporal variation, and it is challenging to find means to capture these variations in a timespecific manner for a large number of people. More evidence is needed, however, to assess the extent to which patterns of word use on Twitter are valid reflections of actual patterns of behavior in the general population. To do this, it is necessary to identify behaviors with temporal variations in frequency that have been identified using other means of population-survey methods (eg, epidemiologic surveys) and then to determine the extent to which the variations in mentions of these behaviors on Twitter “map,” onto the patterns of those behaviors, as measured with these other population-survey methods. A good choice for testing the validity of temporal frequency of word use on Twitter may be cigarette and alcohol consumption. Given the average number of cigarettes smoked by adult daily smokers, only minor variation in the frequency of smoking throughout the day and across the week might be expected. It could then be predicted that frequency of Twitter word use (such as case “cigarette” and “smoke”) would be fairly stable across the day and over the week. In contrast, there is a fairly large variation in alcohol consumption across the day (more in the evening than in the morning) and across the week (more over the weekend than during the week). Does frequency of words (such as “beer” and “wine”) mentioned on Twitter reflect these temporal variations of alcohol consumption? I made use of an online resource (timeu.se), which consists of a large searchable bank of Twitter messages. I entered two words for smoking (“cigarette” and “smoke”) and two words for drinking (“beer” and “wine”). As predicted from temporal patterns reported in epidemiologic surveys, words related to smoking had a fairly consistent pattern throughout the day and across the week, whereas words related to alcohol consumption displayed substantial temporal variation within the day and across the week (see Figure). Twitter seems to be a means to assess patterns of behavior in the general population. As a potential offshoot, Twitter might be useful in measuring changes in patterns of alcohol consumption or cigarette smoking that result from regulations to reduce the availability of these substances. For example, have changes in opening hours for pubs in the United Kingdom led to detectable changes in the patterns of words related to alcohol on Twitter? Do legal restrictions on public smoking (eg, in office buildings, restaurants, and bars) produce measurable changes in patterns of mention of smoking on Twitter? If so, changes in patterns of words related to a specific behavior on Twitter or other social media sites could become an inexpensive, real-time way to assess the impact of changes targeted at improving public health.

Background Alcohol problems are a serious public health concern, and few problem drinkers ever seek treatment. The Internet is one means of promoting access to care, but more research is needed to test the best types of interventions to employ. Evaluation of Internet-based interventions that contain a variety of research-validated cognitive-behavioral tools, which have been shown to be helpful to those with more severe alcohol concerns, should be a priority. Objective To evaluate whether providing access to an extended Internet intervention for alcohol problems offers additional benefits in promoting reductions in alcohol consumption compared with a brief Internet intervention. The hypothesis for the current trial was that respondents who were provided with access to an extended Internet intervention (the Alcohol Help Center [AHC]) would display significantly improved drinking outcomes at 6-month follow-up, compared with respondents who were provided with access to a brief Internet intervention (the Check Your Drinking [CYD] screener). Methods A single-blinded randomized controlled trial with a 6-month follow-up. A general population sample of problem drinkers was recruited through newspaper advertisements in a large metropolitan city. Baseline and follow-up data were collected by postal mail. Results A volunteer sample of problem drinkers of legal drinking age with home access to the Internet were recruited for the trial. Of 239 potential respondents recruited in 2010, 170 met inclusion criteria (average age 45 years; 101/170, 59.4% male; average Alcohol Use Disorders Identification Test [AUDIT] score of 22). Follow-up rates were 90.0% (153/170) with no adverse effects of the interventions reported. A repeated-measures multivariate analysis of variance of the outcome measures using an intent-to-treat approach found a significantly greater reduction in amount of drinking among participants provided access to the AHC than among participants provided access to the CYD (P = .046). Conclusions The provision of the AHC gave additional benefit in the short term to problem drinkers over that seen from the research-validated CYD, indicating the benefits of promoting access to these interventions as one means of helping people with problem drinking concerns. Trial Registration ClinicalTrials.gov NCT01114919; http://clinicaltrials.gov/ct2/show/NCT01114919 (Archived by WebCite at http://www.webcitation.org/68t1dCkRZ)

Comparison of Two Internet-Based Interventions for Problem Drinkers: Randomized Controlled Trial

Background Personalized feedback is a promising self-help for problem gamblers. Such interventions have shown consistently positive results with other addictive behaviours, and our own pilot test of personalized normative feedback materials for gamblers yielded positive findings. The current randomized controlled trial evaluated the effectiveness, and the sustained efficacy, of the personalized feedback intervention materials for problem gamblers. Methodology/Principal Findings Respondents recruited by a general population telephone screener of Ontario adults included gamblers with moderate and severe gambling problems. Those who agreed to participate were randomly assigned to receive: 1) the full personalized normative feedback intervention; 2) a partial feedback that contained all the feedback information provided to those in condition 1 but without the normative feedback content (i.e., no comparisons provided to general population gambling norms); or 3) a waiting list control condition. The primary hypothesis was that problem gamblers who received the personalized normative feedback intervention would reduce their gambling more than problem gamblers who did not receive any intervention (waiting list control condition) by the six-month follow-up. Conclusions/Significance The study found no evidence for the impact of normative personalized feedback. However, participants who received, the partial feedback (without norms) reduced the number of days they gambled compared to participants who did not receive the intervention. We concluded that personalized feedback interventions were well received and the materials may be helpful at reducing gambling. Realistically, it can be expected that the personalized feedback intervention may have a limited, short term impact on the severity of participants' problem gambling because the intervention is just a brief screener. An Internet-based version of the personalized feedback intervention tool, however, may offer an easy to access and non-threatening portal that can be used to motivate participants to seek further help online or in person. Trial Registration ClinicalTrials.gov NCT00578357

A Randomized Controlled Trial of a Personalized Feedback Intervention for Problem Gamblers

Smokers and Non-smokers Differ in Their Beliefs About Their Addiction: Public Health Implications

Objectives:This study aimed to examine barriers in seeking help for gambling problems. Methods:A random digit dialing telephone survey was conducted among adults in Ontario, Canada. Respondents meeting criteria for possible past year gambling problems were asked an open-ended question on why they might hesitate once they had decided to seek help. Results:Of 556 eligible respondents, 47% asserted they would not hesitate to seek help. The most frequently identified possible reasons for hesitation were shame, difficulty acknowledging the problem, and treatment-related issues. Younger gamblers and those with higher problem severity, self-perception of a gambling problem, and past treatment experience were more likely to volunteer shame and treatment-related issues. Gamblers with lower problem severity, no self-perception of a gambling problem, and no history of help seeking more frequently said they would not hesitate to seek help. However, among problem/pathological gamblers, 49% did not self-perceive even a moderate gambling problem; they were more likely than self-perceived problem gamblers in this high severity group to predict no hesitation. Conclusions:In addition to revealing perceived and objective factors that impede help seeking for gambling problems, the identification of possible barriers may indicate, among some disordered gamblers, awareness of gambling problems and consideration given to possible actions. Both tackling barriers and enhancing problem awareness are necessary components of strategies to provide accessible and timely assistance to those with gambling problems.

Hesitation to Seek Gambling-related Treatment Among Ontario Problem Gamblers

Background Like many indigenous peoples, New Zealand Māori bear a heavy burden of alcohol-related harm relative to their non-indigenous compatriots, and disparities are greatest among young adults. We tested the effectiveness of web-based alcohol screening and brief intervention (e-SBI) for reducing hazardous drinking among Māori university students. Methods We ran a double-blind, multi-site, randomised controlled trial. We invited 6697 17–24-year-old Māori students from seven of New Zealand's eight universities to complete a web-based AUDIT-C, a screener for hazardous and harmful drinking. Those screening positive were computer randomised to: <10 min of web-based alcohol assessment and personalised feedback (intervention) or screening alone (control). We conducted a 5 month follow-up assessment with observers and participants blinded to study hypotheses, design, and intervention delivery. Predetermined primary outcomes were: (1) frequency of drinking (2) amount consumed per typical drinking occasion, (3) overall volume of alcohol consumed, and (4) academic problems. Results 1789 respondents were hazardous drinkers (AUDIT-C≥4) and were randomised: 850 to control, 939 to intervention. Follow-up assessments were completed by 682 controls (80%) and 733 intervention group members (78%). Relative to controls, participants receiving intervention drank less often (RR=0·89; 95% CI 0·82 to 0·97), less per drinking occasion (RR=0·92; 0·84 to 1.00), less overall (RR=0·78; 0·69 to 0·89), and had fewer academic problems (RR=0·81; 0·69 to 0·95). Significance Web-based screening and brief intervention reduced hazardous and harmful drinking among non-help-seeking Māori students in a large scale pragmatic trial. This intervention is now being implemented routinely in all New Zealand universities and could be implemented elsewhere. The study has wider implications for behavioural intervention in the important but neglected area of indigenous health.

WEB-BASED INTERVENTION FOR MAORI UNIVERSITY STUDENTS WITH HAZARDOUS DRINKING: DOUBLE-BLIND, MULTI-SITE RANDOMISED CONTROLLED TRIAL

Aims Like many indigenous peoples, New Zealand Māori bear a heavy burden of alcohol-related harm relative to their non-indigenous compatriots, and disparities are greatest among young adults. We tested the effectiveness of web-based alcohol screening and brief intervention (e-SBI) for reducing hazardous drinking among Māori university students. Design Parallel, double-blind, multi-site, randomized controlled trial. Setting Seven of New Zealand's eight universities. Participants In April 2010, we sent e-mail invitations to all 6697 17–24-year-old Māori students to complete a brief web questionnaire including the Alcohol Use Disorders Identification Test (AUDIT)-C, a screening tool for hazardous and harmful drinking. Those screening positive were computer randomized to: <10 minutes of web-based alcohol assessment and personalized feedback (intervention) or screening alone (control). Measurements We conducted a fully automated 5-month follow-up assessment with observers and participants blinded to study hypotheses, design and intervention delivery. Pre-determined primary outcomes were: (i) frequency of drinking, (ii) amount consumed per typical drinking occasion, (iii) overall volume of alcohol consumed and (iv) academic problems. Findings Of the participants, 1789 were hazardous or harmful drinkers (AUDIT-C ≥ 4) and were randomized: 850 to control, 939 to intervention. Follow-up assessments were completed by 682 controls (80%) and 733 intervention group members (78%). Relative to controls, participants receiving intervention drank less often [RR = 0.89; 95% confidence interval (CI): 0.82–0.97], less per drinking occasion (RR = 0.92; 95% CI: 0.84–1.00), less overall (RR = 0.78; 95% CI: 0.69–0.89) and had fewer academic problems (RR = 0.81; 95% CI: 0.69–0.95). Conclusions Web-based screening and brief intervention reduced hazardous and harmful drinking among non-help-seeking Māori students in a large-scale pragmatic trial. The study has wider implications for behavioural intervention in the important but neglected area of indigenous health.

Web-based alcohol intervention for Mäori university students: double-blind, multi-site randomized controlled trial

This ‘For Debate’ paper starts by recognizing the growing trend towards considering alcohol dependence as a chronic relapsing disorder. We argue that the adoption of this model results from focusing on those in treatment for alcohol dependence rather than considering the larger number of people in the general population who meet criteria for alcohol dependence at some point in their lives. The majority of the general population who ever experience alcohol dependence do not behave as though they have a chronic relapsing disorder: they do not seek treatment, resolve their dependence themselves and do not relapse repeatedly. We suggest that caution is therefore needed in using the chronic relapsing disorder label. Our primary concerns are that this formulation privileges biological aspects of dependence to the detriment of psychological and social contributions, it inhibits much-needed developments in understanding alcohol dependence and leads to inefficient distributions of public health and clinical care resources for alcohol dependence. We invite debate on this issue.

Is alcohol dependence best viewed as a chronic relapsing disorder?

Cigarette smokers’ beliefs about recovery may have an impact on whether they attempt to quit.1,2 It is important for those trying to encourage smokers to quit to recognize how beliefs about recovery may differ between smokers and non-smokers. Such information can emphasize when extra support is needed or when information about effective means to quit smoking may increase motivation to change. The present study compared smokers’ and non-smokers’ beliefs about recovery in a sample of the Canadian general population. A random digit dialing telephone survey was conducted between August 2008 and January 2009; 864 Canadians, 18 years and older, participated (response rate of 41%). Interviews were conducted in English or French. Respondents were asked a series of questions, including: 1) how much of a risk it was for someone to get addicted if they tried smoking cigarettes even once (1 = very low risk, 5 = very high risk); 2) if becoming addicted to smoking was the person’s fault or society’s; 3) whether dealing with the addiction was the person’s responsibility or society’s; 4) how likely a person was to be able to fix the addiction a) on their own without treatment and b) if they went to treatment (for each question, 1 = no chance, 6 = very large chance). To simplify the interpretation of the results, all questions were dichotomized such that the highest value on each question was compared to all other responses (e.g., very high risk of becoming addicted compared to all other responses). The survey concluded with a series of demographic questions. Results are presented as weighted values to be representative of the Canadian adult population (sample sizes presented as unweighted values). Of the 864 respondents, 655 did not smoke and 161 were daily smokers (45 occasional smokers and 3 respondents with missing values on this question were excluded from these analyses). Table 1 displays the differences in demographic characteristics between smokers and non-smokers, with non-smokers being older, less likely to be male and more likely to be married as compared to daily smokers. Daily smokers and non-smokers were also compared on their beliefs about addiction to smoking cigarettes (see Table 2). Compared to non-smokers, daily smokers were more likely to believe that there was a very high risk of becoming addicted if someone tried cigarettes, less likely to believe that it was the person’s fault for becoming addicted, and more pessimistic about a smoker’s chances of fixing their addiction both with and without treatment. There are two useful findings from this research. The first is that smokers rate cigarettes as very addictive, even from the time they first tried smoking a cigarette. This information is potentially useful for primary prevention campaigns.3 If there were some way of communicating to people who have not yet started smoking that cigarettes can be very addictive for some people, then this could help to reduce the tendency for youth to experiment, believing that it is easy to stop, when in fact it often leads to committed cigarette smoking. The second useful finding is just how skeptical smokers are about their chances of quitting. Both smokers and non-smokers are dubious about the chances of stopping smoking without treatment. However, current smokers are also quite pessimistic about the chances of stopping even with treatment. This finding emphasizes that ongoing support together with advice about different effective treatment options are needed in order to encourage smokers to try to quit – and to keep on trying if, at first, they do not succeed.4

Canadian journal of public health = Revue canadienne de sante publique

Smokers and non-smokers differ in their beliefs about their addiction: public health implications.

relapse of alcohol-related problems. There is much we do not know about milder forms of risky drinking, and focusing on alcohol dependence perpetuates a ‘pathology’ bias in research that favors studying a homogeneous severe type of the disorder [5]. Debate also continues over whether alcohol abuse should be viewed as a less severe diagnostic category than alcohol dependence, or whether presentations that fall short of a dependence diagnosis should be characterized along several continuous dimensions, rather than categorized hierarchically based on apparent severity [8,9]. Similarly, more research is needed on transitions over time among abstinence, low-risk and high-risk drinking patterns for different population segments (e.g. by gender and age and during pregnancy) and on how to develop and deliver a range of accessible, appealing services to match the needs of different risk groups at different points in problem development or resolution [6]. Understanding population variability in alcohol use and misuse is fundamental to broadening services for alcohol-related problems. The science of behavior change is based increasingly on disciplinary pluralism that recognizes that no single perspective is adequate in isolation as a scientific model [10]. Moreover, clinical and public health perspectives are not mutually exclusive [11]. Rather, alcohol misuse encompasses an extensive, nuanced set of behaviors and consequences, which all have a place on the research agenda. An over-generalized alcohol dependence concept discourages this agenda. If constrained within its boundary conditions of utility in health systems and clinical work, it is a useful organizing framework.

Ultra-brief intervention for problem drinkers: three-month follow-up results from a randomized controlled trial

Background. Substance use is common among youth; however, our understanding of co-morbid tobacco, alcohol and marijuana use remains limited. The school-environment may play an important role in the likelihood a student engages in high risk substance use behaviors, including co-morbid use. Purpose. This study aims to: (i) describe the prevalence of co-morbid substance use behaviors among youth; (ii) identify and compare the characteristics of youth who currently use a single substance, any two substances, and all three substances; (iii) examine if the likelihood of co-morbid use varies by school and; (iv) examine what factors are associated with co-morbid use. Methods. This study used nationally representative data collected from students in grades 9 to 12 (n = 41,886) as part of the 2006-2007 Canadian Youth Smoking Survey (YSS). Demographic and behavioral data were collected including, current cigarette, alcohol and marijuana use. Results. 6.5% (n = 107,000) reported current use of all three substances and 20.3% (n = 333,000) of any two substances. Multi-level analysis revealed significant between school variability in the odds a student used all three substances and any two substances; accounting for 16.9% and 13.5% of the variability, respectively. Co-morbid use was associated with sex, grade, amount of available spending money and perceived academic performance. Conclusions. Co-morbid substance use is high among youth; however, not all schools share the same prevalence. Knowing the school characteristics that place particular schools at risk for student substance use is important for tailoring drug and alcohol education programs. Interventions that target the prevention of co-morbid substance use are required.

Co-morbid substance use behaviors among youth: any impact of school environment?

Background There are a number of evidence-based, in-person clinical inteventions for problem drinkers, but most problem drinkers will never seek such treatments. Reaching the population of non-treatment seeking problem drinkers will require a different approach. Accordingly, this randomized clinical trial evaluated an intervention that has been validated in clinical settings and then modified into an ultra-brief format suitable for use as an indicated public health intervention (i.e., targeting the population of non-treatment seeking problem drinkers). Methodology/Principal Findings Problem drinkers (N = 1767) completed a baseline population telephone survey and then were randomized to one of three conditions – a personalized feedback pamphlet condition, a control pamphlet condition, or a no intervention control condition. In the week after the baseline survey, households in the two pamphlet conditions were sent their respective interventions by postal mail addressed to ‘Check Your Drinking.’ Changes in drinking were assessed post intervention at three-month and six-month follow-ups. The follow-up rate was 86% at three-months and 76% at six-months. There was a small effect (p = .04) in one of three outcome variables (reduction in AUDIT-C, a composite measure of quantity and frequency of drinking) observed for the personalized feedback pamphlet compared to the no intervention control. No significant differences (p>.05) between groups were observed for the other two outcome variables – number of drinks consumed in the past seven days and highest number of drinks on one occasion. Conclusions/Significance Based on the results of this study, we tentatively conclude that a brief intervention, modified to an ultra-brief, public health format can have a meaningful impact. Trial Registration ClinicalTrials.gov NCT00688584.

Ultra-Brief Intervention for Problem Drinkers: Results from a Randomized Controlled Trial

This pilot study reports on the initial usage of an online personalized feedback screener for problem gamblers. The Check Your Gambling screener (CYG; www.CheckYourGambling.net) is an online version of a paper and pencil screener that had shown some promise in an initial evaluation to promote short-term reductions in gambling behaviour. The online CYG screener was linked to two existing Web pages for gambling in Ontario, Canada—the Ontario Problem Gambling Helpline (OPGH) Web page and ProblemGambling.ca. While more participants used the ProblemGambling.ca (n = 730) version than the OPGH version (n = 591), the OPGH version appeared to be more targeted, as almost all of the participants using this Web site were Canadian (and the personalized feedback of the current version of the CYG is generated using Canadian norms). More work is needed to establish whether the online CYG screener can motivate reductions in gambling among participants or motivate treatment-seeking in those requiring assistance in addressing problematic gambling behviour.

Pilot study of an Internet-based personalized feedback intervention for problem gamblers

Aims: Heavy drinkers tend to overestimate how much others drink (normative fallacy), at least in college samples. Little research has been conducted to evaluate whether normative misperceptions about drinking extend beyond the college population. The present study explored normative misperceptions in an adult general population sample of drinkers. Methods: As part of a larger study, in Toronto, Canada, a random digit dialling telephone survey was conducted with 14,009 participants who drank alcohol at least once per month. Respondents with Alcohol Use Disorders Identification Test of eight or more (n = 2757) were asked to estimate what percent of Canadians of their same sex: (a) drank more than they do; (b) were abstinent and (c) drank seven or more drinks per week. Respondents' estimates of these population drinking norms were then compared with the actual levels of alcohol consumption in the Canadian population. Results: A substantial level of normative misperception was observed for estimates of levels of drinking in the general population. Estimates of the proportion of Canadians who were abstinent were fairly accurate. There was some evidence of a positive relationship between the respondents' own drinking severity and the extent of normative misperceptions. Little evidence was found of a relationship between degree of normative misperceptions and age. Conclusion: Normative misperceptions have been successfully targeted in social norms media campaigns as well as in personalized feedback interventions for problem drinkers. The present research solidifies the empirical bases for extending these interventions more widely into the general population.

Normative Misperceptions about Alcohol Use in a General Population Sample of Problem Drinkers from a Large Metropolitan City

Beliefs About Gambling Problems and Recovery: Results from a General Population Telephone Survey

. [1] have conducted a randomized trialcomparing face-to-face brief motivational interviewing(BMI) with two different computer-delivered interven-tions (CDIs) for college students facing sanctions for vio-lating campus alcohol policies in the United States. Theﬁndings,ingeneral,leantowardssupportingthestrengthof the face-to-face BMI over the two CDIs. I applaudCarey’s continued research to attempt to elucidate whatinterventions might work best for problem drinkers andforwhomdifferentinterventionsareeffective(e.g.genderdifferences in the current study). It can be a challenge todemonstrate intervention effects when comparing a briefintervention to a minimally active comparator, let alonewhen comparing the intervention to another putativelyactive intervention.I was, however, left with one primary concern afterreading the study. That is, is it time to start discussingwhat types of computer-delivered interventions arebeing employed in this brief intervention research? BMIis perhaps the most-validated and -researched briefinterventionforproblemdrinkerswithaconsistenttrackrecord of measurable impact [2]. CDIs are still reallyin their infancy but there have been enough trials toconduct several recently published meta-analyses[3,4]. While these analyses note limitations with thecurrentliterature,thereisperhapsenoughresearchcon-ducted to date to at least divide CDIs into two groups: (i)those that have been developed by modifying clinicallyresearched and validated brief interventions for problemdrinkers (e.g. the various personalized feedback inter-ventions that could loosely be said to be descendentsof the Drinker’s Check-up tradition) [5]; and (ii) thosethat are education-orientated, stemming from a desireto promote safe (or no) drinking on American collegecampuses or that are automated versions of educationalprograms for those same students facing sanctions fordrinking on campus. My reading of this literature is thatit is the ﬁrst group of CDIs—those which trace theirdevelopment from clinically based brief interventions—which have generally been more likely to have publishedtrials which report signiﬁcant intervention effects. Cer-tainly, it is too early to say deﬁnitely that one of thesegroups of CDIs is superior to the other. However, it isnot too early to select a CDI which already has someevidence of efﬁcacy (i.e. has at least one publishedrandomized trial with positive results) when settingout to conduct a trial that most readers may take as acomparison of face-to-face brief interventions versuscomputerized interventions. Personally, I suspect that awell-delivered face-to-face intervention from a skilledclinician will always be superior to a computerizedsubstitute. However, it would be good to have a test todemonstrate this superiority using the state-of-the-artversion of both of these candidates.

Is it time to start discussing what type of computer-delivered intervention?

Randomized controlled trial of mailed Nicotine Replacement Therapy to Canadian smokers: study protocol

Emerging technologies, such as the Internet and text messaging, have an ever-growing role in providing services to problem drinkers. This article summarizes selected examples of emerging technologies that have been developed and implemented as stand-alone interventions and as part of other face-to-face interventions. It provides a taste of the different opportunities available for implementing emerging technologies as a way to improve the accessibility and effectiveness of services for problem drinkers.

Is there something peculiar about Finnish views on alcohol addiction? :  A cross-cultural comparison between four northern populations

Is there something peculiar about Finnish views on alcohol addiction? : A cross-cultural comparison between four northern populations

Aims: This study reports on the relative gravity people attribute to various addictive behaviors with respect to other societal concerns in four northern populations with different history, social policy and treatment alternatives for addicted individuals. Methods: Random population surveys were conducted in Canada, Sweden, Finland and St. Petersburg, Russia. In Finland and Sweden, the survey was conducted by mail, in Canada and St. Petersburg by phone. As a part of this survey, the respondents were asked to assess the gravity of various societal problems, some of which involved various addictive behaviors. The data were analyzed by descriptive statistical methods, factor analysis, contextual analysis and multiple regression analysis. Results: Hard drugs, criminality and environmental issues belonged to the topmost problems in all data samples. Overall, Finns and Canadians appeared the least worried about various societal problems, Swedes seemed the most worried and St. Petersburgian views were the most polarized. Two factors were extracted from the combined data. Factor 1 covered criminal behavior and various addictions; it was named Threats to Safety factor. Factor 2 comprised social equality issues. The country context explained 12.5% of the variance of the safety factor and 7.9% of the equality factor. Conclusions: Despite some cultural variation in the gravity assessments, the central core of the social representation of addictive behaviors tends still to be linked with ‘badness’ since they were mainly grouped with various forms of criminal behavior in all these countries.

Perceptions of Addictions as Societal Problems in Canada, Sweden, Finland and St. Petersburg, Russia

Background Both intratreatment and extratreatment social support are associated with increased rates of smoking cessation. Internet-based social support groups have the capability of connecting widely dispersed groups of people trying to quit smoking, making social support available 24 hours a day, seven days a week, at minimal cost. However, to date there has been little research to guide development of this particular feature of Web-assisted tobacco interventions (WATIs). Objective Our objectives were to compare the characteristics of smokers who post in an online smoking cessation support group with smokers who do not post, conduct a qualitative analysis of discussion board content, and determine the time it takes for new users to receive feedback from existing members or moderators. Methods Data were collected from StopSmokingCenter.net version 5.0, a WATI equipped with an online social support network moderated by trained program health educators that was operational from November 6, 2004, to May 15, 2007. Demographic and smoking characteristics for both users and nonusers of the online social support network were analyzed, and qualitative analyses were conducted to explore themes in message content. Posting patterns and their frequency were also analyzed. Results During the study period, 16,764 individuals registered; of these, 70% (11,723) reported being American. The mean age of registrants was 38.9 years and 65% (10,965) were female. The mean number of cigarettes smoked was 20.6 per day. The mean score for the 41% (6849) of users who completed the Fagerström Test for Nicotine Dependence was 5.6. Of all registered members, 15% (2562) made at least one post in the online social support network; 25% of first posts received a response from another member within 12 minutes, 50% within 29 minutes. The most frequent first posts were from recent quitters who were struggling with their quit attempts, and most responses were from members who had quit for a month or more. Differences in demographic and smoking characteristics between members who posted on the support group board at least once and those who did not post were statistically but not clinically significant. Conclusions Peer responses to new users were rapid, indicating that online social support networks may be particularly beneficial to smokers requiring more immediate assistance with their cessation attempt. This function may be especially advantageous for relapse prevention. Accessing this kind of rapid in-person support from a professional would take an inordinate amount of time and money. Further research regarding the effectiveness of WATIs with online social support networks is required to better understand the contribution of this feature to cessation, for both active users (posters) and passive users (“lurkers”) alike.

Online Social and Professional Support for Smokers Trying to Quit: An Exploration of First Time Posts From 2562 Members

AIMS
Internet-based interventions (IBIs) for problem drinkers have been in existence for over a decade. In that time, IBIs have increased in sophistication and there is the beginning of a solid research base suggesting their efficacy. A growing number of problem drinkers are using IBIs and attempts have been made to explore how IBIs can be integrated within primary care and other health-care settings. This symposium provided an overview of IBIs for problem drinkers and highlighted some of the important issues in their development and implementation.

RATIONALE
IBIs appear to be at a 'cusp' as technology and intervention practices are merged together in an attempt to provide better health care for problem drinkers. The timing of the 2009 International Network on Brief Interventions for Alcohol Problems Conference was ideal for a presentation and discussion of the role that IBIs play now that IBIs have started to shift into the mainstream of services for problem drinkers.

SUMMARY
The presentations in this symposium covered the 'bench to bedside' aspects of the development and evaluation of IBIs. They included a systematic review of the research to-date in this field, a report on the results from a just completed randomised controlled trial, a report on an effectiveness trial of implementing IBIs in multiple university settings and a consideration of the cost-effectiveness of IBIs.[Cunningham JA, Khadjesari Z, Bewick BM, Riper H. Internet-based interventions for problem drinkers: From efficacy trials to implementation.

Internet-based interventions for problem drinkers: From efficacy trials to implementation.

Web-based alcohol screening and brief intervention for Māori and non-Māori: the New Zealand e-SBINZ trials

Motivators for Resolving or Seeking Help for Gambling Problems: A Review of the Empirical Literature

Pre-cessation reduction is associated with quitting smoking. However, many smokers reduce the amount consumed but may not quit altogether. Using a representative sample of adult current daily smokers, this project explored future intentions of smokers regarding cigarette consumption. This information is important because it can provide a framework within which to plan tobacco cessation initiatives. A random digit dialing telephone survey was conducted of 889 Canadian current daily smokers, 18 years and older. The response rate was 65% (of households with a smoker in residence, 65% agreed to participate). Analyses focused on the 825 respondents who smoked at least 10 cigarettes per day at some point in their lives. As part of this survey, respondents were asked their future plans about their smoking (maintain, increase, reduce, quit). Of these 825 respondents, the majority of respondents had plans to change their cigarette use, with 55% planning to quit, 18.8% to reduce and 22.5% to maintain the amount they smoked (3.4% did not know and 2 respondents planned to increase). Most smokers who planned to reduce their smoking saw it as a step towards quitting smoking completely. These results present a picture of smokers, the majority of whom appear to be in some form of transition. Many smokers planned to reduce, of which the overwhelming majority saw their reduction as a step towards quitting. Opportunities exist to capitalize on these intentions to change in efforts to promote tobacco cessation.

Future Intentions Regarding Quitting and Reducing Cigarette Use in a Representative Sample of Canadian Daily Smokers: Implications for Public Health Initiatives

Aims: To examine the impact of a web-based personalized feedback intervention, the Check Your Drinking (CYD; www.CheckYourDrinking.net) screener at 12-month follow-up. Methods: Respondents (N = 185) were recruited from a general population telephone survey of Ontario, Canadian adults (≥18 years) by asking risky drinkers if they were willing to help develop and evaluate Internet-based interventions for drinkers. Those randomly assigned to the intervention condition were provided with the web address and a unique password to a study-specific copy of the CYD. Respondents assigned to the control condition were sent a written description of the different components of the CYD and asked how useful they thought each of the components might be. Respondents were followed up at 3, 6 and 12 months. Results: By the 12-month follow-up, the impact of the intervention previously reported at 3 and 6 months of CYD on problem drinkers’ alcohol consumption was no longer apparent (P > 0.05). Conclusions: Recognizing that many people with alcohol concerns will never seek treatment, recent years have seen an increase in efforts to find ways to take treatment to problem drinkers. The CYD is one such intervention that has a demonstrated effect on reducing alcohol consumption in the short term (i.e. 6 months). Other more intensive Internet-based interventions or interventions via other modalities may enhance this positive outcome over the short and long term among problem drinkers who would be otherwise unlikely to access treatment for their alcohol concerns. www.ClinicalTrials.gov registration #NCT00367575.

Twelve-Month Follow-up Results from a Randomized Controlled Trial of a Brief Personalized Feedback Intervention for Problem Drinkers

E-Health programs for mental illness and addictive behaviors have recently emerged as potentially useful self-help resources. Health care professionals will soon have the option of referring clients to free-to-end-user online, expert-moderated e-health programs as complementary means of assisting clients. Such programs will have significant implications for developing improved stepped models of care. This article describes various e-health programs and lessons learned related to access, promotion, user demographics, and patterns of use. In addition, validation procedures, effectiveness and attrition rates, fitting and tailoring, and qualitative analyses of social networks are described. It is difficult to validate e-health programs that are completely anonymous and do not require registration, personal interaction, or membership fees. As competition emerges in the budding e-health industry, best practice guidelines will need to be developed for collecting data and evaluating the utility of these programs.

Using E-Health Programs to Overcome Barriers to the Effective Treatment of Mental Health and Addiction Problems

Pilot study of a personalized feedback intervention for problem gamblers.

This brief report describes the development and first year of use of an Internet-based screener for Cannabis users. Two versions of the Check Your Cannabis screener were compared, one linked to an already established harm reduction website for young Cannabis users (as an exercise called “Check how I compare with others,” on www.WhatsWithWeed.ca) and the other a standalone version (www.CheckYourCannabis.net). The What’s With Weed version attracted ten times more users and had a significantly younger audience as compared to the standalone version, underlining the benefits of targeting a website to a specific audience and linking to websites with already established reputations. Further work is needed to establish any impact on actual Cannabis use from taking the Check Your Cannabis screener.

The Check Your Cannabis Screener: A New Online Personalized Feedback Tool

INTRODUCTION AND AIMS
In recent years, there has been an increase in the number of Internet-based interventions (IBI) for alcohol problems and other addictive behaviours. However, it is risky to assume interventions that have been found to work in face-to-face modalities can be translated into IBI that are equally effective.

DESIGN AND METHODS
Using selected examples from the published works, this paper will identify some of the special considerations that are relevant to the evaluation of IBI. In addition, methodological issues found in the ongoing development and evaluation of the Check Your Drinking screener (http://www.CheckYourDrinking.net), an IBI for problem drinkers, will be discussed.

RESULTS
There have been several randomised control trials with promising results. A primary limitation of much of the research conducted to date is concerns regarding the generalisability of the findings. DISCUSSION AND CONCLUSIONS. Caution should be taken in assuming that the IBI, which have been found to work in tightly controlled efficacy trials, will display similar levels of effectiveness when used in 'naturalistic' settings (i.e. not face-to-face in a research environment). Positive results from studies using a variety of different research designs will advance the potential for IBI, as a new means of helping problem drinkers reduce their alcohol consumption. Because of their accessibility and anonymity, IBI could facilitate a broad provision of treatment services at a population level.

Methodological issues in the evaluation of Internet-based interventions for problem drinking.

Naturlicher Verlauf von problematischem Glucksspiel: Ergebnisse einer Allgemeinbevolkerungsstudie Fragestellung: Die Studie untersucht Grunde fur eine Verhaltensanderung in einer Stichprobe fruherer problematischer Glucksspieler. Methodik: In Ontario, Kanada, wurde an einer Zufallsstichprobe von 8.467 Erwachsenen eine telefonische Erhebung durchgefuhrt. Von den 450 Teilnehmern, die fruher, nicht aber in den letzten 12 Monaten glucksspielbezogene Probleme hatten (n=450) wurden 130 Personen identifiziert, die sich an eine Zeitspanne erinnern konnten, in der sie mehr gespielt haben als aktuell und damals keine Therapie oder eine Selbsthilfegruppe in Anspruch genommen haben. Sie wurden nach den Grunden fur das Aufhoren oder weniger Spielen und zu ihren Ausstiegsstrategien befragt. Ergebnisse: Haufige Grunde waren Veranderungen im Leben durch Reifung (Umzug, Arbeitsplatz, Heirat) oder eine kognitive Neubewertung des Spielens. Spieler mit schwereren Problemen nannten haufiger Anderungsgrunde, di...

Natural history of gambling problems: Results from a general population survey

Barriers to Seeking Help for Gambling Problems: A Review of the Empirical Literature

AIM
The aim of this work was to report on the results of a pilot study of a web-based self-assessment service (DHT) for Finnish drinkers (www.paihdelinkki.fi/testaa/juomatapatesti).

METHOD
During the 7-month recruitment period in 2004 altogether 22,536 anonymous self-assessments were recorded in the database of this service. The study sample was recruited from the 1598 service users who also participated to a survey evaluating the DHT. Those who consented by providing required baseline data and their e-mail address (n = 343) were sent a message asking them to fill in the follow-up questions 3, 6 and 12 months later. Their self-reported use of alcohol and drinking-related problems served as the main outcome variables in this single-group follow-up study.

RESULTS
At 3, 6 and 12 months, 78%, 69% and 61% of the study participants, respectively, responded to the follow-up. The intention-to-treat (ITT) results revealed significant reductions (P < 0.001) in all the outcome measures. The reductions occurred during the first 3 months, after which the changes were non-significant.

The results are in line with previous studies with mostly shorter follow-up periods suggesting that Internet-based self-assessment services can be useful tools in reducing excessive drinking. A randomized controlled trial would, however, increase our certainty about the causes of the observed changes.

Self-assessment of drinking on the Internet--3-, 6- and 12-month follow-ups.

Objective Misuse of alcohol imposes a major public health cost, yet few problem drinkers are willing to access in-person services for alcohol abuse. The development of brief, easily accessible ways to help problem drinkers who are unwilling or unable to seek traditional treatment services could therefore have significant public health benefit. The objective of this project is to conduct a randomized controlled evaluation of the internet-based Check Your Drinking (CYD) screener (http://www.CheckYourDrinking.net). Method Participants (n = 185) recruited through a general telephone population survey were assigned randomly to receive access to the CYD, or to a no-intervention control group. Results Follow-up rates were excellent (92%). Problem drinkers provided access to the CYD displayed a six to seven drinks reduction in their weekly alcohol consumption (a 30% reduction in typical weekly drinking) at both the 3- and 6-month follow-ups compared to a one drink per week reduction among control group respondents. Conclusions The CYD is one of a growing number of internet-based interventions with research evidence supporting its efficacy to reduce alcohol consumption. The internet could increase the range of help-seeking options available because it takes treatment to the problem drinker rather than making the problem drinker come to treatment.

A randomized controlled trial of an internet-based intervention for alcohol abusers

Background Previous research has found that current smokers are less likely to have access to the Internet than nonsmokers. As access to the Internet continues to expand, does this finding remain true? Also, how many smokers are interested in Web-assisted tobacco interventions (WATIs)? These questions are important to determine the potential role that WATIs might play in promoting tobacco cessation. Objectives The aims of the study were to determine whether smokers are less likely than nonsmokers to have access to the Internet and to establish the level of interest in WATIs among a representative sample of smokers. Methods A random digit dialing telephone survey was conducted of 8467 adult respondents, 18 years and older, in Ontario, Canada from September 2006 to August 2007. All respondents were asked their smoking status and whether they used the Internet (at home or work in the past 12 months; where; how often in the past 12 months). To assess the level of interest in WATIs, current daily smokers were asked whether they would be interested in a confidential program that they could access on the Internet, free of charge, that would allow them to check their smoking and compare it to other Canadians. Results Smokers were marginally less likely to have used the Internet than nonsmokers (74% vs 81% in the last year), and, of those who had access to the Internet, smokers used the Internet less often than nonsmokers. Overall, 40% of smokers said they would be interested in a WATI. The number of cigarettes smoked per day was unrelated to level of interest in the WATI, but time to first cigarette after waking was. Smokers who used the Internet were more interested in the WATI than smokers who did not use the Internet (46% vs 20%). Conclusions While the difference in level of Internet use between smokers and nonsmokers was greatly reduced compared to 2002 and 2004 data, smokers still remain marginally less likely to use the Internet than nonsmokers. Overall, there was a substantial level of interest in the WATI among smokers, in particular among smokers who currently use the Internet. These results indicate that WATIs have a substantial potential audience among smokers, and, given the growing body of evidence regarding their efficacy, there is growing support that WATIs have a significant role to play in promoting tobacco cessation.

Access and Interest: Two Important Issues in Considering the Feasibility of Web-Assisted Tobacco Interventions

Ultra-brief intervention for problem drinkers: research protocol

OBJECTIVE
This study examined help seeking for gambling concerns among people with different levels of gambling problems.

METHODS
Ontario adults who had gambled more than dollars 100 (N=4,217) and who screened positive for a possible gambling problem (N=1,205) were classified according to gambling problem severity and asked about their experiences with gambling treatment.

RESULTS
Only 6% of gamblers had ever accessed a service, including a self-help group or self-help materials. With self-help materials excluded, only 3% of gamblers (from 1% of those who met only the initial CLiP screening criteria to 53% of those with pathological gambling) had sought treatment for gambling.

Few gamblers sought treatment for gambling problems; greater problem severity was associated with greater likelihood of using treatment, with self-help materials used most often. Further research is needed on why treatment seeking is low and on the effectiveness of self-help resources in reaching gamblers with problems in earlier stages.

Treatment seeking among Ontario problem gamblers: results of a population survey.

Problem Gamblers' Interest in Self-Help Services. Authors' reply

An online support group for problem drinkers: AlcoholHelpCenter.net.

Public health initiatives to distribute nicotine replacement therapy free of charge as a means of promoting smoking cessation are ongoing. Are there enough smokers interested in using nicotine replacement therapy to have a substantial impact on the prevalence of smoking if this aid were distributed free to all interested smokers? We conducted a telephone survey of 825 randomly selected daily smokers aged 18 years or older who had smoked at least 10 cigarettes per day at some point in their lives. Overall, 58.9% of the respondents said they would be interested in nicotine replacement therapy if it were offered for free. Of those interested, almost all (93.8%) said that they would use the nicotine replacement therapy to help them quit for good. There were differences in the levels of interest: smokers who intended to quit were more interested in using the nicotine replacement therapy than those who planned to reduce or maintain their smoking.

How you assess quit attempts for smoking makes a big difference to your results.

Understanding the process by which problem gamblers recover without formal treatment may improve both formal treatments and assist those who wish to modify their gambling behavior without seeking treatment. Study 1 assessed the recovery process in problem gamblers who had recovered for at least 6 months without formal treatment from those who had recovered with the assistance of formal treatment. The treated recovered gamblers generally had a more severe gambling problem than did untreated recovered gamblers, as indicated by a long problem gambling career and more gambling-related negative consequences (e.g., family, health). Study 2 compared two samples of untreated gamblers, those who had recovered without treatment with a comparable sample of active gamblers who also had never received treatment. The active, untreated gamblers had higher lifetime rates of anxiety and personality disorder. Recovered gamblers may match the behaviorally conditioned problem gamblers as described in Blaszczynski's Pathways Model.

Implications of normative fallacy in young adult smokers aged 19-24 years (American Journal of Public Health (2007) 97, (1399-1400) doi:10.2105/AJPH.2006. 101071

AIMS
Brief alcohol interventions typically have been directed to heavy-drinking patients seeking primary health care and college students. This study examined the efficacy of mailing brief personalized assessment-feedback to interested drinkers recruited from the general public. We hypothesized that problem drinkers would benefit more from the intervention than individuals who were not problem drinkers.

DESIGN
A two-arm, double-blinded, community-based randomized controlled trial with 6-month follow-up.

SETTING AND PARTICIPANTS
A screening interview was administered to a stratified random sample of 10 014 Canadians 18 years of age and older (5621 women and 4393 men; M age = 43.3 years, SD = 15.99; response rate = 65.4%).

Current drinkers interested in receiving alcohol self-help materials (n = 1727) were assigned randomly to receive brief personalized assessment-feedback on male and female population drinking norms by mail, or to a delayed-treatment control group, and were contacted 6 months later (76% retention rate).

Problem drinking status at baseline [using sex-specific Alcohol Use Disorders Identification Test (AUDIT) cut scores], and frequency and quantity of alcohol use at follow-up.

FINDINGS
Analysis of covariance identified the hypothesized interaction of baseline problem drinking status and treatment condition (P < 0.01). Among problem drinkers identified at baseline the intervention caused a 10.1% reduction in per-occasion binge drinking compared to controls, whereas there was no difference in binge drinking across conditions for non-problem drinkers.

The continuum of care for alcohol problems can be broadened by providing brief interventions to interested drinkers in the general population.

Controlled study of brief personalized assessment-feedback for drinkers interested in self-help.

Beliefs about drinking problems: results from a general population telephone survey.

AIMS
To test two central assumptions of stage movement in the Transtheoretical Model (TTM) vis-à-vis alcoholism recovery: (assumption 1) individuals making a forward transition to the action-oriented stages (i.e. preparation/action) will manifest relatively greater drinking improvements than their counterparts remaining in the pre-action stages (i.e. pre-contemplation, contemplation); and (assumption 2) individuals remaining in the pre-action stages across time will not demonstrate clinically relevant improvement in drinking outcomes.

DESIGN AND SETTING
Secondary data analyses of data from Project MATCH, a large multi-site alcoholism treatment-matching study.

At baseline and 3 months post-treatment, the following variables were measured: stage-of-change (based on the University of Rhode Island Change Assessment measure and the most recent stage assignment algorithm), drinks per drinking day (DDD) and percentage days abstinent (PDA).

FINDINGS
Six of the eight tests of assumptions 1 and 2 failed to support the basic tenets of the TTM. Our study demonstrated that individuals making a progressive stage transition to the action-oriented stages (i.e. preparation/action) do not necessarily manifest greater improvements in drinking-related behavior than individuals remaining in the pre-action stages (i.e. pre-contemplation, contemplation), and that individuals remaining in the pre-action stages over time actually do manifest statistically significant and clinically important improvements in drinking-related behavior.

Our findings challenge not only the criterion validity associated with stage movement in the TTM account of alcoholism recovery, but also recent TTM-based substance abuse treatment approaches which systematically promote forward stage transition as a primary clinical goal and marker of therapeutic success.

Does progressive stage transition mean getting better? A test of the Transtheoretical Model in alcoholism recovery.

Internet-based interventions for alcohol, tobacco and other substances of abuse

In a representative sample of 434 daily smokers, half reported that they relight cigarettes at least some of the time. Relighting cigarettes was positively associated with severity of smoking addiction, as well as with being female, with markers of lower socioeconomic status (income, employment status), and with having less education. Smokers contemplating change were less likely to relight cigarettes. Given that previous research has indicated that relighting cigarettes leads to increased harm, the public health implications of this smoking practice are discussed.

Increasing perceived choice about change in smokers: implications.

Internet-based self-assessment of drinking--3-month follow-up data.

We used a random-digit-dialed survey of 434 smokers to demonstrate that approximately three quarters of young adult (aged 19-24 years) smokers overestimated by 20% or more the proportion of their peers who smoked. The effect of this normative fallacy was significantly greater in young adult smokers than in smokers aged 25 years or older. Because of the strength of this false consensus effect in young adult smokers, normative feedback interventions might be especially effective in this age group.

Implications of the normative fallacy in young adult smokers aged 19-24 years.

Social pressure, coercion, and client engagement at treatment entry: a self-determination theory perspective.

Background In recent years, online services for problem drinkers have been developed. This paper describes ongoing efforts to improve one of these services, the Alcohol Help Center. Objective This report summarizes new modules added to the Check Your Drinking (CYD) screener, a component of the Alcohol Help Center, to make the CYD screener more useful to periodic heavy drinkers, as well as to regular alcohol consumers. Participants’ initial reactions to the CYD screener and the changes in their drinking habits at a three-month follow-up are presented. Methods The CYD screener provides a free personalized Final Report that compares the user’s drinking to that of others in the general population of the same age, gender, and country of origin. Current alcohol consumption and demographic characteristics are collected as part of the CYD screening process. After users were presented with a customized Final Report, they were hot-linked to a volunteer feedback survey. The voluntary feedback survey asked about impressions of the CYD Final Report. Respondents agreeing to participate were sent a follow-up survey after three months. Results We recruited 388 volunteers (69% female) who were registered users of another free-to-consumer online eHealth service. Of the 343 respondents agreeing to participate in the three-month follow-up, 138 accessed the survey, and 97 provided complete data (participation rate = 40%; completion rate = 70%). Compared to moderate drinkers, current problem drinkers judged the Final Report to be more useful (34% vs. 69%, χ21 = 41.5, P < .001) and accurate (43% vs. 76%, χ21 = 36.0, P < .001). Respondents who participated in the three-month follow-up displayed reductions in drinking compared to baseline (F4,76 = 12.2, P = .001). Conclusions Improvements can still be made to make the CYD screener more relevant to specific populations, particularly periodic heavy drinkers. There is a need to further tailor algorithms that can present questions only relevant to specific populations. There also appears to be a need to further customize the Final Report for respondents who identify themselves as infrequent heavy drinkers. These improvements will be made, and a randomized controlled trial is planned to conduct a rigorous evaluation of the CYD screener as an intervention to help problem drinkers.

Formative Evaluation and Three-Month Follow-Up of an Online Personalized Assessment Feedback Intervention for Problem Drinkers

Barriers to the dissemination of four harm reduction strategies: a survey of addiction treatment providers in Ontario

AIMS
To assess the prevalence of treatment use in lifetime and past year alcohol dependent respondents. To establish the proportion of problem drinkers who use alcohol treatment that just go to one treatment versus attending multiple different types of treatment in the same year. To explore what treatments are most likely to form part of a multiple treatment package.

METHOD
Analysis of the 2001-2002 National Epidemiologic Survey of Alcohol and Related Conditions, a large (N = 43 039), representative survey of the non-institutionalized adult population of the USA. There were 4781 respondents who met criteria for a lifetime definition of alcohol dependence and 1484 respondents who met criteria for past year alcohol dependence.

RESULTS
Prevalence of lifetime use of alcohol treatment was 25% among those with a lifetime diagnosis of alcohol dependence. Prevalence of past year use of alcohol treatment was 12% among respondents with past year alcohol dependence. Only one-third of past year treatment users had accessed just one type of alcohol treatment.

While treatment services are only used by the minority of people with alcohol dependence, those people who do access alcohol treatment are likely to use several different alcohol treatment services in the same year.

Examining treatment use among alcohol-dependent individuals from a population perspective.

To the Editor

Johnsson and Berglund's recent article evaluating two interventions for high-risk drinking in university freshman could be regarded as a model of appropriately conservative interpretation of experimental results (Johnsson and Berglund, 2006). The authors found statistically significant reductions in drinking from baseline to one-year follow-up but little evidence of differences between the two, randomly assigned intervention conditions. Given these findings they make the point that the results could be due to regression to the mean, an admission that is rare in the clinical trials literature. However, some benefit might be derived from considering alternate explanations for this pattern of results. One explanation is …

Physicians and other health care providers play an important role in tobacco cessation efforts, providing valuable tools and advice to cigarette smokers.[1][1] One of the key tools is nicotine replacement therapy (NRT), but some smokers are reluctant to use NRT.[2–4][2] Finding simple ways to

Motivating smoking reductions by framing health information as safer smoking tips.

The functional overlap of smoking and problem drinking has led researchers to speculate on the need for integrated treatment models. What of online services? With the burgeoning growth of Web-based interventions for smokers and the increasingly common online services for problem drinkers, there is the potential to provide options for smokers to also deal with any alcohol concerns. The integration of these services might also help increase smoking cessation rates, because alcohol consumption is a known trigger to smoking and also for relapse to smoking. This paper presents results of the use of an online personalized feedback assessment for drinking (Check Your Drinking, CYD) by smokers who were recruited from the Stop Smoking Center (SSC; www.stopsmokingcenter.net). Registered users of the SSC (N= 7,741) were invited to complete the CYD (now located as part of an online alcohol reduction program freely available at www.alcoholhelpcenter.net). A total of 963 SSC users responded to the invitation, providing information about their drinking as well as a summary of their current smoking and past experiences of alcohol functioning as a trigger for smoking. One-third of current daily smokers were problem drinkers (24% of occasional smokers and 22% of former smokers were current problem drinkers). Most (82%) daily smokers who were current drinkers reported they frequently or always experienced a strong urge, desire or thoughts about smoking when they drank alcohol. This brief report will explore the implications of the overlap of smoking and drinking by these online participants and will discuss the potential benefits of providing an integrated service for smokers and problem drinkers.

Integrated online services for smokers and drinkers? Use of the check your drinking assessment screener by participants of the Stop Smoking Center.

Background. Expanding Internet-based interventions for substance use will have little benefit if heavy substance users are unlikely to have Internet access. This paper explored whether access to the Internet was a potential barrier to the provision of services for smokers, drinkers and illicit drug users. Methods. As part of a general population telephone survey of adults in Ontario, Canada, respondents were asked about their use of different drugs and also about their use of the Internet. Results. Pack-a-day smokers were less likely (48%) to have home Internet access than non-smokers (69%), and current drinkers (73%) were more likely to have home access than abstainers (50%). These relationships remained true even after controlling for demographic characteristics. Internet access was less clearly associated with cannabis or cocaine use. Conclusions. Even though there is variation in access among smokers, drinkers and illicit drug users, the World Wide Web remains an excellent opportunity to potentially provide services for substance abusers who might never access treatment in person because, in absolute terms, the majority of substance abusers do use the Internet.

Access to the Internet among drinkers, smokers and illicit drug users: Is it a barrier to the provision of interventions on the World Wide Web?

Purpose of review To critique the recent literature on telephone, correspondence-based, and computerized interventions for alcohol problems, which enhance or substitute for practitioner-delivered treatments. Recent findings There is an unmet need for screening, assessment and intervention for alcohol problems, in part because of the difficulty in accessing such treatment within the current health care system. Research on the efficacy of correspondence or electronic (for example Internet-based) interventions is beginning to emerge. In the period 2003–2004 we identified nine acceptability or feasibility studies of these approaches and seven efficacy trials covering a wide range of settings. These modes of intervention are acceptable to patients and the public, and with careful planning, can be implemented in a variety of settings. Treatment trials demonstrate the efficacy of these interventions in reducing hazardous drinking by university students, in delaying initiation of heavy drinking in children and adolescents, and, intriguingly, in addressing insomnia among recovering alcoholics. Summary There is strong support among potential users for alcohol interventions that employ telephone assistance, written correspondence, and the Internet. These new technologies offer the prospect of increasing the reach of interventions for problem drinking and being cost-effective alternatives or supplements to face-to-face health service delivery.

Is level of interest among cannabis users in self-help materials and other services aimed at reducing problem use?

Internet and paper self-help materials for problem drinking: is there an additive effect?

AIMS
To test whether survey respondents who report alcohol misuse in the past year are more likely to be abstinent or binge-free in the past 30 days if they have used treatment, than if they have not.

METHODS
Analysis of data from the 2002 US National Survey on Drug Use and Health was obtained.

RESULTS
A total of 5730 respondents scored positive for alcohol abuse or dependence in the preceding year. Fewer than 10% had used any treatment for alcohol or drugs in this period, but this was associated with a 10% increase in the past-month abstinence and past-month binge-free drinking compared with respondents who did not access treatment. Such an apparent short-term recovery appeared greater in those whose treatment had been received in a formal treatment setting, a doctor's office, or in self-help groups than in the emergency room or in prison.

Even if part of the association between treatment and recent abstinence and non-binge drinking was causal, indicating that treatment has some impact, it is a pathway chosen only by the minority.

Short-term recovery from alcohol abuse or dependence: any evidence of a relationship with treatment use in a general population sample?

Does stage-of-change predict dropout in a culturally diverse sample of adolescents admitted to inpatient substance-abuse treatment? A test of the Transtheoretical Model.

On reasons for drinking less: a framework of methodological considerations.

This study tested the hypothesis that maturing out descriptions of change were more common among respondents whose drinking problems were less severe prior to reduction and that consequence driven changes were more common among those who had a lifetime diagnosis of alcohol dependence, prior to resolution. As part of a general population telephone survey, former heavy drinkers were asked their reasons for change. These responses were tape-recorded, transcribed and then coded into three categories – consequence driven reasons, drifting out reasons and reflective maturational reasons. As predicted, drifting out reasons were more often provided by those with less severe alcohol use and consequence related reasons appeared associated with respondents who had had more severe alcohol problems. The differing descriptions of pathways to change observed in natural history studies may be the result of research that captures only partial samples of the larger population of former heavy drinkers.

Maturing out of drinking problems: perceptions of natural history as a function of severity

Current heavy drinkers' reasons for considering change: results from a natural history general population survey.

Aim: To assess what it means when respondents say they have received treatment on population surveys. Method: Former heavy drinkers recruited through a random digit dialing telephone survey were asked about the type, time, and amount of treatment they had received. Results: When respondents indicated that they had received treatment, it appeared that they had a specific treatment in mind, that they completed the treatment program, and that, for the majority, treatment occurred at roughly the same time as their successful change from heavy drinking. The congruence between age of change and age of treatment use appeared greater among respondents with abstinent versus reduced-drinking recoveries.

“Yes, I've Received Treatment”: What Does This Mean in the Context of Epidemiological Surveys for Alcohol Problems?

Motivation and life events: a prospective natural history pilot study of problem drinkers in the community.

An internet application was created to provide users with personalized normative feedback regarding their use of alcohol, tobacco, and cannabis. Ninety-nine participants completed the alcohol assessment, 52 completed the cannabis assessment, and 60 completed the smoking assessment. Respondents expressed interest in the expansion of the site to include illicit use of prescription medications, hallucinogens, and methamphetamine. As far as the authors know, the present study, at time of preparation of this manuscript, is the first to examine e-mail broadcasting as a recruitment strategy, and to use normative feedback regarding cannabis usage over the internet. The use of personalized feedback over the internet offers an extremely costeffective approach to helping substance users who may not access traditional treatment services.

PROVIDING NORMATIVE FEEDBACK ON THE INTERNET TO STIMULATE SELF-EVALUATION OF ALCOHOL, TOBACCO, AND CANNABIS USE

This study explored the factors associated with reduction from heavy drinking among three groups: current abstinent, moderate, and reduced drinkers. A random-digit-dialing telephone survey was conducted of 3,006 respondents in Ontario, Canada. Of these, 470 respondents (46% female) met criteria as former heavy drinkers (99 abstinent; 237 moderate; 134 reduced but not moderate drinkers). Quantitative and qualitative questions were used to explore current and past drinking, use of treatment, and reasons for change. Qualitative items were tape-recorded and transcribed. Respondents in the abstinent group had more severe problems prior to resolution as compared with those in the moderate group. Reduced drinkers displayed a prior alcohol severity at a level between these two other groups. The most common reasons for change in all groups were new responsibilities, maturation, and health concerns. This study serves as a useful adjunct to other natural-history research, exploring the reasons for change in a representative sample of former heavy drinkers.

Characteristics of Former Heavy Drinkers: Results from a Natural History of Drinking General Population Survey

Only one in three people with alcohol abuse or dependence ever seek treatment.

Using collaterals to validate self-reports of problem drinkers: any impact on client attrition and quantity of drinking reported?

We quantified the prevalence of alcohol problems among Alberta adults and determined relationships between sociodemographic characteristics, problem drinking status, and interest in self-help materials to reduce alcohol use.

METHODS
A computer-aided telephone interview was administered to a stratified random sample of 10,014 Albertans, 18 years of age or older (5,621 women and 4,393 men; M age = 43.3 years, SD = 16.0), with a response rate of 65.4%. Measures included: 1) current drinking status, 2) prior alcohol treatment, 3) problem drinking status (using the Alcohol Use Disorders Identification Test; AUDIT), and 4) interest in receiving free self-help materials to encourage safe drinking. Data were weighted to reflect age, sex, and regional Alberta population.

RESULTS
Of the total sample, 19.3% abstained from drinking in the past year, 4.2% had received treatment for alcohol problems at some point in their lives, and 80.7% were current drinkers (i.e., consumed alcohol in the previous year). Some 15.2% (n = 1,193) of current drinkers were classified as having a drinking problem. Logistic regression analyses showed that problem drinkers had 3.5 times greater odds of being male and 2.3 times greater odds of being interested in self-help interventions, compared to other current drinkers. Being single, of younger age, and not being exposed to post-secondary education also significantly predicted problem drinking status.

INTERPRETATION
Alcohol misuse is common among Alberta drinkers, but many of them are interested in receiving brief public health interventions designed to help them assert control over their behaviour.

Alcohol problems and interest in self-help: a population study of Alberta adults.

Using data from a large, representative survey of the U.S. population, the relation between frequency of prior drug use and treatment utilization was explored. As was hypothesized, the more frequently former drug users had taken an illicit drug, the more likely they were to have accessed treatment. This relationship was true for all illicit drug classes.

Stopping illicit drug use without treatment: any relation to frequency of drug use?

The role of relevancy in normative feedback for university students' drinking patterns.

A comparison is made of drinking patterns in Finland and Ontario (Canada). Respondents in two existing population surveys, the 1996 Joint Nordic Questionnaire and the 1996 Ontario Drug Monitor, were compared on their frequency of alcohol use in the past year, frequency of heavy drinking (6+ on Nordic survey and 5+ in Ontario), and both frequency and typical quantity of beer, wine and liquor consumption in males and females. It appeared that there are fewer nondrinkers and more weekly drinkers in the Finnish sample than in the Ontario sample. Further, both males and females in Ontario consumed 6+ drinks on one occasion more frequently than their Finnish counterparts. However, examination of the patterns of beer, wine and liquor consumption, particularly the distribution of very heavy drinking days (e.g., 12 or more drinks of liquor on one occasion), indicates that there is some evidence for periodic heavy drinking in Finnish males. Contrary to expectations, Canadian and Finnish drinking patterns appeared fairly similar. However, there was some evidence for a higher prevalence of binge drinking by Finnish men as compared with Canadian men.

Interest in self-help materials among a general population sample of smokers.

OBJECTIVE
Two major strategies have typically been used to assess recent drinking: (1) Daily Estimation (DE) measures such as the Timeline Followback (TLFB) and (2) Quantity-Frequency (QF) summary measures. Although QF measures provide a quick and easy measure of consumption, they have been criticized as not being able to capture sporadic and unpatterned drinking (e.g., days that reflect important social and/or health risks). The TLFB, a psychometrically sound drinking assessment method, is able to capture all drinking, including sporadic heavy days and unpatterned drinking. In some situations, however, recall of daily drinking may not be possible or practical (e.g., limited time; no resources). This article compares results obtained by using a QF measure and a DE measure to assess problem drinkers' pretreatment drinking.

METHOD
The current study, part of a large community mail intervention with 825 alcohol abusers, compared results from two drinking measures covering the same time interval that were administered on two different occasions approximately 2.5 weeks apart. Both measures, the Quick Drinking Screen (QDS; a QF summary measure that collected data by telephone) and the TLFB (a self-administered daily estimation measure), collected drinking data for the year prior to the interview.

RESULTS
Although the QDS and the TLFB are very different drinking measures, remarkably similar aggregate drinking data were obtained for five drinking variables.

When it is not necessary or possible to gather detailed drinking data, the QDS produces reliable brief summary measures of drinking, at least for not severely alcohol dependent individuals. Also, respondents do not appear to use a repetitive response pattern when completing the TLFB.

Comparison of a quick drinking screen with the timeline followback for individuals with alcohol problems.

Intravenous and non-intravenous cocaine abusers admitted to inpatient detoxification treatment: a 3-year medical-chart review of patient characteristics and predictors of treatment re-admission.

A prospective natural history study was conducted of problem drinkers who were thinking about quitting or reducing their alcohol consumption. Two primary constructs, cognitive appraisals and life events, were measured in a mailed-out baseline survey. A two month follow-up survey identified those who had made reductions in drinking. Regression analyses revealed some support for a cognitive appraisal explanation of change. Respondents who identified more anticipated costs of change were less likely to reduce their drinking. Plans for phase two of this research project - a one year follow-up to identify sustained change attempts - are discussed.

A Prospective Study of Quit Attempts from Alcohol Problems in a Community Sample: Modeling the Processes of Change

OBJECTIVE
An experimental trial was used to assess the effectiveness of a self-help book and a personalized assessment-feedback intervention, both separately and in combination with each other, in a general population survey.

METHOD
Participants (N = 86; 66.3% male) were recruited through a random digit dialing telephone survey conducted by the Centre for Addiction and Mental Health, Toronto, Ontario, Canada. Respondents were randomly assigned to one of four conditions in a two-by-two factorial design: "no-intervention" control group, "personalized feedback only," "self-help book only" and "both personalized feedback and self-help book." Respondents were followed up in 6 months' time, and differences in drinking status were compared between experimental conditions using a multivariate analysis of covariance with baseline drinking severity as the covariate.

RESULTS
Support was provided for an interaction hypothesis in which respondents who received both interventions reported significantly improved drinking outcomes at 6-month follow-up, compared with respondents who received just one of the interventions or who received no intervention.

Because respondents were recruited from a representative sample of the general population into a randomized trial with a no-intervention control group, this research design maximized both external and internal validity in examining the effectiveness of self-help interventions.

Treating alcohol problems with self-help materials: a population study.

By using a public health approach to the treatment of alcohol problems, this study analyzed the efficacy and cost analysis of two versions of a community-level mail intervention to promote self-change among alcohol abusers who had never sought help or treatment.

METHODS
A total of 825 participants who responded to media solicitations were randomly assigned to one of two interventions: (a) for bibliotherapy/drinking guidelines (n = 411), they were given two pamphlets with information about the effects of alcohol and guidelines for low-risk drinking and self-monitoring, and (b) for motivational enhancement/personalized feedback (n = 414), personalized advice/feedback was provided on the basis of the participants' assessment of their drinking and related behaviors.

RESULTS
Although both groups exhibited significant reductions in drinking from 1 year before to 1 year after intervention, there were no significant differences between the two interventions for any variable. This suggests that the materials, irrespective of whether they were personalized, facilitated the reduction of drinking. Cost analysis revealed that a brief mail intervention could reduce drinking at a very low cost per participant (US$46 to US$97).

A brief community-level mail intervention for problem drinkers who had never sought treatment resulted in sizable reductions in alcohol use over the year after the intervention compared with the year before. Furthermore, many of those with poorer outcomes engaged in a natural stepped-care process by seeking help. These results, coupled with the low cost to deliver the intervention, suggest that public health campaigns could have a substantial effect on reducing alcohol problems and associated costs as well as getting some individuals into treatment. Such an approach would represent a shift from the alcohol field's long-standing clinical focus to a broader public health perspective.

Promoting self-change with alcohol abusers: a community-level mail intervention based on natural recovery studies.

Gender differences in detoxification: predictors of completion and re-admission.

Narratives provided by former heavy drinkers have indicated that respondents who attended AA experienced more abrupt resolutions than respondents who never attended AA. This study explored the extent to which this difference in resolution pattern exists in a representative sample of individuals remitted from a lifetime diagnosis of alcohol dependence.

Exploring Patterns of Remission from Alcohol Dependence with and without Alcoholics Anonymous in a Population Sample

OBJECTIVE
A pilot study assessed the utility of the Timeline Followback (TLFB) method to collect information on help seeking.

METHOD
Using the TLFB method, 34 clients (26 men) who had attended at least one session of an outpatient alcohol treatment program reported on treatment contacts, including any supplemental services (e.g., psychiatric care). TLFB reports of help seeking at that agency were compared with agency records of treatment contacts.

RESULTS
Clients reported on their help-seeking behavior for a period of approximately 8 months after they had completed an initial assessment for the outpatient treatment. With regard to the number of outpatient sessions they attended, intraclass correlations and equivalence testing showed that the TLFB data were comparable to the agency records of treatment contacts. Analysis of week-to-week correspondence of the presence or absence of help-seeking episodes showed good agreement between TLFB and the agency records for most participants, although there was substantial variation. Degree of correspondence was not associated with the length of the recall period or individual differences (e.g., drinking pattern). Older participants, however, tended to have lower week-to-week concordance than did younger participants.

These data provide preliminary support for the utility of a help-seeking TLFB instrument to assess addiction- and mental health-related contacts. This instrument may be especially useful in research in which collecting temporal patterns of help seeking is of interest (e.g., in studies examining factors influencing the delay in help seeking after relapse).

Help-seeking timeline followback for problem drinkers: preliminary comparison with agency records of treatment contacts.

Perceived vulnerability to negative outcomes can motivate heavy drinkers to adopt health-protective behavior, but little is known about determinants of perceived vulnerability to alcohol-related harm. University students (N = 286) were assessed to determine epidemiological risk status on a standardized problem drinking measure, typical reasons for drinking and cutting down, and perceived risk of experiencing alcohol-related harm. Results showed a positive relationship between problem drinking status and perceived risk of experiencing harm. However, at-risk drinkers believed that they were less likely to personally experience harm than comparable peers (p < .001), whereas not-at-risk drinkers showed no self-other differences in perceived vulnerability. Drinking motives significantly improved the prediction of perceived vulnerability when epidemiological risk status was controlled. Perceived vulnerability to alcohol-related harm is affected by problem drinking status and (independently) by the psychological functions that drinking serves.

Perceived vulnerability to alcohol-related harm in young adults: independent effects of risky alcohol use and drinking motives.

Using self-help materials to motivate change at assessment for alcohol treatment.

OBJECTIVE
Examined predictors of nonresponse among respondents who agreed to receive a follow-up questionnaire on alcohol use after participating in a representative telephone survey, and among respondents who did and did not return the follow-up questionnaire.

METHOD
A total of 2,072 (52.2% female) respondents to a representative monthly telephone survey were assessed on sociodemographic variables and alcohol use. Respondents were asked whether they would be willing to fill out an additional mailed questionnaire on alcohol use and attitudes toward drinking. Almost half (n = 956; 46%) of respondents agreed to participate in the follow-up survey; 430 (45%) of those individuals completed and returned the questionnaire.

RESULTS
Agreement to receive the follow-up questionnaire was unrelated to alcohol use. Regarding gender, men were 1.42 times more likely than women to exhibit nonresponse in returning the follow-up questionnaire (95% CI: 1.08-1.42). After adjusting for the impact of demographic factors, respondents who consumed alcohol at least once per week were 1.43 times more likely than respondents who drank less frequently to exhibit nonresponse in returning the questionnaire (95% CI: 1.05-1.93). Respondents who consumed five or more standard drinks at least once per week were 1.83 times more likely to exhibit nonresponse in returning the questionnaire, compared with respondents who engaged in heavy drinking less frequently (95% CI: 1.15-2.92).

Mailout questionnaires following a representative telephone survey may bias samples toward obtaining fewer men, fewer weekly drinkers and fewer heavier drinkers. Although the magnitude of these biases were relatively small, epidemiological studies on alcohol use may wish to oversample men and heavier drinkers in follow-up studies recruiting from population surveys.

Nonresponse in a follow-up to a representative telephone survey of adult drinkers.

Objectives: To explore differences in views concerning adjunctive medications and theoretical orientation among Canadian practitioners from different professional backgrounds who treat alcoholism. Methods: A survey of clinicians from different disciplines was conducted by mail. The response rate was 56%: 95 drug and alcohol counsellors, 46 social workers, 81 nonpsychiatrist addiction physicians, and 74 addiction psychiatrists. The number of items in the questionnaire was reduced using principal component analysis. Group differences were explored using analysis of variance with Bonferroni correction and Scheffé's posthoc comparisons. Results: Physicians and nonphysicians differed in their views on the utility of medications in treating alcohol problems, the disease concept of alcohol problems, and the classification of alcohol abuse or dependence as psychiatric conditions. No group differences emerged on views regarding cognitive-behavioural treatment, pharmacological-only interventions, combined treatment, and recovery without treatment. Psychopathology in the alcoholic was significantly more likely to be considered as secondary to the use of alcohol by nonpsychiatrist physicians. Nonphysician practitioners viewed alcoholic behaviour as self-medication. Conclusions: Groups differed on questionnaire items concerning medication use and the disease concept of alcoholism. Agreement on several areas may facilitate bridging the gap across disciplines. The implications of these results are discussed.

Alcoholism: Beliefs and Attitudes among Canadian Alcoholism Treatment Practitioners

OBJECTIVE
As many as one in four adults in North America experiences some problems due to alcohol consumption. Although most of these problem drinkers do not have concerns that are severe enough to merit formal treatment, such drinking has large economic costs and can place the drinker at risk for long-term negative health and social consequences. The present study evaluated a minimal intervention that used normative feedback about population drinking to motivate changes in alcohol use.

METHOD
An intervention pamphlet was mailed to over 6,000 households in Toronto, randomized by block from a region containing almost 10,000 households. In the month after the mailing, a general population survey was conducted in the region to assess alcohol use.

RESULTS
Respondents from households receiving normative feedback (n = 472) reported significantly lower alcohol use than controls (n = 225), but this effect occurred only among respondents who met an objective criterion for problem drinking and who perceived some risk associated with their drinking.

Viewed from a public health perspective, normative feedback interventions have the potential for a significant payoff because they can be provided at low cost and to problem drinkers who might ordinarily never access any treatment services.

Impact of normative feedback on problem drinkers: a small-area population study.

OBJECTIVE
Perceived vulnerability to harm is widely acknowledged as a determinant of behavior change, but little is known about why some drinkers believe that they are personally "at risk" for problems while others do not. This study examined perceived vulnerability to alcohol-related harm in relation to epidemiological risk status on a standardized problem-drinking measure and two psychosocial measures of drinking context: (1) typical reasons for drinking and cutting down and (2) social network influences related to alcohol use. We evaluated the general hypothesis that these psychosocial variables would independently affect perceived vulnerability to alcohol-related harm, over and above epidemiological risk status.

METHOD
Adults between the ages of 18 and 79 (N = 430; 249 women, 173 men, 8 gender unknown) completed a questionnaire about drinking behavior and drinking-related social and motivational context.

RESULTS
There was a positive relationship between problem-drinking status and perceived risk of experiencing harm, and no support for the idea that objectively "at-risk" drinkers believe that they are less likely to personally experience harm than comparable peers. Drinking motives and social network variables each significantly improved the prediction of perceived vulnerability when epidemiological risk status was controlled.

Interventions designed to alter drinkers' risk perceptions should take into account the reasons that people have for drinking and the social network context of alcohol use, in addition to whether or not individuals are "problem drinkers."

Psychosocial determinants of perceived vulnerability to harm among adult drinkers.

Factors associated with untreated remissions from alcohol abuse or dependence.

OBJECTIVE
This project developed an Internet program that conducts a brief assessment of an individual's drinking habits and then provides normative feedback comparing the user's drinking to that of others of the same gender and age group. The Internet program, "Try Our Free Drinking Evaluation," was based at the Addiction Research Foundation Internet web site (now at http://notes.camh.net/efeed.nsf/ newform).

METHOD
A voluntary survey linked to the participant's feedback summary collected respondents' impressions of the program.

RESULTS
During the trial period, the site received approximately 500 hits per month. While the feedback was generally well received, the weekly summary format was less credible to those individuals who drink less than once per week or whose consumption varies a great deal over time.

Given these pilot results indicating that there is an audience for Internet-based interventions, the next step is to evaluate whether receiving such personalized feedback materials on the Internet leads to any change in drinking behavior by participants

Providing personalized assessment feedback for problem drinking on the Internet: a pilot project.

The consequences of cannabis use are less well described than is true for licit psychoactive substances. Published data on dose-response relationships are almost completely absent. This manuscript takes a first look at the dose-response relationship between cannabis use and the experience of negative consequences. Using data from the 1990-91 Mental Health Supplement to the Ontario Health Survey ( N = 9953), items were selected from the DSM-III-R criteria for cannabis abuse or dependence and interpreted as negative consequence measures for cannabis use. The incidence of one or more of these items in the last year was then related to frequency of cannabis use. As with other substances of abuse, a dose-response relationship was observed. The more frequent the use of cannabis in the last year, the more likely the user was to experience negative consequences. Limitations of this study and future research directions are discussed. \[Cunningham JA, Bondy SJ, Walsh GW. The risks of cannabis use: evidence of a dos...

The risks of cannabis use: evidence of a dose‐response relationship

Sixty outpatient addiction treatment agencies in Ontario, Canada, participated in a case study exploring the factors related to the adoption of research-evaluated treatment technologies. The agencies received free training in a manual-based, brief outpatient treatment program. At a twelve-month follow-up period, managers were interviewed to assess the proportion of agencies using the treatment package and the factors encouraging or discouraging their agencies' use of the program. While the dissemination was a success (49 percent of agencies had used the treatment program and 83 percent had used at least some of the tools), questions remain as to why some agencies adopted the treatment package while others did not.

Disseminating a Treatment Program to Outpatient Addiction Treatment Agencies in Ontario

Defacto client-treatment matching: how clinicians make referrals to outpatient treatments for substance use

Abstract Despite the high incidence of substance abuse problems among offenders, a large proportion of community corrections clients do not receive services addressing these concerns. Training probation and parole officers (PPOs) to provide addiction counselling has been suggested as one way of increasing the accessibility of treatment; however, there is a gap in the literature with respect to the factors influencing the successful dissemination of alcohol and drug training to this population. The present study reports on the results of data collected during a series of seven Structured Relapse Prevention training workshops offered to PPOs in Ontario, Canada. The study found that although the majority of PPOs supported the application of substance abuse counselling in probation and parole offices, time and caseload constraints were major obstacles to implementation.

Attitudes Toward Substance Abuse Treatment Among Probation and Parole Officers

Objectives: The present study reports results on interest in self-help materials for alcohol problems. Method: A representative sample of 408 respondents participated in a telephone survey. Current drinkers were told: 'A self-help book is currently being prepared that would help people decide whether or not they would like to reduce their drinking. If such a book were available, would you be interested in receiving a free copy?' Results: 31.4% of current drinkers and 44.5% of problem drinkers were interested in receiving a free self-help book. Conclusions: Providing self-help materials as common practice may help reduce the harm associated with problem drinking.

Interest in self-help materials in a general population sample of drinkers

Despite abundant indications that resolutions from alcohol problems without treatment are common, there appears to be little awareness that such recoveries occur and a general skepticism regarding their possibility. This paper presents results from a study investigating the impact of hypothetical newspaper articles about self-change and moderate-drinking recoveries on subjects' beliefs. It is concluded that newspaper articles do not appear to have much impact on the public's perceptions. The importance of modifying the general public's knowledge about recoveries from alcohol problems without treatment are discussed.

Changing Perceptions About Self-Change and Moderate-Drinking Recoveries From Alcohol Problems: What Can and Should Be Done?

OBJECTIVE
Prior research indicates that the majority of people who resolve an alcohol problem do so without treatment. Further, a substantial proportion return to moderate drinking. One of the concerns with these findings, however, is that the definition of prior alcohol problems may reflect a less severe problem criterion. Thus, it could be argued that the majority of people "recover" from alcohol problems without treatment because a substantial proportion of these individuals did not actually have a severe alcohol problem.

METHOD
This article systematically replicates earlier findings regarding the predominance of alcohol recoveries without treatment, using data from the 1994 Canadian Alcohol and Drug Survey. Further, variations in estimates of the proportion of resolutions from alcohol problems both with and without treatment, and to abstinence and moderate drinking, were assessed when different definitions of prior alcohol problems were employed.

RESULTS
Of 9,892 adult lifetime drinkers, 2,177 had experienced at least one problem related to their alcohol consumption and, of these, 885 (57.2% male) had experienced no problems in the last year. Estimates of the prevalence of nontreatment recoveries ranged from 87.5% to 53.7% depending on the stringency of the definition of prior alcohol problems employed.

Although a significant proportion of individuals recover from alcohol problems without treatment, such recoveries appear less common among individuals with more severe alcohol problems.

Resolving alcohol-related problems with and without treatment: the effects of different problem criteria.

OBJECTIVE
This article describes results from a study investigating the effects of using long assessment instruments on attrition rates in mailed-out surveys.

METHOD
Participants were randomly assigned to receive one of two versions of a mailed-out survey; one version incorporated a detailed assessment of drinking using the Timeline Follow back method (TLFB; n = 46) and the other employed a brief graduated frequency measure of alcohol consumption (n = 49).

RESULTS
29% fewer respondents who received the TLFB returned any of their survey materials as compared to those respondents who received just the graduated frequency measure (22% vs 51%).

In some situations, e.g., mailed-out surveys, employing detailed survey instruments may not be justified as the increased respondent burden may result in increased attrition rates.

What is the price of perfection? The hidden costs of using detailed assessment instruments to measure alcohol consumption.

This paper describes results from a pilot study that assessed the reasons for change provided by former drug users in a representative sample of the general population. As part of a random digit dialing telephone survey, people were asked about their past use of cannabis, cocaine/crack, tobacco and alcohol. In a series of open-ended questions, participants who had stopped their consumption of the drug (or reduced it to moderate levels for alcohol) were asked what had led them to stop (or reduce) their consumption. Reasons for change among this representative sample are presented along with comparisons across different drugs.

Why do People Stop Their Drug Use? Results from a General Population Sample

Objective: To determine the prevalence of and factors associated with mental health service use in the past year among respondents with an alcohol or other drug use disorder in a general population survey of Ontario adults. Method: Data were obtained from the 1990/1991 Mental Health Supplement to the Ontario Health Survey, which used the University of Michigan Composite International Diagnostic Interview (UM-CIDI). The current study examined 436 respondents aged 15–64 years who met Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) criteria for a substance use disorder in the past year. The 82 respondents who used services for a mental health or substance abuse problem during the past year were compared with the 354 nonusers. Illness severity, disability, health beliefs and attitudes, and predisposing or enabling factors were examined in bivariate and logistic regression analyses. Results: Twenty-two percent of respondents used services in the past year. Having concurrent disorders (comorbidity), troubled relationships with others, and dysfunction in main activity, feeling comfortable talking to a professional about mental health problems, being older and an urban resident, not working or being in school, and having a biological parent with an alcohol or drug problem were all associated with service use. Conclusions: The results suggest that individual determinants, such as severity of illness, disability, attitudes, and predisposing or enabling variables, all have a role in predicting service use among individuals in the general population who suffer from alcohol and other drug disorders.

Mental Health Service Use: A Comparison of Treated and Untreated Individuals with Substance Use Disorders in Ontario

Respondents read a narrative depicting a drunk-driving offender seeking help for alcohol problems and were randomly assigned to receive 1 of 3 types of client motivation (autonomous motivation, compulsory treatment, or impression management) and 1 of 2 types of therapist motivation (autonomous vs. controlled motivation). Maximal treatment efficacy was expected when both client and therapist were autonomously motivated. Minimal treatment efficacy was expected when the client entered treatment only to manage impressions and when the therapist exhibited controlled motivation. Compulsory treatment undermined beliefs about client interest in treatment. Finally, autonomously motivated therapists were expected to be able to reverse expected negative outcomes for compulsory treatment and impression management clients. It was found that expectations about the efficacy of alcohol aeam~nt were affected by the perceived motivation of clients and therapists.

When do people believe that alcohol treatment is effective? The importance of perceived client and therapist motivation.

AIMS
Researchers must develop effective strategies for disseminating research-based treatments. This study evaluates the application of a dissemination model based on principles of social marketing and diffusion theory.

DESIGN
A case study describes how the model was implemented. A qualitative design was employed to examine rates of adoption and adaptation of an early intervention program by a targeted system of addictions agencies.

SETTING
The interventions were developed at the Addiction Research Foundation in Toronto and disseminated to Assessment and Referral (A/R) Centres in Ontario, Canada.

Study participants included the managers and a designated therapist for 33 participating A/R centres.

Managers were asked mainly open-ended questions concerning whether their agency had made a formal decision to adopt the intervention and whether therapists in their agency were using the early intervention program. "Adoption" was operationalized as offering the complete four-session intervention to at least one client.

FINDINGS
At 12 months after the completion of training workshops, 68% of 34 agencies in the target system had adopted the program while 85% of the agencies were using some components of the intervention with clients.

The dissemination model appeared to be effective although its application proved to be time-consuming and labour-intensive. The "market analysis", systems focus and field-test components of the model appeared to contribute to its success.

A social marketing model for disseminating research-based treatments to addictions treatment providers.

This study explores whether a demonstration designed to persuade addiction treatment agencies to adopt a research-based treatment program and to evaluate the program under field conditions was a successful dissemination strategy. The results suggest that a demonstration, as one component of an ongoing dissemination plan, may be useful in persuading community treatment agencies to investigate a research-based treatment program. However, agencies may not adopt a counseling program following a demonstration without first testing it themselves.

The Effectiveness of Demonstrations in Disseminating Research-Based Counseling Programs

Awareness of self-change as a pathway to recovery for alcohol abusers: results from five different groups.

ABSTRACT This paper reports on the results of the field test of a substance abuse treatment protocol to probation and parole officers. Ten Probation and Parole Officers were trained in Structured Relapse Prevention (SRP) and offered treatment to 55 clients over the one-year field test period. This report highlights the incentives and barriers for providing substance abuse treatment in the corrections setting. It is proposed that this type of field test is an effective dissemination technique for encouraging system engagement. First, the field test allowed for the modification of the treatment protocol to better fit the Probation and Parole context. Second, the positive results of the field test served as the basis to justify the widespread dissemination of SRP to Probation and Parole officers province-wide.

Training Probation and Parole Officers to Provide Substance Abuse Treatment: A Field Test

AIMS
Cost containment, a central issue in current health planning, encourages the use of brief interventions. Although brief interventions for problem drinkers have proved successful, a portion of such individuals do not change their alcohol use during treatment.

DESIGN
Repeated measures design (pre-treatment, within-treatment and 6 months post-treatment).

To identify individuals at risk for continued problem drinking, predictors of post-treatment drinking were examined for 212 problem drinkers who presented for treatment in an outpatient treatment clinic.

All participants completed a brief cognitive behavioral motivational intervention.

At the pre-treatment assessment demographic, drinking pattern, severity of dependence and other cognitive variables (e.g. self-efficacy, goal choice) were collected. Within-treatment, drinking pattern and cognitive variables such as self-efficacy and goal choice were again measured.

FINDINGS
Regression analyses showed that therapist prognosis ratings contributed significantly to the prediction of outcome even when pre-treatment variables were controlled. However, when within-treatment variables were included in the prediction, variables such as within treatment drinking eliminated the predictive utility of therapist prognosis ratings. This pattern held for both percentage of days abstinent and drinks per drinking day at a 6-month follow-up.

It is suggested that a stepped care approach based on prediction models that include clients' within-treatment response can be applied to the treatment of problem drinkers who show little initial response to treatment.

Toward a stepped care approach to treating problem drinkers: the predictive utility of within-treatment variables and therapist prognostic ratings.

This article describes the construction and preliminary evaluation of a scale (the Alcohol and Drug Consequences Questionnaire [ADCQ]) assessing the costs and benefits of changing an alcohol or drug problem. The ADCQ's costs and benefits subscales displayed good internal reliability (Cronbach alphas were .90 for the benefits subscale and .92 for the costs subscale). Furthermore, the ADCQ was significantly related to respondents' ratings of the importance of achieving their alcohol or drug treatment goal and to drinking at a 12-month follow-up. Measures assessing the costs and benefits of change appear to be useful indexes of client motivation and for predicting long-term change within the addictions.

Assessing Motivation for Change: Preliminary Development and Evaluation of a Scale Measuring the Costs and Benefits of Changing Alcohol or Drug Use

Results are presented exploring the opinions of different drinker groups toward physicians asking about alcohol use. A sample of problem drinkers in treatment was compared with current problem and nonproblem drinkers recruited at a local science center and with a sample of students from a local university. While there was general agreement that it was appropriate for doctors to ask about their alcohol use, some respondents (especially in the treatment sample) said that they would feel uncomfortable if asked about their alcohol use and might underreport the amount they drank. Reasons stated for this reluctance included a dislike of feeling judged and of possibly being told not to drink any alcohol.

Should physicians be asking about alcohol use? The patient's perspective

Visitors to a science center (N= 189) responded to a questionnaire measuring their agreement with different conceptions of alcohol abuse (disease, sin, habit, and addiction conceptions) and their beliefs regarding treatment for alcohol abusers. Respondents who agreed with a disease concept thought alcohol abuse was a more serious problem, were more skeptical of statements about recovery, and were more likely to feel that treatment was necessary to achieve change, compared to those who disagreed with or were neutral toward the disease concept. Agreement with the sin, habit, and addiction conceptions was not related to beliefs about treatment and outcome. The utility of promoting various conceptualizations of alcohol abuse is discussed.

Are Disease and Other Conceptions of Alcohol Abuse Related To Beliefs about Outcome and Recovery

The purpose of this study was to determine the prevalence of recovery from alcohol problems with and without treatment, including whether such recoveries involved abstinence or moderate drinking.

METHODS
Data from two surveys of randomly selected adults in the general population were analyzed. Random-digit dialing was used to conduct telephone interviews with 11,634 and 1034 respondents. Respondents 20 years of age or older were categorized on the basis of drinking status and history.

RESULTS
Both surveys found that most individuals (77.5% and 77.7%) who had recovered from an alcohol problem for 1 year or more did so without help or treatment. A sizable percentage (38% and 63%) also reported drinking moderately after resolving their problem.

These two surveys are among the first to report prevalence rates for recovery from alcohol problems for treated and untreated individuals and for moderation and abstinence outcomes.

Recovery from alcohol problems with and without treatment: prevalence in two population surveys.

Fostering self-change among problem drinkers: a proactive community intervention.

Resolution from alcohol problems with and without treatment: reasons for change.

Heavy drinking and negative affective situations in a general population and a treatment sample: Alternative explanations.

Severity of penalty, seriousness of the charge, and mock jurors' verdicts

Beliefs about the causes of substance abuse: a comparison of three drugs.

Visitors (N = 579) to a science center read selected scenarios and evaluated the most likely outcome for a hypothetical substance abuser. Respondents were randomly assigned to one of six scenario conditions: a person with one of three different substance abuse problems (alcohol, tobacco, or cocaine) was crossed with two labels reflecting high or low substance dependence. Results indicated that: (1) cigarettes were viewed as a less serious substance abuse problem than were alcohol or cocaine (a person who smoked cigarettes was rated as more likely to recover from his problem, self-change was regarded as more appropriate and less stigma was associated with smoking than with the other two drugs); (2) non-abstinent recoveries of all types were greeted with skepticism; and (3) recovery was rated as more likely to occur from treatment than from self-change.

What's in a label? The effects of substance types and labels on treatment considerations and stigma.

A Life Span Perspective on Natural Recovery (Self-Change) from Alcohol Problems

Barriers to treatment: why alcohol and drug abusers delay or never seek treatment.

The public’s perception of the appropriateness of treatment outcomes.

It is proposed that when Ss are offered a large payment for engaging in an activity, they infer that the activity must be difficult, tedious, risky, or unpleasant in some way. This inference can produce the familiar reverse-incentive effect in induced compliance situations. Unlike other explanations, this analysis predicts that the reverse-incentive effect will occur even when Ss do not engage in the activity and when they have no choice about engaging in it.

Inferred values and the reverse-incentive effect in induced compliance.

A relationship between perceived self-efficacy and quality of life in cancer patients.

"This study attempts to review informatively the status of graduates from the School of Business Administration in that period in which students have first been graduates with a major in accounting."--1.

A Survey of Accounting Majors at North Texas State College from 1944 to 1950 to Evaluate Their Academic Training for the Vocational Positions Now Held

378 Background: Patients with localized or locally advanced ccRCC undergo surgical resection by partial or radical nephrectomy. Approximately 50% of tumors recur within five years after surgery. Currently the only FDA approved drug in the adjuvant setting is sunitinib. However, the absence of an overall survival benefit and the prevalence of side effects limit widespread use of sunitinib. Accurate identification of patients at high risk of recurrence would enhance targeted adjuvant therapy, while sparing low-risk patients from side effects. A single scoring system, transcriptomic signature or genomic classifier, is unlikely to accurately define prognosis. Here, we describe an integrated transcriptomic-metallomic classifier to assess the risk of relapse in localized ccRCC. Methods: We investigated the transcriptomic landscape of Caucasian male patients with stage III ccRCCs who remained disease free (S3DF) or relapsed (S3RL) within 24 months after surgery using the TCGA Firehose Legacy cohort. In a separate cohort of S3RL and S3DF ccRCCs, copper (Cu) content and molecular distribution were analyzed by size exclusion chromatography coupled to inductively coupled plasma mass spectrometry (SEC-ICP-MS). Results: Transcriptomic analysis identified that S3RL tumors were enriched for genes encoding subunits of mitochondrial electron transport chain (ETC) and mitochondrial ribosomal proteins (MRPs), an indication that mitochondrial activity may contribute to the relapse. In contrast, S3DF tumors were enrichedfor genes related to immune responses, including genes encoding members ofMHC-II, suggesting tumor control by the immune system. We established a setof 23 genes (23G) as a signature that stratified ccRCCsinto distinct groups characterized by low, intermediateand high risk of relapse after surgery. Importantly, SEC-ICP-MS analysis identified augmented distribution of Cu to the Cu cytochrome c oxidase complex (Cu-COX) in tumor mitochondria from S3RL, consistent with the prediction of increased ETC activity in the transcriptomic analysis. Conclusions: Integration of the 23G transcriptomic signature and Cu-COX complex measurements in locoregional ccRCC can serve as a prognostic biomarker for recurrence, and as a predictive classifier for novel treatments, including inhibitors of ETC for the S3RL tumors. In particular, a combination classifier using both measurements may have a stronger prognostic/predictive power as compared to either biomarker alone.

Complimentary transcriptomic-metallomic analysis identifies risk of relapse for clear-cell renal cell carcinoma (ccRCC) patients.

ABSTRACT Tobacco smoking (TS) results in reprogramming of major metabolic pathways, including glycolysis, the citric acid (TCA) cycle, oxidative phosphorylation, and metabolism of aspartate, glutamate and glutamine in clear cell renal cell carcinoma (ccRCC). TS alters the distribution and activities of cadmium, arsenic and copper in a manner mechanistically supporting metabolic remodeling. Alterations in metabolism and metal distribution identify new actionable targets for treatment of ccRCC.

Metabolic subtypes of clear cell renal cell carcinoma defined by tobacco smoking

The promise of personalized medicine is a therapeutic advance where tumor signatures obtained from different omics platforms, such as genomics, transcriptomics, proteomics, and metabolomics, in addition to environmental factors including metals and metalloids, are used to guide the treatments. Clear cell renal carcinoma (ccRCC), the most common type of kidney cancer, can be sporadic (frequently) or genetic (rare), both characterized by loss of the von Hippel-Lindau (VHL) gene that controls hypoxia inducible factors. Recently, several genomic subtypes were identified with different prognoses. Transcriptomics, proteomics, metabolomics and metallomic data converge on altered metabolism as the principal feature of the disease. However, in view of multiple biochemical alterations and high level of tumor heterogeneity, identification of clearly defined subtypes is necessary for further improvement of treatments. In the future, single-cell combined multi-omics approaches will be the next generation of analyses gaining deeper insights into ccRCC progression and allowing for design of specific signatures, with better prognostic/predictive clinical applications.

Molecular and Metabolic Subtypes in Sporadic and Inherited Clear Cell Renal Cell Carcinoma

Clear cell renal cell carcinoma (ccRCC) is the most common histologically defined renal cancer. However, it is not a uniform disease and includes several genetic subtypes with different prognosis. ccRCC is also characterized by distinguished metabolic reprogramming. Tobacco smoking (TS) is an established risk factor for ccRCC with unknown effects on tumor pathobiology.

METHODS
We investigated the landscape of ccRCCs and paired normal kidney tissues (NKTs) using integrated transcriptomic, metabolomic and metallomic approaches in a cohort of never smokers (NS) and long-term current smokers (LTS) Caucasian males.

RESULTS
All three Omics domains consistentl identified a distinct metabolic subtype of ccRCCs in LTS, characterized by activation of oxidative phosphorylation (OxPhos) coupled with reprogramming of the malate-aspartate shuttle and metabolism of aspartate, glutamate, glutamine and histidine. Cadmium, copper and inorganic arsenic accumulated in LTS tumors showing redistribution among intracellular pools, including relocation of copper into the cytochrome c oxidase complex. Gene expression signature based on the LTS metabolic subtype provided prognostic stratification of The Cancer Genome Atlas (TCGA) ccRCC tumors that was independent from genomic alterations.

The work identifies the TS related metabolic subtype of ccRCC with vulnerabilities that can be exploited for precision medicine approaches targeting metabolic pathways. The results provide rationale for the development of metabolic biomarkers with diagnostic and prognostic applications using evaluation of OxPhos status. The metallomic analysis reveals the role of disrupted metal homeostasis in ccRCC highlighting the importance of studying effects of metals from e-cigarettes and environmental exposures.

Tobacco smoking induces metabolic reprogramming of renal cell carcinoma.

Translation control of the immune checkpoint in cancer and its therapeutic targeting

The PERK-eIF2α pathway is activated in aggressive prostate cancer and associated with patient outcome, providing a therapeutic target for the disease. Stressing out prostate cancer As tumors grow, they undergo a variety of metabolic changes that facilitate their proliferation. Protein synthesis is one of the cellular processes that is altered in cancer cells, because its continued activation helps drive cancer growth. This is not a benign adaptation, however, and unchecked up-regulation of protein synthesis can be toxic to the cells because it promotes cellular stress. As Nguyen et al. discovered, prostate cancer cells with a specific combination of mutations can override this stress by activating a protein called eIF2α, which protects them from excessive protein synthesis. To target this pathway, the authors identified an inhibitor of eIF2α that blocks this protective mechanism and has therapeutic activity against aggressive and otherwise untreatable prostate cancer. Oncogenic lesions up-regulate bioenergetically demanding cellular processes, such as protein synthesis, to drive cancer cell growth and continued proliferation. However, the hijacking of these key processes by oncogenic pathways imposes onerous cell stress that must be mitigated by adaptive responses for cell survival. The mechanism by which these adaptive responses are established, their functional consequences for tumor development, and their implications for therapeutic interventions remain largely unknown. Using murine and humanized models of prostate cancer (PCa), we show that one of the three branches of the unfolded protein response is selectively activated in advanced PCa. This adaptive response activates the phosphorylation of the eukaryotic initiation factor 2–α (P-eIF2α) to reset global protein synthesis to a level that fosters aggressive tumor development and is a marker of poor patient survival upon the acquisition of multiple oncogenic lesions. Using patient-derived xenograft models and an inhibitor of P-eIF2α activity, ISRIB, our data show that targeting this adaptive brake for protein synthesis selectively triggers cytotoxicity against aggressive metastatic PCa, a disease for which presently there is no cure.

Development of a stress response therapy targeting aggressive prostate cancer

Distinct oncogenic lesions within components of the Myc or PI3K pathways hijack the translation machinery, to establish an aberrant “cancer proteome”, that drives cancer cell growth and tumor development. Invariably, however, increases in the protein synthesis capacity of cancer cells impose a cellular stress that requires an adaptive or evasive response in order for cancer cells to survive and continue proliferating. One of the key cytoprotective stress response pathways is known as the unfolded protein response (UPR), which is engaged when an excess of unfolded/misfolded proteins accumulate within the lumen of the endoplasmic reticulum. How the specific arms of UPR are coupled to increased protein synthesis in cancer etiology and drug response is still poorly understood. In this study we established a new genetic mouse model to address the role of protein synthesis-dependent activation of the UPR in prostate cancer initiation and maintenance promoted by loss of the PTEN tumor suppressor and overexpression of the Myc oncogene. We show that in this epithelial cancer model, Myc hyperactivation and PTEN loss synergize to dramatically stimulate PERK and IRE-1α activity, two major signaling arms of the UPR pathway. Distinct mechanisms transduce adaptive signals under conditions of ER stress: PERK control of protein synthesis through phosphorylation of the key translation initiation factor eIF2α and IRE1α-mediated splicing of the XBP-1 mRNA to produce an active and stable XBP1 transcription factor (XBP1s). Importantly, we observed that UPR activation is associated with formation of prostatic intraepithelial neoplasia (PIN) and invasive carcinoma. Strikingly, the pharmacologic inhibition of eIF2α phosphorylation leads to tumor inhibition. We have further established patient derived xenograft (PDX) models from primary and metastatic human prostate tumors to extend the role of UPR in specific steps of human tumor development. We have also developed a series of novel mouse and human prostate cancer cell culture systems to define the role of localized translation of ER-associated ribosomes during oncogenic transformation. Together this work provides critical insight into a fundamental mechanism by which the augmented protein synthesis requirement of cancer cells is coupled to an adaptation of ER cellular stress, reflecting a new cancer-specific vulnerability that is targetable. Citation Format: Crystal S. Conn, Hao G. Nguyen, Yae Kye, John T. Cunningham, Charles Truillet, Michael Evans, Tony L. Huynh, Peter Walters, Davide Ruggero. Sensing stress in cancer: a novel therapy targeting protein synthesis through the unfolded protein response in prostate cancer development. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A25.

Abstract A25: Sensing stress in cancer: a novel therapy targeting protein synthesis through the unfolded protein response in prostate cancer development

Purpose: mTOR regulates many normal physiological processes and when hyperactive can drive numerous cancers and human diseases. However, it is very challenging to detect and quantify mTOR signaling noninvasively in clinically relevant animal models of disease or man. We hypothesized that a nuclear imaging tool measuring intracellular mTOR activity could address this unmet need. Experimental Design: Although the biochemical activity of mTOR is not directly amenable to nuclear imaging probe development, we show that the transferrin receptor can be used to indirectly measure intracellular changes in mTOR activity. Results: After verifying that the uptake of radiolabeled transferrin (the soluble ligand of the transferrin receptor) is stimulated by active mTORC1 in vitro, we showed that 89Zr-labeled transferrin (Tf) can measure mTORC1 signaling dynamics in normal and cancerous mouse tissues with PET. Finally, we show that 89Zr-Tf can detect the upregulation of mTORC1 by tumor cells to escape the antitumor effects of a standard-of-care antiandrogen, which is to our knowledge the first example of applying PET to interrogate the biology of treatment resistant cancer. Conclusions: In summary, we have developed the first quantitative assay to provide a comprehensive measurement of mTOR signaling dynamics in vivo, in specific normal tissues, and during tumor development in genetically engineered animal models using a nuclear imaging tool that is readily translatable to man. Clin Cancer Res; 23(12); 3045–52. ©2016 AACR.

Noninvasive Measurement of mTORC1 Signaling with 89Zr-Transferrin

Pulses of translation control to gene expression during cancer evolution steer the immune response checkpoint

Insulin sensitivity in liver is characterized by the ability of insulin to efficiently inhibit glucose production and fatty acid oxidation as well as promote de novo lipid biosynthesis. Specific dysregulation of glucose and lipid metabolism in liver is sufficient to cause insulin resistance and type 2 diabetes; this is seen by a selective inability of insulin to suppress glucose production while remaining insulin-sensitive to de novo lipid biosynthesis. We have previously shown that the transcription factor Yin Yang 1 (YY1) controls diabetic-linked glucose and lipid metabolism gene sets in skeletal muscle, but whether liver YY1-targeted metabolic genes impact a diabetic phenotype is unknown. Here we show that decreased genetic dosage of YY1 in liver causes insulin resistance, hepatic lipid accumulation, and dyslipidemia. Indeed, YY1 liver-specific heterozygous mice exhibit blunted activation of hepatic insulin signaling in response to insulin. Mechanistically, YY1, through direct recruitment to promoters, functions as a suppressor of genes encoding for metabolic enzymes of the gluconeogenic and lipogenic pathways and as an activator of genes linked to fatty acid oxidation. These counterregulatory transcriptional activities make targeting hepatic YY1 an attractive approach for treating insulin-resistant diabetes.

Decreased genetic dosage of hepatic Yin Yang 1 causes diabetic-like symptoms.

Protein and Nucleotide Biosynthesis Are Coupled by a Single Rate-Limiting Enzyme, PRPS2, to Drive Cancer

Limited understanding of the functional link between multiple oncogenic pathways is a major barrier in the ongoing effort of cancer biologists to design an effective therapeutic approach to treat malignancies characterized by driver oncogenic network signals. In this issue of Cancer Discovery, Tan and colleagues elucidate a novel PDK1-PLK1-MYC signaling pathway connecting two fundamental oncogenic programs, phosphoinositide 3-kinase and MYC. They define the functional role for PDK1-PLK1-MYC signaling in cancer cell survival and tumor formation and show the therapeutic benefit of inhibiting PDK1 and PLK1 pharmacologically in cancer, tackling the most undruggable tumors defined by elevated levels of the MYC oncoprotein.

New connections between old pathways: PDK1 signaling promotes cellular transformation through PLK1-dependent MYC stabilization.

Investigating Myc-dependent translational regulation in normal and cancer cells.

The proto-oncogene c-Myc paradoxically activates both proliferation and apoptosis. In the pathogenic state, c-Myc-induced apoptosis is bypassed via a critical, yet poorly understood escape mechanism that promotes cellular transformation and tumorigenesis. The accumulation of unfolded proteins in the ER initiates a cellular stress program termed the unfolded protein response (UPR) to support cell survival. Analysis of spontaneous mouse and human lymphomas demonstrated significantly higher levels of UPR activation compared with normal tissues. Using multiple genetic models, we demonstrated that c-Myc and N-Myc activated the PERK/eIF2α/ATF4 arm of the UPR, leading to increased cell survival via the induction of cytoprotective autophagy. Inhibition of PERK significantly reduced Myc-induced autophagy, colony formation, and tumor formation. Moreover, pharmacologic or genetic inhibition of autophagy resulted in increased Myc-dependent apoptosis. Mechanistically, we demonstrated an important link between Myc-dependent increases in protein synthesis and UPR activation. Specifically, by employing a mouse minute (L24+/-) mutant, which resulted in wild-type levels of protein synthesis and attenuation of Myc-induced lymphomagenesis, we showed that Myc-induced UPR activation was reversed. Our findings establish a role for UPR as an enhancer of c-Myc-induced transformation and suggest that UPR inhibition may be particularly effective against malignancies characterized by c-Myc overexpression.

ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth.

ABSTRACT The formation, distribution, and maintenance of functional mitochondria are achieved through dynamic processes that depend strictly on the transcription of nuclear genes encoding mitochondrial proteins. A large number of these mitochondrial genes contain binding sites for the transcription factor Yin Yang 1 (YY1) in their proximal promoters, but the physiological relevance is unknown. We report here that skeletal-muscle-specific YY1 knockout (YY1mKO) mice have severely defective mitochondrial morphology and oxidative function associated with exercise intolerance, signs of mitochondrial myopathy, and short stature. Gene set enrichment analysis (GSEA) revealed that the top pathways downregulated in YY1mKO mice were assigned to key metabolic and regulatory mitochondrial genes. This analysis was consistent with a profound decrease in the level of mitochondrial proteins and oxidative phosphorylation (OXPHOS) bioenergetic function in these mice. In contrast to the finding for wild-type mice, inactivation of the mammalian target of rapamycin (mTOR) did not suppress mitochondrial genes in YY1mKO mice. Mechanistically, mTOR-dependent phosphorylation of YY1 resulted in a strong interaction between YY1 and the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α), a major regulator of mitochondrial function. These results underscore the important role of YY1 in the maintenance of mitochondrial function and explain how its inactivation might contribute to exercise intolerance and mitochondrial myopathies.

Defective Mitochondrial Morphology and Bioenergetic Function in Mice Lacking the Transcription Factor Yin Yang 1 in Skeletal Muscle

Yin Yang 1 deficiency in skeletal muscle protects against rapamycin-induced diabetic-like symptoms through activation of insulin/IGF signaling.

mTOR controls mitochondrial function through the YY1 transcriptional complex

Aberrant regulation of the translation initiation is known to contribute to tumorigenesis. eIF3 plays an important role in translation initiation. eIF3f is the p47 subunit of the eIF3 complex whose function in cancer is not clear. Initial studies from our group indicated that eIF3f expression is decreased in pancreatic cancer. Overexpression of eIF3f induces apoptosis in pancreatic cancer cells. The eIF3f gene is located at chromosome band region 11p15.4. Loss of 11p15.4 is a common event in many tumors including pancreatic cancer. In order to investigate the molecular mechanism of the decreased expression of eIF3f in pancreatic cancer, we performed loss of heterozygosity (LOH) analysis in 32 pancreatic cancer specimens using three microsatellite markers encompassing the eIF3f gene. We showed that the prevalence of LOH ranged from 71% to 93%. We also performed eIF3f gene copy number analysis using quantitative real time PCR to further confirm the specific allelic loss of eIF3f gene in pancreatic cancer. We demonstrated a statistically significant decrease of eIF3f gene copy number in pancreatic tumors compared with normal tissues with a tumor/normal ratio of 0.24. Furthermore, RNA in situ hybridization and tissue microarray immunohistochemistry analysis demonstrated that eIF3f expression is significantly decreased in human pancreatic adenocarcinoma tissues compared to normal pancreatic tissues. These data provides new insight into the understanding of the molecular pathogenesis of eIF3f during pancreatic tumorigenesis. © 2007 Wiley‐Liss, Inc.

Loss of the eukaryotic initiation factor 3f in pancreatic cancer

mTOR controls mitochondrial oxidative function through a YY1–PGC-1α transcriptional complex

Steroid-induced osteoporosis is a common side effect of long-term treatment with glucocorticoid (GC) drugs. GCs have multiple systemic effects that may influence bone metabolism but also directly affect osteoblasts by decreasing proliferation. This may be beneficial at low concentrations, enhancing differentiation. However, high-dose treatment produces a severe deficit in the proliferative osteoblastic compartment. We provide causal evidence that this effect of GC is mediated by induction of the dual-specificity MAPK phosphatase, MKP-1/DUSP1. Excessive MKP-1 production is both necessary and sufficient to account for the impaired osteoblastic response to mitogens. Overexpression of MKP-1 after either GC treatment or transfection ablates the mitogenic response in osteoblasts. Knockdown of MKP-1 using either immunodepletion of MKP-1 before in vitro dephosphorylation assay or short interference RNA transfection prevents inactivation of ERK by GCs. Neither c-jun N-terminal kinase nor p38 MAPK is activated by the mitogenic cocktail in 20% fetal calf serum, but their activation by a DNA-damaging agent (UV irradiation) was inhibited by either GC treatment or overexpression of MKP-1, indicating regulation of all three MAPKs by MKP-1 in osteoblasts. However, an inhibitor of the MAPK/ERK kinase-ERK pathway inhibited osteoblast proliferation whereas inhibitors of c-jun N-terminal kinase or p38 MAPK had no effect, suggesting that ERK is the MAPK that controls osteoblast proliferation. Regulation of ERK by MKP-1 provides a novel mechanism for control of osteoblast proliferation by GCs.

Mitogen-activated protein kinase phosphatase 1/dual specificity phosphatase 1 mediates glucocorticoid inhibition of osteoblast proliferation.

Rapid inhibitory effects of glucocorticoids on ERK activity and osteoblast proliferation occur via transcriptional upregulation of MKP-1

In line with its financial stability and competition objectives the Bank of England has been, and will remain, supportive of firms wishing to become banks and enter the UK banking sector. The UK’s approach to authorising banks aims to strike an appropriate balance between ensuring robust control around the creation of new banks and not being so burdensome that it discourages suitably qualified firms from entering the market. Forty-six new banks have been authorised by the Prudential Regulation Authority (PRA) and the Financial Conduct Authority (FCA) since April 2013.

144 speaker INTERNATIONAL INCIDENT REPORTING: LESSONS FROM ROSIS

exchange rate change is cyclical or trend. A cyclical appreciation increases job destruction, but not job creation, leading to net employment loss, while a trend appreciation increases both job creation and job destruction, not net employment change. In the second part of the book, the authors use what they refer to as case study analysis to examine the effect of NAFTA on three industries-textile and apparel, chemicals, and automobiles-in which there is strong international competition and a substantial reallocation of bilateral trade toward Mexico.

Materials managers must lead when tightening controls. Managing vendors requires planning and a collaborative effort.

When negotiating with suppliers there are steps materials managers can take to ensure a contract is written in the hospital's best interest. One key point is that organizations should use their own contract template instead of the supplier's. This automatically puts a purchasing department at an advantage, as long as the templates are up-to-date. Also, seemingly innocuous language can be financially detrimental in the end, so it is imperative that anyone involved in the process be educated about contract language.

The value and the significance of the intellectual property (IP) in the growth and development of an organization are discussed. IP is shown to be much better than the various tangible assets and hence should be recognized and used appropriately by the employees. The author also presents ways that can be employed for the valuation and application of IP.

I was in Boston in February and had the pleasure of talking at a conference of 300 companies on the topic of commercialising technology, an area of current interest in the US as companies see a strong economic performance over the next five years and wish to use technology as a competitive advantage. The one thing that stood out at the conference was the ease of finding venture capital and the enthusiasm of individuals to invest in venture capital funds as part of their investment portfolios. VC has been around Boston for a long time and is a well proven investment. Boston also has a number of technology feeds, including the Massachusetts Institute of Technology and the head offices of many companies, including Bose and Kodak. While this helps, the major drivers for VC are the attitude of the investors and the enthusiasm of the VC funds managers in achieving results.

The main challenge that small to medium size companies (SMEs) face in New Zealand to achieve growth is a lack of capital for growth. Some of the different initiatives that SMEs can take to obtain capital for growth are highlighted.

A brief note on Caltech Development Capital Fund, which aims to give investors the chance to participate in the growth of technology related companies and reap the rewards of high growth rates from these successes, is presented. The company invests in Agribusiness, Communication encryption and line retail that have very good potential for growth.

Major Asian countries are being perceived as the developing competitive niche markets of the current period. Many New Zealand engineering consultancy companies are seizing the opportunities and are providing more services to countries such as Thailand, Malaysia, Vietnam and Indonesia.

The funding gap that exists for those wishing to borrow funds between $100,000 and $1 million for innovation is discussed. The different things that an entrepreneur can do to find the medium-sized investment money are highlighted.

The two things that help take most developments to the market are a good idea and a good business plan. The pathway to market and the security of the intellectual property are two of the most important aspects of development.

Magnetic skyrmions in thin films with perpendicular magnetic anisotropy are promising candidates for magnetic memory and logic devices, making the development of ways to transport skyrmions efficiently and precisely of significant interest. Here, we investigate the transport of skyrmions by surface acoustic waves (SAWs) via several modalities using micromagnetic simulations. We show skyrmion pinning sites created by standing SAWs at anti-nodes and skyrmion Hall-like motion without pinning driven by travelling SAWs. We also show how orthogonal SAWs formed by combining a longitudinal travelling SAW and a transverse standing SAW can be used for the precise 2D positioning of skyrmions. Our results also suggest SAWs offer a viable approach to the precise transport of multiple skyrmions along multichannel racetrack.

Many quantum technologies rely heavily on propagation of RF and microwave signals through devices at cryogenic temperatures, and detailed understanding of materials and signal propagation is therefore key to improving the performance of quantum circuits. The properties of dielectric substrate materials used for transmission lines (TLs) such as their permittivity need to be precisely determined to design high performance quantum integrated circuits. In this paper, we discuss a measurement technique for determining the effective permittivity of a TL at mK temperatures. The technique utilizes S-parameter measurements of multiple TLs to reliably extract the effective permittivity of the TL implemented in a substrate material. The technique is demonstrated using measured S-parameters of grounded co-planar waveguide (GCPW) at 296 K and 15 mK. The effective permittivity of the TL at 296 K and 15 mK are determined from measurements and compared. We observed the effective permittivity determinations at 15 mK to be approximately frequency independent and calculated the relative permittivity of Rogers RO4350B material at 15 mK to be 3.64. There is no significant deviation from this relative permittivity value with respect to manufacturer data and from measured data at 296 K.

Determination of the Permittivity of Transmission Lines at Milli-Kelvin Temperatures

Finite element method (FEM) simulations (employing ANSYS High Frequency Structure Simulator, HFSS) are used to investigate the response of terahertz (THz) frequency range split‐ring resonators (SRRs) integrated with on‐chip THz waveguides to cancerous tissues. Two‐port S‐parameter simulations are performed to obtain the transmission spectra (S21) of a planar Goubau line (PGL) integrated with an SRR. Permittivity and loss tangent of the colonic tissues are both taken into account in the numerical simulation. The transmission spectra of the SRR integrated PGL are obtained for cancerous and healthy tissues in close proximity to the SRR, and it is found that they can be distinguished by the resonant frequency shift of the SRR induced by dielectric loading. The electric field distribution and magnitude near the SRR for various capacitive gap widths of SRR are investigated to understand how the gap width affects the maximum electric field magnitude and the vertical extent of the electric field in the gap area. The simulated imaging of colonic tissue consisting of healthy and cancerous tissues using the SRR integrated PGL device with a protective layer on it is performed, showing how the technique could in principle be used to distinguish tumor margins with realistic THz dielectric parameters.

Design of a Split Ring Resonator Integrated with On‐Chip Terahertz Waveguides for Colon Cancer Detection

We present a scheme for the full integration of terahertz (THz) frequency quantum cascade lasers (QCLs) within a dilution refrigerator in order to provide a directed delivery of THz power into the sample space. We describe a successful operation of a 2.68 THz QCL located on the pulse tube cooler stage of the refrigerator, with its output coupled onto a two-dimensional electron gas (2DEG) located on a milli-kelvin sample stage via hollow metal waveguides and Hysol thermal isolators, achieving a total loss from QCL to the sample of ∼-9 dB. The thermal isolators limit heat leaks to the sample space, with a base temperature of ∼210 mK being achieved. We observe cyclotron resonance (CR) induced in the 2DEG by the QCL and explore the heating impact of the QCL on all stages of the refrigerator. The CR effect induced by the THz QCL is observable at electron temperatures as low as ∼430 mK. The results show a viable route for the exploitation of THz QCLs within the environment of a dilution refrigerator and for the THz power delivery in very low-temperature (<0.5 K) condensed matter experiments.

Directed delivery of terahertz frequency radiation from quantum cascade lasers within a dry 3He dilution refrigerator.

The control of perpendicular magnetic anisotropy (PMA) in thin films by strain has considerable potential for energy-efficient information storage and data processing. Here, we report on the control of PMA in Pt/Co/Ir thin films by the strain produced by standing surface acoustic waves (SAWs). A significant (∼21%) coercivity reduction (from 4.80 ± 0.03 to 3.80 ± 0.02 mT) can be obtained by applying a standing SAW with a center frequency of 93.35 MHz. Furthermore, the standing SAWs induce a greater-than 11-fold increase in magnetization reversal speed (from 168 ± 3 to up to 2100 ± 80 μm2/s) at 3.2 mT for a total applied RF power of 22.5 dBm. During application of SAWs, wide-field Kerr microscopy reveals the formation of domains in stripes with a periodicity of half of the SAW wavelength. Micromagnetic simulations indicate that the anti-nodes of the standing SAW locally lower the anisotropy due to the magneto-elastic coupling effect, decreasing domain nucleation field while promoting magnetization reversal. Our study suggests the possibility of remote and energy-efficient control of magnetization switching using SAWs.

Local anisotropy control of Pt/Co/Ir thin film with perpendicular magnetic anisotropy by surface acoustic waves

Validating S‐parameter measurements of RF integrated circuits at milli‐Kelvin temperatures

Wide bandwidth THz pulses can be used to record the distinctive spectral fingerprints related to the vibrational or rotational modes of polycrystalline biomolecules, and can be used to resolve the time-dependent dynamics of such systems. Waveguides, owing to their tight spatial confinement of the electromagnetic fields and the longer interaction distance, are promising platforms with which to study small volumes of such systems. The efficient input of sub-ps THz pulses into waveguides is challenging owing to the wide bandwidth of the THz signal. Here, we propose a sensing chip comprised of a pair of back-to-back Vivaldi antennas feeding into, and out from, a 90° bent slotline waveguide to overcome this problem. The effective operating bandwidth of the sensing chip ranges from 0.2 to 1.15 THz, and the free-space to on-chip coupling efficiency is as high as 51% at 0.44 THz. Over the entire band, the THz signal is ∼42 dB above the noise level at room temperature, with a peak of ∼73 dB above the noise. In order to demonstrate the use of the chip, we have measured the characteristic fingerprint of α-lactose monohydrate, and its sharp absorption peak at ∼0.53 THz was successfully observed, demonstrating the promise of our technique. The chip has the merits of efficient in-plane coupling, ultra-wide bandwidth, ease-of-integration, and simple fabrication. It has the potential for large-scale manufacture, and can be a strong candidate for integration into other THz light-matter interaction platforms.

Efficient free-space to on-chip coupling of THz-bandwidth pulses for biomolecule fingerprint sensing.

The fast modulation of lasers is a fundamental requirement for applications in optical communications, high-resolution spectroscopy and metrology. Here, we report a new mechanism to modulate the emission from a terahertz frequency quantum cascade laser (QCL) device , whereby optically-generated acoustic phonon pulses are used to perturb the QCL bandstructure, enabling fast amplitude modulation that can be controlled using the QCL drive current or strain pulse amplitude. We show that this modulation can be explained using a perturbation theory analysis.

High-speed modulation of terahertz quantum cascade lasers by acoustic phonon pulses

All-Electronic Phase-Resolved THz Microscopy Using the Self-Mixing Effect in a Semiconductor Laser

We have used finite-element methods to design and simulate a tunable terahertz frequency range band-stop filter based on coupled split-ring resonators integrated into planar Goubau-line waveguide. Two split-ring resonators with different geometrical lengths and gap widths were designed to resonate at the same frequency. When the two resonators were coupled, resonance splitting was observed in the transmission spectra controlled by the distance between them. The electric field distribution and surface current modes in the coupled resonators were used to identify the origin of the resonance modes. In order to dynamically tune the coupled resonance frequencies, a cantilevered microelectromechanical scheme is proposed, in which the radius of curvature of one split-ring resonator is adjusted with respect to a fixed second split-ring resonator. The coupling strength of the coupled resonators was investigated as a function of the relative separation of the resonators revealing a dispersion relation that shows anti-crossing of the coupled resonances as the cantilever bends.

Tunable terahertz band-stop filter using strongly coupled split ring resonators integrated with on-chip waveguide

We demonstrate engineering of the low-terahertz range plasmonic spectra of two-dimensional electron systems by modifying their geometry. Specifically, we have modelled, fabricated, and measured two devices for comparison. The first device has a rectangular channel, while the second is trapezoidal, designed to support a richer plasmonic spectrum by causing variation in the device width along the direction of plasmon propagation. We show that while plasmon resonant frequencies and field distributions in the rectangular device can largely be described by a simple one-dimensional analytical model, the field distributions modelled in the trapezoidal device shows a more complex pattern with significant variation along the length of the channel, so requiring a two-dimensional treatment. The results illustrate the potential of modifying the channel geometry to obtain different spectra in experiments, with potential applications in the design of novel terahertz-range devices, such as plasmon-based sources and detectors.

Effect of mesa geometry on low-terahertz frequency range plasmons in two-dimensional electron systems

Near-field microscopy techniques operating in the terahertz (THz) frequency band offer the tantalizing possibility of visualizing with nanometric resolution the localized THz fields supported by individual resonators, micro-structured surfaces, and metamaterials. Such capabilities promise to underpin the future development and characterization of a wide range of devices, including THz emitters, detectors, optoelectronic modulators, sensors, and novel optical components. In this work, we report scattering-type scanning near-field optical microscopy using a THz-frequency quantum cascade laser (QCL) to probe coherently the localized field supported by individual micro-resonator structures. Our technique demonstrates deep sub-wavelength mapping of the field distribution associated with in-plane resonator modes in plasmonic dipole antennas and split ring resonator structures. By exploiting electronic tuning of the QCL in conjunction with the coherent self-mixing effect in these lasers, we are able to resolve both the magnitude and the phase of the out-of-plane field. We, furthermore, show that the elliptically polarized state of the QCL field can be exploited for the simultaneous excitation and measurement of plasmonic resonances in these structures while suppressing the otherwise dominant signal arising from the local material permittivity.

Coherent terahertz microscopy of modal field distributions in micro-resonators

We numerically and experimentally demonstrate a broadband single-mode hollow substrate integrated waveguide using one-dimensional photonic crystal as sidewalls in place of metallic via holes. By avoiding the vertical metallic walls, the waveguide can be easily fabricated as a photonic crystal structure on a single planar substrate sandwiched between two parallel metal plates. Such a hybrid flat waveguide can tightly confine the millimeter and terahertz waves in the low-loss air core. With the aid of the photonic crystal sidewalls, high-order competing modes in the waveguide are substantially suppressed based on the so-called modal-filtering effect, allowing the waveguide to be operated in a single-HE01-mode pattern over an octave bandwidth. Benefiting from the less use of metallic walls, the propagation loss of the proposed hybrid waveguide can be less than that of the classic hollow metallic rectangular waveguide at millimeter-wave and terahertz frequencies according to our numerical simulation. A proof-of-concept experimental demonstration operating between 20 to 45 GHz is presented verifying the properties and the advantages of the proposed waveguide. This works offers a promising candidate for an octave-bandwidth single-mode transmission line for millimeter-wave and THz multilayer system-in-package applications.

2021 Research, Invention, and Innovation Congress: Innovation Electricals and Electronics (RI2C)

Broadband Single-Mode Hollow Substrate Integrated Waveguide with Photonic Crystal Sidewalls for Multilayer System-in-Package Applications

We investigate using finite element methods how sub‐micrometer to micrometer‐scale coplanar waveguide (CPW) can be used for the detection of fingerprint spectra of very small (of order 10−14 mL) volumes of analytes in the terahertz (THz) frequency range. The electric field distribution is investigated near the waveguide for various gap widths between the center conductor and ground plane using a finite element simulation (ANSYS High Frequency Structure Simulator, HFSS). Taking lactose monohydrate as an exemplar material, a Drude–Lorentz model is combined for its real and imaginary permittivities with this numerical simulation, finding a significant enhancement in fingerprint detection as the gap width is reduced; the electric field in the CPW is found to increase by a factor ≈14 times moving from a 20 to 0.5‐µm‐wide gap between center conductor and ground plane, while the on‐resonance THz absorption increases ≈14 times. The effective absorption coefficient of the lactose at 530 GHz is investigated as a function of the slot width for various lactose block thicknesses to understand how change in the field confinement and in the effective overlap between the lactose block and incident THz waves affect the effective absorption coefficient.

Enhanced Terahertz Spectral‐Fingerprint Detection of α‐Lactose Using Sub‐Micrometer‐Gap On‐Chip Waveguides

We report on both experiments and theory of low-terahertz frequency range (up to 400 GHz) magnetoplasmons in a gated two-dimensional electron gas at low (<4K) temperatures. The evolution of magnetoplasmon resonances was observed as a function of magnetic field at frequencies up to ∼400 GHz. Full-wave 3D simulations of the system predicted the spatial distribution of plasmon modes in the 2D channel, along with their frequency response, allowing us to distinguish those resonances caused by bulk and edge magnetoplasmons in the experiments. Our methodology is anticipated to be applicable to the low temperature (<4K) on-chip terahertz measurements of a wide range of other low-dimensional mesoscopic systems.

Terahertz magnetoplasmon resonances in coupled cavities formed in a gated two-dimensional electron gas.

Using two rigorous electromagnetic approaches, we study plasmon scattering in two-dimensional systems and show that plasmon amplification is possible in the presence of dc currents. Two scenarios are considered: plasmon scattering from an interface between different two-dimensional channels and plasmon reflection from electric contacts of arbitrary thickness. In each case, the effect of a dc current of the plasmon reflection and transmission coefficients and the plasmon power are both quantified. A resonant system is studied where plasmon roundtrip gain may exceed unity, showing the possibility of plasmon generation.

Scattering-induced amplification of two-dimensional plasmons: Electromagnetic modeling

We investigate the effect of substrate etching on terahertz frequency range metamaterials using finite-element method simulations. A blue shift was found in the metamaterial resonance with increasing substrate etch depth, caused by a decrease in the effective refractive index. The relative contribution of the substrate’s refractive index to the effective refractive index was obtained as a function of the etch depth, finding that the decay length of the electric field magnitude below the LC gap is larger for the etched metamaterials due to their lower effective refractive index. We suggest designs for a terahertz metamaterial liquid sensor utilizing substrate etching which shows a significant enhancement in sensitivity compared to unetched sensors using ethanol as an example analyte. The sensitivity of the liquid sensor was enhanced by up to ~6.7-fold, from 76.4 to 514.5 GHz/RIU, for an ethanol liquid layer with a thickness of 60 μm by the incorporation of a substrate etch depth of 30 µm. Since the region of space close to the metamaterial is the most sensitive, however, we find that for small liquid thicknesses, larger etch depths can act to decrease sensitivity, and provide quantitative estimates of this effect.

Effect of Substrate Etching on Terahertz Metamaterial Resonances and Its Liquid Sensing Applications

High-speed modulation of a terahertz quantum cascade laser by coherent acoustic phonon pulses

We report observations of magnetoplasmons at frequencies up to 400 GHz in gated two-dimensional electron gases (2DEG) at low temperature (∼ 2K). We observed bulk magnetoplasmons for frequencies greater than the cyclotron resonance frequency, and attributed resonances occurring at frequencies below the cyclotron resonance to formation of edge magnetoplasmons (EMPs). Our full-wave 3D electromagnetic simulation results are in good agreement with the experimental findings, allowing us to predict the spatial distribution of both bulk and edge magnetoplasmon modes in the 2DEG.

2020 45th International Conference on Infrared, Millimeter, and Terahertz Waves (IRMMW-THz)

On-chip terahertz spectroscopy of magnetoplasmons in a two-dimensional electron gas

A stand-off photothermal sensor platform has been developed which combines two laser technologies: an external cavity Quantum Cascade Laser (EC-QCL), and a near-infrared laser Doppler vibrometer (NIR-LDV). The former is used as a 'pump' to induce vibrations/acoustic waves in the sample, whereas the latter is used to 'probe' these photothermal (PT) effects as the pump wavelength is varied; yielding spectral information on the target analyte. The EC-QCL uses an acousto-optic deflector (AOD) to obtain single-mode mid-infrared light of high output power with up to 1.6 µm of wavelength tuning. Using this AO based approach allows ultra-fast scanning across the full spectral bandwidth of the QCL gain chip at MHz rates, thus facilitating high speed identification of hazards. Initial validation of this pump-probe platform is demonstrated for the detection of 1,3-dinitrobenzene (DNB) and nitrobenzene (NB) on an aluminium substrate at a distance of several metres.

Towards standoff photothermal spectroscopy of CBRNE hazards using an ultra-fast tunable QCL

We investigate the use of finite-element simulations as a novel method for determining the dielectric property of target materials in the terahertz (THz) frequency range using split-ring resonator (SRR) sensing elements integrated into a planar Goubau line (PGL) waveguide. Five such SRRs were designed to support resonances at specific target frequencies. The origin of resonance modes was identified by investigating the electric field distribution and surface current modes in each SRR. Red-shifts were found in the resonances upon deposition of overlaid test dielectric layers that saturated for thicknesses above 10 µm. We also confirmed that the SRRs can work as independent sensors by depositing the analyte onto each individually. The relation between the permittivity of the target material and the saturated resonant frequency was obtained in each case, and was used to extract the permittivity of a test dielectric layer at six different frequencies in the range of 200–700 GHz as an example application. Our approach enables the permittivity of small volumes of analytes to be determined at a series of discrete frequencies up to ~1 THz.

Determination of Permittivity of Dielectric Analytes in the Terahertz Frequency Range Using Split Ring Resonator Elements Integrated with On-Chip Waveguide

We investigate the effect of the effective substrate refractive index on the sensitivity of terahertz (THz) metamaterials for dielectric sensing by substrate etching. We found the effective refractive index near the metamaterials can be actively controlled by etching, allowing optimization of the sensitivity. Our experimental findings are in good agreement with finite element method (FEM) simulation results.

Increasing the sensitivity of terahertz metamaterials for dielectric sensing by substrate etching

We demonstrate an air-core single-mode hollow hybrid waveguide that uses Bragg reflector structures in place of the vertical metal walls of the standard rectangular waveguide or via holes of the so-called substrate integrated waveguide. The high-order modes in the waveguide are substantially suppressed by a modal-filtering effect, making the waveguide operate in the fundamental mode over more than one octave. Numerical simulations show that the propagation loss of the proposed waveguide can be lower than that of classic hollow metallic rectangular waveguides at terahertz frequencies, benefiting from a significant reduction in Ohmic loss. To facilitate fabrication and characterization, a proof-of-concept 20 to 45 GHz waveguide is demonstrated, which verifies the properties and advantages of the proposed waveguide. A zero group-velocity dispersion point is observed at near the middle of the operating band, which is ideal for reducing signal distortion. This work offers a step towards a hybrid transmission-line medium that can be used in a variety of functional components for multilayer integration and broadband applications.

Substrate integrated Bragg waveguide: an octave-bandwidth single-mode hybrid transmission line for millimeter-wave applications.

We demonstrate an electrically tunable polarizer for terahertz (THz) frequency electromagnetic waves formed from a hybrid graphene-metal metasurface. Broadband (>3 THz) polarization-dependent modulation of THz transmission is demonstrated as a function of the graphene conductivity for various wire grid geometries, each tuned by gating using an overlaid ion gel. We show a strong enhancement of modulation (up to ∼17 times) compared to graphene wire grids in the frequency range of 0.2-2.5 THz upon introduction of the metallic elements. Theoretical calculations, considering both plasmonic coupling and Drude absorption, are in good agreement with our experimental findings.

Tunable broadband terahertz polarizer using graphene-metal hybrid metasurface.

We report measurements of switch-on dynamics, mode competition and frequency selection in a monolithic frequency-tuneable laser using coherent time-domain sampling of the laser emission. We observe hopping between lasing modes on picosecond-timescales and temporal evolution of transient multi-mode emission into steady-state single mode emission.

WC2.3 - Probing Ultrafast Switch-on Dynamics of Frequency Tuneable Semiconductor Lasers Using Terahertz Time-domain Spectroscopy (Invited)

We report measurements of switch-on dynamics, mode competition and frequency selection in a monolithic frequency-tuneable laser using coherent time-domain sampling of the laser emission. We observe hopping between lasing modes on picosecond-timescales and temporal evolution of transient multi-mode emission into steady-state single mode emission. Keywords—laser dynamics, semiconductor lasers, terahertz, quantum cascade lasers, ultrafast

Probing ultrafast switch-on dynamics of frequency tuneable semiconductor lasers using terahertz time-domain spectroscopy

We demonstrate an air-core single-mode hollow waveguide that uses Bragg reflector structures in place of the vertical metal walls of the standard rectangular waveguide or via holes of the so-called substrate integrated waveguide. The high-order modes in the waveguide are substantially suppressed by a modal-filtering effect, making the waveguide operate in the fundamental mode over more than one octave. Numerical simulations show that the propagation loss of the proposed waveguide can be lower than that of classic hollow metallic rectangular waveguides at terahertz frequencies, benefiting from a significant reduction in Ohmic loss. To facilitate fabrication and characterization, a proof-of-concept 20 to 45 GHz waveguide is demonstrated, which verifies the properties and advantages of the proposed waveguide. A zero group-velocity dispersion point is observed at near the middle of the operating band. This work offers a step towards a novel hybrid transmission-line medium that can be used in a variety of functional components for broadband millimeter-wave and terahertz applications.

Substrate Integrated Bragg Waveguide: an Octave-bandwidth Single-mode Functional Transmission-Line for Millimeter-Wave and Terahertz Applications

We demonstrate an air-core single-mode hollow waveguide that uses a Bragg reflector structures in place of the vertical metal walls of the standard rectangular waveguide or via holes of the so-called substrate integrated waveguide. The high-order modes in the waveguide are substantially suppressed by a modal-filtering effect, making the waveguide operate in the fundamental mode over more than one octave. Numerical simulations show that the propagation loss of the proposed waveguide can be lower than that of classic hollow metallic rectangular waveguides at terahertz frequencies, benefiting from a significant reduction in Ohmic loss. To facilitate fabrication and characterization, a proof-of-concept 20 to 45 GHz waveguide is demonstrated, which verifies the properties and advantages of the proposed waveguide. A zero group-velocity dispersion point is observed at near the middle of the operating band. This work offers a step towards a new transmission-line medium that can be integrated within a substrate, either in integrated circuit or multi-chip module technology, for broadband millimeter-wave and terahertz applications.

Substrate Integrated Bragg Waveguide: a New Transmission-Line Medium for Millimeter-Wave and Terahertz Systems Integration

We report on the high detection sensitivity of a laser feedback interferometry scheme based on a terahertz frequency quantum cascade laser (QCL). We show that variations on the laser voltage induced by optical feedback to the laser can be resolved with the reinjection of powers as low as ∼-125  dB of the emitted power. Our measurements demonstrate a noise equivalent power of ∼1.4  pW/√Hz, although, after accounting for the reinjection losses, we estimate that this corresponds to only ∼1  fW/√Hz being coupled to the QCL active region.

Detection sensitivity of laser feedback interferometry using a terahertz quantum cascade laser.

We demonstrate a significant enhancement in the sensitivity of split ring resonator terahertz metamaterial dielectric sensors by the introduction of etched trenches into their inductive-capacitive gap area, both through finite element simulations and in experiments performed using terahertz time-domain spectroscopy. The enhanced sensitivity is demonstrated by observation of an increased frequency shift in response to overlaid dielectric material of thicknesses up to 18 µm deposited on to the sensor surface. We show that sensitivity to the dielectric is enhanced by a factor of up to ∼2.7 times by the incorporation of locally etched trenches with a depth of ∼3.4 µm, for example, and discuss the effect of the etching on the electrical properties of the sensors. Our experimental findings are in good agreement with simulations of the sensors obtained using finite element methods.

Increasing the sensitivity of terahertz split ring resonator metamaterials for dielectric sensing by localized substrate etching.

We report on the development of a large-area photoconductive THz array structure with an LT-GaAs active region fabricated on quartz substrates using a BCB bonding process. These are shown to generate high THz-fields greater than 100kV/cm, with a bandwidth greater than 6 THz.

2019 44th International Conference on Infrared, Millimeter, and Terahertz Waves (IRMMW-THz)

A Lightwave Energy-Efficient Datacenter (LEED) is described that consists of: 1) A novel optically-switched datacenter architecture, 2) a "Rotor" optical switch that can reconfigure a network topology in less than 20 microseconds, and 3) Enhanced link margin burst-mode interconnects that can accommodate an optical switch without the need for optical amplification.

2019 Optical Fiber Communications Conference and Exhibition (OFC)

Ultrafast switch-on dynamics of frequency-tuneable semiconductor lasers

Author Correction: Ultrafast switch-on dynamics of frequency-tuneable semiconductor lasers

The mechanism for electromagnetic (EM) mode transition and filtering in an asymptotically single-HE11-mode hollow THz Bragg fibre is investigated. We designed, fabricated, and measured Bragg fibres with an asymptotically single-mode pattern, achieving measured signal propagation loss of better than 3 dB m−1 at 0.265 THz and with an operating frequency range from 0.246 to 0.276 THz. Mode transition and filtering effects are both verified by 3D full-wave simulations using measured material properties, with geometrical parameters extracted from the fabricated Bragg fibre prototypes. By optimizing the coupling efficiency between the free-space Gaussian beam and the guided Bessel function mode, the optimum distance of mode transition from the Gaussian-beam excitation into the guided mode is calculated to be ~13.7 free-space wavelengths in our fibre, to ensure fast EM-field convergence to the desired asymptotically single-mode mode pattern in the Bragg fibre. After this mode transition region, the electric field amplitude ratio between the desired HE11 mode and the main competing HE12 mode is approximately 7 times, with the HE12 mode attenuation being more than 10 dB m−1 larger than the fundamental HE11 mode; the results indicate that our fibre is one of the best candidates for low-loss asymptotically single-mode terahertz signal interconnections.

Investigation of electromagnetic mode transition and filtering of an asymptotically single-mode hollow THz Bragg fibre

A new bellows free compact vacuum interrupter has been developed which can interrupt fault current with an accuracy of 39 us, without commutation by thyristor. The system has been tested at fault currents of up to 9 kA and is designed to be retrofitable onto low-voltage AC networks. The low latency and high precision of the point-on-wave system permits opening the breaker close to current zero, thereby substantially reducing contact erosion, and extending the vacuum lifetime. During a chaotic fault with a reduced confidence prediction of current zero, custom designed tungsten-carbide radial magnetic flux and axial magnetic flux contacts have been tested to control the vacuum arc until the first current zero, without reignition.

2018 28th International Symposium on Discharges and Electrical Insulation in Vacuum (ISDEIV)

Effect of FePd alloy composition on the dynamics of artificial spin ice

Tapered coplanar waveguides with integrated photoconductors were designed, fabricated, and measured, with pulsed transmission results comparing well with High Frequency Structure Simulator simulations which predict increased confinement and electric field concentration in the tapered region. Devices made with titanium/gold metallisation were used to demonstrate transmission and confinement, while the magnetoresistive properties of devices with cobalt/copper multilayers were used to demonstrate the field concentration. In the latter case, a mathematical framework was developed to understand the relationship between tapering effects and the picosecond magnetoresistance response.

Confinement of picosecond timescale current pulses by tapered coplanar waveguides

We present a novel design of low-loss single-mode flat hollow photonic crystal integrated waveguide (HPCIW). The simulated propagation loss is below 1 dB/cm over the operating frequency range between 0.92 THz and 1.06 THz, with a representative loss of 0.8 dB/cm at 1 THz. Compared with substrate integrated waveguide (SIW) and photonic crystal waveguide, the proposed HPCIW requires no via and can be integrated vertically, which make the HPCIW a promising candidate for multilayer THz system in package (TSiP) applications.

2018 43rd International Conference on Infrared, Millimeter, and Terahertz Waves (IRMMW-THz)

Modelling and Study of a THz Hollow Photonic Crystal Integrated Waveguide

Dependence of switch-on time on Vernier comb alignment in frequency tunable lasers

In this paper, the design and measurement of a three-dimensional-printed low-loss asymptotically single-mode hollow-core terahertz Bragg fiber are reported, operating across the frequency range from 0.246 to 0.276 THz. The HE11 mode is employed as it is the lowest loss propagating mode, with the electromagnetic field concentrated within the air core as a result of the photonic crystal bandgap behavior. The HE11 mode also has large loss discrimination compared to its main competing HE12 mode. This results in asymptotically single-mode operation of the Bragg fiber, which is verified by extensive simulations based on the actual fabricated Bragg fiber dimensions and measured material parameters. The measured average propagation loss of the Bragg fiber is lower than 5 dB/m over the frequency range from 0.246 to 0.276 THz, which is, to the best of our knowledge, the lowest loss asymptotically single-mode all-dielectric microstructured fiber yet reported in this frequency range, with a minimum loss of 3 dB/m at 0.265 THz.

Low-Loss Asymptotically Single-Mode THz Bragg Fiber Fabricated by Digital Light Processing Rapid Prototyping

We report on large-area photoconductive THz emitters and detectors with an LT-GaAs active region fabricated on quartz substrates using a lift-off transfer process. These devices are compared to the same LT-GaAs emitters when fabricated on the growth substrate. We find that the transferred devices show higher optical-to-THz conversion efficiencies and significantly larger breakdown fields.

2017 42nd International Conference on Infrared, Millimeter, and Terahertz Waves (IRMMW-THz)

Investigation into free-space terahertz radiation from a LT-GaAs-on-quartz photoconductive emitter

This dataset includes ASCII data for all figures described in the paper entitled ‘On-chip Terahertz Frequency Measurements of Liquids’,and the HFSS device model used to simulate the device properties.

Dataset relating to ‘On-chip Terahertz Frequency Measurements of Liquids’

Artificial spin ices (ASI) are arrays of single domain nano-magnetic islands, arranged in geometries that give rise to frustrated magnetostatic interactions. It is possible to reach their ground state via thermal annealing. We have made square ASI using different FePd alloys to vary the magnetization via co-sputtering. From a polarized state the samples were incrementally heated and we measured the vertex population as a function of temperature using magnetic force microscopy. For the higher magnetization FePd sample, we report an onset of dynamics at $T = 493$ K, with a rapid collapse into $>90\%$ ground state vertices. In contrast, the low magnetization sample started to fluctuate at lower temperatures, $T = 393$ K and over a wider temperature range but only reached a maximum of $25\%$ of ground state vertices. These results indicate that the interaction strength, dynamic temperature range and pathways can be finely tuned using a simple co-sputtering process. In addition we have compared our experimental values of the blocking temperature to those predicted using the simple N\'{e}el-Brown two-state model and find a large discrepancy which we attribute to activation volumes much smaller than the island volume.

Data associated with 'Effect of FePd alloy composition on the dynamics of artificial spin ice'

THz coplanar waveguides were fabricated on quartz wafers with integrated epitaxially transferred low temperature grown gallium arsenide photoconductive switches. THz radiation was excited on-chip and transmitted through a tapering of the coplanar waveguide structure where it was focused down to ∼ 1.66μm. Theoretical modelling of the device confirms high E-field confinement and concentration.

Tapered THz coplanar waveguides (CPWs) formed from Co/Cu multilayers with embedded low-temperature-grown gallium arsenide photoconductive switches were designed in order to observe giant magnetoresistance (GMR). Pulsed THz radiation was excited using the switches, and was transmitted through both straight and tapered CPWs. GMR-induced changes in the transmitted THz pulse amplitude were demonstrated.

K. W. Goossen, G. D. Boyd, J. E. Cunningham, W.Y. Jan, D. A. B. Miller, D. S. Chemla and R. M. Lum, “GaAs-AlGaAs Multiquantum Well Reflection Modu lators Grown on GaAs and Silicon Substrates' in IEEE Photon. Tech. Lett, vol. 1, p. 304, 1989. P. Barnes, P. Zouganeli, A. Rivers, M. Whitehead, G. Parry, K. Woodbridge, and C. Roberts, "GaAs/Al GaAs Multiple Quantum Well Optical Modulator Using Multilayer reflector Stack Grown on Si Sub strate' in Electron. Letti, vol. 25, p. 995, 1989. P. Barnes, K. Woodbridge, C. Roberts, A. A. Stride, A. Rivers, M. Whitehead, and G. Parry, “GaAs multiple quantum well microresonator modulators grown on |I|||||||||||||||| US005385632A

United States Patent ( 19 ) Goossen 54 METHOD FOR MANUFACTURING INTEGRATED SEMICONDUCTOR DEVICES

Science and technologies based on terahertz frequency electromagnetic radiation (100 GHz–30 THz) have developed rapidly over the last 30 years. For most of the 20th Century, terahertz radiation, then referred to as sub-millimeter wave or far-infrared radiation, was mainly utilized by astronomers and some spectroscopists. Following the development of laser based terahertz time-domain spectroscopy in the 1980s and 1990s the field of THz science and technology expanded rapidly, to the extent that it now touches many areas from fundamental science to ‘real world’ applications. For example THz radiation is being used to optimize materials for new solar cells, and may also be a key technology for the next generation of airport security scanners. While the field was emerging it was possible to keep track of all new developments, however now the field has grown so much that it is increasingly difficult to follow the diverse range of new discoveries and applications that are appearing. At this point in time, when the field of THz science and technology is moving from an emerging to a more established and interdisciplinary field, it is apt to present a roadmap to help identify the breadth and future directions of the field. The aim of this roadmap is to present a snapshot of the present state of THz science and technology in 2017, and provide an opinion on the challenges and opportunities that the future holds. To be able to achieve this aim, we have invited a group of international experts to write 18 sections that cover most of the key areas of THz science and technology. We hope that The 2017 Roadmap on THz science and technology will prove to be a useful resource by providing a wide ranging introduction to the capabilities of THz radiation for those outside or just entering the field as well as providing perspective and breadth for those who are well established. We also feel that this review should serve as a useful guide for government and funding agencies.

The high-performance server compute landscape is changing. The traditional model of building general-purpose enterprise compute boxes that end-users can configure with storage and networking to assemble their desired compute environments, has evolved to purpose-built systems optimized for specific applications. This tight integration of hardware and software components together with high-density midboard optical modules and an optical backplane allows for unprecedented levels of switching and compute efficiencies and has fueled the penetration of optical interconnects deep “inside the box,” particularly for switch scale-up. We briefly review earlier 40 G/port switching systems based on active optical cables, and present our newest system: An all-optically-interconnected 100 G/port 8.2 Tb/s InfiniBand packet switch ASIC with 41 ports running 100 Gb/s per port interconnected by 12-channel midboard optical transceivers with 25 Gb/s per channel per direction of optical I/O. Using a blind-mate optical backplane, these components enable systems with up to 50 Tb/s bandwidth in a 2U standard rack mount configuration with industry-leading density, efficiency, and latency. For even tighter co-integration of optical interconnects with switch and processor ASICs, we discuss photonic multichip module and interposer packaging technologies that will further improve system energy efficiencies and overcome impending system I/O bottlenecks.

This paper demonstrates a novel design technique for single-TE01-mode Bragg fiber using a second-order bandgap achieving signal propagation loss less than 1.2 dB/m from 0.85 THz to 1.15 THz. The TE01 mode intrinsically has a null point in the electric field close to the interface region between the core and the cladding. This makes the TE01 mode preferable to other modes since it shows low signal propagation loss and low electromagnetic interference from cladding defects. Bragg iîber can exhibit a strong mode selectivity as a result of modal-iîltering effects. A large loss discrimination between the desired TE01 mode and competing modes can be designed by appropriately tailoring the photonic bandgap.

2017 10th UK-Europe-China Workshop on Millimetre Waves and Terahertz Technologies (UCMMT)

High-order operating mode selection using second-order bandgap in THz Bragg fiber

We demonstrate quasi-continuous tuning of the emission frequency from coupled cavity terahertz frequency quantum cascade lasers. Such coupled cavity lasers comprise a lasing cavity and a tuning cavity which are optically coupled through a narrow air slit and are operated above and below the lasing threshold current, respectively. The emission frequency of these devices is determined by the Vernier resonance of longitudinal modes in the lasing and the tuning cavities, and can be tuned by applying an index perturbation in the tuning cavity. The spectral coverage of the coupled cavity devices have been increased by reducing the repetition frequency of the Vernier resonance and increasing the ratio of the free spectral ranges of the two cavities. A continuous tuning of the coupled cavity modes has been realized through an index perturbation of the lasing cavity itself by using wide electrical heating pulses at the tuning cavity and exploiting thermal conduction through the monolithic substrate. Single mode emission and discrete frequency tuning over a bandwidth of 100 GHz and a quasi-continuous frequency coverage of 7 GHz at 2.25 THz is demonstrated. An improvement in the side mode suppression and a continuous spectral coverage of 3 GHz is achieved without any degradation of output power by integrating a π-phase shifted photonic lattice in the laser cavity.

Quasi-continuous frequency tunable terahertz quantum cascade lasers with coupled cavity and integrated photonic lattice.

A new method allowing the extraction of both the thickness and complex refractive index of a sample simultaneously is demonstrated; the technique uses a time-segmented transfer function and model. Results are compared to an existing method of extraction.

Time-frequency extraction of sample thickness and spectroscopic parameters using THz TDS

Terahertz-frequency-range measurements can offer potential insight into the picosecond dynamics, and therefore function, of many chemical systems. There is a need to develop technologies capable of performing such measurements in aqueous and polar environments, particularly when it is necessary to maintain the full functionality of biological samples. In this study, we present a proof-of-concept technology comprising an on-chip planar Goubau line, integrated with a microfluidic channel, which is capable of low-loss, terahertz-frequency-range spectroscopic measurements of liquids. We also introduce a mathematical model that accounts for changes in the electric field distribution around the waveguide, allowing accurate, frequency-dependent liquid parameters to be extracted. We demonstrate the sensitivity of this technique by measuring a homologous alcohol series across the 0.1-0.8 THz frequency range.

We present a novel reconfigurable comb laser design that enables channel sparing, and demonstrate its functionality in a III-V/Si external cavity configuration. The laser is comprised of a single shared tunable Si ring mirror Vernier-paired with an array of tunable channel ring filters each coupled to their respective reflective semiconductor optical amplifier. This comb laser is not only tunable, capable of shifting all comb lines together, but it is flexible, able to change the spacing of channels in the comb within a fixed grid defined by the ring mirror. This flexibility results in features not previously demonstrated in a comb, such as mixed channel spacing and channel sparing capability. This is a practical candidate for flexible, scalable wavelength division multiplexed links targeting the next generation of data centers for the cloud.

The Development of a Semtex-H Simulant for Terahertz Spectroscopy

Precise temperature-control is necessary for many spectroscopic measurements. We present the temperature-dependent complex THz refractive index of liquid samples measured in a flowcell, analysed by a numerical method that allows simultaneous extraction of the sample's thickness to verify the temperature-stability of the cell.

THz-TDS of liquids in a temperature-controlled transmission flowcell

We present a real-time approach for stabilizing a III-V/Si hybrid external-cavity laser implemented using microring monitoring and a feedback control loop. Laser mode stabilization over bias current and stage temperature variations are experimentally demonstrated. We achieved single-mode and mode-hop-free laser operation as the bias current was swept across 320 mA. The same feedback control also enabled wavelength-locked laser operation using an intracavity phase control. The feedback control was also applied to an integrated on-chip hybrid laser, and mode-hop-free laser operation was demonstrated over 23 °C substrate temperature variation.

III-V/Si Hybrid Laser Stabilization Using Micro-Ring Feedback Control

We demonstrate a low back reflection grating coupler on a SOI CMOS-compatible process designed for vertical integration of on-chip laser sources. It showed <;-26dB back reflection and 1.9dB coupling loss to a 4μm-diameter laser mode.

2016 Optical Fiber Communications Conference and Exhibition (OFC)

A CMOS-compatible low back reflection grating coupler for on-chip laser sources integration

The server compute landscape is changing. The traditional model of building general-purpose enterprise compute boxes, that end-users can use in various combinations with storage and networking to assemble their desired compute environments, has evolved to purpose-built systems optimized for specific applications. This tight integration of hardware and software components allows for unprecedented levels of switching and compute efficiencies and has fueled the penetration of optical interconnects deep "inside the box", particularly for switch scale-up. We present an 8.2Tb/s Infiniband packet switch with 41 ports running 100Gb/s per port interconnected by 12-channel mid-board optical transceivers with 25Gb/s per channel per direction of optical I/O. These components enable systems with up to 49Tb/s bandwidth in a 2U standard rack mount configuration.

From chip to cloud: Optical interconnects in engineered systems for the enterprise

We report on large-area photoconductive terahertz (THz) emitters with a low-temperature-grown GaAs (LT-GaAs) active layer fabricated on quartz substrates using a lift-off transfer process. These devices are compared to the same LT-GaAs emitters when fabricated on the growth substrate. We find that the transferred devices show higher optical-to-THz conversion efficiencies and significantly larger breakdown fields, which we attribute to reduced parasitic current in the substrate. Through these improvements, we demonstrate a factor of ~8 increase in emitted THz field strength at the maximum operating voltage. In addition we find improved performance when these devices are used for photoconductive detection, which we explain through a combination of reduced parasitic substrate currents and reduced space-charge build-up in the device.

Free-space terahertz radiation from a LT-GaAs-on-quartz large-area photoconductive emitter.

Plasmons in two-dimensional systems find applications in terahertz oscillators, detectors, filters, plasmonic crystals, etc. Numerous approaches to modeling plasmonic spectra exists, but little work has been done to compare results from theoretical calculations with each other, and so to understand their limitations. Using three different techniques (full-wave simulations, mode matching, and trasmission-line model), we analyse here a realistic structure comprising three coupled plasmonic resonators. While the results of all three models offer qualitatively similar results, revealing a rich spectrum of coupled modes, the values of the predicted resonant frequencies differ between the models. The best agreement is found between full-wave simulations and mode matching, both of which are based on rigorous solution of Maxwell's equations.

2016 41st International Conference on Infrared, Millimeter, and Terahertz waves (IRMMW-THz)

Generation of Terahertz Radiation from Fe-doped InGaAsP Using 800 nm to 1550 nm Pulsed Laser Excitation

We present a novel 3.3-μm radius ring modulator design with dramatically reduced resonance wavelength variations. By implementing a multi-mode waveguide design for the ring waveguides, phase errors from processing non-idealities in waveguide width and etching depth are significantly reduced. Measured resonance wavelengths from four 200-mm wafers fabricated in a commercial 130-nm CMOS foundry showed a total of ~5-nm peak-to-peak variation, which is only about 1/6 of the free spectral range of the ring design. With this tighter control over the absolute resonance positions, the tuning range and tuning power requirements of the ring modulators can be significantly reduced, which in turn enhances their functionality for applications in high density, energy-efficient high-performance computing systems.

A Process-Tolerant Ring Modulator Based on Multi-Mode Waveguides

A wafer-level, batch-fabricated, mechanically flexible interconnect (MFI) with a contact tip has been developed for rematable heterogeneous system integration. The contact tip, which exhibits a truncated-cone profile, enhances the scrubbing capability while maintaining the tip lifetime by avoiding tip plastic deformation. Electrical and mechanical characterization has been conducted on various testbeds to verify the performance of the assembled chip links with MFIs. The results indicate that a single MFI has an average electrical resistance of 103.21 mQ and up to 1 A current carrying capability, and can be successfully assembled on nonplanar surfaces with up to 45-μm surface variation.

IEEE Transactions on Components, Packaging and Manufacturing Technology

Mechanically Flexible Interconnects With Contact Tip for Rematable Heterogeneous System Integration

We demonstrate the first 200 GHz III-V/Si hybrid tunable, individually addressable four channel comb laser defined by a single shared tunable Si ring mirror, Vernier-paired with four rings filters using <; 2.5 mW per channel.

We investigate the use of an on-chip terahertz (THz) frequency sensor formed on a flexible, thin-film polyimide substrate to measure the properties of liquids encapsulated in a glass-walled capillary. We observe changes in the attenuation and velocity of the time-domain THz signal, which allows extraction of the broadband THz refractive index and relative attenuation coefficients of the liquid. The technique is used for sensing members of a homologous series of primary alcohols, and the results compared with those obtained from a free-space terahertz frequency time-domain spectroscopy system.

Integrated On-Chip THz Sensors for Fluidic Systems Fabricated Using Flexible Polyimide Films

We report a compact laser on-chip module that is hybrid integrated with photonic circuits. Arrays of III-V MQW lasers were flip-chip bonded onto an SOI interposer along with micro-machined mirrors for optical coupling into a dedicated grating coupler array. This is a new wafer-scale opto-electronic integration platform enabling photonic links with built-in high efficiency light sources.

2016 IEEE 66th Electronic Components and Technology Conference (ECTC)

We report a silicon interposer based 1×4 external-cavity hybrid III-V/Si laser array using a manufacturable back-end-of-the-line integration. All channels are individually-tunable and wavelength-stabilized with a threshold current of 14mA, output powers of >3mW, over 35dB side mode suppression ratio and less then 46kHz linewidth.

2016 IEEE 13th International Conference on Group IV Photonics (GFP)

Manufacturable hybrid silicon array laser source using an interposer based back-end-of-the-line integration

We demonstrated wavelength locking for a high speed ring modulator using a low-power integrated balanced homodyne CMOS controller. Locking for wavelength change of 4 nm and substrate temperature change of 40°C was achieved.

Wavelength locked high-speed microring modulator using an integrated balanced homodyne CMOS control circuit

We present a method of calculating the measurement variance-covariance matrix of a spectroscopic sample's complex refractive index from time-domain statistics in order to estimate uncertainty of a measurement. We compare this method to a numerical analysis and previously derived methodology, and show that our time-based estimate is both accurate and adaptable to complex extraction models.

Estimation of spectroscopic uncertainty and correlation in terahertz time domain spectroscopy

We demonstrate the generation of continuous wave terahertz (THz) frequency radiation from photomixers fabricated on both Fe-doped InGaAs and Fe-doped InGaAsP, grown by metal-organic chemical vapor deposition. The photomixers were excited using a pair of distributed Bragg reflector lasers with emission around 1550 nm, and THz radiation was emitted over a bandwidth of greater than 2.4 THz. Two InGaAs and four InGaAsP wafers with different Fe doping concentrations were investigated, with the InGaAsmaterial found to outperform the InGaAsP in terms of emitted THz power. The dependencies of the emitted power on the photomixer applied bias, incident laser power, and materialdoping level were also studied.

Generation of continuous wave terahertz frequency radiation from metal-organic chemical vapour deposition grown Fe-doped InGaAs and InGaAsP

We have investigated terahertz (THz) frequency magnetoplasmon resonances in a two-dimensional electron system through the direct injection of picosecond duration current pulses. The evolution of the time-domain signals was measured as a function of magnetic field, and the results were found to be in agreement with calculations using a mode-matching approach for four modes observed in the frequency range above 0.1 THz. This introduces a generic technique suitable for sampling ultrafast carrier dynamics in low-dimensional semiconductor nanostructures at THz frequencies.

Time-domain measurement of terahertz frequency magnetoplasmon resonances in a two-dimensional electron system by the direct injection of picosecond pulsed currents

We report the first closed-loop operation of a 100 Gbps polarization-insensitive, 4-channel wavelength-tracking WDM receiver in silicon photonics platform. Error-free operation is achieved with input polarization scrambling over input wavelength change of 4.5 nm using efficient thermal tuning of Si microring demux, corresponding to greater than 60°C fluctuation in temperature.

Error-free operation of a polarization-insensitive 4λ x 25 Gbps silicon photonic WDM receiver with closed-loop thermal stabilization of Si microrings.

The development and use of terahertz-frequency (THz) spectroscopy systems for security screening has shown an increased growth over the past 15 years. In order to test these systems in real world situations, safe simulants of illicit materials are required, particularly of explosives. Ideally simulants should mimic key features of the material of interest, such that it at least resembles or even appears indistinguishable from the material of interest to the interrogating technique(s), whilst not having hazardous or illicit properties. Ideally, simulants should: have similar physical properties such as malleability, density, surface energy, volatility etc; be non-toxic; be easy to clean and decontaminate from surfaces; be recyclable or disposable; and, be useable in a public environment. A THz explosive simulant would require spectral features at similar frequencies to those in a common explosive, in this instance Semtex-H, but would be safe to handle and be non-explosive. Here, we present a method for developing such a simulant based on a database of THz spectra of common organic molecules, and the use of a genetic algorithm to select a mixture of compounds automatically to form such a simulant. We propose four mixtures that could then be used to test the response of any instrument, working at terahertz frequencies, without the need for an explosive substance.

Data associated with 'Design and Development of a Semtex Simulant Suitable for Measurements at THz Frequencies Using a Genetic Algorithm'

We demonstrate a surface-normal coupled tunable hybrid silicon laser array for the first time using passively-aligned, high-accuracy flip chip bonding. A 2x6 III-V reflective semiconductor optical amplifier (RSOA) array with integrated total internal reflection mirrors is bonded to a CMOS SOI chip with grating couplers and silicon ring reflectors to form a tunable hybrid external-cavity laser array. Waveguide-coupled wall plug efficiency (wcWPE) of 2% and output power of 3 mW has been achieved for all 12 lasers. We further improved the performance by reducing the thickness of metal/dielectric stacks and achieved 10mW output power and 5% wcWPE with the same integration techniques. This non-invasive, one-step back end of the line (BEOL) integration approach provides a promising solution to high density laser sources for future large-scale photonic integrated circuits.

Efficient, tunable flip-chip-integrated III-V/Si hybrid external-cavity laser array.

We demonstrate the monolithic integration of AlGaAs/GaAs 2DEGs with short carrier lifetime photoconductive LT-GaAs, allowing the investigation of THz frequency range magnetoplasmon resonances by the direct injection of ~picosecond duration pulses through the system. The evolution of time domain signals with magnetic field were measured, and the results found to be in good agreement with theoretical calculations made using a mode-matching approach for frequencies above 0.1 THz. Our experimental work introduces a generic technique suitable for the study of ultrafast carrier dynamics in low-dimensional semiconductor nanostructures at THz frequencies.

Dataset relating to 'Time domain measurement of terahertz magnetoplasmon resonance in a two-dimensional electron system through direct pulse injection'

In terahertz spectroscopy, multi-layered samples often need to be measured, for instance in a liquid flow cell, and this complicates the extraction of material parameters. We present a spectroscopic parameter extraction algorithm for multilayer samples that can also be used to extract the thickness of an unknown sample layer.

Multilayer extraction of complex refractive index in broadband transmission terahertz time-domain spectroscopy

Stable mode-hop-free operation for a Si/III-V hybrid external-cavity laser was demonstrated during 320mA bias current sweep using a real-time ring monitoring, a fast feedback control loop, and a simple bang-bang control algorithm, by both tunable micro-ring filter and cavity phase section.

Si/III-V hybrid external-cavity laser stabilization using real-time micro-ring monitoring and feedback control

A 1550nm external-cavity hybrid III-V/SOI laser with a room-temperature threshold current of 18mA and output powers up to 4mW was demonstrated with a novel assembly technique. An edge-coupled 1×6 laser array was passively aligned with sub-micron positional tolerance.

Alignment and integration of a hybrid, external-cavity InP-SOI laser

This dataset contains experimental data presented in the paper titled 'Generation of continuous wave terahertz frequency radiation from MOCVD grown Fe-doped InGaAs and InGaAsP'. The IV characteristics, THz signal amplitudes, bias and optical power dependence of the different InGaAs and InGaAsP wafers are given.

Generation of continuous wave terahertz frequency radiation from MOCVD grown Fe-doped InGaAs and InGaAsP

We introduce a method for estimating the permittivity of liquid samples measured using integrated microfluidic/planar Goubau line terahertz waveguides, in which simulation results are combined with practical data to enable more accurate frequency-dependent analysis.

Accurate parameter extraction from liquids measured using on-chip terahertz spectroscopy

Creating arrays of efficient optical sources to enable dense integration of silicon photonic transceivers with silicon very large-scale integration circuits remains a challenge. We review manufacturing strategies and challenges for back-end-of-line integration of tunable, external-cavity lasers using edge-coupled and surface-normal-coupled integration approaches showing that such laser arrays can be manufactured with a fab-less model. We demonstrate, for the first time, hybrid laser arrays using both integration approaches highlighting performance and design differences. We also discuss challenges and opportunities for each method and present experimental techniques to reduce alignment tolerance and improve laser stability and mode control.

III-V/Si Hybrid Laser Arrays Using Back End of the Line (BEOL) Integration

A Si/III-V hybrid laser has been a highly sought after device for energy-efficient and cost-effective high-speed silicon photonics communication. We present a high wall-plug efficiency external-cavity hybrid laser created by integrating an independently optimized SOI ring reflector and a III-V gain chip. In our demonstration, the uncooled integrated laser achieved a waveguide-coupled wall-plug efficiency of 12.2% at room temperature with an optical output power of ~10 mW. The laser operated single-mode near 1550 nm with a linewidth of 0.22 pm. This is a tunable light source with 8 nm wavelength tuning range. A proof-of-concept laser wavelength stabilization technique has also been demonstrated. Using a simple feedback loop, we achieved mode-hop-free operation in a packaged external-cavity hybrid laser as bias current was varied by 60mA.

Demonstration of 12.2% wall plug efficiency in uncooled single mode external-cavity tunable Si/III-V hybrid laser.

We present a design study of an all-polymer low loss single-mode hollow-core photonic crystal (HCPC) terahertz (THz) waveguide with dielectric bridges used as mechanical supports. By exploiting a modal-filtering effect and Brewster phenomenon, we maximize the loss discrimination between the fundamental and other higher order modes resulting in an effectively single-mode operation, though the HCPC THz waveguide is ostensibly multi-mode. Owing to the use of support bridges, which increase the propagation loss, the non-ideal HCPC THz waveguide has higher loss than an ideal one. Nonetheless, the propagation loss of the fundamental HE11 mode can still be minimized, to lower than 5 dB/m over the frequency range from 0.75 to 1.1 THz. In addition, the group velocity dispersion of the HE11 mode is less than -0.5 ps/THz/cm.

2015 40th International Conference on Infrared, Millimeter, and Terahertz waves (IRMMW-THz)

Design study of low loss single-mode hollow core photonic crystal terahertz waveguide with support bridges

We demonstrate the excitation and electrostatic modulation of a planar, resonant plasmonic circuit, comprised of a two-dimensional electron system (2DES) integrated into three different on-chip, terahertz-frequency coplanar waveguides. We utilise a Schottky gate formed across the 2DES in one device to create a resonant cavity in which the carrier concentration, and therefore the cavity resonant frequency, can be tuned by application of a negative DC gate bias, or using an external magnetic field. Using this technique, we demonstrate tuneable plasmon and magnetoplasmon generation and detection at frequencies up to ~ 400 GHz, by injection of terahertz pulses into the 2DES from the waveguide region.

We demonstrate how a transfer function model based parameter extraction method, combined with total variance analysis, allows the extraction of both the complex refractive index and the thickness of a sample over a bandwidth of >6 THz from THz time-domain spectroscopy measurements. We discuss how the techniques developed have been applied to absorbent powders measured at variable low temperatures.

Accurate material parameter extraction from broadband terahertz spectroscopy

Generation of Terahertz Radiation from Fe-doped InGaAsP Using 800 nm to 1550 nm Pulsed Laser Excitation

We propose a method of pinning and propagating domain walls in artificial multiferroic nanowires using electrically induced surface acoustic waves. Using finite-element micromagnetic simulations and 1D semi-analytical modelling, we demonstrate how a pair of interdigitated acoustic transducers can remotely induce an array of attractive domain wall pinning sites by forming a standing stress/strain wave along a nanowire's length. Shifts in the frequencies of the surface acoustic waves allow multiple domain walls to be synchronously transported at speeds up to 50 ms−1. Our study lays the foundation for energy-efficient domain wall devices that exploit the low propagation losses of surface acoustic waves to precisely manipulate large numbers of data bits.

A sound idea: Manipulating domain walls in magnetic nanowires using surface acoustic waves

Excitation, detection, and electrostatic manipulation of terahertz-frequency range plasmons in a two-dimensional electron system

We demonstrate the integration of vertical-cavity surface-emitting lasers (VCSELs) with silicon photonics chip using flip-chip bonding technique, with bidirectional vertical-coupled grating coupler for light coupling.

Vertical-cavity surface-emitting laser flip-chip bonding to silicon photonics chip

We describe a multiwavelength hybrid-integrated solid-state link on a 3 µm silicon-on-insulator (SOI) nanophotonic platform. The link spans three chips and employs germanium-silicon electroabsorption waveguide modulators, silicon transport waveguides, echelle gratings for multiplexing and demultiplexing, and pure germanium waveguide photo-detectors. The 8λ WDM Tx and Rx components are interconnected via a routing "bridge" chip using edge-coupled optical proximity communication. The packaged, retimed digital WDM link is demonstrated at 10 Gb/s and 10(-12) BER, with three wavelength channels consuming an on-chip power below 1.5 pJ/bit, excluding the external laser power.

An all-solid-state, WDM silicon photonic digital link for chip-to-chip communications.

In this work we report on a packaged prototype of a WDM photonic transceiver. It is a hybrid assembly based on a 130 nm SOI photonic circuitry integrated with a 40 nm CMOS VLSI driver. Our prototype supports eight tunable WDM channels operating at 10 Gb/s each capable of both transmitting and receiving data on the same chip. We discuss two options to close the link while using the optical fiber or another waveguide bridge chip. We provide hybridization details and supporting link measurement data to describe packaged photonic module and its power efficient functionality as its on-chip power per channel averaged 1.3pJ/bit, laser electrical power excluded.

2015 IEEE 65th Electronic Components and Technology Conference (ECTC)

Advances in theory are needed to match recent progress in measurements of coupled semiconductor resonators supporting terahertz plasmons. Here, we present a field-based model of plasmonic resonators that comprise gated and ungated two-dimensional electron systems. The model is compared to experimental measurements of a representative system, in which the interaction between the gated and ungated modes leads to a rich spectrum of hybridized resonances. A theoretical framework is thus established for the analysis and design of gated low-dimensional systems used as plasmonic resonators, underlining their potential application in the manipulation of terahertz frequency range signals.

Terahertz plasmons in coupled two-dimensional semiconductor resonators

We report on the use of graphene for room temperature on-chip detection and generation of pulsed terahertz (THz) frequency radiation, exploiting the fast carrier dynamics of light-generated hot carriers, and compare our results with conventional low-temperature-grown gallium arsenide (LT-GaAs) photoconductive (PC) switches. Coupling of picosecond-duration pulses from a biased graphene PC switch into Goubau line waveguides is also demonstrated. A Drude transport model based on the transient photoconductance of graphene is used to describe the mechanism for both detection and generation of THz radiation.

On-Chip Picosecond Pulse Detection and Generation Using Graphene Photoconductive Switches

We present an on-chip time domain terahertz (TD-THz) system in which picosecond pulses are generated in low-temperature-grown gallium arsenide (LT-GaAs) and detected in graphene. The detected pulses were found to vary in amplitude, full width at half maximum (FWHM), and DC offset when sampled optically at different locations along a 50-μm-long graphene photoconductive (PC) detector. The results demonstrate the importance of detection location and switch design in graphene-based on-chip PC detectors.

Spatially resolved on-chip picosecond pulse detection using graphene

We present the packaging of a large multi-chip energy-efficient WDM silicon photonic interconnect prototype enabled by hybrid integration, high-accuracy optical alignment and thermal-mechanical aware design and assembly.

Hybrid integration and packaging of an energy-efficient WDM silicon photonic chip-to-chip interconnect

We demonstrate an external-cavity Si/III-V hybrid laser with a waveguide-coupled wall-plug efficiency of 12.2% at room temperature. The laser operates single-mode in C-band with a linewidth of 0.22 pm and is capable of wavelength tuning.

12.2% waveguide-coupled wall plug efficiency in single mode external-cavity tunable Si/III–V hybrid laser

We report on a packaged prototype of a WDM photonic transceiver. It is an all-solid state hybrid assembly based on 130nm SOI photonic circuitry integrated with a 40nm CMOS VLSI driver. Our prototype supports eight tunable WDM channels operating at 10Gb/s, each capable of both transmitting and receiving data on the same chip. We discuss two options to close the link using the optical fiber or a waveguide bridge chip. We provide integration details and supporting link measurement data to describe packaged photonic module and its power efficient functionality with its on-chip power per channel averaging 1.3pJ/bit, excluding off-chip laser electrical power.

We demonstrate the integration of planar Goubau lines with microfluidic systems for the measurement of liquid samples including water and isopropanol. Picosecond pulses are generated and detected by the inclusion of low-temperature-grown GaAs based photoconductive switches which transmit picosecond pulses along the transmission line. A change in the propagation velocity of pulses is detected and is used to estimate the permittivity of each liquid.

Development of planar Goubau line – microfluidic integrated devices for THz spectroscopy of liquid analytes

Terahertz-frequency quantum cascade lasers (THz QCLs) are compact solid-state sources of coherent radiation in the 1–5 THz region of the electromagnetic spectrum [1]. THz QCLs typically exhibit multiple longitudinal modes characteristic of Fabry–Perot cavities. However, widely-tunable (single-mode) THz QCLs would be ideally suited to many THz- applications, such as atmospheric observations [2], and security screening [3]. Here we demonstrate discrete Vernier tuning using a simple two-section coupled-cavity geometry comprising of a ‘lasing section’, which is electrically driven above the lasing threshold, and a ‘tuning section’, which is driven below threshold. Our THz QCLs, based on a bound-to- continuum design [4], were processed into 150-μm-wide single–metal waveguides with lengths 4.5–4.8 mm. Devices were etched after packaging using a focused ion beam milling system to sculpt a14-μm–wide and 12-μm-deep air gap to form the two-section cavity [Fig. 1 (a)]. Devices were cooled in a continuous-flow helium cryostat and emission spectra measured using a Fourier-transform infrared spectrometer. The tuning section of the laser was heated below threshold using a train of 10-μs-long current pulses at a repetition rate of 8.21 kHz. The lasing section was driven with a single 500-ns-long pulses above threshold. Both the pulse trains were trigerred using a 600-Hz reference frequency. Discrete tuning with a blue shift in frequency was observed over bandwidths of 50 and 85 GHz from two devices with mode spacing of 15 GHz and 30 GHz respectively [Fig. 1 (b, c)]. A red shift in frequency over 30 GHz was also observed in device 2 by simply swapping the function of the lasing and tuning sections [Fig. 1 (c) Inset]. Negligible degradation in output power was observed with tuning current. R. Kohler, A. Tredicucci, F. Beltram, H. E. Beere, E. H. Linfield, A. G. Davies, D. A. Ritchie, R. C. Iotti, and F. Rossi, "Terahertz semiconductor-heterostructure laser," Nature 417, 156–159 (2002). P. H. Siegel, "Terahertz technology," Microw. Theory Tech. IEEE Trans. On 50, 910 –928 (2002). A. G. Davies, A. D. Burnett, W. Fan, E. H. Linfield, and J. E. Cunningham, "Terahertz spectroscopy of explosives and drugs," Mater. Today 11, 18 – 26 (2008). S. Barbieri, J. Alton, H. E. Beere, J. Fowler, E. H. Linfield, and D. A. Ritchie, "2.9 THz quantum cascade lasers operating up to 70 K in continuous wave," Appl. Phys. Lett. 85, 1674–1676 (2004).

Discrete Vernier tuning with constant output power in terahertz quantum cascade lasers using coupled cavities

The effect of temperature on the terahertz-frequency-range material properties of lyophilized and single-crystal hen egg-white lysozyme has been measured using terahertz time-domain spectroscopy, with the results presented and discussed in the context of protein and solvent dynamical and glass transitions. Lyophilized hen egg-white lysozyme was measured over a temperature range from 4 to 290 K, and a change in the dynamical behaviour of the sample at around 100 K was observed through a change in the terahertz absorption spectrum. Additionally, the effect of cryoprotectants on the temperature-dependent absorption coefficient is studied, and it is demonstrated that terahertz time-domain spectroscopy is capable of resolving the true glass transition temperature of single-crystal hen egg-white lysozyme at ∼150 K, which is in agreement with literature values measured using differential scanning calorimetry.

Probing temperature- and solvent-dependent protein dynamics using terahertz time-domain spectroscopy

A highly efficient silicon (Si) hybrid external cavity laser with a wavelength tunable ring reflector is fabricated on a complementary metal-oxide semiconductor (CMOS)-compatible Si-on-insulator (SOI) platform and experimental results with high output power are demonstrated. A III-V semiconductor gain chip is edge-coupled into a SOI cavity chip through a SiN(x) spot size converter and Si grating couplers are incorporated to enable wafer-scale characterization. The laser output power reaches 20 mW and the highest wall-plug efficiency of 7.8% is measured at 17.3 mW in un-cooled condition. The laser wavelength tuning ranges are 8 nm for the single ring reflector cavity and 35 nm for the vernier ring reflector cavity, respectively. The Si hybrid laser is a promising light source for energy-efficient Si CMOS photonic links.

High power and widely tunable Si hybrid external-cavity laser for power efficient Si photonics WDM links.

We demonstrate the feasibility of using graphene as a conductive electrode for the generation and detection of surface acoustic waves at 100 s of MHz on a lithium niobate substrate. The graphene interdigitated transducers (IDTs) show sensitivity to doping and temperature, and the characteristics of the IDTs are discussed in the context of a lossy transmission line model.

Surface acoustic wave generation and detection using graphene interdigitated transducers on lithium niobate

We demonstrate the first germanium-silicon C-band electro-absorption based waveguide modulator array and echelle-grating-based silicon wavelength multiplexer integrated with a digital CMOS driver circuit. A 9-channel, 10Gbps SiGe electro-absorption wavelength-multiplexed modulator array consumed a power of 5.8mW per channel while being modulated at 10.25Gbps by 40nm CMOS drivers delivering peak-to-peak voltage swings of 2V, achieving a modulation energy-efficiency of ~570fJ/bit including drivers. Performance up to 25Gbps on a single-channel SiGe modulator and CMOS driver is also reported.

A low-power, high-speed, 9-channel germanium-silicon electro-absorption modulator array integrated with digital CMOS driver and wavelength multiplexer.

Discrete Vernier frequency tuning of terahertz quantum cascade lasers is demonstrated using a device comprising a two-section coupled-cavity. The two sections are separated by a narrow air gap, which is milled after device packaging using a focused ion beam. One section of the device (the lasing section) is electrically biased above threshold using a short current pulse, while the other section (the tuning section) is biased below threshold with a wider current pulse to achieve controlled localized electrical heating. The resulting thermally-induced shift in the longitudinal cavity modes of the tuning section is engineered to produce either a controllable blue shift or red shift of the emission frequency. This discrete Vernier frequency tuning far exceeds the tuning achievable from standard ridge lasers, and does not lead to any corresponding change in emitted power. Discrete tuning was observed over bandwidths of 50 and 85 GHz in a pair of devices, each using different design schemes. Interchanging the lasing and tuning sections of the same devices yielded red shifts of 20 and 30 GHz, respectively.

Discrete Vernier tuning in terahertz quantum cascade lasers using coupled cavities.

We have investigated experimentally the scaling behaviour of quantum Hall transitions in GaAs/AlGaAs heterostructures of a range of mobility, carrier concentration, and spacer layer width. All three critical scaling exponents γ, κ and p were determined independently for each sample. We measure the localization length exponent to be γ ≈ 2.3, in good agreement with expected predictions from scaling theory, but κ and p are found to possess non-universal values. Results obtained for κ range from κ = 0.16 ± 0.02 to κ = 0.67 ± 0.02, and are found to be Landau level (LL) dependent, whereas p is found to decrease with increasing sample mobility. Our results demonstrate the existence of two transport regimes in the LL conductivity peak; universality is found within the quantum coherent transport regime present in the tails of the conductivity peak, but is absent within the classical transport regime found close to the critical point at the centre of the conductivity peak. We explain these results using a percolation model and show that the critical scaling exponent depends on certain important length scales that correspond to the microscopic description of electron transport in the bulk of a two-dimensional electron system.

Non-universality of scaling exponents in quantum Hall transitions

We report the first complete 10G silicon photonic ring modulator with integrated ultra-efficient CMOS driver and closed-loop wavelength control. A selective substrate removal technique was used to improve the ring tuning efficiency. Limited by the thermal tuner driver output power, a maximum open-loop tuning range of about 4.5nm was measured with about 14mW of total tuning power including the heater driver circuit power consumption. Stable wavelength locking was achieved with a low-power mixed-signal closed-loop wavelength controller. An active wavelength tracking range of > 500GHz was demonstrated with controller energy cost of only 20fJ/bit.

A high-speed, tunable silicon photonic ring modulator integrated with ultra-efficient active wavelength control.

An efficient Si hybrid external cavity laser with a micro-ring reflector is fabricated on SOI platform. The laser output power reaches 20 mW and the highest wall-plug efficiency of 7.8% is measured in an un-cooled condition.

High power and energy-efficient WDM Si/III–V hybrid external-cavity lasers

This paper discusses the use of terahertz time-domain spectroscopy to build a database of the spectral signatures from common explosives in the range <; 5 THz. The effect on the spectra is demonstrated of common obscuring packaging materials which act to degrade the spectra obtained in realistic environments.

2013 6th UK, Europe, China Millimeter Waves and THz Technology Workshop (UCMMT)

THz-TDS analysis of hidden explosives for homeland security scenarios

Stable perfectly-matched-layer boundary conditions for finite-difference time-domain simulation of acoustic waves in piezoelectric crystals

Electronics packaging based on stress-engineered spring interconnects has the potential to enable integrated IC testing, fine pitch, and compliance not readily available with other technologies. We describe new spring contacts which simultaneously achieve low resistance ( <; 100 mΩ) and high compliance (>; 30 μm) in dense 2-D arrays (180 ~ 180-μm pitch). Mechanical characterization shows that individual springs operate at approximately 150-μN force. Electrical measurements and simulations imply that the interface contact resistance contribution to a single contact resistance is <; 40 mΩ . A daisy-chain test die consisting of 2844 contacts is assembled into flip-chip packages with 100% yield. Thermocycle and humidity testing suggest that packages with or without underfill can have stable resistance values and no glitches through over 1000 thermocycles or 6000 h of humidity. This paper suggests that integrated testing and packaging can be performed with the springs, enabling new capabilities for markets such as multichip modules.

We report on a hybrid assembly combining 40 nm bulk CMOS transmitter circuits, 130 nm SOI optical ring modulators, and off-chip lasers. Silicon resistors in the rings enable circuit-based thermal tuning to overcome process variations, resulting in eight 12.6 Gbps channels operating simultaneously at eight different wavelengths. Not counting laser power but including all transmitter circuits, integration parasitics, and static thermal control, the TX array consumes a total of 33 mW, resulting in a net per-channel efficiency of 330 fJ/b.

Design considerations for a 33mW, 12.5 Gbps × 8 channel silicon photonic transmitter array

Broadband time-domain spectroscopy was used to measure the terahertz frequency absorption of protein single crystals in order to study global protein dynamics. Temperature dependent dynamics were measured for lysozyme, and the terahertz frequency spectrum of mouse urinary protein was compared to calculated spectra.

2013 38th International Conference on Infrared, Millimeter, and Terahertz Waves (IRMMW-THz)

Terahertz time-domain spectroscopy of lysozyme and mouse urinary protein single crystals

The Ball-in-Pit passive layer-to-layer self-alignment technique has previously been shown to achieve submicron alignment between stacked chips. This structure sandwiches a precision sapphire ball between inverse pyramidal pits etched on the faces of chips to be aligned. In this work, we present a universal and low-cost fluidic approach to self-populate balls into a large-scale array of etched pits. This population technique could be used to populate pits on a wafer, a multichip interposer, or individual chips.

Large-scale, surface tension assisted Ball-in-Pit self population for chip-to-chip passive alignment

In this work, a description is given of a simulation technique employed to model the interaction between surface acoustic waves and ridge-waveguide quantum cascade lasers (QCLs). Firstly, a finite-difference time-domain (FDTD) scheme for modelling acoustic wave propagation in arbitrary semiconductor structures is outlined, and verified by comparison with experimental measurements of the frequency response of surface acoustic wave transmission between interdigitated transmitters and receivers on a bulk crystal. The model is developed further to represent the ridge-waveguide as a prominence above the surface and the active region of the laser is accounted for by a free-charge region buried within the structure. The modulation of this free charge, or carrier concentration by the propagating surface acoustic wave, is then used as an input to a rate equation model of a QCL to show how the gain will be affected. It is this control of the gain through the amplitude of the surface acoustic wave which will allow for modulation of the mid-infrared or terahertz output of the laser and hence its incorporation in many new applications.

2013 International Conference on Advanced Optoelectronics and Lasers (CAOL 2013)

We report an ultra-low power 100Gbps silicon photonic WDM transmitter tunable with off-chip laser sources. The hybrid CMOS transmitter consists of eight 12.6Gbps WDM channels and consumes a total on-chip power of 33mW.

2013 Optical Fiber Communication Conference and Exposition and the National Fiber Optic Engineers Conference (OFC/NFOEC)

A 33mW 100Gbps CMOS silicon photonic WDM transmitter using off-chip laser sources

We demonstrate optimization of planar terahertz (THz) frequency Goubau lines to achieve a ~ 2 THz bandwidth. This has allowed high resolution, on-chip THz spectra of polycrystalline materials to be recorded over temperatures ranging from 4-292 K.

We present the self-aligned fabrication of on-chip devices in which waveguides, incorporating integrated photoconductive switches, are combined with two-dimensional electron systems to allow probing of the ultrafast (terahertz frequency range) properties of confined semiconductor systems, both at cryogenic temperatures and in high magnetic fields. We demonstrate the direct injection of on-chip terahertz pulses into the mesoscopic system by femtosecond, near infra-red laser excitation of in-plane photoconductive switches formed on an epitaxially grown, low-temperature GaAs layer, which is integrated monolithically with a GaAs∕AlGaAs heterostructure containing a two-dimensional electron system. Both the input and output terahertz signals of an on-chip waveguide are sampled by altering dynamically the photoconductive excitation∕detection arrangement in situ on a single device. We also demonstrate a new method for sub-Kelvin excitation and detection of on-chip terahertz frequency radiation in a (3)He∕(4)He dilution refrigerator that allows the photocurrent and detected terahertz transient to be mapped as function of the near-infrared excitation position at the emitter and the detector, respectively. Furthermore, we demonstrate transmission of terahertz transients through a two-dimensional electron system in a coplanar waveguide under magnetic field at temperatures as low as 200 mK.

On-chip terahertz spectroscopic techniques for measuring mesoscopic quantum systems.

Silicon photonics is the most promising pathway to achieve >10 Tb/s off-chip I/O bandwidth required by next-generation high-performance computing and switching systems. Ring resonator modulators offer the advantages of small footprint, low power, high efficiency, low loss, high speed, and CMOS compatibility for silicon photonic links. This paper presents an in-depth discussion of practical microring modulators in silicon, covering their performance metrics, design tradeoffs, optimization, p-n junction geometries, complex ring configurations, and tuning solutions. Various demonstrated Si ring modulators are reviewed and potential future developments are briefly discussed.

Ring Resonator Modulators in Silicon for Interchip Photonic Links

Optical interconnects play an integral role in large-scale digital computing, switching, and routing systems. The authors describe a path toward future many-chip modules based on silicon photonic interposers that stitch together tens of chips in a dense and efficient communication infrastructure. They review the guiding design principles for this "macrochip" and describe its canonical energy, loss, and area budgets.

We present a unifying model of plateau-to-plateau transitions in the quantum Hall effect based on results from high resolution frequency scaling experiments. We show that as the frequency or quantum coherence length of the two-dimensional electron system is varied, one observes a crossover between classical percolation and quantum percolation in the measured values of the critical scaling exponents of the plateau-to-plateau transitions. This crossover is dependent on the relationship between certain relevant length scales of a two-dimensional system and can be explained using a quantum percolation model. The model explains why quantum criticality can be observed in some systems, but is absent from others.

The quantum percolation model of the scaling theory of the quantum Hall effect: a unifying model for plateau-to-plateau transitions

We report on the development of a test package that utilizes a passive silicon interposer with high density and high aspect ratio TSV's, each integrated with compliant flexible interconnect on one side of the interposer. As opposed to conventional approaches, where TSV interposers are populated with C4 and/or fine pitch micro bumps with multiple interfaces to reflow and permanently attach, our TSV interposers are integrated with micro-spring interconnects on a single side or, potentially, on both sides to provide a truly reworkable or reusable (“rematable”) MCM platform. This makes it possible to test die in package while retaining the ability to replace any that are found flawed. This is a key requirement for increasing assembly yield of advanced MCM packages.

Package demonstration of an interposer with integrated TSVs and flexible compliant interconnects

Efficient multi-wavelength sources are essential to realize sub-pJ/bit modulated silicon photonic links for multi-TB/s interconnect applications. From a complete link perspective, we discuss the efficiency requirement for silicon WDM on-chip sources. A waveguide-coupled wall-plug efficiency (WPE) better than 10% is important to complement ultra-low power silicon photonic components for practical implementations. We propose a non-invasive hybrid, flip-chip integration approach using surface-normal coupling of an un-cooled III/V gain medium with a tunable wavelength selective silicon reflector. We show that a tunable, external-cavity WDM laser using such a hybrid integration approach can achieve high waveguide-coupled WPE when optimized. A proof-of-concept demonstration achieved a C-band tunable laser with an output power of more than 6 mW in the silicon waveguide, a tuning range of 15 nm, and a WPE of over 4.5%.

Efficient WDM Laser Sources Towards Terabyte/s Silicon Photonic Interconnects

Single-mode (SM) operation of terahertz (THz)-frequency quantum cascade lasers (QCLs) is essential for gas sensing and for their use as local oscillators. Whilst such SM operation has been demonstrated previously using distributed feedback gratings and photonic lattices (PLs), an ability to tune SM THz QCLs electronically would be highly desirable for many applications. This work investigates the electronic properties of multiple segment QCLs, and explores possible electronic tuning mechanisms. We have fabricated THz QCLs with PL gratings. Our THz QCLs, based on a bound-to-continuum active region design, were processed into 150-μm-wide surface-plasmon ridge waveguides with lengths 2.5–4.5 mm. The upper waveguide was then patterned into three sections. The outer sections were fully metallised with gold. In the central 530-μm-long section, however, the top n-doped layer was etched away and metallic PLs fabricated using electron-beam lithography, with grating pitch between 14.60 and 15.65 μm. In each device, both the PL and the outer sections were bonded separately to allow independent biasing. Devices were cooled in a continuous-flow helium cryostat and emission spectra measured using a Fourier-transform infrared spectrometer. Standard (unpatterned) devices lased with multiple Fabry–Perot modes in the range 2.70–2.83 THz, whilst single mode emission was observed for devices patterned with a PL (Fig. 2). The emission spectra recorded from devices with PLs of different grating pitch showed stop-band behaviour, with the experimentally-determined stop-band bandwidth of around 25 GHz agreeing with the value of 23 GHz calculated using finite-element modelling. Light-output–current–voltage (LIV) characteristics were acquired under different configurations, including the central PL sections both biased and unbiased. An equivalent circuit model describing the electronic properties of the three-section devices was developed, and was found to reproduce the experimental observations well.

Three-section terahertz quantum cascade lasers with externally biased photonic lattices

We report three-well, resonant-phonon depopulation terahertz quantum cascade lasers with semi-insulating surface-plasmon waveguides and reduced active region (AR) thicknesses. Devices with thicknesses of 10, 7.5, 6, and 5 μm are compared in terms of threshold current density, maximum operating temperature, output power, and AR temperature. Thinner ARs are technologically less demanding for epitaxial growth and result in reduced electrical heating of devices. However, it is found that 7.5-μm-thick devices give the lowest electrical power densities at threshold, as they represent the optimal trade-off between low electrical resistance and low threshold gain.

Terahertz quantum cascade lasers with thin resonant-phonon depopulation active regions and surface-plasmon waveguides

We report a compact 1×8 silicon Mux/DeMux with ring tuning efficiency of <;3μW/GHz using back-side substrate removal technique. Total power of <;4.1mW was measured to tune the device to a 1.6nm wavelength grid.

We demonstrate an uncooled C-band, external-cavity, silicon-assisted hybrid laser and report a waveguide-coupled wall-plug-efficiency of 5.5% at room temperature, output power of 10 mW and tuning efficiency of 2.2 nm/mW using a ring-based tunable reflector.

Vertical-coupled high-efficiency tunable III–V- CMOS SOI hybrid external-cavity laser

We demonstrate improved optical interlayer coupling based on grating couplers with backside metal reflectors. Losses of 1.5dB and 2.0dB are achieved with 145nm and 220nm grating etch depth on a 130nm SOI CMOS platform, respectively.

Low loss optical interlayer coupling using reflector-enhanced grating couplers

We investigate the effect of substrate thickness on the transmission bandwidth of on-chip terahertz-frequency-range planar Goubau lines both experimentally and theoretically. The bandwidth and frequency resolution are improved through substrate thinning and geometry modifications (reducing reflections arising from the THz photoconductive generators and detectors). We demonstrate that the enhanced bandwidth (2 THz) and resolution (3.75 GHz) allows this type of on-chip waveguide to be used for spectroscopic measurements of polycrystalline materials from cryogenic (4 K) to room temperature (292 K) by recording vibrational absorption spectra from overlaid samples of lactose monohydrate.

Spectroscopy of polycrystalline materials using thinned-substrate planar Goubau line at cryogenic temperatures.

The absorption coefficient and refractive index have been measured for a homologous series of tetraalkylammonium bromides over the frequency range 0.3-5.5 THz. Spectral features are found to shift to lower frequencies as the molecular mass is increased, as expected. However, to understand the detailed structure of the observed spectral features, density functional perturbation theory calculations have been performed on the first four crystalline compounds in the series. From these calculations, we find that each spectrum is dominated by three translatory modes involving asymmetric motion of the ammonium cation and bromine counterion, although the overall number of active modes increases with increasing molecular size. The experimentally observed absorption is not completely described by the infrared active phonon modes alone. We show that it is also necessary to include the coupling of the phonon modes with the macroscopic field generated by the collective displacement of the vibrating ions, and we have applied an effective medium theory, which accounts for particle shape to allow for this effect in the calculation of the terahertz spectra.

Effect of molecular size and particle shape on the terahertz absorption of a homologous series of tetraalkylammonium salts.

We show that the terahertz (THz) frequency spectra of powdered ionic crystalline systems are not described by their infrared active phonon modes alone. Instead, it is necessary to include the coupling of the phonon modes with the macroscopic electric field generated by the collective displacement of the vibrating ions.

Understanding the influence of morphology on the terahertz spectra of a powdered ionic crystalline system

We present an experimental demonstration of acoustically induced current in graphene. CVD-grown layers of graphene were transferred to the surface of highly piezoelectric lithium niobate. This allowed integration of graphene with interdigital transducers used to generate and detect surface acoustic waves (SAWs). A continuous wave RF signal applied to the transducers at their resonant frequency generates a DC current flow, which has a linear dependence on the applied RF power and can be induced against an applied bias. These findings could provide the basis for new ways of studying electron transport in graphene.

Integration, processing and performance of low power thermally tunable CMOS-SOI WDM resonators

We report a complete 10Gbps digital CMOS photonic direct chip-to-chip link. The link includes power supply regulation and digital retiming and uses record-low 680 fJ/bit transceivers and an optical power of 1.4 pJ/bit.

A complete 10 Gbps chip-to-chip digital CMOS silicon photonic link

We report on a 10-Gb/s digital-to-digital CMOS silicon photonic link with a 2.1-pJ/bit on-chip energy efficiency, using a photon energy of 1.4-pJ/bit and 680-fJ/bit transceivers that integrate 130-nm SOI CMOS photonic devices with 40-nm bulk CMOS circuits.

We demonstrate the directed control of charge carriers in graphene using the electric field that accompanies the propagation of surface acoustic waves (SAWs) on a piezoelectric surface. Graphene grown by chemical vapor deposition was transferred to the surface of lithium niobate, allowing its direct integration with interdigital transducers used for SAW generation and detection. Radio frequency (RF) signal applied to the transducers at their resonant frequency was found to generate a direct current flow by the transport of p-type charge carriers. The acoustically induced current scales linearly with the applied RF power and can be observed even in presence of a counter-flow current induced by an applied bias.

We demonstrate a high speed GeSi electro-absorption (EA) modulator monolithically integrated on 3 µm silicon-on-insulator (SOI) waveguide. The demonstrated device has a compact active region of 1.0 × 55 μm(2), an insertion loss of 5 dB and an extinction ratio of 6 dB at wavelength of 1550 nm. The modulator has a broad operating wavelength range of 35 nm and a 3 dB bandwidth of 40.7 GHz at 2.8 V reverse bias. This compact and energy efficient modulator is a key building block for optical interconnection applications.

High speed GeSi electro-absorption modulator at 1550 nm wavelength on SOI waveguide.

We describe transmitter and receiver circuits for a 10-Gbps single-ended optical link in a 40-nm CMOS technology. The circuits are bonded using low-parasitic micro-solder bumps to silicon photonic devices on a 130-nm SOI platform. The transmitter drives oval resonant ring modulators with a 2-V swing and employs static thermal tuners to compensate for optical device process variations. The receiver is based on a transimpedance amplifier (TIA) with 4-kΩ gain and designed for an input power of - 15 dBm, a photodiode responsivity of 0.7 A/W, and an input extinction ratio of 6 dB. It employs a pair of interleaved clocked sense-amplifiers for voltage slicing and uses a DLL with phase adjustment for centering the clock in the data eye. Periodic calibration allows for adjustment of both voltage and timing margins. At 10 Gbps, the transmitter extinction ratio exceeds 7 dB and, excluding thermal tuning and laser power, it consumes 1.35 mW. At the same datarate, the receiver consumes 3.95 mW. On-chip PRBS generators and checkers with 231-1 sequences confirm operation at a BER better than 10-12.

10-Gbps, 5.3-mW Optical Transmitter and Receiver Circuits in 40-nm CMOS

The terahertz (THz) frequency quantum cascade laser (QCL) is a semiconductor heterostructure laser that has attracted much research interest over the past decade. We report on the high performance of THz QCLs based on a three-well resonant-phonon (RP) depopulation active region (AR) and operating in the frequency range 2.7 THz to 4.0 THz. Devices, processed into surface-plasmon waveguides, lased up to 116 K in pulsed mode with threshold current densities as low as 840 Acm−2. The effects of the design frequency and laser cavity length on performance are discussed. We also report on the operation of QCLs with reduced AR thicknesses, and show, for the first time, that the AR thickness of RP QCLs processed in a surface plasmon waveguide can be reduced to as little as 5 µm. Finally, we demonstrate the use of an electrically tuneable THz QCL, based on a heterogeneous AR, for spectroscopic imaging of the high-explosive pentaerythritol tetranitrate.

Resonant-phonon depopulation terahertz quantum cascade lasers and their application in spectroscopic imaging

Surface-profiling through self-mixing in a THz quantum cascade laser

A MCM enabled by Proximity Communication (P×C) includes a two-dimensional array of facing chips, including island chips and bridge chips that communicate with each other using P×C I/Os placed in the overlapping regions. In order to maintain the relative vertical spacing of these P×C I/O pads as well as to allow Ball-in-Pit self-alignment technology to work, elastomeric bump interposers are placed in cavities in a substrate, which house the bridge chips, to provide a compressive force on the back surfaces of the bridge chips. These interposers contain compressible structures which are precisely placed to make sure that sufficient and symmetric amount of force is applied to the bridge chip to ensure that facing surfaces of the island chips and the bridge chips, as well as connectors on these surfaces, are held securely and reliably and are approximately coplanar without bending the bridge chips. At the same time, the interposer must also allow the bridge chip to be lowered sufficiently to disengage the ball-pit sites during the reflow process of the island chips. In this paper, the design and fabrication of such compliant mechanical interposers are discussed.

Assembly and alignment of Proximity Communication enabled multi-chip packages using elastomeric bump interposers

Silicon photonic interconnects offer a promising solution to meeting the ever growing demand for more efficient I/O bandwidth density. We report an ultralow power 80 Gb/s arrayed silicon photonic transceiver for dense, large bandwidth inter/intrachip interconnects. Low parasitic microsolder-based hybrid bonding enables close integration of silicon photonic array devices optimized on a 130 nm silicon-on-insulator CMOS platform with CMOS very large scale integration circuits optimized on a 40 nm silicon CMOS platform to achieve unprecedented energy efficiency. The hybrid CMOS transceiver consists of eight 10 Gb/s channels with a total consumed power below 6 mW/channel. The eight-channel wavelength division multiplexing transmitter array using cascaded tunable ring modulators demonstrated better than 100 fJ/bit energy efficiency for 10 Gb/s operation excluding the laser power and tuning power, while the eight-channel receiver array using broadband Ge p-i-n waveguide detectors show sensitivity of better than -15 dBm for a bit error rate of 10-12 at a data rate of 10 Gb/s with energy efficiency of better than 500 fJ/bit.

Ultralow Power 80 Gb/s Arrayed CMOS Silicon Photonic Transceivers for WDM Optical Links

We report design improvements for evanescently coupled Germanium photodetectors grown at low temperature. The resulting photodetectors with 10 μm Ge length manufactured in a commercial CMOS process achieve >0.8 A/W responsivity over the entire C-band, with a device capacitance of <7 fF based on measured data.

Optical ring modulators are highly susceptible to external temperature noise and to self-heating from absorbed optical power. We mitigate both problems through circuit techniques. A control loop at the ring measures output power and controls a local heater to compensate for external temperature noise. A control loop at the receiver dynamically tracks DC variations to compensate for self-heating effects. The design has been implemented in a 40 nm TSMC technology.

A sub-400 fJ/bit thermal tuner for optical resonant ring modulators in 40 nm CMOS

We present a new measurement technique for the sub-Kelvin excitation and detection of on-chip terahertz frequency radiation in high magnetic fields. We present a monolithically integrated heterostructure, which allows a mesoscopic electronic system to be combined with an on-chip terahertz device, and show dynamic imaging of a THz photoconductive switch at 200 mK in a 12 T field, together with THz signal propagation at 100 mK. These capabilities will advance significantly the study of ultrafast phenomena in mesoscopic semiconductor systems.

2012 37th International Conference on Infrared, Millimeter, and Terahertz Waves

On-chip THz generation and detection at milli-Kelvin temperatures for the study of ultrafast phenomena in confined semiconductor systems

We report optical waveguides up to one meter long with 0.026 dB/cm loss fabricated in a 300nm thick SOI CMOS process. Combined with tight bends and compact interlayer grating couplers, we demonstrate a complete toolbox for ultralow-loss, high-density waveguide routing for macrochip interconnects.

Ultralow-loss, high-density SOI optical waveguide routing for macrochip interconnects.

We show enhanced optical bistability induced by free carrier absorption from junction doping in substrate-removed silicon ring modulators. Such linear thermal effects dominate the loss in high-speed depletion silicon ring modulators. Optical bistability was observed with about 100 μW of input optical power. We further show that such thermal interactions causes data-dependent ring resonance shifts, and consequently severely degrade the data modulation quality at low speeds. The frequency response of this effect was measured to be about 100~200 kHz.

Enhanced optical bistability from self-heating due to free carrier absorption in substrate removed silicon ring modulators.

We report a 9.5% wall-plug-efficient un-cooled external-cavity DBR laser built with a III-V-semiconductor reflective-SOA edge-coupled to an SOI waveguide containing a Bragg grating mirror. The hybrid laser is suitable for power efficient, CMOS-compatible optical transmitters.

High-efficiency hybrid III–V/Si external cavity DBR laser for 3-µm SOI waveguides

We have investigated the selective epitaxial growth of GeSi bulk material on silicon-on-insulator substrates by reduced pressure chemical vapor deposition. We employed AFM, SIMS, and Hall measurements, to characterize the GeSi heteroepitaxy quality. Optimal growth conditions have been identified to achieve low defect density, low RMS roughness with high selectivity and precise control of silicon content. Fabricated vertical p-i-n diodes exhibit very low dark current density of 5 mA/cm2 at −1 V bias. Under a 7.5 V/µm E-field, GeSi alloys with 0.6% Si content demonstrate very strong electro-absorption with an estimated effective ∆α/α around 3.5 at 1,590 nm. We compared measured ∆α/α performance to that of bulk Ge. Optical modulation up to 40 GHz is observed in waveguide devices while small signal analysis indicates bandwidth is limited by device parasitics.

Strong Electro-Absorption in GeSi Epitaxy on Silicon-on-Insulator (SOI)

The spatial control of micro-particles is crucial to the development of microfluidic, on-chip platforms for characterisation, modification and sensing applications. We demonstrate the use of surface acoustic waves (SAWs) to generate ordered arrays of microbubbles, and transport these arrays by controlled modulation of the SAW frequency. Micro-particle and microbubble arrays are repeatedly captured at a series of spatial positions in a microfluidic channel. Periodic cycling of the applied SAW frequency across the transducer bandwidth is shown to produce long-range transportation of micro-particle and microbubble arrays. The exquisite control over particle position and transport in microfluidic devices that our technique allows could find wide applications for non-invasive and programmable ordering and transport of biological materials in microfluidic systems.

Acousto-microfluidics: Trapping and transporting microbubbles using surface acoustic waves

We demonstrate a high speed GeSi EA modulator with a broad operating wavelength range of over 30 nm near 1550 nm and a 3 dB bandwidth of 40.7 GHz at 2.8 V reverse bias.

Terahertz Frequency Spectroscopy and its Potential for Security Applications

We report the design and characterization of external-cavity DBR lasers built with a III-V-semiconductor reflective-SOA with spot-size converter edge-coupled to SOI waveguides containing Bragg grating mirrors. The un-cooled lasers have wall-plug-efficiencies of up to 9.5% at powers of 6 mW. The lasers are suitable for making power efficient, hybrid WDM transmitters in a CMOS-compatible SOI optical platform.

We have designed new optical interlayer couplers based on grating couplers with post-processed mirrors to achieve low insertion loss on a 130nm SOI CMOS process. Optimized design shows an interlayer coupling loss of 2.2 dB.

Optical interlayer coupling design for optical interconnects based on mirror enhanced grating couplers

A novel packaging module is described that is based on co-integration of flexible micro-spring interconnects with through silicon copper vias (TSVs) into a passive large area silicon interposer. We report on the packaging test vehicles based on such interposers that are designed to demonstrate a wafer scale integration process to form TSV+spring interconnects with high yield and low resistance. Our goal is to develop a scalable, large area die or MCM packaging platform to enable stress-free, readily reworkable packaging of chips and components with different functionality and technology. We show interposer layouts, share process details and characterization methods.

Integrating through-silicon vias with solder free, compliant interconnects for novel, large area interposers

We report the design and fabrication of silicon rib-waveguide crossings based on taper-integrated multimode-interference. Measured devices built in a 130nm SOI CMOS process showed an insertion loss of 0.1dB/crossing, and an extracted crosstalk below -35dB.

Low-loss low-crosstalk silicon rib waveguide crossing with tapered multimode-interference design

We report new developments on hybrid integration that attaches CMOS driver circuits to silicon photonic (SiPhotonic) devices built in Silicon on Insulator (SOI) technology. This low-parasitic hybrid integration approach enables energy efficient links based on aggressive silicon photonic devices and low power, high speed circuits. The silicon photonic components are fabricated in the 130 nm Cu node of Freescale's SOI-CMOS technology while the CMOS driver circuits are fabricated in 40 nm TSMC ELK technology. The two types of chips are using 20 μm diameter solder bumps. We further present progress on scaling these solder bumps to 10 micron diameter and below as well as developing a wafer scale microsolder process module. Finally, we report progress integrating hybrids that include SOI chips with a partially removed backside. Under full SOI handler removal this bonding geometry is akin to the extreme limit of wafer thinning used in today's vertical chip stacking (3D) approaches.

Scaling hybrid-integration of silicon photonics in Freescale 130nm to TSMC 40nm-CMOS VLSI drivers for low power communications

Terahertz sensing and imaging through self-mixing in a quantum cascade laser

We demonstrate that aqueous suspensions of microbubbles, formed into arrays using standing surface acoustic waves (SSAWs), can be transported by controlled modulation of the SSAW frequency. The array is repeatedly captured at a sequence of spatial positions along the acoustic beam path and long-range transportation is achieved by periodic cycling of the applied frequency across the transducer bandwidth. We also demonstrate that controllable alignment and transport can be achieved in a detachable microfluidic device, where the microfluidic channel, in which particle transport occurs, is separated from the piezoelectric substrate by an acoustic coupling gel. Proof-of-concept transport is first discussed using a test system of latex particles before the non-invasive manipulation technique is applied to arrays of microbubbles. We explore the role of acoustic radiation forces in the spatial control of particles by analysing the dynamics of particle manipulation by SSAWs. Our results highlight the exquisite control which we have over the position and transport of particles and we anticipate that this technique could find wide applications for the accurate and programmable, non-invasive ordering and transport of biological samples in microfluidic systems.

Acousto-microfluidics: Transporting microbubble and microparticle arrays in acoustic traps using surface acoustic waves

We propose a novel chip-to-chip interconnection, called Conductive Ball-in-Pit (CBiP), to simultaneously accomplish micron-scale layer-to-layer alignment and power-distribution that are essential in any Proximity Communication (PxC)-enabled multi-chip package. CBiP interconnects are demonstrated: (1) to be remateable, (2) to achieve a low-resistance contact between chips assembled in a face-to-face configuration, (3) to carry greater than 1.7 A of DC current, and (4) to passively align chips to within 3 μm.

“Dual-purpose” remateable Conductive Ball-in-Pit interconnects for chip powering and passive alignment in Proximity Communication enabled multi-chip packages

We report a high-contrast 40Gb/s ring modulator with integrated thermal tuning fabricated in a 130nm CMOS process. Under 2V modulation, its optical eyes showed extinction ratios of 7dB at 40Gb/s and 2.3dB at 44Gb/s.

Building future data centers requires unprecedented internal bandwidth, at very high per-channel energy efficiency. Optics offers potential solutions for these challenges, especially if we rethink the construction of high-performance computers into compact systems-in-a-package. Here we discuss the drivers for optics in these large-scale systems.

2011 Optical Fiber Communication Conference and Exposition and the National Fiber Optic Engineers Conference

Impact of disorder on frequency scaling in the integer quantum Hall effect

Electroabsorption from GeSi on silicon-on-insulator (SOI) is expected to have promising potential for optical modulation due to its low power consumption, small footprint, and more importantly, wide spectral bandwidth for wavelength division multiplexing (WDM) applications. Germanium, as a bulk crystal, has a sharp absorption edge with a strong coefficient at the direct band gap close to the C-band wavelength. Unfortunately, when integrated onto Silicon, or when alloyed with dilute Si for blueshifting to the C-band operation, this strong Franz-Keldysh (FK) effect in bulk Ge is expected to degrade. Here, we report experimental results for GeSi epi when grown under a variety of conditions such as different Si alloy content, under selective versus non selective growth modes for both Silicon and SOI substrates. We compare the measured FK effect to the bulk Ge material. Reduced pressure CVD growth of GeSi heteroepitaxy with various Si content was studied by different characterization tools: X-ray diffraction (XRD), atomic force microscopy (AFM), secondary ion mass spectrometry (SIMS), Hall measurement and optical transmission/absorption to analyze performance for 1550 nm operation. State-of-the-art GeSi epi with low defect density and low root-mean-square (RMS) roughness were fabricated into pin diodes and tested in a surface-normal geometry. They exhibit low dark current density of 5 mA/cm2 at 1V reverse bias with breakdown voltages of 45 Volts. Strong electroabsorption was observed in our GeSi alloy with 0.6% Si content having maximum absorption contrast of Δα/α ~5 at 1580 nm at 75 kV/cm.

Experimental studies of the Franz-Keldysh effect in CVD grown GeSi epi on SOI

Using low parasitic microsolder bumping, we hybrid integrated efficient photonic devices from different platforms with advanced 40 nm CMOS VLSI circuits to build ultra-low power silicon photonic transmitters and receivers for potential applications in high performance inter/intra-chip interconnects. We used a depletion racetrack ring modulator with improved electro-optic efficiency to allow stepper optical photo lithography for reduced fabrication complexity. Integrated with a low power cascode 2 V CMOS driver, the hybrid silicon photonic transmitter achieved better than 7 dB extinction ratio for 10 Gbps operation with a record low power consumption of 1.35 mW. A received power penalty of about 1 dB was measured for a BER of 10(-12) compared to an off-the-shelf lightwave LiNOb3 transmitter, which comes mostly from the non-perfect extinction ratio. Similarly, a Ge waveguide detector fabricated using 130 nm SOI CMOS process was integrated with low power VLSI circuits using hybrid bonding. The all CMOS hybrid silicon photonic receiver achieved sensitivity of -17 dBm for a BER of 10(-12) at 10 Gbps, consuming an ultra-low power of 3.95 mW (or 395 fJ/bit in energy efficiency). The scalable hybrid integration enables continued photonic device improvements by leveraging advanced CMOS technologies with maximum flexibility, which is critical for developing ultra-low power high performance photonic interconnects for future computing systems.

Ultra-efficient 10 Gb/s hybrid integrated silicon photonic transmitter and receiver.

We demonstrate a compact waveguide-based high-speed Ge electro-absorption (EA) modulator integrated with a single mode 3 µm silicon-on-isolator (SOI) waveguide. The Ge EA modulator is based on a horizontally-oriented p-i-n structure butt-coupled with a deep-etched silicon waveguide, which transitions adiabatically to a shallow-etched single mode large core SOI waveguide. The demonstrated device has a compact active region of 1.0 × 45 µm(2), a total insertion loss of 2.5-5 dB and an extinction ratio of 4-7.5 dB over a wavelength range of 1610-1640 nm with -4V(pp) bias. The estimated Δα/α value is in the range of 2-3.3. The 3 dB bandwidth measurements show that the device is capable of operating at more than 30 GHz. Clear eye-diagram openings at 12.5 Gbps demonstrates large signal modulation at high transmission rate.

30GHz Ge electro-absorption modulator integrated with 3 μm silicon-on-insulator waveguide.

As an enabling building block to support high bandwidth optical interconnections among supercomputing processing elements, we present the first monolithically integrated chip-to-chip wavelength-division multiplexing (WDM) optical proximity coupler with 4-channel × 200GHz-spacing multiplexer/demultiplexer (MUX/DEMUX) functionality utilizing an echelle grating, micro reflective mirrors, and waveguide mode transformers on single silicon-on-insulator (SOI) substrate. This new photonic integrated circuits can be utilized to provide a data-rate independent optical interface that surpasses the throughput bottleneck of current electrical data paths.

2011 IEEE 61st Electronic Components and Technology Conference (ECTC)

Dual-layer WDM routing for wafer-scale packaging of photonically-interconnected computing systems

We present a hybrid integration technology platform for the compact integration of best-in-breed VLSI and photonic circuits. This hybridization solution requires fabrication of ultralow parasitic chip-to-chip interconnects on the candidate chips and assembly of these by a highly accurate flip-chip bonding process. The former is achieved by microsolder bump interconnects that can be fabricated by wafer-scale processes, and are shown to have average resistance <1 ohm/bump and capacitance <25fF/bump. This suite of technologies was successfully used to hybrid integrate high speed VLSI chips built on the 90nm bulk CMOS technology node with silicon photonic modulators and detectors built on a 130nm CMOS-photonic platform and an SOI-photonic platform; these particular hybrids yielded Tx and Rx components with energies as low as 320fJ/bit and 690fJ/bit, respectively. We also report on challenges and ongoing efforts to fabricate microsolder bump interconnects on next-generation 40nm VLSI CMOS chips.

Hybrid-integrated silicon photonic bridge chips for ultralow-energy inter-chip communications

We present the design of a silicon microsystem that utilizes dense, low-power photonic interconnects to enable a highly-compact supercomputer-scale system. We review recent progress in wavelength-division multiplexed, low-power silicon photonic interconnect components and discuss a future roadmap for the technology.

Dense WDM silicon photonic interconnects for compact high-end computing systems

Current crowding of a micro spring pressure contact under high current is studied. The spring conducts > 250 mA electrical current between chips, has large mechanical compliance (> 30 µm) compared to other packaging technologies, and fits in a 180 µm pitch 2d array. At 250 mA and 65 °C, daisy chains of 134 spring contacts in a silicon package show stable resistances and hot spot temperature rises of less than a degree. At 1 A, failure near the spring tip or body is observed. Finite element modeling is performed to study the current density distribution and provide failure spot insight. A strategy is proposed to avoid current crowding.

2011 IEEE 24th International Conference on Micro Electro Mechanical Systems

Current crowding study of a micro spring contact for flip chip packaging

Optical interlayer couplers with 2.8dB insertion loss and 48nm bandwidth were designed and demonstrated in a commercial 130nm SOI CMOS process. 10Gb/s transmission through an interlayer-coupled link showed a power penalty of &#60;0.1dB.

We report an ultra-low power 80 Gbps arrayed silicon photonic transceiver for dense, large bandwidth inter/intra-chip interconnects. The hybrid CMOS transceiver consists of eight 10 Gbps WDM channels with total consumed power below 6 mW/channel.

Ultra-low power arrayed CMOS silicon photonic transceivers for an 80 Gbps WDM optical link

We demonstrate an increase in bandwidth, from 600 GHz to 1.5 THz, of planar Goubau-line on-chip devices with integrated low-temperature-grown (LT) GaAs photoconductive (PC) switches, using a substrate-thinning technique. The effect of substrate thinning was investigated both experimentally and theoretically, and the increase in bandwidth then used for spectroscopy of overlaid polycrystalline materials.

2011 International Conference on Infrared, Millimeter, and Terahertz Waves

Increasing the bandwidth of planar on-chip THz devices for spectroscopic applications

The application of terahertz time-domain spectroscopy and imaging to the study of proteins in crystalline form is demonstrated. Terahertz time-domain spectroscopy is particularly sensitive to the long-range ordering of molecules, with proven utility for the spectroscopy of crystalline biological small molecules. Here, the terahertz time-domain absorption response of a macromolecular protein single crystal is investigated for the first time. In particular, the effect of dehydration on the terahertz absorption coefficient of tetragonal hen egg white lysozyme crystals is reported.

Applying broadband terahertz time‐domain spectroscopy to the analysis of crystalline proteins: a dehydration study

The technologies associated with integration and packaging have a significant impact on the overall system. In this paper, we review a silicon photonic “macrochip” system and its associated packaging that will allow dense wavelength-division multiplexed optical links to be intimately integrated and co-manufactured with the switching electronics. For this to happen, we anticipate a number of integration and packaging advances.

Integration and Packaging of a Macrochip With Silicon Nanophotonic Links

We present two effective approaches to improve the responsivity of high speed waveguide-based Ge photodetectors integrated on a 0.25 μm silicon-on-insulator (SOI) platform. The main cause of poor responsivity is identified as metal absorption from the top contact to Ge. By optimizing Ge thickness and offsetting the contact window, we have demonstrated that the responsivity can be improved from 0.6A/W to 0.95 A/W at 1550 nm with 36 GHz 3 dB bandwidth. We also demonstrate that a wider device with double offset contacts can achieve 1.05 A/W responsivity at 1550 nm and 20 GHz 3 dB bandwidth.

We present the design and fabrication of a waveguide-based Ge electro-absorption (EA) modulator integrated with a 3 µm silicon-on-isolator (SOI) waveguide. The proposed Ge EA modulator employs a butt-coupled horizontally-oriented p-i-n structure. The optical design achieves a low-loss transition from Ge to Si waveguides. The interaction between the optical mode of the waveguide and the bias induced electric field in the p-i-n structure was maximized to achieve high modulation efficiency. By balancing the trade-offs between the extinction ratio and the insertion loss of the device, an optimal working regime was identified. The measurement results from a fabricated device were used to verify the design. Under a -4Vpp reverse bias, the device demonstrates a total insertion loss (including the transition loss) of 2.7-5.2 dB and an extinction ratio of 4.9-8.2 dB over the wavelength range of 1610-1640 nm. Subtracting the contribution of the transition loss, the Δα/α value for the fabricated device was estimated to be between 2.2 and 3.2 with an electric field around 55 kV/cm.

Design and fabrication of 3μm silicon-on-insulator waveguide integrated Ge electro-absorption modulator.

We report a 25Gb/s ring modulator with integrated thermal tuning fabricated in a 130nm CMOS process. With 2Vpp modulation, the optical eye shows >6dB extinction ratio. Modulation energy is estimated &#60;24fJ/bit from circuit modeling.

High-efficiency 25Gb/s CMOS ring modulator with integrated thermal tuning

We demonstrate an add/drop filter based on coupled vertical gratings on silicon. The concept is extended to implement a 1 by 4 wavelength division multiplexer with 3nm bandwidth, 1dB insertion loss and 16dB crosstalk suppression.

Wide bandwidth, low loss 1 by 4 wavelength division multiplexer on silicon for optical interconnects

Digital “assist” circuits can improve the efficiency of traditionally analog circuit blocks, especially as technologies scale to the detriment of analog blocks. We apply some of these techniques to a 10 Gbps optical reciever, and demonstrate 395 fJ/b energy efficiency. Digital calibration blocks wrapped around a simple analog core enabled offset compensation, TIA biasing, and DLL re-timing, and cost negligible performance and power overhead. The assist circuits cost around 40% area overhead.

Digitally-assisted analog circuits for a 10 Gbps, 395 fJ/b optical receiver in 40 nm CMOS

Silicon-based optical interconnects are expected to provide high bandwidth and low power consumption solutions for chip-level communication applications, due to their electronics integration capability, proven manufacturing record and attractive price volume curve. In order to compete with electrical interconnects, the energy requirement is projected to be sub-pJ per bit for an optical link in chip to chip communication. Such low energies pose significant challenges for the optical components used in these applications. In this paper, we review several low power photonic components developed at Kotura for DARPA's Ultraperformance Nanophotonic Intrachip Communications (UNIC) project. These components include high speed silicon microring modulators, wavelength (de)multiplexers using silicon cascaded microrings, low power electro-optic silicon switches, low loss silicon routing waveguides, and low capacitance germanium photodetectors. Our microring modulators demonstrate an energy consumption of ~ 10 fJ per bit with a drive voltage of 1 V. Silicon routing waveguides have a propagation loss of < 0.3 dB/cm, enabling a propagation length of a few tens of centimeters. The germanium photodetectors can have a low device capacitance of a few fF, a high responsivity up to 1.1 A/W and a high speed of >30 GHz. These components are potentially sufficient to construct a full optical link with an energy consumption of less than 1 pJ per bit.

We report terahertz (THz) diffuse reflectance measurements of bulk powdered samples at a frequency of 2.83 THz using a narrowband quantum cascade laser. Samples studied comprise polydisperse powders with absorption coefficients extending over two orders of magnitude from ∼3 cm(-1) to >200 cm(-1). Diffuse reflectance measurements are used to obtain the effective absorption coefficient of these samples from the backscattering cross-section, predicted under the quasi-crystalline approximation (QCA) in the T-matrix formulation and in conjunction with the Percus-Yevick pair distribution function. Results are compared with effective absorption coefficients obtained from THz time-domain spectroscopy measurements on pressed pellet samples, and show good agreement over the range of effective absorption coefficients studied. We observe that the backscattering cross-section predicted under the QCA is strongly dependent on both the real and imaginary components of the complex permittivity of the sample, and we show that reliable determination of the absorption coefficient from diffuse reflectance measurements therefore requires knowledge of the sample's refractive index. This work demonstrates the applicability of diffuse reflectance measurements, using a THz frequency quantum cascade laser, to the high-resolution spectroscopic analysis of bulk powdered samples at THz frequencies.

Measurement and analysis of the diffuse reflectance of powdered samples at terahertz frequencies using a quantum cascade laser.

Silicon photonics is envisioned as a promising solution to address the interconnect bottleneck in large-scale multi-processor computing systems, owing to advantageous attributes such as wide bandwidth, high density, and low latency. To leverage these advantages, optical proximity coupler is one of the critical enablers. Chip-to-chip, layer-to-layer optical proximity couplers with low loss, large bandwidth, small footprint and integration compatibility are highly desirable. In this paper, we demonstrate chip-to-chip optical proximity coupling using grating couplers. We report the experimental results using grating couplers fabricated in a photonically-enabled commercial 130nm SOI CMOS process.

Grating-coupler-based optical proximity coupling for scalable computing systems

We report the detection of terahertz frequency radiation using photoconductive antennas fabricated from Fe-doped InGaAs, grown by metal-organic chemical vapor deposition. Coherent photoconductive detection is demonstrated using femtosecond laser pulses centered at either an 800 or a 1550 nm wavelength. The InGaAs resistivity and the sensitivity of photoconductive detection are both found to depend on the Fe-doping level. We investigate a wide range of probe laser powers, finding a peak in detected signal for ∼5 mW probe power, followed by a reduction at larger powers, attributed to screening of the detected THz field by photo-generated carriers in the material. The measured signal from Fe:InGaAs photoconductive detectors excited at 800 nm is four times greater than that from a low-temperature-grown GaAs photodetector with identical antenna design, despite the use of a ten times smaller probe power.

Terahertz-frequency photoconductive detectors fabricated from metal-organic chemical vapor deposition-grown Fe-doped InGaAs

Ring waveguide resonating structures with high quality factors are the key components servicing silicon photonic links. We demonstrate highly efficient spectral tunability of the microphotonic ring structures manufactured in commercial 130 nm SOI CMOS technology. Our rings are fitted with dedicated heaters and integrated with silicon micro-machined features. Optimized layout and structure of the devices result in their maximized thermal impedance and increased efficiency of the thermal tuning.

A novel packaging approach is described that is based on micro-machined features integrated into CMOS chips. Our solution combines two key self-alignment mechanisms for the first time: solder reflow self-alignment and a novel micro-ball and pyramidal pit for passive self-alignment. We report on the demonstration of a MCM package with large footprint semiconductor CMOS chips interconnected by Proximity Communication (PxC), characterization of their high accuracy assembly process, and metrology of the resulting chip misalignment. Our goal is to develop a scalable, lead-free packaging approach by which large NxN PxC-enabled chip arrays are assembled with high precision on organic substrates in a cost effective manner while using industry standard parts and tooling.

We report a high-speed ring modulator that fits many of the ideal qualities for optical interconnect in future exascale supercomputers. The device was fabricated in a 130 nm SOI CMOS process, with 7.5 μm ring radius. Its high-speed section, employing PN junction that works at carrier-depletion mode, enables 25 Gb/s modulation and an extinction ratio >5 dB with only 1V peak-to-peak driving. Its thermal tuning section allows the device to work in broad wavelength range, with a tuning efficiency of 0.19 nm/mW. Based on microwave characterization and circuit modeling, the modulation energy is estimated ~7 fJ/bit. The whole device fits in a compact 400 μm2 footprint.

25Gb/s 1V-driving CMOS ring modulator with integrated thermal tuning.

We present add-drop filters manufactured as ring resonators in commercial 130 nm SOI CMOS technology with thermal tuning. Their thermal impedance has been dramatically increased by the selective removal of the substrate resulting in a 20,12× increase in tuning efficiency for 100, 30 micron radius device.

Compact, thermally-tuned resonant ring muxes in CMOS with integrated backside pyramidal etch pit

Oracle's scalable hybrid integration technology platform enables continuing improvements in performance and energy efficiency of photonic bridge chips by leveraging advanced CMOS technologies with maximum flexibility, which is critical for developing ultralow power high-performance photonic interconnects for future computing systems. Herein, we report on our second generation of photonic bridge chips comprising electronic drivers and receivers built in 40 nm bulk CMOS technology attached to nanophotonic devices, fabricated using SOI-photonic and 130 nm SOI-CMOS photonic technologies. Hybrid integration by flip-chip bonding is enabled by microsolder bump interconnects scaled down from our previous generation effort and fabricated on singulated dies by a novel batch processing technique based on component embedding. Generation-on-generation, the hybrid integrated Tx and Rx bridge chips achieved 2.3× and 1.7× improvement in energy efficiency, respectively, while operating at 2× the datarate (10 Gbps).

Hybrid integration of silicon nanophotonics with 40nm-CMOS VLSI drivers and receivers

We present the design of a silicon microsystem enabled by silicon photonic interconnects. We review our recent progress in developing key building blocks toward sub pJ/bit optical links for inter/intra-chip interconnects, including ultra-low power silicon photonic transceivers and WDM components with low tuning power.

Sub pJ/bit WDM silicon photonic communications for many-core computing systems

We present manufacturing tolerances of cascaded silicon microring resonators fabricated in a commercial 130-nm complementary-oxide semiconductor (CMOS) foundry using 193-nm lithography and provide statistics gathered from over 500 four-channel microring arrays over multiple wafers and fabrication lots. We quantify intrawafer and interwafer variation of the position and relative spacing of resonance wavelengths for the microring arrays and confirm prior predictions that the absolute resonance positions of such devices cannot be controlled across wafers or even across reticles within a wafer. However, we show that the free spectral range (FSR) of the microrings can be controlled to within 0.66 nm (83 GHz) across wafers and lots, as can the wavelength spacing between closely spaced microrings. To exploit these findings for low-power optical interconnects, we suggest and demonstrate a synthetic resonant comb with FSR ≈ N * δλ, wherein resonance wavelengths are spaced equally across the FSR in order to minimize postfabrication tuning. The experimental CMOS 1 × 8 microring array requires an average tuning of less than 1.2 nm/channel to align to a 200-GHz wavelength division multiplexing (WDM) grid. Monte Carlo simulations on 100 000 sample runs show that an average tuning of 1.72 nm/channel is sufficient for 99% coverage for this component. This indicates that it is possible, with high statistical confidence, to use high-volume CMOS manufacturing to reduce the tuning range and tuning energy requirements of silicon microrings and, hence, enhance their ability to be used in high-density, energy-efficient computing system applications.

Exploiting CMOS Manufacturing to Reduce Tuning Requirements for Resonant Optical Devices

Optical links have successfully displaced electrical links when their aggregated bandwidth-distance product exceeds ~100 Gb/s-m because their link energy per bit per unit distance is lower. Optical links will continue to be adopted at distances of 1 m and below if link power falls below 1 pJ/bit/m. Providing optical links directly to a switching/routing chip can significantly improve the switched energy/bit. We present an early experimental switched CMOS-vertical-cavity surface-emitting laser (VCSEL) system operating at Gigabit Ethernet line rates that achieves a switched interconnect energy of less than 19 pJ/bit for a fully nonblocking network with 16 ports and an aggregate capacity of 20 Gb/s/port. The CMOS-VCSEL switch achieves an optical bandwidth density of 37 Gb/s/mm2 even when operating at a modest line rate of 1.25 Gb/s and is capable of scaling to much higher peak bandwidth densities (~350 Gb/s/mm2) with 5-10 pJ/switched bit. We also review a silicon photonic system design that will lower link energies to 300 fJ/bit, while providing multiterabits per second per square millimeter bandwidth densities. This system will ultimately provide switched optical interconnect at less than a picojoule per switched bit and computer/router system energies of tens of picojoule per bit. We review progress made to date on the silicon photonic components and analyze an energy and bandwidth-density roadmap for future advances toward these goals.

This paper describes 10 Gbps optical modulator and receiver circuits designed for high energy efficiency in a 40 nm process. The transmitter consumes 135 fJ/b when bonded to an external silicon photonic ring modulator. The receiver, at −15 dBm sensitivity, consumes 395 fJ/b when bonded to an external photodiode.

We report a polarization-sensitive terahertz time-domain spectroscopy system, which allows the simultaneous measurement of orthogonal components of the polarization of a free-space propagating terahertz beam using a dual electro-optic detection scheme. We demonstrate the operation of our system by measuring the birefringence of lithium niobate, simultaneously obtaining terahertz spectra from two orthogonal crystallographic directions.

Simultaneous measurement of orthogonal components of polarization in a free-space propagating terahertz signal using electro-optic detection

We have studied the terahertz frequency spectra of a homologous organic series of tetraalkylammonium bromides to investigate how a systematic molecular change directly affects the spectral modes. The spectra overall show similar absorption features, with the modes shifting to lower frequencies as the molecular mass increases.

35th International Conference on Infrared, Millimeter, and Terahertz Waves

Flexible, stress-engineered spring interconnects are a novel technology potentially enabling room temperature assembly approaches to building highly integrated and multi-chip modules (MCMs). Such interconnects are an essential solder-free technology facilitating the MCM package diagnostics and rework. Previously, we demonstrated the performance, functionality, and reliability of compliant micro-spring interconnects under temperature cycling, humidity bias and high-current soak. Currently, we demonstrate for the first time the package with the 1st level conventional fine pitch C4 solder bump interconnects replaced by the arrays of microsprings. Dedicated CMOS integrated circuits (ICs) have been assembled onto substrates using these integrated microsprings. Metrology modules on the ICs are designed and used to characterize the connectivity and resistance of each microspring site.

2010 Proceedings 60th Electronic Components and Technology Conference (ECTC)

A package demonstration with solder free compliant flexible interconnects

We present a 1x4 reconfigurable demultiplexing filter based on cascaded thermally tunable silicon racetrack resonators with ultralow tuning powers. The use of free-standing silicon resonators with undercut structures significantly reduces the tuning power, with a figure of ~2.9 mW per free spectral range. Even with the presence of thermal crosstalk between two adjacent resonators, we demonstrate multiplexing functionality for channel spacings of 200 GHz, 100 GHz, and 50 GHz, with channel wavelengths aligned to International Telecommunication Union (ITU) grid specifications. Crosstalk values for 200 GHz and 50 GHz channel spacings are less than -20 dB and -11.5 dB, respectively. The total power to achieve this performance is in the range of 1.84 mW to 2.4 mW. Such low-power, compact, and reconfigurable filters are particularly useful in chip-scale optical interconnects.

1x4 reconfigurable demultiplexing filter based on free-standing silicon racetrack resonators.

We present a comparative analysis of different physical approaches to chip-to-chip proximity communication, PxC, based on capacitive, inductive and optical signalling. Each method is modeled theoretically and the tolerances for packaging are identified. Analytical formulas for performance in terms of the pad size and pad spacing are derived and compared to reported experimental data. The tolerance of each communication method to misalignment is reported. The design space in terms of channel density and chip separation for capacitive and inductive proximity communication is explored for a specified bit-error-rate (BER) or signal-to-noise ratio (SNR) and transmitter power or voltage. The relative merits of each technology are discussed. A general conclusion is that capacitive proximity communication is advantageous for dense communication with small pads at low voltages and when low raw bit-error rates are required; however a hard requirement for vertical separation between chips is identified, independent of the area of the pads, and fixed by the supply voltage and the technology parameters. On the other hand, inductive communication provides a larger working range of chip separations, and is advantageous when larger pad sizes are used; however the minimum voltage is similarly constrained in order to maintain low bit-error rates. Optical proximity communication potentially provides the largest chip separations, but has low tolerance to in-plane misalignment.

Alignment and Performance Considerations for Capacitive, Inductive, and Optical Proximity Communication

We demonstrate the generation of broadband terahertz (THz) frequency radiation from photoconductive emitters formed from Fe-doped InGaAs (Fe:InGaAs), grown by metal-organic chemical vapor deposition, following pulsed (femtosecond) laser excitation at wavelengths ranging from 830 nm to 1.55 μm. The Fe is incorporated epitaxially during growth, giving precise control over the doping level. Using both single-crystal ZnTe and GaP electro-optic detectors over the same wavelength range, the emission spectra from several Fe:InGaAs wafers with different Fe content were measured, with THz emission from all wafers showing bandwidths in excess of 2.0 THz. The THz output power was found to be strongly dependant on the Fe content, the thickness of the Fe:InGaAs layer, and the excitation wavelength.

Terahertz emission from metal-organic chemical vapor deposition grown Fe:InGaAs using 830 nm to 1.55 μm excitation

We report ultra-low-power (690fJ/bit) operation of an optical receiver consisting of a germanium-silicon waveguide detector intimately integrated with a receiver circuit and embedded in a clocked digital receiver. We show a wall-plug power efficiency of 690microW/Gbps for the photonic receiver made of a 130nm SOI CMOS Ge waveguide detector integrated to a 90nm Si CMOS receiver circuit. The hybrid CMOS photonic receiver achieved a sensitivity of -18.9dBm at 5Gbps for BER of 10(-12). Enabled by a unique low-overhead bias refresh scheme, the receiver operates without the need for DC balanced transmission. Small signal measurements of the CMOS Ge waveguide detector showed a 3dB bandwidth of 10GHz at 1V of reverse bias, indicating that further increases in transmission rate and reductions of energy-per-bit will be possible.

A sub-picojoule-per-bit CMOS photonic receiver for densely integrated systems.

A review is conducted of recent advances in the technology and applications of on-chip integrated terahertz systems, in which pulses of terahertz frequency radiation are generated by a photoconductive material, guided through a planar waveguide, and then detected coherently by photoconductive detection. These integrated systems are highly compact compared with typical free-space time domain terahertz spectroscopy systems, and allow much smaller sample volumes to be investigated, since they concentrate the propagating terahertz field to a length-scale far smaller than the diffraction limit. How both time-domain spectroscopy and imaging can be acheived using on-chip terahertz systems is discussed, along with some potential future applications for on-chip systems in the terahertz spectroscopy of single nanostructures.

The talk will present the design of a silicon microsystem that utilizes photonic interconnects to enable a highly compact supercomputer-scale system. Recent progress in dense, wavelength-division multiplexed, low-power silicon photonic interconnect components will be reviewed.

2010 IEEE Compound Semiconductor Integrated Circuit Symposium (CSICS)

Compacting High-End Computing Systems with Dense, WDM Silicon Photonic Interconnects

Delivering On-chip Bandwidth Off-chip and Out-of-box with Proximity and Optical Communication

Many organic compounds exhibit characteristic absorption features in the terahertz (THz) frequency range. Yet, the precise origin of these features is still, in most cases, unknown. This paper shows how solid-state density functional theory can be used to understand the origin of THz spectra in organic crystals, and calculate the THz active normal modes.

Calculation of terahertz active normal modes in organic crystals

Broadband time-domain spectroscopy has been used to measure the terahertz frequency absorption of single crystal proteins. A dehydration study of tetragonal hen egg-white lysozyme is presented as a proof of concept.

Scaling of high performance, many-core, computing systems calls for disruptive solutions to provide ultra energy efficient and high bandwidth density interconnects at very low cost. Silicon photonics is viewed as a promising solution. For silicon photonics to prevail and penetrate deeper into the computing system interconnection hierarchy, it requires innovative optical devices, novel circuits, and advanced integration. We review our recent progress in key building blocks toward sub pJ/bit optical link for inter/intra-chip applications, ultra-low power silicon photonic transceivers. In particular, compact reverse biased silicon ring modulator was developed with high modulation bandwidth sufficient for 15Gbps modulation, very small junction capacitance of ~50fF, low voltage swing of 2V, high extinction ratio (>7dB) and low optical loss (~2dB at on-state). Integrated with low power CMOS driver circuits using low parasitic microsolder bump technique, we achieved record low power consumption of 320fJ/bit at 5Gbps data rate. Stable operation with biterror- rate better than 10-13 was accomplished with simple thermal management. We further review the first hybrid integrated silicon photonic receiver based on Ge waveguide photo detector using the same integration technique, with which high energy efficiency of 690fJ/bit, and sensitivity of ~18.9dBm at 5Gbps data rate for bit-error-rate of 10-12 were achieved.

Ultra-low power silicon photonic transceivers for inter/intra-chip interconnects

Ring waveguide resonating structures with high quality factors are the key components in the silicon photonics portfolio boosting up its functionality and circuit performance. Due to a number of manufacturing reasons their peak wavelengths are often prone to deviate from designed values. In order to keep the ring resonator operating as specified, its peak wavelength then needs to be corrected in a reliable and power efficient way. We demonstrate the performance of the thermally tunable mux/demux filter ring structures fabricated in the commercial 130 nm SOI CMOS line.

Interconnect Technologies and Advanced Packaging for High Performance Computing

We present a silicon photodiode implemented in a waveguide coupled ring resonator structure. Infrared detection was achieved by Si+ ion implantation. A 15 μm-radius ring-based detector demonstrated an equivalent responsivity to a 3 mm straight waveguide device.

2010 Conference on Optical Fiber Communication (OFC/NFOEC), collocated National Fiber Optic Engineers Conference

Optical interconnects in large-scale systems offer the possibility of new system topologies, with many multi-core processors and memories integrated together and densely co packaged. This opens up new possibilities in large-scale installations like data centers, supporting both commercial and scientific applications. A first step is to explore the optical and electrical circuits and devices required to create optical links, but many interesting research questions remain about how to construct large-scale systems that employ those links.

We present an advanced wavelength-division multiplexing point-to-point network enabled by silicon nanophotonic devices. This network offers strictly non-blocking all-to-all connectivity while maximizing bisection bandwidth, making it ideal for multi-core and multi-processor interconnections. We introduce one of the key components, the nanophotonic grating coupler, and discuss, for the first time, how this device can be useful for practical implementations of the wavelength-division multiplexing network using optical proximity communications. Finite difference time-domain simulation of the nanophotonic grating coupler device indicates that it can be made compact (20 microm x 50 microm), low loss (3.8 dB), and broadband (100 nm). These couplers require subwavelength material modulation at the nanoscale to achieve the desired functionality. We show that optical proximity communication provides unmatched optical I/O bandwidth density to electrical chips, which enables the application of wavelength-division multiplexing point-to-point network in macrochip with unprecedented bandwidth-density. The envisioned physical implementation is discussed. The benefits of such an interconnect network include a 5-6x improvement in latency when compared to a purely electronic implementation. Performance analysis shows that the wavelength-division multiplexing point-to-point network offers better overall performance over other optical network architectures.

A macrochip interconnection network enabled by silicon nanophotonic devices.

Capacitively-coupled communication between chips, commonly known as PxC, represents a new class of I-O signaling that offers substantially improved off-chip bandwidth density. However, this form of communication presents a challenge from a packaging perspective, since tight chip alignment tolerances are required to maintain high signal fidelity and avoid cross coupling between neighboring channels. To mitigate the packaging constraints, capacitive coupling between the communication pads can be enhanced with materials that have high dielectric coefficients. Here, ferroelectrics hold promise over contemporary low- and high-k dielectrics, however their processing conditions need to be better understood and the compatibility with CMOS circuitry has to be established during integration with a back end of the line process module. In this paper we present experimental results on microfabrication modules for various families of ferroelectrics when monolithically deposited on Silicon. Additionally, we report their...

We report a new method that precisely self-aligns face-to-face semiconductor chips or wafers to enable communication between the chips using electromagnetic waves. Our alignment mechanism takes advantage of miniaturized versions of two of nature's idealized shapes: an inverse pyramidal shape defined by a self-terminating wet-etch process in silicon and micro-spheres with radii accurate to submicron accuracy. This approach allows chips to be packaged using passive alignment that is self locating and reaches nearly one micron level of chip misalignment tolerance. Packages for applications to capacitive and optical connections are presented. Additionally, we describe a physical architecture for a multi-chip array packages with ¿bridge¿ and ¿island¿ chips where the function of the bridge is to transfer electromagnetic signals between island chips using either capacitive or optical proximity communication. The bridge chip can provide a predetermined amount of compliance to help maintain alignment and thereby accommodate topology variants in first level package or in chip thickness when required. Experimental packages providing precise alignment between 1-D arrays and 2-D arrays of chips are presented. We show that our precision alignment mechanism enables high fidelity 10 Gb/s optical-proximity-communication with reflecting mirrors micro-machined into Silicon and co-integrated to low loss silicon-on-insulator waveguides for chip-to-chip communication. The alignment mechanism was also applied to a demonstration of chip-to-chip capacitive proximity communication in a linear array of six chips. Alignment measurements on a 4 × 4 array of chips are reported.

Aligning Chips Face-to-Face for Dense Capacitive and Optical Communication

We report, for the first time, high performance three-well, resonant-phonon depopulation, terahertz quantum cascade lasers with thinned active regions. Lasers operated at 3.1 THz in a surface plasmon waveguide. The variation of output power, maximum operating temperature, and threshold current density is presented for active regions of 10 µm, 7,5 µm, 6 µm, and 5 µm thickness, and in each case results are presented as a function of duty cycle.

Three-well, resonant-phonon depopulation, quantum cascade lasers with thinned active regions and surface-plasmon waveguides

Two novel packaging technologies have been developed to serve as essential building blocks for construction of a photonically interconnected large-chip array. Ultralow parasitic microsolder interconnections (on the order of 100 mOhm/bump and 25 fF/bump) allow combination of best-in-class chips, which may be built on different technology platforms, and CMOS compatible ball-in-etch-pit structures provide a non-permanent passive selfaligning mechanism for highly accurate componentto-component placement.

We report a novel high-speed Ge photodetector on a large cross-section SOI waveguide platform. The device is butt-coupled with waveguide using a horizontal p-i-n junction configuration to enable highspeed operation. A very compact Ge detector with an active area of only 0.8 × 10 μm2, greater than 32GHz optical bandwidth at -1V of reverse bias, and a responsivity of 1.1A/W is demonstrated.

Horizontal p-i-n high-speed Ge waveguide detector on large cross-section SOI waveguide

We demonstrate a very efficient high speed silicon carrier-depletion Mach-Zehnder (MZ) modulator with an ultralow π-phase-shift voltage-length product VπL=1.4V-cm. The 3dB bandwidth of a typical 1mm long device was measured to be more than 12GHz.

High Speed Silicon Carrier-Depletion Mach-Zehnder Modulator with 1.4V-cm VπL

We present thermally tunable silicon racetrack resonators with an ultralow tuning power of 2.4 mW per free spectral range. The use of free-standing silicon racetrack resonators with undercut structures significantly enhances the tuning efficiency, with one order of magnitude improvement of that for previously demonstrated thermo-optic devices without undercuts. The 10%-90% switching time is demonstrated to be ~170 µs. Such low-power tunable micro-resonators are particularly useful as multiplexing devices and wavelength-tunable silicon microcavity modulators.

Thermally tunable silicon racetrack resonators with ultralow tuning power.

We report a very compact (1.6μmx10μm) and low dark current (20nA) Germanium p-i-n photodetector integrated on 0.25μm thick silicon-on-insulator (SOI) waveguides. A thin layer of Germanium was selective-epitaxially grown on top of SOI waveguides. Light is evanescently coupled into Germanium layer from the bottom SOI waveguide. The device demonstrates superior performance with demonstrated responsivity of 0.9A/W and 0.56A/W at wavelength of 1300nm and 1550nm, respectively, and dark current less than 20nA at -0.5V bias. The 3dB bandwidth of the device is measured to be 23GHz at -0.5V bias.

A compact high-performance germanium photodetector integrated on 0.25μm thick silicon-on-insulator waveguide

In this paper we present a computing system that uniquely leverages the bandwidth, density, and latency advantages of silicon photonic interconnects to enable highly compact supercomputerscale systems. We present the details of an optically enabled "macrochip" which is a set of contiguous, optically-interconnected chips that deploy wavelength-division multiplexed (WDM) enabled by silicon photonics. We describe the system architecture and the WDM point-to-point network implementation of a "macrochip" providing bisection bandwidth of 10 TBps and discuss system and device level challenges, constraints, and the critical technologies needed to implement this system. We present a roadmap to lowering the energy-per-bit of a silicon photonic interconnect and highlight recent advances in silicon photonics under the UNIC program that facilitate implementation of a "macrochip" system made of arrayed chips.

"Macrochip" computer systems enabled by silicon photonic interconnects

We report the first monolithically integrated chip-to-chip WDM optical proximity coupler with 4-channel × 200GHz-spacing multiplexer/demultiplexer (MUX/DEMUX) functionality utilizing an echelle grating, micro reflective mirrors, and waveguide mode transformers on single silicon-on-insulator (SOI) substrate.

Monolithic chip-to-chip WDM optical proximity coupler utilizing echelle grating multiplexer/demultiplexer integrated with micro mirrors built on SOI platform

We demonstrate spectral tunability for a microphotonic add-drop filter manufactured as ring resonator in commercial 130 nm SOI CMOS technology. The filters are provisioned with an integrated heater built in CMOS for thermal tuning. Their thermal impedance has been dramatically increased by the selective removal of the SOI handler substrate under the device footprint using silicon micromachining technology. An overall ∼20x increase in the tuning efficiency has been demonstrated with a 100 um radii ring that requires 3.9mW of the applied tuning power to shift the filter resonant peak across the entire free spectral range. Our result represents record tuning metrics for this class of device.

The nonparabolic Schrodinger equation for electrons in quantum cascade lasers (QCLs) is a cubic eigenvalue problem (EVP) which cannot be solved directly. While a method for linearizing this cubic EVP has been proposed in principle for quantum dots [Hwang et al., Math. Comput. Modell., 40, 519 (2004)] it was deemed too computationally expensive because of the three-dimensional geometry under consideration. We adapt this linearization approach to the one-dimensional geometry of QCLs, and arrive at a direct and exact solution to the cubic EVP. The method is then compared with the well established shooting method, and it is shown to be more accurate and reliable for calculating the bandstructure of mid-infrared QCLs.

Finite difference method for solving the Schrödinger equation with band nonparabolicity in mid-infrared quantum cascade lasers

The terahertz frequency spectrum of pentaerythritol tetranitrate (PETN) is calculated using Discover with the COMPASS force field, CASTEP and PWscf. The calculations are compared to each other and to terahertz spectra (0.3-3 THz) of crystalline PETN recorded at 4 K. A number of analysis methods are used to characterise the calculated normal modes.

Chemphyschem : a European journal of chemical physics and physical chemistry

Calculation and measurement of terahertz active normal modes in crystalline PETN.

The Ultra-performance Nanophotonic Intrachip Communication (UNIC) project aims to achieve unprecedented high-density, low-power, large-bandwidth, and low-latency optical interconnect for highly compact supercomputer systems. This project, which has started in 2008, sets extremely aggressive goals on power consumptions and footprints for optical devices and the integrated VLSI circuits. In this paper we will discuss our challenges and present some of our first-year achievements, including a 320 fJ/bit hybrid-bonded optical transmitter and a 690 fJ/bit hybrid-bonded optical receiver. The optical transmitter was made of a Si microring modulator flip-chip bonded to a 90nm CMOS driver with digital clocking. With only 1.6mW power consumption measured from the power supply voltages and currents, the transmitter exhibits a wide open eye with extinction ratio >7dB at 5Gb/s. The receiver was made of a Ge waveguide detector flip-chip bonded to a 90nm CMOS digitally clocked receiver circuit. With 3.45mW power consumption, the integrated receiver demonstrated -18.9dBm sensitivity at 5Gb/s for a BER of 10-12. In addition, we will discuss our Mux/Demux strategy and present our devices with small footprints and low tuning energy.

Ultralow-power silicon photonic interconnect for high-performance computing systems

We demonstrate a very efficient high speed silicon modulator with an ultralow pi-phase-shift voltage-length product V(pi)L = 1.4V-cm. The device is based on a Mach-Zehnder interferometer (MZI) fabricated using 0.25microm thick silicon-on-insulator (SOI) waveguide with offset lateral PN junctions. Optimal carrier-depletion induced index change has been achieved through the optimization of the overlap region of carriers and photons. The 3dB bandwidth of a typical 1mm long device was measured to be more than 12GHz. An eye-diagram taken at a transmission rate of 12.5Gb/s confirms the high speed capability of the device.

High speed carrier-depletion modulators with 1.4V-cm V(pi)L integrated on 0.25microm silicon-on-insulator waveguides.

We review recent experiments on the use of terahertz frequency time-domain spectroscopy to sense materials of security relevance. We also explore developments in the use of terahertz quantum cascade lasers to discriminate such materials, and new THz sources that can potentially exploit convenient communication wavelength excitation lasers.

Proceedings of the Fourth European Conference on Antennas and Propagation

We report the first compact silicon CMOS 1x4 tunable multiplexer/ demultiplexer using cascaded silicon photonic ring-resonator based add/drop filters with a radius of 12 microm, and integrated doped-resistor thermal tuners. We measured an insertion loss of less than 1 dB, a channel isolation of better than 16 dB for a channel spacing of 200 GHz, and a uniform 3 dB pass band larger than 0.4 nm across all four channels. We demonstrated accurate channel alignment to WDM ITU grid wavelengths using integrated silicon heaters with a tuning efficiency of 90 pm/mW. Using this device in a 10 Gbps data link, we observed a low power penalty of 0.6 dB.

A tunable 1x4 silicon CMOS photonic wavelength multiplexer/demultiplexer for dense optical interconnects.

Proximity communication (PxC) technology has attracted great attention in recent years for its potential in low power, high bandwidth multi-chip module applications. In our previously demonstrated PxC MCM package, a 3-chip sub-assembly with two Active chips communicated through a Bridge chip and was flip-chip bonded to the substrate. The Bridge and Active chips overlap, and are face-to face bonded with silicone-based adhesive. The low pin count Bridge chip (face-up) relied on the bonded Au wire to deliver power and low speed I/Os. The parasitic inductance of the bondwires limited bandwidth on the Bridge, which motivated an alternative way to power the face-up Bridge chip. In this paper, we report chip-to-chip bonding using Anisotropic Conductive Film (ACF) as the dielectric adhesive between PxC channels. ACF provided direct vertical conductive path to power the Bridge chip. In addition, the introduction of conductive particles could increase the effective dielectric constant of the adhesive which benefits capacitively- signal coupling for proximity communications. The bonding experiment was carried out using a two-stage alignment and bonding/cure process at Sony Chemical & Information Device Corporation. Physical characterizations such as SAT, SEM, EDX were carried out to investigate bond line, alignment and quality of the adhesive interfaces. The effect of the floating metallic particles inside the ACF material on the local capacitive channels was simulated using a commercial FEM solver Q3D Extractor from ANSYS. We also tested conductive channel continuity through boundary scan-chain test of the Island chips. The initial results indicates that ACF sandwiched between two chips formed a uniform, void free bondline.

Direct chip powering and enhancement of proximity communication through Anisotropic Conductive adhesive chip-to-chip bonding

We report the first sub-picojoule per bit (400fJ/bit) operation of a silicon modulator intimately integrated with a driver circuit and embedded in a clocked digital transmitter. We show a wall-plug power efficiency below 400microW/Gbps for a 130nm SOI CMOS carrier-depletion ring modulator flip-chip integrated to a 90nm bulk Si CMOS driver circuit. We also demonstrate stable error-free transmission of over 1.5 petabits of data at 5Gbps over 3.5 days using the integrated modulator without closed-loop ring resonance tuning. Small signal measurements of the CMOS ring modulator, sans circuit, showed a 3dB bandwidth in excess of 15GHz at 1V of reverse bias, indicating that further increases in transmission rate and reductions of energy-per-bit is possible while retaining compatibility with CMOS drive voltages.

Silicon photonics holds tremendous promise as an energy and bandwidth efficient interconnect technology for chip-to-chip and within-chip communications in high-performance computing systems. In this paper, we present a low-parasitic microsolder-based flip-chip integration method used to integrate silicon photonic modulators and photodetectors with high-speed VLSI circuits using chips fabricated on vastly different technology platforms. Both the hybrid-integrated silicon photonic transmit (Tx) and receive (Rx) components were tested to demonstrate record sub-picojoule-per-bit performance at 5 Gbps.

Flip-chip integrated silicon photonic bridge chips for sub-picojoule per bit optical links

The high current properties of a micro spring pressure contact are characterized. The spring has large compliance (>30 µm) compared to other packaging technologies and fits in a 180 µm pitch 2d array. At 250 mA and 65 ˚C, daisy chains of 134 spring contacts in a silicon package show stable resistances and hotspot temperature rises of less than a degree. At 1 amp, failure near the spring tip or body is observed. Finite element modeling is performed to study the current distribution and provide failure mode insight. Simultaneous force and resistance measurements suggest there is no spring force softening. The results suggest a 10

HIGH CURRENT PROPERTIES OF A MICROSPRING CONTACT FOR FLIP CHIP PACKAGING

We review the potential benefits and challenges for achieving optical-interconnects to the chip via the native integration of silicon photonics components with VLSI electronics; and review the “macrochip” - a collection of contiguous silicon chips enabled by optical proximity communication. We summarize recent progress towards achieving low-power photonic links for the macrochip.

The Integration of Silicon Photonics and VLSI Electronics for Computing and Switching Systems

We report a 320fJ/bit transmitter made of a Si microring modulator flip-chip bonded to a CMOS driver. The transmitter consumes only 1.6mW power, and exhibits a wide open eye with extinction ratio >7dB at 5Gb/s.

We demonstrate spectral tunability for microphotonic add-drop filters manufactured as ring resonators in a commercial 130 nm SOI CMOS technology. The filters are provisioned with integrated heaters built in CMOS for thermal tuning. Their thermal impedance has been dramatically increased by the selective removal of the SOI handler substrate under the device footprint using a bulk silicon micromachining process. An overall ~20x increase in the tuning efficiency has been demonstrated with a 100 µm radius ring as compared to a pre-micromachined device. A total of 3.9 mW of applied tuning power shifts the filter resonant peak across one free spectral node of the device. The Q-factor of the resonator remains unchanged after the co-integration process and hence this device geometry proves to be fully CMOS compatible. Additionally, after the cointegration process our result of 2π shift with 3.9 mW power is among the best tuning performances for this class of devices. Finally, we examine scaling the tuning efficiency versus device footprint to develop a different performance criterion for an easier comparison to evaluate thermal tuning. Our criterion is defined as the unit of power to shift the device resonance by a full 2π phase shift.

We report the performance of 3.5 THz quantum cascade lasers in which the laser cavities are formed by wet chemical etching and show that laser ridges can be obtained using angled facets. This opens up the possibility of monolithic integration of quantum cascade lasers into terahertz circuits.

Terahertz quantum cascade lasers with angled facets for monolithic integration

We report a vertical p-i-n thin-film germanium photodetector integrated on 3microm thick large core silicon-on-insulator (SOI) waveguides. The device demonstrates very high external responsivity due to the low fiber coupling loss to the large core waveguides. The germanium width and thickness are carefully designed to achieve high responsivity yet retain high-speed performance. Even with fiber coupling loss included, the device has demonstrated greater than 0.7A/W external responsivity at 1550nm for TM polarization and 0.5A/W for TE polarization. A low dark current of 0.2microA at -0.5V bias is reported. 3dB bandwidths of 12GHz and 8.3GHz at -2.5V bias are also reported for 100microm and 200microm long devices, respectively. The device can cover the communication wavelength spectrum up to 1620nm with a relatively flat responsivity of >0.5A/W. Further studies suggest that with a modified design the device is capable of achieving 1A/W external responsivity for both TE and TM polarizations and greater than 30GHz bandwidth.

Vertical p-i-n germanium photodetector with high external responsivity integrated with large core Si waveguides.

Advances in silicon photonic technology have made possible the use of optical communication in large-scale chip arrays. This article shows how such a structure utilizes the high bandwidth of the optical links through optical proximity communication that enables significant levels of device integration.

We review the potential benefits and challenges for achieving optical-interconnects to the chip via the native integration of silicon photonics components with VLSI electronics; and review the "macrochip" a collection of contiguous silicon chips enabled by optical proximity communication. We summarize recent progress towards achieving low-power photonic links for the macrochip.

Low-power photonic links: Breaking the picojoule-per-bit barrier

We present ultra low power silicon photonic transceivers, including a 320fJ/bit reverse biased ring modulator integrated with CMOS driver, and a 690fJ/bit record-low power receiver with sensitivity of −18.9dBm at 5Gbps for bit-error-rate of 10−12.

Proximity Communication (PxC) enables VLSI chips placed face-to-face to communicate using close-field capacitive coupling. In a 90 nm standard CMOS technology, using the packaging techniques described in this paper, PxC provides chip-to-chip latency of 2.5 ns at 4 Gb/s per channel with less than 2.5 mW/Gb/s, an areal bandwidth density of 0.83 Tb/s/mm2 , and a BER less than 10−15 . At a system level, the benefits of PxC scale directly with the number of chips that can be packaged together, because PxC enables designers to aggregate multiple chips that perform as a single large piece of silicon. The chips can also be heterogeneous to provide an optimized mix of process technology and functionality, such as integrating DRAM chips, NAND flash memory, and CMOS processor chips. In this paper we describe packaging advances and technology prototypes that enable PxC and provide its system-level benefits.Copyright © 2009 by ASME

Integrating Novel Packaging Technologies for Large Scale Computer Systems

We report the development of a terahertz pulsed spectroscopic imaging system based on the concept of compressive sensing. A single-point terahertz detector, together with a set of 40 optimized two-dimensional binary masks, was used to measure the terahertz waveforms transmitted through a sample. Terahertz time- and frequency-domain images of the sample comprising 20×20 pixels were subsequently reconstructed. We demonstrate that both the spatial distribution and the spectral characteristics of a sample can be obtained by this means. Compared with conventional terahertz pulsed imaging, no raster scanning of the object is required, and ten times fewer terahertz spectra need be taken. It is therefore ideal for real-time imaging applications.

Terahertz pulsed spectroscopic imaging using optimized binary masks

A novel packaging approach has been demonstrated for circuits connected with flexible microsprings. The approach is based on silicon micromachined features and results in a highly accurate and low cost packaging solution. The micromachined features were processed into silicon with an anisotropic wet etch forming inverted pyramidal micro-pits. The pits are integrated into the chips along with arrays of flexible and compliant interconnects arranged in a daisy chain arrays on 180 µm pitch. Packages based on two chips with matching set of pits have been assembled and characterized. First level reliability tests have been performed in 0°C–100°C temperature cycling, 85/85 temperature humidity bias and high-current soak. Multiple “remating”; tests were also carried out as the packages were taken apart and reassembled together. The “pit and spring” integration is expected to equally address not only the performance and functionality of the completed package but also its reliability and cost.

Novel packaging with rematable spring interconnect chips for MCM

Recent advances in silicon photonics bring significant benefits to “macrochip” grids made of arrayed chips. Such configurations have global interconnects long enough to benefit from the high speed, low energy, and high bandwidth density of optics. In this paper we consider the constraints of large macrochip systems, and explore modulator drivers and photodetector receivers that match those constraints. We show measured results from a recent 90 nm testchip intended to mate with optical components.

We review the progress and challenges in scaling computing systems; discuss the potential benefits and challenges for achieving optical-interconnects to the chip via the native integration of silicon photonics components with VLSI electronics; and introduce the "macrochip" - a collection of contiguous silicon chips enabled by optical proximity communication

The integration of silicon photonics and VLSI electronics for computing systems intra-connect

The laser excitation wavelength is an important parameter in obtaining Raman spectra from drugs-of-abuse. This article compares the effect of near infrared wavelengths, 785 nm, using both benchtop and portable instrumentation and benchtop 1064 nm on the Raman spectra of seized drugs-of-abuse, including cocaine hydrochloride, cocaine freebase (crack), methylenedioxymethamphetamine ('ecstasy'), amphetamine, diamorphine (heroin) and cannabis. The significant benefit of using 1064 nm for the interrogation of this type of sample is highlighted. Â© 2009 John Wiley & Sons, Ltd.

Comparison of near infrared laser excitation wavelengths and its influence on the interrogation of seized drugs-of-abuse by Raman spectroscopy

We present a novel optically-enabled ball grid array (OBGA) package that integrates conventional electrical I/O, proximity communication (PxC), and optical communication in one industry-compatible BGA package for the first time. The key enabling technologies for such a packaging solution, including the precision alignment needed to combine multiple CMOS chips and compact opto-electronic (OE) subassemblies, are detailed here. We designed and fabricated a 45 mm × 45 mm × 5.2 mm organic cavity-down BGA package with up to 600 solder balls for electrical I/O. Its cavity holds three CMOS chips, with PxC interfaces and optical driver/receiver circuits, as well as two multi-channel optical subassemblies with standard optical fiber connections. We report preliminary testing results.

BGA package integration of electrical, optical, and capacitive interconnects

We report the first 400fJ/bit all-CMOS silicon photonic transmitter made of CMOS depletion ring modulator flip-chip integrated with CMOS driver, and demonstrated error-free 5Gbps transmission of over 1.5Pbits of data without closed-loop ring resonance tuning.

We report dual-frequency imaging using an electrically tunable terahertz frequency quantum cascade laser (QCL). Images of powdered materials including the explosive pentaerythritol tetranitrate (PETN) were acquired at 3.05 THz and 3.24 THz in a single scan. We show that it is possible to distinguish PETN from other materials by taking the difference-transmission and difference-attenuation images. We also demonstrate difference-intensity imaging by combining amplitude modulation of the QCL bias with lock-in detection.

2009 34th International Conference on Infrared, Millimeter, and Terahertz Waves

Dual-frequency imaging using an electrically tunable terahertz quantum cascade laser

The two-dimensional concentration and manipulation of micron-scale particles by orthogonal, surface acoustic, standing waves is demonstrated. The particles are organized by liquid pressure waves in a microfluidic system over a piezoelectric substrate and form a uniform two-dimensional array with a spacing governed by the mechanical nodes of the two orthogonal, surface acoustic, standing waves. The nodal spacing can be controlled in each orthogonal direction independently by adjustment of the radio frequency applied to the separate acoustic wave transducers. This technique could be used to enhance the particle concentrations at sensing locations in DNA or protein array detectors.

Formation and manipulation of two-dimensional arrays of micron-scale particles in microfluidic systems by surface acoustic waves

We review the potential benefits and challenges for achieving optical-interconnects to the chip via the native integration of silicon photonics components with VLSI electronics; and introduce the “macrochip” — a collection of contiguous silicon chips enabled by optical proximity communication.

The integration of silicon photonics and VLSI electronics for computing systems

We present a computing microsystem that uniquely leverages the bandwidth, density, and latency ad- vantages of silicon photonic interconnect to enable highly compact supercomputer-scale systems. We describe and justify single-node and multinode systems interconnected with wave- length-routed optical links, quantify their benefits vis-a`-vis electrically connected systems, analyze the constituent optical component and system requirements, and provide an overview of the critical technologies needed to fulfill this system vision. This vision calls for more than a hundredfold reduction in energy to communicate an optical bit of information. We explore the power dissipation of a photonic link, suggest a roadmap to lower the energy-per-bit of silicon photonic interconnects, and identify the challenges that will be faced by device and circuit designers towards this goal.

Computer Systems Based on Silicon Photonic Interconnects A proposed supercomputer-on-a-chip with optical interconnections between processing elements will require development of new lower-energy optical components and new circuit architectures that match electrical datapaths to complementary optical

We have measured the picosecond-timescale response of Goubau-line waveguides integrated with regions of low-temperature-grown gallium arsenide, which act as both pulsed photoconductive emitters and detectors. We demonstrate, using two pairs of excitation / detection switches, detection of the radial propagation mode of the Goubau-line, with signal components extending above 800 GHz. This waveguide geometry offers advantages compared to microstrip or coplanar-line geometries for on-chip guiding of terahertz radiation.

Terahertz goubau waveguides with integrated photoconductive emitters and mode discriminating detectors

We introduce a novel approach to interconnect multiple chips together with a silicon photonic WDM point-to-point network enabled by optical proximity communications to act as a single large piece of logical silicon much larger than a single reticle limit. We call this structure a macrochip. This non-blocking network provides all-to-all low-latency connectivity while maximizing bisection bandwidth, making it ideal for multi-core and multi-processor interconnections. We envision bisection bandwidth up to TBps for an 8x8 macrochip design. And a 5-6x improvement in latency can be achieved when compared to a purely electronic implementation. We also observe better overall performance over other optical network architectures.

A silicon photonic WDM network for high-performance macrochip communications

We report high-fidelity 10-Gb/s optical-proximity-communication using reflecting mirrors micro-machined into silicon and co-integrated with low-loss silicon-on-insulator waveguides for packaged chip-to-chip communication. Device integration was carried out by dry etching a rib waveguide 8 mum wide that was tapered to a width of 13 mu m and subsequently truncated with a wet-etched, micro-mirror facet forming a 54deg angle with the (100) surface. Light in waveguides on a bottom chip can couple to waveguides on a top chip upon face-to-face positioning so that the reflecting mirrors form a coupled pair and complete an optical proximity hop. High-speed link measurements were accomplished with chips aligned with a six-axis nano-positioner stage and compared with results for a new precision alignment approach that packages silicon chips for proximity signaling. Our new packaging approach is based on the co-integration of pyramidal etch pits micro-machined into silicon that match a precision micro-sphere for accurate chip alignment. Assemblies of chips can self-align in the package using chip placement that is initially coarse. The final chip alignment accuracy of our new packaging approach is limited by photolithographic resolution. Additionally, multichip arrays can be aligned together with global positioning having similar precision. Nonreturn-to-zero data was fiber launched into the waveguides and transported across a package consisting of a three-chip assembly with two optical proximity hops for inter-chip communication. Continuous wave optical losses, eye diagrams, bit error rates, and power penalties were measured. A passively aligned chip-to-chip optical proximity hop in the package was measured to have optical coupling loss of 4.0 dB, which was 1 dB more than when measured with precision-aligned chips with a nano-positioning stage. RMS jitter and amplitude metrics for the eye quality are shown to be nearly identical (to within 1%) when OPxC hops associated with the package is inserted into 10-Gb/s links. This self-aligned mechanism enables chip packages for several classes of proximity communication.

Optical Proximity Communication With Passively Aligned Silicon Photonic Chips

Terahertz frequency time-domain spectroscopy has been used to analyse a wide range of samples containing cocaine hydrochloride, heroin and ecstasy--common drugs-of-abuse. We investigated real-world samples seized by law enforcement agencies, together with pure drugs-of-abuse, and pure drugs-of-abuse systematically adulterated in the laboratory to emulate real-world samples. In order to investigate the feasibility of automatic spectral recognition of such illicit materials by terahertz spectroscopy, principal component analysis was employed to cluster spectra of similar compounds.

Broadband terahertz time-domain spectroscopy of drugs-of-abuse and the use of principal component analysis.

We demonstrate a compact, high speed Ge photodetector efficiently butt-coupled with a large cross-section silicon-on-insulate (SOI) waveguide in which the Ge p-i-n junction is placed in the horizontal direction to enable very high speed operation. The demonstrated photodetector has an active area of only 0.8×10 μm2, greater than 32 GHz optical bandwidth, and a responsivity of 1.1 A/W at a wavelength of 1550 nm. Very importantly the device can readily be integrated with high performance wavelength-division-multiplexing filters based on large cross-section SOI waveguide to form monolithic integrated silicon photonics receivers for multichannel terabit data transmission applications.

High-speed Ge photodetector monolithically integrated with large cross-section silicon-on-insulator waveguide

There have been a number of recent high-profile advances in silicon-integrated optical devices, including low-loss silicon waveguides, integrated laser modulators and photodetectors, optical gratings for surface-normal attach of fibers to chips, and many more. These technologies open the possibility of using silicon-based nano-photonics inside a traditional computer system based on very large scale integration (VLSI) chips using todays most advanced complementary metal-oxide-silicon (CMOS) technologies. Such a system might offer the cost and computing performance advantages of modern microprocessors in conjunction with the low latency and enormous bandwidth of wavelength-division multiplexing (WDM) optics.

2009 International Symposium on VLSI Design, Automation and Test

Communication in macrochips using silicon photonics for high-performance and low-energy computing

We demonstrate the efficient generation of terahertz (THz) radiation from Fe-doped InGaAs-based photoconductive antennas. We present time-domain data showing generation of pulsed THz radiation from antennas fabricated on two different wafers, optimized to maximize the near-infrared-to-THz conversion efficiency. Detection was performed using both (110) ZnTe and GaP crystals, with pump and probe wavelengths being adjusted from 800 nm to 1550 nm using a cavity-tuned OPO pumped by a pulsed near-infrared Ti:Sapphire laser.

THz generation using 800 to 1550 nm excitation of photoconductors

We present a computing microsystem that uniquely leverages the bandwidth, density, and latency advantages of silicon photonic interconnect to enable highly compact supercomputer-scale systems. We describe and justify single-node and multinode systems interconnected with wavelength-routed optical links, quantify their benefits vis-a-vis electrically connected systems, analyze the constituent optical component and system requirements, and provide an overview of the critical technologies needed to fulfill this system vision. This vision calls for more than a hundredfold reduction in energy to communicate an optical bit of information. We explore the power dissipation of a photonic link, suggest a roadmap to lower the energy-per-bit of silicon photonic interconnects, and identify the challenges that will be faced by device and circuit designers towards this goal.

We have measured the picosecond time-domain response of Goubau-line waveguides, formed on quartz substrates, by integrating regions of low-temperature-grown gallium arsenide into the waveguides to act both as pulsed current emitters and detectors. Using one pair of photoconductive switches for excitation and a second pair for detection, pulsed signal propagation of a low dispersion electric field mode was demonstrated in the Goubau-lines, with the signal bandwidth extending beyond 800 GHz. Furthermore, it was demonstrated that terahertz bandstop filters can be integrated into a Goubau-line for removal of specific frequencies from the transmitted pulses.

On-chip terahertz Goubau-line waveguides with integrated photoconductive emitters and mode-discriminating detectors

We review 10Gb/sec Optical Proximity Communication realized with packaged chips that carry SOI optical waveguides and reflecting mirrors micromachined in silicon. The high precision chip to chip alignment and placement was enabled by a new packaging concept based on the co-integration of pyramidal pit features defined by anisotropic silicon etch and matching high precision micro-spheres. We support this novel packaging approach with measured optical transmission data and discuss the extent of it towards other applications of Proximity Communication.

Terahertz time-domain spectroscopy is used to analyze a number of real-world drugs-of-abuse samples, common drug adulterants, and drugs systematically adulterated in the laboratory. Principle component analysis is used to cluster spectra of similar compounds, which could lead to automatic spectral recognition of illicit materials.

2008 33rd International Conference on Infrared, Millimeter and Terahertz Waves

Broadband terahertz time-domain spectroscopy of drugs-of-abuse mixtures and ‘street‘ samples

We report 10Gb/s optical-proximity-communication with reflecting mirrors micro-machined into Si and co-integrated to low loss SOI waveguides for chip to chip communication using a self-aligned-packaging mechanism with measured 4.0 dB coupling loss.

We report on the use of standing surface acoustic waves, formed on a single-crystal piezoelectric substrate, to organize micron-scale latex particles into an array comprising a series of lines in an adjacent microfluidic system. The lines of particles are formed parallel to the substrate surface and perpendicular to the surface acoustic wave vector. They extend across the width of the acoustic beam aperture, with a periodicity of one-half the surface acoustic wavelength. The position and spacing of the particle arrays can be altered by adjusting the acoustic wave frequency within the device passband. We discuss the mechanism responsible for the formation of the lines, which could be widely applicable to the alignment of microscopic objects held in suspension.

Alignment of particles in microfluidic systems using standing surface acoustic waves

Multi-core, multi-threaded processor chips provide opportunity for Si-compatible optical interconnects in the computing system hierarchy. We discuss energy, bandwidth, and density requirements for such interconnects and potentially achieving these requirements with advanced silicon photonics technologies.

We demonstrate that terahertz microstrip-line waveguides can be used to measure absorption spectra of polycrystalline materials with a high frequency resolution (∼2 GHz) and with a spatial resolution that is determined by the microstrip-line dimensions, rather than the free-space wavelength. The evanescent terahertz-bandwidth electric field extending above the microstrip line interacts with, and is modified by, overlaid dielectric samples, thus enabling the characteristic vibrational absorption resonances in the sample to be probed. As an example, the terahertz absorption spectrum of polycrystalline lactose monohydrate was investigated; the lowest lying mode was observed at 534(±2) GHz, in excellent agreement with free-space measurements. This microstrip technique offers both a higher spatial and frequency resolution than free-space terahertz time-domain spectroscopy and requires no contact between the waveguide and sample.

Terahertz vibrational absorption spectroscopy using microstrip-line waveguides

Optical interconnects are useful for high-performance electronic computing systems when the number-of-channels, the bit-rate per channel, the channel density, and the communication distance of electrical links are simultaneously stressed. We review the near-term and longer term opportunities for optical communication at the chassis, chip-package and silicon micro-system levels.

Optical Interconnects for Present and Future High-Performance Computing Systems

A technique for measuring the vibrational absorption spectra of polycrystalline materials in the terahertz (THz) frequency range is demonstrated. We show that the evanescent electric field extending above lithographically-defined on-chip THz microstrip waveguides can be used to measure absorption resonances, offering higher sensitivity than typical free-space THz time-domain spectroscopy systems permit. The results indicate that on-chip THz systems could find new applications in the analysis, quality control, and identification of polycrystalline materials, such as pharmaceutical compounds.

Terahertz vibrational absorption resonances observed using on-chip terahertz circuits

We demonstrate an evanescent field modality for terahertz frequency time-domain measurements, based on the interaction between a sample and the evanescent field extending above lithographically defined terahertz waveguides. We quantify this interaction using freely positionable dielectric samples (GaAs) moved in close proximity to the waveguide (a terahertz microstrip line), finding a reduction in the microstrip-propagating pulse amplitude and an increase in its time delay when the dielectric is brought into the microstrip evanescent field. We also show that the frequency response of resonant passive circuit elements (stub band-stop filters), integrated into the microstrip line, can be used to determine the terahertz frequency properties of scanned samples, opening the way for a terahertz subwavelength imaging modality, the resolution of which is limited by lithographic constraints, rather than by free-space diffraction.

Terahertz evanescent field microscopy of dielectric materials using on-chip waveguides

Optical proximity communication (OPxC) with reflecting mirrors is presented. Direct optical links are demonstrated for silicon chips with better than -2.5dB coupling loss, excluding surface losses. OPxC is a true broadband solution with little impairment to the signal integrity for high-speed optical transmission. With wavelength division multiplexing (WDM) enabled OPxC, very high bandwidth density I/O, orders of magnitude higher than the traditional electrical I/O, can be achieved for silicon chips.

We introduce a silicon photonic WDM point-to-point network enabled by novel optical proximity communications. This strictly non-blocking network provides scalable interconnectivity between chips low latency and high bisection bandwidth.

Silicon photonic WDM point-to-point network for multi-chip processor interconnects

A new technique for quantitative sub-wavelength mapping of terahertz dielectric permittivity is demonstrated, using on-chip resonant terahertz filters. Imaging results on etched semiconductor samples show the viability of the technique, and future applications are discussed.

Sub-wavelength imaging of terahertz dielectric permittivity using planar resonant circuits

We report temperature and magnetic field dependent terahertz time domain spectroscopy measurements on InMnAs. The temperature dependent transmission is shown to vary with Mn content and applied magnetic field strength.

Temperature dependent and magnetic field dependent terahertz spectroscopy of In1-xMnxAs

We have measured the far-infrared cyclotron absorption of a two-dimensional electron systems (2DES), formed in a GaAs/Al0.33Ga0.67As heterojunction, using transmission-mode terahertz (THz) time-domain spectroscopy. The frequency of cyclotron absorption was proportional to applied magnetic field (B-field) across the measurement range, and from this data, the electron effective mass was extracted. The temperature-dependence of the cyclotron absorption was also studied between 1.5-150 K, allowing the dynamics of electron scattering in the 2D electron system to be determined.

2007 Joint 32nd International Conference on Infrared and Millimeter Waves and the 15th International Conference on Terahertz Electronics

Cyclotron absorption in two-dimensional electron systems monitored by terahertz time-domain spectroscopy

Optical pump-probe measurements have been performed on superlattices of self-organised InAs quantum dots embedded in GaAs. These structures exhibit subpicosecond photocarrier lifetimes when excited at 800 nm, which increase with the ex situ annealing temperature.

Ultrafast optical response of InAs quantum dots for photoconductive applications

In this paper we review the growing role of photonics in interconnect applications. Challenges that such applications will present and the key benefits that the photonics platform has to offer will be reviewed. In particular, attention will be paid to a Si based platform which offers monolithic integration of electronic circuitry and photonic devices. System level concepts and issues, devices required and practical challenges were assessed and reviewed.

LEOS 2007 - IEEE Lasers and Electro-Optics Society Annual Meeting Conference Proceedings

Applications and Challenges for Silicon Photonics in Optical Interconnects

We present a 90 nm test chip integrating proximity communication, optics using external lasers and photodiodes, and CML electronics on a single CMOS chip which can route data at multi-Gb/s rates through any combination of its three interconnect interfaces. A robust and flexible unclocked datapath allows independent timing and margin characterization of each path.

CMOS Integration of Capacitive, Optical, and Electrical Interconnects

Broadband terahertz time-domain spectroscopy (THz-TDS) has been shown to be a valuable technique for the detection and analysis of explosives. In this paper, we present recent work on the use of this technique to analyse two pure explosives, 1,3,5-trinitroperhydro-1,3,5-triazine (RDX) and 1,3-dinitrato-2,2-bis(nitratomethyl)propane (PETN) and three plastic explosives (Semtex, SX2 and Metabel). For each explosive, a clear and unique spectral absorption fingerprint is found, which can be attributed to oscillations of the molecular lattice. Temperature dependent terahertz absorption measurements of RDX show that the observed vibrational modes are anharmonic in nature. Terahertz spectra are compared with Raman spectra, and the similarities and differences between the spectra produced by the two techniques are discussed. A molecular mechanics calculation approach is used to calculate vibrational intensities and frequencies, and these results are compared with experimental results at both room temperature and 4 K.

Broadband terahertz time-domain and Raman spectroscopy of explosives

Broadband terahertz time-domain spectroscopy (THz-TDS) has been used to measure the far-infrared (FIR) vibrational spectra of several commonly used pure explosives, including 2,4,6-trinitrotoluene (TNT), 1,3,5-trinitroperhydro-1,3,5-triazine (RDX), 1,3-dinitrato-2,2-bis(nitratomethyl)-propane (PETN), and two types of plastic explosive, SEMTEX and SX2. A number of distinct absorption peaks, originating from FIR-active vibrational modes of these polycrystalline energetic materials, were observed in the frequency range 0.3–7.5 THz (10–250 cm−1). In addition, the temperature-dependent FIR vibrational spectra of PETN were measured between 4 K and 296 K with several well-resolved absorption peaks observed across this temperature range. We find that as the temperature is reduced, the observed absorption peaks resolve into narrower features and shift towards higher frequencies. The temperature dependence of the spectra is explained in terms of the anharmonicity of the vibrational potentials of crystalline compounds, and an empirical fit is given to describe the peak shift with temperature.

Far-Infrared Spectroscopic Characterization of Explosives for Security Applications Using Broadband Terahertz Time-Domain Spectroscopy

The generation of terahertz (THz) transients in photoconductive emitters has been studied by varying the spatial extent and density of the optically excited photocarriers in asymmetrically excited, biased low-temperature-grown GaAs antenna structures. We find a pronounced dependence of the THz pulse intensity and broadband (>6.0 THz) spectral distribution on the pump excitation density and simulate this with a three-dimensional carrier dynamics model. We attribute the observed variation in THz emission to changes in the strength of the screening field.

Excitation-density-dependent generation of broadband terahertz radiation in an asymmetrically excited photoconductive antenna.

Combining the strengths of both proximity communication and optical communication, a new hybrid input-output (I/O) platform delivers on-chip bandwidth off-chip and over distance. We demonstrate, for the first time, a four-channel hybrid I/O interface by integrating proximity communication and vertical-cavity surface-emitting-laser-based parallel optical interconnects on the same commercial 90-nm complementary metal-oxide-semiconductor platform. The optical I/O can operate at 5 Gb/s per channel, and the complete hybrid I/O interface achieved 2.5 Gb/s per channel. We characterize the I/O link performance for various data rates and chip separations, and show 10-mum chip separation tolerance for proximity communication

Optical Transceiver Chips Based on Co-Integration of Capacitively Coupled Proximity Interconnects and VCSELs

Polyharmonic surface acoustic wave control of single-electron transport in semimetallic carbon nanotubes

Compute performance must continue to scale to meet the growing proliferation of computing capability and the reduced price per performance expected from computing systems manufacturers. Indeed, we have already witnessed over 5 orders of magnitude improvement in performance-per-dollar over the last three decades, well in excess of the improvements delivered by technology scaling alone. "Redshift" applications are those that are underserved by Moore's law, and require continued scaling and improvements in efficiencies at the system level. Examples of such applications include content servers and high-performance computing.

Potentials of Group IV Photonics Interconnects for "Red-shift" Computing Applications

We experimentally demonstrate for the first time the focusing of optical beams within an inhomogeneous dielectric metamaterial with space-variant polarizability, implemented by etching subwavelength structures into a Silicon slab. Light focusing is obtained by creating an artificial slab material with graded refractive index profile. The local refractive index within the slab is modulated by controlling the duty cycle of the subwavelength structures. The demonstrated metamaterial based component can be integrated with various other building blocks towards the realization of devices and systems in free space optics on a chip configuration.

Inhomogenous dielectric metamaterials with space-variant polarizability.

We overview and compare free-space and on-chip terahertz time-domain spectroscopy systems. Example spectroscopic applications are given for both types of system: vibrational spectroscopy of crystalline compounds for free-space systems, and assay of dielectric films for on-chip systems.

Terahertz time domain spectroscopy - present and future modalities

Several modalities have previously been presented for the sub-wavelength imaging of objects at terahertz (THz) frequencies. An important limitation of many such techniques is that they require intense near-infrared radiation to be focused onto the sample being studied, making them unsuitable for measuring light sensitive specimens such as biological substrates and charge carriers contained within semiconductor microstructures. We present an alternative approach based on evanescent-field THz time-domain spectroscopy using on-chip THz circuits. In this case, a pulsed evanescent THz electric field, extending above an on-chip THz waveguide is used to probe specimens. A lithographically-defined microstrip waveguide restricts the THz electric field laterally, while the exponential decay of the field above the waveguide into free-space provides controllable sub-wavelength penetration into specimens. We present an overview of recent results showing the interaction of pulsed THz evanescent electric fields with semiconductor samples, and discuss how such on-chip THz waveguides present a useful route towards THz microscopy.

Many materials of interest to the forensic and security services, such as explosives, drugs and biological agents, exhibit characteristic spectral features in the terahertz (THz) frequency range. These spectral features originate from inter-molecular interactions, involving collective motions of molecules. Broadband THz time-domain spectroscopy (THz-TDS) system have been used to analyze a number of drugs-of-abuse and explosives that are of interest to the forensic and security services. These samples ranged from crystalline powders, pressed into pellets, to thin sheets of plastic explosives, and all being measured in transmission geometry in the frequency range 0.1 - 8 THz. To well understand the nature of the observed spectral features and the effects of thermal broadening on these far-infrared signatures, temperature-dependent THz-TDS measurements have also been performed at temperatures as low as 4 K, especially for two types of cocaine. Well-resolved low-frequency absorption peaks were observed in the frequency range 0.1 - 3 THz with high resolution. Some of absorption peaks were found clearly to become more intense and shift to higher frequencies as the temperature was reduced. The results confirm that the low-frequency collective modes are highly sensitive to the structural and spatial arrangement of molecules. Furthermore, a number of common postal packaging materials made from paper, cardboard, even several types of plastic, have been tested with drug sample to assess the ability of THz-TDS in a hostile detection environment.

Time-domain terahertz spectroscopy and applications on drugs and explosives

We present results for VCSEL based links operating PAM-4 signaling using a commercial 0.13microm CMOS technology. We perform a complete link analysis of the Bit Error Rate, Q factor, random and deterministic jitter by measuring waterfall curves versus margins in time and amplitude. We demonstrate that VCSEL based PAM-4 can match or even improve performance over binary signaling under conditions of a bandwidth limited, 100meter multi-mode optical link at 5Gbps. We present the first sensitivity measurements for optical PAM-4 and compare it with binary signaling. Measured benefits are reconciled with information theory predictions.

PAM-4 Signaling over VCSELs with 0.13microm CMOS Chip Technology.

~~~~~~~~~~~2 96 K 30 ~~~~~~~~~~~~~~~~~~~~2 75 K 25 ~4S iN ~ N 245 K ~~~~~~~~~~~~~~~~~~~~ 186 K ~~~~~~~~~~~~6 6 K

of Explosivesand Drugs Measured by Terahertz Time-Domain Spectroscopy

We report on measurements of the excitation, propagation, and detection of picosecond duration electrical pulses at cryogenic (∼4K) temperatures in a microstrip circuit. A reduction is observed in the measured excitation and propagating pulse widths at low temperatures, compared with room temperature. The results indicate both that the electrical properties of low-temperature-grown GaAs make it suitable for photoconductive excitation and detection in cryogenic optoelectric circuits and that an organic polymer is a good transmissive medium for terahertz (THZ) frequency range excitations at low temperatures. This work will prove an invaluable starting point for future guided wave terahertz experiments at cryogenic temperatures.

On-chip photoconductive excitation and detection of pulsed terahertz radiation at cryogenic temperatures

A vertical-cavity surface-emitting laser (VCSEL) 1 times 12 array flip-chip bonded to a 1 times 12 GaAs monitor photodiode array is demonstrated, and faithful monitoring of the VCSEL threshold current, optical power, and subthreshold emission is recorded. Extremely small monitor crosstalk is measured. This is the first published report of an optically monitored VCSEL array

1 /spl times/ 12 VCSEL array with optical monitoring via flip-chip bonding

Using terahertz time-domain spectroscopy, we have measured the temperature dependence of the far-infrared vibrational modes of a number of illegal drugs and high explosives that are of interest to the forensic and security services. Well-resolved low-frequency absorption peaks were observed in the frequency range 0.3-3.0 THz and over the temperature range 4-296 K, some of which were found to become more intense and shift to higher frequencies as the temperature was reduced. Our results confirm that the low-frequency collective modes are highly sensitive to the structural and spatial arrangement of molecules.

2006 Joint 31st International Conference on Infrared Millimeter Waves and 14th International Conference on Teraherz Electronics

Temperature-Dependent Far-Infrared Spectra of Explosives and Drugs Measured by Terahertz Time-Domain Spectroscopy

The on-chip detection of nanolitre volumes of dielectric material is demonstrated using terahertz (THz) pulses. Simultaneous analysis at different frequencies on separate, lithographically defined locations is shown to be possible using THz band-stop filter elements connected by a microstrip line. Integrated thin film low-temperature-grown GaAs photoconductive switches are used for THz pulse generation and detection within the microstrip interconnect. This technique is expected to be useful in sensing organic films such as DNA, and other biomolecular materials, in an on-chip environment.

Guided-wave Terahertz devices for sensing the properties of overlaid dielectric films

Resonant terahertz filters in microstrip lines have been proposed as devices suitable for the detection of the properties of overlaid dielectric materials, with potential applications including the on-chip assay of DNA and other biological molecules. Here, we provide a direct comparison of numerical simulations to calibrated experimental data obtained on our resonant structures. We employ two different codes (HFSS and Sonnet) to cross-check the results of our numerical simulations, and conclude that stub-based THz band-stop filters offer an improvement in sensitivity (of order 100x) per unit active area compared with alternative designs. This is a result of the enhanced THz electric field concentration in the overlaid dielectric which this particular geometry produces.

Measurement and simulation of the sensitivity of terahertz frequency range passive flter elements to overlaid dielectrics

Resonant terahertz filters inmicrostrip lines have beenproposed asdevices suitable forthedetection ofthe properties ofoverlaid dielectric materials, withpotential applications including theon-chip assayofDNA andother biological molecules. Here, weprovide adirect comparison of numerical simulations tocalibrated experimental dataobtained onourresonant structures. We employtwodifferent codes (HFSSandSonnet) tocross-check theresults ofournumerical simulations, andconclude thatstub-based THzband-stop filters offer animprovement insensitivity (oforderlOOx)perunit active areacompared withalternative designs. Thisisaresult oftheenhanced THzelectric field concentration intheoverlaid dielectric whichthis particular geometry produces. d10 / 30~~~~~~~~~~~~~~~~~~V= -30 (a)

Measurement and simulation ofthesensitivity of terahertz frequency range passiveflter elements tooverlaiddielectrics

We demonstrate that, through coherent measurement of the transmitted terahertz frequency electric fields, broadband (0.3 - 8 THz) time-domain spectroscopy can be used to measure far-infrared vibrational modes of a range of drugs-of-abuse and high explosives that are of interest to the forensic and security services. Our results indicate that absorption features in these materials are highly sensitive to the structural and spatial arrangement of the molecules. Terahertz frequency spectra are also compared with high-resolution low-frequency Raman spectra to assist in understanding the low-frequency inter- and intra-molecular vibrational modes of the molecules.

Complementary spectroscopic studies of materials of security interest

We report on a technique for the on-chip sensing of dielectric materials in the terahertz frequency range. We show that an array of band-stop filters, excited by integrated ultrafast photoconductive switches, can be used to sense dielectric loading at a number of distinct lithographically defined locations on a chip simultaneously, each location sensing a different terahertz frequency. This technique is expected to have a range of future applications in the field of on-chip terahertz systems, such as the analysis of deoxyribonucleic acid and other molecular films.

There are widespread potential applications for guided-wave terahertz (THz) frequency measurements in the study of condensed matter physical systems, many of which require a low temperature environment. Here we report on the excitation, propagation and detection of ~picosecond duration (>1 THz bandwidth) electrical pulses at cryogenic temperatures (~4 K) in microstrip circuits. A reduction in both the excitation and propagating pulse widths is observed compared to room temperature data. These results indicate that, in cryogenic THz circuits, the electrical properties of low-temperature-grown GaAs are highly suited to photoconductive excitation and detection, and that benzocyclobutene (BCB) acts an effective THz dielectric material.

Cryogenic excitation and detection of terahertz radiation in microstrip circuits

We evaluate VCSEL interconnects for next-generation High Productivity Computers in which hundreds of terabits of bandwidth are envisioned. We present results for VCSEL based links operating PAM-4 signaling using a commercial 0.13μm CMOS technology. We perform a complete link analysis of the Bit Error Rate, Q factor, random and deterministic jitter by measuring waterfall curves versus margins in time and amplitude. We demonstrate that VCSEL based PAM-4 can match or even improve performance over binary signaling under conditions of bandwidth limited 100meter multi-mode optical link at 5Gbps. We present the first sensitivity measurements for optical PAM-4 and compare it with binary signaling. An empirical relationship for VCSEL scaling versus bit rate and aperture is presented in order to explore reliability of VCSEL-based links. Reliability is found to degrade with aperture with a fourth order power law dependence.

We evaluate vertical-cavity surface-emitting lasers (VCSELs) reliability for next-generation high-productivity computers wherein several hundreds of terabits of bandwidth are envisioned. VCSEL failure rates are modeled, and an empirical relationship for VCSEL scaling versus bit rate and aperture is presented to explore the reliability of VCSEL-based links. The effects of VSCEL sparing, water cooling, and redundancy at the system level are analyzed.

Scaling vertical-cavity surface-emitting laser reliability for petascale systems.

In this paper we generalize this concept further by locally modulating the effective refractive index to engineer various optical device functionalities on a chip and demonstrate experimentally example devices validating this approach

LEOS 2006 - 19th Annual Meeting of the IEEE Lasers and Electro-Optics Society

We report on a numerical study of the sensitivity of electrical terahertz (THz) frequency range passive filters under conditions of dielectric loading. We investigate band-pass filters, ring resonators, and band-stop filters, all of which have been proposed as devices capable of measuring the hybridization state of overlaid DNA films, thereby acting as genetic sensors. The transmission characteristics of these filters are examined when loaded with samples of different relative permittivities and thicknesses, and these results are discussed in the context of recent experimental works. A comparative analysis of the three filter types is performed, and conclusions are drawn on the suitability of the various filters for the analysis of DNA films during genetic testing and other dielectric materials.

Electromagnetic simulation of terahertz frequency range filters for genetic sensing

In this paper, we extend our approach to implement a resonant filter and resonant modulator using lithographically defined nanostructures on sidewalls of a waveguide in silicon on insulator (SOI) material system

Tunable Transmission Resonant Filter and Modulator with Vertical Gratings

We demonstrate that, through coherent measurement of the transmitted terahertz electric fields, broadband (0.3-8THz) time-domain spectroscopy can be used to measure far-infrared vibrational modes of a range of illegal drugs and high explosives that are of interest to the forensic and security services. Our results show that these absorption features are highly sensitive to the structural and spatial arrangement of the molecules. Terahertz frequency spectra are also compared with high-resolution low-frequency Raman spectra to assist in understanding the low frequency inter- and intra-molecular vibrational modes of the molecules.

Analysis of drugs-of-abuse and explosives using terahertz time-domain and Raman spectroscopy

We experimentally demonstrate a novel slab lens realized by etching 1-D subwavelength periodic structures into a Silicon slab. A graded index profile is achieved by gradually modifying the duty cycle of the structure.

Design, Fabrication and Characterization of Subwavelength Based Slab Lens in Silicon

Memory systems for conventional large-scale computers provide only limited bytes/s of data bandwidth when compared to their flop/s of instruction execution rate. The resulting bottleneck limits the bytes/flop that a processor may access from the full memory footprint of a machine and can hinder overall performance. This paper discusses physical and functional views of memory hierarchies and examines existing ratios of bandwidth to execution rate versus memory capacity (or bytes/flop versus capacity) found in a number of large-scale computers. The paper then explores a set of technologies, proximity communication, low-power on-chip networks, dense optical communication, and sea-of-any thing interconnect, that can flatten this bandwidth hierarchy to relieve the memory bottleneck in a large-scale computer that we call "Hero".

Challenges in building a flat-bandwidth memory hierarchy for a large-scale computer with proximity communication

We discuss the technical challenges and potential for implementing optical transceivers with multi-terabit-per-second capacities for chip-multithreading architectures. We will examine typical approaches, discuss bottlenecks that have developed in the interconnect hierarchy, and identify potential solutions.

We report the operation of band-stop filters in the terahertz (THz) frequency range, working at a center frequency of 600GHz. The filters were characterized by embedding them in a microstrip line attached to photoconductive switches which act as THz emitters and detectors. The filters have applications in sensing and detection. The chosen filter design allows cascading of several filters along the same microstrip line, which is of particular importance for a proposed molecular sensing array.

The on-chip detection of nanolitre volumes of dielectric material is demonstrated using terahertz (THz) pulses. Simultaneous analysis at different frequencies on separate, lithographically defined locations is shown to be possible using THz band-stop filter elements connected by a microstrip line. Integrated thin film low-temperature-grown GaAs photoconductive switches are used for THz pulse generation within the microstrip interconnect. This technique is expected to be useful in sensing organic films such as DNA, and other biomolecular materials, in an on-chip environment.

2005 Joint 30th International Conference on Infrared and Millimeter Waves and 13th International Conference on Terahertz Electronics

Pulsed THz sensing of dielectric thin films using cascaded filter arrays

We present results for VCSEL based links operating PAM-4 signaling using a commercial 0.13μm CMOS technology. We perform a complete link analysis of the Bit Error Rate, Q factor, random and deterministic jitter by measuring waterfall curves versus margins in time and amplitude We demonstrate that VCSEL based PAM -4 can match or even improve performance over binary signaling under conditions of bandwidth limited 100meter multi-mode optical link at 5Gbps. We present the first sensitivity measurements for optical PAM-4 and compare it with binary signaling.

We evaluate VCSEL reliability for next-generation High Productivity Computers in which several hundreds of terabits of bandwidth are envisioned. An empirical relationship for VCSEL scaling versus bit rate and aperture is presented in order to explore reliability of VCSEL-based links. Reliability is found to degrade with aperture with a fourth order power law dependence. VSCEL sparing, water-cooling and redundancy though percentage of link failures are analyzed.

Scaling VCSEL reliability up to 250Terabits/s of system bandwidth

In this paper we present a novel slab lens based on artificial graded index medium. The lens is realized by etching 1-D subwavelength gratings into a high index slab waveguide to achieve the desired effective index distribution. A graded index profile is achieved by gradually modifying the duty cycle of the grating along the horizontal axis, whereas the beam is confined in the vertical direction by the slab waveguide. The proposed device is very attractive for various applications, including mode matching, coupling, guiding, imaging, optical signal processing, while offering the intrinsic advantages of monolithic, on-chip integration. The device is analyzed analytically numerically.

Over the last few years we have developed a new method to control single-electrons by isolating and moving them through a submicron width channel formed in a GaAs/AlGaAs heterostructure using a surface acoustic wave. The acoustic wave acts to push electrons through the depleted submicron channel in packets each containing an integer number of electrons. Our primary motivation for studying this system has been to develop a new standard of dc current for metrological purposes, but our recent focus has widened to investigate the possibility of single-photon emission. Here we show new experimental results which demonstrate acoustoelectric current flow in adjacent 1D wires. These results have relevance both to the use of the system in a single-photon emission scheme, as well as in the creation of a proposed acoustoelectric quantum computer.

We measure acoustoelectric current in two submicron-separated quasi-one-dimensional wires formed in an AlGaAs∕GaAs heterostructure. We show that independent control of acoustoelectric current in both wires can be achieved with a suitably chosen geometry of Schottky gates. The implications of the results on two proposed uses of single-electron acoustoelectric current flow are discussed: a single-photon source and an acoustoelectrically driven quantum computer.

We describe the packaging and testing of a two-dimensional array parallel-optics module with 36 channels with each channel operating up to 3.3 Gb/s. This represents the first commercial module based on direct integration of vertical-cavity surface-emitting lasers (VCSELs) onto silicon very large scale integration (VLSI) circuits using a hybrid optoelectronic-VLSI technology. The module eliminates wire bonds between the driver/receiver chips and the corresponding VCSELs thereby reducing crosstalk and power dissipation, simplifying packaging and alignment, and simultaneously improving bandwidth and total link jitter performance.

A 36-channel parallel optical interconnect module based on optoelectronics-on-VLSI technology

The optical properties of strained GaAsSb/GaAs quantum wells grown by molecular beam epitaxy were investigated by photoluminescence spectroscopy as a function of excitation intensity and temperature. Photoluminescence spectra exhibit strong blue shifts of the emission peak with increasing excitation intensity, ascribed to the interplay between band tail filling at low carrier densities and electrostatic band bending at high carrier concentrations. Spectroscopic data are consistent with a type II band alignment, with a small conduction band offset (ΔEc∼100 meV), and gain spectra are blue shifted with respect to the low excitation luminescence. The large material gain and fast carrier recombination lifetimes demonstrate the viability of this material system for the fabrication of 1.3 μm lasers.

Optical properties of strained antimonide-based heterostructures

This study reviews preliminary experimental data on accelerated aging test of VCSEL and detector arrays bonded to either silicon or SiGe application specific integrated circuits (ASICs). When compared with top emitting VCSEL (unbonded), results show that the flip chip bonding technology is more robust, reliable, and environmentally sound. In addition, technological benefits of 2-D array technology in terms of superior reliability over linear array solutions when scaling to high channel count is asserted. Moreover, reliability issues for modules are considered as the VCSEL data rate exceed 10 Gbs.

The 16th Annual Meeting of the IEEE Lasers and Electro-Optics Society, 2003. LEOS 2003.

The intensity noise spectrum is measured for antimonide based 1.3 /spl mu/m vertical-cavity surface emitting lasers. Analysis of the noise spectra indicates a modulation bandwidth of 5.7 GHz with an intrinsic maximum frequency response that exceeds 28 GHz. A discontinuity in the relaxation oscillation resonance frequency is observed, which suggests that the lasing behavior at threshold is assisted by nonlinearities in the gain medium.

Measurements of the low frequency (<2 kHz) noise in the current produced by surface-acoustic-wave-based single-electron pumps are presented. When the current is close to its quantized value I = ef(0) (where e is the electron charge and f(0) is the surface-acoustic-wave frequency), shot noise is seen to be absent at the level of our measurement errors, which are an order of magnitude smaller than the Poissonian value of the shot noise for the same current. By changing the operating conditions so that the current is away from the quantized value, we observe noise that is attributed to switching of impurity states.

Measurements of noise caused by switching of impurity states and of suppression of shot noise in surface-acoustic-wave-based single-electron pumps

K Materials and Devices for Optoelectronics and Photonics Chairs

Summary form only given. GaAsSb/GaAs quantum wells grown on GaAs substrates are a potential active material for the monolithic growth of 1.3 /spl mu/m VCSELs. In this material system we determine a type II band alignment, with a small conduction band offset /spl Delta/E/sub c/ = 100 meV. We measure material gain coefficients comparable to those of type I InGaAs quantum wells, although under flat band conditions the electrons and holes are spatially separated.

Characterization of GaAsSb/GaAs quantum wells for 1.3 /spl mu/m VCSELs

Summary form only given. We report on the room temperature operation of optically pumped vertical-cavity surface-emitting lasers (VCSELs) based on GaAsSb/GaAs quantum wells (QWs). Continuous-wave (CW) operation with 200 /spl mu/W maximum output power at /spl cong/1.275 /spl mu/m, as well as quasi-CW operation up to 1.29 /spl mu/m, has been achieved. These are the first GaAsSb/GaAs QW VCSELs lasing near 1.3 /spl mu/m. The maximum output power approaches communication requirements.

Room temperature CW operation of GaAsSb/GaAs VCSELs near 1.3 /spl mu/m

In this letter, we report continuous-wave room temperature operation of a GaAsSb-GaAs quantum-well vertical-cavity surface-emitting laser near 1.3 /spl mu/m. The device is pumped with 674 nm light and provides 1-QmW total optical output at 1280 nm with 40% differential quantum efficiency. We describe the spatial, angular and spectral properties of the laser. This device sets a record for long wavelength with high output power in the GaAsSb-GaAs system.

Continuous-wave operation of a 1.3-/spl mu/m GaAsSb-GaAs quantum-well vertical-cavity surface-emitting laser at room temperature

We report compositional dependencies of the 2d–3d growth mode transition for GaAsSb on GaAs. In addition, Sb incorporation, desorption, and segregation versus growth temperature and V/III ratio are measured by secondary-ion-mass spectroscopy. Photoluminescence investigations of Sb compositional dependence of GaAsSb quantum wells and confinement in heterojunctions are reported.

Growth and optical properties of GaAsSb quantum wells for 1.3 μm VCSELs

GaAsSb/GaAs quantum wells grown on GaAs substrates are a potential active material for the monolithic growth of 1.3 μm VCSELs.1

Characterization of GaAsSb/GaAs quantum wells for 1.3 urn VCSELs

We report compositional dependencies of the 2 d– 3d growth mode transition for GaAsSb on GaAs. In addition, Sb incorporation, desorption, and segregation versus growth temperature and V/III ratio are measured by secondary-ion-mass spectroscopy. Photoluminescence investigations of Sb compositional dependence of GaAsSb quantum wells and confinement in heterojunctions are reported. ©2001 American Vacuum Society. @DOI: 10.1116/1.1406153 #

Growth and optical properties of GaAsSb quantum wells for 1 . 3 m m VCSELs

We demonstrate the generation of high-energy pulses by using a low-repetition-rate Kerr-lens mode-locked laser. Repetition rates as low as 4 MHz were achieved with a long, multiple-pass cavity and a semiconductor saturable Bragg reflector. The laser generated pulses of 55-fs duration with a pulse energy of 48 nJ when it was mode locked in the net negative dispersion regime. Mode locking in the positive dispersion regime reduces instabilities and enables pulses to have durations of 80 fs and energies as high as 90 nJ. This is, to our knowledge, the highest pulse energy and the lowest repetition rate ever generated directly from a femtosecond laser resonator without cavity dumping.

Generation of 90-nJ pulses with a 4-MHz repetition-rate Kerr-lens mode-locked Ti:Al(2)O(3) laser operating with net positive and negative intracavity dispersion.

High-frequency single-electron transport and the quantized acoustoelectric effect

Room temperature pulsed lasing at 1.29 /spl mu/m in an optically pumped GaAsSb/GaAs quantum well VCSEL on a GaAs substrate is reported. This is the longest wavelength VCSEL reported in this material system.

Room temperature operation of GaAsSb/GaAs quantum well VCSELs at 1.29 /spl mu/m

We show that two-photon photocurrent imaging can be used to nondestructively study vertical cavity surface emitting lasers on a microscopic level. In particular, we study the aperture isolation created by shallow ion implantation. The combination of two-photon backside imaging and a probe station is ideal for internal and full wafer characterization. The required peak and average power levels for testing can be easily satisfied by available compact ultrafast laser sources, making the technique practical and user friendly.

Two-photon photocurrent imaging of vertical cavity surface emitting lasers

We characterize the small-signal frequency response of intracavity contacted /spl sim/970 nm VCSEL's designed for flip-chip bonding to electronic circuits and then modified with reduced capacitance and a novel lateral current injection method to obtain a high-speed response. We measure 3-dB bandwidths in excess of 10 GHz and an extracted K-factor limited f-max of 95 GHz for fabricated single-mode /spl sim/970-nm lasers.

Small-signal characteristics of bottom-emitting intracavity contacted VCSEL's

Quantised Currents in One Dimensional-Channels Induced by Surface Acoustic Waves

High-frequency single-electron charge transport and the quantized acoustoelectricity

The effect of a perpendicular magnetic field on the quantized current induced by a surface acoustic wave in a quasi-one-dimensional channel is studied. The channel was defined in a GaAs heterostructure by a shallow-etching technique. The quantized current in this constriction displayed superior precision (\ifmmode\pm\else\textpm\fi{}60 ppm) and robustness to dc bias relative to that observed previously in Schottky-gate-defined channels. In a perpendicular magnetic field commensurability oscillations were observed in the interval of current between quantized plateaus. The phase of the oscillations changes when a plateau is approached, which leads to an oscillatory change in the slope of the plateaus.

Single-electron acoustic charge transport on shallow-etched channels in a perpendicular magnetic field

A ‘triggered’ transimpedance digital optical receiver is described which is usable in noisy environments typical of dense mixed-signal circuits. Results show enhanced immunity to supply variations compared to conventional transimpedance receivers.

We demonstrate a wavelength monitor and a two-wavelength detector based on two single-quantum-well absorbers that sample a standing wave created by a distributed Bragg reflector. As a wavelength monitor, our device is power independent over a 15 dB range. Wavelength discrimination is linear over a 12 nm range.

Wavelength monitor based on two single-quantum-well absorbers sampling a standing wave pattern

Summary form only given.Two-photon photocurrent imaging is used to quantitatively study VCSELs on a microscopic level. Similar to two-photon backside imaging of ICs, two-photon excitation provides a convenient way of injecting localized carriers through the GaAs substrate, circumventing the problems caused by the opacity of the substrate and the top metal layer. Backside illumination allows the use of ordinary microprobes to contact the VCSELs on the front side, without the restriction of the probe movement and the requirement of long working distance lenses. Thus, high numerical aperture objectives can be used to achieve high spatial resolution (/spl les/1 /spl mu/m). Furthermore, the required peak and average power levels for testing can be easily satisfied by available compact ultrafast laser sources, making the technique practical and user friendly.

Summary form only given. Mode-locked operation at 7.2 MHz has been demonstrated using a novel multipass cavity (MPC) and a SBR. We obtained 23.5 fs nearly transform limited pulses from a Kerr lens mode locked (KLM) Ti:Al/sub 2/O/sub 3/ laser. This unprecedented low repetition rate laser suggests new approaches for achieving a few MHz repetition rates and MW level peak powers.

A 7.2 MHz high power KLM Ti:Al/sub 2/O/sub 3/ laser using multiple pass long cavity and saturable Bragg reflector

Recently, fiber in the loop system have been proposed that could open up new services to individual subscribers by using modulators to communicate information up stream to a central office [1].

Multiple Quantum Well Modulator Reflectivity with 22:1 Contrast Ratio at 155 µm

We describe a "triggered" transimpedance receiver-usable in noisy environments typical of dense OE-VLSI chips that combine analog optoelectronic I/O devices with high-density digital logic. Measured data from such a receiver show enhanced immunity to supply variations compared to a conventional transimpedance receiver.

Single-electron acoustic charge transport by two counterpropagating surface acoustic wave beams

We describe the first integration of vertical-cavity surface-emitting laser arrays with gigabit-per-second CMOS circuits via flip-chip bonding.

Vertical-cavity surface-emitting lasers flip-chip bonded to gigabit-per-second CMOS circuits

We report measurements on the modulation of visible light by a multiple-quantum-well (MQW) modulator designed for normal incidence. The MQW structure is composed of AlAs-Al/sub x/Ga/sub 1-x/As with an Al concentration x=0.41. The structure exhibits an exciton absorption peak at 608 nm in the visible part of the spectrum. The phase and amplitude modulation properties of this structure mere studied using a Michelson interferometer that employed a novel double lock-in detection technique. Phase and amplitude modulation were studied as a function of the wavelength to determine their maxima. In our structure, phase modulation up to 200 and amplitude modulation up to 8% were observed. These values are comparable to what is typically achieved by using waveguide geometry.

Modulation of visible light by AlAs-AlGaAs multiple-quantum-well p-i-n structures

We report the observation of self-sustained photocurrent oscillations in a weakly coupled spatially direct intrinsic GaAs/Al0.3Ga0.7As superlattice. The oscillations are attributed to the dynamics of unstable electric field domains related to the Γ−Γ e1-e2 tunneling resonance. The observed oscillation period is much longer than the carrier recombination time and the interwell tunneling time. The nonlinear behavior shows a complex dependence on the optical power and the external bias.

Photocurrent self-oscillations in a spatially direct GaAs/AlGaAs superlattice

We present a single-chip asynchronous multiprocessor optoelectronic bit-sliced arrayed (AMOEBA) crossbar switch. The AMOEBA switch addresses the challenge to produce a large-scale, nonblocking packet switch through dense integration of photonic devices directly onto silicon VLSI circuits. Optoelectronic-VLSI technology is used to integrate the switch fabric, routing controller, packet buffers, line interface circuits, and optoelectronic conversion devices on a single chip. We show how free-space optical interconnects and wavelength-and-space-division-multiplex networking on single-mode fibers can provide switched interconnection between multiple nodes in a distributed computing environment. An optomechanical transceiver package accomplishes the free-space-to-fiber interfacing. We report the implementation and testing of the key components of a 16-channel AMOEBA prototype switch with a potential capacity of 12.8 Gb/s (or 800 Mb/s/channel), and capable of switching 16 million packets per second.

The AMOEBA switch: an optoelectronic switch for multiprocessor networking using dense-WDM

The recent growth in wavelength division multiplexing has increased the need for integrated wavelength monitors and wavelength-sensitive detectors. We demonstrate a novel standing wave device that contains two, thin-absorber photodetectors at different points in the standing wave. Our device can function as either a multiple wavelength detector or wavelength monitor. It is a surface-normal device that could be readily integrated with silicon electronics, for example by solder bonding. The device is an n-i-p-i-n structure grown by MBE. The DBR mirror stack is n-doped with a concentration of 10/sup 18/ cm/sup -3/ and consists of 15.5 pairs of Al/sub 0.11/Ga/sub 0.89/As/AlAs. The absorbers are single 95 /spl Aring/ GaAs/AlGaAs quantum wells. Each quantum well is placed in the intrinsic region of a p-i-n diode in order to collect the photocurrent that is generated from the absorption of light.

1999 IEEE LEOS Annual Meeting Conference Proceedings. LEOS'99. 12th Annual Meeting. IEEE Lasers and Electro-Optics Society 1999 Annual Meeting (Cat. No.99CH37009)

Wavelength monitor based on two single quantum well absorbers in a standing wave

Work on surface acoustic wave (SAW) induced single electron flow is described. A current given by ef is obtained where e is the electron charge and f is the frequency, near 2.8 GHz. Present accuracy for measurement of e is better than 0.1%. Prospects for improvement will be discussed.

1998 Conference on Precision Electromagnetic Measurements Digest (Cat. No.98CH36254)

High frequency one dimensional single electron transport in GaAs heterostructures

Highly nondegenerate four-wave mixing (NDFWM) is an important optical parametric process attracting increased current interest for applications in all-optical wavelength conversion in wavelength-division-multiplexed systems We report on ND-FWM in a semiconductor quantum well (QW) microcavity and its potential as a wavelength converter.

Technical Digest. Summaries of Papers Presented at the Conference on Lasers and Electro-Optics. Conference Edition. 1998 Technical Digest Series, Vol.6 (IEEE Cat. No.98CH36178)

Efficient generation (1.6%) of highly nondegenerate four-wave mixing signal in a semiconductor microcavity using oblique incidence configuration

Quantized current in one-dimensional channel induced by surface acoustic waves

Test results from a two-dimensional array of 50 CMOS smart-pixel receivers equipped with both optical and electrical outputs are reported. Parallel testing of the array at 311 Mbit/s indicates a /spl sim/2.5 dB penalty for operation of nearly the whole array as compared to a single element.

Parallel operation of 50 element two-dimensional CMOS smart-pixel receiver array

We have noted that for VCSELs at 850 nm, the only LAN standard wavelength where VCSELs have been shown to operate, have thresholds greater than 1.6 volt, so that if it is desirable to operate circuits at lower absolute voltage levels, VCSELs may not be used. However, we have demonstrated a GaAs MQW electro optical modulator that has a contrast of 2:1 at a differential drive of +/- 1.6 volt.

1998 IEEE/LEOS Summer Topical Meeting. Digest. Broadband Optical Networks and Technologies: An Emerging Reality. Optical MEMS. Smart Pixels. Organic Optics and Optoelectronics (Cat. No.98TH8369)

We present the first operation of an OE/VLSI compatible single-beam receiver-transmitter pair operating to 1 Gb/s. The circuits were realized in 0.35 micron CMOS and hybridized via a flip-chip bonding technique to an array of 850 nm MQW modulator/detectors.

1 Gb/s single beam smart-pixel receiver/transmitter realized in hybrid MQW-CMOS OE-VLSI technology

Pure dephasing induced by exciton-phonon interactions in narrow GaAs quantum wells

We approach the question of optimization of surface-normal p-i(multiquantum-well, MQW)-n modulators from the viewpoint of investigating their tolerance to variations in wavelength and temperature and errors in manufacture. The reflection characteristics of two high-quality samples are carefully processed to eliminate Fabry-Perot fringes, and then their spectra at any bias are characterized with six phenomenological parameters which depend on /spl lambda//sub 0/, the zero-field exciton position. The two GaAs-AlAs samples have /spl lambda//sub 0/'s of 833.8 and 842.3 nm, and so cover a range useful for modulators designed to operate near 850 nm in the normally reflecting condition, i.e., reflection decreases with field. A linear interpolation of the parameters of these two samples is used to predict the behavior of MQW diodes with /spl lambda//sub 0/'s around this range, and so a fully comprehensive examination of normally reflecting MQW modulators is performed. The performance aspect that is examined is contrast ratio as a function of nonuniformities in the devices or operating conditions given a voltage swing of 3 V. There are two operational modes discussed. If the voltage offset of the bias is allowed to vary via a feedback circuit, a contrast of 2:1 may be maintained over an operating wavelength change (/spl Delta//spl lambda/) of 17 nm with local variations of wavelength of /spl plusmn/1 nm, which corresponds to a temperature variation of 60/spl deg/C while allowing for variations of laser driver wavelength of /spl plusmn/1 nm. If feedback Is not permitted, we determine that, given tolerances to manufacturing errors, a contrast of 1.5:1 may be maintained over a wavelength range of /spl sim/5 nm by either using stacked diode designs or extremely shallow quantum wells.

On the operational and manufacturing tolerances of GaAs-AlAs MQW modulators

We present very large arrays of InGaAs-InP p-i-n photodetectors flip-chip bonded to Si. The photodiodes are designed for operation at zero bias, e.g., for spectroscopic applications. Our design maintains depletion at zero bias resulting in /spl sim/99% photocurrent collection efficiency. The series resistance of our photodiodes is <1 /spl Omega/ for a 40/spl times/40 /spl mu/m device, including the flip-chip bond, resulting in high tolerance to shunt leakage. We produce arrays of photodiodes as large as 120 and measure leakage currents. We analyze zero-bias photocurrent generation in the presence of leakage and determine that with this technology arrays as large as 128 can be produced with high yield. The concept of redundancy in zero-bias photodiode arrays is presented and explored. Under the assumption that photodiode leakage is produced by microscopic point defects, a substantial increase in uniformity can be achieved in photodetector arrays by employing redundancy.

Very large arrays of flip-chip bonded 1.55 /spl mu/m photodetectors

We report studies of exciton dephasing in quantum dot (QD)-like islands in narrow GaAs quantum wells (QWs). Using three pulse transient four-wave mixing (FWM), we compare dephasing rates directly with population decay rates. This comparison reveals a pure dephasing process that dominates excitonic dephasing at elevated temperatures but does not involve exciton population relaxation.

Technical Digest. Summaries of Papers Presented at the International Quantum Electronics Conference. Conference Edition. 1998 Technical Digest Series, Vol.7 (IEEE Cat. No.98CH36236)

Pure dephasing induced by exciton-phonon interactions in GaAs quantum dots

We have demonstrated and analyzed very large arrays of flip-chip bonded InGaAs/InP photodetectors, in particular paying attention to how their series and shunt resistances affect zero-bias photocurrent and therefore yield for spectrometer applications. Our device design results in very low series resistance of the diode and high photocurrent collection efficiency at zero-bias. It was shown that for an integrated circuit array wherein attention is paid to eliminating resistance between the flip-chip bonding pad and the feedback resistor node, the effect of leaky diodes is nearly eliminated.

Very large arrays of flip-chip bonded 1.55-/spl mu/m photodiodes for spectroscopic monitoring of WDM networks

We demonstrate the performance of InGaAs/InP multiple quantum well modulators for fiber access applications. On/off contrast ratios in reflectivity are 22:1 with a 10:1 level extending over a 26 nm bandwidth at 1.55 micrometers. Arrays of high quality pin InGaAs with low dark and zero bias operation are realized and further applied to avalanche photodiodes.

Gas source molecular beam growth of multiple quantum well modulators, detectors, and avalanche photodiodes at 1.55 μm

We present short cavity erbium/ytterbium fiber lasers that are passively mode-locked with a saturable Bragg reflector. The lasers produce sub-500-fs pulses at fundamental cavity repetition rates as high as 300 MHz. Stable passive harmonic operation increases the repetition rate to 2.0 GHz. The mode-locking mechanism in both the normal and anomalous group velocity dispersion regimes is investigated using complete analytical and numerical models and direct comparison with the experimental results. A simple technique for accurately measuring the total cavity dispersion is presented.

Short cavity erbium/ytterbium fiber lasers mode-locked with a saturable Bragg reflector

We report the observation of ultrafast intensity oscillations in the time resolved optical emission from a semiconductor microcavity resonantly pumped with intense femtosecond pulses. The observed oscillations are pronounced, persist for several picoseconds, and have frequencies varying from 1.4 to 2.7 THz, depending upon the incidence angle of the pump beam. The angular dependence and spectra show that the oscillations result from interference between the pump and surface-normal modes of the microcavity.

THZ OSCILLATIONS IN THE EMISSION FROM A SEMICONDUCTOR MICROCAVITY

We report heating measurements in ${\mathrm{G}\mathrm{a}\mathrm{A}\mathrm{s}/\mathrm{A}\mathrm{l}}_{x}{\mathrm{Ga}}_{1\ensuremath{-}x}\mathrm{As}$ heterostructures with tunable mobilities in the temperature range 100--710 mK. We find a power-law dependence on temperature for the phonon emission power ${P=dT}^{b}.$ With decreasing mobility, the exponent $b$ changes systematically from 5.15\ifmmode\pm\else\textpm\fi{}0.10 to 3.80\ifmmode\pm\else\textpm\fi{}0.02; the prefactor $d$ increases by more than an order of magnitude. These results explicitly corroborate the prediction by Girvin [in Phys. Rev. Lett. 77, 1143 (1996)] that the phonon emission changes character due to a disorder induced change in the screening from static to dynamic.

Effect of disorder on phonon emissions from a two-dimensional electron gas in G a A s / A l x Ga 1 − x As heterostructures

Two-dimensional arrays of optical receivers become interesting as we try to pack more information into smaller spaces, as might be encountered in optical interconnect applications. We have realized a two-dimensional array of such receivers, and coupled their outputs off-chip both electrically and optically, by using a previously described hybrid process whereby multiple-quantum-well modulator/detectors are attached to CMOS circuits. We have demonstrated 622 Mb/s operation of receivers in the array, and found that roughly a 2.5 dB penalty is incurred for operation of nearly the whole array as compared to an isolated element at 311 Mb/s.

Conference Proceedings. LEOS '97. 10th Annual Meeting IEEE Lasers and Electro-Optics Society 1997 Annual Meeting

Operation of a 50-element two-dimensional smart-pixel receiver array

We demonstrate the performance of InGaAs/InP Multiple Quantum Well modulators for fiber access applications. On/off contrast ratios in reflectivity are 22:1 with a 10:1 level extending over a 26 nm bandwidth at 1.55 μm. Arrays of high quality pin InGaAs with low dark and zero bias operation are realized and further applied to Avalanche Photodiodes.

Gas source molecular beam growth of Multiple Quantum well modulators, detectors and avalanche photodeiodes[photodiodes] at 1.55 μm

We report on the various strategies for integrating III–V semiconductors to very large scale integrated Si logic along with their strengths and limitations. We also detail the monolithic integration method involving direct epitaxial growth where several material science issues have arisen. They require fundamental investigation to further advance implementation. Those issues are (i) the need for a highly ordered array of bilayer steps as an initial Si surface condition for heteroepitaxy, (ii) lower Si oxide desorption temperature, e.g., via electron cyclotron resonance plasma treatments to preserve the bilayer step ordering, and (iii) thinner strain relief layers to reduce the III–V on Si topology mismatch.

Integration issues for 850 nm optical modulators on Si electronics by direct epitaxy

We describe a smart-pixel circuit that permits the use of a GaAs/AlGaAs multiple quantum well diode to be used both as a detector for data input and a modulator for data output. The module provides the ability to double the number of inputs or outputs to the array and is well suited to cascaded optoelectronic system architectures that require bidirectional communition.

In conclusion, we have developed an empirical model for GaAs-AlAs MQW reflection modulators and find that for a 3 volt swing, with feedback circuitry to adjust the voltage offset, a wavelength range of 17 nm is possible while maintaining 2:1 contrast, corresponding to a temperature variation of 60 C.

On the operational and manufacturing tolerances of GaAs/AlAs MQW modulators

We report the observation of highly nondegenerate four-wave mixing from a semiconductor microcavity. The phase mismatch originating from the unique relationship between a beam incidence angle and its cavity resonance frequency was minimized by using a new method where both of pump and probe beams are obliquely incident. External efficiency of 1.6% was measured at 10 K for 1.5 THz frequency conversion of probe pulses by using 1 ps pump pulses of 55 pJ incident pulse energy.

Large array of GaAs modulators and detectors flip-chip solder bonded to silicon CMOS using InGaP as the selective etch stop for GaAs substrate removal

We report here efforts to advance 850 nm VCSELs designed specifically for integration to Si- CMOS. Our VCSEL design is based on an oxidized current aperture and oxidized top mirror with the intent that the device operate as a bottom emitter after integration. Our design also employs intercavity contacts and the first non-alloyed buried contact have been realized. The devices produce resonantly enhanced light emission with record output of 70 μW/st.rad.

Progress on 850 nm Flip Chip Bondable VCSEL for Optical Interconnects

We demonstrate noncontact measurements of the Hall mobility of doped semiconductor wafers with roughly 250 μm spatial resolution, using polarization rotation of focused beams of terahertz (THz) radiation in the presence of a static magnetic field. Quantitative and independent images of both carrier density and mobility of a doped semiconductor wafer have been obtained.

Noncontact semiconductor wafer characterization with the terahertz Hall effect

As the demand for telecommunications services continues to increase, the need to switch large bandwidths of data becomes important. While purely electronic solutions are possible, photonic solutions, using the integration of electronics with optical I/O (smart pixels), provides the potential for smaller physical volume, lower latency, lower power dissipation, and lower cost. We describe initial results from two opto-electronic switching chips, one with 1024 differential optical inputs and 1024 differential optical outputs with individual channels tested above 600 Mb/s and a second with 512 differential optical inputs and outputs with individual channels tested up to 900 Mb/s. The technology for the chip consists of flip-chip bonding of 850 nm GaAs/AlGaAs multiple quantum well (MQW) detectors and modulators onto silicon CMOS with substrate removal to allow access to the optical devices [1]

The authors describe an optoelectronic switching chip with 1024 differential optical inputs and 1024 differential optical outputs with individual channels tested above 600 Mbit/s. The technology for the chip consists of 850 nm GaAs-AlGaAs multiquantum well (MQW) detectors and modulators, flip-chip bonded onto silicon CMOS with substrate removal to allow access to the optical devices.

Optoelectronic VLSI switching chip with greater than 1 Tbit/s potential optical I/O bandwidth

We introduce the concept of synchronous smart-pixel optical receivers, and present the first use of a clocked-sense amplifier as a smart-pixel optical receiver. Such a receiver uses the controlled application of positive feedback to obtain low-power compact digital amplification. We describe the design and simulation of two types of optical receivers based on a clamped bit-line sense amplifier (CBLSA), and a conventional sense amplifier (CSA). Both of these circuits have been realized in 0.8 micron-linewidth foundry CMOS with hybrid-bonded GaAs-AlGaAs MQW detectors and modulators attached to the circuit. Operation in excess of 750 Mb/s is demonstrated, within a layout area of 44 /spl mu/m/spl times/22 /spl mu/m, with a bias-dependent estimated power dissipation of 1 to 2 mW. Operation with one or two input beams is possible, with approximate minimum detected photocurrent levels at 320 Mb/s of 8 /spl mu/A (/spl sim/100 fJ) for single-beam operation and 2.5 /spl mu/A/beam (/spl sim/30 fJ/beam) for two-beam operation, all in the CBLSA-based circuit.

Summary form only given. Optical interconnections between electronic devices is expected to alleviate the communication bottleneck that exists in today's electronic switching and computing systems. A particularly attractive approach is to integrate the optical detectors and modulators or sources directly onto electronic circuitry. We believe we present the first high speed optoelectronic VLSI switching chip using this technology. The circuit has 4096 optical detectors, 256 optical modulators, 140 K FETs. The circuit implements 16 16/spl times/16 fully interconnected switches.

Summaries of papers presented at the Conference on Lasers and Electro-Optics

Optoelectronic VLSI switching chip with greater than 4000 optical I/O based on flip chip bonding of GaAs-AlGaAs MQW modulators and detectors to silicon CMOS

A single-ended, asynchronous, transimpedance receiver-transmitter circuit with 5 mW power dissipation, is implemented in 0.8 /spl mu/m silicon CMOS. A hybrid flip-chip bonding technique is used to attach GaAs-AlGaAs MQW detectors and modulators to the circuit. Operation of the circuit at a sensitivity of -19.4 dBm (41 fJ) and a bit error rate <10/sup 9/ at 550 Mbit/s is demonstrated.

Operation of a single-ended 550 Mbit/s, 41 fJ, hybrid CMOS/MQW receiver-transmitter

Physics and scaling of Saturable Bragg Reflector-modelocked diode-pumped solid state ultrafast lasers

Summary form only given. We discuss the design and operation characteristics of dispersion-compensated fiber laser that uses a short Er/Yb:fiber with a semiconductor 1550-nm saturable Bragg reflector. This laser is suitable for the chirped-pulse WDM application.

Summary form only given. We report here the first investigation of femtosecond time-resolved emission from a semiconductor microcavity resonantly excited with intense femtosecond pulses.

Summaries of Papers Presented at the Quantum Electronics and Laser Science Conference

THz oscillations in the optical emission of a semiconductor microcavity

Ultrafast oscillations in the optical emission from a semiconductor microcavity

We demonstrate self-starting passive mode locking of a Cr (4+):YAG laser, using an intracavity nonlinear mirror as a saturable absorber. The pump source is a diode-pumped Nd:YVO(4) laser. Output pulses are centered at 1541 nm, with 26-nm spectral bandwidth and 110-fs pulse width. Output powers of 70 mW are obtained with 8 W of pump power. This mode locking technique is compared with Kerr-lens mode locking.

Saturable Bragg reflector self-starting passive mode locking of a Cr(4+):YAG laser pumped with a diode-pumped Nd:YVO(4) laser.

We discuss saturable Bragg reflector modelocking at 1541 nm in a Cr4+:YAG laser pumped by a high power Nd:YVO4 laser, and compare with Kerr-lens modelocking.

Saturable Bragg reflector mode-locking of Cr 4+ :YAG laser pumped by a diode-pumped Nd:YVO 4 laser

The authors describe an optical package where light from an input fiber is collimated by a GRIN (gradient index) lens and incident at a slight angle on a reflective modulator in the Fourier plane. The modulated output is reflected and focused by the same lens into a separate output fiber placed symmetrically across the optical axis. Conventional ceramic fiber ferrules, with a single hole at the center, are fabricated with submicron tolerances. But the same manufacturing processes do not allow a ferrule with two holes positioned with the required accuracy. Instead we use a radially symmetric ceramic ferrule with a 250 /spl mu/m hole-exactly twice the 125 /spl mu/m fiber diameter-and put both fibers in the same hole. The "transmissive" single mode fiber package has an excess loss of 1 dB.

Conference Proceedings LEOS'96 9th Annual Meeting IEEE Lasers and Electro-Optics Society

We present AMOEBA: a single-chip asynchronous multiprocessor optoelectronic bit-sliced arrayed crossbar switch intended to provide switched interconnection between multiple processors in a distributed computing environment. AMOEBA relies on optoelectronic-VLSI integration, free-space optical interconnects, and wavelength-and-space-division multiplexed networking on single-mode fiber. We report the implementation and testing of a first generation, 16-channel prototype of the switch and a compact opto-mechanical transceiver package that accomplishes the free-space-to-fiber interfacing.

Proceedings of Massively Parallel Processing Using Optical Interconnections

The AMOEBA chip: an optoelectronic switch for multiprocessor networking using dense-WDM

We present a novel application of opto-electronic/VLSI technology to the AMOEBA switch: an Asynchronous Multiprocessor Opto-Electronic Bit-sliced Array switch. The AMOEBA switch is intended to function as a high-performance single-chip central switch on a data network serving multiple processors or computers. The purpose of the opto-electronic/VLSI chip is to provide byte-wide, switched optical interconnection at the processor clock rate.

Digest IEEE/Leos 1996 Summer Topical Meeting. Advanced Applications of Lasers in Materials and Processing

Fabrication and testing of AMOEBA: an opto-electronic switch for multiprocessor networking

We report an in situ electron diffraction measurement which allows In0.53Ga0.47As to be lattice matched to InP during growth. This method uses analysis of the dynamics of intensity oscillations during electron diffraction to determine when lattice matched growth occurs. With this method we demonstrate closely lattice matched ternary alloys; InGaAs on InP, GaInP on GaAs, and quarternary alloys of InAlGaAs on InP.

Accurate in situ lattice matching from the dynamics of high energy electron diffraction

Many-body and disorder effects in the optical spectra of extremely high density Be δ-doped GaAs

Summary form only given. We present the performance of InGaAs/InP multiple quantum well reflection modulators, which meet the specifications for fiber-in-the-loop systems for the first time, to our knowledge. Our devices are surface-normal modulators that exhibit on/off contrast ratios (CR) in reflectivity of 22:1 and have a 10:1 level over a 26-nm bandwidth at 1.55 /spl mu/m.

Reflectivity from multiple quantum well modulators with contrast ratio of 22:1 at 1.55 /spl mu/m

Summary form only given. Mode-locked solid-state lasers with broadband gain have led to rapid advancements in the production of the ultrashort pulses. In 1991, Shestakov et al. reported the first room-temperature cw lasing of Cr/sup 4+/:YAG/sup /in the 550-nm telecommunications window of optical fiber. Kerr-lens mode-locking (KLM) of Cr/sup 4+/:YAG has produced pulses as short as 46 fs. In this paper, we demonstrate self-starting passive femtosecond mode-locking of Cr/sup 4+/:YAG using a nonlinear mirror called a saturable Bragg reflector (SBR). We pump the Cr/sup 4+/:YAG, whose absorption band is centered around 1000 nm, with a diode-pumped Nd:YVO/sub 4/ laser. We discuss the SBR mode-locking of this laser and compare with KLM techniques.

Saturable Bragg reflector mode-locking of Cr/sup 4+/:YAG laser pumped by a diode-pumped Nd:YVO/sub 4/ laser

We present the first high-speed optoelectronic very large scale integrated circuit (VLSI) switching chip using III-V optical modulators and detectors flip-chip bonded to silicon CMOS. The circuit, which consists of an array of 16/spl times/1 switching nodes, has 4096 optical detectors and 256 optical modulators and over 140K transistors. All but two of the 4352 multiple-quantum-well diodes generate photocurrent in response to light. Switching nodes have been tested at data rates above 400 Mb/s per channel, the delay variation across the chip is less than /spl plusmn/400 ps, and crosstalk from neighboring nodes is more than 45 dB below the desired signal. This circuit demonstrates the ability of this hybrid device technology to provide large numbers of high-speed optical I/O with complex electrical circuitry.

High-speed optoelectronic VLSI switching chip with >4000 optical I/O based on flip-chip bonding of MQW modulators and detectors to silicon CMOS

We demonstrate the performance of InGaAs/InP multiple quantum well modulators for fiber access applications. On/off contrast ratios in reflectivity are 22:1 with a 10:1 level extending over a 26 nm bandwidth at 1.55 micrometers . The methodology to produce such devices is described within.

Reflectivity from multiple quantum well modulator with contrast ratio of 22:1 at 1.55 um

We have made two-beam smart-pixel optical receivers using a hybrid attachment of GaAs-AlGaAs multiple quantum-well (MQW) pin devices to foundry-fabricated 0.8-/spl mu/m linewidth CMOS circuits. Results from a repeater in which receiver output is coupled to a transmitter circuit driving a differential pair of MQW modulators are reported. When tested with high-contrast, directly-modulated laser diodes, an optical energy of 26 fJ (-21.5 dBm) in each beam is required to obtain a bit error rate of 1/spl times/10/sup -9/ at 622 Mb/s, and operation at this error rate is observed to 1 Gb/s. The described receiver (one of several we have made) has three amplification stages, with the first being of the transimpedance type. The reported receiver fits easily within a 45/spl times/25 /spl mu/m area, and the entire repeater circuit draws about 2 mA from a 5-V power supply, with the transmitter accounting for about 20 percent of the total.

1-Gb/s two-beam transimpedance smart-pixel optical receivers made from hybrid GaAs MQW modulators bonded to 0.8 μm silicon CMOS

We discuss mode-locking of low-gain solid-state lasers using a semiconductor saturable Bragg reflector structure. This recently developed low-loss mode-locking device consists of a single quantum well which acts as a saturable absorber incorporated into a high-reflectivity Bragg mirror. Highly stable mode-locking in solid-state lasers results from an ultrafast transient reflectivity in the device that is caused by saturation of the excitonic absorption in near-resonant conditions.

Mode-locking ultrafast solid-state lasers with saturable Bragg reflectors

Summary form only given. The ultrafast optical emission of semiconductor microcavities has attracted considerable interest recently. Reported observations include coherent vacuum Rabi oscillations after weak resonant optical excitation, the emission of single pulses after nonresonant optical pumping, and relaxation oscillations after electrical pumping. We report here the first investigation of femtosecond time-resolved emission from a semiconductor microcavity resonantly excited with intense femtosecond pulses.

A two-beam optical repeater circuit operates to 1 Gb/s, consumes 10 mW, occupies about 1100 /spl mu/m/sup 2/, and is realized with a technology capable of providing thousands of optical inputs and outputs to foundry-grade VLSI silicon CMOS circuitry. The technology provides this capability by attaching GaAs/AlGaAs multiple-quantum-well (MQW) modulators and detectors to VLSI CMOS with flip-chip solder bonding. The main unique features are summarized.

1996 IEEE International Solid-State Circuits Conference. Digest of TEchnical Papers, ISSCC

15 /spl mu/m solder bonding of GaAs/AlGaAs MQW devices to MOSIS 0.8 /spl mu/m CMOS for 1 Gb/s two-beam smart-pixel receiver/transmitter

This paper describes the VLSI design, layout, and testing of a Hybrid-SEED smart pixel array for a four-stage intelligent optical backplane. The Hybrid-SEED technology uses CMOS silicon circuitry with GaAs-AlGaAs multiple-quantum-well modulators and detectors. The chip has been designed based on the HyperPlane architecture and is composed of four smart pixels which act as a logical 4-bit parallel optical channel. It has the ability to recognize a 4-bit address header, inject electrical data onto the backplane, retransmit optical data, and extract optical data from the backplane. In addition, the smart pixel array can accommodate for optical inversions and bit permutations by appropriate selections of multiplexers. Initial data pertaining to the electrical performance of the chip will be provided and a complete logical description will be given.

A hybrid-SEED smart pixel array for a four-stage intelligent optical backplane demonstrator

Non-linear As(P) incorporation in GaAs1−yPy on GaAs and InAs1−yPy on InP

Femtosecond self-starting passive mode locking using an AIAs/AlGaAs intracavity saturable Bragg reflector

In semiconductor microcavities, quantization of the photon modes can lead to a unique system where excitons couple coherendy to a single mode of photons. In this paper we present the first coherent nonlinear optical study of a composite exciton-cavity system. The results reveal coherent dynamical behaviors that are not accessible to linear measurements.

Coherent Nonlinear Optical Spectroscopy of Semiconductor Microcavities

We introduce a new semiconductor structure and demonstrate its use as an intracavity femtosecond mode-locker. The structure consists of an AlAs/AlGaAs quarter-wave dielectric stack grown by molecular beam epitaxy. We insert a single quantum well into a quarter wave layer, as shown in Fig. 1a. The reflectivity spectrum (Fig. 1b) shows a characteristic Bragg reflection with a small dip at the exciton wavelength of 850 nm.

AlAs/AlGaAs intracavity Saturable Bragg Reflector for Femtosecond self-starting passive mode-locking

We present results on carrier transport in shallow multiple-quantum-well GaAs-Al/sub x/Ga/sub 1-x/As p-i-n diodes (x=0.02, 0.04, 0.08) at various bias voltages. We show that only carrier drift and enhanced diffusion dominate response times of these devices. We also emphasize that the drift of holes plays different roles in determining the response times: at low bias, the slow drift of holes adds to enhanced diffusion, slowing down the decay-times; at high bias, the drift time of holes can be comparable to the time of electrons and contribute to the rise-times. From picosecond time-resolved pump/probe electroabsorption measurements, we obtain the drift times, effective drift velocities, and effective mobilities of electrons and holes. The effective drift velocities (especially for holes) appear rather insensitive to the Al concentration in the barriers.

Measurement of effective drift velocities of electrons and holes in shallow multiple-quantum-well p-i-n modulators

We report a new, low‐temperature process for monolithically integrating 850 nm modulators to pre‐existing very large scale integrated GaAs electronics. We find pristine GaAs surfaces form below 400 °C in the presence of energetic protons generated by an electron cyclotron resonance plasma. While 850 nm superlattices grown at 430 °C exhibit nearly perfect lattice structure when examined by x‐ray diffraction, nonradiative centers are detected with photoluminescence. Transmission spectroscopy reveals the excitons deteriorate too rapidly under bias voltage to fully utilize the quantum confined Stark effect. Efforts to reduce nonradiative trap generation and improve modulator performance under low‐temperature growth appear more feasible when growth is performed under tightly controlled stoichiometric conditions than with arsenic pulsed layer molecular beam epitaxy methods.We report a new, low‐temperature process for monolithically integrating 850 nm modulators to pre‐existing very large scale integrated GaAs electronics. We find pristine GaAs surfaces form below 400 °C in the presence of energetic protons generated by an electron cyclotron resonance plasma. While 850 nm superlattices grown at 430 °C exhibit nearly perfect lattice structure when examined by x‐ray diffraction, nonradiative centers are detected with photoluminescence. Transmission spectroscopy reveals the excitons deteriorate too rapidly under bias voltage to fully utilize the quantum confined Stark effect. Efforts to reduce nonradiative trap generation and improve modulator performance under low‐temperature growth appear more feasible when growth is performed under tightly controlled stoichiometric conditions than with arsenic pulsed layer molecular beam epitaxy methods.

Low‐temperature growth of 850 nm quantum well modulators for monolithic integration to very large scale integrated electronics on GaAs

The rapid advance of femtosecond laser technology has offered superior time resolution for studying transient carrier transport phenomena, and many studies of these transport processes have been performed [1]. In order of time scale, carrier transport process can be divided into four distinct stages: In the first stage, when a biased semiconductor excited by an ultrashort light pulse, an instantaneous polarization of the photoinjected electron-hole pairs is created [2-4]. In the second stage, carriers undergo ballistic acceleration without scattering by the electric field for times shorter than the mean free scattering time (~10−13s). In the third stage, as scattering processes set in, the acceleration of the carriers stops, and the velocity reaches a maximum. Velocity-overshoot occurs for materials such as GaAs, when hot electrons are scattered into satellite L, X valleys with lower mobility. In the fourth stage, the velocity is maintained at a lower leve1 in steady-state drift. These regimes, while easily defined, have not been clearly separated to date because scattering times limit the ballistic regime to ~ 50 fs for typical conditions.

Identifying the Distinct Phases of Carrier Transport in Semiconductors with 10 fs Resolution

Monolithic integration of 850 nm quantum well modulators to very large scale integrated electronics on GaAs

We introduce a new low-loss semiconductor structure for femtosecond intracavity mode locking in low-gain solidstate lasers. This monolithic device can be engineered to exhibit specif ic saturation characteristics desirable for mode locking solid-state lasers. Self-starting 90-fs pulses are obtained with Ti:sapphire and diode-pumped Cr:LiSAF lasers. We discuss mode-locking mechanisms in quantum-well passively mode-locked solid-state lasers.

Low-loss intracavity AlAs/AlGaAs saturable Bragg reflector for femtosecond mode locking in solid-state lasers.

The authors demonstrate active modelocking of an Nd:YLF laser using a semiconductor quantum-well reflectivity modulator as a cavity end mirror. The laser was modelocked at the fundamental frequency (100 MHz) and at harmonics up to 1.6 GHz. Synchronisation of passively modelocked pulses to an external RF signal was also demonstrated.

Antiresonant Fabry-Perot quantum well modulator to actively modelock and synchronise solid-state lasers

We investigate the optical bandwidth of p-i(multiple quantum well [MQW])-n modulators employing various MQW designs. The optical bandwidth translates directly into an operating temperature range due to the shift of the band gap with temperature. We find that although greater maximum modulation may be obtained with narrow (/spl sim/90 /spl Aring/) quantum wells operating below the band edge (absorption increases with field), uniform large performance may be obtained over a larger bandwidth using wider (/spl sim/110 /spl Aring/) quantum wells operating at the exciton (absorption decreases with field). We obtain a usable bandwidth of 7.7 nm, which translates into a operating temperature range of 27/spl deg/C. >

Optical bandwidth considerations in p-i-n multiple quantum-well modulators

We compare growth of multiple quantum well modulators atop a p‐type or n‐type AlGaAs layer. We find the excitonic absorption edge of the quantum wells broadens 30% less under applied field when grown on a p‐down AlGaAs layer compared to the n‐down case. Auger spectroscopy shows Be surface concentration builds up to 0.3 ML on the p‐type AlGaAs layer whereas Si is smaller than 0.07 ML on an n‐type AlGaAs layer. X‐ray diffraction reveals quantum well crystallinity and interfacial roughness to be improved when grown on p‐down AlGaAs layer. We conclude Be is a surfactant that assists AlGaAs epitaxy.

State-of-the-art developments in electroabsorption modulators that utilize quantum well-semiconductors are reviewed. Optimized Multiple Quantum Well modulators in the GaAs/AlGaAs system have been driven by applications in photonic switching and optical interconnects. Surprisingly, these same structures exhibit a wealth of new behavior that ranges from Bloch oscillations to excitons in Coupled Well, Wannier–Stark and Shallow Well superlattices. Several types of excitonic phases have been identified optically and found to transform as the system dimensionality changes from 2D to 3D. In addition, new material systems have shown that quantum well excitonic absorption quality can be transferred to technologically important wavelengths at 1.06 μm or 1.55 μm.

RECENT DEVELOPMENTS AND APPLICATIONS IN ELECTROABSORPTION SEMICONDUCTOR MODULATORS

We review growth and optical properties of strain balanced, InGaAs/GaAsP Multiple Quantum Well structures on GaAs in order to make defect free, 1.06 µm modulators. Here, we implement strain balancing near the elastic limit on a length scale of strong size quantization so as to open up a special class of semiconductors materials. In this system we find the in-plane electron mass is strain-enhanced by 30 %. This preserves both excitonic binding energy and excitonic oscillator strength. Consequently, quantum well absorption at 1.06 pan can be nearly comparable to that of a GaAs qw. Also, strain balanced materials show an improved capacity over 850 nm MQW to optically modulate light signals through the Quantum Confined Stark Effect. This is attributed to a light -heavy hole splitting of 140 meV that is caused by a large component of shear strain in these systems. Growth of strain balanced materials is challenging because the strain energy can be comparable to the surface energy that bonds atoms to the crystal. In order to accurately predict the critical layer thicknesses for strain relief as well as the reorganized surface topology, we develop a 2D-3D growth mode model.

Strain Balanced InGaAs/GaAsP Multiple Quantum Well Modulators at 1.06 µm

Investigations of femtosecond dynamics of excitons in two different regimes are reported: 1. perturbative or weak coupling regime where the exciton decay is irreversible (i.e. excitons in quantum wells), and 2. non-perturbative or strong coupling regime (i.e. quantum well excitons in microcavities) where the coherent exchange of energy between the coupled cavity and exciton modes dominates the femtosecond dynamics. In the perturbative regime, the first femtosecond luminescence measurements are reported, which show (i) a finite rise time for the emission from resonantly-excited excitons and (ii) femtosecond quantum beats of heavy-hole and light-hole excitons. In microcavities, the first nonlinear measurements are reported, which show quantum beats from the coupled cavity-exciton modes, and provide information about the system not available from linear measurements

Femtosecond dynamics of excitons in quantum wells and quantum well microcavities

The responsivity and transmission performance of 60‐period p‐i‐n multiple‐quantum‐well (MQW) optical modulators having single or double steps in the quantum well (QW) has been experimentally compared to a square‐QW control sample. It has been confirmed that significantly increased shift of the exciton with applied electric field [the quantum confined Stark effect (QCSE)] is obtained in the stepped QWs as compared to a conventional square QW. However, no meaningful increase in optical modulation performance is found, due to broadening of the exciton transition in the stepped QWs. All MQWs contained nominal 45 A Al0.3Ga0.7As barriers. Single‐step QWs consisted of a 15 A GaAs region with an 85 A Al0.1Ga0.9As step. Double‐step QWs consisted of a central Al0.15Ga0.85As plateau, with 20 A GaAs regions on either side. The square QW consisted of 90 A of GaAs. Excellent agreement between measured QCSE and tunneling resonance calculations was found. Our results indicate that stepped MQW devices are intrinsically mo...

Comparison of stepped‐well and square‐well multiple‐quantum‐well optical modulators

The first measurements of subpicosecond dynamics of carrier capture and decay in Be δ‐doped GaAs structures with p‐doping density ranging from 6×1012 to 2×1014 cm−2 and spatial distribution on monolayer scale show that photoexcited carriers are captured in the δ‐doped layer in <1 ps. Luminescence decay rates show a strong dependence on energy of the hole in the two‐dimensional Fermi gas. We attribute this to a change in the spatial electron‐hole overlap resulting from band‐mixing effects. We show that Be density fluctuations lead to strong carrier localization.

Time‐resolved study of carrier capture and recombination in monolayer Be δ‐doped GaAs

We discuss a new low loss semiconductor structure for femtosecond intracavity mode-locking in low-gain solid state lasers. This monolithic device can be engineered to exhibit specific saturation characteristics desirable for modelocking solid state lasers. Self-starting 100 fs pulses are obtained in a diode-pumped Cr:LiSAF laser. We discuss modelocking mechanisms in quantum well passively modelocked solid state lasers, and extensions to other wavelengths.

LEOS '95. IEEE Lasers and Electro-Optics Society 1995 Annual Meeting. 8th Annual Meeting. Conference Proceedings

Diode-pumped femtosecond lasers modelocked with saturable Bragg reflectors

Many systems are contemplated that use surface-normal multiple quantum well (MQW) modulators to imprint data on optical beams. These include "smart pixel" digital processors,1 as well as image processors that employ spatial light modulators. These modulators are typically pi( MQW)-n diodes, grown by techniques such as Molecular Beam Epitaxy (MBE), wherein an integral multilayer mirror is produced underneath the MQW. By reverse biasing the diode the MQW’s absorption is modified and hence the reflectivity of the device is modulated. In simple designs a perfect anti-reflection coating is placed on the surface so multiple reflections do not occur within the modulator. This has the advantage that no strict control of the overall thickness of the device is required.

High yield, low cost Fabry-Perot modulators utilizing correctable partial anti-reflection coatings

PURPOSE: To realize highly accurate lattice matching by calculating a performance index, which is normalized by deciding a intensity deterioration quantity from the initial reflectance to the minimum reflectance of a waveform cycle, in regard to a waveform cycle and adjusting the flux of a second semiconductor material so as to optimize the lattice conformity by maximizing the performance index. CONSTITUTION: The oscillation amplitude of a waveform cycle intensity is monitored by a reflection high energy electronic circuit dynamics(RHEED), and the maximum and minimum intensities of a prescribed waveform cycle are decided. Then, a performance index FM, which is obtained by deciding and normalizing a deterioration quantity from the initial reflectance to the minimum reflectance of the waveform cycle, is calculated for a prescribed waveform cycle by using a formula. Then, a substrate formed of a first semiconductor material is prepared and a second semiconductor material is grown on it. The flux of the second semiconductor material is adjusted so as to optimize lattice matching by maximizing the performance index FM. Thus, lattice mismatching is suppressed to less than 2×10 .

Method for manufacturing semiconductor device and light modulator

We report studies of hydrogenated multiple‐quantum‐well (MQW) optical‐modulator structures via electron‐cyclotron‐resonance‐derived plasmas. Responsivity, optical transmission, current‐voltage, and capacitance‐voltage characterizations of Schottky‐ as well as pin‐diode modulator structures were performed. We find photocurrent‐collection efficiency and photoluminescence intensity to be enhanced by hydrogenation, with measurable improvement in electrically biased exciton‐absorption linewidth also seen. We interpret our results as arising from increased carrier lifetime in the MQW region, because of passivation of deep levels/defects. The improvements were stable after 550 °C heat treatment. These effects may be useful for improving the yield of usable MQW devices grown in a given system.

Hydrogenation of multiple‐quantum‐well optical‐modulator structures

The growth of GaAs quantum well modulators on Si for photonic switching applications is reported. Comparison of modulator’s quantum confined Stark effect atop different miscut Si surfaces demonstrate the need for a highly ordered array of bilayer steps as an initial Si surface condition for heteroepitaxy. Proton implantation into the SiO2/Si system via an electron cyclotron resonance plasma to lower the Si oxide desorption temperature, while perserving step ordering of the surface, is explored.

Growth of GaAs light modulators on Si by gas source molecular‐beam epitaxy for 850 nm optical interconnects

Gas composition dependence of silicon nitride used as gallium diffusion barrier during GaAs molecular beam epitaxy growth on Si complementary metal oxide semiconductor

Strain and As species dependent group V incorporation in GaAsP during gas source molecular beam epitaxy

Several authors have demonstrated that quantum well (QW) structures in which the quantum well is graded, stepped, or otherwise modified from the standard square geometry can have an improved quantum-confined Stark effect (QCSE). However, relatively few of these structures have been studied in geometries containing sufficient quantum wells for real modulator use. Here, we report the experimental study of 60-period multiple-quantum well (MQW) structures with photocurrents and in transmission. We have experimentally compared QW geometries containing single- and double-step structures to a standard square QW.

We present an example of a new class of optoelectronic devices realized by placing thin absorbers in a standing wave. Using quantum wells as absorbers and measuring the photocurrent from each of them separately it is possible to realize devices which accomplish complex tasks like separately detecting more than one wavelength at the same time or measuring the wavelength of a quasimonochromatic beam. In this letter we demonstrate a wavelength‐selective detector based on a single quantum well. It detects at 850 nm with a bandwidth <10 nm, while rejecting at the shorter wavelength of 835 nm by a factor of 120.

Wavelength-selective detector based on a quantum well in a standing wave

Here, we present the first THz study of field screening on such a time scale by using a 10 fs laser, and a correlation technique. We prove for the first time that both the polarisation and the acceleration ofthe electron-hole pairs by the dc electric field contribute to THz emission. We show that the polarization contribution has a speed comparable to the optical pulse duration, while the transport contribution at early times is determined by the ballistic acceleration of the electron hole pairs.

Proceedings of IEE/LEOS Summer Topical Meetings: Integrated Optoelectronics

We present a n-i (multiple quantum well [MQW])-p-i(MQW)-n device wherein the n contacts are tied together and biased with respect to the p contact to form an electroabsorptive modulator. Since the light passes through both MQWs large electroabsorption is obtained with lowered voltages since the field is applied in parallel to both MQWs. In particular, wide optical bandwidth is obtained at moderate voltages since high fields may be applied resulting in large Stark shifts of the MQWs. We measure a change in reflectivity greater than 40 percent over a optical bandwidth of 20 nm for 0-14 volts operation.<<ETX>>

Optical bandwidth considerations in p-i-n multiple quantum well modulators

Selectively excited photoluminescence in microcavity enhanced light-emitting diodes reveals that the coupling between the optical cavity mode and the quantum well exciton can be controlled by the exciting light itself. Optical pumping can also provide information on the internal electrical fields.

Optically controlled mode-coupling in microcavity-enhanced light-emitting diodes

We have used CW photoluminescence and photocurrent spectroscopy to study the vertical transport mechanisms in GaAs/AlxGa1-xAs multiple quantum well p-i-n structures. In an x=0.33 asymmetric coupled well sample we have observed resonant electron tunnelling through barriers as thick as 153 AA above the transition field for spatially indirect recombination. In a superlattice with x=0.4 we have observed both electron and hole resonant tunnelling. The temperature and intensity dependence of the photocurrent suggest that non-resonant tunnelling is assisted by charged impurity scattering below 100 K.

Optical studies of resonant and non-resonant tunnelling in GaAs/AlxGa1-xAs quantum wells

We describe the first investigations of hydrogenation on multiple-quantum-well (MQW) optical modulator structures. In particular, we have studied Schottky-barrier modulator structures. We find that hydrogen has a marked beneficial effect on the photocurrent collection efficiency of Schottky-barrier-based MQW modulators. Further, room temperature photoluminescence intensity of our samples was 25 times larger with hydrogen exposure. Both of these results suggest that carrier lifetimes in our samples are increased by hydrogenation, indicating that deep-level non-radiative recombination centers are passivated by hydrogenation. Further, we find that shallow-donor levels are also passivated.

Hydrogenation of Schottky-barrier multiple-quantum-well modulator structures

Evidence for spin singlet-triplet transitions of two electrons in a quantum dot observed via single-electron tunneling

During the heteroepitaxy of GaAs on CMOS devices, it is necessary to protect the silicon dioxide from gallium, which diffuses readily into SiO2. We have found that such diffusion results in a conductive oxide. Since it has been shown previously that silicon nitride inhibits the diffusion of gallium [ 11, it was used here as the diffusion barrier during MBE growth. In order for the nitride to be successfully used for this purpose however, it must have sufficient resistance to hydrofluoric acid (HF) used to clean the silicon surface prior to growth. In addition, it must be mechanically robust enough to undergo a high temperature (900 "C) oxide desorption step necessary for the successful epitaxy of GaAs on Si without cracking or losing adhesion. The latter is especially critical for sub-micron CMOS, which utilizes a reflowable glass (at 850 "C) to round the edges of the contact holes. We have found that this liquificatioii of the reflow glass places a large stress on the nitride diffusion barrier. We have determined that the conditions during the plasma enhanced chemical vapor deposition (PECVD) of silicon nitride are critical to the ability of the nitride to fulfill both of the above requirements, and they are discussed here. A cross-section of the MOSFET structure just prior to MBE growth is shown in Figure 1. The CMOS fabrication was done in (100) silicon oriented 3" off axis toward the (1 10) as required for high quality GaAs growth on silicon [2]. Due to the high temperatures involved with MBE, it was necessary to perform growth just prior to first level metalization. In submicron CMOS technology such as that used here, the topmost film in the field oxide dielectric structure is required to be a reflowable glass such as phosphosilicate glass or BPTEOS, which has a lower melting point than that of standard Si02. The purpose of the reflow glass is to allow the rounding of the top comers of the contact holes to ensure good step coverage during the metalization of the transistors. This rounding is achieved through a heat treatment at 800-850 OC after the contact holes are opened through the dielectrics [3]. Our wafers were then passivated with a standard PECVD silicon nitride deposited using ammonia and silane. Bare silicon areas for MBE growth were opened by reactive ion etching through the dielectric stack of Si02, reflow glass, and silicon nitride, followed by a specialized wet chemical clean [4] including the use of HF acid in order to prepare the exposed silicon surface for growth. The first step in the growth sequence is the removal of the native oxide which forms on the surface of the open areas of silicon by means of a 900-950 "C oxide desorption done under vacuum in the MBE chamber. Once the oxide is removed, the epitaxial films are grown from which the GaAs/AlGaAs multiple quantum well modulators are formed. The details of this growth are given in a separate publication [5]. When using the standard nitride films from the CMOS foundry, it was determined that the films could not withstand the thermal cycling without cracking. This was true of a n y thickness of nitride film. PECVD silicon nitride films deposited with the use of ammonia have been determined to contain up to 30 % hydrogen resulting in high tensile stress and poor mechanical performance [6]. PECVD nitride films deposited using only silane and nitrogen however have been shown to have a much lower percentage (7-15 %) of hydrogen and tensile stress levels near zero [7]. Therefore here we explore cracking and adhesion of nitride deposited using these gases when subjected to the thermal cycling on submicron CMOS. In addition, we have measured the general properties of these films (HF etch rate and refractive index) over a greatly extended range of nitrogen:silane gas ratios (53: 1 to 1250: 1) compared to that studied in [7] (30:l to 167:l) and find that these properties (especially HF etch rate) vary considerably as shown in Figure 2. We find that mechanical stability and resistance to HF is acheived for the same gas ratios (<300:1), making these films ideally suited for use as a gallium diffusion barrier during MBE on CMOS.

Deposition Condition Dependence Of Silicon Nitride Used As A Diffusion Barrier During MBE Growth Of III-Vs On Silicon VLSI Electronics

Nearly all femtosecond carrier relaxation studies are dominated by electron dynamics. We have investigated femtosecond hole dynamics by a judicious choice of experimental parameters: n-modulation-doped GaAs/AlGaAs quantum wells at low temperatures excited with small excess energy and low photoexcitation density. We show that holes are non-thermal for approximately the first 800 fs and determine the hole-electron energy loss rates by comparing experimental results with Monte Carlo simulations. These results represent the first definitive study of hole relaxation dynamics in a semiconductor.

Femtosecond dynamics of non-thermal holes in n-modulation-doped quantum wells

Recently, the technique of generation and detection of free-space THz radiation has been applied widely to study transient effects in different systems [1-3]. One applications is to use THz emission to probe the screening dynamics of the electric field in the picosecond time domain [2,3]. The usual setup for this application involves two femtosecond pulses. One pulse injects electronhole pairs in the electric field region, which then screen the electric field. The second optical pulse, which comes later, produces THz emission. The change in the THz signal observed from the second pulse at different time delays reflects the screening dynamics of the electric field following the first optical pulse.

Traditional bi-directional optical fiber systems utilizing two lasers, two fibers and two detectors are unattractive for fiber to the home communication applications due to the high component cost. A system for medium range applications has recently been demonstrated in which a surface normal p-i (MQW)-n modulator was successllly used to convert downstream light into upstream data fiom the subscriber terminal [l]. A requirement for these devices to be used in such a system is that they exhibit a contrast ratio on the order of 10: 1. Such contrast ratios have been achieved in devices operating at 860 nm but much lower contrast ratios have been reported for surface normal devices operating at 13001550 nm, corresponding to the low loss-low dispersion window of optical fibers, for long haul communication applications. The highest contrast ratio reported for surface normal devices in this wavelength regime to the best of our knowledge is 2.6: 1 (4.1 dB) at an applied reverse bias of 40 V for a device incorporating a 150 period InGaAs-InP MQW [2] and 3 dB for an Asymmetric Fabry Perot (ASFP) modulator albeit at a low drive voltage of 5 V [3]. The reason for the low contrast ratios is the low value of the absorption coefficient exhibited by this material system (only about 40% of that exhibited by the AIGaAs-GaAs material system). The device structure was grown on top of an n type Inp (Sn doped) wafer by Gas Source MBE using ASH3 and PH3 as the Group V source gases at a growth temperature of 500 C. The structure consisted of a 1.5 pm n-type InP clad layer (Si doped to 3 x 1018 cm-3) followed by an intrinsic region composed of 200, 10 nm &.53%.47As wells lattice matched to 8 nm InP barriers, followed by a 1 pm thick p-type InP clad layer (Be doped to 3 x lo** cm-3). Post growth processing consisted of a mesa etch and p and n type contact metallizations. An Si0 anti reflection coating was then applied to the backside of the wafer. Since the InP substrate is transparent at the wavelength of interest no substrate thinning was performed.

InGaAs/InP P-I (MQW)-N Surface Normal Electroabsorption Modulators Exhibiting Better Than 8:1 Contrast Ratio For 1.55/spl mu/m Applications Grown By Gas Source MBE

Vertical Transport Studied by Sub-Picosecond Four-Wave Mixing Experiments

We measure electroabsorption in GaAs/AlGaAs multiple quantum well modulators with ultranarrow barriers so as to maximize the overall absorption coefficient by removing optically inert barrier material. Reduction <38 A in the width of Al0.3Ga0.7As barriers results in resonant well coupling degrading performance. For AlAs barriers, resonant coupling is eliminated and we observe sharp excitons and the quantum confined Stark effect for barriers as narrow as 10 A. However, optimum normally‐on operation is obtained for 20–30 A AlAs barriers, approximately 20% better than 38 A Al0.3Ga0.7As barriers.

Electroabsorption in ultranarrow‐barrier GaAs/AlGaAs multiple quantum well modulators

PURPOSE: To prevent cracks in a nitride thin film due to stresses at a molecular- beam epitaxial growth process temperature and to improve resistance against etchant of hydrogen fluoride by maintaining the ratio between nitrogen and silane in the growth of silicon nitride to be lower than a specific value. CONSTITUTION: The ratio between nitrogen and silane gas is a dominant factor for the growth of silicon nitride, without ammonia in plasma-promoted chemical vapor deposition process. Accordingly, by maintaining the ratio to be 300:1 or lower, the stresses of the thin film can be reduced to a level such that the nitride thin film can be used without causing mechanical damages. Further, etching speed using hydrofluoric acid can be controlled to a level that the silicon nitride thin film is almost unaffected by acid. COPYRIGHT: (C)1995,JPO

Formation of silicon nitride gallium-diffusing barrier wall for gallium-arsenic molecular-beam epitaxial growth

We report growth of In/sub 0.53/Ga/sub 0.47/ As-InP multiple quantum well (MQW) modulators operating at 1.55 /spl mu/m for fiber-to-the-home applications. By employing a 200-period InGaAs-InP MQW stack in the intrinsic region of a p-i-n structure and working in reflection, we have been able to realize surface-normal modulator devices that exhibit better than an 8:1 contrast ratio. This is the highest contrast ratio reported to date for this type of device working at this wavelength.<<ETX>>

InGaAs-InP P-I (MQW)-N surface-normal electroabsorption modulators exhibiting better than 8:1 contrast ratio for 1.55-/spl mu/m applications grown by gas-source MBE

Optical Enhancement of Terahertz Emission from Bulk Semi-Insulating GaAs

We have used time‐resolved transmission and photocurrent measurements at 1.06 μm to study carrier sweepout in strain‐relaxed InGaAs/GaAs and strain‐balanced InGaAs/GaAsP quantum well modulators. Our results show carrier sweepout on a picosecond time scale from both structures, in agreement with the high saturation intensities measured for these devices. Carrier escape from the InGaAs/GaAs structure is facilitated by a low band offset and occurs in tens of picoseconds even without external bias. In the InGaAs/GaAsP structure, which has a much larger band offset, resonant tunneling reduces the sweepout time from 1.8 ns at zero bias to 10 ps at −6 V.

Picosecond carrier escape by resonant tunneling in pseudomorphic InGaAs/GaAsP quantum well modulators

We find that the incorporation of As and P into GaAs1−yPy, when using gas‐source molecular beam epitaxy, does not depend linearly upon the atomic fluxes within the reactor. Rather, incorporation of As and P into GaAsP goes as the square of the atomic fluxes, i.e., y=fP2/(fP2+βfAs2), where fP(As) is the flux of P(As). β is a fitting parameter and that differs for relaxed and strained GaAsP. The deviation in y from a linear model [y=fP/(fP+fAs)] is as high as a factor of two, whereas our quadratic model is never more than a few percent off. We interpret this as due to surface pairing between two like species (dimerization) in order for them to incorporate into the crystal.

We demonstrate that transient optical dephasing experiments on electrically biased, shallow multiple quantum wells offer the unique possibility of studying the first step in carrier sweep-out, namely the escape tunnelling out of the individual quantum wells. We perform transient four-wave mixing experiments on two shallow GaAs/AlxGa1-xAs multiple quantum well samples with x=0.04 and x=0.06. We find that the electron tunnelling times out of the quasibound n=1 quantum well states into the continuum states decrease with increasing electric field, and lie in the subpicosecond regime at high fields. In addition, for the x=0.06 sample, the experimentally determined escape rate is resonantly enhanced when the quasibound n=1 quantum well state couples to the n=2 state embedded in the continuum above the second-nearest-neighbour well.

Carrier escape tunnelling out of shallow multiple quantum wells studied by transient four-wave mixing

The Nd:YAG laser has been considered as a possible light source for optical computing systems based on p-i(MQW)-n modulators, because of its ability to provide high power with high spectral and spatial quality. However, since this laser operates at 1.064 μm, the GaAs/AlGaAs material system cannot be used. Since the GaAs substrate is a better candidate for large-scale integration than InP, much attention has been focused on InGaAs/GaAs MQWs for this application.1-4 However, since the MQW must be at least 1 μm thick for useful surface-normal modulation, strain-relief is bound to occur in this system. This relaxation of the lattice results in dislocations which propagate upward resulting in a striated surface,3 causing diffraction of the light beams. In addition, the defects make the integration of GaAs transistors problematic.

Measurement of modulation saturation intensity in strain-balanced, undefected InGaAs/GaAsP modulators operating at 1.064 μm

We demonstrate coexisting operation of a GaAs/AlGaAs multiple quantum
 well modulator and a submicron gate length metal-oxide-semiconductor
 transistor fabricated on the same chip, for applications in optical
 interconnects.

Monolithic Integration of GaAs/AlGaAs Multiple Quantum Well Modulators and Silicon Metal-Oxide-Semiconductor Transistors

We systematically studied microcavity enhancement and mode‐coupling effects in photo‐ and electroluminescence of an AlGaAs/GaAs vertical‐cavity light‐emitting diode (LED) by continuously changing the microcavity resonance with respect to the quantum well band gap. At mode overlap we obtained maximum photo‐ and electroluminescence intensities and a minimum emitted linewidth of 4.6 nm at 836 nm with a FWHM divergence of 62°. However, the electrical‐to‐optical efficiency was less than 1 μW/mA. Application issues for optical interconnects are presented.

Recent Developments in Doping Techniques for Compound Semiconductors

We present a n‐i[multiple quantum well (MQW)]‐p‐i(MQW)‐n device wherein the bottom MQW functions as a voltage‐tunable photodetector and the top MQW functions as a voltage‐tunable filter, allowing enhanced detectivity at the exciton wavelength compared to photon energies below or above the band gap. Thus this device more closely approximates a true single wavelength, voltage‐tunable photodetector. We achieve about 2–1 selectivity over a tuning range of 14 nm with 12 V operation.

Voltage‐tunable multiple quantum well photodetector vertically integrated with voltage‐tunable multiple quantum well filter

In recent years, much attention has been focused on carrier emission rates and cross-well motion in semiconductor quantum well structures because the efficiency and response speed of many MQW optoelectronic devices depend on the dynamics of vertical carrier transport processes. Thermionic emission is believed to be the principal mechanism for the escape of the carriers from each individual quantum well. In most cases, measurements of the transport dynamics have been carried out in structures that contain multiple quantum wells. However in multiple well structures, effects such as resonant tunneling and carrier retrapping make it difficult to unambiguously separate the effects from one another. In recent measurements on single quantum wells with asymmetric barriers, we monitored electron and hole sweep-out rates simultaneously as a function of electric field(1), and showed that the carrier emission from the wells is thermionic in nature, but this preliminary analysis did not give very good quantitative agreement with the conventional thermionic emission model(2). In this paper, we will present a study of the emission for both carrier types as a function of temperature and electric field in order to fully evaluate the applicability of the thermionic emission model to the process of carrier escape in a single quantum well.

Temperature Dependence of Electron and Hole Emission Rates from a Single Quantum Well with Asymmetric Barriers

We present asymmetric Fabry-Perot quantum well modulators which are overbalanced, so that at zero bias at the exciton wavelength reflectivity is high. As bias is applied and the quantum well absorption decreases the optical cavity balances, nulling reflection. By partially anti- reflection coating, at zero bias the optical cavity is balanced, so that the reflectivity is near zero, and increases with bias. Therefore we can integrate normally-on and normally-off high- contrast modulators by selective AR coating. With 10 volts bias, we obtain 11:1 contrast ratio for the normally-on devices and 8:1 for the normally-off devices. Possible applications include complementary output of optical logic gates.

Monolithic integration of normally-on and normally-off asymmetric Fabry-Perot modulators by selective antireflection coating

Recently, quantum well electroabsorption modulators have been proposed for use as optoelectronic switches in information processing systems. Recently, a strain-balanced InGaAs/GaAsP system has been shown to have good surface morphology and a surprisingly high saturation intensity. The most likely reason for this favorable result is a high sweepout rate of the carriers from the wells. To investigate the physics of carrier escape in this system, we have recently performed pump-probe transmission measurements with picosecond resolution on biased InGaAs quantum well structures.<<ETX>>

Picosecond measurement of carrier sweepout times in InGaAs quantum wells

Pseudomorphic InGaAs/GaAsP MQW reflection modulator operating at 1.06 µm

We have determined the spin relaxation dynamics of electrons, holes and excitons in GaAs quantum wells by means of subpicosecond studies of the photoluminescence polarization. Our measurements demonstrate that the usual image of instantaneous hole-spin relaxation is not valid in 2D systems. For electrons, the spin relaxation rate is considerably larger than the corresponding value in p-doped bulk GaAs. The processes of spin relaxation of free excitons are far more complicated than those of free carriers: we find that many-body effects play an important role in the spin relaxation of excitons.

The authors have measured the absorption coefficient ( alpha ) and linewidth ( Delta ) of the excitons of GaAs/AlGaAs and strain-balanced InGaAs/GaAsP multiple-quantum-well (MQW) modulators with wavelengths from 850 to 1064 nm. They find that alpha decreases and Delta increases as wavelength increases, but their product, and thus the integrated absorption coefficient, remains roughly constant. Thus, the reduced performance observed for longer wavelength modulators is due to exciton broadening.<<ETX>>

Independence of absorption coefficient-linewidth product to material system for multiple quantum wells with excitons from 850 nm to 1064 nm

We report the observation of a Be segregation rate in GaAs that depends linearly on Be content. When δ‐Be is codoped with δ‐Si this segregation dependence changes and is observed to follow a model of segregation we develop based on Be dimerization. Further, we present the first evidence that GaAs surfaces order upon δ‐Be deposition. The observed surface reconstructions could also result from Be dimerization. The energy gained from dimerization causes Be to segregate during growth.

LEOS 1993 Summer Topical Meeting Digest on Optical Microwave Interactions/Visible Semiconductor Lasers/Impact of Fiber Nonlinearities on Lightwave Systems/Hybrid Optoelectronic Integration and Packagi

As the number and bandwidth requirements of connections to integrated circuit chips approach thousands and hundreds of megahertz, respectively (which is occurring now), the capability of standard electrical chip input/output becomes strained. For this reason optical input/output to chips is being explored by a number of groups.1 In modulator systems, an off-chip laser would be split into an array of beams that illuminates an array of surface-normal modulators. The modulators would be switched by the on-chip electronics to imprint information on the reflected beams. Multiple quantum well (MQW) modulators are attractive because they can produce large enough absorption changes in surface-normal devices with good yields, low intrinsic power dissipation and apparently good reliability. Since the modulators are p-i-n type devices they are also efficient input detectors. 64x64 arrays of operational modulators have been demonstrated.2 Reliable modulators have also been demonstrated on silicon.3

Interleaved-contact electroabsorption modulator using doping-selective electrodes with 25 °C to 95 °C operating range

An InGaAs/GaAsP multiquantum well (MQW) reflection modulator is demonstrated that has no material buffer layer between the mirror and MQW, for superior electronic integration compatibility. A reflectivity change from 32 to 69% is obtained on GaAs substrates for a 0–10 V swing at 1.06 μm. We further demonstrate such a device on a silicon substrate.

Strain-balanced InGaAs/GaAsP multiquantum well reflection modulator operating near 1.06 mu m on GaAs and silicon substrates

We have studied the vertical transport mechanisms in GaAs/AlxGa1−xAs multiple quantum wells in electric fields from the temperature dependence of the photocurrent. On heating from 10 K, we observed a decrease in the photocurrent up to ∼100 K, followed by a steady increase up to room temperature. The decrease is shown to be consistent with charged‐impurity‐assisted nonresonant tunneling which varies as T−1/2 in two dimensions, while the increase is consistent with thermal emission. The low field activation energy measured in a sample with x=0.33 is consistent with the thermal emission of heavy holes.

Carrier escape mechanisms from GaAs/AlxGa1−xAs multiple quantum wells in an electric field

GaAs/AlGaAs p-i-n multiple-quantum-well modulators solder-bonded to a silicon substrate are reported. The GaAs substrate is then chemically removed to allow operation at 850 nm. The gold contact to the modulator is used as the reflector. A change in reflectivity from 26% to 52% is achieved for a 0 to 10 V bias swing. The device has a modulation saturation intensity of 80 kW/cm/sup 2/, demonstrating superb heat-sinking and ohmic contact. The hybrid was cycled from 30 degrees C to 100 degrees C over a 100 times, and it showed no degradation, exhibiting the practicality of the technique.<<ETX>>

Using a strain‐balanced growth approach, we show that the pseudomorphic InAsP/InGaP multiple quantum well structures, grown by chemical beam epitaxy, have superior material properties for 1.06 μm modulator application when compared to the strained InAsP/InP or the lattice‐matched InGaAsP/InP systems. The broadening in absorption edge due to dislocations in the strained system, or composition fluctuations in the lattice‐matched system as a consequence of growth temperature instability, can be greatly minimized. A strong reduction in the nonradiative recombination centers in the strain‐balanced InAsP/InGaP system has been observed.

Growth of strain‐balanced InAsP/InGaP superlattices for 1.06 μm optical modulators

Growth of pseudomorphic InxGa1-xAs/GaPyAs1-y multiple quantum well structures on GaAs by gas source molecular beam epitaxy

We demonstrate that transient optical dephasing experiments on electrically biased, shallow multiple quantum wells offer the unique possibility of studying the first step in carrier sweep‐out, namely, the tunneling escape out of the individual quantum wells. We find that the electron tunneling times out of the quasibound n=1 quantum well states into the continuum states lie in the subpicosecond regime at high electric fields. In addition, the experimentally determined escape rate is resonantly enhanced when the quasibound n=1 quantum well state couples with the resonant n=2 continuum state originating from the second‐nearest neighbor well.

Escape tunneling out of shallow multiple quantum wells studied by transient four‐wave mixing

Narrow-linewidth voltage-tunable multiple quantum well photodetector

A multiple-quantum-well (MQW) modulator with multiple stacked p-i(MQW)-n-i(MQW)-p-regions is demonstrated. Electrodes are deposited such that all the n-layers are connected to one contact and all the p-layers to the other. This allows high fields to be produced in the i-regions with relatively low voltages, since the i-regions may be made thin while retaining large optical interaction because they are stacked. A large usable wavelength range which translates into a large operating temperature range is obtained because of large Stark shifts in the MQWs at high fields. For a 0 to 6 V swing >22% reflectivity change from 25 degrees C to 95 degrees C, or alternatively over a wavelength range of 15 nm at 25 degrees C, is achieved.<<ETX>>

Interleaved-contact electroabsorption modulator using doping-selective electrodes with 25 degrees C to 95 degrees C operating range

Peak-to-valley ratio of 130:1 at 1 K in AlGaAs/GaAs/AlGaAs tunneling structures: evidence for suppressed dopant segregation

AC-Stark shifts of the electronic states are observed when a semiconductor is excited by ultrashort, below band-gap laser pulses. So far, all the studies have been performed in undoped samples [1,2], and the effect has been called "excitonic AC-Stark effect". It has been explained by means of the interaction of "virtual" excitons created by the pump beam with the real excitons created by the weak probe beam [3]. In this talk, we will describe our work on the AC-Stark shifts observed in the absorption spectra of modulation doped quantum wells (MDQW). This effect occurs in a new regime, as the absorption edge in MDQW samples at low temperatures is governed by the "Fermi edge singularity" (FES).

AC-Stark shift of the Fermi edge singularity in modulation doped quantum wells

Summary form only given. In conclusion although we observe the QCSE in GaAs/AlAs MQW modulators for barriers as thin as 10 /spl Aring/, optimum electroabsorption for smart pixels is found for 20-30 /spl Aring/ barrier width.<<ETX>>

Electroabsorption in ultranarrow-barrier GaAs/AlAs multiple quantum well modulators

It is now generally recognized that one likely scenario in which photonics is used in a switching environment is where it is integrated with electronics. This concept takes advantage of the greater capacity of electronics for complexity, functionality, and memory, and the greater capacity of photonics for communications. Silicon electronics seems to be the most effective technology where complex systems such as microprocessors or memory is concerned. Since the benefit of increased communication capacity to the chip is most attractive when the chip contains a great number of computing elements, it appears that the strongest impact of photonics will be as optical input/output for silicon integrated circuits. Since simultaneous operation of large arrays (e.g., thousands) of surface-emitting lasers has not been demonstrated, and their operation would be thermally problematic, whereas such arrays of surface-normal modulators have been demonstrated, it appears that surface-normal modulators grown on silicon ICs are the logical device for this application. In this paper we demonstrate a multiple quantum well (MQW) modulator grown on a silicon IC that was obtained from a standard 0.9-μm linewidth fabrication line. The modulator functioned, although with reduced performance because of spectral misalignment of the integral mirror with the exciton of the MQW. We then metalized and tested a 1-μm gate length transistor on the IC and it functioned near the specifications of the fabrication line.

Monolithic integration of GaAs/AlGaAs multiple quantum well modulators and micron gate-length silicon metal-oxide-semiconductor transistors

Incremental single-electron charging of size-quantized states has been observed in the well in submicrometer double-barrier resonant tunneling devices. In order to distinguish between the effects of size quantization and the single-electron charging, the heterostructure material was grown asymmetrical so that one barrier is substantially less transparent than the other. In the voltage polarity such that the emitter barrier is more transparent than the collector barrier, electrons accumulate in the well; incremental electron occupation of the well is accompanied by Coulomb blockade, which leads to sharp steps of the tunneling current. In the opposite voltage polarity the emitter barrier is less transparent than the collector barrier and the tunneling current reflects resonant tunneling through size-quantized well states.

Observation of Single-Electron Charging in Double-Barrier Heterostructures

A new method for laterally manipulating the morphology of a thin film is presented, which uses the force exerted by light to deflect neutral atoms in an atomic beam during deposition. We have evaluated the dependence of the thickness of a thin metal film on the frequency, intensity, and the spatial structure of the light field, and find that the stimulated component of the force is suitable for laterally organizing atoms from centimeter to submicron dimensions.

One key factor limiting device performance in multiple quantum well p‐i(MQW)‐n modulators is photoexcited carrier escape and transport to the contacts. With deep wells, in the AlGaAs/GaAs system, this problem limits the ultimate switching speed of the device. To reduce the impact of this problem, we have grown shallow quantum well structures containing AlxGa1−xAs barriers as low as x=0.01. Several structures have been grown at 600 °C with x=0.01–0.08 which show sharp excitonic features at room temperature, and good quantum confined stark shifts under an applied field. We report room temperature photocurrent, transmission, x‐ray, and low temperature photoluminesence data of the x=0.02 device.

Growth of shallow AlGaAs/GaAs quantum wells by gas‐source molecular beam epitaxy

We present the results of a comprehensive investigation of spin-relaxation processes of electrons, holes and excitons in quantum wells using subpicosecond spectroscopy of luminescence polarization. Spin relaxation rates of electrons and holes are measured directly in modulation-doped quantum wells and give a good understanding of spin-relaxation processes of electrons and holes. We show that spin-relaxation dynamics of excitons, on the other hand, is quite complicated and is strongly influenced by their formation dynamics, many-body effects and localization dynamics. Although we have made good progress towards understanding exciton spin relaxation processes, some other outstanding issues will require further attention. We compare our results to those in bulk GaAs, and those in quantum wells obtained by other techniques.

Spin relaxation dynamics of excitons and free carriers in quasi-two-dimensional GaAlAs/GaAs structures

Spin relaxation dynamics in GaAs quantum wells: Free carriers and excitons

Previous strain‐relief p‐i‐n InGaAs‐GaAs quantum well (qw) modulators have incurred surface striations upon growth due to defect formation, resulting in an optically rough surface. We present here a qw modulator on a GaAs substrate with InGaAs wells and GaAsP barriers which balance the strain in the wells so that the lattice does not relax, leading to much fewer defects, and an optically smooth surface. We obtain a transmission change from 60% to 80% at 1014 nm for a sample with a 1 μm thick intrinsic region.

The authors have produced a n-p-i (shallow quantum well)-n GaAs-AlGaAs layer structure from which either heterojunction bipolar transistors (HBTs) or surface-normal modulators may be fabricated, allowing single-growth integration of those devices for optical interconnects. The shallow quantum well region provides large electroabsorption while having no impedance to electron transport. The HBTs have a gain of 15. The modulators have a change in transmission from 30.7% to 50.1% for a change in bias from +1 V to -3V.<<ETX>>

Single-layer structure supporting both heterojunction bipolar transistor and surface-normal modulator

A surface-normal GaAs quantum-well absorption modulator has been produced atop a silicon wafer that has been implanted with Co and annealed to form a silicide layer. The silicide layer functions as a mirror allowing reflection mode operation. This substantially reduces the thickness of the modulator compared to devices with AlGaAs-AlAs multilayer reflector stacks. A contrast ratio of 2.5 was obtained with 25 V operation.<<ETX>>

The effect of growth temperature instability in the CBE growth of InxGa1-xAsyP1-y/InP multiple quantum well structures

The authors demonstrate that by using undoped GaAs buffer layers, high-quality GaAs devices (in this case, surface-normal reflection modulator/detectors) may be grown on doped silicon substrates with >30-G Omega isolation. The resistivity of the buffer layers is estimated to be >2.4*10/sup 7/ Omega -cm. Isolation is demonstrated by forming a symmetric self-electrooptic effect device of two of the modulators. Bistable contrasts of 2.9:1 and 1.8:1 are obtained with 7-V and 2-V supply biases, respectively. >

Summer Topical Meeting Digest on Broadband Analog and Digital Optoelectronics, Optical Multiple Access Networks, Integrated Optoelectronics, Smart Pixels

>30 G/spl Omega/ Isolation Of GaAs Devices On Doped Si Via Undoped Buffer Layers; Application To Symmetric Self-electro-optic Effect Devices

Surprisingly, the onset of superlattice (SL)-type electroabsorption (EA) (localization/delocalization and Stark ladder phenomena) as multi-quantum well (MQW) barriers are lowered does not correlate with miniband width. As the barriers of a 100/100 angstroms GaAs/AlxGa-1As MQW are lowered to x equals 0.01, similar (quantum confined Stark effect) EA as for x equals 0.3 samples is seen. For x equals 0.02, as the MQW period (d) is shortened to 140 angstroms, SL-type EA is observed but does not correlate with miniband width. This shows that standard models do not apply for shallow systems. For x equals 0.07 and d equals 175 angstroms SL effects consistent with standard models are observed.

Observation of Wannier-Stark localization in shallow superlattices

Abstract : Optical interconnection of electronic integrated circuit chips is currently of great interest. This would provide a much greater bandwidth of information flow on and off the chip, especially if surface-normal devices are used since then information may flow vertically from the chip and the entire area of the chip may be used rather than just the periphery. Modulators are attractive candidates for active optical input/output. We demonstrate here a simple, elegant scheme for producing a modulator and a heterojunction bipolar transistor (HBT) on the same chip. Our layer structure is generally n-p-i-n from the surface downward, with the top layer forming the emitter, and the i region between base and collector. Separate HBT's and modulators are formed by etching mesas with or without emitter pads and without or with optical windows, respectively. This structure has been investigated previously, in Ref. 1, wherein the i region was a GaAs/Al0.3 Ga 0.7 as a multiple quantum well (MQW). This MQW is pathological to the performance of a HBT, since the high barriers block carriers from leaving the base.

Abstract : Two quantum systems with energy levels in resonance with each other experience a splitting of these levels when the wavefunctions of the systems overlap. In semiconductor structures consisting of pairs of closely spaced quantum wells the wavefunction overlap of charge carriers in the wells leads to a novel kind of intersubband transition. To date, this transition has been studied by interband absorption and luminescence and, most recently, by four-wave-mixing experiments Leo, 1990. Here, we report of the first direct absorption measurements of the split-subband transition in coupled quantum wells.

Terhertz Absorption between Split Subbands in Coupled Quantum Wells

We present asymmetric Fabry–Perot quantum‐well modulators which are overbalanced, so that at zero bias at the exciton wavelength reflectivity is high. As bias is applied and the quantum‐well absorption decreases, the optical cavity balances, nulling reflection. By partially antireflection coating, at zero bias the optical cavity is balanced, so that the reflectivity is near zero, and increases with bias. Therefore, we can integrate normally‐on and normally‐off high‐contrast modulators by selective AR coating. With 10 V bias, we obtain 11:1 contrast ratio for the normally‐on devices and 8:1 for the normally‐off devices.

Monolithic integration of normally‐on and normally‐off asymmetric Fabry–Perot modulators by selective antireflection coating

Recently, the authors reported defect-free, InGaAs-GaAsP multiquantum well modulators operating at 1015nm, but with an unusual dual-peak spectra that resulted in slight degradation in performance. In the Letter, a similar sample grown under reactor gas overpressure that has normal spectra is reported. The dual-peak spectra are therefore attributed to microscopic domain formation that the gas overpressure inhibits by reducing surface atom mobility. The operation has also been extended to 1.06 μm, the Nd: YAG wavelength.

Defect-free modulator at 1.06 mu m using a strain-balanced multiquantum well

Picosecond pump probe measurements on waveguides containing a single GaAs/GaAlAs quantum well have enabled us to determine for the first time both electron and hole escape times from biased quantum wells. Contributions from excitonic saturation and field screening by photogenerated carriers can be clearly identified in the nonlinear transition signal and are quantitatively modeled. Preliminary analysis suggests that thermally assisted escape is dominant at room temperature, but discrepancies are found with conventional thermionic emission models.

Simultaneous measurement of electron and hole escape times from biased single quantum wells

The authors demonstrate that by using undoped GaAs buffer layers, high-quality GaAs devices (in this case, surface-normal reflection modulator/detectors) may be grown on doped silicon substrates with >30-G Omega isolation. The resistivity of the buffer layers is estimated to be >2.4*10/sup 7/ Omega -cm. Isolation is demonstrated by forming a symmetric self-electrooptic effect device of two of the modulators. Bistable contrasts of 2.9:1 and 1.8:1 are obtained with 7-V and 2-V supply biases, respectively.<<ETX>>

>30 G Omega isolation of GaAs devices on doped Si via undoped buffer layers-application to symmetric self-electrooptic effect devices

A concept of doping that permits for the first time the freedom to design the desired activation energy of a dopant in a semiconductor is introduced and demonstrated. This doping engineering (DE) may also offer the possibility of achieving dopings in semiconductors in which a normally employed doping process is not successful, such as in wide band‐gap II‐VI semiconductors. Experimentally, we demonstrated that the normal activation energy, ∼19–25 meV of berrylium (Be) in GaAs was reduced to 4 meV in DE GaAs/δ‐Al0.3Ga0.7As(Be) sample.

Femtosecond excitonic photocurrent transients in quantum wells: parallel and perpendicular field geometries

Femtosecond Time-Resolved Four-Wave Mixing in GaAs Quantum Wells

We passed a transversely cooled sodium atomic beam through an optical standing wave, which channeled the atoms into the intensity minima (maxima) for light tuned below (above) the sodium 32S1/2 → 32P3/2 resonance frequency. The channeled atoms retained their spatial distribution when they were deposited onto the silicon surface. The surface was thus covered by a permanent periodic sodium grating with an area of 1 x 0.1 cm2 and a period of d = 294.3 ±0.3 nm, which is half the wavelength of the standing wave field. The entire grating was completed in 10 min. We measured the period of the grating by backscattering weak probe light. The probe light had a wavelength λ, which we varied between 5580 and 5800 Å, and was incident at an angle ϕ relative to the normal. There is constructive interference when the angle θ with respect to the normal to the grating is such that λ = d(sin θ + sin ϕ). The dependence of θ on ϕ allowed us to measure d. Semiclassical theory suggests the width of the lines in the grating could be of the order of 100 Å.

Electron and hole escape times from a GaAs-AlGaAs quantum well in an electric field at room temperature are measured by picosecond optical pump-probe techniques on samples containing a single quantum well in a waveguide. The use of a single well avoids multiple well transport and resonant tunneling effects. Carriers excited in the quantum well by the pump beam result in a transient bleaching signal from excitonic saturation, and, as they leave the well, a transient electroabsorption signal because the movement of charge partially screens the electric field. Both processes are modeled, including important electrical equilibration processes of the sample as a whole. This modeling and the use of two samples with asymmetric barrier heights allows the measurement of the electron and hole emission as a function of applied electric field. Preliminary analysis suggests that the emission mechanism is thermionic rather than by tunneling, but the results are not well explained by conventional thermionic emission models. >

Simultaneous measurements of electron and hole sweep-out from quantum wells and modeling of photoinduced field screening dynamics

The physics of carrier escape from quantum wells in an electric field is important for improving the quantum well electroabsorptive devices such as the Self Electrooptic Effect Device (SEED) [1]. The carrier lifetime is important not only because it puts a lower limit on the switching time [2], but also because it affects other properties such as the electroabsorption and the exciton saturation intensity [3]. This latter point in fact proves to be very significant for SEED systems, because these systems tend to run at intensity levels much greater than that required to switch a single device. (Sufficient energy must be passed to the next device in the system to switch it after allowing for the system losses.) At these high power levels, the exciton absorption saturates, which puts an upper limit on the intensity which can be used. We have recently shown how the saturation intensity is strongly affected by the design of the quantum well structure, most likely because of the changes in carrier sweep-out times which accompanied the change in design [3].

Monolithic Optically Bistable Circuit With Transistor Gain Using Novel Modulator-HBT Integration Technology

Integration of Heterojunction Bipolar Transistors and Shallow Quantum Well Modulators for Smart Pixel Fabrication

New results with femtosecond four-wave mixing in GaAs quantum wells

Abstract : Excitonic electroabsorption has been used recently to detect ultrafast electrical transients in ultra-thin quantum well coplanar striplines with time resolution as fast at 180 fs . The use of thin films of quantum wells as both generator and detector of electrical signals with coplanar stripline interconnection results in several interesting capabilities. First, since the exciton exhibits a sensitive saturation response with resonant excitation, it can be used as an in-situ calibration of the excitation and probing response functions. This nonlinear response is instantaneous, since it is based on excitonic phase space filling . Second, the exciton exhibits sensitive electroabsorption in either parallel (field ionization mode) or perpendicular (quantum-confined stark effect - field ionization inhibited mode) electric fields.

Femtosecond Spatiotemporal Field Measurements in GaAs Quantum Wells

We evaluate Be and Si segregation in GaAs during growth by gas source molecular‐beam epitaxy and molecular‐beam epitaxy. We find that the dopant segregation lengths, when detected, are thermally activated with an energy of 0.6 eV. These kinetics are too small to be explained by classical models of dopant segregation, but instead lie close to motion energies corresponding to the elementary jumps executed by the dopant near the surface.

Femtosecond excitonic nonlinearities in shallow quantum wells: a case of intermediate dimensionality

We examine growth of Ga1−xInxAs/GaAs1−yPy multiple quantum well structures by gas source molecular beam epitaxy for photonic switching applications at 1.06 μm. For appropriate x and y values these structures can be grown pseudomorphically at the GaAs lattice constant. Such structures show good morphology, room‐temperature photoluminescence and sharp excitonic absorption edges near 1.06 μm.

Growth of Ga1−xInxAs/GaAs1−yPy multiple quantum well structures by gas source molecular beam epitaxy

Electro-optic sampling and tunable infrared femtosecond optical pulses are used to measure photocurrent transients generated in GaAs quantum well coplanar microstrip samples at 77 K. This combination allows us to investigate the dynamics of photocurrent with 300 fs time resolution while exciting near the exciton resonance. We find no evidence for ac–dc Stark effect (below-bandgap field-induced optical rectification) signals at small detunings with the electric field applied either parallel or perpendicular to the quantum wells; however, other photoconductive overshoot transients are observed.

Femtosecond excitonic photocurrent transients in quantum well striplines

We report here the first measurements of k-space carrier scattering times in GaAs as a function of the density of carriers. Studies were performed by measuring the dynamics of anisotropic momentum distribution of carriers created by linearly polarized 9 femtosecond infrared pulses [1] centered at 820 nm.

Abstract : Quantum wells and related layered semiconductor structures show strong electroabsorption that can be applied to make optical switches and modulators. Many different structures are possible, each with different electroabsorption characteristics. In addition to conventional rectangular wells, structures investigated include coupled wells, both symmetric and asymmetric, graded wells, low-barrier wells, and superlattices. The optimum structure depends to some extent on the application. Here we describe a novel, slightly asymmetric coupled well structure designed to operate at very low fields. The resulting operating fields are so low that we can make a self-biased symmetric self-electrooptic effect device(S-SEED); this is an opto-electronic switching device without a power supply, and this is the first demonstration of such a device suitable for use in two-dimensional arrays. For S-SEED operation, we want to use the lowest possible electric field so that we can minimize the switching energies. The optical switching energy is directly proportional to the field change required in switching; this is because all of the charge involved in charging and discharging the internal capacitance, C, of the device is photogenerated by absorption of the incoming light The charge required per unit area (and hence the required absorbed optical energy per unit area) is proportional to the field in the device. In addition, it is obviously important to minimize the operating voltage swing, V, to reduce the electrical energy, since this energy is about (1/2) CV2 for electrically driven modulators.

Low Field Electroabsorption and Self-Biased Self-Electrooptic Effect Device using Slightly Asymmetric Coupled Quantum Wells,

Gas source molecular beam epitaxy growth of heterojunction bipolar transistors containing 1 monolayer δ−Be

Resonant Tunneling from an Accumulation Layer: New Spectroscopy of 2D Electron Systems

We performed photocurrent measurements on GaAs-type-A (Esaki–Tsu-type) doping superlattices produced by a δ-doping technique (impurity growth mode) using a new kind of p- and n-contact on a 500 μm × 500 μm mesa plane. We measured, for the first time, a monotonically increased photocurrent below the gap of the host material with horizontal plateaus, as expected for two-dimensional systems. This is the direct confirmation of the two-dimensional nature of this kind of superlattice. In this context, the influence of the contact distance on the photocurrent response is discussed showing that, in contrast to the general case, a variation of the distance between the contacts not only results in a scaling of the photocurrent spectra but changes the complete shape of the photocurrent response for these two-dimensional structures. The possible energetic transitions between the valence band and the conduction band below the gap of the host material, causing the absorption of the doping superlattice, are calculated a...

Quantum-confined photoresponse tuning of an Esaki–Tsu-type doping superlattice

Heterojunction bipolar transistors (HBTs) with bases composed of a single monolayer of dopant are found to have exponentially increasing current gain as the temperature is lowered, in contrast to the gains of homogeneously doped HBTs, which have little dependence on temperature. We present GaAs‐AlGaAs HBTs with base doping as high as 3×1014 cm−2 with a room‐temperature current gain of 14. The sheet resistance of such a layer is 270 Ω/square at room temperature, and the carriers are restricted to a 15 A layer, implying an extremely short base transit time. AT 77 K the gain increases to 220, while the base resistance decreases to 190 Ω/square. Therefore by operating this HBT at low temperature we have achieved for the first time high gain and low base resistance in a HBT with an infinitesimally thin base.

Monolayer δ‐doped heterojunction bipolar transistor characteristics from 10 to 350 K

Electroabsorption modulation of visible light in AlGaAs quantum wells

Resonant passive mode-locking (RPM) is a new coupled-cavity mode-locking technique where a resonant nonlinear reflector (i.e., quantum well reflector) in a coupled cavity of a cw laser strongly induces mode-locking (Fig. 1). Using a GaAs/AlGaAs multiple-quantum-well (MQW) reflector, a RPM Ti:Sapphire laser produces tunable picosecond pulses1 without dispersion compensation inside the main cavity. Using a strained layer InGaAs/GaAs MQW reflector, an RPM Nd:YLF laser at the wavelength of 1.047 μm produced 4 ps pulses (Fig. 2) with 1.6 nJ pulse energy at a 250 MHz repetition rate (390 mW average power) with 1.5 W pump power from a Ti:Sapphire laser.2

We examine atomic diffusion of Si, when initially δ doped into very pure GaAs layers grown by gas source molecular beam epitaxy. A nonlinear Si diffusion coefficient versus inverse temperature is observed as a two‐component Arrhenius dependence in which the activation energies change by 1.5 eV. Furthermore, when Si diffusion is thermally activated with the lower energy kinetics, the corresponding impurity profile grows in width linearly with the anneal time. We explain the above departures of measured Si diffusivity from classical impurity diffusion via a nonequilibrated concentration of vacancies generated at the δ position during the anneal.

We report a heterostructure bipolar transistor (HBT) in which the base is δ-doped with Be to a concentration of 1×1014 cm-2 and the Be is spatially confined to within 15 Å. To fabricate the HBT without inducing Be redistribution and avoid critical emitter mesa etching, we have developed a new low-temperature base-contacting procedure (Tmax=420°C) which requires no base-emitter etching. A 50 µm diameter δ-HBT shows a current gain of 20. Upon reducing the size of the emitter to 3×8 µm, the current gain of the δ-HBT increases to 30. This, we belive, is due to our new processing technique which eliminates the critical base-emitter etch and hence reduces surface recombination. In addition, we grew and fabricated HBT's in holes that have been pre-etched into the substrates. High quality material has been achieved in the holes.

Planarized Be δ-Doped Heterostructure Bipolar Transistor Fabricated Using Doping Selective Contact and Selective Hole Epitaxy

The authors studied the effects of changing the barrier design of GaAs-Al/sub x/Ga/sub 1-x/As quantum wells on the electroabsorption, exciton saturation, and carrier sweep-out times. Five samples with x values ranging from 0.2 to 0.4 and barrier thicknesses from 35 to 95 AA were studied. Within this range, the authors find that the electroabsorption is not very sensitive to the barrier thickness, but that the ionization field of the excitons approximately doubles for an increase of x from 0.2 to 0.4. The samples with high, thick barriers have lower internal quantum efficiencies than those with low, thin barriers. It was found that the exciton saturation intensity increases with increasing applied field, and decreasing barrier thickness or height. Time-resolved electroabsorption measurements confirm the variation in sweep-out rates between samples, and indicate that the escape mechanism at low field is probably a thermally-assisted tunneling process. >

Quantum well carrier sweep out: relation to electroabsorption and exciton saturation

We have produced AlxGa1−xAs‐AlAs quantum well p‐i‐n diode electroabsorption modulators with x as high as 0.56. Even though the material is indirect in momentum space, strong excitonic absorption exists at the direct band gap which can be modulated with an applied field. For x=0.33, 0.43 and 0.56, we measure relative transmission changes (ΔT/T0, in a surface‐normal configuration) of 62%, 51%, and 23%, respectively, at wavelengths of 677, 622, and 575 nm for 15 V bias with the intrinsic layer being 0.6 μm thick.

AlxGa1-xAs-AlAs quantum well surface-normal electroabsorption modulators operating at visible wavelengths

The authors report an n-p-n heterojunction bipolar transistor (HBT) with a planar (and thus passivated) emitter-base structure fabricated using a simple, low-temperature technique. They use a nonalloyed emitter contact facilitated by delta -doping grown at the surface of the sample, so that the cap layer is only 75 AA thick. The base is contacted by depositing Au-Zn or Au-Be on the surface and alloying at 420 degrees C for 10 s, resulting in an ohmic contact with the base and rectifying contact with the emitter. The authors present large-emitter area (50- mu m diameter) HBTs with homogeneous-doped bases (gain of 170) and delta -doped bases (10/sup 14/ cm/sup -2/, gain of 20). Upon reducing the emitter size of the latter to 3*8 mu m the gain increased to 30, demonstrating excellent surface passivation. >

Planarization of emitter-base structure of heterojunction bipolar transistors by doping selective base contact and nonalloyed emitter contact

It is found that extremely shallow quantum wells (QWs) are capable of modulating high-intensity light due to the enhanced sweep out of photogenerated carriers. These QWs are especially well suited for use in self-electrooptic effect devices (SEEDs) due to the existence of a strong room-temperature exciton that ionizes rapidly with field. For a 3- mu m diameter spot, bistable reflectivity changes (for a symmetric-SEED arrangement using a 7 V power supply) of 18% at 1 mW (24 kW/cm/sup 2/), 10% at 2 mW, and 4% at 3 mW were obtained, compared to 6.8% at 0.4 mW for the previous best sample.<<ETX>>

Characterization of the GaAs:C and AlGaAs:C doping superlattice grown by chemical beam epitaxy

The exciton in quantum wells is a sensitive ultrafast detector of electric fields in quantum wells.1 Using a probe beam focused to the diffraction limit, information can be obtained about the microscopic internal fields in semiconductor devices. Much needs to be learned about how ultrafast electrical transients are generated, propagated, and detected in systems which incorporate metal-semiconductor contacts.

We report that at room temperature the field‐induced escape of photogenerated carriers out of shallow GaAs/AlxGa1−xAs multiple quantum wells is as fast as for pure GaAs of the same thickness, if the value of x does not exceed 0.04. Our experimental findings can be explained by assuming that carriers are efficiently scattered into the unconfined barrier states by absorption of a LO phonon, as long as the effective barrier height is less than the LO‐phonon energy. The application of shallow quantum wells with x≤0.04 in self‐electro‐optic effect devices, providing not only strong excitonic electroabsorption but also fast sweep‐out times at small biases, should lead to shorter switching times.

Fast escape of photocreated carriers out of shallow quantum wells

We present results on the picosecond dynamics of spin relaxation and thermalization of excitons in GaAs quantum wells. The spin relaxation time constant is ≊50 ps for resonant excitation and less than 10 ps for nonresonant excitation, considerably shorter than those for free electrons in the bulk. Photoexcited cold, nonthermal excitons thermalize in ≊50 ps at 10 K and less than 10 ps at 35 K. Exciton‐acoustic phonon energy exchange rates are determined from these measurements.

Spin relaxation and thermalization of excitons in GaAs quantum wells

We have observed Wannier–Stark localization in extremely shallow superlattices (SL) at 77 K, which results in a quasi‐blue shift of the absorption edge at very small electric fields. The formation of a Stark ladder is also clearly shown. The blue shift results in a change in absorption coefficient from 1.7 μm−1 (at 0.2 V/μm) to 0.98 μm−1 (at 0.6 V/μm) for a GaAs/Al0.07Ga0.93As SL; for a GaAs/Al0.02Ga0.98As SL we obtain a change from 2.1 μm−1 (at 1.1 V/μm) to 0.9 μm−1 (at 1.5 V/μm).

Ultrasensitive electroabsorption due to Wannier–Stark localization in extremely shallow superlattices at 77 K

The large bandwidth of Ti:sapphire makes it attractive for short pulse applications. Indeed, recent studies have been focused on passive1–4 mode-locking of the Ti:sapphire laser. Resonant Passive Mode-locking1 features stable picosecond pulse trains and TEM00 mode behavior, without a stabilization of the external cavity. Self-mode-locking by expanding the main cavity symmetrically and chirp compensation as reported by Spence et al.2 shows pulses as short as 60 fs. However, self-starting and pure TEM00 operations are not consistently obtained.

A continuously self-starting mode-locked TEM 00 110-fs Ti:sapphire laser using a quantum-well external resonator

Growth and diffusion study of carbon doped GaAs superlattice grown by chemical beam epitaxy

It is well known that sharp excitonic resonances are observed in quantum wells, even at room temperature; however, it has been recently discovered that these sharp excitonic resonances can also exist in quantum wells in which the barriers are only a few tens of milli-electron- volts deep.1 In such a case, the excitons retain some of the character of bulk material while exhibiting some of the interesting characteristics of the quantum well. Perpendicular electric fields applied to the shallow quantum wells have resulted in quantum-well modulators with high cw saturation intensity compared with "deep" quantum-well modulators, principally because the carrier confinement is significantly reduced.2 In the present paper, we investigate the ultrafast nonlinear-optical properties and parallel field electroabsorption in this potentially important new material system.

We show that an external coupled cavity containing a nonlinear quantum-well reflector can continuously selfstart a dispersion-compensated Ti:sapphire laser, which produces stable time-transform-limited pulses as short as 70 fs in a TEM(00) mode. In this mode of operation, the quantum wells do not control the mode-locking process, as in previous research on the resonant passive mode-locked laser. By separating the mode-locking and starting processes, we show that the presence of higher-order spatial modes is not required to start or sustain mode locking.

Femtosecond pulses from a continuously self-starting passively mode-locked Ti:sapphire laser.

The tunnelling of charge carriers between quantum wells that are separated by a barrier of only a few monolayers thickness leads to a splitting of the energy levels of the quantum wells. Here, we report on the first absorption measurements of the transition between split subbands in the conduction band of coupled quantum wells.

Observation of absorption between split levels in coupled quantum wells

Abstruct-We find that extremely shallow quantum wells (QW’s) are capable of modulating high-intensity light due to the enhanced sweep out of photogenerated carriers. These QW’s are especially well suited for use in self-electrooptic effect devices (SEED’s) due to the existence of a strong room-temperature exciton that ionizes rapidly with field. For a 3-pm-diameter spot, we obtain bistable reflectivity changes (for a symmetricSEED arrangement using a 7 V power supply) of 18% at 1 mW (24 kW/cm2), 10% at 2 mW, and 4% at 3 mW compared to 6.8% at 0.4 mW for our previous best sample. E previously reported the discovery that strong roomW temperature exciton absorption was preserved in GaAs-Al,Ga,-,As quantum wells (QW’s) for x as low as 0.02 113. The exciton for these extremely shallow QW’s (ESQW’s) rapidly ionizes with field, so that for operation on the exciton wavelength, strong electroabsorption occurs. This feature makes ESQW’s ideally suited for use in self-electrooptic effect devices (SEED’S), optical logic devices which are comprised of a QW p-i-n modulator in series with a battery, and a load which may be another QW modulator (i.e., symmetric SEED) 121, [3]. This circuit is bistable because of the negative resistance of the reverse-biased QW modulator when illuminated at the QW exciton peak. For standard QW’s this results from the fact that the exciton red shifts with increasing electric field, causing the absorption, and hence the photocurrent, to decrease with increasing reverse bias. Switching of the SEED is induced by changing the light intensity incident relative to the load’s current-voltage characteristic. Since the transmission of the QW modulator depends on field, it also switches, resulting in optical control of light transmission. SEED switching speeds increase as the operating light intensities increase since the reverse-biased QW modulator is essentially a capacitor, and therefore its charging rate is linearly proportional to the photocurrent. However, build up of photoinduced carriers in the QW’s caused by finite escape time limits the intensity. This is because the exciton saturates at a certain carrier level so that the electroabsorption degrades. In our previous paper, we suggested that ESQW’s should have much greater saturation intensities since there is practically no barrier to transport. Here, we show that,

We have investigated the formation of intrinsic excitons following excitation of electron-hole pairs close to the bandgap by a subpicosecond laser pulse. We show that excitons form very rapidly ('c≤2Ops) and that they are initially in large wavevector states because of energy and momentum conservation requirements. These non-thermal excitons then interact with other excitons and acoustic phonons and relax very slowly (400ps) to the KO states which couple directly to light. This leads to an extremely slow rise of exciton luminescence and unusual dependence of this risetime on temperature, excitation density and excitation energy. These studies raise a number of fundamental issues related to excitons in semiconductors.

We report the remarkable observation of strong room‐temperature excitonic features in the absorption spectra of GaAs‐AlxGa1−xAs quantum wells (QWs) for values of x as low as 0.02. This has important implications for high‐power modulators, since saturation intensities have been shown to be higher in QW modulators with low barriers. In addition, very shallow QWs have enhanced electroabsorption at small biases because of ease of ionization. In our p‐i(multi‐QW)‐n device with x=0.02, we obtain a transmission change from 29% to 47% for a voltage change from +1 to −3 V.

Diffusion limited δ-doping profiles in GaAs grown by gas source molecular beam epitaxy

We have studied excitonic effects in resonantly coupled GaAs/A1GaAs multiple quantum wells. We use photocurrent spectroscopy to deduce the resonant field from the field-dependent exciton energies, and find an unexpected variation of -10% in the resonant field between different excitonic transitions involving the same coupled electron levels. We construct a variational model of the coupled excitons which explains the results in terms of Coulomb mixing of the delocalised electron states.

Enhanced diffusion of Si due to He ion implantation in Si‐delta doped GaAs layers has been observed by the capacitance‐voltage technique. After an 800 °C anneal, an increase as large as an order of magnitude in the diffusion coefficient compared to thermal diffusion was observed. We also observe a decrease in the integrated sheet carrier concentration as a result of the He implants, and the decrease appears independent of annealing time.

Enhanced diffusion of Si due to He ion implantation in Si‐delta doped GaAs layers

We report an investigation of the growth characteristics of GaAs by chemical beam epitaxy using trimethyl‐Ga and arsine. The growth rate behaviors as a function of temperature, As overpressure, and alkyl arrival rate are qualitatively similar to those using triethyl‐Ga with differences that can be explained by differences in the alkyl‐Ga bond strength. A unified description of the growth kinetics assuming a unimolecular reaction mechanism is possible. Lattice parameter is found to decrease with increasing carbon concentration. A high quality GaAs/GaAs:C doping superlattice has been prepared. Although the composition modulation is too small for x‐ray diffraction measurement, the structural deformation gives rise to satellite peaks with order n up to ±7 observed for the first time. X‐ray analysis of the superlattice after annealing has been employed to study the carbon diffusion in GaAs.

Ultrafast Studies of Resonant and Non-Resonant Electron and Hole Tunneling in Quantum Well Structures

LEOS '90. Conference Proceedings IEEE Lasers and Electro-Optics Society 1990 Annual Meeting

Fractional quantized hall effect in a ballistic constriction in a two-dimensional electron gas

Self-biased SEED Using Highly Electroabsorptive Slightly Asymmetric Coupled Quantum Wells

Elimination of Emitter-Mesa Etching and Complete Planarization of Heterojunction Bipolar Transistors via Doping Selective Base Contact and Selective Hole Epitaxy

We have produced a nonabsorbing surface‐normal optical modulator operating at 1.06 μm (e.g., for a high‐power Nd‐YAG pump laser) which has a relative transmission change of 16% for −1 to 1 voltage swing. The structure is a GaAs‐AlAs dielectric mirror with alternating n‐ and p‐type δ doping at each interface. Doping selective contacts are made to the sample so that an applied voltage appears equally across each period of the device, yielding a strong field which changes the index of the GaAs and hence shifts the mirror.

A heterostructure bipolar transistor (HBT) with a base delta -doping of 6*10/sup 14/ cm/sup -2/, near the physical limit of one monolayer (ML) is reported. The devices exhibits a current gain of 15. The doping confinement of the delta layer is 15 AA. To fabricate the HBT without inducing dopant diffusion or using sensitive etching, a new low-temperature base-contacting procedure (T/sub max/=420 degrees C) which requires no base-emitter etching has been developed. This has the additional benefits of greatly reducing surface recombination and yielding a planar structure.

Monolayer Be δ-doped heterostructure bipolar transistor fabricated using doping selective base contact

Excitons1 in semiconductors are highly sensitive probes of crystal quality and applied fields and are usually observed at low temperature in highly pure strain free materials. In the quantum confined limit, the exciton is stabilized at room temperature, and a well resolved resonance is observed.

Excitonic electroabsorption sampling: a new approach to femtosecond optoelectronics

We report the direct imaging of Be δ‐doped layers in GaAs, in the concentration range (0.5–2)×1014/cm2, comparing samples grown by gas source molecular beam epitaxy (MBE) and conventional MBE. The gas source MBE δ layers are ∼15 A wide, and at least at high concentrations, consist of clusters ∼12 A in diameter. At 2×1014 Be atoms/cm2, the MBE δ layer is an order of magnitude wider than that grown at the same temperature by gas source MBE. Our results imply that layers with Be concentrations in excess of 1021/cm3 can be fabricated by gas source MBE.

Two-Dimensional Carrier—Carrier Screening Studied with Femtosecond Photon Echoes

Transmission and reflection probabilities between the ν=1 and the ν=23 quantum hall effects

The investigation of an AlGaAs/GaAs HBT in in which a heavily carbon doped base is grown by chemical beam epitaxy using trimethyl-Ga is reported. A planar technique which reduces surface recombination has been employed for selectively contacting the base region. A base width of 1000 A and a high doping level of 7×10 19 cm −3 is used. The sheet resistance of the base is less than 100Ω/□. This transistor has a maximum current gain of 25 at a current density of 1.3×10 3 A/cm 2

Heterostructure bipolar transistor employing carbon-doped base grown with trimethyl-Ga and arsine

Femtosecond Excitonic Sampling in Submicron Thickness Coplanar Strips

Large Refractive Optical Nonlinearites in GaAs-AlAs Sawtooth Mirror

We present new optoelectronic logic devices or circuits consisting of electrically connected quantum well PIN diodes capable of implementing any boolean logic function. One class of circuits uses single beams to represent the logic levels and compares their intensities to a locally generated reference signal. A second class of circuits routes signals as differential pairs. The connections of diodes in these circuits resemble the transistor connections in NMOS and CMOS logic families. We demonstrate simple optical programmable logic arrays (e.g., E = AB + CD) using both of these classes of circuits.

Optical logic using electrically connected quantum well PIN diode modulators and detectors.

We report on results that compare the planar confinement, diffusion, and surface segregation of Si δ‐doped in GaAs for growth by gas source molecular‐beam epitaxy and conventional molecular‐beam epitaxy. For gas source molecular‐beam epitaxy growth, Si diffusion versus inverse anneal temperature shows a unique two component Arrhenius form in which activation energies for diffusion differ by the fundamental GaAs band gap energy, 1.5 eV. Capacitance–voltage profiles of as‐grown δ‐doped Be and Si layers in GaAs produce record full width at half‐maximum, 1.9 and 2.4 nm, respectively, for the gas source molecular‐beam epitaxy case.

Atomic diffusion and surface segregation of Si in δ‐doped GaAs grown by gas source molecular beam epitaxy

Preface Materials Research Society symposium proceedings Plenary presentation Part I. Structural Accommodation in Strained-Layer Systems Part II. Growth and Characterization of Heteroepitaxial Structures Part III. Noncrystalline Multilayered Structures Part IV. Optical Characterization of Layered Structures Part V. Electrical and Device-Related Studies Author index Subject index Materials index.

Layered structures : heteroepitaxy, superlattices, strain, and metastability : symposium held November 27-December 1, 1989, Boston, Massachusetts, U.S.A.

We study resonant and nonresonant hole tunneling in an asymmetric double quantum well structure by picosecond timeresolved photoluminescence. The tunneling times are directly determined by studying the luminescence decay time in one of the wells. Various hole levels in the two quantum wells are brought in resonance by applying an electric field to the doped layers which clad the inirinsic region containing the quantum well structures. The luminescence decay shows a sharp resonance due to tunneling of carriers when two heavy-hole levels are brought in resonance. The tunneling time at resonance, however, is much longer than expected from a simple theoretical model assuming a coherent tunneling process. We develop a quantitative theory of resonant tunneling under the influence of scattering and relaxation processes. The results predict large increases in the tunneling times in good agreement with the experimental observations.

Hole tunneling in GaAs/AlGaAs heterostructures: coherent versus incoherent resonant tunneling

The investigation of vertical transport in superlattices (SL's) and multiple quantum wells (MQW’s) has recently attracted much attention. Intense research was focused on basic quantum effects such as Bloch transport of electrons and holes in minibands,1 coherent and incoherent, resonant, sequential and Zener tunneling2 in double barriers,3,4 SL’s and MQW’s of GaAs/AlAs,5,6 GaAs/AlGaAs,7 and InGaAs/InP.2,8 In addition to the academic interest, the understanding of the mechanisms of escape from and travel through quantum wells is vital for the recently developed and constantly growing family of electro-optical devices using semiconductor quantum wells. Most of them are based on the quantum-confined Stark effect (QCSE), and they include bistable selfelectro-optic effect devices (SEED’s), tunable detectors, electro-absorption modulators and optical logic elements.9 The basic unit of all of these is an epitaxially grown p-i-n diode, with the quantum well layers in the intrinsic region. By reverse biasing the diode, an electrical field is applied on the quantum wells, controlling its optical absorption spectrum. Since operating wavelengths are close to the excitonic absorption peaks, photoexcited charge is created in the quantum wells and is transported to the electrodes. The mechanisms by which this transport occurs are ultimately responsible for the intrinsic maximum speed or operating intensity of these devices.

Optical Detection of Resonant Tunneling of Electrons in Quantum Wells

We have measured the heavy hole excitation saturation intensity in GaAs/AlGaAs quantum wells as a function of applied electric field and AlGaAs barrier design. We find that the saturation intensity increased with increasing applied field, and decreasing barrier thickness or height, because of increased carrier sweep‐out rates. Time‐resolved sweep‐out time and temperature‐dependent saturation intensity measurement point out the roles of both thermionic emission and tunneling in the field and barrier‐dependent carrier escape time. By reducing the barrier Al composition from 30 to 20%, we achieved an increase in the saturation intensity by a factor of ∼6.

Optical absorption and photoluminescence experiments are performed on GaAs doping superlattices, which have a δ-function-like doping profile of alternating n-type and p-type dopant sheets. Absorption and emission spectra reveal for the first time the clear signature of quantum-confined interband transitions. The peaks of the experimental absorption and luminescence spectra are assigned to calculated energies of quantum-confined transitions with very good agreement. It is shown that the employment of the δ-doping technique results in improved optical properties of doping superlattices.

Quantum-Confined Optical Interband Transitions in 5-Doped Doping Superlattices

We report the first microwave AlAs/GaAs tunnel emitter bipolar transistor utilizing nonequilibrium electron transport in the base. At an emitter current density of 1×105 A cm−2, current gain of greater than unity is measured up to a frequency of 40 GHz. dc current gains of 82 and 53 are measured for devices with emitter stripe widths of 9 and 1.5 μm, respectively. Enhanced device scaling is made possible with the extremely high velocity in the thin base region.

The Atomic Structure of GaAs/AlGaAs Interfaces and Its Correlation with the Optical Properties of Quantum Wells

Transmission and reflection probabilities between ν=1 and ν=23 quantum Hall effects and between ν=23 and ν=13 effects

Exciton saturation adversely limits the switching speed of GaAs/AlxGa1-xAs quantum well electroabsorptive optical modulators. We have studied the dependence of the exciton saturation intensity Isx on the strength of the applied field and the height and width of the AlGaAs barriers. Five PIN photodiodes were grown by molecular beam epitaxy with the quantum wells comprising the intrinsic region. The well width was kept nominally constant, but x ranged from 0.2 to 0.4 and the barrier thickness L
 b
 varied between 31 and 95 Å. We found that Isx increases with applied field, and also depends strongly on x and Lb.For L
 b
 = 65 Å at zero applied field, Isx increased from 1.3 to 43 kW cm−2 on reducing x from 0.4 to 0.2. Similarly, for x = 0.3 at zero bias, Isx increased from 3.1 to 18 kW cm−2 on reducing Lb from 95 to 31 Å. These results can be explained in terms of a reduction of the carrier lifetime caused by barrier and field dependent tunneling rates. The field dependence of the carrier escape time for the sample with x = 0.31 and Lb = 31 Å was measured by the time-resolved electroabsorption technique.1,2 The measured escape time is ~100 ps at fields below 30 kV cm−1 and decreases to ~10 ps at fields above 60 kV cm−1.

Excitonic saturation intensity in GaAs/AlGaAs quantum well optical modulators

GaAs Mulit-Quantum Well Reflection Modulators Grown on GaAs and Silicon Substrates

The Electron-Hole Plasma in Quasi Two-Dimensional and Three-Dimensional Semiconductors

Recently, there has been growing interest in exploring the limits to scaling of semiconductor devices, and in understanding their characteristics in the regime where quantum effects and ballistic transport dominate. Using high‐resolution fabrication techniques on high‐mobility, modulation‐doped AlGaAs/GaAs, it is possible to confine the two‐dimensional electron gas (2DEG) to structures that are smaller than both the inelastic and elastic scattering lengths, and are comparable in size to the electron wavelength. The conduction of such a device should be one dimensional and ballistic. Unlike large samples, the resistance of these ballistic devices does not follow classical equations; it is primarily caused by electron interference and scattering from the geometry of the sample, not by impurities. On this scale, these structures behave as electron waveguides not as diffusive conductors. We have used electron‐beam lithography and high‐resolution reaction ion etching to produce samples with well controlled, co...

One‐dimensional ballistic transport in AlGaAs/GaAs electron waveguides

Tunable stimualted emission of radiation is achieved in AlxGa1−xAs/GaAs double heterostructures, in which the waveguiding GaAs region consists of a delta‐doped doping superlattice. The low‐temperature emission energy is 45 meV below the bulk band gap of GaAs for homogeneous optical excitation of the Fabry–Perot cavity. The emission energy is continuously tunable over 35 A by inhomogeneous excitation of the cavity.

Tunable stimulated emission of radiation in GaAs doping superlattices

Infrared photocurrent in a short period sawtooth doping superlattice

We present multistate self-electrooptic effect devices consisting of electrically connected PIN diodes with quantum wells in the intrinsic regions. By connecting several (for example, N) of these diodes in series with a voltage source, the resultant device has N states, each of which consists of the diode with the least incident optical power having high transmission and the others having low transmission. Like the symmetric SEED, which is a special case of this device when N = 2, the devices are insensitive to optical power supply variations, have time sequential gain, and have good input/output isolation. Therefore, these devices solve many of the critical biasing problems commonly associated with multistable devices. We have measured the characteristics of this device for three such diodes and also demonstrated a special case of this device where two quantum well PIN diodes in series with a n-p-n transistor acts as an electrically enabled S-SEED.

Recently there has been a maturing of the technology of GaAs/AlGaAs multiple quantum well (MQW) p -i (MQW)-n modulators1-4 and related self electro-optic effect (SEED) devices 5-7 grown on GaAs substrates by molecular beam epitaxy (MBE). It has been demonstrated that these devices can operate at several GHz8, and that with the incorporation of an MBE-grown dielectric mirror beneath the modulator they may operate in reflection mode.4 These properties make MQW modulators attractive as a device for communicating off chip via optical signals. Since the majority of electronic devices are silicon, it is important to determine the quality of GaAs MQW modulators grown on Si substrates.

Direct Experimental Comparison of GaAs-AlGaAs Multi-Quantum Well Modulators Grown on GaAs and Silicon Substrates

Very high purity GaAs grown by gas source molecular beam epitaxy

Surface chemical kinetics during the growth of GaAs by chemical beam epitaxy

We present here picosecond time‐resolved electroabsorption measurements in GaAs quantum well p‐i‐n diode structures. While the dynamics of the vertical transport is not completely understood at present, our data reveal the importance of the ‘‘lateral’’ propagation of the photoexcited voltage pulse over the area of the doped regions. We propose a two‐dimensional ‘‘diffusive conduction’’ mechanism, which predicts a fast relaxation of the electrical pulse, with time constants ranging from 50 fs to 500 ps, determined by the size of the exciting spot, the resistivity of the doped regions, and the capacitance of the intrinsic region.

High speed absorption recovery in quantum well diodes by diffusive electrical conduction

Spatial localization of Si in selectively δ-doped AlxGa1−xAs/GaAs heterostructures for high mobility and density realization

GaAs/AlGaAs single quantum well laser with an Intracavity monolithic loss modulator

Nonlinear optical properties of $\delta$-doped multiple quantum well GaAs

An asymmetric δ‐doped GaAs structure is described which exhibits novel photovoltaic effects and low‐intensity nonlinear optics. Of particular interest in this kind of structure is the ability to design the electro‐optical and nonlinear optical properties and the material response time over a wide range by appropriate design of the doping profile.

Narrow Si doping distributions in 6-doped GaAs, Al0.3Ga0.7As and Quantum Wells grown by Gas Source Molecular Beam Epitaxy

Measurements of GaAs-AlGaAs multiple-quantum-well (MQW) reflection modulators grown simultaneously on GaAs and silicon substrates are presented. Comparable electroabsorption is observed, with contrast ratios of about 4:1 for both modulators at 20 V. The absorption spectrum of the GaAs-on-Si quantum well shows a single exciton peak, which leads to certain improvements in modulator performance. This study is very encouraging for the growth of GaAs MQW modulators on silicon integrated circuit chips for off-chip communication.<<ETX>>

GaAs-AlGaAs multiquantum well reflection modulators grown on GaAs and silicon substrates

The light emission characteristic of a GaAs/AlGaAs single quantum well laser with an intracavity monolithic loss modulator has been investigated. Discrete, widely separated, wavelength switching from the first (875 nm) to the second (842 nm) subband is achieved by changing the applied modulator bias. In addition, we show that 2 mW of lasing light power may be modulated with a change in current of 250 μA and a voltage change of 1 V.

Bias‐controlled intersubband wavelength switching in a GaAs/AlGaAs quantum well laser

We report electrical measurements on structures generated by δ doping the AlGaAs barriers of a GaAs quantum well. These structures are made unique by quantum size effects that occur both in the δ‐doped barrier and in the GaAs well. Both the Hall‐effect and capacitance‐voltage measurements reveal that high‐density, 4×1012 cm−2, two‐dimensional electron gas forms in the well along with good mobility. We fabricate field‐effect transistors with this structure to obtain transconductances of 300 mS/mm.

Selectively δ‐doped quantum well transistor grown by gas‐source molecular‐beam epitaxy

Quantum transport in quasi-one-dimensional GaAsAlxGa1−xAs heterostructure devices

Deviation of the quantum hall effect from exact quantization in narrow GaAs-AlxGa1−xAs heterostructure devices

Summary Abstract: A model for the surface chemical kinetics of GaAs deposition by chemical‐beam epitaxy

The authors report on an electrically controlled optical modulator using a novel GaAs sawtooth structure. This structure consists of alternating n-type and p-type delta-doped GaAs. Modulation of tunnelling-assisted absorption is achieved by changing the internal electric field which in turn is controlled by external bias. Modulation of light intensity is demonstrated over a broad spectral range of Delta lambda >100 nm. A contrast ratio of 1:1.7 of the opaque and transparent states is obtained. Low-voltage operation ( Delta V<5 V) and potential high-speed capability make the new device an attractive candidate for future photoionic switching systems.

Photonic switching by tunnelling-assisted absorption modulation in a GaAs sawtooth structure

Breakdown of coherence in resonant tunneling through double-barrier heterostructures

Summary Abstract: Reflection high‐energy electron diffraction intensity oscillation during the growth of GaAs by chemical‐beam epitaxy

Magneto-quantum transport in a quasi-one-dimensional GaAs/AlxGa1-xAs ring

Spatial localization and diffusion of atomic silicon in delta-doped GaAs

We report the measurement of intervalley scattering rates for optically excited carriers in GaAs. The measurements were performed using optical pulses of 6 fs duration and an energy distribution centered at 2.0 eV. The average rates for Γ→X and Γ→L intervalley scattering were separately estimated by varying the sample temperature.

Using triethylgallium and arsine, high‐quality GaAs can be grown at a relatively low substrate temperature of 500 °C by chemical beam epitaxy. Such a low temperature has the advantage of a negligible Si diffusion effect. Capacitance‐voltage (C‐V) measurements of the Si δ‐doped GaAs show extremely narrow profile widths of 22 A at 300 K and 18 A at 77 K, indicating a very high degree of Si spatial localization has been achieved. The subsequent annealing experiments reveal that significant Si segregation and diffusion exist at a high growth temperature of ∼600 °C, usually employed in conventional molecular‐beam epitaxy. The C‐V widths of the annealed δ‐doped structures also provide an excellent measure to determine the Si diffusion constant in GaAs.

Diffusion studies of the Si δ‐doped GaAs by capacitance‐voltage measurement

The conditions under which high quality metal superlattices can be grown with sharp flat interfaces are described. The discussion is illustrated by examples that include the growth of rare earth superlattices in chosen orientations. It is emphasized that epitaxy makes the structure and properties of thin films differ from those of the bulk. In particular, the clamping of a magnetic film by its substrate modifies the magnetoelastic energy and consequently change the magnetic phase diagrams of individual layers. Experiments using MBE-grown antiferromagnetic rare earths films and their superlattices with Y are discussed in the light of these observations. 30 refs., 10 figs.

Growth and properties of superlattices with antiferromagnetic rare earths

We demonstrate an integrated symmetric self‐electro‐optic effect device consisting of two quantum well p‐i‐n diodes electrically connected in series. The device acts as a bistable optical memory element with individual set (S) and reset (R) inputs and complementary outputs (optical S‐R latch). The switching point is determined by the ratio of the two inputs, making the device insensitive to optical power supply fluctuations when both power beams are derived from the same source. The device also shows time‐sequential gain, in that the state can be set using low‐power beams and read out with subsequent high‐power beams. The device showed bistability for voltages greater than 3 V, incident optical switching energy densities of ∼16 fJ/μm2, and was tested to a switching time of 40 ns.

Symmetric self‐electro‐optic effect device: Optical set‐reset latch

Quantum transport in one-dimensional GaAs/AlGaAs microstructures

We report a new structure formed by δ doping the barrier of an AlGaAs heterostructure. Our structure contains a pair of electronically coupled quantum systems that develop from the quantum size effect occurring in the barrier and at the heterointerface. Compared to conventional homogeneous doping, we find enhancements in interface density resulting in δ‐doped structures for all spacer thicknesses. A mobility of 1.9×106 cm2/V s is observed at a spacer layer thickness of 360 A. Systematic dependences of interface mobility and density on spacer thickness are deduced from the quantum Hall effect and variable temperature Hall measurements.

Capacitance‐voltage profiles on δ‐doped GaAs grown by molecular beam epitaxy reveal extremely narrow widths of ≲40 A at room temperature. Subband structure and capacitance‐voltage (C‐V) profiles of δ‐doped GaAs are calculated self‐consistently. Experimental C‐V profiles agree with self‐consistent results, only if we assume that Si impurities are localized on the length scale of the lattice constant in the host GaAs zinc‐blende lattice.

Femtosecond Carrier-Carrier Scattering Dynamics in p-Type and n-Type Modulation-Doped Quantum Wells

We report photoluminescence and transport studies of a very pure GaAs layer grown by gas source molecular beam epitaxy methods. A peak mobility of 300 000 cm2/V s is observed at 60 K. A very shallow donor with binding energy less than 2 meV is observed.

Shallow donors in very pure GaAs grown by gas source molecular beam epitaxy

An experimental and theoretical study has been made of a delta-doped quantum well field-effect transistor, ( delta QWFET), that realizes for the first time the high two-dimensional electron gas concentration, transconductance, saturation current density, and DC gain, and the very low output conductance that are expected for this device. The structure is made unique by the presence of quantum size effects that occur in both delta-doped barriers and the quantum well. The quantum size effects in the barriers and well can thus be tailored independently to suit specific FET requirements while still maintaining the advantage of a spatially confined electron gas. A complete DC characterization of this structure has been carried out using capacitance-voltage, Shubnikov-de Haas, and variable-temperature Hall measurements. A model incorporating quantum size effects has been developed and used as a basis for calculations. >

Experimental and theoretical characterization of delta-doped quantum well field-effect transistors grown by gas-source molecular-beam epitaxy

Small structures in high‐mobility semiconductor heterojunctions are expected to show a variety of quantum mechanical phenomena associated with electron interference. At low temperatures in the high‐mobility two‐dimensional electron gas at a GaAs/AlGaAs heterojunction, both the elastic and inelastic electron scattering lengths are several microns, making it possible to fabricate complete devices contained within these dimensions. In ring shaped devices we have observed periodic magnetoconductance oscillations (Aharonov–Bohm effect) caused by electron interference. The magnitude of this effect is as much as 10% of the total conductance, much larger than seen in previously studied metal systems. High‐resolution electron (e)‐beam lithography and reactive ion etching were used to fabricate rings of 1, 2, and 2.5 μm mean diameters with linewidths of 0.5 μm. The electrical channel width is smaller than the physical channel width because of edge depletion. Samples with conducting channels varying from about 0.6 t...

Observation of Aharonov-Bohm effect in quasi-one-dimensional GaAs/AlGaAs rings

Recently we have reported the measurement of reflection high‐energy electron diffraction intensity oscillations during chemical‐beam epitaxy of GaAs using triethylgallium (TEG) and As2 derived from an arsine cracker [Appl. Phys. Lett. 50, 19 (1987)]. In this study we observed a significant variation of the GaAs growth rate with substrate temperature at constant TEG flux. In addition, the variation of growth rate with incident flux at constant temperature was found to be nonlinear below approximately 500 °C and linear above 500 °C for incident fluxes yielding maximum growth rates between 0.2 and 1.8 monolayers/s. We have developed a model of the surface pyrolysis of triethylgallium which explains the qualitative behavior of the above data. The model assumes the existence of adsorbed triethyl, diethyl, and monoethyl gallium species as well as adsorbed ethyl radicals. As a starting point, the rate limiting step to epitaxial incorporation of atomic gallium is assumed to be cleavage of the second ethyl–gallium...

A model for the surface chemical kinetics of GaAs deposition by chemical‐beam epitaxy

Potential fluctuations due to random dopant distribution are estimated in a doping superlattice for different doping profiles. It is shown that statistical potential fluctuations are minimized by employing a doping profile consisting of a train of δ functions, which result in sawtooth‐shaped band edges. Clearly resolved quantum‐confined optical absorption and luminescence transitions are observed in this improved doping superlattice structure. The sawtooth superlattice provides the basis for a novel GaAs technology which is suited to operate in the minimum dispersion region of silica fibers at a wavelength of λ=1.3 μm.

Minimization of dopant‐induced random potential fluctuations in sawtooth doping superlattices

We report measurements of the current‐voltage characteristics of an asymmetric GaAs/AlGaAs double‐barrier resonant tunneling device. The structure was designed to increase the space charge in the well under forward bias and consequently enhance the electrostatic feedback that leads to intrinsic bistability. The magnetotunneling data demonstrate unambiguously that the observed bistability is the property of the device, rather than the biasing circuit.

Resonant tunneling and intrinsic bistability in asymmetric double‐barrier heterostructures

We have previously described an integrated symmetric self-electrooptic effect device (S- SEED) that acts as a bistable optical memory element with individual set S and reset R inputs and complementary outputs (optical S-R latch).1 New measurements show switching speeds down to 40 ns, contrast ratios of 2.9:1, and total optical switching energies of 16 fJ/μm2. We demonstrate the cascadability of these devices in a photonic ring counter and demonstrate a logic gate that performs nor, nano, or, and and functions.

Photonic ring counter and differential logic gate using the symmetric self-electrooptic effect device

We report measurements of current‐voltage characteristics of AlGaAs/GaAs double‐barrier resonant tunneling structure (DBRTS) with current peak‐to‐valley ratio exceeding 13:1 at 77 K. We also show that space‐charge layers formed in a biased device influence significantly the charge transport in DBRTS.

We demonstrate an integrated symmetric self-electrooptic effect device (S-SEED) consisting of two quantum well PIN diodes electrically connected in a series. The device acts as a bistable optical memory element with individual set S and reset R inputs and complementary outputs (optical S-R latch). The switching point is determined by the ratio of the two inputs, making the device insensitive to optical power supply fluctuations when both power beams are derived from the same source; i.e., it solves the problem of critical biasing common to most optically bistable devices.

X-ray diffraction data on four single-crystal Nb-Ta superlattices with 50 AA wavelength are presented which show that the interfacial mixing is a function of the crystal growth direction. Standard diffusion mechanisms appear inadequate to describe this mixing. Defect configurations of the growing crystal surface are suggested as a possible cause of the anisotropy.

Crystal direction dependence of interfacial mixing in Nb-Ta superlattices

Metastable phase production and transformation in Al-Ge alloy films by rapid crystallization and annealing treatments

GaxIn1−xAsyP1−y epilayers closely lattice matched, Δa/a≲5×10−4, have been reproducibly grown over the whole range of composition (y=2.2x, 1>y>0) by chemical beam epitaxy. The relative sticking coefficient (or equivalently the incorporation efficiency into the solid) of arsenic to phosphorus, i.e., SAs/SP was between 1.5 and 3 depending on the material composition. Such values indicate a very efficient incorporation of phosphorous in this process. Very intense efficient luminescence peaks due to excitonic transitions with linewidths full width at half‐maximum as narrow as 3 meV were obtained. Such a linewidth corresponds closely to the intrinsic linewidth due to alloy broadening in GaInAsP alloys. Furthermore, the photoluminescence spectra revealed that the donor‐to‐acceptor pair recombination was nearly absent. Hall measurements on GaxIn1−xAsyP1−y epilayers lattice matched into InP at 300 and 77 K yielded electron mobility values that agreed closely with theoretical values calculated by using the one‐phon...

We report molecular beam epitaxial (MBE) growth of AlGaAs in the previously unexplored temperature range exceeding 800 °C for which excellent material can be achieved. Photoluminescence reveals bound excitonic linewidth as sharp as 3.6 meV, which is among the narrowest ever reported for material of equivalent Al mole fraction. In this temperature range carbon impurity concentrations are found to be dramatically reduced while temperature‐dependent data provide information from which an understanding of carbon incorporation during MBE growth emerges.

courant-tension structures tunnel risonantes & double barriere (DBRTS), interpretons donnees auto-consistant, formation la zone de charge dans la DBRTS, bistabilite intrimeque contre-reaction du champ electrique des electrons dans le puits sur la densite de courant tunnel. M'e report measurements of current-voltage characteristics of AIG&/Gaks double-barrier resonant tunneling structures (DBRTS) which exhibit intrinsic bistability. We interpret the data with a self-consistent model which takes into account the space-charge formation in DBRTS and show that the intrinsic bistability is due to the feedback of the electrostatic field of the electrons in the well on the tunneling current density.

CHARGE TRANSPORT AND INTRINSIC BISTABILITY IN RESONANT TUNNELING STRUCTURES

Electronic transport measurements are performed at 77 and 300 K on doping superlattices in perpendicular direction to the quantum well planes. The periods of the doping superlattices range from 150 to 600 A. The current‐voltage characteristics in long period doping superlattices (type B) are strongly nonlinear and exhibit a new type of negative differential conductivity. The occurrence of negative differential conductivity is caused by avalanche multiplication in the high‐field regions of the superlattice and accumulation of holes in the valence‐band maxima. In short period doping superlattices (type A) the current‐voltage characteristics are linear at temperatures of 300 and 77 K showing that tunneling through thin barriers dominates perpendicular transport. The calculation of the tunneling current yields a strong dependence on the period (exp−z3/2p).

Recently we have reported the measurement of RHEED intensity oscillations during Chemical Beam Epitaxy(CBE) of GaAs using triethylgallium(TEG) and As 2 derived from an arsine cracker(Appl. Phys. Lett. 50(19), May 11,1987). The existence of RHEED intensity oscillations during CBE growth of GaAs indicates that over the range of conditions studied, growth proceeds via nucleation of islands which grow two-dimensionally as opposed to a vicinal step propagation mechanism. In the same study we observed a significant variation of the GaAs growth rate with substrate temperature at constant flux. In addition, the variation of growth rate with incident flux at constant temperature was found to be non-linear below approximately 500° C and linear above 500'C for incident fluxes yielding maximum growth rates between.2 and 1.8 monolayers/sec. Additional measurements of the dependence of the damping of RHEED intensity oscillations on V/11 ratio have indicated much less sensitivity of the growth front morphology to group V flux in CBE. This behavior is thought to reflect the role of highly mobile, partially saturated ethyl-gallium radicals in epitaxial growth by CBE. Measurements of As 2 arrival rate limited intensity oscillations on gallium rich surfaces prepared by pyrolyzing TEG in the absence of As 2 have shown that the pyrolysis of TEG is not self-limiting at 500°C and that excess gallium can be deposited on gallium rich surfaces. This paper also describes a simple model of the surface pyrolysis of TEG which is consistent with the above experimental observation.

RHEED Intensity Oscillation Studies of the Kinetics of GaAs Deposition During Chemical Beam Epitaxy(CBE)

Enhancements in Two Dimensional Electron Gas Density and Mobility in δ-Doped AiGaAs Heterostructures

High quality GaAs layers have been grown by chemical beam epitaxy using triethylgallium and arsine. Undoped GaAs epilayer with net acceptor concentration NA − ND = 3×1014 cm−3 has been obtained at a low growth temperature of 500°C. Si dopant diffusion at such low temperature during growth is negligible. Using monolayer doping technique epilayers with Si impurities localized in a 2-dimensional plane were prepared. Capacitance-voltage profiling showed a high sheet electron concentration of 1×1013cm−2 and peak widths of 22A and 18A at 300K and 77K, respectively, which are the narrowest ever reported. For samples grown or annealed at higher temperatures, significant impurity diffusion was observed.

Chemical Beam Epitaxial Growth and Capacitance-Voltage Characterization of Si δ-Doped GaAs

The observations of a damped intensity oscillation using reflection high‐energy electron diffraction during the growth of GaAs by chemical beam epitaxy using triethylgallium and arsine are reported. It is experimentally demonstrated that the As flux can be instantly shut off without any memory effect by measuring the Ga‐induced intensity variation and the subsequent As‐induced oscillations. The Ga deposition, free of any background As contamination, makes possible the direct determination of metal‐alkyl adsorption and pyrolysis efficiency on the hot substrate surface. At 530 °C a (4×6) diffraction pattern is observed when Ga is deposited alone. The appearance of this (4×6) reconstruction along with the associated intensity behavior indicates that the first monolayer of Ga grows two‐dimensionally. This can be understood qualitatively in terms of the simple kinematic model involving only surface roughness. These observations support a two‐dimensional growth mechanism in the growth process. Furthermore, the ...

Gallium- and arsenic-induced oscillations of intensity of reflection high-energy electron diffraction in the growth of (001) GaAs by chemical beam epitaxy

The δ‐doping concept is applied to selectively doped heterostructures in the AlxGa1−xAs/GaAs material system. High two‐dimensional electron‐gas concentrations ≥1.5×1012 cm−2 are obtained at T=300 K in such selectively δ‐doped heterostructures due to (i) size quantization in the AlxGa1−xAs and (ii) localization of donor impurities within one atomic monolayer. Shubnikov–de Haas measurements yield n2DEG =1.1×1012 cm−2 at 300 mK and at a spacer thickness of 25 A. Selectively δ‐doped heterostructure transistors (SΔDHT’s) are fabricated and have excellent characteristics due to the enhanced electron‐gas concentrations achieved. A very high transconductance of gm ≂360 mS/mm at a gate length of 1.2 μm is obtained in depletion‐mode SΔDHT’s at T=300 K.

Selectively δ‐doped AlxGa1−xAs/GaAs heterostructures with high two‐dimensional electron‐gas concentrations n2DEG≥1.5×1012 cm−2 for field‐effect transistors

Electron-mobility enhancement and electron-concentration enhancement in δ-doped n-GaAs at T=300K

We report the observation of reflection high‐energy diffraction (RHEED) intensity oscillations during the growth of GaAs using triethylgallium in chemical beam epitaxy (CBE). The oscillation period corresponds exactly to the time required for the growth of one monolayer. RHEED oscillation studies also suggest the absence of flux transients due to switching of gas flows, abrupt and complete initiation and termination of growth with submonolayer resolution, and that CBE is capable of thickness control with submonolayer precision when coupled with the use of in situ RHEED intensity monitoring technique. The temperature and flux dependence of growth rates are also studied using RHEED oscillations. Results indicate that CBE growth is predominantly via a two‐dimensional layer‐by‐layer mechanism.

Observations on intensity oscillations in reflection high‐energy electron diffraction during chemical beam epitaxy

Summary Abstract: High purity molecular beam epitaxy grown AlGaAs

This work describes a self‐aligned Schottky‐gate field‐effect transistor (FET) which uses the δ‐doping technique during crystal growth by molecular beam epitaxy. In this new FET the δ‐doping concepts are employed in three ways: (i) for the highly doped surface to obtain nonalloyed ohmic contacts, (ii) to decrease the parasitic resistances, and (iii) for the electron channel below the gate. A two‐dimensional electron gas in a V‐shaped quantum well is formed by the δ‐doped electron channel. The advantage of nonalloyed ohmic contacts allows us to use a new two‐mask, self‐aligned FET process to further reduce the parasitic resistances. Both enhancement‐mode and depletion‐mode δ‐doped GaAs field‐effect transistors are fabricated. The measured transconductance of the δ‐doped field‐effect transistor is 240 mS/mm and is comparable to values obtained from selectively doped heterostructure transistors of the same geometry.

Self‐aligned enhancement‐mode and depletion‐mode GaAs field‐effect transistors employing the δ‐doping technique

We report on the observation of a morphological defect structure, ‘‘cross‐hatch’’ and the experimental circumstances that lead to its occurence during GaAs homoepitaxy. Photoluminescence, x‐ray diffraction and transmission electron miscroscopy (TEM) results obtained on cross‐hatched samples are presented and discussed in regards to the nature and origin of the defect structure.

Erratum: Delta‐doped ohmic contacts to n‐GaAs [Appl. Phys. Lett. 49, 292 (1986)]

Full widths at half‐maximum intensity of the (004) Bragg reflecton peak as small as 24 arcs are obtained from InGaAs epilayers 4–6 μm thick. Such linewidth is the narrowest reported thus far for an InGaAs epilayer grown by any vapor phase technique reported in literature. Such extreme compositon uniformity is also supported by results from Auger depth profiles and 2 K photoluminescence measurements. Very intense efficient luminescence peaks due to excitonic transitions with linewidths (FWHM) as narrow as 1.2 meV are obtained. This again represents the narrowest linewidth ever reported for InGaAs grown by any technique. In fact, such a linewidth represents the narrowest linewidth ever measured for any alloy semiconductor. Further, the photoluminescence spectra reveal the donor‐to‐acceptor pair recombination is nearly absent. This indicates that the InGaAs is of very high purity. Hall measurements of 2–5‐μm‐thick epilayers grown directly on InP substrates have mobilities of 10 000–12 000 and 40 000–57 000 c...

Chemical beam epitaxial growth of extremely high quality InGaAs on InP

A new type of nonalloyed ohmic contact to GaAs is realized by molecular beam epitaxy. The ohmic characteristic of the metal‐semiconductor junction is obtained by placing a highly δ‐doped donor layer a few lattice constants away from the metal‐semiconductor interface of the contact and thus keeping the tunneling barrier extremely thin. The current‐voltage characteristic of the δ‐doped contacts is strictly linear. The measured contact resistance is in the 10−6 Ω cm2 range. Theoretical analysis of the tunneling current through the triangular barrier predicts contact resistances in the range 10−7–10−9 Ω cm2. In spite of the high doping concentration (≂1021 cm−3) the surface morphology of the sample shows no degradation.

The stacking structure and epitaxial ordering are studied in MBE-grown Ru-Ir superlattices of wavelengths λ = 41\ and 62\. These samples span the fcc-hcp crossover previously found to occur when the Ir component is thinner than about 10 monolayers. Evidence for a new stacking sequence of period 3λ is found in the λ=41\ sample, possibly resulting from stacking faults in the Ir layers. The superconducting transition temperature is significantly higher in the 41\ sample (T c =0.19K) than in the 62\ sample (T c =0.15K).

X-RAY AND TRANSPORT STUDIES OF RUTHENIUM-IRIDIUM BICRYSTAL SUPERLATTICES

The authors report the growth of high-quality bicrystal superlattices formed from alternating layers of HCP Ru and FCC Ir metals. Ir layers which are thick compared with the Ru do grow in the FCC structure, whereas thin Ir layers take the HCP structure, probably owing to strain effects.

We have made proximity-effect electron-tunneling measurements on films of Nb and V, pure and doped with Cr and Mn. In contrast to predictions of the theory of Shiba and Rusinov for magnetically doped superconductors, we see no well-defined bands of states below the superconducting gap edge.

Effects of Cr and Mn dopants on the density of states of superconducting niobium and vanadium

Configurational effects in the optical spectra of Ar and Kr on Mg and Al

Structural Properties of Single Crystal Rare-Earth Thin Films Y and Gd Grown by Molecular Beam Epitaxy

We report optical-excitation spectra of rare-gas atoms adsorbed on alkali-metal surfaces. The data were obtained with the use of differential reflectance methods with synchrotron radiation. Optical absorption appears to increase almost linearly from 0 at a well-defined excitation threshold energy that agrees quantitatively with the theoretical prediction for rare gases adsorbed on metals. The absorption continuum above threshold, for adsorbates distributed at dilution over the surface, is broken by the spin-orbit partner of the ${P}_{\frac{3}{2}}$ threshold process and by excitation to higher atomiclike configurations. Additional features which grow with coverage originate from adsorbate pairs. Both the threshold profile and pair peaks bear noticeable resemblance to the properties of rare-gas atoms alloyed into alkali metals, which have been investigated in earlier work. No theory is currently available to describe either the linear threshold profile or the pair peaks. The data establish unambiguously that the neutral excited rare-gas adsorbate configuration is created by the optical excitation, rather than the ionic configuration produced in photoemission work. These various properties are systematically described by a quantitative phenomenological model.

Neutral excited configuration of rare-gas atoms adsorbed on alkali metals

We report work-function changes caused by Ar, Kr, and Xe adsorbed at various coverages on the simple metals Cs, K, Na, Li, Mg, and Al. These and other data from the literature exhibit considerable scatter, but the trend is generally consistent with the "switching" theory proposed by Flynn and Chen.

Dependence of rare-gas-adsorbate dipole moment on substrate work function

Superconducting proximity-effect tunnelling measurements have been performed on (110)- and (111)- oriented niobium crystals grown by molecular-beam epitaxy. Measurements of ac resistance yield information about the effective phonon density of states; different results were obtained for the two crystal orientations. In situ high-energy electron diffraction studies indicate atomically smooth interfaces in the proximity sandwich and also indicate amorphous-oxide barriers for these junctions. We therefore have a nearly ideal configuration, which may account for the sensitivity to crystal orientation. The failure of the McMillan inversion program to converge for the (111) data suggests the need for a k-dependent formulation of the equations.

Observation of tunnelling anisotropy in superconducting niobium crystals

Reports results of a systematic experimental investigation of Cs 5p, Rb 4p and K 3p core excitation spectra in alkali-alkali alloys containing these atomic species. Various excitation profiles at threshold are observed. These apparently belong to a universal sequence of lineshapes. It is possible to predict which lineshape occurs in any particular alloy using a parameter xi which is a ratio of potential to kinetic energy in the excited configuration. An 'X-ray edge anomaly' occurs only in one limit of the sequence, namely xi large.

Universal X-ray edge behaviour in alkali metals and their alloys

Results are reported for four Nb-Ta single-crystal superlattices with 50 AA wavelength grown simultaneously on chosen substrates such that the crystal growth and superlattice structure take the (100), (110), (111) and (211) orientations in the respective cases.

Growth of single-crystal metal superlattices in chosen orientations

Optical absorption and photoemission of rare gas atoms on simple metal surfaces are treated by means of a configurational description of the many-particle states. This approach provides a framework within which most basic properties of simple physisorbed atoms can be understood rather directly.

Configurational description of rare gas atoms adsorbed on metal surfaces

The authors report Cs5p and Rb4p spectra for these atoms adsorbed at various coverages on clean Mg surfaces. At low coverage, <or approximately=1014 cm-2, Cs exists on Mg part-ionised. The neutral configuration predominates at higher sub-monolayer coverages. The neutral Rb configuration exhibits a greater stability at low coverage than that of Cs. For both species, the spectrum of the first monolayer remains visible as second and higher layers build up and contribute spectral components resembling those of the pure bulk alkali metals.

The authors present 5p excitation spectra for Cs atoms adsorbed on other alkali metals. The spectra near threshold vary systematically with coverage and substrate species. Sharp threshold edges occur only for coverages above one monolayer where the adsorbate spectra resemble that of pure Cs.

The authors report the successful growth of almost perfect single crystal superlattices made from alternating layers of Nb and Ta with superlattice periodicities in the range 20-1000 AA.

Surface Reflectance Core Spectroscopy of Halogens, Rare Gases, Alkalis and Carbon-Monoxide on Metal Surfaces

Surface reflectance core spectroscopy of halogens, rare gases, alkalis and CO on metal surfaces

Surface adsorbates on clean metal surfaces are being studied by vacuum-ultraviolet differential-reflectivity methods. Results for rear gases adsorbed on metals reveal ionic characteristics of the excited configurations and weak coupling to the host electron gas.

From optical data in the energy range 5-11 eV it is deduced that the excited states of Xe physisorbed on clean Au and Ti surfaces couple strongly to conduction states in the metal substrate.

Coupling of electronically excited physisorbed atoms to metal substrates: Xe on Au and Ti

Temperature and density evolution during compaction of a capsule shaped tablet

Understanding variation in roller compaction through finite element-based process modeling

Characterization of the Viscoelastic Behavior of Pharmaceutical Powders Barbara Jane Robinson Antonios Zavaliangos, PhD. Currently, the leading means of drug delivery is by oral administration, and tablets produced by powder compaction are the most widespread form of oral dosage. Understanding the mechanical behavior of powders allows for a rational design of complex compacts (bilayer, core in tablet, etc.). Pharmaceutical formulation development difficulties often arise during the scale up process, due to significant increase in production rate and local strain rates, when problems are the most detrimental, in terms of time and money. Viscoelasticity is one of the rate dependent characteristics of powder compaction. The main goal of this research is to evaluate the role of viscoelasticity on the powder compaction process. Current literature concerning viscoelastic behavior of powder compacts focuses on the modulus of elasticity. Equally, or even more important is the viscoelasticity of the bulk modulus, since few would argue that powder compaction is a bulk phenomenon which is not equivalent to simple tension or simple compression. Additionally, the experimental techniques used in the literature involve primarily out of die viscoelastic testing mechanisms. In die viscoelastic tests would provide a more complete explanation of the viscoelastic role in powder compaction. For the aforementioned reasons, this work is primarily focused on characterizing the viscoelastic behavior of compacts by dynamic mechanical analysis inside of a cylindrical die. This thesis includes a review of the existing literature, experimental results for Starch and MCC compacts, and some numerical simulation to support the experimental results. The results include the evaluation of the role of friction in the accuracy of the measurements, the limits of linear behavior, and the effect of relative density. Contrary to prior references in the literature the bulk modulus is viscoelastic but the corresponding dissipation factor is less than that of the Young’s modulus.

Characterization of the Viscoelastic Behavior of Pharmaceutical Powders

A numerical approach to the prediction of temperature evolution in tablet compaction is presented here. It is based on a coupled thermomechanical finite element analysis and a calibrated Drucker-Prager Cap model. This approach is capable of predicting transient temperatures during compaction, which cannot be assessed by experimental techniques due to inherent test limitations. Model predictions are validated with infrared (IR) temperature measurements of the top tablet surface after ejection and match well with experiments. The dependence of temperature fields on speed and degree of compaction are naturally captured. The estimated transient temperatures are maximum at the end of compaction at the center of the tablet and close to the die wall next to the powder/die interface.

Temperature evolution during compaction of pharmaceutical powders.

Bed humidity is a critical parameter that needs to be controlled in a fluidized bed granulation to ensure reliability. To predict and control the bed humidity during the fluidized bed granulation process, a simple model based on the mass conservation of moisture was developed. The moisture mass balance model quantitatively simulates the effects of spray rate, binder solution concentration, airflow rate, inlet air temperature, and dew point on the bed humidity. The model was validated by a series of granulations performed in different scale granulators including Glatt GPCG-1, GPCG-15, and GPCG-60. Good agreement was observed between the theoretical prediction and the measured loss on drying (LOD). The model developed in the current work enables us to choose the appropriate parameters for the fluidized bed granulation and can be used as a valuable tool in process scaling-up.

Understanding and predicting bed humidity in fluidized bed granulation.

Study growth kinetics in fluidized bed granulation with at-line FBRM.

A numerical approach to the prediction of temperature evolution in tablet compaction is presented here. It is based on a coupled thermomechanical finite element analysis and a calibrated Drucker-Prager Cap model. This approach is capable of predicting transient temperatures during compaction, which cannot be assessed by experimental techniques due to inherent test limitations. Model predictions are validated with infrared (IR) temperature measurements of the top tablet surface after ejection and match well with experiments. The dependence of temperature fields on speed and degree of compaction are naturally captured. The estimated transient temperatures are maximum at the end of compaction at the center of the tablet and close to the die wall next to the powder/die interface. 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:3291-3304, 2008

PHARMACEUTICAL TECHNOLOGY Temperature Evolution during Compaction of Pharmaceutical Powders

Measurement of drug agglomerates in powder blending simulation samples by near infrared chemical imaging.

Applications of NIR in early stage formulation development. Part I. Semi-quantitative blend uniformity and content uniformity analyses by reflectance NIR without calibration models.

Potency and content uniformity of granulation and tablet samples are usually determined by HPLC or UV-VIS. However, these methods are not suitable for the determinations of other important process related attributes. The monitoring of nucleation, granule growth and granule breakage in the granulation process requires different analytical tools. In early formulation development of a new active pharmaceutical ingredient (API), out of trend content uniformity results were observed for batches manufactured using a fluid bed wet granulation process. A qualitative near infrared (NIR) method was used to characterize the process samples, which were separated into fractions with sieve sizes of 40, 60, 80, 100, and 200-mesh. Based on spectral analysis, the method was able to demonstrate changes in relative content of lactose, microcrystalline cellulose and the API at different processing times. The results also showed that the out of trend content uniformity was caused by large particle size of the API. Because lactose and microcrystalline cellulose are commonly used ingredients in wet granulation formulations, the qualitative NIR method may find wide applications.

A qualitative method for monitoring of nucleation and granule growth in fluid bed wet granulation by reflectance near-infrared spectroscopy.

Experimental studies and modeling of the roller compaction of pharmaceutical powders

A Drucker-Prager/cap constitutive model, where the elastic and plastic model parameters are expressed as a function of relative density (RD), was presented in a companion article together with experimental calibration procedures. Here, we examine the RD distribution in curved-faced tablets with special reference to the die wall lubrication conditions. The compaction of powders is examined using finite element analysis, which involves the following factors: constitutive behavior of powder, friction between powder and tooling, geometry of die and punches, sequence of punch motions, and initial conditions that result from die fill. The predictions of the model are validated using experimental RD maps. It is shown that different die wall lubrication conditions induce opposite density distribution trends in identical tablets (weight, height, and material). The importance of the internal tablet structure is illustrated with respect to break force, failure mode, and friability: it is demonstrated that for a given average tablet density the break force and failure mode are not unique. Also, tablet regions having lower density locally have higher propensity for damage. The applicability of finite element analysis for optimizations of formulation design, process development, tablet image, and tool design is discussed.

Analysis of tablet compaction. II. Finite element analysis of density distributions in convex tablets.

Measurement of density variations in tablets using X-ray computed tomography.

In this first of two articles on the modeling of tablet compaction, the experimental inputs related to the constitutive model of the powder and the powder/tooling friction are determined. The continuum-based analysis of tableting makes use of an elasto-plastic model, which incorporates the elements of yield, plastic flow potential, and hardening, to describe the mechanical behavior of microcrystalline cellulose over the range of densities experienced during tableting. Specifically, a modified Drucker-Prager/cap plasticity model, which includes material parameters such as cohesion, internal friction, and hydrostatic yield pressure that evolve with the internal state variable relative density, was applied. Linear elasticity is assumed with the elastic parameters, Young's modulus, and Poisson's ratio dependent on the relative density. The calibration techniques were developed based on a series of simple mechanical tests including diametrical compression, simple compression, and die compaction using an instrumented die. The friction behavior is measured using an instrumented die and the experimental data are analyzed using the method of differential slices. The constitutive model and frictional properties are essential experimental inputs to the finite element-based model described in the companion article.

Analysis of tablet compaction. I. Characterization of mechanical behavior of powder and powder/tooling friction.

Comparison of various modeling methods for analysis of powder compaction in roller press

Analysis of the diametrical compression test and the applicability to plastically deforming materials

The effect of wall friction in the compaction of pharmaceutical tablets with curved faces: a validation study of the Drucker–Prager Cap model

AbstractKnowledge of the time-dependent mechanical properties of pharmaceutical materials is critical to understanding of the compaction of tablets. In effort to determine the time-scale involved during compaction, equations for the dwell time and the consolidation time are proposed in this paper. Expressions for the consolidation time are obtained from generally accepted equations for punch displacement and separation between punch tips. These equations are deduced for rotary tablet machines with pressure rollers of the same and of different sizes. Specifically, the equations are applied to calculate the dwell and consolidation times for Manesty Betapress and Korsch Pharmapress Rotary tablet machines. The results are graphically presented.

Theoretical estimation of dwell and consolidation times in rotary tablet machines

A Framework for Hospital Medicine's Involvement in Disaster Preparedness and Response.

Inspired by the ABIM Foundation’s Choosing Wisely® campaign, the “Things We Do for No ReasonTM” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

Things We Do For No Reason™: Ultrasonography After an Initial Negative CT in Patients Presenting With Acute Abdominal or Pelvic Pain.

a cardiac computed tomography image depicting LA right and indicating nearby structures at risk of injury; potential complications include phrenic nerve injury, pericardial tamponade, atrial-esophageal fistula, and pulmonary vein stenosis.

Clinical Progress Note: Rhythm Control for Patients With Atrial Fibrillation.

Acyclovir-induced neurotoxicity with a positive cerebrospinal fluid varicella zoster PCR result creating a management dilemma: a case report

Looking Back to Find the Missing P Wave and Diagnose a Narrow Complex Tachycardia.

A 22-year-old woman was admitted to the medicine service with generalised abdominal pain and nausea. Medical history included a recent motor vehicle accident resulting in multiple orthopaedic injuries and development of a chronic pain syndrome. The patient denied other pertinent medical, social or family history. Medications included escitalopram, cyclobenzaprine, and oxycodone 10 mg every 6 hours as needed for pain.

The patient’s initial vitals were temperature 37.3°C, heart rate 81 beats/min, respiratory rate 16 breaths/min, and blood pressure 89/59 mm Hg. Pertinent physical exam included diffuse tenderness to palpation of the abdomen without peritoneal signs and no skin hyperpigmentation. Laboratory evaluation revealed a normal complete blood count, basic metabolic panel, liver function, urinalysis, and lipase. A CT scan of the abdomen and pelvis showed …

Secondary adrenal insufficiency: an insidious consequence of the opioid epidemic?

Patient: Female, 72-year-old Final Diagnosis: Cefepime-induced neurotoxicity Symptoms: Aphasia Medication:— Clinical Procedure: — Specialty: General and Internal Medicine Objective: Unusual or unexpected effect of treatment Background: Cefepime-induced neurotoxicity has been described in intensive care units (ICUs) and neuro ICU settings, occurring in patients started on ce fepime for management of severe infections and sepsis. Most cases occur within 1 to 10 days after starting the drug. We publish a case that occurred on the general medical ward of a patient who had been on cefepime therapy for 4 weeks prior to admission. The aim of this study was to improve the knowledge of this serious condition to general internists as our patient was being managed on the general medical ward. Case Report: A 72-year-old female on prolonged intravenous antibiotics for sacral and pelvic osteomyelitis presented with acute encephalopathy and aphasia in the setting of an acute kidney injury. Due to the acute focal neurologic deficit, she was initially admitted as a stroke alert. After a negative magnetic resonance imaging (MRI) of the brain, an electroencephalogram (EEG) was pursued and showed nonconvulsive status epilepticus (NCSE). NCSE was likely a result of cefepime therapy in the setting of an acute kidney injury. Conclusions: Cefepime-induced neurotoxicity should be suspected in any patient on cefepime therapy who develops acute changes in mental status, myoclonus, or evidence of seizures. Risk factors for the disease include older age, renal dysfunction, critical illness, and inappropriate dosing based upon renal function. A high index of suspicion is required and delays in diagnosis are common as there are frequently multiple possible causes for altered mental status in systemically ill patients requiring treatment with broad-spectrum antibiotics.

Cefepime-Induced Neurotoxicity Presenting with Nonconvulsive Status Epilepticus Admitted as a Stroke Alert

A 24-year-old woman with a medical history of chronic lower extremity oedema, abdominal pain, diarrhoea and recurrent pulmonary infections presented with sepsis from right lower extremity cellulitis. Blood cultures grew Morganella morganii. Laboratory evaluation revealed lymphopaenia, hypogammaglobulinaemia, a low CD4+ T-cell count and nutritional deficiencies resulting from protein-losing enteropathy (PLE). CT showed small bowel wall thickening in the jejunum and ileum. Primary intestinal lymphangiectasia (PIL) was the likely diagnosis that explained her PLE and immunodeficiencies. Video capsule endoscopy is an important diagnostic tool for distal small bowel pathology and confirmed patchy areas of lymphangiectasia of the jejunum and ileum. Secondary causes of lymphangiectasia were ruled out. Clinically significant immunodeficiency from PIL has not been frequently documented, and this case adds to the literature of rare infections associated with PIL. Treatment with intravenous antibiotics resolved her septicaemia, while dietary modifications improved her oedema, abdominal pain and diarrhoea.

Primary intestinal lymphangiectasia diagnosed by video capsule endoscopy in a patient with immunodeficiency presenting with Morganella morganii bacteraemia

Hospitalized patients are frequently treated with opioids for pain control, and receipt of opioids at hospital discharge may increase the risk of future chronic opioid use.

OBJECTIVE
To compare inpatient analgesic prescribing patterns and patients' perception of pain control in the United States and non-US hospitals.

DESIGN
Cross-sectional observational study.

SETTING
Four hospitals in the US and seven in seven other countries.

Medical inpatients reporting pain.

Opioid analgesics dispensed during the first 24-36 hours of hospitalization and at discharge; assessments and beliefs about pain.

RESULTS
We acquired completed surveys for 981 patients, 503 of 719 patients in the US and 478 of 590 patients in other countries. After adjusting for confounding factors, we found that more US patients were given opioids during their hospitalization compared with patients in other countries, regardless of whether they did or did not report taking opioids prior to admission (92% vs 70% and 71% vs 41%, respectively; P < .05), and similar trends were seen for opioids prescribed at discharge. Patient satisfaction, beliefs, and expectations about pain control differed between patients in the US and other sites.

LIMITATIONS
Limited number of sites and patients/country.

In the hospitals we sampled, our data suggest that physicians in the US may prescribe opioids more frequently during patients' hospitalizations and at discharge than their colleagues in other countries, and patients have different beliefs and expectations about pain control. Efforts to curb the opioid epidemic likely need to include addressing inpatient analgesic prescribing practices and patients' expectations regarding pain control.

Opioid Utilization and Perception of Pain Control in Hospitalized Patients: A Cross-Sectional Study of 11 Sites in 8 Countries.

A 58-year-old woman with chronic obstructive pulmonary disease had spontaneous bilateral hemothorax and a retroperitoneal hematoma after 4 days of anticoagulation therapy with enoxaparin (1 mg/kg subcutaneously every 12 hours) for suspected pulmonary thromboembolism. The patient was successfully managed with red blood cell and plasma transfusions, multiple thoracenteses for evacuation of blood from the pleural space, short-term mechanical ventilation, and administration of bronchodilators, corticosteroids, and antibiotics. This is the first report of spontaneous hemothorax and the third report of spontaneous retroperitoneal hematoma associated with enoxaparin therapy.

Hemothorax and retroperitoneal hematoma after anticoagulation with enoxaparin.

A monoclonal antibody-based immunofluorescence test for the detection of Pneumocystis carinii was evaluated in comparison with the conventional direct staining by Grocott's silver methenamine technique. A total of 254 respiratory samples from HIV positive and other immunocompromised patients were examined. Cysts were detected in 30 (12%) of samples using the monoclonal test, but only 15 (6%) positives were found using the Grocott method. There is need for a speedy and efficient test for detection of these organisms, and the monoclonal test was found to be more reliable, quicker and more sensitive than the Grocott technique.

Pneumocystis carinii pneumonia: detection of parasites by immunofluorescence based on a monoclonal antibody.

A scrutiny of the problem of pneumonia with the involved physiology of metabolism brings forth a new picture of the malady. Physiologists have opened fields of investigation which bear a close clinical relationship to the problem. In pneumonia there is an invasion of the body by pneumococci. The body reacts by forming antibodies to combat the invasion. The virulence of the invading organism is variable, both at the beginning of the attack and as the disease progresses. The rapidity with which the patient builds antibodies varies. In each person there is a variation in antibody formation (resistance) as the disease progresses. A pneumococcus of low virulence, attacking an individual possessing rapid antibody formation, is soon stopped (abortive pneumonia). On the other hand, the combination of a virulent organism invading an individual with inadequate antibody formation usually results in a fatality. Any therapeutic measure that will elevate or prolong resistance, or

An Approach to Compensation plans for Physician Faculty in Academic Pediatric Departments.

Abstract Analyzing single-cell transcriptomes promises to decipher the plasticity, heterogeneity, and rapid switches in developmental cellular state transitions. Such analyses require the identification of gene markers for semi-stable transition states. However, there are nontrivial challenges such as unexplainable stochasticity, variable population sizes, and alternative trajectory constructions. By advancing current tipping-point theory-based models with feature selection, network decomposition, accurate estimation of correlations, and optimization, we developed BioTIP to overcome these challenges. BioTIP identifies a small group of genes, called critical transition signal (CTS), to characterize regulated stochasticity during semi-stable transitions. Although methods rooted in different theories converged at the same transition events in two benchmark datasets, BioTIP is unique in inferring lineage-determining transcription factors governing critical transition. Applying BioTIP to mouse gastrulation data, we identify multiple CTSs from one dataset and validated their significance in another independent dataset. We detect the established regulator Etv2 whose expression change drives the haemato-endothelial bifurcation, and its targets together in CTS across three datasets. After comparing to three current methods using six datasets, we show that BioTIP is accurate, user-friendly, independent of pseudo-temporal trajectory, and captures significantly interconnected and reproducible CTSs. We expect BioTIP to provide great insight into dynamic regulations of lineage-determining factors.

Detecting critical transition signals from single-cell transcriptomes to infer lineage-determining transcription factors

The lineage-determining transcription factor ETV2 is necessary and sufficient for hematoendothelial fate commitment. We investigated how ETV2-driven gene regulatory networks promote hematoendothelial fate commitment. We resolved the sequential determination steps of hematoendothelial versus cardiac differentiation from mouse embryonic stem cells. Etv2 was strongly induced and bound to the enhancers of hematoendothelial genes in a common cardiomyocyte-hematoendothelial mesoderm progenitor. However, only Etv2 itself and Tal1, not other ETV2-bound genes, were induced. Despite ETV2 genomic binding and Etv2 and Tal1 expression, cardiomyogenic fate potential was maintained. A second wave of ETV2-bound target genes was up-regulated during the transition from the common cardiomyocyte-hematoendothelial progenitor to the committed hematoendothelial population. A third wave of ETV-bound genes were subsequently expressed in the committed hematoendothelial population for sub-lineage differentiation. The shift from ETV2 binding to productive transcription, not ETV2 binding to target gene enhancers, drove hematoendothelial fate commitment. This work identifies mechanistic phases of ETV2-dependent gene expression that distinguish hematoendothelial specification, commitment, and differentiation. HIGHLIGHTS The hematoendothelial master TF ETV2 is expressed in a multipotent mesoderm progenitor. ETV2 binds to target genes in the mesoderm progenitor without target gene activation. ETV2 binding in the mesoderm progenitor does not diminish alternative cardiac fate potential. ETV2-bound target genes are activated upon hematoendothelial fate commitment. GRAPHICAL ABSTRACT

ETV2 primes hematoendothelial gene enhancers prior to hematoendothelial fate commitment

Desmoplastic small round cell tumor (DSRCT) is a rare, highly aggressive malignancy primarily affecting children and young adults. Although modest improvements have been gained by intensification of chemotherapy and radiation, survival of patients with DSRCT remains poor, particularly in those with unresectable or disseminated disease. We report 3 pediatric patients who were treated with a combination of therapy including chemotherapy, surgical debulking, hyperthermic intraperitoneal chemotherapy, whole abdominal irradiation, and autologous hematopoietic stem cell transplantation following busulfan and melphalan conditioning. We find that this approach is well tolerated and may offer improved survival in patients with DSRCT.

The addition of autologous stem cell transplantation to neoadjuvant chemotherapy, radiation, and HIPEC for patients with unresectable desmoplastic small round cell tumor: a single center case series

Abrupt and irreversible changes (or tipping points) are decisive in disease and normal phenotypic progress. Often, however, computational approaches detect critical-transition signals (CTSs) indicating tipping points from longitudinal data -- which often are not available for patient transcriptomes. Here we adopt historical tipping-point approaches to cross-sectional data by modeling high probability spaces of phenotypes. We formulate this task as a generalized CTS-searching problem and derive a robust algorithm to solve it. We construct a comprehensive scoring scheme and successfully apply the scheme to lymphoma, lung-injury, heart-development, and neuroblastoma systems. Thus, we identify a spatial gene-expression feature for systematic dynamics at phenotypic tipping points, which can be exploited to infer functional genetic variations and transcription factors. Our framework (9BioTIP9) can analyze not only time-course but also cross-sectional transcriptomes and is compatible with noncoding RNA profiles. Additional knowledge discovery that explores the critical transition of a system can be tested using our approach.

Adopting tipping-point theory to patient transcriptomes unravels gene regulatory network dynamics

Outcomes following second allogeneic stem cell transplant for disease relapse after T cell depleted transplant correlate with remission status and remission duration after the first transplant

Tipping-point models have had success identifying transcriptional critical-transition signal (CTS) in tumor phenotypes using time-course data. Can these mathematical models be adopted to cross-sectional transcriptome profiles? Furthermore, can the CTS analysis that characterizes tumor progression be applied to lncRNA-expression patterns? This study introduces a novel network-perturbation signature (NPS) scoring scheme to model a phenotype-defined tumor regulatory system. Applying NPS to neuroblastoma transcriptome of two patient populations yielded two CTSs that reproducibly identified a critical system transition between the low-risk and a high-risk state. The coherent expression pattern of one specific CTS, consisting of mRNA and lncRNA components, showed prognostic significance. Associating GWAS-scans with the CTS unveiled four overlooked intergenic loci and five genes with promising clinical significance. Additionally, a new mechanism of CTS-amplifier is proposed, modeling how CTS-transcript fluctuation response to complex master regulators such as c-MYC and HNF4A uniquely in the transition state. Overall, NPS is a powerful computational approach that provides a breakthrough in phenomenological analysis of collective regulatory trajectory by applying tipping-point theory to -omics data.nnHighlightsO_LIWe adopt tipping-point theory to identify distribution-transition in disease regulatory statesnC_LIO_LICritical transcriptional transition happens between low-risk and a high-risk neuroblastoma statesnC_LIO_LIA critical transition signal (CTS) based on coherent expression of genes and lncRNAs shows prognostic significancenC_LIO_LIGWAS-scans with the CTS unveiled five overlooked genes and four lncRNAs with promising clinical implicationsnC_LIO_LIWe propose a CTS-amplifier model that unveils complex but mastering trans-regulation in diseasenC_LI

Adopting tipping-point theory to transcriptome profiles unravels disease regulatory trajectory

Tipping points existing in many biological processes. Identifying gene expression signals in the presence of entropic background is essential to decipher biological tipping points. We introduce a new method BioTIP which accurately, robustly, and reliably identifies tipping points and their significant gene signals. Through application to three benchmark datasets and comparison to previous analyses, we demonstrate that not only can BioTIP be applied to understanding of disease and developmental, but also to data at the cellular or organismal level. We applied BioTIP to two exemplary contexts on which tipping-point analyses had never been done and validated the statistical significance of the identified gene signals using independent datasets. By a literary investigation, we showed how the identified gene signals provide insight into regulatory networks of master transcription factors modulating those transitions. Our open-source software allows for future investigations using tipping point methodology to better characterize the plasticity, heterogeneity, and rapid switches in biological processes. Highlights ∙ Shrinkage estimation reduces errors in the empirical correlation matrix thus inferring tipping point accurately ∙ Refined feature selection and random walk isolate the early-warning signal for tipping point from background noise ∙ Identification of the intermediate-risk stage in neuroblastoma as the most vulnerable and susceptible to treatment ∙ First tipping-point interpretation of Etv2 oscillation that guides the haemato-endothelial bifurcation

Tipping-point analysis uncovers critical transition signals from gene expression profiles

Abstract 411: Risk-dependent enhancer transcription defines oncogenic gene regulatory networks for high-risk neuroblastoma

Motivation Long intergenic noncoding RNAs (lincRNAs) have risen to prominence in cancer biology as new biomarkers of disease. Those lincRNAs transcribed from active cis‐regulatory elements (enhancers) have provided mechanistic insight into cis‐acting regulation; however, in the absence of an enhancer hallmark, computational prediction of cis‐acting transcription of lincRNAs remains challenging. Here, we introduce a novel transcriptomic method: a cis‐regulatory lincRNA‐gene associating metric, termed ‘CisPi’. CisPi quantifies the mutual information between lincRNAs and local gene expression regarding their response to perturbation, such as disease risk‐dependence. To predict risk‐dependent lincRNAs in neuroblastoma, an aggressive pediatric cancer, we advance this scoring scheme to measure lincRNAs that represent the minority of reads in RNA‐Seq libraries by a novel side‐by‐side analytical pipeline. Results Altered expression of lincRNAs that stratifies tumor risk is an informative readout of oncogenic enhancer activity. Our CisPi metric therefore provides a powerful computational model to identify enhancer‐templated RNAs (eRNAs), eRNA‐like lincRNAs, or active enhancers that regulate the expression of local genes. First, risk‐dependent lincRNAs revealed active enhancers, over‐represented neuroblastoma susceptibility loci, and uncovered novel clinical biomarkers. Second, the prioritized lincRNAs were significantly prognostic. Third, the predicted target genes further inherited the prognostic significance of these lincRNAs. In sum, RNA‐Seq alone is sufficient to identify disease‐associated lincRNAs using our methodologies, allowing broader applications to contexts in which enhancer hallmarks are not available or show limited sensitivity. Availability and implementation The source code is available on request. The prioritized lincRNAs and their target genes are in the Supplementary Material. Supplementary information Supplementary data are available at Bioinformatics online.

CisPi: a transcriptomic score for disclosing cis-acting disease-associated lincRNAs

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation

Immune Reconstitution Following Autologous Stem Cell Transplantation in Patients with High-Risk Neuroblastoma at the Time of Immunotherapy.

Incorporating genomic, transcriptomic and clinical data: a prognostic and stem cell-like MYC and PRC imbalance in high-risk neuroblastoma

Acute Chest Syndrome (ACS) is one of the leading causes of death among children with Sickle Cell Disease (SCD). Disruption of microvascular integrity is critical to the pathophysiology of ACS, but the factors governing its phenotypic variability are incompletely understood. Because circulating exosomes have been implicated in vascular dysfunction in various diseases, we hypothesized that exosomes induce endothelial dysfunction in patients who experience ACS.

Exosomes contribute to endothelial integrity and acute chest syndrome risk: Preliminary findings

Implementation of a Sibling Donor Advocate: The University of Chicago Pediatric Stem Cell Transplant Experience

Immune System Profiling Following Autologous Stem Cell Transplant for High-Risk Neuroblastoma Reveals Poor Immune Reconstitution at the Start of Immunotherapy That Predicts Disease-Free Survival

A c-Myc-regulated stem cell-like signature in high-risk neuroblastoma: A systematic discovery (Target neuroblastoma ESC-like signature)

Autologous Stem Cell Transplantation Added to Standard Chemotherapy, Hipec Surgery, and Whole Abdominal Radiation is Well Tolerated and May Increases Progression Free Survival in Patients with Desmoplastic Small Round Cell Tumors

Introduction: The Dependent Coverage Provision (DCP) of the 2010 Affordable Care Act aims to improve (1) access to medical care among individuals aged 18-25 nationwide and (2) the efficiency of care by increasing appropriate outpatient care and reducing avoidable inpatient care. Individuals became eligible for coverage under their parents9 private insurance in late September 2010. Previous studies have demonstrated improvement in access to care among those eligible for DCP, but no studies have examined the experience of young adults with serious disease requiring chronic medical care such as sickle cell disease (SCD). We hypothesized SCD patients aged 18-25 had increased access to commercial insurance, higher use of outpatient and lower use of inpatient care in the years following DCP implementation compared to patients ineligible for DCP. Methods: This national analysis of patients aged 0-30 with qualifying SCD claims was performed using the Truven Health Analytics MarketScan Commercial Claims and Encounters dataset 2003-2013. The dataset contains commercial insurance claims of employees and dependants representing more than 50 million lives annually. We included patients with a continuous 12 month enrollment, and >1 inpatient or outpatient SCD claim in a given year. SCD claims included those with ICD-9 codes for homozygous SCD (HgbSS), sickle cell thalassemias (HgbSC, HgbSbo, HgbSb+) with and without crises, or splenic sequestration and/or acute chest syndrome. We defined 2003-2010 as pre-DCP and 2011-2013 as post-DCP. Inflation adjusted annual average per person spending, defined as reimbursements paid to providers, of SCD related inpatient and outpatient care was calculated. Descriptive statistics of number and share of patients by year and age cohort were calculated. Descriptive statistics of number of outpatient and inpatient claims by year and age cohort were calculated. A segmented regression analysis was performed to test for changes in trend of patient share by age cohort after the DCP. Access is defined as share of individuals having any claim type during the year. A difference-in-differences analysis was performed to study changes in medical care use and spending among individuals aged 18-25 pre and post-DCP, compared to those 26-30 and 12-17. Results: ACCESS: The absolute number of individuals increased in each age cohort during the study years. There was a significant increase in the share of 18-25 aged SCD patients compared to other SCD cohorts after DCP implementation (p = 0.03, Figure 1). USE: SCD patients aged 18-25 experienced a statistically significant increased likelihood of having an outpatient claim after the DCP compared to those 26-30 (p SPENDING: Average per person outpatient spending pre and post DCP were: 18-25 year cohort $132 to $108; 12-17 year cohort $131 to $127; and 26-30 year cohort $134 to $100. Average per person inpatient spending pre- and post-DCP were: 18-25 years- $12064 to $16343; 12-17 years- $12700 to $17017; and 26-30 years- $10967 to $17852. Conclusion: Our analysis is the first to demonstrate early success of the DCP among a young adult population suffering from serious disease requiring chronic medical care. We find 18-25 year old SCD patients accessed private insurance at a greater rate and increased their use of less costly outpatient care after the DCP. Inpatient use did not change significantly among this cohort after DCP implementation. We observe inpatient costs to increase among each age cohort, including those 18-25, after the DCP. This result cannot be attributed to technologic change - no new invasive treatments or procedures have been introduced during the study period. Additional work is needed to better understand this result, including an analysis of frequency and length of stay. Limitations include underestimating the number of SCD patients due to missed ICD9 codes and the lack of clinical correlates within the data. Future analysis should replicate this analysis with other chronic conditions as well as measures of quality of care such as patient reported outcomes. Disclosures Henderson:Seattle Genetics: Research Funding.

The Affordable Care Act Improves Healthcare Access and Utilization Among Young Adults with Sickle Cell Disease

Introduction: Acute Chest Syndrome (ACS) is the leading cause of death among children with sickle cell disease (SCD). While the phenotypic variability of ACS is incompletely understood, aberrant cell-cell interactions involving the endothelium are central to the pathophysiology. Recent studies suggest that circulating cell-derived extracellular vesicles, termed exosomes, can regulate endothelial integrity. We and others recently demonstrated that exosomes from SCD patients differentially affect endothelial integrity in vitro, but the relationship to specific complications of SCD, such as ACS, are unknown. Given the critical role of the endothelium in ACS, we hypothesized that exosomes from patients with a history of ACS induce increased endothelial damage compared to those without a previous ACS episodes. Methods: Plasma was isolated from 33 patients with SCD. Patients were >4 weeks since transfusion and had no new health-related complaints. Control plasma samples were from children without SCD or known medical problems, who had a BMI Results/Discussion: Flow cytometry demonstrated that the absolute exosome number was greatly increased in patients with SCD compared with controls. In contrast, no significant differences in total exosome numbers emerged between SCD patients based on ACS history. The origin of theexosomes was mainly erythroid (controls:9,661 ± 3,195 /100 uL vs. SCD: 31,338 ± 5,323 /100 uL, p Conclusions: The results confirm and expand on our prior observations that circulating exosomes are increased in patients with SCD and contribute to the maintenance of endothelial integrity. Exosomes from ACS(+) patients disrupt the endothelial monolayer in vitro (unlike exosomes from SCD patients who never experienced ACS). We speculate that the increased exosomes contribute to the vascular pathology in all SCD patients. However, some SCD patients are protected by specific exosome cargoes, as in the ACS(-) patients whose exosomes induced eNOS expression by the cultured endothelial cells in vitro, which plays a critical role in endothelial health. Together, the current findings suggest that exosomes are differentially generated based on ACS history, and that their function/cargo (as opposed to their number), modulates endothelial function. Thus, SCD exosomes that induce endothelial dysfunction likely contribute to the pathophysiology of ACS, and may serve as risk-related biomarkers. Disclosures No relevant conflicts of interest to declare.

Exosomes from Patients with Sickle Cell Disease and History of Acute Chest Syndrome Alter Endothelial Integrity In Vitro

Immune System Profiling Following Autologous Stem Cell Transplant for High-Risk Neuroblastoma Predicts Disease-Free Survival

Identification of epigenetic modifications that contribute to pathogenesis in therapy-related AML: Effective integration of genome-wide histone modification with transcriptional profiles

Summary: Seq2pathway is an R/Python wrapper for pathway (or functional gene-set) analysis of genomic loci, adapted for advances in genome research. Seq2pathway associates the biological significance of genomic loci with their target transcripts and then summarizes the quantified values on the gene-level into pathway scores. It is designed to isolate systematic disturbances and common biological underpinnings from next-generation sequencing (NGS) data. Seq2pathway offers Bioconductor users enhanced capability in discovering collective pathway effects caused by both coding genes and cis-regulation of non-coding elements. Availability and implementation: The package is freely available at http://www.bioconductor.org/ packages/release/bioc/html/seq2pathway.html. Contact: xyang2@uchicago.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Genome analysis Seq 2 pathway : an R / Bioconductor package for pathway analysis of next-generation sequencing data

Systematic computation with functional gene-sets among leukemic and hematopoietic stem cells reveals a favorable prognostic signature for acute myeloid leukemia

We have recently established a biobanking and sequencing pipeline at the University of Chicago dubbed Genomics for Risk Evaluation and Anticancer Therapy in Kids. We plan to intersect family and personal history of cancer and other diseases with multidimensional genomic profiling in order to: understand how genetics may have contributed to the development of cancer for each child, and investigate the spectrum of genomic alterations within a tumor spatially (e.g., primary site vs distant metastasis) and over time (e.g., diagnosis vs relapse). This review highlights some of the practical considerations involved in creating such a program including the capacity to use our platform for multi-institutional collaborations.

Establishing a translational genomics infrastructure in pediatric cancer: the GREAT KIDS experience.

Summary: Seq2pathway is an R/Python wrapper for pathway (or functional gene-set) analysis of genomic loci, adapted for advances in genome research. Seq2pathway associates the biological significance of genomic loci with their target transcripts and then summarizes the quantified values on the gene-level into pathway scores. It is designed to isolate systematic disturbances and common biological underpinnings from next-generation sequencing (NGS) data. Seq2pathway offers Bioconductor users enhanced capability in discovering collective pathway effects caused by both coding genes and cis-regulation of non-coding elements. Availability and implementation: The package is freely available at http://www.bioconductor.org/packages/release/bioc/html/seq2pathway.html. Contact: xyang2@uchicago.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Seq2pathway: an R/Bioconductor package for pathway analysis of next-generation sequencing data

The outcome of disease relapse after allogeneic stem cell transplantation (allo-SCT) remains very poor. Second SCT has achieved long term survival in select pts. We retrospectively analyzed the outcomes of 65 pts who underwent 2rd SCT for disease relapse at University of Chicago between September 2002 and September 2013. All except 4 pts received T cell depleted (TCD) SCT as 1 st SCT mainly with fludarabine (flu)/clofarabine-melphalan (mel) -alemtuzumab; flu-busulfan-alemtuzumab for MRD or MUD, and flu-mel-ATG for haplo-cord SCT. The majority of pts had AML (n=46) and high risk MDS (n=5). The median age at 2 nd allo-SCT was 47ys (11-73). 33 pts, 21 pts and 11 pts received MRD, MUD and Haplo-Cord SCT respectively for 2 nd SCT. 13 pts (20%) achieved CR before 2 nd SCT. 71% pts received TCD conditioning for 2 nd SCT. 98% (n=64) and 72% (n=47) pts achieved neutrophil and platelet engraftment at a median time of 11 and 18 days, respectively, following the 2 nd SCT. With a median fellow up of 23 (5.5-140) months for survivors after 2 nd SCT, the estimated 1 year PFS was 29.2% and 1 year OS was 33.8%. The day 100 treatment related mortality (TRM) rate was 28%, and the cumulative incidence of aGVHD and cGVHD were 23% and 8%, respectively. Not surprisingly, the majority of pts died from disease relapse (22/47, 47%), followed by infection (11/47, 23%) and GVHD (6/47, 13%). In the univariate analysis, pts with remission duration after 1 st SCT >=12 months or CR status before 2 nd SCT had significantly better PFS (P=0.001 and 0.009) and OS (P=0.001 and 0.013). The differences of 1 year PFS and OS stratified by these two variables were very striking. The 1 years PFS for pts in CR was 62% compared to 21% for pts not in CR; and 1 year PFS for pts with remission duration >=12 months after 1 st SCT was 57% comparing around 14% for pts 60) had no influence on 1 year PFS (P=0.083), younger pts had better 3 year PFS (P=0.026); Alemtuzumab use (n=37 vs. n=16 without alemtuzumab) in the 2 nd SCT conditioning for related donors significantly worsened 3 years PFS (44% vs. 8%; P=0.027) but not 1 year PFS, and it had no effect on OS. A scoring system using age ( 60), disease status before 2 nd SCT (CR vs. non-CR), and remission duration after 1 st SCT ( =12 months) was generated to attempt to classify the pts into different risk categories. The groups of 0 (n=5), 1-2 (n=34), 3-4 (n=26) could separate the 1 year PFS (80% vs. 32.3% vs. 15.4%) and OS (100% vs. 35.3 vs. 19.2%) nicely. Although the numbers are small, pts with a score of 0 ( =12 months remission duration after 1 st SCT) had excellent outcomes with 1 year PFS of 80%, and 1 year OS of 100%. In conclusion, 2 nd allo-SCT is a viable option for disease relapse after TCD allo-SCT with acceptable GVHD and good engraftment for those entering transplant in remission and/or remission duration >=12 months after 1 st SCT. Disclosures Artz: Miltenyi: Research Funding. Stock: Sigma-Tau: Membership on an entity9s Board of Directors or advisory committees, Research Funding.

The Outcomes of Second Allogeneic Stem Cell Transplantation for Disease Relapse after T Cell Depleted Allogeneic Stem Cell Transplantation: A Single Center Experience-University of Chicago

The outcome of umbilical cord blood transplantation is governed by UCB cell dose and matching. But stringent cell dose requirements limit access to well matched units. In haplo –cord transplant, early engraftment is determined by the adult graft. Elsewhere we have shown that excessive doses of haplo-identical cells resulted in failure of the UCB graft. Here we investigated the effect of a lower UCB cell dose threshold on ability to identify well matching units. We also prospectively evaluated the effects of UCB cell dose and matching (combined with a fixed dose haplo-graft ) on cord engraftment, platelet recovery, neutrophil recovery and acute GVHD, PFS and OS. We enrolled three consecutive cohorts with increasingly lower UCB cell dose thresholds (1) UCB cell dose >2x 10^ NC/kg (2)≥1x 10^ NC/kg and (3)≥.5x 10^ NC/kg. Additional selection criteria included (1) best HLA match (initially based on 6 HLA, as of mid 2013 based on 8 HR antigens (2)UCB viability, (3) avoidance of DSA antibodies and (4) NIMA compatibility. We continued enrollment on each cohort until at least 10 patients were evaluable for day 100 chimerism. If more than 7 of ten evaluable patients in a cohort achieved >40% UCB chimerism by d 100, the next cohort was started. This rate of success was achieved in all three cohorts, so we have continued accrual in the lowest cell dose. Sixty patients have been accrued at two institutions over 19 months. 43/60 pts had AML or MDS. The majority had ASBMT advanced and intermediate disease. Nearly half of the pts were of minority descent. Conditioning in all pts consisted of fludarabine-melphalan (three pts also received TBI 400) and GVHD prophylaxis of tacrolimus and mycophenolate. Haplo identical CD34 selected cells were co-administered at a dose of 3-5 x10^6 CD34 cells/kg. Pt characteristics and preliminary outcomes are summarized in the table below. The average HLA matching was significantly better (P 6/8 match), than in group 1 (6% with >6/8 match). UCB cell doses were significantly lower in groups 2 and 3 (55% with UCB cell dose Seven of 50 evaluable pts had failure of the UCB graft ( This novel cord blood selection algorithm allows identification of well-matched UCB cells (at least 6/8 HR) in two thirds of patients. In approximately one third of cases the best matching UCB unit has a cell dose Disclosures van Besien:Miltenyi Biotec: Research Funding. Stock:Sigma-Tau: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Mark:Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau.

Haplo-Cord UCB SCT with Low Cell Dose, Well Matched UCB Units. a Prospective Multicenter Study

Breast cancer remains the leading cause of cancer-related mortality in women. Comprehensive genomics, proteomics, and metabolomics studies are emerging that offer an opportunity to model disease biology, prognosis, and response to specific therapies. Although many biomarkers have been identified through advances in data mining techniques, few have been applied broadly to make patient-specific decisions. Here, we review a selection of breast cancer prognostic indicators and their implications. Our goal is to provide clinicians with a general evaluation of emerging computational methodologies for outcome prediction.

Loss of chromosome 7 and del(7q) [-7/del(7q)] are recurring cytogenetic abnormalities in hematologic malignancies, including acute myeloid leukemia and therapy-related myeloid neoplasms, and associated with an adverse prognosis. Despite intensive effort by many laboratories, the putative myeloid tumor suppressor(s) on chromosome 7 has not yet been identified.We performed transcriptome sequencing and SNP array analysis on de novo and therapy-related myeloid neoplasms, half with -7/del(7q). We identified a 2.17-Mb commonly deleted segment on chromosome band 7q22.1 containing CUX1, a gene encoding a homeodomain-containing transcription factor. In 1 case, CUX1 was disrupted by a translocation, resulting in a loss-of-function RNA fusion transcript. CUX1 was the most significantly differentially expressed gene within the commonly deleted segment and was expressed at haploinsufficient levels in -7/del(7q) leukemias. Haploinsufficiency of the highly conserved ortholog, cut, led to hemocyte overgrowth and tumor formation in Drosophila melanogaster. Similarly, haploinsufficiency of CUX1 gave human hematopoietic cells a significant engraftment advantage on transplantation into immunodeficient mice. Within the RNA-sequencing data, we identified a CUX1-associated cell cycle transcriptional gene signature, suggesting that CUX1 exerts tumor suppressor activity by regulating proliferative genes. These data identify CUX1 as a conserved, haploinsufficient tumor suppressor frequently deleted in myeloid neoplasms.

CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia.

Saptarshi Mandal, Beverly W. Baron, Maryorie Mischeaux, Khadija James, Joseph Roig, Judy Landers, Samuel L. Volchenboum, John M. Cunningham, Barbara Reardon, Gunta Musa, and Elie M. Richa* Biological Sciences Division, Department of Pathology, University of Chicago, Chicago, Illinois Caridian BCT, Lakewood, Colorado Biological Sciences Division, Department of Pediatrics, University of Chicago, Chicago, Illinois

Collection of peripheral blood stem cells from a 7 month‐old girl weighing 7 kg with the use of combined heparin and citrate anticoagulation

Updated information and services can be found at: (517 articles) Gene Therapy Articles on similar topics can be found in the following Blood collections

bone marrow hematopoietic progenitor cells Functional amelioration of murine galactosialidosis by genetically modified

Allogeneic stem cell transplantation (alloHSCT) is the most common and effective form of immunotherapy used for treatment of pediatric leukemias. A combination of graft manipulation, donor selection, fine-tuning of conditioning regimens, and use of lower and novel forms of immunosuppression following transplant has maximized the tolerability of alloHSCT in children. This outcome has facilitated new advances in disease-specific transplant regimens that seek to amplify the antitumor effects of the allograft, while reducing transplant-related mortality. However, disease relapse remains the preeminent challenge to the success of transplantation as a modality for successful treatment of high-risk disease. Separating graft versus host disease (GVHD) from graft versus leukemia (GVL) remains the most significant obstacle to enhancing disease-free survival. However, with increased clarity and discrimination in the effector mechanisms responsible for GVHD and/or GVL in patients of all ages, a new wave of clinical trials has become feasible that harnesses GVL effects to treat patients with high-risk myeloid and lymphoid malignancies. Exciting progress is being made in the use of alloHSCT with donor lymphocyte infusions (DLIs) in almost all forms of pediatric hematologic malignancies. This advance sets the stage for the use of HSCT and/or DLI in conjunction with novel disease-specific post-transplant therapies using small molecule therapeutics, tumor vaccines, and novel antibody therapies.

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting

Stem cell transplant as an immunomodulatory tool for children with hematologic malignancies.

Identification and characterization of crucial gene target(s) that will allow focused therapeutics development remains a challenge. We have interrogated the putative therapeutic targets associated with the transcription factor Grainy head-like 2 (GRHL2), a critical epithelial regulatory factor. We demonstrate the possibility to define the molecular functions of critical genes in terms of their personalized expression profiles, allowing appropriate functional conclusions to be derived. A novel methodology, relative expression analysis with gene-set pairs (RXA-GSP), is designed to explore the potential clinical utility of cancer-biology discovery. Observing that Grhl2-overexpression leads to increased metastatic potential in vitro, we established a model assuming Grhl2-induced or -inhibited genes confer poor or favorable prognosis respectively for cancer metastasis. Training on public gene expression profiles of 995 breast cancer patients, this method prioritized one gene-set pair (GRHL2, CDH2, FN1, CITED2, MKI67 versus CTNNB1 and CTNNA3) from all 2717 possible gene-set pairs (GSPs). The identified GSP significantly dichotomized 295 independent patients for metastasis-free survival (log-rank tested p = 0.002; severe empirical p = 0.035). It also showed evidence of clinical prognostication in another independent 388 patients collected from three studies (log-rank tested p = 3.3e–6). This GSP is independent of most traditional prognostic indicators, and is only significantly associated with the histological grade of breast cancer (p = 0.0017), a GRHL2-associated clinical character (p = 6.8e–6, Spearman correlation), suggesting that this GSP is reflective of GRHL2-mediated events. Furthermore, a literature review indicates the therapeutic potential of the identified genes. This research demonstrates a novel strategy to integrate both biological experiments and clinical gene expression profiles for extracting and elucidating the genomic impact of a novel factor, GRHL2, and its associated gene-sets on the breast cancer prognosis. Importantly, the RXA-GSP method helps to individualize breast cancer treatment. It also has the potential to contribute considerably to basic biological investigation, clinical tools, and potential therapeutic targets.

Bridging Cancer Biology with the Clinic: Relative Expression of a GRHL2-Mediated Gene-Set Pair Predicts Breast Cancer Metastasis

recruitment to the promoter NF-E4 protein is associated with loss of NF-E2 and RNA polymerase II -globin gene expression by a short isoform of the γ Repression of human

and hemoglobinization in cell lines derived from EKLF null mice Erythroid Kruppel-like factor (EKLF) coordinates erythroid cell proliferation

CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia Megan E. McNerney,1,2 Christopher D. Brown,1,3 Xiaoyue Wang,1,3 Elizabeth T. Bartom,4 Subhradip Karmakar,1 Chaitanya Bandlamudi,1,5 Shan Yu,1,5 Jinkyung Ko,6 Barry P. Sandall,6 Thomas Stricker,7 John Anastasi,2 Robert L. Grossman,1,4 John M. Cunningham,6 Michelle M. Le Beau,1,8 and Kevin P. White1,3,9

CUX 1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia

mediated gene transfer into repopulating hematopoietic cells - Wiskott-Aldrich syndrome are corrected by oncoretroviral vector mediated immunity to influenza virus in murine -

-globin regulatory genes that are differentially expressed in OSI-2040-induced and uninduced cells inthe human erythroleukemia cell line K562. Representational difference analysis (RDA) of cDNA revealed sev-eral genes that were signiﬁcantly up- or down-regulated in OSI-2040-induced cells. One gene whose expressionwas markedly enhanced was the gene for the helix-loop-helix (HLH) transcription factor Id2. Southern analysisof RDA amplicons demonstrated progressive enrichment of Id2 with each successive subtraction of uninducedcDNA from induced cDNA. Northern analysis of OSI-2040-induced K562 cells conﬁrmed that Id2 expressionwas directly up-regulated coordinately with

Globin with a Fungal Compound γ Analysis of K562 Cells Induced To Express Protein by Representational Difference Identification of Id2 as a Globin Regulatory

Effects of Late Gestational High Fat Diet on Body Weight, Metabolic Regulation and Adipokine Expression in Offspring

Defects in insulin secretion and reduction in β-cell mass are associated with type 2 diabetes in humans, and understanding the basis for these dysfunctions may reveal strategies for diabetes therapy. In this study, we show that pancreas-specific knockout of growth factor receptor–binding protein 10 (Grb10), which is highly expressed in pancreas and islets, leads to elevated insulin/IGF-1 signaling in islets, enhanced β-cell mass and insulin content, and increased insulin secretion in mice. Pancreas-specific disruption of Grb10 expression also improved glucose tolerance in mice fed with a high-fat diet and protected mice from streptozotocin-induced β-cell apoptosis and body weight loss. Our study has identified Grb10 as an important regulator of β-cell proliferation and demonstrated that reducing the expression level of Grb10 could provide a novel means to increase β-cell mass and reduce β-cell apoptosis. This is critical for effective therapeutic treatment of both type 1 and 2 diabetes.

Disruption of Growth Factor Receptor–Binding Protein 10 in the Pancreas Enhances β-Cell Proliferation and Protects Mice From Streptozotocin-Induced β-Cell Apoptosis

The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun

Krüppel-like factor 1(KLF1) is a hematopoietic-specific zinc finger transcription factor essential for erythroid gene expression. In concert with the transacting factor GATA1, KLF1 modulates the coordinate expression of the genes encoding the multi-enzyme heme biosynthetic pathway during erythroid differentiation. To explore the mechanisms underpinning KLF1 action at the gene loci regulating the first 3 steps in this process, we have exploited the K1-ERp erythroid cell line, in which KLF1 translocates rapidly to the nucleus in response to treatment with 4-OH-Tamoxifen (4-OHT). KLF1 acts as a differentiation-independent transcriptional co-regulator of delta-aminolevulinic acid dehydratase (Alad), but not 5-aminolevulinate synthase gene (Alas2) or porphobilinogen deaminase (Pbgd). Similar to its role at the β-globin promoter, KLF1 induces factor recruitment and chromatin changes at the Alad1b promoter in a temporally-specific manner. In contrast to these changes, we observed a distinct mechanism of histone eviction at the Alad1b promoter. Furthermore, KLF1-dependent events were not modulated by GATA1 factor promoter co-occupancy alone. These results not only enhance our understanding of erythroid-specific modulation of heme biosynthetic regulation by KLF1, but provide a model that will facilitate the elucidation of novel KLF1-dependent events at erythroid gene loci that are independent of GATA1 activity.

Regulation of Delta-Aminolevulinic Acid Dehydratase by Krüppel-Like Factor 1

ABSTRACT In addition to cancer surveillance, p19Arf plays an essential role in blocking signals stemming from platelet-derived growth factor receptor β (Pdgfrβ) during eye development, but the underlying mechanisms have not been clear. We now show that without Arf, pericyte hyperplasia in the eye results from enhanced Pdgfrβ-dependent proliferation from embryonic day 13.5 (E13.5) of mouse development. Loss of Arf in the eye increases Pdgfrβ expression. In cultured fibroblasts and pericyte-like cells, ectopic p19Arf represses and Arf knockdown enhances the expression of Pdgfrβ mRNA and protein. Ectopic Arf also represses primary Pdgfrβ transcripts and a plasmid driven by a minimal promoter, including one missing the CCAAT element required for high-level expression. p19Arf uses both p53-dependent and -independent mechanisms to control Pdgfrβ. In vivo, without p53, Pdgfrβ mRNA is elevated and eye development abnormalities resemble the Arf −/− phenotype. However, effects of p53 on Pdgfrβ mRNA do not appear to be due to direct p53 or RNA polymerase II recruitment to the promoter. Although p19Arf controls Pdgfrβ mRNA in a p53-dependent manner, it also blunts Pdgfrβ protein expression by blocking new protein synthesis in the absence of p53. Thus, our findings demonstrate a novel capacity for p19Arf to control Pdgfrβ expression by p53-dependent and -independent mechanisms involving RNA transcription and protein synthesis, respectively, to promote the vascular remodeling needed for normal vision.

p19Arf Represses Platelet-Derived Growth Factor Receptor β by Transcriptional and Posttranscriptional Mechanisms

Traditionally, new scientific advances have been applied quickly to the leukemias based on the ease with which relatively pure samples of malignant cells can be obtained. Currently, our arsenal of approaches used to characterize an individual's acute myeloid leukemia (AML) combines hematopathologic evaluation, flow cytometry, cytogenetic analysis, and molecular studies focused on a few key genes. The advent of high-throughput methods capable of full-genome evaluation presents new options for a revolutionary change in the way we diagnose, characterize, and treat AML. Next-generation DNA sequencing techniques allow full sequencing of a cancer genome or transcriptome, with the hope that this will be affordable for routine clinical care within the decade. Microarray-based testing will define gene and miRNA expression, DNA methylation patterns, chromosomal imbalances, and predisposition to disease and chemosensitivity. The vision for the future entails an integrated and automated approach to these analyses, bringing the possibility of formulating an individualized treatment plan within days of a patient's initial presentation. With these expectations comes the hope that such an approach will lead to decreased toxicities and prolonged survival for patients.

An integrated genomic approach to the assessment and treatment of acute myeloid leukemia.

6525 Background: Transplantation of CD34+ stem cells from a haploidentical family member plus a cord blood (UCB) unit is a promising approach for patients (pts) who lack HLA donors that facilitates early engraftment while preserving long-term cord blood reconstitution.

METHODS
We prospectively investigated this approach in combination with reduced intensity conditioning consisting of fludarabine, melphalan and ATG in 39 patients with high-risk hematological malignancies from January 29, 2007 to November 12, 2010. Median age was 48 yrs (20-69); 24 (62%) had active disease at transplant. 12 pts belonged to ethnic minorities.

RESULTS
The median haploidentical donor CD34+ dose was 3.08 x 106/kg (1.0-11); CD3+ cells were 0.8 x 104/kg (0.03-2.4). Median UCB nucleated cell dose was 1.55 x 107/kg (range, 0.86-5.23); CD34+ cells were 0.06 x 106/kg (0.02-0.75). 37 (95%) pts had neutrophil recovery with a median time to ANC >500/mL of 11 days (9-43). 27 (69%) pts became platelet transfusion independent at median time of 19.5 days (10-132). In the majority of pts, early haploidentical engraftment was replaced by durable engraftment of UCB by 100 days. However, 5 pts had persistent haploidentical only chimerism, while 4 pts had delayed engraftment with only UCB. Acute GVHD grade II-IV occurred in 10 pts (26%) with only 2 Grade III GVHD (5%). Day 100 mortality rate was 21%. With a median follow up for survivors of 298 days (89-1133), 19 pts (49%) are currently alive. 8 pts died from disease relapse, 4 from infection, and 3 from graft failure. For the entire cohort 1 yr OS was 47% and PFS 38%. For pts in CR at SCT 1 yr PFS was 63% and OS 70%. For pts with active disease at SCT 1 yr OS and PFS were 37%.

Combined haploidentical donor and UCB transplantation in the large majority of patients results in rapid neutrophil engraftment due to the haplo-identical progenitor cells. Durable engraftment is provided by the UCB graft with a low rate of GVHD and excellent long term disease control, even in patients with active disease at transplant.

Reduced intensity conditioning with combined haploidentical and cord blood transplantation results in rapid engrafment and durable remissions.

Abstract 2094 Kruppel-like factor 1 (KLF1) is a zinc finger-encoding transcription factor that recognizes CACC elements, and is essential for maximal erythroid-specific gene transcription. Several critical mechanisms dependent on KLF1 and required for gene activation have been elucidated, predominantly using the beta-globin locus. KLF1 has been associated with the ordered recruitment of SWI/SNF and RNA polymerase-II complexes, necessary for chromatin remodeling and gene transcription respectively. KLF1 has also been reported to influence erythroid-specific heme biosynthesis. Studies in KLF1-null fetal erythroblasts and a KLF-1 deficient cell line have demonstrated that mRNA levels of the first three enzymes of the biosynthetic pathway are underrepresented. However, although in vitro studies of the rate-limiting enzymes ALAS2 and PBGD suggested a potential regulatory role for KLF1, in vivo studies failed to validate these findings. ALAD is the second enzyme of the pathway. Complete loss of ALAD expression in erythroid cells results in catastrophic events during zebrafish ontogeny. Interestingly, no human erythropoietic defect has been reported as a consequence of aberrant ALAD expression. To extend the analysis of KLF19s regulation of heme biosynthesis, we evaluated KLF1 binding of enzyme regulatory sequences by EMSA and ChIP studies, identifying a KLF1 binding CACC element in the erythroid-specific ALAD promoter. This regulatory element was transactivated specifically by a KLF1 transgene in KLF1-deficient cells. Using a unique 4-OH-Tamoxifen (4-OHT) mediated KLF1-inducible erythroid cell line (K1-ERp), we identified KLF1 as an essential, and early (within 2 hours of induction) activator of transcription of the endogenous ALAD, but not ALAS2 or PBGD genes. Further studies in K1-ERp cells, including DNAseI hypersensitivity and ChIP assays revealed that KLF1 occupancy at the erythroid-specific ALAD promoter triggers a series of molecular events including histone modifications, and enhanced recruitment of the sequence-specific transcription factors, GATA-1, NF-E2 and the TAL-1/SCL multiprotein complex. Importantly, we identified differences in the kinetics of recruitment of the closely related histone acetyltransferases proteins CBP and p300 and the SWI/SNF ATPase Brg1. The latter complex was recruited subsequent to KLF1 binding, although the ALAD promoter was already DNAseI hypersensitive. These results suggest strongly that KLF1 plays a major role in the regulation of heme biosynthesis in erythroid cells. Furthermore, our data challenges a model in which an identical temporal cascade of molecular events are required for transcription at KLF1-dependent promoters. Disclosures: No relevant conflicts of interest to declare.

KLF1 Modulates Delta-Aminolevulinic Acid Dehydratase (ALAD) Gene Transcription in a Context-Specific Manner

PDK 1 During Tumorigenesis and Cardiac Hypertrophy The Deacetylase SIRT 1 Promotes Membrane Localization and Activation of `

Hemophilia B, an X-linked disorder, is ideally suited for gene therapy. We investigated the use of a new gene therapy in patients with the disorder.

METHODS
We infused a single dose of a serotype-8-pseudotyped, self-complementary adenovirus-associated virus (AAV) vector expressing a codon-optimized human factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco) in a peripheral vein in six patients with severe hemophilia B (FIX activity, <1% of normal values). Study participants were enrolled sequentially in one of three cohorts (given a high, intermediate, or low dose of vector), with two participants in each group. Vector was administered without immunosuppressive therapy, and participants were followed for 6 to 16 months.

RESULTS
AAV-mediated expression of FIX at 2 to 11% of normal levels was observed in all participants. Four of the six discontinued FIX prophylaxis and remained free of spontaneous hemorrhage; in the other two, the interval between prophylactic injections was increased. Of the two participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid-specific T cells in the peripheral blood; the other had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these two participants received a short course of glucocorticoid therapy, which rapidly normalized aminotransferase levels and maintained FIX levels in the range of 3 to 11% of normal values.

Peripheral-vein infusion of scAAV2/8-LP1-hFIXco resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects. Although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression. (Funded by the Medical Research Council and others; ClinicalTrials.gov number, NCT00979238.).

Adenovirus-associated virus vector-mediated gene transfer in hemophilia B.

We conducted a 45 patient prospective study of reduced-intensity conditioning (RIC) and transplantation of unrelated umbilical cord blood (UCB) and CD34(+) stem cells from a haploidentical family member. Median age was 50 years; weight was 80 kg. Fifty-eight percent had active disease. Neutrophil engraftment occurred at 11 days (interquartile range [IQR], 9-15) and platelet engraftment at 19 days (IQR, 15-33). In the majority of patients, early haploidentical engraftment was replaced by durable engraftment of UCB by 100 days, with regular persistence of minor host and/or haplo-hematopoiesis. Percentage of haplochimerism at day 100 correlated with the haplo-CD34 dose (P = .003). Cumulative incidence of acute GVHD (aGVHD) was 25% and chronic GVHD (cGVHD) was 5%. Actuarial survival at 1 year was 55%, progression-free survival (PFS) was 42%, nonrelapse mortality (NRM) was 28%, and relapse was 30%. RIC and haplo-cord transplantation results in fast engraftment of neutrophils and platelets, low incidences of aGVHD and cGVHD, low frequency of delayed opportunistic infections, reduced transfusion requirements, shortened length of hospital stay, and promising long-term outcomes. UCB cell dose had no impact on time to hematopoietic recovery. Therefore, UCB selection can prioritize matching, and better matched donors can be identified rapidly for most patients. This study is registered at http://clinicaltrials.gov as NCI clinical trial no. NCT00943800.

Reduced-intensity conditioning with combined haploidentical and cord blood transplantation results in rapid engraftment, low GVHD, and durable remissions.

Deacetylation of Akt and its activating kinase PDK1 promotes cell growth in physiological and pathological settings. Deacetylation for Activation Cell growth can be physiological (such as when heart cells expand in size in response to exercise, a process called cardiac hypertrophy) or pathological (such as in cancer) and is promoted by the kinase Akt. Sundaresan et al. showed that acetylation blocked the activity of Akt and its activating kinase PDK1 by interfering with the lipid-binding sites of these proteins, whereas deacetylation enhanced their activities. Mice injected with cells containing a mutant Akt that mimicked acetylated Akt formed smaller tumors, and the extent of cardiac hypertrophy was decreased in mice that lacked SIRT1, the protein that deacetylated Akt. These results provide insight into understanding the mechanisms that regulate the activity of Akt and may enable the development of new ways to promote or inhibit cell growth. Signaling through the kinase Akt regulates many biological functions. Akt is activated during growth factor stimulation through a process that requires binding of Akt to phosphatidylinositol 3,4,5-trisphosphate (PIP3), which promotes membrane localization and phosphorylation of Akt by the upstream kinase PDK1 (phosphoinositide-dependent protein kinase 1). We show that Akt and PDK1 are acetylated at lysine residues in their pleckstrin homology domains, which mediate PIP3 binding. Acetylation blocked binding of Akt and PDK1 to PIP3, thereby preventing membrane localization and phosphorylation of Akt. Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP3 and promoted their activation. Mice injected with cells expressing a mutant that mimicked a constitutively acetylated form of Akt developed smaller tumors than those injected with cells expressing wild-type Akt. Furthermore, impaired Akt activation in the hearts of SIRT1-deficient mice was associated with reduced cardiac hypertrophy in response to physical exercise and angiotensin II. These findings uncover a key posttranslational modification of Akt that is important for its oncogenic and hypertrophic activities.

The Deacetylase SIRT1 Promotes Membrane Localization and Activation of Akt and PDK1 During Tumorigenesis and Cardiac Hypertrophy

Abstract 3189 Binding of the Kruppel-like Factor 1 (KLF1) to the β-globin gene promoter is required for developmental stage-specific chromatin remodeling and transcriptional initiation. Interaction with a long-range enhancer, the Locus Control Region (LCR) is also required for maximal gene expression. KLF1 binds the LCR, and has been described recently as a facilitator of the proximal clustering of the LCR with the β-globin gene promoter region. To elucidate the role(s) of KLF1 at the LCR and their relationship to β-globin gene activation, we evaluated KLF1-directed events across the β-globin locus using a 4-OH-Tamoxifen KLF-1 inducible erythroid cell line. KLF1 binding was maximal 1 hour post-induction at the LCR, whereas 2 hours elapsed prior to maximal occupancy at the β-globin promoter. The site-specific differential in factor occupancy is consistent with the notion that the LCR serves as a nucleating docking element for sequence-specific transcription factors as well as the RNA Pol-II complex. LCR occupancy by Pol-II, p45 NF-E2, GATA-1 and the SCL/LMO2/Ldb1 complex was KLF1-independent. In contrast, the occupancy of the β-globin promoter by Pol-II and erythroid-restricted factors was dependent on maximal KLF-1 binding. Interestingly, the SCL/LMO2/Ldb1 complex was recruited first, consistent with the idea that this complex is required for LCR/promoter interaction. Interestingly, we have identified a direct protein-protein interaction between the carboxy terminal (aa221–396) domain of KLF1 (Δ221KLF1) and Ldb1, the factor implicated as critical for distal regulatory loci interactions at the β-globin locus. To dissect these events in vivo , we took advantage of a novel KLF1 knock-in strain (Δ221KLF1). In these animals, the endogenous KLF1 gene is replaced with a carboxy-terminal domain (aa221–396) expression cassette, resulting in DNA binding of the mutant factor, with β-globin chromatin remodeling. However, Δ221KLF1 fetal liver erythroblasts fail to activate the KLF1-dependent gene network, and have the identical differentiation defect characteristic of KLF1-null erythroblasts. Chromatin remodeling at the β-globin failed to result in recruitment of GATA-1, NF-E2, or the SCL/LMO2/Ldb1 complex. In contrast, ChIP analyses of the LCR in Δ221KLF1 erythroblasts revealed rescue of RNA Pol-II, GATA-1 and the SCL/LMO2/Ldb1 complex occupancy to wild type levels. Structural studies, utilizing the chromosome conformation capture (3C) assay, revealed that an incomplete re-configuration of the locus in Δ221 KLF1 mice. In conclusion, the chromatin remodeling domain of KLF1 is sufficient to reconfigure the LCR. However, KLF1-dependent Ldb1 recruitment at the LCR is insufficient to promote adequate communication between the two regulatory elements of the β-globin gene. Preliminary data suggest that an adjacent domain (aa163–221) is sufficient to rescue β-globin transcription in vivo . Together, these domains (aa163–396) are sufficient to promote the appropriate loading of transcription factors at the β-globin promoter in conjunction with locus structural re-configuration. Disclosures: No relevant conflicts of interest to declare.

Differing Domain-Specific Roles of KLF1 At the LCR and β-Globin Promoter.,

Abstract 13016: SIRT6 Plays an Essential Role in Regulating IGF Signaling and Aging Associated Cardiac Failure

Abstract 5 Background: Hemophilia B (HB), an X-linked bleeding disorder, is ideally suited for gene therapy. We investigated a novel approach using peripheral vein infusion of a single dose of a serotype-8 pseudotyped self-complementary adeno-associated virus (AAV) vector expressing a codon-optimized coagulation factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco). Methods: Six severe HB subjects (FIX ≤1%) were enrolled sequentially into one of three dose cohorts with two subjects in each group. Vector was administered without immunosuppression. The subjects were followed for 6–16 months post treatment. Results: AAV-mediated expression of FIX at 2–11% of normal was observed in all subjects. Four of the six have discontinued prophylaxis and remain free of spontaneous hemorrhage. The other two have increased the interval between FIX prophylaxes. A high-dose subject developed asymptomatic, transient elevation of serum transaminases associated with detection of AAV8 capsid specific T cells in peripheral blood. The second high-dose subject experienced a slight increase of liver enzymes, of less clear etiology. Treatment of each with a short course of steroids led to rapid normalization of the transaminases and maintenance of FIX levels in the 3–11% range. Conclusion: Peripheral vein administration of scAAV2/8-LP1-hFIXco was well tolerated and resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype. Immune-mediated clearance of AAV-transduced hepatocytes remains a concern but our data suggest that this process may be controlled with a short course of steroids without loss of transgene expression. Hence, our novel approach shows promise for gene therapy of HB and other protein deficiencies. (ClinicalTrials.gov number, NCT00979238) Disclosures: Nathwani:Amsterdam Molecular Therapeutics: Patents & Royalties. Gray:Amsterdam Molecular Therapeutics: Patents & Royalties. Davidoff:Amsterdam Molecular Therapeutics: Patents & Royalties.

Adeno-Associated Viral Vector Mediated Gene Transfer for Hemophilia B

Abstract 830 Haplo-cord transplant, the co-infusion of CD34+ stem cells from a haploidentical (haplo) family member with a cord blood (UCB) unit has been proposed as a method to reduce duration of pancytopenia after UCB SCT. We prospectively investigated reduced intensity conditioning (RIC) of fludarabine, melphalan and rATG followed by haplo-cord SCT in 45 patients with high-risk hematological malignancies. Thirteen patients (29%) belonged to ethnic or racial minorities, and almost half had AML. Median age was 50; weight 80 kg and twenty six (58%) had active disease at the time of transplant. The median CD34+ cell content post-selection of the haplo graft was 3.5 ×10 6 /kg (25%–75% inter quartile range (IQR) 1.36–4.63). Minimal required UCB cell dose was 1×10 7 nucleated cells/kg. Median infused UCB total nucleated cell was 1.55×10 7 (range 1.24 to 2.09). 36 pts (80%) had at least a 5/6 matched UCB. The cumulative incidence of neutrophil recovery at day +50 was 95% (95% CI, 87–100%) with a median time to engraftment of 11 days (IQR 9 –15 days). The cumulative incidence of platelet recovery at day +100 was 83% (95% CI, 69–97%) with median time to platelet engraftment of 19 days (IQR 15–33 days). Patients received a median number of 12 platelet transfusions (IQR 6–22) and 7 red blood cell units (IQR 4–12) after the transplant. The median number of day of hospitalization during the first 100 days after transplant was 26 days (IQR 15–43 days). In the majority of patients, early haploidentical engraftment was replaced by durable engraftment of UCB cells by 100 days. The median percentage of haploidentical cells in unfractionated peripheral blood was 86% on day 30, but declined to 22% by day 100, and to 2% by day 180. Conversely, the median percentage of cells of UCB origin increased from 10% by day 30, to 78% by day 100, and to 95% by day 180. There was also some re-emergence of host hematopoiesis over time. The percentage of day 100 haplo donor chimerism correlated closely with the CD34+ cell content of the haplo-identical graft (10 6 /kg) (r=0.6225; P=0.0003). TNC, CD34+ cells, or CD3+ cells of the UCB did not correlate with cord donor chimerism. The cumulative incidence of acute GVHD (Grade II -IV) was 25% (95% CI 11–39). There were only two patients with chronic GVHD for a cumulative incidence of 6% at 1 year. Cumulative incidence of treatment related mortality was 9% (95% CI 1–17) at day 100 and 28% (95% CI 13–43) at one year. Cumulative incidence of disease recurrence was 11% (95% CI 3–19) at day 100 and 30% (95% CI 14–44) at one year. With a median follow up for survivors of 330 days (range 64–1259), estimated one year survival was 55% (95% CI 39–71) and progression free survival was 42% (95% CI 25–79). Active disease at the time of haplo-cord SCT tended to impair PFS, but this difference did not reach statistical significance (P=0.06). The cumulative incidence of CMV viremia was 42% (95% CI 26–58), but there were only four cases of CMV disease. The cumulative incidence of EBV viremia was 42% (95% CI 26–58%), but most cases were self limited or transient. Five patients developed biopsy or radiological proven PTLD, for a cumulative incidence of 11% (95% CI 0–22). RIC and haplo-cord transplant results in fast engraftment of neutrophils and platelets, low incidences of acute and chronic GVHD, low frequency of delayed opportunistic infections, reduced transfusion requirements, shortened length of hospital stay and promising long term outcomes. UCB cell dose has no impact on time to hematopoietic recovery and UCB selection can prioritize matching, and better matched donors can be identified rapidly for most patients. Disclosures: Off Label Use: Velcade in T-cell and aggressive non-MCL B-cell NHL.

Reduced Intensity Conditioning with Combined Haploidentical and Cord Blood Transplantation Results in Rapid Engraftment and Durable Remissions in Hematological Malignancies

We have investigated how the Arf gene product, p19Arf, is activated by Tgfβ during mouse embryo development to better understand how this important tumor suppressor is controlled. Taking advantage of new mouse models, we provide genetic evidence that Arf lies downstream of Tgfβ signaling in cells arising from the Wnt1-expressing neural crest and that the anti-proliferative effects of Tgfβ depend on Arf in vivo. Tgfβ1, -2, and -3 (but not BMP-2, another member of the Tgfβ superfamily) induce p19Arf expression in wild type mouse embryo fibroblasts (MEFs), and they enhance Arf promoter activity in ArflacZ/lacZ MEFs. Application of chemical inhibitors of Smad-dependent and -independent pathways show that SB431542, a Tgfβ type I receptor (TβrI) inhibitor, and SB203580, a p38 MAPK inhibitor, impede Tgfβ2 induction of Arf. Genetic studies confirm the findings; transient knockdown of Smad2, Smad3, or p38 MAPK blunt Tgfβ2 effects, as does Cre recombinase treatment of Tgfbr2fl/fl MEFs to delete Tgfβ receptor II. Chromatin immunoprecipitation reveals that Tgfβ rapidly induces Smads 2/3 binding and histone H3 acetylation at genomic DNA proximal to Arf exon 1β. This is followed by increased RNA polymerase II binding and progressively increased Arf primary and mature transcripts from 24 through 72 h, indicating that increased transcription contributes to p19Arf increase. Last, Arf induction by oncogenic Ras depends on p38 MAPK but is independent of TβrI activation of Smad 2. These findings add to our understanding of how developmental and tumorigenic signals control Arf expression in vivo and in cultured MEFs.

Tgfβ Signaling Directly Induces Arf Promoter Remodeling by a Mechanism Involving Smads 2/3 and p38 MAPK*

Erratum to Epidermal Wound Repair Is Regulated by the Planar Cell Polarity Signaling Pathway [Developmental Cell, 19, 138-147, (2010)]

Epidermal wound repair is regulated by the planar cell polarity signaling pathway.

Regional neural tube closure defined by the Grainy head-like transcription factors.

Abstract 3378 Poster Board III-266 Introduction: Haploidentical-cord blood transplantation is a promising approach for patients (pts) who lack HLA donors and may improve rates of early engraftment while allowing long term cord blood reconstitution with low rates of GVHD. We enrolled 29 pts (17 AML/MDS, 4 ALL, 3 CML, 4 NHL/HL, 1 severe aplastic anemia) lacking HLA identical donors. The median age was 40 years (range, 4-67), and median weight was 75 kg (range, 14-125). Twenty-two (76%) pts had active disease at time of transplant; 6 had prior autologous transplants. 14 pts were Caucasian; 15 were other race or ethnicity. The haploidentical donor was the mother in 4; father in 3; child in 10; sibling in 10; and half-sibling in 2 cases. The median haploidentical CD34+ dose was 2.51 × 10 6 /kg (range, 1.25-10.95); CD3+ cells were 1.0 × 10 4 /kg (range, 0.3-3.7). Single unrelated CB units were matched by low resolution at HLA-A and B and high-resolution at DRB1, and matched 6/6 in 2 pts; 5/6 in 18 pts; 4/6 in 9 pts. Median cord total nucleated cells equaled 1.93 × 10 7 /kg (range, 1.07-9.36); CD34+ cells were 0.08 × 10 6 /kg (range, 0.03-0.75). The conditioning regimen for 18 pts was fludarabine (Flu) (30 mg/m 2 on d-7 through -3), melphalan (Mel) (70 mg/m 2 on d -3 and -2), and Thymoglobulin (rATG) (1.5 mg/kg on d-7, -5, -3, -1). Eleven pts received Flu, thiotepa (5 mg/kg on d -7 and -6), total-body irradiation (TBI) (12 Gy lateral opposed fields in 2 Gy fractions BID on d-3 through -1), and rATG. GVHD prophylaxis consisted of tacrolimus (Tac) + methylprednisolone or Tac + mycophenolate. Engraftment: Two pts died early (sepsis, CVA). Three other pts failed to engraft with either haploidentical or CB and died of infection on d36, 43, and 63. One of these had anti-donor HLA antibodies. 24 pts engrafted with a median time to ANC >500/mL of 10 days (range, 9-31) and median time to sustained platelets >20,000/mL of 20 days (range, 15-63). In the majority of pts, early haploidentical engraftment was replaced by durable engraftment of CB by 100 days. However, 3 pts had persistent hematopoiesis associated with only the haploidentical donor, while a fourth pt engrafted with only CB on day 31. Late graft failure and death from sepsis occurred in one of the patients with haploidentical engraftment. In unfractionated peripheral blood or bone marrow cells, median haploidentical chimerism was 95% (range, 0-100) on d14; 76% (range, 0-95) on d30; 6% (range, 0-87) on d100. Median unfractionated cord chimerism was haploidentical chimerism was 95% (range, 0-100) on d14; 86% (range, 0-95) on d30; 6% (range, 0-79) on d100. Median CD3+ cord chimerism was 5% (range, 0-100) on d14; 26% (range, 0-100) on d30; 90% (range, 1-100) on d100 . Toxicities and outcome : Other fatal toxicities included VOD (1), EBV-associated PTLD (1), ARDS (1), cardiac arrest (1), intractable seizures (1). Two patients developed TTP and later died of complications related to sepsis. Five pts relapsed of whom 4 have died. Acute GVHD (aGVHD) grade II occurred in 3 pts, one of whom developed the only case of chronic GVHD after failing to continue prograf. No aGVHD grade III-IV was seen. Twelve pts are currently alive; 11 are without disease. The median follow up for survivors is 186 days (range, 16-642). Estimated one year survival is 26% (95%CI, 6-46), and PFS is 19% (1-36). Conclusions: Combined haploidentical and CB transplantation results in early haploidentical engraftment followed by durable CB predominance in a majority of pts. The median times to neutrophil engraftment are considerably shorter - and the range narrower - than with other methods of cord blood transplantation. Early haploidentical engraftment failed in four patients; cord blood engraftment also failed in three of these pts and in three others. Rates of acute and particularly of chronic GVHD are low. Durable remissions can be achieved even in high risk pts regardless of age or remission status at the time of transplant. Disclosures: Rich: Genzyme: Research Funding. Odenike: Genzyme: Honoraria, Membership on an entity9s Board of Directors or advisory committees. van Besien: Genzyme: Research Funding.

Allogeneic Hematopoietic Cell Transplantation From Combined Haploidentical Family Members and Unrelated Cord Blood (CB) Can Benefit High Risk Patients Lacking HLA-Identical Donors.

The Arf tumor suppressor (also known as Cdkn2a) acts as an oncogene sensor induced by `abnormal' mitogenic signals in incipient cancer cells. It also plays a crucial role in embryonic development: newborn mice lacking Arf are blind due to a pathological process resembling severe persistent hyperplastic primary vitreous (PHPV), a human eye disease. The cell-intrinsic mechanism implied in the oncogene sensor model seems unlikely to explain Arf regulation during embryo development. Instead, transforming growth factor β2 (Tgfβ2) might control Arf expression, as we show that mice lacking Tgfβ2 have primary vitreous hyperplasia similar to Arf-/- mice. Consistent with a potential linear pathway, Tgfβ2 induces Arf transcription and p19Arf expression in cultured mouse embryo fibroblasts (MEFs); and Tgfβ2-dependent cell cycle arrest in MEFs is maintained in an Arf-dependent manner. Using a new model in which Arf expression can be tracked by β-galactosidase activity in ArflacZ/+ mice, we show that Tgfβ2 is required for Arf transcription in the developing vitreous as well as in the cornea and the umbilical arteries, two previously unrecognized sites of Arf expression. Chemical and genetic strategies show that Arf promoter induction depends on Tgfβ receptor activation of Smad proteins; the induction correlates with Smad2 phosphorylation in MEFs and Arf-expressing cells in vivo. Chromatin immunoprecipitation shows that Smads bind to genomic DNA proximal to Arf exon 1β. In summary, Tgfβ2 and p19Arf act in a linear pathway during embryonic development. We present the first evidence that p19Arf expression can be coupled to extracellular cues in normal cells and suggest a new mechanism for Arf control in tumor cells.

Expression of the Arf tumor suppressor gene is controlled by Tgfβ2 during development

PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing

Abstract 461 Kruppel-like factor 1 (KLF1) is essential for erythroid gene expression. Key molecular mechanisms modulated by this transacting factor have been elucidated at the b-globin locus. KLF1 has been associated with recruitment of SWI/SNF and RNA polymerase (PolII) complexes necessary for chromatin remodeling and gene transcription respectively, and for facilitating the apposition of the promoter with the far-upstream locus control region. More recently, KLF1 has been implicated in the regulation of an erythroid-specific gene program unlinked to the b-globin locus. Coordinated expression of these genes, including Alpha Hemoglobin-Stabilizing Protein (AHSP), a factor required for globin tetramer stability, and the red cell membrane protein Dematin, are critical for erythroid ontogeny. To compare the role(s) of KLF1 at these loci, we have used a unique 4-OH-Tamoxifen (4-OHT) inducible erythroid cell line, which facilitates the characterization of the temporal kinetics of KLF1-dependent erythroid gene activation. In preliminary experiments, we observed that KLF1 binding was maximal at the three loci within 60 minutes of 4-OHT induction. AHSP and dematin primary RNA transcripts followed similar kinetics, being maximal at 60-90 minutes post-induction. In contrast, b-globin gene transcription reached a plateau 4-6 hours post-induction. From these observations, we hypothesized that transcriptional activation at AHSP and dematin differs from that observed at the b-globin cluster. Consistent with this hypothesis, we observed significant differences in chromatin remodeling at the three loci. At the b-globin promoter, we observed a small but statistically significant increase in DNaseI sensitivity, a measure of chromatin remodeling, with KLF1 binding. In contrast, we observed a complete loss of DNaseI resistance after KLF1 binding at the AHSP and dematin promoters. Consistent with these findings, we observed a five-fold reduction in histone H3 occupancy at the AHSP and dematin promoters, contrasting with no significant change in occupancy at the b-promoter. Importantly, these differences were not observed in regions 1-5 kb upstream of the promoters. These observations, coupled with similar differences in DNaseI hypersensitivity and histone occupancy in fetal liver erythroblasts from wild type and KLF1-null mice, suggest a profound difference in the mechanisms of chromatin remodeling at KLF1-dependent erythroid gene loci. To explore the potential mechanisms underlying these differences in chromatin accessibility, we examined the kinetics of recruitment of other transacting factors and co-activators to the three loci. We observed similar increases in binding of serine-5 phosphorylated PolII, GATA-1, and p45NF-E2 at the promoters. In contrast, binding of BRG1, the core ATPase component of the SWI/SNF complex differed between the b–promoter and the other erythroid genes. Although BRG1 binding was co-incident with KLF1 binding to the b-gene, we observed significant albeit weak binding of this complex to the AHSP and Dematin promoters only after maximal gene transcription had occurred. Our results suggest that different KLF1 multiprotein complexes are recruited to remodel target gene promoters in vivo. Furthermore, we propose that KLF19s chromatin remodeling capabilities are not limited to the recruitment of the SWI/SNF complexes Disclosures: No relevant conflicts of interest to declare.

Context-Specific KLF-1 Mediated Transcriptional Activation at the Alpha Hemoglobin-Stabilizing Protein and Dematin Promoters in Erythroid Cells.

The unique historical aspects of Pelger and Huet's discovery of the Pelger‐Huet cell highlight the diagnostic challenge that this morphologic finding presents to the physician. Making the diagnosis of the benign autosomal dominant anomaly is complicated by the morphologically similar pseudo‐Pelger‐Huet cell, which can signify underlying myeloid dsyplasia. This article relates the history of the Pelger‐Huet anomaly as well as describes the clinical significance and diagnostic workup for the finding of a Pelger‐Huet cell on peripheral smear. Am. J. Hematol., 2009. © 2008 Wiley‐Liss, Inc.

Historical perspective and clinical implications of the Pelger‐Huet cell

Perturbed desmosomal cadherin expression in grainy head‐like 1‐null mice

The zinc finger-encoding transacting factor EKLF binds key regulatory elements of many erythroid-specific genes, and is essential for definitive erythropoiesis. Mice lacking this factor (EKLF−/−) die of anemia by E15.5 of gestation, failing to activate β-globin gene transcription, and demonstrating a block in the erythroid differentiation program at the primitive erythroblast stage. In contrast, megakaryocytic progenitors are amplified in EKLFnull embryos, with increased Fli-1 gene expression (a marker of early megakaryocytic differentiation), consistent with the idea that EKLF modulates the megakaryocyticerythroid (M-E) differentiation switch. We have demonstrated that an amino terminal mutant of EKLF (Δ221EKLF), is required to induce chromatin remodeling at the β-globin promoter in an EKLF-null erythroid cell line, but additional amino terminal sequences are required for initiation of β-globin gene transcription (Brown et al., 2002). To evaluate the role of this chromatin remodeling (CR) domain in erythroid and megakaryocytic differentiation in vivo , we have generated a knock-in allele of EKLFCR allele. Similar to EKLF-null embryos, mice homozygous for this mutant allele die of anemia by E15.5 of gestation. In contrast to erythroid cells lacking EKLF, EKLFCR/CR progenitors demonstrate

1. appropriate binding of the CR encoding domain to all EKLF-regulatory sequences;

2. a block in erythropoiesis at a more a mature stage in differentiation

3. a chromatin architecture and histone modification pattern at erythroid-specific genes that recapitulates the events observed in EKLF+/+ erythroblasts at a similar stage of erythroid ontogeny;

4. a failure of terminal erythroid gene transcription.

Examining the role of EKLFCR in megakaryopoiesis, we observed

1. inhibition of megakaryocytic progenitor amplification in EKLFCR/CR fetal hematopoietic cell populations when compared to EKLF-null embryos;

2. loss of Fli-1 gene expression in EKLFCR expressing cells;

3. binding of the EKLFCR mutant protein to the Fli-1 promoter with inhibition of gene transcription;

4. a repressed chromatin architecture at megakaryocytic gene loci.

In contrast to these results, mice homozygous for a knockin allele encoding the zinc finger DNA binding domain alone (Δ253EKLF), a region shown previously to be sufficient for chromatin remodeling in vitro , demonstrate erythroid and megakaryocytic phenotypes that resemble those observed in EKLF-null hematopoietic progenitors. Taken together, our results suggest strongly that the unique EKLFCR domain is necessary and sufficient to modulate the chromatin-specific roles of EKLF at erythroid- and megakaryocytic-specific loci in definitive hematopoietic cells in vivo .

Altered Erythroid and Megakaryocytic Differentiation in Mice Expressing a Unique Chromatin Remodeling Domain of Erythroid Krüppel-Like Factor (EKLF)

Background: Many patients (pts), particularly minorities, lack matched unrelated donors. Mismatched cord blood (CB) transplantation causes less graft versus host disease (GVHD), but is associated with delayed hematopoietic recovery. We studied an alternative donor regimen using T-cell depleted haploidentical stem cells and unrelated CB pioneered by Magro et al. (Haematologica2006;91:640–8) to confirm engraftment with acceptable rates of GVHD. Patients and Methods: We enrolled 15 pts (7 AML, 1 ALL, 2 MDS, 1 CML, 3 NHL, 1 severe aplastic anemia) lacking HLA identical donors. The median age was 28 years (range, 4–66) and median weight was 75 kg (range, 14–124). Twelve pts had active disease at transplant; 2 had prior autologous transplants. Eight pts were Caucasian; 7 other race or ethnicity. The haploidentical donor was the mother in 3; father in 1; child in 4; sibling in 5; and half-sibling in 2 cases. The median haploidentical CD34+ dose was 2.41 × 10 6 /kg (range, 1.25–6.26); CD3+ cells were 0.8 × 10 4 /kg (range, 0.3–1.3). Single unrelated CB units were matched by low resolution at HLA-A and B and high-resolution at DRB1, and matched 6/6 in 1 pt; 5/6 in 7 pts; 4/6 in 6 pts; 3/6 in 1 pt. Median cord total nucleated cells equaled 2.39 × 10 7 /kg (range, 1.07–9.36); CD34+ cells were 0.14 × 10 6 /kg (range, 0.04–0.75). The conditioning regimen for most pts was fludarabine (Flu) (30 mg/m 2 × 5 days), thiotepa (5 mg/kg × 2 days), total-body irradiation (TBI) (12 Gy lateral opposed fields), and Thymoglobulin® (rATG) (1.5 mg/kg × 4 days). Five pts unable to tolerate TBI received Flu, melphalan (70 mg/m 2 × 2 days), and rATG. GVHD prophylaxis consisted of tacrolimus (Tac) + methylprednisolone or Tac + mycophenolate. Results: Two pts died early (sepsis, CVA). Twelve of the remaining 13 pts engrafted. One pt failed to engraft and died on day (d)36. Median time to ANC >500/mL was 9 days (range, 9–12). Median time to sustained platelets >20,000/mL was 24 days (range, 12–63). Early haploidentical engraftment was replaced by durable engraftment of CB by 100 days. In unfractionated peripheral blood or bone marrow cells, median haploidentical chimerism was 95% (range, 0–100) on d14; 76% (range, 0–93) on d30; 36% (range, 0–83) on d55; 0% (range, 0–42) on d100; and 0% on d180. Median unfractionated cord chimerism was In the CD3+ compartment, median haploidentical chimerism was 94% (range, 0–100) on d14; 72% (range, 0–93) on d30; 24% (range, 0–76) on d55; 0% (range, 0–39) on d100; and 0% on d180. Median CD3+ cord chimerism was 6% (range, 0–100) on d14; 28% cord (range, 7–100) on d30; 76% (range, 24–100) on d55; 100% (range, 61–100) on d100; and 100% (range, 90–100) on d180. Four pts died of sepsis. One pt died of VOD; 2 pts who also received TBI developed interstitial pneumonitis, 1 fatal. Two pts relapsed and died. Cumulative d100 treatment-related mortality (TRM) was 44% (95% CI: 22 to 73%). Acute skin GVHD grade I–II occurred in 3 pts. No cases of chronic GVHD developed. Five pts are currently alive and in remission with complete CB chimerism. The median follow up for survivors is 207 days (range, 23–283). The median age of survivors is 27 years (range, 20–67). Conclusions: Combined haploidentical and CB transplantation is a promising strategy for those lacking HLA identical donors - even in the presence of low CB doses - leading to early haploidentical engraftment followed by durable CB predominance by d100. Acute and chronic GVHD are manageable. Complications such as interstitial pneumonitis may be related to the TBI-containing regimen. This donor combination, with further modifications to decrease TRM, warrants further study in pts lacking HLA identical donors.

Preliminary Results of Combined Haploidentical-Cord Blood Transplantation for Patients Lacking HLA Identical Donors

A phenotype-driven ENU mutagenesis screen to identify modifiers of γ-globin expression and red blood cell biology

The protein methyltransferase pRMT5 links histone H4 methylation to Dnmt3a-dependent DNA methylation and transcriptional silencing of the fetal globin genes

Although allogeneic hematopoietic progenitor cell transplantation (HPCT) can be curative for sickle cell anemia (SCA), most patients lack an HLA matched sibling donor or matched unrelated donor. A 2002 multidisciplinary conference held at St. Jude Children’s Research Hospital reached consensus that pilot studies using parental donors were reasonable and ethical. Subsequently, eight children with a history of clinically overt stroke were transplanted on two sequential pilot studies. Peripheral blood progenitor cells were obtained from parents with sickle cell trait. Conditioning was i.v. busulfan (targeted to Css 900 ng/ml) q 6 hours x 4 days, fludarabine 150–200 mg/m 2 , and OKT3/methylprednisolone and infusion of CD34 + HPCT for 3 patients. Five patients received i.v. busulfan (targeted to Css 900 ng/ml) x 4 days, cyclophosphamide 200 mg/kg, thiotepa 10 mg/kg, OKT3/methylprednisolone, and infusion of both CD34 + cells and CD3 + cells with a fixed T-cell addback of 1.0–1.5 x 10 5 CD3+ cells/kg. Six children received pre-transplant immunosuppression with hydroxyurea and azathioprine. The median follow-up of eight patients is 1.4 years (range 2 months–4 years). Five of eight had durable donor engraftment,4 of whom are alive and free of SCA post-HPCT. Rejection occurred in 4 patients and was successfully reversed with additional CD34 + cells in one of three patients. GVHD occurred in patients receiving a fixed T-cell addback or DLI: two patients had grade II acute graft-versus-host disease (aGVHD), one grade III aGVHD, and three patients developed chronic GVHD, including a fatal case of bronchiolitis obliterans organizing pneumonia (BOOP) and fungal sepsis. One engrafted patient developed medulloblastoma 2 years post-HPCT and is in remission after treatment. Further investigation revealed that this child inherited a novel germline p53 mutation. In this preliminary experience, haploidentical HPCT for children with SCA and stroke was associated with significant graft rejection and chronic GVHD. The addition of pre-transplant hydroxyurea and azathioprine, increased intensity of conditioning, and the use of T-cell addback to the graft did not improve engraftment in the second cohort. While offering the possibility of cure, haploidentical HPCT for SCA as performed in this experience is associated with significant toxicity and should only be pursued in the context of a rigorously designed and controlled prospective clinical trial.

Hematopoietic Progenitor Cell Transplantation from Parental Donors for Children with Sickle Cell Anemia and Stroke.

Co-ordinate high level expression of the murine α- and β-globin genes is regulated in a context-specific manner by erythroid Krüppel-like factor (EKLF)

The protein methyltransferase PRMT5 links histone H4 methylation to Dnmt3a-dependent DNA methylation and transcriptional silencing

ABSTRACT We observed that binding sites for the ubiquitously expressed transcription factor CP2 were present in regulatory regions of multiple erythroid genes. In these regions, the CP2 binding site was adjacent to a site for the erythroid factor GATA-1. Using three such regulatory regions (from genes encoding the transcription factors GATA-1, EKLF, and p45 NF-E2), we demonstrated the functional importance of the adjacent CP2/GATA-1 sites. In particular, CP2 binds to the GATA-1 HS2 enhancer, generating a ternary complex with GATA-1 and DNA. Mutations in the CP2 consensus greatly impaired HS2 activity in transient transfection assays with K562 cells. Similar results were obtained by transfection of EKLF and p45 NF-E2 mutant constructs. Chromatin immunoprecipitation with K562 cells showed that CP2 binds in vivo to all three regulatory elements and that both GATA-1 and CP2 were present on the same GATA-1 and EKLF regulatory elements. Adjacent CP2/GATA-1 sites may represent a novel module for erythroid expression of a number of genes. Additionally, coimmunoprecipitation and glutathione S-transferase pull-down experiments demonstrated a physical interaction between GATA-1 and CP2. This may contribute to the functional cooperation between these factors and provide an explanation for the important role of ubiquitous CP2 in the regulation of erythroid genes.

Functional Interaction of CP2 with GATA-1 in the Regulation of Erythroid Promoters

Elevated levels of fetal hemoglobin ameliorate the severity of sickle cell disease and β-thalassemia, fuelling interest in the mechanisms underpinning the fetal (γ) to adult (β) switch in β-like globin chain subtype. We have previously identified a tripartite protein complex consisting of p22 NF-E4, CP2 and ALY, collectively known as the stage selector protein (SSP) that binds to the proximal γ-promoters, and fosters the preferential expression of the γ-genes in fetal erythroid cells. We have also identified a 14 kDa isoform of the NF-E4 protein that plays a role in γ-gene repression by binding CP2 and sequestering it away from the γ-promoter, resulting in disassembly of the activator SSP complex. Despite the loss of SSP binding, we showed by chromatin immunoprecipitation (ChIP) analysis that p22 NF-E4 remained bound to the γ-promoter in this context. To determine whether p22 NF-E4 could serve as the cornerstone for assembly of a larger repressor complex in this setting, we analyzed the proteins that were co-immunoprecipitated with p22 NF-E4 from K562 cell extract by mass spectrometry. One protein identified was PRMT5, an arginine methyltransferase that has been linked to gene silencing by establishing repressive arginine methyl marks including symmetrical dimethylation of arginine 3 on histone H4 (H4R3me2s). We confirmed the interaction between the two endogenous proteins by direct co-immunoprecipitation, and co-localized p22 NF-E4 and PRMT5 to the γ-globin gene promoters by ChIP. In vitro methylation studies using PRMT5 co-immunoprecipitated with p22 NF-E4 confirmed that histone H4 was the major substrate of the enzyme complex in K562 cells. In accord with this, we demonstrated a marked increase in H4R3me2s at the γ-promoter by ChIP in the setting of enforced expression of wild type PRMT5, accompanied by silencing of γ-gene expression. To determine whether additional factors cooperated with PRMT5 in γ-gene repression, we interrogated PRMT5 containing immunoprecipitates with antisera to a range of candidate proteins. We isolated a large repressor complex containing members of the NuRD complex and the methyl domain-binding proteins (MBD2 and MDB3). We also isolated the DNA methyltransferase 3a (Dnmt3a), a finding of considerable interest in view of the links between γ-gene silencing and methylation of CpG dinucleotides. Using bisulfite DNA sequencing, we demonstrated in K562 cells in which PRMT5 expression had been enforced, an increase in the density of methylated CpG dinucleotides clustered around the transcriptional start site. In contrast, cells transfected with an expression vector stably expressing hairpin short interfering RNAs, which induced a 90% reduction in PRMT5 protein levels, showed complete abrogation of DNA methylation at these CpGs, coincident with a five-fold induction of γ-gene expression. ChIP analysis of the human β-globin locus in βYAC transgenic mice revealed a marked enhancement of H4R3me2s at the γ-promoters in adult erythropoietic cells, and absence of this repressive mark at the γ-promoter in the E12.5 fetal liver. This data establishes a direct link between the PRMT5-induced repressive histone mark H4R3me2s and DNA methylation in developmental regulation of γ-gene expression. It also provides impetus for new strategies aimed at reactivation of fetal globin gene expression.

The Protein Methyltransferase Prmt5 Links Histone H4 Methylation to Dnmt3a-Dependent DNA Methylation and Transcriptional Silencing of the Fetal Globin Genes.

Binding of the stage selector protein (SSP) to the stage selector element (SSE) in the human gamma-globin promoter contributes to the preferential expression of the gamma-gene in fetal erythroid cells. The SSP contains the transcription factor CP2 and an erythroid-specific partner, NF-E4. The NF-E4 gene encodes a 22-kDa polypeptide employing a non-AUG initiation codon. Antisera specific to NF-E4 detects this species and an additional 14 kDa protein, which initiates from an internal methionine. Enforced expression of p14 NF-E4 in the K562 fetal/erythroid cell line, and in primary erythroid cord blood progenitors, results in repression of gamma-gene expression. Biochemical studies reveal that p14 NF-E4 interacts with CP2, resulting in diminished association of CP2 with the SSE in chromatin immunoprecipitation assays. p45 NF-E2 recruitment to the gamma-promoter is also lost, resulting in a reduction in RNA polymerase II and TBP binding and a fall in promoter transcriptional activity. This effect is specific, as enforced expression of a mutant form of p14 NF-E4, which fails to interact with CP2, also fails to repress gamma-gene expression in K562 cells. These findings provide one potential mechanism that could contribute to the autonomous silencing of the human gamma-genes in adult erythroid cells.

Repression of human gamma-globin gene expression by a short isoform of the NF-E4 protein is associated with loss of NF-E2 and RNA polymerase II recruitment to the promoter.

Spatial and temporal expression of the Grainyhead-like transcription factor family during murine development.

Therapy‐related myelodysplastic syndrome (t‐MDS) and acute myeloid leukemia (t‐AML) carry a poor prognosis. We analyzed the results of allogeneic HSCT in 38 children to determine which factors, if any, affected outcome.

Outcome of hematopoietic stem cell transplantation for pediatric patients with therapy‐related acute myeloid leukemia or myelodysplastic syndrome

Binding of EKLF to the proximal promoter CACC motif is essential for high-level tissue-specific β-globin gene expression. More recent studies have demonstrated that EKLF regulates expression of other erythroid-specific genes, suggesting a broad role for EKLF in co-ordinating gene transcription in differentiating erythroblasts. Given these observations, we hypothesized that EKLF may play a role in synchronizing α- and β-globin gene expression. Supporting this model, studies of fetal erythroblasts derived from EKLF-null embryos revealed a 3-fold reduction in murine α-globin gene expression in fetal erythroblasts when compared to wild type littermate controls. A similar reduction in primary α-globin RNA transcripts was observed in these studies. To further examine the molecular consequences of EKLF function at the α- and β-globin genes in vivo , we utilized an erythroid cell line derived from EKLF null fetal liver cells. We have demonstrated previously that introduction into these cells of the wildtype EKLF cDNA, fused in frame with a mutant estrogen response element results in tamoxifen-dependent rescue of β-globin gene expression. Consistent with our observations in primary erythroblasts, α-globin gene expression is present in the absence of functional EKLF. However, with tamoxifen induction, we observed a 3–5 fold increase in α-globin gene transcription. Interestingly, the kinetics of the changes in transcription of the α- and β-gene transcripts were similar. Enhancement in α-gene transcription was associated with EKLF binding at the α- and β-globin promoters as determined by a quantitative chromatin immunoprecipitation (ChIP) assay. Interestingly, maximal EKLF binding and α-gene transcription was observed within 2 hours of tamoxifen induction. We hypothesized that the role of EKLF may differ function at the promoters, given that a basal level of α-globin gene expression occurs in absence of EKLF binding. Supporting this hypothesis, we observed sequential recruitment of p45NF-E2, RNA polymerase II (Pol II) and the co-activator CBP to the β-promoter with tamoxifen induction. No change in GATA-1 binding was observed. In contrast, p45NF-E2 does not bind to the α-promoter and the kinetics of GATA-1 and PolII association is unchanged after tamoxifen induction. Taken together, our results demonstrate that EKLF regulates the co-ordinate high-level transcription of the α- and β-globin genes, binding in a kinetically identical manner to the gene promoters. However, the effects of EKLF on transacting factor recruitment (and chromatin modification) differ between the promoters, consistent with the idea that EKLF acts in a context-specific manner to modulate gene transcription.

Context-Specific Roles for Erythroid Krüppel-Like Factor (EKLF) in Co-Ordinate High Level Expression of the Murine α- and β-Globin Genes.

Understanding the molecular mechanisms that regulate γ-globin gene expression is essential for development of new therapeutic strategies for individuals with sickle cell disease and β-thalassemia. We have previously identified a tissue- and developmentally- specific multiprotein transacting factor complex, the human stage selector protein (SSP), which facilitates the interaction of the g-globin gene promoters with the upstream locus control region enhancer in fetal erythoid cells. This complex interacts with the stage selector element (SSE) in the proximal g-globin promoter, a regulatory motif phylogenetically conserved in primate species with a distinct fetal stage of β-globin like gene expression. Given these observations, we hypothesized that a similar complex modulates γ-globin in the rhesus macaque, a non-human primate model that has been utilized to study β-globin like gene expression. We focused our efforts on NF-E4, given that a human isoform of this factor confers erythroid and fetal specificity to the SSP complex. Fetal liver erythroblasts were obtained from rhesus embryos and analyzed by reverse transcriptase(RT)-PCR analysis for NF-E4 expression. NF-E4 like transcripts were identified in day 60, 80 and 120 embryonic erythroblasts, but not other rhesus tissues, demonstrating an erythroid-specific pattern of expression. Utilizing 5′ RACE, we cloned a full length NF-E4 transcript, identifying an open reading frame encoding a 131 amino acid polypeptide. This 20kD polypeptide shares a high degree of homology with human NF-E4, especially in its carboxy-terminal domain. Like human NF-E4, GST pulldown chromatography confirmed the ability of the rhesus factor to interact directly with CP2 and ALY, the other core components of the SSP. To evaluate rNF-E4 function in vivo , we utilized retrovirally mediated gene transfer to enforce expression of this factor in K562 cells, a model of human fetal erythropoiesis. Initial co-immunoprecipitation studies confirmed the in vivo interaction of rNF-E4 with other components of the SSP. Interestingly, we observed a specific 3-fold induction of γ-globin gene expression in rNF-E4 expressing cells when compared to controls. Moreover, we demonstrated that, like enforced expression of human NF-E4, rNF-E4 induced a significant increase in e-globin gene expression. Taken together, our results suggest a conservation of NF-E4 expression and function in species with a fetal stage of globin gene expression. Moreover, the identification of rNF-E4 provides a platform for the pre-clinical development of therapeutic agents that induce high levels of NF-E4 in adult erythroblasts.

An Erythoid-Specific Component of the Rhesus Stage Selector Protein, rNF-E4, Modulates γ-Globin Gene Expression Specifically.

The presence of an impermeable surface barrier is an essential homeostatic mechanism in almost all living organisms. We have recently described a novel gene that is critical for the developmental instruction and repair of the integument in mammals. This gene, Grainy head-like 3 (Grhl3) is a member of a large family of transcription factors that are homologs of the Drosophila developmental gene grainy head (grh). Mice lacking Grhl3 fail to form an adequate skin barrier, and die at birth due to dehydration. These animals are also unable to repair the epidermis, exhibiting failed wound healing in both fetal and adult stages of development. These defects are due, in part, to diminished expression of a Grhl3 target gene, Transglutaminase 1 (TGase 1), which encodes a key enzyme involved in cross-linking of epidermal structural proteins and lipids into the cornified envelope (CE). Remarkably, the Drosophila grh gene plays an analogous role, regulating enzymes involved in the generation of quinones, which are essential for cross-linking structural components of the fly epidermis. In an extension of our initial analyses, we focus this report on additional defects observed in the Grhl3-null epidermis, namely defective extracellular lipid processing, altered lamellar lipid architecture and cellular hyperproliferation. These abnormalities suggest that Grhl3 plays diverse mechanistic roles in maintaining homeostasis in the skin.

The Epidermis of Grhl3-Null Mice Displays Altered Lipid Processing and Cellular Hyperproliferation

Prospective magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), neuropsychological testing and neurological examinations were performed to determine the long‐term effect of successful haematopoietic stem cell transplantation on the neurological status of nine children with sickle cell disease. A scoring system for severity of brain parenchymal and vascular lesions was developed and applied. Neurological examinations and neuropsychometric tests were stable, but MRI and MRA studies were not. Transient changes occurred early in two patients. Persistent changes occurred in five. Parenchymal lesions occurred in zero of two patients without prior lacunae or infarcts and in all seven with prior lacunae or infarcts (P = 0·0278).

Brain parenchymal damage after haematopoietic stem cell transplantation for severe sickle cell disease

Hemolytic uremic syndrome after bone marrow transplantation: clinical characteristics and outcome in children.

The Drosophila cuticle is essential for maintaining the surface barrier defenses of the fly. Integral to cuticle resilience is the transcription factor grainy head, which regulates production of the enzyme required for covalent cross-linking of the cuticular structural components. We report that formation and maintenance of the epidermal barrier in mice are dependent on a mammalian homolog of grainy head, Grainy head-like 3. Mice lacking this factor display defective skin barrier function and deficient wound repair, accompanied by reduced expression of transglutaminase 1, the key enzyme involved in cross-linking the structural components of the superficial epidermis. These findings suggest that the functional mechanisms involving protein cross-linking that maintain the epidermal barrier and induce tissue repair are conserved across 700 million years of evolution.

A Homolog of Drosophila grainy head Is Essential for Epidermal Integrity in Mice

Hemolytic uremic syndrome (HUS) is an uncommon but potentially life-threatening complication of hematopoietic stem cell transplantation. We retrospectively studied the medical records of 293 children who underwent allogeneic bone marrow transplantation at St. Jude Children’s Research Hospital between 1992 and 1999 to describe the clinical course of and to identify risk factors for transplant-associated HUS. Conditioning regimens included cyclophosphamide, cytarabine, and total body irradiation for patients with hematologic malignancies (n 244); patients with nonmalignant diseases (n 49) received disease-specific regimens. Grafts from unrelated or mismatched related donors were depleted of T lymphocytes, whereas matched sibling grafts were unmanipulated. All patients received cyclosporine as prophylaxis for graft-versus-host disease. Recipients of grafts from matched siblings also received pentoxifylline or short-course methotrexate. HUS developed in 28 (9.6%) patients at a median of 171 days after transplantation. We identified older donor age (P .029), use of antithymocyte globulin in the conditioning regimen (P .008), and recipient CMV seronegativity (P .011) as being associated with an increased risk of HUS. With a multiple regression analysis, the use of antithymocyte globulin ( .86; P .04) and recipient cytomegalovirus seronegativity ( .93; P .035) remained significant risk factors for the development of HUS. © 2005 American Society for Blood and Marrow Transplantation

emolytic Uremic Syndrome after Bone Marrow ransplantation : Clinical Characteristics and Outcome n Children

Morphogen-dependent epidermal-specific transacting factors have not been defined in vertebrates. We demonstrate that a member of the grainyhead transcription factor family, Grainyhead-like 1 (XGrhl1) is essential for ectodermal ontogeny in Xenopus laevis. Expression of this factor is restricted to epidermal cells. Moreover, XGrhl1 is regulated by the BMP4 signaling cascade. Disruption of XGrhl1 activity in vivo results in a severe defect in terminal epidermal differentiation, with inhibition of XK81A1 epidermal keratin gene expression, a key target of BMP4 signaling. Furthermore, transcription of the XK81A1 gene is modulated directly by binding of XGRHL1 to a promoter-localized binding motif that is essential for high-level expression. These results establish a novel developmental role for XGrhl1 as a crucial tissue-specific regulator of vertebrate epidermal differentiation.

BMP4-dependent expression of Xenopus Grainyhead-like 1 is essential for epidermal differentiation

Genome-wide chemical mutagenesis screens have been successfully performed in zebrafish to identify genes involved in erythropoiesis. We have now executed a large-scale screen for genes involved in red cell production in mice by using N-ethyl-N-nitrosurea mutagenesis. Five thousand G1 mice were screened by automated haematological analysis at 7 weeks of age for abnormalities of their red cell indices that lay more than 3 standard deviations outside the normal population average. Mice with co-incident abnormalities in white cell or platelet counts were excluded. Six mutant lines were identified with microcytosis (RBC1-6) that was heritable with subsequent backcrossing. Three of these lines (RBC 1, 4, 5) were found by gene mapping and candidate gene sequence analysis to harbour different mutations in the transferrin receptor gene (TfR) that led to embryonic lethality in their homozygous state. These mutations were clustered in the sequence encoding the domain involved in receptor homodimerisation, providing, for the first time, in vivo functional correlations of the previous structural analyses. The RBC3 line was also mapped to the interval containing the TfR gene, although no mutations were present in the TfR coding region or splice donor/acceptor sites in this line, raising the possibility of a regulatory sequence mutation, which we are investigating. The RBC2 line was mapped to chromosome 8, and found to contain a splice acceptor mutation in the ankyrin gene. This mutation results in a 22 bp deletion with a resultant frame shift in the regulatory domain. Mice homozygous for this mutation are born jaundiced with massive splenomegaly and a blood film consistent with severe spherocytosis, and die within 6 weeks of progressive anemia. As such, this line represents a new mouse model of severe hereditary spherocytosis. The final line, RBC6 displays a profound hypochromic, microcytic anemia in the homozygous state at birth, with apparent normality of all other organ systems. The mutation has been mapped to a chromosomal interval containing only a few genes, none of which have been previously linked to red cell production or differentiation, and therefore represents a novel erythropoietic gene/allele.

Identification of Novel Erythropoietic Genes and Alleles Using a Large-Scale Chemical Mutagenesis Screen in Mice.

Preliminary Experience with Haploidentical Stem Cell Transplantation for Children with Sickle Cell Disease and Stroke.

Functional interaction of CP2 with GATA-1 in the regulation of the expression of erythroid promoters.

179. Oncoretroviral Vector-Mediated Gene Therapy for Murine WAS Fails to Correct Most of the Deficient Biological Responses to S. pneumonia or M. bovis

ABSTRACT LBP-1a and CP2 are ubiquitously expressed members of the grainyhead transcription factor family, sharing significant sequence homology, a common DNA binding motif, and modulating a range of key regulatory and structural genes. We have reported previously that CP2-null mice are viable with no obvious abnormality. LBP-1a provides redundant function in this context. We show here that mice lacking LBP-1a expression develop intrauterine growth retardation at embryonic day 10.5, culminating in death 1 day later. No focal intraembryonic cause for this CP2-independent defect is evident. In contrast, a significant reduction in the thickness of the labyrinthine layer of the placenta is observed in LBP-1a−/− animals. However, expression of trophoblast differentiation markers is unperturbed in this context, and complementation studies utilizing tetraploid wild-type cells failed to rescue or ameliorate the LBP-1a−/− phenotype, excluding a primary trophoblast defect. An explanation for these observations is provided by the prominent angiogenic defect observed in the mutant placentas. LBP-1a−/− allantoic blood vessels fail to penetrate deeply and branch into the complex embryonic vasculature characteristic of the normal placenta. Interestingly, a similar defect in angiogenesis is observed in the yolk sac vasculature, primary endothelial cell-lined capillary tubes, although present, failed to connect into a characteristic intricate vascular network. Collectively, these results demonstrate that LBP-1a plays a critical role in the regulation of extraembryonic angiogenesis.

Defective Extraembryonic Angiogenesis in Mice Lacking LBP-1a, a Member of the grainyhead Family of Transcription Factors

Effective donor lymphohematopoietic reconstitution after haploidentical CD34+-selected hematopoietic stem cell transplantation in children with refractory severe aplastic anemia

The Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disorder caused by mutations in the WASP gene. WASP is an effector protein in the actin polymerization pathway. Characterized by immunodeficiency, micro-thrombocytopenia and eczema, untreated WAS patients may also suffer hemorrhages, recurring infections and potential malignancies. WAS can be cured by bone marrow (BM) transplant but because many patients lack a suitable donor, stem cell-targeted gene transfer is being developed as an alternative therapeutic approach. We have demonstrated correction of the T-cell proliferation defect in Wasp − mice using MSCV oncoretroviral vectors (Blood 102:3108, 2003). However, our competitive repopulation studies in mice with both wild-type (WT) and gene-corrected Wasp − BM, demonstrated only a modest selective advantage for gene modified lymphocytes. Correction of the lymphocytopenia was observed only in animals having high proportions of transduced cells. In addition, variability in the level of gene expression among gene-corrected cells was associated with only partial correction of the T-cell cytokine secretory defects. Thus, the efficiency of stem cell-targeted gene transfer as well as the level and consistency of gene expression are likely to be key factors that determine success in any clinical application of gene transfer for the treatment of WAS. In attempting to improve vector design, we have used lentiviral vectors because of their greater efficiency in transducing repopulating stem cells as we recently demonstrated in a non-human primate model (Blood 103:4062, 2004). The WASP gene is regulated by two promoter regions. The proximal promoter lies immediately adjacent to the translation start site with the distal promoter found 6 kb upstream, followed by an alternate first exon. We have developed a series of third generation, self-inactivating lentiviral vectors containing the MSCV, proximal or distal WASP promoters driving GFP in the reverse transcriptional orientation. The WASP promoters were active in lymphocytes but not HeLa cells in vitro. However, expression was low in lymphocytes and granulocytes in mice transplanted with genetically modified stem cells. In an effort to abrogate any position-effect variegation and enhance expression, we generated a new series of vectors with the transcriptional unit in the forward orientation that also contained the woodchuck post-transcriptional regulatory element, the chicken beta-globin 5′ DNase I hypersensitive site 4 (I) and human beta-interferon scaffold attachment region (S) insulator elements. Either GFP or murine Wasp cDNA were included for expression analysis. Despite the complexity of the SI-containing vectors, titers of concentrated preparations ranged from 9x106 TU/ml to 5x107 TU/ml and enabled transduction of both cell lines and murine hematopoietic stem cells. Low-level GFP expression from the proximal promoter was detected in HeLa cells with higher expression found in lymphocytes (NALM6 and Jurkat cells). Expression of GFP under the control of the proximal WASP promoter was detected in vivo in multiple hematopoietic lineages in mice transplanted with transduced stem cells. Future efforts will focus on further characterization and optimization of vector design with the goal of achieving consistent, high level expression.

Developing Lentiviral Vectors for Gene Therapy of Wiskott-Aldrich Syndrome.

Acetylation provides one mechanism by which the functional diversity of individual transcription factors can be expanded. This is valuable in the setting of complex multigene loci that are regulated by a limited number of proteins, such as the human β-globin locus. We have studied the role of acetylation in the regulation of the transcription factor NF-E4, a component of a protein complex that facilitates the preferential expression of the human γ-globin genes in fetal erythroid cells. We have shown that NF-E4 interacts directly with, and serves as a substrate for, the acetyltransferase co-activator PCAF. Acetylation of NF-E4 is restricted to a single residue (Lys43) in the amino-terminal domain of the protein and results in two important functional consequences. Acetylation of NF-E4 prolongs the protein half-life by preventing ubiquitin-mediated degradation. This stabilization is PCAF-dependent, since enforced expression in fetal/erythroid cells of a mutant form of PCAF lacking the histone acetyltransferase domain (PCAFΔHAT) decreases NF-E4 stability. Acetylation of Lys43 also reduces the interaction between NF-E4 and HDAC1, potentially maximizing the activating ability of the factor at the γ-promoter. These results provide further demonstration that co-activators, such as PCAF, can influence individual transcription factor properties at multiple levels to alter their effects on gene expression.

Site-specific Acetylation of the Fetal Globin Activator NF-E4 Prevents Its Ubiquitination and Regulates Its Interaction with the Histone Deacetylase, HDAC1*

The human stage selector protein, a complex containing the ubiquitous transcription factor CP2 and the erythroid-specific factor p22 NF-E4, facilitates the interaction of the γ-globin genes with the locus control region in fetal erythroid cells. Enforced expression of p22 NF-E4 in K562 cells and human cord blood progenitors increases fetal globin gene expression, and in progenitors, reduces β-globin expression. To examine the role of NF-E4 in an in vivo model of hemoglobin switching, we enforced the expression of p22 NF-E4 in transgenic mice carrying the human β-globin locus yeast artificial chromosome. Although murine erythropoiesis and globin gene expression is unaffected in these mice, the expression profile of the human globin genes is altered. All three transgenic lines displayed an increased γ:β-globin ratio in E12.5–14.5 fetal liver, resulting in a delay in the fetal/adult switch. At E12.5, this is primarily due to a reduction of β-gene expression, whereas at E14.5, the increased γ:β ratio is due to enhanced γ-gene expression. Despite this, the switch in globin subtype is fully completed in the adult bone marrow. These findings indicate that p22 NF-E4 is capable of influencing human globin gene expression in vivo but is incapable of overriding the intrinsic mechanisms governing γ-gene silencing in this context.

Peritransplant toxicity and a delay in effective immune reconstitution have limited the utility of alternate donor transplantation for children with refractory severe aplastic anemia. We have assessed the effectiveness of infusing large numbers of highly purified haploidentical CD34þ cells after immunoablative conditioning in three patients who had failed intensive immunosuppression, lacked unrelated donors, and had active or recent serious infections. One patient rejected the first infusion, but engrafted after a second infusion from the same donor. This patient died 4 months after hematopoietic stem cell transplantation with no evidence of lymphoid reconstitution. Two patients experienced mixed chimerism requiring treatment with antibodies and/or donor lymphocyte infusion. Both currently survive more than 1 year after transplantation with normal blood counts, 100% donor engraftment, effective lymphoid reconstitution, and no chronic graft-versus-host disease. We observed functional thymopoiesis as measured by lymphocyte immunophenotyping, T cell receptor excision circles and T cell receptor Vb spectratyping complexity analysis. Further study is required to validate the initial promise of these preliminary observations. Bone Marrow Transplantation (2004) 33, 411–418. doi:10.1038/sj.bmt.1704358 Published online 15 December 2003

Haploidentical transplants Effective donor lymphohematopoietic reconstitution after haploidentical CD34 þ -selected hematopoietic stem cell transplantation in children with refractory severe aplastic anemia

Encephalopathy in pediatric patients after allogeneic hematopoietic stem cell transplantation is associated with a poor prognosis

Functional correction of T cells derived from patients with the Wiskott–Aldrich syndrome (WAS) by transduction with an oncoretroviral vector encoding the WAS protein

Modulating action of the new polymorphism L436F detected in the GLB1 gene of a type-II GM1 gangliosidosis patient

The Drosophila gene grainyhead is the founding member of a large family of genes encoding developmental transcription factors that are highly conserved from fly to human. The family consists of two main branches, with grainyhead as the ancestral gene for one branch and the recently cloned Drosophila CP2 as the ancestral gene for the other. We now extend this family with the identification of another novel mammalian member, Sister-of-Mammalian Grainyhead (SOM), which is phylogenetically aligned with grainyhead. SOM is closely related to the other mammalian homologues of grainyhead, including Mammalian Grainyhead (MGR) and Brother-of-MGR, sharing a high degree of sequence identity with these factors in the functional DNA-binding, protein dimerization and activation domains. Protein interaction studies demonstrate that SOM can heterodimerize with MGR and Brother-of-MGR, but not with the more distant members of the family. Like grainyhead, the SOM gene too produces several distinct isoforms with differing functional properties through alternative splicing. The tissue distributions of these isoforms differ and all display highly restricted expression patterns. These findings indicate that SOM, like its family members, may play important roles in mammalian development.

The identification and characterization of human Sister-of-Mammalian Grainyhead (SOM) expands the grainyhead-like family of developmental transcription factors.

Purpose To determine the incidence, etiology and outcome of graft failure in pediatric allogeneic bone marrow transplant (BMT) recipients. Patients and Methods Patients with primary or secondary graft failure were identified by database review. A retrospective chart review was performed. Etiologic factors were identified and assessed for statistical significance. Results 309 children underwent allogeneic BMT during the time interval studied. Four cases of primary graft failure and 7 cases of secondary graft failure occurred. Nonmalignant diagnosis, lower total nucleated cell (TNC) dose, and conditioning without total body irradiation were associated with a higher incidence of graft failure. Donor source, donor/recipient CMV status, CD34+ cell dose, and alloimmunization were not associated with graft failure. Conclusions Graft failure is a relatively uncommon occurrence in pediatric patients. Autologous reinfusion may allow time to prepare the patient for a second transplant and decrease complications associated with aplasia. More immunosuppressive conditioning regimens may decrease the incidence of graft failure, particularly in patients with non-malignant diseases or those with lower stem cell doses. More frequent monitoring of chimerism by VNTR analysis may detect late graft failure earlier and allow for more rapid intervention.

Etiology and Outcome of Graft Failure in Pediatric Hematopoietic Stem Cell Transplant Recipients

207Allogeneic bone marrow transplantation for children with hematologic malignancies

203Allogeneic bone marrow transplantation for children with myeloid hematologic malignancies

Inositol- and folate-resistant neural tube defects in mice lacking the epithelial-specific factor Grhl-3

Hemorrhagic cystitis after allogeneic bone marrow transplantation in children: clinical characteristics and outcome.

Allogeneic bone marrow transplantation for children with histiocytic disorders: use of TBI and omission of etoposide in the conditioning regimen

The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by immune dysfunction, thrombocytopenia, and eczema. We used a murine model created by knockout of the WAS protein gene (WASP) to evaluate the potential of gene therapy for WAS. Lethally irradiated, male WASP- animals that received transplants of mixtures of wild type (WT) and WASP- bone marrow cells demonstrated enrichment of WT cells in the lymphoid and myeloid lineages with a progressive increase in the proportion of WT T-lymphoid and B-lymphoid cells. WASP- mice had a defective secondary T-cell response to influenza virus which was normalized in animals that received transplants of 35% or more WT cells. The WASP gene was inserted into WASP- bone marrow cells with a bicistronic oncoretroviral vector also encoding green fluorescent protein (GFP), followed by transplantation into irradiated male WASP- recipients. There was a selective advantage for gene-corrected cells in multiple lineages. Animals with higher proportions of GFP+ T cells showed normalization of their lymphocyte counts. Gene-corrected, blood T cells exhibited full and partial correction, respectively, of their defective proliferative and cytokine secretory responses to in vitro T-cell-receptor stimulation. The defective secondary T-cell response to influenza virus was also improved in gene-corrected animals.

Defects in T-cell-mediated immunity to influenza virus in murine Wiskott-Aldrich syndrome are corrected by oncoretroviral vector-mediated gene transfer into repopulating hematopoietic cells.

Stem cell transplants for patients with X-linked agammaglobulinemia.

ABSTRACT The Polycomb group (PcG) of proteins represses homeotic gene expression through the assembly of multiprotein complexes on key regulatory elements. The mechanisms mediating complex assembly have remained enigmatic since most PcG proteins fail to bind DNA. We now demonstrate that the human PcG protein dinG interacts with CP2, a mammalian member of the grainyhead-like family of transcription factors, in vitro and in vivo. The functional consequence of this interaction is repression of CP2-dependent transcription. The CP2-dinG interaction is conserved in evolution with the Drosophila factor grainyhead binding to dring, the fly homologue of dinG. Electrophoretic mobility shift assays demonstrate that the grh-dring complex forms on regulatory elements of genes whose expression is repressed by grh but not on elements where grh plays an activator role. These observations reveal a novel mechanism by which PcG proteins may be anchored to specific regulatory elements in developmental genes.

Binding of the RING Polycomb Proteins to Specific Target Genes in Complex with the grainyhead-Like Family of Developmental Transcription Factors

ABSTRACT Characterization of the mechanism(s) of action of trans-acting factors in higher eukaryotes requires the establishment of cellular models that test their function at endogenous target gene regulatory elements. Erythroid Krüppel-like factor (EKLF) is essential for β-globin gene transcription. To elucidate the in vivo determinants leading to transcription of the adult β-globin gene, functional domains of EKLF were examined in the context of chromatin remodeling and transcriptional activation at the endogenous locus. Human EKLF (hEKLF) sequences, linked to an estrogen-responsive domain, were studied with an erythroblast cell line lacking endogenous EKLF expression (J2eΔeklf). J2eΔeklf cells transduced with hEKLF demonstrated a dose-dependent rescue of β-globin transcription in the presence of inducing ligand. Further analysis using a series of amino-terminal truncation mutants of hEKLF identified a distinct internal domain, which is sufficient for transactivation. Interestingly, studies of the chromatin structure of the β-promoter revealed that a smaller carboxy-terminal domain generated an open promoter configuration. In vitro and in vivo binding studies demonstrated that this region interacted with BRG1, a component of the SWI/SNF chromatin remodeling complex. However, further study revealed that BRG1 interacted with an even smaller domain of EKLF, suggesting that additional protein interactions are required for chromatin remodeling at the endogenous β-promoter. Taken together, our findings support a stepwise process of chromatin remodeling and coactivator recruitment to the β-globin promoter in vivo. The J2eΔeklf inducible hEKLF system will be a valuable tool for further characterizing the temporal series of events required for endogenous β-globin gene transcription.

Distinct Domains of Erythroid Krüppel-Like Factor Modulate Chromatin Remodeling and Transactivation at the Endogenous β-Globin Gene Promoter

A highly conserved novel family of mammalian developmental transcription factors related to Drosophila grainyhead

Re: measurement of chimerism after hematopoietic stem cell transplantation.

Although bone marrow transplantation has shown curative potential for children with severe manifestations of sickle cell disease (SCD), only a few eligible children have received transplants. The reasons for this are multifactorial and include the absence of suitable matched sibling donors and psychosocial considerations. An expansion of stem cell transplantation (SCT) to patients without matched sibling donors has the potential to provide curative therapy to additional patients. This must be balanced against the potential for toxicity of alternate donor SCT. This June 2000 meeting, which brought together experts in the areas of SCD and allogeneic SCT, was modeled after a similar 1991 consensus conference, before the initiation of a matched sibling donor transplantation study for SCD. The goals of the conference were to discuss different options for the treatment of SCD, to identify children at high risk of significant complications and death associated with the disease, and to identify new SCT strategies for curative therapy with acceptable toxicity.

Summary of Symposium: The Future of Stem Cell Transplantation for Sickle Cell Disease

Protective protein/cathepsin A (PPCA), a lysosomal carboxypeptidase, is deficient in the neurodegenerative lysosomal disorder galactosialidosis (GS). PPCA(-/-) mice display a disease course similar to that of severe human GS, resulting in nephropathy, ataxia, and premature death. Bone marrow transplantation (BMT) in mutant animals using transgenic BM overexpressing the corrective enzyme in either erythroid cells or monocytes/macrophages has proven effective for the improvement of the phenotype, and encouraged the use of genetically modified BM cells for ex vivo gene therapy of GS. Here, we established stable donor hematopoiesis in PPCA(-/-) mice that received hematopoietic progenitors transduced with a murine stem cell virus (MSCV)-based, bicistronic retroviral vector overexpressing PPCA and the green fluorescent protein (GFP) marker. We observed complete correction of the disease phenotype in the systemic organs up to 10 months after transplantation. PPCA(+) BM-derived cells were detected in all tissues, with the highest expression in liver, spleen, BM, thymus, and lung. In addition, a lysosomal immunostaining was seen in nonhematopoietic cells, indicating efficient uptake of the corrective protein by these cells and cross-correction. Expression in the brain occurred throughout the parenchyma but was mainly localized on perivascular areas. However, PPCA expression in the central nervous system was apparently sufficient to delay the onset of Purkinje cell degeneration and to correct the ataxia. The long-term expression and internalization of the PPCA by cells of systemic organs and the clear improvement of the neurologic phenotype support the use of this approach for the treatment of GS in humans. (Blood. 2002;99:3169-3178)

Functional amelioration of murine galactosialidosis by genetically modified bone marrow hematopoietic progenitor cells.

Allogeneic hematopoietic stem cell transplantation (HSCT) corrects the Wiskott-Aldrich syndrome (WAS) phenotype. However, the toxicity and mortality frequently associated with this approach warrant the exploration of new therapeutic strategies. Transplantation studies of a murine model of WAS deficiency have been limited by the occurrence of a radiation-induced fatal exacerbation of a pre-existing colitis in the peritransplantation period. Here we demonstrate that when crossed to a C57/B6 background, WAS-deficient males show little if any colitis and reliably survive HSCT. We show that HSCT corrects the hematologic and functional deficiencies of WAS knockout mice. These results strengthen the analogy between murine and human WAS and provide a basis for the use of WAS-deficient mice to explore novel approaches for correction of the disease phenotype.

Correction of the murine Wiskott-Aldrich syndrome phenotype by hematopoietic stem cell transplantation.

Cellular and transgenic models have provided important insights into the molecular mechanisms required for mammalian globin gene expression. The homology of the human and murine α- and ζ-promoter sequences coupled with in vivo transcriptional analysis suggested that the genes were controlled in a

Erythroid Kruppel-like factor (EKLF) is a transcription factor of the C2H2 zinc-finger class that is essential for definitive erythropoiesis. We generated immortal erythroid cell lines from EKLF(-/-) fetal liver progenitor cells that harbor a single copy of the entire human beta-globin locus and then reintroduced EKLF as a tamoxifen-inducible, EKLF-mutant estrogen receptor (EKLF-ER) fusion protein. Addition of tamoxifen resulted in enhanced differentiation and hemoglobinization, coupled with reduced proliferation. Human beta-globin gene expression increased significantly, whereas gamma-globin transcripts remained elevated at levels close to endogenous mouse alpha-globin transcript levels. We conclude that EKLF plays a role in regulation of the cell cycle and hemoglobinization in addition to its role in beta-globin gene expression. The cell lines we used will facilitate structural and functional analyses of EKLF in these processes and provide useful tools for the elucidation of nonglobin EKLF target genes.

Erythroid Kruppel-like factor (EKLF) coordinates erythroid cell proliferation and hemoglobinization in cell lines derived from EKLF null mice.

The NTF-like family of transcription factors have been implicated in developmental regulation in organisms as diverse asDrosophila and man. The two mammalian members of this family, CP2 (LBP-1c/LSF) and LBP-1a (NF2d9), are highly related proteins sharing an overall amino acid identity of 72%. CP2, the best characterized of these factors, is a ubiquitously expressed 66-kDa protein that binds the regulatory regions of many diverse genes. Consequently, a role for CP2 has been proposed in globin gene expression, T-cell responses to mitogenic stimulation, and several other cellular processes. To elucidate the in vivo role of CP2, we have generated mice nullizygous for the CP2 allele. These animals were born in a normal Mendelian distribution and displayed no defects in growth, behavior, fertility, or development. Specifically, no perturbation of hematopoietic differentiation, globin gene expression, or immunological responses to T- and B-cell mitogenic stimulation was observed. RNA and protein analysis confirmed that the nullizygous mice expressed no full-length or truncated version of CP2. Electrophoretic mobility shift assays with nuclear extracts from multiple tissues demonstrated loss of CP2 DNA binding activity in the −/− lines. However, a slower migrating complex that was ablated with antiserum to NF2d9, the murine homologue of LBP-1a, was observed with these extracts. Furthermore, we demonstrate that recombinant LBP-1a can bind to known CP2 consensus sites and form protein complexes with previously defined heteromeric partners of CP2. These results suggest that LBP-1a/NF2d9 may compensate for loss of CP2 expression in vivo and that further analysis of the role of the NTF family of proteins requires the targeting of the NF2d9 gene.

Targeted Disruption of the CP2 Gene, a Member of the NTF Family of Transcription Factors*

The NTF-like family of transcription factors have been implicated in developmental regulation in organisms as diverse as Drosophila and man. The two mammalian members of this family, CP2 (LBP-1c/LSF) and LBP-1a (NF2d9), are highly related proteins sharing an overall amino acid identity of 72%. CP2, the best characterized of these factors, is a ubiquitously expressed 66-kDa protein that binds the regulatory regions of many diverse genes. Consequently, a role for CP2 has been proposed in globin gene expression, T-cell responses to mitogenic stimulation, and several other cellular processes. To elucidate the in vivo role of CP2, we have generated mice nullizygous for the CP2 allele. These animals were born in a normal Mendelian distribution and displayed no defects in growth, behavior, fertility, or development. Specifically, no perturbation of hematopoietic differentiation, globin gene expression, or immunological responses to Tand B-cell mitogenic stimulation was observed. RNA and protein analysis confirmed that the nullizygous mice expressed no full-length or truncated version of CP2. Electrophoretic mobility shift assays with nuclear extracts from multiple tissues demonstrated loss of CP2 DNA binding activity in the 2/2 lines. However, a slower migrating complex that was ablated with antiserum to NF2d9, the murine homologue of LBP-1a, was observed with these extracts. Furthermore, we demonstrate that recombinant LBP-1a can bind to known CP2 consensus sites and form protein complexes with previously defined heteromeric partners of CP2. These results suggest that LBP1a/NF2d9 may compensate for loss of CP2 expression in vivo and that further analysis of the role of the NTF family of proteins requires the targeting of the NF2d9 gene.

Targeted Disruption of the CP 2 Gene , a Member of the NTF Family of Transcription Factors *

To test whether magnetic resonance angiography can document the evolution of vasculopathy in patients with sickle cell disease, we reviewed records to identify all patients who underwent magnetic resonance angiography from 1993 to 1999. Of 512 angiographies performed, 105 were of sickle cell disease patients, and 24 sickle cell disease patients 7 years of age or older underwent baseline and follow‐up examinations. Films were paired by patient, blinded as to examination date and treatment, and quantitatively compared. Four patients who received allogeneic bone marrow transplantation were compared to 7 patients who received other therapy and to 13 untreated patients. Quantitative analysis revealed a 10% increase in the measured diameter of 64 vessels (p = 0.001) following any treatment. Patients who had undergone allogeneic bone marrow transplantation exhibited a 12% increase in the lumen of 22 vessels (p = 0.041), whereas patients treated with chronic transfusion or hydroxyurea exhibited an 8% increase in 42 vessels (p = 0.016). In 2 patients with severe stenosis, the artery normalized after transplantation, and the blood flow rate was reduced in all patients who underwent transplantation. In untreated patients, there was a trend for the size of the arterial lumen to decrease, which is consistent with disease progression. Results suggest that treatment can reverse progression of vasculopathy. Bone marrow transplantation may enable stenoses to heal and can substantially reduce cranial blood velocity, suggesting that allogeneic bone marrow transplantation may prevent infarction or brain damage. Ann Neurol 2001;49:222–229

Improved cerebrovascular patency following therapy in patients with sickle cell disease: Initial results in 4 patients who received HLA‐identical hematopoietic stem cell allografts

ABSTRACT The stage selector protein (SSP) is a heteromeric complex involved in preferential expression of the human γ-globin genes in fetal-erythroid cells. We have previously identified the ubiquitous transcription factor CP2 as a component of this complex. Using the protein dimerization domain of CP2 in a yeast two-hybrid screen, we have cloned a novel gene, NF-E4, encoding the tissue-restricted component of the SSP. NF-E4 and CP2 coimmunoprecipitate from extract derived from a fetal-erythroid cell line, and antiserum to NF-E4 ablates binding of the SSP to the γ promoter. NF-E4 is expressed in fetal liver, cord blood, and bone marrow and in the K562 and HEL cell lines, which constitutively express the fetal globin genes. Enforced expression of NF-E4 in K562 cells and primary erythroid progenitors induces endogenous fetal globin gene expression, suggesting a possible strategy for therapeutic intervention in the hemoglobinopathies.

Induction of Human Fetal Globin Gene Expression by a Novel Erythroid Factor, NF-E4

Distinct domains of the erythroid transcription factor EKLF are required for chromatin remodeling and transcriptional activation of the endogenous murine beta(maj) globin gene promoter

Interaction of hbrgl with the erythroid transcription factor eklf is essential, but not sufficient for maximal activation of the β-globin promoter

Two distinct domains of the erythnoid transcription factor EKLF are required for maximal activation of the endogenous murine beta-globin gene promoter

ABSTRACT A fungus-derived compound (OSI-2040) which induces fetal globin expression in the absence of erythroid cell differentiation was identified in a high-throughput drug discovery program. We utilized this compound to isolate γ-globin regulatory genes that are differentially expressed in OSI-2040-induced and uninduced cells in the human erythroleukemia cell line K562. Representational difference analysis (RDA) of cDNA revealed several genes that were significantly up- or down-regulated in OSI-2040-induced cells. One gene whose expression was markedly enhanced was the gene for the helix-loop-helix (HLH) transcription factor Id2. Southern analysis of RDA amplicons demonstrated progressive enrichment of Id2 with each successive subtraction of uninduced cDNA from induced cDNA. Northern analysis of OSI-2040-induced K562 cells confirmed that Id2 expression was directly up-regulated coordinately with γ-globin. Analysis of other inducers of fetal globin demonstrated up-regulation of Id2 with sodium butyrate but not with hemin. Retrovirus-mediated overexpression of Id2 in K562 cells reproduced the enhancement of endogenous globin expression observed with OSI-2040 induction. Functional assays demonstrated that an E-box element in hypersensitivity site 2 is required for Id2-dependent enhancement of γ-promoter activity. Protein binding studies suggest that alterations in E-box site occupancy by basic HLH proteins may influence this activity, thus expanding the potential role of these factors in globin gene regulation.

Identification of Id2 as a Globin Regulatory Protein by Representational Difference Analysis of K562 Cells Induced To Express γ-Globin with a Fungal Compound

The zinc finger transcription factor GATA-2 is highly expressed in immature hematopoietic cells and declines with blood cell maturation. To investigate its role in normal adult hematopoiesis, a bicistronic retroviral vector encoding GATA-2 and the green fluorescent protein (GFP) was used to maintain the high levels of GATA-2 that are normally present in primitive hematopoietic cells. Coexpression of the GFP marker facilitated identification and quantitation of vector-expressing cells. Bone marrow cells transduced with the GATA-2 vector expressed GFP as judged by flow cytometry and GATA-2 as assessed by immunoblot analysis. A 50% to 80% reduction in hematopoietic progenitor-derived colony formation was observed with GATA-2/GFP-transduced marrow, compared with marrow transduced with a GFP-containing vector lacking the GATA-2 cDNA. Culture of purified populations of GATA-2/GFP-expressing and nonexpressing cells confirmed a specific ablation of the colony-forming ability of GATA-2/GFP-expressing progenitor cells. Similarly, loss of spleen colony-forming ability was observed for GATA-2/GFP-expressing bone marrow cells. Despite enforced GATA-2 expression, marrow cells remained viable and were negative in assays to evaluate apoptosis. Although efficient transduction of primitive Sca-1(+) Lin- cells was observed with the GATA-2/GFP vector, GATA-2/GFP-expressing stem cells failed to substantially contribute to the multilineage hematopoietic reconstitution of transplanted mice. Additionally, mice transplanted with purified, GATA-2/GFP-expressing cells showed post-transplant cytopenias and decreased numbers of total and gene-modified bone marrow Sca-1(+) Lin- cells. Although Sca-1(+) Lin- bone marrow cells expressing the GATA-2/GFP vector were detected after transplantation, no appreciable expansion in their numbers occurred. In contrast, control GFP-expressing Sca-1(+) Lin- cells expanded at least 40-fold after transplantation. Thus, enforced expression of GATA-2 in pluripotent hematopoietic cells blocked both their amplification and differentiation. There appears to be a critical dose-dependent effect of GATA-2 on blood cell differentiation in that downregulation of GATA-2 expression is necessary for stem cells to contribute to hematopoiesis in vivo.

Enforced expression of the GATA-2 transcription factor blocks normal hematopoiesis.

Gene therapy has been proposed for a wide variety of human conditions including monogenic disorders, such as the haemoglobinopathies and immunodeficiency syndromes, cancer and many other diseases. Prerequisites for the success of this approach include the ability to deliver the therapeutic gene intact to the target cell, persistent levels of transgene expression sufficient to correct the disease phenotype, lack of unwanted side-effects associated with vector exposure or gene transfer and relative simplicity allowing the widespread use of this methodology. Although substantial progress has been made in animal models since the inception of genetic therapy in the early 1980s, significant obstacles remain for human therapy, most notably in the area of vector development. The first generation of gene therapy vectors has failed to overcome many of the biological hurdles cited above necessitating the development of alternate means of gene delivery and expression.

High level expression of many eukaryotic genes is achieved through the action of distal regulatory sequences or enhancers. We have utilized the interaction between the erythroid-specific enhancer in hypersensitivity site 2 (HS2) of the human β-globin locus control region and the globin gene promoters as a model to elucidate the mechanisms governing promoter/enhancer interactions. HS2 contains a 400-base pair core element consisting of tandem AP1/NF-E2 motifs flanked by binding sites for multiple ubiquitous and erythroid-specific factors. We have compared the enhancer activity of this core element with a synthetic enhancer lacking the factor binding sites flanking the AP1/NF-E2 motif (HS2M). In fetal/erythroid K562 cells, enhancement of a linked γ-promoter was significantly greater with wild-type HS2 than with HS2M. In contrast, the increase in β-promoter activity in these cells was equivalent with either enhancer fragment. Truncation of the binding site for the fetal/erythroid-specific stage selector protein in the γ-promoter abolished the additional enhancer activity of HS2. Similarly, insertion of the stage selector protein site into the β-promoter boosted enhancer activity observed with HS2 but not HS2M. In adult erythroid MEL cells, enhancement of a linked β-promoter was significantly greater with HS2 than with HS2M. This effect was dependent on the binding of the adult stage-specific factor, erythroid Kruppel-like factor, to the β-promoter. Taken together, this data suggests that the stage-specific factors binding the proximal globin promoters and the factors flanking the AP1/NF-E2 motif of HS2 act in synergy.

Maximal Activity of an Erythroid-specific Enhancer Requires the Presence of Specific Protein Binding Sites in Linked Promoters*

By the turn of the millennium, 7% of the earth’s population will carry a significant globin gene mutation. These mutations, known collectively as the haemoglobinopathies, are the most prevalent monogenic disorders worldwide. They affect the synthesis of gene products from two multigene loci, the aand b-globin clusters. The globin loci act in concert to produce differing subtypes of haemoglobin in response to changing oxygen requirements during human development. The most significant of these ‘switches’ in subtype occurs at birth, with the change from fetal (HbF) to adult (HbA) haemoglobin production. At the level of gene transcription this equates to a switch solely in the b-cluster, with silencing of the fetal g-genes and dramatic up-regulation of adult b-gene transcription (Stamatoyannopoulos & Nienhuis, 1994). The fetal/adult switch heralds the onset of the devastating haemoglobinopathies, b-thalassaemia and sickle cell disease (SCD). The b-thalassaemias are characterized by dyserythropoiesis, transfusion dependence, iron overload while in SCD, painful crises and organ infarction predominate. Amelioration of the symptoms of these haemoglobinopathies has been documented in patients with elevated levels of HbF (Bunn, 1993). In b-thalassaemia elevated levels of g-chains combine with the redundant a-chains leading to reduced dyserythropoiesis and transfusion requirements. In SCD, HbF is a potent inhibitor of the polymerization of deoxyhaemoglobin S, thus reducing sickling and vascular occlusion (Bunn, 1997). These observations suggest that treatment strategies aimed at preserving or reactivating fetal haemoglobin production after birth should be explored for these diseases. Elevated levels of fetal haemoglobin are observed in adult humans in two significantly different contexts. The first is in the setting of a diverse group of genetic mutations which are unified phenotypically by persistent synthesis of HbF after birth, known collectively as hereditary persistence of fetal haemoglobin (HPFH) (Poncz et al, 1989). The second involves the reactivation of the quiescent fetal genes in adult erythroid progenitors as seen in stress erythropoiesis, drug induction and various other disease states. This paper examines the molecular and cellular mechanisms underlying the production of fetal haemoglobin during normal erythroid development and differentiation, and in the context of HPFH or g-gene reactivation. In addition, we discuss how these mechanisms could be potentially harnessed as therapeutic strategies for the haemoglobinopathies. The b-globin cluster: a myriad of cis-acting sequences and trans-acting factors The human b-globin locus consists of five genes arranged on chromosome 11 in the order in which they are expressed developmentally (e, g, g, d, b). Gene expression is restricted to the erythroid lineage and governed by a precise developmental programme. Embryonic haemoglobin (eglobin) is synthesized in the yolk sac until week 5 of gestation when g-globin gene activation occurs in the fetal liver and expression of the e-gene is silenced. At birth, the second haemoglobin switch occurs when b-globin gene expression commences in the bone marrow with a concomitant silencing of g-gene expression. This highly specific pattern of gene expression is regulated by cis-acting sequences within the genes themselves, distal sequences which provide enhancer activity and trans-acting factors which bind to these regulatory elements (Stamatoyannopoulos & Nienhuis, 1994; Orkin, 1995a; Jane & Cunningham, 1996). The ability to modify fetal globin expression necessitates that we understand the normal mechanisms governing globin gene regulation. To this end, studies in mice transgenic for the human globin genes have provided a number of seminal observations. From these studies it is evident that sequences within or immediately flanking the genes confer the appropriate developmental and tissue specificity of expression. However, expression levels are low in this context and subject to position effects (Starck et al, 1994). Restoration of high-level positionindependent expression is observed when a 14 kb segment of DNA 6–20 kb 5 of the e-gene is included in transgenic constructs (Grosveld et al, 1987). This region, characterized by the presence of four erythroid-specific DNAse I hypersensitivity sites (HS1–4), is known as the locus control region (LCR) (Tuan et al, 1985; Grosveld et al, 1987). The importance of the LCR is highlighted by the thalassaemia phenotype observed in the Hispanic deletion of HS2–4. These patients produce no g-, dor b-chains despite the fact that the individual globin genes remain intact (Driscoll et al, 1989). The LCR appears to influence globin gene expression by predominantly acting as a tissue-specific transcriptional activator (Grosveld et al, 1987). However, roles in insulation of the genes, chromatin opening and locus replication have also been proposed (Fraser et al, 1990; Forrester et al, 1990; Aladjem et al, 1995). The cis-acting sequences in the individual globin genes and the LCR serve as templates for binding of transcription factors. The functions of these proteins are diverse and include transcriptional activation, mediation of the British Journal of Haematology, 1998, 102, 415–422

UNDERSTANDING FETAL GLOBIN GENE EXPRESSION: A STEP TOWARDS EFFECTIVE HbF REACTIVATION IN HAEMOGLOBINOPATHIES

We have used the interaction between the erythroid-specific enhancer in hypersensitivity site 2 of the human beta-globin locus control region and the globin gene promoters as a paradigm to examine the mechanisms governing promoter/enhancer interactions in this locus. We have demonstrated that enhancer-dependent activation of the globin promoters is dependent on the presence of both a TATA box in the proximal promoter and the binding site for the erythroid-specific heteromeric transcription factor NF-E2 in the enhancer. Mutational analysis of the transcriptionally active component of NF-E2, p45NF-E2, localizes the critical region for this function to a proline-rich transcriptional activation domain in the NH2-terminal 80 amino acids of the protein. In contrast to the wild-type protein, expression of p45 NF-E2 lacking this activation domain in an NF-E2 null cell line fails to support enhancer-dependent transcription in transient assays. More significantly, the mutated protein also fails to reactivate expression of the endogenous beta- or alpha-globin loci in this cell line. Protein-protein interaction studies reveal that this domain of p45 NF-E2 binds specifically to a component of the transcription initiation complex, TATA binding protein associated factor TAFII130. These findings suggest one potential mechanism for direct recruitment of distal regulatory regions of the globin loci to the individual promoters.

The activation domain of the enhancer binding protein p45NF-E2 interacts with TAFII130 and mediates long-range activation of the alpha- and beta-globin gene loci in an erythroid cell line.

Erythroid Krüppel-like factor (EKLF) is a trans-acting factor that binds specifically to the beta-globin promoter CACCC box. EKLF is essential for adult erythroid development in mice. We have cloned and sequenced a cDNA encoding the human homologue of this gene, which shares 69% identity with the mEKLF protein. The expression of hEKLF is restricted to fetal liver and adult bone marrow. The genomic locus of hEKLF was mapped to chromosomal band 19p13.12-p13.13, using fluorescence in situ hybridization.

The human erythroid-specific transcription factor EKLF localizes to chromosome 19p13.12-p13.13.

Outcomes of transplantation with matched-sibling and unrelateddonor bone marrow in children with leukaemia

Retroviral gene transfer is widely used in experimental and human gene therapy applications. We have devised a novel method of generating high-titer retroviral producer cell lines based on the P1 bacteriophage recombinase system Cre-loxP. Incorporation of loxP sites flanking a Neo(r)-SVTK cassette in the proviral DNA allows excision of these selectable markers through expression of Cre recombinase after production of a high-titer producer cell line. The resultant producer line contains a single loxP site flanked by the viral long terminal repeats. Retransfection of this line with the Cre expression vector and a plasmid containing a gene of interest flanked by loxP sites allows insertional recombination of the gene into the favorable preexisting site in the genome and the generation of a new line with a titer equivalent to that of the parental producer cell line. The efficiency of the process is sufficient to allow the generation of multiple new producer lines without the addition of antibiotic resistance genes. We have successfully generated retroviral vectors carrying different genes by using this approach and discuss the potential applications of this method in gene therapy.

Development of high-titer retroviral producer cell lines by using Cre-mediated recombination

Use of double marking with retroviral vectors to determine rate of reconstitution of untreated and cytokine expanded CD34+ selected marrow cells in patients undergoing autologous bone marrow transplantation.

Expression of the genes of the human beta-globin cluster is subject to stringent developmental regulation. An integral component of this control is competition between the gamma- and beta-promoters for the upstream regulatory sequences of the Locus Control Region (LCR). We have defined two stage selector elements (SSE and SSE-2), located in the proximal gamma-promoter and gamma-genes 5'UTR which mediate the preferential interaction of the gamma-gene with the LCR in the foetal developmental stage. The activity of both elements is dependent upon the binding of foetal and erythroid-specific proteins. We have purified the protein binding the proximal SSE and characterised it as a complex between the ubiquitous transcription factor CP2 and a 40 hD partner protein. Comparative studies between human CP2 and the chicken stage selector protein, NF-E4, demonstrate homology between the protein complexes. These findings demonstrate that competitive silencing of globin genes mediated by developmentally-specific protein complexes is conserved in evolution.

Interaction between the stage selector element (SSE) in the proximal γ-globin promoter and hypersensitivity site 2 in the locus control region partly mediates the competitive silencing of the β-globin promoter in the fetal developmental stage. We have now demonstrated that a second SSE-like element in the 5′-untranslated region of the γ-gene also contributes to this competitive silencing of the β-gene. Utilizing transient transfection assays in the fetal erythroid cell line, K562, we have shown that the core enhancer of hypersensitivity site 2 can preferentially interact with the proximal γ-promoter in the absence of the SSE, completely silencing a linked β-promoter. Mutation of a 20-base pair sequence of the γ-gene 5′-untranslated region (UTR) led to derepression of β-promoter activity. A marked activation of γ-promoter activity was also observed with this mutation, suggesting the presence of a repressor. Fine mutagenesis dissected these activities to different regions of the 5′-UTR. The stage selector activity was localized to a region centered on nucleotides +13 to +15. Electromobility shift assays utilizing this sequence demonstrated binding of a fetal and erythroid-specific protein. The repressor activity of the 5′-UTR was localized to tandem GATA-like sites, which appear to bind a complex of two proteins, one of which is the erythroid transcription factor GATA-1. These results indicate that the 5′-UTR of the γ-gene contains sequences that may be important for its transcriptional and developmental regulation.

Identification of Two Novel Regulatory Elements within the 5′-Untranslated Region of the Human Sγ-Globin Gene (*)

Corrigendum: Hemoglobin switching in man and chicken is mediated by a heteromeric complex between the ubiquitous transcription factor CP2 and a developmentally specific protein (The EMBO Journal (1995) 14 (97-105))

Considerable progress is being made in the transfer of genetic material to hematopoietic stem cells. In this chapter we describe how gene transfer is being used to: mark marrow and peripheral blood progenitor cells prior to autologous transplantation, to track their fate on reinfusion and to detect contaminating tumorigenic cells; modulate immunocyte function--important in immunologic disorders and perhaps in cancer therapy; generate tumor vaccines from tumor cells isolated from marrow; correct single gene defects--the 'classical' concept of gene therapy; and finally to modify the drug sensitivity of progenitor cells--enabling them to resist the suppressive effects of cytotoxic drugs during cancer therapy and perhaps providing a mechanism for in vivo selection of gene modified cells.

The transcription factor CP2{sup 2} has been shown to bind to several cellular and viral promoters as a homodimer. More recently, we have demonstrated that CP2 can form a heterodimer with a 45-kDa partner protein to form the stage selector protein complex (SSP). This complex binds to a proximal {gamma}-globin promoter regulatory element, the stage selector element (SSE), which appears to be involved in the competitive silencing of the {beta}-gene in the fetal stage of erythropoiesis. Similar SSP-like binding sites have been identified in the {beta}-globin promoter and regulatory elements of the {beta}-globin locus control region (LCR). The importance of the SSP complex is further emphasized by the fact that the chicken stage selector protein, NF-E4, which has been implicated in the competitive silencing of the chicken {epsilon}-globin gene, is the avian homologue of CP2. The purpose of this study is to map human CP2 genomically and define its relationship to previously identified loci. 9 refs., 1 fig.

The human transcription factor CP2 (TFCP2), a component of the human gamma-globin stage selector protein, maps to chromosome region 12q13 and is within 250 kb of the NF-E2 gene.

The human stage selector protein (SSP) has been implicated in the developmental regulation of the globin genes. Binding of SSP to the stage selector element (SSE) in the proximal gamma‐globin promoter is integral to the competitive silencing of a linked beta‐promoter in embryonic/fetal stage erythroleukemia (K562) cells. We now report the biochemical purification of SSP from K562 cell nuclear extract and demonstrate that the ubiquitously expressed transcription factor CP2 is pivotal to, but not sufficient for, SSP binding activity. Although addition of anti‐CP2 antiserum disrupts the formation of the SSP‐SSE complex in the electrophoretic mobility shift assay (EMSA), recombinant CP2 fails to bind to the SSE. Binding of CP2 to the SSE requires a heterodimeric partner present in K562 cells. We have defined the molecular weight of the partner protein as 40‐45 kDa in UV and protein cross‐linking experiments. An element analogous to the human SSE has previously been demonstrated in the chicken beta A‐gene‐promoter. The effects of this element are dependent on the binding of the chicken stage selector protein, NF‐E4. Comparative studies between human CP2 and chicken NF‐E4 demonstrate homology between the protein complexes. SSP binds to the chicken SSE and formation of this complex is ablated by the addition of anti‐CP2 antiserum or a monoclonal antibody to NF‐E4. Western analysis of partially purified NF‐E4 using anti‐CP2 antiserum or the NF‐E4 monoclonal antibody both demonstrate a dominant band at 66 kDa. Similarly, the NF‐E4 antibody recognizes the 66 kDa human CP2 protein in Western analysis of the SSP‐SSE complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemoglobin switching in man and chicken is mediated by a heteromeric complex between the ubiquitous transcription factor CP2 and a developmentally specific protein.

A cis-acting DNA regulatory element 3' to the A gamma-globin gene contains eight distinct regions of DNA-protein interaction distributed over 750 bp of DNA. The sequences of two foot-printed regions (sites I and IV) are A-T rich and generate a highly retarded complex on gel shift analysis with nuclear extract from human erythroleukemia (K562) cells. We have purified a 98-kD protein that reproduces this gel shift. Tryptic cleavage and peptide sequence analysis demonstrated that the 98-kD protein is identical to a recently cloned protein, special A-T-rich binding protein 1 (SATB1), that binds selectively to nuclear matrix/scaffold-associated regions of DNA (MARs/SARs). We have shown by functional analysis that the 3' A gamma regulatory element associates with the nuclear matrix. SATB1 mRNA was identified in K562 cells, and reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated its transcript in several other hematopoietic lines. Antisera to SATB1 caused ablation of the gel shift complex generated by both the crude nuclear extract and the purified 98-kD protein with the site I oligonucleotide. Furthermore, oligonucleotides that bind SATB1 inhibited formation of the site I gel shift complex when added as excess unlabeled competitor. An immunoblot analysis of the site I gel shift complex documented the presence of SATB1. Binding of SATB1 to two sites within the 3' A gamma regulatory element and its MAR/SAR activity suggests that this element may influence gene expression through interaction with the nuclear matrix.

The regulatory element 3' to the A gamma-globin gene binds to the nuclear matrix and interacts with special A-T-rich binding protein 1 (SATB1), an SAR/MAR-associating region DNA binding protein.

Binding ofSpltotheStageSelector Element oftheHumany-Globin GenePromoter May Regulate Developmental Specificity ofExpression

The human gamma-globin gene promoter contains a stage selector element (SSE) responsible for preferential interaction of the promoter with a powerful erythroid-specific enhancer in the fetal developmental stage (S.M. Jane, P.A. Ney, E.F. Vanin, D.L. Gumucio, and A.W. Nienhuis. EMBO J. 11:2691-2699, 1992). The element binds two proteins, the ubiquitous activator Sp1 and a protein previously known as -50 gamma and now named the stage selector protein (SSP). Binding of the second protein correlates with SSE activity in transient-transfection assays. We now report that a de novo binding site for the SSP is created by the -202(C-->G) mutation that causes hereditary persistence of fetal hemoglobin (HPFH). This site functions in an analogous manner to the SSE in hybrid beta-promoter/reporter gene constructs transfected into K562 cells. In contrast, the wild-type -202 sequence, which fails to bind the SSP, is incapable of activating the beta-gene promoter. Both the -50 and -202 HPFH sites for SSP binding overlap a consensus sequence for the transcriptional regulator Sp1. In addition, both sites contain CpG dinucleotides that are contact bases for SSP. Since the gamma promoter is known to be hypomethylated in fetal cells but fully methylated at CpG residues in adult erythroid cells, we examined the effects of this DNA modification on protein binding to the two regions. Gel mobility shift assays with nuclear extract from K562 cells (which contain both Sp1 and SSP) demonstrate preferential binding of SSP to the SSE and HPFH sites under conditions in which probe was limiting. Methylation of the CpG residues reverses this preference only in the SSE site, with a marked increase in the binding of Sp1 at the expense of the SSP. Purified Sp1 binds with 10-fold higher affinity to the methylated than to the nonmethylated -50 probe but with the same affinity to the -202 HPFH probe. The methylation-induced preferential binding of Sp1 to the SSE at the expense of SSP may be part of the mechanism by which the gamma genes are repressed in normal adult erythroid cells. In cells containing the -202 HPFH mutation, the inability of Sp1 to displace SSP in the methylated state may explain the persistence of gamma-promoter activity and gamma-gene expression observed in adults with this mutation.

Methylation-enhanced binding of Sp1 to the stage selector element of the human gamma-globin gene promoter may regulate development specificity of expression

We report a 10 year old girl with congenital thrombocytopenia with absent radii (TAR) syndrome. Unusually this patient has shown no abnormal bleeding tendency despite numerous orthopaedic procedures. There is evidence of an associated immune component to the thrombocytopenia which has not been previously documented.

Thrombocytopenia--radial aplasia (TAR) syndrome with associated immune thrombocytopenia.

"Remote effects" of cancer on the nervous system (paraneoplastic syndromes) are disorders of the nervous system of unknown cause that occur almost exclusively, or with greatly increased frequency, in patients with identifiable or occult cancer. There are several hypotheses concerning the pathogenesis of these rare disorders. One hypothesis is that the underlying tumor and portions of the nervous system share antigens and that an autoimmune response generated against the tumor causes the nervous system disorder. Evidence supporting this hypothesis includes the ability to transmit the Lambert-Eaton Syndrome (a paraneoplastic syndrome involving the neuromuscular junction) to experimental animals by infusing IgG from patients with the disorder, the presence of autoantibodies against Purkinje cell neurons in some patients with paraneoplastic cerebellar degeneration, and the presence of autoantibodies against many neurons in patients with sensory neuronopathy and encephalomyelitis. Other evidence supporting the hypothesis is presented in this review.

Autoimmune pathogenesis of paraneoplastic neurological syndromes.

Nutrition support during the acute care of moderately or severely burned patients.

Characterization of glycated hemoglobin in diabetic patients: usefulness of electrospray mass spectrometry in monitoring the extent and distribution of glycation.

Previous studies indicate that resting energy expenditure is elevated in children with sickle cell anemia, possibly caused in part by hemolysis and increased erythropoietic activity. The purpose of the present investigation was to determine whether erythrocyte transfusion normalizes resting energy expenditure in sickle cell anemia.

METHODS
Five adolescents with sickle cell anemia (12-16 years old; 4 boys, 1 girl) were studied before and 1 week after erythrocyte transfusion before elective surgery or at the initial transfusion for growth failure. Resting energy expenditure was measured by indirect calorimetry, and laboratory measures were determined by routine, validated methods. Data comparisons were by nonparametric analysis.

RESULTS
After erythrocyte transfusion, total hemoglobin levels increased (difference (D) = 15 g/l; p < 0.05), whereas hemoglobin S (D = -0.36; p < 0.05) and reticulocyte count (D = -0.12; p < 0.05) decreased. Mean pretransfusion resting energy expenditure was elevated to 124% above predicted levels (p < 0.05) and increased further to 134% above prediction (p < 0.05 vs. pretransfusion levels). Plasma triiodothyronine (T3) levels increased (D = 0.17 nmol/l; p < 0.05), reverse T3 (rT3) levels tended to decline (D = -0.04 nmol/l; p = 0.14), and rT3/T3 decreased (D = -0.03; p < 0.05). Plasma insulin-like growth factor-I (IGF-I) levels were low-normal before transfusion and did not change, despite the change in resting energy expenditure.

The results confirm that resting energy expenditure is elevated in patients with sickle cell anemia. However, resting energy expenditure further increased after transfusion, despite decreased erythropoietic activity. A posttransfusion decrease in rT3/T3 may contribute to the increased resting energy expenditure. That there was no change in IGF-I implies that the growth hormone-IGF system is not involved in posttransfusion regulation of resting energy expenditure. Therefore, our data are not consistent with the hypothesis that increased resting energy expenditure in sickle cell anemia is directly related to erythropoietic activity. The mechanisms by which resting energy expenditure increases after transfusion in sickle cell anemia require additional investigation.

Effects of red blood cell transfusion on resting energy expenditure in adolescents with sickle cell anemia.

The cellular uptake of vitamin C (ascorbic acid, ASC) is promoted by insulin and inhibited by hyperglycemia. If a rise in plasma ASC is uncoupled from insulin replacement in insulin-dependent diabetes mellitus (IDDM) then the degree of hyperglycemia could account for "tissue scurvy" in IDDM. Leukocyte ASC is lower in IDDMs compared with nondiabetics when vitamin C consumption is adequate and our data suggest that this is a variable component of the pathophysiology of IDDM. The complications of diabetes mellitus are believed to result from either the intracellular accumulation of sorbitol or the nonenzymatic glycoxidation of proteins or both. With respect to the abnormal cellular accumulation of sorbitol, vitamin C supplementation has been shown to be effective in several studies of adults with diabetes; the situation regarding the prevention of protein glycoxidations by supplementation is presently unclear. The roles of ASC as an aldose reductase inhibitor and a water soluble antioxidant in body fluids are potentially very important as adjuncts to tight glycemic control in the management of diabetes. Tissue saturation and maximal physiologic function in IDDM may require supplemental vitamin C intake.

The glucose/insulin system and vitamin C: implications in insulin-dependent diabetes mellitus.

Hyperglycemia portends chronic complications in insulin-dependent diabetes mellitus (IDDM) and substantial benefits are associated with "tight" glycemic control. Other interventions should either enhance glycemic control per se or add benefit to an established degree of glycemic control. Several micronutrients enhance insulin action and others offer promise in countering the untoward consequences of hyperglycemia. Supplements of micronutrients including the vitamins niacin (as niacinamide), C and E and the minerals zinc, chromium and vanadium have been studied. For the purpose of this review, the term "nutriceutic" refers to supplementation on the order of 2 to 10 times the RDA for which a benefit is linked to a mechanism of action. Benefits associated with "nutriceutic" supplementation are reported in small trials for vitamins C and E and these supplements are safe and affordable from food or tablet sources. A dietary strategy adding 200-600 mg of vitamin C and 100 IU of vitamin E to a healthy dietary pattern is worthy of consideration as an intervention for individuals with IDDM.

Micronutrients as nutriceutical interventions in diabetes mellitus.

RESTING ENERGY EXPENDITURE (REE) IN ADOLESCENTS WITH SICKLE CELL ANEMIA(SCA): EFFECTS OF RED BLOOD CELL (RBC) TRANSFUSION THERAPY

Growth retardation is common in children with SCA, in spite of adequate dietary intakes. Previous studies have demonstrated elevated REE in children with SCA. An increased metabolic rate may be secondary to rapid hemolysis of sickled cells and the compensatory erythropoietic activity. The purpose of the current investigation was to determine whether the elevated REE in children with SCA can be normalized by RBC transfusion therapy. Five children aged 12 to 16 years (4 males, 1 female) were studied before and one week after a scheduled RBC transfusion. Measurements included anthropometics (height, weight), REE by indirect calorimetry, hemoglobin, reticulocyte count, and percent HgS. Growth failure was seen in 3 of 5 subjects who were below the 25% ile by NCHS standards for height. Pre-transfusion REE was significantly elevated above predicted REE (28%, p≤0.04, Wilcoxon matched-pairs signed-ranks test) consistent with reports in the literature. Surprisingly, REE increased further after RBC transfusion to 37% on average above predicted REE (pre versus post REE, p≤0.08) despite a significant decrease in erythropoietic activity (reticulocyte count: Δ = -9.3%, p≤0.04). Four of 5 subjects showed an increase in REE after RBC transfusion. The subject who had no change in REE demonstrated an increase one week after receiving a second RBC transfusion. Anemia improved after RBC transfusion with an increase in hemoglobin (Δ=1.5 g/dl, p≤0.04), and decrease in Hgb S (Δ=-31.4%, p≤0.04). These results suggest that REE is not correlated with erythropoietic activity in children with SCA and may, in fact, increase when RBC transfusion decreases erythropoietic activity. A possible explanation for this increase includes the hypothesis that a relatively hypoxic catabolic hypermetabolism exists prior to RBC transfusion that transitions in children with SCA to a more hypermetabolic anabolic state after RBC transfusion. If proven, this might explain the catch-up growth observed in children with SCA who receive chronic RBC transfusion therapy.

The Effect of Red Blood Cell (RBC) Transfusion Therapy on Resting Energy Expenditure (REE) in Patients with Sickle Cell Anemia (SCA). † 658

Energy and protein provisions for adequate wound healing and weight maintenance were examined among severely burned children. Actual intakes were documented for 27 patients admitted with a more than 40% total body surface area burn. Mean energy intake over the 4-week study period averaged 140% of the predicted basal metabolic rate (PBMR), and mean protein intake was 2.8 +/- 0.2 grams per kilogram daily. Wound healing progressed satisfactorily in all patients; at 4 weeks, the open wound area (% open) was 20% or less in 22 patients. Average weight at discharge was 88% +/- 2.6% of ideal body weight. Discharge weights were significantly higher (p < 0.05) among patients whose energy intake exceeded PBMR x 1.7 for at least 1 of the study weeks. We suggest that energy intakes approximating PBMR x 1.2 with a minimum of 3 grams of protein per kilogram will support adequate wound healing, whereas higher energy provisions (PBMR x 1.7) will enhance weight status.

Energy and protein provisions for thermally injured children revisited: an outcome-based approach for determining requirements.

Physiologic hypoalbuminemia, defined as a plasma albumin (pl-ALB) of 1.0 to 2.5 g/dL, is a component of the injury response. A consensus on the need for albumin supplementation in this setting is lacking.

METHODS
We examined 27 consecutive children (age, 7 +/- 6 years) with > 40% body surface burns (mean, 59 +/- 18%) during their initial 4 weeks of care. Patients were managed with an albumin-supplementation protocol that tolerated profound physiologic hypoalbuminemia. Intravenous albumin was administered by infusion of 1 to 2 g/kg/d when pl-ALB fell below 1.0 g/dL, or below 1.5 g/dL in the presence of enteral feeding intolerance or pulmonary dysfunction. Supplementation was stopped when pl-ALB reached 2.0 g/dL.

RESULTS
Mean pl-ALB was 1.7 g/dL overall. Infusion for pl-ALB < 1.0 g/dL was needed for 70% (n = 19) of the patients. Profound physiologic hypoalbuminemia was constant, that is, mean weekly pl-ALB never exceed 2.5 g/dL in any patient. Mean plasma globulin rose during the 4 week period from 2.3 +/- 0.1 at week 1 to 3.1 +/- 0.1 at week 4. Diarrhea was negligible (19 of 756 patient days), nasogastric feedings were well tolerated, PaO2/FiO2 ratios remained well above 150, wounds healed satisfactorily, and all children survived and have been discharged home.

Profound physiologic hypoalbuminemia (pl-ALB of 1.0-2.5 g/dL) does not have adverse effects on pulmonary or gut function, wound healing, or outcome in severely burned children, perhaps because of a compensatory increase in acute-phase proteins reflected in plasma globulin.

Physiologic hypoalbuminemia is well tolerated by severely burned children.

Is potassium needed in sports drinks for fluid replacement during exercise?

Low ceruloplasmin levels during recovery from major burn injury: influence of open wound size and copper supplementation.

Elevated plasma ceruloplasmin in insulin-dependent diabetes mellitus: evidence for increased oxidative stress as a variable complication.

ZINC STATUS, ZINC INTAKE, AND EFFECTS OF VITAMIN C SUPPLEMENTATION IN FEMALE COLLEGIATE SOCCER PLAYERS: 76

Specialized nutrition support is initiated during hospital care on the assumption that sparing the mobilization of body energy reserves is advantageous to recovery. The combined effects of disease and undernutrition on body cell mass, organ function, immune responsiveness, and wound healing are well documented in adults. Children cannot survive a fast as long as adults because of their lesser stores of energy substrates relative to the rate of energy expenditure. The present contribution attempts to estimate the rates of compositional losses for infants and prepubertal children on the basis of available data and reasonable metabolic assumptions. The lesson that emerges from this exercise is one of a very critical need for the early initiation of nutrition support for infants and children. The analysis suggests that an acute risk of protein depletion exists for children of all ages. Especially for infants, the empirical wisdom that "the absence of evidence is not evidence of absence" should be invoked to support early nutrition intervention. This work is submitted for critical review and revision to establish a consensus on the timeline of pediatric morbidity or mortality from semistarvation or starvation.

Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition

Body composition and nutrition support in pediatrics: what to defend and how soon to begin.

Hyperzincuria in individuals with insulin-dependent diabetes mellitus: concurrent zinc status and the effect of high-dose zinc supplementation.

The effects of 9 weeks of daily chromium supplementation (200 microgram Cr as picolinate) were investigated in a double-blind design in football players during spring training. Testing was done pre-, mid-, and postsupplementation on the following criterion measures: urinary chromium excretion, girth and skinfold measures, percent body fat and lean body mass, and isometric and dynamic strength. With the exception of 2 variables (of 65 variables analyzed), no significant group by trials interactions were found (based on a repeated measures ANOVA). The two exceptions were unrelated and inconsequential. For 27 of the 38 subjects, average urinary chromium loss at pre was 0.36 microgram/24 hr, whereas it was undetectable (<0.1 microgram/24 hr) for 10 subjects and excessive in 1 subject (2.4 micrograms/24 hr). Subjects receiving chromium supplements demonstrated urinary chromium losses five times greater than those in the placebo group at mid and post. Chromium picolinate supplementation was ineffective in bringing about changes in body composition or strength during a program of intensive weight-lifting training.

Effects of chromium picolinate supplementation on body composition, strength, and urinary chromium loss in football players.

N x 6.25: recognizing a bivariate expression for protein balance in hospitalized patients.

ROLE OF GROWTH-FACTOR RECEPTOR BLOCKADE IN THE INHIBITION OF INTESTINAL-CELL GROWTH BY INFANT FORMULAS

OBJECTIVE
Diabetic hyperglycemia promotes sorbitol production from glucose via aldose reductase. Since the intracellular accumulation of sorbitol, or its sequelae, are postulated to contribute to the progression of chronic diabetic complications, aldose reductase inhibitors (ARI) offer therapeutic promise. Others have shown that vitamin C at pharmacologic doses decreases erythrocyte (RBC) sorbitol. We examined whether smaller, physiologic doses of vitamin C were also effective in individuals with insulin-dependent diabetes mellitus (IDDM) and whether vitamin C was an ARI in vitro.

METHODS
Vitamin C supplements (100 or 600 mg) were taken daily for 58 days by young adults with IDDM and nondiabetic adults in an otherwise free-living design. Diabetic control was monitored by fasting plasma glucose, glycosylated hemoglobin, and glycosuria and was moderate to poor throughout the study. RBC sorbitol was measured at baseline and again at 30 and 58 days. Three-day dietary records and 24-hour urine collections were performed for each sampling day.

RESULTS
RBC sorbitol levels were significantly elevated in IDDMs, on average doubled, despite their more than adequate dietary intakes of vitamin C and normal plasma concentrations. Vitamin C supplementation at either dose normalized the RBC sorbitol in IDDMs within 30 days. This correction of sorbitol accumulation was independent of changes in diabetic control. Furthermore, our in vitro studies show that ascorbic acid inhibited aldose reductase activity.

Vitamin C supplementation is effective in reducing sorbitol accumulation in the erythrocytes of diabetics. Given its tissue distribution and low toxicity, we suggest a superiority for vitamin C over pharmaceutic ARIs.

Vitamin C: an aldose reductase inhibitor that normalizes erythrocyte sorbitol in insulin-dependent diabetes mellitus.

Patients with burns lose large amounts of water through evaporation from open wounds. Because the wound covering is the first line of defense for maintenance of body fluid balance in these patients, quantification of the evaporative water loss through wound coverings at the bedside would improve the accuracy of estimations of body water loss. The present experiment evaluates the use of a small ventilated capsule system automated with miniature resistance-type dew-point sensors for measurement of evaporative water loss through biologic dressings under simulated wound conditions. Evaporative water loss from wounds was simulated by pilocarpine-induced profuse sweating on the forearm. Evaporative water loss through uncovered skin was compared with that of skin covered with commercially available temporary wound dressings. Compared with an adjacent unstimulated area, forearm dew-point temperature in the capsule (Tcdp) and sweat rate increased immediately after pilocarpine exposure and remained significantly elevated and relatively constant for an additional 60 minutes. Evaporative water loss of the forearm was 29 +/- 4.8 gm/m2/hr (mean +/- SE) at baseline and rose significantly to 275 +/- 18.2 gm/m2/hr after pilocarpine exposure. The pilocarpine-stimulated sweat rate and Tcdp at neutral conditions were similar to those obtained from walking on a treadmill for 60 minutes in a 30 degrees C room. Compared with pilocarpine-induced evaporative water loss of the uncovered skin, temporary wound dressings significantly reduced evaporative water loss by 40% to 60%. No significant differences were observed between varieties of temporary wound dressings differing in thickness and/or porosity.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaporative water losses through a temporary wound dressing under simulated wound conditions.

Copper (Cu) is an essential nutrient with known metabolic roles in wound healing. Ceruloplasmin (CP), the primary Cu-transport protein, responds as an acute-phase reactive protein after trauma. However, for severe burn trauma, this response is absent in the early catabolic phase despite Cu provision. We report data for 14 severely burned children receiving Cu in total parenteral nutrition (TPN-Cu) ranging from 7 to 26 micrograms Cu.kg-1 x day-1. All patients manifested low plasma levels of CP. The reduction in CP reflected burn severity but also appeared to be dependent on the Cu dose. Increasing Cu supplementation to improve CP raises a concern for hepatotoxicity, which is accompanied by an elevation in the plasma nonceruloplasmin Cu (nonCP-Cu). The calculated plasma nonCP-Cu in our series is consistent with a lack of increased risk and suggests that TPN-Cu at the general pediatric guideline of 20 micrograms.kg-1 x day-1 is safe and reasonable for severely burned children. Cu supplementation > 20 micrograms/kg may be beneficial; however, monitoring of both CP and total Cu should continue as standard practice in the management of these patients.

Burn severity, copper dose, and plasma ceruloplasmin in burned children during total parenteral nutrition.

COMPARISON OF HYDROSTATIC WEIGHING TO BIOELECTRICAL IMPEDANCE IN COLLEGE FEMALE CROSS-COUNTRY RUNNERS

URINARY CHROMIUM LOSS AND DIET ANALYSIS IN FOOTBALL PLAYERS: 286

THE EFFECT OF DIETARY COPPER (CU) AND SEVERE THERMAL-INJURY ON MURINE SYSTEMIC AND MUCOSAL IMMUNE-RESPONSE

Alterations in zinc (Zn) and copper (Cu) homeostasis have been reported during the acute recovery period following thermal injury in both children and adults. Increased urinary losses of Zn and Cu and decreased plasma concentrations of Zn, Cu, and ceruloplasmin (CP), the major copper transport protein, occur despite adequate provision of these elements in enteral feedings. We now report data for moderately to severely burned children receiving total parenteral nutrition (TPN) supplemented to provide Zn and Cu. Hyperzincuria occurred consistently when 50 micrograms/kg Zn was delivered daily to older children. Similarly, when younger children received 100 micrograms/kg Zn daily, profound hyperzincuria ensued despite a reduction in total plasma Zn. Hypozincemia was accompanied by low levels of Zn in the plasma subfraction normally associated with albumin-bound Zn. The delivery of Cu via TPN was 4-12 micrograms/kg daily, and urinary Cu losses were not elevated. Plasma total Cu and plasma CP were invariably reduced. These findings are discussed in relation to guidelines published for pediatric trace element supplementation during TPN.

Differences in body composition have often been examined in conjunction with measurements of energy expenditure in men and women. Numerous studies during the past decade examined the relationship between resting energy expenditure (REE) and the components of a two-compartment model of composition, namely the fat-free mass (FFM) and the fat mass (FM). A synthetic review of these studies confirms a primary correlation between REE and FFM in adults over a broad range of body weights. A generalized prediction equation is proposed as REE = 370 +/- 21.6 x FFM. This equation explains 65-90% of the variation in REE. Several studies suggest, further, that FFM predicts total daily energy expenditure (TDEE) equally well. An independent contribution by FM to the prediction of either REE or TDEE is not supported for the general population, perhaps reflecting the relative constancy of the absolute FM in nonobese individuals. In the subset of obese women, FM may be a significant predictor.

Body composition as a determinant of energy expenditure: a synthetic review and a proposed general prediction equation.

Reduced mononuclear leukocyte ascorbic acid content in adults with insulin-dependent diabetes mellitus consuming adequate dietary vitamin C.

The response to injury includes an acute-phase stimulation of plasma ceruloplasmin (CP). Patients recovering from nonburn trauma respond to copper (Cu) supplementation by increasing CP. However, plasma CP has been observed to decrease following moderate to severe burn injury, despite adequate enteral provision of Cu. The authors delivered intravenous Cu via TPN to 10 burned children daily at LOW dose or at HIGH dose during the first 3 weeks of recovery. Plasma CP and total Cu (tot Cu) were measured and nonceruloplasmin' Cu (nonCP-Cu) was calculated assuming 3 ug Cu/mg CP. All patients had low CP (range 6-25 mg/dl, normal = 27-37 mg/dl). The HIGH dose raised both CP and tot Cu without increasing non CP-Cu without increasing nonCp-Cu. CP explained 32% of the tot Cu variance while dose and CP explained 84%. Tot Cu was negatively correlated with % BSA burned. They also observed that this relationship does not hold for burns exceeding 95% BSA. These results are consistent with observations for enteral Cu in burns. They show that CP is responsive to dose in burns and suggest at least 20ug/kg as an appropriate daily Cu dose in TPN for burns.

Plasma ceruloplasmin and total copper levels in burned children receiving parenteral copper: Effect of dose and burn severity

Severely burned adults increase their metabolic energy expenditure (MEE) to levels approaching twice the normal resting metabolic rate (RMR). There are no available measurements of MEE for severely burned infants and toddlers, however, and nutritional support relies on published estimates of MEE that range from 200% to 400% of RMR. We determined the actual calories provided to 10 infants and children ages 3-33 mo during acute care for severe burns (59 +/- 5% total-body-surface burn). Our standard protocol emphasizes the delivery of amino acids at 3 g.kg-1.d-1 in conjunction with prompt excision and grafting. An anabolic state characterized by weight maintenance and healing was supported with far fewer calories than predicted by four published formulas for MEE. We conclude that when greater than 2.5 g.kg-1.d-1 protein is provided, efficient protein utilization for recovery is achieved with calorie provision at 120-200% RMR in severely burned infants and toddlers.

Calorie and protein provision for recovery from severe burns in infants and young children.

Calculation of energy expenditure from indirect calorimetry: assessment of the Weir equation.

In summary, a remarkably close agreement exists for the mean MEE measured in 28 studies of severe burn trauma. This is especially surprising given the variability in sample sizes, measurement techniques, study designs, and DPBs studied. The mean MEE calculated from the data published in these reports is listed in the final column of Table I. For more than 450 cases, an unweighted MEE is 2750 +/- 85 kcal/day. For those studies prior to 1980, the mean MEE exceeds 3000 kcal/day in eight of 14 reports vs only two of 14 published after 1980. Even so, the mean MEE for the pre-1980 reports differs by only 200 kcal/day (2960 +/- 120, n = 14). The accepted notion that the degree of elevation in MEE is in proportion to the % BSAB up to about 60% BSAB is useful in a general sense but must be applied with caution. The recent studies, which include proportionately more burns exceeding 80% BSAB, suggest an elevation in MEE in these cases. Nevertheless, a physiologic plateau apparently exists at or slightly below 2 x normal RMR at the peak of MEE. The magnitude of the MEE response results from an undefined interaction among several factors of which some have been examined while others such as inflammatory mediators are only beginning to receive study. The contributions to reduction in MEE from interventions to control cardiac output and peripheral cooling, core temperature, evaporative water (heat) loss, and substrate cycling have been reviewed. The importance of indirect calorimetry in patient care is highlighted by the large variability in similarly injured individuals and in the unexplained component of regression analyses.(ABSTRACT TRUNCATED AT 250 WORDS)

Factors contributing to increased energy expenditure in thermal injury: a review of studies employing indirect calorimetry.

Major burn trauma produces large elevations in metabolic energy expenditure (MEE) during acute care. However, overfeeding can occur and is detrimental to recovery. The formulae often used to estimate caloric support to meet MEE are based on body weight, predicted resting metabolic rate (RMR), body surface area, or the total body surface area burned (BSAB). These predictive equations originate from studies of less than or equal to 30 patients generally lacking measurements beyond the third week of convalescence. We report 565 measurements by indirect calorimetry for 122 adults between the burn day and day 149 postburn. A standardized protocol of nutritional support and early wound closure was followed. Predictions of MEE are compared in subcategories of BSAB (2-25%; 30-50%; 51-75%; and 76-98%). For major burns exceeding 30% BSAB, 2X the predicted RMR was consistently closest to the measured MEE, assuring adequate calorie provision while minimizing the risk of overfeeding.

Measured and predicted calorie requirements of adults during recovery from severe burn trauma.

PARENTERAL-NUTRITION FOR SEVERELY BURNED CHILDREN - ASSESSMENT OF THE AMA GUIDELINES FOR ZINC, COPPER AND MANGANESE

Bolus intracerebroventricular delivery of corticotropin-releasing factor (CRF) elicits acute responses of both the pituitary-adrenal axis and the sympathetic nervous system. We examined whether these stresslike responses could be maintained over a period of days by central delivery of CRF in nonstressed rats, as would be predicted if this peptide participates in the central nervous system regulation of chronic stress. CRF (4.3 or 21.5 micrograms/day) was continuously delivered into the cerebral ventricle via Alzet minipumps. In contrast to saline-infused controls, rats receiving CRF exhibited elevated excretions of corticosterone, norepinephrine, and urea nitrogen for several days. Thereafter, an attenuation of CRF responsiveness occurred when corticosterone excretion returned to basal levels despite continued central CRF infusion. However, CRF delivered intravenously during attenuation stimulated adrenocorticotropic hormone and corticosterone secretion, implicating a hypothalamic rather than pituitary locus for central CRF resistance. The present data do not permit a conclusion on whether the attenuation of the CRF response with time is the result of an ultrashort-loop negative-feedback mechanism or CRF receptor desensitization.

Chronic intracerebroventricular CRF infusion attenuates ACTH-corticosterone release.

Hypomagnesemia is reportedly a common complication of care during the early period of recovery from major trauma. Aminoglycoside treatment, by provoking inappropriate renal magnesium wasting, may contribute to the frequency of hypomagnesemia. We examined the magnesium (Mg) status of six severely burned adolescents during the early phase of recovery. Although provision of Mg met recommended levels, hypomagnesemia occurred in every patient. Two of five of our patients were hypomagnesemic during gentamycin treatment, and five of five during subsequent tobramycin therapy (including the three not affected by gentamycin). Additional episodes occurred in five patients in the absence of aminoglycosides. An interrelationship between Mg status and efficacy of potassium repletion is detailed for one patient. Hypomagnesemia during tobramycin treatment was associated with refractoriness to potassium repletion. Recurrence of hypokalemia during a subsequent diuresis-induced hypomagnesemia was prevented by Mg supplementation. The Mg requirement is increased during recovery from severe burns and appears to exceed that provided by commercially available enteral formulations.

Hypomagnesemia: a multifactorial complication of treatment of patients with severe burn trauma.

Metabolic defects in obese (fa/fa) Zucker rats have previously been shown to be reversed by adrenalectomy; however, hypercorticosteronemia has not been demonstrated. We now report that the total daily excretion of corticosterone and urea nitrogen are significantly greater (P less than 0.01) in obese Zucker rats than in age-matched lean Zucker rats. This excessive excretion of corticosterone is not of autonomous adrenal origin, since dexamethasone treatment (20 micrograms/kg X day) for 2 days induced a proportionate reduction in corticosterone excretion (approximately 50%) in both obese and lean Zucker rats. Corticosterone excretion was further suppressed to levels not different from those in lean rats after 2 days of dexamethasone (40 micrograms/kg X day). Both the peak and total pituitary beta-endorphin secretion in response to an iv bolus of corticotropin-releasing factor (CRF) were diminished in obese Zuckers. The response to CRF in obese Zucker rats was dampened and superimposable on that of dexamethasone-treated lean Zucker rats, suggesting the existence of chronic hypercorticosteronemia as a component of this genetic obesity. These observations provide evidence for a compensatory alteration of the pituitary-adrenal axis. We suggest that corticosterone turnover may be increased in obese Zucker rats.

Hypercorticosteronuria and diminished pituitary responsiveness to corticotropin-releasing factor in obese Zucker rats.

A closed-circuit metabolic system has been designed and tested for multiple applications. Air pressure within a closed chamber is regulated electronically while allowing for respiratory gas exchange. Compared with a previously reported standard indirect calorimetry system, the new device had by virtue of longer duration of measurement improved precision (coefficient of variation 3% vs. 14%) during studies of O2 consumption both at room temperature and at 5 degrees C. In addition, a more physiological atmospheric environment is maintained. This system has also been utilized for simultaneously labeling groups of up to 20 weanling rats with 18O2 over a 2-day period and for exposure of rats to a hyperoxic (84% O2), normobaric environment for 4-day periods. Potential applications include maintenance of pressure (hypobaric through hyperbaric) and O2 (hypoxic through hyperoxic) controlled environments, exposure to toxic gases, study of diurnal variations in metabolic rate, measurement of metabolic expenditure with activity, and adaptation to other species including humans.

In vivo total body electrical conductivity following perturbations of body fluid compartments in rats.

Cold-exposed rats exhibit hypermetabolism, hyperphagia, and increased glucose oxidation. Their counterregulatory hormone secretion is markedly elevated, while insulin levels fall acutely, gradually returning to basal during acclimation. We assessed both hepatic and peripheral sensitivity to insulin in rats in the basal state and after 5 days of cold (5 C) exposure. The contribution of gluconeogenesis to total glucose turnover was measured and compared to daily urinary corticosterone excretion. Hepatic glucose production was equally suppressed by the infusion of insulin at 1.2 mU/kg X min in both control and cold-acclimated rats, but enhanced hepatic sensitivity to low dose (0.6 mU/kg X min) insulin infusion was only observed after cold exposure. The metabolic clearance of glucose was elevated with cold stress and was insensitive to the infusion of insulin at either level. Insulin resistance was not observed. Urinary excretion of corticosterone and urea nitrogen were markedly increased, but creatinine excretion was unchanged, suggesting that the concurrent increase in gluconeogenesis resulted from increased protein intake rather than increased catabolism of muscle protein.

Enhanced hepatic insulin sensitivity and peripheral glucose uptake in cold acclimating rats.

The analysis of glucose kinetics using a single jugular catheter in awake rats.

Intracerebroventricular (icv) bolus injection of cortico-tropin releasing factor (CRF) induces hypermetabolism, catecholamine surge and excess adrenocortical hormone secretion. Chronic icv CRF infusion in rats induces this stress-like picture for 2-3 days. However, corticosterone (B) excretion falls below that of sham rats by day 5. This dampened response to sustained CRF resembles the “adrenal exhaustion” phenomenon described in severe trauma and led to the present study: Jugular catheters were placed prior to icv cannulation and chronic delivery of CRF 20 ug/d or of saline. Hypersecretion of B on day 2 (0.7 ±0.15 ug/d) in CRF rats was suppressed on day 5 (0.3 ±.05, n=8, p<0.01). A 10 ug iv CRF bolus on day 5 caused exaggerated ACTH coupled with elevated plasma B:These results suggest: a suppressed adrenal function induced by chronic icv CRF similar to that after severe trauma and 2) a hypothalamic abnormality rather than primary pituitary or adrenal failure.

441 SIMULATION OF THE “ADRENAL EXHAUSTION” PHENOMENON BY icv CRF

To evaluate the effects of exercise on net protein catabolism, the losses of urea in sweat and urine and urinary creatinine and 3-methylhistidine (3MH) excretion were determined in eight healthy subjects during cycle ergometer exercise performed at approximately 45% of VO2max for 90 min. The subjects ingested a meat-free diet for 5 days starting 3 days before and continuing for 1 day after the day of exercise. During exercise, total urea excretion (urine + sweat losses) increased 100% above pre- and postexercise values. Thirty percent of the total urea excretion during exercise was in the form of sweat losses. Total protein breakdown (as reflected by urea excretion), however, could account for less than 5% (21 +/- 4 kcal) of total calorie expenditure during the exercise (567 +/- 83 kcal). Urinary creatinine excretion increased by 50% during exercise. Urinary excretion of 3MH also tended to rise, but the ratio of urinary 3MH to creatinine showed no change in response to exercise. We conclude that 1) light to moderate exercise results in an increase in net protein catabolism and an increase in creatinine excretion; 2) sweat losses are an important route for urea excretion during exercise; 3) there is no evidence of a disproportionate increase in breakdown of myofibrillar contractile proteins; and 4) in spite of the increase in the rate of protein catabolism, protein is only a minor source of energy during light to moderate exercise.

Influence of exercise on urea, creatinine, and 3-methylhistidine excretion in normal human subjects.

The plasma amino acid response to cafeteria feeding in the rat: influence of hyperphagia, sucrose intake, and exercise.

Levothyroxine (T4) replacement need in adults with primary hypothyroidism has recently been reported to fall with age. Previous studies have demonstrated that the resting metabolic rate falls with age in euthyroid adults and that this fall is proportional to a reduction in lean body mass (LBM). Since LBM is correlated also with 24‐hour energy expenditure, this study examined the possibility that LBM might be an accurate predictor of T4 requirement. Seventy‐five hypothyroid adults receiving full replacement therapy, ranging in age from 24 to 88 years, were studied retrospectively. Lean body mass was found to be a better predictor of T4 requirement than age or weight for the entire group as well as for subgroups of men and women 51 years old and older. The age‐related reduction in LBM may be responsible for the reported decrease in the rate of fractional thyroxine degradation with age.

Lean Body Mass is a Predictor of the Daily Requirement for Thyroid Hormone in Older Men and Women

Resting metabolic rate (RMR) was determined in 10 obese and 10 nonobese women after an overnight fast and for 3 h after the ingestion of an 800-kcal liquid meal. In the fasting state, absolute energy expenditure in the obese (4.8 +/- 0.2 kJ/min) was 25% greater than in the nonobese (P less than 0.005), but was comparable with the nonobese when expressed in relation to body surface area or lean body mass and was reduced by 20% when expressed per kilogram body weight3/4 (P less than 0.005). Meal ingestion resulted in a 14-16% increase in RMR (postprandial thermogenesis) that was similar in the two groups, so that absolute energy expenditure in the obese remained 22-25% higher than in the nonobese throughout the postprandial period. The estimated overall (fasting and postprandial) increase in resting caloric expenditure in the obese as compared with the nonobese was 350-375 kcal/day.

Energy expenditure in obesity in fasting and postprandial state.

This study was undertaken to examine glucose turnover during a 30-min recovery period following an acute bout of intensive exercise (85% VO2 max) performed to exhaustion (11.7 ± 1.4 min). Plasma glucose (basal 85 ± 2 mg/dl) rose by 10 mg/dl at exhaustion and increased further during the initial phase of recovery, reaching a peak value of 35 mg/dl above basal at 5 min of recovery. Thereafter, there was a gradual decline, but the values remained 15–20 mg/dl above basal at 30 min. The early rise in plasma glucose during recovery was due to an imbalance between glucose production and utilization caused by a more rapid decline in utilization than production. At 5 min of recovery, glucose production was fivefold greater than in the basal state and comparable to peak values observed at exhaustion, while glucose utilization was 33% lower than observed at exhaustion and only 75% higher than in the basal state. Beyond 5 min of recovery glucose utilization and production again differed in the direction of response. Glucose production fell to basal values while glucose utilization remained 70–80% above baseline. The maintenance of basal rates of glucose production and increased rates of glucose utilization occurred in a setting in which plasma insulin levels were increased by 25–50%. Plasma catechol-amines, which rose 5–10-fold during exercise, fell rapidly during the initial 3 min of recovery. We conclude that recovery from exhaustive exercise is characterized by a biphasic imbalance between glucose production and utilization in which production exceeds utilization for the initial 5 min and utilization exceeds production at 10–30 min. The hormone-substrate milieu (modest increments in plasma insulin and glucose) accompanying the changes in glucose kinetics observed beyond 5 min suggests that the recovery period from acute exercise may be characterized by an increase in peripheral sensitivity to insulin, which could provide a mechanism for facilitating muscle glycogen repletion during recovery from intensive exercise.

We examined the relationship among glucose tolerance, efficiency of weight gain, and cellularity of brown adipose tissue (BAT) in rats (initial weight: 362 ± 1 g) made hyperphagic and obese by feeding on a highly palatable “cafeteria” (CAF) diet for 4–8 wk. As compared with chow-fed controls, CAF feeding resulted in a 45–60% increase in caloric intake (P < 0.01), a 40–50% increase in weight gain (P < 0.01), and hyperinsulinemia. Glucose disposal rate (K) on intravenous glucose tolerance test (IVGTT) was ≥ 1.4% in all chow-fed rats, but fell to ≤ 1.3 in 10 of 23 CAF-fed rats. As compared with the chow-fed controls, rats with normal glucose tolerance demonstrated a 12% decline in efficiency of weight gain (g/100 kcal of food consumed) in response to CAF feeding (P < 0.05). In marked contrast, in rats with impaired glucose tolerance, efficiency of weight gain failed to decline in response to overfeeding and was 18% higher than in the overfed group with normal glucose tolerance (P < 0.01). Although CAF feeding increased the mass of interscapular BAT by 110–130% in rats with normal as well as impaired glucose tolerance, DNA content of BAT rose only in the normal-K CAF-fed rats (0.19 ± 0.01 mg DNA/100 mg versus 0.12 ± 0.02 in chow-fed controls and 0.12 ± 0.01 in low-K rats). We conclude that (1) impaired glucose tolerance accompanying dietary-induced obesity is associated with an increase in efficiency of weight gain and (2) failure of BAT cellularity to increase may contribute to the increase in efficiency. These data suggest that the link between obesity and diabetes may be bidirectional: obesity increases the risk of diabetes while impaired glucose tolerance may accelerate the development of obesity by enhancing efficiency of weight gain.

Increased Efficiency of Weight Gain and Altered Cellularity of Brown Adipose Tissue in Rats with Impaired Glucose Tolerance During Diet-induced Overfeeding

A short burst of intensive exercise (100-m swim lasting one minute and resulting in a 12-fold rise in the level of blood lactate) resulted in frank hypernatremia (serum sodium level, greater than 150 mEq/L) in 30% to 40% of well-trained athletes. In contrast, less intensive exercise (800-m swim lasting ten minutes and resulting in a sevenfold rise in the level of blood lactate) failed to cause a rise in serum sodium level despite comparable elevations in hematocrit reading and serum protein levels. Hypernatremia induced by intensive exercise cannot be explained by losses in body fluid or solute ingestion, but is probably a consequence of a shift of hypotonic fluid from the extracellular to the intracellular compartment. Thus, the mechanism of exercise-induced hypernatremia may be unique, as compared with other clinically recognized forms of hypernatremia.

An individualization of dietary requirements for energy in adults.

Resting metabolic rate (RMR) in adults can be viewed from two perspectives. Body surface area is used to index RMR in the clinical perspective. Normal values of RMR are thus sex-specific and appear to be lower in women. However, the physiological perspective is one of an asexual metabolism that differs in the mass of active cells. The body cell mass is relatively reduced in women due to a smaller skeletal muscle mass in tandem with a greater fat mass. RMR is proportionately reduced and thus highly correlated with body cell mass or lean body mass in mixed sex data. Athletic training can negate the differences in body composition and RMR per unit weight. The body mass index is another nonphysiological and sex-specific parameter currently being applied to obesity research. The clinical utility of body surface area for the prediction of RMR results from its correlation with body composition within either sex. The clinical and physiological perspectives of RMR must be clearly distinguished and treated as distinct.

Body composition and resting metabolic rate: the myth of feminine metabolism.

A multiple regression analysis of several factors influencing basal metabolic rate (BMR) was performed using data for 223 subjects from the classic metabolism studies published by Harris and Benedict in 1919. These data had previously been analyzed by Kleiber using metabolic body size, the three-fourths power of body mass, as a predictor of BMR. His prediction equations were separated by sex and each contained components for age and height. Factors in the present analysis included sex, age, height, body mass, and estimated lean body mass (LBM). Lean body mass was found to be the single predictor of BMR. A best estimate prediction equation: BMR(cah/ day) = 500+ 22 (LBM) is proposed. The previously presumed influences of sex and age are shown to add little to this estimation. Ani. J. Clin. Nutr. 33: 2372-2374, 1980. Standard physiology texts list sex, age, and body composition as factors related to basal metabolic rate (BMR) in man. Indeed, differ- ences due to age and sex exist when BMR values are expressed as calories per unit of body surface area. The physiological basis for a body surface relationship has been ques- tioned by Kleiber (1). His expression of BMR on the basis of metabolic size retains age and sex differences. Benedict (2) reported that body mass and body surface area were both inadequate indices for the expression of BMR and suggested that the mass of active proto- plasmic tissue might be useful. In this regard, Miller and Blyth (3) proposed lean body mass (LBM) as a metabolic standard and demon- strated that LBM was a better predictor of oxygen consumption than surface area in 47 young men. The inverse relationship between age and basal oxygen consumption recently has been shown to be wholly attributable to changes in LBM (4, 5). Sex differences have not been examined using LBM as a predictor of BMR The present study estimates LBM as a function of sex, age, and body mass before a regression analysis for the influence of several variables on BMR. Methods

A multiple regression analysis of several factors influencing basal metabolic rate (BMR) was performed using data for 223 subjects from the classic metabolism studies published by Harris and Benedict in 1919. These data had previously been analyzed by Kleiber using metabolic body size, the three-fourths power of body mass, as a predictor of BMR. His prediction equations were separated by sex and each contained components for age and height. Factors in the present analysis included sex, age, height, body mass, and estimated lean body mass (LBM). Lean body mass was found to be the single predictor of BMR. A best estimate prediction equation: BMR(cal/day) = 500 + 22 (LBM) is proposed. The previously presumed influences of sex and age are shown to add little to this estimation.

A reanalysis of the factors influencing basal metabolic rate in normal adults.

Dr. John J. Cunningham. The presentations in this initial session provide ample documentation of the potential for nutrient-based interventions to ameliorate the pathologies associated with several chronic diseases. The important and recurring theme is that evidence is not the plural of anecdote. Intervention trials based on mechanistic hypotheses and published in peer reviewed journals set the standard by which efficacy is clearly established. Additionally, nutrient interventions are acknowledged to be complementary to medical treatments rather than competitive with effective medicines or pharmaceuticals. The image has been one of George and Rodney as noted in the opening remarks for this conference. Our adherence to scientific rigor and standards together with providing clear advice to our constituents will bring us to a future identity as “the twins”. Considerations such as availability, patient acceptance, and cost could favor a single supplement or functional food approach over a prescribed medicine, even when both approaches are equally safe. The spectrum for medical interventions begins with overthe-counter preparations offering analgesia, generalized symptomatic relief or palliative effects. Similarly, nutritionists have long focused on food-based programs to increase the consumption of dietary substances conferring benefit for disease prevention. The presentations in this session suggest that foods rich in phytoestrogens may protect against CVD and cancer and that the consumption of diets rich in glucomannans and oligosaccharides will benefit diabetics. Such regimens could be incorporated into a plan providing high dietary fiber, moderate saturated fat and cholesterol and “five a day” fruits and vegetables, that integrates program recommendations for CVD, cancer, and diabetes. Farther along on the spectrum are the so-called nutraceutic supplement (single bioactive compound) and functional food (enriched matrix component) nutrition approaches. As a generalization, these deliver two to three times the Recommended Dietary Allowance (RDA) for a nutrient or a similarly increased consumption above average for a nonnutrient compound. This session points to soy isoflavones (possibly delivered within their native protein matrix), while recent meta-analyses suggest psyllium or B-glucans for those at risk for CVD. Professor Vuksan makes a compelling case for American Ginseng as a “functional food” or a ginsengoside supplement for diabetics. Finally, both medical and nutritional practitioners consider pharmaceutic therapies at the high end of this spectrum. Antioxidants such as vitamins C and E find applications at 10 to 100 times the RDA. There is no similar benchmark for the blend of herbs collectively termed PC SPES (PC for prostate cancer, “spes” from the Latin “hope”); however, the regimen as prescribed is undoubtedly in this range. For diabetes, the fast insulin analog lispro and the “modified release” sulfonylurea gliclazide target euglycemia through insulin action. The chronic degenerative complications of non-insulin dependent diabetes mellitus (NIDDM) can be prevented by a combination of medical and nutritional interventions employed synergistically. Interventions are founded either on primary treatment—enhancing insulin release; secondary interventions—promoting “tight” (euglycemic) glycemic control; or on ameliorating the consequences of chronic hyperglycemia—as tertiary interventions. The Diabetes Control and Complications Trial (DCCT) revealed an estimated 45%–65% risk reduction for retinopathy, nephropathy and neuropathy from tight control, that is, control approximating 7% glycosylated hemoglobin. Beyond those complications, the majority of patients with NIDDM, perhaps as many as 75%, encounter CVD as a sequela. In that regard, soy phytoestrogens offer great promise. The record thus far for interventions in NIDDM leaves much to be desired. Efforts at primary or secondary treatment demonstrate low long-term success rates (glycolsyaled Hb maintained at 7%) ranging from 10% success with diet to 15% success with metformin and 20% with sulfonureas to a high of 25% with insulin therapy. To be fair, the latest generation of pharmaceutical interventions has well focused effects with minimal untoward consequences and should improve on this picture. Diet strategies, such as the provision of prepared meals or a combination of a customized NIDDM diet with nutraceutic vitamin E (400 mg daily) show positive short-term outcomes that may help to break through this barrier of dismality. The fast-acting insulin analog lispro elicits an earlier insulin response peak, diminishes the total insulin required for glucose clearance (C-peptide measurement) and suppresses endogenous glucose production. The modified release sulfonylurea gliclazide restores the “first phase insulin response,” minimizes rebound hypoglycemia, and is itself an antioxidant. These represent primary medical therapies with good promise. Nutritional strategies target secondary intervention. The multi-center meal study demonstrates that weaknesses in education/intervention can be overridden. A recent study showed an improvement in glycosylated hemoglobin approximating a reduction by two percentage points by diet alone. An additive

The pharmacokinetics of acetanilide and of diphenylhydantoin sodium

The weights, protein concentrations, and concentrations of cyclic AMP and cyclic GMP in the ovaries of prepubertal rats have been measured after induction of follicular growth by administration of pregnant mare serum gonadotrophin (PMSG). Three phases of ovarian growth, the follicular growth phase, the preovulatory phase and the luteal phase were investigated. Ovulation was induced by administration of human chorionic gonadotrophin (hCG). During the follicular phase, ovarian weight, protein content and the content of both cyclic AMP and cyclic GMP increased 2-3 days after administration of PMSG. Administration of hCG 65h after PMSG caused a rapid rise in the concentration of cyclic AMP but the concentration of cyclic GMP tended to fall. During the luteal phase the concentrations of both cyclic nucleotides decreased.

Cyclic GMP concentration in ovarian tissue after administration of gonadotrophin to prepubertal rats.

1 Steady state plasma concentrations (SSPCs) of acetanilide (AA) and its metabolite, paracetamol (PL), were studied in 27 healthy volunteer subjects before and at the end of an 11-day exposure to phenytoin (DPH). Plasma concentrations of DPH were estimated. Plasma concentrations of DPH varied from 5.1 to 20.4 microgram ml-1 (mean +/- s.e.mean 12.2 +/- 0.9). 2 The SSPC of AA before exposure to DPH varied from 0.06 to 0.67 microgram ml-1 (mean +/- s.e.mean 0.24 +/- 0.02), and following exposure from 0.03 to 0.47 microgram ml-1 (mean +/- s.e.mean 0.15 +/- 0.02). 3 The SSPC of PL before exposure to DPH varied from 1.2 to 4.4 microgram ml-1 (mean +/- s.e.mean 2.7 +/- 0.13), and following exposure from 1.1 to 3.8 microgram ml-1 (mean +/- s.e.mean 2.2 +/- 0.13). 4 SSPCs of AA and of PL decreased significantly during DPH administration (P less than 0.01 for AA, P less than 0.001 for PL). 5 Correlations were observed between the SSPCs of the drugs measured, suggesting a common influence on their kinetics. 6 Similarity was observed between the changes in plasma levels of AA and PL following DPH ingestion. There was, however, wide inter-subject variability in this regard. In some subjects no change was observed even though they had DPH demonstrable in their plasma. Consequently it may be speculated that the effects of DPH may be under genetic control.

Acetanilide and paracetamol pharmacokinetics before and during phenytoin administration: genetic control of induction?

The pharmacokinetics of an intravenous injection of disopyramide was studied in five normal subjects and six patients with varying degrees of renal impairment. The elimination rate constant (β) was related to the endogenous creatinine clearance (Clcr). However, a decrease in β was not observed until the Clcr was reduced below 40 ml min−1. Below 40 ml min−1 a linear relationship existed between β and Clcr. Similarly, the plasma elimination half‐life (t½β) showed a significant increase when the Clcr was less than 30 ml min−1. Hence, dosage modification for disopyramide is necessary only when renal function is severely impaired. Overall, the apparent volume of distribution in patients with renal insufficiency was reduced to two‐thirds of that in normal subjects. Therefore, in patients with Clcr less than 40 ml min−1 both the loading and maintenance dose of disopyramide should be reduced.

Disposition kinetics of disopyramide in patients with renal insufficiency

Necrosis of cutaneous and subcutaneous tissue is a rare complication of therapy of with oral anticoagulants, and is related to the use of loading‐dose regimes. Three cases are reported, and demonstrate that the principal histopathological feature is thrombosis within the subcutaneous vasculature. The effect of large doses of anticoagulant on the levels of the vitamin K dependent clotting factors provides a satisfactory model for the temporal sequence of events in this syndrome. The occurrence of intravascular thrombosis with low or absent levels of Factor VII indicates that the intrinsic clotting system is of primary importance in venous thrombosis. This complication of anticoagulant therapy is not seen if loading‐dose regimes are avoided.

Necrosis of cutaneous and subcutaneous tissue is a rare complication of therapy of with oral anticoagulants, and is related to the use of loading-dose regimes. Three cases are reported, and demonstrate that the principal histopathological feature is thrombosis within the subcutaneous vasculature. The effect of large doses of anticoagulant on the levels of the vitamin K dependent clotting factors provides a satisfactory model for the temporal sequence of events in this syndrome. The occurrence of intravascular thrombosis with low or absent levels of Factor VII indicates that the intrinsic clotting system is of primary importance in venous thrombosis. This complication of anticoagulant therapy is not seen if loading-dose regimes are avoided.

Rinsho Yakuri\/japanese Journal of Clinical Pharmacology and Therapeutics

The effect of non-linear disposition kinetics on the systemic availability of disopyramide

The Effects of Urine pH and Plasma Protein Binding on the Renal Clearance of Disopyramide

Proceedings: Investigations of cyclic GMP binding to a protein fraction prepared from rat lung.

SUMMARY Proliferobasidium and Ceraceosorus (Brachybasidiaceae, Brachybasidiales, Basidiomycetes) are described as new genera. Both cause leaf-spot diseases of vascular plants and are characterized by persistent thick-walled probasidia and bisterigmate metabasidia. They differ from Dicellomyces, the most closely related genus, in having indeterminate rather than determinate hymenial thickening and in lacking a fruiting body with extensive sterile tissue. Proliferobasidium is based on P. heliconiae, described as a new species on Heliconia bihai. It has intercellular hyphae and exhibits repeated percurrent proliferation of new basidia from within persistent probasidial walls. Ceraceosorus, with the type species Dicellomyces bombacis on Bombax ceiba, has intracellular hyphae and lacks percurrent proliferation of basidia. Ceraceosorus bombacis is presented as a new combination. Since they have features in common with Uredinales, Dacrymycetales, and corticioid Homobasidiomycetes, Ceraceosorus and Proliferobasidium may prove to be of considerable evolutionary interest.

TWO NEW GENERA OF LEAF-PARASITIC FUNGI (BASIDIOMYCETIDAE: BRACHYBASIDIACEAE)

Proceedings: A pharmacokinetic study of phenylbutazone-associated hypoplastic anaemia.

Urinary D-glucaric acid excretion and acetanilide pharmacokinetics before and during diphenylhydantoin administration

Acetanilide like phenylbutazone is paraoxidized by the liver endoplasmic reticulum as a primary biotransformation step. Both compounds were given at different times to each of 10 healthy volunteer subjects and the plasma disappearances measured. Correlation was shown between plasma clearance values of the two compounds (r = + 0·7067; P < 0·05). Eight patients with hypoplastic anaemia after phenylbutazone therapy were investigated. Plasma clearance values and half lives of acetanilide were measured in this group of patients and compared with those of a group of 30 healthy volunteer controls. There was a significant decrease in clearance (P < 0·01) and lengthening of half lives (P < 0·001 in the patients with phenylbutazone-associated hypoplasia. Five patients with idiopathic aplastic anaemia—that is, without history of antecedent phenylbutazone ingestion—were similarly investigated with acetanilide and there was no significant difference between the results in these patients and those in the control group. It is suggested that relatively poor paraoxidation of phenylbutazone producing high blood concentrations on a given dose may be a factor responsible for the drug-associated hypoplasia even though it does not explain the similar pattern of adverse reactions reported in association with oral administration of the metabolite oxyphenbutazone.

Acetanilide Oxidation in Phenylbutazone-associated Hypoplastic Anaemia

Gyrothrix (Corda) Corda and the closely related Circinotrichum Nees ex Pers were monographed by Pirozynski (11), who recognized 12 and 3 species, respectively. Subsequently, Munjal and Lall (10), Pirozynski and Patil (12), and Hughes and Pirozynski (7) brought the total number of species to 14 for Gyrothrix and 6 for Circinotrichum. Apparently, neither genus has been studied in culture because previous studies have been based on dry specimens and none of the major culture collections lists cultures of either genus (1, 2, 3, 8). In May, 1970, fallen leaves of Robinia pseudoacacia L. were collected in Rockville, Maryland, and kept slightly moist in a Petri dish for several weeks. On one leaf several colonies developed of a fungus which was readily isolated on corn meal agar (CMA) and identified as a species of Gyrothrix. This has been compared with descriptions and illustrations of all species of Gyrothrix and Circinotrichum published to date, and with specimens in Herb. BPI. The new species is distinct from all other species of Gyrothrix in size and shape of the conidia and setae. No other species comes close to having eight or more septa in the setal trunk below the lowest branch. Setae of the new species are intermediate in size and habit of branching between the type species G. podosperma (Corda) Rabenh. and G. macroseta Piroz., but the branches of these species are rough and their conidia differ in size and shape. The conidia of G. indica Munj. & Lall are nearest in size, but their shape differs and the setae of the new species are much taller and entirely smooth.

For about 9 years I have been using a simple mounting fluid to great advantage for many purposes, including permanent slide mounts. I have introduced it to numerous mycology colleagues who had not heard of it before and who now praise its value as I do. I was introduced to Hoyer's mounting fluid through the recipe in the laboratory manual by Alexopoulos and Beneke (1). It is not apparent from their remarks that it makes a very durable permanent mount. Their recipe is actually Andre's (14) modification of the original Hoyer's recipe (8), Hoyer's containing much less chloral hydrate. Farrants was the first to use a gum arabic mountant, prior to 1880, but without chloral hydrate (12). The present article is written because Hoyer's fluid (hereafter referred to as AH is so useful and yet so poorly known to mycologists. It is not mentioned in common microtechnique books under either name (5, 10, 11, 13, 15), but it has been used for mounting other biological materials (2, 3, 4). AH is included in Gatenby and Beams (9) but not indexed there. I have found it to be excellent for permanent reference slides of all types of fungi. AH is used as simply and in the same way as a drop of water is used in making a temporary water mount on a microscope slide. It has several outstanding advantages over other popular mounting media:

A Miracle Mounting Fluid for Permanent Whole-Mounts of Microfungi

Strains of nuclear polyhedrosis viruses displaying different inclusion body shapes.

Comparative effectiveness of different media in serological tests of insect pathogens

Pieces of leaf tissue were soaked in 3% aqueous KOH at about 75 C for 20-30 min, washed, evacuated, dehydrated, embedded in paraffin, and 5-7 μ sections attached to slides with gelatin adhesive. Compared with fresh-fixed control material, dried material stained with less contrast, but the general morphology of cells and tissues was fully restored. Nuclei and chloroplasts were preserved only occasionally, but such delicate structures as hyphae, haustoria, and parenchyma were regularly restored to normally appearing turgor. Long-term storage of dried specimens (one for 84 yr; another 100 yr) was not at all detrimental to restoration.

Rapid alkaline rehydration of dried plant tissues for histologic study.

Ontogeny of Teliospores of Cronartium Paraguayense and Relationship to Didymopsora

Histological studies on penetration oí Pea roots by zoospores of Aphanomyces euteiches.

A massive growth in the lower jaw of an Indian python (Python molurus) was diagnosed from biopsy samples as a fibroma. Moderately satisfactory treatment was achieved by surgical excision.

Lieutenant-Colonel C. A. Gill, i.m.s., Assistant Director of Public Health, Punjab, is appointed to officiate as Director of Public Health, Punjab, with effect from 5th June 1924. Major J. D. Sandes, i.m.s., officiating Civil Surgeon, is transferred from Rajshahi to Serampore, vice Major C. R. O'Brien, i.m.s., granted leave. Major P. F. Gow, d.s.o., i.m.s., is appointed to act as a Civil Surgeon and is posted to Rajshahi, vice Major J. D. Sandes, i.m.s., transferred. Major T. L. Bomford, i.m.s., officiating Civil Surgeon, is transferred from Howrah to Burdwan, vice Rai Hem Chandra Sarkar Bahadur. Major R. Knowles, i.m.s.. Professor of Protozoology, School of Tropical Medicine and Hygiene, Calcutta, is appointed to act, in addition to his own duties, as Professor of Tropical Pathology and Bacteriology and as Director of that institution, during the absence, on leave, of Major H. W. Acton, i.m.s. Major C. J. Stocker, M.c., i.m.s., is appointed to officiate as an Agency Surgeon, with effect from the 26th March 1923. The services of Major C. J. Stocker^ m.c., i.m.s., an officiating Agency Surgeon, are placed at the disposal of the Government of India, Home Department, with effect from the 26th March 1923.

The recognition of the value of suitable occupations in aiding the recovery of the sick is thus no new development, for occasional references, similar to that quoted above, are to be found throughout the literature of the ancient world. Speaking of more recent times, however, the first real incentive to the use of work as a therapeutic measure dates from the adoption of the more humanitarian methods of treatment of the insane, which were introduced towards the end of the eighteenth century by such pioneers as Pinet in France, Hack Tuke in England, Rush in America, and Johanna Reil in Germany. The principles evolved from these new ideas resulted in the revolutionary changes that have since taken place in the treatment of persons suffering from mental disorders, substituting for the mere custodial responsibility previously considered sufficient, an active regime in which occupation plays a great part. With the gradual recognition of the importance of the mental factor in disease in general, the same principles have been extended to the treatment of other affections, with the result that the use of occupation and recreation has been increasingly advocated as an adjunct to other medical and

Further Observations on Indian Relapsing Fever. Part IV. Reinfections and Super-Infections.

Further Observations on Indian Relapsing Fever. Part III. Persistence of Spirochaetes in the Blood and Organs of Infected Animals.

Biology for Medical Students, by C. C. Hentschel, M.Sc., and W. R. Ivimey Cook, B.Sc., Ph.D. (Longmans, 18s.). This work has been prepared primarily to meet the needs of students reading for the first M.B. examination of the University of London or for the premedical examination of the English Conjoint Board. A short account of the cell, cell-division, asexual and sexual reproduction precedes the chapters on amoeba, Paramecium, hydra and obelia, the earthworm, the dogfish, the frog, the rabbit and on vertebrate embryology. In the botanical part of the work the algse hsematococcus and spirogyra, the fern, the flowering plant and plant physiology are successively considered. A short chapter on special modes of life and adaptation to environ-

The Convalescent State and Its Management at the Astley Ainslie Institution

A subject which came up for discussion at the annual Conference of Medical Research Workers in December, 1929, in Calcutta, and which is of considerable interest to our readers is the future of anti-rabic policy in India. Of recent years considerable work has been carried out at certain Pasteur Institutes in Central Europe on the use of an anti-rabic vaccine in which the virus has been attenuated by exposure to ether; this work culminating in the paper Published by Alivisatos in 1922. The attention ?f workers in India having been drawn to this

Notes Oil the Results Of Treatment of Cases of Kala-Azar admitted to the Madras City Hospitals between 1913-1922.

so imperfectly known that the occurrence of cases in localities where the disease has not yet been previously recognised is worthy of record. Between the beginning of February and end of March this year, 8 specimens of blood were received at the King Institute from the Medical Officer in charge of the Base Hospital, Xarasapatnam; the base for the Fituri operations which have up till recently been carried on in the Agency Tracts of this Presidency. All of these specimens were negative to the usual examinations for malaria and fevers of the enteric group. The eighth case, however, gave a Avell marked Weil-Felix reaction. being positive in 1-100. This case was thus proved to be one of typhus fever. As no cases of this type of fever have, so far as we

Controlled Diathermy:* A New Method for the Treatment of Bladder Tumors1

A Table for Operations upon the Kidney through the Lumbar Incision

Transactions of The Royal Society of Tropical Medicine and Hygiene

This communication is a supplementary report of experimental work done on the kidneys of rabbits. The preliminary report of this work done in the Laboratory of Surgical Research of the Harvard Medical School has been published in the Transactions of the American Association of Genito-Urinary Surgeons , 1909. The experimental work which forms the basis of this communication was suggested by an operation on a woman with but a single kidney, which contained calculi. The kidney was exposed in the lumbar region, split in Brodel's line and three calculi of medium size were removed. Another calculus the size of a pea was also detected in the ureter at a point two inches from the pelvic outlet. This stone was worked upward into the kidney pelvis, which was opened on the posterior surface and the stone removed. A ureteral sound was passed through the

THE INFLUENCE OF THE OPERATION OF RESECTION OF THE KIDNEY ON THE FUNCTION OF THE ORGAN: A REPORT OF EXPERIMENTAL WORK ON RABBITS

131. Some Factors in Racial Immunity and Susceptibility to Disease

A Report of Two Cases Reinfected with Syphilis Following Treatment by Salvarsan

Treatment of Prostatic Hypertrophy: The Consideration of the Various Methods of Treatment Based upon the Mortality and the Report of Twenty-Four Cases of Median Perineal Prostatectomy

Dysentery in the Jails of Eastern Bengal. Being the Report of a Special Investigation conducted under the Auspices of the Indian Research Fund Association.

Two Cases of Kidney Infection Illustrating the Value of Cystoscopic Examination and Ureter Catheterization; Treatment of the Cases by Vaccines

Studies in Filariasis. No. 1. A Filarial Survey with a Statistical Enquiry into the Relationship between Filariasis and Elephantiasis.

Further Observations on Latent Dysentery. The Practical Value of the Discovery of Latent Dysentery Cases as a Method of Dysentery Control.

The Radical Cure of Hernia under Local Anesthesia: Combined with Scopolamine and Morphia

120. Some Factors in Racial Immunity and Susceptibility to Disease

The Hydrogen-Ion Content of Vaccine Lymph and its Relation to the Potency and Keeping Properties of Lymph prepared under Tropical Conditions.

At the meeting of the American Association of Genito-Urinary Surgeons in June, 1912, I reported a series of cases of acute unilateral hematogenous infection of the kidney, some treated by nephrectomy, others by decapsulation or drainage, and another group by non-surgical measures. At this time it is my desire to relate the subsequent course of these patients and to refer to others which have come under my observation since that time. Tuberculosis, the most common of all hemic infection of the kidney, is not to be considered. Suppuration within the kidney parenchyma, as is well known, results from infection by one or another of certain varieties of micro-organisms taking place usually in one or two ways, either as an ascending infective process from the lower urinary tract or brought to the kidney by the blood stream; yet rarely the kidney becomes acutely infected by adjacent septic foci or by penetrating

An Epidemiological Study of 663 Cases of Kala-Azar Admitted to the Madras City Hospitals between 1913—1922

A Note on the Effect of Intravenous Injections of Antimony Tartrate upon the Development of Vaccinia Virus

Note on the Types of Pneumococci found in Cases of Pneumonia in Madras, Southern India.

SEVENTH CONGRESS OF THE FAR EASTERN ASSOCIATION OF TROPICAL MEDICINE.

Death Following Rectal Anesthesia in a Patient with Amebic Dysentery

A Method of Producing Ether Narcosis by Rectum, with the Report of Forty-One Cases

A Comparison between the Numerical Content of Certain Bacterial Suspensions obtained by the Haemocytometer Method and Brown's Opacity Tubes.

Facts Regarding the Relation of Tuberculosis of the Kidney to Tuberculosis of the Lungs

Great changes are taking place around us. India is passing through a very definite and important metamorphosis, the results of which are bound to have far-reaching efifects on every branch of thought in the country. The responsibility for her progress in medical science has now devolved upon her people, and her future progress will greatly depend upon the attitude adopted by her political leaders. Science should have no politics, but the scientific communities cannot fail to be in-

India's Debt to Medical Research, Being the Presidential Address Delivered to the Medical Research Section, Indian Science - Congress

Previous to the employment of thex-ray as a means of detection of calculi in the ureter, the error in diagnosis between stones in the kidney and ureter was great. The employment of thex-ray has been of the greatest value in the diagnosis. This method of diagnosis, however, contains a two-fold error: first, the impossibility of detecting pure uric acid calculi; and, second, the presence of questionable shadows in, or near by, the course of the ureter. It has been a common mistake to cut down on supposed ureteral calculi because of shadows present inx-ray plates, and to find no ureteral stone, the shadow being due to a faulty plate, calcified gland, sclerotic artery, phlebolith, calcified bodies in muscle or fascia, or accentuated calcification in the transverse processes of the vertebrae. It has been recognized that a simplex-ray picture is subject to these

Notes on the Results of Treatment of Cases of Kala-Azar Admitted to the Madras City Hospitals between 1913—22

Further Observations on Indian Relapsing Fever. Part I. Types of Splrochaetes found In Experimental Infections.

Note on the Degeneration of Vaccine Lymph on Passage through the Same Vaccinifer.

The Influence of the Operation of Resection of the Kidney upon the Function of the Organ (A) When the Kidney Wound Is Closed by Sutures; (B) When the Kidney Wound Is Drained (A) by a Rubber Tube; (B) by Gauze

104. Some Factors in Racial Immunity and Susceptibility to Disease

A New Method for Gradual Decompression of the Bladder in Cases of Massive Retention1

RECURRENT INTERMITTENT RETENTION OF URINE OCCURRING WITH THE REMISSIONS IN A CASE OF PERNICIOUS ANAEMIA-THE FINAL RESULT OF A BOTTINI OPERATION FOR ASSOCIATED PROSTATIC HYPERTROPHY.

The Classification of the Streptococci found in Tropical Affections.

Transactions of the Seventh Congress of the Far Eastern Association of Tropical Medicine held in British India, December, 1927.

Acute Gonorrheal Epididymitis, with Special Reference to the Operative Treatment

Further Observations on Indian Relapsing Fever. Part II. The Serology of Relapsing Fever in Human Beings.

XI. A Study of Various Forms of Prostatic Hypertrophy from Post-Mortem Specimens and by the Cystoscope, with Reference to Operation.

name by Hanson is very common, especially in children, in Madras during the hot weather. Castellani, in his book on tropical diseases written in conjunction with Chalmers, and in his article on skin diseases in Byam and Archibald's " Practice of Medicine in the Tropics," describes the condition under the name pyosis and names four varieties, pyosis uiansoni, tropica, palmaris and corletti. The particular variety to which we refer fits in

some previous contact with a known endemic area had been established. Kala-azar is not one of the diseases mentioned in the Director of Public Health returns?(although a meeting held in 1919 ot the Directors of Public Health has recommended that it should be so)1?so that no information as to its prevalence is available from this source. Donovan2 in a review of the geographical distribution of the disease in India, published in 1913, mentions 5 cases as occurring in the Presidency outside Madras City. These cases came from

Seminal Vesiculitis and Prostatitis Treated by Vesiculotomy and Prostatic Drainage

A Report of Sixty Cases of Syphilis Treated with Salvarsan (606)

The purpose of this paper is to develop a better understanding of how to define a positive climate for inclusiveness that recognizes the context and social environment of participants. In order to study employees working with Indigenous people and minorities in four organizations, we used a grounded research approach to define what an inclusive environment might look like. The interview questions gathered examples of experiences which employees valued because they felt more included and not excluded from people they worked with. The experiences fell into four categories, as follows: (i) leadership engaged in supporting inclusiveness within the organization; (ii) leadership engaged in seeking inclusiveness within the community; (iii) being involved in multicultural practices within the organization and community; and (iv) participating in initiatives which encourage engagement and involvement. This paper’s conceptualization of a climate of inclusion is different from other studies, possibly because of the unique context in which service organizations are placed, as such organizations typically work with Indigenous people and minorities. Although we are especially mindful of the danger of generalizing our findings without further research, the scope of this paper might provide some direction for future studies of other organizations. We suggest that there is also a need to be open to methods which allow individuals and groups to define a climate of inclusivity that is relevant to their context; this is because context may be essential for recognizing certain groups of people.

Defining the Climate for Inclusiveness and Multiculturalism: Linking to Context

A Self‐Report Measure of Productive Thinking in Solving Insight Problems

Abstract The purpose of the research was to investigate different types of training in insight problem solving. In doing so, we reviewed the literature on experimental tests of procedures for training insight problem solving. The results revealed that most procedures focused either on restructuring or divergent thinking, and provided some evidence for the effectiveness of both approaches. However, we found no studies that compared the effects of the two approaches. The article reports two experiments that compared different training procedures based on restructuring and divergent thinking. For the latter, the methods focused separately on fluency, flexibility and originality training. The first experiment compared a restructuring approach with fluency training and a placebo control condition. The results indicated that the restructuring training was significantly more effective than the others, but only when instructions were verbal, not in script form. The second experiment compared restructuring training with flexibility, fluency and originality training, all presented in script form, and the results indicated that the restructuring training was significantly more effective than both fluency training and flexibility training. Implications for future research are discussed.

Purpose
The purpose of this paper is to analyze the results from two public sector organizations to test a model of the organizational antecedents and health consequences of sickness presenteeism (SP) in the workplace.

The study reports on two surveys of public employees, one including 237 respondents and another of 391 employees. The combined sample allowed for the testing of a model of organizational antecedents and the health consequences of SP.

Findings
The results supported the model, indicating that increased leader support and goal clarity decrease SP indirectly through increased trust. Decreasing presenteeism is associated with decreased sickness absence and better health.

Practical implications
The key practical application is in encouraging managers and scholars to recognize that the costs of presenteeism are as higher or higher than the costs of absenteeism.

The social implications are clear in helping us recognize that when people come to work sick, they are not productive and are endangering the productivity of others.

This is the first time that research had defined and operationalized a causal model linking antecedents such as leader-member relations, goal clarity and trust with SP and absenteeism.

Studies concerned with the interaction between the organization and the family have generally been concerned with one or more specific causal relationships. For instance, a number of researchers have emphasized the similarities between an individual's treatment at work and his treat ment of his family (Oeser and Hammond, 1954); satisfaction derived from the family, work, and leisure (Haavio-Mannila, 1971); and entrepreneuu'al behavior and child rearing practices (Miller and Swanson, 1958). There are an equal number of statements suggesting the general tendency toward dissimilarities between the work situation and family. These studies discuss such factors as the stress produced by travel (Culbert and Renshaw, 1972); the effect of mechanization on the families'domestic activities; and the impact of work tensions on the family structure (Dennis, Henriques, and Slaughter, 1956). In general, these studies respond to specific questions and do not illustrate the overall relationship of the many parts of the organization and family. Relatively little effort has been expended in setting forth the properties of family and organization as social systems. Of course, these different

Designing Compensation Systems to Respond to Equity Requirements

Many innovations in organizations result when people discover insightful solutions to problems. Insightful problem-solving was considered by Gestalt psychologists to be associated with productive, as opposed to re-productive, thinking. Productive thinking is characterized by shifts in perspective which allow the problem solver to consider new, sometimes transformational, approaches. Re-productive thinking, on the other hand, involves the application of familiar, routine, procedures. This article reports a study which investigated how self-reported productive and re-productive thinking are related to an individual's ability to solve insight problems. Our measures were tested against the Kirton Adaption-Innovation Inventory (KAI), and a battery of spatial insight problems. The results indicated that productive and re-productive thinking and the KAI were successful in predicting performance on spatial insight problems. Furthermore, the measures of productive and re-productive thinking accounted for spatial insight performance independently of scores on the KAI. In addition, the results suggested that re-productive thinking consists of two different components—one based on group conventions and the other on personal experience. Each contributed differently to solving insight problems.

Productive and Re-productive Thinking in Solving Insight Problems

This article reviews a research study on developing performance benchmarks to guide Chief Administrative Officer performance in Nova Scotia. The study collected examples of excellent and substandard performance from 22 individuals who were CAOs, members of Council, or provincial advisors. The information was content analysed, revealing 13 competency areas, illustrating four types of competencies. A practical aspect of this study is the suggestion that the competencies might be arranged in a semicausal logic model (or Competency Scorecard, similar to the Balanced Scorecard) and that performance measures might include outcome and activity measures. The framework might guide researchers in calibrating the linkage between competencies and organisational performance measures.

The Effects of Performance Rating, Leader–Member Exchange, Perceived Utility, and Organizational Justice on Performance Appraisal Satisfaction: Applying a Moral Judgment Perspective

Purpose – The purpose of this study is to define characteristics and processes that enhance informal learning in a public sector workplace.Design/methodology/approach – Based on interviews and questionnaires, the authors solicited examples of informal learning practices that 40 supervisors experienced during their careers. The examples were content analyzed to define seven broad themes underlying informal learning.Findings – The findings illustrate seven broad themes describing learning activities and processes. The first three themes describe the types of informal learning activities that supervisors found valuable: relationships; learning opportunities enlarging or redesigning their jobs; and enrichment opportunities that provided higher levels of managerial learning. Four themes describe processes for facilitating informal learning: planning processes; active learning and modelling; relationship dynamics; and tying learning to applications.Originality/value – The value of this study is in presenting a ...

Informal learning in the workplace: key activities and processes

Recent research has reported successful training interventions that improve insight problem solving. In some ways this is surprising, because the processes involved in insight solutions are often assumed to be unconscious, whereas the training interventions focus on conscious cognitive strategies. We propose one mechanism that may help to explain this apparent disconnect. Recognition of a barrier to progress during insight problem solving may provide a point of access to the tacit constraining assumptions that have misled the solution process. We tested this proposal in an experiment that examined the effects of different training routines on problem solving. The experiment compared four training routines, focusing either on barriers and assumptions combined, barriers alone, assumptions alone, or goals, with two control conditions. Outcomes were measured using eleven spatial insight problems. The results indicated that training that combined focus on barriers and assumptions was significantly more effective than all other conditions, supporting the proposition that recognizing and reinterpreting barriers may assist in surfacing the unwarranted assumptions that prevent problem solving.

Training Insight Problem Solving Through Focus on Barriers and Assumptions

Some models of strategic HRM promote the idea of linking HRM's practices so they “fit” line managers' needs for implementing their strategies and objectives. We tried to apply the idea of “fit” by using the HR Scorecard in two public sector organizations: the Victoria Cool Aid Society and the Ministry of Water, Land and Air Protection. In our applications, we took each of the organization's strategic themes and asked a series of questions to identify HRM objectives, activities, initiatives, and measures to respond to internal client needs. The projects focused on the long range outcome of helping each organization achieve its strategies and objectives in an effective and efficient way. It did this by helping develop a better “fit” between HRM's systems, procedures and practices and what various line departments needed.

Promoting Organizational Fit in Strategic HRM: Applying the HR Scorecard in Public Service Organizations

In 1929, thirty-nine mines or prospects in which gold was the element principally sought were listed by the State Mine Inspector of which four actually produced some gold. In his report for 1933, however, the official mentioned lists seventy-four such properties and over half of them produced more or less gold during the year. These facts prove that the depression, which has thrown many men out of work, and the great increase in the price of gold have created an interest in prospecting for and mining gold such as has not existed for many years. Over twenty-six hundred persons are now prospecting for placer or lode deposits of gold or operating on such deposits in Arizona, whereas less than four hundred persons were employed in gold mines in the State in 1929 and only a few score prospectors for gold were then in the field. This tremendously increased interest in gold has created a great demand for information about Arizona's gold resources, which this bulletin is intended to supply. Because Arizona has for many years produced more copper than any other state in the Union, it is not generally recognized that gold ores are widely distributed throughout the State, and it is the hope of the authors that the publication of the facts will attract more capital to Arizona for the development of her gold deposits. It is also hoped that the sections on working small gold lodes, on the laws and regulations relating to the location and retention of lode claims, and on prospecting for gold will be helpful to inexperienced prospectors.

Insight problem solving is characterized by restructuring. We hypothesized that the difficulty of rebus puzzles could be manipulated by systematically varying the restructurings required to solve them. An experiment using rebus puzzles varied the number of restructurings (one or two) required to solve a problem and the level at which the restructuring took place (sub-word level, word level, and supra-word level). Solution rates were higher for one restructuring than two, and higher for restructuring at the supra-word level (relation between words) than at lower levels. To explain the findings, we suggest that rebus puzzles initially engage normal reading processes, which involve extracting meaning at the level of relations between words.

The Effects of Number and Level of Restructuring in Insight Problem Solving

Some older workers are more successful than others in maintaining a high level of functioning despite losses in psychological and biological capacities. In this grounded theory study of the careers of eight older workers, we identified ten Protean-like competencies relating to: replacing beliefs about chronological age with beliefs of psychological age; taking steps to improve health; adjusting preferences to fit life's circumstances; cultivating relationships to improve work and career; developing relationships which recognise a diversity of interests; developing relationships for mentoring others; developing a sense of self in relationships; redefining the contract with the organisation; finding aspects of work which are meaningful and fulfilling; replacing job worth with self-worth. One of the most frequent observations underlying these findings was the variation among the respondents in their beliefs about the ability to control the events they encountered in their lives.

International Journal of Human Resources Development and Management

Individual competencies that older workers use in successfully adapting during their careers

A central question in creativity concerns how insightful ideas emerge. Anecdotal examples of insightful scientific and technical discoveries include Goodyear’s discovery of the vulcanization of rubber, and Mendeleev’s realization that there may be gaps as he tried to arrange the elements into the Periodic Table. Although most people would regard these discoveries as insightful, cognitive psychologists have had difficulty in agreeing on whether such ideas resulted from insights or from conventional problem solving processes. One area of wide agreement among psychologists is that insight involves a process of restructuring. If this view is correct, then understanding insight and its role in problem solving will depend on a better understanding of restructuring and the characteristics that describe it. This article proposes and tests a preliminary classification of insight problems based on several restructuring characteristics: the need to redefine spatial assumptions, the need to change defined forms, the degree of misdirection involved, the difficulty in visualizing a possible solution, the number of restructuring sequences in the problem, and the requirement for figure-ground type reversals. A second purpose of the study was to compare performance on classic spatial insight problems with two types of verbal tests that may be related to insight, the Remote Associates Test (RAT), and rebus puzzles. In doing so, we report on the results of a survey of 172 business students at the University of Waikato in New Zealand who completed classic-type insight, RAT and rebus problems.

Categories of insight and their correlates: An exploration of relationships among classic‐type insight problems, rebus puzzles, remote associates and esoteric analogies

This paper compares the consistency of job evaluators using different job evaluation plans, on a sample of 34 public sector jobs. It describes how job evaluators carried out assignments duplicating the ranking, job classification, factor comparison, and point rating plans. Ratings on the point rating and job classification plans were most consistent, taking overall and individual ratings into account. Analysts, using the point rating plan, were more consistent in their rating of individual jobs, even those which are normally more difficult to rate. Analysts, using the job classification plan, generally perceived most jobs as belonging to particular occupational families (grades), but experienced some difficulty in agreeing upon the appropriate grade levels within the families. Ratings on the ranking and factor comparisons plans are least consistent, on balance. The paper points out that some job evaluation plans are more inclined to be affected by variables such as the norms of an evaluator. 
 
Resume 
 
Dans cet article, l'auteur compare l'uniformite des resultats obtenus par des evaluateurs d'emplois qui utilisent des plans d'evaluation differents sur un echantillon de 34 emplois du secteur public. Il explique comment les evaluateurs ont reproduit la methode de rangement, le classement des emplois, la comparaison des facteurs et les plans d'evaluation des emplois. La cotation des systemes de cote numerique et des plans d'evaluation des emplois, qui tenait compte des cotations generales et individuelles, etait tres uniforme. Les analystes, qui utilisaient le systeme de cote numerique, etaient plus coherents pour les emplois individuels, meme pour les emplois qu'il est d'habitude plus difficile de coter. Les analystes, qui utilisaient le systeme de cote numerique, pensaient generalement que la plupart des emplois faisaient partie de familles professionnelles (grades), mais ils n'arrivaient pas a se mettre d'accord sur les grades a l'interieur des familles. La cotation des systemes de rangement et des systemes de comparaison des facteurs etait la moins uniforme dans l'ensemble. L'auteur signale que certains plans d'evaluation des emplois sont plus susceptibles aux variables telles que les normes d'un evaluateur.

Canadian Journal of Administrative Sciences-revue Canadienne Des Sciences De L Administration

Purpose – The purpose of this paper is to review the importance of various change principles in assisting change in three public sector organizations.Design/methodology/approach – The researchers carried out interviews and used focus groups in assessing the principles and strategies which would be more useful.Findings – The interview and focus group results in three public sector organizations suggest that forming a guiding coalition might be one of the most important principles to observe.Research limitations/implications – The research data used for illustration are based on case evidence and the anecdotal interpretation of change in three settings. The paper does not claim to offer a scientific conclusion.Practical implications – The goal is to encourage a discussion on whether or not certain principles or strategies should be more important.Originality/value – The paper reviews the literature on change and reviews these principles in real experiences. Much of the other literature is conceptual.

Attempts to train people to be more insightful problem solvers have met with mixed success. This article reports the results of a controlled investigation on the effects of training with 40 participants who were equally divided into training and control conditions. Training consisted of 10 minutes of instruction and practice at avoiding or responding to the impasses that arise in insight problems. All participants were then tested on three types of problem, half of them receiving the problems in an artificial puzzle-like format, and half received the same problems set in a more realistic context. The results extended previous findings by indicating an impact of training on a range of puzzle-like problems, but not on the more realistic versions of problems, where performance with or without training was as good as that of puzzle-like problems after training. Future research will investigate whether the training procedure can be adapted to be effective with real-like problems and will examine the implications for training in the field.

Training Insightful Problem Solving: Effects of Realistic and Puzzle-Like Contexts

Purpose – The purpose of this paper is to investigate the relationship of stressful life events and health related events with sickness absenteeism and presenteeism (attending work while ill or injured).Design/methodology/approach – A web‐based survey was conducted within a public service organization which had just undergone a significant downsizing, where the workforce was reduced by over 30 per cent.Findings – The findings indicated that stressful life events were significantly associated with both presenteeism and absenteeism, to the same degree.Research limitations/implications – These results extend previous research in suggesting that employees are substituting presenteeism for absenteeism. However, different health risks (chronic conditions vs needing counselling support) were more likely to predict absenteeism than presenteeism.Originality/value – By supporting a substitution hypothesis, the present study suggests that both presenteeism and absenteeism are important measures of employee health an...

Factors in absenteeism and presenteeism: life events and health events

Purpose – This paper illustrates why consumers are resistant to using internet banking.Design/methodology/approach – A survey was used to acquire data from 127 consumers who were not internet bank users.Findings – Using a content analysis procedure, eight factors were identified which explain why consumers are not using internet banking. In order of frequency, the factors are: perceptions about risk; the need; lacking knowledge; inertia; inaccessibility; human touch; pricing and IT fatigue.Research limitations/implications – A list of those consumers who were not internet banking users could not be sourced, meaning that a random sample could not be carried out. The factors which emerged, however, appear to provide a comprehensive understanding of why certain consumers are not internet banking users. The factors provide a useful basis for researchers to conduct studies to better understand what influences a consumer decision not to use the internet as a means of sourcing banking services.Practical implicat...

Why consumers are not using internet banking: a qualitative study

This article illustrates the application of the Echo approach, originally designed to identify values of different cultures and subcultures, to the generation of questionnaire items for students to evaluate faculty teaching performance. Students preferred items generated using the Echo method over faculty-designed items and items developed by students without prompts. The Echo-generated items also exhibited higher test–retest reliability than items generated in other ways.

The Echo Approach in Developing Items for Student Evaluation of Teaching Performance

Purpose – This study aims to develop a set of dimensions for measuring the service of moneychangers.Design/methodology/approach – Attributes for measuring the moneychanger service were created from exit interviews and a review of the literature, and then administered a survey to consumers who had just completed a currency exchange. Respondent feedback was factor analysed, creating six service dimensions: “appearances of the tangibles”, “cost of service”, “interpersonal skills”, “service delivery”, “administrative matters” and “display board”.Findings – The “service delivery” and the “cost of service” dimensions exceeded customer expectations; the “appearances of tangibles” and the “interpersonal skills” dimensions fell short of expectations; “administrative matters” and the “display board” dimensions merely met expectations. A general finding of this study is that moneychangers, even though they are small businesses, are able to effectively compete with corporate giants (i.e. banks) in exchanging currenci...

This study develops a model for measuring the service quality of e-banks. Our model's seven factors are very consistent with the four core factors of the generic e-SERVQUAL model, but less consistent with its three non-core factors. Appearances and staff qualities, being new factors identified in this study, should be useful to e-bank management because they are factors uniquely relevant for e-bank customers. The seven factors emerged from a content analysis of comments made by consumers about their e-banking experiences.

This study seeks to identify the types of incidents which cause consumers to switch between banks, the weighting of each incident on the switching decision, whether single or multiple incidents influence switching decisions, and the extent to which switchers explain the problems they have faced prior to exiting. The key findings show that bank switching is strongly influenced by three types of incident: service failures, pricing and inconvenience, with pricing being more influential. Seventy‐five percent of bank switching is caused by more than one incident, and some 7 percent of respondents said they had spoken to bank staff in the period before exiting. The implications of these findings are presented.

Personality traits such as anxiety, self‐esteem and aggressive hostility are often thought to affect the stress that a person perceives or manifests. With data from 176 male executives, this study suggests that there are indirect and interacting relationships between personality and general health. This article proposes a cybernetic framework that links personality with other variables in understanding overall health. The framework specifies that personal characteristics (i.e. age), personality, and environment all play a role, each interacting systemically. The framework provides a basis for illustrating these interactions. For example, while type A personalities are more likely to get involved in more stressful situations, their negative health effects might depend on other variables, such as self‐esteem and years in the job. While personality features are important risk factors, they may not, by themselves, predict stress. Stress is the result of interacting variables including age, position, job level, the stress experience, and one's personality.

A cybernetic framework linking personality and other variables in understanding general health

Internet banking is a form of self‐service technology, costing millions of dollars, which leading retail banks have made available in the recent past. An understanding of why users are more accepting of Internet banking services should help bank managers implement this self‐service technology. This study identifies eight characteristics which influenced the rate of adoption. Two of these characteristics, namely accessibility and confidentiality, are new to the literature. The results show that adopters of Internet banking perceive the service to be more convenient, less complex, more compatible to them and more suited to those who are PC proficient. Adopters were also found to be more financially innovative. The perceptions that adopters had about social desirability, confidentiality, accessibility and economic benefits were viewed no differently when adopters were compared with non‐adopters.

Managers and entrepreneurs are increasingly being challenged to respond to a world where it is harder to effectively make and implement their decisions. Over half the decisions managers make are never implemented. We have observed entrepreneurs and managers in a wide range of situations in various countries, who illustrate a different set of assumptions for making decisions. They illustrate an entrepreneurial logic, a process of creatively defining and taking action to make sense out of situations which require new frameworks, assumptions and understandings. They assume that many challenges are not predictable and controllable. Certain control‐oriented attitudes and behaviors inhibit people from thinking this way, such as attempts to make decisions without fully understanding the right question, and overly relying on statistics. Certain reframing attitudes and behaviors – diversity in thinking, asking the right questions, and reframing and adapting quickly – illustrate ways to make sense of the paradoxes and uncertainties in the new economy.

Undergraduates constitute an attractive segment of customers for retail banks in many countries of the world, including Singapore. This study, using a sample of Singapore’s undergraduates, sets out to establish a ranking of the various dimensions which influence their bank selection decision and seeks to determine how homogeneous undergraduates are in relation to their selection decision. Seven bank selection dimensions were identified, the most important being undergraduates should “feel secure”, while the least important dimension was “third party influences”. Responses between those “attending engineering courses and non‐engineering courses” were compared, as were those between “males and females” and “single and multiple bank users”. More significant differences were found when engineering undergraduates were compared with non‐engineering undergraduates. Irrespective of these differences, the sequencing of the seven selection dimensions was invariably in the same order.

Singapore’s undergraduates: how they choose which bank to patronise

Foreword by Janet Bavelas The Approach Introduction An Overview of the Echo Approach Principles Underlying the Echo Approach Immersion Collaboration: A First Step in the Echo Approach Designing a Process that Insures Insight and Creativity Interviewing Individuals with Different Types of Questions Interviewing Groups Combining Interviews and Observations Research Focusing Research Using the Echo Sorting and Content Analysis Procedure Developing Echo Surveys or Questionnaires Developing Experiments Taking Action Communicating Learning and Change Action Research Endnotes Bibliography Index

Researching Organizational Values and Beliefs: The Echo Approach

The article presents results that indicate that trust and job design are complementary concepts in understanding outcomes like intention to quit and satisfaction. We conceptualized a worker's beliefs that a supervisor can be trusted as being composed of three main elements - beliefs in the supervisor's predictability, benevolence and fairness. This was motivated in part by a desire to conceptualize trust in a way that distinguished it from leader-member exchange (LMX) quality. The capacity of this measure of trust to predict self-reported outcomes was then compared with a job's motivational potential score, as a way of testing the trust measure's criterion validity. To do so, the results from two separate surveys were analysed. The first was based on the questionnaire responses of 535 employees in the telephone industry in the province of British Columbia; the second, of 230 service station employees from across Canada. In the studies reported here, supervisor relationships accounted for a significant amount of the variance on a variety of criterion measures. The results also suggested that perceptions of trust act independently of job design factors in affecting the outcome variables of absence, intention to quit, satisfaction and performance. In addition, the results indicated trust to be as important as job design factors in predicting outcomes.

Trust and the Design of Work Complementary Constructs in Satisfaction and Performance

Hotels can be classified as a type of business which not only uses large amounts of capital, but also employs relatively large numbers of people. The present study sets out to establish how Singapore’s Gazetted hotels (i.e. those hotels which have met certain minimum criteria as laid down by the Singapore Tourism Board) select their bank. The study also sought to establish how satisfied these hotels were in relation to the various selection criteria, the range of bank and non‐bank financial products they used and the extent to which they engaged in multiple banking and why. The results showed that pricing and geographical proximity were very important when selecting a bank. Generally, banks were found to more than satisfy the respondents in relation to the selection criteria, especially in regard to geographical convenience and accuracy of bank statements. The Gazetted hotels used a range of borrowing and non‐borrowing products, indicating that they are generators of both fee and interest income for banks. A majority of the respondents engaged in multiple banking and mainly did so in order to seek out the best borrowing rates.

This study, using a sample of adult Singaporeans, established that 76.8 per cent of its respondents engaged in multiple banking. The Post Office Savings Bank was main bank to 61.3 per cent of the respondents, while the local full licence banks were main bank to 35.1 per cent of the respondents. These same banks held 27.6 per cent and 66.1 per cent respectively of subsidiary bank relationships. Multiple bank customers were typified as being people who were tertiary educated, were Chinese and were paid an income of $2,000 p.m. and above. No significant differences were found upon comparing single and multiple banking customers based on five psychographic characteristics.

This study uses a Delphi technique to determine the future challenges in industrial relations (IR) management in Singapore. It attempts to explore whether Singapore needs to make any changes to its consensual IR system. In this respect, it examines whether the IR system that was put in place in the 1960s, when the country embarked on its industrialization process, is congruent with the current shift towards a high value-added and technological economy. The Delphi method is used to tap the views of IR experts on this issue. The results of the study indicate a number of potential problems and challenges facing the Singapore IR system. One such problem is the lack of capable union leaders who can educate the workforce on the need to use skills training and upgrading to improve productivity. The implications of the study are discussed, as are the recommendations arising from the study.

Determining the future challenges in industrial relations management in Singapore: A Delphi approach

An organization’s death exhibits many of the same feelings and reactions that humans experience with the loss of a loved one. People are forced to disconnect from established relationships and to reconnect with others. This disconnecting and reconnecting involves stages of anticipation or uncertainty, confirmation or recognition of the need for change, action, and adjustment. Describes an observational study of an organization which exhibits the feelings and reactions during different stages of an organization’s death. Three propositions explain how people cope during these stages: (i) Those who are able to take positive action have a more pronounced sense of their own ability to control their own destinies (internal locus of control) and a realistic feeling of invulnerability. (ii) The beliefs and illusions about an organization’s pending termination may be created and nourished by very little information, rumours and preconceived beliefs. (iii) Some people, who were more receptive to feedback, have some very realistic beliefs about their future and were very capable of adjusting their “paradigms” of how to respond to their future. The painful feelings of disconnecting might be assisted by feedback and support, while reconnecting to new organizations might depend on one’s attitudes and beliefs.

Establishes that, in Singapore, which has a minority of Muslims in its population, both Muslims and non‐Muslims are generally unaware of the culture of Islamic banking. Also the two separate groups have different attitudes towards the Islamic banking movement, with the degree of difference depending on the nature of the respective matter put to them. For example, when asked what they would do if an Islamic bank did not make sufficient profits to make a distribution in any one year, 62.1 per cent of Muslims said they would keep their deposits within the Islamic banking movement, while 66.5 per cent of non‐Muslims said they would withdraw their deposits. In relation to bank selection criteria, there was general accord as between Muslims and non‐Muslims on the rating of the various criteria. Five significant differences were noted, the most relating to “being paid higher interest on savings”. The desire to be paid higher interest was far stronger with non‐Muslims.

The increased efficiencies to be gained in improving logistics has pushed managers to explore a number of new ideas, technologies, and methods of information management and computerization. However, many companies in Asia are indicating that responsiveness and flexibility are the keys to responding to markets which are rapidly changing and where customers are requiring a range of services. Studies several local and international logistics firms in Singapore and elsewhere as a way of developing a better understanding of their difficulties and reasons for success. Illustrates why certain larger companies which have the capability to develop more sophisticated information and computer systems do not; instead, they chose to rely on more flexible systems which allow for learning and adaptation.

Designing flexible logistics systems: a review of some Singaporean examples

Seeks to better understand the implications of Japanese management methods in non‐Japanese and non‐Western contexts. Utilizes a framework proposed by Young to assess the implementation of Japanese management practices in Singapore. Based on comparative case studies of five Japanese multinational companies in Singapore, explores their ability to use or adapt practices employed in Japan. Concludes that, on the whole, the companies successfully sought to modify features of the Singaporean environment to suit Japanese manufacturing methods, though they were forced to make some concessions to local conditions. Supports Young’s call for further research, where the ability to compare directly the experience of both Japanese subsidiaries and non‐Japanese companies seeking to adopt Japanese manufacturing techniques would be a distinct advantage.

Manufacturing management practices of Japanese subsidiaries in Singapore

Total quality management (TQM) and other quality improvement programs have attracted a great deal of attention during the last few years. Although many managers have viewed such programs as promising for improving productivity and profit, the success ra..

Assessing the Impact of Total Quality Management-Related Programs: A Singaporean Case

This paper analyses some of the difficulties that human resource (HR) managers have in responding to problems of labour turnover and labour shortages.It provides a brief overview of the complex environments in which Singaporean HR managers operate. This paper suggests that, when the roles of management and personnel are ambiguous or when there is tremendous change, line managers and executives take over some of the functions of HR managers, a practice which is seen as a problem for HR managers. However, content analysis of interviews with HR managers shows that this encroachment becomes a problem only when the HR managers lack the skills necessary to perform their duties competently. Thus, it is suggested that HR managers should adopt an HRM approach which focuses on roles and skills necessary to manage ambiguity. In this respect, a more inclusive model should involve roles such as: reconciliation, recruitment and retention, employee relations, planning and internal management.

Skills for managing human resources in a complex environment: the perceptions of human resource managers in Singapore

Factors affecting performance in effective business organisations in Singapore

This paper offers a perspective on using the action research (A.R.) process to improve personnel practices, and illustrates this in a Canadian organization concerned with providing emergency services for those in need. After providing an overview of the action research process, this paper illustrates some of the personnel projects which were undertaken in developing job descriptions, a performance appraisal system for management, a strategic plan, an integrative labor relations process, and a team management process. It suggests that a number of strategic choices will affect the success of projects such as: (i) defining the relationship between organizational versus A.R. activities, (ii) changing people versus changing structures, (iii) using power versus integrative strategies, (iv) resolving technical versus people problems, (v) information gathering versus facilitation, and (vi) top versus bottom-up change.

Strategic Considerations in Using Action Research for Improving Personnel Practices

There are two sets of transitions which most family businesses face. (i) There are often conflicts between fathers, mothers, sons, daughters, and non-family members over who will take over the business. (ii) The family business is also responding to problems relating to growth and adaptation, and the need for management systems that goes beyond the persistence and personality of the founder. This paper provides a framework for understanding how these two processes are interlinked. Family and company transitions both require changes in the organisation’s direction and focus. This paper suggests that family and company transitions provoke different reactions making it necessary to respond in different ways.

The Dynamics Of Growth And Succession In Entrepreneurial Organisations

ABSTRACT Operating a family-owned business is often complicated with problems of who in the family will take over. There are conflicts between fathers, mothers, sons and daughters as well as those with non-family members. The family business is also fighting for its life in responding to problems relating to growth and adaptation. As the company develops, there is a need for management systems that go beyond persistence and personality. The problems and issues surrounding the succession issue are difficult to respond to with planning. Rather, succession is a problem which is emotional and relies on the relationships. This paper suggests that family and company transitions provoke different reactions, making it necessary to respond in different ways.

SUCCESSION IN ENTREPRENEURIAL ORGANIZATIONS: A COMPARISON OF SUCCESSFUL AND LESS SUCCESSFUL CASES

Provides a perspective for creating a more formalized mentoring programme and for developing a culture of mentoring within an organization. Describes certain principles which are applicable to all such programmes, derived from interviews with those who have been mentors and proteges. Identifies two steps in the process of developing a mentoring programme: defining the organization′s need for mentoring; and designing and implementing the mentoring programme. Elaborates on the components of these two steps. Concludes that a healthy mentoring programme should involve people when they are needed, and use them appropriately in assisting personnel development.

Describes the benefits of mentoring in relation to training personnel and gives guidelines on selecting suitable role models as mentors. Discusses in depth the essentials of a good, solid mentor‐prot\?\g\?\ relationship.

Characteristics of the Mentoring Experience: A Qualitative Study

AbstractStories of entrepreneurial successes range from the classical rags-to-riches story to the less-dramatic tale of steady growth through diligence, perseverance and perspiration. The successful entrepreneurs are folk heroes to many people who are contemplating a venture. Yet, we know very little about them. What are they like? How do they think? How do they relate to employees? This paper synthesizes the advice of over 150 entrepreneurs and professional managers and offers their perspective on improving entrepreneurship and small-business management.

Foreword by A.W. McEachern A Definition on Action Research The Need for an Action Research? The Early History of Action Research The Emerging Action Sciences Adjusting Research Methods for Organizational Problem-solving An Action Research Procedural Model Types of Interviews Developing Data Gathering Instruments Observations and Unobtrusive Measures Dealing with Messy Data Carrying out the Process of Change: Some Implementation Steps Focusing the Change Different Stages of the Change Process Action Research and Organization Development Final Consideration

The Conflict Surrounding the Drainage of the River Erne 1881-1890

Suggests that successful managers develop practical theories or frameworks to guide their decision making and problem solving. Describes how managers developed a framework for focusing performance appraisal, training and career development opportunities in a long‐term care hospital.

Many managers have found popular and academic writings on job and organisational design most interesting and have committed a great deal of energy in trying to use them. Terms such as job enrichment, job enlargement, Japanese management, and socio‐technical design have become well known for their potential in responding to problems of job dissatisfaction, labour instability, and poor workmanship. Ways in which “popular paperback” theories, as well as other more systematic organisational theories of design might be customised to the particular needs of the organisation are illustrated.

Planning approaches have long been of interest in identifying opportunities and co‐ordinating decisions. An “action” planning perspective is offered which seeks to assist managers in gaining membership commitment in the planning process.

A perspective on the age old question “How do we train and educate managers?” is provided. The central assumptions underlying most management education and development are at odds with the findings of many studies of management. Programmes for education should teach skills and techniques which relate to: (1) functions and activities to be performed, and (2) the needs and assumptions of specific groups of managers. The need for this proposal is based on the findings of two managerial studies.

The use of traditional methods for job design and redesign can have a negative impact on productivity and employee morale. Four alternatives to the traditional approach are job enrichment, the job characteristics model, Japanese-style management, and quality-of-worklife approaches. The theories of job enrichment and the job characteristics model are based on job content. Japanese-style management techniques focus on strong teamwork, job harmony, and group goals. The quality-of-life approaches are based on improving an organization’s design. A suggested procedure for implementing a large-scale job redesign program involving 12 steps is outlined.

The Investigation into the Attempted Assassination of Folliot Warren Barton near Pettigo, on 31 October 1845

Ask a manager what she/he does. She/he will probably tell you about functions or processes such as planning, organising, budgeting, and controlling (Fayol 1949).

The Landlord, the Minister, the Tenant and the Tithe in Belleek in 1758

General systems theory offers one perspective for defining and understanding the problems that organisations face. The author presents a set of systems problem‐solving principles, and offers a procedure which might be useful when conventional problem‐solving has not been totally successful. The article illustrates this procedure in trying to address a budget deficit problem in a large metropolitan hospital.

This study examines some of the psychological and behavioral effects of a 12-hour compressed shift schedule on coal miners in two organizations in Western Canada. It suggests that young, married compressed shift workers are more satisfied with their family relationship. They spend less of their leisure time with spouses when working shifts, and do not spend any more time with them on their days off. They have less time available for many leisure activities on their workdays. The extra time on days off is not reallocated to the leisure activities they were unable to do on their workdays. Some extra leisure time on days off may be spent on personal hobbies. There is no suggestion that the compressed shift schedule has any negative effect on the individual's health.

A compressed shift schedule: Dealing with some of the problems of shift‐work

The Castle Caldwell Estate in 1780 and the Recent Arrest of the Highwayman Francis McHugh (Prionsias Dubh)

Assumptions Underlying the Use of Different Types of Simulations

A common feature in the assessment of on-going programs is the use of intuition and common sense in selecting and analyzing evidence. Although intuition nay provide rich insights into a specific situation, there is no way to ascertain whether the intuition represents good judgment or good politics. This article describes one means of selecting and analyzing evidence for assessing changing situations, and offers a procedure that light improve research on action-related problems.

Compressed shift schedules: altering the relationship between work and non-work.

Lough Derg and Its Unusual "Guardian" Rev. Alexander Calhoun, Grandfather of John Caldwell Calhoun, Vice-President of the U.S.A.

The growing interest in changing the hours of work is reflected in such arrangements as flex-time (Ebbing et al., 1974; Golembiewski et al., 1974; Stein et al., 1977) and the compressed work week (Dunham and Hawk, 1977; Fottler, 1977; Nord and Costigan, 1973). Among the reasons for implementing these schedules are potential improvements in employee productivity and job satisfaction, as well as potential reductions in absenteeism and labour costs (Calvasina and Boxx, 1975; Goodale and Aagard, 1975; Maklan, 1977). Compressed schedules then appear to have many of the advantages as are claimed for strategies such as job enrichment and job enlargement (Herzberg 1966, 1968). The primary purpose of this note is to examine the effects of the implementation of a compressed work week on job-related variables (satisfaction, involvement and teamspirit) and on non-job-related variables (use of leisure time for social and professional activities). This note, which describes a case study of the implementation of a ten-hour shift schedule in a team of policemen in the Vancouver Police Department, provides some information on the feasibility of developing a hypothesis about these effects.

What is management? In recent years, a number of schools or approaches to management have evolved. What is rather upsetting to the manager is that there are a variety of unrelated approaches without any suggestion of their relationship to each other. Even more upsetting is that some of these approaches seem to be based on the disciplines of particular researchers rather than their ability to help managers. The study explores the rationale underlying two predominant orientations. One is concerned with the process of management, while the other emphasizes the function of management. The managerial process involves such intuitive principles as planning, organizing, and staffing. The managerial function involves arranging equipment to perform functions such as procurement, production, and adaptation. The goal is to illustrate the relationship of these approaches to each other and to specific managerial needs. The study was conducted among top managers in six municipal organizations. The research utilized a questionnaire and decision-making simulation for gathering data on the relationship of each managerial orientation. The results indicate that each orientation deals with different areas of managerial action. Key managerial processes focus on integrating, making decisions, recording information, motivating, and negotiating. The managerial functions, in this study, are part of three subsystem efforts which are administrative, adaptive, and technical. When management is defined as a process, it has no relationship to functions; when it is defined as functions of specific subsystems, there is no positive relationship to the process.

Systems theorists maintain that all organizations, in order to survive, must be able to fulfill certain basic needs. In this article, these needs relate to: (1) the organization's ability to search out and respond to the properties of the external environment; (2) the organization's ability to use its resources to produce outputs and to maintain and restore the system; and (3) the organization's ability to bargain and optimize its use of resources in an environment with a number of decision-makers, each with different objectives. These criteria are used to evaluate the effectiveness of seven local government organizations.

A Systems-Resource Approach for Evaluating Organizational Effectiveness

Seven alternative strategies are presented for assessing organizational effectiveness in different situations: rational goal, systems resource, managerial process, organizational development, bargaining, structural functional, and functional. Each has advantages in the evaluation of specific organizational problems.

Evaluation methodologies for organizational effectiveness : applications of decision theory and game theory

The demonstration of an unusual combination of collateral channels during lymphography--a case report.

Hepatoid adenocarcinoma (HAC) or hepatoid carcinoma is a rare
(adeno)carcinoma with hepatocellular differentiation but arises
from extrahepatic tissues.

Diagnosis of Hepatoid Carcinoma of Extrahepatic Origins: Cell Markers and Pathologic Standards

B104. CRITICAL CARE: CATCH-22 - BEYOND THE VENTILATOR: THE CHALLENGES OF DELIRIUM, ICU-ACQUIRED WEAKNESS, AND REHABILITATION

Early Rehabilitation in Patients Requiring Continuous Renal Replacement Therapy Is Safe and Feasible: A Quality Improvement Initiative

Common Bile Duct Stone Size Is an Independent Predictor of Stone Detection by Magnetic Resonance Imaging: 85

Biliary Tract IPMN Successfully Treated with Roux-en-Y Hepaticojejunostomy: 1268

Diagnostic Yield of EUS over MRI for Detection of Common Bile Duct Stones: A Single Center Experience: 29

Mo1436 Pancreatic Duct Stenting Using a Long Multi-Perforated Soft Plastic Stent Without Flanges (Johlin®) in Patients With Pancreatitis: a Multi-Center Case Series Experience

Purpose: Dabigatran is a new direct thrombin inhibitor which is eff ective in stroke prevention in patients with atrial fi brillation and does not require INR monitoring, has fewer dietary restrictions and potentially less drug-drug interactions. Dabigatran is renally-cleared, raising the possibility of increased risk of bleeding in those with renal insuffi ciency. Furthermore, there is no reversal agent that may be used in the setting of acute bleeding. Anecdotal experience suggests that patients may be at increased risk of severe bleeding while taking this medication. Methods: A single-center retrospective review of all atrial fi brillation patients admitted to Brooke Army Medical Center from November 2010 to October 2012 to evaluate the bleeding incidence, severity and characteristics of those taking dabigatran compared with warfarin. Results: 310 patients were prescribed dabigatran between November 2010 and October 2012. 15/310 (4.8%) admitted with endoscopically confi rmed gastrointestinal bleeding. Th e majority of patients were admitted with overt bleeding such as melena and/or hematochezia (13/15). Every patient taking dabigatran who was admitted for GI bleeding demonstrated small, but signifi cant elevations in prothrombin time (PT), activated thromboplastin time (aPTT), and international normalization ratio (INR). All of which normalized with withdrawal of the medication. Conclusion: Our reported GI bleeding incidence is higher than what was cited in the RE-LY study (2.7% all-cause major bleeding). Th is diff erence may be due to lack of experience with this specifi c medication by ordering physicians or subtle diff erences in the target populations.

Single‐center Experience with Gastrointestinal Bleeding in Patients Taking the New Oral Direct Thrombin Inhibitor Dabigatran: 1637

Dig Deep to Find the Answer: The Utility of Endoscopic Ultrasound with Fine Needle Aspiration for a Difficult Diagnosis of Esophageal Cancer in Chronic Mucosal Candidiasis: 679

A multicenter analysis of safety and outcome of removal of a fully covered self-expandable metal stent during ERCP.

In this report, a patient had a previous diagnosis of cholangiocarcinoma with an extended cholecystectomy. Three years later, he was evaluated for recurrent ascites. The patient had several large volume paracentesis, without evidence of malignant cells. Subsequently, endoscopic ultrasound (EUS) with fine needle aspiration (FNA) of both lymph and omental nodules was utilized. While the lymph nodes were negative for malignancy, the omental nodule was interrogated with multiple antibodies and was found to be positive for neoplasia. EUS with FNA can safely be used in patients with cirrhosis to spare the patient invasive evaluation such as exploratory laparotomy (ex-lap) for diagnosis and staging of cholangiocarcinoma.

Endoscopic ultrasound with biopsy of omental mass for cholangiocarcinoma diagnosis in cirrhosis.

In this report, a patient was exposed to an herbal remedy for hypercholesterolemia. She became acutely jaundiced while taking the remedy and presented for medical care. Endoscopic ultrasound was utilized, and found a distal common bile duct mass. Endoscopic retrograde cholangiopancreatography guided bile duct biopsies revealed that the mass was cholangiocarcinoma (CCA). This case highlights a unique association between autoimmune hepatitis and CCA. It also highlights that EUS can be safely used in patients with cirrhosis to spare invasive evaluation such as exploratory laporotomy for diagnosis and staging of cholangiocarcinoma.

Use of endoscopic ultrasound for diagnosis of cholangiocarcinoma in auto-immune hepatitis.

S1428: A 15 Year Quality Improvement (QI) Exercise for Biopsy (Bx) and Brush Cytology (BrC) of the Common Bile Duct (CBD) for Diagnosis of Malignant Biliary Obstruction (MBO)

A Multicenter Analysis of Safety and Outcome of Removal of Covered Self-Expandable Metal Stents (CSEMS) During Endoscopic Retrograde Cholangiopancreatography (ERCP)

Should Pre-treatment Viral Load Determine Treatment Duration for Chronic Hepatitis C Genotype 3 Patients: 363

Cavernous hemangiomas are among the rarest causes of gastrointestinal bleeding. Here, we report a case of hematochezia resulting from an extensive cavernous hemangioma involving the rectum. We also highlight the difficult therapeutic challenges that can be posed by these lesions.

An uncommon cause for a common scenario: A case of hematochezia caused by a massive cavernous hemangioma

Multiple Sampling Method Increases the Diagnostic Yield in Non Pancreatic Malignant Biliary Obstruction (MBO)

Efficacy and Safety of a Fully Covered Self Expandable Metal Stents (CSEMS) for Distal Biliary Neoplasia: Preliminary Data of a Retrospective Multicenter Study

Updated Guidelines 2008 for the diagnosis, surveillance and therapy of Barrett's esophagus (American Journal of Gastroenterology (March 2008) 103: 3 (788))

Large-diameter biliary orifice balloon dilation to aid in endoscopic bile duct stone removal: a multicenter series.

Large-Diameter Papillary Balloon Dilation to Aid in Endoscopic Bile Duct Stone Removal: A Multicenter Series

To date, antegrade intussusception involving a Roux-en-Y reconstruction has been reported only once. We report a case of acute bowel obstruction due to an intussusception involving two Roux-en-Y limbs in a 40-year-old woman with a history of chronic pancreatitis due to pancreas divisum. Four years preceding this event, the patient had undergone a Whipple procedure, and three years prior to that, a Puestow operation. The patient was successfully treated with bowel resection and a side-to-side anastomosis between the most distal aspect of the bowel and the most distal Roux-en-Y reconstruction, which preserved both Roux-en-Y reconstructions.

Antegrade bowel intussusception after remote Whipple and Puestow procedures for treatment of pancreas divisum.

Efficacy and Safety of a Fully Covered Self Expandable Metal Stents (CSEMS) for Distal Biliary Neoplasia: Preliminary Data of a Multicenter Study: 213

EUS was carried out in both patients. The first patient had a septated cystic lesion 4.6  2.7 cm in size in the pancreatic head (Figure 2a). The second patient had a sep− tated cystic mass measuring 3.7  2.6 cm near the uncinate process (Figure 2 b). The rest of the examination was normal in both patients (Figure 3). At FNA, a thin, milky fluid was aspirated in both cases (Figure 4). Laboratory analysis revealed a triglyceride level of > 5000 mg/dl in both cases. No disease progression or compli− cations such as cyst infections were evi− dent after a follow−up period of 5 months. In both cases, the chylous aspirate with a markedly elevated triglyceride level was diagnostic.

Two cases of cystic lymphangioma of the pancreas: a rare finding in endoscopic ultrasonography.

Pancreatic Duct (PD) Stenting with the Johlin Wedge Stent (JPWS) in Pancreatic Disease: 228

Isolated Right Segmental Hepatic Duct Injury Following Laparoscopic Cholecystectomy

Background and Objectives: At the time of endoscopic retrograde cholangiopancreatography, deep cannulation of the bile duct is a prerequisite to be able to provide endoscopic therapy. We describe a simple technique to assist in difficult bile duct cannulation. Methods: If the pancreatic duct is easily entered but the bile duct cannot be accessed, a guidewire is advanced into the pancreatic duct, and the cannulating catheter is removed leaving the tip of the wire in the mid pancreatic duct. Alongside the pancreatic wire, a catheter, preloaded with a second wire, is advanced via the channel of the endoscope. With the first wire in the pancreatic duct, the second wire is advanced above it in the anticipated bile duct axis. Results: We have used this technique in 12 cases and succeeded in 10. No complications occurred. Discussion: Inserting a pancreatic wire can assist in bile duct cannulation, by straightening and stabilizing the papilla. The use of this new technique can reduce the need for precut sphincterotomy, with its inherent increased risks of pancreatitis, bleeding, and perforation. The approach proposed by us can assist in any difficult bile duct cannulation, but it can be particularly useful when dealing with a papilla that is very prominent with a tortuous intraduodenal segment or a papilla located in a duodenal diverticulum.

A New Technique to Assist in Difficult Bile Duct Cannulation at the Time of Endoscopic Retrograde Cholangiopancreatography

Post-sphincterotomy bleeding after the introduction of microprocessor-controlled electrosurgery: does the new technology make the difference?

Pancreatic Duct (PD) Stenting with the Johlin Wedge Stent (JPWS) in Pancreatic Disease: 202

Biliary stricture is one of the most common complications of liver transplantation. A number of treatment options are available, but a standard approach has not been established.

METHODS
A total of 25 patients with post-liver transplantation anastomotic strictures were treated endoscopically by stent placement. Long-term outcomes (bile duct patency, morbidity, and mortality) were reviewed retrospectively.

RESULTS
Placement of a stent was attempted in 25 patients with anastomotic stricture. Successful stent placement with stricture resolution at the time of stent removal was noted in 22 patients (technical success 88%). In those 22 patients, long-term success (mean follow-up after all stents removed, 54 months) was observed in 20 patients (90%) and partial success in two (10%). Long term, failure did not occur in any patient. There was no procedure- or disease-related mortally. Three mild episodes of cholangitis occurred during the period while the stents were in place, in relation to 79 endoscopic interventions for a procedure-related complication rate of 3.7%.

The long-term outcome for patients with post-liver transplantation biliary anastomotic strictures treated with endoscopic stent placement is excellent, with no therapy- or disease-associated mortality and minimal morbidity.

Long-term outcomes for patients with post-liver transplant anastomotic biliary strictures treated by endoscopic stent placement.

The long-term efficacy of sequential insertion of multiple plastic stents for benign biliary strictures is poorly defined. The aims of this study were to evaluate the long-term outcome (bile duct patency, complications) of this therapy and to identify predictors of a good outcome.

METHODS
Retrospective review of 29 cases of benign biliary strictures treated with sequential plastic stent insertion in progressively increasing numbers and/or of increasing diameter.

RESULTS
Stricture etiology was as follows: postoperative 19 (66%), chronic pancreatitis 9 (31%), and idiopathic 1 (3%). Therapy succeeded in 18 patients (62%) (mean follow-up 48.0 [11.56] months after stent removal). Therapy failed in 11 patients (38%) (mean interval to failure 11.59 [9.79] months after stent removal). The 2 groups of patients in which therapy failed had either a hilar stricture (n = 4, 25% success) or distal common bile duct stricture caused by chronic pancreatitis (n = 9, 44% success). In the remaining cases, therapy succeeded in 13 of 16 (81% success). The observed differences in success rate among subgroups were not statistically significant. There were no ERCP-related deaths. One episode of mild pancreatitis and 2 episodes of cholangitis developed during 126 ERCPs over a period of stent insertion of 36 patient years.

In selected patients with benign biliary strictures, sequential endoscopic insertion of multiple biliary stents may lead to long-term success that could be equal to or superior to surgery with minimal morbidity. Hilar strictures and those caused by chronic pancreatitis appear to respond poorly to this therapy.

Long-term outcome in patients with benign biliary strictures treated endoscopically with multiple stents.

Novel "through-the-endoscope" technique for removing biliary stones trapped in a retrieval basket.

Accuracy of EUS for detection of intraductal papillary mucinous tumor of the pancreas.

BACKGROUND AND STUDY AIMS
Unexplained pancreatitis represents a diagnostic challenge. The aim of this study was to determine the diagnostic utility of endoscopic retrograde cholangiopancreatography (ERCP) with sphincter of Oddi manometry (SOM), bile analysis, and endoscopic ultrasound (EUS) in evaluating such patients.

Of 162 patients referred for evaluation of pancreatitis, 72 with a known cause were excluded. The remainder ( n=90) was classified as having prior acute ( n=24) or recurrent acute pancreatitis ( n=66). Bile sampling and SOM were performed at the time of ERCP. EUS was used to assess for tumors and for chronic pancreatitis. Clinical outcomes were evaluated by questionnaire.

RESULTS
ERCP was successful in 88/89 patients (99 %). Manometry was successful in 63/67 patients (94 %), and 56 patients underwent EUS. Findings were categorized into five distinct etiologies: sphincter of Oddi dysfunction (SOD) ( n=28; 31 %), pancreas divisum ( n=18; 20 %), biliary ( n=18; 20 %), idiopathic ( n=18; 20 %) and tumor-related ( n=8; 9 %). Features of moderate or severe chronic pancreatitis by EUS and ERCP criteria were found in 18 patients (21 %); an additional nine patients had chronic pancreatitis by EUS criteria alone. EUS identified all the tumors. The condition was improved in 96 % of all patients undergoing endoscopic therapy.

An etiology was identified in the majority of patients with unexplained pancreatitis. SOD represented the most common finding. Moderate to severe chronic pancreatitis was found in over one-fifth of these patients. Bile analysis, SOM, and EUS are useful tools in the evaluation of unexplained acute pancreatitis.

Evaluation of unexplained acute and acute recurrent pancreatitis using endoscopic retrograde cholangiopancreatography, sphincter of Oddi manometry and endoscopic ultrasound.

A guidewire-assisted technique for removing retained biliary stents with rat-toothed forceps during endoscopic retrograde cholangiography.

OBJECTIVE:To assess the ability of MRCP to alter the differential diagnosis and to prevent diagnostic and/or therapeutic ERCP. The diagnostic accuracy of magnetic resonance cholangiopancreatography (MRCP) for biliary and pancreatic disease is well documented. Some believe MRCP may prevent diagnostic ERCP or add useful information, however there are no reports of its impact on clinical management.METHODS:Consecutive patients referred for ERCP underwent clinic evaluation, then MRCP, and then ERCP. In Phase 1, the number of differential diagnoses and the perceived need for diagnostic ERCP were evaluated after each step by the endoscopist who performed the ERCP. In Phase 2, the process was repeated after presenting clinical information and MRCP results to different individual physicians: another endoscopist, a hepatologist, a radiologist, and a surgeon (all were blinded to ERCP results).RESULTS:Forty patients were enrolled. Clinical contexts were jaundice (19.7%), abnormal liver enzymes (42.6%), abdominal pain (11.5%), recurrent acute pancreatitis (11.5%), and suspected complications of chronic pancreatitis (14.7%). In Phase 1, adding MRCP information to diagnostic ERCP information did not change the mean number of differential diagnoses significantly and prevented no therapeutic ERCP. In Phase 2, adding MRCP to clinical information only (without ERCP) reduced the differential diagnosis significantly for the radiologist and the surgeon only and would have prevented ≤3% of diagnostic and therapeutic ERCP for all physicians.CONCLUSION:The value of MRCP information may be limited if patient selection is inappropriate and may differ in physicians depending on their speciality.

The decision-making value of magnetic resonance cholangiopancreatography in patients seen in a referral center for suspected biliary and pancreatic disease

Altering the sampling sequence improves the cytologic yield in a multisampling technique in patients with malignant obstructive jaundice (MOJ): a prospective trial

Is a dilated pancreatic duct at ERCP associated with a lower incidence of post-ERCP pancreatitis (PEP)? An analysis of 3298 patients

Placing an additional distal flap prevents migration of polyethylene stents in patients with biliary leaks

Biliary tract leaks occur in over 10% of patients undergoing liver transplantation and are the most common cause of biliary tract-related death in these patients. A number of treatment options are available, but a standard approach has not been established.

METHODS
Twenty-six patients were retrospectively studied who had post-transplantation leaks develop with special reference to those who underwent endoscopic placement of a "leak-bridging" stent.

RESULTS
Endoscopic retrograde cholangiography was performed in all cases with no procedure-related complications. Twenty-four patients had a leak-bridging stent, 1 a transpapillary stent, and 1 a nasobiliary drain. Leak resolution occurred in 23 cases (88%) after initial stent placement. The median time to stent removal was 8 weeks. Three patients did not respond to initial treatment; 2 were successfully treated with another stent and a single patient required surgical repair. Four deaths occurred during follow-up, all unrelated to the biliary leak.

Placement of a leak-bridging stent is a safe and effective initial treatment for post-liver transplantation biliary leaks.

Endoscopic treatment of post-liver transplantation biliary leaks with stent placement across the leak site.

Mechanical lithotripsy for biliary stones: a 5 year university experience

Same-day discharge after endoscopic biliary sphincterotomy: observations from a prospective multicenter complication study. The Multicenter Endoscopic Sphincterotomy (MESH) Study Group.

Comparative costs of metal versus plastic biliary stent strategies for malignant obstructive jaundice by decision analysis.

OBJECTIVE
To provide current information on the risks of endoscopic sphincterotomy for stone.

SUMMARY BACKGROUND DATA
In recent years (since the popularity of laparoscopic cholecystectomy), endoscopic sphincterotomy has been used increasingly for the management of bile duct stones in relatively young and healthy patients. The validity of this trend has been questioned using data on short-term complications derived from earlier decades that involved more elderly and high-risk patients.

METHODS
Seven academic centers collected data prospectively using a common database. Complications within 30 days of the procedures were documented by standard criteria.

RESULTS
Of 1921 patients, 112 (5.8%) developed complications; two thirds of these events were graded as mild (<3 days in hospital). There was no evidence of increased risk in younger patients or in those with smaller bile ducts. There was only one severe complication and there were no fatalities in 238 patients age <60, with bile duct diameters of <9 mm.

Sphincterotomy for stones can be performed very safely by experienced endoscopists.

Endoscopic sphincterotomy for stones by experts is safe, even in younger patients with normal ducts.

Outcome of lateral pancreaticojejunostomy in the management of chronic pancreatitis with nondilated pancreatic ducts

1. One of the most important issues in the field of hypertension research centres on the therapeutic use of inhibitors of the renin‐angiotensin system (RAS). Inhibitors of the RAS have potent anti‐hypertensive effects, even in experimental models of hypertension and in human essential hypertension, where the activity of the peripheral RAS is low or normal.

Diagnostic endoscopic ultrasound of the pancreas may cause acute pancreatitis.

Prospective assessment of the ability of endoscopic ultrasound to diagnose, exclude, or establish the severity of chronic pancreatitis found by endoscopic retrograde cholangiopancreatography.

Pancreatic stenting prevents pancreatitis after biliary sphincterotomy in patients with sphincter of Oddi dysfunction.

Patients with typical symptoms of biliary tract disease but no gallstones on ultrasonography may benefit from cholecystectomy for presumed chronic acalculous cholecystitis. We retrospectively analyzed the outcome of 50 patients with a preoperative diagnosis of chronic acalculous cholecystitis based upon history (chronic or recurrent, postprandial right upper quadrant abdominal pain), the absence of acid-peptic disease, and normal biliary sonography treated with laparoscopic cholecystectomy (LC) and transcholecystic cholangiography from 1991 to 1996. All patients had preoperative cholecystokinin-stimulated hepatobiliary scintigraphy (CCK-HBS). There were 42 women and 8 men with a mean age of 43 years. CCK-HBS was abnormal in 45 patients (< or = 35 per cent gallbladder ejection fraction or nonfilling of the gallbladder). There was no postoperative mortality and one morbidity (urinary retention). All patients had microscopic evidence of chronic cholecystitis. At mean follow-up of 30 months, (range, 7-62 months) 39 patients (78%) were free of abdominal pain. Thirty-five of 45 patients with abnormal CCK-HBS were pain free (positive predictive value, 0.78). Four of five patients with normal CCK-HBS were pain free (negative predictive value, 0.20). The positive and negative likelihood ratios for CCK-HBS were 0.99 and 1.13, respectively, confirming that this test was not useful for predicting benefit from LC. Seven patients with persistent right upper quadrant pain had abnormal postoperative sphincter of Oddi manometry; they improved after endoscopic sphincterotomy. Patients with symptoms typical of biliary colic with normal gallbladder sonography and absence of acid-peptic disease benefit from LC in the majority of cases. Those who remain symptomatic after LC may benefit from endoscopic retrograde cholangiopancreatography with sphincter of Oddi manometry and endoscopic sphincterotomy when manometry is abnormal.

Outcome after laparoscopic cholecystectomy for chronic acalculous cholecystitis.

A Prospective Assessment of the Ability of Endoscopic Ultrasound (EUS) to Diagnose, Exclude, or Establish the Severity of Chronic Pancreatitis Found by Endoscopic Retrograde Pancreatography (ERP)

Chronic pancreatitis can be caused by ductal obstruction resulting from cicatricial papillary stenosis, but sphincter of Oddi motility studies have been inconclusive in patients with established chronic pancreatitis. We sought to determine whether there is an association between papillary sphincter dysfunction and changes of early chronic pancreatitis.

METHODS
Consecutive patients who underwent sphincter of Oddi manometry to investigate unexplained upper abdominal pain (n = 104) were assessed for evidence of chronic pancreatitis by pancreatic ductography, endoscopic ultrasound, and pancreatic fluid bicarbonate concentration.

RESULTS
Sphincter of Oddi dysfunction patients were four times more likely (odds ratio = 4.6) to have evidence of chronic pancreatitis than were those without sphincter dysfunction (p = 0.01). Of 68 patients with sphincter of Oddi dysfunction, 20 (29%) had structural evidence of chronic pancreatitis. Twenty of 23 (87%) patients with chronic pancreatitis had sphincter of Oddi dysfunction.

Sphincter of Oddi dysfunction is associated with changes of chronic pancreatitis in patients with unexplained pancreaticobiliary pain. Longitudinal follow-up is required to confirm these preliminary findings.

Sphincter of Oddi dysfunction is associated with chronic pancreatitis.

Transpapillary stenting of proximal biliary strictures: does biliary sphincterotomy reduce the risk of postprocedure pancreatitis?

The increasing role of ercp in the management of pediatric pancreatitis

A prospective study of multiple sampling methods in the assessment of biliary strictures

Magnetic resonance cholangiopancreatography: A novel approach to the evaluation of suspected pancreaticobiliary neoplasms

Differentiation of benign from malignant pancreatic masses by endoscopic ultrasound

Endoscopic removal of pancreatic duci stones - Better patient selection by endoscopic ultrasound?

Sphincter of Oddi manometry (SOM) of both ducts after conscious sedation with meperidine

Endoscopic identification and removal of an unusual symptomatic esophageal foreign body.

Pitfalls of bile duct stone removal after balloon sphincter dilation.

Trans-esophageal endoscopic ultrasound guided fine needle aspiration: A minimally invasive method for tissue sampling of mediastinal lymph nodes in thoracic malignancies

Biliary stricture sampling by three methods: A prospective comparison

Can Endoscopic Ultrasound (EUS) features of Pancreatic Duct (PD) stone predict removal at initial ERCP

Should stents be changed prophylactically in malignant obstructive jaundice? computer modeling to optimize the use of health care resources

Injury to the extrahepatic bile ducts during laparoscopic cholecystectomy (LC) is a cause of serious long-term patient morbidity. In order to identify management strategies and outcome, we undertook a retrospective review and analysis of patients referred to the Department of Surgery and the Division of Gastroenterology for management of bile duct strictures due to injury at LC. Eighteen patients (15 women, 3 men) with a mean age of 41 years were identified over a 4-year period. Six patients had injuries identified at LC. Ten patients had previously undergone an attempt at operative repair (8 end-to-end anastomoses, 1 choledochoduodenostomy, 1 cystic duct jejunostomy). There were 5 Bismuth Grade I strictures, 6 Grade II, 2 Grade III and 5 Grade IV. Ten patients were managed nonoperatively with stents placed by radiologic or endoscopic techniques. Four patients were managed with operation alone (2 choledochojejunostomy, 1 hepaticojejunostomy, and 1 external T-tube drainage) and 4 patients with a combined endoscopic and operative approach (all 4 with hepaticojejunostomy after initial endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography management). Bile duct strictures due to LC are frequently located in the proximal bile ducts (Bismuth II-IV) and are technically difficult to repair. In the majority of cases, injuries are unrecognized at LC. Both immediate and delayed repair attempts prior to referral were frequently unsuccessful. Many bile duct strictures can be managed successfully in the early postoperative period with endoscopic and radiologic stenting techniques. Strictures which cannot be managed nonoperatively are repaired with Roux-en-Y hepaticojejunostomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Management of biliary strictures due to laparoscopic cholecystectomy.

Complications of endoscopic sphincterotomy in cirrhotics: A prospective multicenter study

Accessory gallbladder bed (Subvesical duct or duct of Luschka's) biliary leaks after laparoscopic cholecystectomy

Upper gastrointestinal findings at ERCP; Why look on the way to the ampulla

Pancreaticobiliary disease in pregnancy is relatively uncommon. The frequency of choledocholithiasis in pregnancy requiring intervention has been reported to be as low as one in 1200 deliveries. Traditionally, intervention in these patients has been surgical. Although surgery has an overall low morbidity and mortality for the expectant mother, it carries with it a 4- to 6-wk recovery period and a possibly increased risk of fetal wastage. Published information regarding the role and safety of ERCP in pregnancy is limited. This series of 23 pregnant patients undergoing ERCP was collected from six different medical centers.

METHODS
Twenty-three pregnant patients with symptomatic pancreaticobiliary disease underwent a total of 29 ERCPs (three patients had diagnostic ERCP, and 20 had therapeutic ERCP). Fifteen, eight, and six procedures were performed in the first, second, and third trimesters, respectively. The only ERCP complication was pancreatitis in one patient. There was one spontaneous abortion (3 months after ERCP) and one neonatal death; however, casual relationship to ERCP was not apparent.

Diagnostic and therapeutic ERCP appears reasonably safe and effective in pregnancy. Cautious and selective use of this procedure offers a viable alternative to surgery or observation in patients with emergent pancreaticobiliary problems.

Is pancreatic duct obstruction secondary to pancreatic sphincter hypertension (PSH) the cause of post-ERCP pancreatitis in patients with sphincter of ODDI dysfunction (SOD)?

Endoscopic sphincterotomy (ES) for gallstone pancreatitis (GSP) with intact gallbladder (GB): A prospective multicenter study

An in vitro comparison of biofilm formation on various biliary stent materials.

A new approach to stenting a tight, angulated post-operative biliary stricture.

Precise preoperative evaluation and staging of cases of painless jaundice is extremely important. Many of the patients are older and may have multiple medical problems that increase their operative risk. Assessment of the distal common bile duct, ampulla of Vater, and head of the pancreas is particularly difficult. Various imaging modalities are available but are not sensitive enough to detect small lesions or local invasion. Endoscopic ultrasonography is a new technique that places the transducer closer to the organ being evaluated, adding a new dimension to defining tumor invasion and extension.

Use of endoscopic ultrasonography for evaluation of painless jaundice.

In patients with malignancy, jaundice may result from hepatic infiltration or metastatic lymph nodal compression along the bile duct. We attempted endoscopic stent placement on 31 consecutive patients with biliary obstruction from malignant adenopathy, with and without computerized tomographic (CT) scan evidence of hepatic parenchymal metastases. Endoscopic or combined endoscopic-percutaneous decompression was accomplished in 28 patients. Fifteen patients (53.6%) had CT evidence of concomitant metastatic disease to the liver. Thirteen patients had obstructing adenopathy only. Mean survival for patients with hepatic metastases after relief of extrahepatic obstruction was 117.4 days (range 9-386 days). Mean survival after biliary decompression in patients without hepatic involvement was significantly longer at 364.3 days (range 52-1098 days; p = 0.0087). Bilirubin levels fell in all patients in this group. No patient died from complications of obstruction or stent placement. Our data support the conclusion that patients with extrahepatic metastatic biliary obstruction without hepatic metastases have improved survival, compared with patients with both obstruction and hepatic involvement. In the absence of hepatic parenchymal involvement, endoscopic stent placement can safely and effectively palliate metastatic extrahepatic obstruction. Controlled trials are needed to assess the effect of such stenting on survival.

Endoscopic stent placement for obstructive jaundice secondary to metastatic malignancy.

Technology assessment status evaluation: endoscopic band ligation of varices.

The subcommittee on Gastrointestinal Toxicology of the Patient Care Committee of the American College of Gastroenterology has reviewed potential effects of exposures to occupational and industrial hazards on the gastrointestinal tract, liver and pancreas. This review is presented to 1) share clinical data concerning gastrointestinal toxicology, 2) emphasize the paucity of available information to the practicing clinician, and 3) stimulate basic research interest in this field.

Occupational and industrial toxin exposures and the gastrointestinal tract. Gastrointestinal Toxicology Subcommittee of the American College of Gastroenterology Patient Care Committee.

Biliary fistulas have in the past been managed by a variety of methods, including surgical correction or endoscopic sphincterotomy. From 1984 to 1989, we used endoscopic indwelling biliary stents in seven consecutive patients with and without sphincterotomy and have attained fistula closure in all patients studied. The etiologies of the fistulous tracts varied, as did the type and number of stents used. The duration of time between stent placement and observed closure of the fistulous tracts ranged from 3 days to 5 months. Of note, all patients had a dramatic reduction of drainage within the first week. From our study we conclude that surgical correction of biliary fistulas is not required, that sphincterotomy is not mandatory for stent placement or fistula management in patients without distal obstruction, and that a single, small caliber stent alone may be effective.

Endoscopic management of biliary fistulas with small caliber stents.

Techniques in Therapeutic Endoscopy, J.D. Waye, J.E. Geenen, D. Fleischer, R.D. Venu. W. B. Saunders, Philadelphia (1987), 160 pp., $75.00

Gastrointestinal telangiectasias cause hemorrhage in patients with chronic renal failure. Therapies using vasoconstrictors, endoscopic application of heat, and surgery have had limited efficacy. Because several reports have suggested that estrogen or estrogen-progesterone therapy may control mucosal bleeding from telangiectasias in patients with hereditary hemorrhagic telangiectasia, we treated seven patients with chronic renal failure and bleeding gastrointestinal telangiectasias with systemic estrogen or estrogen-progesterone in an uncontrolled trial. Bleeding ceased in all patients. Blood transfusion requirements decreased from a mean of 1.2 U/month before treatment to 0.21 U/month after treatment. No significant side effects were noted. Results of this trial indicate the need for controlled investigations of this type of hormonal therapy.

Estrogen-progesterone therapy for bleeding gastrointestinal telangiectasias in chronic renal failure. An uncontrolled trial.

Endoscopic palliation for jaundice associated with malignant biliary obstruction.

Peritoneoscopy in chronic peritoneal dialysis: use in evaluation and management of complications.

L'autopsie revele une thrombose des veines hepatiques et un ulcere perfore du bulbe duodenal

Hepatomegaly and ascites in an elderly woman with polycythemia vera.

Peritoneoscopy: use in the diagnosis of ascites of unknown origin.

Gastric telangiectasias in chronic hemodialysis patients: a report of six cases.

In August 1642 a committee of MPs at Westminster urged the sending of more money to Ireland to maintain Protestant refugees there. Otherwise, they argued, ‘there willbe an inevitable danger of their bringing over the infection of the pestilent fever with them, as hath bene allready done in some parts of Devon’.1 The 1641 rebellion in Ireland clearly posed a risk not only to England’s security, but also to its public health. In wartime Ireland, the dangers of violent death and disease loomed altogether much larger. This circumstance in turn presented opportunities and hazards to medical practitioners of various kinds. Any effort to study practitioners’ experiences, and the Irish medical environment more generally, amidst the upheaval of the 1640s is inevitably hampered by the scarcity of relevant surviving sources. The latter problem is not unique to that decade; for most of Ireland beyond Dublin, we know little about medical practice in the seventeenth century. Fortunately, there is one extant source that enables a range of relevant insights into the situation in the 1640s. The Westminster committee’s resolutions from August 1642 and an enormous quantity of additional information concerning the rebellion in Ireland are preserved in the same archive: the 1641 depositions. The depositions are the best known and most controversial source for the history of Early Modern Ireland. They comprise around 8,000 witness statements and related material concerning the Irish rebellion of 1641 and its aftermath.2 For centuries after the event, the depositions were at the centre of heated debate around the question of what had actually happened in 1641. Protestant writers pointed to their contents as evidence of a premeditated massacre by Catholics of very large numbers of English and Scottish settlers.3 Catholic writers in turn questioned the veracity of the depositions and refused to accept them

The Medical World of Early Modern Ireland: Conference Paper Podcast

The Gookin-Lawrence Pamphlet Debate and Transplantation in Cromwellian Ireland

Investigation of the factors structure of the Kessler 10 across six language communities in Australia

Review of: Jonathan Swift: Political Writer. By J.A. Downie. London: Routledge and Kegan Paul. 1984. xvi + 391 pp. £25.00. Swift: The Man, his Works, and the Age. By Irvin Ehrenpreis. Volume 3: Dean Swift. London: Methuen. 1983. xvi + 1066 pp. £40.00. Swift's Tory Politics. By F.P. Lock. London: Duckworth. 1983. viii + 189 pp. £18.00.

Nagellackkompositioner and the arrangement of the Foer applicering dem.

A marriage of necessity: The coming together of the federal, provincial and municipal governments.

The law relating to parliamentary & municipal elections and petitions

Cataracts in children' The possibility of improving the vision in children with congenital cataract has been with us for many years. It is over 150 years since John Cunningham Saunders,. an ophthalmologist at St Thomas' Hospital, described in great detail his method of treating congenital cataract. Both Saunders (1816) and his Scottish counterpart William MacKenzie (1840) were well aware of many of the problems that still confront us now. In his book on the practical management of diseases of the eye, MacKenzie stated, 'the answer decidedly is, operate in infancy, and if possible before teething commences'; by this statement predating the ophthalmologists who in the last two decades, taught by scientists about amblyopia, started again to recommend early surgery. Apart from minor differences in surgical technique, varying from one to another like the hemlines of fashion, there was little change until the impact of the work begun in the 1960s by Wiesel & Hubel (1963) led to a profusion of exciting studies into visual development. Leinfelder (1968) was perhaps the first to appreciate the importance of this new information to patients with congenital cataract. He thought that 'failure to obtain good vision is usually the result of the coincidental association of congenital amblyopia'. Perhaps his interpretation of congenital amblyopia is not the same as that which a modern developmental ophthalmologist might have, but there is no doubt that amblyopia due to the failure of development of the visual pathways at all levels from the retina to the visual cortex, both neurophysiologically and structurally, that is caused by the defocused image during a critical period of development, is the most important single factor in the preventable part of the visual handicap in congenital cataract. We know that, given appropriately timed surgical and optical treatment, patients with bilateral cataract achieve high levels of vision (Taylor et al. 1979, Gelbart et al. 1982). From the theoretical standpoint it is ofeven greater importance that it is possible to achieve good levels of acuity in patients with unilateral congenital cataracts by very early surgery and optical correction (Beller et al. 1981, Benezra & Paez 1983). It was previously thought that the treatment of unilateral cataract, providing the visual defect was truly congenital, resulted in no significant improvement in the vision because

A Treatise on Some Practical Points Relating to the Diseases of the Eye

Phenylethylhydantoin was introduced under the name "nirvanol" 1 in 1916 as a sedative. The frequent occurrence of severe symptoms such as rash or fever led many authors 2 to warn against its use. In 1919, Roeder 3 recommended phenylethylhydantoin in the treatment for chorea minor. The reports 4 were so encouraging that we undertook a study of the action of this drug in a series of cases of chorea. Since chorea is a highly variable disease, no therapeutic study is convincing unless a fairly large number of cases is included, and unless comparison is made with cases in the same series in which the patients were treated by other methods. So far as we are aware, this has not been done previously. This report is based on the study of twenty-five cases; as the children entered the hospital, every other one was treated with phenylethylhydantoin. The dose for younger children

?J OHN Hesdon, aetat. 24, being, as was supposed, in-* toxieated, fell, at six in the evening, from the waist of His Majesty's ship Gibraltar, into the fore cock-pit, and pitched on his head and right side. He was taken up motionless and insensible, and conveyed to the sick berth, where he was carefully examined. The only sign of local external injury was over the right os mali and temple, where the integuments appeared slightly contused, discoloured, and swelled. The whole cranium was diligently' examined, but no appearance of subjacent fracture could be detected. He remained comatose; breathed as though he were in a natural sleep; and appeared completely insensible to external impressions. His extremities were quite supple, and there was a slight oozing of blood from the nose. His eyes were turned upwards; the pupils firmly contracted, and apparently insensible to the stimulus of light. The pulse was at 80, and felt natural. Vencesectio statim ad |xl from a large orifice; but without producing any relief whatever, or inducing any change in the pulse. The breathing, however, now seemed to be

Case of Fatal Concussion of the Brain, with the Appearances on Dissection

Occasionally during the past, some of the guinea-pigs used in this laboratory were observed to have large, fluctuant swellings of various groups of lymph nodes. Animals suffering from this disease, known as epizootic lymphadenitis or "lumps," had been found in colonies of stock guinea-pigs and in groups of animals used in various experiments. In some instances, the character of the thick or caseous pus led to a superficial diagnosis of tuberculosis or pseudotuberculosis. No detailed attention, however, was paid to the condition until several guinea-pigs, primarily affected with "lumps" died of an acute infection with an hemolytic streptococcus shortly after they had been inoculated with tubercle bacilli, the spirochete of rat-bite fever or other organisms. During a period of six months, following September, 1928, a search for guinea-pigs with this disease was made in a colony averaging about 150 animals. In this period, 20 guinea-pigs with "lumps" were found. From all of these the same unusual type of mucoid hemolytic streptococcus was isolated. The organism was obtained in pure culture from 16 of the animals and in 4 cases only was it associated with staphylococci. As the animals from which mixed cultures were obtained had draining sinuses from ruptured abscesses, it is probable that the staphyloco.cci were secondary invaders, entering through this channel. The prompt removal of infected guinea-pigs from a group reduced the incidence of the disease to a minimum.

Epizootic Lymphadenitis in Guinea-Pigs Due to an Encapsulated Mucoid Hemolytic Streptococcus

We have isolated cDNA’s coding for the complete amino acid sequences of Cholinesterase 1 (ChEl) and Cholinesterase 2 (ChE2) from amphioxus. Both ChE transcripts appear to code for H catalytic subunits, which may become inserted in the membrane via an ethanolamine-glycan-phosphatidylinositol anchor. For ChE2, the acyl pocket, a region of the enzyme important for substrate binding, resembles those of invertebrate ChE’s. A novel acyl-binding pocket characterizes ChEl. In vitro expression in COS-7 cells demonstrates that ChE2 is eserine-sensitive and hydrolyzes acetylthiocholine. In contrast, ChEl is eserine-resistant and hydrolyzes both acetylthiocholine and butyrylthiocholine. Velocity sedimentation and nondenaturing gel electrophoresis in conjunction with digestion by phosphatidylinositol-specific phospholipase C suggest that ChEl and ChE2 are present as ethanolamine-glycan-phosphatidylinositol-anchored G2 forms in vivo and in vitro. Supported by NSF-RUI grant IBN-9319354 to L.P.

cDNA Cloning, In Vitro Expression, and Biochemical Characterization of Cholinesterase 1 and Cholinesterase 2 from Amphioxus

cDNA cloning, in vitro expression, and biochemical characterization of cholinesterase 1 and cholinesterase 2 from amphioxus--comparison with cholinesterase 1 and cholinesterase 2 produced in vivo.

Sequence and expression of the gene encoding the corrinoid/iron-sulfur protein from Clostridium thermoaceticum and reconstitution of the recombinant protein to full activity.

Organizations are faced with the unique big data challenges collecting more data than ever before, both structured and unstructured data. There has never been a greater need for proactive and agile strategies to overcome these struggles in a volatile and competitive economy. Together, SAS and Teradata have joined forces with Hadoop to revolutionize your business by providing enterprise analytics in a harmonious data management platform to deliver strategic insights. This paper discusses how SAS, Teradata with Hadoop are delivering innovation to break through your big data analytics challenges, by exploring the appropriate platforms for the various types of analysis to quickly uncover hidden opportunities.

A time consuming part of statistical analysis is building an analytic data set for statistical procedures. Whether it is recoding input values, transforming variables, or combining data from multiple data sources, the work to create an analytic data set can take time. The DS2 programming language in SAS 9.4 simplifies and speeds data preparation with user-defined methods, storing methods and attributes in shareable packages, and threaded execution on multi-core SMP and MPP machines.

In this perceptive critical study john cunningham places the story within the context of the overall framework of "the canterbury tales", showing how it provides both a complement and contrast to the knights's tale of ideal love that precedes it. He introduces the reader to chaucer and the world in which he lived and gives advice on how to read his work in the original. UK PRIORITY REISSUE

The church history of Scotland : from the commencement of the Christian era to the present time

Natural history of intraductal papillary mucinous tumors of the pancreas: A large single center experience

A concept has been developed for a geostationary seismic imager (GSI), a space telescope in geostationary orbit above the Pacific coast of the Americas that would provide movies of many large earthquakes occurring in the area from Southern Chile to Southern Alaska. The GSI movies would cover a field of view as long as 300 km, at a spatial resolution of 3 to 15 m and a temporal resolution of 1 to 2 Hz, which is sufficient for accurate measurement of surface displacements and photometric changes induced by seismic waves. Computer processing of the movie images would exploit these dynamic changes to accurately measure the rapidly evolving surface waves and surface ruptures as they happen. These measurements would provide key information to advance the understanding of the mechanisms governing earthquake ruptures, and the propagation and arrest of damaging seismic waves. GSI operational strategy is to react to earthquakes detected by ground seismometers, slewing the satellite to point at the epicenters of earthquakes above a certain magnitude. Some of these earthquakes will be foreshocks of larger earthquakes; these will be observed, as the spacecraft would have been pointed in the right direction. This strategy was tested against the historical record for the Pacific coast of the Americas, from 1973 until the present. Based on the seismicity recorded during this time period, a GSI mission with a lifetime of 10 years could have been in position to observe at least 13 (22 on average) earthquakes of magnitude larger than 6, and at least one (2 on average) earthquake of magnitude larger than 7. A GSI would provide data unprecedented in its extent and temporal and spatial resolution. It would provide this data for some of the world's most seismically active regions, and do so better and at a lower cost than could be done with ground-based instrumentation. A GSI would revolutionize the understanding of earthquake dynamics, perhaps leading ultimately to effective warning capabilities, to improved management of earthquake risk, and to improved public safety policies. The position of the spacecraft, its high optical quality, large field of view, and large field of regard will make it an ideal platform for other scientific studies. The same data could be simply reused for other studies. If different data, such as multi-spectral data, is required, additional instruments could share the telescope.

Flaming meteors, dark caves, and raging waters—Geological curiosities of western Wisconsin

Small icebergs and pieces of icebergs are virtually undetectable with conventional marine radar systems. The authors describe a detection scheme for such icebergs. The scheme uses the chirplet transform, a wavelet-inspired transform, to generate images of the Doppler-shifted radar returns from icebergs and ocean surfaces. The images are classified using a neural network trained with the backpropagation algorithm, incorporating weight sharing and optimal brain damage paradigms. The network's architecture is motivated by the known physiology of animal vision. The network design incorporates temporal information. Performance has surpassed the benchmark Fourier-based detection scheme.<<ETX>>

Neural Networks for Signal Processing II Proceedings of the 1992 IEEE Workshop

Neural network detection of small moving radar targets in an ocean environment

Characterization of debris clouds behind impacted meteoroid bumper plates

Abstract : An experimental investigation of the momentum distribution within the debris cloud produced by the impact of 3.17 mm spheres on 0.79 mm thick plates was conducted. Two independent experiments with projectile velocities ranging from 6.65 km/sec to 7.25 km/sec were completed in an attempt to determine momentum distribution. Small metal plates were impacted by the cloud for measurement of the incident momentum. A ballistic pendulum was used in an attempt to capture small segments of the debris cloud and to measure the momentum distribution in the cloud itself. The momentum intensity, as a function of distance from the center of the debris cloud, was determined in each experiment and the results were compared and evaluated.

MOMENTUM DISTRIBUTION IN THE DEBRIS CLOUD PRODUCED BY HYPERVELOCITY PERFORATION OF THIN PLATES

PolySNAP is a program used for analysis of high-throughput powder diffraction data. The
program matches diffraction patterns using Pearson and Spearman correlation coefficients
to measure the similarity of the profiles of each pattern with every other pattern, which
creates a correlation matrix. This correlation matrix is then used to partition the patterns
into groups using a variety of cluster analysis methods. The original version could not
handle any data types other than powder X-ray Diffraction. The aim of this project was to
expand the methods used in PolySNAP to allow it to analyse other data types, in particular
Raman spectroscopy, differential scanning calorimetry and infrared spectroscopy data.
This involves the preparation of suitable compounds which can be analysed using these
techniques. The main compounds studied are sulfathiazole, carbamazepine and piroxicam.
Some additional studies have been carried out on other datasets, including a test on an
unseen dataset to test the efficacy of the methods.
The optimal method for clustering any unknown dataset has also been determined.

Application of cluster analysis to high-throughput multiple data types

In high-throughput crystallography it is possible to accumulate large numbers of powder diffraction patterns on a series of related compounds, often polymorphs, salts or co-crystals. In previous papers [Gilmore, Barr & Paisley (2004). J. Appl. Cryst. 37, 231-242; Barr, Dong & Gilmore (2004). J. Appl. Cryst. 37, 243-252] it has been shown how such data can be analysed by generating an (n x n) correlation matrix, rho, by correlating n full powder diffraction patterns, point by point. The rho matrix is used as a source of dendrograms and metric multidimensional plots in three or more dimensions which classify the patterns into sets related by similarity. In this paper, it is shown how Raman spectroscopy data can be used by themselves or as an adjunct to powder diffraction data by combining the two techniques using the individual differences scaling method (INDSCAL) of Carroll & Chang [Psychometria, (1970), 35, 283-319]. The method is very robust, and can be extended to other forms of spectroscopy. It is available as an option in the commercial PolySNAP3 computer program.

High-throughput powder diffraction V: the use of Raman spectroscopy with and without X-ray powder diffraction data

24 European Crystallographic Meeting, ECM24, Marrakech, 2007 Page s53 Acta Cryst. (2007). A63, s53 MS20 O5 Is PXRD the gold standard in high throughput experiments? Christopher Gilmore, Gordon Barr, Gordon Cunningham and Christopher Frampton WestCHEM, Department of Chemistry, University of Glasgow G12 8QQ, UK. Pharmorphix Limited, 250 Cambridge Science Park, Milton Road, Cambridge, CB4 0WE, UK. E-mail: chris@chem.gla.ac.uk

This paper is a response to William Hasker’s “bring about” argument (1999, reiterated in 2011) against the Molinist theory of divine providence. Hasker’s argument rests on his claim that God’s middle knowledge must be regarded as part of the world’s past history; the primary Molinist response has been to resist this claim. This paper argues that even if this claim about middle knowledge is granted, the intended reductio does not go through. In particular, Hasker’s claim about middle knowledge is shown to undermine his proof of the “power entailment principle.” The paper closes with a critical examination of ideas about free will and the past history of the world that might be supposed to support Hasker’s conviction that Molinism is incompatible with a libertarian view of free will.

Whether you're an expert or simply an enthusiast, you are welcome to attend the following Minnesota Philosophical Society events, including a talk by Dr. William Lycan, noted philosopher. William Lycan teaches at the University of North Carolina at Chapel Hill, where he is the William Rand Kenan, Jr. Distinguished Professor. He is the author of eight books and over 150 articles.

Minnesota Philosophical Society Fall 2014 Conference (2014-10-04)

ð OUR CONVERSATION ABOUT THE SCIENTIFIC ENTERPRISE begins with a semester focused on revolutions in science. We will study three revolutions in some detail: the Copernican revolution, the Darwinian revolution, and the twentieth-century revolution that gave rise to modern neuroscience. We will learn about the landmark scientific theories in each historical episode and about the scientific evidence and arguments of the day; we will also explore the philosophical, religious, and cultural debates that surrounded each theory. In conjunction with our study of these three revolutions, we will examine the scientific enterprise through the lens of Thomas Kuhn’s seminal book, The Structure of Scientific Revolutions. This year marks the 50 th anniversary of that influential and provocative work. Copernicus’ theory of a sun-centered universe was published in 1543. But only after 1600, when scientific heavyweights like Kepler and Galileo began to argue for the truth of the Copernican model, did scientific and religious controversy surrounding it heat up. Galileo in particular became the standardbearer of the new ideas. He not only amassed empirical and theoretical support for Copernicus’ theory, but also argued for revolutionary ideas about the methods and the reach of “natural philosophy” (or as we would call it, natural science). Galileo’s passionate support of Copernicanism eventually resulted in his trial and condemnation by the Catholic Church—in spite of his ardent efforts to convince his own Church that this scientific theory was compatible with Scripture. Half a century later, the Copernican revolution was brought to completion by Newton’s Principia and its unified physics of planets and projectiles. From the seventeenth century, we leap ahead to the nineteenth. Darwin’s theory of evolution by natural selection was the product of decades of careful observation and reflection on the relationships among living things. Darwin and his supporters held up this theory as showing that questions about origins in biology, like questions about planetary motions, could be answered by appeal to general laws. However, there are deep differences between science as exemplified by Darwin’s achievement and science as exemplified in the work of Galileo and Newton; what of Galileo’s insistence on mathematics as essential to scientific understanding, for example? We will consider the scientific and religious responses to the publication of Darwin’s theory in his own day. Next, we stand back and explore Thomas Kuhn’s highly influential theory of the development of science, drawing on our knowledge of the two revolutions we have already studied. Kuhn’s book has been highly influential; just consider that he is responsible for making the term ‘paradigm shift’ part of everyday speech. But many of his ideas are also controversial, and they challenge some commonly-held conceptions about the rationality and objectivity of the scientific enterprise. Finally, we turn to the past century and the development of a “new” science. Neuroscience is an amalgamation of psychology, biology, chemistry, physics, and philosophy, and it utilizes methods of all these disciplines to explore the form and function of the brain. At the present time, much is known about the molecular and cellular aspects of brain function. The big questions, however—questions about how to understand consciousness, memory, and free will in the light of what we know about the brain—remain. We will explore the origins of neuroscience and our ability to probe the mysteries of the human brain, and we will reflect on ways neuroscience challenges previous ideas about science and about ourselves.

Environmental decoherence is widely held to be the key to understanding the emergence of classicality in a quantum universe. However, in conjunction with traditional principles of interpretation, decoherence leaves unanswered a fundamental question, a version of the quantum measurement problem: Why should macroscopic objects have definite properties at all? I critically evaluate a variety of interpretive strategies intended to parlay the formal results of decoherence into the definiteness, or apparent definiteness, of familiar macroscopic properties. I argue that the crucial role of environmental decoherence in accounting for definite properties is effecting the dynamical decoupling of components of the global quantum state for which these properties are definite.This role of decoherence is most evident in the context of the Everett interpretation, where considerations regarding branch dynamics lead naturally to the conclusion that dynamical autonomy (non-interference) of branches is a restriction on any division of the global quantum state into branches. Environmental decoherence results in the requisite dynamical autonomy for branches in which familiar macroscopic observables are definite, thus providing a natural and principled way to identify an interpretation basis.The modal interpretation, with its property ascription rule based on the spectral decomposition of the reduced state, secures the right definite properties only in those cases in which it picks out properties that correspond almost exactly with the non-interfering components of the global quantum state. I argue that the non-interference of these components should be accorded interpretational significance in its own right; then the right properties can be specified without recourse to the distinctive property ascription rules of the modal interpretation.Finally, I criticize attempts of decoherence theorists to account for definite properties by appeal to effects of decoherence such as approximate diagonality of the reduced state and preservation of correlations with respect to a set of privileged states. I argue that definiteness can be accounted for by looking not to these effects but to their cause, the dynamical autonomy of the environmentally-privileged components of the global quantum state. Precisely because they are dynamically autonomous, these states can be accorded physical significance in their own right.

can Symposium week (November 3-8, 1969) at Carnegie-Mellon University, Pittsburgh, Pennsylvania, was initiated and organized by the University's International Club and SPIRIT, the black students club. In addition to evenings of dance and drama and exhibits of African arts and crafts, the week included: ambassadors Davidson Nicol of Sierra Leone and E. M. Debrah of Ghana discussing the interaction of Western and African cultures in Africa; musicologist Halim El-Dabh of Kent State University lecturing and performing on African musical culture south of the Sahara; Richard Stevens of Lincoln University discussing African studies in the United States; and "Drums of Passion," a program of songs and dances performed by the Olatunji ensemble.

This country report discusses some of the developments in the practice and process of geometric road design in Australia over the last 4 years. The paper draws primarily on the activities of the Austroads Road Design Reference Group (RDRG), a peak industry body formed under the auspices of Austroads, the national association of state road authorities in Australia and New Zealand. Since its formation in August, 2000 the RDRG has overseen a number of significant updates to Austroads design guides, and has sponsored research projects investigating some of the fundamental design criteria. The following projects, and some of the significant issues that arose during them, are discussed in this paper: (1) Review of the Austroads Geometric Design Guides for Urban and Rural Roads - including consideration of appropriate values for driver eye height, reaction times, and stopping distances, and refinement of the operating speed model; (2) Designing for Trucks - a research project which sought to answer the question: When is it appropriate to design for trucks?; (3) Shoulder Widths on Dual Carriageway Rural Roads - investigating the relationship between sealed shoulder width and crashes; and (4) Environmental Considerations in Planning and Design - a comprehensive review of literature and guidelines covering environmental issues to be considered in Australia, including water sensitive road design.

Country Report--Australia: Recent Developments in Geometric Design in Australia

This country report discusses some of the developments in the practice and process of geometric road design in Australia over the last 4 years. The paper draws primarily on the activities of the Austroads Road Design Reference Group (RDRG), a peak industry body formed under the auspices of Austroads, the national association of state road authorities in Australia and New Zealand.

Traditionally the basis for the geometric design of roads has been the performance capabilities of the eighty-five percentile car and its driver. While truck tracking characteristics are a primary consideration for intersection geometry and curve widening practices, most road geometric design standards, and particularly alignment design standards, are based on the performance characteristics of passenger cars and car drivers. This approach has generally served well and is one that makes sense in circumstances where cars are the predominant vehicle in the traffic mix. However, the question must be asked whether it is still logical to design for cars if trucks represent a much higher proportion of the vehicle mix. In other words, if it makes sense to design for cars when they make up 90% of the fleet, does it also make sense to design for trucks if the situation is reversed? If the obvious answer to this question is "Yes", then the next question becomes "At what point between these two extremes does it become economically viable to design for trucks rather than cars?" In response to these questions Austroads Project T&EDN - 009 sought to derive truck-based geometric design standards, and establish the traffic volumes and mix at which the adoption of such standards is economically warranted. This paper summarizes the results of the research carried out for Austroads by ARRB-TR and discusses what needs to happen in order to test these results in the design office. The full text of the final Project Report is published as Austroads Publication No. AP-R211 (Austroads (2001).

Analysis of aerospace systems in a teamed engineering environment

Road improvements have for too long been overlooked in the contribution they make to improving road safety. In particular the application of engineering measures to specific accident types or high accident frequency sites has proven to be very cost effective in the past. In the near future as the nature of treatments changes, engineering programs will continue to return high cost effectiveness figures provided that resource allocation is made on a rational needs based approach. This will require the development and acceptance of predictive program assessment methods as the preferred alternative to historical or subjective means of allocating resources.

NIBBLE for Adult Basic Education: Website and Lessons for Low-Literate Learners

In an effort to improve driver education programs, a set of instructional guides were developed for use in preparing programs of instruction for prospective driver educators for secondary schools and commercial driving schools. The development of both guides (secondary school, and commercial driving school) involved four processes: an analysis of both the highway transport system and the instructional system, public and private; identification of the performances, skills, and knowledge required of the driver educator in meeting his instructional requirements; and the preparation and assembly of materials needed to fulfill the instructional objectives. In the analysis of instructional requirements, teacher preparation standards were surveyed and driver educator factors (curriculum development and administration) were analyzed. The determination of sources of information and the organization of the guide content are discussed.

THE DEVELOPMENT OF GUIDES FOR TEACHER PREPARATION IN DRIVER EDUCATION

Regulations Introduced in 1999 obliged water companies In England and Wales to conduct risk assessments of their treatment works to establish whether there was a significant risk from Cryptosporidium oocysts in the water supplied. More than 330 treatment works were identified as being at risk, just over half of which were plants treating groundwater. This paper provides an overview of what water companies themselves identified as the most at‐risk settings for their groundwater‐based works in terms of aquifer and type of supply. Evaluation of results from the subsequent continuous monitoring regulatory regime that came into force on many of these supplies could validate the primarily qualitative nature of the initial assessments of at‐risk settings. There would also be public health benefits from confirmation of whether currently‐employed risk assessment methods are well‐founded because similar procedures could then be applied with confidence to the many small private supplies In Britain.

THE 1999 CRYPTOSPORIDIUM RISK ASSESSMENT EXERCISE IN ENGLAND AND WALES‐ A GROUNDWATER OVERVIEW

Experience in New York Harbor has shown that speed of deployment is the most important criterion for oil booms, and that this depends significantly on boom design. For most harbors, a light, flexible, 18-in. boom with integral strength, weight, and flotation elements is desirable. The lack of standard end connections is presently a serious problem where more than one type of boom is in use in a spill.

Journal of the Waterways, Harbors and Coastal Engineering Division

The report was developed from field tests and actual oil spill control experiences of the Marine Division of the New York Fire Department. The information is intended to assist a community in protecting its area against oil spill damage. Operational procedures described are intended to serve as stop-gap measures, pending the inauguration of clean-up activities by the spiller or responsible Federal Agency. The manual concentrates on the utilization of existing fire department resources. However, a limited amount of useful ancillary equipment was procured or developed. Such equipment is described and its use is explained. The manual describes common sources of oil spills and some ecological effects of oil pollution. Pertinent Federal laws and regulations are outlined. Some feasible techniques for dealing with harbor spills are offered. (Author Modified Abstract)

The Railroad Gap area, consisting of the Railroad Gap field and the deeper pools at Northeast McKittrick and McKittrick Front, is on the west side of the San Joaquin Valley near McKittrick, Kern County, California. The discovery of the Railroad Gap field in February, 1964, by the Standard Oil Company of California led to the deeper-pool discoveries at Northeast McKittrick and McKittrick Front by the same operator during the ensuing 1½ years. Anticlinal closure traps most of the reserves in each field. The folds differ considerably in size, configuration, and orientation. Normal and reverse faults are common, and cause differences in oil-water interfaces within the same accumulation. Nearly all stratigraphic units from the Eocent Point of Rocks Sandstone Member to the Pleistocene Tulare Formation are productive in the area. The primary objectives and most prolific reservoir rocks are the Oligocene Oceanic and the lower Miocene Phacoides and Carneros Sands. The massive Phacoides and Oceanic Sand units differ considerably in thickness and reservoir quality from place to place. The Phacoides permeability variations are particularly surprising, because initial completions range from 100 to 9,000 BOPD at similar structural positions within the same accumulation. The Railroad Gap area was known to be anticlinal, but conclusive evidence of critical closure on the northwest could not be documented by conventional structural studies or geophysical methods. Regional isopachous studies of the middle and upper Miocene, however, indicated the existence of thickness variations of a sufficient magnitude that potential northwesterly closure could be inferred to be present in the underlying lower Miocene sediments. The isopachous contours reflect middle and late Miocene structural growth along the trend, suggesting a favorable geologic history for the area. The lower Miocene and Oligocene, from nearby well data, were known to contain excellent clastic reservoirs, thus completing the knowledge necessary to justify an exploration program. End_of_Article - Last_Page 486------------

The author, in a communication dated January 5, 1846, and addressed to Dr. Buckland, observes, “the small slab which I herewith send contains an impression in intaglio of what I conceive to be the footprints of small birds. They are the only impressions having a resemblance to those of birds that I have hitherto been able to detect among the numerous indications of reptiles associated with them in one of the beds of the Storton quarries, and if they should prove to be Ornithichnites, I do not despair of finding the larger impressions in some of the strata of Storton Hill; but the other quarries around Liverpool are quite barren of all impressions.” In a further communication made on the 30th of March, Mr. Cunningham states, “I am glad to inform you, that on Saturday last, being at Storton, I discovered on the face of a slab three most distinct indurated impressions of a bird's feet of pretty large size, measuring two inches and a half in length. The feet had three toes; the intermediate space between two impressions is ten inches, and so far as they go, the impressions are right and left. There can, I think, be no doubt of the animal that produced them having been a bird, and probably one of the Grallæ. There was no appearance of a web between the toes. “This discovery I consider important, as proving beyond a doubt the existence of warm-blooded animals in this country during the period of the

On some Footmarks and other Impressions observed in the New Red Sandstone Quarries of Storton, near Liverpool

A comparative study of quartz vein‐hosted gold occurrences associated with Palaeozoic metapelites in two areas of Wales and Spain combines new, previously unpublished and published data. Metamorphic grade is greenschist in both areas, but very low‐grade indicators in the host metapelites distance the environment from the greenschist/amphibolite transition zone required for some orogenic gold occurrences. Basin fertility for Au is indicated by the presence of auriferous pyrites in the protolith black shales in Spain. Only minor igneous activity has taken place in both study areas. Mineral parageneses are similar, with early sulphide phases characterized by As/Co and later auriferous phases by Cu/Pb/Zn sulphides. Mesozonal P–T conditions apply at deposition in both terranes. In Spain, mineralisation typically occurs in quartzites near to the metapelites, but not where the veins are in contact with them, and extensional faulting appears to be a stronger control over mineralisation than geochemical interaction with metapelite wall‐rocks. In Wales, both structural and geochemical factors (C content of the wall‐rocks and coupled oxidation of NH4 ions substituted in wall‐rock phyllosilicates to produce CH4 and N2) could have a role in Au deposition. In both areas, minor cross‐fault systems between larger faults are typical hosts of the mineralisation. Assignment is made to different subtypes of the orogenic gold model but these subtypes share the characteristic of a local source. This has implications for exploration methodology in epizonal/anchizonal metapelite‐dominated terranes, where indicators of basin fertility for Au within the protolith itself assume importance.

Black shales and mesozonal quartz vein‐hosted Au: The Truchas Syncline, Spain and the Harlech Dome, Wales, a comparative study

Summary Poor early establishment and growth of regeneration following clearfelling of highland dry Eucalptus delegatensis forests in Tasmania in the 1970s led to the development of alternative practices. Shelterwood retention, shelterwood removal, potential sawlog retention and advance growth retention systems were developed and implemented by forest owners as preferable alternatives to clearfelling in most instances. Less than optimal outcomes following partial harvesting led to the development of formal monitoring procedures. These procedures assess the pre-harvesting forest structure, guide development of the harvesting prescription, follow the course of harvesting, return information on progress to the harvesting contractor, and allow for continuous improvement of operations. Together they ultimately provide improved outcomes for the forest grower. The paper discusses the development of uneven-aged management and describes the processes used to develop and monitor the outcomes.

Silvicultural monitoring in uneven-aged highland dry Eucalyptus delegatensis forests in Tasmania

To our readers, The evaluation of manuscripts submitted to the Journal sometimes generates widely varying peer review outcomes. In such situations, the Editors weigh the importance of informing our readers of promising, cutting-edge approaches against limitations such as cohort size, the likelihood for compliance with an intervention, and follow-on research expectations. In 2014, an article was published in Neurology, the official journal of the American Academy of Neurology, summarizing evidence-based guidelines for complementary and alternative medicine in the treatment of multiple sclerosis. Among the agents presented was fish oil, which was reported as probably ineffective for relapse; however, diet was not addressed. The role of diet in therapy of multiple sclerosis is unclear yet recently has received much attention. The article by Lee et al. in this issue presents preliminary data, and further studies are currently underway to expand our knowledge on this topic. We are guided by a judgment that our readers should be given the opportunity to review the article, discuss it with colleagues, and increase the appreciation of the importance and complexities of research on diet in health care. We are hopeful that further research in the role of diets in multiple sclerosis, as well as other chronic diseases, is promoted through our decisions to publish such works.

La presente invention concerne un procede et un appareil pour le positionnement d'un masque photographique. Plus particulierement, l'invention concerne un procede et un appareil pour le positionnement precis d'un masque photographique capable de tirage sur film d'un substrat (par exemple, une toile) recouvert avec un photopolymere durcissable mouille dans lequel le masque photographique cree un substrat image qui est utilise pour la formation d'images appropriees pour la formation de circuits electriques tels que pour des cartes de circuit imprime, des ecrans d'affichage plats et des circuits souples.

 Almost a third (n=41,000) of all Irish farm holders are aged 65 years or older. Older farmers are vulnerable to Musculoskeletal Disorders (MSD’s) both by virtue of the nature of their work and their age. MSD’s are a known risk factor for workplace accidents and farming is the highest risk occupation in Ireland.
 This study aimed to explore older farmers’ experiences of living with and accessing healthcare for MSD’s.
 
 A qualitative study design employing semi-structured interviews was employed. Nine Irish farmers aged 65 years and over with current or previous experience of MSD's were recruited. All participants continued to farm on either a full-time or part-time basis. Data were analysed using thematic analysis.
 
 Four themes describing older farmers' experiences of MSD’s and healthcare were identified; (1) acceptance of MSD’s as inevitable (2) biomechanical and biological beliefs about MSD’s (3) resilience and a commitment to continuing work in response to MSD’s (4) scepticism and avoidance of healthcare.
 
 To the best of our knowledge this is the first qualitative study of older Irish farmers’ experiences of MSD’s. Findings reveal that older farmer’s experiences differ significantly from those reported by other occupational groups. Commitment to continue working permeated the findings of this study and shaped older farmers' experiences and responses to MSD's. Older farmers accept MSD’s and pain as inevitable consequences of farming, and they respond to MSD’s with stoicism. Lack of healthcare provider knowledge about farming culture and practices contributes to older farmers' negative healthcare experiences and avoidance of healthcare. Given the prevalence of MSD’s in this population future research should focus on developing and evaluating appropriate health promoting and patient-centered interventions to support continued safe farming for older Irish farmers.

Torquing of bolts in composite joints can have significant effects on joint strength [1] and fatigue life [2]. Therefore, it is an important factor to include in finite-element studies of composite joints [3, 4]. Torquing a bolt produces axial load (pre-load), inducing tensile stress in the bolt shank and compressive stress in the washers and material being fastened. The resulting clamping effect is advantageous as when the joint is loaded, a significant percentage of the load can be taken by friction, which delays the onset of the damage of the material because of bearing loads at the hole. However, after torquing, some of the stress introduced will disappear as the fastener and joint members relax because of viscoelastic effects, and hence it is important to allow for this relaxation [5]. While manufacturers may sometimes supply charts relating torque and pre-load, information is often not provided concerning the applicability of these charts when joining different kinds of materials (e.g. metals or composites), and in general little quantified information is available in the literature on how to measure such relationships or on the effects of relaxation of pre-load over time. This technical note describes experiments to measure pre-load caused by torque in composite joints. The effects of relaxation of load over time when joining composite plates and steel plates and the influences of washers are also presented.

Robert Boostrom, University of Southern Indiana, IN, USA Zongyi Deng, Nanyang Technological University, Singapore Linda Chisholm, Human Sciences Research Council, Pretoria, South Africa Anna Clark, University of Technology, Sydney, Australia Norm Friesen, Thompson Rivers University, BC, Canada Philipp Gonon, University of Zurich, Switzerland Brian Hudson, University of Dundee, UK Gjert Langfeldt, University of Agder, Norway Alan Reid, University of Bath, UK David Rutkowski, Indiana University, IN, USA Bernard Schneuwly, University of Geneva, Switzerland Peter Seixas, University of British Columbia, BC, Canada Marcy Singer-Gabella, Vanderbilt University, TN, USA Yuzhen Xu, Capital Normal University, Beijing, China

Robert Boostrom, University of Southern Indiana, IN, USA Zongyi Deng, Nanyang Technological University, Singapore Anna Clark, University of Technology, NSW, Australia Brian Hudson, University of Dundee, UK Gjert Langfeldt, University of Agder, Norway Alan Reid, University of Bath, UK David Rutkowski, Indiana University, IN, USA Bernard Schneuwly, University of Geneva, Switzerland Peter Seixas, University of British Columbia, BC, Canada Marcy Singer-Gabella, Vanderbilt University, PA, USA Yuzhen Xu, Capital Normal University, PR China

This report summarizes the statistical analysis of the findings of a web-based survey conducted by the Digital Methods and Practices Observatory (DiMPO), a working group under VCC2 of the DARIAH research infrastructure (Digital Research Infrastructure for the Arts and Humanities).

In order to provide an evidence-based, up-to-date, and meaningful account of the emerging information practices, needs and attitudes of arts and humanities researchers in the evolving European digital scholarly environment, the web survey involved a transnational team of researchers from more than a dozen countries, and addressed digitally-enabled research practices, attitudes and needs in all areas of Europe and across different arts and humanities disciplines and contexts.

European survey on scholarly practices and digital needs in the arts and humanities Digital Methods and Practices Observatory Working Group (DiMPO) Survey highlights EN

Leonardo seeks to document the ways in which artists and scientists are addressing climate change in a cultural context. As contemporary culture grapples with this critical global issue, this 3-year project will document cross-disciplinary explorations by artists, scientists and engineers, working alone or in teams, addressing themes related to global warming and climate change. Partial list of Leonardo articles and projects concerned with global warming, climate change and related issues:

Lovely Weather: Artists and Scientists on the Cultural Context of Climate Change

Shcolarship, Criticism, and Shakespeare@@@Shakespearian and Other Essays.@@@Elizabethan and Jacobean Drama.@@@The Collected Essays.

L'invention concerne une composition cosmetique et pour soins d'hygiene personnelle, comprenant un polymere fonctionnalise aldonamide filmogene ayant une temperature de transition vitreuse d'au moins 20 °C.

United States Patent US 007052581 B 2 ( 12 ) ( 10 ) Patent No . : US 7 , 052 , 581 B 2 Winterson

Discussion of Vortex Flow Through Horizontal Orifices by John C. Stevens and Richard C. Kolf

THE major claim for distinction of Bremerton, Wash., is the Puget Sound Navy Yard, a diversified industry of major proportions, situated there. During years of peace, the yard has provided a stable and growing payroll, sustaining a population currently estimated at 30,000 within the city limits plus that of substantial suburbs all serviced by the city water system. In addition, the navy yard is a wholesale water customer with a consumption approximately equal to the domestic

THE production and use of wood stave pipe has passed its peak, and it probably will never again find general employment in water works service, although its production will continue for special applications. This paper is intended more as a historical record than as a guide for future design and installation. Wood pipe in the form of bored logs was used in Europe as early as the seventeenth century and, in this country, before the Revolution. Later these logs were reinforced to withstand greater pressures by winding them with steel bands. The author recalls

Abstract : The seizure of threaded connections and other tight fits was found to result from galling of the contacting surfaces. A quantitative method was developed for measuring the galling characteristics of standard metal surfaces under controlled conditions. Anti-seize compounds can be evaluated by observing their effect on these measured characteristics. A seizure tester was designed and constructed which automatically records galling test data and can be used for rapid routing testing. Metal specimens which are used with this machine can be: (1) assembled with an anti-seize compound between the test surfaces, (2) exposed to conditions simulating specific applications, and then (3) tested for seizure. The results of seizure tests made with several commercial anti-seize compounds are included. A preliminary correlation was obtained between these testing procedures and other performance ratings. It is concluded that this basic test method can be used to evaluate anti-seize compounds for: (1) High temperature service (1200 - 2000 F), (2) Aircraft oxygen system service, (3) Liquid oxygen system service, and (4) Similar specific applications.

Northwest have, in recent years, become increasingly aware of the effects of stream pollution and realize the necessity of cleaning up the region's waters. Along with the rapid population growth, this awareness has led to the large-scale planning and construction of sewers and sewage treatment plants that will cost many millions of dollars. In the past, sewers have generally been financed either through local improvement districts by assessing abutting property or through general ad valorem taxation. For various reasons, objections to these methods of financing have arisen, and, as a substitute, sewer-user service charges have been widely adopted . This practice is not peculiar to the Northwest, and there has been extensive discussion of various methods and enabling acts for allocating and collecting sewer-user service charges.

The subject of waterworks intakes is a very broad one, and this paper will cover only a limited field, the diversion of water from flowing streams. The application is particularly to the situation in the Pacific Northwest. This section is naturally favored in its surface water supplies, and a large majority of its waterworks systems have gravity lines diverting from streams. Surface water from a single source will vary greatly in its physical characteristics. In the winter, it may carry slush ice, or be so close to the freezing temperature that the subtraction of a little more heat along the pipe line causes freezing. Freshets, originating in rain or melting snow, usually bring silt and sediment, with resulting high turbities. Floods at the same time usually bring down an accumulation of logs, brush, roots, pine-needles and miscellaneous debris from the stream banks. The summer water conditions are in most cases

Public Schools Bill : a letter addressed to the Rev. Francis Hayward Joyce, M.A. : Vicar of Harrow

Just as waterworks men gain from the study of operating practice in other communities, those interested in management can benefit from the comparison of financial plans and costs. Prerequisite to such study are clear, illuminating and substantially uniform reports giving capital set-ups and annual operating costs. For privately owned plants, most states have adopted the Uniform Classification of Accounts for Water Utilities, prepared by the National Association of Railway and Utilities Commissions. The reports, made to the various state regulatory bodies, are complete and uniform, although companies have methods of juggling items which sometimes distort the true picture. As regards municipal plants, the State of Washington is the only one in the Northwest where any degree of standardization is found. The Washington law and its Division of Municipal Corporations should be adopted by other states. By frequent checking up and supervision of local accounts, excellent control is assured, although, of course, this department cannot dictate to local governments in matters of management. As to the smaller water utilities outside of Washington there is little to be said. With few exceptions, they have no records worth mentioning, and do not know where to start for proper accounting. As a matter of fact no water plant, regardless of size, should be without book records which show clearly its financial status as a department of the general city government. The fundamental information of utility report is contained in two statements; first, the assets and liabilities, giving the capital set up, and second, the revenue and expense statement, usually on an annual basis. Where these records do exist, they should be made readily available in printed form for those interested. It would be immensely valuable if the Washington Division of Municipal Corpora-

A few observations on friendly societies, and their influence on public morals

Friedel-crafts polymerisations with α,α′-dimethoxy-p-xylene—I The initiation step with stannic chloride as catalyst

Friedel-crafts polymerisations with x, x′-dimethoxy-p-xylene—II: Self-polymerisation of x, x′-dimethoxy-p-xylene

Abstract : The photothermal degradation of copolymers of methyl methacrylate and n-butyl acrylate covering the whole composition range has been studied at 165C. The gaseous and liquid products, which consist of hydrogen, carbon monoxide, methane, methyl methacrylate, n-butyl acrylate, n-butanol and n-butyraldehyde were analyzed quantitatively using a gas chromatographic technique and the yields related to copolymer composition. Differences from the thermal reaction and the corresponding reaction in copolymers of methyl methacrylate and methyl acrylate are discussed. It is shown that a number of aromatic compounds, both carbocyclic and heterocyclic, may be copolymerized with dimethoxy-p-xylene with stannic chloride as catalyst. Purification of materials and preparations of copolymers are described. The preparations and thermal degradation of a number of poly(dimethyl siloxanes) are also described.

Classical results establish that ensembles of small models benefit when predictive diversity is encouraged, through bagging, boosting, and similar. Here we demonstrate that this intuition does not carry over to ensembles of deep neural networks used for classification, and in fact the opposite can be true. Unlike regression models or small (unconfident) classifiers, predictions from large (confident) neural networks concentrate in vertices of the probability simplex. Thus, decorrelating these points necessarily moves the ensemble prediction away from vertices, harming confidence and moving points across decision boundaries. Through large scale experiments, we demonstrate that diversity-encouraging regularizers hurt the performance of high-capacity deep ensembles used for classification. Even more surprisingly, discouraging predictive diversity can be beneficial. Together this work strongly suggests that the best strategy for deep ensembles is utilizing more accurate, but likely less diverse, component models.

Decoders for brain-computer interfaces (BCIs) assume constraints on neural activity, chosen to reflect scientific beliefs while yielding tractable computations. We document how low tangling – a typical property of motor-cortex neural trajectories – yields unusual neural geometries. We designed a decoder, MINT, to embrace statistical constraints that are appropriate for these geometries. MINT takes a trajectory-centric approach: a library of neural trajectories (rather than a set of neural dimensions) provides a scaffold approximating the neural manifold. Each neural trajectory has a corresponding behavioral trajectory, allowing straightforward but highly nonlinear decoding. MINT consistently outperformed other interpretable methods, and outperformed expressive machine learning methods in 37 of 42 comparisons. Yet unlike these expressive methods, MINT’s constraints are known rather than the implicit result of optimizing decoder output. MINT performed well across tasks, suggesting its assumptions are generally well-matched to the statistics of neural data. Despite embracing highly nonlinear relationships between behavior and potentially complex neural trajectories, MINT’s computations are simple, scalable, and provide interpretable quantities such as data likelihoods. MINT’s performance and simplicity suggest it may be an excellent candidate for clinical BCI applications.

Ensembling remains a hugely popular method for increasing the performance of a given class of models. In the case of deep learning, the benefits of ensembling are often attributed to the diverse predictions of the individual ensemble members. Here we investigate a tradeoff between diversity and individual model performance, and find that—surprisingly—encouraging diversity during training almost always yields worse ensembles. We show that this tradeoff arises from the Jensen gap between the single model and ensemble losses, and show that Jensen gap is a natural measure of diversity for both the mean squared error and cross entropy loss functions. Our results suggest that to reduce the ensemble error, we should move away from efforts to increase predictive diversity, and instead we should construct ensembles from less diverse (but more accurate) component models.

Study of Low Reynolds Number Effects on Small Wind Turbine Performance

A review of Carina Drury, Irlandiani: Carina Drury, Eimear McGeown, Nathaniel Mander, Aileen Henry, Poppy Walshaw, Penny Fiddle Records (2020), (CD and Digital Album) PFR2005CD.

Lover Through Departure: New and Selected Poems by Rishma Dunlop

I Do Not Think That I Could Love a Human Being by Johanna Skibsrud

Edition of: Marc-Antoine Charpentier, Laudate Dominum, for Soloists, Double Choir and Orchestra, with introduction by P. Holman, THM003

The Collected Works of Pat Lowther, edited by Christine Wiesenthal

Glass Voices lasinäänet by Dorothea Grünzweig, trans. Derk Wynand

CONTENTS 1. INTRODUCTION 1.1 Overview of Oracle Financial Analyzer. 1.2 Objectives of this book 1.3 Road map for the book 2. PROJECT SCOPING FOR ORACLE FINANCIAL ANALYZER 2.1 Identifying the business processes to which OFA can be applied 2.2 Packaged solutions as part of the solution architecture 2.3 Common data sources and business processes 3. ORACLE FINANCIAL ANALYZER KEY FEATURES 3.1 OFA key features and functions 3.2 Controlling the flow of structures and data 3.3 More workstations and their functionality 4. ENTERPRISE ORACLE FINANCIAL ANALYZER, ERP AND THE DATA WAREHOUSE 4.1 The Oracle General Ledger and Oracle Financial Analyzer 4.2 Other ERP systems and Oracle Financial Analyzer 4.3 Operational data stores, the data warehouse and OFA 4.4 OFA, tactical solutions and the data warehouse 5. PROJECT PRINCIPLES 5.1 Sponsorship 5.2 Business process modelling 5.3 Change management planning 5.4 Design of the application architecture 5.5 Database design 5.6 Infrastructure specification 5.7 Documentation 5.8 Roll-out and continuing change management 5.9 Backups, database reorganizations and data archiving 6. CASE STUDY IN THE CONSUMER PACKAGED GOODS (CPG) INDUSTRY 6.1 Company overview 6.2 The requirements of the OFA system 6.3 Sponsorship and change management 6.4 Business process modelling 6.5 Design of the application architecture 6.6 Database design 6.7 Roll-out 6.8 Continuing change management 7. CASE STUDY IN THE FINANCIAL SERVICES INDUSTRY 7.1 Company overview 7.2 The requirements of the OFA system 7.3 Roll-out 7.4 Sponsorship 7.5 Change management 7.6 Requirements 7.7 Design of the application architecture 7.8 Database design: management reporting 7.9 Interface design: management reporting 7.10 Database design: budgeting 7.11 Database design: profitability 7.12 Infrastructure specification 8. CASE STUDIES IN ACTIVITY-BASED MANAGEMENT 8.1 Activity-based costing: the principles 8.2 Oracle Financial Analyzer and activity-based planning and budgeting 8.3 A more detailed look at the generic ABC business process model and OFA REFERENCES APPENDICES A Tuning OFA B Data loading C The GL Link: hints and tips D History, future developments and their potential impact

Implementing oracle financial analyzer: delivering value-added business processes with Oracle analytic solutions

 Background: Bronchial pre-malignant lesions (PMLs) are the putative precursors for bronchial squamous cell carcinoma. PMLs represent a spectrum of histologies, from low-grade lesions (hyperplasia, metaplasia) to high-grade lesions (dysplasia, carcinoma in situ). The majority of these lesions will regress or remain stable without clinical intervention while a subset of lesions will progress to invasive carcinoma. We performed single-cell RNA sequencing (scRNAseq) of these lesions to elucidate the cross-talk between epithelial, stromal, and immune populations in lesions of increasing histological grade.
 Methods: Thirty lesions from seventeen participants were biopsied via bronchoscopy. Cells were sorted by CD45+/- FACS gating and sequenced with the Cel-Seq2 protocol. Celda was used to bi-cluster genes into modules and cells into clusters. Cells were filtered by mitochondrial percentage (%mito < 50%), minimum UMI counts (nUMI > 300), and doublet detection. Cell types were labeled by marker gene expression.
 Results: After filtering low quality cells, we analyzed 4,382 cells. We observed expected smoking related shifts in epithelial cell type proportions, including an increase in secretory cells (χ2 = 31.39, p = 2.11 X 10-8) and a decrease in ciliated cells (χ2 = 4.83, p = 0.028) among current smokers. Distinct differences in expression of transcriptional modules were observed between KRT5+ (basal) cells from different histologic grades. Basal cells from high grade lesions expressed smoking detoxification and cell cycle gene programs, while low grade lesion basal cells expressed differentiation gene programs. We also identified a group of cells from CIS lesions involved in an epithelial-to-mesenchymal transition, marked by an increase in SPARC and COL4A1 expression and a decrease in CDH1 expression. Subpopulations of immune cells identified include macrophages, CD4/8+ T, B, dendritic cells, and natural killer cells. Several clusters of CD4+ and CD8+ T cells displayed an exhausted phenotype, marked by the expression of PD-1, CTLA4, LAG3, and TIGIT. Samples with high grade histology (dysplasia, carcinoma in situ) were enriched in CD4+ Tregs and myeloid cells compared to low grade histology samples (hyperplasia, metaplasia), which were enriched in Natural Killer and cytotoxic CD8+ T cells (χ2 = 298.95, p = 0.001).
 Discussion: Our results suggest that changes in specific transcriptional programs are associated with the transition of epithelial cells to more invasive states and that changes in immune populations are associated with increasing histological grade. These signatures can suggest novel avenues for chemoprevention and cancer interception.
 Citation Format: Conor Shea, Lukas Kalinke, Kitty De Jong, Kate Gowers, Diane Ding, Sherry Zhang, Gang Liu, Jack Cunningham, Ipsita Dey-Guha, Mark Hennon, Sai Yendamuri, Christopher Stevenson, Avrum Spira, Mary E. Reid, Marc E. Lenburg, Sam M. Janes, Jennifer E. Beane, Sarah A. Mazzilli, Joshua D. Campbell. Epithelial, stromal, and immune changes associated with lung squamous premalignant lesion severity identified by single-cell RNA-seq [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2201.

Abstract 2201: Epithelial, stromal, and immune changes associated with lung squamous premalignant lesion severity identified by single-cell RNA-seq

This volume emerged from a symposium held in Jerusalem and Tel Aviv in 1990, during which it became apparent how diverse are the research traditions and perspectives that have guided recent studies on Einstein. The desire of the editors to help establish links between these sometimes disparate branches of research, and thus set them "in context," is one of the principal motivations for publishing this volume. The papers are presented in an order that is determined partly by the chronology of Einstein's biography and partly by the increasing generality of the topics they discuss. The first section presents "The Early Professional Context." Einstein was employed as a technical expert by the Swiss patent office from 1902 to 1909. This period was crucial for his scientific creativity, reaching its first peak in the famous papers of 1905 — although seen with hindsight, Einstein's employment at the patent office might appear to be the waste of a mind. Robert Schulmann's paper sets the tone for a reevaluation of this period. It critically examines the myth of Einstein's "banishment" to a Swiss federal office, which is closely linked to the myth of the isolation of Einstein's achievements from contemporary academic research. Schulmann presents a somewhat speculative reconstruction of the academic politics behind what he sees as Einstein's "tactical retreat" to the patent office, in preparation for a carefully outlined academic career. Schulmann's account throws light on a previously invisible network of social relations around Einstein, as well as on his sometimes astonishing ability to operate within this network. The context of Einstein's early career is that of the emergence of theoretical physics as an autonomous subdiscipline, and Schulmann captures important local aspects of this process. In spite of the groundbreaking work of Jungnickel and McCormmach (1986) on the institutional history of theoretical physics, it remains a task for future research to show exactly how these local aspects are interwoven with the strands of the larger picture. In particular, the relationship between the institutional context and the intellectual content of Einstein's contributions to the growing field of theoretical physics merits further attention.

The summer issue of International Journal has for many years been designated the annual John W. Holmes issue on Canadian Foreign Policy (CFP). This year’s special issue showcases articles from the ‘‘Generations’’ project, which looks at the political and professional socialization of Canadian academic experts on international politics, the changing fortunes of CFP as a field of study, and the connections between them. The project began with a two-day workshop in Toronto, in September 2016, sponsored by the Canadian International Council and the Bill Graham Centre for Contemporary International History, and supporting contributions from ISA-Canada, the Association for Canadian Studies in the United States, and the Center for the Study of Canada and Institute on Quebec Studies at SUNY Plattsburgh. International Journal has played a crucial role in establishing CFP as an academic project, having published many of the articles most often chosen as required readings for CFP courses, and serving as a forum for some of the field’s most important debates. Here we are pleased to present some leading Canadian scholars’ reflections on their own intellectual formation and trajectories, their experiences with CFP, and their views on the future of the field. The collection begins with an introduction by the project’s co-organizers, Brian Bow and Andrea Lane, and then presents short, reflective articles by Denis Stairs, Ellen Gutterman, Bessma Momani, Heather Smith, Srdjan Vucetic, David Haglund, Asa McKercher, and Aisha Ahmad. Other contributions to the Generations project will be published next year, in a volume to be co-edited by Bow and Lane. The rest of this issue features a variety of other interesting pieces on Canadian Foreign Policy. In our Lessons of History article, Adam Chapnick reviews the history of the ‘‘functional principle’’ as a concept structuring debates about Canada’s stature and responsibilities as an international actor. That is followed by an impressive group of book reviews, including Stephen Azzi on Robert Bothwell’s Your Country, My Country; Hunter McGill on the second edition of Stephen Brown, Molly den Heyer, and David Black’s edited volume Rethinking Canadian Aid; and Daryl Copeland on Roland Paris and Taylor Owen’s volume, The World Won’t Wait.

The Middle East, a region that frequently dominates the headlines, looms large in this issue of International Journal. We open with Laura Pelletier and Justin Massie’s probing consideration of the Trudeau government’s decision to withdraw Canadian fighter jets from Iraq and Syria. Then, Liam Hunt offers a fresh analysis of the Iran nuclear deal, through the prism of the decline of realism in US foreign policy. We then switch gears with Steve Wood’s exploration of the problematic relationship between Russia and Germany, clouded as it is by the resonances of ‘‘history.’’ Mischa Hansel and Simon Ruhnke follow with an analysis of military transformation processes, within the framework of regime type and capabilitybased explanations. Then, Anessa Kimball assesses the legalization of informal defence and security arrangements, with attention to the case of Canadian– American agreements from 1955 to 2005. It is back to the Middle East with something of a departure for IJ. Two scholars, Thomas Juneau and Aisha Ahmad, present alternative views on Canada’s policy in the region in two Policy Briefs. Rounding out the issue, our book review section offers timely appraisals of recent volumes on international affairs, under the capable direction of Brendan Kelly. Kate Merriman, who has served IJ as Copy Editor for several years, has departed to pursue other opportunities, and with this issue her responsibilities are taken up by Elena Vardon, an experienced writer and editor based in Toronto. We welcome Elena aboard, and wish Kate all the best in her future endeavours.

The largely Canadian readership of IJ has a natural interest in middle power diplomacy, and we have chosen to devote this special issue to that theme, under the guest editorship of Andrew Cooper of the University of Waterloo and Emel Parlar Dal of Marmara University. Their focus is on the MIKTA (Mexico, Indonesia, Korea, Turkey, and Australia) grouping of middle powers. Cooper and Parlar Dal open with an introductory piece positioning what they see as the third wave of middle power diplomacy. This is followed by a solo article by Cooper in which he assesses the capability of middle powers to act collectively in a world where power has become diffused. Then, Günther Maihold looks at the case of Mexico, and Awidya Santikajaya that of Indonesia. Jongryn Mo examines South Korea’s diplomacy, Emel Parlar Dal and Ali Murat Kurşun that of Turkey, and Susan Harris Rimmer takes a look at the Australian example. Finally, Bruce Gilley examines what he sees as the delusions of grandeur that wait temptingly in the ‘‘Goldilocks Zone.’’ We are pleased to welcome our new book reviews editor, Brendan Kelly. Brendan recently completed his PhD in history at the University of Toronto, and has a special interest in Canadian foreign policy, which makes him a natural fit for IJ.

The Iron mask : being the later adventures of the three musketeers=Le masque de fer

Abstract : The purpose of this study was to determine if planning should proceed to feasibility. The conclusion of the report indicates that raising the height of the existing levee built by the SCS in 1980, along with channel clearing, is an economically feasible plan. While we don't at this time have a sponsor, we are working toward a joint effort with the SCS to perform additional studies and construction of a project. This would be accomplished at 100 percent Federal cost.

Reconnaissance Report, Section 205 Chattooga River Trion, Georgia, Chattooga County

Who Framed Charles I? The Forged Commission for the Irish Rebellion of 1641 Revisited*

John Jenkins: Fantasia-Suites: Review of: John Jenkins: Fantasia-Suites III, ed. Andrew Ashbee, MB CIV (London: Stainer and Bell, 2019)

Musical Exchange between Britain and Europe, 1500-1800: Essays in honour of Peter Holman

Empire and Enterprise: Money, Power and the Adventurers for Irish Land During the British Civil Wars

Milton, John Hall, and Thomas Waring's
 Brief Narration of the Rebellion in Ireland

Patrick Hewetson MD, 1699-1783: Biographical article for the RCPI's 'Lives of the Presidents Project'

Identifying the Apothecary (Archaeological Report, Kevin St., Dublin)

William Smyth MD (d. 1732): Biographical article for the RCPI's 'Lives of the Presidents Project'

The New English, the Past and the Law in the 1640s: Sir William Parsons's 'Examen Hiberniae'

Patrick Mitchell MD, 1671-1750: Biographical article for the RCPI's 'Lives of the Presidents Project'

“An Irishman in an opera!”: Music and nationalism on the London stage in the mid-1770s

Richard Steevens MD (c.1654-1710): BIOGRAPHICAL ARTICLE FOR THE RCPI'S 'LIVES OF THE PRESIDENTS PROJECT'

Abstract Paired in 1911 as Irish ‘rebels’ by Archie Crawford, their mutual mentor, Tom Glynn and Mary Fitzgerald were pioneers of transnational syndicalism, in South Africa. Arriving separately in the country in 1900, they had taken different routes into labour activism, and despite being close political allies, had markedly different outlooks. She was a feminist, whose syndicalism has been judged ‘eclectic’; he, while committed to gender and racial equality, became a proponent of the ‘virile syndicalism’ of the Chicago-line Industrial Workers of the World. This article discusses their journalism in Johannesburg’s Voice of Labour, their roles as leaders in a number of significant labour disputes, the significance of their ‘Irishness’ in a largely British-oriented milieu, their geographical separation in 1911, and the definitive parting of their political ways on the outbreak of the First World War.

Tom Glynn and ‘Pickhandle Mary’ Fitzgerald: Two Irish Syndicalists in Pre-World War One South Africa

The reception and re-use of Thomas Arne’s Shakespeare songs of 1740/1

Review(s) of: Derry labour in the age of agitation, 1889-1923, vol. 2, Larkinism and Syndicalism, 1907-23, by Emmet O'Connor (Dublin, Four Courts Press, 2016), Maynooth Studies in Local History Series, pp. 68. 9.95 paper.

Derry labour in the age of agitation, 1889-1923, vol. 2, Larkinism and Syndicalism, 1907-23 [Book Review]

'An after game at Irish': Clement Walker and the conquest of Ireland in 1649 (Conference Paper Podcast)

John Madden MD, 1649-1703: Biographical article for the RCPI's 'Lives of the Presidents Project'

Abstract The recent digitisation of the 1641 depositions has opened up that large and controversial collection of manuscripts to renewed study. The significance of a substantial section of that archive generated in 1653–4 by the work of the Cromwellian delinquency commissions has hitherto been poorly understood. This article sheds new light on the workings of the commissions and on the ways in which the ‘delinquency depositions’ that they collected helped to shape the implementation of the Cromwellian and Restoration land settlements in Ireland. It also compares the Irish delinquency proceedings to the approach adopted by the Long Parliament in its dealings with royalists in England in the 1640s. In analysing the actual content of the depositions, the article focuses particular attention on County Wexford. The surviving delinquency depositions enable in-depth exploration of many facets of the 1641 rebellion and its aftermath in that region.

Anatomising Irish rebellion: the Cromwellian delinquency commissions, the books of discrimination and the 1641 depositions

The Apothecary in Early Modern Ireland: Conference Paper Podcast

“Solemn and appropriate Shakespearean music”: The Stratford Tercentenary of 1864

Anglo-Irish diplomatic relations and the British Labour Party, 1981–94

From Nationalism to Rapprochement? Hungary and Romania On-Screen

Lawyers and the Law in the Writings of Sir William Parsons: Conference Paper Podcast

11. Szabó, Hungarian Cinema and the Question of Censorship – A Note

Divided Conquerors: the Rump Parliament, Cromwell's Army and Ireland

‘The man who comes from somewhere else is always suspect’; Sunshine

A meeting of Amateur and Professional: Playford's 'Compendious Collection' of Two-Part Airs, Court-Ayres (1655)

The conquest of Ireland between 1649 and 1653 created almost as many problems as it solved for the English government of the country. Not least of these was how, if at all, the majority Catholic population was to be won over to Protestantism. This article reassesses Cromwellian religious policy towards the Catholic laity and traces its evolution up to the end of the decade, taking account also of Catholic responses to official measures. It argues that the supposed leniency of government policy has been overstated and that Catholics who refused to conform to Protestantism in fact risked heavy penalties.

L’Irish Trade Union Congress et le nationalisme irlandais, 1894-1930

Divided Conquerors: Martial Law and the Politics of Conquest in Ireland, 1649-1653: Conference Paper Podcast

Henry Lawes’s music for the songs in A Mask: Volume III: The shorter poems

Book review: Katie Holmes and Stuart Ward (eds) Exhuming Passions: The Pressure of the Past in Ireland and Australia

Francis Patrick Marsh (“Frank”) was born in Birmingham in 1936 and moved to Leeds with his family in early childhood. The son of Horatio and Violet Marsh, he completed his schooling at Leeds Grammar School, from where he gained admission to Caius College, Cambridge, to read medicine, graduating with a first class honours degree in 1957 . He then moved to the London Hospital Medical College as a clinical student, and his medical life thereafter revolved largely around the London Hospital and its associated medical college with sojourns at the Kent and Canterbury Hospital and the Royal Free Hospital along the way. At the age of 34 years he was appointed as a senior lecturer on the medical unit at the London Hospital Medical College under Professor Clifford Wilson (of “Kimmelstiel-Wilson Kidney”) and later as a consultant physician to the London Hospital, a post …

Review(s) of: A labour history of Ireland 1824-2000, by Emmet O'Connor, University College, Dublin Press, Dublin, 2011, pp. 329, 28.00 paper.

Conquest and Land in Ireland: Conquest and land in Cromwellian Ireland, 1649–1652

Bohemia and Ireland in the Seventeenth Centuries: Comparable Histories?: Conference Paper Podcast

Nearly two decades ago Declan Kiberd cleverly posited the question, "If God invented whiskey to prevent the Irish from ruling the world, then who invented Ireland?" (1995: 1). Unlike Kiberd's critical literary approach to this question, John Cunningham's Conquest and Land in Ireland: The Transplantation to Connacht, 1649-1680 (2011), is an in-depth analysis of the historical processes associated with the policies of transplantation to provide a more lucid understanding of the events that so dramatically affected the creation and recreation of modern Ireland. Although this crucial period in Irish history has received significant scholarly attention for well over 100 years (see Prendergast 1868), Cunningham's work is a welcome, detailed, and well researched contribution to this widely known but frequently misunderstood period. While at times suffering from a lack of historical context and a select focus on those holding higher social status or power, Cunningham successfully illustrates the nuances of transplantation policy, politics, and practice without clouding the overall significance and impact of the consequences. Cunningham begins where most historians of this period have focused their attention, with Oliver Cromwell. Using Cromwell as a point of departure, Cunningham begins the volume arguing that, "The history of Ireland in the 1650s is synonymous with Oliver Cromwell and with his supposed pronouncement on the fate of the Catholic population: 'Go to hell or to Connacht'" (1). As Cunningham goes on to explain, Cromwell's legacy is indelibly stamped upon Irish history and memory and has been a focal point of Irish/English historiography (see for example Micheál Ó Siochrú's 2008 volume, God's Executioner: Oliver Cromwell and the Conquest of Ireland). However, Cunningham's thorough literature review indicates that Cromwell's legacy needs to be placed within a larger historical context if we are to more fruitfully unpack the nuances of transplantation. It is within this brief introduction that Cunningham provides the majority of his own historical context, sweeping through prior English plantation efforts in Ireland since the 1550s and the rebellion of 1641 to bring the reader to the Cromwellian invasion of 1649 (8-9).

Conquest and Land in Ireland: The Transplantation to Connacht, 1649-1680

Conquest and Land in Ireland: Towards plantation and transportation, 1652–1654

The Cromwellian settlement of Ireland involved a substantial transfer of property from Catholics to Protestants, and the transplantation of dispossessed Catholic landowners to the western province of Connacht. The latter scheme proved controversial, receiving considerable attention from contemporary Protestant authors, and outright condemnation from all Catholics. Nonetheless, it was little commented upon by historians over the following two centuries.

The transplanters' certificates and the historiography of Cromwellian Ireland

ABSTRACT Oliver Cromwell remains a deeply controversial figure in Ireland. In the past decade, his role in the conquest has received sustained attention. However, in recent scholarship on the settlement of Ireland in the 1650s, he has enjoyed a peculiarly low profile. This trend has served to compound the interpretative problems relating to Cromwell and Ireland which stem in part from the traditional denominational divide in Irish historiography. This article offers a reappraisal of Cromwell's role in designing and implementing the far-reaching ‘Cromwellian’ land settlement. It examines the evidence relating to his dealings with Irish people, both Protestant and Catholic, and his attitude towards the enormous difficulties which they faced post-conquest. While the massacre at Drogheda in 1649 remains a blot on his reputation, in the 1650s Cromwell in fact emerged as an important and effective ally for Irish landowners seeking to defeat the punitive confiscation and transplantation policies approved by the Westminster parliament and favoured by the Dublin government.

This publication contains reprint articles for which IEEE does not hold copyright. Full text is not available on IEEE Xplore for these articles.

Unlikely Radicals: Irish Post-Primary Teachers and the ASTI, 1909-2009

An examination of the work and music of the Royalist composer William Lawes.

Book Review of Robert Armstrong, Protestant War: the 'British' of Ireland and the Wars of the Three Kingdoms (Manchester, 2008)

‘“Some consorts of instruments are sweeter than others”: Further light on the harp of William Lawes’s Harp Consorts

Review of William Lawes: The Harp Consorts, ed. Jane Achtman, et al.

‘“Let them be lusty, smart-speaking viols”: William Lawes and the lyra-viol trio

Francis James Zacharias (“Jim”) served with the Royal Air Force in the Gold Coast and RAF Halton during the later stages of the second world …

A tale of two harps:: Issues arising from recordings of William Lawes’s Harp Consorts

The first half of the seventeenth century was one of the most vibrant periods in English music. William Lawes is arguably one of the finest English composers of the period, and indeed, ranks with the best of his Continental contemporaries. He gained a post among the private musicians of Charles I in 1635, a group known as the Lutes, Viols and Voices (LVV). Much of his surviving consort music appears to have been written for performance by members of LVV; nevertheless, little is known of the internal workings of this elite group. Thus, this dissertation first considers the evidence available from court records in attempting to understand the structure and activities of the LVV. The remainder of the dissertation primarily deals with William Lawes the composer. First, a detailed survey is provided of the autograph sources of Lawes's music. This provides an analysis of the sources and their functions, and offers evidence for their chronology; the development of Lawes's hand throughout the sources is also considered. Second, several studies of Lawes's consort music are presented. The studies generally focus on areas of Lawes's consort music that have received the least scholarly attention: the lyra viol trio, the Royall Consort, the harp consorts, and the pieces for two bass viols and organ. A common theme throughout these studies is Lawes's revision of existing pieces and collections of pieces in order to incorporate elaborate divisions, suggests that this was a growing consideration for Lawes in the mid-to late 1630s. The main aim of this dissertation is to understand better William Lawes as a composer, and to understand the court environment in which he composed during an increasingly turbulent political time.

Music for the privy chamber : studies in the consort music of William Lawes (1602-45)

Nationalism and the Irish Party: Provincial Ireland, 1910–1916. By Michael Wheatley.

From Arcadia to collective farm and beyond: the rural in Hungarian cinema

This text discusses all the major aspects of Hungarian cinema, including avant-garde, animation and representations of the Gypsy and Jewish minorities.

Ash Wednesday throughout holds together the vagaries of any sentient Christian soul in a kind of timeless moment. The soul ever knows at once her Ash Wednesday and also ever rejoices at the brink of Easter. Or, in other words, the soul ‘‘walk[s] in darkness’’ () of Good Friday renunciations and, paradoxically, also stands at the brink of Resurrection ‘‘white light’’ () that is the goal of the fast. Though compounded of discrete experiences that analysis may discover, the soul’s hidden life is one, a unity. Bold to enter upon such a great mystery, Eliot preserves it by refusing chronology, by invoking the elusive ‘‘Lady’’ (or ladies), by using deliberately indeterminate imagery, by risking syntactical impertinences, and by a mixing of tenses (and therefore of times) in sections, and even in parts of sections. Seeing these as pointers to mystery rather than as cruxes to be solved leads one closer to the heart of the poem. A soul’s pilgrimage is never straightforward. Yet Eliot offers an account remarkable for its insight into the life of the soul. We shall discuss the poem from its own point of view so far as we can imagine ourselves into it. In Four Quartets, Eliot proposes that a soul’s

Jack Cunningham - On the Line a solo touring exhibition exploring aspects of place: Glasgow/Paris/Tokyo

Acknowledgements Chapter One: Introduction Chapter Two: 'This Thing Going With My Bride to Straighten Out in America' Chapter Three: Hegemony and the Broad Celebration of Charles Johnson Chapter Four: 'Hey, Mr. Liberace Will You Vote for Zeta?' Looking for the Joto in Chicano Men's Autobiographical Writing Chapter Five: 'His Complexion was of a Tone I Want to Call Flesh-Colored' Bibliography

A sence of place : Jack Cunningham, Linda Green : New York in jewellery and textiles

Arizona Quarterly: A Journal of American Literature, Culture, and Theory

"To Be Men Not Destroyers": The Making of Men and the Reproduction of Culture in Ezra Pound's Cantos

The Sunday school movement has played a paramount role in the development of American Protestant Christian education. Chapter 24 is devoted to the history of this institution. A very cursory description of the nineteenth century Sunday school provides the extent of coverage. Since the authors are Southern Baptist and the Sunday school has played such a crucial role in the growth of the Convention, it is quite surprising that the Sunday school is ?iven su~h scant attention and totally Ignored in the twentieth century. The same might be said of the failure to include the Sunday School Board of the Southern Baptist Convention, which has become the largest religious publishing house in the world, and designed to provide Sunday school materials for the more that 38,000 churches of the Convention. ,In spite of these shortcomings, A HIstory ofChristian Education can serve as a ready resource to help students gain insight into the historical development of Christian education. It will require additional explanation that will enlarge and enhance the study, if it is to be used as.a ,textbook. It may be of help to the ~mIs~er of education by providing a historical summary of the various periods of Christian education and guiding their thinking toward the implications of some of the trends and movements that have shaped the discipline in the past and the implications of those movements for the future educational ministries of the church.

Book Review: Promoting Active Learning: Strategies for the College Classroom

Sutpen's Designs: Masculine Reproduction and the Unmaking of the Self-Made Man in Absalom, Absalom!

Labour in the west of Ireland: Working life and struggle 1890-1914

Christian Allusion, Comedic Structure, and the Metaphor of Baptism in "Great Expectations"

In a previous book, Foundational Issues in Christian Education, Pazmino set forth an integrated model of the educational tasks of the church. His five-task model included the tasks of worship, fellowship, evangelism, Kingdom consciousness, and service. The remainder of Foundationallssues was devoted to discussion of critical issues faced by churches as they organize the Christian education ministry around these tasks. Principles and Practices of Christian Education is an intentional extension of Pazmifto's earlier work. Using slightly revised terminology to describe the five tasks (worship, community, proclamation, advocacy, and service), he engages the reader in a serious discussion of organizing principles and current practices needed to implement the five-task model.

Book Review: IV. Ministry Studies: Principles and Practices of Christian Education: An Evangelical Perspective

De la meme facon que le roman s'ouvre sur une parodie du bapteme, l'apparition de la figure du jeune marie un peu plus loin peut etre lu comme une allusion au Nouveau Testament et a l'image des noces eternelle. Les autres emlois metaphoriques de ces sacrements contiennent cette meme intention comique

New Zealand has witnessed several technological developments in the past and has grown because of them. These technologies also present numerous opportunities for future growth and development but only if they are prioritized properly.

Simple Summary Giant pine scale, Marchalina hellenica Gennadius (Hemiptera, Marchalinidae), is a sap sucking insect native to the Eastern Mediterranean Basin. In 2014, giant pine scale was detected for the first time in Victoria, Australia, feeding on a new host, Pinus radiata. We studied the life cycle and feeding activity of giant pine scale in Victoria over 32 months, with the aim of drawing comparisons between exotic and native populations. Australian life stages of this pest emerged during similar months to Greek seasonal equivalents, although the timing of Australian life stages differed between years. Insect density and feeding activity on infested trees differed among locations and between generations. Strong evidence was found in support of density and feeding intensity being explained by climatic conditions. The value of Pinus radiata as a food source for this insect may fluctuate with climate conditions. Our findings aim to inform future management efforts for this scale insect, including surveillance strategies and optimal seasons for release of biocontrol agents. Our findings also suggest that the impact of this pest in Australia may be exacerbated by climate change. Abstract Invasive insects pose an increasing risk to global agriculture, environmental stability, and public health. Giant pine scale (GPS), Marchalina hellenica Gennadius (Hemiptera: Marchalinidae), is a phloem feeding scale insect endemic to the Eastern Mediterranean Basin, where it primarily feeds on Pinus halepensis and other Pinaceae. In 2014, GPS was detected in the southeast of Melbourne, Victoria, Australia, infesting the novel host Pinus radiata. An eradication program was unsuccessful, and with this insect now established within the state, containment and management efforts are underway to stop its spread; however, there remains a need to understand the insect’s phenology and behaviour in Australia to better inform control efforts. We documented the annual life cycle and seasonal fluctuations in activity of GPS in Australia over a 32 month period at two contrasting field sites. Onset and duration of life stages were comparable to seasons in Mediterranean conspecifics, although the results imply the timing of GPS life stage progression is broadening or accelerating. GPS density was higher in Australia compared to Mediterranean reports, possibly due to the absence of key natural predators, such as the silver fly, Neoleucopis kartliana Tanasijtshuk (Diptera, Chamaemyiidae). Insect density and honeydew production in the Australian GPS population studied varied among locations and between generations. Although insect activity was well explained by climate, conditions recorded inside infested bark fissures often provided the weakest explanation of GPS activity. Our findings suggest that GPS activity is strongly influenced by climate, and this may in part be related to changes in host quality. An improved understanding of how our changing climate is influencing the phenology of phloem feeding insects such as GPS will help with predictions as to where these insects are likely to flourish and assist with management programs for pest species.

Seasonal Phenology and Climate Associated Feeding Activity of Introduced Marchalina hellenica in Southeast Australia

Carpophilus davidsoni (Dobson) is an important pest of Australian stone fruit. Current management practices for this beetle include the use of a trap that contains an attractant lure comprised of aggregation pheromones and a ‘co-attractant’ mixture of volatiles from fruit juice fermented using Baker’s yeast, Saccharomyces cerevisiae (Hansen). We explored whether volatiles from yeasts Pichia kluyveri (Bedford) and Hanseniaspora guilliermondii (Pijper), which are closely associated with C. davidsoni in nature, might improve the effectiveness of the co-attractant. Field trials using live yeast cultures revealed that P. kluyveri trapped higher numbers of C. davidsoni compared to H. guilliermondii, and comparative GC-MS of volatile emissions of the two yeasts led to the selection of isoamyl acetate and 2-phenylethyl acetate for further investigation. In subsequent field trials, trap catches of C. davidsoni were significantly increased when 2-phenylethyl acetate was added to the co-attractant, compared to when isoamyl acetate was added, or both isoamyl acetate and 2-phenylethyl acetate. We also tested different concentrations of ethyl acetate in the co-attractant (the only ester in the original lure) and found contrasting results in cage bioassays and field trails. Our study demonstrates how exploring volatile emissions from microbes that are ecologically associated with insect pests can result in more potent lures for use in integrated pest management strategies. Results from laboratory bioassays screening volatile compounds should be treated with caution when making inferences regarding attraction under field conditions.

Volatiles produced by symbiotic yeasts improve trap catches of Carpophilus davidsoni (Coleoptera: Nitidulidae): an important pest of stone fruits in Australia

Background and Aims. Grape phylloxera in Australia comprises diverse genetic strains that feed on roots and leaves of Vitis spp. The G38 phylloxera strain was detected on roots of Vitis spp., for the first time in North East Victoria in 2015. Prior to 2015, G38 phylloxera was only known to feed on leaves. The aim of this study was to evaluate the survival and development of G38 phylloxera on roots of diverse Vitis spp. under field, controlled laboratory, and greenhouse conditions. Methods and Results. In the field, emergence traps quantified first instars and alates emerging from roots of diverse rootstocks and Vitis vinifera L. High numbers of phylloxera were collected in traps placed at vines of rootstocks 101-14, 3309 Courderc and Schwarzmann. Nodosity were also observed on roots of 101-14, 3309 Courderc and Schwarzmann in the field and in-pot vines experiments. The better performance of G38 phylloxera on these three rootstocks compared to V. vinifera in the field and in potted vines parallelled the excised roots experiments. Conclusions. The relatively high performance of G38 phylloxera on the 101-14, 3309 Courderc and Schwarzmann rootstocks suggest a susceptible response and could be associated with rootstock parentage. Further investigation is warranted to determine implications for rootstocks development. Significance of the Study. These findings are fundamental for decision-making in phylloxera risk assessment and rootstock selection. The study reaffirms the need for triphasic (in vitro, in planta, and in-field) rootstock screening protocols for phylloxera.

Performance of a Leaf-Galling Phylloxera (Daktulosphaira vitifoliae) on Roots of Diverse Vitis spp. Rootstocks in North East Victoria, Australia

Time-Dependent Behavioural Plasticity Influences Oviposition Behaviour in No-Choice and Choice Host-Specificity Trials for a Candidate Weed Biocontrol Agent

The spotted wing drosophila (Drosophila suzukii, Matsumara) is a rapidly spreading global pest of soft and stone fruit production. Due to the similarity of many of its life stages to other cosmopolitan drosophilids, surveillance for this pest is currently bottlenecked by the laborious sorting and morphological identification of large mixed trap catches. DNA metabarcoding presents an alternative high-throughput sequencing (HTS) approach for multi-species identification, which may lend itself ideally to rapid and scalable diagnostics of D. suzukii within unsorted trap samples. In this study, we compared the qualitative (identification accuracy) and quantitative (bias toward each species) performance of four metabarcoding primer pairs on D. suzukii and its close relatives. We then determined the sensitivity of a non-destructive metabarcoding assay (i.e., which retains intact specimens) by spiking whole specimens of target species into mock communities of increasing specimen number, as well as 29 field-sampled communities from a cherry and a stone fruit orchard. Metabarcoding successfully detected D. suzukii and its close relatives Drosophila subpulchrella and Drosophila biarmipes in the spiked communities with an accuracy of 96, 100, and 100% respectively, and identified a further 57 non-target arthropods collected as bycatch by D. suzukii surveillance methods in a field scenario. While the non-destructive DNA extraction retained intact voucher specimens, dropouts of single species and entire technical replicates suggests that these protocols behave more similarly to environmental DNA than homogenized tissue metabarcoding and may require increased technical replication to reliably detect low-abundance taxa. Adoption of high-throughput metabarcoding assays for screening bulk trap samples could enable a substantial increase in the geographic scale and intensity of D. suzukii surveillance, and thus likelihood of detecting a new introduction. Trap designs and surveillance protocols will, however, need to be optimized to adequately preserve specimen DNA for molecular identification.

DNA Metabarcoding Enables High-Throughput Detection of Spotted Wing Drosophila (Drosophila suzukii) Within Unsorted Trap Catches

A Synthetic Blend of Fruit and Live Yeast Odours Shows Promise for Trapping Mated Female Queensland Fruit Fly, Bactrocera tryoni, in the Field

Appropriate design and selection of PCR primers plays a critical role in determining the sensitivity and specificity of a metabarcoding assay. Despite several studies applying metabarcoding to insect pest surveillance, the diagnostic performance of the short “mini-barcodes” required by high-throughput sequencing platforms has not been established across the broader taxonomic diversity of invasive insects. We address this by computationally evaluating the diagnostic sensitivity and predicted amplification bias for 68 published and novel cytochrome c oxidase subunit 1 (COI) primers on a curated database of 110,676 insect species, including 2,625 registered on global invasive species lists. We find that mini-barcodes between 125-257 bp can provide comparable resolution to the full-length barcode for both invasive insect pests and the broader Insecta, conditional upon the subregion of COI targeted and the genetic similarity threshold used to identify species. Taxa that could not be identified by any barcode lengths were phylogenetically clustered within ‘problem groups’, many arising through taxonomic inconsistencies rather than insufficient diagnostic information within the barcode itself. Substantial variation in predicted PCR bias was seen across published primers, with those including 4-5 degenerate nucleotide bases showing almost no mismatch to major insect orders. While not completely universal, a single COI mini-barcode can successfully differentiate the majority of pest and non-pest insects from their congenerics, even at the small amplicon size imposed by 2 × 150 bp sequencing. We provide a ranked summary of high-performing primers and discuss the bioinformatic steps required to curate reliable reference databases for metabarcoding studies.

Computational Evaluation of DNA Metabarcoding for Universal Diagnostics of Invasive Insect Pests

Opiine parasitoids (Hymenoptera: Braconidae) and biological control of fruit flies (Diptera: Tephritidae) in Australia: Past, present and future

Yeasts Influence Host Selection and Larval Fitness in Two Frugivorous Carpophilus Beetle Species

Carpophilus beetles are serious pests of Australian fruit and nut crops, causing significant damage through adult and larval feeding and vectoring plant diseases. Six strains of the entomopathogenic fungus Beauveria bassiana ((Balsamo) Vuillemin; Hypocreales: Cordycipitaceae), isolated from a range of hosts in Australia, together with one commercial strain, were screened for virulence to adult and larval stages of Carpophilus attacking stone fruits (C. davidsoni (Dobson)) and almonds (C. truncatus (Murray)) under laboratory conditions. The two species differed significantly in their susceptibility to the B. bassiana isolates. In the adult beetle assay, C. truncatus had a maximum Abbott’s control corrected mortality of 19% when treated with the most effective isolate, B54, compared to 52% for C.davidsoni. In larval bioassays, mortality rates for the two species were generally higher than adults: four isolates caused greater than 80% mortality in C. davidsoni; while only one isolate was considered effective against C. truncatus (causing 73% mortality), all other isolates caused less than 40% mortality. The results indicate promising potential for B. bassiana to be applied as a biopesticide as part of an integrated pest management strategy, which might take the form of a soil application against larvae or an autodissemination program using adult beetles.

Virulence Screen of Beauveria Bassiana Isolates for Australian Carpophilus (Coleoptera: Nitidulidae) Beetle Biocontrol

Developing a non-destructive metabarcoding protocol for detection of pest insects in bulk trap catches

A diagnostic LAMP assay for the destructive grapevine insect pest, phylloxera (Daktulosphaira vitifoliae)

A LAMP assay for the detection of Bactrocera tryoni Queensland fruit fly (Diptera: Tephritidae)

Associative learning is well documented in Hymenopteran parasitoids, where it is thought to be an adaptive mechanism for increasing successful host location in complex environments. Based on this learning capacity, it has been suggested that providing prerelease training to parasitoids reared for inundative release may lead to a subsequent increase in their efficacy as biological control agents. Using the fruit fly parasitoid Diachasmimorpha krausii we tested this hypothesis in a series of associative learning experiments which involved the parasitoid, two host fruits (tomatoes and nectarine), and one host fly (Bactrocera tryoni). In sequential Y‐tube olfactometer studies, large field‐cage studies, and then open field studies, naïve wasps showed a consistent preference for nectarines over tomatoes. The preference for nectarines was retained, but not significantly increased, for wasps which had prior training exposure to nectarines. However, and again consistently at all three spatial scales, prior experience on tomatoes led to significantly increased attraction to this fruit by tomato‐trained wasps, including those liberated freely in the environment. These results, showing consistency of learning at multiple spatial scales, gives confidence to the many laboratory‐based learning studies which are extrapolated to the field without testing. The experiment also provides direct experimental support for the proposed practice of enhancing the quality of inundatively released parasitoids through associative learning.

From laboratory to the field: consistent effects of experience on host location by the fruit fly parasitoid Diachasmimorpha kraussii (Hymenoptera: Braconidae)

Abstract Trap-based surveillance strategies are widely used for monitoring of invasive insect species, aiming to detect newly arrived exotic taxa as well as track the population levels of established or endemic pests. Where these surveillance traps have low specificity and capture non-target endemic species in excess of the target pests, the need for extensive specimen sorting and identification creates a major diagnostic bottleneck. While the recent development of standardized molecular diagnostics has partly alleviated this requirement, the single specimen per reaction nature of these methods does not readily scale to the sheer number of insects trapped in surveillance programmes. Consequently, target lists are often restricted to a few high-priority pests, allowing unanticipated species to avoid detection and potentially establish populations. DNA metabarcoding has recently emerged as a method for conducting simultaneous, multi-species identification of complex mixed communities and may lend itself ideally to rapid diagnostics of bulk insect trap samples. Moreover, the high-throughput nature of recent sequencing platforms could enable the multiplexing of hundreds of diverse trap samples on a single flow cell, thereby providing the means to dramatically scale up insect surveillance in terms of both the quantity of traps that can be processed concurrently and number of pest species that can be targeted. In this review of the metabarcoding literature, we explore how DNA metabarcoding could be tailored to the detection of invasive insects in a surveillance context and highlight the unique technical and regulatory challenges that must be considered when implementing high-throughput sequencing technologies into sensitive diagnostic applications.

Prospects and challenges of implementing DNA metabarcoding for high-throughput insect surveillance

Good culturing methods play an important role in the study of insect behavior and its application to pest management. Here, we describe and validate a new method for rearing the parasitoid wasp, Diachasmimorpha kraussii, which attacks some of the world's worst fruit fly pests and is an internationally used biological control agent. Our method differs from standard culturing approaches by presenting adult wasps with host‐infested artificial media within a “culturing bag,” which mimics a natural (fruit) oviposition substrate. In laboratory trials using wild collected D. kraussii, the culturing bag method was compared to the use of host‐infested nectarines, and a commonly used laboratory method of presenting host‐infested artificial media within Petri dishes. The culturing bag method proved to be a significant improvement on both methods, combining the advantages of high host survival in artificial media with parasitism levels that were the equivalent to those recorded using host‐infested fruits. In our field study, culturing bags infested with the Queensland fruit fly, Bactrocera tryoni, and hung in a mixed peach and nectarine orchard proved to be effective “artificial fruits” attracting wild D. kraussii for oviposition. Significantly more adult wasps were reared from the culturing bags compared to field collected fruits. This was shown to be due to higher fruit fly larval density in the bags, as similar percentage parasitism rates were found between the culturing bags and ripe fruits. We discuss how this cheap, time‐efficient method could be applied to collecting and monitoring wild D. kraussii populations in orchards, and assist in maintaining genetic variability in parasitoid laboratory cultures.

An improved culturing method for opiine fruit fly parasitoids and its application to parasitoid monitoring in the field

Compared with the extensive body of research on the olfactory behavior of parasitoids of leaf-feeding insects, less is known about the fine-tuning of olfactory behavior in parasitoids that use fruit-feeding insects as hosts. We investigated whether a tephritid fruit fly parasitoid, Diachasmimorpha kraussii (Fullaway) (Hymenoptera: Braconidae), could discriminate between odors of fruits infested by larvae of a host species, Bactrocera tryoni (Froggatt) (Diptera: Tephritidae), compared to fruits infested by non-host larvae, Drosophila melanogaster (Diptera: Drosophilidae). Female wasps showed a significant preference for nectarines infested with B. tryoni, over uninfested fruits or fruits infested with D. melanogaster. When wasps were given prior experience of host or nonhost infested fruit, females demonstrated an increased ability to discriminate between host and nonhost related odors, but only when they were conditioned on host-infested (as opposed to nonhost infested) fruit. Insects provided with both host and nonhost stimuli showed no greater discriminatory learning compared to those provided with the rewarding stimuli alone. Previous experience also influenced postalighting behavior. Naïve females, and females with experience ovipositing at the top of fruit, oriented preferentially to the top of fruits upon alighting, while those with experience ovipositing at the base of fruits showed a significant difference in orientation, with 70% of wasps orientating preferentially toward the base. Similar learning-related changes were seen in search time and probing behavior. We discuss how pre- and post-alighting learning fine-tunes the behavioral responses of foraging wasps to their local environment.

Learning Influences Host Versus Nonhost Discrimination and Postalighting Searching Behavior in the Tephritid Fruit Fly Parasitoid Diachasmimorpha kraussii (Hymenoptera: Braconidae).

The Queensland fruit fly, Bactrocera tryoni, is considered one of the worst horticultural pests in Australia attacking a large variety of fruit crops. To defeat pest insects, olfactory attractants have been developed and widely used in lure and kill strategies. Male B. tryoni are strongly attracted to the compound raspberry ketone and its synthetic analog, cuelure. Despite the strong behavioral response, a recent study failed to show any activation of antennal receptors to cuelure. Therefore, we hypothesized that cuelure may be detected by an accessory olfactory organ, the maxillary palp. Combining behavioral and physiological experiments we clearly demonstrate that male flies, but not female flies, primarily use the maxillary palps and not the antennae to detect and respond to cuelure. Furthermore, regardless of satiety status, male flies always preferred cuelure over a sugar rich source, unless the maxillary palps were excised.

Behavioral and Physiological Evidence for Palp Detection of the Male-Specific Attractant Cuelure in the Queensland Fruit Fly (Bactrocera tryoni)

Two Gut-Associated Yeasts in a Tephritid Fruit Fly have Contrasting Effects on Adult Attraction and Larval Survival

Do Fruit Ripening Volatiles Enable Resource Specialism in Polyphagous Fruit Flies?

Bactrocera tryoni (Froggatt) is Australia's major horticultural insect pest, yet monitoring females remains logistically difficult. We trialled the ‘Ladd trap’ as a potential female surveillance or monitoring tool. This trap design is used to trap and monitor fruit flies in countries other (e.g. USA) than Australia. The Ladd trap consists of a flat yellow panel (a traditional ‘sticky trap’), with a three dimensional red sphere (= a fruit mimic) attached in the middle. We confirmed, in field‐cage trials, that the combination of yellow panel and red sphere was more attractive to B. tryoni than the two components in isolation. In a second set of field‐cage trials, we showed that it was the red‐yellow contrast, rather than the three dimensional effect, which was responsible for the trap's effectiveness, with B. tryoni equally attracted to a Ladd trap as to a two‐dimensional yellow panel with a circular red centre. The sex ratio of catches was approximately even in the field‐cage trials. In field trials, we tested the traditional red‐sphere Ladd trap against traps for which the sphere was painted blue, black or yellow. The colour of sphere did not significantly influence trap efficiency in these trials, despite the fact the yellow‐panel/yellow‐sphere presented no colour contrast to the flies. In 6 weeks of field trials, over 1500 flies were caught, almost exactly two‐thirds of them being females. Overall, flies were more likely to be caught on the yellow panel than the sphere; but, for the commercial Ladd trap, proportionally more females were caught on the red sphere versus the yellow panel than would be predicted based on relative surface area of each component, a result also seen the field‐cage trial. We determined that no modification of the trap was more effective than the commercially available Ladd trap and so consider that product suitable for more extensive field testing as a B. tryoni research and monitoring tool.

‘Ladd traps’ as a visual trap for male and female Queensland fruit fly, Bactrocera tryoni (Diptera: Tephritidae)

We provide the first evidence for interspecific warfare in bees, a spectacular natural phenomenon that involves a series of aerial battles and leads to thousands of fatalities from both attacking and defending colonies. Molecular analysis of fights at a hive of the Australian stingless bee Tetragonula carbonaria revealed that the attack was launched by a related species, Tetragonula hockingsi, which has only recently extended its habitat into southeastern Queensland. Following a succession of attacks by the same T. hockingsi colony over a 4-month period, the defending T. carbonaria colony was defeated and the hive usurped, with the invading colony installing a new queen. We complemented our direct observations with a 5-year study of more than 260 Tetragonula hives and found interspecific hive changes, which were likely to be usurpation events, occurring in 46 hives over this period. We discuss how fighting swarms and hive usurpation fit with theoretical predictions on the evolution of fatal fighting and highlight the many unexplained features of these battles that warrant further study.

Bees at War: Interspecific Battles and Nest Usurpation in Stingless Bees

ABSTRACT 
 Heliothine moths (Lepidoptera: Heliothinae) include some of the world's most devastating pest species. Whereas the majority of nonpest heliothinae specialize on a single plant family, genus, or species, pest species are highly polyphagous, with populations often escalating in size as they move from one crop species to another. Here, we examine the current literature on heliothine host-selection behavior with the aim of providing a knowledge base for research scientists and pest managers. We review the host relations of pest heliothines, with a particular focus on Helicoverpa armigera (Hübner), the most economically damaging of all heliothine species. We then consider the important question of what constitutes a host plant in these moths, and some of the problems that arise when trying to determine host plant status from empirical studies on host use. The top six host plant families in the two main Australian pest species (H. armigera and Helicoverpa punctigera Wallengren) are the same and the top three (Asteraceae, Fabaceae, and Malvaceae) are ranked the same (in terms of the number of host species on which eggs or larvae have been identified), suggesting that these species may use similar cues to identify their hosts. In contrast, for the two key pest heliothines in the Americas, the Fabaceae contains ≈1/3 of hosts for both. For Helicoverpa zea (Boddie), the remaining hosts are more evenly distributed, with Solanaceae next, followed by Poaceae, Asteraceae, Malvaceae, and Rosaceae. For Heliothis virescens (F.), the next highest five families are Malvaceae, Asteraceae, Solanaceae, Convolvulaceae, and Scrophulariaceae. Again there is considerable overlap in host use at generic and even species level. H. armigera is the most widely distributed and recorded from 68 plant families worldwide, but only 14 families are recorded as a containing a host in all geographic areas. A few crop hosts are used throughout the range as expected, but in some cases there are anomalies, perhaps because host plant relation studies are not comparable. Studies on the attraction of heliothines to plant odors are examined in the context of our current understanding of insect olfaction, with the aim of better understanding the connection between odor perception and host choice. Finally, we discuss research into sustainable management of pest heliothines using knowledge of heliothine behavior and ecology. A coordinated international research effort is needed to advance our knowledge on host relations in widely distributed polyphagous species instead of the localized, piecemeal approaches to understanding these insects that has been the norm to date.

Understanding Heliothine (Lepidoptera: Heliothinae) Pests: What is a Host Plant?

Evolutionary theory predicts that herbivorous insects should lay eggs on plants in a way that reflects the suitability of each plant species for larval development. Empirical studies, however, often fail to find any relationship between an adult insect’s choice of host–plant and offspring fitness, and in such cases, it is generally assumed that other ‘missing’ factors (e.g. predation, host–plant abundance, learning and adult feeding sites) must be contributing to overall host suitability. Here, I consider an alternative theory – that a fitness cost inherent in the olfactory mechanism could constrain the evolution of insect host selection. I begin by reviewing current knowledge of odour processing in the insect antennal lobe with the aid of a simple schematic: the aim being to explain the workings of this mechanism to scientists who do not have prior knowledge in this field. I then use the schematic to explore how an insect’s perception of host and non‐host odours is governed by a set of processing rules, or algorithm. Under the assumptions of this mechanistic view, the perception of every plant odour is interrelated, and seemingly bad host choices can still arise as part of an overall adaptive behavioural strategy. I discuss how an understanding of mechanism can improve the interpretation of theoretical and empirical studies in insect behaviour and evolution.

Cotton growing landscapes in Australia have been dominated by dual-toxin transgenic Bt varieties since 2004. The cotton crop has thus effectively become a sink for the main target pest, Helicoverpa armigera. Theory predicts that there should be strong selection on female moths to avoid laying on such plants. We assessed oviposition, collected from two cotton-growing regions, by female moths when given a choice of tobacco, cotton and cabbage. Earlier work in the 1980s and 1990s on populations from the same geographic locations indicated these hosts were on average ranked as high, mid and low preference plants, respectively, and that host rankings had a heritable component. In the present study, we found no change in the relative ranking of hosts by females, with most eggs being laid on tobacco, then cotton and least on cabbage. As in earlier work, some females laid most eggs on cotton and aspects of oviposition behaviour had a heritable component. Certainly, cotton is not avoided as a host, and the implications of these finding for managing resistance to Bt cotton are discussed.

No evidence for change in oviposition behaviour of Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae) after widespread adoption of transgenic insecticidal cotton.

The host location behaviour of foraging caterpillars has received little attention, despite the wealth of theoretical and empirical studies that have been directed at this behavioural trait in adult Lepidoptera. Here, we study caterpillars of the moth Heliothis punctifera Walker (Lepidoptera: Noctuidae), which inhabits the arid inland desert areas of Australia. Caterpillars of this species consume many flowerheads before completing development and can be observed moving across the sand in search of new hosts. Consequently, if host location behaviour favours attraction to certain plant species, it might be expected to influence the distribution and abundance of caterpillars in the field. We present field data showing that H. punctifera caterpillars are unevenly distributed throughout mixed patches of two of its host species, with a higher abundance on Senecio gregorii F. Muell., the annual yellow top, compared to Myriocephalus stuartii (F. Muell. & Sond.) Benth., the poached egg daisy (both Asteraceae). Using laboratory studies, we test whether this distribution may, in part, be due to host location behaviour of caterpillars. Our results show that caterpillars exhibit a preference for locating S. gregorii in their pre‐ and post‐contact foraging behaviour. In addition, our results provide evidence that feeding history plays a role in host location behaviour in this insect. We propose that key features of the desert environment and the ecology of H. punctifera would favour adaptations to host location behaviour by immatures.

Host location behaviour in the desert caterpillar, Heliothis punctifera

SUMMARY It is well established that herbivorous insects respond to changes in plant odour production, but little attention has been given to whether these responses relate to direct fitness costs of plant volatile production on insect growth and survival. Here, we use transgenic Nicotiana tabacum (tobacco) plants that produce relatively large amounts of the volatile (S)-linalool to study whether the responses of egg-laying herbivorous insects to linalool production relate directly to the growth and survival of offspring. In choice tests, fewer eggs were laid on transgenic plants compared with non-transformed controls, indicating that increased linalool emissions have a deterrent effect on Helicoverpa armigera oviposition. Larval survival and larval mass after feeding on transgenic leaves, however, was comparable to non-transformed controls. (S)-linalool, whether in volatile or sequestered form, does not appear to have a direct effect on offspring fitness in this moth. We discuss how the ecology of this polyphagous moth species may necessitate a high tolerance for certain volatiles and their related non-volatile compounds, and suggest that responses by adult female H. armigera moths towards increased linalool production may be context specific and relate to other indirect effects on fitness.

Increased plant volatile production affects oviposition, but not larval development, in the moth Helicoverpa armigera

How host plant variability influences the advantages to learning: a theoretical model for oviposition behaviour in Lepidoptera.

ABSTRACT Wolbachia pipientis is an endosymbiotic bacterium present in diverse insect species. Although it is well studied for its dramatic effects on host reproductive biology, little is known about its effects on other aspects of host biology, despite its presence in a wide array of host tissues. This study examined the effects of three Wolbachia strains on two different Drosophila species, using a laboratory performance assay for insect locomotion in response to olfactory cues. The results demonstrate that Wolbachia infection can have significant effects on host responsiveness that vary with respect to the Wolbachia strain-host species combination. The wRi strain, native to Drosophila simulans, increases the basal activity level of the host insect as well as its responsiveness to food cues. In contrast, the wMel strain and the virulent wMelPop strain, native to Drosophila melanogaster, cause slight decreases in responsiveness to food cues but do not alter basal activity levels in the host. Surprisingly, the virulent wMelPop strain has very little impact on host responsiveness in D. simulans. This novel strain-host relationship was artificially created previously by transinfection. These findings have implications for understanding the evolution and spread of Wolbachia infections in wild populations and for Wolbachia-based vector-borne disease control strategies currently being developed.

Wolbachia Infection Alters Olfactory-Cued Locomotion in Drosophila spp

Coordination of Early Protective Immunity to Viral Infection by Regulatory T Cells

Mixtures of single odours were used to explore the receptor response profile across individual antennae of Helicoverpa armigera (Hubner) (Lepidoptera: Noctuidae). Seven odours were tested including floral and green-leaf volatiles: phenyl acetaldehyde, benzaldehyde, β-caryophyllene, limonene, α-pinene, 1-hexanol, 3Z-hexenyl acetate. Electroantennograms of responses to paired mixtures of odours showed that there was considerable variation in receptor tuning across the receptor field between individuals. Data from some moth antennae showed no additivity, which indicated a restricted receptor profile. Results from other moth antennae to the same odour mixtures showed a range of partial additivity. This indicated that a wider array of receptor types was present in these moths, with a greater percentage of the receptors tuned exclusively to each odour. Peripheral receptor fields show variation in the spectrum of response within a population (of moths) when exposed to high doses of plant volatiles. This may be related to recorded variation in host choice within moth populations as reported by other authors.

Variability in odour reception in the peripheral sensory system of Helicoverpa armigera (Hubner) (Lepidoptera : Noctuidae)

Odours emitted by flowers are complex blends of volatile compounds. These odours are learnt by flower-visiting insect species, improving their recognition of rewarding flowers and thus foraging efficiency. We investigated the flexibility of floral odour learning by testing whether adult moths recognize single compounds common to flowers on which they forage. Dual choice preference tests on Helicoverpa armigera moths allowed free flying moths to forage on one of three flower species; Argyranthemum frutescens (federation daisy), Cajanus cajan (pigeonpea) or Nicotiana tabacum (tobacco). Results showed that, (i) a benzenoid (phenylacetaldehyde) and a monoterpene (linalool) were subsequently recognized after visits to flowers that emitted these volatile constituents, (ii) in a preference test, other monoterpenes in the flowers' odour did not affect the moths' ability to recognize the monoterpene linalool and (iii) relative preferences for two volatiles changed after foraging experience on a single flower species that emitted both volatiles. The importance of using free flying insects and real flowers to understand the mechanisms involved in floral odour learning in nature are discussed in the context of our findings.

Insect odour perception: recognition of odour components by flower foraging moths

L'invention concerne des particules de medicament a liberation prolongee convenant pour la preparation de compositions pharmaceutiques a liberation prolongee, administrees par voie orale. Ces particules de medicament a liberation prolongee comprennent un complexe medicament-resine echangeuse d'ions, et une barriere de diffusion permeable a l'eau entourant au moins une partie du complexe medicament-resine echangeuse d'ions. La barriere de diffusion comprend un polymere filmogene et ne contient pas, ou pas de traces notables, de solvant organique. L'invention concerne egalement des compositions pharmaceutiques a administration orale, par exemple des suspensions a administration orale, contenant ces particules de medicament a liberation prolongee, une methode permettant l'administration regulee d'un medicament a un patient, et un procede permettant de preparer les particules de medicament a liberation prolongee. Ce procede de preparation comprend l'utilisation d'une composition d'enrobage aqueuse contenant un polymere filmogene permeable a l'eau, tel que l'ethylcellulose.

Intra-specific variation for host plant use in Helicoverpa armigera (Hubner) (Lepidoptera : Noctuidae) : implications for management

L'invention concerne une nouvelle composition pharmaceutique de resine granulaire a liberation prolongee comprenant une resine echangeuse d'ions complexee avec une substance pharmaceutique, ce complexe etant incorpore dans une substance a barriere de diffusion et applique sur sa surface. L'invention concerne egalement un nouveau procede destine a preparer ce complexe granule et consistant a utiliser un vehicule de granulation aqueux pour former le complexe et le produit granule, ce qui permet d'eviter l'utilisation de revetements et de grandes quantites de solvants organiques dans le procede.

Preparation granulaire a liberation prolongee et production de cette preparation

Discrepancy Between Antennal and Behavioral Responses for Enantiomers of α-Pinene: Electrophysiology and Behavior of Helicoverpa armigera (Lepidoptera)

SUMMARY Floral volatiles play a major role in plant–insect communication. We examined the influence of two volatiles, phenylacetaldehyde andα -pinene, on the innate and learnt foraging behaviour of the moth Helicoverpa armigera. In dual-choice wind tunnel tests, adult moths flew upwind towards both volatiles, with a preference for phenylacetaldehyde. When exposure to either of these volatiles was paired with a feeding stimulus (sucrose), all moths preferred the learnt odour in the preference test. This change in preference was not seen when moths were exposed to the odour without a feeding stimulus. The learnt preference for the odour was reduced when moths were left unfed for 24 h before the preference test. We tested whether moths could discriminate between flowers that differed in a single volatile component. Moths were trained to feed on flowers that were odour-enhanced using either phenylacetaldehyde or α-pinene. Choice tests were then carried out in an outdoor flight cage, using flowers enhanced with either volatile. Moths showed a significant preference for the flower type on which they were trained. Moths that were conditioned on flowers that were not odour-enhanced showed no preference for either of the odour-enhanced flower types. The results imply that moths may be discriminating among odour profiles of individual flowers from the same species. We discuss this behaviour within the context of nectar foraging in moths and odour signalling by flowering plants.

We develop a general theoretical framework for exploring the host plant selection behaviour of herbivorous insects. This model can be used to address a number of questions, including the evolution of specialists, generalists, preference hierarchies, and learning. We use our model to: (i) demonstrate the consequences of the extent to which the reproductive success of a foraging female is limited by the rate at which they find host plants (host limitation) or the number of eggs they carry (egg limitation); (ii) emphasize the different consequences of variation in behaviour before and after landing on (locating) a host (termed pre- and post-alighting, respectively); (iii) show that, in contrast to previous predictions, learning can be favoured in post-alighting behaviour--in particular, individuals can be selected to concentrate oviposition on an abundant low-quality host, whilst ignoring a rare higher-quality host; (iv) emphasize the importance of interactions between mechanisms in favouring specialization or learning.

A general model for host plant selection in phytophagous insects.

Insect learning can change the preferences an egg laying female displays towards different host plant species. Current hypotheses propose that learning may be advantageous in adult host selection behaviour through improved recognition, accuracy or selectivity in foraging. In this paper, we present a hypothesis for when learning can be advantageous without such improvements in adult host foraging. Specifically, that learning can be an advantageous strategy for egg laying females when larvae must feed on more than one plant in order to complete development, if the fitness of larvae is reduced when they switch to a different host species. Here, larvae benefit from developing on the most abundant host species, which is the most likely choice of host for an adult insect which increases its preference for a host species through learning. The hypothesis is formalised with a mathematical model and we provide evidence from studies on the behavioural ecology of a number of insect species which demonstrate that the assumptions of this hypothesis may frequently be fulfilled in nature. We discuss how multiple mechanisms may convey advantages in insect learning and that benefits to larval development, which have so far been overlooked, should be considered in explanations for the widespread occurrence of learning.

Host selection in phytophagous insects: a new explanation for learning in adults

Recent experimental evidence has shown that learning occurs in the host selection behaviour of Helicoverpa armigera (Hubner), one of the world‘s most important agricultural pests. This paper discusses how the occurrence of learning changes our understanding of the host selection behaviour of this polyphagous moth. Host preferences determined from previous laboratory studies may be vastly different from preferences exhibited by moths in the field, where the abundance of particular hosts may be more likely to determine host preference. In support of this prediction, a number of field studies have shown that the ‘attractiveness’ of different hosts for H. armigera oviposition may depend on the relative abundance of these host species. Insect learning may play a fundamental role in the design and application of present and future integrated pest management strategies such as the use of host volatiles, trap crops and resistant crop varieties for monitoring and controlling this important pest species.

Learning in Helicoverpa armigera (Lepidoptera: Noctuidae): a new look at the behaviour and control of a polyphagous pest

Abstract.1. Learning may enable insects to obtain nectar from flowers more efficiently. Learning in nectar foraging has been shown primarily in studies of bees and butterflies. Here, learning is demonstrated in the nectar foraging behaviour of a noctuid moth, Helicoverpa armigera.

Learning in the nectar foraging behaviour of Helicoverpa armigera

The effect of experience on pre- and post-alighting host selection in adult female Helicoverpa armigera was tested in an indoor flight cage, and in a large greenhouse. The moths had experienced either tobacco or tomato plants (both are hosts of H. armigera) for 3 days, or were given no experience. Individuals were then released and their host selection assessed. All individuals caught in the greenhouse were identified and tested for post-alighting acceptance on each host. Experience significantly influenced both pre- and post-alighting host selection in ovipositing moths. This modification in behaviour is attributed to 'learning', and presents the first detailed evidence for learning in moths. Possible behavioural mechanisms involved are discussed, and a hypothesis is presented regarding learning in post-alighting host acceptance. The existence of learning in H. armigera, a highly polyphagous agricultural pest, is discussed in the light of current theories on environmental predictability and the advantages of learning. Copyright 1998 The Association for the Study of Animal Behaviour.

Learning in host selection in
 Helicoverpa armigera
 (Hübner) (Lepidoptera: Noctuidae)

Composition servant a la liberation prolongee d'un agent therapeutique biologiquement actif, dont la matrice est composee d'un glucide transparent amorphe comprenant un glucide approprie et un agent retardant la recristallisation du glucide, ainsi qu'un agent therapeutique biologiquement actif et une cire insoluble dans l'eau dispersee dans ladite matrice. Les agents therapeutiques biologiquement actifs pouvant etre incorpores dans la matrice en glucide transparent comprennent la prolactine, les hormones de croissance, les albumines seriques, les facteurs de croissance ou tout fragment biologiquement actif ou toute forme recombinante dudit fragment.

Matrice en glucide transparent servant la liberation prolongee d'un agent therapeutique

Glassy kohlenhydratenmatrize for administration of therapeutic agents sustained release

‘Yuchi’ arrowleaf clover (Trifolium vesiculosum Savi) produced more tillers and remained productive longer when cut at 1−, 2−, or 3−week intervals than at 4−, 5−, or 6−week intervals. Total yields were higher from less frequent cutting. Digestible dry matter (DDM) was high from December to maturity in June under all cutting frequencies. Stems of arrowleaf clover were higher in DDM than crimson clover (Trifolium incarnatum L.).

Management Effects on Forage Production and Digestibility of Yuchi Arrowleaf Clover (Trifolium vesiculosum Savi) 1

The thermal and photochemical decompositions of mercury dimethyl have been studied in presence and absence of hydrogen. The thermal process occurs measurably above 290° in absence of hydrogen and is complex, yielding ethane, methane and carbonaceous products. In presence of hydrogen there is no carbonaceous deposit and methane is predominantly formed with consumption of hydrogen, which accelerates the decomposition. The influence of surface effects has been noted. The photo‐decomposition has been studied from 50–300°C. In absence of hydrogen, ethane is practically exclusively formed up to 200°. In presence of hydrogen, methane is formed at all temperatures, in increasing amounts with increase of temperature. A mechanism based on photo‐decomposition to free methyl radicals with association to yield ethane and reaction with hydrogen to yield methane has been quantitatively determined. For the activation energy CH3+H2=CH4+H a value of 9±2 kcal. has been deduced.

A method is described for determining the approximate average rate at which the California mussel, Mytilus californianus, propels water through its gill chambers.The method consists of analyses at frequent intervals of the amount of calcium remaining in suspension (as CaCO3) in a given volume of continually stirred water containing the mussels, which remove the suspended material as they pass the water through their chambers.Mathematical treatment and interpretation of the data obtained, support the conclusions that (1) virtually all of the suspended matter is removed as the water passes over the mucous surfaces of the gills and mantle of the mussel; (2) the mussel propels the water rhythmically through its filtering system at a rate which on an average is constant, varying according to the size and perhaps also according to other physiological attributes of the animals. In medium-sized animals (of 95 to 130 mm. length) the propulsion rate may vary between extreme values of 2.2 and 2.9 liters per hour, an...

The kidneys are frequently involved in several systemic conditions, including autoimmune disorders, vasculitides, haematological conditions, malignancy, and disorders of other organ systems. Moreover, drugs used to treat these conditions could have an effect on the kidneys, presenting as acute kidney injury (AKI), electrolyte disorders due to disruption of the absorptive function of the kidneys, or as a form of glomerulonephritis. Due to the high vasculature and volume of blood flow in the kidneys, autoimmune disorders and vasculitides have been reported to cause immune-complex mediated disorders and inflammatory lesions of both glomeruli and tubulointerstitium. Likewise, monoclonal gammopathies have a propensity for the kidneys, with several reported phenotypes causing characteristic renal lesions. Due to the high capacity for glomerular filtration and excretory function, the kidneys are often the insult of disorders of cellular breakdown such as pigment disorders or tumour lysis syndrome, where AKI is common, resulting in a reduced ability for electrolyte homeostasis. Finally, both cardiorenal and hepatorenal syndromes have been well described, highlighting the interdependency of various organ systems and the pathological response of the kidneys to disorders of heart and liver.

1. Clinical assessment of the renal patient 2. Acute renal failure 3. Chronic kidney disease 4. Renal replacement therapies 5. Hypertension 6. Diseases of the kidney 7. The kidney in systemic disease 8. Urinary tract obstruction 9. Fluid and electrolytes 10. Pregnancy and the kidney 11. Drugs and the kidney 12. Appendices

Kidney transplantation is associated with an increased risk of bone fracture and rapid loss of bone mineral density after kidney transplantation.

Randomized controlled trial.

SETTING & PARTICIPANTS
Patients were randomly assigned to treatment (n = 46) or control (no treatment; n = 47) groups. Patients were stratified according to parathyroid hormone level and sex. Those with parathyroid hormone level less than 150 pg/mL were excluded.

The treatment and control groups received pamidronate, 1 mg/kg, perioperatively and then at 1, 4, 8, and 12 months or no treatment, respectively. All received calcium (500 mg) and vitamin D (400 units) daily. Immunosuppression was cyclosporine and prednisolone, with no difference in dosing between the 2 groups.

OUTCOMES & MEASUREMENTS
Bone mineral density was evaluated by means of dual-energy x-ray absorptiometry of the lumbar spine and hip at baseline and 3, 6, 12, and 24 months, with the primary end point at 1 year of percentage of change in bone mineral density from baseline. Clinical fractures were recorded and also evaluated by means of spinal radiographs at baseline and 1 and 2 years.

RESULTS
Pamidronate protected bone mineral density at the lumbar spine; bone mineral density increased by 2.1% in the treatment group and decreased by 5.7% in the control group at 12 months (P = 0.001). Protection was also seen in Ward's area of the hip (P = 0.002) and the total hip (P = 0.004). There was no difference in femoral neck bone mineral density loss between the 2 groups. Fracture rates in the treatment and control groups were 3.3% and 6.4% per annum, respectively.

This study was not powered to detect differences in fracture rates.

Pamidronate protects against posttransplantation bone loss at the lumbar spine and Ward's area of the hip.

Effect of pamidronate on bone loss after kidney transplantation: a randomized trial.

in the COL4A5 collagen gene in suspected Alport syndrome using PCR and direct DNA sequencing. J Am Soc Nephrol 1998; 9: 2291–2301 28. Mazzucco G, Barsotti P, Muda AO et al. Ultrastructural and immunohistochemical findings in Alport’s syndrome: a study of 108 patients from 97 Italian families with particular emphassis on COL4A5 gene mutation correlations. J Amer Soc Nephrol 1998; 9: 1023–1031 29. Zheng K, Thorner PS, Marrano P, Baumal R, McInnes RR. Canine X chromosome-linked hereditary nephritis: a genetic model for human X-linked hereditary nephritis resulting from a single base mutation in the gene encoding the a5 chain of collagentype IV. Proc Natl Acad Sci USA 1994; 91: 3989–3993 30. Cox M, Lees GE, Kashtan CE, Murphy KE. Genetic cause of X-linked Alport syndrome in a family of domestic dogs. Mamm Genome 2003; 14: 396–403 31. Rheault MN, Kren SM, Thielen BK et al. Mouse model of X-linked Alport syndrome. J Am Soc Nephrol 2004; 15: 1466–1474 32. Ding J, Stitzel J, Berry P, Hawkins E, Kashtan C. Autosomal recessive Alport syndrome: mutation in the COL4A3 gene in a woman with Alport syndrome and posttransplant antiglomerular basement membrane nephritis. J Amer Soc Nephrol 1995; 5: 1714–1717

The ACR Committee on Appropriateness Criteria and its expert panels have developed criteria for determining appropriate imaging examinations for diagnosis and treatment of specified medical condition(s). These criteria are intended to guide radiologists, radiation oncologists and referring physicians in making decisions regarding radiologic imaging and treatment. Generally, the complexity and severity of a patient’s clinical condition should dictate the selection of appropriate imaging procedures or treatments. Only those examinations generally used for evaluation of the patient’s condition are ranked. Other imaging studies necessary to evaluate other co-existent diseases or other medical consequences of this condition are not considered in this document. The availability of equipment or personnel may influence the selection of appropriate imaging procedures or treatments. Imaging techniques classified as investigational by the FDA have not been considered in developing these criteria; however, study of new equipment and applications should be encouraged. The ultimate decision regarding the appropriateness of any specific radiologic examination or treatment must be made by the referring physician and radiologist in light of all the circumstances presented in an individual examination.

Fibrous histiocytoma of the bronchus: treatment by segmental resection.

Endoscopically performed biliary drainage (EPBD) is now an alternative to percutaneous biliary drainage. The morbidity, mortality, and survival statistics of 97 patients with obstructive jaundice who had undergone percutaneous transhepatic biliary drainage (PTBD) and surgery, PTBD alone, EPBD and surgery, or EPBD alone were compared. Overall, the EPBD group had fewer complications and lower mortality than the other groups. When palliative treatment of patients with malignancies was compared, the complication rates associated with EPBD and PTBD were similar; however, mortality was lower with EPBD. No negative effect on survival was found with EPBD. In addition, EPBD offered several additional advantages over PTBD, including fewer bleeding complications, better patient acceptance, and avoidance of external catheter care. EPBD should be considered as a viable alternative to PTBD. Additional studies are needed to determine whether it is to be considered the initial drainage procedure of choice in patients with obstructive jaundice.

Biliary decompression: an institutional comparison of percutaneous and endoscopic methods.

Radiologic evaluation of the biliary tract of the jaundiced patient.

Five patients with coexistent carcinoma of the lung and active tuberculosis within the same pulmonary lesion were studied. These cases represent five distinctly varying radiographic presentations and point out the extreme diversity of the morphological pictures of this particular disease combination. Physicians who regularly deal with patients who might present with either entity alone are cautioned to be alert to the possibility that these two diseases may be present simultaneously within single, specific pulmonary lesions.

Carcinoma of the lung and coexistent active pulmonary tuberculosis: diverse morphologic and radiographic presentations.

Carcinoma of the esophagus is a devastating disease that produces various degrees of esophageal obstruction by virtue of its circumferential, constricting type of growth pattern. Because of the relatively small diameter of the esophageal lumen, a limited-sized tumor can produce severe obstructive symptoms. Carcinoma of the esophagus is, as a rule, fairly well localized to its wall or the immediate mediastinal parietes in cases where there is extension beyond the esophageal musculature.(1) Large, bulky, exophytic types of esophageal carcinomas that produce symptoms mainly as a result of extrinsic pressure are unusual.

A case of vanishing bone disease is presented, with radiologic, endoscopic, and peritoneoscopic evidence of angiomatous involvement of the bones, surrounding soft tissues, and gastrointestinal tract. The diagnosis was made by a combination of radiologic techniques and endoscopy. Areas of absent bone were shown to opacify after intralymphatic injections of contrast material, providing in vivo demonstrations that these areas of vanishing bone are occupied by abnormal lymphatics. The etiology remains obscure, but our review of the literature suggests that this condition may be one of a large spectrum of disorders due to a basic underlying endothelial dysplasia. The lymphatic system, vascular system, or both may be involved, and the condition may manifest itself as an abnormality of the bones, soft tissues, viscera, or a combination of these.

Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer

Terahertz (THz) radiation encompasses a wide spectral range within the electromagnetic spectrum that extends from microwaves to the far infrared (100 GHz–∼30 THz). Within its frequency boundaries exist a broad variety of scientific disciplines that have presented, and continue to present, technical challenges to researchers. During the past 50 years, for instance, the demands of the scientific community have substantially evolved and with a need for advanced instrumentation to support radio astronomy, Earth observation, weather forecasting, security imaging, telecommunications, non-destructive device testing and much more. Furthermore, applications have required an emergence of technology from the laboratory environment to production-scale supply and in-the-field deployments ranging from harsh ground-based locations to deep space. In addressing these requirements, the research and development community has advanced related technology and bridged the transition between electronics and photonics that high frequency operation demands. The multidisciplinary nature of THz work was our stimulus for creating the 2017 THz Science and Technology Roadmap (Dhillon et al 2017 J. Phys. D: Appl. Phys. 50 043001). As one might envisage, though, there remains much to explore both scientifically and technically and the field has continued to develop and expand rapidly. It is timely, therefore, to revise our previous roadmap and in this 2023 version we both provide an update on key developments in established technical areas that have important scientific and public benefit, and highlight new and emerging areas that show particular promise. The developments that we describe thus span from fundamental scientific research, such as THz astronomy and the emergent area of THz quantum optics, to highly applied and commercially and societally impactful subjects that include 6G THz communications, medical imaging, and climate monitoring and prediction. Our Roadmap vision draws upon the expertise and perspective of multiple international specialists that together provide an overview of past developments and the likely challenges facing the field of THz science and technology in future decades. The document is written in a form that is accessible to policy makers who wish to gain an overview of the current state of the THz art, and for the non-specialist and curious who wish to understand available technology and challenges. A such, our experts deliver a ‘snapshot’ introduction to the current status of the field and provide suggestions for exciting future technical development directions. Ultimately, we intend the Roadmap to portray the advantages and benefits of the THz domain and to stimulate further exploration of the field in support of scientific research and commercial realisation.

In this work, near-field imaging of terahertz (THz)-frequency spoof surface plasmons (SSPs) supported by a variety of metal/dielectric metamaterial structures is reported. Our s-SNOM technique demonstrates deep sub-wavelength mapping of the field distribution associated with in-plane resonator modes in plasmonic dipole antennas and split ring resonator structures, as well as SSPs propagating on planar waveguide structures. Experimental results are compared with finite-element simulations and show excellent agreement. Furthermore, all-electronic coherent THz-s-SNOM has been employed to resolve the amplitude and phase images of localized plasmons in dipole antenna structures.

2022 47th International Conference on Infrared, Millimeter and Terahertz Waves (IRMMW-THz)

This work proposes a new flexible terahertz subwavelength fiber using commercial optical fiber as the core medium. The proposed dual-band fiber allows the optical signals to propagate in the innermost two layers and the THz signal to distributed over the optical fiber and mostly in the lossless foam cladding. The propagation loss at 1550 nm and 500 μm are 0.2 dB/km and 0.034 dB/mm, respectively. The proposed fiber is compact and cost-effective, making it a promising candidate for optical and terahertz fusion sensing, imaging, and nonlinear optoelectronics applications.

2021 46th International Conference on Infrared, Millimeter and Terahertz Waves (IRMMW-THz)

While models of terahertz frequency plasmons in 2D electron systems are usually developed by reducing the number of spatial dimensions, fully 3D models may be needed for the design and analysis of realistic structures. Using full-wave electromagnetic simulations, we have analysed the plasmons and magnetoplasmons observed in two recent experiments. Here, we demonstrate agreement between the theoretical and the experimental results, and discuss further device characteristics such as plasmon transmission, reflection, absorption, and field distributions. We then compare the 3D full-wave simulations with a 2D model. Finally, we discuss approaches for increasing signal transmission and reducing reflection, with direct relevance for improving future experiments.

Full-wave modelling of terahertz frequency plasmons in two-dimensional electron systems

TH1E: Components, systems and applications for mm wave and THz imaging

Acoustoelectric charge transport in quasi-one-dimensional systems

Two quantum systems with energy levels in resonance with each other experience a splitting of these levels when the wavefunctions of the systems overlap. In semiconductor structures consisting of pairs of closely spaced quantum wells the wavefunction overlap of charge carriers in the wells leads to a novel kind of intersubband transition. To date, this transition has been studied by interband absorption and luminescence and, most recently, by four-wave-mixing experiments [Leo, 1990]. Here, we report of the first direct absorption measurements of the split-subband transition in coupled quantum wells.

Terahertz absorption between split subbands in coupled quantum wells

Studies of exciton recombination and transport in high purity GaAs using high resolution nonlinear spectroscopy

Impact of MOF defects on the binary adsorption of CO2 and water in UiO-66

Studies of Template-based Photometric Classification of Supernovae

Type Ia supernovae selection and forecast of cosmology constraints for the Dark Energy Survey

Optimization of Type Ia Supernovae Selection, Photometric Typing, and Cosmology Constraints

Nuclear Instruments & Methods in Physics Research Section A-accelerators Spectrometers Detectors and Associated Equipment

We present the result of a search for charged Higgs decays of the top quark, produced in pp̄ collisions at √ s = 1.8 TeV. When the charged Higgs is heavy and decays to a tau lepton, which subsequently decays hadronically, the resulting events have a unique signature: large missing transverse energy and the low-charged-multiplicity tau. Data collected in the period 1992-1993 at the Collider Detector at Fermilab, corresponding to 18.7±0.7 pb, exclude new regions of combined top quark and charged Higgs mass, in extensions to the standard model with two Higgs doublets.

Search for charged Higgs decays of the top quark using hadronic tau decays

We present a measurement of σ · B(W → eν) and σ · B(Z → ee) in proton antiproton collisions at √ s = 1.8 TeV using a significantly improved understanding of the integrated luminosity. The data represent an integrated luminosity of 19.7 pb from the 1992-1993 run with the Collider Detector at Fermilab (CDF). We find σ · B(W → eν) = 2.49 ± 0.12 nb and σ · B(Z → ee) = 0.231 ± 0.012 nb. PACS Numbers: 13.38.-b, 13.60.Hb, 14.70.-e Measurements of the product of the production cross section and the leptonic branching ratio for W and Z bosons, σ · B(W → eν) and σ · B(Z → ee), test the consistency of the standard model couplings [1], the understanding of higher order QCD contributions [2], and the parton distribution functions of the proton. In perturbation theory, the production cross section is predicted to next-to-next-to-leading order (NNLO), with ≈ 20% corrections to the leading order prediction from NLO and additional ≈ 3% corrections at NNLO [2]. In previous measurements at √ s = 1.8 TeV [3, 4, 5], the accuracy of the comparison to theoretical predictions has been limited by systematic uncertainties in the overall normalization and statistical uncertainties in the event samples. In Reference [6], CDF has presented the measured value of the ratio σ ·B(W → eν)/σ ·B(Z0 → ee) from the 1992-1993 data, but not the individual cross sections. In References [7, 8, 9], CDF has presented detailed

Measurement of σ · B ( W → eν ) and σ · B ( Z 0 → e + e − ) in pp collisions at √ s = 1 . 8 TeV

The Track Imaging Cerenov Experiment (TrICE) is an air Cerenkov prototype telescope designed to use multi-anode photomultiplier to acheive a high angular resolution for measuring cosmic-ray composition at TeV-PeV energies. The TrICE camera, composed of 16 Hamamatsu R8900 16-channel multi-anode photomultiplier tubes, achieves 0.086 degree angular width per pixel over 1.5 degree wide field of view. We present a description of the TrICE camera design, calibration and performance.

In distinguishing between the atmospheric Cerenkov light initiated by the primary cosmic ray and its associated air shower, the Track Imaging Cerenkov Experiment (TrICE) is devised to measure the composition of cosmic rays at TeV-PeV energies. The instrument is a fixed-mount zenith telescope that uses a Fresnel lens as a early trigger and 4-m spherical mirrors to produce the image on the focal plane over a 1.5◦ field-of-view. The TrICE camera, composed of multi-anode photomultiplier tubes with 0.086 degree angular spacing, is digitized continuously by a custom ASIC at 53 MHz with a dynamic range of 16 bits. Here we describe the commissioning and calibration of TrICE.

The Track Imaging ˇ Cerenkov Experiment (TrICE) is a prototype imaging atmospheric ˇ Cerenkov telescope designed to use a high resolution method for measuring cosmic-ray composition at TeV-PeV energies. The method aims to separate the fast and compact direct Cerenkov signal produced by primary cosmic-ray nuclei in the upper atmosphere from the light produced by the subsequent air shower cascade. Efficient discrimination of the direct ˇ Cerenkov signal benefits from the use of small camera pixels to improve the angular resolution of the air shower image. Multi-anode photomultipliers are used in the TrICE camera to achieve 0.086 ◦ pixel spacing over a 1.5 ◦ field of view. The telescope was completed in late 2006 at Argonne National Laboratory. We present the results from the first observations with TrICE.

High Resolution Measurements of Cosmic-ray Air Showers with the Track Imaging ˇ

High resolution measurements of cosmic-ray air showers with the track imaging cerenkov experiment

The tri-agency Integrated Program Office (IPO) manages the development of the National Polar-orbiting Operational Environmental Satellite System (NPOESS). NPOESS will replace the Defense Meteorological Satellite Program (DMSP) and Polar-orbiting Operational Environmental Satellites (POES) that have provided global data for weather forecasting and environmental monitoring for over 40 years. Beginning in late 2009, NPOESS spacecraft will be launched into three orbital planes to provide significantly improved operational capabilities and benefits to satisfy critical civil and national security requirements for space-based, remotely sensed environmental data. NPOESS will observe more phenomena simultaneously from space than its operational predecessors and deliver a data volume significantly greater than the POES and DMSP systems with substantially improved delivery of data to users. Higher (spatial, temporal, and spectral) resolution and more accurate imaging and sounding data will enable improvements in short- to medium-range weather forecasts. NPOESS will support the operational needs of meteorological, oceanographic, environmental, climatic, and space environmental remote-sensing programs and provide continuity of data for climate researchers. With the development of NPOESS, we are evolving operational "weather" satellites into integrated global environmental observing systems by expanding our capabilities to observe, assess, and predict the total Earth system-atmosphere, ocean, land, and the space environment.

National Polar-orbiting Operational Environmental Satellite System: meeting future user needs for Earth system observations

The NPOESS (National Polar-orbiting Operational Environmental Satellite System) program represents the merger of the NOAA POES (Polar-orbiting Environmental Satellite) program and the DoD DMSP (Defense Meteorological Satellite Program) satellites. Established by presidential directive in 1994, a tri-agency Integrated Program Office (IPO) in Silver Spring, Maryland, has been managing NPOESS development, and is staffed by representatives of NOAA, DoD, and NASA. NPOESS is being designed to provide 55 atmospheric, oceanographic, terrestrial, and solar-geophysical data products, and will disseminate them to civilian and military users worldwide. The first NPOESS satellite is scheduled to be launched late in this decade, with the other two satellites of the three-satellite constellation due to be launched over the ensuing four years. NPOESS will remain operational for at least ten years. The 55 Environmental Data Records (EDRs) will be provided by a number of instruments, many of which will be briefly described in this paper. The instruments will be hosted in various combinations on three NPOESS platforms in three distinct polar sun-synchronous orbits. The instrument complement represents the combined requirements of the weather, climate, and environmental remote sensing communities. The three critical instruments are VIIRS (Visible/Infrared Imager-Radiometer Suite), CMIS (Conical Microwave Imager/Sounder), and CrIS (Cross-track Infrared Sounder). The other IPO-developed instruments are OMPS (Ozone Mapper/Profiler Suite), GPSOS (Global Positioning System Occultation Sensor), the APS (Aerosol Polarimeter Sensor), and the SESS (Space Environment Sensor Suite). NPOESS will also carry various "leveraged" instruments, i.e., ones that do not require development by the IPO. These include the ATMS (Advanced Technology Microwave Sounder), the TSIS (Total Solar Irradiance Sensor), the ERBS (Earth Radiation Budget Sensor), and the ALT (Radar Altimeter).

Earth remote sensing with NPOESS: instruments and environmental data products

The tri-agency Integrated Program Office (IPO) manages the development of the National Polar-orbiting Operational Environmental Satellite System (NPOESS). NPOESS will replace the Defense Meteorological Satellite Program (DMSP) and Polar-orbiting Operational Environmental Satellites (POES) that have provided global data for weather forecasting and environmental monitoring for over 40 years. Beginning in late 2009, NPOESS spacecraft will be launched into three orbital planes to provide significantly improved operational capabilities and benefits to satisfy critical civil and national security requirements for space-based, remotely sensed environmental data. NPOESS will observe more phenomena simultaneously from space than its operational predecessors and deliver a data volume significantly greater than the POES and DMSP systems with substantially improved delivery of data to users. Higher (spatial, temporal, and spectral) resolution and more accurate imaging and sounding data will enable improvements in short- to medium-range weather forecasts. NPOESS will support the operational needs of meteorological, oceanographic, environmental, climatic, and space environmental remote-sensing programs and provide continuity of data for climate researchers. With the development of NPOESS, we are evolving operational “weather” satellites into integrated global environmental observing systems by expanding our capabilities to observe, assess, and predict the total Earth system - atmosphere, ocean, land, and the space environment.

The NPOESS system: providing improved real-time data to meet future needs

The next generation of U.S. polar orbiting environmental satellites, are now under development. These satellites, jointly developed by the Department of Defense (DoD), the Department of Commerce (DOC), and the National Aeronautics and Space Administration (NASA), will be known as the National Polar-orbiting Operational Environmental Satellite System (NPOESS). It is expected that the first of these satellites will be launched in 2010. NPOESS has been designed to meet the operational needs of the U.S. civilian meteorological, environmental, climatic, and space environmental remote sensing programs, and the Global Military Space and Geophysical Environmental remote sensing programs. This system, however, did not meet all the needs of the user community interested in operational oceanography (particularly in coastal regions). Beginning in the fall of 2000, the Integrated Program Office (IPO), a joint DoD, DOC, and NASA office responsible for the NPOESS development, initiated the Ocean Observer Study (OOS). The purpose of this study was to assess and recommend how best to measure the missing or inadequately sampled ocean parameters. This paper summarizes the ocean measurement requirements documented in the OOS, describes the national need to measure these parameters, and describes the satellite instrumentation required to make those measurements.

Ocean Observer Study: A Proposed National Asset to Augment the Future U. S. Operational Satellite System

In 191 Sydney families comprising both parents and two children aged eight to 12, children's gender-role attitudes were examined as a function of children's and parents' demographic variables, gender-role-related childrearing practices, and performance of gender-related household tasks. Children's gender-role attitudes were associated with both parents' education, religiosity, and political allegiances, as well as with parental encouragement of children's cross-sex interests, tolerance of children's cross-sex behaviours, and a nontraditional division of household tasks. Hierarchical multiple regressions demonstrated that gender-role-related childrearing practices and parental gender-role-attitude scores (and, to a lesser extent, household-task performance) added significant variance to the prediction of children's gender-role-attitude scores beyond the influence of demographic variables. The results were discussed with reference to the multiple pathways by which parents influence their children.

Gender-role Attitudes in Middle Childhood: In What Ways Do Parents Influence Their Children?

Over the last nine years the Integrated Program Office has been developing the National Polar-orbiting Operational Environmental Satellite System (NPOESS). NPOESS spacecraft will be launched into three orbital planes beginning later this decade to provide significantly improved operational capabilities and benefits to satisfy the critical civil and national security requirements for space-based, remotely sensed environmental data.

IGARSS 2003. 2003 IEEE International Geoscience and Remote Sensing Symposium. Proceedings (IEEE Cat. No.03CH37477)

The National Polar-orbiting Operational Environmental Satellite System future US operational Earth observation system

This paper is a brief summary of the synthetic aperture radar (SAR) user requirements, satellite requirements, and instrument requirements for the proposed, but yet unfunded, U.S. Ocean Observer satellite.

Ocean observer satellite study: instrument and satellite constellation architecture options

We present the first measurement of associated direct photon$+$muon production in hadronic collisions, from a sample of 1.8 TeV $p\overline{p}$ collisions recorded with the Collider Detector at Fermilab. Quantum chromodynamics (QCD) predicts that these events are primarily from the Compton scattering process $c\stackrel{\ensuremath{\rightarrow}}{g}c\ensuremath{\gamma},$ with the final state charm quark producing a muon. Hence this measurement is sensitive to the charm quark content of the proton. The measured cross section of $29\ifmmode\pm\else\textpm\fi{}9$ pb is compared to a leading-order QCD parton shower model as well as a next-to-leading-order QCD calculation.

Measurement of the associated γ+μ± production cross section in pp̄ collisions at √s=1.8 TeV

Measurement of the associated [formula presented] production cross section in [formula presented] collisions at [formula presented] TeV

Measurement of the associated gamma+mu(+/-) production cross section in p(p)over-bar collisions at root s=1.8 TeV

Psychology and sociology both deal with a huge range of concepts and methodologies. Information from other disciplines is integrated into psychology and sociology, and vice versa. This reciprocal intellectual relationship must be enhanced so that the social and behavioral sciences can assist in solving the many present and future local and international problems. Such a highly demanding integration among disciplines can be systemized using an invaluable research tool – the Encyclopedia of World Problems and Human Potential.

Jet pseudorapidity distribution in direct photon events in pp̄ collisions at As51.8 TeV F. Abe, M. G. Albrow, S. R. Amendolia, 22 D. Amidei, J. Antos, 28 C. Anway-Wiese, 4 G. Apollinari, H. Areti, M. Atac, P. Auchincloss, 25 F. Azfar, P. Azzi, N. Bacchetta, 20 W. Badgett, 16 M. W. Bailey, J. Bao, 35 P. de Barbaro, 25 A. Barbaro-Galtieri, 14 V. E. Barnes, 24 B. A. Barnett, 12 P. Bartalini, 22 G. Bauer, 15 T. Baumann, 9 F. Bedeschi, 22 S. Behrends, 3 S. Belforte, 22 G. Bellettini, J. Bellinger, 34 D. Benjamin, 31 J. Benlloch, 15 J. Bensinger, 3 D. Benton, 21 A. Beretvas, 7 J. P. Berge, 7 S. Bertolucci, 8 A. Bhatti, K. Biery, M. Binkley, F. Bird, D. Bisello, R. E. Blair, C. Blocker, 3 A. Bodek, W. Bokhari, V. Bolognesi, 22 D. Bortoletto, 24 C. Boswell, 12 T. Boulos, 14 G. Brandenburg, 9 C. Bromberg, 17 E. Buckley-Geer, 7 H. S. Budd, 25 K. Burkett, G. Busetto, 20 A. Byon-Wagner, 7 K. L. Byrum, J. Cammerata, 12 C. Campagnari, 7 M. Campbell, 16 A. Caner, 7 W. Carithers, 14 D. Carlsmith, 34 A. Castro, 20 Y. Cen, F. Cervelli, H. Y. Chao, 28 J. Chapman, 16 M.-T. Cheng, 28 G. Chiarelli, T. Chikamatsu, 32 C. N. Chiou, 28 L. Christofek, 10 S. Cihangir, 7 A. G. Clark, M. Cobal, M. Contreras, 5 J. Conway, 27 J. Cooper, 7 M. Cordelli, C. Couyoumtzelis, 22 D. Crane, 1 J. D. Cunningham, 3 T. Daniels, 15 F. DeJongh, 7 S. Delchamps, 7 S. Dell’Agnello, M. Dell’Orso, L. Demortier, 26 B. Denby, 22 M. Deninno, 2 P. F. Derwent, 16 T. Devlin, M. Dickson, J. R. Dittmann, 6 S. Donati, 22 R. B. Drucker, 14 A. Dunn, K. Einsweiler, 14 J. E. Elias, 7 R. Ely, E. Engels, Jr., 23 S. Eno, 5 D. Errede, 10 S. Errede, 10 Q. Fan, 25 B. Farhat, 15 I. Fiori, B. Flaugher, 7 G. W. Foster, 7 M. Franklin, M. Frautschi, 18 J. Freeman, 7 J. Friedman, 15 H. Frisch, 5 A. Fry, T. A. Fuess, 1 Y. Fukui, S. Funaki, 32 G. Gagliardi, 22 S. Galeotti, 22 M. Gallinaro, A. F. Garfinkel, 24 S. Geer, 7 D. W. Gerdes, 16 P. Giannetti, 22 N. Giokaris, 26 P. Giromini, L. Gladney, 21 D. Glenzinski, 12 M. Gold, J. Gonzalez, 21 A. Gordon, 9 A. T. Goshaw, 6 K. Goulianos, 26 H. Grassmann, 6 A. Grewal, L. Groer, C. Grosso-Pilcher, 5 C. Haber, 14 S. R. Hahn, 7 R. Hamilton, 9 R. Handler, 34 R. M. Hans, 35 K. Hara, B. Harral, R. M. Harris, S. A. Hauger, 6 J. Hauser, 4 C. Hawk, J. Heinrich, 21 D. Cronin-Hennessy, 6 R. Hollebeek, 21 L. Holloway, A. Hölscher, 11 S. Hong, 16 G. Houk, P. Hu, B. T. Huffman, R. Hughes, 25 P. Hurst, 9 J. Huston, 17 J. Huth, 9 J. Hylen, 7 M. Incagli, J. Incandela, 7 H. Iso, H. Jensen, 7 C. P. Jessop, 9 U. Joshi, 7 R. W. Kadel, 14 E. Kajfasz, 7,* T. Kamon, 30 T. Kaneko, 32 D. A. Kardelis, H. Kasha, 35 Y. Kato, L. Keeble, 8 R. D. Kennedy, 27 R. Kephart, 7 P. Kesten, 14 D. Kestenbaum, 9 R. M. Keup, H. Keutelian, 7 F. Keyvan, 4 D. H. Kim, H. S. Kim, S. B. Kim, S. H. Kim, Y. K. Kim, L. Kirsch, P. Koehn, 25 K. Kondo, J. Konigsberg, 9 S. Kopp, 5 K. Kordas, 11 W. Koska, 7 E. Kovacs, 7,* W. Kowald, M. Krasberg, 16 J. Kroll, M. Kruse, S. E. Kuhlmann, 1 E. Kuns, 27 A. T. Laasanen, 24 N. Labanca, 22 S. Lammel, 4 J. I. Lamoureux, 3 T. LeCompte, 10 S. Leone, 22 J. D. Lewis, 7 P. Limon, M. Lindgren, T. M. Liss, N. Lockyer, C. Loomis, 27 O. Long, M. Loreti, E. H. Low, J. Lu, D. Lucchesi, 22 C. B. Luchini, P. Lukens, 7 J. Lys, P. Maas, 34 K. Maeshima, 7 A. Maghakian, 26 P. Maksimovic, 15 M. Mangano, 22 J. Mansour, 17 M. Mariotti, J. P. Marriner, 7 A. Martin, J. A. J. Matthews, 18 R. Mattingly, P. McIntyre, 30 P. Melese, 26 A. Menzione, 22 E. Meschi, 22 G. Michail, S. Mikamo, 13 M. Miller, 5 R. Miller, T. Mimashi, S. Miscetti, 8 M. Mishina, H. Mitsushio, 32 S. Miyashita, 32 Y. Morita, S. Moulding, 26 J. Mueller, 27 A. Mukherjee, 7 T. Muller, P. Musgrave, 11 L. F. Nakae, 29 I. Nakano, 32 C. Nelson, 7 D. Neuberger, 4 C. Newman-Holmes, 7 L. Nodulman, 1 S. Ogawa, 32 S. H. Oh, 6 K. E. Ohl, R. Oishi, T. Okusawa, 19 C. Pagliarone, 22 R. Paoletti, 22 V. Papadimitriou, 31 S. P. Pappas, 35 S. Park, 7 J. Patrick, 7 G. Pauletta, 22 M. Paulini, L. Pescara, 20 M. D. Peters, 14 T. J. Phillips, 6 G. Piacentino, 2 M. Pillai, R. Plunkett, 7 L. Pondrom, 34 N. Produit, 14 J. Proudfoot, 1 F. Ptohos, 9 G. Punzi, 22 K. Ragan, 11 F. Rimondi, L. Ristori, M. Roach-Bellino, 33 W. J. Robertson, 6 T. Rodrigo, 7 J. Romano, 5 L. Rosenson, 15 W. K. Sakumoto, 25 D. Saltzberg, 5 A. Sansoni, 8 V. Scarpine, 30 A. Schindler, 14 P. Schlabach, 9 E. E. Schmidt, 7 M. P. Schmidt, 35 O. Schneider, 14 G. F. Sciacca, 22 A. Scribano, 22 S. Segler, 7 S. Seidel, 18 Y. Seiya, 32 G. Sganos, 11 A. Sgolacchia, 2 M. Shapiro, 14 N. M. Shaw, 24 Q. Shen, 24 P. F. Shepard, 23 M. Shimojima, M. Shochet, 5 J. Siegrist, 29 A. Sill, P. Sinervo, 11 P. Singh, 23 J. Skarha, 12 K. Sliwa, D. A. Smith, F. D. Snider, 12 L. Song, 7 T. Song, 16 J. Spalding, 7 L. Spiegel, 7 P. Sphicas, 15 L. Stanco, 20 J. Steele, 34 A. Stefanini, 22 K. Strahl, J. Strait, 7 D. Stuart, 7 G. Sullivan, 5 K. Sumorok, 15 R. L. Swartz, Jr., 10 T. Takahashi, 19 K. Takikawa, 32 F. Tartarelli, 22 W. Taylor, P. K. Teng, 28 Y. Teramoto, 19 S. Tether, 15 D. Theriot, J. Thomas, 29 T. L. Thomas, 18 R. Thun, 16 M. Timko, P. Tipton, 25 A. Titov, S. Tkaczyk, 7 K. Tollefson, A. Tollestrup, 7 J. Tonnison, 24 J. F. de Troconiz, 9 J. Tseng, 12 M. Turcotte, 29 N. Turini, N. Uemura, 32 F. Ukegawa, 21 G. Unal, S. C. van den Brink, 23 S. Vejcik III, R. Vidal, M. Vondracek, 10 D. Vucinic, R. G. Wagner, 1 R. L. Wagner, 7 N. Wainer, 7 R. C. Walker, 25 C. Wang, 6 C. H. Wang, 28 G. Wang, 22 J. Wang, 5 M. J. Wang, 28 Q. F. Wang, 26 A. Warburton, 11 G. Watts, 25 T. Watts, R. Webb, 30 C. Wei, C. Wendt, 34 H. Wenzel, 14 W. C. Wester III, 7 T. Westhusing, 10 A. B. Wicklund, E. Wicklund, R. Wilkinson, H. H. Williams, P. Wilson, B. L. Winer, J. Wolinski, D. Y. Wu, X. Wu, J. Wyss, 20 A. Yagil, W. Yao, K. Yasuoka, 32 Y. Ye, G. P. Yeh, 7 P. Yeh, 28 M. Yin, J. Yoh, C. Yosef, 17 T. Yoshida, 19 D. Yovanovitch, 7 I. Yu, J. C. Yun, 7 A. Zanetti, F. Zetti, L. Zhang, 34 S. Zhang, 16 W. Zhang, 21 and S. Zucchelli 2

Jet pseudorapidity distribution in direct photon events in pp̄ collisions at √s=1.8 TeV

Jet pseudorapidity distribution in direct photon events in<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"><mml:mi>p</mml:mi><mml:mrow><mml:mrow><mml:mover><mml:mrow><mml:mi>p</mml:mi></mml:mrow><mml:mrow><mml:mi>¯</mml:mi></mml:mrow></mml:mover></mml:mrow></mml:mrow></mml:m

We present the first measurement of the jet pseudorapidity distribution in direct photon events from a sample of p{bar p} collisions at {radical} (s) =1.8TeV, recorded with the Collider Detector at Fermilab. Quantum chromodynamics (QCD) predicts that these events are primarily from hard quark-gluon Compton scattering, qg{r_arrow}q{gamma}, with the final state quark producing the jet of hadrons. The jet pseudorapidity distribution in this model is sensitive to parton momentum fractions between 0.015 and 0.15. We find that the shape of the measured pseudorapidity distribution agrees well with next-to-leading order QCD calculations. {copyright} {ital 1997} {ital The American Physical Society}

Jet pseudorapidity distribution in direct photon events in p{bar p} collisions at {radical} (s) =1.8TeV

Objectives: The purpose of this study was: (i) to examine the incidence of psychological and medical symptomatology, torture and related trauma in a sample of 191 refugee clients of the Service for the Treatment and Rehabilitation of Torture and Trauma Survivors (STARTTS) in New South Wales (NSW), Australia; and (ii) to identify patterns of current symptoms, patterns of torture and trauma experiences and the relationships between symptoms and experiences. Method: Analysis of STARTTS client records permitted the coding of the presence/absence of 41 medical and psychological symptoms and of 33 torture and trauma experiences. Principal components analyses were used to identify patterns of current symptoms and patterns of torture and trauma experiences. Multiple regression analysis was used to identify relationships between current symptoms and traumatic events in the country of origin or en route to Australia. Results: Six factors were extracted for both the symptoms and trauma experiences; the first symptom factor was labelled ‘core posttraumatic stress disorder (PTSD)’. Regression analysis showed that threats and humiliation, and being forced to watch others being tortured best predicted scores on this factor. Conclusions: Although core PTSD is the dominant factor in symptomatology, comorbidity is high, with another three symptom factors emerging as meaningful. However, client reports of threats and humiliation or forced viewing of others being tortured should alert clinicians to the likely development of core PTSD, if it has not already occurred. Other implications of these findings for treatment and service development are discussed.

Patterns of Symptomatology and Patterns of Torture and Trauma Experiences in Resettled Refugees

Measurement of the Lambda(b)(0) lifetime using Lambda(b)(0)->Lambda(c)(+)l(-)(nu)over-bar

We present a search for associated production of the chargino and neutralino supersymmetric particles using up to 1.1 fb{-1} of integrated luminosity collected by the CDF II experiment at the Tevatron pp collider at sq rt[s]=1.96 TeV. We analyze events with a large transverse momentum imbalance and either three charged leptons or two charged leptons of the same electric charge. The numbers of observed events are consistent with standard model expectations. Upper limits on the production cross section are derived in different theoretical models.

Search for chargino-neutralino production in pp collisions at sq rt[s] = 1.96 TeV.

A sample of 186 dating couples completed questionnaires in order to examine the relevance of attachment styles, romantic beliefs, self-esteem, and gender roles to relationship satisfaction. The aim was to assess whether male and female anxiety over abandonment and comfort with closeness, and interactions among them, predicted satisfaction beyond the contribution of the other variables. Using multiple-regression analysis, it was found that attachment styles successfully predicted satisfaction, after controlling for romantic beliers, self-esteem, and gender roles. Both partners were particularly dissatisfied when either partner suffered high anxiety over abandonment or low comfort with closeness. Implications for gender roles, relationship satisfaction, and attachment styles are discussed.

Attachment styles and other predictors of relationship satisfaction in dating couples

Limits onWWZandWWγCouplings fromWWandWZProduction inpp¯Collisions at√s=1.8TeV

A Measurement of the ratio $\sigma \times B(p\bar{p} \to W \to e \nu) / \sigma \times B(p\bar{p} \to Z^0 \to e e)$ in $p\bar{p}$ collisions at $\sqrt{s} = 1800$ GeV

Limits on {ital WWZ} and {ital WW}{gamma} couplings from {ital WW} and {ital WZ} production in {ital p{bar p}} collisions at {radical}{ital s}=1.8TeV

We present the results of a search for second generation leptoquarks {ital S}{sub 2} using 19.3pb{sup {minus}1} of data collected at the Collider Detector at Fermilab (CDF) in {ital p{bar p}} collisions at {radical}{ital s}=1.8 TeV during the 1992--93 collider run. We have searched for {ital S}{sub 2}{ital {bar S}}{sub 2} pairs assuming that each leptoquark decays to a muon + quark with a branching ratio {beta}. We find two candidate events, consistent with an expected background of 1.11{plus_minus}0.48. We obtain upper limits on {sigma}({ital p{bar p}}{r_arrow}{ital S}{sub 2}{ital {bar S}}{sub 2}){beta}{sup 2} as a function of {ital M}{sub {ital S}{sub 2}}. Using a Monte Carlo prediction for {ital S}{sub 2}{ital {bar S}}{sub 2} pair production, we exclude {ital M}{sub {ital S}{sub 2}}{lt}131GeV/{ital c}{sup 2} for {beta}=1 and {ital M}{sub {ital S}{sub 2}}{lt}96GeV/{ital c}{sup 2} for {beta}=0.5 at 95% C.L.

Search for second generation leptoquarks in pp collisions at s=1.8 TeV

In an attempt to define Australian professional psychology's public image, a random sample of Sydney metropolitan area adults and adult clients of psychologists were surveyed to assess their knowledge of and attitudes towards mental health and physical-health professionals. The community group held more favourable opinions of the physical-health professionals than the mental health professionals, with psychologists generally rated quite low. The results for the clients were better but not as favourable as psychologists might wish. A multivariate approach was taken to identify the predictors of favourable attitudes towards psychologists and future usage of psychological services. Findings on respondents' health, knowledge, and attitudes are presented and discussed, along with the clients' reactions to their experiences with psychologists.

Community and Client Perceptions of Psychologists and Other Health Professionals

We report limits on anomalous [ital ZZ][gamma] and [ital Z][gamma][gamma] couplings derived from an analysis of [ital Z]+photon production based upon approximately 20pb[sup [minus]1] of the [bar p] collision data recorded by the Collider Detector at Fermilab. We observe good agreement with the standard model expectation that all [ital Z][gamma] couplings are zero. Confidence level intervals for individual couplings and contours for pairs of [ital CP]-conserving/violating [ital ZZ][gamma] and [ital Z][gamma][gamma] couplings are presented.

Limits on Z-photon couplings from p- p interactions at s=1.8 TeV

We establish the existence of the top quark using a 67 pb^-1 data sample of Pbar-P collisions at Sqrt(s) = 1.8 TeV collected with the Collider Detector at Fermilab (CDF). Employing techniques similar to those we previously published, we observe a signal consistent with t-tbar decay to WW b-bbar, but inconsistent with the background prediction by 4.8 sigma. Additional evidence for the top quark is provided by a peak in the reconstructed mass distribution. We measure the top quark mass to be 176 +/-8(stat) +/- 10(sys.) GeV/c^2, and the t-tbar production cross section to be 6.8 +3.6 -2.4 pb.

We present a measurement of the mass of the {ital W} boson using data collected with the Collider Detector at Fermilab during the 1992--93 collider run at the Fermilab Tevatron. A fit to the transverse mass spectrum of a sample of 3268 {ital W}{r_arrow}{mu}{nu} events recorded in an integrated luminosity of 19.7pb{sup {minus}1} gives a mass {ital M}{sub {ital W}}{sup {mu}}=80.310{plus_minus}0.205(stat){plus_minus}0.130(syst)GeV/{ital c}{sup 2}. A fit to 5718 {ital W}{r_arrow}{ital e}{nu} events recorded in 18.2 pb{sup --1} gives {ital M}{sup {ital e}}{sub {ital W}}=80.490{plus_minus}0.145(stat){plus_minus}0.175(syst)GeV/{ital c}{sup 2}. Combining these results, accounting for correlated uncertainties, yields {ital M}{sub {ital W}}=80.410{plus_minus}0.180GeV/{ital c}{sup 2}.

This Letter reports on measurements of the longitudinal polarization fractions in the decays {ital B}{sub {ital d}}{r_arrow}{ital J}/{psi}{ital K}{sup *0} and {ital B}{sub {ital s}}{r_arrow}{ital J}/{psi}{phi} using data collected with the Collider Detector at Fermilab. {ital B}{sub {ital d}} mesons are reconstructed through the decay chain {ital B}{sub {ital d}}{r_arrow}{ital J}/{psi}{ital K}*, {ital J}/{psi}{r_arrow}{mu}{sup +}{mu}{sup {minus}}, {ital K}{sup *0}{r_arrow}{ital K}{sup +}{pi}{sup {minus}}. A sample of 65{plus_minus}10{ital B}{sub {ital d}} events is used to obtain a longitudinal polarization fraction of {Gamma}{sub {ital L}}/{Gamma}=0.65{plus_minus}0.10(stat){plus_minus}0.04(syst). {ital B}{sub {ital s}} mesons are reconstructed through the decay chain {ital B}{sub {ital s}}{r_arrow}{ital J}/{psi}{phi}, {ital J}/{psi}{r_arrow}{mu}{sup +}{mu}{sup {minus}}, {phi}{r_arrow}{ital K}{sup +}{ital K}{sup {minus}}. A sample of 19{plus_minus}5{ital B}{sub {ital s}} events is used to obtain the result {Gamma}{sub {ital L}}/{Gamma}=0.56{plus_minus}0.21(stat){sub {minus}0.04}{sup +0.02}(syst). Copyright {ital 1995} {ital The} {ital American} {ital Physical} {ital Society}.

Measurement of the polarization in the decays {ital B}{sub {ital d}}{r_arrow}{ital J}/{psi}{ital K}{sup *0} and {ital B}{sub {ital s}}{r_arrow}{ital J}/{psi}{phi}

Measurement of the lifetime of the Bs0 meson using the exclusive decay mode Bs0 → J/ψ φ

Measurement of the ratio σB(pp¯ → W → ev)/σB(pp¯ → Zo →ee) in pp¯ collisions at √s = 1800 GeV

In [ital pp][ital [bar p]p] collisions at [radical][ital s]=1.8TeV we find jet events with a rapidity gap topology. The number of hadrons in the rapidity interval [Delta][eta][sub [ital D]] between leading-jet cones was sampled by charged tracks with [ital P][sub [ital T]][gt]400MeV/[ital c]. We find excess trackless events beyond that expected in a smooth multiplicity distribution. In a control region outside [Delta][eta][sub [ital D]] we see no excess. For [Delta][eta][sub [ital D]][gt]0.8, the fraction of excess trackless events, consistent with estimates based on exchange of color-singlet digluons, is [ital R](gap)=[sigma][sub jet](gap)/[sigma][sub jet]= 0.0085[plus minus]0.0012(stat)[sub [minus]0.0012][sup +0.0024](syst).

Erratum: Precision measurement of the prompt photon cross section in pp collisions at s=1.8 TeV (Physical Review Letters(1995) 74, 10 (1891-1893))

Analysis of jet charged particle momentum distributions for quark - gluon separation in $\bar{p} p$ collisions at $\sqrt{s}$ = 1.8-TeV

We report a measurement of the diffraction dissociation differential cross section [ital d][sup 2][sigma][sub SD]/[ital dM][sup 2][ital dt] for [ital [bar p]p][r arrow][ital [bar p]X] at [radical][ital s] =546 and 1800 GeV, [ital M][sup 2]/[ital s][lt]0.2 and 0[le][minus][ital t][le]0.4 GeV[sup 2]. Our results are compared to theoretical predictions and to extrapolations from experimental results at lower energies.

Measurement of pp single diffraction dissociation at √s = 546 and 1800 GeV

A nationwide Australian survey was conducted in order (1) to distinguish between married couples who either had or had not cohabited prior to marriage and (2) to distinguish between cohabiting couples who either did or did not marry subsequently. A total of 96 cohabiting couples and 117 married couples completed an omnibus 16-page questionnaire covering a variety of demographic, attitudinal, behavioral and personality domains. Couples were recontacted after an interval of 1 1/2 years to identify the kind and extent of changes during the intervening period. In general, as predicted, marrieds with cohabiting experience and cohabitors who avoided marriage revealed a less traditional pattern of responses (e.g. higher feminism scores, wider sexual experience, less stereotyped division of chores, etc.) than their respective counterparts. It was predicted, and found, that the former couples showed greater evidence of autonomy needs and less evidence of attachment needs than the latter.

Cohabitation and Marriage: Retrospective and Predictive Comparisons

This paper reports the measurement of the [ital B] meson and [ital b] quark cross sections through the decay chain [ital B][sup 0][r arrow][ital J]/[psi] K[sup *](892)[sup 0], [ital J]/[psi][r arrow][mu][sup +][mu][sup [minus]], [ital K][sup *](892)[sup 0][r arrow][ital K][sup +][pi][sup [minus]], using 4.3 pb[sup [minus]1] of data collected at the Collider Detector at Fermilab in [ital [bar p]p] collisions at [ital qrts]=1.8 TeV. We obtain [sigma][sub [ital B]]=1.5[plus minus]0.7(stat)[plus minus]0.6(syst) [mu]b for [ital B][sup 0] mesons with transverse momentum [ital P][sub [ital T]][gt]9.0 GeV/[ital c] and rapidity [vert bar][ital y][vert bar][lt]1.0. Using this result, we find [sigma][sub [ital b]]=3.7[plus minus]1.6(stat)[plus minus]1.5(syst) [mu]b for [ital b] quarks with [ital P][sub [ital T]][gt]11.5 GeV/[ital c] and rapidity [vert bar][ital y][vert bar][lt]1.0. The [ital b] quark cross section is compared to next-to-leading order QCD calculations and previous measurements.

Measurement of the [ital B] meson and [ital b] quark cross sections at [radical][ital s] =1. 8 TeV using the exclusive decay [ital B][sup 0][r arrow][ital J]/[psi][ital K][sup *](892)[sup 0]

ATLAS: Technical proposal for a general-purpose p p experiment at the Large Hadron Collider at CERN

We report a measurement of the proton-antiproton total cross section ${\mathrm{\ensuremath{\sigma}}}_{\mathit{T}}$ at c.m.s. energies \ensuremath{\surd}s =546 and 1800 GeV. Using the luminosity-independent method, we find ${\mathrm{\ensuremath{\sigma}}}_{\mathit{T}}$=61.26\ifmmode\pm\else\textpm\fi{}0.93 mb at \ensuremath{\surd}s =546 GeV and 80.03\ifmmode\pm\else\textpm\fi{}2.24 mb at \ensuremath{\surd}s =1800 GeV. In this energy range, the ratio ${\mathrm{\ensuremath{\sigma}}}_{\mathrm{el}}$/${\mathrm{\ensuremath{\sigma}}}_{\mathit{T}}$ increases from 0.210\ifmmode\pm\else\textpm\fi{}0.002 to 0.246\ifmmode\pm\else\textpm\fi{}0.004.

Measurement of the antiproton-proton total cross section at s =546 and 1800 GeV

We summarize a search[1] for the top quark with the Collider Detector at Fermilab (CDF) in a sample of p̄p collisions at √ s= 1.8 TeV with an integrated luminosity of 19.3 pb−1. We find 12 events consistent with either two W bosons, or a W boson and at least one b jet. The probability that the measured yield is consistent with the background is 0.26%. Though the statistics are too limited to establish firmly the existence of the top quark, a natural interpretation of the excess is that it is due to tt̄ production. Under this assumption, constrained fits to individual events yield a top quark mass of 174± 10 −12 GeV/c 2. The tt̄ production cross section is measured to be 13.9 −4.8 pb. PACS numbers: 14.80.Dq, 13.85.Qk, 13.85.Ni, 02.20.Fh The Standard Model has enjoyed outstanding success, yet the top quark, which is required as the weak-isospin partner of the bottom quark, has remained unobserved. Direct searches at the Fermilab Tevatron have placed a 95% confidence level lower limit of Mtop > 131 GeV/c [2]. Global fits to precision electroweak measurements yield a favored mass of Mtop = 174 +11+17 −12−19 GeV/c 2 [3].

Evidence for top quark production in pp collisions at ss =1.8 TeV

We present a measurement of the ratio [sigma][ital B]([ital W][r arrow][ital ev])/[sigma][ital B]([ital Z][sup 0][r arrow][ital e][sup +][ital e][sup [minus]]) in [ital [bar p]p] collisions at [radical][ital s] =1.8 TeV. The data represent an integrated luminosity of 21.7 pb[sup [minus]1] from the 1992--1993 run of the Collider Detector at Fermilab. We find [sigma][ital B]([ital W][r arrow][ital eV])/[sigma][ital B]([ital Z][sup 0][r arrow][ital e][sup +][ital e][sup [minus]])=10.90[plus minus]0.32(stat)[plus minus]0.29(sys t). From this value, we extract a value for the [ital W] width, [Gamma]([ital W])=2.064[plus minus]0.061(stat)[plus minus]0.059(syst) GeV, and the branching ratio, [Gamma]([ital W][r arrow][ital eV])/[Gamma]([ital W])=0.1094[plus minus]0.0033(stat)[plus minus]0.0031(syst), and we set a decay-mode-independent limit on the top quark mass [ital m][sub top][gt]62 GeV/[ital c][sup 2] at the 95% C.L.

Measurement of the ratio [sigma][ital B]([ital W][r arrow][ital e][nu])/[sigma][ital B]([ital Z][sup 0][r arrow][ital e][sup +][ital e][sup [minus]]) in [ital [bar p]p] collisions at [radical][ital s] =1. 8 TeV

We have searched for new, heavy, charged bosons {ital W}{prime} through the decay {ital W}{prime}{r_arrow}{ital e}{nu} in {ital pp}{ovr bar} collisions at {radical}{ital s}=1.8 TeV. The data used in the search represent 19.7 pb{sup --1}collected by the Collider Detector at Fermilab. Limits are placed on {sigma}{ital B}({ital pp}{ovr bar}{r_arrow}{ital W}{prime}{r_arrow}{ital e}{nu}) as a function of {ital M}{sub {ital W}{prime}}. Assuming standard couplings of the {ital W}{prime} to fermions, we establish the limit {ital M}{sub {ital W}{prime}}{gt}652 GeV/{ital c}{sup 2} (95% C.L.).

Search for charged bosons heavier than the W boson in pp̄ collisions at s=1800 GeV

We measure the Drell-Yan differential cross section [ital d][sup 2][sigma]/[ital dM] d[ital y][vert bar][sub [vert bar][ital y][vert bar][lt]1] over the mass range 11[lt][ital M][lt]150 GeV/[ital c][sup 2] using dielectron and dimuon data from [ital [bar p]p] collisions at a center-of-mass energy of [radical][ital s] =1.8 TeV. Our results show the 1/[ital M][sup 3] dependence that is expected from the naive Drell-Yan model. In comparison to the predictions of recent QCD calculations we find our data favor those parton distribution functions with the largest quark contributions in the [ital x] interval 0.006 to 0.03.

Measurement of Drell-Yan electron and muon pair differential cross sections in pp collisions at s=1.8 TeV

We present the results of a search for the top quark in 19.3 pb[sup [minus]1] of [ital [bar p]p] collisions at [radical][ital s] =1.8 TeV. The data were collected at the Fermilab Tevatron collider using the Collider Detector at Fermilab (CDF). The search includes standard model [ital t[bar t]] decays to final states [ital ee][nu][bar [nu]], [ital e][mu][nu][bar [nu]], and [mu][mu][nu][bar [nu]] as well as [ital e]+[nu]+jets or [mu]+[nu]+jets. In the ([ital e],[mu])+[nu]+jets channel we search for [ital b] quarks from [ital t] decays via secondary vertex identification and via semileptonic decays of the [ital b] and cascade [ital c] quarks. In the dilepton final states we find two events with a background of 0.56[sub [minus]0.13][sup +0.25] events. In the [ital e],[mu]+[nu]+jets channel with a [ital b] identified via a secondary vertex, we find six events with a background of 2.3[plus minus]0.3. With a [ital b] identified via a semileptonic decay, we find seven events with a background of 3.1[plus minus]0.3. The secondary vertex and semileptonic-decay samples have three events in common. The probability that the observed yield is consistent with the background is estimated to be 0.26%. The statistics are too limited to firmly establish the existence of the more » top quark; however, a natural interpretation of the excess is that it is due to [ital t[bar t]] production. We present several cross-checks. Some support this hypothesis; others do not. Under the assumption that the excess yield over background is due to [ital t[bar t]], constrained fitting on a subset of the events yields a mass of 174[plus minus]10[sub [minus]12][sup +13] GeV/[ital c][sup 2] for the top quark. The [ital t[bar t]] cross section, using this top quark mass to compute the acceptance, is measured to be 13.9[sub [minus]4.8][sup +6.1] pb. « less

Evidence for top quark production in [ital [bar p]p] collisions at [radical][ital s] =1. 8 TeV

Color coherence effects in [ital p[bar p]] collisions are observed and studied with CDF, the Collider Detector at the Fermilab Tevatron collider. We demonstrate these effects by measuring spatial correlations between soft and leading jets in multijet events. Variables sensitive to interference are identified by comparing the data to the predictions of various shower Monte Carlo programs that are substantially different with respect to the implementation of coherence.

Evidence for color coherence in [ital p[bar p]] collisions at [radical][ital s] =1. 8 TeV

The lifetimes of the [ital B][sup +] and [ital B][sup 0] mesons have been measured using fully reconstructed decays. In a sample of [similar to]49 600[ital J]/[psi][r arrow][mu][sup +][mu][sup [minus]] decays recorded with the Collider Detector at Fermilab, 148[plus minus]16 [ital B][sup +] and 121[plus minus]16[ital B][sup 0] mesons have been reconstructed using the silicon vertex detector. Unbinned likelihood fits to the proper lifetime distributions of these [ital B] mesons give [tau][sup +]=1.61[plus minus]0.16 (stat)[plus minus]0.05 (syst) ps, [tau][sup 0]=1.57[plus minus]0.18 (stat) [plus minus]0.08 (syst) ps, and [tau][sup +]/[tau][sup 0]=1.02[plus minus]0.16 (stat) [plus minus]0.05 (syst).

Measurement of the [ital B][sup +] and [ital B][sup 0] meson lifetimes

We present results of a search for a first-generation leptoquark S 1 in pp collisions at √s = 1. 8 TeV at the Fermilab Tevatron. Using 4.05 pb −1 of data collected during the 1988-1989 CDF run, we have searched for evidence of S 1 S 1 production assuming that each leptoquark decays to an electron + quark pair with a branching ratio β. Three events with two high energy electrons and two high energy jets were found, but are consistent with Z 0 decay. No events were found in the signal region. Assuming a short lived scalar leptoquark with Yukawa coupling strength λ ≥ 2 × 10 −7 , we exclude σβ 2 > 55(4.0) pb at 95% C.L. for M S = 45(125) GeV/c 2 . Using a Monte Carlo prediction for σ(pp → S 1 S 1 + X), we exclude M S < 113(80) GEV/C 2 for β = 100(50)%

Search for first-generation leptoquarks in [ital [bar p]p] collisions at [radical][ital s] =1. 8 TeV

Kinematic properties of four-jet events produced in pp collisions at √ s = 1.8 TeV have been studied using data with an integrated luminosity of 325 nb −1 collected using the Collider Detector at Fermilab during the 1988-1989 Fermilab Collider run. The individual jet p T spectra and the angles between each jet pair are compared to the predictions of leading-order quantum chromodynamics for the double gluon bremsstrahlung process and good agreement is observed. In addition, a search for double parton scattering has been undertaken using variables sensitive to the topology of four-jet events. A small double parton content provides the best description of the data

Study of four-jet events and evidence for double parton interactions in pp̄ collisions at s=1.8 TeV

We report the full reconstruction of χ c mesons through the decay chain χ c → J/ψ γ, J/ψ→μ + m - , using data obtained at the Collider Detector at Fermilab in 2.6±0.2 pb -1 of pp collisions at √s=1.8 TeV. This exclusive χ c sample is used to measure the χ c -meson production cross section times branching fractions. We obtain σ×B=3.2±0.4(stat) -1.1 +1.2 (syst) nb for χ c mesons decaying to J/ψ with p T >6.0 GeV/c and pseudorapidity |η|<0.5

Inclusive χc and b-Quark production in pp collisions at √s=1.8 TeV

The average [ital b]-hadron lifetime has been measured using a high statistics sample of [ital B][r arrow][ital J]/[psi] [ital X] decays recorded with the Collider Detector at Fermilab. The decay vertices of 5344 inclusive [ital J]/[psi][r arrow][mu][sup +][mu][sup [minus]] candidates have been reconstructed using information from a silicon vertex detector. The measured [ital B] lifetime, which is the average over all [ital b] hadrons produced in [ital p[bar p]] collisions at [radical][ital s] =1.8 TeV weighted by their branching ratios into [ital J]/[psi], is 1.46[plus minus]0.06(stat)[plus minus]0.06(syst) ps.

Measurement of the average lifetime of [ital B] hadrons produced in [ital p[bar p]] collisions at [radical][ital s] =1. 8 TeV

A measurement of elastic J/ψ photoproduction cross section at Fermilab E687

This Letter reports the observation and mass measurement of fully reconstructed [ital B][sub [ital s]][sup 0] mesons through the decay chain [ital B][sub [ital s]][sup 0][r arrow][ital J]/[psi] [psi], [ital J]/[psi][r arrow][mu][sup +][mu][sup [minus]], [phi][r arrow][ital K][sup +][ital K[minus]] using data obtained at the Collider Detector at Fermilab in [ital [bar p]p] collisions at [radical][ital s] =1.8 TeV. A signal of 14.0[plus minus]4.7 events is observed. Comparison of the [ital B][sub [ital s]][sup 0] signal with the kinematically similar decays [ital B][sup +][r arrow][ital J]/[psi] [ital K][sup +] and [ital B][sup 0][r arrow][ital J]/[psi] K[sup *](892)[sup 0] is presented. The mass of the [ital B][sub [ital s]][sup 0] meson is determined to be 5383.3[plus minus]4.5(stat)[plus minus]5.0(syst) MeV/[ital c][sup 2].

Observation of the decay [ital B][sub [ital s]][sup 0][r arrow][ital J]/[psi] [phi] in [ital [bar p]p] collisions at [radical][ital s] =1. 8 TeV

Women's emotional dependence on men: Scale construction and test of Russianoff's hypothesis

A wide band photon beam at the Fermilab Tevatron to study heavy flavors

We have searched for the [ital b]-flavored baryon decay [Lambda][sub [ital b]][r arrow][ital J]/[psi] [Lambda][sup 0] in [ital p[bar p]] collisions at [radical][ital s] =1.8 TeV with the Collider Detector at Fermilab (CDF). In the [ital J]/[psi] [Lambda][sup 0] invariant-mass distribution we observe a flat distribution and a small number of events, consistent with no signal. Using the [ital b]-quark cross section measured by the CDF we put an upper limit on the [ital b][r arrow][Lambda][sub [ital b]] production fraction times the branching ratio [ital F]([Lambda][sub [ital b]])[ital B]([Lambda][sub [ital b]][r arrow][ital J]/[psi] [Lambda][sup 0]) of 0.50[times]10[sup [minus]3] at 90% confidence level.

Search for [Lambda][sub [ital b]][r arrow][ital J]/[psi] [Lambda][sup 0] in [ital p[bar p]] collisions at [radical][ital s] =1. 8 TeV

Abstract This study investigated the relationships between husbands' and wives' marital satisfaction, wives' labour force participation, and various aspects of the couples' social networks and social support in a sample of 166 families with at least one preschool-aged child. Wives experienced greater marital satisfaction when more of their own network members were related to each other, when they were friends with their husbands' network members and when their husbands nominated more relatives in their networks. For women with moderate labour force participation only, marital satisfaction decreased when the couple's network was less dense. Husbands experienced higher marital satisfaction when their wives had high or low rather than just moderate participation in the labour force. However, after adjusting for this, they also had higher marital satisfaction when they had more reciprocal relationships with their own network members, when more of their network members were related to their wives' network memb...

Network structure, network support and the marital satisfaction of husbands and wives

The Cross-Section for the Production of $b \bar{b}$ Pairs in the $p\bar{p}$ Collisions at $\sqrt{s}$ = 1.8-TeV

Experiences of Australian mothers who gave birth either at home, at a birth centre, or in hospital labour wards.

We report the full reconstruction of [chi][sub [ital c]] mesons through the decay chain [chi][sub [ital c]][r arrow][ital J]/[psi] [gamma], [ital J]/[psi][r arrow][mu][sup +][mu][sup [minus]], using data obtained at the Collider Detector at Fermilab in 2.6[plus minus]0.2 pb[sup [minus]1] of [ital [bar p]p] collisions at [radical][ital s] =1.8 TeV. This exclusive [chi][sub [ital c]] sample is used to measure the [chi][sub [ital c]]-meson production cross section times branching fractions. We obtain [sigma][times][ital B]=3.2[plus minus]0.4(stat)[sub [minus]1.1][sup +1.2](syst) nb for [chi][sub [ital c]] mesons decaying to [ital J]/[psi] with [ital p][sub [ital T]][gt]6.0 GeV/[ital c] and pseudorapidity [vert bar][eta][vert bar][lt]0.5. From this and the inclusive [ital J]/[psi] cross section we calculate the inclusive [ital b]-quark cross section to be 12.0[plus minus]4.5 [mu]b for [ital p][sub [ital T]][sup [ital b]][gt]8.5 GeV/[ital c] and [vert bar][ital y][sup [ital b]][vert bar][lt]1.

Inclusive [chi][sub [ital c]] and [ital b]-quark production in [ital [bar p]p] collisions at [radical][ital s] =1. 8 TeV

The W production cross section times the branching ratio for W→Iv, l=e,μ decays has been measured as a function of the associated jet multiplicity. The data have been recorded at the Collider Detector at Fermilab during the 1988-89 run. A recent leading order QCD calculation agrees well with the data up to a jet multiplicity of 4

Measurement of jet multiplicity in W events produced in pp̄ collisions at √s =1.8 TeV

Search for $\Lambda_{b}$ --> J/$\psi\Lambda^{0}$ in p$\overline{p}$ collisions at \Sqrt s = 1.8 TeV

Measurement of the decays D0 → π+π+π-π-, D0 → K-K+ and D+ s → f{cyrillic}π+π+π-

Study of D0→KS0π+π− and D0→KS0K+K− in high energy photoproduction☆

We search for the rare decay {ital W}{sup {plus minus}}{r arrow}{gamma}{pi}{sup {plus minus}} in 4.2 pb{sup {minus}1} of {ital p{bar p}} collisions recorded with the Collider Detector at Fermilab. At the 95% confidence level, we find an upper limit on the partial decay width to be {Gamma}({ital W}{sup {plus minus}}{r arrow}{gamma}{pi}{sup {plus minus}})/{Gamma}({ital W}{sup {plus minus}}{r arrow}{ital e}{sup {plus minus}}{nu}){le}7.5{times}10{sup {minus}3}.

Limit on the rare decay W sup + r arrow. gamma. pi. sup + in p p collisions at radical s =1. 8 TeV

The aim of this article is to describe the derivation and use of an index representing mothers' attachment to the workforce. This index is based on the proportion of time (equivalent full-time) the mother had worked since the birth of her first child and can be used as both a continuous and categorical variable. The sample comprised 166 Sydney-area families, each of which had at least one preschool-aged child. Relationships were examined with the mother's current work status and with various demographic characteristics of the women, with the aim of providing some validation for the index. More years of education and smaller family size distinguished between women with high versus low work attachment. In addition, women with high work attachment married at a significantly later age than those with moderate or low work attachment. The usefulness and limitations of the new index are discussed.

This paper investigates some of the factors influencing the labour force attachment of mothers with preschool-aged children in intact families. The sample comprised 166 Sydney-area families. The variables of interest included the mother's expectations about working at the time of her marriage, her educational level, four aspects of her socialisation experiences (i.e., whether traditional or non-traditional interests and activities were encouraged during her childhood, closeness to mother and father during childhood and adolescence, and her own mother's work pattern), and family structure (i.e., number of children and age of youngest and oldest child). Considerable agreement was observed between the women's work attachment and their expectations about working at the time of their marriage. The interrelationships among education, socialisation experiences, family structure and work attachment were investigated using a series of multivariate analyses of variance and covariance. It was found that the set of variables representing socialisation experiences had a small, direct effect on work attachment; education had a direct effect, even after controlling for socialisation; and family structure exerted a strong direct effect over and above its relationships with education and socialisation experiences. The implications of these findings are discussed.

Factors influencing the labour force attachment of mothers with preschool-aged children

Preliminary values are presented for lifetimes of the A: decaying into pK- ir+ and D; decaying into ,Pir. Also presented are preliminary results on samples of D" -+ K" K+ K- , including D 0 -+ K",P , and D" -+ K"Tr+Tr- decays. The data are from the first run of Fermilab experiment E687 using the Fermilab Wide-Band Pho ton Spectrometer. Our lifetime values are (0.20±0.03±0.03) ps for the A: and (0.50±0.06±0.03) ps for then; . We find preliminary values for the branching ratios B(D"-+ K" K+ K- )/B(D" -+ K 0 ir+ir- ) and B(D"-+ K",P )/B(D" -+ K"ir+ir- ) of 0.20 ± 0.06 and 0.16 ± 0.06, respectively; only statistical errors are quoted. Further work is in progress ..

Some lifetimes and branching ratios for charmed hadrons produced in the Fermilab wide band photon beam

The present investigation is a reanalysis of data from Antill and Cunningham (1979, 1980, Marsh, Antill, & Cunningham, 1987) consisting of responses to five masculinity-femininity (MF) instruments, two self-esteem instruments, and two social desirability scales Correlations between M and F for the five instruments varied from 23 to approximately - 10, support for distinguishable (nonbipolar) M and F factors was found for four of the instruments Applying confirmatory factor analysis (CFA) and hierarchical CFA (HCFA), the present study examined the dimensionality of MF and the influence of method/ halo effects m response to specific instruments The best fitting model identified three higher order factors, in support of traditional personality theories one factor was a bipolar MF construct, but m support of androgyny theory the other two factors were distinguishable M and F factors The factor structures were reasonably invanant for men and women, and methodological implications of this important finding were examined In subsequent analyses, the higher order MF factors were related to self-esteem, social desirability, and gender in order to further test interpretations of the MF factors.

Masculinity and Femininity: A Bipolar Construct and Independent Constructs.

This article provides a qualitative and quantitative analysis of the motivations for employment among a sample of 166 Sydney mothers, each of whom had at least one preschool-aged child. Mothers with high and moderate work attachment indicated a multiplicity of motives, of both an extrinsic (financial) and intrinsic (e.g., personal satisfaction, sense of achievement) nature. In contrast, the majority of women with low work attachment cited extreme financial need as the only possible reason that would impel them to enter the labor force. When asked which was, or would be, their most important reason for working, women with high work attachment endorsed more nonfinancial than financial reasons, women with moderate work attachment were about equally likely to give either reason, and women with low work attachment predominantly gave financial reasons. Husbands' perceptions of the reasons their wives were working, or would work, showed some, but not complete, agreement with those of their wives.

A description is given of a high-resolution, gateable scintillating fiber target that has been developed for Fermilab Experiment E687 to study charm and beauty particle production and decay in high-energy photon interactions. The detector consists of a scintillating target of either GS1 cerium glass fibers or polystyrene fibers of 29- mu m cross section, a multistage image intensifier, and an intensified CCD or SIT/VIDICON camera system used in conjunction with a custom-built video data acquisition system. >

A scintillating fiber-optic active target (SFT) for studies of high energy photoproduction

A scintillating glass has been developed containing cerium (3+) oxide in an aluminate host glass. In this material the scintillation emission spectrum is red-shifted relative to that observed for Ce/sup 3+/ in silicate glasses. Emission and absorption spectra are more widely separated in the aluminate composition, suggesting that which glasses might have improved light-transmission properties. The refractive index is high, making it a potentially interesting material for use in fiber-optic tracking detectors. >

A high resolution, fast gateable active target has been developed for Fermilab experiment E687 in order to study charm and beauty particle production and decay in high energy photon and hadron induced processes. The detector consists of a GS1 Cerium scintillating glass fiber-optic target, a multi-stage image intensifier and CCD camera system used in conjunction with a custom-built video data acquisition system. We currently detect ¿ 4 photoelectrons per mm with a resolution per photoelectron of ¿pe < 25¿m.

A Scintillating Glass Fiber-Optic Active Target for Vertex Detection and Tracking Applications in High Energy Physics Experiments

A new family of scintillating glasses has been developed which is based upon Pr3+ oxide in a silicate host. The materials have fast response (30nsec ¿ ¿ ¿ several ¿sec) and good optical transmission. Materials of this kind might find applicability as fiber-optic detectors for high energy physics experiments operating at moderate interaction rates.

ABSTRACT The present investigation is a reanalysis of data from Antill and Cunningham (1979,1980) consisting of responses to five Masculinity-Femininity (MF) instruments, two self-esteem instruments, and two social desirability instruments The present study examined recently developed models of the MF/ esteem relation and the influence of social desirability on this relation The unique contribution of Masculinity (M) to esteem was consistently more positive than that of Femininity (F) which was either ml or negative, did not vary with sex as posited by sex-typed models, and did not interact with F as posited by interactive androgyny models Partialing out the effects of social desirability failed to alter the general pattern of results In contrast to esteem, social desirability was more correlated with F than M, and these findings were consistent with the observation that esteem items may reflect stereotypically masculine characteristics whereas social desirability items reflect stereotypically feminine characteristics The findings of the present study, and those of previous research, were examined in relation to important methodological issues that have been largely ignored by previous research in this area

Masculinity, Femininity, and Androgyny: Relations to Self‐Esteem and Social Desirability

A fiber-optic plate imaging system has been developed for active target and tracking applications, in which the active element is Ce(3+) in a silicate glass. Particle tracks and interactions have been recorded with a hit density of ¿ 4/mm for minimum ionizing particles and with a spatial resolution ¿ ~ 28¿ m.

A Cerium Glass Fiber-Optic Active Target for High Energy Physics Experiments

A CERIUMGLASSFIBER-OPTIC ACTIVETARGETFORHIGHENERGYPHYSICSEXPERIMENTS

We have been developing a scintillating glass fiber-optic imaging system for active target and tracking applications in high energy physics experiments, Extensive measurements have been performed on several scintillating-glass compositions, one of which is a silicate-glass containing 0. 6 mole % of Ce2O3 known commercially as NRL glass. For this material, fabricated into coherent fiber-optic plates of 10 ¿m and 25 ¿m diameter cladded-glass fibers, we have observed: (1) clear particle tracks and interactions; and (2) a yield of ~ 2 photoelectrons per millimeter of path length for minimum ionizing particles, Additionally, for the bulk NRL glass formed in disks of 1" diameter and 4 mm thickness, we have observed a ~80% retention of optical transmission through 4 mm of material at 395 nm (the peak of the fluorescence spectrum) for a radiation dose in excess of 107 rads acquired over several days. Results of these tests and others suggest that Ce2O3 based scintillating glasses constitute very promising materials for the fabrication of high resolution tracking detectors for fixed target and colliding beam applications.

Scintillating Glass, Fiber-Optic Plate Detectors for Active Target and Tracking Applications in High Energy Physics Experiments

Changes in Masculinity and Femininity Across the Family Life Cycle: A Reexamination.

Abstract Findings from the social psychological literature on egotism and in-group favouritism led to the hypothesis that residents of Sydney suburbs would overvalue the prestige of their own suburb as compared with ratings by non-residents, particularly in low-prestige suburbs. As part of an updating of the Congalton (1969) list of Sydney suburbs and their median social standing, 410 respondents selected from 26 Federal electoral districts each rated 160 of 480 suburbs on 1-to-7 Likert scales. In 12 of 30 local government areas (LGAs), residents rated suburbs in their “home” LGA significantly higher than non-residents did; this was also true when ratings were summed over all 30 LGAs. More importantly, 10 of these 12 LGAs were in the lower half of the rank order of mean LGA prestige. Discussion focusses on the conflict between the need to maintain self-esteem and group esteem in low-prestige suburbs and the images of these suburbs conveyed by the mass media.

Egotism in prestige ratings of sydney suburbs: Where i live is better than you think

Sex differences in performance on ability tests as a function of masculinity, femininity, and androgyny.

SynopsisDifferences in self-esteem and selected aspects of the domestic division of labour were compared using a survey sample of 80 married couples, half of whom had a dual-career marriage pattern. Self-esteem was positively related to masculinity in both wives and husbands and was higher for career wives than housewives. The husband’s self-esteem in dual-career marriages was somewhat lower than that in single-career marriages. There was no reduction in household task performance but there was lower decision power and less sharing of responsibility for the career wife. The relationship between career status of the wife and her self-esteem was shown to be mediated by performance of household tasks: wives and husbands who did less relative to their spouses had higher self-esteem.

Self-esteem, sex roles, and domestic labour in single-career and dual-career couples

Fifty married and 50 unmarried, cohabiting couples were asked to describe four problems which occurred in their relationship—problems in which one partner was unhappy about the other's behavior, or in which the two of them disagreed about joint decisions. Despite overall similarity of the kinds of problems reported by married and cohabiting couples, married women were particularly likely to complain that their husbands did not give them sufficient attention. Husbands were especially unlikely to mention that their wives were too independent. After specifying two alternative behaviors for each partner in the problem situation, couples rated their degree of satisfaction with each of the four resulting behavioral combinations. Wives rated themselves as more unhappy when their problem arose than cohabiting partners rated themselves, and husbands were least unhappy. Wives' overall satisfaction was affected by their problem situation most of all, husbands' least of all, and cohabitors' satisfaction to an intermediate degree. Results were discussed with reference to the greater advantage that husbands derive from marriage than wives.

Marital-Status and Sex Differences in Problems Reported by Married and Cohabiting Couples

Interest in the Personal Attribute Questionnaire (PAQ) of Spence et al. (1975) as a measure of androgyny suggests the need to discover whether it exhibits the same factor structure as other androgyny measures, e.g., the Bem Sex-Role Inventory (BSRI; Bem, 1974). Responses from 104 male and 133 female university students were analyzed by the principal components method separately for (1) PAQ items only and for (2) PAQ and BSRI items together. Both analyses yielded independent femininity (Concern for Others) and masculinity (Dominance) factors accounting for the greatest proportion of variance. However, particularly for the PAQ, certain clusters of male-valued and of female-valued items formed subsidiary factors (e.g., Extraversion, Insecurity, Unemotionality, and Independence), raising questions as to the theoretically unitary nature of femininity. That is, masculinity and femininity might each be regarded more profitably as composed of several components.

Comparative Factor Analyses of the Personal Attributes Questionnaire and the Bem Sex-Role Inventory.

Abstract The development of two 50-item parallel forms of an Australian sex-role scale is described. A total of 2,427 subjects rated 512 adjectives in terms of their desirability for Australian males and females, the degree to which they are expected in Australian males and females, and their self-applicability. These ratings were used to construct the two scales — Personal Description Questionnaire Forms A and B. Each scale comprises 10 masculine positive, 10 masculine negative, 10 feminine positive, 10 feminine negative, and 10 social desirability items. The new scales were administered to 282 (144 male, 138 female) high-school students for self-description, and the various psychometric characteristics of the scales and norms for these samples are presented. It is recommended that Australian sex-role researchers use these new scales in preference to past scales based on American college students. As with any new scales there is a need for further normative data to be gathered and a variety of validation...

A 148-item random sample of self-disclosure topics was drawn from the 671-item pool of Taylor and Altman (Note 1) and presented to male and female university students in the U. S. and Australia for ratings of intimacy of content. For S of 13 content categories the same item was regarded as more intimate in opposite-sex than in same-sex conversation. Most items were rated less intimate than in the Taylor and Altman study-evidence that contemporary male students report themselves as more open and disclosing than male students did a decade ago. Sex differences were few, but Austrplians rated items in 7 categories less intimate than Americans did.

Abstract Advocates of androgyny suggest that the development of masculine and feminine characteristics in the one individual may point the way to healthy personality development. However, traditional approaches to masculinity-femininity claim that strong same-sex typing is the way to achieve this end. Two hundred and thirty-seven subjects completed three androgyny instruments, two “traditional” masculinity-femininity instruments, and two measures of self-esteem. Subjects were then classified separately into one of the five sex-role categories of Bern (1974) and one of the four categories of Spence, Helmreich, and Stapp (1975) by each of the five sex-role instruments. For both sexes, both measures of self-esteem, both methods of sex-role classification, and all sex-role instruments, self-esteem generally increased from the feminine to the masculine categories, with masculine persons higher in self-esteem than androgynes in almost every case. For both sexes masculinity also revealed significantly positive c...

The relationship of masculinity, femininity, and androgyny to self-esteem

The recent surge in empirical work on androgyny requires a comparison among the different instruments and different methods by which masculinity, femininity, and androgyny are measured. Subjects (N = 237) completed five instruments, which were scored for androgyny, by both Bem's (1974) t-ratio and Spence, Helmreich, and Stapp's (1975) median-split methods, and for masculinity and femininity. Confirmatory factor analysis of the total scores failed to yield the predicted two-factor structure, and correlations among masculinity and femininity scores varied widely. Despite moderate to high correlations among androgyny scores derived by different instruments, there was at most only 65% agreement between any two instruments in classifying subjects into the five Bem or four Spence et al. sex-role categories.

A Comparison Among Five Masculinity‐Femininity‐Androgyny Instruments and two Methods of Scoring Androgyny

Self as actor, active observer, and passive observer: Implications for causal attributions.

Little attention has been devoted to the effects of childhood achievement experiences as they might determine generalized internal-external control orientations (I-E). It was hypothesized that chronic success or failure on intellectual tasks will lead to expectancies of internal or external control, respectively. Nine- and ten-year-old school children were presented with a competitive dot-counting, task in which success and failure were manipulated. Pre- and post-measures were taken on an itemized I-E instrument derived from three previously used scales. Post-measures were generally unaffected by the success-failure manipulation. However, children who actually performed poorly on the task displayed a more external control orientation than did those who had performed well. Further analysis of the I-E items revealed that those who had actually performed poorly were most likely to attribute their achievement experiences in general to luck. These findings were interpreted as providing a bridge between study of a personality trait (I-E) and the attributional analysis of achievement events.

Effects of success and failure on children's perceptions of internal-external locus of control

Sex differences in comments made during conflict within close heterosexual pairs

Abstract In a recent article, Rowland has presented proportions of males and females scoring masculine, feminine and androgynous on the Bem Sex-Role Inventory (BSRI). Among others, her conclusion that fewer Australian males are masculine sex-typed than their American counterparts is fallacious because of limitations in the design of the study, the analysis and reporting of the data, and the inferences drawn from those results. In the present study the BSRI was administered to first-, second-, and third-year Macquarie University students, postgraduate Master of Business Administration students, and married couples with children. Means, standard deviations, and intercorrelations for the masculinity, femininity, and social desirability scales are reported separately for males and females, together with proportions falling into the 5 Bem sex-role categories and 4 Spence et. al. categories. The generality of the sex-role proportions over the present disparate samples, and their similarity to Bem's, highlight t...

The Measurement of Masculinity, Femininity and Androgyny: A Reply to Rowland (1977)

Two experiments tested the biased-scanning hypothesis that high financial inducement leads to greater cognitive contact with counterattitudinal arguments and thus to greater attitude change. In Experiment I, given time to listen lo only half of the pro- and counterattitudinal material, role-players attended primarily to counterattitudinal arguments. In Experiment II, given sufficient time to listen to all material, role-players sought out pro-altitudinal material first, regardless of inducement. No differences in biased scanning or attitude change were observed as a function of financial inducement. Contrary to the "open-mindedness" formulation, results were interpreted in the framework of reactance and of self-immunization to persuasion.

Boys meet girls: Patterns of interaction and attribution in heterosexual attraction.

A closer examination of causal inference: The roles of consensus, distinctiveness, and consistency information.

Causal attributions for interpersonal events of varying magnitude1

The problem of how an individual arrives at causal attributions for his own successes and failures has been examined in great detail (Weiner et al., 1971). However, lit~, tie attention has been directed to the effects of social influence from others on one’s causal attributions for his own success or failure. Yet anyone who has observed groups of students, employees, or athletes following a performance knows that the air is thick with attribution-relevant exchanges of opinion as to the reasons why they have done well and subsequent behavior of the individuals involved. Comments made by co-actors can influence a person’s attributions for his own behavior (Kiesler, Nisbett, & Zanna, 1969). Research conducted by Deutsch and Gerard (1955) suggests that. persona-are moat susceptible to social influence when they are uncertain

Effects of Social Influence on Attributions for Success and Failure

Interaction analysis: A useful technique for research and science supervision

Observations on the Taxonomy and Natural History of the Rubber Boa, Charina bottae

Leonard, A. B. and J. C. Frye. 1954. Ecological conditions accompanying less deposition in the Great Plains region of the United States. Jour. Geol. 62: 399. Schaffner, J. H. 1926. Observations on the grasslands of central United States. Ohio State Univ. Studies, Contr. Vol. 178: 1-56. Thornber, J. J. 1901. The prairie-grass formation in region I. Rep. Bot. Surv. Univ. Nebr. 5: 29-143. Thornthwaite, C. W. 1931. The climates of North America according to a new classification. Geographical Review 21: 633-655.

Aspects of the Ecology of the Pacific Slender Salamander, Batrachoseps Pacificus, in Southern California

Although having a wide geographic range, the gray shrew ( Notiosorex c. crawfordi Baird) has been one of the most rarely collected North American mammals. Recently, Hoffmeister and Goodpaster (1954) found Notiosorex to be surprisingly common in the Huachuca Mountains of southeastern Arizona. There they were able to secure seven specimens from beneath Agave plants and sight records for two others. It seems probable that Notiosorex is also more common in southern California than has been previously appreciated. The writer wishes to thank Mr. Bill Lower for assistance in field work and Dr. George A. Bartholomew for his many helpful suggestions regarding this study.

Los Angeles County .—Vaughan (1954) reported a Notiosorex taken “beneath a woodpile on the campus of Norton School, two miles northeast of Claremont… .” Cunningham (1956) found that barn owls ( Tyto alba ) and horned owls ( Bubo virginianus ) regularly capture Notiosorex in coastal Los Angeles County. Two skulls of this shrew were found in pellets taken from a barn owl nest and five found in two horned owl nests. In every sample of pellets from these nests, Notiosorex was as common, or more common, than the ornate shrew ( Sorex ornatus ), the shrew most frequently captured by man in this area. Compton (1937) similarly found Notiosorex to be more abundant than Sorex , in a ratio of ten to one, in the Pleistocene deposits of the Rancho La Brea tar pits.

Vegetation of the three …

An understanding of social policy is crucial for social workers as it underpins and shapes the legislative framework that they work within. From safeguarding service users and enabling them to improve their lives, to protecting the most vulnerable in society, social policy also has a vital role to play within social work education. It is important therefore for students to engage critically with social policy. This book introduces policy and shows how it has changed and evolved over time, how it reflects changes in society and how it is applied to everyday practice.

This introduction sets the context for understanding the political involvement and engagement of working class children. It looks at the history of childhood, our understandings of children's roles in society - and how they often challenge these imposed roles by engaging in political movements for change. 
 
This is the introductory chapter to a monograph on the history of school student strikes in Britain.

Schools Out!: The Hidden History of Britain's School Student Strikes

Developing a sociological imagination: Debunking society Poverty and social work users Social exclusion, sociology and social work Families Community Moral Panics Education Social class Looking back, looking forwards: The relevance of sociology for social work

Childrenâs Rights or Employersâ Rights? The âDestigmatisationâ of Child Labour

Despite the controversy surrounding the passage of Section 9 of the Asylum and Immigration (Treatment of Claimants, etc.) Act into law, the Home Office is piloting it in a number of local authorities across England and Wales, with a view to implementing it nationally. The Home Office is conducting its own evaluation of the pilot, but stake-holders remain unconvinced as to its objectivity and validity. This article analyses the implementation of Section 9 and finds that it has been a spectacular failure. Quite apart from failing to achieve its desired aim of securing the return of failed asylum seekers to their country of origin, Section 9 has brought about immeasurable suffering and misery. Attention is drawn to the human impact of the policy, and profiled are some of the families who have faced the impossible choice of destitution or deportation. On a more positive note, the article recognizes the unprecedented and overwhelming support that families have received from local people and the media.

'No choice at all': Destitution or deportation? A commentary on the implementation of Section 9 of the Asylum and Immigration (Treatment of Claimants, etc.) Act 2004

'Demographic Time bomb' or 'Apocalyptic Demography': The Great Pensions Debate

Children, Social Policy and the State: The Dichotomy of Care and Control

This article analyses Section 9 of the Immigration and Asylum (Treatment of Claimants, etc.) Act, which gives the Home Office powers to terminate all welfare support to failed asylum-seeking families deemed to be in a position to leave the United Kingdom. It examines the implications of Section 9 for both practitioners and asylum-seeking families. The article shows that by threatening children with destitution and possible removal from their families, Section 9 flies in the face of the UK’s domestic and international human rights commitments. Moreover, in flatly contradicting accepted childcare principles, Section 9 undermines the Labour government’s stated ambition to ensure that ‘every child matters’.

‘Starve them out’: does every child really matter? A commentary on Section 9 of the Asylum and Immigration (Treatment of Claimants, etc.) Act, 2004

'Globablisation and Child Labour: protection, liberation or anti-capitalism?'

This article looks at the development of citizenship education within schools and assesses its impact on the school strike wave against the war on Iraq that took place during February and March 2003, in part utilizing interview material drawn from active strikers. Although citizenship, as outlined in the Crick Report, should have welcomed young people’s active engagement with the political process, the overwhelming response of the educational establishment was to castigate and punish those who took part in the strikes. In conclusion, the article argues that the actuality of citizenship classes focuses on individual aspects of responsibility and moral education and had little influence on the engaged ‘active citizens’ who demonstrated against war by walking out of their schools.

‘Active Citizens’ or ‘Irresponsible Truants’? School Student Strikes against the War

The Equality Act 2010 and the Impact of it on the Post-Compulsory Education Sector

Parents have a fundamental role in promoting the healthy weight of their children.

To determine parental perceptions of their child's body weight, eating and physical activity (PA) behaviours, and to test a predictive model of parental perceptions regarding their child's PA and healthy eating behaviours.

METHODS
A random-digit telephone survey was conducted among parents of children four to 12 years of age living in the Champlain region of Ontario. Descriptive statistics were used to summarize the responses. Path analysis was used to identify predictors of parental perceptions of PA and healthy eating.

RESULTS
The study sample consisted of 1940 parents/caregivers. Only 0.2% of parents reported their child as being obese; 8.6% reported their child as being overweight. Most parents perceived their child to be physically active and eating healthily. Approximately 25% of parents reported that their child spent 2 h/day or more in front of a screen, and that their child consumed less than three servings of fruits and vegetables daily, and regularly consumed fast food. Variables that correlated with PA perceptions included time spent reading/doing homework, interest in PA, perceived importance of PA, frequency of PA, level of parental PA, participation in organized sport, child weight and parental concern for weight. Variables that predicted perceptions regarding healthy eating were parental education, household income, preparation of home-cooked meals, fruit and vegetable intake, and concern for and influence on the child's weight.

Parents in the present study sample did not appear to understand, or had little knowledge of the recommendations for PA and healthy eating in children. Parents appeared to base their judgment of healthy levels of PA or healthy eating behaviours using minimal criteria; these criteria are inconsistent with those used by health professionals to define adequate PA and healthy eating. The present survey highlights an important knowledge gap between scientific opinion and parental perceptions of the criteria for healthy PA and eating behaviours.

Using path analysis to understand parents' perceptions of their children's weight, physical activity and eating habits in the Champlain region of Ontario.

This article describes the relationship between the perceived norm for marijuana use among peers and the use reported by university students in Chile. This is a qualitative, multicenter, cross-sectional study. A total 449 students participated with free consent. Data collection was performed using a self-administered questionnaire, and SPSS 15.0 was used for data analysis.

RESULTS
most participants were women, single, between 20 and 21 years of age, students of nursing and education. The perceived norm is higher than reports from national studies (32.1% against 21%) and higher than the self-reported use (32.1% against 5.6%). Marijuana use is higher among women, in nursing and education courses. It was confirmed that marijuana use among women begins at the university; as it was used as a recreational drug and there was more tolerance among peers. It was observed that marijuana use was overestimated, which, according to the Theory of Social Norms and Normalization, has an effect on the increase of drug use. This study is a contribution for the country's and the university's policies.

[Perceived norm for marijuana use among university student peers].

The purpose of this study was to assess the difference between perceived norms and peers' drug use among sophomore and junior university students (from the field of education) aged 18 to 24 years. The Social Norms Theory was used as the theoretical framework. In total, 286 students participated in the study, 67% of which reported having consumed alcohol at least once in a lifetime and 28% stated being daily users. Students perceived that 62% of their peers used tobacco and 63% used alcohol. The perceived norm for drug use was slightly higher in women than in men. In conclusion, there is an overestimation between the perceived norm and use of alcohol, tobacco, marijuana and cocaine.

[Perceived norms among Honduran university students about peers and tobacco, alcohol, marijuana and cocaine use].

This quantitative, cross-sectional study was performed to estimate the difference between the perceived norms among university students, based on a survey of 196 nursing students from Lima, Peru. A questionnaire was used to measure the students' perception about drug use and their actual use. Descriptive statistical analysis was performed, considering a value greater, smaller or equal to 10 to establish the difference. The perceived norms for alcohol and tobacco were above 50%, against 6% for marijuana and cocaine; with 57.7% of participants reporting tobacco use, 84.7% alcohol, 2.6% marijuana and 1% cocaine. Marijuana and cocaine use was overestimated, while alcohol use was underestimated. The perception of tobacco use was correct. The study findings are useful to sensitize university authorities and put prevention policies in practice.

[Perceived norms among nursing students about their peers and drug use in Lima, Peru].

This study aimed to analyze the relation between university students' perceived norms and actual drug use among their peers. This cross-sectional study was based on a survey. Evaluations involved all second- and third-year students (ages between 18 and 24 years) of the nursing and medicine courses at the Faculdade de Medicina do ABC, located in the city of Santo André, Brazil. Students were invited to answer a questionnaire that evaluated several variables, including their own drug use and their perception of their peers' drug use. In total, 274 students participated. Data analysis was performed using SPSS and descriptive techniques, including frequencies and means. There was an overestimation of the perception regarding drug use in relation to the actual frequency reported by the students.

[University students' perception regarding drug use among peers in the ABC Region of São Paulo, Brazil].

Adolescent Injury Cross-national Study of Fighting and Weapon Carrying as Determinants of

This study analyzes the relationship between perceived norms about drug use among peers and actual use among university students. This is a qualitative, multicenter study involving sophomore and junior students of the health courses of a Chilean university. Participants were 286 (75.2%) of the total 380 university students.

RESULTS
more than 50% of the students notice that their peers smoke cigarettes on a daily basis, drink alcohol three times a week, and use marijuana once a week and cocaine at least once a year. The university campus it place of highest drug use; cocaine is used at a friend's house. Among students, 68% have smoked once in their life, 57% smoke on a daily basis; 88% have had alcohol once in their life; 26% used marijuana once in their life, 16% used marijuana over the last 12 months. Students do not know about any university policies for drug use. Some results confirm that drug use is underestimated.

[Perceived norms among university students about their peers and drug use at a Chilean university].

The purpose of this study was to estimate differences between perceived and reported drug use among sophomore and junior university students, aged 18 to 24 years, from a public university in Medellin, Colombia.

METHOD
this is a descriptive and cross-sectional study. All second- and third-year students at the Schools of Medicine, Dentistry, Nursing and Public Health were invited to answer an anonymous questionnaire. In total, 427 students participated.

RESULTS
data suggest that students overestimate the use of tobacco, marijuana and cocaine over the last 12 months. Alcohol use was perceived accurately. Students who reported using those substances during that period overestimated their peers' drug use more than those who did not. Furthermore, more women than men overestimated marijuana use.

[Consumption and perceived use of licit and illicit drugs among university students, Antioquia, Medellin, Colombia].

Alcohol is the most prevalent legal drug among university students, and it is used recreationally. The objectives of this study were to identify the perceived norms of alcohol use among university students, contrast the students' perception regarding peer alcohol use and the actual alcohol use prevalence, and compare the subjects' own alcohol use with their perception of peer alcohol use. A survey was performed on 275 students of a public university located in Rio de Janeiro (Brazil), in 2008. The students' perception about peer alcohol use once in a lifetime and over the last 12 years was correct; but their perception regarding the last 30 days was overestimated. Students consume alcoholic beverages recreationally, mainly at parties and bars with friends and peers. Alcohol use is above established standards.

[Perceived norms of peer alcohol use among university students].

OBJECTIVE
to evaluate the difference between perceived norms about drug use among peer and actual drug use as reported by the same university students. The students were between 18 and 24 years old and attended health courses.

METHOD
cross-sectional study based on a survey, using an anonymous questionnaire filled out by the students.

RESULTS
There were 306 participants. Senior students used drugs as follows: 51.3% used tobacco, 90.8% used alcohol, 5.9% used marijuana, and 0.7% used cocaine. Differences were observed between perceived norms and actual drug use for tobacco (70% vs. 51.3%), marijuana (10% vs. 5.9%) and cocaine (8.3% vs. 0.7%).

university students presented an overestimated rate for the use of tobacco, marijuana and cocaine among their peers.

[Perceived norms among Peruvian students for drug use among peers].

The present study interviewed second- and third-year students of three health courses to identify university students' estimates for drug use (perceived norm), the rate of drug use among the subjects (real norm); compare the estimates with the actual frequency; and identify in what conditions the drugs are used. Students overestimated their peers' use of tobacco, marijuana and cocaine in life and over the last 12 months. Alcohol was an exception. The rate values reported by sample students and the general estimated use were rather close. Drugs are usually consumed at parties and among friends from the university. Data analysis was performed in the light of the Social Norms Theory, Causal Attribution and Normalization.

[Perceived norms among university students of three health courses for drug use among peers].

The objective of this study was to estimate the difference between perceived norms for drug use among university students and their peers, with ages between 18 and 24 years, and attending education and health courses. This cross-sectional study was based on a survey and an anonymous self-administered questionnaire.

RESULTS
in total, 365 students participated. The rates for drug use over the last year were as follows: 43.6% for tobacco; 96.2% for alcohol; 8.2% for marijuana; and 2.2% for cocaine. The perceived norm for drug use over the last year was 78.9% for tobacco, 88.3% for alcohol, 35.4% for marijuana and 20.9% for cocaine. The consumption of alcoholic beverages and the perceived norm were very close, but it was overestimated for tobacco use. Regarding access to drugs being easy or very easy on campus, access to cigarettes and cocaine was underestimated, while marijuana was overestimated.

university students overestimate the use of tobacco, marijuana and cocaine by their peers and have a correct perception of alcohol use. Tobacco is the substance with the most overestimated use.

[Perceived norms among university students about their peers and drug use in Bogota, Colombia].

The feasiblity of an observational rating scale which would vovide objective, reliable and quantifiKble measures of social and affective behavior was investigated. The Observation of Socialization Behavior (059), focusing on peer-group behaviot of pre-school children and designed for use in unstructured situations was developed. Two forms of the instrument, one for use with videotaped interaction sessions, and the other for live classroom situations, were developed. A combination time-and event-sampling procedure was used and behavioral events were recorded at twenty-second intervals. Observers were trained by videotaped interaction segments, and computation of observer rellity is explained. Investigations provide favorable in 4 the validity of the instrument for measuring peer-s. uvior of pre-school children. It is concluded that the instrument is useful, flexible, and applicable to early childhood psychometry. (la) DEVELOPMENT OF AN OBSERVATIONAL RATING SCHEDULE FOR PRESCHOOL CHILDREN'S PEER-GROUP BEHAVIOR* Jo Lynn Cunningham and Robert P. Boger U.S. DEPARTMENT OF HEALTH, EDUCATION & WELFARE OFFICE OF EDUCATION THIS DOCUMENT HAS BEEN REPRODUCED EXACTLY AS RECEIVED FROM THE PERSON OP ORGANIZATION ORIGINATING IT. PC \ITS OF VIEW OR OPINIONS STATED 70 OT NECESSAHILY REPRESENT OF--1CIA L OFFICE OF EDUCATION POSITIC CR POLICY. Institute for Family and Child Research Michigan State University East Lansing, Michigan 48823 Presented at the annual meeting of the American Educational Research Association, New York, February, 1971. *This research project was supported by Office of Economic Opportunity Grants No, CG 9931 (1969-70) and No. 4118 (1968-69).

Socialization Behavior (059), focusing on peer-group behaviot of pre-school children and designed for use in unstructured situations

Objectives. We sought to (1) compare estimates of the prevalence of fighting and weapon carrying among adolescent boys and girls in North American and European countries and (2) assess in adolescents from a subgroup of these countries comparative rates of weapon carrying and characteristics of fighting and injury outcomes, with a determination of the association between these indicators of violence and the occurrence of medically treated injury. Design and Setting. Cross-sectional self-report surveys using 120 questions were obtained from nationally representative samples of 161082 students in 35 countries. In addition, optional factors were assessed within individual countries: characteristics of fighting (9 countries); characteristics of weapon carrying (7 countries); and medically treated injury (8 countries). Participants. Participants included all consenting students in sampled classrooms (average age: 11–15 years). Measures. The primary measures assessed included involvement in physical fights and the types of people involved; frequency and types of weapon carrying; and frequency and types of medically treated injury. Results. Involvement in fighting varied across countries, ranging from 37% to 69% of the boys and 13% to 32% of the girls. Adolescents most often reported fighting with friends or relatives. Among adolescents reporting fights, fighting with total strangers varied from 16% to 53% of the boys and 5% to 16% of the girls. Involvement in weapon carrying ranged from 10% to 21% of the boys and 2% to 5% of the girls. Among youth reporting weapon carrying, those carrying handguns or other firearms ranged from 7% to 22% of the boys and 3% to 11% of the girls. In nearly all reporting countries, both physical fighting and weapon carrying were significantly associated with elevated risks for medically treated, multiple, and hospitalized injury events. Conclusions. Fighting and weapon carrying are 2 common indicators of physical violence that are experienced by young people. Associations of fighting and weapon carrying with injury-related health outcomes are remarkably similar across countries. Violence is an important issue affecting the health of adolescents internationally.

Cross-national Study of Fighting and Weapon Carrying as Determinants of Adolescent Injury

Abstract Analyses of civic engagement in the U.S. over almost two centuries have reflected the value of community participation. Service-learning provides opportunities for students to experience such participation by engaging in a form of citizenship education as well as developing professional knowledge and skills. Programs for children and youth from low-income urban families represent a rich context for service-learning in child and family studies. Interaction of professional and civic responsibilities can add depth to students' participation if they approach the experience within a framework emphasizing the reciprocal nature of the experience. Applications of several service-learning models within two programs illustrate the rewards and challenges for students and for faculty who facilitate these experiences. Concerns about safety and different value systems, lifestyles, and standards generally diminished overtime and were replaced by rejection of stereotypes, acceptance of cultural differences, clar...

Service-Learning in Faith-Based Programs for Children and Youth from Low-Income Urban Families

Public policy has been defined as "the sum of government activities, whether acting directly or through agents, as it has an influence on the lives of citizens" (Peters, 1993, p. 4). Family policy, then, may be seen as everything government does that affects families (Zimmerman, 1979). More specific is Aldous and Dumon's (1990) definition of family policy as "objectives concerning family well-being and the specific measures taken by governmental bodies to achieve them" (p. 1137). Family policy can be characterized by such dimensions as "explicit and implicit family objectives, direct and indirect family effects, manifest and latent family content and effects, and intentional and unintentional family effects or consequences" (Zimmerman, 1992, p. 10). It also can be characterized by level (organizational, community, county, state, regional, national, international) and by sector (public, quasi-public, private) (Zimmerman, 1988). Thus, family policy development involves addressing problems affecting family life as perceived by policy makers at all levels (e.g., national or international, local, or intrafamilial) (Anderson, 1993) and in various social systems and institutions. For example, school boards set policies in public educational institutions, legislatures pass laws establishing roles of families in special education services, and the judicial system structures procedures for divorce and custody cases. Policy science has a dual focus on a) public policy development and implementation and (b) policy analysis and evaluation (Monroe, 1988). Most visible and most often examined by family scientists are explicit policies with manifest family content and direct family effects, particularly those from the legislative arena. Specific policies typically are examined using a process such as statutory analysis (Moen & Schorr 1987; Monroe, 1987; Sabatier & Mazmanian, 1979) or policy impact analysis (Culler & Cunningham, 1980; Cunningham, Hughes, Philpot, & Pentz, 1981; Perry, Heathington, Philpot, Pentz, & Lo, 1980). A different level of analysis involves examination of the broader policy framework, or policy infrastructure. This less frequently used approach is the basis of this article. The cultural and historical underpinnings of the U.S. policy infrastructure are individualistic (Aldous, 1987; Hafen, 1990; LeLoup, 1991), making it hard to develop an authentic family policy (Aldous, 1987; Schorr, 1979). In fact, there is no mention of the family in the U.S. constitution (Langley, 1991). Individual freedom, which is tolerated and indeed valued, exists within a framework of limited social control that sometimes results in what are to many members of society unacceptable actions, such as the use of living wills, privacy of adolescents' contraceptive decisions, and abortion. Because our society values the sanctity and privacy of home and family and views these values as rights, it is very hard to institute policies that violate them (Wilcox & O'Keeffe, 1991). Nevertheless, some laws do put protection of the child's welfare over privacy of the family; examples include compulsory education, mandated use of child passenger restraint devices, and obligatory reporting of child abuse. Furthermore, a cornerstone in our nation's policy framework is legal process. This adversarial model, a classic win-lose approach to dispute settlement, presents various problems. It is costly in both money and time, and it often exacerbates existing tensions, resulting in further relationship damage even if the legal outcome is favorable for one of the disputants. The impact of this model, with its hierarchical system of appeals, is magnified by its use in other social systems such as school grievance procedures, methods of dealing with conflicts in the workplace, and current options for addressing conflicts in the health care system. In family-related disputes (both within the family and between the family and other social systems), disruption of relationships is especially unfortunate and potentially destructive, reinforcing contemporary American culture's preoccupation with what often is perceived as the erosion of the family as an institution (Hafen, 1990; Wisensale, 1992). …

Expanding the Policy Infrastructure for Resolving Family-Related Disputes: Mediation as a Technology

This research examined adolescent anger in a cohort of adolescents measured twice, once during the freshman year and again in the senior year of high school. Anger was measured by the Anger Index, a questionnaire developed by Siegel (1984). The purpose of the research was to determine if adolescent anger changed over time and if there were gender differences. Results of the study indicated that anger scores appeared to be stable over time for both boys and girls. There were gender and time differences on individual responses for several items, indicating that certain dimensions of anger may differ over time and by gender. It also appeared possible that the interpretation of certain questions on the anger index was different for the adolescents at the two time intervals.

Journal of child and adolescent psychiatric and mental health nursing

Effect of pencil diameter on the graphomotor skill of preschoolers

There are strong histoical linl<s between church and family. one of the most frequent rytantftstatiorts of this link today is premaital counieting by clerg-ttze source^of tlris upeience for the majoity of couptes in the u.s.cieryt ire the mos,t frequently used source for all penonal and family counseling in this country, and premaital counseling constitutes a major portion of the iotat counseliig done by clergt. Limited research has been done conceming the rote of clergt ai premaital counselors. However, there is evidence that clerg tend to bi relatively poorly prepared for their role as premaital counselon, eithir tlrough their formil educational background or through other means, Recommendaions ari made for faryily life educators, clergt counselorc trained in other disciplines, and researchers to contibute to amelioratirtg the present deficiencies in practice and in the literature, and a model is proposed of improvirtg effectivenesi of clergt as premaital counselors.

Premarital Counseling by Clergy: a Key Link Between Church and Family

An Integrative Nutrition Education Framework for Preschool through Grade 12

Adapting a nutrition education evaluation to field and political realities

A three-way design was used to determine whether teachers' judgments about mentally retarded children would be related to characteristics of the children, characteristics of the teacher, and/or characteristics of an integrated free-play setting. Independent variables were integration ratio, area of teacher's specialization, and target child. The dependent variable was teachers' judgments about handicapped children in an integrated setting. Subjects were 15 regular-education teachers and 15 special-education teachers who taught at the primary school level. Judgment ratings by regular-education teachers depended both on the characteristics of the target child and the integration ratio in the free-play activity. Special-education teachers' judgments also were influenced by characteristics of the child observed but not the integration ratio.

Regular- and special-education teachers' judgments about mentally retarded children in an integrated setting.

The body of literature on children and divorce presents a confusing picture, but the need to understand divorce has never been greater. In an effort to clarify the literature, 18 studies published between 1978 and 1981 were compared and contrasted for conceptual and methodological features. Studies were selected using a multistage sampling technique. Each study was reviewed for conceptual and methodological dimensions, and major conclusions were categorized as positive, neutral, or negative. Both conceptual and methodological issues seem to account for some of the apparent discrepancies in the literature. In particular, the types of variables chosen (a conceptual dimension) and the measurement strategy (a methodological dimension) seemed to account for the most variation across the studies. Future researchers are encouraged to be more cognizant of how conceptual and methodological features of their work will affect their outcomes.

Consensus or Confusion in Research on Children and Divorce: Conceptual and Methodological Issues.

AUTHOR Banta, Trudy; Cunningham, Jo Lynn TITLE A Chance to Do It Right: Assessing the Impact on Participants of a State-Wide Nutrition Education Program. SPONS AGENCY Department of Agriculture, Washington, D.C.; Tennessee Stite Dept. of Education, Nashville. PUB DATE Mar 82 NOTE 9p.; Paper presented at the Annual Meeting of the American Educational Research Association (New York, NY, March 19-23, 1982).

A Chance to Do It Right: Assessing the Impact on Participants of a State-Wide Nutrition Education Program.

Development of CANKAP: a multidimensional measure of nutritional beliefs

Painting behaviors of preschool children at table and easel surfaces were compared. Behaviors investigated were time spent at painting, number of color changes, changes in hand position on brush, and type of stroke. Subjects were 20 children between 33 and 50 months of age. Observa- tional data were collected in two preschool settings using the Children's Painting Behavior Checklist (CPBC). Treatment differences for hand position were noted, as were gender dif- ferences for both hand position and type of stroke. It appeared that the use of tables as a paint- ing surface facilitated the use of more advanced hand positions during painting than did the use of easels. Painting behaviors of preschool children at table and easel surfaces were compared. Behaviors investigated were time spent at painting, number of color changes, changes in hand position on brush, and type of stroke. Subjects were 20 children between 33 and 50 months of age. Observa- tional data were collected in two preschool settings using the Children's Painting Behavior Checklist (CPBC). Treatment differences for hand position were noted, as were gender dif- ferences for both hand position and type of stroke. It appeared that the use of tables as a paint- ing surface facilitated the use of more advanced hand positions during painting than did the use of easels. Painting behaviors of preschool children at table and easel surfaces were compared. Behaviors investigated were time spent at painting, number of color changes, changes in hand position on brush, and type of stroke. Subjects were 20 children between 33 and 50 months of age. Observa- tional data were collected in two preschool settings using the Children's Painting Behavior Checklist (CPBC). Treatment differences for hand position were noted, as were gender dif- ferences for both hand position and type of stroke. It appeared that the use of tables as a paint- ing surface facilitated the use of more advanced hand positions during painting than did the use of easels. In art education there has been some hesi- tancy about adherence to prescriptive ap- proaches because of the priority given to ex- ploration and creative problem solving in art. However, the demands for accountabil- ity that most teachers face today are causing educators to look closely at the reasons behind even the simplest and most basic ex- periences presented to students, with a view to determining their relative importance for the total curriculum. Empirical evidence derived from the theories of Lowenfeld (1975), McFee (1970),

lished under land-grant provisions has been accepted only recently as another specified role of a university. In the early eras of research in universities, much of the research was performed by individuals operating essentially independently. For universities, the research efforts tended to be relatively small projects with few, if any, outside funds to support such efforts. After World War II, and particularly in the 1960's with the emphasis on the social reform and space programs, research became a very large portion of many universities' activities. As universities increased their role in research, team efforts became important. Large projects that required team efforts were developed often at the request of the external research sponsor. Within the past 10 to 15 years, emphasis has been directed toward interdisciplinary research (IDR) and its contribution to the solution of increasingly complex societal problems. With IDR, individuals of differing expertise and backgrounds work together in conducting a research project. Thus, the decision-making process related to the conduct of research is not left to one individual but often must be made in

Management of Interdisciplinary Research in Universities: The State of The Art1

Development of an Observational Procedure for Assessment of Parent-Child Interaction.

A Longitudinal Study of the Social Development of Three-and Four-Year-Old Children in a Preschool Program.

Development of an Observational Rating Schedule for Preschool Children's Peer-Group Behavior.

Simon Bordley (1709-1799) was a Catholic priest of humble status in rural Lancashire for much of the eighteenth century. Despite his rural location and apparently humble status, he played an important part in supporting the Catholic seminaries in France and Portugal by supplying them with students, material goods and financial assistance. Bordley left behind him a lively correspondence relating to these activities which provides us with a valuable insight into the world of eighteenth-century priestly training in the English colleges. It also offers a fascinating glimpse into the world of a churchman who laboured with an impressive level of entrepreneurial skill and independence. This article argues that Bordley defies the common image of the seigneurial Catholic curate in service primarily to a family of the landed gentry in the eighteenth century. In doing so he illustrates an example of the type of energetic cleric who provided a crucial lifeline to a church that came to rely less and less on its aristocracy as the century progressed.

Fr Simon Bordley, eighteenth-century recusant priest, schoolmaster and trader in ‘two-legged cattle’

Canada 1919: A Nation Shaped by War ed. by Tim Cook and J. L. Granatstein (review)

commitment to generative partnerships with non-state actors, be they gallery directors, curators, or artists (Smith); revisit the role of gift exchange in opening up “spaces of equivalence in asymmetrical power relations” (225) to foster meaningful people-topeople and state-to-state dialogue (Mark Kristmanson); and underline the need to develop proficiency in the realms of intercultural relations and international law when partaking in the exhibition of disputed cultural artifacts (Bernard Duhaime and Camille Labadie). The case studies featured may help map the scope of practices that fall under the public diplomacy umbrella, but they also serve to introduce the range of actors called upon to make and project Canada’s image abroad. On this topic, Copeland offers an important reminder when he writes that the “continuing evolution away from statecentricity,”which is a function of today’s dynamic world of networked non-state actors, “requires that diplomacy become more public, inclusive, and participatory” (37). Yet Canada’s Public Diplomacy offers few insights on how best to engage the individuals, groups, and organizations that make up domestic civil society. Listening to indigenous voices and incorporating the perspectives of diaspora communities, for instance, are key to holding Canada to account as it navigates an increasingly complex diplomatic landscape amid a climate crisis bound to negatively impact human rights and democratic governance. As Cull explains, the “most credible partners in global conversations are unlikely to be nation-states, and Ottawa would do well to look to empower” such non-state actors (10). This timely book is thus also an invitation to reflect on the urgent need to take concrete steps in that direction.

Thomas A. Schwartz Henry Kissinger and American Power: A Political Biography

‘That we might be made God’: Pseudo-Dionysius and Robert Grosseteste’s Episcopal Career

The great medieval scholar and bishop of Lincoln, Robert Grosseteste (c. 1168-1253) was the very epitome of the polymath. A scientist, philosopher, translator, theologian and poet; his learning, imagination and his vast wisdom are little short of awe-inspiring. He was also bishop of the largest diocese in England and in this role he came into conflict with the papacy. In particular, he strongly opposed the policy of giving English benefices to absentee Italians, an opposition he was not afraid to voice in the strongest possible terms. For this reason he was much vaunted in later centuries by Church reformers. John Wyclif admired him greatly and by the time we get to the English Reformation writers such as John Foxe were keen to claim Grosseteste as a type of proto-Protestant. In the eighteenth century Fr Philip Perry, the Rector of St Alban’s English seminary in Valladolid, decided to challenge this image by writing a biography of Grosseteste that would restore his reputation as a solid Roman Catholic. However, Perry’s timing could not have been less auspicious. In 1760s English Catholics were close to achieving emancipation, the Vicar Apostolic, Richard Challoner suppressed the polemical text and to this day it remained until now in handwritten manuscript form. Cunningham has produced a critical edition of this work which offers us a fascinating glimpse into both the life of one of England’s greatest ecclesiastics and also into the precarious politics of the eighteenth-century English Catholic Church.

Essay on the life and manners of the venerable Robert Grosseteste, Bishop of Lincoln, by Philip Perry

The educational renaissance in twelfth- and thirteenth-century Western Europe

The Soteriology of James Ussher: The Act and Object of Saving Faith. Richard Snoddy. Oxford Studies in Historical Theology. Oxford: Oxford University Press, 2014. xvi + 288 pp. $74.

Robert Grosseteste and the Pursuit of Learning in the Thirteenth Century

Robert Grosseteste and the pursuit of religious and scientific learning in the middle ages

Christopher McKnight Nichols Promise and Peril: America at the Dawn of a Global Age Cambridge, MA: Harvard University Press;, 201 I ; 464 pp., ISBN: 978-0-674-04984-0, $37.00 (cloth).Christopher McKnight Nichols opens his study of American isolationism by quoting George W. Bush's warning, in his 2006 State of the Union address, that "the road of isolationism and protectionism may seem broad and inviting-yet it ends in danger and decline" (1). The bipartisan proclivity for employing "isolationist" solely as an epithet, Nichols writes, along with its binary opposition to internation- alism, "misconstrues the rich complexity of the origins of isolationism'' (1). Nichols seeks to reinterpret and rehabilitate isolationist thinkers of the period from roughly 1898 to 1940, whose ideas he frames as a response to turn-of-the-century imperialism and the Spanish-American War. This modern isolationism was "a constellation of ideas rather than a single principle or policy position" (352) and compatible with widely divergent approaches to foreign relations. Nichols is intent on proving that isolationism "did not entail cultural, economic, or complete political separation from the rest of the world" although "such a separation from the world is the first reaction that comes to mind." Isolationism was also rooted in conceptions of American domestic arrangements and "frequently turned, in fact and in debate, on the inner life of the nation" (352).This is nowhere near as daring and pathbreaking as it sounds. Not for decades has any serious student of American diplomacy believed that isolationism entailed the construction of impermeable barriers between America and the rest of the world. And there is already a rich literature (indeed, Nichols cites it extensively) that demonstrates how deeply rooted isolationist precepts were in conceptions of the good life at home. For example, Wayne S. Cole's many works on interwar isolationists amply illustrate the centrality of their Midwestern and agrarian roots to their suspicion of entanglements abroad. Yet if these elements of Nichols' larger argument are all too familiar, its parts are often greater than the whole. The ana- lyses of individual figures are discerning, well judged, and show a commendable grasp of the varied archival materials and relevant scholarly literature, even if Nichols' prose is often sloppy and the copy-editing is abysmal.Nichols gets off to a shaky start by choosing as one of his exemplary figures the Republican senator Henry Cabot Lodge, a vehement imperialist and navalist. Lodge was a prominent supporter of the "Large Policy" against which Nichols sees most of his other illustrative figures reacting, and his one isolationist trait was an absolutist conception of national sovereignty. In his case, this ruled out participation in the League of Nations as an intolerable abridgement of Congress's prerogative to decide if and where American troops were deployed and led him, as chairman of the Senate Foreign Relations Committee, to play a crucial role in preventing American ratification of the Treaty of Versailles. If Lodge can be shoehorned into the isolationist camp, questions arise of just who could plausibly be excluded and whether what Nichols surveys is in fact a coherent tradition or world view at all.Fortunately, most of the other individuals to whom Nichols devotes chapters fit the isolationist mould more consistently and amount to something better resem- bling a unified school of thought. Their principal shared preoccupation is with the fate of individual liberty in the wake of the giant industrial and military organizations ushered in by the new century. Nichols turns first to the philosopher William James, previously apolitical but a stalwart of the Anti-Imperialist League after American troops were committed to occupying the Philippines. Aptly enough for a founder of Pragmatism, James judged America's dalliance with empire by its consequences, and feared that however elevated the motives and rhetoric of empire, the reality would be brutality abroad and conformity at home. …

Promise and Peril: America at the Dawn of a Global Age, by Christopher McKnight Nichols

Charles Moore Margaret Thatcher: The Authorized Biography. Vol. I, Not for Turning London: Allen Lane, 2013. 895 pp. $39.00 (cloth) ISBN 978-0713992823The first volume of Charles Moore's official biography of Margaret Thatcher is in some ways surprising. Presumably picked for the task because of his Thatcherite predilections, the long-time Tory journalist wrote with exclusive access to the former prime minister and her papers, as well as many of her associates. The portrait he paints is elegantly crafted if overlong, and, while more richly detailed than the highly critical biographies by Hugo Young and John Campbell, confirms their essential findings. He too finds a leader whose fabled resolve sometimes tips into obstinacy but is as often tempered by a surprising pragmatism. Moore flirts unconvincingly with the idea that Thatcher was an embryonic libertarian from an early age, but more plausibly settles on the view that she identified with, and reflected the views of the small-business, lower-middle-class, Tory grassroots who had never fully reconciled themselves to the party leadership's acceptance of Keynesian economics and the postwar welfare state.Not all of the new material Moore has found rewards his industry. The muchballyhooed discovery of a cache of youthful letters to her sister shows the undergraduate Margaret to have been less preoccupied with politics and more with fashion, food, and previously unknown early boyfriends than other biographers have known. Likewise, it is no more than mildly surprising or illuminating that her eventual husband, Denis, decamped for a time to South Africa during a midlife crisis when "it was... possible that their marriage would end" (175). Moore is on solid ground when he highlights the implausibility of her ascent in light of her humble origins and lack of the standard political gifts of charm and easy eloquence. Instead, she relied on remorseless labour to master her brief; for all her fabled affinity for Ronald Reagan, in her triumph of fortitude over lack of natural talent she is closer to Richard Nixon. Discipline carried her from candidate in unwinnable riding to backbencher to ministerial office in the government of Edward Heath.At crucial moments, she was lucky. In 1975 she won the leadership largely because Heath had not only lost three out of four elections but also alienated even like-minded MPs by his ham-handedness in personal relations. And in much of the run-up to the 1979 election she was significantly less popular than the Labour Party prime minister James Callaghan, who cleaved to the centre ground and himself took steps away from the Keynesian consensus Thatcher was determined to shatter. But Callaghan shied away from calling an election in late 1978, which he might well have won, and by 1979 a resurgence of trade union militancy had destroyed his standing with the electorate and made Thatcher's victory as close to inevitable as politics allows.Moore is sympathetic to the economic program of Thatcher's early years, which stressed the defeat of inflation over that of unemployment, the setting of wages by the free play of market forces rather than government incomes policy, and the control of state spending. There is no discussion here of whether a more measured version of her program (rather than what the Labour politician Denis Healey labeled "sado-monetarism") might have worked better, nor acknowledgement that Thatcher never succeeded in either reducing spending or boosting the prod- uctivity of Britain's economy. Moore provides the most detailed description to date of internal debates over the government's economic direction, and plausibly argues that the public debate between Thatcherites and proponents of a return to the Keynesian consensus was less consequential for the making of policy than debates among those who were in broad agreement about the correctness of the Thatcherite course but differed over the timing and details of implementation. …

Margaret Thatcher: The Authorized Biography. Vol. 1, Not for Turning, by Charles Moore

of topics ranging from aural, visual, and textual examples makes the volume useful as a whole, rather than a compilation of parts. Although readers will no doubt gravitate toward specific chapter topics, the essays are well complemented by the application of differing disciplinary insights. Visual historians, for example, will find language imagery in saints’ liturgy and poetic acrostics, whereas textual scholars will be reminded of the power of marginalia, illuminations, and imaginative postmedieval reconstruction.

Robert Grosseteste and His Intellectual Milieu: New Editions and Studies ed. by John Flood, James R. Ginther, Joseph W. Goering (review)

Lumine de lumine: Light, God and Creation in the thought of Robert Grosseteste

GEORGE F. KENNAN An American Life John Lewis Gaddis New York: The Penguin Press, 2011. 784pp. $46.00 (cloth). ISBN 978-1-59420-312-1A full-scale biography of George F. Kennan is doubly justified, since few American diplomats have wielded such influence as either policymaker or critic as he did in both roles. As minister-counselor at the American embassy in Moscow, he wrote the 1946 "long telegram" interpreting Soviet behaviour and, under the pseudonym "X," published a 1947 article in Foreign Affairs outlining an American strategy to contain Soviet expansion. As the first head of the State Department's policy planning staff from 1947 to 1949, he played a role in implementing that strategy, making him perhaps the most significant American policymaker never to rise above ambassadorial rank. But his influence was on the wane by 1950, and he left government to return only for short stints as ambassador to the USSR and later Yugoslavia. From the mid-i940s on, he commented on Soviet affairs and American foreign policy from a perch at Princeton's Institute for Advanced Study. His combination of experience, literary talent, and sheer longevity (he died in 2005 at 1 01) made him a consequential public intellectual.John Gaddis's 1982 book Strategies of Containment was a biography of Kennan's principal idea, and, at the youthful age of 78, Kennan designated Gaddis as his own official biographer. His subject's longevity gave Gaddis the opportunity to mine Kennan's papers and interview many of his contemporaries, while the fact that Kennan outlived the Cold War allowed Gaddis to situate him in the conflict's overall arc. Gaddis's mastery of his sources and immersion in Kennan's world have resulted in a scrupulously researched and elegantly written biography, though there are important questions that he does not fully address. He uses Kennan's diaries and letters to trace Kennan's emergence from a motherless home in Milwaukee's tonier precincts, his outsider status at Princeton, the febrile nervosity that saw him fall ill at almost every crucial moment of his life, and his affinity with Russian culture and life sparked by the great-uncle and namesake who explored and wrote about that country. Kennan's 1930s musings in favour of restricting the franchise to white males with deep roots in America and his notion of a council of Platonic guardians who would make national policy without regard to electoral whims show, as Gaddis writes, that Kennan was ambivalent at best about democracy and "understood the Soviet Union far better than he did the United States" (117). They also point to an essentialism that could sometimes play Kennan false - as when he doubted the relevance of democracy where it was not deeply entrenched - but that also underpinned his confidence that the Soviet Union could not last.While Kennan doubted the possibility of a lasting modus vivendi with the Soviet regime, he saw Marxist ideology as counting for less than traditional Russian nationalism and the need for a foreign enemy to justify totalitarianism at home. He believed that the Soviet bloc would ultimately fragment because its subject populations differed ethnically and linguistically from their Russian overlords, not only because their national interests diverged. From his wartime reading of Gibbon (whom Gaddis convincingly identifies as a seminal influence) and his experience of Europe under Nazi occupation, Kennan concluded that the forcible maintenance of an extensive, heterogeneous empire was impossible over time.Kennan's strategy of creating positions of strength that would check Soviet expansion pending the regime's mellowing and an eventual settlement of the Cold War was widely accepted because, Gaddis writes, it offered "a path between the appeasement that had failed to prevent World War II and the alternative of a third world war" (694). Since elements of Kennan's analysis were already in the air, his main contribution was to rationalize and clarify the assumptions behind the actions toward which policymakers were already leaning. …

1. It was John Bale, dramatist, virulent anti-Catholic and Bishop of Ossory, who first introduced English audiences to their ancestral father, Samothes. His popular history, The Actes of English Votaryes (1546) described an ancient hero, the offspring of Japheth and grandson of Noah, who made his way to Western Europe and fathered the English nation. Bale's audience seemed unperturbed with the author's description of their ancestors, the Samotheans, as giants.[1] There was, after all, Biblical precedence in Genesis 6; the Geneva Bible of 1560 was categorical when it told its readers that, 'there were giants in the earth in those days.' Significantly the King James' version of 1611 (with perhaps a nod toward the Samotheans) added the words, 'and after that.' Thus the colossus Samothes was launched on his career as an English patriarch, not only in the works of Bale but others including Shakespeare, Philip Sidney and the enormously influential Raphael Holinshed. In Sidney's Old Arcadia, the doleful shepherd Philisides tells us that he is from the land of Samothea, a place 'so famous that, telling you I am of that, I shall not need to extend myself further in telling you what the country is.'[2]2. It seemed, on the face of it, that the English nation and its men of letters had taken an immediate liking to their recovered ancestor, a liking that is not hard to appreciate since Samothes provided them with an heroic parentage that measured up to anything claimed in the classical world. He also gave them a direct root to Noah, a patriarch who was seen as the second Adam, father of all the postdiluvian world. In spite of these benefits by the end of the sixteenth century the career of Samothes was in terminal decline. John Stow's Annales claimed that the founding of England was 'irrecoverable,' and then in the first decade of the seventeenth century the great William Camden dismissed the legend entirely.[3] It has previously been tempting to see the myth of Samothes as being killed offby a new wave of more sober-minded and professional historians. However, it will be argued here that we should not regard writers such as Stow and Camden as Reformation giant-killers. They were not involved in an act of debunking for the sake of a more proof-driven history per se. Far from being unhappy with the mythical nature, or stature, of Samothes they were instead expressing major misgivings with the sources, elsewhere they seemed perfectly content to accept histories that were equally as fabulous. This article sets out to explore the short but remarkable career of Samothes and will argue that the giant was not killed by a shot from the sling of a more modern scholarship that refused to place credence in the mythological; rather he tumbled to his death because he was standing on shaky foundations.3. The story of Samothes as set out in Reformed national histories may be summarized as follows. After the flood Noah took his three sons to the top of a mountain and there he divided the unpopulated world between them. The three portions were Europe, Asia and Africa. In 1587, William Harrison realized that this traditional account needed an update and he made a half-hearted attempt to incorporate the New World into his schema by relating that America was part of the division, though he seems reluctant to dwell on who exactly was allotted this land and the subject is passed over rather hastily. However, Harrison explains that before the flood there were no great seas, so St Augustine need not have troubled himself when he pondered the mystery of how animals that lived on remote islands could have made their way to the Ark.[4] Europe was given to Japheth and when it was latter divided among his progeny it was Samothes, the sixth son, whom the Bible calls Mesach and whom Julius Caesar named Dis, who received both France and England and became the father of the Celtic race. Samothes went on to become a model monarch teaching his people not only the course of the stars but 'many other matters incident to the moral and politic government of man's life. …

England's Adam: The Short Career of the Giant Samothes in English Reformation Thought

LIBERAL LEVIATHAN The Origins, Crisis, and Transformation of the American World Order G. John Ikenberry Princeton: Princeton University Press, 2011. 372pp, $35.50 cloth ISBN 978-0-691-12558-9THE PRESIDENCY OF GEORGE W BUSH A First Historical Assessment Edited by Julian E. Zelizer Princeton: Princeton University Press, 2010. 386pp, $29.95 PaPer ISBN 978-0-691-14901-1John Ikenberry' s book-length study of postwar American internationalism - and the second Bush administration's break from it - offers many insights, but it covers events from 2001 to 2008 in insufficient detail to gauge their significance. By contrast, Julian Zelizer' s edited collection, which emerged from a 2008 Princeton conference of historians, lacks a unifying perspective, a failing characteristic of its genre. Nevertheless, one can infer a persuasive overall interpretation of Bush's policies from the book's diverse essays.Ikenberry begins by recapitulating his earlier work on the construction of an American-led multilateral order after 1945. In this "liberal hegemonic order," the United States supported an open world economy and directed western collective security. It agreeed to "operate within a framework of alliances and multilateral institutions that made the exercise of American power more restrained and predictable" and "provided channels and mechanisms for states within the order to consult on and influence American policy" (216). At the end of the Cold War, Ikenberry continues, bipolarity gave way to a temporary unipolarity. The western economic system expanded and multilateral structures integrated the former eastern bloc. But the evanescence of the Soviet threat left other states less dependent on the United States for their security, and in such conditions of unipolarity "the power of the leading state is rendered salient and worrisome" (246). The second Bush administration regarded multilateral institutions as unnecessary constraints on American freedom of action and sought to weaken them as well as to perpetuate the "unipolar moment." After the 9/11 terrorist attacks, it wholeheartedly embraced a strategy based on ad hoc coalitions, preemptive attacks on state and nonstate threats, and the provision of global security by a dominant United States. In exchange, it expected exemptions from the rules that bound other states. But, as Ikenberry concludes, the "Bush revolution" was undone by the fatal contradiction between its global ambitions and its conservative-nationalist insistence on unilateralist prerogatives. This tension could only have been reconciled if "the United States [had been] wiiling, and able, to enforce order through the systematic exercise of coercion" (2 69). Because it rejected the ruthlessness of outright empire, the United States continued to depend on the goodwill of others, and the insistence on immunity from the usual norms deprived American power of the legitimacy required to purchase cooperation.Ikenberry welcomes the United States's return to multilateralism during the latter Bush years and the Obama administration. He notes that "the United States has been one of the most successful order-building states in world history because it has combined the exercise of its power with the championing of rule-based order" (xv). The possible futures he sees include a liberal order that does not depend upon a hegemonic power (an arrangement whose staying power he doubts given the lack of consensus on a sustaining ideology and norms of international conduct), and a gradual breakdown of the liberal order into a more competitive multipolar system. His preferred option seems to be a renegotiated American hegemony, in which "the United States would agree to greater sharing of authority and decision-making within global security and economic institutions" (309).This is a persuasive assessment of why the Bush administration's bid for unconstrained hegemony failed and why a more predictable and rulebased order would benefit the United States. …

Abstract As the English Church began to develop in the sixteenth and seventeenth centuries the question of its origins became highly significant. From the outset the Henrician Reformation had to demonstrate that its claims to national ecclesiastical sovereignty had not been invented by hard-pressed statesmen to extricate the king from an inconvenient deference to the papacy. Thus began an industry that sent scholars delving into the archives in order to recover a historical precedent for independence. Joseph of Arimathea emerged as an early favourite candidate, and King Lucius, Simon Zealot and Aristobulus followed. Then there were the Samotheans, biblical giants that allowed English Reformers to trace their ancestry to Noah. This paper draws on a wide range of contemporary sources in order to explore how the English Reformation struggled with and ultimately failed to provide its Church with a legitimate ancient birth story.

‘A Little World without the World’: Ecclesiastical Foundation Myths in English Reformation Thought

Review: Liberal Leviathan The Origins, Crisis, and Transformation of the American World Order, the Presidency of George W. Bush A First Historical Assessment

PIVOTAL DECADE How the United States Traded Factories for Finance in the Seventies Judith Stein New Haven and London: Yale University Press, 2010. 367PP, $37.50 cloth ISBN 978-0-300-11818-6STAYIN' ALIVE The 1970s and the Last Days of the Working Class Jefferson Cowie New York and London: The New Press, 2010. 464PP, $36.50 cloth ISBN: 978-1-56584-875-7A striking feature of the American scene is the tendency of economic or geopolitical difficulties to initiate heated arguments over whether the United States is in "decline" as a world power. The 1987 WaU Street crash, for example, helped ensure a bull market for Paul Kennedy's The Rise and Fall of the Great Powers. For months thereafter, op-ed pages and letters columns were dominated by the debate over whether America was succumbing to the same cycle of overextension and contraction that, in Kennedy's version of world history, had struck down past hegemons. The timing was less propitious for the two books under consideration here, which were published when the recovery from the 2008 recession, albeit fitful, had begun and the United States had begun to extricate itself from at least one of its two protracted military commitments. The authors of both works differ in emphasis but agree in dating the origins of the long-term weakening of American power to the 1970s, a decade that is now attracting overdue reconsideration from historians. Judith Stein looks in detail at the impact of economic challenges, particularly oil shocks, stagflation, and the downsizing of heavy industry, on the United States' morale and prosperity. Jefferson Cowie pays more attention to cultural changes and the weakening of organized labour as a force in American politics. Each has something to say about the passing of America's postwar economic and geopolitical primacy and the domestic political alignments it reinforced. But each also either ignores or misconstrues important aspects of the topic.Stein differs with many other historians in seeing globalization not as an American triumph but as the gravest of self-inflicted injuries. According to her interpretation, the unprecedented wealth and productivity of the quarter century after 1945 was undone by unreciprocated generosity. In constructing a liberal international trade order, she writes, America not only gave direct aid to future competitors (via the MarshaU plan and the rebuilding of Japan's industrial base through American military production for the Korean War), but it also granted unprecedented access to its own markets. To guarantee its aUies' prosperity and political stability, the United States encouraged a European Community from which high-value American exports would be shut out, adopted legislation enabling successive presidents of both parties to remove old tariffs and obstruct the imposition of new ones, and foUowed tax policies that promoted the export of American capital and technology. Despite a deteriorating balance of trade, the elite consensus behind free trade largely held firm until nemesis arrived in the 1970s. By 1973, domestic supplies could no longer satisfy American demand for oil, and OPEC was able not only to raise world prices but to cut off exports to the US altogether in retaliation for American aid to Israel in the Yom Kippur War. At the same time, supplies of other raw materials vital to American industry were at the disposal of neutral or hostile regimes.The villains in this account of recent history are the affluent Democratic liberals who sympathized with the antiwar and social liberation movements of the 1960s and disdained organized labour for its materialism, social conservatism, and support for the Vietnam War. Stein attacks these liberals intemperately and distractingly because of their origins in the professional classes and their preference - growing out of their own economic interests - for free trade rather than "buying American." This line of attack smacks of reverse snobbery. She describes Michael Dukakis, for example, as "marinat[ing] in a soup of self-regard fostered by degrees from Swarthmore and Harvard Law School" (274). …

Review: Pivotal Decade How the United States Traded Factories for Finance in the Seventies, Stayin' Alive The 1970s and the Last Days of the Working Class

Abstract In 1550 the last Catholic bishop in Iceland was executed by Icelandic Lutherans and the Danish governors. The country on the outer fringes of the Danish kingdom thus succumbed to a Reformation that had already been established in the other territories of Denmark and Norway. This article examines contemporary sources and modern scholarship in order to demonstrate that the success of the new movement was based largely on two factors. Firstly, this was a Reformation that was deliberately light on theology, a "changing of fashions" as it came to be known in Icelandic. Secondly, it was an inevitable consequence of the growing national strength of early modern Denmark that was keener to establish a firmer grip on its territories than it had ever had before.

Review: No Enchanted Palace The End of Empire and the Ideological Origins of the United Nations: Un Ideas that Changed the World

Jack Cunningham, Nuclear Sharing and Nuclear Crises: A Study in Anglo-American Relations, 1957-1963, Doctor of Philosophy, Department of History, University of Toronto, 2010. Between 1957 and 1963, both Anglo-American discussions of nuclear cooperation and the wider debate on nuclear strategy within NATO were often dominated by the question of whether Britain’s deterrent would be amalgamated or integrated into a wider NATO or European force, such as the proposed MLF (Multilateral Force). This dissertation discusses the development and impact of competing British and American proposals for “nuclear sharing” within the context of European economic and political integration as well as that of discussions within NATO of the appropriate strategy for the alliance in an age of mutual nuclear vulnerability between the superpowers. Particular attention is paid to the context of successive nuclear crises in world politics during this period, from Sputnik to the Soviet ultimatum over Berlin through the Cuban missile crisis. The divergent opinions among the leaders of the major powers over the appropriate responses to these crises shaped the debate over nuclear sharing and form a previously neglected dimension of this topic.

NUCLEAR SHARING AND NUCLEAR CRISES: A STUDY IN ANGLO-AMERICAN RELATIONS, 1957-1963

NO ENCHANTED PALACE The End of Empire and the Ideological Origjns of the United Nations Mark Mazower Princeton: Princeton University Press, 2009. 236PP, $28.95 cloth ISBN 978-0-691-13521-2UN IDEAS THAT CHANGED THE WORLD Richard Jolly, Louis Emmerij, and Thomas G. Weiss Bloomington: Indiana University Press, 2009, 288pp, US$24.95 paper ISBN 978-0-253-35355-9When Barack Obama succeeded George W Bush, there was much speculation about the place of the United Nations in the diplomacy of the new administration, which promised to be less aggressively unilateralist than its predecessor. Similar questions had arisen at the end of the Cold War, when the first President Bush proclaimed the beginning of a new world order. On both occasions, commentators wondered if the changes afoot - the thawing of the Cold War stalemate in the security council in 19 91 and the end of the second Bush administration's disdain for multilateralism in 2009 - would free the UN to fulfil the aspirations of its founders. In different ways, the two books under review illuminate the sources of such hopes and the reasons to doubt that they will bear fruit.Mark Mazower persuasively argues that the creation of the UN marked less of a break with prior conceptions of international order than official rhetoric suggested. There were, he demonstrates, important continuities between the new organization and the League of Nations, even if the tatter's failures required that these be downplayed for public consumption. Moreover, the UN's architects (particularly its British ones) intended it to help preserve, not undermine, their empires. They drew upon "imperial internationalist" ideas about a commonwealth of nations, which, mutatis mutandis, became the blueprint for a wider international community. The UN's main difference from the League was that it was more respectful of national sovereignty than its predecessor because of the veto given to the security council's permanent members in order to secure their membership.Mazowefs account, based on his 2007 Lawrence Stone lectures at Princeton, surveys a neglected tradition of British thinking about international organization. It is too short, however, to provide anything more than a cursory overview of some aspects of his topic, and says little about the other major powers' views of the UN. As a result, it is a somewhat narrower study than advertised. Mazower places exemplary individuals at the centre of most chapters, but since several of them are unrepresentative of the broad themes under discussion, his overall argument is somewhat reductionist. As the epitome of British efforts to perpetuate old-fashioned imperialism under the aegis of the UN, Mazower chooses the South African Jan Smuts, the principal draftsman of the preamble to the UN charter. Smuts sought great power agreement under UN auspices but wanted to ensure that the British empire would be free to continue its "civilizing mission" in Africa. In his conception, the Wilsonian emphasis on national self-determination would be restricted to Europe. Non-white peoples would be subject to European tutelage under a renewed League mandate system (just as Smuts's segregationist policies in South Africa set the foundations for the formal regime of apartheid). But Smuts's old-fashioned and race-inflected imperialism was an anomaly after 1945, making him less than typical of the British official mind. Other policymakers in Whitehall combined imperialist and liberal impulses, but few were as quick as Smuts to subordinate wider geopolitical considerations to imperial ones where the two conflicted. Smuts was similarly out of step with thinking in the rest of the empire. Policymakers in the other dominions saw the UN not as a tool for reviving imperialism but as a vehicle for a wider internationalism. They preferred to loosen their ties to Britain now that it had been superseded by the US as the ranking democracy.The next chapter attempts to illustrate an evolution in British thinking from naive interwar internationalism to a renewed emphasis on realpolitik. …

Abstract The subject of this study, Jón Arason, the last Catholic bishop of Iceland until the modern era, was executed with his two sons in 1550. His legacy is ambiguous; venerated in a Lutheran country as a nationalist hero, but also described by some commentators as illiterate, yet revered by others as the greatest poet of his age. The article will examine this legacy in light of contemporary evidence in order to demonstrate that Arason's life exemplifies much about an overlooked aspect of the Reformation on the fringes of Europe. In addition, because of Iceland's position as part of the Norwegian kingdom under Danish rule, Arason's career exemplifies much about the growth of the modern state. Although a bishop, he provides an interesting example of a medieval chieftain's struggle against the form of direct rule that was an inevitable feature of the developing modern empire.

Jón Arason, ‘the last Icelander’ and the Coming of the Reformation to Iceland

WARMING UP TO THE COLD WAR Canada and the United States' Coalition ofthe Willing, from Hiroshima to Korea Robert Teigrob Toronto: University of Toronto Press, 2009. 288pp, $55.00 cloth ISBN 978-0-8020-9923-5Robert Teigrob' s is hardly the first book-length study of Canadian politics and foreign relations in the early years ofthe Cold War. The milestones he cites are familiar: Igor Gouzenko's defection and subsequent revelations about Soviet atomic espionage, the formation of NATO, and the Korean War. So is his preoccupation with the shift in Canadian attitudes, from expectations of great-power harmony under UN auspices to acceptance of American leadership in a bipolar world. Teigrob examines both the making of Canadian foreign policy and the domestic impact of anti- Communism, and promises a fresh combination of diplomatic and cultural history.But he largely misses the opportunity to advance a genuinely new interpretation of the period. His present-mindedness, which the book's subtitle evinces, is one reason why. In Teigrob's account, the creation of NATO and the UN-authorized "police action" in Korea were exercises in American unilateralism, much like the invasion of Iraq. In 1950 as in 2003, he argues, the preservation of Canadian national sovereignty required abstention rather than participation. But regardless of whether one agrees with his recommendations in each case, the analogy between Korea and Iraq is misleading.Teigrob's is a variation on the argument that Donald Creighton and George Grant advanced. Like them, he holds successive Liberal governments culpable of betraying Canadian independence by military alliance and economic integration with the United States. His additions to the original argument, including a wider apportioning of blame, hardly strengthen his case. He places less emphasis on direct American pressure than did Creighton or Grant, and suggests that the Canadian public - which, under the influence of American media and their Canadian auxiliaries, cloned America's Cold War consensus, albeit for "homegrown" reasons - was an accomplice rather than a victim. Public sentiment forced the government of Prime Minister Louis St. Laurent to follow American preferences more closely than ministers themselves wished, Teigrob concludes, culminating in the decision to send ground troops to Korea.Teigrob replaces the mock- Augustan cadences of Creighton and Grant with the jargon of cultural studies. Corporate media systematically smother social divisions in the interests of the ruling classes, he explains. American mass culture's dominance of the Canadian market, and American assumptions of ideological harmony across the 49th parallel, made official cultural diplomacy superfluous. Washington could rely on lime Magazine to provide the indoctrination that the American government had to furnish on its own elsewhere.A systematic study of the American media's effects on postwar Canadian opinion might be worthwhile, but would require extensive data on circulation, readership, market share, and editorial orientation. Teigrob opts instead for an impressionistic approach in which the representativeness (or otherwise) of an article is more often asserted than proven, with the nuances of individual editorials over-interpreted as if they were painstaking efforts to promote an official line, not immediate responses to daily events.Teigrob' s second modification of Creighton and Grant is chronological. He dates the great betrayal to the period between 1945 and 1950, not the Second World War. The nationalist revolt against American hegemony first became evident in objections to the direction of the Korean War. Subsequent disagreements over nuclear arms and Vietnam, Teigrob claims, intensified Canada's desire to escape American tutelage, but did not, as others claim, create it. He emphasizes the British connection's centrality to the traditional Canadian self-definition, with America the necessary foil, noting the coolness of many Anglo-Canadians to American anti-colonialism until Washington grew tolerant of empire as a bulwark against communism. …

Although the accounts of Joseph of Arimathea's mission to England have their origins in the medieval era, it was during the early modern period that they began to provide a polemical purpose. The English had for centuries used Joseph as proofpositive that their Church had been founded in apostolic times. In the Reformation this usefulness only increased as Joseph could now be used to demonstrate that the English Church had been founded independently of Rome. What emerged was something of a theological oddity. This article discusses how the British Reformed writers used exactly the type of myths that the Reformation had set its face against, and how ultimately these legends fell from grace.

By the time of this writing in the spring of 2009, much (but not enough) has been said about Professor Shepherd’s astounding accomplishments in the field of juvenile advocacy and beyond. As an alumnus of the University of Richmond School of Law, I am awed by his impact, drawn to his resilient message of hope, and proud of the legacy that his tireless work has bestowed upon the school in perpetuity. Indeed, books will be written about Professor Shepherd some day, and at that time we will all have an opportunity to help shape his influence on the human condition.

Professor Robert E. Shepherd, Jr.: Tending to his Flock to Improve Its Lot

When John Bramhall arrived on the shores of Ireland in 1633 to begin his new job as chaplain to the (also newly appointed) lord deputy, Thomas Wentworth, he was probably not yet forty years old. He immediately set about his role with the type of energy and ruthless devotion that came to characterise the Laudian regime that sent him. As John Morrill has indicated, nothing in the previous reign had prepared the Irish Protestant establishment ‘for the onslaught on their church to be mounted by William Laud.’ Historically, one of the problems with the Laudians is that while it is clear what they did, it is less clear why they did it. Typically, and shrewdly, they did not tend to be verbose concerning their motives.

John Bramhall’s other island: a Laudian solution to an Irish problem

The focus of this research lies within the field of contemporary studio jewellery, a discipline that has a variety of strands that includes the purely aesthetic, technique led, through concept based to architectonic. A further hybrid of contemporary jewellery is the narrative genre. More specifically this research examines how narrative might be defined and takes a position viewed from a European perspective. 
 
Chapter 1, Rationale & Contextual Review, examines contemporary studio jewellery and positions a definition of narrative jewellery within this wider framework. 
 
Chapter 2, Defining the Field, identifies global paradigms. The interrogation of the subject examines the correlation between themes and subject matter and the ethnographic factors that influence creative outcomes. The hypothesis proposes that these creative outcomes are universal in their translation whilst reflecting a relationship between environmental influence and ethnographic origin 
 
Chapter 3, Narrative Themes, presents an overview of current European makers. Through the author's role as exhibition curator, this chapter identifies prevalent themes and preoccupations selected from the exhibition ‘Maker-Wearer-Viewer’ which surveyed the work of over seventy makers from twenty European countries. 
 
Chapter 4, Source, Process & Practice, locates the author’s self-reflective practice within the field by examining the correlation of narrative subject matter, source material and the creative process employed. The importance of source material and its influence on the creative process is examined through reflexive practice. Further research examines the interactive relationship between the maker and wearer, and the response of the viewer. 
 
Through practice-based research, the design and making process, the authors’ narrative jewellery is clearly defined within a wider context.

Contemporary European narrative jewellery : the prevalent themes, paradigms and the cognitive interaction between maker, wearer and viewer observed through the process, production and exhibition of narrative jewellery

Preface James Ussher John Bramhall Dogmatic theologies Sacramental theologies Ecclesiastical histories Secular politics Ecclesiastical politics Practical policy Conclusion Bibliography Index.

James Ussher and John Bramhall: The Theology and Politics of Two Irish Ecclesiastics of the Seventeenth Century

An Uninvited Guest: The Federal Death Penalty and the Massachusetts Prosecution of Nurse Kristen Gilbert

Abstract James Ussher, Primate of the Church of Ireland (as Archbishop of Armagh), arrived in England in the early 1640s, a time when the country was in political turmoil. Scots and significant sections of English society were campaigning for the abolition of the episcopacy. During this turmoil Ussher proposed a scheme of limited episcopacy that came to be known by the keyword: the Eirenicon. This scheme offered to keep the bishops but in a form that made them answerable to a team of Presbyters. The Eirenicon failed and Ussher embarked on a literary campaign that defended the divine institution of episcopacy. This move has long been regarded as a U-turn. This paper will argue that rather than there being a change of mind, the Eirenicon and the pro-episcopal writings of Ussher should be seen as a whole, offering a compromise form of ‘primitive episcopacy’.

The Eirenicon and the ‘Primitive Episcopacy’ of James Ussher: An Irish Panacea For Britannia's Ailment

In this issue we have assembled three incisive commentaries on George DeMartino’s important book, Global Economy, Global Justice, along with a response by the author himself. Initially presented in a symposium that was organized by Jack Amariglio for the Marxism and the World Stage conference, these essays explore the resonance and reach both of DeMartino’s critique of the social ethics associated with contemporary neoliberalism and of the alternative approach to economic and social justice he advocates. William Milberg, in the first essay, outlines the major changes that have taken place during the postwar period in neoclassical economists’ analyses of international trade. According to Milberg, mainstream academic economics has largely abandoned its highly abstract, welfare-oriented model-building in favor of a more empiricist approach, thereby creating a theoretical void that ironically has been filled by a return to the market-celebrating claims of neoliberalism. Milberg then credits DeMartino with making explicit, and posing fundamental criticisms of, the ethical norms inherent in contemporary claims concerning the welfare-enhancing effects of free global markets. For Milberg, the task that must accompany contemporary expressions of justifiable outrage concerning the failings of global neoliberalism is precisely the one taken up by DeMartino: to think ‘‘carefully through the logic of neoliberalism, its moral underpinnings and its alternatives.’’ Julie Graham, for her part, applauds DeMartino’s ‘‘courage’’ and ‘‘strength of vision’’ in confronting a series of difficult issues*/affirming a workable model of social justice in the face of the grandiose claims of neoliberalism, identifying and avoiding the pitfalls of both moral objectivism and cultural relativism, and elaborating a concrete policy alternative even when using an antiessentialist framework of analysis. But Graham also expresses her misgivings concerning DeMartino’s proposal for a Social Index Tariff Structure, particularly the ‘‘dreary actualities’’ and violence of institutionalizing and universalizing such a system. The alternative, she suggests, is to see DeMartino’s proposal less as a final outcome and more as an initial attempt to interpellate the ‘‘subjects of global justice,’’ calling into being a politics that can constitute a new global order. DeMartino’s critical approach to the ethical claims of global neoliberalism explicitly draws on the ‘‘functionings’’ and ‘‘capabilities’’ approach of Amartya Sen. But, suggest Maliha Safri and Eray Düzenli, it also embodies a latent politics of radical democracy along the lines proposed by Ernesto Laclau and Chantal Mouffe, albeit with a ‘‘sexy twist.’’ Extending radical democracy into the economic realm and to the global level, DeMartino offers a new ‘‘suture,’’ a criterion of economic and social

Death in the Federal Courts: Expectations and Realities of the Federal Death Penalty Act of 1994

In this paper, we investigate the impact of closures on local access to hospital care. We measured the incremental travel time to alternate hospitals. The results show that even in rural markets, closures nearly always occur near open hospitals, which by itself may imply a minimal effect in terms of human welfare. These results support the view that hospital closures rarely directly limit general access to hospital care.

Inquiry : a journal of medical care organization, provision and financing

Si image sensors with a wide spectral response range and a high robustness to ultraviolet light exposure based on flattened Si surface are described in this paper. A photodiode (PD) fabrication technology is developed to form a thin surface high concentration layer with steep dopant profile on flattened Si surface. Due to this, PDs with a wide spectral response ranging from 200 to 1000nm is achieved with almost 100% internal quantum efficiency to ultraviolet light (UV-light) waveband. In addition, high robustness of light sensitivity and dark current toward UV-light exposure is obtained. The developed technology is applied to in-pixel buried PDs of photodiode arrays and a CMOS image sensor. The advanced performances of fabricated sensors are verified with experimental results.

Si image sensors with wide spectral response and high robustness to ultraviolet light exposure

The GEO-CAPE mission described in NASA's Earth Science and Applications Decadal Survey requires high spatial, temporal, and spectral resolution measurements to monitor and characterize the rapidly changing chemistry of the troposphere over North and South Americas. High-frame-rate focal plane arrays (FPAs) with many pixels are needed to enable such measurements. A high-throughput digital detector readout integrated circuit (ROIC) that meets the GEO-CAPE FPA needs has been developed, fabricated, and tested. The ROIC is based on an innovative charge integrating, fast, high-precision analog-to-digital circuit that is built into each pixel. The 128128-pixel ROIC digitizes all 16,384 pixels simultaneously at frame rates up to 16 kHz to provide a completely digital output on a single integrated circuit at an unprecedented rate of 262 million pixels per second. The approach eliminates the need for off focal plane electronics, greatly reducing volume, mass, and power compared to conventional FPA implementations. A focal plane based on this ROIC will require less than 2 W of power on a 11-cm integrated circuit. The ROIC is fabricated of silicon using CMOS technology. It is designed to be indium bump bonded to a variety of detector materials including silicon PIN diodes, indium antimonide (InSb), indium gallium arsenide (In- GaAs), and mercury cadmium telluride (HgCdTe) detector arrays to provide coverage over a broad spectral range in the infrared, visible, and ultraviolet spectral ranges.

Single-slope analog-to-digital converters (ADCs) are particularly useful for onchip digitization in focal plane arrays (FPAs) because of their inherent monotonicity, relative simplicity, and efficiency for column-parallel applications, but they are comparatively slow. Squareroot encoding can allow the number of code values to be reduced without loss of signal-to-noise ratio (SNR) by keeping the quantization noise just below the signal shot noise. This encoding can be implemented directly by using a quadratic ramp. The reduction in the number of code values can substantially increase the quantization speed. However, in an FPA, the fixed pattern noise (FPN) limits the use of small quantization steps at low signal levels. If the zero-point is adjusted so that the lowest column is onscale, the other columns, including those at the center of the distribution, will be pushed up the ramp where the quantization noise is higher. Additionally, the finite frequency response of the ramp buffer amplifier and the comparator distort the shape of the ramp, so that the effective ramp value at the time the comparator trips differs from the intended value, resulting in errors. Allowing increased settling time decreases the quantization speed, while increasing the bandwidth increases the noise. The FPN problem is solved by breaking the ramp into two portions, with some fraction of the available code values allocated to a linear ramp and the remainder to a quadratic ramp. To avoid large transients, both the value and the slope of the linear and quadratic portions should be equal where they join. The span of the linear portion must cover the minimum offset, but not necessarily the maximum, since the fraction of the pixels above the upper limit will still be correctly quantized, albeit with increased quantization noise. The required linear span, maximum signal and ratio of quantization noise to shot noise at high signal, along with the continuity requirement, determines the number of code values that must be allocated to each portion. The distortion problem is solved by using a lookup table to convert captured code values back to signal levels. The values in this table will be similar to the intended ramp value, but with a correction for the finite bandwidth effects. Continuous-time comparators are used, and their bandwidth is set below the step rate, which smoothes the ramp and reduces the noise. No settling time is needed, as would be the case for clocked comparators, but the low bandwidth enhances the distortion of the non-linear portion. This is corrected by use of a return lookup table, which differs from the one used to generate the ramp. The return lookup table is obtained by calibrating against a stepped precision DC reference. This results in a residual non-linearity well below the quantization noise. This method can also compensate for differential non-linearity (DNL) in the DAC used to generate the ramp. The use of a ramp with a combination of linear and quadratic portions for a single-slope ADC is novel. The number of steps is minimized by keeping the step size just below the photon shot noise. This in turn maximizes the speed of the conversion. High resolution is maintained by keeping small quantization steps at low signals, and noise is minimized by allowing the lowest analog bandwidth, all without increasing the quantization noise. A calibrated return lookup table allows the system to maintain excellent linearity.

Mixed Linear/Square-Root Encoded Single-Slope Ramp Provides Low-Noise ADC with High Linearity for Focal Plane Arrays

We have demonstrated a direct detection of 100-5000 eV electrons with a back-illuminated boron delta-doped hybrid silicon complementary metal-oxide-semiconductor imager operating in full depletion and a silicon electron-multiplying charge-coupled device (CCD) operating in partial depletion. The delta-doping molecular beam epitaxy increases sensitivity to low-energy electrons and improves low-energy electron detection threshold relative to conventional solid-state detectors. We compare the gain measured in these two delta-doped devices with gain measured from control delta-doped CCDs.

Direct Detection of 100–5000 eV Electrons With Delta-Doped Silicon CMOS and Electron-Multiplying CCD Imagers

Solar System Exploration camera implementations to date have involved either single cameras with wide field-of-view (FOV) and consequently coarser spatial resolution, cameras on a movable mast, or single cameras necessitating rotation of the host vehicle to afford visibility outside a relatively narrow FOV. These cameras require detailed commanding from the ground or separate onboard computers to operate properly, and are incapable of making decisions based on image content that control pointing and downlink strategy. For color, a filter wheel having selectable positions was often added, which added moving parts, size, mass, power, and reduced reliability. A system was developed based on a general-purpose miniature visible-light camera using advanced CMOS (complementary metal oxide semiconductor) imager technology. The baseline camera has a 92 FOV and six cameras are arranged in an angled-up carousel fashion, with FOV overlaps such that the system has a 360 FOV (azimuth). A seventh camera, also with a FOV of 92 , is installed normal to the plane of the other 6 cameras giving the system a > 90 FOV in elevation and completing the hemispheric vision system. A central unit houses the common electronics box (CEB) controlling the system (power conversion, data processing, memory, and control software). Stereo is achieved by adding a second system on a baseline, and color is achieved by stacking two more systems (for a total of three, each system equipped with its own filter.) Two connectors on the bottom of the CEB provide a connection to a carrier (rover, spacecraft, balloon, etc.) for telemetry, commands, and power. This system has no moving parts. The system's onboard software (SW) supports autonomous operations such as pattern recognition and tracking.

Flip-chip hybridization, also known as bump bonding, is a packaging technique for microelectronic devices that directly connects an active element or detector to a substrate readout face-to-face, eliminating the need for wire bonding. In order to make conductive links between the two parts, a solder material is used between the bond pads on each side. Solder bumps, composed of indium metal, are typically deposited by thermal evaporation onto the active regions of the device and substrate. While indium bump technology has been a part of the electronic interconnect process field for many years and has been extensively employed in the infrared imager industry, obtaining a reliable, high-yield process for high-density patterns of bumps can be quite difficult. Under the right conditions, a moderate hydrogen plasma exposure can raise the temperature of the indium bump to the point where it can flow. This flow can result in a desirable shape where indium will efficiently wet the metal contact pad to provide good electrical contact to the underlying readout or imager circuit. However, it is extremely important to carefully control this process as the intensity of the hydrogen plasma treatment dramatically affects the indium bump morphology. To ensure the fine-tuning of this reflow process, it is necessary to have realtime feedback on the status of the bumps. With an appropriately placed viewport in a plasma chamber, one can image a small field (a square of approximately 5 millimeters on each side) of the bumps (10-20 microns in size) during the hydrogen plasma reflow process. By monitoring the shape of the bumps in real time using a video camera mounted to a telescoping 12 magnifying zoom lens and associated optical elements, an engineer can precisely determine when the reflow of the bumps has occurred, and can shut off the plasma before evaporation or de-wetting takes place.

Optimization of Indium Bump Morphology for Improved Flip Chip Devices

Focal plane arrays (FPAs) with high frame rates and many pixels benefit several upcoming Earth science missions including GEO-CAPE, GACM, and ACE by enabling broader spatial coverage and higher spectral resolution. FPAs for the PanFTS, a high spatial resolution Fourier transform spectrometer and a candidate instrument for the GEO-CAPE mission are the focus of the developments reported here, but this FPA technology has the potential to enable a variety of future measurements and instruments. The ESTO ACT Program funded the developed of a fast readout integrated circuit (ROIC) based on an innovative in-pixel analog-to-digital converter (ADC). The 128 X 128 pixel ROIC features 60 ?m pixels, a 14-bit ADC in each pixel and operates at a continuous frame rate of 14 kHz consuming only 1.1 W of power. The ROIC outputs digitized data completely eliminating the bulky, power consuming signal chains needed by conventional FPAs. The 128 X 128 pixel ROIC has been fabricated in CMOS and tested at the Jet Propulsion Laboratory. The current version is designed to be hybridized with PIN photodiode arrays via indium bump bonding for light detection in the visible and ultraviolet spectral regions. However, the ROIC design incorporates a small photodiode in each cell to permit detailed characterization of the ROICperformance without the need for hybridization. We will describe the essential features of the ROIC design and present results of ROIC performance measurements.

Fast Imaging Detector Readout Circuits with In-Pixel ADCs for Fourier Transform Imaging Spectrometers

A complementary metal oxide/semiconductor (CMOS) image detector now undergoing development is designed to exhibit less cross-talk and greater full-well capacity than do prior CMOS image detectors of the same type. Imagers of the type in question are designed to operate from low-voltage power supplies and are fabricated by processes that yield device features having dimensions in the deep submicron range. Because of the use of low supply potentials, maximum internal electric fields and depletion widths are correspondingly limited. In turn, these limitations are responsible for increases in cross-talk and decreases in charge-handling capacities. Moreover, for small pixels, lateral depletion cannot be extended. These adverse effects are even more accentuated in a back-illuminated CMOS imager, in which photogenerated charge carriers must travel across the entire thickness of the device. The figure shows a partial cross section of the structure in the device layer of the present developmental CMOS imager. (In a practical imager, the device layer would sit atop either a heavily doped silicon substrate or a thin silicon oxide layer on a silicon substrate, not shown here.) The imager chip is divided into two areas: area C, which contains readout circuits and other electronic circuits; and area I, which contains the imaging (photodetector and photogenerated-charge-collecting) pixel structures. Areas C and I are electrically isolated from each other by means of a trench filled with silicon oxide. The electrical isolation between areas C and I makes it possible to apply different supply potentials to these areas, thereby enabling optimization of the supply potential and associated design features for each area. More specifically, metal oxide semiconductor field-effect transistors (MOSFETs) that are typically included in CMOS imagers now reside in area C and can remain unchanged from established designs and operated at supply potentials prescribed for those designs, while the dopings and the lower supply potentials in area I can be tailored to optimize imager performance. In area I, the device layer includes an n+ -doped silicon layer on which is grown an n-doped silicon layer. A p-doped silicon layer is grown on top of the n -doped layer. The total imaging device thickness is the sum of the thickness of the n+, n, and p layers. A pixel photodiode is formed between a surface n+ implant, a p implant underneath it, the aforementioned p layer, and the n and n+ layers. Adjacent to the diode is a gate for transferring photogenerated charges out of the photodiode and into a floating diffusion formed by an implanted p+ layer on an implanted n-doped region. Metal contact pads are added to the back-side for providing back-side bias.

The single-photon counting imaging sensor is typically an array of silicon Geiger-mode avalanche photodiodes that are monolithically integrated with CMOS (complementary metal oxide semiconductor) readout, signal processing, and addressing circuits located in each pixel and the peripheral area of the chip. The major problem is its single-event method for photon count number registration. A single-event single-photon counting imaging array only allows registration of up to one photon count in each of its pixels during a frame time, i.e., the interval between two successive pixel reset operations. Since the frame time can t be too short, this will lead to very low dynamic range and make the sensor merely useful for very low flux environments. The second problem of the prior technique is a limited fill factor resulting from consumption of chip area by the monolithically integrated CMOS readout in pixels. The resulting low photon collection efficiency will substantially ruin any benefit gained from the very sensitive single-photon counting detection. The single-photon counting imaging sensor developed in this work has a novel multiple-event architecture, which allows each of its pixels to register as more than one million (or more) photon-counting events during a frame time. Because of a consequently boosted dynamic range, the imaging array of the invention is capable of performing single-photon counting under ultra-low light through high-flux environments. On the other hand, since the multiple-event architecture is implemented in a hybrid structure, back-illumination and close-to-unity fill factor can be realized, and maximized quantum efficiency can also be achieved in the detector array.

The readout of detector arrays requires the monolithic or hybrid integration of a integrate circuit multiplexer with the detector array. In most LWIR and VLWIR applications, a hybrid approach is used. For example, the detector array may be built from HgCdTe and the readout integrated circuit may be silicon CMOS [1]. The two integrated circuits are mated through a bump-bonding process in which each detector element has its own metallized interconnect (e.g. indium bump) to a corresponding silicon multiplexer unit cell. The multiplexer unit cell may contain an integrating capacitor and other circuitry for amplification and detector biasing as well as for the unit cell readout selection. The vast majority of integrated circuits for this purpose (and for the majority of most other purposes, as well) have been made of silicon. In this paper, the use of GaAs-based integrated circuits instead of silicon CMOS ICs is explored.

A method of polarimetric imaging, now undergoing development, involves the use of two photoelastic modulators in series, driven at equal amplitude but at different frequencies. The net effect on a beam of light is to cause (1) the direction of its polarization to rotate at the average of two excitation frequencies and (2) the amplitude of its polarization to be modulated at the beat frequency (the difference between the two excitation frequencies). The resulting modulated optical light beam is made to pass through a polarizing filter and is detected at the beat frequency, which can be chosen to equal the frame rate of an electronic camera or the rate of sampling the outputs of photodetectors in an array. The method was conceived to satisfy a need to perform highly accurate polarimetric imaging, without cross-talk between polarization channels, at frame rates of the order of tens of hertz. The use of electro-optical modulators is necessitated by a need to obtain accuracy greater than that attainable by use of static polarizing filters over separate fixed detectors. For imaging, photoelastic modulators are preferable to such other electrio-optical modulators as Kerr cells and Pockels cells in that photoelastic modulators operate at lower voltages, have greater angular acceptances, and are easier to use. Prior to the conception of the present method, polarimetric imaging at frame rates of tens of hertz using photoelastic modulators was not possible because the resonance frequencies of photoelastic modulators usually lie in the range from about 20 to about 100 kHz.

In this paper, we report the latest results on our development of delta-doped, thinned, back-illuminated CMOS imaging arrays. As with charge-coupled devices, thinning and back-illumination are essential to the development of high performance CMOS imaging arrays. Problems with back surface passivation have emerged as critical to the prospects for incorporating CMOS imaging arrays into high performance scientific instruments, just as they did for CCDs over twenty years ago. In the early 1990's, JPL developed delta-doped CCDs, in which low temperature molecular beam epitaxy was used to form an ideal passivation layer on the silicon back surface. Comprising only a few nanometers of highly-doped epitaxial silicon, delta-doping achieves the stability and uniformity that are essential for high performance imaging and spectroscopy. Delta-doped CCDs were shown to have high, stable, and uniform quantum efficiency across the entire spectral range from the extreme ultraviolet through the near infrared. JPL has recently bump-bonded thinned, delta-doped CMOS imaging arrays to a CMOS readout, and demonstrated imaging. Delta-doped CMOS devices exhibit the high quantum efficiency that has become the standard for scientific-grade CCDs. Together with new circuit designs for low-noise readout currently under development, delta-doping expands the potential scientific applications of CMOS imaging arrays, and brings within reach important new capabilities, such as fast, high-sensitivity imaging with parallel readout and real-time signal processing. It remains to demonstrate manufacturability of delta-doped CMOS imaging arrays. To that end, JPL has acquired a new silicon MBE and ancillary equipment for delta-doping wafers up to 200mm in diameter, and is now developing processes for high-throughput, high yield delta-doping of fully-processed wafers with CCD and CMOS imaging devices.

Delta-doped back-illuminated CMOS imaging arrays: progress and prospects

A monolithic silicon-on-insulator (SOI) complementary metal oxide/semiconductor (CMOS) image-detecting integrated circuit of the active-pixel-sensor type, now undergoing development, is designed to operate at visible and near-infrared wavelengths and to offer a combination of high quantum efficiency and low diffusion and capacitive cross-talk among pixels. The imager is designed to be especially suitable for astronomical and astrophysical applications. The imager design could also readily be adapted to general scientific, biological, medical, and spectroscopic applications. One of the conditions needed to ensure both high quantum efficiency and low diffusion cross-talk is a relatively high reverse bias potential (between about 20 and about 50 V) on the photodiode in each pixel. Heretofore, a major obstacle to realization of this condition in a monolithic integrated circuit has been posed by the fact that the required high reverse bias on the photodiode is incompatible with metal oxide/semiconductor field-effect transistors (MOSFETs) in the CMOS pixel readout circuitry. In the imager now being developed, the SOI structure is utilized to overcome this obstacle: The handle wafer is retained and the photodiode is formed in the handle wafer. The MOSFETs are formed on the SOI layer, which is separated from the handle wafer by a buried oxide layer. The electrical isolation provided by the buried oxide layer makes it possible to bias the MOSFETs at CMOS-compatible potentials (between 0 and 3 V), while biasing the photodiode at the required higher potential, and enables independent optimization of the sensory and readout portions of the imager.

NASA Tech Briefs, March 2009 spatially-low-pass subband. The resulting data are converted to sign-magnitude form and compressed in a manner similar to that of a baseline hyperspectral-image-compression method. The mean values are encoded in the compressed bit stream and added back to the data at the appropriate decompression step. The overhead incurred by encoding the mean values — only a few bits per spectral band — is negligible with respect to the huge size of a typical hyperspectral data set. The other method is denoted modified decomposition. This method is so named because it involves a modified version of a commonly used multiresolution wavelet decomposition, known in the art as the 3D Mallat decomposition, in which (a) the first of multiple stages of a 3D wavelet transform is applied to the entire dataset and (b) subsequent stages are applied only to the horizontally-, vertically-, and spectrallylow-pass subband from the preceding stage. In the modified decomposition, in stages after the first, not only is the spatially-low-pass, spectrally-low-pass subband further decomposed, but also spatially-low-pass, spectrally-high-pass subbands are further decomposed spatially. Either method can be used alone to improve the quality of a reconstructed image (see figure). Alternatively, the two methods can be combined by first performing modified decomposition, then subtracting the mean values from spatial planes of spatially-low-pass subbands. This work was done by Matthew Klimesh, Aaron Kiely, Hua Xie, and Nazeeh Aranki of Caltech for NASA’s Jet Propulsion Laboratory. For further information, contact iaoffce@jpl.nasa.gov. NPO-41381

NASA Tech Briefs, August 2008 responding locations on, and as an integral part of, this integrated circuit; or (2) following a flip-chip approach, fabricate the array of energy-storage elements on a separate integrated-circuit chip and then align and bond the two chips together. This work was done by Mohammad Mojarradi, Mahmoud Alahmad, Vinesh Sukumar, Fadi Zghoul, Kevin Buck, Herbert Hess, Harry Li, and David Cox of Caltech for NASA’s Jet Propulsion Laboratory. Further information is contained in a TSP (see page 1). In accordance with Public Law 96-517, the contractor has elected to retain title to this invention. Inquiries concerning rights for its commercial use should be addressed to: Innovative Technology Assets Management JPL Mail Stop 202-233 4800 Oak Grove Drive Pasadena, CA 91109-8099 (818) 354-2240 E-mail: iaoffice@jpl.nasa.gov Refer to NPO-43318, volume and number of this NASA Tech Briefs issue, and the page number.

A nano-multiplication-region avalanche photodiode (NAPD) featuring confinement of a multiplication region and a charging region in a nano-pillar was proposed for realization of novel near-constant-gain mode multiplication, low dark count rate, low afterpulsing and high avalanche initiation probability. Process and device simulations showed that near-constant-gain mode multiplication can be realized in NAPD with a properly doped charging layer. Prototype NAPDs were built with a feasible processing technology. First I-V characteristics of NAPD with plateau structures were observed.

Modeling and Fabrication of a Nano-multiplication-region Avalanche Photodiode

Bedabrata Pain, Chao Sun, Paula Vo, Bruce Hancock, Thomas J. Cunningham, Chris Wrigley, Risaku Toda, Victor White, Amrita Banerjee*, and Durgmadhab Misra* Jet Propulsion Laboratory, California Institute of Technology 4800 Oak Grove Drive, Pasadena, CA 91109 Phone: 818-354-8765; Fax: 818-393-0045; Email: bpain@jpl.nasa.gov * Dept of Electrical & Computer Engineering, New Jersey Institute of Technology 161 Warren St, Newark, NJ 07102

Wafer-Level thinned monolithic CMOS imagers in a bulk-CMOS technology

Many existing and next generation astronomy applications require very large format imager arrays with low dark current and excellent quantum efficiency (QE) and modulation transfer function (MTF) above 1 μm. The requirement of large format arrays makes silicon a natural choice as the detector material, although there has been significant progress in substrate-removed InGaAs or HgCdTe materials [1] for extending higher frequency response of materials that have been more traditionally used for infrared detection.

SOI-based Monolithic Imaging Technology for Scientific Applications

A delta-doped hybrid advanced detector (HAD) is provided which combines at least four types of technologies to create a detector for energetic particles ranging in energy from hundreds of electron volts (eV) to beyond several million eV. The detector is sensitive to photons from visible light to X-rays. The detector is highly energy-sensitive from approximately 10 keV down to hundreds of eV. The detector operates with milliwatt power dissipation, and allows nonsequential readout of the array, enabling various advanced readout schemes.

Date of Patent : Aug . 22 , 2000 DELTA-DOPED HYBRID ADVANCED DETECTOR FOR LOW ENERGY PARTICLE DETECTION

Passive multiangular, multispectral, and polarimetric sensing approaches each have unique strengths for the measurement of tropospheric aerosol column abundances and microphysical properties. Current spaceborne multispectral and multiangular aerosols sensors operate at approximately 1 km resolution. Under NASA's Instrument Incubator Program, we are developing an electro-optic imaging approach that will enable adding high-accuracy polarimetry to such observations. To achieve a degree of linear polarization (DOLP) uncertainty of 0.5%, our approach temporally modulates the linear-polarization component of incoming light at a rapid rate, enabling each detector within a focal-plane array, combined with polarization analyzers, to measure the relative proportions of the linear Stokes components Q or U to the total intensity. Our system uses tandem photoelastic modulators (PEMs) within a high-reflectance, low diattenuation camera design. The two PEMs vibrate at slightly different resonant frequencies, leading to modulation of the polarized light at a heterodyne frequency of ~25 Hz. High-speed (1 kHz) readout of the detector arrays samples the output waveforms from which Q/I and U/I are derived. We report on experimental and theoretical analyses of PEM and optical system performance, along with plans for developing ruggedized PEMs capable of withstanding launch and on-orbit stresses.

Use of Photoelastic Modulators for High-accuracy Spectropolarimetric Imaging of Aerosols

Direct detection of 0.1–20keV electrons is demonstrated using a boron delta doped high purity Si p-i-n diode array. Molecular beam epitaxy is used to grow a delta layer on the back surface of these fully depletable p-i-n diode arrays to form an electrode for detecting shallow-penetrating ionizing radiation. Device structure, processing, and characterization methods used for device testing and measurement of its response to electrons are discussed. Use of this detector for measuring the Si quantum yield over this wide energy range is also discussed.

Direct detection of 0.1–20keV electrons with delta doped, fully depleted, high purity silicon p-i-n diode arrays

Imaging with a back-illuminated CMOS imager provides a number of advantages, especially as the pixel size is reduced. These advantages include high (1 00%) fill-factor and increased quantum efficiency, efficient implementation of antireflection coatings, improved angular response, availability of the traditional “frontside” of the pixel to incorporate in-pixel processing circuits, and increased compatibility with the next generation metals (e.g Cu) and low-k dielectrics.

In this paper, we present the test and characterization results for a back-illuminated megapixel CMOS imager. The imager pixel consists of a standard junction photodiode coupled to a three transistor-per-pixel switched source-follower readout [1]. The imager also consists of integrated timing and control and bias generation circuits, and provides analog output. The analog column-scan circuits were implemented in such a way that the imager could be configured to run in off-chip correlated double-sampling (CDS) mode. The imager was originally designed for normal front-illuminated operation, and was fabricated in a commercially available 0.5 pn triple-metal CMOS-imager compatible process. For backside illumination, the imager was thinned by etching away the substrate was etched away in a post-fabrication processing step.

Direct detection of electrons in the 0.1-20 keV energy range using a delta-doped high purity silicon p-i-n diode array

Techniques for passive remote sensing of aerosol optical and microphysical properties from space include visible, near- and shortwave-infrared imaging (e.g., from MODIS), multiangle intensity imaging (e.g., ATSR-2, AATSR, MISR), near-ultraviolet mapping (e.g., TOMS/OMI), and polarimetry (e.g., POLDER, APS). Each of these methods has unique strengths. In this paper, we present a concept for integrating these approaches into a unified sensor. Design goals include spectral coverage from the near-UV to the shortwave infrared; intensity and polarimetric imaging simultaneously at multiple view angles; global coverage within a few days; kilometer to sub-kilometer spatial resolution; and measurement of the degree of linear polarization (DOLP) for a subset of the spectral complement with an uncertainty of 0.5% or less. This high polarimetric accuracy is the most challenging aspect of the design, and is specified in order to achieve climate-quality uncertainties in optical depth, refractive index, and other microphysical properties. Based upon MISR heritage, a pushbroom multi-camera architecture is envisioned, using separate line arrays to collect imagery within each camera in the different spectral bands and in different polarization orientations. For the polarimetric data, accurate cross-calibration of the individual line arrays is essential. An electro-optic polarization "scrambler", activated periodically during calibration sequences, is proposed as a means of providing this cross-calibration. The enabling component is a rapid retardance modulator. Candidate technologies include liquid crystals, rotating waveplates, and photoelastic modulators (PEMs). The PEM, which uses a piezoelectric transducer to induce rapid time-varying stress birefringence in a glass bar, appears to be the most suitable approach. An alternative measurement approach, also making use of a PEM, involves synchronous demodulation of the oscillating signal to reconstruct the polarization state. The latter method is potentially more accurate, but requires a significantly more complex detector architecture.

An integrated multiangle, multispectral, and polarimetric imaging concept for aerosol remote sensing from space

Biosensors of a proposed type would exploit scattering of light by surface plasmon resonance (SPR). Related prior biosensors exploit absorption of light by SPR. Relative to the prior SPR biosensors, the proposed SPR biosensors would offer greater sensitivity in some cases, enough sensitivity to detect bioparticles having dimensions as small as nanometers. A surface plasmon wave can be described as a light-induced collective oscillation in electron density at the interface between a metal and a dielectric. At SPR, most incident photons are either absorbed or scattered at the metal/dielectric interface and, consequently, reflected light is greatly attenuated. The resonance wavelength and angle of incidence depend upon the permittivities of the metal and dielectric. An SPR sensor of the type most widely used heretofore includes a gold film coated with a ligand a substance that binds analyte molecules. The gold film is thin enough to support evanescent-wave coupling through its thickness. The change in the effective index of refraction at the surface, and thus the change in the SPR response, increases with the number of bound analyte molecules. The device is illuminated at a fixed wavelength, and the intensity of light reflected from the gold surface opposite the ligand-coated surface is measured as a function of the angle of incidence. From these measurements, the angle of minimum reflection intensity is determined

Underwater video cameras of a proposed type (and, optionally, their light sources) would not be housed in pressure vessels. Conventional underwater cameras and their light sources are housed in pods that keep the contents dry and maintain interior pressures of about 1 atmosphere (.0.1 MPa). Pods strong enough to withstand the pressures at great ocean depths are bulky, heavy, and expensive. Elimination of the pods would make it possible to build camera/light-source units that would be significantly smaller, lighter, and less expensive. The depth ratings of the proposed camera/light source units would be essentially unlimited because the strengths of their housings would no longer be an issue. A camera according to the proposal would contain an active-pixel image sensor and readout circuits, all in the form of a single silicon-based complementary metal oxide/semiconductor (CMOS) integrated- circuit chip. As long as none of the circuitry and none of the electrical leads were exposed to seawater, which is electrically conductive, silicon integrated- circuit chips could withstand the hydrostatic pressure of even the deepest ocean. The pressure would change the semiconductor band gap by only a slight amount . not enough to degrade imaging performance significantly. Electrical contact with seawater would be prevented by potting the integrated-circuit chip in a transparent plastic case. The electrical leads for supplying power to the chip and extracting the video signal would also be potted, though not necessarily in the same transparent plastic. The hydrostatic pressure would tend to compress the plastic case and the chip equally on all sides; there would be no need for great strength because there would be no need to hold back high pressure on one side against low pressure on the other side. A light source suitable for use with the camera could consist of light-emitting diodes (LEDs). Like integrated- circuit chips, LEDs can withstand very large hydrostatic pressures. If power-supply regulators or filter capacitors were needed, these could be attached in chip form directly onto the back of, and potted with, the imager chip. Because CMOS imagers dissipate little power, the potting would not result in overheating. To minimize the cost of the camera, a fixed lens could be fabricated as part of the plastic case. For improved optical performance at greater cost, an adjustable glass achromatic lens would be mounted in a reservoir that would be filled with transparent oil and subject to the full hydrostatic pressure, and the reservoir would be mounted on the case to position the lens in front of the image sensor. The lens would by adjusted for focus by use of a motor inside the reservoir (oil-filled motors already exist).

The figure depicts the major functional blocks of a system, now undergoing development, for conditioning neural signals acquired by electrodes implanted in a brain. The overall functions to be performed by this system can be summarized as preamplification, multiplexing, digitization, and high-pass filtering. Other systems under development for recording neural signals typically contain resistor-capacitor analog low-pass filters characterized by cutoff frequencies in the vicinity of 100 Hz. In the application for which this system is being developed, there is a requirement for a cutoff frequency of 5 Hz. Because the resistors needed to obtain such a low cutoff frequency would be impractically large, it was decided to perform low-pass filtering by use of digital rather than analog circuitry. In addition, it was decided to timemultiplex the digitized signals from the multiple input channels into a single stream of data in a single output channel. The signal in each input channel is first processed by a preamplifier having a voltage gain of approximately 50. Embedded in each preamplifier is a low-pass anti-aliasing filter having a cutoff frequency of approximately 10 kHz. The anti-aliasing filters make it possible to couple the outputs of the preamplifiers to the input ports of a multiplexer. The output of the multiplexer is a single stream of time-multiplexed samples of analog signals. This stream is processed by a main differential amplifier, the output of which is sent to an analog-to-digital converter (ADC). The output of the ADC is sent to a digital signal processor (DSP). One function of the DSP is to digitally extract the low-frequency component of the signal from each channel (the component that one seeks to filter out) and to store this component in a lookup table [more precisely, a random-access memory (RAM) configured to implement the electronic equivalent of a lookup table]. Another function of the DSP is to a assign a gain vector (also stored in the lookup table) for each preamplifier. The gain vector for the preamplifier is presented to the main differential amplifier in synchronism with the arrival of the signal from that preamplifier. This approach prevents the saturation of the main differential amplifier and causes the output signal from every input channel to have optimum strength. Other functions of the DSP include sorting of signal spikes, data compression, and preparation of data for wireless transmission to an external data processor. The gain of the main differential amplifier is dynamically adjustable. Furthermore, its negative input terminal receives offset signals from the lookup table via a digital-to-analog converter (DAC) for the purpose of subtracting the unwanted low-frequency components of the input signals and thereby performing high-pass filtering. Initial gain and offset values for each channel are determined empirically and stored in the lookup table in a calibration procedure. During subsequent operation, the offset and gain uniformity of each channel are constantly monitored by use of the combination of the main differential amplifier, ADC, DSP, and lookup table, and the lookup table is periodically refreshed with updated values of the unwanted low-frequency signal components (offsets) and gains. This work was done by Mohammad Mojarradi, Travis Johnson, Monico Ortiz, Thomas Cunningham, and Richard Andersen of Caltech for NASA’s Jet Propulsion Laboratory. Further information is contained in a TSP (see page 1). In accordance with Public Law 96-517, the contractor has elected to retain title to this invention. Inquiries concerning rights for its commercial use should be addressed to: Innovative Technology Assets Management JPL Mail Stop 202-233 4800 Oak Grove Drive Pasadena, CA 91109-8099 (818) 354-2240 E-mail: iaoffice@jpl.nasa.gov Refer to NPO-30841, volume and number of this NASA Tech Briefs issue, and the page number. This Signal-Conditioning System is designed to be part of a system for monitoring neural electrical signals. This system implements a low-pass filter having a cutoff frequency of 5 Hz by digital means. Input Channels

A comparative study between radhard-by-design and radhard-by-foundry approaches for radiation hardening of CMOS imagers is presented. Main mechanisms for performance degradation in CMOS imagers in a radiation environment are identified, and key differences between the radiation effects in CMOS imagers and that in digital logic circuits are explained. Design methodologies for implementation of CMOS imagers operating in a radiation environment are presented. By summarizing the performance results obtained from imagers implemented in both radhard-by-design and radhard-by-foundry approaches, the advantages and shortcomings of both approaches are identified. It is shown that neither approach presents an optimum solution. The paper concludes by discussing an alternate pathway to overcome these limitations and enable the next-generation high-performance radiation-hard CMOS imagers.

Mechanisms for noise coupling in CMOS imagers are complex, since unlike a CCD, a CMOS imager has to be considered as a full digital-system-on-a-chip, with a highly sensitive front-end. In this paper, we analyze the noise sources in a photodiode CMOS imager, and model their propagation through the signal chain to determine the nature and magnitude of noise coupling. We present methods for reduction of noise, and present measured data to show their viability. For temporal read noise reduction, we present pixel signal chain design techniques to achieve near 2 electrons read noise. We model the front-end reset noise both for conventional photodiode and CTIA type of pixels. For the suppression of reset noise, we present a column feedback-reset method to reduce reset noise below 6 electrons. For spatial noise reduction, we present the design of column signal chain that suppresses both spatial noise and power supply coupling noise. We conclude by identifying problems in low-noise design caused by dark current spatial distribution.

Sb delta doping has been explored as a potential back sufface treatment for high purity ntype silicon detectors such as P M diode arrays and Charge Coupled Devices (CCDs). These devices can potentially be used for detection of particles over a wide range of energy. An advantage of high purity silicon devices is that they can be l l l y depleted, however, this also makes them particularly susceptible to surf8ce effects. The presence of surface states on the back side of an unpassivated device causes unfavorable bandbending that prevents the collection of shallow-penetrating ionizing radiation such as low-energy particles (e.g., electrons < 1 keV) and higher energy photons (in the ultraviolet range 400 m). Additionally, high leakage current is associated with full depletion coupled with unpassivated sudaces.

Modification of high purity N-type silicon surfaces by antimony delta doping for detector applications

A new front-end for photodiode-based CMOS imagers is presented. Degradation in imaging performance due to conventional hard- and soft-reset of pixels is analyzed. To overcome these limitations, the design and operation of a flushed-reset pixel is described. The flushed-reset pixel combines the best of hard- and soft-reset to simultaneously provide excellent radiometric accuracy, high linearity, no image lag, high saturation level, and reduced read-noise. The new front-end is implemented by changes to the column-circuitry only, leaving the pixel unchanged, preventing degradation of any unrelated imaging performance. It is compatible with large format imager implementation, has minimal impact on the frame-rate, and does not introduce any additional hot-carrier stress in the pixel. Data from a large format (512/sup 2/) imager demonstrates the efficacy of the flushed-reset pixel approach.

An enhanced-performance CMOS imager with a flushed-reset photodiode pixel

A proposed successive-approximation analog-to-digital converter (ADC) would contain a capacitively terminated chain of identical capacitor cells. Like a conventional successive-approximation ADC containing a bank of binary-scaled capacitors, the proposed ADC would store an input voltage on a sample-and-hold capacitor and would digitize the stored input voltage by finding the closest match between this voltage and a capacitively generated sum of binary fractions of a reference voltage (Vref). However, the proposed capacitor-chain ADC would offer two major advantages over a conventional binary-scaled-capacitor ADC: (1) In a conventional ADC that digitizes to n bits, the largest capacitor (representing the most significant bit) must have 2(exp n-1) times as much capacitance, and hence, approximately 2(exp n-1) times as much area as does the smallest capacitor (representing the least significant bit), so that the total capacitor area must be 2(exp n) times that of the smallest capacitor. In the proposed capacitor-chain ADC, there would be three capacitors per cell, each approximately equal to the smallest capacitor in the conventional ADC, and there would be one cell per bit. Therefore, the total capacitor area would be only about 3(exp n) times that of the smallest capacitor. The net result would be that the proposed ADC could be considerably smaller than the conventional ADC. (2) Because of edge effects, parasitic capacitances, and manufacturing tolerances, it is difficult to make capacitor banks in which the values of capacitance are scaled by powers of 2 to the required precision. In contrast, because all the capacitors in the proposed ADC would be identical, the problem of precise binary scaling would not arise.

Due to substantial mixed analog-digital circuit integration in one chip, CMOS digital imager cannot be considered only as a photoelectric transducer. In this paper, we have identified timing and circuit layout considerations that are critical for implementing a digital CMOS camera-on-a-chip. An optimized binary-scaled tree-topology power routing has been shown to be critical for minimizing chip area and providing low spatial pattern noise. Imaging artifacts due to timing asymmetry have been quantified, and methods for elimination of the artifacts have been demonstrated. The impact of on-chip bias-generation and drive circuits on the on-chip ADC performance has been shown. New timing and circuit layout techniques have been presented for enabling random noise limited performance of a CMOS imager.

16th International Conference on VLSI Design, 2003. Proceedings.

Key optical elements for space qualification plans of photonic devices are overviewed. Device parameters and qualifying procedures were discussed to assure the reliability of newly developed photonic devices needed for potential usage in space environments. The goal is to gradually establish enough data to develop a space qualification guideline for devices using empirical and numerical models to assess reliability including the lifetime degradation of devices for long-term space applications. Optical, electrical and mechanical device requirements of newly integrated photonic devices (diode lasers and detector arrays) were presented. Monolithically integrated active pixel InGaAs detector arrays were compared, as examples, with those hybridized with CMOS silicon multiplexers in terms of their performances and reliability. Adapting the existing fiber optical (1.55 μm) communication technology, this integration will be an ideal optoelectronic system for dual band (0.5-2.5 μm, Visible/IR) applications near room temperature for use in geological material research and in atmospheric gas sensing in space. For target identification on earth, however, there are concerns about the effectiveness of the device quality, reliability, and prevention of device failure in preparation for multifunctional, transportable shipboard surveillance, night vision, and emission spectroscopy in air and on Mars terrestrial applications.

Ultraviolet imaging arrays, particle detector arrays, and quantum dots

This paper discusses common approaches to CMOS APS technology, as well as specific results on the five-wire programmable digital camera-on-a-chip developed at JPL. The paper also reports recent research in the design, operation, and performance of APS imagers for several imager applications.

Integrated imaging sensor systems with CMOS active pixel sensor technology

To develop more cost-effective future satellites and spacecraft systems, instruments and avionics are evolving into smaller/lighter-weight and more power efficient modules. NASA's future missions will require that these lighter weight systems have smaller shielding mass margins and operate at cryogenics temperatures in stressing radiation. JPL has been exploring several approaches to improving the radiation performance of CMOS Active Pixel Sensor (APS) imagers for ultra-low power,

Advances in ultralow-power highly integrated active pixel sensor CMOS imagers for space and radiation environments

We present a new CMOS photodiode imager pixel with ultralow read noise through on-chip suppression of reset noise via column-based feedback circuitry. In a 0.5 /spl mu/m CMOS process, the pixel occupies only 10/spl times/10 /spl mu/m/sup 2/ area. Data from a 256/sup 2/ CMOS imager indicates imager operation with read noise as low as 6 electrons without employing on- or off-chip correlated double sampling. The noise reduction is achieved without introducing any image lag, and with insignificant reduction in quantum efficiency and full-well.

Reset noise suppression in two-dimensional CMOS photodiode pixels through column-based feedback-reset

The paper describes the design, operation, and performance of integrated CMOS imagers that withstand multi-megarad(Si) total dose of ionizing radiation. It reports test result from two imagers - one with on-chip integrated timing and control, and the other with a variety of pixel structures for parametrically investigating the effects of radiation ion imager performance. The CMOS Imager has been shown to response only to ionizing radiation, and is able to withstand high proton fluence. Minimal change in imager performance is observed after being subjected to a proton fluence of 1.2 X 1012 protons/cm2. The imager also exhibits minimal change in optical response after being dosed with 1.5 Megarad(Si). The radiation-induced dark current ins small and is well-behaved over the entire dose range. No change in operation bias is needed either for operating the imager at low-temperature or after irradiation. The parametric test chip indicates that the LOCOS region plays a significant role in determining the total-side-hardness of the pixel. Based on test results, most promising pixel structures for imaging under high radiation environments have been identified.

Switching and amplifying characteristics of a newly developed 2D InGaAs Active Pixel Imager Array are presented. The sensor array is fabricated from InGaAs material epitaxially deposited on an InP substrate. It consists of an InGaAs photodiode connected to InP depletion-mode junction field effect transistors for low leakage, low power and fast control of circuit signal amplifying, buffering, selection and reset. This monolithically integrated active pixel sensor configuration eliminates the need for hybridization with a silicon multiplexer, and in addition, allows the sensor to be front illuminated, making it sensitive to visible as well as near IR signal radiation. Adapting the existing 1.55 micrometers fiber optical communication technology, this integration will be an ideal system of optoelectronic integration for dual band applications near room temperature, for use in atmospheric gas sensing in space and target identification on earth. In this paper, 4 by 4 test arrays will be described. The effectiveness of switching and amplifying circuits will be discussed in terms of circuit in preparation for 2D InGaAs active pixel sensor arrays for applications in multifunctional, transportable shipboard surveillance, night vision and emission spectroscopy.

This paper gives the status of theoretical and experimental efforts at JPL in the development of environmentally robust (Radiation Hard and radiation Tolerant), ultra-low power, high performance CMOS active pixel sensor (APS) imagers for start tracker/imager applications. The work explores the effect of imager performance on star position accuracy, specifically examining the performance of JPL designed APS imagers. Accuracy is estimated as a function of star magnitude for a nominal star tracker optical design. Using these APS sensors, which have wide dynamic range and no blooming, simultaneous imaging of widely differing star magnitudes during the same observation is possible. It is shown that prototype Rad Hard APS imagers meet many next generation, star tracker/imager mission performance requirements when operated at reduced temperatures. These imagers also provide excellent performance at cryogenic operating temperatures appropriate to some anticipate flight missions. APS imagers with their high level of integration, on-chip timing and control, ultra-low power, and environmental robustness are excellent candidates for NASA's earth observing, interplanetary and deep space exploration missions.

CMOS active pixel sensor specific performance effects on star tracker/imager position accuracy

JPL has implemented advances in CMOS APS visible sensors well suited for the development of ultra-low power, miniature, highly integrated image sensor systems. Applications for these low cost, modular, high performance 'camera-on-a-chip' sensors include: remote earth and planetary visible science cameras, wireless payload deployment monitors for large mirrors, solar panels, booms and antennas, and FPAs for star trackers, sun sensors and high bandwidth multi-window optical communication beacon tracker. This paper reports on the newest generation of CMOS APS dubbed the Versatile Integrated Digital Imager or VIDI APS 'camera-on-a-chip.' VIDI is an integrated, digital 'chip-camera' with a 512 X 512 format, 12-um pixels, utilizing a single 3.3 V supply, with analog or 10-bit digital output, fabricated on a standard 0.5 um CMOS process. The chip size is 10 mm X 15.5 mm. Features include a simple, all digital 'five-wire' interface, on-chip timing, control, four five-bit DACs for bias generation, and 512 column parallel ADCs, VIDI offers programmable exposure, resolution, data efficient 'smart' area-of-interest windowed high speed readout, no blooming, while continuing to operate with approximately 20 mW of power in the on-state and approximately 40 uW in the 'sleep' state and has a maximum data rate of 20 Mbits/sec.

Advances in second-generation ultralow-power CMOS active pixel sensor imagers for remote sensing, star tracking, optical comm, and low-cost solar array/antenna boom deployment metrology

The advent of high performance imaging in CMOS technology using active pixel sensors has enabled ultra-low power, miniature, single-chip, digital camera systems. We report at fully digital, programmable, 5-wire, large format (512/spl times/512) camera-on-a-chip that integrates the imager array, control logic, ADC, and bias generation on the same chip. The chip runs off a single (3.3 V) power supply, consumes only 10 mW, is capable of electronic panning, and produces high quality images with a low noise of <40 e/sup -/, and excellent response linearity down to read noise levels.

VLSI Design 2000. Wireless and Digital Imaging in the Millennium. Proceedings of 13th International Conference on VLSI Design

A single-chip programmable digital CMOS imager with enhanced low-light detection capability

Modulation Transfer Function (MTF) is an important figure of merit in focal plane array sensors, especially for accurate target positions such as star trackers. In-situ evaluation by MTF in different stages of imager system developments is necessary for an ideal design of different sensors and their signal processing. Understanding the tradeoff between different figures of merit will enable designers to achieve the most efficient design in specific missions. Advanced active pixel test sensors have been designed and fabricated where different pixel shapes were placed. Research on analyzing the MTF for the proper pixel shape is currently in progress for a centroidal configuration of a star. Explicit formulas for the modulation transfer function have been studied for the rectangular shaped pixel array. MTF will give us a more complete understanding of the tradeoffs opposed by the different pixel designs and by the signal processing conditions. In this paper, preliminary results of two different active pixel sensor (APS) focal plane arrays are presented in terms of crosstalk using a laser. MTF measurements of the APS arrays are achieved by applying only a single image. A rising or falling edge rather than the conventional bar target of slit scanning is needed to perform the measurement in each direction for the evaluation of the design efficiency.

The large imaging format, high sensitivity, compact size, and ease of operation of silicon-based sensors have led instrument designers to choose them for most visible-light imagers and spectrometers for space-based applications, and this will probably remain the case in the near future. In fact, technologies presently under development will tend to strengthen the position of silicon-based sensors. CCD-CMOS hybrids currently being developed may combine the advantages of both imagers and new high-gain amplifiers and could permit photon-counting sensitivity even in large-format imagers. Back-illumination potentially enables silicon detectors to be used for photometry and imaging applications for which front-illuminated devices are poorly suited. Successful detection by back illumination requires treatment of the back surface using techniques such as delta doping. Delta-doped CCDs were developed at the Microdevices Laboratory at the Jet Propulsion Laboratory in 1992. Using molecular beam epitaxy, fully-processed thinned CCDs are modified for UV enhancement by growing 2.5 nm of boron-doped silicon on the back surface. Named delta-doped CCDs because of the sharply-spiked dopant profile in the thin epitaxial layer, these devices exhibit stable and uniform 100% internal quantum efficiency without hysteresis in the visible and ultraviolet regions of the spectrum. In this paper we will discuss, the performance of delta-doped CCDs in UV and EUV, and the response of these devices to low-energy electrons for electron-bombarded CCD (EBCCD) applications. Recent activities on the extension of delta doping to other imaging technologies will also be presented.

The large imaging format, high sensitivity, compact size, and ease of operation of silicon-based sensors have led instrument designers to choose them for most visible-light imagers and spectrometers for space-based applications. This will probably remain the case in the near future. In fact, technologies presently under development will tend to strengthen the position of the silicon-based sensors. CCD-CMOS hybrids currently being developed may combine the advantages of both imagers and new high-gain amplifiers and could permit photon- counting sensitivity even in large-format imagers. Back- illumination potentially enables silicon detectors to be used for photometry and imaging applications for which front- illuminated devices are poorly suited. Successful detection by back illumination requires treatment of the back surface using techniques such as delta doping. Delta-doped CCDs were developed at the Microdevices Laboratory at the Jet Propulsion Laboratory in 1992. Using molecular beam epitaxy, fully- processed thinned CCDs are modified for UV enhancement by growing 2.5 nm of boron-doped silicon on the back surface. Named delta-doped CCDs because of the sharply-spiked dopant profile in the thin epitaxial layer, these devices exhibit stable and uniform 100% internal quantum efficiency without hysteresis in the visible and ultraviolet regions of the spectrum. In this paper we will discuss the performance of delta-doped CCDs in UV and EUV, applicability to electron- bombarded CCD (EBCCD), our in-house thinning capability, and bonding approaches for producing flat focal plane arrays. Recent activities on the extension of delta-doping to other imaging technologies will also be presented.

Using a delta-doped charge-coupled device (CCD), we have demonstrated an order-of-magnitude improvement in the low-energy cutoff for particle detection compared to conventional solid-state detectors.

Single-event keV proton detection using a delta-doped charge-coupled device

Noise in photodiode-type CMOS active pixel sensors (APS) is primarily due to the reset (kTC) noise at the sense node, since it is difficult to implement in-pixel correlated double sampling for a 2-D array. Signal integrated on the photodiode sense node (SENSE) is calculated by measuring difference between the voltage on the column bus (COL) - before and after the reset (RST) is pulsed. Lower than kTC noise can be achieved with photodiode-type pixels by employing "softreset" technique. Soft-reset refers to resetting with both drain and gate of the n-channel reset transistor kept at the same potential, causing the sense node to be reset using sub-threshold MOSFET current. However, lowering of noise is achieved only at the expense higher image lag and low-light-level non-linearity. In this paper, we present an analysis to explain the noise behavior, show evidence of degraded performance under low-light levels, and describe new pixels that eliminate non-linearity and lag without compromising noise.

Analysis and Enhancement of Low-Light-Level Performance of Photodiode-Type CMOS Active Pixel Images Operated with Sub-Threshold Reset

Switching and amplifying characteristics of a newly developed monolithic InGaAs active pixel imager array are presented. The sensor array is fabricated from InGaAs material epitaxially deposited on an InP substrate. It consists of an InGaAs photodiode connected to InP depletion- mode junction field effect transistors for low leakage, low power, and fast control of circuit signal amplifying, buffering, selection, and reset. This monolithically integrated active pixel sensor configuration eliminates the need for hybridization with silicon multiplexer. In addition, the configuration allows the sensor to be front illuminated, making it sensitive to visible as well as near IR signa radiation. Adapting the existing 1.55 micrometers fiber optical communication technology, this integration will be an ideal system of optoelectronic integration for dual band applications near room temperature, for use in atmospheric gas sensing in space, and for target identification on earth. In this paper, two different types of small 4 X 1 test array will be described. The effectiveness of switching and amplifying circuits will be discussed in terms of circuit effectiveness in preparation for the second phase demonstration of integrated, 2D monolithic InGaAs active pixel sensor arrays for applications in transportable shipboard surveillance, night vision, and emission spectroscopy.

Characteristics of monolithically integrated InGaAs active pixel imager array

The progress of the JPL in developing gallium arsenide junction field-effect transistors (GaAs JFETs) for application in RI readout electronics operating below 10 Kelvin is discussed. Results on GaAs JFETs fabricated using a highly isotropic HF-based etchant have been presented previously by our group. The isotropic etch reduced the typical input leakage current at 4K to less than 1 fA. These JFETs had a low frequency noise of just under 1 (mu) V/Hz1/2 at 1 Hz at 4K, while dissipating less than 1 (mu) W of power. Building on this work, we have fabricated small-scale integrated circuits based on this GaAs JFET technology. In this paper we report on the fabrication of small-scale integrated circuit multiplexers and amplifiers. An 8 by 1 source-follower-per-detector multiplexer and a three-transistor differential pair have been fabricated and are fully functional at 4K. The input-referred noise and leakage current is consistent with that for the discrete devices. A systematic study of the device size dependence of the noise has been started, but as yet is inconclusive.

Recent advances in GaAs JFETs for deep cryogenic focal plane readouts

The progress of the Jet Propulsion Laboratory in developing gallium arsenide junction field-effect transistors (GaAs JFETs) for application in infrared readout electronics operating below 10 Kelvin is discussed. Previously we had presented results on GaAs JFETs and shown that by using a highly isotropic HF-based etchant, the typical input leakage current at 4 K can be reduced to less than 1 fA. These same devices had a low frequency noise of just under 1 μV/Hz 1/2 at 1 Hz at 4 K, while dissipating less than 1 μW of power. In this paper we report on the fabrication of small-scale integrated circuit multiplexers and amplifiers made using this GaAs JFET technology. Small 8xl source-follower-per-detector multiplexers and differential pairs have been fabricated and are fully functional at 4 K. The input-referred noise and leakage current is consistent with that for the discrete devices. Differential amplifier pairs were also measured. A systematic study of the device size dependence of the noise has been started, but as yet is inconclusive.

Advances in Discrete GaAs JFETs and Simple Amplifiers for Deep Cryogenic Readouts

Given the current choices of (1) an ever increasing population of large numbers of satellites in low-earth orbit (LEO) constellations for commercial and military global coverage systems, or (2) the alternative of smaller count geosynchronous satellite system constellations in high-earth (HEO), of higher cost and complexity, a number of commercial communications and military operations satellite systems designers are investigating the potential advantages and issues of operating in the mid-earth orbit altitudes (MEO) (between LEO and HEO). At these MEO altitudes both total dose and displacement damage can be traded against the system advantages of fewer satellites required. With growing demand for higher bandwidth communication for real-time earth observing satellite sensor systems, and NASA's interplanetary and deep space virtual unmanned exploration missions in stressing radiation environments, JPL is developing the next generation of smart sensors to address these new requirements of: low-cost, high bandwidth, miniaturization, ultra low-power and mission environment ruggedness. Radiation hardened/tolerant Active Pixel Sensor CMOS imagers that can be adaptively windowed with low power, on-chip control, timing, digital output and provide data-channel efficient on-chip compression, high bandwidth optical communications links are being designed and investigated to reduce size, weight and cost for common optics/hybrid architectures.

Next-generation CMOS active pixel sensors for satellite hybrid optical communications/imaging sensor systems

A new monolithic InGaAs active pixel multispectral image sensor is described. This infrared sensor will utilize high quality InGaAs grown by molecular beam epitaxy on InP substrate for the fabrication of a high speed junction field effect transistor array. In1-xGaxAs is a III-V alloy whose cutoff wavelength can be tuned from 0.8 micrometer (GaAs) to 3.5 micrometer (InAs). Due to the spectral windows of 3 - 5 micrometer and 8 - 12 micrometer in atmosphere, this material has not received much attention to date for infrared focal plane arrays even though the responsivities for the 0.8 - 1.0 micrometer, and 2.0 - 2.5 micrometer windows for the water and carbon dioxide molecules in air are excellent. Steady advancements of InGaAs material growth and devices have been made, primarily driven by the optoelectronics industry and the high speed electronics community. Most of this knowledge exists in the public domain and is readily accessible. Detectors at 1.7 micrometer cutoff can be ideally implemented as lattice matched In0.53Ga0.47As/InP PIN devices. PIN detectors require high material quality to reduce dark current and decrease bit errors. Additionally, the high intrinsic mobility of In0.53Ga0.47As enables very high speed transistors for monolithic microwave integrated circuit applications. The new active pixel sensor technology, a likely successor to charge coupled device, has been successfully developed for low noise, high signal transfer efficiency imaging circuits in silicon at JPL. The silicon active pixel sensor technology is being adapted to InGaAs/InP in this exploratory development effort. In this paper, a preliminary result of the monolithic multispectral (visible/near infrared/short-wavelength infrared) active pixel imaging sensor is discussed for application in transportable shipboard surveillance, night vision and emission spectroscopy.

Monolithic InGaAs JFET active-pixel tunable image sensor (MAPTIS)

A newly fabricated monolithic InGaAs active pixel image sensor is presented, and its readout characteristics are described. The sensor is fabricated from InGaAs epitaxially deposited on an InP substrate. It consists of an InGaAs photodiode connected to InP depletion-mode junction field effect transistors (JFETs) for signal buffering, selection and reset. The monolithic sensor eliminates the need for hybridization with a silicon multiplexer, and in addition, allows the sensor to be front illuminated, making it sensitive to visible as well as IR radiation. With further development, the sensor is ideal for dual band (visible/IR) applications, including optical communication. It is also well suited to applications requiring near room temperature, broad band response such as for atmospheric gas sensing and target identification. Two different types of small 4 by 1 test arrays have been fabricated. One is a source follower per detector architecture. Here the signal charge is integrated on the photodiode capacitance. The photodiode is connected to a gate of a JFET configured as a source-follower, which buffers the photodiode voltage. The other test circuit uses a capacitive transimpedance amplifier. This circuit contains an invertor using an input JFET with a passive JFET load. The photodiode is connected to the JFET gate. A feedback capacitor causes the circuit to act as an integrator, while keeping the diode input bias relatively constant. Both circuits also contain JFET switches for reset and selection. Selection connects the output of the chosen cell onto a common output bus. In this exploratory development effort, the effectiveness of these two different readout circuits will be discussed in terms of leakage, operating frequency, and temperature. These results then will guide for the second phase demonstration of integrated two dimensional monolithic active pixel sensor arrays for application in transportable shipboard surveillance, night vision and emission spectroscopy.

Readout characteristics of integrated monolithic InGaAs active pixel sensor array

Gallium arsenide junction field-effect transistors (GaAs JFETs) can be made immune to carrier freeze-out, making such transistors useful for the readout of detector arrays that operate at 4 K. Typical applications require transistors with very low noise and extremely low leakage current. By using a recently developed etchant for GaAs that is highly isotropic, etched GaAs JFETs have fabricated that have a gently tapered edge. This reduces edge fields, which consequently reduces the edge tunneling current, the dominant source of leakage current at 4 K. JFETs with gate leakage currents below 10 -15 amps have been fabricated. The fabrication technique, including the isotropic etchant is discussed. The leakage current and noise of these JFETs are presented and compared with previous devices using a conventional etch.

Gallium arsenide junction field-effect transistors (GaAs JFETs) can be made immune to carrier freeze-out, allowing them to operate normally from room temperature down to 4 K. This makes GaAs JFETs attractive for the readout of detector arrays that operate at deep cryogenic temperatures (< 10 K). Typical IR readout applications, however, require transistors with very low noise and extremely low input leakage current, and until recently the leakage current of cryogenic GaAs devices was too high for many IR readout applications. By using a recently developed HF-based etchant for GaAs that is highly isotropic, etched GaAs JFETs have been fabricated that have a gently tapered edge. This reduces edge fields, which consequently reduces the edge tunneling current, the dominant source of leakage current at 4 K. JFETs with gate leakage currents below 10-15 amps at 4 K have been fabricated. The fabrication technique, including the isotropic etchant, is discussed. The leakage current and noise of these JFETs are presented and compared with previous devices using a conventional etch.

Detectors measure both positions of incidence and energies of incident charged particles. Stack of detector wafers intercept cosmic ray. Measure positions of incidence to determine cosmic-ray trajectory and charge generated within them (proportional to cosmic-ray energy dissipated within them). Interdigital electrode pattern repeated over many rows and columns on tops of detector wafers in stack. Electrode pattern defines pixels within which points of incidence of incident cosmic rays located.

Monolithic arrays of active-pixel junction field-effect (JFET) devices made from InGaAs proposed for use as imaging sensors sensitive to light in visible and short-wavelength infrared parts of electromagnetic spectrum. Each pixel of such array comprises photodetector monolithically integrated with JFET output-amplifier circuit of source-follower type - structure similar to charge-coupled device (CCD). Sizes of instruments reduced because large cooling systems not needed.

Report discusses aspects of effort to develop low-noise, low-gate-leakage gallium arsenide-based junction field-effect transistors (JFETs) for operation at temperature of about 4 K as readout amplifiers and multiplexing devices for infrared-imaging devices. Transistors needed to replace silicon transistors, relatively noisy at 4 K. Report briefly discusses basic physical principles of JFETs and describes continuing process of optimization of designs of GaAs JFETs for cryogenic operation.

GaAs junction field-effect transistors (JFETs) are promising for deep cryogenic (<10K) readout electronics applications. This paper presents the structure and fabrication of GaAs JFETs and their performance at 4 K. It is shown that these JFETs operate normally at 4 K, with no anomalous behavior such as kinks or hysteresis. The noise voltage follows a 1/√f dependence and is approximately 1 μV/√Hz at 1 Hz for a ring JFET that is 1250 μm in circumference and 5 μm long. The gate leakage current reaches 1 pA at a gate voltage of -6 V

GaAs JFETS Intended for Deep Cryogenic VLWIR Readout Electronics

This paper discusses a characterization at 4 K of the complementary heterojunction field-effect transistor (CHFET), to examine its suitability for deep cryogenic ( >

Deep cryogenic noise and electrical characterization of the complementary heterojunction field-effect transistor (CHFET)

Gallium arsenide junction field-effect transistors (GaAs JFETs) are promising for deep cryogenic (< 10 K) readout electronics applications. This paper presents the structure and fabrication of GaAs (JFETs) and their performance at 4 K. It is shown that these JFETs operate normally at 4 K, with no anomalous behavior such as kinks or hysteresis. The noise voltage follows a 1/(root)f dependence and is approximately 1 (mu) v/(root)Hz at 1 Hz for a ring JFET that is 1250 micrometers in circumference and 20 micrometers long. The gate leakage current reaches 1 pA at a gate voltage of -6 V, and increases exponentially at approximately 1 decade per volt. The noise is within the limits of the requirements for typical VLWIR readout applications; the extrapolated gate leakage current at typical operating biases is higher than the required limit by two orders of magnitude. Planned improvements to reduce the leakage current are discussed.

This paper describes a type of cosmic ray detector suitable for the construction of a small, low power space-based instrument to detect the energy and isotope of energetic nuclei, such as those produced by solar flares. The detector is similar to previous types of silicon PIN detectors where the fully depleted body of the wafer comprises the intrinsic region of the PIN structure. The novel aspect of this detector is that the one surface is divided into a 2D array of pixels, and that the collected holes are divided between a row and a column collector in each pixel, yielding both dimensions of position information from this side of the detector. In a conventional PIN detector, both sides are divided into stripes, and each side provides 1D information. A single large area collector on the opposite side of this new detector is used to determine the energy of the incident nucleus. This scheme requires only a single precision pulse-height amplifier connected to the broad area contract, rather than one for each strip, as in the conventional scheme, resulting in a significant reduction in the mass, power and complexity of the readout electronics. The design, fabrication, and operation of such a detector is discussed. Initial particle tests show a prototype to be functional. The projected power saved by using such as detector is presented.

Two-dimensional interdigitated pixel detector for energetic particle spectrometers

This paper discusses the electrical properties of the complementary heterojunction field-effect transistor (CHFET) at 4 K, induding the gate leakage current, the subthreshold transconductance, and the input-referred noise voltage. The CHFET is a GaAs-based transistor analogous in structure and operation to silicon CMOS, and is being explored for possible application in readout electronics operating at 2-4 K. It is shown that CHFET is fully functional at 4 K, with no anomalous behavior, and that the drain current shows the expected dependence on device size and gate voltage. The input-referred noise is on the order of 1 ~V/.JHz at 100 Hz. The gate current is strongly dependent on the doping at the gate edge, and is on the order of 10-I4 amps for devices with the lightest doping. A simple multiplexed op-amp is presented, along with its transfer characteristics at 4 K.

Noise and Electrical Characterization of Complementary Heterojunction Field-Effect Transistors (CHFET)

In the past year, there has been substantial impetus for NASA to consider missions that are of relatively low cost as a trade off for a higher new mission launch rate. To maintain low mission cost, these missions will be of short duration and will use smaller launch vehicles (e.g., Pegasus). Consequently, very low volume, very low mass instrument (a.k.a. miniature instrument) payloads will be required. Furthermore, it is anticipated that the number of instruments flown on a particular mission will also be highly constrained; consequently increased instrument capability will also be desired. In the case of infrared instruments, focal planes typically require cooling to ensure high performance of the detectors, especially in the case of spectrometers where high D* is necessary. Since a major portion of an instrument's mass and power budget is consumed by the focal plane cooler, detector technologies that require only modest or no cooling can contribute significantly to the realization of a miniature infrared instrument. InGaAs detectors feature high D*, low dark current, and response not only in the 1 - 3 micrometers SWIR regime, but also in the visible regime as well. The latter feature can extend the versatility of a given spectrometer by enabling greater spectral band response while maintaining focal plane simplicity. In this paper, we discuss the InGaAs detector technology and its potential application in miniature infrared instruments.

We describe a new two-dimensional position-sensitive detector, now under 
development, for use in space-borne energetic particle spectrometers. The novel 
feature of this device is the use of interdigitated pixels to provide both dimensions of 
position information from a single side of the detector, while a measurement of the 
energy deposition is derived from the opposite side. An advantage of this approach is 
that significant reductions in the complexity, power, and weight of the associated 
read-out electronics can be realized without sacrificing position or energy resolution.

An Interdigitated Pixel PIN Detector for Energetic Particle Spectroscopy in Space

Low Temperature Noise and Electrical Characterization of the Company Heterojunction Field-Effect Transistor

This paper discusses the latest results of a continuing study of the properties of the complementary heterojunction field-effect transistor (CHFET) at 4 K. The electrical characteristics, including the gate leakage current and the subthreshold transconductance, and the input-referred noise voltage for a new lot of discrete CHFETs is presented and discussed. It is shown that the inclusion of a sidewall spacer on the gate substantially reduced the gate leakage current, as compared to a previous lot without the sidewall spacer. The input-referred noise is approximately the same order of magnitude as previous devices, on the order of 1 (mu) V/(root)Hz at 10 Hz for subthreshold operation. The noise is relatively unaffected by changes in the bias current and drain voltage, but decreases with increasing device size, and is increased by the inclusion of dopants in the channel region. Several simple multiplexer circuits using CHFETs are presented, and the open-loop transfer curve of a multiplexed single gain stage operational amplifier at 4 K is shown.

Noise and electrical characteristics below 10 K of small CHFET circuits and discrete devices

This paper describes a type of cosmic ray detector for isotopic and energy detection of energetic nuclei which derives both dimensions of position information from one side of the detector. This simplifies the required readout electronics, since only one precision amplifier connected to the other side is required for an accurate detection of the energy loss. Two dimensional readout is enabled by the use of pixels consisting of closely spaced interdigitated electrodes alternately connected to row and column lines. Spreading of the charge produced by the cosmic ray results in the charge being collected by more than one electrode producing both a row and column signal on one side of the detector. The design, fabrication, and characterization of the interdigitated-pixel detector is discussed.

Cosmic-ray detector with interdigitated-finger pixels for two-dimensional position information from a single wafer side

Non-Equilibium Al-Ga interdiffusion in MOCVD reactor annealed AIGaAs quantum well heterostructures

Noise and current-voltage characterization of complementary heterojunction field-effect transistor (CHFET) structures below 8 K are presented. It is shown that the CHFET exhibits normal transistor operation down to 6 K. Some of the details of the transistor operation, such as the gate-voltage dependence of the channel potential, are analyzed. The gate current is examined and is shown to be due to several mechanisms acting in parallel. These include field-emission and thermionic-field-emission, conduction through a temperature-activated resistance, and thermionic emission. The input referred noise for n-channel CHFETs is presented and discussed. The noise has the spectral dependence of 1/f noise, but does not exhibit the usual area dependence.

Noise and current-voltage characterization of complementary heterojunction field-effect transistor structures below 8 K

Optical properties of strained layer (111)B Al0.15Ga0.85As-In0.04Ga0.96as quantum well heterostructures

The temperature dependence of the gate current versus the gate voltage in complementary heterojunction field-effect transistors (CHFETs) is examined. An analysis indicates that the gate conduction is due to a combination of thermionic emission, thermionic-field emission, and conduction through a temperature-activated resistance. The thermionic-field emission is consistent with tunneling through the AlGaAs insulator. The activation energy of the resistance is consistent with the ionization energy associated with the DX center in the AlGaAs. Methods to reduce the gate current are discussed.<<ETX>>

An analysis of the temperature dependence of the gate current in complementary heterojunction field-effect transistors

The current–voltage characteristics of annealed In2O3–GaAs devices have been investigated for the purpose of fabricating transparent ohmic contacts to GaAs. A detailed study of the reverse current for as‐deposited structures with degenerately doped n‐type In2O3 on lightly doped n‐type GaAs yields a 0.67‐V high Schottky barrier. After annealing, the barrier height is only slightly modified, but the reverse current increases dramatically. This reverse current follows a voltage dependence that is consistent with a Fowler–Nordheim tunneling mechanism, for which the electric field is enhanced around localized asperities. These data suggest that an optimized annealing schedule might be used to fabricate low‐resistance, transparent In2O3 ohmic contacts to GaAs‐based optoelectronic devices.

Annealed Indium Oxide/gallium Arsenide Heterojunctions for Transparent Ohmic Contacts to Gallium Arsenide

Abstract : For some time interests have been aroused by the III-V quantum well heterostructures (QWHs) and superlattices (SLs) and, in addition to fundamental effects, the special opportunities QWHs and SLs afford in making possible improved forms of lasers, not to mention other devices and optoelectronic systems. In this report, studies have been made of: (1) Al(x)Ga(1-x)As-GaAs lasers on Si, (2) impurity induced layer disordering (which is an especially advantageous phenomenon in QWHs and SLs), (3) phonon-assisted laser operation and its unambiguous identification by control of the cavity Q of QWH samples, (4) the use of cavity Q to fill the recombination spectrum of QWHs, and (5) hydrolization and reliability of Al(x)Ga(1-x)As-GaAs QWHs and SLs, and (6) various other laser problems associated with higher gap crystals such as In(y) (Al(x)Ga(1-x)(1-y)P. Keywords: Lasers; Silicon; Semiconductors.

III-V Semiconductor Quantum Well Lasers and Related Optoelectronic Devices on Silicon (Abstracts)

This paper compares four versions of the effective‐mass approximation to the exact atomic wave function, as determined from a one‐dimensional model potential, in predicting the energies of the bound states in a single quantum well such as those formed in compound semiconductor heterostructures. The model potential consists of delta‐function barriers between atoms with a ‘‘well’’ in the strength of these delta functions. The model yields simple, closed‐form solutions for the bound state energy. The corresponding effective‐mass model that uses the calculated dispersion relations and continuity of the wave function derivatives at the well boundaries predicts bound state energies indistinguishable from those predicted by the exact solution. The parabolic‐band model overestimates the lowest energy level of a 0.4‐eV‐deep, 50‐A‐wide well by about 15%. Continuity of 1/m* times the wave functions underestimates the energies by about the same amount.

A comparison using a delta‐function model of envelope function approximations for quantum wells

Radio frequency performance of an HVDC converter station AC Switchyard

Editors ' Synopsis: In this Article, the author undertakes a comprehen sive analysis of transactions involving deeds in escrow. The Article begins by discussing the general disfavored status of deeds in escrow that accompany a party 's original acquisition of property, and hence resemble a mortgage arrangement. Turning to a deed-in-escrow trans action that arises in the context of a loan workout, the Article examines potential challenges to the escrow transaction based on theories of clog ging and equitable mortgage. The Article then sets out conditions in which a deed-in-escrow transaction is likely to withstand attack. Last, the Article notes a variety of bankruptcy issues that can impact a deed in-escrow transaction. The Article concludes that deeds in escrow can

s and articles for submission should be sent to the Editor, Professor Martin Willis, by email only: WillisM8@cardiff.ac.uk The JLS recommends that an initial email inquiry, including an abstract of the proposed article, should be sent in advance of completed articles in order to ensure that the subject matter is suitable for publication under the JLS’s remit. All articles should be from 6000-9000 words in length, interdisciplinary in focus, and offering an original view of both the literary or artistic subject matter and the science or sciences under consideration. While articles on individual examples of literary and artistic production are welcomed, these should also seek to show the wider significance of their analyses and interpretations. The journal does not publish essays focused exclusively on literature or art, or exclusively on the history and philosophy of science. All submitted articles should be presented in MLA Style, with notes kept to a minimum. JLS articles do not use personal pronouns (e.g. “In this article I will...” is not appropriate, while “This article will...” is appropriate). All spellings should follow British English. All submitted articles should include a short abstract (150 words maximum) below the title and author’s name and ahead of the opening sentence. The JLS aims to complete the first stage of peer review (consideration of articles by the editor and advisory board) within 4 weeks of submission and the second stage of peer review (external, blind, double peerreview) within 8 weeks of the completion of the first stage. All authors whose articles reach the second stage of peer review should expect to have a decision on publication within approximately 12 weeks of the date of their original submission of an article Citing the JLS: the journal’s full title is the Journal of Literature and Science, and its first issue was Volume 1, Number 1 (2007). All page numbers to individual essays can be found when accessing the PDF file of that essay. The journal’s ISSN is 1754-646X. Citations should give Author, ‘Title,’ Journal of Literature and Science Vol, No. (Year): pp., organized according to the specific style guide being used. Open Access Statement iv The Journal of Literature and Science is committed to real and immediate open access for academic work. All of the JLS’s articles and reviews are free to access immediately from the date of publication. There are no author charges (commonly known as APCs) prior to publication, and no charge for any reader to download articles and reviews for their own scholarly use. The JLS does not, therefore, operate either a Gold or Green model of open access, but is free to all at any time and in perpetuity. To facilitate this the JLS depends upon the financial underwriting provided by the University of Westminster’s Department of English, the goodwill of its editorial team and advisory board, and the continuing support of its network of peer reviewers. The Journal of Literature and Science also operates under the Creative Commons Licence CC-BY-NC-ND. This allows for the reproduction of articles, free of charge, for non-commercial use only and with the appropriate citation information. All authors publishing with the JLS accept these as the terms of publication. Please note that copyright of the content of all articles and reviews remains with the designated author of the article or review. Copyright of the layout and design of JLS articles and reviews remains with the Journal of Literature and Science and cannot be used in other publications. The JLS is a member of PILA (Publishers International Linking Association) and submits all articles and reviews, including all works that these cite, to CrossRef for cross-referral. To find JLS articles and reviews via their DOI numbers, use the URL http://dx.doi.org/[DOI number]

The law of Scotland relating to notaries public: with forms of instruments.

Creditors' Rights Risk: A Title Insurer's Perspective, 38 J. Marshall L. Rev. 223 (2004)

or Rate-supported. By Arthur Turnour Murray, Barrister-at-law. Pp. 287. (London: John Murray. Price 10s. 6d. net cash.) It must surely have struck those connected with hospitals, and more especially voluntary hospitals, that no competent lawyer should have set himself the task of collecting all the scattered branches of the law which appertain thereto. Yet, if we set aside the legal handbook for the use of hospital authorities which was compiled some years

This article reviews the history and background of Cobalt and discusses the physics of activation, the specification of source strength, the unit design, and clinical applications. 
 
Keywords: 
 
cobalt; 
mounting; 
porting; 
isocentric; 
radiation beam; 
calibration; 
dosimetry

This paper presents an approach for predicting the solubility of hydrogen in hydrocarbons using a cubic equation of state. Because the α function from the Soave−Redlich−Kwong and Peng−Robinson equations of state is inadequate at temperatures far above the critical temperature, the binary interaction parameters required for hydrogen−hydrocarbon systems using these equations are typically large and strongly dependent on the temperature. An approach is proposed for developing a temperature-dependent α function for hydrogen which minimizes the need for interaction parameters. The minimization of the values of the binary interaction parameters between hydrogen and heavy hydrocarbons is desirable because this produces better predictions when the binary interaction parameters are not known and are set to zero. A universal procedure is also presented for interconverting the binary interaction parameters between the new hydrogen α function developed in this work and the traditional Soave α function or any other ty...

An approach for the application of a cubic equation of state to hydrogen-hydrocarbon systems

An approach for the extension of a 3-parameter cubic equation of state to heavy hydrocarbons

A new generalized alpha function for a cubic equation of state Part 1. Peng-Robinson equation

A new generalized alpha function for a cubic equation of state Part 2. Redlich-Kwong equation

A cubic equation of state: relation between binary interaction parameters and infinite dilution activity coefficients

A cubic equation of state with a new alpha function and a new mixing rule

A major deficiency of current photon calculation methods that are based on the concept of primary and scatter separation is their inability to handle the condition of electronic disequilibrium. This deficiency is examined and it is shown that the limitation is not inherent in the algorithms themselves but is, at least in part, in the data which the algorithms use. A new concept of primary and scatter separation is developed to cover the condition of electronic disequilibrium. This new concept requires little change to the existing algorithms and only additional data are required, which are generated using Monte Carlo calculation methods. The new concept is tested using programs in the Theratronics Theraplan treatment-planning system, and two calculation examples illustrate the ability to model electron transport and also the improvement over the existing algorithms. Close analogy of the extended concept with the convolution/superposition method of dose calculation is also indicated.

Extending the concept of primary and scatter separation to the condition of electronic disequilibrium.

In the convolution/superposition method of photon beam dose calculations, inhomogeneities are usually handled by using some form of scaling involving the relative electron densities of the inhomogeneities. In this paper the accuracy of density scaling as applied to primary electrons generated in photon interactions is examined. Monte Carlo calculations are compared with density scaling calculations for air and cork slab inhomogeneities. For individual primary photon kernels as well as for photon interactions restricted to a thin layer, the results can differ significantly, by up to 50%, between the two calculations. However, for realistic photon beams where interactions occur throughout the whole irradiated volume, the discrepancies are much less severe. The discrepancies for the kernel calculation are attributed to the scattering characteristics of the electrons and the consequent oversimplified modeling used in the density scaling method. A technique called the kernel integration technique is developed to analyze the general effects of air and cork inhomogeneities. It is shown that the discrepancies become significant only under rather extreme conditions, such as immediately beyond the surface after a large air gap. In electron beams all the primary electrons originate from the surface of the phantom and the errors caused by simple density scaling can be much more significant. Various aspects relating to the accuracy of density scaling for air and cork slab inhomogeneities are discussed.

The validity of the density scaling method in primary electron transport for photon and electron beams.

KEYNOTE ADDRESS: DEVELOPMENT OF COMPUTER ALGORITHMS FOR RADIATION TREATMENT PLANNING

As a result of an analysis of data relating tissue response to radiation absorbed dose the ICRU has recommended a target for accuracy of +/- 5 for dose delivery in radiation therapy. This is a difficult overall objective to achieve because of the many steps that make up a course of radiotherapy. The calculation of absorbed dose is only one of the steps and so to achieve an overall accuracy of better than +/- 5% the accuracy in dose calculation must be better yet. The physics behind the problem is sufficiently complicated so that no exact method of calculation has been found and consequently approximate solutions must be used. The development of computer algorithms for this task involves the search for better and better approximate solutions. To achieve the desired target of accuracy a fairly sophisticated calculation procedure must be used. Only when this is done can we hope to further improve our knowledge of the way in which tissues respond to radiation treatments.

Development of computer algorithms for radiation treatment planning.

Evaluation of lung dose correction methods for photon irradiations of thorax phantoms.

Computerized medical imaging and graphics : the official journal of the Computerized Medical Imaging Society

Pencil beam algorithms for the calculation of electron beam dose distributions have come into widespread use. These algorithms, however, have generally exhibited difficulties in reproducing dose distributions for small field dimensions or, more specifically, for those conditions in which lateral scatter equilibrium does not exist. The work described here has determined that this difficulty can arise from the manner in which the width of the pencil beam is calculated. A unique approach for determining the pencil beam widths required to accurately reproduce small field dose distributions in a homogeneous phantom is described and compared with measurements and the results of other calculations. This method has also been extended to calculate electron beam dose distributions in heterogeneous media and the results of this work are presented. Suggestions for further improvements are discussed.

The optimization of pencil beam widths for use in an electron pencil beam algorithm.

Radiographics : a review publication of the Radiological Society of North America, Inc

Many workers have also applied empirical relations to the description of dose distributions in electron beams. Like those for photon beams, they usually consist of a function describing the central-ray data multiplied by a function describing the cross-beam profile. The shapes of electron beams tend to be more individually affected by the design of their collimating system than do photon beams and there is a greater variety of proposed formulae. Again, only a representative set is referred to in this Appendix.

This report continues the series of reports by the International Commission on Radiation Units and Measurements (lCRU) dealing with dosimetric problems in external beam therapy with high-energy photons. Report 23 (ICRU, 1973) dealt with the measurement of absorbed dose in a water phantom irradiated with a single photon beam; Report 24 (ICRU, 1976) dealt with the determination of absorbed dose in a patient irradiated with single and multiple photon beams; Report 29 (ICRU, 1978) gave recommendations for specification of target absorbed dose for reporting purposes. Since the publication of these reports, computers have assumed an increasingly important role in dosimetric and treatment-planning procedures in an increasing number of centers. Computer applications were first developed to give faster and more accurate answers to dosimetric problems handled by manual methods. Soon however, computer techniques became so extensive and diversified, that they completely changed the approaches to the problems. In addition, it became possible to handle new problems which could not have been considered without the aid of computers. Because of this, the ICRU considered it appropriate to produce a report on treatment planning and recording and documentation procedures in external beam therapy as they are now carried out using computers. It is recognized that, owing to the rapid evolution of computer technology, there is a risk that this report will be rapidly outdated; therefore, only the main concepts and basic methods are presented, some specific examples being included as illustrations. Treatment planning, for purposes of this report, is considered to consist of a series of procedures as outlined in Figure 1.1. These procedures begin after the clinical evaluation of the patient and the decision to use external beam therapy have been made. The relevant steps are as follows:

In the text, a number of general statements have been made regarding analytical expressions that have been chosen by various workers to represent dose distributions for radiation beams. The details of these may, nevertheless, be of interest to a number of people, for example, those who wish to do creative work in the field or evaluate treatment planning systems. The list of equations is not, and probably cannot be, complete but should certainly be representative. Much of the discussion is taken from Wood (1974) and Redpath and Wright (1981b). This Appendix deals with photon beams and Appendix B deals with electron beams. Each included equation is accompanied by a very brief explanation of the salient points only and a reference. In Section 2.2.2 it is stated that the dose at a point in an irradiated medium can be expressed as a product of two functions (Eq. 2.1) one describing the central ray and the other giving the cross-beam profile. Appendix A.1 deals with the first of these and Appendix A.2 deals with the second.

The question of accuracy in radiotherapy was discussed in a previous report (ICRU, 1976) and it was recommended that an accuracy of ±5% in the delivery of an absorbed dose should be sought. This was based largely on evidence that differences of this magnitude in absorbed dose can be detected clinically. Since the writing of that report, other evidence (van Dyk et ai., 1981; Johansson, 1982; Westermann et at., 1984; Dutreix, 1984; Wambersie, 1984; AAPM, 1984) has tended to strengthen the conclusion. The dose distributions discussed in the preceding sections are the result of calculations which assign to all input parameters their intended values. In practice, there are many sources of uncertainty in planning and delivering radiation therapy (Dutreix, 1984) and these will lead to uncertainties in the delivered dose. These uncertainties include effects which can lead to an effective dose-scaling uncertainty (such as calibration uncertainties, errors in source-patient-distance); and effects which distort relative dose distribution (such as geometric errors, errors due to changes in patient position, size and shape, relative position of the beams with respect to the patient, misposition of tissue compensators, etc.). The possible consequences of a variation in dose have been investigated and can be derived from the studies of the dose-effect relations, both for tumor control and normal tissue complications. However, in most studies, it is implicitly assumed that the actual relative-dose distribution corresponds to the planned relative-dose distribution (and, in particular, with respect to the target volume, that there was no geometrical miss). This is partly because, in practice, the geometrical errors are more difficult to evaluate than er-

Because absorbed dose distributions in the patient are needed for radiotherapy procedures, and cannot be measured directly, they must be calculated. In order to do this, it is necessary to set up a formalism for the mathematical manipulation of dosimetric data. In this report, such a formalism is referred to as a beam model. The data that must be manipulated are derived from measurements made in a reference medium which is usually water. Various beam models have been proposed and these differ considerably in their requirements of amount and nature of basic data and in the ease with which they can be manipulated. The earliest of these depended on the direct storage of measured data and were thus limited in the number of beams that could be represented. Soon, however, curve fitting procedures were used to decrease the storage requirements while other workers chose semiempirical formulae from considerations of physics but used numerical data derived from specially designed experiments. The subject is developing rapidly and the semi-empirical methods are giving way to calculations based more on sound physical principles. Some basic properties of models in use and the acquisition of the data needed will be discussed in following subsections. It is useful to define a reference situation. This is a beam, usually defined by a square aperture, directed at right angles to the surface of a reference medium, which is a large water or water-equivalent phantom. Output calibrations can be made to apply to the reference situation and by convention, all calculated doses are expressed relative to the dose at a reference point in the reference situation.

Quality assurance (QA) for ion-beam therapy follows essentially the same guidelines as for other external-beam radiotherapy modalities. The general guidelines of the American Association of Physicists in Medicine (AAPM) (Klein et al., 2009) and the general standards of the International Electro-technical Commission (IEC, 2007) should be consulted before setting up a QA program for a specific facility. IEC also gives dedicated standards on the safety and performance of light-ion accelerators (IEC, 2014). For aspects of treatment planning, the recommendations of the International Atomic Energy Agency (IAEA, 2004; 2007b) and the AAPM (Miller et al., 1995) should be also consulted. Most of the aspects of proton therapy discussed in ICRU Report 78 (2007) will also apply to carbon ion-beam therapy. The AAPM has published TG-100 (Huq et al., 2016), which describes modern quality management applied to radiation oncology.

After the selection of the treatment plan, the treatment parameters must be recorded on a special form which will be used as a permanent record during the whole course of treatment. It is conceivable that most of these parameters could be produced by the treatment planning system, transferred automatically to the simulator where the treatment feasibility is checked and then to the treatment machine for monitoring or automatic set-up (Chavaudra et al., 1970).

8. Recording, Monitoring, Automatic Set-Up and Documentation of Treatment

It is reasonable to expect that the introduction of computer technology will improve both the quality of a treatment plan (by permitting more sophisticated plans) and the dosimetric accuracy of the treatments. As with any technological innovation, however, the use of computers will inevitably introduce new risks of error and responsibilities. The computer system has to be checked, and recommended procedures for doing this are discussed in this chapter. The problem of checking the results of a computer calculation of absorbed dose is essentially the same problem as checking the results of a manual calculation of the same quantity. A knowledge of the dose at a point in a patient is the result of three distinct steps: (1) Determination of the absorbed dose at the reference point for the reference situation (see Section 2.1). (2) Calculation, by the computer, of the dose at points in the patient relative to the dose at the reference point. (3) Set-up and treatment of the patient. The uncertainty in the dose delivered is a combination of the uncertainties inherent in each of the above steps. In most applications, the computer is involved only in step (2), the computation of a relative dose. An experimental check of the computer calculation must, therefore, involve measurements at points of interest and a measurement by the same instrument at the reference or normalization point. Many such measurements are described in the literature and can be used [depth dose data (BJR, 1983), isodose charts, etc.]. If additional measurements are to be performed, they must be done under carefully controlled conditions (homogeneous phantom, or one with well-known composition and shape, etc.). A computer-produced dose distribution can then be considered to be accurate enough if it differs from relative dose measurements by less than 2% (or 0.2 cm in position of isodose lines in special circumstances involving very steep dose gradients) in points of relevance for the treatment. Even more severe constraints have been proposed by other authors (Dahlin et al., 1983). To obtain, in routine practice, such a level of accuracy, it is necessary to set up a quality assurance procedure.

(1) simulation of the actual treatment set-up using a simulator (see Section 8.1); (2) transfer of treatment parameters (manually or automatically) to the treatment unit(s) (Section 8.2) for check-and-confirm or even for automatic set-up (Sections 8.3 and 8.4); (3) comparison with data obtained from in vivo dosimetry (Section 9.6); (4) correlation between dose distribution and tissue reactions during treatment; (5) follow-up of the individual patient and scientific evaluation of results of treatment; (6) for legal purposes, if needed.

Journal of the International Commission on Radiation Units and Measurements

8. Recording, Monitoring, Automatic Set-Up and Documentation of Treatment:

The basic representation of a radiation beam specifies the dose-distribution in a reference situation as described in Section 2.1. In practice, it is necessary to deal with patients that are irregularly shaped, heterogeneous in composition, and irradiated in various positions. In order to relate the properties of the radiation beam to those of the patient it is necessary to set up a coordinate system for each of them and to establish the relationship between the two systems. The spatial relation between two such systems is shown in Figure 5.1.

Enormous changes have taken place in computer technology since it was first used for treatment planning in the late 1950's. The early systems were multipurpose, large machines, located in computing centers. They used card readers as input and line printers as output devices. Since then, the general trend has been toward the use of smaller, dedicated computers with terminals having full graphic input, display and output capabilities. Many such systems have been developed both by commercial companies and individuals. These systems usually provide an interactive capability and permit inspection of several treatment plans in order to select the best. It is not easy to choose among the existing systems but in doing so the following criteria are important: accuracy of dose computation, ease of use, degree of interactivity, flexibility and ability to handle all treatment types, speed of computation and considerations of installation and maintenance cost. Multi-user systems are extremely useful in that they permit interactive activities while dose computations are proceeding. The setting up and use of a treatment planning system involves a number of steps and although there is no universal sequence of events, the following sections will serve as illustrative examples.

When the complete clinical status of a patient has been obtained (extent of tumor, grading, staging, etc.) and external-beam therapy has been chosen, additional information on patient anatomy is usually required before treatment planning can be started. This information includes the size and shape of the target volume(s) which is to be defined by the radiotherapist prior to any planning, and the identification of organs at risk, heterogeneities and other relevant anatomical structures. These data are the result of several different types of examination: inspection and palpation, xray examination, CT -scanning, ultrasound scanning, etc. Recent developments in the field of imaging devices such as Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET) and Single Photon Emission Tomography (SPECT) will make more information available to the clinician. In using this information, one must always remember that volumes not areas are being considered. Traditionally, anatomical data are usually represented by a series of transverse parallel sections containing the target volume, etc. In some cases, other sections (sagittal, coronal) may be required. It is, nevertheless, common practice to use only a single transverse section, usually the one that will contain the beam axis, for dose calculation purposes. In doing this, one makes the tacit assumption that the entire irradiated volume, including the target volume, has the same contour and configuration as the section used. Sometimes this is an acceptable assumption but frequently it is not, particularly in the head and neck region. It should always be used with caution. All patient data directly used for treatment planning should be collected with the patient in the treatment position. Utmost care must be taken to ensure consistency in patient positioning during the planning phase and during treatment. Irradiation in different positions (e.g., prone and supine) should be avoided whenever possible. In those cases where the patient must be irradiated in different positions, a composite anatomical section can be used if it approximates the situation met in the treatment. Such sections should be composed so as to assure that the dose distribution in the treated volume and other high-dose areas (e.g., skin) is reproduced as correctly as possible. The effect of using a composite section should be estimated and if used, these sections should be indicated as such. Ideally, all anatomical information (except for peripheral and/or superficial lesions) should be de-

A number of different types of particles, e.g., electrons, neutrons, protons, 7r-mesons, and heavy ions, are in use for radiotherapy. Each has specific requirements relevant to dose planning procedures. Of these, only electrons have gained widespread use, and the representation of electron beams and specific problems associated with them are the subject of this section. Although there are many similarities between the behavior of electron beams and that of photon beams, there are also many differences. Chief among the differences is the steep fall-off of the depth-dose curve beyond the dose maximum and, indeed, it is this feature that makes electron beams attractive for radiotherapy. Another characteristic of electron beams is the broadening of the dose distribution with depth resulting in a bulged pattern in the penumbra region. Also, with increasing energy, bremsstrahlung, produced mainly in the radiation head of the accelerator, but also in a patient, may contribute significantly to the shape of the dose distribution, particularly at depths greater than the electron-beam range. Beam limiting and modifying devices strongly affect both the energy spectrum and the angular distribution of the electrons and thus greatly influence the shape of the dose distribution. Another feature is the complex behavior of electrons in and around tissue inhomogeneities due to the very important multiple scattering processes. All of this makes the calculation of dose distributions for electrons more difficult than for photons, and methods for handling electron beams are less advanced. There is, nevertheless, already an extensive literature on the subject. Nusslin (1979), Mohan et al. (1983b), ICRU (1984), Brahme (1985), Nahum (1985) and others have reviewed methods and models which have been found useful for calculating electron beam dose distributions. Just as for photon beams, the computational procedures are based on matrix methods, beam generating functions and analytical models.

3. Representation and Modification of High-Energy Electron Beams

The Monte Carlo computer code "electron gamma shower" (EGS) has been used to determine photon spectra in a water phantom. Spectra used by Johns and Cunningham and for the AAPM dosimetry protocol have been used as input data and ratios of average mass energy absorption coefficients have been calculated for a number of depths and field sizes. The results show that there is a slight dependence on both of these parameters. For example, (mu en/P) water graphite for cobalt-60 varies from a value of 1.111 for the primary spectrum in air, to 1.135 at a depth of 20 cm in a phantom for a beam approximately 1 m2 in area. This variation of over 2% is relevant for dosimetry. The variation is less than this for high-energy radiation beams and in most cases can be ignored. The effect is greater for high atomic materials such as bone, where the range of variation of (mu en/P)bone water, again for cobalt radiation, may be as great as 15%. This too is less for high-energy bremsstrahlung spectra.

The dependence of mass energy absorption coefficient ratios on beam size and depth in a phantom.

Comments on "Validity of the concept of separating primary and scatter dose".

We have measured the radiation dose in simple heterogeneous phantoms and compared our results with those obtained by various methods of computation. Dose data were obtained both within and distal to simulated regions of lung in order to test the ratio of tissue-air ratios (TAR), Batho, and equivalent TAR methods. These procedures are used routinely in manual and computer-aided planning of radiation therapy, but have been validated primarily for cobalt-60 radiation. Tests performed with 6- and 15-MV x rays reveal that incorrect doses can be computed within or near to a low-density medium, particularly when the field size is small. In these cases, electronic equilibrium is not achieved in the lateral direction, thereby violating an implicit assumption of all the above calculation methods. We quantify the errors in dose calculation for simple slab phantoms, and support our interpretation with a Monte Carlo simulation in which the energy transported by charged particles away from sites of x-ray interactions is considered directly.

Coal liquids produced from SRC-II processing of Powhatan No.6 bituminous coal were distilled into a number of narrow-boiling cuts. Vapour pressure measurements were carried out on 6 cuts at temperatures from 267 to 788 K and pressures to 3.6 MPa. Heats of vaporisation were measured in a flow calorimeter on these same fractions at temperatures from 366 to 755 K. It was found that the modified BWR equation-of-state developed by Brute specifically for coal liquids gave the best representation of vapour pressure data. An empirical method involving a simple BP relationship combined with the Watson equation gave the best predictions of latent heat data.

Industrial & Engineering Chemistry Process Design and Development

Thermophysical properties of coal liquids. 3. Vapor pressure and heat of vaporization of narrow boiling coal liquid fractions

A method for the selection of average stopping-power (L/rho)medair and energy-absorption coefficient (mu en/rho)medair ratios has been developed. The quality of the x-ray beam is characterized by the ratio of ionization chamber readings at depths of 20 and 10 cm in water (TMR)2010. For convenience, a relationship is established between experimental (TMR)2010 and the nominal accelerating potential (MV) of the accelerator. Experimental (TMR)2010 are related to (L/rho)medair and (mu en/rho)medair in a three-step process. First, using experimental and theoretical spectra in the range 60Co to 45 MV, (TMR)2010 were calculated for primary and first-scatter photons, and a graph of experimental versus calculated (TMR)2010 for these same spectra was constructed. Second, (L/rho)medair and (mu en/rho)medair were calculated for a large number of primary spectra [for most of which experimental (TMR)2010 were not available] and a graph constructed that related these quantities and (TMR)2010 calculated as above for this group of spectra. Third, using the graphs from the preceding steps, graphs relating the calculated (L/rho)medair and (mu en/rho)medair with experimental (TMR)2010 were constructed. Data are presented for water, polystyrene, acrylic, graphite, A-150, C-552, Bakelite, and nylon for beams with nominal accelerating potentials in the range 2-45 MV.

On the selection of stopping-power and mass energy-absorption coefficient ratios for high-energy x-ray dosimetry.

The considerations of tissue response to radiation absorbed dose suggest a need for an accuracy of +/- 5% in its delivery. This is very demanding and its regular achievement requires careful quality control. There are three distinct phases to the delivery of the planned treatment: calibration of the radiation beam in a reference situation, calculation of the dose distribution for a patient relative to the reference dose and the delivery of the radiation to the patient as planned. Each has distinctly different quality assurance requirements and must be diligently observed if the desired accuracy is to be achieved.

Quality assurance in radiation therapy: clinical and physical aspects. Quality assurance in dosimetry and treatment planning.

Liquid products from the SRC-II processing of a high volatile bituminous coal were distilled into narrow boiling range fractions with average boiling points ranging up to 800 K. Liquid density, thermal conductivity, and viscosity were measured at temperatures to 505 K, and specific heat was determined to 600 K. Other property determinations included molecular weight, pour point, elemental analyses, water content and solubility, and hydrocarbon types. Both organic oxygen content and water solubility showed a pronounced maximum for the fraction having an average boiling point of 470 K and significantly influenced density. A secondary distillation on six different fractions spaced over the entire boiling range yielded heart cuts spanning 4-26 K that were used for measurement of surface tension, heat of vaporization, and vapor pressure at temperatures to 755 K. Property data for all the fractions are compared with other published data and existing property correlations.

Thermophysical properties of coal liquids; 1: selected physical, chemical, and thermodynamic properties of narrow boiling range coal liquids

Coal liquids produced from SRC-II processing of two Pittsburgh Seam bituminous coals from Powhatan No. 5 and No. 6 Mines were distilled into a number of narrow boiling cuts. The source coal liquids included samples of internal process streams as well as full boiling range products. Molecular weight and specific gravity determinations and chemical characterizations were performed on each fraction, and the results were correlated with the midboiling point of the fraction. Specific gravity, H/C ratio, and oxygen content all yielded correlations with boiling point that exhibited striking trends at boiling points near 470K. Vapor pressures, heats of vaporization, and surface tensions were measured on 12 heart-cuts from these fractions at temperatures to 755K. Methods of correlating and predicting these properties as well as several other thermophysical properties were evaluated.

Density, viscosity, and surface tension of coal liquids have been experimentally determined at temperatues up to 850/degree/F and pressures up to 3200 psia. Measurements were made on liquids produced with the Exxon Donor Solvent process from Illinois and Wyoming coals. Several measurements were also made to determine the effect of dissolved hydrogen on the physical properties of coal liquids. These data were used to investigate the applicability of the existing physical property correlations to coal-derived liquids. Results indicate that the existing correlations are generally satisfactory for the temperature and pressure dependence of density but are unsatisfactory for the viscosity and surface tension of coal-derived liquids. 27 refs.

Density, viscosity, and surface tension of coal liquids at high temperatures and pressures

Tissue Inhomogeneity Corrections in Photon-Beam Treatment Planning

When an (exposure) calibrated ionization chamber is used for the determination of absorbed dose from a photon beam, the reading of the instrument must be multiplied by a number of factors, one of which is an attenuation correction for phantom material displaced by the chamber. the magnitude of this correction must depend on the size and shape of the ionization chamber as well as the energy of the radiation beam. For cobalt-60 radiation, a single number, 0.985, has generally been used. Recent measurements, however, and "first scatter" calculations, of kerma suggest that a more appropriate value for a Farmer-type chamber used in a water phantom would be 0.975. Such a change is small but would be important when dose calculations based on "in phantom" measurements are compared to calculations that are based on in air measurements. Values for the attenuation factor for other beam energies have not been generally available. We have carried out "first scatter' calculations for a rather wide range of energies and spectra. Measurements in 60Co beams and in a high-energy (25 MV) photon beam support the calculations. A set of proposed displacement correction factors is presented.

High energy electrons set into motion by photon interactions with matter lose some of their energy by bremsstrahlung. This loss must be evaluated before energy absorption coefficients may be calculated. Recent extensive tables of data published by Plechaty et al. contain an appreciable error in this quantity. The error results from two simplifying assumptions and for the case of very high photon energies interacting with high atomic number materials can be as much as a factor of two. This has important implications for the evaluation of quantities used in radiation dosimetry.

Calculation of the average energy absorbed in photon interactions.

X-ray transmission computed tomography (CT) has been used primarily in medical diagnostic radiology since 1972. More recently, the application of CT to radiation therapy planning has been developed. In comparison to conventional radiography, CT images provide vastly improved anatomical localization of the tumour and of surrounding healthy tissue. Qualitatively, this information assists in the selection of appropriate radiation fields. Quantitatively, CT data can be processed to yield the electron densities of the tissues for calculation of the corresponding radiation distribution in the patient. In such calculations, the variations in tissue density and the three dimensional nature of structures are considered by employing a series of contiguous transverse section CT images which cover the entire patient volume to be irradiated. In this paper, the utilization of computed tomography for radiotherapy planning and for monitoring tissue response following radiotherapy will be demonstrated with a clinical example (tumour of the chest wall). The results presented were obtained with a computerized treatment planning system (TP-11, Atomic Energy of Canada) modified to interact with a commercial CT scanner (TR-40 Synerview, Picker X-ray Corporation). This system has been in clinical use for the past six months at the Princess Margaret Hospital.

The Application Of Computed Tomographic (CT) Imaging To Radiotherapy Planning

The CT scanner makes three-dimensional anatomical information available for treatment planning, the calculational algorithm being the limiting factor in dose calculations. A method has been developed, called the "effective tissue-air ratio method," that uses all the information but reduces it to manageable proportions. The accuracy is satisfactory for a wide range of photon beam energies and clinical applications. It has been implemented in such a way that the CT scan can be used directly without the intermediate step of manually obtaining structures from either a viewing screen or a hard copy of the CT image.

The equivalent tissue-air ratio method for making absorbed dose calculations in a heterogeneous medium.

Patient inhomogeneity information is investigated for use in radiotherapy planning. Absorbed doses measured in a phantom are compared to doses calculated for photon beams using various treatment planning inhomogeneity correction methods. Delineation of inhomogeneities with a spatial resolution of 5 mm and with an electron density accuracy of 2% in usually sufficient to allow doses to be calculated with a mean accuracy of better than 2% for 60Co and 3% for 25-MV x rays if the authors' Equivalent Tissue-Air Ratio Method is used.

Implications of computed tomography for inhomogeneity corrections in photon beam dose calculations.

Traditional methods for correcting for the presence of tissue inhomogeneities may produce errors as great as 10% at points within or closese to the inhomogeneities. Measurements were made in phantoms containing aluminum or cork inhomogeneities. Agreement between measured and predicted results was usually within 2%-3%.

Corrections to absorbed dose calculations for tissue inhomogeneities.

Laboratory tests demonstrate that in acid stimulation of a sandstone formation, the volume stimulated is much smaller than the volume filled by the acid. As mud acid is injected into the matrix of a sandstone, an acid-mineral reaction zone is developed which moves at a velocity much less than that of the acid itself, and permeability rises rapidly after a time delay correlated with injection rate, HF concentration, and core length. The physical and chemical changes occurring during the acid injection were modeled mathematically to describe the movement of the acid and reaction fronts and determine the rock properties and test conditions that control the fronts. Developed for both the linear test cores and the radial geometry around the well bore, the model can be readily applied to field acid jobs in a specific sandstone by conducting a limited number of linear core tests in the laboratory.

Acidization VI: a new model of the physical and chemical changes in sandstone during acidizing

Calculations for tissue inhomogeneities with experimental verification

A general method is given for the calculation of absorbed dose to an arbitrary point in an irregularly shaped radiation field. This method is recommended either as a routine method or as a standard method against which more rapid approximate methods may be judged for correctness.In addition, limited consideration is given to the problems of secondary blocking, matching adjacent fields, dose to spinal cord, and dose to the gonads or fetus.

The American journal of roentgenology, radium therapy, and nuclear medicine

A method for the calculation of dose in the radiation treatment of Hodgkin's disease.

[Role of the computer in a well-organized radiotherapy department].

The behavior of the dosage distributions produced by synchronous shielding techniques is examined. Shielding of sensitive structures is obtained only at the expense of dose uniformity in the high-dose region. Uniformity can be improved only by shaping the open part of the beam with specially-constructed wedge filters.

An examination of synchronous shielding in 60 Co rotational therapy.

Program IRREG-calculation of dose from irregularly shaped radiation beams.

Scatter-air ratios are empirical quantities derived from tissue-air ratios for use in calculating the dose from scattered radiation at a point in an irradiated phantom. Like tissue-air ratios, for each radiation quality, they depend only on depth and beam cross- section but are independent of the distance from the source. Their use for calculations within uniform and non-uniform radiation beams is outlined and the extension to account for tissue- heterogeneities is discussed.

The 1971 Gordon Richards memorial lecture. The stampede to compute--computers in radiotherapy.

60Co rotation dose distributions were measured for a range of field sizes, rotation angles and phantom cross-sections, using LiF dosemeters in a prestwood phantom. The experimental results were compared with computed distributions obtained from calculations based upon the separation of the dose into its primary and scattered components. The computed and measured dose distributions were found to agree within +or-2% of local value, except in regions of high dose gradient; even here, the disagreement was nowhere greater than +or-6%. The distributions were also used to check the accuracy of the data published in the I.A.E.A. Atlas of moving beam distributions. Very good agreement was again obtained.

A direct experimental evaluation of computed cobalt-60 rotation dose distributions.

METHODS OF COMPUTER CALCULATION OF DOSE DISTRIBUTIONS IN TELETHERAPY.

At least two procedures for determination of dose within an irradiated medium from ionization chamber measurements are in common use. One involves a determination of exposure in air and the application of conversion factors. The second involves the introduction of the ion chamber directly into the medium and a determination of exposure at that point followed by the application of conversion factors. For each of these methods a small attenuation correction must be applied to the exposure determination. The correction is commonly applied to ionization measurements made directly in the medium but is almost universally ignored when the reference exposure determination is made in air.

The calculation of absorbed dose from exposure measurements: practical problems in dosimetry.

EXPERIENCE WITH A REMOTELY CONNECTED TIME-SHARING COMPUTER TERMINAL.

This device was designed to operate in treatment areas of a large radiotherapy centre. In the event of a mechanical or electrical failure an alarm is given if the radiation beam of the unit remains on after the entrance door to the treatment unit has been opened. The device is mains- or battery-operated and can be detached from the interlock system to be usable as a self-contained radiation monitor.

Abstract : An instrumented array consisting of a magnetometer, electric field detector, and hydrophone has been developed. The magnetometer is a set of three mutually orthogonal single turn loops and high gain transformers. The overall sensitivity is given by B=0.0002/f gamma. (Author)

An Instrumented Array for Underwater Measurement of Alternating Magnetic Fields

Effects of different parameters on dose distriubutions in cobalt 60 planar rotation.

Currently available data for tissue-air ratios and scatter functions for 60Co radiation have been extended to large field sizes and depths of 30 cm following ionisation chamber measurements in a water phantom. The measurements were made using circular fields of radii up to 22·5 cm. A small systematic error in currently published data has been noted and the results are presented first in the form of a table of scatter functions for field radii of 2 to 25 cm and a source-to-surface distance of 80 cm. A more versatile form for scatter data, independent of source-to-surface distance, is suggested and a corresponding table of values is presented. Finally, tissue-air ratios for square fields ranging from 4 × 4 to 35 × 35 cm have been prepared using the Clarkson method. The data for field sizes larger than 20 × 20 cm and depths greater than 20 cm are new, while the remainder represent previously published data slightly amended. More detailed tables are available on request.

Measurement of tissue-air ratios and scatter functions for large field sizes, for cobalt 60 gamma radiation.

Effects of nonmagnetic scandium octahedral substitution in yttrium iron garnet were studied in a series of polycrystalline garnets having the unit formula Y3ScxFe2−xFe3O12 where x was varied from 0 to 1.7. Measurements of the lattice parameters, spontaneous magnetization, Curie temperature, and the initial permeability as a function of frequency and temperature are reported. The lattice parameter varied linearly from 12.376±0.003 A for x=0(YIG) to 12.495±0.005 A for x=1.5 Sc3+. Single‐phase garnet was not obtained for x>1.5. The apparent spontaneous magnetization at T=0°K and the Curie temperature dependence on substitution are qualitatively explained using Gilleo's statistical theory of incomplete super‐exchange interactions. The initial permeability at room temperature is strongly affected by the addition of scandium, increasing from 120 (YIG) to a maximum value of 1934 (x=0.9 Sc3+) and then to unity for larger x values. The value of 1934 is the largest room‐temperature initial permeability reported in ...

Initial Permeability and Derived Anisotropy of Scandium‐Substituted Yttrium Iron Garnets

AN EXAMINATION OF THE DEFINITION AND MAGNITUDE OF BACK-SCATTER FACTOR FOR COBALT 60 GAMMA RAYS.

A 137Cs unit for irradiating cell suspensions and small laboratory animals is described. A 25 cm diameter × 4 cm high container is placed in an opening in a lead drawer and is moved midway between two 1000 curies 137Cs sources. Lead compensating filters above and below the capsule hold the field to 116±4 rads/min within the container and the lead shielding of the unit is sufficient to permit its use in an unshielded laboratory.

A Convenient 137Cs Unit for Irradiating Cell Suspensions and Small Laboratory Animals

A NEW METHOD FOR MAKING AIR-CAP COMPENSATING FILTERS AND WEDGES.

excerpt Recent interest in whole-body irradiation of human beings, for example prior to bone marrow transplantation in cases of acute leukemia, has led to studies of suitable facilities to provide uniform dosage (1). While ideally it would seem best to irradiate the whole body at once, patient comfort, length of time of irradiation, and economy of space and equipment must be considered. Methods that have been used or proposed include treatment at a long source-skin distance (SSD) to obtain a sufficiently large field, with or without the patient curled into a small space (2,3), and the use of as many as eight Co60 sources of comparatively low strengths (4). These methods have the disadvantage of requiring a large space devoted specifically to this purpose and generally involving a long irradiation time. There would appear to be little objection to the use of a moving-field technique as long as the treatment time were not unduly protracted. This paper describes such a technique allowing a uniform high dosag...

Radical species detected in γ-irradiated K14NO3 crystals by electron paramagnetic resonance☆

Initial studies on the effect of small substitutions of indium for iron in polycrystalline yttrium iron garnet showed a substantial increase in the initial permeability over that of YIG. Since previous substitution of other ions has produced either little change or a decrease in the permeability, we have studied the effect of indium substitution on the garnet structure in more detail. Due to the size increase of In3+ radii over that of Fe3+, the substitution of In3+ into the garnet structure is limited to the larger of the available Fe3+ sites. The general formula can be written Y3(Fe2−xInx)Fe3O12 where x may take on values up to 2.0. X-ray determination of the lattice parameters for this series shows a linear dependence on x with an apparent change in slope for x>0.6. For x<0.65 there is no “detectable” trace of a second phase and the lattice constants vary from 12.376±0.005 A (x = 0) to 12.445±0.005 A (x = 0.6). For x = 0.65 a small perovskite phase is present, which becomes more apparent with larger x....

Effect of Indium Substitution in Yttrium Iron Garnet. High Permeability Garnets

Complex initial permeability measurements have been made on polycrystalline garnet toroids of the form (3−x)Y2O3·xGd2O3·5Fe2O3 where x ranged from zero (yttrium iron garnet) to three (gadolinium iron garnet). Both the real initial permeability μ′ and the imaginary initial permeability μ′′ were measured at 23°C, −78°C and −196°C over a frequency range of 1 kc to 2000 Mc. At room temperature, the low frequency value of μ′ was found to decrease with increasing gadolinium content. At lower temperatures the low frequency value of μ′ exhibits a minimum in x caused by the temperature dependent behavior of the two different magnetic sublattices. The frequency at which the maximum value of μ′′ occurs was found to increase with the addition of gadolinium. No thermal relaxation was observed in these garnets, but rather the peaks in the curves shifted to slightly higher frequencies with decreasing temperature.

Initial Permeability Characteristics of Mixed Yttrium-Gadolinium Iron Garnets

PERMEABILITY AND PERMITTIVITY MEASUREMENT OF GARNET AND FERRITE MATERIALS

γ-RADIATION AT AIR–GROUND INTERFACES WITH DISTRIBUTED Cs137 SOURCES

Polycrystalline garnets of the form (3 − x)Y2O3·xSm2O3·5Fe2O3 have been prepared where x was varied from 0 to 3 in six steps. Lattice constants were found to vary linearly from 12.374±0.005 A for yttrium iron garnet (x = 0) to 12.533±0.005 A for samarium iron garnet (x = 3). The theoretical x-ray densities were calculated and vary from 5.17 gms/cc for x = 0 to 6.22 gms/cc for x = 3. Magnetic moments were measured from 77° to 600°K. No magnetic compensation points were observed. The Curie temperature for these garnets is 570±10°K. Thermal magnetization curves for this series indicate that samarium substitution for yttrium produces very little change in the magnetization. The relative complex initial permeability was measured from dc to 2 kMc for several temperatures. The results of these measurements are discussed briefly.

A new type of cobalt-60 unit has been constructed to be practical for both fixed-field and rotatton therapy. The perumbra has been kept small through the use of a special collimator and adequate source-to-tumor distance. Devices for accurate besm aligmnent including an x-ray tube have been built into the head. A focussing ion chamber for transmission dose measurements is incorporated in the counterweight. Details of the unit are presented. (auth)

A precision cobalt 60 unit for fixed field and rotation therapy.

Polycrystalline samples were prepared of yttrtum-tron garnet and a number of rare earth garnets. The effect of ionic substitutions on such properties as lattice constants, magnetic moments, d-c conductivtty, permittivity, and permeability is discussed. The magnetic properties of garnets are shown to be explained by the Neel theory using a 2- or 3-sublattice model. The permeability spectrum exhibited two absorption regions, one due to domain wall processes in the r-f region and the other due to spin resonance in the microwave region. Electrical losses are considered to be due to oxygen defects and the reduction of the ferric ion. (auth)

The shear wave velocity and attenuation of GR‐S, Butyl, Hevea, Hycar, and Paracril rubbers have been measured in the frequency range 0.2–7 Mc/sec and the temperature range −60°C to 20°C. To minimize errors arising from interfaces in the acoustic path, a double path technique was used. By combining the shear wave data with bulk wave data the dynamic shear, bulk, and Young's moduli, and their associated viscosities, were calculated. The results were coupled with low‐frequency Young's modulus data on the same materials to give information over many decades of logarithmic frequency, and from this the distribution of relaxation times was determined.To a fair approximation, in the range investigated, it was found that the real and imaginary parts of the dynamic Young's modulus could be taken as equal to three times the corresponding values of the dynamic shear modulus. It was found that the classical Stokes assumption, that the bulk viscosity is negligible in comparison to the shear viscosity, was reasonable fo...

The effect of temperature, rest period, and water content on stress relaxation in doughs held at constant extension has been studied with a relaxometer previously described. Temperature was varied from 13 to 35°C, rest period from 2 to 120 min, and water content from 74.4 percent to 86.0 percent dry basis. It is found that the shape of the relaxation curves on a log time plot does not change with temperature in the above range but that the curve is shifted laterally along the log time axis. This permits the construction of master curves valid in the temperature range and extends the time scale of observation. The long relaxation time end of the distribution of relaxation times is affected most by rest period, decreasing as rest period is increased, and the short time end increases as water content is decreased. Activation energies from 11 to 24 kcal per mole are calculated for relaxation from the shift of the curve on the log time axis. There is an indication that the activation energy depends on temperat...

Relaxation Time Spectrum of Dough and the Influence of Temperature, Rest, and Water Content

A simple method is described for replicating and positioning selected areas of mounted specimens. No special apparatus is required for the manipulation and the method is applicable to a wide range of specimens. The replica is directly manipulated on a plastic coated specimen grid, under an optical microscope; the accuracy of positioning is excellent.

LABORATORY AND WORKSHOP NOTES: Simple method for the control of the liquid level in a manometer

Characterisation of polymers using laser microprobe mass spectrometry

In a previous paper, the one-year retention of composite resin in non-undercut Class V abrasion lesions mediated by self-cure Scotchbond dentine bonding agent without enamel etching was reported. The present paper reports the three-year results. Initially, a total of 310 restorations was placed using Silux, Silar, Ketac-Fil and Fuji II. The percentage cumulative loss of the restorations at two and three years, respectively, was: Silux 27, 30; Silar 58, 58; Ketac-Fil 0, 0; Fuji II 4, 14. Over the total study period, there was a high loss rate of composite restorations in the first six months, and a tendency to increased loss over one to three years. There was a significant increase in marginal discoloration, assessed photographically, over the three-year period, and caries was present around some restorations.

The object of the research was to examine the effectiveness of corrosion potential mapping and concrete resistivity measurements to assess their reliability, reproducibility and sensitivity when applied to marine concrete structures. A number of 70 n/sq mm concrete blocks and slabs, each containing electrically isolated reinforcing bars and electrolyte bridges cast internally, were used to investigate the effects of surface contamination on potential measurements, the choice of electrode type, and the effects of electrical discontinuities between the reinforcing bars in different regions of the structure. In some of the specimens, 3% of chloride (by weight of cement) was added to the mix to promote early corrosion. Exposure of the specimens involved several different conditions which included ponding with either fresh or sea water for periods of up to seven days, combined with drying cycles. Four samples were exposed to pure carbon dioxide for a month before being subjected to the wetting and drying sequence. The surfaces of some of the specimens were also contaminated with oil. Potential monitoring was undertaken using three different reference electrodes (saturated calomel, silver/silver chloride and copper/copper sulphate) and a variety of coupling agents were tried. The influence of surface condition was investigated, including methods for cleaning and preparation. Measurements of apparent resistivity of the surface layer were also undertaken using the wenner method. The tests showed that the copper/copper sulphate electrode was unstable in contact with a sodium hydroxide solution (analogous to pore fluid in concrete) and when in contact with seawater, the electrode potential could vary by up to 150 mv. The other two electrodes generally performed satisfactorily. It was also shown that it was important to achieve good electrical contact between the porous plug of a reference electrode and the concrete surface when measuring potentials. When a resistive layer was present, it was necessary to drill through the layer before applying the electrode. Other methods such as acid etching or use of detergents to remove oil contamination were less successful. It was also found that where electrical discontinuities existed between different parts of the specimen, misleading information could be obtained from the actual values of the potentials measured (when using the single-electrode method). Differences of up to 150 mv were measured under these conditions. This confirmed the importance of checking the electrical continuity of the bars. Measurements of the apparent resistivity of the concrete were shown to provide some measure of the quality of the concrete cover, but the tests were unable to determine whether these measurements were a guide to corrosion risk.

Electro-chemical Methods of Corrosion Monitoring for Marine Concrete Structures

Three hundred and ten non-undercut cervical abrasion lesions in 83 patients were restored with either the photocured resin based restorative material Silux (175 restorations), its chemically cured counterpart Silar (57 restorations), or glass ionomer (78 restorations). A proprietary dentine bonding agent (chemically cured Scotchbond) was used with Silux and Silar in accordance with the manufacturer's instructions, except that no enamel etching was carried out. Restorations were reviewed after six months and one year. At the one year examination, 25 per cent of Silux, 46 per cent of Silar and 2.5 per cent of the glass ionomer restorations had been lost. There was a progressive increase in marginal discoloration around the resin based restorations.

SummaryThe conditions for producing anodic coatings on aluminium for wear and abrasion resistance have been studied. The nucleation and growth of such films have been examined by scanning electron microscopy and potential time measurements. The formation of island blocks of anodic oxide (rosettes) has been explained and the characteristic concentric rings and terraces shown to be growth cracks which are different from craze cracks. The mechanism of hard anodizing is discussed and related to previously published models.

SUMMARYThe composition of chemical polishing and electropolishing solutions and operating conditions which give characteristic pyramid shaped projections on the surface of aluminium (icing defects) have been studied. A mechanism for their formation is proposed and conditions given for their avoidance.

Chemical Polishing of Aluminium in Ammonium Hydrogen Difluoride-Nitric Acid

— The technique of using composite resin for the adhesive in bonding acrylic or natural tooth pontics as a form of fixed prosthesis is presented.

Survival of anaerobic and aerobic bacteria in a commercially available, non-supportive, gassed (oxygen-free) transport container (Anaport) was evaluated quantitatively. Saline-suspended obligate anaerobes survived significantly better in the gassed container in aerobic control tubes (P less than 0.025, t test), and counts were virtually unchanged after 8 h of holding. Similarly, initial counts and relative proportions of a mixture of Bacteroides fragilis and Staphylococcus aureus were maintained for 72 h. The value of the gassed transport system was less apparent when microorganisms were suspended in nutrient broth. The major advantage of the gassed transport system appears to be for holding of specimens collected by saline irrigation.

Survival of anaerobic and aerobic bacteria in a nonsupportive gassed transport system

Malignant Carcinoid Associated with Thoraco‐Abdominal Aneurysm and Analysis of Thirty‐One Cases of Gastrointestinal Carcinoid Tumors

Skin and subcutaneous metastases from gastrointestinal carcinoid tumors.

Although patients with the carcinoid syndrome may have a variety of manifestations which involve the skin, gastrointestinal carcinoids rarely metastasize to the skin or subcutaneous tissue. The literature is reviewed regarding this occurrence, and an additional case is presented. Four of the six patients described had a primary tumor in the small intestine. This is not unexpected since this area has the highest rate of metastasis of carcinoid tumors.

Skin and Subcutaneous Metastases From Gastrointestinal Carcinoid Tumors

Comparison of real-time decision making performance by the different models.

A comparison of estimation methods in the switching task in the T-maze.

Changes to connection strengths after 20 training trials in the spiking neural circuit model.

Schematic illustration of the changes of coupling strengths caused by STDP.

Illustration of the stimuli/task and neural responses for one V1 dataset and one M1 dataset.

The preferred-mode analysis applied to simulated linear dynamical systems.

Reconstruction error as a function of the number of basis elements.

another just under, 1 megagramme-roentgen, each receiving between 100 and 200 roentgens total body irradiation. The other patients had less than half this amount. Immediate and sustained lymphopenia was noted in most of the exposed people. Neutropenia and thrombocytopenia, of a moderate degree and a temporary nature, occurred only in the more heavily irradiated. An initial, and usually marked, granulocytosis was observed in all of them, and a prompt though temporary monocytosis was noted in six. Five of the six asymptomatic survivors developed eosinophilia. Uncoagulability of the blood was observed in one of the fatally injured patients at the time of death, and several of the survivors showed prolongation of the blood-clotting time. Specific chemical changes in the blood were not found. The necropsies on the patients who died showed widespread destruction in the radio-sensitive organs as well as in the superficial tissues. Death of cells during or shortly after mitosis was very conspicuous in the rapidly dividing tissues. The ductal epithelium of the sweat glands alone among the tissues of the body showed a marked proliferative response. This was thought to be secondary to early damage. An inflammatory reaction was found in many tissues, an unusual feature being an almost complete absence Of granulocytes in the cellular exudate. The conclusions reached from this study were of two kinds. The fundamental nature of the acute radiation syndrome is widespread destruction of tissues throughout the body: this is the basis of the observed physiological and clinical responses. The destructive process differs from the tissue damage caused by other common toxic agents in that they occur primarily in the radiosensitive tissues wherever they may be situated. In this sense the injury is more akin to that caused by certain chemical poisons with a selective action on particular organs rather than to traumatic injuries resulting from heat or crushing. Another outstanding feature is the delay in the appearance of signs of tissue destruction, this delay varying from organ to organ. But in general the overall clinical and constitutional response of a person suffering from the acute radiation syndrome is similar to that observed in other diseases in which tissue death is the prominent feature. The other group of conclusions are related to the treatment. The first is that at present there is no form of treatment which will help the heavily irradiated patient to survive the acute phase of the illness. Tissues may be protected from damage, but there is no known method of saving cells once injury has occurred. But the regenerative powers of most tissues are so great that considerable if not complete recovery will occur if the patient survives the critical toxic stage. Antibiotics, transfusions, and maintenance of the fluid and electrolyte balance are therefore suggested as being helpful. Work on animals has shown that the number of those surviving after a single large dose of total body irradiation can be increased by measures instituted after the radiation injury has been sustained. These measures include intraperitoneal implants of splenic tissue or injections of embryo suspensions, or intravenous injections of homologous bone-marrow suspensions. The evidence suggests that the substance which helps to overcome the effects of radiation injury under these conditions is likely to be non-cellular and capable of instituting recovery of certain tissues of the body vital to the survival of the animal. Similar results can be attained by shielding certain parts of the animal, notably the spleen, during the exposure to radiation. Jacobson2 has reviewed the evidence for the existence of a humoral factor concerned in recovery from radiation injury, and further work may provide some opportunity for developing methods of treating those suffering from the acute radiation syndrome who have not received an overwhelming integral dose.

Cet article explore quelques paradoxes qui font de l’art dramatique et du theâtre un medium puissant mais complexe pour l’enseignement et l’apprentissage. La question principale porte sur la vraie nature du dialogue en art dramatique et en pedagogie ainsi que sur les transferts relationnels ou de pouvoirs qui doivent avoir lieu entre l’enseignant et l’apprenant lorsqu’ils utilisent de facon implicite ou explicite la notion de « manteau de l’expert ». Certains exemples decrits et analyses sont issus de la propre experience de l’auteur et visent a clarifier ces relations qui menent a un autre paradoxe : si l’art dramatique peut conduire a une appropriation de l’autonomie, autant pour les enseignants que pour les apprenants, c’est par l’entremise d’une desappropriation temporaire.

L'invention concerne une serie de composes d'arylpiperazine, constituant des medicaments efficaces pour traiter les etats lies ou dus au recepteur 1A de la serotonine. Ces composes constituent des antagonistes particulierement efficaces de ce recepteur, et sont particulierement utiles pour soulager les symptomes du syndrome de sevrage a la nicotine ou au tabac.

Arylpiperazines pour lutter contre le recepteur 1a de la serotonine

Detection and localization of subincisional abscesses with gray scale echography.

Most cases of ventral hernias are easily diagnosed by palpation, but palpation is a subjective examination that may be difficult or even misleading, especially in obese patients. In cases of diagnostic uncertainty, ultrasonic examinations offer an objective means of distinguishing between a mass in the abdominal wall and one actually deep to the peritoneum. In addition, if such a mass is detected, these studies provide information that can characterize its physical nature.

Ultrasonic evaluation of ventral hernias disguised as intra-abcominal neoplasms.

Altered coagulation states may develop in patients secondary to numerous metabolic or drug-related disorders. Bleeding complications such as gastrointestinal hemorrhage, hematuria, pulmonary hemorrhage, hemarthrosis, or a variety of extravisceral hemorrhages are common in this patient population. Most of these complications are easily detected because the site and nature of the bleeding are clinically obvious. But the detection and localization of a nonvisceral abdominal hemorrhage by physical examination, conventional radiographic techniques, or isotopic procedures is difficult and such studies may even be misleading. Gray-scale ultrasonic examinations can detect and localize masses within the abdominal wall, in the peritoneal cavity, or in the retroperitoneal space. In addition, sonic techniques provide information characterizing the physical nature of such a mass. These capabilities make echography uniquely suitable to evaluate for the presence of abdominal hemorrhage. REPORT OF CASES Case 1.—Periluminal Hematoma.— An 18-year-old factor-VIII-deficient hemophiliac was initially seen with acute onset of

Echographic detection and characterization of abdominal hemorrhages in patients with altered coagulation states.

To the Editor.— Even though acupuncture is of Chinese invention, the Japanese have widely practiced this form of folk medicine for many centuries. Occasionally, an acupuncture needle may accidentally break off during therapy and if a roentgenogram is taken, the needle becomes recognizable as a slender metal wire imbedded in an organ or in soft tissues. A more dramatic roentgenographic pattern may be observed in hari , a form of acupuncture peculiar to Japan. To perform hari , the practitioner inserts thin gold needles into the subcutaneous tissues and cuts off the needle at the skin surface. When roentgenograms of these patients are seen, slender metal wires are visible that may number in the hundreds. 1 We have recently taken roentgenograms of a patient who practices Japanese folk medicine with metal foreign bodies quite different from those employed in either acupuncture or hari . Report of a Case.— An elderly Japanese woman was

Two patients had convincing mass lesions demonstrated with gray-scale echography and strongly supporting clinical evidence for intra-abdominal abscesses. Neither patient had a lesion at the time of surgery. Although modern echography is an accurate diagnostic method for intra-abdominal abscess, false-positive results can occur.

False-positive gray-scale ultrasonography for intra-abdominal abscesses.

Bilateral nummiform fibromyomas of the nipples with unilateral fibromyoma and papilloma mamillae

Abstract N on-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndromethat presents mostly with hypoinsulinemic hypoglycemia and is associated with benign and malignant neoplasms other than insulinoma. Doege-Potter Syndrome (DPS) is characterized when NICTH is secondary to a solitary fibrous tumor (SFT). The following is a case of DPS in which the patient presented with refractory hypoglycemia. An 81-year-old Caucasian male presented to emergency department with a 10-day history of worseningneuroglycopenic symptoms in fasting state. He experienced worsening night sweats, unsteadiness while walking, dizziness, and irritation, which resolved after breakfast each morning. Five years prior to this admission, he was diagnosed with a malignant mediastinal SFT (atypical spindle cell neoplasm). He was treated with radiation followed by mass resection (9.5×6.5×7.9 cm). Despite treatment with 3 lines of therapy of phase 1 clinical trial, his disease continued to progress with a right paraspinal mass and bilateral lung metastases being subsequently found. In ED, his initial blood glucose was 53 mg/dL. Despite receiving IV dextrose pushes and a continual dextrose infusion, he continued to be hypoglycemic. Upon admission, blood work revealed blood glucose of 41 mg/dL, low insulin level of 0.4 uIU/mL (2.6-24.9 uIU/mL) and low C-peptide level of 0.9 ng/mL (1.1-4.4ng/mL). Proinsulin (4.4pmol/L), Cortisol (17.2mcg/dL) and A1c (5.2%) were all within normal limits. Serum and urine ketones as well as a blood sulfonylurea panel were negative. He was started on hydrocortisone 50 mg 8 hourly for insulin-independent hypoglycemia. His IGF1 level was 46 ng/mL (55-166ng/mL), and IGF2 level was 564 ng/mL (333-967ng/mL) with a high IGF2: IGF1 ratio of 12. He was discharged home with same hydrocortisone regimen. On follow-up, hydrocortisone dose was reduced to 30-30-20 mg. He passed away 4 months later after being hospitalized for hypoxic respiratory failure secondary to a pleural effusion. Interestingly, he was maintained on the same regimen of hydrocortisone up until his death and did not have recurrence of severe hypoglycemic episodes. The main mechanism of NICTH is tumoral overexpression of the IGF2 gene and aberrant post-translational processing, resulting in partially processed high-molecular-weight IGF2 (big-IGF2). Big- IGF2 has a lower affinity for IGF-binding proteins, which favors its own availability to IGF1 and insulin related receptors resulting in profound hypoglycemia and occasionally acromegaloid features. Diagnosis of NICTH is typically made byan IGF2: IGF1 ratio of greater than 10 (normal 3: 1)due to unavailability of commercial assays for big-IGF2. Radical tumor resection is the definitive treatment of NICTH. In unresectable neoplasms, tumor debulking, or medical therapies such as glucocorticoids, recombinant GH, and glucagon are used to alleviate hypoglycemic symptoms. Exploring more about effectiveness of chemotherapy regimens in controlling NICTH will be helpful in inoperable tumors. Presentation: No date and time listed

ODP267 Doege-Potter Syndrome in a Patient With Mediastinal Solitary Fibrous Tumor

The testes develop in the abdomen and descend during the third trimester into the scrotum. The testicle can be arrested anywhere during its descent or it can migrate into an abnormal position. Undescended testis, otherwise known as cryptorchidism, is a well-described disorder with a spectrum of complications ranging from torsion to necrosis, infertility, and atrophy. The risk of developing testicular cancer in an undescended testicle has been well-documented, as high as 32 times the general population if the testicle is not brought down before the age of 12. In clinical practice, surgical exploration for the testicle and definitive fixation in the scrotum is warranted at age two to three if it fails to descend to the normal position, with clinical success rate of 90%. However, the problem with an undescended testicle arises when surgical exploration is negative, and the usefulness of other approaches, including imaging tests, in this setting is not clearly established. We report a case of a 45 year-old man with history of undescended left testicle diagnosed at birth, and repeated negative surgical explorations presenting with symptomatic pelvic mass, and eventually diagnosed with testicular tumor. This case highlights the potential difficulty in establishing this diagnosis despite the generally favorable outcomes with orchiopexy. Given its high prevalence, testicular neoplasm must be included in the differential diagnosis of patients with a history of an undescended testicle who present with an acute abdomen. Surgical resection without pelvic lymph node dissection is the standard of care for an abdominal testicle found at exploration.

Surgical outcomes following pancreatic resection at a low-volume community hospital: do all patients need to be sent to a regional cancer center?

Necrotizing fasciitis is an uncommon infectious entity that poses difficult diagnostic and therapeutic management decisions.

PURPOSE
This paper addresses the presentation, evaluation and management of the patient with a necrotizing soft tissue infection.

CASE REPORT
A 54-year-old man presented to his physician with pain and swelling of the left anterior chest wall following a presumed insect bite several days prior. He was treated with oral antibiotics but returned to the office three days later with increased swelling, pain, and erythema in the axilla. Necrotizing fasciitis was diagnosed. He was hospitalized and taken to the operating room for debridement of the chest wall. Extensive necrosis of the skin, subcutaneous tissue and muscle was encountered. Muscle debridement extended from the pectoralis major and both obliques anteriorly to the latissimus dorsi and para-spinalis muscles posteriorly. Multiple operative debridements were performed over several days. The patient developed septic shock requiring blood pressure support, and multiple organ system failure requiring hemodialysis, prolonged ventilatory support and eventual tracheostomy. Split-thickness skin grafts were placed during the third operative debridement and concluded on the 15th day of hospitalization. The patient eventually recovered and on the 53rd hospital day was transferred to the rehabilitation service, where he spent the next four weeks recovering movement in the left arm.

Necrotizing fasciitis is an infectious entity that requires rapid diagnosis, surgical debridement, and tissue coverage if the patient is to survive.

Necrotizing fasciitis: a plea for early diagnosis and treatment.

A 15-year-old girl with known Peutz-Jeghers syndrome and with nausea and vomiting of all ingested food was transferred from an outside institution. Physical examination revealed a palpable upper abdominal mobile mass. Upper gastrointestinal series revealed a stacked coin appearance consistent with small bowel intussusception. An abdominal computed tomographic scan showed a left upper quadrant sausage-shaped mass with invagination of bowel into bowel suggestive of small bowel intussusception. The patient was taken to the operating room for a combined upper endoscopy and laparoscopy. Laparoscopy confirmed the radiologic findings and a jejuno-jejunal intussusception was identified and reduced laparoscopically. The endoscope could not be passed to the level of the polyp, thus, this loop of small bowel was resected laparoscopically. The final pathologic diagnosis was multiple hamartomas. We conclude that laparoscopy is a safe and effective method of managing intussusception in the Peutz-Jegher syndrome because the pathologic lead point is a benign hamartoma. A combined endoscopic and laparoscopic approach can be used to treat proximal small bowel intussusception and this could possibly eliminate the need for laparotomy and reduce the post-operative complications associated with multiple reoperations in this patient population.

The role of laparoscopy in the management of intussusception in the Peutz-Jeghers syndrome: case report and review of the literature.

Thoracoabdominal esophagogastrectomy is associated with a number of potential life-threatening complications.

PATIENTS
We describe a patient with intraoperative hypotension in which a number of therapeutic maneuvers eventually led to the diagnosis of cardiac tamponade.

RESULTS
Once the diagnosis of tamponade was made, it was successfully treated by the release of intrapericardial blood.

Although rare, tamponade should be considered as a cause of hemodynamic instability whenever intraoperative manipulation of the heart has occurred.

Intraoperative cardiac tamponade complicating esophagogastrectomy.

The current approach to the treatment of locally advanced breast cancer is sequential chemotherapy, surgery and/or radiation, and consolidation chemotherapy. Although significant tumor response is seen with this regimen, there are few studies that compare this approach to postoperative chemotherapy. The purpose of this study was to compare the disease-free and overall survival of patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and surgery to patients treated with surgery followed by adjuvant chemotherapy. Ninety-four patients with stage IIB, IIIA, and IIIB breast cancer were treated with a standardized chemotherapy regimen. The first group, 60 patients who were followed prospectively, was treated with neoadjuvant chemotherapy (NCT) consisting of vincristine, prednisone, cytoxan, methotrexate, and 5-FU (CVFMP) followed by surgery and consolidation chemotherapy with adriamycin. The second group, 34 patients evaluated retrospectively, had surgery followed by postoperative chemotherapy (PCT) with CVFMP followed by adriamycin. Overall median follow-up was 38 months. In the NCT group, 45/60 (75%) patients had a clinical response to induction therapy and the median reduction in tumor size was 50%. The rates of local recurrence, distant recurrence, and death from disease were similar in the two groups. The time to local recurrence was similar for the two groups. However, the median time to distant recurrence was shorter in the NCT group (19 month vs. 31 months, p = NS). Overall median survival among the NCT patients was shorter than for the PCT group (30 vs. 47 months, p = NS). The current study suggests that postoperative therapy is comparable to a neoadjuvant regimen in patients with locally advanced breast cancer with regard to local recurrence, distant recurrence, and overall survival.

The efficacy of neoadjuvant chemotherapy compared to postoperative therapy in the treatment of locally advanced breast cancer.

Abstract: Thirty‐five patients with pregnancy‐associated breast carcinoma diagnosed between 1985 and 1995 were identified and characterized from a prospectively generated database. Twenty‐two of these patients had stage 1 or 2 disease and were therefore potential candiates for conservative surgical management. The median age was 36 years. Two thirds of the patients were pregnant at the time of diagnosis; the median gestational age of the fetus at diagnosis was 7 months. Twenty‐one of the 22 of the patients presented with a palpable mass. The majority of tumors were estrogen‐receptor negative. Nine patients were treated with breast‐conservation therapy, and 13 were treated with mastectomy. In the breast‐conservation therapy group, there were three distant recurrences and no local recurrences with a median follow‐up of 24 months. In the mastectomy group, two patients developed distant metastases and one developed a local recurrence with a median follow‐up of 28 months. The results of breast‐conservation therapy are similar to the results of mastectomy for stage 1 and 2 cancers associated with pregnancy. Therefore, breast‐conservation therapy is an option for selected patients with pregnancy‐associated breast cancer.

Conservative Surgery for Breast Carcinoma Associated with Pregnancy

Indications for surgical resection of metastatic ocular melanoma

Loss of heterozygosity and homozygous deletion of the tpr locus in human gastric cancer.

Salvage therapy for pelvic recurrence following curative rectal cancer resection

Small bowel neoplasms account for only a small percentage of gastrointestinal tumors, but their prognosis is one of the worst.

PURPOSE
This study examines the histopathology, treatment, recurrence, and overall survival of a group of patients with primary small bowel tumors.

METHODS
From 1970 to 1991, a retrospective review identified 73 patients with primary small bowel tumors. Four histologic groups were identified: 1) group 1, adenocarcinoma, 29 patients; group 2, lymphoma, 18 patients; group 3, sarcoma, 8 patients; and group 4, carcinoid, 18 patients. There were 44 men and 29 women. The median age was 57 years (range, 26 to 90). Median follow-up was 15 months. Survival analysis was by the Mantel-Cox and Breslow methods.

RESULTS
The most common, by type, was group 1, duodenum; group 2, jejunum; group 3, jejunum; and group 4, ileum. The preoperative diagnosis was made in only 14 patients. The median survival for adenocarcinomas and lymphomas was 13 months, 18 months for sarcomas, and 36 months for carcinoids. Curative resection could be achieved in 48 (65%) of 73 patients, and the median survival was significantly longer for this group (26 months vs. 11 months, p < 0.05). Of the 48 curative resections, 20 patients (42%) recurred: group 1, 8/19 (42%); group 2, 4/12 (33%); group 3, 4/13 (31%); group 4, 4/4 (100%). The median time to recurrence was 17 months, and the median survival after recurrence was 20 months. Adjuvant chemotherapy-radiation therapy did not alter survival in any group.

The preoperative diagnosis of small bowel tumors rarely is made because symptoms are vague and nonspecific. Surgical resection for cure results in improved survival. Recurrence is common and survival after recurrence is poor. Other treatment methods have no role in the management of these patients.

Malignant small bowel neoplasms: histopathologic determinants of recurrence and survival.

The use of spiral computed tomography in the evaluation of vessel encasement for pancreatic cancer

New laparoscopic instrumentation coupled with standard surgical techniques allows one to perform procedures previously thought impossible via the laparoscope. This report reviews the natural history, the indications for resection, and the technique of laparoscopic resection of hepatic hemangiomata. Two women, 24 and 62 years of age, were first seen with abdominal pain. A diagnosis of hemangioma was made in each case, and both lesions were removed laparoscopically. Operative blood loss was 200 cc in each case, and neither patient required transfusion. Diets were started on the first postoperative day (POD), and the patients were discharged on the second and fourth PODs without narcotic analgesia. If the size and location of the tumor are favorable, laparoscopic resection of liver hemangiomata can be performed safely. Blood loss comparable to that of open procedures and a quicker recovery support an endosurgical approach to resection of liver hemangiomata in selected cases.

Transactions - Pennsylvania Academy of Ophthalmology and Otolaryngology

Dermatomyositis and polymyositis are rare disorders of connective tissue that manifest themselves primarily as muscular weakness. Fifty-five percent of 45 patients with this diagnosis at Thomas Jefferson University Hospital had symptoms referable to the head and neck. While dysphagia and the cutaneous manifestation predominate, such symptoms as facial swelling and oral mucosal disorders may require the treating physician to seek the advice of an otolaryngologist before the patient suffers any muscular changes. A thorough knowledge of this disease entity is essential to specialists in head and neck diseases.

Defence employment standards project, infantry and airfield defence guards: Report 9: trade task analysis: infantry and ADG.

Predictions of the temperature profile within composite sheets during pre-heating

Overall, the HTGR graphite situation is in excellent shape. In both of the critical requirements, fuel blocks and support structures, adequate graphites are at hand and improved grades are sufficiently far along in truncation. In the aerospace field, GraphNOL N3M permits vehicle performance with confidence in trajectories unobtainable with any other existing material. For fusion energy applications, no other graphite can simultaneously withstand both extreme thermal shock and neutron damage. Hence, the material promises to create new markets as well as to offer a better candidate material for existing applications.

The use of radiation from synchrotron sources has started a renaissance in materials, physics, chemistry, and biology. Synchrotron radiation has advantages over conventional x rays in that its source brightness is a thousand times greater throughout a continuous energy spectrum, and resonances are produced with specific electron energy levels. Two major synchrotron radiation sources are operated by DOE: the Stanford Synchrotron Radiation Laboratory at SLAC, and the National Synchrotron Light Source at Brookhaven. (DLC)

Several findings emanating from materials research that should have a beneficial impact on technological advancement in the future are described. The report deals with the GRAPHNOL, a new class of high-temperature brazing alloy for joining refractory components, gel-sphere-pac process for manufacture of nuclear fuel, and noble-metal fuel cladding for service in radioisotope thermoelectric generators designed to provide auxiliary power aboard spacecraft for planetary exploration.

Development of advanced high-uranium-density reduced-enrichment plat-type fuels

Handbook of remote control & automation techniques , Handbook of remote control & automation techniques , مرکز فناوری اطلاعات و اطلاع رسانی کشاورزی

Abstract : Several test programs have been conducted in recent years to define the level of damage sustained by airfield pavement systems which are subjected to conventional weapon detonations. Knowledge of airfield damage and the capability to predict damage from possible hostile attack are required to allow Bomb Damage Repair (BDR) personnel to plan base recovery activity and rapid runway repair. The objective of the effort reported herein was to collect existing data on airfield pavement effects, as functions of pavement and weapon parameters, identify those parameters having a significant effect on pavement damage, repair time and effort, and generate damage prediction relationships for use by BDR engineers.

Bomb Damage Repair (BDR) Damage Prediction. Volume 1. Technical Discussion

Abstract : Knowledge of airfield damage and the capability to predict damage from possible hostile attack are required to allow Bomb Damage Repair (BDR) personnel to plan base recovery activity and rapid runway repair. The objective of this effort was to collect existing data on airfield pavement effects, as functions of pavement and weapon parameters, identify those parameters having a significant effect on pavement damage, repair time effort, and to generate damage prediction relationships for use by BDR engineers. The collected data were placed in a consistent format in a computerized data file. By plotting the data and subjecting them to various analytical procedures, significant parameters affecting damage were identified. Mathematical relationships were developed between the data, and damage prediction nomographs were generated for the three repair levels considered. These prediction relationships are in a format readily usable by field personnel and enable rapid damage prediction computations and subsequent runway repair planning operations.

Bomb Damage Repair (BDR) Damage Prediction. Volume II. Appendices.

The effect of mission attitude timelines on consumables requirements for the proposed shuttle orbiter heat rejection systems

The integrated systems program is capable of simulating both nominal and anomalous operation of the Apollo cryogenics storage system (CSS). Two versions of the program exist; one for the Apollo 14 configuration and the other for J Type Mission configurations. The program consists of two mathematical models which are dynamically coupled. A model of the CSS components and lines determines the oxygen and hydrogen flowrate from each storage tank given the tank pressures and temperatures, and the electrical power subsystem and environmental control subsystem flow demands. Temperatures and pressures throughout the components and lines are also determined. A model of the CSS tankage determines the pressure and temperatures in the tanks given the flowrate from each tank and the thermal environment. The model accounts for tank stretch and includes simplified oxygen tank heater and stratification routines. The program is currently operational on the Univac 1108 computer.

FAILURE OF BONUS REACTOR SUPER-HEATER FUEL ASSEMBLY TRACED TO FAULTY WELD PRACTICE

BONUS REACTOR SUPERHEATER FUEL ASSEMBLIES-AN INVESTIGATION OF FAILURE AND METHOD OF CORRECTION

Geology of the North Tumacacori foothills, Santa Cruz County, Arizona

Primary cardiac rhabdomyosarcoma presenting as pulmonary stenosis

Third ‐ Trimester Rupture of the Pregnant Uterus: A Five‐Year Survey

Neutron-absorbing rods containing europium will be utilized to maintain safety and control excess reactivity during operation of the second core loading of the Stationary Medium Power Reactor (SM-1), formerly designated as the Army Package Power Reactor (APPR-1). The specifications and fabrication procedures developed and adopted for manufacturing the prototype component are presented. The basic criteria on which the absorber rod was designed for radioactive service in 450 deg F pressurized water are presented along with a general description of the component. The technological factors, such as chemical compatibility, nuclear characteristics, and irradiation behavior which led to the selection of Eu/sub 2/O/sub 3/ as the absorber material, elemental stainless powders as the matrix material, and type 304 L stainless steel as the cladding material, are reviewed. Requirements for manufacturing the control rod absorber sections are outlined. Also detailed material specifications and dimensional requirements are provided. The fabrication procedures for manufacturing the component are presented in detail, and quality control measures adopted to consistently produce components within dimensional tolerances on a pilotplant basis are described. Requirements for supplier qualification include the preparation and testing of fullsized plates and absorber assemblies. Trouble-free operation from such problems as inhomogeneity, excessive fragmentation, and stningering ofmore » the europium oxide, as well as sensitization and surface contamination of the cladding, and lack of metallurgical bonding of the composite plate, must be demonstrated. (auth)« less

SPECIFICATIONS AND FABRICATION PROCEDURES ON EUROPIUM-BEARING ABSORBER RODS FOR REACTIVITY CONTROL IN CORE II OF SM-1

Report regarding the design requirements and manufacturing procedures for the stationary fuel component proposed for operation in the second core loading of the Army Package Power Reactor at Fort Belvoir, Virginia.

Specifications and Fabrication Procedures for APPR-1 Core II Stationary Fuel Elements

Report presenting the design and fabrication specifications for stainless steel-base control rod fuel elements.

Specifications and Fabrication Procedures for SM-1 Core II Control Rod Fuel Elements

The major differences in operating conditions for Al-base fuel elements in pool- and tank-type reactors are pointed out. The limiting or life- determining factor for both cases is discussed. Recent and signiflcant developments in the field of Al-base fuel elements designed for research reactors are described. The fuel element of curved-plate design is presently being used in more than thirty reactors. (W.D.M)

RECENT DEVELOPMENTS IN ALUMINUM-BASE FUEL ELEMENTS FOR RESEARCH REACTORS

Light-water solutions of U/sup 235/ and U/sup 238/ in the form of uranyl fluoride have been prepared and dispensed to the Zero Energy Thermal Reactor. The development of the process, equipment, and handling techniques are described along with experimental criticality test techniques, results, and an analysis of the results. (auth)

CRITICAL ASSEMBLIES OF AQUEOUS URANYL FLUORIDE SOLUTIONS. PART II. PREPARATION AND HANDLING OF SOLUTIONS

The designs manufacture, and operation characteristics of the fuel components developed for the Army Package Power Reactor are discussed. The technological factors, such as compatibility, corrosion resistance, and irradiation behavior, which led to the selection of UO/sub 2/ as the fuel dispersant, B/sub 4/C as the burnout poison, and austenitic stainless steel as the cladding and matrix material, are reviewed. The main features of the component engineered for service in power-producing reactors of compact-core design and high-performance characteristics are described. Highly enriched fuel in the form of a refractory oxide is dispersed in a metallic matrix to maximize the heat-transfer surface available for each gram of U-235. It is contained in a stainless steel jacket to afford corrosion protection and retain the highly poisonous by-products of fission. The use of a burnout poison to facilitate control and prolong the life of the heavy-investment fuel component is discussed. Specifications covering the material, dimensional, thermal, and nuclear characteristics of the product are tabulated. The fabricational procedures developed and adopted for manufacturing the component are fully presented. This includes incorporation of the UO/sub 2/ and B/sub 4/C into stainiess steel compacts by powdermetallurgy techniques, methods for preparing composite fuel plates by roll cladding,more » and assembly and joining the thin plates into an integral unit by brazing with a nickel-base alloy. The fabrication problems associated with composition, chemical stability, homogeneity, fragmentation of the oxide and carbide particles, as well as sensitization, bond integrity, and the brazejoint design are discussed in detail. Quality control measures adopted to produce components within dimensional tolerance on a pilot-plant basis are described. These long-life fuel components are inexpensive to produce and their performance to date in the environment of pressurized-water and organic media has been excellent. The irradiation performance of the stainless steel -UO/sub 2/ materials combination under various degrees of burn-up as well as pertinent mechanicalproperty data are presented. A cost analysis is made on the over-all fuel cycle. (auth)« less

STAINLESS STEEL-URANIUM DIOXIDE FUEL COMPONENTS FOR ARMY PACKAGE POWER REACTOR

In the APPB, highly enriched fuel in the form of a refractory oxide is dispersed in a metallic matrix to maximize the heat-transfer surface available for each gram of uranium-235. It is contained in a stainless the highly poisonous by-products of fission. The use of a burnout poison to facilitate control and prolong the life of the heavy-investment fuel element is discussed. The technological factors, such as compatibility, corrosion resistance and irradiation effects, which led to the selection of UO/sub 2/ as the fuel dispersant, B/sub 4/C as the burnout poison, and austenitic stainless steel as the cladding and matrix material, are reviewed. Specifications covering the material, dimensional, thermal and nuclear characteristics of the products are tubulated. The fabrication procedures developed and adopted for manufacturing the fuel component are described. Enriched UO/sub 2/ and a small quantity of B/ sub 4/C are incorporated into the fuel element by powder-metallurgy techniques. The resultant compact, containing 25 wt.% UO/sub 2/ and 0.18 wt. % Bi/sub 4/ dispersed in stainless steel powder, is clad with austenitic stainless steel by roll bonding to produce a composite fuel plate of 30-mils over-all thickness and 5-mils cladding on each side. Assembly and processing the thin platesmore » into an integral unit by brazing with a nickel-base alloy are described. The fabrication problems associated with the interaction ef B/sub 4/C and stainless steel, homogeneity and fragmentation ef the oxide particles, sensitization, bond integrity, and the braze-joint design are discussed in detail. Qualitycontrol measures adopted to produce components within dimensional tolerance on a pilot- plant basis are described. This type of dispersion has demonstrated its utility in a 550 deg F pressurized-water reactor. Its application, however, is not limited to such relatively low temperature reactors. Data are presented on the behavior of this combination under irradiation at temperatures up to 1650 deg F, along with elevated temperature, physical and mechanical property data. Material selection and fabrication effects become more significant when the UO/sub 2/- stainless steel system is considered for higher temperature application, and the important factors are described and evaluated. (auth)« less

THE APPLICATION OF LOW-ENRICHMENT URANIUM DIOXIDE TO ALUMINUM PLATE-TYPE FUEL ELEMENTS

Static corrosion tests in sodium and in fused-fluoride-salt mixture on type 310 stainless steel T-joints brazed with various alloys by the Wall Colmonoy Corporation indicate that the 9% Si-2.5% P-88.5% Ni alloy has fair resistance to both media.

Metallurgy Division SemiAnnual Progress Report for Period Ending October 10, 1955

Rising costs and diminishing reimbursements require hospitals to continually find ways to improve efficiency and productivity. The operating room (OR) is a costintensive environment requiring efficient and effective management. The power of performance of the OR is crucially dependent on the cooperation of the surgical, anaesthesia, nursing and allied health professionals involved. Dr O’Donnell and colleagues from the Department of Anaesthesia, Cork University Hospital, Ireland studied the effects of a number of work practice changes, including modification of patient processing and additional manpower, on non-operating time, number of cases performed and patient cancellations in a dedicated soft-tissue trauma surgical unit [1]. Work practice changes included a transition from sequential patient processing to parallel patient processing and increased use of regional anaesthesia, when feasible. The study findings were disappointing because, despite additional anaesthesia input and limited work practice changes, there was no increased operating room capacity or reduction in non-operative time. A remarkable average 2 hours of operating room time was lost daily due to avoidable delays. Not unexpectedly, the expansion of regional anaesthesia use for upper extremity surgery reduced the duration of recovery room utilization and stay. Why did the context-specific work practice changes adopted in this study design fail so spectacularly to achieve the desired primary and secondary patient outcomes? Study design and methodology limitations included an anaesthesia rather than a surgeon team DOI: http://dx.doi.org/10.21454/rjaic.7518.242.cnn

Improving operating room productivity and efficiency - are there any simple strategies?

Emergence agitation (EA) is a well-known complication of general anesthesia. Awake extubation is preferred in patients after nasal surgery, but it may also intensify EA. Dexmedetomidine reduces agitation from general anesthesia in children and from ventilator weaning in intensive care unit patients. Whether it has the same effects in adults emerging from general anesthesia is still unknown. This randomized, double-blind, placebo-controlled study was performed to determine the effects of intraoperative dexmedetomidine on EA and quality of recovery (QoR) after nasal surgery in adult patients. The 100 adults were aged 20 to 58 years and had nasal surgery with nasal packing on each side until 24 hours postoperatively. Fifty patients received dexmedetomidine (group D) at a rate of 0.4 μg/kg per hour from induction of anesthesia until extubation. Fifty controls (group C) received a volume-matched normal saline infusion as placebo. Routine monitors were applied, and vital signs were monitored at 5-minute intervals. General anesthesia was induced with fentanyl and propofol and maintained with desflurane to a bispectral index (BIS) of 40 to 60. Emergence was defined as the time from “time zero” to 2 minutes after extubation. The level of agitation was evaluated using the Ricker sedation-agitation scale. Grade of cough during emergence was assessed using a 4-point scale of no cough to persistent cough lasting 5 seconds or longer. Other aspects evaluated included BIS reading and respiratory rate at extubation and heart rate and mean arterial pressure before, during, and after surgery and at and after extubation; desaturation, laryngospasm, and other complications were also assessed. In the postanesthesia care unit (PACU), residual sedation and pain were assessed. The QoR was assessed 24 hours after surgery using a 40-item QoR questionnaire (QoR-40) that included emotional state, physical comfort, psychological support, physical independence, and pain. The primary end point was the incidence of EA. Statistical analyses

Efficacy of Intraoperative Dexmedetomidine Infusion on Emergence Agitation and Quality of Recovery After Nasal Surgery

Among drugs causing rare intraoperative anaphylaxis, neuromuscular-blocking drugs (NMBDs) are the most common. Which one is the least likely to cause anaphylaxis is uncertain, and the likelihood of cross-reactivity to alternative NMBDs is not known for patients who have had previous anaphylactic reactions. This study was undertaken to estimate a rate of anaphylaxis to NMBDs by analyzing cases of NMBD anaphylaxis referred to a specialized diagnostic center in Western Australia. Patients underwent skin testing to the NMBD administered and all other possible triggering agents. Intradermal testing was done for the aminosteroid agents with a 1:1000 dilution of rocuronium, vecuronium, or pancuronium (10, 4, and 2 mg/mL, respectively. Atracurium was tested at a dilution of 1:10,000 (10 mg/mL) or cisatracurium at 1:1000 (2 mg/mL). Succinylcholine (50 mg/mL) was diluted to 1:1000. Avolume of 0.02 mL was injected in the volar forearm to yield a 4-mm intradermal bleb. If the wheal increased to 8 mm or greater at 20 minutes, the response was considered to be positive. Cross-reactivity testing was done for those with NMBD anaphylaxis. The severity of anaphylaxis was graded as follows: grade 1 had cutaneous signs only; grade 2 had the presence of measurable but not lifethreatening symptoms, including a decrease in arterial pressure by greater than 30% along with tachycardia and cutaneous signs, cough, or difficulty in mechanical ventilation; grade 3 had lifethreatening reactions, including cardiovascular collapse; and grade 4 had circulatory inefficacy or cardiac arrest. The number of patients exposed to NMBDs during the 10-year period was extrapolated from 5 years of NMBD ampoule sales data for Western Australia. A rate of NMBD anaphylaxis for each agent was calculated. During the study period, 80 patientswere diagnosedwith lifethreatening anaphylaxis to an NMBD; 56%, 21%, 11%, 9%, and 3% of the reactions were triggered by rocuronium, succinylcholine, vecuronium, atracurium, and mivacurium, respectively. No events were triggered by pancuronium or cisatracurium. Eleven patients (14%) had a grade 4 intraoperative anaphylaxis to an NMBD, and 10 of these individuals received external cardiac compressions. Grades 3 and 2 reactions occurred in 55 and 14 patients, respectively. The 3 most often implicated agents showed no difference in the severity of reactions. Surgery was halted in 60%, and the patient was admitted to an intensive care unit in 57% of cases. Rocuronium had the highest rate of anaphylaxis, 8.0 episodes/100,000 administrations during the 10-year period. The rate for vecuronium was 2.8/100,000 administrations. This difference was statistically significant when considered during the study period (P = 0.0013) or when limited to the 5 years that had sales data available (0.2 vs 3.1/100,000; P = 0.01). Atracurium had a rate of 4.01/100,000. Rocuronium, vecuronium, and atracurium caused 49%, 14%, and 11% of anaphylactic reactions during the 10-year period, respectively, but had 49%, 28%, and 15% share of the intermediate-duration market, respectively, during the 5-year period for which data are available. Patients with NMBD anaphylaxis most often had a cross-reaction with succinylcholine (30 of 63 patients tested). Eleven of 34 patients cross-reacted with rocuronium, 20 of 70 with vecuronium, and 16 of 76 patients with pancuronium. Benzylisoquinoliniums cross-reacted less often. Patients with rocuronium anaphylaxis were more apt to have positive skin tests for succinylcholine and vecuronium (44% and 40%, respectively); pancuronium and atracurium were cross-reactors at rates of 19% and 20%, respectively. Cisatracurium cross-reacted at a rate of only 5%. Anaphylaxis to NMBDs is a known major clinical problem. Although rocuronium causes immunoglobulin E (IgE)Ymediated anaphylaxis at a higher rate than vecuronium, this characteristic of rocuronium is often ignored. Clinicians should recognize that anaphylaxis to rocuronium is increased when they are evaluating a patient’s need for an intermediate-duration NMBD.

Anaphylaxis to Neuromuscular Blocking Drugs: Incidence and Cross-Reactivity in Western Australia

Transversus abdominis plane block in cadaveric renal transplantation: a randomized trial: 8AP5-6

reduced volume providing a decreased local anesthetic dose (1.875 mg kg-1). Conclusion(s): LVHC caudal bupivacaine provided a similar perioperative analgesia quality, time and safety profile compared to conventional bupivacaine doses in awake neonates undergoing circumcision. Low volume, high concentration bupivacaine may be used to reduce the risk of local anesthetic toxicity in outpatient neonates.

Transversus abdominis plane block in cadaveric renal transplantation: a randomized trial

Protective role of cyclooxygenase (COX)-2 in experimental lung injury: evidence of a lipoxin A4-mediated effect.

BACKGROUND:The transversus abdominis plane (TAP) block has proven effective in reducing opioid requirements and pain scores for some procedures involving the lower abdominal wall. In this study we assessed its efficacy in patients with end-stage renal failure undergoing cadaveric renal transplantation. METHODS:Sixty-five adult renal transplant recipients were prospectively randomized to receive a standard general anesthetic technique supplemented with levobupivacaine 0.375% 20 mL TAP block or sham block with 20 mL 0.9% saline. Both groups received patient-controlled morphine analgesia and acetaminophen. Patient assessment occurred in the postanesthetic care unit and at 2, 4, 6, 12, and 24 hours. The primary outcome was total morphine consumption in the first 24 hours after renal transplantation. Other outcomes assessed included pain scores, presence of nausea or vomiting, excessive sedation, and respiratory depression. RESULTS:Morphine requirements did not differ between the 2 groups, 31.6 ± 5.6 mg in the TAP group and 32.6 ± 5.5 mg in the control group (95% confidence interval [CI], −8.96 to 7.09, P = 0.817). Pain scores also did not differ significantly at any time point after surgery. Nausea was reported in 53% of the TAP group and 24% of the control group. The relative risk of nausea associated with treatment was 2.2 (95% CI, 1.1 –4.3, P = 0.017). No patient exhibited excessive sedation or respiratory depression. CONCLUSIONS:The addition of a TAP block to the analgesia regimen for renal transplantation did not reduce morphine requirements.

Transversus Abdominis Plane Block for Analgesia in Renal Transplantation: A Randomized Controlled Trial

Robert AVERY 1 Huyton Lane Prescot Merseyside L34 1NS The Conservative Party Candidate Audrey S Davies Edna M Lebrocq Pauline Rooney Brian Rooney Roy Griffiths Brian Carrier John Vaughan Helen B Davies Barbara Kay David J Davies Mike KEARNS 6 Cotsford Way Huyton Knowsley Merseyside L36 2LH Labour Party Candidate Anthony J Cunningham Robert J Whiley Linda S Whiley Joanna Doyle Robert Arnall Delyth Arnall Shannon Arnall Sandra Hare Ann Woods Mary T Sheppard Ian SMITH 3 Chorley Road Prescot Merseyside L34 1NT Liberal Democrats Samantha C Smith John M Wynn John R Nield John Wickham Frank E Lyle Edith L Appleton Henry J Glover Sarah Fe Wynn Frances E Wynn Lily Glover Steve WHATHAM 6 Guild Hey Knowsley Prescot Merseyside L34 0HU Trade Unionists and Socialists Against Cuts Carole I Whatham Gemma Whatham Joanne R Edwards Craig R Edwards Arthur J Roberts Maureen E Roberts Lisa R Whatham Eileen Nye Andrew Thompson Lillian J Rose

KNOWSLEY METROPOLITAN BOROUGH COUNCIL ELECTION OF A BOROUGH COUNCILLOR

Maintenance of a normal to low intraocular pressure during ocular surgery is of critical importance. The prime considerations for anaesthetic management include adequate depth of anaesthesia, normal carbon dioxide and arterial oxygen tensions, stable cardiovascular status and avoidance of stimuli likely to raise central venous pressure. Non-depolarizing muscle relaxants are associated with a reduction in intraocular pressure. Metocurine, a non-depolarizing relaxant, formerly known as dimethyltubocurarine, has been recently reintroduced into clinical practice. Metocurine has been reported to be 1.8 times more potent than d-tubocurarine and has the clinically advantageous cardiovascular effects of stable heart rate and mean blood pressure with minimal associated histamine release. When combined with pancuronium, metocurine potentiates the neuromuscular blocking properties, so that small doses of both drugs in combination produce effective neuromuscular block. This study was designed to assess the suitability of metocurine 0.3 mg-kgand metocurine 0.08 mg kgplus pancuronium 0.02 mg kgas muscle relaxants for ocular surgery. The results demonstrated that metocurine and metocurine-pancuronium combination in the above doses combined with sodium thiopentone 5 mg'kg -t produced ideal conditions for intubation of the trachea in 4.45 (---0.19 SE) minutes and 4.35 (-0.16 SE) minutes respectively. In both treatment groups intraocular pressure was reduced below control values and a pattern of intraocular pressure stability ideal for ocular surgery was obtained during the 10 minutes observation period. The delayed onset of sufficient paralysis for tracheal intubation 4.45 (---0.19 SE) minutes for metocurine and 4.35 (• SE) minutes for the combination makes these techniques unsuitable for emergency ocular surgery because of the long interval when the airway is unprotected.

THE EFFECT OF M E T O C U R I N E AND METOCURINE-PANCURONIUM COMBINATION ON INTRAOCULAR PRESSURE ANTHONY J. CUNNINGHAM, C. PATRICK KELLY, JAMES FARMER AND A. GARNER WATSON

Background and objective: The objectives of this study were, firstly, to characterize the inter‐patient variability in the dose of propofol required to achieve a bispectral index <70 and ‘time to eye opening’ following propofol infusion and, secondly, to determine if the pharmacodynamic parameter ‘time to achieve bispectral index <70’ was influenced by genotype of the sex‐linked drug receptor gene GABRE or if pharmacokinetic parameters such as clearance and ‘time to eye opening’ were influenced by the genotype of the metabolizing enzyme CYP2B6. Methods: One hundred and fifty patients received a standardized anaesthetic. Apparent systemic clearance values were estimated. Correlation was sought between carriers of different CYP2B6 and GABRE genotypes and apparent systemic clearance, ‘time to achieve bispectral index <70’ and ‘time to eye opening’. Results: Propofol induction/emergence characteristics varied, with slow recovery times in a subset of males. Time to loss of verbal contact and time to bispectral index <70 varied 6.6‐ and 4.3‐fold, respectively. At emergence, there was a 15.5‐ to 111‐fold variability in the measured time intervals. Clearance varied from 9.1 to 55.8 mL min−1 kg−1. The CYP2B6 C1459T (R487C) genotype frequencies were TT 1%, TC 22% and CC 67%. The three major haplotypes of CYP2B6 (R487C, K262R and Q172H variants) were not significantly associated with time to eye opening or clearance. Clearance was similar in 487C carriers and 487RR genotypes. There was no statistically significant correlation between the four major haplotypes of GABRE variants investigated ([mRNA358]G/T, 20118C/T, 20326C/T and 20502 A/T) and the observed anaesthesia induction time. Conclusions: Great inter‐patient variability exists in the dose of propofol required to achieve bispectral index <70, apparent systemic propofol clearance and time to eye opening. Common haplotypic differences at the CYP2B6 and GABRE genes do not appear to account for the majority of the observed inter‐patient variability.

An investigation of potential genetic determinants of propofol requirements and recovery from anaesthesia

The Section and Board of Anaesthesiology of the European Union of Medical Specialists aims (EUMS/UEMS) at harmonization of training of anaesthesiologists and at improvement of patient care throughout Europe. Pain medicine is considered to be an area of expertise in anaesthesiology although exclusivity is not claimed. The Section and Board has approved both a core syllabus for pain medicine to be part of the specialist training in anaesthesiology and an additional qualification in pain medicine following the completion of a 5 yr basic specialty training in anaesthesiology. These proposals were prepared by the Working Party on Pain Medicine of the Section and Board. It considers a multidisciplinary approach to pain to contribute to quality in care and has taken the initiative to set up a Multidisciplinary Joint Committee on Pain Medicine within the EUMS/UEMS, for which these guidelines define the area of expertise of anaesthesiology.

Guidelines for anaesthesiologist specialist training in pain medicine.

The sitting position in neurosurgery — Unresolved hemodynamic consequences!

The Effect of Diabetes on the Interrelationship Between Jugular Venous Oxygen Saturation Responsiveness to Phenylephrine Infusion and Cerebrovascular Carbon Dioxide Reactivity

Perioperative Cardiorespiratory Complications in Adults With Mediastinal Mass: Incidence and Risk Factors

Jugular Bulb Oxygen Saturation Under Propofol or Sevoflurane/Nitrous Oxide Anesthesia During Deliberate Mild Hypothermia in Neurosurgical Patients

A Comparison of the Clinical Usefulness of Three Different Electroencephalogram Monitors: Bispectral Index, Processed Electroencephalogram, and Alaris Auditory Evoked Potentials

Continuous Assessment of Cerebral Autoregulation in Subarachnoid Hemorrhage

Is This Patient Dead, Vegetative, or Severely Neurologically Impaired? Assessing Outcome for Comatose Survivors of Cardiac Arrest

Anaesthesia for Carotid Endarterectomy: Comparison of Hypnotic- and Opioid-Based Techniques

Early-Onset Pneumonia: Risk Factors and Consequences in Head Trauma Patients

Preconditioning With Prolonged Oxygen Exposure Induces Ischemic Tolerance in the Brain Via Oxygen Free Radical Formation

Re: Iohom G, Fitzgerald D, Cunningham AJ. Principles of pharmacogenetics--implications for the anaesthetist. Br J Anaesth 2004; 93: 440-50.

Arteriojugular Difference of Oxygen Content and Outcome After Head Injury

Tobacco smoking is the only known etiologic agent that causes pancreatic cancer. The tobacco-specific nitrosamine 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone (NNK) is a potent carcinogen in laboratory rodents that, independent of the route of administration, induces primarily lung adenocarcinoma

4-Hydroxy-1-(3-pyridyl)-1-butanone, an Indicator for 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone–Induced DNA Damage, Is Not Detected in Human Pancreatic Tissue

Epidural Ropivacaine Versus Epidural Morphine and the Catabolic Response to Colonic Surgery: Stable Isotope Kinetic Studies in the Fasted State and During Infusion of Glucose

High Intraoperative Blood Loss May Be A Risk Factor for Postoperative Hematoma

Comparative Evaluation of Narcotrend???, Bispectral Index???, and Classical Electroencephalographic Variables During Induction, Maintenance, and Emergence of a Propofol/Remifentanil Anesthesia

The Comparative Effects of Desflurane and Isoflurane on Lumbar Cerebrospinal Fluid Pressure in Patients Undergoing Craniotomy for Supratentorial Tumors

Assessment of the Lower Limit for Cerebral Perfusion Pressure in Severe Head Injuries by Bedside Monitoring of Regional Energy Metabolism

A Silicone-Based Wire-Reinforced Tracheal Tube with a Hemispherical Bevel Reduces Nasal Morbidity for Nasotracheal Intubation

Routine Cleaning and Autoclaving Does Not Remove Protein Deposits from Reusable Laryngeal Mask Devices

Cardiovascular Responses to Endotracheal Intubation in Patients with Acute and Chronic Spinal Injuries

Cerebral Oxygen Vasoreactivity and Cerebral Tissue Oxygen Reactivity

Pharmocokinetics and Hemodynamics of Ketamine in Intensive Care Patients with Brain or Spinal Cord Injury

Comparison of Ximelagatran with Warfarin for the Prevention of Venous Thromboembolism after Total Knee Replacement

Intracranial Pressure and Cerebral Hemodynamics in Patients with Cerebral Tumors: A Randomized Prospective Study of Patients Subjected to Craniotomy with Propofol-Fentanyl, Isoflurane-Fentanyl, or Sevoflurane-Fentanyl Anesthesia

Principles of pharmacogenetics--implications for the anaesthetist.

The Efficacy of Dexmedetomidine Versus Morphine for Postoperative Analgesia After Major Inpatient Surgery

Ocular microtremor (OMT) is a fine physiologic tremor of the eye related to neuronal activity in the reticular formation of the brainstem. The frequency of OMT is suppressed by propofol and sevoflurane and predicts the response to command at emergence from anesthesia. Previous studies have relied on post hoc computer analysis of OMT wave forms or on real-time measurements confirmed visually on an oscilloscope. Our overall aim was to evaluate an automated system of OMT signal analysis in a diverse patient population undergoing general anesthesia. In a multicenter trial involving four centers in three countries, we examined the accuracy of OMT to identify the unconscious state and to predict movement in response to airway instrumentation and surgical stimulation. We also tested the effects of neuromuscular blockade and patient position on OMT. We measured OMT continuously by using the closed-eye piezoelectric technique in 214 patients undergoing extracranial surgery with general anesthesia using a variety of anesthetics. OMT decreased at induction in all patients, increased transiently in response to surgical incision or airway instrumentation, and increased at emergence. The frequency of OMT predicted movement in response to laryngeal mask airway insertion and response to command at emergence. Neuromuscular blockade did not affect the frequency of OMT but decreased its amplitude. OMT frequency was unaffected by changes in patient position. We conclude that OMT, measured by an automated signal analysis module, accurately determines the anesthetic state in surgical patients, even during profound neuromuscular blockade and after changes in patient position.

Ocular Microtremor During General Anesthesia: Results of a Multicenter Trial Using Automated Signal Analysis

Fenoldopam Mesylate for the Prevention of Contrast-Induced Nephropathy: A Randomized Controlled Trial

Nefopam, a Nonsedative Benzoxazocine Analgesic, Selectively Reduces the Shivering Threshold in Unanesthetized Subjects

Acetazolamide Reduces Referred Postoperative Pain after Laparoscopic Surgery with Carbon Dioxide Insufflation

Acute Neurogenic Pulmonary Edema: Case Reports and Literature Review

Acetylcysteine for Prevention of Acute Deterioration of Renal Function Following Elective Coronary Angiography and Intervention: A Randomized Controlled Trial

Sevoflurane Provides Faster Recovery and Postoperative Neurological Assessment Than Isoflurane in Long-Duration Neurosurgical Cases

Monitoring of Neuromuscular Block After Administration of Vecuronium in Patients with Diabetes Mellitus

Comparison of the Standard Laryngeal Mask Airway and the ProSeal Laryngeal Mask Airway in Obese Patients

Comparison of the Effects of Sevoflurane and Propofol on Cooling and Rewarming During Deliberate Mild Hypothermia for Neurosurgery

Perioperative Epidural Analgesia and Outcome After Major Abdominal Surgery in High-Risk Patients

Treatment of Comatose Survivors of Out-of-hospital Cardiac Arrest With Induced Hypothermia

Vasoactive Modulators During and After Craniotomy: Relation to Postoperative Hypertension

Hypertonic Saline Ameliorates Cerebral Edema Associated With Experimental Brain Tumor

Dexmedetomidine May Impair Cognitive Testing During Endovascular Embolization of Cerebral Arteriovenous Malformations: A Retrospective Case Report Series

Does Tissue Oxygen-Tension Reliably Reflect Cerebral Oxygen Delivery and Consumption?

A Prospective Study of the Quality of Pre-Hospital Emergency Ventilation in Patients With Severe Head Injury

Cardiac arrest with widespread cerebral ischemia frequently leads to severe neurologic impairment. We studied whether mild systemic hypothermia increases the rate of neurologic recovery after resuscitation from cardiac arrest due to ventricular fibrillation.

METHODS
In this multicenter trial with blinded assessment of the outcome, patients who had been resuscitated after cardiac arrest due to ventricular fibrillation were randomly assigned to undergo therapeutic hypothermia (target temperature, 32 degrees C to 34 degrees C, measured in the bladder) over a period of 24 hours or to receive standard treatment with normothermia. The primary end point was a favorable neurologic outcome within six months after cardiac arrest; secondary end points were mortality within six months and the rate of complications within seven days.

RESULTS
Seventy-five of the 136 patients in the hypothermia group for whom data were available (55 percent) had a favorable neurologic outcome (cerebral-performance category, 1 [good recovery] or 2 [moderate disability]), as compared with 54 of 137 (39 percent) in the normothermia group (risk ratio, 1.40; 95 percent confidence interval, 1.08 to 1.81). Mortality at six months was 41 percent in the hypothermia group (56 of 137 patients died), as compared with 55 percent in the normothermia group (76 of 138 patients; risk ratio, 0.74; 95 percent confidence interval, 0.58 to 0.95). The complication rate did not differ significantly between the two groups.

In patients who have been successfully resuscitated after cardiac arrest due to ventricular fibrillation, therapeutic mild hypothermia increased the rate of a favorable neurologic outcome and reduced mortality.

Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest.

Background and objective: Preoperative bedside screening tests for difficult tracheal intubation may be neither sensitive nor specific enough for clinical use. The aim was to investigate if a combination of the Mallampati classification of the oropharyngeal view with either the thyromental or sternomental distance measurement improved the predictive value. Methods: A total of 212 (109 male, 103 female) non-obstetric surgical patients, aged > 18 yr, undergoing elective surgical procedures requiring tracheal intubation were assessed preoperatively with respect to the oropharyngeal (modified Mallampati) classification, thyromental and sternomental distances. An experienced anaesthetist, blinded to the preoperative airway assessment, performed laryngoscopy and graded the view according to Cormack and Lehane's classification. Results: Twenty tracheal intubations (9%) were difficult as defined by a Cormack and Lehane Grade 3 or 4, or the requirement for a bougie in patients with Cormack and Lehane Grade 2. Used alone, the Mallampati oropharyngeal view, and thyromental and sternomental distances were associated with poor sensitivity, specificity and positive predictive values. Combining the Mallampati Class III or IV with either a thyromental distance <6.5 cm or a sternomental distance <12.5 cm decreased the sensitivity (from 40 to 25 and 20%, respectively), but maintained a negative predictive value of 93%. The specificity and positive predictive values increased from 89 and 27% respectively for Mallampati alone to 100%. Conclusions: The findings suggest that the Mallampati classification, in conjunction with measurement of the thyromental and sternomental distances, may be a useful routine screening test for preoperative prediction of difficult tracheal intubation.

Anaesthesia for Awake Craniotomy-Evolution of a Technique That Facilitates Awake Neurological Testing

Neuroprotective and Neurotoxic Properties of the “Inert” Gas, Xenon

Antinociceptive Effect of Low-Dose Intrathecal Neostigmine Combined with Intrathecal Morphine Following Gynecologic Surgery

A Comparison of Three Anesthetic Techniques in Patients Undergoing Craniotomy for Supratentorial Intracranial Surgery

Moderate Hypothermia Depresses Arterial Baroreflex Control of Heart Rate During, and Delays Its Recovery After, General Anesthesia in Humans

BACKGROUND AND OBJECTIVE
Postoperative renal impairment is a recognized complication of infrarenal aortic cross-clamping. Our hypothesis was that the renal vasodilating and natriuretic effects of fenoldopam mesylate, a selective dopamine (DA1) agonist, would preserve renal function in patients undergoing elective infrarenal aortic cross-clamping.

METHODS
A prospective, randomized, double blind controlled clinical trial was performed. Twenty-eight ASA II-III patients undergoing elective aortic surgery requiring infrarenal aortic cross-clamping were studied. According to random allocation, patients received either fenoldopam (0.1 microg kg(-1) min(-1)) or placebo intravenously prior to surgical skin incision until release of the aortic clamp. Plasma creatinine, creatinine clearance, urinary output, fractional excretion of sodium, and free water clearance were measured: (a) prior to admission to hospital; (b) during the period from insertion of the urinary catheter until application of the aortic cross-clamp; (c) during the period of aortic cross-clamping; (d) 0-4 h, and (e) 4-8 h after release of the clamp and on days 1, 2, 3, and 5 postoperatively.

RESULTS
Fenoldopam (0.1 microg kg(-1)min(-1)) administration was not associated with haemodynamic instability. On application of the aortic cross-clamp creatinine clearance decreased significantly in the placebo (83 +/- 20 to 42 +/- 29 mL min(-1) (mean +/- SD)) (P < 0.01) but not in the fenoldopam group, and this decrease persisted for at least 8 h after release of the cross-clamp (83 +/- 20 to 54 +/- 33 mL min(-1) (mean +/- SD)) (P < 0.05). Plasma creatinine concentration increased significantly from baseline on the first postoperative day in the placebo group (87 +/- 12 to 103 +/- 28 micromolL(-1) (mean +/- SD)) (P < 0.01) but not in the fenoldopam group.

These findings are consistent with the hypothesis that fenoldopam possesses a renoprotective effect during and after infrarenal aortic cross-clamping.

The effects of fenoldopam on renal function in patients undergoing elective aortic surgery.

A practical and reliable monitor of depth of anaesthesia would be a major advance on current clinical practice. None of the present monitors is both simple to use and accurate. Ocular microtremor (OMT) is a physiological tremor that is suppressed by propofol in a dose-dependent manner. We studied OMT during propofol induction and nitrous oxide-oxygen-sevoflurane maintenance of anaesthesia in 30 patients, and compared OMT with the bispectral index (BIS) as a predictor of response to verbal command.

METHODS
OMT was measured using the closed-eye piezoelectric strain-gauge technique. OMT and BIS were measured at specific times during the anaesthetic, including at loss of consciousness, at end-tidal sevoflurane 1 and 2%, and at emergence.

RESULTS
OMT decreased significantly after induction, did not decrease as end-tidal sevoflurane was increased from 1 to 2%, and increased at emergence in all patients. By logistic regression, OMT was more sensitive and specific than BIS in distinguishing the awake from the anaesthetized state (OMT, 84.9 and 93.1% respectively; BIS, 75.7 and 69.0%).

OMT is suppressed by sevoflurane and accurately predicts response to verbal command. OMT may be a useful monitor of depth of hypnosis.

Comparison of ocular microtremor and bispectral index during sevoflurane anaesthesia.

Changes of Haemostasis in Patients Undergoing Major Abdominal Surgery: Is There a Difference Between Elderly and Younger Patients?

The Effect of Perioperative Aspirin Therapy in Peripheral Vascular Surgery: A Decision Analysis

Purpose of review Ambulatory surgery is now one of the major areas of surgical and anesthetic practice, with up to 70% of procedures performed in the ambulatory setting. This review focuses on some of the recent studies performed in day case anesthesia. Recent findings Emphasizing the economic benefits of ambulatory surgery, investigators have studied the cost implications of various anesthetic techniques and their impact on patient recovery, discharge times and readmission rates. Quality anesthetic management measures such as mortality, morbidity, postoperative stay and patient satisfaction ensure that perioperative care and treatment are optimized. Summary Careful patient selection can minimize perioperative events. The concept of multimodal analgesic and antiemetic therapy, in combination with newer anesthetic drugs, help expand the field of ambulatory surgery.

Benzodiazepine premedication may attenuate the stress response in daycase anesthesia: a pilot study

A Comparison of the Effects of Nitroglycerin and Esmolol on Splanchnic Blood Flow during Infrarenal Aortic Cross Clamping: [2002][A-635]

Cancer of the pancreas is the fourth leading cause of cancer mortality in the USA with an estimated 28 900 deaths in 2001. Several factors have been implicated in the etiology of this disease. However, at present, only cigarette smoking has been positively associated with pancreatic cancer. It is our working hypothesis that tobacco-derived compounds can be delivered to the pancreas where, upon metabolic activation, they can initiate carcinogenesis. Our current investigation was conducted to determine whether cotinine and tobacco-specific nitrosamines (TSNA) are present in human pancreatic juice. Smoking status was assessed by the determination of levels of urinary cotinine and was further supported by quantifying nicotine in hair. The TSNA were extracted from the pancreatic juice of 18 smokers and 9 nonsmokers by supercritical carbon dioxide that contained 10% methanol. The extracts were analyzed for TSNA, namely, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN), by gas chromatography with mass spectrometric detection using a selected ion monitoring technique (GC-SIM-MS). Twenty-three extracts of human pancreatic juice were also analyzed for the presence of the NNK metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by GC-SIM-MS and by gas chromatography interfaced wit a thermal energy analyzer (GC-TEA; TEA, a nitrosamine-specific detector). Cotinine was detected in all analyzed samples of pancreatic juice from smokers (129 +/- 150 ng/mL juice; mean +/- standard deviation) and was present in only two of the nine samples of pancreatic juice from nonsmokers. Its levels in these two samples were 7 and 9 ng/mL juice. NNK was detected in 15 of 18 samples (83%) from smokers at levels from 1.37 to 604 ng/mL pancreatic juice. In nine samples of pancreatic juice from nonsmokers, NNK ranged from not detected (in three samples) to 96.8 ng/mL juice. In pancreatic juice from smokers the mean level of NNK (88.7 +/- 161 ng/mL juice) was significantly higher (p < 0.04) than in that from nonsmokers (12.4 +/- 31.7 ng/mL juice). In addition to NNK, NNN was found in two samples of pancreatic juice of smokers at levels of 68.1 and 242 ng/mL juice; NNN was not detected in any other sample. NNAL was present in 8 of 14 pancreatic juice samples (57%) from smokers and in three of nine samples (33%) from nonsmokers. This research presents preliminary data that supports the hypothesis that pancreatic tissue is exposed to TSNA and that they may be important contributors to pancreatic carcinogenesis in humans.

Identification of tobacco-derived compounds in human pancreatic juice.

A Randomized, Controlled Trial of Surgery for Temporal-Lobe Epilepsy

Minimally invasive surgical procedures aim to minimize the trauma of the interventional process but still achieve a satisfactory therapeutic result. Tissue trauma is significantly less than that with conventional open procedures, offering the advantages of reduced post-operative pain, shorter hospital stay, more rapid return to normal activities and significant cost savings. Laparoscopic cholecystectomy is now a routinely performed procedure and has replaced conventional open cholecystectomy as the procedure of choice for symptomatic cholelithiasis. Public expectation and developments in instrumentation have fuelled this change. The physiological effects of intraperitoneal carbon dioxide insufflation combined with variations in patient positioning can have a major impact on cardiorespiratory function, particularly in elderly patients with co-morbidities. Intra-operative complications may include traumatic injuries associated with blind trocar insertion, gas embolism, pneumothorax and surgical emphysema associated with extraperitoneal insufflation. Appropriate monitoring and a high index of suspicion can result in early diagnosis of, and treatment of, complications. Laparoscopic cholecystectomy has proven to be a major advance in the treatment of patients with symptomatic gallbladder disease.

The clinical use of doxorubicin, an anthracycline chemotherapeutic agent, is limited by cardiotoxicity, particularly when combined with herceptin, an antibody that blocks the HER2 receptor. Doxorubicin induces cyclooxygenase-2 (COX-2) activity in rat neonatal cardiomyocytes. This expression of COX-2 limits doxorubicin-induced cardiac cell injury, raising the possibility that the administration of a prostaglandin may protect the heart during the in vivo administration of doxorubicin. Doxorubicin (15 mg/kg) administered to adult male Sprague Dawley rats induced COX-2 expression and activity in cardiac tissue. Prostacyclin generation measured as the excretion of 2,3-dinor-6-keto-PGF(1alpha) also increased, and this was blocked by a COX-2 inhibitor, SC236. In contrast, administration of a COX-1 inhibitor SC560 at a dose that reduced serum thromboxane B2 by more than 80% did not prevent the doxorubicin-induced increase in prostacyclin generation. Doxorubicin increased cardiac injury, detected as a rise in plasma cardiac troponin T, serum lactate dehydrogenase, and cardiomyocyte apoptosis; this was aggravated by coadministration of SC236 but not SC560. The degree of injury in animals treated with a combination of doxorubicin and SC236 was attenuated by prior administration of the prostacyclin analogue iloprost. These data raise the possibility of protecting the heart during the administration of doxorubicin by prior administration of prostacyclin.

Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury in vivo.

The effects of selective cyclo-oxygenase-2 inhibition on postoperative analgesia and prostaglandin formation

Dopexamine hydrochloride does not modify hemodynamic response or tissue oxygenation or gut permeability during abdominal aortic surgery

A previously healthy 25-yr-old female developed flaccid areflexic tetraplegia, with intact cranial nerve function, 36 h after the diagnosis of bacterial meningitis. Polymerase chain reaction studies of cerebrospinal fluid and blood were positive for Neisseria meningitidis, serogroup B. Magnetic resonance of the cervicothoracic spine revealed increased signal intensity and expansion in the lower medulla, upper cervical cord and cerebellar tonsils. Neurosurgical consultation recommended hyperventilation, dexamethasone and regular mannitol therapy rather than decompressive intervention. The clinical course over the following 12 days was complicated by the development of progressive central nervous and multisystem organ failure with disseminated intravascular coagulopathy. Autopsy revealed cerebral oedema with cystic infarction extending from the medulla to the upper cervical cord and cerebellar tonsils. Flaccid areflexic tetraplegia with spinal cord infarction has not been reported following bacterial infection in an adult. The clinical implications would suggest complete central nervous system evaluation of patients recovering from meningococcal meningitis, since spinal cord lesions, although uncommon, do occur. In those very rare situations where a patient develops significant peripheral neurological deficits, urgent magnetic resonance imaging is warranted, to rule out an infective focus or an underlying anatomical anomaly.

Spinal cord infarction and tetraplegia--rare complications of meningococcal meningitis.

The duration of preoperative fasting from solid food and liquids, a time-honoured anaesthetic practice, has been the subject of extensive clinical investigations [1,2], editorial comment [3] and speciality guidelines [4,5] in the past decade. Dr Pearse and colleagues’ study of current UK clinical practice relating to the duration of preoperative fasting of adult patients and compliance with ongoing cardiac drug administration is therefore timely [6]. Historically, preoperative fasting has not always been a prerequisite of safe, prudent anaesthetic practice. Lister, in the late 19th century, advised oral fluid intake up to two hours before anaesthesia [7]. Despite a body of recent evidence in support of Lister’s conclusions, clinicians have continued to err on the side of caution and practice the maxim that ‘longer is better’. Mendelson described the risk of gastric acid aspiration during obstetric anaesthesia with the consequent development of pneumonitis in his landmark 1946 study [8]. The conventional wisdom was that techniques to minimize the volume and increase the pH of the gastric contents would reduce the risk of Mendelson’s syndrome. The concept of ‘nil by mouth’ (or in North America NPO), encompassing both fluids and food after midnight, was regarded as a logical practice to ensure an empty stomach at the time of surgery. Prolonged preoperative fasting contributes to patient discomforts, including dry mouth and thirst. In addition, the practice may, in some situations, lead to dehydration, hypovolaemia, and nausea and vomiting [9]. If excess gastric acidity was also a consequence, surely the practice should warrant a major review? The most noteworthy data arising from Pearse and colleagues’ study involving 153 adult patients were the range of fasting times. For solids, the range was from 4 h and 30 min to 48 h

Preoperative fasting and administration of regular medications in adult patients presenting for elective surgery. Has new evidence changed clinical practice?

Preoperative anaesthesia information — what do patients need to know?

This case describes a 39-yr-old male, presenting with left hemiplegia after a road traffic accident involving frontal deceleration and airbag deployment. Brain computerized tomography (CT) scan revealed a right parietal lobe infarct. Contrast angiography demonstrated bilateral internal carotid artery dissection and fibromuscular dysplasia. The patient was treated with systemic heparinization. Neurological improvement, evidenced by full return of touch sensation, proprioception and nociception began 10 days after the injury. To our knowledge, this is the first case report of carotid artery dissection associated with airbag deployment. Forced neck extension in such settings may result in carotid artery dissection because of shear force injury at the junction of the extracranial and intrapetrous segments of the vessel. Clinicians should consider carotid artery injury when deterioration in neurological status occurs after airbag deployment. We propose that the risk of carotid artery dissection was increased by the presence of fibromuscular dysplasia.

Traumatic bilateral internal carotid artery dissection following airbag deployment in a patient with fibromuscular dysplasia.

An objective evaluation of benzodiazepine premedication in attenuating the stress reponse in daycase anaesthesia

REVIEW ARTICLE The sitting position in neurosurgery: a critical appraisal

The potential for serious complications after venous air embolism and successful malpractice liability claims are the principle reasons for the dramatic decline in the use of the sitting position in neurosurgical practice. Although there have been several studies substantiating the relative safety compared with the prone or park bench positions, its use will continue to decline as neurosurgeons abandon its application and trainees in neurosurgery are not exposed to its relative merits. How can individual surgeons continue to use this position? Will individual, difficult surgical access cases be denied the obvious technical advantages of the sitting position? Limited use of the sitting position should remain in the neurosurgeon's armamentarium. However, several caveats must be emphasized. Assessment of the relative risk-benefit, based on the individual patient's physical status and surgical implications for the particular intracranial pathology, is of paramount importance. The patient should be informed of the specific risks of venous air embolism, quadriparesis and peripheral nerve palsies. Appropriate charting of patient information provided and special consent issues are essential. An anaesthetic input into the decision to use the sitting position is a sine qua non. The presence of a patient foramen ovale is an absolute contraindication. Preoperative contrast echocardiography should be used as a screening technique to detect the population at risk of paradoxical air embolism caused by the presence of a patent foramen ovale. The technique involves i.v. injection of saline agitated with air and a Valsalva manoeuvre is applied and released. Use of this position necessitates supplementary monitoring to promptly detect and treat venous air embolism. Doppler ultrasonography is the most sensitive of the generally available monitors to detect intracardiac air. The use of a central venous catheter is recommended, with the tip positioned close to the superior vena cava junction with the right atrium, to aspirate intravascular gas. Measures to minimize hypotension associated with the sitting position include a slow, staged positioning over 5-10 min and use of the 'G suit' inflated with compressed air applied to the lower extremities and pelvis. Use of the sitting or upright position for patients undergoing posterior fossa and cervical spine surgery presents unique challenges for the anaesthetist. With appropriate patient selection and preparation, and using prudent intraoperative monitoring and anaesthetic techniques, selected patients should still benefit from the optimum access to mid-line lesions, improved cerebral venous decompression, lower intracranial pressure and enhanced gravity drainage of blood and CSF associated with the sitting position.

Auditory evoked potentials are effected by benzodiazepines, as is cortical processing of auditory stimuli. The effect of benzodiazepines on auditory sensitivity has not, however, been studied. We designed the present study to investigate the effect of sedative doses of midazolam on pure tone and speech audiometry and on audiological reaction times in healthy volunteers. Thirty volunteers underwent baseline audiological assessment for pure tones and speech and had their audiological reaction times measured at 10 and 50 dB above their threshold hearing level at a frequency of 1 kHz. Subjects were then randomly assigned to one of two groups. Group A (n = 15) received midazolam (0.04 mg/kg) IV, and Group B (n = 15) received a similar volume of placebo IV. The audiological tests were repeated 5 min later, and performance was compared with baseline data. Scheffé post hoc tests were used to assess the significance of changes in each group. There was no pre- to posttest change in audiological performance in either the placebo group (P = 0.194) or the midazolam group (P = 0.957). Speech audiometry performance was likewise unaffected by midazolam (P = 0.154). Reaction time at the 10-dB and 50-dB sensation levels were both significantly prolonged after midazolam administration (P = 0.023 and P = 0.012, respectively). In this study, we demonstrate that sedation with midazolam (0.04 mg/kg) does not alter pure tone or speech audiometric thresholds, but it does significantly delay the reaction time to auditory stimuli. Medical practitioners should advise midazolam-sedated patients of their impaired reaction to auditory warning signals (e.g., traffic and car horns) as part of the day-ward discharge recommendations.

In this study, we demonstrate that sedation of healthy volunteers with the benzodiazepine midazolam, in the common clinical dosage, does not affect their hearing capability as measured by pure tone and speech audiometry. However, one's ability to react to auditory signals is impaired after midazolam, which may have implications for patients after day-case procedures.

The effects of midazolam on pure tone audiometry, speech audiometry, and audiological reaction times in human volunteers.

Iontophoretic vincristine in the treatment of postherpetic neuralgia: a double-blind, randomized, controlled trial.

Coexistent cardiovascular disease is common in patients presenting for repair of aortic aneurysms. However, preoperative cardiac evaluation prior to abdominal aortic aneurysm (AAA) surgery remains contentious with significant variations in practice between countries, institutions and individual anesthetists. The following case report raises some everyday issues confronting clinical anesthetists.

Preoperative evaluation of a patient for abdominal aortic aneurysm repair.

Minimally invasive therapy aims to minimize the trauma of any interventional process but still achieve a satisfactory therapeutic result. The development of "critical pathways," rapid mobilization and early feeding have contributed towards the goal of shorter hospital stay. This concept has been extended to include laparoscopic cholecystectomy and hernia repair. Reports have been published confirming the safety of same day discharge for the majority of patients. However, we would caution against overenthusiastic ambulatory laparoscopic cholecystectomy on the rational but unproven assumption that early discharge will lead to occasional delays in diagnosis and management of postoperative complications. Intraoperative complications of laparoscopic surgery are mostly due to traumatic injuries sustained during blind trocar insertion and physiologic changes associated with patient positioning and pneumoperitoneum creation. General anesthesia and controlled ventilation comprise the accepted anesthetic technique to reduce the increase in PaCO2. Investigators have recently documented the cardiorespiratory compromise associated with upper abdominal laparoscopic surgery, and particular emphasis is placed on careful perioperative monitoring of ASA III-IV patients during insufflation. Setting limits on the inflationary pressure is advised in these patients. Anesthesiologists must maintain a high index of suspicion for complications such as gas embolism, extraperitoneal insufflation and surgical emphysema, pneumothorax and pneumomediastinum. Postoperative nausea and vomiting are among the most common and distressing symptoms after laparoscopic surgery. A highly potent and selective 5-HT3 receptor antagonist, ondansetron, has proven to be an effective oral and IV prophylaxis against postoperative emesis in preliminary studies. Opioids remain an important component of the anesthesia technique, although the introduction of newer potent NSAIDs may diminish their use. A preoperative multimodal analgesic regimen involving skin infiltration with local anesthesia. NSAIDs to attenuate peripheral pain and opioids for central pain may reduce postoperative discomfort and expedite patient recovery/discharge. There is no conclusive evidence to demonstrate clinically significant effects of nitrous oxide on surgical conditions during laparoscopic cholecystectomy or on the incidence of postoperative emesis. Laparoscopic cholecystectomy has proven to be a major advance in the treatment of patients with symptomatic gallbladder disease.

Minimally invasive therapy aimstominimize thetrauma ofanyinterventional process butstill achieve asatisfactory therapeutic result. Thedevelopment of "critical pathways," rapid mobilization andearly feeding havecontributed towards thegoalofshorter hospital stay. Thisconcept hasbeenextended to include laparoscopic cholecystectomy andhernia repair. Reports havebeenpublished confirming thesafety ofsamedaydischarge forthemajority ofpatients. However, wewouldcaution against overenthusiastic ambulatory laparoscopic cholecystectomy ontherational butunproven assumption that early discharge will leadtooccasional delays indiagnosis andmanagement ofpostoperative complications. Intraoperative complications oflaparoscopic surgery aremostly duetotraumaticinjuries sustained during blind trocar insertion andphysiologic changes associated withpatient positioning andpneumoperitoneum creation. General anesthesia andcontrolled ventilation comprise theaccepted anesthetic technique to reduce theincrease inPaCO2. Investigators haverecently documented thecardiorespiratory compromise associated withupperabdominal laparoscopic surgery, andparticular emphasis isplaced oncareful perioperative monitoring ofASAIII-IV patients during insufflation. Setting limits ontheinflationary pressure isadvised inthese patients. Anesthesiologists mustmaintain ahigh index ofsuspicion forcomplications suchasgasembolism, extraperitoneal insufflation andsurgical emphysema, pneumothorax andpneumomediastinum. Postoperative nausea andvomiting areamongthemostcommonanddistressing symptoms after laparoscopic surgery. A highly potent andselective 5-HT3 receptor antagonist, ondansetron, hasproven tobeaneffective oral andIVprophylaxis against postoperative emesis inpreliminary studies. Opioids remain an important component oftheanesthesia technique, although theintroduction of newerpotent NSAIDsmaydiminish their use. Apreoperative multimodal analgesic regimen involving skin infiltration withlocal anesthesia. NSAIDstoattenuateperipheral pain andopioids forcentral pain mayreduce postoperative discomfort andexpedite patient recovery/discharge. Thereisnoconclusive evidence todemonstrate clinically significant effects ofnitrous oxide onsurgical conditions during laparoscopic cholecystectomy orontheincidence ofpostoperative emesis. Laparoscopic cholecystectomy hasproven tobeamajor advance inthetreatment ofpatients withsymptomatic gallbladder disease.

European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery

The effects of recombinant human growth hormone on cardiopulmonary function in elective abdominal aortic aneurysm repair.

We report the case of a previously healthy 51-yr-old male who underwent an uneventful total hip replacement under spinal anaesthesia. His immediate postoperative course was complicated by the development of a severe frontal headache. Initial conservative treatment included oral analgesics and an epidural blood patch. The headache persisted and was followed by progressive vision loss and a right partial third nerve palsy. The patient was almost blind at the time of transfer to our neurosurgical unit. Relevant investigations revealed marked hyponatraemia (serum sodium concentration 122 mmol litre-1) and second-degree heart block (Mobitz I). A CT scan showed a pituitary tumour and confirmed the clinical diagnosis of pituitary apoplexy. Urgent craniotomy was scheduled and a large necrotic pituitary adenoma was excised. The postoperative course was uneventful with return of near normal vision at the time of discharge. Clinicians should consider this diagnosis when focal neurological deficits occur with post-dural puncture headache.

EVALUATION OF DOPEXAMINE HYDROCHLORIDE ON HAEMODYNAMIC FUNCTION; TISSUE OXYGENATION AND GUT PERMEABILITY DURING ABDOMINAL AORTIC SURGERY

Effects of Sevoflurane With and Without Nitrous Oxide in Human Cerebral Circulation: Transcranial Doppler Study

CARDIO‐RESPIRATORY FUXCTION FOLLOWING ELECTIVE AORTIC SURGERY: THE EFFECT OF PERI‐OPERATIVE RECOMBINANT HUMANGROWTH HORMONE: 618

NUTRITIONAL EFFECTS OF RECOMBINANT HUMAN GROWTH HORMONE IN PATIENTS UNDERGOING ABDOMINAL AORTIC ANEURYSM (AAA) REPAIR: 622

Postoperative respiratory dysfunction: is the site of surgery crucial?

We have assessed the potential for myocardial ischaemia during laparoscopic cholecystectomy in 16 otherwise healthy patients. Continuous ambulatory ECG monitoring was commenced 12 h before operation and continued for 24 h after operation. The neuroendocrine stress response was assessed by measuring plasma concentrations of adrenaline and noradrenaline, human growth hormone, cortisol, renin and aldosterone, and prolactin, at specified times during surgery. Acute ST segment changes in the ECG occurred in only two patients. These episodes were independent of creation of pneumoperitoneum and changes in position. Acute intraoperative increases in MAP were noted during insufflation of carbon dioxide and reverse Trendelenburg positioning (P < 0.05). A four-fold increase in plasma concentrations of renin and aldosterone was noted after pneumoperitoneum and reverse Trendelenburg positioning (P > 0.05). There was a linear correlation between changes in plasma renin and aldosterone concentrations and MAP (r = 0.97 and r = 0.85, respectively). Prolactin concentrations increased four-fold after induction of anaesthesia. Cortisol, HGH, adrenaline and noradrenaline concentrations increased after deflation of the pneumoperitoneum. The time profile-concentration changes of increased MAP and renin-aldosterone suggests a cause-effect relationship. Increased intra-abdominal pressure and reverse Trendelenburg positioning may reduce cardiac output and renal blood flow. The early increase in prolactin concentration was probably secondary to the effect of the opioid fentanyl.

Laparoscopic cholecystectomy: haemodynamic and neuroendocrine responses after pneumoperitoneum and changes in position.

Paul Tessier had the idea for this monograph in 1999, after reading a report on a symposium on biomaterials and bone substitutes1 in which there was considerable discussion of various alloplastic materials but very little discussion of what he believed was the very best bone substitute, an autogenous bone graft. Craniofacial surgery exists today as a separate surgical discipline because of the pioneering work of Paul Tessier. Indeed, the main difference between the successful Le Fort III-type osteotomies performed by Tessier in the late 1950s and early 1960s and the earlier, similar operation performed by Sir Harold Gillies was that Tessier placed bone grafts in his surgically created gaps and had a stable result, whereas Gillies did not and had a relapse requiring a subsequent “camouflaging” operation. Gillies’ case is presented in brief in Gillies and Millard.2 The patient appears to have a mild Crouzon syndrome, and Gillies performed what was certainly the first Le Fort III osteotomy in 1942. There was a significant relapse, and in 1949 Gillies reoperated on the patient. With Hugo Obwegeser3 as the assistant, he performed an orbital expansion and placed ox cartilage grafts on the infraorbital rims and nose, and did nothing for the malocclusion. Of the case, Gillies and Millard said, “In light of subsequent experience, even this small loss could have been avoided by packing chip grafts into the strategic osteotomy chinks.” The “classic” operations of craniofacial surgery–-the Le Fort III-type osteotomy, the correction of orbital hypertelorism and other orbital dystopias, the correction of posttraumatic enophthalmos and other sequelae of facial fractures, the correction of the facial difference of Treacher-Collins-Franceschetti syndrome, and the monobloc frontofacial advancement–-were all developed by Tessier. All of these operations relied on the use of autogenous bone grafts, and all continue to be used successfully as he described them. At just about the time Dr. Tessier retired from active surgical practice, a new mode of treatment came on the scene: distraction osteogenesis. He welcomed this new method of treatment enthusiastically, and in fact gave it an acronym that has stuck: DOG. Distraction osteogenesis has extended the frontiers in that many conditions, such as hemifacial microsomia, the Pierre Robin anomalad, and midface deficiency, can be treated earlier and without the need for bone grafting. However, distraction osteogenesis has not rendered orthognathic surgery obsolete, as some had predicted, nor has it changed the indications for most of the “classic” craniofacial procedures. Knowing how to harvest an autogenous bone graft is still important, and many of us are astonished when a new craniofacial fellow shows up for service having just completed an entire plastic surgery residency in which he or she did not see a single autogenous bone graft taken. Bone morphogenic protein-2 has received U.S. Food and Drug Administration approval for use in spine surgery and for alveolar bone grafts. It may help autogenous bone form without a bone graft in some areas, and it may help increase the take of free bone grafts. We are enthusiastic about its possibilities. It is still very expensive, and it is unlikely that it will replace the need for autogenous bone grafts. In the time that has passed since Gosain and Persing’s 1999 publication,1 which was the impetus for this entire work, another publication

A.48 Gastric and colonic mucosal pH changes during abdominal aortic surgery — correlation with oxygen delivery and consumption

We have assessed the potential for myocardial ischaemia during laparoscopic cholecystectomy in 16 otherwise healthy patients. Continuous ambulatory ECG monitoring was commenced 12 h before operation and continued for 24 h after operation. The neuroendocrine stress response was assessed by measuring plasma concentrations of adrenaline and noradrenaline, human growth hormone, cortisol, renin and aldosterone, and prolactin, at specified times during surgery. Acute ST segment changes in the ECG occurred in only two patients. These episodes were independent of creation of pneumoperitoneum and changes in position. Acute intraoperative increases in MAP were noted during insufflation of carbon dioxide and reverse Trendelenburg positioning (P 0.05). There was a linear correlation between changes in plasma renin and aldosterone concentrations and MAP (r = 0.97 and r = 0.85, respectively). Prolactin concentrations increased four-fold after induction of anaesthesia. Cortisol, HGH, adrenaline and noradrenaline concentrations increased after deflation of the pneumoperitoneum. The time profile-concentration changes of increased MAP and renin-aldosterone suggests a cause-effect relationship. Increased intra-abdominal pressure and reverse Trendelenburg positioning may reduce cardiac output and renal blood flow. The early increase in prolactin concentration was probably secondary to the effect of the opioid fentanyl.

Laparoscopic cholecystectomy: haemodynamic and neuroendocrine responses after pneumoperitoneum and changes in position†

T racheobronchial rupture is a rare but well recognized complication of blunt chest trauma (1). This case report describes a patient who experienced blunt thoracic trauma with a resulting bronchial tear that was not initially diagnosed. Bronchoscopic evaluation of the airway was not initially performed because the lungs reexpanded immediately with chest drainage and there was minimal air leak. Subsequent stricture formation resulted in atelectasis, obstructive pulmonary sepsis, and arterial hypoxemia from intrapulmonary shunting. This report describes the consequences of delayed diagnosis of a bronchial rupture after a decelerating chest injury. The anesthetic implications are discussed.

alpha 2 macroglobulin (alpha 2M), a 725 kDa plasma protein, has been reported to bind a range of cytokines. We have therefore investigated its effect on a number of commercial cytokine assays. The methylamine converted fast form of the molecule was found to reproducibly depress, by 26% or more, the standard curves obtained with certain commercial assays for IL-2 and for tumor necrosis factor alpha, and had a small inhibitory effect on some IL-4 assays. In contrast it slightly enhanced or had no effect on ELISAs for IL-1 beta and IL-6. The inhibition observed was directly proportional to the concentration of alpha 2 M used in the range 0.5-5 mg/ml. Studies in the IL-2 system also revealed that it was largely attributable to the fast form of alpha 2M. Preliminary evidence suggests that the effects observed may be dependent on the assay source. These findings may be relevant to the assay of biological fluids in which alpha 2 M is present.

The effect of alpha 2 macroglobulin in commercial cytokine assays.

There is the need for a simple, effective procedure for separating alpha 2 macroglobulin-cytokine complexes from free cytokine in order that the nature and possible immunological significance of cytokine-binding by alpha 2 macroglobulin (alpha 2-M) might be further investigated. This presentation describes a method which exploits the presence of zinc-binding sites on alpha 2-M which permit the isolation of complexes from other proteins by zinc-affinity chromatography. Furthermore the method may be used in either a column or batch format.

A simple method for isolating alpha 2 macroglobulin-cytokine complexes.

Minimally invasive or minimal access surgery is associated with significantly less trauma than conventional surgical access. The technology required is expensive and its adoption has major implications for patient services, hospital design, operating room equipment, surgical speciality alignment, and training. Intraoperative complications are mostly due to traumatic injuries sustained during blind trocar insertion and physiological changes associated with pneumoperitoneum and patient position.

the lungs of a patient who has a tube in the oesophagus if the proximal end of the tube is brought under the rim of the face masks. In patients with limited mouth opening, our technique may be easier than insertion of the Oesophageal Vent-Laryngeal Mask, as the oesophageal rube can be moved over to the left side of the mouth. Clearly, further assessment and comparison of these techniques in cases of difficult and failed tracheal intubation would be interesting. impedes placement of the laryngeal mask airway and subsequent txachcal intubation through the mask. Sir,—The modified laryngeal mask described by Akhtar [1] reflects a line of enquiry pursued by the inventor of the laryngeal mask airway (LMA) between 1983 and 1987. Figure 1 shows one of the patented designs, which closely resembles Akhtar's modification, but has a communication between the two cuffs, permitting simultaneous inflation from a single inflation port. The device, which was made entirely from silicone, can be seen in the LMA Museum at the Royal Berkshire Hospital, Reading. The reasons for not continuing with this development may be of interest. The addition of an integral oesophageal tube increases the difficulty of insertion, the invasiveness of the procedure and the complexity (and hence the likely price) of the device. Such a development therefore is not likely to be attractive as a general-purpose airway. If it is desired to pass a rube into the oesophagus, this can be done easily after placing a standard LMA using a well-lubricated tracheal rube. The LMA is only moderately inflated (for example 25 ml in a size 4) and the trachcal tube is passed blindly and gently with the head extended. Not only is this easier, FIG. 1. One of the patented designs of the laryngeal mask airway. but there is a further advantage in that the mask serves to shield the glottis from the tube as the latter is passed downwards, guiding it into the upper oesophageal sphincter. A characteristic pressure is felt as the tube encounters and passes through the sphincter, so that it is not difficult to judge the level of tube placement. Sir,—Thank you for the opportunity to reply to the comments made on the Oesophageal Vent-Laryngeal Mask. The device described is only a prototype that requires refinement to allow better conformation to the oropharyngeal anatomy which could make placement no more difficult than the standard laryngeal mask airway …

When Hypotension During Laparoscopic Cholecystectomy Indicates Termination of the Laparoscopy To the Editor

Laparoscopic-assisted surgery has found many applications in the treatment of intraabdominal and gynecologic pathology. Traumatic diaphragmatic rupture is a difficult clinical diagnosis, and diagnostic laparoscopy has been advocated in the management of this condition (1). However, insufflation of c

A simple method for isolating a2 macroglobulin-cytokine complexes

Laparoscopic cholecystectomy is a rela- tively new surgical procedure which is enjoying ever- increasing popularity and presenting new anesthetic challenges. The advantages of shorter hospital stay and more rapid return to normal activities are com- bined with less pain associated with the small limited incisions and less postoperative ileus compared with the traditional open cholecystectomy. The efficacy of laparoscopic appendectomy and hemicolectomy has been recently evaluated. However, there have been no prospective randomized studies to date comparing lap- aroscopic with traditional laparotomy techniques. The physiological effects of prolonged pneumoperitoneum and the longer duration of surgery with the laparoscop- ic techniques are of concern. The application of lapa- roscopic inguinal hernia repair may be limited be- cause, unlike traditional surgical hepair, general anes- thesia is required and concerns have been expressed about the duration of surgery and the possibility of hernia recurrence. Notwithstanding case reports and series describing successful diaphragmatic and hiatus hernia repair using a laparoscopic surgical technique, the frequently encountered complications of cervical surgical emphysema, pneumothorax, and pneumome- diastinum, attributed to passage of insufflating gas through weak points or defects in the diaphragm, must be of major concern. Anesthesiologists must maintain a high index of suspicion for these potential complica- tion and must undertake appropriate monitoring. If there is clinical evidence of a tension pneumothorax, immediate chest tube decompression is indicated. Intraoperative complications of laparoscopic sur- gery are mostly due to traumatic injuries sustained during blind trocar insertion and physiological changes associated with patient positioning and pneumoperito- neum creation. The choice of anesthetic technique for upper abdominal laparoscopic procedures is most fre- quently limited to general anesthesia. Controlled ven- tilation avoids hypercarbia, and an anesthetic tech- nique incorporating antiemetics and nonsteroidal anti- inflammatory agents has reduced postoperative nausea and vomiting following laparoscopic cholecys- tectomy. The use of nitrous oxide during laparoscopic procedures remains controversial. Laparoscopic cholecystectomy is a major advance in the management of patients with symptomatic gall- bladder disease. However, in the present era of cost containment, older and sicker patients may present for this procedure on the day of surgery without adequate preoperative evaluation. Anesthesiologists should thus be prepared to recommend deflation of the pneu- moperitoneum and possibly conversion to an open procedure if hemodynamic, oxygenation, or ventila- tion difficulties arise during the procedure.

We have measured cardiovascular changes associated with insufflation of carbon dioxide and the reverse Trendelenburg position during laparoscopic cholecystectomy, using transoesophageal echocardiography in 13 healthy patients. End-tidal carbon dioxide values increased after insufflation of carbon dioxide, with values significantly (P < 0.05) increased after lateral tilt positioning. Creation of a pneumoperitoneum was associated with increases (P < 0.05) in left ventricular end-systolic wall stress, concomitant with increases (P < 0.01) in peak airway pressure and systemic arterial pressure. In addition, left ventricular end-diastolic area decreased (P < 0.05) after reverse Trendelenburg positioning. Left ventricular ejection fraction was maintained throughout the study.

Transoesophageal echocardiographic assessment of haemodynamic function during laparoscopic cholecystectomy.

Laparoscopic cholecystectomy is a relatively new surgical procedure, enjoying ever-increasing popularity and presenting new anesthetic challenges. The advantages of shorter hospital stay and more rapid return to normal activities are combined with less pain associated with the small limited incisions and less postoperative ileus compared with the traditional open cholecystectomy. Complications are mostly due to traumatic injuries sustained during blind trocar insertion, and physiologic changes associated with patient positioning and pneumoperitoneum creation. The choice of anesthetic technique for laparoscopic cholecystectomy is limited most frequently to general anesthesia. Controlled ventilation avoids hypercarbia, and an anesthetic technique incorporating antiemetics and nonsteroidal antiinflammatory agents has reduced postoperative nausea and vomiting. The use of nitrous oxide and narcotics during laparoscopic cholecystectomy is controversial. Laparoscopic cholecystectomy is a major advance in the management of patients with symptomatic gallbladder disease. However, in the present era of cost containment, older and sicker patients may present for this procedure on the day of surgery without adequate preoperative evaluation. Anesthesiologists thus should be prepared to recommend conversion to an open procedure if hemodynamic, oxygenation, or ventilation difficulties occur during the procedure.

Background:Spinal cord perfusion pressure may be reduced when sodium nitroprusside is used to control proximal aortic hypertension during thoracic aortic clamping. The effect of esmolol infusion on spinal cord perfusion pressure during thoracic aortic clamping is unknown. This study compares spinal cord perfusion pressure following control of proximal hypertension with either sodium nitroprusside or esmolol during thoracic aortic clamping. Methods:The thoracic aorta was cross-clamped for 30 min in 18 dogs anesthetized with halothane. A control group (n = 6) received no treatment of proximal hypertension during cross-clamping. In two other groups, proximal arterial pressure was controlled (100 mmHg) by infusion of either sodium nitroprusside (n = 6) or esmolol (n = 6). Brachial and femoral arterial pressures, spinal cord perfusion pressure, pulmonary artery occlusion, central venous pressures, and cardiac output were monitored. Neurologic assessment was performed 24 h following surgery. Results:Femoral arterial pressure was lower with nitroprusside (14 ± 3 mmHg) compared to esmolol (24 ± 4 mmHg) after 15 min of aortic cross-clamping. Cerebrosplnal fluid pressure Increased during aortic cross-clamping in the sodium nitroprusside group (from 7 ± 5 to 16 ± 6 mmHg) but not in esmolol or control groups. Spinal cord perfusion pressure was lower with nitroprusside at 15 min of aortic cross-clamping (2 ± 4 mmHg) compared to control (15 ± 7 mmHg) and esmolol groups (17 ± 11 mmHg). Esmolol Infusion reduced cardiac output and increased ventricular filling pressures compared to control and nitroprusside groups. Conclusions:Esmolol was associated with greater spinal cord perfusion pressure, but adverse hemodynamic effects, when compared with nitroprusside during thoracic aortic cross-damping. When only surviving dogs (4 control, 5 esmolol, 6 nitroprusside) are considered, the Incidence of neurologic deficit was greater in nitroprusside-treated dogs than in either control or esmolol-treated dogs. No difference in outcome was present when all dogs are considered.

Spinal Cord Perfusion Pressure in Dogs after Control of Proximal Aortic Hypertension during Thoracic Aortic Cross‐clamping with Esmolol or Sodium Nitroprusside

The relative merits of general vs regional anesthesia for patients undergoing major vascular surgery has been the subject of debate over the past decade. Previous studies of regional vs general anesthesia often were deficient in experimental design and, therefore, did not produce definitive answers. Some of these deficiencies related to non-standardized, poorly conducted, and/or described general anesthetic techniques, nonstandardized methods of postoperative analgesia in the general anesthesia groups, and variations in preoperative cardiac status in the study groups. Furthermore, most studies did not conclusively demonstrate a cause and effect relationship between the proposed mechanisms of the beneficial effect of regional anesthesia and outcome. Recent studies, however, have claimed improvements in outcome following regional anesthesia in patients undergoing peripheral vascular procedures. The reported beneficial effects have included amelioration of the neuroendocrine stress response to surgery, improvement in pulmonary function, cardiovascular stability, enhancement of lower limb blood flow, reduction in the incidence of graft thrombosis, and a reduction in the thrombic response to surgery. Skeptics still question whether recent studies have the power to determine whether regional anesthesia decreases the incidence of cardiac and pulmonary complications following major vascular surgery. Furthermore, the issue of whether the beneficial effects of regional anesthesia on the incidence of graft thrombosis and the thrombotic response to surgery relating to intraoperative or postoperative regional anesthesia/analgesia, to regional anesthesia per se, or to the systemic effects of absorbed local anesthetics remains unresolved.

Liquid crystal skin thermometry: an accurate reflection of core temperature?

Neuroendocrine and haemodynamic responses to abdominal aortic cross clamp and release during high-dose opiate-oxygen-isoflurane anaesthesia.

A case of phaeochromocytoma is reported in which perioperative hypertension was controlled with an infusion of esmolol. Transoesophageal echocardiography was used in addition to conventional monitoring to manage i.v. fluid administration and assess perioperative changes in left ventricular function.

Use of transoesophageal echocardiography to manage beta-adrenoceptor block and assess left ventricular function in a patient with phaeochromocytoma.

ow naded rom http:urnals.lw w om /anestia-analgesia by hD M fePH bH 4TIm qVAH xkFJpPk1L/H vM G w qM xG jw O deJPG +b4D lKuA44qu/vw zm c= on 070/2018 Downloadedfromhttp://journals.lww.com/anesthesia-analgesiabyBhDMf5ePHKbH4TTImqenVAHxkFJp/XpPk1L/H3vMGwqMxG9jwOd8eJPG+b4DlKuAX44qu/vwzmc=on07/30/2018 Intraoperative Hypoxemia Complicating Laparoscopic Cholecystectomy in a Patient With Sickle Hemoglobinopathy

Intraoperative hypoxemia complicating laparoscopic cholecystectomy in a patient with sickle hemoglobinopathy.

Royal academy of medicine in Ireland section of biomedical sciences

This review highlights recent advances in our understanding of the pathogenesis of abdominal aortic aneurysm (AAA) formation; preoperative cardiac evaluation strategies for patients undergoing major vascular surgery; large-scale outcome studies, especially following carotid endarterectomy as well as the perioperative management of patients undergoing abdominal aortic reconstruction, peripheral vascular procedures and carotid endarterectomy.

Aortic disease, carotid artery disease, and peripheral arterial disease

We measured cardiac output in 12 patients undergoing elective abdominal vascular surgery at specific times during the procedure with simultaneous thermodilution and transoesophageal pulsed Doppler echocardiographic techniques. No patient had clinical evidence of valvular heart disease before surgery. Five patients had echocardiographic evidence of mitral regurgitation on colour-coded Doppler. Using Bland and Altman analysis to compare the cardiac output measurement by the two techniques, the Doppler method overestimated the cardiac output (bias = 0.86 litre min-1) compared with the thermodilution technique and there were wide limits of agreement between the two techniques (+2.4 to -4.1 litre min-1). However, in the seven patients with no evidence of mitral regurgitation, closer agreement (bias 0.14 litre min-1) and narrower limits (+1.6 to -1.3 litre min-1) were observed. We conclude that, in patients with competent mitral valves, transoesophageal echocardiograph may provide accurate determination of cardiac output.

Transoesophageal pulsed wave Doppler measurement of cardiac output during major vascular surgery: comparison with the thermodilution technique.

The objectives of the review are to highlight the clinical characteristics of the patient population; to assess multivariate risk factor analysis and the invasive/non-invasive techniques available for risk factor identification and management in this high-risk surgical population; to assess the major hemodynamic, metabolic, and regional blood flow changes associated with aortic cross-clamping/unclamping procedures and techniques for their modification or attenuation; and to assess the influence of perioperative anesthetic techniques and management on patient outcome.

The objectives of this study were to assess midazolam and propofol as sedative agents for outpatient gastrointestinal endoscopy, with particular reference to recovery profile, amnesic effects, and haemodynamic state and oxygenation during the procedure. Forty consecutive patients were allocated randomly to two groups. Patients in group I (n = 19) received midazolam 81 (SEM 32) micrograms kg-1; those in group II (n = 21) received propofol 950 (400) micrograms kg-1. Both agents were administered as single injections to similar end-points of sedation. Psychomotor function was assessed using the digit symbol substitution test (DSST). Amnesia was measured with a visual memory test and subjective questionnaire. Patients in group I had a lower DSST score than those in group II (P less than 0.01), indicating a hangover effect from midazolam. Amnesia was similar in the two groups up to the time of removal of the endoscope. More patients in group II remembered removal of the endoscope (P less than 0.001). Oxygen desaturation from baseline was similar in both groups (P less than 0.01). An increase in heart rate and decrease in mean arterial pressure were noted in both groups. Propofol provided more rapid recovery compared with midazolam, but was associated with pain on injection, a short amnesia span, and reduced patient acceptance.

Propofol sedation for outpatient upper gastrointestinal endoscopy: comparison with midazolam.

Fifteenth Sir Peter Freyer Memorial Lecture and Surgical Symposium Proceedings of meeting held 14th & 15th September, 1990 at University College, Galway

Myocardial contractility and ischaemia in the isolated perfused rat heart with propofol and thiopentone

PROLONGED PROPOFOL/N2O ANESTHESIA - HEMODYNAMIC, NEUROENDOCRINE AND RECOVERY FEATURES

TRANSCONJUNCTIVAL OXYGEN MONITORING DURING EXPERIMENTAL CHANGES IN OXYGEN DELIVERY IN DOGS

COMPARISON OF THE EFFECTS OF PROPOFOL AND THIOPENTAL ON MYOCARDIAL CONTRACTILITY AND ISCHEMIA, USING THE ISOLATED PERFUSED RAT HEART.

Royal academy of medicine in ireland section of biological sciences

The influence of collateral vascularisation on haemodynamic performance during abdominal aortic surgery

The brain is highly vulnerable to damage from even a brief imbalance of oxygen delivery and demand. Most cerebral hypoxic damage is reversible, but infarction and permanent brain damage may result.

The effect of local anaesthetics on epine-phrine absorption following rectal mucosal infiltration

Review Article Anaesthesia for ab- dominal aortic surgery - a review (Part II)

Interscalene brachial plexus blockade with lidocaine in chronic renal failure - a pharmacokinetic study

Radionuclide ventriculography and two dimensional echocardiography as predictors of left ventricular performance during aortic vascular surgery.

Royal Academy of Medicine in Ireland Section of Biological Sciences Proceedings of Summer Meeting held on Tuesday and Wednesday, 22nd and 23rd June, 1987

A 52‐year‐old apparently healthy, normotensive woman who presented for elective cholecystectomy experienced intra‐operative hypertension and tachycardia, which were controlled by propranolol. Oesophageal temperature increased, there was a metabolic and respiratory acidosis with hypoxaemia, and malignant hyperthermia was diagnosed. Severe cardiogenic pulmonary oedema ensued, and was treated with intravenous glyceryl trinitrate. Ventricular fibrillation caused cardiac arrest, and this was treated successfully. Postoperatively a phaeochromocytoma was discovered, and removed at a subsequent operation. The case illustrates the similarities in presentation of malignant hyperthermia and phaeochromocytoma, and the possibility that misdiagnosis may exacerbate the crisis.

Phaeochromocytoma—a presentation mimicking malignant hyperthermia

Royal Academy of Medicine in Ireland Section of Anaesthesia Proceedings of meeting held on Thursday, 17th December, 1987

Visual evoked potentials were recorded in 10 patients undergoing transurethral prostatectomy under subarachnoid anaesthesia. They were compared with those obtained in a control group (n = 5) having other operative procedures also under spinal anaesthesia. Serum concentrations of glycine, ammonia, glucose and sodium, and osmolality, were determined during the perioperative period. The prostatectomy group demonstrated a significant prolongation of visual evoked potential P2 latency in the postoperative period when compared with preoperative values (P less than 0.01). No significant changes in latency occurred in the control group when measured at similar times. The prostatectomy group demonstrated a significant increase in serum glycine concentration (P less than 0.01); changes in serum ammonia and sodium concentrations and osmolality were not significant. There was no correlation between visual evoked potential latency and changes in serum glycine concentration. Changes in visual evoked potential during transurethral prostatectomy may be the result of an accumulation of a metabolite of glycine.

Visual evoked potentials and changes in serum glycine concentration during transurethral resection of the prostate.

Intraocular pressure -physiology and implications for anaesthetic management

Aspiration pneumonia and coma — an unusual presentation of dystrophica myotonia

Osteogenesis Imperfecta: Anesthetic Management of a Patient for Cesarean Section

Ventricular arrhythmia may follow the infiltration of dilute, epinephrine-containing solutions to achieve hemostasis during surgery. The objective of this study was to determine the cardiovascular and metabolic changes associated with the infiltration of 1.5μg/kg epinephrine 1 : 200,000 in 0.5% lidocaine into the cervix of patients having a cervical cone biopsy under epidural anesthesia. These observations were compared with a control group who were infiltrated with 0.5% plain lidocaine under similar epidural anesthesia during cone biopsy. In the epinephrine-treated group, marked heart rate, rhythm, and systolic/diastolic blood pressure changes from baseline values were observed as well as significant glycogenolysis, lactic acidosis, and hypokalemia. Based on these observations, the total dose of injected epinephrine should be less than 1 μg/kg; the solution should be diluted to 1 : 400,000 concentration, and the injection, after careful aspiration, should be performed over at least five minutes into the less vascular anterior and posterior cervix sites.

Cardiovascular and Metabolic Effects of Cervical Epinephrine Infiltration

Ventricular arrhythmias and adrenaline infiltration during gynaecological surgery.

Osteogenesis imperfecta: anesthetic management of a patient for cesarean section: a case report.

Single Injection Spinal Anaesthesia with Amethocaine and Morphine for Transurethral Prostatectomy

The intrathecal administration of amethocaine plus morphine as an anaesthetic technique for providing surgical anaesthesia and postoperative analgesia was evaluated in 24 patients undergoing transurethral resection of the prostate. The efficacy of the technique was compared with that observed following spinal anaesthesia with amethocaine alone. Twelve patients (group I) received spinal anaesthesia with amethocaine 12-14 mg and a further 12 patients (group II) received spinal anaesthesia with amethocaine 12-14 mg plus morphine 1 mg. In group II the addition of morphine 1 mg to the amethocaine produced excellent surgical anaesthesia and postoperative analgesia and these patients had significantly less postoperative pain than the patients who received amethocaine alone. There was a high frequency of side-effects associated with intrathecal morphine in group II, for example, subtle respiratory depression, nausea, vomiting and pruritus.

Single injection spinal anaesthesia with amethocaine and morphine for transurethral prostatectomy.

The effect of metocurine and metocurine-pancuronium combination on intraocular pressure

A Jehovah's Witness with disabling rheumatoid arthritis, and a normocytic, normochromic anaemia, underwent on separate occasions a staged total hip and a shoulder replacement. Controlled hypotension with therapeutic doses of sodium nitroprusside was used to minimize blood loss, and haemodiluoon with crystalloid fluids was used to maintain normal cardiac output

Controlled hypotension to minimize blood loss of anaemic Jehovah's witness patient undergoing total hip and shoulder replacement.

Abstracts of papers presented at the annual meeting, canadian anaesthetists’ society, june 13-17, 1981

The effect of intravenous diazepam on rise of intraocular pressure following succinylcholine

s of Papers Presented at the Annual Meeting SESSION 1 A: PUSHING AND PULLING: THE PROCESS OF MIGRATION Mexican Immigrants to the United States: Evidence on Selection and Economic Performance from 1910-1990 This study analyzes changes in education and wage performance of Mexican immigrants from 1910 to 1990 and the factors that have contributed to the selection of these immigrants from their population of origin. The study uses data from the Immigration Commission Report of the Commissioner General of Immigration from 1910 to 1930 and from the Mexican and U.S. censuses for 1910 to 1990. Mexican immigrants are found to be either more educated or as educated as their population of origin. The education advantage of immigrants has decreased over time with the exception of 1960 to 1970. Earnings of Mexican immigrants relative to native whites have declined over time. Lower costs of transportation, the growth of Mexican enclaves in the United States, and the Bracero program were associated with decreases in the skill of immigrants. The introduction of the literacy test in the United States in 1917 and the Mexican Revolution (1910-1920) were associated with increases in the skill level of immigrants. ZADIA FELICIANO, Queens College, CUNY Patterns of Import Trade and Immigration in the Late Nineteenth-Century United States The connection between immigrants and international trade in goods is explored in this paper using a modified gravity equation. We determine that during the period 1870 to 1910 the stock of immigrants living in the United States had a positive effect on imports from their respective home countries. Commodity imports are considered for 56 individual commodities from 17 countries. We use a measure of relative income similarity to determine if a Linder-type relationship exists, where a country tends to trade with other countries that have similar tastes as indexed by per capita income. Migrant stock and the relative income coefficients imply that imports are greater from those countries that have similar per capita incomes and have a stock of immigrants living in the United States. The standard gravity equation variables—distance and population—exhibit the expected relationship with imports. JAMES A. DUNLEVY AND WILLIAM K. HUTCHINSON, Miami University To Part or Not to Part: Emigration and Inheritance Institutions in Nineteenth-Century Hesse-Cassel This paper examines whether the principle inheritance institutions of western German principalities, specifically partible inheritance and primogeniture, influenced the propensity to emigrate. In an analysis of emigration from the principality of Hesse-Cassel in the 1840s and 1850s, I suggest that such traditions have an influence on the resulting economic structure of a village. Inheritance tradition primarily affects occupational choice and personal wealth and thus produces distinct economic outcomes for peasants. Given these outcomes, the attraction to the migration option varies across village type. Although families and individuals found important reasons to leave under both systems, it is the primo-

Fungi isolated front stored and waste foodstuffs in Papua New Guinea.

Preliminary investigation of possible contribution of natural hepatotoxins in indigenous foodstuffs to the aetiology of acute and chronic liver disease in Papua New Guinea.

THE PREVENTION AND MANAGEMENT OF PLACENTAL SITE HÆMORRHAGE IN THE HOME

How to develop an effective compliance program An effective corporate compliance program is a physician group's best defense against illegal business conduct. Design your practice's program with your resources and needs in mind.

Doing the right thing right. How to develop an effective compliance program.

Goitre incidence in workers and their families on the East/West highway (British section).

The purpose of this study was: (a) to describe the self-reported use of the methods and products of research by medical-surgical nurses, and (b) to identify attitudes toward the use of research-based knowledge in clinical nursing practice. Two hundred and twelve registered nurses completed the Research Utilization Questionnaire. Survey results indicated that it was difficult for respondents to change practice based on research. Nurses were willing to participate in research if investigations were relevant to practice. Articles from nursing research journals were ranked low by the respondents as sources of knowledge, while information gained from individual patients was ranked high.

Medsurg nursing : official journal of the Academy of Medical-Surgical Nurses

Medical-surgical nurses' utilization of research methods and products.

Has the physical examination become obsolete? The usefulness of abdominal computed tomography ordered from the emergency room

Radiolytic decomposition of chlorinated hydrocarbons and other toxic compounds has been experimentally measured using ionizing radiation produced by electron accelerator and nuclear isotope sources. This process has been experimentally demonstrated at Lawrence Livermore National Laboratory's (LLNL's) Site 300, a Superfund site. A portable, commercially available electron accelerator was set up at Site 300 where vacuum extraction wells were removing trichloroethylene (TCE) from a spill into unsaturated soil. The accelerator was retrofitted into the existing vacuum extraction system. The extracted vapor containing TCE passed through the accelerator beam for treatment. This paper will review the technical aspects of that process.

Radiolytic remediation of TCE in soil at a Superfund site, using an electron accelerator

Type basis risk and the potential for woolgrowers to effectively hedge using the Sydney Futures Exchange 22 micron wool futures contract

[Excerpt] “Absent an agreement among the parties to the contrary, business entity fiduciary duties arise automatically under state common law and applicable statutory law whenever one person entrusts the management of his or her business to another person and the other person agrees to accept this entrustment. The two principal fiduciary duties are the duty of care and the duty of loyalty. The duty of care requires that business managers carry out their management responsibilities non-negligently. The duty of loyalty requires that business managers avoid conflicts of interest with the entity that they have agreed to manage. However, the common law of Delaware implies that managers are subject not only to a general duty of loyalty but also to seven separate subsidiary fiduciary duties implicit in that duty. As discussed below, these subsidiary duties probably apply also under the New Hampshire LLC Act.”

Handling Fiduciary Issues in Limited Liability Company Formations Under the New Hampshire Limited Liability Company Act—A Practical Introduction

PLUNGING WATER JETS: EVALUATING AN INNOVATIVE HIGH-CURRENT DIVERSIONARY BOOM

ABSTRACT Dispersants have been a controversial oil spill response technique since their introduction during the Torrey Canyon oil spill off the coast of the United Kingdom in 1967. Despite reductions in the toxicity of dispersants and improvements in their application since then, dispersants have not been used extensively in the United States because of logistical difficulties, unfavorable weather conditions, and a lack of demonstrated effectiveness during actual spill conditions. In addition, there is a widely held perception in the United States that dispersant use has been limited by complex authorization procedures. This paper reviews the dispersant policies of several European nations and Canada and compares them with those of the United States. Recent developments in U. S. dispersant policy are outlined, particularly those designed to expedite decision making. The paper concludes by examining some recent U. S. oil spills in which dispersant use was considered.

ABSTRACT According to the authorization-of-use procedures outlined in the National Contingency Plan (NCP), a state with jurisdiction over navigable waters polluted by an oil spill must concur with the decision to apply dispersants or other chemical oil spill control agents. To be effective, a dispersant must be applied quickly, but reaching consensus among the necessary parties can be slow unless all the participants are well prepared at the outset. Ideally, consideration of dispersant use should take place prior to an emergency in order to reach a timely decision. Several states and Regional Response Teams have active programs that are addressing dispersant use planning and technical and environmental considerations. In several states where the use of dispersants is an emerging issue, there appears to be a willingness to consider their use on a case-by-case basis and a genuine interest in learning more about their effectiveness and toxicity.

DECISION-MAKING ON THE USE OF DISPERSANTS: THE ROLE OF THE STATES

Professor Ruttan is a distinguished agricultural economist who has drawn on a lifetime of both academic and practical experience in setting down a personal view of agricultural research policy. His book is loosely structured he says it consists of a series of essays and covers a range of issues. For readers uninterested in the philosophical aspects, the most welcome section will be the descriptions of national agricultural research organizations (in the United Kingdom, Germany, the United States, Japan, India, Brazil and Malaya) and of the International Agricultural Research Institutes. Those concerned with national research policy will find valuable background though of course no dramatically new concepts emerge. Technically, the weakest parts are the social science model of 'induced innovation' and the presentation (yet again!) of the economic analysis of research benefits. The treatment here is really too broad-brush and some of the supporting material is flawed. It would be churlish, however, to end on a carping note. Agricultural research policy is a big, sprawling and untidy subject. Professor Ruttan approaches it with dignity and calm a civilized book, worth reading. W. S. Wise

Food, Nutrition and Climate. Eds K. L. Blaxter and L. Fowden. Barking, England: Applied Science Publishers (Elsevier) (1982), pp. 420, £36.00.

Abstract : this report presents the results of a study to determine general requirements for the development of core avionics equipment for common usage by Naval aircraft. The study addresses the core avionics architecture and the relationship between existing core avionics equipment and advanced subsystems under development. The report provides specific recommendations regarding: procurement policies; the application of standards to electronic interfaces; and the development of the basic architectural components.

Investigation of Functional Commonality Avionics Systems in Naval Aircraft

ABSTRACT The Oil Spill Prevention Program of the Environmental Protection Agency is discussed as it has evolved from the implementing legislation: section 311(j)(l)(C) of the Federal Water Pollutio...

Theoretical Consideration of the Perforation Pattern in a Screen Pipe

The contribution of all who participated in the many workshops was much appreciated. LE EXECUTIVE SUMMARY This master plan study was undertaken at an important point in the history of the University of Massachusetts Amherst Libraries, which is on the edge of significant change moving into a new era serving scholars, researchers and learners in the 21st Century. Over the last decade the Library has been a leader in many initiatives: increasing development of digital resources; collaborating with the Five Colleges Consortium, which was one of the first in the country to develop a shared book depository; developing a highly successful Learning Commons that engages partners in providing a broad range of services and settings for learners; providing services through partners welcomed into library facilities, such the peer learning activities of the Learning Resources Center; and converting space to nontraditional library uses that are compatible with the mission of the library with facilities like the Teaching Commons. The visioning and conceptual development that was done for this study sought to build on the success of these initiatives, improve library space, and seek new types of blended facilities with partners that could enhance what the library offers the campus community. 1 The Libraries master plan is aligned with the University's strategic plan to become a major research institution through growth of new areas for research and academic development, and to grow its student body. Whereas the previous decade focused a great deal on supporting undergraduate learning and research, for the next decade the Library plans to improve support for scholars, researchers and graduate students, combined with expanded services for undergraduates. A primary component of this vision is the proposed Research Commons, which could become a model for the comprehensiveness of its co-located services. The Du Bois tower is in need of major renovation, upgrading to enable new types of activities, as well as to support traditional study and scholarship more effectively. Many options were studied for conversion of spaces to new activities or functions compatible with the library's mission, and these are outlined in the sections that follow. Du Bois tower was the primary challenge: how to find ways to exploit the building's potential yet mitigate its challenges. • Conduct a condition assessment of the Du Bois library and study deferred maintenance and regulatory requirements affecting future uses • Examine existing uses of library facilities and identify underutilized spaces. Determine what …

Science Education Information Reports, Research Review Series - Science Paper 5. A Summary of Research in Science Education for the Years 1963-64, Elementary School Level.

Because the biological element in most of the current elementary school science projects is just beginning to develop, it is difficult to do more than briefly identify and describe the several groups. Like most of the secondary school projects, these elementary programs are generally financed by the NSF. Unlike the secondary projects, however, the elementary groups do not, in general, want to produce separate programs in biology, chemistry, physics, and the earth sciences but, instead, aim to produce a sequence of activities that will familiarize the child with science per se. Some projects are producing an articulated sequence of topics, others interesting investigations for children that pedagogs can use at the level they see fit. None of the emerging biological programs is understandable apart from the trend in elementary school science itself. Some projects aim to introduce the child to certain intellectual "inventions" found useful by man in his history for interpreting natural phenomena (e.g., SCIS, MINNEMAST) while others do the same for man's useful "processes" of investigating the world (e.g., AAAS). Still others are developing investigations into biological phenomena that are more open-ended and that include both of the above elements (e.g., ESS). Brief descriptions are given below of selected projects.

Addendum to the proceedings on Object-oriented programming systems, languages, and applications

Smalltalk under the umbrella: the Travelers' Smalltalk experience

Water, Earth, and Fire: Land Use in the New Jersey Pine Barrens. By Jonathan Berger and John W. Sinton. (Baltimore: Johns Hopkins University Press, 1985

Abstract : The transfer of arms between countries plays a significant role in the political, economic, and military affairs of the entire world, and is, consequently, subject to constant criticism and review from many quarters. Because of the complexity of the relationships in, and the diversity of opinion about arms transfer, a concise policy which will satisfy everyone is virtually impossible to devise. This thesis is an attempt to bring together all of the significant variables concerning the arms transfer system, with particular emphasis on the welfare of United States national interests. While this model will not be able to produce policies which will keep all interested parties satisfied, it should depict the consequences of arms transfer decisions in terms of the major variables. The model will also facilitate the examination of policies such as the dollar ceiling on sales in terms of impact on the strategic position and economy of the United States. (Author)

A Dynamic Policy Model of the United States Arms Transfer Process.

This 1864 lithograph shows Dr. Solomon Andrews airship, The Aereon, as it cruised on a famous trip of 30 miles in 14 and half minutes.

rebuilt in Restoration Ireland. With a geographical range embracing Ireland, Rome and theWest Indies, the lack of maps in this publication is a serious lacuna. The volume exemplifies the increasing engagement of scholars of various linguistic backgrounds with the Irish diaspora in the early modern era— a welcome development. However, in this book the quality of English is at times poor, and the text suffers as a result. A more rigorous language check is required. Based on exhaustive archival research, and comprehensive use of secondary literature, the volume delineates the limited contribution of two Irish colleges in Rome to priestly supply in mid seventeenth century Ireland, and offers a similar analysis for the Irish in the West Indies. It thus marks a significant contribution to the study of the Irish Catholic community, and of pastoral provision in an English Atlantic setting, in the seventeenth century.

Irish Jesuit annual letters, 1604–1674. Edited by Vera Moynes. 2 volumes. Pp xxvii, 1013. Dublin: Irish Manuscripts Commission. 2019. €80.

ABSTRACT:St. Mary’s University College, 28 Merrion Square, Dublin, was the first establishment in Ireland to provide for the university education of Catholic women, and its records testify to a revolution in female education. Originally generated to support its foundation and function, these records now provide information on the administration, actions, and achievements of this institution established in the 19th century by the Dominican Sisters of Eccles Street, Dublin. Both the University Education (Ireland) Act, 1879 and the Irish Universities Act, 1908 provide the fundamental context of their creation and original function. Although not all items are afforded consideration, this survey provides a sense of the variety and extent of the records preserved, discusses the motivations that favoured their preservation, and asserts that the records demonstrate an archival sensibility ahead of written norms and obligations. The records that now survive provide authoritative evidence of the manner and means of the foundation of St. Mary’s and of its purpose, character, context, and demise. RÉSUMÉ:St. Mary’s University College, 28 Merrion Square, Dublin, a été le premier établissement en Irlande à fournir une éducation universitaire aux femmes catholiques et ses documents témoignent d’une révolution en matière d’éducation des femmes. Générés d’abord afin d’appuyer son établissement et ses fonctions, ces documents fournissent maintenant de l’information sur l’administration, les actions et les accomplissements de cette institution mise sur pied au XIXe siècle par les sœurs dominicaines d’Eccles Street à Dublin. La University Education (Ireland) Act, 1879 et la Irish Universities Act, 1908 offrent toutes deux le contexte fondamental de leur création et de leur fonction initiale. Bien que chaque item ne soit pas abordé, ce recensement offre une idée de la variété et de l’étendue des dossiers conservés, élabore sur les motivations derrière leur conservation et avance que les dossiers témoignent d’une sensibilité archivistique qui dépasse les obligations et les normes écrites. Les documents qui sont survécu fournissent un témoignage fiable de la façon dont St. Mary’s a été fondée, de sa mission, ses caractéristiques, son contexte et sa disparition.

The Written Memory of St. Mary’s University College, Dublin (1893–1912): The Pioneer College for the Higher Education of Catholic Women in Ireland

ably a forerunner to the more familiar stifling period of Catholic action in mid-twentieth century Ireland. Chapters on the first decades of the twentieth century, through war and revolution, portray an organisation holding ground in the middle of upheaval. Doyle forcefully argues that the movement emerged as a real state-building force in the first decade of the century, and that real societal change was happening at a mundane level. This, he states with justification, has been overlooked in favour of the more eye-catching political and military developments of the period. Wider political events certainly impacted upon the movement, yet that is not Doyle’s only concern here. Tensions within international co-operative alliances are shown to have had an impact upon the Irish situation, specifically between the consumer-focused Co-operative Wholesale Society, and the producer-centred I.A.O.S. Doyle suggests what began as a ‘philosophical impasse’ grew into an ‘irresolvable economic conflict’. The scope of the study is wide, from the second half of the nineteenth century, through to an independent Free State. The author expertly weaves the bread and butter issues with those of high politics and constitutional questions, both of which had a profound impact upon the fortunes on the movement at various points. Indeed, there is much within this work which helps us to understand the glue which held Irish society together during those turbulent decades.

Seán Murray: Marxist-Leninist and Irish socialist republicanism. By Seán Byers. Pp xii + 228. Dublin: Irish Academic Press. 2015. €24.99.

Anguish Language approaches language as a core aspect of the present social crisis. The project engages in solidarity with forms of self-publishing, poetry, criticism, experimental writing and declamation that have arisen in the wake of the 2007-8 financial crisis, considering language among and through the social struggles responding to its consequences.

Salvador Ryan and Clodagh Tait (eds.), Religion and Politics in Urban Ireland, c. 1500–c. 1750. Essays in Honour of Colm Lennon. Dublin: Four Courts, 2016. 280pp. €55 hbk.

‘Better to die by the sword than to die of starvation’: Popular Resistance to Food
 Exports in Ireland and Scotland, 1846–7

The court of admiralty of Ireland, 1575–1893 . By Kevin Costello. Pp xvii, 294. Dublin: Four Courts Press. 2011. €55.

Niamh Puirseil. The Irish Labour Party, 1922–73 . Dublin: University College Dublin Press, 2007. Pp. 428. $54.95 (paper).

A    on Monday,  June , throngs of people passed through the streets of Limerick.Their first port of call was a few miles away, at Plassey, where laborers on the Shannon Navigation Works were demanding a pay rise to enable them “to meet the state of the markets.”1 Manager William Owen was surrounded by men clamoring for work but insisting that they would not accept less than the s. d. a day sought by those already employed. Owen refused and the men departed.2 By  , when it marshalled on the city quays, the crowd had swollen to two thousand, having been reinforced by Plassey workers and others. At Baal’s Bridge, within sight of the police barracks, carts and kishes were seized.These belonged to “forestallers,” dealers accused of charging eight pence per stone for potatoes—three times the usual price, and two-thirds of a laborer’s daily pay. Depositing the potatoes on the quays, members of the crowd dumped the containers in the river. Proceeding next to the house of the mayor, the people waited to place their complaints before him. In the mayor’s absence lesser officials assured the protestors that

"Compelled to their bad acts by hunger": Three Irish Urban Crowds, 1817–45

I de den nya laroplanen for gymnasieskolan GY11 blir historieamnet dels gymnasiegemensamt, det vill saga obligatoriskt, och dels delas det in i tva olika kurser. 1a1 for de yrkesforberedande programmen och 1b for de studieforberedande programmen. Syftet for denna undersokning ar att se vilka skillnader som finns mellan olika laromedel for de tva olika inledande gymnasiekurserna i historia. Speciellt fokus laggs vid att jamfora de olika bockerna inom samma forlag. En textanalys gors av hur de hanterar epokbegreppet och tydliggor epokindelningen, hur de hanterar kallkritik och hur de presenterar den franska revolutionen. Dessa delar har valts for att de av olika skal kan tankas ge en representativ bild for hur larobockerna skiljer sig at. De olika laromedlen skiljer sig pa ett flertal punkter. De kanske viktigaste skillnaderna ligger i faktaanalysen och mangden information som de erbjuder, dar texterna for 1b-kursen gar djupare i sin analys och ger mer detaljerade beskrivningar av det som presenteras.

I de den nya laroplanen for gymnasieskolan GY11 blir historieamnet dels gymnasiegemensamt, det vill saga obligatoriskt, och dels delas det in i tva olika kurser. 1a1 for de yrkesforberedande progra ...

Historia för alla? Historieläromedel för gymnasieskolans yrkes- och studieförberedande program

Att forbattra sina dryckesvanor : om olika monster for forandring och om vad varden betyder

Att förbättra sina alkoholvanor: Om olika mönster för förändring och om vad vården betyder

Two of the main impediments to learning complex tasks are that relationships between different stimuli, including rewards, can be uncertain and context-dependent. Reinforcement learning (RL) provides a framework for learning, by predicting total future reward directly (model-free RL), or via predictions of future states (model-based RL). Within this framework, "successor representation" (SR) predicts total future occupancy of all states. A recent theoretical proposal suggests that the hippocampus encodes the SR in order to facilitate prediction of future reward. However, this proposal does not take into account how learning should adapt under uncertainty and switches of context. Here, we introduce a theory of learning SRs using prediction errors which includes optimally balancing uncertainty in new observations versus existing knowledge. We then generalize that approach to a multicontext setting, allowing the model to learn and maintain multiple task-specific SRs and infer which one to use at any moment based on the accuracy of its predictions. Thus, the context used for predictions can be determined by both the contents of the states themselves and the distribution of transitions between them. This probabilistic SR model captures animal behavior in tasks which require contextual memory and generalization, and unifies previous SR theory with hippocampal-dependent contextual decision-making. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A probabilistic successor representation for context-dependent learning.

By collaborating with others, humans can pool their limited knowledge, skills, and resources to achieve goals that outstrip the abilities of any one person. What cognitive capacities make human collaboration possible? Here, we propose that collaboration is grounded in an intuitive understanding of how others think and of what they can do-in other words, of their mental states and competence. We present a belief-desire-competence framework that formalizes this proposal by extending existing models of commonsense psychological reasoning. Our framework predicts that agents recursively reason how much effort they and their partner will allocate to a task, based on the rewards at stake and on their own and their collaborator's competence. Across three experiments (N = 249), we show that the belief-desire-competence framework captures human judgments in a variety of contexts that are critical to collaboration, including predicting whether a joint activity will succeed (Experiment 1), selecting incentives for collaborators (Experiment 2), and choosing which individuals to recruit for a collaborative task (Experiment 3). Our work provides a theoretical framework for understanding how commonsense psychological reasoning contributes to collaborative achievements. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Collaborative decision making is grounded in representations of other people's competence and effort.

To behave adaptively, animals must learn to predict future reward, or value. To do this, animals are thought to learn reward predictions using reinforcement learning. However, in contrast to classical models, animals must learn to estimate value using only incomplete state information. Previous work suggests that animals estimate value in partially observable tasks by first forming “beliefs”—optimal Bayesian estimates of the hidden states in the task. Although this is one way to solve the problem of partial observability, it is not the only way, nor is it the most computationally scalable solution in complex, real-world environments. Here we show that a recurrent neural network (RNN) can learn to estimate value directly from observations, generating reward prediction errors that resemble those observed experimentally, without any explicit objective of estimating beliefs. We integrate statistical, functional, and dynamical systems perspectives on beliefs to show that the RNN’s learned representation encodes belief information, but only when the RNN’s capacity is sufficiently large. These results illustrate how animals can estimate value in tasks without explicitly estimating beliefs, yielding a representation useful for systems with limited capacity. Author Summary Natural environments are full of uncertainty. For example, just because my fridge had food in it yesterday does not mean it will have food today. Despite such uncertainty, animals can estimate which states and actions are the most valuable. Previous work suggests that animals estimate value using a brain area called the basal ganglia, using a process resembling a reinforcement learning algorithm called TD learning. However, traditional reinforcement learning algorithms cannot accurately estimate value in environments with state uncertainty (e.g., when my fridge’s contents are unknown). One way around this problem is if agents form “beliefs,” a probabilistic estimate of how likely each state is, given any observations so far. However, estimating beliefs is a demanding process that may not be possible for animals in more complex environments. Here we show that an artificial recurrent neural network (RNN) trained with TD learning can estimate value from observations, without explicitly estimating beliefs. The trained RNN’s error signals resembled the neural activity of dopamine neurons measured during the same task. Importantly, the RNN’s activity resembled beliefs, but only when the RNN had enough capacity. This work illustrates how animals could estimate value in uncertain environments without needing to first form beliefs, which may be useful in environments where computing the true beliefs is too costly.

Emergence of belief-like representations through reinforcement learning

Value-based decisions are often guided by past experience. If a choice led to a good outcome, we are more likely to repeat it. This basic idea is well-captured by reinforcement-learning models. However, open questions remain about how we assign value to options we did not choose and which we therefore never had the chance to learn about directly. One solution to this problem is proposed by policy gradient reinforcement-learning models; these do not require direct learning of value, instead optimizing choices according to a behavioral policy. For example, a logistic policy predicts that if a chosen option was rewarded, the unchosen option would be deemed less desirable. Here, we test the relevance of these models to human behavior and explore the role of memory in this phenomenon. We hypothesize that a policy may emerge from an associative memory trace formed during deliberation between choice options. In a preregistered study (n = 315) we show that people tend to invert the value of unchosen options relative to the outcome of chosen options, a phenomenon we term inverse decision bias. The inverse decision bias is correlated with memory for the association between choice options; moreover, it is reduced when memory formation is experimentally interfered with. Finally, we present a new memory-based policy gradient model that predicts both the inverse decision bias and its dependence on memory. Our findings point to a significant role of associative memory in valuation of unchosen options and introduce a new perspective on the interaction between decision-making, memory, and counterfactual reasoning. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Over the last few decades, psychologists have developed precise quantitative models of human recall performance in visual working memory (VWM) tasks. However, these models are tailored to a particular class of artificial stimulus displays and simple feature reports from participants (e.g., the color or orientation of a simple object). Our work has two aims. The first is to build models that explain people’s memory errors in continuous report tasks with natural images. Here, we use image generation algorithms to generate continuously varying response alternatives that differ from the stimulus image in natural and complex ways, in order to capture the richness of people’s stored representations. The second aim is to determine whether models that do a good job of explaining memory errors with natural images also explain errors in the more heavily studied domain of artificial displays with simple items. We find that: (i) features taken from state-of-the-art deep encoders explain coarse-grained and some fine-grained aspects of trial-by-trial difficulty in natural images, while several reasonable baselines do not; and (ii) deep visual encoders could reproduce set-size effects but overall offered a poorer explanation of human data in the artificial domain. Together, our results suggest that people may rely on distinct cognitive systems or brain areas in artificial versus natural task domains. Moving forward, our approach offers a scalable way to build a more generalized understanding of VWM representations by combining recent advances in both AI and cognitive modeling.

Exploration is essential in reinforcement learning, particularly in environments where external rewards are sparse. Here we focus on exploration with intrinsic rewards, where the agent transiently augments the external rewards with self-generated intrinsic rewards. Although the study of intrinsic rewards has a long history, existing methods focus on composing the intrinsic reward based on measures of future prospects of states, ignoring the information contained in the retrospective structure of transition sequences. Here we argue that the agent can utilise retrospective information to generate explorative behaviour with structure-awareness, facilitating efficient exploration based on global instead of local information. We propose Successor-Predecessor Intrinsic Exploration (SPIE), an exploration algorithm based on a novel intrinsic reward combining prospective and retrospective information. We show that SPIE yields more efficient and ethologically plausible exploratory behaviour in environments with sparse rewards and bottleneck states than competing methods. We also implement SPIE in deep reinforcement learning agents, and show that the resulting agent achieves stronger empirical performance than existing methods on sparse-reward Atari games.

Produced and Counterfactual Effort Contribute to Responsibility Attributions in Collaborative Tasks

Correlation does not imply causation, but this does not necessarily stop people from drawing causal inferences from correlational statements. We show that people do in fact infer causality from statements of association, under minimal conditions. In Study 1, participants interpreted statements of the form “X is associated with Y” to imply that Y causes X. In Studies 2 and 3, participants interpreted statements of the form “X is associated with an increased risk of Y” to imply that X causes Y. Thus, even the most orthodox correlational language can give rise to causal inferences.

Teaching enables humans to impart vast stores of culturally specific knowledge and skills. However, little is known about the neural computations that guide teachers' decisions about what information to communicate. Participants (N = 28) played the role of teachers while being scanned using fMRI; their task was to select examples that would teach learners how to answer abstract multiple-choice questions. Participants' examples were best described by a model that selects evidence that maximizes the learner's belief in the correct answer. Consistent with this idea, participants' predictions about how well learners would do closely tracked the performance of an independent sample of learners (N = 140) who were tested on the examples they had provided. In addition, regions that play specialized roles in processing social information, namely the bilateral temporoparietal junction and middle and dorsal medial prefrontal cortex, tracked learners' posterior belief in the correct answer. Our results shed light on the computational and neural architectures that support our extraordinary abilities as teachers.

Teachers recruit mentalizing regions to represent learners' beliefs.

People make fast and reasonable predictions about the physical behavior of everyday objects. To do so, people may use principled mental shortcuts, such as object simplification, similar to models developed by engineers for real-time physical simulations. We hypothesize that people use simplified object approximations for tracking and action (the body representation), as opposed to fine-grained forms for visual recognition (the shape representation). We used three classic psychophysical tasks (causality perception, time-to-collision, and change detection) in novel settings that dissociate body and shape. People's behavior across tasks indicates that they rely on coarse bodies for physical reasoning, which lies between convex hulls and fine-grained shapes. Our empirical and computational findings shed light on basic representations people use to understand everyday dynamics, and how these representations differ from those used for recognition. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

An approximate representation of objects underlies physical reasoning.

The different strategies that animals use for predicting reward are often classified as model-based or model-free reinforcement learning (RL) algorithms. Model-based RL involves explicit simulation the future to make decisions while model-free strategies rely on learning associations between stimuli and predicted reward by trial and error. An alternative, intermediate strategy for RL is based on the “successor representation” (SR), an encoding of environmental states in terms of predicted future states. A recent theoretical proposal suggests that the hippocampus encodes the SR in order to facilitate prediction of future reward. However, this proposal does not take into account how learning should adapt under uncertainty and switches of context. Here, we introduce a theory of learning SRs using prediction errors which includes optimally balancing uncertainty in new observations versus existing knowledge. We then generalise that approach to a multi-context setting, allowing the model to learn and maintain multiple task-specific SRs and infer which one to use at any moment based on the accuracy of its predictions. Thus, the context used for predictions can be determined by both the contents of the states themselves and the distribution of transitions between them. This probabilistic SR model captures animal behaviour in tasks which require contextual memory and generalisation, and unifies previous SR theory with hippocampal-dependent contextual decision making.

A probabilistic successor representation for context-dependent prediction

The matching law describes the tendency of agents to match the ratio of choices allocated to the ratio of rewards received when choosing among multiple options (Herrnstein, 1961). Perfect matching, however, is infrequently observed. Instead, agents tend to undermatch or bias choices toward the poorer option. Overmatching, or the tendency to bias choices toward the richer option, is rarely observed. Despite the ubiquity of undermatching, it has received an inadequate normative justification. Here, we assume agents not only seek to maximize reward, but also seek to minimize cognitive cost, which we formalize as policy complexity (the mutual information between actions and states of the environment). Policy complexity measures the extent to which the policy of an agent is state dependent. Our theory states that capacity-constrained agents (i.e., agents that must compress their policies to reduce complexity) can only undermatch or perfectly match, but not overmatch, consistent with the empirical evidence. Moreover, using mouse behavioral data (male), we validate a novel prediction about which task conditions exaggerate undermatching. Finally, in patients with Parkinson's disease (male and female), we argue that a reduction in undermatching with higher dopamine levels is consistent with an increased policy complexity. SIGNIFICANCE STATEMENT The matching law describes the tendency of agents to match the ratio of choices allocated to different options to the ratio of reward received. For example, if option a yields twice as much reward as option b, matching states that agents will choose option a twice as much. However, agents typically undermatch: they choose the poorer option more frequently than expected. Here, we assume that agents seek to simultaneously maximize reward and minimize the complexity of their action policies. We show that this theory explains when and why undermatching occurs. Neurally, we show that policy complexity, and by extension undermatching, is controlled by tonic dopamine, consistent with other evidence that dopamine plays an important role in cognitive resource allocation.

Humans learn internal models of the environment that support efficient planning and flexible generalization in complex, real-world domains. Yet it remains unclear how such internal models are represented and learned in the brain. We approach this question within the framework of theory-based reinforcement learning, a strong form of model-based reinforcement learning in which the model is an intuitive theory – a rich, abstract, causal model of the environment built on a natural ontology of physical objects, intentional agents, relations, and goals. We used a theory-based reinforcement learning model to analyze brain data from human participants learning to play different Atari-style video games while undergoing functional MRI. Theories inferred by the theory-based model explained the signal in inferior frontal gyrus and other prefrontal areas better than several alternative models. Brain activity increased in response to theory update events in inferior frontal gyrus, occipital cortex, and fusiform gyrus, with separate learning signals for different theory components. This corresponded with a transient strengthening of theory representations in those regions. Finally, the effective connectivity pattern during theory updating suggests that information flows top-down from theory-coding regions in the prefrontal cortex to theory updating regions in occipital and temporal cortex. These results are consistent with a neural architecture in which top-down theory representations originating in prefrontal regions shape sensory predictions in visual areas, where factorized theory prediction errors are computed and in turn trigger bottom-up updates of the theory. This initial sketch provides a foundation for understanding of the neural representations and computations that support efficient theory-based reinforcement learning in complex, naturalistic environments.

Across many domains of decision making, people seem both rational and irrational. We review recent work that aims to reconcile these apparently contradictory views by modeling human decisions as optimal under a set of cognitive resource constraints. This “resource-rational” analysis connects psychology and neuroscience to ideas from engineering, economics, and machine learning. Here, we focus on an information-theoretic formalization of cognitive resources, highlighting its implications for understanding three important and widespread phenomena: reference dependence, stochastic choice, and perseveration. While these phenomena have traditionally been viewed as irrational biases or errors, we suggest that they may arise from a rational solution to the problem of resource-limited decision making.

Rate-distortion theory provides a powerful framework for understanding the nature of human memory by formalizing the relationship between information rate (the average number of bits per stimulus transmitted across the memory channel) and distortion (the cost of memory errors). Here we show how this abstract computational-level framework can be realized by a model of neural population coding. The model reproduces key regularities of visual working memory, including some that were not previously explained by population coding models. We verify a novel prediction of the model by reanalyzing recordings of monkey prefrontal neurons during an oculomotor delayed response task.

Rate-distortion theory of neural coding and its implications for working memory

Studies of human exploration frequently cast people as serendipitously stumbling upon good options. Yet these studies may not capture the richness of exploration strategies that people exhibit in more complex environments. We study human behavior in a large data set of 29,493 players of the richly-structured online game "Little Alchemy 2''. In this game, players start with four elements, which they can combine to create up to 720 complex objects. We find that players are driven to create objects that empower them to create even more objects. We find that this drive for empowerment is eliminated when people play a version of the game that lacks recognizable semantics, indicating that they use their knowledge about the world to guide their exploration. Our results suggest that the drive for empowerment may be a potent source of intrinsic motivation in richly structured domains, particularly those that lack explicit reward signals.

Intrinsic Exploration as Empowerment in a Richly Structured Online Game

Neurons in the medial entorhinal cortex exhibit multiple, periodically organized, firing fields which collectively appear to form an internal representation of space. Neuroimaging data suggest that this grid coding is also present in other cortical areas such as the prefrontal cortex, indicating that it may be a general principle of neural functionality in the brain. In a recent analysis through the lens of dynamical systems theory, we showed how grid coding can lead to the generation of a diversity of empirically observed sequential reactivations of hippocampal place cells corresponding to traversals of cognitive maps. Here, we extend this sequence generation model by describing how the synthesis of multiple dynamical systems can support compositional cognitive computations. To empirically validate the model, we simulate two experiments demonstrating compositionality in space or in time during sequence generation. Finally, we describe several neural network architectures supporting various types of compositionality based on grid coding and highlight connections to recent work in machine learning leveraging analogous techniques.

Compositional Sequence Generation in the Entorhinal–Hippocampal System

Studies of human exploration frequently cast people as serendipitously stumbling upon good options. Yet these studies may not capture the richness of exploration strategies that people exhibit in more complex environments. We study human behavior in a large data set of 29,493 players of the richly-structured online game “Little Alchemy 2”. In this game, players start with four elements, which they can combine to create up to 720 complex objects. We find that players are driven to create objects that empower them to create even more objects. We find that this drive for empowerment is eliminated when people play a version of the game that lacks recognizable semantics, indicating that they use their knowledge about the world to guide their exploration. Our results suggest that the drive for empowerment may be a potent source of intrinsic motivation in richly structured domains, particularly those that lack explicit reward signals.

Corrigendum: Gradual extinction prevents the return of fear: implications for the discovery of state

When holding others morally responsible, we care about what they did, and what they thought. Traditionally, research in moral psychology has relied on vignette studies, in which a protagonist's actions and thoughts are explicitly communicated. While this research has revealed what variables are important for moral judgment, such as actions and intentions, it is limited in providing a more detailed understanding of exactly how these variables affect moral judgment. Using dynamic visual stimuli that allow for a more fine-grained experimental control, recent studies have proposed a direct mapping from visual features to moral judgments. We embrace the use of visual stimuli in moral psychology, but question the plausibility of a feature-based theory of moral judgment. We propose that the connection from visual features to moral judgments is mediated by an inference about what the observed action reveals about the agent's mental states, and what causal role the agent's action played in bringing about the outcome. We present a computational model that formalizes moral judgments of agents in visual scenes as computations over an intuitive theory of physics combined with an intuitive theory of mind. We test the model's quantitative predictions in three experiments across a wide variety of dynamic interactions.

Moral dynamics: Grounding moral judgment in intuitive physics and intuitive psychology

Reinforcement learning (RL) studies how an agent comes to achieve reward in an environment through interactions over time. Recent advances in machine RL have surpassed human expertise at the world’s oldest board games and many classic video games, but they require vast quantities of experience to learn successfully — none of today’s algorithms account for the human ability to learn so many different tasks, so quickly. Here we propose a new approach to this challenge based on a particularly strong form of model-based RL which we call Theory-Based Reinforcement Learning, because it uses human-like intuitive theories — rich, abstract, causal models of physical objects, intentional agents, and their interactions — to explore and model an environment, and plan effectively to achieve task goals. We instantiate the approach in a video game playing agent called EMPA (the Exploring, Modeling, and Planning Agent), which performs Bayesian inference to learn

Human-Level Reinforcement Learning through Theory-Based Modeling, Exploration, and Planning

Why, when, and how do stereotypes change? This paper develops a computational account based on the principles of structure learning: stereotypes are governed by probabilistic beliefs about the assignment of individuals to groups. Two aspects of this account are particularly important. First, groups are flexibly constructed based on the distribution of traits across individuals; groups are not fixed, nor are they assumed to map on to categories we have to provide to the model. This allows the model to explain the phenomena of group discovery and subtyping, whereby deviant individuals are segregated from a group, thus protecting the group’s stereotype. Second, groups are hierarchically structured, such that groups can be nested. This allows the model to explain the phenomenon of subgrouping, whereby a collection of deviant individuals is organized into a refinement of the superordinate group. The structure learning account also sheds light on several factors that determine stereotype change, including perceived group variability, individual typicality, cognitive load, and sample size.

At the heart of human intelligence rests a fundamental puzzle: How are we incredibly smart and stupid at the same time? No existing machine can match the power and flexibility of human perception, language, and reasoning. Yet, we routinely commit errors that reveal the failures of our thought processes. This book makes sense of this paradox by arguing that our cognitive errors are not haphazard. Rather, they are the inevitable consequences of a brain optimized for efficient inference and decision making within the constraints of time, energy, and memory—in other words, data and resource limitations. Framing human intelligence in terms of these constraints, the book shows how a deeper computational logic underpins the “stupid” errors of human cognition. Embarking on a journey across psychology, neuroscience, computer science, linguistics, and economics, the book presents unifying principles that govern human intelligence. First, inductive bias: any system that makes inferences based on limited data must constrain its hypotheses in some way before observing data. Second, approximation bias: any system that makes inferences and decisions with limited resources must make approximations. Applying these principles to a range of computational errors made by humans, the book demonstrates that intelligent systems designed to meet these constraints yield characteristically human errors. Examining how humans make intelligent and maladaptive decisions, the book delves into the successes and failures of cognition.

Modeling complex phenomena typically involves the use of both discrete and continuous variables. Such a setting applies across a wide range of problems, from identifying trends in time-series data to performing effective compositional scene understanding in images. Here, we propose Hybrid Memoised Wake-Sleep (HMWS), an algorithm for effective inference in such hybrid discrete-continuous models. Prior approaches to learning suffer as they need to perform repeated expensive inner-loop discrete inference. We build on a recent approach, Memoised Wake-Sleep (MWS), which alleviates part of the problem by memoising discrete variables, and extend it to allow for a principled and effective way to handle continuous variables by learning a separate recognition model used for importance-sampling based approximate inference and marginalization. We evaluate HMWS in the GP-kernel learning and 3D scene understanding domains, and show that it outperforms current state-of-the-art inference methods.

Hybrid Memoised Wake-Sleep: Approximate Inference at the Discrete-Continuous Interface

The role of dopamine as a reward prediction error signal in reinforcement learning tasks has been well-established over the past decades. Recent work has shown that the reward prediction error interpretation can also account for the effects of dopamine on interval timing by controlling the speed of subjective time. According to this theory, the timing of the dopamine signal relative to reward delivery dictates whether subjective time speeds up or slows down: Early DA signals speed up subjective time and late signals slow it down. To test this bidirectional prediction, we reanalyzed measurements of dopaminergic neurons in the substantia nigra pars compacta of mice performing a self-timed movement task. Using the slope of ramping dopamine activity as a read-out of subjective time speed, we found that trial-by-trial changes in the slope could be predicted from the timing of dopamine activity on the previous trial. This result provides a key piece of evidence supporting a unified computational theory of reinforcement learning and interval timing.

Policy compression: An information bottleneck in action selection

Evaluating choices in multi-step tasks is thought to involve mentally simulating trajectories. Recent theories propose that the brain simplifies these laborious computations using temporal abstraction: storing actions’ consequences, collapsed over multiple timesteps (the Successor Representation; SR). Although predictive neural representations and, separately, behavioral errors (“slips of action”) consistent with this mechanism have been reported, it is unknown whether these neural representations support choices in a manner consistent with the SR. We addressed this question by using fMRI to measure predictive representations in a setting where the SR implies specific errors in multi-step expectancies and corresponding behavioral errors. By decoding measures of state predictions from sensory cortex during choice evaluation, we identified evidence that behavioral errors predicted by the SR are accompanied by predictive representations of upcoming task states reflecting SR predicted erroneous multi-step expectancies. These results provide neural evidence for the SR in choice evaluation and contribute toward a mechanistic understanding of flexible and inflexible decision making.

Neural evidence for the successor representation in choice evaluation

The question of whether single cells can learn led to much debate in the early 20th century. The view prevailed that they were capable of non-associative learning but not of associative learning, such as Pavlovian conditioning. Experiments indicating the contrary were considered either non-reproducible or subject to more acceptable interpretations. Recent developments suggest that the time is right to reconsider this consensus. We exhume the experiments of Beatrice Gelber on Pavlovian conditioning in the ciliate Paramecium aurelia, and suggest that criticisms of her findings can now be reinterpreted. Gelber was a remarkable scientist whose absence from the historical record testifies to the prevailing orthodoxy that single cells cannot learn. Her work, and more recent studies, suggest that such learning may be evolutionarily more widespread and fundamental to life than previously thought and we discuss the implications for different aspects of biology.

Trait somatic anxiety is associated with reduced directed exploration and underestimation of uncertainty

Flexibility is one of the hallmarks of human problem-solving. In everyday life, people adapt to changes in common tasks with little to no additional training. Much of the existing work on flexibility in human problem-solving has focused on how people adapt to tasks in new domains by drawing on solutions from previously learned domains. In real-world tasks, however, humans must generalize across a wide range of within-domain variation. In this work we argue that representational abstraction plays an important role in such within-domain generalization. We then explore the nature of this representational abstraction in realistically complex tasks like video games by demonstrating how the same model-based planning framework produces distinct generalization behaviors under different classes of task representation. Finally, we compare the behavior of agents with these task representations to humans in a series of novel grid-based video game tasks. Our results provide evidence for the claim that within-domain flexibility in humans derives from task representations composed of propositional rules written in terms of objects and relational categories.

CCNLab is a benchmark for evaluating computational cognitive neuroscience models on empirical data. As a starting point, its focus is classical conditioning, which studies how animals predict reward and punishment in the environment. CCNLab includes a collection of simulations of seminal experiments expressed under a common API, as wells as tools for visualizing and comparing simulated data with empirical data. CCNLab is broad, incorporating representative experiments from different categories of phenomena; flexible, allowing the straightforward addition of new experiments; and easy-to-use, so researchers can focus on developing better models. We envision CCNLab as a testbed for unifying computational theories of learning in the brain. We also hope that it can broadly accelerate neuroscience research and facilitate interaction between the fields of neuroscience, psychology, and artificial intelligence.

CCNLab: A Benchmarking Framework for Computational Cognitive Neuroscience

Impulsivity and risk-seeking as Bayesian inference under dopaminergic control

Flexible modulation of sequence generation in the entorhinal-hippocampal system

The Reward Prediction Error hypothesis proposes that phasic activity in the midbrain dopaminergic system reflects prediction errors needed for learning in reinforcement learning. Besides the well-documented association between dopamine and reward processing, dopamine is implicated in a variety of functions without a clear relationship to reward prediction error. Fluctuations in dopamine levels influence the subjective perception of time, dopamine bursts precede the generation of motor responses, and the dopaminergic system innervates regions of the brain, including hippocampus and areas in prefrontal cortex, whose function is not uniquely tied to reward. In this manuscript, we propose that a common theme linking these functions is representation, and that prediction errors signaled by the dopamine system, in addition to driving associative learning, can also support the acquisition of adaptive state representations. In a series of simulations, we show how this extension can account for the role of dopamine in temporal and spatial representation, motor response, and abstract categorization tasks. By extending the role of dopamine signals to learning state representations, we resolve a critical challenge to the Reward Prediction Error hypothesis of dopamine function.

Slow-timescale (tonic) changes in dopamine (DA) contribute to a wide variety of processes in reinforcement learning, interval timing, and other domains. Furthermore, changes in tonic DA exert distinct effects depending on when they occur (e.g., during learning vs. performance) and what task the subject is performing (e.g., operant vs. classical conditioning). Two influential theories of tonic DA—the average reward theory and the Bayesian theory in which DA controls precision—have each been successful at explaining a subset of empirical findings. But how the same DA signal performs two seemingly distinct functions without creating crosstalk is not well understood. Here we reconcile the two theories under the unifying framework of ‘rational inattention,’ which (1) conceptually links average reward and precision, (2) outlines how DA manipulations affect this relationship, and in so doing, (3) captures new empirical phenomena. In brief, rational inattention asserts that agents can increase their precision in a task (and thus improve their performance) by paying a cognitive cost. Crucially, whether this cost is worth paying depends on average reward availability, reported by DA. The monotonic relationship between average reward and precision means that the DA signal contains the information necessary to retrieve the precision. When this information is needed after the task is performed, as presumed by Bayesian inference, acute manipulations of DA will bias behavior in predictable ways. We show how this framework reconciles a remarkably large collection of experimental findings. In reinforcement learning, the rational inattention framework predicts that learning from positive and negative feedback should be enhanced in high and low DA states, respectively, and that DA should tip the exploration-exploitation balance toward exploitation. In interval timing, this framework predicts that DA should increase the speed of the internal clock and decrease the extent of interference by other temporal stimuli during temporal reproduction (the central tendency effect). Finally, rational inattention makes the new predictions that these effects should be critically dependent on the controllability of rewards, that post-reward delays in intertemporal choice tasks should be underestimated, and that average reward manipulations should affect the speed of the clock—thus capturing empirical findings that are unexplained by either theory alone. Our results suggest that a common computational repertoire may underlie the seemingly heterogeneous roles of DA. Author Summary The roles of tonic dopamine (DA) have been the subject of much speculation, partly due to the variety of processes it has been implicated in. For instance, tonic DA modulates how we learn new information, but also affects how previously learned information is used. DA affects the speed of our internal timing mechanism, but also modulates the degree to which our temporal estimates are influenced by context. DA improves performance in some tasks, but seems only to affect confidence in others. Are there common principles that govern the role of DA across these domains? In this work, we introduce the concept of ‘rational inattention,’ originally borrowed from economics, to the DA literature. We show how the rational inattention account of DA unites two influential theories that are seemingly at odds: the average reward theory and the Bayesian theory of tonic DA. We then show how this framework reconciles the diverse roles of DA, which cannot be addressed by either theory alone.

Pavlovian associations drive approach towards reward-predictive cues, and avoidance of punishment-predictive cues. These associations “misbehave” when they conflict with correct instrumental behavior. This raises the question of how Pavlovian and instrumental influences on behavior are arbitrated. We test a computational theory according to which Pavlovian influence will be stronger when inferred controllability of outcomes is low. Using a model-based analysis of a Go/NoGo task with human subjects, we show that theta-band oscillatory power in frontal cortex tracks inferred controllability, and that these inferences predict Pavlovian action biases. Functional MRI data revealed an inferior frontal gyrus correlate of action probability and a ventromedial prefrontal correlate of outcome valence, both of which were modulated by inferred controllability.

Neural signatures of arbitration between Pavlovian and instrumental action selection

Decision letter: The roles of online and offline replay in planning

Erratum to Gershman and Niv (2012), Learning & Behavior, 40, 255-268

Publisher Correction: Controllability governs the balance between Pavlovian and instrumental action selection

Social-structure learning is the process by which social groups are identified on the basis of experience. Building on models of structure learning in other domains, we formalize this problem within a Bayesian framework. According to this framework, the probabilistic assignment of individuals to groups is computed by combining information about individuals with prior beliefs about group structure. Experiments with adults and children provide support for this framework, ruling out alternative accounts based on dyadic similarity. More broadly, we highlight the implications of social-structure learning for intergroup cognition, stereotype updating, and coalition formation.

Dissociable neural correlates of uncertainty underlie different exploration strategies

Attributing outcomes to your own actions or to external causes is essential for appropriately learning which actions lead to reward and which actions do not. Our previous work showed that this type of credit assignment is best explained by a Bayesian reinforcement learning model which posits that beliefs about the causal structure of the environment modulate reward prediction errors (RPEs) during action value updating. In this study, we investigated the brain networks underlying reinforcement learning that are influenced by causal beliefs using functional magnetic resonance imaging while human participants (n = 31; 13 males, 18 females) completed a behavioral task that manipulated beliefs about causal structure. We found evidence that RPEs modulated by causal beliefs are represented in dorsal striatum, while standard (unmodulated) RPEs are represented in ventral striatum. Further analyses revealed that beliefs about causal structure are represented in anterior insula and inferior frontal gyrus. Finally, structural equation modeling revealed effective connectivity from anterior insula to dorsal striatum. Together, these results are consistent with a possible neural architecture in which causal beliefs in anterior insula are integrated with prediction error signals in dorsal striatum to update action values. SIGNIFICANCE STATEMENT Learning which actions lead to reward—a process known as reinforcement learning—is essential for survival. Inferring the causes of observed outcomes—a process known as causal inference—is crucial for appropriately assigning credit to one's own actions and restricting learning to effective action–outcome contingencies. Previous studies have linked reinforcement learning to the striatum, and causal inference to prefrontal regions, yet how these neural processes interact to guide adaptive behavior remains poorly understood. Here, we found evidence that causal beliefs represented in the prefrontal cortex modulate action value updating in posterior striatum, separately from the unmodulated action value update in ventral striatum posited by standard reinforcement learning models.

Numerous researchers have put forward heuristics as models of human decision making. However, where such heuristics come from is still a topic of ongoing debates. In this work we propose a novel computational model that advances our understanding of heuristic decision making by explaining how different heuristics are discovered and how they are selected. This model, called bounded meta-learned inference, is based on the idea that people make environment-specific inferences about which strategies to use, while being efficient in terms of how they use computational resources. We show that our approach discovers two previously suggested types of heuristics – one reason decision making and equal weighting – in specific environments. Furthermore, the model provides clear and precise predictions about when each heuristic should be applied: knowing the correct ranking of attributes leads to one reason decision making, knowing the directions of the attributes leads to equal weighting, and not knowing about either leads to strategies that use weighted combinations of multiple attributes. This allows us to gain new insights on mixed results of prior empirical work on heuristic decision making. In three empirical paired comparison studies with continuous features, we verify predictions of our theory, and show that it captures several characteristics of human decision making not explained by alternative theories.

FROM BOUNDED META-LEARNED INFERENCE 3 Heuristics From Bounded Meta-Learned Inference Imagine having to decide which of two movies you are going to watch tonight : Movie

We present Language-mediated, Object-centric Representation Learning (LORL), a paradigm for learning disentangled, object-centric scene representations from vision and language. LORL builds upon recent advances in unsupervised object discovery and segmentation, notably MONet and Slot Attention. While these algorithms learn an object-centric representation just by reconstructing the input image, LORL enables them to further learn to associate the learned representations to concepts, i.e., words for object categories, properties, and spatial relationships, from language input. These object-centric concepts derived from language facilitate the learning of object-centric representations. LORL can be integrated with various unsupervised object discovery algorithms that are language-agnostic. Experiments show that the integration of LORL consistently improves the performance of unsupervised object discovery methods on two datasets via the help of language. We also show that concepts learned by LORL, in conjunction with object discovery methods, aid downstream tasks such as referring expression comprehension.

Action selection requires a policy that maps states of the world to a distribution over actions. The amount of memory needed to specify the policy (the policy complexity) increases with the state-dependence of the policy. If there is a capacity limit for policy complexity, then there will also be a trade-off between reward and complexity, since some reward will need to be sacrificed in order to satisfy the capacity constraint. This paper empirically characterizes the trade-off between reward and complexity for both schizophrenia patients and healthy controls. Schizophrenia patients adopt lower complexity policies on average, and these policies are more strongly biased away from the optimal reward-complexity trade-off curve compared to healthy controls. However, healthy controls are also biased away from the optimal trade-off curve, and both groups appear to lie on the same empirical trade-off curve. We explain these findings using a cost-sensitive actor-critic model. Our empirical and theoretical results shed new light on cognitive effort abnormalities in schizophrenia.

Planning: S1 Appendix Momchil S. Tomov1,2, Samyukta Yagati3, Agni Kumar3, Wanqian Yang4 , Samuel J. Gershman2 1Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA 2Department of Psychology and Center for Brain Science, Harvard University, Cambridge, MA 02138, USA 3Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA 4School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA

Discovery of Hierarchical Representations for Efficient Planning: S1 Appendix

When humans and other animals make repeated choices, they tend to repeat previously chosen actions independently of their reward history. This paper locates the origin of perseveration in a trade-off between two computational goals: maximizing rewards and minimizing the complexity of the action policy. We develop an information-theoretic formalization of policy complexity and show how optimizing the trade-off leads to perseveration. Analysis of two data sets reveals that people attain close to optimal trade-offs. Parameter estimation and model comparison supports the claim that perseveration quantitatively agrees with the theoretically predicted functional form.

Origin of perseveration in the trade-off between reward and complexity

The rational use of causal inference to guide reinforcement learning strengthens with age

Author response: Social structure learning in human anterior insula

The same persuasive message can be interpreted in a positive or negative way, challenging our ability to predict its effectiveness. Here, we analyze theoretically and experimentally how causal reasoning contributes to this process of interpretation and can produce attitude reversals due to the network structure of beliefs. We conduct two vignette experiments, one based on the famous slogan of the car rental agency Avis (“We’re No. 2—that means we try harder”), and the other based on online product reviews. When participants’ contextual beliefs about the economic environment are manipulated, message effectiveness changes as predicted by a Bayesian mechanism in which seemingly negative information is “explained away” in a more positive light, or vice versa. Thus, causal reasoning may help account for certain counterintuitive kinds of high-level attitude change.

Numerous researchers have put forward heuristics as models of human decision-making. However, where such heuristics come from is still a topic of ongoing debate. In this work, we propose a novel computational model that advances our understanding of heuristic decision-making by explaining how different heuristics are discovered and how they are selected. This model-called bounded meta-learned inference (BMI)-is based on the idea that people make environment-specific inferences about which strategies to use while being efficient in terms of how they use computational resources. We show that our approach discovers two previously suggested types of heuristics-one reason decision-making and equal weighting-in specific environments. Furthermore, the model provides clear and precise predictions about when each heuristic should be applied: Knowing the correct ranking of attributes leads to one reason decision-making, knowing the directions of the attributes leads to equal weighting, and not knowing about either leads to strategies that use weighted combinations of multiple attributes. In three empirical paired comparison studies with continuous features, we verify predictions of our theory and show that it captures several characteristics of human decision-making not explained by alternative theories. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Research into the development of Theory of Mind (ToM) has shown how children from a very early age infer other people's goals. However, human behaviour is sometimes driven not by plans to achieve goals, but by habits, which are formed over long periods of reinforcement. Habitual and goal-directed behaviours are often aligned with one another but can diverge when the optimal behavioural policy changes without being directly reinforced (thus specifically hobbling the habitual learning strategy). Unlike the flexibility of goal-directed behaviour, rigid habits can cause agents to persist in behaviour that is no longer adaptive. In the current study, all children predict agents will tend to behave consistently with their goals, but between the ages of five and ten children showed an increasing understanding of how habits can cause agents to persistently take suboptimal actions. These findings stand out from the typical way the development of social reasoning is examined, which instead focuses on children's increasing appreciation of how others' beliefs or expectations affect how they will act in service of their goals. The current findings show that children also learn that under certain circumstances, people's actions are suboptimal despite potentially "knowing better".

Bayesian models successfully account for several of dopamine (DA)’s effects on contextual calibration in interval timing and reward estimation. In these models, DA controls the precision of stimulus encoding, which is weighed against contextual information when making decisions. When DA levels are high, the animal relies more heavily on the (highly precise) stimulus encoding, whereas when DA levels are low, the context affects decisions more strongly. Here, we extend this idea to intertemporal choice tasks, in which agents must choose between small rewards delivered soon and large rewards delivered later. Beginning with the principle that animals will seek to maximize their reward rates, we show that the Bayesian model predicts a number of curious empirical findings. First, the model predicts that higher DA levels should normally promote selection of the larger/later option, which is often taken to imply that DA decreases ‘impulsivity.’ However, if the temporal precision is sufficiently decreased, higher DA levels should have the opposite effect—promoting selection of the smaller/sooner option (more impulsivity). Second, in both cases, high enough levels of DA can result in preference reversals. Third, selectively decreasing the temporal precision, without manipulating DA, should promote selection of the larger/later option. Fourth, when a different post-reward delay is associated with each option, animals will not learn the option-delay contingencies, but this learning can be salvaged when the post-reward delays are made more salient. Finally, the Bayesian model predicts a correlation between behavioral phenotypes: Animals that are better timers will also appear less impulsive. Significance Statement Does dopamine make animals more or less impulsive? Though impulsivity features prominently in several dopamine-related conditions, how dopamine actually influences impulsivity has remained unclear. In intertemporal choice tasks (ITCs), wherein animals must choose between small rewards delivered soon and large rewards delivered later, administering dopamine makes animals more willing to wait for larger/later rewards in some conditions (consistent with lower impulsivity), but less willing in others. We hypothesize that dopamine does not necessarily influence impulsivity at all, but rather gates the influence of contextual information during decision making. We show that this account explains an array of curious findings in ITCs, including the seemingly conflicting results above. Our work encourages a reexamination of ITCs as a method for assessing impulsivity.

Decision letter: Impaired adaptation of learning to contingency volatility in internalizing psychopathology

This chapter surveys rational models of memory, which posit that memory is optimized to store information that will be needed in the future, subject to the constraint that information can only be stored with a limited amount of precision. This optimization problem can be formalized using the framework of rate-distortion theory, which addresses the trade-oﬀ between memory precision and task performance. The design principles that emerge from this framework shed light on numerous regularities of memory, as well as how cognitive and environmental factors shape these regularities.

Bayesian theories of cognition assume that people can integrate probabilities rationally. However, several empirical findings contradict this proposition: human probabilistic inferences are prone to systematic deviations from optimality. Puzzlingly, these deviations sometimes go in opposite directions. Whereas some studies suggest that people under-react to prior probabilities (base rate neglect), other studies find that people under-react to the likelihood of the data (conservatism). We argue that these deviations arise because the human brain does not rely solely on a general-purpose mechanism for approximating Bayesian inference that is invariant across queries. Instead, the brain is equipped with a recognition model that maps queries to probability distributions. The parameters of this recognition model are optimized to get the output as close as possible, on average, to the true posterior. Because of our limited computational resources, the recognition model will allocate its resources so as to be more accurate for high probability queries than for low probability queries. By adapting to the query distribution, the recognition model “learns to infer.” We show that this theory can explain why and when people under-react to the data or the prior, and a new experiment demonstrates that these two forms of under-reaction can be systematically controlled by manipulating the query distribution. The theory also explains a range of related phenomena: memory effects, belief bias, and the structure of response variability in probabilistic reasoning. We also discuss how the theory can be integrated with prior sampling-based accounts of approximate inference.

Running head : LEARNING TO INFER 1 A theory of learning to infer

Cells in the hippocampus tuned to spatial location (place cells) typically change their tuning when an animal changes context, a phenomenon known as remapping. A fundamental challenge to understanding remapping is the fact that what counts as a “context change” has never been precisely defined. Furthermore, different remapping phenomena have been classified on the basis of how much the tuning changes after different types and degrees of context change, but the relationship between these variables is not clear. We address these ambiguities by formalizing remapping in terms of hidden state inference. According to this view, remapping does not directly reflect objective, observable properties of the environment, but rather subjective beliefs about the hidden state of the environment. We show how the hidden state framework can resolve a number of puzzles about the nature of remapping.

What place should formal or computational methods occupy in social psychology? We consider this question in historical perspective, survey the current state of the field, introduce the several new contributions to this special issue, and reflect on the future.

The place cells of the hippocampus collectively form distinct maps of each context, a process known as hippocampal remapping. Past work has asked which features of an experience determine which map is used, but no consistent answer has been reached. However, this approach has ignored the place of context identification as part of a learning process. We suggest that context identification corresponds to an unsupervised clustering problem, where the animal receives a stream of observations and must cluster them in a data-driven manner. Each cluster corresponds to a particular context, and therefore a particular hippocampal map. Formalizing context learning as a clustering problem allows us to capture a range of experimental results that have not yet been explained by a single theoretical framework. In particular, our results highlight the role that learning plays in hippocampal remapping. This model also provides novel predictions, such as the effect of variability in training.

Decision letter: Unimodal statistical learning produces multimodal object-like representations

Suicide is a leading cause of death worldwide. Despite decades of clinical and theoretical accounts that suggest that suicidal thoughts and behaviors are efforts to escape painful emotions, little prior research has examined decision making involved in escaping aversive states. We compared the performance of 85 suicidal participants to 44 nonsuicidal psychiatric patients on a novel reinforcement learning task with choices to make either active (i.e., “go”) or passive responses (i.e., “no-go”) to either escape or avoid an aversive stimulus. We used a computational cognitive model to isolate decision-making biases. We hypothesized that suicidal participants would exhibit a relatively elevated bias for making active responses to escape an aversive state and would show worse performance when escape required a passive response (i.e., “doing nothing” to escape). Our hypotheses were supported: The computational model revealed that suicidal participants exhibited a higher bias for an active response to escape compared with nonsuicidal psychiatric controls, suggesting that this finding was not just the result of the presence of psychopathology. The bias parameter also accounted for unique variance in predicting group status among several constructs previously related to suicidal thoughts and behaviors. This study provides a new method for testing escape decision making and does so using a computational cognitive model, allowing us to precisely index processes underlying suicidal and related behaviors. Future research examining escape decision making from a computational perspective could help link neural processes or environmental stressors to suicidal thoughts or behaviors.

Suicidal Thoughts and Behaviors Are Associated With an Increased Decision-Making Bias for Active Responses to Escape Aversive States

The modulation of interval timing by dopamine (DA) has been well established over decades of research. The nature of this modulation, however, has remained controversial: Although the pharmacological evidence has largely suggested that time intervals are overestimated with higher DA levels, more recent optogenetic work has shown the opposite effect. In addition, a large body of work has asserted DA's role as a "reward prediction error" (RPE), or a teaching signal that allows the basal ganglia to learn to predict future rewards in reinforcement learning tasks. Whether these two seemingly disparate accounts of DA may be related has remained an open question. By taking a reinforcement learning-based approach to interval timing, we show here that the RPE interpretation of DA naturally extends to its role as a modulator of timekeeping and furthermore that this view reconciles the seemingly conflicting observations. We derive a biologically plausible, DA-dependent plasticity rule that can modulate the rate of timekeeping in either direction and whose effect depends on the timing of the DA signal itself. This bidirectional update rule can account for the results from pharmacology and optogenetics as well as the behavioral effects of reward rate on interval timing and the temporal selectivity of striatal neurons. Hence, by adopting a single RPE interpretation of DA, our results take a step toward unifying computational theories of reinforcement learning and interval timing. NEW & NOTEWORTHY How does dopamine (DA) influence interval timing? A large body of pharmacological evidence has suggested that DA accelerates timekeeping mechanisms. However, recent optogenetic work has shown exactly the opposite effect. In this article, we relate DA's role in timekeeping to its most established role, as a critical component of reinforcement learning. This allows us to derive a neurobiologically plausible framework that reconciles a large body of DA's temporal effects, including pharmacological, behavioral, electrophysiological, and optogenetic.

The tension between habits and plans is reflected in everyday decision-making. Habits are computationally cheap, but fail to flexibly adapt to changes in the environment. Planning is a flexible decision-making strategy, but requires greater resources. Arbitration between habits and plans has been formalized using reinforcement learning algorithms that distinguish between model-free control (habits) and model-based control (plans). Evidence about these two decision-making approaches suggests model-based control follows a developmental trajectory, emerging during adolescence, strengthening during young adulthood, and declining in older adulthood. The normative decline in planning (model-based control) presents the opportunity to develop interventions to increase flexible decision-making. Therefore, we asked if incentives could be used to increase model-based control in older adults. We expected older adults would fail to increase model-based control in response to incentives. This prediction was based upon prior research suggesting older adulthood is associated with deficits in representing and updating the expected value of rewards. Contrary to our expectations, in Experiment 1 we found that incentives could be used to boost model-based control in older adults sampled from an online population. We hypothesized this may be due to previous experience with the task (or with similar tasks). In Experiment 2, a naïve sample of older adults did not boost model-based control in response to incentives. These results suggest that incentives may be a useful intervention to increase model-based planning in older adulthood, but this may require extensive experience with the incentive structure.

The free energy principle has been proposed as a unifying account of brain function. It is closely related, and in some cases subsumes, earlier unifying ideas such as Bayesian inference, predictive coding, and active learning. This article clarifies these connections, teasing apart distinctive and shared predictions.

Humans form social coalitions in every society, yet we know little about how we learn and represent social group boundaries. Here we derive predictions from a computational model of latent structure learning to move beyond explicit category labels and interpersonal, or dyadic, similarity as the sole inputs to social group representations. Using a model-based analysis of functional neuroimaging data, we find that separate areas correlate with dyadic similarity and latent structure learning. Trial-by-trial estimates of ‘allyship’ based on dyadic similarity between participants and each agent recruited medial prefrontal cortex/pregenual anterior cingulate (pgACC). Latent social group structure-based allyship estimates, in contrast, recruited right anterior insula (rAI). Variability in the brain signal from rAI improved prediction of variability in ally-choice behavior, whereas variability from the pgACC did not. These results provide novel insights into the psychological and neural mechanisms by which people learn to distinguish ‘us’ from ‘them.’

Rapid phasic activity of midbrain dopamine neurons are thought to signal reward prediction errors (RPEs), resembling temporal difference errors used in machine learning. Recent studies describing slowly increasing dopamine signals have instead proposed that they represent state values and arise independently from somatic spiking activity. Here, we developed novel experimental paradigms using virtual reality that disambiguate RPEs from values. We examined the dopamine circuit activity at various stages including somatic spiking, axonal calcium signals, and striatal dopamine concentrations. Our results demonstrate that ramping dopamine signals are consistent with RPEs rather than value, and this ramping is observed at all the stages examined. We further show that ramping dopamine signals can be driven by a dynamic stimulus that indicates a gradual approach to a reward. We provide a unified computational understanding of rapid phasic and slowly ramping dopamine signals: dopamine neurons perform a derivative-like computation over values on a moment-by-moment basis.

Cumulative culture depends on the ﬁdelity of learning be- tween successive generations, and the robustness with which the lessons of one generation apply to the problems of the next. How do humans accomplish these twin goals? We formalize social learning as a kind of program induction, and provide an experimental test of a key prediction. To do this, we exploit a key fact: When humans learn from others, in addition to ob- serving inputs and outputs we often observe the process that led to that output. For instance, when preparing a meal, we don’t just observe a pile of vegetables and then a ratatouille. Instead, we observe a causal process that transforms those in- gredients into a ﬁnished food. Here, we use probabilistic programs to represent causal processes and show that the observa- tion of an execution trace speeds up program induction, even when learning from only a single example. This model pre- dicts that the inferences and behavior of people will be structured by these execution traces. In two behavioral experiments, we show that human judgments and behavior are affected by the execution trace in the systematic ways predicted by our for- mal model. These ﬁndings shed light on the mechanisms that underlie high ﬁdelity social learning in humans, and unify the role of emulation and imitation in social learning.

Downloading Culture.zip: Social learning by program induction with execution traces

Significance We study how people make choices among a large number of options when they have limited experience. In a large dataset of online food delivery purchases, we find evidence for sophisticated exploration strategies predicted by contemporary theories. People actively seek to reduce their uncertainty about restaurants and use similarity-based generalization to guide their selections. Our findings suggest that theories of exploratory choice have real-world validity. Making good decisions requires people to appropriately explore their available options and generalize what they have learned. While computational models can explain exploratory behavior in constrained laboratory tasks, it is unclear to what extent these models generalize to real-world choice problems. We investigate the factors guiding exploratory behavior in a dataset consisting of 195,333 customers placing 1,613,967 orders from a large online food delivery service. We find important hallmarks of adaptive exploration and generalization, which we analyze using computational models. In particular, customers seem to engage in uncertainty-directed exploration and use feature-based generalization to guide their exploration. Our results provide evidence that people use sophisticated strategies to explore complex, real-world environments.

Structured, uncertainty-driven exploration in real-world consumer choice

Significance Explicit (i.e., self-reported) and implicit (i.e., indirectly measured) evaluations are central to organizing social cognition and drive behavior in intergroup relations, consumer choice, psychopathology, and close relationships. Here we use a distinction rooted in animal learning and now formalized in computer science to show that explicit evaluations are responsive to model-free and model-based reinforcement learning, whereas implicit evaluations are sensitive to the former but impervious to the latter. This result, which demonstrates a partial dissociation in computations underlying explicit vs. implicit evaluations, accounts for a wide range of existing findings and productively generates predictions for future research. Moreover, it suggests that enduring change in implicit evaluations may be achieved via retraining model-free value representations across a number of different contexts. Evaluating stimuli along a good–bad dimension is a fundamental computation performed by the human mind. In recent decades, research has documented dissociations and associations between explicit (i.e., self-reported) and implicit (i.e., indirectly measured) forms of evaluations. However, it is unclear whether such dissociations arise from relatively more superficial differences in measurement techniques or from deeper differences in the processes by which explicit and implicit evaluations are acquired and represented. The present project (total N = 2,354) relies on the computationally well-specified distinction between model-based and model-free reinforcement learning to investigate the unique and shared aspects of explicit and implicit evaluations. Study 1 used a revaluation procedure to reveal that, whereas explicit evaluations of novel targets are updated via model-free and model-based processes, implicit evaluations depend on the former but are impervious to the latter. Studies 2 and 3 demonstrated the robustness of this effect to (i) the number of stimulus exposures in the revaluation phase and (ii) the deterministic vs. probabilistic nature of initial reinforcement. These findings provide a framework, going beyond traditional dual-process and single-process accounts, to highlight the context-sensitivity and long-term recalcitrance of implicit evaluations as well as variations in their relationship with their explicit counterparts. These results also suggest avenues for designing theoretically guided interventions to produce change in implicit evaluations.

Model-free and model-based learning processes in the updating of explicit and implicit evaluations

People learn differently from good and bad outcomes. We argue that valence-dependent learning asymmetries are partly driven by beliefs about the causal structure of the environment. If hidden causes can intervene to generate bad (or good) outcomes, then a rational observer will assign blame (or credit) to these hidden causes, rather than to the stable outcome distribution. Thus, a rational observer should learn less from bad outcomes when they are likely to have been generated by a hidden cause, and this pattern should reverse when hidden causes are likely to generate good outcomes. To test this hypothesis, we conducted two experiments (N = 80, N = 255) in which we explicitly manipulated the behavior of hidden agents. This gave rise to both kinds of learning asymmetries in the same paradigm, as predicted by a novel Bayesian model. These results provide a mechanistic framework for understanding how causal attributions contribute to biased learning.

When predicting or explaining another person’s actions, we often appeal to the physical effort they require; a person who works hard for something, for instance, must really like it (Liu, Ullman, Tenenbaum, & Spelke, 2017). But people are not only motivated to avoid physical effort; they also seek to avoid mental effort (Shenhav et al., 2017; Kool & Botvinick, 2018). Here, we ask whether mental effort enters into preschoolers’ understanding of other people’s actions. Across 4 experiments (N=112), we presented 4and 5-year-old children with an agent (naive in Exp 1, 2 and 4, and knowledgeable in Exp 3) who can either move through a simple or complex maze environment with a specific goal (in Exp 1-3, to reach a play structure beyond the mazes, and in Exp 4, to practice solving the mazes). We found that children were sensitive to the physical and mental effort associated with more complex mazes, and to the trade-offs between effort and gain in skill. The intuition that choices impose costs on our bodies and minds appears to guide children’s understanding of other people.

Hard choices: Children's understanding of the cost of action selection

Editors' Introduction: Computational Approaches to Social Cognition

How do people generalize and explore structured spaces? We study human behavior on a multi-armed bandit task, where rewards are influenced by the connectivity structure of a graph. A detailed predictive model comparison shows that a Gaussian Process regression model using a diffusion kernel is able to best describe participant choices, and also predict judgments about expected reward and confidence. This model unifies psychological models of function learning with the Successor Representation used in reinforcement learning, thereby building a bridge between different models of generalization.

From social networks to public transportation, graph structures are a ubiquitous feature of life. Yet little is known about how humans learn functions on graphs, where relationships are defined by the connectivity structure. We adapt a Bayesian framework for function learning to graph structures, and propose that people perform generalization by diffusing observed function values across the graph. We test the predictions of this model by asking participants to make predictions about passenger volume in a virtual subway network. The model captures both generalization and confidence judgments, and is a quantitatively superior account relative to several heuristic models. Our work suggests that people exploit graph structure to make generalizations about functions in complex discrete spaces.

Cells in the hippocampus tuned to spatial location (place cells) typically change their tuning when an animal changes context, a phenomenon known as remapping. A fundamental challenge to understanding remapping is the fact that what counts as a “context change” has never been precisely defined. Furthermore, different remapping phenomena have been classified on the basis of how much the tuning changes after different types and degrees of context change, but the relationship between these variables is not clear. We address these ambiguities by formalizing remapping in terms of hidden state inference. According to this view, remapping does not directly reflect objective, observable properties of the environment, but rather subjective beliefs about the hidden state of the environment. We show how the hidden state framework can resolve a number of puzzles about the nature of remapping. Hippocampal Remapping as Hidden State Inference Honi Sanders, Matthew A. Wilson, and Samuel J. Gershman Center for Brains Minds and Machines Picower Institute for Learning and Memory and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, United States 3 Department of Psychology and Center for Brain Science, Harvard University, United States

In order to discover the most rewarding actions, agents must collect information about their environment, potentially foregoing reward. The optimal solution to this "explore-exploit" dilemma is often computationally challenging, but principled algorithmic approximations exist. These approximations utilize uncertainty about action values in different ways. Some random exploration algorithms scale the level of choice stochasticity with the level of uncertainty. Other directed exploration algorithms add a "bonus" to action values with high uncertainty. Random exploration algorithms are sensitive to total uncertainty across actions, whereas directed exploration algorithms are sensitive to relative uncertainty. This paper reports a multi-armed bandit experiment in which total and relative uncertainty were orthogonally manipulated. We found that humans employ both exploration strategies, and that these strategies are independently controlled by different uncertainty computations.

The idea that the brain learns generative models of the world has been widely promulgated. Most approaches have assumed that the brain learns an explicit density model that assigns a probability to each possible state of the world. However, explicit density models are difficult to learn, requiring approximate inference techniques that may find poor solutions. An alternative approach is to learn an implicit density model that can sample from the generative model without evaluating the probabilities of those samples. The implicit model can be trained to fool a discriminator into believing that the samples are real. This is the idea behind generative adversarial algorithms, which have proven adept at learning realistic generative models. This paper develops an adversarial framework for probabilistic computation in the brain. It first considers how generative adversarial algorithms overcome some of the problems that vex prior theories based on explicit density models. It then discusses the psychological and neural evidence for this framework, as well as how the breakdown of the generator and discriminator could lead to delusions observed in some mental disorders.

Mikhael JG, Gershman SJ. Adapting the flow of time with dopamine. J Neurophysiol 121: 1748–1760, 2019. First published March 13, 2019; doi:10.1152/jn.00817.2018.—The modulation of interval timing by dopamine (DA) has been well established over decades of research. The nature of this modulation, however, has remained controversial: Although the pharmacological evidence has largely suggested that time intervals are overestimated with higher DA levels, more recent optogenetic work has shown the opposite effect. In addition, a large body of work has asserted DA’s role as a “reward prediction error” (RPE), or a teaching signal that allows the basal ganglia to learn to predict future rewards in reinforcement learning tasks. Whether these two seemingly disparate accounts of DA may be related has remained an open question. By taking a reinforcement learning-based approach to interval timing, we show here that the RPE interpretation of DA naturally extends to its role as a modulator of timekeeping and furthermore that this view reconciles the seemingly conflicting observations. We derive a biologically plausible, DA-dependent plasticity rule that can modulate the rate of timekeeping in either direction and whose effect depends on the timing of the DA signal itself. This bidirectional update rule can account for the results from pharmacology and optogenetics as well as the behavioral effects of reward rate on interval timing and the temporal selectivity of striatal neurons. Hence, by adopting a single RPE interpretation of DA, our results take a step toward unifying computational theories of reinforcement learning and interval timing.

Higher Neural Functions and Behavior Adapting the flow of time with dopamine X

Reinforcement learning models of the basal ganglia map the phasic dopamine signal to reward prediction errors (RPEs). Conventional models assert that, when a stimulus predicts a reward with fixed delay, dopamine activity during the delay should converge to baseline through learning. However, recent studies have found that dopamine ramps up before reward in certain conditions even after learning, thus challenging the conventional models. In this work, we show that sensory feedback causes an unbiased learner to produce RPE ramps. Our model predicts that, when feedback gradually decreases during a trial, dopamine activity should resemble a ‘bump,’ whose ramp-up phase should furthermore be greater than that of conditions where the feedback stays high. We trained mice on a virtual navigation task with varying brightness, and both predictions were empirically observed. In sum, our theoretical and experimental results reconcile the seemingly conflicting data on dopamine behaviors under the RPE hypothesis.

Decision-makers consistently exhibit violations of rational choice theory when they choose among several alternatives in a set (e.g., failing to buy the best product in a set when it is presented alongside high-quality alternatives). Many of society’s most significant social decisions similarly involve the joint evaluation of multiple candidates. Are social decisions subject to the same violations, and if so, what account best characterizes the nature of the violations? Across five studies, we tested whether decision-makers exhibit context-dependent preferences in hiring scenarios and past U.S. congressional race outcomes and co¬mpared different models of value coding as sources of the hypothesized context-dependence. Studies 1a, 1b, and 1d revealed that a divisive normalization value coding scheme best characterized participants’ choices across a series of hiring decisions, and that participants exhibited context-dependent preferences. However, the distractor had the opposite effect of that predicted by divisive normalization once we accounted for the random effect of participant: as the value of the distractor increased, participants were more likely to hire the highest-valued candidate. In Study 2, we used a combination of archival electoral data and survey data to examine whether normalization models could explain the outcomes of congressional elections. Electoral outcomes were predicted by political candidates’ inferred competence, but this time in line with the divisive normalization account. Our findings offer mixed support for a formal, neurobiologically-derived account of when and how specific alternatives exert their effects on social evaluation and choice and highlight conditions under which high-value distractors increase versus decrease relative choice accuracy.

Comparing value coding models of context-dependence in social choice

As modern deep networks become more complex, and get closer to human-like capabilities in certain domains, the question arises as to how the representations and decision rules they learn compare to the ones in humans. In this work, we study representations of sentences in one such artificial system for natural language processing. We first present a diagnostic test dataset to examine the degree of abstract composable structure represented. Analyzing performance on these diagnostic tests indicates a lack of systematicity in representations and decision rules, and reveals a set of heuristic strategies. We then investigate the effect of training distribution on learning these heuristic strategies, and we study changes in these representations with various augmentations to the training set. Our results reveal parallels to the analogous representations in people. We find that these systems can learn abstract rules and generalize them to new contexts under certain circumstances-similar to human zero-shot reasoning. However, we also note some shortcomings in this generalization behavior-similar to human judgment errors like belief bias. Studying these parallels suggests new ways to understand psychological phenomena in humans as well as informs best strategies for building artificial intelligence with human-like language understanding.

Analyzing machine-learned representations: A natural language case study

Abstract Reinforcement learning models of the basal ganglia map the phasic dopamine signal to reward prediction errors (RPEs). Conventional models assert that, when a stimulus reliably predicts a reward with fixed delay, dopamine activity during the delay period and at reward time should converge to baseline through learning. However, recent studies have found that dopamine exhibits a gradual ramp before reward in certain conditions even after extensive learning, such as when animals are trained to run to obtain the reward, thus challenging the conventional RPE models. In this work, we begin with the limitation of temporal uncertainty (animals cannot perfectly estimate time to reward), and show that sensory feedback, which reduces this uncertainty, will cause an unbiased learner to produce RPE ramps. On the other hand, in the absence of feedback, RPEs will be flat after learning. These results reconcile the seemingly conflicting data on dopamine behaviors under the RPE hypothesis.

Controllability governs the balance between Pavlovian and instrumental action selection

Humans spontaneously organize a continuous experience into discrete events and use the learned structure of these events to generalize and organize memory. We introduce the Structured Event Memory (SEM) model of event cognition, which accounts for human abilities in event segmentation, memory, and generalization. SEM is derived from a probabilistic generative model of event dynamics defined over structured symbolic scenes. By embedding symbolic scene representations in a vector space and parametrizing the scene dynamics in this continuous space, SEM combines the advantages of structured and neural network approaches to high-level cognition. Using probabilistic reasoning over this generative model, SEM can infer event boundaries, learn event schemata, and use event knowledge to reconstruct past experience. We show that SEM can scale up to high-dimensional input spaces, producing human-like event segmentation for naturalistic video data, and accounts for a wide array of memory phenomena.

Structured event memory: a neuro-symbolic model of event cognition

Significance Behavioral research has made rapid progress toward revealing the processes by which we make choices between options that are presented simultaneously. Decisions in everyday life are typically more complex. We often encounter choices where options are separated in space and time and therefore the question is, “When is the right time to stop searching?” We suggest that humans use a probabilistic threshold. A model in which this threshold changes linearly over time, where the optimal policy prescribes a nonlinear change, provides an excellent account to the data, even in real-life settings. In many real-life decisions, options are distributed in space and time, making it necessary to search sequentially through them, often without a chance to return to a rejected option. The optimal strategy in these tasks is to choose the first option that is above a threshold that depends on the current position in the sequence. The implicit decision-making strategies by humans vary but largely diverge from this optimal strategy. The reasons for this divergence remain unknown. We present a model of human stopping decisions in sequential decision-making tasks based on a linear threshold heuristic. The first two studies demonstrate that the linear threshold model accounts better for sequential decision making than existing models. Moreover, we show that the model accurately predicts participants’ search behavior in different environments. In the third study, we confirm that the model generalizes to a real-world problem, thus providing an important step toward understanding human sequential decision making.

Decision letter: Dopaminergic modulation of the exploration/exploitation trade-off in human decision-making

Incentives Boost Model-Based Control Across a Range of Severity on Several Psychiatric Constructs

Dopamine neurons respond to errors in predicting value-neutral sensory information. These data, combined with causal evidence that dopamine transients support sensory-based associative learning, suggest that the dopamine system signals a multidimensional prediction error. Yet such complexity is not evident in individual neuron or average neural activity. How then do downstream areas know what to learn in response to these signals? One possibility is that information about content is contained in the pattern of firing across many dopamine neurons. Consistent with this, here we show that the pattern of firing across a small group of dopamine neurons recorded in rats signals the identity of a mis-predicted sensory event. Further, this same information is reflected in the BOLD response elicited by sensory prediction errors in human midbrain. These data provide evidence that ensembles of dopamine neurons provide highly specific teaching signals, opening new possibilities for how this system might contribute to learning.

Dopamine neuron ensembles signal the content of sensory prediction errors

Recent years have seen a boom in interest in interpretable machine learning systems built on models that can be understood, at least to some degree, by domain experts. However, exactly what kinds of models are truly human-interpretable remains poorly understood. This work advances our understanding of precisely which factors make models interpretable in the context of decision sets, a specific class of logic-based model. We conduct carefully controlled human-subject experiments in two domains across three tasks based on human-simulatability through which we identify specific types of complexity that affect performance more heavily than others-trends that are consistent across tasks and domains. These results can inform the choice of regularizers during optimization to learn more interpretable models, and their consistency suggests that there may exist common design principles for interpretable machine learning systems.

Proceedings of the ... AAAI Conference on Human Computation and Crowdsourcing

Integrating Models of Interval Timing and Reinforcement Learning

The Medial Prefrontal Cortex Shapes Dopamine Reward Prediction Errors under State Uncertainty

People can learn about the effects of their actions either by performing physical experiments or by running mental simulations. Physical experiments are reliable but risky; mental simulations are unreliable but safe. We investigate how people negotiate the balance between these strategies. Participants attempted to shoot a ball at a target, and could pay to take practice shots (physical experiments). They could also simply think (run mental simulations), but were incentivized to act quickly by paying for time. We demonstrate that the amount of thinking time and physical experiments is sensitive to trial characteristics in a way that is consistent with a model that integrates information across simulation and experimentation and decides online when to perform each.

Learning to act by integrating mental simulations and physical experiments

Reinforcement learning is the process by which an agent learns to predict long-term future reward. We now understand a great deal about the brain's reinforcement learning algorithms, but we know considerably less about the representations of states and actions over which these algorithms operate. A useful starting point is asking what kinds of representations we would want the brain to have, given the constraints on its computational architecture. Following this logic leads to the idea of the successor representation, which encodes states of the environment in terms of their predictive relationships with other states. Recent behavioral and neural studies have provided evidence for the successor representation, and computational studies have explored ways to extend the original idea. This paper reviews progress on these fronts, organizing them within a broader framework for understanding how the brain negotiates tradeoffs between efficiency and flexibility for reinforcement learning.

The Successor Representation: Its Computational Logic and Neural Substrates

An important frontier in the quest for human-like AI is compositional semantics: how do we design systems that understand an infinite number of expressions built from a finite vocabulary? Recent research has attempted to solve this problem by using deep neural networks to learn vector space embeddings of sentences, which then serve as input to supervised learning problems like paraphrase detection and sentiment analysis. Here we focus on 'natural language inference' (NLI) as a critical test of a system's capacity for semantic compositionality. In the NLI task, sentence pairs are assigned one of three categories: entailment, contradiction, or neutral. We present a new set of NLI sentence pairs that cannot be solved using only word-level knowledge and instead require some degree of compositionality. We use state of the art sentence embeddings trained on NLI (InferSent, Conneau et al. (2017)), and find that performance on our new dataset is poor, indicating that the representations learned by this model fail to capture the needed compositionality. We analyze some of the decision rules learned by InferSent and find that they are largely driven by simple heuristics at the word level that are ecologically valid in the SNLI dataset on which InferSent is trained. Further, we find that augmenting the training dataset with our new dataset improves performance on a held-out test set without loss of performance on the SNLI test set. This highlights the importance of structured datasets in better understanding, as well as improving the performance of, AI systems.

Making good decisions requires people to appropriately explore their available options and generalize what they have learned. While computational models have successfully explained exploratory behavior in constrained laboratory tasks, it is unclear to what extent these models generalize to complex real world choice problems. We investigate the factors guiding exploratory behavior in a data set consisting of 195,333 customers placing 1,613,967 orders from a large online food delivery service. We find important hallmarks of adaptive exploration and generalization, which we analyze using computational models. We find evidence for several theoretical predictions: (1) customers engage in uncertainty-directed exploration, (2) they adjust their level of exploration to the average restaurant quality in a city, and (3) they use feature-based generalization to guide exploration towards promising restaurants. Our results provide new evidence that people use sophisticated strategies to explore complex, real-world environments.

In order to maximize long-term rewards, agents must balance exploitation (choosing the option with the highest payoff) and exploration (gathering information about options that might have higher payoffs). Although the optimal solution to this trade-off is intractable, humans make use of two effective strategies: selectively exploring options with high uncertainty (directed exploration), and increasing the randomness of their choices when they are more uncertain (random exploration). Using a task that independently manipulates these two forms of exploration, we show that single nucleotide polymorphisms related to dopamine are associated with individual differences in exploration strategies. Variation in a gene linked to prefrontal dopamine (COMT) predicted the degree of directed exploration, as well as the overall randomness of responding. Variation in a gene linked to striatal dopamine (DARPP-32) predicted the degree of both directed and random exploration. These findings suggest that dopamine makes multiple contributions to exploration, depending on its afferent target.

Dopaminergic genes are associated with both directed and random exploration

Decision letter: Control of entropy in neural models of environmental state

Decision-making algorithms face a basic tradeoff between accuracy and effort (i.e., computational demands). It is widely agreed that humans can choose between multiple decision-making processes that embody different solutions to this tradeoff: Some are computationally cheap but inaccurate, whereas others are computationally expensive but accurate. Recent progress in understanding this tradeoff has been catalyzed by formalizing it in terms of model-free (i.e., habitual) versus model-based (i.e., planning) approaches to reinforcement learning. Intuitively, if two tasks offer the same rewards for accuracy but one of them is much more demanding, we might expect people to rely on habit more in the difficult task: Devoting significant computation to achieve slight marginal accuracy gains would not be “worth it.” We test and verify this prediction in a sequential reinforcement learning task. Because our paradigm is amenable to formal analysis, it contributes to the development of a computational model of how people balance the costs and benefits of different decision-making processes in a task-specific manner; in other words, how we decide when hard thinking is worth it.

Recent years have seen a boom in interest in machine learning systems that can provide a human-understandable rationale for their predictions or decisions. However, exactly what kinds of explanation are truly human-interpretable remains poorly understood. This work advances our understanding of what makes explanations interpretable in the specific context of verification. Suppose we have a machine learning system that predicts X, and we provide rationale for this prediction X. Given an input, an explanation, and an output, is the output consistent with the input and the supposed rationale? Via a series of user-studies, we identify what kinds of increases in complexity have the greatest effect on the time it takes for humans to verify the rationale, and which seem relatively insensitive.

How do Humans Understand Explanations from Machine Learning Systems? An Evaluation of the Human-Interpretability of Explanation

This paper reviews progress in the application of computational models to personality, developmental and clinical neuroscience. We first describe the concept of a computational phenotype, a collection of parameters derived from computational models fit to behavioral and neural data. This approach represents individuals as points in a continuous parameter space, complementing traditional trait and symptom measures. One key advantage of this representation is that it is mechanistic: the parameters have interpretations in terms of cognitive processes, which can be translated into quantitative predictions about future behavior and brain activity. We illustrate with several examples how this approach has led to new scientific insights into individual differences, developmental trajectories, and psychopathology. We then survey some of the challenges that lay ahead.

1 Computational phenotyping : using models to understand individual differences in personality , development , and mental illness

Midbrain dopamine neurons are commonly thought to report a reward prediction error, as hypothesized by reinforcement learning theory. While this theory has been highly successful, several lines of evidence suggest that dopamine activity also encodes sensory prediction errors unrelated to reward. Here we develop a new theory of dopamine function that embraces a broader conceptualization of prediction errors. By signaling errors in both sensory and reward predictions, dopamine supports a form of reinforcement learning that lies between model-based and model-free algorithms. This account remains consistent with current canon regarding the correspondence between dopamine transients and reward prediction errors, while also accounting for new data suggesting a role for these signals in phenomena such as sensory preconditioning and identity unblocking, which ostensibly draw upon knowledge beyond reward predictions.

The Medial Prefrontal Cor tex Shapes Dopamine Reward Prediction Errors under State Uncertainty Highlights

How do humans search for rewards? This question is commonly studied using multi-armed bandit tasks, which require participants to trade off exploration and exploitation. Standard multi-armed bandits assume that each option has an independent reward distribution. However, learning about options independently is unrealistic, since in the real world options often share an underlying structure. We study a class of structured bandit tasks, which we use to probe how generalization guides exploration. In a structured multi-armed bandit, options have a correlation structure dictated by a latent function. We focus on bandits in which rewards are linear functions of an option’s spatial position. Across 5 experiments, we find evidence that participants utilize functional structure to guide their exploration, and also exhibit a learning-to-learn effect across rounds, becoming progressively faster at identifying the latent function. The experiments rule out several heuristic explanations, and show that the same findings obtain with non-linear functions. Comparing several models of learning and decision making, we find that the best model of human behavior in our tasks combines three computational mechanisms: (1) function learning, (2) clustering of reward distributions across rounds, and (3) uncertainty-guided exploration. Our results suggest that human reinforcement learning can utilize latent structure in sophisticated ways to improve efficiency.

Toward a universal decoder of linguistic meaning from brain activation

We propose that humans spontaneously organize environments into clusters of states that support hierarchical planning, enabling them to tackle challenging problems by breaking them down into sub-problems at various levels of abstraction. People constantly rely on such hierarchical presentations to accomplish tasks big and small – from planning one’s day, to organizing a wedding, to getting a PhD – often succeeding on the very first attempt. We formalize a Bayesian model of hierarchy discovery that explains how humans discover such useful abstractions. Building on principles developed in the robotics literature, the model predicts that hierarchy discovery should be sensitive to the topological structure, reward distribution, and distribution of tasks in the environment. In five simulations, we show that the model accounts for previously reported effects of environment structure on planning behavior, such as detection of bottleneck states and transitions. We then test the novel predictions of the model in seven behavioral experiments, demonstrating how the distribution of tasks and rewards can additionally influence planning behavior via the discovered hierarchy, sometimes facilitating and sometimes hindering performance. We also show that people use uncertainty to guide their learning in a way that is informative for hierarchy discovery. Finally, we propose how hierarchy discovery and hierarchical planning might be implemented in the brain. Together, these findings present an important advance in our understanding of how the brain might use Bayesian inference to uncover and exploit the hidden hierarchical structure of the world.

Discovery of hierarchical representations for efficient planning

We often desire our models to be interpretable as well as accurate. Prior work on optimizing models for interpretability has relied on easy-to-quantify proxies for interpretability, such as sparsity or the number of operations required. In this work, we optimize for interpretability by directly including humans in the optimization loop. We develop an algorithm that minimizes the number of user studies to find models that are both predictive and interpretable and demonstrate our approach on several data sets. Our human subjects results show trends towards different proxy notions of interpretability on different datasets, which suggests that different proxies are preferred on different tasks.

Abstract Zwaan et al. and others discuss the importance of the inevitable differences between a replication experiment and the corresponding original experiment. But these discussions are not informed by a principled, quantitative framework for taking differences into account. Bayesian confirmation theory provides such a framework. It will not entirely solve the problem, but it will lead to new insights.

The same persuasive message can be interpreted in a positive or negative way, challenging our ability to predict its effectiveness. Here, we analyze theoretically and experimentally how causal reasoning contributes to this process of interpretation and can produce attitude reversals due to the network structure of beliefs. We conduct two vignette experiments, one based on the famous slogan of the car rental agency Avis ("We're No. 2—that means we try harder"), and the other based on online product reviews. When participants' contextual beliefs about the economic environment are manipulated, message effectiveness changes as predicted by a Bayesian mechanism in which seemingly negative information is "explained away" in a more positive light, or vice versa. Thus causal reasoning may help account for certain counterintuitive kinds of high-level attitude change.

How do people perceive and communicate structure? We investigate this question by letting participants play a communication game, where one player describes a pattern, and another player redraws it based on the description alone. We use this paradigm to compare two models of pattern description, one compositional (complex structures built out of simpler ones) and one non-compositional. We find that compositional patterns are communicated more effectively than non-compositional patterns, that a compositional model of pattern description predicts which patterns are harder to describe, and that this model can be used to evaluate participants’ drawings, producing human-like quality ratings. Our results suggest that natural language can tap into a compositionally structured pattern description language.

Remembrance of inferences past: Amortization in human hypothesis generation

Previous work on morality has proposed psychophysical and/or qualitative models for moral judgment. While these models capture the data found in their respective studies, we believe they miss the underlying concepts on which people base their moral judgments. Here, we propose a quantitative model of morality grounded in our current understanding of intuitive theories of physics, psychology, and causality. We detail how peoples intuitions of physics and causality can be used to infer the desire and intent of an agent to bring about or prevent harm and how this process can qualitatively predict empirical findings of previous work on moral judgment and quantitatively predict results in new scenarios involving an agent harming or helping another.

To survive in complex environments, animals need to have mechanisms to select effective actions quickly, with minimal computational costs. As perhaps the computationally most parsimonious of these systems, Pavlovian control accomplishes this by hardwiring specific stereotyped responses to certain classes of stimuli. It is well documented that appetitive cues initiate a Pavlovian bias toward vigorous approach; however, Pavlovian responses to aversive stimuli are less well understood. Gaining a deeper understanding of aversive Pavlovian responses, such as active avoidance, is important given the critical role these behaviors play in several psychiatric conditions. The goal of the current study was to establish a behavioral and computational framework to examine aversive Pavlovian responses (activation vs. inhibition) depending on the proximity of an aversive state (escape vs. avoidance). We introduce a novel task in which participants are exposed to primary aversive (noise) stimuli and characterized behavior using a novel generative computational model. This model combines reinforcement learning and drift-diffusion models so as to capture effects of invigoration/inhibition in both explicit choice behavior as well as changes in RT. Choice and RT results both suggest that escape is associated with a bias for vigorous action, whereas avoidance is associated with behavioral inhibition. These results lay a foundation for future work seeking insights into typical and atypical aversive Pavlovian responses involved in psychiatric disorders, allowing us to quantify both implicit and explicit indices of vigorous choice behavior in the context of aversion.

Competition and Cooperation Between Multiple Reinforcement Learning Systems

Abstract This paper reviews progress in the application of computational models to personality, developmental, and clinical neuroscience. We first describe the concept of a computational phenotype, a collection of parameters derived from computational models fit to behavioral and neural data. This approach represents individuals as points in a continuous parameter space, complementing traditional trait and symptom measures. One key advantage of this representation is that it is mechanistic: The parameters have interpretations in terms of cognitive processes, which can be translated into quantitative predictions about future behavior and brain activity. We illustrate with several examples how this approach has led to new scientific insights into individual differences, developmental trajectories, and psychopathology. We then survey some of the challenges that lay ahead.

Computational Phenotyping: Using Models to Understand Individual Differences in Personality, Development, and Mental Illness

In order to discover the most rewarding actions, agents must collect information about their environment, potentially foregoing reward. The optimal solution to this “explore-exploit” dilemma is often computationally challenging, but principled algorithmic approximations exist. These approximations utilize uncertainty about action values in different ways. Some random exploration algorithms scale the level of choice stochasticity with the level of uncertainty. Other directed exploration algorithms add a “bonus” to action values with high uncertainty. Random exploration algorithms are sensitive to total uncertainty across actions, whereas directed exploration algorithms are sensitive to relative uncertainty. This paper reports a multi-armed bandit experiment in which total and relative uncertainty were orthogonally manipulated. We found that humans employ both exploration strategies, and that these strategies are independently controlled by different uncertainty computations.

Modern theories of decision making emphasize the reference-dependency of decision making under risk. In particular, people tend to be risk-averse for outcomes greater than their reference point, and risk-seeking for outcomes less than their reference point. A key question is where reference points come from. A common assumption is that reference points correspond to expectations about outcomes, but it is unclear whether people rely on a single global expectation, or multiple local expectations. If the latter, how do people determine which expectation to apply in a particular situation? We argue that people discover reference points using a form of Bayesian structure learning, which partitions outcomes into distinct contexts, each with its own reference point corresponding to the expected outcome in that context. Consistent with this theory, we show experimentally that dramatic change in the distribution of outcomes can induce the discovery of a new reference point, with systematic effects on risk preferences. By contrast, when changes are gradual, a single reference point is continuously updated.

Corticostriatal signatures of learning efficient internal models for control

In an optimal stopping problem, people encounter a sequence of options and are tasked with choosing the best one; once an option is rejected, it is no longer available. Recent studies of optimal stopping suggest that people compare the current option with an internal threshold and accept it when the option exceeds the threshold. In contrast, we propose that humans decide to accept or reject an option based on an estimate of the probability that a better option will be observed in the future. We develop a computational model that formalizes this idea, and compare the model to the optimal policy in two experiments. Our model provides a better account of the data than the optimal model. In particular, our model explains how the distributional structure of option values affects stopping behavior, providing a step towards a more complete psychological theory of optimal stopping.

Supplementary material from "Rethinking dopamine as generalized prediction error"

Humans form social coalitions in every society on earth, yet we know very little about how social group boundaries are learned and represented. We derive predictions from a computational model of latent structure learning to move beyond explicit category labels and mere similarity as the sole inputs to social group representations. Four experiments examine (a) how evidence for group boundaries is accumulated in a consequential social context (i.e., learning about others’ political values), (b) to what extent learning about these boundaries drives one’s own choices as well as attributions about other agents in the environment, and (c) whether these latent groups affect choice even in the presence of group labels that contradict the latent group structure. Our results suggest that people integrate information about how agents in the environment relate to one another in addition to oneself to infer social group structure. We argue that this mechanism is a plausible explanation of other theories of social relations—for example, balance theory.

Natural learners must compute an estimate of future outcomes that follow from a stimulus in continuous time. Widely used reinforcement learning algorithms discretize continuous time and estimate either transition functions from one step to the next (model-based algorithms) or a scalar value of exponentially discounted future reward using the Bellman equation (model-free algorithms). An important drawback of model-based algorithms is that computational cost grows linearly with the amount of time to be simulated. An important drawback of model-free algorithms is the need to select a timescale required for exponential discounting. We present a computational mechanism, developed based on work in psychology and neuroscience, for computing a scale-invariant timeline of future outcomes. This mechanism efficiently computes an estimate of inputs as a function of future time on a logarithmically compressed scale and can be used to generate a scale-invariant power-law-discounted estimate of expected future reward. The representation of future time retains information about what will happen when. The entire timeline can be constructed in a single parallel operation that generates concrete behavioral and neural predictions. This computational mechanism could be incorporated into future reinforcement learning algorithms.

The perceived similarity between two objects varies with the distribution of other objects in the same context. The most famous theory of similarity judgment, Tversky’s contrast model, can capture some of these contextual effects by assuming that the context changes the weighting of shared and distinctive object features in determining similarity judgment. However, the contrast model does not by itself explain how the weights are determined by context. This paper shows how a Bayesian theory of similarity judgment, first proposed by Kemp, Bernstein, and Tenenbaum (2005), can fill the gap. The key ideas are that (a) perceived similarity reflects the posterior probability that two objects arose from the same generative process; and (b) the parameters of the generative process are estimated based on all the objects in the context. The Bayesian theory is mathematically equivalent to Tversky’s contrast model, but now the weights are directly determined by the estimated parameters. Several context effects can be captured using this theory, supporting the claim that similarity judgment is a form of inference.

Human behavior is sometimes determined by habit and other times by goal-directed planning. Modern reinforcement-learning theories formalize this distinction as a competition between a computationally cheap but inaccurate model-free system that gives rise to habits and a computationally expensive but accurate model-based system that implements planning. It is unclear, however, how people choose to allocate control between these systems. Here, we propose that arbitration occurs by comparing each system’s task-specific costs and benefits. To investigate this proposal, we conducted two experiments showing that people increase model-based control when it achieves greater accuracy than model-free control, and especially when the rewards of accurate performance are amplified. In contrast, they are insensitive to reward amplification when model-based and model-free control yield equivalent accuracy. This suggests that humans adaptively balance habitual and planned action through on-line cost-benefit analysis.

Cost-Benefit Arbitration Between Multiple Reinforcement-Learning Systems

Our understanding of probabilistic inference in the brain has progressed rapidly. However, there remains a big gap between the relatively simple probabilistic inference problems facing low-level sensory systems and the intractably complex problems facing high-level cognitive systems. Psychologists have begun exploring cognitively plausible algorithms for approximately solving complex inference problems. We review recent attempts to connect these algorithmic accounts to neural circuit mechanisms, and argue that neural mechanisms for solving low-level sensory inference problems can be extended to tackle complex inference problems.

Midbrain dopamine neurons are commonly thought to report a reward prediction error, as hypothesized by reinforcement learning theory. While this theory has been highly successful, several lines of evidence suggest that dopamine activity also encodes sensory prediction errors unrelated to reward. Here we develop a new theory of dopamine function that embraces a broader conceptualization of prediction errors. By signaling errors in both sensory and reward predictions, dopamine supports a form of reinforcement learning that lies between model-based and model-free algorithms. We show that the theory can account for the role of dopamine in phenomena such as sensory preconditioning and identity unblocking, which ostensibly draw upon knowledge beyond reward predictions.

Dopamine reward prediction errors reflect hidden state inference across time

The hypothesis that the phasic dopamine response reports a reward prediction error has become deeply entrenched. However, dopamine neurons exhibit several notable deviations from this hypothesis. A coherent explanation for these deviations can be obtained by analyzing the dopamine response in terms of Bayesian reinforcement learning. The key idea is that prediction errors are modulated by probabilistic beliefs about the relationship between cues and outcomes, updated through Bayesian inference. This account can explain dopamine responses to inferred value in sensory preconditioning, the effects of cue pre-exposure (latent inhibition) and adaptive coding of prediction errors when rewards vary across orders of magnitude. We further postulate that orbitofrontal cortex transforms the stimulus representation through recurrent dynamics, such that a simple error-driven learning rule operating on the transformed representation can implement the Bayesian reinforcement learning update.

A cognitive map has long been the dominant metaphor for hippocampal function, embracing the idea that place cells encode a geometric representation of space. However, evidence for predictive coding, reward sensitivity and policy dependence in place cells suggests that the representation is not purely spatial. We approach this puzzle from a reinforcement learning perspective: what kind of spatial representation is most useful for maximizing future reward? We show that the answer takes the form of a predictive representation. This representation captures many aspects of place cell responses that fall outside the traditional view of a cognitive map. Furthermore, we argue that entorhinal grid cells encode a low-dimensionality basis set for the predictive representation, useful for suppressing noise in predictions and extracting multiscale structure for hierarchical planning.

The theory of decision by sampling (DbS) proposes that an attribute’s subjective value is its rank within a sample of attribute values retrieved from memory. This can account for instances of context dependence beyond the reach of classic theories which assume stable preferences. In this paper, we provide a normative justification for DbS that is based on the principle of efficient coding. The efficient representation of information in a noiseless communication channel is characterized by a uniform response distribution, which the rank transformation implements. However, cognitive limitations imply that decision samples are finite, introducing noise. Efficient coding in a noisy channel requires smoothing of the signal, a principle that leads to a new generalization of DbS. This generalization is closely connected to range-frequency theory, and helps descriptively account for a wider set of behavioral observations, such as how context sensitivity varies with the number of available response categories.

Decision by sampling implements efficient coding of psychoeconomic functions

Balancing exploration and exploitation is a fundamental problem in reinforcement learning. Previous neuroimaging studies of the exploration–exploitation dilemma could not completely disentangle these two processes, making it difficult to unambiguously identify their neural signatures. We overcome this problem using a task in which subjects can either observe (pure exploration) or bet (pure exploitation). Insula and dorsal anterior cingulate cortex showed significantly greater activity on observe trials compared to bet trials, suggesting that these regions play a role in driving exploration. A model-based analysis of task performance suggested that subjects chose to observe until a critical evidence threshold was reached. We observed a neural signature of this evidence accumulation process in the ventromedial prefrontal cortex. These findings support theories positing an important role for anterior cingulate cortex in exploration, while also providing a new perspective on the roles of insula and ventromedial prefrontal cortex.

Pure correlates of exploration and exploitation in the human brain

Abstract We were encouraged by the broad enthusiasm for building machines that learn and think in more human-like ways. Many commentators saw our set of key ingredients as helpful, but there was disagreement regarding the origin and structure of those ingredients. Our response covers three main dimensions of this disagreement: nature versus nurture, coherent theories versus theory fragments, and symbolic versus sub-symbolic representations. These dimensions align with classic debates in artificial intelligence and cognitive science, although, rather than embracing these debates, we emphasize ways of moving beyond them. Several commentators saw our set of key ingredients as incomplete and offered a wide range of additions. We agree that these additional ingredients are important in the long run and discuss prospects for incorporating them. Finally, we consider some of the ethical questions raised regarding the research program as a whole.

Ingredients of intelligence: From classic debates to an engineering roadmap

Behavioral evidence suggests that beliefs about causal structure constrain associative learning, determining which stimuli can enter into association, as well as the functional form of that association. Bayesian learning theory provides one mechanism by which structural beliefs can be acquired from experience, but the neural basis of this mechanism is poorly understood. We studied this question with a combination of behavioral, computational, and neuroimaging techniques. Male and female human subjects learned to predict an outcome based on cue and context stimuli while being scanned using fMRI. Using a model-based analysis of the fMRI data, we show that structure learning signals are encoded in posterior parietal cortex, lateral prefrontal cortex, and the frontal pole. These structure learning signals are distinct from associative learning signals. Moreover, representational similarity analysis and information mapping revealed that the multivariate patterns of activity in posterior parietal cortex and anterior insula encode the full posterior distribution over causal structures. Variability in the encoding of the posterior across subjects predicted variability in their subsequent behavioral performance. These results provide evidence for a neural architecture in which structure learning guides the formation of associations. SIGNIFICANCE STATEMENT Animals are able to infer the hidden structure behind causal relations between stimuli in the environment, allowing them to generalize this knowledge to stimuli they have never experienced before. A recently published computational model based on this idea provided a parsimonious account of a wide range of phenomena reported in the animal learning literature, suggesting a dedicated neural mechanism for learning this hidden structure. Here, we validate this model by measuring brain activity during a task that involves both structure learning and associative learning. We show that a distinct network of regions supports structure learning and that the neural signal corresponding to beliefs about structure predicts future behavioral performance.

Humans and animals are capable of evaluating actions by considering their long-run future rewards through a process described using model-based reinforcement learning (RL) algorithms. The mechanisms by which neural circuits perform the computations prescribed by model-based RL remain largely unknown; however, multiple lines of evidence suggest that neural circuits supporting model-based behavior are structurally homologous to and overlapping with those thought to carry out model-free temporal difference (TD) learning. Here, we lay out a family of approaches by which model-based computation may be built upon a core of TD learning. The foundation of this framework is the successor representation, a predictive state representation that, when combined with TD learning of value predictions, can produce a subset of the behaviors associated with model-based learning, while requiring less decision-time computation than dynamic programming. Using simulations, we delineate the precise behavioral capabilities enabled by evaluating actions using this approach, and compare them to those demonstrated by biological organisms. We then introduce two new algorithms that build upon the successor representation while progressively mitigating its limitations. Because this framework can account for the full range of observed putatively model-based behaviors while still utilizing a core TD framework, we suggest that it represents a neurally plausible family of mechanisms for model-based evaluation. Author Summary According to standard models, when confronted with a choice, animals and humans rely on two separate, distinct processes to come to a decision. One process deliberatively evaluates the consequences of each candidate action and is thought to underlie the ability to flexibly come up with novel plans. The other process gradually increases the propensity to perform behaviors that were previously successful and is thought to underlie automatically executed, habitual reflexes. Although computational principles and animal behavior support this dichotomy, at the neural level, there is little evidence supporting a clean segregation. For instance, although dopamine — famously implicated in drug addiction and Parkinson’s disease — currently only has a well-defined role in the automatic process, evidence suggests that it also plays a role in the deliberative process. In this work, we present a computational framework for resolving this mismatch. We show that the types of behaviors associated with either process could result from a common learning mechanism applied to different strategies for how populations of neurons could represent candidate actions. In addition to demonstrating that this account can produce the full range of flexible behavior observed in the empirical literature, we suggest experiments that could detect the various approaches within this framework.

Predictive representations can link model-based reinforcement learning to model-free mechanisms

Atari games are an excellent testbed for studying intelligent behavior, as they offer a range of tasks that differ widely in their visual representation, game dynamics, and goals presented to an agent. The last two years have seen a spate of research into artificial agents that use a single algorithm to learn to play these games. The best of these artificial agents perform at better-than-human levels on most games, but require hundreds of hours of game-play experience to produce such behavior. Humans, on the other hand, can learn to perform well on these tasks in a matter of minutes. In this paper we present data on human learning trajectories for several Atari games, and test several hypotheses about the mechanisms that lead to such rapid learning.

Author response: The computational nature of memory modification

Imagination enables us not only to transcend reality but also to learn about it. In the context of reinforcement learning, an agent can rationally update its value estimates by simulating an internal model of the environment, provided that the model is accurate. In a series of sequential decision-making experiments, we investigated the impact of imaginative simulation on subsequent decisions. We found that imagination can cause people to pursue imagined paths, even when these paths are suboptimal. This bias is systematically related to participants' optimism about how much reward they expect to receive along imagined paths; providing feedback strongly attenuates the effect. The imagination effect can be captured by a reinforcement learning model that includes a bonus added onto imagined rewards. Using fMRI, we show that a network of regions associated with valuation is predictive of the imagination effect. These results suggest that imagination, although a powerful tool for learning, is also susceptible to motivational biases.

Imaginative Reinforcement Learning: Computational Principles and Neural Mechanisms

Computational neuroscience is, to first order, dominated by two approaches: the “bottom-up” approach, which searches for statistical patterns in large-scale neural recordings, and the “top-down” approach, which begins with a theory of computation and considers plausible neural implementations. While this division is not clear-cut, we argue that these approaches should be much more intimately linked. From a Bayesian perspective, computational theories provide constrained prior distributions on neural data—albeit highly sophisticated ones. By connecting theory to observation via a probabilistic model, we provide the link necessary to test, evaluate, and revise our theories in a data-driven and statistically rigorous fashion. This review highlights examples of this theory-driven pipeline for neural data analysis in recent literature and illustrates it with a worked example based on the temporal difference learning model of dopamine.

Using computational theory to constrain statistical models of neural data

The ubiquity of systems using artificial intelligence or "AI" has brought increasing attention to how those systems should be regulated. The choice of how to regulate AI systems will require care. AI systems have the potential to synthesize large amounts of data, allowing for greater levels of personalization and precision than ever before|applications range from clinical decision support to autonomous driving and predictive policing. That said, common sense reasoning [McCarthy, 1960] remains one of the holy grails of AI, and there exist legitimate concerns about the intentional and unintentional negative consequences of AI systems [Bostrom, 2003, Amodei et al., 2016, Sculley et al., 2014]. 
 
There are many ways to hold AI systems accountable. In this work, we focus on one: explanation. Questions about a legal right to explanation from AI systems was recently debated in the EU General Data Protection Regulation [Goodman and Flaxman, 2016, Wachter et al., 2017], and thus thinking carefully about when and how explanation from AI systems might improve accountability is timely. Good choices about when to demand explanation can help prevent negative consequences from AI systems, while poor choices may not only fail to hold AI systems accountable but also hamper the development of much-needed beneficial AI systems. 
 
Below, we briefly review current societal, moral, and legal norms around explanation, and then focus on the different contexts under which explanation is currently required under the law. We find that there exists great variation around when explanation is demanded, but there also exists important consistencies: when demanding explanation from humans, what we typically want to know is how and whether certain input factors affected the final decision or outcome. 
 
These consistencies allow us to list the technical considerations that must be considered if we desired AI systems that could provide kinds of explanations that are currently required of humans under the law. Contrary to popular wisdom of AI systems as indecipherable black boxes, we find that this level of explanation should often be technically feasible but may sometimes be practically onerous|there are certain aspects of explanation that may be simple for humans to provide but challenging for AI systems, and vice versa. As an interdisciplinary team of legal scholars, computer scientists, and cognitive scientists, we recommend that for the present, AI systems can and should be held to a similar standard of explanation as humans currently are; in the future we may wish to hold an AI to a different standard.

We routinely observe others' choices and use them to guide our own. Whose choices influence us more, and why? Prior work has focused on the effect of perceived similarity between two individuals (self and others), such as the degree of overlap in past choices or explicitly recognizable group affiliations. In the real world, however, any dyadic relationship is part of a more complex social structure involving multiple social groups that are not directly observable. Here we suggest that human learners go beyond dyadic similarities in choice behaviors or explicit group memberships; they infer the structure of social influence by grouping individuals (including themselves) based on choices, and they use these groups to decide whose choices to follow. We propose a computational model that formalizes this idea, and we test the model predictions in a series of behavioral experiments. In Experiment 1, we reproduce a well-established finding that people's choices are more likely to be influenced by someone whose past choices are more similar to their own past choices, as predicted by our model as well as dyadic similarity models. In Experiments 2-5, we test a set of unique predictions of our model by looking at cases where the degree of choice overlap between individuals is equated, but their choices indicate a latent group structure. We then apply our model to prior empirical results on infants' understanding of others' preferences, presenting an alternative account of developmental changes. Finally, we discuss how our model relates to classical findings in the social influence literature and the theoretical implications of our model. Taken together, our findings demonstrate that structure learning is a powerful framework for explaining the influence of social information on decision making in a variety of contexts.

The “blessing of abstraction” refers to the observation that acquiring abstract knowledge sometimes proceeds more quickly than acquiring more speciﬁc knowledge. This observation can be formalized and reproduced by hierarchical Bayesian models. The key notion is that more abstract layers of the hierarchy have a larger “effective” sample size, because they combine information across multiple speciﬁc instances lower in the hierarchy. This notion relies on speciﬁc variables being relatively concentrated around the abstract “overhypothesis”. If the variables are highly dispersed, then the effective sample size for the abstract layers will not be appreciably larger than for the speciﬁc layers. Moreover, the blessing of abstraction is counterbalanced by the fact that data are more informative about lower levels of the hierarchy, because there is necessarily less stochasticity intervening between speciﬁc variables and the data. Thus, in certain cases abstract knowledge will be acquired more slowly than speciﬁc knowledge. This paper reports an experiment that shows how manipulating dispersion can produce both fast and slow acquisition of abstract knowledge in the same paradigm.

Bayesian models of cognition posit that people compute probability distributions over hypotheses, possibly by constructing a sample-based approximation. Since people encounter many closely related distributions, a computationally efficient strategy is to selectively reuse computations – either the samples themselves or some summary statistic. We refer to these reuse strategies as amortized inference. In two experiments, we present evidence consistent with amortization. When sequentially answering two related queries about natural scenes, we show that answers to the second query vary systematically depending on the structure of the first query. Using a cognitive load manipulation, we find evidence that people cache summary statistics rather than raw sample sets. These results enrich our notions of how the brain approximates probabilistic inference.

This chapter reviews the diverse roles that causal knowledge plays in reinforcement learning. The first half of the chapter contrasts a “model-free” system that learns to repeat actions that lead to reward with a “model-based” system that learns a probabilistic causal model of the environment which it then uses to plan action sequences. Evidence suggests that these two systems coexist in the brain, both competing and cooperating with each other. The interplay of two systems allows the brain to negotiate a balance between cognitively cheap but inaccurate model-free algorithms and accurate but expensive model-based algorithms. The second half of the chapter reviews research on hidden state inference in reinforcement learning. The problem of inferring hidden states can be construed in terms of inferring the latent causes that give rise to sensory data and rewards. Because hidden state inference a↵ects both model-based and model-free reinforcement learning, causal knowledge impinges upon both systems.

Running head : DECISION BY SAMPLING IMPLEMENTS EFFICIENT CODING 2

Bayesian models of cognition assume that people compute probability distributions over hypotheses. However, the required computations are frequently intractable or prohibitively expensive. Since people often encounter many closely related distributions, selective reuse of computations (amortized inference) is a computationally efficient use of the brain’s limited resources. We present three experiments that provide evidence for amortization in human probabilistic reasoning. When sequentially answering two related queries about natural scenes, participants’ responses to the second query systematically depend on the structure of the first query. This influence is sensitive to the content of the queries, only appearing when the queries are related. Using a cognitive load manipulation, we find evidence that people amortize summary statistics of previous inferences, rather than storing the entire distribution. These findings support the view that the brain trades off accuracy and computational cost, to make efficient use of its limited cognitive resources to approximate probabilistic inference.

People can judge whether they will enjoy dishes like waffles with horseradish cream sauce or broccoli ice cream even if they have never tried them. What representations and computations support reasoning in such situations? We develop a theory of decision making in combinatorial domains. Its central claim is that utility functions can be compositionally structured: The utility of a combination is a function of its constituents’ utilities and the rules for combining them. Utilities are induced from experience by probabilistic reasoning over the structured space of utility functions. In a series of experiments, we show how this theory can capture human evaluations of novel food combinations. We first show that the theory quantitatively predicts evaluations of novel food combinations. We then report more strongly controlled experiments (using unfamiliar foods) that rule out several alternative theories. Taken together, these experiments demonstrate how compositionally structured representations of utility can support decision making in combinatorial domains.

Many models of prospective coding in the hippocampus have drawn inspiration from the well-documented ordered temporal structure of firing in hippocampus relative to the theta phase1–3, and considered the many ways in which replaying hippocampal sweeps during sharp wave ripple events might be used for planning4–9. The firing of cells in hippocampus is aligned to theta such that cells encoding more distant places fire later during a theta cycle than immediately upcoming states (a phenomenon referred to as theta precession). States fire in a sequence ordered according to when they will next appear, suggesting a likely mechanism for forward sequential planning2, 10. However, precession alone is probably not sufficient to enact backward expansion of place fields in CA1, since NMDA antagonists that disrupt the persistent, backward expansion of place fields leave theta precession intact11. Furthermore, precession in CA1 likely originates outside of the hippocampus, as it arises in MEC independently12, and depends crucially on input from surrounding areas such as MEC and CA313, 14. Thus, we think that it is worthwhile to consider the possible contributions of this backward expansion to planning in addition to the contributions of the hippocampal temporal code examined by this prior work. The type of prospective coding implemented by theta precession and sharp wave ripple events is reminiscent of model-based, sequential forward planning3; many experiments and theoretical proposals have looked at how replaying these sequences at decision points and at rest can underlie planning4–6, 8, 9. By integrating the reward reactivated at each state along a sweep through upcoming states, the value of a specific upcoming trajectory can be predicted. The SR is a different type of prospective code, with different tradeoffs. The SR marginalizes over all possible sequences of actions, making predictions over an arbitrarily long timescale in constant time. This results in a loss of flexibility relative to model-based planning, but greater computational efficiency. Thus, the SR cannot replace the full functionality of model-based sweeps. However, as we allude to in the article, the SR can provide a useful adjunct to the sweeps. In Fig. S15, we illustrate how performing sweeps in the successor representation space (Fig. S15F) or performing sweeps that terminate on a successor representation of the terminal state (Fig. S15G) can extend the range of these predictions, making the hippocampal representations a more powerful substrate for planning. This is tantamount to a “bootstrapped search” algorithm, variants of which have been successful in a range of applications15, 16.

Supplementary information for “ The hippocampus as a predictive map ”

&NA; We review the psychology and neuroscience of reinforcement learning (RL), which has experienced significant progress in the past two decades, enabled by the comprehensive experimental study of simple learning and decision‐making tasks. However, one challenge in the study of RL is computational: The simplicity of these tasks ignores important aspects of reinforcement learning in the real world: (a) State spaces are high‐dimensional, continuous, and partially observable; this implies that (b) data are relatively sparse and, indeed, precisely the same situation may never be encountered twice; furthermore, (c) rewards depend on the long‐term consequences of actions in ways that violate the classical assumptions that make RL tractable. A seemingly distinct challenge is that, cognitively, theories of RL have largely involved procedural and semantic memory, the way in which knowledge about action values or world models extracted gradually from many experiences can drive choice. This focus on semantic memory leaves out many aspects of memory, such as episodic memory, related to the traces of individual events. We suggest that these two challenges are related. The computational challenge can be dealt with, in part, by endowing RL systems with episodic memory, allowing them to (a) efficiently approximate value functions over complex state spaces, (b) learn with very little data, and (c) bridge long‐term dependencies between actions and rewards. We review the computational theory underlying this proposal and the empirical evidence to support it. Our proposal suggests that the ubiquitous and diverse roles of memory in RL may function as part of an integrated learning system.

Reinforcement Learning and Episodic Memory in Humans and Animals: An Integrative Framework

How do people learn about complex functional structure? Taking inspiration from other areas of cognitive science, we propose that this is accomplished by harnessing compositionality: complex structure is decomposed into simpler building blocks. We formalize this idea within the framework of Bayesian regression using a grammar over Gaussian process kernels. We show that participants prefer compositional over non-compositional function extrapolations, that samples from the human prior over functions are best described by a compositional model, and that people perceive compositional functions as more predictable than their non-compositional but otherwise similar counterparts. We argue that the compositional nature of intuitive functions is consistent with broad principles of human cognition.

Learning robust value functions given raw observations and rewards is now possible with model-free and model-based deep reinforcement learning algorithms. There is a third alternative, called Successor Representations (SR), which decomposes the value function into two components -- a reward predictor and a successor map. The successor map represents the expected future state occupancy from any given state and the reward predictor maps states to scalar rewards. The value function of a state can be computed as the inner product between the successor map and the reward weights. In this paper, we present DSR, which generalizes SR within an end-to-end deep reinforcement learning framework. DSR has several appealing properties including: increased sensitivity to distal reward changes due to factorization of reward and world dynamics, and the ability to extract bottleneck states (subgoals) given successor maps trained under a random policy. We show the efficacy of our approach on two diverse environments given raw pixel observations -- simple grid-world domains (MazeBase) and the Doom game engine.

Traditional topic models do not account for semantic regularities in language. Recent distributional representations of words exhibit semantic consistency over directional metrics such as cosine similarity. However, neither categorical nor Gaussian observational distributions used in existing topic models are appropriate to leverage such correlations. In this paper, we propose to use the von Mises-Fisher distribution to model the density of words over a unit sphere. Such a representation is well-suited for directional data. We use a Hierarchical Dirichlet Process for our base topic model and propose an efficient inference algorithm based on Stochastic Variational Inference. This model enables us to naturally exploit the semantic structures of word embeddings while flexibly discovering the number of topics. Experiments demonstrate that our method outperforms competitive approaches in terms of topic coherence on two different text corpora while offering efficient inference.

Proceedings of the conference. Association for Computational Linguistics. Meeting

How do people recognize and learn about complex functional structure? Taking inspiration from other areas of cognitive science, we propose that this is achieved by harnessing compositionality: complex structure is decomposed into simpler building blocks. We formalize this idea within the framework of Bayesian regression using a grammar over Gaussian process kernels, and compare this approach with other structure learning approaches. Participants consistently chose compositional (over non-compositional) extrapolations and interpolations of functions. Experiments designed to elicit priors over functional patterns revealed an inductive bias for compositional structure. Compositional functions were perceived as subjectively more predictable than non-compositional functions, and exhibited other signatures of predictability, such as enhanced memorability and reduced numerosity. Taken together, these results support the view that the human intuitive theory of functions is inherently compositional.

COMPOSITIONAL INDUCTIVE BIASES 3 Compositional Inductive Biases in Function Learning

Retrieving a memory can modify its influence on subsequent behavior. Whether this phenomenon arises from modification of the contents of the memory trace or its accessibility is a matter of considerable debate. We develop a computational theory that incorporates both mechanisms. Modification of the contents of the memory trace occurs through classical associative learning, but which memory trace is accessed (and thus made eligible for modification) depends on a structure learning mechanism that discovers the units of association by segmenting the stream of experience into statistically distinct clusters (latent causes). New memories are formed when the structure learning mechanism infers that a new latent cause underlies current sensory observations. By the same token, old memories are modified when old and new sensory observations are inferred to have been generated by the same latent cause. We derive this framework from probabilistic principles, and present a computational implementation. Simulations demonstrate that our model can reproduce the major experimental findings from studies of memory modification in the Pavlovian conditioning literature, including dependence on the strength and age of memories, the interval between memory retrieval and extinction, and prediction errors following retrieval.

Running title : THEORY OF MEMORY MODIFICATION The Computational Nature of Memory Modification

Many accounts of decision making and reinforcement learning posit the existence of two distinct systems that control choice: a fast, automatic system and a slow, deliberative system. Recent research formalizes this distinction by mapping these systems to “model-free” and “model-based” strategies in reinforcement learning. Model-free strategies are computationally cheap, but sometimes inaccurate, because action values can be accessed by inspecting a look-up table constructed through trial-and-error. In contrast, model-based strategies compute action values through planning in a causal model of the environment, which is more accurate but also more cognitively demanding. It is assumed that this trade-off between accuracy and computational demand plays an important role in the arbitration between the two strategies, but we show that the hallmark task for dissociating model-free and model-based strategies, as well as several related variants, do not embody such a trade-off. We describe five factors that reduce the effectiveness of the model-based strategy on these tasks by reducing its accuracy in estimating reward outcomes and decreasing the importance of its choices. Based on these observations, we describe a version of the task that formally and empirically obtains an accuracy-demand trade-off between model-free and model-based strategies. Moreover, we show that human participants spontaneously increase their reliance on model-based control on this task, compared to the original paradigm. Our novel task and our computational analyses may prove important in subsequent empirical investigations of how humans balance accuracy and demand.

Human success and even survival depends on our ability to predict what others will do by guessing what they are thinking. If I accelerate, will he yield? If I propose, will she accept? If I confess, will they forgive? Psychologists call this capacity “theory of mind.” According to current theories, we solve this problem by assuming that others are rational actors. That is, we assume that others design and execute efficient plans to achieve their goals, given their knowledge. But if this view is correct, then our theory of mind is startlingly incomplete. Human action is not always a product of rational planning, and we would be mistaken to always interpret others’ behaviors as such. A wealth of evidence indicates that we often act habitually—a form of behavioral control that depends not on rational planning, but rather on a history of reinforcement. We aim to test whether the human theory of mind includes a theory of habitual action and to assess when and how it is deployed. In a series of studies, we show that human theory of mind is sensitive to factors influencing the balance between habitual and planned behavior.

Reinforcement Learning Trade-offs 1 Abstract Many accounts of decision making and reinforcement learning posit the existence of two distinct systems that control choice: a fast, automatic system and a slow, deliberative system. Recent research formalizes this distinction by mapping these systems to " model-free " and " model-based " strategies in reinforcement learning. Model-free strategies are computationally cheap, but sometimes inaccurate, because action values can be accessed by inspecting a look-up table constructed through trial-and-error. In contrast, model-based strategies compute action values through planning in a causal model of the environment, which is more accurate but also more cognitively demanding. It is assumed that this trade-off between accuracy and computational demand plays an important role in the arbitration between the two strategies, but we show that the hallmark task for dissociating model-free and model-based strategies, as well as several related variants, do not embody such a trade-off. We describe five factors that reduce the effectiveness of the model-based strategy on these tasks by reducing its accuracy in estimating reward outcomes and decreasing the importance of its choices. Based on these observations, we describe a version of the task that formally and empirically obtains an accuracy-demand trade-off between model-free and model-based strategies. Moreover, we show that human participants spontaneously increase their reliance on model-based control on this task, compared to the original paradigm. Our novel task and our computational analyses may prove important in subsequent empirical investigations of how humans balance accuracy and demand. Reinforcement Learning Trade-offs 2 Author Summary When you make a choice about what groceries to get for dinner, you can rely on two different strategies. You can make your choice by relying on habit, simply buying the items you need to make a meal that is second nature to you. However, you can also plan your actions in a more deliberative way, realizing that the friend who will join you is a vegetarian, and therefore you should not make the burgers that have become a staple in your cooking. These two strategies differ in how computationally demanding and accurate they are. While the habitual strategy is less computationally demanding (costs less effort and time), the deliberative strategy is more accurate. Scientists have been able to study the distinction between these strategies using a task that allows them to measure how much people rely on habit and planning strategies. Interestingly, we have discovered that in this task, the …

Running head : Reinforcement Learning Trade-offs When does model-based control pay off ?

Abstract Recent progress in artificial intelligence has renewed interest in building systems that learn and think like people. Many advances have come from using deep neural networks trained end-to-end in tasks such as object recognition, video games, and board games, achieving performance that equals or even beats that of humans in some respects. Despite their biological inspiration and performance achievements, these systems differ from human intelligence in crucial ways. We review progress in cognitive science suggesting that truly human-like learning and thinking machines will have to reach beyond current engineering trends in both what they learn and how they learn it. Specifically, we argue that these machines should (1) build causal models of the world that support explanation and understanding, rather than merely solving pattern recognition problems; (2) ground learning in intuitive theories of physics and psychology to support and enrich the knowledge that is learned; and (3) harness compositionality and learning-to-learn to rapidly acquire and generalize knowledge to new tasks and situations. We suggest concrete challenges and promising routes toward these goals that can combine the strengths of recent neural network advances with more structured cognitive models.

How does misspecifying prior smoothness assumptions about the target function affect the performance of Bayesian optimization routines? We show that misspecifying smoothness leads to an increase in regret, that this effect gets worse in higher dimensions, and that it remains substantial even if hyper-parameters are optimized.

ABSTRACT In this paper we carry out an extensive comparison of many off-the-shelf distributed semantic vectors representations of words, for the purpose of making predictions about behavioural results or human annotations of data. In doing this comparison we also provide a guide for how vector similarity computations can be used to make such predictions, and introduce many resources available both in terms of datasets and of vector representations. Finally, we discuss the shortcomings of this approach and future research directions that might address them.

A comparative evaluation of off-the-shelf distributed semantic representations for modelling behavioural data

Models of concept learning and theory acquisition often invoke a stochastic search process, in which learners generate hypotheses through some structured random process and then evaluate them on some data measuring their quality or value. To be successful within a reasonable time-frame, these models need ways of generating good candidate hypotheses even before the data are considered. Schulz (2012a) has proposed that studying the origins of new ideas in more everyday contexts, such as how we think up new names for things, can provide insight into the cognitive processes that generate good hypotheses for learning. We propose a simple generative model for how people might draw on their experience to propose new names in everyday domains such as pub names or action movies, and show that it captures surprisingly well the names that people actually imagine. We discuss the role for an analogous hypothesis-generation mechanism in enabling and constraining causal theory learning. Clerk: Occupation? Comicus: Stand-up philosopher. I coalesce the vapors of human experience into a viable and meaningful comprehension. Clerk: Oh, a bullshit artist! (History of the World, Part 1. Dir. Mel Brooks)

Coalescing the Vapors of Human Experience into a Viable and Meaningful Comprehension

Retrieval can render memories labile, allowing them to be modified or erased by behavioral or pharmacological intervention. This phenomenon, known as reconsolidation, defies explanation in terms of classical associative learning theories, prompting a reconsideration of basic learning mechanisms in the brain. We propose that two mechanisms interact to produce reconsolidation: an associative learning mechanism of the form posited by classical theories, and a structure learning mechanism that discovers the units of association by segmenting the stream of experience into statistically distinct clusters (latent causes). We derive this framework from statistical principles, and present a mechanistic implementation. Simulations demonstrate that it can reproduce the major experimental findings from studies of reconsolidation, including dependence on the strength and age of memories, the interval between memory retrieval and extinction, and prediction errors following retrieval. In addition, we present new experimental data confirming the theory’s prediction that performing part of extinction prior to retrieval attenuates reconsolidation.

Running title : THEORY OF RECONSOLIDATION The Computational Nature of Memory Reconsolidation

In noisy, dynamic environments, organisms must distinguish genuine change (e.g., the movement of prey) from noise (e.g., the rustling of leaves). Expectations should be updated only when the organism believes genuine change has occurred. Although individual variables can be highly unreliable, organisms can take advantage of the fact that changes tend to be correlated (e.g., movement of prey will tend to produce changes in both visual and olfactory modalities). Thus, observing a change in one variable provides information about the rate of change for other variables. We call this the penumbra of learning. At the neural level, the penumbra of learning may offer an explanation for why strong plasticity in one synapse can rescue weak plasticity at another (synaptic tagging and capture). At the behavioral level, it has been observed that weak learning of one task can be rescued by novelty exposure before or after the learning task. Here, using a simple number prediction task, we provide direct behavioral support for the penumbra of learning in humans, and show that it can be accounted for by a normative computational theory of learning.

How do we perceive the predictability of functions? We derive a rational measure of a function’s predictability based on Gaussian process learning curves. Using this measure, we show that the smoothness of a function can be more important to predictability judgments than the variance of additive noise or the number of samples. These patterns can be captured well by the learning curve for Gaussian process regression, which in turn crucially depends on the eigenvalue spectrum of the covariance function. Using approximate bounds on the learning curve, we model participants’ predictability judgments about sampled functions and find that smoothness is indeed a better predictor for perceived predictability than both the variance and the sample size. This means that it can sometimes be preferable to learn about noisy but smooth functions instead of deterministic complex ones.

Computational models of semantics have emerged as powerful tools for natural language processing. Recent work has developed models to handle compositionality, but these models have typically been evaluated on large, uncontrolled corpora. In this paper, we constructed a controlled set of phrase pairs and collected phrase similarity judgments, revealing novel insights into human semantic representation. None of the computational models that we considered were able to capture the pattern of human judgments. The results of a second experiment, using the same stimuli with a transformational judgment task, support a transformational account of similarity, according to which the similarity between phrases is inversely related to the number of edits required to transform one mental model into another. Taken together, our results indicate that popular models of compositional semantics do not capture important facets of human semantic representation.

In reinforcement learning (RL), a decision maker searching for the most rewarding option is often faced with the question: What is the value of an option that has never been tried before? One way to frame this question is as an inductive problem: How can I generalize my previous experience with one set of options to a novel option? We show how hierarchical Bayesian inference can be used to solve this problem, and we describe an equivalence between the Bayesian model and temporal difference learning algorithms that have been proposed as models of RL in humans and animals. According to our view, the search for the best option is guided by abstract knowledge about the relationships between different options in an environment, resulting in greater search efficiency compared to traditional RL algorithms previously applied to human cognition. In two behavioral experiments, we test several predictions of our model, providing evidence that humans learn and exploit structured inductive knowledge to make predictions about novel options. In light of this model, we suggest a new interpretation of dopaminergic responses to novelty.

Novelty and Inductive Generalization in Human Reinforcement Learning

In recent years, ideas from the computational field of reinforcement learning have revolutionized the study of learning in the brain, famously providing new, precise theories of how dopamine affects learning in the basal ganglia. However, reinforcement learning algorithms are notorious for not scaling well to multidimensional environments, as is required for real-world learning. We hypothesized that the brain naturally reduces the dimensionality of real-world problems to only those dimensions that are relevant to predicting reward, and conducted an experiment to assess by what algorithms and with what neural mechanisms this “representation learning” process is realized in humans. Our results suggest that a bilateral attentional control network comprising the intraparietal sulcus, precuneus, and dorsolateral prefrontal cortex is involved in selecting what dimensions are relevant to the task at hand, effectively updating the task representation through trial and error. In this way, cortical attention mechanisms interact with learning in the basal ganglia to solve the “curse of dimensionality” in reinforcement learning.

Reinforcement Learning in Multidimensional Environments Relies on Attention Mechanisms

Two important ideas about associative learning have emerged in recent decades: (1) Animals are Bayesian learners, tracking their uncertainty about associations; and (2) animals acquire long-term reward predictions through reinforcement learning. Both of these ideas are normative, in the sense that they are derived from rational design principles. They are also descriptive, capturing a wide range of empirical phenomena that troubled earlier theories. This article describes a unifying framework encompassing Bayesian and reinforcement learning theories of associative learning. Each perspective captures a different aspect of associative learning, and their synthesis offers insight into phenomena that neither perspective can explain on its own.

After growing up together, and mostly growing apart in the second half of the 20th century, the fields of artificial intelligence (AI), cognitive science, and neuroscience are reconverging on a shared view of the computational foundations of intelligence that promotes valuable cross-disciplinary exchanges on questions, methods, and results. We chart advances over the past several decades that address challenges of perception and action under uncertainty through the lens of computation. Advances include the development of representations and inferential procedures for large-scale probabilistic inference and machinery for enabling reflection and decisions about tradeoffs in effort, precision, and timeliness of computations. These tools are deployed toward the goal of computational rationality: identifying decisions with highest expected utility, while taking into consideration the costs of computation in complex real-world problems in which most relevant calculations can only be approximated. We highlight key concepts with examples that show the potential for interchange between computer science, cognitive science, and neuroscience.

Computational rationality: A converging paradigm for intelligence in brains, minds, and machines

Probability theory forms a natural framework for explaining the impressive success of people at solving many difficult inductive problems, such as learning words and categories, inferring the relevant features of objects, and identifying functional relationships. Probabilistic models of cognition use Bayes’ rule to identify probable structures or representations that could have generated a set of observations, whether the observations are sensory input or the output of other psychological processes. In this chapter we address an important question that arises within this framework: How do people infer representations that are complex enough to faithfully encode the world but not so complex that they “overfit” noise in the data? We discuss nonparametric Bayesian models as a potential answer to this question. To do so, first we present the mathematical background necessary to understand nonparametric Bayesian models. We then delve into nonparametric Bayesian models for three types of hidden structure: clusters, features, and functions. Finally, we conclude with a summary and discussion of open questions for future research.

Temporal difference learning models of dopamine assert that phasic levels of dopamine encode a reward prediction error. However, this hypothesis has been challenged by recent observations of gradually ramping stratal dopamine levels as a goal is approached. This note describes conditions under which temporal difference learning models predict dopamine ramping. The key idea is representational: a quadratic transformation of proximity to the goal implies approximately linear ramping, as observed experimentally.

Reinforcement learning (RL) models have been influential in understanding many aspects of basal ganglia function, from reward prediction to action selection. Time plays an important role in these models, but there is still no theoretical consensus about what kind of time representation is used by the basal ganglia. We review several theoretical accounts and their supporting evidence. We then discuss the relationship between RL models and the timing mechanisms that have been attributed to the basal ganglia. We hypothesize that a single computational system may underlie both RL and interval timing—the perception of duration in the range of seconds to hours. This hypothesis, which extends earlier models by incorporating a time-sensitive action selection mechanism, may have important implications for understanding disorders like Parkinson's disease in which both decision making and timing are impaired.

Time representation in reinforcement learning models of the basal ganglia

Hippocampal place fields have been shown to reflect behaviorally relevant aspects of space. For instance, place fields tend to be skewed along commonly traveled directions, they cluster around rewarded locations, and they are constrained by the geometric structure of the environment. We hypothesize a set of design principles for the hippocampal cognitive map that explain how place fields represent space in a way that facilitates navigation and reinforcement learning. In particular, we suggest that place fields encode not just information about the current location, but also predictions about future locations under the current transition distribution. Under this model, a variety of place field phenomena arise naturally from the structure of rewards, barriers, and directional biases as reflected in the transition policy. Furthermore, we demonstrate that this representation of space can support efficient reinforcement learning. We also propose that grid cells compute the eigendecomposition of place fields in part because is useful for segmenting an enclosure along natural boundaries. When applied recursively, this segmentation can be used to discover a hierarchical decomposition of space. Thus, grid cells might be involved in computing subgoals for hierarchical reinforcement learning.

Information Selection in Noisy Environments with Large Action Spaces Pedro Tsividis (tsividis@mit.edu), Samuel J. Gershman (sjgershm@mit.edu), Joshua B. Tenenbaum (jbt@mit.edu), Laura Schulz (lshulz@mit.edu) Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 77 Massachusetts Ave., Cambridge, MA 02139 USA Abstract A critical aspect of human cognition is the ability to effec- tively query the environment for information. The ‘real’ world is large and noisy, and therefore designing effec- tive queries involves prioritizing both scope – the range of hypotheses addressed by the query – and reliability – the likelihood of obtaining a correct answer. Here we de- signed a simple information-search game in which partic- ipants had to select an informative query from a large set of queries, trading off scope and reliability. We find that adults are effective information-searchers even in large, noisy environments, and that their information search is best explained by a model that balances scope and re- liability by selecting queries proportionately to their ex- pected information gain. Keywords: exploration; information search; active learn- ing; information gain. Introduction As scientists, we sometimes encounter (or conduct) experimental work that is stunning in its breadth but dis- appointing in its rigor, or work that is categorically deci- sive but disappointingly narrow in scope. As child or adult intuitive scientists searching for information, we often deal with these epistemic virtues – scope and rigor – as well; we can make general queries that drastically narrow the hypothesis space of answers or make nar- rower ones, and we can seek information from reliable sources that are more likely to give us correct answers, or from sources that are less so. Our success, whether as professional or intuitive scientists, hinges on our abil- ity to balance these two dimensions in order to produce queries whose answers will be informative. Early work on information search seemed to show that people fail to make rational decisions when it comes to information acquisition; in the Wason (1968) selection task, with a fairly small (12) action set, only 4% of sub- jects made the normative information-acquisition selec- tion. However, as Oaksford & Chater (1994) pointed out, the selection made most often by participants in the original Wason task was normative when environmental statistics were taken into account. Specifically, partici- pants’ decisions were best explained as maximizing ex- pected information gain in the service of helping them to decide between competing hypotheses. More recent work on information search has shown that children have strong intuitions about questions’ use- fulness and search adaptively (Nelson et al., 2013) and that adults can value information over explicit reward when the two are put in opposition (Markant & Gureckis, Our interest is in whether these trends persist when people are confronted with the large, noisy information spaces characteristic of the real world. As we explore the world and its affordances, we must select queries that have scope, in that they rule out large numbers of hy- potheses at once. And, inasmuch as we can help it, we should minimize noise by querying reliable sources. In the real world, these are often in opposition. So, we ask: how do people trade off scope and reliability when ex- ploring large, noisy information spaces? And when the potential questions are many, do they ask the right ones? Information-search task To begin to answer these questions, we designed a novel information-search task. Our goal was for it to be as simple as possible, while having as many features approaching natural exploration as possible. Thus we paired a very simple game – identifying a hidden number on a number line – with a relatively complex search pro- cedure. In playing the game, participants make queries that vary in the abstract features of scope and reliabil- ity. Additionally, at each point in the game, partici- pants are faced with a very large number of potential specific queries to choose from. Our task is similar to the Markant & Gureckis (2012) task in that it involves exploring a geometric space to test particular hypothe- ses, but we wanted to make explicit the abstract features of questions, rather than have these be implicit as a func- tion of the hypotheses at hand. Participants play by asking ‘questions’ about the hid- den number’s location, using ‘scanners’ that turn blue if the number is under the scanned region and red if the number is not. In each trial, a participant is given four scanners (Fig. 1). In some conditions, the scanners vary in size. Larger scanners can cover larger regions of the number line, ruling out (or in) a larger set of hypotheses than a smaller scanner. Thus, in the context of this study, the ‘scope’ is directly related to the length of the scan- ner. However, the scanners are not deterministic; they also vary in their reliability, which is the probability of providing an accurate signal about the presence of the hidden number (false positives and false negatives are equally likely). To efficiently find the hidden number, participants have to select scanners that provide a good trade-off be-

Information Selection in Noisy Environments with Large Action Spaces

Psychophysical and neurophysiological studies have suggested that memory is not simply a carbon copy of our experience: Memories are modified or new memories are formed depending on the dynamic structure of our experience, and specifically, on how gradually or abruptly the world changes. We present a statistical theory of memory formation in a dynamic environment, based on a nonparametric generalization of the switching Kalman filter. We show that this theory can qualitatively account for several psychophysical and neural phenomena, and present results of a new visual memory experiment aimed at testing the theory directly. Our experimental findings suggest that humans can use temporal discontinuities in the structure of the environment to determine when to form new memory traces. The statistical perspective we offer provides a coherent account of the conditions under which new experience is integrated into an old memory versus forming a new memory, and shows that memory formation depends on inferences about the underlying structure of our experience.

Statistical Computations Underlying the Dynamics of Memory Updating

In Section 1, we present proofs of the propositions and lemmas that appeared in the main paper. In Section 2, we present a Markov chain Monte Carlo algorithm for approximate inference. Finally, in Section 3, we present analysis of data in which a non-exchangeable model might be expected to help, but does not.

Supplementary Materials for Distance Dependent Infinite Latent Feature Models

Amortized Inference in Probabilistic Reasoning Samuel J. Gershman 1 (sjgershm@mit.edu) and Noah D. Goodman 2 (ngoodman@stanford.edu) 1 Department of Brain and Cognitive Sciences, MIT of Psychology, Stanford University 2 Department Abstract similar or related queries. For example, as you view an im- age, your head and eyes are continuously moving, generating an infinitude of slightly different queries. For these queries, it may be inaccurate to reuse a stored inference without modifi- cation. This raises the problem of amortized inference: how to flexibly reuse inferences so as to answer a variety of re- lated queries. Recently, Stuhlm¨uller et al. (2013) addressed this problem by using stored samples to estimate local condi- tional distributions, and then approximating answers to more complex queries by composing the local distributions. The work described in this paper seeks experimental evidence for a similar kind of flexible reuse in human reasoning. We presented subjects with a simple Bayesian network and asked them to answer a series of queries about it. One of these queries (the “target”) could be answered by reusing the answer to another query (the “sub-query”). We hypothesized that the effects of reuse would be evident compared to an in- ference with the same structure but no re-usable sub-query. Further, we hypothesized that this effect would be present only if the target was presented after the sub-query. Accord- ingly, we manipulated (between subjects) whether the target came before or after the sub-query. This design allowed us to look for two key signatures of reuse: correlations between related inferences (Experiment 1) and faster responses for in- ferences that exploit reuse (Experiment 2). Recent studies of probabilistic reasoning have postulated general-purpose inference algorithms that can be used to an- swer arbitrary queries. These algorithms are memoryless, in the sense that each query is processed independently, without reuse of earlier computation. We argue that the brain oper- ates in the setting of amortized inference, where numerous related queries must be answered (e.g., recognizing a scene from multiple viewpoints); in this setting, memoryless algo- rithms can be computationally wasteful. We propose a simple form of flexible reuse, according to which shared inferences are cached and composed together to answer new queries. We present experimental evidence that humans exploit this form of reuse: the answer to a complex query can be systematically predicted from a person’s response to a simpler query if the simpler query was presented first and entails a sub-inference (i.e., a sub-component of the more complex query). People are also faster at answering a complex query when it is preceded by a sub-inference. Our results suggest that the astonishing ef- ficiency of human probabilistic reasoning may be supported by interactions between inference and memory. Keywords: induction, Bayesian inference, memory “Cognition is recognition.” – Hofstadter (1995) Introduction One view of probabilistic reasoning holds that our brains are equipped with general-purpose inference algorithms that can be used to answer arbitrary queries (Griffiths et al., 2012; Pouget et al., 2013). An under-appreciated property of such algorithms borrowed from computer science is that they are memoryless: each query is (at least in principle) processed independently of others. While this property guarantees that inferences will not interfere with one another, it can also lead to gross computational inefficiency, since inferences are never reused; memorylessness implies that answering the same query twice requires the same amount of computation as answer two unique queries. 1 Whatever inference algorithms the brain uses, they are un- likely to be memoryless. Consider, for example, the image in Figure 1 (Gregory, 1970). Upon viewing it for the first time, most observers find it extremely difficult to identify what the image depicts. 2 However, once the image has been deciphered, all subsequent views are instantly recognized. Clearly, the visual system is not running a computationally expensive inference algorithm upon each viewing; the infer- ence is simply reused. In reality, it is rare to be faced with the exact same query multiple times. Much more pervasive is the appearance of Figure 1: What does this image depict? Amortized inference in Bayesian networks 1 To be fair, inference algorithms for dynamical systems, like Kalman filtering, involve reuse in a certain sense. However, these algorithms are not designed to reuse inferences when applied to sev- eral independent time series (even if the time series are identical). 2 Answer: a dalmatian. In this paper, we will restrict our attention to amortized in- ference for Bayesian networks. Let p(x) denote a probability distribution on variables x = {x 1 , . . . , x M }. A Bayesian net- work G is a directed acyclic graph with nodes corresponding

The SR-based critic learns an estimate of the value function, using the SR as its feature representation. Unlike standard actor-critic methods, the critic does not use reward-based temporal difference errors to update its value estimate; instead, it relies on the fact that the value function is given by V (s) = ∑ s′ M(s, s ′)R(s′), where M is the successor representation andR is the expected reward in each state. Thus, learningM andR is sufficient to construct an estimate of V .

Supplemental Information for Design Principles of the Hippocampal Cognitive Map

Learning in humans and animals is accompanied by a penumbra: Learning one task benefits from learning an unrelated task shortly before or after. At the cellular level, the penumbra of learning appears when weak potentiation of one synapse is amplified by strong potentiation of another synapse on the same neuron during a critical time window. Weak potentiation sets a molecular tag that enables the synapse to capture plasticity-related proteins synthesized in response to strong potentiation at another synapse. This paper describes a computational model which formalizes synaptic tagging and capture in terms of statistical learning mech- anisms. According to this model, synaptic strength encodes a probabilistic inference about the dynamically changing association between pre- and post-synaptic firing rates. The rate of change is itself inferred, coupling together different synapses on the same neuron. When the inputs to one synapse change rapidly, the inferred rate of change increases, amplifying learning at other synapses.

The penumbra of learning: A statistical theory of synaptic tagging and capture

Decomposing spatiotemporal brain patterns into topographic latent sources

How do we apply learning from one situation to a similar, but not identical, situation? The principles governing the extent to which animals and humans generalize what they have learned about certain stimuli to novel compounds containing those stimuli vary depending on a number of factors. Perhaps the best studied among these factors is the type of stimuli used to generate compounds. One prominent hypothesis is that different generalization principles apply depending on whether the stimuli in a compound are similar or dissimilar to each other. However, the results of many experiments cannot be explained by this hypothesis. Here, we propose a rational Bayesian theory of compound generalization that uses the notion of consequential regions, first developed in the context of rational theories of multidimensional generalization, to explain the effects of stimulus factors on compound generalization. The model explains a large number of results from the compound generalization literature, including the influence of stimulus modality and spatial contiguity on the summation effect, the lack of influence of stimulus factors on summation with a recovered inhibitor, the effect of spatial position of stimuli on the blocking effect, the asymmetrical generalization decrement in overshadowing and external inhibition, and the conditions leading to a reliable external inhibition effect. By integrating rational theories of compound and dimensional generalization, our model provides the first comprehensive computational account of the effects of stimulus factors on compound generalization, including spatial and temporal contiguity between components, which have posed long-standing problems for rational theories of associative and causal learning.

Explaining compound generalization in associative and causal learning through rational principles of dimensional generalization.

Recent computational theories of decision making in humans and animals have portrayed 2 systems locked in a battle for control of behavior. One system--variously termed model-free or habitual--favors actions that have previously led to reward, whereas a second--called the model-based or goal-directed system--favors actions that causally lead to reward according to the agent's internal model of the environment. Some evidence suggests that control can be shifted between these systems using neural or behavioral manipulations, but other evidence suggests that the systems are more intertwined than a competitive account would imply. In 4 behavioral experiments, using a retrospective revaluation design and a cognitive load manipulation, we show that human decisions are more consistent with a cooperative architecture in which the model-free system controls behavior, whereas the model-based system trains the model-free system by replaying and simulating experience.

Retrospective revaluation in sequential decision making: a tale of two systems.

Approximate inference in high-dimensional, discrete probabilistic models is a central problem in computational statistics and machine learning. This paper describes discrete particle variational inference (DPVI), a new approach that combines key strengths of Monte Carlo, variational and search-based techniques. DPVI is based on a novel family of particle-based variational approximations that can be fit using simple, fast, deterministic search techniques. Like Monte Carlo, DPVI can handle multiple modes, and yields exact results in a well-defined limit. Like unstructured mean-field, DPVI is based on optimizing a lower bound on the partition function; when this quantity is not of intrinsic interest, it facilitates convergence assessment and debugging. Like both Monte Carlo and combinatorial search, DPVI can take advantage of factorization, sequential structure, and custom search operators. This paper defines DPVI particle-based approximation family and partition function lower bounds, along with the sequential DPVI and local DPVI algorithm templates for optimizing them. DPVI is illustrated and evaluated via experiments on lattice Markov Random Fields, nonparametric Bayesian mixtures and block-models, and parametric as well as non-parametric hidden Markov models. Results include applications to real-world spike-sorting and relational modeling problems, and show that DPVI can offer appealing time/accuracy trade-offs as compared to multiple alternatives.

Multitasking versus multiplexing: Toward a normative account of limitations in the simultaneous execution of control-demanding behaviors

This work was supported by AFOSR FA9550-07-1-0075 and ONR 
N00014-07-1-0937. SJG was supported by a Graduate Research Fellowship from the NSF.

Bayesian Vector Analysis and the Perception of Hierarchical Motion Samuel J. Gershman 1 (sjgershm@mit.edu), Frank J¨akel 2 (fjaekel@uos.de), Joshua B. Tenenbaum 1 (jbt@mit.edu) 1 Department 2 Institute of Brain and Cognitive Sciences, MIT of Cognitive Science, University of Osnabr¨uck Abstract objects. In the example of biological motion (see Johans- son, 1973), the global motion of the body is subtracted from the image, revealing the relative motions of body parts; these parts are further decomposed by the same subtraction opera- tion. While the vector analysis theory provides a compelling explanation of numerous motion phenomena (we describe several below), it is incomplete from a computational point of view, since it relies on the theorist to provide the un- derlying motion components and their organization; it lacks a mechanism for discovering a hierarchical decomposition from sensory data. This is especially important in complex scenes where many different vector analyses are consistent with the scene. Various principles have been proposed for how the visual system resolves this ambiguity. For exam- ple, Restle (1979) proposed a “minimum principle,” accord- ing to which simpler motion interpretations (i.e., those with a shorter description length) are preferred over more complex ones. Gogel (1974) argued for an “adjacency principle,” ac- cording to which the motion interpretation is determined by relative motion cues between nearby points. However, there is still no unified computational theory that can encompass all these ideas. In this paper, we recast Johansson’s vector analysis the- ory in terms of a Bayesian model of motion perception. The model discovers the hierarchical structure of a moving scene, resolving the ambiguity of multiple vector analyses using a set of probabilistic constraints. We show that this model can account for several classic phenomena in the motion percep- tion literature that are challenging for existing models. Scenes filled with moving objects are often hierarchically or- ganized: the motion of a migrating goose is nested within the flight pattern of its flock, the motion of a car is nested within the traffic pattern of other cars on the road, the motion of body parts are nested in the motion of the body. Humans perceive hierarchical structure even in stimuli with two or three moving dots. An influential theory of hierarchical motion perception holds that the visual system performs a “vector analysis” of moving objects, decomposing them into common and relative motions. However, this theory does not specify how to resolve ambiguity when a scene admits more than one vector analysis. We describe a Bayesian theory of vector analysis and show that it can account for classic results from dot motion experiments. Our theory takes a step towards understanding how moving scenes are parsed into objects. Keywords: motion perception; Bayesian inference; structure learning Introduction Motion is a powerful cue for understanding the organization of a visual scene. Infants use motion to individuate objects, even when it contradicts property/kind information (Kellman & Spelke, 1983; Xu et al., 1999). The primacy of motion in- formation is also evident in adult object perception (Mitroff & Alvarez, 2007). In addition to individuating and tracking objects, motion is used by the visual system to decompose objects into parts. In biological motion, for example, the mo- tion of body parts are nested in the motion of the body. Object motion may be hierarchically organized into multiple layers: an arm’s motion may be further decomposed into jointed seg- ments, including the hand, which can itself be decomposed into fingers, and so on. The hierarchical organization of motion presents a formidable challenge to current models of motion process- ing. It is widely accepted that the visual system balances motion integration over space and time (necessary for solv- ing the aperture problem) and motion segmentation in order to perceive multiple objects simultaneously (Braddick, 1993). However, it is unclear how simple segmentation mechanisms can be used to build a hierarchically structured representation of a moving scene. Segmentation lacks a notion of nesting: when an object moves, its parts should move with it. To un- derstand nesting, it is crucial to represent the underlying de- pendencies between objects and their parts. The experimental and theoretical foundations of hierarchi- cal motion perception were laid by the pioneering work of Johansson (1950), who demonstrated that surprisingly com- plex percepts could arise from simple dot motions. Johansson proposed that the visual system performs a “vector analysis” of moving scenes into common and relative motions between Bayesian vector analysis In this section, we describe our computational model for- mally. We start by describing a probabilistic generative model of motion—a set of assumptions about the environment that we impute to the observer. The generative model can be thought of as stochastic “recipe” for generating moving im- ages. We then describe how Bayesian inference can be used to invert this generative model and recover the underlying hi- erarchical structure from observations of moving images. Generative model Our model describes the process by which a sequence of two- dimensional visual element positions {s n (t)} Nn=1 is generated, y where s n (t) = [s xn (t), s n (t)] is the x and y position of element n at time step t. Elements can refer to objects, parts or features; 1 This representation assumes that basic perceptual preprocessing has taken place (e.g., the correspondence problem has been solved).

Bayesian vector analysis and the perception of hierarchical motion

Moderate levels of activation lead to forgetting in the think/no-think paradigm

We examined the maturation of decision-making from early adolescence to mid-adulthood using fMRI of a variant of the Iowa gambling task. We have previously shown that performance in this task relies on sensitivity to accumulating negative outcomes in ventromedial PFC and dorsolateral PFC. Here, we further formalize outcome evaluation (as driven by prediction errors [PE], using a reinforcement learning model) and examine its development. Task performance improved significantly during adolescence, stabilizing in adulthood. Performance relied on greater impact of negative compared with positive PEs, the relative impact of which matured from adolescence into adulthood. Adolescents also showed increased exploratory behavior, expressed as a propensity to shift responding between options independently of outcome quality, whereas adults showed no systematic shifting patterns. The correlation between PE representation and improved performance strengthened with age for activation in ventral and dorsal PFC, ventral striatum, and temporal and parietal cortices. There was a medial-lateral distinction in the prefrontal substrates of effective PE utilization between adults and adolescents: Increased utilization of negative PEs, a hallmark of successful performance in the task, was associated with increased activation in ventromedial PFC in adults, but decreased activation in ventrolateral PFC and striatum in adolescents. These results suggest that adults and adolescents engage qualitatively distinct neural and psychological processes during decision-making, the development of which is not exclusively dependent on reward-processing maturation.

Neural and Psychological Maturation of Decision-making in Adolescence and Young Adulthood

Fear memories are notoriously difficult to erase, often recovering over time. The longstanding explanation for this finding is that, in extinction training, a new memory is formed that competes with the old one for expression but does not otherwise modify it. This explanation is at odds with traditional models of learning such as Rescorla-Wagner and reinforcement learning. A possible reconciliation that was recently suggested is that extinction training leads to the inference of a new state that is different from the state that was in effect in the original training. This solution, however, raises a new question: under what conditions are new states, or new memories formed? Theoretical accounts implicate persistent large prediction errors in this process. As a test of this idea, we reasoned that careful design of the reinforcement schedule during extinction training could reduce these prediction errors enough to prevent the formation of a new memory, while still decreasing reinforcement sufficiently to drive modification of the old fear memory. In two Pavlovian fear-conditioning experiments, we show that gradually reducing the frequency of aversive stimuli, rather than eliminating them abruptly, prevents the recovery of fear. This finding has important implications for theories of state discovery in reinforcement learning.

Gradual extinction prevents the return of fear: implications for the discovery of state

Any aspect of cognition that is concerned with learning faces the same basic question: when are old memories modified, and when are new memories formed? For example, since Pavlov’s first studies of classical conditioning, it has been believed that extinction of an associative memory entails new learning rather than modification of an old memory (Pavlov, 1927; Bouton, 2004). The same question arises in the domain of episodic memory, where the notion of an ‘episode’ hinges crucially on the ability to parse the stream of experience into distinct chunks. The question attains vivid clinical significance in the psychopathology of fear and addiction, where patients struggle to modify or erase a persistent, maladaptive memory.

Memory modification in the brain: Computational and experimental investigations

A number of accounts of human and animal behavior posit the operation of parallel and competing valuation systems in the control of choice behavior. In these accounts, a flexible but computationally expensive model-based reinforcement-learning system has been contrasted with a less flexible but more efficient model-free reinforcement-learning system. The factors governing which system controls behavior—and under what circumstances—are still unclear. Following the hypothesis that model-based reinforcement learning requires cognitive resources, we demonstrated that having human decision makers perform a demanding secondary task engenders increased reliance on a model-free reinforcement-learning strategy. Further, we showed that, across trials, people negotiate the trade-off between the two systems dynamically as a function of concurrent executive-function demands, and people’s choice latencies reflect the computational expenses of the strategy they employ. These results demonstrate that competition between multiple learning systems can be controlled on a trial-by-trial basis by modulating the availability of cognitive resources.

What causes new information to be mistakenly attributed to an old experience? Some theories predict that reinstating the context of a prior experience allows new information to be bound to that context, leading to source memory confusion. To examine this prediction, we had human participants study two lists of items (visual objects) on separate days while undergoing functional magnetic resonance imaging. List 1 items were accompanied by a stream of scene images during the intertrial interval, but list 2 items were not. As in prior work by Hupbach et al. (2009), we observed an asymmetric pattern of misattributions on a subsequent source memory test: participants showed a strong tendency to misattribute list 2 items to list 1 but not vice versa. We hypothesized that these memory errors were due to participants reinstating the list 1 context during list 2. To test this hypothesis, we used a pattern classifier to measure scene-related neural activity during list 2 study. Because scenes were visually present during list 1 but not list 2, scene-related activity during list 2 study can be used as a time-varying neural indicator of how much participants were reinstating the list 1 context during list 2 study. In keeping with our hypothesis, we found that prestimulus scene activation during the study of list 2 items was significantly higher for items subsequently misattributed to list 1 than for items subsequently correctly attributed to list 2. We conclude by discussing how these findings relate to theories of memory reconsolidation.

Theoretical models of unsupervised category learning postulate that humans “invent” categories to accommodate new patterns, but tend to group stimuli into a small number of categories. This “Occam's razor” principle is motivated by normative rules of statistical inference. If categories influence perception, then one should find effects of category invention on simple perceptual estimation. In a series of experiments, we tested this prediction by asking participants to estimate the number of colored circles on a computer screen, with the number of circles drawn from a color-specific distribution. When the distributions associated with each color overlapped substantially, participants' estimates were biased toward values intermediate between the two means, indicating that subjects ignored the color of the circles and grouped different-colored stimuli into one perceptual category. These data suggest that humans favor simpler explanations of sensory inputs. In contrast, when the distributions associated with each color overlapped minimally, the bias was reduced (i.e., the estimates for each color were closer to the true means), indicating that sensory evidence for more complex explanations can override the simplicity bias. We present a rational analysis of our task, showing how these qualitative patterns can arise from Bayesian computations.

Traditional approaches to analyzing experimental functional magnetic resonance imaging (fMRI) data entail fitting per-voxel parameters to explain how the observed images reflect the thoughts and stimuli a participant experienced during the experiment. These methods implicitly assume that voxel responses are independent and that the unit of analysis should be the voxel. However, both of these assumptions are known to be untrue: it is well known that voxel activations exhibit strong spatial correlations, and common sense tells us that the true underlying brain activations are independent of the resolution at which the brain image happened to be taken. Here we propose a fundamentally different approach, whereby brain images are represented as weighted sums of spatial functions. Our technique yields compact representations of the brain images that leverage spatial correlations in the data and are independent of the image resolution.

Factor Topographic Latent Source Analysis : Factor Analysis for Brain Images ?

The successor representation was introduced into reinforcement learning by Dayan (1993) as a means of facilitating generalization between states with similar successors. Although reinforcement learning in general has been used extensively as a model of psychological and neural processes, the psychological validity of the successor representation has yet to be explored. An interesting possibility is that the successor representation can be used not only for reinforcement learning but for episodic learning as well. Our main contribution is to show that a variant of the temporal context model (TCM; Howard & Kahana, 2002), an influential model of episodic memory, can be understood as directly estimating the successor representation using the temporal difference learning algorithm (Sutton & Barto, 1998). This insight leads to a generalization of TCM and new experimental predictions. In addition to casting a new normative light on TCM, this equivalence suggests a previously unexplored point of contact between different learning systems.

Variational methods are widely used for approximate posterior inference. However, their use is typically limited to families of distributions that enjoy particular conjugacy properties. To circumvent this limitation, we propose a family of variational approximations inspired by nonparametric kernel density estimation. The locations of these kernels and their bandwidth are treated as variational parameters and optimized to improve an approximate lower bound on the marginal likelihood of the data. Unlike most other variational approximations, using multiple kernels allows the approximation to capture multiple modes of the posterior. We demonstrate the efficacy of the nonparametric approximation with a hierarchical logistic regression model and a nonlinear matrix factorization model. We obtain predictive performance as good as or better than more specialized variational methods and MCMC approximations. The method is easy to apply to graphical models for which standard variational methods are difficult to derive.

Normative theories of learning and decision-making are motivated by a computational-level analysis of the task facing an animal: what should the animal do to maximize future reward? However, much of the recent excitement in this field originates in how the animal arrives at its decisions and reward predictions—-algorithmic questions about which the computational-level analysis is silent. Answers to these algorithmic questions are essentially claims about dynamics (learning/adjustment across trials or the transformation of decision variables within trials). These depend crucially on the computational quantities and how they are manipulated algorithmically, the focus of this chapter.

Ambiguous images present a challenge to the visual system: How can uncertainty about the causes of visual inputs be represented when there are multiple equally plausible causes? A Bayesian ideal observer should represent uncertainty in the form of a posterior probability distribution over causes. However, in many real-world situations, computing this distribution is intractable and requires some form of approximation. We argue that the visual system approximates the posterior over underlying causes with a set of samples and that this approximation strategy produces perceptual multistability—stochastic alternation between percepts in consciousness. Under our analysis, multistability arises from a dynamic sample-generating process that explores the posterior through stochastic diffusion, implementing a rational form of approximate Bayesian inference known as Markov chain Monte Carlo (MCMC). We examine in detail the most extensively studied form of multistability, binocular rivalry, showing how a variety of experimental phenomena—gamma-like stochastic switching, patchy percepts, fusion, and traveling waves—can be understood in terms of MCMC sampling over simple graphical models of the underlying perceptual tasks. We conjecture that the stochastic nature of spiking neurons may lend itself to implementing sample-based posterior approximations in the brain.

Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Ambiguous images present a challenge to the visual system: How can uncertainty about the causes of visual inputs be represented when there are multiple equally plausible causes? A Bayesian ideal observer should represent uncertainty in the form of a posterior probability distribution over causes. However, in many real-world situations, computing this distribution is intractable and requires some form of approximation. We argue that the visual system approximates the posterior over underlying causes with a set of samples and that this approximation strategy produces perceptual multistability—stochastic alternation between percepts in consciousness. Under our analysis, multistability arises from a dynamic sample-generating process that explores the posterior through stochas-tic diffusion, implementing a rational form of approximate Bayesian inference known as Markov chain Monte Carlo (MCMC). We examine in detail the most extensively studied form of multistability, binocular rivalry , showing how a variety of experimental phenomena—gamma-like stochastic switching, patchy percepts, fusion, and traveling waves—can be understood in terms of MCMC sampling over simple graphical models of the underlying perceptual tasks. We conjecture that the stochastic nature of spiking neurons may lend itself to implementing sample-based posterior approximations in the brain.

Latent feature models are widely used to decompose data into a small number of components. Bayesian nonparametric variants of these models, which use the Indian buffet process (IBP) as a prior over latent features, allow the number of features to be determined from the data. We present a generalization of the IBP, the distance dependent Indian buffet process (dd-IBP), for modeling non-exchangeable data. It relies on distances defined between data points, biasing nearby data to share more features. The choice of distance measure allows for many kinds of dependencies, including temporal and spatial. Further, the original IBP is a special case of the dd-IBP. We develop the dd-IBP and theoretically characterize its feature-sharing properties. We derive a Markov chain Monte Carlo sampler for a linear Gaussian model with a dd-IBP prior and study its performance on real-world non-exchangeable data.

Computational, Neuroscientific, and Lifespan Perspectives on the Exploration-Exploitation Dilemma A. Ross Otto 1 (Moderator) , Bradley W. Knox 2 , and Bradley C. Love 1 Department of Psychology, 2 Department of Computer Science, University of Texas at Austin Sam Gershman and Yael Niv Department of Psychology, Princeton University Darrell A. Worthy 1 and W. Todd Maddox 2 Department of Psychology, Texas AM computational modeling; cogni- tive neuroscience, information search Consider the following real-life decisions that we make: deciding which route to take home to minimize time spent traveling, choosing amongst a set of known restaurants or a new restaurant when dining out, deciding between reading a new book by a consistently good author versus an author whose books vary widely in quality. All of these decisions involve balancing the conflicting demands of exploiting pre- vious knowledge in order maximize payoffs versus explor- ing less-known options in order to gain information about the currently optimal course of action. Indeed, successfully balancing these competing demands is a non-trivial problem of interest to artificial intelligence and neural Reinforcement Learning (RL) research communities alike (Cohen, McClure, & Yu, 2007; Daw et al., 2006; Sutton & Barto, 1998). There are adverse consequences for failing to properly balance these demands in the above examples: solely making exploita- tive choices entails the possibility of ignorance about better courses of action, while exploring too frequently incurs large opportunity costs. The goal of the proposed symposium is to bring together researchers from a variety of perspectives who are working to better understand the psychological and neurobiological mechanisms underlying exploratory choice. In recent years, novel computational modeling approaches have been developed and applied to understanding how hu- mans incorporate the demands of information gathering into their patterns of choice. These modeling techniques have yielded insight not only in describing human choice behav- ior, but also in understanding the neurobiological and physio- logical correlates of exploratory decision-making in humans (Daw et al., 2006; Jepma & Niewenhuis, in press). The re- searchers who have agreed to participate in this symposium are all applying computational models to better understand the psychological and neurobiological mechanisms under- pinning peoples negotiation of the exploration-exploitation tradeoff. The modeling approaches taken by these speakers are indeed diverse, ranging from uncovering hidden variables underlying decision-makers’ choices in order to unpack neu- robiological and physiological measurements to describing aging-related changes in exploratory choice behavior. The proposed symposium will provide a forum for highlighting recent advances in applications of computational modeling to human exploratory choice. The speakers who have agreed to participate in this symposium–while each performing research that elucidates psychological and neurobiological mechanisms underlying exploratory decision-making—offer different perspectives on the issue. The research described includes 1) aging work examining lifespan changes in exploratory decision-making, elucidating the underlying neurobiology of these types of choices (Worthy & Maddox), 2) a Bayesian account of effect of novelty–when humans are presented with new, potentially rewarding options–on exploratory choice, and how these nov- elty signals are represented in the brain in order to compute values and guide choices (Gershman & Niv), 3) how individu- als incorporate uncertainty and information search costs when planning courses of action in situations with sequential de- pendencies between choices and outcomes (Hotaling, Buse- meyer, & Shiffrin), and 4) how internally calculated uncer- tainty about the environment directs exploratory choice and manifests itself physiologically over the course of decision- making (Otto, Knox, & Love). In addition to proposing an- swers to a diverse set of important psychological and neuro- scientific questions, the lines of research described by these speakers rely upon laboratory tasks with monetary incentives that, each in their own way, incorporate ecologically interest- ing choice and reward dynamics. Belief-directed Exploration in Human Decision-Makers: Behavioral and Physiological Evidence A Ross Otto, W. Bradley Knox, & Bradley C. Love Decision-making in uncertain environments poses a con- flict between the goals of exploiting past knowledge in or- der to maximize rewards and exploring less-known options in order to gather information. However, the descriptive mod- eling framework utilized in previous studies of exploratory choice behavior characterizes exploration as the result of choices, rather than a process reflecting beliefs and/or un-

Computational, Neuroscientific, and Lifespan Perspectives on the Exploration-Exploitation Dilemma

Human memory reconsolidation can be explained using the temporal context model

A. Redish et al. (2007) proposed a reinforcement learning model of context-dependent learning and extinction in conditioning experiments, using the idea of "state classification" to categorize new observations into states. In the current article, the authors propose an interpretation of this idea in terms of normative statistical inference. They focus on renewal and latent inhibition, 2 conditioning paradigms in which contextual manipulations have been studied extensively, and show that online Bayesian inference within a model that assumes an unbounded number of latent causes can characterize a diverse set of behavioral results from such manipulations, some of which pose problems for the model of Redish et al. Moreover, in both paradigms, context dependence is absent in younger animals, or if hippocampal lesions are made prior to training. The authors suggest an explanation in terms of a restricted capacity to infer new causes.

Theoretical models of unsupervised category learning postulate that humans “invent” categories to accommodate new patterns, but tend to group stimuli into a small number of categories. This “Ockham’s razor” principle is motivated by normative rules of statistical inference. If categories influence perception, then one should find effects of category invention on simple perceptual judgments. In two experiments, we tested this prediction by asking participants to estimate the number of colored circles on a computer screen, with the the number of circles drawn from a color-specific distribution. When the distributions associated with each color overlapped, paricipants’ estimates were biased towards values intermediate between the two means, indicating that subjects ignored the color of the circles and grouped all stimuli into a single perceptual category. These data suggest that humans favor simpler explanations of sensory inputs. In contrast, when the distributions associated with each color overlapped minimally, the bias was reduced, indicating that sensory evidence for more complex explanations can override the simplicity bias.

Running head : OCKHAM ’ S RAZOR AND PERCEPTION Perceptual Judgment Obeys Ockham ’ s Razor

Learning to Selectively Attend Samuel J. Gershman (sjgershm@princeton.edu) Jonathan D. Cohen (jdc@princeton.edu) Yael Niv (yael@princeton.edu) Department of Psychology and Neuroscience Institute, Princeton University Princeton, NJ 08540 USA Abstract bias: Restricting attention to only a few dimensions is akin to the belief that only those dimensions are relevant for earning reward. This has the effect of reducing the space of possible value functions to a much smaller subspace. While Bayesian probability theory stipulates the ideal learner, in general it may not be computationally tractable to perform the necessary calculations exactly (Kruschke, 2006; Daw & Courville, 2008). We therefore consider a “hybrid” model that combines the computational efficiency of model- free RL with the statistical efficiency of Bayesian inference. We compare the Bayesian and hybrid models to naive RL (no sparsity bias) and show that models that exploit structured knowledge better capture choice behavior in our experiment. How is reinforcement learning possible in a high-dimensional world? Without making any assumptions about the struc- ture of the state space, the amount of data required to effec- tively learn a value function grows exponentially with the state space’s dimensionality. However, humans learn to solve high- dimensional problems much more rapidly than would be ex- pected under this scenario. This suggests that humans em- ploy inductive biases to guide (and accelerate) their learning. Here we propose one particular bias—sparsity—that amelio- rates the computational challenges posed by high-dimensional state spaces, and present experimental evidence that humans can exploit sparsity information when it is available. Keywords: reinforcement learning; attention; Bayes. Introduction Reinforcement learning (RL) in high-dimensional state spaces is a notoriously difficult problem in machine learn- ing (Sutton & Barto, 1998), primarily because of the curse of dimensionality: The number of states grows exponentially with dimensionality (Bellman, 1957), and thus if one were naively to represent a separate value (expected reward) for each state, one would require astronomical amounts of data to effectively learn the value function (and thereby behave adap- tively). Nonetheless, humans appear to learn rapidly from small amounts of data. Thus, while substantial evidence has accumulated that human behavior follows the predictions of RL models (Dayan & Niv, 2008), these models may funda- mentally underestimate the learning capabilities of humans. Following work in other areas of cognition (Braun, Mehring, & Wolpert, 2009; Kemp & Tenenbaum, 2009), we suggest that rapid learning arises from the exploitation of structured knowledge in the form of inductive biases. In par- ticular, our proposal is that humans employ a sparsity bias: the assumption that only one (or a small number) of dimen- sions (input features) is relevant at any given time for predict- ing reward. For example, when you are at a stoplight, only the color of the light matters, not its shape, size, etc. In other do- mains (such as ordering food in a restaurant), you may know that dimensional relevance is sparse, but not which particu- lar dimensions are relevant (does it matter which restaurant it is? which table I am sitting at? who the chef is? who the waiter is?); for this purpose, one requires a learning al- gorithm that can exploit sparsity. We formalize this idea in terms of rational statistical inference, and present new exper- imental evidence that human behavior is consistent with such a model. Central to our analysis is the idea that selective attention is a direct consequence of Bayesian inference with a sparsity The Computational Problem For concreteness, we consider one particular example of the general class of reinforcement learning problems for which the sparsity assumption holds. This example is meant to cap- ture the abstract structure of many problems facing humans in the real world, where they must make choices between sev- eral multidimensional stimuli under conditions where most dimensions are unpredictive of reward. This example will also serve as a formal description of the task that we asked human subjects to perform, the results of which we report in a later section. The subject plays N trials, and observes M stimuli simulta- neously on each trial. The ith stimulus on trial n is denoted by a D-dimensional vector x ni , where each integer-valued com- ponent x ni j indicates the property of the jth stimulus dimen- sion (for instance, [color = green, shape = triangle, texture = dots]). Each set of trials has a target dimension d (e.g., ‘shape’) and target property f on that dimension (e.g., ‘cir- cle’). The subject chooses a stimulus c n on each trial and observes a binary reward r n . The probability of reward given choice and target is θ 1 if x nc n d = f P(r n = 1|c n , d, f , X n ) = θ 0 otherwise, In other words, the subject receives a reward with probability θ 1 if the chosen stimulus posseses the target property on the target dimension, and with probability θ 0 otherwise. Bayesian Model Given uncertainty about the target dimension and property, a Bayesian model would use Bayes’ rule to infer the posterior over the target dimensions and property and then calculate the

Optimal control entails combining probabilities and utilities. However, for most practical problems, probability densities can be represented only approximately. Choosing an approximation requires balancing the benefits of an accurate approximation against the costs of computing it. We propose a variational framework for achieving this balance and apply it to the problem of how a neural population code should optimally represent a distribution under resource constraints. The essence of our analysis is the conjecture that population codes are organized to maximize a lower bound on the log expected utility. This theory can account for a plethora of experimental data, including the reward-modulation of sensory receptive fields, GABAergic effects on saccadic movements, and risk aversion in decisions under uncertainty.

Humans and animals are endowed with a large number of effectors. Although this enables great behavioral flexibility, it presents an equally formidable reinforcement learning problem of discovering which actions are most valuable because of the high dimensionality of the action space. An unresolved question is how neural systems for reinforcement learning—such as prediction error signals for action valuation associated with dopamine and the striatum—can cope with this “curse of dimensionality.” We propose a reinforcement learning framework that allows for learned action valuations to be decomposed into effector-specific components when appropriate to a task, and test it by studying to what extent human behavior and blood oxygen level-dependent (BOLD) activity can exploit such a decomposition in a multieffector choice task. Subjects made simultaneous decisions with their left and right hands and received separate reward feedback for each hand movement. We found that choice behavior was better described by a learning model that decomposed the values of bimanual movements into separate values for each effector, rather than a traditional model that treated the bimanual actions as unitary with a single value. A decomposition of value into effector-specific components was also observed in value-related BOLD signaling, in the form of lateralized biases in striatal correlates of prediction error and anticipatory value correlates in the intraparietal sulcus. These results suggest that the human brain can use decomposed value representations to “divide and conquer” reinforcement learning over high-dimensional action spaces.

Human Reinforcement Learning Subdivides Structured Action Spaces by Learning Effector-Specific Values

We develop a probabilistic model of human memory performance in free recall experiments. In these experiments, a subject first studies a list of words and then tries to recall them. To model these data, we draw on both previous psychological research and statistical topic models of text documents. We assume that memories are formed by assimilating the semantic meaning of studied words (represented as a distribution over topics) into a slowly changing latent context (represented in the same space). During recall, this context is reinstated and used as a cue for retrieving studied words. By conceptualizing memory retrieval as a dynamic latent variable model, we are able to use Bayesian inference to represent uncertainty and reason about the cognitive processes underlying memory. We present a particle filter algorithm for performing approximate posterior inference, and evaluate our model on the prediction of recalled words in experimental data. By specifying the model hierarchically, we are also able to capture inter-subject variability.

While many perceptual and cognitive phenomena are well described in terms of Bayesian inference, the necessary computations are intractable at the scale of real-world tasks, and it remains unclear how the human mind approximates Bayesian computations algorithmically. We explore the proposal that for some tasks, humans use a form of Markov Chain Monte Carlo to approximate the posterior distribution over hidden variables. As a case study, we show how several phenomena of perceptual multistability can be explained as MCMC inference in simple graphical models for low-level vision.

Why are human inferences sometimes remarkably close to the Bayesian ideal and other times systematically biased? One notable instance of this discrepancy is that tasks where the candidate hypotheses are explicitly available result in close to rational inference over the hypothesis space, whereas tasks requiring the self-generation of hypotheses produce systematic deviations from rational inference. We propose that these deviations arise from algorithmic processes approximating Bayes' rule. Specifically in our account, hypotheses are generated stochastically from a sampling process, such that the sampled hypotheses form a Monte Carlo approximation of the posterior. While this approximation will converge to the true posterior in the limit of infinite samples, we take a small number of samples as we expect that the number of samples humans take is limited by time pressure and cognitive resource constraints. We show that this model recreates several well-documented experimental findings such as anchoring and adjustment, subadditivity, superadditivity, the crowd within as well as the self-generation effect, the weak evidence, and the dud alternative effects. Additionally, we confirm the model's prediction that superadditivity and subadditivity can be induced within the same paradigm by manipulating the unpacking and typicality of hypotheses, in 2 experiments. This work was supported by the Center for Brains, Minds and Machines (CBMM), funded by NSF STC award CCF-1231216. Where do hypotheses come from? Ishita Dasgupta Department of Physics and Center for Brain Science Harvard University Eric Schulz Department of Experimental Psychology University College London Samuel J. Gershman Department of Psychology and Center for Brain Science Harvard University

CBMM Memo No . 056 October 24 , 2016 Where do hypotheses come from ?

1 Intramural Research program of the National Institute on Drug Abuse, NIH; 6 2 Department of Psychology and Center for Brain Science, Harvard University; 7 3 Department of Neurology, Feinberg School of Medicine, Northwestern University; 8 4 Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, 9 Northwestern University; 10 5 Department of Psychology, Weinberg College of Arts and Sciences, Northwestern 11 University; 12 6 Department of Anatomy and Neurobiology, University of Maryland School of Medicine; 13 7 Department of Neuroscience, Johns Hopkins School of Medicine. 14

Living systems face both environmental complexity and limited access to free-energy resources. Survival under these conditions requires a control system that can activate, or deploy, available perception and action resources in a context specific way. In this Part I, we introduce the free-energy principle (FEP) and the idea of active inference as Bayesian prediction-error minimization, and show how the control problem arises in active inference systems. We then review classical and quantum formulations of the FEP, with the former being the classical limit of the latter. In the accompanying Part II, we show that when systems are described as executing active inference driven by the FEP, their control flow systems can always be represented as tensor networks (TNs). We show how TNs as control systems can be implemented within the general framework of quantum topological neural networks, and discuss the implications of these results for modeling biological systems at multiple scales.

IEEE Transactions on Molecular, Biological and Multi-Scale Communications

Control Flow in Active Inference Systems—Part I: Classical and Quantum Formulations of Active Inference

Coherent, time-shifted patterns of microstructural plasticity during motor-skill learning

Background Predicting the future UK COVID-19 epidemic provides a baseline of a vaccine-only mitigation policy from which to judge the effects of additional public health interventions. A previous 12-month prediction of the size of the epidemic to October 2022 underestimated its sequelae by a fifth. This analysis seeks to explain the reasons for the underestimation before offering new long-term predictions. Methods A Dynamic Causal Model was used to identify changes in COVID-19 transmissibility and the public's behavioral response in the 12-months to October 2022. The model was then used to predict the future trends in infections, long-COVID, hospital admissions and deaths over 12-months to October 2023. Findings The model estimated that the secondary attack rate increased from 0.4 to 0.5, the latent period shortened from 2.7 to 2.6 and the incubation period shortened from 2.0 to 1.95 days between October 2021 and October 2022. During this time the model also estimated that antibody immunity waned from 177 to 160 days and T-cell immunity from 205 to 180 days. This increase in transmissibility was associated with a reduction in pathogenicity with the proportion of infections developing acute respiratory distress syndrome falling for 6–2% in the same twelve-month period. Despite the wave of infections, the public response was to increase the tendency to expose themselves to a high-risk environment (e.g., leaving home) each day from 33–58% in the same period. The predictions for October 2023 indicate a wave of infections three times larger this coming year than last year with significant health and economic consequences such as 120,000 additional COVID-19 related deaths, 800,000 additional hospital admissions and 3.5 million people suffering acute-post-COVID-19 syndrome lasting more than 12 weeks. Interpretation The increase in transmissibility together with the public's response provide plausible explanations for why the model underestimated the 12-month predictions to October 2022. The 2023 projection could well-underestimate the predicted substantial next wave of COVID-19 infection. Vaccination alone will not control the epidemic. The UK COVID-19 epidemic is not over. The results call for investment in precautionary public health interventions.

Using a Dynamic Causal Model to validate previous predictions and offer a 12-month forecast of the long-term effects of the COVID-19 epidemic in the UK

Cerebellar computations are necessary for fine behavioural control and are thought to rely on internal probabilistic models performing state estimation. We propose that the cerebellum infers how states contextualise (i.e., interact with) each other, and coordinates extra-cerebellar neuronal dynamics underpinning a range of behaviours. To support this claim, we describe a cerebellar model for state estimation that includes states interactions, and link the underlying inference with the neuronal architecture and dynamics observed empirically. This is formalised using the free energy principle, which provides a dual perspective on a system in terms of both the dynamics of its physical – in this case neuronal – states, and the inference process they entail. As a proof of principle, we simulate cerebellar-dependent synchronisation of whisking and respiration, which are known to be tightly coupled in rodents. In summary, we suggest that cerebellar-dependent contextualisation of behaviour can explain its ubiquitous involvement in most aspects of behaviour.

Cerebellar state estimation enables resilient coupling across behavioural domains

This paper presents a model of consciousness that follows directly from the free-energy principle (FEP). We first rehearse the classical and quantum formulations of the FEP. In particular, we consider the inner screen hypothesis that follows from the quantum information theoretic version of the FEP. We then review applications of the FEP to the known sparse (nested and hierarchical) neuro-anatomy of the brain. We focus on the holographic structure of the brain, and how this structure supports (overt and covert) action.

The inner screen model of consciousness: applying the free energy principle directly to the study of conscious experience

Abstract I enjoyed reading this compelling account of Conviction Narrative Theory (CNT). As a theoretical neurobiologist, I recognised – and applauded – the tenets of CNT. My commentary asks whether its claims could be installed into a Bayesian mechanics of decision-making, in a way that would enable theoreticians to model, reproduce and predict decision-making.

Corrigendum: Small steps for mankind: Modeling the emergence of cumulative culture from joint active inference communication

Functional asymmetry and the consequences of action: Comment on: Left and right temporal-parietal junctions (TPJs) as "match/mismatch" hedonic machines: A unifying account of TPJ function by Fabrizio Doricchi et al.

Although the increase in the use of dynamical modeling in the literature on cultural evolution makes current models more mathematically sophisticated, these models have yet to be tested or validated. This paper provides a testable deep active inference formulation of social behavior and accompanying simulations of cumulative culture in two steps: First, we cast cultural transmission as a bi-directional process of communication that induces a generalized synchrony (operationalized as a particular convergence) between the belief states of interlocutors. Second, we cast social or cultural exchange as a process of active inference by equipping agents with the choice of who to engage in communication with. This induces trade-offs between confirmation of current beliefs and exploration of the social environment. We find that cumulative culture emerges from belief updating (i.e., active inference and learning) in the form of a joint minimization of uncertainty. The emergent cultural equilibria are characterized by a segregation into groups, whose belief systems are actively sustained by selective, uncertainty minimizing, dyadic exchanges. The nature of these equilibria depends sensitively on the precision afforded by various probabilistic mappings in each individual's generative model of their encultured niche.

Small steps for mankind: Modeling the emergence of cumulative culture from joint active inference communication

Living systems face both environmental complexity and limited access to free-energy resources. Survival under these conditions requires a control system that can activate, or deploy, available perception and action resources in a context specific way. We show here that when systems are described as executing active inference driven by the free-energy principle (and hence can be considered Bayesian prediction-error minimizers), their control flow systems can always be represented as tensor networks (TNs). We show how TNs as control systems can be implmented within the general framework of quantum topological neural networks, and discuss the implications of these results for modeling biological systems at multiple scales.

Cultural mechanics: Comment on: "To copy or not to copy? That is the question! From chimpanzees to the foundation of human technological culture" by Héctor M. Manrique, and Michael J. Walker.

This paper investigates the prospect of developing human-interpretable, explainable artificial intelligence (AI) systems based on active inference and the free energy principle. We first provide a brief overview of active inference, and in particular, of how it applies to the modeling of decision-making, introspection, as well as the generation of overt and covert actions. We then discuss how active inference can be leveraged to design explainable AI systems, namely, by allowing us to model core features of ``introspective'' processes and by generating useful, human-interpretable models of the processes involved in decision-making. We propose an architecture for explainable AI systems using active inference. This architecture foregrounds the role of an explicit hierarchical generative model, the operation of which enables the AI system to track and explain the factors that contribute to its own decisions, and whose structure is designed to be interpretable and auditable by human users. We outline how this architecture can integrate diverse sources of information to make informed decisions in an auditable manner, mimicking or reproducing aspects of human-like consciousness and introspection. Finally, we discuss the implications of our findings for future research in AI, and the potential ethical considerations of developing AI systems with (the appearance of) introspective capabilities.

Designing explainable artificial intelligence with active inference: A framework for transparent introspection and decision-making

Living systems face both environmental complexity and limited access to free-energy resources. Survival under these conditions requires a control system that can activate, or deploy, available perception and action resources in a context specific way. In Part I, we introduced the free-energy principle (FEP) and the idea of active inference as Bayesian prediction-error minimization, and show how the control problem arises in active inference systems. We then review classical and quantum formulations of the FEP, with the former being the classical limit of the latter. In this accompanying Part II, we show that when systems are described as executing active inference driven by the FEP, their control flow systems can always be represented as tensor networks (TNs). We show how TNs as control systems can be implemented within the general framework of quantum topological neural networks, and discuss the implications of these results for modeling biological systems at multiple scales.

Control Flow in Active Inference Systems—Part II: Tensor Networks as General Models of Control Flow

Predictive coding (PC) accounts of perception now form one of the dominant computational theories of the brain, where they prescribe a general algorithm for inference and learning over hierarchical latent probabilistic models. Despite this, they have enjoyed little export to the broader field of machine learning, where comparative generative modelling techniques have flourished. In part, this has been due to the poor performance of models trained with PC when evaluated by both sample quality and marginal likelihood. By adopting the perspective of PC as a variational Bayes algorithm under the Laplace approximation, we identify the source of these deficits to lie in the exclusion of an associated Hessian term in the PC objective function, which would otherwise regularise the sharpness of the probability landscape and prevent over-certainty in the approximate posterior. To remedy this, we make three primary contributions: we begin by suggesting a simple Monte Carlo estimated evidence lower bound which relies on sampling from the Hessian-parameterised variational posterior. We then derive a novel block diagonal approximation to the full Hessian matrix that has lower memory requirements and favourable mathematical properties. Lastly, we present an algorithm that combines our method with standard PC to reduce memory complexity further. We evaluate models trained with our approach against the standard PC framework on image benchmark datasets. Our approach produces higher log-likelihoods and qualitatively better samples that more closely capture the diversity of the data-generating distribution.

Curvature-Sensitive Predictive Coding with Approximate Laplace Monte Carlo

We consider the theoretical constraints on interactions between coupled cortical columns. Each column comprises a set of neural populations, where each population is modelled as a neural mass. The existence of semi-stable states — within a cortical column — has been shown to be dependent on the type of interaction between the constituent neuronal subpopulations, i.e., the form of the implicit synaptic convolution kernels. Current-to-current coupling has been shown – in contrast to potential-to-current coupling — to create semi-stable states within a cortical column. In this analytic and numerical study, the interaction between semi-stable states is characterized by equations of motion for ensemble activity. We show that for small excitations, the dynamics follow the Kuramoto model. However, in contrast to previous work, we derive coupled equations between phase and amplitude dynamics. This affords the possibility of defining connectivity as a dynamic variable. The turbulent flow of phase dynamics — found in networks of Kuramoto oscillators — indicate turbulent changes in dynamic connectivity for coupled cortical columns. Crucially, this is something that has been recorded in epileptic seizures. We used the results we derived to estimate a seizure propagation model, which allowed for relatively straightforward inversions using variational Laplace (a.k.a., Dynamic Causal Modelling). The face validity of the ensuing seizure propagation model was established using simulated data as a prelude to future work; which will investigate dynamic connectivity from empirical data. This model also allows predictions of seizure evolution, induced by virtual lesions to synaptic connectivity: something that could be of clinical use, when applied to epilepsy surgical cases.

A Mathematical Model for Neuronal Activity and Brain Information Processing Capacity

This paper introduces a variational formulation of natural selection, paying special attention to the nature of ‘things’ and the way that different ‘kinds’ of ‘things’ are individuated from—and influence—each other. We use the Bayesian mechanics of particular partitions to understand how slow phylogenetic processes constrain—and are constrained by—fast, phenotypic processes. The main result is a formulation of adaptive fitness as a path integral of phenotypic fitness. Paths of least action, at the phenotypic and phylogenetic scales, can then be read as inference and learning processes, respectively. In this view, a phenotype actively infers the state of its econiche under a generative model, whose parameters are learned via natural (Bayesian model) selection. The ensuing variational synthesis features some unexpected aspects. Perhaps the most notable is that it is not possible to describe or model a population of conspecifics per se. Rather, it is necessary to consider populations of distinct natural kinds that influence each other. This paper is limited to a description of the mathematical apparatus and accompanying ideas. Subsequent work will use these methods for simulations and numerical analyses—and identify points of contact with related mathematical formulations of evolution.

A Variational Synthesis of Evolutionary and Developmental Dynamics

Estimating the changes of epidemiological parameters, such as instantaneous reproduction number, Rt, is important for understanding the transmission dynamics of infectious diseases. Current estimates of time-varying epidemiological parameters often face problems such as lagging observations, averaging inference, and improper quantification of uncertainties. To address these problems, we propose a Bayesian data assimilation framework for time-varying parameter estimation. Specifically, this framework is applied to estimate the instantaneous reproduction number Rt during emerging epidemics, resulting in the state-of-the-art ‘DARt’ system. With DARt, time misalignment caused by lagging observations is tackled by incorporating observation delays into the joint inference of infections and Rt; the drawback of averaging is overcome by instantaneously updating upon new observations and developing a model selection mechanism that captures abrupt changes; the uncertainty is quantified and reduced by employing Bayesian smoothing. We validate the performance of DARt and demonstrate its power in describing the transmission dynamics of COVID-19. The proposed approach provides a promising solution for making accurate and timely estimation for transmission dynamics based on reported data.

Bayesian data assimilation for estimating instantaneous reproduction numbers during epidemics: Applications to COVID-19

Computational models of visual attention in artificial intelligence and robotics have been inspired by the concept of a saliency map. These models account for the mutual information between the (current) visual information and its estimated causes. However, they fail to consider the circular causality between perception and action. In other words, they do not consider where to sample next, given current beliefs. Here, we reclaim salience as an active inference process that relies on two basic principles: uncertainty minimization and rhythmic scheduling. For this, we make a distinction between attention and salience. Briefly, we associate attention with precision control, i.e., the confidence with which beliefs can be updated given sampled sensory data, and salience with uncertainty minimization that underwrites the selection of future sensory data. Using this, we propose a new account of attention based on rhythmic precision-modulation and discuss its potential in robotics, providing numerical experiments that showcase its advantages for state and noise estimation, system identification and action selection for informative path planning.

Reclaiming saliency: Rhythmic precision-modulated action and perception

Much of current artificial intelligence (AI) and the drive toward artificial general intelligence (AGI) focuses on developing machines for functional tasks that humans accomplish. These may be narrowly specified tasks as in AI, or more general tasks as in AGI – but typically these tasks do not target higher-level human cognitive abilities, such as consciousness or morality; these are left to the realm of so-called “strong AI” or “artificial consciousness.” In this paper, we focus on how a machine can augment humans rather than do what they do, and we extend this beyond AGI-style tasks to augmenting peculiarly personal human capacities, such as wellbeing and morality. We base this proposal on associating such capacities with the “self,” which we define as the “environment-agent nexus”; namely, a fine-tuned interaction of brain with environment in all its relevant variables. We consider richly adaptive architectures that have the potential to implement this interaction by taking lessons from the brain. In particular, we suggest conjoining the free energy principle (FEP) with the dynamic temporo-spatial (TSD) view of neuro-mental processes. Our proposed integration of FEP and TSD – in the implementation of artificial agents – offers a novel, expressive, and explainable way for artificial agents to adapt to different environmental contexts. The targeted applications are broad: from adaptive intelligence augmenting agents (IA’s) that assist psychiatric self-regulation to environmental disaster prediction and personal assistants. This reflects the central role of the mind and moral decision-making in most of what we do as humans.

Augmenting Human Selves Through Artificial Agents – Lessons From the Brain

The aim of this paper is to introduce a field of study that has emerged over the last decade, called Bayesian mechanics. Bayesian mechanics is a probabilistic mechanics, comprising tools that enable us to model systems endowed with a particular partition (i.e. into particles), where the internal states (or the trajectories of internal states) of a particular system encode the parameters of beliefs about external states (or their trajectories). These tools allow us to write down mechanical theories for systems that look as if they are estimating posterior probability distributions over the causes of their sensory states. This provides a formal language for modelling the constraints, forces, potentials and other quantities determining the dynamics of such systems, especially as they entail dynamics on a space of beliefs (i.e. on a statistical manifold). Here, we will review the state of the art in the literature on the free energy principle, distinguishing between three ways in which Bayesian mechanics has been applied to particular systems (i.e. path-tracking, mode-tracking and mode-matching). We go on to examine a duality between the free energy principle and the constrained maximum entropy principle, both of which lie at the heart of Bayesian mechanics, and discuss its implications.

Empirical applications of the free-energy principle are not straightforward because they entail a commitment to a particular process theory, especially at the cellular and synaptic levels. Using a recently established reverse engineering technique, we confirm the quantitative predictions of the free-energy principle using in vitro networks of rat cortical neurons that perform causal inference. Upon receiving electrical stimuli—generated by mixing two hidden sources—neurons self-organised to selectively encode the two sources. Pharmacological up- and downregulation of network excitability disrupted the ensuing inference, consistent with changes in prior beliefs about hidden sources. As predicted, changes in effective synaptic connectivity reduced variational free energy, where the connection strengths encoded parameters of the generative model. In short, we show that variational free energy minimisation can quantitatively predict the self-organisation of neuronal networks, in terms of their responses and plasticity. These results demonstrate the applicability of the free-energy principle to in vitro neural networks and establish its predictive validity in this setting.

Experimental validation of the free-energy principle with in vitro neural networks

Bistable perception follows from observing a static, ambiguous, (visual) stimulus with two possible interpretations. Here, we present an active (Bayesian) inference account of bistable perception and posit that perceptual transitions between different interpretations (i.e., inferences) of the same stimulus ensue from specific eye movements that shift the focus to a different visual feature. Formally, these inferences are a consequence of precision control that determines how confident beliefs are and change the frequency with which one can perceive – and alternate between – two distinct percepts. We hypothesised that there are multiple, but distinct, ways in which precision modulation can interact to give rise to a similar frequency of bistable perception. We validated this using numerical simulations of the Necker's cube paradigm and demonstrate the multiple routes that underwrite the frequency of perceptual alternation. Our results provide an (enactive) computational account of the intricate precision balance underwriting bistable perception. Importantly, these precision parameters can be considered the computational homologues of particular neurotransmitters – i.e., acetylcholine, noradrenaline, dopamine – that have been previously implicated in controlling bistable perception, providing a computational link between the neurochemistry and perception.

I overthink—Therefore I am not: An active inference account of altered sense of self and agency in depersonalisation disorder

Reply to ‘Towards a cross-cultural framework for predictive coding of music’

In this article, we aim to conceptualize and formalize the construct of resilience using the tools of active inference, a new physics-based modeling approach apt for the description and analysis of complex adaptive systems. We intend this as a first step toward a computational model of resilient systems. We begin by offering a conceptual analysis of resilience, to clarify its meaning, as established in the literature. We examine an orthogonal, threefold distinction between meanings of the word “resilience”: (i) inertia, or the ability to resist change (ii) elasticity, or the ability to bounce back from a perturbation, and (iii) plasticity, or the ability to flexibly expand the repertoire of adaptive states. We then situate all three senses of resilience within active inference. We map resilience as inertia onto high precision beliefs, resilience as elasticity onto relaxation back to characteristic (i.e., attracting) states, and resilience as plasticity onto functional redundancy and structural degeneracy.

Cognitive computational neuroscience (CCN) suggests that to gain a mechanistic understanding of brain function, hypothesis driven experiments should be accompanied by biologically plausible computational models. This novel research paradigm oﬀers a way from alchemy to chemistry, in auditory neuroscience.Withaspecial focus on tinnitus – as the prime example of auditory phantom perception – we review recent work at the intersection of artiﬁcial intelligence, psychology, and neuroscience, foregrounding the idea that experiments will yield mechanistic insight only when employed to test formal or computational models. This view challenges the popular notion that tinnitus research is primarily data limited, and that producing large, multi-modal, and complex data-sets, analyzed with advanced data analysis algorithms, will lead to

Predictive Coding and Stochastic Resonance: Towards a Unified Theory of Auditory (Phantom) Perception

Objective. In the theoretical framework of predictive coding and active inference, the brain can be viewed as instantiating a rich generative model of the world that predicts incoming sensory data while continuously updating its parameters via minimization of prediction errors. While this theory has been successfully applied to cognitive processes—by modelling the activity of functional neural networks at a mesoscopic scale—the validity of the approach when modelling neurons as an ensemble of inferring agents, in a biologically plausible architecture, remained to be explored. Approach. We modelled a simplified cerebellar circuit with individual neurons acting as Bayesian agents to simulate the classical delayed eyeblink conditioning protocol. Neurons and synapses adjusted their activity to minimize their prediction error, which was used as the network cost function. This cerebellar network was then implemented in hardware by replicating digital neuronal elements via a low-power microcontroller. Main results. Persistent changes of synaptic strength—that mirrored neurophysiological observations—emerged via local (neurocentric) prediction error minimization, leading to the expression of associative learning. The same paradigm was effectively emulated in low-power hardware showing remarkably efficient performance compared to conventional neuromorphic architectures. Significance. These findings show that: (a) an ensemble of free energy minimizing neurons—organized in a biological plausible architecture—can recapitulate functional self-organization observed in nature, such as associative plasticity, and (b) a neuromorphic network of inference units can learn unsupervised tasks without embedding predefined learning rules in the circuit, thus providing a potential avenue to a novel form of brain-inspired artificial intelligence.

Emergence of associative learning in a neuromorphic inference network

Multi-modal and multi-model interrogation of large-scale functional brain

During resting-state EEG recordings, alpha activity is more prominent over the posterior cortex in eyes-closed (EC) conditions compared to eyes-open (EO). In this study, we characterized the difference in spectra between EO and EC conditions using dynamic causal modelling. Specifically, we investigated the role of intrinsic and extrinsic connectivity—within the visual cortex—in generating EC-EO alpha power differences over posterior electrodes. The primary visual cortex (V1) and the bilateral middle temporal visual areas (V5) were equipped with bidirectional extrinsic connections using a canonical microcircuit. The states of four intrinsically coupled subpopulations—within each occipital source—were also modelled. Using Bayesian model selection, we tested whether modulations of the intrinsic connections in V1, V5 or extrinsic connections (or a combination thereof) provided the best evidence for the data. In addition, using parametric empirical Bayes (PEB), we estimated group averages under the winning model. Bayesian model selection showed that the winning model contained both extrinsic connectivity modulations, as well as intrinsic connectivity modulations in all sources. The PEB analysis revealed increased extrinsic connectivity during EC. Overall, we found a reduction in the inhibitory intrinsic connections during EC. The results suggest that the intrinsic modulations in V5 played the most important role in producing EC-EO alpha differences, suggesting an intrinsic disinhibition in higher order visual cortex, during EC resting state. Author summary One of the strongest signals that can be measured using EEG are so called alpha rhythms. These are neural oscillations that fall within the 8-12Hz frequency range. Alpha rhythms are most prominent when the eyes are closed and are seen at the electrodes placed at the back of the head. In this study, we studied the mechanism of alpha rhythms changes when going from eyes-open to an eyes-closed state. We used a biologically plausible model including different neural populations. We focused on modelling connections within and between different neural sources of the visual cortex and how they are modulated when going from eyes-open to an eyes closed state. We found evidence that inhibitory neurons play an important role in alpha rhythms.

Dynamic causal modelling shows a prominent role of local inhibition in alpha power modulation in higher visual cortex

A rich repertoire of oscillatory signals is detected from human brains with electro- and magnetoencephalography (EEG/MEG). However, the principles underwriting coherent oscillations and their link with neural activity remain under debate. Here, we revisit the mechanistic hypothesis that transient brain rhythms are a signature of metastable synchronization, occurring at reduced collective frequencies due to delays between brain areas. We consider a system of damped oscillators in the presence of background noise – approximating the short-lived gamma-frequency oscillations generated within neuronal circuits – coupled according to the diffusion weighted tractography between brain areas. Varying the global coupling strength and conduction speed, we identify a critical regime where spatially and spectrally resolved metastable oscillatory modes (MOMs) emerge at sub-gamma frequencies, approximating the MEG power spectra from 89 healthy individuals at rest. Further, we demonstrate that the frequency, duration, and scale of MOMs – as well as the frequency-specific envelope functional connectivity – can be controlled by global parameters, while the connectome structure remains unchanged. Grounded in the physics of delay-coupled oscillators, these numerical analyses demonstrate how interactions between locally generated fast oscillations in the connectome spacetime structure can lead to the emergence of collective brain rhythms organized in space and time. The mechanisms underlying transient brain rhythms and weekly stable synchronization of distant brain areas and their link with neural activity is still a matter of debate. Here, the authors use a brain network model to study spatio-temporal synchronization dynamics of brain regions and find that there is an optimal regime where spatially and spectrally resolved metastable oscillatory modes, similar to human magnetoencephalography data, emerge.

Metastable oscillatory modes emerge from synchronization in the brain spacetime connectome

This paper presents a meta-theory of the usage of the free energy principle (FEP) and examines its scope in the modelling of physical systems. We consider the so-called ‘map-territory fallacy’ and the fallacious reiﬁcation of model properties. By showing that the FEP is a consistent, physics-inspired theory of inferences of inferences, we disprove the assertion that the map-territory fallacy contradicts the principled usage of the FEP. As such, we argue that deploying the map-territory fallacy to criticise the use of the FEP and Bayesian mechanics itself constitutes a fallacy: what we call the map-territory fallacy fallacy . In so doing, we emphasise a few key points: the uniqueness of the FEP as a model of particles or agents that model their environments; the restoration of convention to the FEP via its relation to the principle of constrained maximum entropy; the ‘Jaynes optimality’ of the FEP under this relation; and ﬁnally, the way that this meta-theoretical approach to the FEP clariﬁes its utility and scope as a formal modelling tool. Taken together, these features make the FEP, uniquely, the ideal model of generic systems in statistical physics.

We show how any finite physical system with morphological, i.e. three-dimensional embedding or shape, degrees of freedom and locally limited free energy will, under the constraints of the free energy principle, evolve over time towards a neuromorphic morphology that supports hierarchical computations in which each ‘level’ of the hierarchy enacts a coarse-graining of its inputs, and dually, a fine-graining of its outputs. Such hierarchies occur throughout biology, from the architectures of intracellular signal transduction pathways to the large-scale organization of perception and action cycles in the mammalian brain. The close formal connections between cone-cocone diagrams (CCCD) as models of quantum reference frames on the one hand, and between CCCDs and topological quantum field theories on the other, allow the representation of such computations in the fully-general quantum-computational framework of topological quantum neural networks.

In this paper, we introduce a word repetition generative model (WORM), which—when combined with an appropriate belief updating scheme—is capable of inferring the word that should be spoken when presented with an auditory cue. Our generative model takes a deep temporal form, combining both discrete and continuous states. This allows a (synthetic) WORM agent to perform categorical inference on continuous acoustic signals, and—based on the same model—to repeat heard words at the appropriate time. From the perspective of word production, the model simulates how high-level beliefs about discrete lexical, prosodic and context attributes give rise to continuous acoustic signals at the sensory level. From the perspective of word recognition, it simulates how continuous acoustic signals are recognised as words and, how (and when) they should be repeated. We establish the face validity of our generative model by simulating a word repetition paradigm in which a synthetic agent or a human subject hears a target word and subsequently reproduces that word. The repeated word should be the target word but differs acoustically. The results of these simulations reveal how the generative model correctly infers what must be repeated, to the extent it can successfully interact with a human subject. This provides a formal process theory of auditory perception and production that can be deployed in health and disease. We conclude with a discussion of how the generative model could be scaled-up to include a larger phonetic and phonotactic repertoire, complex higher-level attributes (e.g., semantic, concepts, etc.), and produce more elaborate exchanges.

This paper describes a path integral formulation of the free energy principle. The ensuing account expresses the paths or trajectories that a particle takes as it evolves over time. The main results are a method or principle of least action that can be used to emulate the behaviour of particles in open exchange with their external milieu. Particles are defined by a particular partition, in which internal states are individuated from external states by active and sensory blanket states. The variational principle at hand allows one to interpret internal dynamics - of certain kinds of particles - as inferring external states that are hidden behind blanket states. We consider different kinds of particles, and to what extent they can be imbued with an elementary form of inference or sentience. Specifically, we consider the distinction between dissipative and conservative particles, inert and active particles and, finally, ordinary and strange particles. Strange particles can be described as inferring their own actions, endowing them with apparent autonomy or agency. In short - of the kinds of particles afforded by a particular partition - strange kinds may be apt for describing sentient behaviour.

Humans display astonishing skill in learning about the environment in which they operate. They assimilate a rich set of affordances and interrelations among different elements in particular contexts, and form flexible abstractions (i.e., concepts) that can be generalised and leveraged with ease. To capture these abilities, we present a deep hierarchical Active Inference model of goal-directed behaviour, and the accompanying belief update schemes implied by maximising model evidence. Using simulations, we elucidate the potential mechanisms that underlie and influence concept learning in a spatial foraging task. We show that the representations formed–as a result of foraging–reflect environmental structure in a way that is enhanced and nuanced by Bayesian model reduction, a special case of structure learning that typifies learning in the absence of new evidence. Synthetic agents learn associations and form concepts about environmental context and configuration as a result of inferential, parametric learning, and structure learning processes–three processes that can produce a diversity of beliefs and belief structures. Furthermore, the ensuing representations reflect symmetries for environments with identical configurations.

Structure learning enhances concept formation in synthetic Active Inference agents

Humans are highly proficient in learning about the environments in which they operate. They form flexible spatial representations of their surroundings that can be leveraged with ease during spatial foraging and navigation. To capture these abilities, we present a deep Active Inference model of goal-directed behavior, and the accompanying belief updating. Active Inference rests upon optimizing Bayesian beliefs to maximize model evidence or marginal likelihood. Bayesian beliefs are probability distributions over the causes of observable outcomes. These causes include an agent’s actions, which enables one to treat planning as inference. We use simulations of a geocaching task to elucidate the belief updating—that underwrites spatial foraging—and the associated behavioral and neurophysiological responses. In a geocaching task, the aim is to find hidden objects in the environment using spatial coordinates. Here, synthetic agents learn about the environment via inference and learning (e.g., learning about the likelihoods of outcomes given latent states) to reach a target location, and then forage locally to discover the hidden object that offers clues for the next location.

Synthetic Spatial Foraging With Active Inference in a Geocaching Task

Abstract. The Rorschach offers a unique and interesting paradigm from the perspective of the (Bayesian) brain. This contribution to the cross-disciplinary special issue considers the Rorschach from the perspective of perceptual inference in the brain and how it might inform subject-specific differences in perceptual synthesis. Before doing so, we provide a broad overview of active inference in its various manifestations. In brief, active inference supposes that our perceptions are the best hypothesis to explain sensory impressions. On a Bayesian account, the requisite belief updating rests sensitively upon the precision or confidence ascribed to sensory input, relative to prior beliefs about the causes of sensations. This focus – on the balance between sensory and prior precision – has been a useful construct in both cognitive science (e.g., as a formal explanation for attention) and neuropsychology (e.g., as a formal explanation for aberrant or false inference in hallucinations). In this setting, false inference is generally understood as abnormally high precision afforded to high-level hypotheses or explanations for visual input, which may compensate for a failure to attenuate sensory precision. On this view, the Rorschach offers an interesting paradigm because the amount of precise information about the causes of visual input is deliberately minimized – and rendered ambiguous – thereby placing greater emphasis on prior beliefs entertained by the respondent. We close by exploring this issue and several other areas of intersection between Rorschach responding and active inference.

This paper offers theoretical explanations for why “guided touch” or manual touch with verbal communication can be an effective way of treating the body (e.g., chronic pain) and the mind (e.g., emotional disorders). The active inference theory suggests that chronic pain and emotional disorders can be attributed to distorted and exaggerated patterns of interoceptive and proprioceptive inference. We propose that the nature of active inference is abductive. As such, to rectify aberrant active inference processes, we should change the “Rule” of abduction, or the “prior beliefs” entailed by a patient’s generative model. This means pre-existing generative models should be replaced with new models. To facilitate such replacement—or updating—the present treatment proposes that we should weaken prior beliefs, especially the one at the top level of hierarchical generative models, thereby altering the sense of agency, and redeploying attention. Then, a new prior belief can be installed through inner communication along with manual touch. The present paper proposes several hypotheses for possible experimental studies. If touch with verbal guidance is proven to be effective, this would demonstrate the relevance of active inference and the implicit prediction model at a behavioral level. Furthermore, it would open new possibilities of employing inner communication interventions, including self-talk training, for a wide range of psychological and physical therapies.

An Active Inference Account of Touch and Verbal Communication in Therapy

In the brain, the insular cortex receives a vast amount of interoceptive information, ascending through deep brain structures, from multiple visceral organs. The unique hierarchical and modular architecture of the insula suggests specialization for processing interoceptive afferents. Yet, the biological significance of the insula's neuroanatomical architecture, in relation to deep brain structures, remains obscure. In this opinion piece, we propose the Insula Hierarchical Modular Adaptive Interoception Control (IMAC) model to suggest that insula modules (granular, dysgranular and agranular), forming parallel networks with the prefrontal cortex and striatum, are specialized to form higher order interoceptive representations. These interoceptive representations are recruited in a context-dependent manner to support habitual, model-based and exploratory control of visceral organs and physiological processes. We discuss how insula interoceptive representations may give rise to conscious feelings that best explain lower order deep brain interoceptive representations, and how the insula may serve to defend the body and mind against pathological depression.

An insula hierarchical network architecture for active interoceptive inference

Very particular: Comment on "How particular is the physics of the free energy principle?"

The ultimate trick?: Comment on: "The Markov blanket trick: On the scope of the free energy principle and active inference" by Raja et al.

In this paper, we provide a computational account of changes in synaptic connectivity within two regions of the fronto-parietal network, the dorsolateral prefrontal cortex and the pre-supplementary motor area, applying Dynamic Causal Models to electrocorticogram recordings from two macaque monkeys performing a problem-solving task that engages working memory, and induces time-on-task effects. We find that forward connections between the two regions increased in strength when task demands were increased, and as the experimental session progressed. Similarities in the effects of task demands and time on task allow us to interpret changes in frontal connectivity in terms of increased effort allocation that compensates cognitive fatigue.

Frontal effective connectivity increases with task demands and time on task: a DCM study on electrocorticogram in macaque monkeys

Stress and its sequelae: An active inference account of the etiological pathway from allostatic overload to depression

A rich repertoire of oscillatory signals is detected from human brains with electro- and magnetoencephalography (EEG/MEG). However, the principles underwriting coherent oscillations and their link with neural activity remain unclear. Here, we hypothesise that the emergence of transient brain rhythms is a signature of weakly stable synchronization between spatially distributed brain areas, occurring at network-specific collective frequencies due to non-negligible conduction times. We test this hypothesis using a phenomenological network model to simulate interactions between neural mass potentials (resonating at 40Hz) in the structural connectome. Crucially, we identify a critical regime where metastable oscillatory modes emerge spontaneously in the delta (0.5-4Hz), theta (4-8Hz), alpha (8-13Hz) and beta (13-30Hz) frequency bands from weak synchronization of subsystems, closely approximating the MEG power spectra from 89 healthy individuals. Grounded in the physics of delay-coupled oscillators, these numerical analyses demonstrate the role of the spatiotemporal connectome in structuring brain activity in the frequency domain.

Synchronization in the connectome: Metastable oscillatory modes emerge from interactions in the brain spacetime network

Neural mass models are used to simulate cortical dynamics and to explain the electrical and magnetic fields measured using electro- and magnetoencephalography. Simulations evince a complex phase-space structure for these kinds of models; including stationary points and limit cycles and the possibility for bifurcations and transitions among different modes of activity. This complexity allows neural mass models to describe the itinerant features of brain dynamics. However, expressive, nonlinear neural mass models are often difficult to fit to empirical data without additional simplifying assumptions: e.g., that the system can be modelled as linear perturbations around a fixed point. In this study we offer a mathematical analysis of neural mass models, specifically the canonical microcircuit model, providing analytical solutions describing slow changes in the type of cortical activity, i.e. dynamical itinerancy. We derive a perturbation analysis up to second order of the phase flow, together with adiabatic approximations. This allows us to describe amplitude modulations in a relatively simple mathematical format providing analytic proof-of-principle for the existence of semi-stable states of cortical dynamics at the scale of a cortical column. This work allows for model inversion of neural mass models, not only around fixed points, but over regions of phase space that encompass transitions among semi or multi-stable states of oscillatory activity. Crucially, these theoretical results speak to model inversion in the context of multiple semi-stable brain states, such as the transition between interictal, pre-ictal and ictal activity in epilepsy.

Synaptic loss occurs early in many neurodegenerative diseases and contributes to cognitive impairment even in the absence of gross atrophy. Currently, for human disease there are few formal models to explain how cortical networks underlying cognition are affected by synaptic loss. We advocate that biophysical models of neurophysiology offer both a bridge from clinical to preclinical models of pathology, and quantitative assays for experimental medicine. Such biophysical models can also disclose hidden neuronal dynamics generating neurophysiological observations like electro- and magneto-encephalography (MEG). Here, we augment a biophysically informed mesoscale model of human cortical function by inclusion of synaptic density estimates as captured by [11C]UCB-J positron emission tomography, and provide insights into how regional synapse loss affects neurophysiology. We use the primary tauopathy of progressive supranuclear palsy (Richardson's syndrome) as an exemplar condition, with high clinicopathological correlations. Progressive supranuclear palsy causes a marked change in cortical neurophysiology in the presence of mild atrophy and is associated with a decline in cognitive functions associated with the frontal lobe. Using (parametric empirical) Bayesian inversion of a conductance-based canonical microcircuit model of MEG data, we show that the inclusion of regional synaptic density - as a subject-specific prior on laminar specific neuronal populations - markedly increases model evidence. Specifically, model comparison suggests that a reduction in synaptic density in inferior frontal cortex affects superficial and granular layer glutamatergic excitation. This predicted individual differences in behaviour, demonstrating the link between synaptic loss, neurophysiology, and cognitive deficits. The method we demonstrate is not restricted to progressive supranuclear palsy or the effects of synaptic loss: such pathology-enriched dynamic causal models can be used to assess the mechanisms of other neurological disorders, with diverse non-invasive measures of pathology, and is suitable to test the effects of experimental pharmacology.

Neurophysiological consequences of synapse loss in progressive supranuclear palsy

How is information processed in the brain during perception? Mechanistic insight is achieved only when experiments are employed to test formal or computational models. In analogy to lesion studies, phantom perception may serve as a vehicle to understand the fundamental processing principles underlying auditory perception. With a special focus on tinnitus – as the prime example of auditory phantom perception – we review recent work at the intersection of artiﬁcial intelligence, psychology, and neuroscience. In particular, we discuss why everyone with tinnitus suﬀers from hearing loss, but not everyone with hearing loss suﬀers from tinnitus. We argue that the increase of sensory precision due to Bayesian inference could be caused by intrinsic neural noise and lead to a prediction error in the cerebral cortex. Hence, two fundamental processing principles - being ubiquitous in the brain - provide the most explanatory power for the emergence of tinnitus: predictive coding as a top-down, and stochastic resonance as a complementary bottom-up mechanism. We conclude that both principles play a crucial role in healthy auditory perception.

Predictive coding and stochastic resonance as fundamental principles of auditory perception

Osteopathy is a person-centred healthcare discipline that emphasizes the body’s structure-function interrelationship—and its self-regulatory mechanisms—to inform a whole-person approach to health and wellbeing. This paper aims to provide a theoretical framework for developing an integrative hypothesis in osteopathy, which is based on the enactivist and active inference accounts. We propose that osteopathic care can be reconceptualised under (En)active inference as a unifying framework. Active inference suggests that action-perception cycles operate to minimize uncertainty and optimize an individual’s internal model of the lived world and, crucially, the consequences of their behaviour. We argue that (En)active inference offers an integrative framework for osteopathy, which can evince the mechanisms underlying dyadic and triadic (e.g., in paediatric care) exchanges and osteopathic care outcomes. We propose that this theoretical framework can underpin osteopathic care across the lifespan, from preterm infants to the elderly and those with persistent pain and other physical symptoms. In situations of chronicity, as an ecological niche, the patient-practitioner dyad provides the osteopath and the patient with a set of affordances, i.e., possibilities for action provided by the environment, that through shared intentionally, can promote adaptations and restoration of productive agency. Through a dyadic therapeutic relationship, as they engage with their ecological niche’s affordances—a structured set of affordances shared by agents—osteopath and patient actively construct a shared sense-making narrative and realise a shared generative model of their relation to the niche. In general, touch plays a critical role in developing a robust therapeutic alliance, mental state alignment, and biobehavioural synchrony between patient and practitioner. However, its role is particularly crucial in the fields of neonatology and paediatrics, where it becomes central in regulating allostasis and restoring homeostasis. We argue that from an active inference standpoint, the dyadic shared ecological niche underwrites a robust therapeutic alliance, which is crucial to the effectiveness of osteopathic care. Considerations and implications of this model—to clinical practice and research, both within- and outside osteopathy—are critically discussed.

Osteopathic Care as (En)active Inference: A Theoretical Framework for Developing an Integrative Hypothesis in Osteopathy

In the neurological model of language, repeating heard speech involves four left hemisphere regions: primary auditory cortex for processing sounds; Wernicke’s area for processing auditory images of speech; Broca’s area for processing motor images of speech; and primary motor cortex for overt speech articulation. Previous functional-MRI (fMRI) studies confirm that auditory repetition activates these regions. Here, we used dynamic causal modelling (DCM) to test how the four regions interact with each other during single word and pseudoword auditory repetition. Contrary to expectation, we found that, for both word and pseudoword repetition, the effective connectivity between Wernicke’s and Broca’s areas was predominantly bidirectional and inhibitory; activity in the motor cortex could be driven by either Wernicke’s area or Broca’s area; and the latter effect varied both within and between individuals. Such variability speaks to degenerate functional architectures that support auditory repetition and may explain resilience to functional loss after brain damage.

Degeneracy in the neurological model of auditory speech repetition

The ability to adapt to a changing environment underwrites sentient behaviour e.g., wearing a raincoat when walking in the rain but removing it when indoors. In such instances, agents act to satisfy some preferred mode of behaviour that leads to predictable states necessary for survival, i.e., states that are characteristic of that agent. In this chapter, we describe how active inference agents, equipped with preference learning, can exhibit these distinct behavioural modes – influenced by environment dynamics – to aptly trade-off between preference satisfaction and exploration. We validate this in a modified OpenAI Gym FrozenLake environment (without any extrinsic signal) with and without volatility under a fixed model of the environment. In a static (i.e., without volatility) environment, preference-learning agents accumulate confident (Bayesian) beliefs about their behaviour and act to satisfy them. In contrast, volatile dynamics led to preference uncertainty and exploratory behaviour. This demonstrates that active inference agents, equipped with preference learning, have the appropriate machinery to (i) engage in adaptive behaviour under appropriate levels of volatility, and (ii) learn context-dependent subjective preferences.

Abstract It is a pleasure to comment on Bruineberg et al. – who raise some interesting questions of a philosophical and technical nature. I will try to answer three questions posed by the authors. Are Pearl and Friston blankets different things? Are Markov blankets used in an ontological sense? Is there a privileged Markov blanket?

Selective attention implements preferential routing of attended stimuli, likely through increasing the influence of the respective synaptic inputs on higher-area neurons. As the inputs of competing stimuli converge onto postsynaptic neurons, presynaptic circuits might offer the best target for attentional top-down influences. If those influences enabled presynaptic circuits to selectively entrain postsynaptic neurons, this might lead to selective routing. Indeed, when two visual stimuli induce two gamma rhythms in V1, only the gamma induced by the attended stimulus entrains gamma in V4. Here, we modeled this selective entrainment with a Dynamic Causal Model for Cross-Spectral Densities and found that it can be explained by attentional modulation of intrinsic V1 connections. Specifically, local inhibition was decreased in the granular input layer and increased in the supragranular output layer of the V1 circuit that processed the attended stimulus. Thus, presynaptic attentional influences and ensuing entrainment were sufficient to mediate selective routing.

Selective V1-to-V4 communication of attended stimuli mediated by attentional effects in V1

When do bursts matter in the primary motor cortex? Investigating changes in the intermittencies of beta rhythms associated with movement states

Publisher Correction: Brain information processing capacity modelling

Geometric Methods for Sampling, Optimisation, Inference and Adaptive Agents

Recognizing and aligning individuals’ unique adaptive beliefs or “priors” through cooperative communication is critical to establishing a therapeutic relationship and alliance. Using active inference, we present an empirical integrative account of the biobehavioral mechanisms that underwrite therapeutic relationships. A significant mode of establishing cooperative alliances—and potential synchrony relationships—is through ostensive cues generated by repetitive coupling during dynamic touch. Established models speak to the unique role of affectionate touch in developing communication, interpersonal interactions, and a wide variety of therapeutic benefits for patients of all ages; both neurophysiologically and behaviorally. The purpose of this article is to argue for the importance of therapeutic touch in establishing a therapeutic alliance and, ultimately, synchrony between practitioner and patient. We briefly overview the importance and role of therapeutic alliance in prosocial and clinical interactions. We then discuss how cooperative communication and mental state alignment—in intentional communication—are accomplished using active inference. We argue that alignment through active inference facilitates synchrony and communication. The ensuing account is extended to include the role of (C-) tactile afferents in realizing the beneficial effect of therapeutic synchrony. We conclude by proposing a method for synchronizing the effects of touch using the concept of active inference.

Therapeutic Alliance as Active Inference: The Role of Therapeutic Touch and Synchrony

Neurochemistry-enriched dynamic causal models of magnetoencephalography, using magnetic resonance spectroscopy

Recent advances in neuroscience have characterised brain function using mathematical formalisms and first principles that may be usefully applied elsewhere. In this paper, we explain how active inference—a well-known description of sentient behaviour from neuroscience—can be exploited in robotics. In short, active inference leverages the processes thought to underwrite human behaviour to build effective autonomous systems. These systems show state-of-the-art performance in several robotics settings; we highlight these and explain how this framework may be used to advance robotics.

1 Department of Collective Behaviour, Max Planck Institute of Animal Behavior, 78457 Konstanz, Germany 2 Centre for the Advanced Study of Collective Behaviour, 78457 Konstanz, Germany 3 Department of Biology, University of Konstanz, 78457 Konstanz, Germany 4 VERSES Research Lab, Los Angeles, California, USA 5 MRC Brain Networks Dynamics Unit, University of Oxford, Oxford, UK 6 Department of Computing, Imperial College London, London, UK 7 Network Science Institute, Northeastern University, Boston, MA, USA 8 Laboratory for the Modeling of Biological and Socio-Technical Systems, Northeastern University, Boston, USA 9 Wellcome Centre for Human Neuroimaging, Queen Square Institute of Neurology, University College London, London WC1N 3AR, UK 10 Sussex AI Group, Department of Informatics, University of Sussex, Brighton, UK 11 Sackler Centre for Consciousness Science, University of Sussex, Brighton, UK ¶ Corresponding author DOI: 10.21105/joss.04098

pymdp: A Python library for active inference in discrete state spaces

Predicting the Health Effects of the COVID-19 Epidemic in the UK to October 2023 Using a Dynamic Causal Model

We apply Dynamic Causal Models to electrocorticogram recordings from two macaque monkeys performing a problem-solving task that engages working memory, and induces time-on-task effects. We thus provide a computational account of changes in effective connectivity within two regions of the fronto-parietal network, the dorsolateral prefrontal cortex and the pre-supplementary motor area. We find that forward connections between the two regions increased in strength when task demands increased, and as the experimental session progressed. Similarities in the effects of task demands and time on task allow us to interpret changes in frontal connectivity in terms of increased attentional effort allocation that compensates cognitive fatigue.

Frontal effective connectivity increases with task demands and time on task: a Dynamic Causal Model of electrocorticogram in macaque monkeys

This paper provides a concise description of the free energy principle, starting from a formulation of random dynamical systems in terms of a Langevin equation and ending with a Bayesian mechanics that can be read as a physics of sentience. It rehearses the key steps using standard results from statistical physics. These steps entail (i) establishing a particular partition of states based upon conditional independencies that inherit from sparsely coupled dynamics, (ii) unpacking the implications of this partition in terms of Bayesian inference and (iii) describing the paths of particular states with a variational principle of least action. Teleologically, the free energy principle offers a normative account of self-organisation in terms of optimal Bayesian design and decision-making, in the sense of maximising marginal likelihood or Bayesian model evidence. In summary, starting from a description of the world in terms of random dynamical systems, we end up with a description of self-organisation as sentient behaviour that can be interpreted as self-evidencing; namely, self-assembly, autopoiesis or active inference.

This presentation considers deep temporal models in the brain. It builds on previous formulations of active inference to simulate behaviour and electrophysiological responses under deep (hierarchical) generative models of discrete state transitions. The deeply structured temporal aspect of these models means that evidence is accumulated over distinct temporal scales, enabling inferences about narratives (i.e., temporal scenes). We illustrate this behaviour in terms of Bayesian belief updating – and associated neuronal processes – to reproduce the epistemic foraging seen in reading. These simulations reproduce these sort of perisaccadic delay period activity and local field potentials seen empirically; including evidence accumulation and place cell activity. These simulations are presented as an example of how to use basic principles to constrain our understanding of system architectures in the brain – and the functional imperatives that may apply to neuronal networks.

The emerging neurocomputational vision of humans as embodied, ecologically embedded, social agents—who shape and are shaped by their environment—offers a golden opportunity to revisit and revise ideas about the physical and information-theoretic underpinnings of life, mind, and consciousness itself. In particular, the active inference framework (AIF) makes it possible to bridge connections from computational neuroscience and robotics/AI to ecological psychology and phenomenology, revealing common underpinnings and overcoming key limitations. AIF opposes the mechanistic to the reductive, while staying fully grounded in a naturalistic and information-theoretic foun-dation, using the principle of free energy minimization. The latter provides a theoretical basis for a unified treatment of particles, organisms, and interactive machines, spanning from the inorganic to organic, non-life to life, and natural to artificial agents. We provide a brief introduction to AIF, then explore its implications for evolutionary theory, ecological psychology, embodied phenomenology, and robotics/AI research. We conclude the paper by considering implications for machine consciousness.

Open Research Online The Active Inference Approach to Ecological Perception: General Information Dynamics for Natural and Artiﬁcial Embodied Cognition

This article considers the evolution of brain architectures for predictive processing. We argue that brain mechanisms for predictive perception and action are not late evolutionary additions of advanced creatures like us. Rather, they emerged gradually from simpler predictive loops (e.g. autonomic and motor reflexes) that were a legacy from our earlier evolutionary ancestors—and were key to solving their fundamental problems of adaptive regulation. We characterize simpler-to-more-complex brains formally, in terms of generative models that include predictive loops of increasing hierarchical breadth and depth. These may start from a simple homeostatic motif and be elaborated during evolution in four main ways: these include the multimodal expansion of predictive control into an allostatic loop; its duplication to form multiple sensorimotor loops that expand an animal's behavioural repertoire; and the gradual endowment of generative models with hierarchical depth (to deal with aspects of the world that unfold at different spatial scales) and temporal depth (to select plans in a future-oriented manner). In turn, these elaborations underwrite the solution to biological regulation problems faced by increasingly sophisticated animals. Our proposal aligns neuroscientific theorising—about predictive processing—with evolutionary and comparative data on brain architectures in different animal species. This article is part of the theme issue ‘Systems neuroscience through the lens of evolutionary theory’.

The evolution of brain architectures for predictive coding and active inference

Natural language syntax yields an unbounded array of hierarchically structured expressions. We claim that these are used in the service of active inference in accord with the free-energy principle (FEP). While conceptual advances alongside modelling and simulation work have attempted to connect speech segmentation and linguistic communication with the FEP, we extend this program to the underlying computations responsible for generating elementary syntactic objects. We argue that recently proposed principles of economy in language design—such as “minimal search” and “least effort” criteria from theoretical syntax—adhere to the FEP. This permits a greater degree of explanatory power to the FEP—with respect to higher language functions—and presents linguists with a grounding in first principles of notions pertaining to computability. More generally, we explore the possibility of migrating certain topics in linguistics over to the domain of fields that investigate the FEP, such as complex polysemy. We aim to align concerns of linguists with the normative model for organic self-organisation associated with the FEP, marshalling evidence from theoretical linguistics and psycholinguistics to ground core principles of efficient syntactic computation within active inference.

In this treatment of random dynamical systems, we consider the existence—and identification—of conditional independencies at nonequilibrium steady-state. These independencies underwrite a particular partition of states, in which internal states are statistically secluded from external states by blanket states. The existence of such partitions has interesting implications for the information geometry of internal states. In brief, this geometry can be read as a physics of sentience, where internal states look as if they are inferring external states. However, the existence of such partitions—and the functional form of the underlying densities—have yet to be established. Here, using the Lorenz system as the basis of stochastic chaos, we leverage the Helmholtz decomposition—and polynomial expansions—to parameterise the steady-state density in terms of surprisal or self-information. We then show how Markov blankets can be identified—using the accompanying Hessian—to characterise the coupling between internal and external states in terms of a generalised synchrony or synchronisation of chaos. We conclude by suggesting that this kind of synchronisation may provide a mathematical basis for an elemental form of (autonomous or active) sentience in biology.

The active inference framework, and in particular its recent formulation as a partially observable Markov decision process (POMDP), has gained increasing popularity in recent years as a useful approach for modeling neurocognitive processes. This framework is highly general and flexible in its ability to be customized to model any cognitive process, as well as simulate predicted neuronal responses based on its accompanying neural process theory. It also affords both simulation experiments for proof of principle and behavioral modeling for empirical studies. However, there are limited resources that explain how to build and run these models in practice, which limits their widespread use. Most introductions assume a technical background in programming, mathematics, and machine learning. In this paper we offer a step-by-step tutorial on how to build POMDPs, run simulations using standard MATLAB routines, and fit these models to empirical data. We assume a minimal background in programming and mathematics, thoroughly explain all equations, and provide exemplar scripts that can be customized for both theoretical and empirical studies. Our goal is to provide the reader with the requisite background knowledge and practical tools to apply active inference to their own research. We also provide optional technical sections and multiple appendices, which offer the interested reader additional technical details. This tutorial should provide the reader with all the tools necessary to use these models and to follow emerging advances in active inference research.

A step-by-step tutorial on active inference and its application to empirical data

In order to interact seamlessly with robots, users must infer the causes of a robot’s behavior–and be confident about that inference (and its predictions). Hence, trust is a necessary condition for human-robot collaboration (HRC). However, and despite its crucial role, it is still largely unknown how trust emerges, develops, and supports human relationship to technological systems. In the following paper we review the literature on trust, human-robot interaction, HRC, and human interaction at large. Early models of trust suggest that it is a trade-off between benevolence and competence; while studies of human to human interaction emphasize the role of shared behavior and mutual knowledge in the gradual building of trust. We go on to introduce a model of trust as an agent’ best explanation for reliable sensory exchange with an extended motor plant or partner. This model is based on the cognitive neuroscience of active inference and suggests that, in the context of HRC, trust can be casted in terms of virtual control over an artificial agent. Interactive feedback is a necessary condition to the extension of the trustor’s perception-action cycle. This model has important implications for understanding human-robot interaction and collaboration–as it allows the traditional determinants of human trust, such as the benevolence and competence attributed to the trustee, to be defined in terms of hierarchical active inference, while vulnerability can be described in terms of information exchange and empowerment. Furthermore, this model emphasizes the role of user feedback during HRC and suggests that boredom and surprise may be used in personalized interactions as markers for under and over-reliance on the system. The description of trust as a sense of virtual control offers a crucial step toward grounding human factors in cognitive neuroscience and improving the design of human-centered technology. Furthermore, we examine the role of shared behavior in the genesis of trust, especially in the context of dyadic collaboration, suggesting important consequences for the acceptability and design of human-robot collaborative systems.

Trust as Extended Control: Human-Machine Interactions as Active Inference

<p><strong>We formalize the resilience of the Earth system under the free energy principle (Friston 2013; Parr et al, 2019; Rubin et al, 2020). This allows us to understand resilience as the self-maintenance of a non-equilibrium steady-state. This autopoietic steady-state depends on gradient flows that counter entropic dissipation by random fluctuations. These flows can also be interpreted in a statistical sense, which amounts to the claim that resilience depends upon the Earth system possessing a Markov blanket were blanket states (i.e., active and sensory states) separate internal states from external states. Our formalization rests on how the metabolic rates of the biosphere (i.e., internal states) relate vicariously to solar radiation at the Earth&#8217;s surface (i.e., external states), through the changes in greenhouse and albedo effects (i.e. active states) and ocean-driven global temperature changes (i.e. sensory states). Describing the interaction between the metabolic rates and solar radiation as climatic states&#8212;via a Markov blanket&#8212;amounts to describing the dynamics of the internal states as actively inferring external states. This underwrites climatic non-equilibrium steady-state through variational free energy minimization&#8212;and thus a form of Earth resilience, through active inference at the planetary scale.</strong></p><p><strong>References</strong></p><p>Friston, K., 2013. Life as we know it.&#160;Journal of the Royal Society Interface,&#160;10(86), p.20130475.</p><p>Parr, T., Da Costa, L. and Friston, K., 2019. Markov blankets, information geometry and stochastic thermodynamics. <em>Philosophical Transactions of the Royal Society A</em>, <em>378</em>(2164), p.20190159.</p><p>Rubin, S., Parr, T., Da Costa, L. and Friston, K., 2020. Future climates: Markov blankets and active inference in the biosphere.&#160;<em>Journal of the Royal Society Interface</em>,&#160;17(172), p.20200503.</p>

AI ethics in computational psychiatry: From the neuroscience of consciousness to the ethics of consciousness

Schizophrenia is hypothesized to be caused by impaired functional integration in the brain, and this could hypothetically be caused by white matter disruptions, synaptic dysfunction, or both. Neuroimaging studies consistently show reduced fractional anisotropy, a measure of white matter integrity, in patients with schizophrenia. Using Mendelian randomization, we show that these white matter changes are likely to be the consequence of a primary synaptopathy in schizophrenia.

White matter disruption as a cause or consequence of schizophrenia: A Mendelian randomization study

The active visual system comprises the visual cortices, cerebral attention networks, and oculomotor system. While fascinating in its own right, it is also an important model for sensorimotor networks in general. A prominent approach to studying this system is active inference—which assumes the brain makes use of an internal (generative) model to predict proprioceptive and visual input. This approach treats action as ensuring sensations conform to predictions (i.e., by moving the eyes) and posits that visual percepts are the consequence of updating predictions to conform to sensations. Under active inference, the challenge is to identify the form of the generative model that makes these predictions—and thus directs behavior. In this paper, we provide an overview of the generative models that the brain must employ to engage in active vision. This means specifying the processes that explain retinal cell activity and proprioceptive information from oculomotor muscle fibers. In addition to the mechanics of the eyes and retina, these processes include our choices about where to move our eyes. These decisions rest upon beliefs about salient locations, or the potential for information gain and belief-updating. A key theme of this paper is the relationship between “looking” and “seeing” under the brain's implicit generative model of the visual world.

Author Correction: Dynamic causal modelling of immune heterogeneity

Rendering neuronal state equations compatible with the principle of stationary action

System-specific brain responses—time-locked to rapid eye movements (REMs) in sleep—are characteristically widespread, with robust and clear activation in the primary visual cortex and other structures involved in multisensory integration. This pattern suggests that REMs underwrite hierarchical processing of visual information in a time-locked manner, where REMs index the generation and scanning of virtual-world models, through multisensory integration in dreaming—as in awake states. Default mode network (DMN) activity increases during rest and reduces during various tasks including visual perception. The implicit anticorrelation between the DMN and task-positive network (TPN)—that persists in REM sleep—prompted us to focus on DMN responses to temporally-precise REM events. We timed REMs during sleep from the video recordings and quantified the neural correlates of REMs—using functional MRI (fMRI)—in 24 independent studies of 11 healthy participants. A reanalysis of these data revealed that the cortical areas exempt from widespread REM-locked brain activation were restricted to the DMN. Furthermore, our analysis revealed a modest temporally-precise REM-locked decrease—phasic deactivation—in key DMN nodes, in a subset of independent studies. These results are consistent with hierarchical predictive coding; namely, permissive deactivation of DMN at the top of the hierarchy (leading to the widespread cortical activation at lower levels; especially the primary visual cortex). Additional findings indicate REM-locked cerebral vasodilation and suggest putative mechanisms for dream forgetting.

fMRI Evidence for Default Mode Network Deactivation Associated with Rapid Eye Movements in Sleep

This paper develops a Bayesian mechanics for adaptive systems. Firstly, we model the interface between a system and its environment with a Markov blanket. This affords conditions under which states internal to the blanket encode information about external states. Second, we introduce dynamics and represent adaptive systems as Markov blankets at steady state. This allows us to identify a wide class of systems whose internal states appear to infer external states, consistent with variational inference in Bayesian statistics and theoretical neuroscience. Finally, we partition the blanket into sensory and active states. It follows that active states can be seen as performing active inference and well-known forms of stochastic control (such as PID control), which are prominent formulations of adaptive behaviour in theoretical biology and engineering.

 Humans can produce complex movements when interacting with their surroundings. This relies on the planning of various movements and subsequent execution. In this paper, we investigated this fundamental aspect of motor control in the setting of autonomous robotic operations. We consider hierarchical generative modelling—for autonomous task completion—that mimics the deep temporal architecture of human motor control. Here, temporal depth refers to the nested time scales at which successive levels of a forward or generative model unfold: for example, the apprehension and delivery of an object requires both a global plan that contextualises the fast coordination of multiple local limb movements. This separation of temporal scales can also be motivated from a robotics and control perspective. Specifically, to ensure versatile sensorimotor control, it is necessary to hierarchically structure high-level planning and low-level motor control of individual limbs. We use numerical experiments to establish the efficacy of this formulation and demonstrate how a humanoid robot can autonomously solve a complex task requiring locomotion, manipulation, and grasping, using a hierarchical generative model. In particular, the humanoid robot can retrieve and deliver a box, open and walk through a door to reach the final destination. Our approach, and experiments, illustrate the effectiveness of using human-inspired motor control algorithms, which provide a scalable hierarchical architecture for autonomous performance of complex goal-directed tasks.

The body sends interoceptive visceral information through deep brain structures to the cerebral cortex. The insula cortex, organized in hierarchical modules, is the major cortical region receiving interoceptive afferents and contains visceral topographic maps. Yet, the biological significance of the insula’s modular architecture in relation to deep brain regions remains unsolved. In this opinion, we propose the Insula Hierarchical Modular Adaptive Interoception Control (IMAC) model to suggest that insula modules (granular, dysgranular and agranular subregions), forming networks with prefrontal (supplementary motor area, dorsolateral and ventromedial cortices) and striatum (posterior, dorsomedial and ventromedial) subregions, are specialized for higher-order interoceptive representations, recruited in a context-dependent manner to support habitual, model-based and exploratory adaptive behavior. We then discuss how insula interoceptive representations, or metaceptions, could give rise to conscious interoceptive feelings built up from low-order visceral representations and associated basic emotions located in deep interoceptive brain structures.

Insula Interoception, Active Inference and Feeling Representation

Meta-awareness refers to the capacity to explicitly notice the current content of consciousness and has been identified as a key component for the successful control of cognitive states, such as the deliberate direction of attention. This paper proposes a formal model of meta-awareness and attentional control using hierarchical active inference. To do so, we cast mental action as policy selection over higher-level cognitive states and add a further hierarchical level to model meta-awareness states that modulate the expected confidence (precision) in the mapping between observations and hidden cognitive states. We simulate the example of mind-wandering and its regulation during a task involving sustained selective attention on a perceptual object. This provides a computational case study for an inferential architecture that is apt to enable the emergence of these central components of human phenomenology, namely, the ability to access and control cognitive states. We propose that this approach can be generalized to other cognitive states, and hence, this paper provides the first steps towards the development of a computational phenomenology of mental action and more broadly of our ability to monitor and control our own cognitive states. Future steps of this work will focus on fitting the model with qualitative, behavioural, and neural data.

Publisher’s note to: towards a computational phenomenology of mental action: modelling meta-awareness and attentional control with deep parametric active inference

Variational free energy, individual fitness, and population dynamics under acute stress: Comment on "Dynamic and thermodynamic models of adaptation" by Alexander N. Gorban et al.

This study highlights the importance of looking beyond the main effect of movement to study alterations in functional response in the presence of central nervous system pathologies such as multiple sclerosis (MS). Data show that MS selectively affects regional BOLD (blood oxygenation level dependent) responses to variable grip forces (GF). It is known that the anterior and posterior BA 4 areas (BA 4a and BA 4p) are anatomically and functionally distinct. It has also been shown in healthy volunteers that there are linear (first order, typical of BA 4a) and nonlinear (second to fourth order, typical of BA 4p) BOLD responses to different levels of GF applied during a dynamic motor paradigm. After modeling the BOLD response with a polynomial expansion of the applied GFs, the particular case of BA 4a and BA 4p were investigated in healthy volunteers (HV) and MS subjects. The main effect of movement (zeroth order) analysis showed that the BOLD signal is greater in MS compared with healthy volunteers within both BA 4 subregions. At higher order, BOLD-GF responses were similar in BA 4a but showed a marked alteration in BA 4p of MS subjects, with those with greatest disability showing the greatest deviations from the healthy response profile. Therefore, the different behaviors in HV and MS could only be uncovered through a polynomial analysis looking beyond the main effect of movement into the two BA 4 subregions. Future studies will investigate the source of this pathophysiology, combining the present fMRI paradigm with blood perfusion and nonlinear neuronal response analysis.

Blood Oxygenation Level-Dependent Response to Multiple Grip Forces in Multiple Sclerosis: Going Beyond the Main Effect of Movement in Brodmann Area 4a and 4p

We recently described a dynamic causal model of a COVID-19 outbreak within a single region. Here, we combine several instantiations of this (epidemic) model to create a (pandemic) model of viral spread among regions. Our focus is on a second wave of new cases that may result from loss of immunity—and the exchange of people between regions—and how mortality rates can be ameliorated under different strategic responses. In particular, we consider hard or soft social distancing strategies predicated on national (Federal) or regional (State) estimates of the prevalence of infection in the population. The modelling is demonstrated using timeseries of new cases and deaths from the United States to estimate the parameters of a factorial (compartmental) epidemiological model of each State and, crucially, coupling between States. Using Bayesian model reduction, we identify the effective connectivity between States that best explains the initial phases of the outbreak in the United States. Using the ensuing posterior parameter estimates, we then evaluate the likely outcomes of different policies in terms of mortality, working days lost due to lockdown and demands upon critical care. The provisional results of this modelling suggest that social distancing and loss of immunity are the two key factors that underwrite a return to endemic equilibrium.

Second waves, social distancing, and the spread of COVID-19 across the USA

The gut microbiome as a biomarker of differential susceptibility to SARS-CoV-2

In this paper, we introduce a new generative model for an active inference account of preparatory and selective attention, in the context of a classic 'cocktail party' paradigm. In this setup, pairs of words are presented simultaneously to the left and right ears and an instructive spatial cue directs attention to the left or right. We use this generative model to test competing hypotheses about the way that human listeners direct preparatory and selective attention. We show that assigning low precision to words at attended-relative to unattended-locations can explain why a listener reports words from a competing sentence. Under this model, temporal changes in sensory precision were not needed to account for faster reaction times with longer cue-target intervals, but were necessary to explain ramping effects on event-related potentials (ERPs)-resembling the contingent negative variation (CNV)-during the preparatory interval. These simulations reveal that different processes are likely to underlie the improvement in reaction times and the ramping of ERPs that are associated with spatial cueing.

Active inference, selective attention, and the cocktail party problem

Dissipative accounts of structure formation show that the self-organisation of complex structures is thermodynamically favoured, whenever these structures dissipate free energy that could not be accessed otherwise. These structures therefore open transition channels for the state of the universe to move from a frustrated, metastable state to another metastable state of higher entropy. However, these accounts apply as well to relatively simple, dissipative systems, such as convection cells, hurricanes, candle flames, lightning strikes, or mechanical cracks, as they do to complex biological systems. Conversely, interesting computational properties—that characterize complex biological systems, such as efficient, predictive representations of environmental dynamics—can be linked to the thermodynamic efficiency of underlying physical processes. However, the potential mechanisms that underwrite the selection of dissipative structures with thermodynamically efficient subprocesses is not completely understood. We address these mechanisms by explaining how bifurcation-based, work-harvesting processes—required to sustain complex dissipative structures—might be driven towards thermodynamic efficiency. We first demonstrate a simple mechanism that leads to self-selection of efficient dissipative structures in a stochastic chemical reaction network, when the dissipated driving chemical potential difference is decreased. We then discuss how such a drive can emerge naturally in a hierarchy of self-similar dissipative structures, each feeding on the dissipative structures of a previous level, when moving away from the initial, driving disequilibrium.

A Drive towards Thermodynamic Efficiency for Dissipative Structures in Chemical Reaction Networks

From Generative Models to Generative Passages: A Computational Approach to (Neuro) Phenomenology

Abstract Under the Bayesian brain hypothesis, behavioral variations can be attributed to different priors over generative model parameters. This provides a formal explanation for why individuals exhibit inconsistent behavioral preferences when confronted with similar choices. For example, greedy preferences are a consequence of confident (or precise) beliefs over certain outcomes. Here, we offer an alternative account of behavioral variability using Rényi divergences and their associated variational bounds. Rényi bounds are analogous to the variational free energy (or evidence lower bound) and can be derived under the same assumptions. Importantly, these bounds provide a formal way to establish behavioral differences through an α parameter, given fixed priors. This rests on changes in α that alter the bound (on a continuous scale), inducing different posterior estimates and consequent variations in behavior. Thus, it looks as if individuals have different priors and have reached different conclusions. More specifically, α→0+ optimization constrains the variational posterior to be positive whenever the true posterior is positive. This leads to mass-covering variational estimates and increased variability in choice behavior. Furthermore, α→+∞ optimization constrains the variational posterior to be zero whenever the true posterior is zero. This leads to mass-seeking variational posteriors and greedy preferences. We exemplify this formulation through simulations of the multiarmed bandit task. We note that these α parameterizations may be especially relevant (i.e., shape preferences) when the true posterior is not in the same family of distributions as the assumed (simpler) approximate density, which may be the case in many real-world scenarios. The ensuing departure from vanilla variational inference provides a potentially useful explanation for differences in behavioral preferences of biological (or artificial) agents under the assumption that the brain performs variational Bayesian inference.

The evolution of epidemiological parameters, such as instantaneous reproduction number Rt, is important for understanding the transmission dynamics of infectious diseases. Current estimates of time-varying epidemiological parameters often face problems such as lagging observations, averaging inference, and improper quantification of uncertainties. To address these problems, we propose a Bayesian data assimilation framework for time-varying parameter estimation. Specifically, this framework is applied to Rt estimation, resulting in the state-of-the-art DARt system. With DARt, time misalignment caused by lagging observations is tackled by incorporating observation delays into the joint inference of infections and Rt;the drawback of averaging is overcome by instantaneously updating upon new observations and developing a model selection mechanism that captures abrupt changes;the uncertainty is quantified and reduced by employing Bayesian smoothing. We validate the performance of DARt and demonstrate its power in revealing the transmission dynamics of COVID-19. The proposed approach provides a promising solution for accurate and timely estimating transmission dynamics from reported data.

Bayesian data assimilation for estimating epidemic evolution: a COVID-19 study

Felix Schoeller, Massachusetts Institute of Technology, Cambridge, MA, United States. Gonda Multidisciplinary Brain Centre, Bar Ilan University, Israel Mark Miller, Center for Human Nature, Artificial Intelligence and Neuroscience, Hokkaido, Japan; Department of Informatics, University of Sussex, UK. Roy Salomon, Gonda Multidisciplinary Brain Centre, Bar Ilan University, Israel Karl J. Friston, Wellcome Trust Centre for Neuroimaging, University College London, London, UK.

Trust as Extended Control: Active Inference and User Feedback During Human-Robot Collaboration

The ability to plan ahead efficiently is key for both living organisms and artificial systems. Model-based planning and prospection are widely studied in cognitive neuroscience and artificial intelligence (AI), but from different perspectives--and with different desiderata in mind (biological realism versus scalability) that are difficult to reconcile. Here, we introduce a novel method to plan in POMDPs--Active Inference Tree Search (AcT)--that combines the normative character and biological realism of a leading planning theory in neuroscience (Active Inference) and the scalability of tree search methods in AI. This unification enhances both approaches. On the one hand, tree searches enable the biologically grounded, first principle method of active inference to be applied to large-scale problems. On the other hand, active inference provides a principled solution to the exploration-exploitation dilemma, which is often addressed heuristically in tree search methods. Our simulations show that AcT successfully navigates binary trees that are challenging for sampling-based methods, problems that require adaptive exploration, and the large POMDP problem 'RockSample'--in which AcT reproduces state-of-the-art POMDP solutions. Furthermore, we illustrate how AcT can be used to simulate neurophysiological responses (e.g., in the hippocampus and prefrontal cortex) of humans and other animals that solve large planning problems. These numerical analyses show that Active Tree Search is a principled realisation of neuroscientific and AI planning theories, which offer both biological realism and scalability.

The social environment presents the human brain with the most complex information processing demands. The computations that the brain must perform occur in parallel, combine social and nonsocial cues, produce verbal and nonverbal signals and involve multiple cognitive systems, including memory, attention, emotion and learning. This occurs dynamically and at timescales ranging from milliseconds to years. Here, we propose that during social interactions, seven core operations interact to underwrite coherent social functioning; these operations accumulate evidence efficiently—from multiple modalities—when inferring what to do next. We deconstruct the social brain and outline the key components entailed for successful human–social interaction. These include (i) social perception; (ii) social inferences, such as mentalizing; (iii) social learning; (iv) social signaling through verbal and nonverbal cues; (v) social drives (e.g. how to increase one’s status); (vi) determining the social identity of agents, including oneself and (vii) minimizing uncertainty within the current social context by integrating sensory signals and inferences. We argue that while it is important to examine these distinct aspects of social inference, to understand the true nature of the human social brain, we must also explain how the brain integrates information from the social world.

Multivariate approaches to social neuroscience Special Issue Seven computations of the social brain

Biological forms depend on a progressive specialization of pluripotent stem cells. The differentiation of these cells in their spatial and functional environment defines the organism itself; however, cellular mutations may disrupt the mutual balance between a cell and its niche, where cell proliferation and specialization are released from their autopoietic homeostasis. This induces the construction of cancer niches and maintains their survival. In this paper, we characterise cancer niche construction as a direct consequence of interactions between clusters of cancer and healthy cells. Explicitly, we evaluate these higher-order interactions between niches of cancer and healthy cells using Kikuchi approximations to the free energy. Kikuchi’s free energy is measured in terms of changes to the sum of energies of baseline clusters of cells (or nodes) minus the energies of overcounted cluster intersections (and interactions of interactions, etc.). We posit that these changes in energy node clusters correspond to a long-term reduction in the complexity of the system conducive to cancer niche survival. We validate this formulation through numerical simulations of apoptosis, local cancer growth, and metastasis, and highlight its implications for a computational understanding of the etiopathology of cancer.

An active inference account of protective behaviours during the COVID-19 pandemic

Computational Modeling of Electroencephalography and Functional Magnetic Resonance Imaging Paradigms Indicates a Consistent Loss of Pyramidal Cell Synaptic Gain in Schizophrenia

Traditionally, short-term memory (STM) has been assessed by asking participants to remember words, visual objects, or numbers for a short amount of time before their recall or recognition of those items is tested. However, this focus on memory for past sensory input might have obscured potential theoretical insights into the function of this cognitive faculty. Here, we suggest that STM may have an important role in predicting future sensory input. This reconceptualization of STM may provide a functional explanation for its capacity limitation.

The Predictive Brain Must Have a Limitation in Short-Term Memory Capacity

Biological agents have meaningful interactions with their environment despite the absence of immediate reward signals. In such instances, the agent can learn preferred modes of behaviour that lead to predictable states -- necessary for survival. In this paper, we pursue the notion that this learnt behaviour can be a consequence of reward-free preference learning that ensures an appropriate trade-off between exploration and preference satisfaction. For this, we introduce a model-based Bayesian agent equipped with a preference learning mechanism (pepper) using conjugate priors. These conjugate priors are used to augment the expected free energy planner for learning preferences over states (or outcomes) across time. Importantly, our approach enables the agent to learn preferences that encourage adaptive behaviour at test time. We illustrate this in the OpenAI Gym FrozenLake and the 3D mini-world environments -- with and without volatility. Given a constant environment, these agents learn confident (i.e., precise) preferences and act to satisfy them. Conversely, in a volatile setting, perpetual preference uncertainty maintains exploratory behaviour. Our experiments suggest that learnable (reward-free) preferences entail a trade-off between exploration and preference satisfaction. Pepper offers a straightforward framework suitable for designing adaptive agents when reward functions cannot be predefined as in real environments.

Exploration and preference satisfaction trade-off in reward-free learning

Active inference, a corollary of the free energy principle, is a formal way of describing the behavior of certain kinds of random dynamical systems—that have the appearance of sentience. In this chapter, we describe how active inference combines Bayesian decision theory and optimal Bayesian design principles under a single imperative to minimize expected free energy. It is this aspect of active inference that allows for the natural emergence of information-seeking behavior. When removing prior outcomes preferences from expected free energy, active inference reduces to optimal Bayesian design, i.e., information gain maximization. Conversely, active inference reduces to Bayesian decision theory in the absence of ambiguity and relative risk, i.e., expected utility maximization. Using these limiting cases, we illustrate how behaviors differ when agents select actions that optimize expected utility, expected information gain, and expected free energy. Our T-maze simulations show optimizing expected free energy produces goal-directed information-seeking behavior while optimizing expected utility induces purely exploitive behavior—and maximizing information gain engenders intrinsically motivated behavior.

We derive a theoretical construct that allows for the characterisation of both scalable and scale free systems within the dynamic causal modelling (DCM) framework. We define a dynamical system to be “scalable” if the same equation of motion continues to apply as the system changes in size. As an example of such a system, we simulate planetary orbits varying in size and show that our proposed methodology can be used to recover Kepler’s third law from the timeseries. In contrast, a “scale free” system is one in which there is no characteristic length scale, meaning that images of such a system are statistically unchanged at different levels of magnification. As an example of such a system, we use calcium imaging collected in murine cortex and show that the dynamical critical exponent, as defined in renormalization group theory, can be estimated in an empirical biological setting. We find that a task-relevant region of the cortex is associated with higher dynamical critical exponents in task vs. spontaneous states and vice versa for a task-irrelevant region.

Motor skill learning relies on neural plasticity in the motor and limbic systems. However, the spatial and temporal dependencies of these changes—and their microstructural underpinnings—remain unclear. Eighteen healthy males received training in a computer-controlled motion game 4 times a week, for 4 weeks. Performance improvements were observed in all trained participants. Serial myelin-sensitive multiparametric mapping at 3T during this period of intensive motor skill acquisition revealed temporally and spatially distributed, performance-related myelin-sensitive microstructural changes in the grey and white matter across the corticospinal system and hippocampus. Interestingly, analysis of the trajectory of these transient changes revealed a time-shifted choreography across white and grey matter of the corticospinal system as well as with changes in the hippocampus. Crucially, in the cranial corticospinal tracts, myelin-sensitive changes during training in the posterior part of the limb of the internal capsule were of greater magnitude in lower-limb trainees compared to upper limb trainees. Motor skill learning is depended on coherent waves of plasticity within a corticospinal-hippocampal loop.

Wellcome Centre for Human Neuroimaging, Queen Square Institute of Neurology, University College London, London, United Kingdom, Department of Psychology, Technische Universität Dresden, Dresden, Germany, Division of Social and Transcultural Psychiatry, Department of Psychiatry, McGill University, Montreal, QC, Canada, Spatial Web Foundation, Los Angeles, CA, United States, NestedMinds Network, London, United Kingdom, Laureate Institute for Brain Research, Tulsa, OK, United States, Amsterdam Brain and Cognition Center, University of Amsterdam, Amsterdam, Netherlands

In theoretical biology, we are often interested in random dynamical systems—like the brain—that appear to model their environments. This can be formalized by appealing to the existence of a (possibly non-equilibrium) steady state, whose density preserves a conditional independence between a biological entity and its surroundings. From this perspective, the conditioning set, or Markov blanket, induces a form of vicarious synchrony between creature and world—as if one were modelling the other. However, this results in an apparent paradox. If all conditional dependencies between a system and its surroundings depend upon the blanket, how do we account for the mnemonic capacity of living systems? It might appear that any shared dependence upon past blanket states violates the independence condition, as the variables on either side of the blanket now share information not available from the current blanket state. This paper aims to resolve this paradox, and to demonstrate that conditional independence does not preclude memory. Our argument rests upon drawing a distinction between the dependencies implied by a steady state density, and the density dynamics of the system conditioned upon its configuration at a previous time. The interesting question then becomes: What determines the length of time required for a stochastic system to ‘forget’ its initial conditions? We explore this question for an example system, whose steady state density possesses a Markov blanket, through simple numerical analyses. We conclude with a discussion of the relevance for memory in cognitive systems like us.

We provide a proof of principle for an evolutionary systems theory (EST) of depression. This theory suggests that normative depressive symptoms counter socioenvironmental volatility by increasing interpersonal support via social signalling and that this response depends upon the encoding of uncertainty about social contingencies, which can be targeted by neuromodulatory antidepressants. We simulated agents that committed to a series of decisions in a social two-arm bandit task before and after social adversity, which precipitated depressive symptoms. Responses to social adversity were modelled under various combinations of social support and pharmacotherapy. The normative depressive phenotype responded positively to social support and simulated treatments with antidepressants. Attracting social support and administering antidepressants also alleviated anhedonia and social withdrawal, speaking to improvements in interpersonal relationships. These results support the EST of depression by demonstrating that following adversity, normative depressed mood preserved social inclusion with appropriate interpersonal support or pharmacotherapy.

Why Depressed Mood is Adaptive: A Numerical Proof of Principle for an Evolutionary Systems Theory of Depression

Abstract Meta-awareness refers to the capacity to explicitly notice the current content of consciousness and has been identified as a key component for the successful control of cognitive states, such as the deliberate direction of attention. This paper proposes a formal model of meta-awareness and attentional control using hierarchical active inference. To do so, we cast mental action as policy selection over higher-level cognitive states and add a further hierarchical level to model meta-awareness states that modulate the expected confidence (precision) in the mapping between observations and hidden cognitive states. We simulate the example of mind-wandering and its regulation during a task involving sustained selective attention on a perceptual object. This provides a computational case study for an inferential architecture that is apt to enable the emergence of these central components of human phenomenology, namely, the ability to access and control cognitive states. We propose that this approach can be generalized to other cognitive states, and hence, this paper provides the first steps towards the development of a computational phenomenology of mental action and more broadly of our ability to monitor and control our own cognitive states. Future steps of this work will focus on fitting the model with qualitative, behavioural, and neural data.

Towards a computational phenomenology of mental action: modelling meta-awareness and attentional control with deep parametric active inference

In this paper, we introduce an active inference model of ant colony foraging behavior, and implement the model in a series of in silico experiments. Active inference is a multiscale approach to behavioral modeling that is being applied across settings in theoretical biology and ethology. The ant colony is a classic case system in the function of distributed systems in terms of stigmergic decision-making and information sharing. Here we specify and simulate a Markov decision process (MDP) model for ant colony foraging. We investigate a well-known paradigm from laboratory ant colony behavioral experiments, the alternating T-maze paradigm, to illustrate the ability of the model to recover basic colony phenomena such as trail formation after food location discovery. We conclude by outlining how the active inference ant colony foraging behavioral model can be extended and situated within a nested multiscale framework and systems approaches to biology more generally.

Active Inferants: An Active Inference Framework for Ant Colony Behavior

This paper presents a biologically plausible generative model and inference scheme that is capable of simulating the generation and comprehension of language, when synthetic subjects talk to each other. Building on active inference formulations of dyadic interactions, we simulate linguistic exchange to explore generative models that support dialogues. These models employ high-order interactions among abstract (discrete) states in deep (hierarchical) models. The sequential nature of language processing mandates generative models with a particular factorial structure—necessary to accommodate the rich combinatorics of language. We illustrate this by simulating a synthetic subject who can play the ‘Twenty Questions’ game. In this game, synthetic subjects take the role of the questioner or answerer, using the same generative model. This simulation setup is used to illustrate some key architectural points and demonstrate that many behavioural and neurophysiological correlates of language processing emerge under variational (marginal) message passing, given the right kind of generative model. For example, we show that theta-gamma coupling is an emergent property of belief updating, when listening to another.

This paper proposes a formal reconstruction of the script construct by leveraging the active inference framework, a behavioral modeling framework that casts action, perception, emotions, and attention as processes of (Bayesian or variational) inference. We propose a first principles account of the script construct that integrates its different uses in the behavioral and social sciences. We begin by reviewing the recent literature that uses the script construct. We then examine the main mathematical and computational features of active inference. Finally, we leverage the resources of active inference to offer a formal model of scripts. Our integrative model accounts for the dual nature of scripts (as internal, psychological schema used by agents to make sense of event types and as constitutive behavioral categories that make up the social order) and also for the stronger and weaker conceptions of the construct (which do and do not relate to explicit action sequences, respectively).

Directed coupling in multi-brain networks underlies generalized synchrony during social exchange

How can the free energy principle contribute to research on neural correlates of consciousness, and to the scientific study of consciousness more generally? Under the free energy principle, neural correlates should be defined in terms of neural *dynamics*, not neural states, and should be complemented by the research on *computational* correlates of consciousness -- defined in terms of probabilities encoded by neural states.We argue that these restrictions brighten the prospects of a computational explanation of consciousness, by addressing two central problems. The first is to account for consciousness in the absence of sensory stimulation and behaviour. The second is to allow for the possibility of systems that implement computations associated with consciousness, without being conscious, which requires differentiating between computational systems that merely simulate conscious beings and computational systems that are conscious in and of themselves.Given the notion of computation entailed by the free energy principle, we will derive constraints on the ascription of consciousness in controversial cases (e.g., in the absence of sensory stimulation and behaviour). We show that this also has implications for what it means to *be*, as opposed to merely *simulate* a conscious system.

The neural correlates of consciousness under the free energy principle: From computational correlates to computational explanation

Abstract Active inference is a probabilistic framework for modeling the behavior of biological and artificial agents, which derives from the principle of minimizing free energy. In recent years, this framework has been applied successfully to a variety of situations where the goal was to maximize reward, often offering comparable and sometimes superior performance to alternative approaches. In this article, we clarify the connection between reward maximization and active inference by demonstrating how and when active inference agents execute actions that are optimal for maximizing reward. Precisely, we show the conditions under which active inference produces the optimal solution to the Bellman equation, a formulation that underlies several approaches to model-based reinforcement learning and control. On partially observed Markov decision processes, the standard active inference scheme can produce Bellman optimal actions for planning horizons of 1 but not beyond. In contrast, a recently developed recursive active inference scheme (sophisticated inference) can produce Bellman optimal actions on any finite temporal horizon. We append the analysis with a discussion of the broader relationship between active inference and reinforcement learning.

The ubiquity and importance of narratives in human adaptation has been recognized by many scholars. Research has identified several functions of narratives that are conducive to individuals’ well-being and adaptation as well as to coordinated social practices and enculturation. In this paper, we characterize the social and cognitive functions of narratives in terms of the framework of active inference. Active inference depicts the fundamental tendency of living organisms to adapt by creating, updating, and maintaining inferences about their environment. We review the literature on the functions of narratives in identity, event segmentation, episodic memory, future projection, storytelling practices, and enculturation. We then re-cast these functions of narratives in terms of active inference, outlining a parsimonious model that can guide future developments in narrative theory, research, and clinical applications.

We recently described a dynamic causal model of a COVID-19 outbreak within a single region. Here, we combine several instantiations of this (epidemic) model to create a (pandemic) model of viral spread among regions. Our focus is on a second wave of new cases that may result from loss of immunity-and the exchange of people between regions-and how mortality rates can be ameliorated under different strategic responses. In particular, we consider hard or soft social distancing strategies predicated on national (Federal) or regional (State) estimates of the prevalence of infection in the population. The modelling is demonstrated using timeseries of new cases and deaths from the United States to estimate the parameters of a factorial (compartmental) epidemiological model of each State and, crucially, coupling between States. Using Bayesian model reduction, we identify the effective connectivity between States that best explains the initial phases of the outbreak in the United States. Using the ensuing posterior parameter estimates, we then evaluate the likely outcomes of different policies in terms of mortality, working days lost due to lockdown and demands upon critical care. The provisional results of this modelling suggest that social distancing and loss of immunity are the two key factors that underwrite a return to endemic equilibrium.

Second waves, social distancing, and the spread of COVID-19 across the USA.

Metacognition refers to the capacity to access, monitor, and control aspects of one’s mental operations and is central to the human condition and experience. Disorders of metacognition are a hallmark of many psychiatric conditions and the training of metacognitive skills is central in education and in many psychotherapies. This paper provides first steps towards the development of a formal neurophenomenology of metacognition. To do so, we leverage the tools of the active inference framework, extending a previous computational model of implicit metacognition by adding a hierarchical level to model explicit (conscious) meta-awareness and the voluntary control of attention through covert action. Using the example of mind-wandering and its regulation in focused attention, we provide a computational proof of principle for an inferential architecture apt to enable the emergence of central components of metacognition: namely, the ability to access, monitor, and control cognitive states.

Towards a computational (neuro)phenomenology of mental action: modelling meta-awareness and attentional control with deep-parametric active inference

Active inference under visuo-proprioceptive conflict: Simulation and empirical results

Sophisticated Affective Inference: Simulating Anticipatory Affective Dynamics of Imagining Future Events

Neuronal message passing using Mean-field, Bethe, and Marginal approximations

The hierarchically mechanistic mind: an evolutionary systems theory of the human brain, cognition, and behavior

Perceptual awareness depends upon the way in which we engage with our sensorium. This notion is central to active inference, a theoretical framework that treats perception and action as inferential processes. This variational perspective on cognition formalizes the notion of perception as hypothesis testing and treats actions as experiments that are designed (in part) to gather evidence for or against alternative hypotheses. The common treatment of perception and action affords a useful interpretation of certain perceptual phenomena whose active component is often not acknowledged. In this article, we start by considering Troxler fading – the dissipation of a peripheral percept during maintenance of fixation, and its recovery during free (saccadic) exploration. This offers an important example of the failure to maintain a percept without actively interrogating a visual scene. We argue that this may be understood in terms of the accumulation of uncertainty about a hypothesized stimulus when free exploration is disrupted by experimental instructions or pathology. Once we take this view, we can generalize the idea of using bodily (oculomotor) action to resolve uncertainty to include the use of mental (attentional) actions for the same purpose. This affords a useful way to think about binocular rivalry paradigms, in which perceptual changes need not be associated with an overt movement.

The emergence of synchrony in networks of mutually inferring neurons

The purpose of this review was to integrate leading paradigms in psychology and neuroscience with a theory of the embodied, situated human brain, called the Hierarchically Mechanistic Mind (HMM). The HMM describes the brain as a complex adaptive system that functions to minimize the entropy of our sensory and physical states via action-perception cycles generated by hierarchical neural dynamics. First, we review the extant literature on the hierarchical structure of the brain. Next, we derive the HMM from a broader evolutionary systems theory that explains neural structure and function in terms of dynamic interactions across four nested levels of biological causation (i.e., adaptation, phylogeny, ontogeny, and mechanism). We then describe how the HMM aligns with a global brain theory in neuroscience called the free-energy principle, leveraging this theory to mathematically formulate neural dynamics across hierarchical spatiotemporal scales. We conclude by exploring the implications of the HMM for psychological inquiry.

UvA-DARE (Digital Academic The hierarchically mechanistic mind an evolutionary systems theory of the human brain, cognition, and behavior

Modeling subjective belief states in computational psychiatry: interoceptive inference as a candidate framework

Introducing a Bayesian model of selective attention based on active inference

Linking structural and effective brain connectivity: structurally informed Parametric Empirical Bayes (si-PEB)

S62. Computational diagnosis of ion channel dysfunction in NMDA receptor antibody encephalitis

From cognitivism to autopoiesis: towards a computational framework for the embodied mind

This article explores the notion that the brain is genetically endowed with an innate virtual reality generator that – through experience-dependent plasticity – becomes a generative or predictive model of the world. This model, which is most clearly revealed in rapid eye movement (REM) sleep dreaming, may provide the theater for conscious experience. Functional neuroimaging evidence for brain activations that are time-locked to rapid eye movements (REMs) endorses the view that waking consciousness emerges from REM sleep – and dreaming lays the foundations for waking perception. In this view, the brain is equipped with a virtual model of the world that generates predictions of its sensations. This model is continually updated and entrained by sensory prediction errors in wakefulness to ensure veridical perception, but not in dreaming. In contrast, dreaming plays an essential role in maintaining and enhancing the capacity to model the world by minimizing model complexity and thereby maximizing both statistical and thermodynamic efﬁciency. This perspective suggests that consciousness corresponds to the embodied process of inference, realized through the generation of virtual realities (in both sleep and wakefulness). In short, our premise or hypothesis is that the waking brain engages with the world to predict the causes of sensations, while in sleep the brain’s generative model is actively reﬁned so that it generates more efﬁcient predictions during waking. We review the evidence in support of this hypothesis – evidence that grounds consciousness in biophysical computations whose neuronal and neurochemical infrastructure has been disclosed by sleep research.

Virtual reality and consciousness inference in dreaming Please share how this access benefits you. Your story matters

This article provides a neurobiological account of symptoms that have been called ‘hysterical’, ‘psychogenic’ or ‘medically unexplained’, which we will call functional motor and sensory symptoms. We use a neurobiologically informed model of hierarchical Bayesian inference in the brain to explain functional motor and sensory symptoms in terms of perception and action arising from inference based on prior beliefs and sensory information. This explanation exploits the key balance between prior beliefs and sensory evidence that is mediated by (body focused) attention, symptom expectations, physical and emotional experiences and beliefs about illness. Crucially, this furnishes an explanation at three different levels: (i) underlying neuromodulatory (synaptic) mechanisms; (ii) cognitive and experiential processes (attention and attribution of agency); and (iii) formal computations that underlie perceptual inference (representation of uncertainty or precision). Our explanation involves primary and secondary failures of inference; the primary failure is the (autonomous) emergence of a percept or belief that is held with undue certainty (precision) following top-down attentional modulation of synaptic gain. This belief can constitute a sensory percept (or its absence) or induce movement (or its absence). The secondary failure of inference is when the ensuing percept (and any somatosensory consequences) is falsely inferred to be a symptom to explain why its content was not predicted by the source of attentional modulation. This account accommodates several fundamental observations about functional motor and sensory symptoms, including: (i) their induction and maintenance by attention; (ii) their modification by expectation, prior experience and cultural beliefs and (iii) their involuntary and symptomatic nature.

Active inference and agency: optimal control without cost functions

R. Henson , J. Mattout , K. Friston , S. Hassel , A. Hillebrand, G.R. Barnes & K.D. Singh 1. MRC Cognition & Brain Sciences Unit, Cambridge, England, 2. Functional Imaging Laboratory, University College London, England, 3. Wellcome Trust Laboratory for MEG Studies, Aston University, England Introduction We tested recent methods for distributed source localisation using Restricted Maximum Likelihood (ReML) [1] on an MEG dataset that isolated the M170 component believed specific to faces. Unlike previous methods, multiple constraints on the covariance of the sources and/or sensor noise can be applied, and their weightings (hyperparameters) estimated automatically from the data.

Distributed source localisation of the M 170 using multiple constraints

We assess the suitability of conventional parametric statistics for analyzing oscillatory activity, as measured with electroencephalography/magnetoencephalography (EEG/MEG). The approach we consider is based on narrow‐band power time–frequency decompositions of single‐trial data. The ensuing power measures have a χ2‐distribution. The use of the general linear model (GLM) under normal error assumptions is, therefore, difficult to motivate for these data. This is unfortunate because the GLM plays a central role in classical inference and is the standard estimation and inference framework for neuroimaging data. The key contribution of this work is to show that, in many circumstances, one can appeal to the central limit theorem and assume normality for generative models of power. If this is not appropriate, one can transform the data to render the error terms approximately normal. These considerations allow one to analyze induced and evoked oscillations using standard frameworks like statistical parametric mapping. We establish the validity of parametric tests using synthetic and real data and compare its performance to established nonparametric procedures. Hum Brain Mapp, 2005. © 2005 Wiley‐Liss, Inc.

Parametric analysis of oscillatory activity as measured with EEG/MEG

We describe a comprehensive framework for performing rapid and automatic nonlabel‐based nonlinear spatial normalizations. The approach adopted minimizes the residual squared difference between an image and a template of the same modality. In order to reduce the number of parameters to be fitted, the nonlinear warps are described by a linear combination of low spatial frequency basis functions. The objective is to determine the optimum coefficients for each of the bases by minimizing the sum of squared differences between the image and template, while simultaneously maximizing the smoothness of the transformation using a maximum a posteriori (MAP) approach. Most MAP approaches assume that the variance associated with each voxel is already known and that there is no covariance between neighboring voxels. The approach described here attempts to estimate this variance from the data, and also corrects for the correlations between neighboring voxels. This makes the same approach suitable for the spatial normalization of both high‐quality magnetic resonance images, and low‐resolution noisy positron emission tomography images. A fast algorithm has been developed that utilizes Taylor's theorem and the separable nature of the basis functions, meaning that most of the nonlinear spatial variability between images can be automatically corrected within a few minutes. Hum. Brain Mapping 7:254–266, 1999. © 1999 Wiley‐Liss, Inc.

Abstract Pain and tinnitus share common pathophysiological mechanisms, clinical features, and treatment approaches. A source-localized resting-state EEG study was conducted in 150 participants: 50 healthy controls, 50 pain, and 50 tinnitus patients. Resting-state activity as well as functional and effective connectivity was computed in source space. Pain and tinnitus were characterized by increased theta activity in the pregenual anterior cingulate cortex, extending to the lateral prefrontal cortex and medial anterior temporal lobe. Gamma-band activity was increased in both auditory and somatosensory cortex, irrespective of the pathology, and extended to the dorsal anterior cingulate cortex and parahippocampus. Functional and effective connectivity were largely similar in pain and tinnitus, except for a parahippocampal-sensory loop that distinguished pain from tinnitus. In tinnitus, the effective connectivity between parahippocampus and auditory cortex is bidirectional, whereas the effective connectivity between parahippocampus and somatosensory cortex is unidirectional. In pain, the parahippocampal-somatosensory cortex is bidirectional, but parahippocampal auditory cortex unidirectional. These modality-specific loops exhibited theta–gamma nesting. Applying a Bayesian brain model of brain functioning, these findings suggest that the phenomenological difference between auditory and somatosensory phantom percepts result from a vicious circle of belief updating in the context of missing sensory information. This finding may further our understanding of multisensory integration and speaks to a universal treatment for pain and tinnitus—by selectively disrupting parahippocampal-somatosensory and parahippocampal-auditory theta–gamma activity and connectivity.

A parahippocampal-sensory Bayesian vicious circle generates pain or tinnitus: a source-localized EEG study

Therapeutic affective touch has been recognized as essential for survival, nurturing supportive interpersonal interactions, accelerating recovery—including reducing hospitalisations, and promoting overall health and building robust therapeutic alliances. Through the lens of active inference, we present an integrative model, combining therapeutic touch and communication, to achieve biobehavioural synchrony. This model speaks to how the brain develops a generative model required for recovery, developing successful therapeutic alliances, and regulating allostasis within paediatric manual therapy. We apply active inference to explain the neurophysiological and behavioural mechanisms that underwrite the development and maintenance of synchronous relationships through touch. This paper foregrounds the crucial role of therapeutic touch in developing a solid therapeutic alliance, the clinical effectiveness of paediatric care, and triadic synchrony between health care practitioner, caregiver, and infant in a variety of clinical situations. We start by providing a brief overview of the significance and clinical role of touch in the development of social interactions in infants; facilitating a positive therapeutic alliance and restoring homeostasis through touch to allow a more efficient process of allostatic regulation. Moreover, we explain the role of CT tactile afferents in achieving positive clinical outcomes and updating prior beliefs. We then discuss how touch is implemented in treatment sessions to promote cooperative interactions in the clinic and facilitate theory of mind. This underwrites biobehavioural synchrony, epistemic trust, empathy, and the resolution of uncertainty. The ensuing framework is underpinned by a critical application of the active inference framework to the fields of pediatrics and neonatology.

Therapeutic touch and therapeutic alliance in pediatric care and neonatology: An active inference framework

Abstract Objectives Schizophrenia is a mental illness that presents with thought disorders including delusions and disorganized speech. Thought disorders have been regarded as a consequence of the loosening of associations between semantic concepts since the term “schizophrenia” was first coined by Bleuler. However, a mechanistic account of this cardinal disturbance in terms of functional dysconnection has been lacking. To evaluate how aberrant semantic connections are expressed through brain activity, we characterized large-scale network structures of concept representations using functional magnetic resonance imaging (fMRI). Study Design We quantified various concept representations in patients’ brains from fMRI activity evoked by movie scenes using encoding modeling. We then constructed semantic brain networks by evaluating the similarity of these semantic representations and conducted graph theory-based network analyses. Study Results Neurotypical networks had small-world properties similar to those of natural languages, suggesting small-worldness as a universal property in semantic knowledge networks. Conversely, small-worldness was significantly reduced in networks of schizophrenia patients and was correlated with psychological measures of delusions. Patients’ semantic networks were partitioned into more distinct categories and had more random within-category structures than those of controls. Conclusions The differences in conceptual representations manifest altered semantic clustering and associative intrusions that underlie thought disorders. This is the first study to provide pathophysiological evidence for the loosening of associations as reflected in randomization of semantic networks in schizophrenia. Our method provides a promising approach for understanding the neural basis of altered or creative inner experiences of individuals with mental illness or exceptional abilities, respectively.

Disorganization of Semantic Brain Networks in Schizophrenia Revealed by fMRI

COPYRIGHT © 2022 Yufik, Friston and Moran. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Editorial: Understanding in the human and the machine

P551. Modelling of P300 and P50 Paradigms in the BSNIP Dataset Indicate Loss of NMDAR Function in Psychosis

Introduction Schizophrenia (SZ) and bipolar disorder (BD) are severe mental illnesses with large overlapping heritability. Both disorders are associated with altered neurophysiological responses, as measured with magnetoencephalography (MEG) or electroencephalography (EEG), particularly reduced mismatch negativity (MMN) and 40 Hz auditory steady-state responses (ASSR). These deficits could potentially both serve as early markers of illness and provide insight into the underlying pathophysiology as endophenotypes. First-degree relatives to patients with SZ and BD also show some neurophysiological deficits, however whether these deficits can be detected in adolescent offspring of patients is undetermined. Objectives We aim to investigate whether adolescents at familial high risk of schizophrenia and bipolar disorder show aberrant MMN and ASSR compared to population-based controls. Methods We will investigate MMN and 40 Hz ASSR in 15 year old adolescents (n ≈ 175) born to parents diagnosed with either SZ (FHR-SZ), BD (FHR-BD), or neither SZ or BD (population-based controls, PBC) using MEG. We will first perform sensor-level analyses and subsequently apply dynamic causal modeling (DCM) to investigate effective connectivity and make inferences about the underlying neurobiological mechanisms. We will investigate whether current psychopathology, cognitive status, and genetic risk for SZ and BD predict neurophysiological responses in the adolescents. Investigations are part of The Danish High Risk and Resilience Study - VIA (VIA15), a population-based longitudinal cohort study integrating social, psychological and biological risk factors and outcomes for SZ and BD. Results Final results are expected in 2024 Conclusions The VIA15 study will allow for unprecedented insight into the neurobiological development of schizophrenia and bipolar disorder. Disclosure No significant relationships.

Identifying prodromal biomarkers for schizophrenia and bipolar disorder using magnetoencephalography

This paper proposes an integrative perspective on evolutionary, cultural and computational approaches to psychiatry. These three approaches attempt to frame mental disorders as multiscale entities and offer modes of explanations and modeling strategies that can inform clinical practice. Although each of these perspectives involves systemic thinking, each is limited in its ability to address the complex developmental trajectories and larger social systemic interactions that lead to mental disorders. Inspired by computational modeling in theoretical biology, this paper aims to integrate the modes of explanation offered by evolutionary, cultural and computational psychiatry in a multilevel systemic perspective. We apply the resulting Evolutionary, Cultural and Computational (ECC) model to Major Depressive Disorder (MDD) to illustrate how this integrative approach can guide research and practice in psychiatry.

Integrating Evolutionary, Cultural, and Computational Psychiatry: A Multilevel Systemic Approach

This white paper lays out a vision of research and development in the field of artificial intelligence for the next decade (and beyond). Its denouement is a cyber-physical ecosystem of natural and synthetic sense-making, in which humans are integral participants$\unicode{x2014}$what we call ''shared intelligence''. This vision is premised on active inference, a formulation of adaptive behavior that can be read as a physics of intelligence, and which inherits from the physics of self-organization. In this context, we understand intelligence as the capacity to accumulate evidence for a generative model of one's sensed world$\unicode{x2014}$also known as self-evidencing. Formally, this corresponds to maximizing (Bayesian) model evidence, via belief updating over several scales: i.e., inference, learning, and model selection. Operationally, this self-evidencing can be realized via (variational) message passing or belief propagation on a factor graph. Crucially, active inference foregrounds an existential imperative of intelligent systems; namely, curiosity or the resolution of uncertainty. This same imperative underwrites belief sharing in ensembles of agents, in which certain aspects (i.e., factors) of each agent's generative world model provide a common ground or frame of reference. Active inference plays a foundational role in this ecology of belief sharing$\unicode{x2014}$leading to a formal account of collective intelligence that rests on shared narratives and goals. We also consider the kinds of communication protocols that must be developed to enable such an ecosystem of intelligences and motivate the development of a shared hyper-spatial modeling language and transaction protocol, as a first$\unicode{x2014}$and key$\unicode{x2014}$step towards such an ecology.

Open science communication: The first year of the UK's Independent Scientific Advisory Group for Emergencies

Neural Networks special issue on Artificial Intelligence and Brain Science

Touch is recognised as crucial for survival, fostering cooperative communication, accelerating recovery, reducing hospital stays, and promoting overall wellness and the therapeutic alliance. In this hypothesis and theory paper, we present an entwined model that combines touch for alignment and active inference to explain how the brain develops “priors” necessary for the health care provider to engage with the patient effectively. We appeal to active inference to explain the empirically integrative neurophysiological and behavioural mechanisms that underwrite synchronous relationships through touch. Specifically, we offer a formal framework for understanding – and explaining – the role of therapeutic touch and hands-on care in developing a therapeutic alliance and synchrony between health care providers and their patients in musculoskeletal care. We first review the crucial importance of therapeutic touch and its clinical role in facilitating the formation of a solid therapeutic alliance and in regulating allostasis. We then consider how touch is used clinically – to promote cooperative communication, demonstrate empathy, overcome uncertainty, and infer the mental states of others – through the lens of active inference. We conclude that touch plays a crucial role in achieving successful clinical outcomes and adapting previous priors to create intertwined beliefs. The ensuing framework may help healthcare providers in the field of musculoskeletal care to use hands-on care to strengthen the therapeutic alliance, minimise prediction errors (a.k.a., free energy), and thereby promote recovery from physical and psychological impairments.

Therapeutic Alliance as Active Inference: The Role of Therapeutic Touch and Biobehavioural Synchrony in Musculoskeletal Care

 In an effort to build intelligent, autonomous systems, robotics has repeatedly used neuroscience as a source of inspiration for perception and control. This corresponds well with advances in neuroscience, particularly the free energy principle; a unified theory of the brain, integrating together notions of action, perception, and learning. Crucially for robotics, it provides a simple recipe to synthesise autonomous agents under the framework of active inference.
 
 We conducted a literature search assessing the practicality of autonomous agency within surgical robotics, and to understand the potential of applying the free energy principle to surgical robotics in a bid to optimise locomotion, spatial awareness, planning, and artificial curiosity.
 
 Numerous real-life examples demonstrate the feasibility of applying bayesian inference to humanoid robotics. Here we demonstrate a similar approach to adapting surgical robotics through the representation of sensory data through a probability density function over a group of unknown variables. In this manner, surgical robotics will be able to utilise sensory signals and can provide different weights to sensory cues, thereby efficiently integrating sensory input over space and time.
 
 The free energy principle may be applied to surgical robotics to provide additional feedback, and control to improve patient prognosis.

This paper considers the phenomenology of depersonalisation disorder, in relation to predictive processing and its associated pathophysiology. To do this, we first establish a few mechanistic tenets of predictive processing that are necessary to talk about phenomenal transparency, mental action, and self as subject. We briefly review the important role of ‘predicting precision’ and how this affords mental action and the loss of phenomenal transparency. We then turn to sensory attenuation and the phenomenal consequences of (pathophysiological) failures to attenuate or modulate sensory precision. We then consider this failure in the context of depersonalisation disorder. The key idea here is that depersonalisation disorder reflects the remarkable capacity to explain perceptual engagement with the world via the hypothesis that “I am an embodied perceiver, but I am not in control of my perception”. We suggest that individuals with depersonalisation may believe that ‘another agent’ is controlling their thoughts, perceptions or actions, while maintaining full insight that the ‘another agent’ is ‘me’ (the self). Finally, we rehearse the predictions of this formal analysis, with a special focus on the psychophysical and physiological abnormalities that may underwrite the phenomenology of depersonalisation.

I overthink—therefore I am not: Altered Sense of Self and Agency in Depersonalisation Disorder

This report describes a dynamic causal model that could be used to address questions about the rollout and efficacy of vaccines in the United Kingdom. For example, is suppression of community transmission a realistic aspiration? And, if not, what kind of endemic equilibrium might be achieved? What percentage of the population needs to be vaccinated? And over what timescale? It focuses on the synergies among (i) vaccination, (ii) the supported isolation of contacts of confirmed cases and (iii) restrictions on contact rates (i.e., lockdown and social distancing). To model these mitigations, we used a dynamic causal model that embeds an epidemiological model into agent-based behavioural model. The model structure and parameters were optimised to best explain responses to the first and subsequent waves enabling predictions over the forthcoming year under counterfactual scenarios. Illustrative analyses suggest that the full potential of vaccination is realised by increasing the efficacy of contact tracing: for example, under idealised (best case) assumptions of an effective vaccine and efficient isolation of infected pre-symptomatic cases suppression of community transmission would require 50% herd immunity by vaccinating 22% by the end of 2021; i.e., 15 million people or about 50,000 per day. With no change in the isolation of contacts, 36% would require vaccination, i.e., 25 million people. These figures should not be read as estimates of the actual number of people requiring vaccination; however, they illustrate the potential of this kind of model to quantify interactions among public health interventions. We anticipate using this model in a few months to estimate the average effectiveness of vaccines when more data become available.

How vaccination and contact isolation might interact to suppress transmission of Covid-19: a DCM study

Neuroimaging studies of psychedelics have advanced our understanding of hierarchical brain organization and the mechanisms underlying their subjective and therapeutic effects. The primary mechanism of action of classic psychedelics is binding to serotonergic 5-HT2A receptors. Agonist activity at these receptors leads to neuromodulatory changes in synaptic efficacy that can have a profound effect on hierarchical message-passing in the brain. Here, we review the cognitive and neuroimaging evidence for the effects of psychedelics: in particular, their influence on selfhood and subject-object boundaries—known as ego dissolution—surmised to underwrite their subjective and therapeutic effects. Agonism of 5-HT2A receptors, located at the apex of the cortical hierarchy, may have a particularly powerful effect on sentience and consciousness. These effects can endure well after the pharmacological half-life, suggesting that psychedelics may have effects on neural plasticity that may play a role in their therapeutic efficacy. Psychologically, this may be accompanied by a disarming of ego resistance that increases the repertoire of perceptual hypotheses and affords alternate pathways for thought and behavior, including those that undergird selfhood. We consider the interaction between serotonergic neuromodulation and sentience through the lens of hierarchical predictive coding, which speaks to the value of psychedelics in understanding how we make sense of the world and specific predictions about effective connectivity in cortical hierarchies that can be tested using functional neuroimaging. Significance Statement Classic psychedelics bind to serotonergic 5-HT2A receptors. Their agonist activity at these receptors leads to neuromodulatory changes in synaptic efficacy, resulting in a profound effect on information processing in the brain. Here, we synthesize an abundance of brain imaging research with pharmacological and psychological interpretations informed by the framework of predictive coding. Moreover, predictive coding is suggested to offer more sophisticated interpretations of neuroimaging findings by bridging the role between the 5-HT2A receptors and large-scale brain networks.

A weak version of the life-mind continuity thesis entails that every living system also has a basic mind (with a non-representational form of intentionality). The strong version entails that the same concepts that are sufficient to explain basic minds (with non-representational states) are also central to understanding non-basic minds (with representational states). We argue that recent work on the free energy principle supports the following claims with respect to the life-mind continuity thesis: (i) there is a strong continuity between life and mind; (ii) all living systems can be described as if they had representational states; (iii) the ’as-if representationality’ entailed by the free energy principle is central to understanding both basic forms of intentionality and intentionality in non-basic minds. In addition to this, we argue that the free energy principle also renders realism about computation and representation compatible with a strong life-mind continuity thesis (although the free energy principle does not entail computational and representational realism). In particular, we show how representationality proper can be grounded in ’as-if representationality’.

Examining the Continuity between Life and Mind: Is There a Continuity between Autopoietic Intentionality and Representationality?

Diminished synaptic gain - the sensitivity of postsynaptic responses to neural inputs - may be a fundamental synaptic pathology in schizophrenia. Evidence for this is indirect, however. Furthermore, it is unclear whether pyramidal cells or interneurons (or both) are affected, or how these deficits relate to symptoms. Participants with schizophrenia (Scz, n=108), their relatives (n=57), and controls (n=107) underwent three electroencephalography paradigms - resting, mismatch negativity, and 40 Hz auditory steady-state response - and resting functional magnetic resonance imaging. Dynamic causal modelling was used to quantify synaptic connectivity in cortical microcircuits. Across all four paradigms, characteristic Scz data features were best explained by models with greater self-inhibition (decreased synaptic gain), in pyramidal cells. Furthermore, disinhibition in auditory areas predicted abnormal auditory perception (and positive symptoms) in Scz, in three paradigms. Thus, psychotic symptoms of Scz may result from a downregulation of inhibitory interneurons that may compensate for diminished postsynaptic gain in pyramidal cells.

Computational Modelling of EEG and fMRI Paradigms Reveals a Consistent Loss of Pyramidal Cell Synaptic Gain in Schizophrenia

Significance Research into neurobiology of depression primarily focuses on its complex psychological aspects. Here we propose an alternative approach and target sensorimotor alterations—a prominent but often neglected feature of depression. We demonstrated using resting-state functional MRI data and computational modeling that top-down and bottom-up information flow in sensory and motor cortices is altered with increasing depression severity in a way that is consistent with depression symptoms. Depression-associated changes were found to be consistent across sessions, amenable to treatment and of effect size sufficiently large to predict whether somebody has mild or severe depression. These results pave the way for an avenue of research into the neural underpinnings of mental health conditions. Functional neuroimaging research on depression has traditionally targeted neural networks associated with the psychological aspects of depression. In this study, instead, we focus on alterations of sensorimotor function in depression. We used resting-state functional MRI data and dynamic causal modeling (DCM) to assess the hypothesis that depression is associated with aberrant effective connectivity within and between key regions in the sensorimotor hierarchy. Using hierarchical modeling of between-subject effects in DCM with parametric empirical Bayes we first established the architecture of effective connectivity in sensorimotor cortices. We found that in (interoceptive and exteroceptive) sensory cortices across participants, the backward connections are predominantly inhibitory, whereas the forward connections are mainly excitatory in nature. In motor cortices these parities were reversed. With increasing depression severity, these patterns are depreciated in exteroceptive and motor cortices and augmented in the interoceptive cortex, an observation that speaks to depressive symptomatology. We established the robustness of these results in a leave-one-out cross-validation analysis and by reproducing the main results in a follow-up dataset. Interestingly, with (nonpharmacological) treatment, depression-associated changes in backward and forward effective connectivity partially reverted to group mean levels. Overall, altered effective connectivity in sensorimotor cortices emerges as a promising and quantifiable candidate marker of depression severity and treatment response.

Altered effective connectivity in sensorimotor cortices is a signature of severity and clinical course in depression

Objectives Predicting the future UK COVID-19 epidemic allows other countries to compare their epidemic with one unfolding without public health measures except a vaccine program. Methods A Dynamic Causal Model was used to estimate key model parameters of the UK epidemic, such as vaccine effectiveness and increased transmissibility of Alpha and Delta variants, the effectiveness of the vaccine program roll-out and changes in contact rates. The model predicts the future trends in infections, long-COVID, hospital admissions and deaths. Results Two-dose vaccination given to 66% of the UK population prevents transmission following infection by 44%, serious illness by 86% and death by 93%. Despite this, with no other public health measures used, cases will increase from 37 million to 61 million, hospital admissions from 536,000 to 684,000 and deaths from 136,000 to 142,000 over 12 months. A retrospective analysis (conducted after the original submission of this report) allowed a comparison of these predictions of morbidity and mortality with actual outcomes. Conclusion Vaccination alone will not control the epidemic. Relaxation of mitigating public health measures carries several risks, which include overwhelming the health services, the creation of vaccine resistant variants and the economic cost of huge numbers of acute and chronic cases.

A 12-month projection to September 2022 of the COVID-19 epidemic in the UK using a dynamic causal model

This report considers three mechanisms that might underlie the course of the secondary peak of coronavirus infections in the United Kingdom. It considers: (i) fluctuations in transmission strength; (ii) seasonal fluctuations in contact rates and (iii) fluctuations in testing. Using dynamic causal modelling, we evaluated the contribution of all combinations of these three mechanisms using Bayesian model comparison. We found overwhelming evidence for the combination of all mechanisms, when explaining 16 types of data. Quantitatively, there was clear evidence for an increase in transmission strength of 57% over the past months (e.g., due to viral mutation), in the context of increased contact rates (e.g., rebound from national lockdowns) and increased test rates (e.g., due to the inclusion of lateral flow tests). Models with fluctuating transmission strength outperformed models with fluctuating contact rates. However, the best model included all three mechanisms suggesting that the resurgence during the second peak can be explained by an increase in effective contact rate that is the product of a rebound of contact rates following a national lockdown and increased transmission risk due to viral mutation.

Viral mutation, contact rates and testing: a DCM study of fluctuations

Abstract The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as γ-aminobutyric acid (GABA). Here, we quantify the GABAergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study. We analysed 17 patients with bvFTD, 15 patients with progressive supranuclear palsy, and 20 healthy age- and gender-matched controls. In addition to neuropsychological assessment and structural MRI, participants undertook two magnetoencephalography sessions using a roving auditory oddball paradigm: once on placebo and once on 10 mg of the oral GABA reuptake inhibitor tiagabine. A subgroup underwent ultrahigh-field magnetic resonance spectroscopy measurement of GABA concentration, which was reduced among patients. We identified deficits in frontotemporal processing using conductance-based biophysical models of local and global neuronal networks. The clinical relevance of this physiological deficit is indicated by the correlation between top-down connectivity from frontal to temporal cortex and clinical measures of cognitive and behavioural change. A critical validation of the biophysical modelling approach was evidence from parametric empirical Bayes analysis that GABA levels in patients, measured by spectroscopy, were related to posterior estimates of patients’ GABAergic synaptic connectivity. Further evidence for the role of GABA in frontotemporal lobar degeneration came from confirmation that the effects of tiagabine on local circuits depended not only on participant group, but also on individual baseline GABA levels. Specifically, the phasic inhibition of deep cortico-cortical pyramidal neurons following tiagabine, but not placebo, was a function of GABA concentration. The study provides proof-of-concept for the potential of dynamic causal modelling to elucidate mechanisms of human neurodegenerative disease, and explains the variation in response to candidate therapies among patients. The laminar- and neurotransmitter-specific features of the modelling framework, can be used to study other treatment approaches and disorders. In the context of frontotemporal lobar degeneration, we suggest that neurophysiological restoration in selected patients, by targeting neurotransmitter deficits, could be used to bridge between clinical and preclinical models of disease, and inform the personalized selection of drugs and stratification of patients for future clinical trials.

GABAergic cortical network physiology in frontotemporal lobar degeneration

The aim of this paper is to introduce and study the notion of NncZo-sets in Nnc topological space. Some characterizations of these notions are presented.

1. Asymptotics of ergodic distribution of the stochastic BDIM The ergodic (or stationary) distribution (1.2) of the stochastic BDIM is completely defined by the asymptotic expansion (1.5) of the function χ(i), χ(i)=λi-1/δi =iθ (1-γ/i + O(1/i)) where s and γ are real numbers and θ is positive. The following main assertions describe all possible asymptotic behaviors of the stationary probabilities depending on different orders of balance in BDIM (as defined in the formulation of the theorem below). Theorem 1. (i) if s≠0 (non-balanced BDIM), then pi ~ Γ(i)θ i where Γ(i) is the Γfunction; (ii) if s=0 and θ≠1 (first-order balanced BDIM), then pi ~ θ i; (iii) if s=0; θ=1 and a≠0 (second-order balanced BDIM), then pi ~ i; (iv) if s=0; θ=1 and a=0 (high-order balanced BDIM), then pi ~ 1. Proof The condition (1.5) can be rewritten as λi-1/δi=iθ(1-γ/i+O(1/i))=iθ (1-γ/i)(1+ O(1/i)). Thus we can choose S in such a way that (1+ O(1/s ∏ =S s ∞

Why is psychiatry unable to define clinically useful biomarkers? We explore this question from the vantage of data and decision science and consider biomarkers as a form of phenotypic data that resolves a well-defined clinical decision. We introduce a framework that systematizes different forms of phenotypic data and further introduce the concept of decision model to describe the strategies a clinician uses to seek out, combine, and act on clinical data. Though many medical specialties rely on quantitative clinical data and operationalized decision models, we observe that, in psychiatry, clinical data are gathered and used in idiosyncratic decision models that exist solely in the clinician's mind and therefore are outside empirical evaluation. This, we argue, is a fundamental reason why psychiatry is unable to define clinically useful biomarkers: because psychiatry does not currently quantify clinical data, decision models cannot be operationalized and, in the absence of an operationalized decision model, it is impossible to define how a biomarker might be of use. Here, psychiatry might benefit from digital technologies that have recently emerged specifically to quantify clinically relevant facets of human behavior. We propose that digital tools might help psychiatry in two ways: first, by quantifying data already present in the standard clinical interaction and by allowing decision models to be operationalized and evaluated; second, by testing whether new forms of data might have value within an operationalized decision model. We reference successes from other medical specialties to illustrate how quantitative data and operationalized decision models improve patient care.

Decision Models and Technology Can Help Psychiatry Develop Biomarkers

Abstract We propose a computational neurology of movement based on the convergence of theoretical neurobiology and clinical neurology. A significant development in the former is the idea that we can frame brain function as a process of (active) inference, in which the nervous system makes predictions about its sensory data. These predictions depend upon an implicit predictive (generative) model used by the brain. This means neural dynamics can be framed as generating actions to ensure sensations are consistent with these predictions—and adjusting predictions when they are not. We illustrate the significance of this formulation for clinical neurology by simulating a clinical examination of the motor system using an upper limb coordination task. Specifically, we show how tendon reflexes emerge naturally under the right kind of generative model. Through simulated perturbations, pertaining to prior probabilities of this model’s variables, we illustrate the emergence of hyperreflexia and pendular reflexes, reminiscent of neurological lesions in the corticospinal tract and cerebellum. We then turn to the computational lesions causing hypokinesia and deficits of coordination. This in silico lesion-deficit analysis provides an opportunity to revisit classic neurological dichotomies (e.g. pyramidal versus extrapyramidal systems) from the perspective of modern approaches to theoretical neurobiology—and our understanding of the neurocomputational architecture of movement control based on first principles.

Aberrant temporal–spatial complexity of intrinsic fluctuations in major depression

Objective To track the interplay between (micro-) structural changes along the trajectories of nociceptive pathways and its relation to the presence and intensity of neuropathic pain (NP) after spinal cord injury (SCI). Methods A quantitative neuroimaging approach employing a multiparametric mapping protocol was used, providing indirect measures of myelination (via contrasts such as magnetisation transfer (MT) saturation, longitudinal relaxation (R1)) and iron content (via effective transverse relaxation rate (R2*)) was used to track microstructural changes within nociceptive pathways. In order to characterise concurrent changes along the entire neuroaxis, a combined brain and spinal cord template embedded in the statistical parametric mapping framework was used. Multivariate source-based morphometry was performed to identify naturally grouped patterns of structural variation between individuals with and without NP after SCI. Results In individuals with NP, lower R1 and MT values are evident in the primary motor cortex and dorsolateral prefrontal cortex, while increases in R2* are evident in the cervical cord, periaqueductal grey (PAG), thalamus and anterior cingulate cortex when compared with pain-free individuals. Lower R1 values in the PAG and greater R2* values in the cervical cord are associated with NP intensity. Conclusions The degree of microstructural changes across ascending and descending nociceptive pathways is critically implicated in the maintenance of NP. Tracking maladaptive plasticity unravels the intimate relationships between neurodegenerative and compensatory processes in NP states and may facilitate patient monitoring during therapeutic trials related to pain and neuroregeneration.

Microstructural plasticity in nociceptive pathways after spinal cord injury

When listening to music, pitch deviations are more salient and elicit stronger prediction error responses when the melodic context is predictable and when the listener is a musician. Yet, the neuronal dynamics and changes in synaptic efficacy underlying such effects remain unclear. Here, we employed dynamic causal modeling (DCM) to investigate whether the magnetic mismatch negativity response (MMNm)—and its modulation by context predictability and musical expertise—are associated with enhanced neural gain of auditory areas, as a plausible mechanism for encoding precision-weighted prediction errors. Using Bayesian model comparison, we asked whether models with intrinsic connections within primary auditory cortex (A1) and superior temporal gyrus (STG)—typically related to gain control—or extrinsic connections between A1 and STG—typically related to propagation of prediction and error signals—better explained magnetoencephalography (MEG) responses. We found that, compared to regular sounds, out-of-tune pitch deviations were associated with lower intrinsic (inhibitory) connectivity in A1 and STG, and lower backward (inhibitory) connectivity from STG to A1, consistent with disinhibition and enhanced neural gain in these auditory areas. More predictable melodies were associated with disinhibition in right A1, while musicianship was associated with disinhibition in left A1 and reduced connectivity from STG to left A1. These results indicate that musicianship and melodic predictability, as well as pitch deviations themselves, enhance neural gain in auditory cortex during deviance detection. Our findings are consistent with predictive processing theories suggesting that precise and informative error signals are selected by the brain for subsequent hierarchical processing. Significance statement In complex auditory contexts, being able to identify informative signals is of paramount importance. Such is the case of music listening, where surprising sounds play a fundamental role in its perceptual, aesthetical, and emotional experience. Crucially, surprising sounds in the pitch dimension are more easily detected and generate stronger cortical responses when melodies are predictable and when the listener is a musician. Using Dynamic Causal Modelling, here we show that such effects arise from a local increase in neural gain within auditory areas, rather than from passing of prediction and error signals between brain regions. Consistent with predictive processing theories, this suggests that the enhanced precision of auditory predictive models—through melodic predictability and musical training—up-regulates the processing of informative error signals in the brain.

Musicianship and melodic predictability enhance neural gain in auditory cortex during pitch deviance detection

Abstract The social environment presents the human brain with the most complex information processing demands. The computations that the brain must perform occur in parallel, combine social and nonsocial cues, produce verbal and nonverbal signals and involve multiple cognitive systems, including memory, attention, emotion and learning. This occurs dynamically and at timescales ranging from milliseconds to years. Here, we propose that during social interactions, seven core operations interact to underwrite coherent social functioning; these operations accumulate evidence efficiently—from multiple modalities—when inferring what to do next. We deconstruct the social brain and outline the key components entailed for successful human–social interaction. These include (i) social perception; (ii) social inferences, such as mentalizing; (iii) social learning; (iv) social signaling through verbal and nonverbal cues; (v) social drives (e.g. how to increase one’s status); (vi) determining the social identity of agents, including oneself and (vii) minimizing uncertainty within the current social context by integrating sensory signals and inferences. We argue that while it is important to examine these distinct aspects of social inference, to understand the true nature of the human social brain, we must also explain how the brain integrates information from the social world.

I was struck by the number of phrases and constructs that link the two fields. For example, "belief as processes" that underwrite evaluation "by inference of some form". This is exactly how active inference works, were the process of Bayesian belief updating is used to assimilate evidence from the environment (i.e., perception) to form (posterior) beliefs about states of affairs in the world. The same Bayesian principles are then applied to beliefs about policies or plans: e.g., (Schwartenbeck et al., 2019). Evaluation then becomes a problem of inferring ‘what is the most likely thing I will do?’. This entails the selection of a particular plan following its evaluation in terms of the things that the COM–B model brings to the table, specifically, prior beliefs about the plausibility of a plan and its outcomes (often described in terms of prior preferences or goals).

Review of: "A brief introduction to the COM-B Model of behaviour and the PRIME Theory of motivation"

Immunoceptive inference: why are psychiatric disorders and immune responses intertwined?

In vitro neurons learn and exhibit sentience when embodied in a simulated game-world

Functional recovery after brain damage varies widely and depends on many factors, including lesion site and extent. When a neuronal system is damaged, recovery may occur by engaging residual (e.g., perilesional) components. When damage is extensive, recovery depends on the availability of other intact neural structures that can reproduce the same functional output (i.e., degeneracy). A system’s response to damage may occur rapidly, require learning or both. Here, we simulate functional recovery from four different types of lesions, using a generative model of word repetition that comprised a default premorbid system and a less used alternative system. The synthetic lesions (i) completely disengaged the premorbid system, leaving the alternative system intact, (ii) partially damaged both premorbid and alternative systems, and (iii) limited the experience-dependent plasticity of both. The results, across 1000 trials, demonstrate that (i) a complete disconnection of the premorbid system naturally invoked the engagement of the other, (ii) incomplete damage to both systems had a much more devastating long-term effect on model performance and (iii) the effect of reducing learning capacity within each system. These findings contribute to formal frameworks for interpreting the effect of different types of lesions.

Special Issue: Computational Methods in Social Neuroscience Seven computations of the social brain

Hemodynamic latency is associated with reduced intelligence across the lifespan: an fMRI DCM study of aging, cerebrovascular integrity, and cognitive ability

Review for "Biophysical mechanisms governing large‐scale brain network dynamics underlying individual‐specific variability of perception"

Abstract The syndrome of anosognosia for hemiplegia, or the lack of awareness for one’s paralysis following right hemisphere stroke, can provide unique insights into the neurocognitive mechanisms of self-awareness. Yet it remains unclear whether anosognosia for hemiplegia is a modality-specific deficit of sensorimotor monitoring, or whether domain-general processes of attention and belief-updating converge to cause anosognosia for hemiplegia. Using a Bayesian learning framework, we formalized and empirically investigated the hypothesis that failures to update anosognosic beliefs can be explained by abnormalities in the relative uncertainty (i.e. precision) ascribed to prior beliefs versus sensory information in different contexts. We designed a new motor belief-updating task that manipulated both the temporal (prospective and retrospective) and spatial (hemispace most affected by inattention and hemispace less affected by inattention) conditions in which beliefs had to be updated, and we validated its sensitivity to anosognosia for hemiplegia in 26 patients with right hemisphere stroke. We then computed and empirically tested two different Bayesian predictors of prospective beliefs using two proxies for precision in anosognosia for hemiplegia patients: (i) standardized, neuropsychological measures of objective attention abilities, i.e. visuospatial neglect scores and (ii) subjective uncertainty reports, i.e. confidence ratings. Our results suggest that while neglect does not affect local, sensorimotor error monitoring, it does seem to affect the degree to which observed errors are used to update more general, prospective beliefs about counterfactual motor abilities in anosognosia for hemiplegia. Difficulties in such ‘counterfactual’ belief-updating were associated with disruptions in tracts of the ventral attentional network (i.e. superior longitudinal fasciculus connecting the temporo-parietal junction and ventral frontal cortex) and associated lesions to the insula, inferior parietal cortex and superior temporal regions. These results suggest that self-awareness extends beyond local, retrospective monitoring, requiring also salience-based, convergence of beliefs about the self that go beyond the ‘here-and-now’ of sensorimotor experience.

Updating beliefs beyond the here-and-now: the counter-factual self in anosognosia for hemiplegia

30 PuhanMA, FreyM, Buchi S, Schunemann HJ. Theminimal important difference of the Hospital Anxiety and Depression Scale in patients with chronic obstructive pulmonary disease. Health Qual Life Outcomes 2008; 6: 46. 31 Farran CJ, Paun O, Cothran F, Etkin CD, Rajan KB, Eisenstein A, et al. Impact of an individualized physical activity intervention On improving mental health outcomes in family caregivers of persons with dementia: a randomized controlled trial. AIMS Medical Science 2015; 3: 31.

Transcriptome-wide association study reveals two genes that influence mismatch negativity

Seizure activity is a ubiquitous and pernicious pathophysiology that, in principle, should yield to mathematical treatments of (neuronal) ensemble dynamics - and therefore interventions on stochastic chaos. A seizure can be characterised as a deviation of neural activity from a stable dynamical regime, i.e. one in which signals fluctuate only within a limited range. In silico treatments of neural activity are an important tool for understanding how the brain can achieve stability, as well as how pathology can lead to seizures and potential strategies for mitigating instabilities, e.g. via external stimulation. Here, we demonstrate that the (neuronal) state equation used in Dynamic Causal Modelling generalises to a Fokker-Planck formalism when propagation of neuronal activity along structural connections is considered. Using the Jacobian of this generalised state equation, we show that an initially unstable system can be rendered stable via a reduction in diffusivity (i.e., connectivity that disperses neuronal fluctuations). We show, for neural systems prone to epileptic seizures, that such a reduction can be achieved via external stimulation. Specifically, we show that this stimulation should be applied in such a way as to temporarily mirror epileptic activity in the areas adjoining an affected brain region - thus 'fighting seizures with seizures'. We offer proof of principle using simulations based on functional neuroimaging data collected from patients with idiopathic generalised epilepsy, in which we successfully suppress pathological activity in a distinct sub-network. Our hope is that this technique can form the basis for real-time monitoring and intervention devices that are capable of suppressing or even preventing seizures in a non-invasive manner.

Fighting seizures with seizures: diffusion and stability in neural systems

Disconnection and Diaschisis: Active Inference in Neuropsychology

 In epidemiological modelling, the instantaneous reproduction number, Rt, is important to understand the transmission dynamics of infectious diseases. Current Rt estimates often suffer from problems such as lagging, averaging and uncertainties demoting the usefulness of Rt. To address these problems, we propose a new method in the framework of sequential Bayesian inference where a Data Assimilation approach is taken for Rt estimation, resulting in the state-of-the-art ‘DARt’ system for Rt estimation. With DARt, the problem of time misalignment caused by lagging observations is tackled by incorporating observation delays into the joint inference of infections and Rt; the drawback of averaging is improved by instantaneous updating upon new observations and a model selection mechanism capturing abrupt changes caused by interventions; the uncertainty is quantified and reduced by employing Bayesian smoothing. We validate the performance of DARt through simulations and demonstrate its power in revealing the transmission dynamics of COVID-19.

Revealing the Transmission Dynamics of COVID-19: A Bayesian Framework for Rt Estimation

Neural and phenotypic representation under the free-energy principle

Background: Following stringent social distancing measures, some European countries are beginning to report a slowed or negative rate of growth of daily case numbers testing positive for the novel coronavirus. The notion that the first wave of infection is close to its peak begs the question of whether future peaks or second waves are likely. We sought to determine the current size of the effective (i.e. susceptible) population for seven European countries - to estimate immunity levels following this first wave. We compare these numbers to the total population sizes of these countries, in order to investigate the potential for future peaks. Methods: We used Bayesian model inversion to estimate epidemic parameters from the reported case and death rates from seven countries using data from late January 2020 to April 5th 2020. Two distinct generative model types were employed: first a continuous time dynamical-systems implementation of a Susceptible-Exposed-Infectious-Recovered (SEIR) model and second: a partially observable Markov Decision Process (MDP) or hidden Markov model (HMM) implementation of an SEIR model. Both models parameterise the size of the initial susceptible population (S0), as well as epidemic parameters. Parameter estimation (data fitting) was performed using a standard Bayesian scheme (variational Laplace) designed to allow for latent unobservable states and uncertainty in model parameters. Results: Both models recapitulated the dynamics of transmissions and disease as given by case and death rates. The peaks of the current waves were predicted to be in the past for four countries (Italy, Spain, Germany and Switzerland) and to emerge in 0.5-2 weeks in Ireland and 1-3 weeks in the UK. For France one model estimated the peak within the past week and the other in the future in two weeks. Crucially, Maximum a posteriori (MAP) estimates of S0 for each country indicated effective population sizes of below 20% (of total population size), under both the continuous time and HMM models. Using for all countries, with a Bayesian weighted average across all seven countries and both models, we estimated that 6.4% of the total population would be immune. From the two models the maximum percentage of the effective population was estimated at 19.6% of the total population for the UK, 16.7% for Ireland, 11.4% for Italy, 12.8% for Spain, 18.8% for France, 4.7% for Germany and 12.9% for Switzerland. Conclusion: Our results indicate that after the current wave, a large proportion of the total population will remain without immunity. This suggests that in the absence of strong seasonal effects, new medications or more comprehensive contact tracing, a further set of epidemic waves in different geographic centres are likely. These findings may have implications for exit strategies from any lockdown stage.

Estimating required lockdown cycles before immunity to SARS-CoV-2: Model-based analyses of susceptible population sizes, S0, in seven European countries including the UK and Ireland

Previous research showed that the ability to make inferences about our own and other’s mental states rely on common brain pathways; particularly in the case of close relationships (e.g., romantic relationships). Despite the evidence for shared neural representations of self and others, less is known about the distributed processing within these common neural networks, particularly whether there are specific patterns of internode communication when focusing on other vs. self. This study aimed to characterize context-sensitive coupling among social brain regions involved in self and other understanding. Participants underwent an fMRI while watching emotional video vignettes of their romantic partner and elaborated on their partner’s (other-condition) or on their own experience (self-condition). We used dynamic causal modeling (DCM) to quantify the associated changes in effective connectivity (EC) in a network of brain regions involved in social cognition including the temporoparietal junction (TPJ), the posterior cingulate (PCC)/precuneus and middle temporal gyrus (MTG). DCM revealed that: the PCC plays a central coordination role within this network, the bilateral MTG receives driving inputs from other nodes suggesting that social information is first processed in language comprehension regions; the right TPJ evidenced a selective increase in its sensitivity when focusing on the other’s experience, relative to focusing on oneself.

Changes in the Effective Connectivity of the Social Brain When Making Inferences About Close Others vs. the Self

The propagation of epileptic seizure activity in the brain is a widespread pathophysiology that, in principle, should yield to intervention techniques guided by mathematical models of neuronal ensemble dynamics. During a seizure, neural activity will deviate from its current dynamical regime to one in which there are significant signal fluctuations. In silico treatments of neural activity are an important tool for the understanding of how the healthy brain can maintain stability, as well as of how pathology can lead to seizures. The hope is that, contained within the mathematical foundations of such treatments, there lie potential strategies for mitigating instabilities, e.g. via external stimulation. Here, we demonstrate that the dynamic causal modelling neuronal state equation generalises to a Fokker-Planck formalism if one extends the framework to model the ways in which activity propagates along the structural connections of neural systems. Using the Jacobian of this generalised state equation, we show that an initially unstable system can be rendered stable via a reduction in diffusivity–i.e., by lowering the rate at which neuronal fluctuations disperse to neighbouring regions. We show, for neural systems prone to epileptic seizures, that such a reduction in diffusivity can be achieved via external stimulation. Specifically, we show that this stimulation should be applied in such a way as to temporarily mirror the activity profile of a pathological region in its functionally connected areas. This counter-intuitive method is intended to be used pre-emptively–i.e., in order to mitigate the effects of the seizure, or ideally even prevent it from occurring in the first place. We offer proof of principle using simulations based on functional neuroimaging data collected from patients with idiopathic generalised epilepsy, in which we successfully suppress pathological activity in a distinct sub-network prior to seizure onset. Our hope is that this technique can form the basis for future real-time monitoring and intervention devices that are capable of treating epilepsy in a non-invasive manner.

Neural diffusivity and pre-emptive epileptic seizure intervention

Cognition coming about: Self-organisation and free-energy: Commentary on Wright, J.J. and Bourke, P.D. (2020) "The growth of cognition: Free energy minimization and the embryogenesis of cortical computation".

Erratum to ‘Dynamic effective connectivity’ [Neuroimage, 207 (2020) 116453]

In this paper, we address reports of “selfless” experiences from the perspective of active inference and predictive processing. Our argument builds upon grounding self-modelling in active inference as action planning and precision control within deep generative models – thus establishing a link between computational mechanisms and phenomenal selfhood. We propose that “selfless” experiences can be interpreted as (rare) cases in which normally congruent processes of computational and phenomenal self-modelling diverge in an otherwise conscious system. We discuss two potential mechanisms – within the Bayesian mechanics of active inference – that could lead to such a divergence by attenuating the experience of selfhood: “self-flattening” via reduction in the depth of active inference and “self-attenuation” via reduction of the expected precision of self-evidence.

This letter considers a class of biologically plausible cost functions for neural networks, where the same cost function is minimized by both neural activity and plasticity. We show that such cost functions can be cast as a variational bound on model evidence under an implicit generative model. Using generative models based on partially observed Markov decision processes (POMDP), we show that neural activity and plasticity perform Bayesian inference and learning, respectively, by maximizing model evidence. Using mathematical and numerical analyses, we establish the formal equivalence between neural network cost functions and variational free energy under some prior beliefs about latent states that generate inputs. These prior beliefs are determined by particular constants (e.g., thresholds) that define the cost function. This means that the Bayes optimal encoding of latent or hidden states is achieved when the network's implicit priors match the process that generates its inputs. This equivalence is potentially important because it suggests that any hyperparameter of a neural network can itself be optimized—by minimization with respect to variational free energy. Furthermore, it enables one to characterize a neural network formally, in terms of its prior beliefs.

Reverse-Engineering Neural Networks to Characterize Their Cost Functions

Model-based prediction of muscarinic receptor function from auditory mismatch negativity responses

We recently described a dynamic causal model of a COVID-19 outbreak within a single region. Here, we combine several of these (epidemic) models to create a (pandemic) model of viral spread among regions. Our focus is on a second wave of new cases that may result from loss of immunity-and the exchange of people between regions-and how mortality rates can be ameliorated under different strategic responses. In particular, we consider hard or soft social distancing strategies predicated on national (Federal) or regional (State) estimates of the prevalence of infection in the population. The modelling is demonstrated using timeseries of new cases and deaths from the United States to estimate the parameters of a factorial (compartmental) epidemiological model of each State and, crucially, coupling between States. Using Bayesian model reduction, we identify the effective connectivity between States that best explains the initial phases of the outbreak in the United States. Using the ensuing posterior parameter estimates, we then evaluate the likely outcomes of different policies in terms of mortality, working days lost due to lockdown and demands upon critical care. The provisional results of this modelling suggest that social distancing and loss of immunity are the two key factors that underwrite a return to endemic equilibrium.

Second waves, social distancing, and the spread of COVID-19 across America.

Cortical beta oscillations reflect the contextual gating of visual action feedback

The proper intensity of MR Brain volume calculation to estimate the Alzheimer’s disease depth is dealt in this paper. As Alzheimer’s is a progressive degenerative disease that attacks brain, the estimation of its intensity is highly required. The work here is concerned with Voxel Based Morphometry to render the first part segmentation. The result gives an active region which further needs an evaluation to justify the diagnosis. VBM works on SPM platform. When

Fuzzy Integrated Voxel Based Morphometric approach to compute MR Brain Volume for Proper Intensity diagnosis of Alzheimer’s

This report uses dynamic causal modelling of daily cases and deaths to distinguish between secondary and second waves, in terms of the underlying mechanisms and associated mortality due to SARS-CoV2. Here, secondary waves are taken to reflect a spread of the virus through the population, reaching previously unexposed communities after the first wave has peaked. Conversely, second waves refer to the reinfection of a previously exposed population, due to a loss of effective (population) immunity. Our quantitative modelling suggests that the fatality rates that accompany both secondary and second waves are substantially less than the first wave—and an order of magnitude less than predictions based upon prevalent epidemiological models that ignore heterogeneity in viral exposure, susceptibility and transmission.

This paper aims to leverage the free-energy principle and active inference to make sense of some central facets of the first-person conscious experience of human beings. More precisely, we explore two central facets of the first-person conscious experience of human beings via the free-energy principle and active inference. We examine how active inference is able to account for temporal nestedness of conscious experience and for the concern or care that is the main structure of first-person experience according to phenomenological philosophy. We investigate the breakdown of these features in depression—and explain some of the core aspects of the phenomenology of depression by appealing to the active inference framework.

Deep neurophenomenology: An active inference account of some features of conscious experience and of their disturbance in major depressive disorder

Adaptive agents must act in intrinsically uncertain environments with complex latent structure. Here, we elaborate a model of visual foraging – in a hierarchical context – wherein agents infer a higher-order visual pattern (a ‘scene’) by sequentially sampling ambiguous cues. Inspired by previous models of scene construction – that cast perception and action as consequences of approximate Bayesian inference – we use active inference to simulate decisions of agents categorizing a scene in a hierarchically-structured setting. Under active inference, agents develop probabilistic beliefs about their environment, while actively sampling it to maximise the evidence for their internal generative model. This approximate evidence maximization (i.e. self-evidencing) comprises drives to both maximise rewards and resolve uncertainty about hidden states. This is realised via minimization of a free energy functional of posterior beliefs about both the world as well as the actions used to sample or perturb it, corresponding to perception and action, respectively. We show that active inference, in the context of hierarchical scene construction, gives rise to many empirical evidence accumulation phenomena, such as noise-sensitive reaction times and epistemic saccades. We explain these behaviours in terms of the principled drives that constitute the expected free energy, the key quantity for evaluating policies under active inference. In addition, we report novel behaviours exhibited by these active inference agents that furnish new predictions for research on evidence accumulation and perceptual decision-making. We discuss the implications of this hierarchical active inference scheme for tasks that require planned sequences of information-gathering actions to infer compositional latent structure (such as visual scene construction and sentence comprehension). Finally, we propose experiments to contextualise active inference in relation to other formulations of evidence accumulation (e.g. drift-diffusion models) in tasks that require planning in uncertain environments with higher-order structure.

Biehl et al. (2021) present some interesting observations on an early formulation of the free energy principle. We use these observations to scaffold a discussion of the technical arguments that underwrite the free energy principle. This discussion focuses on solenoidal coupling between various (subsets of) states in sparsely coupled systems that possess a Markov blanket—and the distinction between exact and approximate Bayesian inference, implied by the ensuing Bayesian mechanics.

What kind of explanation is the constructing and coasting strategy?: Comment on: "The sense of should: A biologically-based framework for modeling social pressure" by Jordan E. Theriault, Liane Young, and Lisa Feldman Barrett.

It is a great pleasure to comment on Solms’ Rosetta Stone. This commentary focuses on the New Project as a natural science. As such, the New Project has to conform to natural laws. In the physical sciences, there is only one principle we have to worry about, namely, Hamilton’s principle of stationary action. From this principle, one has to elaborate a physics of sentience. I think that Solms meets this challenge, casting Freud’s Project in a light – and language – that physicists and neurobiologists would be comfortable with. This is a remarkable achievement but not entirely unanticipated. I refer here to a line of thinking that inherits from the students of Plato, through Kant and Helmholtz, to modern day treatments of the Bayesian brain (Helmholtz 1878/1971). Given that Freud built upon the foundations laid by Helmholtz, the [re]union of Freudian and Helmholtzian thinking – on offer in the New Project – should be of no surprise. Although the mathematical details may take a few years to tie down with precision (sic) and grace, I think all the heavy lifting has been accomplished with this [re]visionary monograph. This commentary focuses on what the Solms’ [re]vision brings to the table, in terms of the functional architectures that underwrite a physics of sentience. There are some beautifully phrased sentences in it that speak to the fundaments of the free energy principle – and some that take us into new territory. I will frame my critique around these key observations and unpack them from the perspective of active inference.

The importance of being precise: Commentary on “New Project for a Scientific Psychology: General Scheme” by Mark Solms

Abstract Choosing actions that result in advantageous outcomes is a fundamental function of nervous systems. All computational decision-making models contain a mechanism that controls the variability of (or confidence in) action selection, but its neural implementation is unclear—especially in humans. We investigated this mechanism using two influential decision-making frameworks: active inference (AI) and reinforcement learning (RL). In AI, the precision (inverse variance) of beliefs about policies controls action selection variability—similar to decision ‘noise’ parameters in RL—and is thought to be encoded by striatal dopamine signaling. We tested this hypothesis by administering a ‘go/no-go’ task to 75 healthy participants, and measuring striatal dopamine 2/3 receptor (D2/3R) availability in a subset (n = 25) using [11C]-(+)-PHNO positron emission tomography. In behavioral model comparison, RL performed best across the whole group but AI performed best in participants performing above chance levels. Limbic striatal D2/3R availability had linear relationships with AI policy precision (P = 0.029) as well as with RL irreducible decision ‘noise’ (P = 0.020), and this relationship with D2/3R availability was confirmed with a ‘decision stochasticity’ factor that aggregated across both models (P = 0.0006). These findings are consistent with occupancy of inhibitory striatal D2/3Rs decreasing the variability of action selection in humans.

Variability in Action Selection Relates to Striatal Dopamine 2/3 Receptor Availability in Humans: A PET Neuroimaging Study Using Reinforcement Learning and Active Inference Models

Active inference is a normative framework for generating behaviour based upon the free energy principle, a theory of self-organisation. This framework has been successfully used to solve reinforcement learning and stochastic control problems, yet, the formal relation between active inference and reward maximisation has not been fully explicated. In this paper, we consider the relation between active inference and dynamic programming under the Bellman equation, which underlies many approaches to reinforcement learning and control. We show that, on partially observable Markov decision processes, dynamic programming is a limiting case of active inference. In active inference, agents select actions to minimise expected free energy. In the absence of ambiguity about states, this reduces to matching expected states with a target distribution encoding the agent's preferences. When target states correspond to rewarding states, this maximises expected reward, as in reinforcement learning. When states are ambiguous, active inference agents will choose actions that simultaneously minimise ambiguity. This allows active inference agents to supplement their reward maximising (or exploitative) behaviour with novelty-seeking (or exploratory) behaviour. This clarifies the connection between active inference and reinforcement learning, and how both frameworks may benefit from each other.

The relationship between dynamic programming and active inference: the discrete, finite-horizon case

Active inference is a normative framework for explaining behaviour under the free energy principle—a theory of self-organisation originating in neuroscience. It specifies neuronal dynamics for state-estimation in terms of a descent on (variational) free energy—a measure of the fit between an internal (generative) model and sensory observations. The free energy gradient is a prediction error—plausibly encoded in the average membrane potentials of neuronal populations. Conversely, the expected probability of a state can be expressed in terms of neuronal firing rates. We show that this is consistent with current models of neuronal dynamics and establish face validity by synthesising plausible electrophysiological responses. We then show that these neuronal dynamics approximate natural gradient descent, a well-known optimisation algorithm from information geometry that follows the steepest descent of the objective in information space. We compare the information length of belief updating in both schemes, a measure of the distance travelled in information space that has a direct interpretation in terms of metabolic cost. We show that neural dynamics under active inference are metabolically efficient and suggest that neural representations in biological agents may evolve by approximating steepest descent in information space towards the point of optimal inference.

Neural Dynamics under Active Inference: Plausibility and Efficiency of Information Processing

Research in clinical neuroscience is founded on the idea that a better understanding of brain (dys)function will improve our ability to diagnose and treat neurological and psychiatric disorders. In recent years, neuroscience has converged on the notion that the brain is a ‘prediction machine,’ in that it actively predicts the sensory input that it will receive if one or another course of action is chosen. These predictions are used to select actions that will (most often, and in the long run) maintain the body within the narrow range of physiological states consistent with survival. This insight has given rise to an area of clinical computational neuroscience research that focuses on characterizing neural circuit architectures that can accomplish these predictive functions, and on how the associated processes may break down or become aberrant within clinical conditions. Here, we provide a brief review of examples of recent work on the application of predictive processing models of brain function to study clinical (psychiatric) disorders, with the aim of highlighting current directions and their potential clinical utility. We offer examples of recent conceptual models, formal mathematical models, and applications of such models in empirical research in clinical populations, with a focus on making this material accessible to clinicians without expertise in computational neuroscience. In doing so, we aim to highlight the potential insights and opportunities that understanding the brain as a prediction machine may offer to clinical research and practice.

Recent advances in the application of predictive coding and active inference models within clinical neuroscience

Generative models, linguistic communication and active inference

: Changes in neurovascular coupling are associated with both Alzheimer’s disease and vascular dementia in later life, but this may be confounded by cerebrovascular risk. We hypothesized that hemodynamic latency would be associated with reduced cognitive functioning across the lifespan, holding constant demographic and cerebrovascular risk. In 387 adults aged 18-85 (mean = 48.82), dynamic causal modeling was used to estimate the hemodynamic response function in the left and right V1 and V3 regions of the visual cortex in response to a simple checkerboard stimulus with minimal cognitive demands. The hemodynamic latency (transit time) in the visual cortex was used to predict general cognitive ability (Full-Scale IQ), controlling for demographic variables (age, race, education, socioeconomic status) and cerebrovascular risk factors (hypertension, alcohol use, smoking, high cholesterol, BMI, type 2 diabetes, cardiac disorders). Increased hemodynamic latency in the visual cortex predicted impaired cognitive function holding constant demographic and cerebrovascular was associated with reduced overall cognitive function (Full Scale while cardiac disorders (Full Scale IQ 3.3 IQ pts; p<0.05), high cholesterol (Full Scale IQ 3.9 pts; p<0.05), and years of education (2 IQ pts/year; p<0.001) were associated with higher general cognitive ability. Increased hemodynamic latency was associated with reduced executive functioning (p<0.05) as well as deficits in verbal concept formation (p<0.05) and the ability to synthesize and analyze abstract visual information (p<0.01). Hemodynamic latency is associated with reduced cognitive ability across the lifespan, independently of other demographic and cerebrovascular risk factors. adjusted using with a threshold p<0.005 (t-test) and extent threshold k>30 contiguous voxels. latency latency

Hemodynamic latency is associated with reduced intelligence: an fMRI DCM study of aging, cerebrovascular integrity, and cognitive ability

Object recognition is enabled by an experience-dependent appraisal of visual features in the brain’s value system

Previous studies suggest that the practice of long-term (months to years) mindfulness meditation induces structural plasticity in gray matter. However, it remains unknown whether short-term (<30 days) mindfulness meditation in novices could induce similar structural changes. Our previous randomized controlled trials (RCTs) identified white matter changes surrounding the anterior cingulate cortex (ACC) and the posterior cingulate cortex (PCC) within 2 to 4 weeks, following 5-10 h of mindfulness training. Furthermore, these changes were correlated with emotional states in healthy adults. The PCC is a key hub in the functional anatomy implicated in meditation and other perspectival processes. In this longitudinal study using a randomized design, we therefore examined the effect of a 10 h of mindfulness training, the Integrative Body-Mind Training (IBMT) on gray matter volume of the PCC compared to an active control—relaxation training (RT). We found that brief IBMT increased ventral PCC volume and that baseline temperamental trait—an index of individual differences was associated with a reduction in training-induced gray matter increases. Our findings indicate that brief mindfulness meditation induces gray matter plasticity, suggesting that structural changes in ventral PCC—a key hub associated with self-awareness, emotion, cognition, and aging—may have important implications for protecting against mood-related disorders and aging-related cognitive declines.

Brief Mindfulness Meditation Induces Gray Matter Changes in a Brain Hub

This technical report addresses a pressing issue in the trajectory of the coronavirus outbreak; namely, the rate at which effective immunity is lost following the first wave of the pandemic. This is a crucial epidemiological parameter that speaks to both the consequences of relaxing lockdown and the propensity for a second wave of infections. Using a dynamic causal model of reported cases and deaths from multiple countries, we evaluated the evidence models of progressively longer periods of immunity. The results speak to an effective population immunity of about three months that, under the model, defers any second wave for approximately six months in most countries. This may have implications for the window of opportunity for tracking and tracing, as well as for developing vaccination programmes, and other therapeutic interventions.

Effective immunity and second waves: a dynamic causal modelling study

Two important theories in cognitive neuroscience are predictive coding and the global workspace theory. A key research task is to understand how these two theories relate to one another, and particularly, how the brain transitions from a predictive early state to the eventual engagement of a brain-scale state (the global workspace). To address this question, we present a source-localisation of EEG responses evoked by the local-global task – an experimental paradigm that engages a predictive hierarchy, which encompasses the global workspace. The results of our source reconstruction suggest three-phases of processing. The first phase involves the sensory (here auditory) regions of the superior temporal lobe and predicts sensory regularities over a short timeframe (as per the local effect). The third phase is brain-scale, involving inferior frontal, as well as inferior and superior parietal regions; consistent with a global neuronal workspace (as per the global effect). Crucially, our analysis suggests that there is an intermediate (second) phase, involving modulatory interactions between inferior frontal and superior temporal regions. Furthermore, sedation with propofol reduces modulatory interactions in the second phase. This selective effect is consistent with a predictive coding explanation of sedation, with propofol acting on descending predictions of the precision of prediction errors; thereby constraining access to the global neuronal workspace.

Sedation modulates fronto-temporal predictive coding circuits and the double surprise acceleration effect

Active inference offers a first principle account of sentient behavior, from which special and important cases—for example, reinforcement learning, active learning, Bayes optimal inference, Bayes optimal design—can be derived. Active inference finesses the exploitation-exploration dilemma in relation to prior preferences by placing information gain on the same footing as reward or value. In brief, active inference replaces value functions with functionals of (Bayesian) beliefs, in the form of an expected (variational) free energy. In this letter, we consider a sophisticated kind of active inference using a recursive form of expected free energy. Sophistication describes the degree to which an agent has beliefs about beliefs. We consider agents with beliefs about the counterfactual consequences of action for states of affairs and beliefs about those latent states. In other words, we move from simply considering beliefs about “what would happen if I did that” to “what I would believe about what would happen if I did that.” The recursive form of the free energy functional effectively implements a deep tree search over actions and outcomes in the future. Crucially, this search is over sequences of belief states as opposed to states per se. We illustrate the competence of this scheme using numerical simulations of deep decision problems.

Effective immunity and second waves: a dynamic causal modelling study.

The aim of this paper is twofold: (1) to assess whether the construct of neural representations plays an explanatory role under the variational free-energy principle and its corollary process theory, active inference; and (2) if so, to assess which philosophical stance—in relation to the ontological and epistemological status of representations—is most appropriate. We focus on non-realist (deflationary and fictionalist-instrumentalist) approaches. We consider a deflationary account of mental representation, according to which the explanatorily relevant contents of neural representations are mathematical, rather than cognitive, and a fictionalist or instrumentalist account, according to which representations are scientifically useful fictions that serve explanatory (and other) aims. After reviewing the free-energy principle and active inference, we argue that the model of adaptive phenotypes under the free-energy principle can be used to furnish a formal semantics, enabling us to assign semantic content to specific phenotypic states (the internal states of a Markovian system that exists far from equilibrium). We propose a modified fictionalist account—an organism-centered fictionalism or instrumentalism. We argue that, under the free-energy principle, pursuing even a deflationary account of the content of neural representations licenses the appeal to the kind of semantic content involved in the ‘aboutness’ or intentionality of cognitive systems; our position is thus coherent with, but rests on distinct assumptions from, the realist position. We argue that the free-energy principle thereby explains the aboutness or intentionality in living systems and hence their capacity to parse their sensory stream using an ontology or set of semantic factors.

Is the Free-Energy Principle a Formal Theory of Semantics? From Variational Density Dynamics to Neural and Phenotypic Representations

Active inference is a Bayesian framework for understanding biological intelligence. The underlying theory brings together perception and action under one single imperative: minimizing free energy. However, despite its theoretical utility in explaining intelligence, computational implementations have been restricted to low-dimensional and idealized situations. In this paper, we present a neural architecture for building deep active inference agents operating in complex, continuous state-spaces using multiple forms of Monte-Carlo (MC) sampling. For this, we introduce a number of techniques, novel to active inference. These include: i) selecting free-energy-optimal policies via MC tree search, ii) approximating this optimal policy distribution via a feed-forward `habitual' network, iii) predicting future parameter belief updates using MC dropouts and, finally, iv) optimizing state transition precision (a high-end form of attention). Our approach enables agents to learn environmental dynamics efficiently, while maintaining task performance, in relation to reward-based counterparts. We illustrate this in a new toy environment, based on the dSprites data-set, and demonstrate that active inference agents automatically create disentangled representations that are apt for modeling state transitions. In a more complex Animal-AI environment, our agents (using the same neural architecture) are able to simulate future state transitions and actions (i.e., plan), to evince reward-directed navigation - despite temporary suspension of visual input. These results show that deep active inference - equipped with MC methods - provides a flexible framework to develop biologically-inspired intelligent agents, with applications in both machine learning and cognitive science.

Comparing dynamic causal models of neurovascular coupling with fMRI and EEG/MEG

Controlled Optimism: Reply to Sun and Firestone on the Dark Room Problem

In contrast to the symmetries of translation in space, rotation in space, and translation in time, the known laws of physics are not universally invariant under transformation of scale. However, a special case exists in which the action is scale invariant if it satisfies the following two constraints: 1) it must depend upon a scale-free Lagrangian, and 2) the Lagrangian must change under scale in the same way as the inverse time, 1t. Our contribution lies in the derivation of a generalised Lagrangian, in the form of a power series expansion, that satisfies these constraints. This generalised Lagrangian furnishes a normal form for dynamic causal models–state space models based upon differential equations–that can be used to distinguish scale symmetry from scale freeness in empirical data. We establish face validity with an analysis of simulated data, in which we show how scale symmetry can be identified and how the associated conserved quantities can be estimated in neuronal time series.

Conservation laws by virtue of scale symmetries in neural systems

We introduce a unified objective for action and perception of intelligent agents. Extending representation learning and control, we minimize the joint divergence between the combined system of agent and environment and a target distribution. Intuitively, such agents use perception to align their beliefs with the world, and use actions to align the world with their beliefs. Minimizing the joint divergence to an expressive target maximizes the mutual information between the agent's representations and inputs, thus inferring representations that are informative of past inputs and exploring future inputs that are informative of the representations. This lets us explain intrinsic objectives, such as representation learning, information gain, empowerment, and skill discovery from minimal assumptions. Moreover, interpreting the target distribution as a latent variable model suggests powerful world models as a path toward highly adaptive agents that seek large niches in their environments, rendering task rewards optional. The framework provides a common language for comparing a wide range of objectives, advances the understanding of latent variables for decision making, and offers a recipe for designing novel objectives. We recommend deriving future agent objectives the joint divergence to facilitate comparison, to point out the agent's target distribution, and to identify the intrinsic objective terms needed to reach that distribution.

At the inception of human brain mapping, two principles of functional anatomy underwrote most conceptions—and analyses—of distributed brain responses: namely, functional segregation and integration. There are currently two main approaches to characterizing functional integration. The first is a mechanistic modeling of connectomics in terms of directed effective connectivity that mediates neuronal message passing and dynamics on neuronal circuits. The second phenomenological approach usually characterizes undirected functional connectivity (i.e., measurable correlations), in terms of intrinsic brain networks, self-organized criticality, dynamical instability, and so on. This paper describes a treatment of effective connectivity that speaks to the emergence of intrinsic brain networks and critical dynamics. It is predicated on the notion of Markov blankets that play a fundamental role in the self-organization of far from equilibrium systems. Using the apparatus of the renormalization group, we show that much of the phenomenology found in network neuroscience is an emergent property of a particular partition of neuronal states, over progressively coarser scales. As such, it offers a way of linking dynamics on directed graphs to the phenomenology of intrinsic brain networks.

The pandemic spread of the COVID-19 virus has, as of 20th of April 2020, reached most countries of the world. In an effort to design informed public health policies, many modelling studies have been performed to predict crucial outcomes of interest, including ICU solicitation, cumulated death counts, etc... The corresponding data analyses however, mostly rely on restricted (openly available) data sources, which typically include daily death rates and confirmed COVID cases time series. In addition, many of these predictions are derived before the peak of the outbreak has been observed yet (as is still currently the case for many countries). In this work, we show that peak phase and data paucity have a substantial impact on the reliability of model predictions. Although we focus on a recent model of the COVID pandemics, our conclusions most likely apply to most existing models, which are variants of the so-called 'Susceptible-Infected-Removed' or SIR framework. Our results highlight the need for performing systematic reliability evaluations for all models that currently inform public health policies. They also motivate a plea for gathering and opening richer and more reliable data time series (e.g., ICU occupancy, negative test rates, social distancing commitment reports, etc).

On the reliability of model-based predictions in the context of the current COVID epidemic event: impact of outbreak peak phase and data paucity

Active inference provides a biologically plausible process theory of brain function. It specifies neuronal dynamics for state-estimation in terms of a gradient descent on (variational) free energy -- a measure of the fit between an internal (generative) model and sensory observations. When formulated for discrete state-space generative models, the free energy gradient turns out to be a prediction error -- plausibly encoded in the average membrane potentials of neuronal populations. Conversely, the expected probability of a state can then be expressed in terms of firing rates. We establish a construct validity to this scheme -- by showing that it is consistent with current models of neuronal dynamics -- and face validity, as it is able to synthesize a wide range of biologically plausible electrophysiological responses. We then show that these neuronal dynamics approximate natural gradient descent, a well-known optimisation algorithm from information geometry that prescribes locally optimal belief updates. Lastly, numerical simulations suggest that both schemes perform equally well on average. The performance of belief updating is scored in terms of information length, a measure of the distance traveled in information space, which has a direct interpretation in terms of metabolic efficiency. These results show that active inference is consistent with state-of-the-art models of neuronal dynamics and coincides with the natural gradient. This suggests that natural selection, by selecting the phenotypes that optimise metabolic and computational efficiency, has implicitly approximated the steepest direction in information space; namely, natural gradient descent.

Significance How do we infer absence of emotion? As opposed to the brain mechanisms for recognizing emotions, this issue has remained underinvestigated. Present findings bond communication between the amygdala and insula with the ability to infer the absence of emotion in body language. Previously, both the amygdala and insula have been associated with emotion perception. The outcome of this study extends the conceptualization of these brain regions and their interplay to the processing of social signals without emotional content. This may have wide-ranging implications for better understanding neuropsychiatric conditions characterized by misinterpretation of neutral for emotional signals, such as depression or schizophrenia. The findings call for interdisciplinary research on how the brain infers the lack of emotional valence in social signals. Adaptive social behavior and mental well-being depend on not only recognizing emotional expressions but also, inferring the absence of emotion. While the neurobiology underwriting the perception of emotions is well studied, the mechanisms for detecting a lack of emotional content in social signals remain largely unknown. Here, using cutting-edge analyses of effective brain connectivity, we uncover the brain networks differentiating neutral and emotional body language. The data indicate greater activation of the right amygdala and midline cerebellar vermis to nonemotional as opposed to emotional body language. Most important, the effective connectivity between the amygdala and insula predicts people’s ability to recognize the absence of emotion. These conclusions extend substantially current concepts of emotion perception by suggesting engagement of limbic effective connectivity in recognizing the lack of emotion in body language reading. Furthermore, the outcome may advance the understanding of overly emotional interpretation of social signals in depression or schizophrenia by providing the missing link between body language reading and limbic pathways. The study thus opens an avenue for multidisciplinary research on social cognition and the underlying cerebrocerebellar networks, ranging from animal models to patients with neuropsychiatric conditions.

Brain circuits signaling the absence of emotion in body language

Abstract Gilead et al. raise some fascinating issues about representational substrates and structures in the predictive brain. This commentary drills down on a core theme in their arguments; namely, the structure of models that generate predictions. In particular, it highlights their factorial nature – both in terms of deep hierarchies over levels of abstraction and, crucially, time – and how this underwrites agency.

Recent reports using conventional Susceptible, Exposed, Infected and Removed models suggest that the next wave of the COVID-19 pandemic in the UK could overwhelm health services, with fatalities exceeding the first wave. We used Bayesian model comparison to revisit these conclusions, allowing for heterogeneity of exposure, susceptibility and transmission. We used dynamic causal modelling to estimate the evidence for alternative models of daily cases and deaths from the USA, the UK, Brazil, Italy, France, Spain, Mexico, Belgium, Germany and Canada over the period 25 January 2020 to 15 June 2020. These data were used to estimate the proportions of people (i) not exposed to the virus, (ii) not susceptible to infection when exposed and (iii) not infectious when susceptible to infection. Bayesian model comparison furnished overwhelming evidence for heterogeneity of exposure, susceptibility and transmission. Furthermore, both lockdown and the build-up of population immunity contributed to viral transmission in all but one country. Small variations in heterogeneity were sufficient to explain large differences in mortality rates. The best model of UK data predicts a second surge of fatalities will be much less than the first peak. The size of the second wave depends sensitively on the loss of immunity and the efficacy of Find-Test-Trace-Isolate-Support programmes. In summary, accounting for heterogeneity of exposure, susceptibility and transmission suggests that the next wave of the SARS-CoV-2 pandemic will be much smaller than conventional models predict, with less economic and health disruption. This heterogeneity means that seroprevalence underestimates effective herd immunity and, crucially, the potential of public health programmes.

As with the Spanish Flu a century ago, authorities have responded to the current COVID-19 pandemic with extraordinary public health measures. In particular, lockdown and related social distancing policies are motivated in some countries by the need to slow virus propagation down, so that the primary wave of patients suffering from severe forms of COVID infection do not exceed the capacity of intensive care units. But unlocking poses a critical issue because relaxing social distancing may, in principle, generate secondary waves. Ironically however, the dynamic repertoire of established epidemiological models that support this kind of reasoning is limited to single epidemic outbreaks. In turn, predictions regarding secondary waves are tautologically derived from imposing assumptions about changes in the so-called "effective reproduction number". In this work, we depart from this approach and extend the LIST (Location-Infection-Symptom-Testing) model of the COVID pandemic with realistic nonlinear feedback mechanisms that under certain conditions, cause lockdown-induced secondary outbreaks. The original LIST model captures adaptive social distancing, i.e. the transient reduction of the number of person-to-person contacts (and hence the rate of virus transmission), as a societal response to salient public health risks. Here, we consider the possibility that such pruning of socio-geographical networks may also temporarily isolate subsets of local populations from the virus. Crucially however, such unreachable people will become susceptible again when adaptive social distancing relaxes and the density of contacts within socio-geographical networks increases again. Taken together, adaptive social distancing and network unreachability thus close a nonlinear feedback loop that endows the LIST model with a mechanism that can generate autonomous (lockdown-induced) secondary waves. However, whether and how secondary waves arise depend upon the interaction with other nonlinear mechanisms that capture other forms of transmission heterogeneity. We apply the ensuing LIST model to numerical simulations and exhaustive analyses of regional French epidemiological data. In brief, we find evidence for this kind of nonlinear feedback mechanism in the empirical dynamics of the pandemic in France. However, rather than generating catastrophic secondary outbreaks (as is typically assumed), the model predicts that the impact of lockdown-induced variations in population susceptibility and transmission may eventually reduce to a steady-state endemic equilibrium with a low but stable infection rate.

Abstract Bridging the gap between symmetric, direct white matter brain connectivity and neural dynamics that are often asymmetric and polysynaptic may offer insights into brain architecture, but this remains an unresolved challenge in neuroscience. Here, we used the graph Laplacian matrix to simulate symmetric and asymmetric high-order diffusion processes akin to particles spreading through white matter pathways. The simulated indirect structural connectivity outperformed direct as well as absent anatomical information in sculpting effective connectivity, a measure of causal and directed brain dynamics. Crucially, an asymmetric diffusion process determined by the sensitivity of the network nodes to their afferents best predicted effective connectivity. The outcome is consistent with brain regions adapting to maintain their sensitivity to inputs within a dynamic range. Asymmetric network communication models offer a promising perspective for understanding the relationship between structural and functional brain connectomes, both in normalcy and neuropsychiatric conditions.

Asymmetric high-order anatomical brain connectivity sculpts effective connectivity

Abstract The notions of degeneracy and redundancy are important constructs in many areas, ranging from genomics through to network science. Degeneracy finds a powerful role in neuroscience, explaining key aspects of distributed processing and structure–function relationships in the brain. For example, degeneracy accounts for the superadditive effect of lesions on functional deficits in terms of a “many-to-one” structure–function mapping. In this paper, we offer a principled account of degeneracy and redundancy, when function is operationalized in terms of active inference, namely, a formulation of perception and action as belief updating under generative models of the world. In brief, “degeneracy” is quantified by the “entropy” of posterior beliefs about the causes of sensations, while “redundancy” is the “complexity” cost incurred by forming those beliefs. From this perspective, degeneracy and redundancy are complementary: Active inference tries to minimize redundancy while maintaining degeneracy. This formulation is substantiated using statistical and mathematical notions of degenerate mappings and statistical efficiency. We then illustrate changes in degeneracy and redundancy during the learning of a word repetition task. Finally, we characterize the effects of lesions—to intrinsic and extrinsic connections—using in silico disconnections. These numerical analyses highlight the fundamental difference between degeneracy and redundancy—and how they score distinct imperatives for perceptual inference and structure learning that are relevant to synthetic and biological intelligence.

By equipping a previously reported dynamic causal modelling of COVID-19 with an isolation state, we were able to model the effects of self-isolation consequent on testing and tracking. Specifically, we included a quarantine or isolation state occupied by people who believe they might be infected but are asymptomatic—and could only leave if they test negative. We recovered maximum posteriori estimates of the model parameters using time series of new cases, daily deaths, and tests for the UK. These parameters were used to simulate the trajectory of the outbreak in the UK over an 18-month period. Several clear-cut conclusions emerged from these simulations. For example, under plausible (graded) relaxations of social distancing, a rebound of infections is highly unlikely. The emergence of a second wave depends almost exclusively on the rate at which we lose immunity, inherited from the first wave. There exists no testing strategy that can attenuate mortality rates, other than by deferring or delaying a second wave. A testing and tracking policy—implemented at the present time—will defer any second wave beyond a time horizon of 18 months. Crucially, this deferment is within current testing capabilities (requiring an efficacy of tracing and tracking of about 20% of asymptomatic infected cases, with 50,000 tests per day). These conclusions are based upon a dynamic causal model for which we provide some construct and face validation—using a comparative analysis of the United Kingdom and Germany, supplemented with recent serological studies.

Testing and tracking in the UK: A dynamic causal modelling study

Abstract Paradoxical lesions are secondary brain lesions that ameliorate functional deficits caused by the initial insult. This effect has been explained in several ways; particularly by the reduction of functional inhibition, or by increases in the excitatory-to-inhibitory synaptic balance within perilesional tissue. In this article, we simulate how and when a modification of the excitatory–inhibitory balance triggers the reversal of a functional deficit caused by a primary lesion. For this, we introduce in-silico lesions to an active inference model of auditory word repetition. The first in-silico lesion simulated damage to the extrinsic (between regions) connectivity causing a functional deficit that did not fully resolve over 100 trials of a word repetition task. The second lesion was implemented in the intrinsic (within region) connectivity, compromising the model’s ability to rebalance excitatory–inhibitory connections during learning. We found that when the second lesion was mild, there was an increase in experience-dependent plasticity that enhanced performance relative to a single lesion. This paradoxical lesion effect disappeared when the second lesion was more severe because plasticity-related changes were disproportionately amplified in the intrinsic connectivity, relative to lesioned extrinsic connections. Finally, this framework was used to predict the physiological correlates of paradoxical lesions. This formal approach provides new insights into the computational and neurophysiological mechanisms that allow some patients to recover after large or multiple lesions.

This technical report describes a dynamic causal model of the spread of coronavirus through a population The model is based upon ensemble or population dynamics that generate outcomes, like new cases and deaths over time The purpose of this model is to quantify the uncertainty that attends predictions of relevant outcomes By assuming suitable conditional dependencies, one can model the effects of interventions (e g , social distancing) and differences among populations (e g , herd immunity) to predict what might happen in different circumstances Technically, this model leverages state-of-the-art variational (Bayesian) model inversion and comparison procedures, originally developed to characterise the responses of neuronal ensembles to perturbations Here, this modelling is applied to epidemiological populationsâ€”to illustrate the kind of inferences that are supported and how the model per se can be optimised given timeseries data Although the purpose of this paper is to describe a modelling protocol, the results illustrate some interesting perspectives on the current pandemic;for example, the nonlinear effects of herd immunity that speak to a self-organised mitigation process

Dynamic causal modelling of COVID-19 [version 1;peer review: awaiting peer review]

Previous studies have shown that physical exercise and mindfulness meditation can both lead to improvement in physical and mental health. However, it is unclear whether these two forms of training share the same underlying mechanisms. We compared two groups of older adults with 10 years of mindfulness meditation (integrative body-mind training, IBMT) or physical exercise (PE) experience to demonstrate their effects on brain, physiology and behavior. Healthy older adults were randomly selected from a large community health project and the groups were compared on measures of quality of life, autonomic activity (heart rate, heart rate variability, skin conductance response, respiratory amplitude/rate), immune function (secretory Immunoglobulin A, sIgA), stress hormone (cortisol) and brain imaging (resting state functional connectivity, structural differences). In comparison with PE, we found significantly higher ratings for the IBMT group on dimensions of life quality. Parasympathetic activity indexed by skin conductance response and high-frequency heart rate variability also showed more favorable outcomes in the IBMT group. However, the PE group showed lower basal heart rate and greater chest respiratory amplitude. Basal sIgA level was significantly higher and cortisol concentration was lower in the IBMT group. Lastly, the IBMT group had stronger brain connectivity between the dorsal anterior cingulate cortex (dACC) and the striatum at resting state, as well as greater volume of gray matter in the striatum. Our results indicate that mindfulness meditation and physical exercise function in part by different mechanisms, with PE increasing physical fitness and IBMT inducing plasticity in the central nervous systems. These findings suggest combining physical and mental training may achieve better health and quality of life results for an aging population.

Long-Term Physical Exercise and Mindfulness Practice in an Aging Population

Abstract Two important theories in cognitive neuroscience are predictive coding (PC) and the global workspace (GW) theory. A key research task is to understand how these two theories relate to one another, and particularly, how the brain transitions from a predictive early state to the eventual engagement of a brain-scale state (the GW). To address this question, we present a source-localization of EEG responses evoked by the local-global task—an experimental paradigm that engages a predictive hierarchy, which encompasses the GW. The results of our source reconstruction suggest three phases of processing. The first phase involves the sensory (here auditory) regions of the superior temporal lobe and predicts sensory regularities over a short timeframe (as per the local effect). The third phase is brain-scale, involving inferior frontal, as well as inferior and superior parietal regions, consistent with a global neuronal workspace (GNW; as per the global effect). Crucially, our analysis suggests that there is an intermediate (second) phase, involving modulatory interactions between inferior frontal and superior temporal regions. Furthermore, sedation with propofol reduces modulatory interactions in the second phase. This selective effect is consistent with a PC explanation of sedation, with propofol acting on descending predictions of the precision of prediction errors; thereby constraining access to the GNW.

Sedation Modulates Frontotemporal Predictive Coding Circuits and the Double Surprise Acceleration Effect

The principle of stationary action is a cornerstone of modern physics, providing a powerful framework for investigating dynamical systems found in classical mechanics through to quantum field theory. However, computational neuroscience, despite its heavy reliance on concepts in physics, is anomalous in this regard as its main equations of motion are not compatible with a Lagrangian formulation and hence with the principle of stationary action. Taking the Dynamic Causal Modelling neuronal state equation, Hodgkin-Huxley model, and the Leaky Integrate-and-Fire model as examples, we show that it is possible to write complex oscillatory forms of these equations in terms of a single Lagrangian. We therefore bring mathematical descriptions in computational neuroscience under the remit of the principle of stationary action and use this reformulation to express symmetries and associated conservation laws arising in neural systems.

This paper offers a prospectus of what might be achievable in the development of emotional recognition devices. It provides a conceptual overview of the free energy principle; including Markov blankets, active inference, and—in particular—a discussion of selfhood and theory of mind, followed by a brief explanation of how these concepts can explain both neural and cultural models of emotional inference. The underlying hypothesis is that emotion recognition and inference devices will evolve from state-of-the-art deep learning models into active inference schemes that go beyond marketing applications and become adjunct to psychiatric practice. Specifically, this paper proposes that a second wave of emotion recognition devices will be equipped with an emotional lexicon (or the ability to epistemically search for one), allowing the device to resolve uncertainty about emotional states by actively eliciting responses from the user and learning from these responses. Following this, a third wave of emotional devices will converge upon the user's generative model, resulting in the machine and human engaging in a reciprocal, prosocial emotional interaction, i.e., sharing a generative model of emotional states.

An Investigation of the Free Energy Principle for Emotion Recognition

The segregation of neural processing into distinct streams has been interpreted by some as evidence in favour of a modular view of brain function. This implies a set of specialised ‘modules’, each of which performs a specific kind of computation in isolation of other brain systems, before sharing the result of this operation with other modules. In light of a modern understanding of stochastic non-equilibrium systems, like the brain, a simpler and more parsimonious explanation presents itself. Formulating the evolution of a non-equilibrium steady state system in terms of its density dynamics reveals that such systems appear on average to perform a gradient ascent on their steady state density. If this steady state implies a sufficiently sparse conditional independency structure, this endorses a mean-field dynamical formulation. This decomposes the density over all states in a system into the product of marginal probabilities for those states. This factorisation lends the system a modular appearance, in the sense that we can interpret the dynamics of each factor independently. However, the argument here is that it is factorisation, as opposed to modularisation, that gives rise to the functional anatomy of the brain or, indeed, any sentient system. In the following, we briefly overview mean-field theory and its applications to stochastic dynamical systems. We then unpack the consequences of this factorisation through simple numerical simulations and highlight the implications for neuronal message passing and the computational architecture of sentience.

Review for "Predictive processing: is the future just a memory?"

Dynamics versus dualism: Comment on "Is temporo-spatial dynamics the 'common currency' of brain and mind?" by Georg Northoff et al.

The neurophysiological architecture of semantic dementia: spectral dynamic causal modelling of a neurodegenerative proteinopathy

Abstract The target article “Thinking Through Other Minds” (TTOM) offered an account of the distinctively human capacity to acquire cultural knowledge, norms, and practices. To this end, we leveraged recent ideas from theoretical neurobiology to understand the human mind in social and cultural contexts. Our aim was both synthetic – building an integrative model adequate to account for key features of cultural learning and adaptation; and prescriptive – showing how the tools developed to explain brain dynamics can be applied to the emergence of social and cultural ecologies of mind. In this reply to commentators, we address key issues, including: (1) refining the concept of culture to show how TTOM and the free-energy principle (FEP) can capture essential elements of human adaptation and functioning; (2) addressing cognition as an embodied, enactive, affective process involving cultural affordances; (3) clarifying the significance of the FEP formalism related to entropy minimization, Bayesian inference, Markov blankets, and enactivist views; (4) developing empirical tests and applications of the TTOM model; (5) incorporating cultural diversity and context at the level of intra-cultural variation, individual differences, and the transition to digital niches; and (6) considering some implications for psychiatry. The commentators’ critiques and suggestions point to useful refinements and applications of the model. In ongoing collaborations, we are exploring how to augment the theory with affective valence, take into account individual differences and historicity, and apply the model to specific domains including epistemic bias.

TTOM in action: Refining the variational approach to cognition and culture

The theme of this special issue of the Journal of Abnormal Psychology is on predictive processing and how it can improve our fundamental understanding of neuropsychiatric disorders. Several articles focus on psychosis and demonstrate how the field of computational psychosis research has evolved and matured in recent years through the application of predictive processing theory. These articles suggest that whereas the computational mechanisms underlying psychosis may be complex, careful empirical and theoretical work-using more sophisticated models-can bridge gaps between previous results that appeared to be at odds while providing more explanatory power. There is a particular focus on processing hierarchies; defining which priors are maladaptive and at what stage of illness they become so; and finding compelling neurobiological correlates of computational processes. These articles provide a blueprint for future empirical work. This work-that is licensed theoretically by predictive processing-may improve our understanding of psychosis and its treatment and open new avenues for biomarker and therapeutic development. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

All grown up: Computational theories of psychosis, complexity, and progress.

This essay addresses Cartesian duality and how its implicit dialectic might be repaired using physics and information theory. Our agenda is to describe a key distinction in the physical sciences that may provide a foundation for the distinction between mind and matter, and between sentient and intentional systems. From this perspective, it becomes tenable to talk about the physics of sentience and ‘forces’ that underwrite our beliefs (in the sense of probability distributions represented by our internal states), which may ground our mental states and consciousness. We will refer to this view as Markovian monism, which entails two claims: (1) fundamentally, there is only one type of thing and only one type of irreducible property (hence monism). (2) All systems possessing a Markov blanket have properties that are relevant for understanding the mind and consciousness: if such systems have mental properties, then they have them partly by virtue of possessing a Markov blanket (hence Markovian). Markovian monism rests upon the information geometry of random dynamic systems. In brief, the information geometry induced in any system—whose internal states can be distinguished from external states—must acquire a dual aspect. This dual aspect concerns the (intrinsic) information geometry of the probabilistic evolution of internal states and a separate (extrinsic) information geometry of probabilistic beliefs about external states that are parameterised by internal states. We call these intrinsic (i.e., mechanical, or state-based) and extrinsic (i.e., Markovian, or belief-based) information geometries, respectively. Although these mathematical notions may sound complicated, they are fairly straightforward to handle, and may offer a means through which to frame the origins of consciousness.

Sentience and the Origins of Consciousness: From Cartesian Duality to Markovian Monism

Morphogenesis as Bayesian inference: A variational approach to pattern formation and control in complex biological systems.

The perceptual experience of architecture is enacted by the sensory and motor system. When we act, we change the perceived environment according to a set of expectations that depend on our body and the built environment. The continuous process of collecting sensory information is thus based on bodily affordances. Affordances characterize the fit between the physical structure of the body and capacities for movement in the built environment. Since little has been done regarding the role of architectural design in the emergence of perceptual experience on a neuronal level, this paper offers a first step towards the role of architectural design in perceptual experience. An approach to synthesize concepts from computational neuroscience with architectural phenomenology into a computational neurophenomenology is considered. The outcome is a framework under which studies of architecture and cognitive neuroscience can be cast.

Anticipation in architectural experience: a computational neurophenomenology for architecture?

Abstract Timing emerges from a hierarchy of computations ranging from early encoding of physical duration (time sensation) to abstract time representations (time perception) suitable for storage and decisional processes. However, the neural basis of the perceptual experience of time remains elusive. To address this, we dissociate brain activity uniquely related to lower-level sensory and higher-order perceptual timing operations, using event-related fMRI. Participants compared subsecond (500 msec) sinusoidal gratings drifting with constant velocity (standard) against two probe stimuli: (1) control gratings drifting at constant velocity or (2) accelerating gratings, which induced illusory shortening of time. We tested two probe intervals: a 500-msec duration (Short) and a longer duration required for an accelerating probe to be perceived as long as the standard (Long—individually determined). On each trial, participants classified the probe as shorter or longer than the standard. This allowed for comparison of trials with an “Objective” (physical) or “Subjective” (perceived) difference in duration, based on participant classifications. Objective duration revealed responses in bilateral early extrastriate areas, extending to higher visual areas in the fusiform gyrus (at more lenient thresholds). By contrast, Subjective duration was reflected by distributed responses in a cortical/subcortical areas. This comprised the left superior frontal gyrus and the left cerebellum, and a wider set of common timing areas including the BG, parietal cortex, and posterior cingulate cortex. These results suggest two functionally independent timing stages: early extraction of duration information in sensory cortices and Subjective experience of duration in a higher-order cortical–subcortical timing areas.

We formalize the Gaia hypothesis about the Earth climate system using advances in theoretical biology based on the minimization of variational free energy. This amounts to the claim that non-equilibrium steady-state dynamics—that underwrite our climate—depend on the Earth system possessing a Markov blanket. Our formalization rests on how the metabolic rates of the biosphere (understood as Markov blanket's internal states) change with respect to solar radiation at the Earth's surface (i.e. external states), through the changes in greenhouse and albedo effects (i.e. active states) and ocean-driven global temperature changes (i.e. sensory states). Describing the interaction between the metabolic rates and solar radiation as climatic states—in a Markov blanket—amounts to describing the dynamics of the internal states as actively inferring external states. This underwrites climatic non-equilibrium steady-state through free energy minimization and thus a form of planetary autopoiesis.

Future climates: Markov blankets and active inference in the biosphere

This study highlights the importance of looking beyond the main effect of movement to study alterations in functional response in the presence of central nervous system pathologies such as multiple sclerosis (MS). Data show that MS selectively affects regional BOLD (Blood Oxygenation Level Dependent) responses to variable grip forces (GF). It is known that the anterior and posterior BA 4 areas (BA 4a and BA 4p) are anatomically and functionally distinct. It has also been shown in Healthy volunteers that there are linear (1st order, typical of BA 4a) and non-linear (2nd-4th order, typical of BA 4p) BOLD responses to different levels of GF applied during a dynamic motor paradigm. After modelling the BOLD response with a polynomial expansion of the applied GFs, the particular case of BA 4a and BA 4p were investigated in Healthy Volunteers (HV) and MS subjects. The main effect of movement (0th order) analysis showed that the BOLD signal is greater in MS compared to healthy volunteers within both BA 4 sub-regions. At higher order, BOLD-GF responses were similar in BA 4a but showed a marked alteration in BA 4p of MS subjects, with those with greatest disability showing the greatest deviations from the healthy response profile. Therefore, the different behaviour in HV and MS could only be uncovered through a polynomial analysis looking beyond the main effect of movement into the two BA 4 sub-regions. Future studies will investigate the source of this pathophysiology, combining the present fMRI paradigm with blood perfusion and non-linear neuronal response analysis.

BOLD response to multiple grip forces in MS: going beyond the main effect of movement in BA 4a and BA 4p

Integrating variational approaches to pattern formation into a deeper physics: Reply to comments on "Morphogenesis as Bayesian inference: A variational approach to pattern formation and manipulation in complex biological systems".

Cognitive niche construction is the process whereby organisms create and maintain cause–effect models of their niche as guides for fitness influencing behavior. Extended mind theory claims that cognitive processes extend beyond the brain to include predictable states of the world. Active inference and predictive processing in cognitive science assume that organisms embody predictive (i.e., generative) models of the world optimized by standard cognitive functions (e.g., perception, action, learning). This paper presents an active inference formulation that views cognitive niche construction as a cognitive function aimed at optimizing organisms' generative models. We call that process of optimization extended active inference.

Extended active inference: Constructing predictive cognition beyond skulls

Objective This article offers a philosophical thesis for psychiatric disorders that rests upon some simple truths about the mind and brain. Specifically, it asks whether the dual aspect monism—that emerges from sleep research and theoretical neurobiology—can be applied to pathophysiology and psychopathology in psychiatry. Methods Our starting point is that the mind and brain are emergent aspects of the same (neuronal) dynamics; namely, the brain–mind. Our endpoint is that synaptic dysconnection syndromes inherit the same dual aspect; namely, aberrant inference or belief updating on the one hand, and a failure of neuromodulatory synaptic gain control on the other. We start with some basic considerations from sleep research that integrate the phenomenology of dreaming with the neurophysiology of sleep. Results We then leverage this treatment by treating the brain as an organ of inference. Our particular focus is on the role of precision (i.e., the representation of uncertainty) in belief updating and the accompanying synaptic mechanisms. Conclusions Finally, we suggest a dual aspect approach—based upon belief updating (i.e., mind processes) and its neurophysiological implementation (i.e., brain processes)—has a wide explanatory compass for psychiatry and various movement disorders. This approach identifies the kind of pathophysiology that underwrites psychopathology—and points to certain psychotherapeutic and psychopharmacological targets, which may stand in mechanistic relation to each other.

Background Recent reports based on conventional SEIR models suggest that the next wave of the COVID-19 pandemic in the UK could overwhelm health services, with fatalities that far exceed the first wave. These models suggest non-pharmaceutical interventions would have limited impact without intermittent national lockdowns and consequent economic and health impacts. We used Bayesian model comparison to revisit these conclusions, when allowing for heterogeneity of exposure, susceptibility, and viral transmission. Methods We used dynamic causal modelling to estimate the parameters of epidemiological models and, crucially, the evidence for alternative models of the same data. We compared SEIR models of immune status that were equipped with latent factors generating data; namely, location, symptom, and testing status. We analysed daily cases and deaths from the US, UK, Brazil, Italy, France, Spain, Mexico, Belgium, Germany, and Canada over the period 25-Jan-20 to 15-Jun-20. These data were used to estimate the composition of each country's population in terms of the proportions of people (i) not exposed to the virus, (ii) not susceptible to infection when exposed, and (iii) not infectious when susceptible to infection. Findings Bayesian model comparison found overwhelming evidence for heterogeneity of exposure, susceptibility, and transmission. Furthermore, both lockdown and the build-up of population immunity contributed to viral transmission in all but one country. Small variations in heterogeneity were sufficient to explain the large differences in mortality rates across countries. The best model of UK data predicts a second surge of fatalities will be much less than the first peak (31 vs. 998 deaths per day. 95% CI: 24-37)--substantially less than conventional model predictions. The size of the second wave depends sensitively upon the loss of immunity and the efficacy of find-test-trace-isolate-support (FTTIS) programmes. Interpretation A dynamic causal model that incorporates heterogeneity of exposure, susceptibility and transmission suggests that the next wave of the SARS-CoV-2 pandemic will be much smaller than conventional models predict, with less economic and health disruption. This heterogeneity means that seroprevalence underestimates effective herd immunity and, crucially, the potential of public health programmes.

Governments across Europe are preparing for the emergence from lockdown, in phases, to prevent a resurgence in cases of COVID-19. Along with social distancing (SD) measures, contact tracing comprising find, track, trace and isolate (FTTI) policies are also being implemented. Here, we investigate FTTI policies in terms of their impact on the endemic equilibrium. We used a generative model, the dynamic causal 'Location', 'Infection', 'Symptom' and 'Testing' (LIST) model to identify testing, tracing, and quarantine requirements. We optimised LIST model parameters based on time series of daily reported cases and deaths of COVID-19 in England and based upon reported cases in the nine regions of England and in all 150 upper tier local authorities. Using these optimised parameters, we forecasted infection rates and the impact of FTTI for each area; national, regional, and local. Predicting data from early June 2020, we find that under conditions of medium-term immunity, a '40%' FTTI policy (or greater), could reach a distinct endemic equilibrium that produces a significantly lower death rate and a decrease in ICU occupancy. Considering regions of England in isolation, some regions could substantially reduce death rates with 20% efficacy. We characterise the accompanying endemic equilibria in terms of dynamical stability, observing bifurcation patterns whereby relatively small increases in FTTI efficacy result in stable states with reduced overall morbidity and mortality. These analyses suggest that FTTI will not only save lives, even if only partially effective, and could underwrite the stability of any endemic steady-state we manage to attain.

Using the LIST model to Estimate the Effects of Contact Tracing on COVID-19 Endemic Equilibria in England and its Regions

Understanding the aetiology of the diverse recovery patterns in bilingual aphasia is a theoretical challenge with implications for treatment. Loss of control over intact language networks provides a parsimonious starting point that can be tested using in-silico lesions. We simulated a complex recovery pattern (alternate antagonism and paradoxical translation) to test the hypothesis—from an established hierarchical control model—that loss of control was mediated by constraints on neuromodulatory resources. We used active (Bayesian) inference to simulate a selective loss of sensory precision; i.e., confidence in the causes of sensations. This in-silico lesion altered the precision of beliefs about task relevant states, including appropriate actions, and reproduced exactly the recovery pattern of interest. As sensory precision has been linked to acetylcholine release, these simulations endorse the conjecture that loss of neuromodulatory control can explain this atypical recovery pattern. We discuss the relevance of this finding for other recovery patterns.

Neuromodulatory Control and Language Recovery in Bilingual Aphasia: An Active Inference Approach

This technical report describes a dynamic causal model of the spread of coronavirus through a population. The model is based upon ensemble or population dynamics that generate outcomes, like new cases and deaths over time. The purpose of this model is to quantify the uncertainty that attends predictions of relevant outcomes. By assuming suitable conditional dependencies, one can model the effects of interventions (e.g., social distancing) and differences among populations (e.g., herd immunity) to predict what might happen in different circumstances. Technically, this model leverages state-of-the-art variational (Bayesian) model inversion and comparison procedures, originally developed to characterise the responses of neuronal ensembles to perturbations. Here, this modelling is applied to epidemiological populations—to illustrate the kind of inferences that are supported and how the model per se can be optimised given timeseries data. Although the purpose of this paper is to describe a modelling protocol, the results illustrate some interesting perspectives on the current pandemic; for example, the nonlinear effects of herd immunity that speak to a self-organised mitigation process.

This technical report describes the rationale and technical details for the dynamic causal modelling of mitigated epidemiological outcomes based upon a variety of timeseries data. It details the structure of the underlying convolution or generative model (at the time of writing on 6-Nov-20). This report is intended for use as a reference that accompanies the predictions in following dashboard: https://www.fil.ion.ucl.ac.uk/spm/covid-19/dashboard

By equipping a previously reported dynamic causal model of COVID-19 with an isolation state, we modelled the effects of self-isolation consequent on tracking and tracing. Specifically, we included a quarantine or isolation state occupied by people who believe they might be infected but are asymptomatic, and only leave if they test negative. We recovered maximum posteriori estimates of the model parameters using time series of new cases, daily deaths, and tests for the UK. These parameters were used to simulate the trajectory of the outbreak in the UK over an 18-month period. Several clear-cut conclusions emerged from these simulations. For example, under plausible (graded) relaxations of social distancing, a rebound of infections within weeks is unlikely. The emergence of a later second wave depends almost exclusively on the rate at which we lose immunity, inherited from the first wave. There exists no testing strategy that can attenuate mortality rates, other than by deferring or delaying a second wave. A sufficiently powerful tracking and tracing policy--implemented at the time of writing (10th May 2020)--will defer any second wave beyond a time horizon of 18 months. Crucially, this deferment is within current testing capabilities (requiring an efficacy of tracing and tracking of about 20% of asymptomatic infected cases, with less than 50,000 tests per day). These conclusions are based upon a dynamic causal model for which we provide some construct and face validation, using a comparative analysis of the United Kingdom and Germany, supplemented with recent serological studies.

Tracking and tracing in the UK: a dynamic causal modelling study

This technical report describes a dynamic causal model of the spread of coronavirus through a population. The model is based upon ensemble or population dynamics that generate outcomes, like new cases and deaths over time. The purpose of this model is to quantify the uncertainty that attends predictions of relevant outcomes. By assuming suitable conditional dependencies, one can model the effects of interventions (e.g., social distancing) and differences among populations (e.g., herd immunity) to predict what might happen in different circumstances. Technically, this model leverages state-of-theart variational (Bayesian) model inversion and comparison procedures, originally developed to characterise the responses of neuronal ensembles to perturbations. Here, this modelling is applied to epidemiological populations—to illustrate the kind of inferences that are supported and how the model per se can be optimised given timeseries data. Although the purpose of this paper is to describe a modelling protocol, the results illustrate some interesting perspectives on the current pandemic; for example, the nonlinear effects of herd immunity that speak to a self-organised mitigation process.

Dynamic causal modelling of COVID-19 [ version 2 ; peer review : 2 approved ]

This technical report describes a dynamic causal model of the spread of coronavirus through a population. The model is based upon ensemble or population dynamics that generate outcomes, like new cases and deaths over time. The purpose of this model is to quantify the uncertainty that attends predictions of relevant outcomes. By assuming suitable conditional dependencies, one can model the effects of interventions (e.g., social distancing) and differences among populations (e.g., herd immunity) to predict what might happen in different circumstances. Technically, this model leverages state-of-the-art variational (Bayesian) model inversion and comparison procedures, originally developed to characterise the responses of neuronal ensembles to perturbations. Here, this modelling is applied to epidemiological populations-to illustrate the kind of inferences that are supported and how the model per se can be optimised given timeseries data. Although the purpose of this paper is to describe a modelling protocol, the results illustrate some interesting perspectives on the current pandemic; for example, the nonlinear effects of herd immunity that speak to a self-organised mitigation process.

This technical note introduces parametric dynamic causal modelling, a method for inferring slow changes in biophysical parameters that control fluctuations of fast neuronal states. The application domain we have in mind is inferring slow changes in variables (e.g., extracellular ion concentrations or synaptic efficacy) that underlie phase transitions in brain activity (e.g., paroxysmal seizure activity). The scheme is efficient and yet retains a biophysical interpretation, in virtue of being based on established neural mass models that are equipped with a slow dynamic on the parameters (such as synaptic rate constants or effective connectivity). In brief, we use an adiabatic approximation to summarise fast fluctuations in hidden neuronal states (and their expression in sensors) in terms of their second order statistics; namely, their complex cross spectra. This allows one to specify and compare models of slowly changing parameters (using Bayesian model reduction) that generate a sequence of empirical cross spectra of electrophysiological recordings. Crucially, we use the slow fluctuations in the spectral power of neuronal activity as empirical priors on changes in synaptic parameters. This introduces a circular causality, in which synaptic parameters underwrite fast neuronal activity that, in turn, induces activity-dependent plasticity in synaptic parameters. In this foundational paper, we describe the underlying model, establish its face validity using simulations and provide an illustrative application to a chemoconvulsant animal model of seizure activity.

A growing body of evidence highlights the intricate linkage of exteroceptive perception to the rhythmic activity of the visceral body. In parallel, interoceptive inference theories of emotion and self-consciousness are on the rise in cognitive science. However, thus far no formal theory has emerged to integrate these twin domains; instead most extant work is conceptual in nature. Here, we introduce a formal model of cardiac active inference, which explains how ascending cardiac signals entrain exteroceptive sensory perception and confidence. Through simulated psychophysics, we reproduce the defensive startle reflex and commonly reported effects linking the cardiac cycle to fear perception. We further show that simulated ‘interoceptive lesions’ blunt fear expectations, induce psychosomatic hallucinations, and exacerbate metacognitive biases. Through synthetic heart-rate variability analyses, we illustrate how the balance of arousal-priors and visceral prediction errors produces idiosyncratic patterns of physiological reactivity. Our model thus offers the possibility to computationally phenotype disordered brain-body interaction.

In the Body’s Eye: The computational anatomy of interoceptive inference

Knowing how another’s preferences relate to our own is a central aspect of everyday decision-making, yet how the brain performs this transformation is unclear. Here, we ask whether the putative role of the hippocampal–entorhinal system in transforming relative and absolute spatial coordinates during navigation extends to transformations in abstract decision spaces. During functional magnetic resonance imaging (fMRI), subjects learned a stranger’s preference for an everyday activity—relative to one of three personally known individuals—and subsequently decided how the stranger's preference relates to the other two individuals’ preferences. We observed entorhinal/subicular responses to the absolute distance between the ratings of the stranger and the familiar choice options. Notably, entorhinal/subicular signals were sensitive to which familiar individuals were being compared to the stranger. In contrast, striatal signals increased when accurately determining the ordinal position of choice options in relation to the stranger. Paralleling its role in navigation, these data implicate the entorhinal/subicular region in assimilating relatively coded knowledge within abstract metric spaces.

Over the last 30 years, representationalist and dynamicist positions in the philosophy of cognitive science have argued over whether neurocognitive processes should be viewed as representational or not. Major scientific and technological developments over the years have furnished both parties with ever more sophisticated conceptual weaponry. In recent years, an enactive generalization of predictive processing – known as active inference – has been proposed as a unifying theory of brain functions. Since then, active inference has fueled both representationalist and dynamicist campaigns. However, we believe that when diving into the formal details of active inference, one should be able to find a solution to the war; if not a peace treaty, surely an armistice of a sort. Based on an analysis of these formal details, this paper shows how both representationalist and dynamicist sensibilities can peacefully coexist within the new territory of active inference.

Representation Wars: Enacting an Armistice Through Active Inference

Identifying a coupled dynamical system out of many plausible candidates, each of which could serve as the underlying generator of some observed measurements, is a profoundly ill-posed problem that commonly arises when modelling real-world phenomena. In this review, we detail a set of statistical procedures for inferring the structure of nonlinear coupled dynamical systems (structure learning), which has proved useful in neuroscience research. A key focus here is the comparison of competing models of network architectures—and implicit coupling functions—in terms of their Bayesian model evidence. These methods are collectively referred to as dynamic causal modelling. We focus on a relatively new approach that is proving remarkably useful, namely Bayesian model reduction, which enables rapid evaluation and comparison of models that differ in their network architecture. We illustrate the usefulness of these techniques through modelling neurovascular coupling (cellular pathways linking neuronal and vascular systems), whose function is an active focus of research in neurobiology and the imaging of coupled neuronal systems. This article is part of the theme issue ‘Coupling functions: dynamical interaction mechanisms in the physical, biological and social sciences'.

Structure learning in coupled dynamical systems and dynamic causal modelling

COGNITIVE EFFORT MODULATES FRONTAL EFFECTIVE CONNECTIONS: A DYNAMIC CAUSAL MODELING STUDY ON MACAQUE MONKEYS

To what extent is predictive processing enactivist? This overview of predictive processing and active inference offers an account of embodied exchange with the world that associates neuronal processing with inferring the causes of our sensations. Crucially, one of the most important causes of the sensorium is our own behaviour, which—perhaps counterintuitively—has to be inferred. The agenda—in active inference—is to link formal (mathematical) descriptions of dynamical systems to a description of active perception in terms of beliefs and goals. In short, it tries to understand why and how we gather evidence for our own existence. There are several approaches to this sort of formulation. This chapter compares and contrasts a Helmholtzian or Kantian (bottom-up) approach—via perception—with the sort of (top-down) approaches offered by the statistical physics of self-organisation in sentient systems.

Using resting-state DMN effective connectivity to characterize the neurofunctional architecture of empathy

The positive-negative axis of emotional valence has long been recognized as fundamental to adaptive behavior, but its origin and underlying function have largely eluded formal theorizing and computational modeling. Using deep active inference, a hierarchical inference scheme that rests on inverting a model of how sensory data are generated, we develop a principled Bayesian model of emotional valence. This formulation asserts that agents infer their valence state based on the expected precision of their action model—an internal estimate of overall model fitness (“subjective fitness”). This index of subjective fitness can be estimated within any environment and exploits the domain generality of second-order beliefs (beliefs about beliefs). We show how maintaining internal valence representations allows the ensuing affective agent to optimize confidence in action selection preemptively. Valence representations can in turn be optimized by leveraging the (Bayes-optimal) updating term for subjective fitness, which we label affective charge (AC). AC tracks changes in fitness estimates and lends a sign to otherwise unsigned divergences between predictions and outcomes. We simulate the resulting affective inference by subjecting an in silico affective agent to a T-maze paradigm requiring context learning, followed by context reversal. This formulation of affective inference offers a principled account of the link between affect, (mental) action, and implicit metacognition. It characterizes how a deep biological system can infer its affective state and reduce uncertainty about such inferences through internal action (i.e., top-down modulation of priors that underwrite confidence). Thus, we demonstrate the potential of active inference to provide a formal and computationally tractable account of affect. Our demonstration of the face validity and potential utility of this formulation represents the first step within a larger research program. Next, this model can be leveraged to test the hypothesized role of valence by fitting the model to behavioral and neuronal responses.

Deeply Felt Affect: The Emergence of Valence in Deep Active Inference

This paper characterizes impulsive behavior using a patch-leaving paradigm and active inference—a framework for describing Bayes optimal behavior. This paradigm comprises different environments (patches) with limited resources that decline over time at different rates. The challenge is to decide when to leave the current patch for another to maximize reward. We chose this task because it offers an operational characterization of impulsive behavior, namely, maximizing proximal reward at the expense of future gain. We use a Markov decision process formulation of active inference to simulate behavioral and electrophysiological responses under different models and prior beliefs. Our main finding is that there are at least three distinct causes of impulsive behavior, which we demonstrate by manipulating three different components of the Markov decision process model. These components comprise (i) the depth of planning, (ii) the capacity to maintain and process information, and (iii) the perceived value of immediate (relative to delayed) rewards. We show how these manipulations change beliefs and subsequent choices through variational message passing. Furthermore, we appeal to the process theories associated with this message passing to simulate neuronal correlates. In future work, we will use this scheme to identify the prior beliefs that underlie different sorts of impulsive behavior—and ask whether different causes of impulsivity can be inferred from the electrophysiological correlates of choice behavior.

Somatosensory input generated by one's actions (i.e., self-initiated body movements) is generally attenuated. Conversely, externally caused somatosensory input is enhanced, for example, during active touch and the haptic exploration of objects. Here, we used functional magnetic resonance imaging (fMRI) to ask how the brain accomplishes this delicate weighting of self-generated versus externally caused somatosensory components. Finger movements were either self-generated by our participants or induced by functional electrical stimulation (FES) of the same muscles. During half of the trials, electrotactile impulses were administered when the (actively or passively) moving finger reached a predefined flexion threshold. fMRI revealed an interaction effect in the contralateral posterior insular cortex (pIC), which responded more strongly to touch during self-generated than during FES-induced movements. A network analysis via dynamic causal modeling revealed that connectivity from the secondary somatosensory cortex via the pIC to the supplementary motor area was generally attenuated during self-generated relative to FES-induced movements-yet specifically enhanced by touch received during self-generated, but not FES-induced movements. Together, these results suggest a crucial role of the parietal operculum and the posterior insula in differentiating self-generated from externally caused somatosensory information received from one's moving limb.

Action-Dependent Processing of Touch in the Human Parietal Operculum and Posterior Insula.

The moment‐to‐moment focus of our mind's eye results from a complex interplay of voluntary and involuntary influences on attention. Previous neuroimaging studies suggest that the brain networks of voluntary versus involuntary attention can be segregated into a frontal‐versus‐parietal or a dorsal‐versus‐ventral partition—although recent work suggests that the dorsal network may be involved in both bottom‐up and top‐down attention. Research with nonhuman primates has provided evidence that a key distinction between top‐down and bottom‐up attention may be the direction of connectivity between frontal and parietal areas. Whereas typical fMRI connectivity analyses cannot disambiguate the direction of connections, dynamic causal modeling (DCM) can model directionality. Using DCM, we provide new evidence that directed connections within the dorsal attention network are differentially modulated for voluntary versus involuntary attention. These results suggest that the intraparietal sulcus exerts a baseline inhibitory effect on the frontal eye fields that is strengthened during exogenous orienting and attenuated during endogenous orienting. Furthermore, the attenuation from endogenous attention occurs even with salient peripheral cues when those cues are known to be counter predictive. Thus, directed connectivity between frontal and parietal regions of the dorsal attention network is highly influenced by the type of attention that is engaged.

Top‐down versus bottom‐up attention differentially modulate frontal–parietal connectivity

This technical note presents a framework for investigating the underlying mechanisms of neurovascular coupling in the human brain using multi-modal magnetoencephalography (MEG) and functional magnetic resonance (fMRI) neuroimaging data. This amounts to estimating the evidence for several biologically informed models of neurovascular coupling using variational Bayesian methods and selecting the most plausible explanation using Bayesian model comparison. First, fMRI data is used to localise active neuronal sources. The coordinates of neuronal sources are then used as priors in the specification of a DCM for MEG, in order to estimate the underlying generators of the electrophysiological responses. The ensuing estimates of neuronal parameters are used to generate neuronal drive functions, which model the pre or post synaptic responses to each experimental condition in the fMRI paradigm. These functions form the input to a model of neurovascular coupling, the parameters of which are estimated from the fMRI data. This establishes a Bayesian fusion technique that characterises the BOLD response - asking, for example, whether instantaneous or delayed pre or post synaptic signals mediate haemodynamic responses. Bayesian model comparison is used to identify the most plausible hypotheses about the causes of the multimodal data. We illustrate this procedure by comparing a set of models of a single-subject auditory fMRI and MEG dataset. Our exemplar analysis suggests that the origin of the BOLD signal is mediated instantaneously by intrinsic neuronal dynamics and that neurovascular coupling mechanisms are region-specific. The code and example dataset associated with this technical note are available through the statistical parametric mapping (SPM) software package.

Neurovascular coupling: insights from multi-modal dynamic causal modelling of fMRI and MEG

A guide to group effective connectivity analysis, part 1: First level analysis with DCM for fMRI

Abstract Perceptual awareness depends upon the way in which we engage with our sensorium. This notion is central to active inference, a theoretical framework that treats perception and action as inferential processes. This variational perspective on cognition formalizes the notion of perception as hypothesis testing and treats actions as experiments that are designed (in part) to gather evidence for or against alternative hypotheses. The common treatment of perception and action affords a useful interpretation of certain perceptual phenomena whose active component is often not acknowledged. In this article, we start by considering Troxler fading – the dissipation of a peripheral percept during maintenance of fixation, and its recovery during free (saccadic) exploration. This offers an important example of the failure to maintain a percept without actively interrogating a visual scene. We argue that this may be understood in terms of the accumulation of uncertainty about a hypothesized stimulus when free exploration is disrupted by experimental instructions or pathology. Once we take this view, we can generalize the idea of using bodily (oculomotor) action to resolve uncertainty to include the use of mental (attentional) actions for the same purpose. This affords a useful way to think about binocular rivalry paradigms, in which perceptual changes need not be associated with an overt movement.

Recent theoretical work in developmental psychology suggests that humans are predisposed to align their mental states with those of other individuals. One way this manifests is in cooperative communication; that is, intentional communication aimed at aligning individuals’ mental states with respect to events in their shared environment. This idea has received strong empirical support. The purpose of this paper is to extend this account by proposing an integrative model of the biobehavioral dynamics of cooperative communication. Our formulation is based on active inference. Active inference suggests that action-perception cycles operate to minimize uncertainty and optimize an individual’s internal model of the world. We propose that humans are characterized by an evolved adaptive prior belief that their mental states are aligned with, or similar to, those of conspecifics (i.e., that ‘we are the same sort of creature, inhabiting the same sort of niche’). The use of cooperative communication emerges as the principal means to gather evidence for this belief, allowing for the development of a shared narrative that is used to disambiguate interactants’ (hidden and inferred) mental states. Thus, by using cooperative communication, individuals effectively attune to a hermeneutic niche composed, in part, of others’ mental states; and, reciprocally, attune the niche to their own ends via epistemic niche construction. This means that niche construction enables features of the niche to encode precise, reliable cues about the deontic or shared value of certain action policies (e.g., the utility of using communicative constructions to disambiguate mental states, given expectations about shared prior beliefs). In turn, the alignment of mental states (prior beliefs) enables the emergence of a novel, contextualizing scale of cultural dynamics that encompasses the actions and mental states of the ensemble of interactants and their shared environment. The dynamics of this contextualizing layer of cultural organization feedback, across scales, to constrain the variability of the prior expectations of the individuals who constitute it. Our theory additionally builds upon the active inference literature by introducing a new set of neurobiologically plausible computational hypotheses for cooperative communication. We conclude with directions for future research.

Hallucinations, including auditory verbal hallucinations (AVH), occur in both the healthy population and in psychotic conditions such as schizophrenia (often developing after a prodromal period). In addition, hallucinations can be in-context (they can be consistent with the environment, such as when one hallucinates the end of a sentence that has been repeated many times), or out-of-context (such as the bizarre hallucinations associated with schizophrenia). In previous work, we introduced a model of hallucinations as false (positive) inferences based on a (Markov decision process) formulation of active inference. In this work, we extend this model to include content – to disclose the computational mechanisms behind in- and out-of-context hallucinations. In active inference, sensory information is used to disambiguate alternative hypotheses about the causes of sensations. Sensory information is balanced against prior beliefs, and when this balance is tipped in the favor of prior beliefs, hallucinations can occur. We show that in-context hallucinations arise when (simulated) subjects cannot use sensory information to correct prior beliefs about hearing a voice, but beliefs about content (i.e. the sequential order of a sentence) remain accurate. When hallucinating subjects also have inaccurate beliefs about state transitions, out-of-context hallucinations occur; i.e. their hallucinated speech content is disordered. Furthermore, subjects with inaccurate beliefs about state transitions but an intact ability to use sensory information do not hallucinate and are reminiscent of prodromal patients. This work demonstrates the different computational mechanisms that may underlie the spectrum of hallucinatory experience – from the healthy population to psychotic states.

Hallucinations both in and out of context: An active inference account

In this paper we are interested in the computational and formal analysis of the persuasive impact that an argument can have on a human. We present a preliminary account of the listener mental process (representation and reasoning mechanisms of the dual process cognitive model) as well as her engagement based on the ELM model. This engagement determines the reasoning process that the agent will adopt in order to evaluate and incorporate the uttered argument.

MRI in traumatic spinal cord injury: from clinical assessment to neuroimaging biomarkers

The ability to conceptualize and understand one’s own affective states and responses – or “emotional awareness” (EA) – is reduced in multiple psychiatric populations; it is also positively correlated with a range of adaptive cognitive and emotional traits. While a growing body of work has investigated the neurocognitive basis of EA, the neurocomputational processes underlying this ability have received limited attention. Here, we present a formal Active Inference (AI) model of emotion conceptualization that can simulate the neurocomputational (Bayesian) processes associated with learning about emotion concepts and inferring the emotions one is feeling in a given moment. We validate the model and inherent constructs by showing (i) it can successfully acquire a repertoire of emotion concepts in its “childhood”, as well as (ii) acquire new emotion concepts in synthetic “adulthood,” and (iii) that these learning processes depend on early experiences, environmental stability, and habitual patterns of selective attention. These results offer a proof of principle that cognitive-emotional processes can be modeled formally, and highlight the potential for both theoretical and empirical extensions of this line of research on emotion and emotional disorders.

Simulating emotions: An active inference model of emotional state inference and emotion concept learning

In contrast to the symmetries of translation in space, rotation in space, and translation in time, the known laws of physics are not universally invariant under transformation of scale. However, the action can be invariant under change of scale in the special case of a scale free dynamical system that can be described in terms of a Lagrangian, that itself scales inversely with time. Crucially, this means symmetries under change of scale can exist in dynamical systems under certain constraints. Our contribution lies in the derivation of a generalised scale invariant Lagrangian - in the form of a power series expansion - that satisfies these constraints. This generalised Lagrangian furnishes a normal form for dynamic causal models (i.e., state space models based upon differential equations) that can be used to distinguish scale invariance (scale symmetry) from scale freeness in empirical data. We establish face validity with an analysis of simulated data and then show how scale invariance can be identified - and how the associated conserved quantities can be estimated - in neuronal timeseries.

Estimating quantities conserved by virtue of scale invariance in timeseries

&NA; Action observation (AO) is crucial for motor planning, imitation learning, and social interaction, but it is not clear whether and how an action execution‐observation network (AEON) processes the effort of others engaged in performing actions. In this functional magnetic resonance imaging (fMRI) study, we used a “squeeze ball” task involving different grip forces to investigate whether AEON activation showed similar patterns when executing the task or observing others performing it. Both in action execution, AE (subjects performed the visuomotor task) and action observation, AO (subjects watched a video of the task being performed by someone else), the fMRI signal was detected in cerebral and cerebellar regions. These responses showed various relationships with force mapping onto specific areas of the sensorimotor and cognitive systems. Conjunction analysis of AE and AO was repeated for the “0th” order and linear and nonlinear responses, and revealed multiple AEON nodes remapping the detection of actions, and also effort, of another person onto the observer's own cerebrocerebellar system. This result implies that the AEON exploits the cerebellum, which is known to process sensorimotor predictions and simulations, performing an internal assessment of forces and integrating information into high‐level schemes, providing a crucial substrate for action imitation.

I See Your Effort: Force-Related BOLD Effects in an Extended Action Execution–Observation Network Involving the Cerebellum

Subthalamic nucleus deep brain stimulation is an effective treatment for advanced Parkinson's disease; however, its therapeutic mechanism is unclear. Previous modelling of functional MRI data has suggested that deep brain stimulation has modulatory effects on a number of basal ganglia pathways. This work uses an enhanced data collection protocol to collect rare functional MRI data in patients with subthalamic nucleus deep brain stimulation. Eleven patients with Parkinson's disease and subthalamic nucleus deep brain stimulation underwent functional MRI at rest and during a movement task; once with active deep brain stimulation, and once with deep brain stimulation switched off. Dynamic causal modelling and Bayesian model selection were first used to compare a series of plausible biophysical models of the cortico-basal ganglia circuit that could explain the functional MRI activity at rest in an attempt to reproduce and extend the findings from our previous work. General linear modelling of the movement task functional MRI data revealed deep brain stimulation-associated signal increases in the primary motor and cerebellar cortices. Given the significance of the cerebellum in voluntary movement, we then built a more complete model of the motor system by including cerebellar-basal ganglia interactions, and compared the modulatory effects deep brain stimulation had on different circuit components during the movement task and again using the resting state data. Consistent with previous results from our independent cohort, model comparison found that the rest data were best explained by deep brain stimulation-induced increased (effective) connectivity of the cortico-striatal, thalamo-cortical and direct pathway and reduced coupling of subthalamic nucleus afferent and efferent connections. No changes in cerebellar connectivity were identified at rest. In contrast, during the movement task, there was functional recruitment of subcortical-cerebellar pathways, which were additionally modulated by deep brain stimulation, as well as modulation of local (intrinsic) cortical and cerebellar circuits. This work provides in vivo evidence for the modulatory effects of subthalamic nucleus deep brain stimulation on effective connectivity within the cortico-basal ganglia loops at rest, as well as further modulations in the cortico-cerebellar motor system during voluntary movement. We propose that deep brain stimulation has both behaviour-independent effects on basal ganglia connectivity, as well as behaviour-dependent modulatory effects.

Deep brain stimulation has state-dependent effects on motor connectivity in Parkinson's disease.

Significance Lysergic acid diethylamide (LSD) is a psychedelic drug that reliably induces an altered state of consciousness. Interest in psychedelic compounds is growing due to their remarkable potential for understanding altered neural states and potential clinical applications. However, there are major knowledge gaps regarding LSD’s neuropharmacology. Using cutting-edge neuroimaging methods we investigated directed connectivity between cortico–striato–thalamo-cortical (CSTC) regions after administration of LSD together with the specific role of the serotonin 2A receptor. Our results provide evidence that LSD alters directed connectivity within CSTC pathways in humans, suggesting that a disintegration of information processing within these loops is underlying the psychedelic state. These results inform the neurobiology of altered states of consciousness with critical implications for rational development of novel treatments. Psychedelics exert unique effects on human consciousness. The thalamic filter model suggests that core effects of psychedelics may result from gating deficits, based on a disintegration of information processing within cortico–striato–thalamo-cortical (CSTC) feedback loops. To test this hypothesis, we characterized changes in directed (effective) connectivity between selected CTSC regions after acute administration of lysergic acid diethylamide (LSD), and after pretreatment with Ketanserin (a selective serotonin 2A receptor antagonist) plus LSD in a double-blind, randomized, placebo-controlled, cross-over study in 25 healthy participants. We used spectral dynamic causal modeling (DCM) for resting-state fMRI data. Fully connected DCM models were specified for each treatment condition to investigate the connectivity between the following areas: thalamus, ventral striatum, posterior cingulate cortex, and temporal cortex. Our results confirm major predictions proposed in the CSTC model and provide evidence that LSD alters effective connectivity within CSTC pathways that have been implicated in the gating of sensory and sensorimotor information to the cortex. In particular, LSD increased effective connectivity from the thalamus to the posterior cingulate cortex in a way that depended on serotonin 2A receptor activation, and decreased effective connectivity from the ventral striatum to the thalamus independently of serotonin 2A receptor activation. Together, these results advance our mechanistic understanding of the action of psychedelics in health and disease. This is important for the development of new pharmacological therapeutics and also increases our understanding of the mechanisms underlying the potential clinical efficacy of psychedelics.

Effective connectivity changes in LSD-induced altered states of consciousness in humans

The effect of global signal regression on DCM estimates of noise and effective connectivity from resting state fMRI

To exhibit social intelligence, animals have to recognize whom they are communicating with. One way to make this inference is to select among internal generative models of each conspecific who may be encountered. However, these models also have to be learned via some form of Bayesian belief updating. This induces an interesting problem: When receiving sensory input generated by a particular conspecific, how does an animal know which internal model to update? We consider a theoretical and neurobiologically plausible solution that enables inference and learning of the processes that generate sensory inputs (e.g., listening and understanding) and reproduction of those inputs (e.g., talking or singing), under multiple generative models. This is based on recent advances in theoretical neurobiology—namely, active inference and post hoc (online) Bayesian model selection. In brief, this scheme fits sensory inputs under each generative model. Model parameters are then updated in proportion to the probability that each model could have generated the input (i.e., model evidence). The proposed scheme is demonstrated using a series of (real zebra finch) birdsongs, where each song is generated by several different birds. The scheme is implemented using physiologically plausible models of birdsong production. We show that generalized Bayesian filtering, combined with model selection, leads to successful learning across generative models, each possessing different parameters. These results highlight the utility of having multiple internal models when making inferences in social environments with multiple sources of sensory information.

Bayesian Filtering with Multiple Internal Models: Toward a Theory of Social Intelligence

Abstract The processes underwriting the acquisition of culture remain unclear. How are shared habits, norms, and expectations learned and maintained with precision and reliability across large-scale sociocultural ensembles? Is there a unifying account of the mechanisms involved in the acquisition of culture? Notions such as “shared expectations,” the “selective patterning of attention and behaviour,” “cultural evolution,” “cultural inheritance,” and “implicit learning” are the main candidates to underpin a unifying account of cognition and the acquisition of culture; however, their interactions require greater specification and clarification. In this article, we integrate these candidates using the variational (free-energy) approach to human cognition and culture in theoretical neuroscience. We describe the construction by humans of social niches that afford epistemic resources called cultural affordances. We argue that human agents learn the shared habits, norms, and expectations of their culture through immersive participation in patterned cultural practices that selectively pattern attention and behaviour. We call this process “thinking through other minds” (TTOM) – in effect, the process of inferring other agents’ expectations about the world and how to behave in social context. We argue that for humans, information from and about other people's expectations constitutes the primary domain of statistical regularities that humans leverage to predict and organize behaviour. The integrative model we offer has implications that can advance theories of cognition, enculturation, adaptation, and psychopathology. Crucially, this formal (variational) treatment seeks to resolve key debates in current cognitive science, such as the distinction between internalist and externalist accounts of theory of mind abilities and the more fundamental distinction between dynamical and representational accounts of enactivism.

Thinking through other minds: A variational approach to cognition and culture

The study of perceptual awareness in biology often relies upon the study of clinical conditions with either absent or abnormal awareness. In this article, we argue that the same approach may be fruitful in investigating artificial consciousness. To illustrate this, we draw upon recent examples in which disorders of awareness have been induced in artificial systems. Specifically, we call upon the induction of hallucinatory phenomena, and upon visual neglect: a classical disorder of awareness that manifests as a disruption of the action-perception cycle. The key ideas we seek to emphasise from these are the presence of an internal model that generates perceptual content, and the capacity to actively engage with the sensorium.

Abstract The dysconnection hypothesis of schizophrenia (SZ) proposes that psychosis is best understood in terms of aberrant connectivity. Specifically, it suggests that dysconnectivity arises through aberrant synaptic modulation associated with deficits in GABAergic inhibition, excitation–inhibition balance and disturbances of high-frequency oscillations. Using a computational model combined with a graded-difficulty visual orientation discrimination paradigm, we demonstrate that, in SZ, perceptual performance is determined by the balance of excitation–inhibition in superficial cortical layers. Twenty-eight individuals with a DSM-IV diagnosis of SZ, and 30 age- and gender-matched healthy controls participated in a psychophysics orientation discrimination task, a visual grating magnetoencephalography (MEG) recording, and a magnetic resonance spectroscopy (MRS) scan for GABA. Using a neurophysiologically informed model, we quantified group differences in GABA, gamma measures, and the predictive validity of model parameters for orientation discrimination in the SZ group. MEG visual gamma frequency was reduced in SZ, with lower peak frequency associated with more severe negative symptoms. Orientation discrimination performance was impaired in SZ. Dynamic causal modeling of the MEG data showed that local synaptic connections were reduced in SZ and local inhibition correlated negatively with the severity of negative symptoms. The effective connectivity between inhibitory interneurons and superficial pyramidal cells predicted orientation discrimination performance within the SZ group; consistent with graded, behaviorally relevant, disease-related changes in local GABAergic connections. Occipital GABA levels were significantly reduced in SZ but did not predict behavioral performance or oscillatory measures. These findings endorse the importance, and behavioral relevance, of GABAergic synaptic disconnection in schizophrenia that underwrites excitation–inhibition balance.

Oscillatory, Computational, and Behavioral Evidence for Impaired GABAergic Inhibition in Schizophrenia

This paper considers the relationship between thermodynamics, information and inference. In particular, it explores the thermodynamic concomitants of belief updating, under a variational (free energy) principle for self-organization. In brief, any (weakly mixing) random dynamical system that possesses a Markov blanket—i.e. a separation of internal and external states—is equipped with an information geometry. This means that internal states parametrize a probability density over external states. Furthermore, at non-equilibrium steady-state, the flow of internal states can be construed as a gradient flow on a quantity known in statistics as Bayesian model evidence. In short, there is a natural Bayesian mechanics for any system that possesses a Markov blanket. Crucially, this means that there is an explicit link between the inference performed by internal states and their energetics—as characterized by their stochastic thermodynamics. This article is part of the theme issue ‘Harmonizing energy-autonomous computing and intelligence’.

Philosophical transactions. Series A, Mathematical, physical, and engineering sciences

Markov blankets, information geometry and stochastic thermodynamics

Scale free dynamics are observed in a variety of physical and biological systems. These include neural activity in which evidence for scale freeness has been reported using a range of imaging modalities. Here, we derive the ways in which connections within a network must transform - relative to system size - in order to maintain scale freeness and test these theoretical transformations via simulations. First, we explore the known invariance of planetary motion for orbits varying in size. Using parametric empirical Bayesian modelling and a generic dynamical systems model, we show that we recover Kepler's third law from orbital timeseries, using our proposed transformations; thereby providing construct validation. We then demonstrate that the dynamical critical exponent is inversely proportional to the time rescaling exponent, in the context of coarse graining operations. Using murine calcium imaging data, we then show that the dynamical critical exponent can be estimated in an empirical biological setting. Specifically, we compare dynamical critical exponents - associated with spontaneous and task states in two regions of imaged cortex - that are classified as task-relevant and task-irrelevant. We find, consistently across animals, that the task-irrelevant region exhibits higher dynamical critical exponents during spontaneous activity than during task performance. Conversely, the task-relevant region is associated with higher dynamical critical exponents in task vs. spontaneous states. These data support the idea that higher dynamical critical exponents, within relevant cortical structures, underwrite neuronal processing due to the implicit increase in cross-scale information transmission.

Within computational neuroscience, the algorithmic and neural basis of structure learning remains poorly understood. Concept learning is one primary example, which requires both a type of internal model expansion process (adding novel hidden states that explain new observations), and a model reduction process (merging different states into one underlying cause and thus reducing model complexity via meta-learning). Although various algorithmic models of concept learning have been proposed within machine learning and cognitive science, many are limited to various degrees by an inability to generalize, the need for very large amounts of training data, and/or insufficiently established biological plausibility. Using concept learning as an example case, we introduce a novel approach for modeling structure learning within the active inference framework and its accompanying neural process theory. This approach is based on the idea that a generative model can be equipped with extra (hidden state or cause) ‘slots’ that can be engaged when an agent learns about novel concepts. This can be combined with a Bayesian model reduction process, in which any concept learning – associated with these slots – can be reset in favor of a simpler model with higher model evidence. We use simulations to illustrate this model’s ability to add new concepts to its state space (with relatively few observations) and increase the granularity of the concepts it currently possesses. We also simulate the predicted neural basis of these processes. We further show that it accomplishes a simple form of ‘one-shot’ generalization to new stimuli. Although deliberately simple, these results suggest that this general approach to modeling concept learning within active inference research may also offer useful resources in developing neurocomputational models of structure learning more generally.

An Active Inference Approach to Modeling Structure Learning: Concept Learning as an Example Case

Active inference is a first principle account of how autonomous agents operate in dynamic, nonstationary environments. This problem is also considered in reinforcement learning, but limited work exists on comparing the two approaches on the same discrete-state environments. In this letter, we provide (1) an accessible overview of the discrete-state formulation of active inference, highlighting natural behaviors in active inference that are generally engineered in reinforcement learning, and (2) an explicit discrete-state comparison between active inference and reinforcement learning on an OpenAI gym baseline. We begin by providing a condensed overview of the active inference literature, in particular viewing the various natural behaviors of active inference agents through the lens of reinforcement learning. We show that by operating in a pure belief-based setting, active inference agents can carry out epistemic exploration—and account for uncertainty about their environment—in a Bayes-optimal fashion. Furthermore, we show that the reliance on an explicit reward signal in reinforcement learning is removed in active inference, where reward can simply be treated as another observation we have a preference over; even in the total absence of rewards, agent behaviors are learned through preference learning. We make these properties explicit by showing two scenarios in which active inference agents can infer behaviors in reward-free environments compared to both Q-learning and Bayesian model-based reinforcement learning agents and by placing zero prior preferences over rewards and learning the prior preferences over the observations corresponding to reward. We conclude by noting that this formalism can be applied to more complex settings (e.g., robotic arm movement, Atari games) if appropriate generative models can be formulated. In short, we aim to demystify the behavior of active inference agents by presenting an accessible discrete state-space and time formulation and demonstrate these behaviors in a OpenAI gym environment, alongside reinforcement learning agents.

Passive motion and active inference: Commentary on "Muscleless motor synergies and actions without movements: From motor neuroscience to cognitive robotics" by Vishwanathan Mohan, Ajaz Bhat and Pietro Morasso.

How do humans come to acquire shared expectations about how they ought to behave in distinct normalized social settings? This paper offers a normative framework to answer this question. We introduce the computational construct of ‘deontic value’ – based on active inference and Markov decision processes – to formalize conceptions of social conformity and human decision-making. Deontic value is an attribute of choices, behaviors, or action sequences that inherit directly from deontic cues in our econiche (e.g., red traffic lights); namely, cues that denote an obligatory social rule. Crucially, the prosocial aspect of deontic value rests upon a particular form of circular causality: deontic cues exist in the environment in virtue of the environment being modified by repeated actions, while action itself is contingent upon the deontic value of environmental cues. We argue that this construction of deontic cues enables the epistemic (i.e., information-seeking) and pragmatic (i.e., goal- seeking) values of any behavior to be ‘cached’ or ‘outsourced’ to the environment, where the environment effectively ‘learns’ about the behavior of its denizens. We describe the process whereby this particular aspect of value enables learning of habitual behavior over neurodevelopmental and transgenerational timescales.

Regimes of Expectations: An Active Inference Model of Social Conformity and Human Decision Making

This work considers a class of biologically plausible cost functions for neural networks, where the same cost function is minimised by both neural activity and plasticity. We show that such cost functions can be cast as a variational bound on model evidence under an implicit generative model. Using generative models based on Markov decision processes (MDP), we show, analytically, that neural activity and plasticity perform Bayesian inference and learning, respectively, by maximising model evidence. Using mathematical and numerical analyses, we then confirm that biologically plausible cost functions—used in neural networks—correspond to variational free energy under some prior beliefs about the prevalence of latent states that generate inputs. These prior beliefs are determined by particular constants (i.e., thresholds) that define the cost function. This means that the Bayes optimal encoding of latent or hidden states is achieved when, and only when, the network’s implicit priors match the process that generates the inputs. Our results suggest that when a neural network minimises its cost function, it is implicitly minimising variational free energy under optimal or sub-optimal prior beliefs. This insight is potentially important because it suggests that any free parameter of a neural network’s cost function can itself be optimised—by minimisation with respect to variational free energy.

Reverse engineering neural networks to characterise their cost functions

Abstract The algorithmic and neural basis of concept learning remains poorly understood. In this paper, we articulate a novel, biologically plausible approach to concept learning based on active inference, and on the idea that a generative model can be equipped with extra (hidden state or cause) ‘slots’ that can be engaged when an agent learns about novel concepts. This can be combined with a Bayesian model reduction process, in which any concept learning – associated with these slots – can be reset in favor of a simpler model with higher model evidence. We use simulations to illustrate this model’s ability to add new concepts to its state space, increase the granularity of the concepts it currently possesses, and accomplish a simple form of ‘one-shot’ generalization to new stimuli. Although deliberately simple, these results suggest that active inference may offer useful resources in developing neurocomputational models of concept learning.

How do the computations of the cerebral cortex and subcortical structures account for human perception, cognition, and affect? Answering this question requires understanding how the neurobiological and functional properties of the human brain give rise to the repertoire of human faculties and behavior, and hence, an understanding of the neural mechanisms that implement these functions. While research over the past decades has made substantial progress toward this end, signifi cant challenges still lie ahead, and new opportunities open up daily as neuroscience and related fi elds develop and implement new theories and technologies. To (begin to) address these challenges, this chapter explores conceptual and methodological aspects inherent to the study of the neurobiology of the human mind that are at the core of the current “central paradigm” (Kuhn 1962) in neuroscience, but are often taken for granted and undergo little scrutiny. In particular, it discusses what defi nes or constitutes “uniquely human” mental capacities, the promises and pitfalls of using animal models to understand the human brain, whether neural solutions and computations are shared across species or repurposed for potentially uniquely human capacities, and what inspiration and information can be drawn from recent developments in artifi cial intelligence. Attention is given to laying out desiderata for future investigations into the human mind. Group photos (top left to bottom right) Lucia Melloni, David Poeppel, Bijan Pesaran, Karl Friston, Elizabeth Buffalo, Scott Grafton, Asif Ghazanfar, Stan Dehaene, Anne-Lise Giraud, Lucia Melloni, Christopher Petkov, Saskia Haegens, Bijan Pesaran, Scott Grafton, Elizabeth Buffalo, Christopher Petkov, Stan Dehaene, Anne-Lise Giraud, Asif Ghazanfar, David Poeppel, Karl Friston From “The Neocortex,” edited by W. Singer, T. J. Sejnowski and P. Rakic. Strüngmann Forum Reports, vol. 27, J. R. Lupp, series editor. Cambridge, MA: MIT Press. ISBN 978-0-262-04324-3 324 L. Melloni et al. Singular or Not? The Human Animal To understand the structure and function of human brains, one must address the question of potential uniqueness or singularity, ever cognizant that the word “uniqueness” raises its own set of provocative questions. The human cortex has structural and physiological properties that underwrite neuronal activity which in turn underpins the implementation of computations that may or may not be specifi c to the function of the human brain. Further defi nition, however, is required when we ask whether the potential distinctions between human brain, computational inventory, or behavioral repertoire, compared to other species, are a matter of degree, as argued for by Darwin (1888), or systemic discontinuities (Fitch 2012; Parravicini and Pievani 2018; Ghazanfar, this volume). Discontinuity of evolution is clearly not an idea that is widely endorsed. Rather than rehearse potential uniqueness features, we might instead pursue the argument of commonalities. We contend, however, that this is just as diffi cult as identifying properties that are apparently found only in human cortex. For the sake of argument, we take the position that some distinctions between humans and other species can be readily identifi ed, and we take it as our task to understand how to account for such species-typical features. One example that points to human-specifi c organization concerns the suite of operations that comprise combinatorics. These come to light in language, mathematics, music, theory of mind, and potentially in other domains not yet understood as well in terms of formalization. In the language domain, it has long been argued that only humans have the capacity to produce the kinds of representations characteristic of syntax (e.g., Merge). To date, there is no clear case of a nonhuman primate that has learned to combine words systematically according to a complex grammar (Terrace et al. 1979; Yang 2013). In the few cases in which nonhuman primates have been able to produce sequences adhering to a supra-regular grammar, this was only accomplished after extensive training (over 10,000 trials), whereas preschool children master this behavior in less than fi ve trials (Wang et al. 2018). In numerical cognition (i.e., the sense of number and capacity for mathematical thinking), it is well established that monkeys and humans start life with a similar approximate number system (Dehaene 2011). The acquisition of verbal counting and a system of Arabic numerals allows human children to move from an approximate, compressive representation of numerical quantities to an exact, linear system of number (Siegler and Opfer 2003; Dehaene 2011). In the absence of formal education (e.g., in indigenous Amazon populations), the approximate system remains largely unchanged in human adults (Pica et al. 2004). Monkeys can be taught some number symbols, and this leads them to become somewhat more precise in a number comparison task (Livingstone et al. 2010). They may even begin to understand the rudiments of addition and subtraction (Livingstone et al. 2014). Yet, they continually make errors, even under highly motivating reinforcement schedules, and never perform at From “The Neocortex,” edited by W. Singer, T. J. Sejnowski and P. Rakic. Strüngmann Forum Reports, vol. 27, J. R. Lupp, series editor. Cambridge, MA: MIT Press. ISBN 978-0-262-04324-3 Computation and Its Neural Implementation in Human Cognition 325 the level of precision and exactness attained even by young human children. Arguably, sharp distinctions between precise consecutive numbers, as those between truth and falsehood, may be unique to humans: the formation of a complex combinatorial system of arithmetic certainly is. Accepting that there are domains of behavior that may be singular to humans leads us to ask in which ways those operations are different: Are they rooted in simpler forms of behavior that can be useful to study when trying to understand how uniquely human behaviors emerged? In which way are the structure of the cerebral cortex and its neural codes different, relative to the brains and codes that implement these more basic behaviors? Have neural codes been exapted or created de novo for new functions? Addressing these questions is inextricably linked with exploring neural solutions in other species to establish convergence and divergence. The usefulness of a comparative approach to understand the human brain and its dysfunctions is clear, yet there are a number of outstanding challenges that complicate such an enterprise. These challenges must be factored into any discussion if progress is to be made in understanding which neural solutions and computations might be shared across species or repurposed for potentially uniquely human

The role of the hippocampus in weighting expectations during inference under uncertainty

M42 A TRANSCRIPTOME-WIDE ASSOCIATION STUDY OF MISMATCH NEGATIVITY

Being confident in whether a stimulus is present or absent (a detection judgment) is qualitatively distinct from being confident in the identity of that stimulus (a discrimination judgment). In particular, in detection, evidence can only be available for the presence, not the absence, of a target object. This asymmetry suggests that higher-order cognitive and neural processes may be required for confidence in detection, and more specifically, in judgments about absence. In a within-subject, pre-registered and performance-matched fMRI design, we observed quadratic confidence effects in frontopolar cortex for detection but not discrimination. Furthermore, in the right temporoparietal junction, confidence effects were enhanced for judgments of target absence compared to judgments of target presence. We interpret these findings as reflecting qualitative differences between the neural basis of metacognitive evaluation of detection and discrimination, potentially in line with counterfactual or higher-order models of confidence formation in detection.

Distinct neural contributions to metacognition for detecting, but not discriminating visual stimuli

Living creatures must accurately infer the nature of their environments. They do this despite being confronted by stochastic and context sensitive contingencies—and so must constantly update their beliefs regarding their uncertainty about what might come next. In this work, we examine how we deal with uncertainty that evolves over time. This prospective uncertainty (or imprecision) is referred to as volatility and has previously been linked to noradrenergic signals that originate in the locus coeruleus. Using pupillary dilatation as a measure of central noradrenergic signalling, we tested the hypothesis that changes in pupil diameter reflect inferences humans make about environmental volatility. To do so, we collected pupillometry data from participants presented with a stream of numbers. We generated these numbers from a process with varying degrees of volatility. By measuring pupillary dilatation in response to these stimuli—and simulating the inferences made by an ideal Bayesian observer of the same stimuli—we demonstrate that humans update their beliefs about environmental contingencies in a Bayes optimal way. We show this by comparing general linear (convolution) models that formalised competing hypotheses about the causes of pupillary changes. We found greater evidence for models that included Bayes optimal estimates of volatility than those without. We additionally explore the interaction between different causes of pupil dilation and suggest a quantitative approach to characterising a person’s prior beliefs about volatility.

With an eye on uncertainty: Modelling pupillary responses to environmental volatility

The aim of this article is to clarify how best to interpret some of the central constructs that underwrite the free-energy principle (FEP) – and its corollary, active inference – in theoretical neuroscience and biology: namely, the role that generative models and variational densities play in this theory. We argue that these constructs have been systematically misrepresented in the literature, because of the conflation between the FEP and active inference, on the one hand, and distinct (albeit closely related) Bayesian formulations, centred on the brain – variously known as predictive processing, predictive coding or the prediction error minimisation framework. More specifically, we examine two contrasting interpretations of these models: a structural representationalist interpretation and an enactive interpretation. We argue that the structural representationalist interpretation of generative and recognition models does not do justice to the role that these constructs play in active inference under the FEP. We propose an enactive interpretation of active inference – what might be called enactive inference. In active inference under the FEP, the generative and recognition models are best cast as realising inference and control – the self-organising, belief-guided selection of action policies – and do not have the properties ascribed by structural representationalists.

This paper formulates the action of psychedelics by integrating the free-energy principle and entropic brain hypothesis. We call this formulation relaxed beliefs under psychedelics (REBUS) and the anarchic brain, founded on the principle that—via their entropic effect on spontaneous cortical activity—psychedelics work to relax the precision of high-level priors or beliefs, thereby liberating bottom-up information flow, particularly via intrinsic sources such as the limbic system. We assemble evidence for this model and show how it can explain a broad range of phenomena associated with the psychedelic experience. With regard to their potential therapeutic use, we propose that psychedelics work to relax the precision weighting of pathologically overweighted priors underpinning various expressions of mental illness. We propose that this process entails an increased sensitization of high-level priors to bottom-up signaling (stemming from intrinsic sources), and that this heightened sensitivity enables the potential revision and deweighting of overweighted priors. We end by discussing further implications of the model, such as that psychedelics can bring about the revision of other heavily weighted high-level priors, not directly related to mental health, such as those underlying partisan and/or overly-confident political, religious, and/or philosophical perspectives. Significance Statement Psychedelics are capturing interest, with efforts underway to bring psilocybin therapy to marketing authorisation and legal access within a decade, spearheaded by the findings of a series of phase 2 trials. In this climate, a compelling unified model of how psychedelics alter brain function to alter consciousness would have appeal. Towards this end, we have sought to integrate a leading model of global brain function, hierarchical predictive coding, with an often-cited model of the acute action of psychedelics, the entropic brain hypothesis. The resulting synthesis states that psychedelics work to relax high-level priors, sensitising them to liberated bottom-up information flow, which, with the right intention, care provision and context, can help guide and cultivate the revision of entrenched pathological priors.

REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics

Correction: A unifying Bayesian account of contextual effects in value-based choice

Selective Prefrontal Disinhibition in a Roving Auditory Oddball Paradigm Under N-Methyl-D-Aspartate Receptor Blockade

To select among competing generative models of timeseries data, it is necessary to balance the goodness of fit (accuracy) and model complexity. Bayesian methods are a mathematically principled way to achieve this balance. However, when performing simulations – to assess the identifiability of models (face validation) – the best model identified by Bayesian model comparison might appear more complex than the model that actually generated the data. We illustrate this using dynamic causal models of human electrophysiological data, where models with multiple parameter modulations are selected as the best model, even if the true modulations are sparse. We explain this by the form of the complexity penalty, which is equivalent to weighted L2 norm. This phenomenon is an example of implicit prior biases that necessarily entail a complexity penalty.

2019 IEEE International Conference on Systems, Man and Cybernetics (SMC)

There’s no such thing as a ‘true’ model: the challenge of assessing face validity*

In this paper, we draw from recent theoretical work on active perception, which suggests that the brain makes use of an internal (i.e., generative) model to make inferences about the causes of sensations. This view treats visual sensations as consequent on action (i.e., saccades) and implies that visual percepts must be actively constructed via a sequence of eye movements. Oculomotor control calls on a distributed set of brain sources that includes the dorsal and ventral frontoparietal (attention) networks. We argue that connections from the frontal eye fields to ventral parietal sources represent the mapping from “where”, fixation location to information derived from “what” representations in the ventral visual stream. During scene construction, this mapping must be learned, putatively through changes in the effective connectivity of these synapses. Here, we test the hypothesis that the coupling between the dorsal frontal cortex and the right temporoparietal cortex is modulated during saccadic interrogation of a simple visual scene. Using dynamic causal modeling for magnetoencephalography with (male and female) human participants, we assess the evidence for changes in effective connectivity by comparing models that allow for this modulation with models that do not. We find strong evidence for modulation of connections between the two attention networks; namely, a disinhibition of the ventral network by its dorsal counterpart. SIGNIFICANCE STATEMENT This work draws from recent theoretical accounts of active vision and provides empirical evidence for changes in synaptic efficacy consistent with these computational models. In brief, we used magnetoencephalography in combination with eye-tracking to assess the neural correlates of a form of short-term memory during a dot cancellation task. Using dynamic causal modeling to quantify changes in effective connectivity, we found evidence that the coupling between the dorsal and ventral attention networks changed during the saccadic interrogation of a simple visual scene. Intuitively, this is consistent with the idea that these neuronal connections may encode beliefs about “what I would see if I looked there”, and that this mapping is optimized as new data are obtained with each fixation.

A Multi-scale View of the Emergent Complexity of Life: A Free-Energy Proposal

This paper offers a formal account of policy learning, or habitual behavioural optimisation, under the framework of Active Inference. In this setting, habit formation becomes an autodidactic, experience-dependent process, based upon what the agent sees itself doing. We focus on the effect of environmental volatility on habit formation by simulating artificial agents operating in a partially observable Markov decision process. Specifically, we used a ‘two-step’ maze paradigm, in which the agent has to decide whether to go left or right to secure a reward. We observe that in volatile environments with numerous reward locations, the agents learn to adopt a generalist strategy, never forming a strong habitual behaviour for any preferred maze direction. Conversely, in conservative or static environments, agents adopt a specialist strategy; forming strong preferences for policies that result in approach to a small number of previously-observed reward locations. The pros and cons of the two strategies are tested and discussed. In general, specialization offers greater benefits, but only when contingencies are conserved over time. We consider the implications of this formal (Active Inference) account of policy learning for understanding the relationship between specialisation and habit formation. Author Summary Active inference is a theoretical framework that formalizes the behaviour of any organism in terms of a single imperative – to minimize surprise. Starting from this principle, we can construct simulations of simple “agents” (artificial organisms) that show the ability to infer causal relationships and learn. Here, we expand upon currently-existing implementations of Active Inference by enabling synthetic agents to optimise the space of behavioural policies that they can pursue. Our results show that by adapting the probabilities of certain action sequences (which may correspond biologically to the phenomenon of synaptic plasticity), and by rejecting improbable sequences (synaptic pruning), the agents can begin to form habits. Furthermore, we have shown our agent’s habit formation to be environment-dependent. Some agents become specialised to a constant environment, while other adopt a more general strategy, each with sensible pros and cons. This work has potential applications in computational psychiatry, including in behavioural phenotyping to better understand disorders.

A Bayesian Account of Generalist and Specialist Formation Under the Active Inference Framework

Comparing visual discrimination and detection: the special status of ‘no’ responses

This monograph attempts a theory of every 'thing' that can be distinguished from other things in a statistical sense. The ensuing statistical independencies, mediated by Markov blankets, speak to a recursive composition of ensembles (of things) at increasingly higher spatiotemporal scales. This decomposition provides a description of small things; e.g., quantum mechanics - via the Schrodinger equation, ensembles of small things - via statistical mechanics and related fluctuation theorems, through to big things - via classical mechanics. These descriptions are complemented with a Bayesian mechanics for autonomous or active things. Although this work provides a formulation of every thing, its main contribution is to examine the implications of Markov blankets for self-organisation to nonequilibrium steady-state. In brief, we recover an information geometry and accompanying free energy principle that allows one to interpret the internal states of something as representing or making inferences about its external states. The ensuing Bayesian mechanics is compatible with quantum, statistical and classical mechanics and may offer a formal description of lifelike particles.

Network analyses are now considered fundamental for understanding brain function. Nonetheless neuroimaging characterisations of connectivity are just emerging in clinical neuroscience. Here, we briefly outline the concepts underlying structural, functional and effective connectivity, and discuss some cutting-edge approaches to the quantitative assessment of brain architecture and dynamics. As illustrated by recent evidence, comprehensive and integrative network analyses offer the potential for refining pathophysiological concepts and therapeutic strategies in neurological and psychiatric conditions across the lifespan.

Frontal beta band power has been shown to increase both as a consequence of elevated task demands and with time on task. Beta band power may thus be a neural correlate of cognitive effort. The present study report effective connections between the prefrontal and premotor cortex, areas known to be involved in cognitive control, and shows that these effective connections change in line with frontal beta band power. The changes in frontal connections, however, are unrelated to signs of mental fatigue. The interactions between task-relevant brain areas may thus be related to cognitive effort and not mental fatigue.

Abstract Individuals with Down syndrome (DS) show high inter-subject variability in cognitive ability and have an ultra-high risk of developing dementia (90% lifetime prevalence). Elucidating factors underlying variability in cognitive function can inform us about intellectual disability (ID) and may improve our understanding of factors associated with later cognitive decline. Increased neuronal inhibition has been posited to contribute to ID in DS. Combining electroencephalography (EEG) with dynamic causal modeling (DCM) provides a non-invasive method for investigating excitatory/inhibitory mechanisms. Resting-state EEG recordings were obtained from 36 adults with DS with no evidence of cognitive decline. Theta–alpha activity (4–13 Hz) was characterized in relation to general cognitive ability (raw Kaufmann’s Brief Intelligence Test second Edition (KBIT-2) score). Higher KBIT-2 was associated with higher frontal alpha peak amplitude and higher theta–alpha band power across distributed regions. Modeling this association with DCM revealed intrinsic self-inhibition was the key network parameter underlying observed differences in 4–13 Hz power in relation to KBIT-2 and age. In particular, intrinsic self-inhibition in right V1 was negatively correlated with KBIT-2. Results suggest intrinsic self-inhibition within the alpha network is associated with individual differences in cognitive ability in adults with DS, and may provide a potential therapeutic target for cognitive enhancement.

Dynamic Causal Modeling of the Relationship between Cognition and Theta–alpha Oscillations in Adults with Down Syndrome

The presence of interictal epileptiform discharges on electroencephalography (EEG) may indicate increased epileptic seizure risk and on invasive EEG are the signature of the irritative zone. In highly epileptogenic lesions – such as cortical tubers in tuberous sclerosis – these discharges can be recorded with intracranial stereotactic EEG as part of the evaluation for epilepsy surgery. Yet the network mechanisms that underwrite the generation and spread of these discharges remain poorly understood, limiting their current diagnostic use. Here, we investigate the dynamics of interictal epileptiform discharges using a combination of quantitative analysis of invasive EEG recordings and mesoscale neural mass modelling of cortical dynamics. We first characterise spatially organised local dynamics of discharges recorded from 36 separate tubers in 8 patients with tuberous sclerosis. We characterise these dynamics with a set of competing explanatory network models using dynamic causal modelling. Bayesian model comparison of plausible network architectures suggests that the recurrent coupling between neuronal populations within – and adjacent to – the tuber core explains the travelling wave dynamics observed in these patient recordings. Our results – based on interictal activity – unify competing theories about the pathological organisation of epileptic foci and surrounding cortex in patients with tuberous sclerosis. Coupled oscillator dynamics have previously been used to describe ictal activity, where fast travelling ictal discharges are commonly observed within the recruited seizure network. The interictal data analysed here add the insight that this functional architecture is already established in the interictal state. This links observations of interictal EEG abnormalities directly to pathological network coupling in epilepsy, with possible implications for epilepsy surgery approaches in tuberous sclerosis. Significance Statement Interictal epileptiform discharges (IEDs) are clinically important markers of an epileptic brain. Here we link local IED spread to network coupling through a combination of clinical recordings in paediatric patients with tuberous sclerosis complex, quantitative EEG analysis of interictal discharges spread, and Bayesian inference on coupled neural mass model parameters. We show that the kinds of interictal discharges seen in our patients require recurrent local network coupling extending beyond the putative seizure focus and that in fact only those recurrent coupled networks can support seizure-like and interictal dynamics when run in simulation. Our findings provide a novel integrated perspective on emergent epileptic dynamics in human patients.

Interictal discharges spread along local recurrent networks between tubers and surrounding cortex

Abstract We discuss how uncertainty underwrites exploration and epistemic foraging from the perspective of active inference: a generic scheme that places pragmatic (utility maximization) and epistemic (uncertainty minimization) imperatives on an equal footing – as primary determinants of proximal behavior. This formulation contextualizes the complementary motivational incentives for reward-related stimuli and environmental uncertainty, offering a normative treatment of their trade-off.

The hierarchically mechanistic mind: A free-energy formulation of the human psyche

Predictive processing (e.g., predictive coding) is a predominant paradigm in cognitive neuroscience. This Primer considers the various levels of commitment neuroscientists have to the neuronal process theories that accompany the principles of predictive processing. Specifically, it reviews and contextualises a recent PLOS Biology study of alpha oscillations and travelling waves. We will see that alpha oscillations emerge naturally under the computational architectures implied by predictive coding-and may tell us something profound about recurrent message passing in brain hierarchies. Specifically, the bidirectional nature of forward and backward waves speaks to opportunities to understand attention and how it nuances bottom-up and top-down influences.

In our everyday lives, we are often required to follow a conversation when background noise is present (“speech-in-noise” perception). Speech-in-noise perception varies widely—and people who are worse at speech-in-noise perception are also worse at fundamental auditory grouping, as assessed by figure-ground tasks. Here, we examined the cortical processes that link difficulties with speech-in-noise perception to difficulties with figure-ground perception using functional magnetic resonance imaging (fMRI). We found strong evidence that the earliest stages of the auditory cortical hierarchy (left core and belt areas) are similarly disinhibited when speech-in-noise and figure-ground tasks are more difficult (i.e., at target-to-masker ratios corresponding to 60% than 90% thresholds)—consistent with increased cortical gain at lower levels of the auditory hierarchy. Overall, our results reveal a common neural substrate for these basic (figure-ground) and naturally relevant (speech-in-noise) tasks—which provides a common computational basis for the link between speech-in-noise perception and fundamental auditory grouping.

Difficulties with Speech-in-Noise Perception Related to Fundamental Grouping Processes in Auditory Cortex

Active inference is a first (Bayesian) principles account of how autonomous agents might operate in dynamic, non-stationary environments. The optimization of congruent formulations of the free energy functional (variational and expected), in active inference, enables agents to make inferences about the environment and select optimal behaviors. The agent achieves this by evaluating (sensory) evidence in relation to its internal generative model that entails beliefs about future (hidden) states and sequence of actions that it can choose. In contrast to analogous frameworks $-$ by operating in a pure belief-based setting (free energy functional of beliefs about states) $-$ active inference agents can carry out epistemic exploration and naturally account for uncertainty about their environment. Through this review, we disambiguate these properties, by providing a condensed overview of the theory underpinning active inference. A T-maze simulation is used to demonstrate how these behaviors emerge naturally, as the agent makes inferences about the observed outcomes and optimizes its generative model (via belief updating). Additionally, the discrete state-space and time formulation presented provides an accessible guide on how to derive the (variational and expected) free energy equations and belief updating rules. We conclude by noting that this formalism can be applied in other engineering applications; e.g., robotic arm movement, playing Atari games, etc., if appropriate underlying probability distributions (i.e. generative model) can be formulated.

It has been suggested that the brain controls hand movements via internal models that rely on visual and proprioceptive cues about the state of the hand. In active inference formulations of such models, the relative influence of each modality on action and perception is determined by how precise (reliable) it is expected to be. The ‘top-down’ affordance of expected precision to a particular sensory modality presumably corresponds to attention. Here, we asked whether increasing attention to (i.e., the precision of) vision or proprioception would enhance performance in a hand-target phase matching task, in which visual and proprioceptive cues about hand posture were incongruent. We show that in a simple simulated agent—using a neurobiologically informed predictive coding formulation of active inference—increasing either modality’s expected precision improved task performance under visuo-proprioceptive conflict. Moreover, we show that this formulation captured the behaviour and self-reported attentional allocation of human participants performing the same task in a virtual reality environment. Together, our results show that selective attention can balance the impact of (conflicting) visual and proprioceptive cues on action—rendering attention a key mechanism for a flexible body representation for action. Author summary When controlling hand movements, the brain can rely on seen and felt hand position or posture information. It is thought that the brain combines these estimates into a multisensory hand representation in a probabilistic fashion, accounting for how reliable each estimate is in the given context. According to recent formal accounts of action, the expected reliability or ‘precision’ of sensory information can—to an extent—also be influenced by attention. Here, we tested whether this mechanism can improve goal-directed behaviour. We designed a task that required tracking a target’s oscillatory phase with either the seen or the felt hand posture, which were decoupled by introducing a temporal conflict via a virtual reality environment. We first simulated the behaviour of an artificial agent performing this task, and then compared the simulation results to behaviour of human participants performing the same task. Together, our results showed that increasing attention to the seen or felt hand was accompanied by improved target tracking. This suggests that, depending on the current behavioural demands, attention can balance how strongly the multisensory hand representation is relying on visual or proprioceptive sensory information.

Active inference under intersensory conflict: Simulation and empirical results

We review a recent shift in conceptions of interoception and its relationship to hierarchical inference in the brain. The notion of interoceptive inference means that bodily states are regulated by autonomic reflexes that are enslaved by descending predictions from deep generative models of our internal and external milieu. This re-conceptualization illuminates several issues in cognitive and clinical neuroscience with implications for experiences of selfhood, and emotion. We first contextualize interoception in terms of active (Bayesian) inference in the brain; highlighting its enactivist (embodied) aspects. We then consider the key role of uncertainty or precision and how this might translate into neuromodulation. We next examine the implications for understanding the functional anatomy of the emotional brain, surveying recent observations on agranular cortex. Finally, we turn to theoretical issues; namely, the role of interoception in shaping a sense of embodied self and feelings. We will draw links between physiological homeostasis and allostasis, early cybernetic ideas of predictive control, and hierarchical generative models in predictive processing. The explanatory scope of interoceptive inference ranges from explanations for autism and depression, through to consciousness. We offer a brief survey of these exciting developments.

Interoceptive inference 1 ACTIVE INTEROCEPTIVE INFERENCE AND THE EMOTIONAL BRAIN

The selective attention for identification model (SAIM) is an established model of selective visual attention. SAIM implements translation-invariant object recognition, in scenes with multiple objects, using the parallel distributed processing (PDP) paradigm. Here, we show that SAIM can be formulated as Bayesian inference. Crucially, SAIM uses excitatory feedback to combine top-down information (i.e. object knowledge) with bottom-up sensory information. By contrast, predictive coding implementations of Bayesian inference use inhibitory feedback. By formulating SAIM as a predictive coding scheme, we created a new version of SAIM that uses inhibitory feedback. Simulation studies showed that both types of architectures can reproduce the response time costs induced by multiple objects—as found in visual search experiments. However, due to the different nature of the feedback, the two SAIM schemes make distinct predictions about the motifs of microcircuits mediating the effects of top-down afferents. We discuss empirical (neuroimaging) methods to test the predictions of the two inference architectures.

Excitatory versus inhibitory feedback in Bayesian formulations of scene construction

Dynamic causal modelling of neurological pathology : Using neural mass models to understand dynamic dysfunction in NMDA-receptor antibody encephalitis

A guide to group effective connectivity analysis, part 2: Second level analysis with PEB

The meta-problem of consciousness (Chalmers (this issue)) is the problem of explaining the behaviors and verbal reports that we associate with the so-called ‘hard problem of consciousness’. These may include reports of puzzlement, of the attractiveness of dualism, of explanatory gaps, and the like. We present and defend a solution to the meta-problem. Our solution takes as its starting point the emerging picture of the brain as a hierarchical inference engine. We show why such a device, operating under familiar forms of adaptive pressure, may come to represent some of its mid-level inferences as especially certain. These mid-level states confidently re-code raw sensory stimulation in ways that (they are able to realize) fall short of fully determining how properties and states of affairs are arranged in the distal world. This drives a wedge between experience and the world. Advanced agents then represent these mid-level inferences as irreducibly special, becoming increasingly puzzled as a result.

Emotional awareness (EA) is recognized as clinically relevant to the vulnerability to, and maintenance of, psychiatric disorders. However, the neurocomputational processes that underwrite individual variations remain unclear. In this paper, we describe a deep (active) inference model that reproduces the cognitive-emotional processes and self-report behaviors associated with EA. We then present simulations to illustrate (seven) distinct mechanisms that (either alone or in combination) can produce phenomena – such as somatic misattribution, coarse-grained emotion conceptualization, and constrained reflective capacity – characteristic of low EA. Our simulations suggest that the clinical phenotype of impoverished EA can be reproduced by dissociable computational processes. The possibility that different processes are at work in different individuals suggests that they may benefit from distinct clinical interventions. As active inference makes particular predictions about the underlying neurobiology of such aberrant inference, we also discuss how this type of modelling could be used to design neuroimaging tasks to test predictions and identify which processes operate in different individuals – and provide a principled basis for personalized precision medicine.

Neurocomputational mechanisms underlying emotional awareness: Insights afforded by deep active inference and their potential clinical relevance

In this chapter, we provide an overview of the principles of active inference. We illustrate how different forms of short-term memory are expressed formally (mathematically) through appealing to beliefs about the causes of our sensations, and about the actions we pursue. This is used to motivate an approach to active vision that depends upon inferences about the causes of ‘what I have seen’ and learning about ‘what I would see if I were to look there’. The former could manifest as persistent ‘delay-period’ activity – of the sort associated with working memory, while the latter is better suited to changes in synaptic efficacy – of the sort that underlies short-term learning and adaptation. We review formulations of these ideas in terms of active inference, their role in directing visual exploration, and the consequences – for active vision – of their failures. To illustrate the latter, we draw upon some of our recent work on the computational anatomy of visual neglect.

Novelty and neglect 1 Chapter : Active inference , novelty , and neglect

The ability to conceptualize and understand one’s own affective states and responses – or “Emotional awareness” (EA) – is reduced in multiple psychiatric populations; it is also positively correlated with a range of adaptive cognitive and emotional traits. While a growing body of work has investigated the neurocognitive basis of EA, the neurocomputational processes underlying this ability have received limited attention. Here, we present a formal Active Inference (AI) model of emotion conceptualization that can simulate the neurocomputational (Bayesian) processes associated with learning about emotion concepts and inferring the emotions one is feeling in a given moment. We validate the model and inherent constructs by showing (i) it can successfully acquire a repertoire of emotion concepts in its “childhood”, as well as (ii) acquire new emotion concepts in synthetic “adulthood,” and (iii) that these learning processes depend on early experiences, environmental stability, and habitual patterns of selective attention. These results offer a proof of principle that cognitive-emotional processes can be modeled formally, and highlight the potential for both theoretical and empirical extensions of this line of research on emotion and emotional disorders.

Simulating Emotions: An Active Inference Model of Emotional State Inference and Emotion Concept Learning

Active inference, stressors, and psychological trauma: A neuroethological model of (mal)adaptive explore-exploit dynamics in ecological context

Abstract To control our actions efficiently, our brain represents our body based on a combination of visual and proprioceptive cues, weighted according to how (un)reliable—how precise—each respective modality is in a given context. However, perceptual experiments in other modalities suggest that the weights assigned to sensory cues are also modulated “top-down” by attention. Here, we asked whether during action, attention can likewise modulate the weights (i.e., precision) assigned to visual versus proprioceptive information about body position. Participants controlled a virtual hand (VH) via a data glove, matching either the VH or their (unseen) real hand (RH) movements to a target, and thus adopting a ``visual'' or ``proprioceptive'' attentional set, under varying levels of visuo-proprioceptive congruence and visibility. Functional magnetic resonance imaging (fMRI) revealed increased activation of the multisensory superior parietal lobe (SPL) during the VH task and increased activation of the secondary somatosensory cortex (S2) during the RH task. Dynamic causal modeling (DCM) showed that these activity changes were the result of selective, diametrical gain modulations in the primary visual cortex (V1) and the S2. These results suggest that endogenous attention can balance the gain of visual versus proprioceptive brain areas, thus contextualizing their influence on multisensory areas representing the body for action.

Attentional Modulation of Vision Versus Proprioception During Action

ABSTRACT Introduction: Recent advances in research on stress and, respectively, on disorders of perception, learning, and behaviour speak to a promising synthesis of current insights from (i) neurobiology, cognitive neuroscience and psychology of stress and post-traumatic stress disorder (PTSD), and (ii) computational psychiatry approaches to pathophysiology (e.g. of schizophrenia and autism). Methods: Specifically, we apply this synthesis to PTSD. The framework of active inference offers an embodied and embedded lens through which to understand neuronal mechanisms, structures, and processes of cognitive function and dysfunction. In turn, this offers an explanatory model of how healthy mental functioning can go awry due to psychopathological conditions that impair inference about our environment and our bodies. In this context, auditory phenomena—known to be especially relevant to studies of PTSD and schizophrenia—and traditional models of auditory function can be viewed from an evolutionary perspective based on active inference. Results: We assess and contextualise a range of evidence on audition, stress, psychosis, and PTSD, and bring some existing partial models of PTSD into multilevel alignment. Conclusions: The novel perspective on PTSD we present aims to serve as a basis for new experimental designs and therapeutic interventions that integrate fundamentally biological, cognitive, behavioural, and environmental factors.

Reframing PTSD for computational psychiatry with the active inference framework

Abstract The prefrontal cortex is vital for a range of cognitive processes, including working memory, attention, and decision-making. Notably, its absence impairs the performance of tasks requiring the maintenance of information through a delay period. In this paper, we formulate a rodent task—which requires maintenance of delay-period activity—as a Markov decision process and treat optimal task performance as an (active) inference problem. We simulate the behavior of a Bayes optimal mouse presented with 1 of 2 cues that instructs the selection of concurrent visual and auditory targets on a trial-by-trial basis. Formulating inference as message passing, we reproduce features of neuronal coupling within and between prefrontal regions engaged by this task. We focus on the micro-circuitry that underwrites delay-period activity and relate it to functional specialization within the prefrontal cortex in primates. Finally, we simulate the electrophysiological correlates of inference and demonstrate the consequences of lesions to each part of our in silico prefrontal cortex. In brief, this formulation suggests that recurrent excitatory connections—which support persistent neuronal activity—encode beliefs about transition probabilities over time. We argue that attentional modulation can be understood as the contextualization of sensory input by these persistent beliefs.

Thalamocortical dynamics underlying spontaneous transitions in beta power in Parkinsonism

Successful behaviour depends on the right balance between maximising reward and soliciting information about the world. Here, we show how different types of information-gain emerge when casting behaviour as surprise minimisation. We present two distinct mechanisms for goal-directed exploration that express separable profiles of active sampling to reduce uncertainty. ‘Hidden state’ exploration motivates agents to sample unambiguous observations to accurately infer the (hidden) state of the world. Conversely, ‘model parameter’ exploration, compels agents to sample outcomes associated with high uncertainty, if they are informative for their representation of the task structure. We illustrate the emergence of these types of information-gain, termed active inference and active learning, and show how these forms of exploration induce distinct patterns of ‘Bayes-optimal’ behaviour. Our findings provide a computational framework to understand how distinct levels of uncertainty induce different modes of information-gain in decision-making.

Computational mechanisms of curiosity and goal-directed exploration

Variability and reliability of effective connectivity within the core default mode network: A multi-site longitudinal spectral DCM study

The locus coeruleus (LC) in the pons is the major source of noradrenaline (NA) in the brain. Two modes of LC firing have been associated with distinct cognitive states: changes in tonic rates of firing are correlated with global levels of arousal and behavioural flexibility, whilst phasic LC responses are evoked by salient stimuli. Here, we unify these two modes of firing by modelling the response of the LC as a correlate of a prediction error when inferring states for action planning under Active Inference (AI). We simulate a classic Go/No-go reward learning task and a three-arm foraging task and show that, if LC activity is considered to reflect the magnitude of high level ‘state-action’ prediction errors, then both tonic and phasic modes of firing are emergent features of belief updating. We also demonstrate that when contingencies change, AI agents can update their internal models more quickly by feeding back this state-action prediction error – reflected in LC firing and noradrenaline release – to optimise learning rate, enabling large adjustments over short timescales. We propose that such prediction errors are mediated by cortico-LC connections, whilst ascending input from LC to cortex modulates belief updating in anterior cingulate cortex (ACC). In short, we characterise the LC/ NA system within a general theory of brain function. In doing so, we show that contrasting, behaviour-dependent firing patterns are an emergent property of the LC’s crucial role in translating prediction errors into an optimal mediation between plasticity and stability. Author Summary The brain uses sensory information to build internal models and make predictions about the world. When errors of prediction occur, models must be updated to ensure desired outcomes are still achieved. Neuromodulator chemicals provide a possible pathway for triggering such changes in brain state. One such neuromodulator, noradrenaline, originates predominantly from a cluster of neurons in the brainstem – the locus coeruleus (LC) – and plays a key role in behaviour, for instance, in determining the balance between exploiting or exploring the environment. Here we use Active Inference (AI), a mathematical model of perception and action, to formally describe LC function. We propose that LC activity is triggered by errors in prediction and that the subsequent release of noradrenaline alters the rate of learning about the environment. Biologically, this describes an LC-cortex feedback loop promoting behavioural flexibility in times of uncertainty. We model LC output as a simulated animal performs two tasks known to elicit archetypal responses. We find that experimentally observed ‘phasic’ and ‘tonic’ patterns of LC activity emerge naturally, and that modulation of learning rates improves task performance. This provides a simple, unified computational account of noradrenergic computational function within a general model of behaviour.

Locus Coeruleus tracking of prediction errors optimises cognitive flexibility: An Active Inference model

Free-energy minimization in joint agent-environment systems: A niche construction perspective

Energy homeostasis depends on behavior to predictively regulate metabolic states within narrow bounds. Here we review three theories of homeostatic control and ask how they provide insight into the circuitry underlying energy homeostasis. We offer two contributions. First, we detail how control theory and reinforcement learning are applied to homeostatic control. We show how these schemes rest on implausible assumptions; either via circular definitions, unprincipled drive functions, or by ignoring environmental volatility. We argue active inference can elude these shortcomings while retaining important features of each model. Second, we review the neural basis of energetic control. We focus on a subset of arcuate subpopulations that project directly to, and are thus in a privileged position to opponently modulate, dopaminergic cells as a function of energetic predictions over a spectrum of time horizons. We discuss how this can be interpreted under these theories, and how this can resolve paradoxes that have arisen. We propose this circuit constitutes a homeostatic-reward interface that underwrites the conjoint optimisation of physiological and behavioural homeostasis.

Is self-consciousness necessary for consciousness? The answer is yes. So there you have it—the answer is yes. This was my response to a question I was asked to address in a recent AEON piece (https://aeon.co/essays/consciousness-is-not-a-thing-but-a-process-of-inference). What follows is based upon the notes for that essay, with a special focus on self-organization, self-evidencing and self-modeling. I will try to substantiate my (polemic) answer from the perspective of a physicist. In brief, the argument goes as follows: if we want to talk about creatures, like ourselves, then we have to identify the characteristic behaviors they must exhibit. This is fairly easy to do by noting that living systems return to a set of attracting states time and time again. Mathematically, this implies the existence of a Lyapunov function that turns out to be model evidence (i.e., self-evidence) in Bayesian statistics or surprise (i.e., self-information) in information theory. This means that all biological processes can be construed as performing some form of inference, from evolution through to conscious processing. If this is the case, at what point do we invoke consciousness? The proposal on offer here is that the mind comes into being when self-evidencing has a temporal thickness or counterfactual depth, which grounds inferences about the consequences of my action. On this view, consciousness is nothing more than inference about my future; namely, the self-evidencing consequences of what I could do.

Am I Self-Conscious? (Or Does Self-Organization Entail Self-Consciousness?)

Models of coupled oscillators are useful in describing a wide variety of phenomena in physics, biology and economics. These models typically rest on the premise that the oscillators are weakly coupled, meaning that amplitudes can be assumed to be constant and dynamics can therefore be described purely in terms of phase differences. Whilst mathematically convenient, the restrictive nature of the weak coupling assumption can limit the explanatory power of these phase-coupled oscillator models. We therefore propose an extension to the weakly-coupled oscillator model that incorporates both amplitude and phase as dependent variables. We use the bilinear neuronal state equations of dynamic causal modelling as a foundation in deriving coupled differential equations that describe the activity of both weakly and strongly coupled oscillators. We show that weakly-coupled oscillator models are inadequate in describing the processes underlying the temporally variable signals observed in a variety of systems. We demonstrate that phase-coupled models perform well on simulations of weakly coupled systems but fail when connectivity is no longer weak. On the other hand, using Bayesian model selection, we show that our phase-amplitude coupling model can describe non-weakly coupled systems more effectively despite the added complexity associated with using amplitude as an extra dependent variable. We demonstrate the advantage of our phase-amplitude model in the context of model-generated data, as well as of a simulation of inter-connected pendula, neural local field potential recordings in rodents under anaesthesia and international economic gross domestic product data.

Breaking the bonds of weak coupling: the dynamic causal modelling of oscillator amplitudes

Accurate perceptual inference fundamentally depends upon accurate beliefs about the reliability of sensory data. In this paper, we describe a Bayes optimal and biologically plausible scheme that refines these beliefs through a gradient descent on variational free energy. To illustrate this, we simulate belief updating during visual foraging and show that changes in estimated sensory precision (i.e., confidence in visual data) are highly sensitive to prior beliefs about the contents of a visual scene. In brief, confident prior beliefs induce an increase in estimated precision when consistent with sensory evidence, but a decrease when they conflict. Prior beliefs held with low confidence are rapidly updated to posterior beliefs, determined by sensory data. These induce much smaller changes in beliefs about sensory precision. We argue that pathologies of scene construction may be due to abnormal priors, and show that these can induce a reduction in estimated sensory precision. Having previously associated this precision with cholinergic signaling, we note that several neurodegenerative conditions are associated with visual disturbances and cholinergic deficits; notably, the synucleinopathies. On relating the message passing in our model to the functional anatomy of the ventral visual stream, we find that simulated neuronal loss in temporal lobe regions induces confident, inaccurate, empirical prior beliefs at lower levels in the visual hierarchy. This provides a plausible, if speculative, computational mechanism for the loss of cholinergic signaling and the visual disturbances associated with temporal lobe Lewy body pathology. This may be seen as an illustration of the sorts of hypotheses that may be expressed within this computational framework.

This paper addresses the formation of infant attachment types within the context of active inference: a holistic account of action, perception and learning in the brain. We show how the organised forms of attachment (secure, avoidant and ambivalent) might arise in (Bayesian) infants. Specifically, we show that these distinct forms of attachment emerge from a minimisation of free energy—over interoceptive states relating to internal stress levels—when seeking proximity to caregivers who have a varying impact on these interoceptive states. In line with empirical findings in disrupted patterns of affective communication, we then demonstrate how exteroceptive cues (in the form of caregiver-mediated AMBIANCE affective communication errors, ACE) can result in disorganised forms of attachment in infants of caregivers who consistently increase stress when the infant seeks proximity, but can have an organising (towards ambivalence) effect in infants of inconsistent caregivers. In particular, we differentiate disorganised attachment from avoidance in terms of the high epistemic value of proximity seeking behaviours (resulting from the caregiver’s misleading exteroceptive cues) that preclude the emergence of coherent and organised behavioural policies. Our work, the first to formulate infant attachment in terms of active inference, makes a new testable prediction with regards to the types of affective communication errors that engender ambivalent attachment.

Intrinsic and extrinsic motivators of attachment under active inference

Objective To quantify atrophy, demyelination, and iron accumulation over 2 years following acute spinal cord injury and to identify MRI predictors of clinical outcomes and determine their suitability as surrogate markers of therapeutic intervention. Methods We assessed 156 quantitative MRI datasets from 15 patients with spinal cord injury and 18 controls at baseline and 2, 6, 12, and 24 months after injury. Clinical recovery (including neuropathic pain) was assessed at each time point. Between-group di ﬀ erences in linear and nonlinear trajectories of volume, myelin, and iron change were estimated. Structural changes by 6 months were used to predict clinical outcomes at 2 years. The majority of patients showed clinical improvement with recovery stabilizing at 2 years. Cord atrophy decelerated, while cortical white and gray matter atrophy progressed over 2 years. Myelin content in the spinal cord and cortex decreased progressively over time, while cerebellar loss decreases decelerated. As atrophy progressed in the thalamus, sustained iron accumulation was evident. Smaller cord and cranial corticospinal tract atrophy, and myelin changes within the sensorimotor cortices, by 6 months predicted recovery in lower extremity motor score at 2 years. Whereas greater cord atrophy and microstructural changes in the cerebellum, anterior cingulate cortex, and secondary sensory cortex by 6 months predicted worse sensory impairment and greater neuropathic pain intensity at 2 years. in-timate relationships among neurodegenerative processes in the cord and brain. These mea-surable changes are su ﬃ ciently large, systematic, and predictive to render them viable outcome measures for clinical trials. SCI patients show volumetric declines, and progressive alterations in spinal cord, cortical and subcortical measures of myelination and iron-accumulation compared to controls. Various 6-month MRI changes can predict 2-year clinical outcomes. trajectory, for aspects and iron accumulation. This study provides longitudinal evidence (with 5 scans within patients) for cord and brain progression over 2 years after injury and evidence that the changes detected on structural MRI data between baseline and 6 months post-SCI can predict long-term outcomes.

Progressive neurodegeneration following spinal cord injury Implications for clinical trials

In previous papers, we introduced a normative scheme for scene construction and epistemic (visual) searches based upon active inference. This scheme provides a principled account of how people decide where to look, when categorising a visual scene based on its contents. In this paper, we use active inference to explain the visual searches of normal human subjects; enabling us to answer some key questions about visual foraging and salience attribution. First, we asked whether there is any evidence for ‘epistemic foraging’; i.e. exploration that resolves uncertainty about a scene. In brief, we used Bayesian model comparison to compare Markov decision process (MDP) models of scan-paths that did–and did not–contain the epistemic, uncertainty-resolving imperatives for action selection. In the course of this model comparison, we discovered that it was necessary to include non-epistemic (heuristic) policies to explain observed behaviour (e.g., a reading-like strategy that involved scanning from left to right). Despite this use of heuristic policies, model comparison showed that there is substantial evidence for epistemic foraging in the visual exploration of even simple scenes. Second, we compared MDP models that did–and did not–allow for changes in prior expectations over successive blocks of the visual search paradigm. We found that implicit prior beliefs about the speed and accuracy of visual searches changed systematically with experience. Finally, we characterised intersubject variability in terms of subject-specific prior beliefs. Specifically, we used canonical correlation analysis to see if there were any mixtures of prior expectations that could predict between-subject differences in performance; thereby establishing a quantitative link between different behavioural phenotypes and Bayesian belief updating. We demonstrated that better scene categorisation performance is consistently associated with lower reliance on heuristics; i.e., a greater use of a generative model of the scene to direct its exploration.

Human visual exploration reduces uncertainty about the sensed world

We compare two free energy functionals for active inference under Markov decision processes. One of these is a functional of beliefs about states and policies, but a function of observations, while the second is a functional of beliefs about all three. In the former (expected free energy), prior beliefs about outcomes are not part of the generative model (because they are absorbed into the prior over policies). Conversely, in the second (generalised free energy); priors over outcomes become an explicit component of the generative model. When using the free energy function, which is blind to counterfactual (i.e., future) observations, we equip the generative model with a prior over policies that ensure preferred (i.e., priors over) outcomes are realised. In other words, selected policies minimise uncertainty about future outcomes by minimising the free energy expected in the future. When using the free energy functional – that effectively treats counterfactual observations as hidden states – we show that policies are inferred or selected that realise prior preferences by minimising the free energy of future expectations. Interestingly, the form of posterior beliefs about policies (and associated belief updating) turns out to be identical under both formulations, but the quantities used to compute them are not.

Generalised free energy and active inference: can the future cause the past?

Auditory verbal hallucinations (AVH) are often distressing symptoms of several neuropsychiatric conditions, including schizophrenia. Using a Markov decision process formulation of active inference, we develop a novel model of AVH as false (positive) inference. Active inference treats perception as a process of hypothesis testing, in which sensory data are used to disambiguate between alternative hypotheses about the world. Crucially, this depends upon a delicate balance between prior beliefs about unobserved (hidden) variables and the sensations they cause. A false inference that a voice is present, even in the absence of auditory sensations, suggests that prior beliefs dominate perceptual inference. Here we consider the computational mechanisms that could cause this imbalance in perception. Through simulation, we show that the content of (and confidence in) prior beliefs depends on beliefs about policies (here sequences of listening and talking) and on beliefs about the reliability of sensory data. We demonstrate several ways in which hallucinatory percepts could occur when an agent expects to hear a voice in the presence of imprecise sensory data. This model expresses, in formal terms, alternative computational mechanisms that underwrite AVH and, speculatively, can be mapped onto neurobiological changes associated with schizophrenia. The interaction of action and perception is important in modeling AVH, given that speech is a fundamentally enactive and interactive process—and that hallucinators often actively engage with their voices.

Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul, South Korea BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea The Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom, Bioimaging Research Team, Korea Basic Science Institute, Cheongju-si, Chungcheongbuk-do, South Korea Department of Cognitive Science, Yonsei University, Seoul, South Korea, Department of Bioconvergence Analysis, Korea Basic Science Institute, Cheongju-si, Chungcheongbuk-do, South Korea

Effective connectivity under task and resting states : a DCM study

The proportional recovery rule asserts that most stroke survivors recover a fixed proportion of lost function. To the extent that this is true, recovery from stroke can be predicted accurately from baseline measures of acute post-stroke impairment alone. Reports that baseline scores explain more than 80%, and sometimes more than 90%, of the variance in the patients’ recoveries, are rapidly accumulating. Here, we show that these headline effect sizes are likely inflated. The key effects in this literature are typically expressed as, or reducible to, correlation coefficients between baseline scores and recovery (outcome scores minus baseline scores). Using formal analyses and simulations, we show that these correlations will be extreme when outcomes are significantly less variable than baselines, which they often will be in practice regardless of the real relationship between outcomes and baselines. We show that these effect sizes are likely to be over-optimistic in every empirical study that we found that reported enough information for us to make the judgement, and argue that the same is likely to be true in other studies as well. The implication is that recovery after stroke may not be as proportional as recent studies suggest.

Corrigendum: Rapid Eye Movements in Sleep Furnish a Unique Probe Into Consciousness

Knowing how other people’s preferences relate to our own is a central aspect of social cognition, yet how the brain performs this perspective taking is unclear. Here, we ask whether the putative role of the hippocampal formation in transforming first person and extrapersonal spatial cues during navigation extends to social learning. In our experiment, subjects learn a stranger’s preference for an everyday activity – relative to a personally familiar individual – and subsequently decide how the stranger's preference relates to further familiar people. We observed hippocampal responses during decisions that require precise social judgments. Investigating reference frame sensitive responses, we identified an entorhinal/subicular region responding to finely resolved decisions involving self-comparisons, but more straightforward choices otherwise. Our data highlight a potential hippocampal-entorhinal division of labor that helps assimilate newly learned information about others into our prior beliefs about the prosocial world.

The hippocampal formation facilitates social decision-making by transforming reference frames.

Interoceptive inference: From computational neuroscience to clinic

To infer the causes of its sensations, the brain must call on a generative (predictive) model. This necessitates passing local messages between populations of neurons to update beliefs about hidden variables in the world beyond its sensory samples. It also entails inferences about how we will act. Active inference is a principled framework that frames perception and action as approximate Bayesian inference. This has been successful in accounting for a wide range of physiological and behavioral phenomena. Recently, a process theory has emerged that attempts to relate inferences to their neurobiological substrates. In this paper, we review and develop the anatomical aspects of this process theory. We argue that the form of the generative models required for inference constrains the way in which brain regions connect to one another. Specifically, neuronal populations representing beliefs about a variable must receive input from populations representing the Markov blanket of that variable. We illustrate this idea in four different domains: perception, planning, attention, and movement. In doing so, we attempt to show how appealing to generative models enables us to account for anatomical brain architectures. Ultimately, committing to an anatomical theory of inference ensures we can form empirical hypotheses that can be tested using neuroimaging, neuropsychological, and electrophysiological experiments.

The emerging neurocomputational vision of humans as embodied, ecologically embedded, social agents—who shape and are shaped by their environment—offers a golden opportunity to revisit and revise ideas about the physical and information-theoretic underpinnings of life, mind, and consciousness itself. In particular, the active inference framework (AIF) makes it possible to bridge connections from computational neuroscience and robotics/AI to ecological psychology and phenomenology, revealing common underpinnings and overcoming key limitations. AIF opposes the mechanistic to the reductive, while staying fully grounded in a naturalistic and information-theoretic foundation, using the principle of free energy minimization. The latter provides a theoretical basis for a unified treatment of particles, organisms, and interactive machines, spanning from the inorganic to organic, non-life to life, and natural to artificial agents. We provide a brief introduction to AIF, then explore its implications for evolutionary theory, ecological psychology, embodied phenomenology, and robotics/AI research. We conclude the paper by considering implications for machine consciousness.

The Active Inference Approach to Ecological Perception: General Information Dynamics for Natural and Artificial Embodied Cognition

You are well known for being the founder of the free energy principle, a wideranging theoretical framework aiming to unify the psychological, neural and biological nature of living beings (Friston, 2010, 2013; Ramstead, Badcock, & Friston, 2017). When did you first come up with the idea of the free energy principle? How did this first insight gradually develop to the point of being such a groundbreaking framework?

Of woodlice and men A Bayesian account of cognition , life and consciousness

To exhibit social intelligence, animals have to recognize who they are communicating with. One way to make this inference is to select among multiple internal generative models of each conspecific. This induces an interesting problem: when receiving sensory input generated by a particular conspecific, how does an animal know which internal model to update? We consider a theoretical and neurobiologically plausible solution that enables inference and learning under multiple generative models by integrating active inference and (online) Bayesian model selection. This scheme fits sensory inputs under each generative model. Model parameters are then updated in proportion to the probability it could have generated the current input (i.e., model evidence). We show that a synthetic bird who employs the proposed scheme successfully learns and distinguishes (real zebra finch) birdsongs generated by several different birds. These results highlight the utility of having multiple internal models to make inferences in complicated social environments.

Dynamic causal modelling (DCM) for resting state fMRI – namely spectral DCM – is a recently developed and widely adopted method for inferring effective connectivity in intrinsic brain networks. Most research applying spectral DCM has focused on group-averaged connectivity within large-scale intrinsic brain networks; however, the consistency of subject- and session-specific estimates of effective connectivity has not been evaluated. Establishing reliability (within subjects) is crucial for its clinical use; e.g., as a neurophysiological phenotype of disease progression. Effective connectivity during rest is likely to vary due to changes in cognitive, behavioural, and physical states. Determining the sources of fluctuations in effective connectivity may yield greater understanding of brain processes and inform clinical applications about potential confounds. In the present study, we investigated the consistency of effective connectivity within and between subjects, as well as potential sources of variability (e.g., hemispheric asymmetry). We further investigated how standard procedures for data processing and signal extraction affect this consistency. DCM analyses were applied to four longitudinal resting state fMRI datasets. Our sample consisted of 20 subjects with 653 resting state fMRI sessions in total. These data allowed to quantify the robustness of connectivity estimates for each subject, and to draw conclusions beyond specific data features. We found that subjects contributing to all datasets showed systematic and reliable patterns of hemispheric asymmetry. When asymmetry was taken into account, subjects showed very similar connectivity patterns. We also found that various processing procedures (e.g. global signal regression and ROI size) had little effect on inference and reliability of connectivity for the majority of subjects. Bayesian model reduction increased reliability (within-subjects) and stability (between-subjects) of connectivity patterns.

Variability and reliability of effective connectivity within the core default mode network: A longitudinal spectral DCM study

To act upon the world, creatures must change continuous variables such as muscle length or chemical concentration. In contrast, decision making is an inherently discrete process, involving the selection among alternative courses of action. In this article, we consider the interface between the discrete and continuous processes that translate our decisions into movement in a Newtonian world—and how movement informs our decisions. We do so by appealing to active inference, with a special focus on the oculomotor system. Within this exemplar system, we argue that the superior colliculus is well placed to act as a discrete-continuous interface. Interestingly, when the neuronal computations within the superior colliculus are formulated in terms of active inference, we find that many aspects of its neuroanatomy emerge from the computations it must perform in this role.

The Discrete and Continuous Brain: From Decisions to Movement—And Back Again

Effective connectivity during working memory and resting states: A DCM study

Understanding the neural substrates of depression is crucial for diagnosis and treatment. Here, we review recent studies of functional and effective connectivity in depression, in terms of functional integration in the brain. Findings from these studies, including our own, point to the involvement of at least four networks in patients with depression. Elevated connectivity of a ventral limbic affective network appears to be associated with excessive negative mood (dysphoria) in the patients; decreased connectivity of a frontal‐striatal reward network has been suggested to account for loss of interest, motivation, and pleasure (anhedonia); enhanced default mode network connectivity seems to be associated with depressive rumination; and diminished connectivity of a dorsal cognitive control network is thought to underlie cognitive deficits especially ineffective top‐down control of negative thoughts and emotions in depressed patients. Moreover, the restoration of connectivity of these networks—and corresponding symptom improvement—following antidepressant treatment (including medication, psychotherapy, and brain stimulation techniques) serves as evidence for the crucial role of these networks in the pathophysiology of depression.

A brain network model for depression: From symptom understanding to disease intervention

Knowing how another’s preferences relate to our own is a central aspect of everyday decision-making, yet how the brain performs this transformation is unclear. Here, we ask whether the putative role of the hippocampal-entorhinal system in transforming first person and extra-personal spatial cues during navigation extends to transformations in abstract decision spaces. In our functional magnetic resonance imaging study, subjects learned a stranger’s preference for an everyday activity – relative to a personally known individual – and subsequently decided how the stranger’s preference relates to other familiar people’s preferences. Across reference frames, we observed signals in the retrosplenial cortex and hippocampal body during decisions that require precise memories for preferences. In contrast, the entorhinal cortex/subiculum exhibited reference frame-sensitive responses to the relative distance between the ratings of the stranger and the familiar choice options. Taken together, these data implicate the hippocampal-entorhinal system in the assimilation of knowledge in an abstract metric space.

Hippocampal-entorhinal transformations in abstract frames of reference

Investigating the relationship between cardiac interoception and autonomic cardiac control using a predictive coding framework

Knowing when to stop: Aberrant precision and evidence accumulation in schizophrenia

One of the central claims of the Self-model Theory of Subjectivity is that the experience of being someone – even in a minimal form – arises through a transparent phenomenal self-model, which itself can in principle be reduced to brain processes. Here, we consider whether it is possible to distinguish between phenomenally transparent and opaque states in terms of active inference. We propose a relationship of phenomenal opacity to expected uncertainty or precision; i.e., the capacity for introspective attention and implicit mental action. Thus we associate introspective attention with the deployment of ‘precision’ that may render the perceptual evidence (for action) opaque, while treating transparency as a necessary aspect of beliefs about action, i.e., ‘what I am’ doing. We conclude by proposing how we may have to nuance our conception of minimal phenomenal selfhood and agency in light of this active inference conception of transparency-opacity.

‘Seeing the Dark’: Grounding Phenomenal Transparency and Opacity in Precision Estimation for Active Inference

A fundamental question in systems neuroscience is how spontaneous activity at rest is reorganized during task performance. Recent studies suggest a strong relationship between resting and task FC. Furthermore, the relationship between resting and task FC has been shown to reflect individual differences. Particularly, various studies have demonstrated that the FC has higher reliability and provides enhanced detection of individual differences while viewing natural scenes. Although the large-scale organization of FC during rest and movie-viewing conditions have been well studied in relation to individual variations, the re-organization of FC during viewing natural scenes have not been studied in depth. In this study, we used principal component analysis on FC during rest and movie-viewing condition to characterize the dimensionality of FC patterns across conditions and subjects. We found that the variations in FC patterns related to viewing natural scenes can be explained by a single component, which enables identification of the task over subjects with 100% accuracy. We showed that the FC mode associated to viewing natural scenes better reflects individual variations. Furthermore, we investigated the signatures of movie-viewing-specific functional modes in dynamic FC based on phase-locking values between brain regions. We found that the movie-specific functional mode is persistent across time; suggesting the emergence of a stable processing mode. To explain the reorganization of whole-brain FC through the changes in local dynamics, we appeal to a large-scale computational model. This modelling suggested that the reorganization of whole-brain FC is associated to the interaction between frontal-parietal and frontal-temporal activation patterns.

Distinct Functional Connectivity Mode during Viewing Natural Scenes Revealed by Principal Component Analysis

effective connectivity: a Dynamic causal modeling of ASL data Martin Havlicek, Alard Roebroeck, Karl J. Friston, Anna Gardumi, Dimo Ivanov, Kamil Uludag 1 Dept. of Cognitive Neuroscience, Faculty of Psychology and Neuroscience, Maastricht University, 6200MD Maastricht, The Netherlands; 2 Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London WC1N 3BG, United Kingdom.

On the importance of modeling fMRI response transients for effective connectivity: a Dynamic causal modeling of ASL data

Variational neuroethology: Answering further questions: Reply to comments on "Answering Schrödinger's question: A free-energy formulation".

This paper reviews recent developments in statistical structure learning; namely, Bayesian model reduction. Bayesian model reduction is a method for rapidly computing the evidence and parameters of probabilistic models that differ only in their priors. In the setting of variational Bayes this has an analytical solution, which finesses the problem of scoring large model spaces in model comparison or structure learning. In this technical note, we review Bayesian model reduction and provide the relevant equations for several discrete and continuous probability distributions. We provide worked examples in the context of multivariate linear regression, Gaussian mixture models and dynamical systems (dynamic causal modelling). These examples are accompanied by the Matlab scripts necessary to reproduce the results. Finally, we briefly review recent applications in the fields of neuroimaging and neuroscience. Specifically, we consider structure learning and hierarchical or empirical Bayes that can be regarded as a metaphor for neurobiological processes like abductive reasoning.

Using predictions based on environmental regularities is fundamental for adaptive behavior. While it is widely accepted that predictions across different stimulus attributes (e.g., time and content) facilitate sensory processing, it is unknown whether predictions across these attributes rely on the same neural mechanism. Here, to elucidate the neural mechanisms of predictions, we combine invasive electrophysiological recordings (human electrocorticography in 4 females and 2 males) with computational modeling while manipulating predictions about content (“what”) and time (“when”). We found that “when” predictions increased evoked activity over motor and prefrontal regions both at early (∼180 ms) and late (430–450 ms) latencies. “What” predictability, however, increased evoked activity only over prefrontal areas late in time (420–460 ms). Beyond these dissociable influences, we found that “what” and “when” predictability interactively modulated the amplitude of early (165 ms) evoked responses in the superior temporal gyrus. We modeled the observed neural responses using biophysically realistic neural mass models, to better understand whether “what” and “when” predictions tap into similar or different neurophysiological mechanisms. Our modeling results suggest that “what” and “when” predictability rely on complementary neural processes: “what” predictions increased short-term plasticity in auditory areas, whereas “when” predictability increased synaptic gain in motor areas. Thus, content and temporal predictions engage complementary neural mechanisms in different regions, suggesting domain-specific prediction signaling along the cortical hierarchy. Encoding predictions through different mechanisms may endow the brain with the flexibility to efficiently signal different sources of predictions, weight them by their reliability, and allow for their encoding without mutual interference. SIGNIFICANCE STATEMENT Predictions of different stimulus features facilitate sensory processing. However, it is unclear whether predictions of different attributes rely on similar or different neural mechanisms. By combining invasive electrophysiological recordings of cortical activity with experimental manipulations of participants' predictions about content and time of acoustic events, we found that the two types of predictions had dissociable influences on cortical activity, both in terms of the regions involved and the timing of the observed effects. Further, our biophysical modeling analysis suggests that predictability of content and time rely on complementary neural processes: short-term plasticity in auditory areas and synaptic gain in motor areas, respectively. This suggests that predictions of different features are encoded with complementary neural mechanisms in different brain regions.

Not All Predictions Are Equal: “What” and “When” Predictions Modulate Activity in Auditory Cortex through Different Mechanisms

MULAN: Evaluation and ensemble statistical inference for functional connectivity

We summarize our recently introduced Projective Consciousness Model (PCM) (Rudrauf et al., 2017) and relate it to outstanding conceptual issues in the theory of consciousness. The PCM combines a projective geometrical model of the perspectival phenomenological structure of the field of consciousness with a variational Free Energy minimization model of active inference, yielding an account of the cybernetic function of consciousness, viz., the modulation of the field’s cognitive and affective dynamics for the effective control of embodied agents. The geometrical and active inference components are linked via the concept of projective transformation, which is crucial to understanding how conscious organisms integrate perception, emotion, memory, reasoning, and perspectival imagination in order to control behavior, enhance resilience, and optimize preference satisfaction. The PCM makes substantive empirical predictions and fits well into a (neuro)computationalist framework. It also helps us to account for aspects of subjective character that are sometimes ignored or conflated: pre-reflective self-consciousness, the first-person point of view, the sense of minenness or ownership, and social self-consciousness. We argue that the PCM, though still in development, offers us the most complete theory to date of what Thomas Metzinger has called “phenomenal selfhood.”

This article proposes a formal model that integrates cognitive and psychodynamic psychotherapeutic models of psychopathy to show how two major psychopathic traits called lacks remorse and self-aggrandizing can be understood as a form of abnormal Bayesian inference about the self. This model draws on the predictive coding (i.e., active inference) framework, a neurobiologically plausible explanatory framework for message passing in the brain that is formalized in terms of hierarchical Bayesian inference. In summary, this model proposes that these two cardinal psychopathic traits reflect entrenched maladaptive Bayesian inferences about the self, which defend against the experience of deep-seated, self-related negative emotions, specifically shame and worthlessness. Support for the model in extant research on the neurobiology of psychopathy and quantitative simulations are provided. Finally, we offer a preliminary overview of a novel treatment for psychopathy that rests on our Bayesian formulation.

A Bayesian Account of Psychopathy: A Model of Lacks Remorse and Self-Aggrandizing

Accumulating evidence suggests that autonomic signals and their cortical representations are closely linked to emotional processes, and that related abnormalities could lead to social deficits. Although socio-emotional impairments are a defining feature of autism spectrum disorder (ASD), empirical evidence directly supporting the link between autonomic, cortical, and socio-emotional abnormalities in ASD is still lacking. In this study, we examined autonomic arousal indexed by skin conductance responses (SCR), concurrent cortical responses measured by functional magnetic resonance imaging, and effective brain connectivity estimated by dynamic causal modeling in seventeen unmedicated high-functioning adults with ASD and seventeen matched controls while they performed an empathy-for-pain task. Compared to controls, adults with ASD showed enhanced SCR related to empathetic pain, along with increased neural activity in the anterior insular cortex, although their behavioral empathetic pain discriminability was reduced and overall SCR was decreased. ASD individuals also showed enhanced correlation between SCR and neural activities in the anterior insular cortex. Additional Supporting Information may be found in the online version of this article. Contract grant sponsor: National Institute of Health [NIH]; Contract grant number: R21 MH083164; Contract grant sponsor: Icahn School of Medicine at Mount Sinai (to J.F.); Contract grant sponsor: James S. McDonnell Foundation Grant; Contract grant number: 22002078 (to P.R.H.); Contract grant sponsor: Wellcome Trust (to K.J.F.); Contract grant sponsor: Wellcome Trust Principal Award (Dr. Read Montague) (to X.G.) Correction added on 05 October 2015, after first online publication. *Correspondence to: Xiaosi Gu, PhD; Wellcome Trust Centre for Neuroimaging, University College London, London WC1N 3BG, UK. E-mail: xiaosi.gu@ucl.ac.uk and Jin Fan, PhD; Department of Psychology, Queens College, The City University of New York, Flushing, New York 11367. E-mail: jin.fan@qc.cuny.edu Received for publication 8 January 2015; Revised 8 April 2015; Accepted 3 May 2015. DOI: 10.1002/hbm.22840 Published online 21 May 2015 in Wiley Online Library (wileyonlinelibrary.com). r Human Brain Mapping 36:3323–3338 (2015) r VC 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Importantly, significant group differences in effective brain connectivity were limited to greater reduction in the negative intrinsic connectivity of the anterior insular cortex in the ASD group, indicating a failure in attenuating anterior insular responses to empathetic pain. These results suggest that aberrant interoceptive precision, as indexed by abnormalities in autonomic activity and its central representations, may underlie empathy deficits in ASD. Hum Brain Mapp 36:3323–3338, 2015. VC 2015 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc.

Queens College 5-21-2015 Autonomic and Brain Responses Associated with Empathy Deficits in Autism Spectrum Disorder

In this technical note, we address an unresolved challenge in neuroimaging statistics: how to determine which of several datasets is the best for inferring neuronal responses. Comparisons of this kind are important for experimenters when choosing an imaging protocol—and for developers of new acquisition methods. However, the hypothesis that one dataset is better than another cannot be tested using conventional statistics (based on likelihood ratios), as these require the data to be the same under each hypothesis. Here we present Bayesian data comparison (BDC), a principled framework for evaluating the quality of functional imaging data, in terms of the precision with which neuronal connectivity parameters can be estimated and competing models can be disambiguated. For each of several candidate datasets, neuronal responses are modeled using Bayesian (probabilistic) forward models, such as General Linear Models (GLMs) or Dynamic Casual Models (DCMs). Next, the parameters from subject-specific models are summarized at the group level using a Bayesian GLM. A series of measures, which we introduce here, are then used to evaluate each dataset in terms of the precision of (group-level) parameter estimates and the ability of the data to distinguish similar models. To exemplify the approach, we compared four datasets that were acquired in a study evaluating multiband fMRI acquisition schemes, and we used simulations to establish the face validity of the comparison measures. To enable people to reproduce these analyses using their own data and experimental paradigms, we provide general-purpose Matlab code via the SPM software.

Objective To quantify atrophy, demyelination, and iron accumulation over 2 years following acute spinal cord injury and to identify MRI predictors of clinical outcomes and determine their suitability as surrogate markers of therapeutic intervention. Methods We assessed 156 quantitative MRI datasets from 15 patients with spinal cord injury and 18 controls at baseline and 2, 6, 12, and 24 months after injury. Clinical recovery (including neuropathic pain) was assessed at each time point. Between-group differences in linear and nonlinear trajectories of volume, myelin, and iron change were estimated. Structural changes by 6 months were used to predict clinical outcomes at 2 years. Results The majority of patients showed clinical improvement with recovery stabilizing at 2 years. Cord atrophy decelerated, while cortical white and gray matter atrophy progressed over 2 years. Myelin content in the spinal cord and cortex decreased progressively over time, while cerebellar loss decreases decelerated. As atrophy progressed in the thalamus, sustained iron accumulation was evident. Smaller cord and cranial corticospinal tract atrophy, and myelin changes within the sensorimotor cortices, by 6 months predicted recovery in lower extremity motor score at 2 years. Whereas greater cord atrophy and microstructural changes in the cerebellum, anterior cingulate cortex, and secondary sensory cortex by 6 months predicted worse sensory impairment and greater neuropathic pain intensity at 2 years. Conclusion These results draw attention to trauma-induced neuroplastic processes and highlight the intimate relationships among neurodegenerative processes in the cord and brain. These measurable changes are sufficiently large, systematic, and predictive to render them viable outcome measures for clinical trials.

Significance Visual perception of body motion is of substantial value for social cognition and everyday life. By using an integrative approach to brain connectivity, the study sheds light on architecture and functional principles of the underlying cerebro-cerebellar network. This circuity is organized in a parallel rather than hierarchical fashion. This may explain why body-language reading is rather resilient to focal brain damage but severely affected in neuropsychiatric conditions with distributed network alterations. Furthermore, visual sensitivity to body motion is best predicted by specific top-down feedback to the early visual cortex, as well as functional communication (effective connectivity) and presence of white-matter pathways between the right fusiform gyrus and superior temporal sulcus. The findings allow better understanding of the social brain. The perception of actions underwrites a wide range of socio-cognitive functions. Previous neuroimaging and lesion studies identified several components of the brain network for visual biological motion (BM) processing, but interactions among these components and their relationship to behavior remain little understood. Here, using a recently developed integrative analysis of structural and effective connectivity derived from high angular resolution diffusion imaging (HARDI) and functional magnetic resonance imaging (fMRI), we assess the cerebro-cerebellar network for processing of camouflaged point-light BM. Dynamic causal modeling (DCM) informed by probabilistic tractography indicates that the right superior temporal sulcus (STS) serves as an integrator within the temporal module. However, the STS does not appear to be a “gatekeeper” in the functional integration of the occipito-temporal and frontal regions: The fusiform gyrus (FFG) and middle temporal cortex (MTC) are also connected to the right inferior frontal gyrus (IFG) and insula, indicating multiple parallel pathways. BM-specific loops of effective connectivity are seen between the left lateral cerebellar lobule Crus I and right STS, as well as between the left Crus I and right insula. The prevalence of a structural pathway between the FFG and STS is associated with better BM detection. Moreover, a canonical variate analysis shows that the visual sensitivity to BM is best predicted by BM-specific effective connectivity from the FFG to STS and from the IFG, insula, and STS to the early visual cortex. Overall, the study characterizes the architecture of the cerebro-cerebellar network for BM processing and offers prospects for assessing the social brain.

Structural and effective brain connectivity underlying biological motion detection

Background The proportional recovery rule asserts that most stroke survivors recover a fixed proportion of lost function. Reports that the rule can be used to predict recovery, extraordinarily accurately, are rapidly accumulating. Here, we show that the rule may not be as powerful as it seems. Methods We provide a formal analysis of the relationship between baseline scores (X), outcomes (Y) and recovery (Y-X), to highlight the shortcomings of the proportional recovery rule, and illustrate those problems with simulations in which synthetic recovery data are derived from different types of recovery processes. Findings When the correlation between baseline scores and recovery is stronger than that between baselines scores and outcomes, the former can create an inflated impression of how predictable outcomes really are given baseline scores. This often happens when outcomes are less variable than baseline scores, as is common in empirical studies of recovery after stroke. Moreover, we cannot use the results of these correlations to distinguish proportional recovery from recovery which is either not consistently proportional, or not proportional at all. Interpretation Analyses relating baseline scores to subsequent change are a minefield: our formal analysis applies as consistently outside the area of stroke as it does within it. One implication of our analysis is that the proportional recovery rule is not as predictive of real recovery after stroke as recent empirical studies suggest. Another is that different analytical methods will be required to ascertain whether recovery is even proportional at all.

Convolutional and Recurrent, deep neural networks have been successful in machine learning systems for computer vision, reinforcement learning, and other allied fields. However, the robustness of such neural networks is seldom apprised, especially after high classification accuracy has been attained. In this paper, we evaluate the robustness of three recurrent neural networks to tiny perturbations, on three widely used datasets, to argue that high accuracy does not always mean a stable and a robust (to bounded perturbations, adversarial attacks, etc.) system. Especially, normalizing the spectrum of the discrete recurrent network to bound the spectrum (using power method, Rayleigh quotient, etc.) on a unit disk produces stable, albeit highly non-robust neural networks. Furthermore, using the $\epsilon$-pseudo-spectrum, we show that training of recurrent networks, say using gradient-based methods, often result in non-normal matrices that may or may not be diagonalizable. Therefore, the open problem lies in constructing methods that optimize not only for accuracy but also for the stability and the robustness of the underlying neural network, a criterion that is distinct from the other.

Computational theories of brain function have become very influential in neuroscience. They have facilitated the growth of formal approaches to disease, particularly in psychiatric research. In this paper, we provide a narrative review of the body of computational research addressing neuropsychological syndromes, and focus on those that employ Bayesian frameworks. Bayesian approaches to understanding brain function formulate perception and action as inferential processes. These inferences combine ‘prior’ beliefs with a generative (predictive) model to explain the causes of sensations. Under this view, neuropsychological deficits can be thought of as false inferences that arise due to aberrant prior beliefs (that are poor fits to the real world). This draws upon the notion of a Bayes optimal pathology – optimal inference with suboptimal priors – and provides a means for computational phenotyping. In principle, any given neuropsychological disorder could be characterized by the set of prior beliefs that would make a patient’s behavior appear Bayes optimal. We start with an overview of some key theoretical constructs and use these to motivate a form of computational neuropsychology that relates anatomical structures in the brain to the computations they perform. Throughout, we draw upon computational accounts of neuropsychological syndromes. These are selected to emphasize the key features of a Bayesian approach, and the possible types of pathological prior that may be present. They range from visual neglect through hallucinations to autism. Through these illustrative examples, we review the use of Bayesian approaches to understand the link between biology and computation that is at the heart of neuropsychology.

Active Inference in OpenAI Gym: A Paradigm for Computational Investigations Into Psychiatric Illness.

The neural correlates of rapid eye movements (REMs) in sleep are extraordinarily robust; including REM-locked multisensory-motor integration and accompanying activation in the retrosplenial cortex, the supplementary eye field and areas encompassing cholinergic basal nucleus (Hong et al., 2009). The phenomenology of REMs speaks to the notion that perceptual experience in both sleep and wakefulness is a constructive process – in which we generate predictions of sensory inputs and then test those predictions through actively sampling the sensorium with eye movements. On this view, REMs during sleep may index an internalized active sampling or ‘scanning’ of self-generated visual constructs that are released from the constraints of visual input. If this view is correct, it renders REMs an ideal probe to study consciousness as “an exclusively internal affair” (Metzinger, 2009). In other words, REMs offer a probe of active inference – in the sense of predictive coding – when the brain is isolated from the sensorium in virtue of the natural blockade of sensory afferents during REM sleep. Crucially, REMs are temporally precise events that enable powerful inferences based on time series analyses. As a natural, task-free probe, (REMs) could be used in non-compliant subjects, including infants and animals. In short, REMs constitute a promising probe to study the ontogenetic and phylogenetic development of consciousness and perhaps the psychopathology of schizophrenia and autism, which have been considered in terms of aberrant predictive coding.

Rapid Eye Movements in Sleep Furnish a Unique Probe Into Consciousness

Distinct modes of functional connectivity induced by movie-watching

We offer a scientific approach to the philosophical ‘hard problem’ of consciousness, as formulated by David Chalmers in this journal. Our treatment is based upon two recent insights concerning (1) the endogenous nature of consciousness and (2) the minimal thermodynamic conditions for being alive. We suggest that a combination of these insights specifies sufficient conditions for attributing feeling to being.

How and why consciousness arises: Some considerations from physics and physiology

Dynamic causal modelling of fluctuating connectivity in resting-state EEG

See Roberts and Breakspear (doi:10.1093/brain/awy136) for a scientific commentary on this article. Patients with anti-NMDA-receptor encephalitis display diverse early symptoms and no clear imaging marker of the disease is currently available. Symmonds et al. report that using EEG alone, it is possible to identify the common underlying abnormality in NMDA receptor function, facilitating early diagnosis and potentially improving patient outcomes.

Ion channels in EEG: isolating channel dysfunction in NMDA receptor antibody encephalitis

Movement-related theta oscillations in rodent hippocampus coordinate ‘forward sweeps’ of location-specific neural activity that could be used to evaluate spatial trajectories online. This raises the possibility that increases in human hippocampal theta power accompany the evaluation of upcoming spatial choices. To test this hypothesis, we measured neural oscillations during a spatial planning task that closely resembles a perceptual decision-making paradigm. In this task, participants searched visually for the shortest path between a start and goal location in novel mazes that contained multiple choice points, and were subsequently asked to make a spatial decision at one of those choice points. We observed ~4-8 Hz hippocampal/medial temporal lobe theta power increases specific to sequential planning that were negatively correlated with subsequent decision speed, where decision speed was inversely correlated with choice accuracy. These results implicate the hippocampal theta rhythm in decision tree search during planning in novel environments.

Human hippocampal theta oscillations reflect sequential dependencies during spatial planning

Abstract The neurobiological understanding of mood, and by extension mood disorders, remains elusive despite decades of research implicating several neuromodulator systems. This review considers a new approach based on existing theories of functional brain organisation. The free energy principle (a.k.a. active inference), and its instantiation in the Bayesian brain, offers a complete and simple formulation of mood. It has been proposed that emotions reflect the precision of – or certainty about – the predicted sensorimotor/interoceptive consequences of action. By extending this reasoning, in a hierarchical setting, we suggest mood states act as (hyper) priors over uncertainty (i.e. emotions). Here, we consider the same computational pathology in the proprioceptive and interoceptive (behavioural and autonomic) domain in order to furnish an explanation for mood disorders. This formulation reconciles several strands of research at multiple levels of enquiry.

This work addresses the autonomous organization of biological systems. It does so by considering the boundaries of biological systems, from individual cells to Home sapiens, in terms of the presence of Markov blankets under the active inference scheme—a corollary of the free energy principle. A Markov blanket defines the boundaries of a system in a statistical sense. Here we consider how a collective of Markov blankets can self-assemble into a global system that itself has a Markov blanket; thereby providing an illustration of how autonomous systems can be understood as having layers of nested and self-sustaining boundaries. This allows us to show that: (i) any living system is a Markov blanketed system and (ii) the boundaries of such systems need not be co-extensive with the biophysical boundaries of a living organism. In other words, autonomous systems are hierarchically composed of Markov blankets of Markov blankets—all the way down to individual cells, all the way up to you and me, and all the way out to include elements of the local environment.

The Markov blankets of life: autonomy, active inference and the free energy principle

Our behavior entails a flexible and context-sensitive interplay between brain areas to integrate information according to goal-directed requirements. Nevertheless, the neural mechanisms governing the integration and entrainment of functionally specialized brain areas remain poorly understood. Here, we introduce a theoretical framework that discloses these mechanisms – at the whole brain level – based on fMRI data. Our approach relies on a model of functional connectivity that allows for the estimation of the strengths of (extrinsic) cortico-cortical interactions, as well as the input or baseline activity (intrinsic) to each cortical region. We examine quantitatively the contributions of effective connectivity and intrinsic input to changes in functional integration during movie viewing. Our results show how the interactions between cortical areas are moderately, but significantly, modified to select pathways that integrate sensory influxes from the visual and auditory systems to high-level areas in the frontal and central parts of the brain. Meanwhile, opposing changes in (intrinsic) input and (extrinsic) connectivity preserve a balance of distributed responses. To characterize this balance, we define an ‘effective drive’ that quantifies the propagation of neuronal activity (measured by the amplitude of fMRI fluctuations) between cortical regions. Finally, homotopic regions in opposite hemispheres increased their effective connectivity and drive during movie viewing, whereas they are effectively disconnected when watching a black screen. These findings speak to a dynamic and balanced functional integration that underlies hierarchical processing in the brain.

Effective dynamics analysis of fMRI data points to reconfiguration of cortical information processing during visual and auditory perception

The proportional recovery rule asserts that most stroke survivors recover a ﬁxed proportion of lost function. To the extent that this is true, recovery from stroke can be predicted accurately from baseline measures of acute post-stroke impairment alone. Reports that baseline scores explain more than 80%, and sometimes more than 90%, of the variance in the patients’ recoveries, are rapidly accumulating. Here, we show that these headline effect sizes are likely inﬂated. The key effects in this literature are typically expressed as, or reducible to, correlation coefﬁcients between baseline scores and recovery (outcome scores minus baseline scores). Using formal analyses and simulations, we show that these correlations will be extreme when outcomes are signiﬁcantly less variable than baselines, which they often will be in practice regardless of the real relationship between outcomes and baselines. We show that these effect sizes are likely to be over-optimistic in every empirical study that we found that reported enough information for us to make the judgement, and argue that the same is likely to be true in other studies as well. The implication is that recovery after stroke may not be as proportional as recent studies suggest.

Generic dynamic causal modelling: An illustrative application to Parkinson's disease

F245. Hallucinations and Self-Generated Imprecision: A Markov Decision Process Model of Auditory Hallucinations

The neurobiological understanding of mood, and by extension mood disorders, remains elusive despite decades of research implicating several neuromodulator systems. This review considers a new approach based on existing theories of functional brain organisation. The free energy principle (a.k.a. active inference), and its instantiation in the Bayesian brain, offers a complete and simple formulation of mood. It has been proposed that emotions reflect the precision of – or certainty about – the predicted sensorimotor/interoceptive consequences of action. By extending this reasoning, in a hierarchical setting, we suggest mood states act as (hyper) priors over uncertainty (i.e. emotions). Here, we consider the same computational pathology in the proprioceptive and interoceptive (behavioural and autonomic) domain in order to furnish an explanation for mood disorders. This formulation reconciles several strands of research at multiple levels of enquiry. The current predicament Mood disorders are heterogeneous and complex and depend upon the interplay of several neuromodulator systems and genetic and epigenetic factors (Hirschfeld, 2000; Holsboer, 2000; Nestler & Carlezon, 2006; Nutt et al. 2007; Dowlati et al. 2010; Möhler, 2012). As a result, current approaches to diagnosis and classification of mood disorders suffer several shortcomings (Nesse & Stein, 2012), and advances in understanding the underlying neurobiology have been slow. We argue that progress may be facilitated by an appreciation of the dynamic and selforganising nature of neurobiological systems (Seth, 2013; Fotopoulou, 2015; Clark et al. 2016). The brain is a generative organ Traditional hypotheses propose that the neurobiological underpinnings of a variety of disorders arise from structural or functional abnormalities in the brain consequent on a combination of environmental stress and genetic vulnerabilities (Videbech & Ravnkilde, 2004; Ota & Duman, 2013; Duman, 2014). Similarly, it has been argued that pharmacotherapy may work via its effects on neurogenesis and synaptic plasticity (Santarelli et al. 2003; Anacker et al. 2011; Castrén & Hen, 2013) and that stressors may leave an indelible scar on key neurobiological systems that disrupts their structure and/or function. In this sense, the traditional hypothesis is that brain abnormalities develop throughout the lifespan and result in the onset and maintenance of psychopathology. However, modern accounts of brain function reject the classical notion of the brain as a passive organ in favour of theories of embodiment and self-organisation (Friston, 2010; Seth, 2013; Corlett & Fletcher, 2014). Specifically, recent theoretical accounts propose that the brain works towards an equilibrium in which its environment is rendered predictable; i.e. surprise is minimised and uncertainty resolved (Friston, 2009). Essentially, the brain embodies a generative model that encodes prior beliefs about sensory input and their causes. This model generates predictions which are tested against actual input to produce prediction errors (surprise). These prediction errors are then used by the brain to revise its model of the world. In so doing, it updates its predictions and minimises prediction error (Friston, 2010). On this view, prior beliefs about the world, as discussed above, are represented in terms of probability distributions. The sufficient statistics for these distributions may be labelled as ‘expectation’ and ‘precision’ and, if the brain embodies such priors, it follows that they must be represented in its physical activity and anatomy. It is thought that expectations (and subsequent predictions) are encoded by synaptic activity, while precision, or uncertainty, is encoded by the extent to which this activity is attenuated or amplified (Friston & Kiebel, 2009), e.g. through careful synaptic efficacy or gain control. In current predictive coding formulations of the Bayesian brain, expectation and prediction error units are thought to occupy deep and superficial pyramidal layers of cortex, respectively (Friston & Kiebel, 2009; Bastos et al. 2012; Shipp et al. 2013); such that predictions generated, from expectations, at one level of the cortical hierarchy descend to form prediction errors in superficial layers of the level below. These prediction error units then send ascending signals to update expectations. Crucially, the precision or confidence placed in prediction errors is then associated with the synaptic gain or efficacy of superficial pyramidal cells – that itself depends upon interactions with inhibitory interneurons and modulatory neurotransmission. This is a brief description of hierarchical predictive coding. In what follows, we look more closely at the back story to predictive coding; namely, free energy minimisation and allostasis. The free energy principle The brain, like other biological systems, seeks to maintain its physiological (and psychological) state in the face of a constantly changing internal and external environment and must therefore minimise entropy over external states (where entropy is a mathematical measure of uncertainty or expected surprise). Directly computing surprise is intractable, but by appealing to variational principles, we can calculate an upper boundary on surprise, namely free energy, which systems will (or will appear to) minimise (Friston et al. 2006). Given that surprise is the inverse of model evidence, if the brain is minimising a free energy bound on surprise, it is necessarily trying to maximise the sensory evidence for its model of the world and is inherently self-evidencing (Hohwy, 2016). Under some simplifying assumptions, one can equate surprise with (precision weighted) prediction error. In brief, the brain can minimise (precision weighted) prediction error in three ways. First, expectations can be updated (by changing neuronal activity) so that predictions provide a better explanation for sensory inputs (Friston et al. 2006). Alternatively, the brain can change the world or the way it is sampled (by engaging motor and autonomic reflexes) so that sensations fall into line with predictions. This provides a simple explanation for behaviour, which becomes the fulfilment of predicted (proprioceptive and somatosensory) motor sensations. Finally, both of these processes (perception and action) can be nuanced by optimising the precision of prediction errors. In cognitive neuroscience, this optimisation has been framed in terms of attention and attenuation. In other words, attending to a sensory stream corresponds to increasing its sensory precision through appropriate synaptic gain control. Conversely, sensory attenuation corresponds to the reduction of precision by attending away from or ignoring the consequences of one’s own action. The active minimisation of free energy is known as active inference, which means the brain can selectively sample from data that concur with its current expectations (Friston et al. 2011; Pezzulo, 2012). In the interoceptive domain, the resolution of prediction errors through autonomic reflexes provides a simple account of homoeostasis. This formulation can be extended by appealing to hierarchical generative models such that predictions at higher levels pre-empt the need for homoeostasis [e.g. in a hypoglycaemic state, by attenuating the precision of prediction errors reporting hypoglycaemia, we can suspend the reflex mobilisation of glucose and act on the world (by eating) to fulfil and maintain higher level predictions] (Pezzulo et al. 2015). This hierarchical minimisation of prediction errors allows allostatic control over homoeostatic reflexes (Sterling & Eyer, 1988; McEwen, 1998; Ramsay & Woods, 2014). Note that the balance between allostasis and homoeostasis depends on attenuating interoceptive prediction errors, which will be an important theme in what follows. In this way, a self-regulating embodied loop of circular causality is constructed in which the brain constructs the external environment (and internal milieu) it expects to encounter, which in turn reinforces its predictions (Seth, 2014; Barrett & Simmons, 2015). Free energy and emotion Recent theoretical arguments have converged on the idea that emotional states reflect changes in the uncertainty about the somatic consequences of action (Joffily & Coricelli, 2013; Wager et al. 2015; Seth & Friston, 2016). This uncertainty refers to the precision with which motor and physiological states can be predicted. In this setting, negative emotions contextualise events that induce expectations of unpredictability, while positive emotions refer to events that resolve uncertainty and confer a feeling of control (Barrett & Satpute, 2013; Gu et al. 2013). This ties emotional states to the resolution of uncertainty and, through the biophysical encoding of precision, to neuromodulation and cortical gain control (Brown & Friston, 2012). In summary, one can associate the valence of emotional stimuli with the precision of prior beliefs about the consequences of action. In this view, positively valenced brain states are necessarily associated with increases in the precision of predictions about the (controllable) future – or, more simply, predictable consequences of motor or autonomic behaviour. Conversely, negative emotions correspond to a loss of prior precision and a sense of helplessness and uncertainty about the consequences of action.

I know little about social psychology and less about cognitive consistency theory; however, I greatly enjoyed reading the deconstruction of this paradigm by Kruglanski et al. (this issue). I learned a lot and was struck repeatedly by the consilience between their treatment and complementary formulations in theoretical neurobiology. The underlying tenets of their argument emerge—in my world—from a Bayesian or variational treatment of perception and self-organized behavior. This is variously known as the free energy principle, active inference, predictive processing, or self-evidencing (Clark, 2013, Friston, 2010; Friston, FitzGerald, Rigoli, Schwartenbeck, & Pezzulo, 2017; Hohwy, 2016). Particular flavors of this formulation have dominated cognitive neuroscience and aspects of philosophy for the past decade. For example, the Bayesian brain hypothesis (Kersten, Mamassian, & Yuille, 2004; Knill & Pouget, 2004) and predictive processing (Barrett & Simmons, 2015; Michael & De Bruin, 2015; Rao & Ballard 1999; Seth, 2013) are now predominant paradigms in cognitive neuroscience. Active inference generalizes this approach to provide an enactive or embodied treatment of action and perception. This resulting treatment bears some remarkable similarities to the ideas reviewed in Kruglanski et al. This commentary tries to establish the formal links between active inference and constructs in cognitive consistency theory in the hope that there may be some useful cross-fertilisation. In what follows, I briefly overview active inference with a special focus on the quantities needed to describe affective responses to new information and then unpack some key dialectics that speak to cognitive consistency, epistemic and motivational value, specific and nonspecific closure, and so on.

In evolutionary biology, niche construction is sometimes described as a genuine evolutionary process whereby organisms, through their activities and regulatory mechanisms, modify their environment such as to steer their own evolutionary trajectory, and that of other species. There is ongoing debate, however, on the extent to which niche construction ought to be considered a bona fide evolutionary force, on a par with natural selection. Recent formulations of the variational free-energy principle as applied to the life sciences describe the properties of living systems, and their selection in evolution, in terms of variational inference. We argue that niche construction can be described using a variational approach. We propose new arguments to support the niche construction perspective, and to extend the variational approach to niche construction to current perspectives in various scientific fields.

Compared to other mammals, primates have a large number of visual areas in neocortex, as well as expanded posterior parietal cortex and premotor and prefrontal areas of cortex. Visual areas that directly or indirectly project to posterior parietal cortex are considered to be in the dorsal stream of cortical networks for selecting and producing complex behaviors. Our research in monkeys and prosimian galagos indicates that a large part of posterior parietal cortex is subdivided into eight or more small regions or domains where electrical stimulation evokes a specific but different action such as reaching, grasping, running, or looking. Each domain of posterior parietal cortex selectively activates functionally matched domains in motor and premotor cortex, where the motor domains are necessary components of the functional networks. We regard the three sets of interconnected domains as three levels of decision making, where sensory information, cognitive and memory components, and motor planning sources of information successfully influence the motor outcome. The nature of the fractured motor maps in premotor and motor cortex suggest that their domains include a mixture of functionally different microcolumns that together reflect the functions of the domains. Biography. Jon H. Kaas (b. September 13, 1937 in Fargo, ND, USA) received a B.A. from Northland College (Ashland, WI) in 1959 and Ph.D. in 1965 from Duke University (NC, USA) with Irving Diamond as his thesis advisor where he studied brain organization in a variety of mammalian species. From 1965 to 1968 Jon was a postdoctoral fellow with Clinton Woolsey at University of Wisconsin, Madison, where he studied the visual system in monkeys. He is currently Distinguished, Centennial Professor of Psychology at Vanderbilt University, where he has been since 1973. Dr. Kaas was elected to the National Academy of Sciences in 2000, and the American Academy of Arts and Sciences in 2001. He received the Distinguished Scientific Contribution Award from the American Psychological Association, the Karl Spencer Lashley Award from the American Philosophical Society, the George A. Miller Prize in Cognitive Neuroscience from the Cognitive Neuroscience Society in 2014, Honorary Life Member, J. B. Johnson Club for Evolutionary Neuroscience in 2014, and the Palay Award from the Journal of Comparative Neurology, 2014. He has published over 540 papers and review articles, and edited many volumes including a fourvolume series "The Evolution of Nervous Systems" in 2007 and 2017. In 2009 he received the Graduate Mentoring Award from Vanderbilt University. Two of Jon's PhD students have won the MacArthur "genius" award. Current research includes investigations of the somatosensory, auditory and motor systems in a range of mammals including a number of species of prosimian and simian primates, as well as the study of brain material obtained after natural death from apes and humans. Researchers in the Kaas laboratory have published extensively on the organization of sensory and motor systems in primates, the plasticity of these systems in developing and mature brains, and the coding properties of neurons in these systems, especially somatosensory cortex. Many studies are concerned with how brains differ in organization across species in order to deduce how complex brains such as the human brain evolved. A relatively new focus of investigation focuses on how numbers of neurons scale with brain size and size of brain parts.

Invited Speakers for the 1st International Conference on Neuroscience, Neuroinformatics, Neurotechnology and Neuro-Psycho- Pharmacology

Supplementary material from "A variational approach to niche construction"

Rapid imaging techniques are increasingly used in functional MRI studies because they allow a greater number of samples to be acquired per unit time, thereby increasing statistical power. However, temporal correlations limit the increase in functional sensitivity and must be accurately accounted for to control the false‐positive rate. A common approach to accounting for temporal correlations is to whiten the data prior to estimating fMRI model parameters. Models of white noise plus a first‐order autoregressive process have proven sufficient for conventional imaging studies, but more elaborate models are required for rapidly sampled data. Here we show that when the “FAST” model implemented in SPM is used with a well‐controlled number of parameters, it can successfully prewhiten 80% of grey matter voxels even with volume repetition times as short as 0.35 s. We further show that the temporal signal‐to‐noise ratio (tSNR), which has conventionally been used to assess the relative functional sensitivity of competing imaging approaches, can be augmented to account for the temporal correlations in the time series. This amounts to computing the t‐score testing for the mean signal. We show in a visual perception task that unlike the tSNR weighted by the number of samples, the t‐score measure is directly related to the t‐score testing for activation when the temporal correlations are correctly modeled. This score affords a more accurate means of evaluating the functional sensitivity of different data acquisition options.

Accurate modeling of temporal correlations in rapidly sampled fMRI time series

We agree with Dr. Domingue's observation that the trajectory of recovery after spinal cord injury (SCI) is complex and difficult to predict. We should clarify that in the present study, we investigated the effects of traumatic SCI on neurodegeneration across the neuroaxis.1 However, we and others have shown that in cervical spondolytic myelopathy (i.e., nontraumatic SCI) remote tissue specific cord pathology is also evident.2,3 Surprisingly, the extent of neurodegeneration is similar to traumatic SCI, although these patients with nontraumatic SCI had only mild clinical symptoms.2 This suggests that, in a slow progressive disease (e.g., cervical spondolytic myelopathy), the CNS can compensate for neurodegenerative processes for much longer; however, with time, the competition between processes of reorganization and neurodegeneration is lost in favor of the latter. Nevertheless, the clinical viability of MRI-based structural measures for monitoring and predicting recovery after nontraumatic and traumatic SCI is feasible and will provide a tool to improve our understanding of the disease mechanism, which affects not only the spinal cord but also the brain after SCI.3–5 These new insights will enable us to better predict individual recovery trajectories and identify patients who could profit from further interventions to delay, or even prevent, further clinical deterioration.

Author response: Progressive neurodegeneration following spinal cord injury: Implications for clinical trials

This commentary considers three key themes in the target article, from the perspective of the self-evidencing brain. In brief, I examine the notion of minimal selfhood in terms of inference to the best explanation; in particular, an explanation for sensations that are uniquely available to a self. This begs the question of how self differs from non-self and how non-self differs from the concept of another. From an (active) inference point of view, the building of generative models that entail minimal selfhood rests on structure learning and Bayesian model selection. In this setting, I focus on the role of generalized synchrony – and the implicit closure of action-perception cycles – in dyadic interactions. Finally, I touch on the importance of interoception awareness and the implications of how interoceptive signals are contextualized for translating the ideas in the target article into developmental psychopathology.

Self-evidencing babies: Commentary on “Mentalizing homeostasis: The social origins of interoceptive inference” by Fotopoulou & Tsakiris

Distinct Top-down and Bottom-up Brain Connectivity During Visual Perception and Imagery

Clinical Applications of Stochastic Dynamic Models of the Brain, Part I: A Primer.

Hierarchical disruption in the Bayesian brain: Focal epilepsy and brain networks

Inferring Adaptive Goal-Directed Behavior Within Recurrent Neural Networks

Uncovering the underlying mechanisms and whole-brain dynamics of deep brain stimulation for Parkinson’s disease

The Emperor's new topology: Comment on "Topodynamics of metastable brains" by Arturo Tozzi et al.

This article describes a process theory based on active inference and belief propagation. Starting from the premise that all neuronal processing (and action selection) can be explained by maximizing Bayesian model evidence—or minimizing variational free energy—we ask whether neuronal responses can be described as a gradient descent on variational free energy. Using a standard (Markov decision process) generative model, we derive the neuronal dynamics implicit in this description and reproduce a remarkable range of well-characterized neuronal phenomena. These include repetition suppression, mismatch negativity, violation responses, place-cell activity, phase precession, theta sequences, theta-gamma coupling, evidence accumulation, race-to-bound dynamics, and transfer of dopamine responses. Furthermore, the (approximately Bayes’ optimal) behavior prescribed by these dynamics has a degree of face validity, providing a formal explanation for reward seeking, context learning, and epistemic foraging. Technically, the fact that a gradient descent appears to be a valid description of neuronal activity means that variational free energy is a Lyapunov function for neuronal dynamics, which therefore conform to Hamilton’s principle of least action.

In this article we account for the way plants respond to salient features of their environment under the free-energy principle for biological systems. Biological self-organization amounts to the minimization of surprise over time. We posit that any self-organizing system must embody a generative model whose predictions ensure that (expected) free energy is minimized through action. Plants respond in a fast, and yet coordinated manner, to environmental contingencies. They pro-actively sample their local environment to elicit information with an adaptive value. Our main thesis is that plant behaviour takes place by way of a process (active inference) that predicts the environmental sources of sensory stimulation. This principle, we argue, endows plants with a form of perception that underwrites purposeful, anticipatory behaviour. The aim of the article is to assess the prospects of a radical predictive processing story that would follow naturally from the free-energy principle for biological systems; an approach that may ultimately bear upon our understanding of life and cognition more broadly.

The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order) in which cues are presented. These simulations provide a (Bayes-optimal) model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors) to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson’s disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level. Citation: Friston KJ, Shiner T, FitzGerald T, Galea JM, Adams R, et al. (2012) Dopamine, Affordance and Active Inference. PLoS Comput Biol 8(1): e1002327. doi:10.1371/journal.pcbi.1002327 Editor: Olaf Sporns, Indiana University, United States of America Received September 4, 2011; Accepted November 10, 2011; Published January 5, 2012 Copyright: 2012 Friston et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was funded by the Wellcome Trust, and the Biotechnology and Biological Sciences Research Council (BBSRC) and the European Research Council (ERC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: k.friston@fil.ion.ucl.ac.uk

University of Birmingham Dopamine , affordance and active inference

Citation: Li B, Razi A and Friston KJ (2017) Editorial: Mapping Psychopathology with fMRI and Effective Connectivity Analysis. Editorial on the Research Topic Mapping Psychopathology with fMRI and Effective Connectivity Analysis Distributed networks of interacting brain systems—rather than a single area—are usually involved in the execution of a specific cognitive task. Recent advances in neuroimaging techniques now allow us to see how these interacting brain regions are integrated and cooperate with each other to prosecute cognitive operations (Razi and Friston, 2016). Brain connectivity analyses based on electroencephalography (EEG), magnetoencephalography (MEG), and functional magnetic resonance imaging (fMRI) signals characterize neuronal responses in terms of how brain activity is induced by external stimuli and propagates among distributed brain regions, and thus may help answer key questions about functional brain architectures. The insights that brain connectivity analyses offer is also crucial for us to elucidate the neurobiological correlates underlying many neuropsychiatric disorders. Functional connectivity and effective connectivity are generally used to measure functional integration in neuroimaging. The former examines (undirected) statistical dependencies (e.g., temporal correlations) between brain regions and has been extensively studied to characterize brain networks at rest. However, understanding the precise mechanisms mediating cognitive processes depend on directed information flow within brain networks. Thus, the current research topic focuses on mapping psychopathology with (directed) effective connectivity analysis, which models causal interactions among brain regions. We attempt to further improve current understanding of the neural mechanisms of major neuropsychiatric disorders by exploring how signals are transmitted differently from one region to another in healthy controls and patients. This comparison may help explain the pathophysiology and psychopathology seen in these disorders—at a network and possibly synaptic level. In this research topic, we invited world-renowned experts to present their recent work that have utilized various models of directed connectivity; including psychophysiological interactions (PPI), Granger causality (GC), and dynamic causal modeling (DCM) to investigate directed connectivity in healthy subjects and patients with neuropsychiatric disorders. The papers in this research topic further our knowledge of the neurobiological mechanisms underlying neurological and psychiatric disorders. We will see that young people with OCD exhibit increased dorsal anterior cingulate cortex (dACC) modulatory effects during the performance of working memory tasks (Diwadkar et al.). There is also new evidence suggesting that neurodegenerative disorders like Parkinson's disease (Yan et al.) and Huntington's disease (Minkova et al.) are characterized by impaired causal

Editorial: Mapping Psychopathology with fMRI and Effective Connectivity Analysis

Biological systems—like ourselves—are constantly faced with uncertainty. Despite noisy sensory data, and volatile environments, creatures appear to actively maintain their integrity. To account for this remarkable ability to make optimal decisions in the face of a capricious world, we propose a generative model that represents the beliefs an agent might possess about their own uncertainty. By simulating a noisy and volatile environment, we demonstrate how uncertainty influences optimal epistemic (visual) foraging. In our simulations, saccades were deployed less frequently to regions with a lower sensory precision, while a greater volatility led to a shorter inhibition of return. These simulations illustrate a principled explanation for some cardinal aspects of visual foraging—and allow us to propose a correspondence between the representation of uncertainty and ascending neuromodulatory systems, complementing that suggested by Yu & Dayan (Yu & Dayan 2005 Neuron 46, 681–692. (doi:10.1016/j.neuron.2005.04.026)).

This paper considers functional integration in the brain from a computational perspective. We ask what sort of neuronal message passing is mandated by active inference—and what implications this has for context-sensitive connectivity at microscopic and macroscopic levels. In particular, we formulate neuronal processing as belief propagation under deep generative models. Crucially, these models can entertain both discrete and continuous states, leading to distinct schemes for belief updating that play out on the same (neuronal) architecture. Technically, we use Forney (normal) factor graphs to elucidate the requisite message passing in terms of its form and scheduling. To accommodate mixed generative models (of discrete and continuous states), one also has to consider link nodes or factors that enable discrete and continuous representations to talk to each other. When mapping the implicit computational architecture onto neuronal connectivity, several interesting features emerge. For example, Bayesian model averaging and comparison, which link discrete and continuous states, may be implemented in thalamocortical loops. These and other considerations speak to a computational connectome that is inherently state dependent and self-organizing in ways that yield to a principled (variational) account. We conclude with simulations of reading that illustrate the implicit neuronal message passing, with a special focus on how discrete (semantic) representations inform, and are informed by, continuous (visual) sampling of the sensorium. Author Summary This paper considers functional integration in the brain from a computational perspective. We ask what sort of neuronal message passing is mandated by active inference—and what implications this has for context-sensitive connectivity at microscopic and macroscopic levels. In particular, we formulate neuronal processing as belief propagation under deep generative models that can entertain both discrete and continuous states. This leads to distinct schemes for belief updating that play out on the same (neuronal) architecture. Technically, we use Forney (normal) factor graphs to characterize the requisite message passing, and link this formal characterization to canonical microcircuits and extrinsic connectivity in the brain.

Dynamic Causal Modelling of Dynamic Dysfunction in NMDA-Receptor Antibody Encephalitis

Abnormal Effective Connectivity in the Brain is Involved in Auditory Verbal Hallucinations in Schizophrenia

Supplementary material from "The perceptual shaping of anticipatory actions"

On the importance of modeling fMRI transients when estimating effective connectivity: A dynamic causal modeling study using ASL data

Exploring the social brain: Combined structural and effective connectivity

The relationship between the BOLD response and an applied force was quantified in the cerebellum using a power grip task. To investigate whether the cerebellum responds in an on/off way to motor demands or contributes to motor responses in a parametric fashion, similarly to the cortex, five grip force levels were investigated under visual feedback. Functional MRI data were acquired in 13 healthy volunteers and their responses were analyzed using a cerebellum‐optimized pipeline. This allowed us to evaluate, within the cerebellum, voxelwise linear and non‐linear associations between cerebellar activations and forces. We showed extensive non‐linear activations (with a parametric design), covering the anterior and posterior lobes of the cerebellum with a BOLD‐force relationship that is region‐dependent. Linear responses were mainly located in the anterior lobe, similarly to the cortex, where linear responses are localized in M1. Complex responses were localized in the posterior lobe, reflecting its key role in attention and executive processing, required during visually guided movement. Given the highly organized responses in the cerebellar cortex, a key question is whether deep cerebellar nuclei show similar parametric effects. We found positive correlations with force in the ipsilateral dentate nucleus and negative correlations on the contralateral side, suggesting a somatotopic organization of the dentate nucleus in line with cerebellar and cortical areas. Our results confirm that there is cerebellar organization involving all grey matter structures that reflect functional segregation in the cortex, where cerebellar lobules and dentate nuclei contribute to complex motor tasks with different BOLD response profiles in relation to the forces. Hum Brain Mapp 38:2566–2579, 2017. © 2017 Wiley Periodicals, Inc.

Cerebellar lobules and dentate nuclei mirror cortical force‐related‐BOLD responses: Beyond all (linear) expectations

Abstract The default mode network (DMN) is thought to reflect endogenous neural activity, which is considered as one of the most intriguing phenomena in cognitive neuroscience. Previous studies have found that key regions within the DMN are highly interconnected. Here, we characterized the genetic influences on causal or directed information flow within the DMN during the resting state. In this study, we recruited 46 pairs of twins and collected fMRI imaging data using a 3.0 T scanner. Dynamic causal modeling was conducted for each participant, and a structural equation model was used to calculate the heritability of DMN in terms of its effective connectivity. Model comparison favored a full‐connected model. Structural equal modeling was used to estimate the additive genetics (A), common environment (C) and unique environment (E) contributions to variance for the DMN effective connectivity. The ACE model was preferred in the comparison of structural equation models. Heritability of DMN effective connectivity was 0.54, suggesting that the genetic made a greater contribution to the effective connectivity within DMN. Establishing the heritability of default‐mode effective connectivity endorses the use of resting‐state networks as endophenotypes or intermediate phenotypes in the search for the genetic basis of psychiatric or neurological illnesses.

Heritability of the Effective Connectivity in the Resting‐State Default Mode Network

Expectation violation and attention to pain jointly modulate neural gain in somatosensory cortex

Clinical Applications of Stochastic Dynamic Models of the Brain, Part II: A Review.

Computational neuroimaging strategies for single patient predictions

Normative models of human cognition often appeal to Bayesian filtering, which provides optimal online estimates of unknown or hidden states of the world, based on previous observations. However, in many cases it is necessary to optimise beliefs about sequences of states rather than just the current state. Importantly, Bayesian filtering and sequential inference strategies make different predictions about beliefs and subsequent choices, rendering them behaviourally dissociable. Taking data from a probabilistic reversal task we show that subjects’ choices provide strong evidence that they are representing short sequences of states. Between-subject measures of this implicit sequential inference strategy had a neurobiological underpinning and correlated with grey matter density in prefrontal and parietal cortex, as well as the hippocampus. Our findings provide, to our knowledge, the first evidence for sequential inference in human cognition, and by exploiting between-subject variation in this measure we provide pointers to its neuronal substrates.

Sequential inference as a mode of cognition and its correlates in fronto-parietal and hippocampal brain regions

There are considerable gaps in our understanding of the relationship between human brain activity measured at different temporal and spatial scales by intracranial electroencephalography and fMRI. By comparing individual features and summary descriptions of intracranial EEG activity we determined which best predict fMRI changes in the sensorimotor cortex in two brain states: at rest and during motor performance. We also then examine the specificity of this relationship to spatial colocalisation of the two signals. We acquired electrocorticography and fMRI simultaneously (ECoG-fMRI) in the sensorimotor cortex of 3 patients with epilepsy. During motor activity, high gamma power was the only frequency band where the electrophysiological response was colocalised with fMRI measures across all subjects. The best model of fMRI changes was its principal components, a parsimonious description of the entire ECoG spectrogram. This model performed much better than a model based on the classical frequency bands both during task and rest periods or models derived on a summary of cross spectral changes (e.g. ‘root mean squared EEG frequency’). This suggests that the region specific fMRI signal is reflected in spatially and spectrally distributed EEG activity.

Measurement of the mapping between intracranial EEG and fMRI recordings in the human brain

How doctors diagnose diseases and prescribe treatments: an fMRI study of diagnostic salience

Uncertainty and stress: Why it causes diseases and how it is mastered by the brain

This paper considers the identification of large directed graphs for resting-state brain networks based on biophysical models of distributed neuronal activity, that is, effective connectivity. This identification can be contrasted with functional connectivity methods based on symmetric correlations that are ubiquitous in resting-state functional MRI (fMRI). We use spectral dynamic causal modeling (DCM) to invert large graphs comprising dozens of nodes or regions. The ensuing graphs are directed and weighted, hence providing a neurobiologically plausible characterization of connectivity in terms of excitatory and inhibitory coupling. Furthermore, we show that the use of Bayesian model reduction to discover the most likely sparse graph (or model) from a parent (e.g., fully connected) graph eschews the arbitrary thresholding often applied to large symmetric (functional connectivity) graphs. Using empirical fMRI data, we show that spectral DCM furnishes connectivity estimates on large graphs that correlate strongly with the estimates provided by stochastic DCM. Furthermore, we increase the efficiency of model inversion using functional connectivity modes to place prior constraints on effective connectivity. In other words, we use a small number of modes to finesse the potentially redundant parameterization of large DCMs. We show that spectral DCM—with functional connectivity priors—is ideally suited for directed graph theoretic analyses of resting-state fMRI. We envision that directed graphs will prove useful in understanding the psychopathology and pathophysiology of neurodegenerative and neurodevelopmental disorders. We will demonstrate the utility of large directed graphs in clinical populations in subsequent reports, using the procedures described in this paper.

We are remarkably adept at inferring the consequences of our actions, yet the neuronal mechanisms that allow us to plan a sequence of novel choices remain unclear. We used functional magnetic resonance imaging (fMRI) to investigate how the human brain plans the shortest path to a goal in novel mazes with one (shallow maze) or two (deep maze) choice points. We observed two distinct anterior prefrontal responses to demanding choices at the second choice point: one in rostrodorsal medial prefrontal cortex (rd-mPFC)/superior frontal gyrus (SFG) that was also sensitive to (deactivated by) demanding initial choices and another in lateral frontopolar cortex (lFPC), which was only engaged by demanding choices at the second choice point. Furthermore, we identified hippocampal responses during planning that correlated with subsequent choice accuracy and response time, particularly in mazes affording sequential choices. Psychophysiological interaction (PPI) analyses showed that coupling between the hippocampus and rd-mPFC increases during sequential (deep versus shallow) planning and is higher before correct versus incorrect choices. In short, using a naturalistic spatial planning paradigm, we reveal how the human brain represents sequential choices during planning without extensive training. Our data highlight a network centred on the cortical midline and hippocampus that allows us to make prospective choices while maintaining initial choices during planning in novel environments.

The Neural Representation of Prospective Choice during Spatial Planning and Decisions

Corrigendum: Perceptual learning to discriminate the intensity and spatial location of nociceptive stimuli

Linking canonical microcircuits and neuronal activity: Dynamic causal modelling of laminar recordings

Epileptic seizure activity shows complicated dynamics in both space and time. To understand the evolution and propagation of seizures spatially extended sets of data need to be analysed. We have previously described an efficient filtering scheme using variational Laplace that can be used in the Dynamic Causal Modelling (DCM) framework (Friston et al., 2003) to estimate the temporal dynamics of seizures recorded using either invasive or non-invasive electrical recordings (EEG/ECoG). Spatiotemporal dynamics are modelled using a partial differential equation – in contrast to the ordinary differential equation used in our previous work on temporal estimation of seizure dynamics (Cooray et al., 2016). We provide the requisite theoretical background for the method and test the ensuing scheme on simulated seizure activity data and empirical invasive ECoG data. The method provides a framework to assimilate the spatial and temporal dynamics of seizure activity, an aspect of great physiological and clinical importance.

N-methyl-D-aspartate receptors (NMDARs) are expressed widely throughout the human cortex. Yet disturbances in NMDAR transmission – as implicated in patients with schizophrenia or pharmacologically induced – can cause a regionally specific set of electrophysiological effects. Here, we present a double-blind placebo-controlled study of the effects of the NMDAR blocker ketamine in human volunteers. We employ a marker of auditory learning and putative synaptic plasticity – the mismatch negativity – in a roving auditory oddball paradigm. Using recent advances in Bayesian modelling of group effects in dynamic causal modelling, we fit biophysically plausible network models of the auditory processing hierarchy to whole-scalp evoked response potential recordings. This allowed us to identify the regionally specific effects of ketamine in a distributed network of interacting cortical sources. Under placebo, our analysis replicated previous findings regarding the effects of stimulus repetition and deviance on connectivity within the auditory hierarchy. Crucially, we show that the effect of ketamine is best explained as a selective change in intrinsic inhibition, with a pronounced ketamine-induced reduction of inhibitory interneuron connectivity in frontal sources. These results are consistent with findings from invasive recordings in animal models exposed to NMDAR blockers, and provide evidence that inhibitory-interneuron specific NMDAR dysfunction may be sufficient to explain electrophysiological abnormalities of sensory learning induced by ketamine in human subjects. Significance Statement Dysfunction of N-methyl-D-aspartate receptors (NMDARs) has been implicated in a range of psychopathologies, yet mechanisms translating receptor-level abnormalities to whole-brain pathology remain unclear. We use computational modelling to infer microcircuit mechanisms by which ketamine, an NMDAR-blocker, alters brain responses to changing sequences of sounds that rely on sensory learning. This dynamic causal modelling (DCM) approach shows that ketamine-effects can be explained with brain region specific changes in inhibitory interneuron coupling alone, with a striking reduction in inhibition in the prefrontal cortex. This suggests that NMDAR-effects on excitation-inhibition balance differ between brain regions, and provides evidence from healthy human subjects that NMDAR blockade may cause prefrontal cortex disinhibition, one of the mechanisms hypothesised to underlie psychopathology in schizophrenia.

NMDA receptor blockade causes selective prefrontal disinhibition in a roving auditory oddball paradigm

In recent decades, embodiment has become an influential concept in psychology and cognitive neuroscience. Embodiment denotes the study of the reciprocal (causal) relationships between mind and body, with the mind not only affecting the body but also vice versa. Embodied cognition comes to the fore in sensorimotor coupling, predictive coding, and nonverbal behavior. Additionally, the embodiment of the mind constitutes the basis of social interaction and communication, as evident in research on nonverbal synchrony and mimicry. These theoretical and empirical developments portend a range of implications for schizophrenia research and treatment. Sensorimotor dysfunctions are closely associated with affective and psychotic psychopathology, leading to altered timing in the processing of stimuli and to disordered appraisals of the environment. Problems of social cognition may be newly viewed as disordered embodied communication. The embodiment perspective suggests novel treatment strategies through psychotherapy and body-oriented interventions, and may ultimately provide biomarkers for diagnosis.

Embodiment and Schizophrenia: A Review of Implications and Applications.

Empirical evidence suggests the incentive value of an option is affected by other options available during choice and by options presented in the past. These contextual effects are hard to reconcile with classical theories and have inspired accounts where contextual influences play a crucial role. However, each account only addresses one or the other of the empirical findings and a unifying perspective has been elusive. Here, we offer a unifying theory of context effects on incentive value attribution and choice based on normative Bayesian principles. This formulation assumes that incentive value corresponds to a precision-weighted prediction error, where predictions are based upon expectations about reward. We show that this scheme explains a wide range of contextual effects, such as those elicited by other options available during choice (or within-choice context effects). These include both conditions in which choice requires an integration of multiple attributes and conditions where a multi-attribute integration is not necessary. Moreover, the same scheme explains context effects elicited by options presented in the past or between-choice context effects. Our formulation encompasses a wide range of contextual influences (comprising both within- and between-choice effects) by calling on Bayesian principles, without invoking ad-hoc assumptions. This helps clarify the contextual nature of incentive value and choice behaviour and may offer insights into psychopathologies characterized by dysfunctional decision-making, such as addiction and pathological gambling.

A unifying Bayesian account of contextual effects in value-based choice

Theoretical arguments and empirical evidence in neuroscience suggests that organisms represent or model their environment by minimizing a variational free-energy bound on the surprise associated with sensory signals from the environment. In this paper, we study phase transitions in coupled dissipative dynamical systems (complex Ginzburg-Landau equations) under a variety of coupling conditions to model the exchange of a system (agent) with its environment. We show that arbitrary coupling between sensory signals and the internal state of a system -- or those between its action and external (environmental) states -- do not guarantee synchronous dynamics between external and internal states: the spatial structure and the temporal dynamics of sensory signals and action (that comprise the system's Markov blanket) have to be pruned to produce synchrony. This synchrony is necessary for an agent to infer environmental states -- a pre-requisite for survival. Therefore, such sentient dynamics, relies primarily on approximate synchronization between the agent and its niche.

Sentient Self-Organization: Minimal dynamics and circular causality

Effective connectivity inferred from fMRI transition dynamics during movie viewing points to a balanced reconfiguration of cortical interactions

Causal Modeling: Methods and Their Application to Speech and Language

Active inference is a corollary of the Free Energy Principle that prescribes how self-organizing biological agents interact with their environment. The study of active inference processes relies on the definition of a generative probabilistic model and a description of how a free energy functional is minimized by neuronal message passing under that model. This paper presents a tutorial introduction to specifying active inference processes by Forney-style factor graphs (FFG). The FFG framework provides both an insightful representation of the probabilistic model and a biologically plausible inference scheme that, in principle, can be automatically executed in a computer simulation. As an illustrative example, we present an FFG for a deep temporal active inference process. The graph clearly shows how policy selection by expected free energy minimization results from free energy minimization per se, in an appropriate generative policy model.

Abstract An important characteristic of spontaneous brain activity is the anticorrelation between the core default network (cDN) and the dorsal attention network (DAN) and the salience network (SN). This anticorrelation may constitute a key aspect of functional anatomy and is implicated in several brain disorders. We used dynamic causal modeling to assess the hypothesis that a causal hierarchy underlies this anticorrelation structure, using resting-state fMRI of healthy adolescent and young adults (N = 404). Our analysis revealed an asymmetric effective connectivity, such that the regions in the SN and DAN exerted an inhibitory influence on the cDN regions; whereas the cDN exerted an excitatory influence on the SN and DAN regions. The relative strength of efferent versus afferent connections places the SN at the apex of the hierarchy, suggesting that the SN modulates anticorrelated networks with descending hierarchical connections. In short, this study of directed neuronal coupling reveals a causal hierarchical architecture that generates or orchestrates anticorrelation of brain activity. These new findings shed light on functional integration of intrinsic brain networks at rest and speak to future dynamic causal modeling studies of large-scale networks.

The Hierarchical Organization of the Default, Dorsal Attention and Salience Networks in Adolescents and Young Adults

Abstract Background: The “dysconnection hypothesis” of psychosis suggests that a disruption of functional integration underlies cognitive deficits and clinical symptoms. Impairments in the P300 potential are well documented in psychosis. We investigated intrinsic (self-)connectivity in a cortical hierarchy during a P300 experiment. We used Dynamic Causal Modeling to estimate how evoked activity results from the dynamics of coupled neural populations and how neural coupling changes with the experimental factors. Methods: Twenty-four patients with psychosis, 24 unaffected relatives, and 25 controls underwent EEG recordings during an auditory oddball paradigm. We analyzed 16 frontoparietal models (primary auditory, superior parietal, and superior frontal sources) and identified an optimal model of neural coupling, explaining diagnosis and genetic risk effects, as well as their interactions with task condition. Results: The winning model included changes in connectivity at all 3 hierarchical levels. Patients showed decreased self-inhibition (ie, increased cortical excitability) in left superior frontal gyrus across task conditions, compared to unaffected participants. Relatives had similar increases in excitability in left superior frontal and right superior parietal sources, and a reversal of the normal synaptic gain changes in response to targets, relative to standard tones. Conclusion: We confirmed that both subjects with psychosis and their relatives show a context-independent loss of synaptic gain control at the highest levels of the hierarchy. The relatives also showed abnormal gain modulation responses to task-relevant stimuli. These may be caused by NMDA-receptor and/or GABAergic pathologies that change the excitability of superficial pyramidal cells and may be a potential biological marker for psychosis.

SU72. Abnormal Frontal Synaptic Gain Mediating the P300 in Patients With Psychosis and Their Unaffected Relatives

Biological self-organisation is a process of spontaneous pattern formation; namely the emergence of coherent and stable systemic configurations that distinguish themselves from their environment. This process can occur at various spatial scales: from the microscopic (giving rise to cells) to the macroscopic (the emergence of organisms). Self-organisation at each level is essential to account for the hierarchical organisation of living organisms (organelles within cells, within tissues, within organs, etc.). In this paper, we pursue the idea that Markov blankets – statistical boundaries separating states that are external to a system from its internal states – emerge at every possible level of the description of the (living) system. Through simulations, we show that the concept of a Markov blanket is fundamental in defining biological systems and underwrites the nature and form of interactions between successive levels of hierarchical structure. We demonstrate the validity of our argument using simulations, based on the normative principle of variational free energy minimisation. Specifically, we adopt a top-down approach to provide a proof of concept for the claim that the self-organisation of Markov blankets (and blankets of blankets) underwrites the self-evidencing, autopoietic behaviour of living systems.

Thalamotomy at the ventralis intermedius nucleus for essential tremor is known to cause changes in motor circuitry, but how a focal lesion leads to progressive changes in connectivity is not clear. To understand the mechanisms by which thalamotomy exerts enduring effects on motor circuitry, a quantitative analysis of directed or effective connectivity among motor-related areas is required. We characterized changes in effective connectivity of the motor system following thalamotomy using (spectral) dynamic causal modeling (spDCM) for resting-state fMRI. To differentiate long-lasting treatment effects from transient effects, and to identify symptom-related changes in effective connectivity, we subject longitudinal resting-state fMRI data to spDCM, acquired 1 day prior to, and 1 day, 7 days, and 3 months after thalamotomy using a non-cranium-opening MRI-guided focused ultrasound ablation technique. For the group-level (between subject) analysis of longitudinal (between-session) effects, we introduce a multilevel parametric empirical Bayes (PEB) analysis for spDCM. We found remarkably selective and consistent changes in effective connectivity from the ventrolateral nuclei and the supplementary motor area to the contralateral dentate nucleus after thalamotomy, which may be mediated via a polysynaptic thalamic–cortical–cerebellar motor loop. Crucially, changes in effective connectivity predicted changes in clinical motor-symptom scores after thalamotomy. This study speaks to the efficacy of thalamotomy in regulating the dentate nucleus in the context of treating essential tremor. Furthermore, it illustrates the utility of PEB for group-level analysis of dynamic causal modeling in quantifying longitudinal changes in effective connectivity; i.e., measuring long-term plasticity in human subjects non-invasively.

Hierarchical Dynamic Causal Modeling of Resting-State fMRI Reveals Longitudinal Changes in Effective Connectivity in the Motor System after Thalamotomy for Essential Tremor

Integration of Structural and Effective Connectivity to Explore the Social Brain

In this series of behavioural and electroencephalography (EEG) experiments, we investigate the extent to which repeating patterns of sounds capture attention. Work in the visual domain has revealed attentional capture by statistically predictable stimuli, consistent with predictive coding accounts which suggest that attention is drawn to sensory regularities. Here, stimuli comprised rapid sequences of tone pips, arranged in regular (REG) or random (RAND) patterns. EEG data demonstrate that the brain rapidly recognizes predictable patterns manifested as a rapid increase in responses to REG relative to RAND sequences. This increase is reminiscent of the increase in gain on neural responses to attended stimuli often seen in the neuroimaging literature, and thus consistent with the hypothesis that predictable sequences draw attention. To study potential attentional capture by auditory regularities, we used REG and RAND sequences in two different behavioural tasks designed to reveal effects of attentional capture by regularity. Overall, the pattern of results suggests that regularity does not capture attention. This article is part of the themed issue ‘Auditory and visual scene analysis’.

Is predictability salient? A study of attentional capture by auditory patterns

Significance Recently, autoantibodies against NMDA receptors (NMDARs) were identified as a major cause of autoimmune encephalitis. They cause abnormalities in brain function often associated with significant changes in patients’ brain dynamics. Here we use computational modeling to identify how NMDAR dysfunction causes abnormalities in brain dynamics using patient EEGs and local field potential recordings in a mouse model of NMDAR-Ab encephalitis. NMDAR autoantibodies cause a specific shift in excitatory coupling within cortical circuits that places the circuits closer to pathological transitions between dynamic brain states. Because of the proximity to these phase transitions, otherwise benign fluctuations in neuronal coupling cause abnormal EEG responses in the presence of the antibodies. Our modeling results thus explain fluctuating abnormalities in brain dynamics observed in patients. NMDA-receptor antibodies (NMDAR-Abs) cause an autoimmune encephalitis with a diverse range of EEG abnormalities. NMDAR-Abs are believed to disrupt receptor function, but how blocking this excitatory synaptic receptor can lead to paroxysmal EEG abnormalities—or even seizures—is poorly understood. Here we show that NMDAR-Abs change intrinsic cortical connections and neuronal population dynamics to alter the spectral composition of spontaneous EEG activity and predispose brain dynamics to paroxysmal abnormalities. Based on local field potential recordings in a mouse model, we first validate a dynamic causal model of NMDAR-Ab effects on cortical microcircuitry. Using this model, we then identify the key synaptic parameters that best explain EEG paroxysms in pediatric patients with NMDAR-Ab encephalitis. Finally, we use the mouse model to show that NMDAR-Ab–related changes render microcircuitry critically susceptible to overt EEG paroxysms when these key parameters are changed, even though the same parameter fluctuations are tolerated in the in silico model of the control condition. These findings offer mechanistic insights into circuit-level dysfunction induced by NMDAR-Ab.

Humans display anticipatory motor responses to minimize the adverse effects of predictable perturbations. A widely accepted explanation for this behavior relies on the notion of an inverse model that, learning from motor errors, anticipates corrective responses. Here, we propose and validate the alternative hypothesis that anticipatory control can be realized through a cascade of purely sensory predictions that drive the motor system, reflecting the causal sequence of the perceptual events preceding the error. We compare both hypotheses in a simulated anticipatory postural adjustment task. We observe that adaptation in the sensory domain, but not in the motor one, supports the robust and generalizable anticipatory control characteristic of biological systems. Our proposal unites the neurobiology of the cerebellum with the theory of active inference and provides a concrete implementation of its core tenets with great relevance both to our understanding of biological control systems and, possibly, to their emulation in complex artefacts.

This article provides an illustrative treatment of psychiatric morbidity that offers an alternative to the standard nosological model in psychiatry. It considers what would happen if we treated diagnostic categories not as causes of signs and symptoms, but as diagnostic consequences of psychopathology and pathophysiology. This reformulation (of the standard nosological model) opens the door to a more natural description of how patients present—and of their likely responses to therapeutic interventions. In brief, we describe a model that generates symptoms, signs, and diagnostic outcomes from latent psychopathological states. In turn, psychopathology is caused by pathophysiological processes that are perturbed by (etiological) causes such as predisposing factors, life events, and therapeutic interventions. The key advantages of this nosological formulation include (i) the formal integration of diagnostic (e.g., DSM) categories and latent psychopathological constructs (e.g., the dimensions of the Research Domain Criteria); (ii) the provision of a hypothesis or model space that accommodates formal, evidence-based hypothesis testing (using Bayesian model comparison); and (iii) the ability to predict therapeutic responses (using a posterior predictive density), as in precision medicine. These and other advantages are largely promissory at present: The purpose of this article is to show what might be possible, through the use of idealized simulations.

This paper is about the fitting or inversion of dynamic causal models (DCMs) of fMRI time series. It tries to establish the validity of stochastic DCMs that accommodate random fluctuations in hidden neuronal and physiological states. We compare and contrast deterministic and stochastic DCMs, which do and do not ignore random fluctuations or noise on hidden states. We then compare stochastic DCMs, which do and do not ignore conditional dependence between hidden states and model parameters (generalised filtering and dynamic expectation maximisation, respectively). We first characterise statenoise by comparing the log evidence of models with different a priori assumptions about its amplitude, form and smoothness. Face validity of the inversion scheme is then established using data simulated with and without state-noise to ensure that DCM can identify the parameters and model that generated the data. Finally, we address construct validity using real data from an fMRI study of internet addiction. Our analyses suggest the following. (i) The inversion of stochastic causal models is feasible, given typical fMRI data. (ii) State-noise has nontrivial amplitude and smoothness. (iii) Stochastic DCM has face validity, in the sense that Bayesian model comparison can distinguish between data that have been generated with high and low levels of physiological noise and model inversion provides veridical estimates of effective connectivity. (iv) Relaxing conditional independence assumptions can have greater construct validity, in terms of revealing group differences not disclosed by variational schemes. Finally, we note that the ability to model endogenous or random fluctuations on hidden neuronal (and physiological) states provides a new and possibly more plausible perspective on how regionally specific signals in fMRI are generated. DOI: https://doi.org/10.1016/j.neuroimage.2011.01.085 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-49235 Originally published at: Li, Baojuan; Daunizeau, Jean; Stephan, Klaas E; Penny, Will; Hu, Dewen; Friston, Karl J (2011). Generalised filtering and stochastic DCM for fMRI. NeuroImage, 58(2):442-457. DOI: https://doi.org/10.1016/j.neuroimage.2011.01.085 Generalised filtering and stochastic DCM for fMRI Baojuan Li , Jean Daunizeau , Klaas E. Stephan , Will Penny , Dewen Hu , Karl Friston a,⁎ a The Wellcome Trust Centre for Neuroimaging, University College London, Queen Square, London WC1N 3BG, UK b Laboratory for Social and Neural Systems Research, Institute of Empirical Research in Economics, University of Zurich, Zurich, Switzerland c College of Mechatronic Engineering and Automation, National University of Defense Technology, Changsha, Hunan 410073, PR China a b s t r a c t a r t i c l e i n f o

Investigating the relationship between multiple grip forces and BOLD signal in the Cerebellum and dentate nuclei of MS subjects

Different functional networks observed in multiple sclerosis during rest and motor task fMRI

Categorization is a fundamental ability for efficient behavioral control. It allows organisms to remember the correct responses to categorical cues and not for every stimulus encountered (hence eluding computational cost or complexity), and to generalize appropriate responses to novel stimuli dependant on category assignment. Assuming the brain performs Bayesian inference, based on a generative model of the external world and future goals, we propose a computational model of categorization in which important properties emerge. These properties comprise the ability to infer latent causes of sensory experience, a hierarchical organization of latent causes, and an explicit inclusion of context and action representations. Crucially, these aspects derive from considering the environmental statistics that are relevant to achieve goals, and from the fundamental Bayesian principle that any generative model should be preferred over alternative models based on an accuracy-complexity trade-off. Our account is a step toward elucidating computational principles of categorization and its role within the Bayesian brain hypothesis.

In a published paper (Sengupta et al., 2016), we have proposed that the brain (and other selforganized biological and artificial systems) can be characterized via the mathematical apparatus of a gauge theory. The picture that emerges from this approach suggests that any biological system (from a neuron to an organism) can be cast as resolving uncertainty about its external milieu, either by changing its internal states or its relationship to the environment. Using formal arguments, we have shown that a gauge theory for neuronal dynamics – based on approximate Bayesian inference – has the potential to shed new light on phenomena that have thus far eluded a formal description, such as attention and the link between action and perception. Here, we describe the technical apparatus that enables such a variational inference on manifolds. Particularly, the novel contribution of this paper is an algorithm that utlizes a Schild’s ladder for parallel transport of sufficient statistics (means, covariances, etc.) on a statistical manifold.

Correction: Sequential inference as a mode of cognition and its correlates in fronto-parietal and hippocampal brain regions

The “dysconnection hypothesis” of psychosis suggests that a disruption of functional integration underlies cognitive deficits and clinical symptoms. Impairments in the P300 potential are well documented in psychosis. Intrinsic (self‐)connectivity in a frontoparietal cortical hierarchy during a P300 experiment was investigated. Dynamic Causal Modeling was used to estimate how evoked activity results from the dynamics of coupled neural populations and how neural coupling changes with the experimental factors. Twenty‐four patients with psychotic disorder, twenty‐four unaffected relatives, and twenty‐five controls underwent EEG recordings during an auditory oddball paradigm. Sixteen frontoparietal network models (including primary auditory, superior parietal, and superior frontal sources) were analyzed and an optimal model of neural coupling, explaining diagnosis and genetic risk effects, as well as their interactions with task condition were identified. The winning model included changes in connectivity at all three hierarchical levels. Patients showed decreased self‐inhibition—that is, increased cortical excitability—in left superior frontal gyrus across task conditions, compared with unaffected participants. Relatives had similar increases in excitability in left superior frontal and right superior parietal sources, and a reversal of the normal synaptic gain changes in response to targets relative to standard tones. It was confirmed that both subjects with psychotic disorder and their relatives show a context‐independent loss of synaptic gain control at the highest hierarchy levels. The relatives also showed abnormal gain modulation responses to task‐relevant stimuli. These may be caused by NMDA‐receptor and/or GABAergic pathologies that change the excitability of superficial pyramidal cells and may be a potential biological marker for psychosis. Hum Brain Mapp 38:3262–3276, 2017. © 2017 Wiley Periodicals, Inc.

Abnormal frontoparietal synaptic gain mediating the P300 in patients with psychotic disorder and their unaffected relatives

The neuronal mechanisms underlying arithmetic calculations are not well understood but the differences between mental addition and subtraction could be particularly revealing. Using fMRI and dynamic causal modeling (DCM), this study aimed to identify the distinct neuronal architectures engaged by the cognitive processes of simple addition and subtraction. Our results revealed significantly greater activation during subtraction in regions along the dorsal pathway, including the left inferior frontal gyrus (IFG), middle portion of dorsolateral prefrontal cortex (mDLPFC), and supplementary motor area (SMA), compared with addition. Subsequent analysis of the underlying changes in connectivity – with DCM – revealed a common circuit processing basic (numeric) attributes and the retrieval of arithmetic facts. However, DCM showed that addition was more likely to engage (numeric) retrieval‐based circuits in the left hemisphere, while subtraction tended to draw on (magnitude) processing in bilateral parietal cortex, especially the right intraparietal sulcus (IPS). Our findings endorse previous hypotheses about the differences in strategic implementation, dominant hemisphere, and the neuronal circuits underlying addition and subtraction. Moreover, for simple arithmetic, our connectivity results suggest that subtraction calls on more complex processing than addition: auxiliary phonological, visual, and motor processes, for representing numbers, were engaged by subtraction, relative to addition. Hum Brain Mapp 38:3210–3225, 2017. © 2017 Wiley Periodicals, Inc.

The functional architectures of addition and subtraction: Network discovery using fMRI and DCM

Working memory (WM) impairment is regarded as a core aspect of schizophrenia. However, the neural mechanisms behind this cognitive deficit remain unclear. The connectivity of a frontoparietal network is known to be important for subserving WM. Using functional magnetic resonance imaging, the current study investigated whether WM-dependent modulation of effective connectivity in this network is affected in a group of first-episode schizophrenia (FES) patients compared with similarly performing healthy participants during a verbal n-back task. Dynamic causal modeling (DCM) of the coupling between regions (left inferior frontal gyrus (IFG), left inferior parietal lobe (IPL), and primary visual area) identified in a psychophysiological interaction (PPI) analysis was performed to characterize effective connectivity during the n-back task. The PPI analysis revealed that the connectivity between the left IFG and left IPL was modulated by WM and that this modulation was reduced in FES patients. The subsequent DCM analysis confirmed this modulation by WM and found evidence that FES patients had reduced forward connectivity from IPL to IFG. These findings provide evidence for impaired WM modulation of frontoparietal effective connectivity in the early phase of schizophrenia, even with intact WM performance, suggesting a failure of context-sensitive coupling in the schizophrenic brain.

Working Memory Modulation of Frontoparietal Network Connectivity in First-Episode Schizophrenia

The brain network for emotional body language reading: Combined structural and effective connectivity

1 Division of Psychiatry, University College London, UK. 2 Department of Basic Psychology II – Cognitive processes, Faculty of Psychology, Complutense University of Madrid, Spain. 3 Laboratory of Cognitive and Computational Neuroscience − Centre for Biomedical Technology (CTB), Complutense University and Technical University of Madrid, Spain. 4 The Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, UK. 5 The Picower Institute for Learning & Memory and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA. 6 North East London NHS Foundation Trust, London, UK. 7 Institute of Psychiatry, Psychology & Neuroscience – King’s College London, UK. 8 Psychosis Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, MA, USA. 9 Institute of Cognitive Neuroscience, UniverFsity College London, UK.

Abnormal frontoparietal synaptic gain mediating the P 300 in patients with psychotic disorder and their unaffected relatives Human Brain Mapping ( 2017 ) in press

Stimulus predictability can lead to substantial modulations of brain activity, such as shifts in sustained magnetic field amplitude, measured with magnetoencephalography (MEG). Here, we provide a mechanistic explanation of these effects using MEG data acquired from healthy human volunteers (N = 13, 7 female). In a source-level analysis of induced responses, we established the effects of orthogonal predictability manipulations of rapid tone-pip sequences (namely, sequence regularity and alphabet size) along the auditory processing stream. In auditory cortex, regular sequences with smaller alphabets induced greater gamma activity. Furthermore, sequence regularity shifted induced activity in frontal regions toward higher frequencies. To model these effects in terms of the underlying neurophysiology, we used dynamic causal modeling for cross-spectral density and estimated slow fluctuations in neural (postsynaptic) gain. Using the model-based parameters, we accurately explain the sensor-level sustained field amplitude, demonstrating that slow changes in synaptic efficacy, combined with sustained sensory input, can result in profound and sustained effects on neural responses to predictable sensory streams. SIGNIFICANCE STATEMENT Brain activity can be strongly modulated by the predictability of stimuli it is currently processing. An example of such a modulation is a shift in sustained magnetic field amplitude, measured with magnetoencephalography. Here, we provide a mechanistic explanation of these effects. First, we establish the oscillatory neural correlates of independent predictability manipulations in hierarchically distinct areas of the auditory processing stream. Next, we use a biophysically realistic computational model to explain these effects in terms of the underlying neurophysiology. Finally, using the model-based parameters describing neural gain modulation, we can explain the previously unexplained effects observed at the sensor level. This demonstrates that slow modulations of synaptic gain can result in profound and sustained effects on neural activity.

The Cumulative Effects of Predictability on Synaptic Gain in the Auditory Processing Stream

Hierarchies feature prominently in anatomical accounts of cortical organisation. An open question is which computational (algorithmic) processes are implemented by these hierarchies. One renowned hypothesis is that cortical hierarchies implement a model of the world's causal structure and serve to infer environmental states from sensory inputs. This view, which casts perception as hierarchical Bayesian inference, has become a highly influential concept in both basic and clinical neuroscience. So far, however, a direct correspondence between the predicted order of hierarchical Bayesian computations and the sequence of evoked neuronal activity has not been demonstrated. Here, we present evidence for this correspondence from neuroimaging and electrophysiological data in healthy volunteers. Trial-wise sequences of hierarchical computations were inferred from participants' behaviour during a social learning task that required multi-level inference about intentions. We found that the temporal sequence of neuronal activity matched the order of computations as predicted by the theory. These findings provide strong evidence for the operation of hierarchical Bayesian inference in human cortex. Furthermore, our approach offers a novel strategy for the combined computational-physiological phenotyping of patients with disorders of perception, such as schizophrenia or autism.

This article offers a formal account of curiosity and insight in terms of active (Bayesian) inference. It deals with the dual problem of inferring states of the world and learning its statistical structure. In contrast to current trends in machine learning (e.g., deep learning), we focus on how people attain insight and understanding using just a handful of observations, which are solicited through curious behavior. We use simulations of abstract rule learning and approximate Bayesian inference to show that minimizing (expected) variational free energy leads to active sampling of novel contingencies. This epistemic behavior closes explanatory gaps in generative models of the world, thereby reducing uncertainty and satisfying curiosity. We then move from epistemic learning to model selection or structure learning to show how abductive processes emerge when agents test plausible hypotheses about symmetries (i.e., invariances or rules) in their generative models. The ensuing Bayesian model reduction evinces mechanisms associated with sleep and has all the hallmarks of “aha” moments. This formulation moves toward a computational account of consciousness in the pre-Cartesian sense of sharable knowledge (i.e., con: “together”; scire: “to know”).

Epileptic seizure activity shows complicated dynamics in both space and time. To understand the evolution and propagation of seizures spatially extended sets of data need to be analysed. We have previously described an efficient filtering scheme using variational Laplace that can be used in the Dynamic Causal Modelling (DCM) framework [Friston, 2003] to estimate the temporal dynamics of seizures recorded using either invasive or non-invasive electrical recordings (EEG/ECoG). Spatiotemporal dynamics are modelled using a partial differential equation -- in contrast to the ordinary differential equation used in our previous work on temporal estimation of seizure dynamics [Cooray, 2016]. We provide the requisite theoretical background for the method and test the ensuing scheme on simulated seizure activity data and empirical invasive ECoG data. The method provides a framework to assimilate the spatial and temporal dynamics of seizure activity, an aspect of great physiological and clinical importance.

The brain is thought to generate internal predictions to optimize behaviour. However, it is unclear whether predictions signalling is an automatic brain function or depends on task demands. Here, we manipulated the spatial/temporal predictability of visual targets, and the relevance of spatial/temporal information provided by auditory cues. We used magnetoencephalography (MEG) to measure participants’ brain activity during task performance. Task relevance modulated the influence of predictions on behaviour: spatial/temporal predictability improved spatial/temporal discrimination accuracy, but not vice versa. To explain these effects, we used behavioural responses to estimate subjective predictions under an ideal-observer model. Model-based time-series of predictions and prediction errors (PEs) were associated with dissociable neural responses: predictions correlated with cue-induced beta-band activity in auditory regions and alpha-band activity in visual regions, while stimulus-bound PEs correlated with gamma-band activity in posterior regions. Crucially, task relevance modulated these spectral correlates, suggesting that current goals influence PE and prediction signalling.

Task relevance modulates the behavioural and neural effects of sensory predictions

Pathophysiological explanations of epilepsy typically focus on either the micro/mesoscale (e.g. excitation-inhibition imbalance), or on the macroscale (e.g. network architecture). Linking abnormalities across spatial scales remains difficult, partly because of technical limitations in measuring neuronal signatures concurrently at the scales involved. Here we use light sheet imaging of the larval zebrafish brain during acute epileptic seizure induced with pentylenetetrazole. Empirically measured spectral changes of spontaneous neuronal activity during the seizure are then modelled using neural mass models, allowing Bayesian inference on changes in effective network connectivity and their underlying synaptic dynamics. This dynamic causal modelling of seizures in the zebrafish brain reveals concurrent changes in synaptic coupling at macro- and mesoscale. Fluctuations of synaptic connection strength and their temporal dynamics are both required to explain observed seizure patterns. These findings challenge a simple excitation-inhibition account of seizures, and highlight changes in synaptic transmission dynamics as a possible seizure generation pathomechanism. Abbreviations LFP local field potential PTZ pentylenetetrazole DCM dynamic causal modelling CSD cross spectral densities PEB Parametric Empirical Bayes

Calcium imaging and dynamic causal modelling reveal brain-wide changes in effective connectivity and synaptic dynamics during epileptic seizures

Neurophysiologically-informed markers of individual variability and pharmacological manipulation of human cortical gamma

Abstract Visual neglect is a debilitating neuropsychological phenomenon that has many clinical implications and—in cognitive neuroscience—offers an important lesion deficit model. In this article, we describe a computational model of visual neglect based upon active inference. Our objective is to establish a computational and neurophysiological process theory that can be used to disambiguate among the various causes of this important syndrome; namely, a computational neuropsychology of visual neglect. We introduce a Bayes optimal model based upon Markov decision processes that reproduces the visual searches induced by the line cancellation task (used to characterize visual neglect at the bedside). We then consider 3 distinct ways in which the model could be lesioned to reproduce neuropsychological (visual search) deficits. Crucially, these 3 levels of pathology map nicely onto the neuroanatomy of saccadic eye movements and the systems implicated in visual neglect.

Posttraumatic stress disorder (PTSD) is associated with decreased top–down emotion modulation from medial prefrontal cortex (mPFC) regions, a pathophysiology accompanied by hyperarousal and hyperactivation of the amygdala. By contrast, PTSD patients with the dissociative subtype (PTSD + DS) often exhibit increased mPFC top–down modulation and decreased amygdala activation associated with emotional detachment and hypoarousal. Crucially, PTSD and PTSD + DS display distinct functional connectivity within the PFC, amygdala complexes, and the periaqueductal gray (PAG), a region related to defensive responses/emotional coping. However, differences in directed connectivity between these regions have not been established in PTSD, PTSD + DS, or controls. Methods: To examine directed (effective) connectivity among these nodes, as well as group differences, we conducted resting‐state stochastic dynamic causal modeling (sDCM) pairwise analyses of coupling between the ventromedial (vm)PFC, the bilateral basolateral and centromedial (CMA) amygdala complexes, and the PAG, in 155 participants (PTSD [n = 62]; PTSD + DS [n = 41]; age‐matched healthy trauma‐unexposed controls [n = 52]). Results: PTSD was characterized by a pattern of predominant bottom–up connectivity from the amygdala to the vmPFC and from the PAG to the vmPFC and amygdala. Conversely, PTSD + DS exhibited predominant top–down connectivity between all node pairs (from the vmPFC to the amygdala and PAG, and from the amygdala to the PAG). Interestingly, the PTSD + DS group displayed the strongest intrinsic inhibitory connections within the vmPFC. Conclusions: These results suggest the contrasting symptom profiles of PTSD and its dissociative subtype (hyper‐ vs. hypo‐emotionality, respectively) may be driven by complementary changes in directed connectivity corresponding to bottom–up defensive fear processing versus enhanced top–down regulation. Hum Brain Mapp 38:5551–5561, 2017. © 2017 Wiley Periodicals, Inc.

Dynamic causal modeling in PTSD and its dissociative subtype: Bottom–up versus top–down processing within fear and emotion regulation circuitry

REVIEWING EDITORS Jose Manuel Alonso Dora Angelaki Christopher I. Baker Tracy L. Bale Christophe Bernard Jeffrey Diamond Mark Farrant Alyson Fournier Vittorio Gallo Michael Gold Jay A. Gottfried Ege T. Kavalali Paul J. Kenny Eric Klann James Knierim Gary E. Landreth Daeyeol Lee Joseph LoTurco Diane Merry Farzan Nadim Anna Christina Nobre Sam Pleasure Dan H. Sanes Geoffrey Schoenbaum Charles Schroeder Ruth S. Slack Jane M. Sullivan Ivan Toni Catherine S. Woolley

Prefrontal and parietal cortex, including the default mode network (DMN; medial prefrontal cortex (mPFC), and posterior cingulate cortex, PCC), have been implicated in addiction. Nonetheless, it remains unclear which brain regions play a crucial role in smoking addiction and the relationship among these regions. Since functional connectivity only measures correlations, addiction-related changes in effective connectivity (directed information flow) among these distributed brain regions remain largely unknown. Here we applied spectral dynamic causal modeling (spDCM) to resting state fMRI to characterize changes in effective connectivity among core regions in smoking addiction. Compared to nonsmokers, smokers had reduced effective connectivity from PCC to mPFC and from RIPL to mPFC, a higher self-inhibition within PCC and a reduction in the amplitude of endogenous neuronal fluctuations driving the mPFC. These results indicate that spDCM can differentiate the functional architectures between the two groups, and may provide insight into the brain mechanisms underlying smoking addiction. Our results also suggest that future brain-based prevention and intervention in addiction should consider the amelioration of mPFC-PCC-IPL circuits.

See Moll and Engel (doi:10.1093/aww308) for a scientific commentary on this article. Brain regions dynamically engage and disengage with one another to execute everyday actions from movement to decision making. Pathologies such as Parkinson’s disease and tremor emerge when brain regions controlling movement cannot readily decouple, compromising motor function. Here, we propose a novel stimulation strategy that selectively regulates neural synchrony through phase-specific stimulation. We demonstrate for the first time the therapeutic potential of such a stimulation strategy for the treatment of patients with pathological tremor. Symptom suppression is achieved by delivering stimulation to the ventrolateral thalamus, timed according to the patient’s tremor rhythm. Sustained locking of deep brain stimulation to a particular phase of tremor afforded clinically significant tremor relief (up to 87% tremor suppression) in selected patients with essential tremor despite delivering less than half the energy of conventional high frequency stimulation. Phase-specific stimulation efficacy depended on the resonant characteristics of the underlying tremor network. Selective regulation of neural synchrony through phase-locked stimulation has the potential to both increase the efficiency of therapy and to minimize stimulation-induced side effects.

Stimulating at the right time: phase-specific deep brain stimulation

Given the amount of knowledge and data accruing in the neurosciences, is it time to formulate a general principle for neuronal dynamics that holds at evolutionary, developmental, and perceptual timescales? In this paper, we propose that the brain (and other self-organised biological systems) can be characterised via the mathematical apparatus of a gauge theory. The picture that emerges from this approach suggests that any biological system (from a neuron to an organism) can be cast as resolving uncertainty about its external milieu, either by changing its internal states or its relationship to the environment. Using formal arguments, we show that a gauge theory for neuronal dynamics—based on approximate Bayesian inference—has the potential to shed new light on phenomena that have thus far eluded a formal description, such as attention and the link between action and perception.

Significance We reveal the temporal dynamics and underlying neural sources of the process by which the brain discovers complex temporal patterns in rapidly unfolding sound sequences. We demonstrate that the auditory system, supported by a network of auditory cortical, hippocampal, and frontal sources, continually scans the environment, efficiently represents complex stimulus statistics, and rapidly (close to the bounds implied by an ideal observer model) responds to emergence of regular patterns, even when these are not behaviorally relevant. Neuronal activity correlated with the predictability of ongoing auditory input, both in terms of deterministic structure and the entropy of random sequences, providing clear neurophysiological evidence of the brain's capacity to automatically encode high-order statistics in sensory input. We use behavioral methods, magnetoencephalography, and functional MRI to investigate how human listeners discover temporal patterns and statistical regularities in complex sound sequences. Sensitivity to patterns is fundamental to sensory processing, in particular in the auditory system, because most auditory signals only have meaning as successions over time. Previous evidence suggests that the brain is tuned to the statistics of sensory stimulation. However, the process through which this arises has been elusive. We demonstrate that listeners are remarkably sensitive to the emergence of complex patterns within rapidly evolving sound sequences, performing on par with an ideal observer model. Brain responses reveal online processes of evidence accumulation—dynamic changes in tonic activity precisely correlate with the expected precision or predictability of ongoing auditory input—both in terms of deterministic (first-order) structure and the entropy of random sequences. Source analysis demonstrates an interaction between primary auditory cortex, hippocampus, and inferior frontal gyrus in the process of discovering the regularity within the ongoing sound sequence. The results are consistent with precision based predictive coding accounts of perceptual inference and provide compelling neurophysiological evidence of the brain's capacity to encode high-order temporal structure in sensory signals.

Brain responses in humans reveal ideal observer-like sensitivity to complex acoustic patterns

Perceptual learning to discriminate the intensity and spatial location of nociceptive stimuli

This chapter provides an illustrative treatment of psychiatric morbidity that offers an alternative to the standard nosological model in psychiatry. It considers what would happen if we treated diagnostic categories not as putative causes of signs and symptoms, but as diagnostic consequences of psychopathology and pathophysiology. This reconstitution (of the standard model) opens the door to a more natural formulation of how patients present and their likely response to therapeutic interventions. The chapter describes a model that generates symptoms, signs, and diagnostic outcomes from latent psychopathological states. In turn, psychopathology is caused by pathophysiological processes that are perturbed by (etiological) causes, such as predisposing factors, life events, and therapeutic interventions. The key advantages of this nosological formulation include: (a) the formal integration of diagnostic (e.g., DSM) categories and latent psychopathological constructs (e.g., the dimensions of RDoC); (b) the provision of a hypothesis or model space that accommodates formal evidence-based hypothesis testing or model selection (using Bayesian model comparison); (c) the ability to predict therapeutic responses (using a posterior predictive density), as in precision medicine; and (d) a framework that allows one to test hypotheses about the interactions between pharmacological and psychotherapeutic interventions. These and other advantages are largely promissory at present: the purpose of this chapter is to show what might be possible, through the use of idealized simulations. These simulations can be regarded as a (conceptual) prospectus that motivates a computational nosology for psychiatry.

Computational Nosology and Precision Psychiatry A Proof of Concept

R ecently, there have been several concerted international efforts—the BRAIN Initiative, the European Human Brain Project, and the Human Connectome Project, to name a few—that hope to revolutionize our under­ standing of the connected brain. During the past two de ­ cades, functional neuroimaging has emerged as the predominant technique in systems neuroscience. This is foreshadowed by an ever­increasing number of publications on functional connectivity, causal modeling, connectomics, and multivariate analyses of distributed patterns of brain responses. In this article, we summarize pedagogically the (deep) history of brain mapping. We highlight the theoretical advances made in the (dynamic) causal modeling of brain function, which may have escaped the wider audience of this article, and provide a brief overview of recent developments and interesting clinical applications. We hope that this arti­ cle engages the signal processing community by showcasing the inherently multidisciplinary nature of this important topic and the intriguing questions that are being addressed.

This article offers an account of embodied exchange with the world that associates conscious operations with actively inferring the causes of our sensations. Its agenda is to link formal (mathematical) descriptions of dynamical systems to a description of perception in terms of beliefs and goals. The argument has two parts: the first calls on the lawful dynamics of any (weakly mixing ergodic) system that persists in a changing environment – from a single cell organism to a human brain. These lawful dynamics suggest that (internal) states can be interpreted as modelling or predicting the (external) causes of sensory perturbations. In other words, if a system exists, its internal states must encode probabilistic beliefs about external states. Heuristically, this means that if I exist (am) then I must have beliefs (think). The second part of the argument is that the only tenable beliefs I can entertain about myself are that I exist. This may seem rather facile; however, if we associate existing with ergodicity, then (ergodic) systems that exist by predicting external states can only possess prior beliefs that their environment is predictable. It transpires that this is equivalent to believing that the world – and the way it is sampled – will minimise uncertainty about the causes of sensations. We conclude by illustrating the behaviour that emerges under these beliefs using simulations of saccadic searches – and considering them in the light of conscious perception.

The experience of coincidence: An integrated psychological and neurocognitive perspective

Balancing habitual and deliberate forms of choice entails a comparison of their respective merits—the former being faster but inflexible, and the latter slower but more versatile. Here, we show that arbitration between these two forms of control can be derived from first principles within an Active Inference scheme. We illustrate our arguments with simulations that reproduce rodent spatial decisions in T-mazes. In this context, deliberation has been associated with vicarious trial and error (VTE) behavior (i.e., the fact that rodents sometimes stop at decision points as if deliberating between choice alternatives), whose neurophysiological correlates are “forward sweeps” of hippocampal place cells in the arms of the maze under consideration. Crucially, forward sweeps arise early in learning and disappear shortly after, marking a transition from deliberative to habitual choice. Our simulations show that this transition emerges as the optimal solution to the trade-off between policies that maximize reward or extrinsic value (habitual policies) and those that also consider the epistemic value of exploratory behavior (deliberative or epistemic policies)—the latter requiring VTE and the retrieval of episodic information via forward sweeps. We thus offer a novel perspective on the optimality principles that engender forward sweeps and VTE, and on their role on deliberate choice.

Active Inference, epistemic value, and vicarious trial and error

The association between in-scanner head motion and intrinsic functional connectivity (iFC) may confound explanations for individual differences in functional connectomics. However, the etiology of the correlation between head motion and iFC has not been established. This study aimed to investigate genetic and environmental contributions on the association between head motion and iFC using a twin dataset (175 same-sex twin pairs, aged 14-23 years, 48% females). After establishing that both head motion and default network iFC are moderately heritable, we found large genetic correlations (-0.52 to -0.73) between head motion and the default network iFCs. Common genes can explain 48% - 61% of the negative phenotypic correlation between the two phenotypes. These results advance our understanding of the relationship between head motion and iFC, and may have profound implications for interpreting individual differences in default network connectivity in clinical research and brain-behavior association.

Genetic overlap between in-scanner head motion and the default network connectivity

This article describes the first application of a generic (empirical) Bayesian analysis of between‐subject effects in the dynamic causal modeling (DCM) of electrophysiological (MEG) data. It shows that (i) non‐invasive (MEG) data can be used to characterize subject‐specific differences in cortical microcircuitry and (ii) presents a validation of DCM with neural fields that exploits intersubject variability in gamma oscillations. We find that intersubject variability in visually induced gamma responses reflects changes in the excitation‐inhibition balance in a canonical cortical circuit. Crucially, this variability can be explained by subject‐specific differences in intrinsic connections to and from inhibitory interneurons that form a pyramidal‐interneuron gamma network. Our approach uses Bayesian model reduction to evaluate the evidence for (large sets of) nested models—and optimize the corresponding connectivity estimates at the within and between‐subject level. We also consider Bayesian cross‐validation to obtain predictive estimates for gamma‐response phenotypes, using a leave‐one‐out procedure. Hum Brain Mapp 37:4597–4614, 2016. © The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Intersubject variability and induced gamma in the visual cortex: DCM with empirical Bayes and neural fields

Corrigendum to "Active inference and epistemic value" [Cognitive Neuroscience, 6 (2015), 187-214. doi: 10.1080/17588928.2015.1020053]

Prediction, precision, and context: dynamic causal modelling of MEG and ECoG

Dynamic causal modelling of electrographic seizure activity using Bayesian belief updating

Dynamic causal modeling of touch-evoked potentials in the rubber hand illusion

Corrigendum to ‘Optimal inference with suboptimal models: Addiction and active Bayesian inference’ [Med. Hypotheses 84 (2015) 109–117]

Background: The fact that surplus connections and neurons are pruned during development is well established. We complement this selectionist picture by a proof-of-principle model of evolutionary search in the brain, that accounts for new variations in theory space. We present a model for Darwinian evolutionary search for candidate solutions in the brain. Methods: We combine known components of the brain - recurrent neural networks (acting as attractors), the action selection loop and implicit working memory - to provide the appropriate Darwinian architecture. We employ a population of attractor networks with palimpsest memory. The action selection loop is employed with winners-share-all dynamics to select for candidate solutions that are transiently stored in implicit working memory. Results: We document two processes: selection of stored solutions and evolutionary search for novel solutions. During the replication of candidate solutions attractor networks occasionally produce recombinant patterns, increasing variation on which selection can act. Combinatorial search acts on multiplying units (activity patterns) with hereditary variation and novel variants appear due to (i) noisy recall of patterns from the attractor networks, (ii) noise during transmission of candidate solutions as messages between networks, and, (iii) spontaneously generated, untrained patterns in spurious attractors. Conclusions: Attractor dynamics of recurrent neural networks can be used to model Darwinian search. The proposed architecture can be used for fast search among stored solutions (by selection) and for evolutionary search when novel candidate solutions are generated in successive iterations. Since all the suggested components are present in advanced nervous systems, we hypothesize that the brain could implement a truly evolutionary combinatorial search system, capable of generating novel variants.

Breeding novel solutions in the brain: a model of Darwinian neurodynamics.

Abstract Computational psychiatry is a rapidly emerging field that uses model-based quantities to infer the behavioral and neuronal abnormalities that underlie psychopathology. If successful, this approach promises key insights into (pathological) brain function as well as a more mechanistic and quantitative approach to psychiatric nosology—structuring therapeutic interventions and predicting response and relapse. The basic procedure in computational psychiatry is to build a computational model that formalizes a behavioral or neuronal process. Measured behavioral (or neuronal) responses are then used to infer the model parameters of a single subject or a group of subjects. Here, we provide an illustrative overview over this process, starting from the modeling of choice behavior in a specific task, simulating data, and then inverting that model to estimate group effects. Finally, we illustrate cross-validation to assess whether between-subject variables (e.g., diagnosis) can be recovered successfully. Our worked example uses a simple two-step maze task and a model of choice behavior based on (active) inference and Markov decision processes. The procedural steps and routines we illustrate are not restricted to a specific field of research or particular computational model but can, in principle, be applied in many domains of computational psychiatry.

ID 202 – Characterising seizures in anti-NMDA-receptor encephalitis with Dynamic Causal Modelling

Recently, there have been several concerted international efforts-the BRAIN Initiative, the European Human Brain Project, and the Human Connectome Project, to name a few-that hope to revolutionize our understanding of the connected brain. During the past two decades, functional neuroimaging has emerged as the predominant technique in systems neuroscience. This is foreshadowed by an ever-increasing number of publications on functional connectivity, causal modeling, connectomics, and multivariate analyses of distributed patterns of brain responses. In this article, we summarize pedagogically the (deep) history of brain mapping. We highlight the theoretical advances made in the (dynamic) causal modeling of brain function, which may have escaped the wider audience of this article, and provide a brief overview of recent developments and interesting clinical applications. We hope that this article engages the signal processing community by showcasing the inherently multidisciplinary nature of this important topic and the intriguing questions that are being addressed.

Quantification of degeneracy in Hodgkin-Huxley neurons on Newman-Watts small world network.

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This article is motivated by a formulation of biotic self-organization in Friston (2013), where the emergence of “life” in coupled material entities (e.g., macromolecules) was predicated on bounded subsets that maintain a degree of statistical independence from the rest of the network. Boundary elements in such systems constitute a Markov blanket; separating the internal states of a system from its surrounding states. In this article, we ask whether Markov blankets operate in the nervous system and underlie the development of intelligence, enabling a progression from the ability to sense the environment to the ability to understand it. Markov blankets have been previously hypothesized to form in neuronal networks as a result of phase transitions that cause network subsets to fold into bounded assemblies, or packets (Yufik and Sheridan, 1997; Yufik, 1998a). The ensuing neuronal packets hypothesis builds on the notion of neuronal assemblies (Hebb, 1949, 1980), treating such assemblies as flexible but stable biophysical structures capable of withstanding entropic erosion. In other words, structures that maintain their integrity under changing conditions. In this treatment, neuronal packets give rise to perception of “objects”; i.e., quasi-stable (stimulus bound) feature groupings that are conserved over multiple presentations (e.g., the experience of perceiving “apple” can be interrupted and resumed many times). Monitoring the variations in such groups enables the apprehension of behavior; i.e., attributing to objects the ability to undergo changes without loss of self-identity. Ultimately, “understanding” involves self-directed composition and manipulation of the ensuing “mental models” that are constituted by neuronal packets, whose dynamics capture relationships among objects: that is, dependencies in the behavior of objects under varying conditions. For example, movement is known to involve rotation of population vectors in the motor cortex (Georgopoulos et al., 1988, 1993). The neuronal packet hypothesis associates “understanding” with the ability to detect and generate coordinated rotation of population vectors—in neuronal packets—in associative cortex and other regions in the brain. The ability to coordinate vector representations in this way is assumed to have developed in conjunction with the ability to postpone overt motor expression of implicit movement, thus creating a mechanism for prediction and behavioral optimization via mental modeling that is unique to higher species. This article advances the notion that Markov blankets—necessary for the emergence of life—have been subsequently exploited by evolution and thus ground the ways that living organisms adapt to their environment, culminating in their ability to understand it.

Life and Understanding: The Origins of “Understanding” in Self-Organizing Nervous Systems

Active inference is a general framework for perception and action that is gaining prominence in computational and systems neuroscience but is less known outside these fields. Here, we discuss a proof-of-principle implementation of the active inference scheme for the control or the 7-DoF arm of a (simulated) PR2 robot. By manipulating visual and proprioceptive noise levels, we show under which conditions robot control under the active inference scheme is accurate. Besides accurate control, our analysis of the internal system dynamics (e.g. the dynamics of the hidden states that are inferred during the inference) sheds light on key aspects of the framework such as the quintessentially multimodal nature of control and the differential roles of proprioception and vision. In the discussion, we consider the potential importance of being able to implement active inference in robots. In particular, we briefly review the opportunities for modelling psychophysiological phenomena such as sensory attenuation and related failures of gain control, of the sort seen in Parkinson's disease. We also consider the fundamental difference between active inference and optimal control formulations, showing that in the former the heavy lifting shifts from solving a dynamical inverse problem to creating deep forward or generative models with dynamics, whose attracting sets prescribe desired behaviours.

The two cytoarchitectonic divisions of BA 4 show distinguishable BOLD-force profiles in multiple sclerosis

ID: 2794 that showed decreased connectivity to aCBL with increasing disability. Fig.5. rsfMRI using ROI-ROIs analysis where the seeds are the ones used in the PPI and target areas are identified with the PPI results. The figure shows results in HV (top row) and MS (bottom row). A t-value bar is also provided.

Disruption of functional connectivity of M1 and cerebellum in Multiple sclerosis: a long-range functional dysconnection?

This chapter proposes a new framework for diagnostic nosology based on Bayesian principles. This novel integrative framework builds upon and improves the current diagnostic system in psychiatry. Instead of starting from the assumption that a diagnosis describes a specifi c unitary dysfunction that causes a set of symptoms, it is assumed that the underlying disease causes the clinician to make a diagnosis. Thus, unlike the current diagnostic system, this framework treats both symptoms and diagnostic classifi cation as consequences of the underlying pathophysiology. Comorbidities are therefore easily incorporated into the framework and inform, rather than hinder, the diagnostic process. Further, the proposed framework provides a bridge—which did not previously exist—that links putative constructs related to pathophysiology (e.g., RDoC domains) and clinical diagnoses (e.g., DSM categories) related to signs and symptoms. The model is fl exible; it is expandable and collapsible, and can integrate a diverse array of data at multiple levels. Crucially, this novel framework explicitly provides an iterative approach, updating and selecting the best model, based on the highest-quality available evidence at any point. In fact, the scheme can, in principle, automatically ignore data that is not relevant or informative to the diagnostic trajectory. Finally, the proposed framework can account for and incorporate the longitudinal course of an illness. This Group photos (top left to bottom right) Shelly Flagel, Danny Pine, David Redish, Jordan Smoller, Susanne Ahmari, Karl Friston, Michael First, Katharina Schmack, Danny Pine, Katharina Schmack, group discussion, Susanne Ahmari, Anita Thapar, Christoph Mathys, Michael First, David Redish, Karl Friston, Shelly Flagel, Jordan Smoller, Anita Thapar, Christoph Mathys From “Computational Psychiatry: New Perspectives on Mental Illness,” A. David Redish and Joshua A. Gordon, eds. 2016. Strüngmann Forum Reports, vol. 20, series ed. J. Lupp. Cambridge, MA: MIT Press. ISBN 978-0-262-03542-2. 170 S. B. Flagel et al. chapter details the theoretical basis for this framework and provides clinical examples to illustrate its utility and application. Multiple iterations of this framework will be required based on available information. It is hoped that, with time, the framework will enhance our understanding of individual differences in brain function and behavior and ultimately improve treatment outcomes in psychiatry.

Utilizing an Integrative Framework to Improve the Diagnostic Process

The pragmatic turn : toward action-oriented views in cognitive science

Previous studies investigated the distinct roles played by different cognitive regions and suggested that the patterns of connectivity of these regions are associated with working memory (WM). However, the specific causal mechanism through which the neuronal circuits that involve these brain regions contribute to WM is still unclear. Here, in a large sample of healthy young adults, we first identified the core WM regions by linking WM accuracy to resting-state functional connectivity with the bilateral dorsolateral prefrontal cortex (dLPFC; a principal region in the central-executive network, CEN). Then a spectral dynamic causal modeling (spDCM) analysis was performed to quantify the effective connectivity between these regions. Finally, the effective connectivity was correlated with WM accuracy to characterize the relationship between these connections and WM performance. We found that the functional connections between the bilateral dLPFC and the dorsal anterior cingulate cortex (dACC) and between the right dLPFC and the left orbital fronto-insular cortex (FIC) were correlated with WM accuracy. Furthermore, the effective connectivity from the dACC to the bilateral dLPFC and from the right dLPFC to the left FIC could predict individual differences in WM. Because the dACC and FIC are core regions of the salience network (SN), we inferred that the inter- and causal-connectivity between core regions within the CEN and SN is functionally relevant for WM performance. In summary, the current study identified the dLPFC-related resting-state effective connectivity underlying WM and suggests that individual differences in cognitive ability could be characterized by resting-state effective connectivity.

Resting-State Coupling between Core Regions within the Central-Executive and Salience Networks Contributes to Working Memory Performance

Profiling neuronal ion channelopathies with non-invasive brain imaging and dynamic causal models: Case studies of single gene mutations

This study investigates how multiple sclerosis (MS) selectively affects regional BOLD response to variable grip forces (GF). It is known that the anterior and posterior BA4 areas are anatomically and functionally distinguishable – and that in healthy subjects there are linear and non-linear BOLD response components. After modelling BOLD responses with a polynomial expansion of the applied GF during task, we showed that in BA4a MS subjects respond like healthy subjects. BOLD response in BA4p, instead, was altered in MS, with those with greatest disability showing the greatest deviations from the non-linear profile of the healthy response.

BA 4p BOLD response profile distinguishes low and high MS morbidity

Computational psychiatry promises a fresh and formal approach to mental health, and autism has become its socalled poster child. Key concepts from computational neuroscience are now finding their way into discussions about the pathophysiology and psychopathology of autism spectrum disorder (ASD) (1–4). This is exemplified beautifully by Sevgi et al. (5), who report that “higher autistic traits in healthy subjects are related to lower scores in a learning task that requires social cue integration.” Careful Bayesian modeling of this learning suggests that trait-related differences are not explained by a failure to process social stimuli per se, but rather by the extent to which participants afford precision to— or attend—social cues. So why is it important? For people unfamiliar with things like the Bayesian brain and precision, we start with a brief review of the ideas that motivated Sevgi et al. (5).

Abstract The main question that Firestone & Scholl (F&S) pose is whether “what and how we see is functionally independent from what and how we think, know, desire, act, and so forth” (sect. 2, para. 1). We synthesize a collection of concerns from an interdisciplinary set of coauthors regarding F&S's assumptions and appeals to intuition, resulting in their treatment of visual perception as context-free.

The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order) in which cues are presented. These simulations provide a (Bayes-optimal) model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors) to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson’s disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level. DOI: 10.1371/journal.pcbi.1002327 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: http://doi.org/10.5167/uzh-62420 Published Version Originally published at: Friston, K J; Shiner, T; FitzGerald, T; Galea, J M; Adams, R; Brown, H; Dolan, R J; Moran, R; Stephan, K E; Bestmann, S (2012). Dopamine, affordance and active inference. PLoS Computational Biology, 8(1):e1002327. DOI: 10.1371/journal.pcbi.1002327 Dopamine, Affordance and Active Inference Karl J. Friston*, Tamara Shiner, Thomas FitzGerald, Joseph M. Galea, Rick Adams, Harriet Brown, Raymond J. Dolan, Rosalyn Moran, Klaas Enno Stephan, Sven Bestmann 1 The Wellcome Trust Centre for Neuroimaging, University College London, Queen Square, London, United Kingdom, 2 Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology, Queen Square, London, United Kingdom

Neural processes mediating contextual influences on human choice behaviour

Computational modelling of movement-related beta-oscillatory dynamics in human motor cortex☆

Deep brain stimulation (DBS) for Parkinson’s disease is a highly effective treatment in controlling otherwise debilitating symptoms yet the underlying brain mechanisms are currently not well understood. We used whole-brain computational modeling to disclose the effects of DBS ON and OFF during collection of resting state fMRI in ten Parkinson’s Disease patients. Specifically, we explored the local and global impact of DBS in creating asynchronous, stable or critical oscillatory conditions using a supercritical bifurcation model. We found that DBS shifts the global brain dynamics of patients nearer to that of healthy people by significantly changing the bifurcation parameters in brain regions implicated in Parkinson’s Disease. We also found higher communicability and coherence brain measures during DBS ON compared to DBS OFF. Finally, by modeling stimulation we identified possible novel DBS targets. These results offer important insights into the underlying effects of DBS, which may in time offer a route to more efficacious treatments.

Uncovering the underlying mechanisms and whole-brain dynamics of therapeutic deep brain stimulation for Parkinson’s disease

Granger causality (GC) and dynamic causal modeling (DCM) are the two key approaches used to determine the directed interactions among brain areas. Recent discussions have provided a constructive account of the merits and demerits. GC, on one side, considers dependencies among measured responses, whereas DCM, on the other, models how neuronal activity in one brain area causes dynamics in another. In this study, our objective was to establish construct validity between GC and DCM in the context of resting state functional magnetic resonance imaging (fMRI). We first established the face validity of both approaches using simulated fMRI time series, with endogenous fluctuations in two nodes. Crucially, we tested both unidirectional and bidirectional connections between the two nodes to ensure that both approaches give veridical and consistent results, in terms of model comparison. We then applied both techniques to empirical data and examined their consistency in terms of the (quantitative) in-degree of key nodes of the default mode. Our simulation results suggested a (qualitative) consistency between GC and DCM. Furthermore, by applying nonparametric GC and stochastic DCM to resting-state fMRI data, we confirmed that both GC and DCM infer similar (quantitative) directionality between the posterior cingulate cortex (PCC), the medial prefrontal cortex, the left middle temporal cortex, and the left angular gyrus. These findings suggest that GC and DCM can be used to estimate directed functional and effective connectivity from fMRI measurements in a consistent manner.

Bridging the Gap: Dynamic Causal Modeling and Granger Causality Analysis of Resting State Functional Magnetic Resonance Imaging

Supplementary material from "Is predictability salient? A study of attentional capture by auditory patterns"

Processing of emotional body language within the visual social cognition network

We would like to thank Dolega and Dewhurst (2015) for a thought-provoking and informed deconstruction of our article, which we take as (qualified) applause from valued members of our audience. In brief, we fully concur with the theatre-free formulation offered by Dolega and Dewhurst and take the opportunity to explain why (and how) we used the Cartesian theatre metaphor. We do this by drawing an analogy between consciousness and evolution. This analogy is used to emphasize the circular causality inherent in the free energy principle (aka active inference). We conclude with a comment on the special forms of active inference that may be associated with selfawareness and how they may be especially informed by dream states.

Substantial evidence indicates that incentive value depends on an anticipation of rewards within a given context. However, the computations underlying this context sensitivity remain unknown. To address this question, we introduce a normative (Bayesian) account of how rewards map to incentive values. This assumes that the brain inverts a model of how rewards are generated. Key features of our account include (i) an influence of prior beliefs about the context in which rewards are delivered (weighted by their reliability in a Bayes-optimal fashion), (ii) the notion that incentive values correspond to precision-weighted prediction errors, (iii) and contextual information unfolding at different hierarchical levels. This formulation implies that incentive value is intrinsically context-dependent. We provide empirical support for this model by showing that incentive value is influenced by context variability and by hierarchically nested contexts. The perspective we introduce generates new empirical predictions that might help explaining psychopathologies, such as addiction. DOI: http://dx.doi.org/10.7554/eLife.16127.001

This paper describes an active inference scheme for visual searches and the perceptual synthesis entailed by scene construction. Active inference assumes that perception and action minimize variational free energy, where actions are selected to minimize the free energy expected in the future. This assumption generalizes risk-sensitive control and expected utility theory to include epistemic value; namely, the value (or salience) of information inherent in resolving uncertainty about the causes of ambiguous cues or outcomes. Here, we apply active inference to saccadic searches of a visual scene. We consider the (difficult) problem of categorizing a scene, based on the spatial relationship among visual objects where, crucially, visual cues are sampled myopically through a sequence of saccadic eye movements. This means that evidence for competing hypotheses about the scene has to be accumulated sequentially, calling upon both prediction (planning) and postdiction (memory). Our aim is to highlight some simple but fundamental aspects of the requisite functional anatomy; namely, the link between approximate Bayesian inference under mean field assumptions and functional segregation in the visual cortex. This link rests upon the (neurobiologically plausible) process theory that accompanies the normative formulation of active inference for Markov decision processes. In future work, we hope to use this scheme to model empirical saccadic searches and identify the prior beliefs that underwrite intersubject variability in the way people forage for information in visual scenes (e.g., in schizophrenia).

Integrating costs and benefits is crucial for optimal decision-making. Although much is known about decisions that involve outcome-related costs (e.g., delay, risk), many of our choices are attached to actions and require an evaluation of the associated motor costs. Yet how the brain incorporates motor costs into choices remains largely unclear. We used human fMRI during choices involving monetary reward and physical effort to identify brain regions that serve as a choice comparator for effort-reward trade-offs. By independently varying both options' effort and reward levels, we were able to identify the neural signature of a comparator mechanism. A network involving supplementary motor area and the caudal portion of dorsal anterior cingulate cortex encoded the difference in reward (positively) and effort levels (negatively) between chosen and unchosen choice options. We next modeled effort-discounted subjective values using a novel behavioral model. This revealed that the same network of regions involving dorsal anterior cingulate cortex and supplementary motor area encoded the difference between the chosen and unchosen options' subjective values, and that activity was best described using a concave model of effort-discounting. In addition, this signal reflected how precisely value determined participants' choices. By contrast, separate signals in supplementary motor area and ventromedial prefrontal cortex correlated with participants' tendency to avoid effort and seek reward, respectively. This suggests that the critical neural signature of decision-making for choices involving motor costs is found in human cingulate cortex and not ventromedial prefrontal cortex as typically reported for outcome-based choice. Furthermore, distinct frontal circuits seem to drive behavior toward reward maximization and effort minimization. SIGNIFICANCE STATEMENT The neural processes that govern the trade-off between expected benefits and motor costs remain largely unknown. This is striking because energetic requirements play an integral role in our day-to-day choices and instrumental behavior, and a diminished willingness to exert effort is a characteristic feature of a range of neurological disorders. We use a new behavioral characterization of how humans trade off reward maximization with effort minimization to examine the neural signatures that underpin such choices, using BOLD MRI neuroimaging data. We find the critical neural signature of decision-making, a signal that reflects the comparison of value between choice options, in human cingulate cortex, whereas two distinct brain circuits drive behavior toward reward maximization or effort minimization.

Neural Signatures of Value Comparison in Human Cingulate Cortex during Decisions Requiring an Effort-Reward Trade-off

Abstract Deep brain stimulation of the pedunculopontine nucleus and surrounding region (PPNR) is a novel treatment strategy for gait freezing in Parkinson's disease (PD). However, clinical results have been variable, in part because of the paucity of functional information that might help guide selection of the optimal surgical target. In this study, we use simultaneous magnetoencephalography and local field recordings from the PPNR in seven PD patients, to characterize functional connectivity with distant brain areas at rest. The PPNR was preferentially coupled to brainstem and cingulate regions in the alpha frequency (8‐12 Hz) band and to the medial motor strip and neighboring areas in the beta (18‐33 Hz) band. The distribution of coupling also depended on the vertical distance of the electrode from the pontomesencephalic line: most effects being greatest in the middle PPNR, which may correspond to the caudal pars dissipata of the pedunculopontine nucleus. These observations confirm the crucial position of the PPNR as a functional node between cortical areas such as the cingulate/ medial motor strip and other brainstem nuclei, particularly in the dorsal pons. In particular they suggest a special role for the middle PPNR as this has the greatest functional connectivity with other brain regions.

Functional Connectivity of the Pedunculopontine Nucleus and Surrounding Region in Parkinson's Disease

Bayesian model reduction and empirical Bayes for group (DCM) studies

From a systems biology perspective, the brain and spinal cord are interwoven with the body: they are ‘embodied’. Freund et al. propose an integrative framework based on biophysical models that aims to characterize neurological disorders and minimize their impact on patients by considering functional interactions between supra-spinal, spinal and peripheral regions simultaneously.

Embodied neurology: an integrative framework for neurological disorders

Dynamic causal modelling of eye movements during pursuit: Confirming precision-encoding in V1 using MEG

This technical report revisits the analysis of family‐wise error rates in statistical parametric mapping—using random field theory—reported in (Eklund et al. [ ]: arXiv 1511.01863). Contrary to the understandable spin that these sorts of analyses attract, a review of their results suggests that they endorse the use of parametric assumptions—and random field theory—in the analysis of functional neuroimaging data. We briefly rehearse the advantages parametric analyses offer over nonparametric alternatives and then unpack the implications of (Eklund et al. [ ]: arXiv 1511.01863) for parametric procedures. Hum Brain Mapp, 40:2052–2054, 2019. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Analysis of family‐wise error rates in statistical parametric mapping using random field theory

Resting functional connectivity does not mirror task functional connectivity in multiple sclerosis

Functional response to a complex visuo-motor task supports local compensatory mechanisms in Multiple Sclerosis

This letter offers a computational account of Pavlovian conditioning in the cerebellum based on active inference and predictive coding. Using eyeblink conditioning as a canonical paradigm, we formulate a minimal generative model that can account for spontaneous blinking, startle responses, and (delay or trace) conditioning. We then establish the face validity of the model using simulated responses to unconditioned and conditioned stimuli to reproduce the sorts of behavior that are observed empirically. The scheme’s anatomical validity is then addressed by associating variables in the predictive coding scheme with nuclei and neuronal populations to match the (extrinsic and intrinsic) connectivity of the cerebellar (eyeblink conditioning) system. Finally, we try to establish predictive validity by reproducing selective failures of delay conditioning, trace conditioning, and extinction using (simulated and reversible) focal lesions. Although rather metaphorical, the ensuing scheme can account for a remarkable range of anatomical and neurophysiological aspects of cerebellar circuitry—and the specificity of lesion-deficit mappings that have been established experimentally. From a computational perspective, this work shows how conditioning or learning can be formulated in terms of minimizing variational free energy (or maximizing Bayesian model evidence) using exactly the same principles that underlie predictive coding in perception.

We review a recent shift in conceptions of interoception and its relationship to hierarchical inference in the brain. The notion of interoceptive inference means that bodily states are regulated by autonomic reflexes that are enslaved by descending predictions from deep generative models of our internal and external milieu. This re-conceptualization illuminates several issues in cognitive and clinical neuroscience with implications for experiences of selfhood and emotion. We first contextualize interoception in terms of active (Bayesian) inference in the brain, highlighting its enactivist (embodied) aspects. We then consider the key role of uncertainty or precision and how this might translate into neuromodulation. We next examine the implications for understanding the functional anatomy of the emotional brain, surveying recent observations on agranular cortex. Finally, we turn to theoretical issues, namely, the role of interoception in shaping a sense of embodied self and feelings. We will draw links between physiological homoeostasis and allostasis, early cybernetic ideas of predictive control and hierarchical generative models in predictive processing. The explanatory scope of interoceptive inference ranges from explanations for autism and depression, through to consciousness. We offer a brief survey of these exciting developments. This article is part of the themed issue ‘Interoception beyond homeostasis: affect, cognition and mental health’.

Anterior insula coordinates hierarchical processing of tactile mismatch responses

Repetition suppression and its contextual determinants in predictive coding

Estimating anatomical trajectories with Bayesian mixed-effects modeling

Active inference and oculomotor pursuit: The dynamic causal modelling of eye movements

Estimating Directed Connectivity from Cortical Recordings and Reconstructed Sources

Huntington's disease is an incurable neurodegenerative disease caused by inheritance of an expanded cytosine‐adenine‐guanine (CAG) trinucleotide repeat within the Huntingtin gene. Extensive volume loss and altered diffusion metrics in the basal ganglia, cortex and white matter are seen when patients with Huntington's disease (HD) undergo structural imaging, suggesting that changes in basal ganglia‐cortical structural connectivity occur. The aims of this study were to characterise altered patterns of basal ganglia‐cortical structural connectivity with high anatomical precision in premanifest and early manifest HD, and to identify associations between structural connectivity and genetic or clinical markers of HD. 3‐Tesla diffusion tensor magnetic resonance images were acquired from 14 early manifest HD subjects, 17 premanifest HD subjects and 18 controls. Voxel‐based analyses of probabilistic tractography were used to quantify basal ganglia‐cortical structural connections. Canonical variate analysis was used to demonstrate disease‐associated patterns of altered connectivity and to test for associations between connectivity and genetic and clinical markers of HD; this is the first study in which such analyses have been used. Widespread changes were seen in basal ganglia‐cortical structural connectivity in early manifest HD subjects; this has relevance for development of therapies targeting the striatum. Premanifest HD subjects had a pattern of connectivity more similar to that of controls, suggesting progressive change in connections over time. Associations between structural connectivity patterns and motor and cognitive markers of disease severity were present in early manifest subjects. Our data suggest the clinical phenotype in manifest HD may be at least partly a result of altered connectivity. Hum Brain Mapp 36:1728–1740, 2015. © 2015 Wiley Periodicals, Inc.

Basal ganglia‐cortical structural connectivity in Huntington's disease

Motor fMRI studies, comparing dominant (DH) and nondominant (NDH) hand activations have reported mixed findings, especially for the extent of ipsilateral (IL) activations and their relationship with task complexity. To date, no study has directly compared DH and NDH activations using an event‐related visually guided dynamic power‐grip paradigm with parametric (three) forces (GF) in healthy right‐handed subjects. We implemented a hierarchical statistical approach aimed to: (i) identify the main effect networks engaged when using either hand; (ii) characterise DH/NDH responses at different GFs; (iii) assess contralateral (CL)/IL‐specific and hemisphere‐specific activations. Beyond confirming previously reported results, this study demonstrated that increasing GF has an effect on motor response that is contextualised also by the use of DH or NDH. Linear analysis revealed increased activations in sensorimotor areas, with additional increased recruitments of subcortical and cerebellar areas when using the NDH. When looking at CL/IL‐specific activations, CL sensorimotor areas and IL cerebellum were activated with both hands. When performing the task with the NDH, several areas were also recruited including the CL cerebellum. Finally, there were hand‐side‐independent activations of nonmotor‐specific areas in the right and left hemispheres, with the right hemisphere being involved more extensively in sensori‐motor integration through associative areas while the left hemisphere showing greater activation at higher GF. This study shows that the functional networks subtending DH/NDH power‐grip visuomotor functions are qualitatively and quantitatively distinct and this should be taken into consideration when performing fMRI studies, particularly when planning interventions in patients with specific impairments. Hum Brain Mapp 36:5079–5100, 2015. © 2015 Wiley Periodicals, Inc.

Differential involvement of cortical and cerebellar areas using dominant and nondominant hands: An FMRI study

This technical note addresses some key reproducibility issues in the dynamic causal modelling of group studies of event related potentials. Specifically, we address the reproducibility of Bayesian model comparison (and inferences about model parameters) from three important perspectives namely: (i) reproducibility with independent data (obtained by averaging over odd and even trials); (ii) reproducibility over formally distinct models (namely, classic ERP and canonical microcircuit or CMC models); and (iii) reproducibility over inversion schemes (inversion of the grand average and estimation of group effects using empirical Bayes). Our hope was to illustrate the degree of reproducibility one can expect from DCM when analysing different data, under different models with different analyses.

Empirical Bayes for Group (DCM) Studies: A Reproducibility Study

Temporal difference learning models propose phasic dopamine signaling encodes reward prediction errors that drive learning. This is supported by studies where optogenetic stimulation of dopamine neurons can stand in lieu of actual reward. Nevertheless, a large body of data also shows that dopamine is not necessary for learning, and that dopamine depletion primarily affects task performance. We offer a resolution to this paradox based on an hypothesis that dopamine encodes the precision of beliefs about alternative actions, and thus controls the outcome-sensitivity of behavior. We extend an active inference scheme for solving Markov decision processes to include learning, and show that simulated dopamine dynamics strongly resemble those actually observed during instrumental conditioning. Furthermore, simulated dopamine depletion impairs performance but spares learning, while simulated excitation of dopamine neurons drives reward learning, through aberrant inference about outcome states. Our formal approach provides a novel and parsimonious reconciliation of apparently divergent experimental findings.

Dynamic causal modelling for functional near-infrared spectroscopy

The contribution of dopamine to working memory has been studied extensively [1–3]. Here, we exploited its well characterized effects [1–3] to validate a novel human in vivo assay of ongoing synaptic [4, 5] processing. We obtained magnetoencephalographic (MEG) measurements from subjects performing a working memory (WM) task during a withinsubject, placebo-controlled, pharmacological (dopaminergic) challenge. By applying dynamic causal modeling (DCM), a Bayesian technique for neuronal system identification [6], to MEG signals from prefrontal cortex, we demonstrate that it is possible to infer synaptic signaling by specific ion channels in behaving humans. Dopamineinduced enhancement of WM performance was accompanied by significant changes in MEG signal power, and a DCM assay disclosed related changes in synaptic signaling. By estimating the contribution of ionotropic receptors (AMPA, NMDA, and GABAA) to the observed spectral response, we demonstrate changes in their function commensurate with the synaptic effects of dopamine. The validity of our model is reinforced by a striking quantitative effect on NMDA and AMPA receptor signaling that predicted behavioral improvement over subjects. Our results provide a proof-of-principle demonstration of a novel framework for inferring, noninvasively, neuromodulatory influences on ion channel signaling via specific ionotropic receptors, providing awindowon the hidden synaptic eventsmediating discrete psychological processes in humans.

Understanding how organisms establish their form during embryogenesis and regeneration represents a major knowledge gap in biological pattern formation. It has been recently suggested that morphogenesis could be understood in terms of cellular information processing and the ability of cell groups to model shape. Here, we offer a proof of principle that self-assembly is an emergent property of cells that share a common (genetic and epigenetic) model of organismal form. This behaviour is formulated in terms of variational free-energy minimization—of the sort that has been used to explain action and perception in neuroscience. In brief, casting the minimization of thermodynamic free energy in terms of variational free energy allows one to interpret (the dynamics of) a system as inferring the causes of its inputs—and acting to resolve uncertainty about those causes. This novel perspective on the coordination of migration and differentiation of cells suggests an interpretation of genetic codes as parametrizing a generative model—predicting the signals sensed by cells in the target morphology—and epigenetic processes as the subsequent inversion of that model. This theoretical formulation may complement bottom-up strategies—that currently focus on molecular pathways—with (constructivist) top-down approaches that have proved themselves in neuroscience and cybernetics.

Knowing one's place: a free-energy approach to pattern regulation

Significance Noninvasive brain imaging of humans identifies prominent networks related to sensory and cognitive functions in the resting state; however, the signaling hierarchy and directionality among these networks remain largely unknown. Integrating simultaneously recorded measures for network identification and regional energy metabolism, we propose metabolic connectivity mapping (MCM) as a novel measure to reveal signaling directionality in the human brain. Comparing simple “eyes closed” and “eyes open” conditions in healthy subjects, MCM revealed stable bidirectional signaling among visual cortices and top-down signaling from parietal control regions. Additional top-down signaling from a salience network occurs only during the eyes open condition. We propose MCM as a measure for investigating signaling directions among brain networks in healthy and diseased brains. Directionality of signaling among brain regions provides essential information about human cognition and disease states. Assessing such effective connectivity (EC) across brain states using functional magnetic resonance imaging (fMRI) alone has proven difficult, however. We propose a novel measure of EC, termed metabolic connectivity mapping (MCM), that integrates undirected functional connectivity (FC) with local energy metabolism from fMRI and positron emission tomography (PET) data acquired simultaneously. This method is based on the concept that most energy required for neuronal communication is consumed postsynaptically, i.e., at the target neurons. We investigated MCM and possible changes in EC within the physiological range using “eyes open” versus “eyes closed” conditions in healthy subjects. Independent of condition, MCM reliably detected stable and bidirectional communication between early and higher visual regions. Moreover, we found stable top-down signaling from a frontoparietal network including frontal eye fields. In contrast, we found additional top-down signaling from all major clusters of the salience network to early visual cortex only in the eyes open condition. MCM revealed consistent bidirectional and unidirectional signaling across the entire cortex, along with prominent changes in network interactions across two simple brain states. We propose MCM as a novel approach for inferring EC from neuronal energy metabolism that is ideally suited to study signaling hierarchies in the brain and their defects in brain disorders.

Metabolic connectivity mapping reveals effective connectivity in the resting human brain

Complex motor task associated with non-linear BOLD responses in cerebro-cortical areas and cerebellum

UNCORRECTED PROOF 1Q2 Characterising seizures in anti-NMDA-receptor encephalitis with 2 dynamic causal modelling

Patients with melancholia report a distinct and intrusive dysphoric state during internally generated thought. Melancholia has long been considered to have a strong biological component, but evidence for its specific neurobiological origins is limited. The distinct neurocognitive, psychomotor, and mood disturbances observed in melancholia do, however, suggest aberrant coordination of frontal-subcortical circuitry, which may best be captured through analysis of complex brain networks.

OBJECTIVE
To investigate the effective connectivity between spontaneous (resting-state) brain networks in melancholia, focusing on networks underlying attention and interoception.

We performed a cross-sectional, observational, resting-state functional magnetic resonance imaging study of 16 participants with melancholia, 16 with nonmelancholic depression, and 16 individuals serving as controls at a hospital-based research institute between August 30, 2010, and June 27, 2012. We identified 5 canonical resting-state networks (default mode, executive control, left and right frontoparietal attention, and bilateral anterior insula) and inferred spontaneous interactions among these networks using dynamic causal modeling.

Graph theoretic measures of brain connectivity, namely, in-degree and out-degree of each network and edge connectivity, between regions composed our principal between-group contrasts.

RESULTS
Melancholia was characterized by a pervasive disconnection involving anterior insula and attentional networks compared with participants in the control (Mann-Whitney, 189.00; z = 2.38; P = .02) and nonmelancholic depressive (Mann-Whitney, 203.00; z = 2.93; P = .004) groups. Decreased effective connectivity between the right frontoparietal and insula networks was present in participants with melancholic depression compared with those with nonmelancholic depression (χ2 = 8.13; P = .004). Reduced effective connectivity between the insula and executive networks was found in individuals with melancholia compared with healthy controls (χ2 = 8.96; P = .003).

We observed reduced effective connectivity in resting-state functional magnetic resonance imaging between key networks involved in attention and interoception in melancholia. We propose that these abnormalities underlie the impoverished variety and affective quality of internally generated thought in this disorder.

Disrupted effective connectivity of cortical systems supporting attention and interoception in melancholia.

In a recent paper, Rosenberg et al. (1) present a compelling explanation for the perceptual symptoms of autism in terms of a failure of divisive normalization. In divisive normalization the output of individual neurons is scaled (or divided) by the combined activity of the neural population in which they are embedded, and thus local visual context provides a means of gain control—a volume dial—for stimulus-evoked responses. However, to properly understand the wider mechanistic implications, beyond local inhibition or gain in the visual cortex, one has to posit a biologically plausible instantiation of context-sensitive neural responses across multiple timescales and hierarchical levels that allows for the influence of attention and prior beliefs, which the authors so elegantly simulate.

SENSITIVITY TO THE EMERGENCE OF PREDICTABLE STRUCTURE IN SOUND SEQUENCES

A longstanding idea is that emotional information can be “privileged” over other information during stimulus processing — so-called affective primacy. There is some behavioral evidence for affective primacy even when processing single emotional words, presented in isolation of any preceding context: where frequent words are typically read and responded to faster than infrequent words, emotional words can be processed with disproportionate speed even when they are infrequent (consider hearing the word “avalanche!” shouted in your direction). We used ERPs to ask when and at which level of processing this emotion advantage is incurred, and whether it is driven primarily by the valence or by the arousal properties of emotional words. Previous ERP studies have established that the lexical frequency effect for words presented in isolation typically manifests between 300-400ms (the early N400), with more frequent words evoking a smaller N400, reflecting facilitated lexico-semantic processing. We conducted a mixedeffects regression on trial-by-trial ERP amplitudes for 468 English words that varied widely by Valence, Arousal, and Frequency. We found that more emotional words showed significantly diminished frequency effects on the N400 (between 300-400ms over posterior electrode sites), and that this was driven primarily by arousal. These data suggest that highly arousing words are facilitated during lexico-semantic processing, regardless of their frequency, and provide strong evidence for affective primacy on words appearing even in the absence of sentence or discourse contexts.

THE AVALANCHE EFFECT: EMOTIONALLY SALIENT WORDS ARE NEVER RARE TO YOUR BRAIN

Losing Control Under Ketamine: Suppressed Cortico-Hippocampal Drive Following Acute Ketamine in Rats

Optimal inference with suboptimal models: Addiction and active Bayesian inference

Despite similar behavioral effects, attention and expectation influence evoked responses differently: Attention typically enhances event-related responses, whereas expectation reduces them. This dissociation has been reconciled under predictive coding, where prediction errors are weighted by precision associated with attentional modulation. Here, we tested the predictive coding account of attention and expectation using magnetoencephalography and modeling. Temporal attention and sensory expectation were orthogonally manipulated in an auditory mismatch paradigm, revealing opposing effects on evoked response amplitude. Mismatch negativity (MMN) was enhanced by attention, speaking against its supposedly pre-attentive nature. This interaction effect was modeled in a canonical microcircuit using dynamic causal modeling, comparing models with modulation of extrinsic and intrinsic connectivity at different levels of the auditory hierarchy. While MMN was explained by recursive interplay of sensory predictions and prediction errors, attention was linked to the gain of inhibitory interneurons, consistent with its modulation of sensory precision.

Attentional Enhancement of Auditory Mismatch Responses: a DCM/MEG Study

I would like to thank our commentators for their most thoughtful and enlightening commentaries. Three themes emerge from six commentaries, which we now take the opportunity to respond to. These themes relate to the (1) the complexity and detail with which we model our world, (2) the key relationship between drives or preferences and priors defined in terms of probability distributions and, (3) the metacognitive aspects of knowing what we know and epistemic emotions.

Adaptive Control: Neurocomputational Substrates and Implications for Neuropsychiatric Disease.

Evidence for surprise minimization over value maximization in choice behavior

We offer a formal treatment of choice behavior based on the premise that agents minimize the expected free energy of future outcomes. Crucially, the negative free energy or quality of a policy can be decomposed into extrinsic and epistemic (or intrinsic) value. Minimizing expected free energy is therefore equivalent to maximizing extrinsic value or expected utility (defined in terms of prior preferences or goals), while maximizing information gain or intrinsic value (or reducing uncertainty about the causes of valuable outcomes). The resulting scheme resolves the exploration-exploitation dilemma: Epistemic value is maximized until there is no further information gain, after which exploitation is assured through maximization of extrinsic value. This is formally consistent with the Infomax principle, generalizing formulations of active vision based upon salience (Bayesian surprise) and optimal decisions based on expected utility and risk-sensitive (Kullback-Leibler) control. Furthermore, as with previous active inference formulations of discrete (Markovian) problems, ad hoc softmax parameters become the expected (Bayes-optimal) precision of beliefs about, or confidence in, policies. This article focuses on the basic theory, illustrating the ideas with simulations. A key aspect of these simulations is the similarity between precision updates and dopaminergic discharges observed in conditioning paradigms.

[PDF]  [Full Text]  [Abstract] , April 6, 2005; 25 (14): 3593-3600. J. Neurosci. D.-J. Yi and M. M. Chun Parahippocampal Cortex Attentional Modulation of Learning-Related Repetition Attenuation Effects in Human [PDF]  [Full Text]  [Abstract] , April 27, 2005; 25 (17): 4294-4306. J. Neurosci. H. Sawamura, S. Georgieva, R. Vogels, W. Vanduffel and G. A. Orban of Shape Processing by Humans and Monkeys Using Functional Magnetic Resonance Imaging to Assess Adaptation and Size Invariance [PDF]  [Full Text]  [Abstract] , August 1, 2005; 17 (8): 1245-1260. J. Cogn. Neurosci. P. Vuilleumier, S. Schwartz, S. Duhoux, R. J. Dolan and J. Driver Visual Memory: Suppressions and Enhancements Revealed by fMRI Selective Attention Modulates Neural Substrates of Repetition Priming and "Implicit" [PDF]  [Full Text]  [Abstract] , February 1, 2006; 95 (2): 995-1007. J Neurophysiol R. Sayres and K. Grill-Spector Object-Selective Cortex Exhibits Performance-Independent Repetition Suppression [PDF]  [Full Text]  [Abstract] , February 1, 2006; 95 (2): 862-881. J Neurophysiol J. Larsson, M. S. Landy and D. J. Heeger Cortex Orientation-Selective Adaptation to Firstand Second-Order Patterns in Human Visual

Ventral Visual Areas Depend on Spatial Attention BOLD Repetition Decreases in Object-Responsive

The deployment of visuospatial attention and the programming of saccades are governed by the inferred likelihood of events. In the present study, we combined computational modeling of psychophysical data with fMRI to characterize the computational and neural mechanisms underlying this flexible attentional control. Sixteen healthy human subjects performed a modified version of Posner's location-cueing paradigm in which the percentage of cue validity varied in time and the targets required saccadic responses. Trialwise estimates of the certainty (precision) of the prediction that the target would appear at the cued location were derived from a hierarchical Bayesian model fitted to individual trialwise saccadic response speeds. Trial-specific model parameters then entered analyses of fMRI data as parametric regressors. Moreover, dynamic causal modeling (DCM) was performed to identify the most likely functional architecture of the attentional reorienting network and its modulation by (Bayes-optimal) precision-dependent attention. While the frontal eye fields (FEFs), intraparietal sulcus, and temporoparietal junction (TPJ) of both hemispheres showed higher activity on invalid relative to valid trials, reorienting responses in right FEF, TPJ, and the putamen were significantly modulated by precision-dependent attention. Our DCM results suggested that the precision of predictability underlies the attentional modulation of the coupling of TPJ with FEF and the putamen. Our results shed new light on the computational architecture and neuronal network dynamics underlying the context-sensitive deployment of visuospatial attention. SIGNIFICANCE STATEMENT Spatial attention and its neural correlates in the human brain have been studied extensively with the help of fMRI and cueing paradigms in which the location of targets is pre-cued on a trial-by-trial basis. One aspect that has so far been neglected concerns the question of how the brain forms attentional expectancies when no a priori probability information is available but needs to be inferred from observations. This study elucidates the computational and neural mechanisms under which probabilistic inference governs attentional deployment. Our results show that Bayesian belief updating explains changes in cortical connectivity; in that directional influences from the temporoparietal junction on the frontal eye fields and the putamen were modulated by (Bayes-optimal) updates.

Cortical Coupling Reflects Bayesian Belief Updating in the Deployment of Spatial Attention

Characterising seizures in anti-NMDA-receptor encephalitis with dynamic causal modelling

This paper considers neuronal architectures from a computational perspective and asks what aspects of neuroanatomy and neurophysiology can be disclosed by the nature of neuronal computations? In particular, we extend current formulations of the brain as an organ of inference—based upon hierarchical predictive coding—and consider how these inferences are orchestrated. In other words, what would the brain require to dynamically coordinate and contextualize its message passing to optimize its computational goals? The answer that emerges rests on the delicate (modulatory) gain control of neuronal populations that select and coordinate (prediction error) signals that ascend cortical hierarchies. This is important because it speaks to a hierarchical anatomy of extrinsic (between region) connections that form two distinct classes, namely a class of driving (first-order) connections that are concerned with encoding the content of neuronal representations and a class of modulatory (second-order) connections that establish context—in the form of the salience or precision ascribed to content. We explore the implications of this distinction from a formal perspective (using simulations of feature–ground segregation) and consider the neurobiological substrates of the ensuing precision-engineered dynamics, with a special focus on the pulvinar and attention.

Cerebral hierarchies: predictive processing, precision and the pulvinar

Individual differences in cognitive efficiency, particularly in relation to working memory (WM), have been associated both with personality dimensions that reflect enduring regularities in brain configuration, and with short‐term neural plasticity, that reflects task‐related changes in brain connectivity. To elucidate the relationship of these two divergent mechanisms, we tested the hypothesis that personality dimensions, which reflect enduring aspects of brain configuration, inform about the neurobiological framework within which short‐term, task‐related plasticity, as measured by effective connectivity, can be facilitated or constrained. As WM consistently engages the dorsolateral prefrontal (DLPFC), parietal (PAR), and anterior cingulate cortex (ACC), we specified a WM network model with bidirectional, ipsilateral, and contralateral connections between these regions from a functional magnetic resonance imaging dataset obtained from 40 healthy adults while performing the 3‐back WM task. Task‐related effective connectivity changes within this network were estimated using Dynamic Causal Modelling. Personality was evaluated along the major dimensions of Neuroticism, Extraversion, Openness to Experience, Agreeableness, and Conscientiousness. Only two dimensions were relevant to task‐dependent effective connectivity. Neuroticism and Conscientiousness respectively constrained and facilitated neuroplastic responses within the WM network. These results suggest individual differences in cognitive efficiency arise from the interplay between enduring and short‐term plasticity in brain configuration. Hum Brain Mapp 36:4158–4163, 2015. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Neuroticism and conscientiousness respectively constrain and facilitate short‐term plasticity within the working memory neural network

The rubber hand illusion (RHI) paradigm—in which illusory bodily ownership is induced by synchronous tactile stimulation of a participant's (hidden) hand and a (visible) surrogate—allows one to investigate how the brain resolves conflicting multisensory evidence during perceptual inference. To identify the functional anatomy of the RHI, we used multichannel EEG, acquired under three conditions of tactile stimulation. Evoked potentials were averaged from EEG signals registered to the timing of brushstrokes to the participant's hand. The participant's hand was stroked either in the absence of an artificial hand (REAL) or synchronously with an artificial hand, which either lay in an anatomically plausible (CONGRUENT) or impossible (INCONGRUENT) position. The illusion was reliably elicited in the CONGRUENT condition. For right-hand stimulation, significant differences between conditions emerged at the sensor level around 55 msec after the brushstroke at left frontal and right parietal electrodes. Response amplitudes were smaller for illusory (CONGRUENT) compared with nonillusory (INCONGRUENT and REAL) conditions in the contralateral perirolandic region (pre- and postcentral gyri), superior and inferior parietal lobule, whereas veridical perception of the artificial hand (INCONGRUENT) amplified responses at a scalp region overlying the contralateral postcentral gyrus and inferior parietal lobule compared with the remaining two conditions. Left-hand stimulation produced similar contralateral patterns. These results are consistent with predictive coding models of multisensory integration and may reflect the attenuation of somatosensory precision that is required to resolve perceptual hypotheses about conflicting multisensory input.

Sensory Processing and the Rubber Hand Illusion—An Evoked Potentials Study

The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity

A DCM study of spectral asymmetries in feedforward and feedback connections between visual areas V1 and V4 in the monkey

Accumulating evidence suggests that autonomic signals and their cortical representations are closely linked to emotional processes, and that related abnormalities could lead to social deficits. Although socio‐emotional impairments are a defining feature of autism spectrum disorder (ASD), empirical evidence directly supporting the link between autonomic, cortical, and socio‐emotional abnormalities in ASD is still lacking. In this study, we examined autonomic arousal indexed by skin conductance responses (SCR), concurrent cortical responses measured by functional magnetic resonance imaging, and effective brain connectivity estimated by dynamic causal modeling in seventeen unmedicated high‐functioning adults with ASD and seventeen matched controls while they performed an empathy‐for‐pain task. Compared to controls, adults with ASD showed enhanced SCR related to empathetic pain, along with increased neural activity in the anterior insular cortex, although their behavioral empathetic pain discriminability was reduced and overall SCR was decreased. ASD individuals also showed enhanced correlation between SCR and neural activities in the anterior insular cortex. Importantly, significant group differences in effective brain connectivity were limited to greater reduction in the negative intrinsic connectivity of the anterior insular cortex in the ASD group, indicating a failure in attenuating anterior insular responses to empathetic pain. These results suggest that aberrant interoceptive precision, as indexed by abnormalities in autonomic activity and its central representations, may underlie empathy deficits in ASD. Hum Brain Mapp 36:3323–3338, 2015. © 2015 The Authors Human Brain Mapping Published byWiley Periodicals, Inc.

Autonomic and brain responses associated with empathy deficits in autism spectrum disorder

This book constitutes the proceedings of the International Conference on Brain Informatics and Health, BIH 2015, held in London, UK, in August/September 2015. The 42 full papers presented were carefully reviewed and selected from 82 submissions. Following the success of past conferences in this series, BIH 2015 has a strong emphasis on emerging trends of big data analysis and management technology for brain research, behavior learning, and real-world applications of brain science in human health and wellbeing.

Brain Informatics and Health - 8th International Conference, BIH 2015, London, UK, August 30 - September 2, 2015. Proceedings

All organisms must integrate cognition, emotion, and motivation to guide action toward valuable (goal) states, as described by active inference. Within this framework, cognition, emotion, and motivation interact through the (Bayesian) fusion of exteroceptive, proprioceptive, and interoceptive signals, the precision-weighting of prediction errors, and the "affective tuning" of neuronal representations. Crucially, misregulation of these processes may have profound psychopathological consequences.

Active inference and cognitive-emotional interactions in the brain.

Active Inference, homeostatic regulation and adaptive behavioural control

The mismatch negativity (MMN) evoked potential, a preattentive brain response to a discriminable change in auditory stimulation, is significantly reduced in psychosis. Glutamatergic theories of psychosis propose that hypofunction of NMDA receptors (on pyramidal cells and inhibitory interneurons) causes a loss of synaptic gain control. We measured changes in neuronal effective connectivity underlying the MMN using dynamic causal modeling (DCM), where the gain (excitability) of superficial pyramidal cells is explicitly parameterised. EEG data were obtained during a MMN task—for 24 patients with psychosis, 25 of their first‐degree unaffected relatives, and 35 controls—and DCM was used to estimate the excitability (modeled as self‐inhibition) of (source‐specific) superficial pyramidal populations. The MMN sources, based on previous research, included primary and secondary auditory cortices, and the right inferior frontal gyrus. Both patients with psychosis and unaffected relatives (to a lesser degree) showed increased excitability in right inferior frontal gyrus across task conditions, compared to controls. Furthermore, in the same region, both patients and their relatives showed a reversal of the normal response to deviant stimuli; that is, a decrease in excitability in comparison to standard conditions. Our results suggest that psychosis and genetic risk for the illness are associated with both context‐dependent (condition‐specific) and context‐independent abnormalities of the excitability of superficial pyramidal cell populations in the MMN paradigm. These abnormalities could relate to NMDA receptor hypofunction on both pyramidal cells and inhibitory interneurons, and appear to be linked to the genetic aetiology of the illness, thereby constituting potential endophenotypes for psychosis. Hum Brain Mapp 37:351–365, 2016. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Impaired prefrontal synaptic gain in people with psychosis and their relatives during the mismatch negativity

This technical note considers a simple but important methodological issue in estimating effective connectivity; namely, how do we integrate measurements from multiple subjects to infer functional brain architectures that are conserved over subjects. We offer a solution to this problem that rests on a generalization of random effects analyses to Bayesian inference about nonlinear models of electrophysiological time-series data. Specifically, we present an empirical Bayesian scheme for group or hierarchical models, in the setting of dynamic causal modeling (DCM). Recent developments in approximate Bayesian inference for hierarchical models enable the efficient estimation of group effects in DCM studies of multiple trials, sessions, or subjects. This approach estimates second (e.g., between-subject) level parameters based on posterior estimates from the first (e.g., within-subject) level. Here, we use empirical priors from the second level to iteratively optimize posterior densities over parameters at the first level. The motivation for this iterative application is to finesse the local minima problem inherent in the (first level) inversion of nonlinear and ill-posed models. Effectively, the empirical priors shrink the first level parameter estimates toward the global maximum, to provide more robust and efficient estimates of within (and between-subject) effects. This paper describes the inversion scheme using a worked example based upon simulated electrophysiological responses. In a subsequent paper, we will assess its robustness and reproducibility using an empirical example.

Cerebro-cerebellar Circuitry for Recognition of Emotional Body Language

Tracking slow modulations in synaptic gain using dynamic causal modelling: Validation in epilepsy

Precision and neuronal dynamics in the human posterior parietal cortex during evidence accumulation

Abstract Deciding how much evidence to accumulate before making a decision is a problem we and other animals often face, but one that is not completely understood. This issue is particularly important because a tendency to sample less information (often known as reflection impulsivity) is a feature in several psychopathologies, such as psychosis. A formal understanding of information sampling may therefore clarify the computational anatomy of psychopathology. In this theoretical letter, we consider evidence accumulation in terms of active (Bayesian) inference using a generic model of Markov decision processes. Here, agents are equipped with beliefs about their own behavior—in this case, that they will make informed decisions. Normative decision making is then modeled using variational Bayes to minimize surprise about choice outcomes. Under this scheme, different facets of belief updating map naturally onto the functional anatomy of the brain (at least at a heuristic level). Of particular interest is the key role played by the expected precision of beliefs about control, which we have previously suggested may be encoded by dopaminergic neurons in the midbrain. We show that manipulating expected precision strongly affects how much information an agent characteristically samples, and thus provides a possible link between impulsivity and dopaminergic dysfunction. Our study therefore represents a step toward understanding evidence accumulation in terms of neurobiologically plausible Bayesian inference and may cast light on why this process is disordered in psychopathology.

THE HEALTHY HUMAN CEREBELLUM ENGAGING IN COMPLEX PATTERNS: AN FMRI STUDY Adnan A.S. Alahmadi, Matteo Pardini, Rebecca S Samson, Karl J Friston, Ahmed T Toosy, Egidio D’Angelo, and Claudia A.M. Wheeler-Kingshott NMR Research Unit, Department of Neuroinflammation, Queen Square MS Centre, UCL Institute of Neurology, London, England, United Kingdom, Department of Diagnostic Radiology, Faculty of Applied Medical Science, KAU, Jeddah, Saudi Arabia, Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, Genoa, Italy, Wellcom Centre for Imaging Neuroscience, UCL, Institute of Neurology, London, United Kingdom, NMR Research Unit, Department of Brain Repair and Rehabilitation, Queen Square MS Centre, UCL Institute of Neurology, London, United Kingdom, C. Mondino National, Neurological Institute, Pavia, Italy, Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy

The healthy human cerebellum engaging in complex patterns: An fMRI study

Over the last decade, synchronized resting-state fluctuations of blood oxygenation level-dependent (BOLD) signals between remote brain areas [so-called BOLD resting-state functional connectivity (rs-FC)] have gained enormous relevance in systems and clinical neuroscience. However, the neural underpinnings of rs-FC are still incompletely understood. Using simultaneous positron emission tomography/magnetic resonance imaging we here directly investigated the relationship between rs-FC and local neuronal activity in humans. Computational models suggest a mechanistic link between the dynamics of local neuronal activity and the functional coupling among distributed brain regions. Therefore, we hypothesized that the local activity (LA) of a region at rest determines its rs-FC. To test this hypothesis, we simultaneously measured both LA (glucose metabolism) and rs-FC (via synchronized BOLD fluctuations) during conditions of eyes closed or eyes open. During eyes open, LA increased in the visual system, and the salience network (i.e., cingulate and insular cortices) and the pattern of elevated LA coincided almost exactly with the spatial pattern of increased rs-FC. Specifically, the voxelwise regional profile of LA in these areas strongly correlated with the regional pattern of rs-FC among the same regions (e.g., LA in primary visual cortex accounts for ∼50%, and LA in anterior cingulate accounts for ∼20% of rs-FC with the visual system). These data provide the first direct evidence in humans that local neuronal activity determines BOLD FC at rest. Beyond its relevance for the neuronal basis of coherent BOLD signal fluctuations, our procedure may translate into clinical research particularly to investigate potentially aberrant links between local dynamics and remote functional coupling in patients with neuropsychiatric disorders.

Local Activity Determines Functional Connectivity in the Resting Human Brain: A Simultaneous FDG-PET/fMRI Study

Autism is a pervasive developmental disorder characterized by profound social and verbal communication deficits, stereotypical motor behaviors, restricted interests, and cognitive abnormalities. Autism affects approximately 1% of children in developing countries. Given this prevalence, identifying risk factors and therapeutic interventions are pressing objectives—objectives that rest on neurobiologically grounded and psychologically informed theories about the underlying pathophysiology. In this article, we review the evidence that autism could result from a dysfunctional oxytocin system early in life. As a mediator of successful procreation, not only in the reproductive system, but also in the brain, oxytocin plays a crucial role in sculpting socio-sexual behavior. Formulated within a (Bayesian) predictive cod-

The brain adapts to dynamic environments by adjusting the attentional gain or precision afforded to salient and predictable sensory input. Previous research suggests that this involves the regulation of cortical excitability (reflected in prestimulus alpha oscillations) before stimulus onset that modulates subsequent stimulus processing (reflected in stimulus-bound gamma oscillations). We present two spatial attention experiments in humans, where we first replicate the classic finding of prestimulus attentional alpha modulation and poststimulus gamma modulation. In the second experiment, the task-relevant target was a stimulus change that occurred after stimulus onset. This enabled us to show that attentional alpha modulation reflects the predictability (precision) of an upcoming sensory target, rather than an attenuation of alpha activity induced by neuronal excitation related to stimulus onset. In particular, we show that the strength of attentional alpha modulations increases with the predictability of the anticipated sensory target, regardless of current afferent drive. By contrast, we show that the poststimulus attentional gamma enhancement is stimulus-bound and decreases when the subsequent target becomes more predictable. Hence, this pattern suggests that the strength of gamma oscillations is not merely a function of cortical excitability, but also depends on the relative mismatch of predictions and sensory evidence. Together, these findings support recent theoretical proposals for distinct roles of alpha/beta and gamma oscillations in hierarchical perceptual inference and predictive coding.

Attentional Modulation of Alpha/Beta and Gamma Oscillations Reflect Functionally Distinct Processes

Postulating that the brain performs approximate Bayesian inference generates principled and empirically testable models of neuronal function—the subject of much current interest in neuroscience and related disciplines. Current formulations address inference and learning under some assumed and particular model. In reality, organisms are often faced with an additional challenge—that of determining which model or models of their environment are the best for guiding behavior. Bayesian model averaging—which says that an agent should weight the predictions of different models according to their evidence—provides a principled way to solve this problem. Importantly, because model evidence is determined by both the accuracy and complexity of the model, optimal inference requires that these be traded off against one another. This means an agent's behavior should show an equivalent balance. We hypothesize that Bayesian model averaging plays an important role in cognition, given that it is both optimal and realizable within a plausible neuronal architecture. We outline model averaging and how it might be implemented, and then explore a number of implications for brain and behavior. In particular, we propose that model averaging can explain a number of apparently suboptimal phenomena within the framework of approximate (bounded) Bayesian inference, focusing particularly upon the relationship between goal-directed and habitual behavior.

This scientific commentary refers to ‘On the nature of seizure dynamics’, by V. Jirsa et al. (doi:10.1093/brain/awu133).

The superior temporal sulcus (STS) in the human and monkey is sensitive to the motion of complex forms such as facial and bodily actions. We used functional magnetic resonance imaging (fMRI) to explore network-level explanations for how the form and motion information in dynamic facial expressions might be combined in the human STS. Ventral occipitotemporal areas selective for facial form were localized in occipital and fusiform face areas (OFA and FFA), and motion sensitivity was localized in the more dorsal temporal area V5. We then tested various connectivity models that modeled communication between the ventral form and dorsal motion pathways. We show that facial form information modulated transmission of motion information from V5 to the STS, and that this face-selective modulation likely originated in OFA. This finding shows that form-selective motion sensitivity in the STS can be explained in terms of modulation of gain control on information flow in the motion pathway, and provides a substantial constraint for theories of the perception of faces and biological motion.

Network Interactions Explain Sensitivity to Dynamic Faces in the Superior Temporal Sulcus

Ever since their discovery, mirror neurons have generated much interest and debate. A commonly held view of mirror neuron function is that they transform "visual information into knowledge," thus enabling action understanding and non-verbal social communication between con-specifics (Rizzolatti & Craighero 2004). This functionality is thought to be so important that it has been argued that mirror neurons must be a result of selective pressure.

We report the first stochastic dynamic causal modeling (sDCM) study of effective connectivity within the default mode network (DMN) in schizophrenia. Thirty-three patients (9 women, mean age = 25.0 years, SD = 5) with a first episode of psychosis and diagnosis of schizophrenia—according to the Diagnostic and Statistic Manual of Mental Disorders, 4th edition, revised criteria—were studied. Fifteen healthy control subjects (4 women, mean age = 24.6 years, SD = 4) were included for comparison. All subjects underwent resting state functional magnetic resonance imaging (fMRI) interspersed with 2 periods of continuous picture viewing. The anterior frontal (AF), posterior cingulate (PC), and the left and right parietal nodes of the DMN were localized in an unbiased fashion using data from 16 independent healthy volunteers (using an identical fMRI protocol). We used sDCM to estimate directed connections between and within nodes of the DMN, which were subsequently compared with t tests at the between subject level. The excitatory effect of the PC node on the AF node and the inhibitory self-connection of the AF node were significantly weaker in patients (mean values = 0.013 and −0.048 Hz, SD = 0.09 and 0.05, respectively) relative to healthy subjects (mean values = 0.084 and −0.088 Hz, SD = 0.15 and 0.77, respectively; P < .05). In summary, sDCM revealed reduced effective connectivity to the AF node of the DMN—reflecting a reduced postsynaptic efficacy of prefrontal afferents—in patients with first-episode schizophrenia.

Dysconnectivity Within the Default Mode in First-Episode Schizophrenia: A Stochastic Dynamic Causal Modeling Study With Functional Magnetic Resonance Imaging

Impaired Frontal-Basal Ganglia Connectivity in Adolescents with Internet Addiction

This volume contains the papers selected for presentation at the 2014 IEEE/WIC/ACM International Conference on Web Intelligence (WI'14), held as part of the 2014 Web Intelligence Congress (WIC'14) at the University of Warsaw, Warsaw, Poland, from 11 to 14 in August, 2014. The conference was sponsored and co-organized by the IEEE Computer Society, the Web Intelligence Consortium (WIC), Association for Computing Machinery (ACM), the University of Warsaw, Polish Mathematical Society and Warsaw University of Technology.

A Standardized [18F]-FDG-PET Template for Spatial Normalization in Statistical Parametric Mapping of Dementia

The physiological basis for musical hallucinations (MH) is not understood. One obstacle to understanding has been the lack of a method to manipulate the intensity of hallucination during the course of experiment. Residual inhibition, transient suppression of a phantom percept after the offset of a masking stimulus, has been used in the study of tinnitus. We report here a human subject whose MHwere residually inhibited by short periods of music. Magnetoencephalography (MEG) allowed us to examine variation in the underlying oscillatory brain activity in different states. Source-space analysis capable of single-subject inference defined left-lateralised power increases, associated with stronger hallucinations, in the gamma band in left anterior superior temporal gyrus, and in the beta band in motor cortex and posteromedial cortex. The data indicate that these areas form a crucial network in the generation of MH, and are consistent with a model in which MH are generated by persistent reciprocal communication in a predictive coding hierarchy. a 2013 The Authors. Published by Elsevier Ltd. All rights reserved.

Algorithmic procedures for Bayesian MEG/EEG source reconstruction in SPM☆

1 The Wellcome Trust Centre for Neuroimaging, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 2 INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Centre, Brain Dynamics and Cognition Team, Lyon, F-69500, France 3 Max Planck Institute for Human Cognitive and Brain Sciences, 04303 Leipzig, Germany 4 Cyclotron Research Centre, University of Liège, 4000 Liège, Belgium 5 MRC Cognition and Brain Sciences Unit, Cambridge CB2 7EF, UK 6 Donders Institute for Brain, Cognition, and Behaviour, Radboud University Nijmegen, 6500 HB Nijmegen, The Netherlands

The effects of striatal dopamine (DA) on behavior have been widely investigated over the past decades, with “phasic” burst firings considered as the key expression of a reward prediction error responsible for reinforcement learning. Less well studied is “tonic” DA, where putative functions include the idea that it is a regulator of vigor, incentive salience, disposition to exert an effort and a modulator of approach strategies. We present a model combining tonic and phasic DA to show how different outflows triggered by either intrinsically or extrinsically motivating stimuli dynamically affect the basal ganglia by impacting on a selection process this system performs on its cortical input. The model, which has been tested on the simulated humanoid robot iCub interacting with a mechatronic board, shows the putative functions ascribed to DA emerging from the combination of a standard computational mechanism coupled to a differential sensitivity to the presence of DA across the striatum.

Keep focussing: striatal dopamine multiple functions resolved in a single mechanism tested in a simulated humanoid robot

Aim: To investigate areas exhibiting non-linear correlates of BOLD fMRI signal to variable grip force (GF) levels using dominant (DH) or non-dominant hand (NDH) in healthy subjects (HS). Methods: 13 right-handed HS performed unimanually a visually guided event-related fMRI paradigm. The power grip design comprised of 75 trials divided into 5 GF targets (20, 30, 40, 50, and 60% of Maximum Voluntary Contraction). Signal changes were fitted with higher-order polynomial expansions using a parametric design. Results: Two major findings: 1) Performing the task using the NDH revealed widespread brain activations compared to DH, irrespective of GF, including different motor and non-motor regions; 2) Non-linear BOLD responses have a clear regional specificity using either hands, although force related brain network changes were more distributed when using the NDH (consistently with result 1). These complex responses were seen in associative areas (including premotor, sensory, parietal areas) as well as in M1 and cerebellar areas. Conclusion: Signal modulation with GF can be interpreted as follows: Zero order effect highlights areas involved in the grasping task. First order positive linear response areas relate to motor function and force generation. Higher order effects represent motor control processes such as motor planning, attention and complex sensory-feedback. The additional activations seen using the NDH especially in the right hemisphere suggests the presence of subconscious data elaboration, e.g. geometrical representation of the task. Also the consistent bilateral involvement of the cerebellum suggests its involvement in error tracking or in synkinetic processes between DH and NDH.

Associative areas and cerebellum show non-linear modulation of fmri signal especially when using non-dominant hand

Consciousness, Dreams, and Inference The Cartesian Theatre Revisited

a b s t r a c t Autism is a pervasive developmental disorder characterized by profound social and verbal communication deficits, stereotypical motor behaviors, restricted interests, and cognitive abnormalities. Autism affects approximately 1% of children in developing countries. Given this prevalence, identifying risk factors and therapeutic interventions are pressing objectives—objectives that rest on neurobiologically grounded and psychologically informed theories about the underlying pathophysiology. In this article, we review the evidence that autism could result from a dysfunctional oxytocin system early in life. As a mediator of successful procreation, not only in the reproductive system, but also in the brain, oxytocin plays a crucial role in sculpting socio-sexual behavior. Formulated within a (Bayesian) predictive coding framework, we propose that oxytocin encodes the saliency or precision of interoceptive signals and enables the neuronal plasticity necessary for acquiring a generative model of the emotional and social ‘self.’ An aberrant oxytocin system in infancy could therefore help explain the marked deficits in language and social communication – as well as the sensory, autonomic, motor, behavioral, and cognitive abnormalities – seen in autism. © 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license

The Impact of Active Inference on Engineering [Further Thoughts]

This volume contains the papers selected for presentation at the 2014 IEEE/WIC/ACM International Conference on Intelligent Agent Technology (IAT'14), held as part of the 2014 Web Intelligence Congress (WIC'14) at the University of Warsaw, Warsaw, Poland, from 11 to 14 in August, 2014. The conference was sponsored and co-organized by the IEEE Computer Society, the Web Intelligence Consortium (WIC), Association for Computing Machinery (ACM), the University of Warsaw, Polish Mathematical Society and Warsaw University of Technology.

Abnormalities in White Matter Microstructure Associated with Chronic Ketamine Use

Methylphenidate and brain activity in a reward/conflict paradigm: Role of the insula in task performance

Introduction: We propose that active Bayesian inference—a general framework for decision-making—can equally be applied to interpersonal exchanges. Social cognition, however, entails special challenges. We address these challenges through a novel formulation of a formal model and demonstrate its psychological significance. Method: We review relevant literature, especially with regards to interpersonal representations, formulate a mathematical model and present a simulation study. The model accommodates normative models from utility theory and places them within the broader setting of Bayesian inference. Crucially, we endow people's prior beliefs, into which utilities are absorbed, with preferences of self and others. The simulation illustrates the model's dynamics and furnishes elementary predictions of the theory. Results: (1) Because beliefs about self and others inform both the desirability and plausibility of outcomes, in this framework interpersonal representations become beliefs that have to be actively inferred. This inference, akin to “mentalizing” in the psychological literature, is based upon the outcomes of interpersonal exchanges. (2) We show how some well-known social-psychological phenomena (e.g., self-serving biases) can be explained in terms of active interpersonal inference. (3) Mentalizing naturally entails Bayesian updating of how people value social outcomes. Crucially this includes inference about one's own qualities and preferences. Conclusion: We inaugurate a Bayes optimal framework for modeling intersubject variability in mentalizing during interpersonal exchanges. Here, interpersonal representations are endowed with explicit functional and affective properties. We suggest the active inference framework lends itself to the study of psychiatric conditions where mentalizing is distorted.

Spontaneous neuronal activity predicts intersubject variations in executive control of attention

This paper considers psychotic symptoms in terms of false inferences or beliefs. It is based on the notion that the brain is an organ of inference that actively constructs hypotheses to explain or predict its sensations. This perspective provides a normative (Bayes optimal) account of action and perception that emphasises probabilistic representations; in particular, the confidence or precision of beliefs about the world. We consider sensory attenuation deficits, catatonia and delusions as various expressions of the same core pathology: namely, an aberrant encoding of precision in a predictive coding hierarchy. In predictive coding, precision is thought to be encoded by the postsynaptic gain of neurons reporting prediction error. This suggests that both pervasive trait abnormalities and florid failures of inference in the psychotic state can be linked to factors controlling postsynaptic gain—such as NMDA receptor function and (dopaminergic) neuromodulation. We illustrate these points using a biologically plausible simulation of attribution of agency—showing how a reduction in the precision of prior beliefs, relative to sensory evidence, can lead to false inference.

Please Comment on the Predictive Tenet of the Protoconsciousness Hypothesis. Is This Idea Consistent with the Helmholtzian Model of Free Energy That You Are Developing

In recent years there has been a paradigm shift in theoretical neuroscience in which the brain—as a passive processor of sensory information—is now considered an active organ of inference, generating predictions and hypotheses about the causes of its sensations. In this commentary, we try to convey the basic ideas behind this perspective, describe their neurophysiologic underpinnings, and highlight the potential importance of this formulation for clinical neuroscience. The formalism it provides—and the implementation of active inference in the brain—may have the potential to reveal aspects of functional neuroanatomy that are compromised in conditions ranging from Parkinson disease to schizophrenia. In particular, many neurologic and neuropsychiatric conditions may be understandable in terms of a failure to modulate the postsynaptic gain of neuronal populations reporting prediction errors during action and perception. From the perspective of the predictive brain, this represents a failure to encode the precision of—or confidence in—sensory information. We propose that the predictive or inferential perspective on brain function offers novel insights into brain diseases.

The functional anatomy of schizophrenia: A dynamic causal modeling study of predictive coding

This paper shows how gamma oscillations can be combined with neural population models and dynamic causal modeling (DCM) to distinguish among alternative hypotheses regarding cortical excitability and microstructure. This approach exploits inter-subject variability and trial-specific effects associated with modulations in the peak frequency of gamma oscillations. Neural field models are used to evaluate model evidence and obtain parameter estimates using invasive and non-invasive gamma recordings. Our overview comprises two parts: in the first part, we use neural fields to simulate neural activity and distinguish the effects of post synaptic filtering on predicted responses in terms of synaptic rate constants that correspond to different timescales and distinct neurotransmitters. We focus on model predictions of conductance and convolution based field models and show that these can yield spectral responses that are sensitive to biophysical properties of local cortical circuits like synaptic kinetics and filtering; we also consider two different mechanisms for this filtering: a nonlinear mechanism involving specific conductances and a linear convolution of afferent firing rates producing post synaptic potentials. In the second part of this paper, we use neural fields quantitatively —to fit empirical data recorded during visual stimulation. We present two studies of spectral responses obtained from the visual cortex during visual perception experiments: in the first study, MEG data were acquired during a task designed to show how activity in the gamma band is related to visual perception, while in the second study, we exploited high density electrocorticographic (ECoG) data to study the effect of varying stimulus contrast on cortical excitability and gamma peak frequency.

Gamma Oscillations and Neural Field DCMs Can Reveal Cortical Excitability and Microstructure

Poster #M80 SCHIZOTYPY IS ASSOCIATED WITH A “REVERSAL INFERENCE” DEFICIT BUT NO “JUMPING TO CONCLUSIONS”

The exact mechanisms whereby the cholinergic neurotransmitter system contributes to attentional processing remain poorly understood. Here, we applied computational modeling to psychophysical data (obtained from a spatial attention task) under a psychopharmacological challenge with the cholinesterase inhibitor galantamine (Reminyl). This allowed us to characterize the cholinergic modulation of selective attention formally, in terms of hierarchical Bayesian inference. In a placebo-controlled, within-subject, crossover design, 16 healthy human subjects performed a modified version of Posner's location-cueing task in which the proportion of validly and invalidly cued targets (percentage of cue validity, % CV) changed over time. Saccadic response speeds were used to estimate the parameters of a hierarchical Bayesian model to test whether cholinergic stimulation affected the trial-wise updating of probabilistic beliefs that underlie the allocation of attention or whether galantamine changed the mapping from those beliefs to subsequent eye movements. Behaviorally, galantamine led to a greater influence of probabilistic context (% CV) on response speed than placebo. Crucially, computational modeling suggested this effect was due to an increase in the rate of belief updating about cue validity (as opposed to the increased sensitivity of behavioral responses to those beliefs). We discuss these findings with respect to cholinergic effects on hierarchical cortical processing and in relation to the encoding of expected uncertainty or precision.

Cholinergic Stimulation Enhances Bayesian Belief Updating in the Deployment of Spatial Attention

Dopamine plays a key role in learning; however, its exact function in decision making and choice remains unclear. Recently, we proposed a generic model based on active (Bayesian) inference wherein dopamine encodes the precision of beliefs about optimal policies. Put simply, dopamine discharges reflect the confidence that a chosen policy will lead to desired outcomes. We designed a novel task to test this hypothesis, where subjects played a “limited offer” game in a functional magnetic resonance imaging experiment. Subjects had to decide how long to wait for a high offer before accepting a low offer, with the risk of losing everything if they waited too long. Bayesian model comparison showed that behavior strongly supported active inference, based on surprise minimization, over classical utility maximization schemes. Furthermore, midbrain activity, encompassing dopamine projection neurons, was accurately predicted by trial-by-trial variations in model-based estimates of precision. Our findings demonstrate that human subjects infer both optimal policies and the precision of those inferences, and thus support the notion that humans perform hierarchical probabilistic Bayesian inference. In other words, subjects have to infer both what they should do as well as how confident they are in their choices, where confidence may be encoded by dopaminergic firing.

The Dopaminergic Midbrain Encodes the Expected Certainty about Desired Outcomes

Abstract I greatly enjoyed Seth’s compelling synthesis of sensorimotor contingencies and active inference. I would also like to thank Jim Hopkins for sending me the quote (below)—which speaks directly to the embodied nature of perceptual inference that underlies the perspectives reconciled in Seth (this issue). These perspectives include perception as hypothesis testing, affordance, and sensorimotor contingencies. This commentary briefly rehearses the fundaments of active inference and offers a formal basis for Seth’s key argument.

EPA-0242 – Personality Dimensions Modulate Working Memory-related Changes in Functional Brain Connectivity

This paper combines recent formulations of self- organization and neuronal processing to provide an account of cognitive dynamics from basic principles. We start by showing that inference (and autopoiesis) are emergent features of any (weakly mixing) ergodic random dynamical system. We then apply the emergent dynamics to action and perception in a way that casts action as the fulfillment of (Bayesian) beliefs about the causes of sensations. More formally, we formulate ergodic flows on global random attractors as a generalized descent on a free energy functional of the internal states of a system. This formulation rests on a partition of states based on a Markov blanket that separates internal states from hidden states in the external milieu. This separation means that the internal states effectively represent external states probabilistically. The generalized descent is then related to classical Bayesian (e.g., Kalman-Bucy) filtering and predictive codingVof the sort that might be implemented in the brain. Finally, we present two simulations. The first simulates a primordial soup to illustrate the emergence of a Markov blanket and (active) inference about hidden states. The second uses the same emergent dynamics to simulate action and action observation.

Cognitive Dynamics: From Attractors to Active Inference This paper provides a link from statistical dynamics of ergodic systems to the inferential nature of human perception and ensuing action on the world.

This technical note introduces a conductance-based neural field model that combines biologically realistic synaptic dynamics—based on transmembrane currents—with neural field equations, describing the propagation of spikes over the cortical surface. This model allows for fairly realistic inter-and intra-laminar intrinsic connections that underlie spatiotemporal neuronal dynamics. We focus on the response functions of expected neuronal states (such as depolarization) that generate observed electrophysiological signals (like LFP recordings and EEG). These response functions characterize the model's transfer functions and implicit spectral responses to (uncorrelated) input. Our main finding is that both the evoked responses (impulse response functions) and induced responses (transfer functions) show qualitative differences depending upon whether one uses a neural mass or field model. Furthermore, there are differences between the equivalent convolution and conductance models. Overall, all models reproduce a characteristic increase in frequency, when inhibition was increased by increasing the rate constants of inhibitory populations. However, convolution and conductance-based models showed qualitatively different changes in power, with convolution models showing decreases with increasing inhibition, while conductance models show the opposite effect. These differences suggest that conductance based field models may be important in empirical studies of cortical gain control or pharmacological manipulations.

Neural masses and fields: modeling the dynamics of brain activity

Re-thinking the role of motor cortex: Context-sensitive motor outputs?

You might find this additional info useful...This article cites 84 articles, 31 of which can be accessed free at:/content/89/5/2823.full.html#ref-list-1 This article has been cited by 69 other HighWire hosted articles, the first 5 are:€[Abstract] [Full Text] [PDF] J. Neurosci., February 26, 2014; 34 (9): 3279-3290.Marianna Yanike and Vincent P. FerreraRepresentation of Outcome Risk and Action in the Anterior Caudate Nucleus€[Abstract] [Full Text] [PDF] Learn. Mem., April , 2014; 21 (4): 223-231.Luca Aquili, Andrew W. Liu, Mayumi Shindou, Tomomi Shindou and Jeffery R. Wickensaccumbens shell during specific time segmentsBehavioral flexibility is increased by optogenetic inhibition of neurons in the nucleus€[Abstract] [Full Text] [PDF] Soc Cogn Affect Neurosci, June , 2014; 9 (6): 864-872.HabelNils Kohn, Irina Falkenberg, Thilo Kellermann, Simon B. Eickhoff, Ruben C. Gur and UteNeural correlates of effective and ineffective mood induction€[Abstract] [Full Text] [PDF] Neurology 2014; 83 (12): 1112-1118.Fabienne Picard and Karl FristonPredictions, perception, and a sense of self€[Abstract] [Full Text] [PDF] J. Neurosci., October 15, 2014; 34 (42): 14147-14162.Sara E. Morrison and Saleem M. NicolaNeurons in the Nucleus Accumbens Promote Selection Bias for Nearer ObjectsUpdated information and services including high resolution figures, can be found at:/content/89/5/2823.full.html Additional material and information about Journal of Neurophysiology can be found at:http://www.the-aps.org/publications/jnThis information is current as of October 16, 2014.€

Magnitudes on Neuronal Activity in Primate Striatum Effects of Expectations for Different Reward

This paper considers goal-directed decision-making in terms of embodied or active inference. We associate bounded rationality with approximate Bayesian inference that optimizes a free energy bound on model evidence. Several constructs such as expected utility, exploration or novelty bonuses, softmax choice rules and optimism bias emerge as natural consequences of free energy minimization. Previous accounts of active inference have focused on predictive coding. In this paper, we consider variational Bayes as a scheme that the brain might use for approximate Bayesian inference. This scheme provides formal constraints on the computational anatomy of inference and action, which appear to be remarkably consistent with neuroanatomy. Active inference contextualizes optimal decision theory within embodied inference, where goals become prior beliefs. For example, expected utility theory emerges as a special case of free energy minimization, where the sensitivity or inverse temperature (associated with softmax functions and quantal response equilibria) has a unique and Bayes-optimal solution. Crucially, this sensitivity corresponds to the precision of beliefs about behaviour. The changes in precision during variational updates are remarkably reminiscent of empirical dopaminergic responses—and they may provide a new perspective on the role of dopamine in assimilating reward prediction errors to optimize decision-making.

This article explores the notion that the brain is genetically endowed with an innate virtual reality generator that – through experience-dependent plasticity – becomes a generative or predictive model of the world. This model, which is most clearly revealed in rapid eye movement (REM) sleep dreaming, may provide the theater for conscious experience. Functional neuroimaging evidence for brain activations that are time-locked to rapid eye movements (REMs) endorses the view that waking consciousness emerges from REM sleep – and dreaming lays the foundations for waking perception. In this view, the brain is equipped with a virtual model of the world that generates predictions of its sensations. This model is continually updated and entrained by sensory prediction errors in wakefulness to ensure veridical perception, but not in dreaming. In contrast, dreaming plays an essential role in maintaining and enhancing the capacity to model the world by minimizing model complexity and thereby maximizing both statistical and thermodynamic efficiency. This perspective suggests that consciousness corresponds to the embodied process of inference, realized through the generation of virtual realities (in both sleep and wakefulness). In short, our premise or hypothesis is that the waking brain engages with the world to predict the causes of sensations, while in sleep the brain’s generative model is actively refined so that it generates more efficient predictions during waking. We review the evidence in support of this hypothesis – evidence that grounds consciousness in biophysical computations whose neuronal and neurochemical infrastructure has been disclosed by sleep research.

Contrast gain control and horizontal interactions in V1: A DCM study

Functional movement disorders require attention to manifest yet patients report the abnormal movement to be out of their control. In this study we explore the phenomenon of sensory attenuation, a measure of the sense of agency for movement, in this group of patients by using a force matching task. Fourteen patients and 14 healthy control subjects were presented with forces varying from 1 to 3 N on the index finger of their left hand. Participants were required to match these forces; either by pressing directly on their own finger or by operating a robot that pressed on their finger. As expected, we found that healthy control subjects consistently overestimated the force required when pressing directly on their own finger than when operating a robot. However, patients did not, indicating a significant loss of sensory attenuation in this group of patients. These data are important because they demonstrate that a fundamental component of normal voluntary movement is impaired in patients with functional movement disorders. The loss of sensory attenuation has been correlated with the loss of sense of agency, and may help to explain why patients report that they do not experience the abnormal movement as voluntary.

Loss of sensory attenuation in patients with functional (psychogenic) movement disorders.

Auditory Cortex is Highly Sensitive to Regularity in Sound Sequences

Resting EEG in psychosis and at-risk populations — A possible endophenotype?

Various methods have been proposed to characterize the functional connectivity between nodes in a network measured with different modalities (electrophysiology, functional magnetic resonance imaging etc.). Since different measures of functional connectivity yield different results for the same dataset, it is important to assess when and how they can be used. In this work, we provide a systematic framework for evaluating the performance of a large range of functional connectivity measures—based upon a comprehensive portfolio of models generating measurable responses. Specifically, we benchmarked 42 methods using 10,000 simulated datasets from 5 different types of generative models with different connectivity structures. Since all functional connectivity methods require the setting of some parameters (window size and number, model order etc.), we first optimized these parameters using performance criteria based upon (threshold free) ROC analysis. We then evaluated the performance of the methods on data simulated with different types of models. Finally, we assessed the performance of the methods against different levels of signal-to-noise ratios and network configurations. A MATLAB toolbox is provided to perform such analyses using other methods and simulated datasets.

Effective connectivity during animacy perception – dynamic causal modelling of Human Connectome Project data

Self-Organization and Compositionality in Cognitive Brains [Further Thoughts]

Detecting the location of salient sounds in the environment rests on the brain's ability to use differences in sounds arriving at both ears. Functional neuroimaging studies in humans indicate that the left and right auditory hemispaces are coded asymmetrically, with a rightward attentional bias that reflects spatial attention in vision. Neuropsychological observations in patients with spatial neglect have led to the formulation of two competing models: the orientation bias and right-hemisphere dominance models. The orientation bias model posits a symmetrical mapping between one side of the sensorium and the contralateral hemisphere, with mutual inhibition of the ipsilateral hemisphere. The right-hemisphere dominance model introduces a functional asymmetry in the brain's coding of space: the left hemisphere represents the right side, whereas the right hemisphere represents both sides of the sensorium. We used Dynamic Causal Modeling of effective connectivity and Bayesian model comparison to adjudicate between these alternative network architectures, based on human electroencephalographic data acquired during an auditory location oddball paradigm. Our results support a hemispheric asymmetry in a frontoparietal network that conforms to the right-hemisphere dominance model. We show that, within this frontoparietal network, forward connectivity increases selectively in the hemisphere contralateral to the side of sensory stimulation. We interpret this finding in light of hierarchical predictive coding as a selective increase in attentional gain, which is mediated by feedforward connections that carry precision-weighted prediction errors during perceptual inference. This finding supports the disconnection hypothesis of unilateral neglect and has implications for theories of its etiology.

Effective Connectivity Reveals Right-Hemisphere Dominance in Audiospatial Perception: Implications for Models of Spatial Neglect

The aging brain shows a progressive loss of neuropil, which is accompanied by subtle changes in neuronal plasticity, sensory learning and memory. Neurophysiologically, aging attenuates evoked responses—including the mismatch negativity (MMN). This is accompanied by a shift in cortical responsivity from sensory (posterior) regions to executive (anterior) regions, which has been interpreted as a compensatory response for cognitive decline. Theoretical neurobiology offers a simpler explanation for all of these effects—from a Bayesian perspective, as the brain is progressively optimized to model its world, its complexity will decrease. A corollary of this complexity reduction is an attenuation of Bayesian updating or sensory learning. Here we confirmed this hypothesis using magnetoencephalographic recordings of the mismatch negativity elicited in a large cohort of human subjects, in their third to ninth decade. Employing dynamic causal modeling to assay the synaptic mechanisms underlying these non-invasive recordings, we found a selective age-related attenuation of synaptic connectivity changes that underpin rapid sensory learning. In contrast, baseline synaptic connectivity strengths were consistently strong over the decades. Our findings suggest that the lifetime accrual of sensory experience optimizes functional brain architectures to enable efficient and generalizable predictions of the world.

The Brain Ages Optimally to Model Its Environment: Evidence from Sensory Learning over the Adult Lifespan

Autism is a neurodevelopmental disorder characterized by problems with social-communication, restricted interests and repetitive behavior. A recent and thought-provoking article presented a normative explanation for the perceptual symptoms of autism in terms of a failure of Bayesian inference (Pellicano and Burr, 2012). In response, we suggested that when Bayesian inference is grounded in its neural instantiation—namely, predictive coding—many features of autistic perception can be attributed to aberrant precision (or beliefs about precision) within the context of hierarchical message passing in the brain (Friston et al., 2013). Here, we unpack the aberrant precision account of autism. Specifically, we consider how empirical findings—that speak directly or indirectly to neurobiological mechanisms—are consistent with the aberrant encoding of precision in autism; in particular, an imbalance of the precision ascribed to sensory evidence relative to prior beliefs.

Objective The brain bases of musical hallucinations (MH) is not understood. A major problem in this effort is the lack of a suitable method to experimentally manipulate MH during the course of experiment. In this work we present a method to systematically manipulate MH using an external masker stimulus. Furthermore, we make use of the manipulation of MH to compare brain activity as a function of intensity of hallucination. We then combine our results with the computational theories of brain function to propose a model of how the brain generates and maintain MH. Method We used a residual inhibition (RI) paradigm to manipulate MH. In the RI, an external masking stimulus (music in the current work) is presented which suppresses hallucinations. The intensity of hallucinations remain low after the offset of masking stimulus before the hallucinations come back to normal level. We make use of the RI to manipulate MH while brain activity being acquired using Magnetoencephalography (MEG). Results Our results show that (i) MH can residually suppress the MH for up to a minute (ii) Source-space analysis capable of single-subject inference defined left-lateralised power increases, associated with stronger hallucinations, in the gamma band in left anterior superior temporal gyrus, and in the beta band in motor cortex and posteromedial cortex. Conclusion The data indicate that these areas form a crucial network in the generation of MH, and are consistent with a model in which MH are generated by persistent reciprocal communication in a predictive coding hierarchy.

Extracting novel information from neuroimaging data using neural fields

In its full sense, perception rests on an agent's model of how its sensory input comes about and the inferences it draws based on this model. These inferences are necessarily uncertain. Here, we illustrate how the Hierarchical Gaussian Filter (HGF) offers a principled and generic way to deal with the several forms that uncertainty in perception takes. The HGF is a recent derivation of one-step update equations from Bayesian principles that rests on a hierarchical generative model of the environment and its (in)stability. It is computationally highly efficient, allows for online estimates of hidden states, and has found numerous applications to experimental data from human subjects. In this paper, we generalize previous descriptions of the HGF and its account of perceptual uncertainty. First, we explicitly formulate the extension of the HGF's hierarchy to any number of levels; second, we discuss how various forms of uncertainty are accommodated by the minimization of variational free energy as encoded in the update equations; third, we combine the HGF with decision models and demonstrate the inversion of this combination; finally, we report a simulation study that compared four optimization methods for inverting the HGF/decision model combination at different noise levels. These four methods (Nelder–Mead simplex algorithm, Gaussian process-based global optimization, variational Bayes and Markov chain Monte Carlo sampling) all performed well even under considerable noise, with variational Bayes offering the best combination of efficiency and informativeness of inference. Our results demonstrate that the HGF provides a principled, flexible, and efficient—but at the same time intuitive—framework for the resolution of perceptual uncertainty in behaving agents.

Deep brain stimulation is an established therapy for Parkinson’s disease, although its mechanism of action remains unclear. Kahan et al. use resting state fMRI and dynamic causal modelling to study changes in ‘effective’ connectivity within the basal ganglia. Analyses implicate subthalamic afferents and the direct pathway in the clinical response.

Resting state functional MRI in Parkinson’s disease: the impact of deep brain stimulation on ‘effective’ connectivity

This paper combines recent formulations of self-organization and neuronal processing to provide an account of cognitive dynamics from basic principles. We start by showing that inference (and autopoiesis) are emergent features of any (weakly mixing) ergodic random dynamical system. We then apply the emergent dynamics to action and perception in a way that casts action as the fulfillment of (Bayesian) beliefs about the causes of sensations. More formally, we formulate ergodic flows on global random attractors as a generalized descent on a free energy functional of the internal states of a system. This formulation rests on a partition of states based on a Markov blanket that separates internal states from hidden states in the external milieu. This separation means that the internal states effectively represent external states probabilistically. The generalized descent is then related to classical Bayesian (e.g., Kalman-Bucy) filtering and predictive coding-of the sort that might be implemented in the brain. Finally, we present two simulations. The first simulates a primordial soup to illustrate the emergence of a Markov blanket and (active) inference about hidden states. The second uses the same emergent dynamics to simulate action and action observation.

Proceedings of the 2014 IEEE/WIC/ACM International Joint Conferences on Web Intelligence (WI) and Intelligent Agent Technologies (IAT) - Volume 02

The symbol grounding problem as understood today can be traced back at least to Cartesian dualism and medieval times. René Descartes postulated that the mind is an immaterial thinking thing essentially distinct from the nonthinking material body, only then to face the ‘‘problem of interactionism,’’ i.e., explaining how an immaterial mind can cause anything in a material body, and vice versa. Today’s symbol grounding problem addresses the same concern, asking how symbols understood as arbitrary shapes or tokens defined in nonmetric space can interact densely with sensory-motor reality defined in an effectively physical and material metric space. In his paper, ‘‘Self-organization and compositionality in cognitive brains: A neurorobotic study,’’ Tani attempts to constructively resolve this long-standing problem of mind and body. The paper details experimental trials, inspired by Merleau–Ponty’s philosophy of embodiment, in which Tani has engineered self-organizing nonlinear dynamic systems into robotic platforms in order to test the conjecture that neurodynamic structures self-organize via accumulated learning of the continuous flow of sensory-motor experience. This learning grounds higher level cognition in perceptual reality without suffering the disjunction between lower and higher level operations found in hybrid models employing symbolic compositional operations. Instead, iterative interactions between top–down subjective intentional processes (acting on the objective world) and the bottom–up recognition of perceptual reality result in the modification of top–down intention by circular causality. As such, Tani’s models demonstrate what Merleau–Ponty metaphorically described as the reciprocal insertion and intertwining of one (the subject) and the other (the object) through which those two become inseparable entities [1]. This sketch might not be easily appreciated by proponents of cognitivism such as that laid out by Chomsky in response to Skinner’s behaviorism, i.e., that symbolic language cannot be acquired merely through conditioning, as the cognitivist may assume the following two aspects of human cognition. The first assumption may be that an essential aspect of human cognition can be adequately described in terms of logical symbol systems, the great strength of which being that they can support an infinite range of recursive expressions. And, the second assumption may be that a less or nonessential sensory-motor or semantic system is not necessary for the composition or recursion taking place in terms of such symbol systems, either at all or at least not in any noteworthy depth [2]. The crucial question for Tani, here, is whether it is necessary for the daily behaviors and thoughts of human beings to be supported by such an infinite range of recursive compositions. In normal situations, he argues, human beings speak only with a limited depth of embedded sentences, and make action plans composed of only a limited length of primitive sequences at each level. In neither case is an infinite depth of recursive compositions required. And, the series of experimental studies that he describes in his contribution to this issue confirm this characterization. Recurrent neural networks (RNNs) can learn to mimic stochastic sequences through self-organizing deterministic chaos with the complexity of finite state machines, but not with that of infinite ones. Although mathematical study [3] has established the possibility that analog computational models, including RNNs, can exhibit a computational capability beyond the Turing limit, the construction of such Turing machines through learning is practically impossible because the corresponding connectivity weights can be found only in nonmeasurable points in the weight space. And, to make matters worse, even if an equivalence of such a Turing machine could be reconstructed in an RNN by chance, such a parameter-sensitive system may not function reliably, situated in the noisy sensory-motor reality that its practical embodiment may require. This situation should be the same for ordinary human cognitive processes, which rely on working memory of relatively limited size and accuracy. Psychological studies Digital Object Identifier: 10.1109/JPROC.2014.2308625

Further thoughts on the paper by Tani Self-Organization and Compositionality in Cognitive Brains

Dopamine is implicated in multiple functions, including motor execution, action learning for hedonically salient outcomes, maintenance, and switching of behavioral response set. Here, we used a novel within-subject psychopharmacological and combined functional neuroimaging paradigm, investigating the interaction between hedonic salience, dopamine, and response set shifting, distinct from effects on action learning or motor execution. We asked whether behavioral performance in response set shifting depends on the hedonic salience of reversal cues, by presenting these as null (neutral) or salient (monetary loss) outcomes. We observed marked effects of reversal cue salience on set-switching, with more efficient reversals following salient loss outcomes. l-Dopa degraded this discrimination, leading to inappropriate perseveration. Generic activation in thalamus, insula, and striatum preceded response set switches, with an opposite pattern in ventromedial prefrontal cortex (vmPFC). However, the behavioral effect of hedonic salience was reflected in differential vmPFC deactivation following salient relative to null reversal cues. l-Dopa reversed this pattern in vmPFC, suggesting that its behavioral effects are due to disruption of the stability and switching of firing patterns in prefrontal cortex. Our findings provide a potential neurobiological explanation for paradoxical phenomena, including maintenance of behavioral set despite negative outcomes, seen in impulse control disorders in Parkinson's disease.

Dopamine, Salience, and Response Set Shifting in Prefrontal Cortex

P329: Functional connectivity of predictive coding in schizophrenia

We have investigated non-linear responses in BOLD signals using a parametric fMRI power grip motor experiment with five target grip force levels in healthy volunteers. We have demonstrated the ability to detect a complex BOLD response to grip force modulation, affecting different brain regions. The study showed linear and non-linear BOLD responses to varying grip forces in the primary motor cortex and non-linear responses (up to the 4th order) in other motor and non-motor areas. We concluded that BOLD signal and force have a complicated relationship that is far from a simple correlation and further physiological confirmations are warranted.

Parametric event related fMRI to investigate non-linear BOLD effects in motor task

Surprise drives learning. Various neural “prediction error” signals are believed to underpin surprise‐based reinforcement learning. Here, we report a surprise signal that reflects reinforcement learning but is neither un/signed reward prediction error (RPE) nor un/signed state prediction error (SPE). To exclude these alternatives, we measured surprise responses in the absence of RPE and accounted for a host of potential SPE confounds. This new surprise signal was evident in ventral striatum, primary sensory cortex, frontal poles, and amygdala. We interpret these findings via a normative model of surprise. Hum Brain Mapp 35:4805–4814, 2014. © 2014 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc.

In the complex scenes of everyday life, our brains must select from among many competing inputs for perceptual synthesis—so that only the most relevant are fully processed and irrelevant (distracting) information is suppressed. At the same time, we must remain responsive to salient events outside our current focus of attention—and balancing these two processing modes is a fundamental task our brain constantly needs to solve. 
 
This Research Topic examines how attentional control is guided by sensory predictions, prior knowledge, reward, task sets, and emotional factors. Moreover, the neural signatures of these mechanisms are investigated in Original Research Articles or summarized in Review, Perspective and Hypothesis and Theory Articles. Findings from a wide range of state-of-the-art complementary neuroscientific methods such as fMRI, M/EEG, TMS, and ALE-based meta-analysis are presented. 
 
The collection of papers of this Research Topic provides an overview over our current knowledge in the field and also presents novel stimulating hypotheses on how attention is controlled in the human brain. It moreover bridges the gap to other disciplines such as decision-making and social and affective neuroscience.

Attention, predictions and expectations, and their violation: attentional control in the human brain

Inferring the environment's statistical structure and adapting behavior accordingly is a fundamental modus operandi of the brain. A simple form of this faculty based on spatial attentional orienting can be studied with Posner's location-cueing paradigm in which a cue indicates the target location with a known probability. The present study focuses on a more complex version of this task, where probabilistic context (percentage of cue validity) changes unpredictably over time, thereby creating a volatile environment. Saccadic response speed (RS) was recorded in 15 subjects and used to estimate subject-specific parameters of a Bayesian learning scheme modeling the subjects' trial-by-trial updates of beliefs. Different response models—specifying how computational states translate into observable behavior—were compared using Bayesian model selection. Saccadic RS was most plausibly explained as a function of the precision of the belief about the causes of sensory input. This finding is in accordance with current Bayesian theories of brain function, and specifically with the proposal that spatial attention is mediated by a precision-dependent gain modulation of sensory input. Our results provide empirical support for precision-dependent changes in beliefs about saccade target locations and motivate future neuroimaging and neuropharmacological studies of how Bayesian inference may determine spatial attention.

Spatial Attention, Precision, and Bayesian Inference: A Study of Saccadic Response Speed

To behave adaptively, an organism must balance the accurate maintenance of information stored in working memory with the ability to update that information when the context changes. This trade-off between fidelity and flexibility may depend upon the anticipated likelihood that updating will be necessary. To address the neurobiological basis of anticipatory optimization, we acquired functional magnetic resonance imaging data, while healthy human subjects performed a modified delayed-response task. This task used cues that predicted memory updating, with high or low probability, followed by a contingent updating or maintenance event. This enabled us to compare behavior and neuronal activity during conditions in which updating was anticipated with high and low probability, and measure responses to expected and unexpected memory updating. Based on the known role of dopamine in cognitive flexibility and working memory updating, we hypothesized that differences in anticipatory set would be manifest in the dopaminergic midbrain and striatum. Consistent with our predictions, we identified sustained activation in the dopaminergic midbrain and the striatum, associated with anticipations of high versus low updating probability. We also found that this anticipatory factor affected neural responses to subsequent updating processes, which suppressed, rather than elevated, midbrain and striatal activity. Our study addresses for the first time an important and hitherto understudied aspect of working memory.

Working Memory and Anticipatory Set Modulate Midbrain and Putamen Activity

This paper reviews the foundation for a role of the human anterior insular cortex (AIC) in emotional awareness, defined as the conscious experience of emotions. We first introduce the neuroanatomical features of AIC and existing findings on emotional awareness. Using empathy, the awareness and understanding of other people's emotional states, as a test case, we then present evidence to demonstrate: 1) AIC and anterior cingulate cortex (ACC) are commonly coactivated as revealed by a meta‐analysis, 2) AIC is functionally dissociable from ACC, 3) AIC integrates stimulus‐driven and top‐down information, and 4) AIC is necessary for emotional awareness. We propose a model in which AIC serves two major functions: integrating bottom‐up interoceptive signals with top‐down predictions to generate a current awareness state and providing descending predictions to visceral systems that provide a point of reference for autonomic reflexes. We argue that AIC is critical and necessary for emotional awareness. J. Comp. Neurol. 521:3371‐3388, 2013. © 2013 Wiley Periodicals, Inc.

Acetylcholine (ACh) is a neuromodulatory transmitter implicated in perception and learning under uncertainty. This study combined computational simulations and pharmaco-electroencephalography in humans, to test a formulation of perceptual inference based upon the free energy principle. This formulation suggests that ACh enhances the precision of bottom-up synaptic transmission in cortical hierarchies by optimizing the gain of supragranular pyramidal cells. Simulations of a mismatch negativity paradigm predicted a rapid trial-by-trial suppression of evoked sensory prediction error (PE) responses that is attenuated by cholinergic neuromodulation. We confirmed this prediction empirically with a placebo-controlled study of cholinesterase inhibition. Furthermore, using dynamic causal modeling, we found that drug-induced differences in PE responses could be explained by gain modulation in supragranular pyramidal cells in primary sensory cortex. This suggests that ACh adaptively enhances sensory precision by boosting bottom-up signaling when stimuli are predictable, enabling the brain to respond optimally under different levels of environmental uncertainty.

Free Energy, Precision and Learning: The Role of Cholinergic Neuromodulation

Recent formulations of attention—in terms of predictive coding—associate attentional gain with the expected precision of sensory information. Formal models of the Posner paradigm suggest that validity effects can be explained in a principled (Bayes optimal) fashion in terms of a cue-dependent setting of precision or gain on the sensory channels reporting anticipated target locations, which is updated selectively by invalid targets. This normative model is equipped with a biologically plausible process theory in the form of predictive coding, where precision is encoded by the gain of superficial pyramidal cells reporting prediction error. We used dynamic causal modeling to assess the evidence in magnetoencephalographic responses for cue-dependent and top-down updating of superficial pyramidal cell gain. Bayesian model comparison suggested that it is almost certain that differences in superficial pyramidal cells gain—and its top-down modulation—contribute to observed responses; and we could be more than 80% certain that anticipatory effects on post-synaptic gain are limited to visual (extrastriate) sources. These empirical results speak to the role of attention in optimizing perceptual inference and its formulation in terms of predictive coding.

The Age of Insight by Eric Kandel is a brutal and beautiful book. Its pages burgeon with beautiful images and beautiful ideas. The ideas are pursued with relentless honesty and diligence for more than 600 pages. There are parts of this book that should only be read in private. I know this after a slightly fraught flight to London, trying to read the book while covering its pictures of masturbating women with my boarding card—I did not want to offend the sensibilities of an Indian gentleman, who showed a polite interest in my reading material. I am not quite sure why I did this, perhaps because I am English; or perhaps because I found the pictures curiously arousing—despite their innocent titles {e.g. ‘Seated Woman in Armchair’ by Gustav Klimt [(1862–1918): c.1913], pencil and white chalk}. Happily, the book explained why I found them so alluring. 

THE AGE OF INSIGHT: THE QUEST TO UNDERSTAND THE UNCONSCIOUS IN ART, MIND, AND BRAIN, FROM VIENNA 1900 TO THE PRESENT By Eric R. Kandel 2012 New York: Random House ISBN: 978-1-4000-6871-5 Price: $40.00

Kandel’s treatment is a book of two parts. The first deals with innovative thinking and insights in science and art in turn of the century Vienna. The second overviews the neurobiology of perception and emotion, bringing the reader back to deep questions about perspective taking and neuroaesthetics. The premise that underpins both parts is that the brain is an inference machine, generating hypotheses and fantasies that are tested against sensory data. Put simply, the brain is—literally—a fantastic organ (fantastic: from Greek phantastikos , able to create mental images, from phantazesthai ). For me, the story starts with Hermann von Helmholtz (1821–94) and the notion of unconscious inference (Helmholtz, 1866/1962). Kandel places this story in the context of history and art, in an …

An improved algorithm for model-based analysis of evoked skin conductance responses☆

A dynamic system for the analysis of acoustic features and valence of aversive sounds in the human brain.

Traumatic spinal cord injury is often disabling and recovery of function is limited. As a consequence of damage, both spinal cord and brain undergo anatomical and functional changes. Besides clinical measures of recovery, biomarkers that can detect early anatomical and functional changes might be useful in determining clinical outcome—during the course of rehabilitation and recovery—as well as furnishing a tool to evaluate novel treatment interventions and their mechanisms of action. Recent evidence suggests an interesting three-way relationship between neurological deficit and changes in the spinal cord and of the brain and that, importantly, noninvasive magnetic resonance imaging techniques, both structural and functional, provide a sensitive tool to lay out these interactions. This review describes recent findings from multimodal imaging studies of remote anatomical changes (i.e., beyond the lesion site), cortical reorganization, and their relationship to clinical disability. These developments in this field may improve our understanding of effects on the nervous system that are attributable to the injury itself and will allow their distinction from changes that result from rehabilitation (i.e., functional retraining) and from interventions affecting the nervous system directly (i.e., neuroprotection or regeneration).

This paper considers agency in the setting of embodied or active inference. In brief, we associate a sense of agency with prior beliefs about action and ask what sorts of beliefs underlie optimal behavior. In particular, we consider prior beliefs that action minimizes the Kullback–Leibler (KL) divergence between desired states and attainable states in the future. This allows one to formulate bounded rationality as approximate Bayesian inference that optimizes a free energy bound on model evidence. We show that constructs like expected utility, exploration bonuses, softmax choice rules and optimism bias emerge as natural consequences of this formulation. Previous accounts of active inference have focused on predictive coding and Bayesian filtering schemes for minimizing free energy. Here, we consider variational Bayes as an alternative scheme that provides formal constraints on the computational anatomy of inference and action—constraints that are remarkably consistent with neuroanatomy. Furthermore, this scheme contextualizes optimal decision theory and economic (utilitarian) formulations as pure inference problems. For example, expected utility theory emerges as a special case of free energy minimization, where the sensitivity or inverse temperature (of softmax functions and quantal response equilibria) has a unique and Bayes-optimal solution—that minimizes free energy. This sensitivity corresponds to the precision of beliefs about behavior, such that attainable goals are afforded a higher precision or confidence. In turn, this means that optimal behavior entails a representation of confidence about outcomes that are under an agent's control.

Beginning at “with physiologically grounded models of neuroimaging data…” in the first paragraph of the Introduction, the citations are incorrect throughout the text. 
 
The correct citation(s) for each citation block, delineated by [X], can be found two blocks further on in the text. 
 
For example: in the Introduction section, the sentence “…with physiologically grounded models of neuroimaging data [4,5]” should instead cite reference [1] from the paragraph below. 
 
Consequently the last line of the manuscript is incorrect and should read: 
 
“Similarly, extensions of this model could also be used to better understand the effects of drugs, such as ketamine [70,71], or neuromodulators, such as acetylcholine [72], on the MMN. We hope to pursue this avenue of research in future work.”

Correction: A Neurocomputational Model of the Mismatch Negativity

This paper reviews recent developments under the free energy principle that introduce a normative perspective on classical economic (utilitarian) decision-making based on (active) Bayesian inference. It has been suggested that the free energy principle precludes novelty and complexity, because it assumes that biological systems—like ourselves—try to minimize the long-term average of surprise to maintain their homeostasis. However, recent formulations show that minimizing surprise leads naturally to concepts such as exploration and novelty bonuses. In this approach, agents infer a policy that minimizes surprise by minimizing the difference (or relative entropy) between likely and desired outcomes, which involves both pursuing the goal-state that has the highest expected utility (often termed “exploitation”) and visiting a number of different goal-states (“exploration”). Crucially, the opportunity to visit new states increases the value of the current state. Casting decision-making problems within a variational framework, therefore, predicts that our behavior is governed by both the entropy and expected utility of future states. This dissolves any dialectic between minimizing surprise and exploration or novelty seeking.

Cognitive impairment is common in patients with schizophrenia, and even those with relatively preserved function perform worse than healthy volunteers (HVs) on attentional tasks. This is consistent with the hypothesis that connectivity – in the frontoparietal network (FPN) activated during attention – is disrupted in schizophrenia. We examined attentional effects on connectivity in the FPN, in schizophrenia, using magnetoencephalography (MEG). Twenty-three HVs and 19 first-episode schizophrenia patients were scanned during a simple visual change test, known to activate the FPN, in which attention was monitored and directed with an orthogonal flicker-detection task. Dynamic causal modeling (DCM) of evoked responses was used to assess effective connectivity – and its modulation by changes in the attended stimulus dimension – in the following network: higher visual area; temporoparietal junction (TPJ); intraparietal sulcus (IPS); dorsal anterior cingulate cortex; and ventrolateral prefrontal cortex. The final MEG analysis included 18 HVs and 14 schizophrenia patients. While all participants were able to maintain attention, HVs responded slightly, but non-significantly, more accurately than schizophrenia patients. HVs, but not schizophrenia patients, exhibited greater cortical responses to attended visual changes. Bayesian model comparison revealed that a DCM with attention dependent changes in both top-down and bottom-up connections best explained responses by patients with schizophrenia, while in HVs the best model required only bottom-up changes. Quantitative comparison of connectivity estimates revealed a significant group difference in changes in the right IPS-TPJ connection: schizophrenia patients showed relative reductions in connectivity during attended stimulus changes. Crucially, this reduction predicted lower intelligence. These data are consistent with the hypothesis that functional dysconnections in the FPN contribute to cognitive impairment in schizophrenia.

Dysconnectivity in the Frontoparietal Attention Network in Schizophrenia

Network reconfiguration and working memory impairment in mesial temporal lobe epilepsy

Tracking Changes following Spinal Cord Injury : Insights from Neuroimaging

Reflections on agranular architecture: predictive coding in the motor cortex

Analysing connectivity with Granger causality and dynamic causal modelling

Anatomical connectivity and the resting state activity of large cortical networks

I greatly enjoyed reading Mark Solms’s piece on the conscious id. Mindful of writing this commentary, I noted (in the margins of the target article) points of contact between his formulation and our more formal—if somewhat dryer—treatment using Helmholtzian notions of free energy. It was clear, after a few pages, that I was not going to be able to cover every aspect of the remarkable consilience between the two approaches. Instead, I focus on substantiating Solms’s key conclusions from the perspective of hierarchical inference in the Bayesian brain.

Background The human brain presents a puzzling and challenging paradox: Despite a fixed anatomy, characterized by its connectivity, its functional repertoire is vast, enabling action, perception, and cognition. This contrasts with organs like the heart that have a dynamic anatomy but just one function. The resolution of this paradox may reside in the brain's network architecture, which organizes local interactions to cope with diverse environmental demands—ensuring adaptability, robustness, resilience to damage, efficient message passing, and diverse functionality from a fixed structure. This review asks how recent advances in understanding brain networks elucidate the brain’s many-to-one (degenerate) function-structure relationships. In other words, how does diverse function arise from an apparently static neuronal architecture? We conclude that the emergence of dynamic functional connectivity, from static structural connections, calls for formal (computational) approaches to neuronal information processing that may resolve the dialectic between structure and function. Schematic of the multiscale hierarchical organization of brain networks. Brain function or cognition can be described as the global integration of local (segregated) neuronal operations that underlies hierarchical message passing among cortical areas, and which is facilitated by hierarchical modular network architectures. Advances Much of our understanding of brain connectivity rests on the way that it is measured and modeled. We consider two complementary approaches: the first has its basis in graph theory that aims to describe the network topology of (undirected) connections of the sort measured by noninvasive brain imaging of anatomical connections and functional connectivity (correlations) between remote sites. This is compared with model-based definitions of context-sensitive (directed) effective connectivity that are grounded in the biophysics of neuronal interactions. Recent topological network analyses of brain circuits suggest that modular and hierarchical structural networks are particularly suited for the functional integration of local (functionally specialized) neuronal operations that underlie cognition. Measurements of spontaneous activity reveal functional connectivity patterns that are similar to structural connectivity, suggesting that structural networks constrain functional networks. However, task-related responses that require context-sensitive integration disclose a divergence between function and structure that appears to rest mainly on long-range connections. In contrast to methods that describe network topology phenomenologically, model-based theoretical and computational approaches focus on the mechanisms of neuronal interactions that accommodate the dynamic reconfiguration of effective connectivity. We highlight the consilience between hierarchical topologies (based on structural and functional connectivity) and the effective connectivity that would be required for hierarchical message passing of the sort suggested by computational neuroscience. Outlook In summary, neuronal interactions represent dynamics on a fixed structural connectivity that underlie cognition and behavior. Such divergence of function from structure is, perhaps, the most intriguing property of the brain and invites intensive future research. By studying the dynamics and self-organization of functional networks, we may gain insight into the true nature of the brain as the embodiment of the mind. The repertoire of functional networks rests upon the (hidden) structural architecture of connections that enables hierarchical functional integration. Understanding these networks will require theoretical models of neuronal processing that underlies cognition. How rich functionality emerges from the invariant structural architecture of the brain remains a major mystery in neuroscience. Recent applications of network theory and theoretical neuroscience to large-scale brain networks have started to dissolve this mystery. Network analyses suggest that hierarchical modular brain networks are particularly suited to facilitate local (segregated) neuronal operations and the global integration of segregated functions. Although functional networks are constrained by structural connections, context-sensitive integration during cognition tasks necessarily entails a divergence between structural and functional networks. This degenerate (many-to-one) function-structure mapping is crucial for understanding the nature of brain networks. The emergence of dynamic functional networks from static structural connections calls for a formal (computational) approach to neuronal information processing that may resolve this dialectic between structure and function.

Structural and Functional Brain Networks: From Connections to Cognition

Nonlinear coupling between occipital and motor cortex during motor imagery: A dynamic causal modeling study

Dynamic causal modelling of lateral interactions in the visual cortex

, (2013); 342  Science Hae-Jeong Park and Karl Friston Cognition Structural and Functional Brain Networks: From Connections to This copy is for your personal, non-commercial use only. clicking here. colleagues, clients, or customers by , you can order high-quality copies for your If you wish to distribute this article to others here. following the guidelines can be obtained by Permission to republish or repurpose articles or portions of articles ):  November 1, 2013  www.sciencemag.org (this information is current as of The following resources related to this article are available online at http://www.sciencemag.org/content/342/6158/1238411.full.html version of this article at: including high-resolution figures, can be found in the online Updated information and services, http://www.sciencemag.org/content/342/6158/1238411.full.html#related found at: can be related to this article A list of selected additional articles on the Science Web sites http://www.sciencemag.org/content/342/6158/1238411.full.html#ref-list-1 , 19 of which can be accessed free: cites 47 articles This article

Cognition Structural and Functional Brain Networks : From Connections to

The empirical investigation of unobservable psychological processes usually rests on operational definitions. As an alternative, we propose the use of explicit causal models. This is particularly useful in psychophysiology, where formal models can be expressed mathematically, exploiting biophysical constraints, and inverted to yield estimates of unobservable processes. In psychophysiology, recent advances have been made in causal modeling for skin conductance responses, which we discuss to exemplify the development of such models. Empirical evidence suggests that these methods have a greater validity compared to operational approaches. This review concludes by considering the theoretical implications for the field of psychophysiology and benefits for practical data analysis.

Model-based analysis of skin conductance responses: Towards causal models in psychophysiology.

Predicting IQ change from brain structure: A cross-validation study

This paper presents a model-based investigation of mechanisms underlying the reduction of mismatch negativity (MMN) amplitudes under the NMDA-receptor antagonist ketamine. We applied dynamic causal modeling and Bayesian model selection to data from a recent ketamine study of the roving MMN paradigm, using a cross-over, double-blind, placebo-controlled design. Our modeling was guided by a predictive coding framework that unifies contemporary "adaptation" and "model adjustment" MMN theories. Comparing a series of dynamic causal models that allowed for different expressions of neuronal adaptation and synaptic plasticity, we obtained 3 major results: 1) We replicated previous results that both adaptation and short-term plasticity are necessary to explain MMN generation per se; 2) we found significant ketamine effects on synaptic plasticity, but not adaptation, and a selective ketamine effect on the forward connection from left primary auditory cortex to superior temporal gyrus; 3) this model-based estimate of ketamine effects on synaptic plasticity correlated significantly with ratings of ketamine-induced impairments in cognition and control. Our modeling approach thus suggests a concrete mechanism for ketamine effects on MMN that correlates with drug-induced psychopathology. More generally, this demonstrates the potential of modeling for inferring on synaptic physiology, and its pharmacological modulation, from electroencephalography data.

Modeling ketamine effects on synaptic plasticity during the mismatch negativity.

MRI investigation of the sensorimotor cortex and the corticospinal tract after acute spinal cord injury: a prospective longitudinal study

This paper presents a heuristic proof (and simulations of a primordial soup) suggesting that life—or biological self-organization—is an inevitable and emergent property of any (ergodic) random dynamical system that possesses a Markov blanket. This conclusion is based on the following arguments: if the coupling among an ensemble of dynamical systems is mediated by short-range forces, then the states of remote systems must be conditionally independent. These independencies induce a Markov blanket that separates internal and external states in a statistical sense. The existence of a Markov blanket means that internal states will appear to minimize a free energy functional of the states of their Markov blanket. Crucially, this is the same quantity that is optimized in Bayesian inference. Therefore, the internal states (and their blanket) will appear to engage in active Bayesian inference. In other words, they will appear to model—and act on—their world to preserve their functional and structural integrity, leading to homoeostasis and a simple form of autopoiesis.

1. The symptoms Hallucinations (false perceptions) and delusions (false beliefs) are characteristic symptoms of schizophrenia. Typical hallucinations include: hearing people talking to you or about you, hearing a running commentary on your actions, and hearing your thoughts spoken aloud. Typical delusions include; believing that other people can hear your thoughts, believing that your actions are being controlled by external forces, and believing that people are sending you secret messages (Mellor 1970). When reporting these symptoms, patients are trying to describe extremely unusual experiences and, as is indicated by the typical verbatim examples given below, the symptom labels listed above do not fully capture these experiences (examples from Kambeitz-Ilankovic et al. 2012).

In this note, we assess the predictive validity of stochastic dynamic causal modeling (sDCM) of functional magnetic resonance imaging (fMRI) data, in terms of its ability to explain changes in the frequency spectrum of concurrently acquired electroencephalography (EEG) signal. We first revisit the heuristic model proposed in Kilner et al. (2005), which suggests that fMRI activation is associated with a frequency modulation of the EEG signal (rather than an amplitude modulation within frequency bands). We propose a quantitative derivation of the underlying idea, based upon a neural field formulation of cortical activity. In brief, dense lateral connections induce a separation of time scales, whereby fast (and high spatial frequency) modes are enslaved by slow (low spatial frequency) modes. This slaving effect is such that the frequency spectrum of fast modes (which dominate EEG signals) is controlled by the amplitude of slow modes (which dominate fMRI signals). We then use conjoint empirical EEG-fMRI data—acquired in epilepsy patients—to demonstrate the electrophysiological underpinning of neural fluctuations inferred from sDCM for fMRI.

The mismatch negativity (MMN) is an event related potential evoked by violations of regularity. Here, we present a model of the underlying neuronal dynamics based upon the idea that auditory cortex continuously updates a generative model to predict its sensory inputs. The MMN is then modelled as the superposition of the electric fields evoked by neuronal activity reporting prediction errors. The process by which auditory cortex generates predictions and resolves prediction errors was simulated using generalised (Bayesian) filtering – a biologically plausible scheme for probabilistic inference on the hidden states of hierarchical dynamical models. The resulting scheme generates realistic MMN waveforms, explains the qualitative effects of deviant probability and magnitude on the MMN – in terms of latency and amplitude – and makes quantitative predictions about the interactions between deviant probability and magnitude. This work advances a formal understanding of the MMN and – more generally – illustrates the potential for developing computationally informed dynamic causal models of empirical electromagnetic responses.

Psychedelic drugs produce profound changes in consciousness, but the underlying neurobiological mechanisms for this remain unclear. Spontaneous and induced oscillatory activity was recorded in healthy human participants with magnetoencephalography after intravenous infusion of psilocybin—prodrug of the nonselective serotonin 2A receptor agonist and classic psychedelic psilocin. Psilocybin reduced spontaneous cortical oscillatory power from 1 to 50 Hz in posterior association cortices, and from 8 to 100 Hz in frontal association cortices. Large decreases in oscillatory power were seen in areas of the default-mode network. Independent component analysis was used to identify a number of resting-state networks, and activity in these was similarly decreased after psilocybin. Psilocybin had no effect on low-level visually induced and motor-induced gamma-band oscillations, suggesting that some basic elements of oscillatory brain activity are relatively preserved during the psychedelic experience. Dynamic causal modeling revealed that posterior cingulate cortex desynchronization can be explained by increased excitability of deep-layer pyramidal neurons, which are known to be rich in 5-HT2A receptors. These findings suggest that the subjective effects of psychedelics result from a desynchronization of ongoing oscillatory rhythms in the cortex, likely triggered by 5-HT2A receptor-mediated excitation of deep pyramidal cells.

Broadband Cortical Desynchronization Underlies the Human Psychedelic State

A Free Energy Formulation of Music Generation and Perception: Helmholtz Revisited

Model 3 parameter estimates are summarised in Fig.4. Mean (SD) intraclass correlation coefficient (ICC) between sessions 2 and 3 is 0.321 (0.253), which is comparable to functional connectivity results reported by Shehzad et al. (2009); however, ICCs between session 1 and 2 or 1 and 3 are poor. Overall . SPM8: fMRI data were realigned; anatomical scans underwent unified (“new”) segmentation, yielding a bias-corrected skull-stripped image; fMRI data were co-registered to this image; spatial normalisation used warps from unified segmentation; 6mm smoothing was applied.

Stochastic DCM of the DMN using resting-state fMRI: test-retest reliability

Network recon fi guration and working memory impairment in mesial temporal lobe epilepsy

Abstracts of Presentations at the International Conference on Basic and Clinical Multimodal Imaging (BaCI), a Joint Conference of the International Society for Neuroimaging in Psychiatry (ISNIP), the International Society for Functional Source Imaging (ISFSI), the International Society for Bioelectr

Dynamic causal modeling (DCM) provides a framework for the analysis of effective connectivity among neuronal subpopulations that subtend invasive (electrocorticograms and local field potentials) and non-invasive (electroencephalography and magnetoencephalography) electrophysiological responses. This paper reviews the suite of neuronal population models including neural masses, fields and conductance-based models that are used in DCM. These models are expressed in terms of sets of differential equations that allow one to model the synaptic underpinnings of connectivity. We describe early developments using neural mass models, where convolution-based dynamics are used to generate responses in laminar-specific populations of excitatory and inhibitory cells. We show that these models, though resting on only two simple transforms, can recapitulate the characteristics of both evoked and spectral responses observed empirically. Using an identical neuronal architecture, we show that a set of conductance based models—that consider the dynamics of specific ion-channels—present a richer space of responses; owing to non-linear interactions between conductances and membrane potentials. We propose that conductance-based models may be more appropriate when spectra present with multiple resonances. Finally, we outline a third class of models, where each neuronal subpopulation is treated as a field; in other words, as a manifold on the cortical surface. By explicitly accounting for the spatial propagation of cortical activity through partial differential equations (PDEs), we show that the topology of connectivity—through local lateral interactions among cortical layers—may be inferred, even in the absence of spatially resolved data. We also show that these models allow for a detailed analysis of structure–function relationships in the cortex. Our review highlights the relationship among these models and how the hypothesis asked of empirical data suggests an appropriate model class.

This paper considers psychotic symptoms in terms of false inferences or beliefs. It is based on the notion that the brain is an inference machine that actively constructs hypotheses to explain or predict its sensations. This perspective provides a normative (Bayes-optimal) account of action and perception that emphasizes probabilistic representations; in particular, the confidence or precision of beliefs about the world. We will consider hallucinosis, abnormal eye movements, sensory attenuation deficits, catatonia, and delusions as various expressions of the same core pathology: namely, an aberrant encoding of precision. From a cognitive perspective, this represents a pernicious failure of metacognition (beliefs about beliefs) that can confound perceptual inference. In the embodied setting of active (Bayesian) inference, it can lead to behaviors that are paradoxically more accurate than Bayes-optimal behavior. Crucially, this normative account is accompanied by a neuronally plausible process theory based upon hierarchical predictive coding. In predictive coding, precision is thought to be encoded by the post-synaptic gain of neurons reporting prediction error. This suggests that both pervasive trait abnormalities and florid failures of inference in the psychotic state can be linked to factors controlling post-synaptic gain – such as NMDA receptor function and (dopaminergic) neuromodulation. We illustrate these points using biologically plausible simulations of perceptual synthesis, smooth pursuit eye movements and attribution of agency – that all use the same predictive coding scheme and pathology: namely, a reduction in the precision of prior beliefs, relative to sensory evidence.

In systems biology, questions concerning the molecular and cellular makeup of an organism are of utmost importance, especially when trying to understand how unreliable components—like genetic circuits, biochemical cascades, and ion channels, among others—enable reliable and adaptive behaviour. The repertoire and speed of biological computations are limited by thermodynamic or metabolic constraints: an example can be found in neurons, where fluctuations in biophysical states limit the information they can encode—with almost 20–60% of the total energy allocated for the brain used for signalling purposes, either via action potentials or by synaptic transmission. Here, we consider the imperatives for neurons to optimise computational and metabolic efficiency, wherein benefits and costs trade-off against each other in the context of self-organised and adaptive behaviour. In particular, we try to link information theoretic (variational) and thermodynamic (Helmholtz) free-energy formulations of neuronal processing and show how they are related in a fundamental way through a complexity minimisation lemma.

Early visual learning induces long-lasting connectivity changes during rest in the human brain

Why do brains have so many connections? The principles exposed by Andy Clark provide answers to questions like this by appealing to the notion that brains distil causal regularities in the sensorium and embody them in models of their world. For example, connections embody the fact that causes have particular consequences. This commentary considers the imperatives for this form of embodiment.

A Treatment-Resistant Default Mode Subnetwork in Major Depression

The mismatch negativity (MMN) is a differential brain response to violations of learned regularities. It has been used to demonstrate that the brain learns the statistical structure of its environment and predicts future sensory inputs. However, the algorithmic nature of these computations and the underlying neurobiological implementation remain controversial. This article introduces a mathematical framework with which competing ideas about the computational quantities indexed by MMN responses can be formalized and tested against single-trial EEG data. This framework was applied to five major theories of the MMN, comparing their ability to explain trial-by-trial changes in MMN amplitude. Three of these theories (predictive coding, model adjustment, and novelty detection) were formalized by linking the MMN to different manifestations of the same computational mechanism: approximate Bayesian inference according to the free-energy principle. We thereby propose a unifying view on three distinct theories of the MMN. The relative plausibility of each theory was assessed against empirical single-trial MMN amplitudes acquired from eight healthy volunteers in a roving oddball experiment. Models based on the free-energy principle provided more plausible explanations of trial-by-trial changes in MMN amplitude than models representing the two more traditional theories (change detection and adaptation). Our results suggest that the MMN reflects approximate Bayesian learning of sensory regularities, and that the MMN-generating process adjusts a probabilistic model of the environment according to prediction errors.

The visual cortex is sensitive to emotional stimuli. This sensitivity is typically assumed to arise when amygdala modulates visual cortex via backwards connections. Using human fMRI, we compared dynamic causal connectivity models of sensitivity with fearful faces. This model comparison tested whether amygdala modulates distinct cortical areas, depending on dynamic or static face presentation. The ventral temporal fusiform face area showed sensitivity to fearful expressions in static faces. However, for dynamic faces, we found fear sensitivity in dorsal motion-sensitive areas within hMT+/V5 and superior temporal sulcus. The model with the greatest evidence included connections modulated by dynamic and static fear from amygdala to dorsal and ventral temporal areas, respectively. According to this functional architecture, amygdala could enhance encoding of fearful expression movements from video and the form of fearful expressions from static images. The amygdala may therefore optimize visual encoding of socially charged and salient information.

The danger of systematic bias in group-level FMRI-lag-based causality estimation

Global network dynamics over distributed brain areas emerge from the local dynamics of each brain area. Conversely, global dynamics constrain local activity such that the whole system becomes self-organizing. The implicit coupling between local and global scales induces a form of circular causality that is characteristic of complex, coupled systems that show self-organization, such as the brain. Here we present a network model based on spiking neurons at the local level and large-scale anatomic connectivity matrices at the global level. We demonstrate that this multiscale network displays endogenous or autonomous dynamics of the sort observed in resting-state studies. Our special focus here is on the genesis of itinerant (wandering) dynamics and the role of multistable attractors, which are involved in the generation of empirically known functional connectivity patterns, if the global coupling causes the dynamics to operate in the critical regime. Our results provide once again support for the hypothesis that endogenous brain activity is critical.

If perception corresponds to hypothesis testing (Gregory, 1980); then visual searches might be construed as experiments that generate sensory data. In this work, we explore the idea that saccadic eye movements are optimal experiments, in which data are gathered to test hypotheses or beliefs about how those data are caused. This provides a plausible model of visual search that can be motivated from the basic principles of self-organized behavior: namely, the imperative to minimize the entropy of hidden states of the world and their sensory consequences. This imperative is met if agents sample hidden states of the world efficiently. This efficient sampling of salient information can be derived in a fairly straightforward way, using approximate Bayesian inference and variational free-energy minimization. Simulations of the resulting active inference scheme reproduce sequential eye movements that are reminiscent of empirically observed saccades and provide some counterintuitive insights into the way that sensory evidence is accumulated or assimilated into beliefs about the world.

Functional MRI evaluation of therapeutic STN DBS in Parkinson's disease

Self-organisation, inference and cognition: comment on "Consciousness, crosstalk, and the mereological fallacy: an evolutionary perspective" by Rodrick Wallace.

The consideration of time or dynamics is fundamental for all aspects of mental activity--perception, cognition, and emotion--because the main feature of brain activity is the continuous change of the underlying brain states even in a constant environment. The application of nonlinear dynamics to the study of brain activity began to flourish in the 1990s when combined with empirical observations from modern morphological and physiological observations. This book offers perspectives on brain dynamics that draw on the latest advances in research in the field. It includes contributions from both theoreticians and experimentalists, offering an eclectic treatment of fundamental issues.

Dynamic causal modelling (DCM) was originally proposed as a hypothesis driven procedure in which a small number of neurobiologically motivated models are compared. Model comparison in this context usually proceeds by individually fitting each model to data and then approximating the corresponding model evidence with a free energy bound. However, a recent trend has emerged for comparing very large numbers of models in a more exploratory manner. This led Friston and Penny (2011) to propose a posthoc approximation to the model evidence, which is computed by optimising only the largest (full) model of a set of models. The evidence for any (reduced) submodel is then obtained using a generalisation of ree energy bound ynamic causal modelling MRI onnectivity the Savage-Dickey density ratio (Dickey, 1971). The benefit of this post-hoc approach is a huge reduction in the computational time required for model fitting. This is because only a single model is fitted to data, allowing a potentially huge model space to be searched relatively quickly. In this paper, we explore the relationship between the free energy bound and post-hoc approximations to the model evidence in the context of deterministic (bilinear) dynamic causal models (DCMs) for functional magnetic resonance imaging data.

Interictal generalized epileptiform discharges may impair cognition. We used simultaneous video‐electroencephalography and functional imaging to quantify changes, induced by epileptiform discharges, in the task‐related activations during a spatial working‐memory paradigm. The number of epileptiform discharges increased during the task with its level of complexity, but were not significantly associated with wrong responses during the task. We observed hemodynamic responses in working‐memory related frontal‐lobe‐network, motor‐cortex, precuneus, and parietal lobes in the absence of epileptiform discharges. In the presence of epileptiform discharges during the task, task‐related hemodynamic changes were seen only in motor‐cortex, precuneus, and parietal lobes. These findings suggest that generalized epileptiform discharges during a high demanding working memory task may change the working memory‐related hemodynamic responses in frontal‐lobe‐network. Hum Brain Mapp 34:2910–2917, 2013. © 2012 Wiley Periodicals, Inc.

Imaging the interaction: Epileptic discharges, working memory, and behavior

Decoding episodic memory in ageing: A Bayesian analysis of activity patterns predicting memory

Dynamic causal modelling of precision and synaptic gain in visual perception — an EEG study

Why are you reading this abstract? In some sense, your answer will cast the exercise as valuable—but what is value? In what follows, we suggest that value is evidence or, more exactly, log Bayesian evidence. This implies that a sufficient explanation for valuable behavior is the accumulation of evidence for internal models of our world. This contrasts with normative models of optimal control and reinforcement learning, which assume the existence of a value function that explains behavior, where (somewhat tautologically) behavior maximizes value. In this paper, we consider an alternative formulation—active inference—that replaces policies in normative models with prior beliefs about the (future) states agents should occupy. This enables optimal behavior to be cast purely in terms of inference: where agents sample their sensorium to maximize the evidence for their generative model of hidden states in the world, and minimize their uncertainty about those states. Crucially, this formulation resolves the tautology inherent in normative models and allows one to consider how prior beliefs are themselves optimized in a hierarchical setting. We illustrate these points by showing that any optimal policy can be specified with prior beliefs in the context of Bayesian inference. We then show how these prior beliefs are themselves prescribed by an imperative to minimize uncertainty. This formulation explains the saccadic eye movements required to read this text and defines the value of the visual sensations you are soliciting.

Competitive dynamics in the brain: Comment on "Information flow dynamics in the brain" by M.I. Rabinovich et al.

In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: a b s t r a c t a r t i c l e i n f o Keywords: Statistical testing Sample-size Effect size Power Classical inference As an expert reviewer, it is sometimes necessary to ensure a paper is rejected. This can sometimes be achieved by highlighting improper statistical practice. This technical note provides guidance on how to critique the statistical analysis of neuroimaging studies to maximise the chance that the paper will be declined. We will review a series of critiques that can be applied universally to any neuroimaging paper and consider responses to potential rebuttals that reviewers might encounter from authors or editors. Introduction This technical note is written for reviewers who may not have sufficient statistical expertise to provide an informed critique during the peer-reviewed process, but would like to recommend rejection on the basis of inappropriate or invalid statistical analysis. This guidance follows the 10 simple rules format and hopes to provide useful tips and criticisms for reviewers who find themselves in this difficult position. These rules are presented for reviewers in an ironic way 1 that makes it easier (and hopefully more entertaining) to discuss the issues from the point of view of both the reviewer and author — and to caricature both sides of the arguments. Some key issues are presented more formally in (non-ironic) appendices. There is a perceived need to reject peer-reviewed papers with the advent of open access publishing and the large number of journals available to authors. Clearly, there may be idiosyncratic reasons to block a paper – to ensure your precedence in the literature, personal rivalry etc. – however, we will assume that there is an imperative to reject papers for the good of the community: handling editors are often happy to receive recommendations to decline a paper. This is because they are placed under pressure to maintain a high rejection rate. This pressure is usually exerted by the editorial board (and publishers) and enforced by circulating quantitative information about their rejection rates (i.e., naming and shaming lenient editors). All journals want to maximise rejection rates, because this increases the quality of submissions, increases their impact factor …

' s personal copy Comments and Controversies Ten ironic rules for non-statistical reviewers

No evidence for a negative prediction error signal in peripheral indicators of sympathetic arousal

Deep brain stimulation of the subthalamic nucleus (STN DBS) has become an accepted treatment for patients experiencing the motor complications of Parkinson's disease (PD). While its successes are becoming increasingly apparent, the mechanisms underlying its action remain unclear. Multiple studies using radiotracer-based imaging have investigated DBS-induced regional changes in neural activity. However, little is known about the effect of DBS on connectivity within neural networks; in other words, whether DBS impacts upon functional integration of specialized regions of cortex. In this work, we report the first findings of fMRI in 10 subjects with PD and fully implanted DBS hardware receiving efficacious stimulation. Despite the technical demands associated with the safe acquisition of fMRI data from patients with implanted hardware, robust activation changes were identified in the insula cortex and thalamus in response to therapeutic STN DBS. We then quantified the neuromodulatory effects of DBS and compared sixteen dynamic causal models of effective connectivity between the two identified nodes. Using Bayesian model comparison, we found unequivocal evidence for the modulation of extrinsic (between region), i.e. cortico-thalamic and thalamo-cortical connections. Using Bayesian model parameter averaging we found that during voluntary movements, DBS reversed the effective connectivity between regions of the cortex and thalamus. This casts the therapeutic effects of DBS in a fundamentally new light, emphasising a role in changing distributed cortico-subcortical interactions. We conclude that STN DBS does impact upon the effective connectivity between the cortex and thalamus by changing their sensitivities to extrinsic afferents. Furthermore, we confirm that fMRI is both feasible and is tolerated well by these patients provided strict safety measures are adhered to.

Therapeutic Subthalamic Nucleus Deep Brain Stimulation Reverses Cortico-Thalamic Coupling during Voluntary Movements in Parkinson's Disease

This study addresses the neuronal representation of aversive sounds that are perceived as unpleasant. Functional magnetic resonance imaging in humans demonstrated responses in the amygdala and auditory cortex to aversive sounds. We show that the amygdala encodes both the acoustic features of a stimulus and its valence (perceived unpleasantness). Dynamic causal modeling of this system revealed that evoked responses to sounds are relayed to the amygdala via auditory cortex. While acoustic features modulate effective connectivity from auditory cortex to the amygdala, the valence modulates the effective connectivity from amygdala to the auditory cortex. These results support a complex (recurrent) interaction between the auditory cortex and amygdala based on object-level analysis in the auditory cortex that portends the assignment of emotional valence in amygdala that in turn influences the representation of salient information in auditory cortex.

Features versus Feelings: Dissociable Representations of the Acoustic Features and Valence of Aversive Sounds

Pablo Campo, Marta I. Garrido, Rosalyn J. Moran, Fernando Maestú, Irene Garcı́a-Morales, Antonio Gil-Nagel, Francisco del Pozo, Raymond J. Dolan and Karl J. Friston Department of Basic Psychology, Autonoma University of Madrid, 28049 Madrid, Spain, Center for Biomedical Technology, Laboratory of Cognitive and Computational Neuroscience, Complutense University of Madrid–Polytechnic University of Madrid, 28223 Madrid, Spain, Institute of Neurology, Wellcome Trust Centre for Neuroimaging, University College London, London WC1N3BG, UK, Epilepsy Unit, Department of Neurology, University Hospital of San Carlos, 28040 Madrid, Spain and Epilepsy Unit, Department of Neurology, Hospital Ruber Internacional, 28034 Madrid, Spain

Effective Connectivity Analysis : DCM Determining effective connectivity requires a causal model of the interactions among the constituents of the neural network subject to study

This paper describes a free energy principle that tries to explain the ability of biological systems to resist a natural tendency to disorder. It appeals to circular causality of the sort found in synergetic formulations of self-organization (e.g., the slaving principle) and models of coupled dynamical systems, using nonlinear Fokker Planck equations. Here, circular causality is induced by separating the states of a random dynamical system into external and internal states, where external states are subject to random fluctuations and internal states are not. This reduces the problem to finding some (deterministic) dynamics of the internal states that ensure the system visits a limited number of external states; in other words, the measure of its (random) attracting set, or the Shannon entropy of the external states is small. We motivate a solution using a principle of least action based on variational free energy (from statistical physics) and establish the conditions under which it is formally equivalent to the information bottleneck method. This approach has proved useful in understanding the functional architecture of the brain. The generality of variational free energy minimisation and corresponding information theoretic formulations may speak to interesting applications beyond the neurosciences; e.g., in molecular or evolutionary biology.

The default mode network (DMN) has recently attracted widespread interest. Previous studies have found that task-related processing can induce deactivation and changes in the functional connectivity of this network. However, it remains unclear how tasks modulate the underlying effective connectivity within the DMN. Using recent advances in dynamic causal modeling (DCM), we investigated the modulatory effect of (gender judgment) task performance on directed connectivity within the DMN. Sixteen healthy subjects were scanned twice: at rest and while performing a gender judgment task. Group independent component analysis was used to identify independent spatial components. Four subject-specific regions of interest (ROIs) were defined according to the ensuing default mode component: the posterior cingulate cortex, the left lateral parietal cortex, the right lateral parietal cortex, and the medial prefrontal cortex. Effective connectivity among these regions was then characterized with stochastic DCM, revealing enhanced (extrinsic) between region connectivity within the DMN during task sessions – and a universal decrease in (intrinsic) self-inhibition – relative to resting sessions. These results suggest a distributed but systematic modulatory effect of cognitive and attentional set on the effective connectivity subtending the DMN: an effect that increases its sensitivity to inputs and may optimize distributed processing during task performance.

Task-Dependent Modulation of Effective Connectivity within the Default Mode Network

Accumulating evidence suggests a role for the medial temporal lobe (MTL) in working memory (WM). However, little is known concerning its functional interactions with other cortical regions in the distributed neural network subserving WM. To reveal these, we availed of subjects with MTL damage and characterized changes in effective connectivity while subjects engaged in WM task. Specifically, we compared dynamic causal models, extracted from magnetoencephalographic recordings during verbal WM encoding, in temporal lobe epilepsy patients (with left hippocampal sclerosis) and controls. Bayesian model comparison indicated that the best model (across subjects) evidenced bilateral, forward, and backward connections, coupling inferior temporal cortex (ITC), inferior frontal cortex (IFC), and MTL. MTL damage weakened backward connections from left MTL to left ITC, a decrease accompanied by strengthening of (bidirectional) connections between IFC and MTL in the contralesional hemisphere. These findings provide novel evidence concerning functional interactions between nodes of this fundamental cognitive network and sheds light on how these interactions are modified as a result of focal damage to MTL. The findings highlight that a reduced (top-down) influence of the MTL on ipsilateral language regions is accompanied by enhanced reciprocal coupling in the undamaged hemisphere providing a first demonstration of “connectional diaschisis.”

Remote Effects of Hippocampal Sclerosis on Effective Connectivity during Working Memory Encoding: A Case of Connectional Diaschisis?

Andre M. Bastos,1,2,6 W. Martin Usrey,1,3,4 Rick A. Adams,8 George R. Mangun,2,3,5 Pascal Fries,6,7 and Karl J. Friston8,* 1Center for Neuroscience 2Center for Mind and Brain 3Department of Neurology 4Department of Neurobiology, Physiology and Behavior 5Department of Psychology University of California, Davis, Davis, CA 95618 USA 6Ernst Strüngmann Institute (ESI) for Neuroscience in Cooperation with Max Planck Society, Deutschordenstraße 46, 60528 Frankfurt, Germany 7Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Kapittelweg 29, 6525 EN Nijmegen, Netherlands 8The Wellcome Trust Centre for Neuroimaging, University College London, Queen Square, London WC1N 3BG, UK *Correspondence: k.friston@ucl.ac.uk http://dx.doi.org/10.1016/j.neuron.2012.10.038

Neuron Perspective Canonical Microcircuits for Predictive Coding

The influence of spontaneous activity on stimulus processing in primary visual cortex

Parental substance abuse and function of the motivation and behavioral inhibition systems in drug-naïve youth

Estimating the value of potential actions is crucial for learning and adaptive behavior. We know little about how the human brain represents action-specific value outside of motor areas. This is, in part, due to a difficulty in detecting the neural correlates of value using conventional (region of interest) functional magnetic resonance imaging (fMRI) analyses, due to a potential distributed representation of value. We address this limitation by applying a recently developed multivariate decoding method to high-resolution fMRI data in subjects performing an instrumental learning task. We found evidence for action-specific value signals in circumscribed regions, specifically ventromedial prefrontal cortex, putamen, thalamus, and insula cortex. In contrast, action-independent value signals were more widely represented across a large set of brain areas. Using multivariate Bayesian model comparison, we formally tested whether value–specific responses are spatially distributed or coherent. We found strong evidence that both action-specific and action-independent value signals are represented in a distributed fashion. Our results suggest that a surprisingly large number of classical reward-related areas contain distributed representations of action-specific values, representations that are likely to mediate between reward and adaptive behavior.

Action-Specific Value Signals in Reward-Related Regions of the Human Brain

Attentional orientation to a spatial cue and reorientation—after invalid cueing—are mediated by two distinct networks in the human brain. A bilateral dorsal frontoparietal network, comprising the intraparietal sulcus (IPS) and the frontal eye fields (FEF), controls the voluntary deployment of attention and may modulate visual cortex in preparation for upcoming stimulation. In contrast, reorienting attention to invalidly cued targets engages a right-lateralized ventral frontoparietal network comprising the temporoparietal junction (TPJ) and ventral frontal cortex. The present fMRI study investigated the functional architecture of these two attentional systems by characterizing effective connectivity during lateralized orienting and reorienting of attention, respectively. Subjects performed a modified version of Posner's location-cueing paradigm. Dynamic causal modeling (DCM) of regional responses in the dorsal and ventral network, identified in a conventional (SPM) whole-brain analysis, was used to compare different functional architectures. Bayesian model selection showed that top-down connections from left and right IPS to left and right visual cortex, respectively, were modulated by the direction of attention. Moreover, model evidence was highest for a model with directed influences from bilateral IPS to FEF, and reciprocal coupling between right and left FEF. Invalid cueing enhanced forward connections from visual areas to right TPJ, and directed influences from right TPJ to right IPS and IFG (inferior frontal gyrus). These findings shed further light on the functional organization of the dorsal and ventral attentional network and support a context-sensitive lateralization in the top-down (backward) mediation of attentional orienting and the bottom-up (forward) effects of invalid cueing.

Deconstructing the Architecture of Dorsal and Ventral Attention Systems with Dynamic Causal Modeling

The mechanisms underlying anesthesia-induced loss of consciousness remain a matter of debate. Recent electrophysiological reports suggest that while initial propofol infusion provokes an increase in fast rhythms (from beta to gamma range), slow activity (from delta to alpha range) rises selectively during loss of consciousness. Dynamic causal modeling was used to investigate the neural mechanisms mediating these changes in spectral power in humans. We analyzed source-reconstructed data from frontal and parietal cortices during normal wakefulness, propofol-induced mild sedation, and loss of consciousness. Bayesian model selection revealed that the best model for explaining spectral changes across the three states involved changes in corticothalamic interactions. Compared with wakefulness, mild sedation was accounted for by an increase in thalamic excitability, which did not further increase during loss of consciousness. In contrast, loss of consciousness per se was accompanied by a decrease in backward corticocortical connectivity from frontal to parietal cortices, while thalamocortical connectivity remained unchanged. These results emphasize the importance of recurrent corticocortical communication in the maintenance of consciousness and suggest a direct effect of propofol on cortical dynamics.

Connectivity Changes Underlying Spectral EEG Changes during Propofol-Induced Loss of Consciousness

This paper introduces a model of oculomotor control during the smooth pursuit of occluded visual targets. This model is based upon active inference, in which subjects try to minimise their (proprioceptive) prediction error based upon posterior beliefs about the hidden causes of their (exteroceptive) sensory input. Our model appeals to a single principle – the minimisation of variational free energy – to provide Bayes optimal solutions to the smooth pursuit problem. However, it tries to accommodate the cardinal features of smooth pursuit of partially occluded targets that have been observed empirically in normal subjects and schizophrenia. Specifically, we account for the ability of normal subjects to anticipate periodic target trajectories and emit pre-emptive smooth pursuit eye movements – prior to the emergence of a target from behind an occluder. Furthermore, we show that a single deficit in the postsynaptic gain of prediction error units (encoding the precision of posterior beliefs) can account for several features of smooth pursuit in schizophrenia: namely, a reduction in motor gain and anticipatory eye movements during visual occlusion, a paradoxical improvement in tracking unpredicted deviations from target trajectories and a failure to recognise and exploit regularities in the periodic motion of visual targets. This model will form the basis of subsequent (dynamic causal) models of empirical eye tracking measurements, which we hope to validate, using psychopharmacology and studies of schizophrenia.

Smooth Pursuit and Visual Occlusion: Active Inference and Oculomotor Control in Schizophrenia

This commentary considers how far one can go in making inferences about functional modularity or segregation, based on the sorts of analyses used by Caplan & Waters in relation to the underlying neuronal infrastructure. Specifically, an attempt is made to relate the “functionalist” approach adopted in the target article to “neuroreductionist” perspectives

ALTERED INTERACTIONS WITHIN NEURAL NETWORK SUPPORTING VERBAL WORKING MEMORY DUE TO HIPPOCAMPAL SCLEROSIS

Functional neurosurgery has afforded the opportunity to assess interactions between populations of neurons in the human cerebral cortex and basal ganglia in patients with Parkinson's disease (PD). Interactions occur over a wide range of frequencies, and the functional significance of those >30 Hz is particularly unclear. Do they improve movement, and, if so, in what way? We acquired simultaneously magnetoencephalography and direct recordings from the subthalamic nucleus (STN) in 17 PD patients. We examined the effect of synchronous and sequential finger movements and of the dopamine prodrug levodopa on induced power in the contralateral primary motor cortex (M1) and STN and on the coherence between the two structures. We observed discrete peaks in M1 and STN power at 60–90 Hz and at 300–400 Hz. All these power peaks increased with movement and levodopa treatment. Only STN activity at 60–90 Hz was coherent with activity in M1. Directionality analysis showed that STN gamma activity at 60–90 Hz tended to drive gamma activity in M1. The effects of levodopa on both local and distant synchronization at 60–90 Hz correlated with the degree of improvement in bradykinesia-rigidity as did local STN activity at 300–400 Hz. Despite this, there were no effects of movement type, nor interactions between movement type and levodopa in the STN, nor in the coherence between STN and M1. We conclude that synchronization at 60–90 Hz in the basal ganglia cortical network is prokinetic but likely through a modulatory effect rather than any involvement in explicit motor processing.

Movement-Related Changes in Local and Long-Range Synchronization in Parkinson's Disease Revealed by Simultaneous Magnetoencephalography and Intracranial Recordings

This paper considers state-dependent dynamics that mediate perception in the brain. In particular, it considers the formal basis of self-organized instabilities that enable perceptual transitions during Bayes-optimal perception. The basic phenomena we consider are perceptual transitions that lead to conscious ignition (Dehaene and Changeux, 2011) and how they depend on dynamical instabilities that underlie chaotic itinerancy (Breakspear, 2001; Tsuda, 2001) and self-organized criticality (Beggs and Plenz, 2003; Plenz and Thiagarajan, 2007; Shew et al., 2011). Our approach is based on a dynamical formulation of perception as approximate Bayesian inference, in terms of variational free energy minimization. This formulation suggests that perception has an inherent tendency to induce dynamical instabilities (critical slowing) that enable the brain to respond sensitively to sensory perturbations. We briefly review the dynamics of perception, in terms of generalized Bayesian filtering and free energy minimization, present a formal conjecture about self-organized instability and then test this conjecture, using neuronal (numerical) simulations of perceptual categorization.

Background Traumatic spinal cord injury (SCI) leads to disruption of axonal architecture and macroscopic tissue loss with impaired information flow between the brain and spinal cord—the presumed basis of ensuing clinical impairment. Objective The authors used a clinically viable, multimodal MRI protocol to quantify the axonal integrity of the cranial corticospinal tract (CST) and to establish how microstructural white matter changes in the CST are related to cross-sectional spinal cord area and cortical reorganisation of the sensorimotor system in subjects with traumatic SCI. Methods Nine volunteers with cervical injuries resulting in bilateral motor impairment and 14 control subjects were studied. The authors used diffusion tensor imaging to assess white matter integrity in the CST, T1-weighted imaging to measure cross-sectional spinal cord area and functional MRI to compare motor task-related brain activations. The relationships among microstructural, macrostructural and functional measures were assessed using regression analyses. Results Diffusion tensor imaging revealed significant differences in the CST of SCI subjects—compared with controls—in the pyramids, the internal capsule, the cerebral peduncle and the hand area. The microstructural white matter changes observed in the left pyramid predicted increased task-related responses in the left M1 leg area, while changes in the cerebral peduncle were predicted by reduced cord area. Conclusion The observed microstructural changes suggest trauma-related axonal degeneration and demyelination, which are related to cortical motor reorganisation and macrostructure. The extent of these changes may reflect the plasticity of motor pathways associated with cortical reorganisation. This clinically viable multimodal imaging approach is therefore appropriate for monitoring degeneration of central pathways and the evaluation of treatments targeting axonal repair in SCI.

Axonal integrity predicts cortical reorganisation following cervical injury

Stochastic dynamic causal modelling of fMRI data: Should we care about neural noise?

Waking and dreaming consciousness: Neurobiological and functional considerations

Adaptive behavior often exploits generalizations from past experience by applying them judiciously in new situations. This requires a means of quantifying the relative importance of prior experience and current information, so they can be balanced optimally. In this study, we ask whether the brain generalizes in an optimal way. Specifically, we used Bayesian learning theory and fMRI to test whether neuronal responses reflect context-sensitive changes in ambiguity or uncertainty about experience-dependent beliefs. We found that the hippocampus expresses clear ambiguity-dependent responses that are associated with an augmented rate of learning. These findings suggest candidate neuronal systems that may be involved in aberrations of generalization, such as over-confidence.

DCM for complex-valued data: Cross-spectra, coherence and phase-delays

Understanding processes that result from the interaction of multiple elements requires mathematical models of system dynamics. This increasingly important theme has led to the revitalization of “systems biology,” with a focus on molecular questions. However, system models have been used for much longer in computational neuroscience and neuroimaging to infer on causal mechanisms of neuronal dynamics, for example, effective connectivity. In this chapter, system models are reviewed for inferring effective connectivity from brain activity data obtained by functional magnetic resonance imaging or electroencephalography. Following an outline of general systems theory, a generic framework is provided for formalizing the description of systems; this guides the subsequent description of various models of effective connectivity. Attention is focused particularly on dynamic causal modeling (DCM), a Bayesian system identification approach which distinguishes between neuronal state equations and biophysical forward models, as well as methods for Bayesian model selection. 
 
Keywords: 
 
Synaptic plasticity; 
Neuromodulation; 
Dopamine; 
Acetylcholine; 
Dynamic causal modeling (DCM); 
Granger causality; 
Psychophysiological interactions; 
Structural equation modeling; 
Bayesian model selection

Abstract Gotts, Chow and Martin provide a very nice review of repetition priming and suppression that reaches a compelling conclusion—we need to look more closely at synchronization in learning and priming. Indeed, current modeling work focuses on this issue—namely, the dynamic causal modeling of electrophysiological responses to address the role of synchrony in Bayesian explaining away. This commentary revisits the nature and relationships among the four theories in Gotts et al. and nuances some of their empirical predictions. In particular, I emphasize precision or uncertainty in predictive coding as a unifying consideration.

What does functional MRI measure? Two complementary perspectives

The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order) in which cues are presented. These simulations provide a (Bayes-optimal) model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors) to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson's disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level.

Forum: Science & Society 489 Brain network: social media and the cognitive scientist

The problem of low variance voxels in statistical parametric mapping; a new hat avoids a ‘haircut’

Existing evidence suggests that reward and attentional networks function in concert and that activation in one system influences the other in a reciprocal fashion; however, the nature of these influences remains poorly understood. We therefore developed a three‐component task to assess the interaction effects of reward anticipation and conflict resolution on the behavioral performance and the activation of brain reward and attentional systems. Sixteen healthy adult volunteers aged 21–45 years were scanned with functional magnetic resonance imaging (fMRI) while performing the task. A two‐way repeated measures analysis of variance (ANOVA) with cue (reward vs. non‐reward) and target (congruent vs. incongruent) as within‐subjects factors was used to test for main and interaction effects. Neural responses to anticipation, conflict, and reward outcomes were tested. Behaviorally there were main effects of both reward cue and target congruency on reaction time. Neuroimaging results showed that reward anticipation and expected reward outcomes activated components of the attentional networks, including the inferior parietal and occipital cortices, whereas surprising non‐rewards activated the frontoinsular cortex bilaterally and deactivated the ventral striatum. In turn, conflict activated a broad network associated with cognitive control and motor functions. Interaction effects showed decreased activity in the thalamus, anterior cingulated gyrus, and middle frontal gyrus bilaterally when difficult conflict trials (e.g., incongruent targets) were preceded by reward cues; in contrast, the ventral striatum and orbitofrontal cortex showed greater activation during congruent targets preceded by reward cues. These results suggest that reward anticipation is associated with lower activation in attentional networks, possibly due to increased processing efficiency, whereas more difficult, conflict trials are associated with lower activity in regions of the reward system, possibly because such trials are experienced as less rewarding.

Effects of motivation on reward and attentional networks: an fMRI study

Background Traumatic spinal cord injury (SCI) leads to disruption of axons and macroscopic tissue loss. Using diffusion tensor imaging (DTI), we assessed degeneration of the corticospinal tract (CST) in the cervical cord above a traumatic lesion and explored its relationship with cervical atrophy, remote axonal changes within the cranial CST and upper limb function. Methods Nine cervical injured volunteers with bilateral motor and sensory impairment and ten controls were studied. DTI of the cervical cord and brain provided measurements of fractional anisotropy (FA), while anatomical MRI assessed cross-sectional spinal cord area (i.e. cord atrophy). Spinal and central regions of interest (ROI) included the bilateral CST in the cervical cord and brain. Regression analysis identified correlations between spinal FA and cranial FA in the CST and disability. Results In individuals with SCI, FA was significantly lower in both CSTs throughout the cervical cord and brain when compared with controls (p≤0.05). Reduced FA of the cervical cord in patients with SCI was associated with smaller cord area (p = 0.002) and a lower FA of the cranial CST at the internal capsule level (p = 0.001). Lower FA in the cervical CST also correlated with impaired upper limb function, independent of cord area (p = 0.03). Conclusion Axonal degeneration of the CST in the atrophic cervical cord, proximal to the site of injury, parallels cranial CST degeneration and is associated with disability. This DTI protocol can be used in longitudinal assessment of microstructural changes immediately following injury and may be utilised to predict progression and monitor interventions aimed at promoting spinal cord repair.

Degeneration of the Injured Cervical Cord Is Associated with Remote Changes in Corticospinal Tract Integrity and Upper Limb Impairment

Recent years have seen the emergence of an important new fundamental theory of brain function. This theory brings information-theoretic, Bayesian, neuroscientific, and machine learning approaches into a single framework whose overarching principle is the minimization of surprise (or, equivalently, the maximization of expectation). The most comprehensive such treatment is the “free-energy minimization” formulation due to Karl Friston (see e.g., Friston and Stephan, 2007; Friston, 2010a,b – see also Fiorillo, 2010; Thornton, 2010). A recurrent puzzle raised by critics of these models is that biological systems do not seem to avoid surprises. We do not simply seek a dark, unchanging chamber, and stay there. This is the “Dark-Room Problem.” Here, we describe the problem and further unpack the issues to which it speaks. Using the same format as the prolog of Eddington’s Space, Time, and Gravitation (Eddington, 1920) we present our discussion as a conversation between: an information theorist (Thornton), a physicist (Friston), and a philosopher (Clark).

Computational modeling of perceptual inference: A hierarchical Bayesian approach that allows for individual and contextual differences in weighting of input

Recognition of sequences of sequences using nonlinear dynamical systems

We review recent methodological developments within a parametric empirical Bayesian (PEB) framework for reconstructing intracranial sources of extracranial electroencephalographic (EEG) and magnetoencephalographic (MEG) data under linear Gaussian assumptions. The PEB framework offers a natural way to integrate multiple constraints (spatial priors) on this inverse problem, such as those derived from different modalities (e.g., from functional magnetic resonance imaging, fMRI) or from multiple replications (e.g., subjects). Using variations of the same basic generative model, we illustrate the application of PEB to three cases: (1) symmetric integration (fusion) of MEG and EEG; (2) asymmetric integration of MEG or EEG with fMRI, and (3) group-optimization of spatial priors across subjects. We evaluate these applications on multi-modal data acquired from 18 subjects, focusing on energy induced by face perception within a time–frequency window of 100–220 ms, 8–18 Hz. We show the benefits of multi-modal, multi-subject integration in terms of the model evidence and the reproducibility (over subjects) of cortical responses to faces.

A Parametric Empirical Bayesian Framework for the EEG/MEG Inverse Problem: Generative Models for Multi-Subject and Multi-Modal Integration

This chapter considers addiction from a purely theoretical point of view. It tries to substantiate the idea that addictive behaviour is a natural consequence of abnormal perceptual learning. In short, addictive behaviours emerge when behaviour confounds its own acquisition. Specifically, we consider what would happen if behaviour interfered with the neurotransmitter systems responsible for optimising the conditional certainty or precision of inferences about causal structure in the world. We will pursue this within a rather abstract framework provided by free-energy formulations of action and perception. Although this treatment does not touch upon many of the neurobiological or psychosocial issues in addiction research, it provides a principled framework within which to understand exchanges with the environment and how they can be disturbed. Our focus will be on behaviour as active inference and the key role of prior expectations. These priors play the role of policies in reinforcement learning and place crucial constraints on perceptual inference and subsequent action. A dynamical treatment of these policies suggests a fundamental distinction between fixed-point policies that lead to a single attractive state and itinerant policies that support wandering behavioural orbits among sets of attractive states. Itinerant policies may provide a useful metaphor for many forms of behaviour and, in particular, addiction. Under these sorts of policies, neuromodulatory (e.g., dopaminergic) perturbations can lead to false inference and consequent learning, which produce addictive and preservative behaviour.

British Journal of Psychiatry (1995), 167, 343-349Since the classic study of Ingvar & Franzen (1974),there have been many investigations of schizophreniaby functional brain imaging (Andreasen eta!, 1992).Most (â€”â€˜6001o)have observed a relative reduction infrontal metabolism in patients scanned at rest(hypofrontality). However, many studies (â€”400lo)found no evidence of hypofrontality and a fewobserved hyperfrontality. There are good reasons whyresting scans of schizophrenic patients should lead tocontradictory results. Mental activity is associatedwith detectable brain activity even when no overtbehaviour occurs (e.g. Stephan et al, 1995).Schizophrenic patients vary widely in their currentmental state, and thus varying patterns of cerebralblood flow are to be expected in unselected groups.Liddle eta! (1992) confirmed that current symptomsare related to regional cerebral blood flow (rCBF).Hypofrontality (particularly in the left dorsolateralprefrontal cortex (DLPFC)) wasfound to be associatedwith psychomotor poverty (poverty of speech,flattening of affect, and motor retardation).However, even though schizophrenic symptomssegregate into clusters, and different patterns ofresting cerebral blood flow can be associated withthese syndromes, it remains likely that a coreabnormality is present in all schizophrenic patients.An important approach to the problem of thevariability in mental states during brain imaging isto control mental state, at the time of scanning, byapplying a psychological challenge. This involvespresenting a task during the scan which elicitsspecificmental processes. This method can not only reducevariability between subjects, but also highlight brainareas of interest. For this purpose, various studieshave used psychological tasks sensitiveto frontal lobedamage. When normal volunteers perform suchtasks, there is an associated increase in frontal bloodflow. However, in schizophrenic patients, whoperform such tasks poorly, this increase is oftenreduced or absent (Weinberger, 1986). Thisobservation is particularly marked in patients withnegative features (Andreasen et a!, 1992). At the

performance of a verbal fluency task Regional brain activity in chronic schizophrenic patients during the

Perception is the foundation of cognition and is fundamental to our beliefs and consequent action planning. The Editorial (this issue) asks: “what mechanisms, if any, mediate between perceptual and cognitive processes?” It has recently been argued that attention might furnish such a mechanism. In this paper, we pursue the idea that action planning (motor preparation) is an attentional phenomenon directed toward kinesthetic signals. This rests on a view of motor control as active inference, where predictions of proprioceptive signals are fulfilled by peripheral motor reflexes. If valid, active inference suggests that attention should not be limited to the optimal biasing of perceptual signals in the exteroceptive (e.g., visual) domain but should also bias proprioceptive signals during movement. Here, we investigate this idea using a classical attention (Posner) paradigm cast in a motor setting. Specially, we looked for decreases in reaction times when movements were preceded by valid relative to invalid cues. Furthermore, we addressed the hierarchical level at which putative attentional effects were expressed by independently cueing the nature of the movement and the hand used to execute it. We found a significant interaction between the validity of movement and effector cues on reaction times. This suggests that attentional bias might be mediated at a low level in the motor hierarchy, in an intrinsic frame of reference. This finding is consistent with attentional enabling of top-down predictions of proprioceptive input and may rely upon the same synaptic mechanisms that mediate directed spatial attention in the visual system.

Increasing levels of depression after tryptophan depletion were associated with diminished neural activity in the ventral anterior cingulate, orbitofrontal cortex and caudate nucleus regions. In addition, depressive relapse attenuated cognitive task-related activation in the anterior cingulate cortex.

depletion.cognitive impairment following acute tryptophan Brain mechanisms associated with depressive relapse and

Dynamic modeling of neuronal responses in fMRI using cubature Kalman filtering

This review highlights the key role of modularity and the additive factors method in functional neuroimaging. Our focus is on structure–function mappings in the human brain and how these are disclosed by brain mapping. We describe how modularity of processing (and possibly processes) was a key point of reference for establishing functional segregation as a principle of brain organization. Furthermore, modularity plays a crucial role when trying to characterize distributed brain responses in terms of functional integration or coupling among brain areas. We consider additive factors logic and how it helped to shape the design and interpretation of studies at the inception of brain mapping, with a special focus on factorial designs. We look at factorial designs in activation experiments and in the context of lesion–deficit mapping. In both cases, the presence or absence of interactions among various experimental factors has proven essential in understanding the context-sensitive nature of distributed but modular processing and discerning the nature of (potentially degenerate) structure–function relationships in cognitive neuroscience.

Nucleus and Pulvinar Functional Imaging of the Human Lateral Geniculate

In this work, we show that electrophysiological responses during pitch perception are best explained by distributed activity in a hierarchy of cortical sources and, crucially, that the effective connectivity between these sources is modulated with pitch strength. Local field potentials were recorded in two subjects from primary auditory cortex and adjacent auditory cortical areas along the axis of Heschl's gyrus (HG) while they listened to stimuli of varying pitch strength. Dynamic causal modeling was used to compare system architectures that might explain the recorded activity. The data show that representation of pitch requires an interaction between nonprimary and primary auditory cortex along HG that is consistent with the principle of predictive coding.

Quiz • What is the most important characteristic of the cortical system in the brain?. Please give an answer with the consideration of the structure of multilayered neural network and 6 layers in cortex.

Dynamic causal modeling and Granger causality Comments on: The identification of interacting networks in the brain using fMRI: Model selection, causality and deconvolution

Generative models of neuroimaging and electrophysiological data present new opportunities for accessing hidden or latent brain states. Dynamic causal modeling (DCM) uses Bayesian model inversion and selection to infer the synaptic mechanisms underlying empirically observed brain responses. DCM for electrophysiological data, in particular, aims to estimate the relative strength of synaptic transmission at different cell types and via specific neurotransmitters. Here, we report a DCM validation study concerning inference on excitatory and inhibitory synaptic transmission, using different doses of a volatile anaesthetic agent (isoflurane) to parametrically modify excitatory and inhibitory synaptic processing while recording local field potentials (LFPs) from primary auditory cortex (A1) and the posterior auditory field (PAF) in the auditory belt region in rodents. We test whether DCM can infer, from the LFP measurements, the expected drug-induced changes in synaptic transmission mediated via fast ionotropic receptors; i.e., excitatory (glutamatergic) AMPA and inhibitory GABAA receptors. Cross- and auto-spectra from the two regions were used to optimise three DCMs based on biologically plausible neural mass models and specific network architectures. Consistent with known extrinsic connectivity patterns in sensory hierarchies, we found that a model comprising forward connections from A1 to PAF and backward connections from PAF to A1 outperformed a model with forward connections from PAF to A1 and backward connections from A1 to PAF and a model with reciprocal lateral connections. The parameter estimates from the most plausible model indicated that the amplitude of fast glutamatergic excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) behaved as predicted by previous neurophysiological studies. Specifically, with increasing levels of anaesthesia, glutamatergic EPSPs decreased linearly, whereas fast GABAergic IPSPs displayed a nonlinear (saturating) increase. The consistency of our model-based in vivo results with experimental in vitro results lends further validity to the capacity of DCM to infer on synaptic processes using macroscopic neurophysiological data.

Dynamic Causal Models and Physiological Inference: A Validation Study Using Isoflurane Anaesthesia in Rodents

In one of neuroimaging's key papers, Worsley et al. (1992) introduced the concept of a resolution element (resel) as an intuitive parametrisation of the roughness-adjusted search volume underlying random field theory's expression for corrected p-values. In another key development, Worsley and Friston (1995) showed that temporal correlation in a linear model reduced the effective degrees of freedom (eDF). Here, we illustrate a surprising connection between these quantities, which may have application to multiple comparison correction on data with elaborate statistical dependence that can make RFT over-conservative.

Over the past 20 years, neuroimaging has become a predominant technique in systems neuroscience. One might envisage that over the next 20 years the neuroimaging of distributed processing and connectivity will play a major role in disclosing the brain's functional architecture and operational principles. The inception of this journal has been foreshadowed by an ever-increasing number of publications on functional connectivity, causal modeling, connectomics, and multivariate analyses of distributed patterns of brain responses. I accepted the invitation to write this review with great pleasure and hope to celebrate and critique the achievements to date, while addressing the challenges ahead.

Academic Software Applications for Electromagnetic Brain Mapping Using MEG and EEG

corticocortical connections Distinct functions for direct and transthalamic

In this paper, we pursue recent observations that, through selective dendritic filtering, single neurons respond to specific sequences of presynaptic inputs. We try to provide a principled and mechanistic account of this selectivity by applying a recent free-energy principle to a dendrite that is immersed in its neuropil or environment. We assume that neurons self-organize to minimize a variational free-energy bound on the self-information or surprise of presynaptic inputs that are sampled. We model this as a selective pruning of dendritic spines that are expressed on a dendritic branch. This pruning occurs when postsynaptic gain falls below a threshold. Crucially, postsynaptic gain is itself optimized with respect to free energy. Pruning suppresses free energy as the dendrite selects presynaptic signals that conform to its expectations, specified by a generative model implicit in its intracellular kinetics. Not only does this provide a principled account of how neurons organize and selectively sample the myriad of potential presynaptic inputs they are exposed to, but it also connects the optimization of elemental neuronal (dendritic) processing to generic (surprise or evidence-based) schemes in statistics and machine learning, such as Bayesian model selection and automatic relevance determination.

Consistent spectral predictors for dynamic causal models of steady-state responses

In this paper, we review the nature of illusions using the free-energy formulation of Bayesian perception. We reiterate the notion that illusory percepts are, in fact, Bayes-optimal and represent the most likely explanation for ambiguous sensory input. This point is illustrated using perhaps the simplest of visual illusions; namely, the Cornsweet effect. By using plausible prior beliefs about the spatial gradients of illuminance and reflectance in visual scenes, we show that the Cornsweet effect emerges as a natural consequence of Bayes-optimal perception. Furthermore, we were able to simulate the appearance of secondary illusory percepts (Mach bands) as a function of stimulus contrast. The contrast-dependent emergence of the Cornsweet effect and subsequent appearance of Mach bands were simulated using a simple but plausible generative model. Because our generative model was inverted using a neurobiologically plausible scheme, we could use the inversion as a simulation of neuronal processing and implicit inference. Finally, we were able to verify the qualitative and quantitative predictions of this Bayes-optimal simulation psychophysically, using stimuli presented briefly to normal subjects at different contrast levels, in the context of a fixed alternative forced choice paradigm.

Computational learning models are critical for understanding mechanisms of adaptive behavior. However, the two major current frameworks, reinforcement learning (RL) and Bayesian learning, both have certain limitations. For example, many Bayesian models are agnostic of inter-individual variability and involve complicated integrals, making online learning difficult. Here, we introduce a generic hierarchical Bayesian framework for individual learning under multiple forms of uncertainty (e.g., environmental volatility and perceptual uncertainty). The model assumes Gaussian random walks of states at all but the first level, with the step size determined by the next highest level. The coupling between levels is controlled by parameters that shape the influence of uncertainty on learning in a subject-specific fashion. Using variational Bayes under a mean-field approximation and a novel approximation to the posterior energy function, we derive trial-by-trial update equations which (i) are analytical and extremely efficient, enabling real-time learning, (ii) have a natural interpretation in terms of RL, and (iii) contain parameters representing processes which play a key role in current theories of learning, e.g., precision-weighting of prediction error. These parameters allow for the expression of individual differences in learning and may relate to specific neuromodulatory mechanisms in the brain. Our model is very general: it can deal with both discrete and continuous states and equally accounts for deterministic and probabilistic relations between environmental events and perceptual states (i.e., situations with and without perceptual uncertainty). These properties are illustrated by simulations and analyses of empirical time series. Overall, our framework provides a novel foundation for understanding normal and pathological learning that contextualizes RL within a generic Bayesian scheme and thus connects it to principles of optimality from probability theory.

This paper is about inferring or discovering the functional architecture of distributed systems using Dynamic Causal Modelling (DCM). We describe a scheme that recovers the (dynamic) Bayesian dependency graph (connections in a network) using observed network activity. This network discovery uses Bayesian model selection to identify the sparsity structure (absence of edges or connections) in a graph that best explains observed time-series. The implicit adjacency matrix specifies the form of the network (e.g., cyclic or acyclic) and its graph-theoretical attributes (e.g., degree distribution). The scheme is illustrated using functional magnetic resonance imaging (fMRI) time series to discover functional brain networks. Crucially, it can be applied to experimentally evoked responses (activation studies) or endogenous activity in task-free (resting state) fMRI studies. Unlike conventional approaches to network discovery, DCM permits the analysis of directed and cyclic graphs. Furthermore, it eschews (implausible) Markovian assumptions about the serial independence of random fluctuations. The scheme furnishes a network description of distributed activity in the brain that is optimal in the sense of having the greatest conditional probability, relative to other networks. The networks are characterised in terms of their connectivity or adjacency matrices and conditional distributions over the directed (and reciprocal) effective connectivity between connected nodes or regions. We envisage that this approach will provide a useful complement to current analyses of functional connectivity for both activation and resting-state studies.

Diffeomorphic registration using geodesic shooting and Gauss–Newton optimisation

Spontaneous fluctuations (SF) in skin conductance are often used to index sympathetic arousal and emotional states. SF are caused by sudomotor nerve activity (SNA), which is a direct indicator of sympathetic arousal. Here, we describe a dynamic causal model (DCM) of how SNA causes SF, and apply variational Bayesian model inversion to infer SNA, given empirically observed SF. The estimated SNA bears a relationship to the number of SF as derived from conventional (semi-visual) analysis. Crucially, we show that, during public speaking induced anxiety, the estimated number of SNA bursts is a better predictor of the (known) psychological state than the number of SF. We suggest dynamic causal modeling of SF potentially allows a more precise and informed inference about arousal than purely descriptive methods.

Dynamic causal modeling of spontaneous fluctuations in skin conductance

Recent studies have established a relation between ongoing brain activity fluctuations and intertrial variability in evoked neural responses, perception, and motor performance. Here, we extended these investigations into the domain of cognitive control. Using functional neuroimaging and a sparse event-related design (with long and unpredictable intervals), we measured ongoing activity fluctuations and evoked responses in volunteers performing a Stroop task with color-word interference. Across trials, prestimulus activity of several regions predicted subsequent response speed and across subjects this effect scaled with the Stroop effect size, being significant only in subjects manifesting behavioral interference. These effects occurred only in task relevant as the dorsal anterior cingulate and dorsolateral prefrontal cortex as well as ventral visual areas sensitive to color and visual words. Crucially, in subjects showing a Stroop effect, reaction times were faster when prestimulus activity was higher in task-relevant (color) regions and slower when activity was higher in irrelevant (word form) regions. These findings suggest that intrinsic brain activity fluctuations modulate neural mechanisms underpinning selective voluntary attention and cognitive control. Rephrased in terms of predictive coding models, ongoing activity can hence be considered a proxy of the precision (gain) with which prediction error signals are transmitted upon sensory stimulation.

Ongoing brain activity fluctuations directly account for intertrial and indirectly for intersubject variability in Stroop task performance.

King et al. raise some technical issues about our recent study showing impaired top-down processes in the vegetative state. We welcome the opportunity to provide more details about our methods and results and to resolve their concerns. We substantiate our interpretation of the results and provide a point-by-point response to the issues raised.

Response to Comment on “Preserved Feedforward But Impaired Top-Down Processes in the Vegetative State”

Controlling false positive rates in mass-multivariate tests for electromagnetic responses

Discerning the neural correlates of (un)consciousness sheds light on the mechanisms underlying vegetative states. Frontoparietal cortex is involved in the explicit processing (awareness) of stimuli. Frontoparietal activation has also been found in studies of subliminal stimulus processing. We hypothesized that an impairment of top-down processes, involved in recurrent neuronal message-passing and the generation of long-latency electrophysiological responses, might provide a more reliable correlate of consciousness in severely brain-damaged patients, than frontoparietal responses. We measured effective connectivity during a mismatch negativity paradigm and found that the only significant difference between patients in a vegetative state and controls was an impairment of backward connectivity from frontal to temporal cortices. This result emphasizes the importance of top-down projections in recurrent processing that involve high-order associative cortices for conscious perception.

Preserved Feedforward But Impaired Top-Down Processes in the Vegetative State

The perception of facial affect engages a distributed cortical network. We used functional magnetic resonance imaging and dynamic causal modeling to characterize effective connectivity during explicit (conscious) categorization of affective stimuli in the human brain. Specifically, we examined the modulation of connectivity from posterior regions of the face-processing network to the lateral ventral prefrontal cortex (VPFC) during affective categorization and we tested for a potential role of the amygdala (AMG) in mediating this modulation. We found that explicit processing of facial affect led to prominent modulation (increase) in the effective connectivity from the inferior occipital gyrus (IOG) to the VPFC, while there was less evidence for modulation of the afferent connections from fusiform gyrus and AMG to VPFC. More specifically, the forward connection from IOG to the VPFC exhibited a selective increase under anger (as opposed to fear or sadness). Furthermore, Bayesian model comparison suggested that the modulation of afferent connections to the VPFC was mediated directly by facial affect, as opposed to an indirect modulation mediated by the AMG. Our results thus suggest that affective information is conveyed to the VPFC along multiple parallel pathways and that AMG activity is not sufficient to account for the gating of information transfer to the VPFC during explicit emotional processing.

Effective Connectivity during Processing of Facial Affect: Evidence for Multiple Parallel Pathways

SPM is a free and open source software written in MATLAB (The MathWorks, Inc.). In addition to standard M/EEG preprocessing, we presently offer three main analysis tools: (i) statistical analysis of scalp-maps, time-frequency images, and volumetric 3D source reconstruction images based on the general linear model, with correction for multiple comparisons using random field theory; (ii) Bayesian M/EEG source reconstruction, including support for group studies, simultaneous EEG and MEG, and fMRI priors; (iii) dynamic causal modelling (DCM), an approach combining neural modelling with data analysis for which there are several variants dealing with evoked responses, steady state responses (power spectra and cross-spectra), induced responses, and phase coupling. SPM8 is integrated with the FieldTrip toolbox , making it possible for users to combine a variety of standard analysis methods with new schemes implemented in SPM and build custom analysis tools using powerful graphical user interface (GUI) and batching tools.

Cortico-basal ganglia-thalamocortical circuits are severely disrupted by the dopamine depletion of Parkinson's disease (PD), leading to pathologically exaggerated beta oscillations. Abnormal rhythms, found in several circuit nodes are correlated with movement impairments but their neural basis remains unclear. Here, we used dynamic causal modelling (DCM) and the 6-hydroxydopamine-lesioned rat model of PD to examine the effective connectivity underlying these spectral abnormalities. We acquired auto-spectral and cross-spectral measures of beta oscillations (10–35 Hz) from local field potential recordings made simultaneously in the frontal cortex, striatum, external globus pallidus (GPe) and subthalamic nucleus (STN), and used these data to optimise neurobiologically plausible models. Chronic dopamine depletion reorganised the cortico-basal ganglia-thalamocortical circuit, with increased effective connectivity in the pathway from cortex to STN and decreased connectivity from STN to GPe. Moreover, a contribution analysis of the Parkinsonian circuit distinguished between pathogenic and compensatory processes and revealed how effective connectivity along the indirect pathway acquired a strategic importance that underpins beta oscillations. In modelling excessive beta synchrony in PD, these findings provide a novel perspective on how altered connectivity in basal ganglia-thalamocortical circuits reflects a balance between pathogenesis and compensation, and predicts potential new therapeutic targets to overcome dysfunctional oscillations.

Alterations in Brain Connectivity Underlying Beta Oscillations in Parkinsonism

Both phenotype and treatment response vary in patients with Parkinson's disease. Anatomical and functional imaging studies suggest that individual symptoms may represent malfunction of different segregated networks running in parallel through the basal ganglia. In this study, we use a newly described, electrophysiological method to describe cortico-subthalamic networks in humans. We performed combined magnetoencephalographic and subthalamic local field potential recordings in thirteen patients with Parkinson's disease at rest. Two spatially and spectrally separated networks were identified. A temporoparietal-brainstem network was coherent with the subthalamic nucleus in the alpha (7-13 Hz) band, whilst a predominantly frontal network was coherent in the beta (15-35 Hz) band. Dopaminergic medication modulated the resting beta network, by increasing beta coherence between the subthalamic region and prefrontal cortex. Subthalamic activity was predominantly led by activity in the cortex in both frequency bands. The cortical topography and frequencies involved in the alpha and beta networks suggest that these networks may be involved in attentional and executive, particularly motor planning, processes, respectively.

Resting oscillatory cortico-subthalamic connectivity in patients with Parkinson's disease.

This article presents the first attempt to formalize the optimization of experimental design with the aim of comparing models of brain function based on neuroimaging data. We demonstrate our approach in the context of Dynamic Causal Modelling (DCM), which relates experimental manipulations to observed network dynamics (via hidden neuronal states) and provides an inference framework for selecting among candidate models. Here, we show how to optimize the sensitivity of model selection by choosing among experimental designs according to their respective model selection accuracy. Using Bayesian decision theory, we (i) derive the Laplace-Chernoff risk for model selection, (ii) disclose its relationship with classical design optimality criteria and (iii) assess its sensitivity to basic modelling assumptions. We then evaluate the approach when identifying brain networks using DCM. Monte-Carlo simulations and empirical analyses of fMRI data from a simple bimanual motor task in humans serve to demonstrate the relationship between network identification and the optimal experimental design. For example, we show that deciding whether there is a feedback connection requires shorter epoch durations, relative to asking whether there is experimentally induced change in a connection that is known to be present. Finally, we discuss limitations and potential extensions of this work.

Optimizing Experimental Design for Comparing Models of Brain Function

It has been suggested recently that action and perception can be understood as minimising the free energy of sensory samples. This ensures that agents sample the environment to maximise the evidence for their model of the world, such that exchanges with the environment are predictable and adaptive. However, the free energy account does not invoke reward or cost-functions from reinforcement-learning and optimal control theory. We therefore ask whether reward is necessary to explain adaptive behaviour. The free energy formulation uses ideas from statistical physics to explain action in terms of minimising sensory surprise. Conversely, reinforcement-learning has its roots in behaviourism and engineering and assumes that agents optimise a policy to maximise future reward. This paper tries to connect the two formulations and concludes that optimal policies correspond to empirical priors on the trajectories of hidden environmental states, which compel agents to seek out the (valuable) states they expect to encounter.

The impact of traumatic spinal cord injury on structural integrity, cortical reorganization and ensuing disability is variable and may depend on a dynamic interaction between the severity of local damage and the capacity of the brain for plastic reorganization. We investigated trauma-induced anatomical changes in the spinal cord and brain, and explored their relationship to functional changes in sensorimotor cortex. Structural changes were assessed using cross-sectional cord area, voxel-based morphometry and voxel-based cortical thickness of T1-weighted images in 10 subjects with cervical spinal cord injury and 16 controls. Cortical activation in response to right-sided (i) handgrip; and (ii) median and tibial nerve stimulation were assessed using functional magnetic resonance imaging. Regression analyses explored associations between cord area, grey and white matter volume, cortical activations and thickness, and disability. Subjects with spinal cord injury had impaired upper and lower limb function bilaterally, a 30% reduced cord area, smaller white matter volume in the pyramids and left cerebellar peduncle, and smaller grey matter volume and cortical thinning in the leg area of the primary motor and sensory cortex compared with controls. Functional magnetic resonance imaging revealed increased activation in the left primary motor cortex leg area during handgrip and the left primary sensory cortex face area during median nerve stimulation in subjects with spinal cord injury compared with controls, but no increased activation following tibial nerve stimulation. A smaller cervical cord area was associated with impaired upper limb function and increased activations with handgrip and median nerve stimulation, but reduced activations with tibial nerve stimulation. Increased sensory deficits were associated with increased activations in the left primary sensory cortex face area due to median nerve stimulation. In conclusion, spinal cord injury leads to cord atrophy, cortical atrophy of primary motor and sensory cortex, and cortical reorganization of the sensorimotor system. The degree of cortical reorganization is predicted by spinal atrophy and is associated with significant disability.

Disability, atrophy and cortical reorganization following spinal cord injury

Background In medical practice, diagnostic hypotheses are often made by physicians in the first moments of contact with patients; sometimes even before they report their symptoms. We propose that generation of diagnostic hypotheses in this context is the result of cognitive processes subserved by brain mechanisms that are similar to those involved in naming objects or concepts in everyday life. Methodology and Principal Findings To test this proposal we developed an experimental paradigm with functional magnetic resonance imaging (fMRI) using radiological diagnosis as a model. Twenty-five radiologists diagnosed lesions in chest X-ray images and named non-medical targets (animals) embedded in chest X-ray images while being scanned in a fMRI session. Images were presented for 1.5 seconds; response times (RTs) and the ensuing cortical activations were assessed. The mean response time for diagnosing lesions was 1.33 (SD ±0.14) seconds and 1.23 (SD ±0.13) seconds for naming animals. 72% of the radiologists reported cogitating differential diagnoses during trials (3.5 seconds). The overall pattern of cortical activations was remarkably similar for both types of targets. However, within the neural systems shared by both stimuli, activation was significantly greater in left inferior frontal sulcus and posterior cingulate cortex for lesions relative to animals. Conclusions Generation of diagnostic hypotheses and differential diagnoses made through the immediate visual recognition of clinical signs can be a fast and automatic process. The co-localization of significant brain activation for lesions and animals suggests that generating diagnostic hypotheses for lesions and naming animals are served by the same neuronal systems. Nevertheless, diagnosing lesions was cognitively more demanding and associated with more activation in higher order cortical areas. These results support the hypothesis that medical diagnoses based on prompt visual recognition of clinical signs and naming in everyday life are supported by similar brain systems.

How Doctors Generate Diagnostic Hypotheses: A Study of Radiological Diagnosis with Functional Magnetic Resonance Imaging

This paper reviews a simple solution to the continuous-discrete Bayesian nonlinear state estimation problem that has been proposed recently. The key ideas are analytic noise processes, variational Bayes, and the formulation of the problem in terms of generalized coordinates of motion. Some of the algorithms, specifically dynamic expectation maximization and variational filtering, have been shown to outperform existing approaches like extended Kalman filtering and particle filtering. A pedagogical review of the theoretical formulation is presented, with an emphasis on concepts that are not as widely known in the filtering literature. We illustrate the appliction of these concepts using a numerical example.

Effective connectivity: Influence, causality and biophysical modeling

What is coordination and how is it achieved? This chapter begins with a discussion of the concept and key features of dynamic coordination. Next, its relation to cognitive functions and learning processes are explored, as is the role of neural oscillations in different frequency bands for dynamic coordination. Thereafter, modulation of coordination at the systems level is reviewed, and the relation of the mechanisms discussed to neuropsychiatric disorders is pursued. The purpose of this chapter is not to delineate all properties of coordination or all of its different manifestations. Instead, our intent is to portray the multifaceted problem that stands before us.

Mathematical models of scientific data can be formally compared using Bayesian model evidence. Previous applications in the biological sciences have mainly focussed on model selection in which one first selects the model with the highest evidence and then makes inferences based on the parameters of that model. This “best model” approach is very useful but can become brittle if there are a large number of models to compare, and if different subjects use different models. To overcome this shortcoming we propose the combination of two further approaches: (i) family level inference and (ii) Bayesian model averaging within families. Family level inference removes uncertainty about aspects of model structure other than the characteristic of interest. For example: What are the inputs to the system? Is processing serial or parallel? Is it linear or nonlinear? Is it mediated by a single, crucial connection? We apply Bayesian model averaging within families to provide inferences about parameters that are independent of further assumptions about model structure. We illustrate the methods using Dynamic Causal Models of brain imaging data.

Ongoing brain activity has been observed since the earliest neurophysiological recordings and is found over a wide range of temporal and spatial scales. It is characterized by remarkably large spontaneous modulations. Here, we review evidence for the functional role of these ongoing activity fluctuations and argue that they constitute an essential property of the neural architecture underlying cognition. The role of spontaneous activity fluctuations is probably best understood when considering both their spatiotemporal structure and their functional impact on cognition. We first briefly argue against a “segregationist” view on ongoing activity, both in time and space, which would selectively associate certain frequency bands or levels of spatial organization with specific functional roles. Instead, we emphasize the functional importance of the full range, from differentiation to integration, of intrinsic activity within a hierarchical spatiotemporal structure. We then highlight the flexibility and context-sensitivity of intrinsic functional connectivity that suggest its involvement in functionally relevant information processing. This role in information processing is pursued by reviewing how ongoing brain activity interacts with afferent and efferent information exchange of the brain with its environment. We focus on the relationship between the variability of ongoing and evoked brain activity, and review recent reports that tie ongoing brain activity fluctuations to variability in human perception and behavior. Finally, these observations are discussed within the framework of the free-energy principle which – applied to human brain function – provides a theoretical account for a non-random, coordinated interaction of ongoing and evoked activity in perception and behavior.

The Relation of Ongoing Brain Activity, Evoked Neural Responses, and Cognition

Individuals with autism spectrum conditions (ASCs) have a core difficulty in recursively inferring the intentions of others. The precise cognitive dysfunctions that determine the heterogeneity at the heart of this spectrum, however, remains unclear. Furthermore, it remains possible that impairment in social interaction is not a fundamental deficit but a reflection of deficits in distinct cognitive processes. To better understand heterogeneity within ASCs, we employed a game-theoretic approach to characterize unobservable computational processes implicit in social interactions. Using a social hunting game with autistic adults, we found that a selective difficulty representing the level of strategic sophistication of others, namely inferring others' mindreading strategy, specifically predicts symptom severity. In contrast, a reduced ability in iterative planning was predicted by overall intellectual level. Our findings provide the first quantitative approach that can reveal the underlying computational dysfunctions that generate the autistic “spectrum.”

Functional neuroimaging techniques are used widely in cognitive neuroscience to investigate aspects of functional specialization and functional integration in the human brain. Functional integration can be characterized in two ways, functional connectivity and effective connectivity. While functional connectivity describes statistical dependencies between data, effective connectivity rests on a mechanistic model of the causal effects that generated the data. This review addresses the conceptual and methodological basis of established techniques for characterizing effective connectivity using functional magnetic resonance imaging (fMRI) data. In particular, we focus on dynamic causal modeling (DCM) of fMRI data and emphasize the importance of model selection procedures and nonlinear mechanisms for context-dependent changes in connection strengths. Copyright © 2010 John Wiley & Sons, Ltd. For further resources related to this article, please visit the WIREs website.

Analyzing effective connectivity with functional magnetic resonance imaging.

Effective Connectivity within the Network of Fearful Facial Affect Recognition in Patients with Bipolar Disorder Compared to Healthy Controls

Humans have the arguably unique ability to understand the mental representations of others. For success in both competitive and cooperative interactions, however, this ability must be extended to include representations of others' belief about our intentions, their model about our belief about their intentions, and so on. We developed a “stag hunt” game in which human subjects interacted with a computerized agent using different degrees of sophistication (recursive inferences) and applied an ecologically valid computational model of dynamic belief inference. We show that rostral medial prefrontal (paracingulate) cortex, a brain region consistently identified in psychological tasks requiring mentalizing, has a specific role in encoding the uncertainty of inference about the other's strategy. In contrast, dorsolateral prefrontal cortex encodes the depth of recursion of the strategy being used, an index of executive sophistication. These findings reveal putative computational representations within prefrontal cortex regions, supporting the maintenance of cooperation in complex social decision making.

PW01-148 - Effective Connectivity Within The Network Of Fearful Facial Affect Recognition In Patients With Bipolar Disorder Compared To Healthy Controls

We suggested recently that attention can be understood as inferring the level of uncertainty or precision during hierarchical perception. In this paper, we try to substantiate this claim using neuronal simulations of directed spatial attention and biased competition. These simulations assume that neuronal activity encodes a probabilistic representation of the world that optimizes free-energy in a Bayesian fashion. Because free-energy bounds surprise or the (negative) log-evidence for internal models of the world, this optimization can be regarded as evidence accumulation or (generalized) predictive coding. Crucially, both predictions about the state of the world generating sensory data and the precision of those data have to be optimized. Here, we show that if the precision depends on the states, one can explain many aspects of attention. We illustrate this in the context of the Posner paradigm, using the simulations to generate both psychophysical and electrophysiological responses. These simulated responses are consistent with attentional bias or gating, competition for attentional resources, attentional capture and associated speed-accuracy trade-offs. Furthermore, if we present both attended and non-attended stimuli simultaneously, biased competition for neuronal representation emerges as a principled and straightforward property of Bayes-optimal perception.

We describe an asymmetric approach to fMRI and MEG/EEG fusion in which fMRI data are treated as empirical priors on electromagnetic sources, such that their influence depends on the MEG/EEG data, by virtue of maximizing the model evidence. This is important if the causes of the MEG/EEG signals differ from those of the fMRI signal. Furthermore, each suprathreshold fMRI cluster is treated as a separate prior, which is important if fMRI data reflect neural activity arising at different times within the EEG/MEG data. We present methodological considerations when mapping from a 3D fMRI Statistical Parametric Map to a 2D cortical surface and thence to the covariance components used within our Parametric Empirical Bayesian framework. Our previous introduction of a canonical (inverse‐normalized) cortical mesh also allows deployment of fMRI priors that live in a template space; for example, from a group analysis of different individuals. We evaluate the ensuing scheme with MEG and EEG data recorded simultaneously from 12 participants, using the same face‐processing paradigm under which independent fMRI data were obtained. Because the fMRI priors become part of the generative model, we use the model evidence to compare (i) multiple versus single, (ii) valid versus invalid, (iii) binary versus continuous, and (iv) variance versus covariance fMRI priors. For these data, multiple, valid, binary, and variance fMRI priors proved best for a standard Minimum Norm inversion. Interestingly, however, inversion using Multiple Sparse Priors benefited little from additional fMRI priors, suggesting that they already provide a sufficiently flexible generative model. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.

A Parametric Empirical Bayesian framework for fMRI‐constrained MEG/EEG source reconstruction

Adaptive and aberrant reward prediction signals in the human brain

Neural activity dynamics considering the effects of experimental conditions Mapping from neural activity to BOLD signal (nonlinear)

Dynamic causal modelling of anticipatory skin conductance responses

Developments in M/EEG analysis allows for models that are sophisticated enough to capture the full richness of the data. This chapter focuses on dynamic causal modeling (DCM) for M/EEG, which entails the inversion of informed spatiotemporal models of observed responses. The idea is to model condition-specific responses over channels and peristimulus time with the same model, where the differences among conditions are explained by changes in only a few key parameters. The face and predictive validity of DCM have been established, which makes it a potentially useful tool for group studies.

Analyzing functional and effective connectivity with EEG and MEG

We describe a Bayesian filtering scheme for nonlinear state-space models in continuous time. This scheme is called Generalised Filtering and furnishes posterior conditional densities on hidden states and unknown parameters generating observed data. Crucially, the scheme operates online, assimilating data to optimize the conditional density on time-varying states and time-invariant parameters. In contrast to Kalman and Particle smoothing, Generalised Filtering does not require a backwards pass. In contrast to variational schemes, it does not assume conditional independence between the states and parameters. Generalised Filtering optimises the conditional density with respect to a free-energy bound on the model’s log-evidence. This optimisation uses the generalised motion of hidden states and parameters, under the prior assumption that the motion of the parameters is small. We describe the scheme, present comparative evaluations with a fixed-form variational version, and conclude with an illustrative application to a nonlinear state-space model of brain imaging time-series.

An fMRI study of associative learning and prediction error signalling in daily ketamine abusers

In this paper, we present a generic approach that can be used to infer how subjects make optimal decisions under uncertainty. This approach induces a distinction between a subject's perceptual model, which underlies the representation of a hidden “state of affairs” and a response model, which predicts the ensuing behavioural (or neurophysiological) responses to those inputs. We start with the premise that subjects continuously update a probabilistic representation of the causes of their sensory inputs to optimise their behaviour. In addition, subjects have preferences or goals that guide decisions about actions given the above uncertain representation of these hidden causes or state of affairs. From a Bayesian decision theoretic perspective, uncertain representations are so-called “posterior” beliefs, which are influenced by subjective “prior” beliefs. Preferences and goals are encoded through a “loss” (or “utility”) function, which measures the cost incurred by making any admissible decision for any given (hidden) state of affair. By assuming that subjects make optimal decisions on the basis of updated (posterior) beliefs and utility (loss) functions, one can evaluate the likelihood of observed behaviour. Critically, this enables one to “observe the observer”, i.e. identify (context- or subject-dependent) prior beliefs and utility-functions using psychophysical or neurophysiological measures. In this paper, we describe the main theoretical components of this meta-Bayesian approach (i.e. a Bayesian treatment of Bayesian decision theoretic predictions). In a companion paper (‘Observing the observer (II): deciding when to decide’), we describe a concrete implementation of it and demonstrate its utility by applying it to simulated and real reaction time data from an associative learning task.

Observing the Observer (I): Meta-Bayesian Models of Learning and Decision-Making

This article explores the notion that Freudian constructs may have neurobiological substrates. Specifically, we propose that Freud’s descriptions of the primary and secondary processes are consistent with self-organized activity in hierarchical cortical systems and that his descriptions of the ego are consistent with the functions of the default-mode and its reciprocal exchanges with subordinate brain systems. This neurobiological account rests on a view of the brain as a hierarchical inference or Helmholtz machine. In this view, large-scale intrinsic networks occupy supraordinate levels of hierarchical brain systems that try to optimize their representation of the sensorium. This optimization has been formulated as minimizing a free-energy; a process that is formally similar to the treatment of energy in Freudian formulations. We substantiate this synthesis by showing that Freud’s descriptions of the primary process are consistent with the phenomenology and neurophysiology of rapid eye movement sleep, the early and acute psychotic state, the aura of temporal lobe epilepsy and hallucinogenic drug states.

The default-mode, ego-functions and free-energy: a neurobiological account of Freudian ideas

The synchronous discharge of neuronal assemblies is thought to facilitate communication between areas within distributed networks in the human brain. This oscillatory activity is especially interesting, given the pathological modulation of specific frequencies in diseases affecting the motor system. Many studies investigating oscillatory activity have focused on same frequency, or linear, coupling between areas of a network. In this study, our aim was to establish a functional architecture in the human motor system responsible for induced responses as measured in normal subjects with magnetoencephalography. Specifically, we looked for evidence for additional nonlinear (between-frequency) coupling among neuronal sources and, in particular, whether nonlinearities were found predominantly in connections within areas (intrinsic), between areas (extrinsic) or both. We modeled the event-related modulation of spectral responses during a simple hand-grip using dynamic casual modeling. We compared models with and without nonlinear connections under conditions of symmetric and asymmetric interhemispheric connectivity. Bayesian model comparison suggested that the task-dependent motor network was asymmetric during right hand movements. Furthermore, it revealed very strong evidence for nonlinear coupling between sources in this distributed network, but interactions among frequencies within a source appeared linear in nature. Our results provide empirical evidence for nonlinear coupling among distributed neuronal sources in the motor system and that these play an important role in modulating spectral responses under normal conditions.

Functional integration in the brain rests on anatomical connectivity (the presence of axonal connections) and effective connectivity (the causal influences mediated by these connections). The deployment of anatomical connections provides important constraints on effective connectivity, but does not fully determine it, because synaptic connections can be expressed functionally in a dynamic and context-dependent fashion. Although it is generally assumed that anatomical connectivity data is important to guide the construction of neurobiologically realistic models of effective connectivity; the degree to which these models actually profit from anatomical constraints has not yet been formally investigated. Here, we use diffusion weighted imaging and probabilistic tractography to specify anatomically informed priors for dynamic causal models (DCMs) of fMRI data. We constructed 64 alternative DCMs, which embodied different mappings between the probability of an anatomical connection and the prior variance of the corresponding of effective connectivity, and fitted them to empirical fMRI data from 12 healthy subjects. Using Bayesian model selection, we show that the best model is one in which anatomical probability increases the prior variance of effective connectivity parameters in a nonlinear and monotonic (sigmoidal) fashion. This means that the higher the likelihood that a given connection exists anatomically, the larger one should set the prior variance of the corresponding coupling parameter; hence making it easier for the parameter to deviate from zero and represent a strong effective connection. To our knowledge, this study provides the first formal evidence that probabilistic knowledge of anatomical connectivity can improve models of functional integration.

Perceptual decisions can be made when sensory input affords an inference about what generated that input. Here, we report findings from two independent perceptual experiments conducted during functional magnetic resonance imaging (fMRI) with a sparse event-related design. The first experiment, in the visual modality, involved forced-choice discrimination of coherence in random dot kinematograms that contained either subliminal or periliminal motion coherence. The second experiment, in the auditory domain, involved free response detection of (non-semantic) near-threshold acoustic stimuli. We analysed fluctuations in ongoing neural activity, as indexed by fMRI, and found that neuronal activity in sensory areas (extrastriate visual and early auditory cortex) biases perceptual decisions towards correct inference and not towards a specific percept. Hits (detection of near-threshold stimuli) were preceded by significantly higher activity than both misses of identical stimuli or false alarms, in which percepts arise in the absence of appropriate sensory input. In accord with predictive coding models and the free-energy principle, this observation suggests that cortical activity in sensory brain areas reflects the precision of prediction errors and not just the sensory evidence or prediction errors per se.

Predictive Coding or Evidence Accumulation? False Inference and Neuronal Fluctuations

The diverse nature of cerebral activity, as measured using neuroimaging techniques, has been recognised long ago. It seems obvious that using single modality recordings can be limited when it comes to capturing its complex nature. Thus, it has been argued that moving to a multimodal approach will allow neuroscientists to better understand the dynamics and structure of this activity. This means that integrating information from different techniques, such as electroencephalography (EEG) and the blood oxygenated level dependent (BOLD) signal recorded with functional magnetic resonance imaging (fMRI), represents an important methodological challenge. In this work, we review the work that has been done thus far to derive EEG/fMRI integration approaches. This leads us to inspect the conditions under which such an integration approach could work or fail, and to disclose the types of scientific questions one could (and could not) hope to answer with it.

EEG-fMRI integration: a critical review of biophysical modeling and data analysis approaches.

Perception entails interactions between activated brain visual areas and the records of previous sensations, allowing for processes like figure–ground segregation and object recognition. The aim of this study was to characterize top-down effects that originate in the visual cortex and that are involved in the generation and perception of form. We performed a functional magnetic resonance imaging experiment, where subjects viewed 3 groups of stimuli comprising oriented lines with different levels of recognizable high-order structure (none, collinearity, and meaning). Our results showed that recognizable stimuli cause larger activations in anterior visual and frontal areas. In contrast, when stimuli are random or unrecognizable, activations are greater in posterior visual areas, following a hierarchical organization where areas V1/V2 were less active with “collinearity” and the middle occipital cortex was less active with “meaning.” An effective connectivity analysis using dynamic causal modeling showed that high-order visual form engages higher visual areas that generate top-down signals, from multiple levels of the visual hierarchy. These results are consistent with a model in which if a stimulus has recognizable attributes, such as collinearity and meaning, the areas specialized for processing these attributes send top-down messages to the lower levels to facilitate more efficient encoding of visual form.

Top-down Modulations in the Visual Form Pathway Revealed with Dynamic Causal Modeling

In a companion paper [1], we have presented a generic approach for inferring how subjects make optimal decisions under uncertainty. From a Bayesian decision theoretic perspective, uncertain representations correspond to "posterior" beliefs, which result from integrating (sensory) information with subjective "prior" beliefs. Preferences and goals are encoded through a "loss" (or "utility") function, which measures the cost incurred by making any admissible decision for any given (hidden or unknown) state of the world. By assuming that subjects make optimal decisions on the basis of updated (posterior) beliefs and utility (loss) functions, one can evaluate the likelihood of observed behaviour. In this paper, we describe a concrete implementation of this meta-Bayesian approach (i.e. a Bayesian treatment of Bayesian decision theoretic predictions) and demonstrate its utility by applying it to both simulated and empirical reaction time data from an associative learning task. Here, inter-trial variability in reaction times is modelled as reflecting the dynamics of the subjects' internal recognition process, i.e. the updating of representations (posterior densities) of hidden states over trials while subjects learn probabilistic audio-visual associations. We use this paradigm to demonstrate that our meta-Bayesian framework allows for (i) probabilistic inference on the dynamics of the subject's representation of environmental states, and for (ii) model selection to disambiguate between alternative preferences (loss functions) human subjects could employ when dealing with trade-offs, such as between speed and accuracy. Finally, we illustrate how our approach can be used to quantify subjective beliefs and preferences that underlie inter-individual differences in behaviour.

Analytic measures for quantification of arousal from spontaneous skin conductance fluctuations

Embodied Inference : or “ I think therefore I am , if I am what I think ”

Neuroimaging produces data that are continuous in one or more dimensions. This calls for an inference framework that can handle data that approximate functions of space, for example, anatomical images, time-frequency maps and distributed source reconstructions of electromagnetic recordings over time. Statistical parametric mapping (SPM) is the standard framework for whole-brain inference in neuroimaging: SPM uses random field theory to furnish p-values that are adjusted to control family-wise error or false discovery rates, when making topological inferences over large volumes of space. Random field theory regards data as realizations of a continuous process in one or more dimensions. This contrasts with classical approaches like the Bonferroni correction, which consider images as collections of discrete samples with no continuity properties (i.e., the probabilistic behavior at one point in the image does not depend on other points). Here, we illustrate how random field theory can be applied to data that vary as a function of time, space or frequency. We emphasize how topological inference of this sort is invariant to the geometry of the manifolds on which data are sampled. This is particularly useful in electromagnetic studies that often deal with very smooth data on scalp or cortical meshes. This application illustrates the versatility and simplicity of random field theory and the seminal contributions of Keith Worsley (1951-2009), a key architect of topological inference.

Both perceptual inference and motor responses are shaped by learned probabilities. For example, stimulus-induced responses in sensory cortices and preparatory activity in premotor cortex reflect how (un)expected a stimulus is. This is in accordance with predictive coding accounts of brain function, which posit a fundamental role of prediction errors for learning and adaptive behavior. We used functional magnetic resonance imaging and recent advances in computational modeling to investigate how (failures of) learned predictions about visual stimuli influence subsequent motor responses. Healthy volunteers discriminated visual stimuli that were differentially predicted by auditory cues. Critically, the predictive strengths of cues varied over time, requiring subjects to continuously update estimates of stimulus probabilities. This online inference, modeled using a hierarchical Bayesian learner, was reflected behaviorally: speed and accuracy of motor responses increased significantly with predictability of the stimuli. We used nonlinear dynamic causal modeling to demonstrate that striatal prediction errors are used to tune functional coupling in cortical networks during learning. Specifically, the degree of striatal trial-by-trial prediction error activity controls the efficacy of visuomotor connections and thus the influence of surprising stimuli on premotor activity. This finding substantially advances our understanding of striatal function and provides direct empirical evidence for formal learning theories that posit a central role for prediction error-dependent plasticity.

Optimized beamforming for simultaneous MEG and intracranial local field potential recordings in deep brain stimulation patients

Characterisation of resting oscillatory cortico-subthalamic connectivity in patients with Parkinson's disease

Aim of Investigation: Heritability is measured with twins studies, where the correlation of monozygotic (MZ, identical) and dizygotic (DZ, fraternal) twins indicates shared variation due to common environmental and/or genetic influences. The simplest estimate of narrow-sense (additive genetic) heritability is Falconer's estimate (Falconer, 1996). Another estimate comes from a components-of-variance approach, where a structured covariance model expresses the shared genetic and environmental effects (Neale, 1998). This approach has much greater flexibility and can be more powerful (Christian, 1995). While best practice in statistical genetics is to use the components-of-variance/SEM approach, Falconer's method is still widely used in imaging genetics studies. The purpose of this work is to demonstrate the poor performance of Falconer's method and demonstrate the limitations of even the best-practice approch at typical sample sizes.

Dangers of using Falconer’s Heritability estimate with typical imaging genetic sample sizes

We present a review of dynamic causal modeling (DCM) for magneto‐ and electroencephalography (M/EEG) data. DCM is based on a spatiotemporal model, where the temporal component is formulated in terms of neurobiologically plausible dynamics. Following an intuitive description of the model, we discuss six recent studies, which use DCM to analyze M/EEG and local field potentials. These studies illustrate how DCM can be used to analyze evoked responses (average response in time), induced responses (average response in time‐frequency), and steady‐state responses (average response in frequency). Bayesian model comparison plays a critical role in these analyses, by allowing one to compare equally plausible models in terms of their model evidence. This approach might be very useful in M/EEG research; where correlations among spatial and neuronal model parameter estimates can cause uncertainty about which model best explains the data. Bayesian model comparison resolves these uncertainties in a principled and formal way. We suggest that DCM and Bayesian model comparison provides a useful way to test hypotheses about distributed processing in the brain, using electromagnetic data. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.

Selecting forward models for MEG source-reconstruction using model-evidence

Dynamical causal modelling for M/EEG: Spatial and temporal symmetry constraints

In this paper, we suggest that perception could be modeled by assuming that sensory input is generated by a hierarchy of attractors in a dynamic system. We describe a mathematical model which exploits the temporal structure of rapid sensory dynamics to track the slower trajectories of their underlying causes. This model establishes a proof of concept that slowly changing neuronal states can encode the trajectories of faster sensory signals. We link this hierarchical account to recent developments in the perception of human action; in particular artificial speech recognition. We argue that these hierarchical models of dynamical systems are a plausible starting point to develop robust recognition schemes, because they capture critical temporal dependencies induced by deep hierarchical structure. We conclude by suggesting that a fruitful computational neuroscience approach may emerge from modeling perception as non-autonomous recognition dynamics enslaved by autonomous hierarchical dynamics in the sensorium.

People track facial expression dynamics with ease to accurately perceive distinct emotions. Although the superior temporal sulcus (STS) appears to possess mechanisms for perceiving changeable facial attributes such as expressions, the nature of the underlying neural computations is not known. Motivated by novel theoretical accounts, we hypothesized that visual and motor areas represent expressions as anticipated motion trajectories. Using magnetoencephalography, we show predictable transitions between fearful and neutral expressions (compared with scrambled and static presentations) heighten activity in visual cortex as quickly as 165 ms poststimulus onset and later (237 ms) engage fusiform gyrus, STS and premotor areas. Consistent with proposed models of biological motion representation, we suggest that visual areas predictively represent coherent facial trajectories. We show that such representations bias emotion perception of subsequent static faces, suggesting that facial movements elicit predictions that bias perception. Our findings reveal critical processes evoked in the perception of dynamic stimuli such as facial expressions, which can endow perception with temporal continuity.

Modulation of Perception and Brain Activity by Predictable Trajectories of Facial Expressions

This paper questions the need for reinforcement learning or control theory when optimising behaviour. We show that it is fairly simple to teach an agent complicated and adaptive behaviours using a free-energy formulation of perception. In this formulation, agents adjust their internal states and sampling of the environment to minimize their free-energy. Such agents learn causal structure in the environment and sample it in an adaptive and self-supervised fashion. This results in behavioural policies that reproduce those optimised by reinforcement learning and dynamic programming. Critically, we do not need to invoke the notion of reward, value or utility. We illustrate these points by solving a benchmark problem in dynamic programming; namely the mountain-car problem, using active perception or inference under the free-energy principle. The ensuing proof-of-concept may be important because the free-energy formulation furnishes a unified account of both action and perception and may speak to a reappraisal of the role of dopamine in the brain.

Vowel-specific mismatch responses in the anterior superior temporal gyrus: An fMRI study

This paper considers prediction and perceptual categorization as an inference problem that is solved by the brain. We assume that the brain models the world as a hierarchy or cascade of dynamical systems that encode causal structure in the sensorium. Perception is equated with the optimization or inversion of these internal models, to explain sensory data. Given a model of how sensory data are generated, we can invoke a generic approach to model inversion, based on a free energy bound on the model's evidence. The ensuing free-energy formulation furnishes equations that prescribe the process of recognition, i.e. the dynamics of neuronal activity that represent the causes of sensory input. Here, we focus on a very general model, whose hierarchical and dynamical structure enables simulated brains to recognize and predict trajectories or sequences of sensory states. We first review hierarchical dynamical models and their inversion. We then show that the brain has the necessary infrastructure to implement this inversion and illustrate this point using synthetic birds that can recognize and categorize birdsongs.

DCM for Steady State Responses: a case study of anaesthesia depth.

Bayesian model selection for group studies (vol 46, pg 1005, 2009)

This paper describes the use of dynamic causal modelling to test hypotheses about the genesis of evoked responses. Specifically, we consider the mismatch negativity (MMN), a well characterised response to deviant sounds and one of the most widely studied evoked responses. There have been several mechanistic accounts of how the MMN might arise. It has been suggested that the MMN results from a comparison between sensory input and a memory trace of previous input but others have argued that local adaptation, due to stimulus repetition, is sufficient to explain the MMN. Thus, the precise mechanisms underlying the generation of the MMN remain unclear. This paper tests some biologically plausible spatiotemporal dipole models that rest on changes in extrinsic top-down connections (that enable comparison) and intrinsic changes (that model adaption). Dynamic causal modelling (DCM) suggested that responses to deviants are best explained by changes in effective connectivity both within and between cortical sources in a hierarchical network of distributed sources. Our model comparison suggests that both adaptation and memory comparison operate in concert to produce the early (N1 enhancement) and late (MMN) parts of the response to frequency deviants. We consider these mechanisms in the light of predictive coding and hierarchical inference in the brain.

DCM of the MMN 1 1 Dynamic causal modelling of the response to frequency deviants

Background Generalised spike wave (GSW) discharges are the electroencephalographic (EEG) hallmark of absence seizures, clinically characterised by a transitory interruption of ongoing activities and impaired consciousness, occurring during states of reduced awareness. Several theories have been proposed to explain the pathophysiology of GSW discharges and the role of thalamus and cortex as generators. In this work we extend the existing theories by hypothesizing a role for the precuneus, a brain region neglected in previous works on GSW generation but already known to be linked to consciousness and awareness. We analysed fMRI data using dynamic causal modelling (DCM) to investigate the effective connectivity between precuneus, thalamus and prefrontal cortex in patients with GSW discharges. Methodology and Principal Findings We analysed fMRI data from seven patients affected by Idiopathic Generalized Epilepsy (IGE) with frequent GSW discharges and significant GSW-correlated haemodynamic signal changes in the thalamus, the prefrontal cortex and the precuneus. Using DCM we assessed their effective connectivity, i.e. which region drives another region. Three dynamic causal models were constructed: GSW was modelled as autonomous input to the thalamus (model A), ventromedial prefrontal cortex (model B), and precuneus (model C). Bayesian model comparison revealed Model C (GSW as autonomous input to precuneus), to be the best in 5 patients while model A prevailed in two cases. At the group level model C dominated and at the population-level the p value of model C was ∼1. Conclusion Our results provide strong evidence that activity in the precuneus gates GSW discharges in the thalamo-(fronto) cortical network. This study is the first demonstration of a causal link between haemodynamic changes in the precuneus - an index of awareness - and the occurrence of pathological discharges in epilepsy.

Causal Hierarchy within the Thalamo-Cortical Network in Spike and Wave Discharges

Recent advances in data analysis and modeling allow the use of fMRI data to ask not just which brain regions are involved in various cognitive and perceptual tasks, but also how they communicate with each other. Karl Friston examines two different state-of-the-art approaches to modeling brain connectivity using neuroimaging.

Causal Modelling and Brain Connectivity in Functional Magnetic Resonance Imaging

This paper presents an extension of the Dynamic Causal Modelling (DCM) framework to the analysis of phase-coupled data. A weakly coupled oscillator approach is used to describe dynamic phase changes in a network of oscillators. The use of Bayesian model comparison allows one to infer the mechanisms ccepted 17 June 2009

False discovery rate revisited: FDR and topological inference using Gaussian random fields

Over the last 2 decades, a large number of neurophysiological and neuroimaging studies of patients with schizophrenia have furnished in vivo evidence for dysconnectivity, ie, abnormal functional integration of brain processes. While the evidence for dysconnectivity in schizophrenia is strong, its etiology, pathophysiological mechanisms, and significance for clinical symptoms are unclear. First, dysconnectivity could result from aberrant wiring of connections during development, from aberrant synaptic plasticity, or from both. Second, it is not clear how schizophrenic symptoms can be understood mechanistically as a consequence of dysconnectivity. Third, if dysconnectivity is the primary pathophysiology, and not just an epiphenomenon, then it should provide a mechanistic explanation for known empirical facts about schizophrenia. This article addresses these 3 issues in the framework of the dysconnection hypothesis. This theory postulates that the core pathology in schizophrenia resides in aberrant N-methyl-D-aspartate receptor (NMDAR)–mediated synaptic plasticity due to abnormal regulation of NMDARs by neuromodulatory transmitters like dopamine, serotonin, or acetylcholine. We argue that this neurobiological mechanism can explain failures of self-monitoring, leading to a mechanistic explanation for first-rank symptoms as pathognomonic features of schizophrenia, and may provide a basis for future diagnostic classifications with physiologically defined patient subgroups. Finally, we test the explanatory power of our theory against a list of empirical facts about schizophrenia.

Dysconnection in Schizophrenia: From Abnormal Synaptic Plasticity to Failures of Self-monitoring

Most experiments on the “neural correlates of consciousness” employ stimulus reportability as an operational definition of what is consciously perceived. The interpretation of such experiments therefore depends critically on understanding the neural basis of stimulus reportability. Using a high volume of fMRI data, we investigated the neural correlates of stimulus reportability using a partial report object detection paradigm. Subjects were presented with a random array of circularly arranged disc-stimuli and were cued, after variable delays (following stimulus offset), to report the presence or absence of a disc at the cued location, using variable motor actions. By uncoupling stimulus processing, decision, and motor response, we were able to use signal detection theory to deconstruct the neural basis of stimulus reportability. We show that retinotopically specific responses in the early visual cortex correlate with stimulus processing but not decision or report; a network of parietal/temporal regions correlates with decisions but not stimulus presence, whereas classical motor regions correlate with report. These findings provide a basic framework for understanding the neural basis of stimulus reportability without the theoretical burden of presupposing a relationship between reportability and consciousness.

There is much current debate about the existence of mirror neurons in humans. To identify mirror neurons in the inferior frontal gyrus (IFG) of humans, we used a repetition suppression paradigm while measuring neural activity with functional magnetic resonance imaging. Subjects either executed or observed a series of actions. Here we show that in the IFG, responses were suppressed both when an executed action was followed by the same rather than a different observed action and when an observed action was followed by the same rather than a different executed action. This pattern of responses is consistent with that predicted by mirror neurons and is evidence of mirror neurons in the human IFG.

A change of meaning causes connectivity changes within higher levels of the auditory cortical heirarchy

Patients with impaired auditory comprehension activate the ‘dorsal' temporo-frontal stream when listening to intelligible speech

This paper summarizes our recent attempts to integrate action and perception within a single optimization framework. We start with a statistical formulation of Helmholtz's ideas about neural energy to furnish a model of perceptual inference and learning that can explain a remarkable range of neurobiological facts. Using constructs from statistical physics it can be shown that the problems of inferring the causes of our sensory inputs and learning regularities in the sensorium can be resolved using exactly the same principles. Furthermore, inference and learning can proceed in a biologically plausible fashion. The ensuing scheme rests on Empirical Bayes and hierarchical models of how sensory information is generated. The use of hierarchical models enables the brain to construct prior expectations in a dynamic and context-sensitive fashion. This scheme provides a principled way to understand many aspects of the brain's organization and responses. We will demonstrate the brain-like dynamics that this scheme entails by using models of birdsongs that are based on chaotic attractors with autonomous dynamics. This provides a nice example of how non-linear dynamics can be exploited by the brain to represent and predict dynamics in the environment.

The brain's decoding of fast sensory streams is currently impossible to emulate, even approximately, with artificial agents. For example, robust speech recognition is relatively easy for humans but exceptionally difficult for artificial speech recognition systems. In this paper, we propose that recognition can be simplified with an internal model of how sensory input is generated, when formulated in a Bayesian framework. We show that a plausible candidate for an internal or generative model is a hierarchy of ‘stable heteroclinic channels’. This model describes continuous dynamics in the environment as a hierarchy of sequences, where slower sequences cause faster sequences. Under this model, online recognition corresponds to the dynamic decoding of causal sequences, giving a representation of the environment with predictive power on several timescales. We illustrate the ensuing decoding or recognition scheme using synthetic sequences of syllables, where syllables are sequences of phonemes and phonemes are sequences of sound-wave modulations. By presenting anomalous stimuli, we find that the resulting recognition dynamics disclose inference at multiple time scales and are reminiscent of neuronal dynamics seen in the real brain.

Variational Bayesian identification and prediction of stochastic nonlinear dynamic causal models

Processing of speech and nonspeech sounds occurs bilaterally within primary auditory cortex and surrounding regions of the superior temporal gyrus; however, the manner in which these regions interact during speech and nonspeech processing is not well understood. Here, we investigate the underlying neuronal architecture of the auditory system with magnetoencephalography and a mismatch paradigm. We used a spoken word as a repeating “standard” and periodically introduced 3 “oddball” stimuli that differed in the frequency spectrum of the word's vowel. The closest deviant was perceived as the same vowel as the standard, whereas the other 2 deviants were perceived as belonging to different vowel categories. The neuronal responses to these vowel stimuli were compared with responses elicited by perceptually matched tone stimuli under the same paradigm. For both speech and tones, deviant stimuli induced coupling changes within the same bilateral temporal lobe system. However, vowel oddball effects increased coupling within the left posterior superior temporal gyrus, whereas perceptually equivalent nonspeech oddball effects increased coupling within the right primary auditory cortex. Thus, we show a dissociation in neuronal interactions, occurring at both different hierarchal levels of the auditory system (superior temporal versus primary auditory cortex) and in different hemispheres (left versus right). This hierarchical specificity depends on whether auditory stimuli are embedded in a perceptual context (i.e., a word). Furthermore, our lateralization results suggest left hemisphere specificity for the processing of phonological stimuli, regardless of their elemental (i.e., spectrotemporal) characteristics.

Changing meaning causes coupling changes within higher levels of the cortical hierarchy

In this, the 21st century, human-brain mapping celebrates 21 years of cognitive activation studies. This review looks at imaging neuroscience and key ideas it has pursued; some ideas portend exciting developments, and others have failed gloriously. In terms of achievements, there is much to celebrate, in the sense that it is difficult to imagine modern neuroscience without brain imaging. I will look at recent advances from the perspectives of functional segregation and integration in the brain, paying special attention to approaches that deal with the distributed and integrated nature of neuronal processing and the questions they address.

Short-term adaptation to a simple motor task: A physiological process preserved in multiple sclerosis

Time-series analysis for rapid event-related skin conductance responses

Corrigendum to “Bayesian model selection for group studies” [NeuroImage 46 (2009) 1005–1017]

Forward and backward connections in the brain: A DCM study of functional asymmetries

Marginal utility theory prescribes the relationship between the objective property of the magnitude of rewards and their subjective value. Despite its pervasive influence, however, there is remarkably little direct empirical evidence for such a theory of value, let alone of its neurobiological basis. We show that human preferences in an intertemporal choice task are best described by a model that integrates marginally diminishing utility with temporal discounting. Using functional magnetic resonance imaging, we show that activity in the dorsal striatum encodes both the marginal utility of rewards, over and above that which can be described by their magnitude alone, and the discounting associated with increasing time. In addition, our data show that dorsal striatum may be involved in integrating subjective valuation systems inherent to time and magnitude, thereby providing an overall metric of value used to guide choice behavior. Furthermore, during choice, we show that anterior cingulate activity correlates with the degree of difficulty associated with dissonance between value and time. Our data support an integrative architecture for decision making, revealing the neural representation of distinct subcomponents of value that may contribute to impulsivity and decisiveness.

Dynamic causal modelling of distributed electromagnetic responses

Decoding functional dedifferentiation in aging: Evidence from Bayesian decoding of episodic memory formation

This article describes the use of dynamic causal modeling to test hypotheses about the genesis of evoked responses. Specifically, we consider the mismatch negativity (MMN), a well-characterized response to deviant sounds and one of the most widely studied evoked responses. There have been several mechanistic accounts of how the MMN might arise. It has been suggested that the MMN results from a comparison between sensory input and a memory trace of previous input, although others have argued that local adaptation, due to stimulus repetition, is sufficient to explain the MMN. Thus the precise mechanisms underlying the generation of the MMN remain unclear. This study tests some biologically plausible spatiotemporal dipole models that rest on changes in extrinsic top-down connections (that enable comparison) and intrinsic changes (that model adaptation). Dynamic causal modeling suggested that responses to deviants are best explained by changes in effective connectivity both within and between cortical sources in a hierarchical network of distributed sources. Our model comparison suggests that both adaptation and memory comparison operate in concert to produce the early (N1 enhancement) and late (MMN) parts of the response to frequency deviants. We consider these mechanisms in the light of predictive coding and hierarchical inference in the brain.

MEG and EEG data fusion: Simultaneous localisation of face-evoked responses

Attractor models of working memory and their modulation by reward

To identify and categorize complex stimuli such as familiar objects or speech, the human brain integrates information that is abstracted at multiple levels from its sensory inputs. Using cross-modal priming for spoken words and sounds, this functional magnetic resonance imaging study identified 3 distinct classes of visuoauditory incongruency effects: visuoauditory incongruency effects were selective for 1) spoken words in the left superior temporal sulcus (STS), 2) environmental sounds in the left angular gyrus (AG), and 3) both words and sounds in the lateral and medial prefrontal cortices (IFS/mPFC). From a cognitive perspective, these incongruency effects suggest that prior visual information influences the neural processes underlying speech and sound recognition at multiple levels, with the STS being involved in phonological, AG in semantic, and mPFC/IFS in higher conceptual processing. In terms of neural mechanisms, effective connectivity analyses (dynamic causal modeling) suggest that these incongruency effects may emerge via greater bottom-up effects from early auditory regions to intermediate multisensory integration areas (i.e., STS and AG). This is consistent with a predictive coding perspective on hierarchical Bayesian inference in the cortex where the domain of the prediction error (phonological vs. semantic) determines its regional expression (middle temporal gyrus/STS vs. AG/intraparietal sulcus).

The effect of prior visual information on recognition of speech and sounds.

Diffusion-based spatial priors for functional magnetic resonance images

This paper describes a general model that subsumes many parametric models for continuous data. The model comprises hidden layers of state-space or dynamic causal models, arranged so that the output of one provides input to another. The ensuing hierarchy furnishes a model for many types of data, of arbitrary complexity. Special cases range from the general linear model for static data to generalised convolution models, with system noise, for nonlinear time-series analysis. Crucially, all of these models can be inverted using exactly the same scheme, namely, dynamic expectation maximization. This means that a single model and optimisation scheme can be used to invert a wide range of models. We present the model and a brief review of its inversion to disclose the relationships among, apparently, diverse generative models of empirical data. We then show that this inversion can be formulated as a simple neural network and may provide a useful metaphor for inference and learning in the brain.

Graph-partitioned spatial priors for functional magnetic resonance images

Integrated Bayesian models of learning and decision making for saccadic eye movements☆

Induced oscillatory activity in the auditory cortex peaks at around 40 Hz in humans. Using regional cerebral blood flow and positron emission tomography we previously confirmed frequency-selective cortical responses to 40-Hz tones in auditory primary cortices and concomitant bilateral activation of the cerebellar hemispheres. In this study, using functional magnetic resonance imaging (fMRI) we estimated the influence of 40-Hz auditory stimulation on the coupling between auditory cortex and superior temporal sulcus (STS) and Crus II, using a dynamic causal model of the interactions between medial geniculate nuclei, auditory superior temporal gyrus (STG)/STS, and the cerebellar Crus II auditory region. Specifically, we tested the hypothesis that 40-Hz-selective responses in the cerebellar Crus II auditory region could be explained by frequency-specific enabling of interactions in the auditory cortico–cerebellar–thalamic loop. Our model comparison results suggest that input from auditory STG/STS to cerebellum is enhanced selectively at gamma-band frequencies around 40 Hz.

Frequency-Specific Coupling in the Cortico-Cerebellar Auditory System

Influence of Uncertainty and Surprise on Human Corticospinal Excitability during Preparation for Action

Objective: In order to demonstrate cortical motor control a pinch grip task is used, requiring subjects to execute an isometric muscular contraction. In this task electromyographic activity (EMG) recorded from finger muscles oscillates coherently with brain activity recorded over primary motor cortex using electro(EEG) or magnetoencephalography (MEG)[1]. Looking at the derivative of the phase with respect to frequency the time delay between brain signals and EMG is inferred. Phase differences between EMG and the brain signal as well as the topography of the coherent activity are usually estimated for individual frequencies. In order to improve the estimates of topography, phase shifts and time lags a new approach is presented. Methods: In this method the estimate of topography and phase is based on an extended frequency range. The complex coherence spectrum for different channels c and frequencies f, B=(bcf), is regarded as linear combination of the topographies of different sources s, L=(lcs) that are weighted by a complex matrix W=(wsf) describing phase shifts and contributions of different sources. Decomposing the coherence spectrum B=LW using a least-square fit approach, phase angles, topographies and weights are obtained. Results: Simulations and the analysis of experimental data are presented, demonstrating the applicability of the method. Conclusion: The method allows for robust estimates of source topographies of cortico-motor coherence as well as phase information. Moreover, the method is also useful for the study of cortico-cortical coherence. A slightly modified approach can be even used for the removal of powerline artifacts taking into account the specific topography of the artifact. References & Acknowledgments: [1] Braun et al. 2007. Supported by BMBF Bernstein-Project 01GQ0761 and DFG (SFB 550/C6).

Magnetomyographic Recording And Identification Of Uterine Contractions Using Hilbert-Wavelet Transform

Variational Bayesian inversion of the equivalent current dipole model in EEG/MEG

It Is Time to Take a Stand for Medical Research and Against Terrorism Targeting Medical Scientists

An important and unresolved question is how the human brain processes speech for meaning after initial analyses in early auditory cortical regions. A variety of left-hemispheric areas have been identified that clearly support semantic processing, although a systematic analysis of directed interactions among these areas is lacking. We applied dynamic causal modeling of functional magnetic resonance imaging responses and Bayesian model selection to investigate, for the first time, experimentally induced changes in coupling among three key multimodal regions that were activated by intelligible speech: the posterior and anterior superior temporal sulcus (pSTS and aSTS, respectively) and pars orbitalis (POrb) of the inferior frontal gyrus. We tested 216 different dynamic causal models and found that the best model was a “forward” system that was driven by auditory inputs into the pSTS, with forward connections from the pSTS to both the aSTS and the POrb that increased considerably in strength (by 76 and 150%, respectively) when subjects listened to intelligible speech. Task-related, directional effects can now be incorporated into models of speech comprehension.

Background It has been suggested that some psychotic symptoms reflect ‘aberrant salience’, related to dysfunctional reward learning. To test this hypothesis we investigated whether patients with schizophrenia showed impaired learning of task-relevant stimulus–reinforcement associations in the presence of distracting task-irrelevant cues. Method We tested 20 medicated patients with schizophrenia and 17 controls on a reaction time game, the Salience Attribution Test. In this game, participants made a speeded response to earn money in the presence of conditioned stimuli (CSs). Each CS comprised two visual dimensions, colour and form. Probability of reinforcement varied over one of these dimensions (task-relevant), but not the other (task-irrelevant). Measures of adaptive and aberrant motivational salience were calculated on the basis of latency and subjective reinforcement probability rating differences over the task-relevant and task-irrelevant dimensions respectively. Results Participants rated reinforcement significantly more likely and responded significantly faster on high-probability-reinforced relative to low-probability-reinforced trials, representing adaptive motivational salience. Patients exhibited reduced adaptive salience relative to controls, but the two groups did not differ in terms of aberrant salience. Patients with delusions exhibited significantly greater aberrant salience than those without delusions, and aberrant salience also correlated with negative symptoms. In the controls, aberrant salience correlated significantly with ‘introvertive anhedonia’ schizotypy. Conclusions These data support the hypothesis that aberrant salience is related to the presence of delusions in medicated patients with schizophrenia, but are also suggestive of a link with negative symptoms. The relationship between aberrant salience and psychotic symptoms warrants further investigation in unmedicated patients.

Action, perception and free-energy (Thursday May 29th) Value-learning and perceptual learning have been an important focus over the past decade, attracting the concerted attention of experimental psychologists, neurobiologists and the machine learning community. Despite some formal connections; e.g., the role of prediction error in optimising some function of sensory states, both fields have developed their own rhetoric and postulates.  In work, we show that perceptual learning is, literally,...

A Free energy principle for the brain. Résumé des conférences du Collège de France (2007-2008)

In this paper, we suggest that cortical anatomy recapitulates the temporal hierarchy that is inherent in the dynamics of environmental states. Many aspects of brain function can be understood in terms of a hierarchy of temporal scales at which representations of the environment evolve. The lowest level of this hierarchy corresponds to fast fluctuations associated with sensory processing, whereas the highest levels encode slow contextual changes in the environment, under which faster representations unfold. First, we describe a mathematical model that exploits the temporal structure of fast sensory input to track the slower trajectories of their underlying causes. This model of sensory encoding or perceptual inference establishes a proof of concept that slowly changing neuronal states can encode the paths or trajectories of faster sensory states. We then review empirical evidence that suggests that a temporal hierarchy is recapitulated in the macroscopic organization of the cortex. This anatomic-temporal hierarchy provides a comprehensive framework for understanding cortical function: the specific time-scale that engages a cortical area can be inferred by its location along a rostro-caudal gradient, which reflects the anatomical distance from primary sensory areas. This is most evident in the prefrontal cortex, where complex functions can be explained as operations on representations of the environment that change slowly. The framework provides predictions about, and principled constraints on, cortical structure–function relationships, which can be tested by manipulating the time-scales of sensory input.

Predictive coding explains binocular rivalry: An epistemological review

This paper introduces a model of ‘theory of mind’, namely, how we represent the intentions and goals of others to optimise our mutual interactions. We draw on ideas from optimum control and game theory to provide a ‘game theory of mind’. First, we consider the representations of goals in terms of value functions that are prescribed by utility or rewards. Critically, the joint value functions and ensuing behaviour are optimised recursively, under the assumption that I represent your value function, your representation of mine, your representation of my representation of yours, and so on ad infinitum. However, if we assume that the degree of recursion is bounded, then players need to estimate the opponent's degree of recursion (i.e., sophistication) to respond optimally. This induces a problem of inferring the opponent's sophistication, given behavioural exchanges. We show it is possible to deduce whether players make inferences about each other and quantify their sophistication on the basis of choices in sequential games. This rests on comparing generative models of choices with, and without, inference. Model comparison is demonstrated using simulated and real data from a ‘stag-hunt’. Finally, we note that exactly the same sophisticated behaviour can be achieved by optimising the utility function itself (through prosocial utility), producing unsophisticated but apparently altruistic agents. This may be relevant ethologically in hierarchal game theory and coevolution.

Bayesian estimation of synaptic physiology from the spectral responses of neural masses

This issue's front section features a special Review: The Dynamic Brain: From Spiking Neurons to Neural Masses and Cortical Fields. I was asked to write this Editorial on behalf of the editors and coauthors of the article, as an introduction— an introduction that we hope will serve as an aperitif for the article itself. The Review was solicited by Rolf Kotter (PLoS Computational Biology Reviews Editor) at one of the annual Brain Connectivity Workshops (http://www.hirnforschung.net/bcw), which we cofounded many years ago. These are highly interactive, discussion-orientated meetings that focus on the latest advances in modelling functional integration and coupling in the brain. They naturally attract a broad range of computational neuroscientists, neurophysiologists, neuroanatomists, and cognitive scientists. That year, we seemed drawn to computational neurobiology and the models of neuronal dynamics that were being used to understand interactions in the brain. 
 
After a couple of days, it became clear that we were all using exactly the same rhetoric in reference to completely different things. Terms such as mean-field approximations, mass-action, neural-mass models, neural-field models, density-dynamics, etc., were used with exuberance but did not really help us to communicate. As a result, Rolf challenged us to define and synthesise these perspectives in a coherent and pragmatic way; the response to that challenge is the article in this issue of PLoS Computational Biology by Deco, Jirsa, Robinson, Breakspear, and Friston, which took more than two years to prepare. The difficulties became evident quickly when we started to integrate our respective contributions. These were far from coherent and disclosed some fundamental differences in the perspectives adopted on modelling distributed brain activity at a statistical level. These differences ranged from the semantic (e.g., what does “mass” mean in neural-mass models) to the sublime (e.g., some of us clearly found it difficult, if not heartbreaking, to give up our favourite variables to ensure notational consistency). This, in part, reflects the fact that the coauthors are all autonomous and senior scientists in their own fields, working on different continents, and emerging from very distinct intellectual backgrounds. Even the way in which these models were being used differed markedly among the contributors. After numerous iterations and cross-revision, the end product started to attain a degree of coherence (although some might argue there is still room for improvement). 
 
The basic issue our synthesis tries to address is how different models, used to simulate and predict observed brain dynamics, can be traced back to their common fundaments. We then try to illustrate the diversity of applications that can be entertained with these models. The basis of these models rests on modelling, not on the behaviour of individual nerve cells or neurons, but on the probability density over ensembles or populations of similar neurons. The Fokker-Planck formalism becomes central here and can be harnessed using neuronal models that are cast in terms of differential equations, with or without discrete behaviours (e.g., neuronal spiking or firing). From the density dynamics afforded by the Fokker-Planck equation, we then pursue various simplifications and special cases. An important example is when the density becomes a point-mass over the expected states of a population. These are referred to as neural-mass models and predominate in the computational neuroscience literature. A key generalisation of these neural-mass models is to neural-field models, where the location of the mass or expected state of a population becomes a function of both time and position on the brain's cortical surface or subcortical structures. These models generate all sorts of interesting and neuronally plausible patterns and self-organising phenomena, which can be inferred through invasive or non-invasive electrophysiological recordings of real brains. 
 
The applications of these models are essentially twofold; some authors use them to understand the basic principles of neuronal dynamics and implicit computations; for example, understanding dynamics in terms of nonlinear mechanisms such as bifurcations, understanding perceptual categorisation in terms of multistability, or identifying the domains of parameter–space that support commonly observed spatiotemporal patterns of activity. Other authors use these models as forward or generative models, whose parameters can be optimised to reproduce an observed dataset. This is known as model inversion and allows one to estimate important biophysical constants and parameters from empirical data. In this context, one can also explore model spaces and use data to adjudicate among various neural-mass or field models. We have chosen a few key examples that highlight the necessary role of density-dynamics and mean-field approximations in computational neuroscience. 
 
Participating in this Review has been an enormously enlightening experience; at the same time it was exhausting and something I will think twice about before engaging in again. This is not meant to be a brief orientation to the field but more an attempt to provide a reference framework for people to understand their own contributions, in relation to others. It is a Review that I look forward to giving to my students; although I suspect they will take more than a weekend to digest it.

213 – Towards model-based indices of pathophysiological mechanisms in schizophrenia

The Israel Society for Neuroscience—ISFN—was founded in 1993 by a group of Israeli leading scientists conducting research in the area of neurobiology. The primary goal of the society was to promote and disseminate the knowledge and understanding acquired by its members, and to strengthen interactions between them. Since then, the society holds its annual meeting every year in Eilat usually during December. At this annual meetings, the senior Israeli neurobiologists, their teams, and their graduate students, as well as foreign scientists and students, present their recent research findings in platform and poster presentations, and the program of the meeting is mainly based on the 338 received abstracts which are published in this volume. The meeting also offers the opportunity for the researchers to exchange information with each other, often leading to the initiation of collaborative studies. Both the number of members of the society and those participating in the annual meeting is constantly increasing, and it is anticipated that this year about 600 scientists will convene at the Princess Hotel in Eilat, Israel. Further information concerning the Israel Society for Neuroscience can be found at http://www.isfn.org.il. Committee: Shlomo Rotshenker (President) Hebrew University of Jerusalem Talma Brenner Hadassah–Hebrew University Medical Center Yoram Rami Grossman Ben Gurion University of the Negev Mmouna Maroun University of Haifa Yoel Yaari Hebrew University of Jerusalem Gal Yadid Bar-Ilan University Zvi Wollberg (Past President) Tel Aviv University Lili Anglister (Treasurer) Hebrew University of Jerusalem Michal Gilady (Administrator) Rishon Le Zion

Abstracts of the 16th Annual Meeting of The Israel Society for Neuroscience Eilat, Israel, November 25–27, 2007

Statistical parametric mapping is the application of Random Field Theory to make inferences about the topological features of statistical processes that are continuous functions of space or time. It is usually used to identify regionally specific effects (e.g., brain activations) in neuroimaging data to characterize functional anatomy and disease-related changes.

The cortex is a complex system, characterized by its dynamics and architecture, which underlie many functions such as action, perception, learning, language, and cognition. Its structural architecture has been studied for more than a hundred years; however, its dynamics have been addressed much less thoroughly. In this paper, we review and integrate, in a unifying framework, a variety of computational approaches that have been used to characterize the dynamics of the cortex, as evidenced at different levels of measurement. Computational models at different space–time scales help us understand the fundamental mechanisms that underpin neural processes and relate these processes to neuroscience data. Modeling at the single neuron level is necessary because this is the level at which information is exchanged between the computing elements of the brain; the neurons. Mesoscopic models tell us how neural elements interact to yield emergent behavior at the level of microcolumns and cortical columns. Macroscopic models can inform us about whole brain dynamics and interactions between large-scale neural systems such as cortical regions, the thalamus, and brain stem. Each level of description relates uniquely to neuroscience data, from single-unit recordings, through local field potentials to functional magnetic resonance imaging (fMRI), electroencephalogram (EEG), and magnetoencephalogram (MEG). Models of the cortex can establish which types of large-scale neuronal networks can perform computations and characterize their emergent properties. Mean-field and related formulations of dynamics also play an essential and complementary role as forward models that can be inverted given empirical data. This makes dynamic models critical in integrating theory and experiments. We argue that elaborating principled and informed models is a prerequisite for grounding empirical neuroscience in a cogent theoretical framework, commensurate with the achievements in the physical sciences.

The Dynamic Brain: From Spiking Neurons to Neural Masses and Cortical Fields

The functional anatomy of the MMN: A DCM study of the roving paradigm

Population dynamics: Variance and the sigmoid activation function

Confronted with a rich sensory environment, the brain must learn statistical regularities across sensory domains to construct causal models of the world. Here, we used functional magnetic resonance imaging and dynamic causal modeling (DCM) to furnish neurophysiological evidence that statistical associations are learnt, even when task-irrelevant. Subjects performed an audio-visual target-detection task while being exposed to distractor stimuli. Unknown to them, auditory distractors predicted the presence or absence of subsequent visual distractors. We modeled incidental learning of these associations using a Rescorla–Wagner (RW) model. Activity in primary visual cortex and putamen reflected learning-dependent surprise: these areas responded progressively more to unpredicted, and progressively less to predicted visual stimuli. Critically, this prediction-error response was observed even when the absence of a visual stimulus was surprising. We investigated the underlying mechanism by embedding the RW model into a DCM to show that auditory to visual connectivity changed significantly over time as a function of prediction error. Thus, consistent with predictive coding models of perception, associative learning is mediated by prediction-error dependent changes in connectivity. These results posit a dual role for prediction-error in encoding surprise and driving associative plasticity.

Extra-classical receptive field effects measured in striate cortex with fMRI

Dynamic causal modelling of evoked responses: The role of intrinsic connections

Dynamic causal modeling: A generative model of slice timing in fMRI

The mechanisms underlying interhemispheric integration (IHI) remain poorly understood, particularly for lateralized cognitive processes. To test competing theories of IHI, we constructed and fitted dynamic causal models to functional magnetic resonance data from two visual tasks that operated on identical stimuli but showed opposite hemispheric dominance. Using a systematic Bayesian model selection procedure, we found that, in the ventral visual stream, which was activated by letter judgments, interhemispheric connections mediated asymmetric information transfer from the nonspecialized right to the specialized left hemisphere when the latter did not have direct access to stimulus information. Notably, this form of IHI did not engage all areas activated by the task but was specific for areas in the lingual and fusiform gyri. In the dorsal stream, activated by spatial judgments, it did not matter which hemisphere received the stimulus: interhemispheric coupling increased bidirectionally, reflecting recruitment of the nonspecialized left hemisphere. Again, not all areas activated by the task were involved in this form of IHI; instead, it was restricted to interactions between areas in the superior parietal gyrus. Overall, our results provide direct neurophysiological evidence, in terms of effective connectivity, for the existence of context-dependent mechanisms of IHI that are implemented by specific visual areas during task-driven lateralization.

Interhemispheric Integration of Visual Processing during Task-Driven Lateralization

In an age where the amount of data collected from brain imaging is increasing constantly, it is of critical importance to analyse those data within an accepted framework to ensure proper integration and comparison of the information collected. This book describes the ideas and procedures that underlie the analysis of signals produced by the brain. The aim is to understand how the brain works, in terms of its functional architecture and dynamics. This book provides the background and methodology for the analysis of all types of brain imaging data, from functional magnetic resonance imaging to magnetoencephalography. Critically,Statistical Parametric Mappingprovides a widely accepted conceptual framework which allows treatment of all these different modalities. This rests on an understanding of the brain's functional anatomy and the way that measured signals are caused experimentally. The book takes the reader from the basic concepts underlying the analysis of neuroimaging data to cutting edge approaches that would be difficult to find in any other source. Critically, the material is presented in an incremental way so that the reader can understand the precedents for each new development. This book will be particularly useful to neuroscientists engaged in any form of brain mapping; who have to contend with the real-world problems of data analysis and understanding the techniques they are using. It is primarily a scientific treatment and a didactic introduction to the analysis of brain imaging data. It can be used as both a textbook for students and scientists starting to use the techniques, as well as a reference for practicing neuroscientists. The book also serves as a companion to the software packages that have been developed for brain imaging data analysis. * An essential reference and companion for users of the SPM software * Provides a complete description of the concepts and procedures entailed by the analysis of brain images * Offers full didactic treatment of the basic mathematics behind the analysis of brain imaging data * Stands as a compendium of all the advances in neuroimaging data analysis over the past decade * Adopts an easy to understand and incremental approach that takes the reader from basic statistics to state of the art approaches such as Variational Bayes * Structured treatment of data analysis issues that links different modalities and models * Includes a series of appendices and tutorial-style chapters that makes even the most sophisticated approaches accessible. © 2007 Elsevier Ltd All rights reserved.

Statistical Parametric Mapping: The Analysis of Functional Brain Images

Dynamic causal modelling of evoked potentials: A reproducibility study

Sensory information from the external world is inherently ambiguous, necessitating prior experience as a constraint on perception. Prolonged experience (adaptation) induces perception of ambiguous morph faces as a category different from the adapted category, suggesting sensitivity in underlying neural codes to differences between input and recent experience. Using magnetoencephalography, we investigated the neural dynamics of such experience-dependent visual coding by focusing on the timing of responses to morphs after facial expression adaptation. We show that evoked fields arising from the superior temporal sulcus (STS) reflect the degree to which a morph and adapted expression deviate. Furthermore, adaptation effects within STS predict the magnitude of behavioral aftereffects. These findings show that the STS codes expressions relative to recent experience rather than absolutely and may bias perception of expressions. One potential neural mechanism for the late timing of both effects appeals to hierarchical models that ascribe a central role to backward connections in mediating predictive codes.

Experience-dependent coding of facial expression in superior temporal sulcus

The sections in this article are 
 
1 
Introduction 
 
2 
Functional Specialization and Integration 
 
3 
Spatial Realignment and Anatomical Normalization 
 
4 
Statistical Parametric Mapping and Functional Specialization 
 
5 
A Signal Processing Perspective 
 
6 
Epoch- and Event-Related fMRI 
 
7 
Inferences about Subjects and Populations 
 
8 
Effective Connectivity and Functional Integration 
 
9 
Acknowledgements 
 
10 
Biographical Sketch 
 
Related Articles

Spatial , Temporal , and Spatiotemporal IndependentComponent Analysis of fMRI

This work examines the computational architecture used by the brain during the analysis of the spectral envelope of sounds, an important acoustic feature for defining auditory objects. Dynamic causal modelling and Bayesian model selection were used to evaluate a family of 16 network models explaining functional magnetic resonance imaging responses in the right temporal lobe during spectral envelope analysis. The models encode different hypotheses about the effective connectivity between Heschl's Gyrus (HG), containing the primary auditory cortex, planum temporale (PT), and superior temporal sulcus (STS), and the modulation of that coupling during spectral envelope analysis. In particular, we aimed to determine whether information processing during spectral envelope analysis takes place in a serial or parallel fashion. The analysis provides strong support for a serial architecture with connections from HG to PT and from PT to STS and an increase of the HG to PT connection during spectral envelope analysis. The work supports a computational model of auditory object processing, based on the abstraction of spectro-temporal “templates” in the PT before further analysis of the abstracted form in anterior temporal lobe areas.

Spatial normalization of lesioned brains: Performance evaluation and impact on fMRI analyses

We describe a simple and efficient solution to the problem of reconstructing electromagnetic sources into a canonical or standard anatomical space. Its simplicity rests upon incorporating subject-specific anatomy into the forward model in a way that eschews the need for cortical surface extraction. The forward model starts with a canonical cortical mesh, defined in a standard stereotactic space. The mesh is warped, in a nonlinear fashion, to match the subject's anatomy. This warping is the inverse of the transformation derived from spatial normalization of the subject's structural MRI image, using fully automated procedures that have been established for other imaging modalities. Electromagnetic lead fields are computed using the warped mesh, in conjunction with a spherical head model (which does not rely on individual anatomy). The ensuing forward model is inverted using an empirical Bayesian scheme that we have described previously in several publications. Critically, because anatomical information enters the forward model, there is no need to spatially normalize the reconstructed source activity. In other words, each source, comprising the mesh, has a predetermined and unique anatomical attribution within standard stereotactic space. This enables the pooling of data from multiple subjects and the reporting of results in stereotactic coordinates. Furthermore, it allows the graceful fusion of fMRI and MEG data within the same anatomical framework.

CHAPTER 37 – Functional connectivity: eigenimages and multivariate analyses

Is it possible to understand the intentions of other people by simply observing their movements? Many neuroscientists believe that this ability depends on the brain's mirror-neuron system, which provides a direct link between action and observation. Precisely how intentions can be inferred through movement-observation, however, has provoked much debate. One problem in inferring the cause of an observed action, is that the problem is ill-posed because identical movements can be made when performing different actions with different goals. Here we suggest that this problem is solved by the mirror-neuron system using predictive coding on the basis of a statistical approach known as empirical Bayesian inference. This means that the most likely cause of an observed movement can be inferred by minimizing the prediction error at all cortical levels that are engaged during movement observation. This account identifies a precise role for the mirror-neuron system in our ability to infer intentions from observed movement and outlines possible computational mechanisms.

Population-level inferences for distributed MEG source localization under multiple constraints: Application to face-evoked fields

Since the brain may engage different neuronal systems for a single behavioral goal, activation may show intersubject variability expressed in the systematic recruitment of multiple distinct networks. We apply a principal component analysis (PCA) to activation over task conditions and subjects to reveal cortical networks that may underlie this intersubject variability. Normal subjects were presented with novel meaningless objects, which appeared in personally familiar or unfamiliar places. During a subsequent, event‐related functional MRI (fMRI) experiment, each subject was presented with learned or novel objects in isolation and performed a learned/novel judgment. Recollection of places was not essential for the task, and may exhibit large intersubject variations. The right posterodorsal posterior cingulate cortex (pPCC) and left retrosplenial cortex, whose involvement in place‐recognition has been previously established, were selected as regions of interest for the PCA. Neural responses to objects associated with familiar relative to unfamiliar places in pPCC, but not in the retrosplenial cortex, were negatively correlated with task‐related activation (common over all objects) in the right anterolateral prefrontal cortex and the left intraparietal sulcus. The latter areas have been implicated previously in cognitive control and object recognition, respectively. These results suggest right prefrontal control over neural processes both in the left parietal cortex, related to object‐recognition (enhancement), and pPCC, related to nonessential recollection of place‐memory (suppression), but not in the retrosplenial cortex, related to the sense of familiarity. This analysis revealed an important aspect of functional anatomy that was not detectable using a conventional analysis of average activations. Hum. Brain Mapp, 2007. © 2006 Wiley‐Liss, Inc.

Analysis of intersubject variability in activation: An application to the incidental episodic retrieval during recognition test

Dynamic causal models of neural system dynamics: current state and future extensions

Neuronal responses to stimuli, measured electrophysiologically, unfold over several hundred milliseconds. Typically, they show characteristic waveforms with early and late components. It is thought that early or exogenous components reflect a perturbation of neuronal dynamics by sensory input bottom-up processing. Conversely, later, endogenous components have been ascribed to recurrent dynamics among hierarchically disposed cortical processing levels, top-down effects. Here, we show that evoked brain responses are generated by recurrent dynamics in cortical networks, and late components of event-related responses are mediated by backward connections. This evidence is furnished by dynamic causal modeling of mismatch responses, elicited in an oddball paradigm. We used the evidence for models with and without backward connections to assess their likelihood as a function of peristimulus time and show that backward connections are necessary to explain late components. Furthermore, we were able to quantify the contribution of backward connections to evoked responses and to source activity, again as a function of peristimulus time. These results link a generic feature of brain responses to changes in the sensorium and a key architectural component of functional anatomy; namely, backward connections are necessary for recurrent interactions among levels of cortical hierarchies. This is the theoretical cornerstone of most modern theories of perceptual inference and learning.

Coregistration of functional PET and T1{weighted MR images is a necessary step for combining functional information from PET images with anatomical information in MR images. Several coregistration algorithms have been published and are used in functional brain imaging studies. In this paper, we present a comparison and crossvalidation of the two most widely used coregistration routines (Friston et al., 1995; Woods et al., 1993). Several transformations were applied to high{ resolution anatomical MR images to generate simulated PET images so that the exact (rigid body) transformations between each MR image and its associated simulated PET images were known. The estimation error of a coregistration in relation to the known transformation allows a comparison of the performance of di erent coregistration routines. Under the assumption that the simulated PET images embody the salient features of real PET images with respect to coregistration, this study shows that the routines examined reliably solve the MRI to PET coregistration problem. 2 Introduction In neuroimaging, coregistration of functional PET and anatomical MR images is essential for combining information from both image modalities. The bene t of having coregistered images is that it enables the visualization of functional PET data by superimposing it on a high-resolution anatomical MR image and therefore improves localization of neural activation loci. Several algorithms have been proposed by various authors (Andersson et al., 1995; Ardekani et al., 1995; Friston et al., 1995; Mangin et al., 1994; Woods et al., 1993). We chose two widely used coregistration algorithms (Woods et al., 1993; Friston et al., 1995) to crossvalidate on the same test data set. The rst routine is contained in the Automated Image Registration-package (AIR, version 2.03) and the second is part of the Statistical Parametric Mapping-package (SPM95). This crossvalidation includes an empirical validation of the SPM -routine, which had not been undertaken before, and facilitates a comparison of the performance of both routines. To generate a suitable PET data set, we used simulated PET images, which were generated by applying a series of transformations to some MR images. Rigid body transformations, applied to the simulated PET images were used to simulate misregistrations between the PET and MR data. After running both coregistration routines on the MR and simulated PET images, it was possible to assess and compare the errors associated with them. Methods We describe the basic concepts of MRI and PET coregistration, followed by an overview and theoretical comparison of the AIRand SPM -algorithms. We also describe the crossvalidation procedure, particularly generation of simulated PET images. 3 Basic Concepts Generally, an MRI to PET coregistration algorithm transforms an MR image M in such a way that each voxel in the transformed MR image M 0 and in the PET image P correspond to the same voxel in real brain space. Since images of both modalities are acquired from the same subject, a rigid body transformation T maps M to M 0. We assume that the scanning processes have not introduced non-rigid spatial transformations into either the PET or MR image or that these distortions are small. We also assume that no spatial scaling factor of the data is introduced by inaccurate voxel sizes. The required transformation can then be described by translations and rotations in three dimensions so that any coregistration algorithm computes six parameters: x-, y-, z-translation, pitch, roll and yaw. The main challenge in MRI and PET coregistration is that, even if both images are perfectly coregistered, there is no 'simple' function which maps voxel intensities from the MR uniquely to the PET image. For instance, scalp and white matter produce roughly the same voxel intensities within an MR image, but are associated with di erent voxel values within a PET image. Therefore, coregistration based only on the voxel intensities of both images is di cult, if not impossible. To address this issue, the images can be preprocessed to eschew this problem of non-unique mapping. An example is the often used (manual) scalp-editing of the MR image prior to coregistration. This sort of preprocessing renders the coregistration problem solvable, however, it is desirable to automate this preprocessing task and incorporate it into a coregistration routine, since manual scalp-editing can be laborious for the user. The SPM -algorithm is an example of this non supervised class of algorithm. Since we will use the standard (4 4)-matrix format throughout the text to represent a transformation T , this matrix format is described in the following. A (4 4)-transformation matrix, which we also interchangeably denote by T , is 4 given by T = BBBBBBBB@ t11 t12 t13 t14 t21 t22 t23 t24 t31 t32 t33 t34 0 0 0 1 CCCCCCCCA (1) where the elements of the rst three rows of T are chosen in a way such that BBBBBBBB@ y1 y2 y3 1 CCCCCCCCA = T BBBBBBBB@ x1 x2 x3 1 CCCCCCCCA (2) where x = (x1; x2; x3)0 is a voxel position in the original image M and y = (y1; y2; y3)0 is the according voxel position in M 0 after transformation with T . For instance, the matrix Tt = BBBBBBBB@ 1 0 0 t14 0 1 0 t24 0 0 1 t34 0 0 0 1 CCCCCCCCA (3) would represent a three dimensional translation by t14 in x-, t24 in yand t34 in z-direction (voxels). The rotations rx; ry; rz (radians) around the three axes (pitch, roll and yaw) are similarly coded by Trx = BBBBBBBB@ 1 0 0 0 0 cos(rx) sin(rx) 0 0 sin(rx) cos(rx) 0 0 0 0 1 CCCCCCCCA (4) Try = BBBBBBBB@ cos(ry) 0 sin(ry) 0 0 1 0 0 sin(ry) 0 cos(ry) 0 0 0 0 1 CCCCCCCCA (5) 5 Trz = BBBBBBBB@ cos(rz) sin(rz) 0 0 sin(rz) cos(rz) 0 0 0 0 1 0 0 0 0 1 CCCCCCCCA (6) The advantage of this matrix representation is that several sequentially applied transformations Ti, i = 1; : : : ; Q can be expressed by only one transformation matrix T : T = Q Y i=1Ti (7) (Note that T1 is not the rst, but the last applied transformation.) In this way, we can represent a rigid body transformation with six parameters by one transformation matrix. Another important property of these matrices is that the inverse of the matrix T (denoted by T 1) is also the inverse of the transformation T . SPM and AIR basically use the same format except for the order of rotations, which does matter as one can see from equations 4 6. In SPM , a rigid body transformation matrix is given by T = Tt Trx Try Trz and in AIR it is T = Tt Try Trx Trz . The AIR-algorithm We used the AIR 2.03 routine with the cost function based upon the standard deviation of the 'ratio image' for crossvalidation. Although version 2.03 of the AIR-package also o ers a second routine for coregistration, we chose the rst routine, since it had been described in (Woods et al., 1993) and already crossvalidated with other coregistration routines (Strother et al., 1994). The approach taken by the AIR-algorithm is to de ne a cost function for measuring the MRI and PET misregistration. A transformation matrix is then found by iterative, nonlinear minimization of this cost function. The AIR-algorithm is based on the key assumption that similar voxel intensities 6 in the MR image correspond to the same tissue type. We refer to this assumption as the 'similarity assumption' in the remainder of text. The similarity assumption is roughly valid, if the T1-weighted MR image is scalp-edited, i.e. voxels not corresponding to brain tissue are set to zero. This scalp-editing has to be done prior to coregistration. Assuming that the similarity assumption holds not only for MR images but also for PET images, the idea is to nd a rigid body transformation T so that all MR voxels with the same intensity value are mapped to a set of similar PET voxel intensity values. The similarity of a set of PET voxels can be measured by the ratio of its standard deviation and mean. Described more formally, the algorithm uses a histogram segmentation to segment the MR image into K voxel intensity partitions Pi and minimizes a weighted ratio of the standard deviations and means of the PET voxels corresponding to Pi by manipulating the transformation matrix T . The key formula of the algorithm is f(PET;MRI; T ) = 1 N K Xj nj j aj (8) where PET is the PET image, MRI is the MR image, T stands for the transformation matrix, nj is the number of MRI-voxels with an intensity of j, N = PKj nj, aj is the mean of all PET voxel values with a corresponding MRI voxel intensity in partition j, and j is their standard deviation. Changing T , for example translating the MRI in relation to the PET image by 1 mm, means changing the value of j aj for all j. The aim of the algorithm is to nd T such that the right hand side of equation 8 is minimized. This computation requires a nonlinear minimization scheme, because the additive components in equation 8 are not independent. The minimization method chosen is Southwell's Relaxation Search (Pierre, 1986), which is an iterative, univariate Newton{Raphson search. The overall minimization is performed iteratively, each step producing a new transformation matrix T , which is subsequently used in the next Newton-Raphson iteration. When the coregistration is good enough, i.e. the minimization process arrives at a global or local minimum 7 in the parameter space of T , or when a prespeci ed maximum of iteration steps is reached, the algorithm will stop and return the computed transformation matrix T . The SPM-algorithm The basic strategy of the SPM -algorithm is to transform the MR image to an emulated PET image and to map this image to the real PET image. The rst step is to segment the MR image into four partitions: grey matter, white matter, cerebrospinal uid (CSF) and 'everything else'. Because of this preprocessing segmentation it is possible to use either a scalp-edited or a non scalp-edited MR image for coregistration: The algorithm should segment any MRI into its four partitions. In the case of a non scalp-edite

Mri and Pet Coregistration | a Crossvalidation of Spm and Air Running Title Mri and Pet Coregistration | a Crossvalidation Address for Correspondence

Lesion and functional imaging studies in humans have suggested that the dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex (VLPFC), and intraparietal sulcus (IPS) are involved in orienting attention. A functional magnetic resonance imaging study supplemented by a behavioral experiment examined the effects of 5 Hz repetitive transcranial magnetic stimulation (rTMS) conditioning to the right and left DLPFC on reaction times and synaptic activity as indexed by changes in the blood oxygenation level-dependent (BOLD) signal during a cued choice reaction time task. Orienting precues were either correct (valid) or incorrect (invalid) with respect to the subsequent move cue. The effects of real and sham rTMS were compared for each site of stimulation. Invalid trials showed a significant increase in response times and increases in the BOLD signal in right frontal and parietal regions when compared with valid trials. Conditioning left DLPFC with rTMS led to decreased BOLD signal during performance of this reorienting task in areas including left VLPFC and left IPS. Comparing invalid to valid trials after right DLPFC conditioning revealed decreased BOLD signal in right VLPFC. Data from the behavioral study showed that right DLPFC rTMS selectively increases response times in invalid trials. This effect was only present in the first 10 min after rTMS conditioning. No effect was found in either validly or invalidly cued trials with left DLPFC conditioning. These results suggest that 5 Hz rTMS over right DLPFC exerts remote effects on the activity of areas that functionally interact with the DLPFC during attentional processes, particularly when the reorienting of attention is more demanding as in invalid trials.

Acute Changes in Frontoparietal Activity after Repetitive Transcranial Magnetic Stimulation over the Dorsolateral Prefrontal Cortex in a Cued Reaction Time Task

In this chapter we discuss the application of Bayesian methods to neuroimag-ing data. This includes data from positron emission tomography (PET), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and magnetoencephalography (MEG). We concentrate on fMRI but the concepts, methodologies, and modeling approaches apply to all modalities. A general issue in the analysis of brain imaging data is the relationship between the neurobiological hypothesis one posits and the statistical models adopted to test that hypothesis. One key distinction is between functional specialization and integration. Briefly, fMRI was originally used to provide functional maps showing which regions are specialized for specific functions, a classic example being the study by Zeki et al. [27] who identified V4 and V5 as being specialized for the processing of color and motion, respectively. More recently, these analyses have been augmented by functional integration studies, which describe how functionally specialized areas interact and how these interactions depend on changes of context. A recent example is the study by Buchel et al. [1] who found that the success with which a subject learned an object-location association task was correlated with the coupling between regions in the dorsal and ventral visual streams. Functionally specialized brain responses are typically characterized using the general linear model (GLM). An fMRI data set comprises a time series of volumetric data. In "mass-univariate" approaches GLMs are fitted to fMRI time series at each voxel (volume element), resulting in a set of voxel-specific parameters. These parameters are then used to form posterior probability maps (PPMs) that characterize regionally specific responses to experimental manipulation. Figure 5.5, for example, shows a PPM highlighting regions that are sensitive to visual motion stimuli. Analyses of functional integration are implemented using multivariate approaches that examine the changes in multiple brain areas induced by experimental manipulation. Although there a number of methods for doing this we

Inferences about brain function, using functional neuroimaging data, require models of how the data were caused. A variety of models are used in practice that range from conceptual models of functional anatomy to nonlinear mathematical models of hemodynamic responses (e.g. as measured by functional magnetic resonance imaging, fMRI) and neuronal responses. In this review, we discuss the most important models used to analyse functional imaging data and demonstrate how they are interrelated. Initially, we briefly review the anatomical foundations of current theories of brain function on which all mathematical models rest. We then introduce some basic statistical models (e.g. the general linear model) used for making classical (i.e. frequentist) and Bayesian inferences about where neuronal responses are expressed. The more challenging question, how these responses are caused, is addressed by models that incorporate biophysical constraints (e.g. forward models from the neural to the hemodynamic level) and/or consider causal interactions between several regions, i.e. models of effective connectivity. Some of the most refined models to date are neuronal mass models of electroencephalographic (EEG) responses. These models enable mechanistic inferences about how evoked responses are caused, at the level of neuronal subpopulations and the coupling among them.

Dynamic causal modelling of evoked responses in EEG/MEG with lead field parameterization

By formulating Helmholtz’s ideas about perception, in terms of modern-day theories, one arrives at a model of perceptual inference and learning that can explain a remarkable range of neurobiological facts: using constructs from statistical physics, the problems of inferring the causes of sensory input and learning the causal structure of their generation can be resolved using exactly the same principles. Furthermore, inference and learning can proceed in a biologically plausible fashion. The ensuing scheme rests on Empirical Bayes and hierarchical models of how sensory input is caused. The use of hierarchical models enables the brain to construct prior expectations in a dynamic and context-sensitive fashion. This scheme provides a principled way to understand many aspects of cortical organisation and responses. In this paper, we show these perceptual processes are just one aspect of emergent behaviours of systems that conform to a free energy principle. The free energy considered here measures the difference between the probability distribution of environmental quantities that act on the system and an arbitrary distribution encoded by its configuration. The system can minimise free energy by changing its configuration to affect the way it samples the environment or change the distribution it encodes. These changes correspond to action and perception respectively and lead to an adaptive exchange with the environment that is characteristic of biological systems. This treatment assumes that the system’s state and structure encode an implicit and probabilistic model of the environment. We will look at the models entailed by the brain and how minimisation of its free energy can explain its dynamics and structure. 2006 Published by Elsevier Ltd.

Au th or ' s pe rs on al co py A free energy principle for the brain

Recovery of motor function after subcortical stroke appears to be related to the integrity of descending connections from the ipsilesional cortical motor system, a view supported by the observation of greater than normal movement-related activation in ipsilesional motor regions in chronic subcortical stroke patients. This suggests that damage to the descending output fibres from one region of the cortical motor system may be compensated by activity in areas that retain corticofugal outputs. Though the trajectories of corticofugal fibres from each major component of the motor system through the corona radiata and internal capsule are well described in non-human primates, they have not been described fully in humans. Our study set out to map the trajectories of these connections in a group of healthy volunteers (8 male, 4 female; age range = 31-68 years, median = 48.5 years) and establish whether this knowledge can be used to assess stroke-induced disconnection of the cortical motor system and better interpret functional reorganization of the cortical motor system. We describe the trajectories of the connections from each major component of the motor system to the cerebral peduncle using diffusion-weighted imaging and probabilistic tractography in normal subjects. We observed good reproducibility of these connections over subjects. The comparative topography of these connections revealed many similarities between humans and other primates. We then inferred damage to corticofugal pathways in stroke patients (n = 3) by comparing the overlap between regions of subcortical white matter damage with the trajectories of the connections to each motor area. In a small series of case studies, we found that inferred disconnections could explain enhanced hand-grip-related responses, as assessed with functional MRI, in the ipsilesional motor system. These results confirm that selective disruption of motor corticofugal fibres influences functional reorganization and outcome in individual patients.

Non-invasive mapping of corticofugal fibres from multiple motor areas--relevance to stroke recovery.

Bayesian estimation of cerebral perfusion using a physiological model of microvasculature

Functional neuroimaging can be used to characterize two types of abnormality in patients with neurological deficits: abnormal functional segregation and abnormal functional integration. In this paper we consider the factors that influence the experimental design, analysis, and interpretation of such studies. With respect to experimental design, we emphasize that: 1) task selection is constrained to tasks the patient is able to perform correctly, and 2) the most sensitive designs entail presenting stimuli of the same type close together. In terms of data preprocessing, prior to statistical analysis, we note that structural pathology may call for constraints on nonlinear transformations, used by spatial normalization, to prevent distortion of intact tissue. This means that one may have to increase spatial smoothing to reduce the impact of inaccurate normalization. Important issues in statistical modeling concern the first level of analysis (estimation of activation within subject), which has to distinguish correct from incorrect responses. At the second level (between subjects), inference should be based on between‐subjects variance. Provided that these and other constraints are met, deficits in functional segregation are indicated when activation in one or a set of regions is higher or lower in patients relative to control subjects. In contrast, deficits in functional integration are implied when the influence of one brain region on another is stronger or weaker in patients relative to control subjects. J. Magn. Reson. Imaging 2006. © 2006 Wiley‐Liss, Inc.

Design and analysis of fMRI studies with neurologically impaired patients

The cognitive and neural mechanisms mediating category-selective responses in the human brain remain controversial. Using functional magnetic resonance imaging and effective connectivity analyses (Dynamic Causal Modelling), we investigated animal- and tool-selective responses by manipulating stimulus modality (pictures versus words) and task (implicit versus explicit semantic). We dissociated two distinct mechanisms that engender category selectivity: in the ventral occipito-temporal cortex, tool-selective responses were observed irrespective of task, greater for pictures and mediated by bottom-up effects. In a left temporo-parietal action system, tool-selective responses were observed irrespective of modality, greater for explicit semantic tasks and mediated by top-down modulation from the left prefrontal cortex. These distinct activation and connectivity patterns suggest that the two systems support different cognitive operations, with the ventral occipito-temporal regions engaged in structural processing and the dorsal visuo-motor system in strategic semantic processing. Consistent with current semantic theories, explicit semantic processing of tools might thus rely on reactivating their associated action representations via top-down modulation. In terms of neuronal mechanisms, the category selectivity may be mediated by distinct top-down (task-dependent) and bottom-up (stimulus-dependent) mechanisms.

Two distinct neural mechanisms for category-selective responses.

Identification of degenerate neuronal systems based on intersubject variability

Modelling cardiac signal as a confound in EEG-fMRI and its application in focal epilepsy studies

We present a method for detecting event-related responses in functional magnetic resonance imaging (fMRI). The occurrence of time-locked activations is formulated in terms of the general linear model, i.e., multiple linear regression. This permits the use of established statistical techniques that correct for multiple comparisons in the context of spatially smooth and serially correlated data. Responses are modelled using event-related temporal basis functions. Inferences are then made about all components of the model, using the F-ratio at all voxels in the image, to produce a statistical parametric map (SPM5F6). This method allows for the experimental design to relate the timing of events to the acquisition of data to give a temporal resolution (with respect to the event-related response) far better than the scanning repeat time. Hum. Brain Mapping 5:243–248, 1997. r 1997 Wiley-Liss, Inc.

The Proceedings of the Annual Convention of the Japanese Psychological Association

There is extensive evidence suggesting abnormal structure and function of the brain in schizophrenia (Andreasen, 1986), but the majority of the reported brain abnormalities occur in only a proportion of cases. Furthermore, the clinical manifestations of schizophrenia are diverse. It is tempting to propose that the clinical heterogeneity of the illness reflects a heterogeneity in the underlying neuropathology. However, attempts to divide the illness into discrete subtypes have been only partially successful. For example, the classicsubdivision into simple, catatonic, hebephrenic, and paranoid schizophrenia is un satisfactory because many cases show features characteristic of more than one subtype. Crow (1980) proposed that there are two patho logical processes in schizophrenia that can occur either separately or together in an individual case. Crow's type 1syndrome is characterised by positive symptoms and tends to be acute, while the type 2 syndrome is characterised by negative symptoms and is usually chronic. However, Crow's formulation raises the issue of whether it is symptom type or the degree of chronicity that is the important distinguishing factor. Furthermore, there is debate about whether formal thought disorder should be regarded as a positive or negative symptom (Crow, 1985). To address these issues, Liddle (1984, 1987a) examined the pattern of correlation between schizo phrenic symptoms in a group of patients with similar chronicity, and found that the symptoms segregated into three distinguishable syndromes: psychomotor poverty (poverty of speech, flatness of affect, decreased spontaneous movement); disorganisation (disorders of the form of thought and inappropriate affect); and reality distortion (delusions and hallucinations). This pattern of segregation into three syndromes has been replicated (Liddle & Barnes, 1990), and similar patterns of segregation have been found in other studies employing factor analysis of schizophrenic symptoms (Bilder et al, 1985; Mortimer et al, 1990; Arndt et al, 1991; Pantelis et al, 1991; Sauer et al, 1991). The symptoms xmprising the psychomotor poverty, disorganisation and reality distortion syndromes show some congruence with the clinical features of three of the classic subtypes of schizophrenia: catatoma, hebephrenia, and paranoid schizophrenia, respectively. However, the three syndromes are not three separate subtypes of schizophrenia. The segregation of symptoms into three syndromes that are clearly distinguishable, but nonetheless often coexist, suggests the existence of three dis tinguishable, but related, neuropathological processes in schizophrenia. Neuropsychological studies (Liddle, 1987b; Liddle & Morris, 1991) show that each syndrome is characterised by a specific pattern of test performance, suggesting that each syndrome is associated with a specific pattern of disordered brain function. In particular, the evidence suggests that psychomotor poverty is associated with impairment in the self-directed generation of mental activity, while disorganisation is associated with impaired ability to suppress intrusion of irrelevant mental activity. Reality distortion is associated with less extensive neuropsychological impairment than the other two syndromes, implying that the relevant psychological deficit is relatively subtle. The evidence that left temporal lobe epilepsy is associated with a psychosis characterised by delusions and hallucinations, but with relatively few symptoms of the psychomotor poverty or disorganisation syndromes (Parnas et al, 1982), suggests that the reality distortion syndrome arises from left temporal dysfunction.

syndromes, implying that the relevant psychological deficit is relatively subtle. The evidence that left temporal lobe epilepsy is associated with a psychosis characterised by delusions and hallucinations, but with relatively few symptoms of the psychomotor poverty or disorganisation syndromes

We describe an extension of our empirical Bayes approach to magnetoencephalography/electroencephalography (MEG/EEG) source reconstruction that covers both evoked and induced responses. The estimation scheme is based on classical covariance component estimation using restricted maximum likelihood (ReML). We have focused previously on the estimation of spatial covariance components under simple assumptions about the temporal correlations. Here we extend the scheme, using temporal basis functions to place constraints on the temporal form of the responses. We show how the same scheme can estimate evoked responses that are phase‐locked to the stimulus and induced responses that are not. For a single trial the model is exactly the same. In the context of multiple trials, however, the inherent distinction between evoked and induced responses calls for different treatments of the underlying hierarchical multitrial model. We derive the respective models and show how they can be estimated efficiently using ReML. This enables the Bayesian estimation of evoked and induced changes in power or, more generally, the energy of wavelet coefficients. Hum Brain Mapp, 2006. © 2006 Wiley‐Liss, Inc.

Repetitive transcranial magnetic stimulation (rTMS) is an established technique for non-invasive stimulation of human cortex. Although studies have shown an influence of rTMS on single cortical regions and on simple behavioral response patterns, its influences on the dynamics of task-related activity in cortical networks have not been characterized. We provide such a characterization by showing that 5 Hz rTMS over primary somatosensory cortex (SI) induces a reconfiguration of activity patterns in a sensorimotor network, comprising the stimulated region and ipsilateral primary motor cortex (MI). These plastic changes endure for up to 120 min and are correlated with behavioral improvement in discrimination. Dynamic causal modeling showed that this reconfiguration could be explained by an rTMS-induced increase in SI excitability (self-connection) and an increase in the effective connectivity from SI to MI. Thus, our data demonstrate that rTMS can temporarily induce behaviorally relevant reorganization within a complex cortical network underlying human somatosensory experience.

Repetitive Transcranial Magnetic Stimulation-Induced Changes in Sensorimotor Coupling Parallel Improvements of Somatosensation in Humans

The neural processes underlying tactile decisions in the human brain remain elusive. We addressed this question in a functional magnetic resonance imaging study using a somatosensory discrimination task, requiring participants to compare the frequency of two successive tactile stimuli. Tactile stimuli per se engaged somatosensory, parietal, and frontal cortical regions. Using a statistical model that accounted for the relative difference in frequencies (i.e., Weber fraction) and discrimination accuracy (i.e., correct or incorrect), we show that trial-by-trial relative frequency difference is represented linearly by activity changes in the left dorsolateral prefrontal cortex (DLPFC), the dorsal anterior cingulate cortex, and bilateral anterior insular cortices. However, a circumscribed region within the left DLPFC showed a different response pattern expressed as activity changes that were monotonically related to relative stimulation difference only for correct but not for incorrect trials. Our findings suggest that activity in the left DLPFC encodes stimulus representations that underlie veridical tactile decisions in humans.

Neural Coding of Tactile Decisions in the Human Prefrontal Cortex

MEG source localization under multiple constraints: An extended Bayesian framework

Functional MRI in SUNCT (Short-lasting Unilateral Neuralgiform headache attacks with Conjunctival injection and Tearing) and SUNA (Short-lasting Unilateral Neuralgiform headache attacks with cranial Autonomic symptoms) shows differential hypothalamic activation with increasing pain

Hemodynamic correlates of epileptiform discharges: An EEG-fMRI study of 63 patients with focal epilepsy

Commentary on: Divide and conquer; a defence of functional localisers

Cortical activity is the product of interactions among neuronal populations. Macroscopic electrophysiological phenomena are generated by these interactions. In principle, the mechanisms of these interactions afford constraints on biologically plausible models of electrophysiological responses. In other words, the macroscopic features of cortical activity can be modelled in terms of the microscopic behaviour of neurons. An evoked response potential (ERP) is the mean electrical potential measured from an electrode on the scalp, in response to some event. The purpose of this paper is to outline a population density approach to modelling ERPs. We propose a biologically plausible model of neuronal activity that enables the estimation of physiologically meaningful parameters from electrophysiological data. The model encompasses four basic characteristics of neuronal activity and organization: (i) neurons are dynamic units, (ii) driven by stochastic forces, (iii) organized into populations with similar biophysical properties and response characteristics and (iv) multiple populations interact to form functional networks. This leads to a formulation of population dynamics in terms of the Fokker–Planck equation. The solution of this equation is the temporal evolution of a probability density over state-space, representing the distribution of an ensemble of trajectories. Each trajectory corresponds to the changing state of a neuron. Measurements can be modelled by taking expectations over this density, e.g. mean membrane potential, firing rate or energy consumption per neuron. The key motivation behind our approach is that ERPs represent an average response over many neurons. This means it is sufficient to model the probability density over neurons, because this implicitly models their average state. Although the dynamics of each neuron can be highly stochastic, the dynamics of the density is not. This means we can use Bayesian inference and estimation tools that have already been established for deterministic systems. The potential importance of modelling density dynamics (as opposed to more conventional neural mass models) is that they include interactions among the moments of neuronal states (e.g. the mean depolarization may depend on the variance of synaptic currents through nonlinear mechanisms). Here, we formulate a population model, based on biologically informed model-neurons with spike-rate adaptation and synaptic dynamics. Neuronal sub-populations are coupled to form an observation model, with the aim of estimating and making inferences about coupling among sub-populations using real data. We approximate the time-dependent solution of the system using a bi-orthogonal set and first-order perturbation expansion. For didactic purposes, the model is developed first in the context of deterministic input, and then extended to include stochastic effects. The approach is demonstrated using synthetic data, where model parameters are identified using a Bayesian estimation scheme we have described previously.

This editorial takes a perspective on this issue’s articles afforded by theories of inference and learning in the brain. It starts with a brief précis of the disconnection hypothesis and ensuing cognitive dysmetria, given recent developments in theoretical and computational neurobiology. (Dysmetria is defined as “conditions where there is improper measuring of distances required for muscular acts” by the University of Connecticut Health Center Research Computing Support [http://penguin.uchc.edu/~cns/ CNScases/Definitions/dysmetria.htm].) We will then review some major findings of the four articles, in light of these theoretical considerations.

In this paper, we propose the use of bilinear dynamical systems (BDS)s for model-based deconvolution of fMRI time-series. The importance of this work lies in being able to deconvolve haemodynamic time-series, in an informed way, to disclose the underlying neuronal activity. Being able to estimate neuronal responses in a particular brain region is fundamental for many models of functional integration and connectivity in the brain. BDSs comprise a stochastic bilinear neurodynamical model specified in discrete time, and a set of linear convolution kernels for the haemodynamics. We derive an expectation-maximization (EM) algorithm for parameter estimation, in which fMRI time-series are deconvolved in an E-step and model parameters are updated in an M-Step. We report preliminary results that focus on the assumed stochastic nature of the neurodynamic model and compare the method to Wiener deconvolution.

Effect of the 5-HT1A partial agonist buspirone on regional cerebral blood flow in man

Functional brain imaging in acute migraine has proved challenging because of the logistic problems associated with an episodic condition. Since the seminal observation of brainstem activation in migraine, there has been only a single case substantiating this finding.

OBJECTIVE
To test the hypothesis that brainstem activation could be detected in migraine and to refine the anatomic localization with higher-resolution positron emission tomography than previously used.

DESIGN
Using positron emission tomography with radioactive water (H(2)15O), we studied acute migraine attacks occurring spontaneously. Five patients underwent imaging in ictal and interictal states, and the differences were analyzed by means of statistical parametric mapping.

SETTING

PATIENTS
Six volunteers with episodic migraine were recruited from advertisements in migraine newsletters. One patient was excluded because of use of preventive medication.

Brainstem activation during migraine state vs interictal state.

RESULTS
Two patients had a typical migrainous aura before the onset of the headache. All of the attacks studied fulfilled standard diagnostic criteria for migraine. Comparing the migraine scans with interictal scans, there was significant activation in the dorsal pons, lateralized to the left (small volume correction, P = .003). Activation was also seen in the right anterior cingulate, posterior cingulate, cerebellum, thalamus, insula, prefrontal cortex, and temporal lobes. There was an area of deactivation in the migraine phase also located in the pons, lateralized to the right.

Our findings provide clear evidence of dorsal pontine activation in migraine and reinforce the view that migraine is a subcortical disorder modulating afferent neural traffic.

Frequency specific changes in regional cerebral blood flow and motor system connectivity following rTMS to the primary motor cortex

Previous studies of patients with phonological and surface alexia have demonstrated a double dissociation between the reading of pseudo words and words with atypical spelling-to-sound relationships. A corresponding double dissociation in the neuronal activation patterns for pseudo words and exception words has not, however, been consistently demonstrated in normal subjects. Motivated by the literature on acquired alexia, the present study contrasted pseudo words to exception words and explored how neuronal interactions within the reading system are influenced by word type. Functional magnetic resonance imaging was used to measure neuronal responses during reading in 22 healthy volunteers. The direct comparison of reading pseudo words and exception words revealed a double dissociation within the left frontal cortex. Pseudo words preferentially increased left dorsal premotor activation, whereas exception words preferentially increased left pars triangularis activation. Critically, these areas correspond to those previously associated with phonological and semantic processing, respectively. Word-type dependent interactions between brain areas were then investigated using dynamic causal modeling. This revealed that increased activation in the dorsal premotor cortex for pseudo words was associated with a selective increase in effective connectivity from the posterior fusiform gyrus. In contrast, increased activation in the pars triangularis for exception words was associated with a selective increase in effective connectivity from the anterior fusiform gyrus. The present investigation is the first to identify distinct neuronal mechanisms for semantic and phonological contributions to reading.

Dissociating Reading Processes on the Basis of Neuronal Interactions

Inferences about brain function, using neuroimaging data, rest on models of how the data were caused. These models can be quite diverse, ranging from conceptual models of functional anatomy to nonlinear mathematical models of hemodynamics. However, they all have to be internally consistent because they model the same thing. This consistency encompasses many levels of description and places constraints on the statistical models, adopted for data analysis, and the experimental designs they embody. The aim of this review is to introduce the key models used in imaging neuroscience and how they relate to each other. We start with anatomical models of functional brain architectures, which motivate some of the fundaments of neuroimaging. We then turn to basic statistical models (e.g., the general linear model) used for making classical and Bayesian inferences about where neuronal responses are expressed. By incorporating biophysical constraints, these basic models can be finessed and, in a dynamic setting, rendered causal. This allows us to infer how interactions among brain regions are mediated.

Learning-related fMRI activation associated with a rotational visuo-motor transformation.

Opponent appetitive-aversive neural processes underlie predictive learning of pain relief

This commentary takes a closer look at how “constructive models of subjective perception,” referred to by Collerton et al. (sect. 2), might contribute to the Perception and Attention Deficit (PAD) model. It focuses on the neuronal mechanisms that could mediate hallucinations, or false inference – in particular, the role of cholinergic systems in encoding uncertainty in the context of hierarchical Bayesian models of perceptual inference (Friston 2002b; Yu & Dayan 2002).

Activation in Posterior Superior Temporal Sulcus Parallels Parameter Inducing the Percept of Animacy

Early visual deprivation induces structural plasticity in gray and white matter

Cover Photo. Rows 1 and 2 show left lateral, posterior, and right lateral views of PET activation reflecting brain regions tied to visual-verbal (row 1) and auditory-verbal (row 2) encoding processes. Rows 3 and 4 show left lateral, superior, and right lateral views of PET activation reflecting brain regions mediating working memory processes for visually (row 3) and aurally (row 4) presented verbal material. See the article by Schumacher et al. in this issue. Current models of verbal working memory assume that modality-specific representations are translated into phonological representations before entering the working memory system. We report an experiment that tests this assumption. Positron emission tomogra-phy measures were taken while subjects performed a verbal working memory task. Stimuli were presented either visually or aurally, and a visual or auditory search task, respectively, was used as a control. Results revealed an almost complete overlap between the active memory areas regardless of input modality. These areas included dorsolateral frontal, Broca's area, SMA, and premotor cortex in the left hemisphere; bilateral superior and posterior parietal cortices and anterior cingulate; and right cerebellum. These results correspond well with previous research and suggest that verbal working memory is modality independent and is mediated by a circuit involving frontal, parietal, and cerebellar mechanisms. o 1996Academic Press, Inc.

Visual Memory-Control Auditory Memory-Control Left Lateral Superior Right Lateral

The morphology of the human cortex varies remarkably across individuals, regardless of overall brain size. It is currently unclear whether related cortical regions covary in gray matter density, as a result of mutually trophic influences or common experience-related plasticity. We acquired a structural magnetic resonance imaging scan from 172 subjects and extracted the regional gray matter densities from 12 readily identifiable regions of interest involved in sensorimotor or higher-order cognitive functions. We then used these values to predict regional densities in the remaining areas of the cortex, using voxel-based morphometry. This revealed patterns of positive and negative covariance that provide insight into the topographical organization of multiple cortical regions. We report that the gray matter density of a region is a good predictor of the density of the homotopic region in the contralateral hemisphere, with the striking exception of primary visual cortex. Whereas some regions express patterns of regional covariance that are mirror symmetrical relative to the interhemispheric fissure, other regions express asymmetric patterns of regional covariance. Finally, patterns of covariance are remarkably consistent between males and females, with the exception of the left amygdala, which is positively associated with the left and right anterior inferior temporal cortex in males and with the right angular gyrus in females. Our study establishes that the density of different cortical regions is coordinated within an individual. The coordinated variations we report are likely to be determined by both genetic and environmental factors and may be the basis for differences in individual behavior.

A major conceptual tenet of modern neuroscience, stated explicitly in the work of its founders ([Freund 2002][1]), is that the computational properties of the brain are a direct consequence of its circuitry. This insight has been cumulatively validated over the years, but has received unprecedented

This article concerns the nature of evoked brain responses and the principles underlying their generation. We start with the premise that the sensory brain has evolved to represent or infer the causes of changes in its sensory inputs. The problem of inference is well formulated in statistical terms. The statistical fundaments of inference may therefore afford important constraints on neuronal implementation. By formulating the original ideas of Helmholtz on perception, in terms of modern-day statistical theories, one arrives at a model of perceptual inference and learning that can explain a remarkable range of neurobiological facts. It turns out that the problems of inferring the causes of sensory input (perceptual inference) and learning the relationship between input and cause (perceptual learning) can be resolved using exactly the same principle. Specifically, both inference and learning rest on minimizing the brain's free energy, as defined in statistical physics. Furthermore, inference and learning can proceed in a biologically plausible fashion. Cortical responses can be seen as the brain’s attempt to minimize the free energy induced by a stimulus and thereby encode the most likely cause of that stimulus. Similarly, learning emerges from changes in synaptic efficacy that minimize the free energy, averaged over all stimuli encountered. The underlying scheme rests on empirical Bayes and hierarchical models of how sensory input is caused. The use of hierarchical models enables the brain to construct prior expectations in a dynamic and context-sensitive fashion. This scheme provides a principled way to understand many aspects of cortical organization and responses. The aim of this article is to encompass many apparently unrelated anatomical, physiological and psychophysical attributes of the brain within a single theoretical perspective. In terms of cortical architectures, the theoretical treatment predicts that sensory cortex should be arranged hierarchically, that connections should be reciprocal and that forward and backward connections should show a functional asymmetry (forward connections are driving, whereas backward connections are both driving and modulatory). In terms of synaptic physiology, it predicts associative plasticity and, for dynamic models, spike-timing-dependent plasticity. In terms of electrophysiology, it accounts for classical and extra classical receptive field effects and long-latency or endogenous components of evoked cortical responses. It predicts the attenuation of responses encoding prediction error with perceptual learning and explains many phenomena such as repetition suppression, mismatch negativity (MMN) and the P300 in electroencephalography. In psychophysical terms, it accounts for the behavioural correlates of these physiological phenomena, for example, priming and global precedence. The final focus of this article is on perceptual learning as measured with the MMN and the implications for empirical studies of coupling among cortical areas using evoked sensory responses.

Information theory, novelty and hippocampal responses: unpredicted or unpredictable?

The aim of this note is to revisit the analysis of conjunctions in imaging data. We review some conceptual issues that have emerged from recent discussion (Nichols, T., Brett, M., Andersson, J., Wager, T., Poline, J.-B., this issue. Valid Conjunction Inference with the Minimum Statistic.) and reformulate the conjunction of null hypotheses as a conjunction of k or more effects. Analyses based on minimum statistics have typically used the null hypothesis that k = 0. This enables inferences about one or more effects (k N 0). However, this does not provide control over false-positive rates (FPR) for inferences about a conjunction of k = n effects, over n tests. This is the key point made by Nichols et al., who suggest a procedure based on supremum P values that provides an upper bound on FPR for k = n. Although valid, this is a very conservative procedure, particularly in the context of multiple comparisons. We suggest that an inference on a conjunction of k = n effects is generally unnecessary and distinguish between congruent contrasts that test for the same treatment and incongruent contrasts of the sort used in cognitive conjunctions. For congruent contrasts, the usual inference, k N 0, is sufficient. With incongruent contrasts it is sufficient to infer a conjunction of k N u effects, where u is the number of contrasts that share some uninteresting effect. The issues highlighted by Nichols et al., have important implications for the design and analysis of cognitive conjunction studies and have motivated a change to the SPM software, that affords a test for the more general hypothesis k N u. This more general conjunction test is described.

Functional imaging studies have identified a matrix of structures in the brain that respond to noxious stimuli. Within this matrix, a division of function between sensory‐discriminative and affective responses has so far been demonstrated by manipulating either pain intensity or unpleasantness under hypnosis in two different normal volunteer groups studied on separate occasions. Our study used positron emission tomography (PET) to demonstrate this division of function under more natural conditions in a healthy group of volunteers, using a CO2 laser to provide nociceptive stimuli that selectively activate A‐delta and C‐fibres without contamination by touch sensations. We measured the differential cerebral responses to noxious and innocuous laser stimuli during conditions of selective attention to either the unpleasantness or location of the stimuli. Attention to location increased responses in the contralateral (right) primary somatosensory and inferior parietal cortices. This result implies that these components of the lateral pain system are concerned mainly with the localization of pain. In contrast, attention to unpleasantness increased responses in bilateral perigenual cingulate and orbitofrontal cortices, contralateral (right) amygdala, ipsilateral (left) hypothalamus, posterior insula, M1 and frontal pole. These areas comprise key components of the medial pain and neuroendocrine systems and the results suggest that they have a role in the affective response to pain. Our results indicate the importance of attentional effects on the pattern of nociceptive processing in the brain. They also provide the first clear demonstration, within a single experiment, of a major division of function within the neural pain matrix.

Attention to pain localization and unpleasantness discriminates the functions of the medial and lateral pain systems

An empirical Bayesian solution to the source reconstruction problem in EEG

In recent years, a whole-brain unbiased objective technique, known as voxel-based morphometry (VBM), has been developed to characterise brain differences in vivo using structural magnetic resonance images. The present review provides a brief description of VBM and then focuses on exemplar applications in healthy and diseased subjects. The procedure involves normalising high-resolution structural magnetic resonance images to a standard template in stereotactic space. Normalised images are then segmented into gray and white matter and smoothed using an isotropic Gaussian kernel. Finally, a series of voxel-wise comparisons of gray and white matter in different groups of subjects are performed, using Random Field theory to correct for multiple comparisons. VBM has been useful in characterizing subtle changes in brain structure in a variety of diseases associated with neurological and psychiatric dysfunction. These include schizophrenia, developmental and congenital disorders, temporal lobe epilepsy and even cluster headache. In addition, VBM has been successful in identifying gross structural abnormalities, such as those observed in herpes simplex encephalitis, multiple sclerosis and Alzheimer's disease. Studies of normal subjects, on the other hand, have focussed on the impact of learning and practice on brain structure. These studies have led to the finding that environmental demands may be associated with changes in gray and white matter. For instance, it has been reported that the structure of the brain alters when human beings learn to navigate, read music, speak a second language and even perform a complex motor task such as juggling. We conclude the present review by discussing the potential limitations of the technique.

Voxel-based morphometry of the human brain: Methods and applications

Cognitive scientists have traditionally specified the functional components of cognitive skills on the basis of behavioural studies of normal and neurologically impaired subjects. The results of functional imaging studies are challenging these classical models because there is a high degree of overlap among the neural systems activated by tasks that share no cognitive components. This suggests that a given neuronal structure can perform multiple functions that depend on the areas with which it interacts. However, there will be a limited range of functions that an area can perform given that its anatomical (intrinsic and extrinsic) connectivity is fixed. Assigning labels that encompass the operations that each area performs should enable a task to be re-described in terms of the functions of the areas activated. In other words, function should predict the structure and conversely structure should predict function. These systematic descriptions are referred to as ontologies. We argue that a systematic ontology for cognition would facilitate the integration of cognitive and anatomical models and organise the cognitive components of diverse tasks into a single framework. These points are illustrated with cognitive and anatomical models of reading and object recognition.

Functional ontologies for cognition: The systematic definition of structure and function

The anatomy of the corpus callosum has been described in considerable detail. Tracing studies in animals and human postmortem experiments are currently complemented by diffusion‐weighted imaging, which enables noninvasive investigations of callosal connectivity to be conducted. In contrast to the wealth of anatomical data, little is known about the principles by which interhemispheric integration is mediated by callosal connections. Most importantly, we lack insights into the mechanisms that determine the functional role of callosal connections in a context‐dependent fashion. These mechanisms can now be disclosed by models of effective connectivity that explain neuroimaging data from paradigms that manipulate interhemispheric interactions. In this article, we demonstrate that dynamic causal modeling (DCM), in conjunction with Bayesian model selection (BMS), is a powerful approach to disentangling the various factors that determine the functional role of callosal connections. We first review the theoretical foundations of DCM and BMS before demonstrating the application of these techniques to empirical data from a single subject.

Investigating the Functional Role of Callosal Connections with Dynamic Causal Models

Two identical stimuli, such as a pair of electrical shocks to the skin, are readily perceived as two separate events in time provided the interval between them is sufficiently long. However, as they are presented progressively closer together, there comes a point when the two separate stimuli are perceived as a single stimulus. Damage to posterior parietal cortex, peri-supplementary motor area (peri-SMA), and basal ganglia can disturb this form of temporal discrimination. Our aim was to establish, in healthy subjects, the brain areas that are involved in this process. During functional magnetic resonance imaging scanning, paired electrical pulses, separated by variable inter-stimulus intervals (5-110 msec), were delivered to different sites on one forearm (8-64 mm from the midline). Subjects were required to simply detect the stimulus (control task) or to identify a stimulus property. For temporal discrimination (TD), subjects reported whether they felt one or two stimuli. For spatial discrimination, they reported whether the stimuli were located on the right or left side of the forearm. Subjects reported their choice by pressing a button with the opposite hand. Our results showed that discrimination, as opposed to simply detection, activated several brain areas. Most were common to both discrimination tasks. These included regions of prefrontal cortex, right postcentral gyrus and inferior parietal lobule, basal ganglia, and cerebellum. However, activation of pre-SMA and anterior cingulate was found to be specific to the TD task. This suggests that these two frontal regions may play a role in the temporal processing of somatosensory events.

Involvement of the basal ganglia in "automatic" processing of tactile temporal discrimination.

Functional MRI in SUNCT shows differential hypothalamic activation with increasing pain

This updated second edition provides the state of the art perspective of the theory, practice and application of modern non-invasive imaging methods employed in exploring the structural and functional architecture of the normal and diseased human brain. Like the successful first edition, it is written by members of the Functional Imaging Laboratory - the Wellcome Trust funded London lab that has contributed much to the development of brain imaging methods and their application in the last decade. This book should excite and intrigue anyone interested in the new facts about the brain gained from neuroimaging and also those who wish to participate in this area of brain science. © 2004 Elsevier Inc. All rights reserved.

The neural systems that sustain sentence comprehension after left anterior temporal lobe resection for refractory epilepsy

Statistical parametric mapping for event-related potentials: I. Generic considerations

Functional magnetic resonance imaging (fMRI) is used to investigate where the neural implementation of specific cognitive processes occurs. The standard approach uses linear convolution models relating experimentally designed inputs, through a hemodynamic response function (HRF), to observed blood oxygen level dependent (BOLD) signals. However, these models are blind to the causal mechanisms that underlie observed BOLD responses, both in terms of neural dynamics and neurovascular coupling. This article reviews current developments towards causal models of how BOLD responses are generated. We focus on (i) biophysical input-state-output models with neural and hemodynamic state equations, and (ii) models of functional integration that explain local dynamics through interactions with remote areas. Forward models with parameters at the neural level, e.g. Dynamic Causal Modeling, combine both approaches, modeling the entire causal chain from external stimuli, via induced neural dynamics, to observed BOLD responses.

Opponent temporal difference models describe learning in tonic pain

The remarkable resilience of cognitive functions to focal brain damage suggests that multiple neural systems can sustain the same function either via similar mechanisms or by implementing different cognitive strategies. Two classes of ‘multiple neural systems’ can be distinguished based on the time courses of their underlying neural mechanisms. First, multiple degenerate neural systems might be present in the normal brain where they are either co-activated or remain latent during task performance. In this case plastic changes are immediate and rely on unmasking of a pre-existing but functionally latent system. Second, there might be only one system in the normal brain while an alternative system emerges in the pathological brain owing to functional reorganization, i.e. long-term plastic changes induced by the underlying pathological process. We discuss how multiple neural systems can be revealed using (1) intersubject variability or (2) an iterative approach integrating information from lesion and functional imaging studies.

Evaluation of different measures of functional connectivity using a neural mass model

Statistical parametric mapping for event-related potentials (II): a hierarchical temporal model

Functional magnetic resonance imaging (fMRI) studies have identified category-selective regions in ventral occipito-temporal cortex that respond preferentially to faces and other objects. The extent to which these patterns of activation are modulated by bottom-up or top-down mechanisms is currently unknown. We combined fMRI and dynamic causal modelling to investigate neuronal interactions between occipito-temporal, parietal and frontal regions, during visual perception and visual imagery of faces, houses and chairs. Our results indicate that, during visual perception, category-selective patterns of activation in extrastriate cortex are mediated by content-sensitive forward connections from early visual areas. In contrast, during visual imagery, category-selective activation is mediated by content-sensitive backward connections from prefrontal cortex. Additionally, we report content-unrelated connectivity between parietal cortex and the category-selective regions, during both perception and imagery. Thus, our investigation revealed that neuronal interactions between occipito-temporal, parietal and frontal regions are task- and stimulus-dependent. Sensory representations of faces and objects are mediated by bottom-up mechanisms arising in early visual areas and top-down mechanisms arising in prefrontal cortex, during perception and imagery respectively. Additionally non-selective, top-down processes, originating in superior parietal areas, contribute to the generation of mental images, regardless of their content, and their maintenance in the 'mind's eye'.

Where bottom-up meets top-down: neuronal interactions during perception and imagery.

One of the major in imaging neuroscience is the integration of cognitive science with the empiricism of neurophysiology. The cognitive architectures and principles offered by cognitive science have been essential in shaping experimental design and image analysis strategies from the outset. Now some of the cognitive models and their assumptions (for example, cognitive subtraction) are being resvaluated in the light of how the brain actually implements putative components and processes. In this review we will consider experimental designs that go beyond cognitive subtraction and also consider how functional imaging can be used to assess the context-sensitivity of cognitive processing (using conjunction analyses), and the integration of different processes (in terms of interactions, using factorial designs) and how both these themes can be developed in the context of parametric designs. These new a reflect an ongoing discourse between cognitive science and the emerging prkiptas of functional anatomy.

Modelling functional integration: a comparison of structural equation and dynamic causal models

The remarkable resilience of cognitive functions to focal brain damage suggests that multiple degenerate neuronal systems can sustain the same function either via similar mechanisms or by implementing different cognitive strategies. In degenerate functional neuroanatomy, multiple degenerate neuronal systems might be present in a single brain where they are either co‐activated or remain latent during task performance. In degeneracy over subjects, a particular function may be sustained by only one neuronal system within a subject, but by different systems over subjects. Degeneracy over subjects might have arisen from (ab)normal variation in neurodevelopmental trajectories or long‐term plastic changes following structural lesions. We discuss how degenerate neuronal systems can be revealed using (1) intersubject variability, (2) multiple lesion studies and (3) an iterative approach integrating information from lesion and functional imaging studies.

Migraine is a common disabling condition likely to be associated with dysfunction of brain pathways involved in pain and other sensory modalities. A cardinal, indeed signature, feature of the disorder that led to its name is that the pain may be lateralized. H(2)15O-labelled PET was used to study 24 migraineurs and eight healthy controls. The migraineurs were divided into three groups according to the site of their headache: right, left or bilateral. In each group, a migraine was induced using a glyceryl trinitrate (GTN) infusion. The subjects were scanned at predefined points: pre-infusion, during GTN, during migraine and post-migraine. SPM99 software was used to analyse the data. Significant brainstem activation was seen in the dorsal lateral pons (P < 0.05 after small volume correction) during the migraine state versus the pain-free state when comparing migraineurs with controls. When each group was analysed separately, to investigate laterality, it was found that the dorsal pontine activation was ipsilateral in the right-sided and left-sided groups and bilateral in the bilateral headache group with a left-sided preponderance. Consistent with previous work, the activation persisted after pain was controlled by sumatriptan. These results suggest that lateralization of pain in migraine is due to lateralized brain dysfunction.

A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate.

Medline/pubmed/index Medicus Science Citation Index ® Special Issue on Functional Connectivity

The role of the prefrontal cortex remains controversial. Neuroimaging studies support modality-specific and process-specific functions related to working memory and attention. Its role may also be defined by changes in its influence over other brain regions including sensory and motor cortex. We used functional magnetic imaging (fMRI) to study the free selection of actions and colours. Control conditions used externally specified actions and colours. The prefrontal cortex was activated during free selection, regardless of modality, in contrast to modality-specific activations outside prefrontal cortex. Structural equation modelling (SEM) of fMRI data was used to test the hypothesis that although the same regions of prefrontal cortex may be active in tasks within different domains, there is task-dependent effective connectivity between prefrontal cortex and non-prefrontal cortex. The SEM included high-order interactions between modality, selection and regional activity. There was greater coupling between prefrontal cortex and motor cortex during free selection and action tasks, and between prefrontal cortex and visual cortex during free selection of colours. The results suggest that the functions of the prefrontal cortex may be defined not only by selection-specific rather than modality-specific processes, but also by changing patterns of effective connectivity from prefrontal cortex to motor and sensory cortices.

The prefrontal cortex shows context-specific changes in effective connectivity to motor or visual cortex during the selection of action or colour.

Autoimmune disease is accompanied by T-cell invasion of the CNS, a realm from which they are normally banned. But while we generally think of oligodendrocytes as the primary victims in demyelinating autoimmune disorders such as multiple sclerosis (MS), Nitsch et al. show this week that neurons themselves are under attack from T cells as well. The authors exposed mouse brain slices with intact cellular architecture to activated T cells. T cells were stimulated with oligodendrocytederived proteolipid protein (PLP) or ovalbumin (not expressed in mice). The T cells encountered, bound, and killed neurons, whereas unstimulated T cells did not invade the slice. Using two-photon microscopy and ion-sensitive dyes, the authors tracked the real-time movements of the stimulated T cells. T cells, traveling quickly (2.5 m/sec at 34°C), assailed neurons with a veritable neuronal kryptonite: calcium oscillations. They identified two seemingly cooperative pathways for the excitotoxic calcium: perforin release from T cells and neuronal glutamate receptor activation. Click the movie and watch them go!

Week in The Journal F Cellular / Molecular Close Encounters between T Cells and Neurons

We set out a new general framework for making inferences from neuroimaging data, which includes a standard approach to neuroimaging analysis, statistical parametric mapping (SPM), as a special case. The model offers numerous conceptual and statistical advantages that derive from analyzing data at the "cluster level" rather than the "voxel level" and from explicit modeling of the shape and position of clusters of activation. This provides a natural and principled way to pool data from nearby voxels for parameter and variance-component estimation. The model can also be viewed as performing a spatio-temporal cluster analysis. The parameters of the model are estimated using an expectation maximization (EM) algorithm.

Imaging Brain Structure and Function in Schizophrenia: New Techniques Encounter old Problems

Modeling regional and psychophysiologic interactions in fMRI: the importance of hemodynamic deconvolution

Repetitive transcranial magnetic stimulation (rTMS) of human primary motor cortex (M1) changes cortical excitability at the site of stimulation and at distant sites without affecting simple motor performance. The aim of this study was to explore how rTMS changes regional excitability and how the motor system compensates for these changes. Using functional brain imaging, activation was mapped at rest and during freely selected finger movements after 30 min of 1 Hz rTMS. rTMS increased synaptic activity in the stimulated left M1 and induced widespread changes in activity throughout areas engaged by the task. In particular, movement-related activity in the premotor cortex of the nonstimulated hemisphere increased after 1 Hz rTMS. Analyses of effective connectivity confirmed that the stimulated part of M1 became less responsive to input from premotor and mesial motor areas. Conversely, after rTMS our results were consistent with increased coupling between an inferomedial portion of left M1 and anterior motor areas. These results are important for three reasons. First, they show changes in motor excitability to central inputs from other cortical areas (as opposed to peripheral or exogenous inputs used in previous studies). Second, they suggest that maintenance of task performance may involve activation of premotor areas contralateral to the site of rTMS, similar to that seen in stroke patients. Third, changes in motor activations at the site of rTMS suggest an rTMS-induced remodeling of motor representations during movement. This remapping may provide a neural substrate for acute compensatory plasticity of the motor system in response to focal lesions such as stroke.

Acute Remapping within the Motor System Induced by Low-Frequency Repetitive Transcranial Magnetic Stimulation

A disturbance of nonlinear interdependence in scalp EEG of subjects with first episode schizophrenia

The amygdala, which plays a critical role in emotional learning and social cognition, is structurally and functionally sexually dimorphic in humans. We used magnetic neuroimaging and molecular genetic analyses with healthy subjects and patients possessing X-chromosome anomalies to find dosage-sensitive genes that might influence amygdala development. If such X-linked genes lacked a homologue on the Y-chromosome they would be expressed in one copy in normal 46,XY males and two copies in normal 46,XX females. We showed by means of magnetic neuroimaging that 46,XY males possess significantly increased amygdala volumes relative to normal 46,XX females. However, females with Turner syndrome (45,X) have even larger amygdalae than 46,XY males. This finding implies that haploinsufficiency for one or more X-linked genes influences amygdala development irrespective of a direct or indirect (endocrinological) mechanism involving the Y-chromosome. 45,X females also have increased grey matter volume in the orbitofrontal cortex bilaterally, close to a region implicated in emotional learning. They are as poor as patients with bilateral amygdalectomies in the recognition of fear from facial expressions. We attempted to localize the gene(s) responsible for these deficits in X-monosomy by means of a deletion mapping strategy. We studied female patients possessing structural X-anomalies of the short arm. A genetic locus (no greater than 4.96 Mb in size) at Xp11.3 appears to play a key role in amygdala and orbitofrontal structural and (by implication) functional development. Females with partial X-chromosome deletions, in whom this critical locus is deleted, have normal intelligence. Their fear recognition is as poor as that of 45,X females and their amygdalae are correspondingly enlarged. This 4.96 Mb region contains, among others, the genes for monoamine oxidase A (MAOA) and B (MAOB), which are involved in the oxidative deamination of several neurotransmitters, including dopamine and serotonin. Abnormal activity of these neurotransmitters has been implicated in the aetiology of several neurodevelopmental disorders in which social cognitive deficits are prominent. These associated deficits include a specific lack of fear recognition from facial expressions. We show that the thrombocytic activity of MAOB is proportionate to the number of X-chromosomes, and hypothesize that haploinsufficiency of this enzyme in 45,X females predisposes to their deficits in social cognition.

Dosage-sensitive X-linked locus influences the development of amygdala and orbitofrontal cortex, and fear recognition in humans.

Early onset blindness provides a lesion model to investigate whether experience-dependent mechanisms subtend the functional anatomy of semantic retrieval. In particular, visual deprivation might alter the neural systems underlying retrieval of semantic information that is acquired via visual experience. Using functional MRI, we demonstrate that both early blind and sighted subjects activate a left-lateralized fronto-temporal 'core' semantic retrieval system and show common effects for retrieval of visually experienced semantic information. However, irrespective of the type of semantics, blind subjects activate additional extrastriate regions, which are coupled with frontal and temporal semantic regions. The resilience of semantic retrieval responses to visual deprivation suggests a considerable degree of innate and epigenetic specification of the semantic system. In contrast, the exuberant functional connectivity between extrastriate and 'core' semantic retrieval regions might be explained by abnormal pruning processes during early neurodevelopment.

Effects of visual deprivation on the organization of the semantic system.

This article reviews the dysconnection hypothesis of schizophrenia with an account of how dysfunctional integration among neuronal systems might arise, based upon the role of neuronal plasticity in shaping the connections and ensuing dynamics that underlie brain function. The hypothesis is that the pathophysiology of schizophrenia is expressed at the level of modulation of associative changes in synaptic efficacy; specifically plasticity in those brain systems responsible for learning, memory and emotion. This modulation is mediated by ascending neurotransmitter systems that; (i) have been implicated in schizophrenia and (ii) are known to be involved in consolidating synaptic connections during learning. This would translate, in functional terms, into a disruption of the reinforcement of adaptive behaviour that is consistent with the disintegrative aspects of schizophrenic neuropsychology.

In this paper, complex dynamical synchronization in a non-linear model of a neural system is studied, and the computational significance of the behaviours is explored. The local neural dynamics is determined by voltage-and ligand-gated ion channels and feedback between densely interconnected excitatory and inhibitory neurons. A mesoscopic array of local networks is modelled by introducing coupling between the local networks via weak excitatory-to-excitatory connectivity. It is shown that with modulation of this long-range synaptic coupling, the system undergoes a transition from independent oscillations to stable chaotic synchronization. Between these states exists a ‘weakly’ stable state associated with complex, intermittent behaviour in the temporal domain and clusters of synchronous regions in the spatial domain. The paper concludes with a discussion of the putative relevance of such processes in the brain, including the role of neuromodulatory systems and the mechanisms underlying sensory perception, adaptation, computation and complexity.

Modulation of excitatory synaptic coupling facilitates synchronization and complex dynamics in a biophysical model of neuronal dynamics

Hierarchical models are central to many current analyses of functional imaging data including random effects analysis, models using fMRI as priors for EEG source localization and spatiotemporal Bayesian modelling of imaging data [3]. These hierarchical models posit linear relations between variables with error terms that are Gaussian. The General Linear Model (GLM), which to date has been so central to the analysis of functional imaging data, is a special case of these hierarchical models consisting of just a single layer. Model fitting and statistical inference for hierarchical models can be implemented using a Parametric Empirical Bayes (PEB) algorithm described in Chapter 17 and in [4]. The algorithm is sufficiently general to accomodate multiple levels in the hierarchy and allows for the error covariances to take on arbitrary form. This generality is particularly appealing as it renders the method applicable to a wide variety of modelling scenarios. Because of this generality, however, and the complexity of scenarios in which the method is applied, readers wishing to learn about PEB for the first time are advised to read this chapter first. We provide an introduction to hierarchical models and focus on some relatively simple examples. Each model and PEB algorithm we present is a special case of that described in [4]. Whilst there are a number of tutorials on hierarchical modelling [9],[2] what we describe here has been tailored for functional imaging applications. We also note that a tutorial on hierarchical models is, to our minds, also a tutorial on Bayesian inference as higher levels act as priors for parameters in lower levels. Readers are therefore encouraged to also consult background texts on Bayesian inference, such as [5]. We restrict our attention to two-level models and show, in section 2, how one computes the posterior distributions over the firstand second-level parameters. These are derived, initially, for completely general design and error covariance matrices. We then consider two special cases (i) models with equal error variances and (ii) separable models. In section 3 of the chapter we show how the parameters and covariance components can be estimated using PEB. In section 4 we show how a two-level hierarchical model can be used for Random-Effects Analysis. For equal subject error variances at the first level and the same first-level design matrices (ie. balanced designs) we show that

This chapter describes a method of segmenting MR images into different tissue classes, using a modified Gaussian Mixture Model. By knowing the prior spatial probability of each voxel being grey matter, white matter or cerebro-spinal fluid, it is possible to obtain a more robust classification. In addition, a step for correcting intensity non-uniformity is also included, which makes the method more applicable to images corrupted by smooth intensity variations.

We studied a patient with idiopathic generalized epilepsy and frequent absences, using electroencephalogram‐correlated functional magnetic resonance imaging. Four prolonged runs of generalized spike‐wave discharge occurred during a 35‐minute experiment. Time‐locked activation was observed bilaterally within the thalami in conjunction with widespread but symmetrical cortical deactivation with a frontal maximum. We demonstrate the reciprocal participation of focal thalamic and widespread cortical networks during human absence seizures and suggest reductions in cortical blood flow, in response to synchronized electroencephalogram activity. Ann Neurol 2003;53:663–667

Comparing event-related and epoch analysis in blocked design fMRI

Hypoxic–ischemic events sustained within the first year of life can result in developmental amnesia, a disorder characterized by markedly impaired episodic memory and relatively preserved semantic memory, in association with medial temporal pathology that appears to be restricted to the hippocampus. Here we compared children who had hypoxic–ischemic events before 1 year of age (early group, n = 6) with others who showed memory problems after suffering hypoxic–ischemic events between the ages of 6 and 14 years (late group, n = 5). Morphometric analyses of the whole brain revealed that, compared with age-matched controls, both groups had bilateral abnormalities in the hippocampus, putamen, and posterior thalamus, as well as in the right retrosplenial cortex. The two groups also showed similar reductions (≈40%) in hippocampal volumes. Neuropsychologically, the only significant differences between the two were on a few tests of immediate memory, where the early group surpassed the late group. The latter measures provided the only clear indication that very early injury can lead to greater functional sparing than injury acquired later in childhood, due perhaps to the greater plasticity of the infant brain. On measures of long-term memory, by contrast, the two groups had highly similar profiles, both showing roughly equivalent preservation of semantic memory combined with marked impairment in episodic memory. It thus appears that, if this selective memory disorder is a special syndrome related to the early occurrence of hypoxia-induced damage, then the effective age at injury for this syndrome extends from birth to puberty.

This article is about how the brain data mines its sensory inputs. There are several architectural principles of functional brain anatomy that have emerged from careful anatomic and physiologic studies over the past century. These principles are considered in the light of representational learning to see if they could have been predicted a priori on the basis of purely theoretical considerations. We first review the organisation of hierarchical sensory cortices, paying special attention to the distinction between forward and backward connections. We then review various approaches to representational learning as special cases of generative models, starting with supervised learning and ending with learning based upon empirical Bayes. The latter predicts many features, such as a hierarchical cortical system, prevalent top-down backward influences and functional asymmetries between forward and backward connections that are seen in the real brain. The key points made in this article are: (i) hierarchical generative models enable the learning of empirical priors and eschew prior assumptions about the causes of sensory input that are inherent in non-hierarchical models. These assumptions are necessary for learning schemes based on information theory and efficient or sparse coding, but are not necessary in a hierarchical context. Critically, the anatomical infrastructure that may implement generative models in the brain is hierarchical. Furthermore, learning based on empirical Bayes can proceed in a biologically plausible way. (ii) The second point is that backward connections are essential if the processes generating inputs cannot be inverted, or the inversion cannot be parameterised. Because these processes involve many-to-one mappings, are non-linear and dynamic in nature, they are generally non-invertible. This enforces an explicit parameterisation of generative models (i.e. backward connections) to afford recognition and suggests that forward architectures, on their own, are not sufficient for perception. (iii) Finally, nonlinearities in generative models, mediated by backward connections, require these connections to be modulatory, so that representations in higher cortical levels can interact to predict responses in lower levels. This is important in relation to functional asymmetries in forward and backward connections that have been demonstrated empirically. q 2003 Elsevier Ltd. All rights reserved.

Autism is a psychiatric syndrome characterized by impairments in three domains: social interaction, communication, and restricted and repetitive behaviours and interests. Recent findings implicate the amygdala in the neurobiology of autism. In this paper, we report the results of a series of novel experimental investigations focusing on the structure and function of the amygdala in a group of children with autism. The first section attempts to determine if abnormality of the amygdala can be identified in an individual using magnetic resonance imaging in vivo. Using single-case voxel-based morphometric analyses, abnormality in the amygdala was detected in half the children with autism. Abnormalities in other regions were also found. In the second section, emotional modulation of the startle response was investigated in the group of autistic children. Surprisingly, there were no significant differences between the patterns of emotional modulation of the startle response in the autistic group compared with the controls.

This chapter covers three principle morphometric methods, that will be called voxelbased, deformation-based and tensor-based morphometry. Deformation-based morphometry (DBM) is a method for identifying macroscopic anatomical differences among the brains of different populations of subjects. The method involves spatially normalizing the structural MR images of a number of subjects so that they all conform to the same stereotaxic space. Multivariate statistics are then applied to the parameters describing the estimated nonlinear deformations that ensue. Tensor-based morphometry (TBM) is introduced as a method of identifying regional structural differences from the gradients of deformations fields. Deformation

This chapter is about warping brain images of different subjects to the same stereotaxic space. However, unlike Chapter 3, this method uses thousands or millions of parameters, so is potentially able to obtain much more precision. A high dimensional

A heuristic for the degrees of freedom of statistics based on multiple variance parameters

Introduction Experimental design and Statistical Parametric Mapping

In this paper, complex dynamical synchronization in a non-linear model of a neural system is studied, and the computational significance of the behaviours is explored. The local neural dynamics is determined by voltage- and ligand-gated ion channels and feedback between densely interconnected excitatory and inhibitory neurons. A mesoscopic array of local networks is modelled by introducing coupling between the local networks via weak excitatory-to-excitatory connectivity. It is shown that with modulation of this long-range synaptic coupling, the system undergoes a transition from independent oscillations to stable chaotic synchronization. Between these states exists a 'weakly' stable state associated with complex, intermittent behaviour in the temporal domain and clusters of synchronous regions in the spatial domain. The paper concludes with a discussion of the putative relevance of such processes in the brain, including the role of neuromodulatory systems and the mechanisms underlying sensory perception, adaptation, computation and complexity.

Modulation of excitatory synaptic coupling facilitates synchronization and complex dynamics in a biophysical model of neuronal dynamics.

Estimating efficiency a priori: a comparison of blocked and randomized designs

The principles underlying human hemispheric specialization are poorly understood. We used functional magnetic resonance imaging of letter and visuospatial decision tasks with identical word stimuli to address two unresolved problems. First, hemispheric specialization depended on the nature of the task rather than on the nature of the stimulus. Second, analysis of frontal candidate regions for cognitive control showed increased coupling between left anterior cingulate cortex (ACC) and left inferior frontal gyrus during letter decisions, whereas right ACC showed enhanced coupling with right parietal areas during visuospatial decisions. Cognitive control is thus localized in the same hemisphere as task execution.

Lateralized Cognitive Processes and Lateralized Task Control in the Human Brain

Philosophical transactions of the Royal Society of London. Series B, Biological sciences

Investigating individual differences in brain abnormalities in autism.

In this study, we combined functional magnetic resonance imaging (fMRI) and dynamic causal modeling (DCM) to investigate whether object category effects in the occipital and temporal cortex are mediated by inputs from early visual cortex or parietal regions. Resolving this issue may provide anatomical constraints on theories of category specificity which make different assumptions about the underlying neurophysiology. The data were acquired by Ishai, Ungerleider, Martin, Schouten, and Haxby (1999, 2000) and provided by the National fMRI Data Center (http://www.fmridc.org). The original authors used a conventional analysis to estimate differential effects in the occipital and temporal cortex in response to pictures of chairs, faces, and houses. We extended this approach by estimating neuronal interactions that mediate category effects using DCM. DCM uses a Bayesian framework to estimate and make inferences about the influence that one region exerts over another and how this is affected by experimental changes. DCM differs from previous approaches to brain connectivity, such as multivariate autoregressive models and structural equation modeling, as it assumes that the observed hemodynamic responses are driven by experimental changes rather than endogenous noise. DCM therefore brings the analysis of brain connectivity much closer to the analysis of regionally specific effects usually applied to functional imaging data. We used DCM to estimate the influence that V3 and the superior/inferior parietal cortex exerted over category-responsive regions and how this was affected by the presentation of houses, faces, and chairs. We found that category effects in occipital and temporal cortex were mediated by inputs from early visual cortex. In contrast, the connectivity from the superior/inferior parietal area to the category-responsive areas was unaffected by the presentation of chairs, faces, or houses. These findings indicate that category effects in the occipital and temporal cortex can be mediated by bottomup mechanismsa finding that needs to be embraced by models of category specificity.

A Dynamic Causal Modeling Study on Category Effects: BottomUp or TopDown Mediation?

In Friston et al. ((2002) Neuroimage 16: 465-483) we introduced empirical Bayes as a potentially useful way to estimate and make inferences about effects in hierarchical models. In this paper we present a series of models that exemplify the diversity of problems that can be addressed within this framework. In hierarchical linear observation models, both classical and empirical Bayesian approaches can be framed in terms of covariance component estimation (e.g., variance partitioning). To illustrate the use of the expectation-maximization (EM) algorithm in covariance component estimation we focus first on two important problems in fMRI: nonsphericity induced by (i) serial or temporal correlations among errors and (ii) variance components caused by the hierarchical nature of multisubject studies. In hierarchical observation models, variance components at higher levels can be used as constraints on the parameter estimates of lower levels. This enables the use of parametric empirical Bayesian (PEB) estimators, as distinct from classical maximum likelihood (ML) estimates. We develop this distinction to address: (i) The difference between response estimates based on ML and the conditional means from a Bayesian approach and the implications for estimates of intersubject variability. (ii) The relationship between fixed- and random-effect analyses. (iii) The specificity and sensitivity of Bayesian inference and, finally, (iv) the relative importance of the number of scans and subjects. The forgoing is concerned with within- and between-subject variability in multisubject hierarchical fMRI studies. In the second half of this paper we turn to Bayesian inference at the first (within-voxel) level, using PET data to show how priors can be derived from the (between-voxel) distribution of activations over the brain. This application uses exactly the same ideas and formalism but, in this instance, the second level is provided by observations over voxels as opposed to subjects. The ensuing posterior probability maps (PPMs) have enhanced anatomical precision and greater face validity, in relation to underlying anatomy. Furthermore, in comparison to conventional SPMs they are not confounded by the multiple comparison problem that, in a classical context, dictates high thresholds and low sensitivity. We conclude with some general comments on Bayesian approaches to image analysis and on some unresolved issues.

Our understanding of brain function has developed considerably since the advent of cognitive neuroscience and functional neuroimaging. Apparently, there are two central principles that functional brain architectures conform to: functional specialisation and functional integration. The former posits that brain systems are specialised for various perceptual and cognitive functions, and the latter emphasises interactions among these specialised systems. This integration is mediated by the functional equivalent of anatomical connections, i.e. effective connectivity (defined as the influence one neuronal system exerts over another). The notion of effective connectivity engendered the disconnection hypothesis, which represented an attempt to understand schizophrenia in mechanistic terms. This paper reviews the disconnection hypothesis and its implications for how one might use the powerful tools that are emerging from functional neuroimaging and genomics, to pinpoint the mechanisms that might cause schizophrenia.

World psychiatry : official journal of the World Psychiatric Association

In this study we demonstrate the importance of distributed sampling of peristimulus time in blocked design fMRI studies. Distributed sampling ensures all the components of an event-related hemodynamic response are sampled and avoids the bias incurred when stimulus presentation is time-locked to data acquisition. We found that differences in the temporal offset between stimulus presentation and data acquisition had a significant effect on some language-related activations. These effects, induced by simply shifting stimulus presentation by a fraction of the interscan interval, suggest that fixed sampling does indeed bias estimated responses, even in blocked designs.

The Importance of Distributed Sampling in Blocked Functional Magnetic Resonance Imaging Designs

We describe the use of anatomically informed basis functions (AIBF) in the analysis of multisubject functional imaging studies. AIBF are used to specify an anatomically informed spatial model that embodies anatomical knowledge for the statistical analysis of neuroimaging data. In a previous communication, we showed how AIBF can be used to incorporate prior anatomical constraints in single subject functional magnetic resonance image (fMRI) analyses to augment their anatomical precision. In this paper, we extend AIBF such that it can be applied to multisubject studies using fMRI or PET. The key concept is that, after spatial normalization, a canonical cortical surface can be used to generate a forward model of signal sources for all subjects. By estimating the hemodynamic signal in this canonical AIBF‐space and then projecting it back into the voxel‐space, one effectively extracts functional activity that is smooth, within and only within, the cortical sheet while attenuating other components unrelated to the physiological process of interest. The ensuing procedure can be considered as a highly non‐stationary, anisotropic anatomically informed [de]convolution or smoothing. It is shown that this procedure offers various advantages compared to existing conventional methods for the analysis of multisubject studies, in particular it is more sensitive to underlying activations. Hum. Brain Mapping 16:36–46, 2002. © 2002 Wiley‐Liss, Inc.

We investigated the accuracy of spatial basis function normalization using anatomical landmarks to determine how precisely homologous regions are colocalized. We examined precision in terms of: (1) the number of nonlinear basis functions used by the normalization procedure; (2) the degree of (Bayesian) regularization; and (3) the effect of substituting different templates and how this interacted with the number of basis functions. The face validity of spatial normalization was assessed as a function of these parameters, using the colocalization of homologous landmarks in a test sample of 20 normally developing children and 5 children with bilateral hippocampal pathology. Our results suggest that when optimal normalization parameters are used, anatomical landmarks in the medial temporal lobes are colocalized to within a standard deviation of about 1 mm. When suboptimal parameters are used this standard deviation can increase up to 3 mm. Interestingly the optimal parameters are those that provide a rather constrained normalization as opposed to those that optimize intensity matching at the expense of rendering the warps "unlikely." The implications of our results, for users of voxel-based morphometry, are discussed.

The Precision of Anatomical Normalization in the Medial Temporal Lobe Using Spatial Basis Functions

The ability to find targets embedded within complex visual environments requires the dynamic programming of visuomotor search behaviors. Functional magnetic resonance imaging was used to image subjects while they visually searched for targets embedded among foils. Visuomotor search activated the posterior parietal cortex and the frontal eye fields. Both regions showed a greater number of activated voxels on the right, consistent with the known pattern of right hemispheric dominance for spatial attention. The superior colliculus showed prominent activation in the search versus eye movement contrast, demonstrating, for the first time in humans, activation of this region specifically related to an exploratory attentional contingency. An analysis of effective connectivity demonstrated that the search-dependent variance in the activity of the superior colliculus was significantly influenced by the activity in a network of cortical regions including the right frontal eye fields and bilateral parietal and occipital cortices. These experiments also revealed the presence of a mosaic of activated sites within the frontal eye field region wherein saccadic eye movements, covert shifts of attention, and visuomotor search elicited overlapping but not identical zones of activation. In contrast to the existing literature on functional imaging, which has focused on covert shifts of spatial attention, this study helps to characterize the functional anatomy of overt spatial exploration.

Functional Anatomy of Visual Search: Regional Segregations within the Frontal Eye Fields and Effective Connectivity of the Superior Colliculus

Analyses of brain structure in genetic speech and language disorders provide an opportunity to identify neurobiological phenotypes and further elucidate the neural bases of language and its development. Here we report such investigations in a large family, known as the KE family, half the members of which are affected by a severe disorder of speech and language, which is transmitted as an autosomal-dominant monogenic trait. The structural brain abnormalities associated with this disorder were investigated using two morphometric methods of MRI analysis. A voxel-based morphometric method was used to compare the amounts of grey matter in the brains of three groups of subjects: the affected members of the KE family, the unaffected members and a group of age-matched controls. This method revealed a number of mainly motor- and speech-related brain regions in which the affected family members had significantly different amounts of grey matter compared with the unaffected and control groups, who did not differ from each other. Several of these regions were abnormal bilaterally, including the caudate nucleus, which was of particular interest because this structure was also found to show functional abnormality in a related PET study. We performed a more detailed volumetric analysis of this structure. The results confirmed that the volume of this nucleus was reduced bilaterally in the affected family members compared with both the unaffected members and the group of age-matched controls. This reduction in volume was most evident in the superior portion of the nucleus. The volume of the caudate nucleus was significantly correlated with the performance of affected family members on a test of oral praxis, a test of non-word repetition and the coding subtest of the Wechsler Intelligence Scale. These results thus provide further evidence of a relationship between the abnormal development of this nucleus and the impairments in oromotor control and articulation reported in the KE family.

MRI analysis of an inherited speech and language disorder: structural brain abnormalities.

The Neural Structures Expressing Perceptual Hysteresis in Visual Letter Recognition

Functional magnetic resonance imaging (fMRI) provides an indirect measure of neural activity changes in the brain. fMRI designs use a sequence of events (such as the presentation of a picture to the subject). A common goal of fMRI data analysis is to estimate the amplitudes of local brain responses to these experimental events. Designs involving a random component in the temporal structure of the event sequence are called stochastic. Stochastic designs are favored in situations where predictability of the event sequence is a potential confound. In this paper, discrete-time models of the efficiency of response amplitude estimation (using generalized least-squares) in single event-type, stationary stochastic fMRI designs (FRISTON et al., 1999) are extended to continuous-time. This allows one to determine certain results concerning efficiency as the average spacing between experimental events gets very small. Furthermore, we derive expressions for efficiency in the frequency domain. This provides a direct connection between efficiency and formulations of designs and noise in the frequency domain. This is useful from a signal processing and filtering perspective. These results can be used, given other constraints, to optimize fMRI stochastic design parameters.

We compared voxel-based morphometry (VBM) with independent accurate region-of-interest (ROI) measurements of temporal lobe structures in order to validate the usefulness of this fully automated and unbiased technique in Alzheimer's disease (AD) and semantic dementia (SD). In AD, ROI analyses appear more sensitive to volume loss in the amygdalae, whereas VBM analyses appear more sensitive to right middle temporal gyrus and regional hippocampal volume loss. In SD, ROI analyses appear more sensitive to left middle and inferior temporal gyrus volume loss, whereas VBM appears more sensitive to regional hippocampal volume loss. In addition the significance of volume reductions was generally less in VBM owing to more stringent corrections for multiple comparisons. In conclusion, the automated technique detects a general trend of atrophy similar to that of expertly labeled ROI measurements in AD and SD, although there are discrepancies in the ranking of severity and in the significance of volume reductions that are more marked in AD.

Automatic Differentiation of Anatomical Patterns in the Human Brain: Validation with Studies of Degenerative Dementias

Functional imaging studies of neuropsychologically impaired patients have not enjoyed the immediate success that was attained by functional imaging studies of normal subjects. This is largely because it has taken time to appreciate some of the deeper issues surrounding study design, analysis and interpretation. The most significant limitation is that functional imaging experiments with patients need tasks that the patients can perform. This precludes direct investigations of the physiological correlates of cognitive deficits. Nevertheless, functional imaging studies of brain-damaged patients who retain task competence can provide information that is not available from structural imaging, behavioural assessments or functional imaging with normal subjects. This is because intact task performance, following a brain lesion, does not necessarily entail normal neuronal responses in undamaged cortical areas. Abnormal neuronal responses, in the context of normal performance, can indicate alternative neuronal and cognitive mechanisms for supporting the same task. This, in turn, has important implications for understanding the mechanisms that mediate recovery and the organizational principles that underlie functional architectures in the human brain.

Functional Imaging Studies of Neuropsychological Patients: Applications and Limitations

Distributed linear solutions of the EEG source localization problem are used routinely. Here we describe an approach based on the weighted minimum norm method that imposes constraints using anatomical and physiological information derived from other imaging modalities to regularize the solution. In this approach the hyperparameters controlling the degree of regularization are estimated using restricted maximum likelihood (ReML). EEG data are always contaminated by noise, e.g., exogenous noise and background brain activity. The conditional expectation of the source distribution, given the data, is attained by carefully balancing the minimization of the residuals induced by noise and the improbability of the estimates as determined by their priors. This balance is specified by hyperparameters that control the relative importance of fitting and conforming to prior constraints. Here we introduce a systematic approach to this regularization problem, in the context of a linear observation model we have described previously. In this model, basis functions are extracted to reduce the solution space a priori in the spatial and temporal domains. The basis sets are motivated by knowledge of the evoked EEG response and information theory. In this paper we focus on an iterative "expectation-maximization" procedure to jointly estimate the conditional expectation of the source distribution and the ReML hyperparameters on which this solution rests. We used simulated data mixed with real EEG noise to explore the behavior of the approach with various source locations, priors, and noise levels. The results enabled us to conclude: (i) Solutions in the space of informed basis functions have a high face and construct validity, in relation to conventional analyses. (ii) The hyperparameters controlling the degree of regularization vary largely with source geometry and noise. The second conclusion speaks to the usefulness of using adaptative ReML hyperparameter estimates.

Systematic Regularization of Linear Inverse Solutions of the EEG Source Localization Problem

Inter Subject Registration of Functional and Anatomical Data Using SPM

The neural basis of attention to action was studied in 12 patients with Parkinson's disease (Hoehn and Yahr grades II and III) and 12 healthy age-matched controls. The subjects were studied by functional MRI (fMRI) during performance of a simple paced overlearned motor sequence task, with and without an additional attentional task. For the attentional task, subjects were instructed to attend either to their actions or to a visual distractor task. Statistical parametric mapping was used to implement a random effects analysis of the regional task-related activations in patient and control populations. Structural equation modelling of fMRI time series was used to measure effective connectivity among prefrontal and premotor areas. In both groups, the motor task was associated with activation of a distributed network including the premotor, motor and parietal cortex, striatum and cerebellum. In control subjects, but not patients, attention to action (relative to execution of an overlearned sequence) was associated with further activation of prefrontal, parietal and paracingulate cortex, and the supplementary motor area (SMA). Patients with Parkinson's disease showed greater than normal activation of the SMA during execution of the simple overlearned motor sequence, but less augmentation when attending to their actions. In control subjects, attention to action, but not attention to the visual distractor task, increased the effective connectivity between prefrontal cortex and both the lateral premotor cortex and the SMA. This represents a specific increase in effective connectivity. Attentional modulation of effective connectivity between the prefrontal, premotor cortex and SMA was not observed in patients. This deficit indicates a context-specific functional disconnection between the prefrontal cortex and the supplementary and premotor cortex in Parkinson's disease.

Attention to action in Parkinson's disease: impaired effective connectivity among frontal cortical regions.

Distributed linear solutions have frequently been used to solve the source localization problem in EEG. Here we introduce an approach based on the weighted minimum norm (WMN) method that imposes constraints using anatomical and physiological information derived from other imaging modalities. The anatomical constraints are used to reduce the solution space a priori by modeling the spatial source distribution with a set of basis functions. These spatial basis functions are chosen in a principled way using information theory. The reduced problem is then solved with a classical WMN method. Further (functional) constraints can be introduced in the weighting of the solution using fMRI brain responses to augment spatial priors. We used simulated data to explore the behavior of the approach over a range of the model's hyperparameters. To assess the construct validity of our method we compared it with two established approaches to the source localization problem, a simple weighted minimum norm and a maximum smoothness (Loreta-like) solution. This involved simulations, using single and multiple sources that were analyzed under different levels of confidence in the priors.

Anatomically Informed Basis Functions for EEG Source Localization: Combining Functional and Anatomical Constraints

Statistics I: experimental design and statistical parametric mapping

Unsupervised models of how the brain identifies and categorizes the causes of its sensory input can be divided into two classes: those that minimize the mutual information (i.e., redundancy) among evoked responses and those that minimize the prediction error. Although these models have the same goal, the way that goal is attained, and the functional architectures required, are fundamentally different. This review describes the differences, in the functional anatomy of sensory cortical hierarchies, implied by the two models. We then consider how neuroimaging can be used to disambiguate between them. The key distinction reduces to whether backward connections are employed by the brain to generate a prediction of sensory inputs. To ascertain whether backward influences are evident empirically requires a characterization of functional integration among brain systems. This review summarizes the approaches to measuring functional integration in terms of effective connectivity and proceeds to address the question posed by the theoretical considerations. In short, it will be shown that the conjoint manipulation of bottom-up and top-down inputs to an area can be used to test for interactions between them, in elaborating cortical responses. The conclusion, from these sorts of neuroimaging studies, points to the prevalence of top-down influences and the plausibility of generative models of sensory brain function.

Beyond phrenology: what can neuroimaging tell us about distributed circuitry?

This paper presents a method for estimating the conditional or posterior distribution of the parameters of deterministic dynamical systems. The procedure conforms to an EM implementation of a Gauss-Newton search for the maximum of the conditional or posterior density. The inclusion of priors in the estimation procedure ensures robust and rapid convergence and the resulting conditional densities enable Bayesian inference about the model parameters. The method is demonstrated using an input-state-output model of the hemodynamic coupling between experimentally designed causes or factors in fMRI studies and the ensuing BOLD response. This example represents a generalization of current fMRI analysis models that accommodates nonlinearities and in which the parameters have an explicit physical interpretation. Second, the approach extends classical inference, based on the likelihood of the data given a null hypothesis about the parameters, to more plausible inferences about the parameters of the model given the data. This inference provides for confidence intervals based on the conditional density.

Bayesian Estimation of Dynamical Systems: An Application to fMRI

Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations

Modulation of Excitatory Synaptic Coupling Facilitates Synchronization and Complex Dynamics in a Nonlinear Model of Neuronal Dynamics

Cholinergic Modulation of Experience-Dependent Plasticity in Human Auditory Cortex

22 – Statistics I: Experimental Design and Statistical Parametric Mapping

This article is about intersubject variability in the functional integration of activity in different brain regions. Previous studies of functional and effective connectivity have dealt with intersubject variability by analyzing data from different subjects separately or pretending the data came from the same subject. These approaches do not allow one to test for differences among subjects. The aim of this work was to illustrate how differences in connectivity among subjects can be addressed explicitly using structural equation modeling. This is enabled by constructing a multisubject network that comprises m regions of interest for each of the n subjects studied, resulting in a total of m x n nodes. Constructing a network of regions from different subjects may seem counterintuitive but embodies two key advantages. First, it allows one to test directly for differences among subjects by comparing models that do and do not allow a particular connectivity parameter to vary over subjects. Second, a multisubject network provides additional degrees of freedom to estimate the model's free parameters. Any neurobiological hypothesis normally addressed by single-subject or group analyses can still be tested, but with greater sensitivity. The common influence of experimental variables is modeled by connecting a virtual node, whose time course reflects stimulus onsets, to the sensory or "input" region in all subjects. Further experimental changes in task or cognitive set enter through modulation of the connections. This approach allows one to model both endogenous (or intrinsic) variance and exogenous effects induced by experimental design. We present a functional magnetic resonance imaging study that uses a multisubject network to investigate intersubject variability in functional integration in the context of single word and pseudoword reading. We tested whether the effect of word type on the reading-related coupling differed significantly among subjects. Our results showed that a number of forward and backward connections were stronger for reading pseudowords than words, and, in one case, connectivity showed significant intersubject variability. The discussion focuses on the implications of our findings and on further applications of the multisubject network analysis.

Effective Connectivity and Intersubject Variability: Using a Multisubject Network to Test Differences and Commonalities

We introduce a new method for detecting differences in the latency of blood oxygenation level-dependent (BOLD) responses to brief events within the context of the General Linear Model. Using a first-order Taylor approximation in terms of the temporal derivative of a canonical hemodynamic response function, statistical parametric maps of differential latencies were estimated via the ratio of derivative to canonical parameter estimates. This method was applied to two example datasets: comparison of words versus nonwords in a lexical decision task and initial versus repeated presentations of faces in a fame-judgment task. Tests across subjects revealed both magnitude and latency differences within several brain regions. This approach offers a computationally efficient means of detecting BOLD latency differences over the whole brain. Precise characterization of the hemodynamic latency and its interpretation in terms of underlying neural differences remain problematic, however.

Detecting Latency Differences in Event-Related BOLD Responses: Application to Words versus Nonwords and Initial versus Repeated Face Presentations

Many cognitive theories of semantic organization stem from reports of patients with selective, category-specific deficits for particular classes of objects (e.g., fruit). The anatomical assumptions underlying the competing claims can be evaluated with functional neuroimaging but the findings to date have been inconsistent and insignificant when standard statistical criteria are adopted. We hypothesized that category differences in functional brain responses might be small and task dependent. To test this hypothesis, we entered data from seven PET studies into a single multifactorial design which crossed category (living vs man-made) with a range of tasks. Reliable category-specific effects were observed but only for word retrieval and semantic decision tasks. Living things activated medial aspects of the anterior temporal poles bilaterally while tools activated a left posterior middle temporal region. These category-by-task interactions provide robust evidence for an anatomical double dissociation according to category and place strong constraints on cognitive theories of the semantic system. Furthermore they reconcile some of the apparent inconsistencies between lesion studies and functional neuroimaging data.

Anatomic Constraints on Cognitive Theories of Category Specificity

This paper describes the construction of posterior probability maps that enable conditional or Bayesian inferences about regionally-specific effects in neuroimaging. Posterior probability maps are images of the probability or confidence that an activation or effect exceeds some specified threshold, given the data. Posterior probability maps (PPMs) represent a complementary alternative to statistical parametric maps (SPMs) that are used to make classical inferences. However, a key problem in Bayesian inference is the specification of appropriate priors. This problem can be eschewed by using empirical Bayes in which prior variances are estimated from the data, under some simple assumptions about their form. Empirical Bayes requires a hierarchical observation model, in which higher levels can be regarded as providing prior constraints on lower levels. In neuroimaging observations of the same effect over voxels provides a natural, two-level hierarchy that enables an empirical Bayesian approach. We present a brief motivation and the operational details of a simple empirical Bayesian method for computing posterior probability maps. We then compare Bayesian and classical inference through the equivalent PPMs and SPMs testing for the same effects in the same data.

Proceedings of the 9th International Conference on Neural Information Processing, 2002. ICONIP '02.

In this paper we address the assumptions about the distribution of errors made by voxel-based morphometry. Voxel-based morphometry (VBM) uses the general linear model to construct parametric statistical tests. In order for these statistics to be valid, a small number of assumptions must hold. A key assumption is that the model's error terms are normally distributed. This is usually ensured through the Central Limit Theorem by smoothing the data. However, there is increasing interest in using minimal smoothing (in order to sensitize the analysis to regional differences at a small spatial scale). The validity of such analyses is investigated. In brief, our results indicate that nonnormality in the error terms can be an issue in VBM. However, in balanced designs, provided the data are smoothed with a 4-mm FWHM kernel, nonnormality is sufficiently attenuated to render the tests valid. Unbalanced designs appear to be less robust to violations of normality: a significant number of false positives arise at a smoothing of 4 and 8 mm when comparing a single subject to a group. This is despite the fact that conventional group comparisons appear to be robust, remaining valid even with no smoothing. The implications of the results for researchers using voxel-based morphometry are discussed.

This paper reviews hierarchical observation models, used in functional neuroimaging, in a Bayesian light. It emphasizes the common ground shared by classical and Bayesian methods to show that conventional analyses of neuroimaging data can be usefully extended within an empirical Bayesian framework. In particular we formulate the procedures used in conventional data analysis in terms of hierarchical linear models and establish a connection between classical inference and parametric empirical Bayes (PEB) through covariance component estimation. This estimation is based on an expectation maximization or EM algorithm. The key point is that hierarchical models not only provide for appropriate inference at the highest level but that one can revisit lower levels suitably equipped to make Bayesian inferences. Bayesian inferences eschew many of the difficulties encountered with classical inference and characterize brain responses in a way that is more directly predicated on what one is interested in. The motivation for Bayesian approaches is reviewed and the theoretical background is presented in a way that relates to conventional methods, in particular restricted maximum likelihood (ReML). This paper is a technical and theoretical prelude to subsequent papers that deal with applications of the theory to a range of important issues in neuroimaging. These issues include; (i) Estimating nonsphericity or variance components in fMRI time-series that can arise from serial correlations within subject, or are induced by multisubject (i.e., hierarchical) studies. (ii) Spatiotemporal Bayesian models for imaging data, in which voxels-specific effects are constrained by responses in other voxels. (iii) Bayesian estimation of nonlinear models of hemodynamic responses and (iv) principled ways of mixing structural and functional priors in EEG source reconstruction. Although diverse, all these estimation problems are accommodated by the PEB framework described in this paper.

Attention to Action: Specific Modulation of Cortico-Cortical Connectivity Measured Using FMRI

© Oxford University Press 2001. All rights reserved. This chapter shows that new methods for measuring effective connectivity allow us to characterize the interactions between brain regions which underlie the complex interactions among different processing stages of functional architectures. It reviews the basic concepts of effective connectivity in neuroimaging. The methods introduced to assess effective connectivity are multiple linear regression, covariance structural equation modelling and variable parameter regression. The first example demonstrates that non-linear interactions can be characterized using simple extensions of linear models, while in the second, structural equation modelling is introduced as a device that allows one to combine observed changes in cortical activity and anatomical models. Finally, the chapter concludes that the approach to neuroimaging data and regional interactions is an exciting endeavour, which is starting to attract more attention.

This article has been written in response to Dr. Fred L. Bookstein's article entitled '"Voxel-Based Morphometry" Should Not Be Used with Imperfectly Registered Images' in this issue of NeuroImage. We will address three main issues: (i) Dr. Bookstein appears to have misunderstood the objective of voxel-based morphometry (VBM) and the nature of the continuum we referred to. (ii) We agree with him when he states that findings from VBM can pertain to systematic registration errors during spatial normalization. (iii) His argument about voxelwise tests on smooth data holds in the absence of error variance, but is of no consequence when using actual data. We first review the tenets of VBM, paying particular attention to the relationship between VBM and tensor-based morphometry. The last two sections of this response deal with the specific concerns raised by Dr. Bookstein.

Systematic noise regularisation for linear inverse solution of the source localisation problem in EEG

Catriona Diana GOOD Dr1, Ingrid JOHNSRUDE Dr2, John Ashburner3, Karl J. FRISTON4, Richard S. FRACKOWIAK5 1Wellcome Dept of Cognitive Neurolgy, ION, London, UK, UCL, 12 Queen Square, London, WC1N 3BG, UK, London, UK; 2MRC, ; 3WDCN, Institute of Neurology, 12 Queen Square, London, UK, London, UK; 4University College London, Institute of Neurology, Wellcome Dept of Cognitive Neurology, London, United Kingdom; 5University College London, Queen Square, London, United Kingdom;

Cerebral asymmetry: A voxel based morphometry study of 465 normal adult brains

The brain can be regarded as an ensemble of connected dynamical systems and as such conforms to some simple principles relating the inputs and outputs of its constituent parts. The ensuing implications, for the way we think about, and measure, neuronal interactions, can be quite profound. These range from 1) implications for which aspects of neuronal activity are important to measure and how to characterize coupling among neuronal populations; 2) implication for understanding the emergence of dynamic receptive fields and functionally specialized brain architectures; and 3) teleological implications pertaining to the genesis of dynamic instability and complexity, which is necessary for adaptive self-organization. This review focuses on the first set of implications by looking at neuronal interactions, coupling, and implicit neuronal codes from a dynamical perspective. By considering the brain in this light, one can show that a sufficient description of neuronal activity must comprise activity at the current time and its recent history. This history constitutes a neuronal transient. Such transients represent an essential metric of neuronal interactions and, implicitly, a code employed in the functional integration of brain systems. The nature of transients, expressed conjointly in different neuronal populations, reflects the underlying coupling among brain systems. A complete description of this coupling, or effective connectivity, can be expressed in terms of generalized convolution kernels (Volterra kernels) that embody high-order or nonlinear interactions. This coupling may be synchronous, and possibly oscillatory, or asynchronous. A critical distinction between synchronous and asynchronous coupling is that the former is essentially linear and the latter is nonlinear. The nonlinear nature of asynchronous coupling enables the rich, context-sensitive interactions that characterize real brain dynamics, suggesting that it plays an important role in functional integration.

Book Review: Brain Function, Nonlinear Coupling, and Neuronal Transients

Voxel-based morphometry (VBM) is a powerful tool for analyzing changes in gray or white matter density of the brain. By using an automated segmentation procedure and standardized parametric statistics it avoids biases inherent in operator-dependent morphological operations (J. Ashburner and K. J. Friston, 2000, NeuroImage 11, 805-821). Since its introduction in 1995, VBM has been used to examine anatomical changes in a variety of diseases associated with neurologic and psychiatric dysfunction. Given the power of this technique for discerning subtle anatomical changes, we wanted to assess its performance on brains with gross structural abnormalities. Such results could have implications regarding the difficulties to be faced when examining other types of distorted brains (e.g., brains with changes due to degenerative disease). This report describes the use of VBM for examining individual and group changes in gray matter concentration in five patients who had recovered from herpes simplex encephalitis (HSE) compared with age- and sex-matched controls. Because HSE tends to affect a specific set of brain regions we thought that this would (1) provide an opportunity to assess the anatomical face validity of VBM, (2) allow us to assess the problems of this technique when used on distorted brains, and (3) provide an in vivo demonstration of the gray matter changes due to HSE. We found that, despite problems in normalizing and segmenting these severely distorted brains, VBM was able to identify correctly a number of the regional gray matter abnormalities in HSE. The results, while consistent with the well-known histopathology of the disease, also demonstrate potential difficulties with this method.

Behavioural and neuropathological evidence for medial temporal lobe abnormality in children with Autism

Attention to action: specific modulation of cortico-cortical interactions in humans

This article has been written in response to Dr. Fred L. Bookstein’s article entitled ‘“Voxel-Based Morphometry” Should Not Be Used with Imperfectly Registered Images’ in this issue of NeuroImage. We will address three main issues: (i) Dr. Bookstein appears to have misunderstood the objective of voxel-based morphometry (VBM) and the nature of the continuum we referred to. (ii) We agree with him when he states that findings from VBM can pertain to systematic registration errors during spatial normalization. (iii) His argument about voxelwise tests on smooth data holds in the absence of error variance, but is of no consequence when using actual data. We first review the tenets of VBM, paying particular attention to the relationship between VBM and tensor-based morphometry. The last two sections of this response deal with the specific concerns raised by Dr. Bookstein. © 2001 Academic Press

COMMENTS AND CONTROVERSIES Why Voxel-Based Morphometry Should Be Used

Even after realignment there is residual movement-related variance present in fMRI time-series, causing loss of sensitivity and, potentially, also specificity. One cause is the differential deformation of the sampling matrix, by field inhomogeneities, at different object positions, i.e., a movement-by-inhomogeneity interaction. This has been addressed previously by using empirical field measurements. In the present paper we suggest a forward model of how data is affected by an inhomogeneous field at different object positions. From this model we derive a method to solve the inverse problem of estimating the field inhomogeneities and their derivatives with respect to object position, directly from the EPI data and estimated realignment parameters. The field is modeled as a linear combination of cosine basis fields, which facilitates a fast way of implementing the necessary matrix operations. Simulations suggest that the solution is tractable and that the fields are estimable given the deformed images and knowledge of the relative positions at which they have been acquired. An experiment on a subject performing voluntary movements in the scanner yielded plausible estimates of the deformation fields and their application to "unwarp" the time series significantly reduced movement-related variance.

The aim of this work was to investigate the dependence of BOLD responses on different patterns of stimulus input/neuronal changes. In an earlier report, we described an input-state-output model that combined (i) the Balloon/Windkessel model of nonlinear coupling between rCBF and BOLD signals, and (ii) a linear model of how regional flow changes with synaptic activity. In the present investigation, the input-state-output model was used to explore the dependence of simulated PET (rCBF) and fMRI (BOLD) signals on various parameters pertaining to experimental design. Biophysical simulations were used to estimate rCBF and BOLD responses as functions of (a) a prior stimulus, (b) epoch length (for a fixed SOA), (c) SOA (for a fixed number of events), and (d) stimulus amplitude. We also addressed the notion that a single neuronal response may differ, in terms of the relative contributions of early and late neural components, and investigated the effect of (e) the relative size of the late or "endogenous" neural component. We were interested in the estimated average rCBF and BOLD responses per stimulus or event, not in the statistical efficiency with which these responses are detected. The BOLD response was underestimated relative to rCBF with a preceding stimulus, increasing epoch length, and increasing SOA. Furthermore, the BOLD response showed some highly nonlinear behaviour when varying stimulus amplitude, suggesting some form of hemodynamic "rectification." Finally, the BOLD response was underestimated in the context of large late neuronal components. The difference between rCBF and BOLD is attributed to the nonlinear transduction of rCBF to BOLD signal. Our simulations support the idea that varying parameters that specify the experimental design may have differential effects in PET and fMRI. Moreover, they show that fMRI can be asymmetric in its ability to detect deactivations relative to activations when an absolute baseline is stipulated. Finally, our simulations suggest that relative insensitivity to BOLD signal in specific regions, such as the temporal lobe, may be partly explained by higher cognitive functions eliciting a relatively large late endogenous neuronal component.

Nonlinear Coupling between Evoked rCBF and BOLD Signals: A Simulation Study of Hemodynamic Responses

Functional disconnectivity in people with schizophrenia and relatives at high genetic risk: Evidence for trait disconnectivities of bilateral superior temporal gyri

We used voxel-based morphometry (VBM) to examine human brain asymmetry and the effects of sex and handedness on brain structure in 465 normal adults. We observed significant asymmetry of cerebral grey and white matter in the occipital, frontal, and temporal lobes (petalia), including Heschl's gyrus, planum temporale (PT) and the hippocampal formation. Males demonstrated increased leftward asymmetry within Heschl's gyrus and PT compared to females. There was no significant interaction between asymmetry and handedness and no main effect of handedness. There was a significant main effect of sex on brain morphology, even after accounting for the larger global volumes of grey and white matter in males. Females had increased grey matter volume adjacent to the depths of both central sulci and the left superior temporal sulcus, in right Heschl's gyrus and PT, in right inferior frontal and frontomarginal gyri and in the cingulate gyrus. Females had significantly increased grey matter concentration extensively and relatively symmetrically in the cortical mantle, parahippocampal gyri, and in the banks of the cingulate and calcarine sulci. Males had increased grey matter volume bilaterally in the mesial temporal lobes, entorhinal and perirhinal cortex, and in the anterior lobes of the cerebellum, but no regions of increased grey matter concentration.

Cerebral Asymmetry and the Effects of Sex and Handedness on Brain Structure: A Voxel-Based Morphometric Analysis of 465 Normal Adult Human Brains

Correcting for non-sphericity in imaging data using classical and Bayesian approaches

Are there reading specific brain areas? A meta-analysis of PET data from 72 subjects

Non linear coupling between evoked rCBF and BOLD signals: A simulation study of hemodynamic responses

Herpes simplex encephalitis: Structural changes analyzed with voxel-based morphometry

Voxel-based-morphometry (VBM) is a whole-brain, unbiased technique for characterizing regional cerebral volume and tissue concentration differences in structural magnetic resonance images. We describe an optimized method of VBM to examine the effects of age on grey and white matter and CSF in 465 normal adults. Global grey matter volume decreased linearly with age, with a significantly steeper decline in males. Local areas of accelerated loss were observed bilaterally in the insula, superior parietal gyri, central sulci, and cingulate sulci. Areas exhibiting little or no age effect (relative preservation) were noted in the amygdala, hippocampi, and entorhinal cortex. Global white matter did not decline with age, but local areas of relative accelerated loss and preservation were seen. There was no interaction of age with sex for regionally specific effects. These results corroborate previous reports and indicate that VBM is a useful technique for studying structural brain correlates of ageing through life in humans.

A Voxel-Based Morphometric Study of Ageing in 465 Normal Adult Human Brains

The global activity is an important confound when analyzing PET data in that its inclusion in the statistical model can substantially reduce error variance and increase sensitivity. However, by defining global activity as the average over all voxels one introduces a bias that is collinear with experimental factors. This leads to an underestimation of true activations and the introduction of artefactual deactivations. We propose a novel estimator for the global activity based on the notion of finding a maximally nonlocal mode in a multivariate characterization of the data, while maximizing the locality of the remaining modes. The approach uses singular value decomposition (SVD) to find a provisional set of modes, which are subsequently rotated such that a metric based on the above heuristic is maximized. This metric is a version of the stochastic sign change (SSC) criterion that has been used previously for normalizing medical images with focal defects. The estimator was evaluated on simulated and real functional imaging (PET) data. The simulations show that the bias of the global mean, introduced by focal activations, is reduced by 80--90% with the new estimator. Comparison with a previous unbiased estimator, using the empirical data, yielded similar results. The advantage of the new estimator is that it is not informed of experimental design and relies only on general assumptions regarding the nature of the signal.

Morphometric analysis of structural MRI of the children who suffered hypoxic events perinatally has demonstrated bilateral reduction in grey matter density in the putamen, hippocampus and thalamus (2). The purpose of this study was to determine the differences and commonalities in the pattern of neuropathology between the group of children whose pathology was incurred early in life and the children whose pathology was incurred later in childhood. Methods The early group consisted of six children who suffered hypoxic episodes aged < 1 year. The late group consisted of four children who suffered hypoxic episodes between the ages of 6 and 14. Two control groups were chosen, age-matched to the early group and the late group respectively. All subjects were scanned on a 1.5T Siemens Vision system, using a T1-weighted MPRAGE sequence. The 3D data sets were analysed in SPM99 (Wellcome Department of Cognitive Neurology, London, UK). Each scan was normalised and then segmented as described in Ashburner et al. (1997) (3). The images were smoothed with an isotropic Gaussian kernel. This renders the voxel values equal to the amount of grey matter per unit volume under the smoothing kernel. Two smoothing kernels were used, 4mm and 8mm, in order to sensitise the analysis to the spatial scale of the expected neuropathology (hippocampus and putamen respectively).

Age at Hypoxia and the Pattern of Neuropathology in Children with Developmental Amnesia

Despite a need for rule learning in everyday life, the brain regions involved in explicit rule induction remain undetermined. Here we use event-related functional magnetic resonance imaging to measure learning-dependent neuronal responses during an explicit categorization task. Subjects made category decisions, with feedback, to exemplar letter strings for which the rule governing category membership was periodically changed. Bilateral fronto-polar prefrontal cortices were selectively engaged following rule change. This activation pattern declined with improving task performance reflecting rule acquisition. The vocabulary of letters comprising the exemplars was also periodically changed, independently of rule changes. This exemplar change modulated activation in left anterior hippocampus. Our finding that fronto-polar cortex mediates rule learning supports a functional contribution of this region to generic reasoning and problem-solving behaviours.

The representational capacity and inherent function of any neuron, neuronal population or cortical area in the brain is dynamic and context-sensitive. Functional integration, or interactions among brain systems, that employ driving (bottom up) and backward (top-down) connections, mediate this adaptive and contextual specialisation. A critical consequence is that neuronal responses, in any given cortical area, can represent different things at different times. This can have fundamental implications for the design of brain imaging experiments and the interpretation of their results. Our arguments are developed under generative models of brain function, where higher-level systems provide a prediction of the inputs to lower-level regions. Conflict between the two is resolved by changes in the higher-level representations, which are driven by the ensuing error in lower regions, until the mismatch is "cancelled". From this perspective the specialisation of any region is determined both by bottom-up driving inputs and by top-down predictions. Specialisation is therefore not an intrinsic property of any region but depends on both forward and backward connections with other areas. Because the latter have access to the context in which the inputs are generated they are in a position to modulate the selectivity or specialisation of lower areas. The implications for classical models (e.g., classical receptive fields in electrophysiology, classical specialisation in neuroimaging and connectionism in cognitive models) are severe and suggest these models may provide incomplete accounts of real brain architectures. Here we focus on the implications for cognitive neuroscience in the context of neuroimaging.

Degeneracy in neural systems revealed by inter-subject variability in normal and abnormal activation patterns

Tsuda examines the potential contribution of nonlinear dynamical systems, with many degrees of freedom, to understanding brain function. We offer suggestions concerning symmetry and transients to strengthen the physiological motivation and theoretical consistency of this novel research direction: Symmetry plays a fundamental role, theoretically and in relation to real brains. We also highlight a distinction between chaotic "transience" and "itineracy".

Symmetries and itineracy in nonlinear systems with many degrees of freedom

Functional neuroimaging of neuropsychologically impaired patients

Zero-lag synchronous dynamics in triplets of interconnected cortical areas

Classical and bayesian approaches to imaging data analysis with authors / 画像データ分析に対する古典的及びベイズ的アプローチ

Effective connectivity during reading: the effects of word type and stimulus rate

The prefrontal cortex may exert cognitive control by a general mechanism of attentional selection of neuronal representations. We used functional magnetic resonance imaging to test this hypothesis in the motor system. Normal volunteers were scanned during performance of a simple motor task, with their attention either directed towards their actions, or diverted towards a visual search task, or neither. Attention to action increased activity in prefrontal, premotor and parietal cortex, compared with unattended performance of the same movements. Analysis of cortical activity by structural equation modelling of regional fMRI time series was used to measure effective connectivity among prefrontal, premotor and parietal cortices. Attention to action enhanced effective connectivity between dorsal prefrontal cortex and premotor cortex, whereas non-motor attention diminished it. These effects were not attributable to common inputs from parietal cortex to the prefrontal and premotor cortex. The results suggest a supra-modal role for the dorsal prefrontal cortex in attentional selection, operating within the motor system as well as sensory and mnemonic domains.

Attention to Action: Specific Modulation of Corticocortical Interactions in Humans

Analysis of multisubject neuroimaging data using anatomically informed basis functions

The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry

In this experiment we address the pharmacological modulation of repetition priming, a basic form of learning, using event-related functional magnetic resonance imaging. We measured brain activity in a word-stem completion paradigm in which, before study, volunteers were given either placebo, lorazepam (2 mg orally), or scopolamine (0.4 mg, i.v.). Relative to placebo, both drugs attenuated the behavioral expression of priming. Repetition was associated with a decreased neuronal response in left extrastriate, left middle frontal, and left inferior frontal cortices in the placebo group. Both drugs abolished these “repetition suppression” effects. By showing a concurrence of behavioral and neuronal modulations, the results suggest that GABAergic and cholinergic systems influence the neuronal plasticity necessary for repetition priming.

Pharmacological Modulation of Behavioral and Neuronal Correlates of Repetition Priming

Functional neuroimaging was used to investigate how lesions to the Broca's area impair neuronal responses in remote undamaged cortical regions. Four patients with speech output problems, but relatively preserved comprehension, were scanned while viewing words relative to consonant letter strings. In normal subjects, this results in left lateralized activation in the posterior inferior frontal, middle temporal, and posterior inferior temporal cortices. Each patient activated normally in the middle temporal region but abnormally in the damaged posterior inferior frontal cortex and the undamaged posterior inferior temporal cortex. In the damaged frontal region, activity was insensitive to the presence of words but in the undamaged posterior inferior temporal region, activity decreased in the presence of words rather than increasing as it did in the normal individuals. The reversal of responses in the left posterior inferior temporal region illustrate the context-sensitive nature of the abnormality and that failure to activate the left posterior temporal region could not simply be accounted for by insufficient demands on the underlying function. We propose that, in normal individuals, visual word presentation changes the effective connectivity among reading areas and, in patients, posterior temporal responses are abnormal when they depend upon inputs from the damaged inferior frontal cortex. Our results serve to introduce the concept of dynamic diaschisis; the anatomically remote and context-sensitive effects of focal brain lesions. Dynamic diaschisis reveals abnormalities of functional integration that may have profound implications for neuropsychological inference, functional anatomy and, vicariously, cognitive rehabilitation.

Dynamic Diaschisis: Anatomically Remote and Context-Sensitive Human Brain Lesions

This paper summarizes five major themes of discussion stemming from a recent workshop at the University of Toronto. The focus of the workshop was whether the phenomenology of cognition has a direct translation to the biological processes of the brain. The study of this translation is the goal of cognitive neuroscience. The themes were: (1) the influence of context on the understanding of brain function, in which regional activity may have different functional relevance depending on activity in the rest of the brain; (2) the merger of anatomy and function, emphasizing how interfacing at the systems level can have the potential to aid in the understanding of how anatomy constrains function; (3) the development of mathematical measures that take advantage of organizing principles of the nervous system; (4) the observation that the relation between "top-down" and "bottom-up" both neurally and conceptually could be better appreciated through a more principled mathematical approach; and (5) a central role for large-scale neural modeling to bridge basic neurophysiology and anatomy. Despite the consensus on these themes, there are several challenges for the field. Significant obstacles arise from the multidisciplinary nature of cognitive neuroscience, in which terms do not mean the same thing across disciplines (e.g., networks and systems). The imprecision of explanations for cognitive neuroscience data was also seen as a significant problem, suggesting that more principled attempts at explicit model specifications and prediction will be necessary for the field to develop.

High-sensitivity functional MRI of medial temporal lobes detects encoding-related perirhinal responses

Further, given the profound cognitive impairment associated with Autism and that unilateral brain damage in children is unlikely to result in severe cognitive sequelae, it is reasonable to suspect that the critical neuropathology in Autism affects the medial temporal lobe system bilaterally. Voxel-based morphometry was developed to characterise cerebral grey and white matter differences in structural MRI scans. It compares segmented images using statistical parametric mapping (SPM) to identify and make inferences about regionally specific differences. Recent theoretical developments enable voxel-based morphometry to be constrained to search exclusively for bilateral structural

Evidence for Medial Temporal Lobe Pathology in Children with Autism

Functional integration: methods for assessing interactions among neuronal systems using brain imaging

Direct extraction of realistic constraints from T1 structural MR image for electromagnetic source localisation

A direct quantitative relationship between the functional properties of human and macaque V5

The nonlinear nature of integration among cortical brain areas renders the effective connectivity between them inherently dynamic and context-sensitive. One emerging architectural principle of functional brain organization, which rests explicitly on these nonlinear interactions, is that neuronal responses expressed at any level in a sensory hierarchy reflect an interaction between (i) bottom up "driving" afferents from lower cortical areas and (ii) backwards "modulatory" inputs from higher areas that mediate top-down contextual effects. A compelling example is attentional modulation of responses in functionally specialized sensory areas. The aim of this work was to demonstrate that parietal regions may mediate selective attention to motion by modulating the effective connectivity from early visual cortex to the motion-sensitive area V5/MT. Using functional magnetic resonance imaging, and an analysis of effective connectivity based on nonlinear system identification, we found that backwards modulatory influences from the posterior parietal cortex are sufficient to account for a significant component of attentional modulation of V5/MT responses to "driving" inputs from V2. By explicitly modeling interactions among inputs to V5/MT, we were able to make inferences about the influences of V2 inputs and their concomitant activity-dependent modulation by parietal afferents. The latter effects embody dynamic changes in effective connectivity that may underlie attentional mechanisms. These results speak to the context-sensitive nature of functional integration in the brain and provide empirical evidence that attentional effects may be mediated by backwards connections, of a modulatory sort, in humans.

Attentional modulation of effective connectivity from V2 to V5/MT in humans.

At its simplest, voxel-based morphometry (VBM) involves a voxel-wise comparison of the local concentration of gray matter between two groups of subjects. The procedure is relatively straightforward and involves spatially normalizing high-resolution images from all the subjects in the study into the same stereotactic space. This is followed by segmenting the gray matter from the spatially normalized images and smoothing the gray-matter segments. Voxel-wise parametric statistical tests which compare the smoothed gray-matter images from the two groups are performed. Corrections for multiple comparisons are made using the theory of Gaussian random fields. This paper describes the steps involved in VBM, with particular emphasis on segmenting gray matter from MR images with nonuniformity artifact. We provide evaluations of the assumptions that underpin the method, including the accuracy of the segmentation and the assumptions made about the statistical distribution of the data.

Neural responses associated with cue evoked emotional states and heroin in opiate addicts.

Perception involves the processing of sensory stimuli and their translation into conscious experience. A novel percept can, once synthesized, be maintained or discarded from awareness. We used event–related funtional magnetic resonance imaging to separate the neural responses associated with the maintenance of a percept, produced by single–image, random–dot stereograms, from the response evoked at the onset of the percept. The latter was associated with distributed bilateral activation in the posterior thalamus and regions in the occipito–temporal, parietal and frontal cortices. In contrast, sustained perception was associated with activation of the pre–frontal cortex and hippocampus. This observation suggests that sustaining a visual percept involves neuroanatomical systems which are implicated in memory function and which are distinct from those engaged during perceptual synthesis.

Proceedings of the Royal Society of London. Series B: Biological Sciences

Assessing interactions among neuronal systems using functional neuroimaging

Time-dependent functional connectivity between the neocortex and cerebellum during stimulus omission

To assess the effect of various analysis parameters on the sensitivity of event-related fMRI analyses, 36 analyses were performed on a single fMRI data-set, varying parameters along four axes: (1) resampled voxel size; (2) spatial smoothing; (3) temporal smoothing; and (4) the set of basis functions used to model event-related responses. Sensitivity (i.e., the probability of detecting an activation given it exists) was assessed in terms of Z scores and by a metric for corrected P values, the negative log of the expected Euler characteristic. Sixteen brain regions distributed across cortical and subcortical areas were included in the meta-analysis. Main effects on sensitivity were found for resampled voxel size, spatial smoothing, temporal smoothing, and the set of basis functions chosen. The analysis parameters that generally produced the most sensitive analyses were a 2-mm(3) resampled voxel size, 10-mm spatial smoothing, 4-s temporal smoothing, and a basis set comprising a hemodynamic response function and its temporal derivative.

A Study of Analysis Parameters That Influence the Sensitivity of Event-Related fMRI Analyses

Multivariate SPM: Application to basis function characterisations of event-related fMRI responses

Structural MRI in X-linked Kallmann’s syndrome: voxel-based morphometry demonstrates hypoplasia of the entorhinal cortex

This paper concerns temporal filtering in fMRI time-series analysis. Whitening serially correlated data is the most efficient approach to parameter estimation. However, if there is a discrepancy between the assumed and the actual correlations, whitening can render the analysis exquisitely sensitive to bias when estimating the standard error of the ensuing parameter estimates. This bias, although not expressed in terms of the estimated responses, has profound effects on any statistic used for inference. The special constraints of fMRI analysis ensure that there will always be a misspecification of the assumed serial correlations. One resolution of this problem is to filter the data to minimize bias, while maintaining a reasonable degree of efficiency. In this paper we present expressions for efficiency (of parameter estimation) and bias (in estimating standard error) in terms of assumed and actual correlation structures in the context of the general linear model. We show that: (i) Whitening strategies can result in profound bias and are therefore probably precluded in parametric fMRI data analyses. (ii) Band-pass filtering, and implicitly smoothing, has an important role in protecting against inferential bias.

To Smooth or Not to Smooth? Bias and Efficiency in fMRI Time-Series Analysis

This paper presents a nonlinear principal component analysis (PCA) that identifies underlying sources causing the expression of spatial modes or patterns of activity in neuroimaging time-series. The critical aspect of this technique is that, in relation to conventional PCA, the sources can interact to produce (second-order) spatial modes that represent the modulation of one (first-order) spatial mode by another. This nonlinear PCA uses a simple neural network architecture that embodies a specific form for the nonlinear mixing of sources that cause observed data. This form is motivated by a second-order approximation to any general nonlinear mixing and emphasizes interactions among pairs of sources. By introducing these nonlinearities principal components obtain with a unique rotation and scaling that does not depend on the biologically implausible constraints adopted by conventional PCA. The technique is illustrated by application to functional (positron emission tomography and functional magnetic resonance imaging) imaging data where the ensuing first- and second-order modes can be interpreted in terms of distributed brain systems. The interactions among sources render the expression of any one mode context-sensitive, where that context is established by the expression of other modes. The examples considered include interactions between cognitive states and time (i.e. adaptation or plasticity in PET data) and among functionally specialized brain systems (using a fMRI study of colour and motion processing).

Nonlinear PCA: characterizing interactions between modes of brain activity.

The effect of stimulus rate and its interaction with stimulus type on brain activity during reading was investigated using functional magnetic resonance imaging (fMRI). This (i) enabled the segregation of brain regions showing differential responses, (ii) identified the optimum experimental design parameters for maximizing sensitivity, and (iii) allowed us to evaluate further the sources of discrepancy between positron emission tomography (PET) and fMRI signals. The effect of visual word rate has already been investigated in a previous PET study. However, rate effects can be very different in PET and fMRI, as seen in previous studies of auditory word processing. In this work, we attempt to replicate rate-sensitive activations observed with PET using fMRI. Our objective was to characterize the discrepancies in regionally specific rate-sensitive effects between the two imaging modalities. Subjects were presented with words and pseudowords at varying rates while performing a silent reading task. The analysis specifically identified regions showing (i) an effect of stimulus rate on brain activity during reading; (ii) modulation of this effect by word type; and (iii) increased activity during reading relative to rest, but with no dependence on stimulus rate. The results identified similar effects of rate for words and pseudowords (no interactions between rate and word type reached significance). Irrespective of word type, strong positive linear effects of rate (i.e., activity increasing with rate) were detected in visual areas, right superior temporal gyrus, and bilateral precentral gyrus. These findings replicate the results of the previous PET study, confirming that activation in regions associated with visual processing and response generation increases with the number of stimuli. Likewise, we detected rate-independent effects reported in the previous PET study in bilateral anterior middle temporal, inferior frontal, and superior parietal regions. These results differentiate the functionally specific responses in rate-dependent and rate-independent areas. However, for negative effects of rate, fMRI did not replicate the effects seen in PET, suggesting some form of hemodynamic rectification. The discussion focuses on differences between evoked rCBF and BOLD signals.

The Effects of Presentation Rate During Word and Pseudoword Reading: A Comparison of PET and fMRI

The results from a single functional magnetic resonance imaging session are typically reported as indicative of the subject's functional neuroanatomy. Underlying this interpretation is the implicit assumption that there are no responses specific to that particular session, i.e., that the potential variability of response between sessions is negligible. The present study sought to examine this assumption empirically. A total of 99 sessions, comprising 33 repeats of simple motor, visual, and cognitive paradigms, were collected over a period of 2 months on a single male subject. For each paradigm, the inclusion of session-by-condition interactions explained a significant amount of error variance (P < 0.05 corrected for multiple comparisons) over a model assuming a common activation magnitude across all sessions. However, many of those voxels displaying significant session-by-condition interactions were not seen in a multisession fixed-effects analysis of the same data set; i.e., they were not activated on average across all sessions. Most voxels that were both significantly variable and activated on average across all sessions did not survive a random-effects analysis (modeling between-session variance). We interpret our results as demonstrating that correct inference about subject responses to activation tasks can be derived through the use of a statistical model which accounts for both within- and between-session variance, combined with an appropriately large session sample size. If researchers have access to only a single session from a single subject, erroneous conclusions are a possibility, in that responses specific to this single session may be claimed to be typical responses for this subject.

The successive expression of neuronal transients is related to dynamic correlations and, as shown in this paper, to dynamic instability. Dynamic instability is a form of complexity, typical of neuronal systems, which may be crucial for adaptive brain function from two perspectives. The first is from the point of view of neuronal selection and self-organizing systems: if selective mechanisms underpin the emergence of adaptive neuronal responses then dynamic instability is, itself, necessarily adaptive. This is because dynamic instability is the source of diversity on which selection acts and is therefore subject to selective pressure. In short, the emergence of order, through selection, depends almost paradoxically on the instabilities that characterize the diversity of brain dynamics. The second perspective is provided by information theory.

In this article we used biologically plausible simulations of coupled neuronal populations to address the relationship between phasic and fast coherent neuronal interactions and macroscopic measures of activity that are integrated over time, such as the BOLD response in functional magnetic resonance imaging. Event-related, dynamic correlations were assessed using joint peristimulus time histograms and, in particular, the mutual information between stimulus-induced transients in two populations. This mutual information can be considered as an index of functional connectivity. Our simulations showed that functional connectivity or dynamic integration between two populations increases with mean background activity and stimulus-related rate modulation. Furthermore, as the background activity increases, the populations become increasingly sensitive to the intensity of the stimulus in terms of a predisposition to transient phase locking. This reflects an interaction between background activity and stimulus intensity in producing dynamic correlations, in that background activity augments stimulus-induced coherence modulation. This is interesting from a computational perspective because background activity establishes a context that may have a profound effect on event-related interactions or functional connectivity between neuronal populations. Finally, total firing rates, which subsume both background activity and stimulus-related rate modulation, were almost linearly related to the expression of dynamic correlations over large ranges of activities. These observations show that under the assumptions implicit in our model, rate-specific metrics based on rate or coherence modulation may be different perspectives on the same underlying dynamics. This suggests that activity (averaged over all peristimulus times), as measured in neuroimaging, may be tightly coupled to the expression of dynamic correlations.

Relating Macroscopic Measures of Brain Activity to Fast, Dynamic Neuronal Interactions

The global brain: imaging and modelling: Introduction: 2000 Special Issue

Fronto-temporal functional connectivity in schizophrenics is correlated with psychopathology

In this paper, we present a post hoc method for identifying regions where functional MRI data are subject to signal reduction that may compromise sensitivity to activations. The motivation for developing this technique derives from recent language studies that showed responses in the inferior temporal lobe that could be detected by PET but not by fMRI. Reduced signal is due mostly to susceptibility artifacts and can be identified by comparing the T2* images (which are subject to susceptibility artifacts) with T2 images (which are not). However, T2 images are not usually acquired in fMRI studies. Therefore, we propose that areas with reduced signal can be identified by comparing T2* images that are corrected for nonuniformity with the original uncorrected images. The technique provides a voxel-wise characterization of signal reduction that pertains to the particular data that enter into a statistical model. It requires only the functional data and can thus be applied post hoc and without any additional scans.

There is a growing appreciation of the importance of nonlinearities in evoked responses in fMRI, particularly with the advent of event-related fMRI. These nonlinearities are commonly expressed as interactions among stimuli that can lead to the suppression and increased latency of responses to a stimulus that are incurred by a preceding stimulus. We have presented previously a model-free characterization of these effects using generic techniques from nonlinear system identification, namely a Volterra series formulation. At the same time Buxton et al. (1998) described a plausible and compelling dynamical model of hemodynamic signal transduction in fMRI. Subsequent work by Mandeville et al. (1999) provided important theoretical and empirical constraints on the form of the dynamic relationship between blood flow and volume that underpins the evolution of the fMRI signal. In this paper we combine these system identification and model-based approaches and ask whether the Balloon model is sufficient to account for the nonlinear behaviors observed in real time series. We conclude that it can, and furthermore the model parameters that ensue are biologically plausible. This conclusion is based on the observation that the Balloon model can produce Volterra kernels that emulate empirical kernels. To enable this evaluation we had to embed the Balloon model in a hemodynamic input-state-output model that included the dynamics of perfusion changes that are contingent on underlying synaptic activation. This paper presents (i) the full hemodynamic model (ii), how its associated Volterra kernels can be derived, and (iii) addresses the model's validity in relation to empirical nonlinear characterizations of evoked responses in fMRI and other neurophysiological constraints.

Nonlinear Responses in fMRI: The Balloon Model, Volterra Kernels, and Other Hemodynamics

Background PET studies of verbal fluency in schizophrenia report a failure of ‘deactivation’ of left superior temporal gyrus (STG) in the presence of activation of left dorsolateral prefrontal cortex (DLPFC), which deficit has been attributed to underlying ‘functional disconnectivity’. Aim To test whether these findings provide trait-markers for schizophrenia. Method We used H2 15O PET to examine verbal fluency in 10 obligate carriers of the predisposition to schizophrenia, 10 stable patients and 10 normal controls. Results We found no evidence of a failure of left STG deactivation in carriers or patients. Instead, patients failed to deactivate the precuneus relative to other groups. We found no differences in functional connectivity between left DLPFC and left STG but patients exhibited significant disconnectivity between left DLPFC and anterior cingulate cortex. Conclusions Failure of left STG ‘deactivation’ and left fronto-temporal disconnectivity are not consistent findings in schizophrenia; neither are they trait-markers for genetic risk. Prefrontal functional disconnectivity here may characterise the schizophrenic phenotype.

Functional anatomy of verbal fluency in people with schizophrenia and those at genetic risk

Reward is one of the most important influences shaping behavior. Single-unit recording and lesion studies in experimental animals have implicated a number of regions in response to reinforcing stimuli, in particular regions of the extended limbic system and the ventral striatum. In this experiment, functional neuroimaging was used to assess neural response within human reward systems under different psychological contexts. Nine healthy volunteers were scanned using functional magnetic resonance imaging during the performance of a gambling task with financial rewards and penalties. We demonstrated neural sensitivity of midbrain and ventral striatal regions to financial rewards and hippocampal sensitivity to financial penalties. Furthermore, we show that neural responses in globus pallidus, thalamus, and subgenual cingulate were specific to high reward levels occurring in the context of increasing reward. Responses to both reward level in the context of increasing reward and penalty level in the context of increasing penalty were seen in caudate, insula, and ventral prefrontal cortex. These results demonstrate dissociable neural responses to rewards and penalties that are dependent on the psychological context in which they are experienced.

The observation that we note the exceptional over the mundane has been the subject of extensive psychological and electrophysiological analysis in "oddball" paradigms. Whether detection of a sensory oddball reflects the operation of a generic mechanism or, alternatively, mechanisms sensitive to specific attributes of stimulus deviance is unknown. To address this question we used event-related functional MRI (fMRI) to measure neural responses during presentation of nouns, of which a proportion were perceptually, semantically, or emotionally deviant. Oddballs, regardless of deviant attributes and depth of processing, activated right inferior prefrontal and bilateral posterior fusiform cortices. Attribute-specific responses, independent of depth of processing, were evident in bilateral fusiform cortices for perceptual oddballs and left amygdala for emotional oddballs. By contrast, an interaction with depth of processing was evident in left prefrontal cortex for semantic oddballs. We conclude that detection of oddballs reflects the operation of a generic "deviance detection system," involving right prefrontal and fusiform cortices in addition to specific brain regions sensitive to the stimulus attributes that determine the qualitative characteristics of deviance.

Brain Mechanisms for Detecting Perceptual, Semantic, and Emotional Deviance

In this, the first of three papers, the nature of, and motivation for, neuronal transients is described in relation to characterizing brain dynamics. This paper deals with some basic aspects of neuronal dynamics, interactions, coupling and implicit neuronal codes. The second paper develops neuronal transients and nonlinear coupling in the context of dynamic instability and complexity, and suggests that instability or lability is necessary for adaptive self-organization. The final paper addresses the role of neuronal transients through information theory and the emergence of spatio-temporal receptive fields and functional specialization. By considering the brain as an ensemble of connected dynamic systems one can show that a sufficient description of neuronal dynamics comprises neuronal activity at a particular time and its recent history This history constitutes a neuronal transient. As such, transients represent a fundamental metric of neuronal interactions and, implicitly, a code employed in the functional integration of brain systems. The nature of transients, expressed conjointly in distinct neuronal populations, reflects the underlying coupling among populations. This coupling may be synchronous (and possibly oscillatory) or asynchronous. A critical distinction between synchronous and asynchronous coupling is that the former is essentially linear and the latter is nonlinear. The nonlinear nature of asynchronous coupling enables the rich, context-sensitive interactions that characterize real brain dynamics, suggesting that it plays a role in functional integration that may be as important as synchronous interactions. The distinction between linear and nonlinear coupling has fundamental implications for the analysis and characterization of neuronal interactions, most of which are predicated on linear (synchronous) coupling (e.g. cross-correlograms and coherence). Using neuromagnetic data it is shown that nonlinear (asynchronous) coupling is, in fact, more abundant and can be more significant than synchronous coupling.

The labile brain. I. Neuronal transients and nonlinear coupling.

In this paper we report three neuroimaging studies of language that investigate potential sources of inconsistency in measured hemodynamic responses: (1) between sessions for fMRI, including differences in hormonal status, (2) between sessions for PET, and (3) between scanning modalities (PET and fMRI). Differences in evoked responses between sessions of the same modality were small. In particular we did not find any effect of hormone levels when testing during the first and third weeks of the menstrual cycle (although we cannot exclude the possibility that activation in the temporoparietal regions is sensitive to hormonal status). Comparing the two modalities showed that prefrontal regions were more activated in fMRI than in PET. This may relate to task switching between blocks in fMRI that is not induced by PET paradigms or increased error variance in these regions for PET. In contrast, temporal activations were found in PET more than in fMRI. We attribute the lack of temporal activations, in fMRI, to a combination of factors, including susceptibility artifacts, anticipatory activity during the control condition, discontinuous sampling of peristimulus time, and differences in the source, acquisition, and analysis of the measured signals. It is concluded that although there is sufficient reproducibility of results for these paradigms within each modality, the regionally specific differences in sensitivity found between modalities warrant further investigation. These regionally specific differences are important for a properly qualified interpretation of activation profiles in fMRI.

Regionally Specific Sensitivity Differences in fMRI and PET: Where Do They Come From?

Voxel based morphometry in deletion mapping studies of the X chromosome

Characterization of PET data using anatomically informed basis functions

In this paper we consider an approach to neuronal transients that is predicated on the information they contain. This perspective is provided by information theory, in particular the principle of maximum information transfer. It is illustrated here in application to visually evoked neuronal transients. The receptive fields that ensue concur with those observed in the real brain, predicting, almost exactly, functional segregation of the sort seen in the visual system. This information theoretical perspective can be reconciled with a selectionist stance by noting that a high mutual information among neuronal systems and the environment has, itself, adaptive value and will be subject to selective pressure, at any level one cares to consider.

The labile brain. III. Transients and spatio-temporal receptive fields.

&NA; This study demonstrates the neural system potentially involved in the representation of, and choice between, stimulus classifications in an ambiguous, novel, decision‐making task. This difficult choice behaviour is taken as an example of a basic executive processing task. Subjects heard sounds that were consonant‐vowel combinations that had been distorted and were required to categorize each stimulus as speech‐like or not‐speech‐like. Cerebral activity was measured with positron emission tomography. A neural system (thalamic and medial prefrontal cortical regions) was demonstrated; there was greater activity involved in assigning the sound to the larger class of not‐speech‐like sounds than to the more restricted category of speech‐like sounds. We interpret this activity as reflecting process and representation in a simple central executive task.

A thalamo‐prefrontal system for representation in executive response choice

Noradrenergically Mediated Plasticity in a Human Attentional Neuronal Network Volume 10, Number 6 (1999), pages 705–715 (doi:10.1006/nimg.1999.0513)

This paper introduces the general framework, concepts, and procedures of anatomically informed basis functions (AIBF), a new method for the analysis of functional magnetic resonance imaging (fMRI) data. In contradistinction to existing voxel-based univariate or multivariate methods the approach described here can incorporate various forms of prior anatomical knowledge to specify sophisticated spatiotemporal models for fMRI time-series. In particular, we focus on anatomical prior knowledge, based on reconstructed gray matter surfaces and assumptions about the location and spatial smoothness of the blood oxygenation level dependent (BOLD) effect. After reconstruction of the grey matter surface from an individual's high-resolution T1-weighted MRI, we specify a set of anatomically informed basis functions, fit the model parameters for a single time point, using a regularized solution, and finally make inferences about the estimated parameters over time. Significant effects, induced by the experimental paradigm, can then be visualized in the native voxel-space or on the reconstructed folded, inflated, or flattened cortical surface. As an example, we apply the approach to a fMRI study (finger opposition task) and compare the results to those of a voxel-based analysis as implemented in the Statistical Parametric Mapping package (SPM99). Additionally, we show, using simulated data, that the approach offers several desirable features particularly in terms of superresolution and localization.

OBJECTIVE To apply statistical parametric mapping to 18F-dopa PET data sets, to examine the regional distribution of changes in dopaminergic metabolism in early asymmetric Parkinson’s disease. METHODS Thirteen normal volunteers (age 57.7 (SD 16.5) years; four women, nine men ) and six patients (age 50.3 (SD 13.5) years; three women, three men) with asymmetric (right sided) Parkinson’s disease were studied. Images from each dynamic dopa PET dataset were aligned and parametric images of18F-dopa influx (Ki) were created for each subject. The Ki images were transformed into standard stereotactic space. The Ki values of the caudate and putamen on spatially normalised images were compared with the Ki values before normalisation. The application of statistical parametric mapping (SPM) allowed statistical comparison of regional Ki values on a voxel by voxel basis between healthy volunteers and patients with Parkinson’s disease. RESULTS There was a strong correlation between the Ki values before and after spatial normalisation (r=0.898, p=0.0001). Significant decreases in the Ki values were found for the Parkinson’s desease group throughout the entire left putamen (p< 0.001) and focally in the dorsal right putamen (p< 0.001). Decreased Ki values were also shown bilaterally in the substantia nigra (p< 0.01). CONCLUSION Using (SPM) and 18F-dopa PET, reductions in both striatal and nigral brain dopaminergic function could be demonstrated in early Parkinson’s disease.

Statistical parametric mapping with 18F-dopa PET shows bilaterally reduced striatal and nigral dopaminergic function in early Parkinson’s disease

Erratum: Signal-, set- and movement-related activity in the human brain: An event-related fMRI study (Cerebral Cortex (January/February 1999) 9:1 (35- 49

Correlation between structural and functional changes in brain in an idiopathic headache syndrome

In this paper we present an approach to making inferences about generic activations in groups of subjects using fMRI. In particular we suggest that activations common to all subjects reflect aspects of functional anatomy that may be "typical" of the population from which that group was sampled. These commonalities can be identified by a conjunction analysis of the activation effects in which the contrasts, testing for an activation, are specified separately for each subject. A conjunction is the joint refutation of multiple null hypotheses, in this instance, of no activation in any subject. The motivation behind this use of conjunctions is that fixed-effect analyses are generally more "sensitive" than equivalent random-effect analyses. This is because fixed-effect analyses can harness the large degrees of freedom and small scan-to-scan variability (relative to the variability in responses from subject to subject) when assessing the significance of an estimated response. The price one pays for the apparent sensitivity of fixed-effect analyses is that the ensuing inferences pertain to, and only to, the subjects studied. However, a conjunction analysis, using a fixed-effect model, allows one to infer: (i) that every subject studied activated and (ii) that at least a certain proportion of the population would have shown this effect. The second inference depends upon a meta-analytic formulation in terms of a confidence region for this proportion. This approach retains the sensitivity of fixed-effect analyses when the inference that only a substantial proportion of the population activates is sufficient.

In the past decade the importance of synchronized dynamics in the brain has emerged from both empirical and theoretical perspectives. Fast dynamic synchronous interactions of an oscillatory or nonoscillatory nature may constitute a form of temporal coding that underlies feature binding and perceptual synthesis. The relationship between synchronization among neuronal populations and the population firing rates addresses two important issues: the distinction between rate coding and synchronization coding models of neuronal interactions and the degree to which empirical measurements of population activity, such as those employed by neuroimaging, are sensitive to changes in synchronization. We examined the relationship between mean population activity and synchronization using biologically plausible simulations. In this article, we focus on continuous stationary dynamics. (In a companion article, Chawla (forth-coming), we address the same issue using stimulus-evoked transients.) By manipulating parameters such as extrinsic input, intrinsic noise, synaptic efficacy, density of extrinsic connections, the voltage-sensitive nature of postsynaptic mechanisms, the number of neurons, and the laminar structure within the populations, we were able to introduce variations in both mean activity and synchronization under a variety of simulated neuronal architectures. Analyses of the simulated spike trains and local field potentials showed that in nearly every domain of the model's parameter space, mean activity and synchronization were tightly coupled. This coupling appears to be mediated by an increase in synchronous gain when effective membrane time constants are lowered by increased activity. These observations show that under the assumptions implicit in our models, rate coding and synchrony coding in neural systems with reciprocal interconnections are two perspectives on the same underlying dynamic. This suggests that in the absence of specific mechanisms decoupling changes in synchronization from firing levels, indexes of brain activity that are based purely on synaptic activity (e.g., functional magnetic resonance imaging) may also be sensitive to changes in synchronous coupling.

The Relationship Between Synchronization Among Neuronal Populations and Their Mean Activity Levels

This paper is about warping a brain image from one subject (the object image) so that it matches another (the template image). A high-dimensional model is used, whereby a finite element approach is employed to estimate translations at the location of each voxel in the template image. Bayesian statistics are used to obtain a maximum a posteriori (MAP) estimate of the deformation field. The validity of any registration method is largely based upon the constraints or, in this instance, priors incorporated into the model describing the transformations. In this approach we assume that the priors should have some form of symmetry, in that priors describing the probability distribution of the deformations should be identical to those for the inverses (i.e., warping brain A to brain B should not be different probabilistically from warping B to A). The fundamental assumption is that the probability of stretching a voxel by a factor of n is considered to be the same as the probability of shrinking n voxels by a factor of n(-1). In the Bayesian framework adopted here, the priors are assumed to have a Gibbs form, where the Gibbs potential is a penalty function that embodies this symmetry. The penalty function of choice is based upon the singular values of the Jacobian having a lognormal distribution. This enforces a continuous one-to-one mapping. A gradient descent algorithm is presented that incorporates the above priors in order to obtain a MAP estimate of the deformations. We demonstrate this approach for the two-dimensional case, but the principles can be extended to three dimensions. A number of examples are given to demonstrate how the method works.

The neurobiological mechanisms of opiate addictive behaviour in humans are unknown. A proposed model of addiction implicates ascending brainstem neuromodulatory systems, particularly dopamine. Using functional neuroimaging, we assessed the neural response to heroin and heroin‐related cues in established opiate addicts. We show that the effect of both heroin and heroin‐related visual cues are maximally expressed in the sites of origin of ascending midbrain neuromodulatory systems. These context‐specific midbrain activations predict responses to salient visual cues in cortical and subcortical regions implicated in reward‐related behaviour. These findings implicate common neurobiological processes underlying drug and drug‐cue‐related effects.

This article reviews the disconnection hypothesis of schizophrenia and presents a mechanistic account of how dysfunctional integration among neuronal systems might arise. This neurobiological account is based on some simple observations about schizophrenia and the central role that neuronal plasticity plays in shaping the connections, and the ensuing dynamics, that underlie brain function. The particular hypothesis put forward here is that the pathophysiology of schizophrenia is expressed at the level of modulation of associative changes in synaptic efficacy, specifically the modulation of plasticity in those brain systems that are responsible for learning, memory and emotion. This modulation is mediated by ascending neurotransmitter systems that (i) have been implicated in schizophrenia and (ii) are known to be involved in consolidating synaptic connections during learning. The proposed pathophysiology would translate, in functional terms, into a disruption of the reinforcement of adaptive behaviour that is consistent with the disintegrative aspects of schizophrenic neuropsychology.

Objective—To apply statistical parametric mapping to 18 F-dopa PET data sets, to examine the regional distribution of changes in dopaminergic metabolism in early asymmetric Parkinson’s disease. Methods—Thirteen normal volunteers (age 57.7 (SD 16.5) years; four women, nine men ) and six patients (age 50.3 (SD 13.5) years; three women, three men) with asymmetric (right sided) Parkinson’s disease were studied. Images from each dynamic dopa PET dataset were aligned and parametric images of 18 F-dopa influx (Ki) were created for each subject. The Ki images were transformed into standard stereotactic space. The Ki values of the caudate and putamen on spatially normalised images were compared with the Ki values before normalisation. The application of statistical parametric mapping (SPM) allowed statistical comparison of regional Ki values on a voxel by voxel basis between healthy volunteers and patients with Parkinson’s disease. Results—There was a strong correlation between the Ki values before and after spatial normalisation (r=0.898, p=0.0001). Significant decreases in the Ki values were found for the Parkinson’s desease group throughout the entire left putamen (p< 0.001) and focally in the dorsal right putamen (p< 0.001). Decreased Ki values were also shown bilaterally in the substantia nigra (p< 0.01). Conclusion—Using (SPM) and 18 F-dopa PET, reductions in both striatal and nigral brain dopaminergic function could be demonstrated in early Parkinson’s disease. (J Neurol Neurosurg Psychiatry 1999;66:754‐758)

shows bilaterally reduced striatal and nigral dopaminergic function in early Parkinson's disease

Functional neuroimaging provides a novel means of exploring neurophysiological function in schizophrenia. However, most of the studies that have been carried out report their findings in terms of regionally localized abnormalities. In this paper we propose an alternative method of data analysis that emphasizes global integration rather than isolated regional changes in response to psychological tasks. In doing so, we suggest that brain abnormalities in schizophrenia are best characterized as a disturbance in the integration of activity across a number of brain regions. Using a hypothesis-led analysis, we show that the condition is associated with a disruption of the normal anterior cingulate modulation of prefronto-temporal integration. This analytical technique, we suggest, provides a conceptually powerful approach to the imaging of abnormal brain function in psychopathological conditions.

Abnormal Cingulate Modulation of Fronto-Temporal Connectivity in Schizophrenia

Changes in cingulo-thalamic connectivity during fear conditioning assessed with event-related fMRI

It is now accepted that hippocampal lesions impair episodic memory. However, the precise functional role of the hippocampus in episodic memory remains elusive. Recent functional imaging data implicate the hippocampus in processing novelty, a finding supported by human in vivo recordings and event-related potential studies. Here we measure hippocampal responses to novelty, using functional MRI (fMRI), during an item-learning paradigm generated from an artificial grammar system. During learning, two distinct types of novelty were periodically introduced: perceptual novelty, pertaining to the physical characteristics of stimuli (in this case visual characteristics), and exemplar novelty, reflecting semantic characteristics of stimuli (in this case grammatical status within a rule system). We demonstrate a left anterior hippocampal response to both types of novelty and adaptation of these responses with stimulus familiarity. By contrast to these novelty effects, we also show bilateral posterior hippocampal responses with increasing exemplar familiarity. These results suggest a functional dissociation within the hippocampus with respect to the relative familiarity of study items. Neural responses in anterior hippocampus index generic novelty, whereas posterior hippocampal responses index familiarity to stimuli that have behavioral relevance (i.e., only exemplar familiarity). These findings add to recent evidence for functional segregation within the human hippocampus during learning.

In fMRI there are two classes of inference: one aims to make a comment about the "typical" characteristics of a population, and the other about "average" characteristics. The first pertains to studies of normal subjects that try to identify some qualitative aspect of normal functional anatomy. The second class necessarily applies to clinical neuroscience studies that want to make an inference about quantitative differences of a regionally specific nature. The first class of inferences is adequately serviced by conjunction analyses and fixed-effects models with relatively small numbers of subjects. The second requires random-effect analyses and larger cohorts.

In a previous paper, we used fMRI to examine motion-sensitive responses in human area V5 as a function of stimulus speed. As predicted by electrophysiological findings, we observed optimal responses at intermediate speeds of around 7 to 30 degrees /s. These results revealed a nonlinear (inverted "U") dependency on speed that was also evident in V3a. In this paper we repeated the experiment using an improved stimulus and a larger range of speeds. We replicated our previous findings and extended our characterization of speed-dependent responses: Optimal responses were seen in V5 at speeds of 4 and 8 degrees /s and in V3a at speeds of 4 to 16 degrees /s. We were also able to show an interaction between speed (fast vs slow) and contrast (color > luminance) in V5. This interaction was anticipated on the basis of the different properties of the geniculate and extrageniculate inputs to V5. Finally, we were also able to demonstrate an interaction between motion (moving vs stationary) and contrast (color > luminance) in V4. This suggests that for V4, color-specific responses are augmented in the context of motion; or equivalently, that color contrast enhances any motion-sensitive responses in V4.

During this time of economic uncertainty, we are delighted that readers continue to support Traditional Dwellings and Settlements Review. This issue is particularly illustrative of the inter-disciplinary approach of the International Association for the Study of Traditional Environments (iaste). In it, a range of scholars — geographers, historians, architects and planners — present compelling work from across the globe, showing how questions of tradition, in its many forms, continue to have tremendous impact on how we interpret the built environment. The issue begins with an examination of hyperrealism in China and the United States — a fascinating juxtaposition that allows a deep interrogation of questions of authenticity, reproduction , and cultural identity. The author, Thorsten Botz-Bornstein, looks in particular at the invocation of the past in China and at " Disneyfication " in the United States to uncover how two different cultures create a sense of authenticity that is, in essence, a mental construct. The next article, an adaptation of one of the best student papers at our 2010 conference, looks to the contradictions inherent to nationalist imaginaries in Israel and Palestine. Its author, Ron Smith points to the concept of the nation-state as both a space of utopian possibility and dystopic violence and repression. Following this, Mohamed Gamal Abdelmonem examines the complex idea of " home " in the neighborhoods of Old Cairo. His purpose is to argue for an understanding of flexible socio-spatial dwelling practices as a means to improve future housing and preservation efforts in Egypt and elsewhere. Our fourth feature article, by Yael Allweil, recounts the conflicts attendant on the development of early Israeli housing policies. She explains how repeated change in these policies in response to a series of perceived threats eventually created the basis for a contract between state and citizen that remains a core political principle in the country to this day. The issue concludes with a field report from Sarawak (Malaysian Borneo) by Ian Ewart examining how " traditional " architecture is rarely stable. In this case, the agent of change is the arrival of the globalized logging industry, which has introduced local people to new materials, building technologies, and cultural images. Exciting plans are underway for our biennial conference, to be held this year in Portland, Oregon. I hope to see many of you there October 4–7 to examine " The Myth of Tradition. " Nezar AlSayyad

At what levels of brain organization might pathological change in schizophrenia be anatomically expressed: global, regional or supraregional? We hypothesised that brain structure reflects a set of supra-regional anatomical systems with common developmental influences. We conducted an exploratory analysis to identify supraregional brain systems and to investigate whether abnormal brain architecture in schizophrenia is manifested within one or more of these systems. Magnetic resonance (MR) images were acquired from 27 patients with schizophrenia and 37 control subjects. After segmentation and registration of each individual MRI dataset in the standard space of Talairach and Tournoux, grey matter and ventricular-cerebrospinal fluid (CSF) maps were automatically parcellated into 104 regions. We used principal components analysis of the multiple regional grey matter and ventricular-CSF measurements, on all 64 subjects, to extract the five main normative supra-regional systems. The first two of these components represented global variation in grey matter and ventricular-CSF regional measures. We interpreted the other three components as representing supra-regional systems comprising: a frontal-parietal system, a frontal-temporal system and a frontal-basal ganglia system. Schizophrenic group mean scores on the first component (global grey matter-ventricular contrast) and fourth component (frontal-temporal system) were significantly reduced compared to controls. These results suggest that pathological change in schizophrenia may be expressed at two mutually independent levels of anatomical organization: global change in a grey matter/ventricular system and supra-regional change in a frontal-temporal system.

Supra-regional brain systems and the neuropathology of schizophrenia.

This paper demonstrates how functional imaging studies of neuropsychological patients can provide a way of determining which areas in a cognitive network are jointly necessary and sufacient. The approach is illustrated with an investigation of the neural system underlying semantic similarity judgments. Functional neuroimaging demonstrates that normal subjects activate left temporal, parietal, and inferior frontal cortices during this task relative to physical size judgments. Neuropsychology demonstrates that damage to the temporal and parietal regions results in semantic deacits, indicating that these areas are necessary for task performance. In contrast, damage to the inferior frontal cortex does not impair task performance, indicating that the inferior frontal cortex might not be necessary. However, there are two other possible accounts of intact performance following frontal lobe damage: (1) there is functional reorganization involving the right frontal cortex and (2) there is peri-infarct activity around the damaged left-hemisphere tissue. Functional imaging of the patient is required to discount these possibilities. We investigated a patient (SW), who was able to associate words and pictures on the basis of semantic relationships despite extensive damage to the left frontal, inferior parietal, and superior temporal cortices. Although SW showed peri-infarct activation in left extrasylvian temporal cortices, no activity was observed in either left or right inferior frontal cortices. These andings demonstrate that activity in extrasylvian temporo-parietal and medial superior frontal regions is sufacient to perform semantic similarity judgments. In contrast, the left inferior frontal activations detected in each control subject appear not to be necessary for task performance. In conclusion, necessary and sufacient brain systems can be delineated by functional imaging of brain-damaged patients who are not functionally impaired.

Dissociable neural responses associated with reward, punishment and risk-taking

Dynamic diaschisis: Anatomically remote and task specific effects of human brain lesions

In this work, we present a nonlinear principal component analysis (PCA) that identifies underlying sources causing the expression of spatial modes or patterns of activity in neuroimaging time series where these sources can interact to produce second‐order modes. This nonlinear PCA uses a neural network architecture that embodies a specific form for the mixing of sources that is based on a second‐order approximation to any general nonlinear mixing. The modes obtained have a unique rotation and scaling that does not depend on the biologically implausible constraints adopted by conventional PCA. Interactions among sources render the expression of any mode or brain system sensitive to the expression of others. The example considers interactions among functionally specialized brain systems (using a fMRI study of colour and motion processing). Hum. Brain Mapping 8:92–97, 1999. © 1999 Wiley‐Liss, Inc.

This paper concerns the experimental design and statistical models employed by fMRI activation studies which block presentation of linguistic stimuli. In particular, we note that the relationship between the timing of stimulus presentation and data acquisition can have a substantial impact on the ability to detect activations in critical language areas, even when the stimuli are presented in blocks. Using a blocked word rhyming paradigm and repeated investigations on a single subject, activation was observed in Broca's area (left inferior frontal cortex) and Wernicke's area (left posterior temporoparietal cortex) when (i) the timing of data acquisition was distributed throughout the peristimulus time and (ii) an event-related analysis was used to model the phasic nature of the hemodynamic response within each block of repeated word stimuli. In contrast, when the timing of data acquisition relative to stimulus presentation was fixed, activation was detected in Broca's area but not consistently in Wernicke's area. Our results indicate that phasic responses to stimuli occur even in a blocked design and that the sampling and proper modeling of these responses can have profound effects on their detection. Specifically, distributed sampling over peristimulus time is essential in order to detect small activations particularly when they are transient. These findings are likely to generalize to the detection of transient signals in any cognitive paradigm.

The Critical Relationship between the Timing of Stimulus Presentation and Data Acquisition in Blocked Designs with fMRI

The assessment of significant activations in functional imaging using voxel-based methods often relies on results derived from the theory of Gaussian random fields. These results solve the multiple comparison problem and assume that the spatial correlation or smoothness of the data is known or can be estimated. End results (i. e., P values associated with local maxima, clusters, or sets of clusters) critically depend on this assessment, which should be as exact and as reliable as possible. In some earlier implementations of statistical parametric mapping (SPM) (SPM94, SPM95) the smoothness was assessed on Gaussianized t-fields (Gt-f) that are not generally free of physiological signal. This technique has two limitations. First, the estimation is not stable (the variance of the estimator being far from negligible) and, second, physiological signal in the Gt-f will bias the estimation. In this paper, we describe an estimation method that overcomes these drawbacks. The new approach involves estimating the smoothness of standardized residual fields which approximates the smoothness of the component fields of the associated t-field. Knowing the smoothness of these component fields is important because it allows one to compute corrected P values for statistical fields other than the t-field or the Gt-f (e.g., the F-map) and eschews bias due to deviation from the null hypothesis. We validate the method on simulated data and demonstrate it using data from a functional MRI study.

Robust Smoothness Estimation in Statistical Parametric Maps Using Standardized Residuals from the General Linear Model

We present an overview of the types of imaging experiments that can be performed on psychologically impaired patients. The critical observation from such studies is a differential pattern of activation in the patients and normals. Underactivity is interpretable only when the patients make normal responses. In this context, a failure to activate a component region of the normal system implies that this region was not necessary for task performance. Overactivity indicates either cognitive or neuronal reorganisation. Neuronal reorganisation is indicated only if the patient performs the task using the same set of cognitive operations as normal subjects. Cognitive reorganisation can be demonstrated if the same activation pattern is elicited by normals when they are co‐erced into using the same cognitive implementation as the patient. We conclude that the interpretation of neuroimaging studies of psychologically impaired patients depends on intact task performance and a detailed task analysis. When these criteria are met, patient studies can be used to identify: (1) necessary and sufficient brain systems, (2) dysfunction at sites distant to damage, (3) peri‐damage activation, and (4) compensation either at a neuronal level when pre‐existing cognitive strategies are re‐instantiated using duplicated neuronal systems (degeneracy), or at a cognitive level when alternative cognitive strategies (and their corresponding brain systems) are adopted. Hum. Brain Mapping 8:102–108, 1999. © 1999 Wiley‐Liss, Inc.

Background Acute tryptophan depletion lowers brain serotonin synthesis and results in a transient, but striking, clinical relapse in recovered depressed patients. Aims To identify brain regions which change their activity as an acute depressive relapse evolves and to determine how pathological mood might modulate neural activity during a cognitive task. Method We used H2 15O positron-emission tomography (PET) to study eight recovered depressed men after tryptophan depletion and after a control procedure. During both PET scan sessions, subjects performed a paced verbal fluency task which alternated with a control verbal repetition task. Results Increasing levels of depression after tryptophan depletion were associated with diminished neural activity in the ventral anterior cingulate, orbitofrontal cortex and caudate nucleus regions. In addition, depressive relapse attenuated cognitive task-related activation in the anterior cingulate cortex. Conclusions Our data indicate that changes in neural activity in distinct brain regions mediate the clinical phenomena of depression and depression-related cognitive impairment following acute tryptophan depletion. These changes could be associated with the widespread distribution of serotonin neurons in brain pathways associated with the expression of affect and cognitive performance.

Brain mechanisms associated with depressive relapse and associated cognitive impairment following acute tryptophan depletion

Noradrenaline is implicated in the modulation of attention and arousal, but the neuroanatomical basis of this effect in humans is unknown. A previous functional neuroimaging study failed to find clear effects of clonidine (alpha2 adrenoceptor agonist) on activity of brain regions implicated in attention. Therefore, we now investigate whether clonidine affects the functional integration of a neuroanatomical attentional network, by modulating connectivity between brain regions rather than activity within discrete regions. Following infusion of either clonidine or placebo, positron emission tomography measurements of brain activity were collected in 13 normal subjects while they were either resting or performing an attentional task. Effective connectivity analysis showed that during rest, clonidine decreased the functional strength of connections both from frontal cortex to thalamus and in pathways to and from visual cortex. Conversely, during the attentional task, functional integration generally increased, with changes being centered on parietal cortex (increased connectivity from locus coeruleus to parietal cortex and from parietal cortex to thalamus and frontal cortex). A drug-induced increase in the modulatory effects of frontal cortex on projections from locus coeruleus to parietal cortex was also observed. Collectively, these results highlight cognitively dissociable effects of clonidine on interactions among functionally integrated brain regions and implicate the noradrenergic system in mediating the functional integration of attentional brain systems. The context-sensitive nature of the changes are consistent with observations that noradrenergic drugs have differential effects on brain processes depending on subjects' underlying arousal levels. More generally, the results illustrate the dynamic plasticity of cognitive brain systems following neurochemical challenge.

Noradrenergically Mediated Plasticity in a Human Attentional Neuronal Network

We have studied focal changes in dopaminergic function throughout the brain volume in early and advanced Parkinson's disease by applying statistical parametric mapping (SPM) to 3D [(18)F]dopa-PET. Data from seven early hemi-Parkinson's disease and seven advanced bilateral Parkinson's disease patients were compared with that from 12 normal controls. Parametric images of [(18)F]dopa influx rate constant (K(i)(o)) were generated for each subject from dynamic 3D [(18)F]dopa datasets and transformed into standard stereotactic space. Significant changes in mean voxel [(18)F]dopa K(i)(o) values between the normal control group and each Parkinson's disease group were localized with SPM. Conventional region of interest analysis was also applied to comparable regions on the untransformed image datasets. In early left hemi-Parkinson's disease, significant extrastriatal increases in [(18)F]dopa K(i)(o) were observed in the left anterior cingulate gyrus and the dorsal midbrain region (P < 0.05, corrected) along with decreases in striatal [(18)F]dopa K(i)(o). In advanced Parkinson's disease, significant extrastriatal decreases in [(18)F]dopa K(i)(o) were observed in the ventral and dorsal midbrain regions (P < 0.05, corrected). No significant changes in [(18)F]dopa K(i)(o) were observed in the anterior cingulate region. In a direct comparison between the early and late Parkinson's disease groups, we observed relative [(18)F]dopa K(i)(o) reductions in ventral and dorsal midbrain, and dorsal pontine regions along with striatal [(18)F]dopa K(i)(o) reductions. Similiar results were found with a region of interest approach, on non-transformed data, except for the focal midbrain [(18)F]dopa K(i)(o) increase seen in early Parkinson's disease. In conclusion, using SPM with [(18)F]dopa-PET, we have objectively localized changes in extrastriatal, pre-synaptic dopaminergic function in Parkinson's disease. The significance of the increased dopaminergic activity of anterior cingulate in early Parkinson's disease remains unclear, but may be compensatory. The [(18)F]dopa signal in dorsal midbrain and pontine regions suggests that [(18)F]dopa is taken up by serotonergic and noradrenergic neurons which also degenerate in advanced Parkinson's disease. This suggests, therefore, that Parkinson's disease is a monoaminergic neurodegenerative disorder.

Frontal, midbrain and striatal dopaminergic function in early and advanced Parkinson's disease A 3D [(18)F]dopa-PET study.

Objective: To investigate the etiology of mirror movements in patients with X-linked Kallmann’s syndrome (xKS) through statistical analysis of pooled white matter data from structural MR images. Background: Mirror movements occur in 85% of xKS patients. Previous electrophysiologic studies have suggested an abnormal ipsilateral corticospinal tract projection in xKS patients exhibiting mirror movements. However, an alternative hypothesis has proposed a functional lack of transcallosal inhibitory fibers. Methods: T1-weighted brain scans were normalized into stereotaxic space with segregation of gray and white matter to allow comparison of pooled white matter data on a voxel-by-voxel basis using SPM-96 software. Nine xKS patients were compared with two age-matched groups of nonmirroring individuals: nine patients with autosomal Kallmann’s syndrome (aKS) and nine age-matched normal (healthy) men. Results: Hypertrophy of the corpus callosum was found in both Kallmann’s syndrome groups: the anterior and midsection in xKS, and the genu and posterior section in aKS. Bilateral hypertrophy of the corticospinal tract was found only in the group of xKS patients exhibiting mirror movements. SPM analysis was validated by an independent region of interest analysis of corpus callosum size. Conclusion: Although morphometry on its own cannot determine the cause of mirror movements, the specific finding of a hypertrophied corticospinal tract in xKS is consistent with electrophysiologic evidence suggesting that mirror movements in xKS result from abnormal development of the ipsilateral corticospinal tract fibers.

Lexical decision: differences in magnitude and onset as indexed by event-related fMRI

This paper describes a Bayesian method for three‐dimensional registration of brain images. A finite element approach is used to obtain a maximum a posteriori estimate of the deformation field at every voxel of a template volume. The priors used by the MAP estimate penalize unlikely deformations and enforce a continuous one‐to‐one mapping. The deformations are assumed to have some form of symmetry, in that priors describing the probability distribution of the deformations should be identical to those for the inverses (i.e., warping brain A to brain B should not be different probablistically from warping B to A). A gradient descent algorithm is presented for estimating the optimum deformations. Hum. Brain Mapping 9:212–225, 2000. © 2000 Wiley‐Liss, Inc.

A priori informed spatio-temporal basis functions in minimum norm solutions

Previous functional neuroimaging studies have characterized brain systems mediating associative learning using classical delay conditioning paradigms. In the present study, we used event-related functional magnetic resonance imaging to characterize neuronal responses mediating aversive trace conditioning. During conditioning, neutral auditory tones were paired with an aversive sound [unconditioned stimulus (US)]. We compared neuronal responses evoked by conditioned (CS+) and nonconditioned (CS−) stimuli in which a 50% pairing of CS+ and the US enabled us to limit our analysis to responses evoked by the CS+ alone. Differential responses (CS+ vs CS−), related to conditioning, were observed in anterior cingulate and anterior insula, regions previously implicated in delay fear conditioning. Differential responses were also observed in the amygdala and hippocampus that were best characterized with a time × stimulus interaction, indicating rapid adaptation of CS+-specific responses in medial temporal lobe. These results are strikingly similar to those obtained with a previous delay conditioning experiment and are in accord with a preferential role for medial temporal lobe structures during the early phase of conditioning. However, an additional activation of anterior hippocampus in the present experiment supports a view that its role in trace conditioning is to maintain a memory trace between the offset of the CS+ and the delayed onset of the US to enable associative learning in trace conditioning.

Amygdala–Hippocampal Involvement in Human Aversive Trace Conditioning Revealed through Event-Related Functional Magnetic Resonance Imaging

This commentary considers how far one can go in making inferences about functional modularity or segregation, based on the sorts of analyses used by Caplan & Waters in relation to the underlying neuronal infrastructure. Specifically, an attempt is made to relate the “functionalist” approach adopted in the target article to “neuroreductionist” perspectives on the same issue.

A striking feature of schizophrenia is the diversity of the phenomenology both within and between patients. This diversity can be contrasted with the well‐circumscribed and stable deficits seen in classic neuropsychological syndromes. The argument will be advanced that the classic lesion model, based on the notion of a segregated deficit, is inappropriate in schizophrenia. Instead the idea will be developed that a more appropriate model is one derived from concepts of neural integration across large‐scale brain networks. Empirical data derived from positron emission tomography (PET) within our laboratory that provide support fur this suggestion will be presented. One critical observation from these data is a disruption of prefrontal‐temporal interactions. under a variety of cognitive activation paradigms, in both chronic medicated and acute unmediated schizophrenic patients. Furthermore, these data indicate that both regional and interregional neuronal function, including prefrontal‐temporal interactions, can be significantly modulated by a neurochetnical perturbation of ascending dopaminergic systems. The latter observations suggest that the deficit of abnormal cortico‐cortical interactions are to some extent modifiable by neuromociulatory neurotransmitter systems.

Abnormal neural integration related to cognition in schizophrenia

Autism is a biological disorder which affects social cognition, and understanding brain abnormalities of the former will elucidate the brain basis of the latter. We report structural MRI data on 15 high-functioning individuals with autistic disorder. A voxel-based whole brain analysis identified grey matter differences in an amygdala centered system relative to 15 age- and IQ-matched controls. Decreases of grey matter were found in anterior parts of this system (right paracingulate sulcus, left inferior frontal gyrus). Increases were found in posterior parts (amygdala/peri-amygdaloid cortex, middle temporal gyrus, inferior temporal gyrus), and in regions of the cerebellum. These structures are implicated in social cognition by animal, imaging and histopathological studies. This study therefore provides converging evidence of the physiological basis of social cognition.

The neuroanatomy of autism: a voxel-based whole brain analysis of structural scans.

The physiological basis of attentional modulation in extrastriate visual areas

This article considers the efficiency of event-related fMRI designs in terms of the optimum temporal pattern of stimulus or trial presentations. The distinction between "stochastic" and "deterministic" is used to distinguish between designs that are specified in terms of the probability that an event will occur at a series of time points (stochastic) and those in which events always occur at prespecified time (deterministic). Stochastic designs may be "stationary," in which the probability is constant, or nonstationary, in which the probabilities change with time. All these designs can be parameterized in terms of a vector of occurrence probabilities and a prototypic design matrix that embodies constraints (such as the minimum stimulus onset asynchrony) and the model of hemodynamic responses. A simple function of these parameters is presented and used to compare the relative efficiency of different designs. Designs with slow modulation of occurrence probabilities are generally more efficient than stationary designs. Interestingly the most efficient design is a conventional block design. A critical point, made in this article, is that the most efficient design for one effect may not be the most efficient for another. This is particularly important when considering evoked responses and the differences among responses. The most efficient designs for evoked responses, as opposed to differential responses, require trial-free periods during which baseline levels can be attained. In the context of stochastic, rapid-presentation designs this is equivalent to the inclusion of "null events."

The [18F]fluorodeoxyglucose ([18F]FDG) method for measuring brain metabolism has not the wide clinical application that one might expect, partly because of its high cost and the complexity of the quantification procedure, but also because of reporting techniques based on region of interest (ROI) analysis, which are time-consuming and not fully objective. In this paper we report a clinical validation of statistical parametric mapping (SPM) using rCMRglc (quantitative) and radioactivity distribution (nonquantitative) [18F]FDG PET data. We show that a 10-min noninteractive voxel-based SPM analysis on a standard workstation enables objective assessment, including localization in stereotactic space, of regional glucose consumption abnormalities, whose reliability can be assessed on statistical and clinical grounds. Clinical validity was established using a small series of patients with degenerative or developmental disorders, including probable Alzheimer's disease, progressive aphasia, multiple sclerosis, developmental specific language impairment, and epilepsy. Analysis of quantitative and nonquantitative data showed the same pattern of results, suggesting that, for clinical purposes, quantitation and invasive arterial cannulation can be avoided. This should facilitate a wider application of the technique and the extension of SPM clinical analysis to H215O PET or high resolution SPECT perfusion studies.

Rapid Assessment of Regional Cerebral Metabolic Abnormalities in Single Subjects with Quantitative and Nonquantitative [18F]FDG PET: A Clinical Validation of Statistical Parametric Mapping

Linear inverse Solutions have been applied extensively to solve the bioelectromagnetic inverse problem. In contrast to discrete dipole models, linear inverse solutions do not require any assumptions about the number of active sources and lead to a fully 3D representation of the electrical activity of the brain. However, the problem is underdetermincd: there are many more parameters to estimate (relative to the number of dipole locations considered) than data available (relative to the number of electrodes). In order to ensure the uniqueness of the solution, existing linear methods generally apply constraints on the solution, for example: minimum 2-norm, maximum smoothness [1], optimal resolution [2], etc. These methods provide solutions with relatively poor spatial resolution because they neglect, wholly or in part, anatomical Information relevant to the real source distribution. Our method aims to model the spatial source distribution by using a sei of basis functions. By appropriately defining these basis functions, we are able to include a priori Information about the sources and our Solutions will de facto belong to the subspace spanned by these basis functions. The priors enter äs constraints on the covariance structure of the source power (over space), and are used to motivate the selection of a spatial basis set that maximises the Information between the sources and their projection on that set. The orientation of each dipole is fixed and orthogonal to the cortical sheet, and therefore only the amplitude of the sources remains unknown. In a second step, we solve for the source distribution using a "classical" minimum norm method. Other methods could also be applied äs the informed basis functions are generated before the computation of the solution. Here we lest our method using a realistic head model and noiseless instantaneous simulated data.

Informed spatial basis functions in minimum norm solutions for the electromagnetic source localisation problem.

Mapping of grey matter changes in schizophrenia
 1
 This work was presented, in part, at the VIth International Congress on Schizophrenia Research, Colorado Springs, Colorado, USA, April 1997.
 
 1
 
The desiderata for functional neuroimaging are high spatial and high temporal resolution. Recent developments in rapid echo-planar functional resonance imaging (fMRI) and event-related analyses [1,2] combine a spatial resolution of millimetres with a temporal resolution of seconds. A fundamental trade-off remains however: large brain coverage at high spatial resolution requires many, thin image planes (slices), resulting in a longer interscan interval (TR) and hence poorer temporal resolution. Though staggering stimulus times relative to scan times allows a higher effective sampling rate, existing volume-based analysis techniques such as SPM [2] assume simultaneous sampling of all slices. We show that this assumption can result in poor model fits and hence type II errors. Two popular solutions are compared: the use of multiple regressors and the interpolation of data in time.

Abnormal serotonergic function is implicated in the pathogenesis of affective disorders. We induced transient depressive relapses in volunteer patients by rapidly depleting plasma tryptophan, the precursor of serotonin (5-HT), and measured neural activity during different cognitive tasks using positron emission tomography (PET). Neural activity in several 5-HT-related brain areas, e.g., dorsal raphé, habenula, septal region, amygdala, and orbitofrontal cortex, covaried significantly with plasma levels of tryptophan and ratings of depressed mood. Task-specific responses in left amygdala and left anterior cingulate were attenuated by tryptophan depletion. We used these PET data to test the hypothesis that projections from the habenula modulate dorsal raphé activity and that this modulation is enhanced in patients experiencing a profound mood change following serotonergic challenge. A strong linear correlation (r(2) > 0.5) between habenula and raphé activity was observed in subjects with postdepletion ratings >/=10 on a modified Hamilton depression scale, whereas subjects experiencing milder changes in mood had weaker habenula-raphé coupling (r(2) < 0.5). These data support a model of the serotonergic system in which the habenula projection to the raphé represents a convergent feedback pathway that controls the release of 5-HT throughout the brain. In our experiment we were able to engage this system in patients who were sensitive to tryptophan depletion.

Covariation of Activity in Habenula and Dorsal Raphé Nuclei Following Tryptophan Depletion

We assessed time-dependent neuronal activity accompanying learning using functional magnetic resonance imaging (fMRI). An artificial grammar learning paradigm enabled us to dissociate activations associated with individual item learning from those involved in learning the underlying grammar system. We show that a localized region of right prefrontal cortex (PFC) is preferentially sensitive to individual item learning during the early stages of the experiment, while the left PFC region is sensitive to grammar learning which occurred across the entire course of the experiment. In addition to dissociating these two types of learning, we were able to characterize the effect of rule acquisition on neuronal responses associated with explicit learning of individual items. This effect was expressed as modulation of the time-dependent right PFC activations such that the early increase in activation associated with item learning was attenuated as the experiment progressed. In a further analysis we used structural equation modelling to explore time-dependent changes in inter-regional connectivity as a function of both item and grammar rule learning. Although there were no significant effects of item learning on the measured path strengths, rule learning was associated with a decrease in right fronto-parietal connectivity and an increase in connectivity between left and right PFC. Further fronto-parietal path strengths were observed to change, with an increase in left fronto-parietal and a decrease in right fronto-parietal connectivity path strength from right PFC to left parietal cortex. We interpret our findings in terms of a left frontal system mediating the semantic analysis of study items and directly influencing a right fronto-parietal system associated with episodic memory retrieval.

Learning-related neuronal responses in prefrontal cortex studied with functional neuroimaging.

This paper demonstrates how functional imaging studies of neuropsychological patients can provide a way of determining which areas in a cognitive network are jointly necessary and sufficient. The approach is illustrated with an investigation of the neural system underlying semantic similarity judgments. Functional neuroimaging demonstrates that normal subjects activate left temporal, parietal, and inferior frontal cortices during this task relative to physical size judgments. Neuropsychology demonstrates that damage to the temporal and parietal regions results in semantic deficits, indicating that these areas are necessary for task performance. In contrast, damage to the inferior frontal cortex does not impair task performance, indicating that the inferior frontal cortex might not be necessary. However, there are two other possible accounts of intact performance following frontal lobe damage: (1) there is functional reorganization involving the right frontal cortex and (2) there is peri-infarct activity around the damaged left-hemisphere tissue. Functional imaging of the patient is required to discount these possibilities. We investigated a patient (SW), who was able to associate words and pictures on the basis of semantic relationships despite extensive damage to the left frontal, inferior parietal, and superior temporal cortices. Although SW showed peri-infarct activation in left extrasylvian temporal cortices, no activity was observed in either left or right inferior frontal cortices. These ndings demonstrate that activity in extrasylvian temporo-parietal and medial superior frontal regions is sufcient to perform semantic similarity judgments. In contrast, the left inferior frontal activations detected in each control subject appear not to be necessary for task performance. In conclusion, necessary and sufcient brain systems can be delineated by functional imaging of brain-damaged patients who are not functionally impaired.

Delineating Necessary and Sufficient Neural Systems with Functional Imaging Studies of Neuropsychological Patients

Methodology for Statistical Parametric Mapping of [ 18 F]Fluorodopa Uptake Rate Using Three-Dimensional PET 1 1Transcripts of the BRAINPET97 discussion of this chapter can be found in Section VIII.

Identifying Global Anatomical Differences: Deformation-Based Morphometry

Methodology for Statistical Parametric Mapping of [18F]Fluorodopa Uptake Rate Using Three-Dimensional PET

Functional magnetic resonance imaging of the human brain: data acquisition and analysis

We present an approach to characterizing the differences among event-related hemodynamic responses in functional magnetic resonance imaging that are evoked by different sorts of stimuli. This approach is predicated on a linear convolution model and standard inferential statistics as employed by statistical parametric mapping. In particular we model evoked responses, and their differences, in terms of basis functions of the peri-stimulus time. This facilitates a characterization of the temporal response profiles that has a high effective temporal resolution relative to the repetition time. To demonstrate the technique we examined differential responses to visually presented words that had been seen prior to scanning or that were novel. The form of these differences involved both the magnitude and the latency of the response components. In this paper we focus on bilateral ventrolateral prefrontal responses that show deactivations for previously seen words and activations for novel words.

Abstract This fMRI study examined motion-sensitive responses in human area V5 as a function of stimulus speed. Consistent with electrophysiological findings, we observed optimal responses at intermediate speeds of around 7°/s to 30°/s. The results are consistent with a nonlinear (inverted “U”) dependency on speed that was also observed in V3a. V1 activation was observed to decrease linearly as speed increased. This is consistent with the fact that speed-sensitive cells in V1 have been shown to be tuned to much slower speeds than in V5.

Investigation of the three-generation KE family, half of whose members are affected by a pronounced verbal dyspraxia, has led to identification of their core deficit as one involving sequential articulation and orofacial praxis. A positron emission tomography activation study revealed functional abnormalities in both cortical and subcortical motor-related areas of the frontal lobe, while quantitative analyses of magnetic resonance imaging scans revealed structural abnormalities in several of these same areas, particularly the caudate nucleus, which was found to be abnormally small bilaterally. A recent linkage study [Fisher, S., Vargha-Khadem, F., Watkins, K. E., Monaco, A. P. & Pembry, M. E. (1998) Nat. Genet. 18, 168-170] localized the abnormal gene (SPCH1) to a 5. 6-centiMorgan interval in the chromosomal band 7q31. The genetic mutation or deletion in this region has resulted in the abnormal development of several brain areas that appear to be critical for both orofacial movements and sequential articulation, leading to marked disruption of speech and expressive language.

Time dependent changes in effective connectivity during learning assessed using fMRI

Parametric study designs proved very useful in characterizing the relationship between experimental parameters (e.g., word presentation rate) and regional cerebral blood flow in positron emission tomography studies. In a previous paper we presented a method that fits nonlinear functions of stimulus or task parameters to hemodynamic responses, using second-order polynomial expansions. Here we expand this approach to model nonlinear relationships between BOLD responses and experimental parameters, using fMRI. We present a framework that allows this technique to be implemented in the context of the general linear model employed by statistical parametric mapping (SPM). Statistical inferences, in this instance, are based on F statistics and in this respect we emphasize the use of corrected P values for F fields (i.e., SPM¿F¿). The approach is illustrated with a fMRI study that looked at the effect of increasing auditory word-presentation rate. Our parametric design allowed us to characterize different forms of rate-dependent responses in three critical regions: (i) bilateral frontal regions showed a categorical response to the presence of words irrespective of rate, suggesting a role for this region in establishing cognitive (e.g., attentional) set; (ii) in bilateral occipitotemporal regions activations increased linearly with increasing word rate; and (iii) posterior auditory association cortex exhibited a nonlinear (inverted U) relationship to word rate.

Characterizing Stimulus–Response Functions Using Nonlinear Regressors in Parametric fMRI Experiments

Localized amygdalar lesions in humans produce deficits in the recognition of fearful facial expressions. We used functional neuroimaging to test two hypotheses: (i) that the amygdala and some of its functionally connected structures mediate specific neural responses to fearful expressions; (ii) that the early visual processing of emotional faces can be influenced by amygdalar activity. Normal subjects were scanned using PET while they performed a gender discrimination task involving static grey-scale images of faces expressing varying degrees of fear or happiness. In support of the first hypothesis, enhanced activity in the left amygdala, left pulvinar, left anterior insula and bilateral anterior cingulate gyri was observed during the processing of fearful faces. Evidence consistent with the second hypothesis was obtained by a demonstration that amygdalar responses predict expression-specific neural activity in extrastriate cortex.

A neuromodulatory role for the human amygdala in processing emotional facial expressions.

This paper presents an approach to characterizing evoked hemodynamic responses in fMRI based on nonlinear system identification, in particular the use of Volterra series. The approach employed enables one to estimate Volterra kernels that describe the relationship between stimulus presentation and the hemodynamic responses that ensue. Volterra series are essentially high‐order extensions of linear convolution or “smoothing.” These kernels, therefore, represent a nonlinear characterization of the hemodynamic response function that can model the responses to stimuli in different contexts (in this work, different rates of word presentation) and interactions among stimuli. The nonlinear components of the responses were shown to be statistically significant, and the kernel estimates were validated using an independent event‐related fMRI experiment. One important manifestation of these nonlinear effects is a modulation of stimulus‐specific responses by preceding stimuli that are proximate in time. This means that responses at high‐stimulus presentation rates saturate and, in some instances, show an inverted U behavior. This behavior appears to be specific to BOLD effects (as distinct from evoked changes in cerebral blood flow) and may represent a hemodynamic “refractoriness.” The aim of this paper is to describe the theory and techniques upon which these conclusions were based and to discuss the implications for experimental design and analysis.

A key issue in developmental neuroscience is the role of activity-dependent mechanisms in the epigenetic induction of functional organization in visual cortex. Ocular blindness and ensuing visual deprivation is one of the rare models available for the investigation of experience-dependent cortical reorganization in man. In a PET study we demonstrate that congenitally blind subjects show task-specific activation of extrastriate visual areas and parietal association areas during Braille reading, compared with auditory word processing. In contrast, blind subjects who lost their sight after puberty show additional activation in the primary visual cortex with the same tasks. Studies in blind-raised monkeys show that crossmodal responses in extrastriate areas can be elicited by somatosensory stimulation. This is consistent with the crossmodal extrastriate activations elicited by tactile processing in our congenitally blind subjects. Since primary visual cortex does not show crossmodal responses in primate studies, the differential activation in late and congenitally blind subjects highlights the possibility of reciprocal activation by visual imagery in subjects with early visual experience.

Different activation patterns in the visual cortex of late and congenitally blind subjects.

Brain Systems Mediating Aversive Conditioning: an Event-Related fMRI Study

This article reviews some recent trends in imaging neuroscience. A distinction is made between making maps of functional responses in the brain and discerning the rules or principles that underlie their organization. After considering developments in the characterization of brain imaging data, several examples are presented that highlight the context-sensitive nature of neuronal responses that we measure. These contexts can be endogenous and physiological, reflecting the fact that each cortical area, or neuronal population, expresses its dynamics in the context of interactions with other areas. Conversely, these contexts can be experimental or psychological and can have a profound effect on the regional effects elicited. In this review we consider experimental designs and analytic strategies that go beyond cognitive subtraction and speculate on how functional imaging can be used to address both the details and principles underlying functional integration and specialization in the brain.

Functional neuroimaging experiments have implicated prefrontal cortex (PFC) in memory processes. Several studies of schizophrenic patients have shown failure of activation in the dorsolateral region of PFC (DLPFC). We used a graded memory challenge to characterize functional neuroanatomical differences between schizophrenic and control subjects. The graded manipulation of task demands enabled us to assess group differences in the context of normal and abnormal psychological task performance.

METHODS
Memory-related activity was assessed using positron emission tomography in schizophrenic patients and age-matched controls during performance of a graded memory task. Subjects underwent scanning while learning and recalling word lists of variable length.

RESULTS
We used a model that assessed linear and nonlinear effects of memory load. Nonlinear group differences in DLPFC activation were observed. Controls showed a steepening slope of DLPFC increase as task demands increased. By contrast, schizophrenic subjects showed initial DLPFC increases that fell away with increasing memory load. The DLPFC response in schizophrenic subjects was closely related to measured task performance. In addition, schizophrenic subjects failed to show task-related decreases in activity in the left superior temporal and inferior parietal gyrus.

Patients with schizophrenia showed a failure in DLPFC activation only in the face of diminished performance measures, suggesting that a full characterization of task-related changes in DLPFC activation must consider performance levels. However, striking failures of deactivation in superior temporal and inferior parietal regions were independent of task performance, possibly reflecting a core abnormality of the condition.

Brain activations in schizophrenia during a graded memory task studied with functional neuroimaging.

Psychosis and the Experience of Self: Brain Systems Underlying Self‐Monitoring

Learning-related changes in effective connectivity studied with fMRI

Attention can enhance or modulate neural responses to stimuli at early and late stages of sensory processing. We were interested in the modulatory effect of attention to visual motion on cortical responses as measured by functional MRI. Subjects were scanned during repeated presentations of identical stimuli (visual motion) while only the attentional component of the task was varied. Enhanced haemodynamic responses during attentive conditions defined an occipitoparietofrontal system, including sensory and association areas, as well as the medial thalamus and superior colliculus. Attentional modulation was not restricted to extrastriate areas (including V3a and the V5 complex) but was also evident, to a lesser degree, in early visual areas close to the calcarine fissure (V1/V2 border). Attention-related enhancement of cortical responsiveness is discussed in terms of data that implicate modulatory short-term changes in synaptic efficacy and reciprocal connections between striate, extrastriate, parietal and frontal areas. Given the similarity of our attentional network to that controlling eye movements, the results of this study are in accord with theories linking oculomotor control and attention.

The functional anatomy of attention to visual motion. A functional MRI study.

The aim of this study was to investigate the functional anatomy of distributed cortical and subcortical motor areas in the human brain that participate in the central control of overlearned complex sequential unimanual finger movements. On the basis of previous research in nonhuman primates, a principal involvement of basal ganglia medial premotor loops [corrected] was predicted for central control of finger sequences performed automatically. In pertinent areas, a correlation of activation levels with the complexity of a motor sequence was hypothesized. H2 15O positron emission tomography (PET) was used in a group of seven healthy male volunteers [mean age 32.0 +/- 10.4 yr] to determine brain regions where levels of regional cerebral blood flow (rCBF) correlated with graded complexity levels of five different key-press sequences. All sequences were overlearned before PET and involved key-presses of fingers II-V of the right hand. Movements of individual fingers were kept constant throughout all five conditions by external pacing at 1-Hz intervals. Positive correlations of rCBF with increasing sequence complexity were identified in the contralateral rostral supplementary motor area (pre-SMA) and the associated pallido-thalamic loop, as well as in right parietal area 7 and ipsilateral primary motor cortex (M1). In contrast, while rCBF in contralateral M1 and [corrected] extensive parts of caudal SMA was increased compared with rest during task performance, significant correlated increases of rCBF with sequence complexity were not observed. Inverse correlations of rCBF with increasing sequence complexity were identified in mesial prefrontal-, medial temporal-, and anterior cingulate areas. The findings provide further evidence in humans supporting the notion of a segregation of SMA into functionally distinct subcomponents: although pre-SMA was differentially activated depending on the complexity of a sequence of learned finger movements, such modulation was not detectable in caudal SMA (except the most antero-superior part), implicating a motor executive role. Our observations of complexity-correlated rCBF increases in anterior globus pallidus suggest a specific role for the basal ganglia in the process of sequence facilitation and control. They may act to filter and focus input from motor cortical areas as patterns of action become increasingly complex.

Role of the human rostral supplementary motor area and the basal ganglia in motor sequence control: investigations with H2 15O PET.

Functional Integration Between Colour and Motion Processing Pathways in the Brain : an fMRI Study

Characterization of Functional Maps using Anatomically Informed Basis Functions

Selection is the essence of attention, whether of a train of thought, an object or a spatial location. The most general way of characterising selectivity is as task-dependent modulation of neural activity. Such task-dependent modulation by attention of sensory input or motor output can take two forms. Activity in an area involved in a sensorimotor or cognitive task may be modulated in either a stimulus-dependent (phasic) or a stimulus independent (tonic) fashion. Conventional PET methodology cannot distinguish between these two types of modulation, as all neural activity within the scanning window is lumped together. However, by varying the rate of stimulus presentation orthogonally with task, these two types of modulation by attention can be distinguished. This is illustrated with a PET study of selective attention. In a nonspatial selective attention task, subjects identified visual targets defined by colour, orientation, or the conjunction of colour and orientation. A region in right dorsolateral prefrontal cortex was the only area specifically activated by the conjunction task, in a location that has previously been implicated in the performance of conjunction tasks in monkeys. A distributed network of cortical art:as including prestriate cortex, motor and premotor cortex and inferior temporal cortex :shows activity correlated with increasing stimulus presentation rate. Within this network of areas we demonstrate that inferior temporal cortex, premotor cortex and cerebellum are modulated by selective attention to visual conjunctions in the conjunction task. Moreover the manner of modulation differs in different areas, being stimulus related in premotor cortex and left cerebellum ("phasic") and stimulus-independent ("tonic") in inferior temporal cortex and right cerebellum. This is the first demonstration in humans of two physiologically distinct types of modulation of cortical activity by selective attention. We suggest that this technique can distinguish between the site and source of attentional modulation.

Characterising selective attention with positron emission tomography - Neurophysiological investigations

Statistical parametric mapping in functional neuroimaging: beyond PET and fMRI activation studies.

Learning-related Modulation of Tonotopic Responses in Human Auditory Cortex

The aim of this paper is to illustrate a method for identifying macroscopic anatomical differences among the brains of different populations of subjects. The method involves spatially normalizing the structural MR images of a number of subjects so that they all conform to the same stereotactic space. Multivariate statistics are then applied to the parameters describing the estimated nonlinear deformations that ensue. To illustrate the method, we compared the gross morphometry of male and female subjects. We also assessed brain asymmetry, the effect of handedness, and interactions among these effects. Hum. Brain Mapping 6:348–357, 1998. © 1998 Wiley‐Liss, Inc.

Identifying global anatomical differences: Deformation‐based morphometry

Necessary and Sufficient Functional Brain Systems: The case for neuroimaging of neuropsychological patients.

Experience–dependent plasticity of receptive fields in the auditory cortex has been demonstrated by electrophysiological experiments in animals. In the present study we used PET neuroimaging to measure regional brain activity in volunteer human subjects during discriminatory classical conditioning of high (8000 Hz) or low (200 Hz) frequency tones by an aversive 100 dB white noise burst. Conditioning–related, frequency–specific modulation of tonotopic neural responses in the auditory cortex was observed. The modulated regions of the auditory cortex positively covaried with activity in the amygdala, basal forebrain and orbitofrontal cortex, and showed context–specific functional interactions with the medial geniculate nucleus. These results accord with animal single–unit data and support neurobiological models of auditory conditioning and value–dependent neural selection.

Experience–dependent modulation of tonotopic neural responses in human auditory cortex

Brain systems mediating aversive conditioning: An event related fMRI study

A functional neuroimaging study of patterns of frontal lobe activity in schizophrenia during memory encoding and retrieval

A technique for connecting a plurality of telephone channels operated on a pulse code modulated basis, in a conference arrangement. Digital signals are not converted to analog, rather binary words are compared from the participating channels, with the largest binary number selected as the speaker.

Role of the human rostral supplementary motor area and the basal ganglia in motor sequence control: Investigations with H-2 O-15 PET (vol 79, pg 1070, 1998)

Objective: To use functional MRI (fMRI) to study grouped patterns of cerebral activation and the course of hemodynamic responses during performance of two activation tasks (paradigms) using a hand-held joystick to perform movements in a repetitively fixed direction and movements in freely selected random directions. Background: Evidence from lesion, electrophysiologic, and functional imaging studies implicates prefrontal and mesial frontal cortex in motor preparation and primary motor cortex in motor execution. fMRI can be used to study cerebral activation and has practical advantages over other methods of functional neuroimaging. Methods: We acquired 100 multislice T2* -weighted data sets from five healthy volunteers during performance of each paradigm using conventional fMRI. For each paradigm, rest and movement epochs were alternated every 30 seconds. After coregistration and spatial normalization, we combined the data for group studies. We used statistical parametric mapping to compare the early (first 15 seconds) components of the movement epochs with rest as well as the late (last 15 seconds) components of the movement epochs with rest. Results: During the early phase of both paradigms, significant activation was present in rostral and caudal mesial premotor cortex. Right prefrontal cortex was significantly activated during the early component of freely selected joystick movements. Activation of rostral supplementary motor area was maintained during the late component of freely selected movements but decreased during repetitively fixed movements. In contrast, significant activation in contralateral sensorimotor cortex was maintained during both early and late components of both paradigms. Conclusions: fMRI can detect cortical activation. The temporal resolution of fMRI also allows adaptation of blood oxygenation level-dependent (BOLD) contrast signal to be detected in association cortex. However, the level of BOLD contrast signal in primary motor cortex remained significantly elevated throughout task performance.

Exploring the temporal nature of hemodynamic responses of cortical motor areas using functional MRI

Modes or models: a critique on independent component analysis for fMRI

Deep dyslexia is a striking reading disorder that results from left-hemisphere brain damage and is characterized by semantic errors in reading single words aloud (e.g., reading spirit as whisky). Two types of explanation for this syndrome have been advanced. One is that deep dyslexia results from a residual left-hemisphere reading system that has lost the ability to pronounce a printed word without reference to meaning. The second is that deep dyslexia reflects right-hemisphere word processing. Although previous attempts to adjudicate between these hypotheses have been inconclusive, the controversy can now be addressed by mapping functional anatomy. In this study, we demonstrate that reading by two deep dyslexic patients (CJ and JG) involves normal or enhanced activity in spared left-hemisphere regions associated with naming (Broca's area and the left posterior inferior temporal cortex) and with the meanings of words (the left posterior temporo-parietal cortex and the left anterior temporal cortex). In the right-hemisphere homologues of these regions, there was inconsistent activation within the normal group and between the deep dyslexic patients. One (CJ) showed enhanced activity (relative to the normals) in the right anterior inferior temporal cortex, the other (JG) in the right Broca's area, and both in the right frontal operculum. Although these differential right-hemisphere activations may have influenced the reading behavior of the patients, their activation patterns primarily reflect semantic and phonological systems in spared regions of the left hemisphere. These results preclude an explanation of deep dyslexia in terms of purely right-hemisphere word processing.

A Functional Neuroimaging Description of Two Deep Dyslexic Patients

Characterising Selective Attention with Positron Emission Tomography

The neural mechanisms involved in the selective processing of salient or behaviourally important stimuli are uncertain. We used an aversive conditioning paradigm in human volunteer subjects to manipulate the salience of visual stimuli (emotionally expressive faces) presented during positron emission tomography (PET) neuroimaging. Increases in salience, and conflicts between the innate and acquired value of the stimuli, produced augmented activation of the pulvinar nucleus of the right thalamus. Furthermore, this pulvinar activity correlated positively with responses in structures hypothesized to mediate value in the brain–right amygdala and basal forebrain (including the cholinergic nucleus basalis of Meynert). The results provide evidence that the pulvinar nucleus of the thalamus plays a crucial modulatory role in selective visual processing, and that changes in perceptual salience are mediated by value–dependent plasticity in pulvinar responses.

We present a method for detecting event‐related responses in functional magnetic resonance imaging (fMRI). The occurrence of time‐locked activations is formulated in terms of the general linear model, i.e., multiple linear regression. This permits the use of established statistical techniques that correct for multiple comparisons in the context of spatially smooth and serially correlated data. Responses are modelled using event‐related temporal basis functions. Inferences are then made about all components of the model, using the F‐ratio at all voxels in the image, to produce a statistical parametric map (SPM{F}). This method allows for the experimental design to relate the timing of events to the acquisition of data to give a temporal resolution (with respect to the event‐related response) far better than the scanning repeat time. Hum. Brain Mapping 5:243–248, 1997. © 1997 Wiley‐Liss, Inc.

475 Functional connectivity during word generation in schizophrenia

Applications of fMRI in functional brain imaging are mainly confined to single subject designs, prohibiting the assessment of subject or group by condition interactions (i.e., differential activations) or areas of conjoint activation. In this paper a framework for fMRI group designs, using statistical parametric mapping, is introduced. It is generally believed that intersubject averaging, which requires spatial normalization and smoothing, will decrease the effective spatial resolution of fMRI or its sensitivity. A subcortical activation of the lateral geniculate nucleus (LGN) was therefore chosen to demonstrate the feasibility and power of intersubject averaging in the context of fMRI. Seven volunteers were studied, while looking at a blank screen or radially moving dots. LGN activation was demonstrated in all single subject analyses and in the group analysis.

Lateral geniculate activations can be detected using intersubject averaging and fMRI

In this paper we introduce the idea of explaining responses, in one cortical area, in terms of an interaction between the influence of another area and some experimental (sensory or task-related) parameter. We refer to these effects as psychophysiological interactions and relate them to interactions based solely on experimental factors (i.e., psychological interactions), in factorial designs, and interactions among neurophysiological measurements (i.e., physiological interactions). We have framed psychophysiological interactions in terms of functional integration by noting that the degree to which the activity in one area can be predicted, on the basis of activity in another, corresponds to the contribution of the second to the first, where this contribution can be related to effective connectivity. A psychophysiological interaction means that the contribution of one area to another changes significantly with the experimental or psychological context. Alternatively these interactions can be thought of as a contribution-dependent change in regional responses to an experimental or psychological factor. In other words the contribution can be thought of as modulating the responses elicited by a particular stimulus or psychological process. The potential importance of this approach lies in (i) conferring a degree of functional specificity on this aspect of effective connectivity and (ii) providing a model of modulation, where the contribution from a distal area can be considered to modulate responses to the psychological or stimulus-specific factor defining the interaction. Although distinct in neurobiological terms, these are equivalent perspectives on the same underlying interaction. We illustrate these points using a functional magnetic resonance imaging study of attention to visual motion and a position emission tomography study of visual priming. We focus on interactions among extrastriate, inferotemporal, and posterior parietal regions during visual processing, under different attentional and perceptual conditions.

Selective processing of nouns and function words in the human brain

We present a simple way of assessing dynamic or time-dependent changes in displacement during single-subject radioligand positron emission tomography (PET) activation studies. The approach is designed to facilitate dynamic activation studies using selective radioligands. These studies are, in principle, capable of characterising functional neurochemistry by analogy with the study of functional neuroanatomy using rCBF activation studies. The proposed approach combines time-dependent compartmental models of tracer kinetics and the general linear model used in statistical parametric mapping. This provides for a comprehensive, voxel-based and data-led assessment of regionally specific effects. The statistical model proposed in this paper is predicated on a single-compartment model extended to allow for time-dependent changes in kinetics. We have addressed the sensitivity and specificity of the analysis, as it would be used operationally, by applying the analysis to 11C-Flumazenil dynamic displacement studies. The activation used in this demonstration study was a pharmacological (i.v. midazolam) challenge, 30 min after administration of the tracer. We were able to demonstrate, and make statistical inferences about, regional increases in k2 (or decreases in the volume of distribution) in prefrontal and other cortical areas.

Analysis of Dynamic Radioligand Displacement or “Activation” Studies

This paper investigates the relationship between the blood oxygenation level dependent (BOLD) contrast effect and regional cerebral blood flow using the techniques of functional MRI (fMRI) and positron emission tomography (PET). A passive listening paradigm with parametric variation in word presentation rate was used to investigate the rate dependency of both BOLD contrast fMRI and H215O PET in primary auditory cortex. We attempted to equate the stimulus presentation acoustic environments by using prerecorded echoplanar imaging sounds during the PET paradigm. We show that there is a linear relationship between word presentation rate and cerebral blood flow in primary auditory cortex, whereas the relationship between BOLD contrast and stimulus presentation rate is highly nonlinear, showing a saturable effect. Two possible explanations for our results are discussed: a nonlinearity in the relationship between BOLD contrast and deoxyhemoglobin concentration or a nonlinear rate dependency of the physiological mechanisms causing changes in deoxyhemoglobin concentration.

Characterizing the Relationship between BOLD Contrast and Regional Cerebral Blood Flow Measurements by Varying the Stimulus Presentation Rate

In the past decade functional neuroimaging has been extremely successful in establishing functional segregation as a principle of organisation in the human brain. Functional segregation is usually inferred by the presence of activation foci in change or statistical parametric maps. The nature of the functional specialisation is then attributed to the sensorimotor or cognitive process that has been manipulated experimentally. Newer approaches have addressed the integration of functionally specialised areas through characterising neurophysiological activations in terms of distributed changes (e.g. McIntosh et al 1994a, Friston et al 1993a, Friston et al 1993b, Lagreze et al 1993, McIntosh & Gonzalez-Lima 1991, Horwitz et al., 1995; Horwitz and Sporns, 1994). These approaches have introduced a number of concepts into neuroimaging (e.g. functional and effective connectivity, eigenimages, spatial modes, information theory, multidimensional scaling) and their application to issues in imaging neuroscience (e.g. functional systems, cortical integration, associative plasticity, and nonlinear cortical interactions). The study of effective connectivity will also gain importance for relating cognitive theories (eg. attention) to brain operations. For example categorical comparisons of functional brain imaging data suggests modulation of extrastriate cortical responses by attentional processes (Corbetta et al 1991). It would be very compelling to demonstrate the modulation of responsiveness of these areas in terms of attention-dependent changes in the interactions or effective connectivity among.

We present a simple method that allows statistical inferences to be made about the significance of regional effects in statistical parametric maps (SPMs) when the approximate location of the effect is specified in advance. The test can be thought of as analogous to assessing activations with uncorrected P values based on the height of SPMs but, in this instance, using the spatial extent or volume of the nearest activated region. The advantage of the current test is that it eschews a correction for multiple comparisons even though the exact location of the expected activation may not be known. Hum. Brain Mapping 5:133–136, 1997. © 1997 Wiley‐Liss, Inc.

This paper introduces the concepts and procedures of "cognitive conjunction," a new approach to designing and analyzing cognitive activation experiments. Cognitive conjunction compliments categorical approaches such as cognitive subtraction and requires a specific form of statistical inference that involves the conjunction of several hypotheses. While cognitive subtraction studies are designed such that a pair of tasks differ only by the processing component(s) of interest, cognitive conjunction studies are designed such that two or more distinct task pairs each share a common processing difference. The neural correlates of the process of interest are then associated with the common areas of activation for each task pair. There are two main advantages of cognitive conjunction relative to cognitive subtraction. The first is that it provides a greater latitude for selecting baseline tasks because it is not necessary to control for all but the component of interest. The only constraint on selecting the baseline is that the component of interest is the only process that differs in each task pair. The second advantage is that cognitive conjunction does not depend on "pure insertion"--the assumption that the addition of an extra processing component in the activation task has no effect on the implementation of processes that are also engaged by the baseline task. The differences between the design and the statistical analysis of experiments based on cognitive subtraction, cognitive conjunction, and factorial designs are illustrated with a study of phonological retrieval. Cognitive conjunction analysis indicates that irrespective of whether subjects name words, objects, letters, or colors, there is activation of the left posterior basal temporal lobe, the left frontal operculum, the left thalamus, and the midline cerebellum.

Cognitive Conjunction: A New Approach to Brain Activation Experiments

This paper presents the conjecture that functional integration may be mediated by the mutual induction and maintenance of stereotyped spatiotemporal patterns of activity (i.e., transients) in different neuronal populations. In contradistinction to temporal and rate coding models of neuronal interactions, transient coding considers that transactions among neuronal systems use transient dynamics that are distributed in a structured way over both space and time. In contrast to synchronization models, transient coding does not depend on interactions at the same frequencies, in different parts of the brain, but involves covariations among different frequencies and can therefore be considered a more general form of coding. Using an analysis of the correlations among the spectral density of neuromagnetic signals, measured at different cortical regions, this hypothesis was confirmed. For example high (gamma)-frequency oscillations in the prefrontal cortex are associated with low (20 Hz)-frequency oscillations in the parietal cortex. The results are consistent with transient coding and suggest that transient dynamics endure for at least 40-200 ms. Transient coding means that correlations (rate coding) and coherence (synchrony) are neither complete nor sufficient characterizations of neuronal interactions. Although temporal coding, rate coding, and synchrony are important aspects of neuronal interactions, the results speak to further integrative neuronal mechanisms of a more general nature.

The time-course of activity in motor areas during motor learning

This work represents an attempt to bring together two important themes in neuronal dynamics. The first is the characterization of dynamic correlations in multiunit recordings of spike activity using joint‐peri‐stimulus time histograms (J‐PSTHs) [Aertsen and Preissl, 1991: Non Linear Dynamics and Neural Networks]. The second is transient phase‐locking at high (gamma) frequencies, either in terms of spiking in separable spike trains [e.g., Eckhorn et al., 1988: Biol Cybern 60:121–130, Gray and Singer, 1989 Proc Natl Acad Sci USA 86:1698–1702], or using continuous electrical or biomagnetic signals [e.g., Desmedt and Tomberg, 1994 Neurosci Lett 168:126–129]. In this paper we suggest that transient phase‐locking is necessary for frequency‐specific, dynamic event‐related correlations. This point is demonstrated using the gamma‐frequency (36 Hz) component of neuromagnetic signals measured in the prefrontal and partial regions of a subject during self‐paced movements. A J‐PSTH analysis revealed dynamic changes in prefronto‐parietal correlations in relation to movement onset. These frequency‐specific dynamic correlations were associated with changes in the degree of phase‐locking, of the sort reported by Desmedt and Tomberg [1994 Neurosci Lett 168:126–129]. Hum. Brain Mapping 5:48–57, 1997. © 1997 Wiley‐Liss, Inc.

Transient phase‐locking and dynamic correlations: Are they the same thing?

A stopper structure is provided for downward removable insertion into the drain opening of a tub or shower stall and a water pump assembly is also provided including a water inlet and a water outlet with the water inlet supported relative to the stopper closely above the latter. A shower head water spray structure is also provided and the water outlet of the pump is communicated therewith. When it is desired to recirculate shower water, the conventional shower or tub water valve is operated after the stopper structure has been utilized to plug the shower or tub drain and until a sufficient quantity of water is collected in the shower or tub bottom. Thereafter, the water pump of the recirculating shower may be actuated whereupon the water collected in the bottom of the shower or tub may be pumped therefrom and outwardly from the shower head water spray structure.

The first step in the spatial normalization of brain images is usually to determine the affine transformation that best maps the image to a template image in a standard space. We have developed a rapid and automatic method for performing this registration, which uses a Bayesian scheme to incorporate prior knowledge of the variability in the shape and size of heads. We compared affine registrations with and without incorporating the prior knowledge. We found that the affine transformations derived using the Bayesian scheme are much more robust and that the rate of convergence is greater.

Different activation patterns in the occipital cortex of late and congenitally blind subjects

Background Symptoms in schizophrenia duster into syndromes, each of which may be associated with a particular pattern of cerebral blood flow. We sought to investigate whether these syndromes are also related to neuroanatomical changes. Method A semi-automated method was used to examine structural magnetic resonance images in 12 patients with schizophrenia. The relationship between the relative regional grey matter volume and ratings of the syndromes of psychomotor poverty, disorganisation and reality distortion was investigated. Results There was a significant negative correlation between psychomotor poverty score and the relative volume of the left ventro-medial prefrontal grey matter, and a significant positive correlation between disorganisation and the relative volumes of the hippocampus, and the parahippocampal/fusiform gyrus bilaterally. Conclusion The correlation between psychomotor poverty and left prefrontal grey matter volume resembles that previously seen with prefrontal blood flow in the same patients, suggesting that this functional abnormality is related to an underlying anatomical change.

Using [11C]flumazenil-PET and statistical parametric mapping (SPM), we have shown recently that regions of increased and decreased benzodiazepine receptor density may be seen in patients with localization-related epilepsy due to malformations of cortical development. These abnormalities were seen both within and beyond lesions visually apparent on high-resolution MRI. We have also shown, using an interactive anatomical segmentation technique and volume-of-interest measurements, that subtle and unsuspected abnormalities of cortical grey matter volume were found in the same group of patients on high-resolution MRI, beyond the lesions visually apparent. In 10 patients with localization-related epilepsy and malformations of cortical development, we have now applied the automated and objective technique of SPM to the analysis of high-resolution structural MRI. Each individual patient was compared with 16 normal control subjects. We have then simultaneously compared the structural and functional data obtained for each individual patient with normal control high-resolution MRI and [11C]flumazenil-PET image using a novel technique. This comparison allowed the detection of functional abnormalities that were not accounted for by either visible or unsuspected structural abnormalities, in an automated and statistically rigorous manner. Five patients had abnormalities of cortical grey matter volume detected using SPM; only these five patients had been found abnormal using the previous volume-of-interest technique. Six of the 10 patients showed regions of cerebral cortex with disproportionate flumazenil binding compared with local grey matter volume. This included regions not found to have abnormal flumazenil binding on analysis of the PET data alone. Furthermore, regions found to have abnormal binding on examination of the PET data alone were, in some instances, shown to be accounted for by abnormalities of cortical grey matter volume. We conclude that the analysis of ligand PET data should always include a comparison with structural MRI; such comparisons are greatly facilitated by the novel approach described.

Cortical grey matter and benzodiazepine receptors in malformations of cortical development. A voxel-based comparison of structural and functional imaging data.

How the brain learns to see objects and faces in an impoverished context

This paper contrasts different experimental designs for revealing the neural correlates of phonological retrieval (i.e., naming). Cognitive subtraction designs require a minimum of one task pair and the comparison between tasks reveals the differing functional task components. Conjunction analysis requires a minimum of two task pairs, each differing by the same component, and this component is revealed as the difference which is common to both task pairs. Two different limitations of cognitive subtraction are highlighted: 1) the difficulty of finding baseline tasks that activate all but the process of interest, and 2) activation differences (between the two tasks of a pair) include the interaction term, i.e., the effect that the added component in the activation task has on preexisting components. The problem of baseline selection can be overcome by conjunction analysis, for which there may be many processing differences for each task pair, providing that the only common difference between pairs is the component of interest. The problem of interactions can be overcome when the experimental design is factorial. This permits the effect that an added component has on the expression of preexisting components (i.e., the interaction term) to be evaluated explicitly. We demonstrate that when the design is factorial, conjunction analysis reveals commonalities in activation, while the interactions reveal task‐specific effects. Hum. Brain Mapping 5:264–272, 1997. © 1997 Wiley‐Liss, Inc.

Subtractions, conjunctions, and interactions in experimental design of activation studies

Cerebral mechanisms associated with learning to see in an impoverished context

Correction for movement-related effects arising from data interpolation in fMRI time-series

Statistical parametric mapping (SPM) of mucociliary clearance of inhaled radioaerosols.

Abstract This study used Positron Emission Tomography (PET) to define areas of brain activation during musical hallucinosis in a single subject with deafness but no psychiatric or central neurologic condition. The subject had a history of less than 6 months of continual hallucinosis in the form of hearing one or more singers singing familiar songs with indistinguishable lyrics. A parametric design was used to identify areas where blood flow increased as a function of the intensity of the hallucination, and revealed significant activation in the posterior middle right temporal lobe. A region in the anterior superior right temporal lobe just failed to reach significance. Significant decreases in blood flow with increasing intensity of the hallucination were demonstrated in the occipital cortex. These data implicate right temporal lobe mechanisms beyond the primary auditory cortex in musical imagery.

Principles and methods: Linking brain and behaviour, C. Frith Analyzing brain images - principles and overview, K. Friston Registering brain images to anatomy, J. Ashbumer, K. Friston Characterizing brain images with the general linear model, A. Holmes et al Making statistical inferences, J. Poline et al Characterizing distributed functional systems, K. Friston Characterizing functional integration, C. Buechel, K. Friston A taxonomy of study design, K. Friston et al. Functional anatomy: Dynamism of a PET image - studies of visual function, S. Zeki Mapping somatosensory systems, E. Paulesu, R. Frackowiak Functional organization of the motor system, R. Passingham The cerebral basis of functional recovery, R. Frackowiak Functional anatomy of reading, C. Price Higher cognitive processes, C. Frith, R. Dolan Human memory systems, R. Dolan et al Measuring neuromodulation with functional imaging, R. Dolan et al Brain maps - linking the present with the future, J. Mazziotta et al Functional imaging with magnetic resonance, R. Turner et al.

2 The General Linear Model 2 2.1 The General Linear Model | Introduction : : : : : : : : : : : : : : : : : 3 2.2 Matrix formulation : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 4 2.3 Estimation : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 4 2.4 Overdetermined models : : : : : : : : : : : : : : : : : : : : : : : : : : : : 5 2.5 Geometrical Perspective : : : : : : : : : : : : : : : : : : : : : : : : : : : 8 2.6 Inference : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 8

This paper is about neuronal dynamics and how their special complexity can be understood in terms of nonlinear dynamics. There are many aspects of neuronal interactions and connectivity that engender the complexity of brain dynamics. In this paper we consider (i) the nature of this complexity and (ii) how it depends on connections between neuronal systems (e.g., neuronal populations or cortical areas). The main conclusion is that simulated neural systems show complex behaviors, reminiscent of neuronal dynamics, when these extrinsic connections are sparse. The patterns of activity that obtain, under these conditions, show a rich form of intermittency with the recurrent and self-limiting expression of stereotyped transient-like dynamics. Despite the fact that these dynamics conform to a single (complex) attractor this metastability gives the illusion of a dynamically changing attractor manifold (i.e., a changing surface upon which the dynamics unfold). This metastability is characterized using a measure that is based on the entropy of the time series' spectral density.

Within the framework of statistical mapping, there are up to now only two tests used to assess the regional significance in functional images. One is based on the magnitude of the foci and tends to detect high intensity signals, while the second is based on the spatial extent of regions defined by a simple thresholding of the statistical map, a test that is more sensitive to extended signals. The aim of this paper is to combine the two tests into a single test that is more sensitive to a wider range of signals. This combined test is based on an analytical approximation of the distribution of these two parameters (size and height) and is applied in the context of statistical maps. The risk of error in noise-only 2D or 3D volumes is assessed under a wide range of experimental conditions obtained by varying both the resolution of the map and the threshold at which clusters are defined. In addition, we have investigated this new test on simulated signals, and applied it to an experimental PET dataset. The experimental risk of error is close to the predicted one, and the overall sensitivity increases when analyzing a volume containing different types of signals.

Combining Spatial Extent and Peak Intensity to Test for Activations in Functional Imaging

Methods for mapping and modeling the human brain: Proceedings of the BrainMap '96 workshop, San Antonio, December 1996

The temporal dynamics of evoked brain responses are normally characterized using electrophysiological techniques but the positron emission tomography study presented here revealed a temporal aspect of reading by correlating the duration a word remained in the visual field with evoked haemodynamic response. Three distinct types of effects were observed: in visual processing areas, there were linear increases in activity with duration suggesting that visual processing endures throughout the time the stimulus remains in the visual field. In right hemisphere areas, there were monotonic decreases in activity with increased duration which we relate to decreased attention for longer stimulus durations. In left hemisphere word processing areas there were inverted U–shaped dependencies between activity and word duration indicating that, after 400–600 ms, activity in word processing areas is progressively reduced if the word remains in the visual field. We conclude that these inverted U effects in left hemisphere language areas reflect the temporal dynamics of visual word processing and we highlight the implication of these effects for the design of activation studies involving reading.

7 Discussion and conclusion 17 7.1 Which test should be used and when ? : : : : : : : : : : : : : : : : : : : 17 7.2 Sensitivity and Speci city : : : : : : : : : : : : : : : : : : : : : : : : : : 18 7.3 How do we choose the parameters ? : : : : : : : : : : : : : : : : : : : : : 18 7.4 Smoothness Variability : : : : : : : : : : : : : : : : : : : : : : : : : : : : 19 7.5 Smoothness estimation on the residuals : : : : : : : : : : : : : : : : : : : 20 7.6 A priori hypothesis : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 22 7.7 Testing for commonalities : : : : : : : : : : : : : : : : : : : : : : : : : : 22

2 Testing for the intensity of an activation in SPMs 2 . 1 Theory

Coregistration of functional PET and T1-weighted MR images is a necessary step for combining functional information from PET images with anatomical information in MR images. Several coregistration algorithms have been published and are used in functional brain imaging studies. In this paper, we present a comparison and cross validation of the two most widely used coregistration routines (Friston et al., 1995, Hum. Brain Map. 2: 165-189; Woods et al., 1993, J. Comput. Assisted Tomogr: 17: 536-546). Several transformations were applied to high-resolution anatomical MR images to generate simulated PET images so that the exact (rigid body) transformations between each MR image and its associated simulated PET images were known. The estimation error of a coregistration in relation to the known transformation allows a comparison of the performance of different coregistration routines. Under the assumption that the simulated PET images embody the salient features of real PET images with respect to coregistration, this study shows that the routines examined reliably solve the MRI to PET coregistration problem.

MRI and PET Coregistration—A Cross Validation of Statistical Parametric Mapping and Automated Image Registration

Functional magnetic resonance neuroimaging is a technique which can be used to perform similar brain activation studies to PET, although non-invasively, but it can also provide additional information to that available from PET. The study of brain activity using functional magnetic resonance imaging (fMRI) poses an additional set of problems, both from an acquisition and processing standpoint, to those that have been comprehensively addressed for PET in previous chapters. The statistical and image processing framework for fMRI has been laid out in some of those chapters. In this chapter we will discuss the particular issues, in both imaging physics and physiology, which pertain to the design of fMRI experiments; and how we go about carrying out the data analysis in the context of the hypothesis which we are testing. Much of this work is ongoing in this laboratory and many others. Nevertheless we will review the substantial progress made in these areas and highlight some outstanding issues which need to be resolved in order for fMRI to become a routine tool.We can group this work into three broad categories.

OBJECTIVE
Positron emission tomography was used to investigate the neural substrates of normal human emotional and their dependence on the types of emotional stimulus.

METHOD
Twelve healthy female subjects underwent 12 measurements of regional brain activity following the intravenous bolus administration of [15O]H2O as they alternated between emotion-generating and control film and recall tasks. Automated image analysis techniques were used to characterize and compare the increases in regional brain activity associated with the emotional response to complex visual (film) and cognitive (recall) stimuli.

RESULTS
Film- and recall-generated emotion were each associated with significantly increased activity in the vicinity of the medial prefrontal cortex and thalamus, suggesting that these regions participate in aspects of emotion that do not depend on the nature of the emotional stimulus. Film-generated emotion was associated with significantly greater increases in activity bilaterally in the occipitotemporparietal cortex, lateral cerebellum, hypothalamus, and a region that includes the anterior temporal cortex, amygdala, and hippocampal formation, suggesting that these regions participate in the emotional response to certain exteroceptive sensory stimuli. Recall-generated sadness was associated with significantly greater increases in activity in the vicinity of the anterior insular cortex, suggesting that this region participates in the emotional response to potentially distressing cognitive or interoceptive sensory stimuli.

While this study should be considered preliminary, it identified brain regions that participate in externally and internally generated human emotion.

Neuroanatomical correlates of externally and internally generated human emotion.

This paper presents a new method for characterizing brain responses in both PET and fMRI data. The aim is to capture the correlations between the scans of an experiment and a set of external predictor variables that are thought to affect the scans, such as type, intensity, or shape of stimulus response. Its main feature is a Canonical Variates Analysis (CVA) of the estimated effects of the predictors from a multivariate linear model (MLM). The advantage of this over current methods is that temporal correlations can be incorporated into the model, making the MLM method suitable for fMRI as well as PET data. Moreover, tests for the presence of any correlation, and inference about the number of canonical variates needed to capture that correlation, can be based on standard multivariate statistics, rather than simulations. When applied to an fMRI data set previously analyzed by another CVA method, the MLM method reveals a pattern of responses that is closer to that detected in an earlier non-CVA analysis.

Characterizing the Response of PET and fMRI Data Using Multivariate Linear Models

Non-invasive physiological measures of in vivo brain function, derived from positron emission tomography (PET) and functional magnetic resonance (fMRI), are now standard tools in cognitive neuroscience. These techniques provide a powerful context for addressing critical questions regarding both the localization and mechanisms of higher brain functions. A general overview of the history and development of imaging techniques in relation to cognitive science is that of Posner & Raichle (1994). The conceptual background and methodological approaches available for neurobiological based psychiatric research, in conjunction with functional imaging, provides the focus for the present review. Major psychiatric disorders, such as schizophrenia and depression, represent disturbances at the highest level of brain function. Providing a neurobiological account of these conditions presents the most formidable problem in clinical neuroscience. Questions posed by neurobiological perspectives on psychiatric disorders are necessarily embedded in theoretical assumptions about how we think that the brain works. From this, it follows that an important limiting factor in any neurobiological account of psychiatric disease is the stage of development and theoretical conceptualization of brain function in general.

Clinical validation of statistical parametric mapping 1995 for the assessment of 18F-FDG PET brain scans in individual patients.

We used positron emission tomography (PET) to measure brain activity in healthy control subjects and unmedicated patients with schizophrenia. Subjects were scanned in the context of a combined psychological and pharmacological challenge, and we examined the effects of apomorphine, a drug acting on dopamine receptors, on brain systems engaged by a paced verbal fluency task. This factorial design enabled comparison of control subjects and schizophrenics in terms of the activations engendered by the cognitive task and the pharmacological challenge and the interaction of the two. We report a failure of cognitive task-related activation in anterior cingulate cortex and of task-related deactivation in the left superior temporal gyrus in the schizophrenic subjects. Compared with controls, the impaired cingulate activation was significantly reversed by apomorphine. Additionally, there was a trend for the abnormal fronto-temporal pattern of activation in schizophrenic subjects to be normalized by the drug. Overall, in schizophrenic subjects the effect of apomorphine, which we interpret in terms of a net dopaminergic antagonism, was to modify the brain activity, making the pattern more akin to that seen in control subjects. The results indicate both a regionally specific abnormality of brain function in schizophrenia and an abnormal pattern of fronto-temporal interactions.

Local and Distributed Effects of Apomorphine on Fronto-Temporal Function in Acute Unmedicated Schizophrenia

P449 The role of rostral supplementary motor area and basal ganglia in motor sequence control

Fully three-dimensional nonlinear spatial normalisation: A new approach

In neuroimaging, functional mapping usually implies mapping function into an anatomical space, for example, using statistical parametric mapping to identify activation foci, or the characterization of distributed changes with spatial modes (eigenimages or principal components) (Friston et al., 1993a). This article is about a complementary approach, namely, mapping anatomy into a functional space. We describe a simple variant of multidimensional scaling (principal coordinates analysis; Gower, 1966) that uses functional connectivity as its metric. The scaling transformation maps anatomy into a functional space. The topography, or proximity relationships, in this space embody the functional connectivity among brain regions. The higher the functional connectivity, the closer the regions. Functional connectivity is defined here as the correlation between remote neurophysiological events. The technique represents a descriptive characterization of anatomically distributed changes in the brain that reveals the structure of corticocortical interactions in terms of functional correlations. To illustrate the approach we have analyzed data from normal subjects and schizophrenic patients obtained with PET during the performance of word generation tasks. In particular, we focus on prefrontotemporal integration in normal subjects and show that, in schizophrenia, the left temporal regions and prefrontal cortex evidence abnormal functional connectivity.

Functional topography: multidimensional scaling and functional connectivity in the brain.

Testing for activations using both signal peak intensity and spatial extent

Correlation between grey matter volume and syndrome scores in schizophrenia: A data-led approach

This paper concerns the spatial and intensity transformations that are required to adjust for the confounding effects of subject movement during functional MRI (fMRI) activation studies. An approach is presented that models, and removes, movement‐related artifacts from fMRI time‐series. This approach is predicated on the observation that movement‐related effects are extant even after perfect realignment. Movement‐related effects can be divided into those that are a function of position of the object in the frame of reference of the scanner and those that are due to movement in previous scans. This second component depends on the history of excitation experienced by spins in a small volume and consequent differences in local saturation. The spin excitation history thus will itself be a function of previous positions, suggesting an autoregression‐moving average model for the effects of previous displacements on the current signal. A model is described as well as the adjustments for movement‐related components that ensue. The empirical analyses suggest that (in extreme situations) over 90% of fMRI signal can be attributed to movement, and that this artifactual component can be successfully removed.

Analysis of fMRI data using the general linear statistical model

The intention of our study was to compare functional magnetic resonance imaging (fMRI) with positron emission tomography (PET). We used the same force-related motor paradigm for both techniques, which allows for quantification of stimulus intensity. Regional cerebral blood flow (rCBF) was determined with PET in six male subjects (age 30 +/- 3) using the slow bolus injection technique and oxygen-15-labeled water. Scans were collected during six different conditions: at rest and during repetitive Morse key press at 1 Hz, with the right index finger at a range of different forces. In a second series of experiments fMRI data were acquired under similar conditions in six volunteers in a single slice parallel to and 51 +/- 3 mm dorsal to the anterior and posterior commissure (AC-PC). A conventional 1.5-T clinical magnetic resonance (MR) system and the FLASH technique were used. The data obtained in both series of experiments were subjected to the same statistical analyses. Statistical parametric maps (SPM) were generated by two different approaches: a correlation between peak force and rCBF or fMRI signal and using a categorical comparison of force exerted with rest. SPMs were coregistered with anatomical MR images. PET and fMRI measurements demonstrated activation in the primary motor cortex (M1) and posterior supplementary motor cortex in all subjects. Correlation analysis demonstrated foci in the M1 in four subjects with PET and in only one subject with fMRI. Locations of activation peaks differed by 2 to 8 mm between imaging methods. The relationship between fMRI signal or rCBF and peak force was logarithmic. The maximum increase in fMRI signal was 5.0% +/- 0.9 at 60% of the maximum voluntary contraction while the corresponding increase in rCBF was 13.7% +/- 1.2. The ratio of percentage rCBF change to percentage fMRI signal change was very similar across all force levels. The high degree of correspondence between PET and fMRI data provides good cross-validation for the two techniques.

Quantitative Comparison of Functional Magnetic Resonance Imaging with Positron Emission Tomography Using a Force-Related Paradigm

Robust smoothness estimation in statistical parametric maps using residuals from the general linear model

Methods for analysing functional imaging data have evolved rapidly over the last ten years. Standardized techniques based on formal mathematical and statistical theory and rigorous empirical validation have been proposed to facilitate comparisons of biological results between laboratories. This paper examines an image analysis technique that appears to identify unexpectedly large numbers of activated brain areas for the data collected. It concludes that the method may not adequately control for false positives, rendering interpretation of the functional anatomy difficult.

A Critique of a New Analysis Proposed for Functional Neuroimaging

In this paper we present a critique of pure insertion. Pure insertion represents an implicit assumption behind many (but not all) studies that employ cognitive subtraction. The main contention is that pure insertion is not valid in relation to the neuronal instantiation of cognitive processes. Pure insertion asserts that there are no interactions among the cognitive components of a task. It is possible to evaluate and refute this assumption by testing explicitly for interactions using factorial experimental designs. It is proposed that factorial designs are more powerful than subtraction designs in characterizing cognitive neuroanatomy, precisely because they allow for interactions and eschew notions like pure insertion. In particular we suggest that the effect of a cognitive component (i.e., an effect that is independent of other components) is best captured by the main (activation) effect of that component and that the integration among components (i.e., the expression of one cognitive process in the context of another) can be assessed with the interaction terms. In this framework a complete characterization of cognitive neuroanatomy includes both regionally specific activations and regionally specific interactions. To illustrate our point we have used a factorial experimental design to show that inferotemporal activations, due to object recognition, are profoundly modulated by phonological retrieval of the object's name. This interaction implicates the inferotemporal regions in phonological retrieval, during object naming, despite the fact that phonological retrieval does not, by itself, activate this region.

Cross-validation of FMRI and PET using a quantitative force-related paradigm

Parametric study designs can reveal information about the relationship between a study parameter (e.g., word presentation rate) and regional cerebral blood flow (rCBF) in functional imaging. The brain's responses in relation to study parameters might be nonlinear, therefore the (linear) correlation coefficient as often used in the analysis of parametric studies might not be a proper characterization. We present a noninteractive method, which fits nonlinear functions of stimulus or task parameters to rCBF responses, using second-order polynomial expansions. This technique is implemented in the context of the general linear model and statistical parametric mapping. We also consider the usefulness of statistical inferences, based on F fields, about similarities and differences of these nonlinear responses in different groups. This approach is illustrated with a 12-run H215O PET activation study using an auditory paradigm of increasing word presentation rates. A patient who had recovered from severe aphasia and a normal control were studied. We demonstrate the ability of this new technique to identify brain regions where rCBF is closely related to increasing word presentation rate in both subjects without constraining the nature of this relationship and where these nonlinear responses differ.

PET activation studies are performed widely to study human brain function. The question of reproducibility, reliability, and comparability of the results of such experiments has never been addressed on a large scale. Recently, 12 European PET centers performed the same cognitive activation experiment in a European Union funded concerted action. The experiment involved a standardized and validated cross-lingual experimental and control task involving verbal fluency. Each center contributed at least 6 subjects. In total there were 77 subjects and 247 scans in each of the two conditions, giving 494 scans in total. We have analyzed each center's dataset and pooled datasets using statistical parametric mapping. We present results that address the consistency of these analyses, discuss the factors that influence their sensitivity, and comment on a number of related methodological issues. We used a MANOVA to test for center, condition, and centre by condition effects and found a strong condition and center effect and weaker interactions. The main effect determining reproducibility was the overall sensitivity of the experiment, to which the scanner and number of scans contribute in a major way, with a marked advantage for 3D scanners and a large field of view. An important conclusion is that data from different centers can be pooled to improve the reliability of results, which is of particular importance for studies in patients with rare conditions.

Reproducibility of PET Activation Studies: Lessons from a Multi-Center European Experiment EU Concerted Action on Functional Imaging

This paper is about detecting activations in statistical parametric maps and considers the relative sensitivity of a nested hierarchy of tests that we have framed in terms of the level of inference (voxel level, cluster level, and set level). These tests are based on the probability of obtaining c, or more, clusters with k, or more, voxels, above a threshold u. This probability has a reasonably simple form and is derived using distributional approximations from the theory of Gaussian fields. The most important contribution of this work is the notion of set-level inference. Set-level inference refers to the statistical inference that the number of clusters comprising an observed activation profile is highly unlikely to have occurred by chance. This inference pertains to the set of activations reaching criteria and represents a new way of assigning P values to distributed effects. Cluster-level inferences are a special case of set-level inferences, which obtain when the number of clusters c = 1. Similarly voxel-level inferences are special cases of cluster-level inferences that result when the cluster can be very small (i.e., k = 0). Using a theoretical power analysis of distributed activations, we observed that set-level inferences are generally more powerful than cluster-level inferences and that cluster-level inferences are generally more powerful than voxel-level inferences. The price paid for this increased sensitivity is reduced localizing power: Voxel-level tests permit individual voxels to be identified as significant, whereas cluster-and set-level inferences only allow clusters or sets of clusters to be so identified. For all levels of inference the spatial size of the underlying signal f (relative to resolution) determines the most powerful thresholds to adopt. For set-level inferences if f is large (e.g., fMRI) then the optimum extent threshold should be greater than the expected number of voxels for each cluster. If f is small (e.g., PET) the extent threshold should be small. We envisage that set-level inferences will find a role in making statistical inferences about distributed activations, particularly in fMRI.

Detecting Activations in PET and fMRI: Levels of Inference and Power

By correlating rCBF with rate of presentation of tones we used PET to identify brain regions where auditory signals elicited a transient neural response. In one condition volunteers were asked to attend to the tones and ignore visual signals, while in the second condition they were asked to attend to the visual signals and ignore the tones. Activity in primary auditory cortex and adjacent areas was strongly correlated with rate of tone presentation, but this relationship was not affected by the direction of attention. In only one area, the right midthalamus, was the response to tones modulated by attention. In this area responses to tones occurred when attention was directed to sound, but not when attention was directed to visual stimuli. There is considerable evidence that the EEG evoked response to tones (N100/Nd response) is strongly modulated by attention and arises in auditory cortex. The ERP is the sum of activity from many sources. The amplitude of this response reflects not only the amount of activity in these sources, but also the degree of synchrony between them. The difference between these typical ERP results and our result from PET could be resolved if we assume that, in our paradigm, attention did not increase the amount of neural activity in auditory cortex, but rather the degree of synchrony between many sources. The signal in the thalamus, which we observed only when volunteers were attending to the tones, might provide the basis for this synchrony.

The Role of the Thalamus in “Top Down” Modulation of Attention to Sound

This paper presents a multivariate analysis of evoked responses and their spatiotemporal dynamics as measured with electro- or magnetoencephalography. This analysis uses standard techniques (ManCova) to make possible statistical inference about differential responses, after the data have been transformed using singular value decomposition. The generality of this approach is limited only by the assumptions implicit in the general linear model and can range from simple analyses like Hotelling's T2 test (in comparing evoked responses among different conditions) to complex analyses of a multivariate regression type (e.g., characterizing the response components associated with a behavioral or psychophysical parameter). To illustrate the technique we have characterized time-dependent changes (both within and between trials) in magnetic fields, evoked by self-paced movements. Our illustrative analysis showed that movement-evoked components were less prone to adaptation than premovement components, suggesting that functionally distinct (preparatory and early executive) biomagnetic signals show differential adaptation.

We objectively delineated the extent of abnormalities in central benzodiazepine receptor (cBZR) binding using [11C]flumazenil (FMZ)-PET and high resolution volumetric MRI in 12 patients with mesial temporal lobe epilepsy (mTLE) associated with unilateral hippocampal sclerosis, who underwent presurgical evaluation and subsequent temporal lobe surgery. We compared parametric 3D-images of regional cerebral [11C]FMZ volume of distribution (Vd) obtained from individuals and groups of patients with [11C]FMZ-Vd from a group of 17 healthy controls using statistical parametric mapping (SPM). The [12C]FMZ-Vd was significantly reduced (P < 0.001) in the affected hippocampus in the group of 12 patients with unilateral hippocampal sclerosis. Analysis of individual patients reflected the group finding and there was no significant abnormality of cBZR binding outside the hippocampus in any patient. We conclude that SPM is an useful objective method for detecting changes in regional cerebral [11C]FMZ binding and that in patients with mTLE and unilateral hippocampal sclerosis reduction of cBZR binding is restricted to the area of hippocampal sclerosis with no abnormalities being detected in the temporal neocortex or elsewhere in the neocortex.

Cerebral benzodiazepine receptors in hippocampal sclerosis. An objective in vivo analysis.

Assessment of 18F-FDG PET brain scans in individual patients with statistical parametric mapping. A clinical validation

CHAPTER 52 – The Analysis of Brain PET Radioligand Displacement Studies

This chapter addresses the idea that schizophrenia is a 'disconnection syndrome' from a theoretical and computational perspective. The distinction between anatomical and functional connectivity is reviewed and used as a framework to introduce empirical and computational evidence that schizophrenia involves, at some level, a disintegration of neuronal interactions. The chapter concludes with an example of computational neuroscience that relates observations on the dimensional complexity of neuronal dynamics in schizophrenia to the disconnection hypothesis.

Phonological retrieval and semantic processing during naming tasks

The neural systems involved in hearing and repeating single words were investigated in a series of experiments using PET. Neuropsychological and psycholinguistic studies implicate the involvement of posterior and anterior left perisylvian regions (Wernicke's and Broca's areas). Although previous functional neuroimaging studies have consistently shown activation of Wernicke's area, there has been only variable implication of Broca's area. This study demonstrates that Broca's area is involved in both auditory word perception and repetition but activation is dependent on task (greater during repetition than hearing) and stimulus presentation (greater when hearing words at a slow rate). The peak of frontal activation in response to hearing words is anterior to that associated with repeating words; the former is probably located in Brodmann's area 45, the latter in Brodmann's area 44 and the adjacent precentral sulcus. As Broca's area activation is more subtle and complex than that in Wernicke's area during these tasks, the likelihood of observing it is influenced by both the study design and the image analysis technique employed. As a secondary outcome from the study, the response of bilateral auditory association cortex to 'own voice' during repetition was shown to be the same as when listening to "other voice' from a prerecorded tape.

Hearing and saying. The functional neuro-anatomy of auditory word processing.

In this paper we present a general multivariate approach to the analysis of functional imaging studies. This analysis uses standard multivariate techniques to make statistical inferences about activation effects and to describe the important features of these effects. More specifically, the proposed analysis uses multivariate analysis of covariance (ManCova) with Wilk's lambda to test for specific effects of interest (e.g., differences among activation conditions), and canonical variates analysis (CVA) to characterize differential responses in terms of distributed brain systems. The data are subject to ManCova after transformation using their principal components or eigenimages. After significance of the activation effect has been assessed, underlying changes are described in terms of canonical images. Canonical images are like eigenimages but take explicit account of the effects of error or noise. The generality of this approach is assured by the general linear model used in the ManCova. The design and inferences sought are embodied in the design matrix and can, in principle, accommodate most parametric statistical analyses. This multivariate analysis may provide a statistical approach to PET activation studies that 1) complements univariate approaches like statistical parametric mapping, and 2) may facilitate the extension of existing multivariate techniques, like the scaled subprofile model and eigenimage analysis, to include hypothesis testing and statistical inference. © 1996 Wiley‐Liss, Inc.

In a functional imaging study of cued paired associate retrieval, in which the strength of association between pair members was systematically varied, we predicted increased right frontal activity as a function of weakening semantic linkage. An initial univariate analysis found the opposite effect, with greater right frontal activity during recall of strongly linked paired associates. This unexpected result led us to perform a multivariate analysis of covariance (MANCOVA), an approach which proved more informative. This analysis showed that the most significant source of task-related variance was accounted for by a nonlinear relationship not predicted by the prior hypothesis and not revealed by the standard univariate approach. This application of the MANCOVA supports the assertion that multivariate analysis can provide an important adjunct to univariate approaches like statistical parametric mapping (SPM). New perspectives engendered by the MANCOVA still allow for statistical inference but are not constrained by explicit hypotheses about specific task-dependent effects.

Is Multivariate Analysis of PET Data More Revealing Than the Univariate Approach? Evidence from a Study of Episodic Memory Retrieval

Statistical parametric analysis of F-18-fluorodopa PET in early Parkinson's disease

Central processing of increasingly complex learned finger sequences: Correlational analysis of 3D H-2 O-15 PET data

We present a unified statistical theory for assessing the significance of apparent signal observed in noisy difference images. The results are usable in a wide range of applications, including fMRI, but are discussed with particular reference to PET images which represent changes in cerebral blood flow elicited by a specific cognitive or sensorimotor task. Our main result is an estimate of the P‐value for local maxima of Gaussian, t, χ2 and F fields over search regions of any shape or size in any number of dimensions. This unifies the P‐values for large search areas in 2‐D (Friston et al. [1991]: J Cereb Blood Flow Metab 11:690–699) large search regions in 3‐D (Worsley et al. [1992]: J Cereb Blood Flow Metab 12:900–918) and the usual uncorrected P‐value at a single pixel or voxel. © 1996 Wiley‐Liss, Inc.

A unified statistical approach for determining significant signals in images of cerebral activation

This positron emission tomography study dissociates the neural correlates of object recognition and naming. Stimuli comprised coloured outline drawings of objects and coloured nonsense shapes. Subjects either viewed or explicitly named objects, similarly they viewed or named the colour of the shapes. Activations common to object and colour naming were identified by contrasting the explicit naming conditions (objects and colours) with the control (viewing) conditions. Activations associated with object recognition were identified by contrasting both object conditions (naming and viewing) with both shape conditions and activations specific to object or colour naming were identified by contrasting object naming (relative to object viewing) with colour naming (relative to shape viewing). The results associate: (i) object recognition with left middle occipital and bilateral anterior temporal cortices; (ii) modality independent naming with left posterior basal temporal lobe and the left prefrontal cortex; (iii) areas specific to object naming with left temporal extrasylvian regions, left anterior insula and right cerebellum; and (iv) areas specific to colour naming with left posterior lingual and fusiform gyri and midline cerebellum. These results are discussed in relation to previous neuroimaging and neuropsychological findings.

CHAPTER 69 – Smoothness Variance Estimate and Its Effects on Probability Values in Statistical Parametric Maps

Dopaminergic modulation of abnormal brain activations in untreated schizophrenia

The effect of the muscarinic antagonist scopolamine on regional cerebral blood flow during the performance of a memory task

This paper presents a general approach to the analysis of functional MRI time-series from one or more subjects. The approach is predicated on an extension of the general linear model that allows for correlations between error terms due to physiological noise or correlations that ensue after temporal smoothing. This extension uses the effective degrees of freedom associated with the error term. The effective degrees of freedom are a simple function of the number of scans and the temporal auto correlation function. A specific form for the latter can be assumed if the data are smoothed, in time, to accentuate hemodynamic responses with a neural basis. This assumption leads to an expedient implementation of a flexible statistical framework. The importance of this small extension is that, in contradistinction to our previous approach, any parametric statistical analysis can be implemented. We demonstrate this point using a multiple regression analysis that tests for effects of interest (activations due to word generation), while taking explicit account of some obvious confounds.

Brain PET radioligand displacement studies: modelling 11-C flumazenil displacement by i.v. midazolam in man

In this paper we present a multivariate analysis of evoked hemodynamic responses and their spatiotemporal dynamics as measured with fast fMRI. This analysis uses standard multivariate statistics (MANCOVA) and the general linear model to make inferences about effects of interest and canonical variates analysis (CVA) to describe the important features of these effects. We have used these techniques to characterize the form of hemodynamic transients that are evoked during a cognitive or sensorimotor task. In particular we do not assume that the neural or hemodynamic response reaches some "steady state" but acknowledge that these physiological changes could show profound task-dependent adaptation and time-dependent changes during the task. To address this issue we have modeled hemodynamic responses using appropriate temporal basis functions and estimated their exact form within the general linear model using MANCOVA. We do not propose that this analysis is a particularly powerful way to make inferences about functional specialization (or more generally functional anatomy) because it only provides statistical inferences about the distributed (whole brain) responses evoked by different conditions. However, its application to characterizing the temporal aspects of evoked hemodynamic responses reveals some compelling and somewhat unexpected perspectives on transient but stereotyped responses to changes in cognitive or sensorimotor processing. The most remarkable observation is that these responses can be biphasic and show profound differences in their form depending on the extant task or condition. Furthermore these differences can be seen in the absence of changes in mean signal.

Characterizing Dynamic Brain Responses with fMRI: A Multivariate Approach

Background This study examined the pattern of cerebral blood flow observed in chronic schizophrenic patients while they performed a paced verbal fluency task. Such tasks engage a distributed brain system associated with willed action. Since willed action is impaired in many chronic schizophrenic patients we hypothesised that task performance would be associated with an abnormal pattern of blood flow. Method Positron emission tomography (PET) was applied to 18 chronic schizophrenic patients stratified into three groups on the basis of verbal fluency performance and current symptoms. Regional cerebral blood flow (rCBF) was measured while the patients performed (a) verbal fluency, (b) word categorisation, and (c) word repetition. Results were compared with six normal controls matched for age, sex and premorbid IQ. Analysis was restricted to six brain regions previously identified in studies of normal volunteers. Results In five brain areas, including the left dorsolateral prefrontal cortex, the patients showed the same pattern of activation as control subjects. However, in the left superior temporal cortex, all patient groups failed to show the normal decrease in blood flow when verbal fluency was compared with word repetition. Conclusion These observations suggest that (a) chronic schizophrenic patients can show a normal magnitude of frontal activation when matched for performance with controls, and (b) they fail to show the expected reductions of activity in the superior temporal cortex. This latter result may reflect abnormal functional connectivity between frontal and temporal cortex.

Regional Brain Activity in Chronic Schizophrenic Patients during the Performance of a Verbal Fluency Task

We describe a novel technique for characterizing regional cerebral gray and white matter differences in structural magnetic resonance images by the application of methods derived from functional imaging. The technique involves automatic scalp-editing of images followed by segmentation, smoothing, and spatial normalization to a symmetrical template brain in stereotactic Talairach space. The basic idea is (i) to convert structural magnetic resonance image data into spatially normalized images of gray (or white) matter density, effected by segmenting the images and smoothing, and then (ii) to use Statistical Parametric Mapping to make inferences about the relationship between gray (or white) matter density and symptoms (or other pathophysiological measures) in a regionally specific fashion. Because the whole brain sum of gray (or white) matter indices is treated as a confound, the analysis reduces to a characterization of relative gray (or white) matter density on a voxel by voxel basis. We suggest that this is a powerful approach to voxel-based statistical anatomy. Using the technique, we constructed maps of the regional cerebral gray and white matter density correlates of syndrome scores (distinct psychotic symptoms) in a group of 15 schizophrenic patients. There was a negative correlation between the score for the reality distortion syndrome and regional gray matter density in the left superior temporal lobe (P = 0.01) and regional white matter density in the corpus callosum (P < 0.001). These abnormalities may be associated with functional changes predisposing to auditory hallucinations and delusions. This method permits the detection of structural differences within the entire brain (as opposed to selected regions of interest) and may be of value in the investigation of structural gray and white matter abnormalities in a variety of brain diseases.

A Voxel-Based Method for the Statistical Analysis of Gray and White Matter Density Applied to Schizophrenia

Commentary and Opinion: II. Statistical Parametric Mapping: Ontology and Current Issues

Dopaminergic modulation of impaired cognitive activation in the anterior cingulate cortex in schizophrenia

Medial frontal lobe overactivity in reality distortion syndrome during word generation: A pet study

Objective The smoothness parameter that characterises the spatial dependence of pixel values in functional brain images is usually estimated empirically from the data. Since this parameter is essential for the assessment of significant changes in brain activity, it is important to know (a) the variance of its estimator and (b) how this variability affects the results of the ensuing statistical analysis. Materials and Methods In this article, we derive an approximate expression for the variance of the smoothness estimator and investigate the effects of this variability on assessing the significance of cerebral activation in statistical parametric maps using a verbal fluency PET activation experiment. Results Our results suggest that, for p values around 0.05, the variability in the p value (due to smoothness estimation) is ∼20%. Conclusion The effect of the assessment of the spatial dependency of the data is far from being negligible, and this suggests a more comprehensive methodology for functional imaging than the one used so far. This work provides a simple tool for taking into account this effect. Index Terms Emission computed tomography, physics and instrumentation—Maps and mapping—Emission computed tomography.

Estimating Smoothness in Statistical Parametric Maps: Variability of p Values

Most approaches to detecting changes in functional brain images assume activations are focal or very localized. However the brain’s response to cognitive or sensorimotor challenge may be spatially or anatomically distributed. In this paper we consider the usefulness of a test based on the mean sum of squares of statistical parametric maps. The performance of this test is evaluated using simulated and real data, and compared to the γ2 test (Fox et al., 1989), a test proposed by Friston et al. (1990) on the size of the activated region, and a focal activation test based on the intensity of local maxima (Friston et al., 1991; Worsley et al., 1992). We demonstrate that the mean sum of squares test is more sensitive to non-focal signals and propose that it could be used to complement approaches that are more sensitive to focal activations.

This paper concerns the spatial and intensity transformations that map one image onto another. We present a general technique that facilitates nonlinear spatial (stereotactic) normalization and image realignment. This technique minimizes the sum of squares between two images following nonlinear spatial deformations and transformations of the voxel (intensity) values. The spatial and intensity transformations are obtained simultaneously, and explicitly, using a least squares solution and a series of linearising devices. The approach is completely noninteractive (automatic), nonlinear, and noniterative. It can be applied in any number of dimensions.

A recent letter to Nature (Vaadia et al. Nature, Lond. 373, 515-518 (1995)) presented compelling results concerning neuronal interactions in monkey cortex. Vaadia et al. made two fundamental points: (i) it is possible that cortical function is mediated by dynamic modulation of coherent firing among neurons; and (ii) these time-dependent changes in correlations can emerge without modulation of firing rates. These observations have severe implications for models of neural coding and empirical approaches that are based on firing rates (e. g. neuroimaging). This communication presents a simpler explanation for the results presented in Vaadia et al., by noting they are consistent with the correlated expression of stereotyped neuronal transients following (or preceding) a salient event. This re-formulation is important because: (i) correlations measured in terms of transients are not time-dependent, allowing prevailing models of neural coding to be ‘reinstated’; and (ii) it suggests a powerful analysis based on singular value decomposition of firing rates.

We review the evidence of pathophysiological changes in the prefrontal and temporal cortices of schizophrenic subjects and of abnormal integration of the physiological dynamics in these two regions. The argument we develop is that some schizophrenic phenomena are best understood in terms of abnormal interactions between different areas, not only at the levels of physiology and functional anatomy, but at the level of cognitive and sensorimotor functioning. We discuss recent functional imaging evidence suggesting abnormal prefronto-temporal interactions in relation to a psychological analysis of experiential symptoms in schizophrenia. Cortico-cortical interactions have been assessed in terms of functional connectivity and eigenimages, using time series of neurophysiological data obtained with positron emission tomography. The results of these analyses suggest that there is a profound disruption of large-scale prefronto-temporal interactions in schizophrenia. These disruptions are particularly relevant if one considers that many positive symptoms of schizophrenia reflect a failure to integrate intrinsically generated behaviour and concurrent perception.

Local changes in cerebral hemodynamics are observed within a few hundred milliseconds of changes in neural activity. If hemodynamic responses are mediated by passive diffusion of a spatial signal (from the site of neural activity to the microvessels) then the dynamics of the response suggest a lower limit on the signal's apparent diffusion and elimination. The aim of this work was to estimate these limits and narrow the field of possible candidate substances.

Regulation of rCBF by diffusible signals: An analysis of constraints on diffusion and elimination

Friston et al. (1995, NeuroImage 2:45-53) presented a method for detecting activations in fMRI time-series based on the general linear model and a heuristic analysis of the effective degrees of freedom. In this communication we present corrected results that replace those of the previous paper and solve the same problem without recourse to heuristic arguments. Specifically we introduce a proper and unbiased estimator for the error terms and provide a more generally correct expression for the effective degrees of freedom. The previous estimates of error variance were biased and, in some instances, could have led to a 10-20% overestimate of Z values. Although the previous results are almost correct for the random regressors chosen for validation, the present theoretical results are exact for any covariate or waveform. We comment on some aspects of experimental design and data analysis, in the light of the theoretical framework discussed here.

We describe an implementation of the general linear model that facilitates the characterization of evoked hemodynamic responses to sensorimotor or cognitive processing, when the exact form of these responses is not known. The importance of this approach is that one can test for differential responses among tasks that may elude more conventional analyses. In particular, we suppose that an evoked response has early and late components and that a differential response may involve (i) both components to the same degree, as in a conventional "activation" or (ii) differential expression of the early and late components in two tasks, as might be seen in differential adaptation, or differences associated with the tasks (e.g., requiring and not requiring sustained attention). Using this approach we were able to demonstrate that the anterior cingulate differentiates, in terms of its response, between two motor tasks that did and did not require sustained attention. This differential response was observed even though there was no classical "activation" (i.e., there was no difference in the mean activity associated with the two conditions). It is suggested that these demonstration results point to the possibility of making greater use of the temporal resolution afforded by fast fMRI techniques.

P-11-33 The analysis of brain pet radioligand displacement studies

This work addresses the complexity of neuronal interactions, the nature of this complexity and how it can be characterised in real neurophysiological processes. A measure of complexity has been introduced recently (Tononi et al. [1994]: Proc Natl Acad Sci USA 91:5033–5037) that is sensitive to the joint constraints imposed by two principles of brain organisation: functional segregation and functional integration. Functional segregation implies that the dynamics of a cortical area should reflect the multidimensional attributes for which that area is specialised (in other words, regional dynamics should show a relatively high entropy). Conversely, functional integration implies a distributed and divergent influence of every cortical area on the remaining areas (i.e., the overall dynamics should show a low entropy). Our measure is based on the profile of entropies of different sized regions of the brain. Complexity is high when smaller regions have (on average) a relatively high entropy with respect to the entropy of the whole system. This measure is equivalent to the (average) mutual information between all small regions and the rest of the system in question.

Most approaches to detecting changes in functional brain images assume that activations are focal or very localized. However, the brain's response to cognitive of sensorimotor challenge may be spatially or anatomically distributed. In this paper we consider the usefulness of a test based on the mean sum of squares of statistical parametric maps. The performance of this test is evaluated using simulated and real data and is compared to the gamma 2 test, a test of the size of the activated region, and a focal activation test based on the intensity of local maxima. We demonstrate that the mean sum of squares test is more sensitive to nonfocal signals and propose that it could be used to complement approaches that are more sensitive to focal activations.

In order to study brain activity associated with “incidental” cognitive processing, regional cerebral blood flow (rCBF) was measured in six volunteers while they monitored a sequence of pseudo‐words (e.g., FLOPE) for the rare occasions when the letters were displayed in blue rather than white. In the control condition, the same pseudo‐word was presented repeatedly. In one experimental condition all 60 pseudo‐words were different, while in the other there were 18 repetitions. Although it was not necessary to “read” the pseudo‐words to perform the monitoring task, subsequent forced choice recognition memory for these stimuli was significantly greater than chance. Furthermore, there were significant differences in blood flow between the three conditions. When different pseudo‐words were presented there was significantly greater activity in brain areas concerned with shape and object identity (extrastriate cortex bilaterally), with visual word form (left inferior temporal gyrus), and with articulatory word form (Broca's area) even though none of this information about the pseudo‐words was needed for performance of the monitoring task. In the condition in which some of the words were repeated, there was significantly reduced activity in the right lingual gyrus. This area may therefore be a possible anatomical locus for repetition priming with verbal stimuli. These results indicate the importance of taking into account incidental processing when designing tasks for functional imaging experiments. © 1995 Wiley‐Liss, Inc.

Regional cerebral activity associated with the incidental processing of pseudo‐words

Activation of Human Hippocampal Formation During Memory for Faces: A Pet Study

A pet study of obligate carriers of the predisposition to schizophrenia

Abnormal frontotemporal interactions in patients with schizophrenia

The most established functional MR imaging technique for activation studies relies on a T2*-weighted contrast. This signal arises primarily from a blood oxygen level dependent contrast generated by an imbalance between the increase in regional cerebral blood flow and oxygen metabolism in the brain during activation. As predicted by theory, the percentage signal changes observed in functional MR imaging experiments are considerably smaller than those detected by positron emission tomography, which directly measures regional cerebral blood flow as an index of neuronal activity. Cross-validation of functional MR imaging with an established technique such as positron emission tomography would be extremely valuable for determining the correlation between functional MR image signal change and regional cerebral blood flow change and for assessing the sensitivity of the functional MR imaging technique. The authors report on such cross-validation experiments in three subjects challenged with a verbal working memory task and show that satisfactory replication of positron emission tomography results with functional MR imaging was achieved in two subjects. Limitations owing to magnetic field strength used and single-slice sampling may have contributed to the lack of signal detection in the case where no reliable activation pattern was detected with functional MR imaging.

Functional MR imaging correlations with positron emission tomography. Initial experience using a cognitive activation paradigm on verbal working memory.

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The localised PET cerebral correlates of the painful experience in the normal human brain have previously been demonstrated. This study examined whether these responses are different in patients with chronic atypical facial pain. The regional cerebral responses to non-painful and painful thermal stimuli in six female patients with atypical facial pain and six matched female controls were studied by taking serial measurements of regional blood flow by PET. Both groups displayed highly significant differences in responses to painful heat compared with non-painful heat in the thalamus, anterior cingulate cortex (area 24), lentiform nucleus, insula, and prefrontal cortex. These structures are closely related to the "medial pain system". The atypical facial pain group had increased blood flow in the anterior cingulate cortex and decreased blood flow in the prefrontal cortex. These findings show the importance of the anterior cingulate cortex and the reciprocal (possibly inhibitory) connections with the prefrontal cortex in the processing of pain in patients with this disorder. A hypothesis is proposed to explain the mechanisms of cognitive and pharmacological manipulation of these pain processes.

Cerebral responses to pain in patients with atypical facial pain measured by positron emission tomography.

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Current approaches to detecting significantly activated regions of cerebral tissue use statistical parametric maps, which are thresholded to render the probability of one or more activated regions of one voxel, or larger, suitably small (e. g., 0.05). We present an approximate analysis giving the probability that one or more activated regions of a specified volume, or larger, could have occurred by chance. These results mean that detecting significant activations no longer depends on a fixed (and high) threshold, but can be effected at any (lower) threshold, in terms of the spatial extent of the activated region. The substantial improvement in sensitivity that ensues is illustrated using a power analysis and a simulated phantom activation study. © 1994 Wiley‐Liss, Inc.

Assessing the significance of focal activations using their spatial extent

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The brain appears to adhere to two principles of functional organization; functional segregation and functional integration. The integration within and between functionally specialized areas is mediated by functional or effective connectivity. The characterization of this sort of connectivity is an important theme in many areas of neuroscience. This article presents one approach that has been used in functional imaging.

Functional and effective connectivity in neuroimaging: A synthesis

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Positron emission tomography measurements of regional cerebral blood flow (rCBF) were performed in normal volunteers during a graded auditory-verbal memory task. Subjects were required to remember and then immediately, and freely, recall a series of auditorily presented word lists varying from two to 13 words in length. Significant regional correlations between rCBF and memory load (word list length) were identified using statistical parametric mapping. Increasing memory load correlated with increasing rCBF in the cerebellar vermis and hemispheres, thalamus bilaterally, the superior and middle frontal gyri bilaterally, anterior insular regions bilaterally, anterior cingulate, precuneus and left and right lateral premotor areas. Increasing memory load also correlated with decreasing rCBF in the left and right superior temporal/insular regions, medial frontal gyrus, Brodmann's area 37 bilaterally, cuneus, inferior parietal lobule bilaterally and the mid-portion of the cingulate cortex. The pattern of rCBF change closely resembled that identified in a previously reported study using a cognitive subtraction paradigm and provides further evidence for a widespread neural system subserving auditory-verbal memory. The patterns of rCBF response suggest that the areas identified are associated with limited capacity processes for encoding and retrieval.

A graded task approach to the functional mapping of brain areas implicated in auditory-verbal memory.

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Reversible cooling experiments in monkey visual cortex have demonstrated that visually driven neuronal activity in V2 depends on feedforward projections from V1, whereas neuronal activity in V1 is modulated by feedback, or reentrant, projections from V2. We present evidence for a homologous asymmetry in reciprocal connections between V1 and V2 in human cortex using physiological measurements obtained with functional MRI. The analysis was based on a nonlinear model of effective connectivity that partitioned the influence that one region exerted over another into an obligatory effect (an effect that depended only on the input) and a modulatory effect (an effect that represented an interaction between input and activity intrinsic to the target region). Using estimates of the modulatory effect we tested two related hypotheses: (1) that V2 would be a major source of modulatory influences on V1; and (2) that the modulatory effects of V2 on V1 would be greater than those of V1 on V2. The first constitutes a hypothesis about the regional or topographic organization of (modulatory) effective connectivity and the second hypothesis directly addresses the functional asymmetry suggested by reversible cooling experiments. The results confirmed that the origins of feedback modulatory effects on V1 were regionally specific and most pronounced in V2. In contrast, feedforward modulatory influences on V1 on V2 were negligible. This apparent asymmetry between feedforward and feedback modulatory interactions was evident in both hemispheres and appears to be a fairly robust feature of nonlinear interactions between striate and extrastriate cortex. © 1995 Wiley‐Liss, Inc.

Characterizing modulatory interactions between areas V1 and V2 in human cortex: A new treatment of functional MRI data

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A method for detecting significant and regionally specific correlations between sensory input and the brain's physiological response, as measured with functional magnetic resonance imaging (MRI), is presented in this paper. The method involves testing for correlations between sensory input and the hemodynamic response after convolving the sensory input with an estimate of the hemodynamic response function. This estimate is obtained without reference to any assumed input. To lend the approach statistical validity, it is brought into the framework of statistical parametric mapping by using a measure of cross‐correlations between sensory input and hemodynamic response that is valid in the presence of intrinsic autocorrelations. These autocorrelations are necessarily present, due to the hemodynamic response function or temporal point spread function. © 1994 Wiley‐Liss, Inc.

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Statistical parametric maps are spatially extended statistical processes that are used to test hypotheses about regionally specific effects in neuroimaging data. The most established sorts of statistical parametric maps (e.g., Friston et al. [1991]: J Cereb Blood Flow Metab 11:690–699; Worsley et al. [1992]: J Cereb Blood Flow Metab 12:900–918) are based on linear models, for example ANCOVA, correlation coefficients and t tests. In the sense that these examples are all special cases of the general linear model it should be possible to implement them (and many others) within a unified framework. We present here a general approach that accomodates most forms of experimental layout and ensuing analysis (designed experiments with fixed effects for factors, covariates and interaction of factors). This approach brings together two well established bodies of theory (the general linear model and the theory of Gaussian fields) to provide a complete and simple framework for the analysis of imaging data.

Statistical parametric maps in functional imaging: A general linear approach

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Positron emission tomography (PET) is a noninvasive radiotracer-based technique which increasingly is being applied to describe the functional anatomy of the human brain in life. It is a technically sophisticated approach to perfusion mapping, and is predicated on the fact that increases and decreases of synaptic activity in the brain are accompanied by appropriate and equivalent changes in local glucose consumption and perfusion (Raichle, 1987; Mata et al. 1980; Fox and Raichle, 1986). The achievable, practical resolution of the scans presently approximates 6 x 6 x 6 mm, which is sufficient to identify focal perfusion changes as little as 2 mm apart if sequential bloodflow maps are compared and hence to permit analysis of functional activation in the brain at the level of maps, networks and systems. It is theoretically possible that technical advances will one day allow some resolution at a cortical modular level. The tracer of perfusion most commonly used is water, labelled with radioactive, positron-emitting oxygen (15O), which has a short 2.1 min half-life. There is some interest in using 15O labelled butanol which has, in theory, certain possible advantages over water as a perfusion tracer. 15O-water can be used to record up to 12 estimations of the distribution of cerebral perfusion at one sitting in normal subjects and is very easy to use. The resultant radiation dose is very small, safe and within international guidelines for the use of radioactivity for research in normal human volunteers (5 mSv).

Functional neuroanatomy of the human brain: positron emission tomography--a new neuroanatomical technique.

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Functional Connectivity: The Principal-Component Analysis of Large (PET) Data Sets

The biological relevance of principal component analysis (PCA) learning algorithms is addressed by: (i) describing a plausible biological mechanism which accounts for the changes in synaptic efficacy implicit in Oja’s ‘Subspace’ algorithm (Int. J. neural Syst. 1, 61 (1989)); and (ii) establishing a potential role for PCA-like mechanisms in the development of functional segregation, PCA learning algorithms comprise an associative Hebbian term and a decay term which interact to find the principal patterns of correlations in the inputs shared by a group of units. We propose that the presynaptic component of this decay could be regulated by retrograde signals that are translocated from the terminal arbors of presynaptic neurons to their cell bodies. This proposal is based on reported studies of structural plasticity in the nervous system. By using simulations we demonstrate that PCA-like mechanisms can eliminate afferent connections whose signals are unrelated to the prevalent pattern of afferent activity. This elimination may be instrumental in refining extrinsic cortico-cortical connections that underlie functional segregation.

Principal component analysis learning algorithms: a neurobiological analysis

A voxel‐based method of measuring the effective connectivity between brain regions is presented. The approach is based on electrophysiological concepts and is applied to neurophysiological data obtained with [positron emission tomography (PET)] functional imaging. Time‐dependent changes in effective connectivity were assessed during a verbal fluency activation paradigm using 12 consecutive measurements of regional cerebral blood flow (rCBF). The changes observed were predicted by an associative (Hebbian) model of plasticity, applied to cortical activity, measured in terms of rCBF. The main finding was, in most regions, a selective enhancement of effective connections from the distributed brain regions exhibiting the dominant pattern of correlated activity. © 1993 Wiley‐Liss, Inc.

Time‐dependent changes in effective connectivity measured with PET

Activation of the human hippocampal formation during auditory-verbal long-term memory function

Fronto-limbic integration in schizophrenia: abnormal functional connectivity measured with PET

Neurophysiological deficits in the left dorsolateral prefrontal cortex (DLPFC) have been described in positron emission tomography studies of schizophrenia and depression. In schizophrenia and depression this deficit has been associated with the syndromes of psychomotor poverty and psychomotor retardation, respectively. Such findings lead to a prediction that DLPFC dysfunction is symptom rather than disease related. This prediction was empirically tested in a retrospective study that pooled data from 40 patients meeting research diagnostic criteria for depression and 30 patients meeting DSM-III R criteria for schizophrenia. The patients were categorised into those with and without poverty of speech, a symptom that is an observable manifestation of psychomotor impairment. The profile of regional cerebral blood flow (rCBF), measured in all subjects under resting conditions, was subsequently compared in these two groups. Patients with poverty of speech had significantly lower rCBF in the left DLFPC. This reduction of rCBF was independent of diagnosis. The findings support the view that the study of symptoms, or symptom clusters, can provide information additional to that of traditional diagnostic systems in the study of the major psychoses.

Dorsolateral prefrontal cortex dysfunction in the major psychoses; symptom or disease specificity?

Synopsis We have previously reported focal abnormalities of regional cerebral blood flow (rCBF) in a group of 33 patients with major depression. This report, on an extended sample of 40 patients who demonstrated identical regional deficits to those previously described, examines the relationships between depressive symptoms and patterns of rCBF. Patients' symptom ratings were subjected to factor analysis, producing a three-factor solution. The scores for these three factors, which corresponded to recognizable dimensions of depressive illness, were then correlated with rCBF. The first factor had high loadings for anxiety and correlated positively with rCBF in the posterior cingulate cortex and inferior parietal lobule bilaterally. The second factor had high loadings for psychomotor retardation and depressed mood and correlated negatively with rCBF in the left dorsolateral prefrontal cortex and left angular gyrus. The third factor had a high loading for cognitive performance and correlated positively with rCBF in the left medial prefrontal cortex. These data indicate that symptomatic specificity may be ascribed to regional functional deficits in major depressive illness.

Regional cerebral blood flow in depression measured by positron emission tomography: the relationship with clinical dimensions

Synopsis Apomorphine, a non-selective dopamine agonist, has been used as a pharmacological probe for investigating central dopaminergic neurotransmission in psychiatric illness. In this study repeated measurements of regional cerebral blood flow (rCBF) were made in normal volunteers before, and after, the administration of apomorphine (5 or 10 μg/kg), or placebo. The difference in rCBF, before and after drug (apomorphine versus placebo), was used to identify brain areas affected by apomorphine. Compared to placebo, both doses of apomorphine increased blood flow in the anterior cingulate cortex. Apomorphine 10 μg/kg also increased prefrontal rCBF (right > left). No decreases in rCBF were noted following either dose of apomorphine. Apomorphine-induced increases of anterior cingulate blood flow might serve as an in vivo index of central dopamine function. Such an approach would complement established neuroendocrine challenge paradigms for investigating central dopamine neurotransmission in psychiatric illness.

The effect of the dopamine agonist, apomorphine, on regional cerebral blood flow in normal volunteers

Positron emission tomography measurements of regional cerebral blood flow (rCBF) were performed in normal volunteers during two auditory--verbal memory tasks: a subspan and supraspan task. The difference in rCBF between tasks was used to identify brain areas/systems involved in auditory--verbal long-term memory. Increases in rCBF were observed in the left and right prefrontal cortex, precuneus and the retrosplenial area of the cingulate gyrus. Decreases in blood flow were centred in the superior temporal gyrus bilaterally. Separate comparisons were also made between each span task and a resting state. Brain regions showing increases in rCBF in these comparisons included the thalamus, left anterior cingulate, right parahippocampal gyrus, cerebellum and the superior temporal gyrus. The brain areas identified in these comparison define a number of the neuroanatomical components of a distributed system for signal processing and storage relevant to auditory--verbal memory function.

Functional mapping of brain areas implicated in auditory--verbal memory function.

We have previously shown bilateral activation of motor pathways and the recruitment of additional motor areas in studies of groups of patients with recovery from motor stroke. We have now deveoloped a new positron emission tomographic technique to measure the changes in regional cerebral blood flow elicated duringsd a motor task in individual patients, relative to the cerebral activatuion found in normal subjects. The patterns of cerebral activation in each of 8 individual patients with capuslar lesion of the pyramidal tract and complete recovery from hemiplegia are described by compression with the pattern found in a representative sample of 10 normal subjects. We found a large ventral extension of the hand field of the contralateral (sensori)motor cortex in all patients with lesions of the posterior limb of the internal capsule. Greater activation than in normal subjects was found in varible combination of the supplementray motor areas, the insula, the frontal operculum, and the paterial cortex. Structures belonging to motor pathways ipsilateral to the recovered limb were also more activated in the patients than in normal subjects. However, additional activation of the ipsilateral (sensori)motor cortex was only found in the 4 patients who exhibited associated movements of the unaffected hand when the recovered hand performed the motor task. We conclude that recovery from motor stroke due to striatocapsular damage is associated with individually different patterns of functional reorganization of the brain. These patterns are dependent on the site of the subcortical lesion and the somatotopicorganization of the pyramidal tract, both of which may determine the precise poetntial for recovery of limb function following this type of brain injury.

Individual patterns of functional reorganization in the human cerebral cortex after capsular infraction

1. The primary objective of this study was to examine in man, how induced changes in global cerebral blood flow (gCBF) affected a regional cerebral blood flow (rCBF) increase resulting from a neural activation task (opening of eyes). A secondary objective was to quantify how such induced changes in gCBF were distributed between representative regions of either predominantly grey matter or white matter. 2. Positron emission tomography with intravenous infusion of H2(15)O, was used to measure gCBF in six normal males. Concomitant measures of rCBF were obtained in three different regions of interest (ROI): a representative area of predominantly grey matter, a representative area of predominantly white matter and an area of visual cortex. 3. Cerebral blood flow was altered by establishing steady‐state changes in PCO2 at a near constant ventilation of approximately 30 l min‐1. The mean PET,CO2 (+/‐ S.D.) levels (mmHg) that resulted were: low, 21.8 +/‐ 1.8; normal, 39.8 +/‐ 1.0, and high, 54.8 +/‐ 1.2. The normal and high levels were obtained by adding appropriate amounts of CO2 to the inspirate. The corresponding mean gCBF levels across all six subjects with eyes closed were: low, 24.2 +/‐ 4.6; normal, 37.2 +/‐ 3.9 and high, 66.8 +/‐ 7.6 ml min‐1 dl‐1. 4. Blood flow in grey matter (insular cortex) and white matter (centrum semiovale) at normal levels of PCO2 averaged 56.8 +/‐ 10.1 and 20.3 +/‐ 3.4 ml min dl‐1 respectively. As PCO2 rose, the increase in rCBF to grey matter was approximately three times greater than that to white matter. 5. An activation state of eyes open in a brightly lit room was compared to a baseline state of eyes closed in a darkened room at the three levels of PCO2 (and hence at three levels of gCBF). Over the whole gCBF range a significant (P = 0.028) effect of increasing rCBF in the visual cortex ROI was found in response to opening the eyes; the effect of this activation on rCBF was not significantly dependent (P = 0.34) on the PCO2 (and hence gCBF) level. The effect of the activation on the rCBF was apparently ‘additive’ to the rise of rCBF associated with PCO2‐related gCBF increase. 6. The results confirm the need to normalize for changes in gCBF during studies of rCBF in response to an activation protocol. They also provide support for the use of an ‘additive’ model to achieve such normalization provided that other cortical areas behave in a similar manner to that of the visual cortex.

Changes in global cerebral blood flow in humans: effect on regional cerebral blood flow during a neural activation task.

Investigations of the functional anatomy of attention using the stroop test

The patterns of cerebral blood flow associated with three syndromes of schizophrenic symptoms are compared with the loci of cerebral activation in normal subjects during the performance of mental processes implicated in the three syndromes. The psychomotor poverty syndrome, which has been shown to involve a diminished ability to generate words, is associated with decreased perfusion of the dorsolateral prefrontal cortex at a locus which is activated in normal subjects during the internal generation of words. The disorganization syndrome, which has been shown to involve impaired suppression of inappropriate responses (eg in the Stroop test), is associated with increased perfusion of the right anterior cingulate gyrus at a location activated in normal subjects performing the Stroop test. The reality distortion syndrome, which evidence suggests arises from disordered internal monitoring of activity, is associated with increased perfusion in the medial temporal lobe at a locus activated in normal subjects during the internal monitoring of eye movements.

We have used positron tomography (PET) to demonstrate that some parts of the motor system exhibit physiological adaptation during the repeated performance of a simple motor task, but others do not. In contrast to the primary sensori-motor cortex, the cerebellum exhibits a decrease in physiological activation (increases in regional blood flow during performance) with practice. A new application of factorial experimental design to PET activation studies was used to make these measurements in four normal males. This design allow ed adaptation to be examined by testing for an interaction between regional cerebral blood flow (rCBF) increases brought about by a motor task and the number of trials (time). These findings are interpreted as the neurophysiological correlates of synaptic changes in the cerebellum associated with motor learning in man.

Motor practice and neurophysiological adaptation in the cerebellum: a positron tomography study

Synopsis Using positron emission tomography (PET) and 15Oxygen, regional cerebral blood flow (rCBF) was measured in 33 patients with primary depression, 10 of whom had an associated severe cognitive impairment, and 23 age-matched controls. PET scans from these groups were analysed on a pixel-by-pixel basis and significant differences between the groups were identified on Statistical Parametric Maps (SPMs). In the depressed group as a whole rCBF was decreased in the left anterior cingulate and the left dorsolateral prefrontal cortex (P < 0·05 Bonferroni-corrected for multiple comparisons). Comparing patients with and without depression-related cognitive impairment, in the impaired group there were significant decreases in rCBF in the left medial frontal gyrus and increased rCBF in the cerebellar vermis (P < 0·05 Bonferroni-corrected). Therefore an anatomical dissociation has been described between the rCBF profiles associated with depressed mood and depression-related cognitive impairment. The pre-frontal and limbic areas identified in this study constitute a distributed anatomical network that may be functionally abnormal in major depressive disorder.

The anatomy of melancholia – focal abnormalities of cerebral blood flow in major depression

The functional anatomy of motor skill acquisition was investigated in six normal human subjects who learned to perform a pursuit rotor task with their dominant right hand during serial positron emission tomography (PET) imaging of relative cerebral blood flow (relCBF). The effect of motor execution, rather than learning, was identified by a comparison of four motor performance scans with two control scans (eye movements only). Motor execution was associated with activation of a distributed network involving cortical, striatonigral, and cerebellar sites. Second, the effect of early motor learning was examined. Performance improved from 17% to 66% mean time on target across the four PET scans obtained during pursuit rotor performance. Across the same scans, significant longitudinal increases of relCBF were located in the left primary motor cortex, the left supplementary motor area, and the left pulvinar thalamus. The results demonstrate that changes of regional cerebral activity associated with early learning of skilled movements occur in sites that are a subset of a more widely distributed network that is active during motor execution.

Functional anatomy of human procedural learning determined with regional cerebral blood flow and PET

In vivo Measurement of the Volume of Distribution of Water in Cerebral Grey Matter: Effects on the Calculation of Regional Cerebral Blood Flow

Positron emission tomography was used to study the relationship between rCBF and symptom profiles in 30 schizophrenic patients. Factor analysis confirmed that the symptoms segregated into three syndromes – psychomotor poverty, disorganisation, and reality distortion – described previously. Analysis of the correlations between syndrome scores and rCBF revealed that each syndrome was associated with a specific pattern of perfusion in paralimbic and association cortex, and in related subcortical nuclei. The study confirmed predictions that psychomotor poverty and disorganisation are associated with altered perfusion at different loci in the pre-frontal cortex, and reality distortion with altered perfusion in the medial temporal lobe. The perfusion patterns suggest that the abnormalities of brain function underlying each of the three syndromes are not confined to single loci, but involve distributed neuronal networks.

Psychopharmacological activation, in conjunction with positron emission tomographic measurements of regional cerebral blood flow (rCBF), was used to investigate the neurotransmitter basis of a specific cognitive function in man. Monoaminergic neurotransmission was pharmacologically manipulated during performance of auditory – verbal memory tasks. Statistical parametric mapping was used to identify the brain sites of interaction between memory‐induced increases in rCBF and active drugs. Memory task‐induced increases in rCBF in the left prefrontal cortex were attenuated by apomorphine, a non‐selective dopamine agonist, whilst buspirone, a serotonin1A partial agonist, augmented rCBF increases in this area. In addition, apomorphine and buspirone augmented memory‐induced increases in rCBF centred in the posterior cingulate cortex, whilst buspirone alone attenuated rCBF increases in the retrosplenial cortex and posterior parahippocampal gyrus. These regionally selective interactions may represent neuromodulatory effects of monoaminergic neurotransmission on a specific cognitive function in man.

The Effect of Apomorphine and Buspirone on Regional Cerebral Blood Flow During the Performance of a Cognitive Task—Measuring Neuromodulatory Effects of Psychotropic Drugs in Man

Positron emission tomography was used to investigate changes in regional cerebral blood flow (rCBF) in neurologically normal subjects during word reading and word repetition. The blood flow in these conditions was compared with control conditions where subjects were presented with stimuli of comparable auditory and visual complexity to real words and said the same word on presentation of each stimulus. The control condition for word repetition (hearing spoken words presented backwards) resulted in bilateral activation of the superior temporal gyrus. Word repetition caused a significant increase in rCBF over this control condition in the left superior and middle temporal gyri. The control condition for word reading (seeing stimuli written in 'false fonts', i.e. non-existent letter-like forms) resulted in significant changes in rCBF bilaterally in the striate and extrastriate cortex. Word reading caused a significant increase in blood flow relative to this control in the posterior part of the left middle temporal gyrus. The implications of these results are discussed, and it is argued that they are consistent with localization of a lexicon for spoken word recognition in the middle part of the left superior and middle temporal gyri, and a lexicon for written word recognition in the posterior part of the left middle temporal gyrus.

The cortical localization of the lexicons. Positron emission tomography evidence.

Measuring the neuromodulatory effects of drugs in man with positron emission tomography

Regional response differences within the human auditory cortex when listening to words

Functional segregation requires convergence and divergence of neuroanatomical connections. Furthermore, the nature of functional segregation suggests that (1) signals in convergent afferents are correlated and (2) signals in divergent efferents are uncorrelated. The aim of this article is to show that this arrangement can be predicted mathematically, using information theory and an idealized model of cortical processing. In theory, the existence of bifurcating axons limits the number of independent output channels from any small cortical region, relative to the number of inputs. An information theoretic analysis of this special (high input:output ratio) constraint indicates that the maximal transfer of information between inputs, to a cortical region, and its outputs will occur when (1) extrinsic connectivity to the area is organized such that the entropy of neural activity in afferents is optimally low and (2) connectivity intrinsic to the region is arranged to maximize the entropy measured at the initial segments of projection neurons. Under the constraints of the model, a low entropy is synonymous with high correlations between axonal firing rates (and vice versa). Consequently this antisymmetric arrangement of functional activity in convergent and divergent connections underlying functional segregation is exactly that predicted by the principle of maximum preservation of information, considered in the context of axonal bifurcation. The hypothesis that firing in convergent afferents is correlated (has low entropy) and spatially coherent was tested using positron emission tomographic measurements of cortical synaptic function in man. This hypothesis was confirmed.

Entropy and cortical activity: information theory and PET findings.

Regional cerebral blood flow (rCBF) was measured in 30 schizophrenic patients with severe, persistent and stable symptoms using positron emission tomography (PET). Directed and non-directed correlational analysis of the relationship between psychopathology and rCBF was used to identify brain structures implicated in three behavioural subsyndromes of schizophrenia. Psychopathology and neurophysiology (rCBF) exhibited high correlations in the left medial temporal region, mesencephalic, thalamic and left striatal structures. The highest correlation was in the left parahippocampal region. A canonical analysis of the same data highlighted the left parahippocampal region and left striatum (globus pallidus) as sites which linked the behavioural subsyndromes in terms of shared rCBF correlates. Increasing severity of psychopathology was associated with increased rCBF in these regions. Disinhibition of left medial temporal lobe activity mediated by fronto-limbic connections is a possible explanation for these findings; however, the prefrontal component appears to be critically dependent on the behavioural subsyndrome.

Depression with cognitive impairment, so called depressive pseudodementia, is commonly mistaken for a neurodegenerative dementia. Using positron emission tomography (PET) derived measures of regional cerebral blood flow (rCBF) a cohort of 33 patients with major depression was studied. Ten patients displayed significant and reversible cognitive impairment. The patterns of rCBF of these patients were compared with a cohort of equally depressed non-cognitively impaired depressed patients. In the depressed cognitively impaired patients a profile of rCBF abnormalities was identified consisting of decreases in the left anterior medial prefrontal cortex and increases in the cerebellar vermis. These changes were additional to those seen in depression alone and are distinct from those described in neurodegenerative dementia. The cognitive impairment seen in a proportion of depressed patients would seem to be associated with dysfunction of neural systems distinct from those implicated in depression alone or the neurodegenerative dementias.

Regional cerebral blood flow abnormalities in depressed patients with cognitive impairment.

We used positron emission tomography (PET) to study organizational changes in the functional anatomy of the brain in 10 patients following recovery from striatocapsular motor strokes. Comparisons of regional cerebral blood flow maps at rest between the patients and 10 normal subjects revealed significantly lower regional cerebral blood flow in the basal ganglia, thalamus, sensorimotor, insular, and dorsolateral prefrontal cortices, in the brainstem, and in the ipsilateral cerebellum in patients, contralateral to the side of the recovered hand. These deficits reflect the distribution of dysfunction caused by the ischemic lesion. Regional cerebral blood flow was significantly increased in the contralateral posterior cingulate and premotor cortices, and in the caudate nucleus ipsilateral to the recovered hand. During the performance of a motor task by the recovered hand, patients activated the contralateral cortical motor areas and ipsilateral cerebellum to the same extent as did normal subjects. However, activation was greater than in normal subjects in both insulae; in the inferior parietal (area 40), prefrontal and anterior cingulate cortices; in the ipsilateral premotor cortex and basal ganglia; and in the contralateral cerebellum. The pattern of cortical activation was also abnormal when the unaffected hand, contralateral to the hemiplegia, performed the task. We showed that bilateral activation of motor pathways and the recruitment of additional sensorimotor areas and of other specific cortical areas are associated with recovery from motor stroke due to striatocapsular infarction. Activation of anterior and posterior cingulate and prefrontal cortices suggests that selective attentional and intentional mechanisms may be important in the recovery process. Our findings suggest that there is considerable scope for functional plasticity in the adult human cerebral cortex.

Functional reorganization of the brain in recovery from striatocapsular infarction in man

Comparing Functional (PET) Images: The Assessment of Significant Change

Identification of the main areas in the brain that respond specifically to the "suffering" components of pain has been achieved by using serial dynamic measurements of blood flow as an index of synaptic activity. Specific response to a repeated painful thermal stimulus as compared to a non-painful thermal stimulus in normal male volunteers identified the anterior cingulate cortex and the thalamus contralateral to the side of stimulation as the main sites of significant response. It was concluded that it was these areas where pain was likely to be experienced. Changes in opioid receptor binding in the brain was measured using 11C-diprenorphine and positron emission tomography in three patients with rheumatoid arthritis. In the two patients with active rheumatoid arthritis substantial changes in opioid receptor binding in the brain are described. The significance of these findings are discussed.

Endogenous opiate response to pain in rheumatoid arthritis and cortical and subcortical response to pain in normal volunteers using positron emission tomography.

The neuromodulatory effect of manipulating monoaminergic receptor function was assessed by combining a psychological and a pharmacological activation during repeated positron emission tomographic (PET) scans. The effects of buspirone (a 5-HT1A receptor partial agonist) on changes in regional cerebral blood flow (rCBF) associated with free word recall were examined. A factorial design was used to demonstrate a significant interaction (changes in rCBF brought about by psychological activation which depend on drug administration) in the left parahippocampal region. This interaction was an attenuation of increases in local neuronal activity (rCBF) related to memory function. Buspirone-induced decreases in rCBF, independent of the memory effect, were seen in the left prefrontal and parietal cortices. We suggest that combined psychological and pharmacological activation is a way of measuring direct (main) drug effects and modulatory effects on neurotransmission associated with cognitive functions (interaction).

The neurotransmitter basis of cognition: psychopharmacological activation studies using positron emission tomography.

We used positron emission tomography to contrast changes in cerebral blood flow associated with willed and routine acts. In the six tasks used, volunteers had to make a series of responses to a sequence of stimuli. For the routine acts, each response was completely specified by the stimulus. For the willed acts, the response was open-ended and therefore volunteers had to make a deliberate choice. Willed acts in the two response modalities studied (speaking a word, or lifting a finger) were associated with increased blood flow in the dorsolateral prefrontal cortex (Brodmann area 46). Willed acts were also associated with decreases in blood flow, but the location of these decreases was modality dependent.

Willed action and the prefrontal cortex in man: a study with PET

1. Regional cerebral blood flow (rCBF) was measured using positron emission tomography in six normal volunteers while at rest and while performing four different repetitive movements of the right arm. 2. The four movements were performed in random order and consisted of abduction of the index finger, making a fist, sequential thumb to digit opposition, and shoulder flexion. All the movements were done at the same rate, using an auditory cue and involved displacements through similar amounts of the physiological range at each joint. 3. Increases in rCBF were interpreted as evidence of local neural activation and all four movements were associated with significant increases in CBF in the contralateral sensorimotor and premotor areas and in the supplementary motor area (SMA). 4. The average increase in blood flow in the contralateral sensorimotor cortex was significantly greater for the shoulder movement (31%) than for the three other movements. The increases with finger opposition (21%) and fist-making (24%) were not significantly different, and both were significantly greater than with index finger movement (13%). These data indicate that neither "fractionation" nor distal movement per se cause selective activation of sensorimotor cortex. 5. Significantly greater increases in blood flow in both the contralateral premotor cortex and the SMA ("nonprimary motor areas") occurred with shoulder movement than with the other movements. Because this difference may be related to the significantly greater activation occurring concurrently in the sensorimotor cortex, this finding does not prove unequivocally a "selective" role of the nonprimary motor areas in proximal movement. 6. Neither of the two nonprimary motor areas showed selective activation when a simple sequence of finger movements was performed compared with repetitive contractions of the same fingers. 7. Shoulder movement alone was associated with significant increases in rCBF in the ipsilateral sensorimotor cortex (10%), the superior vermis of the cerebellum (19%), and Brodmann areas 5 and 40 in the contralateral hemisphere. 8. The average location of the center of excitation in the sensorimotor cortex and SMA differed for the four movements and was interpreted as evidence of within-limb somatotopy. The shoulder focus lay highest in the sensorimotor cortex and lowest in the SMA.

Regional cerebral blood flow during voluntary arm and hand movements in human subjects.

Six normal volunteers were studied with positron emission tomography to identify the cortical neural networks that participate in the processing of single words. Activity-related changes in regional cerebral blood flow were measured consecutively on 6 occasions in each subject, 2 while the subject was at rest and 4 while single word language tasks were being performed. The data from each subject were standardized for brain shape and size, reconstructed parallel to the intercommissural line, normalized for global flow differences, and then averaged for each activation condition across the 6 subjects. Significant areas of change in rCBF (P less than 0.05, with appropriate Bonferroni corrections) between task and rest conditions were displayed with reference to the coordinates of a standard neuroanatomical atlas. We have demonstrated that categorical judgements on heard pairs of real words activate neural networks along both superior temporal gyri, but with an anatomical distribution no different from that seen when the subjects listened to nonwords: the tasks would appear to be very different in cognitive demands but not in terms of the distribution of activation. However, during a verb generation task that involved thinking of verbs appropriate to heard nouns presented at a slow rate, the only temporal region activated was the left posterior superior temporal association cortex (Wernicke's area). Further analysis showed that whereas activation in other superior temporal regions, both left and right, correlated with rates of word presentation during the 4 tasks, there was no such correlation in Wernicke's area; evidence that this site is responsible for more than early acoustic processing. During verb generation there was also activation of left premotor and prefrontal cortex (including Broca's area and the supplementary motor area). The supplementary motor area is thought to be involved in the motor planning of speech. The subjects did not vocalize during the task, and therefore it would appear that the act of retrieving words from semantic memory activates networks concerned with the production of speech sounds. We conclude that single word comprehension and retrieval activate very different distributed regions of cerebral cortex, with Wernicke's area the only region engaged by both processes and with participation during silent word generation of networks involved in vocalization.

Distribution of cortical neural networks involved in word comprehension and word retrieval.

We have used positron emission tomography (PET), which measures regional cerebral blood flow (rCBF), to demonstrate directly the specialization of function in the normal human visual cortex. A novel technique, statistical parametric mapping, was used to detect foci of significant change in cerebral blood flow within the prestriate cortex, in order to localize those parts involved in the perception of color and visual motion. For color, we stimulated the subjects with a multicolored abstract display containing no recognizable objects (Land color Mondrian) and contrasted the resulting blood flow maps with those obtained when subjects viewed an identical display consisting of equiluminous shades of gray. The comparison identified a unique area (area V4) located in the lingual and fusiform gyri of the prestriate cortex. For motion, blood flow maps when subjects viewed moving or stationary black and white random-square patterns were contrasted. The comparison identified a unique area located in the region of the temporo-parieto-occipital junction (area V5). We thus provide direct evidence to show that, just as in the macaque monkey, different areas of the human prestriate visual cortex are specialized for different attributes of vision. The striate cortex (V1) and the contiguous visual area (V2), which in the monkey brain feed both the homologous areas, were active in all 4 conditions. This pattern of activity allowed us to use an extension of the approach to assess the functional relationship between the 3 areas during color and motion stimulation. This is based on an hypothesis-led analysis of the covariance structure of the blood flow maps and promises to be a powerful tool for inferring anatomical pathways in the normal human brain.(ABSTRACT TRUNCATED AT 250 WORDS)

A direct demonstration of functional specialization in human visual cortex

A quantitative study of the regional cerebral responses to non-painful and painful thermal stimuli in six normal volunteers has been done by monitoring serial measurements of regional blood flow measured by positron emission tomography (PET). In comparison to a baseline of warm stimulation no statistically significant changes in blood flow were seen in relation to increasing non-painful heat. However, highly significant increases in blood flow were seen in response to painful heat in comparison to non-painful heat. These changes were in the contralateral cingulate cortex, thalamus and lenticular nucleus. These findings are discussed in relation to previous physiological observations of responses to nociceptive stimuli in man and primates.

Cortical and subcortical localization of response to pain in man using positron emission tomography

Cerebral function in aging and Alzheimer's disease: the role of PET.

By using positron emission tomography (pet) we examined the biological validity of a network model describing changes in cerebral activity associated with intrinsic and extrinsic word generation. The production of words not specified by an extrinsic stimulus constitutes willed or intrinsic generation. Perceiving a heard word is an example of extrinsic generation. The model incorporates three neuronal systems: a pool that stores word representations in a distributed fashion, an afferent system conveying sensory input to the pool and a modulating system that alters the responsivity of neurons in the pool. Simulations based on the model suggested that intrinsic generation would be associated with low activity in the pool, consequent on reduced modulation, and extrinsic generation with high activity. We measured cerebral activity with pet during intrinsic (verbal fluency) and extrinsic (responding to heard words) word generation and found this pattern of changes in the left superior temporal region. We were able to designate this region the site of the distributed word store and implicate the left dorsolateral prefrontal cortex (dlpfc) as the source of modulation. The relation between the superior temporal gyrus and dlpfc was shown by examining the correlation between the two regions in terms of cerebral activity. We conclude that the left dlpfc is responsible for modulating the responsivity of a neural system in the superior temporal gyrus and is the probable mediator of changes in attentional and intentional states that underlies the intrinsic generation of words.

Investigating a network model of word generation with positron emission tomography

Cortical areas and the selection of movement: a study with positron emission tomography

Positron emission tomography as a research tool in the investigation of psychiatric and psychological disorders.

A theory and technique are presented that allow nonlinear resampling of positron emission tomography data to remove nonlinear differences in brain shape. The resampling is determined empirically by a function relating the observed image and a desired template. The validity, reliability, and precision of the plastic transformation are compared with linear rescaling alone, within, and between subjects.

5-HT neuroendocrine responses during psychotropic drug treatment: an investigation of the effects of lithium

Positron Emission Tomography (PET) represents a major advance in neuroimaging techniques enabling for the first time the quantitative acquisition of in. vivo pharmacological information in humans. This review will outline the range of its applications as a pharmacological tool with specific reference to its use in the measurement of neuroreceptors and in pharmacodynamic studies. A new and potentially more exciting application of PET is in pharmacological challenge combined with cognitive activation paradigms. The key issues in the design and implementation of this latter approach are detailed.

Positron emission tomography (PET) differs fundamentally from computerised tomography (CT) and magnetic resonance imaging (MRI) in that it is a method for measuring function as opposed to structure. It is the most powerful tool available for the measurement of in-vivo brain function. This review describes the basic principles of the technique and its application to the study of brain metabolism in neurological and psychiatric disorder. The development of resting-state metabolic studies by the application of specific activation paradigms, a major current focus of the technique, is discussed.

Positron Emission Tomography in the Study of Brain Metabolism in Psychiatric and Neuropsychiatric Disorders

Lithium increases slow wave sleep: possible mediation by brain 5-HT2 receptors?

Localisation in PET Images: Direct Fitting of the Intercommissural (AC—PC) Line

PET is potentially the most powerful tool yet available for the direct, in vivo investigation of the biologic basis of psychiatric and neuropsychiatric disorders. The fulfillment of its potential rests on the development of methodologies and study design appropriate to psychiatric disorders. To date, findings in both schizophrenia and affective disorder, using protocols largely based on resting state data acquisition, suggest altered regional metabolism. These approaches need to be extended, particularly by the application of protocols that utilize PET to obtain longitudinal data under controlled experimental situations. In two conditions traditionally ascribed to psychologic causes, OCD and PD, there is intriguing evidence of specific biologic abnormalities, which, if confirmed, would lead to a fundamental revision of their nosologic status. In neuropsychiatric disorders PET findings, although preliminary in nature, offer an alternative paradigm to traditional clinicopathologic correlations by suggesting that clinical impairments relate to physiologic effects at sites distant from structural lesions.

Positron emission tomography in psychiatric and neuropsychiatric disorders.

The role of striatal prediction errors in modulating cortical coupling

With regard to Professor Crow's stimu-With regard to Professor Crow's stimulating commentary (Crow, 2000) on our relating commentary (Crow, 2000) on our recent paper (Spence cent paper (Spence et al et al, 2000), we write to , 2000), we write to correct some errors of fact and interpret-correct some errors of fact and interpretation which appeared in his article. ation which appeared in his article. In our paper we demonstrated that In our paper we demonstrated that during word generation people with schizo-during word generation people with schizo-phrenia exhibited a `functional disconnec-phrenia exhibited a `functional disconnec-tion' between neural activity in dorsolateral tion' between neural activity in dorsolateral prefrontal and anterior cingulate cortices re-prefrontal and anterior cingulate cortices relative to controls, as stated by Crow. People lative to controls, as stated by Crow. People with schizophrenia also exhibited relative with schizophrenia also exhibited relative overactivity of the precuneus compared to overactivity of the precuneus compared to controls and those at genetic risk (not only controls and those at genetic risk (not only to controls, as stated by Crow). to controls, as stated by Crow). Crow criticised our choice of an Crow criticised our choice of an a priori a priori hypothesis, based as it was on previous hypothesis, based as it was on previous studies of word generation (summarised in studies of word generation (summarised in Table 1 of our paper). We examined the hy-Table 1 of our paper). We examined the hypothesis that focal or distributed brain dys-pothesis that focal or distributed brain dys-function might provide a trait marker for function might provide a trait marker for schizophrenia, specifically implicating the schizophrenia, specifically implicating the left superior temporal gyrus, and a proposed left superior temporal gyrus, and a proposed frontotemporaìdisconnection' (Friston frontotemporaìdisconnection' (Friston et et al al, 1995). Crow suggested that we should , 1995). Crow suggested that we should have specified a dysfunction of right pre-have specified a dysfunction of right pre-frontal cortex, despite the absence of such frontal cortex, despite the absence of such a finding from previous studies or statistical a finding from previous studies or statistical confirmation of such`dysfunction' in our confirmation of such`dysfunction' in our data-set. Indeed, despite many papers on data-set. Indeed, despite many papers on the relevance of language to schizophrenia, the relevance of language to schizophrenia, Crow has never previously hypothesised Crow has never previously hypothesised such a specific region of dysfunction. …

Commenting on Neuroimaging Commenting on Neuroimaging Further Comments on Jerusalem Further Comments on Jerusalem Syndrome Syndrome

Experimental Setup and Stimuli Arbitrary visual cues (CS) and imperative stimuli (IS) were presented for 250 ms (Figure 1A). After CS presentation, the IS was presented approximately 1000 ms later [6 a random value sampled from a normal distribution N(m = 0, s = 40)]. The CS or IS did not provide any spatial information and were arbitrarily mapped onto required finger responses; CS and IS were arbitrarily assigned to a right thumb or right little finger button press, respectively, prior to the experiment. Visual stimuli (upward triangle or ellipsoid) were equated for surface area and subjectively matched for brightness in a behavioral pilot experiment. The mean intertrial interval was 1850 ms. Visual stimuli were presented centrally against a gray background on a 21 inch computer screen refreshed at 60 Hz at a viewing distance of 400 mm, subtending w4 of visual angle. A small central cross (w0.5 of visual angle) helped to maintain central fixation.

Influence of Uncertainty and Surprise itability during Preparation for Action

Bayesian model selection for group studies BAYESIAN MODEL SELECTION FOR GROUP STUDIES

Please check your proof carefully and mark all corrections at the appropriate place in the proof (e.g., by using on-screen annotation in the PDF file) or compile them in a separate list. Note: if you opt to annotate the file with software other than Adobe Reader then please also highlight the appropriate place in the PDF file. To ensure fast publication of your paper please return your corrections within 48 hours. We were unable to process your file(s) fully electronically and have proceeded by Scanning (parts of) your article Rekeying (parts of) your article Scanning the artwork Any queries or remarks that have arisen during the processing of your manuscript are listed below and highlighted by flags in the proof. Click on the 'Q' link to go to the location in the proof. Location in article Query / Remark: click on the Q link to go Please insert your reply or correction at the corresponding line in the proof Q1, Q16 Would you consider changing the data " channels 2, 5, and channels 3, 4 " to " channels 2, 5, 3, and 4 " ? Please check, and amend as necessary. Q2 Please check if the layout/presentation of Table 1 is appropriate, and correct if necessary. Q3 Your article is registered as a regular item and is being processed for inclusion in a regular issue of the journal. If this is NOT correct and your article belongs to a Special Issue/Collection please contact r.prasad@elsevier.com immediately prior to returning your corrections. Q4 The data "Dynamic Causal Modelling" has been changed to "Dynamic Causal Modeling" in the article title and its subsequent occurrences in the article for consistency. Please check if appropriate and amend if necessary. Q5, Q17 Please confirm that given names and surnames have been identified correctly. Q6 As per journal specification, the article requires unnumbered section headings. Thus, the citations "Section 2", "Section 3" and "Section 4" have been changed to "the Methods section ", "the Results section " and "the Discussion section", respectively. Please check if the changes made are appropriate and amend if necessary. Q7 The term "comprise" in this sentence has been changed to "comprises" as it was assumed that the subject is "specification". Please check if the change made is appropriate and amend if necessary. Q8 As per journal specification, the article requires unnumbered section headings. Thus, the citations "Section 2.7" have been changed …

Proofs of [ YNIMG _ 12006 ] Dynamic causal modeling for functional near-infrared spectroscopy

Multi-scale computational modelling of neuronal dynamics in genetic epilepsies

Sample_RAND15_1 from Is predictability salient? A study of attentional capture by auditory patterns

Sample RAND10 1 from Is predictability salient? A study of attentional capture by auditory patterns

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Sample_REG10_1 from Is predictability salient? A study of attentional capture by auditory patterns

Electrophysiological Data and the Biophysical Modelling of Local Cortical Circuits

Characterization of the synaptic mechanisms underlying seizure onset with Dynamic Causal Modelling

Changes in effective connectivity in a working memory network related to hippocampal sclerosis

DCM of evoked brain responses: analysis of effective connectivity

Ever since the first discovery of human brain waves in 1929, brain rhythm has been attracting interest in the field of neuroscience. The integration of distributed brain functions similar to small-scale circuits for the same task in a larger scale network which oscillations facilitate offers a means to study the brain at work. Importantly, changes in synchronized brain oscillations may reveal important aspects of pathophysiology. For example, excess beta rhythms are characteristic of Parkinson's brain. However, various spatial distributions and frequencies of neuronal oscillations and nonlinear and complicated neuronal processes make it difficult to understand neuronal messages, and it is needed to find an appropriate model. Thus, we present a brief review of techniques used in characterizing frequency-related local fluctuations and interactions between neuronal assemblies by measuring electroencephalography (EEG) or MEG. Specifically, we focus on the objectives of these methods, including: (1) inferential versus non-inferential, (2) linear versus nonlinear, (3) uni-versus multi-variate, and (4) power modulation versus phase-synchrony. Three practical issues – that are typically confronted when applying these methods – are also discussed. This article aims to provide readers who are not familiar with current methods an accessible overview – that may help the neuroscientists to interpret the similar findings of this study.

Measuring Electromagnetic Oscillatory Brainwaves and Networks: Methodological Considerations

Introduction The extinction of fear memories is an important component in regulating defensive behaviors, contributing toward adaptive processes essential for survival. The cerebellar medial nucleus (MCN) has bidirectional connections with the ventrolateral periaqueductal gray (vlPAG) and is implicated in the regulation of multiple aspects of fear, such as conditioned fear learning and the expression of defensive motor outputs. However, it is unclear how communication between the MCN and vlPAG changes during conditioned fear extinction. Methods We use dynamic causal models (DCMs) to infer effective connectivity between the MCN and vlPAG during auditory cue-conditioned fear retrieval and extinction in the rat. DCMs determine causal relationships between neuronal sources by using neurobiologically motivated models to reproduce the dynamics of post-synaptic potentials generated by synaptic connections within and between brain regions. Auditory event related potentials (ERPs) during the conditioned tone offset were recorded simultaneously from MCN and vlPAG and then modeled to identify changes in the strength of the synaptic inputs between these brain areas and the relationship to freezing behavior across extinction trials. The DCMs were structured to model evoked responses to best represent conditioned tone offset ERPs and were adapted to represent PAG and cerebellar circuitry. Results With the use of Parametric Empirical Bayesian (PEB) analysis we found that the strength of the information flow, mediated through enhanced synaptic efficacy from MCN to vlPAG was inversely related to freezing during extinction, i.e., communication from MCN to vlPAG increased with extinction. Discussion The results are consistent with the cerebellum contributing to predictive processes that underpin fear extinction.

Dynamic causal modeling reveals increased cerebellar- periaqueductal gray communication during fear extinction

204. Dynamic Causal Modeling of Pitch MMN in First Episode Psychosis Reveals Impaired A1-STG Communication and Selective Dysfunction of NMDA Receptor

The role of cognitive control in the positive symptoms of psychosis

Gut inflammation is thought to modify brain activity and behaviour via modulation of the gut-brain axis. However, how relapsing and remitting exposure to peripheral inflammation over the natural history of inflammatory bowel disease (IBD) contributes to altered brain dynamics is poorly understood. Here, we used electroencephalography (EEG) to characterise changes in spontaneous spatiotemporal brain states in Crohn’s Disease (CD) (n = 40) and Ulcerative Colitis (UC) (n = 30), compared to healthy individuals (n = 28). We first provide evidence of a significantly perturbed and heterogeneous microbial profile in CD, consistent with previous work showing enduring and long-standing dysbiosis in clinical remission. Results from our brain state assessment show that CD and UC exhibit alterations in the temporal properties of states implicating default-mode network, parietal, and visual regions, reflecting a shift in the predominance from externally to internally-oriented attentional modes. We investigated these dynamics at a finer sub-network resolution, showing a CD-specific and highly selective enhancement of connectivity between the insula and mPFC, regions implicated in cognitive-interoceptive appraisal mechanisms. Alongside overall higher anxiety scores in CD, we also provide preliminary support to suggest that the strength of chronic interoceptive hyper-signalling in the brain co-occurs with disease duration. Together, our results demonstrate that a long-standing diagnosis of CD is, in itself, a key factor in determining the risk of developing altered brain network signatures.

Closed-loop stimulation for targeted modulation of brain signals has emerged as a promising strategy for episodic memory restoration. In parallel, closed-loop neuromodulation strategies have been applied to treat brain conditions including drug-resistant depression, Parkinson’s Disease, and epilepsy. In this study, we seek to apply control theoretical principles to achieve closed loop modulation of hippocampal oscillatory activity. We focus on hippocampal gamma power, a signal with an established association for episodic memory processing, which may be a promising ‘biomarker’ for the modulation of memory performance. To develop a closed-loop stimulation paradigm that effectively modulates hippocampal gamma power, we use a novel data-set in which open-loop stimulation was applied to the posterior cingulate cortex and hippocampal gamma power was recorded during the encoding of episodic memories. The dataset was used to design and evaluate a linear quadratic integral (LQI) servo-controller in order to determine its viability for in-vivo use. In our simulation framework, we demonstrate that applying an LQI servo controller based on an autoregressive with exogenous input (ARX) plant model achieves effective control of hippocampal gamma power in 15 out of 17 experimental subjects. We demonstrate that we are able to modulate gamma power using stimulation thresholds that are physiologically safe and on time scales that are reasonable for application in a clinical system. We outline further experimentation to test our proposed system and compare our findings to emerging closed-loop neuromodulation strategies.

IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society

A Control-Theoretical System for Modulating Hippocampal Gamma Oscillations Using Stimulation of the Posterior Cingulate Cortex

Pain perception is decreased by shifting attentional focus away from a threatening event. This attentional analgesia engages parallel descending control pathways from anterior cingulate (ACC) to locus coeruleus, and ACC to periaqueductal grey (PAG) – rostral ventromedial medulla (RVM), indicating possible roles for noradrenergic or opioidergic neuromodulators. To determine which pathway modulates nociceptive activity in humans, we used simultaneous whole brain-spinal cord pharmacological-fMRI (N = 39) across three sessions. Noxious thermal forearm stimulation generated somatotopic-activation of dorsal horn (DH) whose activity correlated with pain report and mirrored attentional pain modulation. Activity in an adjacent cluster reported the interaction between task and noxious stimulus. Effective connectivity analysis revealed that ACC interacts with PAG and RVM to modulate spinal cord activity. Blocking endogenous opioids with Naltrexone impairs attentional analgesia and disrupts RVM-spinal and ACC-PAG connectivity. Noradrenergic augmentation with Reboxetine did not alter attentional analgesia. Cognitive pain modulation involves opioidergic ACC-PAG-RVM descending control which suppresses spinal nociceptive activity.

Simultaneous brain, brainstem, and spinal cord pharmacological-fMRI reveals involvement of an endogenous opioid network in attentional analgesia

Fine-tuning neural excitation/inhibition for tailored ketamine use in treatment-resistant depression

Cognitive control network connectivity differentially disrupted in treatment resistant schizophrenia

Author Correction: Computational models link cellular mechanisms of neuromodulation to large-scale neural dynamics

There is growing recognition that the composition of the gut microbiota influences behaviour, including responses to threat. The cognitive-interoceptive appraisal of threat-related stimuli relies on dynamic neural computations between the anterior insular (AIC) and the dorsal anterior cingulate (dACC) cortices. If, to what extent, and how microbial consortia influence the activity of this cortical threat processing circuitry is unclear. We addressed this question by combining a threat processing task, neuroimaging, 16S rRNA profiling, and computational modelling in healthy participants. Results showed interactions between high-level ecological indices with threat-related AIC-dACC neural dynamics. At finer taxonomic resolutions, the abundance of Ruminococcus was differentially linked to connectivity between, and activity within the AIC and dACC during threat updating. Functional inference analysis provides a strong rationale to motivate future investigations of microbiota-derived metabolites in the observed relationship with threat-related brain processes.

Microbiota links to neural dynamics supporting threat processing

There is growing recognition that the composition of the gut microbiota influences behaviour, including responses to threat. The cognitive-interoceptive appraisal of threat-related stimuli relies on dynamic neural computations between the anterior insular (AIC) and the dorsal anterior cingulate (dACC) cortices. If, to what extent, and how microbial consortia influence the activity of this cortical threat processing circuitry is unclear. We addressed this question by combining a threat processing task, neuroimaging, 16S rRNA profiling and computational modelling in healthy participants. Results showed interactions between high-level ecological indices with threat-related AIC-dACC neural dynamics. At finer taxonomic resolutions, the abundance of Ruminococcus was differentially linked to connectivity between, and activity within the AIC and dACC during threat updating. Functional inference analysis provides a strong rationale to motivate future investigations of microbiota-derived metabolites in the observed relationship with threat-related brain processes.

Microbiota links to neural dynamics supporting threat processing.

Humans often act in the best interests of others. However, how we learn which actions result in good outcomes for other people and the neurochemical systems that support this ‘prosocial learning’ remain poorly understood. Using computational models of reinforcement learning, functional magnetic resonance imaging and dynamic causal modelling, we examined how different doses of intranasal oxytocin, a neuropeptide linked to social cognition, impact how people learn to benefit others (prosocial learning) and whether this influence could be dissociated from how we learn to benefit ourselves (self-oriented learning). We show that a low dose of oxytocin prevented decreases in prosocial performance over time, despite no impact on self-oriented learning. Critically, oxytocin produced dose-dependent changes in the encoding of prediction errors (PE) in the midbrain-subgenual anterior cingulate cortex (sgACC) pathway specifically during prosocial learning. Our findings reveal a new role of oxytocin in prosocial learning by modulating computations of PEs in the midbrain-sgACC pathway.

Oxytocin modulates neurocomputational mechanisms underlying prosocial reinforcement learning

Author response: Simultaneous brain, brainstem, and spinal cord pharmacological-fMRI reveals involvement of an endogenous opioid network in attentional analgesia

Computational models link cellular mechanisms of neuromodulation to large-scale neural dynamics

Pain perception is decreased by shifting attentional focus away from a threatening event. This attentional analgesia engages parallel descending control pathways from anterior cingulate (ACC) to locus coeruleus, and ACC to periaqueductal grey (PAG) – rostral ventromedial medulla (RVM), indicating possible roles for noradrenergic or opioidergic neuromodulators. To determine which pathway modulates nociceptive activity in humans we used simultaneous whole brain-spinal cord pharmacological-fMRI (N=39) across three sessions. Noxious thermal forearm stimulation generated somatotopic-activation of dorsal horn (DH, C6 segment) whose activity mirrored attentional pain modulation. Activity in an adjacent cluster reported the interaction between task and noxious stimulus. Effective connectivity analysis revealed that ACC recruits PAG and RVM to modulate spinal cord activity. Blocking endogenous opioids with Naltrexone impairs attentional analgesia and disrupts RVM-DH and ACC-PAG connectivity. Noradrenergic augmentation with Reboxetine did not alter attentional analgesia. Cognitive pain modulation is mediated by opioidergic ACC-PAG-RVM descending control which supresses spinal nociceptive activity.

Simultaneous Brain, Brainstem and Spinal Cord pharmacological-fMRI reveals endogenous opioid network interactions mediating attentional analgesia

We propose a computational model of visual search that incorporates Bayesian interpretations of the neural mechanisms that underlie categorical perception and saccade planning. To enable meaningful comparisons between simulated and human behaviours, we employ a gaze-contingent paradigm that required participants to classify occluded MNIST digits through a window that followed their gaze. The conditional independencies imposed by a separation of time scales in this task are embodied by constraints on the hierarchical structure of our model; planning and decision making are cast as a partially observable Markov Decision Process while proprioceptive and exteroceptive signals are integrated by a dynamic model that facilitates approximate inference on visual information and its latent causes. Our model is able to recapitulate human behavioural metrics such as classification accuracy while retaining a high degree of interpretability, which we demonstrate by recovering subject-specific parameters from observed human behaviour.

The temporal pole (TP) is an associative cortical region required for complex cognitive functions such as social and emotional cognition. However, functional mapping of the TP with functional magnetic resonance imaging is technically challenging and thus understanding of its interaction with other key emotional circuitry, such as the amygdala, remain elusive. We exploited the unique advantages of stereo-electroencephalography (SEEG) to assess the responses of the TP and the amygdala during the perception of emotionally salient stimuli of pictures, music and movies. These stimuli consistently elicited high gamma responses (70-140 Hz) in both the TP and the amygdala, accompanied by functional connectivity in the low frequency range (2-12 Hz). Computational analyses suggested the TP driving this effect in the theta-alpha frequency range and which was modulated by the emotional salience of the stimuli. Of note, cross-frequency analysis indicated the phase of theta-alpha oscillations in the TP modulated the amplitude of high gamma activity in the amygdala. These results were reproducible with three types of stimuli including naturalistic stimuli suggesting a hierarchical influence of the TP over the amygdala in non-threatening stimuli.

Intracranial-EEG evidence for medial temporal pole driving amygdala activity induced by multi-modal emotional stimuli

Abstract Altered connectivity within neuronal networks is often observed in Alzheimer’s disease. However, delineating pro-cognitive compensatory changes from pathological network decline relies on characterizing network and task effects together. In this study, we interrogated the dynamics of occipito-temporo-frontal brain networks responsible for implicit and explicit memory processes using high-density EEG and dynamic causal modelling. We examined source-localized network activity from patients with Alzheimer’s disease (n = 21) and healthy controls (n = 21), while they performed both visual recognition (explicit memory) and implicit priming tasks. Parametric empirical Bayes analyses identified significant reductions in temporo-frontal connectivity and in subcortical visual input in patients, specifically in the left hemisphere during the recognition task. There was also slowing in frontal left hemisphere signal transmission during the implicit priming task, with significantly more distinct dropout in connectivity during the recognition task, suggesting that these network drop-out effects are affected by task difficulty. Furthermore, during the implicit memory task, increased right frontal activity was correlated with improved task performance in patients only, suggesting that right-hemisphere compensatory mechanisms may be employed to mitigate left-lateralized network dropout in Alzheimer’s disease. Taken together, these findings suggest that Alzheimer’s disease is associated with lateralized memory circuit dropout and potential compensation from the right hemisphere, at least for simpler memory tasks.

Lateralized memory circuit dropout in Alzheimer’s disease patients

Abstract Background It is estimated that one third of patients with schizophrenia fail to adequately respond to antipsychotic medication, termed ‘treatment-resistance’. This occurs despite adequate blockade of D2 receptors in the brain. The parsimonious options are that treatment resistance could arise through a failure of cognitive control over the dopaminergic dysfunction in the striatum; or has a different primary non-dopaminergic mechanism that isn’t targeted by current antipsychotics. Contemporary models suggest that schizophrenia is associated with reduced reward prediction errors (RPE) and consequent aberrant salience driven by increased dopamine levels that ‘drown out’ phasic signals. This causes positive symptoms and impaired reward learning. However, RPE signalling in treatment-resistant patients appears intact despite sub-optimal behavioural performance. It is therefore unclear how reward learning is impaired in these patients. Methods We investigated how reward learning is disrupted at the network level in 21 medicated treatment-responsive and 20 medicated treatment-resistant patients with schizophrenia compared with 24 healthy controls (HC). Participants learnt to associate one of two emotional faces with a reward during a reinforcement learning task in an MRI scanner. Functional MRI BOLD signal was extracted from four brain regions (fusiform cortex, amygdala, caudate and anterior cingulate cortex (ACC)) activated in response to face cues and RPEs. These formed a network of interacting brain regions supporting reward learning. Dynamic Causal Modelling assessed how effective connectivity between regions in this cortico-striatal-limbic network is disrupted in each patient group compared to HC. Connectivity was also examined with respect to symptoms and salience. Finally, cognitive control and the role of glutamate were assessed by relating top-down connectivity from the ACC with glutamate levels measured from the same region of the ACC. Results In responsive patients, there was enhanced top-down connectivity from the ACC to sensory regions (fusiform and amygdala) and reduced input to the caudate compared to HC. Increased top-down connectivity was inversely correlated with symptom severity and sensory-salience. This suggests the presence of an effective compensatory mechanism for unreliable sensory information in responsive patients. Resistant patients however showed normal network connectivity compared to HC except abnormal connectivity within the ACC. This supports an alternative, non-dopaminergic mechanism disrupting reward learning in this refractory group. Increasing connectivity from ACC to caudate was related to positive symptom severity and salience in this group. Moreover, ACC glutamate levels were related to key top-down connections in HC and responsive patients but were not related to any connections in resistant patients. This suggests that glutamate may not be modulating connectivity effectively in this network to exert cognitive control and update reward predictions. Discussion In summary, differential mechanisms underlie disrupted reward learning between responsive and resistant groups. Resistant patients show similar RPE signalling and network connectivity to HC suggesting their dopaminergic functioning is intact. Impaired glutamate function may present a key mechanism that disrupts reward learning – and why dopaminergic drugs are ineffective. This finding is important for developing new drugs (e.g. glutamatergic targets) and guiding treatment strategies (e.g. giving clozapine earlier) in resistant patients. Future research probing cognitive control mechanisms and glutamate function will be useful to elucidate this putative pathology in treatment resistance.

T164. NETWORK CONNECTIVITY SUPPORTING REWARD LEARNING DIFFERENTIALLY DISRUPTED IN TREATMENT RESISTANT SCHIZOPHRENIA

Phase-Amplitude Coupled DCM and Time-Frequency Analysis of EEG Data from AD Patients

Methods: Forty-nine individuals with SocAhn and 33 well-matched controls underwent a fMRI session, during which they were instructed to envision positive or neutral future events in next year in response to the cue words. Each trial was divided into construction phase and elaboration phase. After scanning, participants received an interview to confirm they were able to project themselves into future and rated their experience in future events. Results: Three contrasts were identified to examine the main effect of emotion [Positive Neutral] and phase [Construction Elaboration], and their interaction [(Positive_Construction – Neutral_Construction) – (Positive_Elaboration – Neutral_Elaboration)]. One sample t test was conducted on these contrasts in each group and the results demonstrated that, in the control group, a set of regions including the bilateral caudate, bilateral amygdala, the left medial prefrontal (mPFC), and the left inferior parietal lobe were more engaged in envisioning positive future episodes relative to neutral episodes. However, preferential engagement of these regions was not observed in the SocAhn group. Both the SocAhn and control groups exhibited similar brain activation for the phase contrast. In addition, no significant clusters were shown for the interaction contrast in both groups, which may reflect no significant emotion difference in construction and elaboration of future events in these participants. Two sample t test results indicated that compared to controls, individuals with SocAhn exhibited hypo-activation in the right caudate and the right precuneus cortex when envisioning positive future events (relative to neutral events). Subsequent ROI analysis indicated that social interaction in positive future events was correlated with the engagement of bilateral amygdala (left, r = 0.46, p = 0.001; right, r = 0.43, p = 0.003) in the SocAhn group. In the control group, social interaction was correlated with activation of the left mPFC (r = 0.43, p = 0.02). Discussion: The present findings suggest there is reduced engagement of the caudate and the precuneus cortex in individuals with SocAhn when they envision positive future events. In addition, social interaction involved in positive future episodes is related to activation in different regions in individuals with SocAhn and controls.

S74. HYPERACTIVATION OF LEFT MEDIAL FRONTAL AND CINGULATE GYRUS MEDIATES SOUND-INDUCED FLASH ILLUSION IN NON-AFFECTIVE PSYCHOSIS

Cortical recordings of task-induced oscillations following subanaesthetic ketamine administration demonstrate alterations in amplitude, including increases at high-frequencies (gamma) and reductions at low frequencies (theta, alpha). To investigate the population-level interactions underlying these changes, we implemented a thalamo-cortical model capable of recapitulating broadband spectral responses. Compared with placebo, ketamine was found to increase the decay rate of NMDA receptor currents, decrease the decay rate of GABA-B receptor currents, but had no effect on AMPA or GABA-A currents. Furthermore, ketamine decreased the inhibitory self-modulation of superficial pyramidal populations, increased the inhibitory self-modulation of inhibitory interneurons and increased the strength of the cortico-thalamic projection from layer 6 into thalamus. In-silico rectification of each of these parameters to their placebo state revealed the accompanying spectral changes. Similar broadband effects were demonstrated for the NMDA constant and intrinsic connectivity changes, whereby rectification resulted in normalising the amplitude of alpha (increased) and gamma (decreased). While supporting theories of superficial pyramidal disinhibition following ketamine administration, our results suggest a role for altered cortico-thalamic connectivity relevant to understanding ketamine induced cortical responses and potentially identifies a system-level mechanism contributing to its antidepressant effects.

In-silico evidence that increased cortico-thalamic connectivity and superficial pyramidal disinhibition underlie broadband task-related spectral changes induced by ketamine

ABSTRACT Sixteen years ago, Sereno and Rayner (2003. Measuring word recognition in reading: eye movements and event-related potentials. Trends in Cognitive Sciences, 7(11), 489–493) illustrated how “by means of review and comparison” eye movement (EM) and event-related potential (ERP) studies may advance our understanding of visual word recognition. Attempts to simultaneously record EMs and ERPs soon followed. Recently, this co-registration approach has also been transferred to fMRI and oscillatory EEG. With experimental settings close to natural reading, co-registration enables us to directly integrate insights from EM and neuroimaging studies. This should extend current experimental paradigms by moving the field towards studying sentence-level processing including effects of context and parafoveal preview. This article will introduce the basic principles and applications of co-registration and selectively review how this approach may shed light on one of the most controversially discussed issues in reading research, contextual predictions in online language processing.

Co-registration of eye movements and neuroimaging for studying contextual predictions in natural reading

We begin by demonstrating that the neuronal state equation from Dynamic Causal Modelling takes on the form of the discretized Fokker-Planck equation upon the inclusion of local activity gradients within a network. Using the Jacobian of this modified neuronal state equation, we show that an initially unstable system can be rendered stable via a decrease in diffusivity. Therefore, if a node within the system is known to be unstable due to a tendency toward epileptic seizures for example, then our results indicate that intervention techniques should take the counter-intuitive approach of mirroring activity in the nodes immediately surrounding a pathological region - effectively fighting seizures with seizures. Finally, using a two-region system as an example, we show that one can also tune diffusivity in such a way as to allow for the suppression of oscillatory activity during epileptic seizures.

The Importance of Standards for Sharing of Computational Models and Data

Generative modelling of the thalamo-cortical circuit mechanisms underlying the neurophysiological effects of ketamine

We introduce a random sensing approach to neurotransmitter detection that provides concurrent, co-localized detection of dopamine, serotonin, norepinephrine and pH. The approach generates high quality out-of-sample predictions at 10 milliseconds per estimate. Similar high-quality estimates result when the data are down-sampled suggesting that even more dramatic speedups are possible. The method also works using electrophysiological probes in routine use in clinical preparations thus transforming these and similar electrodes into ultra-fast sources of multi-transmitter information.

The analysis of neural circuits can provide critical insights into the mechanisms of neurodegeneration and dementias, and offer potential quantitative biological tools to assess novel therapeutics. Here we use behavioural variant frontotemporal dementia (bvFTD) as a model disease. We demonstrate that inversion of canonical microcircuit models to non-invasive human magnetoecphalography can identify the regional- and laminar-specificity of bvFTD pathophysiology, and their parameters can accurately differentiate patients from matched healthy controls. Using such models, we show that changes in local coupling in frontotemporal dementia underlie the failure to adequately establish sensory predictions, leading to altered prediction error responses in a cortical information-processing hierarchy. Using machine learning, this model-based approach provided greater case-control classification accuracy than conventional evoked cortical responses. We suggest that this approach provides an in vivo platform for testing mechanistic hypotheses about disease progression and pharmacotherapeutics.

In Vivo Assay of Cortical Microcircuitry in Frontotemporal Dementia: A Platform for Experimental Medicine Studies

Objective. The objective of this paper is to didactically compare resting state connectivity networks computed using two different methods called phase locking value (PLV) and convergent cross-mapping (CCM). PLV is a ubiquitous measure of connectivity in electrophysiological research but is less often applied to fMRI BOLD timeseries since this model-based metric assumes that oscillatory coupling is a sufficient condition for connectivity. Alternatively, CCM is a model-free method, which detects potentially nonlinear causal influences based on the ability to estimate one timeseries with another and does not assume an oscillatory structure. Approach. We use a toy dataset to test the PLV and CCM algorithms under different known synchronization conditions. Additionally, experimental resting state EEG and fMRI datasets are used for comparison. Main results. The results show that the resting state brain networks computed using both algorithms produce similar results for both resting state EEG and fMRI datasets. For both neuroimaging datasets, the network characteristics follow the same trends and the similarity between the computed networks, for both algorithms, is highly significant. Significance. CCM is able to identify low or one-way connection strengths better than PLV but takes exponentially longer to compute. Based on these results, PLV provides a good metric for on-line network identification because it is both computationally fast and an excellent approximation of the network computed with CCM.

Comparing brain connectivity metrics: a didactic tutorial with a toy model and experimental data

NMDA Receptor Function during Mnemonic Processing in Patient’s with AD: The Good, The Bad and the Ugly

Indexing sensory plasticity: Evidence for distinct Predictive Coding and Hebbian learning mechanisms in the cerebral cortex

LSD modulates effective connectivity and neural adaptation mechanisms in an auditory oddball paradigm

Propofol-Induced Unresponsiveness is Associated with Impaired Feedforward Connectivity in the Cortical Hierarchy

Objective. Synchronization in activated regions of cortical networks affect the brain’s frequency response, which has been associated with a wide range of states and abilities, including memory. A non-invasive method for manipulating cortical synchronization is binaural beats. Binaural beats take advantage of the brain’s response to two pure tones, delivered independently to each ear, when those tones have a small frequency mismatch. The mismatch between the tones is interpreted as a beat frequency, which may act to synchronize cortical oscillations. Neural synchrony is particularly important for working memory processes, the system controlling online organization and retention of information for successful goal-directed behavior. Therefore, manipulation of synchrony via binaural beats provides a unique window into working memory and associated connectivity of cortical networks. Approach. In this study, we examined the effects of different acoustic stimulation conditions during an N-back working memory task, and we measured participant response accuracy and cortical network topology via EEG recordings. Six acoustic stimulation conditions were used: None, Pure Tone, Classical Music, 5 Hz binaural beats, 10 Hz binaural beats, and 15 Hz binaural beats. Main results. We determined that listening to 15 Hz binaural beats during an N-Back working memory task increased the individual participant’s accuracy, modulated the cortical frequency response, and changed the cortical network connection strengths during the task. Only the 15 Hz binaural beats produced significant change in relative accuracy compared to the None condition. Significance. Listening to 15 Hz binaural beats during the N-back task activated salient frequency bands and produced networks characterized by higher information transfer as compared to other auditory stimulation conditions.

The effect of binaural beats on verbal working memory and cortical connectivity

An efficiency framework for valence processing systems inspired by soft cross-wiring

Circadian dynamics in measures of cortical excitation and inhibition balance

Abstract In humans and monkeys, face perception activates a distributed cortical network that includes extrastriate, limbic, and prefrontal regions. Within face‐responsive regions, emotional faces evoke stronger responses than neutral faces (“valence effect”). We used fMRI and Dynamic Causal Modeling (DCM) to test the hypothesis that emotional faces differentially alter the functional coupling among face‐responsive regions. Three monkeys viewed conspecific faces with neutral, threatening, fearful, and appeasing expressions. Using Bayesian model selection, various models of neural interactions between the posterior (TEO) and anterior (TE) portions of inferior temporal (IT) cortex, the amygdala, the orbitofrontal (OFC), and ventrolateral prefrontal cortex (VLPFC) were tested. The valence effect was mediated by feedback connections from the amygdala to TE and TEO, and feedback connections from VLPFC to the amygdala and TE. Emotional faces were associated with differential effective connectivity: Fearful faces evoked stronger modulations in the connections from the amygdala to TE and TEO; threatening faces evoked weaker modulations in the connections from the amygdala and VLPFC to TE; and appeasing faces evoked weaker modulations in the connection from VLPFC to the amygdala. Our results suggest dynamic alterations in neural coupling during the perception of behaviorally relevant facial expressions that are vital for social communication.

Facial Expressions Evoke Differential Neural Coupling in Macaques

Inputs to prefrontal cortex support visual recognition in the aging brain

Scientists and clinicians can utilize a model-based framework to develop computational approaches to psychiatric practice and bring scientifi c discoveries to a clinical interface. This chapter describes a general modeling perspective, which complements those derived in previous chapters, and provides distinct examples to highlight the scientifi c and preclinical research that can evolve out of a computational framework to offer new tools for clinical practice. It begins by reviewing areas of theoretical and modeling studies that have reached a critical mass and outlines the pathophysiological insights that have been revealed. Three particular models are used to demonstrate how clinical questions, relating to understanding disease mechanisms and predicting treatment response, could be potentially addressed using an integrated computational framework. First, the phasic dopamine temporal difference model shows how neurophysiological and neuroanatomical research, incorporated into a learning circuit model, provides a constrained hypothesis testing framework, related to the likely multiple mechanisms contributing to addiction. Second, a potential application of generative models of neuroimaging measurements (dynamic causal models of EEG data) Group photos (top left to bottom right) Rosalyn Moran, Klaas Stephan, Cameron Carter, Michael Breakspear, Read Montague, Frederike Petzschner, Matthew Botvinick, Martin Paulus, Peter Kalivas, Read Montague, Rosalyn Moran, Matthew Botvinick, Martin Paulus, Peter Kalivas, group discussion, Michael Breakspear, Frederike Petzschner, Klaas Stephan, Matthew Botvinick and Read Montague, Rosalyn Moran, Cameron Carter From “Computational Psychiatry: New Perspectives on Mental Illness,” A. David Redish and Joshua A. Gordon, eds. 2016. Strüngmann Forum Reports, vol. 20, series ed. J. Lupp. Cambridge, MA: MIT Press. ISBN 978-0-262-03542-2.

Candidate Examples for a Computational Approach to Address Practical Problems in Psychiatry

Aging is accompanied by stereotyped changes in functional brain activations, for example a cortical shift in activity patterns from posterior to anterior regions is one hallmark revealed by functional magnetic resonance imaging (fMRI) of aging cognition. Whether these neuronal effects of aging could potentially contribute to an amelioration of or resistance to the cognitive symptoms associated with psychopathology remains to be explored. We used a visual illusion paradigm to address whether aging affects the cortical control of perceptual beliefs and biases. Our aim was to understand the effective connectivity associated with volitional control of ambiguous visual stimuli and to test whether greater top-down control of early visual networks emerged with advancing age. Using a bias training paradigm for ambiguous images we found that older participants (n = 16) resisted experimenter-induced visual bias compared to a younger cohort (n = 14) and that this resistance was associated with greater activity in prefrontal and temporal cortices. By applying Dynamic Causal Models for fMRI we uncovered a selective recruitment of top-down connections from the middle temporal to Lingual gyrus (LIN) by the older cohort during the perceptual switch decision following bias training. In contrast, our younger cohort did not exhibit any consistent connectivity effects but instead showed a loss of driving inputs to orbitofrontal sources following training. These findings suggest that perceptual beliefs are more readily controlled by top-down strategies in older adults and introduce age-dependent neural mechanisms that may be important for understanding aberrant belief states associated with psychopathology.

Aging into Perceptual Control: A Dynamic Causal Modeling for fMRI Study of Bistable Perception

Minimum statistical standards for submissions to Neuroimage: Clinical

Memory impairments and heightened prefrontal cortical (PFC) activity are hallmarks of cognitive and neurobiological human aging. While structural integrity of PFC gray matter and interregional white matter tracts are thought to impact memory processing, the balance of neurotransmitters within the PFC itself is less well understood. We used fMRI to establish whole-brain networks involved in a memory encoding task and dynamic causal models (DCMs) for fMRI to determine the causal relationships between these areas. These data revealed enhanced connectivity from PFC to medial temporal cortex that negatively correlated with recall ability. To better understand the intrinsic activity within the PFC, DCM for EEG was employed after continuous theta burst transcranial magnetic stimulation (TMS) to the PFC to assess the effect on excitatory/inhibitory (E/I) synaptic ratios and behavior. These data revealed that the young cohort had a stable E/I ratio that was unaffected by the TMS intervention, while the aged cohort exhibited lower E/I ratios driven by a greater intrinsic inhibitory tone. TMS to the aged cohort resulted in decreased intrinsic inhibition and a decrement in memory performance. These results demonstrate increased top-down influence of PFC upon medial temporal lobe in healthy aging that is associated with decreased memory and may be due to unstable local inhibitory tone within the PFC.

Altered Prefrontal Excitation/Inhibition Balance and Prefrontal Output: Markers of Aging in Human Memory Networks.

Binaural beats utilize a phenomenon that occurs within the cortex when two different frequencies are presented separately to each ear. This procedure produces a third phantom binaural beat, whose frequency is equal to the difference of the two presented tones and which can be manipulated for non-invasive brain stimulation. The effects of binaural beats on working memory, the system in control of temporary retention and online organization of thoughts for successful goal directed behavior, have not been well studied. Furthermore, no studies have evaluated the effects of binaural beats on brain connectivity during working memory tasks. In this study, we determined the effects of different acoustic stimulation conditions on participant response accuracy and cortical network topology, as measured by EEG recordings, during a visuospatial working memory task. Three acoustic stimulation control conditions and three binaural beat stimulation conditions were used: None, Pure Tone, Classical Music, 5Hz binaural beats, 10Hz binaural beats, and 15Hz binaural beats. We found that listening to 15Hz binaural beats during a visuospatial working memory task not only increased the response accuracy, but also modified the strengths of the cortical networks during the task. The three auditory control conditions and the 5Hz and 10Hz binaural beats all decreased accuracy. Based on graphical network analyses, the cortical activity during 15Hz binaural beats produced networks characteristic of high information transfer with consistent connection strengths throughout the visuospatial working memory task.

The Effect of Binaural Beats on Visuospatial Working Memory and Cortical Connectivity

State space models and their spectral decomposition in dynamic causal modeling

Following the discovery of the antidepressant properties of ketamine, there has been a recent resurgence in the interest in this NMDA receptor antagonist. Although detailed animal models of the molecular mechanisms underlying ketamine's effects have emerged, there are few MEG/EEG studies examining the acute subanesthetic effects of ketamine infusion in man. We recorded 275 channel MEG in two experiments (n = 25 human males) examining the effects of subanesthetic ketamine infusion. MEG power spectra revealed a rich set of significant oscillatory changes compared with placebo sessions, including decreases in occipital, parietal, and anterior cingulate alpha power, increases in medial frontal theta power, and increases in parietal and cingulate cortex high gamma power. Each of these spectral effects demonstrated their own set of temporal dynamics. Dynamic causal modeling of frontoparietal connectivity changes with ketamine indicated a decrease in NMDA and AMPA-mediated frontal-to-parietal connectivity. AMPA-mediated connectivity changes were sustained for up to 50 min after ketamine infusion had ceased, by which time perceptual distortions were absent. The results also indicated a decrease in gain of parietal pyramidal cells, which was correlated with participants' self-reports of blissful state. Based on these results, we suggest that the antidepressant effects of ketamine may depend on its ability to change the balance of frontoparietal connectivity patterns. SIGNIFICANCE STATEMENT In this paper, we found that subanesthetic doses of ketamine, similar to those used in antidepressant studies, increase anterior theta and gamma power but decrease posterior theta, delta, and alpha power, as revealed by magnetoencephalographic recordings. Dynamic causal modeling of frontoparietal connectivity changes with ketamine indicated a decrease in NMDA and AMPA-mediated frontal-to-parietal connectivity. AMPA-mediated connectivity changes were sustained for up to 50 min after ketamine infusion had ceased, by which time perceptual distortions were absent. The results also indicated a decrease in gain of parietal pyramidal cells, which was correlated with participants' self-reports of blissful state. The alterations in frontoparietal connectivity patterns we observe here may be important in generating the antidepressant response to ketamine.

Evidence that Subanesthetic Doses of Ketamine Cause Sustained Disruptions of NMDA and AMPA-Mediated Frontoparietal Connectivity in Humans

Deep brain stimulation for neurodegenerative disease: a computational blueprint using dynamic causal modeling.

Dynamic Causal Models for Human Electrophysiology: EEG, MEG, and LFPs

Animal [Vyazovskiy et al., 2011] and human [Huber et al., 2012] data indicate that neuronal excitability linearly increases with time awake. However, recent animal data posit that synaptic efficacy and morphology depend on time of day and on the biological clock [Liston et al., 2013]. Collectively, these data point to uncertainties about how brain dynamics are orchestrated by sleepand biological clock-dependent processes. Dynamic Causal Modelling for electroencephalography (DCM-EEG) provides a validated non-invasive framework for inferences on in vivo neuronal architectures that generate electrophysiological measures, based on physiologically plausible priors [Friston et al., 2003; Moran et al., 2015]. Here, our aim was to apply DCM-EEG to the EEG evoked responses evoked by Transcranial Magnetic Stimulation (EEG-TMS) over the prefrontal cortex (PFC, highly sensitive to sleep pressure [Finelli et al., 2000]), to investigate the dynamics of human neuronal excitation/inhibition as a function of sleep need and of the biological clock.

Neuronal excitation/inhibition balance is set by the need for sleep and the biological clock

Advances in deep brain stimulation (DBS) therapeutics for neurological and psychiatric disorders represent a new clinical avenue that may potentially augment or adjunct traditional pharmacological approaches to disease treatment. Using modern molecular biology and genomics, pharmacological development proceeds through an albeit lengthy and expensive pipeline from candidate compound to preclinical and clinical trials. Such a pathway, however, is lacking in the field of neurostimulation, with developments arising from a selection of early sources and motivated by diverse fields including surgery and neuroscience. In this chapter, I propose that biophysical models of connected brain networks optimized using empirical neuroimaging data from patients and healthy controls can provide a principled computational pipeline for testing and developing neurostimulation interventions. Dynamic causal modeling (DCM) provides such a computational framework, serving as a method to test effective connectivity between and within regions of an active brain network. Importantly, the methodology links brain dynamics with behavior by directly assessing experimental task effects under different behavioral or cognitive sets. Therefore, healthy brain dynamics in circuits of interest can be defined mathematically with stimulation interventions in pathological counterparts simulated with the goal of restoring normal functionality. In this chapter, I outline the dynamic characterization of brain circuits using DCM and propose a blueprint for testing in silico, the effects of stimulation in neurodegenerative disorders affecting cognition. In particular, the models can be simulated to test whether neuroimaging correlates of nondiseased brain dynamics can be reinstantiated in a pathological setting using Progress in Brain Research, ISSN 0079-6123, http://dx.doi.org/10.1016/bs.pbr.2015.07.002 © 2015 Elsevier B.V. All rights reserved. 1 ARTICLE IN PRESS

BOX 1 OUTLOOK OF ONGOING TRIALS FOR THE DEVELOPMENT OF DBS THERAPEUTICS IN EXEMPLAR PSYCHIATRIC DISORDER : TREATMENT-RESISTANT EPILEPSY

Human cortical excitability and excitation/inhibition balance is set by the circadian timing system

Parkinson's Disease (PD), characterized by tremor, rigidity, and bradykinesia, is one of the most prevalent neurodegenerative disorders in the world. The pathological hallmark of PD is the loss of dopaminergic cells in the substantia nigra and other brain regions. The pathophysiological mechanisms by which dopaminergic cell loss leads to the motor manifestations of PD are yet to be fully elucidated. A growing body of evidence has revealed abnormal neuronal oscillations within and between multiple brain regions in PD. Unique oscillatory patterns are associated with specific motor abnormalities in PD. Therapies, such as dopaminergic medication and deep brain stimulation that disrupt these abnormal neuronal oscillatory patterns produce symptomatic improvement in PD patients. These findings emphasize the importance of abnormal neuronal oscillations in the pathophysiology of PD, making the disruption of these oscillatory patterns a promising target in the development of effective PD treatments.

The circadian system sets the temporal organization of basic human neuronal function

Dynamics of human cortical ensembles are set by circadian system and sleep homeostasis

Acetylcholine (ACh) is a neuromodulatory transmitter implicated in perception and learning under uncertainty. This study combined computationalsimulationsandpharmaco-electroencephalographyinhumans,totestaformulationofperceptualinferencebasedupon the free energy principle. This formulation suggests that ACh enhances the precision of bottom-up synaptic transmission in cortical hierarchies by optimizing the gain of supragranular pyramidal cells. Simulations of a mismatch negativity paradigm predicted a rapid trial-by-trial suppression of evoked sensory prediction error (PE) responses that is attenuated by cholinergic neuromodulation. We confirmed this prediction empirically with a placebo-controlled study of cholinesterase inhibition. Furthermore, using dynamic causal modeling, we found that drug-induced differences in PE responses could be explained by gain modulation in supragranular pyramidal cells in primary sensory cortex. This suggests that ACh adaptively enhances sensory precision by boosting bottom-up signaling when stimuliarepredictable,enablingthebraintorespondoptimallyunderdifferentlevelsofenvironmentaluncertainty.

The neuroscience of human decision-making has focused on localizing brain activity correlating with decision variables and choice, most commonly using functional MRI (fMRI). Poor temporal resolution means these studies are agnostic in relation to how decisions unfold in time. Consequently, here we address the temporal evolution of neural activity related to encoding of risk using magnetoencephalography (MEG), and show modulations of electromagnetic power in posterior parietal and dorsomedial prefrontal cortex (DMPFC) which scale with both variance and skewness in a lottery, detectable within 500 ms following stimulus presentation. Electromagnetic responses in somatosensory cortex following this risk encoding predict subsequent choices. Furthermore, within anterior insula we observed early and late effects of subject-specific risk preferences, suggestive of a role in both risk assessment and risk anticipation during choice. The observation that cortical activity tracks specific and independent components of risk from early time-points in a decision-making task supports the hypothesis that specialized brain circuitry underpins risk perception.

Detecting sudden environmental changes is crucial for the survival of humans and animals. In the human auditory system the mismatch negativity (MMN), a component of auditory evoked potentials (AEPs), reflects the violation of predictable stimulus regularities, established by the previous auditory sequence. Given the considerable potentiality of the MMN for clinical applications, establishing valid animal models that allow for detailed investigation of its neurophysiological mechanisms is important. Rodent studies, so far almost exclusively under anesthesia, have not provided decisive evidence whether an MMN analogue exists in rats. This may be due to several factors, including the effect of anesthesia. We therefore used epidural recordings in awake black hooded rats, from two auditory cortical areas in both hemispheres, and with bandpass filtered noise stimuli that were optimized in frequency and duration for eliciting MMN in rats. Using a classical oddball paradigm with frequency deviants, we detected mismatch responses at all four electrodes in primary and secondary auditory cortex, with morphological and functional properties similar to those known in humans, i.e., large amplitude biphasic differences that increased in amplitude with decreasing deviant probability. These mismatch responses significantly diminished in a control condition that removed the predictive context while controlling for presentation rate of the deviants. While our present study does not allow for disambiguating precisely the relative contribution of adaptation and prediction error processing to the observed mismatch responses, it demonstrates that MMN-like potentials can be obtained in awake and unrestrained rats.

Mismatch Responses in the Awake Rat: Evidence from Epidural Recordings of Auditory Cortical Fields

Dynamic Causal Models for Human Electrophysiology: EEG, MEG, and Local Field Potentials

Magnetoencephalography studies in humans have shown word-selective activity in the left inferior frontal gyrus (IFG) approximately 130 ms after word presentation ( Pammer et al. 2004; Cornelissen et al. 2009; Wheat et al. 2010). The role of this early frontal response is currently not known. We tested the hypothesis that the IFG provides top-down constraints on word recognition using dynamic causal modeling of magnetoencephalography data collected, while subjects viewed written words and false font stimuli. Subject-specific dipoles in left and right occipital, ventral occipitotemporal and frontal cortices were identified using Variational Bayesian Equivalent Current Dipole source reconstruction. A connectivity analysis tested how words and false font stimuli differentially modulated activity between these regions within the first 300 ms after stimulus presentation. We found that left inferior frontal activity showed stronger sensitivity to words than false font and a stronger feedback connection onto the left ventral occipitotemporal cortex (vOT) in the first 200 ms. Subsequently, the effect of words relative to false font was observed on feedforward connections from left occipital to ventral occipitotemporal and frontal regions. These findings demonstrate that left inferior frontal activity modulates vOT in the early stages of word processing and provides a mechanistic account of top-down effects during word recognition.

Reading Front to Back: MEG Evidence for Early Feedback Effects During Word Recognition

Theta oscillations in the local field potential of neural ensembles are considered key mediators of human working memory. Theoretical accounts arising from animal hippocampal recordings propose that the phase of theta oscillations serves to instantiate sequential neuronal firing to form discrete representations of items held online. Human evidence of phase relationships in visual working memory has enhanced this theory, implicating long theta cycles in supporting greater memory capacity. Here we use human magnetoencephalographic recordings to examine a novel, alternative principle of theta functionality. The principle we hypothesize is derived from information theory and predicts that rather than long (low frequency) theta cycles, short (high frequency) theta cycles are best suited to support high information capacity. From oscillatory activity recorded during the maintenance period of a visual working memory task we show that a network of brain regions displays an increase in peak 4–12 Hz frequency with increasing memory load. Source localization techniques reveal that this network comprises bilateral prefrontal and right parietal cortices. Further, the peak of oscillation along this theta–alpha frequency axis is significantly higher in high capacity individuals compared to low capacity individuals. Importantly while we observe the adherence of cortical neuronal oscillations to our novel principle of theta functioning, we also observe the traditional inverse effect of low frequency theta maintaining high loads, where critically this was located in medial temporal regions suggesting parallel, dissociable hippocampal-centric, and prefrontal-centric theta mechanisms.

Peak Frequency in the Theta and Alpha Bands Correlates with Human Working Memory Capacity

Detection of auditory evoked potentials and mismatch negativity-like responses in the awake and unrestrained rat.

Previous event‐related potential (ERP) studies have identified the superior parietal lobule (SPL) as actively multisensory. This study compares effective, or contextually active, connections to this region under unisensory and multisensory conditions. Effective connectivity, the influence of one brain region over another, during unisensory visual, unisensory auditory and multisensory audiovisual stimulation was investigated. ERPs were recorded from subdural electrodes placed over the parietal lobe of three patients while they conducted a rapid reaction‐time task. A generative model of interacting neuronal ensembles for ERPs was inverted in a scheme allowing investigation of the connections from and to the SPL, a multisensory processing area. Important features of the ensemble model include inhibitory and excitatory feedback connections to pyramidal cells and extrinsic input to the stellate cell pool, with extrinsic forward and backward connections delineated by laminar connection differences between ensembles. The framework embeds the SPL in a plausible connection of distinct neuronal ensembles mirroring the integrated brain regions involved in the response task. Bayesian model comparison was used to test competing feed‐forward and feed‐backward models of how the electrophysiological data were generated. Comparisons were performed between multisensory and unisensory data. Findings from three patients show differences in summed unisensory and multisensory ERPs that can be accounted for by a mediation of both forward and backward connections to the SPL. In particular, a negative gain in all forward and backward connections to the SPL from other regions was observed during the period of multisensory integration, while a positive gain was observed for forward projections that arise from the SPL.

Changes in effective connectivity of human superior parietal lobule under multisensory and unisensory stimulation

Objectives: The aim of this project was to evaluate the diagnostic accuracy of an automated, remote system for correctly identifying vocal fold paralysis. Methods: Consecutive patients presenting for vocal analysis at the Beaumont Hospital Voice Clinic were enrolled in this prospective, blinded study. Control patients were enlisted from routine otolaryngology clinics. All patients were assessed by standard history, clinical examination, and flexible laryngoscopy or videostroboscopy. The subjects were blindly assessed by remote voice analysis. Sustained phonation was recorded over a standard telephone network. Each recording was subjected to automated, remote analysis of extracted features, including measures of pitch perturbation, amplitude perturbation, and harmonics-to-noise ratio. The presence or absence of a vocal fold paralysis as determined by the automated classifier was recorded and correlated with clinical findings. Results: Seventy-eight consecutive patients were enrolled in the study. The automated speech analysis system demonstrated 92% sensitivity and 75% specificity for detecting vocal fold paralysis. Conclusions: This pilot study, assessing an automated system that analyzes audiological data remotely over the standard telephone network, suggests that with further “training” it may become a reliable, simple, and convenient means for screening patients for voice disorders.

Performance of an Automated, Remote System to Detect Vocal Fold Paralysis

A recent neural mass model of ERP generation (David, Friston et al. Modelling event-related responses in the brain. NeuroImage 25, 2005.) has identified different ERP patterns dependent on the type of hierarchy in which a given cortical area is embedded. These hierarchies include (i) bottom-up processing with intrinsic excitation, where the feedforward structure may extend for one to many areas, (ii) top-down processing from high-level cortical areas and (iii) lateral processes with excitation from anatomically local neuronal pools. 
 
Here, in the area of the lateral superior parietal lobule Event Related Potentials have been extracted for unimodal audio and visual, and multimodal AV behavioural, button-press response tasks using intracranial EEG. This study presents a methodology where this neural mass model may be fitted to these ERPs, for the purpose of examining multimodal integration. 
 
Results show that pertinent ERP features, including important late components, are best fitted to real data by the optimisation of delay and area connectivity parameters. Model parameters that describe intrinsic area connections and operation (e.g. max EPSP, max IPSP, maximum firing rate) are less significant when attempting to fit the model set to real intracranial EEG. 
 
This work is a necessary precursor to developing an optimisation scheme for multimodal, data-driven models.

Fitting Intracranial multimodal ERPs to an exploratory, hierarchically arranged neural mass model.

A neural mass model of interacting macro-columns is stimulated to reproduce unisensory, auditory and visually evoked potentials and multisensory (concurrent audiovisual) evoked potentials. These were elicited from patients conducting a reaction response task and recorded from intracranial electrodes placed on the parietal lobe. Important features of this model include inhibitory and excitatory feedback connections to pyramidal cells and extrinsic input to the stellate cell pool, with provision for hierarchical positioning depending on extrinsic connections. Both auditory and visually evoked potentials were best fit using a top-down paradigm. The multisensory response reconstructed from its constituent models was then compared to the actual multisensory EP. Fitting of the multisensory response from constituent models to the actual response required no significant changes to the architecture but did require a decrease in top-down feedback delay. This suggests that multisensory integration, and its related improvement in reaction behavior is not an automatic process but instead controlled by a central executive functioning

Neural Mass Model of multisensory integration in the Superior Parietal Lobe using intracranial EEG

A system of remotely detecting vocal fold pathologies using telephone quality speech is presented. Using VoiceXML, a database of 631 clean speech files of the sustained phonation of the vowel sound /a/ (58 normal subjects, 573 pathologic) from the Disordered Voice Database Model 4337 was transmitted over telephone channels to produce a test corpus. Pitch perturbation features, amplitude perturbation features and a set of measures of the harmonic-to-noise ratio are extracted from the clean and transmitted speech files. These feature sets are used to test and train automatic classifiers, employing the method of Linear Discriminant Analysis. Cross-fold validation was employed to measure classifier performances. While a sustained phonation can be classified as normal or pathologic with accuracy greater than 90%, results indicate that a telephone quality speech can be classified as normal or pathologic with an accuracy of 74.15%. Amplitude perturbation features proving most robust in channel transmission. This study highlights the real possibility for remote diagnosis of voice pathology.

Telephone Based Voice Pathology Assessment using Automated Speech Analysis and VoiceXML

A system of remotely detecting vocal fold pathologies using telephone quality speech recorded during a telephone dialogue is presented. This study aims at developing a dialogue system using VoiceXML for remote diagnosis of voice pathology. To assess the accuracy of the system, a database of 631 clean speech files of the sustained phonation of the vowel sound /a/ (58 normal subjects, 573 pathologic) from the Disordered Voice Database Model 4337 was transmitted over telephone channels to produce a test corpus. Pitch perturbation features, amplitude perturbation features and a set of measures of the harmonicto-noise ratio are extracted from the clean and transmitted speech files. These feature sets are used to test and train automatic classifiers, employing the method of Linear Discriminant Analysis. Cross-fold validation was employed to measure classifier performances. While a sustained phonation can be classified as normal or pathologic with accuracy greater than 90%, results indicate that a telephone quality speech can be classified as normal or pathologic with an accuracy of 74.15%. Amplitude perturbation features proving most robust in channel transmission. This study highlights the real possibility for remote diagnosis of voice pathology.

Voice Pathology Assessment Based on a Dialogue System and Speech Analysis

1) Anaesthesia, Pain & Critical Care Sciences, School of Physiology, Pharmacology & 6 Neuroscience, Biomedical Sciences Building, University of Bristol, Bristol, BS8 1TD, UK. 7 2) Clinical Research and Imaging Centre, School of Psychological Science, University of 8 Bristol, Bristol, BS8 1TU, UK 9 3) Medical Physics, University Hospitals Bristol & Weston NHS Trust, Bristol, BS2 8HW, 10 UK. 11 4) Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, 12 King's College London, London, SE5 8AF, UK. 13 5) Wellcome Wolfson Brain Imaging Centre, School of Psychology, Lawrence Stenhouse 14 Building, University of East Anglia, Norwich, NR4 7TJ, UK. 15 6) Department of Anesthesiology, University of California San Diego, 9500 Gilman Dr, La 16 Jolla, CA 92093, USA. 17

Item-level analysis of mental health symptom trajectories during the COVID-19 pandemic in the UK: Associations with age, sex and pre-existing psychiatric conditions

Peripheral brain-derived neurotrophic factor (BDNF) in insomnia: A systematic review and meta-analysis.

Information is increasingly digital, creating opportunities to respond to pressing issues about human populations using linked datasets that are large, complex, and diverse. The potential social and individual benefits that can come from data-intensive science are large, but raise challenges of balancing individual privacy and the public good, building appropriate socio-technical systems to support data-intensive science, and determining whether defining a new field of inquiry might help move those collective interests and activities forward. A combination of expert engagement, literature review, and iterative conversations led to our conclusion that defining the field of Population Data Science (challenge 3) will help address the other two challenges as well. We define Population Data Science succinctly as the science of data about people and note that it is related to but distinct from the fields of data science and informatics. A broader definition names four characteristics of: data use for positive impact on citizens and society; bringing together and analyzing data from multiple sources; finding population-level insights; and developing safe, privacy-sensitive and ethical infrastructure to support research. One implication of these characteristics is that few people possess all of the requisite knowledge and skills of Population Data Science, so this is by nature a multi-disciplinary field. Other implications include the need to advance various aspects of science, such as data linkage technology, various forms of analytics, and methods of public engagement. These implications are the beginnings of a research agenda for Population Data Science, which if approached as a collective field, can catalyze significant advances in our understanding of trends in society, health, and human behavior.

A Position Statement on Population Data Science: The Science of Data about People

This consensus statement reflects the deliberations of an international group of stakeholders with a range of expertise in public involvement and engagement (PI&E) relating to data-intensive health research. It sets out eight key principles to establish a secure role for PI&E in and with the research community internationally and ensure best practice in its execution. Our aim is to promote culture change and societal benefits through ensuring a socially responsible trajectory for innovations in this field. 
Our key premise is that the public should not be characterised as a problem to be overcome but a key part of the solution to establish socially beneficial data-intensive health research for all.

Consensus Statement on Public Involvement and Engagement with Data Intensive Health Research

The report presents a model along with proposals for the types of infrastructure and services required to enable safe access, usage and linkage of data in relation to the health research field.

The DASSL or Data Access, Storage, Sharing and Linkage Model & Proposals for an Enabling Data Environment for Health and Related Research in Ireland

The institutional response to mental disorder in Ireland: censuses of Irish asylums, psychiatric hospitals and units 1844–2014

Investigadores del proyecto: Angel Bodoque, Jose Miguel Garcia, Andrea Murillo, Juan Emilio Oviedo, Clara Penin, Maria Dolores Millan, Elena Dominguez, Rosa Ana Moran, Ignacio Ubaldo, Pedro Perez Enciso, Marc Robinson, Mar Jimeno, Rosa Rocha, Javier Luis Parra, Willem F. Korthals Altes, Jose Manuel Sanchez

Study on judicial cooperation, mutual legal assistance and extradition of drug traffickers and other drug-related crime offenders, between the EU and its Member States and Latin American and Caribbean (LAC) countries

It's good to talk: distress disclosure and psychological wellbeing

This is the first population-based mental health telephone survey that allows for direct comparisons between the Republic of Ireland and Northern Ireland. 
 
The findings show: 
 
 * A higher prevalence of self-reported mental health problems in the North than in the Republic 
 * A higher use of psychotropic medication for the Northern Ireland than the Republic * A higher proportion of people in Northern Ireland attended the GP for mental helath problems than in the Republic 
 * There were no differences between the jurisdictions in the use of secondary mental health services or in the preferred sources of support which included the GP and family and friends

Mental health and associated health service use on the island of Ireland

The main aims of this report are to determine the socio-demographic characteristics of 
the Irish adult population who were experiencing symptoms of psychological distress 
or who had reported mental health problems in the previous year. In addition, the 
report describes primary care service use for mental health problems and secondary 
mental health services use over a one-year period. The findings were extrapolated to 
the general population and set against other available data relating to mental health 
service use in Ireland. This information is the most comprehensive to date on the 
extent of psychological distress and mental health problems in Ireland and the use of 
services by people seeking help with these problems.

Psychological distress, mental health problems and use of health services in Ireland

This report presents data on all admissions to, discharges from, and deaths in, Irish psychiatric units and hospitals obtained from the National Psychiatric In-patient Reporting System (NPIRS) in 2007. Data are presented nationally, regionally by HSE area, and locally, by county, by hospital type and by individual unit and hospital. Rates reported are per 100,000 total population.

Activities of Irish psychiatric units and hosptials 2007. HRB Statistics series 5.

This paper investigated the demographic attributes of Internet users in Ireland, 
and provided an in-depth analysis of demographic and self-reported mental health 
characteristics of Internet users who search for health information online. It also 
examined the willingness of respondents who do not use the Internet as a source of 
information on health, to potentially use it for health information.

Internet use and seeking health information online in Ireland: demographic characteristics and mental health characteristics of users and non-users.

The study describes and evaluates the nature and quality of community residential accommodation and the extent to which it met the needs of residents. The functioning of community residences with reference to the appropriateness of premises and their operational role in providing for the residents is discussed. Residents themselves were the prime reporting agents as to the view of their lives and their degree of satisfaction with current service provision. The interaction of the residents with their neighbourhood and environment was also investigated. Enquiry was made as to their ‘citizenisation’, such as voting registration, participation in social amenities and use of community services. In addition, staff understanding of the aims and functions of the residences and their perceptions of the factors that promoted or impeded independent living were investigated.

Happy living here... A survey and evaluation of community residential mental health services in Ireland.

A census of high support community residences in Ireland was carried out on the night of the 31 March 2006. The purpose of the census was to gather information on resident in high support community residences provided by the mental health services on the night of the census. The 2006 census, the second in the series, has expanded the scope of the previous census by gathering information on diagnosis and daytime activities such as employment, attendance at day centres, and training. All residences operating under the provisions of the Mental Health Act (2001) were reviewed.

High support community residences census 2006. HRB Statistics Series 1.

Summary To summarise, the age distribution of the sample mirrored that of the national adult population, with 86% of the sample between the ages of 18 years and 64 years and 14% of the sample aged 65 years or over. Nearly one-half of the sample was married, more than one-half was employed, one-fifth was professionals/managers, while over one-quarter reported other non-manual occupations. The majority of respondents had attained second-level education; more than one-half was in the category main earners; and one-half was in paid employment. The reported weekly household income of one-half of the respondents was in the range of 500–749 Euro. Nearly one-half of respondents lived in a small town with a population less than 5,000 people, with about one-third being from the city and county of Dublin. Nearly one-half had private medical insurance, and the majority did not have any dependent children living with them. The majority of those who had children had one or two dependent children living in their household.

HRB National psychological wellbeing and distress survey: baseline results

This paper investigated the relationship between levels of distress disclosure and psychological wellbeing in the general population. Two measures of psychological wellbeing were used – the 12–item General Health Questionnaire (GHQ12) and a self–reported rating of participants’ mental health in the previous 12 months. Distress disclosure was measured using a 12–item Likert scale called the Distress Disclosure Index. Distress disclosure was defined as an individual’s willingness to disclose distressing personal information to others. A nationally representative sample of 2,711 adults aged 18 years and over living in private households in Ireland was surveyed. Four socio–demographic determinants of levels of distress disclosure were explored including gender, age, marital status and geographic location. 
 
The association between distress disclosure and psychological wellbeing was investigated. The Distress Disclosure Index was found to be a statistically valid, unidimensional measure. Statistically significant differences were found in levels of distress disclosure in terms of the four socio–demographic variables and significant correlations were found between levels of distress disclosure and psychological wellbeing. Those most willing to disclose distressing information to others were females and those in the younger age groups. Furthermore a greater willingness to disclose distressing information was related to better mental health. The findings have implications for the promotion of psychological health and wellbeing and help seeking behaviour.

It's good to talk: distress disclosure and psychological wellbeing. HRB Research Series 1.

Psychiatric day care: an underused option? The purposes and functions of psychiatric day hospitals and day centres: a study in two health boards / by Tara Hickey, Rosalyn Moran and Dermot Walsh

This collection of papers was developed as part of the work undertaken by the 
Drug Misuse Research Division (DMRD) in the context of its work as Focal Point 
to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). 
The EMCDDA is a European Union (EU) institution providing information 
concerning drugs and drug addiction and their consequences. The EMCDDA 
works to improve the comparability of drug-related data in the member states, 
and to disseminate information and co-operate with international bodies dealing 
with drug-related issues. In fulfilling its role, the EMCDDA co-operates with a 
network of 'focal points' or national centres dealing with drug-related issues in 
the member states. This network is called the REITOX network (European 
Information Network on Drugs and Drug Addiction). The DMRD of the Health 
Research Board (HRB) is the designated Irish Focal Point for the REITOX 
network. Focal Points act as an information resource to the EMCDDA in relation 
to the national situation in each member state and disseminate European-level 
information nationally.

This chapter reports results of studies that examined certain social issues associated with drug misuse, including housing, homelessness, public nuisance, and community problems. The need for more research into social and economic costs of drug misuse is highlighted. Findings from the first national survey of public attitudes to drugs, drug users, drug policy etc. carried by the Drug Misuse Research Division of the Health Research Board, are discussed. Some drug-related issues, which have been the subject of recent public debate, are outlined.

This publication provides an overview of issues related to drug misuse in Ireland, 
focusing on information available up to mid-2000. The term 'drug misuse', as used in 
rhis report, refers to the taking of a legal and/or illegal drug that harms the physical, 
mental or social well being of the individual, the group or society. 
A general overview of the situation in Ireland regarding different aspects of the drugs 
phenomenon is presented. The content is descriptive rather than analytic. The authors 
envisage thar the document will be used as a resource document. Much of the 
information presented is not readily available in the Irish context; thus, this volume, 
which gathers a wide range of information together, should be of use to individuals and 
groups interested in rhe drugs area in Ireland.

This chapter describes Irish government strategy in relation to illegal drugs, the main institutional mechanism to implement this strategy, and the budget and funding arrangements to resource implementation. The Government's approach to the drugs problem is embedded by in the broad social inclusion framework outlined in the various social partnership arrangements, and this approach will be reflected in the National Drug Strategy currently being framed. The key objectives of the current strategy and the basic principles that underlie this strategy are outlined. The role of the Local Drug Task Forces and the Young People's Facilities and Services Fund in this overall strategy are explained. The institutional mechanisms, involving several individual government departments and various inter-departmental committees, are described. The section on budget and funding arrangements provides details of the funding to support the drugs initiative and social inclusion measures under the National Development Plan 2000-2006.

This chapter describes a number of demand reduction programmes or interventions, which fall under the general headings - prevention, harm minimisation and treatment. The authors highlight the need to develop a culture of evaluation around the development of programmes aiming to reduce the demand for drugs, and the need for on-going training and support of such evaluation. The chapter also presents an overview of the training courses available in Ireland in the drugs area. A number of initiatives in disseminating information on drug misuse in Ireland are noted, including DrugNet Ireland - the newsletter of the Drug Misuse Research Division - the Exchange on Drug Demand Reduction Action - an EMCDDA sponsored database- and the National Documentation Centre on Drug Misuse.

In 2000 there were 24,282 admissions to Irish psychiatric hospitals and units, a rate of 901.0 per 
100,000 population aged 16 years and over. There were 7,290 first admissions, representing a rate of 
270.5 per 100,000 population. The re-admission rate was 630.5, representing 70% of all admissions. 
Males accounted for over half (53%) of all admissions. Similarly, over half of all admissions (54%) were 
for single persons. The 45-54 year age group had the highest rate of admission at 1,129.2 per 
100,000, while the 16-19 year age group had the lowest at 295.7. Among occupational groups, the 
unskilled had the highest rate of admission at 1,182.6 per l00,000 while own account workers had the 
lowest at 60.7. Three main diagnoses accounted for over two thirds of all admissions with depressive 
disorders accounting for 31 % and schizophrenia and alcoholic disorders each accounting for 19%. 
Eleven per cent of all admissions were non-voluntary.

This report presents the findings of a nation-wide survey of public attitudes towards, and perceptions of, aspects of the drug issue in Ireland. The questionnaire on which the research was based constituted a module of the 1998 Irish Social Omnibus Survey. A total of 1,000 individuals, randomly selected from the 1997 Register of Electors for Ireland (26 counties), took part in the study. Data was collected using face-to-face interviews between February and April 1998. The survey found that members of the general public were generally aware of the kinds of illegal drugs most commonly used. Self-reported cannabis use (as measured by lifetime prevalence) stood at 12 per cent. The younger urban sector of society tended to have greater personal experience of cannabis, to know people who had taken cannabis or had 'a drug problem'. The results indicated a high level of concern about the current drug situation among the general public. Three quarters of the respondents were of the opinion that the current drug situation in Ireland was 'out of control'. There was concern also regarding the legal drug, alcohol. Over half of respondents (56%) considered that alcohol abuse caused more problems in society than drug abuse. A substantial proportion of respondents believed that experimentation with drugs was commonplace among young people. Respondents generally regarded illegal drug taking as a dangerous pursuit. Social avoidance and fear of drug users and those addicted to drugs were high among respondents. Moreover, sympathy for drug addicted individuals was relatively low, with over half the respondents believing that those with a drug problem had only themselves to blame. Those with personal knowledge of someone 'with a drug problem' typically held more positive attitudes towards those who were addicted to drugs. Consistent with the widespread concern about the severity of the current drug situation was an overwhelmingly high level of support for drug prevention. Current harm reduction initiatives, including the provision of heroin substitutes such as methadone, and needle exchange facilities to heroin dependent clients, received support from two thirds of respondents (63% and 66% respectively).

Drug-related knowledge, attitudes and beliefs in Ireland: report of a nation wide survey.

This report serves both as a report on the specific drug situation in Ireland and as the Irish submission for the European Monitoring Centre for Drugs and Drug Addiction annual report on the state of the drugs problem in the European Union. 
 
The first section outlines Irish drug policy with regard to legislation, administration and organisation, and new developments in the reporting year. Part 2 describes the epidemiological situation. The 3rd and 4th sections describe demand reduction interventions, and key issues respectively.

Annotated bibliography of drug misuse in Ireland / Aoife O'Brien, Rosalyn Moran, Mary O'Brien

The first section outlines Irish drug policy with regard to legislation, administration and organisation, and new developments in the reporting year. Part2 provides an overview of drug monitoring systems and sources of information. The 3rd and 4th sections describe the epidemiological situation and demand reduction interventions, respectively.

The health consequences of drug use are a priority area for the EMCDDA and impaired driving and road traffic accidents linked to drugs constitute an important topic on which comprehensive information is lacking. The literature review addressed inter alia the relationship between different patterns of drug consumption, impaired driving and traffic accidents. In addition drug testing procedures and associated legislation regarding drug-impaired driving in the different EU Member States were described and the issues raised by such testing reviewed. The outcomes of the study included a scientific literature review and annotated bibliography on the relation between drug use, impaired driving and traffic accidents. Download as PDF English (en) [1]

Literature Review on the Relation between Drug Use, Impaired Driving and Traffic Accidents

The legal hazards of driving under the influence (DUI) are frequently not appreciated by alcohol users. Physicians who treat such patients following collisions are often unaware of the judicial disposition following hospital discharge. We examined the courthouse records of 5 1 1 intoxicated drivers involved in collisions and admitted to one Level 1 Trauma Center to determine if DUI arrests and convictions were obtained. The proportion arrested for DUI ranged from 6%-54% (mean 4 1 %) depending on county of

An inventory of literature on the relation between drug use, impaired driving and traffic accidents.

The issue of childcare in drug treatment facilities has implications for the equality of access to treatment (mostly for women), quality of treatment, quality of working life for staff in the treatment centres and emotional and educational development of children of drug misusers. This report aims to bridge the gap in research on creche facilities in drug treatment centres to inform policy and planning. All drug treatment centres in Dublin were consulted. Of the 45 centres, 9 provided creche facilities. All of the creches studied operated from premises on or near the treatment service. Treatment staff, parents/ guardians and children form 6 of the 9 centres were interviewed using a semi-structured questionnaire. In all of the centres studied, the creche facilities could only be utilised when the parent/ guardian was receiving treatment. In 5 of the 6 centres the children use the creche for a short time while the parent/ guardian received treatment. The sixth centre provided an all day creche in association with a reintegration/ rehabilitation programme. Without access to these creches many clients could not have availed of the treatment and rehabilitation programmes provided. The study revealed that drug-misusing parents (mostly women) often felt limited in tackling their drug dependence without access to regular childminding arrangements, thus highlighting the importance of creche facilities in attempting to treat drug misuse.

The availability, use and evaluation of the provision of crèche facilities in association with drug treatment.

The Drug Misuse Research Division of the Health Research Board operates the National Drug Treatment Reporting System (NDTRS). The system is used to provide epidemiological information on treated problem drug misuse in Ireland and informs policy makers, researchers and the general public. The NDTRS collates data from participating treatment centres in all Health Board areas, however a gap in information exists in that drug misusers in treatment units within prisons and those treated by General Practitioners are not included. This study aims to determine the feasibility of including these two groups to increase coverage of the NDTRS and outlines preliminary steps for their inclusion.

A Study on the Feasibility of the Inclusion of General Practitioners and Prisons in the National Drug Treatment Reporting System: Plan for the Implementation of the NDTRS in Prison and GP Services

This book includes sections on drug policy, epidemiology of drug use and demand reduction intervention.

The Drugs Research Division of the Health Research Board was established in 1989 to 
provide information on the growing problem of drug misuse in Ireland. 
The core activities centre around the maintenance and development of the National Drug 
Treatment Reporting System, drug misuse research and the dissemination of information on 
drug misuse. 
The Drugs Research Division is the designated Irish Focal Point for the European Monitoring 
Centre for Drugs and Drug Addiction. In addition, it participates in the Epidemiology 
Committee of the Pompidou Group in the Council of Europe.

This report provides information on all admissions, discharges and deaths occurring within the 
inpatient psychiatric service in Ireland for the year 1990. 
Data on admissions first admissions, discharges and deaths are reported firstly for the country 
as a whole, secondly by health board area of origin of patient, then by individual hospital and 
finally by hospital type. A range of classificatory variables is used in presenting the data I.e . 
gender, age, marital status, socio-economic group, voluntary/ non-voluntary status, diagnosis and 
length of stay. Selected findings and trends are commented on. 
The report is one of a series of annual reports of patient movement produced by the Mental 
Health Section of The Health Research Board and its predecessor the Medico-Social Research 
Board. As part of its epidemiological work in the mental health area, The Health Research 
Board, in addition maintains four Psychiatric Case Registers and carries out censuses of the 
psychiatric inpatient population from time to time. The Psychiatric Case Registers are 
maintained in association with St. Loman's Hospital Dublin, the Carlow-South Kildare, 
Roscommon and Westmeath mental health services. A complete listing of on-going publications 
from the Mental Health Section of The Health Research Board is produced in Appendix

The electronic home : social and spatial aspects : a scoping report

Architectural Design Aspects of Home - Based Telework for People with Physical Disabilities - a Case Study

This study develops a comprehensive operationalization of the defensible space concept (Newman, 1972). A total of 11 indicators of defensible space were developed that take the contextual reality of the person-environment relationship into account. Then 23 telephone kiosks in Dublin city, Ireland, were rated on these indicators. A SSA-1 analysis of the structure of these indicators defined two distinct environmental contexts in which kiosks were located-public and semipublic environments. Subsequent analyses of the structure of the indicators within these environments demonstrated that the meaning of indicators is inextricably bound to the environmental context of which they are part. These findings helped to clarify contradictory findings in the literature regarding the defensive role of some indicators and suggest that definition of environmental contexts is a prerequisite to prediction of crime or vandalism occurrence.

This is the fourth national census report of patients in psychiatric hospitals to be 
published by the Health Research Board (HRB) and iLS predecessor the Medico-Social 
Research Board. The previous publications covered the years 1963, 1971 and 1981 
(Walsh 1963, O'Hare and Walsh 1971 and 1981, Appendix 1). The present publication 
provides information on patients resident in psychiatric hospitals and units operating 
within the provisions of the Mental Treatment Act 1945 on a specific night 31st March 
1991. This report will comment on the 1991 relllms and make some comparisons with 
previous census data. 
These censuses provide a valuable database for the planning and development of 
psychiatric services at a time of extensive and rapid change in care delivery. The data 
allows for the comparison of services within Ireland with each other and over time. In 
addition the data provide a basis for international comparisons.

Study of factor structure of attitudinal measures of major social psychological constructs in an Irish sample

P-115 Modeling large-scale functional brain networks across signal modalities: A two-fold approach

Detection of pathological high-frequency oscillations in refractory epilepsy patients undergoing simultaneous stereo-electroencephalography and magnetoencephalography

FV 11 Exploring a link between the spectral 1/f-exponent and connectivity in Parkinson’s disease

Spontaneous transient states of fronto-temporal and default-mode networks altered by suicide attempt in major depressive disorder

Dynamic sensitivity analysis: Defining personalised strategies to drive brain state transitions via whole brain modelling

Functional connectivity maps of theta/alpha and beta coherence within the subthalamic nucleus region

Synchronization of neural oscillations is thought to facilitate communication in the brain. Neurodegenerative pathologies such as Parkinson’s disease (PD) can result in synaptic reorganization of the motor circuit, leading to altered neuronal dynamics and impaired neural communication. Treatments for PD aim to restore network function via pharmacological means such as dopamine replacement, or by suppressing pathological oscillations with deep brain stimulation. We tested the hypothesis that brain stimulation can operate beyond a simple “reversible lesion” effect to augment network communication. Specifically, we examined the modulation of beta band (14–30 Hz) activity, a known biomarker of motor deficits and potential control signal for stimulation in Parkinson’s. To do this we setup a neural mass model of population activity within the cortico-basal ganglia-thalamic (CBGT) circuit with parameters that were constrained to yield spectral features comparable to those in experimental Parkinsonism. We modulated the connectivity of two major pathways known to be disrupted in PD and constructed statistical summaries of the spectra and functional connectivity of the resulting spontaneous activity. These were then used to assess the network-wide outcomes of closed-loop stimulation delivered to motor cortex and phase locked to subthalamic beta activity. Our results demonstrate that the spatial pattern of beta synchrony is dependent upon the strength of inputs to the STN. Precisely timed stimulation has the capacity to recover network states, with stimulation phase inducing activity with distinct spectral and spatial properties. These results provide a theoretical basis for the design of the next-generation brain stimulators that aim to restore neural communication in disease.

Stimulating at the right time to recover network states in a model of the cortico-basal ganglia-thalamic circuit

CerCo, CNRS, Paul Sabatier University, Toulouse, France, 2 Swartz Center for Computational Neurosciences, Institute of Neural Computation, University of California, San Diego, San Diego, CA, United States, Donders Institute for Brain, Cognition, and Behaviour, Radboud University, Nijmegen, Netherlands, NatMEG, Karolinska Institutet, Stockholm, Sweden, 5 Signal and Image Processing Institute, University of Southern California, Los Angeles, CA, United States, Université Paris-Saclay, Inria, CEA, Palaiseau, France, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States, Welcome Centre for Human Neuroimaging, UCL Queen Square Institute of

Editorial: From Raw MEG/EEG to Publication: How to Perform MEG/EEG Group Analysis With Free Academic Software

Inference of brain networks with approximate Bayesian computation – assessing face validity with an example application in Parkinsonism

Separating Neural Oscillations from Aperiodic 1/f Activity: Challenges and Recommendations

Abstract Exaggerated local field potential bursts of activity at frequencies in the low beta band are a well-established phenomenon in the subthalamic nucleus of patients with Parkinson’s disease. However, such activity is only moderately correlated with motor impairment. Here we test the hypothesis that beta bursts are just one of several dynamic states in the subthalamic nucleus local field potential in Parkinson’s disease, and that together these different states predict motor impairment with high fidelity. Local field potentials were recorded in 32 patients (64 hemispheres) undergoing deep brain stimulation surgery targeting the subthalamic nucleus. Recordings were performed following overnight withdrawal of anti-parkinsonian medication, and after administration of levodopa. Local field potentials were analysed using hidden Markov modelling to identify transient spectral states with frequencies under 40 Hz. Findings in the low beta frequency band were similar to those previously reported; levodopa reduced occurrence rate and duration of low beta states, and the greater the reductions, the greater the improvement in motor impairment. However, additional local field potential states were distinguished in the theta, alpha and high beta bands, and these behaved in an opposite manner. They were increased in occurrence rate and duration by levodopa, and the greater the increases, the greater the improvement in motor impairment. In addition, levodopa favoured the transition of low beta states to other spectral states. When all local field potential states and corresponding features were considered in a multivariate model it was possible to predict 50% of the variance in patients’ hemibody impairment OFF medication, and in the change in hemibody impairment following levodopa. This only improved slightly if signal amplitude or gamma band features were also included in the multivariate model. In addition, it compares with a prediction of only 16% of the variance when using beta bursts alone. We conclude that multiple spectral states in the subthalamic nucleus local field potential have a bearing on motor impairment, and that levodopa-induced shifts in the balance between these states can predict clinical change with high fidelity. This is important in suggesting that some states might be upregulated to improve parkinsonism and in suggesting how local field potential feedback can be made more informative in closed-loop deep brain stimulation systems.

Balance between competing spectral states in subthalamic nucleus is linked to motor impairment in Parkinson’s disease

Transcranial magnetic stimulation (TMS) is a noninvasive method for stimulating the human brain based on the principle of electromagnetic induction.The present research aimed at developing new methods for characterization of the immediate and long-term effects of TMS on the brain and for developing more precise stimulation protocols that would allow purposeful modification of the brain’s functional state and connectivity. Electroencephalography (EEG) was chosen as the neuroimaging method due to its high temporal resolution and the possibility to combine it with TMS.Three studies were carried out. The first was aimed at characterizing EEG responses to TMS applied to the left and right primary motor cortex. For this purpose it was necessary to solve the problem of TMS artifacts hampering the analysis of several tens of milliseconds immediately following the stimulus. This was achieved by analyzing data recorded with a specially adapted recording system and subtracting the residual artifact in software. Combining these two approaches enabled almost complete removal of the artifact without distorting physiological brain signals. Based on the artifact-free data, a model of the response that revealed remarkable symmetry between the responses to stimulation at the left and right sides of the brain was suggested.The second study examined the long-term effects of TMS. The specific protocol tested - paired associative stimulation (PAS) is an attempt to mimic natural neural learning mechanisms. PAS consists of pairing an electrical stimulus of the median nerve at the wrist with magnetic stimulation of the primary somatosensory cortex. A long series of such paired stimuli has been found to modify the amplitude of a particular peak in the EEG response to median nerve stimulation. Our aim was to better understand the mechanism of this modification and test whether it affects the perceptual discrimination ability. We showed that PAS affects synapses at superficial layers of cortical area 3b which is responsible for processing tactile information. We also found significant effects of PAS on behavioral performance related to changes in the EEG response.The third study addressed the variability of muscular responses to TMS pulses delivered under identical conditions. We showed that this variability is, at least partially, related to oscillatory activity in the sensorimotor cortical areas. The finding that increase in the power of the oscillations was associated with a larger muscular response to TMS challenges the accepted view that oscillations appear during an idling state of the motor system.

Analysis of the Effects of Transcranial Magnetic Stimulation on Functional States and Connectivity of the Human Cerebral Cortex Using Electroencephalography

Excessive sensitivity to certain visual stimuli (cortical hyperexcitability) is associated with a number of neurological disorders including migraine, epilepsy, multiple sclerosis, autism and possibly dyslexia. Others show disruptive sensitivity to visual stimuli with no other obvious pathology or symptom profile (visual stress) which can extend to discomfort and nausea. We used event‐related potentials (ERPs) to explore the neural correlates of visual stress and headache proneness. We analysed ERPs in response to thick (0.37 cycles per degree [c/deg]), medium (3 c/deg) and thin (12 c/deg) gratings, using mass univariate analysis, considering three factors in the general population: headache proneness, visual stress and discomfort. We found relationships between ERP features and the headache and discomfort factors. Stimulus main effects were driven by the medium stimulus regardless of participant characteristics. Participants with high discomfort ratings had larger P1 components for the initial presentation of medium stimuli, suggesting initial cortical hyperexcitability that is later suppressed. The participants with high headache ratings showed atypical N1‐P2 components for medium stripes relative to the other stimuli. This effect was present only after repeated stimulus presentation. These effects were also explored in the frequency domain, suggesting variations in intertrial theta band phase coherence. Our results suggest that discomfort and headache in response to striped stimuli are related to different neural processes; however, more exploration is needed to determine whether the results translate to a clinical migraine population.

The missing N1 or jittered P2: Electrophysiological correlates of pattern glare in the time and frequency domain

Author response for "The Missing N1 or Jittered P2: Electrophysiological Correlates of Pattern‐Glare in the Time and Frequency Domain"

The utility of Magnetoencephalography in multiple sclerosis – A systematic review

Abstract Our lives unfold as sequences of events. We experience these events as seamless, although they are composed of individual images captured in between the interruptions imposed by eye blinks and saccades. Events typically involve visual imagery from the real world (scenes), and the hippocampus is frequently engaged in this context. It is unclear, however, whether the hippocampus would be similarly responsive to unfolding events that involve abstract imagery. Addressing this issue could provide insights into the nature of its contribution to event processing, with relevance for theories of hippocampal function. Consequently, during magnetoencephalography (MEG), we had female and male humans watch highly matched unfolding movie events composed of either scene image frames that reflected the real world, or frames depicting abstract patterns. We examined the evoked neuronal responses to each image frame along the time course of the movie events. Only one difference between the two conditions was evident, and that was during the viewing of the first image frame of events, detectable across frontotemporal sensors. Further probing of this difference using source reconstruction revealed greater engagement of a set of brain regions across parietal, frontal, premotor, and cerebellar cortices, with the largest change in broadband (1–30 Hz) power in the hippocampus during scene-based movie events. Hippocampal engagement during the first image frame of scene-based events could reflect its role in registering a recognizable context perhaps based on templates or schemas. The hippocampus, therefore, may help to set the scene for events very early on.

Watching Movies Unfold, a Frame-by-Frame Analysis of the Associated Neural Dynamics

Neural signatures of hyperdirect pathway activity in Parkinson’s disease

Both magnetoencephalography and stereo-electroencephalography are used in presurgical epilepsy assessment, with contrasting advantages and limitations. It is not known whether simultaneous stereo-electroencephalography–magnetoencephalography recording confers an advantage over both individual modalities, in particular whether magnetoencephalography can provide spatial context to epileptiform activity seen on stereo-electroencephalography. Twenty-four adult and paediatric patients who underwent stereo-electroencephalography study for pre-surgical evaluation of drug-resistant focal epilepsy, were recorded using simultaneous stereo-electroencephalography–magnetoencephalography, of which 14 had abnormal interictal activity during recording. The 14 patients were divided into two groups; those with detected superficial (n1⁄47) and deep (n1⁄4 7) brain interictal activity. Interictal spikes were independently identified in stereo-electroencephalography and magnetoencephalography. Magnetoencephalography dipoles were derived using a distributed inverse method. There was no significant difference between stereo-electroencephalography and magnetoencephalography in detecting superficial spikes (P1⁄4 0.135) and stereo-electroencephalography was significantly better at detecting deep spikes (P1⁄40.002). Mean distance across patients between stereo-electroencephalography channel with highest average spike amplitude and magnetoencephalography dipole was 20.7 6 4.4 mm. for superficial sources, and 17.8 6 3.7 mm. for deep sources, even though for some of the latter (n1⁄4 4) no magnetoencephalography spikes were detected and magnetoencephalography dipole was fitted to a stereo-electroencephalography interictal activity triggered average. Removal of magnetoencephalography dipole was associated with 1 year seizure freedom in 6/7 patients with superficial source, and 5/6 patients with deep source. Although stereo-electroencephalography has greater sensitivity in identifying interictal activity from deeper sources, a magnetoencephalography source can be localized using stereo-electroencephalography information, thereby providing useful whole brain context to stereo-electroencephalography and potential role in epilepsy surgery planning.

Abstract Both magnetoencephalography and stereo-electroencephalography are used in presurgical epilepsy assessment, with contrasting advantages and limitations. It is not known whether simultaneous stereo-electroencephalography–magnetoencephalography recording confers an advantage over both individual modalities, in particular whether magnetoencephalography can provide spatial context to epileptiform activity seen on stereo-electroencephalography. Twenty-four adult and paediatric patients who underwent stereo-electroencephalography study for pre-surgical evaluation of drug-resistant focal epilepsy, were recorded using simultaneous stereo-electroencephalography–magnetoencephalography, of which 14 had abnormal interictal activity during recording. The 14 patients were divided into two groups; those with detected superficial (n = 7) and deep (n = 7) brain interictal activity. Interictal spikes were independently identified in stereo-electroencephalography and magnetoencephalography. Magnetoencephalography dipoles were derived using a distributed inverse method. There was no significant difference between stereo-electroencephalography and magnetoencephalography in detecting superficial spikes (P = 0.135) and stereo-electroencephalography was significantly better at detecting deep spikes (P = 0.002). Mean distance across patients between stereo-electroencephalography channel with highest average spike amplitude and magnetoencephalography dipole was 20.7 ± 4.4 mm. for superficial sources, and 17.8 ± 3.7 mm. for deep sources, even though for some of the latter (n = 4) no magnetoencephalography spikes were detected and magnetoencephalography dipole was fitted to a stereo-electroencephalography interictal activity triggered average. Removal of magnetoencephalography dipole was associated with 1 year seizure freedom in 6/7 patients with superficial source, and 5/6 patients with deep source. Although stereo-electroencephalography has greater sensitivity in identifying interictal activity from deeper sources, a magnetoencephalography source can be localized using stereo-electroencephalography information, thereby providing useful whole brain context to stereo-electroencephalography and potential role in epilepsy surgery planning.

The use of simultaneous stereo-electroencephalography and magnetoencephalography in localizing the epileptogenic focus in refractory focal epilepsy

The comparative performance of DBS artefact rejection methods for MEG recordings

Parkinson’s disease (PD) is characterised by the emergence of pathological patterns of oscillatory synchronisation across the cortico-basal-ganglia circuit. The relationship between anatomical connectivity and oscillatory synchronisation within this system remains poorly understood. We address this by integrating evidence from invasive electrophysiology, magnetoencephalography, tractography and computational modelling in patients. Coupling between supplementary motor area (SMA) and subthalamic nucleus (STN) within the high beta frequency (21-30 Hz) range correlated with fibre tract densities between these two structures. Additionally within the STN, non-linear waveform features suggestive of cortical synchronisation correlated with cortico-STN fibre densities. Finally, computational modelling revealed that exaggerated hyperdirect cortical inputs to the STN in the upper beta frequency range can provoke the generation of widespread pathological synchrony at lower beta (13-20 Hz) frequencies. These observations reveal a spectral signature of the hyperdirect pathway at high beta frequencies and provide evidence for its pathophysiological role in oscillatory network dysfunction in PD. One sentence summary Signatures of the hyperdirect pathway and its likely role in pathological network disruption in Parkinson’s disease are identified.

Neural signatures of pathological hyperdirect pathway activity in Parkinson’s disease

Both Magnetoencephalography (MEG) and stereo-electroencephalography (SEEG) are used in presurgical epilepsy assessment, with contrasting advantages and limitations. It is not known whether combined recording using both modalities can maintain inherent advantages whilst overcoming these limitations e.g. recording from deep brain sources whilst preserving good spatial resolution.24 adult and paediatric patients who underwent SEEG study for pre-surgical evaluation of focal drug-resistant epilepsy, were recorded using simultaneous SEEG-MEG, of which 14 had abnormal interictal activity during recording. The 14 patients were divided into two groups; those with presumed superficial (n=7) and deep (n=7) brain interictal activity.There was no significant difference between SEEG and MEG in identifying superficial spikes (p=0.135) and SEEG was significantly better at detecting deep spikes (p=0.002). Mean distance across patients between SEEG channel with highest average spike amplitude and MEG dipole was 26.6+/-3.6 mm for superficial sources, and 21.5 +/- 2.04 mm for deep sources, even though for some of the latter (n=4) no MEG spikes were detected and MEG dipole was fitted to a SEEG interictal activity triggered average. Removal of MEG dipole was associated with 1 year seizure freedom in 5/6 patients with superficial source, and 4/6 patients with deep source.Although SEEG has greater sensitivity in identifying interictal activity from deeper sources, an MEG source can be localised using SEEG information, thereby providing useful whole brain context to SEEG and potential role in epilepsy surgery planning.

The use of simultaneous SEEG and MEG in localising seizure onset zone

There has been considerable debate and concern as to whether there is a replication crisis in the scientific literature. A likely cause of poor replication is the multiple comparisons problem. An important way in which this problem can manifest in the M/EEG context is through post hoc tailoring of analysis windows (a.k.a. regions-of-interest, ROIs) to landmarks in the collected data. Post hoc tailoring of ROIs is used because it allows researchers to adapt to inter-experiment variability and discover novel differences that fall outside of windows defined by prior precedent, thereby reducing Type II errors. However, this approach can dramatically inflate Type I error rates. One way to avoid this problem is to tailor windows according to a contrast that is orthogonal (strictly parametrically orthogonal) to the contrast being tested. A key approach of this kind is to identify windows on a fully flattened average. On the basis of simulations, this approach has been argued to be safe for post hoc tailoring of analysis windows under many conditions. Here, we present further simulations and mathematical proofs to show exactly why the Fully Flattened Average approach is unbiased, providing a formal grounding to the approach, clarifying the limits of its applicability and resolving published misconceptions about the method. We also provide a statistical power analysis, which shows that, in specific contexts, the fully flattened average approach provides higher statistical power than Fieldtrip cluster inference. This suggests that the Fully Flattened Average approach will enable researchers to identify more effects from their data without incurring an inflation of the false positive rate.

Breaking the circularity in circular analyses: Simulations and formal treatment of the flattened average approach

Abstract Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) are related conditions that are associated with cholinergic system dysfunction. Dysfunction of the nucleus basalis of Meynert (NBM), a basal forebrain structure that provides the dominant source of cortical cholinergic innervation, has been implicated in the pathogenesis of both PDD and DLB. Here we leverage the temporal resolution of magnetoencephalography with the spatial resolution of MRI tractography to explore the intersection of functional and structural connectivity of the NBM in a unique cohort of PDD and DLB patients undergoing deep brain stimulation of this structure. We observe that NBM-cortical structural and functional connectivity correlate within spatially and spectrally segregated networks including: (i) a beta band network to supplementary motor area, where activity in this region was found to drive activity in the NBM; (ii) a delta/theta band network to medial temporal lobe structures encompassing the parahippocampal gyrus; and (iii) a delta/theta band network to visual areas including lingual gyrus. These findings reveal functional networks of the NBM that are likely to subserve important roles in motor control, memory and visual function, respectively. Furthermore, they motivate future studies aimed at disentangling network contribution to disease phenotype.

Cortical connectivity of the nucleus basalis of Meynert in Parkinson’s disease and Lewy body dementias

L-dopa treatment increases oscillatory power in the motor cortex of Parkinson's disease patients

Dynamic analysis on simultaneous iEEG-MEG data via hidden Markov model

Resting state activity and connectivity of the nucleus basalis of Meynert and globus pallidus in Lewy body dementia and Parkinson's disease dementia

Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) are related conditions that are associated with cholinergic system dysfunction. Dysfunction of the nucleus basalis of Meynert (NBM), a basal forebrain structure that provides the dominant source of cortical cholinergic innervation, has been implicated in the pathogenesis of both PDD and DLB. Here we leverage the temporal resolution of magnetoencephalography (MEG) with the spatial resolution of MRI tractography in order to explore the intersection of functional and structural connectivity of the NBM in a unique cohort of PDD and DLB patients undergoing Deep Brain Stimulation (DBS) of this structure. We observe that NBM-cortical structural and functional connectivity correlate within spatially and spectrally segregated networks including: 1) a beta band network to supplementary motor area (SMA), where activity in the SMA was found to drive activity in the NBM, 2) a delta/theta band network to medial temporal lobe structures encompassing the parahippocampal gyrus and 3) a delta/theta band network to visual areas including lingual gyrus. These findings reveal functional networks of the NBM that are likely to subserve important roles in motor control, memory and visual function respectively. Furthermore, they motivate future studies aimed at disentangling network contribution to disease phenotype.

Intersection of structural and functional connectivity of the nucleus basalis of Meynert in Parkinson’s disease dementia and Lewy body dementia

Making accurate decisions often involves the integration of current and past evidence. Here, we examine the neural correlates of conflict and evidence integration during sequential decision-making. Female and male human patients implanted with deep-brain stimulation (DBS) electrodes and age-matched and gender-matched healthy controls performed an expanded judgment task, in which they were free to choose how many cues to sample. Behaviorally, we found that while patients sampled numerically more cues, they were less able to integrate evidence and showed suboptimal performance. Using recordings of magnetoencephalography (MEG) and local field potentials (LFPs; in patients) in the subthalamic nucleus (STN), we found that β oscillations signaled conflict between cues within a sequence. Following cues that differed from previous cues, β power in the STN and cortex first decreased and then increased. Importantly, the conflict signal in the STN outlasted the cortical one, carrying over to the next cue in the sequence. Furthermore, after a conflict, there was an increase in coherence between the dorsal premotor cortex and STN in the β band. These results extend our understanding of cortico-subcortical dynamics of conflict processing, and do so in a context where evidence must be accumulated in discrete steps, much like in real life. Thus, the present work leads to a more nuanced picture of conflict monitoring systems in the brain and potential changes because of disease. SIGNIFICANCE STATEMENT Decision-making often involves the integration of multiple pieces of information over time to make accurate predictions. We simultaneously recorded whole-head magnetoencephalography (MEG) and local field potentials (LFPs) from the human subthalamic nucleus (STN) in a novel task which required integrating sequentially presented pieces of evidence. Our key finding is prolonged β oscillations in the STN, with a concurrent increase in communication with frontal cortex, when presented with conflicting information. These neural effects reflect the behavioral profile of reduced tendency to respond after conflict, as well as relate to suboptimal cue integration in patients, which may be directly linked to clinically reported side-effects of deep-brain stimulation (DBS) such as impaired decision-making and impulsivity.

Conflict Detection in a Sequential Decision Task Is Associated with Increased Cortico-Subthalamic Coherence and Prolonged Subthalamic Oscillatory Response in the β Band

State-of-the-art therapeutic brain stimulation strategies are delivered open loop, using fixed parameters. However, brain states exhibit spontaneous fluctuations dependent upon different behavioural or disease states. Here, we use a model of the cortico-basal ganglia-thalamic circuit to demonstrate how connectivity underpins changes in subcortical beta oscillations – a commonly used control parameter for deep brain stimulation in Parkinson’s disease. We show that recurrent cortical-subcortical loops involving either the cortico-subthalamic or pallido-subthalamic pathways can act in antagonism to modulate the expression of beta band activity (14-30 Hz). These pathways alter the relative timing of intermittent activity across the network, with increased pallido-subthalamic connectivity increasing the propensity of the circuit to enter a state of autonomous oscillation. We demonstrate that phase-locked stimulation can modulate these oscillations, with an efficacy that ultimately depends upon the connectivity across the circuit. This work outlines critical factors required to implement state-adaptive closed-loop brain stimulation. Highlights Converging inputs to the subthalamic nucleus arriving via the external segment of globus pallidus and cortex act in antagonism and promote different beta rhythms. Phase locked stimulation has the capacity to selectively enhance or suppress a brain rhythm depending on the stimulation timing. The efficacy of stimulation and the parameters required to deliver it, e.g. stimulation timing, effective sensing and stimulation locations, are functions of network state.

State Dependent Beta Oscillations in the Cortico-Basal Ganglia Circuit and their Neuromodulation under Phase-Locked Inputs

Identification of nonlinear features in cortical and subcortical signals of Parkinson's Disease patients via a novel efficient measure

The subthalamic nucleus (STN) is a common target for deep brain stimulation (DBS) treatment in Parkinson’s disease (PD) but much less frequently targeted for other disorders. Here we report the results of simultaneous local field potential (LFP) recordings and magnetoencephalography (MEG) in a single patient who was implanted bilaterally in the STN for the treatment of dystonia induced by chorea-acanthocytosis. Consistent with the previous results in PD, the dystonia patient showed significant subthalamo-cortical coherence in the high beta band (28–35 Hz) on both sides localized to the mesial sensorimotor areas. In addition, on the right side, significant coherence was found in the theta-alpha band (4–12 Hz) that localized to the medial prefrontal cortex with the peak in the anterior cingulate gyrus. Comparison of STN power spectra with a previously reported PD cohort showed increased power in the theta and alpha bands and decreased power in the low beta band in dystonia which is consistent with most of the previous studies. The present report extends the range of disorders for which cortico-subthalamic oscillatory connectivity has been characterized. Our results strengthen the evidence that at least some of the subthalamo-cortical oscillatory coherent networks are a feature of the healthy brain, although we do not rule out that coherence magnitude could be affected by disease.

Cortico-subthalamic Coherence in a Patient With Dystonia Induced by Chorea-Acanthocytosis: A Case Report

Brain networks and the dynamics that unfold upon them are of vital importance at many scales of systems neuroscience. The parameterization of generative models from empirical data (inverse modelling) has become of great utility to theoretical understanding in this domain. However, it has become difficult to infer mechanisms of spontaneous neural activity with existing tools due to the adoption of simplifying model assumptions that appeal to steady-state approximations of neural dynamics. In this work we describe a framework employing Approximate Bayesian Computation (ABC) for the inversion of neural models that can be used to flexibly model any statistical feature of empirically recorded data without assuming any specific form of dynamics. Further, we demonstrate how Bayesian model comparison can be applied to ABC fitted models to facilitate the selection of competing dynamical hypotheses. This work provides a validation of this approach in the context of a Parkinsonian electrophysiology, using a set of multisite recordings from Parkinsonian rats to demonstrate convergence, consistency, and uniqueness of parameter estimation; face validity of the model comparison procedures; and its utility in answering biologically relevant problems. From the validation and example applications presented here we conclude that the proposed framework is likely to be of value to a wide range of researchers aiming to explain how brain dynamics emerge from neural circuits.

Mechanistic Inference of Brain Network Dynamics with Approximate Bayesian Computation

Measuring directed functional connectivity using non-parametric directionality analysis: Validation and comparison with non-parametric Granger Causality

Comparison of beamformer implementations for MEG source localization

We describe the steps involved in analysis of multi-modal, multi-subject human neuroimaging data using the SPM12 free and open source software (https://www.fil.ion.ucl.ac.uk/spm/) and a publically-available dataset organized according to the Brain Imaging Data Structure (BIDS) format (https://openneuro.org/datasets/ds000117/). The dataset contains electroencephalographic (EEG), magnetoencephalographic (MEG), and functional and structural magnetic resonance imaging (MRI) data from 16 subjects who undertook multiple runs of a simple task performed on a large number of famous, unfamiliar and scrambled faces. We demonstrate: (1) batching and scripting of preprocessing of multiple runs/subjects of combined MEG and EEG data, (2) creation of trial-averaged evoked responses, (3) source-reconstruction of the power (induced and evoked) across trials within a time-frequency window around the “N/M170” evoked component, using structural MRI for forward modeling and simultaneous inversion (fusion) of MEG and EEG data, (4) group-based optimisation of spatial priors during M/EEG source reconstruction using fMRI data on the same paradigm, and (5) statistical mapping across subjects of cortical source power increases for faces vs. scrambled faces.

Brain networks and the neural dynamics that unfold upon them are of great interest across the many scales of systems neuroscience. The tools of inverse modelling provide a way of both constraining and selecting models of large scale brain networks from empirical data. Such models have the potential to yield broad theoretical insights in the understanding of the physiological processes behind the integration and segregation of activity in the brain. In order to make inverse modelling computationally tractable, simplifying model assumptions have often been adopted that appeal to steady-state approximations to neural dynamics and thus prevent the investigation of stochastic or intermittent dynamics such as gamma or beta burst activity. In this work we describe a framework that uses the Approximate Bayesian Computation (ABC) algorithm for the inversion of neural models that can flexibly represent any statistical feature of empirically recorded data and eschew the need to assume a locally linearized system. Further, we demonstrate how Bayesian model comparison can be applied to fitted models to enable the selection of competing hypotheses regarding the causes of neural data. This work establishes a validation of the procedures by testing for both the face validity (i.e. the ability to identify the original model that has generated the observed data) and predictive validity (i.e. the consistency of the parameter estimation across multiple realizations of the same data). From the validation and example applications presented here we conclude that the proposed framework provides a novel opportunity to researchers aiming to explain how complex brain dynamics emerge from neural circuits.

Model Based Inference of Large Scale Brain Networks with Approximate Bayesian Computation

We demonstrate the first use of Optically Pumped Magnetoencephalography (OP‐MEG) in an epilepsy patient with unrestricted head movement. Current clinical MEG uses a traditional SQUID system, where sensors are cryogenically cooled and housed in a helmet in which the patient’s head is fixed. Here, we use a different type of sensor (OPM), which operates at room temperature and can be placed directly on the patient’s scalp, permitting free head movement. We performed OP‐MEG recording in a patient with refractory focal epilepsy. OP‐MEG‐identified analogous interictal activity to scalp EEG, and source localized this activity to an appropriate brain region.

MEG-BIDS, the brain imaging data structure extended to magnetoencephalography

Cognitive neuroscience using wearable magnetometer arrays: Non-invasive assessment of language function

During a decision process, the evidence supporting alternative options is integrated over time, and the choice is made when the accumulated evidence for one of the options reaches a decision threshold. Humans and animals have an ability to control the decision threshold, that is, the amount of evidence that needs to be gathered to commit to a choice, and it has been proposed that the subthalamic nucleus (STN) is important for this control. Recent behavioral and neurophysiological data suggest that, in some circumstances, the decision threshold decreases with time during choice trials, allowing overcoming of indecision during difficult choices. Here we asked whether this within-trial decrease of the decision threshold is mediated by the STN and if it is affected by disrupting information processing in the STN through deep brain stimulation (DBS). We assessed 13 patients with Parkinson disease receiving bilateral STN DBS six or more months after the surgery, 11 age-matched controls, and 12 young healthy controls. All participants completed a series of decision trials, in which the evidence was presented in discrete time points, which allowed more direct estimation of the decision threshold. The participants differed widely in the slope of their decision threshold, ranging from constant threshold within a trial to steeply decreasing. However, the slope of the decision threshold did not depend on whether STN DBS was switched on or off and did not differ between the patients and controls. Furthermore, there was no difference in accuracy and RT between the patients in the on and off stimulation conditions and healthy controls. Previous studies that have reported modulation of the decision threshold by STN DBS or unilateral subthalamotomy in Parkinson disease have involved either fast decision-making under conflict or time pressure or in anticipation of high reward. Our findings suggest that, in the absence of reward, decision conflict, or time pressure for decision-making, the STN does not play a critical role in modulating the within-trial decrease of decision thresholds during the choice process.

Deep Brain Stimulation of the Subthalamic Nucleus Does Not Affect the Decrease of Decision Threshold during the Choice Process When There Is No Conflict, Time Pressure, or Reward

We present a significant extension of the Brain Imaging Data Structure (BIDS) to support the specific aspects of magnetoencephalography (MEG) data. MEG provides direct measurement of brain activity with millisecond temporal resolution and unique source imaging capabilities. So far, BIDS has provided a solution to structure the organization of magnetic resonance imaging (MRI) data, which nature and acquisition parameters are different. Despite the lack of standard data format for MEG, MEG-BIDS is a principled solution to store, organize and share the typically-large data volumes produced. It builds on BIDS for MRI, and therefore readily yields a multimodal data organization by construction. This is particularly valuable for the anatomical and functional registration of MEG source imaging with MRI. With MEG-BIDS and a growing range of software adopting the standard, the MEG community has a solution to minimize curation overheads, reduce data handling errors and optimize usage of computational resources for analytics. The standard also includes well-defined metadata, to facilitate future data harmonization and sharing efforts.

MEG-BIDS: an extension to the Brain Imaging Data Structure for magnetoencephalography

In Parkinson’s disease (PD), dopaminergic treatment-driven changes in akinesia and rigidity (AR), but not tremor, are associated with changes in local field potential (LFP) beta (1330 Hz) power spectral density (PSD). The PSD of these oscillations has recently successfully been applied as a biomarker for adaptive deep brain stimulation. However, it remains unclear whether beta PSD also correlates with OFFdopaminergic AR. In their recent study Neumann and colleagues report a strong correlation between OFF total Unified Parkinson’s Disease Rating Scale (UPDRS) III score and the LFP PSD over a broad 8 to 35 Hz band and more specifically in a narrow 10 to 14 Hz range. The following 3 questions arise: (1) What was the rational for using the total UPDRS scores (including tremor and bilaterality)? (2) Are the correlations in this narrow 10 to 14 Hz band reproducible? (3) Does it relate to a particular symptom complex? For this reason, we replicated the study of Neumann and colleagues but also investigated the contributions of AR, tremor, and axial symptoms. We investigated 39 PD patients (35 male, mean age 58.6 6 7.2 y.o., average disease duration 11.3 6 5.2 years, mean OFF UPDRS 42.3 6 12.8) with bilaterally implanted STN-DBS contacts. OFF UPDRS scores were obtained from the preoperative levodopa challenge. From these total scores, (contralateral) AR (items 22-26), tremor (items 20-21), and axial symptom (items 27-31) scores were obtained. LFPs were analyzed as described by Neumann and colleagues. This included the rejection of epochs with artefacts and normalization to 5 to 45 Hz and 55 to 95 Hz. However, to assess lateralized items we used the PSD LFP average per STN and not across both STNs. We were not able to reproduce the highly significant correlation between the 8 to 35 Hz PSD and total UPDRS score (rho 5 0.28, P 5 .07), nor between this and LFP PSD over 10 to 14 Hz (rho 5 0.23, P 5 .14). We only found an uncorrected significant correlation between total UPDRS and the 19 Hz PSD bin and between the 17 to 22 Hz PSD bins for AR. No significant correlation was found for either tremor or axial symptoms. However, when correlating maximum LFP beta peak PSD over 13 to 30 Hz in each STN (regardless of precise frequency), a highly significant correlation (rho 5 0.40, P< .0005) with contralateral AR UPDRS items was present (Fig. 1). Given the undifferentiated motor profile of the population enrolled in the study of Neumann and colleagues, it is difficult to pinpoint the reason why we were not able to replicate their precise findings. However, it is possible that it is the degree of neural synchronization (as indexed by PSD) rather than any specific frequency over the 8 to 35 Hz band that is most important. Moreover, our data suggest that PSD correlations may be strongest with AR. Other factors that might underlie the differences are the lower UPDRS score in the Neumann and colleagues study and the distribution of recording sites within the STN.

Oscillatory Beta Power Correlates With Akinesia‐Rigidity in the Parkinsonian Subthalamic Nucleus

Some motor impairments associated with Parkinson’s disease are thought to arise from pathological activity in the neuronal networks formed by the basal ganglia (BG) and motor cortex. To evaluate several hypotheses proposed to explain the emergence of pathological oscillations in Parkinsonism, we investigated changes to the directed connectivity in these networks following dopamine depletion. We recorded local field potentials in the cortex and basal ganglia of anesthetized rats rendered Parkinsonian by injection of 6-hydroxydopamine (6-OHDA), with dopamine-intact rats as controls. We performed systematic analyses of the networks using a novel tool for estimation of directed neural interactions, as well as a conditioned variant which permits the analysis of the dependence of a connection upon a third reference signal. We find evidence of the dopamine dependency of both low beta (14-20 Hz) and high beta/low gamma (20-40 Hz) directed interactions within the BG and cortico-BG networks. Notably, 6-OHDA lesions were associated with enhancement of the cortical “hyperdirect” connection to the subthalamic nucleus (STN), as well the STN’s feedback to the cortex and striatum. We find beta synchronization to be robust to conditioning using signals from any one structure. Conversely, we find that high beta/gamma drive from the cortex to subcortical regions is weakened by 6-OHDA lesions and is susceptible to conditioning. Furthermore, we provide evidence that gamma is routed from striatum in a pathway that is independent of STN. These results further inform our understanding of the substrates for pathological rhythms in salient brain networks in Parkinsonism. New & Noteworthy We present a novel analysis of electrophysiological recordings in the cortico-basal ganglia network with the aims of evaluating several hypotheses concerning the origins of abnormal brain rhythms associated with Parkinson’s disease. We present evidence for changes in the directed connections within the network following chronic dopamine depletion in rodents. These findings speak to the plausibility of a “short-circuiting” of the network that gives rise to the conditions from which pathological synchronization may arise.

Propagation of beta/gamma rhythms in the cortico-basal ganglia circuits of the parkinsonian rat

Localization of beta and high-frequency oscillations within the subthalamic nucleus region

21 The functional impairment of the motor system associated with Parkinson’s Disease is thought to arise 22 as a result of pathological synchronization of the networks formed by the basal ganglia and motor 23 cortex. In this paper, we investigate changes to the directed connectivity in these networks following 24 chronic dopamine depletion to evaluate the plausibility of a number of hypotheses proposed to explain 25 . CC-BY-NC-ND 4.0 International license not peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/180455 doi: bioRxiv preprint first posted online Aug. 24, 2017;

Propagation of Beta / Gamma Rhythms bioRxiv Submission v 4 . 0 in the Parkinsonian Rat 24 / 08 / 2017 1 Propagation of Beta / Gamma Rhythms in the 1 Cortico-Basal Ganglia Circuits of the 2 Parkinsonian Rat 3

Low-beta cortico-pallidal coherence decreases during movement and correlates with overall reaction time

In this paper we investigated the dopaminergic modulation of neuronal interactions occurring in the subthalamic nucleus (STN) during Parkinson's disease (PD). We utilized linear measures of local and long range synchrony such as power and coherence, as well as Detrended Fluctuation Analysis for Phase Synchrony (DFA-PS)- a recently developed non-linear method that computes the extent of long tailed autocorrelations present in the phase interactions between two coupled signals. Through analysis of local field potentials (LFPs) taken from the STN we seek to determine changes in the neurodynamics that may underpin the pathophysiology of PD in a group of 12 patients who had undergone surgery for deep brain stimulation. We demonstrate up modulation of alpha-theta (5–12 Hz) band power in response to L-DOPA treatment, whilst low beta band power (15–20 Hz) band-power is suppressed. We also find evidence for significant local connectivity within the region surrounding STN although there was evidence for its modulation via administration of L-DOPA. Further to this we present evidence for a positive correlation between the phase ordering of bilateral STN interactions and the severity of bradykinetic and rigidity symptoms in PD. Although, the ability of non-linear measures to predict clinical state did not exceed standard measures such as beta power, these measures may help identify the connections which play a role in pathological dynamics.

The Parkinsonian Subthalamic Network: Measures of Power, Linear, and Non-linear Synchronization and their Relationship to L-DOPA Treatment and OFF State Motor Severity

Analysis of simultaneous MEG and intracranial LFP recordings during Deep Brain Stimulation: a protocol and experimental validation

SP 4. Distribution of oscillatory activities in MRI confirmed subthalamic nucleus subregions

Oswal et al . characterise the effect of deep brain stimulation (DBS) on STN–cortical synchronisation in Parkinson–s disease. They propose that cortical driving of the STN in beta frequencies is subdivided anatomically and spectrally, corresponding to the hyperdirect and indirect pathways. DBS predominantly suppresses the former.

Deep brain stimulation modulates synchrony within spatially and spectrally distinct resting state networks in Parkinson’s disease

Subthalamic nucleus phase–amplitude coupling correlates with motor impairment in Parkinson’s disease

Corrigendum to “The mirror illusion induces high gamma oscillations in the absence of movement”

Stopping is a critical aspect of brain function. Like other voluntary actions, it is defined by its context as much as by its execution. Its neural substrate must therefore reflect both. Here, we distinguish those elements of the underlying brain circuit that preferentially reflect contextual aspects of stopping from those related to its execution. Contextual complexity of stopping was modulated using a novel “Stop/Change-signal” task, which also allowed us to parameterize the duration of the stopping process. Human magnetoencephalographic activity and behavioral responses were simultaneously recorded. Whereas theta/alpha frequency activity in the right inferior frontal gyrus was most closely associated with the duration of the stopping process, earlier gamma frequency activity in the pre-supplementary motor area was unique in showing contextual modulation. These results differentiate the roles of 2 key frontal regions involved in stopping, a crucial aspect of behavioral control.

The nucleus accumbens is thought to contribute to action selection by integrating behaviorally relevant information from multiple regions, including prefrontal cortex. Studies in rodents suggest that information flow to the nucleus accumbens may be regulated via task-dependent oscillatory coupling between regions. During instrumental behavior, local field potentials (LFP) in the rat nucleus accumbens and prefrontal cortex are coupled at delta frequencies (Gruber AJ, Hussain RJ, O'Donnell P. PLoS One 4: e5062, 2009), possibly mediating suppression of afferent input from other areas and thereby supporting cortical control (Calhoon GG, O'Donnell P. Neuron 78: 181–190, 2013). In this report, we demonstrate low-frequency cortico-accumbens coupling in humans, both at rest and during a decision-making task. We recorded LFP from the nucleus accumbens in six epilepsy patients who underwent implantation of deep brain stimulation electrodes. All patients showed significant coherence and phase-synchronization between LFP and surface EEG at delta and low theta frequencies. Although the direction of this coupling as indexed by Granger causality varied between subjects in the resting-state data, all patients showed a cortical drive of the nucleus accumbens during action selection in a decision-making task. In three patients this was accompanied by a significant coherence increase over baseline. Our results suggest that low-frequency cortico-accumbens coupling represents a highly conserved regulatory mechanism for action selection.

Cortical drive of low-frequency oscillations in the human nucleus accumbens during action selection

V44. Spatially distinct cortico-thalamic networks identified by parallel iEEG and MEG recordings in patients with tremor

Primary dystonia has been associated with an underlying dysfunction of a wide network of brain regions including the motor cortex, basal ganglia, cerebellum, brainstem and spinal cord. Dystonia can be effectively treated by pallidal deep brain stimulation although the mechanism of this effect is not well understood. Here, we sought to characterize cortico-basal ganglia functional connectivity using a frequency-specific measure of connectivity-coherence. We recorded direct local field potentials from the human pallidum simultaneously with whole head magnetoencephalography to characterize functional connectivity in the cortico-pallidal oscillatory network in nine patients with idiopathic dystonia. Three-dimensional cortico-pallidal coherence images were compared to surrogate images of phase shuffled data across patients to reveal clusters of significant coherence (family-wise error P < 0.01, voxel extent 1000). Three frequency-specific, spatially-distinct cortico-pallidal networks have been identified: a pallido-temporal source of theta band (4-8 Hz) coherence, a pallido-cerebellar source of alpha band (7-13 Hz) coherence and a cortico-pallidal source of beta band (13-30 Hz) coherence over sensorimotor areas. Granger-based directionality analysis revealed directional coupling with the pallidal local field potentials leading in the theta and alpha band and the magnetoencephalographic cortical source leading in the beta band. The degree of pallido-cerebellar coupling showed an inverse correlation with dystonic symptom severity. Our data extend previous findings in patients with Parkinson's disease describing motor cortex-basal ganglia oscillatory connectivity in the beta band to patients with dystonia. Source coherence analysis revealed two additional frequency-specific networks involving the temporal cortex and the cerebellum. Pallido-cerebellar oscillatory connectivity and its association with dystonic symptoms provides further confirmation of cerebellar involvement in dystonia that has been recently reported using functional magnetic resonance imaging and fibre tracking.

Cortico-pallidal oscillatory connectivity in patients with dystonia.

S28: Oscillatory brain networks in movement disorders: an insight from combined MEG and intracranial recordings

The mirror illusion induces high gamma oscillations in the absence of movement

P377: Cortico-pallidal oscillatory connectivity in patients with dystonia

Mirror illusion triggers high gamma oscillations in the absence of movement

Purpose of the review Developments in functional neurosurgery for movement disorders and recent advances in electrophysiological techniques have allowed important insights into the role of oscillations in corticobasal ganglia circuits, both in health and in neurological disease states. Here we review recent developments in our understanding of how abnormally synchronized oscillatory activity within the corticobasal ganglia loop may play a key role in the pathophysiology of cognitive and motor phenotypes in Parkinson’s disease. Recent findings Recent developments highlight the motor and non-motor roles of a, b and g oscillations in the context of Parkinson’s disease. They also emphasize the importance of oscillatory coupling between basal ganglia and cortex and draw attention to the importance of interactions between different frequency bands. Summary Oscillatory activities across multiple frequency bands and their cross-frequency interactions within spatially segregated loops of the basal ganglia-thalamo-cortical system may relate to distinct components of clinical impairment, both motor and non-motor. It is hoped that this characterization will lead to improved interventions like deep brain stimulation, tailored to specific components of clinical impairment and their associated spatial and spectral signatures.

C URRENT OPINION Synchronized neural oscillations and the pathophysiology of Parkinson's disease

Modulation of effective connectivity during vocalization with perturbed auditory feedback

PURPOSE OF THE REVIEW
Developments in functional neurosurgery for movement disorders and recent advances in electrophysiological techniques have allowed important insights into the role of oscillations in corticobasal ganglia circuits, both in health and in neurological disease states. Here we review recent developments in our understanding of how abnormally synchronized oscillatory activity within the corticobasal ganglia loop may play a key role in the pathophysiology of cognitive and motor phenotypes in Parkinson's disease.

Recent developments highlight the motor and non-motor roles of α, β and γ oscillations in the context of Parkinson's disease. They also emphasize the importance of oscillatory coupling between basal ganglia and cortex and draw attention to the importance of interactions between different frequency bands.

SUMMARY
Oscillatory activities across multiple frequency bands and their cross-frequency interactions within spatially segregated loops of the basal ganglia-thalamo-cortical system may relate to distinct components of clinical impairment, both motor and non-motor. It is hoped that this characterization will lead to improved interventions like deep brain stimulation, tailored to specific components of clinical impairment and their associated spatial and spectral signatures.

Synchronized neural oscillations and the pathophysiology of Parkinson's disease.

Movement is accompanied by changes in the degree to which neurons in corticobasal ganglia loops synchronize their activity within discrete frequency ranges. Although two principal frequency bands—beta (15–30 Hz) and gamma (60–90 Hz)—have been implicated in motor control, the precise functional correlates of their activities remain unclear. Local field potential (LFP) recordings in humans with Parkinson's disease undergoing surgery for deep brain stimulation to the subthalamic nucleus (STN) indicate that spectral changes both anticipate movement and occur perimovement. The extent to which such changes are modulated by cognitive factors involved in making a correct response seems critical in characterizing the functional associations of these oscillations. Accordingly, by recording LFP activity from the STN in parkinsonian patients, we demonstrate that perimovement beta and gamma reactivity is modulated by task complexity in a dopamine-dependent manner, despite the dynamics of the movement remaining unchanged. In contrast, spectral changes occurring in anticipation of future movement were limited to the beta band and, although modulated by dopaminergic therapy, were not modulated by task complexity. Our findings suggest two dopamine-dependent processes indexed by spectral changes in the STN: (1) an anticipatory activity reflected in the beta band that signals the likelihood of future action but does not proactively change with the cognitive demands of the potential response, and (2) perimovement activity that involves reciprocal beta and gamma band changes and is not exclusively related to explicit motor processing. Rather perimovement activity can also vary with, and may reflect, the cognitive complexity of the task.

Cognitive Factors Modulate Activity within the Human Subthalamic Nucleus during Voluntary Movement in Parkinson's Disease

Movement related dynamics of subthalmo-cortical alpha connectivity in Parkinson's disease

Oscillatory activity in the beta frequency band has been shown to be modulated during the preparation and execution of voluntary movements at both cortical and subcortical levels. The exaggeration of beta activity in the basal ganglia of patients with Parkinson's disease has heightened interest in this phenomenon. However, the precise function, if any, subserved by modulations in beta activity remains unclear. Here we test the hypothesis that beta reactivity can be dissociated from processing of specific actions and can index the salience of cues with respect to future behavior in a way that might help prospectively prioritize resources. To this end we used an experimental paradigm designed to dissociate salient warning cues from processing of specific motor or cognitive actions. We recorded local field potential activity from the subthalamic nucleus of humans undergoing functional neurosurgery for the treatment of Parkinson's disease, while the same patients were on or off the dopamine prodrug levodopa. In this way we demonstrate that beta reactivity is indeed dependent on the salience of cues with respect to future motor and cognitive action and is promoted by dopamine. The loss of normal beta encoding of saliency may underlie some of the motor and cognitive features of basal ganglia disorders such as Parkinson's disease.

Beta Reactivity, Prospective Facilitation of Executive Processing, and Its Dependence on Dopaminergic Therapy in Parkinson's Disease

Characterization of oscillatory interactions between the cortex and pedunculopontine nucleus using simultaneous magnetoencephalography and intracranial recordings in deep brain stimulation patients

A multimodal neuroimaging study of virtual spatial navigation extends the role of the hippocampal theta rhythm to human memory and self-directed learning.

Movement-Related Theta Rhythm in Humans: Coordinating Self-Directed Hippocampal Learning

An MEG signature corresponding to an axiomatic model of reward prediction error

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Boly Vegetative State Preserved Feedforward But Impaired Top-Down Processes in the

Changes in the location of cortico-muscular coherence following stroke☆

Subthalamic γ Activity Depends on Movement Amplitude and Velocity

Differences in TMS-evoked responses between schizophrenia patients and healthy controls can be observed without a dedicated EEG system

It is unclear how subthalamic nucleus activity is modulated by the cerebral cortex. Here we investigate the effect of transcranial magnetic stimulation (TMS) of the cortex on oscillatory subthalamic local field potential activity in the 8–35 Hz (alpha/beta) band, as exaggerated synchronization in this band is implicated in the pathophysiology of parkinsonism. We studied nine patients with Parkinson’s disease (PD) to test whether cortical stimulation can modulate synchronized oscillations in the human subthalamic nucleus. With patients at rest, single‐pulse TMS was delivered every 5 s over each primary motor area and supplementary motor area at intensities of 85–115% resting motor threshold. Subthalamic local field potentials were recorded from deep brain stimulation electrodes implanted into this nucleus for the treatment of PD. Motor cortical stimulation suppressed beta activity in the subthalamic nucleus from ∼0.2 to 0.6 s after TMS (repeated measures anova; main effect of time, P < 0.01; main effect of side, P = 0.03), regardless of intensity. TMS over the supplementary motor area also reduced subthalamic beta activity at 95% (P = 0.05) and 115% resting motor threshold (P = 0.01). The oscillatory activity decreased to 80 ± 26% of baseline (averaged across sites and stimulation intensities). Suppression with subthreshold stimuli confirmed that these changes were centrally driven and not due to peripheral afference. The results may have implications for mechanisms underlying the reported therapeutic benefits of cortical stimulation.

Suppression of beta oscillations in the subthalamic nucleus following cortical stimulation in humans

The pedunculopontine nucleus has recently been introduced as a new therapeutic target for deep brain stimulation in patients suffering from Parkinson's disease, particularly those with severe gait and postural impairment. Stimulation at this site is typically delivered at low frequencies in contrast to the high frequency stimulation required for therapeutic benefit in the subthalamic nucleus. Therefore, we looked for and demonstrated evidence of low frequency synchronization of activity in the pedunculopontine nucleus of a patient with Parkinson's disease that increased after treatment with dopamine and which might be mimicked by local deep brain stimulation at low frequency.

Local field potential recordings from the pedunculopontine nucleus in a Parkinsonian patient

Amplitude of motor evoked potentials at rest is positively correlated with EEG-oscillations over sensorimotor cortex

Oscillatory activity in the pedunculopontine area of patients with Parkinson's disease

Artifact correction and source analysis of early electroencephalographic responses evoked by transcranial magnetic stimulation over primary motor cortex

Excessive synchronization of basal ganglia neurons at 20 Hz slows movement in Parkinson's disease

Synchronized oscillatory activity in the beta frequency band (13–30 Hz) can be detected in the cerebral motor cortex of healthy humans in the form of corticomuscular coherence. Elevated beta activity is associated with impaired processing of new movements and with more efficient postural or tonic contraction. Accordingly, beta activity is suppressed prior to voluntary movements, rebounding thereafter in the face of peripheral afferance. However, it remains to be established whether synchronized activity in the beta band can be up‐regulated in a task‐appropriate way independently of confounding changes in sensory afferance. Here we show that there is a systematic and prospective increase in beta synchrony prior to an expected postural challenge. This up‐regulation of beta synchrony is associated with improved behavioural performance. We instructed nine healthy subjects to perform a reaction‐time movement of the index finger in response to an imperative visual cue or to resist a stretch to the finger in the same direction. These events were preceded by congruent and less common incongruent warning cues. Beta synchrony was temporally increased when subjects were warned of an impending stretch and decreased following a warning cue signalling a forthcoming reaction‐time task. Finger positions were less successfully maintained in the face of stretches and reaction times were longer when warning cues were incongruent. The results suggest that the beta state is modulated in a task‐relevant way with accompanying behavioural consequences.

Anticipatory changes in beta synchrony in the human corticospinal system and associated improvements in task performance

Paired associative stimulation (PAS), which combines repetitive peripheral nerve stimulation with transcranial magnetic stimulation (TMS), may induce neuroplastic changes in somatosensory cortex (S1), possibly by long‐term potentiation‐like mechanisms. We used multichannel median nerve somatosensory evoked potential (MN‐SSEP) recordings and two‐point tactile discrimination testing to examine the location and behavioural significance of these changes. When TMS was applied to S1 near‐synchronously to an afferent signal containing mechanoreceptive information, MN‐SSEP changes (significant at 21–31 ms) could be explained by a change in a tangential source located in Brodmann area 3b, with their timing and polarity suggesting modification of upper cortical layers. PAS‐induced MN‐SSEP changes between 28 and 32 ms were linearly correlated with changes in tactile discrimination. Conversely, when the near‐synchronous afferent signal contained predominantly proprioceptive information, PAS‐induced MN‐SSEP changes (20–29 ms) were shifted medially, and tactile performance remained stable. With near‐synchronous mechanoreceptive stimulation subtle differences in the timing of the two interacting signals tended to influence the direction of tactile performance changes. PAS performed with TMS delivered asynchronously to the afferent pulse did not change MN‐SSEPs. Hebbian interaction of mechanoreceptive afferent signals with TMS‐evoked activity may modify synaptic efficacy in superficial cortical layers of Brodmann area 3b and is associated with timing‐dependent and qualitatively congruent behavioural changes.

LTP‐like changes induced by paired associative stimulation of the primary somatosensory cortex in humans: source analysis and associated changes in behaviour

The Israel Society for Neuroscience (ISFN) was founded in 1993 by a group of Israeli leading scientists conducting research in the area of neurobiology. The primary goal of the society was to promote and disseminate the knowledge and understanding acquired by its members, and to strengthen interactions between them. Since then, the society holds its annual meeting every year in Eilat during the month of December. At these annual meetings the senior Israeli neurobiologists, their teams, and their graduate students, as well as foreign scientists and students, present their recent research findings in platform and poster presentations. The meeting also offers the opportunity for the researchers to exchange information with each other, often leading to the initiation of collaborative studies. Both the number of members of the society and of those participating in the annual meeting is constantly increasing, and it is anticipated that this year about 600 scientists will convene at the Princess Hotel in Eilat, Israel. Further information concerning the Israel Society for Neuroscience can be found at http://www.isfn.org.il. Committee: Zvi Wollberg (President) Tel Aviv University Edi Barkai University of Haifa Etti Grauer Israel Institute for Biological Research, Ness Ziona Yoram Rami Grossman Ben Gurion University of the Negev Yoel Yaari Hebrew University of Jerusalem Gal Yadid Bar-Ilan University Shlomo Rotshenker (President Elect) Hebrew University of Jerusalem Ettie Grauer (Treasurer) Israel Institute for Biological Research, Ness Ziona Michal Gilady (Administrator) Rishon Le Zion

Abstracts of the 15th Annual Meeting of the Israel Society for Neuroscience Eilat, Israel, December 3–5, 2006

Characterization of the effect of associative cortical and peripheral nerve stimulation on the somatosensory evoked potentials and tactile discrimination performance in human subjects

The capability of feedforward networks composed of multiple layers of integrate-and-fire neurons to transmit rate code was examined. Synaptic connections were made only from one layer to the next, and excitation was balanced by inhibition. When time is discrete and the synaptic potentials rise instantaneously, we show that, for random uncorrelated input to layer one, the mean rate of activity in deep layers is essentially independent of input firing rate. This implies that the input rate cannot be transmitted reliably in such feedforward networks because neurons in a given layer tend to synchronize partially with each other because of shared inputs. As a result of this synchronization, the average firing rate in deep layers will either decay to zero or reach a stable fixed point, depending on model parameters. When time is treated continuously and the synaptic potentials rise instantaneously, these effects develop slowly, and rate transmission over a limited number of layers is possible. However, the correlations among neurons at the same layer hamper reliable assessment of firing rate by averaging over 100 msec (or less). When the synaptic potentials develop gradually, as is the realistic case, transmission of rate code fails. In a network in which inhibition only balances the mean excitation but is not timed precisely with it, neurons in each layer fire together, and this volley successively propagates from layer to layer. We conclude that the transmission of rate code in feedforward networks is highly unlikely.

On the Transmission of Rate Code in Long Feedforward Networks with Excitatory–Inhibitory Balance

Hierarchical Bayesian models of perception and learning feature prominently in contemporary cognitive neuroscience where, for example, they inform computational concepts of mental disorders. This includes predictive coding and hierarchical Gaussian filtering (HGF), which differ in the nature of hierarchical representations. Predictive coding assumes that higher levels in a given hierarchy influence the state (value) of lower levels. In HGF, however, higher levels determine the rate of change at lower levels. Here, we extend the space of generative models underlying HGF to include a form of nonlinear hierarchical coupling between state values akin to predictive coding and artificial neural networks in general. We derive the update equations corresponding to this generalization of HGF and conceptualize them as connecting a network of (belief) nodes where parent nodes either predict the state of child nodes or their rate of change. This enables us to (1) create modular architectures with generic computational steps in each node of the network, and (2) disclose the hierarchical message passing implied by generalized HGF models and to compare this to comparable schemes under predictive coding. We find that the algorithmic architecture instantiated by the generalized HGF is largely compatible with that of predictive coding but extends it with some unique predictions which arise from precision and volatility related computations. Our developments enable highly flexible implementations of hierarchical Bayesian models for empirical data analysis and are available as open source software.

Conditioned Hallucinations and Prior Overweighting Are State-Sensitive Markers of Hallucination Susceptibility

Psychiatry faces fundamental challenges with regard to mechanistically guided differential diagnosis, as well as prediction of clinical trajectories and treatment response of individual patients. This has motivated the genesis of two closely intertwined fields: (i) Translational Neuromodeling (TN), which develops “computational assays” for inferring patient-specific disease processes from neuroimaging, electrophysiological, and behavioral data; and (ii) Computational Psychiatry (CP), with the goal of incorporating computational assays into clinical decision making in everyday practice. In order to serve as objective and reliable tools for clinical routine, computational assays require end-to-end pipelines from raw data (input) to clinically useful information (output). While these are yet to be established in clinical practice, individual components of this general end-to-end pipeline are being developed and made openly available for community use. In this paper, we present the Translational Algorithms for Psychiatry-Advancing Science (TAPAS) software package, an open-source collection of building blocks for computational assays in psychiatry. Collectively, the tools in TAPAS presently cover several important aspects of the desired end-to-end pipeline, including: (i) tailored experimental designs and optimization of measurement strategy prior to data acquisition, (ii) quality control during data acquisition, and (iii) artifact correction, statistical inference, and clinical application after data acquisition. Here, we review the different tools within TAPAS and illustrate how these may help provide a deeper understanding of neural and cognitive mechanisms of disease, with the ultimate goal of establishing automatized pipelines for predictions about individual patients. We hope that the openly available tools in TAPAS will contribute to the further development of TN/CP and facilitate the translation of advances in computational neuroscience into clinically relevant computational assays.

TAPAS: An Open-Source Software Package for Translational Neuromodeling and Computational Psychiatry

Recent advances in computational psychiatry have identified latent cognitive and perceptual states that predispose to psychotic symptoms. Behavioral data fit to Bayesian models have demonstrated an over-reliance on priors during perception in select samples of individuals with hallucinations. However, the clinical utility of this observation depends on whether it reflects static symptom risk or current symptom state. To determine whether task performance and estimated prior weighting related to specific elements of symptom expression, a large, heterogeneous, and deeply-phenotyped sample of hallucinators (N = 249) and non-hallucinators (N=209) performed the Conditioned Hallucination (CH) task. CH rates were sensitive to hallucination state, correlating with hallucination severity measures over the two days leading up to task completion and driven by heightened reliance on past experiences (priors). To further test this relationship, a subset of AH+ participants (N = 40) performed a repeated-measures version of the CH task. Changes in both CH frequency and relative prior precision varied with changes in AH frequency on follow-up. These results support the use of CH rate and prior hyper-precision as state markers of hallucination status, potentially useful in tracking disease development and treatment response.

Conditioned hallucinations and prior hyper-precision are state-sensitive markers of hallucination susceptibility

Inferring in Circles: Active Inference in Continuous State Space Using Hierarchical Gaussian Filtering of Sufficient Statistics

In this paper we discuss variational message passing-based (VMP) inference in a switching Hierarchical Gaussian Filter (HGF). An HGF is a flexible hierarchical state space model that supports closed-form VMP-based approximate inference for tracking of both states and slowly time-varying parameters. Since natural signals often submit to regime-switching dynamics, there is a need for low-complexity closed-form inference in switching state space models. Here we extend the HGF model with parameter switching mechanics and derive closed-form VMP update rules for plug-in applications in factor graph-based models. These VMP rules support both tracking of latent variables and variational free energy as a model performance measure. We show that the switching HGF performs better than a non-switching HGF on modelling of a stock market data set.

Bayesian modelling captures inter-individual differences in social belief computations in the putamen and insula

Cholinergic and dopaminergic effects on prediction error and uncertainty responses during sensory associative learning

ABSTRACT Mark Solms's “New Project for a Scientific Psychology” represents an invaluable step in the direction of a generative model of the mental apparatus. In particular, the idea of drawing a connection between conscious processing and variations in the precision of predictions, is an idea worth pursuing. However, the imperative always to minimize free energy is far too limiting. There is no stronger sign of evolutionary fitness than not needing to minimize it and instead playing with it. We may therefore assume that the mental apparatus, and conscious processing especially, have evolved also in order to display their skill at allowing for and handling an abundance of free energy.

Psychiatric disorders are ubiquitously characterized by debilitating social impairments. These difficulties are thought to emerge from aberrant social inference. In order to elucidate the underlying computational mechanisms, patients diagnosed with major depressive disorder (N = 29), schizophrenia (N = 31), and borderline personality disorder (N = 31) as well as healthy controls (N = 34) performed a probabilistic reward learning task in which participants could learn from social and non-social information. Patients with schizophrenia and borderline personality disorder performed more poorly on the task than healthy controls and patients with major depressive disorder. Broken down by domain, borderline personality disorder patients performed better in the social compared to the non-social domain. In contrast, controls and major depressive disorder patients showed the opposite pattern and schizophrenia patients showed no difference between domains. In effect, borderline personality disorder patients gave up a possible overall performance advantage by concentrating their learning in the social at the expense of the non-social domain. We used computational modeling to assess learning and decision-making parameters estimated for each participant from their behavior. This enabled additional insights into the underlying learning and decision-making mechanisms. Patients with borderline personality disorder showed slower learning from social and non-social information and an exaggerated sensitivity to changes in environmental volatility, both in the non-social and the social domain, but more so in the latter. Regarding decision-making the modeling revealed that compared to controls and major depression patients, patients with borderline personality disorder and schizophrenia showed a stronger reliance on social relative to non-social information when making choices. Depressed patients did not differ significantly from controls in this respect. Overall, our results are consistent with the notion of a general interpersonal hypersensitivity in borderline personality disorder and schizophrenia based on a shared computational mechanism characterized by an over-reliance on beliefs about others in making decisions and by an exaggerated need to make sense of others during learning specifically in borderline personality disorder.

Aberrant computational mechanisms of social learning and decision-making in schizophrenia and borderline personality disorder

Abstract Background Persecutory delusions (PD) are a prominent symptom in first episode psychosis and psychosis patients. PD have been linked to abnormalities in probabilistic reasoning and social inference (e.g., attribution styles). Predictive Coding theories of delusion formation suggest that rigid delusional beliefs could be formalized as precise (i.e. held with certainty) high-level prior beliefs, which were formed to explain away overly precise low-level prediction errors (PEs). Rigid reliance on high-level prior beliefs would in turn lead to diminished updating of high-level PEs, i.e. decreased learning and updating of high-level beliefs. Methods We tested the prediction that subclinical PD ideation is related to altered social inference and beliefs about others’ intentions. To that end, N=1’145 participants from the general population were pre-screened with the Paranoia Checklist (PCL) and assigned to groups of high (“high PD”) or low PD tendencies (“low PD”). Participants with intermediate scores were excluded, participants assigned to either group filled in the PCL again after four weeks, only individuals whose score remained inside the cut-offs for either group were subsequently invited to the study. We invited 162 participants and included 151 participants in the analyses based on exclusion criteria defined in an analysis plan, which was time-stamped before the conclusion of data acquisition. Participants performed a probabilistic advice-taking task with dynamic changes in the advice-outcome mapping (volatility) under one of two experimental frames. These frames differentially emphasised possible reasons behind unhelpful advice: (i) the adviser’s possible intentions (dispositional frame) or (ii) the rules of the game (situational frame). Our design was thus 2-by-2 factorial (high vs. low delusional ideation, dispositional vs. situational frame). Participants were matched regarding age, gender, and education in years. In addition to analyses of variance on participants’ behaviour, we applied computational modeling to test the predictions regarding prior beliefs and belief updating mentioned above. Results We found significant group-by-frame interactions, indicating that in the situational frame high PD participants took advice less into account than low scorers (df = (1,150), F = 5.77, p = 0.018, partial η2= 0.04). This was also reflected in the model parameters of the model explaining participants’ learning under uncertainty best in comparison to other learning models (e.g. tonic evolution rate omega2: df = (1,150), F = 4.75, p = 0.03). Discussion Our findings suggest that social inference in individuals with subclinical PD tendencies is shaped by rigid negative prior beliefs about the intentions of others. High PD participants were less sensitive to the attributional framing and updated their beliefs less vs. low PD participants thereby preventing them to make adaptive use of social information in “safe” contexts.

T64. LINKING SUBCLINICAL PERSECUTORY IDEATION TO INFLEXIBLE SOCIAL INFERENCE UNDER UNCERTAINTY

Hierarchical Gaussian Filtering of Sufficient Statistic Time Series for Active Inference

While persecutory delusions (PDs) have been linked to fallacies of reasoning and social inference, computational characterizations of delusional tendencies are rare. Here, we examined 151 individuals from the general population on opposite ends of the PD spectrum (Paranoia Checklist [PCL]). Participants made trial-wise predictions in a probabilistic lottery, guided by advice from a more informed human and a nonsocial cue. Additionally, 2 frames differentially emphasized causes of invalid advice: (a) the adviser's possible intentions (dispositional frame) or (b) the rules of the game (situational frame). We applied computational modeling to examine possible reasons for group differences in behavior. Comparing different models, we found that a hierarchical Bayesian model (hierarchical Gaussian filter) explained participants' responses better than other learning models. Model parameters determining participants' belief updates about the adviser's fidelity and the contribution of prior beliefs about fidelity to trial-wise decisions, respectively, showed significant Group × Frame interactions: High PCL scorers held more rigid beliefs about the adviser's fidelity across both experimental frames and relied less on advice in situational frames than low scorers. These results suggest that PD tendencies are associated with rigid beliefs and prevent adaptive use of social information in "safe" contexts. This supports previous proposals of a link between PD and aberrant social inference. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Hierarchical Bayesian models of social inference for probing persecutory delusional ideation.

Subjective estimates of uncertainty during gambling and impulsivity after subthalamic deep brain stimulation for Parkinson’s disease

Volatility Estimates Increase Choice Switching and Relate to Prefrontal Activity in Schizophrenia.

29.1 COMPUTATIONAL MODELING OF PERCEPTION AND BEHAVIOR REVEALS HIDDEN INSIGHTS INTO MECHANISMS OF PSYCHOTIC SYMPTOMS

Decision making often requires integrating self-gathered information with information acquired from observing others. Depending on the situation, it may be beneficial to rely more on one than the other source, taking into account that either information may be imprecise or deceiving. The process by which one source is selected over the other based on perceived reliability, here defined as arbitration, has not been fully elucidated. In this study, we formalised arbitration as the relative reliability (precision) of predictions afforded by each learning system using hierarchical Bayesian models. In a probabilistic learning task, participants predicted the outcome of a lottery using recommendations from a more informed advisor and self-sampled outcomes. The number of points participants wagered on their predictions reflected arbitration: The higher the relative precision of one learning system over the other and the lower the intention volatility, the more points participants wagered on a given trial. Functional neuroimaging demonstrated that the arbitration signal was independent of decision confidence and involved modalityspecific brain regions. Arbitrating in favour of self-gathered information activated the dorsolateral prefrontal cortex and the midbrain whereas arbitrating in favour of social information engaged ventromedial prefrontal cortex and the temporoparietal junction. These findings are in line with domain specificity and indicate that relative precision captures arbitration between social and individual learning systems at both the behavioural and neural level.

Neural arbitration between social and individual learning systems

The auditory mismatch negativity (MMN) is significantly reduced in schizophrenia. Notably, a similar MMN reduction can be achieved with NMDA receptor (NMDAR) antagonists. Both phenomena have been interpreted as reflecting an impairment of predictive coding or, more generally, the “Bayesian brain” notion that the brain continuously updates a hierarchical model to infer the causes of its sensory inputs. Specifically, neurobiological interpretations of predictive coding view perceptual inference as an NMDAR-dependent process of minimizing hierarchical precision-weighted prediction errors (PEs), and disturbances of this putative process play a key role in hierarchical Bayesian theories of schizophrenia. Here, we provide empirical evidence for this theory, demonstrating the existence of multiple, hierarchically related PEs in a “roving MMN” paradigm. We applied a hierarchical Bayesian model to single-trial EEG data from healthy human volunteers of either sex who received the NMDAR antagonist S-ketamine in a placebo-controlled, double-blind, within-subject fashion. Using an unrestricted analysis of the entire time-sensor space, our trial-by-trial analysis indicated that low-level PEs (about stimulus transitions) are expressed early (102–207 ms poststimulus), while high-level PEs (about transition probability) are reflected by later components (152–199 and 215–277 ms) of single-trial responses. Furthermore, we find that ketamine significantly diminished the expression of high-level PE responses, implying that NMDAR antagonism disrupts the inference on abstract statistical regularities. Our findings suggest that NMDAR dysfunction impairs hierarchical Bayesian inference about the world's statistical structure. Beyond the relevance of this finding for schizophrenia, our results illustrate the potential of computational single-trial analyses for assessing potential pathophysiological mechanisms.

Ketamine Affects Prediction Errors about Statistical Regularities: A Computational Single-Trial Analysis of the Mismatch Negativity

Editorial Note to: Hierarchical Prediction Errors in Midbrain and Basal Forebrain during Sensory Learning

Background Reward-based decision-making is impaired in patients with schizophrenia (PSZ) as reflected by increased choice switching. The underlying cognitive and motivational processes as well as associated neural signatures remain unknown. Reinforcement Learning (RL) and hierarchical Bayesian learning account for choice switching in different ways. We hypothesized that enhanced choice switching, as seen in PSZ during reward-based decision-making, relates to higher-order beliefs about environmental volatility and examined the associated neural activity. Methods 46 medicated PSZ and 43 healthy controls (HC) performed a reward-based decision-making task requiring flexible responses to changing action-outcome contingencies during functional Magnetic Resonance Imaging (fMRI). Detailed computational modeling of choice data was performed, including RL and the hierarchical Gaussian filter (HGF). Trajectories of learning from computational modeling informed the analysis of fMRI data. Results A three-level HGF accounted best for the observed choice data. This model revealed a heightened initial belief about environmental volatility and a stronger influence of volatility on lower-level learning of action-outcome contingencies in PSZ as compared to HC. This was replicated in an independent sample of non-medicated PSZ. Beliefs about environmental volatility were reflected by higher activity in dorsolateral prefrontal cortex of PSZ as compared to HC. Conclusions Our study suggests that PSZ inferred the environment as overly volatile, which may explain increased choice switching. In PSZ, activity in dorsolateral prefrontal cortex was more strongly related to beliefs about environmental volatility. Our computational phenotyping approach may provide useful information to dissect clinical heterogeneity and could improve prediction of outcome.

Volatility estimates increase choice switching and relate to prefrontal activity in schizophrenia

Atypical processing of uncertainty in individuals at risk for psychosis

In schizophrenia, increased aberrant salience to irrelevant events and reduced learning of relevant information may relate to an underlying deficit in relevance detection. So far, subjective estimates of relevance have not been probed in schizophrenia patients. The mechanisms underlying belief formation about relevance and their translation into decisions are unclear. Using novel computational methods, we investigated relevance detection during implicit learning in 42 schizophrenia patients and 42 healthy individuals. Participants underwent functional magnetic resonance imaging while detecting the outcomes in a learning task. These were preceded by cues differing in color and shape, which were either relevant or irrelevant for outcome prediction. We provided a novel definition of relevance based on Bayesian precision and modeled reaction times as a function of relevance weighted unsigned prediction errors (UPE). For aberrant salience, we assessed responses to subjectively irrelevant cue manifestations. Participants learned the contingencies and slowed down their responses following unexpected events. Model selection revealed that individuals inferred the relevance of cue features and used it for behavioral adaption to the relevant cue feature. Relevance weighted UPEs correlated with dorsal anterior cingulate cortex activation and hippocampus deactivation. In patients, the aberrant salience bias to subjectively task-irrelevant information was increased and correlated with decreased striatal UPE activation and increased negative symptoms. This study shows that relevance estimates based on Bayesian precision can be inferred from observed behavior. This underscores the importance of relevance detection as an underlying mechanism for behavioral adaptation in complex environments and enhances the understanding of aberrant salience in schizophrenia.

Modeling subjective relevance in schizophrenia and its relation to aberrant salience

Subthalamic deep brain stimulation (DBS) for Parkinson’s disease (PD) may modulate chronometric and instrumental aspects of choice behaviour, including motor inhibition, decisional slowing, and value sensitivity. However, it is unknown whether subthalamic DBS affects more complex aspects of decision-making, such as estimating the uncertainty around the probability of obtaining rewarding outcomes and the tendency of this probability to change over time. In this study, 38 participants with PD played a slot-machine in a virtual casino prior to subthalamic DBS (whilst ‘on’ medication) and again, 3-months postoperatively (whilst ‘on’ stimulation). Gambling behaviour during game play reflected self-reported measures of impulsivity, as quantified by the Barratt Impulsiveness Scale. We fit several computational models, including a hierarchical model of decision-making in the presence of uncertainty (the Hierarchical Gaussian Filter, HGF) and a reinforcement learning model (based on the Rescorla-Wagner formalism), to choices during slot machine play. The HGF was superior in accounting for the behaviour of our participants. Estimates of the perceptual model parameters, which encoded a participant’s uncertainty regarding the winning probability of the slot machine and its volatility, were significantly associated with impulsivity. Moreover, preoperative parameter estimates enabled significant out-of-sample predictions of the maximum postoperative change in impulsivity during longitudinal follow up. Our findings suggest that impulsivity in PD patients may be underpinned by uncertainty, and implicate a role for the subthalamic nucleus in the modulation of outcome certainty.

Subjective estimates of uncertainty and volatility during gambling predict impulsivity after subthalamic deep brain stimulation for Parkinson’s disease

34 35 Subjects with a diagnosis of schizophrenia (Scz) overweight unexpected 36 evidence in probabilistic inference: such evidence becomes ‘aberrantly salient’. A 37 neurobiological explanation for this effect is that diminished synaptic gain (e.g. 38 hypofunction of cortical N-methyl-D-aspartate receptors) in Scz destabilizes 39 quasi-stable neuronal network states (or ‘attractors’). This attractor instability 40 account predicts that i) Scz would overweight unexpected evidence but 41 underweight consistent evidence, ii) belief updating would be more vulnerable 42 to stochastic fluctuations in neural activity, and iii) these effects would correlate. 43 44 Hierarchical Bayesian belief updating models were tested in two independent 45 datasets (n=80 and n=167, male and female) comprising human subjects with 46 schizophrenia, and both clinical and non-clinical controls (some tested when 47 unwell and on recovery) performing the ‘probability estimates’ version of the 48 beads task (a probabilistic inference task). Models with a standard learning rate, 49 or including a parameter increasing updating to ‘disconfirmatory evidence’, or a 50 parameter encoding belief instability were formally compared. 51 52 The ‘belief instability’ model (based on the principles of attractor dynamics) had 53 most evidence in all groups in both datasets. Two of four parameters differed 54 between Scz and non-clinical controls in each dataset: belief instability and 55 response stochasticity. These parameters correlated in both datasets. 56 Furthermore, the clinical controls showed similar parameter distributions to Scz 57 when unwell, but were no different to controls once recovered. 58 59 These findings are consistent with the hypothesis that attractor network 60 instability contributes to belief updating abnormalities in Scz, and suggest that 61 similar changes may exist during acute illness in other psychiatric conditions. 62

Attractor-like dynamics in belief 1 updating in schizophrenia 2 3 4

Subjects with a diagnosis of schizophrenia (Scz) overweight unexpected evidence in probabilistic inference: such evidence becomes “aberrantly salient.” A neurobiological explanation for this effect is that diminished synaptic gain (e.g., hypofunction of cortical NMDARs) in Scz destabilizes quasi-stable neuronal network states (or “attractors”). This attractor instability account predicts that (1) Scz would overweight unexpected evidence but underweight consistent evidence, (2) belief updating would be more vulnerable to stochastic fluctuations in neural activity, and (3) these effects would correlate. Hierarchical Bayesian belief updating models were tested in two independent datasets (n = 80 male and n = 167 female) comprising human subjects with Scz, and both clinical and nonclinical controls (some tested when unwell and on recovery) performing the “probability estimates” version of the beads task (a probabilistic inference task). Models with a standard learning rate, or including a parameter increasing updating to “disconfirmatory evidence,” or a parameter encoding belief instability were formally compared. The “belief instability” model (based on the principles of attractor dynamics) had most evidence in all groups in both datasets. Two of four parameters differed between Scz and nonclinical controls in each dataset: belief instability and response stochasticity. These parameters correlated in both datasets. Furthermore, the clinical controls showed similar parameter distributions to Scz when unwell, but were no different from controls once recovered. These findings are consistent with the hypothesis that attractor network instability contributes to belief updating abnormalities in Scz, and suggest that similar changes may exist during acute illness in other psychiatric conditions. SIGNIFICANCE STATEMENT Subjects with a diagnosis of schizophrenia (Scz) make large adjustments to their beliefs following unexpected evidence, but also smaller adjustments than controls following consistent evidence. This has previously been construed as a bias toward “disconfirmatory” information, but a more mechanistic explanation may be that in Scz, neural firing patterns (“attractor states”) are less stable and hence easily altered in response to both new evidence and stochastic neural firing. We model belief updating in Scz and controls in two independent datasets using a hierarchical Bayesian model, and show that all subjects are best fit by a model containing a belief instability parameter. Both this and a response stochasticity parameter are consistently altered in Scz, as the unstable attractor hypothesis predicts.

Abstract Background A central theme of contemporary neuroscience is the notion that the brain embodies a generative model of its sensory inputs to infer on the underlying environmental causes, and that it uses hierarchical prediction errors (PEs) to continuously update this model. In two pharmacological EEG studies, we investigate trial-wise hierarchical PEs during the auditory mismatch negativity (MMN), an electrophysiological response to unexpected events, which depends on NMDA-receptor mediated plasticity and has repeatedly been shown to be reduced in schizophrenia. Methods Study1: Reanalysis of 64 channel EEG data from a previously published MMN study (Schmidt et al., 2012) using a placebo-controlled, within-subject design (N=19) to examine the effect of S-ketamine. Study2: 64 channel EEG data recorded during MMN (between subjects, double-blind, placebo-controlled design, N=73), to examine the effects of amisulpride and biperiden. Using the Hierarchical Gaussian Filter, a Bayesian learning model, we extracted trial-by-trial PE estimates on two hierarchical levels. These served as regressors in a GLM of trial-wise EEG signals at the sensor level. Results We find strong correlations of EEG with both PEs in both samples: lower-level PEs show effects early on (Study1: 133ms post-stimulus, Study2: 177ms), higher-level PEs later (Study1: 240ms, Study2: 450ms). The temporal order of these signatures thus mimics the hierarchical relationship of the PEs, as proposed by our computational model, where lower level beliefs need to be updated before learning can ensue on higher levels. Ketamine significantly reduced the representation of the higher-level PE in Study1. (Study2 has not been unblinded.) Discussion These studies present first evidence for hierarchical PEs during MMN and demonstrate that single-trial analyses guided by a computational model can distinguish different types (levels) of PEs, which are differentially linked to neuromodulators of demonstrated relevance for schizophrenia. Our analysis approach thus provides better mechanistic interpretability of pharmacological MMN studies, which will hopefully support the development of computational assays for diagnosis and treatment predictions in schizophrenia.

F157. HIERARCHICAL PREDICTION ERRORS DURING AUDITORY MISMATCH UNDER PHARMACOLOGICAL MANIPULATIONS: A COMPUTATIONAL SINGLE-TRIAL EEG ANALYSIS

S196. Evidence for ‘Unstable Attractor' Dynamics in Inference in Schizophrenia

148/150) Insistence on sameness and intolerance of change are part of the diagnostic criteria for Autism Spectrum Disorder (ASD) but there is little research addressing how people with ASD represent and respond to environmental change. Here, we find that behavioural and pupillometric measurements show adults with ASD are less surprised than neurotypical adults when expectations are violated, with reduced surprise predicting greater symptom severity. A hierarchical Bayesian model of learning suggests that in ASD a tendency to over-learn about volatility in the face of environmental change drives a corresponding reduction in learning about probabilistically aberrant events – putatively rendering them less surprising. Participant-specific modelled estimates of surprise about environmental conditions are linked to pupil size in the ASD group, suggesting heightened phasic noradrenergic responsivity in line with neural gain impairments. This study offers novel insight into the behavioural, algorithmic and physiological mechanisms that underlie responses to environmental volatility in ASD.

Title: Adults with autism over-estimate the volatility of the sensory environment. Authors:

Abstract Background Reward-based decision-making is impaired in schizophrenia, as reflected by increased switching between choices. The underlying cognitive mechanisms and associated neural signatures remain unknown. Reinforcement learning (RL) and hierarchical Bayesian learning account for this behavior in different ways. We hypothesized that enhanced switching during flexible reward-based decision-making in schizophrenia relates to higher-order beliefs about environmental volatility and examined the associated neural signatures. Methods 46 medicated schizophrenia patients and 43 controls underwent a reward-based decision-making task requiring flexible behavior to changing action-outcome contingencies during functional Magnetic Resonance Imaging (fMRI). Computational modeling of behavior was performed, including RL and the Hierarchical Gaussian Filter (HGF). The estimated learning trajectories informed the analysis of fMRI data. Results A three-level HGF accounted best for the observed choice data and revealed a heightened prior belief about environmental volatility and a stronger influence of volatility on lower-level learning of action-outcome contingencies in schizophrenia. This finding was replicated in an independent sample of unmedicated patients. Beliefs about environmental volatility were reflected by higher activity in dorsolateral prefrontal cortex (dlPFC) of patients compared to controls. Discussion This study suggests a mechanistic explanation for instable behavior in schizophrenia: patients inferred the environment as being too volatile and thus overestimated environmental changes, leading to maladaptive choice switching. Our data suggest enhanced dlPFC activity related to beliefs about environmental volatility as a neural learning signature of instable behavior. Such detailed ‘computational phenotyping’ may provide useful information to dissect clinical heterogeneity and could improve prediction of outcome.

F150. OVERESTIMATING ENVIRONMENTAL VOLATILITY INCREASES SWITCHING BEHAVIOR AND IS LINKED TO ACTIVATION OF DORSOLATERAL PREFRONTAL CORTEX IN SCHIZOPHRENIA

Representational Uncertainty in the Brain During Threat Conditioning and the Link With Psychopathic Traits.

Adults with autism over-estimate the volatility of the sensory environment

Neural mechanisms for hallucinations Pairing a stimulus in one modality (vision) with a stimulus in another (sound) can lead to task-induced hallucinations in healthy individuals. After many trials, people eventually report perceiving a nonexistent stimulus contingent on the presence of the previously paired stimulus. Powers et al. investigated how different groups of volunteers and patients respond to this conditioning paradigm. They used behavior, neuroimaging, and computational modeling to dissect the effect of perceptual priors versus sensory evidence on such induced hallucinations. People who are more prone to hear voices were more susceptible to the induced auditory hallucinations. The network of brain regions that was active during the conditioned hallucinations resembled the network observed during clinical symptom capture in individuals who hallucinate while in a brain scanner. Science, this issue p. 596 Perceptual beliefs, stimulus associations, and belief volatility drive task-induced hallucinations in voice-hearers. Some people hear voices that others do not, but only some of those people seek treatment. Using a Pavlovian learning task, we induced conditioned hallucinations in four groups of people who differed orthogonally in their voice-hearing and treatment-seeking statuses. People who hear voices were significantly more susceptible to the effect. Using functional neuroimaging and computational modeling of perception, we identified processes that differentiated voice-hearers from non–voice-hearers and treatment-seekers from non–treatment-seekers and characterized a brain circuit that mediated the conditioned hallucinations. These data demonstrate the profound and sometimes pathological impact of top-down cognitive processes on perception and may represent an objective means to discern people with a need for treatment from those without.

Pavlovian conditioning–induced hallucinations result from overweighting of perceptual priors

Abstract Social learning is fundamental to human interactions, yet its computational and physiological mechanisms are not well understood. One prominent open question concerns the role of neuromodulatory transmitters. We combined fMRI, computational modelling and genetics to address this question in two separate samples (N = 35, N = 47). Participants played a game requiring inference on an adviser’s intentions whose motivation to help or mislead changed over time. Our analyses suggest that hierarchically structured belief updates about current advice validity and the adviser’s trustworthiness, respectively, depend on different neuromodulatory systems. Low-level prediction errors (PEs) about advice accuracy not only activated regions known to support ‘theory of mind’, but also the dopaminergic midbrain. Furthermore, PE responses in ventral striatum were influenced by the Met/Val polymorphism of the Catechol-O-Methyltransferase (COMT) gene. By contrast, high-level PEs (‘expected uncertainty’) about the adviser’s fidelity activated the cholinergic septum. These findings, replicated in both samples, have important implications: They suggest that social learning rests on hierarchically related PEs encoded by midbrain and septum activity, respectively, in the same manner as other forms of learning under volatility. Furthermore, these hierarchical PEs may be broadcast by dopaminergic and cholinergic projections to induce plasticity specifically in cortical areas known to represent beliefs about others.

Hierarchical prediction errors in midbrain and septum during social learning

Psychiatry has found it diffi cult to develop a nosology that allows for the targeted treatment of disorders of the mind. The historic inability of the fi eld to agree on a nosology based on clinical experience has led it to retreat to diagnoses based on symptom checklists as laid down in the Diagnostic and Statistical Manual of Mental Disorders (DSM). While this has increased the reliability of diagnoses, hopes that biological fi ndings would lead to the emergence of mechanistically founded diagnostic entities have not been realized despite considerable advances in neurobiology. This article sets out a possible way forward: harnessing systems theory to provide the conceptual constraints needed to link clinical phenomena with neurobiology. This approach builds on the insight that the mind is a system which, to regulate its environment, needs to have a model of that environment and needs to update predictions about it using the rules of inductive logic (i.e., Bayesian inference). The application of the rules of inductive logic is called Bayesian inference because Bayes’s theorem is the most important consequence of these rules, prescribing how beliefs need to be updated in response to new information. Importantly, while Bayesian inference is by defi nition consistent with the rules of inductive logic, it can still be false (to the point of being pathological), in the sense of leading to false predictions, because the model underlying the inference is inadequate. Further, it can be shown that Bayesian inference can be reduced to updating beliefs based on precision-weighted prediction errors, where a prediction error is the difference between actual and predicted input, and precision is the confi dence associated with the input prediction. Precision weighting of prediction errors entails that a given discrepancy between outcome and prediction means more, and leads to greater belief updates, the more confi dently the prediction was made. This provides a conceptual framework linking clinical experience with the pathophysiology underlying disorders of the mind. Limitations of this approach are discussed and ways to work around them illustrated with examples. Finally, initial steps and possible future directions toward a nosology based on failures of precision weighting are discussed. From “Computational Psychiatry: New Perspectives on Mental Illness,” A. David Redish and Joshua A. Gordon, eds. 2016. Strüngmann Forum Reports, vol. 20, series ed. J. Lupp. Cambridge, MA: MIT Press. ISBN 978-0-262-03542-2.

Understanding impaired flexible reward-based decision-making by hierarchical Bayesian learning: A computational fMRI study in schizophrenia

Computations of uncertainty mediate acute stress responses in humans

This paper outlines a hierarchical Bayesian framework for interoception, homeostatic/allostatic control, and meta-cognition that connects fatigue and depression to the experience of chronic dyshomeostasis. Specifically, viewing interoception as the inversion of a generative model of viscerosensory inputs allows for a formal definition of dyshomeostasis (as chronically enhanced surprise about bodily signals, or, equivalently, low evidence for the brain's model of bodily states) and allostasis (as a change in prior beliefs or predictions which define setpoints for homeostatic reflex arcs). Critically, we propose that the performance of interoceptive-allostatic circuitry is monitored by a metacognitive layer that updates beliefs about the brain's capacity to successfully regulate bodily states (allostatic self-efficacy). In this framework, fatigue and depression can be understood as sequential responses to the interoceptive experience of dyshomeostasis and the ensuing metacognitive diagnosis of low allostatic self-efficacy. While fatigue might represent an early response with adaptive value (cf. sickness behavior), the experience of chronic dyshomeostasis may trigger a generalized belief of low self-efficacy and lack of control (cf. learned helplessness), resulting in depression. This perspective implies alternative pathophysiological mechanisms that are reflected by differential abnormalities in the effective connectivity of circuits for interoception and allostasis. We discuss suitably extended models of effective connectivity that could distinguish these connectivity patterns in individual patients and may help inform differential diagnosis of fatigue and depression in the future.

Allostatic Self-efficacy: A Metacognitive Theory of Dyshomeostasis-Induced Fatigue and Depression

Conventional paradigms can successfully capture many cognitive processes, unveiling several (patho-)physiological mechanisms. However, often they come at the cost of tedious tasks for the participants, which can impose critical restrictions especially when it comes to certain neurocognitive conditions. Immersive videogames could provide an entertaining alternative of higher ecological validity. Eye or other body movements could then be modeled for unveiling cognition, for example by modeling frameworks based on predictive coding theories for brain function. In this project, we present an approach that combines video games, eye tracking and Bayesian modeling (i.e. HGF, [1]) for studying learning and decision-making. To that end, first, an interactive videogame was developed. The player’s goal was to maximize a score by efficiently exploiting regularities in the environment, i.e. the game’s structure. Second, we conducted a proof-of-concept study with 10 healthy volunteers, considering different probabilistic conditions across two spatial dimensions. Behavior was monitored by recording eye-gaze and/or mouse-movements. Third, the behavioral responses were modeled with a two-dimensional Bayesian framework using hierarchical-Gaussian-filtering, as well as classic reinforcement learning, yielding insights about both learning and decision-making processes. Bayesian model comparison was used to infer on the cognitive strategy applied by the participants. According to the winning model, subjects appeared to use a volatility dependent learning rate. Their response variability was found to be highly influenced by the precision (i.e. confidence) of predictions and responses appeared to be spatially correlated. Finally, spillover effects between the learning and the response model were identified across dimensions for certain subjects. The 2D computational framework implemented in this study provides a first step towards interactive paradigms that allow for a detailed investigation of multimodal prediction precision. As such it could be well suited to study spectrum conditions such as autism or schizophrenia for which aberrant precision has been hypothesized. 1. Mathys C, Daunizeau J, Friston KJ, & Stephan KE. (2011). A Bayesian foundation for individual learning under uncertainty. Frontiers in human neuroscience, 5:39.

Inferring cognitive traits of individual subjects through gaze controlled video games

Attention-deficit/hyperactivity disorder (ADHD) has been associated with deficient decision making and learning. Models of ADHD have suggested that these deficits could be caused by impaired reward prediction errors (RPEs). Reward prediction errors are signals that indicate violations of expectations and are known to be encoded by the dopaminergic system. However, the precise learning and decision-making deficits and their neurobiological correlates in ADHD are not well known.

OBJECTIVE
To determine the impaired decision-making and learning mechanisms in juvenile ADHD using advanced computational models, as well as the related neural RPE processes using multimodal neuroimaging.

Twenty adolescents with ADHD and 20 healthy adolescents serving as controls (aged 12-16 years) were examined using a probabilistic reversal learning task while simultaneous functional magnetic resonance imaging and electroencephalogram were recorded.

Learning and decision making were investigated by contrasting a hierarchical Bayesian model with an advanced reinforcement learning model and by comparing the model parameters. The neural correlates of RPEs were studied in functional magnetic resonance imaging and electroencephalogram.

RESULTS
Adolescents with ADHD showed more simplistic learning as reflected by the reinforcement learning model (exceedance probability, Px = .92) and had increased exploratory behavior compared with healthy controls (mean [SD] decision steepness parameter β: ADHD, 4.83 [2.97]; controls, 6.04 [2.53]; P = .02). The functional magnetic resonance imaging analysis revealed impaired RPE processing in the medial prefrontal cortex during cue as well as during outcome presentation (P < .05, family-wise error correction). The outcome-related impairment in the medial prefrontal cortex could be attributed to deficient processing at 200 to 400 milliseconds after feedback presentation as reflected by reduced feedback-related negativity (ADHD, 0.61 [3.90] μV; controls, -1.68 [2.52] μV; P = .04).

The combination of computational modeling of behavior and multimodal neuroimaging revealed that impaired decision making and learning mechanisms in adolescents with ADHD are driven by impaired RPE processing in the medial prefrontal cortex. This novel, combined approach furthers the understanding of the pathomechanisms in ADHD and may advance treatment strategies.

Role of the medial prefrontal cortex in impaired decision making in juvenile attention-deficit/hyperactivity disorder.

Correction: Inferring on the Intentions of Others by Hierarchical Bayesian Learning

Inferring on others' (potentially time-varying) intentions is a fundamental problem during many social transactions. To investigate the underlying mechanisms, we applied computational modeling to behavioral data from an economic game in which 16 pairs of volunteers (randomly assigned to “player” or “adviser” roles) interacted. The player performed a probabilistic reinforcement learning task, receiving information about a binary lottery from a visual pie chart. The adviser, who received more predictive information, issued an additional recommendation. Critically, the game was structured such that the adviser's incentives to provide helpful or misleading information varied in time. Using a meta-Bayesian modeling framework, we found that the players' behavior was best explained by the deployment of hierarchical learning: they inferred upon the volatility of the advisers' intentions in order to optimize their predictions about the validity of their advice. Beyond learning, volatility estimates also affected the trial-by-trial variability of decisions: participants were more likely to rely on their estimates of advice accuracy for making choices when they believed that the adviser's intentions were presently stable. Finally, our model of the players' inference predicted the players' interpersonal reactivity index (IRI) scores, explicit ratings of the advisers' helpfulness and the advisers' self-reports on their chosen strategy. Overall, our results suggest that humans (i) employ hierarchical generative models to infer on the changing intentions of others, (ii) use volatility estimates to inform decision-making in social interactions, and (iii) integrate estimates of advice accuracy with non-social sources of information. The Bayesian framework presented here can quantify individual differences in these mechanisms from simple behavioral readouts and may prove useful in future clinical studies of maladaptive social cognition.

Inferring on the Intentions of Others by Hierarchical Bayesian Learning

Hierarchical Prediction Errors in Midbrain and Basal Forebrain during Sensory Learning

Variational Bayesian mixed-effects inference for classification studies

Classification algorithms are frequently used on data with a natural hierarchical structure. For instance, classifiers are often trained and tested on trial-wise measurements, separately for each subject within a group. One important question is how classification outcomes observed in individual subjects can be generalized to the population from which the group was sampled. To address this question, this paper introduces novel statistical models that are guided by three desiderata. First, all models explicitly respect the hierarchical nature of the data, that is, they are mixed-effects models that simultaneously account for within-subjects (fixed-effects) and across-subjects (random-effects) variance components. Second, maximum-likelihood estimation is replaced by full Bayesian inference in order to enable natural regularization of the estimation problem and to afford conclusions in terms of posterior probability statements. Third, inference on classification accuracy is complemented by inference on the balanced accuracy, which avoids inflated accuracy estimates for imbalanced data sets. We introduce hierarchical models that satisfy these criteria and demonstrate their advantages over conventional methods usingMCMC implementations for model inversion and model selection on both synthetic and empirical data. We envisage that our approach will improve the sensitivity and validity of statistical inference in future hierarchical classification studies.

Bayesian mixed-effects inference on classification performance in hierarchical data sets

The neural basis of the human brain's ability to discriminate pitch has been investigated by functional neuroimaging and the study of lesioned brains, indicating the critical importance of right and left Heschl's gyrus (HG) in pitch perception. Nonetheless, there remains some uncertainty with regard to localization and lateralization of pitch discrimination, partly because neuroimaging results do not allow us to draw inferences about the causality. To address the problem of causality in pitch discrimination functions, we used transcranial direct current stimulation to downregulate (via cathodal stimulation) and upregulate (via anodal stimulation) excitability in either left or right auditory cortex and measured the effect on performance in a pitch discrimination task in comparison with sham stimulation. Cathodal stimulation of HG on the left and on the right hemispheres adversely affected pitch discrimination in comparison to sham stimulation, with the effect on the right being significantly stronger than on the left. Anodal stimulation on either side had no effect on performance in comparison to sham. Our results indicate that both left and right HG are causally involved in pitch discrimination, although the right auditory cortex might be a stronger contributor.

Non-Invasive Brain Stimulation Applied to Heschl's Gyrus Modulates Pitch Discrimination

Modulating Regional Cerebral Blood Flow With Transcranial Direct Current Stimulation (tDCS)

We show the instability of two self-tuning brane world models with gauge invariant linear perturbation theory. This general method confirms a known instability of the original model with vanishing bulk potential. We also show the dynamical instability of a recently proposed self-tuning "smooth" brane model and its limit, the Randall-Sundrum model. Astonishingly, we also find instability under purely gravitational perturbations.

Corrigendum : Adults with autism overestimate the volatility of the sensory environment

Our daily behaviour requires a flexible arbitration between actions we do out of habit and actions that are directed towards a specific goal. Drugs that target opioid and dopamine receptors are notorious for inducing maladaptive habitual drug consumption, yet how the opioidergic and dopaminergic neurotransmitter systems contribute to the arbitration between habitual and goal-directed behaviour is poorly understood. By combining pharmacological challenges with a well-established decision-making task and a novel computational model, we show that the administration of the D2 dopamine receptor antagonist amisulpride led to an increase in goal-directed or ‘model-based’ relative to habitual or ‘model-free’ behaviour, whereas the non-selective opioid receptor antagonist naltrexone had no appreciable effect. These findings highlight the distinct functional contributions of dopamine and opioid receptors to goal-directed and habitual behaviour and support the notion that D2 receptor antagonists promote stabilisation of goal-relevant information.

Effects of dopamine D2/3 and opioid receptor antagonism on the trade-off between model-based and model-free behaviour in healthy volunteers

The ability to flexibly adjust beliefs about other people is crucial for human social functioning. Dopamine has been proposed to regulate the precision of beliefs, but direct behavioural evidence of this is lacking. We investigated how a relatively high dose of the selective D2/D3 dopamine receptor antagonist sulpiride impacts learning about other people’s prosocial attitudes in a repeated trust game. Using a Bayesian model of belief updating, we show that sulpiride increased the volatility of beliefs, which led to higher precision-weights on prediction errors. This effect was entirely driven by participants with genetically conferring higher dopamine availability (Taq1a polymorphism). Higher precision weights were reflected in higher reciprocal behaviour in the repeated trust game but not in single-round trust games. This finding suggests that antipsychotic medication might acutely reduce rigidity of pathological beliefs.

Blocking D2/D3 dopamine receptors increases volatility of beliefs when we learn to trust others

National Policy Opportunities to Support Blue Carbon Conservation

Trial history biases and lapses are two of the most common suboptimalities observed during perceptual decision-making. These suboptimalities are routinely assumed to arise from distinct processes. However, several hints in the literature suggest that they covary in their prevalence and that their proposed neural substrates overlap – what could underlie these links? Here we demonstrate that history biases and apparent lapses can both arise from a common cognitive process that is normative under misbeliefs about non-stationarity in the world. This corresponds to an accumulation- to-bound model with history-dependent updates to the initial state of the accumulator. We test our model’s predictions about the relative prevalence of history biases and lapses, and show that they are robustly borne out in two distinct rat decision-making datasets, including data from a novel reaction time task. Our model improves the ability to precisely predict decision-making dynamics within and across trials, by positing a process through which agents can generate quasi-stochastic choices.

Trial-history biases in evidence accumulation can give rise to apparent lapses

Corrigendum: An accumulation-of-evidence task using visual pulses for mice navigating in virtual reality

Stable choice coding in rat frontal orienting fields across model-predicted changes of mind

Trial history biases in decision-making tasks are thought to reflect systematic updates of decision variables, therefore their precise nature informs conclusions about underlying heuristic strategies and learning processes. However, random drifts in decision variables can corrupt this inference by mimicking the signatures of systematic updates. Hence, identifying the trial-by-trial evolution of decision variables requires methods that can robustly account for such drifts. Recent studies (Lak’20, Mendonça‘20) have made important advances in this direction, by proposing a convenient method to correct for the influence of slow drifts in decision criterion, a key decision variable. Here we apply this correction to a variety of updating scenarios, and evaluate its performance. We show that the correction fails for a wide range of commonly assumed systematic updating strategies, distorting one’s inference away from the veridical strategies towards a narrow subset. To address these limitations, we propose a model-based approach for disambiguating systematic updates from random drifts, and demonstrate its success on real and synthetic datasets. We show that this approach accurately recovers the latent trajectory of drifts in decision criterion as well as the generative systematic updates from simulated data. Our results offer recommendations for methods to account for the interactions between history biases and slow drifts, and highlight the advantages of incorporating assumptions about the generative process directly into models of decision-making.

Limitations of a proposed correction for slow drifts in decision criterion

Author response: Interrogating theoretical models of neural computation with emergent property inference

Successes and failures of simpliﬁed models for a network of real neurons

How do we choose the best action in a constantly-changing environment? Many natural decisions unfold in dynamic environments where newer observations carry better information about the present state of the world. Recent work has shown that rats can learn to optimally discount old evidence, updating their provisional decision when the environmental state changes. Provisional decisions are thought to be represented in the Frontal Orienting Fields (FOF), but this has only been tested in static environments where the provisional and final decisions are not easily dissociated. Here, we characterize the representation of accumulated evidence in rat FOF during decision-making in a dynamic environment. We find that FOF encodes evidence throughout decision formation with a temporal gain modulation that rises until the period when the animal may need to act. Using a behavioral model to predict the timing of changes of mind revealed that FOF neurons respond rapidly to these events, representing the new provisional decisions in their firing rates. Our results suggest that the FOF represents provisional decisions even in dynamic, uncertain environments, allowing for rapid motor execution when it is time to act.

DataBlitz Session 1 14:40 – 15:00 Katja Reinhard The neural basis of defensive behavior evolution in Peromyscus mice 15:10 – 15:30 Felix Effenberger Harmonic oscillator recurrent networks 15:10 – 15:30 Katharine Shapcott Experimental control of an immersive dome virtual environment for non-human and human behaviour created with Unreal Engine 15:00 – 15:20 Jennifer Hoy Development of visually guided prey capture behavior in mouse 15:30 – 15:50 Amr Farahat Shape representation in Convolutional Neural Networks 15:30 – 15:50 Owen Martin Visual communication of synchronous firefly swarms in natural and virtual realities

Volumetric imaging and morphometry for comparative rodent neuroscience

Studies of neural dynamics in lateral orbitofrontal cortex (lOFC) have shown that subsets of neurons that encode distinct aspects of behavior, such as value, may project to common downstream targets. However, it is unclear whether reward history, which may subserve lOFC’s well-documented role in learning, is represented by functional subpopulations in lOFC. Previously, we analyzed neural recordings from rats performing a value-based decision-making task, and we documented trial-by-trial learning that required lOFC (Constantinople et al., 2019). Here we characterize functional subpopulations of lOFC neurons during behavior, including their encoding of task variables. We found five distinct clusters of lOFC neurons, either based on clustering of their trial-averaged peristimulus time histograms (PSTHs), or a feature space defined by their average conditional firing rates aligned to different task variables. We observed weak encoding of reward attributes, but stronger encoding of reward history, the animal’s left or right choice, and reward receipt across all clusters. Only one cluster, however, encoded the animal’s reward history at the time shortly preceding the choice, suggesting a possible role in integrating previous and current trial outcomes at the time of choice. This cluster also exhibits qualitatively similar responses to identified corticostriatal projection neurons in a recent study (Hirokawa et al., 2019), and suggests a possible role for subpopulations of lOFC neurons in mediating trial-by-trial learning.

Subpopulations of neurons in lOFC encode previous and current rewards at time of choice

Biological networks exhibit complex, coordinated patterns of activity. Can these patterns be captured precisely in simple models? Here we use measurements of simultaneous activity in 1000+ neurons in the mouse brain to test the validity of models grounded in statistical physics. When cells are dense samples from a small region, we find extremely detailed quantitative agreement between theory and experiment; sparse samples from larger regions lead to model failures. These results show we can aspire to more than qualitative agreement between simplifying theoretical ideas and the detailed behavior of a complex biological system.

Successes and failures of simple statistical physics models for a network of real neurons

How does the brain internally represent a sequence of sensory information that jointly drives a decision-making behavior? Studies of perceptual decision-making have often assumed that sensory cortices provide noisy but otherwise veridical sensory inputs to downstream processes that accumulate and drive decisions. However, sensory processing in even the earliest sensory cortices can be systematically modified by various external and internal contexts. We recorded from neuronal populations across posterior cortex as mice performed a navigational decision-making task based on accumulating randomly timed pulses of visual evidence. Even in V1, only a small fraction of active neurons had sensory-like responses time-locked to each pulse. Here, we focus on how these ‘cue-locked’ neurons exhibited a variety of amplitude modulations from sensory to cognitive, notably by choice and accumulated evidence. These task-related modulations affected a large fraction of cue-locked neurons across posterior cortex, suggesting that future models of behavior should account for such influences.

Author response: Amplitude modulations of cortical sensory responses in pulsatile evidence accumulation

Amplitude modulations of cortical sensory responses in pulsatile evidence accumulation

The use of Neuropixels probes for chronic neural recordings is in its infancy and initial studies leave questions about long-term stability and probe reusability unaddressed. Here we demonstrate a new approach for chronic Neuropixels recordings over a period of months in freely moving rats. Our approach allows multiple probes per rat and multiple cycles of probe reuse. We found that hundreds of units could be recorded for multiple months, but that yields depended systematically on anatomical position. Explanted probes displayed a small increase in noise compared to unimplanted probes, but this was insufficient to impair future single-unit recordings. We conclude that cost-effective, multi-region, and multi-probe Neuropixels recordings can be carried out with high yields over multiple months in rats or other similarly sized animals. Our methods and observations may facilitate the standardization of chronic recording from Neuropixels probes in freely moving animals.

An approach for long-term, multi-probe Neuropixels recordings in unrestrained rats

Cortical areas seem to form a hierarchy of intrinsic timescales, but whether this is causal to cognitive behavior remains unknown. In particular, decisions requiring the gradual accrual of sensory evidence over time recruit widespread areas across this hierarchy. Here, we causally tested the hypothesis that this recruitment is related to the intrinsic integration timescales of these widespread areas. We trained mice to accumulate evidence over seconds while navigating in virtual reality, and optogenetically silenced the activity of many cortical areas during different brief trial epochs. We found that the inactivation of different areas primarily affected the evidence-accumulation computation per se, rather than other decision-related processes. Specifically, we observed selective changes in the weighting of evidence over time, such that frontal inactivations led to deficits on longer timescales than posterior cortical ones. Likewise, large-scale cortical Ca2+ activity during task performance displayed different temporal integration windows matching the effects of inactivation. Our findings suggest that distributed cortical areas accumulate evidence by leveraging their hierarchy of intrinsic timescales.

Multiple timescales of sensory-evidence accumulation across the dorsal cortex

How do animals make behavioral decisions based on noisy sensory signals, which are moreover a tiny fraction of ongoing activity in the brain? Some theories suggest that sensory responses should be accumulated through time to reduce noise. Others suggest that feedback-based gain control of sensory responses allow small signals to be selectively amplified to drive behavior. We recorded from neuronal populations across posterior cortex as mice performed a decision-making task based on accumulating randomly timed pulses of visual evidence. Here we focus on a subset of neurons, with putative sensory responses that were time-locked to each pulse. These neurons exhibited a variety of amplitude (gain-like) modulations, notably by choice and accumulated evidence. These neural data inspired a hypothetical accumulation circuit with a multiplicative feedback-loop architecture, which parsimoniously explains deviations in perceptual discrimination from Weber-Fechner Law. Our neural observations thus led to a model that synthesizes both accumulation and feedback hypotheses.

Amplitude modulations of sensory responses, and deviations from Weber’s Law in pulsatile evidence accumulation

Quantifying success and failure in simple models of large neural populations

Sequential and efficient neural-population coding of complex task information

Neural Correlates of Cognition in Primary Visual versus Downstream Posterior Cortices During Evidence Accumulation

Presented on March 11, 2019 at 11:!5 a.m. in the Krone Engineered Biosystems Building, Room 100.

Studies of perceptual decision-making have often assumed that the main role of sensory cortices is to provide sensory input to downstream processes that accumulate and drive behavioral decisions. We performed a systematic comparison of neural activity in primary visual (V1) to secondary visual and retrosplenial cortices, as mice performed a task where they should accumulate pulsatile visual cues through time to inform a navigational decision. Even in V1, only a small fraction of neurons had sensory-like responses to cues. Instead, in all areas neurons were sequentially active, and contained information ranging from sensory to cognitive, including cue timings, evidence, place/time, decision and reward outcome. Per-cue sensory responses were amplitude-modulated by various cognitive quantities, notably accumulated evidence. This inspired a multiplicative feedback-loop circuit hypothesis that proposes a more intricate role of sensory areas in the accumulation process, and furthermore explains a surprising observation that perceptual discrimination deviates from Weber-Fechner Law. Highlights / eTOC Blurb Mice made navigational decisions based on accumulating pulsatile visual cues The bulk of neural activity in visual cortices was sequential and beyond-sensory Accumulated pulse-counts modulated sensory (cue) responses, suggesting feedback A feedback-loop neural circuit explains behavioral deviations from Weber’s Law In a task where navigation was informed by accumulated pulsatile visual evidence, neural activity in visual cortices predominantly coded for cognitive variables across multiple timescales, including outside of a visual processing context. Even sensory responses to visual pulses were amplitude-modulated by accumulated pulse counts and other variables, inspiring a multiplicative feedback-loop circuit hypothesis that in turn explained behavioral deviations from Weber-Fechner Law.

Neural Correlates of Cognition in Primary Visual versus Neighboring Posterior Cortices during Visual Evidence-Accumulation-based Navigation

Task-Dependent Changes in the Large-Scale Dynamics and Necessity of Cortical Regions

Individual choices are not made in isolation but are embedded in a series of past experiences, decisions, and outcomes. The effects of past experiences on choices, often called sequential biases, are ubiquitous in perceptual and value-based decision-making, but their neural substrates are unclear. We trained rats to choose between cued guaranteed and probabilistic rewards in a task in which outcomes on each trial were independent. Behavioral variability often reflected sequential effects, including increased willingness to take risks following risky wins, and spatial ‘win-stay/lose-shift’ biases. Recordings from lateral orbitofrontal cortex (lOFC) revealed encoding of reward history and receipt, and optogenetic inhibition of lOFC eliminated rats’ increased preference for risk following risky wins, but spared other sequential effects. Our data show that different sequential biases are neurally dissociable, and the lOFC’s role in adaptive behavior promotes learning of more abstract biases (here, biases for the risky option), but not spatial ones.

Lateral orbitofrontal cortex promotes trial-by-trial learning of risky, but not spatial, biases

Author response: Lateral orbitofrontal cortex promotes trial-by-trial learning of risky, but not spatial, biases

Individual choices are not made in isolation but are embedded in a series of past experiences, decisions, and outcomes. The effects of past experiences on choices, often called sequential biases, are ubiquitous in perceptual and value-based decision-making, but their neural substrates are unclear. We trained rats to choose between explicitly cued guaranteed and probabilistic rewards in a task in which outcomes on each trial were independent. Behavioral variability often reflected the effects of previous trials, including increased willingness to take risks following risky wins, and spatial “win-stay/lose-shift” biases. Electrophysiological recordings from lateral orbitofrontal cortex (lOFC) revealed strong encoding of reward history and receipt, and optogenetic inhibition of lOFC during choice reporting eliminated rats’ increased preference for risk on subsequent trials following risky wins, but spared other sequential effects. Our data show that different sequential biases are neurally dissociable, and that the lOFC’s role in adaptive behavior promotes learning of more abstract, task-specific biases (here, biases for the risky option), but not spatial ones. These data are consistent with proposals that the OFC represents the animal’s location in an abstract representation of task states, and highlight the lOFC’s role in learning.

Orbitofrontal cortex promotes trial-by-trial learning of risky, but not spatial, biases

Decision letter: Reinforcement biases subsequent perceptual decisions when confidence is low, a widespread behavioral phenomenon

How our brains measure the passage of time is still largely open for debate. One behavioral task commonly used to study how durations are perceived is the Temporal Bisection Task, in which subjects categorize time durations as either “short” or “long.” The duration equally likely to be categorized as short or long is known as the bisection point. It has been consistently demonstrated that for humans, the bisection point is near the arithmetic mean of the longest and shortest durations the subject was trained on. In contrast, for non-human subjects it has been consistently found near the geometric mean. This difference implies that humans may process or represent temporal durations differently than other species. Here we present a behavioral model that reconciles the differences by demonstrating that rats’ performance on this task is driven not only by their noisy estimates of duration, but also by the temporally-discounted value of future rewards. The model correctly predicts shifts in the bisection point induced by unequal rewards and explains otherwise-paradoxical psychometric reversals documented three decades ago. Furthermore, as predicted by the model, we found that modifying the Temporal Bisection Task to eliminate the temporally-discounted reward component shifted the rats’ bisection point from the geometric mean to the arithmetic mean, thus bringing the rat results into line with the human results. We therefore propose that humans and rats (and perhaps other non-human subjects as well) process temporal information similarly, and that the difference between them in the Temporal Bisection Task may be simply due to rats weighing temporal discounting of future rewards more strongly than humans.

Controlling for temporal discounting shifts rats from geometric to human-like arithmetic bisection

Imaging Cortical Dynamics in GCaMP Transgenic Rats with a Head-Mounted Widefield Macroscope

Rats adopt the optimal timescale for evidence integration in a dynamic environment

A broad range of decision-making processes involve gradual accumulation of evidence over time, but the neural circuits responsible for this computation are not yet established. Recent data indicates that cortical regions prominently associated with accumulating evidence, such as posterior parietal cortex and the frontal orienting fields, are not necessary for computing it. Which, then, are the regions responsible? Regions directly involved in evidence accumulation should satisfy the criteria of being necessary for accumulation-based decision-making behavior, having a graded neural encoding of accumulated evidence and causal contributing throughout the accumulation process. Here, we investigated the role of the anterior dorsal striatum (ADS) in a rodent auditory evidence accumulation task using a combination of behavioral, pharmacological, optogenetic, electrophysiological and computational approaches. We find that the ADS is the first brain region known to satisfy these criteria. Thus, the ADS may be the first identified node in the network responsible for evidence accumulation.

Causal contribution and dynamical encoding in the striatum during evidence accumulation

We develop a phenomenological coarse-graining procedure for activity in a large network of neurons, and apply this to recordings from a population of 1000+ cells in the hippocampus. Distributions of coarse-grained variables seem to approach a fixed non-Gaussian form, and we see evidence of scaling in both static and dynamic quantities. These results suggest that the collective behavior of the network is described by a nontrivial fixed point.

Coarse Graining, Fixed Points, and Scaling in a Large Population of Neurons.

In many systems we can describe emergent macroscopic behaviors, quantitatively, using models that are much simpler than the underlying microscopic interactions; we understand the success of this simplification through the renormalization group. Could similar simplifications succeed in complex biological systems? We develop explicit coarse-graining procedures that we apply to experimental data on the electrical activity in large populations of neurons in the mouse hippocampus. Probability distributions of coarse-grained variables seem to approach a fixed non-Gaussian form, and we see evidence of power-law dependencies in both static and dynamic quantities as we vary the coarse-graining scale over two decades. Taken together, these results suggest that the collective behavior of the network is described by a non-trivial fixed point.

Coarse--graining and hints of scaling in a population of 1000+ neurons

Author Correction: Dorsal hippocampus contributes to model-based planning

Cognitive models are a fundamental tool in computational neuroscience, embodying in software precise hypotheses about the algorithms by which the brain gives rise to behavior. The development of such models is often a hypothesis-first process, drawing on inspiration from the literature and the creativity of the individual researcher to construct a model, and afterwards testing the model against experimental data. Here, we adopt a complementary approach, in which richly characterizing and summarizing the patterns present in a dataset reveals an appropriate cognitive model, without recourse to an a priori hypothesis. We apply this approach to a large behavioral dataset from rats performing a dynamic reward learning task. The revealed model suggests that behavior in this task can be understood as a mixture of three components with different timescales: a quick-learning reward-seeking component, a slower-learning perseverative component, and a very slow “gambler’s fallacy” component.

From predictive models to cognitive models: Separable behavioral processes underlying reward learning in the rat

Humans and animals make predictions about the rewards they expect to receive in different situations. In formal models of behavior, these predictions are known as value representations, and they play two very different roles. Firstly, they drive choice: the expected values of available options are compared to one another, and the best option is selected. Secondly, they support learning: expected values are compared to rewards actually received, and future expectations are updated accordingly. Whether these different functions are mediated by different neural representations remains an open question. Here we employ a recently-developed multi-step task for rats that computationally separates learning from choosing. We investigate the role of value representations in the rodent orbitofrontal cortex, a key structure for value-based cognition. Electrophysiological recordings and optogenetic perturbations indicate that these representations do not directly drive choice. Instead, they signal expected reward information to a learning process elsewhere in the brain that updates choice mechanisms.

Value representations in the rodent orbitofrontal cortex drive learning, not choice

Cognitive models are a fundamental tool in computational neuroscience, embodying in software precise hypotheses about the algorithms by which the brain gives rise to behavior. The development of such models is often largely a hypothesis-first process, drawing on inspiration from the literature and the creativity of the individual researcher to construct a model, and afterwards testing the model against experimental data. Here, we adopt a complementary data-first approach, in which richly characterizing and summarizing the patterns present in a dataset reveals an appropriate cognitive model, without recourse to an a priori hypothesis. We apply this approach to a large behavioral dataset from rats performing a dynamic reward learning task. The model revealed suggests that behavior on this task can be understood as a mixture of three components with different timescales: a quick-learning reward-seeking component, a slower-learning perseverative component, and a very slow “gambler’s fallacy” component.

From predictive models to cognitive models: An analysis of rat behavior in the two-armed bandit task

Investigating neuronal populations that are truly large – can we keep our models small?

Fronto-parietal Cortical Circuits Encode Accumulated Evidence with a Diversity of Timescales

Planning can be defined as action selection that leverages an internal model of the outcomes likely to follow each possible action. Its neural mechanisms remain poorly understood. Here we adapt recent advances from human research for rats, presenting for the first time an animal task that produces many trials of planned behavior per session, making multitrial rodent experimental tools available to study planning. We use part of this toolkit to address a perennially controversial issue in planning: the role of the dorsal hippocampus. Although prospective hippocampal representations have been proposed to support planning, intact planning in animals with damaged hippocampi has been repeatedly observed. Combining formal algorithmic behavioral analysis with muscimol inactivation, we provide causal evidence directly linking dorsal hippocampus with planning behavior. Our results and methods open the door to new and more detailed investigations of the neural mechanisms of planning in the hippocampus and throughout the brain.

The gradual accumulation of sensory evidence is a crucial component of perceptual decision making, but its neural mechanisms are still poorly understood. Given the wide availability of genetic and optical tools for mice, they can be useful model organisms for the study of these phenomena; however, behavioral tools are largely lacking. Here, we describe a new evidence-accumulation task for head-fixed mice navigating in a virtual reality environment. As they navigate down the stem of a virtual T-maze, they see brief pulses of visual evidence on either side, and retrieve a reward on the arm with the highest number of pulses. The pulses occur randomly with Poisson statistics, yielding a diverse yet well-controlled stimulus set, making the data conducive to a variety of computational approaches. A large number of mice of different genotypes were able to learn and consistently perform the task, at levels similar to rats in analogous tasks. They are sensitive to side differences of a single pulse, and their memory of the cues is stable over time. Moreover, using model-free and model-based analyses, we show that the mice indeed accumulate evidence: they use multiple pulses of evidence from throughout the cue region of the maze to make their decision, albeit with a small overweighting of earlier cues, and their performance is affected by the magnitude but not the duration of evidence. Additionally, analysis of the mice’s running patterns revealed that trajectories are fairly stereotyped yet modulated by the amount of sensory evidence, suggesting that the navigational component of this task may provide a continuous readout correlated to the underlying cognitive variables. Our task, which can be readily integrated with state-of-the-art techniques, is thus a valuable tool to study the circuit mechanisms and dynamics underlying perceptual decision making, particularly under more complex behavioral contexts.

An Accumulation-of-Evidence Task Using Visual Pulses for Mice Navigating in Virtual Reality

Planning can be defined as a process of action selection that leverages an internal model of the environment. Such models provide information about the likely outcomes that will follow each selected action, and their use is a key function underlying complex adaptive behavior. However, the neural mechanisms supporting this ability remain poorly understood. In the present work, we adapt for rodents recent advances from work on human planning, presenting for the first time a task for animals which produces many trials of planned behavior per session, allowing the experimental toolkit available for use in trial-by-trial tasks for rodents to be applied to the study of planning. We take advantage of one part of this toolkit to address a perennially controversial issue in planning research: the role of the dorsal hippocampus. Although prospective representations in the hippocampus have been proposed to support model-based planning, intact planning in hippocampally damaged animals has been observed in a number of assays. Combining formal algorithmic behavioral analysis with muscimol inactivation, we provide the first causal evidence directly linking dorsal hippocampus with planning behavior. The results reported, and the methods introduced, open the door to new and more detailed investigations of the neural mechanisms of planning, in the hippocampus and throughout the brain.

Posterior parietal cortex represents sensory history and mediates its effects on behaviour

How choices are made within noisy environments is a central question in the neuroscience of decision making. Previous work has characterized temporal accumulation of evidence for decision-making in static environments. However, real-world decision-making involves environments with statistics that change over time. This requires discounting old evidence that may no longer inform the current state of the world. Here we designed a rat behavioral task with a dynamic environment, to probe whether rodents can optimally discount evidence by adapting the timescale over which they accumulate it. Extending existing results about optimal inference in a dynamic environment, we show that the optimal timescale for evidence discounting depends on both the stimulus statistics and noise in sensory processing. We found that when both of these components were taken into account, rats accumulated and temporally discounted evidence almost optimally. Furthermore, we found that by changing the dynamics of the environment, experimenters could control the rats’ accumulation timescale, switching them from accumulating over short timescales to accumulating over long timescales and back. The theoretical framework also makes quantitative predictions regarding the timing of changes of mind in the dynamic environment. This study establishes a quantitative behavioral framework to control and investigate neural mechanisms underlying the adaptive nature of evidence accumulation timescales and changes of mind.

Rats optimally accumulate and discount evidence in a dynamic environment

Two-node attractor networks are flexible models for neural activity during decision making. Depending on the network configuration, these networks can model distinct aspects of decisions including evidence integration, evidence categorization, and decision memory. Here, we use attractor networks to model recent causal perturbations of the frontal orienting fields (FOF) in rat cortex during a perceptual decision-making task (Erlich, Brunton, Duan, Hanks, & Brody, 2015). We focus on a striking feature of the perturbation results. Pharmacological silencing of the FOF resulted in a stimulus-independent bias. We fit several models to test whether integration, categorization, or decision memory could account for this bias and found that only the memory configuration successfully accounts for it. This memory model naturally accounts for optogenetic perturbations of FOF in the same task and correctly predicts a memory-duration-dependent deficit caused by silencing FOF in a different task. Our results provide mechanistic support for a “postcategorization” memory role of the FOF in upcoming choices.

Rat Prefrontal Cortex Inactivations during Decision Making Are Explained by Bistable Attractor Dynamics

Learning about memory from (very) large scale hippocampal networks.

Collective Behavior of Place and Non-place Neurons in the Hippocampal Network

Can simple interactions capture complex features of neural activity underlying behavior in a virtual reality environment

Recent years have seen a surge of research into the neuroscience of planning. Much of this work has taken advantage of a two-step sequential decision task developed by Daw et al. (2011), which gives the ability to diagnose whether or not subjects’ behavior is the result of planning. Here, we present simulations which suggest that the techniques most commonly used to analyze data from this task may be confounded in important ways. We introduce a new analysis technique, which suffers from fewer of these issues. This technique also presents a richer view of behavior, making it useful for characterizing patterns in behavior in a theory-neutral manner. This allows it to provide an important check on the assumptions of more theory-driven analysis such as agent-based model-fitting.

Identifying Model-Based and Model-Free Patterns in Behavior on Multi-Step Tasks

Decision-making behavior is often characterized by substantial variability, but its source remains unclear. We developed a visual accumulation of evidence task designed to quantify sources of noise and to be performed during voluntary head restraint, enabling cellular resolution imaging in future studies. Rats accumulated discrete numbers of flashes presented to the left and right visual hemifields and indicated the side that had the greater number of flashes. Using a signal-detection theory-based model, we found that the standard deviation in their internal estimate of flash number scaled linearly with the number of flashes. This indicates a major source of noise that, surprisingly, is not consistent with the widely used 'drift-diffusion modeling' (DDM) approach but is instead closely related to proposed models of numerical cognition and counting. We speculate that this form of noise could be important in accumulation of evidence tasks generally. DOI: http://dx.doi.org/10.7554/eLife.11308.001

Sources of noise during accumulation of evidence in unrestrained and voluntarily head-restrained rats

Numerous brain regions have been shown to have neural correlates of gradually accumulating evidence for decision-making, but the causal roles of these regions in decisions driven by accumulation of evidence have yet to be determined. Here, in rats performing an auditory evidence accumulation task, we inactivated the frontal orienting fields (FOF) and posterior parietal cortex (PPC), two rat cortical regions that have neural correlates of accumulating evidence and that have been proposed as central to decision-making. We used a detailed model of the decision process to analyze the effect of inactivations. Inactivation of the FOF induced substantial performance impairments that were quantitatively best described as an impairment in the output pathway of an evidence accumulator with a long integration time constant (>240ms). In contrast, we found a minimal role for PPC in decisions guided by accumulating auditory evidence, even while finding a strong role for PPC in internally-guided decisions.

Distinct effects of prefrontal and parietal cortex inactivations on an accumulation of evidence task in the rat

Cortical and Subcortical Contributions to Short-Term Memory for Orienting Movements

Author response: Sources of noise during accumulation of evidence in unrestrained and voluntarily head-restrained rats

Requirement of Prefrontal and Midbrain Regions for Rapid Executive Control of Behavior in the Rat

Distinct relationships of parietal and prefrontal cortices to evidence accumulation

A low-frequency oscillatory neural signal in humans encodes a developing decision variable

How to Make Decisions Recently, a number of methods to probe internal properties of nonlinear neural systems have been developed. In these methods, highly variable stimuli are used to explore the input space of the system. Neural responses are then studied using models that take advantage of the known trial-by-trial stimulus information. Brunton et al. (p. 95) adapted this combined approach to decision-making. Both in rats and humans, the diffusion constant of the drift-diffusion model of decision-making was zero, implying that the noise is all in the processing of sensory input and not in the evidence accumulator. In addition, rats gradually accumulated evidence for decision-making, with strong effects of sensory adaptation on gradual accumulation of evidence. A model of decision-making that is based on the accumulative processing of noisy information is described. The gradual and noisy accumulation of evidence is a fundamental component of decision-making, with noise playing a key role as the source of variability and errors. However, the origins of this noise have never been determined. We developed decision-making tasks in which sensory evidence is delivered in randomly timed pulses, and analyzed the resulting data with models that use the richly detailed information of each trial’s pulse timing to distinguish between different decision-making mechanisms. This analysis allowed measurement of the magnitude of noise in the accumulator’s memory, separately from noise associated with incoming sensory evidence. In our tasks, the accumulator’s memory was noiseless, for both rats and humans. In contrast, the addition of new sensory evidence was the primary source of variability. We suggest our task and modeling approach as a powerful method for revealing internal properties of decision-making processes.

Rats and Humans Can Optimally Accumulate Evidence for Decision-Making

Cellular Resolution Functional Imaging in Behaving Rats Using Voluntary Head Restraint

Semi-automated atlas-based analysis of brain histological sections

We present a behavioral paradigm for the study of duration perception in the rat, and report the result of neurotoxic lesions that have the goal of identifying sites that mediate duration perception. Using a two-alternative forced-choice paradigm, rats were either trained to discriminate durations of pure tones (range = [200,500] ms; boundary = 316 ms; Weber fraction after training = 0.24 ± 0.04), or were trained to discriminate frequencies of pure tones (range = [8,16] kHz; boundary = 11.3 kHz; Weber = 0.16 ± 0.11); the latter task is a control for non-timing-specific aspects of the former. Both groups discriminate the same class of sensory stimuli, use the same motions to indicate decisions, have identical trial structures, and are trained to psychophysical threshold; the tasks are thus matched in a number of sensorimotor and cognitive demands. We made neurotoxic lesions of candidate timing-perception areas in the cerebral cortex of both groups. Following extensive bilateral lesions of the auditory cortex, the performance of the frequency discrimination group was significantly more impaired than that of the duration discrimination group. We also found that extensive bilateral lesions of the medial prefrontal cortex resulted in little to no impairment of both groups. The behavioral framework presented here provides an audition-based approach to study the neural mechanisms of time estimation and memory for durations.

Minimal Impairment in a Rat Model of Duration Discrimination Following Excitotoxic Lesions of Primary Auditory and Prefrontal Cortices

We examined neural spike recordings from prefrontal cortex (PFC) while monkeys performed a delayed somatosensory discrimination task. In general, PFC neurons displayed great heterogeneity in response to the task. That is, although individual cells spiked reliably in response to task variables from trial-to-trial, each cell had idiosyncratic combinations of response properties. Despite the great variety in response types, some general patterns held. We used linear regression analysis on the spike data to both display the full heterogeneity of the data and classify cells into categories. We compared different categories of cells and found little difference in their ability to carry information about task variables or their correlation to behavior. This suggests a distributed neural code for the task rather than a highly modularized one. Along this line, we compared the predictions of two theoretical models to the data. We found that cell types predicted by both models were not represented significantly in the population. Our study points to a different class of models that should embrace the inherent heterogeneity of the data, but should also account for the nonrandom features of the population.

Heterogenous Population Coding of a Short-Term Memory and Decision Task

How does the brain store information over a short period of time? Typically, the short-term memory of items or values is thought to be stored in the persistent activity of neurons in higher cortical areas. However, the activity of these neurons often varies strongly in time, even if time is unimportant for whether or not rewards are received. To elucidate this interaction of time and memory, we reexamined the activity of neurons in the prefrontal cortex of monkeys performing a working memory task. As often observed in higher cortical areas, different neurons have highly heterogeneous patterns of activity, making interpretation of the data difficult. To overcome these problems, we developed a method that finds a new representation of the data in which heterogeneity is much reduced, and time- and memory-related activities became separate and easily interpretable. This new representation consists of a few fundamental activity components that capture 95% of the firing rate variance of >800 neurons. Surprisingly, the memory-related activity components account for <20% of this firing rate variance. The observed heterogeneity of neural responses results from random combinations of these fundamental components. Based on these components, we constructed a generative linear model of the network activity. The model suggests that the representations of time and memory are maintained by separate mechanisms, even while sharing a common anatomical substrate. Testable predictions of this hypothesis are proposed. We suggest that our method may be applied to data from other tasks in which neural responses are highly heterogeneous across neurons, and dependent on more than one variable.

Functional, But Not Anatomical, Separation of “What” and “When” in Prefrontal Cortex

In a complex world, a sensory cue may prompt different actions in different contexts. A laboratory example of context-dependent sensory processing is the two-stimulus-interval discrimination task. In each trial, a first stimulus (f1) must be stored in short-term memory and later compared with a second stimulus (f2), for the animal to come to a binary decision. Prefrontal cortex (PFC) neurons need to interpret the f1 information in one way (perhaps with a positive weight) and the f2 information in an opposite way (perhaps with a negative weight), although they come from the very same secondary somatosensory cortex (S2) neurons; therefore, a functional sign inversion is required. This task thus provides a clear example of context-dependent processing. Here we develop a biologically plausible model of a context-dependent signal transformation of the stimulus encoding from S2 to PFC. To ground our model in experimental neurophysiology, we use neurophysiological data recorded by R. Romo's laboratory from both cortical area S2 and PFC in monkeys performing the task. Our main goal is to use experimentally observed context-dependent modulations of firing rates in cortical area S2 as the basis for a model that achieves a context-dependent inversion of the sign of S2 to PFC connections. This is done without requiring any changes in connectivity (Salinas, 2004b). We (1) characterize the experimentally observed context-dependent firing rate modulation in area S2, (2) construct a model that results in the sign transformation, and (3) characterize the robustness and consequent biological plausibility of the model.

Context-Dependent Modulation of Functional Connectivity: Secondary Somatosensory Cortex to Prefrontal Cortex Connections in Two-Stimulus-Interval Discrimination Tasks

Animals learn tasks requiring a sequence of actions over time. Waiting a given time before taking an action is a simple example. Mimicry is a complex example, e.g. in humans, humming a brief tune you have just heard. Re-experiencing a sensory pattern mentally must involve reproducing a sequence of neural activities over time. In mammals, neurons in prefrontal cortex have time-dependent firing rates that vary smoothly and slowly in a stereotyped fashion. We show through modeling that a Many are Equal computation can use such slowly-varying activities to identify each timepoint in a sequence by the population pattern of activity at the timepoint. The MAE operation implemented here is facilitated by a common inhibitory conductivity due to a theta rhythm. Sequences of analog values of discrete events, exemplified by a brief tune having notes of different durations and intensities, can be learned in a single trial through STDP. An action sequence can be played back sped up, slowed down, or reversed by modulating the system that generates the slowly changing stereotyped activities. Synaptic adaptation and cellular post-hyperpolarization rebound contribute to robustness. An ability to mimic a sequence only seconds after observing it requires the STDP to be effective within seconds.

Sequence reproduction, single trial learning, and mimicry based on a mammalian-like distributed code for time

Neurons that sustain elevated firing in the absence of stimuli have been found in many neural systems. In graded persistent activity, neurons can sustain firing at many levels, suggesting a widely found type of network dynamics in which networks can relax to any one of a continuum of stationary states. The reproduction of these findings in model networks of nonlinear neurons has turned out to be nontrivial. A particularly insightful model has been the bump attractor, in which a continuous attractor emerges through an underlying symmetry in the network connectivity matrix. This model, however, cannot account for data in which the persistent firing of neurons is a monotonicrather than a bell-shapedfunction of a stored variable. Here, we show that the symmetry used in the bump attractor network can be employed to create a whole family of continuous attractor networks, including those with monotonic tuning. Our design is based on tuning the external inputs to networks that have a connectivity matrix with Toeplitz symmetry. In particular, we provide a complete analytical solution of a line attractor network with monotonic tuning and show that for many other networks, the numerical tuning of synaptic weights reduces to the computation of a single parameter.

Design of Continuous Attractor Networks with Monotonic Tuning Using a Symmetry Principle

Although gamma frequency oscillations are common in the brain, their functional contributions to neural computation are not understood. Here we report in vitro electrophysiological recordings to evaluate how noisy gamma frequency oscillatory input interacts with the overall activation level of a neuron to determine the precise timing of its action potentials. The experiments were designed to evaluate spike synchrony in a neural circuit architecture in which a population of neurons receives a common noisy gamma oscillatory synaptic drive while the firing rate of each individual neuron is determined by a slowly varying independent input. We demonstrate that similarity of firing rate is a major determinant of synchrony under common noisy oscillatory input: Near coincidence of spikes at similar rates gives way to substantial desynchronization at larger firing rate differences. Analysis of this rate-specific synchrony phenomenon reveals distinct spike timing “fingerprints” at different firing rates that emerge through a combination of phase shifting and abrupt changes in spike patterns. We further demonstrate that rate-specific synchrony permits robust detection of rate similarity in a population of neurons through synchronous activation of a postsynaptic neuron, supporting the biological plausibility of a Many Are Equal computation. Our results reveal that spatially coherent noisy oscillations, which are common throughout the brain, can generate previously unknown relationships among neural rate codes, noisy interspike intervals, and precise spike synchrony codes. All of these can coexist in a self-consistent manner because of rate-specific synchrony.

Rate-specific synchrony: Using noisy oscillations to detect equally active neurons

Interacting with a dynamic world requires the capacity to perceive and represent temporal intervals and patterns. Often, as in speech or music perception, patterns composed of multiple temporal intervals are of importance. Using the auditory input modality, and following Penel, Hollweg and Brody [1], we have presented sequences of three brief tone pips (i.e., sequences of two temporal intervals) to human subjects. Participants had to reproduce the presented sequences via either tapping, or vocal responses, or placing two vertical lines on a screen at a position that represented the timing of the second and third pips. In contrast to Penel et al’s previous study, here the total time between the first and last pip was not fixed, but varied from trial to trial within the range 700 to 1300ms. The timing of the middle pip was drawn, for each trial, from a uniform distribution between the first and the last pip.

EXAMINING THE PERCEPTION OF TEMPORAL INTER- VALS SEQUENCES USING DIFFERENT STIMULUS AND RESPONSE MODALITIES

In a complex world, processing of signals from the environment must be flexible: a sensory cue may prompt different actions in different contexts. A laboratory example of context-dependent sensory processing is the two-stimulus-interval discrimination task. In each trial, a first stimulus (f1) must be stored in short-term memory, and later compared to a second stimulus (f2), in order to come to a binary decision as the result of the comparison (was f1 > f2? Y or N). The two stimuli, applied to the very same sensory receptors, must be treated quite differently. This task thus provides a clear example of context-dependent processing.

Context-dependent modulation of functional connectivity: S2 to PFC connections in two-stimulus-interval discrimination tasks

The lateral nucleus of the amygdala (LA) and the medial prefrontal cortex (mPFC) seem to play opposing roles in the regulation of fear: activity in the LA covaries positively with fear expression and activity in the mPFC covaries negatively with fear expression [1]. Based on the putative roles of these structures, we hypothesized that the LA would signal the onset of fear and the mPFC would signal the offset of fear. Rats lick at 6-8 Hz, thus conditioned lick suppression allows for the measure of the onset and offset of fear at a temporal resolution of ~100 ms, an order of magnitude faster than freezing, which is the most common measure of fear expression. By combining this measure of fear expression with single unit recording from awake rats, we could analyze neural and behavior activity at millisecond timescales. We found that neural activity in the LA and mPFC was not simply negatively correlated. Rather, neurons in the LA seemed to use an adaptive code to trigger the onset and offset of fear: activity ramped up before the onset of fear and ramped down before the offset of fear, with essentially no activity during sustained behavior. In the mPFC we found ‘up’ neurons that covaried positively with fear and also ‘down’ neurons that covaried negatively with fear. The timing of changes in neural activity in relation to the onset and offset of lick suppression was consistent with the notion that the LA drives fear and the mPFC inhibits fear. The existence of ‘up’ and ‘down’ neurons in mPFC is reminiscent of other reports of prefrontal activity. An elegant explanation for this type of redundant encoding is that these two populations can instantiate an attractor network via mutual inhibition, which subserves working memory and decision-making [2]. We are currently investigating whether the ‘up’ and ‘down’ neurons might encode a working memory of fear in the mPFC. Acknowledgments

Distinct contributions of the amygdala and prefrontal cortex in the regulation of fear.

During short-term memory maintenance, different neurons in prefrontal cortex (PFC), recorded under identical conditions, show a wide variety of temporal dynamics and response properties [1]. These data are a specific example of the more general finding that neural recordings from frontal cortices often reveal that different neurons have very different response characteristics. Modeling this complexity of responses has been difficult. Most commonly, some features of the responses are focused on, and models that fit those reduced features are built (e.g., [2]). But can the full complexity of responses be easily captured?

Neural codes for perceptual discrimination in primary somatosensory cortex

Erratum: A recurrent network model of somatosensory parametric working memory in the prefrontal cortex (Cerebral Cortext (November 2003) 13:11 (1208-1218) DOI:10.1093/cercor/bhg101

Networks adapt to environmental demands by switching between distinct dynamical behaviors. The activity of frontal-lobe neurons during two-interval discrimination tasks is an example of these adaptable dynamics. Subjects first perceive a stimulus, then hold it in working memory, and finally make a decision by comparing it with a second stimulus. We present a simple mutual-inhibition network model that captures all three task phases within a single framework. The model integrates both working memory and decision making because its dynamical properties are easily controlled without changing its connectivity. Mutual inhibition between nonlinear units is a useful design motif for networks that must display multiple behaviors.

Flexible Control of Mutual Inhibition: A Neural Model of Two-Interval Discrimination

A clamping unit for clamping the mold of an injection molding machine has at least one removable protective cover for covering the clamping unit in the area of the mold. The cover has at least three protective cover plates arranged to be moved independently of one another in the opening direction of the clamping unit between an open position and a protective position. Switches and a safety valve are associated with the cover for interrupting the main current and fluid flows of the injection molding machine when all of the cover plates are in their open position.

Basic mechanisms for graded persistent activity: discrete attractors, continuous attractors, and dynamic representations

Plasticity in connections between neurons allows learning and adaptation, but it also allows noise to degrade the function of a network. Ongoing network self-repair is thus necessary. We describe a method to derive spike-timing-dependent plasticity rules for self-repair, based on the firing patterns of a functioning network. These plasticity rules for self-repair also provide the basis for unsupervised learning of new tasks. The particular plasticity rule derived for a network depends on the network and task. Here, self-repair is illustrated for a model of the mammalian olfactory system in which the computational task is that of odor recognition. In this olfactory example, the derived rule has qualitative similarity with experimental results seen in spike-timing-dependent plasticity. Unsupervised learning of new tasks by using the derived self-repair rule is demonstrated by learning to recognize new odors.

Learning rules and network repair in spike-timing-based computation networks

Simple Networks for Spike-Timing-Based Computation, with Application to Olfactory Processing

We trained monkeys to compare the frequencies of two mechanical vibrations applied sequentially to the tip of a finger and to report which of the two stimuli had the higher frequency. This task requires remembering the first frequency during the delay period between the two stimuli. Recordings were made from neurons in the inferior convexity of the prefrontal cortex (PFC) while the monkeys performed the task. We report neurons that fire persistently during the delay period, with a firing rate that is a monotonic function of the frequency of the first stimulus. Separately from, and in addition to, their correlation with the first stimulus, the delay period firing rates of these neurons were correlated with the behavior of the monkey, in a manner consistent with their interpretation as the neural substrate of working memory during the task. Most neurons had firing rates that varied systematically with time during the delay period. We suggest that this time-dependent activity may encode time itself and may be an intrinsic part of active memory maintenance mechanisms.

Timing and neural encoding of somatosensory parametric working memory in macaque prefrontal cortex.

A parametric working memory network stores the information of an analog stimulus in the form of persistent neural activity that is monotonically tuned to the stimulus. The family of persistent firing patterns with a continuous range of firing rates must all be realizable under exactly the same external conditions (during the delay when the transient stimulus is withdrawn). How this can be accomplished by neural mechanisms remains an unresolved question. Here we present a recurrent cortical network model of irregularly spiking neurons that was designed to simulate a somatosensory working memory experiment with behaving monkeys. Our model reproduces the observed positively and negatively monotonic persistent activity, and heterogeneous tuning curves of memory activity. We show that fine-tuning mathematically corresponds to a precise alignment of cusps in the bifurcation diagram of the network. Moreover, we show that the fine-tuned network can integrate stimulus inputs over several seconds. Assuming that such time integration occurs in neural populations downstream from a tonically persistent neural population, our model is able to account for the slow ramping-up and ramping-down behaviors of neurons observed in prefrontal cortex.

A recurrent network model of somatosensory parametric working memory in the prefrontal cortex.

Humans and monkeys have similar abilities to discriminate the difference in frequency between two consecutive mechanical vibrations applied to their fingertips. This task can be conceived as a chain of neural operations: encoding the two consecutive stimuli, maintaining the first stimulus in working memory, comparing the second stimulus with the memory trace left by the first stimulus and communicating the result of the comparison to the motor apparatus. We studied this chain of neural operations by recording and manipulating neurons from different areas of the cerebral cortex while monkeys performed the task. The results indicate that neurons of the primary somatosensory cortex (S1) generate a neural representation of vibrotactile stimuli which correlates closely with psychophysical performance. Discrimination based on microstimulation patterns injected into clusters of S1 neurons is indistinguishable from that produced by natural stimuli. Neurons from the secondary somatosensory cortex (S2), prefrontal cortex and medial premotor cortex (MPC) display at different times the trace of the first stimulus during the working-memory component of the task. Neurons from S2 and MPC appear to show the comparison between the two stimuli and correlate with the behavioural decisions. These neural operations may contribute to the sensory-discrimination process studied here.

Exploring the cortical evidence of a sensory-discrimination process.

In a typical sequential sensory discrimination task, subjects are required to make a decision based on comparing a sensory stimulus against the memory trace left by a previous stimulus. What is the neuronal substrate for such comparisons and the resulting decisions? This question was studied by recording neuronal responses in a variety of cortical areas of awake monkeys (Macaca mulatta), trained to carry out a vibrotactile sequential discrimination task. We describe methods to analyse responses obtained during the comparison and decision phases of the task, and describe the resulting findings from recordings in secondary somatosensory cortical area (S2). A subset of neurons in S2 become highly correlated with the monkey's decision in the task.

Analysing neuronal correlates of the comparison of two sequentially presented sensory stimuli.

Neuronal correlates of decision-making in secondary somatosensory cortex

A previous paper described a network of simple integrate-and-fire neurons that contained output neurons selective for specific spatiotemporal patterns of inputs; only experimental results were described. We now present the principles behind the operation of this network and discuss how these principles point to a general class of computational operations that can be carried out easily and naturally by networks of spiking neurons. Transient synchrony of the action potentials of a group of neurons is used to signal "recognition" of a space-time pattern across the inputs of those neurons. Appropriate synaptic coupling produces synchrony when the inputs to these neurons are nearly equal, leaving the neurons unsynchronized or only weakly synchronized for other input circumstances. When the input to this system comes from timed past events represented by decaying delay activity, the pattern of synaptic connections can be set such that synchronization occurs only for selected spatiotemporal patterns. We show how the recognition is invariant to uniform time warp and uniform intensity change of the input events. The fundamental recognition event is a transient collective synchronization, representing "many neurons now agree," an event that is then detected easily by a cell with a small time constant. If such synchronization is used in neurobiological computation, its hallmark will be a brief burst of gamma-band electroencephalogram noise when and where such a recognition event or decision occurs.

What is a moment? Transient synchrony as a collective mechanism for spatiotemporal integration.

In contrast to networks of neurons where behavior is governed by average firing rate, what computations are implemented most easily, efficiently, and robustly by networks of neurons that spike? Spiking neurons synchronize much more readily when their firing rates are similar than when they are different. This property can be used to very simply and robustly implement, in a network of appropriately connected spiking neurons, a many are equals operation: synchronization indicates that many of the neurons' firing rates are similar. Such an operation is computationally very powerful. The computation is robust to outliers, and contains a natural invariance: over a broad range of firing rates, the synchronization phenomenon depends only on rate similarity, and not on the precise firing rate level. We demonstrate the computational power of this operation by constructing a simple network of spiking neurons with output neurons that respond selectively to a complex spectrotemporal pattern, the spoken word one. The response is invariant to uniform time-warp. Time is encoded by slowly decaying firing rates, and the selectivity is largely speaker-independent. We posit many are equals synchronization is a simple yet powerful computational building block for spiking neural networks.

Transient synchrony and the integration of spectrotemporal information

Recognition of complex temporal sequences is a general sensory problem that requires integration of information over time. We describe a very simple "organism" that performs this task, exemplified here by recognition of spoken monosyllables. The network's computation can be understood through the application of simple but generally unexploited principles describing neural activity. The organism is a network of very simple neurons and synapses; the experiments are simulations. The network's recognition capabilities are robust to variations across speakers, simple masking noises, and large variations in system parameters. The network principles underlying recognition of short temporal sequences are applied here to speech, but similar ideas can be applied to aspects of vision, touch, and olfaction. In this article, we describe only properties of the system that could be measured if it were a real biological organism. We delay publication of the principles behind the network's operation as an intellectual challenge: the essential principles of operation can be deduced based on the experimental results presented here alone. An interactive web site (http://neuron.princeton.edu/ approximately moment) is available to allow readers to design and carry out their own experiments on the organism.

What is a moment? "Cortical" sensory integration over a brief interval.

Sensing without Touching Psychophysical Performance Based on Cortical Microstimulation

Neuronal correlates of parametric working memory in the prefrontal cortex

This note gives a closed form expression for the linear transform computed by an optimally trained linear heteroencoder network of arbitrary topology trained to minimize squared error. The transform can be thought of as a restricted rank version of the basic linear least-squares regression (discrete Wiener filter) between input and output. The rank restriction is set by the “bottleneck” size of the network – the minimum number of hidden units in any layer. A special case of this expression is the well known result that linear autoencoders with a bottleneck of size r perform a transform equivalent to projecting into the subspace spanned by the first r principal components of the data. This result eliminates the need to explicitly train linear heteroencoder networks. Linear Heteroencoders Sam Roweis Gatsby Unit Carlos Brody Computation and Neural Systems California Institute of Technology 1 Linear autoencoders Because they are fast to train and require few parameters, linear networks1 provide an important performance comparison with more complex data analysis methods. The equivalent linear transform computed by a linear autoencoder network with a bottleneck of size r has long been known to be the projection into the subspace spanned by the first r principal components of the training data. This is true if the training algorithm minimizes squared error at the output and achieves the global minimum of that error. Furthermore, Bourlard and Kamp (1988) have shown that if all layers of the network after the bottleneck are linear the optimal transformation remains unchanged even if nonlinear transfer functions are added to units before the bottleneck. In other words, the result still holds for networks that are merely output-linear. These results are important because they eliminate the need to explicitly train linear or output-linear autoencoders. Algorithms such as the singular-value decomposition can be used to quickly compute the optimal transform. These algorithms run in a known fixed time, results are easily reproducible, they are guaranteed to achieve the global minimum of error, and they produce an ordered set of orthogonal eigenvectors. In this note, we present the analogous results for linear (and output-linear) heteroencoder networks with a bottleneck. Enforcing such a bottleneck may be important in cases where high dimensionality of the input space leads to overtraining and poor generalization. The results below allow the equivalent transform (and thus performance) of an optimally trained network to be easily computed without explicit training. Many previous authors [Baldi and Hornik, 1989, Kung and Diamantaras, 1991] [Diamantaras and Kung, 1994, Scharf, 1991, Stoica and Viberg, 1996, Ghahramani, 1996] have proved portions of the results we review below. However, the proofs are often part of a more detailed or lengthy discussion and as a result are sometimes mathematically more complex. The goal of this note is to provide a short and simple exposition of these results along with practical expressions for their implementation. † Based on a May 1997 version. During writing, the authors were supported in part by the Center for Neuromorphic Systems Engineering as a part of the National Science Foundation Engineering Research Center Program under grant EEC-9402726 and by the Natural Sciences and Engineering Research Council of Canada under an NSERC 1967 Award. We refer to any network in which the transfer function of every unit is linear as a linear network. Similarly we use the term linear layer for layers in which every unit’s transfer function is a linear function. A network has a bottleneck of size r if no layer has fewer than r units. A network has no bottleneck if all layers have at least as many units as both the input dimension and output dimension. If all layers after the bottleneck layer (or after the last bottleneck if there are several) are linear, we call the network output-linear.

Peaks in spike train correlograms are usually taken as indicative of spike timing synchronization between neurons. Strictly speaking, however, a peak merely indicates that the two spike trains were not independent. Two biologically plausible ways of departing from independence that are capable of generating peaks very similar to spike timing peaks are described here: covariations over trials in response latency and covariations over trials in neuronal excitability. Since peaks due to these interactions can be similar to spike timing peaks, interpreting a correlogram may be a problem with ambiguous solutions. What peak shapes do latency or excitability interactions generate? When are they similar to spike timing peaks? When can they be ruled out from having caused an observed correlogram peak? These are the questions addressed here. The previous article in this issue proposes quantitative methods to tell cases apart when latency or excitability covariations cannot be ruled out.

Covariations in neuronal latency or excitability can lead to peaks in spike train covariograms that may be very similar to those caused by spike timing synchronization (see companion article). Two quantitative methods are described here. The first is a method to estimate the excitability component of a covariogram, based on trial-by-trial estimates of excitability. Once estimated, this component may be subtracted from the covariogram, leaving only other types of contributions. The other is a method to determine whether the covariogram could potentially have been caused by latency covariations.

In this thesis I consider the cross-correlation analysis of spike train data, in two parts. In the first part, I consider the question of the proper interpretation of peaks in covariograms: It is known that peaks in the covariogram of the spike trains of two cells are due to covariations, not time-locked to the stimulus, in the responses of the two cells. Such peaks, even when they have widths on the order of 10s of milliseconds, are often interpreted as evidence of spike timing coordination between the two cells. However, there are other ways to covary which can generate very similar peaks. I describe two of them here: (1) covariations, over different trials, in the overall latency of the response; and (2) covariations, over different trials, in the overall excitability (i.e. average firing rate) of the response. I show how each of these leads to a peak in the covariogram, and how to distinguish such peaks from each other and from peaks due to spike timing coordination. In particular, I describe how to separate the excitability and spike timing components of a covariogram when both types of correlations are present.

The second part of the thesis studies the spike train data obtained in multiple-cell recordings in LGN of cat by Adam Sillito and colleagues (Sillito, Jones, Gerstein and West, 1994, Nature 369(6480):479-482). Analysis of this data, including the use of some of the novel insights and methods described in the first part of the thesis, shows that (1) the observed correlations between pairs of cells can be well described in terms of covariations in the latencies and excitabilities of the two cells; (2) the correlations have a time scale of lOs of seconds (20-100 s); (3) the correlations are not specific to the orientation of the drifting sine wave gratings used to drive the geniculate cells under study. A computational model, based on Huguenard and McCormick's (1992) model of thalamic cells, shows that covariations in the resting membrane potential of the two covarying cells can lead to covariogram peaks similar to those found in the experimental data. Together with Sillito et al.'s observation that correlations between pairs of cells only occurred when both members of the pair had the same receptive field types (On/Off/X/Y), and the observation that in some of the records, cells not only fail to positively covary but even anti-covary, this suggests that Silltio et al.'s data holds evidence for an intriguing and hitherto undocumented phenomenon: the possibly diffuse, but cell class-specific, control of resting membrane potential in LGN neurons.

Analysis and modeling of spike train correlations in the lateral geniculate nucleus

Slow covariations in neuronal resting potentials can lead to artefactually fast cross-correlations in their spike trains. J. Neurophysiol. 80: 3345-3351, 1998. A model of two lateral geniculate nucleus (LGN) cells, which interact only through slow (tens of seconds) covariations in their resting membrane potentials, is used here to investigate the effect of such covariations on cross-correlograms taken during stimulus-driven conditions. Despite the slow timescale of the interactions, the model generates cross-correlograms with peak widths in the range of 25-200 ms. These bear a striking resemblance to those reported in studies of LGN cells by Sillito et al., which were taken at the time as evidence of a fast spike timing synchronization interaction; the model highlights the possibility that those correlogram peaks may have been caused by a mechanism other than spike synchronization. Slow resting potential covariations are suggested instead as the dominant generating mechanism. How can a slow interaction generate covariogram peaks with a width 100-1,000 times thinner than its timescale? Broad peaks caused by slow interactions are modulated by the cells' poststimulus time histograms (PSTHs). When the PSTHs have thin peaks (e.g., tens of milliseconds), the cross-correlogram peaks generated by slow interactions will also be thin; such peaks are easily misinterpretable as being caused by fast interactions. Although this point is explored here in the context of LGN recordings, it is a general point and applies elsewhere. When cross-correlogram peak widths are of the same order of magnitude as PSTH peak widths, experiments designed to reveal short-timescale interactions must be interpreted with the issue of possible contributions from slower interactions in mind.

Slow covariations in neuronal resting potentials can lead to artefactually fast cross-correlations in their spike trains.

Most computational engineering based loosely on biology uses continuous variables to represent neural activity. Yet most neurons communicate with action potentials. The engineering view is equivalent to using a rate-code for representing information and for computing. An increasing number of examples are being discovered in which biology may not be using rate codes. Information can be represented using the timing of action potentials, and efficiently computed with in this representation. The "analog match" problem of odour identification is a simple problem which can be efficiently solved using action potential timing and an underlying rhythm. By using adapting units to effect a fundamental change of representation of a problem, we map the recognition of words (having uniform time-warp) in connected speech into the same analog match problem. We describe the architecture and preliminary results of such a recognition system. Using the fast events of biology in conjunction with an underlying rhythm is one way to overcome the limits of an event-driven view of computation. When the intrinsic hardware is much faster than the time scale of change of inputs, this approach can greatly increase the effective computation per unit time on a given quantity of hardware.

Simplified models of the lateral geniculate nucles (LGN) and striate cortex illustrate the possibility that feedback to the LGN may be used for robust, low-level pattern analysis. The information fed back to the LGN is rebroadcast to cortex using the LGN's full fan-out, so the cortex→LGN→cortex pathway mediates extensive cortico-cortical communication while keeping the number of necessary connections small.

A method for transforming performance evaluation signals distal both in space and time into proximal signals usable by supervised learning algorithms, presented in [Jordan & Jacobs 90], is examined. A simple observation concerning differentiation through models trained with redundant inputs (as one of their networks is) explains a weakness in the original architecture and suggests a modification: an internal world model that encodes action-space exploration and, crucially, cancels input redundancy to the forward model is added. Learning time on an example task, cartpole balancing, is thereby reduced about 50 to 100 times.

As humans and animals experience the world, they learn to associate states and actions with the expected values of the reward that is likely to follow​1–3​. Neural correlates of expected value are found in many brain regions, including the orbitofrontal cortex (OFC)​4–9​. While OFC value representations have been identified across many tasks and species​10–15​, their computational role remains controversial​16–18​. ​One influential hypothesis holds that they drive value-based choosing: The OFC represents the expected values of available options, and choices are made by comparing these values to one another​4,7,9​. A contrasting hypothesis holds that they drive learning: The OFC represents the expected values of immediately impending outcomes, which are compared to rewards actually received, so as to learn and adapt expectations to match the world​5,6,19,20​. ​In common laboratory tasks the items to be decided between are also the items to be learned about, making the two hypothesized roles difficult to distinguish. Here, we use a recently-developed multi-step task for rats​21​ that separates choosing from learning. In a first step, rats choose one of two ports (“choice ports”) whose expected values are computed using planning, and are not learned. In the second step, rats are led to one of two other ports (“outcome ports”) which are not chosen between, but whose expected values are learned based on reward history. We found relatively weak OFC encoding of choice port values, needed for choosing but not learning, but far stronger encoding of outcome port values, needed for learning but not choosing. Moreover, temporally-specific silencing of OFC during outcome port entry was sufficient to disrupt behavior, and the nature of this disruption was consistent with impairment of a value learning process, but was not consistent with impairment of a choice process. We therefore suggest that value representations in the OFC directly drive learning, but do not directly drive choice.

Value Representations in Orbitofrontal Cortex Drive Learning, but not Choice

of white noise will be examined in future work. The birds exposed to the adaptive protocol showed changes in their songs similar to those of deafened birds. Because deafening can be caused by prolonged exposure to excessively loud sounds 7 , we used a behavioural test to demonstrate that the conditions used in our experiment did not cause deafness. Zebra finches respond to sounds by vocalizing. At the beginning and the end of the feedback period, we examined differences in the calling probability of two of the adaptive protocol birds to the playback of quiet sounds versus no sounds. The sounds were a variety of natural stimuli including conspecific calls and sounds. Both birds produced significantly more calls during the presentation of quiet sounds (P Ͻ 0:001, generalized likelihood-ratio test for Bernoulli random variables), which indicates that the birds could hear the sounds. Syllable-triggered perturbation. Recognition of the target syllable was achieved by using a series of IIR filters in conjunction with each other to perform a logical operation (for example, power in band X and not in band Y). The triggering was based on a small segment of the time-varying spectrum of the target syllable which was unique to that syllable. An original copy of the crystallized trigger syllable was used as the playback stimulus for the duration of the experiment. Typical zebra finch syllables are 80–150 ms in length. The triggering resolution was 50 ms, which was short enough to ensure that the feedback always overlapped the trigger syllable itself (and, partially, the following syllable). The other syllables of the song received no feedback. Spectral analysis. We calculated the time-frequency spectrogram for each song with a sliding window (5–8 ms) in which each time point consisted of the direct multitaper estimate of the power spectrum (with a time-bandwidth product NW of 3 or 4) (ref. 13). The data shown in Fig. 2 were analysed in this manner. A harmonic analysis was then used to determine the location and magnitude of the jumps in the discrete spectrum of each syllable by calculating the F-spectrum 14 of each of the multitapered spectral estimates. This analysis revealed additional statistically significant harmonic frequencies in the target syllable after the feedback was presented to the bird (P Ͻ 0:01) (Fig. 3). Syllable classification. For each syllable, we extracted the length and a number of time-varying parameters (envelope, peak frequency, pitch, goodness of pitch …

Neuronal correlatesof parametricworkingmemory in theprefrontal cortex

13 Humans and animals make predictions about the rewards they expect to receive in different 14 situations. In formal models of behavior, these predictions are known as value representations, 15 and they play two very different roles. Firstly, they drive choice: the expected values of available 16 options are compared to one another, and the best option is selected. Secondly, they support 17 learning: expected values are compared to rewards actually received, and future expectations are 18 updated accordingly. Whether these different functions are mediated by different neural 19 representations remains an open question. Here we employ a recently-developed multi-step task 20 for rats that computationally separates learning from choosing. We investigate the role of value 21 representations in the rodent orbitofrontal cortex, a key structure for value-based cognition. 22 Electrophysiological recordings and optogenetic perturbations indicate that these representations 23 do not directly drive choice. Instead, they signal expected reward information to a learning 24 process elsewhere in the brain that updates choice mechanisms. 25 26

Value Representations in the Rodent Orbitofrontal Cortex 1 Drive Learning , not Choice 2 3

The Poisson clicks task: long time constant of neural integration of discrete packets of evidence

Neural correlates of spatial short-term memory in the rodent frontal orienting field

Superior colliculus activates new perspectives on decision-making

Author Correction: Superior colliculus activates new perspectives on decision-making

Dopamine neurons evaluate natural fluctuations in performance quality

Low-dimensional encoding of decisions in parietal cortex reflects long-term training history

Single neurons can dynamically change the gain of their spiking responses to account for shifts in stimulus variance. Moreover, gain adaptation can occur across multiple timescales. Here, we examine the ability of a simple statistical model of spike trains, the generalized linear model (GLM), to account for these adaptive effects. The GLM describes spiking as a Poisson process whose rate depends on a linear combination of the stimulus and recent spike history. The GLM successfully replicates gain scaling observed in Hodgkin-Huxley simulations of cortical neurons that occurs when the ratio of spike-generating potassium and sodium conductances approaches one. Gain scaling in the GLM depends on the length and shape of the spike history filter. Additionally, the GLM captures adaptation that occurs over multiple timescales as a fractional derivative of the stimulus variance, which has been observed in neurons that include long timescale after hyperpolarization conductances. Fractional differentiation in GLMs requires long spike history that span several seconds. Together, these results demonstrate that the GLM provides a tractable statistical approach for examining single-neuron adaptive computations in response to changes in stimulus variance.

Capturing Multiple Timescales of Adaptation to Second-Order Statistics With Generalized Linear Models: Gain Scaling and Fractional Differentiation

Sensory systems encounter remarkably diverse stimuli in the external environment. Natural stimuli exhibit timescales and amplitudes of variation that span a wide range. Mechanisms of adaptation, a ubiquitous feature of sensory systems, allow for the accommodation of this range of scales. Are there common rules of adaptation across different sensory modalities? We measured the membrane potential responses of individual neurons in the visual, somatosensory, and auditory cortices of male and female mice to discrete, punctate stimuli delivered at a wide range of fixed and nonfixed frequencies. We find that the adaptive profile of the response is largely preserved across these three areas, exhibiting attenuation and responses to the cessation of stimulation, which are signatures of response to changes in stimulus statistics. We demonstrate that these adaptive responses can emerge from a simple model based on the integration of fixed filters operating over multiple time scales. SIGNIFICANCE STATEMENT Our recent sensations affect our current expectations and perceptions of the environment. Neural correlates of this process exist throughout the brain and are loosely termed adaptation. Adaptive processes have been described across sensory cortices, but direct comparisons of these processes have not been possible because paradigms have been tailored specifically for each modality. We developed a common stimulus set that was used to characterize adaptation in somatosensory, visual, and auditory cortex. We describe here the similarities and differences in adaptation across these cortical areas and demonstrate that adaptive responses may emerge from a set of static filters that operate over a broad range of timescales.

Multiple Timescales Account for Adaptive Responses across Sensory Cortices

Many studies of neural activity in behaving animals aim to discover interpretable low-dimensional structure in large-scale neural population recordings. One approach to this problem is demixed principal component analysis (dPCA), a supervised linear dimensionality reduction technique to find components that depend on particular experimental parameters. Here, I introduce kernel dPCA (kdPCA) as a nonlinear extension of dPCA by applying kernel least-squares regression to the demixing problem. I consider simulated examples of neural populations with low-dimensional activity to compare the components recovered from dPCA and kdPCA. These simulations demonstrate that neurally relevant nonlinearities, such as stimulus-dependent gain and rotation, interfere with linear demixing of neural activity into components that represent to individual experimental parameters. However, kdPCA can still recover interpretable components in these examples. Finally, I demonstrate kdPCA using two examples of neural populations recorded during perceptual decision-making tasks.

Nonlinear demixed component analysis for neural population data as a low-rank kernel regression problem

Statistical approaches for unraveling the neural code in the visual system

Sensory cortex is able to encode a broad range of stimulus features despite a great variation in signal strength. In cat primary visual cortex (V1), for example, neurons are able to extract stimulus features like orientation or spatial configuration over a wide range of stimulus contrasts. The contrast-invariant spatial tuning found in V1 neuron responses has been modeled as a gain control mechanism, but at which stage of the visual pathway it emerges has remained unclear. Here we describe our findings that contrast-invariant spatial tuning occurs not only in the responses of lateral geniculate nucleus (LGN) relay cells but also in their afferent retinal input. Our evidence suggests that a similar contrast-invariant mechanism is found throughout the stages of the early visual pathway, and that the contrast-invariant spatial selectivity is evident in both retinal ganglion cell and LGN cell responses.

Generalization of Figure-Ground Segmentation from Binocular to Monocular Vision in an Embodied Biological Brain Model

A neural network model for object recognition in cluttered scenes using motion and binocular disparity

663. Safety and Biodistribution Study of rAAV2tYF-CB-hRS1 in Nonhuman Primates

Intravenous solid tip lead placement in telemetry implanted dogs. Part 1: Surgical methods, signal quality, and pathological endpoints.

Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie

Response letter from Clinical Pathology Interest Group of the Society of Toxicologic Pathology (STP) for manuscript entitled International recommendations for training future toxicologic pathologists participating in regulatory-type, nonclinical toxicity studies by Bolon et al.

Abstract. Congenital tremors (CT) type A2 is associated with porcine circovirus (PCV) and deﬁcient andabnormal myelin. The aim of this study was to determine the tissue distribution and genetic type of PCV in 1–2-day-old pigs with naturally occurring CT type A2 using in situ hybridization, polymerase chain reaction(PCR), and indirect ﬂuorescent antibody tests on frozen tissue sections. CT-affected and clinically normal pigswere selected from 4 farms in the midwestern USA that were undergoing outbreaks of CT type A2. All CTand most normal pigs were infected with PCV. PCV was widely distributed in tissues of infected pigs and wasmost common in tissues of the central nervous system and liver. In all infected pigs, there were more PCV-infected cells in brain and spinal cord than in nonneural tissues. CT pigs had many more PCV-infected cells inthe brain and spinal cord than did clinically normal pigs because of a more diffuse distribution and a largerproportion of infected cells. The cells most commonly infected with PCV in brain and spinal cord were largeneurons. In nonneural tissues, macrophages were the most frequent cell type infected. PCR analysis demon-strated only PCV type 2 and not PCV type 1 in all PCV-infected pigs on all 4 farms.Congenital tremors (CT) in pigs are associated withmyelin deﬁciency and may be caused by genetic ab-normalities,

Congenital Tremors Tissue Distribution and Genetic Typing of Porcine Circoviruses in Pigs with Naturally Occurring

Feather Disease Polyomavirus Encephalopathy in a Ducorps Cockatoo (Cacatua Ducorpsii) with Psittacine Beak and

OF PSITTACINE BEAK AND FEATHER DISEASE CHARACTERISITICS OF THE PBFD VIRUS

The 2011 annual National Toxicology Program (NTP) Satellite Symposium, entitled “Pathology Potpourri,” was held in Denver, Colorado in advance of the Society of Toxicologic Pathology’s 30th Annual Meeting. The goal of the NTP Symposium is to present current diagnostic pathology or nomenclature issues to the toxicologic pathology community. This article presents summaries of the speakers’ presentations, including diagnostic or nomenclature issues that were presented, along with select images that were used for audience voting or discussion. Some lesions and topics covered during the symposium include: proliferative lesions from various fish species including ameloblastoma, gas gland hyperplasia, nodular regenerative hepatocellular hyperplasia, and malignant granulosa cell tumor; spontaneous cystic hyperplasia in the stomach of CD1 mice and histiocytic aggregates in the duodenal villous tips of treated mice; an olfactory neuroblastoma in a cynomolgus monkey; various rodent skin lesions, including follicular parakeratotic hyperkeratosis, adnexal degeneration, and epithelial intracytoplasmic accumulations; oligodendroglioma and microgliomas in rats; a diagnostically challenging microcytic, hypochromic, responsive anemia in rats; a review of microcytes and microcytosis; nasal lesions associated with green tea extract and Ginkgo biloba in rats; corneal dystrophy in Dutch belted rabbits; valvulopathy in rats; and lymphoproliferative disease in a cynomolgus monkey.

Proceedings of the 2011 National Toxicology Program Satellite Symposium

Abstract Increased activities of certain biochemical enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], lactate dehydrogenase [LDH], alkaline phosphatase [ALP]) have been associated with blunt liver injury in many species. To evaluate changes in plasma hepatic biochemical parameters in acute avian liver disease caused by trauma and to compare biochemical changes with histologic lesions in hepatic parenchyma, 30 healthy fasted Indian ring-necked parakeets (Psittacula krameri manillensis) were divided into 2 groups, and traumatic liver injury was caused by endoscopic liver biopsy (group 1) or by liver biopsy and crushing injury to the hepatic parenchyma with endoscopic forceps (group 2) in anesthetized birds. Blood samples were collected at baseline and at 12, 24, 36, 48, 60, 72, 84, 96, 108, and 120 hours in alternate groups to compare analyte values after injury with those at baseline. Results showed consistently decreased plasma ALP activity (excluding 1 time point) throughout the study, which was thought to be associated with isoflurane administration. Plasma glutamate dehydrogenase activity initially increased but rapidly declined thereafter and was attributed to acute focal hepatocellular injury. In both groups, increases in plasma AST, ALT, and LDH activities was most likely caused by muscle injury because creatine kinase activity was concurrently increased. Compared with baseline values, bile acid concentration and γ-glutamyl transferase activity were not affected by liver biopsy or crush injury. Plasma sorbitol dehydrogenase activity was the most specific indicator of liver injury in both groups. Histologic changes correlated poorly with biochemical results, possibly because the small area of hepatic parenchyma that was damaged did not affect enzyme values substantially.

Improved Clinicopathologic Assessments of Acute Liver Damage due to Trauma in Indian Ring-necked Parakeets (Psittacula krameri manillensis)

OBJECTIVE
To determine whether the presence of Chlamydophila psittaci antigen, plasma cholesterol concentration, diet, sex, species, and age are risk factors for the development of atherosclerosis in pet psittacine birds.

DESIGN
Retrospective case-control study.

ANIMALS
31 psittacine birds with atherosclerosis (study birds) and 31 psittacine birds without atherosclerosis (control birds).

PROCEDURES
Necropsy reports were reviewed, birds with a histopathologic diagnosis of atherosclerosis were identified, and available medical records were reviewed. Signalment, history, clinicopathologic findings, and other relevant data were recorded and evaluated. Control birds did not have atherosclerosis and were chosen by both convenience sampling and population demographics. Histologic sections of great vessels from all birds (study and control birds) were reviewed and then submitted for immunohistochemical staining for the presence of C psittaci antigen.

RESULTS
Result of immunohistochemical staining for C psittaci antigen in blood vessels was significantly associated with atherosclerosis. After adjusting for age, species origin, and type of illness, the odds of atherosclerosis was 7 times as high for birds with positive immunohistochemical staining for C psittaci antigen, compared with that of birds with negative immunohistochemical staining. Study birds and control birds differed significantly only with respect to plasma cholesterol concentrations. The median plasma cholesterol concentration of study birds (421 mg/dL) was significantly higher than that of control birds (223 mg/dL).

CONCLUSIONS AND CLINICAL RELEVANCE
Infection with C psittaci and a high plasma cholesterol concentration may be risk factors for developing atherosclerosis in pet psittacine birds.

Evaluation of Chlamydophila psittaci infection and other risk factors for atherosclerosis in pet psittacine birds.

Immunohistochemistry (IHC) and in situ hybridization (ISH) can be used either to detect or to differentiate between Eastern equine encephalitis virus (EEEV) and West Nile virus (WNV) within formalin-fixed, paraffin-embedded (FFPE) brain tissue of horses. To compare the diagnostic sensitivity and specificity of ISH and IHC, FFPE brain tissue from 20 EEEV-positive horses and 16 WNV-positive horses were tested with both EEEV and WNV oligoprobes and EEEV- and WNV-specific antibodies. Reverse transcription polymerase chain reaction (RT-PCR) for detection of EEEV and WNV was used as the gold standard to confirm infection. All horses that tested positive for EEEV by RT-PCR also tested positive by IHC and ISH, except for 1 case that was false-negative by ISH. In contrast, all horses that tested positive for WNV by RT-PCR tested negative by IHC and only 2 horses tested positive by ISH. No false-positives were detected with either method for both viruses. Both IHC and ISH are highly specific and sensitive diagnostic methods to detect EEEV in equine FFPE brain tissues, although neither appear effective for the diagnosis of WNV in equine neurologic cases.

Diagnostic sensitivity and specificity of in situ hybridization and immunohistochemistry for Eastern equine encephalitis virus and West Nile virus in formalin-fixed, paraffin-embedded brain tissue of horses

Contributing Authors. Preface. Acknowledgments. Chapter 1. Erythrocytes. Chapter 2. Leukocytes. Chapter 3. Hematopoietic Neoplasia. Chapter 4. Hemostasis. Chapter 5. Water, Electrolytes, and Acid Base. Chapter 6. Proteins, Lipids, and Carbohydrates. Chapter 7. Liver. Chapter 8. Digestive System. Chapter 9. Urinary System. Chapter 10. Muscle. Chapter 11. Endocrine System. Chapter 12. Cytology. Chapter 13. Generating and Interpreting Test Results: Test Validity, Quality Control, Reference Values, and Basic Epidemiology. Case Studies. Index.

Duncan & Prasse's veterinary laboratory medicine : clinical pathology

Tienda online donde Comprar Duncan and Prasse's Veterinary Laboratory Medicine: Clinical Pathology, 5th Edition al precio 59,54 € de Keith Prasse | Edward Mahaffey | Kenneth S Latimer, tienda de Libros de Medicina, Libros de Veterinaria - Medicina y Cirugia Animal

Comprar Duncan and Prasse's Veterinary Laboratory Medicine: Clinical Pathology, 5th Edition | Keith Prasse | 9780813820149 | Blackwell Publishing

Osteogenic melanoma is a rare variant of metaplastic malignant melanoma in human medicine and appears to be a similarly rare variant in dogs. Two dogs with oral malignant melanoma with neoplastic bone formation are reported in this study. Both tumors were characterized by malignant melanocytes that transitioned into neoplastic bone at the deep margins of the neoplasm. Immunohistochemical analysis revealed S100- and Melan-A–positive neoplastic cells adjacent to, and occasionally embedded within, an osteoid and chondroblastic matrix. Scattered clusters of neoplastic cells were also positive for osteocalcin. The findings indicate that in dogs, as in humans, neoplastic melanocytes have metaplastic potential and can be osteogenic.

Identification and genetic characterization of Cytauxzoon felis in asymptomatic domestic cats and bobcats.

The National Toxicology Program (NTP) Satellite Symposium is a one-day meeting that is held in conjunction with the annual Society of Toxicologic Pathology (STP) meeting. The topic of the 2009 Symposium was ‘‘Tumor Pathology and INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Nomenclature.’’ The goal of this article is to provide summaries of each speaker’s presentation, including the diagnostic or nomenclature issues that were presented, along with a few select images that were used for voting. The results of the voting process and interesting points of discussion that were raised during the presentation are also provided. A supplemental file with voting choices and voting results for each case presented at the symposium is available at http://tpx.sagepub.com/supplemental.

Proceedings of the 2009 National Toxicology Program Satellite Symposium

Large granular lymphosarcaoma / leukemia is a neoplastic disease of lymphocytes that contain intracytoplasmic azurophilic granules. Large granular lymphocytes (LGL) can be found in the blood of healthy domestic species and usually constitute 10% or less of the total circulating lymphocyte pool.2,7 Large granular lymphocytes have lymphocyte morphology, possessing a round or bean-shaped nucleus, and slightly basophilic cytoplasm. The major morphologic difference between LGLs and typical lymphocytes is that the former contain varying numbers (3 or more) of small to large azurophilic granules in their cytoplasm. Granular size usually is inversely proportional to the number of cytoplasmic granules.5 In cats, the granules may be large with internal vesicles.6 The exact origin of LGLs is unknown, however, studies have shown that at least two lines (cytotoxic T lymphocytes and natural killer cells) produce large granular lymphocytes. Studies show that most large granular lymphocytes in dogs are of T cell origin, with the minority of natural killer (NK) cell origin.2,9 Most cases of LGL leukemia originate outside of the bone marrow and thus are technically lymphosarcoma. Infiltration of the bone marrow subsequently can occur, and patients will present with a leukemic blood picture.2

A novel siadenovirus was identified in the Sulawesi tortoise (Indotestudo forsteni). A group of 105 Sulawesi tortoises was obtained by the Turtle Survival Alliance. Many of the tortoises were in poor health. Clinical signs included anorexia, lethargy, mucosal ulcerations and palatine erosions of the oral cavity, nasal and ocular discharge, and diarrhea. Initial diagnostic tests included fecal testing for parasites, complete blood count and plasma biochemical analysis, mycoplasma serology, and polymerase chain reaction (PCR) testing for intranuclear coccidia and chelonian herpesvirus. Treatment included administration of antibiotics, antiparasitic medications, parenteral fluids, and nutritional support. Tissue samples from animals that died were submitted for histopathologic evaluation. Histopathologic examination revealed systemic inflammation and necrosis associated with intranuclear inclusions consistent with a systemic viral infection in 35 tortoises out of 50 examined. Fecal testing results and histopathologic findings revealed intestinal and hepatic amoebiasis and nematodiasis in 31 animals. Two of 5 tortoises tested by PCR were positive for Chlamydophila sp. Aeromonas hydrophila and Escherichia coli were cultured from multiple organs of 2 animals. The mycoplasma serology and PCR results for intranuclear coccidia and chelonian herpesvirus were negative. Polymerase chain reaction testing of tissues, plasma, and choanal/cloacal samples from 41 out of 42 tortoises tested were positive for an adenovirus, which was characterized by sequence analysis and molecular phylogenetic inference as a novel adenovirus of the genus Siadenovirus. The present report details the clinical and anatomic pathologic findings associated with systemic infection of Sulawesi tortoises by this novel Siadenovirus, which extends the known reptilian adenoviruses to the chelonians and extends the known genera of reptilian Adenoviridae beyond Atadenovirus to include the genus Siadenovirus.

Systemic Adenovirus Infection in Sulawesi Tortoises (Indotestudo Forsteni) Caused by a Novel Siadenovirus

Although cytauxzoonosis has historically been nearly 100% fatal in domestic cats, increasing number of reports of infected cats that demonstrate less-severe disease suggest the existence of different strains of Cytauxzoon felis. To test this hypothesis, the genetic variability of C. felis was examined in blood samples from naturally infected domestic cats from Arkansas and Georgia by using the first and second ribosomal internal transcribed spacer regions (ITS1, ITS2) as markers to assess genotypic variability. In addition, the clinical outcome of infection (survival vs. fatal disease) was analyzed. Within the C. felis ITS1 region, there were a total of 8 single nucleotide polymorphisms (SNP) and a single nucleotide insertion. Within the ITS2 region, there were a total of 4 SNPs and a single 40 base pair insertion. When taken together, the ITS1 and ITS2 sequence data defined a total of 11 different sequences and 3 unique genotypes. One unique ITS1-ITS2 genotype was detected in samples submitted exclusively from Arkansas, and a second unique genotype was submitted exclusively from Georgia. There was a significant association between infection with C. felis that contained particular ITS genotypes and survival of the infected domestic cat. The identification of unique C. felis genotypes obtained from different geographic areas and the association of particular ITS genotypes with the outcome of infection suggest the existence of parasite strains that may vary in pathogenicity to the domestic cat and offer an explanation for the survival of some infected cats in more recent case studies.

Genetic Variability of Cytauxzoon Felis from 88 Infected Domestic Cats in Arkansas and Georgia

Abstract An adult male Boelen's python, Morelia boeleni, presented with acute neurologic disease and was euthanatized. Histologic examination revealed nonsuppurative meningoencephalitis. Occasional eosinophilic intracytoplasmic inclusions were noted in glial cells. On the basis of clinical signs and histopathology, inclusion body disease of boid snakes was suspected, but inclusions were not seen in other organs commonly affected with the disease. Moreover, electron microscopy revealed that the inclusions contained stacks of filaments 13–14 nm wide. With the use of a generic paramyxovirus cDNA probe, sections of brain and esophageal ganglion demonstrated hybridization. The findings indicate that paramyxovirus was the likely cause of the encephalomyelitis in this python, and this virus should be included in the differential diagnosis of pythons exhibiting central nervous system disease.

MENINGOENCEPHALITIS IN A BOELEN'S PYTHON (MORELIA BOELENI) ASSOCIATED WITH PARAMYXOVIRUS INFECTION

Cytauxzoon felis infection in domestic cats has historically been nearly 100% fatal. However, increasing reports of domestic cats that survive cytauxzoonosis and reports of asymptomatic cats with C. felis infections suggest the existence of different parasite strains that vary in pathogenicity. The objective of the current study was to obtain epidemiologic information about cytauxzoonosis through genotypic characterization of archived histologic specimens from domestic cats with C. felis infections that were diagnosed in Georgia between 1995 and 2007. Such retrospective data on genetic variability will provide an historic context for current studies of C. felis genotype frequencies. Cytauxzoon felis DNA was obtained from formalin-fixed, paraffin-embedded tissues from infected cats diagnosed with cytauxzoonosis at necropsy. Genetic characterization of C. felis was performed using sequence analysis of the polymerase chain reaction–amplified ribosomal internal transcribed spacer regions 1 and 2 (ITS1, ITS2). Eleven different combined ITS1 and ITS2 sequences were identified, the majority of which were identical to those previously reported in fatally infected cats from Georgia. The findings of the current study document the existence of genetically distinct C. felis populations in historical samples and, together with data from contemporary samples, demonstrate a diverse population structure for C. felis.

Genetic Variability of Archived Cytauxzoon Felis Histologic Specimens from Domestic Cats in Georgia, 1995–2007

Abstract Currently used dosages for external-beam megavoltage radiation therapy in birds have been extrapolated from mammalian patients and often appear to provide inadequate doses of radiation for effective tumor control. To determine the tolerance doses of cutaneous and mucosal tissues of normal birds in order to provide more effective radiation treatment for tumors that have been shown to be radiation responsive in other species, ingluvial mucosa and the skin over the ingluvies of 9 ring-necked parakeets (Psittacula krameri) were irradiated in 4-Gy fractions to a total dose of either 48, 60, or 72 Gy using an isocentric cobalt-60 teletherapy unit. Minimal radiation-induced epidermal changes were present in the high-dose group histologically. Neither dose-related acute nor chronic radiation effects could be detected in any group grossly in cutaneous or mucosal tissue over a 9-month period. Radiation doses of 72 Gy in 4-Gy fractions were well tolerated in the small number of ring-necked parakeets in this initial tolerance dose study.

Tolerance Doses of Cutaneous and Mucosal Tissues in Ring-necked Parakeets (Psittacula krameri) for External Beam Megavoltage Radiation

A unique form of pulmonary malignancy develops in cockatiels. This report describes the gross, histologic, electron microscopic, and immunohistochemical features of this tumor in 6 cockatiels. DNA in-situ hybridization for polyomavirus in the neoplasm was also performed. The tumor was comprised predominantly of compact sheets of anaplastic round to polygonal cells. All tumors had a high mitotic index, and had occasional large clear to slightly basophilic intranuclear inclusions that caused peripheral dispersal or complete masking of chromatin. Tumors were invasive but convincing metastases were not observed. Transmission electron microscopy identified intracytoplasmic intermediate filaments, desmosomes between cells, and intranuclear cytoplasmic invaginations corresponding to the intranuclear inclusions in light microscopic sections. Neoplastic cells stained positive for vimentin, lysozyme, and in 1 bird, pan cytokeratin. All 6 pulmonary neoplasms were negative for avian polyomavirus using the FN-19/FN-40 cocktail and the long VP-1 probe. We propose that these tumors may be poorly differentiated carcinomas of pulmonary or thymic origin.

Histologic, Immunohistochemical, and Electron Microscopic Features of a Unique Pulmonary Tumor in Cockatiels (Nymphicus hollandicus)

Important Findings All fledgling canaries (Serinum canarius) in a small private aviary died from atoxoplasmosis during a single breeding season. The birds were clinically normal when removed from their parents at 2 months of age, but by 3 months of age all had died following an illness characterized by progressive lethargy, anorexia, and debilitation. Microscopically, there was striking infiltration of the intestinal lamina propria by mononuclear cells that contained intracytoplasmic protozoa consistent with Atoxoplasma serini. The infected cells were examined with an electron microscope and had features typical of lymphocytes. In addition, the majority of parasitized cells in the intestine were immunopositive for CD-79 antigen consistent with B lymphocytes. The following year, after egg-laying was completed, adults were treated with sulfadimethoxine, and no further fledgling losses occurred.

Atoxoplasmosis in Canary Fledglings: Severe Lymphocytic Enteritis with Preferential Parasitism of B Lymphocytes

Abstract All fledgling canaries (Serinum canarius) in a small private aviary died from atoxoplasmosis during a single breeding season. The birds were clinically normal when removed from their parents at 2 mo of age, but by 3 mo of age all had died following an illness characterized by progressive lethargy, anorexia, and debilitation. Cachexia, splenomegaly, and pale foci in the liver were evident at necropsy. Microscopically, there was striking infiltration of the intestinal lamina propria by mononuclear cells that contained intracytoplasmic protozoa. Protozoa were also observed in mononuclear cells in splenic and hepatic sinusoids and in vascular or perivascular spaces of other organs, but were much less numerous. Ultrastructural features of infected enteric mononuclear cells were suggestive of lymphocytes, and the majority of parasitized cells in paraffin sections of intestine were positive for CD-79 antigen, consistent with B lymphocytes. CD-3 staining was minimal, suggesting little or no T-cell infection. The following year, after egg-laying was completed, adults were treated with sulfadimethoxine, and no further fledgling losses occurred.

Nineteen map turtles (Graptemys spp.) maintained under natural conditions were investigated because of chronic shell abnormalities. Animals were evaluated using a novel shell scoring system that divided the 54 scutes into six regions, with each region scored for lesion extent and severity, and summated to produce a total shell disease score (TSDS). Complete blood counts and various biochemistry analytes (total protein, albumin, globulin, urea, uric acid, 25-hydroxycholecalciferol, phosphorus, and ionized and total calcium) were measured. Under ketamine-medetomidine-morphine anesthesia, cytology tape strips and full thickness shell biopsies were collected aseptically for microbiologic, histologic (including scoring of biopsy quality), and ultrastructural evaluations. The TSDSs were low and ranged from 4 to 22 (median=9) out of a possible score of 54. There were no correlations between TSDS and any hematologic or biochemistry parameter. The histologic quality of shell biopsies was good, and normal shell structure, by both light and electron microscopy, is described. Small clefts and pitting lesions were noted in 8/19 sections. There was no evidence of erosion, ulceration, inflammation, or infectious agents, but algae and diatoms were observed. Six biopsies yielded aerobic isolates (Chryseobacterium indologenes, Aeromonas hydrophila, Ralstonia pickettii, and Morganella morganii), whereas 11 shell samples grew various clostridial anerobes. No fungal organisms were cultured. Although the etiology of the lesions described remains unknown, the use of a scoring system in conjunction with full thickness biopsies is suggested to help standardize investigations into chelonian shell disease in the future.

OBJECTIVE
To evaluate endoscopic liver biopsy and compare that technique with a standard coeliotomy biopsy technique in fish.

DESIGN
Randomized controlled clinical trial.

ANIMALS
30 channel catfish (Ictalurus punctatus).

10 fish were randomly assigned into control, coeliotomy, and coelioscopy groups. Anesthesia was performed with a recirculating anesthesia machine. Body weight, PCV, and total protein (TP) concentration in blood as well as plasma activities of aspartate aminotransferase, creatinine phosphokinase, lactate dehydrogenase, and sorbitol dehydrogenase were measured before and after surgery. Standard ventral coeliotomy or coelioscopy was performed, and the biopsy specimens were scored histologically.

RESULTS
Coeliotomy and coelioscopy procedures were well tolerated without acute deaths. Blood TP concentration and PCV decreased after surgery in the coelioscopy group because of intracoelomic fluid administration to aid visualization. Minor changes in activities for hepatic and muscular enzyme activities were apparent, but were not significantly different between the coelioscopy and coeliotomy groups. Coelioscopy and coeliotomy yielded biopsy specimens of similar diagnostic quality. However, coelioscopy permitted a more extensive evaluation of the viscera, and all 10 surgical wounds healed completely, compared with severe wound dehiscence in 3 of 10 fish that underwent coeliotomy.

Both coelioscopy and coeliotomy were capable of yielding antemortem liver biopsy specimens of diagnostic quality in catfish. Coelioscopy permitted a more detailed examination of the coelomic viscera through a smaller surgical incision, was less traumatic, and resulted in decreased wound dehiscence.

Comparison between coelioscopy and coeliotomy for liver biopsy in channel catfish.

ABSTRACT A 1.5-year-old male Moluccan cockatoo (Cacatua moluccensis) presented to Kansas State University Veterinary Medical Teaching Hospital with a 4-month history of lethargy and weakness. Hematologic and radiographic diagnostic testing revealed profound leukocytosis and coelomic and pulmonary granulomatous masses of unknown origin. The bird died during laparoscopic evaluation under general anesthesia. Necropsy revealed multiple pulmonary and hepatic soft-tissue nodules and an intracoelomic mass over the left kidney communicating with external subcutaneous masses and a pericloacal mass of similar gross appearance. Histopathologic findings identified a severe, disseminated, inflammatory infiltration of multiple tissues and multiple granulomas containing bizarre multinucleated cells. No causative agent of this granulomatous disease was identified. To our knowledge, this is the first report of systemic atypical granulomatous disease in Moluccan cockatoo. Traditional causes of granulomatous disease include mycotic disease, bacterial (ie, Mycobacterium) disease, and neoplasia. Attempts to identify an causative agent or neoplasia were unsuccessful. A retrospective review of pathology records revealed 2 additional cases with identical pathologic lesions. All 3 cases occurred in young Moluccan cockatoos and are assumed to be a disease of unknown origin that could be unique to this species.

Three Cases of Systemic Atypical Granulomatous Disease in Moluccan Cockatoos (Cacatua Moluccensis): A New Syndrome

SUMMARY. Sarcocystosis in psittaciform birds occurs in several different presentations, making ante-mortem diagnosis challenging without specific laboratory tests. This study followed the course of 11 birds diagnosed with sarcocystosis by serologic analysis and/or post-mortem examinations during a 10-month period in 2006–07. The disease presented in three different clinical forms: an acute pulmonary disease (three birds), muscular disease (five), and neurological disease (three). Early diagnosis of sarcocystosis was possible through the combined used of plasma protein electrophoresis and indirect fluorescent antibody serology in birds presented with the neurological and muscular forms of the disease. In three of these birds the plasma electrophoretic patterns revealed marked hypergammaglobulinemia. All of the birds that presented with the acute pulmonary form developed similar gross and microscopic lesions. Definitive diagnosis was ultimately made by microscopic observation of intravascular pulmonary schizonts containing merozoites. Schizonts were identified in the cerebellum and brainstem in two birds with the neurological form of disease. Those birds that initially presented with severe lethargy and weakness were considered to suffer from the muscular form of disease if they had extreme elevations of muscle enzyme activities (creatine phosphokinase, aspartate aminotransferase) and beta and gamma globulins concentrations, and were seropositive for antibodies to Sarcocystis falcatula. In this group the progression of the disease varied. Two birds recovered completely, and secondary aspergillosis was diagnosed in three birds. The histopathological lesions observed are discussed and interpreted in light of earlier findings from experimental infections in budgerigars, which provide insights into the natural course of sarcocystosis in psittaciform birds.

Clinical Presentation and Pathology of Sarcocystosis in Psittaciform Birds: 11 Cases

Repeated polymerase chain reaction (PCR) testing of 3 asymptomatic domestic cats were positive for Cytauxzoon felis DNA, suggesting persistent infection. Two cats initially presented with clinical signs consistent with acute cytauxzoonosis and, in both cases, signs of illness resolved after treatment. Parasitemia was detected in peripheral blood smears from these cats upon presentation with illness and, at subsequent follow-up appointments, in the absence of clinical illness. Polymerase chain reaction analysis was positive for C. felis from blood sampled at each time point. A third cat, a housemate of a cat fatally infected with C. felis, was preventatively treated for infection at the time of the housemate cat's death. This contact cat, having never shown signs of clinical illness consistent with cytauxzoonosis infection, had no detectable parasitemia but was positive for C. felis on repeated PCR testing. Detection of asymptomatically infected cats allows for the possibility of a yet unrecognized population of infected domestic cats that may have the capacity to serve as an additional reservoir host for C. felis, altering the currently accepted paradigm of C. felis transmission to domestic cats through bobcats as the reservoir host. In cases of very low parasitemia, more sensitive means of parasite detection, such as PCR testing, may be necessary to detect infected cats. Increased detection of asymptomatically infected cats will aid in understanding the epidemiology of C. felis infection and enhance the ability to prevent this highly fatal infectious disease of domestic cats.

Detection of Persistent Cytauxzoon Felis Infection by Polymerase Chain Reaction in Three Asymptomatic Domestic Cats

Abstract Sarcocystosis in psittaciform birds occurs in several different presentations, making ante-mortem diagnosis challenging without specific laboratory tests. This study followed the course of 11 birds diagnosed with sarcocystosis by serologic analysis and/or post-mortem examinations during a 10-month period in 2006–07. The disease presented in three different clinical forms: an acute pulmonary disease (three birds), muscular disease (five), and neurological disease (three). Early diagnosis of sarcocystosis was possible through the combined used of plasma protein electrophoresis and indirect fluorescent antibody serology in birds presented with the neurological and muscular forms of the disease. In three of these birds the plasma electrophoretic patterns revealed marked hypergammaglobulinemia. All of the birds that presented with the acute pulmonary form developed similar gross and microscopic lesions. Definitive diagnosis was ultimately made by microscopic observation of intravascular pulmonary schizonts containing merozoites. Schizonts were identified in the cerebellum and brainstem in two birds with the neurological form of disease. Those birds that initially presented with severe lethargy and weakness were considered to suffer from the muscular form of disease if they had extreme elevations of muscle enzyme activities (creatine phosphokinase, aspartate aminotransferase) and beta and gamma globulins concentrations, and were seropositive for antibodies to Sarcocystis falcatula. In this group the progression of the disease varied. Two birds recovered completely, and secondary aspergillosis was diagnosed in three birds. The histopathological lesions observed are discussed and interpreted in light of earlier findings from experimental infections in budgerigars, which provide insights into the natural course of sarcocystosis in psittaciform birds.

Abstract Turtle populations are decreasing dramatically due to habitat loss and collection for the food and pet market. This study sought to determine hematologic values in two species of turtles to help assess health status of captive and wild populations. Blood samples were collected from 12 individuals of the Pascagoula map turtle (Graptemys gibbonsi) and seven individuals of the southeast Asian box turtle (Cuora amboinensis) from the Savannah River Ecology Laboratory (South Carolina, USA). The hematologic data included hematocrit, total solids, erythrocyte count, leukocyte count, and differential and percentage leukocyte counts. Low hematocrit values and high basophil counts were found in both species. The basophil was the most abundant leukocyte in the Pascagoula map turtle (median = 0.80 × 109/L), whereas in the Southeast Asian box turtle the most abundant leukocyte was the heterophil (median = 2.06 × 109/L).

Hematology of the Pascagoula Map Turtle (Graptemys Gibbonsi) and the Southeast Asian Box Turtle (Cuora amboinensis)

A two-phase cross-over therapeutic study was performed with 19 green iguanas (Iguana iguana) maintained within a preferred optimum temperature range of 26 to 37°C. During phase 1, they were fed a normal vegetarian diet and medicated orally with either allopurinol or a placebo control once a day for seven days. Uric acid concentrations, total protein, packed-cell volumes (pcv) and bodyweights were recorded from each lizard before and after treatment to determine the effects of allopurinol. In phase 2, after a 10-day washout period, the iguanas were fed a high protein diet to induce hyperuricaemia. Normo- and hyperuricaemic iguanas that received 24·2 (3·2) mg/kg allopurinol had significantly lower mean (sd) uric acid concentrations (100·3 [53·1] μmol/l) than the controls (159μ3 [100·3] μmol/l). There were no detectable interactions between the doses of allopurinol or placebo, and the iguanas' diet, weight, pcv or total protein. The allopurinol was well tolerated, and there was no significant clinical, gross or histological evidence of hepatic or renal toxicity in the iguanas that received the drug. However, in the kidneys of the hyperuricaemic iguanas that did not receive allopurinol there were proliferative changes in the glomeruli and degeneration of tubular epithelia. Allopurinol given orally at 25 mg/kg daily is able to reduce plasma uric acid levels by 41 to 45 per cent, and is therefore recommended for the treatment of hyperuricaemia in the green iguana.

Effects of allopurinol on plasma uric acid levels in normouricaemic and hyperuricaemic green iguanas (Iguana iguana)

ABSTRACT A male black rat snake, Elaphe obsoleta, was presented to the University of Georgia, College of Veterinary Medicine with a soft, spongy extracoelomic mass, approximately 10 cm by 3 cm by 3 cm, on the dorsal mid- body. The snake had no clinical signs associated with the mass, but an excisional biopsy was performed due to increasing size of the mass. Histopathologic examination of the mass revealed an infiltrative lipoma. For two years postoperatively, the snake continued to thrive with no recurrence of the neoplasia. Approximately two years after the surgical procedure, the owner reported a small mass cranial to the scar from the previous surgery.

ABSTRACT The effects of dipotassium ethylenediaminetetraacetic acid (EDTA) and lithium heparin on hematologic values of yellow-blotched map turtles, Graptemys flavimaculata, were compared. Ten animals confiscated by the Department of Natural Resources, Georgia had blood drawn from the occipital sinus as part of a health evaluation. Length and width of red blood cells were compared between different treatment groups (EDTA, lithium heparin and fresh blood). A complete blood count and hemoparasite examination were performed on each anticoagulated sample. There were no significant differences in lengths between groups, but widths were significantly smaller (P<0.05) in anticoagulated blood smears than in fresh blood smears. Using a paired t test, EDTA and lithium heparin samples were significantly different (P<0.05) for packed cell volume percentage, plasma protein, white blood cell count, heterophils, eosinophils, monocytes, azurophils, and combined monocytes and azurophils counts. The data showed that EDTA i...

Comparison of the Effects of Dipotassium Ethylenediaminetetraacetic Acid and Lithium Heparin on Hematologic Values in Yellow-blotched Map Turtles, Graptemys flavimaculata

Mycobacterium avium-intracellulare, a member of the M avium complex (MAC), is a ubiquitous, saprophytic, slowgrowing, acid-fast bacillus that is widely distributed in the environment (Greene and Gunn-Moore 2006). Clinical signs associated with MAC infection are typically organ-specific, depending on the route of infection. Dissemination can occur in immunocompromised hosts. The treatment of localised disease consists of surgical removal of the infected tissue, with or without medical therapy (Kaufman and others 1995, Malik and others 1998). The treatment of disseminated MAC infection in cats has recently been reported to be successful with a variety of combination drug regimens, including clofazimine and clarithromycin as essential components (Baral and others 2006). This short communication describes the treatment of a cat with disseminated M avium infection with a multidrug regimen and the associated side effects. A five-year-old, male neutered Abyssinian cat was evaluated by a private veterinarian because of a history of weight loss and anorexia. Physical examination revealed an abdominal mass, which was removed surgically. Pyogranulomatous inflammation was observed on histopathological examination of the mass. Tests for feline leukaemia virus (FeLV) antigen and feline immunodeficiency virus (FIV) antibody were negative. Treatment with prednisone was initiated, but within two weeks the cat became tachypnoeic and was referred to the University of Georgia Veterinary Teaching Hospital. Thoracic radiography revealed a diffuse, nodular interstitial lung pattern. Pyogranulomatous inflammation without visible microorganisms was detected on bronchoalveolar lavage (BAL) and on transthoracic lung aspirates. The results of aerobic bacterial and fungal cultures and tests for cryptococcal antigen (latex agglutination test), toxoplasmosis antibodies (immunoglobulin M [IgM] and immunoglobulin G [IgG] ELISAs) and coronavirus antibody (immunoflourescent antibody test), were negative. On an empirical basis, the cat was discharged on 10 mg/kg clindamycin and 5 mg/kg itraconazole, both administered orally every 12 hours. Two months later, the cat was re-presented because of persisting anorexia and tachypnoea. At that time (day 0) the cat was thin (bodyweight 2·7 kg) and had a normal rectal temperature and a markedly increased respiratory rate, with increased expiratory effort. Thoracic auscultation revealed increased normal breath sounds bilaterally, and abdominal palpation revealed a 6 x 7 cm, irregular, non-painful mass in the mid-abdomen. Laboratory abnormalities included mild neutrophilia (15,768 cells/μl, reference range [RR], 2500 to 12,500 cells/μl) with left shift (bands, 1944 cells/μl, RR 0 to 300 cells/μl), hyperglobulinemia (51 g/l, RR 30 to 34 g/l) and hypercalcemia (total calcium 4·0 mmol/l, RR 2·25 to 2·7 mmol/l; ionised calcium 1·59 mmol/l, RR 1·22 to 1·3 mmol/ l). A severe bronchointerstitial lung pattern was detected on thoracic radiography (Fig 1). Abdominal ultrasonography revealed multiple irregularly marginated hypoechoic masses in the mesentery and/or omentum. The results of repeated FIV antibody, FeLV antigen, coronavirus antibody and toxoplasmosis antibody (IgM and IgG) tests were negative. An abdominal laparotomy revealed multiple nodular lesions within the omentum and moderate mesenteric lymphadenomegaly. A section of the omentum and two mesenteric lymph nodes were excised and submitted for aerobic, anaerobic, mycobacterial and fungal culture, direct fluorescent antibody testing for intralesional coronavirus, and routine histopathological evaluation, which demonstrated pyogranulomatous inflammation. The results of special staining (Giemsa, acid-fast, periodic acid-Schiff) for bacteria and fungi and the fluorescent antibody test on serum for coronavirus were negative. The cat was discharged from the hospital six days later. Over the next two months, the cat was clinically stable. No growth was reported on the aerobic, anaerobic or fungal cultures. After 65 days’ culture carried out by the Centers for Disease Control and Prevention [CDC], the mycobacterial culture yielded growth of an organism. Pending definitive identification, it was considered to be a member of the MAC because of its very slow growth and the clinical presence of gastrointestinal involvement with respiratory dissemination (Greene and Gunn-Moore 2006). Treatment was started with a multidrug regimen consisting of 4·4 mg/kg clarithromycin every 12 hours, 50 mg clofazimine every 24 hours and 12·5 mg/kg doxycycline every 12 hours, all administered orally. A dramatic clinical improvement was seen; four weeks later (94 days after the cat had been re-presented), the pulmonary densities had a markedly decreased opacity on radiography. Abdominal ultrasonography revealed that the masses had disappeared, although the mesenteric lymphadenomegaly persisted. On day 120, the isolate was identified as M avium-intracellulare by the CDC, which was sensitive only to rifampin. Because of the obvious clinical and radiographic improvements, the treatment protocol was not altered. On day 134, the cat’s appetite suddenly decreased. Increased serum activities of alanine aminotransferase (ALT) (727 U/l, RR 31 to 104 U/l) and alkaline phosphatase (ALP) (73 U/l, RR 0 to 50 U/l) were noted. Hepatotoxicity due to the medications was suspected, and the clarithromycin was discontinued. On day 146, the serum ALP activity was within the reference range (45 U/l) and the serum ALT activity had decreased to 301 U/l. Enroflaxacin (2·5 mg/kg every 12 hours, administered orally) was added to the protocol. At re-evaluation 20 days later, the cat was clinically healthy and serum liver enzyme activities were within reference limits. The radiographic lung densities had continued to decrease, and mesenteric lymphadenomegaly was no longer detected ultrasonographically (Fig 2). Eight weeks later (day 230), the owner chose to discontinue all medications. At the time of writing, the cat has been reevaluated on a periodic basis for approximately 900 days, and had remained clinically healthy. Reports of M avium infection in cats are uncommon, leading to the suspicion that cats have some resistance to this Veterinary Record (2007) 160, 131-132

Long-term cure of disseminated Mycobacterium avium infection in a cat

This report describes the use of polymerase chain reaction and DNA in situ hybridization to diagnose Aleutian mink disease parvovirus DNA in various tissue specimens from 2 companion striped skunks. Clinical, laboratory, and microscopic findings also support a clinical diagnosis of Aleutian disease in these mink.

Aleutian Disease in Two Domestic Striped Skunks (Mephitis mephitis)

Four female and 3 male Taita falcons (Falco fasciinucha) out of a breeding colony of 14 Taita falcons (7 pairs) died during the breeding season after showing lethargy and anorexia for 1 to 2 days. All animals were submitted for necropsy. Gross lesions in the female falcons were characterized by anemia secondary to marked hemorrhage into the ovary and oviduct, serofibrinous effusion into the cardioabdominal cavity and serosal petechiae. In addition, marked necrotizing splenitis and pulmonary hemorrhage were present. Histologically, the female falcons had mild necrotizing hepatitis with numerous intranuclear inclusion bodies and necrotizing splenitis with rare inclusion bodies. There were no gross lesions in the male falcons, and the histological lesions were characterized by urate deposition and rare intranuclear inclusion bodies in the renal tubular epithelial cells. Adenoviral particles were found by electron microscopy in the cloacal contents of the female Taita falcons but not in the male falcons. DNA in situ hybridization revealed widespread aviadenoviral nucleic acid within the nuclei of hepatocytes, renal tubular epithelial cells, and adrenal cells in the female falcons but no aviadenoviral nucleic acid in 1 male falcon and only a low quantity of adenoviral nucleic acid in the liver and kidney of another male Taita falcon. PCR amplified aviadenoviral DNA in the liver and intestine of all Taita falcons. The amplicons were sequenced, and the virus was identified as falcon adenovirus. The deaths of the female and male birds were attributed to the aviadenovirus infection.

Falcon Adenovirus Infection in Breeding Taita Falcons (Falco Fasciinucha)

ABSTRACT Techniques for endoscopic biopsy of the spleen and bursa of Fabricius were evaluated in 71 juvenile and adult white Carneau pigeons (Columba livia). Splenic biopsy was performed under isoflurane anesthesia by a left lateral approach to the coelom from behind the last rib. From within the left abdominal air sac, the spleen was located just caudal to the isthmus of the proventriculus and ventriculus and ventral to the gonad in 86% of pigeons examined. In the remaining 14%, extensive reproductive activity within mature female pigeons prevented visualization of the spleen. Splenic biopsy samples were successfully obtained from all birds in which the spleen could be found, and all were determined to be of good to excellent histologic quality. Endoscopic biopsy of the bursa of Fabricius was accomplished by cloacoscopy and saline irrigation with the pigeons in dorsal recumbency. The bursa of Fabricius was located and a biopsy was done in 28 (39%) of 71 pigeons. Initial histopathologic evaluation indicated that only 30% of the biopsy samples possessed lymphoid tissue of diagnostic quality. Splenic biopsy via coelioscopy appeared safe and rewarding in pigeons. Cloacoscopy provided an excellent view of the cloaca and appeared to be well tolerated; however, biopsy of the bursa of Fabricius is not recommended because of poor diagnostic value of the specimens and the risk of cloacal perforation.

Evaluation of Coelioscopic Splenic Biopsy and Cloacoscopic Bursa of Fabricius Biopsy Techniques in Pigeons (Columba livia)

ABSTRACT Pre- and post-prandial plasma 3α-hydroxy bile acids and other biochemical reference intervals were established for a group of 11 healthy male green iguanas, Iguana iguana. All animals were fasted for 48 hr and then fed a herbivorous, commercially available critical care diet containing 606 +/− 52.6 mg of fat per kg body weight to stimulate bile release. Pre-prandial bile acid concentrations (7.5 ± 7.8 μmol/L) significantly increased at 3 and 7.5 hr post-prandially to 33.3 ± 22.0 μmol/L and 32.5 ± 8.4 μmol/L, respectively. Liver histopathology and general necropsy findings were unremarkable. This study demonstrated a significant increase in post-prandial plasma 3α-hydroxy bile acid concentration in healthy green iguanas. This study suggests that fasting status should be considered when evaluating bile acid concentrations.

Preliminary Evaluation of Pre- and Post-Prandial 3α- Hydroxy Bile Acids in the Green Iguana, Iguana iguana

Intracytoplasmic inclusion bodies suggestive of iridovirus infection were observed in formalin-fixed, paraffin-embedded tissues from a nautilus (Nautilus spp.) that died without premonitory signs. Transmission electron microscopy revealed enveloped, hexagonal, viral particles that measured approximately 176 nm in diameter. Virions contained a dense central core and morphology typical of iridoviruses. Extracted DNA was amplified using primers homologous to conserved iridovirus sequences. The amplicons were cloned, sequenced, and determined to be approximately 60% similar to reported amphibian iridovirus sequences. A polymerase chain reaction-generated digoxigenin probe was used to detect viral nucleic acid in tissue sections by DNA in situ hybridization and high-affinity cytochemistry. The detected nucleic acid corresponded to the inclusion bodies observed microscopically. This represents a novel iridovirus of mollusks.

A 2-year-old domestic ferret that appeared clinically healthy was repeatedly seropositive for Aleutian mink disease parvovirus (ADV) over a 2-year observation period. Antibody titers, determined by counter-immunoelectrophoresis, ranged from 1024 to 4096. Viral DNA also was identified in serum, urine, feces, and blood cell fractions by polymerase chain reaction analysis. Ultimately, DNA in situ hybridization revealed ADV DNA in histologic sections of various tissues and organs. These data indicate that this asymptomatic ferret was persistently infected with ADV.

Persistent Viral Shedding during Asymptomatic Aleutian Mink Disease Parvoviral Infection in a Ferret

Ten veterinary pathologists independently assigned histologic grades to the same 60 canine cutaneous mast cell tumors using the Patnaik classifications. The degree of agreement in grading among the pathologists was compared with the degree of agreement among the same pathologists in a previous study, in which each pathologist used the reference for grading that he/she uses routinely. Mean agreement improved significantly from 50.3% to 62.1% with uniform use of the Patnaik classifications (P = 0.00001), suggesting that there is value in uniform application of a single grading scheme for canine cutaneous mast cell tumors. Agreement among pathologists was still not 100%, suggesting that a more objective grading scheme should be developed and that other histologic indicators of prognosis should be investigated.

Variation among Pathologists in the Histologic Grading of Canine Cutaneous Mast Cell Tumors with Uniform Use of a Single Grading Reference

Abstract An adult female, radiated tortoise (Geochelone radiata) presented with a grossly swollen left forelimb that restricted mobility and prevented limb withdrawal. Clinical pathology revealed leukopenia (1.9 × 109/L) and hyperproteinemia (69 g/L) that on protein electrophoresis was attributed to increased acute-phase proteins in the alpha fraction (26.4 g/L). Biopsy revealed a poorly differentiated soft tissue sarcoma. Surgical amputation at the proximal humerus was curative. To encourage postoperative mobility, a novel methylmethacrylate prosthesis, molded from a lubricated transected tennis ball, was adhered to the plastron using three cortical bone screws. This is the first recorded case of a sarcoma in the genus Geochelone.

UNDIFFERENTIATED SARCOMA RESOLVED BY FORELIMB AMPUTATION AND PROSTHESIS IN A RADIATED TORTOISE (GEOCHELONE RADIATA)

Three taita falcon (Falco fasc??nucha) nestlings and 3 cohoused hybrid falcon (F rus t?colus X F peregrinus) nestlings died after showing lethargy and anorexia for 4-5 days. Major lesions in the falcons were necrotizing hepatitis, splenitis, and lymphoplasmacytic nephritis. One hybrid falcon also had a heterophilic nephritis. Intranuclear inclusion bodies were present in the hepatocytes of the taita falcons and in the renal tubular epithelial cells of 1 hybrid falcon. Adenoviral particles were found in the cloacal content of 2 taita falcons. DNA in situ hybridization revealed aviadenoviral nucleic acid within the nuclei of hepatocytes of a taita falcon and a hybrid falcon and in the tubular epithelial cells of a hybrid falcon. Aviadenoviral DNA was amplified by Poly merase chain reaction in the liver of taita falcons and hybrid falcons. The death of these birds was attributed to the aviadenovirus infection; however, the source of the virus was not determined. Predisposing factors for the outbreak of the viral infection in these falcons may have included transport stress, lack of quarantine measures, and cohousing of falcon species originating from isolated populations with other falcon species.

Adenovirus Infection in Taita Falcons {Falco fasc??nucha) and Hybrid Falcons

Comparison of three animal viruses with circular single-stranded DNA genomes

Multifocal hyperemic nodules and plaques associated with the cloacal mucosa of juvenile alligators (Alligator mississippiensis) at a public aquarium were investigated. Grossly, pale pink to dark red multifocal, circular lesions of varying degrees of severity were identified on the cloacal and, in males, phallus mucosa. Cloacal mucosa biopsies were obtained from 2 of the alligators. These samples were examined histologically and by polymerase chain reaction (PCR) using consensus primers targeting a conserved region of the herpesvirus polymerase gene. Microscopically, the lesions were characterized as submucosal lymphoid follicles with hyperemia and hemorrhage. No inclusion bodies were observed. Minimal to no anisokaryosis was present, and no etiologic agents were identified. Through PCR, a band consistent in size with herpesvirus was observed. Tissues showing similar clinical, histopathologic, and PCR findings were collected from animals at an alligator farm several months later. Sequencing of the PCR amplicon resulted in a 180-base pair sequence that shared 85% sequence identity with tortoise herpesvirus-1.

Lymphoid Follicular Cloacal Inflammation Associated with a Novel Herpesvirus in Juvenile Alligators (Alligator Mississippiensis)

Proventricular dilatation disease (PDD) continues to cause morbidity and mortality among companion and aviary birds. Field observations have been used to suggest that the etiologic agent of PDD can be spread through horizontally and vertically. To evaluate issues related to the natural transmission of the PDD agent, breeding pairs of cockatiels in which at least one individual of each pair was histologically positive for PDD were placed in enclosures to facilitate breeding and both the adults and their offspring were followed to determine the rate of transmission in the population. Introduction Proventricular dilatation disease (PDD) is used to describe an inflammatory response characterized by the accumulation of lymphocytes and plasma cells in the central and peripheral nervous systems, especially the nerves that supply the muscles in the proventriculus and other digestive organs including crop, ventriculus and small intestine. Central nervous system signs associated with PDD, which may occur in addition to or independent of gastrointestinal signs, may include ataxia, abnormal head movements, seizures and proprioceptive or motor deficits. 1 The most common clinical signs of PDD include depression, weight loss (with or without decreased appetite), constant or intermittent regurgitation, and/or passage of undigested food in the feces indicating a malabsorptive or maldigestive disorder. 1 This disease was first discussed in the late 1970's in birds imported into the United States and Germany. 1,2 Subsequently, a PDD epornitic has been occurring in psittacine birds in North America and Europe, probably as a result of the widespread importation and shipment of birds to satisfy the demands of the pet trade. There is no reference to spontaneous disease in free-ranging psittacine birds; however, they should be considered psittacine or non-psittacine birds susceptible. Given the severe nature of PDD and its potential to affect a wide range of bird species, the importation of psittacine birds or their eggs into any region with indigenous Psittaciformes must be considered extremely risky. Etiology of PDD Since its initial description in the late 1970's, multiple etiologies have been proposed for PDD; however, none have been proven to be the etiologic agent.1-6 Adenovirus-like particles were demonstrated within intranuclear inclusion bodies in one affected bird. Paramyxovirus-like viral particles were demonstrated within inclusion bodies located in the neural cells of the spinal cord and in visceral nerve ganglia of another bird. Similar inclusion bodies have been described in the nerves of pigeons with paramyxovirus infections.2 Birds with PDD have been shown to lack detectable levels of antibodies to paramyxovirus (serotypes 1, 2, 3, 4, 6 and 7), Pacheco's disease virus (an avian

Epizootiology of Proventricular Dilatation Disease in Breeding Cockatiels

Abstract A 13-year-old female double yellow-headed Amazon parrot (Amazona ochrocephala oratrix) was examined for respiratory distress and partial anorexia. Radiographs, ultrasonography, and computed tomography revealed a soft-tissue opacity in the right cranial coelom with a necrotic or fluid-filled center. Endoscopy was used to visualize the mass, collect diagnostic samples, and treat the patient by cyst ablation and fistula formation. The symptoms returned within weeks after each treatment, and the bird died 36 days after initial presentation. Gross and histopathologic examination revealed the mass was a hemangiosarcoma that was attached to the right internal carotid artery.

Interclavicular Hemangiosarcoma in a Double Yellow-headed Amazon Parrot (Amazona ochrocephala oratrix)

Ten veterinary pathologists at 1 veterinary institution independently assigned histologic grades to the same 60 canine cutaneous mast cell tumors (MCTs). There was significant variation among pathologists in grading the MCTs (P < 0.001). The probability of assigning a low grade was significantly higher for the pathologists in this study who use a published reference for histologic grading of canine cutaneous MCTs that allows subcutaneous MCTs or MCTs with mitotic figures to be included in the low-grade category (P < 0.0001 and P < 0.0001, respectively).

Variation among Pathologists in Histologic Grading of Canine Cutaneous Mast Cell Tumors

Ten veterinary pathologists at 1 veterinary institution independently assigned histologic grades to the same 60 canine cutaneous mast cell tumors (MCTs). There was significant variation among pathologists in grading the MCTs (P , 0.001). The probability of assigning a low grade was significantly higher for the pathologists in this study who use a published reference for histologic grading of canine cutaneous MCTs that allows subcutaneous MCTs or MCTs with mitotic figures to be included in the low-grade category ( , 0.0001 and P , 0.0001, respectively). 10 These tumors vary widely in their behavior from nearly benign to highly invasive and meta- static. It has been recognized for more than 30 years that histologic grading is prognostic for the behavior of canine cutaneous MCTs. 2,4,7 The 2 most widely recognized grading systems classify MCTs into 3 grades based on histologic characteristics that include: cellularity, cell morphology, in- vasiveness, mitotic activity, and stromal reaction. 2,7 Both grading systems correlate with the survival rate of canine patients with MCT. Well-differentiated, low-grade (Patnaik Grade I, Bostock Grade 3) MCTs are generally benign in behavior and are usually cured by surgical excision. Poorly differentiated, high-grade (Patnaik Grade III, Bostock Grade 1) MCTs are generally locally invasive, more likely to me- tastasize, and associated with a poor survival rate. The his- tologic appearances and clinical courses of intermediate- grade MCTs range between those of high- and low-grade MCTs.

BRIEF COMMUNICATIONS Variation among pathologists in histologic grading of canine cutaneous mast cell tumors

A reproducible, experimental model of columnaris disease was developed to study the pathogenesis of cutaneous disease associated with Flavobacterium columnare infection in koi (Cyprinus carpio). In experimental infections, lesions were usually restricted to skin and fins; gill necrosis was not a consistent finding. Cytologic and histopathologic examinations provided a presumptive diagnosis of columnaris disease. Specific detection of F. columnare was done using the polymerase chain reaction and DNA in situ hybridization (ISH). Polymerase chain reaction allowed the detection of F. columnare in fresh biological material and in formalin-fixed, paraffin-embedded tissues. The DNA ISH technique allowed the identification and localization of F. columnare in formalin-fixed, paraffin-embedded tissues. Using these molecular techniques, F. columnare was readily detected in skin specimens from infected fish; however, the bacterium was infrequently detected in specimens of liver, kidney, and spleen. These observations suggest that columnaris disease generally presents as a cutaneous disease that is unassociated with systemic infection in koi. Hematologic studies indicated that most infected koi developed microcytic, normochromic, nonregenerative anemia and leukopenia characterized by lymphopenia, mild neutrophilia, and monocytosis. Biochemical changes in diseased fish included significant hyperglycemia, hyponatremia, and hypochloridemia.

Development and Evaluation of an Experimental Model of Cutaneous Columnaris Disease in Koi Cyprinus Carpio

Varanid herpesvirus 1: a novel herpesvirus associated with proliferative stomatitis in green tree monitors (Varanus prasinus).

Abstract A juvenile Meyer's parrot (Poicephalus meyeri) was presented for acute depression and crop stasis and died. On histopathologic examination, intranuclear inclusion bodies were seen in the liver, spleen, proventriculus, and intestinal mucosa. DNA in situ hybridization of tissues was positive for adenovirus and negative for herpesvirus, polyomavirus, and circovirus. Degenerate (polymerase chain reaction [PCR]) primers targeting a conserved region of adenovirus DNA–dependent DNA polymerase were used to amplify and sequence a product from paraffin-embedded tissue. This is the first sequence information available for a psittacine adenovirus. Phylogenetic and comparative sequence analysis indicated that this virus is a member of the genus Aviadenovirus and is here termed Meyer's parrot adenovirus 1. Consensus nested PCR and sequencing can be used to rapidly identify novel adenoviruses, and DNA in situ hybridization may be used for rapid localization of novel viruses in tissues. Identification of adenoviral types and species will provide useful diagnostic, prognostic, and epidemiologic information for clinicians.

Identification and Initial Characterization of an Adenovirus Associated With Fatal Hepatic and Lymphoid Necrosis in a Meyer's Parrot (Poicephalus meyeri)

Abstract Three taita falcon (Falco fasciinucha) nestlings and 3 cohoused hybrid falcon (F rusticolus × F peregrinus) nestlings died after showing lethargy and anorexia for 4–5 days. Major lesions in the falcons were necrotizing hepatitis, splenitis, and lymphoplasmacytic nephritis. One hybrid falcon also had a heterophilic nephritis. Intranuclear inclusion bodies were present in the hepatocytes of the taita falcons and in the renal tubular epithelial cells of 1 hybrid falcon. Adenoviral particles were found in the cloacal content of 2 taita falcons. DNA in situ hybridization revealed aviadenoviral nucleic acid within the nuclei of hepatocytes of a taita falcon and a hybrid falcon and in the tubular epithelial cells of a hybrid falcon. Aviadenoviral DNA was amplified by polymerase chain reaction in the liver of taita falcons and hybrid falcons. The death of these birds was attributed to the aviadenovirus infection; however, the source of the virus was not determined. Predisposing factors for the outbreak of the viral infection in these falcons may have included transport stress, lack of quarantine measures, and cohousing of falcon species originating from isolated populations with other falcon species.

Adenovirus Infection in Taita Falcons (Falco fasciinucha) and Hybrid Falcons (Falco rusticolus × Falco peregrinus)

Cancer is relatively common in birds, and ofthe 27 orders of the Aves class, psittaciformbirds have the highest reported incidence of neoplasia. In fact, neoplasms are more commonly reported in the budgerigar than in any other vertebrate animal. Despite the fact that cancer is a common problem in companion birds, treatment for avian patients with neoplasms has lagged far behind the technology available for other companion animals. This paper will focus on a few of the most common types of cancer that affect companion parrots, diagnosis, and the medical and surgical treatment options available. Neoplasms of the integumentary system are common in psittacine birds and reportedly account for anywhere from 12 to 70% of all avian neoplasms. Lipomas and fi brosarcomas are the most frequently observed. Lipomas (benign fatty tumors) are the most common neoplasm of companion birds, with a reported incidence of 10% to 40% in budgerigars. Diagnosis is usually easily made from aspiration of the mass. Lipomas can be large and may interfere with normal locomotion and breeding. Surgical excision is often necessary if the tumor is causing clinical problems. Lipomas can be highly vascular in birds and hemostasis is of the utmost importance. The Cavitron Ultrasonic Surgical Aspirator (CUSA System 200, Valleylab, Boulder, CO, USA) has been shown to have a wide variety of surgical applications in humans, dogs and other mammals. The CUSA is an ultrasonically powered aspirator that selectively fragments and aspirates parenchymal tissue while sparing vascular or ductal structures. The CUSA’s potential applications in avian species is just beginning to be explored at UGA. Preliminary evaluation suggests that when used to resect lipomas in avian patients, the CUSA may provide decreased tissue necrosis and hemorrhage, increased visibility, and shortened operating and recovery times in comparison to more conventional surgical methods such as cold knife, bipolar cautery and CO2 laser. Other integumentary neoplasms seen in birds include lymphosarcoma, fi brosarcoma, and squamous cell carcinoma, to name some of the most common. Diagnosis is usually via surgical biopsy. Treatment may involve radiation therapy, chemotherapy, surgical removal, or other modalities. For most humans and mammalian companion animals, radiation therapy is an important part of treatment for many of these neoplasms. An understanding of the tolerance of normal tissues included in the treatment field is essential in radiation treatment planning for any animal. Dose response and normal tissue injury have been evaluated extensively in many companion animals. However, there have been no controlled studies of external beam radiation therapy in any avian species. Currently used dosages for external beam megavoltage radiation therapy in birds have been extrapolated from mammalian patients and often appear to provide...

Abstract We compared the effects of dipotassium ethylenediaminetetraacetic acid (EDTA) and lithium heparin on hematologic values of green iguanas (Iguana iguana). Thirty-two privately owned sibling iguanas had blood drawn, and the sample was divided into three components: an EDTA tube, a heparin tube, and a nonanticoagulated blood smear. A full reptilian complete blood count was performed on each anticoagulated sample, and white blood cell (WBC) and leukocyte differential counts were performed on the whole-blood smears. Heparin and EDTA samples differed significantly in absolute values of thrombocytes, WBC, heterophils, and monocytes. The EDTA had no significant effect on the packed cell volume or plasma protein values, and the white blood count and differential counts produced with EDTA were more similar to those of the nonanticoagulated blood smear than were the counts produced with heparin.

COMPARISON OF THE EFFECT OF DIPOTASSIUM ETHYLENEDIAMINETETRAACETIC ACID AND LITHIUM HEPARIN ON HEMATOLOGIC VALUES IN THE GREEN IGUANA (IGUANA IGUANA)

Abstract The Cavitron Ultrasonic Surgical Aspirator (CUSA) is an ultrasonically powered aspirator that selectively fragments and aspirates parenchymal tissue while sparing vascular and ductal structures. We evaluated the CUSA and the CO2 laser for removal of lipomatous masses in 16 budgerigars (Melopsittacus undulatus). With both methods, the level of hemorrhage and length of operating time was acceptable. However, the CUSA, which irrigates and aspirates continuously, provided superior visibility of the surgical field. Results of this study indicate that either the CO2 laser or the CUSA may be safe and effective in removing lipomas from birds.

Comparison of the Cavitron Ultrasonic Surgical Aspirator and CO2 Laser for Lipoma Resection in Budgerigars (Melopsittacus undulatus)

ABSTRACT Chronic monocytic leukemia with infiltration to the liver, small intestine, kidneys, and subconjunctival tissues was diagnosed in a 5-year-old, male, captive-bred inland bearded dragon, Pogona vitticeps, that presented with lethargy, weight loss, and dehydration. Characterization of the neoplastic cells was aided by the use of cytochemical and immunohistochemical techniques.

Chronic Monocytic Leukemia in an Inland Bearded Dragon, Pogona vitticeps

Identification of ophidian paramyxovirus (OPMV) nucleic acid was accomplished in 11 of 14 snakes by a reverse transcriptase–polymerase chain reaction (RT-PCR) assay that detected a 153-bp region of the OPMV genome in total RNA extracted from paraffin-embedded tissues and cell culture. The RT-PCR protocol amplified a portion of the OPMV RNA genome, producing a 153-bp complementary DNA (cDNA) product from both fresh and paraffin-embedded tissue samples. In addition, cDNA:RNA in situ hybridization localized OPMV in formalin-fixed, paraffin-embedded tissue specimens to specific tissues and cells. This latter technique increased the degree of specificity with which a diagnosis of OPMV could be made.

Molecular Diagnosis of Paramyxovirus Infection in Snakes Using Reverse Transcriptase–Polymerase Chain Reaction and Complementary Deoxyribonucleic Acid:Ribonucleic Acid in Situ Hybridization

Hematologic data are used routinely in the health care of humans and domestic mammals. Similar data for fish are largely fragmentary or have not been collected.

The primary purpose of this study was to determine hematologic reference intervals for koi, an ornamental strain of the common carp (Cyprinus carpio). Secondarily, the morphology, cytochemical reactions, and ultrastructure of koi blood cells were characterized.

METHODS
A CBC was performed manually on heparin-anticoagulated blood specimens using Natt and Herrick's diluent and a Neubauer-ruled hemacytometer. Leukocyte differential counts were done on Wright-Leishman- and Diff-Quik-stained blood smears. Cytochemical reactions of koi leukocytes were determined using commercial kits. Transmission electron microscopy was performed to characterize the ultrastructural features of koi blood cells.

RESULTS
Hematologic reference intervals were established for healthy koi for PCV (30-34%), hemoglobin concentration (6.3-7.6 g/dL), RBC count (1.7-1.9 X 10(6)/ microL), WBC count (19.8-28.1 X 10(3)/ microL), RBC indices, and differential leukocyte counts. Lymphocytes were the predominant leukocyte (accounting for up to 80% of all leukocytes), whereas eosinophils were rare. Basophils were positive with PAS staining. Naphthol AS-D chloroacetate esterase activity was observed only in eosinophils. alpha-Naphthyl butyrate esterase and beta-glucuronidase activities were positive in monocytes. Some lymphocytes were reactive for alpha-naphthyl butyrate esterase and acid phosphatase activity. Ultrastructurally, leukocytes, erythrocytes, and thrombocytes were identified on the basis of cytoplasmic organelles and granule appearance.

Hematologic reference intervals and knowledge of the cytochemical reactions and ultrastructural characteristics of koi leukocytes will help standardize hematologic studies in this species.

Hematologic reference intervals for koi (Cyprinus carpio), including blood cell morphology, cytochemistry, and ultrastructure.

In March 2000, an approximately 30-yr-old, male coastal mountain kingsnake (Lampropeltis zonata multifasciata) presented with disequilibrium and unresponsiveness to stimuli that ultimately lead to euthanasia. Histologically, there were foci of gliosis primarily within the caudal cerebrum, brainstem, and cervical spinal cord. Several glial cells and endothelial cells contained magenta, intranuclear inclusion bodies. Electron microscopy of the inclusions revealed paracrystalline arrays of 79–82 nm, viral-like particles. DNA in situ hybridization of sections of formalin-fixed brain using a mixture of two digoxigenin-end-labeled, adenovirus specific, oligonucleotide probes at low and high stringency was positive for adenovirus.

Degenerative Encephalopathy in a Coastal Mountain Kingsnake (Lampropeltis zonata multifasciata) due to Adenoviral-like Infection

Duncan and Prasse's Veterinary Laboratory Medicine: Clinical Pathology, 5th Edition - Libros de Medicina - Medicina y Cirugia Animal - 56,70

Duncan and Prasse's Veterinary Laboratory Medicine: Clinical Pathology, 5th Edition

Branson W. Ritchie, DVM, PhD, Diplomate ABVP Christopher R. Gregory, DVM, PhD Kenneth S. Latimer, DVM, PhD, Diplomate ACVP Raymond P. Campagnoli, MS Denise Pesti, MS University of Georgia, College of Veterinary Medicine Athens, GA Paula Ciembor, DVM, PhD Director, Molecular Testing Infectious Diseases Laboratory University of Georgia, College of Veterinary Medicine Athens, GA Madeline Rae, DVM, MS, Diplomate ABVP Amazon Veterinary Diagnostics Salem, OR Holly H. Reed, DVM Point Defiance Zoo & Aquarium Point Defiance, WA Brian L. Speer, DVM Oakley Veterinary Hospital Oakley, CA Brian G. Loudis, DVM, Diplomate ABVP Carlsbad, CA H.L. Shivaprasad, BVSc, PhD, Diplomate ACPV California Animal Health and Food Safety Lab System University of California Davis, CA Michael M. Garner, DVM, Diplomate ACVP

Documentation of a PBFD virus Variant and its Importance to PBFD Testing

A 4-year-old Labrador Retriever was referred for evaluation of 2 ulcerative nodular cutaneous lesions. One lesion was located on the medial aspect of the right carpus; the other was located on the medial aspect of the left tarsus. The dog had spent its entire life in the southeastern part of the United States and approximately half of its time outdoors with free access to a nearby lake. Histologic examination of full-thickness wedge biopsy specimens from both lesions revealed severe, multifocal, puruloeosinophilic to pyogranulomatous deep dermatitis with intralesional filamentous structures, fibroplasia, and neovascularization. Examination of sections stained with Gomori methenamine silver stain revealed a moderate number of wide, bulbous, irregularly septate, branching hyphae. Results of an immunodiffusion test and an ELISA for anti-Pythium insidiosum antibodies were positive. Amputation was eliminated as a treatment option because lesions involved 2 limbs. Long-term systemic antifungal treatment was also rejected because of the cost, lack of therapeutic effect in many cases, and potential for adverse effects. The dog was treated with 2 doses of an anti-P insidiosum vaccine administered 2 weeks apart. One month later, the lesions were nearly completely healed, and values obtained via the immunodiffusion test and ELISA had decreased. Results of the immunodiffusion test and ELISA were negative 1 year later, and the dog had not had any recurrences.

Immunotherapy for treatment of multicentric cutaneous pythiosis in a dog.

Abstract SUMMARY. The purpose of this experiment was to characterize a lesion of the rhamphotheca associated with tryptophan (TRP) deficiency, search for other histological abnormalities, and determine whether bird size and housing conditions are contributing factors to these lesions. Day-old broiler chicks (Ross × Ross 308) were placed in either floor pens with fresh pine shavings or Petersime battery brooders with two pens of 10 chicks each per treatment. Broiler chicks from 0 to 21 days of age were fed adequate (0.24%) and deficient (0.09%) levels of TRP in diets based on corn, corn gluten meal, and gelatin. Separate groups of control chicks were pair fed daily with the deficient chicks. Deficient chicks grew less efficiently than did the pair-fed controls. Upon gross examination, a lesion of the maxillary rhamphotheca in the vicinity of the nares was observed in 61% of TRP-deficient birds housed in the battery and 13% of the birds housed in floor pens. A similar gross lesion was only observed in one control bird. These lesions were located along the upper portion of the beak between the nares and appeared as a crusty or scab-like area on gross examination, composed of detritus, heterophils, and plasma protein. Inflammation occasionally was observed at the dermoepidermal junction. The incidence of lesions was reduced in floor pens compared to battery brooders, but similarly sized birds did not exhibit the lesion. The number of lesions seen grossly and histologically in TRP-deficient birds, as compared to control birds, supports the hypothesis that TRP deficiency is the primary cause of these lesions around the nares of broilers. Secondary environmental factors, perhaps coprophagy, also influence the incidence of the lesion.

Pathology and Histology of Dietary Tryptophan Deficiency in Broiler Chicks

Adenovirus infections are documented in at least 12 different species of reptiles. In contrast to their mammalian and avian counterparts reptilian adenoviruses are not well characterized as to their pathogenic potential and their ability to cause primary disease. In the diagnostic setting, fresh tissues are often not available for virus isolation, and the confirmation of reptilian adenovirus infections is dependent largely upon electron microscopy for the identification of intranuclear viral inclusions associated with histopathologic changes. The diagnosis of adenovirus infection in 2 different species of snake was confirmed by the application of DNA in situ hybridization. Using an aviadenovirus specific oligoprobe, adenoviral DNA was observed in the nuclei of hepatocytes, Kupffer cells, endothelial cells, and enterocytes. Electron microscopy of the liver confirmed the presence of intranuclear viral particles morphologically consistent with an adenovirus. DNA in situ hybridization on formalin-fixed tissues can serve as a suitable alternative to electron microscopy in the diagnosis of reptilian adenovirus infections. Both affected snakes had other concurrent diseases, suggesting that the adenovirus may not have been the primary pathogen.

Detection and Confirmation of Reptilian Adenovirus Infection by in Situ Hybridization

Abstract An adult finch was presented with a 1-cm mass near the thoracic inlet. Histologically, the mass was diagnosed as a thymoma of lymphocytic type. The clinical signs and histologic findings related to the thymoma are presented. The similarities and differences between thymomas in birds and mammals are discussed briefly.

Hepatic hyaline globules, similar to those reported in some human livers, were observed in liver tissue from an Eclectus parrot (Eclectus roratus). The cytoplasmic inclusions were periodic acid-Schiff positive and diastase resistant and failed to stain by acid-fast or Congo red techniques. Ultrastructurally, the hepatic globules were composed of granular amorphous material with small peripheral striations that extended into the cytoplasm.

Hepatic Hyaline Globules in an Eclectus Parrot (Eclectus Roratus)

Congenital tremors (CT) type A2 is associated with porcine circovirus (PCV) and deficient and abnormal myelin. The aim of this study was to determine the tissue distribution and genetic type of PCV in 1–2-day-old pigs with naturally occurring CT type A2 using in situ hybridization, polymerase chain reaction (PCR), and indirect fluorescent antibody tests on frozen tissue sections. CT-affected and clinically normal pigs were selected from 4 farms in the midwestern USA that were undergoing outbreaks of CT type A2. All CT and most normal pigs were infected with PCV. PCV was widely distributed in tissues of infected pigs and was most common in tissues of the central nervous system and liver. In all infected pigs, there were more PCV-infected cells in brain and spinal cord than in nonneural tissues. CT pigs had many more PCV-infected cells in the brain and spinal cord than did clinically normal pigs because of a more diffuse distribution and a larger proportion of infected cells. The cells most commonly infected with PCV in brain and spinal cord were large neurons. In nonneural tissues, macrophages were the most frequent cell type infected. PCR analysis demonstrated only PCV type 2 and not PCV type 1 in all PCV-infected pigs on all 4 farms.

Tissue Distribution and Genetic Typing of Porcine Circoviruses in Pigs with Naturally Occurring Congenital Tremors

Eight-week-old BALB/c mice were either sham inoculated (control mice) or were inoculated intraperitoneally (IP) and intranasally (IN) with a single (sPCV mice) or multiple (mPCV mice) doses of porcine circovirus 2 (PCV2). Four control mice and 4 sPCV mice were sacrificed 7, 14, 28, and 42 days postinoculation (PI). All 4 mPCV mice were sacrificed 42 days PI. In addition, 7-day and 14-day pregnant BALB/c mice were either sham inoculated (control mice) or were inoculated IP and IN with a single dose of PCV2. Newborn mice were euthanatized 1, 8, and 15 days after birth. Necropsies were performed on all euthanatized mice and tissues were collected for histopathology, electron microscopy, in situ hybridization, and polymerase chain reaction (PCR). PCV2 replicated in 8-week-old BALB/c mice that were inoculated with PCV2 and caused fetal infection when inoculated into pregnant BALB/c mice at 7 days and 14 days of gestation. PCV was detected by in situ hybridization and PCR in sPCV mice on days 7, 14, 28, and 42 PI; in mPCV mice on day 42 PI; and in newborn mice from mothers inoculated with PCV at 7 days and 14 days of gestation at 1, 8, and 15 days after birth, but not in control mice. No clinical signs or gross lesions were found in sPCV or mPCV mice during the study. Microscopic lesions in sPCV mice and mPCV mice were characterized by expansion of germinal centers in lymphoid organs with large numbers of histiocytic cells and lymphoblasts, apoptosis of histiocytic cells in germinal centers, and mild lymphoid depletion of the paracortex. PCV nucleic acid was detected in the nuclei and cytoplasm of histiocytes and apoptotic cells in germinal centers in lymphoid tissues as well as in the nuclei of hepatocytes in the liver, in the nuclei of renal tubular epithelial cells, and in the cytoplasm of single lymphocytes in the thymus. Congenitally infected mice only had PCV nucleic acid detected in putative Kupffer cells in livers.

Viral Replication and Lesions in BALB/c Mice Experimentally Inoculated with Porcine Circovirus Isolated from a Pig with Postweaning Multisystemic Wasting Disease

Small multifocal lesions of proliferative pododermatitis were observed in an emaciated adult male northern gannet (Morus bassanus). Ultrastructurally, these lesions were associated with numerous virus-like particles with a size and morphology suggestive of Papovaviridae. DNA in situ hybridization with probes for avian polyomaviral and papillomaviral nucleic acid and an immunohistochemical test for the presence of papillomaviral antigen failed to identify this virus further. To our knowledge, papovavirus-like particles have not been recognized previously in this avian species.

Proliferative Pododermatitis Associated with Virus-like Particles in a Northern Gannet

This presentation describes two types of adverse reactions to polyomavirus vaccination. These reactions included the formation of proliferative masses at the sites of intradermal or intramuscular that did not resolve spontaneously (11 birds, 0.022% overall incidence) and the development of sepsis due to a contaminated nursery environment or improper hygiene related to the vaccination procedure (6 birds).

Adverse Reactions Associated with Avian Polyomavirus Vaccination

Abstract Confirmed or suspected circoviral infection recently has been reported in several nonpsittacine birds. An overview of clinical signs of disease, gross lesions, and microscopic pathology of circoviral infections reported in nonpsittacine birds is presented. In addition, current methods of disease diagnosis, management, and prevention are discussed.

A boa constrictor was submitted for postmortem evaluation. At necropsy, there were no substantial lesions except in the liver. Light microscopy revealed severe multifocal to coalescing coagulative necrotic hepatitis, with basophilic and eosinophilic intranuclear inclusions in hepatocytes within the necrotic foci. The histopathological findings suggested a viral hepatitis. An adenoviral infection was diagnosed by means of transmission electronic microscopy and in situ hybridization techniques.

Pelger–Huët Anomaly in Australian Shepherds: 87 Cases (1991–1997)

This paper describes the signs, clinical pathology, and postmortem findings in 14 young African grey parrots (Psittacus erithacus erithacus) that were naturally infected with psittacine beak and feather disease (PBFD) virus (psittacine circovirus). All but two of the parrots had severe leukopenia at clinical presentation. Two other parrots also had severe anemia. All birds died within 3 wk after presentation. Postmortem examination documented liver necrosis in 11 of 14 birds and secondary bacterial or fungal infections in 9 of 14 birds. Tests for Chlamydia psittaci, polyomavirus, and Salmonella sp. were negative. PBFD viral infection could be demonstrated in all birds by polymerase chain reaction. Supporting evidence of PBFD viral infection was gathered by histologic examination of the bursa of Fabricius, electron microscopy, and DNA in situ hybridization. Electron microscopic examination of both the bursa of Fabricius and liver revealed virus particles resembling circovirus. DNA in situ hybridization of six liver tissue samples confirmed the presence of PBFD virus and excluded the presence of avian polyomavirus. Our findings suggest that a specific presentation of peracute PBFD viral infection, characterized by severe leukopenia, anemia, or pancytopenia and liver necrosis in the absence of feather and beak abnormalities, may occur in young African grey parrots.

Severe leukopenia and liver necrosis in young African grey parrots (Psittacus erithacus erithacus) infected with psittacine circovirus.

Four of the most common viral infections affecting psittacine birds have been studied in detail: (1) avian polyomavirus, (2) proventricular dilatation disease (PDD), (3) Pacheco's disease and (4) psittacine beak and feather disease (PBFD). The Psittacine Disease Research Group, University of Georgia, has been actively involved in this research. Proventricular dilatation disease has been reported in more than 50 psittacine species and in species in other families, while PBFD affects over 40 psittacine species. The acute and chronic clinical characteristics of the diseases, pathological features, diagnosis, and transmission prevention and control, including vaccination, are described. The vaccine for avian polyomavirus is safe and effective in captive birds, and, when used in high-risk situations, vaccination against Pacheco's disease (a psittacine herpesvirus) can prevent high mortality. A safe vaccine for PBFD is being evaluated. Specific tests for viral nucleic acid (DNA probe tests) for avian polyomavirus and PBFD virus, and anti-virus antibody assays for avian polyomavirus and Pacheco's disease have been developed which will facilitate the diagnosis and monitoring of disease. The benefits and limitations of screening psittacines for disease are also discussed.

Fifteen pigs from five farms on which there had been a previous clinical and histopathological diagnosis of postweaning multisystemic wasting syndrome (PMWS) were investigated. At necropsy, enlargement of lymph nodes was the most obvious lesion; other lesions were non-collapsed lungs, ulceration of the gastric pars oesophagica, and cranioventral pulmonary consolidation. Microscopical lesions attributable to PMWS were found in lymphoid organs (including lymph nodes, tonsil, Peyer's patches and spleen), liver, kidney and lungs. Varying degrees of lymphocellular depletion, affecting both lymphoid follicles and parafollicular zones, and progressive multifocal to diffuse infiltration of lymphoid tissue by large histiocytic cells were the characteristic lesions. Syncytial cells were seen frequently, especially in lymphoid organs. A prominent finding was the presence of sharply demarcated, spherical, basophilic, cytoplasmic inclusions in histiocytic cells. The lymphoid lesions were suggestive of immunosuppression. Non-lymphoid lesions included interstitial pneumonia, periportal mononuclear inflammatory infiltration of the liver in varying degrees, and interstitial nephritis. Porcine circovirus (PCV) antigen and nucleic acid were regularly found in lymphoid organs, lung, liver and, to a lesser degree, kidney. Target cells for PCV replication included monocyte/macrophage lineage and antigen-presenting cells. To a lesser extent, epithelial cells such as renal tubular, bronchial and bronchiolar cells, endothelial cells, hepatocytes and lymphocytes were also labelled. One pig did not show PCV nucleic acid; sequence differences among different viral isolates are discussed as the probable cause of this lack of labelling by the in-situ hybridization PCV-specific probe.

Pathological, immunohistochemical, and in-situ hybridization studies of natural cases of postweaning multisystemic wasting syndrome (PMWS) in pigs.

A 3 cm diameter mass from the metacarpus of a Puerto Rican Amazon parrot was diagnosed as a granular cell tumour based on light microscopy. The cytoplasmic granules were periodic-acid Schiff positive and diastase resistant. Ultrastructural characteristics of the cells included convoluted nuclei and the presence of numerous cytoplasmic tertiary lysosomes. This is only the second granular cell tumour reported in a bird. We speculate that most granular cell tumours are derived from cells that are engaged in some type of cellular degradative process, creating a similar morphologic appearance, but lacking a uniform histogenesis.

Granular cell tumour in an endangered Puerto Rican Amazon parrot (Amazon vittata ).

Bobcats (Lynx rufus) are the reservoir hosts for Cytauxzoon felis, the causative agent of cytauxzoonosis. Cytauxzoonosis is a highly fatal tickborne blood protozoal disease of domestic and exotic cats. Treatment of clinically affected cats has generally been unrewarding. In our report, 6 of 7 cats had signs of illness and laboratory findings indicative of cytauxzoonosis and were successfully treated with 2 i.m. injections of diminazene aceturate or imidocarb dipropionate (2 mg/kg [0.9 mg/lb] of body weight, each). One cat died after the first injection of diminazene. Additional treatment with isotonic fluids i.v. and heparin s.c. were used as supportive care for dehydration and disseminated intravascular coagulation that were detected by laboratory testing between diminazene or imidocarb treatments. Atropine was effective in recovery and preventing adverse reactions associated with imidocarb treatment of 1 cat.

Administration of diminazene aceturate or imidocarb dipropionate for treatment of cytauxzoonosis in cats.

Beak and feather disease virus and porcine circovirus genomes: intermediates between the geminiviruses and plant circoviruses

A dual natural infection with psittacine beak and feather disease virus and budgerigar fledgling disease virus in a breeding aviary of budgerigars (Melopsittacus undulatus) is described. One-hundred per cent of newly-hatched birds were affected and mortality was high (85%). Most surviving birds had diarrhoea, feather alterations and 30% mortality after a 5- to 10-week period. Necropsies of 1-week-old and 2-month-old birds demonstrated non-specific lesions, but histologically nuclear inclusions suggestive of viral infection (adenovirus, herpesvirus, polyomavirus) and also cytoplasmic inclusions suggestive of beak and feather disease were seen in integument and internal organs. Staining of tissues with viral specific DNA probes for psittacine beak and feather disease virus and for avian polyomavirus demonstrated simultaneous presence of viral DNA from both viruses in some birds. This is the first description of a concurrent outbreak of psittacine beak and feather disease virus and avian polyomavirus infection in a breeding aviary.

A concurrent outbreak of psittacine beak and feather disease virus, and avian polyomavirus infection in budgerigars (Melopsittacus undulatus).

ABSTRACT Blood samples were collected from ten juvenile loggerhead sea turtles, Caretta caretta, from two months to one year of age. The turtles were also weighed and measured at the time of venipuncture. The morphological features and staining characteristics of the blood cells are described as are the hematologic changes noted with age. Presumptive normal hematologic, size and weight values are listed. Presumptive abnormal outliers for each group, based on wounds, non-linear weight gain or lymph dilution are also listed. The data provides additional physiological and morphometric information, with trends noted over time, that may be used to assess health status and aid in conservation and rehabilitation of this species.

Hemogram Values, Morphological Characteristics of Blood Cells and Morphometric Study of Loggerhead Sea Turtles, Caretta Caretta, in the First Year of Life

An adult Moluccan cockatoo (Cacatua moluccensis) was diagnosed with a cystadenocarcinoma in the right axillary region that was treated symptomatically with surgical debulking and periodic drainage. The bird eventually died and a necropsy was performed. The neoplasm extended through the humerus, and small neoplastic foci were seen within the ipsilateral lung parenchyma. Rare groupings of microvilli were observed lining intercellular canalicular lumens on electron microscopy within the axillary tumor. These findings suggest a respiratory neoplasm, although the tissue of origin remained undetermined.

Axillary cystadenocarcinoma in a Moluccan cockatoo (Cacatua moluccensis).

Microsporidia are obligate, intracellular, protozoan parasites of a wide variety of vertebrates and invertebrates. Confirmed reports of microsporidial infection of avian species are few (lovebirds, a parrot, and a group of budgerigar chicks). At slaughter, a 14-mo-old ostrich was found to have small intestinal serosal hemorrhages during postmortem inspection. Histologic examination of the small intestine revealed a chronic lymphoplasmacytic to purulent enteritis with mucosal hyperplasia, muscular hypertrophy, and numerous microsporidia that were located within the superficial enterocytes and the lamina propria. Microsporidia have a ubiquitous distribution in nature and are suspected as possible zoonotic agents.

Colonic adenocarcinoma was diagnosed by surgical biopsy in a domestically raised 3-yr-old male corn snake (Elaphe guttata guttata). The snake presented with a history of constipation. Several masses were palpated in the distal coelomic cavity. On proctoscopy, a nodular firm white mass encircled the distal colon proximal to the cloaca. The histologic diagnosis was transmural mucinous colonic adenocarcinoma with scirrhous reaction. Resection of the affected region alleviated intestinal obstruction for at least 4 mo, after which the snake was lost to follow-up.

Journal of zoo and wildlife medicine : official publication of the American Association of Zoo Veterinarians

Colonic adenocarcinoma in a corn snake (Elaphe guttata guttata).

A Sarcocystis-like organism was associated with encephalitis and myocarditis in an ataxic, emaciated adult male turkey (Meleagris gallopavo) from Gilmer County, West Virginia. Protozoal schizonts and merozoites were associated with areas of inflammation and occasionally necrosis in both the heart and the brain. The organisms divided by endopolygeny and stained positively with anti-Sarcocystis cruzi serum in an immunohistochemical test.

Sarcocystis-associated encephalitis and myocarditis in a wild turkey (Meleagris gallopavo).

Capillaria aerophila, which is found commonly in the respiratory tract of many carnivores,1 has not been reported in raccoons. Capillaria sp. have frequently been described in epithelia of the alimentary tract of raccoons.6,9,10 A recent histopathological survey of Capillaria sp. in alimentary and urinary epithelia of raccoons has revealed a variable prevalence, from a low of 24% in South Carolina to a high of 71% in parts of Pennsylvania.6 The life cycle of Capillaria in raccoons is unknown; therefore, it is difficult to explain this geographic difference. The authors of the survey did not examine the animals’ anal sacs. It appears that capillariasis of raccoons’ anal sacs is common in Oregon, and the sacs get impacted only in isolated cases. This finding may also be true for raccoons in other parts of North America. Further investigations are required to elucidate the extent of infection by Capillaria sp. in the anal sacs of raccoons and to positively identify the species of the nematode. Acknowledgements. I thank Michael Schadt and Sarah Miller for their technical assistance. This project was funded by the Dean’s Office, College of Veterinary Medicine, Oregon State University, Corvallis, Oregon.

Cilia-Associated Respiratory Bacillus Infection and Pneumonia in a Pig

Feather dystrophy associated with circovirus infection in columbiformes

Nine flocks of psittacine birds were examined because of sudden death of neonates. In each flock, cause of death was determined to be polyomavirus infection, by means of DNA testing and in situ hybridization. Contaminated areas of aviaries were cleaned and disinfected, and vaccination programs, using a recently approved inactivated polyomavirus vaccine, were instituted. Use of the vaccine was found to be safe and efficacious.

Use of an inactivated virus vaccine to control polyomavirus outbreaks in nine flocks of psittacine birds.

OBJECTIVE
To determine safety, immunogenicity, and efficacy of an inactivated avian polyomavirus vaccine in nonbudgerigar psittacine birds that varied in age, species, and immunologic status.

ANIMALS
Safety of the vaccine was evaluated in 1,823 psittacines representing more than 80 species. Immunogenicity was evaluated in 285 birds (260 of various Psittaciformes species, 25 chickens). Efficacy was evaluated in 104 birds (78 of various Psittaciformes species, 26 chickens).

Safety was evaluated by vaccinating birds that were determined to be seronegative or seropositive (titer > 1:10) prior to vaccination. Birds were then evaluated for clinically detectable systemic or local reactions for 2 months to 2 years. Immunogenicity was evaluated by testing for virus-neutralizing antibodies, vaccinating each bird twice, and then testing for a significant change in antibody titer. Efficacy was evaluated by vaccinating birds, followed in 2 to 4 weeks by intramuscular or intravenous challenge exposure. After challenge exposure, protection was evaluated by attempting to recover virus from tissues or by observing birds for clinical signs of disease and testing for a significant change in titer.

Avian polyomavirus vaccine is safe, immunogenic, and efficacious for use in multiple species of mature and immature psittacines.

CLINICAL RELEVANCE
Until now, prevention of polyomavirus infection in psittacine birds could only be accomplished through strict isolation to reduce potential exposure to the virus. The USDA-registered inactivated avian polyomavirus vaccine can safely be used to protect vaccinates from infection and control spread of this virus in flocks.

Safety, immunogenicity, and efficacy of an inactivated avian polyomavirus vaccine.

Proventricular dilatation syndrome (PDS) is a fatal disorder of several avian species. The histopathologic lesions of proventricular dilatation syndrome and avian viral serositis, a disease caused by eastern equine encephalomyelitis (EEE) virus, are similar. A study was done of samples from 56 psittacine birds, including 45 birds affected with PDS and 11 birds with no histologic changes associated with PDS, to determine if EEE is the causative agent of PDS. Methods used included DNA in situ hybridization with a 40-base oligomer complementary to a conserved region of the EEE virus genome, reverse-transcriptase-polymerase chain reaction (RT-PCR) with primers complementary to this conserved region, and virus isolation. The presence of EEE virus or EEE- viral RNA was not detected in birds with PDS. Virus-neutralizing titers were measured in the sera of 17 birds to determine if those with PDS had been exposed to EEE virus. Exposure to EEE virus, represented by a positive virus-neutralization titer >8, was observed in the serum of 1 of 13 birds with PDS and in the sera of three of four birds that tested negative for PDS. From the results of this study, we conclude that EEE virus is not the causative agent of PDS.

Investigations of Eastern Equine Encephalomyelitis Virus as the Causative Agent of Psittacine Proventricular Dilatation Syndrome

A 14-month-old crossbred goat was presented for slaughter at a federally inspected slaughter plant. On antemortem inspection, the goat was thin with no other abnormalities. Gross findings on postmortem examination included splenic enlargement (5 x normal), green proliferative tissue extending from the pericardial surface, fibrous epicardial tags, and variable enlargement of all lymph nodes with inguinal lymph node hemorrhage and greenish discoloration of a purulent exudate. The liver was discarded before inspection. The kidneys appeared normal grossly. Samples of kidney, lung, spleen, heart, muscle, pericardium, bone marrow (sternum), and lymph nodes were fixed in 10% neutral buffered formalin and shipped to the US Department of Agriculture, Pathology Division, Athens, Georgia, for histopathologic examination. Tissues were routinely processed, embedded in paraffin, sectioned at 4 μm, and stained with hematoxylin and eosin. Formalin-fixed lymph node, spleen, and pericardial tissue were further processed by sectioning into 2-3-mm cubes, rinsing for 1 hour in distilled deionized water, and postfixing in picric acid fixative Figure 1. Lymph node; goat. Granules within promyelocytes (2% glutaraldehyde, 2% paraformaldehyde, 0.2% picric acid (arrow). Bar = 10 μm. in 0.1 M cacodylate buffer). These tissues were then routinely processed and sectioned for transmission electron microscells and promyelocytes predominating) and increased maccopy. rophage activity. Significant histologic findings were limited to the lymph Transmission electron microscopic examination of perinodes, pericardial tissue, pleural adipose tissue, spleen, and cardial tissue revealed a consistent population of neoplastic bone marrow. Lymph nodes exhibited variable replacement cells with granules typical of primary (electron dense, large, of normal architecture and invasion of perinodal fat by large oval to elongate), secondary (more granular center with no cells with hyperchromatic nuclei with coarse stippled or veelectron dense core), and tertiary (bacilliform) granules of sicular chromatin and, rarely, a small eosinophilic nucleolus. neutrophils. 6 Nuclei were indicative of juvenile and myeloThese cells had scant to moderate lightly basophilic cytocyte levels of differentiation with dispersed chromatin, scant plasm with variably distinct borders. There were 1 or 2 michromocenters, and primitive nucleoli (Fig. 2). Occasional totic figures per 40 x field of view. Admixed with these cells mature eosinophils had large granules containing central were cells with round to band-shaped nuclei with marginated crystalloids (Fig. 3). chromatin and 1 or 2 darkly basophilic chromocenters. These cells also had moderate to abundant homogeneous eosinophilic cytoplasm with distinct eosinophilic granules (Fig. 1). Smaller numbers of mature neutrophils and occasional eosinophils were admixed with these cells. Prominent single cell necrosis and scattered, occasionally confluent areas of hemorrhage with necrosis were observed. Pericardial tissue (adipose) and pleural adipose tissue were similarly infiltrated and expanded. The spleen was markedly congested with marked extramedullary hematopoiesis (megakaryocytes, nucleated red blood cells). There were rare myelocytes or juvenile granulocytes within sinuses. The bone marrow was markedly hypercellular with granulocytic hyperplasia (blast

Multiple, firm, white, 0.5- to 2-cm dermal nodules and three discrete 0.5- to 1-cm pulmonary masses were discovered in a hen carcass at slaughter. Microscopic examination of both dermal and pulmonary tumours revealed solid sheets of individual cells with central round nuclei and granular to vacuolated cytoplasm. Both toluidine blue and Giemsa stains revealed numerous cells with metachromatic cytoplasmic granules. Dermal tumours contained both collagen degeneration and infiltrates of eosinophils. Ultrastructural examination of tumour cells confirmed the presence of typical avian mast cell granules.

Surgery or cryosurgery is one of the most common treatments for squamous cell carcinoma (Kwa and others 1992, Withrow and Madewell 1996). However, in the flock studied the location of the tumour on the eyelid rendered this type of treatment unsuitable. Bovine squamous cell carcinoma are responsive to immunotherapy, which results in the complete or partial regression of the tumours in the majority of cases (Spradbrow and others 1977). However, the application of immunotherapy to the condition in sheep has so far proved negative, and has resulted in the enhancement of tumour growth and -an increased risk of metastasis (Jun 1978, Jun and others 1979, Swan and others 1983). Chemotherapy with cyclophosphamide (200 mg weekly for 10 weeks) induced the partial or complete regression of the early lesions in a flock of sheep (Jun and Johnson 1979); the treatment was subsequently recommended for all the sheep in the flock with early lesions, but owing to the cost, the owner decided not to apply it. The clinical and pathological characteristics of the outbreak of squamous cell carcinoma described here suggest that the breed of sheep, its lack of skin pigmentation, the farm's southern latitude, and factors related to the type of farming played a decisive role in the development of squamous cell carcinoma in these sheep.

First report of post-weaning multisystemic wasting syndrome in pigs in Spain

Cloacal and oral papillomas from 27 psittacine birds of various species were examined for the presence of parrot papillomavirus by DNA in situ hybridization, DNA in situ polymerase chain reaction, and nested polymerase chain reaction. Parrot papillomavirus was detected in one oral papilloma from an African grey parrot by all three techniques. In addition, rare basophilic intranuclear inclusions were observed by light microscopy in tissue sections of the oral papilloma from this parrot. The remaining lesions were negative for parrot papillomavirus DNA. This study suggests that parrot papillomavirus may be involved in the development of papillomas in African grey parrots, but apparently is not responsible for development of similar lesions in unrelated species of psittacine birds.

Investigation of parrot papillomavirus in cloacal and oral papillomas of psittacine birds.

Disseminated mycobacteriosis was diagnosed in a 4-year-old, castrated male Domestic Shorthair cat following the observation of one to three retractile, non-staining bacilli in neutrophils and monocytes on a Wright-Leishman-stained blood smear Organisms were bright red following acid-fast staining by Kinyoun's technique. The cat had a history of progressive weight loss, anemia, fever, and sporadic vomiting after eating. In addition to blood smears, mycobacteria also were observed in bone marrow aspirates. During necropsy, multiple small white nodules were observed in the spleen and liver. An enlarged sternal lymph node and ascites also were present. In histologic sections, mycobacteria were observed in granulomas within the lungs, liver, spleen, colon, mesenteric and sternal lymph nodes, omentum, and kidney. Mycobacterium avium complex was isolated from cultures of liver, spleen, lung, and kidney. Occult feline leukemia virus infection, detected by immunofluorescent testing of bone marrow aspirates, may have predisposed this cat to bacterial infection. The serum ELISA test for group-specific feline leukemia virus antigen was negative.

Disseminated Mycobacterium avium complex infection in a cat: presumptive diagnosis by blood smear examination.

Three DNA oligonucleotide probes designated FN-23, FN-48, and FN-96 were evaluated for the diagnosis of aviadenovirus infections by DNA in situ hybridization. Paraffin-embedded tissues were obtained from birds with confirmed adenovirus infection, birds with putative adenovirus infections, and birds with intranuclear inclusions caused by herpesvirus and polyomavirus. In birds with confirmed adenovirus infection, probes FN-23 and FN-96 identified 78% and 72% of diseased individuals, respectively. Only probe FN-48 detected chickens with group II adenovirus infection. In birds with putative adenovirus infection, the DNA probes confirmed aviadenovirus infections in 76% of the population. Probes FN-23, FN-96, and FN-48 detected 85%, 74%, and 18% of adenovirus-infected birds, respectively. None of the DNA probes cross-hybridized with tissues from polyomavirus-infected psittaciform birds or with tissues from a chicken with infectious laryngotracheitis. In contrast, probe FN-23 did cross-hybridize to herpesvirus-infected tissues from two of eight psittaciform birds with Pacheco's parrot disease. Probes FN-48 and FN-96 did not react with these tissues.

Diagnosis of avian adenovirus infections using DNA in situ hybridization.

An adult female canebrake rattlesnake (Crotalus horridus atricaudatus) at Zoo Atlanta (Atlanta, Georgia, USA) had a subcutaneous mass on the left lateral abdomen. Microscopically, the tumor contained a pleomorphic population of cells with abundant intracytoplasmic brown to gold nonrefractile pigment (chromatophores), large stellate cells resembling neurons, and small stellate cells whose cytoplasmic processes formed a fibrillar matrix. The pigment stained black with the Fontana-Masson technique and was positive with the periodic acid-Schiff technique (prior to and after diastase treatment). Neuron-specific enolase was detected in the large stellate cells using an immunohistochemical staining technique. In addition, glial fibrillary acidic and S-100 proteins were detected in the chromatophores with immunohistochemical staining. The smaller stellate cells were strongly S-100 positive. Ultrastructurally, chromatophores contained intracytoplasmic structures composed of concentric lamellar membranes bordered by a triple-layer outer membrane. The morphology of these structures was compatible with pterinosomes. Three fluorescent pigments were isolated from the neoplasm by one-dimensional chromatography and characterized by spectrophotometry and spectrofluorometry.

Malignant chromatophoroma in a canebrake rattlesnake (Crotalus horridus atricaudatus).

Histologic sections of crop tissue were evaluated for the presence of lymphoplasmacytic infiltrates within mesenteric ganglia. All birds with proventricular dilatation syndrome that had lymphoplasmacytic infiltrates in crop ganglia had similar infiltrates in the proventricular and/or ventricular ganglia. False-negative crop biopsy results occurred approximately 24% of the time. More invasive procedures, such as proventricular or ventricular biopsy, may be necessary if the crop biopsy is nondiagnostic in a bird with clinical signs of proventricular dilatation syndrome.

Histologic Evaluation of the Crop for Diagnosis of Proventricular Dilatation Syndrome in Psittacine Birds

Lymphoma and leukemic blood picture in an emu (Dromaius novaehollandiae).

Eastern equine encephalomyelitis (EEE) virus was detected in infected formalin-fixed horse and emu tissues and in infected chicken embryo fibroblasts. Results of in situ hybridization using a digoxigenin-labeled 40-base DNA probe complementary to a conserved region of the EEE virus RNA compared favorably with results of both virus isolation and serum neutralization tests. This technique may be useful for diagnosis of EEE virus infection in various animal species, especially when fresh tissues are not available for analysis, and also will provide a means for studying the involvement of alphaviruses in pathogenesis studies.

Detection of Eastern Equine Encephalomyelitis Virus RNA in Formalin-Fixed, Paraffin-Embedded Tissues using DNA in Situ Hybridization

An inactivated avian polyomavirus vaccine is safe and immunogenic in various Psittaciformes.

The objectives of the present study were to examine proventriculi of broiler chicks for lesions, and to classify and record the incidence of these lesions. Deep non-purulent necrotizing proventriculitis (accompanied by adenoepithelial hypertrophy and hyperplasia) was the most common (109/220 = 49.5%) light microscopic diagnosis in the proventriculi examined. Degenerating and necrotic alveolar secretory cells had amorphous, granular or vacuolated cytoplasm. Nuclei usually were either pyknotic, karyorrhectic or karyolytic; however, fewer attached or sloughed cells had swollen nuclei with marginated chromatin and clear centres. Basophilic inclusion bodies were never seen. In five cases examined ultrastructurally, hexagonal virus particles were found in intact nuclei (average size = 68.9 nm, n = 89), associated with unbound condensed chromatin, and within vacuolated spaces in the cytoplasm (average size = 62.3 nm, n = 109). DNA in situ hybridization failed to detect adenovirus or polyomavirus nucleic acids. The presence of intralesional virus suggests that a causal relationship might exist between the virus and the proventricular lesions.

Necropsy tissues were examined from an adult wild-caught Ducorps cockatoo (Cacatua ducorpsii) with progressive neurologic signs. Of the tissue specimens selected for histologic evaluation, only the brain contained rare amphophilic, glassy intranuclear inclusions within astrocytes and some neurons. Astrocyte and neuronal degeneration and necrosis also were observed. Scattered astrocytes, with and without discernable inclusions, contained avian polyomavirus (APV) nucleic acid, as determined by DNA in situ hybridization. In addition, endothelial cells and intravascular leukocytes contained psittacine beak and feather disease viral nucleic acid, as determined by DNA in situ hybridization, indicating dual viral infection. Electron microscopic examination of formalin-fixed brain tissue revealed typical intranuclear APV particles in some astrocytes. Encephalopathy ultimately was attributed to APV infection.

Polyomavirus Encephalopathy in a Ducorps Cockatoo (Cacatua Ducorpsii) with Psittacine Beak and Feather Disease

populations of bacilli. Various numbers of rod-shaped bacteria were present in the sinusoids of the liver. Lymphocytic depletion was evident in splenic sections. All bursal sections were affected with moderate to severe lymphoid atrophy. The affected flocks in this report were suffering environmental insults, including overcrowding, high humidity, and poor litter conditions. The bursal and splenic lymphocytic atrophy was suggestive of the birds being immunodeficient. Poor environmental conditions and immunodeficiency have been implicated as contributing factors in the occurrence of GD associated with C. septicum. 2-4,7,10,11 In addition, the periodic recurrence of GD in a single broiler unit as described in this report suggests a possible dose relationship. Clostridial organisms are generally accepted to be ubiquitous, even in locations where the presence of animals is rare. Although work has been done on the population dynamics of C. septicum in various soils, little is known about the relative populations of the organism in modem poultry production facilities. Specific housing units may be contaminated with unusually high numbers of organisms. The possible contribution of high levels of environmental contamination should be considered when evaluating an increased incidence of GD. Intensive cleaning efforts in specific housing units might limit the occurrence of GD when management is unable to control contributing factors such as immunosuppression and overcrowding.

Metastatic Renal Carcinoma in an African Grey Parrot (Psittacus Erithacus Erithacus)

Extreme eosinophilia with disseminated eosinophilic granulomatous disease is described in a 4-year-old Arabian mare. Clinical signs included weight loss, coughing, jugular distention, and ventral edema. Cutaneous lesions were not observed. Eosinophilic inflammation was observed in cytologic specimens from the respiratory tract, body cavities, and lymph nodes. At necropsy, a 20-cm diameter intrathoracic mass was observed. Smaller nodules were present in the lymph nodes, liver, spleen, adrenal glands, pancreas, and skeletal muscle. Histologically, these masses and nodules were characterized by infiltrates of eosinophils, macrophages, and multinucleated giant cells, reactive fibroplasia; and multifocal eosinophilic coagula. Microscopically, mild eosinophilic infiltrates were observed in sections of stomach, small intestine, colon, and pleura; however, gross lesions were not observed in these tissues at necropsy. The etiology of the extreme eosinophilia and disseminated eosinophilic granulomatous disease in this horse was not determined.

Extreme eosinophilia with disseminated eosinophilic granulomatous disease in a horse.

The present study describes the use of DNA in situ hybridization for the rapid diagnosis of massive necrotizing adenovirus hepatitis and pancreatitis in broiler chicks. A light microscope and DNA probes were used to identify avian adenovirus in replicate sections of formalin-fixed paraffin-embedded liver and pancreas from field and experimental chicks. Avian adenovirus infection was confirmed by transmission electron microscopy and virus isolation.

DNA in situ hybridization for the rapid diagnosis of massive necrotizing avian adenovirus hepatitis and pancreatitis in chicks.

Myelolipomas are benign extramarrow neoplasms that are composed of various proportions of fat and hematopoietic cells. These tumors are reported infrequently in human being~,’.*.’~ domestic and exotic cats,Io and dogsI4 but have not been reported in birds. The purpose of this brief communication is to report myelolipomas originating from the subcutis or liver in four exotic birds. All neoplasms were encountered over a 5-year period in routine surgical biopsy or necropsy tissues submitted to the Department of Veterinary Pathology and Athens Diagnostic Laboratory, College of Veterinary Medicine, University of Georgia. An adult female saffron toucanet (Baillonius bailloni) died suddenly following a brief period of weakness. At necropsy, the liver appeared enlarged and had multiple white foci ranging from 2-3 mm to 1 cm in diameter. The presumptive clinical diagnosis was avian mycobacteriosis. A 4-year-old female society finch (Lonchura domestica) was submitted for examination of an elevated, broad-based, slowly enlarging, semisoft, 2x 2.5x I-cm subcutaneous mass over the right thigh. The size of the mass interfered with perching, balance, and limb movement. Neoplasia was suspected, and the bird was euthanatized. The only lesion observed at necropsy was the subcutaneous mass. On gross section, the mass appeared brownish yellow with a pale tan to white center. An adult hyacinth macaw (Anodorhynchus hyacinthinus) of undetermined sex was presented for examination of a slowly enlarging 3x 5x 2.5-cm dermal mass over the right thigh. A lipoma was suspected clinically, and the mass was surgically excised under general anesthesia. Recovery from anesthesia was uneventful, and tumor regrowth was not observed following surgical resection. On cut surface, the mass appeared circumscribed, soft, and pale off-white to yellow-brown. A 10-year-old male cockatiel (Nymphicus hollundicus) was presented for a slowly enlarging 4x 4x 3-cm mass over the left thorax. Neoplasia was suspected clinically, and surgical excision was attempted by the refemng veterinarian. The bird died from intraoperative hemorrhage. A necropsy was not performed; however, the excised subcutaneous mass was submitted for histopathologic examination. On cut surface, the mass was firm and yellow. All tissue specimens were preserved in 10% neutral buffered formalin, processed routinely, embedded in paraffin, sectioned at 3 pm, and stained with hematoxylin and eosin (HE). Liver sections from the toucanet also were stained for iron by Perl’s technique. Additional hepatic specimens from the toucanet were examined ultrastructurally for the presence of retrovirus and herpesvirus, which can induce various hemolymphatic neoplasms in poultry.’ Tissue was transferred from formalin to Trump’s fixative and processed routinely for transmission electron microscopy. Specimens were postfixed in osmium tetroxide, dehydrated in graded alcohols, embedded in Spurr plastic, sectioned, placed on formvar-coated copper grids, stained with uranyl acetate and lead citrate, and examined at 80 kVp. Table 1 contains a summary of the signalment of the four birds and some general characteristics of the myelolipomas. Upon gross inspection, all of the neoplasms were circumscribed to lobulated and soft to semisoft and had an appearance suggestive of adipose tissue with hemorrhage. Microscopically, the hepatic myelolipomas were clearly demarcated form the adjacent parenchyma but were unencapsulated (Fig. 1). In contrast, the subcutaneous neoplasms were encapsulated partially by a thin layer of connective tissue (Fig. 2). All neoplasms were composed of various percentages of lipocytes and hematopoietic cells. Within the

Myelolipomas are uncommon benign tumors composed of mature fat cells and hematopoietic cells (myeloid, erythroid, and lymphoid) in various proportions. In humans, these neoplasms rarely cause symptoms unless they are unusually large or unless they hemorrhage. Myelolipomas have been found incidentally at postmortem examination; however, their antemortem diagnosis is becoming more common in humans with increased use of ultrasound and computed tomography. In contrast, myelolipomas are reported infrequently in animals. Carcinomas (malignant tumors of epithelial origin) are found in many species of animals. In this report, we describe 2 intraabdominal myelolipomas and a cranial thoracic carcinoma of undetermined origin in a lovebird. An 8-year-old female lovebird had an 11-month history of depression, emaciation, fluffed feathers, labored breathing, recurring posture of tilting its head down with tail elevated, and loss of appetite. Treatment with oral doxycycline had improved the bird’s appetite and demeanor for several months, but the bird was found dead following a short reappearance of these signs. The attending veterinarian performed a necropsy on the bird and encountered 1 oval 0.9cm-diameter tissue mass in the cranial thorax near the thoracic inlet and 2 other round, tan l-cm-diameter masses in the left and right sides of the abdomen. No other abnormalities were observed at necropsy. The tissue masses and liver were submitted in buffered formalin to the Oregon State University Veterinary Diagnostic Laboratory for histologic examination. Two encapsulated round masses, 5 mm x 9 mm and 6 mm x 11 mm, contained a uniform mixture of 50% mature adipocytes and 50% hematopoietic cells (Fig. 1). The hematopoietic cells were immature myeloid cells, primarily of the heterophilic series, and erythroid precursors (Fig. 2). Cells resembling blast-type cells with slightly dispersed chromatin, vesicular round to oval nuclei, and scant basophilic cytoplasm also were present throughout the mass. The mitotic rate of the hematopoietic cells was 1 or 2 mitoses/40 x field. Stromal elements included scattered capillaries and foci of smooth muscle. Multifocal infiltrations of the fibrous capsule by immature heterophils and blasts were observed. The presence of a fibrous connective tissue capsule and smooth muscle trabeculae could indicate that the tumor originated from splenic tissue. The masses were diagnosed as myelolipomas. The mass from the thoracic area was composed of tubules

Thoracoabdominal Myelolipomas and Carcinoma in a Lovebird (Agapomis sp.)

Adrenal carcinoma was diagnosed in a 4-year-old budgerigar (Melopsittacus undulatus) with anorexia, weight loss, dyspnea, abdominal distention, and ataxia. Diagnosis was made on the basis of light and electron microscopic features of the neoplastic cells. Although neoplastic cells infiltrated the testicular capsule, anterior kidney, and air sac, distant metastases were not observed.

A malignant melanocytic tumor was found in an 8-week-old chicken. The tumor, which was composed of melanocytes, ganglion cells, nerves, and primitive pressure receptors, was examined by light microscopy, transmission electron microscopy, and immunohistochemistry. Antibodies to neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), and S-100 protein variably stained nerves, but melanocytes were only rarely immunolabelled by NSE antibodies and there was no specific staining of these cells for S-100 or GFAP. Ultrastructurally, neoplastic melanocytes contained melanin within melanosomes and premelanosomes and did not resemble Schwann cells.

Malignant Melanocytic Neural Crest Tumor in a Young Chicken (Gallus domesticus)

Tissues from a tawny frogmouth that died acutely in a zoo collection were submitted for histopathologic examination. A small yellow nodule was observed grossly on the ventricular wall by the zoo veterinarian during collection of tissues. Histologically, the epicardial nodule consisted of a well-circumscribed, thinly encapsulated cyst, 4 mm in diameter. The cyst was composed of gradually keratinizing, attenuated, stratified squamous epithelium, one to three cell layers in thickness. The cyst was filled with laminated keratin and a few keratinized epithelial cells. The cyst was separated from the myocardium by a thin layer of adipose tissue. Based on these observations, the structure was diagnosed as an epicardial keratinaceous cyst.

Epicardial keratinaceous cyst in a tawny frogmouth (Podargus strigoides plumiferus).

The evaluation of the usefulness of DNA probes in a diagnostic setting to identify nuclear inclusions in selected viral infections (psittacine beak and feather disease viral infection, avian polyomavirus infection, adenovirus infection and Pacheco's parrot disease) is reported. A DNA in situ hybridization method was used to detect viral nucleic acid in sections of paraffin-embedded tissues coming from birds naturally and/or experimentally infected. It is concluded that DNA probes used for polyomavirus (FN-19) and adenovirus (FN-23) are able to identify nucleic acid of each virus in the cells with nuclear inclusions, and when used for psittacine beak and feather disease virus (FN-8), and Pacheco's parrot disease virus (FN-49) are able to detect viral nucleic acid in cells with or without inclusions.

Diagnosis of psittacine beak and feather disease (PBFD) viral infection, avian polyomavirus infection, adenovirus infection and herpesvirus infection in psittacine tissues using DNA in situ hybridization.

Histological examination of the bursae from 12 pigeons under 4 months old revealed basophilic globular inclusion bodies, 5 to 25 microns in diameter, in the cytoplasm and the nuclei of the various bursal follicular cells. Electron microscopy of these inclusions revealed large electron-dense areas containing non-enveloped icosahedral viral particles, 14-19 nm in diameter, either loosely arranged or in paracrystalline array. Similar basophilic globular inclusion bodies were seen in the spleen and cecal tonsils of a few pigeons and in the duodenum of one pigeon. There were various degrees of lymphoid depletion in the bursa, spleen, and bone marrow. The morphology of the inclusions in the bursa and size of the viral particles are most consistent with circovirus. Preliminary studies on the bursae of two pigeons were negative for psittacine beak and feather disease (PBFD) viral antigen and nucleic acid by immunoperoxidase staining, DNA in situ hybridization, and polymerase chain reaction techniques, suggesting that this virus differs from PBFD virus. Most of the pigeons had concurrent infections such as paramyxovirus-1, salmonellosis, herpesvirus, and hepatic and cerebral trichomoniasis associated with adenovirus.

Particles resembling circovirus in the bursa of Fabricius of pigeons.

A 4-year-old, neutered male Domestic Shorthair cat with a history of depression, anorexia, and weight loss was diagnosed with acute myelogenous leukemia (AML). The cat tested positive by both the feline immunodeficiency virus antibody test and feline leukemia virus enzyme-linked immunosorbent assay test. Results of cytochemical stains on peripheral blood and bone marrow specimens indicated acute myeloid leukemia with unusual basophilic differentiation (AML, M-2B).

Acute myeloid leukemia with basophilic differentiation (AML, M-2B) in a cat.

Goitrous enlargement of the thyroid glands is relatively rare in reptiles but has been observed occasionally in giant terrestrial tortoises (Geochelone elephantopus and Testudo gzgantea).4 These tortoises are prone to develop hyperplastic goiter in captivity when fed diets high in goitrogenic vegetables. They seem to possess a particularly high metabolic requirement for iodine, which is met in their native habitat by ingesting plants that sequester halogen^.^ Goiter is uncommon in snakes. Out of 48 1 snake necropsy accessions at the National Zoological Park, Washington, D.C., since 1975, only two had a diagnosis of goiter (D. K. Nichols, personal communication). The present case report describes colloid goiter in a captive eastern diamondback rattlesnake (Crotalus adamanteus). An adult female eastern diamondback rattlesnake that had been in the Zoo Atlanta collection since 1976 was found dead in its cage. No premonitory signs had been reported. At necropsy, a 2.5x 1-cm multilobulated thoracic mass was found cranial to the heart (Fig. 1). No other gross abnormalities were noted. Multiple tissues were collected, fixed in 10% neutral buffered formalin, and submitted to the Department of Pathology, College of Veterinary Medicine, University of Georgia. Following gross examination, the submitted tissues were trimmed, embedded in paraffin, and sectioned at 3 Mm, and sections were stained with hematoxylin and eosin (HE). Macroscopically, the mass was presumed to be thyroid tissue because of its appearance and location. In snakes, the thyroid is unpaired and located ventral to the trachea and cranial to the heart.5 Microscopically, the mass was confirmed to be thyroid gland, and all follicles were distended markedly by abundant amounts of colloid (Fig. 2) . The majority of the epithelial cells were flattened and attenuated (Fig. 3); however, some cells were more cuboidal to columnar in shape and contained intracytoplasmic colloid (Fig. 4). Mild infiltrates of lymphocytes and plasma cells were within the perivascular connective tissue. The liver had mild diffuse hepatocellular lipidosis. The kidneys had mild to moderate hemosiderin accumulation within renal tubular epithelial cells. A very mild lymphocytic infiltrate was scattered diffusely throughout the tracheal submucosa. The specific cause of the snake's death could not be determined histologically. In both young adult and adult mammals, colloid goiter is a result of diffuse hyperplastic goiter involution after sufficient iodine has been added to the diet and/or goitrogenic compounds have been removed from the diet.' The hyperplastic cells continue to produce colloid; however, the colloid accumulates because of reduction of colloid endocytosis by the follicular epithelial cells due to decreased circulating levels of thyrotropin secondary to the return of thyroxine and triiodothyronine levels to norma1.l Older animals tend to have diminished requirements for thyroxine and diminished pituitary thyrotropin secretion, conditions that also lead to follicular distention due to diminished colloid endocytosis. I

Colloid Goiter in an Eastern Diamondback Rattlesnake (Crotalus adamanteus)

A Review of Proventricular Dilatation Syndrome Author(s): Christopher R-Gregory, Kenneth S. Latimer, Frank D. Niagro, Branson W. Ritchie, Raymond P. Campagnoil, Terry M. Norton, Rita McManamon, Cheryl B. Greenacre Source: Journal of the Association of Avian Veterinarians, Vol. 8, No. 2 (1994), pp. 69-75 Published by: Association of Avian Veterinarians Stable URL: http://www.jstor.org/stable/27671120 Accessed: 11/01/2010 07:09

Circovirus infections were diagnosed in 12 pigeons from the United States, 4 pigeons from Australia, and 1 pigeon from Canada (1986-1993). Circovirus was identified by electron microscopic examination of basophilic botryoid cytoplasmic inclusions that had a histologic appearance similar to that of psittacine beak and feather disease virus inclusions. Inclusions were seen in splenic, bursal, gut-associated, and bronchus-associated lymphoid tissue macrophages and in bursal epithelial cells. Inclusions were composed of paracrystalline arrays of tightly packed, nonenveloped icosahedral virions 14-17 nm in diameter. Histologic changes in the spleens ranged from lymphofollicular hyperplasia with mild discrete lymphocellular necrosis to lymphoid depletion and diffuse histiocytosis. Lesions in the bursa of Fabricius ranged from mild lymphocellular necrosis to severe cystic bursal atrophy. Remaining histologic findings coincided with concurrent bacterial, viral, fungal, and parasitic infections. Immunoperoxidase staining and DNA in situ hybridization demonstrated that pigeon circovirus is distinct from psittacine beak and feather disease virus; however, both viruses apparently share some homologous DNA sequences. Clinical and diagnostic findings indicate that pigeon circovirus may be similar to psittacine beak and feather disease virus with respect to acquired immunodeficiency and subsequent multiple secondary infections.

A Retrospective Study of Circovirus Infection in Pigeons: Nine Cases (1986–1993)

Multilobular tumour of bone is a rare neoplasm of cartilage, bone and connective tissue that is seen almost exclusively in association with the skull of veterinary patients. A four-year-old, spayed Jack Russell terrier was presented to the University of Georgia Veterinary Teaching Hospital because of a progressive swelling in the right axilla. Radiographs of the region showed the mass to be caudal to the scapula, unattached to bone and to have numerous punctate calcific opacities throughout its substance. Excisional biopsy of the mass was carried out under general anaesthesia and histopathological examination showed it to be multilobular tumour of bone. This case report documents the occurrence of multilobular tumour of bone at a site other than the head. This tumour should be considered in the differential diagnosis of soft tissue masses with calcific opacities.

Multilobular tumour of bone at an unusual location in the axilla of a dog

Avian polyomavirus (APV) infection was diagnosed in a closed research colony of seedcrackers (Pyrenestes sp.) and blue-bills (Spermophaga haematina) using DNA in situ hybridization. The DNA probe was a 1-kbp double-stranded PCR-generated probe that recognized a conserved nucleotide sequence within the VP-1 gene. Using this technique, APV infection was diagnosed, in 25 of 45 birds based upon examination of formalin-fixed paraffin embedded tissues. Birds infected with APV apparently had a higher incidence of hepatic necrosis, hepatitis, bacterial infections and parasitism than did birds without APV.

Diagnosis of polyomavirus infection in seedcrackers (Pyrenestes sp.) and blue bills (Spermophaga haematina) using DNA in situ hybridization.

Antibody Response and Local Reactions to Adjuvanted Avian Polyomavirus Vaccines in Psittacine Birds

Liver sections from 32 psittacine birds with multifocal to coalescing hepatocellular necrosis were examined to determine the cause of disease. Avian polyomavirus (APV) infection (19 of 32 birds), bacterial hepatitis (5 of 32 birds), and chlamydiosis (3 of 32 birds) were major causes of hepatic disease. The presence of APV inclusions or nucleic acid was demonstrated using hematoxylin and eosin (HE) staining, DNA in situ hybridization, and DNA amplification with Southern blotting. Amphophilic intranuclear inclusions, suggestive of APV infection, were observed in HE-stained liver sections from 5 of 32 birds. Hepatocellular karyomegaly was present in liver tissues from 10 birds (5 birds with typical APV inclusions and 5 birds without discernable inclusions). DNA in situ hybridization recognized intranuclear APV nucleic acid in liver sections of 18 of 32 birds. DNA amplification with Southern or dot blots also identified APV nucleic acid in processed, paraffin-embedded livers of 18 of 32 birds. This study demonstrates that acute APV infection is a frequent cause of multifocal to coalescing hepatocellular necrosis in psittacine birds. Furthermore, APV infection is best diagnosed using DNA probes, especially when typical intranuclear inclusions are not observed microscopically.

Diagnosis of Polyomavirus-Induced Hepatic Necrosis in Psittacine Birds Using DNA Probes

References 1 Capen CC: The endocrine glands. In: Pathology of Domestic Animals, ed. Jubb KVF, Kennedy PC, and Palmer N, 4th ed., vol. 3, pp. 3 15-3 17. Academic Press, San Diego, CA, 1993 2 Chiu KW, Lynn WG: Further observations on the role of the thyroid in skin shedding in the shovel-nosed snake, Chionactis occipitalis. Gen Comp Endocrinol17:508-5 1 1, 1971 3 Chiu KW, Phillips JC, Maderson PFA: Seasonal changes in the thyroid gland in the male cobra, Nuja nuja L. Biol

Avian Polyomavirus Infection in Three Black-Bellied Seed Crackers (Pyrenestes ostrinus)

Diagnosis of Concurrent Avian Polyomavirus and Psittacine Beak and Feather Disease Virus Infections Using DNA Probes

Eight commercially available disinfectants, representing several major classes of chemical disinfectants, were evaluated for their ability to inactivate avian polyomavirus (Budgerigar fledgling disease virus). These disinfectants and their sources are listed in Table 1. Avian polyomavirus was considered to be a good test pathogen for a disinfectant because this nonenveloped virus is a frequently encountered pathogen that is considered to be relatively stable in the environment. Disinfectants were diluted according to the manufacturer's recommendations. Infectious virus preparations were placed in con tact with each diluted disinfectant for one minute or for five minutes at room temperature. After removal of the disinfectant by gel filtration, each sample was then placed on cultured cells to determine whether the virus was inactivated. Of the eight disinfectants tested, 0.525% sodium hypochlorite (Clorox) was considered the most economical. A stabilized chlorine dioxide (Dent-A-Gene) was effective and would be expected to be the safest. Chlorohexadine (Nolvasan) reduced but did not eliminate the infectivity of avian polyomavirus, which may explain why aviaries that use this disinfectant in the nursery frequently experience polyomavirus outbreaks. Heating the virus to 60°C for 5 minutes or 30 minutes reduced the titer of the virus, but did not eliminate infectivity. An Overview of Avian Polyomavirns The first acute, generalized infection associated with a polyomavirus was described in young psittacine birds and was called Budgerigar fledgling disease (BFD). 1•5 A virus that is similar to the one that causes Budgerigar fledgling disease has been shown to be associated with high levels of sickness, and in some cases death, in finches and a number of different genera of psittacine birds. It should be noted that while the polyomaviruses that infect Budgerigars, finches and larger psittacine birds have similarities, the clinical presentation, distribution of lesions and problems that the viruses cause within a flock are dramatically different among susceptible species."!' Infected Budgerigar neonates typically develop abdominal distention, subcutaneous hemorrhage, tremors of the head and neck and ataxia. Survivors may exhibit symmetrical feather abnormalities characterized by abnor- ma 11 y formed primary and tail feathers, lack of down feathers on the back and abdomen and lack of filo- plumes on the head and neck. When feather lesions are present, the disease is often referred to as French Molt. In larger psittacine birds, polyomavirus infections may cause a peracute death with no premonitory signs or death 24 to 48 hours after developing clinical signs including depression and anorexia, delayed crop emptying, regurgitation, weight loss, subcutaneous hemorrhages and diarrhea. Infections may occur in both parent and handraised babies and clinical signs are most common at the time of weaning.v" 12-14 The feather abnormalities that are relatively common with polyomavirus infections in Budgerigars are described less frequently in other psittacine species. In addition to clinical changes in neonates, polyomavirus infections have also been documented in an eight-month-old Splendid Parakeet Neopbema splendida and as the cause of sporadic, acute deaths in fully fledged lovebirds less than one year old.13.is An adult Moluccan Cockatoo Cacatua moluccensis with neurologic signs was diagnosed as having polyornavirus." An outbreak of polyomavirus in an aviary with numerous psittacine species resulted in the deaths of an adult Eclectus Parrot Eclectus roratus, a Painted Conure Pyrrhura picta and three of eleven adult White-bellied Caiques Pionites leucogaster in the collection. The affected birds were two to two and a half years old and had lesions similar to those seen with polyomavirus infections in psittacine fledglings.16 Avian polyomavirus infections have been described throughout the world. Characteristic lesions associated with the virus have been demonstrated in companion birds from the United States+" Canada,17·18 japan,'? Italy," Hungary,21 Germany22 and Australia.13·15 Avian polyomavirus has been associated with disease in a number of different species of companion and aviary birds including Budgerigars, caiques, macaws, Amazon parrots, conures, cockatoos, lovebirds, Splendid Parakeets, Pionus Parrots, African Grey Parrots, Eclectus Parrots, Cockatiels, Crimson Seed-crackers, finches and lories.l+ s-e, 12-15, 23, 24 The factors involved in polyomavirus infections are not fully understood. One of the formidable problems that occurs with polyomavirus is that normal adults and neonates from infected parents are thought to act as polyomavirus carriers.

Adult Filarioid Nematodes (Chandlerella sp.) from the Right Atrium and Major Veins of a Ducorps' Cockatoo (Cacatua ducorpsii)

Four adult dogs received experimentally controlled stings in the dorsolateral abdominal skin by imported fire ants (Solenopsis invicta). The sites were examined grossly 15 minutes and at 1, 2, 3, 4, 5, 6, 24, 48, and 72 hours and histologically 15 minutes and 6, 24, 48, and 72 hours after stinging. The initial gross lesions at 15 minutes were swelling and erythema, and the microscopic changes were vascular congestion and superficial dermal edema. By 6 hours, the lesions consisted of bright erythematous pruritic papules characterized microscopically by a band of full thickness dermal necrosis and inflammation. By 24 hours and continuing to the end of the study at 72 hours, the sites appeared completely normal grossly. Biopsies taken 24, 48, and 72 hours after stings contained microscopic changes similar to those present at 6 hours after stings. These histologic changes are unlike those described for human beings stung by imported fire ants. In human beings, fire ant stings are characterized histologically by an initial superficial vesicle that evolves into a sterile pustule.

Clinical and Histologic Characterization of Cutaneous Reactions to Stings of the Imported Fire Ant (Solenopsis invicta) in Dogs

4,7,10-13 These viruses are similar in that they are small (15-17 nm), icosahedral, and nonenveloped and contain single-stranded circular DNA. Each virus, however, has distinct DNA sequences and antigenicity. Psittacine beak and feather disease virus has the largest host range and has been reported in over 35 species of Old World and New World psittaciforms but has never been reported in other avian families. 4 This is the first case report of circovirus-like infection in a pigeon (Columbiformes). A young female racing pigeon was submitted for necropsy to the Davis branch of the California Veterinary Diagnostic Laboratory System in the fall 1990. The owner had 50 birds (adult and young), and mortality in the squabs was 100%. Three to 5 birds had died per week. Squabs exhibited anorexia and lethargy and died 3-4 days after clinical signs appeared. On gross examination, the pigeon was emaciated, with pectoral muscle atrophy. The mucosal wall of the intestinal tract was slightly red, and luminal contents were foamy and yellow-green. The spleen was enlarged. Air sacs were edematous, and there were caseous cores within the primary bronchi of both lungs. The right lung was consolidated and red. A defined bursa of Fabricius was not evident on gross examination of the site dorsal to the cloaca. The lung and liver were cultured aerobically on blood agar. A Pasteurella sp. was isolated from the lung. Bacteria were not isolated from the liver. Air sacs cultured on selective media for Mycoplasma sp. exhibited no growth. Chlamydia was not identified in Gimenez-stained impression smears of the liver, air sac, and spleen nor in liver, air sac, and spleen impression smears stained with fluorescence-labeled monoclonal antibody specific for Chlamydia a and examined with ultraviolet light. However, Chlamydia psittaci was isolated in a McCoy cell culture system from an organ pool of liver, air sac, and spleen. Viruses were not isolated from pooled tissue homogenates of liver, spleen, lung, brain, and intestine

Just as your physician cannot accurately determine your health status without conducting appropriate tests, veterinarians and aviculturists cannot tell if birds are infected with the Psittacine Beak and Feather Disease (PBFD) virus or polyomavirus without appropriate diagnostic tests. Bird enthusiasts now have the opportunity to determine whether birds are latently infected with the PBFD virus or if they are shedding polyomavirus. The DNA probe tests developed by the Psittacine Disease Research Group at the University of Georgia College of Veterinary Medicine are currently available in the United States through Avian Research Associates, 100 Techne Center, Suite 101, Milford, OH 45150. These tests will provide the aviby cultural community with the knowledge necessary to manage two of the most contagious and devastating viral diseases of psittacine birds. To control the spread of PBFD virus and polyomavirus, and to improve the professional standard of aviculture, all birds should have a documentable medical history of testing (traceable record) for these diseases, by which anyone who comes into possession of a bird can review its history to know that it is a relatively "safe bird." Pet shop owners, bird dealers, breeders and veterinarians need to protect themselves from accusations that they raised or sold a diseased bird. (Table 1) The PBFD test can be used to screen blood for the presence of PBFD virus before birds develop obvious clinical signs. The polyomavirus test can be used to determine if birds are shedding this virus. Both the PBFD virus and the polyomavirus tests can be used to screen walls, caging, air circulating ducts and equipment, in the home or hospital, to determine if one of these viruses is contaminating a bird's environment. These tests are inexpensive ($25 range), particularly when one considers the devastation of losing a special pet, or suffering with a nursery or pet shop outbreak caused by PBFD virus or polyomavirus that could have been prevented. These tests will provide the avian community with the best methods for controlling these viruses until effective vaccines are available. These tests are extremely sensitive and specific and results should be available within two weeks of being received in the laboratory. If you are a pet bird owner, it is in your pet's best interest to know its status with respect to these two viruses. All psittacine birds should be tested to determine if they are shedding polyomavirus or are infected with PBFD virus. The species of psittacine birds that have currently been shown to be susceptible to PBFD virus are listed in Table 2. Both PBFD virus and polyomavirus can be transmitted in feather or fecal dust which you can carry on your clothes to other birds in your home, to a friend's home, to a bird show or to a pet shop. Not knowing if your birds are infected with one of these two viruses places any bird that you may contact in jeopardy. If you are a breeder, it is critical that you have your adult birds tested for PBFD virus and polyomavirus to pre vent epidemic outbreaks of these diseases in your nursery. Every bird that is shipped from your facility should be tested to make certain that it is not latently infected with PBFD virus or shedding polyomavirus. This will provide you with a documented status report for all your birds should one of them be involved in an outbreak. If your birds have not been tested, guess who may be left holding the bag (or picking up the bill) in the event that one of your birds is later diagnosed with one of these viruses?

Cryptosporidiosis was diagnosed in 4 cockatoos with psittacine beak and feather disease. Three of the birds had cryptosporidiosis confined to the epithelium covering the bursa of Fabricius. One bird had generalized parasitism of the small intestine, large intestine, and bursal epithelium. All of the birds had intermittent to protracted diarrhea before death. Presumably, acquired immunodeficiency from psittacine beak and feather disease promoted establishment of cryptosporidiosis and other secondary diseases including septicemia, peritonitis, chlamydiosis, and mycotic ventriculitis.

Cryptosporidiosis in four cockatoos with psittacine beak and feather disease.

Recognition and Interpretation of Selected Gross Necropsy Lesions and Anatomical Variations

Clinical pathology testing in nonclinical toxicity and safety studies is an important part of safety assessment. In recent years, clinical laboratory testing has rapidly expanded and improved. Some government regulatory agencies provide guidelines for clinical pathology testing in nonclinical toxicity and safety studies. To improve these testing guidelines and the resultant safety assessments, the American Association for Clinical Chemistry's Division of Animal Clinical Chemistry and the American Society for Veterinary Clinical Pathology formed a joint committee to provide expert recommendations for clinical pathology testing of laboratory species involved in subchronic and chronic nonclinical toxicity and safety studies. These recommendations include technical recommendations on blood collection techniques and hematology, serum chemistry, and urinalysis tests.

Clinical Pathology Testing Recommendations for Nonclinical Toxicity and Safety Studies

Psittacine Beak and Feather Disease in a Scarlet Macaw (Ara macao)

Monoclonal antibodies specific for the virus that causes psittacine beak and feather disease (PBFD) were produced by fusing spleen cells from mice immunized with purified concentrated PBFD virus with mouse myeloma cell line Sp2/0. The resulting hybridomas were tested for reactivity against whole purified virus by an enzyme-linked immunosorbent assay (ELISA) system. Four clones, designated 15H8, 8E3, 11G12, and 2C3, were subcloned by limiting dilution. Isotyping indicated that clone 15H8 was secreting IgG, whereas the remaining clones secreted IgM. The secreted immunoglobulins were characterized by reactivity against purified PBFD virus using immunoblotting procedures, by immunohistochemical staining of virus-induced lesions in infected tissues, and by inhibition of PBFD virus agglutination of cockatoo erythrocytes. Antibodies secreted by clones 15H8 and 8E3 had the strongest activity against purified whole virus. Only immunoglobulin secreted by the clone 15H8 could be used to detect viral antigen in infected tissues. None of the monoclonal antibodies had hemagglutination-inhibition activity.

Production and Characterization of Monoclonal Antibodies to Psittacine Beak and Feather Disease Virus

Canine leishmaniasis, a generally fatal parasitic disease, was diagnosed in 2 dogs with a medical history of foreign travel, lymphadenopathy, emaciation, anorexia, intermittent fever, and cutaneous lesions. Clinically, hyperproteinemia, proteinuria, azotemia, and glomerulopathy were evident. Isolation of Leishmania species was done using Schneider's Drosophila medium. Syrian hamsters were used for infectivity studies. Clear taxonomic identification was done biochemically by isoenzyme analysis and comparison of zymogram banding patterns with 6 World Health Organization reference strains. Based on the geographic origin of affected dogs, clinicopathologic presentation, visceralization with hepatosplenomegaly in hamsters, and isoenzyme analysis, a diagnosis of Leishmania leishmania infantum was made. This study, representing the first taxonomic identification of an isolate from canine leishmaniasis, demonstrates the Zoonotic and epidemiologic implications of this disease.

Canine Leishmaniasis Caused by Leishmania Leishmania Infantum in Two Labrador Retrievers

Adult umbrella cockatoos, Moluccan cockatoos, African grey parrots, and a yellow-headed Amazon parrot were inoculated IM or SC with beta-propiolactone-treated psittacine beak and feather disease (PBFD) virus. Thirty- to 45-day-old African grey parrot, umbrella cockatoo, and sulphur-crested cockatoo chicks also were vaccinated with the same inoculum. The hemagglutination inhibition (HI) and agar-gel diffusion tests were used to assay for post-vaccination development of anti-PBFD virus antibodies. All adult vaccinates seroconverted and had increases in HI and precipitating antibodies. The vaccinated chicks had increased concentrations of HI antibodies, but precipitating antibodies could not be detected. To demonstrate that chicks from vaccinated hens are protected from PBFD virus challenge, 3 African grey parrot chicks and 2 umbrella cockatoo chicks from vaccinated hens and 1 African grey parrot chick and 1 umbrella cockatoo chick from nonvaccinated hens were exposed to purified PBFD virus. Chicks from the vaccinated hens remained clinically normal during the 50-day test period. Chicks from the nonvaccinated hens developed clinical and histologic lesions of PBFD. Infected tissues from these birds were confirmed to contain viral antigen, using immunohistochemical staining techniques. The PBFD virus was recovered from the affected birds. These findings indicate that adult and 30- to 45-day-old psittacine birds will seroconvert following vaccination with beta-propiolactone-treated PBFD virus. Also, hens inoculated with beta-propiolactone-treated PBFD virus produce chicks that are, at least temporarily, resistant to virus challenge.

Antibody response to and maternal immunity from an experimental psittacine beak and feather disease vaccine.

An adult male black palm cockatoo (Probosciger aterrimus) had a 10-mo history of anorexia, weight loss, episodic depression, muscular tremors, and bilateral leg paresis. The bird died and was sent to the University of Georgia College of Veterinary Medicine for pathologic evaluation. At necropsy, a greenish-white proliferative cavitating mass was found in the left abdominal air sac with extension into the left kidney. Histologic lesions included inflammation and necrosis of the kidney and the sacral plexus, including the ischiatic nerve. Fungal hyphae morphologically com patible with Aspergillus sp. were found in the necrotic areas. These findings suggest that aspergillosis in birds can cause leg paresis without respiratory signs.

LEG PARESIS IN A BLACK PALM COCKATOO (PROBOSCIGER A TERRIMUS) CAUSED BY ASPERGILLOSIS

Comparison of DNA dot-blot hybridization, immunoperoxidase staining and routine histopathology in the diagnosis of psittacine beak and feather disease in paraffin-embedded cutaneous tissues

What is your diagnosis? Cerebrospinal fluid from a 5-day-old foal.

Squamous cell carcinoma is an uncommon tumor of the cornea in dogs. A 12-year-old Shih Tzu with a history of chronic keratoconjunctivitis sicca was diagnosed as having squamous cell carcinoma of the corneoscleral limbus. The lesion was treated by surgical resection and cryotherapy. One year after surgery, multiple tumors, apparently unrelated to the first tumor, appeared on the same cornea. Keratoconjunctivitis sicca may have predisposed the dog to corneal squamous cell carcinoma development.

Spiking mortality syndrome (SMS) in chickens resembles cocklebur toxicity in cattle, sheep, pigs, and rats. In order to determine if cockleburs are toxic to broiler chicks, crushed burs were fed (25% wt:wt) to broilers for 21 days. Ingestion of cockleburs resulted in significant failure to properly gain body weight. Otherwise, chicks did not develop clinical signs of illness or gross or microscopic lesions. Although there were some significant differences in serum chemistry values among chick groups, there were no consistent patterns. Severe hypoglycemia is said to be a characteristic finding in chicks that die with SMS. Because glucose levels were not low in chicks that were fed cockleburs, we feel certain that cockleburs do not cause SMS.

Toxicological pathology of cockleburs (Xanthium spp.) for broiler chickens.

Porcine small intestinal explants maintained in vitro were inoculated with Salmonella choleraesuis to study the characteristics of its invasion of enterocytes. The explants were fixed at selected intervals for up to 12 hours after inoculation and examined by conventional light microscopy, immunoperoxidase staining, and transmission electron microscopy. Although there was diffuse loss of villous enterocytes during the first hour of incubation, the villi were reepithelialized by the end of 2 hours of culture, and the mucosal epithelium remained intact and appeared to be viable through 12 hours of culture. Intraepithelial S choleraesuis were not detected before 6 hours after inoculation, but after 12 hours of incubation, bacteria were numerous within enterocytes. Ultrastructurally, penetration of the brush border by S choleraesuis resulted in focal loss of microvilli. Bacteria were endocytosed into membrane-bound vacuoles where most remained, but a few were free within the cytoplasm of enterocytes. Invasion of the explants closely resembled that described for live animal and cell culture models of Salmonella spp invasion.

Invasion of enterocytes in cultured porcine small intestinal mucosal explants by Salmonella choleraesuis.

Blood and bone marrow smears from 49 dogs and cats, believed to have myeloproliferative disorders (MPD), were examined by a panel of 10 clinical pathologists to develop proposals for classification of acute myeloid leukemia (AML) in these species. French-American-British (FAB) group and National Cancer Institute (NCI) workshop definitions and criteria developed for classification of AML in humans were adapted. Major modifications entailed revision of definitions of blast cells as applied to the dog and cat, broadening the scope of leukemia classification, and making provisions for differentiating erythremic myelosis and undifferentiated MPD. A consensus cytomorphologic diagnosis was reached in 39 (79.6%) cases comprising 26 of AML, 10 of myelodysplastic syndrome (MDS), and 3 of acute lymphoblastic leukemia (ALL). Diagnostic concordance for these diseases varied from 60 to 81% (mean 73.3 +/- 7.1%) and interobserver agreement ranged from 51.3 to 84.6% (mean 73.1 +/- 9.3%). Various subtypes of AML identified included Ml, M2, M4, M5a, M5b, and M6. Acute undifferentiated leukemia (AUL) was recognized as a specific entity. M3 was not encountered, but this subclass was retained as a diagnostic possibility. The designations M6Er and MDS-Er were introduced where the suffix "Er" indicated preponderance of erythroid component. Chief hematologic abnormalities included circulating blast cells in 98% of the cases, with 36.7% cases having >30% blast cells, and thrombocytopenia and anemia in approximately 86 to 88% of the cases. Bone marrow examination revealed panmyeloid dysplastic changes, particularly variable numbers of megaloblastoid rubriblasts and rubricytes in all AML subtypes and increased numbers of eosinophils in MDS. Cytochemical patterns of neutrophilic markers were evident in most cases of Ml and M2, while monocytic markers were primarily seen in M5a and M5b cases. It is proposed that well-prepared, Romanowsky-stained blood and bone marrow smears should be examined to determine blast cell types and percentages for cytomorphologic diagnosis of AML. Carefully selected areas of stained films presenting adequate cellular details should be used to count a minimum of 200 cells. In cases with borderline diagnosis, at least 500 cells should be counted. The identity of blast cells should be ascertained using appropriate cytochemical markers of neutrophilic, monocytic, and megakaryocytic differentiation. A blast cell count of > 30% in blood and/or bone marrow indicates AML or AUL, while a count of < 30% blasts in bone marrow suggests MDS, chronic myeloid leukemias, or even a leukemoid reaction. Myeloblasts, monoblasts, and megakaryoblasts comprise the blast cell count. The FAB approach with additional criteria should be used to distinguish AUL and various subtypes of AML (Ml to M7 and M6Er) and to differentiate MDS, MDS-ER, chronic myeloid leukemias, and leukemoid reaction. Bone marrow core biopsy and electron microscopy may be required to confirm the specific diagnosis. Immunophenotyping with lineage specific antibodies is in its infancy in veterinary medicine. Development of this technique is encouraged to establish an undisputed identity of blast cells. Validity of the proposed criteria needs to be substantiated in large prospective and retrospective studies. Similarly, clinical relevance of cytomorphologic, cytochemical, and immunophenotypic characterizations of AML in dogs and cats remains to be determined.

Proposed criteria for classification of acute myeloid leukemia in dogs and cats.

Blood from 48 chicks was examined for anemia (packed cell volume), and plasma was examined for virus particles by direct transmission electron microscopy (DTEM). There was agreement between the occurrence of anemia and the presence of CAA virus particles in plasma from anemic chicks (Kappa = 0.2425, Z = 2.096, P = 0.036). Although DTEM is a method that can be used to diagnose CAA in chicks, more sensitive, economical and less laborious diagnostic assays are needed.

Diagnoses of infections by the so-called chick anemia agent: anemia and direct transmission electron microscopic detection of virus.

Conditions for psittacine beak and feather disease (PBFD) virus hemagglutination and hemagglutination-inhibition (HI) test reactions are defined. The PBFD virus was found to hemagglutinate cockatoo and some guinea pig erythrocytes. The HI test was used to assay serum antibody titer in birds with active PBFD virus infections and in others that had been exposed to diseased birds. On the basis of HI antibody titers in psittacine birds that had been exposed to PBFD virus, but remained clinically normal, we suggest that some birds exposed to the virus are able to mount an effective immune response. Birds with active PBFD virus infections had lower antibody values than did birds that had been exposed to the virus, but remained clinically normal. On the basis of these findings, the ability to develop a suitable HI antibody response may be crucial in determining the disease status of susceptible birds exposed to the PBFD virus. If HI antibodies are found to have neutralizing activity, then the fact that a high HI titer was induced in birds inoculated with purified PBFD virus might suggest that an immunization program would be effective in preventing PBFD virus infections.

Hemagglutination by psittacine beak and feather disease virus and use of hemagglutination inhibition for detection of antibodies against the virus.

Heterophil function was evaluated in 16 healthy chickens and in 46 chickens with experimentally induced staphylococcal tenosynovitis. In paired blood samples, heterophils from chickens with tenosynovitis had a significant increase in adherence, chemotaxis, phagocytosis, and bacterial killing of Staphylococcus aureus compared to heterophils from healthy chickens. The percent adherence of heterophils to nylon fiber columns increased significantly from a 78.4% mean ± 6.6% standard deviation to 87.6% ± 3.2% after induction of staphylococcal tenosynovitis. Heterophil movement following in vitro exposure to saline or endotoxin was increased in chickens with tenosynovitis; 3 ± 1 heterophils/0.25 mm2 to 10 ± 6 heterophils/0.25 mm2 and 136 ± 29 heterophils/0.25 mm2 to 340 ± 74 heterophils/0.25 mm2, respectively. Endotoxin-activated serum was chemoattractive for heterophils from all chickens. Flow cytometry was used to define the heterophil population on light scatter histograms, evaluate individual cell phagocytosis of latex beads, and quantitate the number of beads phagocytosed per heterophil. When incubated with increased numbers of beads, only heterophils from chickens with tenosynovitis phagocytosed higher numbers of beads. At heterophil to bead ratios of 1:10, the percentage of heterophils that phagocytosed beads increased from baseline values of 37.8% ± 9.0% to postinfection values of 67.3% ± 7.5%. Using 1:20 heterophil to bead ratios, heterophil phagocytosis increased from 38.7% ± 9.9% to post-infection values of 79.8% ± 7.3%. Heterophils from all chickens were able to phagocytose and kill log phase staphylococcal bacteria. After phagocytosis, the heterophils from chickens with staphylococcal tenosynovitis rapidly decreased the number of viable bacterial colony forming-units per milliliter by approximately one log. Circulating heterophils from chickens with experimentally induced staphylococcal tenosynovitis therefore appear to have increased functional capabilities in this bacterial inflammatory disease.

Heterophil Function in Healthy Chickens and in Chickens with Experimentally Induced Staphylococcal Tenosynovitis

Small intestinal explants from weaned pigs were cultured under a variety of conditions. Explants maintained villus-to-crypt ratio between 1:1 and 1.5:1 for 48 hours. The mucosal epithelium remained well preserved and retained good cellular morphologic features, as determined by light and electron microscopy. Between 48 and 72 hours, considerable mucosal degeneration was evident. Best results were obtained when the explants were cultured on a rocking platform placed in an atmosphere of 95% O2 and 5% CO2, using supplemented RPMI 1640 cell culture medium.

Culture and morphologic features of small intestinal mucosal explants from weaned pigs.

A virulent field isolate and 2 vaccine strains of Pasteurella multocida A:3,4 were compared for resistance to phagocytosis by turkey macrophages and heterophils, using in vitro assays. The least virulent vaccine strain (M-9) was phagocytosed to a greater degree than was the field isolate or the other vaccine strain (Clemson University). All 3 bacteria differed significantly from each other in the amount of capsular material present as measured by polycationic ferritin labeling and electron microscopy. Removal of the capsule with hyaluronidase resulted in a significant increase in phagocytosis of the field isolate.

Resistance of Pasteurella multocida A:3,4 to phagocytosis by turkey macrophages and heterophils.

Packed cell volume (PCV) reference intervals were established for use in diagnosing anemia and polycythemia in young chickens. Blood samples were collected from 3-to-35-day-old specific-pathogen-free leghorn chicks. PCVs were determined and analyzed. PCVs regressed significantly (P less than 0.0001) on age, which shows that neonatal physiologic anemia occurs in chicks as well as in mammals. The definition for anemia in chicks varies with age. We defined anemia as a PCV less than or equal to 23%, 25%, 26%, 28%, 31%, and 30%, respectively, for chicks 3, 7, 14, 21, 28 and 35 days old. We defined polycythemia as a PCV greater than or equal to 36%, 37%, 38%, 37%, 41%, and 40%, respectively, for chicks 3, 7, 14, 21, 28, and 35 days old. Healthy chicks have PCVs within established reference intervals. Results provide guidelines to detect anemia and polycythemia in young leghorn chicks of various ages.

Packed cell volume reference intervals to aid in the diagnosis of anemia and polycythemia in young leghorn chickens.

What is your diagnosis? Mediastinal mass aspirate from a 10-year-old dog.

The nature of feather inclusions was characterized in 32 psittacine birds (30 cockatoos, one peachfaced lovebird (Agapornis roseicollis), and one red-lored Amazon parrot (Amazona autumnalis autumnalis)) with naturally-acquired psittacine beak and feather disease. Intranuclear inclusions within feather epithelial cells and intracytoplasmic inclusions within macrophages in the feather epithelium and pulp cavity contained psittacine beak and feather disease viral antigen when stained by the avidin-biotin complex immunoperoxidase technique. Ultrastructurally, inclusions were observed primarily within macrophages and to a lesser extent within epithelial cell nuclei. Macrophage inclusions appeared as paracrystalline arrays of viral particles. Intranuclear inclusions were less well defined, although scattered viral particles were present. Intracytoplasmic and intranuclear particles in ultrastructural preparations were identified by colloidal gold labeling as psittacine beak and feather disease virus. Feather epithelium was more frequently and severely involved in the disease process than was adjacent follicular epithelium. Plucked feathers with an intact epidermal collar and feather epithelium were preferred to follicular biopsies for histopathologic examination.

A Novel DNA Virus Associated with Feather Inclusions in Psittacine Beak and Feather Disease

Psittacine beak and feather disease (PBFD) virus was recovered from the feces and crop washings from various species of psittacine birds diagnosed with PBFD. High concentrations of the virus also could be demonstrated in feather dust collection from a room where 22 birds with active cases of PBFD were being housed. The virions recovered from the feces, crop, and feather dust were confirmed to be PBFD virus by ultrastructural, physical, or antigenic characteristics. Virus recovered from the feather dust and feces hemagglutinated cockatoo erythrocytes. The specificity of the agglutination was confirmed by hemagglutination inhibition, using rabbit antibodies against PBFD virus. During the test period, 26% (8 of 31) of the birds screened were found to be excreting PBFD virus in their feces, and 21% (3 of 14) of crop washings were positive for PBFD virus. Some birds in the sample group had active cases of diarrhea, whereas others had normal-appearing feces. Diarrhea was found to be the only significant indicator of whether a bird was likely to be excreting virus from the digestive tract. These findings suggest that exposure of susceptible birds to PBFD virus may occur from contact with contaminated feather dust, feces, or crop secretions. Viral particles that were morphologically similar to parvovirus (20- to 24 nm-icosahedral nonenveloped virions) also were recovered from feces of some of the birds.

Routes and prevalence of shedding of psittacine beak and feather disease virus.

Compendium on Continuing Education for The Practicing Veterinarian

A technique of entraosseous cannulation for intravenous therapy in birds.

interested in mast cell and basophil regulation of immune responses and modulation of nonimmunologic functions. Others will also benefit in becoming aware that mast cells are heterogeneous in differentiation and in function and that these cells may potentially have a role in the many diverse pathologic processes we study everyday. This book might also provide a stimulus for us to examine mast cell biology in domestic animals, an almost untapped area of research in veterinary pathology.

If you have endured the helplessness of having a bird diagnosed with Psittacine Beak and Feather Disease (PBFD), we are sure you will understand the degree of pain and suffering represented by the photographs you see in this article. If you maintain susceptible species of psittacine birds and have not yet been plagued by this disease, be patient! Sooner or later you may experience an outbreak. You may be lucky, and the PBFD virus will only destroy one of your cherished pets. You may, on the other hand, be unlucky and the virus may infect an entire nursery of young psittacine birds. Some choice! We must reach a point where we can control this disease in the same manner in which we prevent distemper, parvovirus and rabies in our dogs and cats. Aviculture needs an effective vaccine for the PBFD virus. It was in the mid-1970s that a slowly debilitating disease was first described in Old World and South Pacific psittacine birds. The syndrome was identified by varying degrees of symmetric feather malformation and loss, development of beak deformities and, usually, death.!-' Through the last decade, this disease has been given many names, including cockatoo beak and feather disease, beak rot, fungal dermatitis, cockatoo feather picking syndrome, molt disease, feather maturatino syndrome, adrenal insufficiency, thyroid insufficiency and French molt. All of these names describe characteristics which have been associated with the disease. Since the syndrome has been diagnosed in numerous psittacine species in addition to cockatoos, the currently accepted name for the syndrome is psittacine beak and feather disease. In Australia, French molt and PBFD have been shown to be caused by the same virus, while in the United States they are currently thought to be two distinct diseases, caused by two different vlruses.> What birds are most at risk for PBFD? If you own psittacine birds, you should be concerned about the spread of this fatal disease. Currently, some 30 species of psittacines are considered susceptible to...

Psittacine Beak & Feather Disease: Will One of Your Birds Die Next?

Cytochemistry was used to differentiate chicken heterophils and eosinophils in blood smears and cytospin preparations of isolated leukocytes. Cytochemical staining also was performed to evaluate any alteration of cell staining characteristics after heterophils had been isolated using discontinuous Ficoll-Hypaque gradients. Cytochemical staining reactions of heterophils and eosinophils were the same before and after discontinuous gradient cell separation. Characteristic positive reactions did not occur when chicken heterophils were stained with alkaline phosphatase, peroxidase, Sudan black B, acid phosphatase, alpha-naphthyl acetate esterase, naphthol AS-D chloroacetate esterase, periodic acid-Schiff, or Luna's eosinophil granule techniques. Chicken eosinophils stained positively when peroxidase, Sudan black B, acid phosphatase, and Luna methods were performed. In highly cellular cytospin preparations, peroxidase reactions readily distinguished the few contaminating eosinophils (< 1%) from the heterophils.

Cytochemical staining characteristics of chicken heterophils and eosinophils.

The purpose of this study was to determine the ability of three strains or isolates of Pasteurella multocida (serotype 3,4) to generate chemotactic factors for heterophils when exposed to pooled turkey serum. Results indicated that each bacterial strain or isolate (M-9, CU, and 86-1913) was associated with the production of chemotactic factors, but the more pathogenic bacterial isolate (86-1913) elicited greater heterophil migration in chemotaxis studies.

Turkey heterophil chemotaxis to Pasteurella multocida (serotype 3,4)-generated chemotactic factors.

Adherence of chicken heterophils was evaluated at 37 C using preconstructed columns containing various weights of nylon fiber (75 mg, 100 mg, or 125 mg) and whole blood anticoagulated with sodium heparin or 10% disodium ethylenediamine tetraacetic acid (EDTA). Additionally, 50-mg and 75-mg nylon fiber columns incubated at 41 C were used to evaluate heterophil adherence at an increased temperature. The mean percent adherence for heparin-anticoagulated blood applied to 75-mg, 100-mg, and 125-mg nylon fiber columns at 37 C was 76%, 92% and 97.4%, respectively. Samples applied to 50-mg and 75-mg columns at 41 C had adherence values of 27% and 85%, respectively. When paired samples of blood anticoagulated with EDTA or heparin were evaluated, the EDTA samples had significantly decreased heterophil adherence (paired t-test). Results indicate that increased or decreased adherence of chicken heterophils would best be detected using 75-mg nylon fiber columns incubated 37 C and whole blood collected in sodium heparin.

Thirty-five birds that died with naturally acquired psittacine beak and feather disease (PBFD) were necropsied to identify extracutaneous viral inclusions. Inclusions were found in various tissue sections from 34 of 35 birds. By immunoperoxidase staining, intranuclear and intracytoplasmic inclusion bodies were shown to contain PBFD viral antigen. Inclusion-bearing lesions were widely disseminated but often closely associated with the alimentary tract. Lesions within the palate, esophagus, crop, intestine, bursa of Fabricius, and liver probably serve as sources for viral shedding into the feces.

Extracutaneous Viral Inclusions in Psittacine Beak and Feather Disease

Psittacine beak and feather disease (PBFD) virus, was purified from diseased tissues of a lesser sulphur-crested cockatoo (Cacatua sulphurea), a black palm cockatoo (Probosiger aterrimus), a red-lored Amazon parrot (Amazona autumnalis), and a peach-faced lovebird (Agapornis roseicollis). The histopathology of diseased feathers and follicular epithelium from the different species was compared; basophilic intranuclear inclusion bodies were identified in the follicular epithelium and intracytoplasmic globular inclusions were observed within macrophages located in the feather pulp from the four species. Psittacine beak and feather disease virus antigen was specifically detected by colloidal gold immunoelectron microscopy. The different preparations of purified virions displayed an icosahedral symmetry, were non-enveloped, and had a mean diameter that varied from 12 to 15 nm when negatively stained. Two major viral-associated proteins with approximate molecular weights of 26 and 23 kilodaltons (kd) were consistently demonstrated from the four viral preparations. Purified virions from the four genera were antigenically related. These findings suggest that the PBFD virus purified from numerous genera of diseased birds is similar based on ultrastructural characteristics, protein composition and antigenic reactivity.

ULTRASTRUCTURAL, PROTEIN COMPOSITION, AND ANTIGENIC COMPARISON OF PSITTACINE BEAK AND FEATHER DISEASE VIRUS PURIFIED FROM FOUR GENERA OF PSITTACINE BIRDS

Cardiac sarcocystosis is described in a grand eclectus parrot and a Moluccan cockatoo. Many cysts containing metrocytes were observed within cardiac muscle fibers on tissue sections stained with hematoxylin and eosin. Characteristic ultrastructural features of the cyst walls included the presence of villous projections containing microtubules. Compartmentalization of the cysts resulted from inward extensions of the cyst wall. The differential diagnosis of sarcocystosis, the life cycle of the parasite, and control measures are discussed.

Myocardial sarcocystosis in a grand eclectus parrot (Eclectus roratus) and a Moluccan cockatoo (Cacatua moluccensis).

Rapid separation of avian heterophils from anticoagulated whole blood was achieved using Ficoll-Hypaque discontinuous gradients. An average of 14.4% of blood heterophils was harvested with a mean purity exceeding 99%. Heterophil viability, as determined by trypan blue dye exclusion, averaged 99.8%. The integrity of isolated heterophils was evaluated by cytochemical staining and ultrastructural examination. Cytochemical staining reactions of heterophils in whole blood and of isolated cell suspensions were similar. No ultrastructural abnormalities were observed. Using this procedure, viable intact heterophils were rapidly isolated from blood with an acceptable cell yield and purity for cell function studies.

Separation of avian heterophils from blood using Ficoll-Hypaque discontinuous gradients.

Characterization of a new virus from cockatoos with psittacine beak and feather disease.

The effect of cyclosporine A on reovirus-infected male broiler chickens was studied. Beginning at 1 or 10 days of age, 3 groups of 15 broilers were injected in the pectoral muscle with 50 mg of cyclosporine A (CSA) in oil per kg body weight every 3 days until 28 days. Controls were injected with olive oil. Two CSA-injected groups and one untreated group were orally infected with 1000 TCID50 of reovirus at 1 day of age. Cell-mediated immunity was evaluated at 17 and 24 days by a delayed-wattle-response test to injected phytohemagglutinin (PHA-M). Cyclosporine A and reovirus significantly (P less than 0.001) depressed the wattle response following the first injection of PHA-M but not the second. At necropsy 28 days postinoculation (PI), no gross lesions were apparent. Histologic lesions in birds infected with reovirus were lymphocytic pericarditis and tenosynovitis; synovial cells were hyperplastic, and heterophils and fibrin were in synovial spaces. Thymic medullary diameters were significantly (P less than 0.001) smaller in all CSA-treated birds. Although CSA suppressed cell-mediated immunity somewhat, there were no apparent differences in severity of microscopic lesions among reovirus-infected groups.

Plasma and serum protein concentrations were determined in chickens and turkeys by refractometry (with human and veterinary refractometers) and by the biuret method. Chicken and turkey serum protein values were significantly lower than respective plasma protein values according to both methods. Refractometer readings for both plasma and serum correlated closely with the results of the biuret test (r2 = 0.72 to 0.97). These findings indicate that plasma and serum protein values may be determined accurately in chickens and turkeys with a handheld refractometer.

Determination of chicken and turkey plasma and serum protein concentrations by refractometry and the biuret method.

A Review of Psittacine Beak and Feather Disease: Characteristics of the PBFD Virus

Leukocyte function was evaluated in five dogs with Pelger-Huet (P-H) anomaly and in five control dogs. No significant differences were found between groups In neutrophil adherence, random movement, chemotaxis, phagocytosis, or bacterial killing of Staph ylococcus intermedlus. Neutrophils migrated rapidly into inflammatory sites where progressIve nuclear lobulation was noted over time. Antibody titers to exogenous antigens were similar in the P-H and control groups indicating B- and 1-lymphocyte cooperation in humoral immunity. Lymphocyte biastogenesis to phytohemagglutinin also was similar in both groups suggestIng the presence of a responsive T-lymphocyte population. These findings indicate that no apparent predisposition to infection or immunodeficiency exists in dogs with P-H anomaly.

A 9-year-old cat was evaluated for left-sided enophthalmos and protrusion of the third eyelid. A primary orbital fibrosarcoma was diagnosed. During the orbital exploration, normal periorbital fascia could not be identified in the lateral and ventral region, thus accounting for the enophthalmos.

A method is presented to separate turkey heterophils from anticoagulated whole blood using two-step Ficoll-Hypaque discontinuous gradients and ammonium chloride lysis of contaminating erythrocytes. Heterophils can be isolated from multiple blood samples within 3 to 4 hours. Using this technique, 66.4 +/- 18.4% (mean +/- standard deviation) of blood heterophils were harvested. Final cell isolates averaged 96.0 +/- 2.9% heterophils with few contaminating eosinophils (2.5 +/- 2.3%) or basophils (1.6 +/- 1.8%). Cell viability, as determined by trypan blue dye exclusion, was 98.0 +/- 1.4%.

Separation of turkey heterophils from blood using two-step Ficoll-Hypaque discontinuous gradients.

Adult wild-trapped opossums were infected with Leishmania donovani (Khartoum strain, WR 378) and evaluated as an animal model of visceral leishmaniasis. All infected opossums died within 32 days. Loss of body fat, hepatomegaly, and petechiae of skin and abdominal musculature were seen at necropsy. Microscopically, numerous amastigote-laden macrophages were seen in histologic sections of liver, spleen, and lymph nodes; fewer parasite-laden macrophages were in the bronchial-associated lymphoid tissues and renal glomeruli. Hematological findings included thrombocytopenia (terminal), neutropenia, and lymphopenia. Blood lymphocyte blastogenesis in response to concanavalin A and phytohemagglutinin was decreased markedly at day 24 post-infection (PI). Serum antibodies (1:40 dilution) to promastigotes of L. donovani were detected in five of eight infected opossums tested on days 10 and 24 PI. Total bilirubin concentrations and alanine aminotransferase and aspartate aminotransferase activities were increased after day 25 PI. Activated partial thromboplastin times and one-stage prothrombin times were prolonged before death. Concurrently, factors V, VIII, and XII activities were decreased.

Leukocyte function was evaluated in five dogs with Pelger‐Huët (P‐H) anomaly and in five control dogs. No significant differences were found between groups in neutrophil adherence, random movement, chemotaxis, phagocytosis, or bacterial killing of Staphylococcus intermedius. Neutrophils migrated rapidly into inflammatory sites where progressive nuclear lobulation was noted over time. Antibody titers to exogenous antigens were similar in the P‐H and control groups indicating B‐ and T‐lymphocyte cooperation in humoral immunity. Lymphocyte blastogenesis to phytohemagglutinin also was similar in both groups suggesting the presence of a responsive T‐lymphocyte population. These findings indicate that no apparent predisposition to infection or immunodeficiency exists in dogs with P‐H anomaly.

Mucocutaneous plasmacytomas were diagnosed in 75 dogs. Medical records and communication with owners and referring veterinarians provided information regarding location and description of the tumor, clinicopathologic data, treatment, and postoperative status of the dogs. Males and females were equally represented, and most dogs were aged adults (mean, 9.7 years). Tumors developed most commonly in the mouth, on the feet or trunk, and in the ears. Plasmacytomas were confined to the skin and mucosa in 70 dogs. Two dogs had disseminated lymphoid neoplasia, and 1 dog developed cutaneous plasmacytoma during clinical remission of lymphosarcoma. Two dogs had multiple myeloma, which was diagnosed concurrently or within a few weeks of diagnosis of the cutaneous tumor. Multiple plasmacytomas were found in 10 dogs but were not associated with clinical signs of generalized disease. Tumors did not recur after surgical excision. Clinicopathologic values, when determined, were normal in all dogs with localized plasmacytomas.

A 4-month-old Pomeranian pup was examined because of anorexia, salivation, and persistent vomiting. Initial laboratory testing revealed marked hemolytic anemia with spherocytosis. Survey abdominal radiography revealed 4 metal objects which, when removed by gastrotomy, were identified as pennies. Of 4 pennies, 3 were minted since 1983 and were heavily pitted over the surface and rim. Partially digested pennies were composed of a copper-plated high zinc concentration alloy. Further laboratory testing indicated a marked increase in serum zinc concentration in the pup (28.8 mg/L), confirming metal toxicosis. Serum zinc concentrations decreased during recovery.

Zinc-induced hemolytic anemia caused by ingestion of pennies by a pup.

In order to better characterize spontaneous respiratory cryptosporidiosis in chickens, a retrospective examination of histopathology reports from the Georgia Poultry Laboratories for an 18-mo period (4/1/86 to 9/30/87) was made; 12 cases were found. Collected data were analyzed and certain epidemiologic and histologic features were identified. Eleven of the 12 cases involved broiler type chickens. The ages of chickens with respiratory cryptosporidiosis were evenly distributed between 17 and 52 days of age. The infected birds were always clinically ill. Viruses or bacteria or both often accompanied respiratory Cryptosporidium sp. infections. Histologic lesions (including those of ciliary-adherent bacteria) are described. As the inflammatory response in infected organs became progressively nonpurulent (lymphocytes and plasma cells predominate), numbers of Cryptosporidium diminished. Cytologic preparations were useful for making diagnoses of respiratory cryptosporidiosis in chickens. Identification of epidemiologic features of respiratory cryptosporidiosis, and improved ability to make accurate and prompt diagnoses of Cryptosporidium sp. infection, are vital for a more complete understanding of the impact of this disease on poultry health.

Renal tubular carcinoma was believed responsible for hematuria and extreme leukocytosis in a dog. Other paraneoplastic syndromes possibly associated with this neoplasm included fever, thoracolumbar hyperesthesia, and anemia attributable to myelophthisis. All clinical and clinicopathologic abnormalities resolved after unilateral nephrectomy. Neutrophil cytochemical stains were used to differentiate leukemoid reaction from myelocytic leukemia as the cause of the leukocytosis. The extreme leukocytosis in this dog may have been leukemoid reaction caused by production of colony-stimulating factor by the renal tubular carcinoma.

Hematuria and extreme neutrophilic leukocytosis in a dog with renal tubular carcinoma.

Pelger-Huet anomaly is an inherited disorder of leukocyte development characterized by persistent nuclear hyposegmentation of granulocytes and monocytes in the presence of a mature, coarse chromatin pattern. The anomaly has been reported sporadically in humans, but is rare in In humans and animals, Pelger-Huet anomaly usually is encountered in the heterozygous form where most blood granulocytes and monocytes have indented, band-shaped, or bilobed nuclei. In the homozygous form of Pelger-Huet anomaly, however, granulocytes and monocytes generally have round to oval nuclei with a very coarse chromatin pattern.2 The homozygous form of the anomaly is extremely rare, and has only been described in rabbits6 and, presumably, in nine human^.^,^ In a prospective breeding study, a brother-sister test mating of two cats that were heterozygous for the Pelger-Huet trait7 produced a litter of five kittens, three of which were stillborn (Table 1). One stillborn kitten was small and had a domeshaped skull with a flattened face and protruding tongue. The hard palate was intact. All limbs were short, thickened, and had severe medial deviation (Fig. 1). Survey radiographs demonstrated extensive axial and appendicular skeletal changes when compared to the other two stillborn littermates (Fig. 2). A dome-shaped skull and shortenednasal bones were apparent. Vertebral bodies were shortened longitudinally with concave ends, and the ribs also were shortened with flared costochondral junctions. The costochondral cartilage was longer than in the unaffected littermates. Appendicular skeletal abnormalities consisted of shortened long bones with cup-shaped metaphyses. Radiographic skeletal lesions were not seen in the remaining stillborn kittens. One live littermate also had skeletal abnormalities, including pectus excavatum, lordosis, longitudinal compression of the vertebral bodies, and flaring of the distal radial metaphyses. The remaining live kitten had no radiographic abnormalities of the skeletal system. Radiographic findings in both affected kittens were compatible with chondrodysplasia. Examination of Wright-stained smears of umbilical cord blood made at birth revealed that the runted stillborn kitten had a differential leukocyte count of 43% neutrophils, 9% monocytes, 42% lymphocytes, 3% eosinophils, and 3% basophils. The majority of blood granulocytes and monocytes had round to oval nuclei (Fig. 3). All leukocytes, including lymphocytes, had a very coarse, patchy chromatin pattern. Toxic changes of the neutrophil cytoplasm were not observed. Based on the leukocyte phenotype, the hematologic diagnosis was homozygous Pelger-Huet anomaly. In contrast, umbilical cord blood smears from three of the four remaining kittens had band to bilobed leukocyte nuclei which were considered typical of the heterozygous state of PelgerHuet anomaly. In these individuals, the chromatin pattern was less aggregated than in the homozygous kitten. The live chondrodysplastic kitten had a normal leukocyte phenotype, with most neutrophils having three nuclear lobes. Neutrophil mean nuclear scores were calculated, following published guidelines, on blood smears from each kitten.’ The calculated mean nuclear score (1.39) of the homozygous Pelger-Huet kitten was significantly lower than the neutrophil mean nuclear scores of the heterozygous Pelger-Huet (3.13-3.23) and normal phenotype (4.62) littermates (Table 1). The three stillborn kittens were necropsied, and tissues were collected in 10% buffered formalin. Evidence of hydrocephalus in the runted kitten was not found on gross inspection of coronal brain sections. Skeletal tissues were decalcified, and all tissues were processed routinely, embedded in paraffin, sectioned at 5 pm, and stained with hematoxylin and eosin (HE). Microscopic lesions were seen only within the skeletal system of the runted stillborn kitten and involved both the axial and appendicular skeleton and were consistent with chondrodysplasia. Long bones of the limbs were shortened, thickened, and had broad, mushroom-shaped epiphyses (especially noticeable in the distal epiphyses). The physeal zones were incompletely formed with partial or irregular endochondral ossification at the center of the physis and more normal endochondral ossification at the periphery of the physis. Central areas of the physis occasionally were necrotic and associated with a failure of vascular invasion.

Homozygous Pelger-Huët Anomaly and Chondrodysplasia in a Stillborn Kitten

Leukocyte changes in chickens with turpentine-induced inflammation were investigated sequentially at 0, 6, 12, and 24 hours and at 2, 3, 4, 7, and 14 days. During acute inflammation, significant leukocytosis and heterophilia developed by 6 hours and persisted through 7 days. The peak mean heterophil and leukocyte counts occurred at 12 hours and 3 days, respectively. Left shifts were present at 12 and 24 hours as detected by 100-cell leukocyte differential counts. Heterophil mean nuclear scores documented nuclear hyposegmentation (left shift) during early inflammation and nuclear hypersegmentation (right shift) during convalescence. Mean monocyte and lymphocyte counts peaked at 2 and 3 days, respectively. Basophil and eosinophil counts were erratic. Toxic changes of heterophils were most apparent during intense left shifts and consisted of cell swelling, degranulation, cytoplasmic vacuolation, and cytoplasmic basophilia. Cytoplasmic basophilia was the last aspect of toxic change to resolve. Ultrastructurally, toxic heterophils had intracellular edema, dissolution of granules, retention of ribosomes, nuclear membrane blebs, and decreased heterochromatin density. All inflammation-associated alterations in cell counts and morphology returned to baseline values and appearance by 14 days after turpentine administration.

Leukocyte changes associated with acute inflammation in chickens.

A method is presented for the rapid cytologic detection of cryptosporidial oocysts in Diff-Quik and modified Kinyoun acid-fast-stained tracheal imprints. On Diff-Quik-stained preparations, cryptosporidial oocysts were observed attached to the apical ends of respiratory epithelial cells or scattered throughout the imprint. These oocysts were round to oval, measured approximately 6 to 7 micron in diameter, and appeared faintly blue with fine pink granules. In modified Kinyoun acid-fast-stained tracheal imprints, the oocysts usually were pink to bright red against a blue background. Cytologic examination of tracheal imprints following Diff-Quik and modified Kinyoun acid-fast staining provides a rapid, reliable, and economical method for diagnosis of respiratory cryptosporidiosis in poultry.

Rapid cytologic diagnosis of respiratory cryptosporidiosis in chickens.

A squamous cell carcinoma in situ (corneal intraepithelial neoplasia) was diagnosed in the right eye of an 11-year-old female Golden Retriever. Papillomavirus antigen was not detected in the excised tissues, and the tumor was suspected to be a sequel to previous injury. The tumor was removed by lamellar keratectomy, and the surgical bed was subjected to double freeze-thaw cryotherapy. Tumor regrowth was not apparent approximately one year after treatment.

Nuclear segmentation, ultrastructure, and cytochemistry of blood cells from dogs with Pelger-Huët anomaly.

Intact Haemophilus pleuropneumoniae cells (strain Shope 1, serotype 1), highly purified lipopolysaccharide (LPS) obtained from this strain of H pleuropneumoniae, as well as from Escherichia coli O111:B4, filter-sterilized H pleuropneumoniae cell-free culture supernatant fluid, and heat-inactivated supernatant fluid were given intranasally to CF1 mice and intratracheally to pigs. Pulmonary lesions induced by H pleuropneumoniae in mice were similar to those induced by H pleuropneumoniae in pigs. Histologically, lungs of mice and pigs killed 1 or 2 days after inoculation with 200 micrograms of highly purified H pleuropneumoniae LPS had lesions similar to one another and were similar to those in mice and pigs given intact H pleuropneumoniae, except that little or no necrosis or hemorrhage was observed. In mice killed 1 or 2 days after inoculation of 200 micrograms of E coli O111:B4 LPS, pulmonary lesions were similar to those in mice given H pleuropneumoniae LPS. Pulmonary lesions in mice given cell-free culture supernatant fluid obtained from a midlog-phase growth culture of H pleuropneumoniae cultivated in a chemically defined medium were severe and consisted of neutrophil infiltration and extensive necrosis. In mice, the heat-inactivated supernatant fluid produced mild lesions that consisted of foci of neutrophil aggregation and no necrosis. Extensive necrosis observed in lesions caused by cell-free culture supernatant fluid could be attributed to the action of a heat-labile component, perhaps by the extracellular heat-labile hemolysin produced by H pleuropneumoniae cultivated in chemically defined medium. A LPS endotoxin and a heat-labile factor may be involved in the pulmonary lesion development in the acute phase of porcine Haemophilus pleuropneumonia.

Role of haemophilus pleuropneumoniae lipopolysaccharide endotoxin in the pathogenesis of porcine Haemophilus pleuropneumonia.

Food hypersensitivity was diagnosed in a 4-year-old Siamese cat. Clinical signs included intense erythema, with alopecia, excoriations, erosions, and crusts involving the ventral portion of the abdomen, inguinal region, medial aspect of each thigh, and cranial and lateral aspects of all 4 limbs. The cat was intensely pruritic. Histologically, there was cutaneous mast cell hyperplasia and diffuse infiltration of eosinophils in the dermis. Blood eosinophilia also was found. Clinical signs resolved after exclusive feeding of a hypoallergenic diet.

Continuous-flow centrifugation leukapheresis techniques were used to collect 300-ml volumes of leukocyte-rich plasma from 5 nonmedicated horses and from 5 corticosteroid-stimulated horses. White blood cell counts and differential counts were performed on the horses before (base line) and up to 48 hours after leukapheresis. Systemic administration of hydrocortisone increased numbers of total WBC and neutrophils and improved harvest of these cells. Nonmedicated horses had a mean yield of 3.38 X 10(10) leukocytes in the 300-ml volume. Stimulated horses yielded a mean of 6.88 X 10(10) leukocytes. After leukapheresis, WBC counts decreased a mean of 38% in nonstimulated horses and decreased a mean of 30% in stimulated horses. By 6 hours after leukapheresis, circulating WBC counts of horses in both groups had returned to preleukapheresis values. The relationship between neutrophil yield and the 4 variables (preleukapheresis WBC count, preleukapheresis neutrophil count, preleukapheresis lymphocyte count, and the PCV of the leukocyte-rich plasma) were examined, using simple (pair-wise) correlation and multiple linear regression. A significant positive correlation was found between neutrophil yield and preleukapheresis WBC and neutrophil counts. Because sodium citrate was used in the collection system to prevent extracorporeal blood coagulation, ionized and total serum calcium concentrations were monitored before and after leukapheresis. Although total serum calcium concentrations remained unchanged, ionized calcium concentrations decreased approximately 33% from base-line values during the 2-hour leukapheresis procedures. Occasional mild muscle fasciculations were the only adverse clinical signs of citrate toxicity exhibited by the horses.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of leukapheresis and thrombocytapheresis in the horse.

In a continuous-flow centrifugation apheresis technique adapted for blood-component separation and collection in horses, hydroxyethyl starch was not required for erythrocyte sedimentation. The efficacy and separation characteristics of whole blood from 10 horses were evaluated at various gravitational forces (700 to 1,500 rpm), using a constant withdrawal rate (100 ml/min). Maximum leukocyte collection occurred at 700 rpm (P less than 0.01), and optimal neutrophil collection occurred at 700 to 750 rpm (P less than 0.01). Although neutrophil counts decreased and lymphocyte counts remained constant at higher rpm settings, an optimal rpm range could not be determined for lymphocyte collection. Peak platelet collection occurred at 1,500 rpm. The response of whole blood from 5 horses was evaluated at lower (500 to 700 rpm) and higher (1,400 to 2,200 rpm) centrifuge speeds. A constant whole blood withdrawal rate of 100 ml/min and a leukocyte collection rate of 3 ml/min were maintained. The optimal rpm settings were determined and compared with values obtained from the 10 horses. Significant differences (P less than 0.01) did not exist between maximum numbers of leukocytes collected at low and high speeds. There was a significant (P less than 0.01) decrease in neutrophils and a concomitant increase in the numbers of lymphocytes recovered at the higher rpm. Platelet yields increased as rpm was increased to 2,000.

Pelger-Huët anomaly was diagnosed in a young male cat on the basis of persistent nuclear hyposegmentation of blood granulocytes, absence of clinical disease or feline leukemia virus infection, and demonstration of genetic transmission of the anomaly. Neutrophils, eosinophils, basophils, and monocytes had significantly less nuclear segmentation when compared to similar leukocyte types from a control cat. On smears of bone marrow, megakaryocytes also appeared hyposegmented. A test mating with an unaffected queen produced a litter of five kittens (three males, two females). One male and one female kitten had the Pelger-Huët trait on examination of blood smears. Autosomal dominant transmission of this anomaly is suspected based on these findings.

A micromethod was used in order to quantitate intestinal D-xylose absorption in young and extremely small birds. This test was performed in broilers collected from two farms from which birds were extremely uneven in body size and were passing poorly digested or undigested feed. A similar syndrome had been seen on all grow-outs during the 6 months before this investigation. Broilers were also collected and tested from three farms where no clinical signs of disease were seen. D-Xylose absorption peaks and curves for normal broilers closely resembled those observed in normal humans. Mean plasma D-xylose concentrations for virus-infected broilers and for broilers with pale-bird syndrome were consistently lower than concentrations for normal broilers (P = 0.009). Reoviruses, small coronavirus-like particles, small round virus particles, and abundant bacterial flagellar fragments were seen in fecal samples from broilers with pale-bird syndrome. Production performance was lowest on farms showing clinical signs of this syndrome.

Quantitation of intestinal D-xylose absorption in normal broilers and in broilers with pale-bird syndrome.

Transient diabetes mellitus associated with prednisone therapy in a dog.

Altered immune function in a dog with disseminated protothecosis.

Both a standard method and a modified micromethod of quantitating intestinal D-xylose absorption were successfully performed in turkeys. Absorption peaks and curves for both tests closely resembled those observed in humans. The micromethod was preferred because it could be performed in poults as young as 3 days of age, required a smaller sample size, and was more economical and less time-consuming. Both tests were suitable for experimental and clinical determination of small intestinal absorptive function in the turkey.

Quantitation of intestinal D-xylose absorption in normal turkeys.

Dirofilaria immitis ova in a transthoracic fine-needle aspirate from a dog.

A micromethod was modified to quantitate intestinal D-xylose absorption in young and extremely small birds. This test was performed in control and cloned-reovirus-inoculated turkey poults to investigate intestinal absorptive function. Absorption peaks and curves for control poults closely resembled those observed in normal humans. Poult groups absorbed significantly less D-xylose at 24 and 72 hours (P less than 0.0001 and P less than 0.0008, respectively) but not at 120 hours (P = 0.3178) after receiving a single oral dose of cloned reovirus. The modified D-xylose absorption test is suitable for experimental and clinical determination of absorptive function of the small intestine in the fowl.

Quantitation of intestinal D-xylose absorption in normal and reovirus-inoculated turkeys.

Neutrophil adherence, random movement, and chemotaxis were quantitated in healthy nondiabetic dogs and in dogs with experimentally induced diabetes mellitus. On the basis of glycosylated serum protein values, the diabetic dogs were subdivided into well-controlled and poorly controlled groups. Neutrophil adherence was decreased significantly in poorly controlled diabetic dogs, but significant differences in neutrophil adherences were not found between nondiabetic and well-controlled diabetic dogs. Significant differences in neutrophil random or chemotactic movements were not found between non-diabetic and diabetic dogs. The decreased neutrophil adherence observed in poorly controlled diabetic dogs may predispose these animals to bacterial infection. Therefore, stringent regulation of blood glucose concentrations may decrease the frequency of secondary bacterial infections in spontaneous diabetes mellitus in dogs.

Neutrophil adherence and movement in poorly and well-controlled diabetic dogs.

Neutrophilic movement was studied in dogs with atopy, 3 bacterial pyoderma syndromes, flea allergy dermatitis, and generalized demodicosis. Random neutrophil movement was decreased in generalized demodicosis, and this deficit correlated with the extent of body surface skin lesions. Neutrophilic chemotactic movement was decreased in 2 bacterial pyoderma syndromes: bacterial pyoderma, and staphyloccocal pyoderma. Although serum samples from diseased dogs showed no significant differences in chemoattractive qualities from normal pooled canine serum, control canine neutrophils incubated in demodectic dog serum showed decreased chemotactic responsiveness. It was postulated that demodectic dog serum had an inhibitor or deactivator of neutrophil chemotaxis.

Complete blood cell counts and peritoneal lavage (PL) were done 2 days before and 2 days after abdominal surgery. Abdominal surgery consisted of intestinal resection/anastomosis and cystotomy in 18 dogs in group 1 and gastrotomy, pyloromyotomy, and repair of diaphragmatic laceration in 20 dogs in group 2. Insertion of the dialysis catheter for PL preoperatively in a right paramedian location resulted in more PL samples contaminated with blood than when the catheter was inserted on the abdominal midline. The number of nucleated cells found in PL fluid when the catheter was inserted in a right paramedian location was not significantly different (P less than 0.05) from that observed in PL fluid collected after insertion of the catheter through the abdominal midline. The predominant cell type in preoperative PL fluid was the segmented neutrophil. In groups 1 and 2, WBC counts and nucleated cell counts in PL fluid were significantly increased (P less than 0.05) postoperatively. Segmented neutrophils and macrophages were most frequently present in postoperative PL fluid. Degenerative neutrophils in postoperative PL fluid were associated with the appearance of immature neutrophils in the blood and increased rectal temperature. Dogs with these findings appeared to have more peritoneal inflammation at necropsy than did others in their groups. Concentrations of alkaline phosphatase, alanine aminotransferase, amylase, and creatinine in preoperative PL fluid were extremely low. Except for creatinine in group 2, all of these were significantly increased (P less than 0.05) postoperatively. The complication rate associated with the performance of PL on dogs postoperatively was not greater than that which was observed preoperatively.

Diagnostic peritoneal lavage before and after abdominal surgery in dogs.

Random and chemotactic neutrophilic movements in a Basenji with Pelger-Huët (P-H) anomaly was compared with such movement in 5 healthy control dogs. Duplicate samples of neutrophils were quantitated after 5, 10, 15, 30, and 45 minutes of incubation. On the basis of population mean responses, no significant difference (P greater than 0.05) was found between P-H and control neutrophils for any type of movement at any time interval examined. These findings indicate that the movement of neutrophils with P-H anomaly may be unaffected by the nuclear abnormality.

A transient neutrophilic chemotactic deficit was confirmed in a 3 1/2-year-old castrated male dog with recurrent staphylococcal pyoderma accompanied by a persistent eosinophilia and intermittent basophilia. Neutrophilic chemotaxis was quantitatively assessed over the next seven months, and the disappearance of the chemotactic deficit correlated with complete clinical remission of the skin lesions. Aberrations of the complement system were not discovered, and the dog's serum showed increased chemoattractiveness for control neutrophil preparations.

A Transient Deficit in Neutrophilic Chemotaxis in a Dog with Recurrent Staphylococcal Pyoderma

A quantitative evaluation of neutrophilic chemotaxis was performed, using neutrophils from 12 healthy Beagles. Dextran sedimentation, differential centrifugation, and hypotonic lysis allowed separation of a neutrophil-rich cell suspension. Chemotaxis was studied, using blind-well chambers with 3-micrometers (APD) polycarbonate filters. A frozen (-80 C) bank of pooled normal canine serum was used as the chemotactant, and the chemotactant properties of the serum were destroyed by heat inactivation at 56 C for 30 minutes. Based on membrane and lower blind-well chamber solution neutrophil counts, a method was devised to distinguish between normal neutrophilic chemotaxis, normal neutrophilic chemotaxis with decreased neutrophilic adherence, and defective neutrophilic chemotaxis.

Reliable data on the risk of transmission of N. gonorrhoeae would enhance our understanding of the importance of host defenses against gonorrhea and would aid in the evaluation of prophylactic measures. This paper examines the risk of transmission of gonorrhea from infected female to male and the role that variables such as race, prophylaxis and amount of exposure play in the development of gonococcal urethritis. Volunteer crew members of a large naval vessel were followed prospectively as a cohort to study their risk of acquiring gonococcal infection during a four-day liberty period in the Far East. At the same time the prevalence of N. gonorrhoeae was determined in a population of females to whom the sailors were exposed. The calculated risk of transmission per exposure with an infected partner was .19 for whites and .53 for blacks. A statistically significant relationship was noted between the risk of transmission of gonorrhea and both the number of partners and the frequency of sexual intercourse. Further, the increasing infection rate with increasing numbers of exposures in men who had a single sex partner suggests that the majority of men are in fact susceptible to gonorrhea if the quantity of exposure is sufficient.

Cohort study of venereal disease. I: the risk of gonorrhea transmission from infected women to men.

In January 1976, 79 persons in Jamaica were acutely poisoned by the organophosphorus insecticide parathion. Seventeen died. Cases occurred in three episodes at separate locations, but all patients had consumed wheat flour from a single lot consisting of 5264 cotton bags. Parathion in concentrations of less than 1 to 9900 ppm was identified in flour from six bags in this lot; three had splash marks. The flour had been milled in Western Europe from European wheat, carried in trucks to a dockside warehouse, and loaded aboard ship after 2-5 days' storage. In Jamaica, the flour had moved from quayside to outbreak locations along separate routes through two import houses. Site inspections and review of shipping records suggested that the likely point of contamination was the European port, where foodstuffs and insecticides were stored in the same warehouse.

Fatal parathion poisoning caused by contamination of flour in international commerce.

It is widely believed that the rising incidence of venereal diseases (especially syphilis and gonorrhea) observed in numerous countries over the past decade is likely to continue in coming years. This line of thought has encouraged health administrators to plan and implement measures that will broaden our knowledge of this problem and lead to more effective control. In view of the need to revitalize and develop such programs in many parts of the Americas, some comments on difficulties revealed by past experience are in order. For one thing, the economic situation faced by developing countries limits the financial resources available for specific measures. For another-despite incomplete evidence-it seems likely that the major health problem posed by these diseases is itself aggravated by various environmental factors resulting from underdevelopment (I). Compounding this, the health service infrastructure, which is frequently inadequate and ill-supplied

Alternative designs and methods for venereal disease control programs

Boletin de la Oficina Sanitaria Panamericana. Pan American Sanitary Bureau

Throughout the Covid‐19 pandemic, we have become used to seeing daily numbers of cases and deaths go up and down. But in some countries, the reported numbers show very little movement over days and weeks – they are “underdispersed”, says Dmitry Kobak, and this may be a sign that all is not right with the data

Neighbor embedding methods t -SNE and UMAP are the de facto standard for visualizing high-dimensional datasets. They appear to use very different loss functions with different motivations, and the exact relationship between them has been unclear. Here we show that UMAP is effectively negative sampling applied to the t -SNE loss function. We explain the difference between negative sampling and noise-contrastive estimation (NCE), which has been used to optimize t -SNE under the name NCVis. We prove that, unlike NCE, negative sampling learns a scaled data distribution. When applied in the neighbor embedding setting, it yields more compact embeddings with increased attraction, explaining differences in appearance between UMAP and t -SNE. Further, we generalize the notion of negative sampling and obtain a spectrum of embeddings, encompassing visualizations similar to t -SNE, NCVis, and UMAP. Finally, we explore the connection between representation learning in the SimCLR setting and neighbor embeddings, and show that (i) t -SNE can be optimized using the InfoNCE loss and in a parametric setting; (ii) various contrastive losses with only few noise samples can yield competitive performance in the SimCLR setup.

t-SNE Highlights Phylogenetic and Temporal Patterns of SARS-CoV-2 Spike and Nucleocapsid Protein Evolution

Data on excess deaths in Russia in 2020 paint a much bleaker picture of the Covid‐19 death toll than the official daily updated number, argues Dmitry Kobak

Comparing the impact of the COVID-19 pandemic between countries or across time is difficult because the reported numbers of cases and deaths can be strongly affected by testing capacity and reporting policy. Excess mortality, defined as the increase in all-cause mortality relative to the recent average, is widely considered as a more objective indicator of the COVID-19 death toll. However, there has been no central, frequently-updated repository of the all-cause mortality data across countries. To fill this gap, we have collected weekly, monthly, or quarterly all-cause mortality data from 77 countries, openly available as the regularly-updated World Mortality Dataset. We used this dataset to compute the excess mortality in each country during the COVID-19 pandemic. We found that in the worst-affected countries the annual mortality increased by over 50%, while in several other countries it decreased by over 5%, presumably due to lockdown measures decreasing the non-COVID mortality. Moreover, we found that while some countries have been reporting the COVID-19 deaths very accurately, many countries have been underreporting their COVID-19 deaths by an order of magnitude or more. Averaging across the entire dataset suggests that the world's COVID-19 death toll may be at least 1.6 times higher than the reported number of confirmed deaths.

The World Mortality Dataset: Tracking excess mortality across countries during the COVID-19 pandemic

Erratum: Lipovsek et al., “Patch-seq: Past, Present, and Future”

Author response: Tracking excess mortality across countries during the COVID-19 pandemic with the World Mortality Dataset

Single-cell transcriptomic approaches are revolutionizing neuroscience. Integrating this wealth of data with morphology and physiology, for the comprehensive study of neuronal biology, requires multiplexing gene expression data with complementary techniques. To meet this need, multiple groups in parallel have developed “Patch-seq,” a modification of whole-cell patch-clamp protocols that enables mRNA sequencing of cell contents after electrophysiological recordings from individual neurons and morphologic reconstruction of the same cells. In this review, we first outline the critical technical developments that enabled robust Patch-seq experimental efforts and analytical solutions to interpret the rich multimodal data generated. We then review recent applications of Patch-seq that address novel and long-standing questions in neuroscience. These include the following: (1) targeted study of specific neuronal populations based on their anatomic location, functional properties, lineage, or a combination of these factors; (2) the compilation and integration of multimodal cell type atlases; and (3) the investigation of the molecular basis of morphologic and functional diversity. Finally, we highlight potential opportunities for further technical development and lines of research that may benefit from implementing the Patch-seq technique. As a multimodal approach at the intersection of molecular neurobiology and physiology, Patch-seq is uniquely positioned to directly link gene expression to brain function.

Comparing the impact of the COVID-19 pandemic between countries or across time is difficult because the reported numbers of cases and deaths can be strongly affected by testing capacity and reporting policy. Excess mortality, defined as the increase in all-cause mortality relative to the expected mortality, is widely considered as a more objective indicator of the COVID-19 death toll. However, there has been no global, frequently updated repository of the all-cause mortality data across countries. To fill this gap, we have collected weekly, monthly, or quarterly all-cause mortality data from 103 countries and territories, openly available as the regularly updated World Mortality Dataset. We used this dataset to compute the excess mortality in each country during the COVID-19 pandemic. We found that in several worst-affected countries (Peru, Ecuador, Bolivia, Mexico) the excess mortality was above 50% of the expected annual mortality (Peru, Ecuador, Bolivia, Mexico) or above 400 excess deaths per 100,000 population (Peru, Bulgaria, North Macedonia, Serbia). At the same time, in several other countries (e.g. Australia and New Zealand) mortality during the pandemic was below the usual level, presumably due to social distancing measures decreasing the non-COVID infectious mortality. Furthermore, we found that while many countries have been reporting the COVID-19 deaths very accurately, some countries have been substantially underreporting their COVID-19 deaths (e.g. Nicaragua, Russia, Uzbekistan), by up to two orders of magnitude (Tajikistan). Our results highlight the importance of open and rapid all-cause mortality reporting for pandemic monitoring.

Tracking excess mortality across countries during the COVID-19 pandemic with the World Mortality Dataset

Initialization is critical for preserving global data structure in both t-SNE and UMAP

plebiscite was held in Russia concerning 206 constitutional amendments. Voters could only vote yes to all amendments or no to all amendments. Yes won. One amendment allows Vladimir Putin to run for president two more times, potentially remaining leader until 2036. This was not a normal vote. It did not technically qualify as a referendum under Russian constitutional law, so it was not held according to referendum laws. Instead, it was conducted under a set of ad hoc rules, ostensibly to reduce the risk of Covid-19 infection. The rules meant that the vote lasted an entire week rather than a single day, with many makeshift polling stations Suspect peaks in Russia’s “referendum” results

One of the most ubiquitous analysis tools employed in single-cell transcriptomics and cytometry is t-distributed stochastic neighbor embedding (t-SNE) [1], used to visualize individual cells as points on a 2D scatter plot such that similar cells are positioned close together. Recently, a related algorithm, called uniform manifold approximation and projection (UMAP) [2] has attracted substantial attention in the single-cell community. In Nature Biotechnology, Becht et al. [3] argued that UMAP is preferable to t-SNE because it better preserves the global structure of the data and is more consistent across runs. Here we show that this alleged superiority of UMAP can be entirely attributed to different choices of initialization in the implementations used by Becht et al.: t-SNE implementations by default used random initialization, while the UMAP implementation used a technique called Laplacian eigenmaps [4] to initialize the embedding. We show that UMAP with random initialization preserves global structure as poorly as t-SNE with random initialization, while t-SNE with informative initialization performs as well as UMAP with informative initialization. Hence, contrary to the claims of Becht et al., their experiments do not demonstrate any advantage of the UMAP algorithm per se, but rather warn against using random initialization.

UMAP does not preserve global structure any better than t-SNE when using the same initialization

Author response: State-dependent geometry of population activity in rat auditory cortex

A conventional wisdom in statistical learning is that large models require strong regularization to prevent overfitting. This rule has been recently challenged by deep neural networks: despite being expressive enough to fit any training set perfectly, they still generalize well. Here we show that the same is true for linear regression in the under-determined n p situation, provided that one uses the minimum-norm estimator. The case of linear model with least squares loss allows full and exact mathematical analysis. We prove that augmenting a model with many random covariates with small constant variance and using minimum-norm estimator is asymptotically equivalent to adding the ridge penalty. Using toy example simulations as well as real-life high-dimensional data sets, we demonstrate that explicit ridge penalty often fails to provide any improvement over this implicit ridge regularization. In this regime, minimum-norm estimator achieves zero training error but nevertheless has low expected error.

Implicit ridge regularization provided by the minimum-norm least squares estimator when $n\ll p$

A conventional wisdom in statistical learning is that large models require strong regularization to prevent overfitting. Here we show that this rule can be violated by linear regression in the underdetermined $n\ll p$ situation under realistic conditions. Using simulations and real-life high-dimensional data sets, we demonstrate that an explicit positive ridge penalty can fail to provide any improvement over the minimum-norm least squares estimator. Moreover, the optimal value of ridge penalty in this situation can be negative. This happens when the high-variance directions in the predictor space can predict the response variable, which is often the case in the real-world high-dimensional data. In this regime, low-variance directions provide an implicit ridge regularization and can make any further positive ridge penalty detrimental. We prove that augmenting any linear model with random covariates and using minimum-norm estimator is asymptotically equivalent to adding the ridge penalty. We use a spiked covariance model as an analytically tractable example and prove that the optimal ridge penalty in this case is negative when $n\ll p$.

The Optimal Ridge Penalty for Real-world High-dimensional Data Can Be Zero or Negative due to the Implicit Ridge Regularization

Two years ago, Dmitry Kobak, Sergey Shpilkin and Maxim S. Pshenichnikov uncovered anomalies in Russia's election data. Following President Vladimir Putin's re‐election in March this year, they take a fresh look at two new sets of data – but find much the same story within

The accuracy of the sensory neural code depends on the relationship between variability in population activity caused by the stimuli versus variability caused by noise. Whereas a large body of work has addressed this issue at a theoretical level, there have been few systematic empirical investigations using large-scale simultaneous recordings. We studied the geometry of the population code in the rat auditory cortex using sound stimuli varying across two orthogonal dimensions: the difference in sound level between the two ears, and the average level across the ears. We quantified the structure of the code across recordings spanning a wide range of brain states along the activation/inactivation continuum. We found that the nature of the code, both in terms of the stimulus and the noise subspaces, depends strongly on the degree of cortical activation. During the inactive (or synchronized) state, the code is characterized by a prevalence of contra-lateral tuning, a preference for loud sounds, gain-modulated tuning curves and coherent global noise fluctuations overlapping with the signal subspace. In contrast, in the most active (or desynchronized) recordings, there is an approximately symmetric preference between contra-, ipsi-, quiet and loud sounds, no systematic changes in the gain of lateralization tuning curves by sound intensity, and noise fluctuations span dimensions orthogonal to those evoked by the stimuli. Logistic regression could predict the sound lateralization with accuracy similar to the behaving rats, but only during cortical activation. Furthermore, also exclusively during the active state, the lateralization of sounds of different overall level could be decoded with the same accuracy, even by the same decoder, due to an orthogonal representation of level-differences and overall level across the population. Decoding accuracy from surrogate datasets with independent noise across neurons still displays strong state-dependence, suggesting that tuning curve reorganization plays a critical role in the overall effect of brain state on the population code. Our results provide an empirical foundation for the geometry and state dependence of cortical population codes.

State-dependent geometry of population activity in rat auditory cortex

Author response: Demixed principal component analysis of neural population data

Distributed and Mixed Information in Monosynaptic Inputs to Dopamine Neurons

Protests greeted the results of Russia's federal election in 2011, with accusations of vote‐rigging and fraud. With the country heading to the polls again this September, Dmitry Kobak, Sergey Shpilkin and Maxim S. Pshenichnikov shine a light on several anomalies in the election data set

Neurons in higher cortical areas, such as the prefrontal cortex, are often tuned to a variety of sensory and motor variables, and are therefore said to display mixed selectivity. This complexity of single neuron responses can obscure what information these areas represent and how it is represented. Here we demonstrate the advantages of a new dimensionality reduction technique, demixed principal component analysis (dPCA), that decomposes population activity into a few components. In addition to systematically capturing the majority of the variance of the data, dPCA also exposes the dependence of the neural representation on task parameters such as stimuli, decisions, or rewards. To illustrate our method we reanalyze population data from four datasets comprising different species, different cortical areas and different experimental tasks. In each case, dPCA provides a concise way of visualizing the data that summarizes the task-dependent features of the population response in a single figure. DOI: http://dx.doi.org/10.7554/eLife.10989.001

Distributed and Mixed Info rmation in Monosynaptic Inputs to Dopamine Neurons Highlights

We hypothesize that if election results are manipulated or forged, then, due to the well-known human attraction to round numbers, the frequency of reported round percentages can be increased. To test this hypothesis, we analyzed raw data from seven federal elections held in the Russian Federation during the period from 2000 to 2012 and found that in all elections since 2004 the number of polling stations reporting turnout and/or leader's result expressed by an integer percentage (as opposed to a fractional value) was much higher than expected by pure chance. Monte Carlo simulations confirmed high statistical significance of the observed phenomenon, thereby suggesting its man-made nature. Geographical analysis showed that these anomalies were concentrated in a specific subset of Russian regions which strongly suggests its orchestrated origin. Unlike previously proposed statistical indicators of alleged electoral falsifications, our observations can hardly be explained differently but by a widespread election fraud.

Neurons in higher cortical areas, such as the prefrontal cortex, are known to be tuned to a variety of sensory and motor variables. The resulting diversity of neural tuning often obscures the represented information. Here we introduce a novel dimensionality reduction technique, demixed principal component analysis (dPCA), which automatically discovers and highlights the essential features in complex population activities. We reanalyze population data from the prefrontal areas of rats and monkeys performing a variety of working memory and decision-making tasks. In each case, dPCA summarizes the relevant features of the population response in a single ﬁgure. The population activity is decomposed into a few demixed components that capture most of the variance in the data and that highlight dynamic tuning of the population to various task parameters, such as stimuli, decisions, rewards, etc. Moreover, dPCA reveals strong, condition-independent components of the population activity that remain unnoticed with conventional approaches.

Demixed principal component analysis of population activity in higher cortical areas reveals independent representation of task parameters

We investigated motor skill learning using a path tracking task, where human subjects had to track various curved paths as fast as possible, in the absence of any external perturbations. Subjects became better with practice, producing faster and smoother movements even when tracking novel untrained paths. Using a "searchlight" paradigm, where only a short segment of the path ahead of the cursor was shown, we found that subjects with a higher tracking skill took a longer chunk of the future path into account when computing the control policy for the upcoming movement segment. We observed the same effects in a second experiment where tracking speed was fixed and subjects were practicing to increase their accuracy. These findings demonstrate that human subjects increase their planning horizon when acquiring a motor skill.

Motor skill learning by increasing the movement planning horizon

After extensive practice with motor tasks sharing structural similarities (e.g., different dancing movements, or different sword techniques), new tasks of the same type can be learned faster. According to the recent “structure learning” hypothesis (Braun et al., 2009a), such rapid generalization of related motor skills relies on learning the dynamic and kinematic relationships shared by this set of skills. As a consequence, motor adaptation becomes constrained, effectively leading to a dimensionality reduction of the learning problem; at the same time, adaptation to tasks lying outside the structure becomes biased toward the structure. We tested these predictions by investigating how previously learned structures influence subsequent motor adaptation. Human subjects were making reaching movements in 3D virtual reality, experiencing perturbations either in the vertical or in the horizontal plane. Perturbations were either visuomotor rotations of varying angle or velocity-dependent forces of varying strength. We found that, after extensive training with both kinematic or dynamic perturbations, adaptation to unpracticed, diagonal, perturbations happened along the previously learned structure (vertical or horizontal), and resulting adaptation trajectories were curved. This effect is robust, can be observed on the single-subject level, and occurs during adaptation both within and across trials. Additionally, we demonstrate that structure learning changes involuntary visuomotor reflexes and therefore is not exclusively a high-level cognitive phenomenon.

Adaptation Paths to Novel Motor Tasks Are Shaped by Prior Structure Learning

Here we perform a statistical analysis of the official data from recent Russian parliamentary and presidential elections (held on December 4th, 2011 and March 4th, 2012, respectively). A number of anomalies are identified that persistently skew the results in favour of the pro-government party, United Russia (UR), and its leader Vladimir Putin. The main irregularities are: (i) remarkably high correlation between turnout and voting results; (ii) a large number of polling stations where the UR/Putin results are given by a round number of percent; (iii) constituencies showing improbably low or (iv) anomalously high dispersion of results across polling stations; (v) substantial difference between results at paper-based and electronic polling stations. These anomalies, albeit less prominent in the presidential elections, hardly conform to the assumptions of fair and free voting. The approaches proposed here can be readily extended to quantify fingerprints of electoral fraud in any other problematic elections.

Statistical anomalies in 2011-2012 Russian elections revealed by 2D correlation analysis

This article describes current and planned developments on the Croatian railway network. Modernisation is being planned to prepare for Croatia becoming a member state of the European Union. The railways have been restructured into four sections: passenger transport, cargo, train traction and infrastructure. Staff reductions and redeployment will be necessary. An infrastructure project will include construction of new lines, reconstruction of existing ones, and remote train control installation. This project will also concern revitalisation of ports and improved suburban freight services. Joining the European Union will mean competition from other countries' operators. Track maintenance causes delays and line closures, and makes the routes uncompetitive with those through neighbouring countries. Co-operation is being investigated with Slovenian Railways to use trains carrying lorries: alliances between countries are seen as the way forward.

The restructuring and modernisation of Croatian Railways, part of preparations for the accession of Croatia to the European Union, are described. The problems facing Hrvatske Zeljeznice (HZ) in transforming from a state monopolist undertaking to a company operating on market principles are outlined. The restructuring process included reducing the numbers of staff and separating the non-core business activities and core activities (passenger and freight transport) from Croatian Railways. Infrastructure management will be separated from transport operations, in harmonisation with EU rail regulations. Investment has been made in modernising the infrastructure and rolling stock, particularly in the Croatian sections of the Pan-European traffic corridors. New tilting trains and freight wagons will be purchased and existing rolling stock refurbished.

Scientific datasets often have hierarchical structure: for example, in surveys, individual participants (samples) might be grouped at a higher level (units) such as their geographical region. In these settings, the interest is often in exploring the structure on the unit level rather than on the sample level. Units can be compared based on the distance between their means, however this ignores the within-unit distribution of samples. Here we develop an approach for exploratory analysis of hierarchical datasets using the Wasserstein distance metric that takes into account the shapes of within-unit distributions. We use t-SNE to construct 2D embeddings of the units, based on the matrix of pairwise Wasserstein distances between them. The distance matrix can be efficiently computed by approximating each unit with a Gaussian distribution, but we also provide a scalable method to compute exact Wasserstein distances. We use synthetic data to demonstrate the effectiveness of our Wasserstein t-SNE, and apply it to data from the 2017 German parliamentary election, considering polling stations as samples and voting districts as units. The resulting embedding uncovers meaningful structure in the data.

Die Übersterblichkeit macht den wahren Opferzoll deutlich, den Corona in Russland fordert

Supplementary data to "Integer percentages as electoral falsification fingerprints"

Neighbor embedding methods $t$-SNE and UMAP are the de facto standard for visualizing high-dimensional datasets. Motivated from entirely different viewpoints, their loss functions appear to be unrelated. In practice, they yield strongly differing embeddings and can suggest conflicting interpretations of the same data. The fundamental reasons for this and, more generally, the exact relationship between $t$-SNE and UMAP have remained unclear. In this work, we uncover their conceptual connection via a new insight into contrastive learning methods. Noise-contrastive estimation can be used to optimize $t$-SNE, while UMAP relies on negative sampling, another contrastive method. We find the precise relationship between these two contrastive methods and provide a mathematical characterization of the distortion introduced by negative sampling. Visually, this distortion results in UMAP generating more compact embeddings with tighter clusters compared to $t$-SNE. We exploit this new conceptual connection to propose and implement a generalization of negative sampling, allowing us to interpolate between (and even extrapolate beyond) $t$-SNE and UMAP and their respective embeddings. Moving along this spectrum of embeddings leads to a trade-off between discrete / local and continuous / global structures, mitigating the risk of over-interpreting ostensible features of any single embedding. We provide a PyTorch implementation.

Across many brain areas, neural population activity appears to be constrained to a low-dimensional manifold within a neural state space of considerably higher dimension. Recent studies of the primary motor cortex (M1) suggest that the activity within the low-dimensional manifold, rather than the activity of individual neurons, underlies the computations required for planning and executing movements. To date, these studies have been limited to data obtained in constrained laboratory settings where monkeys executed repeated, stereotyped tasks. An open question is whether the observed low dimensionality of the neural manifolds is due to these constraints; the dimensionality of M1 activity during the execution of more natural and unconstrained movements, like walking and picking food, remains unknown. We have now found similarly low-dimensional manifolds associated with various unconstrained natural behaviors, with dimensionality only slightly higher than those associated with constrained laboratory behaviors. To quantify the extent to which these low-dimensional manifolds carry task-relevant information, we built task-specific linear decoders that predicted EMG activity from M1 manifold activity. In both settings, decoding performance based on activity within the estimated low-dimensional manifold was the same as decoding performance based on the activity of all recorded neurons. These results establish functional links between task-specific manifolds and motor behaviors, and highlight that both constrained and unconstrained behaviors are associated with low-dimensional M1 manifolds.

Low-dimensional neural manifolds for the control of constrained and unconstrained movements

Neuroscience has long been an essential driver of progress in artificial intelligence (AI). We propose that to accelerate progress in AI, we must invest in fundamental research in NeuroAI. A core component of this is the embodied Turing test, which challenges AI animal models to interact with the sensorimotor world at skill levels akin to their living counterparts. The embodied Turing test shifts the focus from those capabilities like game playing and language that are especially well-developed or uniquely human to those capabilities, inherited from over 500 million years of evolution, that are shared with all animals. Building models that can pass the embodied Turing test will provide a roadmap for the next generation of AI.

Toward Next-Generation Artificial Intelligence: Catalyzing the NeuroAI Revolution

Intracortical brain-computer interfaces (iBCIs) enable paralyzed persons to generate movement, but current methods require large amounts of both neural and movement-related data to be collected from the iBCI user for supervised decoder training. We hypothesized that the low-dimensional latent neural representations of motor behavior, known to be preserved across time, might also be preserved across individuals, and allow us to circumvent this problem. We trained a decoder to predict the electromyographic (EMG) activity for a “source” monkey from the latent signals of motor cortex. We then used Canonical Correlation Analysis to align the latent signals of a “target” monkey to those of the source. These decoders were as accurate across monkeys as they were across sessions for a given monkey. Remarkably, the same process with latent signals from a human participant with tetraplegia was within 90% of the with-monkey decoding across session accuracy. Our findings suggest that consistent representations of motor activity exist across animals and even species. Discovering this common representation is a crucial first step in designing iBCI decoders that perform well without large amounts of data and supervised subject-specific tuning.

Mean-field theory links the physiological properties of individual neurons to the emergent dynamics of neural population activity. These models provide an essential tool for studying brain function at different scales; however, for their application to neural populations on large scale, they need to account for differences between distinct neuron types. The Izhikevich single neuron model can account for a broad range of different neuron types and spiking patterns, thus rendering it an optimal candidate for a mean-field theoretic treatment of brain dynamics in heterogeneous networks. Here we derive the mean-field equations for networks of all-to-all coupled Izhikevich neurons with heterogeneous spiking thresholds. Using methods from bifurcation theory, we examine the conditions under which the mean-field theory accurately predicts the dynamics of the Izhikevich neuron network. To this end, we focus on three important features of the Izhikevich model that are subject here to simplifying assumptions: (i) spike-frequency adaptation, (ii) the spike reset conditions, and (iii) the distribution of single-cell spike thresholds across neurons. Our results indicate that, while the mean-field model is not an exact model of the Izhikevich network dynamics, it faithfully captures its different dynamic regimes and phase transitions. We thus present a mean-field model that can represent different neuron types and spiking dynamics. The model comprises biophysical state variables and parameters, incorporates realistic spike resetting conditions, and accounts for heterogeneity in neural spiking thresholds. These features allow for a broad applicability of the model as well as for a direct comparison to experimental data.

Macroscopic dynamics of neural networks with heterogeneous spiking thresholds.

The brain is composed of complex networks of interacting neurons that express considerable heterogeneity in their physiology and spiking characteristics. How does neural heterogeneity aﬀect macroscopic neural dynamics and how does it contribute to neurodynamic functions? In this letter, we address these questions by studying the macroscopic dynamics of networks of heterogeneous Izhikevich neurons. We derive mean-ﬁeld equations for these networks and examine how heterogeneity in the spiking thresholds of Izhikevich neurons aﬀects the emergent macroscopic dynamics. Our results suggest that the level of heterogeneity of inhibitory populations controls resonance and hysteresis properties of systems of coupled excitatory and inhibitory neurons. Neural heterogeneity may thus serve as a means to control the dynamic repertoire of mesoscopic brain circuits.

Effects of Neural Heterogeneity on Spiking Neural Network Dynamics

Natural scenes statistics have been studied extensively using collections of natural images and sound recordings. These studies have yielded important insights about how the brain might exploit regularities and redundancies in visual and auditory stimuli. In contrast, natural scenes for somatosensation have remained largely unexplored. Here we use three-dimensional scans of natural and human-made objects to quantify natural scene statistics at the scale of the human fingertip. Using measurements of distance, slope, and curvature from the object surfaces, we show that the first order statistics follow similar trends as have been observed for images of natural and human-made environments. In addition, independent component analysis of curvature measurements reveals Gabor-like basis vectors similar to those found in natural images. A simple neural model using these filters showed responses that accurately capture the statistics of responses in primate primary somatosensory cortex.

Statistical characterization of tactile scenes in three-dimensional environments reveals filter properties of somatosensory cortical neurons

Learning to execute precise, yet complex, motor actions through practice is a trait shared by most organisms. Here we develop a novel experimental approach for the comprehensive investigation and characterization of the learning dynamics of practiced motion. Following the dynamical systems framework, we consider a high-dimensional behavioral space in which a trial-by-trial sequence of motor outputs defines a trajectory that converges to a fixed point - the desired motor output. In this scenario, details of the internal dynamics and the trial-by-trial learning mechanism cannot be disentangled from behavioral noise for nonlinear systems or even well estimated for linear systems with many parameters. To overcome this problem, we introduce a novel approach: the sporadic application of systematic target perturbations that span the behavioral space and allow us to estimate the linearized dynamics in the vicinity of the fixed point. The steady-state Lyapunov equation then allows us to identify the noise covariance. We illustrate the method by analyzing sequence-generating neural networks with either intrinsic or extrinsic noise, at time resolutions that span from spike timing to spiking rates. We demonstrate the utility of our approach in experimentally plausible and realizable settings and show that this method can fully characterize the linearized between-trials learning dynamics as well as extract meaningful internal properties of the unknown mechanism that drives the motor output within each trial. We then illustrate how the approach can be extended to nonlinear learning dynamics through a flexible choice of the basis and magnitude of perturbations. Significance statement Movement control ties brain activity to measurable external actions in real time, providing a useful tool for both neuroscientists interested in the emergence of stable behavior and biomedical engineers interested in the design of neural prosthesis and brain-machine interfaces. We approach the question of motor skill learning by introducing artificial errors through a novel perturbative scheme amenable to analytic examination in the linearized regime close to the desired behavior. Numerical simulations then demonstrate how to probe the learning dynamics in both linear and nonlinear systems. These findings stress the usefulness of analyzing responses to deliberately induced errors and the importance of properly designing such perturbation experiments. Our approach provides a novel generic tool for monitoring the acquisition of motor skills.

A novel approach to the empirical characterization of learning in biological systems

It is generally accepted that the number of neurons in a given brain area far exceeds the information that area encodes. For example, motor areas of the human brain contain tens of millions of neurons that control the activation of tens or at most hundreds of muscles. This massive redundancy implies the covariation of many neurons, which constrains the population activity to a low-dimensional manifold within the space of all possible patterns of neural activity. To gain a conceptual understanding of the complexity of the neural activity within a manifold, it is useful to estimate its dimensionality, which quantifies the number of degrees of freedom required to describe the observed population activity without significant information loss. While there are many algorithms for dimensionality estimation, we do not know which are well suited for analyzing neural activity. The objective of this study was to evaluate the efficacy of several representative algorithms for estimating linearly and nonlinearly embedded data. We generated synthetic neural recordings with known intrinsic dimensionality and used them to test the algorithms’ accuracy and robustness. We emulated some of the important challenges associated with experimental data by adding noise, altering the nature of the embedding from the low-dimensional manifold to the high-dimensional recordings, varying the dimensionality of the manifold, and limiting the amount of available data. We demonstrated that linear algorithms overestimate the dimensionality of nonlinear, noise-free data. In cases of high noise, most algorithms overestimated dimensionality. We thus developed a denoising algorithm based on deep learning, the “Joint Autoencoder”, which significantly improved subsequent dimensionality estimation. Critically, we found that all algorithms failed when the dimensionality was high (above 20) or when the amount of data used for estimation was low. Based on the challenges we observed, we formulated a pipeline for estimating the dimensionality of experimental neural data. Author Summary The number of neurons that we can record from has increased exponentially for decades; today we can simultaneously record from thousands of neurons. However, the individual firing rates are highly redundant. One approach to identifying important features from redundant data is to estimate the dimensionality of the neural recordings, which represents the number of degrees of freedom required to describe the data without significant information loss. Better understanding of dimensionality may also uncover the mechanisms of computation within a neural circuit. Circuits carrying out complex computations might be higher-dimensional than those carrying out simpler computations. Typically, studies have quantified neural dimensionality using one of several available methods despite a lack of consensus on which method would be most appropriate for neural data. In this work, we used several methods to investigate the accuracy of simulated neural data with properties mimicking those of actual neural recordings. Based on these results, we devised an analysis pipeline to estimate the dimensionality of neural recordings. Our work will allow scientists to extract informative features from a large number of highly redundant neurons, as well as quantify the complexity of information encoded by these neurons.

Estimating the dimensionality of the manifold underlying multi-electrode neural recordings

Long-term stability of cortical population dynamics underlying consistent behavior

 In vitro validation of in silico identified inhibitory interactions

Somatosensation is composed of two distinct modalities: touch, arising from sensors in the skin, and proprioception, resulting primarily from sensors in the muscles, combined with these same cutaneous sensors. In contrast to the wealth of information about touch, we know quite less about the nature of the signals giving rise to proprioception at the cortical level. Likewise, while there is considerable interest in developing encoding models of touch-related neurons for application to brain machine interfaces, much less emphasis has been placed on an analogous proprioceptive interface. Here we investigate the use of Artificial Neural Networks (ANNs) to model the relationship between the firing rates of single neurons in area 2, a largely proprioceptive region of somatosensory cortex (S1) and several types of kinematic variables related to arm movement. To gain a better understanding of how these kinematic variables interact to create the proprioceptive responses recorded in our datasets, we train ANNs under different conditions, each involving a different set of input and output variables. We explore the kinematic variables that provide the best network performance, and find that the addition of information about joint angles and/or muscle lengths significantly improves the prediction of neural firing rates. Our results thus provide new insight regarding the complex representations of the limb motion in S1: that the firing rates of neurons in area 2 may be more closely related to the activity of peripheral sensors than it is to extrinsic hand position. In addition, we conduct numerical experiments to determine the sensitivity of ANN models to various choices of training design and hyper-parameters. Our results provide a baseline and new tools for future research that utilizes machine learning to better describe and understand the activity of neurons in S1.

A medical student learning to perform a laparoscopic procedure as well as a recently paralyzed user of a powered wheelchair must learn to operate machinery via interfaces that translate their actions into commands for the external device. Mathematically, we describe this type of learning as a deterministic dynamical process, whose state is the evolving forward and inverse internal models of the interface. The forward model predicts the outcomes of actions while the inverse model generates actions designed to attain desired outcomes. Both the mathematical analysis of learning dynamics and the performance observed in a group of subjects demonstrate first-order exponential convergence of the learning process toward a particular state that depends only on the initial inverse and forward models and on the supplied sequence of targets. Noise is not only present but necessary for the convergence of learning through the minimization of the difference between actual and predicted outcomes. Author summary Several studies have suggested that as we learn a new skill our brain forms representations, or “internal models”, of the skill and of the environment in which we operate. Theories of motor learning postulate that the brain builds forward models that predict the sensory consequences of motor commands, and inverse models that generate successful commands from planned movements. We test this hypothesis taking advantage of a special interface that generates a novel relation between the subject’s actions and the position of a cursor on a computer monitor, thus allowing subjects to control an external device by movements of their body. We recorded the motions of the body and of the cursor, and obtained estimates of both forward and inverse models. We followed how these estimates evolved in time as subjects practiced and acquired a new skill. We found that the description of learning as a simple deterministic process driven by the sequence of targets is sufficient to capture the observed convergence to a single solution of the inverse model among an infinite variety of alternative possibilities. This work is relevant to the study of fundamental learning mechanisms as well as to the design of intelligent interfaces for people with paralysis.

The dynamics of motor learning through the formation of internal models

Significance An animal’s primary sensory neurons (PSNs) translate information about the environment into neural signals that allow perception and action. While much is known about visual and auditory PSN responses to complex stimuli, somatosensory neurons have been characterized with simplified and repeatable stimuli. Thus, knowledge of somatosensory PSN representational capacity remains incomplete. We used the rodent whisker system to examine how tactile mechanical information is represented in PSNs of the trigeminal ganglion (Vg) when the whiskers receive complex three-dimensional stimulation. In contrast to proposed codes in which subpopulations of Vg neurons encode select stimulus features, our results show that individual Vg neurons represent multiple stimulus features in a tiled and continuous manner, thus encoding large regions of a complex sensory space. Across all sensory modalities, first-stage sensory neurons are an information bottleneck: they must convey all information available for an animal to perceive and act in its environment. Our understanding of coding properties of primary sensory neurons in the auditory and visual systems has been aided by the use of increasingly complex, naturalistic stimulus sets. By comparison, encoding properties of primary somatosensory afferents are poorly understood. Here, we use the rodent whisker system to examine how tactile information is represented in primary sensory neurons of the trigeminal ganglion (Vg). Vg neurons have long been thought to segregate into functional classes associated with separate streams of information processing. However, this view is based on Vg responses to restricted stimulus sets which potentially underreport the coding capabilities of these neurons. In contrast, the current study records Vg responses to complex three-dimensional (3D) stimulation while quantifying the complete 3D whisker shape and mechanics, thereby beginning to reveal their full representational capabilities. The results show that individual Vg neurons simultaneously represent multiple mechanical features of a stimulus, do not preferentially encode principal components of the stimuli, and represent continuous and tiled variations of all available mechanical information. These results directly contrast with proposed codes in which subpopulations of Vg neurons encode select stimulus features. Instead, individual Vg neurons likely overcome the information bottleneck by encoding large regions of a complex sensory space. This proposed tiled and multidimensional representation at the Vg directly constrains the computations performed by more central neurons of the vibrissotrigeminal pathway.

Continuous, multidimensional coding of 3D complex tactile stimuli by primary sensory neurons of the vibrissal system

Cortical population activity within a preserved neural manifold underlies multiple motor behaviors

Animals readily execute learned motor behaviors in a consistent manner over long periods of time, yet similarly stable neural correlates remained elusive up to now. How does the cortex achieve this stable control? Using the sensorimotor system as a model of cortical processing, we investigated the hypothesis that the dynamics of neural latent activity, which capture the dominant co-variation patterns within the neural population, are preserved across time. We recorded from populations of neurons in premotor, primary motor, and somatosensory cortices for up to two years as monkeys performed a reaching task. Intriguingly, despite steady turnover in the recorded neurons, the low-dimensional latent dynamics remained stable. Such stability allowed reliable decoding of behavioral features for the entire timespan, while fixed decoders based on the recorded neural activity degraded substantially. We posit that latent cortical dynamics within the manifold are the fundamental and stable building blocks underlying consistent behavioral execution.

A stable, long - term cortical signature underlying consistent behavior

A stable, long-term cortical signature underlying consistent behavior

Brain-Machine Interfaces (BMIs) have recently emerged as a clinically viable option to restore voluntary movements after paralysis. These devices are based on the ability to extract information about movement intent from neural signals recorded using multi-electrode arrays chronically implanted in the motor cortices of the brain. However, the inherent loss and turnover of recorded neurons requires repeated recalibrations of the interface, which can potentially alter the day-to-day user experience. The resulting need for continued user adaptation interferes with the natural, subconscious use of the BMI. Here, we introduce a new computational approach that decodes movement intent from a low-dimensional latent representation of the neural data. We implement various domain adaptation methods to stabilize the interface over significantly long times. This includes Canonical Correlation Analysis used to align the latent variables across days; this method requires prior point-to-point correspondence of the time series across domains. Alternatively, we match the empirical probability distributions of the latent variables across days through the minimization of their Kullback-Leibler divergence. These two methods provide a significant and comparable improvement in the performance of the interface. However, implementation of an Adversarial Domain Adaptation Network trained to match the empirical probability distribution of the residuals of the reconstructed neural signals outperforms the two methods based on latent variables, while requiring remarkably few data points to solve the domain adaptation problem.

Adversarial Domain Adaptation for Stable Brain-Machine Interfaces

Understanding how neuronal signals propagate in local network is an important step in understanding information processing. As a result, spike trains recorded with Multi-electrode Arrays (MEAs) have been widely used to study behaviors of neural connections. Studying the dynamics of neuronal networks requires the identification of both excitatory and inhibitory connections. The detection of excitatory relationships can robustly be inferred by characterizing the statistical relationships of neural spike trains. However, the identification of inhibitory relationships is more difficult: distinguishing endogenous low firing rates from active inhibition is not obvious. In this paper, we propose an in silico interventional procedure that makes predictions about the effect of stimulating or inhibiting single neurons on other neurons, and thereby gives the ability to accurately identify inhibitory causal relationships. To experimentally test these predictions, we have developed a Neural Circuit Probe (NCP) that delivers drugs transiently and reversibly on individually identified neurons to assess their contributions to the neural circuit behavior. With the help of NCP, three inhibitory connections identified by our in silico modeling were validated through real interventional experiments. Together, these methods provide a basis for mapping complete neural circuits.

Use of a Neural Circuit Probe to Validate in silico Predictions of Inhibitory Connections

How do populations of cortical neurons have the flexibility to perform different functions? We investigated this question in primary motor cortex (M1), where populations of neurons are able to generate a rich repertoire of motor behaviors. We recorded neural activity while monkeys performed a variety of wrist and reach-to-grasp motor tasks, each requiring a different pattern of neural activity. We characterized the flexibility of M1 movement control by comparing the “neural modes” that capture covariation across neurons, believed to arise from network connectivity. We found large similarities in the structure of the neural modes across tasks, as well as striking similarities in their temporal activation dynamics. These similarities were only apparent at the population level. Moreover, a subset of these well-preserved modes captured a task-independent mapping onto muscle commands. We hypothesize that this system of flexibly combined, stable neural modes gives M1 the flexibility to generate our wide-ranging behavioral repertoire.

Multiple tasks viewed from the neural manifold: Stable control of varied behavior

Objective. We have previously demonstrated a brain-machine interface neuroprosthetic system that provided continuous control of functional electrical stimulation (FES) and restoration of grasp in a primate model of spinal cord injury (SCI). Predicting intended EMG directly from cortical recordings provides a flexible high-dimensional control signal for FES. However, no peripheral signal such as force or EMG is available for training EMG decoders in paralyzed individuals. Approach. Here we present a method for training an EMG decoder in the absence of muscle activity recordings; the decoder relies on mapping behaviorally relevant cortical activity to the inferred EMG activity underlying an intended action. Monkeys were trained at a 2D isometric wrist force task to control a computer cursor by applying force in the flexion, extension, ulnar, and radial directions and execute a center-out task. We used a generic muscle force-to-endpoint force model based on muscle pulling directions to relate each target force to an optimal EMG pattern that attained the target force while minimizing overall muscle activity. We trained EMG decoders during the target hold periods using a gradient descent algorithm that compared EMG predictions to optimal EMG patterns. Main results. We tested this method both offline and online. We quantified both the accuracy of offline force predictions and the ability of a monkey to use these real-time force predictions for closed-loop cursor control. We compared both offline and online results to those obtained with several other direct force decoders, including an optimal decoder computed from concurrently measured neural and force signals. Significance. This novel approach to training an adaptive EMG decoder could make a brain-control FES neuroprosthesis an effective tool to restore the hand function of paralyzed individuals. Clinical implementation would make use of individualized EMG-to-force models. Broad generalization could be achieved by including data from multiple grasping tasks in the training of the neuron-to-EMG decoder. Our approach would make it possible for persons with SCI to grasp objects with their own hands, using near-normal motor intent.

Author response: Decoupling kinematics and mechanics reveals coding properties of trigeminal ganglion neurons in the rat vibrissal system

The human motor system is capable of remarkably precise control of movements—consider the skill of professional baseball pitchers or surgeons. This precise control relies upon stable representations of movements in the brain. Here, we investigated the stability of cortical activity at multiple spatial and temporal scales by recording local field potentials (LFPs) and action potentials (multiunit spikes, MSPs) while two monkeys controlled a cursor either with their hand or directly from the brain using a brain–machine interface. LFPs and some MSPs were remarkably stable over time periods ranging from 3 d to over 3 years; overall, LFPs were significantly more stable than spikes. We then assessed whether the stability of all neural activity, or just a subset of activity, was necessary to achieve stable behavior. We showed that projections of neural activity into the subspace relevant to the task (the “task-relevant space”) were significantly more stable than were projections into the task-irrelevant (or “task-null”) space. This provides cortical evidence in support of the minimum intervention principle, which proposes that optimal feedback control (OFC) allows the brain to tightly control only activity in the task-relevant space while allowing activity in the task-irrelevant space to vary substantially from trial to trial. We found that the brain appears capable of maintaining stable movement representations for extremely long periods of time, particularly so for neural activity in the task-relevant space, which agrees with OFC predictions. SIGNIFICANCE STATEMENT It is unknown whether cortical signals are stable for more than a few weeks. Here, we demonstrate that motor cortical signals can exhibit high stability over several years. This result is particularly important to brain–machine interfaces because it could enable stable performance with infrequent recalibration. Although we can maintain movement accuracy over time, movement components that are unrelated to the goals of a task (such as elbow position during reaching) often vary from trial to trial. This is consistent with the minimum intervention principle of optimal feedback control. We provide evidence that the motor cortex acts according to this principle: cortical activity is more stable in the task-relevant space and more variable in the task-irrelevant space.

Long-Term Stability of Motor Cortical Activity: Implications for Brain Machine Interfaces and Optimal Feedback Control

Tactile information available to the rat vibrissal system begins as external forces that cause whisker deformations, which in turn excite mechanoreceptors in the follicle. Despite the fundamental mechanical origin of tactile information, primary sensory neurons in the trigeminal ganglion (Vg) have often been described as encoding the kinematics (geometry) of object contact. Here we aimed to determine the extent to which Vg neurons encode the kinematics vs. mechanics of contact. We used models of whisker bending to quantify mechanical signals (forces and moments) at the whisker base while simultaneously monitoring whisker kinematics and recording single Vg units in both anesthetized rats and awake, body restrained rats. We employed a novel manual stimulation technique to deflect whiskers in a way that decouples kinematics from mechanics, and used Generalized Linear Models (GLMs) to show that Vg neurons more directly encode mechanical signals when the whisker is deflected in this decoupled stimulus space. DOI: http://dx.doi.org/10.7554/eLife.13969.001

Decoupling kinematics and mechanics reveals coding properties of trigeminal ganglion neurons in the rat vibrissal system

Objective. Brain machine interfaces (BMIs) that decode control signals from motor cortex have developed tremendously in the past decade, but virtually all rely exclusively on vision to provide feedback. There is now increasing interest in developing an afferent interface to replace natural somatosensation, much as the cochlear implant has done for the sense of hearing. Preliminary experiments toward a somatosensory neuroprosthesis have mostly addressed the sense of touch, but proprioception, the sense of limb position and movement, is also critical for the control of movement. However, proprioceptive areas of cortex lack the precise somatotopy of tactile areas. We showed previously that there is only a weak tendency for neighboring neurons in area 2 to signal similar directions of hand movement. Consequently, stimulation with the relatively large currents used in many studies is likely to activate a rather heterogeneous set of neurons. Approach. Here, we have compared the effect of single-electrode stimulation at subthreshold levels to the effect of stimulating as many as seven electrodes in combination. Main results. We found a mean enhancement in the sensitivity to the stimulus (d′) of 0.17 for pairs compared to individual electrodes (an increase of roughly 30%), and an increase of 2.5 for groups of seven electrodes (260%). Significance. We propose that a proprioceptive interface made up of several hundred electrodes may yield safer, more effective sensation than a BMI using fewer electrodes and larger currents.

Multi-electrode stimulation in somatosensory cortex increases probability of detection

PDZ domains are protein-protein interaction modules widely used to assemble membranous signaling complexes including those found in the neuronal synapse. PDZ-containing genes encoded in metazoan genomes vastly outnumber those in prokaryotes, plants, and fungi. By comparing 40 proteomes to track the evolutionary history of the PDZ domain, we observed that the variety of associations between PDZ and other domains expands greatly along the stem leading to metazoans and choanoflagellates. We asked whether the expansion of PDZ domains was due to random or specific sequence changes. Studying the sequence signatures of 58 PDZ lineages that are common to bilaterian animals, we showed that six common amino acid residues are able to classify 96% of PDZ domains to their correct evolutionary lineage. In PDZ domain-ligand cocrystals, four of these "classifying positions" lie in direct contact with the -1 and -3 residues of the ligand. This suggests coevolution of the more flexible regions of the binding interaction as a central mechanism of specialization inherent within the PDZ domain. To identify these positions, we devised two independent algorithms--a metric termed within-clade entropy (WCE) and an average mutual information (AvgMI) score--that both reached similar results. Extending these tools to the choanoflagellate, Monosiga brevicollis, we compared its PDZ domains with their putative metazoan orthologs. Interestingly, the M. brevicollis genes lack conservation at the classifying positions suggesting dissociation between domain organization in multidomain proteins and specific changes within the PDZ domain.

Loss of hand use is considered by many spinal cord injury survivors to be the most devastating consequence of their injury. Functional electrical stimulation (FES) of forearm and hand muscles has been used to provide basic, voluntary hand grasp to hundreds of human patients. Current approaches typically grade pre-programmed patterns of muscle activation using simple control signals, such as those derived from residual movement or muscle activity. However, the use of such fixed stimulation patterns limits hand function to the few tasks programmed into the controller. In contrast, we are developing a system that uses neural signals recorded from a multi-electrode array implanted in the motor cortex; this system has the potential to provide independent control of multiple muscles over a broad range of functional tasks. Two monkeys were able to use this cortically controlled FES system to control the contraction of four forearm muscles despite temporary limb paralysis. The amount of wrist force the monkeys were able to produce in a one-dimensional force tracking task was significantly increased. Furthermore, the monkeys were able to control the magnitude and time course of the force with sufficient accuracy to track visually displayed force targets at speeds reduced by only one-third to one-half of normal. Although these results were achieved by controlling only four muscles, there is no fundamental reason why the same methods could not be scaled up to control a larger number of muscles. We believe these results provide an important proof of concept that brain-controlled FES prostheses could ultimately be of great benefit to paralyzed patients with injuries in the mid-cervical spinal cord.

Toward the Restoration of Hand Use to a Paralyzed Monkey: Brain-Controlled Functional Electrical Stimulation of Forearm Muscles

The interest in Brain Machine Interface (BMI) systems has increased tremendously in recent times; many groups have become involved in this type of research, and progress has been quite encouraging. However, two fundamental limitations remain: 1) With a few notable exceptions, BMIs extract only kinematic information from the brain, ignoring the wealth of force or kinetic information also present in the primary motor cortex, and 2) most existing BMIs depend exclusively on natural vision to guide movement, lacking the rapid proprioceptive feedback that is critical for normal movement. The work reported here describes our efforts to address both of these limitations.

for an Invited Paper for the MAR08 Meeting of The American Physical Society Patterns of Neural Activity in Networks with Complex Connectivity SARA A. SOLLA, Northwestern University An understanding of emergent dynamics on complex networks requires investigating the interplay between the intrinsic dynamics of the node elements and the connectivity of the network in which they are embedded. In order to address some of these questions in a specific scenario of relevance to the dynamical states of neural ensembles, we have studied the collective behavior of excitable model neurons in a network with small-world topology. The small-world network has local lattice order, but includes a number of randomly placed connections that may provide connectivity shortcuts. This topology bears a schematic resemblance to the connectivity of the cerebral cortex, in which neurons are most strongly coupled to nearby cells within fifty to a hundred micrometers, but also make projections to cells millimeters away. We find that the dynamics of this small-world network of excitable neurons depend mostly on both the density of shortcuts and the delay associated with neuronal projections. In the regime of low shortcut density, the system exhibits persistent activity in the form of propagating waves, which annihilate upon collision and are spawned anew via the re-injection of activity through shortcut connections. As the density of shortcuts reaches a critical value, the system undergoes a transition to failure. The critical shortcut density results from matching the time associated with a recurrent path through the network to an intrinsic recovery time of the individual neurons. Furthermore, if the delay associated with neuronal interactions is sufficiently long, activity reemerges above the critical density of shortcuts. The activity in this regime exhibits long, chaotic transients composed of noisy, large-amplitude population bursts.

Patterns of Neural Activity in Networks with Complex Connectivity

The Cambridge Handbook of Computational Psychology: Models of Motor Control

Top-down laminar organization of the excitatory network in motor cortex

eralization by weight-elimination with application to forecasting. A statistical approach to learning and generalization in layered neural networks. [OH91] M. Opper and D. Haussler. Generalised performance of Bayes optimal classi-cation algorithm for learning a perceptron. [EJM90] A. El-Jaroudi and J. Makhoul. A new error criterion for posterior probability estimation with neural nets. [Hau91] D. Haussler. A decision theoretic generalization of the PAC learning model and its application to some feed-forward neural networks. [HP90] J.B. Hampshire II and B.A. Pearlmutter. Equivalence proofs for multi-layer perceptron classiers and the Bayesian discrimination function. [Ish90] M. Ishikawa. A structural learning algorithm with forgetting of link weights. 31 Once some local minima have been found, inference can be done on new patterns. Relevant approximate predictions are described in Section 7.2 that apply if the weight variances are small. Standard inference does forward propagation of the inputs for the new pattern to obtain the output. The adjustments described involve approximation of output posterior variance of the output (error bars), better approximation of expected output and variance, and averaging over multiple local minima. These adjustments to the standard back-propagation procedure increase computation during back-propagation in most cases by at most a factor. Subsequent inference such as calculating variances require matrix calculations that can be done using fast standard matrix packages. While these methods come with the normative backing of Bayesian statistics, implementation often reveals lessons on how the various approximations and optimizations could be better made. One important issue here is the quality of the Gaussian approximation to the posterior of the weights. Since the whole approach rests on this, more evaluation and experience is required. A smooth transition also needs to be developed between Bayesian and uniform convergence methods to handle those cases where training samples become larger.

parameters such as cr and A, that is Pr(lw , or) = Pr(). Posterior probabilities of network weights are as follows. For regression with Gaussian error and unknown a,

We study Schapire's Boosting Algorithm(SBA) for use in practice. SBA is analyzed in terms of its representation and its search. We show that the SBA representation is a piecewise tiling of the domain and that if the weak learner has low coverage ability, SBA's search may fail to boost or may give a sub-optimal solution. We present a rejection boosting algorithm that trades-oo exploration and exploitation: It requires fewer pattern labels at the expense of lower boosting ability.

Quite recently, it has become possible to use signals recorded simultaneously from large numbers of cortical neurons for real-time control. Such brain machine interfaces (BMIs) have allowed animal subjects and human patients to control the position of a computer cursor or robotic limb under the guidance of visual feedback. Although impressive, such approaches essentially ignore the dynamics of the musculoskeletal system, and they lack potentially critical somatosensory feedback. In this mini-symposium, we will initiate a discussion of systems that more nearly mimic the control of natural limb movement. The work that we will describe is based on fundamental observations of sensorimotor physiology that have inspired novel BMI approaches. We will focus on what we consider to be three of the most important new directions for BMI development related to the control of movement. (1) We will present alternative methods for building decoders, including structured, nonlinear models, the explicit incorporation of limb state information, and novel approaches to the development of decoders for paralyzed subjects unable to generate an output signal. (2) We will describe the real-time prediction of dynamical signals, including joint torque, force, and EMG, and the real-time control of physical plants with dynamics like that of the real limb. (3) We will discuss critical factors that must be considered to incorporate somatosensory feedback to the BMI user, including its potential benefits, the differing representations of sensation and perception across cortical areas, and the changes in the cortical representation of tactile events after spinal injury.

A mathematical model describing the coupling between two independent amplification mechanisms in auditory hair cells is proposed and analyzed. Hair cells are cells in the inner ear responsible for translating sound-induced mechanical stimuli into an electrical signal that can then be recorded by the auditory nerve. In nonmammals, two separate mechanisms have been postulated to contribute to the amplification and tuning properties of the hair cells. Models of each of these mechanisms have been shown to be poised near a Hopf bifurcation. Through a weakly nonlinear analysis that assumes weak periodic forcing, weak damping, and weak coupling, the physiologically based models of the two mechanisms are reduced to a system of two coupled amplitude equations describing the resonant response. The predictions that follow from an analysis of the reduced equations, as well as performance benefits due to the coupling of the two mechanisms, are discussed and compared with published experimental auditory nerve data.

Physical review. E, Statistical, nonlinear, and soft matter physics

Amplification in the auditory periphery: the effect of coupling tuning mechanisms.

Movement representation by the motor cortex (M1) has been a theoretical interest for many years, but in the past several years it has become a more practical question, with the advent of the brain–machine interface. An increasing number of groups have demonstrated the ability to predict a variety of kinematic signals on the basis of M1 recordings and to use these predictions to control the movement of a cursor or robotic limb. We, on the other hand, have undertaken the prediction of myoelectric (EMG) signals recorded from various muscles of the arm and hand during button pressing and prehension movements. We have shown that these signals can be predicted with accuracy that is similar to that of kinematic signals, despite their stochastic nature and greater bandwidth. The predictions were made using a subset of 12 or 16 neural signals selected in the order of each signal's unique, output-related information content. The accuracy of the resultant predictions remained stable through a typical experimental session. Accuracy remained above 80% of its initial level for most muscles even across periods as long as two weeks. We are exploring the use of these predictions as control signals for neuromuscular electrical stimulation in quadriplegic patients.

Prediction of upper limb muscle activity from motor cortical discharge during reaching

We study the dynamical states of a small-world network of recurrently coupled excitable neurons, through both numerical and analytical methods. The dynamics of this system depend mostly on both the number of long-range connections or "shortcuts", and the delay associated with neuronal interactions. We find that persistent activity emerges at low density of shortcuts, and that the system undergoes a transition to failure as their density reaches a critical value. The state of persistent activity below this transition consists of multiple stable periodic attractors, whose number increases at least as fast as the number of neurons in the network. At large shortcut density and for long enough delays the network dynamics exhibit exceedingly long chaotic transients, whose failure times follow a stretched exponential distribution. We show that this functional form arises for the ensemble-averaged activity if the failure time for each individual network realization is exponentially distributed.

Multiple attractors, long chaotic transients, and failure in small-world networks of excitable neurons.

A robust identification algorithm has been developed for linear, time-invariant, multiple-input single-output systems, with an emphasis on how this algorithm can be used to estimate the dynamic relationship between a set of neural recordings and related physiological signals. The identification algorithm provides a decomposition of the system output such that each component is uniquely attributable to a specific input signal, and then reduces the complexity of the estimation problem by discarding those input signals that are deemed to be insignificant. Numerical difficulties due to limited input bandwidth and correlations among the inputs are addressed using a robust estimation technique based on singular value decomposition. The algorithm has been evaluated on both simulated and experimental data. The latter involved estimating the relationship between up to 40 simultaneously recorded motor cortical signals and peripheral electromyograms (EMGs) from four upper limb muscles in a freely moving primate.The algorithm performed well in both cases:it provided reliable estimates of the system output and significantly reduced the number of inputs needed for output prediction. For example, although physiological recordings from up to 40 different neuronal signals were available, the input selection algorithm reduced this to 10 neuronal signals that made signicant contributions to the recorded EMGs.

Identification of Multiple-Input Systems with Highly Coupled Inputs: Application to EMG Prediction from Multiple Intracortical Electrodes

Sara Solla explores what it means for groups of neurons to most efficiently represent information in the sensory world.

We have developed an algorithm for selecting an optimal set of inputs for use in linear multiple-input, single-output system identification processes. The algorithm provides a decomposition of the system output such that each component is uniquely attributable to a specific input This reduces the complexity of the estimation problem by optimally selecting inputs according to the uniqueness of their output contribution and is useful in when subsets of the inputs are highly correlated or do not contribute significantly to the system output. The algorithm was evaluated on experimental data consisting of up to 40 simultaneously recorded motor cortical signals and peripheral electromyograms (EMGs) from four upper limb muscles in a freely moving primate. It was used to select the optimal motor cortical signals for predicting each of the EMGs and significantly reduced the number of inputs needed to generate accurate EMG predictions. For example, although physiological recordings from up to 40 different neuronal signals were available, the input selection algorithm reduced this 10 neuronal signals that made significant contributions to the recorded EMGs

Conference Proceedings. 2nd International IEEE EMBS Conference on Neural Engineering, 2005.

Optimal Input Selection for MISO Systems Identification: Applications to BMIs

The neural control of movement requires the ability to deal with changes, both in the environment and in the parameters that characterize the mechanical structure of the organism. Here we discuss the three types of coordinate representations that sensory and motor systems use to generate and control movements, and argue that the intrinsic redundancy of the musculoeskeletal system can be exploited to implement control signals that result in successful task completion while allowing for variance in trajectory parameters not relevant to the task. We also argue that muscle synergies activated through the stimulation of specific loci along the spinal cord provide evidence for the existence of a vocabulary of motor primitives that can be combined, either simultaneously or sequentially, to generate a broad repertoire of complex movements.

Single-unit activity in the neostriatum of awake monkeys shows a marked dependence on expected reward. Responses to visual cues differ when animals expect primary reinforcements, such as juice rewards, in comparison to secondary reinforcements, such as tones. The mechanism of this reward-dependent modulation has not been established experimentally. To assess the hypothesis that direct neuromodulatory effects of dopamine on spiny neurons can account for this modulation, we develop a computational model based on simplified representations of key ionic currents and their modulation by D1 dopamine receptor activation. This minimal model can be analyzed in detail. We find that D1-mediated increases of inward rectifying potassium and L-type calcium currents cause a bifurcation: the native up/down state behavior of the spiny neuron model becomes truly bistable, which modulates the peak firing rate and the duration of the up state and introduces a dependence of the response on the past state history. These generic consequences of dopamine neuromodulation through bistability can account for both reward-dependent enhancement and suppression of spiny neuron single-unit responses to visual cues. We validate the model by simulating responses to visual targets in a memory-guided saccade task; our results are in close agreement with the main features of the experimental data. Our model provides a conceptual framework for understanding the functional significance of the short-term neuromodulatory actions of dopamine on signal processing in the striatum.

Modulation of striatal single units by expected reward: a spiny neuron model displaying dopamine-induced bistability.

An analysis of activity of primary motor cortex (Ml) and muscle activity in the form of EMGs suggests that Ml contains a large amount of muscle related information. The simultaneous activity of a population of Ml neurons was recorded using a multi-electrode, intracortical array while recording arm muscle EMGs from a rhesus monkey during a multi-target, reaching task. Using multiple-input system identification techniques, linear, non-parametric filters relating the firing rates of the neuronal signals to the muscle EMGs were estimated. These filters were able to reconstruct and predict EMG signals directly from the recorded neuronal tiring rates with a high level of accuracy. Initial cross-validations of the filters suggest that the relationships between Ml and muscles contain time and task dependencies as the quality of the predictions drop for longer time periods between filter estimation and EMG prediction and for cross-validations that involve movements to individual targets. Further tests involving more data sets and cross-validations are necessary to determine more precisely the temporal and task-specific stability of these filters. This will greatly increase our knowledge of how arm movement and muscle activity is encoded in the brain and offer practical applications in the harvesting of neural control signals.

Proceedings of the 25th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (IEEE Cat. No.03CH37439)

Prediction of EMG from multiple electrode recordings in primary motor cortex

We study the dynamics of excitable integrate-and-fire neurons in a small-world network. At low densities p of directed random connections, a localized transient stimulus results either in self-sustained persistent activity or in a brief transient followed by failure. Averages over the quenched ensemble reveal that the probability of failure changes from 0 to 1 over a narrow range in p; this failure transition can be described analytically through an extension of an existing mean-field result. Exceedingly long transients emerge at higher densities p; their activity patterns are disordered, in contrast to the mostly periodic persistent patterns observed at low p. The times at which such patterns die out follow a stretched-exponential distribution, which depends sensitively on the propagation velocity of the excitation.

Self-sustained activity in a small-world network of excitable neurons.

Single unit activity in the striatum of awake monkeys shows a marked dependence on the expected reward that a behavior will elicit. We present a computational model of spiny neurons, the principal neurons of the striatum, to assess the hypothesis that direct neuromodulatory effects of dopamine through the activation of Dl receptors mediate the reward dependency of spiny neuron activity. Dopamine release results in the amplification of key ion currents, leading to the emergence of bistability, which not only modulates the peak firing rate but also introduces a temporal and state dependence of the model's response, thus improving the detectability of temporally correlated inputs.

Dopamine Induced Bistability Enhances Signal Processing in Spiny Neurons

Advances in neural information processing systems: Proceedings of the first 12 conferences (CDROM)

Dynamics of supervised learning with restricted training sets and noisy teachers

One of the greatest challenges of manufacturing sheet metal parts is to obtain consistent part dimensions. Springback, the elastic material recovery when the tooling is removed, is the major cause of variations and inconsistencies in the final part geometry. Obtaining a consistent and desirable amount of springback is extremely difficult due to the nonlinear effects and interactions between process and material parameters. In this paper, the exceptional ability of a neural network along with a stepped binder force trajectory to control springback angle and maximum principal strain in a simulated channel forming process is demonstrated. When faced with even large variations in material properties, sheet thickness, and friction condition, the control system produces a robust final part shape.

Journal of Engineering Materials and Technology-transactions of The Asme

Consistent and Minimal Springback Using a Stepped Binder Force Trajectory and Neural Network Control

Advances in Neural Information Processing Systems 12, [NIPS Conference, Denver, Colorado, USA, November 29 - December 4, 1999]

Proceedings of the 12th International Conference on Neural Information Processing Systems

uhlenbein, M. Georges-Schleuter, and O. Kramer, \Evolution Algorithms in Combinatorial Optimization," Parallel Computing 7 (1988), pp. 65{85. [20] C. Papadimitriou, \The Complexity of the Lin-Kernighan Heuristic for the Traveling Saleman Problem", SIAM J. Computing 21 (3), 450-465 (1992). [21] S. A. Solla, G. B. Sorkin and S. R. White, \Con guration Space Analysis for Optimization Problems", in E. Bienenstock et al., eds., Disordered Systems and Biological Organization, Springer-Verlag, 1986, 283-292. [22] G. B. Sorkin, \E cient Simulated Annealing on Fractal Energy Landscapes", Algorithmica 6, 367-418 (1991). [23] G. B. Sorkin, personal communication, May 1993. [24] N. Sourlas, \Statistical Mechanics and the Travelling Salesman Problem", Europhysics Letters 2 (12), 919-923 (1986). [25] N.L.J. Ulder, E.H.L. Aarts, H.-J. Bandelt, P.J.M. van Laarhoven, and E. Pesch, \Genetic Local Search Algorithms for the Traveling Salesman Problem," in Parallel Problem Solving from Nature edited by H.-P. Schwefel and R. Manner, Springer-Verlag, 1990, pp. 109{116. [26] Y. C. Wei and C. K. Cheng, \A Two-Level Two-Way Partitioning Algorithm", in Proc. IEEE Intl. Conf. on Computer-Aided Design, Nov. 1990, 516-519. [27] E. Weinberger, \Correlated and Uncorrelated Fitness Landscapes and How to Tell the Di erence", Biological Cybernetics 63, 325-336 (1990).

[19] H. Muhlenbein, M. Georges-Schleuter, and O. Kramer, \Evolution Algorithms in Combinatorial Optimization," Parallel Computing 7 (1988), pp. 65{85.

Proceedings of the 11th International Conference on Neural Information Processing Systems

Complex traits are generally taken to be under the influence of multiple genes, which may interact with each other to confer susceptibility to disease. Statistical methods in current use for localizing such genes essentially work under single-gene models, either implicitly or explicitly. In genomic screens for complex disease genes, some of the marker loci must be in tight linkage with disease susceptibility genes. We developed a general multi-locus approach to identify sets of such marker loci. Our approach focuses on affected sib pair data and employs a nonparametric pattern recognition technique using artificial neural networks. This technique analyzes all markers simultaneously in order to detect patterns of locus interactions. When applied to previously published sib pair data on type I diabetes, our approach finds the same genes as in the published report in addition to some new loci. For a specific two-locus model of inheritance, the power of our approach is higher than that of the currently used analysis standard.

Multi-Locus Nonparametric Linkage Analysis of Complex Trait Loci with Neural Networks

Gaussian processes provide natural non-parametric prior distributions over regression functions. In this paper we consider regression problems where there is noise on the output, and the variance of the noise depends on the inputs. If we assume that the noise is a smooth function of the inputs, then it is natural to model the noise variance using a second Gaussian process, in addition to the Gaussian process governing the noise-free output value. We show that prior uncertainty about the parameters controlling both processes can be handled and that the posterior distribution of the noise rate can be sampled from using Markov chain Monte Carlo methods. Our results on a synthetic data set give a posterior noise variance that well-approximates the true variance.

Regression with input-dependent noise: A Gaussian process treatment

A better understanding of pruning methods based on a ranking of weights according to their saliency in a trained network requires further information on the statistical properties of such saliencies. We focus on two-layer networks with either a linear or nonlinear output unit, and obtain analytic expressions for the distribution of saliencies and their logarithms. Our results reveal unexpected universal properties of the log-saliency distribution and suggest a novel algorithm for saliency-based weight ranking that avoids the numerical cost of second derivative evaluations.

Universal Distribution of Saliencies for Pruning in Layered Neural Networks

In a Bayesian approach to online learning a simple approximate parametric form for posterior is updated in each online learning step. Usually in online learning only an estimate of the solution is updated. The Bayesian online approach is applied to two simple learning scenarios, learning a perceptron rule with respectively a spherical and a binary weight prior. In the rst case we rederive the results for the optimal Hebb-type online algorithm for spherical input distribution.

Proceedings of the 10th International Conference on Neural Information Processing Systems

We analyze the generalization ability of a simple perceptron acting on a structured input distribution for the simple case of two clusters of input data and a linearly separable rule. The generalization ability computed for three learning scenarios: maximal stability, Gibbs, and optimal learning, is found to improve with the separation between the clusters, and is bounded from below by the result for the unstructured case, recovered as the separation between clusters vanishes. The asymptotic behavior for large training sets is the same for structured and unstructured input distributions. For small training sets, the generalization error of the maximally stable perceptron exhibits a nonmonotonic dependence on the number of examples for certain values of the model parameters.

We study the effect of noise and regularization in an on-line gradient-descent learning scenario for a general two-layer student network with an arbitrary number of hidden units. Training examples are randomly drawn input vectors labeled by a two-layer teacher network with an arbitrary number of hidden units; the examples are corrupted by Gaussian noise affecting either the output or the model itself. We examine the effect of both types of noise and that of weight-decay regularization on the dynamical evolution of the order parameters and the generalization error in various phases of the learning process.

Learning with Noise and Regularizers in Multilayer Neural Networks

We analyze the generalization ability of a simple perceptron acting on a struc-tured input distribution for the simple case of two clusters of input data and a linearly separable rule. The generalization ability computed for three learning scenarios: maximal stability, Gibbs, and optimal learning, is found to improve with the separation between the clusters, and is bounded from below by the result for the unstructured case, recovered as the separation between clusters vanishes. The asymptotic behavior for large training sets is the same for structured and unstructured input distributions. For small training sets, the generalization error of the maximally stable perceptron exhibits a nonmonotonic dependence on the number of examples for certain values of the model parameters.

We consider the problem of on-line gradient descent learning for general two-layer neural networks. An analytic solution is presented and used to investigate the role of the learning rate in controlling the evolution and convergence of the learning process.

Dynamics of On-Line Gradient Descent Learning for Multilayer Neural Networks

In this paper we analyse the effect of introducing a structure in the input distribution on the generalization ability of a simple perceptron. The simple case of two clusters of input data and a linearly separable rule is considered. We find that the generalization ability improves with the separation between the clusters, and is bounded from below by the result for the unstructured case, recovered as the separation between clusters vanishes. The asymptotic behaviour for large training sets, however, is the same for structured and unstructured input distributions. For small training sets, the dependence of the generalization error on the number of examples is observed to be non-monotonic for certain values of the model parameters.

We analyse on{line learning of a linearly separable rule with a simple percep-tron. Example inputs are taken from two overlapping clusters of data and the rule is deened through a teacher vector which is in general not aligned with the connection line of the cluster centers. We nd that the Hebb algorithm cannot learn the rule perfectly in general. Moreover the dependence of the generalization error on the number of examples is nonmonotonic for certain choices of the model parameters. Perceptron and AdaTron training, however, approach perfect generalization with increasing size of the training set, and the asymptotic behavior is the same as for unstructured input data.

On{line Learning from Clustered Input Examples On{line Learning from Clustered Input Examples

Training classifiers on large databases is computationally demanding. It is desirable to develop efficient procedures for a reliable prediction of a classifier's suitability for implementing a given task, so that resources can be assigned to the most promising candidates or freed for exploring new classifier candidates. We propose such a practical and principled predictive method. Practical because it avoids the costly procedure of training poor classifiers on the whole training set, and principled because of its theoretical foundation. The effectiveness of the proposed procedure is demonstrated for both single- and multi-layer networks.

Achieving good performance in statistical pattern recognition requires matching the capacity of the classifier to the amount of training data. If the classifier has too many adjustable parameters (large capacity), it is likely to learn the training data without difficulty, but will probably not generalize properly to patterns that do not belong to the training set. Conversely, if the capacity of the classifier is not large enough, it might not be able to learn the task at all. In between, there is an optimal classifier capacity which ensures the best expected generalization for a given amount of training data. The method of structural risk minimization (SRM) refers to tuning the capacity of the classifier to the available amount of training data. This paper illustrates the method of SRM with several examples of algorithms. Experiments confirm theoretical predictions of performance improvement in application to handwritten digit recognition.<<ETX>>

Proceedings., 11th IAPR International Conference on Pattern Recognition. Vol.II. Conference B: Pattern Recognition Methodology and Systems

The method of Structural Risk Minimization refers to tuning the capacity of the classifier to the available amount of training data. This capacity is influenced by several factors, including: (1) properties of the input space, (2) nature and structure of the classifier, and (3) learning algorithm. Actions based on these three factors are combined here to control the capacity of linear classifiers and improve generalization on the problem of handwritten digit recognition.

The learning time of a simple neural network model is obtained through an analytic computation of the eigenvalue spectrum for the Hessian matrix, which describes the second order properties of the cost function in the space of coupling coefficients. The form of the eigenvalue distribution suggests new techniques for accelerating the learning process, and provides a theoretical justification for the choice of centered versus biased state variables.

Second Order Properties of Error Surfaces: Learning Time and Generalization

A feedforward layered network implements a mapping required to control an unknown stochastic nonlinear dynamical system. Training is based on a novel approach that combines stochastic approximation ideas with backpropagation. The method is applied to control admission into a queueing system operating in a time-varying environment.

Hardware architectures for character recognition are discussed, and choices for possible circuits are outlined. An advanced (and working) reconfigurable neural-net chip that mixes analog and digital processing is described. It is found that different approaches to image recognition often lead to neural-net architectures that have limited connectivity and repeated use of the same set of weights. This architecture is ideal for time-multiplexing (a combined parallel-series processing) on hardware systems that would be too small to evaluate the entire network in parallel. To make this process efficient, a chip needs to have shift registers to format the input data and additional registers to store intermediate results. Within this framework, it is possible to design chips that have broad utility, large connection capacity, and high speed. This was demonstrated by a new chip with 32000 reconfigurable connections

Hardware requirements for neural-net optical character recognition

Exhaustive exploration of an ensemble of networks is used to model learning and generalization in layered neural networks. A simple Boolean learning problem involving networks with binary weights is numerically solved to obtain the entropy Sm and the average generalization ability Gm as a function of the size m of the training set. Learning curves Gm vs m are shown to depend solely on the distribution of generalization abilities over the ensemble of networks. Such distribution is determined prior to learning, and provides a novel theoretical tool for the prediction of network performance on a specific task.

A general statistical description of the problem of learning from examples is presented. Learning in layered networks is posed as a search in the network parameter space for a network that minimizes an additive error function of a statistically independent examples. By imposing the equivalence of the minimum error and the maximum likelihood criteria for training the network, the Gibbs distribution on the ensemble of networks with a fixed architecture is derived. The probability of correct prediction of a novel example can be expressed using the ensemble, serving as a measure to the network's generalization ability. The entropy of the prediction distribution is shown to be a consistent measure of the network's performance. The proposed formalism is applied to the problems of selecting an optimal architecture and the prediction of learning curves. >

A statistical approach to learning and generalization in layered neural networks

The problem of learning a general input-output relation using a layered neural network is discussed in a statistical framework. By imposing the consistency condition that the error minimization be equivalent to a likelihood maximization for training the network, the authors arrive at a Gibbs distribution on a canonical ensemble of networks with the same architecture. This statistical description enables them to evaluate the probability of a correct prediction of an independent example, after training the network on a given training set. The prediction probability is highly correlated with the generalization ability of the network, as measured outside the training set. This suggests a general and practical criterion for training layered networks by minimizing prediction errors. The authors demonstrate the utility of this criterion for selecting the optimal architecture in the continuity problem. As a theoretical application of the statistical formalism, they discuss the question of learning curves and estimate the sufficient training size needed for correct generalization, in a simple example.<<ETX>>

Consistent inference of probabilities in layered networks: predictions and generalizations

Proceedings of the annual Conferences on Advances in Neural Information Processing Systems. Volumes 7 and later are available from The MIT Press.

Advances in neural information processing systems : proceedings of the ... conference

Advances in Neural Information Processing Systems 1, [NIPS Conference, Denver, Colorado, USA, 1988]

We have used information-theoretic ideas to derive a class of practical and nearly optimal schemes for adapting the size of a neural network. By removing unimportant weights from a network, several improvements can be expected: better generalization, fewer training examples required, and improved speed of learning and/or classification. The basic idea is to use second-derivative information to make a tradeoff between network complexity and training set error. Experiments confirm the usefulness of the methods on a real-world application.

Abstracts from the CECAM workshop on computer simulations of cellular automata

Abst ract . Learning in layered neu ral networks is posed as the mini­ miz at ion of an error function defined over t he training set. A proba­ bilistic interpretation of the target act ivities sugges ts th e use of rela­ t ive entro py as an error measure. We investigate t he merits of using this error function over t he traditional quad ratic function for gradient descent learni ng. Com parative numerical sim ulations for the conrf­ guity problem show marked redu ct ion s in learn ing t imes. This im ­ provement is explained in terms of the characteristic steepness of the landscape defined by the error function in configuration space.

Since an tiquity, man has dreamed of building a de vice that would "learn from examples" 1 "form generalizations", and "discover t he rules" behind patt ern s in t he data. Recent work has shown that a high ly connected , layered networ k of simple an alog processing element s can be astonishingly successful at this, in some cases . In ord er to be precise about what has been observed, we give defini t ions of memorization, generalization , and rule ex traction. T he most im portant part of this paper proposes a way to measure th e ent ropy or information content of a learni ng task a nd the effi ciency wit h which a network ext racts informat ion from the dat a. We also a rgue that the way in which the ne tworks ca n compactly represent a wid e class of Boolean (an d othe r) functi ons is analogous to t he way in which polynomials or other famili es of functions can be "curve fit" to gene ral data; specifically, they ex tend the domain, a nd average noisy data. Alas , findi ng a suitable rep rese ntation is generall y an ill-posed and ill-cond itio ned problem. E ven whe n the problem has bee n " regularized", what rem ain s is a difficult combinatoria l opt imizatio n problem. Whe n a network is given mo re resou rces than the mi nimu m needed to solve a given t ask , the symmetric, low-order , local solut ions that hum an s see m to pre fer are not the ones that the network chooses from th e vast number of solut ions avai la ble; ind eed , th e generalized delt a method a nd similar learning procedures do not usually hold t he "human " solut ions stable against perturbations. Fortuna tely, the re are © 1987 Comp lex Systems Publications, Inc. 878 Denker, Schwart z, Wittner, Solla, Howard , J ackel, and Hopfield ways of "program ming" into t he networ k a preference for appropriately chosen symmetries . 1. Overview of the contents Section 2 gives seve ral examples that illustra te t he import ance of automatic learning from examples . Section 3 poses a tes t -case problem ("c l umps") which will be used t hroughout the paper to illustrate the issues of interest. Section 4 describes the class of networks we are considering and introdu ces t he notation. Section 5 presents a proof by construction t hat a two-layer network can rep resent any Boolean function, and section 6 shows t hat there is an elegant representation for the c lumps tas k, using very few weights and processing units. Sections 7 an d 8 argue that the ob jective function E(W ) has a complicated st ruct ure: good solutions are generally not points in W space, bu t rat her parameteri zed fam ilies of points. Furt hermore, in all but the simplest sit uations, the E su rface is riddled with local minim a, and any automatic lear ning procedure must take firm measures to deal with t his. Section 9 shows that our c l umps tas k is a very simple prob lem, accordin g to the various schemes that have been proposed to quantify the complexity of network tasks and solut ions. Section 10 shows that a general network does no t prefer t he simple solut ions t hat hum ans seem to prefer. Sect ion 11 discusses the crucial effect of changes of representation on the feasibility of aut oma t ic learni ng. We prove that "automat ic learn ing will always succeed, given t he right preprocessor," but we also show t hat t his statement is grossly misleading since there is no automati c procedure for const ruct ing the requ ired preprocessor. Sections 12 and 13 propose definit ions of rule ext ract ion and genera liza t ion and emphas ize th e disti nction between th e two. Sect ion 14 calculates th e entropy budget for ru le ext ract ion and est imates the informat ion available from the t rain ing data and from the "programming" or "architecture" of t he network. This leads to an ap proximate express ion for t he efficiency with which the learni ng procedu re ext rac ts infor mat ion from t he t ra ining data. Sect ion 16 presents a simple model which allows us to calculate the erro r rate duri ng t he learn ing process. Sect ion 17 discusses the rela t ionship bet ween rule ext ract ion in general and assoc iat ive memo ry in particular . In sect ion 18, we arg ue that when special informat ion is availabl e, such as infor mation about the symmetry, geomet ry, or topology of the task at hand, the netwo rk must be provided this information. We also discuss various ways in which this informat ion can be "programmed" into t he net wor k. Section 19 dr aws the analogy between th e family of functions t hat can be implemented by networks with limited amounts of resour ces and other families of funct ions such as polynomials of limited degree. App endix A contains detai ls of th e condit ions under which our data was taken. Large Automa.tic Learning) Rule Extraction, and Generaliza.tion 879 2. Why lea r n from examples? Automa t ic learning from exa mples is a top ic of enormo us importan ce. There are many application s where there is no ot her way to approach the task. For example, consider th e problem of recognizing hand-wri t ten characters. The raw image can be fed to a preprocessor that will detect salient fea tures such as straight line segments, arcs, terminations, et c., in various parts of the field. But what then? Th ere is no mathematical expression t hat will tell you what features correspo nd to a "7" or a "Q" . The task is defined purely by th e statist ics of what features convent iona lly go with what meaningt here is no ot her definition. T here is no way to prog ram it ; the solut ion must be learned by examp les [6,11]. Another example is the task of producing the correct pronunciation of a segment of written English . There are pattern s and rules of pron unciation , but th ey are so complex that a network th at could "discover t he rules" on its own would save an enormous amount of labor [37J. Another example concerns clinical medicine: t he task of mapping a set of symptoms onto a diagnosis. Here t he inputs have physical meaningth ey are not purely convent iona l as in the previous exa mplesbut we are st ill a long way from writing down an equat ion or a computer program that will perform the task a priori. We must learn from the statist ics of past exa mp les (41). Other examples include classifying sonar returns [10], recogni zing speech [5,16,30,23], and predi cting the secondary st ruct ure of proteins from the primary sequence [42]. In th e foregoing examples, t here was rea lly no alte rnat ive to learni ng from exa mples. However, in order to learn more about the power and limit ations of var ious learnin g methods and evaluate new methods as they are prop osed , people have st udied a number of "test cases" where t here was an alternativeth at is, where the "correct" solut ion was well understood. T hese includ e classifying input pattern s accord ing to th eir parity [33], geometric shape [33,35], or spatial symmetry [36J. 3. Example : tvo-or-more clumps Th e tes t case that we will use throughout t his pap er is a simple geometric task which an adaptive network ought to be able to handle. Th e network's inp ut pattern s will be Nbit binary st rings. Somet imes we will tr ea t the pattern s as numbers, so we can speak of numerical order ; somet imes we will also treat them as one-dimensional images, in which false bits (Fs) repr esent white pixels and true bits (Ts) rep resent black pixels. A cont iguous clump of T s represents a solid black bar . We th en choose the following rule to determine th e desired output of the network, as shown in table 1: if the inpu t pattern is such that all the T s appear in one cont iguous clump , th en th e output should be F , and if there are two or more dumps, th en t he 880 Denker, Schwartz, Wittner, Solla, Howard, Jackel, and Hopfield Input pattern Outpu t Interpretation ffft ttffff F 1 clump fffttftfff T 2 clumps ftt ttttttt F 1 clump tttffttff t T 3 clumps ffffffffff F no clumps Tabl e 1: Exa mples of the t woor-more clumps predicate. output should be T . We call this t he two-or-more clumps predicate.1 We will consider numerous variat ions of t his problem, such as three-versus -two clumps and so for t h. The one-versus-two clumps version is a lso known as t he contiguity predi cate [25]. Questions of connectedness have played an importan t role in the history of network s and automatic learning: Minsky a nd P ap er t devoted a sizable por t ion of t hei r book [27] to this sort of qu est ion. There a re a host of important questions that immedi a tely a rise, some of whi ch are list ed below. In some cases , we give summary answe rs ; the details of t he an swers will be given in following sections . Ca n any network of t he type we are con sid ering actua lly rep resen t such a fu nct ion? (Yes.) This is not a t rivial resu lt , since Minsky and Paper t [27J showed that a Perce ptron (with one layer of adjustable weight s) absolutely could not perform a wide class of functions, and our fun ction is in th is class. Can it perform the funct ion efficient ly? (Yes .) This is in cont ras t, say, to a solut ion of the par ity function usin g a standard programmable logic array (PLA) [26], which is possibl e but requires enormo us numbers of hardware components (O(2N ) gates). Can the net work learn to perform this function , by learn ing from examples? (Yes.) How qui ckly can it learn it ? (It de pen ds; see below.) How many layers are required , an d how many hidden units in eac h layer? How do t he answers to t he prev ious ques t ions de pen d on t he architecture (i.e. size an d shape) of th e network? How sensit ive a re the resul t s to t he num erical me t hods and other details of the implementation , such as t he an alog represe ntation of T and F, "moment um term s" , "weight decay te rms" , step size, et c.? Does t he solut ion (i. e. the configuration of weights) t hat the net work find s make sense? Is it s imilar to the solut ions t hat human s would choose , given t he task of designing

Electronic neural networks can perform the function of associative memory. Given an input pattern, the network searches through its stored memories to find which of them best matches the input. Thus the network does a combination of content-addressable search and error correction. The number of random memories that a network can store is limited to a fraction of the number of electronic neurons in the circuit. We propose a method for building a hierarchy of networks that allows the fast parallel search through a list of memories that is too large to store in a single network. We have demonstrated the principle of this approach by an example in image vector quantization.

Building a hierarchy with neural networks: an example-image vector quantization.

We study the way in which the properties of associative memory networks are changed when the interactions between the units are not symmetrical. For a class of analog networks subject to thermal noise (Langevin models), the results indicate that the memory states are not seriously degraded; their critical temperature is simply lowered from its value in the corresponding symmetric model. On the other hand, spin glass states, which occur in the symmetric case when the number of memories becomes a finite fraction of the number of units in the system, are rendered unstable by the introduction of asymmetry. This suggests that asymmetric couplings may make retrieval of the desired memory states faster, since the system will not get trapped in the spin glass states.

We treat a fault as an array of asperities with a prescribed statistical distribution of strengths. When an asperity fails, the stress on the failed asperity is transferred to one or more adjacent asperities. For a linear array the stress is transferred to a single adjacent asperity and for a two-dimensional array to three adjacent asperities. Using a renormalization group (RG) method, we investigate the properties of a scale invariant hierarchical model for the stochastic growth of fault breaks through induced failure by stress transfer. An extrapolation to arbitrarily large scales shows the existence of a critical applied stress at which the solutions bifurcate. At stresses less than the critical stress, virtually no asperities fail on a large scale, and the fault is locked. Above the critical stress, asperity failure cascades away from the nucleus of failure; we interpret this catastrophic failure as an earthquake and it corresponds to the transition from stick to slip behavior on the fault. Thus the stick-slip behavior of most faults can be attributed to the distribution of asperities on the fault. We propose our stochastic mechanism as an alternative to the traditional hypotheses for the stick-slip behavior of faults. A major advantage of our approach is the inclusion of scale invariance. Thus the observed frequency-magnitude relation for seismicity is a natural consequence of our basic hypothesis.

A renormalization group approach to the stick-slip behavior of faults

The helicity moduli of various dilute, classical $\mathrm{XY}$ models on three-dimensional lattices are studied with a view to understanding some aspects of the superfluidity of $^{4}\mathrm{He}$ in Vycor glass. A spinwave calculation is used to obtain the low-temperature helicity modulus of a regularly-diluted $\mathrm{XY}$ model. A similar calculation is performed for the randomly bond-diluted and site-diluted $\mathrm{XY}$ models in the limit of low dilution. A Monte Carlo simulation is used to obtain the helicity modulus of the randomly bond-diluted $\mathrm{XY}$ model over a wide range of temperature and dilution. It is found that the randomly diluted models do agree and the regularly diluted model does not agree with certain experimentally found features of the variation in superfluid fraction with coverage of $^{4}\mathrm{He}$ in Vycor glass.

Monte Carlo studies of a Laplacian roughening model for two-dimensional melting

A fault which is treated as an array of asperities with a prescribed statistical distribution of strengths is described. For a linear array the stress is transferred to a single adjacent asperity and for a two dimensional array to three ajacent asperities. It is shown that the solutions bifurcate at a critical applied stress. At stresses less than the critical stress virtually no asperities fail on a large scale and the fault is locked. At the critical stress the solution bifurcates and asperity failure cascades away from the nucleus of failure. It is found that the stick slip behavior of most faults can be attributed to the distribution of asperities on the fault. The observation of stick slip behavior on faults rather than stable sliding, why the observed level of seismicity on a locked fault is very small, and why the stress on a fault is less than that predicted by a standard value of the coefficient of friction are outlined.

A renormalization group model for the stick-slip behavior of faults

Critical and Thermodynamic Properties of the Bond - Planar Model in Two Dimensions.

The density of vortex excitations and their contribution to the specific heat are discussed for the Villain planar model. Exact results are derived for the low- and high-temperature limits, and a renormalization-group interpolation scheme is developed for intermediate temperatures.

Vortex excitations and specific heat of the planar model in two dimensions

This study examines the influence of a button response task on the event-related potential (ERP) in a semantic priming experiment. Of particular interest is the N400 component. In many semantic priming studies, subjects are asked to respond to a stimulus as fast and accurately as possible by pressing a button. Response time (RT) is recorded in parallel with an electroencephalogram (EEG) for ERP analysis. In this case, the response occurs in the time window used for ERP analysis and response-related components may overlap with stimulus-locked ones such as the N400. This has led to a recommendation against such a design, although the issue has not been explored in depth. Since studies keep being published that disregard this issue, a more detailed examination of influence of response-related potentials on the ERP is needed. Two experiments were performed in which subjects pressed one of two buttons with their dominant hand in response to word-pairs with varying association strength (AS), indicating a personal judgement of association between the two words. In the first experiment, subjects were instructed to respond as fast and accurately as possible. In the second experiment, subjects delayed their button response to enforce a one second interval between the onset of the target word and the button response. Results show that in the first experiment a P3 component and motor-related potentials (MRPs) overlap with the N400 component, which can cause a misinterpretation of the latter. In order to study the N400 component, the button response should be delayed to avoid contamination of the ERP with response-related components.

Response-Related Potentials during Semantic Priming: The Effect of a Speeded Button Response Task on ERPs

Objective. The performance and usability of brain–computer interfaces (BCIs) can be improved by new paradigms, stimulation methods, decoding strategies, sensor technology etc. In this study we introduce new stimulation and decoding methods for electroencephalogram (EEG)-based BCIs that have targets flickering at the same frequency but with different phases. Approach. The phase information is estimated from the EEG data, and used for target command decoding. All visual stimulation is done on a conventional (60-Hz) LCD screen. Instead of the ‘on/off’ visual stimulation, commonly used in phase-coded BCI, we propose one based on a sampled sinusoidal intensity profile. In order to fully exploit the circular nature of the evoked phase response, we introduce a filter feature selection procedure based on circular statistics and propose a fuzzy logic classifier designed to cope with circular information from multiple channels jointly. Main results. We show that the proposed visual stimulation enables us not only to encode more commands under the same conditions, but also to obtain EEG responses with a more stable phase. We also demonstrate that the proposed decoding approach outperforms existing ones, especially for the short time windows used. Significance. The work presented here shows how to overcome some of the limitations of screen-based visual stimulation. The superiority of the proposed decoding approach demonstrates the importance of preserving the circularity of the data during the decoding stage.

Sampled sinusoidal stimulation profile and multichannel fuzzy logic classification for monitor-based phase-coded SSVEP brain–computer interfacing

This paper describes our first attempt to port a brain-computer interface (BCI), created in a research lab and running on expensive equipment, to consumer grade equipment, allowing one to reach a much broader audience and raise public awareness of this new technology. With the BCI, the user can perform a complicated task through mind control only: playing a tactical video-game. Reliable control is accomplished by adapting a Steady-State Visual Evoked Potential (SSVEP) classifier to be robust enough to cope with the signal quality of the consumer grade electroencephalography (EEG) device used, i.e. the Emotiv EPOC. The difference in performance of the game running on research grade EEG equipment versus the Emotiv EPOC is examined. The game was tested by a broad audience during a public event and was well received.

2012 ISSNIP Biosignals and Biorobotics Conference: Biosignals and Robotics for Better and Safer Living (BRC)

Designing a brain-computer interface controlled video-game using consumer grade EEG hardware

Good scientific practice in EEG and MEG research: Progress and perspectives

Summary The development of the Brain Imaging Data Structure (BIDS; Gorgolewski et al., 2016) gave the neuroscientific community a standard to organize and share data. BIDS prescribes file naming conventions and a folder structure to store data in a set of already existing file formats. Next to rules about organization of the data itself, BIDS provides standardized templates to store associated metadata in the form of Javascript Object Notation (JSON) and tab separated value (TSV) files. It thus facilitates data sharing, eases metadata querying, and enables automatic data analysis pipelines. BIDS is a rich system to curate, aggregate, and annotate neuroimaging databases.

MNE-BIDS: Organizing electrophysiological data into the BIDS format and facilitating their analysis

Unorganized heaps of analysis code are a growing liability as data analysis pipelines are getting longer and more complicated. This is worrying, as neuroscience papers are getting retracted due to programmer error. In this paper, some guidelines are presented that help keep analysis code well organized, easy to understand and convenient to work with: 
1. Each analysis step is one script 
2. A script either processes a single recording, or aggregates across recordings, never both 
3. One master script to run the entire analysis 
4. Save all intermediate results 
5. Visualize all intermediate results 
6. Each parameter and filename is defined only once 
7. Distinguish files that are part of the official pipeline from other scripts 
In addition to discussing the reasoning behind each guideline, an example analysis pipeline is presented as a case study to see how each guideline translates into code.

Linear machine learning models “learn” a data transformation by being exposed to examples of input with the desired output, forming the basis for a variety of powerful techniques for analyzing neuroimaging data. However, their ability to learn the desired transformation is limited by the quality and size of the example dataset, which in neuroimaging studies is often notoriously noisy and small. In these cases, it is desirable to fine-tune the learned linear model using domain information beyond the example dataset. To this end, we present a framework that decomposes the weight matrix of a fitted linear model into three subcomponents: the data covariance, the identified signal of interest, and a normalizer. Inspecting these subcomponents in isolation provides an intuitive way to inspect the inner workings of the model and assess its strengths and weaknesses. Furthermore, the three subcomponents may be altered, which provides a straightforward way to inject prior information and impose additional constraints. We refer to this process as “post-hoc modification” of a model and demonstrate how it can be used to achieve precise control over which aspects of the model are fitted to the data through machine learning and which are determined through domain information. As an example use case, we decode the associative strength between words from electroencephalography (EEG) reading data. Our results show how the decoding accuracy of two example linear models (ridge regression and logistic regression) can be boosted by incorporating information about the spatio-temporal nature of the data, domain information about the N400 evoked potential and data from other participants. Highlights We present a framework to decompose any linear model into three subcomponents that are straightforward to interpret. By modifying the subcomponents before re-assembling them into a linear model, prior information and further constraints may be injected into the model. As an example, we boost the performance of a linear regressor and classifier by injecting knowledge about the spatio-temporal nature of the data, the N400 evoked potential and data from other participants.

Post-hoc modification of linear models: Combining machine learning with domain information to make solid inferences from noisy data

Communication between brain regions is thought to be facilitated by the synchronization of oscillatory activity. Hence, large-scale functional networks within the brain may be estimated by measuring synchronicity between regions. Neurophysiological recordings, such as magnetoencephalography (MEG) and electroencephalography (EEG), provide a direct measure of oscillatory neural activity with millisecond temporal resolution. In this paper, we describe a full data analysis pipeline for functional connectivity analysis based on dynamic imaging of coherent sources (DICS) of MEG data. DICS is a beamforming technique in the frequency-domain that enables the study of the cortical sources of oscillatory activity and synchronization between brain regions. All the analysis steps, starting from the raw MEG data up to publication-ready group-level statistics and visualization, are discussed in depth, including methodological considerations, rules of thumb and tradeoffs. We start by computing cross-spectral density (CSD) matrices using a wavelet approach in several frequency bands (alpha, theta, beta, gamma). We then provide a way to create comparable source spaces across subjects and discuss the cortical mapping of spectral power. For connectivity analysis, we present a canonical computation of coherence that facilitates a stable estimation of all-to-all connectivity. Finally, we use group-level statistics to limit the network to cortical regions for which significant differences between experimental conditions are detected and produce vertex-and parcel-level visualizations of the different brain networks. Code examples using the MNE-Python package are provided at each step, guiding the reader through a complete analysis of the freely available openfMRI ds000117 “familiar vs. unfamiliar vs. scrambled faces” dataset. The goal is to educate both novice and experienced data analysts with the “tricks of the trade” necessary to successfully perform this type of analysis on their own data.

Analysis of Functional Connectivity and Oscillatory Power Using DICS: From Raw MEG Data to Group-Level Statistics in Python

Modern multivariate methods have enabled the application of unsupervised techniques to analyze neurophysiological data without strict adherence to predefined experimental conditions. We demonstrate a multivariate method that leverages priming effects on the evoked potential to perform hierarchical clustering on a set of word stimuli. The current study focuses on the semantic relationships that play a key role in the organization of our mental lexicon of words and concepts. The N400 component of the event-related potential is considered a reliable neurophysiological response that is indicative of whether accessing one concept facilitates subsequent access to another (i.e., one “primes” the other). To further our understanding of the organization of the human mental lexicon, we propose to utilize the N400 component to drive a clustering algorithm that can uncover, given a set of words, which particular subsets of words show mutual priming. Such a scheme requires a reliable measurement of the amplitude of the N400 component without averaging across many trials, which was here achieved using a recently developed multivariate analysis method based on beamforming. We validated our method by demonstrating that it can reliably detect, without any prior information about the nature of the stimuli, a well-known feature of the organization of our semantic memory: the distinction between animate and inanimate concepts. These results motivate further application of our method to data-driven exploration of disputed or unknown relationships between stimuli.

Exploring the Organization of Semantic Memory through Unsupervised Analysis of Event-related Potentials

Previous research has shown by using event-related potentials (ERPs) that the human brain can process and understand music at a pre-attentive level. Music-specific ERPs include the Early Right Anterior Negativity (ERAN) and a late Negativity (N5). This study aims to further investigate this issue using two types of syntactic manipulations in music: mild violations, containing no out-of-key tones and strong violations, containing out-of-key tones. We will examine whether both manipulations will elicit the same ERPs.

2017 22nd International Conference on Digital Signal Processing (DSP)

How does the brain process mild versus strong violations in music? A pilot study using event-related potentials

World Academy of Science, Engineering and Technology, International Journal of Computer and Information Engineering

Processing Mild versus Strong Violations in Music: A Pilot Study Using Event-Related Potentials

Goal: For statistical analysis of event-related potentials (ERPs), there are convincing arguments against averaging across stimuli or subjects. Multivariate filters can be used to isolate an ERP component of interest without the averaging procedure. However, we would like to have certainty that the output of the filter accurately represents the component. Methods: We extended the linearly constrained minimum variance (LCMV) beamformer, which is traditionally used as a spatial filter for source localization, to be a flexible spatiotemporal filter for estimating the amplitude of ERP components in sensor space. In a comparison study on both simulated and real data, we demonstrated the strengths and weaknesses of the beamformer as well as a range of supervised learning approaches. Results: In the context of measuring the amplitude of a specific ERP component on a single-trial basis, we found that the spatiotemporal LCMV beamformer is a filter that accurately captures the component of interest, even in the presence of both structured noise (e.g., other overlapping ERP components) and unstructured noise (e.g., ongoing brain activity and sensor noise). Conclusion: The spatiotemporal LCMV beamformer method provides an accurate and intuitive way to conduct analysis of a known ERP component, without averaging across trials or subjects. Significance: Eliminating averaging allows us to test more detailed hypotheses and apply more powerful statistical models. For example, it allows the usage of multilevel regression models that can incorporate between subject/stimulus variation as random effects, test multiple effects simultaneously, and control confounding effects by partial regression.

Single-Trial ERP Component Analysis Using a Spatiotemporal LCMV Beamformer

The N400 is an event-related potential (ERP) that reflects the processing of semantics in the brain. When reading sentences, the N400 amplitude is modulated by both the cloze probability of the sentence and the association strength between individual words. When contradicted in strongly constraining sentences, that is, the beginning of the sentence builds a strong expectation of the final word; the cloze probability overrules the effect of association strength. We evidence that this is also the case for non-constraining sentences, such as the ones with low to moderate cloze probabilities. Our results give the evidences that if the sentence generates even weak to moderate expectations about the final word, word association plays almost no role in the processing of this word.

2014 4th International Workshop on Cognitive Information Processing (CIP)

Amplitude of N400 component unaffected by lexical priming for moderately constraining sentences

In this paper, we introduce a game in which the player navigates an avatar through a maze by using a brain-computer interface (BCI) that analyzes the steady-state visual evoked potential (SSVEP) responses recorded with electroencephalography (EEG) on the player's scalp. The four-command control game, called The Maze, was specifically designed around an SSVEP BCI and validated in several EEG setups when using a traditional electrode cap with relocatable electrodes and a consumer-grade headset with fixed electrodes (Emotiv EPOC). We experimentally derive the parameter values that provide an acceptable tradeoff between accuracy of game control and interactivity, and evaluate the control provided by the BCI during gameplay. As a final step in the validation of the game, a population study on a broad audience was conducted with the EPOC headset in a real-world setting. The study revealed that the majority (85%) of the players enjoyed the game in spite of its intricate control (mean accuracy 80.37%, mean mission time ratio 0.90). We also discuss what to take into account while designing BCI-based games.

Steady-State Visual Evoked Potential-Based Computer Gaming on a Consumer-Grade EEG Device

Preprocessing and Decoding Steady-State Visual Evoked Potentials for Brain-Computer Interfaces

In this position paper, we investigate whether a parallel factor analysis (Parafac) decomposition is beneficial to the decoding of steady-state visual evoked potentials (SSVEP) present in electroencephalogram (EEG) recordings taken from the subject’s scalp. In particular, we develop an automatic algorithm aimed at detecting the stimulation frequency after Parafac decomposition. The results are validated on recordings made from 54 subjects using consumer-grade EEG hardware (Emotiv’s EPOC headset) in a real-world environment. The
detection of one frequency among 12, 4 and 2 possible was considered to assess the feasibility for Brain Computer Interfacing (BCI). We determined the frequencies subsets, among all subjects, that maximize the detection rate.

Feasibility of Error-Related Potential Detection as Novelty Detection Problem in P300 Mind Spelling

In this chapter, several decoding methods for the Steady State Visual Evoked Potential (SSVEP) paradigm are discussed, as well as their use in Brain Computer Interfaces (BCIs). The chapter starts with the concept of BCI, the different categories and their relevance for speechand motor disabled patients. The SSVEP paradigm is explained in detail. The discussed processing and decoding methods employ either time-domain or spectral domain features. Finally, to show the usability of these methods and of SSVEPbased BCIs in general, three applications are described: a spelling system, the “Maze” game and the “Tower Defense” game. We conclude the chapter by addressing some challenges for future research.

2 Processing and Decoding Steady-State Visual Evoked Potentials for Brain-Computer Interfaces

In this paper, we present an application that is a synergy of two research disciplines: visual object detection (and localization) and brain-computer interfacing. The goal is to construct an alternative way for a person to select real objects in the environment, without using speech, or any other form of muscular activity. Due to the latter, our application is potentially useful for patients that suffer from severe motor impairments since it would enable them to engage in a high-level interaction process with objects.

2011 IEEE International Workshop on Machine Learning for Signal Processing

Combining object detection and brain computer interfacing: Towards a new way of subject-environment interaction

Steady State Visual Evoked Potential Based Computer Gaming - The Maze

Decoding Phase-Based Information from Steady-State Visual Evoked Potentials with Use of Complex-Valued Neural Network

Offline analysis pipelines have been developed and evaluated for the detection of covert attention from electroen-cephalography recordings, and the detection of overt attention in terms of eye movement based on electrooculographic measurements. Some additional analysis were done in order to prepare the pipelines for use in a real-time system. This real-time system and a game application in which these pipelines are to be used were implemented. The game is set in a virtual environment where player is a wildlife photographer on an uninhabited island. Overt attention is used to adjust the angle of the first person camera, when the player is tracking animals. When making a photograph, the animal will flee when it notices it is looked at directly, so covert attention is required to get a good shot. Future work will entail user tests with this system to evaluate usability, user experience, and characteristics of the signals related to overt and covert attention when used in such an immersive environment.

We present an overview of our Brain-computer interface (BCI) research, invasive as well as non-invasive, during the past four years. The invasive BCIs are based on local field-and action potentials recorded with microelectrode arrays implanted in the visual cortex of the macaque monkey. The non-invasive BCIs are based on electroencephalogram (EEG) recorded from a human subject's scalp. Several EEG paradigms were used to enable the subject to type text or to select icons on a computer screen, without having to rely on one's fingers, gestures, or any other form of motor activity: the P300 event-related potential, the steady-state visual evoked potential, and the error related potential. We report on the status of our EEG BCI tests on healthy subjects as well as patients with severe communication disabilities, and our demonstrations to a broad audience to raise the public awareness of BCI.

Brain-computer interface research at Katholieke Universiteit Leuven

In this paper, we report on the decoding of phase-based information, from steady-state visual evoked potential (SSVEP) recordings, by means of different classifiers. In addition to the ones reported in the literature, we also consider other types of classifiers such as the multilayer feedforward neural network based on multi-valued neurons (MLMVN), and the classifier based on fuzzy logic, which we especially tuned for phase-based SSVEP decoding. The dependency of the decoding accuracy on the number of targets and on the decoding window size are discussed. When comparing existing phase-based SSVEP decoding methods with the proposed ones, we are able to show that the latter ones perform better, for different parameter settings, but especially when having multiple targets. The necessity of optimizing the target frequencies to the individual subject is also discussed.

Decoding phase-based information from SSVEP recordings: A comparative study

In this paper, we report on the decoding of phase-based information from steady-state visual evoked potential (SSVEP) recordings by means of a multilayer feedforward neural network based on multivalued neurons. Networks of this kind have inputs and outputs which are well fitted for the considered task. The dependency of the decoding accuracy w.r.t. the number of targets and the decoding window size is discussed. Comparing existing phase-based SSVEP decoding methods with the proposed approach, we show that the latter performs better for the larger amount of target classes and the sufficient size of decoding window. The necessity of the proper frequency selection for each subject is discussed.

Decoding Phase-based Information from SSVEP Recordings with Use of Complex-Valued Neural Network

We report on the development of a four command Brain-Computer Interface (BCI) based on steady-state visual evoked potential (SSVEP) responses detected from human electroencephalograms (EEGs). The proposed system combines spatial filtering, feature extraction and selection, and a classifier. Two types of classifiers were compared: one based on equal treatment of all harmonics in all EEG channels and the second based on preliminary training resulting in a weighted treatment of the harmonics. Results from six healthy subjects are evaluated.

Proceedings of the 6th IEEE International Conference on Intelligent Data Acquisition and Advanced Computing Systems

Subject-adaptive steady-state visual evoked potential detection for brain-computer interface

Guessing What's on Your Mind: Using the N400 in Brain Computer Interfaces

The Assessment of Reading Competence by Teachers: the Use of Grades versus the CEF

In this paper, a method of automatically reducing EOG artifacts in an EEG recording is evaluated in a BCI context. The methods were incorporated into a system for classifying 4 types of imagined movement and the performance of the system was used for comparison. It is shown that the EOG regression method can be used in combination with frequency filtering and does improve the performance of the classifier. It is also shown that it is beneficial to recalculate the noise/signal mixing matrix for each trial.

The paper describes a novel method for opinion elicitation, which is based on the popular 3D online world of “Second Life”. Here people, as avatars, are put into a somewhat realistic context related to the topic for which opinions are sought. We hypothesize that this kind of concrete, interactive context supports the evocation of opinions better than non-context methods, e.g. only showing related images. To confirm our hypothesis, we conducted a small pilot study, which compares the influence of static and interactive context methods on the opinions expressed by subjects. The opinion elicitation scenario in Second Life is supported by the automatic retrieval of opinions from the web. The results of a study indicate that subjects show more reasoned opinions in the interactive condition. A demo illustrating the content of this paper is available.

interfaces (BCI) can help handicapped people by allowing them to enter a text using thought alone. One of the current methods to achieve this is the P300 speller, where the P300 potential is detected to select a symbol from a 6 x 6 table. In this paper, the use of an intelligent application is proposed. Intelligent applications take the input language into account and facilitate the input of more likely symbols. The intelligent application proposed is Dasher, an application that uses zooming and probability scores to select symbols. To test how Dasher performs in comparison to the P300 speller, a small empirical experiment is proposed. The paper also describes the different aspects of setting up the BCI.

To better understand the computational steps that the brain performs during reading, we used a convolutional neural network as a computational model of visual word recognition, the first stage of reading. In contrast to traditional models of reading, our model directly operates on the pixel values of an image containing text, and has a large vocabulary of 10k Finnish words. The same stimuli can thus be presented unmodified to both the model and human volunteers in a magnetoencephalography (MEG) scanner. In a direct comparison between model and brain activity, we show that the model accurately predicts the amplitude of three evoked MEG response components commonly observed during reading. We conclude that the deep learning techniques that revolutionized models of object recognition can also create models of reading that can be straightforwardly compared to neuroimaging data, which will greatly facilitate testing and refining theories on language processing in the brain.

A large-scale computational model to accurately predict early brain activity in response to written words

Our understanding of the surrounding world and communication with other people are tied to mental representations of concepts. In order for the brain to recognize an object, it must determine which concept to access based on information available from sensory inputs. In this study, we combine magnetoencephalography and machine learning to investigate how concepts are represented and accessed in the brain over time. Using brain responses from a silent picture naming task, we track the dynamics of semantic processing, and show that the brain gradually accumulates semantic information before eventually reaching a plateau. The timing of this plateau point varies across individuals, indicating differences in the temporal domain of semantic processing, a new dimension of individual variability in the faculty of language.

Cortical time-course of evidence accumulation during semantic processing

Good Scientific Practice (GSP) refers to both explicit and implicit rules or guidelines that help scientists to produce work that is of the highest quality at any given time, and to efficiently share that work with the community for further scrutiny or utilization. For experimental research using magneto- and electroencephalography (MEEG), GSP includes specific standards and guidelines for technical competence, which are periodically updated whenever new findings come to light. However, GSP also needs to be periodically revisited in a broader light. At the LiveMEEG 2020 conference, a reflection on GSP was fostered that included explicitly documented guidelines and technical advances, but also emphasised intangible GSP: a general awareness of personal, organisational, and societal realities and how they can influence MEEG research. This article provides an extensive report on most of the LiveMEEG contributions and new literature, with the additional aim to synthesize ongoing cultural changes in GSP. It first covers GSP with respect to cognitive biases and logical fallacies, pre-registration as a tool to avoid those and other early pitfalls, and a number of resources to enable collaborative and reproducible research as a general approach to minimize misconceptions. Second, GSP with respect to data acquisition, analysis, reporting, and sharing is discussed, including new tools and frameworks to support collaborative work. Finally, GSP is considered in light of ethical implications of MEEG research and the resulting responsibility that scientists have to engage with societal challenges. Considering among other things the benefits of peer review and open access at all stages, the need to coordinate larger international projects, the complexity of MEEG subject matter, and today's prioritization of fairness, privacy, and the environment, we find that current GSP tends to favour collective and cooperative work, for both scientific and for societal reasons.

Good Scientific Practice in MEEG Research: Progress and Perspectives

In order to describe how humans represent meaning in the brain, one must be able to account for not just concrete words but, critically, also abstract words, which lack a physical referent. Hebbian formalism and optimization are basic principles of brain function, and they provide an appealing approach for modeling word meanings based on word co‐occurrences. We provide proof of concept that a statistical model of the semantic space can account for neural representations of both concrete and abstract words, using MEG. Here, we built a statistical model using word embeddings extracted from a text corpus. This statistical model was used to train a machine learning algorithm to successfully decode the MEG signals evoked by written words. In the model, word abstractness emerged from the statistical regularities of the language environment. Representational similarity analysis further showed that this salient property of the model co‐varies, at 280–420 ms after visual word presentation, with activity in regions that have been previously linked with processing of abstract words, namely the left‐hemisphere frontal, anterior temporal and superior parietal cortex. In light of these results, we propose that the neural encoding of word meanings can arise through statistical regularities, that is, through grounding in language itself.

The neural representation of abstract words may arise through grounding word meaning in language itself

In neuroimaging, as in many fields, the journey of the data from the measurement equipment to a figure in a publication is growing longer and more complicated. New preprocessing steps are added at the beginning of the pipeline [1–3], new multivariate techniques in the middle [4–6], and new statistical methods at the end [7]. Using these new techniques often requires writing pieces of programming code referred to as "scripts," and, in accordance with the growing data analysis pipelines, these scripts also tend to increase in length and complexity. When programming code becomes sufficiently convoluted, even the most experienced programmers will make mistakes, which can ultimately lead to erroneous conclusions. Papers have had to be retracted due to programmer error [8–10]. Ideally, analysis code should be a testament to the scientific rigor and technological creativity of the researcher, in much the same way as the scientific articles they write. This means dealing with the disorder that arises as ideas get tried and discarded, mistakes are made and fixed, and smaller analyses are made on the side. The tips in this article aim to facilitate a successful organization of the analysis code, thereby keeping the complexity of data analysis code within tolerable limits and reducing errors. This article is a guide for those who have already written their own data analysis pipelines and wish to improve their designs. Those looking for information on how to get started writing a data analysis pipeline for neuroimaging are referred to other works [11–15]. There is a large body of literature on managing complexity and reducing the chance for programmer error in software [16–20]. However, most of it deals with the construction of programs and software libraries intended to be used across projects. This article focuses on analysis scripts that sit at the point at which the general purpose functionality that is exposed by software libraries meets the specific demands of a single study [21]. This makes scripts somewhat of an outlier in the software landscape, as they are pieces of code that are not reusable (pieces that need to be reusable are better implemented in a software library), only have to function correctly on one specific data set (hence there is little need to test for "edge cases"), and will generally only be used by yourself and your collaborators (save the occasional run for review purposes and replication studies). Therefore, many of the standard practices of the software industry do not apply or need translation in order to arrive at concrete advice of what to do and what to avoid when writing analysis scripts. To move beyond mere truisms, the analysis pipeline developed by van Vliet and colleagues [22] has been extended to implement all tips in this paper and will be used as case study to discuss the practical consequences of each tip in terms of code. The example pipeline starts from the raw magnetoencephalography (MEG) and structural magnetic resonance imaging (MRI) data from the Wakeman and colleagues [23] data set and performs several artifact reduction steps, source estimations, functional connectivity analyses, cluster permutation statistics, and PLOS COMPUTATIONAL BIOLOGY

In order to describe how humans represent meaning in the brain, one must be able to account for not just concrete words but, critically, also abstract words which lack a physical referent. Hebbian formalism and optimization are basic principles of brain function, and they provide an appealing approach for modeling word meanings based on word co-occurrences. Here, we built a model of the semantic space based on word statistics in a large text corpus, which was able to decode items from brain signals. In the model, word abstractness emerged from the statistical regularities of the language environment. This salient property of the model co-varied, at 280–420 ms after word presentation, with activity in the left-hemisphere frontal, anterior temporal and superior parietal cortex that have been linked with processing of abstract words. In light of these results, we propose that the neural encoding of word meanings is importantly grounded in language through statistical regularities.

Cracking the problem of neural representations of abstract words: grounding word meanings in language itself

In many experimental paradigms of electroencephalography (EEG), timing accuracy in presenting experimental stimuli as visualized on a computer screen is of importance. This paper describes a software package enabling students and researchers to easily set up suitable visual stimulation sequences for simple experiment. We describe the mechanisms employed by the software to achieve good timing accuracy on a common laptop, running Microsoft Windows. With a light sensor, the synchronization of the visual stimulation and the EEG hardware is evaluated. The results demonstrate a maximum variance of 2ms between the synchronization marker sent to the EEG hardware and the presentation of the stimulus on screen. We also confirm the software’s ability to display a flickering stimulus, used in steady-state visual evoked potential (SSVEP) experiments, with a precise frequency.

Accurate Visual Stimulus Presentation Software for EEG Experiments

As more and more of the world becomes digital, and documents become easily available over the Internet, we are suddenly able to access all kinds of information. The downside of this however is that information that is not digital becomes less accessed, and is liable to be lost to us and to future generations. Whereas there are many scanning projects underway, such as Google books and the Open Library Alliance, these projects are not going to know about, much less find, the specialized scientific literature within various fields. This short paper describes the beginnings of a project to digitize some of the older literature in the information retrieval field. The paper finishes with some thoughts for future work on making more of our IR literature available for searching.

Behind the scenes of the digital museum of information retrieval research

Review of Novel Shoulder Arthroplasty Planning Technologies and Potential Conflicts of Interest

Outpatient total joint arthroplasty (TJA) gained favor during the COVID-19 pandemic. Our objective was to critically evaluate the safety and short-term outcomes of outpatient total hip arthroplasty (THA) and total knee arthroplasty (TKA) throughout the pandemic compared with pre-pandemic given their increased use. This was a retrospective review of 941 patients who underwent elective, outpatient TKA and THA at a single institution. Patients were divided into two cohorts: pre-pandemic (N=611) and pandemic (N=330). Data points included demographics, comorbidities, failure of same calendar day discharge (SCDD), and 90-day readmissions and re-operations. The pandemic cohort was older (61.0 vs 59.0 years; P=.001) and had a higher Charlson Comorbidity Index (2 vs 1; P=.004). There were no differences between the pandemic and pre-pandemic cohorts regarding SCDD failures (23.3% vs 21.9%; P=.623) and reoperations (4.2% vs 6.2%; P=.205). The pandemic cohort had a lower readmission rate (4.8% vs 8.2%; P=.056). Overall, patients who had failure of SCDD more commonly underwent TKA than THA (63.5% vs 36.5%; P<.001), were older (63.0 vs 58.5 years; P<.001), had a higher body mass index (30.8 vs 29.9 kg/m2; P=.006) and Charlson Comorbidity Index (2 vs 1; P<.001), had an American Society of Anesthesiologists class greater than 2 (51.2% vs 31.6%; P<.001), received physical therapy later postoperatively (4.15 vs 3.12 hours; P<.001), and had a history significant for myocardial infarction (P=.025), chronic kidney disease (P=.004), or diabetes (P=.003). This study supports broadening indications for outpatient TJA because we found a shift toward older patients with more comorbidities successfully undergoing the procedure. [Orthopedics. 202x;4x(x):xx-xx.].

A Role for Outpatient Total Joint Arthroplasty During the COVID-19 Pandemic.

This study investigated the rate of acromial insufficiency fractures (AIF) in patients undergoing reverse shoulder arthroplasty (RSA) with concomitant distal clavicle excision (DCE). Patients who underwent primary RSA with DCE by a single surgeon from 2010 to 2021 were identified. Exclusion criteria included revision RSA, RSA for fracture, or cases utilizing an augmented baseplate or bone graft. AIF was defined as a radiographically proven acromion or scapular spine fracture. Pain without an identifiable fracture on imaging was defined as an acromial insufficiency reaction. Patient demographics, implant information, and radiograph measurements were compared between patients with and without acromial pathology. One hundred and seventy-five patients were included. Mean age was 72.8 years, and 67% of patients were female. There were 3/174 acromial insufficiency fractures (1.7%). AIF occurred at a mean of 9.3 months after surgery. Twelve patients had insufficiency reactions (6.9%). Patients with acromial pathology were more likely to be female ( p = .003) and have a diagnosis of osteoporosis ( p = .047) and inflammatory arthritis ( p = .049). There was no significant difference between groups in terms of other factors. The AIF rate in patients who underwent RSA with DCE was 1.7%. These findings suggest that DCE in the setting of RSA may have a protective role against AIF.

Low acromial insufficiency fracture rate in reverse shoulder arthroplasty with distal clavicle excision

Complications after Operative Treatment of High Grade Acromioclavicular Injuries.

Arthroscopic Treatment of Glenohumeral Arthritis in the Young Patient

Patient-Specific E-mailed Discharge Instructions Improve Patient Satisfaction and Patient Understanding After Surgical Arthroscopy

Efficacy of Waterproof Cast Protectors and Their Ability to Keep Casts Dry.

Midterm outcomes and survivorship of arthroscopic elbow debridement: a comparison of posttraumatic versus primary degenerative osteoarthritis

A randomized clinical trial of 30 patients with refractory lumbar disc disease with evidence of a herniation at a single intervertebral space on the myelogram is presented. Collagenase or a saline placebo was injected into the affected disc. Lack of pain reduction or lack of functional improvement was considered a therapeutic failure. Patients who failed to respond to the placebo could subsequently receive a collagenase injection. Thirty-three percent (33%) of the 15 patients who received a placebo and 80% of the 15 patients who received collagenase were rated successful 8 weeks after injection. The study demonstrates a statistically significant effectiveness of collagenase in the treatment of herniated lumbar disc disease.

Double-Blind Evaluation of Collagenase Injections for Herniated Lumbar Discs

Fetal liver zinc finger protein (FLIZ1, ZC3H8) was previously described as a negative regulator of GATA3 expression in T cells. GATA3 also is an important determinant of mammary cell fate and breast tumor cell behavior. We hypothesized that FLIZ1 also regulates GATA3 in the mammary gland, thereby influencing normal and tumor cell processes controlled by GATA3. We identified tumor cell lines with high levels of FLIZ1 expression, and transfected them with vectors driving expression of FLIZ1-interfering RNAs. Stable transfectants (Flizout cells) were evaluated for ability to migrate in a wound healing assay, and were found to have decreased mobility. Flizout cells also grew more slowly and with more pronounced epithelial morphology in media containing charcoal-stripped serum, suggesting increased dependence on steroid hormones. Flizout cells were compared to control cells in proliferation assays, and were found to grow at equivalent rates in standard media, but Flizout cells grew at decreased rates in the presence of tamoxifen. We implanted Flizout cells and controls into the mammary glands of syngeneic female mice, which were then treated with tamoxifen or peanut oil vehicle alone. Flizout cells grew more slowly in tamoxifen-treated animals, and tissue weights were significantly less than controls. In order to determine if FLIZ1 plays a role in the normal mammary gland, we assessed its expression during stages of mouse mammary gland development by immunoblot, and found FLIZ1 expression increased during mammary involution. These data are consistent with a role for FLIZ1 in regulation of mammary cell growth and tumor cell behavior. Citation Format: Torri Anderson, Christopher Cali, Katherine Bell, Keith G. Danielson, Ashley Klein, Christina Martin, Sara Radecki, Adam Santoro, John A. Schmidt, Janice E. Knepper. Alteration of mammary tumor cell behavior by FLIZ1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3391. doi:10.1158/1538-7445.AM2014-3391

Abstract 3391: Alteration of mammary tumor cell behavior by FLIZ1

Dengue virus (DV)-induced changes in the host cell protein synthesis machinery are not well understood. We investigated the transcriptional changes related to initiation of protein synthesis. The human hepatoma cell line, HepG2, was infected with DV serotype 2 for 1 h at a multiplicity of infection of one. RNA was extracted after 6, 24 and 48 h. Microarray results showed that 36.5% of the translation factors related to initiation of protein synthesis had significant differential expression (Z-score >or= +/-2.0). Confirmation was obtained by quantitative real-time reverse transcription-PCR. Of the genes involved in the activation of mRNA for cap-dependent translation (eIF4 factors), eIF4A, eIF4G1 and eIF4B were up-regulated while the negative regulator of translation eIF4E-BP3 was down-regulated. This activation was transient since at 24 h post-infection levels were not significantly different from control cells. However, at 48 h post-infection, eIF4A, eIF4E, eIF4G1, eIF4G3, eIF4B, and eIF4E-BP3 were down-regulated, suggesting that cap-dependent translation could be inhibited during the progression of infection. To test this hypothesis, phosphorylation of p70S6K and 4E-BP1, which induce cap-dependent protein synthesis, was assayed. Both proteins remained phosphorylated when assayed at 6 h after infection, while infection induced dephosphorylation of p70S6K and 4E-BP1 at 24 and 48 h of infection, respectively. Taken together, these results provide biological evidence suggesting that in HepG2 cells DV sustains activation of the cap-dependent machinery at early stages of infection, but progression of infection switches protein synthesis to a cap-independent process.

Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas

Dengue virus-induced regulation of the host cell translational machinery.

We have studied a patient with acute myeloid leukemia (AML) and t(10;11)(q23;p15) as the sole cytogenetic abnormality. Molecular analysis revealed a translocation involving nucleoporin 98 (NUP98) fused to the DNA binding domain of the hematopoietically expressed homeobox gene (HHEX). Expression of NUP98/HHEX in murine bone marrow cells leads to aberrant self-renewal and a block in normal differentiation which depends on the integrity of the NUP98 GFLG repeats and the HHEX homeodomain. Transplantation of bone marrow cells expressing NUP98/HHEX leads to transplantable acute leukemia characterized by extensive infiltration of leukemic blasts expressing myeloid markers (Gr1+) as well as markers of the B-cell lineage (B220+). A latency period of 9 months and its clonal character suggest that NUP98/HHEX is necessary but not sufficient for disease induction. Expression of EGFP-NUP98/HHEX fusions showed a highly similar nuclear localization pattern as for other NUP98/homeodomain fusions, such as NUP98/HOXA9. Comparative gene expression profiling in primary bone marrow cells provided evidence for the presence of common targets in cells expressing NUP98/HOXA9 or NUP98/HHEX. Some of these genes (Hoxa5, Hoxa9, Flt3) are deregulated in NUP98/HHEX induced murine leukemia as well as in human blasts carrying this fusion and might represent bona fide therapeutic targets. 2 For personal use only. on August 20, 2017. by guest www.bloodjournal.org From

From cloning of a new fusion involving the nucleoporin 98 (NUP98) gene to a common NUP98-homedomain fusion gene genetic footpri

Large transformer-based models are able to perform in-context few-shot learning, without being explicitly trained for it. This observation raises the question: what aspects of the training regime lead to this emergent behavior? Here, we show that this behavior is driven by the distributions of the training data itself. In-context learning emerges when the training data exhibits particular distributional properties such as burstiness (items appear in clusters rather than being uniformly distributed over time) and having large numbers of rarely occurring classes. In-context learning also emerges more strongly when item meanings or interpretations are dynamic rather than fixed. These properties are exemplified by natural language, but are also inherent to naturalistic data in a wide range of other domains. They also depart significantly from the uniform, i.i.d. training distributions typically used for standard supervised learning. In our initial experiments, we found that in-context learning traded off against more conventional weight-based learning, and models were unable to achieve both simultaneously. However, our later experiments uncovered that the two modes of learning could co-exist in a single model when it was trained on data following a skewed Zipfian distribution -- another common property of naturalistic data, including language. In further experiments, we found that naturalistic data distributions were only able to elicit in-context learning in transformers, and not in recurrent models. In sum, our findings indicate how the transformer architecture works together with particular properties of the training data to drive the intriguing emergent in-context learning behaviour of large language models, and how future work might encourage both in-context and in-weights learning in domains beyond language.

Data Distributional Properties Drive Emergent In-Context Learning in Transformers

Language models demonstrate both quantitative improvement and new qualitative capabilities with increasing scale. Despite their potentially transformative impact, these new capabilities are as yet poorly characterized. In order to inform future research, prepare for disruptive new model capabilities, and ameliorate socially harmful effects, it is vital that we understand the present and near-future capabilities and limitations of language models. To address this challenge, we introduce the Beyond the Imitation Game benchmark (BIG-bench). BIG-bench currently consists of 204 tasks, contributed by 450 authors across 132 institutions. Task topics are diverse, drawing problems from linguistics, childhood development, math, common-sense reasoning, biology, physics, social bias, software development, and beyond. BIG-bench focuses on tasks that are believed to be beyond the capabilities of current language models. We evaluate the behavior of OpenAI's GPT models, Google-internal dense transformer architectures, and Switch-style sparse transformers on BIG-bench, across model sizes spanning millions to hundreds of billions of parameters. In addition, a team of human expert raters performed all tasks in order to provide a strong baseline. Findings include: model performance and calibration both improve with scale, but are poor in absolute terms (and when compared with rater performance); performance is remarkably similar across model classes, though with benefits from sparsity; tasks that improve gradually and predictably commonly involve a large knowledge or memorization component, whereas tasks that exhibit"breakthrough"behavior at a critical scale often involve multiple steps or components, or brittle metrics; social bias typically increases with scale in settings with ambiguous context, but this can be improved with prompting.

Beyond the Imitation Game: Quantifying and extrapolating the capabilities of language models

It would be useful for machines to use computers as humans do so that they can aid us in everyday tasks. This is a setting in which there is also the potential to leverage large-scale expert demonstrations and human judgements of interactive behaviour, which are two ingredients that have driven much recent success in AI. Here we investigate the setting of computer control using keyboard and mouse, with goals specified via natural language. Instead of focusing on hand-designed curricula and specialized action spaces, we focus on developing a scalable method centered on reinforcement learning combined with behavioural priors informed by actual human-computer interactions. We achieve state-of-the-art and human-level mean performance across all tasks within the MiniWob++ benchmark, a challenging suite of computer control problems, and find strong evidence of cross-task transfer. These results demonstrate the usefulness of a unified human-agent interface when training machines to use computers. Altogether our results suggest a formula for achieving competency beyond MiniWob++ and towards controlling computers, in general, as a human would.

An important goal in artificial intelligence is to create agents that can both interact naturally with humans and learn from their feedback. Here we demonstrate how to use reinforcement learning from human feedback (RLHF) to improve upon simulated, embodied agents trained to a base level of competency with imitation learning. First, we collected data of humans interacting with agents in a simulated 3D world. We then asked annotators to record moments where they believed that agents either progressed toward or regressed from their human-instructed goal. Using this annotation data we leveraged a novel method - which we call"Inter-temporal Bradley-Terry"(IBT) modelling - to build a reward model that captures human judgments. Agents trained to optimise rewards delivered from IBT reward models improved with respect to all of our metrics, including subsequent human judgment during live interactions with agents. Altogether our results demonstrate how one can successfully leverage human judgments to improve agent behaviour, allowing us to use reinforcement learning in complex, embodied domains without programmatic reward functions. Videos of agent behaviour may be found at https://youtu.be/v_Z9F2_eKk4.

Improving Multimodal Interactive Agents with Reinforcement Learning from Human Feedback

Creating agents that can interact naturally with humans is a common goal in artificial intelligence (AI) research. However, evaluating these interactions is challenging: collecting online human-agent interactions is slow and expensive, yet faster proxy metrics often do not correlate well with interactive evaluation. In this paper, we assess the merits of these existing evaluation metrics and present a novel approach to evaluation called the Standardised Test Suite (STS). The STS uses behavioural scenarios mined from real human interaction data. Agents see replayed scenario context, receive an instruction, and are then given control to complete the interaction offline. These agent continuations are recorded and sent to human annotators to mark as success or failure, and agents are ranked according to the proportion of continuations in which they succeed. The resulting STS is fast, controlled, interpretable, and representative of naturalistic interactions. Altogether, the STS consolidates much of what is desirable across many of our standard evaluation metrics, allowing us to accelerate research progress towards producing agents that can interact naturally with humans. A video may be found at https://youtu.be/YR1TngGORGQ.

Human language learners are exposed to a trickle of informative, context-sensitive language, but a flood of raw sensory data. Through both social language use and internal processes of rehearsal and practice, language learners are able to build high-level, semantic representations that explain their perceptions. Here, we take inspiration from such processes of"inner speech"in humans (Vygotsky, 1934) to better understand the role of intra-agent speech in embodied behavior. First, we formally pose intra-agent speech as a semi-supervised problem and develop two algorithms that enable visually grounded captioning with little labeled language data. We then experimentally compute scaling curves over different amounts of labeled data and compare the data efficiency against a supervised learning baseline. Finally, we incorporate intra-agent speech into an embodied, mobile manipulator agent operating in a 3D virtual world, and show that with as few as 150 additional image captions, intra-agent speech endows the agent with the ability to manipulate and answer questions about a new object without any related task-directed experience (zero-shot). Taken together, our experiments suggest that modelling intra-agent speech is effective in enabling embodied agents to learn new tasks efficiently and without direct interaction experience.

New neurons are continuously generated in the subgranular zone of the dentate gyrus throughout adulthood. These new neurons gradually integrate into hippocampal circuits, forming new naïve synapses. Viewed from this perspective, these new neurons may represent a significant source of ‘wiring’ noise in hippocampal networks. In machine learning, such noise injection is commonly used as a regularization technique. Regularization techniques help prevent overfitting training data, and allow models to generalize learning to new, unseen data. Using a computational modeling approach, here we ask whether a neurogenesis-like process similarly acts as a regularizer, facilitating generalization in a category learning task. In a convolutional neural network (CNN) trained on the CIFAR-10 object recognition dataset, we modeled neurogenesis as a replacement/turnover mechanism, where weights for a randomly chosen small subset of neurons in a chosen hidden layer were re-initialized to new values as the model learned to categorize 10 different classes of objects. We found that neurogenesis enhanced generalization on unseen test data compared to networks with no neurogenesis. Moreover, neurogenic networks either outperformed or performed similarly to networks with conventional noise injection (i.e., dropout, weight decay, and neural noise). These results suggest that neurogenesis can enhance generalization in hippocampal learning through noise-injection, expanding on the roles that neurogenesis may have in cognition. Author Summary In deep neural networks, various forms of noise injection are used as regularization techniques to prevent overfitting and promote generalization on unseen test data. Here, we were interested in whether adult neurogenesis– the lifelong production of new neurons in the hippocampus– might similarly function as a regularizer in the brain. We explored this question computationally, assessing whether implementing a neurogenesis-like process in a hidden layer within a convolutional neural network trained in a category learning task would prevent overfitting and promote generalization. We found that neurogenesis regularization was as least as effective as, or more effective than, conventional regularizers (i.e., dropout, weight decay and neural noise) in improving model performance. These results suggest that optimal levels of hippocampal neurogenesis may improve memory-guided decision making by preventing overfitting, thereby promoting the formation of more generalized memories that can be applied in a broader range of circumstances. We outline how these predictions may be evaluated behaviorally in rodents with altered hippocampal neurogenesis.

Significance In deep neural networks, various forms of noise injection are used as regularization techniques to prevent overfitting and promote generalization on unseen test data. Here, we were interested in whether adult neurogenesis—the lifelong production of new neurons in the hippocampus—might similarly function as a regularizer in the brain. We explored this question computationally, by implementing a neurogenesis-like process within a convolutional neural network trained on a category learning task. We found that neurogenesis regularization was at least as effective as conventional regularizers (e.g., dropout) in improving model performance. These results suggest that optimal levels of neurogenesis may improve memory-guided decision making by promoting the formation of generalizable memories that can be applied in a broader range of circumstances.

Recent works have investigated the role of graph bottlenecks in preventing long-range information propagation in message-passing graph neural networks, causing the so-called ‘over-squashing’ phenomenon. As a remedy, graph rewiring mechanisms have been proposed as preprocessing steps. Graph Echo State Networks (GESNs) are a reservoir computing model for graphs, where node embeddings are recursively computed by an untrained message-passing function. In this paper, we show that GESNs can achieve a signiﬁcantly better accuracy on six heterophilic node classiﬁcation tasks without altering the graph connectivity, thus suggesting a different route for addressing the over-squashing problem

Since the earliest days of reinforcement learning, the workhorse method for assigning credit to actions over time has been temporal-difference (TD) learning, which propagates credit backward timestep-by-timestep. This approach suffers when delays between actions and rewards are long and when intervening unrelated events contribute variance to long-term returns. We propose state-associative (SA) learning, where the agent learns associations between states and arbitrarily distant future rewards, then propagates credit directly between the two. In this work, we use SA-learning to model the contribution of past states to the current reward. With this model we can predict each state's contribution to the far future, a quantity we call"synthetic returns". TD-learning can then be applied to select actions that maximize these synthetic returns (SRs). We demonstrate the effectiveness of augmenting agents with SRs across a range of tasks on which TD-learning alone fails. We show that the learned SRs are interpretable: they spike for states that occur after critical actions are taken. Finally, we show that our IMPALA-based SR agent solves Atari Skiing -- a game with a lengthy reward delay that posed a major hurdle to deep-RL agents -- 25 times faster than the published state-of-the-art.

A common vision from science fiction is that robots will one day inhabit our physical spaces, sense the world as we do, assist our physical labours, and communicate with us through natural language. Here we study how to design artificial agents that can interact naturally with humans using the simplification of a virtual environment. We show that imitation learning of human-human interactions in a simulated world, in conjunction with self-supervised learning, is sufficient to produce a multimodal interactive agent, which we call MIA, that successfully interacts with non-adversarial humans 75% of the time. We further identify architectural and algorithmic techniques that improve performance, such as hierarchical action selection. Altogether, our results demonstrate that imitation of multi-modal, real-time human behaviour may provide a straightforward and surprisingly effective means of imbuing agents with a rich behavioural prior from which agents might then be fine-tuned for specific purposes, thus laying a foundation for training capable agents for interactive robots or digital assistants. A video of MIA's behaviour may be found at https://youtu.be/ZFgRhviF7mY

Creating Multimodal Interactive Agents with Imitation and Self-Supervised Learning

Inferring the abstract relational and causal structure of the world is a major challenge for reinforcement-learning (RL) agents. For humans, language--particularly in the form of explanations--plays a considerable role in overcoming this challenge. Here, we show that language can play a similar role for deep RL agents in complex environments. While agents typically struggle to acquire relational and causal knowledge, augmenting their experience by training them to predict language descriptions and explanations can overcome these limitations. We show that language can help agents learn challenging relational tasks, and examine which aspects of language contribute to its benefits. We then show that explanations can help agents to infer not only relational but also causal structure. Language can shape the way that agents to generalize out-of-distribution from ambiguous, causally-confounded training, and explanations even allow agents to learn to perform experimental interventions to identify causal relationships. Our results suggest that language description and explanation may be powerful tools for improving agent learning and generalization.

Tell me why! - Explanations support learning of relational and causal structure

The ability to use symbols is the pinnacle of human intelligence, but has yet to be fully replicated in machines. Here we argue that the path towards symbolically fluent artificial intelligence (AI) begins with a reinterpretation of what symbols are, how they come to exist, and how a system behaves when it uses them. We begin by offering an interpretation of symbols as entities whose meaning is established by convention. But crucially, something is a symbol only for those who demonstrably and actively participate in this convention. We then outline how this interpretation thematically unifies the behavioural traits humans exhibit when they use symbols. This motivates our proposal that the field place a greater emphasis on symbolic behaviour rather than particular computational mechanisms inspired by more restrictive interpretations of symbols. Finally, we suggest that AI research explore social and cultural engagement as a tool to develop the cognitive machinery necessary for symbolic behaviour to emerge. This approach will allow for AI to interpret something as symbolic on its own rather than simply manipulate things that are only symbols to human onlookers, and thus will ultimately lead to AI with more human-like symbolic fluency.

Abstract Artificial intelligence (AI) shares many generalizability challenges with psychology. But the fields publish differently. AI publishes fast, through rapid preprint sharing and conference publications. Psychology publishes more slowly, but creates integrative reviews and meta-analyses. We discuss the complementary advantages of each strategy, and suggest that incorporating both types of strategies could lead to more generalizable research in both fields.

Publishing fast and slow: A path toward generalizability in psychology and AI

Neural networks have achieved success in a wide array of perceptual tasks, but it is often stated that they are incapable of solving tasks that require higher-level reasoning. Two new task domains, CLEVRER and CATER, have recently been developed to focus on reasoning, as opposed to perception, in the context of spatio-temporal interactions between objects. Initial experiments on these domains found that neuro-symbolic approaches, which couple a logic engine and language parser with a neural perceptual front-end, substantially outperform fully-learned distributed networks, a finding that was taken to support the above thesis. Here, we show on the contrary that a fully-learned neural network with the right inductive biases can perform substantially better than all previous neural-symbolic models on both of these tasks, particularly on questions that most emphasize reasoning over perception. Our model makes critical use of both self-attention and learned "soft" object-centric representations, as well as BERT-style semi-supervised predictive losses. These flexible biases allow our model to surpass the previous neuro-symbolic state-of-the-art using less than 60% of available labelled data. Together, these results refute the neuro-symbolic thesis laid out by previous work involving these datasets, and they provide evidence that neural networks can indeed learn to reason effectively about the causal, dynamic structure of physical events.

Object-based attention for spatio-temporal reasoning: Outperforming neuro-symbolic models with flexible distributed architectures

A common vision from science fiction is that robots will one day inhabit our physical spaces, sense the world as we do, assist our physical labours, and communicate with us through natural language. Here we study how to design artificial agents that can interact naturally with humans using the simplification of a virtual environment. This setting nevertheless integrates a number of the central challenges of artificial intelligence (AI) research: complex visual perception and goal-directed physical control, grounded language comprehension and production, and multi-agent social interaction. To build agents that can robustly interact with humans, we would ideally train them while they interact with humans. However, this is presently impractical. Therefore, we approximate the role of the human with another learned agent, and use ideas from inverse reinforcement learning to reduce the disparities between human-human and agent-agent interactive behaviour. Rigorously evaluating our agents poses a great challenge, so we develop a variety of behavioural tests, including evaluation by humans who watch videos of agents or interact directly with them. These evaluations convincingly demonstrate that interactive training and auxiliary losses improve agent behaviour beyond what is achieved by supervised learning of actions alone. Further, we demonstrate that agent capabilities generalise beyond literal experiences in the dataset. Finally, we train evaluation models whose ratings of agents agree well with human judgement, thus permitting the evaluation of new agent models without additional effort. Taken together, our results in this virtual environment provide evidence that large-scale human behavioural imitation is a promising tool to create intelligent, interactive agents, and the challenge of reliably evaluating such agents is possible to surmount.

When thrust into an unfamiliar environment and charged with solving a series of tasks, an effective agent should (1) leverage prior knowledge to solve its current task while (2) efficiently exploring to gather knowledge for use in future tasks, and then (3) plan using that knowledge when faced with new tasks in that same environment. We introduce two domains for conducting research on this challenge, and find that state-of-the-art deep reinforcement learning (RL) agents fail to plan in novel environments. We develop a recursive implicit planning module that operates over episodic memories, and show that the resulting deep-RL agent is able to explore and plan in novel environments, outperforming the nearest baseline by factors of 2-3 across the two domains. We find evidence that our module (1) learned to execute a sensible information-propagating algorithm and (2) generalizes to situations beyond its training experience.

Cognitive consequences of structured education in a connectionist model of analogical reasoning

Neural networks have achieved success in a wide array of perceptual tasks but often fail at tasks involving both perception and higher-level reasoning. On these more challenging tasks, bespoke approaches (such as modular symbolic components, independent dynamics models or semantic parsers) targeted towards that specific type of task have typically performed better. The downside to these targeted approaches, however, is that they can be more brittle than general-purpose neural networks, requiring significant modification or even redesign according to the particular task at hand. Here, we propose a more general neural-network-based approach to dynamic visual reasoning problems that obtains state-of-the-art performance on three different domains, in each case outperforming bespoke modular approaches tailored specifically to the task. Our method relies on learned object-centric representations, self-attention and self-supervised dynamics learning, and all three elements together are required for strong performance to emerge. The success of this combination suggests that there may be no need to trade off flexibility for performance on problems involving spatio-temporal or causal-style reasoning. With the right soft biases and learning objectives in a neural network we may be able to attain the best of both worlds.

Attention over Learned Object Embeddings Enables Complex Visual Reasoning

Reinforcement learning algorithms use correlations between policies and rewards to improve agent performance. But in dynamic or sparsely rewarding environments these correlations are often too small, or rewarding events are too infrequent to make learning feasible. Human education instead relies on curricula –the breakdown of tasks into simpler, static challenges with dense rewards– to build up to complex behaviors. While curricula are also useful for artificial agents, hand-crafting them is time consuming. This has lead researchers to explore automatic curriculum generation. Here we explore automatic curriculum generation in rich,dynamic environments. Using a setter-solver paradigm we show the importance of considering goal validity, goal feasibility, and goal coverage to construct useful curricula. We demonstrate the success of our approach in rich but sparsely rewarding 2D and 3D environments, where an agent is tasked to achieve a single goal selected from a set of possible goals that varies between episodes, and identify challenges for future work. Finally, we demonstrate the value of a novel technique that guides agents towards a desired goal distribution. Altogether, these results represent a substantial step towards applying automatic task curricula to learn complex, otherwise unlearnable goals, and to our knowledge are the first to demonstrate automated curriculum generation for goal-conditioned agents in environments where the possible goals vary between episodes.

Automated curriculum generation through setter-solver interactions

Analogical reasoning has been a principal focus of various waves of AI research. Analogy is particularly challenging for machines because it requires relational structures to be represented such that they can be flexibly applied across diverse domains of experience. Here, we study how analogical reasoning can be induced in neural networks that learn to perceive and reason about raw visual data. We find that the critical factor for inducing such a capacity is not an elaborate architecture, but rather, careful attention to the choice of data and the manner in which it is presented to the model. The most robust capacity for analogical reasoning is induced when networks learn analogies by contrasting abstract relational structures in their input domains, a training method that uses only the input data to force models to learn about important abstract features. Using this technique we demonstrate capacities for complex, visual and symbolic analogy making and generalisation in even the simplest neural network architectures.

Learning to Make Analogies by Contrasting Abstract Relational Structure

Abstract Brette contends that the neural coding metaphor is an invalid basis for theories of what the brain does. Here, we argue that it is an insufficient guide for building an artificial intelligence that learns to accomplish short- and long-term goals in a complex, changing environment.

The question of whether deep neural networks are good at generalising beyond their immediate training experience is of critical importance for learning-based approaches to AI. Here, we demonstrate strong emergent systematic generalisation in a neural network agent and isolate the factors that support this ability. In environments ranging from a grid-world to a rich interactive 3D Unity room, we show that an agent can correctly exploit the compositional nature of a symbolic language to interpret never-seen-before instructions. We observe this capacity not only when instructions refer to object properties (colors and shapes) but also verb-like motor skills (lifting and putting) and abstract modifying operations (negation). We identify three factors that can contribute to this facility for systematic generalisation: (a) the number of object/word experiences in the training set; (b) the invariances afforded by a first-person, egocentric perspective; and (c) the variety of visual input experienced by an agent that perceives the world actively over time. Thus, while neural nets trained in idealised or reduced situations may fail to exhibit a compositional or systematic understanding of their experience, this competence can readily emerge when, like human learners, they have access to many examples of richly varying, multi-modal observations as they learn.

The field of reinforcement learning (RL) is facing increasingly challenging domains with combinatorial complexity. For an RL agent to address these challenges, it is essential that it can plan effectively. Prior work has typically utilized an explicit model of the environment, combined with a specific planning algorithm (such as tree search). More recently, a new family of methods have been proposed that learn how to plan, by providing the structure for planning via an inductive bias in the function approximator (such as a tree structured neural network), trained end-to-end by a model-free RL algorithm. In this paper, we go even further, and demonstrate empirically that an entirely model-free approach, without special structure beyond standard neural network components such as convolutional networks and LSTMs, can learn to exhibit many of the characteristics typically associated with a model-based planner. We measure our agent's effectiveness at planning in terms of its ability to generalize across a combinatorial and irreversible state space, its data efficiency, and its ability to utilize additional thinking time. We find that our agent has many of the characteristics that one might expect to find in a planning algorithm. Furthermore, it exceeds the state-of-the-art in challenging combinatorial domains such as Sokoban and outperforms other model-free approaches that utilize strong inductive biases toward planning.

Reinforcement learning algorithms use correlations between policies and rewards to improve agent performance. But in dynamic or sparsely rewarding environments these correlations are often too small, or rewarding events are too infrequent to make learning feasible. Human education instead relies on curricula--the breakdown of tasks into simpler, static challenges with dense rewards--to build up to complex behaviors. While curricula are also useful for artificial agents, hand-crafting them is time consuming. This has lead researchers to explore automatic curriculum generation. Here we explore automatic curriculum generation in rich, dynamic environments. Using a setter-solver paradigm we show the importance of considering goal validity, goal feasibility, and goal coverage to construct useful curricula. We demonstrate the success of our approach in rich but sparsely rewarding 2D and 3D environments, where an agent is tasked to achieve a single goal selected from a set of possible goals that varies between episodes, and identify challenges for future work. Finally, we demonstrate the value of a novel technique that guides agents towards a desired goal distribution. Altogether, these results represent a substantial step towards applying automatic task curricula to learn complex, otherwise unlearnable goals, and to our knowledge are the first to demonstrate automated curriculum generation for goal-conditioned agents in environments where the possible goals vary between episodes.

The question of whether deep neural networks are good at generalising beyond their immediate training experience is of critical importance for learning-based approaches to AI. Here, we consider tests of out-of-sample generalisation that require an agent to respond to never-seen-before instructions by manipulating and positioning objects in a 3D Unity simulated room. We first describe a comparatively generic agent architecture that exhibits strong performance on these tests. We then identify three aspects of the training regime and environment that make a significant difference to its performance: (a) the number of object/word experiences in the training set; (b) the visual invariances afforded by the agent's perspective, or frame of reference; and (c) the variety of visual input inherent in the perceptual aspect of the agent's perception. Our findings indicate that the degree of generalisation that networks exhibit can depend critically on particulars of the environment in which a given task is instantiated. They further suggest that the propensity for neural networks to generalise in systematic ways may increase if, like human children, those networks have access to many frames of richly varying, multi-modal observations as they learn.

Environmental drivers of systematicity and generalization in a situated agent

Artificial intelligence (AI) has undergone a renaissance recently, making major progress in key domains such as vision, language, control, and decision-making. This has been due, in part, to cheap data and cheap compute resources, which have fit the natural strengths of deep learning. However, many defining characteristics of human intelligence, which developed under much different pressures, remain out of reach for current approaches. In particular, generalizing beyond one's experiences--a hallmark of human intelligence from infancy--remains a formidable challenge for modern AI. 
The following is part position paper, part review, and part unification. We argue that combinatorial generalization must be a top priority for AI to achieve human-like abilities, and that structured representations and computations are key to realizing this objective. Just as biology uses nature and nurture cooperatively, we reject the false choice between "hand-engineering" and "end-to-end" learning, and instead advocate for an approach which benefits from their complementary strengths. We explore how using relational inductive biases within deep learning architectures can facilitate learning about entities, relations, and rules for composing them. We present a new building block for the AI toolkit with a strong relational inductive bias--the graph network--which generalizes and extends various approaches for neural networks that operate on graphs, and provides a straightforward interface for manipulating structured knowledge and producing structured behaviors. We discuss how graph networks can support relational reasoning and combinatorial generalization, laying the foundation for more sophisticated, interpretable, and flexible patterns of reasoning. As a companion to this paper, we have released an open-source software library for building graph networks, with demonstrations of how to use them in practice.

Throughout life neurons are continuously generated in the subgranular zone of the hippocampus. The subsequent integration of newly generated neurons alters patterns of dentate gyrus input and output connectivity, potentially rendering memories already stored in those circuits harder to access. Consistent with this prediction, we previously showed that increasing hippocampal neurogenesis after training induces forgetting of hippocampus-dependent memories, including contextual fear memory. However, the brain regions supporting contextual fear memories change with time, and this time-dependent memory reorganization might regulate the sensitivity of contextual fear memories to fluctuations in hippocampal neurogenesis. By virally expressing the inhibitory designer receptor exclusively activated by designer drugs, hM4Di, we first confirmed that chemogenetic inhibition of dorsal hippocampal neurons impairs retrieval of recent (day-old) but not remote (month-old) contextual fear memories in male mice. We then contrasted the effects of increasing hippocampal neurogenesis at recent versus remote time points after contextual fear conditioning in male and female mice. Increasing hippocampal neurogenesis immediately following training reduced conditioned freezing when mice were replaced in the context 1 month later. In contrast, when hippocampal neurogenesis was increased time points remote to training, conditioned freezing levels were unaltered when mice were subsequently tested. These temporally graded forgetting effects were observed using both environmental and genetic interventions to increase hippocampal neurogenesis. Our experiments identify memory age as a boundary condition for neurogenesis-mediated forgetting and suggest that, as contextual fear memories mature, they become less sensitive to changes in hippocampal neurogenesis levels because they no longer depend on the hippocampus for their expression. SIGNIFICANCE STATEMENT New neurons are generated in the hippocampus throughout life. As they integrate into the hippocampus, they remodel neural circuitry, potentially making information stored in those circuits harder to access. Consistent with this, increasing hippocampal neurogenesis after learning induces forgetting of the learnt information. The current study in mice asks whether these forgetting effects depend on the age of the memory. We found that post-training increases in hippocampal neurogenesis only impacted recently acquired, and not remotely acquired, hippocampal memories. These experiments identify memory age as a boundary condition for neurogenesis-mediated forgetting, and suggest remote memories are less sensitive to changes in hippocampal neurogenesis levels because they no longer depend critically on the hippocampus for their expression.

Elevation of Hippocampal Neurogenesis Induces a Temporally Graded Pattern of Forgetting of Contextual Fear Memories

We introduce an approach for deep reinforcement learning (RL) that improves upon the efficiency, generalization capacity, and interpretability of conventional approaches through structured perception and relational reasoning. It uses self-attention to iteratively reason about the relations between entities in a scene and to guide a model-free policy. Our results show that in a novel navigation and planning task called Box-World, our agent finds interpretable solutions that improve upon baselines in terms of sample complexity, ability to generalize to more complex scenes than experienced during training, and overall performance. In the StarCraft II Learning Environment, our agent achieves state-of-the-art performance on six mini-games -- surpassing human grandmaster performance on four. By considering architectural inductive biases, our work opens new directions for overcoming important, but stubborn, challenges in deep RL.

Whether neural networks can learn abstract reasoning or whether they merely rely on superficial statistics is a topic of recent debate. Here, we propose a dataset and challenge designed to probe abstract reasoning, inspired by a well-known human IQ test. To succeed at this challenge, models must cope with various generalisation `regimes' in which the training and test data differ in clearly-defined ways. We show that popular models such as ResNets perform poorly, even when the training and test sets differ only minimally, and we present a novel architecture, with a structure designed to encourage reasoning, that does significantly better. When we vary the way in which the test questions and training data differ, we find that our model is notably proficient at certain forms of generalisation, but notably weak at others. We further show that the model's ability to generalise improves markedly if it is trained to predict symbolic explanations for its answers. Altogether, we introduce and explore ways to both measure and induce stronger abstract reasoning in neural networks. Our freely-available dataset should motivate further progress in this direction.

Learning Visual Question Answering by Bootstrapping Hard Attention

Animals execute goal-directed behaviours despite the limited range and scope of their sensors. To cope, they explore environments and store memories maintaining estimates of important information that is not presently available. Recently, progress has been made with artificial intelligence (AI) agents that learn to perform tasks from sensory input, even at a human level, by merging reinforcement learning (RL) algorithms with deep neural networks, and the excitement surrounding these results has led to the pursuit of related ideas as explanations of non-human animal learning. However, we demonstrate that contemporary RL algorithms struggle to solve simple tasks when enough information is concealed from the sensors of the agent, a property called "partial observability". An obvious requirement for handling partially observed tasks is access to extensive memory, but we show memory is not enough; it is critical that the right information be stored in the right format. We develop a model, the Memory, RL, and Inference Network (MERLIN), in which memory formation is guided by a process of predictive modeling. MERLIN facilitates the solution of tasks in 3D virtual reality environments for which partial observability is severe and memories must be maintained over long durations. Our model demonstrates a single learning agent architecture that can solve canonical behavioural tasks in psychology and neurobiology without strong simplifying assumptions about the dimensionality of sensory input or the duration of experiences.

The backpropagation of error algorithm (BP) is impossible to implement in a real brain. The recent success of deep networks in machine learning and AI, however, has inspired proposals for understanding how the brain might learn across multiple layers, and hence how it might approximate BP. As of yet, none of these proposals have been rigorously evaluated on tasks where BP-guided deep learning has proved critical, or in architectures more structured than simple fully-connected networks. Here we present results on scaling up biologically motivated models of deep learning on datasets which need deep networks with appropriate architectures to achieve good performance. We present results on the MNIST, CIFAR-10, and ImageNet datasets and explore variants of target-propagation (TP) and feedback alignment (FA) algorithms, and explore performance in both fully- and locally-connected architectures. We also introduce weight-transport-free variants of difference target propagation (DTP) modified to remove backpropagation from the penultimate layer. Many of these algorithms perform well for MNIST, but for CIFAR and ImageNet we find that TP and FA variants perform significantly worse than BP, especially for networks composed of locally connected units, opening questions about whether new architectures and algorithms are required to scale these approaches. Our results and implementation details help establish baselines for biologically motivated deep learning schemes going forward.

Assessing the Scalability of Biologically-Motivated Deep Learning Algorithms and Architectures

Relational data can generally be represented as graphs. For processing such graph structured data, we propose LanczosNet, which uses the Lanczos algorithm to construct low rank approximations of the graph Laplacian for graph convolution. Relying on the tridiagonal decomposition of the Lanczos algorithm, we not only efficiently exploit multi-scale information via fast approximated computation of matrix power but also design learnable spectral filters. We benchmark our model against 8 recent deep graph networks on QM8 quantum chemistry dataset. Experimental results show that our model achieves the state-of-the-art performance.

We introduce hyperbolic attention networks to endow neural networks with enough capacity to match the complexity of data with hierarchical and power-law structure. A few recent approaches have successfully demonstrated the benefits of imposing hyperbolic geometry on the parameters of shallow networks. We extend this line of work by imposing hyperbolic geometry on the activations of neural networks. This allows us to exploit hyperbolic geometry to reason about embeddings produced by deep networks. We achieve this by re-expressing the ubiquitous mechanism of soft attention in terms of operations defined for hyperboloid and Klein models. Our method shows improvements in terms of generalization on neural machine translation, learning on graphs and visual question answering tasks while keeping the neural representations compact.

Memory-based neural networks model temporal data by leveraging an ability to remember information for long periods. It is unclear, however, whether they also have an ability to perform complex relational reasoning with the information they remember. Here, we first confirm our intuitions that standard memory architectures may struggle at tasks that heavily involve an understanding of the ways in which entities are connected -- i.e., tasks involving relational reasoning. We then improve upon these deficits by using a new memory module -- a \textit{Relational Memory Core} (RMC) -- which employs multi-head dot product attention to allow memories to interact. Finally, we test the RMC on a suite of tasks that may profit from more capable relational reasoning across sequential information, and show large gains in RL domains (e.g. Mini PacMan), program evaluation, and language modeling, achieving state-of-the-art results on the WikiText-103, Project Gutenberg, and GigaWord datasets.

Relational reasoning is a central component of generally intelligent behavior, but has proven difficult for neural networks to learn. In this paper we describe how to use Relation Networks (RNs) as a simple plug-and-play module to solve problems that fundamentally hinge on relational reasoning. We tested RN-augmented networks on three tasks: visual question answering using a challenging dataset called CLEVR, on which we achieve state-of-the-art, super-human performance; text-based question answering using the bAbI suite of tasks; and complex reasoning about dynamic physical systems. Then, using a curated dataset called Sort-of-CLEVR we show that powerful convolutional networks do not have a general capacity to solve relational questions, but can gain this capacity when augmented with RNs. Our work shows how a deep learning architecture equipped with an RN module can implicitly discover and learn to reason about entities and their relations.

Our world can be succinctly and compactly described as structured scenes of objects and relations. A typical room, for example, contains salient objects such as tables, chairs and books, and these objects typically relate to each other by their underlying causes and semantics. This gives rise to correlated features, such as position, function and shape. Humans exploit knowledge of objects and their relations for learning a wide spectrum of tasks, and more generally when learning the structure underlying observed data. In this work, we introduce relation networks (RNs) - a general purpose neural network architecture for object-relation reasoning. We show that RNs are capable of learning object relations from scene description data. Furthermore, we show that RNs can act as a bottleneck that induces the factorization of objects from entangled scene description inputs, and from distributed deep representations of scene images provided by a variational autoencoder. The model can also be used in conjunction with differentiable memory mechanisms for implicit relation discovery in one-shot learning tasks. Our results suggest that relation networks are a potentially powerful architecture for solving a variety of problems that require object relation reasoning.

Discovering objects and their relations from entangled scene representations

Deep neural networks (DNNs) have achieved unprecedented performance on a wide range of complex tasks, rapidly outpacing our understanding of the nature of their solutions. This has caused a recent surge of interest in methods for rendering modern neural systems more interpretable. In this work, we propose to address the interpretability problem in modern DNNs using the rich history of problem descriptions, theories and experimental methods developed by cognitive psychologists to study the human mind. To explore the potential value of these tools, we chose a well-established analysis from developmental psychology that explains how children learn word labels for objects, and applied that analysis to DNNs. Using datasets of stimuli inspired by the original cognitive psychology experiments, we find that state-of-the-art one shot learning models trained on ImageNet exhibit a similar bias to that observed in humans: they prefer to categorize objects according to shape rather than color. The magnitude of this shape bias varies greatly among architecturally identical, but differently seeded models, and even fluctuates within seeds throughout training, despite nearly equivalent classification performance. These results demonstrate the capability of tools from cognitive psychology for exposing hidden computational properties of DNNs, while concurrently providing us with a computational model for human word learning.

Cognitive Psychology for Deep Neural Networks: A Shape Bias Case Study

Abstract We agree with Lake and colleagues on their list of “key ingredients” for building human-like intelligence, including the idea that model-based reasoning is essential. However, we favor an approach that centers on one additional ingredient: autonomy. In particular, we aim toward agents that can both build and exploit their own internal models, with minimal human hand engineering. We believe an approach centered on autonomous learning has the greatest chance of success as we scale toward real-world complexity, tackling domains for which ready-made formal models are not available. Here, we survey several important examples of the progress that has been made toward building autonomous agents with human-like abilities, and highlight some outstanding challenges.

We consider the general problem of modeling temporal data with long-range dependencies, wherein new observations are fully or partially predictable based on temporally-distant, past observations. A sufficiently powerful temporal model should separate predictable elements of the sequence from unpredictable elements, express uncertainty about those unpredictable elements, and rapidly identify novel elements that may help to predict the future. To create such models, we introduce Generative Temporal Models augmented with external memory systems. They are developed within the variational inference framework, which provides both a practical training methodology and methods to gain insight into the models' operation. We show, on a range of problems with sparse, long-term temporal dependencies, that these models store information from early in a sequence, and reuse this stored information efficiently. This allows them to perform substantially better than existing models based on well-known recurrent neural networks, like LSTMs.

Despite recent breakthroughs in the applications of deep neural networks, one setting that presents a persistent challenge is that of "one-shot learning." Traditional gradient-based networks require a lot of data to learn, often through extensive iterative training. When new data is encountered, the models must inefficiently relearn their parameters to adequately incorporate the new information without catastrophic interference. Architectures with augmented memory capacities, such as Neural Turing Machines (NTMs), offer the ability to quickly encode and retrieve new information, and hence can potentially obviate the downsides of conventional models. Here, we demonstrate the ability of a memory-augmented neural network to rapidly assimilate new data, and leverage this data to make accurate predictions after only a few samples. We also introduce a new method for accessing an external memory that focuses on memory content, unlike previous methods that additionally use memory location-based focusing mechanisms.

Over the course of systems consolidation, there is a switch from a reliance on detailed episodic memories to generalized schematic memories. This switch is sometimes referred to as “memory transformation.” Here we demonstrate a previously unappreciated benefit of memory transformation, namely, its ability to enhance reinforcement learning in a dynamic environment. We developed a neural network that is trained to find rewards in a foraging task where reward locations are continuously changing. The network can use memories for specific locations (episodic memories) and statistical patterns of locations (schematic memories) to guide its search. We find that switching from an episodic to a schematic strategy over time leads to enhanced performance due to the tendency for the reward location to be highly correlated with itself in the short-term, but regress to a stable distribution in the long-term. We also show that the statistics of the environment determine the optimal utilization of both types of memory. Our work recasts the theoretical question of why memory transformation occurs, shifting the focus from the avoidance of memory interference toward the enhancement of reinforcement learning across multiple timescales. SIGNIFICANCE STATEMENT As time passes, memories transform from a highly detailed state to a more gist-like state, in a process called “memory transformation.” Theories of memory transformation speak to its advantages in terms of reducing memory interference, increasing memory robustness, and building models of the environment. However, the role of memory transformation from the perspective of an agent that continuously acts and receives reward in its environment is not well explored. In this work, we demonstrate a view of memory transformation that defines it as a way of optimizing behavior across multiple timescales.

Memory Transformation Enhances Reinforcement Learning in Dynamic Environments

Despite recent breakthroughs in the applications of deep neural networks, one setting that presents a persistent challenge is that of “one-shot learning.” Traditional gradient-based networks require a lot of data to learn, often through extensive iterative training. When new data is encountered, the models must inefficiently relearn their parameters to adequately incorporate the new information without catastrophic interference. Architectures with augmented memory capacities, such as Neural Turing Machines (NTMs), offer the ability to quickly encode and retrieve new information, and hence can potentially obviate the downsides of conventional models. Here, we demonstrate the ability of a memory-augmented neural network to rapidly assimilate new data, and leverage this data to make accurate predictions after only a few samples. We also introduce a new method for accessing an external memory that focuses on memory content, unlike previous methods that additionally use memory locationbased focusing mechanisms.

Significance Channelrhodopsins are membrane proteins that enable cellular regulation of transmembrane ion conductance through light-gated pores; these proteins have found application in optogenetics. This paper tests the hypothesis that selectivity of channelrhodopsins is determined by surface potential of the pore region: Cations are conducted by a negatively charged pore, and chloride ions are conducted by a pore that has neutral and positively charged residues. In confirming this hypothesis and applying the resulting principles, we engineer improved chloride-conducting channels with higher chloride selectivity and conductivity. We also provide insights into the distinct mechanisms underlying inhibition mediated by higher-efficiency chloride channels compared with ion pumps. Finally, we demonstrate initial utility of light-gated microbial opsin-based chloride channels in controlling behavior of freely moving animals. The structure-guided design of chloride-conducting channelrhodopsins has illuminated mechanisms underlying ion selectivity of this remarkable family of light-activated ion channels. The first generation of chloride-conducting channelrhodopsins, guided in part by development of a structure-informed electrostatic model for pore selectivity, included both the introduction of amino acids with positively charged side chains into the ion conduction pathway and the removal of residues hypothesized to support negatively charged binding sites for cations. Engineered channels indeed became chloride selective, reversing near −65 mV and enabling a new kind of optogenetic inhibition; however, these first-generation chloride-conducting channels displayed small photocurrents and were not tested for optogenetic inhibition of behavior. Here we report the validation and further development of the channelrhodopsin pore model via crystal structure-guided engineering of next-generation light-activated chloride channels (iC++) and a bistable variant (SwiChR++) with net photocurrents increased more than 15-fold under physiological conditions, reversal potential further decreased by another ∼15 mV, inhibition of spiking faithfully tracking chloride gradients and intrinsic cell properties, strong expression in vivo, and the initial microbial opsin channel-inhibitor–based control of freely moving behavior. We further show that inhibition by light-gated chloride channels is mediated mainly by shunting effects, which exert optogenetic control much more efficiently than the hyperpolarization induced by light-activated chloride pumps. The design and functional features of these next-generation chloride-conducting channelrhodopsins provide both chronic and acute timescale tools for reversible optogenetic inhibition, confirm fundamental predictions of the ion selectivity model, and further elucidate electrostatic and steric structure–function relationships of the light-gated pore.

Structural foundations of optogenetics: Determinants of channelrhodopsin ion selectivity

A computational model of systems consolidation: optimizing memory-guided behavior using abstracted hippocampal and cortical networks Adam Santoro Doctor of Philosophy Graduate Department of The Institute of Medical Science University of Toronto 2015 Learning is not a isolated event, as nearly every encoding event occurs on a backdrop of previous knowledge. This idea is tightly intertwined with that of memory consolidation, which is a concept that describes the fate of memories post-encoding. After the brain encodes some episode, the encoded information undergoes a transition from hippocampal dependence to cortical dependence. Contemporary memory consolidation theories emphasize the nature of the computations that occur during this transfer, pointing to the extraction of statistical regularities, or the formation of schemas, as critical components. The work presented in this thesis analyzes memory consolidation from a computational perspective. Firstly, it describes necessary conditions for the extraction of statistical regularities across individually learned episodes, demonstrating that a consolidation-like mechanism best captures this phenomenon. Next, it probes a possible purpose of memory consolidation within a two-memory system, showing that a joint hippocampal and cortical network optimizes memory-guided behavior in a foraging-like task. Finally, some anatomical evidence is explored within the context of a major tenet of memory consolidation, namely the slow changes in interconnectivity between distributed neocortical regions during the consolidation period. The work presented in this thesis constitutes a highly comprehensive model of memory consolidation and provides a basis for further inquiry into the nuances of consolidation phenomena, such as the effects of memory interference, neurogenesis, and forgetting.

A computational model of systems consolidation: optimizing memory-guided behavior using abstracted hippocampal and cortical networks

The dentate gyrus (DG) is postulated to be a “pattern separator” (Marr, 1971; Rolls, 1989a,b, 1990; Treves and Rolls, 1994). Yet, the definition of pattern separation has become a haze, with researchers using the term interchangeably to describe computational processes, changes in cell ensemble activity, and even behavioral phenomena (Leutgeb et al., 2007; McHugh et al., 2007; Clelland et al., 2009; Bakker et al., 2010). To accurately assess the large influx of papers purporting to attribute pattern separation to the DG, the concept must be reassessed; the original definition of pattern separation as a computational process and its newer, colloquial definition as a form of behavioral context discrimination must be accurately parsed if relations between the data are to be made.

In this paper, we introduce the ﬁrst learning-based planner to drive a car in dense, urban trafﬁc using Inverse Reinforcement Learning (IRL). Our planner, DriveIRL, generates a diverse set of trajectory proposals, ﬁlters these trajectories with a lightweight and interpretable safety ﬁlter, and then uses a learned model to score each remaining trajectory. The best trajectory is then tracked by the low-level controller of our self-driving vehicle. We train our trajectory scoring model on a 500 + hour real-world dataset of expert driving demonstrations in Las Vegas within the maximum entropy IRL framework. DriveIRL’s beneﬁts include: a simple design due to only learning the trajectory scoring function, relatively interpretable features, and strong real-world performance. We validated DriveIRL on the Las Vegas Strip and demonstrated fully autonomous driving in heavy trafﬁc, including scenarios involving cut-ins, abrupt braking by the lead vehicle, and hotel pickup/dropoff zones. Our dataset will be made public to help further research in this area.

Structure Learning and Uncertainty-Guided Exploration in the Human Brain

This article deals with a method that offers the possibility to simulate and estimate the impact of a component change in a complex system on its electromagnetic signature. To realise the modelling, the MKME (Modified Kron's Method for Electromagnetic) is the method chosen for the topological analysis of the complex systems. This method is combined with change-of-basis matrix allowing connections and disconnections of sub-systems inside the system. After a brief review of the Kron's method, we will define the process to use. At first, the minimal description for sub-system will be detailed, and then the application of the change-of-basis matrix that allows combining the sub-systems to generate the whole complex system. This method uses the electromagnetic analytical coupling functions and once the topology and the functions of interaction constructed, it's easy to take into account any variation in the system.

In this article, we present the system development of Virtual EMC Lab (“Virtual Electromagnetic Compatibility Laboratory”). It is a toolkit developed for the electronic and electric product/system design, modelling, simulation, analysis, diagnosis and assessment tailored to the electromagnetic compatibility problems. The toolkit includes a solid modelling front-end which simplifies the geometrical structure of equipment under test (EUT), analytical and numerical solvers for different applications, and visualization tools. It is dedicated to solve electromagnetic interference, immunity and emission problems in board level and system level.

The paper presents a simulation study of the electromagnetic far-field radiation from a hard disk drive (HDD) with multiple slots. The modeling is achieved by introducing appropriate compact models using a transmission line matrix (TLM) time-domain method. The slots are designed with different configurations in the hard disk drive, which simulates the physical system. The effect of the slots interaction on resonance of enclosure is predicted accurately without increasing practical design cost and time. The measures to reduce field radiation are discussed thus immunity of HDD can be improved.

Numerical evaluation of EMI immunity of hard disk drive with multiple slots

[Purpose] Robot positioning and construction of the environmental map is an important guarantee for its own task. In the unknown environment, problems of robot positioning and map creation are interdependent. Researchers have put forward the problems of simultaneous robot positioning and map creation (SLAM). 
[Method] In this paper, the landmark extraction algorithm based on RANSAC method is studied for the two-dimensional environment, and the algorithm is improved according to the application requirements of SLAM problem. Finally, the mobile robot is used to experiment 
on the landmark extraction and EKF-SLAM algorithm. 
[Results] The results show that the algorithm of Landmark extraction and EKF-SLAM is valid.

In order to solve the problem that the robot can coexist harmoniously with human beings and provide better service in the human settlement environment. Based on the Mecanum wheel mobile robot platform, by introducing the pyramid optical flow algorithm and CamShift algorithm, empirical results show that the robot can quickly predict the movement tendency and speed of the moving object according to the moving characteristics and color characteristic information of the moving object as well as accurate identification of tracking. Based on the above algorithm research, it can effectively improve the ability of robot motion planning and 
executing tasks in complex environment.

This work takes the Mecanum wheel mobile robot as experimental platform, Microsoft Visual 2010 and OpenCV (Open Source Computer Vision Library) based on 2.4.9 platform for the development of research on mobile robot vision system. The main work is as follows: first, build the Mecanum wheel robot platform, realizes the mobile robot with full mobility. Second, the Kinect vision sensor is used to acquire the image information in the robot’s visual field and to process the image. Including Canny edge detection, histogram equalization, Harris corner detection algorithm, sub-pixel level corner detection, localization, image affine transformation, Hof line transform, data processing center. Third, the obtained image is processed, and the image quality is improved by image preprocessing, so that the image clarity is improved. Based on the above image information processing, the algorithm is improved on the basis of Harris corner detection algorithm, and the corner coordinate is obtained at sub-pixel precision. Fourth, the processed image information is decided and analyzed in the database of the data center to form the motion control command of the mobile robot. The feasibility of the system is verified by experiments.

Research on Visual Image Processing of Mobile Robot Based on OpenCV

Bose–Einstein condensates in concentrically coupled annular traps with spin–orbit coupling and rotation

Common-Mode Noise Filter Design based on Defected Ground Structure (DGS) for Multilayer PCBs

The paper discusses the advantages of constructing China-South Korea First Free Trade Zone in Shandong Peninsula,basing on the analysis of the development of CJK Free Trade Zone and the connotation of first district.Finally, several pathes are proposed to construct first experimental area from the following four aspects.Firstly,taking Qingdao qianwan bonded port and Yantai bonded port as a breakthrough,carry out the experimental unit of free trade port;Secondly.regarding the establishment of a highly open regional bank -Bank of Northeast Asia-as a key,try to be the leading and experimental area in the regional financial cooperation;Thirdly,looking the construction of trans-strait passage in Bohai Strait and China-South Korea railway ferry as an opportunity,promote China and South Korea to be regional integration through blending traffic;Lastly,thinking of the cooperation among regional important industries as a channel,explore the road to achieve industrial integration.

Thoughts over Construction of China-South Korea First Free Trade Zone in Shandong Peninsula

The method of D401 cation exchange resin modified through ion exchanging in Fe2+ soln was described.According to this modified resin with the property of that the redox of Fe2+ and chlorine,the aim of removing the mini content of residual chlorine from the water was achieved.The experiments indicate that when the iron content in the resin is 39.648 mg/g,reaction time is 3 h and the pH value is between 5 and 8,the removal rate of residual chlorine in the water is 98.56%.The ordinary coexisting ions in water do not affect the capability of the resin.The 0.5% VC solution is able to recreate the resin and the circulation use of resin do not reduce the efficiency of removing chlorine.In addition,this method does not bring other ions into the water.A new remarkable method of removing the nocuous residual chlorine from the drinking water was obtained.

Study on properties of removing residual chlorine from drinking water using cation exchange resin of carrying ferrum

An ultrawideband frequency selective surface (FSS) absorber with high angular stability and polarization independency applied in a microwave band is proposed. The absorber is composed of three identical Teflon layers and dual FSS layers with distinct patterns. The miniaturized FSSs with unique patterns demonstrate advantages of facile manipulation of the impedance and multiple resonances in an ultrawide frequency range. The use of identical dielectric substrate greatly reduces the complexity in the absorber design, compared with the conventional way that requires variable dielectric constants for a multilayer structure. Experimental results reveal that more than 90% absorption rate in the frequency range of 2.79–20.62 GHz for normal incidence is achieved. The absorption rate can still retain more than 80% in the range of 4.41–20.93 GHz for both TE and TM polarizations with an incidence of 60°.

An Ultrawideband Frequency Selective Surface Absorber With High Polarization-Independent Angular Stability

A Wideband Tangential Electric Probe based on Common Mode Absorbing

A quasi-static periodic Green's function (PGF) is proposed for modeling and designing metasurfaces in the form of two-dimensional (2D) periodic structures. By introducing a novel quasi-static approximation on the full-wave PGF in the spectrum domain, the quasi-static PGF is derived that can retain the contribution from propagating and evanescent modes below resonant frequency by a second-order polynomial of frequency. Unlike full-wave PGF, the proposed quasi-static PGF polynomial coefficients are frequency-invariant. Consequently, it can save the modeling time significantly by calculating the coefficients only once for a frequency band of interest. Moreover, a quasi-static PEEC model is developed from the proposed quasi-static PGF. It circumvents the breakdown problem around near-zero frequencies since the singularity in PGF is separated in the quasi-static PGF and eliminated analytically in model development. Therefore, both the time- and frequency-domain analysis can be conducted easily using a SPICE-like solver on the PEEC model. Two examples are given, one of which validates the accuracy of the proposed quasi-static PGF in a 2D periodic unit cell working at 0–12 GHz; the other demonstrates the superior performance in terms of model efficiency and stability by a Jerusalem-cross frequency selective surface (FSS) working at 0–20 GHz. The numerical results show that the proposed method is accurate and efficient in a wide band for metasurfaces made of two-dimensional periodic structures.

IEEE Journal on Multiscale and Multiphysics Computational Techniques

PEEC Model Based on a Novel Quasi-Static Green's Function for Two-Dimensional Periodic Structures

Least Squares Polynomial Chaos Regression for Stochastic Analysis of Transmission Lines without and with Noise

In this article, a compact partial element equivalent circuit (c-PEEC) model is presented for characterizing the electromagnetic (EM) problems with finite-sized piecewise homogeneous dielectrics. Unlike in conventional PEEC models where dielectrics are described by massive subcircuits, the proposed c-PEEC model addresses the composite conductor-dielectric problems via circuit elements resident on conductors only. Novel null-field boundary integral equations (n-BIEs) are formulated based on the surface equivalent principle and quasi-static assumption. The elimination of the magnetic field-related equivalent sources avoids the low-frequency breakdown problem caused by the weak EM coupling at low frequencies and improves the accuracy by inhibiting the numerical errors in discretizing magnetic sources. The computational cost is significantly reduced compared with the conventional models. Furthermore, the concise configuration of the c-PEEC model extends the model-order reduction (MOR) algorithms for fundamental homogeneous models to heterogeneous integration. Three numerical examples including a resonator, a radio frequency (RF) embedded passive circuit, and an interconnection problem, are studied to validate the stability, efficiency, and accuracy of the c-PEEC model. A micro-modeling circuit is obtained from the c-PEEC model to demonstrate its compatibility with the MOR algorithms.

Compact Quasi-Static PEEC Modeling of Electromagnetic Problems With Finite-Sized Dielectrics

This paper elaborates the near-field scanning and modeling technique developed for electromagnetic interference (EMI) analysis. The technique has been increasingly deployed in many R&D labs of universities and testing centers of industry companies due to its advantages in terms of time and cost, comparing with conventional EMI measurement methods. The major research works related to the near-field scanning and modeling are probe design and source reconstruction method (SRM). In this article, the working principle of electric and magnetic probes are firstly introduced. Probe parameters including calibration factor, electric center, sensitivity, spatial resolution and bandwidth are discussed. Next, the equivalent radiation source modeling approach is presented. Through SRM, a complex and unknown EMI source is substituted with the simplified equivalent radiation source based on the electromagnetic fields measured by magnetic and/or electric probes. The phaseless SRM is thereafter discussed for addressing the limitations in conventional SRM and its applications prove that the near-field scanning and modeling technique can effectively predict EMI far-field radiation and near-field coupling.

Probe Design and Source Reconstruction for Near-Field Scanning and Modeling

In this work, a full-wave partial element equivalent circuit (PEEC) model for 2-D periodic metallic structures is proposed. The mixed potential integral equations (MPIEs) with periodic Green’s function (GF) are interpreted as loop equations following Kirchhoff’s voltage law (KVL) in a circuit domain. The impact of gauge freedom in the MPIE on the corresponding PEEC model is discussed. A tailored gauge function is introduced to form a generalized PEEC model for periodic structures, which demonstrates superior passivity and frequency stability. With the proposed PEEC model, lumped and active elements can be easily integrated with conducting bodies for field-circuit co-simulation. Through the distributed circuit including coupling elements, the PEEC model provides a clear physical insight into the electromagnetic behavior of the physical models for design and optimization. Three numerical examples, including frequency-selective surface (FSS), array antenna, and pixelwise meta-atom, are given to illustrate the accuracy and efficiency of the proposed PEEC model.

A Full-Wave Generalized PEEC Model for Periodic Metallic Structure With Arbitrary Shape

Reconstructing the electromagnetic properties of an unknown electronic component with limited or little information is challenging. In this paper, a new circuit modeling approach for a component in a "black-box" is proposed by tackling nonlinear inverse scattering problems (ISPs). A pixel-to-pixel generative adversarial network (pix2pix GAN) is built to infer the conductor structures within a space of interest from the measured electric/magnetic fields in a near-field region. The circuit model of the component is subsequently generated by the partial element equivalent circuit (PEEC) method based on the derived conductor structures. The proposed pix2pix GAN is developed and optimized according to computational electromagnetics principles and numerical experiment. Learning from a tailored training set that imitates the conducting traces of integrated circuit, the pix2pix GAN confines the solutions to a physically meaningful subset. The proof-of-concept example shows that a well-trained pix2pix GAN can effectively reconstruct conductor structures with high confidence and have excellent agreement with the ground truth.

2022 Asia-Pacific International Symposium on Electromagnetic Compatibility (APEMC)

A Novel Circuit Modeling Approach for Electromagnetic "Black-box" Problems based on Generative Adversarial Networks and Partial Element Equivalent Circuit Method

This paper presents the global sensitivity analysis of cable crosstalk against uncertainty of parameters using the Sobol' method. The impact of these uncertain parameters is ranked based on the Sobol' indices. The result shows that the Sobol' method is feasible for global sensitivity analysis of three-conductor transmission line crosstalk model.

Global Sensitivity Analysis for Crosstalk of Three-Conductor Transmission Line using Sobol ′ Method

The measurement of radiated emission (RE) in an anechoic chamber becomes very challenging at high frequencies, up to 60 GHz, because the scanning plane of the receiver is in measurement standard deviation from the actual wavefront. As a result, the RE intensity of the devices may be underestimated, resulting in electromagnetic interference. The deviation between the electric field at the far-field vertical scanning point and the actual wavefront is researched. Then, in an anechoic chamber, a hybrid deep learning amendment model of convolutional neural network (CNN) and transformer is proposed to correct the RE measurement at a 3 m distance. The results indicate that the correction is reliable, with an average error of 6.35% for a 3 m distance in a semianechoic chamber and less than 4.83% for other test scenarios. The proposed method provides a promising solution for RE measurement at a millimeter wave band in an anechoic chamber.

Field Deviation in Radiated Emission Measurement in Anechoic Chamber for Frequencies up to 60 GHz and Deep Learning-Based Correction

A distinctive frequency selective surface (FSS) to effectively enhance the electromagnetic shielding performance of high-speed electronic systems while preserving good mechanical ventilation is proposed in this article. The FSS consists of periodic segmented circular patterns in two-dimensional view and hollow vent holes in spatial, which exhibits a wide 2 GHz stopband at the interested frequency of 28 GHz. The new design also demonstrates stability to wave oblique incidence and polarization. The FSS shielding panel is prototyped and measured for validation. A satisfactory agreement between simulation and physical experiment is achieved.

Angularly Independent Frequency Selective Surface With Good Ventilation for Millimeter Wave EM Shielding

A single-layer dual-band FSS working as a band rejection filter in the two frequency ranges of 0 to 4.7 GHz and 25.3 to 30.0 GHz is proposed for 5G electromagnetic shielding in this paper. The proposed FSS unit cell consisting of a metallic square ring and four bent arms that occupy 42 percent of the cell's area, provides good electromagnetic shielding while retains sufficient light transmittance. The simulated results illustrate the stable shielding performance in the interested two bands with polarization independence and angular stability up to 40°.

2022 International Symposium on Electromagnetic Compatibility – EMC Europe

A Single-layer Dual-band Frequency Selective Surface for 5G Shielding

A broadband absorber based on frequency selective surface (FSS) for electromagnetic shielding is proposed in this paper. The proposed absorber consists of a lossy FSS layer and a ground-backed Polymethylacrylimide (PMI) Foam. The lossy FSS layer composes of a square ring and a meandered square spiral made of indium tin oxide (ITO), which is a resistive material with square resistance of 15 Ω/sq. Results show that the proposed absorber achieves more than 90% absorption in the frequency range of 7.4 - 18.7 GHz, with angular incidence stability up to 35° for both TE and TM polarizations.

This work explores the role of metamaterial-based absorber (MA) in improving performance of electromagnetic bandgap (EBG) structure to restrain the simultaneous switching noise (SSN) in high-speed digital systems. A meander line-shaped MA (ML-MA) is proposed with bandwidth from 7.0 - 14.7 GHz of which the absorption achieves more than 80%. A novel checkerboard-shaped EBG structure is formed by arranging the MA and tricyclic nested EBG unit periodically achieving wideband suppression of SSN ranges from 0.3GHz to more than 30 GHz. With the composite effect, the suppression depth is enhanced up to 28.5 dB in the ML-MA absorption band.

Checkerboard-Shaped Electromagnetic Bandgap Structure Combining Metamaterial-Based Absorber for Simultaneous Switching Noise Suppression

An optically transparent ultra-wide stopband frequency selective surface (FSS) for electromagnetic shielding in millimeter wave is proposed in this paper. The proposed FSS is realized by etching distinctive patterns on non-conductive glass coated with transparent conductive indium tin oxide (ITO). Full-wave electromagnetic simulations demonstrate that the FSS can achieve electromagnetic shielding from 19 to 36.6 GHz with 20 dB shielding effectiveness and exhibit response stability to oblique incidence up to 40° under both TE and TM polarizations. Finally, a prototype is fabricated and the measured results are in good agreement with the simulation.

A Transparent Ultra-Wide Stopband Frequency Selective Surface for Millimeter Wave Electromagnetic Shielding

An effective electromagnetic interference (EMI) source reconstruction method based on dynamic differential evolution (DDE) is proposed in this article. In this method, an unknown EMI source is represented by an equivalent dipole array by using the scanned phaseless magnetic near fields. Different from the conventional differential evolution (CDE) method, DDE individually updates every equivalent dipole instead of the whole dipole array for each iteration. It converges faster and takes less computing time than CDE. The equivalent dipole model reconstructed by DDE can thereafter predict the near field and 3-m far field efficiently. The results of numerical and measurement examples have verified the effectiveness and robustness of the proposed method.

An Effective EMI Source Reconstruction Method Based on Phaseless Near-Field and Dynamic Differential Evolution

In this paper, a deep learning-based macro circuit model approach for black-box electromagnetic compatibility (EMC) problems is proposed. The concept of the partial element equivalent circuit (PEEC) method is deployed in constructing the circuit topology in the full-space mesh of a black-box device. The mesh-based circuit model can serve as a powerful tool in solving the emission and immunity of the system-level EMC problems. A physics based deep neural network (DNN) is designed and optimized with the electromagnetic and circuit theories. The approach is validated by a proof-of-concept numerical example. The training and validation data are obtained by solving simplified PEEC models of randomly generated routes on a pre-defined mesh set of a black box problem. Good agreement and efficiency are observed.

2021 IEEE International Joint EMC/SI/PI and EMC Europe Symposium

A Deep Learning Based Macro Circuit Modeling for Black-box EMC Problems

Near field scanning is one of the most useful methods for electromagnetic interference (EMI) diagnosis. However, large scanning points and long scanning time are the major obstacles when the device under test is complex. To resolve the issue, a novel hybrid method including two steps to quickly predict the near field pattern of an unknown EMI source is proposed. The first step is to reconstruct a full field pattern from a sparse scanning using the joint Schatten p-norm and Lp-norm method, where less sampling points are required on the original scanning plane. The second step is the near–near field transformation based on the plane wave spectrum method. It uses one single field pattern to derive the field distributions on multiplanes around the EMI source by introducing a calibration factor. The source reconstruction method in the second step can also be used to predict far field and coupled power to the victim circuit. Both simulation and experimental examples have validated the feasibility of the proposed method.

A Hybrid Schatten p-Norm and Lp-Norm With Plane Wave Expansion Method for Near–Near Field Transformation

The electromagnetic interference (EMI) problems are crucial for system-in-package (SiP) due to the high demand of miniaturization and dense integration. Shielding methods are generally employed to protect SiP from EMI, through assessing the key performance index, i.e., shielding effectiveness (SE). In this article, the SE of a SiP is evaluated by using near-field scanning method. The SEs derived by using maximum near-field values and average near-field values are comparatively analyzed. The difference in near-field patterns of the unshielded and shielded SiPs may incur overestimation of the SE by using maximum field values. Both simulation and measurement results manifest that the gap between SiP and printed circuit board (PCB) will significantly change the radiation pattern of a shielded SiP, and thus has a great impact on the SE, especially when the frequency is above 1 GHz. However, a good correlation is found between the SE based on average near-field and the SE derived from the radiated power. This study has revealed the near-field shielding properties of SiP, which is helpful for building and analyzing the correlation among the SEs measured by different methods, including the near-field scanning, transverse electromagnetic (TEM) cell and reverberation chamber.

Near-Field Scanning Based Shielding Effectiveness Analysis of System in Package

A side-positioned coil array printed on a PCB slab effectively suppressing the magnetic field leakage of a magnetic resonant wireless power transfer (WPT) system while preserving good transfer efficiency is presented in this paper. Based on a basic two-coil WPT system working at 6.78 MHz, a slab with four coils printed on both sides is proposed and fabricated. The effect of the slab on the magnetic field shielding and power transfer efficiency is investigated through physical experiment, when the slab is placed at the side of the WPT system. The magnetic fields around the WPT with and without the slab are measured by a magnetic probe under the control of a 3D scanning system. The measured results show that the proposed coil array reduces the magnetic field leakage by an average of 6.42 dB without degrading the transfer efficiency, instead it improves the efficiency of the WPT system at an average of about 27%.

Magnetic Field Leakage Reduction and Efficiency Enhancement of Wireless Power Transfer by Using Side-Positioned Coil Array

An effective broadband electromagnetic interference (EMI) source reconstruction method is proposed in this letter. An equivalent dipole model incorporating the global optimization method is developed to reconstruct EMI sources on printed circuit boards (PCBs) based on the scanned magnetic near-field magnitudes of device under test (DUT). Different to conventional approaches, the locations and quantity of the equivalent dipoles are fixed for all frequencies in the interesting band. The moments and locations of these dipoles are acquired by deploying interpolation based on near-field data at three predefined frequencies only. The near-field patterns at all frequencies can thus be obtained by customizing the dipoles moments. The values of the coupled powers derived from these models are used for near-field prediction. Through numerical and physical examples, the effectiveness of this broadband modeling method is verified.

Broadband Radiation Source Reconstruction Based on Phaseless Magnetic Near-Field Scanning

An alternating high‐low impedance common‐mode filter for differential striplines

A novel ultra-wide bandstop frequency selective surface (FSS) for 5G electromagnetic shielding applications is proposed in this paper. The proposed FSS is evolvement of a double-layer planar metallic circular loops structure by extending the loops in the vertical direction to form a 3D configuration. Simulated results using CST demonstrate that the proposed FSS has the advantages of miniaturization, good shielding performance at the frequency range of 24 GHz - 30 GHz, angular stability of up to 60° and polarization independence. The BW|SE=30dB is about 12.7 GHz and the BW|SE=50dB can reach 6 GHz for both TE and TM modes.

2020 International Symposium on Electromagnetic Compatibility - EMC EUROPE

A Novel 3D Ultra-wide Stopband Frequency Selective Surface for 5G Electromagnetic Shielding

In this article, a simple and accurate method is proposed to extract the sheet resistance of a thin conductive film by using the enhanced one-port waveguide in a microwave frequency. A shorted quarter-wavelength waveguide is supplemented to the main waveguide as its open boundary to ensure the TE10 mode during the measurement. Unlike the available waveguide with the metal flange, the dielectric flange of the shorted quarter-wavelength waveguide is proposed to eliminate the transverse electromagnatic (TEM) wave propagation and leakage in the gap between two waveguide flanges. The conductive film deposited on the substrate is attached to the main waveguide flange, and the equivalent circuit model is generated thereof. By measuring S11 parameters of the bare substrate and conductive film with the substrate, respectively, the unknown sheet resistance of the conductive film can be easily extracted. Even a large sheet resistance could be measured accurately. Both numerical and measurement results are presented for effectiveness validation of the proposed method. In comparison with the available dual-port method and waveguide with the metal flange method, the dielectric flange raises the measurement accuracy sharply in aspects of substrate thickness, substrate materials, and sheet resistance.

An Enhanced One-Port Waveguide Method for Sheet Resistance Extraction

This paper presents the shielding effectiveness (SE) study for enclosure incorporating a newly developed frequency selective surface (FSS) with consideration of the ratio of vent hole array and the oblique wave incidence. Not only is the SE at the center of the enclosure analyzed, but also the global shielding effectiveness (GSE) is evaluated as a complementary approach for more reasonable prediction. Compared to an enclosure commonly shielded by metal with the same vent hole array, the shielding effectiveness of the enclosure with the FSS shield is about 20 dB higher in the frequency range of 23 GHz - 25.5 GHz, which meet the requirements of SE >= 30 dB and BW|SE=30dB > 2 GHz. The results also show that the ratio of vent hole array to one surface of the enclosure has impact on the shielding effectiveness of enclosure. Importantly, the study indicates that FSS technology can be a promising alternative when conventional metallic shielding is limited due to ventilation requirement in the high frequency applications.

Electromagnetic Shielding Effectiveness Analysis of Enclosure Incorporating Frequency Selective Surface

The high-order modes of the periodic-stub-loaded stripline are studied by using an equivalent circuit, which shows a good accuracy and efficiency. Due to the similarity, the proposed structure is compared with the spoof surface plasmon transmission line developed in recent years, and it reveals advantages for electromagnetic compatibility. Two approaches are introduced to suppress different transmission modes of the proposed structure. The first is the gradual transition structure, which could suppress higher order modes to form a low-pass (dc—9.2 GHz) filter. The second is the half-mode structure. It could suppress the fundamental and the second higher order modes to constitute a bandpass (9.6–27.6 GHz) filter. Both filters have selective transmission modes, broad stop band, steep transition and low-loss features. The prototypes are fabricated and measured. The measured filtering performance agrees well with the simulation data. Benefitting from aforementioned advantages, the proposed filters will be effective alternatives in practical high-speed integrated circuit.

Modeling and Analyzing High-Order Modes in Periodic-Stub-Loaded Stripline for Wideband Filter Design

The accurate extraction of small parasitic resistances of surface mount components in electromagnetic compatibility modeling is a great challenge. In this paper, a simple yet efficient LC resonant measurement method is proposed to solve this issue. A surface mount capacitor and an inductor with the unknown parasitic resistances are connected in parallel to form an LC resonator. The effect of parasitic resistance on the measured S-parameters is thus magnified so that the measurement error introduced during the de-embedding procedure is relatively diminished. A mobile phone inverted F antenna with LC components is measured to verify the efficiency of the proposed method. In comparison with the direct de-embedding method, the proposed approach demonstrates a higher accuracy in the extraction of parasitic resistance, while it is simple and cost-effective.

An LC Resonant Method for the Accurate Extraction of Small Parasitic Resistance

The papers in this special section were presented at two major EMC events in 2018. These include the 2018 Joint IEEE International Symposium on Electromagnetic Compatibility and Asia-Pacific International Symposium on Electromagnetic Compatibility (APEMC) and the 2018 IEEE Symposium on Electromagnetic Compatibility, and Signal and Power Integrity.

Guest Editorial Introduction to the Special Issue for the Joint 2018 IEEE EMC and APEMC Symposium in Singapore and IEEE EMC+SIPI Symposium in Long Beach USA

In order to enhance the lightning protection and electromagnetic shielding capabilities of composite aircraft, the electromagnetic behavior of carbon fiber reinforced polymer (CFRP) composite is characterized in this paper. Through the study of lightning direct effect in terms of current density distribution in each composite ply under lightning strike, the scheme to increase electrical conductivity is proposed for different fiber configurations of composite. The high frequency electromagnetic shielding effectiveness of composite is also studied and analyzed by extracting the equivalent permittivity using Nicholson-Ross-Weir method based on the measured scattering parameters. Reasonable agreement is observed between the results of simulation and validation experiment for shielding effectiveness of the composite.

2019 International Symposium on Electromagnetic Compatibility - EMC EUROPE

Lightning Direct Effect and Electromagnetic Shielding Analysis of Conductive Aircraft Composite

The near-field scanning is an effective technology for electromagnetic interference (EMI) diagnosis. An accurate and efficient near-field-to-near-field transformation in the reactive near-field region of the EMI radiation source plays an important role in the near-field scanning. In this paper, an efficient near-field-to-near-field transformation based on the electromagnetic probe calibration is proposed. By using the plane wave spectrum expansion of the probe output, the magnetic fields under test on multiplanes are obtained through a single-plane probe scanning. The proposed transformation can be considered as the extension of the prior probe compensation/calibration methods (where the field on only one plane is derived). The proposed method is validated with both numerical and experimental examples. A good agreement between the results of the proposed method and the full-wave simulation is achieved. In comparison with prior probe calibration methods, the proposed method does well, especially in determining the fields below the probe’s scanning plane. This is deterministically useful for accurately identifying the potential radiation sources during the EMI diagnosis.

An Efficient Probe Calibration Based Near-Field-to-Near-Field Transformation for EMI Diagnosis

Accuracy of urban positioning depends on the quality of signals received by a Global Navigation Satellite System (GNSS) receiver that can be a combination of light of sight, reflection and diffraction signals. The more light of sight signals are received, the more accurate positioning can be achieved. To evaluate signal propagation thus availability of GNSS satellites in urban environments, a ray-tracing based modelling technique is proposed that can predict the light of sight, reflection and diffraction signals together with 3D city model. The developed techniques are validated against in-situ measurements in urban areas with different scenarios.

2019 8th Asia-Pacific Conference on Antennas and Propagation (APCAP)

Satellite Visibility and Geometry Analysis for GNSS Positioning in an Urban Environment

A frequency selective surface (FSS) based electromagnetic shielding structure with vent holes is proposed for 5G electromagnetic (EM) shielding. The proposed FSS structure is developed for the demanding requirements of EM shielding at 28 GHz without worsening the ventilation. Through a number of simulations using full-wave analysis, the optimized FSS achieves a bandwidth of more than 2 GHz with 30 dB shielding effectiveness. Moreover, the proposed FSS-based shielding structure has the advantage of response stability to the incident angle from 0° up to 60° for both TE and TM polarization. Results show that there is a good agreement between the measurement and the simulation.

An Angularly Stable Frequency Selective Surface with Vent Holes for 5G Electromagnetic Shielding

A fast and efficient analytical approach based on the extended Baum-Liu-Tesche (BLT) equation is proposed in this paper to evaluate the external electromagnetic field coupling to transmission lines (TLs) loaded in a metallic enclosure with apertures. The scattering matrix to describe the aperture coupling characteristics required in the BLT equation is effectively derived based on the equivalent circuit theory. The analytical modeling function for calculating internal modal fields coupling to TLs is investigated and developed. Thus, the extended BLT equation can be directly employed in the assessment of current induced at the loads of TLs in the enclosure, which is illuminated by external electromagnetic fields. Via different case studies, the results calculated using the proposed analytical approach have been validated and have been in a good agreement with those simulated by numerical methods. The computational efficiency, in terms of time and memory, has also been improved much for the electromagnetic interference problems.

A Fast and Efficient Analytical Modeling Approach for External Electromagnetic Field Coupling to Transmission Lines in a Metallic Enclosure

Metamaterial-based common-mode noise filter with NGD effect for multilayer PCB

This paper presents a finite-difference time-domain (FDTD) method for multilayer carbon-fiber-reinforced polymer (CFRP) panel using tensorial conductivity matrix. By proper interpolation, all the electromagnetic field components involved in the FDTD update equations are all located in the Yee's cell in a staggered manner. Based on the measured tensorial conductivity matrix, the anisotropic characteristic of multilayer CFRP panel with different fiber orientations in different layers is modeled. A unidirectional CFRP panel is simulated to show the current density distributions for different tensorial conductivity matrice. In addition, a lightning-like source striking at an infinite large multilayer multidirectional CFRP panel truncated by convolutional perfectly matched layer (CPML) is also simulated. The current densities and the electric fields at the center point for the top four layers testify the conductive loss along the in-depth direction.

2018 IEEE International Symposium on Electromagnetic Compatibility and 2018 IEEE Asia-Pacific Symposium on Electromagnetic Compatibility (EMC/APEMC)

Finite-difference time-domain method for multilayer carbon-fiber-reinforced polymer panel using tensorial conductivity matrix

Due to the special negative electromagnetic properties, metamaterial has gained wide attention and also been increasingly applied in electromagnetic compatibility (EMC). In the paper, the metamaterial associated EMC design has been addressed through two case studies, one is defected ground structure for common-mode noise inhibition and another is frequency selective surface for the sake of shielding effectiveness for high speed electronics. The results manifest that metamaterial can provide effective solutions to tackle electromagnetic interference issues where conventional EMC approaches are difficult to be deployed or even lose efficacy.

The electrical conductivity of a carbon fiber reinforced plastic (CFRP) panel is highly anisotropic due to its varied fiber orientations. This paper presents an effective modeling method for studying the lightning direct effect on a multidirectional CFRP panel based on an electrical conductivity characterization of unidirectional samples. The characterization using 4-probe method is done with a simple measurement setup. The measured DC conductivity is validated by comparing the sample's behavior in AC regime (lightning spectrum) obtained from measurement and simulation. It is subsequently used in the modeling of a 32-layer multidirectional CFRP panel excited by a lightning current. Simulation results show that the proposed method is able to effectively model multidirectional CFRP panels, which might be useful to studying the current-carrying capacity of CFRP panels under lightning strikes.

2017 XXXIInd General Assembly and Scientific Symposium of the International Union of Radio Science (URSI GASS)

Effective modeling of multidirectional CFRP panels based on characterizing unidirectional samples for studying the lightning direct effect

The paper presents a study on the electromagnetic behavior of aircraft composite when lightning strikes on an aircraft. As the lightning phenomenon and its direct effect are very complex, the intrinsic electric characteristics of composite material are thus needed to be understood for lightning strike protection. Effective medium method is employed to model carbon fiber composite. By using an example, electric fields and magnetic fields of composite have been studied. The results have shown that the current-carrying capability of composite can be improved if the effective electric conductivity of composite increases.

2017 International Symposium on Electromagnetic Compatibility - EMC EUROPE

Electromagnetic behavior analysis of aircraft composite under lightning direct effect

The subject of this paper is the robust and quality-oriented design of an electromagnetic wave absorber. Taguchi's parameter design is employed first to optimize the absorption efficiency of the wave absorber over a wide bandwidth while reducing the sensitivity of the optimized performance to a number of hard-to-control variables. However, the variation of the optimized product performance after Taguchi's parameter design might not be within the desired target due to certain design requirements and market expectations. Therefore, a new design scheme is studied with the employment of Taguchi's tolerance design. The results illustrate that the absorption efficiency could be further enhanced by tightening the performance variation level, so that the quality of the absorber is improved.

Quality Synthesis Based Robust Optimization for Electromagnetic Wave Absorbers Using Taguchi's Tolerance Design Method

This paper presents a robust design approach that not only optimizes the absorption efficiency of an electromagnetic wave absorber over a wide bandwidth, but also reduces the sensitivity of the optimized performance to a number of hard-to-control variables. The optimizable object is a planar multilayer electromagnetic absorber. The important design variables are identified, and the influence of each variable on the performance is analyzed. A robust design of the absorber is realized by employing the signal-to-noise ratio of the absorption efficiency.

Robust Design of Electromagnetic Wave Absorber Using the Taguchi Method

request of the publishers," we have a brief account and an analysis of the background and fundamental causes by which "a house-painter's mate" rose from obscurity to the head of a great state. The abstract theories of the "very learned professors of political science" in pre-war Germany had not inoculated the minds of the masses with any tangible program by which to meet and overcome the depression which followed the lost war. And the more the learned solutions under the Republic piled on one another, the more deeply the country sank into distress.

In recent years, there is an influx of deep learning models for 3D vehicle object detection. However, little attention was paid to orientation prediction. Existing research work proposed various vehicle orientation representation methods for deep learning, however a holistic, systematic review has not been conducted. Through our experiments, we categorize and compare the accuracy performance of various existing orientation representations using the KITTI 3D object detection dataset, and propose a new form of orientation representation: Tricosine. Among these, the 2D Cartesian-based representation, or Single Bin, achieves the highest accuracy, with additional channeled inputs (positional encoding and depth map) not boosting prediction performance. Our code is published on GitHub: https://github.com/umd-fire-coml/KITTI-orientation-learning

SoK: Vehicle Orientation Representations for Deep Rotation Estimation

The High Luminosity Large Hadron Collider provides a data challenge. The amount of data recorded from the experiments and transported to hundreds of sites will see a thirty fold increase in annual data volume. A systematic approach to contrast the performance of different Third Party Copy (TPC) transfer protocols arises. Two contenders, XRootD-HTTPS and the GridFTP are evaluated in their performance for transferring files from one server to another over 100Gbps interfaces. The benchmarking is done by scheduling pods on the Pacific Research Platform Kubernetes cluster to ensure reproducible and repeatable results. This opens a future pathway for network testing of any TPC transfer protocol.

Systematic benchmarking of HTTPS third party copy on 100Gbps links using XRootD

Biosecurity risk material (BRM) presents a clear and significant threat to national and international environmental and economic assets. Intercepting BRM carried by non-compliant international passengers is a key priority of border biosecurity services. Global travel rates are constantly increasing, which complicates this important responsibility, and necessitates judicious intervention. Selection of passengers for intervention is generally performed manually, and the quality of the selection depends on the experience and judgement of the officer making the selection. In this article we report on a case study to assess the predictive ability of statistical profiling methods that predict non-compliance with biosecurity regulations using data obtained from regulatory documents as inputs. We then evaluate the performance arising from using risk predictions to select higher risk passengers for screening. We find that both prediction performance and screening higher risk passengers from regulatory documents are superior to manual and random screening, and recommend that authorities further investigate statistical profiling for efficient intervention of biosecurity risk material on incoming passengers.

Statistical profiling to predict the biosecurity risk presented by non-compliant international passengers

Decision letter: Neural excitability and sensory input determine intensity perception with opposing directions in initial cortical responses

Decision letter: Intrinsic excitation-inhibition imbalance affects medial prefrontal cortex differently in autistic men versus women

Complex cognitive functions such as working memory and decision-making require information maintenance over many timescales, from transient sensory stimuli to long-term contextual cues. While theoretical accounts predict the emergence of a corresponding hierarchy of neuronal timescales, direct electrophysiological evidence across the human cortex is lacking. Here, we infer neuronal timescales from invasive intracranial recordings. Timescales increase along the principal sensorimotor-to-association axis across the entire human cortex, and scale with single-unit timescales within macaques. Cortex-wide transcriptomic analysis shows direct alignment between timescales and expression of excitation- and inhibition-related genes, as well as genes specific to voltage-gated transmembrane ion transporters. Finally, neuronal timescales are functionally dynamic: prefrontal cortex timescales expand during working memory maintenance and predict individual performance, while cortex-wide timescales compress with aging. Thus, neuronal timescales follow cytoarchitectonic gradients across the human cortex, and are relevant for cognition in both short- and long-terms, bridging microcircuit physiology with macroscale dynamics and behavior.

Neuronal timescales are functionally dynamic and shaped by cortical microarchitecture

NitroSynapsin ameliorates hypersynchronous neural network activity in Alzheimer hiPSC models

A recent issue of Topics in Cognitive Science featured 11 thoughtful commentaries responding to our article "What happened to cognitive science?" (Núñez et al., 2019). Here, we identify several themes that arose in those commentaries and respond to each. Crucial to understanding our original article is the fundamental distinction between multidisciplinary and interdisciplinary endeavors: Cognitive science began (and has stayed) as multidisciplinary but has failed to move on to form a cohesive interdisciplinary field. We clarify and elaborate our original argument and reiterate the importance of a data-driven evaluation of the current status of the field, which exhibits a marked disciplinary imbalance, a lack of a coherent conceptual core, and a striking absence of a consistent curriculum in the institutions that grant degrees in this domain. Half a century after the creation of cognitive science, it may now be a good time to revisit goals and visions for how to best approach the ever-fascinating scientific study of the mind(s).

For the Sciences They Are A-Changin': A Response to Commentaries on Núñez et al.'s (2019) "What Happened to Cognitive Science?"

Parameterizing neural power spectra into periodic and aperiodic components

Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice

Complex Oscillatory Waves Emerging from Cortical Organoids Model Early Human Brain Network Development.

Populations of neurons exhibit time-varying fluctuations in their aggregate activity. These data are often collected using common magnetoand electrophysiological methods, such as magneto or electroencephalography (M/EEG), intracranial EEG (iEEG) or electrocorticography (ECoG), and local field potential (LFP) recordings (Buzsáki, Anastassiou, & Koch, 2012). While there are existing Python tools for digital signal processing (DSP), such as scipy.signal, neural data exhibit specific properties that warrant specialized analysis tools focused on idiosyncrasies of neural data. Features of interest in neural data include periodic properties—such as band-limited oscillations (Buzsáki & Draguhn, 2004) and transient or ‘bursty’ events—as well as an aperiodic signal that is variously referred to as the 1/f-like background (Freeman & Zhai, 2009; Miller, Sorensen, Ojemann, & Nijs, 2009), or noise (Voytek et al., 2015), or scale-free activity (He, 2014), and that may carry information about the current generators, such as the ratio of excitation and inhibition (Gao, Peterson, & Voytek, 2017). NeuroDSP is a package specifically designed to be used by neuroscientists for analyzing neural time series data, in particular for examing their time-varying properties related to oscillatory and 1/f-like components.

Computational Cognitive Neuroscience aims to characterize the neural computations underlying behavior. To do so, we must integrate our understanding of cognition across its different subfields: cognitive science, computational neuroscience, cognitive neuroscience, and machine learning. One key challenge is evaluating whether the structure of cognitive processes – their definitions and interrelations – in each subfield is similar. If not, how different are they and how can we measure and ameliorate those differences? To answer these questions, we mined scientific abstracts from conferences representative of subfields to learn fieldspecific word embeddings of cognitive concepts using Word2Vec. Vector representations are then used to generate hierarchical and 2D visualizations, forming empirical cognitive ontologies for each subfield. We find that robust ontologies, such as clusters representing language-related concepts, are automatically generated from each corpus. While differences between corpora are evident, exploratory analysis with word vectors can perform similarity queries, as well as more complex algebraic queries, e.g., “working memory” without “memory” retrieves “attention”. These results demonstrate the utility of automated text-mining and natural language processing in serving as a hypothesisgenerating procedure to populate manually-maintained ontologies in cognitive science, as well as suggesting potentially overlooked research opportunities across subfields.

The Structure of Cognition Across Computational Cognitive Neuroscience

Electrophysiological field data is comprised of both periodic components — neural oscillations — and aperiodic activity, sometimes called scale-free or 1/f activity. Investigations of aperiodic activity have established that it is dynamic and systematically varies within and between individuals, and relates to aging, and task performance. Currently, however, there are a wide variety of conceptual frameworks and methods for interpreting and analyzing aperiodic activity, the relationships between which are unclear. Here, we evaluate extant methods for measuring aperiodic activity in neural data. We briefly summarize available methods, focusing on spectral fitting approaches. We introduce simulation procedures for creating statistically representative neural time series and power spectra. Using simulations with known parameters, we systematically compare available methods, testing those that measure aperiodic activity by fitting 1/f properties in neural power spectra. We find that the most accurate approach is one that explicitly parameterizes neural power spectra. We highlight future plans for extending this framework to explore other available methods, aimed at defining best practices for measuring aperiodic neural activity, and seek to consolidate across currently disparate approaches.

A Simulation-Based Comparison of Methods for Analyzing Aperiodic Neural Activity

Oscillatory brain activity observed in neural field potentials has been widely used to index behavior, cognition, and disease. There is emerging evidence, however, that oscillations can exist in different modes, such as sustained versus bursting, that have different physiological origins and different behavioral relevance. Additionally, there exist other, non-oscillatory components in the field potential that can obscure or be mistaken for oscillations, especially in the mean power spectral density (PSD). One such component is the aperiodic signal that gives rise to the 1/f power law background in the field potential PSD, which has been proposed to reflect synaptic potentials induced by Poisson population spiking. It remains an ongoing challenge to consistently define, operationalize, and isolate oscillatory and non-oscillatory neural dynamics. In this work, we begin with a model of the field potential as a superposition of the aperiodic (Poisson) component and oscillatory components. We use two measures – spectral coefficient of variation (SCV) and deviation from noise power distribution – that are able to separate these components in simulation. Finally, we demonstrate the existence and separation of these components in a range of experimental data, focusing on human electrocorticography during movement in this paper.

Spectral Power Variation Separates Oscillatory from Non-Oscillatory Stochastic Neural Dynamics

Background Neural oscillations are often quantified as average power relative to a cognitive, perceptual, and/or behavioral task. This is commonly done using Fourier-based techniques, such as Welch’s method for estimating the power spectral density, and/or by estimating narrowband oscillatory power across trials, conditions, and/or groups. The core assumption underlying these approaches is that the mean is an appropriate measure of central tendency. Despite the importance of this assumption, it has not been rigorously tested. New method We introduce extensions of common approaches that are better suited for the physiological reality of how neural oscillations often manifest: as nonstationary, high-power bursts, rather than sustained rhythms. Log-transforming, or taking the median power, significantly reduces erroneously inflated power estimates. Results Analyzing 101 participants’ worth of human electrophysiology, totaling 3,560 channels and over 40 hours data, we show that, in all cases examined, spectral power is not Gaussian distributed. This is true even when oscillations are prominent and sustained, such as visual cortical alpha. Power across time, at every frequency, is characterized by a substantial long tail, which implies that estimates of average power are skewed toward large, infrequent high-power oscillatory bursts. Comparison with existing methods In a simulated event-related experiment we show how introducing just a few high-power oscillatory bursts, as seen in real data, can, perhaps erroneously, cause significant differences between conditions using traditional methods. These erroneous effects are substantially reduced with our new methods. Conclusions These results call into question the validity of common statistical practices in neural oscillation research. Highlights Analyses of oscillatory power often assume power is normally distributed. Analyzing >40 hours of human M/EEG and ECoG, we show that in all cases it is not. This effect is demonstrated in simple simulation of an event-related task. Overinflated power estimates are reduced via log-transformation or median power.

Structural and transcriptional changes during early brain maturation follow fixed developmental programs defined by genetics. However, whether this is true for functional network activity remains unknown, primarily due to experimental inaccessibility of the initial stages of the living human brain. Here, we developed cortical organoids that spontaneously display periodic and regular oscillatory network events that are dependent on glutamatergic and GABAergic signaling. These nested oscillations exhibit cross-frequency coupling, proposed to coordinate neuronal computation and communication. As evidence of potential network maturation, oscillatory activity subsequently transitioned to more spatiotemporally irregular patterns, capturing features observed in preterm human electroencephalography (EEG). These results show that the development of structured network activity in the human neocortex may follow stable genetic programming, even in the absence of external or subcortical inputs. Our approach provides novel opportunities for investigating and manipulating the role of network activity in the developing human cortex. HIGHLIGHTS Early development of human functional neural networks and oscillatory activity can be modeled in vitro. Cortical organoids exhibit phase-amplitude coupling between delta oscillation (2 Hz) and high-frequency activity (100-400 Hz) during network-synchronous events. Differential role of glutamate and GABA in initiating and maintaining oscillatory network activity. Developmental impairment of MECP2-KO cortical organoids impacts the emergence of oscillatory activity. Cortical organoid network electrophysiological signatures correlate with human preterm neonatal EEG features. eTOC Brain oscillations are a candidate mechanism for how neural populations are temporally organized to instantiate cognition and behavior. Cortical organoids initially exhibit periodic and highly regular nested oscillatory network events that eventually transition to more spatiotemporally complex activity, capturing features of late-stage preterm infant electroencephalography. Functional neural circuitry in cortical organoids exhibits emergence and development of oscillatory network dynamics similar to those found in the developing human brain.

Nested oscillatory dynamics in cortical organoids model early human brain network development

Electrophysiological signals across species and recording scales exhibit both periodic and aperiodic features. Periodic oscillations have been widely studied and linked to numerous physiological, cognitive, behavioral, and disease states, while the aperiodic “background” 1/f component of neural power spectra has received far less attention. Most analyses of oscillations are conducted on a priori, canonically-defined frequency bands without consideration of the underlying aperiodic structure, or verification that a periodic signal even exists in addition to the aperiodic signal. This is problematic, as recent evidence shows that the aperiodic signal is dynamic, changing with age, task demands, and cognitive state. It has also been linked to the relative excitation/inhibition of the underlying neuronal population. This means that standard analytic approaches easily conflate changes in the periodic and aperiodic signals with one another because the aperiodic parameters—along with oscillation center frequency, power, and bandwidth—are all dynamic in physiologically meaningful, but likely different, ways. In order to overcome the limitations of traditional narrowband analyses and to reduce the potentially deleterious effects of conflating these features, we introduce a novel algorithm for automatic parameterization of neural power spectral densities (PSDs) as a combination of the aperiodic signal and putative periodic oscillations. Notably, this algorithm requires no a priori specification of band limits and accounts for potentially-overlapping oscillations while minimizing the degree to which they are confounded with one another. This algorithm is amenable to large-scale data exploration and analysis, providing researchers with a tool to quickly and accurately parameterize neural power spectra.

Inferring Synaptic E : I Balance from Field Potentials 1 Title : Inferring Synaptic Excitation / Inhibition Balance from Field Potentials 1 Authors :

A key goal of cognitive science is to understand and map the relationship between cognitive processes. Previous works have manually curated cognitive terms and relations, effectively creating an ontology, but do they reflect how cognitive scientists study cognition in practice? In addition, cognitive science should provide theories that inform experimentalists in neuroscience studying implementations of cognition in the brain. But do neuroscientists and cognitive scientists study the same things? We set out to answer these questions in a data-driven way by text-mining and automated clustering to build a cognitive ontology from existing literature. We find automatically generated relationships to be missing in existing ontologies, and that cognitive science does not always inform neuroscience. Thus, our work serves as an efficient hypothesis-generating mechanism, inferring relationships between cognitive processes that can be manually refined by experts. Furthermore, our results highlight the gap between theories of cognition and the study of their implementation.

Neural circuits sit in a dynamic balance between excitation (E) and inhibition (I). Fluctuations in this E:I balance have been shown to influence neural computation, working memory, and information processing. While more drastic shifts and aberrant E:I patterns are implicated in numerous neurological and psychiatric disorders, current methods for measuring E:I dynamics require invasive procedures that are difficult to perform in behaving animals, and nearly impossible in humans. This has limited the ability to examine the full impact that E:I shifts have in neural computation and disease. In this study, we develop a computational model to show that E:I ratio can be estimated from the power law exponent (slope) of the electrophysiological power spectrum, and validate this relationship using previously published datasets from two species (rat local field potential and macaque electrocorticography). This simple method--one that can be applied retrospectively to existing data--removes a major hurdle in understanding a currently difficult to measure, yet fundamental, aspect of neural computation.

Inferring synaptic excitation/inhibition balance from field potentials

Recent experimental findings suggest that there may be rich physiological information embedded within the power spectrum of neurophysiological recordings, which, in addition to power in specific oscillatory frequencies, can be extracted with the appropriate model. This article reviews previous empirical and modeling results, as well as the canonical power law model that is often used to describe the power spectrum. In addition, a modified power law model with parameters estimating synaptic and spiking contributions is proposed.

Field Potential Reflects the Balance of Synaptic Excitation and Inhibition

31 Recent experimental findings suggest that there may be rich physiological information embedded 32 within the power spectrum of neurophysiological recordings, which, in addition to power in 33 specific oscillatory frequencies, can be extracted with the appropriate model. This article reviews 34 previous empirical and modeling results, as well as the canonical power-law model that is often 35 used to describe the power spectrum. In addition, a modified power-law model with parameters 36 estimating synaptic and spiking contributions is proposed. 37 38 39 Extracellular electrophysiological recordings, including local field potential (LFP), 40 electrocorticogram (ECoG), and electroencephalogram (EEG), have been invaluable in 41 investigating the relationship between neurophysiology and behavior. Like all time series data, 42 they can be perfectly characterized by their frequency domain representation through the Fourier 43 Transform, i.e., their power and phase spectra. Neuroscientists have leveraged this identity for 44 decades to examine the relationship between neural activity and cognition, behavior, and disease, 45 with an interest in specific oscillatory bands such as theta (4-8Hz) and alpha (8-12Hz). These 46 oscillations are often quantified as changes in signal power in specific narrow frequency bands, 47 and are assumed to be caused solely by periodic neural activity. Recently, however, evidence has 48 been accumulating regarding the significance of the power spectrum as a unified statistical entity 49 (Voytek and Knight 2015). In this view, oscillations are defined as a special subset of the 50 information contained in the power spectrum, often identified as perturbations (or “bumps”) that 51 rise above the background activity (Lopes da Silva 2013). Equally important, though, is the 52 background activity itself, where recent empirical evidence (Manning et al. 2009; Podvalny et al. 53 2015; Miller et al. 2007) and computational models (Freeman and Zhai 2009; Miller et al. 2009; 54 Baranauskas et al. 2012; Milstein et al. 2009) have demonstrated that its characterization does 55 not only serve as a convenient description of the equivalent time series, but is also closely linked 56 with behavioral variables. 57 58 Decomposing the Power Spectrum 59 We begin from the fact that the electrophysiological power spectral density (PSD) can be 60 said to follow an inverse power law relationship of the form P(f) ~ Af, with χ typically ranging 61 from -4 to -1.5, in addition to oscillatory peaks on top of the 1/f background (see Figure 2c in 62 target article, as well as Buzsaki and Draguhn 2004; Buzsaki et al. 2012). This is mathematically 63 equivalent to a negative linear relationship in the log-log domain (logP(f) ~ logA + χlogf ). We 64 will thus refer to χ as the slope and logA as the offset. In 2009, Manning et al., observed that the 65 firing rate of a local neuronal population correlates with an increased offset in the spectrum of 66 the concurrently recorded local field potential in human neurological patients performing a 67 virtual-navigation task, while the slope remained qualitatively unchanged (Manning et al. 2009). 68 Miller and colleagues subsequently supported this observation through computational modeling 69 of the LFP, while also having observed activation-related shifts and a stable slope in power 70 spectra of human ECoG, after accounting for a bend, or knee, at ~70Hz (Miller et al. 2007, 2009). 71 Recently, Podvalny et al., reported slope changes in the 10-100Hz range in human ECoG PSD 72 during a visuomotor attention task, corresponding to a “rotation” of the spectrum with slopes 73 between -3 and -1 (Podvalny et al. 2015). Similar observations were made in both rabbit and 74 human ECoG data previously, where Freeman and Zhai attributed the overall rotation of the 75 spectrum to changes in rise times of the impulse response of a recurrent excitatory network 76 (Freeman and Zhai, 2009). 77 While both an increase in overall slope and increase in offset of the PSD have been 78 linked to, broadly speaking, neural activation, it is unclear whether the two effects are 79 interdependent, and whether they arise from the same neurological mechanism. Nonetheless, the 80 power law model is able to accurately capture changes in both. A separate phenomenon is 81 observed, however, where more broadband high gamma (>80Hz), a non-oscillatory section of 82 the LFP, can increase in power through an increase in slope only in that particular frequency 83 range, independent of the slope of the lower frequencies (see Figure 2a in target article, as well 84 as Freeman and Zhai, 2009). In other words, it appears that rotation of the high frequency 85 spectrum can occur independently of the overall PSD, at an axis frequency in the gamma range, 86 producing an upward deflection about a “knee” frequency. Furthermore, the data reported by 87 Podvalny and colleagues shows the axis of overall rotation (named intersection frequency) to be 88 around 30Hz, and that the shifting of this rotational axis to lower frequencies is correlated with 89 increased gamma power. These findings imply that the change in spectrum slope may be more 90 than simply a change in the parameter χ, as would be the case if there existed a constant axis of 91 rotation at 1Hz. This pair of observations appears to be inconsistent with the current power law 92 model, as high frequency deflections cannot be captured through changing the slope and offset 93 due to the constraint that the slope remains constant over all frequencies. 94 95 Population Spiking Contribution in the Power-Law PSD 96 To account for this independent rotation, we propose an appended model of the LFP 97 power spectrum, with the addition of a constant B, such that P(f) ~ Afχ + B, with B representing 98 the addition of a signal with a flat spectrum. Furthermore, we propose that this flat-spectrum 99 signal corresponds to the detection of decorrelated (Poisson-like) firing in a large neuronal 100 population, each with a small Dirac delta-like spike waveform at the resolution detectable in 101 ECoG, the summation of which results in a noisy broadband signal that adds linearly to the LFP 102 and can be detected by mesoand macro-scale measurements. Using a population of Poisson 103 spiking neurons, we simulate their spontaneous spike-train and sum across the population for the 104 aggregate activity. We observe that the PSD of the aggregate spike-train has a flat spectrum, 105 resembling that of white noise, and experiences a constant gain in all frequencies in response to 106 an increased firing rate (Figure 1A). 107 With this, we are able to explain several key findings raised by Podvalny and colleagues 108 within a simplified mathematical framework. First, it’s observed that the addition of a flat109 spectrum signal dominates the low power (high frequency) portions of the power law PSD, 110 flattening the slope at those frequencies while having no effect in the lower frequencies, thus 111 introducing an upward deflection (Figure 1B). Secondly, when a robust linear fit is applied in the 112 range of 10-100Hz, we see a rotational effect on the slope of the line of best fit, mainly due to the 113 increase in the higher frequencies, though it is not a true rotation of the whole spectrum, as 114 would be obtained by only increasing χ. Lastly, as the magnitude of the flat-spectrum signal 115 increases as a result of increased firing rate, the axis of rotation (knee) varies in response to the 116 magnitude of the upward deflection. Specifically, an increase of flat-spectrum signal power will 117 shift the axis of rotation to a lower frequency (Figure 1B, inset), consistent with experimental 118 observations by Podvalny et al. (see Figure 3f in target article). Code for simulation can be found 119 at http://voyteklab.com/code-data/. 120 121 Discussion 122 Electrophysiological recordings are invaluable in illuminating the neural correlates of 123 behavior and cognition, though simply working with the signals in time domain is not always 124 informative. The Fourier power spectrum, or frequency representation, can often shed more 125 insight on the phenomenon we are interested in, as exemplified by the target article, a recent 126 study from Podvalny and colleagues. The target article showed several behaviorally relevant 127 changes in the power spectrum slope that are not captured by the inverse power law model (P(f) 128 ~ Afχ). Here, we demonstrate that the addition of a flat-spectrum signal to the current power law 129 model can explain a range of experimental observations, particularly the independent increase in 130 high frequency slope, as well as the apparent changes in slope with a shifting axis of rotation. 131 Under the proposed model, the LFP has two explicitly separate contributors: the first is 132 synaptic events, which canonically have been the leading explanation for the origin of the LFP 133 and depend largely on the activity of the presynaptic population. These events give rise to the 134 general 1/f background. The flat-spectrum signal, we propose, arises from the aggregate spiking 135 activity of the local population, which has been previously cited as a probable contributor to the 136 LFP (Schomburg et al. 2012; Buzsaki et al. 2012). In reality, the two signals are likely 137 interrelated, as changes in presynaptic activity, which are possibly reflected in the broadband 138 shift seen in (Manning et al. 2009; Miller et al. 2007), will certainly cause changes in local 139 population activity. As such, the proposed model will undoubtedly benefit from further empirical 140 work that would delineate the two contributors. From a broader perspective, the new model of 141 the PSD moves from a strictly descriptive point of view to a semi-mechanistic one, with 142 parameters that correspond to physiological variables, thus enabling further theories and testable 143 hypotheses in 

In the following study, I attempt to model funniness as a function of linguistic features. The dataset consists of a subset of 1.6 million Yelp business reviews, each of which can be voted as " funny " by review readers. I design a normalized funniness rating, or F Index, and predict a review's hilarity with n-gram features learned through linear models. The model performs better than baseline, and I observe that the funniest reviews are apparently those involving terrible businesses, bad owners, and horrific dining experiences suffered with one's wife.

6 We explore the role of specific GABAergic current conductance and decay 7 time in specific inhibitory synapses in driving macroscopic cortical 8 oscillations based on two computational neuron models. Simulations using a 9 previously established thalamocortical network model demonstrate that: 1) 10 oscillation frequency changes due to increased inhibitory conductance are 11 dependent on post-synaptic neuron type, 2) changes in inhibitory current 12 decay time have no effect on oscillation frequency, and 3) large changes in 13 inhibitory conductance can produce dynamic changes in the network 14 behavior that is uncaptured by peak oscillation frequency. These results 15 warrant careful treatment of different types of GABA recipients in 16 computational models, and motivate further investigat ion in the effects of 17 substances which promote GABAergic activity, such as propofol. 18

Effects of Inhibitory Synaptic Current Parameters on Thalamocortical Oscillations

An equivalent circuit model (ECM) for capacitance determination of resonant reactive shielding (RRS) coil in magnetic resonant wireless power transfer (MR-WPT) system is proposed in this paper. The magnetic coupling between RRS coil and the transmitting (Tx) coil of a MR-WPT system is analyzed using the proposed ECM. The relationship between the compensative capacitance of RRS coil and the resonant capacitance of Tx coil is deduced and validated using full wave simulation.

Equivalent Circuit Modeling for Capacitance Determination of Resonant Reactive Magnetic Shield in Wireless Power Transfer

This paper presents a study on the design guidelines for the common-mode filters with cavity-backed dumbbell-shaped defected ground structures (CB-DB-DGSs). An equivalent circuit model was first developed to explain the physical insight of the CB-DB-DGS common-mode filter. With the help of the equivalent circuit model, the design parameters of the DGS and the frequency behavior of the filter are correlated. Typical ways to tune the equivalent capacitance and inductance are also explored. As a result, a design guideline towards a CB-DB-DGS filter with desirable frequency responses is developed.

2016 IEEE MTT-S International Conference on Numerical Electromagnetic and Multiphysics Modeling and Optimization (NEMO)

Exploration of design guidelines for cavity-backed dumbbell-shaped DGS common-mode filters

Models for human choice prediction in preference learning and psychophysics often consider only binary response data, requiring many samples to accurately learn preferences or perceptual detection thresholds. The response time (RT) to make each choice captures additional information about the decision process, however existing models incorporating RTs for choice prediction do so in fully parametric settings or over discrete stimulus sets. This is in part because the de-facto standard model for choice RTs, the diffusion decision model (DDM), does not admit tractable, differentiable inference. The DDM thus cannot be easily integrated with flexible models for continuous, multivariate function approximation, particularly Gaussian process (GP) models. We propose a novel differentiable approximation to the DDM likelihood using a family of known, skewed three-parameter distributions. We then use this new likelihood to incorporate RTs into GP models for binary choices. Our RT-choice GPs enable both better latent value estimation and held-out choice prediction relative to baselines, which we demonstrate on three real-world multivariate datasets covering both human psychophysics and preference learning applications.

Response Time Improves Choice Prediction and Function Estimation for Gaussian Process Models of Perception and Preferences

The Model AI Assignments session seeks to gather and disseminate the best assignment designs of the Artificial Intelligence (AI) Education community. Recognizing that assignments form the core of student learning experience, we here present abstracts of nine AI assignments from the 2020 session that are easily adoptable, playfully engaging, and flexible for a variety of instructor needs. Assignment specifications and supporting resources may be found at http://modelai.gettysburg.edu.

How the Internally Organized Direction Sense Is Used to Navigate

Gamma oscillations are readily observed in a variety of brain regions during both waking and sleeping states. Computational models of gamma oscillations typically involve simulations of large networks of synaptically coupled spiking units. These networks can exhibit strongly synchronized gamma behavior, whereby neurons fire in near synchrony on every cycle, or weakly modulated gamma behavior, corresponding to stochastic, sparse firing of the individual units on each cycle of the population gamma rhythm. These spiking models offer valuable biophysical descriptions of gamma oscillations; however, because they involve many individual neuronal units they are limited in their ability to communicate general network-level dynamics. Here we demonstrate that few-variable firing rate models with established synaptic timescales can account for both strongly synchronized and weakly modulated gamma oscillations. These models go beyond the classical formulations of rate models by including at least two dynamic variables per population: firing rate and synaptic activation. The models' flexibility to capture the broad range of gamma behavior depends directly on the timescales that represent recruitment of the excitatory and inhibitory firing rates. In particular, we find that weakly modulated gamma oscillations occur robustly when the recruitment timescale of inhibition is faster than that of excitation. We present our findings by using an extended Wilson-Cowan model and a rate model derived from a network of quadratic integrate-and-fire neurons. These biophysical rate models capture the range of weakly modulated and coherent gamma oscillations observed in spiking network models, while additionally allowing for greater tractability and systems analysis. NEW & NOTEWORTHY Here we develop simple and tractable models of gamma oscillations, a dynamic feature observed throughout much of the brain with significant correlates to behavior and cognitive performance in a variety of experimental contexts. Our models depend on only a few dynamic variables per population, but despite this they qualitatively capture features observed in previous biophysical models of gamma oscillations that involve many individual spiking units.

Experimental and theoretical studies demonstrate that neuronal gamma oscillations crucially depend on interneurons, but current models do not consider the diversity of known interneuron subtypes. Moreover, in CA1 of the hippocampus, experimental evidence indicates the presence of multiple gamma oscillators, two of which may be coordinated by differing interneuron populations. In this article, we show that models of networks with competing interneuron populations with different postsynaptic effects are sufficient to generate, within CA1, distinct oscillatory regimes. We find that strong mutual inhibition between the interneuron populations permits distinct fast and slow gamma states, whereas weak mutual inhibition generates mixed gamma states. We develop idealized firing rate models to illuminate dynamic properties of these competitive gamma networks, and reinforce these concepts with basic spiking models. The models make several explicit predictions about gamma oscillators in CA1. Specifically, interneurons of different subtype phase-lock to different gamma states, and one population of interneurons is silenced and the other active during fast and slow gamma events. Finally, mutual inhibition between interneuron populations is necessary to generate distinct gamma states. Previous experimental studies indicate that fast and slow gamma oscillations reflect different information processing modes, although it is unclear whether these rhythms are intrinsic or imposed. The models outlined demonstrate that basic architectures can locally generate these oscillations, as well as capture other features of fast and slow gamma, including theta-phase preference and spontaneous transitions between gamma states. These models may extend to describe general dynamics in networks with diverse interneuron populations.NEW & NOTEWORTHY The oscillatory coordination of neural signals is crucial to healthy brain function. We have developed an idealized neuronal model that generates distinct fast and slow gamma oscillations, a known feature of the rodent hippocampus. Our work provides a mechanism of this phenomenon, as well as a theoretical framework for future experiments concerning hippocampal gamma. It moreover offers a tractable model of competitive gamma oscillations that is generalizable across the nervous system.

Modeling fast and slow gamma oscillations with interneurons of different subtype.

Distinct and competing interneuron populations can generate fast and slow gamma in oscillatory models of CA1

A Semi-Parametric Model for Decision Making in High-Dimensional Sensory Discrimination Tasks

Successful weed control before seeding is necessary for proper turfgrass establishment. However, herbicide labels differ in the time required between application and seeding. The objective of this research was to determine the influence of four postemergence broadleaf combination herbicides on tall fescue (Festuca arundinacea) cover, normalized difference vegetation index (NDVI), and canopy height when seeded 0, 3, 7, and 14 days after herbicide application. Herbicide treatments included the following: 1) a nontreated control; 2) 0.03 lb/acre carfentrazone-ethyl + 0.09 lb/acre methylchlorophenoxypropionic acid (MCPP) + 1.44 lb/acre 2,4-dichlorophenoxyacetic acid (2,4-D) + 0.30 lb/acre dicamba; 3) 0.20 lb/acre fluroxypyr + 0.01 lb/acre halauxifen-methyl + 1.44 lb/acre 2,4-D choline; 4) 0.20 lb/acre triclopyr + 0.003 lb/acre pyraflufen-ethyl + 1.72 lb/acre 2,4-D + 0.14/acre dicamba; and 5) 0.04 lb/acre penoxsulam + 0.04 lb/acre sulfentrazone + 0.40 lb/acre 2,4-D + 0.11 lb/acre dicamba. Penoxsulam + sulfentrazone + 2,4-D + dicamba reduced tall fescue cover, NDVI, and canopy height compared with the nontreated. This research demonstrates seeding between 0 to 14 days after an application of carfentrazone-ethyl + MCPP + 2,4-D + dicamba, fluroxypyr + halauxifen-methyl + 2,4-D choline, or triclopyr + pyraflufen-ethyl + 2,4-D + dicamba will result in successful tall fescue establishment under the conditions evaluated in these experiments.

Establishment of Tall Fescue Seeded after Postemergence Broadleaf Herbicide Application

Effects of Drip Irrigation and Cultivation Methods on Establishment of Seeded Tall Fescue

Abstract Carfentrazone-ethyl is one of few herbicides labeled for control of silvery-thread moss (STM) in golf course putting greens, but common use rates are up to three times higher than for broadleaf weeds. Our objective was to determine the efficacy of a single POST application of carfentrazone-ethyl for STM control in greenhouse and field dose response studies. In the greenhouse, carfentrazone-ethyl was applied at 0, 14, 28, 56, 112, and 224 g ai ha–1 to pots containing established STM and creeping bentgrass. Percent gametophyte injury was visually estimated at 14, 28, 49, and 77 d after treatment (DAT). Shoot viability was determined by excising shoots from treated pots and plating them in Petri dishes containing sand. The 28- and 49-DAT ED90 (doses required to cause 90% gametophyte injury) were 26.8 and 54.3 g ha–1, respectively; both of these doses are substantially lower than the label rates for long- and short-term control, respectively. All doses reduced the viability of transplanted shoots at 10 DAT compared to untreated STM; however, regrowth occurred in all Petri dishes by 17 DAT. Field studies were initiated in Manhattan, KS and San Luis Obispo, CA to corroborate greenhouse results. Averaged across locations, carfentrazone-ethyl applied at 56 and 112 g ha–1 caused 76% and 84% STM injury at 14 DAT, but STM injury quickly lessened to 45% and 48% by 28 DAT, respectively. In greenhouse and field studies, STM recovery did not occur until 2 wk after treatment (WAT), which indicates the label-stipulated application interval of 2 wk is too short. Our research suggests that 56 g ha–1 can provide similar burndown control of STM as compared to the highest label rate (112 g ha–1), and turfgrass managers should consider extending the reapplication interval to 3 or 4 wk when moss recovery is observed. Nomenclature: Carfentrazone-ethyl; silvery-thread moss; Bryum argenteum Hedw.; creeping bentgrass; Agrostis stolonifera L.

Dose responses of silvery-thread moss (Bryum argenteum) to carfentrazone-ethyl

Effective weed control prior to seeding is essential for proper turfgrass establishment since competition from weeds can cause sward establishment to fail. Herbicides with multiple active ingredients from different chemical families could increase weed control efficacy, but hinder the establishment of newly seeded turf. Research trials were initiated in the fall of 2020 in Olathe and Manhattan, KS, to determine if tall fescue (Schedonorus arundinaceus) could be seeded earlier after application than stated on the herbicide labels. Overall, this study demonstrated that seeding between 0 to 14 days after an application of carfentrazone-ethyl + MCPP + 2,4-D + dicamba (SpeedZone), fluroxypyr + halauxifen-methyl + 2,4-D Choline (GameOn); or triclopyr + pyraflufen-ethyl + 2,4-D + dicamba (4-Speed XT) had little or no effect on tall fescue growth under the conditions evaluated in these experiments. In general, herbicide manufacturers must consider altering label reseeding intervals before using the results reported herein as guidelines.

Emergence and Growth of Tall Fescue Seedlings after Postemergence Broadleaf Herbicide Application

When turfgrass stands are under renovation, a common problem is removing weeds prior to seeding because seedling turf does not emerge and compete well with weeds that are present. However, most herbicide labels recommend waiting for a defined period of time prior to seeding. If seeding is done prior to the date prescribed on the herbicide label, seed germination and seedling growth may be inhibited. A greenhouse study was conducted to determine the effects of irrigation prior to seeding on seedling growth after herbicide application. Overall, irrigation had no influence on the impact of herbicides on shoot or root growth in these greenhouse experiments. Our results suggest delaying seeding by more than 3 days after the application of 2,4-D + MCPP + dicamba (Trimec Classic) may not be necessary.

Influence of Herbicides and Irrigation on Tall Fescue Shoot and Root Growth

Establishing seeded tall fescue with covers and drip irrigation methods

During a lawn renovation, weeds are often a major problem because they grow more aggressively than seedling turf. Turfgrass seedlings need starter fertilizer and plenty of water for proper establishment, which makes an ideal environment for weeds to thrive as well. With current herbicide label restrictions, there are limited weed control strategies during the critical establishment period. Research trials were initiated in the fall of 2019 in Manhattan, KS, to determine if tall fescue (Schedonorus arundinaceus) and Kentucky bluegrass (Poa pratensis) could be seeded into a stand at different intervals after herbicide application before restrictions on the label. The results showed greater than 90% visual coverage of tall fescue seeded at 0, 3, 7, and 14 days after the application of Trimec Classic, Drive 75 DF, and SedgeHammer. Kentucky bluegrass had over 75% coverage at all seeding intervals when treated with Trimec Classic, Drive 75 DF, as well as plots seeded 3 days after the application of SedgeHammer in the Manhattan, KS, field study.

Testing Label Restrictions on Seeding Timings of Tall Fescue and Kentucky Bluegrass after Herbicide Application

Water restrictions on irrigation are generally not science-based and may cause irreversible damage to turfgrass or inadvertently waste water. The objectives of our study were to evaluate effects of minimum water applications to ‘Meyer’ zoysiagrass (Zoysia japonica Steud.) on 1) turfgrass performance during prolonged dry downs; and 2) survival and recovery thereafter. Zoysiagrass was watered with 0, 5, 10, 15, 20, 25, and 30% reference evapotranspiration (ET) replacement for two months in two consecutive summers under an automated rainout shelter (excluded all rainfall) near Manhattan, KS. Results indicated that irrigation at 20 to 30% ET slowed the decline in zoysiagrass performance compared with no water inputs. Irrigation at 30% ET maintained zoysiagrass at >75 percentage green cover (PGC) in the first year, and even with no water inputs (0% ET) or irrigation at only 5% ET replacement, zoysiagrass recovered after full irrigation resumed. In the second year, irrigation at 30% ET maintained zoysiagrass at >25 PGC throughout the dry down and it recovered thereafter, but plots with no water inputs (0% ET) or irrigated with 5% ET replacement only recovered to 30–42 PGC after 50 days of full irrigation. Water restrictions during severe droughts may conserve more water and reduce turfgrass damage by limiting irrigation of zoysiagrass to 20–30% ET than by using traditional standards such as allowing irrigation for only one day per week.

Water Requirements of ‘Meyer’ Zoysiagrass for Survival and Recovery After Prolonged Drought

Minimum water requirements of cool‐season turfgrasses for survival and recovery after prolonged drought

Sodded tall fescue (TF) and Kentucky bluegrass (KBG) turfgrasses were exposed to prolonged drought at several levels of deficit irrigation from 0% to 50% of reference evapotranspiration (ET) within the first year of establishment. Tall fescue watered at 40% and 50% ET maintained minimally acceptable performance longer during the dry-down phases and recovered faster after rewatering than lower ET treatments. Tall fescue with no water input (0% ET) maintained minimally acceptable performance for about 5 weeks, which was longer than KBG watered at 50% ET, which remained acceptable for less than 3 weeks during the dry down. Although KBG watered at 50% ET performed best among irrigation treatments for a short period, all treatments went into dormancy similarly in 6–9 weeks and didn’t recover after rewatering in either year. In both years of this study, TF and KBG were sodded the prior fall and thus, had been established for less than 1 year before exposure to severe drought and deficit irrigation. Results indicate that under the conditions of this study (i.e., limited or no irrigation during the first summer after fall sodding in good soil (silty clay loam) of the transition zone of Kansas), TF is a better selection than KBG.

Minimal Water Requirements of Cool-Season Turfgrasses for Survival and Recovery After Prolonged Drought

Abstract Silvery-Thread Moss (Bryum argenteum Hedw.) is an undesirable invader of golf course putting greens across North America, establishing colonies and proliferating despite practices to suppress it. The goal was to grow genotypes of green (growing in putting greens) and native (growing in habitats outside of putting greens) B. argenteum in a common garden experiment, allowing an experimental test of life-history traits between genotypes from these two habitats. Seventeen collections of green and 17 collections of native B. argenteum were cloned to single genotypes and raised through a minimum of two asexual generations in the lab. A culture of each genotype was initiated using a single detached shoot apex and was allowed to grow for 6 mo under conditions of inorganic nutrients present and absent. Compared with genotypes from native habitats, genotypes of B. argenteum from putting greens exhibited earlier shoot regeneration and shoot induction, faster protonemal extension, longer (higher) shoots, lower production of gemmae and bulbils, and greater aerial rhizoid cover, and showed similar tendencies of chlorophyll fluorescence properties and chlorophyll content. Cultures receiving no inorganic nutrients produced less chlorophyll content, greatly reduced growth, and bleaching of shoots. Mosses from putting greens establish more quickly, grow faster, produce more abundant rhizoids, and yet do not produce as many specialized asexual propagules compared with mosses of the same species from native habitats. The highly managed putting green environment has either selected for a suite of traits that allow the moss to effectively compete with grasses, or genotypic diversity is very high in this species, allowing a set of specialized genotypes to colonize the putting green from native habitats. Successful golf course weeds have been able to adapt to this highly competitive environment by selection acting on traits or genotypes to produce plants more successful in competing with golf course grasses.

Divergence in Life-History and Developmental Traits in Silvery-Thread Moss (Bryum argenteum Hedw.) Genotypes between Golf Course Putting Greens and Native Habitats

Mowing Height and Cultivation Effects on Tall Fescue Conversion to Buffalograss

Buffalograss Divot Recovery as Affected by Nitrogen Source and Rate

Cultivation Reduces Infestation of Silvery‐Thread Moss in a Creeping Bentgrass Putting Green

Percent green cover will ultimately decrease over time when traffic is applied to dormant buffalograss with turfgrass colorants. Data suggests that an additional five weeks of acceptable green cover can be achieved under high traffic situations when Endurant Premium is applied to dormant turf.

Evaluating the Effects of Simulated Golf Cart Traffic on Dormant Buffalograss and Turfgrass Colorants

Abstract Many bryophytes are intolerant of osmotic stresses; nevertheless, Bryum argenteum often spreads in golf course greens irrigated with water containing a moderate amount of sodium and/or bicarbonates. The ability of B. argenteum to survive in this stressful environment could be linked to the use of acid injection systems, which are often retrofitted to irrigation systems to combat the negative effects of these harmful salts. The objective of this study was to determine if altering the pH of sodic irrigation water using either sulfuric or hydrochloric acid affects the growth of B. argenteum. Secondarily, if growth of B. argenteum was affected, we sought to understand whether that effect was due to differences in nutrient uptake or availability under the different water pHs and/or acidifying sources. Phosphate buffer solutions (0.01 M, pH  =  9) were titrated with each acid to obtain pHs 5, 6, 7 and 8. Irrigation solutions were applied daily to pots containing a sand substrate and nascent B. argenteum for 28 d. Acid source had no effect on moss cover, but pH significantly affected B. argenteum cover. Generally, pots irrigated with pHs 5 and 6 had six- to seven-fold increases in B. argenteum cover compared to pHs 7 and 8. Additionally, the shoot tissue of pots treated with pH 5 contained twice as much potassium compared to pots irrigated with pH 9. These results indicate the growth of B. argenteum increases when acid injection systems are used to amend sodic irrigation water.

Effect of irrigation water pH and acidifying source on silvery-thread moss (Bryum argenteum Hedw.) establishment

All treatments, except the control that received no glyphosate application, resulted in acceptable buffalograss establishment (>90% buffalograss green cover) by 70 days after seeding (DAS). However, any treatment not sprayed prior to seeding date or that received a 7 DAS application lagged behind in establishment for 6 weeks after seeding.

Influence of Glyphosate Timings on Conversion of Golf Course Rough from Tall Fescue to ‘Sharps Improved II’ Buffalograss

C ONTROLLING AND PREVENTING the spread of silvery-thread moss (Bryum argenteum Hedw.) in golf course putting greens is a diicult task for superintendents. Bryum argenteum is undesirable because it can negatively afect ball roll and surface uniformity. he prevalence of B. argenteum in golf course putting greens has received attention from several researchers in recent decades (Boesch and Mitkowski, 2005; Borst et al., 2010; Kennelly et al., 2010; hompson et al., 2011). Although no published research has directly established a connection between mercury-based fungicides and the prevalence of B. argenteum on putting greens, some researchers speculate the discontinued use of mercury-based fungicides plays an important role (Boesch and Mitkowski, 2005; Borst et al., 2010; Burnell et al., 2004; Happ, 1998; Rossi, 2002; Yelverton, 2005) because bryophytes are relatively intolerant of heavy metals (Weber and McAvoy, 2003). Additionally, in recent decades there have been improvements in equipment technology, nutrient management, putting green construction, and changes in golfer expectations that have inluenced the intensity and scope of cultural practices utilized by golf course superintendents. It is likely several of these cultural practices are impacting the establishment and infestation of B. argenteum (Kennelly et al., 2010; hompson et al., 2011). Furthermore, a thorough understanding of a target weed’s biology, morphology, and physiology is essential to formulating hypotheses for testing best management practices for efective weed control (Radosevich et al., 2007; Sutherland, 2004). herefore, the objective of this literature review is to discuss relevant biological and ecological traits of B. argenteum and how they potentially interact with current turfgrass management practices utilized by golf course superintendents. With this information, researchers and practitioners will be better equipped to develop successful longterm management strategies for B. argenteum in golf course putting greens. Published in Crop, Forage & Turfgrass Management DOI: 10.2134/cftm2014.0094 © 2015 American Society of Agronomy and Crop Science Society of America 5585 Guilford Rd., Madison, WI 53711

A Review: Establishment, Dispersal, and Management of Silvery‐thread Moss (Bryum argenteum Hedw.) in Putting Greens

Lawn care and lawn watering practices of residential homeowners were significantly affected by home value and home age, but lot size was less a factor.

Effects of Home Value, Home Age, and Lot Size on Lawn Watering Practices of Residential Homeowners

Effect of Nitrogen Source and Spray Volume on the Establishment and Colonization of Silvery‐Thread Moss (Bryum argenteum Hedw.) in Putting Greens

S UMMARY . Urbanization is increasing the land area covered with turfgrasses, which may affect water quantity and quality. Our objective was to understand lawn-watering habits of homeowners in Olathe and Wichita, KS, based on home value, home age, and lot size. Surveys were mailed to 9992 homeowners in Olathe and 15,534 in Wichita, with a return rate of 12%. Owners of more expensive and/or newer homes were more likely to water frequently, water on a routine schedule, feel it was important to have a green lawn, have an in-ground sprinkler system, and sweep or blow grass clippings and lawn care products off impervious surfaces. Owners of less expensive and/or older homes were more likely to never water or water infrequently, water based on the lawn’s appearance rather than on a routine schedule, consider it less important to have a green lawn; not have an in-ground sprinkler system, and leave grass clippings and lawn care products on impervious surfaces rather than blowing them off. A small percentage of homeowners who swept or blew clippings and/or lawn-care products did so into streets/storm drains. Owners of less expensive and/or older homes were somewhat more likely to engage in this practice. Educational efforts to improve lawn water conservation should be concentrated on homeowners in more expensive and/or newer homes because they water more frequently and routinely. Efforts to protect surface water quality should include homeowners of less expensive and/or older homes.

Effects of Home Value, Home Age, and Lot Size on Lawn-watering Perceptions and Behaviors of Residential Homeowners

Application of 2 and 3 lb N/1,000 ft2 resulted in acceptable buffalograss quality when subjected to simulated golf cart traffic. Across all fertilizer treatments, traffic rates of 8 and 16 passes per week resulted in unacceptable quality ratings for the study duration.

Influence of Simulated Golf Cart Traffic and Nitrogen Rate on Buffalograss Quality

Application of quick-release nitrogen fertilizer increased buffalograss divot recovery. A quick-release fertilizer at 1 lb N/1,000 ft2 resulted in 50% divot recovery 6.3 days quicker compared to the untreated control.

Influence of Fertilizer Source and Rate on Buffalograss Divot Recovery

This report is brought to you for free and open access by New Prairie Press. It has been accepted for inclusion in Kansas Agricultural Experiment Station Research Reports by an authorized administrator of New Prairie Press. Copyright January 2015 Kansas State University Agricultural Experiment Station and Cooperative Extension Service.

Response and Recovery Characteristics of Kentucky Bluegrass Cultivars to Extended Drought

Combined Effects of Topdressing, Cultivation, and Carfentrazone-ethyl on Silvery-Thread Moss Infestation

Slit-seeding buffalograss provided the quickest (85% cover, 8 weeks after seeding) establishment of all the cultivation practices. Mowing height had no effect on establishment success.

Influence of Cultivation Practice and Mowing Height on Conversion of Golf Course Rough from Tall Fescue to ‘Sharps Improved II’ Buffalograss

Volatility of Broadleaf Weed Herbicides When Applied to Turfgrass

Although spring is not considered the optimal time for herbicidal control of most cool-season broadleaf weeds in turfgrass, spring applications are often required. Most new postemergence broadleaf herbicides combine several active ingredients, possibly resulting in synergistic, antagonistic, or additive effects. Therefore, as new herbicides become available, information is needed about their performance when applied in the spring. The objective of our study was to determine the effect of spring application timing on dandelion control with seven commercially available postemergence herbicides. Products were applied at their lowest labeled rate for dandelion control at three spring application timings, which coincided with dandelion anthesis stages (pre-, peak-, or post-bloom). A grid was used to determine percent dandelion control at several rating dates. The 2010 site had a denser turfgrass stand with smaller dandelions and was irrigated more frequently compared with the 2011 site. In 2010, all herbicides gave 98% or greater control at 30 days after treatment (DAT) when applied post-bloom; when applied preor peak-bloom, control was 80% or greater for all herbicides except for two products applied peak-bloom. At preand peak-bloom, products combining a protoporphyrinogen oxidase (PPO) inhibitor with a 2,4-D ester formulation were superior to most other herbicides. When evaluated at the end of the growing season in 2010, all herbicides provided 89% or greater control at all three timings. In 2011, with a less dense turfgrass stand, larger dandelions, and less frequent irrigation, control was more variable and shorter-lived among herbicides. When applied pre-bloom, all products containing 2,4-D provided 87% or greater control 60 DAT. Post-bloom application generally gave similar control to the pre-bloom timing. Peak-bloom application resulted in the poorest overall control at 60 DAT, but products combining a PPO inhibitor with a 2,4-D ester formulation performed better than most other herbicides. By the end of the season, dandelion regrowth caused reduced overall control at all timings, but overall control was poorest when applied at peak-bloom. In summary, peak-bloom applications should be avoided, especially if dandelion pressure is high. Products combining PPO inhibitors with ester forms of 2,4-D were most effective across all spring application timings. Products containing amine forms of 2,4-D may provide effective control if applied preor post-bloom. Common dandelion (Taraxacum officinale Weber) is one of the most widely recognized weeds of turfgrass. It is a simple perennial, forming a basal rosette of leaves and bright yellow flowers (Uva et al., 1997). Dandelions can reproduce through wind-dispersed seeds or from taproot fragments (McCarty et al., 2001). Dandelions are apomictic, so pollination is not needed to produce viable seeds (Uva et al., 1997). The wind-dispersed seeds can travel long distances and infest previously weed-free areas. Mechanical control of dandelion is difficult because the taproot must effectively be removed or destroyed. A study comparing dandelion control with 2,4-D and mechanical treatments found no measure of control was achieved with hand-weeding alone (Mann, 1981). Many turf managers have achieved acceptable dandelion control using selective herbicides (Christians, 2007; Gardner, 2009; Loughner and Nolting, 2010). Most products used for broadleaf weed control in turfgrass are combination products that contain several active ingredients, which allow turf managers to control a wide array of broadleaf weeds with a single product. However, because the interaction between active ingredients may be additive, synergistic, or antagonistic when combined (Zhang et al., 1995), it is difficult to predict the performance of a new combination herbicide based on the performance of its components applied singly. Many of the active ingredients found in these products such as 2,4-D, dicamba, mecoprop, clopyralid, fluroxypyr, and triclopyr are in the synthetic auxin class of herbicides (Senseman, 2007). Synthetic auxin herbicides are highly selective because most grasses can inactivate these compounds by conjugation, whereas broadleaf weeds cannot and thus are controlled. In recent years, some products have also included an active ingredient from the PPO-inhibiting class such as pyraflufen-ethyl, carfentrazone-ethyl, or sulfentrazone (Senseman, 2007). These compounds inhibit PPO, an enzyme in chlorophyll synthesis needed for catalyzing the oxidation of protoporphyrinogen IX to protoporphyrin IX (Cobb and Reade, 2010). Inhibition of PPO causes an increase in both triplet and singlet state oxygen, resulting in cellular leakage through lipid peroxidation (Senseman, 2007). One reason PPO inhibitors may be included in tank mixes with synthetic auxin herbicides is to provide more rapid necrosis of foliage. Many researchers have reported acceptable control of perennial broadleaf weeds using such combination products (Haley et al., 1995; Loughner and Nolting, 2010; Olson and Hall, 1988; Reicher and Weisnenberger, 2007; Watschke and Borger, 1999). However, previous research has shown that PPO inhibitors can reduce the efficacy of some non-phenoxy herbicides. Ashigh and Hall (2010) reported reduced glyphosate activity when combined with the PPO inhibitor saflufenacil and hypothesized the rapid contact activity of saflufenacil limited the translocation of glyphosate. Similarly, a study conducted by Breeden and McElroy (2006) found that carfentrazone significantly reduced white clover (Trifolium repens L.) control when tank-mixed with foramsulfuron compared with foramsulfuron alone. Fall is considered the best time for herbicidal control of cool-season perennial broadleaf weeds in turfgrass (Branham, 1990; McCarty et al., 2001; Reicher and Weisnenberger, 2007; Wilson and Michiels, 2003). Branham (1990) posited that herbicidal control in the fall is effective because plants are moving carbohydrate reserves to underground storage structures, which is believed to aid in the movement of xenobiotics to their site of action. However, although fall applications may be optimal, turf managers frequently need herbicidal options in the spring to meet clients’ expectations. Spring herbicide applications coincide with one of three dandelion anthesis stages: pre-bloom, peak-bloom, or post-bloom. To the casual observer, the extent of a dandelion infestation may not be apparent until the flush of bright flowers occurs during the bloom stage. Gray et al. (1973) reported less than one flowering dandelion stem/m in the first 13 weeks of the growing in a home lawn in Kentucky; however, in the fourteenth week (4 to 10 Apr.), flowering increased to 68 stems/m. Unfortunately, dandelion control may be reduced if herbicides are applied during the Received for publication 2 Mar. 2014. Accepted for publication 15 July 2014. Mention of a trademark, proprietary product, or vendor does not constitute a guarantee or warranty of the product(s) by Kansas State University and does not imply its approval to the exclusion of other products or vendors that also may be suitable. Graduate Research Assistant. Professor. To whom reprint requests should be addressed; e-mail zane12@ksu.edu. 1212 HORTSCIENCE VOL. 49(9) SEPTEMBER 2014 production of flowers and seeds (Schleicher, 1997). The movement of auxinic herbicides in plants is largely controlled by the physiochemical properties of the herbicide such as pKa and log Kow values (Cobb and Reade, 2010). Once absorbed into the shoot of a susceptible plant, auxinic herbicides such as 2,4-D (pKa = 2.8) typically exist as a free acid because cellular pH is 5.0 (Sterling, 1994). The non-ionized 2,4-D molecules can readily pass through the cell membrane and into the phloem. However, phloem pH is higher ( 8.0), and incoming 2,4-D molecules are immediately ionized and essentially ‘‘trapped’’ because anions have reduced membrane permeability (Sterling and Hall, 1997). Once trapped in the phloem, the movement of the 2,4-D anion is passive and primarily determined by the strength of source-to-sink partitioning (Cobb and Reade, 2010). In perennial weeds, underground storage structures may become a strong sink for surplus photosynthate produced in mature leaves (Coble et al., 1970), which is believed to enhance the efficacy of herbicide applications by increasing basipetal movement of weak-acid herbicides to underground storage organs (Tworkoski, 1992). Oppositely, during anthesis, the production of flowers and seeds is likely a major sink for photosynthate; therefore, basipetal movement of auxinic herbicides may be limited, resulting in reduced control. Turf managers need information on herbicide performance in the spring, and our literature search revealed no reports in the refereed literature concerning the influence of spring application timing on dandelion control with postemergence broadleaf herbicides currently used on turfgrass. Furthermore, because these herbicides typically contain multiple active ingredients that may be additive, synergistic, or antagonistic, each combination herbicide itself should be tested rather than testing its individual components. Therefore, the objective of our study was to determine the effect of spring application timing on dandelion control with seven commercially available postemergence broadleaf herbicides. Materials and Methods Site characteristics and experimental design. Field studies were conducted in 2010 and 2011 on adjacent sites at the Rocky Ford Turfgrass Research Center in Manhattan, KS. The soil at both sites was a Chase Silt Loam (fine, smectitic, mesic, Aquertic Argiudoll) with a pH of 6.9. Soil tests indicated adequate levels of phosphorus and potassium. The 1.2 · 1.8-m plots were mown at 7.6 cm. The 2010 site contained turf-type tall fescue (Festuca arundinacea Schreb. Syn Schedonorous arundinaceus Schreb.) with an existing dandelion stand and was irrigated

Springtime Dandelion (Taraxacum officinale) Control with Seven Postemergence Herbicides Applied at Three Anthesis Stages

Distance education and the number of courses offered online have grown rapidly in recent years. A survey method was developed to measure student learning in an online course entitled “Water Issues in the Lawn and Landscape” offered at Kansas State University. This course examines critical water issues related to irrigation in urbanizing watersheds and is designed for students and industry professionals who want to enhance their knowledge and careers through distance education. This class is co-taught by four professors, each contributing from their area of expertise. In addition to conveying relevant content to students, the instructors focused on the process in which the material was presented. Specifically, they emphasized creating sense and meaning while developing each assignment and lecture. If a lecture makes sense and has meaning for the learner, the probability of retaining information may be higher. A pre- and post-test was used to measure the level of student learning in each of seven course modules, and surveys were used to evaluate the level of sense and meaning that each lecture, assignment, and exam had for the students. Scores increased from pre- to post-test, indicating the students learned concepts presented in the modules. Survey results revealed that 87% of the course content made sense and 80% had meaning for the students. Within these high values of sense and meaning, student learning improved as meaning increased but was unaffected by sense.

Assessing Student Learning with Surveys and a Pre-Test/Post-Test in an Online Course

Urbanization is increasing the land area covered with turfgrasses, which may have implications for water quantity and quality. The largest sector of turfgrass is residential lawns. Our objectives were to survey residential homeowners in three Kansas cities about their perceptions, knowledge, and behaviors when irrigating their lawns; each city has distinctive water quantity and quality issues. Surveys were mailed to 15,500 homeowners in Wichita, 10,000 in Olathe, and 5,000 in Salina; the return rate was 11-13%. Wichita residents watered more frequently than Olathe and Salina, possibly because of greater evaporative demand than Olathe, and cheaper water and less concern about water shortages than Salina; Salina and Wichita have similar evaporative demands but Salina had a recent water crisis. Salina homeowners were most concerned about keeping their water bill from getting too high, probably because of higher water costs than the other cities. Overall, 45-60% indicated it was moderately to very important their lawns looked green all the time, while 65-77% ranked water conservation at the same level of importance. Significantly, 61-63% did not know how much water their lawns required and 71-77% did not know how much water they applied to their lawns when they irrigated. About 7-9% swept or blew clippings or lawn-care products directly into streets or storm drains, which run directly into local streams or reservoirs; 9% in Wichita is ~9,000 homeowners. The homeowner’s lawn irrigation knowledge and habits must be improved to help conserve water and protect water quality. INTRODUCTION With urbanization, significant tracts of natural ecosystem and agricultural land are being replaced with turfgrass (U.S. Geological Survey, 1999; Alig et al., 2004). In the United States, turfgrasses are estimated to cover 16 to 20 million ha of urbanized land, or up to 18% of the land area in some regions (Morris, 2003; National Agricultural Statistics Service, 2004, 2006); this represents an area three times larger than any irrigated crop (Milesi et al., 2005). Furthermore, urbanization in the USA and elsewhere is projected to continue to increase rapidly (Alig et al., 2004), indicating a continued expansion of land area covered with turfgrasses. The rapid increase of turfgrass in the landscape may have significant implications for water quality and quantity. A number of studies have linked urbanization with declining water quality in surface and ground water reservoirs due to increased concentrations of nutrients and pesticides, some of which are used in lawns (King and Balogh, 2001; U.S. Geological Survey, 2001; Hamilton et al., 2004; Petrovic and Easton, 2005). Irrigation of turfgrass is typical in many urban areas, which increases demand for water resources. Water scarcity is most critical in arid or semi-arid regions experiencing rapid urban growth (Reisner, 1993). Water quality in urban areas may be affected by runoff or leaching of fertilizer nutrients and pesticides from lawns, but runoff from impervious surfaces is the greatest concern. Runoff from lawns or impervious surfaces may happen during intense rainstorms, when turfgrass is over irrigated, or when irrigation systems are improperly adjusted (Morton et al., 1988; Petrovic, 1990; Brezonik and Stadelmann, 2002). The extent of excessively irrigated turfgrass is not known, but apparently over irrigation has altered the hydrologic system of the Las Vegas Valley such that historically ephemeral washes have become perennial streams in urbanized areas (Mizell and French, 1995). This indicates a critical need to change the behavior of urbanites to reduce their irrigation inputs and thus, conserve water and improve water quality. The greatest opportunity for conserving water and minimizing runoff and leaching in urban areas may be in residential lawns. From 50% to as much as 80% of all land area covered with turfgrass in the US is composed of residential lawns (Grounds Maintenance, 1996; National Agricultural Statistics Service, 2004, 2006), and up to 75% of residential water use may be for outdoor purposes (Vickers et al., 2001). Improper perceptions about water requirements for turfgrass or embellished expectations about lawn appearance (e.g., maintaining perfectly green lawns even during drought) may result in over-irrigation. Data are lacking, however, to quantify the prevalence of such perceptions, including how they affect lawn-watering practices. Presumably, the perceptions and practices of homeowners about lawn watering may be influenced by a number of factors including demographics, local climate, water costs, water shortages, etc. Consequently, a first step towards improving water quality and conservation in urban watersheds is to carefully evaluate fundamental perceptions and practices of homeowners in watering their lawns. Our objectives were to understand the perceptions, knowledge, and behaviors of residential homeowners about the irrigation of their lawns during summer months. In this study, we surveyed residential homeowners in three separate Dale J. Bremer, Steven J. Keeley and Jack D. Fry, Dept. of Horticulture, Forestry and Recreation Resources, Kansas State University, Manhattan, KS 66506 USA; Abigail Jager, Dept. of Statistics, Kansas State University, Manhattan, KS 66506 USA. Contribution no. 12-411-J from the Kansas Agric. Exp. Station. *Corresponding author: (bremer@ksu.edu).

Lawn-watering perceptions and behaviors of residential homeowners in three Kansas (USA) cities: implications for water quantity and quality

A critical challenge facing the turf industry is increasingly limited water supplies. Identifying cultivars that use less water while maintaining acceptable quality may mitigate irrigation demands. Our objectives were to identify Kentucky bluegrass (Poa pratensis L.) (KBG) cultivars and phenotypic groups that maintained better visual quality with less water. Thirty bluegrass selections were evaluated in a 2-yr field study under a rainout shelter near Manhattan, KS. Irrigation (2.5 cm) was applied when >50% of a plot exhibited visible wilt symptoms. Visual quality was rated daily. Average irrigation applications ranged widely from 23.3 cm (mean = 2.2 mm d⁻¹) in Bedazzled to 44.9 cm (mean = 4.2 mm d⁻¹) in Kenblue, and days to wilt between irrigations ranged from 6.4 d in Kenblue to 13.1 d in Cabernet. Visual quality averaged at or slightly below 6.0, defined as “minimally acceptable,” but this may be adequate when water conservation is a priority and some dormancy is tolerable; irrigation at <50% wilt is recommended for improved quality. Based on statistical range tests, 15 of the 30 cultivars were grouped as both receiving the least water and having the greatest visual quality. Overall, the Compact America and Mid-Atlantic KBG groups exhibited the greatest days to wilt and received the least water. Results suggest that Compact America and Mid-Atlantic phenotypes have the greatest potential for integrating reduced water inputs with maintenance of acceptable visual quality.

Wilt‐Based Irrigation in Kentucky Bluegrass: Effects on Visual Quality and Irrigation Amounts Among Cultivars

A Comparison of Web-Based and Traditional Instruction for Teaching Turfgrass Identification1

Urbanization is increasing the land area covered with turfgrasses, which may have implications for water quantity and quality. The largest sector of turfgrass is residential lawns. Our objectives were to compare lawn-irrigation perceptions, knowledge, and behaviors of residential homeowners with and without in-ground sprinkler systems (IGS and NIGS, respectively); homeowners were surveyed in three Kansas cities, each with distinctive water quantity and quality issues. Surveys were mailed to 15,500 homeowners in Wichita, 10,000 in Olathe, and 5000 in Salina; the return rate was 11% to 13%. Homeowners with IGS watered more frequently than NIGS; 67% to 90% of IGS and 19% to 31% of NIGS homeowners watered two to three times per week or more. More IGS homeowners watered routinely and applied the same amount of water each time than NIGS homeowners, who mostly watered and adjusted watering amounts based on lawn dryness. More IGS than NIGS homeowners wanted their lawn green all the time, followed lawncare guidelines, and considered their neighborhood appearance important. Among IGS homeowners, 41% to 54% claimed to know how much water their lawns required compared with only 29% to 33% of NIGS homeowners. However, 65% to 83% in both groups did not know how much water they applied when they irrigated. About 7% to 9% of homeowners swept or blew clippings or lawn-care products into streets or storm drains; this percentage was unaffected by whether they had IGS or not. All homeowners’ lawn irrigation knowledge and habits must be improved to help conserve water and protect water quality, but educational efforts should concentrate on IGS homeowners because they water more frequently.

In-ground irrigation systems affect lawn-watering behaviors of residential homeowners

Relationships between NDVI and visual quality 1 in turfgrasses : Effects of mowing height 2 3 4

Normalized difference vegetation index (NDVI, computed as [near infrared (NIR) – Red)]/[NIR + Red]) may provide an objective means to evaluate visual quality of turfgrass. The NDVI is infl uenced by red (visible) and NIR refl ectance (invisible), but each may respond differently to environmental factors; basic information is lacking about the two components in relation to turf quality. In this 3-yr study near Manhattan, KS, we examined relationships of NDVI and its component refl ectances along with visual quality ratings in Kentucky bluegrass (Poa pratensis L., ‘Apollo’), two Kentucky bluegrass × Texas bluegrass (Poa arachnifera Torr.) hybrids (‘Thermal Blue’ and ‘Reveille’), and tall fescue (Festuca arundinacea Schreb., ‘Dynasty’). Percentage green cover was measured with digital image analysis and shoot density was estimated visually to evaluate their impacts on turf quality and refl ectance. Differences in NDVI and red and NIR refl ectances were observed among turfgrasses at each level of quality. Across the range of turf quality, NDVI was infl uenced more strongly by red than NIR refl ectance. Red refl ectance was strongly affected by density (r = 0.85) and green cover (r = 0.86); NIR refl ectance was affected by density (r = 0.63) but negligibly by green cover. Results suggest other fundamental factors that are poorly understood may be affecting NIR refl ectance and, hence, NDVI in turf. These factors may confound relationships between NDVI and turf quality and require further study.

Relationships between Normalized Difference Vegetation Index and Visual Quality in Cool‐Season Turfgrass: II. Factors Affecting NDVI and its Component Reflectances

Canopy spectral refl ectance may provide an objective means to evaluate visual quality of turfgrass, but evaluations of quality may be confounded by cultural practices that affect refl ectance, such as mowing height. In this 2-yr study near Manhattan, KS, we examined effects of mowing height on relationships between normalized difference vegetation index (NDVI) and visual quality ratings in Kentucky bluegrass (KBG; Poa pratensis L., ‘Apollo’) and in a KBG × Texas bluegrass (Poa arachnifera Torr.) hybrid (HBG; ‘Thermal Blue’). Mowing heights were 7.62 cm (high) and 3.81 cm (low). The NDVI averaged 4.5 to 7% greater in high- than in low-mown plots. Distinct regression models of visual quality were found at each mowing height and in each species (r 2 from 0.40 to 0.81); separate relationships between NDVI and visual quality were also found between years in the same plots. Correlations between NDVI and visual quality were stronger at high than at low mowing heights, possibly because of greater green biomass at high mowing heights. The 95% confi dence intervals surrounding predictions of visual quality from NDVI ranged from ±1.34 to 2.75 (on a 1-to-9 scale). Thus, lack of precision is a concern when using these models for detection of differences between treatments. Results indicate that when using NDVI to evaluate turfgrass quality, evaluations should be limited to plots maintained at the same mowing height and with the same species to reduce variability in NDVI.

Relationships between Normalized Difference Vegetation Index and Visual Quality in Turfgrasses: Effects of Mowing Height

Canopy spectral refl ectance may provide an objective means to evaluate visual quality of turfgrass, but evaluations of visual quality may be confounded by differences in refl ectance among species or cultivars. In this 3-yr study near Manhattan, KS, we examined effects of species and cultivars on relationships between normalized difference vegetation index (NDVI) and visual quality ratings in Kentucky bluegrass (Poa pratensis L., ‘Apollo’), two Kentucky bluegrass × Texas bluegrass (Poa arachnifera Torr.) hybrids (‘Thermal Blue’ and ‘Reveille’), and tall fescue (Festuca arundinacea Schreb., ‘Dynasty’). A broad range of visual quality was imposed on all four grasses through defi cit irrigation and NDVI was measured using broadband spectral radiometry across this range for each grass. Distinct linear regression models of visual quality were found for each grass, and models were also distinct among years in each grass. Relationships between NDVI and visual quality were stronger in the bluegrasses (r2 = 0.41 to 0.83) because they had a greater range in quality under defi cit irrigation than tall fescue. The 95% confi dence intervals surrounding predictions of visual quality from NDVI ranged from ± 1.25 to 2.10 (on a 1 to 9 scale). Results indicated that the requirement to develop separate models for each grass and in each year, combined with relatively wide confi dence intervals, represents a practical limitation to predicting visual quality with NDVI. D.J. Bremer and S.J. Keeley, Dep. of Horticulture, Forestry & Recreation Resources, 2021 Throckmorton Hall, Kansas State Univ., Manhattan, KS 66506; H. Lee, Dep. of Plant Pathology, 4024 Throckmorton Hall, Kansas State Univ., Manhattan, KS 66506; K. Su, Dep. of Horticulture and Landscape Architecture, Oklahoma State Univ., Stillwater, OK 74078. Contribution no. 11-181-J from the Kansas Agric. Exp. Station. Received 23 Dec. 2010. *Corresponding author (bremer@ksu.edu). Abbreviations: NDVI, normalized diff erence vegetation index; R661, refl ectance at 661 nm; R935, refl ectance at 935 nm. Published in Crop Sci. 51:2212–2218 (2011). doi: 10.2135/cropsci2010.12.0728 Published online 6 July 2011. © Crop Science Society of America | 5585 Guilford Rd., Madison, WI 53711 USA All rights reserved. No part of this periodical may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permission for printing and for reprinting the material contained herein has been obtained by the publisher.

Relationships between Normalized Difference Vegetation Index and Visual Quality in Cool‐Season Turfgrass: I. Variation among Species and Cultivars

The area of land covered with turfgrasses is increasing with urbanization, which has significant implications for water quantity and quality. Excessive irrigation may waste limited water resources and increase leaching or runoff of lawn chemicals into the environment. Residential lawns represent the largest sector of turfgrass cover and the greatest opportunity for reducing water waste and detrimental impacts on water quality in urban areas. Our objectives were to investigate perceptions of homeowners about their lawns and their lawn-irrigation behaviors in three metropolitan areas in Kansas, USA, each with distinct water quantity and quality issues. Survey responses were received from 1,885 residential homeowners in Wichita, 1,297 in Olathe, and 757 in Salina. Seventy one to 77% of homeowners did not know how much water they were applying when irrigating their lawns, and more than 60% did not know how much water their lawns required during hot summer months. This indicates a need for basic education about lawn-irrigation requirements and irrigation auditing of their sprinkler systems. More than half of all homeowners felt it was moderately to very important that their lawns looked green all the time, regardless of weather conditions. Nevertheless, 63 to 79% felt that water conservation was moderately to very important, indicating a willingness to adapt water-saving lawn-irrigation practices. The relevance of this project to the goals of NIWQP is to use survey results along with related research to develop educational and extension programs aimed at water conservation and improvement of water quality in urbanizing watersheds.

Residential Homeowners: How Much Do They Know about Watering their Lawns?

Drought stress is common among cool-season turfgrasses during summer in the U.S. transition zone. A two-year field study was conducted near Manhattan, Kansas, USA, to evaluate rooting characteristics and effects of drought on canopy physiology and appearance of ‘Apollo’ Kentucky bluegrass (Poa pratensis L.) (KBG), ‘Dynasty’ tall fescue (Festuca arundincea Schreb.) (TF), and two hybrid bluegrasses (HBG) ‘Reveille’ and ‘Thermal Blue’; HBG are genetic crosses between native Texas bluegrass (Poa arachnifera Torr.) and KBG. Rooting characteristics were measured in the field and greenhouse under well-watered conditions to evaluate root contributions to drought avoidance. Two irrigation treatments in the field included: 1) 60% (water-deficit); and 2) 100% (well-watered) evapotranspiration (ET) replacement. Ninety to 96% of all root length (0-80 cm) in the field and 74 to 80% of all root length (0-120 cm) in the greenhouse were in the upper 30 cm among Thermal Blue, Reveille, and KBG while in TF, only 86% and 70% of all root length in the field and greenhouse, respectively, were in the top 30 cm. In the field, tall fescue had 3 to 12 times greater root length in the lower profile (60-80 cm) among turfgrasses. Visual quality and gross photosynthesis (Pg) were greatest in TF among turfgrasses in both irrigation treatments. Reveille used more water from the 0-50 cm profile and performed better than Thermal Blue during water-deficit, but both HBG recovered from waterdeficit slightly faster than KBG. Performances in visual quality and Pg generally ranked: TF > Reveille ≥ Thermal Blue = KBG.

Rooting Characteristics and Responses of Photosynthesis to Irrigation Deficit of Two Hybrid Bluegrasses, Kentucky Bluegrass, and Tall Fescue

Hybrid bluegrasses (HBG) resemble Kentucky bluegrass (Poa pratensis L.)(KBG) but HBG may have greater heat and drought tolerance. Little is known about the performance of HBG under low mowing heights and during drought. A two-year field study was conducted near Manhattan, Kansas, USA to investigate effects of mowing and drought on visual quality and gross canopy photosynthesis (Pg) in a KBG (‘Apollo’) and HBG (‘Thermal Blue’). Treatments included three main factors at two levels each: 1) species (Apollo, Thermal Blue); 2) mowing height (7.6 cm or 3.8 cm); and 3) irrigation (100% [well watered] and 60% [drought] evapotranspiration [ET] replacement). Visual quality in Thermal Blue was similar to or lower than Apollo during both years. Visual quality and Pg declined at the lower mowing height in both species in 2004 and in Thermal Blue in 2005, but visual quality in Apollo improved slightly in 2005 including under drought. At the lower mowing height, visual quality in Thermal Blue was nine to 15% lower than Apollo in 2005, perhaps because KBG had greater leaf area and extracted more soil moisture than Thermal Blue. When well watered, Pg was lower in Thermal Blue than in Apollo but differences converged as drought progressed. Drought reduced visual quality of both grasses during both years. Data suggest that Apollo may be better suited than Thermal Blue as a turfgrass selection for the transition zone. Further research is needed to identify new cultivars of HBG that may perform better than KBG at low mowing and during drought. A growing challenge facing the turfgrass industry is limited availability of water for irrigation (Snow, 2001). Local water-use restrictions may be imposed during drought that limit growth and cause severe declines in the visual quality of many cool-season turfgrasses (Perdomo et al., 1996; Bonos and Murphy, 1999). On golf courses, lower mowing heights in fairways may result in additional stress to turfgrass during drought because lower mowing typically reduces root growth and development (Parr et al., 1984; Liu and Huang, 2002). Research is needed to identify species or cultivars of cool-season turfgrasses that may perform better under drought stress and at lower mowing heights (2 to 4 cm). Hybrid bluegrasses (HBG), which are genetic crosses between native Texas bluegrass (Poa arachnifera Torr.) and Kentucky bluegrass (KBG), may have greater drought and heat resistance than other cool-season grasses (Read et al., 1999). Hybrid bluegrasses have similar visual qualities as KBG, which is a fine-textured cool-season turfgrass that is commonly used on

Mowing and drought effects on a hybrid bluegrass compared with a Kentucky bluegrass

Hybrid bluegrasses (HBG) are crosses between Kentucky bluegrass (Poa pratensis L.) (KBG) and Texas bluegrass (Poa arachnifera Torr.), which may exhibit better heat tolerance and drought resistance than other cool-season turfgrasses. Two HBG cultivars (‘Thermal Blue’ [HBG1] and ‘Dura Blue’ [HBG2]), one KBG (‘Apollo’), and one tall fescue (Festuca arundinacea Schreb.; ‘Dynasty’ [TF]) were evaluated for two years in northeastern Kansas for establishment rates after seeding, visual quality and growth characteristics, and drought resistance. Irrigation treatments included 60% and 100% evapotranspiration (ET) replacement and a control receiving only natural precipitation. Tall fescue reached full cover 37, 52, and >73 days faster than HBG1, KBG, and HBG2, respectively. In both years, average quality over the growing season ranked: TF > KBG > HBG1 > HBG2; an infestation of bluegrass billbugs (Sphenophorus parvulus Gyllenhal) in 2003 reduced quality among bluegrasses but not TF. Canopy density was lower in HBG2 and higher in TF among treatments. Clipping biomass of TF was 42 to 73% higher than that of the bluegrasses. Vertical growth rates were highest in HBG1 and TF and lowest in KBG. Drought generally reduced quality among bluegrasses, but effects on TF were negligible. Results indicate that TF is better adapted than HBG where soils are deep in the transition zone. Further research is needed using new cultivars of HBG and in areas with different soils.

Performance in the Transition Zone of Two Hybrid Bluegrasses Compared with Kentucky Bluegrass and Tall Fescue

Tall fescue (Festuca arundinacea Shreb.) is usually classified as a bunch grass, but produces short rhizomes. Newer tall fescue cultivars have been developed that reportedly produce longer and more numerous rhizomes. This study was conducted to evaluate the establishment rate and lateral spread of ‘Grande II’ and ‘Regiment II’, cultivars with greater rhizome forming capability according to breeders; Water Saver RTF tall fescue blend (RTF blend), which contains the rhizomatous tall fescue ‘Labarinth’; ‘Barlexus’ tall fescue, a non-rhizomatous turf-type cultivar; ‘Kentucky-31’ tall fescue, a non-rhizomatous cultivar originally developed for forage; and SR2284 Kentucky bluegrass (Poa pratensis L.). By six weeks after seeding at Manhattan, KS, USA, Kentucky-31 tall fescue plots had the greatest coverage (80%) and Kentucky bluegrass had the least (60%). Ten months after seeding, plugs were removed from plots and transplanted into bare soil in Manhattan and Olathe, KS. Twenty-one months after transplanting, Kentucky bluegrass plugs had grown to a diameter over twice the size of tall fescue cultivars at Olathe and three times the diameter in Manhattan. Voids were created by cutting a 30.5-cm wide by 10.2-cm deep section sod from the center of each plot, filled with the same field soil, and monitored for encroachment from plants on the perimeter of the void. Void diameters 21 months after creation were 1.0 cm for Kentucky bluegrass and >18 cm for all tall fescue cultivars and the blend, none of which differed in void size. Use of rhizomatous tall fescue cultivars, or a blend containing one such cultivar, did not increase establishment rate or lateral spread relative to tall fescue cultivars not marketed as rhizomatous cultivars.

Establishment rate and lateral spread of Festuca arundinacea cultivars

Drought stress is common among cool-season turfgrasses during summer in the U.S. transition zone. A 2-yr field study was conducted near Manhattan, KS, to evaluate rooting characteristics and effects of drought on canopy physiology and appearance of 'Apollo' Kentucky bluegrass (Poa pratensis L.) (KBG), 'Dynasty' tall fescue (Festuca arundincea Schreb.) (TF), and two hybrid bluegrasses (HBG) 'Reveille' and 'Thermal Blue'; HBG are genetic crosses between native Texas bluegrass (P. arachnifera Torr.) and KBG. Rooting characteristics were measured in the field and greenhouse under well-watered conditions to evaluate root contributions to drought avoidance. Two irrigation treatments in the field included: (i) 60% (water-deficit); and (ii) 100% (well-watered) evapotranspiration (ET) replacement. Ninety to 96% of all root length (0-80 cm) in the field and 74 to 80% of all root length (0-120 cm) in the greenhouse were in the upper 30 cm among Thermal Blue, Reveille, and KBG while in TF, only 86 and 70% of all root length in the field and greenhouse, respectively, were in the top 30 cm. In the field, tall fescue had 3 to 12 times greater root length in the lower profile (60-80 cm) among turfgrasses. Visual quality and gross photosynthesis (P g ) were greatest in TF among turfgrasses in both irrigation treatments. Reveille used more water from the 0 to 50 cm profile and performed better than Thermal Blue during water-deficit, but both HBG recovered from water-deficit slightly faster than KBG. Performances in visual quality and P g generally ranked: TF > Reveille 2 Thermal Blue = KBG.

Rooting Characteristics and Canopy Responses to Drought of Turfgrasses Including Hybrid Bluegrasses

Texas bluegrass hybrid turf, or "hybrid bluegrass" for short, is the latest turfgrass to enter the scene in the ongoing quest for more heat-tolerant, drought-resistant coolseason turfgrass. Hybrid bluegrass is a genetic cross between native Texas bluegrass (Poa arachnifera Torr.) and Kentucky bluegrass (Poa pratensis L.). It looks a lot like Kentucky bluegrass and could potentially be used for golf course tees, fairways, and roughs in areas where cool-season grasses are grown. Early reports claimed that hybrid bluegrass had greater heat tolerance and drought resistance than other cool-season grasses (Read et al., 1999), but because it is a relatively new turfgrass, research has been limited. Our research, consisting of both growth chamber and field studies, investigated the heat and drought performance of hybrid bluegrass in comparison to turf-type tall fescue and Kentucky bluegrass.

High temperature and drought stresses may reduce quality in cool-season turfgrasses during summer months in the transition zone. This growth chamber study was conducted to evaluate effects of high temperature and drought on physiology and growth of 'Apollo' Kentucky bluegrass (Poa pratensis L.) (KBG), 'Dynasty' tall fescue (Festuca arundincea Schreb.) (TF), and 'Thermal Blue', a hybrid (HBG) between KBG and Texas bluegrass (Poa arachnifera Torr.). Turfgrasses were exposed for 48 d to supra-optimal (high temperature; 35/25°C, 14-h day/10-h night) and optimal (control; 22/15°C, 14-h day/10-h night) temperatures under well-watered (100% evapotranspiration [ET] replacement) and deficit (60% ET replacement) irrigation. Heat resistance was greater in HBG, which had greater visual quality, gross photosynthesis (Pg), dry matter production, and lower electrolyte leakage and soil surface temperatures than KBG and TF under high temperature. Cumulative Pg during the study was 16 and 24% greater in HBG than in KBG and TF, respectively. Green leaf area index (LAI) in HBG was not affected by high temperature, but LAI was reduced by 29% in KBG and 38% in TF. Differences in drought resistance were negligible among species. The combination of high temperature and drought caused rapid declines in visual quality and dry matter production, but HBG generally performed better. Results indicated greater heat resistance, but not drought resistance, in HBG than in KBG or TF.

Effects of High Temperature and Drought on a Hybrid Bluegrass Compared with Kentucky Bluegrass and Tall Fescue

INTRODUCTION: A growing challenge facing the turfgrass industry is limited availability of water for irrigation. Local water-use restrictions may be imposed during drought that limit growth and cause severe declines in the visual quality of many cool-season turfgrasses. In golf courses, lower mowing heights in fairways may result in additional stress to turfgrass during drought because lower mowing typically reduces root growth and development. Texas bluegrass hybrids, which are genetic crosses between native Texas bluegrass and Kentucky bluegrasses, may have greater heat and drought resistance than other cool-season grasses. Hybrid bluegrasses have similar visual qualities to Kentucky bluegrass, which is a fine-textured, cool-season turfgrass commonly used in lawns and golf courses in the United States. Consequently, new cultivars of hybrid bluegrasses are being investigated as potential water-saving, heat-resistant alternatives to current cool-season turfgrasses. Research is needed to identify species or cultivars of cool-season turfgrasses that may perform better under drought stress, including maintenance at lower mowing heights.

Mowing Height and Drought Effects on a Texas Bluegrass Hybrid Compared with Kentucky bluegrass

Ball marks result from golf ball impact on putting greens, and recovery of the surface may depend upon the repair strategy employed. Our objective was to compare three ball mark repair techniques for their influence on golf green surface quality and 'L-93' creeping bentgrass (Agrostis palustris Huds.) recovery. Studies were conducted on a practice putting green on a golf course (Study I) and on a research green (Study II) near Manhattan, Kansas. Ball marks were made by a golfer striking golf balls with a pitching wedge from 100 m in Study I and from 70 m in Study II. Five treatments were imposed on the ball marks immediately after they were created: (i) no ball mark (control); (ii) unrepaired ball mark; (iii) Greenfix tool; (iv) traditional ball mark repair tool used improperly; and (v) traditional ball mark repair tool used properly. In both studies, ball marks repaired properly with the traditional tool or with the Greenfix, recovered completely in 16 to 21 days; recovery was 4 days faster with the Greenfix tool than the traditional tool in Study I. Marks repaired with the Greenfix had poorer surface quality due to the presence of an uneven surface at 3 days after the ball mark was made (ABM) in Study I and up to 10 days ABM in Study II. Using the traditional tool improperly resulted in the poorest surface quality at > 17 days ABM due to a persistent ball mark scar and poor turf quality in the mark area. Improperly repaired marks required > 38 days for recovery, 19 days longer than unrepaired marks in Study I, and at least 8 days longer than unrepaired marks in Study II. Proper use of the traditional tool or use of the Greenfix allowed for most rapid improvement in creeping bentgrass surface quality and fewest days to recovery; however, improper use of the traditional tool reduced surface quality and doubled the time for surface recovery compared to its proper use.

Turfgrass managers often desire to overseed thin areas during midsummer or late summer, but seeding desirable species too soon after a preemergence herbicide application can interfere with seedling growth. This study was conducted to compare the effects of three herbicides on Kentucky bluegrass seedling growth and to determine whether seeding method affects the interval before seeding can safely occur. Dithiopyr, prodiamine, and pendimethalin were applied to ‘Kentucky 31’ tall fescue plots in late April at 0.56, 0.84, and 3.36 kg ai/ha, respectively. At 2, 4, 8, 12, and 16 wk after treatment, soil cores were extracted from each plot, the existing turf was killed, and the cores were either broadcast seeded or slit seeded with Kentucky bluegrass. Slit seeding resulted in greater and more extended seedling growth suppression than broadcast seeding for all herbicides. Prodiamine suppressed Kentucky bluegrass seedling growth longer than dithiopyr and pendimethalin. Unacceptable seedling growth suppression occurred unless broadcast seeding was delayed for about 6, 8, and 14 wk after dithiopyr, pendimethalin, and prodiamine application, respectively. The required interval between herbicide application and slit seeding was approximately 11, 10, and 16 wk, respectively. Use of dithiopyr or pendimethalin rather than prodiamine and broadcast seeding instead of slit seeding allows earlier overseeding with Kentucky bluegrass. Nomenclature: Dithiopyr; pendimethalin; prodiamine; Kentucky bluegrass, Poa pratensis L. #3 POAPR ‘Unique’; tall fescue, Festuca arundinacea Schreb. # FESAR ‘Kentucky 31’. Additional index words: Broadcast seeding, overseeding, seeding interval, slit seeding, vertical mowing. Abbreviation: WAT, weeks after treatment.

Preemergence Herbicide and Seeding Method Effects on Seedling Growth of Kentucky Bluegrass1

Many golf course superintendents wish to convert perennial ryegrass (Lolium perenne L.) fairways to other cool-season species such as Kentucky bluegrass (Poa pratensis L.) because of the former's high fungicide requirement. However, interseeding into a mature turfgrass stand often results in poor seedling survival became of competition from the existing stand. The objective of this research was to evaluate methods for enhancing Kentucky bluegrass (KB) establishment when interseeded into a mature perennial ryegrass fairway turf. Core aeration, scalping, plant growth regulators (PGRs), postseeding low mowing (PSLM), high seeding rates, and multiple seedings were used singly and in factorial combinations. Postseeding low mowing (0.6 cm twice weekly for 4 wk) and high seeding rates [196 kg pure live seed (PLS) ha -1 ] were most effective in enhancing KB establishment. Plots receiving PSLM averaged 31.9% KB 21 months after seeding (MAS) compared with 18.1% in non-PSLM plots. Seeding KB at 196 kg PLS ha -1 , both fall and spring, resulted in an average of 29.8% KB 21 MAS while seeding at 98 kg PLS ha -1 , in the fall only, resulted in only 19.7% KB. A single preseeding core aeration or scalping treatment did not increase KB establishment, nor did preseeding applications of the PGR trinexapac-ethyl [4-(cyclopropyl-α-hydroxy-methylene)-3,5-dioxo-cyclohexane-carboxylic acid ethyl ester], Mefluidide {-[2,4-dimethyl-5-[[(trifluoromethyl)-sulfonyl]amino]phenyl] acetamide} increased KB establishment at 6 MAS, but the effect was gone by 21 MAS. Where nonselective herbicides are not used, fastest conversion to KB will occur with a combination of PSLM and high seeding rates.

Conversion of fairway-height perennial ryegrass turf to Kentucky bluegrass without nonselective herbicides

A greenhouse study was conducted to determine the effectiveness of adjuvants on postemergence large crabgrass control with dithiopyr. Using barriers to isolate foliage or soil, the primary site of dithiopyr uptake was found to be via foliage. Laboratory and greenhouse studies elucidated the factors involved in enhancement of crabgrass control by dithiopyr with nine superior adjuvants. Two adjuvants increased dithiopyr absorption by 3.7 to 4.3% over the herbicide alone. However, none of the adjuvants increased dithiopyr translocation out of the treated leaf. Treatment of a single large crabgrass leaf indicated that enhancement of dithiopyr activity by adjuvants involved an effect on translocation, on spray retention, and on the external movement of the spray solution to the apical meristem, with the relative importance of any 1 factor depending on the particular adjuvant used. Because of the large losses of dithiopyr during absorption/translocation studies, a separate volatilization experiment determined that 70% of the applied dithiopyr volatilized within 24 h at 24 C. Dithiopyr absorption decreased and volatilization increased with each 10 C increase in temperature. Nonrecoverable dithiopyr ranged from 46 to 55% at 5 C to 92 to 95% at 35 C. Volatility losses of this magnitude may mitigate adjuvant enhancement of postemergence grass activity of dithiopyr.

Adjuvant enhancement of large crabgrass (Digitaria sanguinalis) control with dithiopyr

Memories are made of this: The impact of the Vietnam War on the Persian Gulf War in rural America

Australian critical care : official journal of the Confederation of Australian Critical Care Nurses

Early mobilisation in critically ill children: Does routine patient screening reduce time to commencing mobilisation?

P0049 / #710: EARLY MOBILISATION IN CRITICALLY ILL CHILDREN: DOES ROUTINE PATIENT SCREENING CHANGE PRACTICE?

P0495 / #1898: UNDERSTANDING THE PATIENT LEVEL BARRIERS TO EARLY MOBILISATION IN AN AUSTRALIAN PAEDIATRIC INTENSIVE CARE UNIT

We aimed to determine whether using a balanced salt solution, Hartmann's solution (HS), in diabetic ketoacidosis (DKA) shortens the time to normalise acid–base status through the avoidance of hyperchloremic metabolic acidosis compared with 0.9% normal saline (NS).

Controlled trial of Hartmann's solution versus 0.9% saline for diabetic ketoacidosis

Physical interventions, including restraint, are a necessary but controversial component of mental health care. This paper outlines developments in one trust to prioritise this area and take an integrated, whole trust approach. The paper discusses ‘physical interventions’, describes the organisational approach to support the development and outlines the training package developed to promote safe and effective practice. In addition the approach is reviewed using team members' views within the National Patient Safety Agency's seven steps to patient safety. Data on incidences of interventions prior to and following the approach are presented and conclusions and recommendations to further guide practice are proposed.

Physical interventions training and organisational management in mental health: an integrated approach to promote patient safety

Aim:  Traditional paediatric intravenous maintenance fluids are prescribed using hypotonic fluids and the weight‐based 4:2:1 formula for administration rate. However, this may cause hyponatraemia in sick and post‐operative children. We studied the effect of two types of intravenous maintenance fluid and two administration rates on plasma sodium concentration in intensive care patients.

To the Editor: We wish to report evidence of unacceptably high rates of administration of diphtheria-tetanus vaccine (DT) in place of diphtheria-tetanus-pertussis vaccine (DTP) for the vaccination of children up to the age of two years. From data supplied to the then Health Department Victoria in the 1991 municipal annual report, we calculated the rate of DT administration for the third dose of the primary vaccination schedule as a proportion of the total of DTP plus DT administered up to the age of two years. The statewide average proportion of DT administration for the third dose was 4.6%. Aggregate ratios for health regions varied from a low of 2% in the Central Highlands/ Wimmera region, to a high of 9% in the Loddon/Campaspe/Mallee region (see Table). The combined rural rate of 4.1% was slightly lower than the Melbourne urban rate of 5.4%. Thirty-four municipalities recorded rates of DT administration of 4% or more. Two large urban municipalities had third-dose DT administration rates of 35% and 26%, representing 511 and 1169 babies respectively who were inadequately vaccinated against pertussis. Further evidence of unacceptably high rates of use of DT in place of DTP is provided by vaccine purchase figures from Health and Community Services Victoria. We examined the total numbers of DT doses purchased in the years 1986 and 1991. After subtracting 60 000 doses from each year's total to allow for the doses administered in the first year of school, we expressed this figure as a proportion of total DTP plus DT. This proportion has varied between 9% and 16% in these years. Rates of DTP/DT primary vaccination courses completed in children aged 12-24 months at 30 June 1992 were calculated from maternal and child health nurse records. The overall rate for Victoria was 89.3% completed courses (without distinguishing between doses of DT and DTP). This rate has remained stable since 1987 when a rate of 88.2% was reported.' However, our data indicate that the rate of DT administration is perhaps four to five times higher than it should be, and that there are concentrations of high rates of DT administration within specific municipalities. This results in geographically clustered populations of children who have inadequate pertussis protection, a factor which could promote epidemic outbreaks.sA recent survey of health professionals' attitudes to pertussis vaccine showed that up to 45% would give DT where DTP was clearly indicated.s More education of both health professionals and the public is needed to combat misconceptions about the pertussis vaccine.

Objective: To present the first report of ruptured spleen associated with meningococcal septicaemia.

Severe meningococcal septicaemia associated with splenic rupture

Four neonates suffered caval thrombosis secondary to indwelling central catheters. Dissolution of thrombus with recombinant tissue plasminogen activator (rt-PA) as a low-dose infusion (0.05 mg/kg/hr) directly into thrombus was successful in three patients. rt-PA was ceased after three days in the fourth patient because of catheter malposition. Thrombolysis was achieved between four and ten days. Rethrombosis occurred in one patient despite heparin prophylaxis. Plasminogen activator infusions were titrated to maintain fibrinogen levels above 100 mg/dl. One neonate suffered an intracranial haemorrhage. Regional rt-PA is an alternative to thrombectomy in critically ill neonates.

Caval Thrombolysis in Neonates Using Low Doses of Recombinant Human Tissue-Type Plasminogen Activator

Tissue plasminogen activator for gangrene in fulminant meningococcaemia

Fulminant hepatic failure causes a bleeding diathesis as a result of impaired synthesis of hepatic clotting factors, thrombocytopenia, fibrinolysis and disseminated intravascular coagulation. Administration of clotting factor concentrates can cause thrombosis in patients with acute hepatic failure. Regional infusion of recombinant tissue‐type plasminogen activator may be used to induce local thrombolysis. A case report of a five‐year‐old child is presented and the literature is reviewed.

Prothrombinex‐induced thrombosis and its management with regional plasminogen activator in hepatic failure

With the rise of machines to human-level performance in complex recognition tasks, a growing amount of work is directed toward comparing information processing in humans and machines. These studies are an exciting chance to learn about one system by studying the other. Here, we propose ideas on how to design, conduct, and interpret experiments such that they adequately support the investigation of mechanisms when comparing human and machine perception. We demonstrate and apply these ideas through three case studies. The first case study shows how human bias can affect the interpretation of results and that several analytic tools can help to overcome this human reference point. In the second case study, we highlight the difference between necessary and sufficient mechanisms in visual reasoning tasks. Thereby, we show that contrary to previous suggestions, feedback mechanisms might not be necessary for the tasks in question. The third case study highlights the importance of aligning experimental conditions. We find that a previously observed difference in object recognition does not hold when adapting the experiment to make conditions more equitable between humans and machines. In presenting a checklist for comparative studies of visual reasoning in humans and machines, we hope to highlight how to overcome potential pitfalls in design and inference.

Five points to check when comparing visual perception in humans and machines

With the rise of machines to human-level performance in complex recognition tasks, a growing amount of work is directed towards comparing information processing in humans and machines. These works have the potential to deepen our understanding of the inner mechanisms of human perception and to improve machine learning. Drawing robust conclusions from comparison studies, however, turns out to be difficult. Here, we highlight common shortcomings that can easily lead to fragile conclusions. First, if a model does achieve high performance on a task similar to humans, its decision-making process is not necessarily human-like. Moreover, further analyses can reveal differences. Second, the performance of neural networks is sensitive to training procedures and architectural details. Thus, generalizing conclusions from specific architectures is difficult. Finally, when comparing humans and machines, equivalent experimental settings are crucial in order to identify innate differences. Addressing these shortcomings alters or refines the conclusions of studies. We show that, despite their ability to solve closed-contour tasks, our neural networks use different decision-making strategies than humans. We further show that there is no fundamental difference between same-different and spatial tasks for common feed-forward neural networks and finally, that neural networks do experience a "recognition gap" on minimal recognizable images. All in all, care has to be taken to not impose our human systematic bias when comparing human and machine perception.

The Notorious Difficulty of Comparing Human and Machine Perception

Fronto-striatal circuits have been extensively implicated in the cognitive control of behavioral output for both social and appetitive rewards. The functional diversity of prefrontal cortical populations is strongly dependent on their synaptic targets, with control of motor output strongly mediated by connectivity to the dorsal striatum. Despite evidence for functional diversity along the anterior-posterior axis of the dorsomedial striatum (DMS), it is unclear how distinct fronto- striatal sub-circuits support neural computations essential for action selection. Here we identify prefrontal populations targeting distinct DMS subregions and characterize their functional roles. We first performed neural circuit tracing to reveal segregated prefrontal populations defined by anterior/posterior dorsomedial striatal target. We then probed the functional relevance of these parallel circuits via in vivo calcium imaging and temporally precise causal manipulations during a feedback-based 2-alternative choice task. Single-photon imaging revealed circuit-specific representations of task-relevant information with prelimbic neurons targeting anterior DMS (PL::A- DMS) uniquely encoded choices and responses to negative outcomes, while prelimbic neurons targeting posterior DMS (PL::P-DMS) encoded internal representations of value and positive outcomes contingent on prior choice. Consistent with this distributed coding, optogenetic inhibition of PL::A-DMS circuits strongly impacted choice monitoring and behavioral control in response to negative outcomes while perturbation of PL::P-DMS signals impaired task engagement and strategies following positive outcomes. Di-synaptic retrograde tracing uncovered differences in afferent connectivity that may underlie these pathways functional divergence. Together our data uncover novel PL populations engaged in distributed processing for action control. SUMMARY Prelimbic cortex engages A- and P-DMS via distinct circuits PL::A-DMS and PL::P-DMS pathways encode divergent aspects of a simple goal-directed task PL::A-DMS pathways shape responding to negative outcomes via multiple mechanisms PL::P-DMS pathways guide engagement and choices in response to positive outcomes Afferent connectomes of PL neurons defined by A-P DMS target are distinct

Distributed processing for action control by prelimbic circuits targeting anterior-posterior dorsal striatal subregions

Temporal stability of stimulus representation increases along rodent visual cortical hierarchies

We present embo, a Python package to analyze empirical data using the Information Bottleneck (IB) method and its variants, such as the Deterministic Information Bottleneck (DIB). Given two random variables X and Y, the IB finds the stochastic mapping M of X that encodes the most information about Y, subject to a constraint on the information that M is allowed to retain about X. Despite the popularity of the IB, an accessible implementation of the reference algorithm oriented towards ease of use on empirical data was missing. Embo is optimized for the common case of discrete, low-dimensional data. Embo is fast, provides a standard data-processing pipeline, offers a parallel implementation of key computational steps, and includes reasonable defaults for the method parameters. Embo is broadly applicable to different problem domains, as it can be employed with any dataset consisting in joint observations of two discrete variables. It is available from the Python Package Index (PyPI), Zenodo and GitLab.

Embo: a Python package for empirical data analysis using the Information Bottleneck

Efficient processing of sensory data requires adapting the neuronal encoding strategy to the statistics of natural stimuli. Previously, in Hermundstad et al. 2014, we showed that local multipoint correlation patterns that are most variable in natural images are also the most perceptually salient for human observers, in a way that is compatible with the efficient coding principle. Understanding the neuronal mechanisms underlying such adaptation to image statistics will require performing invasive experiments that are impossible in humans. Therefore, it is important to understand whether a similar phenomenon can be detected in animal species that allow for powerful experimental manipulations, such as rodents. Here we selected four image statistics (from single- to four-point correlations) and trained four groups of rats to discriminate between white noise patterns and binary textures containing variable intensity levels of one of such statistics. We interpreted the resulting psychometric data with an ideal observer model, finding a sharp decrease in sensitivity from 2- to 4-point correlations and a further decrease from 4- to 3-point. This ranking fully reproduces the trend we previously observed in humans, thus extending a direct demonstration of efficient coding to a species where neuronal and developmental processes can be interrogated and causally manipulated.

Rat sensitivity to multipoint statistics is predicted by efficient coding of natural scenes

The efficient coding hypothesis postulates that neurons shape their response properties to match their dynamic range to the statistics of incoming signals. However, whether and how the dynamics of efficient neuronal adaptation inform behavior has not been directly shown. Here, we trained mice to detect a target presented in background noise shortly after a change in the background contrast. The observed changes in cortical gain and detection behavior followed the predictions of a normative model of efficient cortical sound processing; specifically, target detection and sensitivity to target volume improved in low contrast backgrounds relative to high contrast backgrounds. Additionally, the time course of target detectability adapted asymmetrically depending on contrast, decreasing rapidly after a transition to high contrast, and increasing more slowly after a transition to low contrast. Auditory cortex was required for detection of targets in background noise and cortical neuronal responses exhibited the patterns of target detectability observed during behavior and in the normative model. Furthermore, variability in cortical gain predicted behavioral performance beyond the effect of stimulus-driven gain control. Combined, our results demonstrate that efficient neural codes in auditory cortex directly influence perceptual behavior.

Different learning strategies are thought to fall along a continuum that ranges from simple, inflexible, and fast model-free strategies, to more complex, flexible, and deliberative model-based strategies. Here we show that, contrary to this proposal, strategies at both ends of this continuum can be equally flexible, effective, and time-intensive. We analyzed behavior of adult human subjects performing a canonical learning task used to distinguish between model-free and model-based strategies. Subjects using either strategy showed similarly high information complexity, a measure of strategic flexibility, and comparable accuracy and response times. This similarity was apparent despite the generally higher computational complexity of model-based algorithms and fundamental differences in how each strategy learned: model-free learning was driven primarily by observed past responses, whereas model-based learning was driven primarily by inferences about latent task features. Thus, model-free and model-based learning differ in the information they use to learn but can support comparably flexible behavior.

The complexity of model-free and model-based learning strategies

Different learning strategies are thought to fall along a continuum that ranges from simple, inflexible, and fast “model-free” strategies, to more complex, flexible, and deliberative “model-based strategies”. Here we show that, contrary to this proposal, strategies at both ends of this continuum can be equally flexible, effective, and time-intensive. We analyzed behavior of adult human subjects performing a canonical learning task used to distinguish between model-free and model-based strategies. Subjects using either strategy showed similarly high information complexity, a measure of strategic flexibility, and comparable accuracy and response times. This similarity was apparent despite the generally higher computational complexity of model-based algorithms and fundamental differences in how each strategy learned: model-free learning was driven primarily by observed past responses, whereas model-based learning was driven primarily by inferences about latent task features. Thus, model-free and model-based learning differ in the information they use to learn but can support comparably flexible behavior. Statement of Relevance The distinction between model-free and model-based learning is an influential framework that has been used extensively to understand individual- and task-dependent differences in learning by both healthy and clinical populations. A common interpretation of this distinction that model-based strategies are more complex and therefore more flexible than model-free strategies. However, this interpretation conflates computational complexity, which relates to processing resources and generally higher for model-based algorithms, with information complexity, which reflects flexibility but has rarely been measured. Here we use a metric of information complexity to demonstrate that, contrary to this interpretation, model-free and model-based strategies can be equally flexible, effective, and time-intensive and are better distinguished by the nature of the information from which they learn. Our results counter common interpretations of model-free versus model-based learning and demonstrate the general usefulness of information complexity for assessing different forms of strategic flexibility.

The comparable strategic flexibility of model-free and model-based learning

Summary Along the ventral stream, cortical representations of brief, static stimuli become gradually more invariant to identity-preserving transformations. In the presence of long, ethologically relevant dynamic stimuli, higher invariance should imply temporally persistent representations at the top of this functional hierarchy. However, such stimuli could engage adaptive and predictive processes, whose impact on neural coding dynamics is unknown. More generally, coding dynamics in the presence of temporally structured stimuli are not understood. By probing the rodent analogue of the ventral stream with movies, we uncovered a hierarchy of temporal scales along this pathway, with deeper areas encoding visual information more persistently. Furthermore, the impact of intrinsic dynamics on the stability of stimulus representations gradually grows along the hierarchy. These results suggest that feedforward computations in the cortical hierarchy build up invariance even for dynamic, temporally structured stimuli, and that intrinsic processing contributes to the stabilization of representations in noisy, changing environments.

Intrinsic dynamics enhance temporal stability of stimulus representation along a visual cortical hierarchy

This is the Editorial article summarizing the scope and contents of the Special Issue, Information Theory in Neuroscience.

The ability to synthesize realistic patterns of neural activity is crucial for studying neural information processing. Here we used the Generative Adversarial Networks (GANs) framework to simulate the concerted activity of a population of neurons. We adapted the Wasserstein-GAN variant to facilitate the generation of unconstrained neural population activity patterns while still benefiting from parameter sharing in the temporal domain. We demonstrate that our proposed GAN, which we termed Spike-GAN, generates spike trains that match accurately the firstand second-order statistics of datasets of tens of neurons and also approximates well their higher-order statistics. We applied Spike-GAN to a real dataset recorded from salamander retina and showed that it performs as well as state-ofthe-art approaches based on the maximum entropy and the dichotomized Gaussian frameworks. Importantly, Spike-GAN does not require to specify a priori the statistics to be matched by the model, and so constitutes a more flexible method than these alternative approaches. Finally, we show how to exploit a trained SpikeGAN to construct ’importance maps’ to detect the most relevant statistical structures present in a spike train. Spike-GAN provides a powerful, easy-to-use technique for generating realistic spiking neural activity and for describing the most relevant features of the large-scale neural population recordings studied in modern systems neuroscience.

Open Source Brain: A Collaborative Resource for Visualizing, Analyzing, Simulating, and Developing Standardized Models of Neurons and Circuits

The ability to synthesize realistic patterns of neural activity is crucial for studying neural information processing. Here we used the Generative Adversarial Networks (GANs) framework to simulate the concerted activity of a population of neurons. We adapted the Wasserstein-GAN variant to facilitate the generation of unconstrained neural population activity patterns while still benefiting from parameter sharing in the temporal domain. We demonstrate that our proposed GAN, which we termed Spike-GAN, generates spike trains that match accurately the first- and second-order statistics of datasets of tens of neurons and also approximates well their higher-order statistics. We applied Spike-GAN to a real dataset recorded from salamander retina and showed that it performs as well as state-of-the-art approaches based on the maximum entropy and the dichotomized Gaussian frameworks. Importantly, Spike-GAN does not require to specify a priori the statistics to be matched by the model, and so constitutes a more flexible method than these alternative approaches. Finally, we show how to exploit a trained Spike-GAN to construct 'importance maps' to detect the most relevant statistical structures present in a spike train. Spike-GAN provides a powerful, easy-to-use technique for generating realistic spiking neural activity and for describing the most relevant features of the large-scale neural population recordings studied in modern systems neuroscience.

Synthesizing realistic neural population activity patterns using Generative Adversarial Networks

Determining how much of the sensory information carried by a neural code contributes to behavioral performance is key to understand sensory function and neural information flow. However, there are as yet no analytical tools to compute this information that lies at the intersection between sensory coding and behavioral readout. Here we develop a novel measure, termed the information-theoretic intersection information $I_{II}(S;R;C)$, that quantifies how much of the sensory information carried by a neural response R is used for behavior during perceptual discrimination tasks. Building on the Partial Information Decomposition framework, we define $I_{II}(S;R;C)$ as the part of the mutual information between the stimulus S and the response R that also informs the consequent behavioral choice C. We compute $I_{II}(S;R;C)$ in the analysis of two experimental cortical datasets, to show how this measure can be used to compare quantitatively the contributions of spike timing and spike rates to task performance, and to identify brain areas or neural populations that specifically transform sensory information into choice.

Quantifying how much sensory information in a neural code is relevant for behavior

Utilities for computing the subatomic partial positive information decomposition for distributions over three random variables, according to the definitions given in Pica et al 2017.

Cracking the Neural Code for Sensory Perception by Combining Statistics, Intervention, and Behavior

In a system of three stochastic variables, the Partial Information Decomposition (PID) of Williams and Beer dissects the information that two variables (sources) carry about a third variable (target) into nonnegative information atoms that describe redundant, unique, and synergistic modes of dependencies among the variables. However, the classification of the three variables into two sources and one target limits the dependency modes that can be quantitatively resolved, and does not naturally suit all systems. Here, we extend the PID to describe trivariate modes of dependencies in full generality, without introducing additional decomposition axioms or making assumptions about the target/source nature of the variables. By comparing different PID lattices of the same system, we unveil a finer PID structure made of seven nonnegative information subatoms that are invariant to different target/source classifications and that are sufficient to describe the relationships among all PID lattices. This finer structure naturally splits redundant information into two nonnegative components: the source redundancy, which arises from the pairwise correlations between the source variables, and the non-source redundancy, which does not, and relates to the synergistic information the sources carry about the target. The invariant structure is also sufficient to construct the system’s entropy, hence it characterizes completely all the interdependencies in the system.

Invariant Components of Synergy, Redundancy, and Unique Information among Three Variables

It has long been recognised that neuronal networks are complex systems, whose dynamics depend on the properties of the individual synapses and neurons and the way in which they are interconnected. However, establishing clear links between network structure and function has proven difficult. 
 
To address this question I applied tools and techniques from computational neuroscience, neuroinformatics, information theory, machine learning, spatial point process theory and network theory, deploying them on a suitable HPC infrastructure where appropriate. Moreover, access to electrophysiological and anatomical data enabled me to develop biologically accurate models and to compare my theoretical predictions with analyses of raw data. 
 
In this work, I focused on the granule cell layer (GCL), the input stage of the cerebellar cortex. The GCL is particularly well suited to this type of analysis, as its structural characteristics are comparatively regular, well known and conserved across animal species, and several of its basic functions are relatively well understood. 
 
I showed that the synaptic connectivity in simple feed forward networks like the GCL governs the trade-off between information transmission and sparsification of incoming signals. This suggests a link between the functional requirements for the network and the strong evolutionary conservation of the anatomy of the cerebellar GCL. Furthermore, I investigated how the geometry of the GCL interacts with the spatial constraints of synaptic connectivity and gives rise to the statistical features of the chemically and electrically coupled networks formed by mossy fibres, granule cells and Golgi cells. Finally, I studied the influence of the spatial structure of the Golgi cell network on the robustness of the synchronous activity state it can support.

Network structure and function in the input stage of the cerebellar cortex

Computational models are increasingly important for studying complex neurophysiological systems. As scientific tools, it is essential that such models can be reproduced and critically evaluated by a range of scientists. However, published models are currently implemented using a diverse set of modeling approaches, simulation tools, and computer languages making them inaccessible and difficult to reproduce. Models also typically contain concepts that are tightly linked to domain-specific simulators, or depend on knowledge that is described exclusively in text-based documentation. To address these issues we have developed a compact, hierarchical, XML-based language called LEMS (Low Entropy Model Specification), that can define the structure and dynamics of a wide range of biological models in a fully machine readable format. We describe how LEMS underpins the latest version of NeuroML and show that this framework can define models of ion channels, synapses, neurons and networks. Unit handling, often a source of error when reusing models, is built into the core of the language by specifying physical quantities in models in terms of the base dimensions. We show how LEMS, together with the open source Java and Python based libraries we have developed, facilitates the generation of scripts for multiple neuronal simulators and provides a route for simulator free code generation. We establish that LEMS can be used to define models from systems biology and map them to neuroscience-domain specific simulators, enabling models to be shared between these traditionally separate disciplines. LEMS and NeuroML 2 provide a new, comprehensive framework for defining computational models of neuronal and other biological systems in a machine readable format, making them more reproducible and increasing the transparency and accessibility of their underlying structure and properties.

LEMS: a language for expressing complex biological models in concise and hierarchical form and its use in underpinning NeuroML 2

Network Structure within the Cerebellar Input Layer Enables Lossless Sparse Encoding

Advanced 3D visualisation of detailed neuronal models using the Open Source Brain repository and interaction with other neuroinformatics resources

The Open Source Brain Initiative: enabling collaborative modelling in computational neuroscience

Occam’s razor is the principle that, all else being equal, simpler explanations should be preferred over more complex ones. This principle is thought to play a role in human perception and decision-making, but the nature of our presumed preference for simplicity is not understood. Here we use preregistered behavioral experiments informed by formal theories of statistical model selection to show that, when faced with uncertain evidence, human subjects exhibit preferences for particular, theoretically grounded forms of simplicity of the alternative explanations. These forms of simplicity can be understood in terms of geometrical features of statistical models treated as manifolds in the space of the probability distributions, in particular their dimensionality, boundaries, volume, and curvature. The simplicity preferences driven by these features, which are also exhibited by artificial neural networks trained to optimize performance on comparable tasks, generally improve decision accuracy, because they minimize over-sensitivity to noisy observations (i.e., overfitting). However, unlike for artificial networks, for human subjects these preferences persist even when they are maladaptive with respect to the task training and instructions. Thus, these preferences are not simply transient optimizations for particular task conditions but rather a more general feature of human decision-making. Taken together, our results imply that principled notions of statistical model complexity have direct, quantitative relevance to human and machine decision-making and establish a new understanding of the computational foundations, and behavioral benefits, of our predilection for inferring simplicity in the latent properties of our complex world.

Sensory systems appear to learn to transform incoming sensory information into perceptual representations, or “objects”, that can inform and guide behavior with minimal explicit supervision. Here, we propose that the auditory system can achieve this goal by using time as a supervisor, i.e., by learning features of a stimulus that are temporally regular. We will show that this procedure generates a feature space sufficient to support fundamental computations of auditory perception. In detail, we consider the problem of discriminating between instances of a prototypical class of natural auditory objects, i.e., rhesus macaque vocalizations. We test discrimination in two ethologically relevant tasks: discrimination in a cluttered acoustic background and generalization to discriminate between novel exemplars. We show that an algorithm that learns these temporally regular features affords better or equivalent discrimination and generalization than conventional feature-selection algorithms, i.e., principal component analysis and independent component analysis. Our findings suggest that the slow temporal features of auditory stimuli may be sufficient for parsing auditory scenes and that the auditory brain could utilize these slowly changing temporal features.

Time as a supervisor: temporal regularity and auditory object learning

Neurons throughout the sensory pathway adapt their responses depending on the statistical structure of the sensory environment. Contrast gain control is a form of adaptation in the auditory cortex, but it is unclear whether the dynamics of gain control reflect efficient adaptation, and whether they shape behavioral perception. Here, we trained mice to detect a target presented in background noise shortly after a change in the contrast of the background. The observed changes in cortical gain and behavioral detection followed the dynamics of a normative model of efficient contrast gain control; specifically, target detection and sensitivity improved slowly in low contrast, but degraded rapidly in high contrast. Auditory cortex was required for this task, and cortical responses were not only similarly affected by contrast but predicted variability in behavioral performance. Combined, our results demonstrate that dynamic gain adaptation supports efficient coding in auditory cortex and predicts the perception of sounds in noise.

Dynamics of cortical contrast adaptation predict perception of signals in noise

A fundamental problem for any sensory system is that the motion of the sensory organ introduces a disturbance in sensory measurement. Nevertheless, animal nervous systems can distinguish and compensate for the sensory consequences of movement by keeping track of them. Hypotheses for estimating the motion of a sensory organ include a corollary discharge associated with motor output and mechanosensory inputs from the moving sense organ. However, how motion-related mechanosensory inputs can reduce motion-dependent sensory ambiguity is unknown. We addressed this question in the olfactory system, where changes in inhalation dynamics alter the sorption of odor molecules by the nasal mucosa and mechanically activate olfactory sensory neurons. We found that changes in inhalation dynamics varied the odor concentration reported by the individual neurons in the piriform cortex. However, the actual odor concentration could be decoded from the population activity regardless of the inhalation dynamics. Dynamics-invariant decoding was possible because piriform cortex neurons have a heterogeneously mixed sensitivity for odor concentration and inhalation dynamics. Thus, the mechanosensory input generated by inhalation expanded the dimensionality of the olfactory encoding space and disentangled the decoding of the actual odor concentration from the disturbance caused by the sniff. Orthogonal integration of motion-related mechanosensory information during the encoding stage may be a canonical strategy adopted by nervous systems to mitigate the sensory ambiguities generated by the motion of the sensory organ.

A mixed mechano-olfactory code for sniff-invariant odor representations

Distributed processing for value-based choice by prelimbic circuits targeting anterior-posterior dorsal striatal subregions in male mice

Visual object recognition has been extensively studied in both neuroscience and computer vision. Recently, the most popular class of artificial systems for this task, deep convolutional neural networks (CNNs), has been shown to provide excellent models for its functional analogue in the brain, the ventral stream in visual cortex. This has prompted questions on what, if any, are the common principles underlying the reformatting of visual information as it flows through a CNN or the ventral stream. Here we consider some prominent statistical patterns that are known to exist in the internal representations of either CNNs or the visual cortex and look for them in the other system. We show that intrinsic dimensionality (ID) of object representations along the rat homologue of the ventral stream presents two distinct expansion-contraction phases, as previously shown for CNNs. Conversely, in CNNs, we show that training results in both distillation and active pruning (mirroring the increase in ID) of low- to middle-level image information in single units, as representations gain the ability to support invariant discrimination, in agreement with previous observations in rat visual cortex. Taken together, our findings suggest that CNNs and visual cortex share a similarly tight relationship between dimensionality expansion/reduction of object representations and reformatting of image information.

Prune and distill: similar reformatting of image information along rat visual cortex and deep neural networks

Neural circuits in the periphery of the visual, auditory, and olfactory systems are believed to use limited resources efficiently to represent sensory information by adapting to the statistical structure of the natural environment. This “efficient coding” principle has been used to explain many aspects of early visual circuits including the distribution of photoreceptors, the mosaic geometry and center-surround structure of retinal receptive fields, the excess OFF pathways relative to ON pathways, saccade statistics, and the structure of simple cell receptive fields in V1. We know less about the extent to which such adaptations may occur in deeper areas of cortex beyond V1. We thus review recent developments showing that the perception of visual textures, which depends on processing in V2 and beyond in mammals, is adapted in rats and humans to the multi-point statistics of luminance in natural scenes. These results suggest that central circuits in the visual brain are adapted for seeing key aspects of natural scenes. We conclude by discussing how adaptation to natural temporal statistics may aid in learning and representing visual objects, and propose two challenges for the future: (1) explaining the distribution of shape sensitivity in the ventral visual stream from the statistics of object shape in natural images, and (2) explaining cell types of the vertebrate retina in terms of feature detectors that are adapted to the spatio-temporal structures of natural stimuli. We also discuss how new methods based on machine learning may complement the normative, principles-based approach to theoretical neuroscience.

Optical photons present many interesting aspects in the context of the research for suitable physical representations of quantum bits. Photons are chargeless particles, and do not interact strongly with each other, or even with most matter. They can be guided along long distances with low loss in optical fibers, delayed efficiently using phase shifters, and combined easily using beamsplitters. Photons exhibit typical quantum phenomena, such as the interference produced in two-slit experiments. Furthermore, in principle, photons can be made interact with each other if carefully handled. There are many practical problems with this approach; nevertheless it presents, beyond what has already been noted, an appealing conceptual simplicity.The purpose of this work is to present - at least, in its fundamental principles - a set of optical photon quantum gates that is universal for quantum computation. To do so, we begin by gathering the necessary mathematical and physical tools. We discuss canonical quantization for the electromagnetic field, and we formalize in an abstract context the characteristic properties of every realization of the Fock canonical commutation relationships (CCR). We analize the class of the spaces where it is possible to give such a realization, and that naturally lend themselves to host the physical model of our interest. Once acquired these bases, we turn ourselves to a particular optic system, the Mach-Zehnder interferometer, and we study the general properties of this system and of its essential constituents. At this point we choose a particular encoding of quantum bit and we look at the optical devices just discussed as elements of a quantum circuit. We then discuss the fundamental ideas that may guide the implementation of some important quantum gates: Hadamard gate, $\pi/8$ gate and controlled-NOT. We conclude by showing that these three quantum gates form a universal set of gates for quantum computation.

The classic view that neural populations in sensory cortices preferentially encode responses to incoming stimuli has been strongly challenged by recent experimental studies. Despite the fact that a large fraction of variance of visual responses in rodents can be attributed to behavioral state and movements, trial-history, and salience, the effects of contextual modulations and expectations on sensory-evoked responses in visual and association areas remain elusive. Here, we present a comprehensive experimental and theoretical study showing that hierarchically connected visual and association areas differentially encode the temporal context and expectation of naturalistic visual stimuli, consistent with the theory of hierarchical predictive coding. We measured neural responses to expected and unexpected sequences of natural scenes in the primary visual cortex (V1), the posterior medial higher order visual area (PM), and retrosplenial cortex (RSP) using 2-photon imaging in behaving mice collected through the Allen Institute Mindscope’s OpenScope program. We found that information about image identity in neural population activity depended on the temporal context of transitions preceding each scene, and decreased along the hierarchy. Furthermore, our analyses revealed that the conjunctive encoding of temporal context and image identity was modulated by expectations of sequential events. In V1 and PM, we found enhanced and specific responses to unexpected oddball images, signaling stimulus-specific expectation violation. In contrast, in RSP the population response to oddball presentation recapitulated the missing expected image rather than the oddball image. These differential responses along the hierarchy are consistent with classic theories of hierarchical predictive coding whereby higher areas encode predictions and lower areas encode deviations from expectation. We further found evidence for drift in visual responses on the timescale of minutes. Although activity drift was present in all areas, population responses in V1 and PM, but not in RSP, maintained stable encoding of visual information and representational geometry. Instead we found that RSP drift was independent of stimulus information, suggesting a role in generating an internal model of the environment in the temporal domain. Overall, our results establish temporal context and expectation as substantial encoding dimensions in the visual cortex subject to fast representational drift and suggest that hierarchically connected areas instantiate a predictive coding mechanism.

Differential encoding of temporal context and expectation under representational drift across hierarchically connected areas

During sensory-guided behavior, an animal’s decision-making dynamics unfold through sequences of distinct performance states, even while stimulus-reward contingencies remain static. Little is known about the factors that underlie these changes in task performance. We hypothesize that these decision-making dynamics can be predicted by externally observable measures, such as uninstructed movements and changes in arousal. Here, combining behavioral experiments in mice with computational modeling, we uncovered lawful relationships between transitions in strategic task performance states and an animal’s arousal and uninstructed movements. Using hidden Markov models applied to behavioral choices during sensory discrimination tasks, we found that animals fluctuate between minutes-long optimal, sub-optimal and disengaged performance states. Optimal state epochs were predicted by intermediate levels, and reduced variability, of pupil diameter, along with reduced variability in face movements and locomotion. Our results demonstrate that externally observable uninstructed behaviors can predict optimal performance states, and suggest mice regulate their arousal during optimal performance.

Decision-making dynamics are predicted by arousal and uninstructed movements

Transitions between discrete performance states in auditory and visual tasks are predicted by arousal and uninstructed movements

Naturalistic animal behavior exhibits a strikingly complex organization in the temporal domain, with variability arising from at least three sources: hierarchical, contextual, and stochastic. What neural mechanisms and computational principles underlie such intricate temporal features? In this review, we provide a critical assessment of the existing behavioral and neurophysiological evidence for these sources of temporal variability in naturalistic behavior. Recent research converges on an emergent mechanistic theory of temporal variability based on attractor neural networks and metastable dynamics, arising via coordinated interactions between mesoscopic neural circuits. We highlight the crucial role played by structural heterogeneities as well as noise from mesoscopic feedback loops in regulating flexible behavior. We assess the shortcomings and missing links in the current theoretical and experimental literature and propose new directions of investigation to fill these gaps.

Neural mechanisms underlying the temporal organization of naturalistic animal behavior

Changes in an animal's behavioral state, such as arousal and movements, induce {complex modulations of the baseline input currents to sensory areas, eliciting sensory modality-specific effects. A simple computational principle explaining the effects of baseline modulations to recurrent cortical circuits is lacking. We investigate the benefits of baseline modulations using a reservoir computing approach in recurrent neural networks with random couplings. Baseline modulations unlock a set of new network phases and phenomena, including chaos enhancement, neural hysteresis and ergodicity breaking. Strikingly, baseline modulations enable reservoir networks to perform multiple tasks, without any optimization of the network couplings.} Baseline control of network dynamics opens new directions for brain-inspired artificial intelligence and sheds new light on behavioral modulations of cortical activity.

Temporal associations between sensory stimuli separated in time rely on the interaction between the hippocam- 1 pus and medial prefrontal cortex (mPFC). However, it is not known how changes in their neural activity support 2 the emergence of temporal association learning. Here, we use simultaneous electrophysiological recordings in 3 the hippocampal CA1 region and mPFC of mice to elucidate the neural dynamics underlying memory formation 4 in an auditory trace conditioning task. We found that in both areas conditioned (CS+/CS-) and unconditioned 5 stimuli (US) evoked similar temporal sequences of neural responses that progressively diverged during learning. 6 Additionally, persistent CS representations emerged in mPFC after learning, supported by CS+ coding states 7 whose transient reactivation reliably predicted lick onset and behavioral performance on single trials. These 8 results show that coordination of temporal sequences in CA1 and persistent activity in mPFC may underlie 9 temporal association learning, and that transient reactivations of engrams in mPFC predict the animal behavior. 10

Emergence of persistent and sequential representations in the hippocampal-prefrontal circuitry during associative learning

Temporal associations between sensory stimuli separated in time rely on the interaction between the hippocampus and medial prefrontal cortex (mPFC). However, it is not known how changes in their neural activity support the emergence of temporal association learning. Here, we use simultaneous electrophysiological recordings in the hippocampal CA1 region and mPFC of mice to elucidate the neural dynamics underlying memory formation in an auditory trace conditioning task. We found that in both areas conditioned (CS+/CS-) and unconditioned stimuli (US) evoked similar temporal sequences of neural responses that progressively diverged during learning. Additionally, persistent CS representations emerged in mPFC after learning, supported by CS+ coding states whose transient reactivation reliably predicted lick onset and behavioral performance on single trials. These results show that coordination of temporal sequences in CA1 and persistent activity in mPFC may underlie temporal association learning, and that transient reactivations of engrams in mPFC predict the animal behavior. Highlights Temporal representation of CS+, but not CS- and US, strengthens in CA1 after learning. Similarity between stimulus and reward temporal representations decrease with learning, but is recovered in error trials. Representation of stimulus identity is strong and stable in PFC since stimulus onset, while it only emerges in CA1 during trace period. Neural states defined on faster time-scales reveal the emergence of CS coding states in PFC whose onset predicts lick times and task performance. PFC-CA1 states are relatively less coordinated during late CS+ stimulus and trace.

Coexisting persistent and dynamic representations of stimulus, time and trial outcome emerge in the hippocampus-prefrontal circuitry during learning of a temporal association

Changes in behavioral state, such as arousal and movements, strongly affect neural activity in sensory areas. Recent evidence suggests that they may be mediated by top-down projections regulating the statistics of baseline input currents to sensory areas, inducing qualitatively different effects across sensory modalities. What are the computational benefits of these baseline modulations? We investigate this question within a brain-inspired framework for reservoir computing, where we vary the quenched baseline inputs to a random neural network. We found that baseline modulations control the dynamical phase of the reservoir network, unlocking a vast repertoire of network phases. We uncover a new zoo of bistable phases exhibiting the simultaneous coexistence of fixed points and chaos, of two fixed points, and of weak and strong chaos. Crucially, we discovered a host of novel phenomena, including noise-driven enhancement of chaos and ergodicity breaking; neural hysteresis, whereby transitions across phase boundary retain the memory of the initial phase. Strikingly, we found that baseline control can achieve optimal performance without any fine tuning of recurrent couplings. In summary, baseline control of network dynamics opens new directions for brain-inspired artificial intelligence and provides a new interpretation for the ubiquitously observed behavioral modulations of cortical activity.

Baseline control of optimal performance in recurrent neural networks

In natural contexts, sensory processing and motor output are closely coupled, which is reflected in the fact that many brain areas contain both sensory and movement signals. However, standard reductionist paradigms decouple sensory decisions from their natural motor consequences, and head-fixation prevents the natural sensory consequences of self-motion. In particular, movement through the environment provides a number of depth cues beyond stereo vision that are poorly understood. To study the integration of visual processing and motor output in a naturalistic task, we investigated distance estimation in freely moving mice. We found that mice use vision to accurately jump across a variable gap, thus directly coupling a visual computation to its corresponding ethological motor output. Monocular eyelid suture did not affect gap jumping success, thus mice can use cues that do not depend on binocular disparity and stereo vision. Under monocular conditions, mice altered their head positioning and performed more vertical head movements, consistent with a shift from using stereopsis to other monocular cues, such as motion or position parallax. Finally, optogenetic suppression of primary visual cortex impaired task performance under both binocular and monocular conditions when optical fiber placement was localized to binocular or monocular zone V1, respectively. Together, these results show that mice can use monocular cues, relying on visual cortex, to accurately judge distance. Furthermore, this behavioral paradigm provides a foundation for studying how neural circuits convert sensory information into ethological motor output.

Distance estimation from monocular cues in an ethological visuomotor task

The temporal activity of many biological systems, including neural circuits, exhibits fluctuations simultaneously varying over a large range of timescales. The mechanisms leading to this temporal heterogeneity are yet unknown. Here we show that random neural networks endowed with a distribution of self-couplings, representing functional neural clusters of different sizes, generate multiple timescales of activity spanning several orders of magnitude. When driven by a time-dependent broadband input, slow and fast neural clusters preferentially entrain slow and fast spectral components of the input, respectively, suggesting a potential mechanism for spectral demixing in cortical circuits.

To thrive in dynamic environments, animals must be capable of rapidly and flexibly adapting behavioral responses to a changing context and internal state. Examples of behavioral flexibility include faster stimulus responses when attentive and slower responses when distracted. Contextual or state-dependent modulations may occur early in the cortical hierarchy and may be implemented via top-down projections from corticocortical or neuromodulatory pathways. However, the computational mechanisms mediating the effects of such projections are not known. Here, we introduce a theoretical framework to classify the effects of cell type-specific top-down perturbations on the information processing speed of cortical circuits. Our theory demonstrates that perturbation effects on stimulus processing can be predicted by intrinsic gain modulation, which controls the timescale of the circuit dynamics. Our theory leads to counterintuitive effects, such as improved performance with increased input variance. We tested the model predictions using large-scale electrophysiological recordings from the visual hierarchy in freely running mice, where we found that a decrease in single-cell intrinsic gain during locomotion led to an acceleration of visual processing. Our results establish a novel theory of cell type-specific perturbations, applicable to top-down modulation as well as optogenetic and pharmacological manipulations. Our theory links connectivity, dynamics, and information processing via gain modulation. SIGNIFICANCE STATEMENT To thrive in dynamic environments, animals adapt their behavior to changing circumstances and different internal states. Examples of behavioral flexibility include faster responses to sensory stimuli when attentive and slower responses when distracted. Previous work suggested that contextual modulations may be implemented via top-down inputs to sensory cortex coming from higher brain areas or neuromodulatory pathways. Here, we introduce a theory explaining how the speed at which sensory cortex processes incoming information is adjusted by changes in these top-down projections, which control the timescale of neural activity. We tested our model predictions in freely running mice, revealing that locomotion accelerates visual processing. Our theory is applicable to internal modulation as well as optogenetic and pharmacological manipulations and links circuit connectivity, dynamics, and information processing.

State-Dependent Regulation of Cortical Processing Speed via Gain Modulation

Natural animal behavior displays rich lexical and temporal dynamics, even in a stable environment. This implies that behavioral variability arises from sources within the brain, but the origin and mechanics of these processes remain largely unknown. Here, we focus on the observation that the timing of self-initiated actions shows large variability even when they are executed in stable, well-learned sequences. Could this mix of reliability and stochasticity arise within the same circuit? We trained rats to perform a stereotyped sequence of self-initiated actions and recorded neural ensemble activity in secondary motor cortex (M2), which is known to reflect trial-by-trial action timing fluctuations. Using hidden Markov models we established a robust and accurate dictionary between ensemble activity patterns and actions. We then showed that metastable attractors, representing activity patterns with the requisite combination of reliable sequential structure and high transition timing variability, could be produced by reciprocally coupling a high dimensional recurrent network and a low dimensional feedforward one. Transitions between attractors were generated by correlated variability arising from the feedback loop between the two networks. This mechanism predicted a specific structure of low-dimensional noise correlations that were empirically verified in M2 ensemble dynamics. This work suggests a robust network motif as a novel mechanism to support critical aspects of animal behavior and establishes a framework for investigating its circuit origins via correlated variability.

Metastable attractors explain the variable timing of stable behavioral action sequences

To thrive in dynamic environments, animals can generate flexible behavior and rapidly adapt responses to a changing context and internal state. Examples of behavioral flexibility include faster stimulus responses when attentive and slower responses when distracted. Contextual modulations may occur early in the cortical hierarchy and may be implemented via afferent projections from top-down pathways or neuromodulation onto sensory cortex. However, the computational mechanisms mediating the effects of such projections are not known. Here, we investigate the effects of afferent projections on the information processing speed of cortical circuits. Using a biologically plausible model based on recurrent networks of excitatory and inhibitory neurons arranged in cluster, we classify the effects of cell-type specific perturbations on the circuit’s stimulus-processing capability. We found that perturbations differentially controlled processing speed, leading to counterintuitive effects such as improved performance with increased input variance. Our theory explains the effects of all perturbations in terms of gain modulation, which controls the timescale of the circuit dynamics. We tested our model using large-scale electrophysiological recordings from the visual hierarchy in freely running mice, where a decrease in single-cell gain during locomotion explained the observed acceleration of visual processing speed. Our results establish a novel theory of cell-type specific perturbations linking connectivity, dynamics, and information processing via gain modulations. ar X iv :2 00 4. 04 19 0v 1 [ qbi o. N C ] 8 A pr 2 02 0

State-dependent control of cortical processing speed via gain modulation

Decision letter: Impact of precisely-timed inhibition of gustatory cortex on taste behavior depends on single-trial ensemble dynamics

Expectation-induced modulation of metastable activity underlies faster coding of sensory stimuli

Episodic memory requires linking events in time, a function dependent on the hippocampus. In “trace” fear conditioning, animals learn to associate a neutral cue with an aversive stimulus despite their separation in time by a delay period on the order of tens of seconds. But how this temporal association forms remains unclear. Here we use 2-photon calcium imaging to track neural population dynamics over the complete time-course of learning and show that, in contrast to previous theories, the hippocampus does not generate persistent activity to bridge the time delay. Instead, learning is concomitant with broad changes in the active neural population in CA1. While neural responses were highly stochastic in time, cue identity could be reliably read out from population activity rates over longer timescales after learning. These results question the ubiquity of neural sequences during temporal association learning, and suggest that trace fear conditioning relies on mechanisms that differ from persistent activity accounts of working memory.

Hippocampal Network Reorganization Underlies the Formation of a Temporal Association Memory

O18. Changes in Effective Hippocampal Network Coupling Mediate Learning and Memory of Associations Between Temporally Discontiguous Stimuli

Single-trial analyses of ensemble activity in alert animals demonstrate that cortical circuits dynamics evolve through temporal sequences of metastable states. Metastability has been studied for its potential role in sensory coding, memory, and decision-making. Yet, very little is known about the network mechanisms responsible for its genesis. It is often assumed that the onset of state sequences is triggered by an external stimulus. Here we show that state sequences can be observed also in the absence of overt sensory stimulation. Analysis of multielectrode recordings from the gustatory cortex of alert rats revealed ongoing sequences of states, where single neurons spontaneously attain several firing rates across different states. This single-neuron multistability represents a challenge to existing spiking network models, where typically each neuron is at most bistable. We present a recurrent spiking network model that accounts for both the spontaneous generation of state sequences and the multistability in single-neuron firing rates. Each state results from the activation of neural clusters with potentiated intracluster connections, with the firing rate in each cluster depending on the number of active clusters. Simulations show that the model's ensemble activity hops among the different states, reproducing the ongoing dynamics observed in the data. When probed with external stimuli, the model predicts the quenching of single-neuron multistability into bistability and the reduction of trial-by-trial variability. Both predictions were confirmed in the data. Together, these results provide a theoretical framework that captures both ongoing and evoked network dynamics in a single mechanistic model.

Dynamics of Multistable States during Ongoing and Evoked Cortical Activity

The activity of ensembles of simultaneously recorded neurons can be represented as a set of points in the space of firing rates. Even though the dimension of this space is equal to the ensemble size, neural activity can be effectively localized on smaller subspaces. The dimensionality of the neural space is an important determinant of the computational tasks supported by the neural activity. Here, we investigate the dimensionality of neural ensembles from the sensory cortex of alert rats during periods of ongoing (intertrial) and stimulus-evoked activity. We find that dimensionality grows linearly with ensemble size, and grows significantly faster during ongoing activity compared to evoked activity. We explain these results using a spiking network model based on a clustered architecture. The model captures the difference in growth rate between ongoing and evoked activity and predicts a characteristic scaling with ensemble size that could be tested in high-density multi-electrode recordings. Moreover, we present a simple theory that predicts the existence of an upper bound on dimensionality. This upper bound is inversely proportional to the amount of pair-wise correlations and, compared to a homogeneous network without clusters, it is larger by a factor equal to the number of clusters. The empirical estimation of such bounds depends on the number and duration of trials and is well predicted by the theory. Together, these results provide a framework to analyze neural dimensionality in alert animals, its behavior under stimulus presentation, and its theoretical dependence on ensemble size, number of clusters, and correlations in spiking network models.

Most of the research on cortical processing of taste has focused on either the primary gustatory cortex (GC) or the orbitofrontal cortex (OFC). However, these are not the only areas involved in taste processing. Gustatory information can also reach another frontal region, the medial prefrontal cortex (mPFC), via direct projections from GC. mPFC has been studied extensively in relation to its role in controlling goal-directed action and reward-guided behaviors, yet very little is known about its involvement in taste coding. The experiments presented here address this important point and test whether neurons in mPFC can significantly process the physiochemical and hedonic dimensions of taste. Spiking responses to intraorally delivered tastants were recorded from rats implanted with bundles of electrodes in mPFC and GC. Analysis of single-neuron and ensemble activity revealed similarities and differences between the two areas. Neurons in mPFC can encode the chemosensory identity of gustatory stimuli. However, responses in mPFC are sparser, more narrowly tuned, and have a later onset than in GC. Although taste quality is more robustly represented in GC, taste palatability is coded equally well in the two areas. Additional analysis of responses in neurons processing the hedonic value of taste revealed differences between the two areas in temporal dynamics and sensitivities to palatability. These results add mPFC to the network of areas involved in processing gustatory stimuli and demonstrate significant differences in taste-coding between GC and mPFC.

Processing of Hedonic and Chemosensory Features of Taste in Medial Prefrontal and Insular Networks

The computation of anomalous dimensions of gauge invariant operators is a central problem in non-abelian gauge theories. For example, they are related to the parton distribution function in the DIS regime of QCD. Typically, one can compute such quantities in perturbation theory at weak coupling. Solving this problem in the strong coupling regime or even at finite values of the coupling has been a formidable challenge and requires new insights. In the case of four-dimensional N = 4 super Yang-Mills theory, this seemingly hopeless task can be attacked using the methods of integrability and exploiting the holographic duality between gauge theories and superstring theory [1]. In the planar limit of the gauge theory, the interplay between these two approaches led eventually to the conjecture that the anomalous dimensions of all gauge invariant operators can be computed at any value of the coupling, using the so called Ysystem [2]. By solving a complicated system of integral equations, one can numerically estimate the strong coupling expansion coefficients of such conformal dimensions. This conjecture has passed several checks, in particular in the sector of long gauge invariant operators, constructed using an asymptotically large number of elementary fields, both at weak and at strong coupling [1]. An extensive numerical study of the Y-system has been carried out and compared to semi-classical techniques. However, short non-protected operators, that constitute the most natural sector from the gauge theory point of view, are hard to study and existing methods are not reliable in this regime. In this talk, we will report on a new method [3] to compute the anomalous dimensions of operators in N = 4 super Yang-Mills theory at strong coupling, using the

We derive a holographic dual description of free quantum field theory in arbitrary dimensions, by reinterpreting the exact renormalization group to obtain a higher spin gravity theory of the general type which had been proposed and studied as a dual theory. We show that the dual theory reproduces all correlation functions.

We show that the relation between the 't Hooft coupling and the radius of AdS is not renormalized at one-loop in the sigma model perturbation theory. We prove this by computing the quantum effective action for the superstring on AdS5 × S5 and showing that it does not receive any finite α' corrections. We also show that the central charge of the interacting worldsheet conformal field theory vanishes at one-loop.

We consider candidates for dark matter in models of gauge mediated super- symmetry breaking, in which the supersymmetry breaking sector is weakly coupled and calculable. Such models typically contain classically flat directions, that receive one-loop masses of a few TeV. These pseudo-flat directions provide a new mechanism to account for the cold dark matter relic abundance. We discuss also the possibility of heavy (∼ 1GeV) gravitino dark matter in such models.

Dark matter and pseudo-flat directions in weakly coupled SUSY breaking sectors

We analyze an R-symmetry breaking deformation of the ISS model for a direct mediation of supersymmetry breaking from a metastable vacuum. The model is weakly coupled and calculable. The LSP gravitino is light (m3/2 < 16 eV) and the MSSM spectrum is natural with a light Higgs. The supersymmetry breaking sector, which is usually hidden, is observable (m ~ 1 TeV) and may be a candidate for cold dark matter. We discuss its production and signature at LHC. We propose a UV completion of the model in terms of a duality cascade.

Direct Mediation and a Visible Metastable Supersymmetry Breaking Sector

We analyze an R-symmetry breaking deformation of the ISS model for a direct mediation of supersymmetry breaking from a metastable vacuum. The model is weakly coupled and calculable. The LSP gravitino is light (m 3 2 < 16 eV) and the MSSM spectrum is natural with a light Higgs. The supersymmetry breaking sector, which is usually hidden, is observable (m ∼ 1TeV) and may be a candidate for cold dark matter. We discuss its production and signature at LHC. We propose a UV completion of the model in terms of a duality cascade.

We construct gravitational non-relativistic brane solutions of type IIA/IIB string theories and M-theory and their near-horizon geometries. The non-relativistic M2 and M5-brane metrics have Schrodinger symmetries with dynamical exponent z = 3/2 and z = 3, respectively, whereas the known D3-brane solution has z = 2. The non-relativistic D-brane, NS5-brane, F-string and KK monopole metrics have asymptotically space and time translations, space rotations, Galilean symmetries and a particle number symmetry. We construct two different gravitational backgrounds of a non-relativistic D1-D5 system, both having asymptotically Schrodinger symmetry with exponent z = 2. We study the properties of the solutions and their phase diagram.

We consider intersecting brane configurations realizing = 2 supersymmetric gauge theories broken to = 1 by multitrace superpotentials, and softly to = 0. We analyze, in the framework of M5-brane wrapping a curve, the supersymmetric vacua and the analogs of spontaneous supersymmetry breaking and soft supersymmetry breaking in gauge theories. We show that the M5-brane does not exhibit the analog of metastable spontaneous supersymmetry breaking, and does not have non-holomorphic minimal volume curves with holomorphic boundary conditions. However, we find that any point in the = 2 moduli space can be rotated to a non-holomorphic minimal volume curve, whose boundary conditions break supersymmetry. We interpret these as the analogs of soft supersymmetry breaking vacua in the gauge theory.

We consider type II superstrings on AdS backgrounds with Ramond-Ramond flux in various dimensions. We realize the backgrounds as supercosets and analyze explicitly two classes of models: non-critical superstrings on AdS2d and critical superstrings on AdSp × Sp × CY. We work both in the Green-Schwarz and in the pure spinor formalisms. We construct a one-parameter family of flat currents (a Lax connection), leading to an infinite number of conserved non-local charges, which imply the classical integrability of both sigma-models. In the pure spinor formulation, we use the BRST symmetry to prove the quantum integrability of the sigma-model. We discuss how classical κ-symmetry implies one-loop conformal invariance. We consider the addition of space-filling D-branes to the pure spinor formalism.

Integrability of type II superstrings on Ramond-Ramond backgrounds in various dimensions

We construct non-critical pure spinor superstrings in two, four and six dimen- sions. We find explicitly the map between the RNS variables and the pure spinor ones in the linear dilaton background. The RNS variables map onto a patch of the pure spinor space and the holomorphic top form on the pure spinor space is an essential ingredient of the mapping. A basic feature of the map is the requirement of doubling the superspace, which we analyze in detail. We study the structure of the non-critical pure spinor space, which is different from the ten-dimensional one, and its quantum anomalies. We compute the pure spinor lowest lying BRST cohomology and find an agreement with the RNS spec- tra. The analysis is generalized to curved backgrounds and we construct as an example the non-critical pure spinor type IIA superstring on AdS4 with RR 4-form flux.

We study the effective superpotential of = 1 supersymmetric gauge theories with a mass gap, whose analytic properties are encoded in an algebraic curve. We propose that the degree of the curve equals the number of semiclassical branches of the gauge theory. This is true for supersymmetric QCD with one adjoint and polynomial superpotential, where the two sheets of its hyperelliptic curve correspond to the gauge theory pseudoconfining and higgs branches. We verify this proposal in the new case of supersymmetric QCD with two adjoints and superpotential V(X)+XY2, which is the confining phase deformation of the Dn+2 SCFT. This theory has three kinds of classical vacua and its curve is cubic. Each of the three sheets of the curve corresponds to one of the three semiclassical branches of the gauge theory. We show that one can continuously interpolate between these branches by varying the couplings along the moduli space.

Remarks on the analytic structure of supersymmetric effective actions

We study electric-magnetic duality in the chiral ring of a supersymmetric U(Nc) gauge theory with adjoint and fundamental matter, in presence of a general confining phase superpotential for the adjoint and the mesons. We find the magnetic solution corresponding to both the pseudoconfining and Higgs electric vacua. By means of the Dijkgraaf-Vafa method, we match the effective glueball superpotentials and show that in some cases duality works exactly offshell. We give also a picture of the analytic structure of the resolvents in the magnetic theory, as we smoothly interpolate between different Higgs vacua on the electric side.

We propose that the = 2 SYM instanton moduli space maps to the one of punctured spheres, in the framework of the Liouville F-models. This leads to a bilinear recursion relation for the instanton contributions, resembling Hurwitz numbers, and predicts the asymptotic form of the GW invariants. The map is interpreted in the frameworks of the geometric engineering approach to the gauge theory, i.e. the topological A-model, and of the noncritical string theory. We speculate on the extension to the gravitational background and its relation to the uniformization program. Finally, we show an intriguing analogy with the gravitational version of the SU(2) self-dual YM equations where surprisingly the same Hauptmodule of the SW solution appears.

The Liouville geometry of = 2 instantons and the moduli of punctured spheres

We consider the chiral ring of the pure = 1 supersymmetric gauge theory with SU(N) gauge group and show that the classical relation SclN2 = 0 is modified to the exact quantum relation (SN−Λ3N)N = 0.

In the framework of the matrix model/gauge theory correspondence, we consider supersymmetric U(N) gauge theory with U(1)N symmetry breaking pattern. Due to the presence of the Veneziano–Yankielowicz effective superpotential, in order to satisfy the F–term condition ∑iSi = 0, we are forced to introduce additional terms in the free energy of the corresponding matrix model with respect to the usual formulation. This leads to a matrix model formulation with a cubic potential which is free of parameters and displays a branched structure. In this way we naturally solve the usual problem of the identification between dimensionful and dimensionless quantities. Furthermore, we need not introduce the = 1 scale by hand in the matrix model. These facts are related to remarkable coincidences which arise at the critical point and lead to a branched bare coupling constant. The latter plays the role of the = 1 and = 2 scales tuning parameter. We then show that a suitable rescaling leads to the correct identification of the = 2 variables. Finally, by means of the mentioned coincidences, we provide a direct expression for the = 2 prepotential, including the gravitational corrections, in terms of the free energy. This suggests that the matrix model provides a triangulation of the istanton moduli space.

Branched matrix models and the scales of supersymmetric gauge theories

The superembedding origin of the Berkovits pure spinor covariant quantization of superstrings

Introduction: Microphysiological systems (MPS; organ-on-a-chip) aim to recapitulate the 3D organ microenvironment and improve clinical predictivity relative to previous approaches. Though MPS studies provide great promise to explore treatment options in a multifactorial manner, they are often very complex. It is therefore important to assess and manage technical confounding factors, to maximise power, efficiency and scalability. Methods: As an illustration of how MPS studies can benefit from a systematic evaluation of confounders, we developed an experimental design approach for a bone marrow (BM) MPS and tested it for a specified context of use, the assessment of lineage-specific toxicity. Results: We demonstrated the accuracy of our multicolour flow cytometry set-up to determine cell type and maturity, and the viability of a “repeated measures” design where we sample from chips repeatedly for increased scalability and robustness. Importantly, we demonstrated an optimal way to arrange technical confounders. Accounting for these confounders in a mixed-model analysis pipeline increased power, which meant that the expected lineage-specific toxicities following treatment with olaparib or carboplatin were detected earlier and at lower doses. Furthermore, we performed a sample size analysis to estimate the appropriate number of replicates required for different effect sizes. This experimental design-based approach will generalise to other MPS set-ups. Discussion: This design of experiments approach has established a groundwork for a reliable and reproducible in vitro analysis of BM toxicity in a MPS, and the lineage-specific toxicity data demonstrate the utility of this model for BM toxicity assessment. Toxicity data demonstrate the utility of this model for BM toxicity assessment.

Optimal experimental design for efficient toxicity testing in microphysiological systems: A bone marrow application

Journal of the Royal Statistical Society: Series A (Statistics in Society)

Bayesian Modeling and Computation in Python LearningOsvaldo A.Martin, RavinKumar, JunpengLao, 2021, Chapman & Hall/CRC Press, Boca Raton, FL, 422 pages, £74.99 (hardcover), ISBN: 978‐0367894368

Artificial intelligence and causal inference By Momiao Xiong (2022), Chapman & Hall/
 CRC
 Press, Boca Raton, FL. 368 pp., £99.99 (hardcover),
 ISBN
 : 978‐0367859404

A Computational Approach to Statistical LearningTaylorArnold, MichaelKane, Bryan W.Lewis, CRC Press, Boca Raton, FL. 374p., ISBN: 9780367570613

Most scientific disciplines use significance testing to draw conclusions about experimental or observational data. This classical approach provides a theoretical guarantee for controlling the number of false positives across a set of hypothesis tests, making it an appealing framework for scientists seeking to limit the number of false effects or associations that they claim to observe. Unfortunately, this theoretical guarantee applies to few experiments, and the true false positive rate (FPR) is much higher. Scientists have plenty of freedom to choose the error rate to control, the tests to include in the adjustment, and the method of correction, making strong error control difficult to attain. In addition, hypotheses are often tested after finding unexpected relationships or patterns, the data are analysed in several ways, and analyses may be run repeatedly as data accumulate. As a result, adjusted p-values are too small, incorrect conclusions are often reached, and results are harder to reproduce. In the following, I argue why the FPR is rarely controlled meaningfully and why shrinking parameter estimates is preferable to p-value adjustments.

Why multiple hypothesis test corrections provide poor control of false positives in the real world

Medical Risk Prediction Models: With Ties to Machine LearningThomas A.Gerds and Michael W.Kattan (2021), Chapman & Hall/CRC Press, Boca Raton, FL, 312 pages, £74.99 (hardcover), ISBN: 978‐1138384477

In high grade serous ovarian cancer (HGSOC), there is a spectrum of sensitivity to first line platinum‐based chemotherapy. This study molecularly characterizes HGSOC patients from two distinct groups of chemotherapy responders (good vs. poor).

Tumor genomic, transcriptomic, and immune profiling characterizes differential response to first‐line platinum chemotherapy in high grade serous ovarian cancer

A proteolysis-targeting chimera (PROTAC) is a new technology that marks proteins for degradation in a highly specific manner. During screening, PROTAC compounds are tested in concentration–response (CR) assays to determine their potency, and parameters such as the half-maximal degradation concentration (DC50) are estimated from the fitted CR curves. These parameters are used to rank compounds, with lower DC50 values indicating greater potency. However, PROTAC data often exhibit biphasic and polyphasic relationships, making standard sigmoidal CR models inappropriate. A common solution includes manual omitting of points (the so-called masking step), allowing standard models to be used on the reduced data sets. Due to its manual and subjective nature, masking becomes a costly and nonreproducible procedure. We therefore used a Bayesian changepoint Gaussian processes model that can flexibly fit both nonsigmoidal and sigmoidal CR curves without user input. Parameters such as the DC50, maximum effect Dmax, and point of departure (PoD) are estimated from the fitted curves. We then rank compounds based on one or more parameters and propagate the parameter uncertainty into the rankings, enabling us to confidently state if one compound is better than another. Hence, we used a flexible and automated procedure for PROTAC screening experiments. By minimizing subjective decisions, our approach reduces time and cost and ensures reproducibility of the compound-ranking procedure. The code and data are provided on GitHub (https://github.com/elizavetasemenova/gp_concentration_response).

Flexible Fitting of PROTAC Concentration–Response Curves with Changepoint Gaussian Processes

Quantifying sources of uncertainty in drug discovery predictions with probabilistic models

A multi-batch design to deliver robust estimates of efficacy and reduce animal use – a syngeneic tumour case study

A Bayesian predictive approach for dealing with pseudoreplication

Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the “ARRIVE Essential 10,” which constitutes the minimum requirement, and the “Recommended Set,” which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.

The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research*

Drug induced liver injury (DILI) can require significant risk management in drug development, and on occasion can cause morbidity or mortality, leading to drug attrition. Optimising candidates preclinically can minimise hepatotoxicity risk but it is difficult to predict due to multiple aetiologies encompassing DILI, often with multifactorial and overlapping mechanisms. In addition to epidemiological risk factors, physicochemical properties, dose, disposition, lipophilicity, and hepatic metabolic function are also relevant for DILI risk. Better human relevant, predictive models are required to improve hepatotoxicity risk assessment in drug discovery. Our hypothesis is that integrating mechanistically relevant hepatic safety assays with Bayesian machine learning will improve hepatic safety risk prediction. We present a quantitative and mechanistic risk assessment for candidate nomination using data from in vitro assays (hepatic spheroids, BSEP, mitochondrial toxicity and bioactivation), together with physicochemical (cLogP) and exposure (Cmaxtotal) variables from a chemically diverse compound set (33 no/low-, 40 medium- and 23 high-severity DILI compounds). The Bayesian model predicts the continuous underlying DILI severity and uses a data-driven prior distribution over the parameters to prevent overfitting. The model quantifies the probability that a compound falls into either no/low, medium, or high-severity categories, with a balanced accuracy of 63% on held-out samples, and a continuous prediction of DILI severity along with uncertainty in the prediction. For a binary yes/no DILI prediction, the model has a balanced accuracy of 86%, a sensitivity of 87%, a specificity of 85%, a positive predictive value of 92%, and a negative predictive value of 78%. Combining physiologically relevant assays, improved alignment with FDA recommendations, and optimal statistical integration of assay data, leads to improved DILI risk prediction.

Predicting Drug-Induced Liver Injury with Bayesian Machine Learning.

Determining organ weight toxicity with Bayesian causal models: Improving on the analysis of relative organ weights

Predicting the toxicity of a compound preclinically enables better decision making, thereby reducing development costs and increasing patient safety. It is a complex issue, but in vitro assays and physico-chemical properties of compounds can be used to predict clinical toxicity. Neural networks (NNs) are a popular predictive tool due to their flexibility and ability to model non-linearities, but they are prone to overfitting and therefore are not recommended for small data sets. Furthermore, they don’t quantify uncertainty in the predictions. Bayesian neural networks (BNNs) are able to avoid these pitfalls by using prior distributions on the parameters of a NN model and representing uncertainty about the predictions in the form of a distribution. We model the severity of drug-induced liver injury (DILI) to provide an example of a BNN performing better than a traditional but less flexible proportional odds logistic regression (POLR) model. We use appropriate metrics to evaluate predictions of the ordinal data type. To demonstrate the effect of a hierarchical prior for BNNs as an alternative to hyperparameter optimisation for NNs, we compare the performance of a BNN against NNs with dropout or penalty regularisation. We reduce the task to multiclass classification in order to be able to perform this comparison. A BNN trained for the multiclass classification produces poorer results than a BNN that captures the order. The current work lays a foundation for more complex models built on larger datasets, but can already be adopted by safety pharmacologists for risk quantification.

The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research

Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the “ARRIVE Essential 10,” which constitutes the minimum requirement, and the “Recommended Set,” which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration (E&E) document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.

Predicting the safety of a drug from preclinical data is a major challenge in drug discovery, and progressing an unsafe compound into the clinic puts patients at risk and wastes resources. In drug safety pharmacology and related fields, methods and analytical decisions known to provide poor predictions are common and include creating arbitrary thresholds, binning continuous values, giving all assays equal weight, and multiple reuse of information. In addition, the metrics used to evaluate models often omit important criteria and models’ performance on new data are often not assessed rigorously. Prediction models with these problems are unlikely to perform well, and published models suffer from many of these issues. We describe these problems in detail, demonstrate their negative consequences, and propose simple solutions that are standard in other disciplines where predictive modelling is used.

Improving drug safety predictions by reducing poor analytical practices

A proteolysis targeting chimera (PROTAC) is a new technology that marks proteins for degradation in a highly specific manner. During screening, PROTAC compounds are tested in concentration-response (CR) assays to determine their potency, and parameters such as the half-maximal degradation concentration (DC50) are estimated from the fitted CR curves. These parameters are used to rank compounds, with lower DC50 values indicating greater potency. However, PROTAC data often exhibit bi-phasic and poly-phasic relationships, making standard sigmoidal CR models inappropriate. A common solution includes manual omitting of points (the so called “masking” step) allowing standard models to be used on the reduced datasets. Due to its manual and subjective nature, masking becomes a costly and non-reproducible procedure. We, therefore, used a Bayesian changepoint Gaussian Processes model that can flexibly fit both non-sigmoidal and sigmoidal CR curves without user input. Parameters, such as the DC50, the maximum effect Dmax, and the point of departure (PoD) are estimated from the fitted curves. We then rank compounds based on one or more parameters, and propagate the parameter uncertainty into the rankings, enabling us to confidently state if one compound is better than another. Hence, we used a flexible and automated procedure for PROTAC screening experiments. By minimizing subjective decisions, our approach reduces time, cost, and ensures reproducibility of the compound ranking procedure. The code and data are provided on GitHub (https://github.com/elizavetase-menova/gp_concentration_response).

Flexible fitting of PROTAC concentration-response curves with changepoint Gaussian Processes

Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into two sets, the ‘ARRIVE Essential 10’, which constitutes the minimum requirement, and the ‘Recommended Set’, which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.

The ARRIVE guidelines 2.0: updated guidelines for reporting animal research

Due to strain-specific behavioral idiosyncrasies, inbred mouse strains are suboptimal research models for behavioral aging studies. The aim of this study is to determine age-related behavioral changes of F2 hybrid C57BL/6NxBALB/c male and female mice. Lifespan was followed (nmales=48, nfemales=51) and cohorts of mature adult (7 months), middle-aged (15 months), and old mice (22 months of age; n=7-12 per group) were assessed regarding open-field activity, exploration, passive avoidance learning/memory, and depressive-like behavior. We found that both males and females demonstrated decreased exploratory behavior with age, while memory and depressive-like behavior were maintained. Females exhibited enhanced depressive-like behavior compared to males; however, a correlation between fat mass and swimming activity in the test directly accounted for 30-46% of this behavioral sex difference. In addition, we suggest a method to qualitatively estimate natural lifespan from survival analyses in which animals with signs of pain or severe disease are euthanized. This is, to our knowledge, the first behavioral study to consider both sex and aging in hybrid mice. We here define decreased exploratory behavior as a conserved hallmark of aging independent of sex, highlight the effect of buoyancy in water tests, and provide a method to assay lifespan with reduced animal suffering.

Conclusions from a behavioral aging study on male and female F2 hybrid mice on age-related behavior, buoyancy in water-based tests, and an ethical method to assess lifespan

Integrated in vitro models for hepatic safety and metabolism: evaluation of a human Liver-Chip and liver spheroid

Likelihood Methods in Biology and Ecology: a Modern Approach to StatisticsM.Brimacombe2019Boca RatonCRC Press 202 pp., £74.99 ISBN 978‐1‐584‐88788‐1

Designing stem-cell-based dopamine cell replacement trials for Parkinson’s disease

Bayesian Regression Modeling with INLAX.WangY. R.Yue and J. J.Faraway2018Boca Raton CRC Press 312 pp., £66.99 ISBN 978‐1‐498‐72725‐9

This Formal Comment responds to Jordan et al., and stresses that if scientific findings are to be robust, training in experimental design and statistics is critical to ensure that research questions, design considerations, and analyses are aligned.

Training in experimental design and statistics is essential: Response to Jordan

Underpowered experiments have three problems: true effects are harder to detect, the true effects that are detected tend to have inflated effect sizes and as power decreases so does the probability that a statistically significant result represents a true effect. Many biology experiments are underpowered and recent calls to change the traditional 0.05 significance threshold to a more stringent value of 0.005 will further reduce the power of the average experiment. Increasing power by increasing the sample size is often the only option considered, but more samples increases costs, makes the experiment harder to conduct and is contrary to the 3Rs principles for animal research. We show how the design of an experiment and some analytical decisions can have a surprisingly large effect on power.

Four simple ways to increase power without increasing the sample size

Experimental Design for Laboratory Biologists: Maximising Information and Improving Reproducibility. By Stanley E. Lazic. Cambridge and New York: Cambridge University Press. $175.00 (hardcover); $64.99 (paper). xv + 412 p.; ill.; index. ISBN: 978-1-107-07429-3 (hc); 978-1-107-42488-3 (pb); 978-1-316

Motivation: Identifying phenotypes based on high‐content cellular images is challenging. Conventional image analysis pipelines for phenotype identification comprise multiple independent steps, with each step requiring method customization and adjustment of multiple parameters. Results: Here, we present an approach based on a multi‐scale convolutional neural network (M‐CNN) that classifies, in a single cohesive step, cellular images into phenotypes by using directly and solely the images’ pixel intensity values. The only parameters in the approach are the weights of the neural network, which are automatically optimized based on training images. The approach requires no a priori knowledge or manual customization, and is applicable to single‐ or multi‐channel images displaying single or multiple cells. We evaluated the classification performance of the approach on eight diverse benchmark datasets. The approach yielded overall a higher classification accuracy compared with state‐of‐the‐art results, including those of other deep CNN architectures. In addition to using the network to simply obtain a yes‐or‐no prediction for a given phenotype, we use the probability outputs calculated by the network to quantitatively describe the phenotypes. This study shows that these probability values correlate with chemical treatment concentrations. This finding validates further our approach and enables chemical treatment potency estimation via CNNs. Availability and Implementation: The network specifications and solver definitions are provided in Supplementary Software 1. Contact: william_jose.godinez_navarro@novartis.com or xian‐1.zhang@novartis.com Supplementary information: Supplementary data are available at Bioinformatics online.

A multi‐scale convolutional neural network for phenotyping high‐content cellular images

Biologists establish the existence of experimental effects by applying treatments or interventions to biological entities or units, such as people, animals, slice preparations, or cells. When done appropriately, independent replication of the entity-intervention pair contributes to the sample size (N) and forms the basis of statistical inference. However, sometimes the appropriate entity-intervention pair may not be obvious, and the wrong choice can make an experiment worthless. We surveyed a random sample of published animal experiments from 2011 to 2016 where interventions were applied to parents but effects examined in the offspring, as regulatory authorities have provided clear guidelines on replication with such designs. We found that only 22% of studies (95% CI = 17% to 29%) replicated the correct entity-intervention pair and thus made valid statistical inferences. Approximately half of the studies (46%, 95% CI = 38% to 53%) had pseudoreplication while 32% (95% CI = 26% to 39%) provided insufficient information to make a judgement. Pseudoreplication artificially inflates the sample size, leading to more false positive results and inflating the apparent evidence supporting a scientific claim. It is hard for science to advance when so many experiments are poorly designed and analysed. We argue that distinguishing between biological units, experimental units, and observational units clarifies where replication should occur, describe the criteria for genuine replication, and provide guidelines for designing and analysing in vitro, ex vivo, and in vivo experiments.

Drug toxicity is a major source of attrition in drug discovery and development. Pharmaceutical companies routinely use preclinical data to predict clinical outcomes and continue to invest in new assays to improve predictions. However, there are many open questions about how to make the best use of available data, combine diverse data, quantify risk, and communicate risk and uncertainty to enable good decisions. The costs of suboptimal decisions are clear: resources are wasted and patients may be put at risk. We argue that Bayesian methods provide answers to all of these problems and use hERG-mediated QT prolongation as a case study. Benefits of Bayesian machine learning models include intuitive probabilistic statements of risk that incorporate all sources of uncertainty, the option to include diverse data and external information, and visualisations that have a clear link between the output from a statistical model and what this means for risk. Furthermore, Bayesian methods are easy to use with modern software, making their adoption for safety screening straightforward. We include R and Python code to encourage the adoption of these methods.

Predicting drug safety and communicating risk: benefits of a Bayesian approach

There has been significant focus on drug-induced QT interval prolongation caused by block of the human ether-a-go-go-related gene (hERG)-encoded potassium channel. Regulatory guidance has been implemented to assess QT interval prolongation risk: preclinical guidance requires a candidate drug's potency as a hERG channel blocker to be defined and also its effect on QT interval in a non-rodent species; clinical guidance requires a "Thorough QT Study" during development, although some QT prolonging compounds are identified earlier via a Phase I study. Clinical, heart rate-corrected QT interval (QTc) data on 24 compounds (13 positives; 11 negatives) were compared with their effect on dog QTc and the concentration of compound causing 50% inhibition (IC50) of hERG current. Concordance was assessed by calculating sensitivity and specificity across a range of decision thresholds, thus yielding receiver operating characteristic curves of sensitivity versus (1-specificity). The area under the curve of ROC curves (for which 0.5 and 1 indicate chance and perfect concordance, respectively) was used to summarize concordance. Three aspects of preclinical data were compared with the clinical outcome (receiver operating characteristic area under the curve values shown in brackets): absolute hERG IC50 (0.78); safety margin between hERG IC50 and clinical peak free plasma exposure (0.80); safety margin between QTc effects in dogs and clinical peak free plasma exposure (0.81). Positive and negative predictive values of absolute hERG IC50 indicated that from an early drug discovery perspective, low potency compounds can be progressed on the basis of a low risk of causing a QTc increase.

An Analysis of the Relationship Between Preclinical and Clinical QT Interval-Related Data

An open-label study to assess the feasibility and tolerability of rilmenidine for the treatment of Huntington’s disease

Journal of The Royal Statistical Society Series A-statistics in Society

Modern Adaptive Randomized Clinical Trials: Statistical and Practical Aspects O. Sverdlov (ed.), 2016 Boca Raton, Chapman and Hall–CRC 534 pp., £69.99 ISBN 978‐1‐482‐23988‐1

I believe sanity and realism can be restored to the teaching of Mathematical Statistics most easily and directly by entrusting such teaching largely to men and women who have had personal experience of research in the Natural Sciences. Sir Ronald A. Fisher, FRS Replication is a fundamental concept in both science and statistics and is used in the everyday sense of the term to mean ‘doing something more than once’. The ‘more than once’ part is straightforward, but it is often unclear what exactly needs to be done multiple times, especially when many parts of an experiment can be replicated. In the experimental sciences, there is always a treatment or intervention applied to an entity, which in our case will be a biological entity such as a person, animal, or cell. A basic requirement for replication is to have multiple independent entity–intervention pairs. Suppose that the intervention is a drug given orally to a patient. Each patient–drug pair is considered one replication and provides independent information about the effect of the drug. The effect is then compared with placebo–patient pairs. If the question is ‘what is the effect of the drug on patients’ then replicating the patient–drug pair and patient–placebo pair enables the question to be addressed. Other aspects of this experiment could be replicated. For example, we could measure the outcome on each person more than once and replicate the measurement procedure. Or, we could give the drug to the same person multiple times and on each occasion record the outcome. Alternatively, we could even conduct the whole experiment multiple times, say once in England and once in America. Experimenters need to decide what to replicate and often the wrong part is chosen, wasting time and resources. In addition, one occasionally sees that the critical aspect of the experiment is not replicated at all, or only replicated a few times. In such cases it is either impossible to test the hypothesis of interest or the power is so low that the objectives of the experiment are unlikely to be met. A clever statistical analysis cannot fix the problem; it needs to be planned at the design stage.

The discovery of adult‐born neurons in the hippocampus has triggered a wide range of studies that link the new neurons to various behavioral functions. However, the role of new neurons in behavior is still equivocal. Conflicting results may be due to the difficulty in manipulating neurogenesis without off‐target effects as well as the statistical approach used, which fail to account for neurogenesis‐independent effects of experimental manipulations on behavior. In this study, we apply a more comprehensive statistical and conceptual approach. Instead of between‐group analyses, we consider the within‐group relationships between neurogenesis and behavior (ANCOVA and mediation analysis) in a large‐scale experiment, in which distinct age‐ (3 and 5 months) and strain‐ (DBA and C57) related differences in basal levels of neurogenesis in mice are compared with a large number (∼1,500) of behavioral read outs. The analysis failed to detect any association between anxiety and motor impulsivity with neurogenesis. However, within‐group adult hippocampal neurogenesis is associated with the reaction to novelty. Specifically, more neurogenesis is associated with a longer latency to explore and a lower frequency of exploratory actions, overall indicative of a phenotype where animals with more neurogenesis were slower to explore a novel environment. This effect is observed in 5‐months‐old, but not in 3‐months‐old mice of both strains. An association between the reaction to novelty and adult neurogenesis can have a major impact on results from previous studies using classical behavioral experiments, in which animals are tested in a—for the animal—novel experimental set‐up. The neurogenesis–novelty association found here is also a necessary link in the relation that has been suggested to exist between neurogenesis and psychiatric disorders marked by a failure to cope with novelty. © 2015 Wiley Periodicals, Inc.

Large‐scale phenotyping links adult hippocampal neurogenesis to the reaction to novelty

In functional genomics experiments, researchers often select genes to follow-up or validate from a long list of differentially expressed genes. Typically, sharp thresholds are used to bin genes into groups such as significant/non-significant or fold change above/below a cut-off value, and ad hoc criteria are also used such as favouring well-known genes. Binning, however, is inefficient and does not take the uncertainty of the measurements into account. Furthermore, p-values, fold-changes, and other outcomes are treated as equally important, and relevant genes may be overlooked with such an approach. Desirability functions are proposed as a way to integrate multiple selection criteria for ranking, selecting, and prioritising genes. These functions map any variable to a continuous 0–1 scale, where one is maximally desirable and zero is unacceptable. Multiple selection criteria are then combined to provide an overall desirability that is used to rank genes. In addition to p-values and fold-changes, further experimental results and information contained in databases can be easily included as criteria. The approach is demonstrated with a breast cancer microarray data set. The functions and an example data set can be found in the desiR package on CRAN (https://cran.r-project.org/web/packages/desiR/) and the development version is available on GitHub (https://github.com/stanlazic/desiR).

Ranking, selecting, and prioritising genes with desirability functions

Analytical strategies for the marble burying test: avoiding impossible predictions and invalid p-values

Huntington disease (HD) is a fatal autosomal dominant, neurodegenerative condition characterized by progressively worsening motor and nonmotor problems including cognitive and neuropsychiatric disturbances, along with sleep abnormalities and weight loss. However, it is not known whether sleep disturbances and metabolic abnormalities underlying the weight loss are present at a premanifest stage.

Sleep deficits but no metabolic deficits in premanifest Huntington's disease

The study was funded from a grant from CHDI Foundation, Inc.CHDI-RG50786. RAB received grants from NIHR BRC-RG64473. PS is funded by an MRC Programme grant (Physiological Modelling and Metabolic Risk: MC_UP_A090_1005).

Sleep, But No Metabolic, Deficits In Pre-Manifest Huntington's Disease

Early life stress (ES) increases vulnerability to psychopathology and impairs cognition in adulthood. These ES‐induced deficits are associated with lasting changes in hippocampal plasticity. Detailed information on the neurobiological basis, the onset, and progression of such changes and their sex‐specificity is currently lacking but is required to tailor specific intervention strategies. Here, we use a chronic ES mouse model based on limited nesting and bedding material from postnatal day (P) 2–9 to investigate; (1) if ES leads to impairments in hippocampus‐dependent cognitive function in adulthood and (2) if these alterations are paralleled by changes in developmental and/or adult hippocampal neurogenesis. ES increased developmental neurogenesis (proliferation and differentiation) in the dentate gyrus (DG) at P9, and the number of immature (NeurD1+) cells migrating postnatally from the secondary dentate matrix, indicating prompt changes in DG structure in both sexes. ES lastingly reduced DG volume and the long‐term survival of developmentally born neurons in both sexes at P150. In adult male mice only, ES reduced survival of adult‐born neurons (BrdU/NeuN+ cells), while proliferation (Ki67+) and differentiation (DCX+) were unaffected. These changes correlated with impaired performance in all learning and memory tasks used here. In contrast, in female mice, despite early alterations in developmental neurogenesis, no lasting changes were present in adult neurogenesis after ES and the cognitive impairments were less prominent and only apparent in some cognitive tasks. We further show that, although neurogenesis and cognition correlate positively, only the hippocampus‐dependent functions depend on changes in neurogenesis, whereas cognitive functions that are not exclusively hippocampus‐dependent do not. This study indicates that chronic ES has lasting consequences on hippocampal structure and function in mice and suggests that male mice are more susceptible to ES than females. Unraveling the mechanisms that underlie the persistent ES‐induced effects may have clinical implications for treatments to counteract ES‐induced deficits. © 2014 Wiley Periodicals, Inc.

Chronic early life stress alters developmental and adult neurogenesis and impairs cognitive function in mice

Title: SLEEP, BUT NO METABOLIC, DEFICITS IN PRE-MANIFEST HUNTINGTON'S DISEASE

A retrospective analysis of hand tapping as a longitudinal marker of disease progression in Huntington’s disease

Few studies that examine the neurogenesis-behaviour relationship formally establish covariation between neurogenesis and behaviour or rule out competing explanations. The behavioural relevance of neurogenesis might therefore be overestimated if other mechanisms account for some, or even all, of the experimental effects. All publicly available data was reanalysed using causal mediation analysis, which can estimate the unique contribution of new hippocampal neurons to behaviour separately from other mechanisms that might be operating. The results from eleven individual studies were then combined to increase precision (representing data from 215 animals) and showed that neurogenesis made a negligible contribution to behaviour (standarised effect = 0.15; 95% CI = -0.04 to 0.34; p = 0.128); other mechanisms accounted for the majority of experimental effects (standardised effect = 1.06; 95% CI = 0.74 to 1.38; p = 1.7 $\times 10^{-11}$).

Leaps of logic: quantifying the behavioural relevance of hippocampal neurogenesis

Trio study and meta-analysis support the association of genetic variation at the serotonin transporter with early-onset obsessive–compulsive disorder

Few studies that examine the neurogenesis–behaviour relationship formally establish covariation between neurogenesis and behaviour or rule out competing explanations. The behavioural relevance of neurogenesis might therefore be overestimated if other mechanisms account for some, or even all, of the experimental effects. A systematic review of the literature was conducted and the data reanalysed using causal mediation analysis, which can estimate the behavioural contribution of new hippocampal neurons separately from other mechanisms that might be operating. Results from eleven eligible individual studies were then combined in a meta-analysis to increase precision (representing data from 215 animals) and showed that neurogenesis made a negligible contribution to behaviour (standarised effect  = 0.15; 95% CI  = −0.04 to 0.34; p = 0.128); other mechanisms accounted for the majority of experimental effects (standardised effect  = 1.06; 95% CI  = 0.74 to 1.38; p = 1.7×10−11).

Quantifying the Behavioural Relevance of Hippocampal Neurogenesis

Giovanoli et al. (Reports, 1 March 2013, p. 1095) applied an immune challenge to pregnant females, and therefore to all offspring, and subsequently applied stress to offspring on a per cage basis. The data, however, were analyzed as a completely randomized design, which is inappropriate given these restrictions on randomization. This will increase both false positives and false negatives.

Comment on "Stress in Puberty Unmasks Latent Neuropathological Consequences of Prenatal Immune Activation in Mice"

Improving basic and translational science by accounting for litter-to-litter variation in animal models

The brains of sengis (elephant shrews, order Macroscelidae) have long been known to contain a hippocampus that in terms of allometric progression indices is larger than that of most primates and equal in size to that of humans. In this report, we provide descriptions of hippocampal cytoarchitecture in the eastern rock sengi (Elephantulus myurus), of the distributions of hippocampal calretinin, calbindin, parvalbumin, and somatostatin, of principal neuron numbers, and of cell numbers related to proliferation and neuronal differentiation in adult hippocampal neurogenesis. Sengi hippocampal cytoarchitecture is an amalgamation of characters that are found in CA1 of, e.g., guinea pig and rabbits and in CA3 and dentate gyrus of primates. Correspondence analysis of total cell numbers and quantitative relations between principal cell populations relate this sengi to macaque monkeys and domestic pigs, and distinguish the sengi from distinct patterns of relations found in humans, dogs, and murine rodents. Calretinin and calbindin are present in some cell populations that also express these proteins in other species, e.g., interneurons at the stratum oriens/alveus border or temporal hilar mossy cells, but neurons expressing these markers are often scarce or absent in other layers. The distributions of parvalbumin and somatostatin resemble those in other species. Normalized numbers of PCNA+ proliferating cells and doublecortin-positive (DCX+) differentiating cells of neuronal lineage fall within the overall ranges of murid rodents, but differed from three murid species captured in the same habitat in that fewer DCX+ cells relative to PCNA+ were observed. The large and well-differentiated sengi hippocampus is not accompanied by correspondingly sized cortical and subcortical limbic areas that are the main hippocampal sources of afferents and targets of efferents. This points to intrinsic hippocampal information processing as the selective advantage of the large sengi hippocampus.

The hippocampus of the eastern rock sengi: cytoarchitecture, markers of neuronal function, principal cell numbers, and adult neurogenesis

Beagle dogs are widely used in preclinical pharmacokinetic, safety, and formulation studies. However, little is known about intestinal and hepatic distribution of major enzymes and transporters involved in oral absorption and presystemic drug metabolism. We characterized mRNA levels of CYP3A12, CYP3A26, CYP2D15, UGT1A6, ABCB1 (MDR1), ABCC1 (MRP1), ABCG2 (BCRP), SLC15A1 (PEPT1), and SLC22A1 (OCT1) in dog liver and along the intestine by real-time quantitative reverse transcription-polymerase chain reaction. Tissue protein levels of CYP2D15, MDR1, and PEPT1 were obtained by Western blot. Gene distribution and expression variability was statistically described by a generalized additive mixed model smoothing function and correspondence analysis. Results were compared with the expression pattern known for the human orthologs. Hepatic mRNA levels for metabolic enzymes were generally higher than those for membrane transporters, whereas in the intestine the opposite was observed. Hepatic mRNA levels followed the order CYP2D15 > UGT1A6 ≈ CYP3A26 > ABCB1 ≈ SLC15A1 ≈ SLC22A1 > ABCG2 > ABCC1 ≈ CYP3A12. Along the gut, the genes were differentially distributed with greatest expression in duodenum/upper jejunum (ABCG2), middle jejunum (ABCB1 and SLC15A1), or in cecum/colon (ABCC1 and CYP2D15). CYP3A12, CYP3A26, SLC22A1, and UGT1A6 had a rather uniform expression. Intestinal mRNA profiles of CYP2D15, ABCB1, and SLC15A1 correlated with the respective protein levels. Canine CYP3A12/26, CYP2D15, and ABCB1 colonic distributions differed from those of human orthologs, whereas UGT1A6, ABCC1, ABCG2, SLC15A1, and SLC22A1 were comparable to those of humans in both small and large intestine. We aim to apply these data to better interpret pharmacokinetic studies in dogs with respect to their human relevance.

Expression Profiles of Metabolic Enzymes and Drug Transporters in the Liver and along the Intestine of Beagle Dogs

Brain microvascular endothelial cells (BEC) constitute the blood-brain barrier (BBB) which forms a dynamic interface between the blood and the central nervous system (CNS). This highly specialized interface restricts paracellular diffusion of fluids and solutes including chemicals, toxins and drugs from entering the brain. In this study we compared the transcriptome profiles of the human immortalized brain endothelial cell line hCMEC/D3 and human primary BEC. We identified transcriptional differences in immune response genes which are directly related to the immortalization procedure of the hCMEC/D3 cells. Interestingly, astrocytic co-culturing reduced cell adhesion and migration molecules in both BECs, which possibly could be related to regulation of immune surveillance of the CNS controlled by astrocytic cells within the neurovascular unit. By matching the transcriptome data from these two cell lines with published transcriptional data from freshly isolated mouse BECs, we discovered striking differences that could explain some of the limitations of using cultured BECs to study BBB properties. Key protein classes such as tight junction proteins, transporters and cell surface receptors show differing expression profiles. For example, the claudin-5, occludin and JAM2 expression is dramatically reduced in the two human BEC lines, which likely explains their low transcellular electric resistance and paracellular leakiness. In addition, the human BEC lines express low levels of unique brain endothelial transporters such as Glut1 and Pgp. Cell surface receptors such as LRP1, RAGE and the insulin receptor that are involved in receptor-mediated transport are also expressed at very low levels. Taken together, these data illustrate that BECs lose their unique protein expression pattern outside of their native environment and display a more generic endothelial cell phenotype. A collection of key genes that seems to be highly regulated by the local surroundings of BEC within the neurovascular unit are presented and discussed.

Transcriptional Profiling of Human Brain Endothelial Cells Reveals Key Properties Crucial for Predictive In Vitro Blood-Brain Barrier Models

It was reported that oseltamivir (Tamiflu) absorption was mediated by human peptide transporter (hPEPT) 1. Understanding the exact mechanism(s) of absorption is important in the context of drug-drug and diet-drug interactions. Hence, we investigated the mechanism governing the intestinal absorption of oseltamivir and its active metabolite (oseltamivir carboxylate) in wild-type [Chinese hamster ovary (CHO)-K1] and hPEPT1-transfected cells (CHO-PEPT1), in pharmacokinetic studies in juvenile and adult rats, and in healthy volunteers. In vitro cell culture studies showed that the intracellular accumulation of oseltamivir and its carboxylate into CHO-PEPT1 and CHO-K1 was always similar under a variety of experimental conditions, demonstrating that these compounds are not substrates of hPEPT1. Furthermore, neither oseltamivir nor its active metabolite was capable of inhibiting Gly-Sar uptake in CHO-PEPT1 cells. In vivo pharmacokinetic studies in juvenile and adult rats showed that the disposition of oseltamivir and oseltamivir carboxylate, after oral administration of oseltamivir, was sensitive to the feed status but insensitive to the presence of milk and Gly-Sar. Moreover, oseltamivir and oseltamivir carboxylate exhibited significantly higher exposure in rats under fasted conditions than under fed conditions. In humans, oral dosing after a high-fat meal resulted in a statistically significant but moderate lower exposure than after an overnight fasting. This change has no clinical implications. Taken together, the results do not implicate either rat Pept1 or hPEPT1 in the oral absorption of oseltamivir.

Role of the Intestinal Peptide Transporter PEPT1 in Oseltamivir Absorption: In Vitro and In Vivo Studies

A call for transparent reporting to optimize the predictive value of preclinical research

Translational neuroscience requires better design and analysis of preclinical studies

Fusion oncogenes in acute myeloid leukemia (AML) promote self-renewal from committed progenitors, thereby linking transformation and self-renewal pathways. Like most cancers, AML is a genetically and biologically heterogeneous disease, but it is unclear whether transformation results from common or overlapping genetic programs acting downstream of multiple mutations or by the engagement of unique genetic programs acting cooperatively downstream of individual mutations. This distinction is important, because the involvement of common programs would imply the existence of common molecular targets to treat AML, no matter which oncogenes are involved. Here we show that the ability to promote self-renewal is a generalized property of leukemia-associated oncogenes. Disparate oncogenes initiated overlapping transformation and self-renewal gene expression programs, the common elements of which were defined in established leukemic stem cells from an animal model as well as from a large cohort of patients with differing AML subtypes, where they strongly predicted pathobiological character. Notably, individual genes commonly activated in these programs could partially phenocopy the self-renewal function of leukemia-associated oncogenes in committed murine progenitors. Furthermore, they could generate AML following expression in murine bone marrow. In summary, our findings reveal the operation of common programs of self-renewal and transformation downstream of leukemia-associated oncogenes, suggesting that mechanistically common therapeutic approaches to AML are likely to be possible, regardless of the identity of the driver oncogene involved.

Common and overlapping oncogenic pathways contribute to the evolution of acute myeloid leukemias.

A causal modelling approach demonstrates that the effect of exercise on pattern separation is independent of hippocampal neurogenesis

Meta‐analysis and Combining Information in Genetics and Genomics

Model based Inference in the Life Sciences: a Primer on Evidence

There has been a substantial amount of research on the relationship between hippocampal neurogenesis and behaviour over the past 15 years, but the causal role that new neurons have on cognitive and affective behavioural tasks is still far from clear. This is partly due to the difficulty of manipulating levels of neurogenesis without inducing off-target effects, which might also influence behaviour. In addition, the analytical methods typically used do not directly test whether neurogenesis mediates the effect of an intervention on behaviour. Previous studies may have incorrectly attributed changes in behavioural performance to neurogenesis because the role of known (or unknown) neurogenesis-independent mechanisms was not formally taken into consideration during the analysis. Causal models can tease apart complex causal relationships and were used to demonstrate that the effect of exercise on pattern separation is via neurogenesis-independent mechanisms. Many studies in the neurogenesis literature would benefit from the use of statistical methods that can separate neurogenesis-dependent from neurogenesis-independent effects on behaviour.

Using causal models to distinguish between neurogenesis-dependent and -independent effects on behaviour

Modeling hippocampal neurogenesis across the lifespan in seven species

Relating hippocampal neurogenesis to behavior: the dangers of ignoring confounding variables

The problem of pseudoreplication in neuroscientific studies: is it affecting your analysis?

Background: Pseudoreplication occurs when observations are not statistically independent, but treated as if they are. This can occur when there are multiple observations on the same subjects, when samples are nested or hierarchically organised, or when measurements are correlated in time or space. Analysis of such data without taking these dependencies into account can lead to meaningless results, and examples can easily be found in the neuroscience literature. 
 
Results: A single issue of Nature Neuroscience provided a number of examples and is used as a case study to highlight how pseudoreplication arises in neuroscientific studies, why the analyses in these papers are incorrect, and appropriate analytical methods are provided. 12% of papers had pseudoreplication and a further 36% were suspected of having pseudoreplication, but it was not possible to determine for certain because insufficient information about the analysis was provided. 
 
Conclusions: Pseudoreplication undermines the conclusions from statistical analysis of data, and it would be easier to detect if the sample size, degrees of freedom, the test statistic, and precise p-values are reported. This information should be a requirement for all publications.

Pseudoreplication invalidates the results of many neuroscientific studies

Visualising disease progression on multiple variables with vector plots and path plots

Statistical evaluation of methods for quantifying gene expression by autoradiography in histological sections

Synergistic effects of dehydroepiandrosterone and fluoxetine on proliferation of progenitor cells in the dentate gyrus of the adult male rat

DNA Methylation Microarrays: Experimental Design and Statistical Analysis

Cell replacement therapies offer promise in the treatment of neurotrauma and neurodegenerative disorders and have concentrated on the use of primary fetal brain tissue. However, there is a growing promise of using neural stem cells, in which case other factors may be important in their successful engraftment. We therefore investigated whether the co‐expression of the major developmental transcription factor (Pax7 in this study) of donor tissue to graft site influences transplant survival and differentiation in the rat midbrain. Neural progenitor cells were prepared from either the Pax7‐expressing dorsal (DM) or non‐Pax7‐expressing ventral mesencephalon (VM) of embryonic EGFP+/+ rats. Cells were dissociated and grafted into the adult rat superior colliculus (SC) lesioned with quinolinic acid 3 days previously, a time shown to be associated with the up‐regulation of Pax7. Grafts were then examined 4 weeks later. Our results suggest the origin of the graft tissue did not alter graft survival in the SC; however, dorsal grafts appear to have a higher incidence of neuronal survival, whereas ventral grafts have a higher incidence of astrocytic survivors.

Graft outcomes influenced by co‐expression of Pax7 in graft and host tissue

Why we should use simpler models if the data allow this: relevance for ANOVA designs in experimental biology

Polysomnographic and quantitative EEG analysis of subjects with long-term insomnia complaints associated with mild traumatic brain injury

Background: Cancer stem cells (CSCs) are a small subpopulation of the tumour mass that are capable of sustaining its growth, are resistant to many cancer specific therapies, and can reinitiate disease relapse. CSCs are resistant to current cancer treatments due to specialised transporters, cell cycle changes, DNA repair and antiapoptotic mechanisms. Objective: This paper reviews CSC biology and diagnostic and therapeutic patents as well as those associated with the isolation of CSCs. Methods: Literature and patent searches using the NCBI PubMed, European Patent Office, Scopus, and PATENTSCOPE® websites were conducted to examine and link CSC biology and therapy development with current patent literature. Conclusion: Development in basic CSC biology research is increasing the patents filed in this area; however, therapeutic patents directly targeting CSCs are more limited, as research in this area remains in its infancy.

Hand tapping: A simple, reproducible, objective marker of motor dysfunction in Huntington’s disease

Olfactory abnormalities in Huntington’s disease: Decreased plasticity in the primary olfactory cortex of R6/1 transgenic mice and reduced olfactory discrimination in patients

Correspondence Analysis and Data Coding with Java and R by F. Murtagh

International journal of psychophysiology : official journal of the International Organization of Psychophysiology

Lack of efficacy of music to improve sleep: a polysomnographic and quantitative EEG analysis.

Previous work has demonstrated that the transgenic R6/1 mouse model of Huntington's disease has decreased proliferation of neural precursor cells (NPCs) in the dentate gyrus of the hippocampus. This study therefore examined the survival and differentiation of NPCs in presymptomatic and symptomatic R6/1 mice and the effects of environmental enrichment on these variables. Here it is demonstrated that the survival of bromodeoxyuridine‐positive (BrdU+) NPCs in the dentate gyrus is decreased in the transgenic mice. In addition, the number of doublecortin‐positive (DCX+) cells is greatly reduced in these mice, as is the total number of new mature neurons, while the proportion of BrdU+ cells differentiating into mature neurons was not significantly different between genotypes. Furthermore, the DCX+ cells in the R6/1 mice had smaller and irregular‐shaped somas, shorter neurites, and migrated a shorter distance into the granular cell layer compared with wild‐type mice. Older symptomatic mice housed in an enriched environment had an increased number of BrdU+ and DCX+ cells as well as longer neurites and increased migration of DCX+ cells. There was no significant difference between genotypes or environments in the number of BrdU+ cells in the subventricular zone. These results suggest that decreased neurogenesis might be responsible, in part, for the hippocampal deficits observed in these mice and that environmental enrichment produces morphological changes in newborn granule neurons in both wild‐type and R6/1 mice, which could underlie some of the beneficial effects of enrichment.

Neurogenesis in the R6/1 transgenic mouse model of Huntington's disease: effects of environmental enrichment

P08.1 Hand tapping: A reproducible, objective marker of clinical phenotype in Huntington’s disease

There are few effective pharmacological-based treatments for acute neurological trauma or chronic neurodegenerative diseases. This has created a demand for innovative therapeutic approaches including gene therapy, deep brain stimulation and cell-based therapies. This review, briefly updates the progress made in recent clinical trials of neurotransplantation in Parkinson’s and Huntington’s disease, discusses challenges that still have to be overcome, and reviews the progress in meeting these challenges. The main focus of this review, however, will be on recent advances in using endogenous neural precursor cells (NPCs) to promote brain repair. The physiological role of NPCs, their response to various types of injury and other endogenous and exogenous factors will be discussed. Finally, their therapeutic potential and relevance to human disease will be considered.

In order to ascertain whether disturbances of neurogenesis occur in chronic neurodegenerative disorders, we assessed hippocampal cell proliferation in the R6/1 transgenic mouse model of Huntington's disease (HD). Using BrdU labelling for dividing cells at two different time points (5 and 20 weeks) in transgenic and wild type control mice, we have shown that cell proliferation in the hippocampus was similar in younger asymptomatic R6/1 mice and wild type controls, but that older R6/1 mice had significantly fewer BrdU+ cells than controls. Such a decrease in cell proliferation may be relevant to some of the deficits seen in these mice, although further work is needed to prove this.

Decreased hippocampal cell proliferation in R6/1 Huntington's mice

Rapid decline in motor symptoms in HD neural transplant patients prior to surgery

Parkinson's disease is a common neurodegenerative disease with a lifetime incidence of 2.5% and a prevalence of at least 2% in individuals over 70 years old. Patients can be effectively treated with drugs that target the dopaminergic nigro-striatal pathway, but over time the efficacy of these medications is limited by the development of profound motor fluctuations and dyskinesias. This has prompted the search for alternative treatments, including the use of cell replacement therapies. Over the last decade, human fetal nigral transplants have demonstrated that dopaminergic neurons can survive and provide clinical benefit for patients with Parkinson's disease. However, there are clearly ethical concerns and a limit to the supply of this tissue as well as more recently anxieties over side effects. As a result, alternative sources of tissue have been investigated, and one such source are stem cells, which provide an attractive renewable tissue supply. In this review, we will discuss the current state-of-the-art and the characteristics of Parkinson's disease that increase its attraction as a target of stem cell therapy against results of current clinical trials using fetal neural grafts. Then we will discuss the various types and sources of stem cells, and some early transplantation results in animal models of Parkinson's disease. Finally we will discuss the prospect of using stem cells to deliver drugs and neurotrophic factors involved in neuroprotective and neuroreparative strategies in Parkinson's disease and other neurodegenerative conditions.

The future of cell-based transplantation therapies for neurodegenerative disorders.

Pax7 in the establishment of tectal polarity and the retino-tectal map

Expression profiles suggest a role for Pax7 in the establishment of tectal polarity and map refinement

Distinct prefrontal top-down circuits differentially modulate sensorimotor behavior

Author Correction: Task-dependent representations of stimulus and choice in mouse parietal cortex

Task-dependent representations of stimulus and choice in mouse parietal cortex

The immense behavioral repertoire of animals necessitates mechanisms that select and suppress specific actions depending on current goals. The prefrontal cortex (PFC) has been suggested to orchestrate these processes by biasing activity in its target structures, but how its vastly converging inputs and diverging outputs are coordinated to control goal-oriented actions remains unclear. Here we use a bilateral task in which mice select between symmetric but opposing actions to show that distinct outputs from a subdivision of the PFC, the anterior cingulate cortex (ACC), promote correct and suppress incorrect actions. Surprisingly, ACC outputs to the superior colliculus principally inhibit incorrect actions. Optogenetic analyses and a projection-based activity model make the unexpected prediction that feedback from the ACC to the visual cortex promotes correct actions, which we confirm. Our results show that anatomically non-overlapping but functionally complementary PFC outputs bidirectionally control actions, and suggest a candidate organizing principle for PFC circuits.

Bidirectional control of goal-oriented action selection by distinct prefrontal cortex circuits

Ray Guillery made major contributions to our understanding of the development and function of the brain. One of his principal conceptual insights, developed together with Murray Sherman [S.M. Sherman & R.W. Guillery (2001) Exploring the Thalamus. Elsevier, Amstrerdam; S. Sherman & R. Guillery (2006) Exploring the Thalamus and Its Role in Cortical Functioning. Academic Press, New York, NY; S.M. Sherman & R.W. Guillery (2013) Functional Connections of Cortical Areas: A New View from the Thalamus. MIT Press, Cambridge, MA and then in his last book (R. Guillery (2017) The Brain as a Tool: A Neuroscientist's Account. Oxford University Press, Oxford, UK)], was that the brain is a ‘tool’ to understand the world. In this view, the brain does not passively process sensory information and use the result to inform motor outputs. Rather, sensory and motor signals are widely broadcast and inextricably linked, with ongoing sensorimotor transformations serving as the basis for interaction with the outside world. Here, we describe recent studies from our laboratory and others which demonstrate this astute framing of the link among sensation, perception, and action postulated by Guillery and others [G. Deco & E.T. Rolls (2005) Prog Neurobiol, 76, 236–256; P. Cisek & J.F. Kalaska (2010) Annu Rev Neurosci, 33, 269‐298]. Guillery situated his understanding in the deeply intertwined relationship between the thalamus and cortex, and importantly in the feedback from cortex to thalamus which in turn influences feed‐forward drive to cortex [S.M. Sherman & R.W. Guillery (2001) Exploring the Thalamus. Elsevier, Amstrerdam; S. Sherman & R. Guillery (2006) Exploring the Thalamus and Its Role in Cortical Functioning. Academic Press, New York, NY]. We extend these observations to argue that brain mechanisms for sensorimotor transformations involve cortical and subcortical circuits that create internal models as a substrate for action, that a key role of sensory inputs is to update such models, and that a major function of sensorimotor processing underlying cognition is to enable action selection and execution.

Neural mechanisms of sensorimotor transformation and action selection

Perceptual decision-making is an important and
experimentally tractable paradigm for uncovering general principles
of neural information processing and cognitive function. While the
process of mapping sensory stimuli onto motor actions may appear to
be simple, its neural underpinnings are poorly understood. The goal
of this thesis is to better understand the neural mechanisms
underlying perceptual decision-making by exploring three major
questions: How is decision-relevant information encoded across the
cortex? What cortical areas are necessary for perceptual
decision-making? And finally, what neural mechanisms underlie the
mapping of sensory percepts to appropriate motor outputs? We
investigated the roles of visual (V1), posterior parietal (PPC),
and frontal motor (fMC) cortices of mice during a memory-guided
visual decision task. Large-scale calcium imaging revealed that
neurons in each area were heterogeneous and spanned all task epochs
(stimulus, delay, response). However, information encoding was
distinct across regions, with V1 encoding stimulus, fMC encoding
choice, and PPC multiplexing the two variables. Optogenetic
inhibition during behavior showed that all regions were necessary
during the stimulus epoch, but only fMC was required during the
delay and response epochs. Stimulus information was therefore
rapidly transformed into behavioral choice, requiring V1, PPC, and
fMC during the transformation period, but only fMC for maintaining
the choice in memory prior to execution. We further investigated
whether the role of PPC was specific to visual processing or to
sensorimotor transformation. Using calcium imaging during both
engaged behavior and passive viewing, we found that unlike V1
neurons, most PPC neurons responded exclusively during task
performance, although a minority exhibited contrast-dependent
visual responses. By re-training mice on a reversed task
contingency, we discovered that neurons in PPC but not V1 reflected
the new sensorimotor contingency. Population analyses additionally
revealed that task-specific information was represented in a
dynamic code in PPC but not in V1. The strong task dependence,
heterogeneity, and dynamic coding of PPC activity point to a
central role in sensorimotor transformation. By measuring and
manipulating activity across multiple cortical regions, we have
gained insight into how the cortex processes information during
sensorimotor decisions, paving the way for future mechanistic
studies using the mouse system.

Sensorimotor transformation and information coding across cortex during perceptual decisions

Mapping specific sensory features to future motor actions is a crucial capability of mammalian nervous systems. We investigated the role of visual (V1), posterior parietal (PPC), and frontal motor (fMC) cortices for sensorimotor mapping in mice during performance of a memory-guided visual discrimination task. Large-scale calcium imaging revealed that V1, PPC, and fMC neurons exhibited heterogeneous responses spanning all task epochs (stimulus, delay, response). Population analyses demonstrated unique encoding of stimulus identity and behavioral choice information across regions, with V1 encoding stimulus, fMC encoding choice even early in the trial, and PPC multiplexing the two variables. Optogenetic inhibition during behavior revealed that all regions were necessary during the stimulus epoch, but only fMC was required during the delay and response epochs. Stimulus identity can thus be rapidly transformed into behavioral choice, requiring V1, PPC, and fMC during the transformation period, but only fMC for maintaining the choice in memory prior to execution. DOI: http://dx.doi.org/10.7554/eLife.13764.001

Distinct roles of visual, parietal, and frontal motor cortices in memory-guided sensorimotor decisions

Purpose:  To investigate the effects of low frequency stimulation (LFS) of a fiber tract for the suppression of spontaneous seizures in a rat model of human temporal lobe epilepsy.

Low frequency stimulation of ventral hippocampal commissures reduces seizures in a rat model of chronic temporal lobe epilepsy

Cortical stimulation for the treatment of epilepsy is currently being studied in both animals and humans; however, because the mechanisms are not well understood, optimal stimulation parameters and target have yet to be been determined. This paper describes the effects of low frequency stimulation (LFS) using a novel target, the hippocampal commissural fibers, in a rat model of human mesial temporal lobe epilepsy (MTLE). Epilepsy was induced in adult Sprague-Dawley rats (n=7) by one single electrical stimulation episode of the amygdala. After a three month period of epileptogenesis, baseline spontaneous seizure frequency was determined by continuous video and electrographic monitoring of the bilateral hippocampi for 2 weeks. Then, LFS (1 Hz) was applied continuously for 60 minutes ON and 15 minutes OFF, for two weeks, and the mean seizure frequency before, during and after treatment were compared. A statistically significant difference (p = 0.008) between the baseline and treatment states was observed. In 7 animals, 90% decrease in seizure frequency was observed during treatment and a 57% decrease in seizure frequency during the period following treatment when compared to the seizure frequency before stimulation. These findings support the hypothesis that the hippocampal commissures may be an effective target in low frequency stimulation for the suppression of spontaneous seizures in mesial temporal lobe epilepsy.

2011 5th International IEEE/EMBS Conference on Neural Engineering

Low frequency stimulation decreases seizure frequency in a rat model of temporal lobe epilepsy

Abstract Continuous monitoring using commercial-grade wearable technology was used to quantify the physiological response to reported COVID-19 infections and vaccinations in five biometric measurements. Larger responses were observed following confirmed COVID-19 infection reported by unvaccinated versus vaccinated individuals. Responses following reported vaccination were smaller in both magnitude and duration compared to infection and mediated by both dose number and age. Our results suggest commercial-grade wearable technology as a potential platform on which to build screening tools for early detection of illness, including COVID-19 breakthrough cases.

Feasibility of Measuring Physiological Responses to Breakthrough Infections and COVID-19 Vaccine Using a Wearable Ring Sensor

This study proposes a method to reduce the wideband radar cross‐section (RCS) of a microstrip antenna while maintaining its dimensions. Modifications to the design of the antenna consist of patch slotting, ground slotting, and coplanar split‐ring loading without changing its size. The results of simulations show that a significant reduction in the RCS can be obtained in the range of frequency of 1–3 GHz. The maximum in‐band RCS and out‐of‐band RCS are 20.8 and 38 dB, respectively. Prototypes of the reference antenna and the proposed composite antenna are manufactured and tested, and the results are consistent with those of the simulation.

International Journal of RF and Microwave Computer‐Aided Engineering

A low RCS microstrip antenna based on a composite technology of slotting and loading split‐rings

Subway is a key node running through the developmental history of a city.Subway culture can extend and enhance the culture of a city.And thus the spirit to erect a subway culture is to reflect the civilization of the city.This paper discusses the basic conception of the subway culture construction in three dimensions: passenger,administrator and infrastructure.Only when we completely get rid of egoism,try hard to arouse passengers ’ public awareness,transform administrators’ opinion of regulation to the kindness to passengers,and pursue the value of aesthetic value instead of instrumentalism,can we truly show the deep meaning of the subway culture.

The Basic Conception of the Subway Culture Construction——For example Homgzhon Metro

Effect of Y203 on microstructure and property of laser surface alloying on 40Cr steel

Base on the innovation theory of historic linguistics,this paper discusses problems on the phonetic evolution of modern Chinese and the division of dialects.The author emphasizes that the same language line of dialect geography and the phenomenon of speech sound keeping ancient sound cannot be taken as criteria to classify dialects.

The Influence of Changes in Era Aesthetic Concepts on Advertising Design

In response to the growing concern on drug safety issues, the U.S. Food and Drug Administration (FDA) has implemented major moves in its inspection regime to ensure that the agency allocates more inspection resources to the low-quality manufacturing facilities. The actions of the government agency implicitly assume that the frequent inspections at low-quality facilities could reduce the drug safety concerns. However, whether more monitoring guarantees better quality remains unclear. In this study, we directly examine the validity of this assumption in the generic drug industry and test the impact of inspection frequency on the manufacturing quality. We first perform a recurrent-event cox proportional hazards model with instrumental variables to investigate the impact of inspection frequency on the gap time between successive recall events. We observe a significant increase in the recall hazard rate for those facilities experiencing decreases in the inspection frequency; on the contrary, there is no significant change in the recall hazard for facilities experiencing more frequent quality monitoring. We then exploit a shift of inspection resources from domestic to foreign facilities and compare the recall rate before and after the resource shift. The consistent results reassure our findings. Overall, we do not find evidence that supports the link between more frequent inspections and fewer recall events, suggesting that the current risk-based inspection model alone might not help bring down the quality failures in drug products. We propose two explanations for the results -- the organizational culture and the inherent quality levels -- and discuss the potential actions the FDA and the relevant regulators could take to augment the inspection regime.

The More Monitoring, the Better Quality? Empirical Evidence from the Generic Drug Industry

This study primarily focuses on pay-to-bid auctions in which bidders pay a fixed fee for each bid to increase the price and explores the reputation of bidders within the auctions. The reputation effects can be discovered from sample observations in pay-to-bid auction websites. Pay-to-bid auctions are highly susceptible to manipulative behaviors by an aggressive bidder. To explain the phenomenon, a basic model in which two bidders take part in a series of pay-to-bid auctions is developed and an extension of a multiplayer model builds on the basic model. The question of an optimal auction from the auctioneer’s standpoint, in an asymmetric setting, is addressed. It is expected to theoretically show that the results from previous symmetric pay-to-bid auction models do not carry over to repeated auctions when one of the bidders is endowed with a reputation for bidding aggressively.

On the valuation of goods and selection of the best design alternative

Frequency dependence of sound field effect on microstructure and wear performance of plasma sprayed Ni-10 wt.%Al coatings

Abstract: In this study, AZ31 magnesium alloy and 6061 aluminum alloy were joined with Sn-xZn (x = 5, 10, 20 and 30 wt.%) fillers containing trace rare earth elements at 250 ◦C in air without the use of flux or a wetting layer. The bond shear strengths of AZ31 magnesium alloy/6061 aluminum alloy joints with Sn-5Zn-0.1RE, Sn-10Zn-0.1RE, Sn-20Zn-0.1RE, and Sn-30Zn-0.1RE fillers were determined to be 14.84, 17.08, 19.39 and 20.86 MPa, respectively. The shear strengths increased with increasing Zn content. The joint strengths of all four alloys significantly decreased with increasing aging time at 150 ◦C.

Joining of AZ 31 Magnesium Alloy to 6061 Aluminum Alloy with Sn-Zn Filler Metals Containing Trace Rare Earth Elements

In this study, AZ31 magnesium alloy and 6061 aluminum alloy were joined with Sn-xZn (x = 5, 10, 20 and 30 wt.%) fillers containing trace rare earth elements at 250 °C in air without the use of flux or a wetting layer. The bond shear strengths of AZ31 magnesium alloy/6061 aluminum alloy joints with Sn-5Zn-0.1RE, Sn-10Zn-0.1RE, Sn-20Zn-0.1RE, and Sn-30Zn-0.1RE fillers were determined to be 14.84, 17.08, 19.39 and 20.86 MPa, respectively. The shear strengths increased with increasing Zn content. The joint strengths of all four alloys significantly decreased with increasing aging time at 150 °C.

Joining of AZ31 Magnesium Alloy to 6061 Aluminum Alloy with Sn-Zn Filler Metals Containing Trace Rare Earth Elements

Modified alkaline electrolyte with 8-hydroxyquinoline and ZnO complex additives to improve Al-air battery

Transcranial Photobiomodulation (tPBM) has demonstrated its ability to alter electrophysiological activity in the human brain. However, it is unclear how tPBM modulates brain electroencephalogram (EEG) networks and is related to human cognition. In this study, we recorded 64-channel EEG from 44 healthy humans before, during, and after 8-min, right-forehead, 1,064-nm tPBM or sham stimulation with an irradiance of 257 mW/cm2. In data processing, a novel methodology by combining group singular value decomposition (gSVD) with the exact low-resolution brain electromagnetic tomography (eLORETA) was implemented and performed on the 64-channel noise-free EEG time series. The gSVD+eLORETA algorithm produced 11 gSVD-derived principal components (PCs) projected in the 2D sensor and 3D source domain/space. These 11 PCs took more than 70% weight of the entire EEG signals and were justified as 11 EEG brain networks. Finally, baseline-normalized power changes of each EEG brain network in each EEG frequency band (delta, theta, alpha, beta and gamma) were quantified during the first 4-min, second 4-min, and post tPBM/sham periods, followed by comparisons of frequency-specific power changes between tPBM and sham conditions. Our results showed that tPBM-induced increases in alpha powers occurred at default mode network, executive control network, frontal parietal network and lateral visual network. Moreover, the ability to decompose EEG signals into individual, independent brain networks facilitated to better visualize significant decreases in gamma power by tPBM. Many similarities were found between the cortical locations of SVD-revealed EEG networks and fMRI-identified resting-state networks. This consistency may shed light on mechanistic associations between tPBM-modulated brain networks and improved cognition outcomes.

Combination of Group Singular Value Decomposition and eLORETA Identifies Human EEG Networks and Responses to Transcranial Photobiomodulation

Billions of neurons in the human brain form neural networks with oscillation rhythms. Infra-slow oscillation (ISO) presents three main physiological sources: endogenic, neurogenic, and myogenic vasomotions. Having an in vivo methodology for the absolute quantification of ISO from the human brain can facilitate the detection of brain abnormalities in cerebral hemodynamic and metabolic activities. In this study, we introduced a novel measurement-plus-analysis framework for the non-invasive quantification of prefrontal ISO by (1) taking dual-channel broadband near infrared spectroscopy (bbNIRS) measurements from 12 healthy humans during a 6-min rest and 4-min post transcranial photobiomodulation (tPBM) and (2) performing wavelet transform coherence (WTC) analysis on the measured time series data. The WTC indexes (IC, between 0 and 1) enabled the assessment of ipsilateral hemodynamic-metabolic coherence and bilateral functional connectivity in each ISO band of the human prefrontal cortex. At rest, bilateral hemodynamic connectivity was consistent across the three ISO bands (IC ≅ 0.66), while bilateral metabolic connectivity was relatively weaker. For post-tPBM/sham comparison, our analyses revealed three key findings: 8-min, right-forehead, 1064-nm tPBM (1) enhanced the amplitude of metabolic oscillation bilaterally, (2) promoted the bilateral metabolic connectivity of neurogenic rhythm, and (3) made the main effect on endothelial cells, causing alteration of hemodynamic-metabolic coherence on each side of the prefrontal cortex.

Metabolic Connectivity and Hemodynamic-Metabolic Coherence of Human Prefrontal Cortex at Rest and Post Photobiomodulation Assessed by Dual-Channel Broadband NIRS

Our group previously examined 8 min photobiomodulation (PBM) by 1064 nm laser on the human forearm in vivo to determine its significant effects on vascular hemodynamics and cytochrome c oxidase redox activity. Since PBM uses a wide array of wavelengths, in this paper, we investigated (i) whether different wavelengths of lasers induced different PBM effects, and (ii) if a light-emitting diode (LED) at a similar wavelength to a laser could induce similar PBM effects. A broadband near-infrared spectroscopy (bbNIRS) system was utilized to assess concentration changes in oxygenated hemoglobin (Δ[HbO]) and oxidized cytochrome c oxidase (Δ[oxCCO]) during and after PBM with lasers at 800 nm, 850 nm, and 1064 nm, as well as a LED at 810 nm. Two groups of 10 healthy participants were measured before, during, and after active and sham PBM on their forearms. All results were tested for significance using repeated measures ANOVA. Our results showed that (i) lasers at all three wavelengths enabled significant increases in Δ[HbO] and Δ[oxCCO] of the human forearm while the 1064 nm laser sustained the increases longer, and that (ii) the 810-nm LED with a moderate irradiance (≈135 mW/cm2) induced measurable and significant rises in Δ[HbO] and Δ[oxCCO] with respect to the sham stimulation on the human forearm.

Photobiomodulation at Different Wavelengths Boosts Mitochondrial Redox Metabolism and Hemoglobin Oxygenation: Lasers vs. Light-Emitting Diodes In Vivo

 Transcranial photobiomodulation (tPBM) of the prefrontal cortex can improve human cognition and increase electroencephalogram (EEG) alpha and beta powers, but it was unclear whether tPBM-induced heat would influence EEG oscillation powers. This study aimed to prove that tPBM-induced increases in anterior-posterior EEG powers at alpha and beta bands would be significant after removal of tPBM-associated thermal effects. We performed both sham-controlled tPBM and sham-controlled thermal stimulation (thermo_stim) experiments under the eyes-closed resting state with concurrent recordings of 64-channel EEG before, during, and after 8-min tPBM at 1064-nm wavelength and thermo_stim with temperature from 33 to 41 °C, respectively, from healthy humans (n=46 for tPBM; n=14 for thermo_stim). Sham-subtracted topographies of EEG powers at five frequency bands were averaged at the group level during and post both stimulations. Two-sample t-tests with FDR correction and effect size were calculated for comparing tPBM and thermal effects at all five frequency bands. Right-frontal tPBM induced significant increases in EEG anterior-posterior alpha and beta powers under the eyes-closed conditions, consistent with the results previously reported in the eyes-open tPBM experiments. In contrast, right-frontal thermal stimulation under the eyes-closed resting state resulted in opposite effects on EEG power patterns with respect to those by tPBM. tPBM-induced enhancement in alpha and beta oscillations occurred during the 8-min intervention after exclusion of thermal effects. The ability of tPBM to synchronize alpha and beta oscillations in the anterior-posterior regions may be linked to the enhancement of frontoparietal network and the improvement of human cognition.

Significant Increases in EEG Anterior-Posterior Alpha and Beta Powers By Transcranial Photobiomodulation (tPBM) in Healthy Humans With Exclusion of Thermal Effects

Transcranial photobiomodulation and thermal stimulation induce distinct topographies of EEG alpha and beta power changes in healthy humans

Transcranial photobiomodulation with light emitting diodes increases vigilance performance and EEG alpha power of the human brain

To understand the mechanism of action of transcranial photobiomodulation, we measured and compared alpha rhythms evoked by transcranial laser and thermal stimulations. The two types of stimulations resulted in distinct difference in alpha topographs.

Topography of alpha rhythms evoked by transcranial laser neuromodulation and thermal stimulation

Transcranial photobiomodulation enhances power of local slow-oscillations in the human brain as measured by broadband near-infrared spectroscopy

In our previous proof‐of‐principle study, transcranial photobiomodulation (tPBM) with 1,064‐nm laser was reported to significantly increase concentration changes of oxygenated hemoglobin (∆[HbO]) and oxidized‐state cytochrome c oxidase (∆[oxi‐CCO]) in the human brain. This paper further investigated (i) its validity in two different subsets of young human subjects at two study sites over a period of 3 years and (ii) age‐related effects of tPBM by comparing sham‐controlled increases of ∆[HbO] and ∆[oxi‐CCO] between young and older adults.

Transcranial Photobiomodulation (tPBM) With 1,064‐nm Laser to Improve Cerebral Metabolism of the Human Brain In Vivo

MiR-145 promotes TNF-α-induced apoptosis by facilitating the formation of RIP1-FADDcaspase-8 complex in triple-negative breast cancer

Characterization of mammary epithelial stem/progenitor cells and their changes with aging in common marmosets

Breast cancer incidence increases during aging, yet the mechanism of age-associated mammary tumorigenesis is unclear. Mammary stem cells are believed to play an important role in breast tumorigenesis, but how their function changes with age is unknown. We compared mammary epithelial cells isolated from young and old mammary glands of different cohorts of C57BL6/J and BALB/c mice, and our findings revealed that old mammary glands were characterized by increased basal cell pool comprised of mostly CD49fhi cells, altered luminal-to-basal cell ratio, and irregular ductal morphology. More interestingly, basal stem cells in old mice were increased in frequency, but showed a functional decline of differentiation and increased neoplastic transformation potential. Gene signature enrichment analysis revealed a significant enrichment of a luminal cell gene expression signature in the basal stem cell-enriched population from old mice, suggesting some luminal cells were expressing basal markers. Immunofluorescence staining confirmed the presence of luminal cells with high CD49f expression in hyperplastic lesions implicating these cells as undergoing luminal to basal phenotypic changes during aging. Whole transcriptome analysis showed elevated immune and inflammatory responses in old basal stem cells and stromal cells, which may be the underlying cause for increased CD49fhi basal-like cells in aged glands.

Aging is associated with an expansion of CD49fhi mammary stem cells that show a decline in function and increased transformation potential

Abstract P6-04-03: Transcriptome profiling reveals enrichment of luminal feature in aged basal cell population in murine mammary gland

Murine mammary stem/progenitor cell isolation: Different method matters?

Perinatal exposure to bisphenol A (BPA) has been shown to cause aberrant mammary gland morphogenesis and mammary neoplastic transformation. Yet, the underlying mechanism is poorly understood. We tested the hypothesis that mammary glands exposed to BPA during a susceptible window may lead to its susceptibility to tumorigenesis through a stem cell–mediated mechanism. We exposed 21-day-old Balb/c mice to BPA by gavage (25 μg/kg/d) during puberty for 3 weeks, and a subset of animals were further challenged with one oral dose (30 mg/kg) of 7,12-dimethylbenz(a)anthracene (DMBA) at 2 months of age. Primary mammary cells were isolated at 6 weeks, and 2 and 4 months of age for murine mammary stem cell (MaSC) quantification and function analysis. Pubertal exposure to the low-dose BPA increased lateral branches and hyperplasia in adult mammary glands and caused an acute increase of MaSC in 6-week-old glands and a delayed increase of luminal progenitors in 4-month-old adult gland. Most importantly, pubertal BPA exposure altered the function of MaSC from different age groups, causing early neoplastic lesions in their regenerated glands similar to those induced by DMBA exposure, which indicates that MaSCs are susceptible to BPA-induced transformation. Deep sequencing analysis on MaSC-enriched mammospheres identified a set of aberrantly expressed genes associated with early neoplastic lesions in patients with human breast cancer. Thus, our study for the first time shows that pubertal BPA exposure altered MaSC gene expression and function such that they induced early neoplastic transformation. Cancer Prev Res; 7(4); 445–55. ©2014 AACR.

Pubertal Bisphenol A Exposure Alters Murine Mammary Stem Cell Function Leading to Early Neoplasia in Regenerated Glands

Age is the number one risk fact for breast cancer with only 5% of all breast cancers occurring in women under 40 years old and age specific incidence of invasive breast cancer increases from less than 1.5% at age 40, to about 3% at age 50 and over 4% by age 70 in American women. Recent research implicated that adult mammary stem cells (MaSCs) might be responsible for the initiation and progression of certain types of breast cancer. Our preliminary study showed that aging is associated with a significant increase of MaSC frequency, but with a functional decline of self-renewal and differentiation as well as increased neoplastic transformation potential. These findings indicate that aged MaSCs might be the precursors of preneoplastic lesions and serve as the cell of origin for malignant transformation in breast tissue. Therefore, intervention of MaSC aging process could be an effective method for cancer prevention. The drug of rapamycin has been shown to extend life span and ameliorate age-related pathologies (e.g., cancer) in murine models, and a recent study suggested that rapamycin9s anti-aging effect may partially act through enhancing the function of tissue-specific stem cells. It is unknown whether rapamycin treatment will also enhance the function of aged MaSCs and decrease their transformation potential. In this study, we fed C57BL/6 mice with microencapsulated rapamycin-containing food (14 mg/kg, food designed to deliver ∼2.24 mg of rapamycin per kg body weight/day to achieve about 4 ng/ml of rapamycin per kg body weight/day) or control diet with empty capsules for 2 year (starting at 2-month old) or 5-10 days (starting at 25.5-month old) and then isolated primary mammary cells at 26-month old for MaSC quantification using an in vitro mammosphere formation and 3D-ECM sphere differentiation assay as well as by the in vivo cleared mammary fat pad transplantation assay. Our findings indicate that short-term (5-10 days) or long-term (> 2 year) rapamycin treatment reversed phenotypic changes associated with aged MaSC, which was mainly characterized by decreased luminal-to-basal cell ratio and increased MaSC frequency. Histological analysis of regenerated glands of aged MaSCs derived from control and rapamycin-treated mice showed a significant decrease of early neoplastic transformation potential in rapamycin-treated group. Subsequent in vivo serial transplantation and mating experiments revealed that rapamycin treatment reverted aged MaSCs more resemble to young MaSCs in self-renewal/differentiation function during regeneration and improved lobulo-alveolar differentiation function for lactation. In conclusion, our findings suggest that rapamycin can rejuvenate the function of aged MaSCs as well as reduce their incidence of preneoplastic transformation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-03-03.

Abstract P5-03-03: Effect of rapamycin on the function and transformation of aged murine mammary stem cells

The number one risk fact for breast cancer is aging. Recent research implicated that adult mammary stem cells (MaSCs) might be responsible for the initiation and progression of certain types of breast cancer. We tested the hypothesis that aging-associated mammary tumorigenesis may be due to altered number and function of MaSCs using mouse models. MaSC-enriched basal cells, characterized by their immunophenotype (Lin - CD49f high CD24 med ), were utilized for the evaluation of MaSC frequency and function during aging by in vitro mammosphere formation and 3D-ECM sphere differentiation assays and by in vivo cleared mammary fat pad transplantation (IVT) as we reported recently (Stem Cell Res. 2013). We found that the basal-to-luminal cell ratios analyzed by FACS and the frequency of MaSCs analyzed with in vitro assays increased steadily with increasing age in various strains of mice. Subsequent IVT using mammosphers or 3D-ECM structures formed by young (4 months) or old (28 months) MaSCs derived from C57BL/6 mice showed similar in vivo functional mammary gland regenerative capacity indicating similar self-renewal/differentiation ability between young and old MaSCs. However, we found that the regenerated glands from old MaSCs had significantly higher number of spontaneous hyperplastic and atypical ductal hyperplastic lesions than those from young MaSCs. These findings indicate that aged MaSCs can serve as the cell of origin for early neoplastic transformation in breast tissue. Because rapamycin treatment has been shown to ameliorate age-related pathologies including cancer in murine models, we fed old C57BL/6 mice with microencapsulated rapamycin-containing food or control diet to determine whether rapamycin treatment can inhibit the aging-associated alteration of MaSC number and function. Our findings indicate that short-term (5-10 days) or long-term (> 2 year) rapamycin treatment reversed phenotypic changes associated with aged mammary gland, which were mainly characterized by decreased luminal-to-basal cell ratio and increased MaSC frequency. Histological analysis of regenerated glands by aged MaSCs derived from control and rapamycin-treated mice showed a significant decrease of early neoplastic lesions in rapamycin-treated group. Subsequent whole genome transcriptome analysis with the second generation sequencing revealed age-associated differential expression of genes involved in immune, inflammatory, and wounding responses in both mammosphere-forming cells and stromal cells suggesting that these may be the main cellular processes contributing to the altered MaSC phenotypes and inhibited by rapamycin. In conclusion, our findings suggest that aging causes MaSC to increase its pool and to form early neoplastic lesions, which can be inhibited by rapamycin treatment. Citation Format: Lu-Zhe Sun, Abhik Bandyopadhyay, Qiaoxiang Dong, Hui Gao, Xiang Gu, Danhan Wang, Anqi Wu, Changjiang Huang. Preneoplastic transformation of murine mammary stem cells by aging and inhibition by rapamycin. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B035.

Abstract B035: Preneoplastic transformation of murine mammary stem cells by aging and inhibition by rapamycin

Abstract P5-03-06: Bisphenol A and mammary stem cells: implications in breast cancer susceptibility

Epidemiological studies have shown that the risk of getting breast cancer progressively increases with age. A woman is 100 times more susceptible to develop breast cancer in her 60s than in her 20s. A better understanding of altered cellular and molecular mechanisms leading to the development of sporadic breast cancers as a result of aging are urgently needed for its prevention and treatment in growing population of older women. Recent research implicated that adult mammary stem cells (MaSCs) might be responsible for the initiation and progression of certain types of breast cancer. But no studies have been reported on how lifelong exposure of MaSCs to endogenous and environmental stresses during aging compromises their self-renewal and differentiation function and predispose them to neoplastic transformation either spontaneously or after carcinogen exposure. In our study, we have investigated the effect of progressive aging and carcinogen exposure on MaSC number and function in a murine model. The FACS isolated MaSC enriched basal cells, characterized by their immunophenotype (Lin − CD49f high CD24 med ) were utilized to evaluate MaSC frequency and function during aging by in vitro mammosphere formation and 3D-ECM sphere differentiation assay as well as by in vivo cleared mammary fat pad transplantation (IVT). The results of our study showed that the percentage of MaSCs analyzed by both FACS profile and in vitro assays, increased steadily with increasing age observed at 2, 7, 17 and 25 month-old C57BL/6 mice. Subsequent IVT using mammosphers or 3D structures formed by young (4 months) and old MaSCs (28 months) derived from C57BL/6 mice showed similar in vivo functional mammary gland regenerative capacity indicating similar self-renewal/differentiation ability between young and old MaSCs. However, we found that the regenerated glands from old MaSCs had significantly higher number of spontaneous pre-neoplastic lesions (52.0%) than those from young MaSCs (18.3%). Significantly, MaSC frequency was also increased by the in vivo exposure of a carcinogen, N-Methyl-N-Nitrosourea (MNU, 25 mg/kg body weight, once a week for three consecutive weeks), in old mice with no effect on total mammary cell number. Furthermore, the old MaSCs expanded by MNU treatment were still capable of in vivo regeneration with similar success rate as that of normal old MaSCs. But, we observed increased frequency of hyperplasia and dysplasia in the regenerated glands initiated by MNU treated old MaSC. Our results indicate that MaSCs might be the precursors of preneoplastic lesions and old MaSCs appear to be predisposed to premalignant transformation, which is enhanced by the exposure to a DNA damaging agent. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-03-04.

Abstract P5-03-04: Effect of aging on the function and transformation of murine mammary stem cells

The presence of hazardous chemicals such as lead (Pb) or other heavy metals in the environment poses significant threats to human health. Industrial activities can increase the concentrations of these toxic metals in the soil, water and air where people live, work and play. When exposed to lead, residents face a higher risk of neurological damage, anemia or developmental delays. Urban soil lead levels, for example, are usually higher than the natural background lead levels due to the historical usage of lead paint, leaded gasoline and proximity to industrial activities. We explored a case in southeastern Los Angeles County, where lead contamination in the soil has been a particular concern near a lead-acid battery smelter. In this case study, we investigated soil lead levels across the neighborhoods surrounding the smelter as a mean to support this clean-up decision making. We used a hot spot analysis to identify clusters of high soil lead levels at a neighborhood scale. This case study can be used to teach higher-division undergraduate and graduate students to incorporate spatial thinking and exploratory spatial analysis approaches into the decision-making process for remediation of environmental contamination. Through this case study, the students will develop the knowledge about soil lead contamination and associated health risks, learn how exploratory spatial data analysis can assist examining the distribution of soil lead contamination and discuss potential strategies to improve the environmental remediation process in the urban environment.

Assessing Spatial Characteristics of Soil Lead Contamination in the Residential Neighborhoods Near the Exide Battery Smelter

Global Model for Failure Prediction for Rod Pump Artificial Lift Systems

Multitask Learning has been proven to be more effective than the traditional single task learning on many real-world problems by simultaneously transferring knowledge among different tasks which may suffer from limited labeled data. However, in order to build a reliable multitask learning model, nontrivial effort to construct the relatedness between different tasks is critical. When the number of tasks is not large, the learning outcome may suffer if there exists outlier tasks that inappropriately bias majority. Rather than identifying or discarding such outlier tasks, we present a weighted regularized multitask learning framework based on regularized multitask learning, which uses statistical metrics, such as Kullback-Leibler divergence, to assign weights prior to regularization process that robustly reduces the impact of outlier tasks and results in better learned models for all tasks. We then show that this formulation can be solved using dual form like optimizing a standard support vector machine with varied kernels. We perform experiments using both synthetic dataset and real-world dataset from petroleum industry which shows that our methodology outperforms existing methods.

2013 IEEE 13th International Conference on Data Mining Workshops

Optical and photoelectrochemical properties of Cu2SrSnS4 thin film fabricated by a facial ball-milling method

The Nd3+-doped Bi4Ge3O12 (BGO) single-crystal fiber (SCF) was successfully grown by the micro-pulling-down method with the resistance heating system. The fluorescence spectrum and transmission spectrum of the Nd:BGO SCF were measured. Excited by a continuous-wave 808-nm laser diode, a fluorescence peak around 1064 nm was observed. At an absorbed pump power of 15.25 W, the Nd:BGO SCF laser delivered a power of 3.37 W with a slope efficiency of 31.2%.

Growth and laser properties of Nd3+-doped Bi4Ge3O12 single-crystal fiber.

Computer simulation is a new research approach for corrosion science. A simple model is proposed to describe uniform corrosion process which is a common corrosion failure type for carbon steel. As a lot of chemical and physical processes take place during corrosion reaction with complexity and random, we have to simplify the complex process to establish a math model which is suitable for a simulation calculation. The computational model based on cellular automata (CA) approach uses local rules to govern the electrochemical reactions, and simulate the corrosion system as a discrete dynamical system. As a result the simulation computational solution is compared with experimental data in this work, both of which show the same characteristics of data distribution. The results presented the feasibility of the cellular automata approach to simulate the corrosion process and to describe change of surface topography in company with the increase of corrosion quantity.

Computer Simulation of Uniform Corrosion Process for Carbon Steel

To increase the mechanical properties of the metal rollers, Mo and Mo+Y2O3 alloy powders were designed. And a kind of coating fabricated by a continuous wave CO2 laser surface alloying(LSA) on 40Cr steel roller was obtained. The effect of Mo and Mo+Y2O3 on microstructure, hardness and wearing resistance of alloying coating were studied by OM, SEM, XRD, microhardness tester and wearing tester. The experimental results indicate that the grain size in alloying coating is obviously fined, and the grain boundary is strengthened. The uniformity and density of microstructure are improved. The microhardness and wear resistance of alloying coating are significantly increased.

Process Characterization of 40Cr Steel Roller by Laser Surface Alloying with Rare Earths Oxide Y2O3

Influence of yttrium on laser surface alloying organization of 40Cr steel

Deposition of High-Temperature Superconducting Thin Films on Metallic and Nometallic Substrates by Laser Ablation.

The expression forms of the languange have closed relationships with models of the senses on meanings,and the forms of senses on meanings bind the formation and changes of the grammar.The machanism of the modle of the senses on and semantic meanings that affect froms of sentence structures is also discussed in this paper.

The loanwords from Austronesian and Chinese in Kam-Dai Languages should not be as the proof to explain their genetic relationships.The more comparisons show that the Kam-Dai language had genetic relationship with Tibeto-Burman and Chinese(Sino-Tibetan),and their basic words have their cognate correspondences in Austronesian and Austro-Asiatic,and all of them were from Huanan Languages.

The study on historical sound evolution in Kam-Dai(侗台) languages is the base of the research on the genetical relationship of the language. This paper focuses on discussion of the historical sound evolution in those languages, based on the explanation of the divergences in them and their Chinese loanwords and Austronesian substratum words in different times.

Austronesian scholars in Taiwan(台湾) hold that all the languages were from the Proto-Taiwanese. The first innovation for division they proposed is the expansion of *Cand *t found in Malayo-Polynesian. But the comparison shows that the opposition between (?) and *t still exists in some Austronesians out of Taiwan(台湾), such asalagasy, in which there is the opposition between (?) and t from Proto-Austronesian.In this paper, Austronesians are ivided into four branches: Atayal, Tsou-Pyuma, Malayo-Tagalog and Melanesian-Micronesian, by their historical innovations.

Based on the contrastive analysis, this paper points out that the developing thoughts and direction of auto distributing business in Guizhou province is to apply the mode of marketing mix.

Research on the Mode of Marketing Mix in AutoDistributing Business in Guizhou Province

The social support returns to college education in China: Evidence from online medical crowdfunding

Disaster Management Through Digital Platforms: Online Crowdfunding Communities Respond to the COVID-19 Pandemic

This article aims to find out how the differences of policy, market and culture between Korean and Chinese influence the process of Chinese localization and the development of Chinese television industry. The collection of literature summaries from journals and news, the research methods of the literature review are used to discover that much literature in social science focus on how the television programs introduced from Korea influence Chinese people, but lack the summary articles about specific analyzing the differences of Korea and China. The results of this article are as followed: Firstly, under the guidance of policies, the TV industries of China and South Korea aim to get rid of the shackles of cultural imperialism. After transplanting foreign TV programs to develop their TV industries, they are now carrying out the localised development of the TV industry. Secondly, different progresses of development in television industry lead to two distinctive market structures. Korea focuses on entertainment shows and aims to spread out to Asian market. Chinese market lacks diversification, and the television industry is stably developed by directly purchasing Korean programs for localization. Finally, cultural differences about food and etiquette have some obstacles to Chinese localization, while these differences helps Chinese television stations to increase awareness of promoting creativity and self-made programs. This article analyzes the influence of Korean programs on the development of China’s television industry. Under the guidance of policies, the Chinese television industry combines its market development and cultural advantages to carry out original localized programs.

Localizing the Korean Variety Shows in China Review of the Differences Between Policy, Market and Culture

Assortative matching and commercial insurance participation: Evidence from the China Household Finance Survey

Over the last two decades, grassroots altruism, enabled through platforms such as DonorsChoose.org, has resulted in successful funding of innumerable and essential public school projects across the country. While such channels become critical fundraising mechanisms, there is an unintended possibility of crowding out of these sources by governmental initiatives which aim to shed light on, and address public school resource deﬁcits. In this study, with a focus on major public policy announcements, we examine whether there is an unintended effect of external measures, such as the signing of the Every Student Succeeds Act (ESSA), on grassroots altruism, which is possible to examine on online philanthropy platforms. We surmise that, in such platforms, donors could become complacent and take comfort in the cognizance of an external agency addressing the problems they care about – we call this the savior effect. Importantly, from our analysis of panel data on the platform, we ﬁnd that the savior effect: (a) results in declined donations toward under-served public school projects on the platform, and (b) makes donations more local, disproportionately impacting schools with high concentrations of low-income and minority students, which receive fewer instructional resources to begin with. Our work has important policy implications for public schools, donor communities, and online fundraising platforms.

Could Government Measures Crowd Out Grassroots Philanthropy? Empirical Evidence from an Education Crowdfunding Platform

We study how digital crowdfunding platforms can help replenish the sudden economic deficiencies that accompany a global crisis. Specifically, we examine whether public schools, which suffered severe setbacks during the COVID-19 crisis, were able to generate support from online fundraising communities. We study how the shutdown of schools and the shift to online learning in the United States affected private fundraising on the DonorsChoose.org platform. We find evidence that, after the exogenous shock caused by the pandemic (and resulting stay-at-home orders), donations to schools increased, implying both demand-side and supply-side effects. We observe an increased level of concern from existing platform contributors through increased per-donor contributions, especially toward high-need schools. Moreover, we found a shift in donation patterns, wherein donors swiftly adapted to renewed priorities and redistributed their resources to immediate needs around digital learning infrastructure. Our findings reveal the pivotal role digital platforms can play in facilitating community resilience during times of crisis.

Keeping Kids Learning: Online Crowdfunding Communities Respond to the COVID­-19 Pandemic

Over the last two decades, grassroots altruism, enabled through online platforms such as DonorsChoose.org, has resulted in the successful funding of numerous essential public school projects across the country. While such channels become critical fundraising mechanisms, there is an unintended possibility of the crowding out of these sources by governmental initiatives that aim to address public school welfare and quality of education. In this study, with a focus on major public policy announcements, we examine whether there is an unintended effect of external measures, such as the signing of the Every Student Succeeds Act (ESSA), on grassroots altruism, as observed on online philanthropy platforms. We surmise that, in such platforms, donors could become complacent and take comfort in the cognizance of an external agency addressing the problems they care about — we term this the “savior effect”. Importantly, from our analysis of panel data on an education crowdfunding platform, we find (a) a decline in donations toward public school projects on the platform, and (b) that donations become more local, disproportionately impacting schools with high concentrations of low-income and minority students, which receive fewer instructional resources to begin with. Our work has important policy implications for public schools, donor communities, and online fundraising platforms.

Unintended Consequences: The Effect of Education Policy Announcements on Online Philanthropy

Evolving strategies of e-commerce and express delivery enterprises with public supervision

This paper uses the population density, population concentration index, population center of gravity and population distribution Gini coefficient to analyze the spatial-temporal characteristics and non-equilibrium of county population distribution in Northwest China from 2001 to 2016. The results show that between 2001 and 2016, the population of northwestern China continued to grow, but the distribution was extremely uneven. The population density of different counties was much different, and the number of counties with negative annual growth increased; the population concentration index decreased slightly. The population center of gravity is located in the southeast of the geometric center which moves slowly from southeast to northwest. The Gini coefficient of population distribution fluctuates around 0.77. Introduction The spatial distribution of population can reflect the state of social and economic development of a region [1]. Due to the influence of specific natural, economic and social environment, the spatial-temporal changes of population often show significant differences and non-equilibrium [2], population changes and spatial redistribution will also act on the sustainable development of regional economy [3]. The spatial distribution and evolution trend of population is the starting point of studying many phenomena and laws [4]. A reasonable population distribution will accelerate the sustained and stable economic development, while the unreasonable population distribution will hinder economic development [5]. Northwest China includes Gansu, Shaanxi, Qinghai, Ningxia Hui Autonomous Region and Xinjiang Uygur Autonomous Region. It has jurisdiction over 360 county-level administrative units with a total land area of 3.1 million km2, accounting for 33.27% of the national land area. The population density of more than 70% of the county units is lower than the national average. Meanwhile, the population density of the suitable areas for human habitation is too high. Exceed the critical level of population density in arid and semi-arid areas designated by the United Nations. Therefore, it is significance to study the population quantity and its spatial distribution evolution in this region, explore the non-equilibrium degree of population distribution within the region, and further grasp the regularity of population spatial distribution, promote the rational distribution of population, optimize the allocation of resources, and realize the healthy development of economy. Data and Methods Data Sources This paper takes 2001-2016 as the research period, and the demographic data are from the statistical yearbook of corresponding years. Data of administrative division boundaries are derived from the National Basic Geographic Information Center in 2015. Research Method Population Concentration Index. The concentration index is often used to analyze the concentration of population distribution [6], the equation is as follows: International Conference on Advanced Education, Management and Humanities (AEMH 2019) Copyright © 2019, the Authors. Published by Atlantis Press. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/). Advances in Social Science, Education and Humanities Research, volume 352

Proceedings of the 2019 International Conference on Advanced Education, Management and Humanities (AEMH 2019)

Non-equilibrium Analysis of Population Distribution in Northwest China from 2001 to 2016

Casals-Gorsky-Gorsky-Simental realized all positroid strata of the complex Grassmannian as augmentation varieties of Legendrians called positroid links. We prove that the partial order on strata induced by Zariski closure also has a symplectic interpretation, given by exact Lagrangian cobordism.

. We show that any knot which is smoothly the closure of a 3-braid cannot be Lagrangian concordant to and from the maximum Thurston-Bennequin Legendrian unknot except the unknot itself. Our obstruction comes from drawing the Weinstein handlebody diagrams of particular symplectic ﬁllings of cyclic branched double covers of knots in S 3 . We use the Legendrian contact homology diﬀerential graded algebra of the links in these diagrams to compute the symplectic homology of these ﬁllings to derive a contradiction. As a corollary, we ﬁnd an inﬁnite family of contact manifolds which are rational homology spheres but do not embed in R 4 as contact type hypersurfaces.

In this paper, we study left-invariant Einstein-like metrics on the compact Lie group G. Assume that there exist two subgroups, H⊂K⊂G, such that G/K is a compact, connected, irreducible, symmetric space, and the isotropy representation of G/H has exactly two inequivalent, irreducible summands. We prove that the left metric ⟨·,·⟩t1,t2 on G defined by the first equation, must be an A-metric. Moreover, we prove that compact Lie groups do not admit non-naturally reductive left-invariant B-metrics, such as ⟨·,·⟩t1,t2.

Suppose $X$ is a compact connected metric space and $f: X \to X$ is metrically cxc in the sense of Ha\"issinsky-Pilgrim. If $X$ contains a homeomorphic copy of the letter "Y", then $\operatorname{hdim}(X)>1$.

Quasi-self-similar fractals containing "Y" have dimension larger than one

Author(s): Wu, Angela Anqi | Advisor(s): Bonk, Mario | Abstract: We study certain approximately self-similar metric spaces that arise from expanding Thurston maps $f: \mathbb{S}^2 \to \mathbb{S}^2$ called visual spheres. It is known [HP09, Theorem 4.2.11][BM17, Theorem 18.1(ii')]that the quasisymmetry class of a visual sphere of $f$ is related to the rationality of $f$. We prove that a visual sphere is indeed approximately self-similar if $f$ does not have periodic critical points. This is done by picking a nice visual metric of an expanding Thurston map. Using the nice metric, we study the solenoid of $f$. We put a specific metric on the leaves of $f$ and show that the leaves and weak tangents are almost the same thing. We then study the visual spheres of expanding Thurston maps with an emphasis on a quasisymmetric invariant, called the Ahlfors regular conformal dimension. We show that the Ahlfors regular conformal dimension of any weak tangent of a visual sphere is the same as the Ahlfors regular conformal dimension of the visual sphere itself, and that the Ahlfors regular conformal dimension of any weak tangent is attainable if and only if Ahlfors regular conformal dimension of the visual sphere is attainable. We show by an example that the same does not hold for more general metric spaces. Finally, we show that a visual sphere has $p$-thick curve family supported on an $f$-invariant porous subset if $f$ has a irreducible $p$-thick $f$-stable multicurve. We give an example to show that when $p = 2$, the condition of a $p$-thick $f$-stable multicurve is sharp.

Visual Spheres of Expanding Thurston Maps: Their Weak Tangents and Porous Subsets

We show that for all $n \geq 2$, there exists a doubling linearly locally contractible metric space $X$ that is topologically a $n$-sphere such that every weak tangent is isometric to $\R^n$ but $X$ is not quasisymmetrically equivalent to the standard $n$-sphere. The same example shows that $2$-Ahlfors regularity in Theorem 1.1 of \cite{BK02} on quasisymmetric uniformization of metric $2$-spheres is optimal.

A metric sphere not a quasisphere but for which every weak tangent is Euclidean

Generalized iterated wreath products of symmetric groups and generalized rooted trees correspondence

Generalized iterated wreath products of cyclic groups and rooted trees correspondence

An Introduction to Weinstein Handlebodies for Complements of Smoothed Toric Divisors

The question of whether each building of housing estate has equal access to nearby social service resources (e.g., public transportation service, catering, entertainment, etc.) is a major concern of citizens. This paper takes Wuhan as a case to explore the equality in social service resource sharing of the housing estate at a microscopic level by analyzing the accessibility of each building under different travel patterns. To estimate the accessibility of each building, we developed a novel model with multi-travel modes and residential suitability evaluation of residents. The specific values of the parameters involved in the proposed model were extracted from the multi-source spatial data such as social media data, census data, point of interest, and road network data. These data were acquired from multiple platforms, e.g., Gaode map, OSM (OpenStreetMap), and GeoQ. We chose three types of districts in the city of Wuhan, including the old central district, new central district, and suburban district. We applied the proposed model to assess the accessibility of communities in these districts. Based on the results, we further analyzed whether and to what extent the distribution of each building in urban communities is equitable for social service resource sharing in China.

Accessibility Assessment of Buildings Based on Multi-Source Spatial Data: Taking Wuhan as a Case Study

Flexible strain sensors can detect physical signals (e.g., temperature, humidity, and flow) by sensing electrical deviation under dynamic deformation, and they have been used in diverse fields such as human motion detection, medical care, speech recognition, and robotics. Existing sensing materials have relatively low adaptability and durability and are not stretchable and flexible enough for complex tasks in motion detection. In this work, a highly flexible self-healing conductive polymer composite consisting of graphene, poly(acrylic acid) and amorphous calcium carbonate is prepared via a biomineralization-inspired process. The polymer composite shows good editability and processability and can be fabricated into stretchable strain sensors of various structures (sandwich structures, fibrous structures, self-supporting structures, etc.). The developed sensors can be attached on different types of surfaces (e.g., flat, cambered) and work well both in air and under water in detecting various biosignals, including crawling, undulatory locomotion, and human body motion.

Highly Stretchable, Adaptable, and Durable Strain Sensing Based on a Bioinspired Dynamically Cross-Linked Graphene/Polymer Composite.

This study revealed the heterogeneity of E. coli strains from pigs, including two strains studied by both in silico and wet experiments in detail and 14 strains studied by bioinformatics analysis. E. coli Y18J may improve the adaptability of pigs toward disease resistance through the production of colicins B and M. Our findings could shed light on the pathogenic and harmless roles of E. coli in modern animal husbandry, leading to a better understanding of intestinal-microbe–pathogen interactions in the course of evolution. ABSTRACT Gut microbes can affect host adaptation to various environment conditions. Escherichia coli is a common gut species, including pathogenic strains and nonpathogenic strains. This study was conducted to investigate the effects of different E. coli strains in the gut on the health of pigs. In this study, the complete genomes of two E. coli strains isolated from pigs were sequenced. The whole genomes of Y18J and the enterotoxigenic E. coli strain W25K were compared to determine their roles in pig adaptation to disease. Y18J was isolated from feces of healthy piglets and showed strong antimicrobial activity against W25K in vitro. Gene knockout experiments and complementation analysis followed by modeling the microbe-microbe interactions demonstrated that the antagonistic mechanism of Y18J against W25K relied on the bacteriocins colicin B and colicin M. Compared to W25K, Y18J is devoid of exotoxin-coding genes and has more secondary-metabolite-biosynthetic gene clusters. W25K carries more genes involved in genome replication, in accordance with a shorter cell cycle observed during a growth experiment. The analysis of gut metagenomes in different pig breeds showed that colicins B and M were enriched in Laiwu pigs, a Chinese local breed, but were scarce in boars and Duroc pigs. IMPORTANCE This study revealed the heterogeneity of E. coli strains from pigs, including two strains studied by both in silico and wet experiments in detail and 14 strains studied by bioinformatics analysis. E. coli Y18J may improve the adaptability of pigs toward disease resistance through the production of colicins B and M. Our findings could shed light on the pathogenic and harmless roles of E. coli in modern animal husbandry, leading to a better understanding of intestinal-microbe–pathogen interactions in the course of evolution.

Colicins of Escherichia coli Lead to Resistance against the Diarrhea-Causing Pathogen Enterotoxigenic E. coli in Pigs

Recently, network topology has become a pop research field in complex networks. The small-world and scalefree character can be used in community detection. In this paper, we propose a folding contraction method (FCM) for community partition detection based on scale-free networks feature. And a framework of this method has been provided. Experimental results show that the proposed method has high accuracy and good performance.

2017 International Conference on Industrial Informatics - Computing Technology, Intelligent Technology, Industrial Information Integration (ICIICII)

PLC, abbreviation for power line communication technology, is the use of the existing low voltage distribution network as a transmission medium to transfer data and exchange information. In order to realize high speed Internet access and multimedia information transmission by using power line, in this paper, the power line Ethernet adapter is researched and improved by taking advantage of 220V/380V low voltage power line. Firstly, OFDM modulation technology is analyzed and simulated by the Matlab partially, then INT6400 is chosen as adapter main control chip, additionally, a bandpass filter and an Ethernet transformer are added to adapter for implementation of 100Mbps high speed broadband access. Finally, the response time, data transmission rate of the adapter designed has been tested. Test results show that the adapter based on power line communication can reach performance requirements of 100M network basically.

2016 International Conference on Industrial Informatics - Computing Technology, Intelligent Technology, Industrial Information Integration (ICIICII)

Research and Improvement of Ethernet Adapter Based on Power Line Communication

The mutation operator of Biogeography-Based Optimization (BBO) makes a large advance for the diversity of the solution space. Generally speaking, the quality of a solution is closely related with the maximum mutation rate, which is always decided by experience. But for the different situations, the maximum mutation rate may be different. In this paper, we propose an Intelligent Mutation Operator of Biogeography-Based Optimization (IMOBBO), which could find the suitable maximum mutation rate in overall benign ranges. Extensive simulation results are provided to demonstrate the effectiveness and the sharpness of the algorithm.

Intelligent Mutation Operator of Biogeography-Based Optimization Algorithm

As plant-specific transcription regulators, YABBYs are involved in plant growth, development and stress responses. However, little information is available about genome-wide screening and identification of OsYABBY-interacting proteins. In this study, phylogenetic relationship, gene structure, protein structure and gene expression profile of eight OsYABBYs were carried out, all of which indicated that OsYABBYs were involved in different developmental processes and had functional differentiation. More importantly, PPI (protein-protein interaction) analysis and molecular docking simulation predicted that WUSCHEL-related homeobox (WOX) proteins might be interacting proteins of OsYABBYs. Yeast two-hybrid (Y2H) and luciferase complementation imaging assays (LCI) further confirmed that OsYABBYs (except for OsYABBY7) could interact with OsWOX3A in vitro and in vivo. In addition, OsYABBY3 and OsYABBY5 also could interact with OsWUS. Taken together, our results provided valuable information for further elucidating OsYABBYs regulation mechanism in improving rice performance.

Comprehensive study of rice YABBY gene family: evolution, expression and interacting proteins analysis

DNA demethylases remodel DNA methylation in rice gametes and zygote and are required for reproduction.

Gene expression is regulated at many levels, including mRNA transcription, translation, and post-translational modification. Compared with transcriptional regulation, mRNA translational control is a more critical step in gene expression and allows for more rapid changes of encoded protein concentrations in cells. Translation is highly regulated by complex interactions between cis-acting elements and trans-acting factors. Initiation is not only the first phase of translation, but also the core of translational regulation, because it limits the rate of protein synthesis. As potent cis-regulatory elements in eukaryotic mRNAs, upstream open reading frames (uORFs) generally inhibit the translation initiation of downstream major ORFs (mORFs) through ribosome stalling. During the past few years, with the development of RNA-seq and ribosome profiling, functional uORFs have been identified and characterized in many organisms. Here, we review uORF identification, uORF classification, and uORF-mediated translation initiation. More importantly, we summarize the translational regulation of uORFs in plant metabolic pathways, morphogenesis, disease resistance, and nutrient absorption, which open up an avenue for precisely modulating the plant growth and development, as well as environmental adaption. Additionally, we also discuss prospective applications of uORFs in plant breeding.

In this communication, a low radar cross section (RCS) antenna array with reconfigurable scattering patterns based on digital antenna units is proposed. The digital antenna unit has two scattering states that are controlled by p-i-n diodes. For <inline-formula> <tex-math notation="LaTeX">$y$ </tex-math></inline-formula>-polarized normally incident waves, the phases of the two reflected states exhibit a 180° phase difference at approximately 5 GHz. For <inline-formula> <tex-math notation="LaTeX">$x$ </tex-math></inline-formula>-polarized incident waves, the antenna units act as meta-absorbers, and the incident power is absorbed by the antenna units. Moreover, the radiation properties of these two states are approximately the same at 5 GHz. Thus, the scattering patterns of the antenna array can be tuned by controlling the scattering states of the digital antenna units without affecting the radiation performance. By tuning the directions of the scattering pattern nulls to dynamically align to the direction of the incident wave, both the monostatic and bistatic RCS can be significantly reduced. An <inline-formula> <tex-math notation="LaTeX">$8\,\, {\times }\,\,8$ </tex-math></inline-formula> antenna array was fabricated and measured to validate the proposed concept. The measured results are in good agreement with the simulated ones. This indicates that the proposed antenna array is a promising solution to address the challenges of bistatic radar systems.

Low RCS Antenna Array With Reconfigurable Scattering Patterns Based on Digital Antenna Units

This letter presents a dual-polarization frequency-selective rasorber (FSR) with independently controlled dual-band transmission response. The rasorber consists of a lossy layer and a lossless layer. These two layers are separated by an air gap. The upper lossy layer is constructed by four square rings with two stubs, which realizes the two-band transmission response. Frequencies of the two passbands can be independently controlled by changing the lengths of the two stubs individually. The four square rings are connected by a rhombus metallic strip inserted with four resistors producing good absorptivity. As to the bottom frequency-selective surface layer, two square slots are chosen which can realize the same two transmission bands as the upper layer. Equivalent circuit model is also constructed to explain the performance of the proposed FSR. Simulation shows that low insertion losses of 0.39 and 0.64 dB under TE polarization and 0.40 and 0.66 dB under TM polarization are obtained at 8 and 11.9 GHz, respectively. The band with reflection coefficient lower than −10 dB covers 5–12.8 GHz. Prototype of the proposed FSR is fabricated and measured, which shows a good agreement with the simulated results.

Dual-Polarization Frequency-Selective Rasorber With Independently Controlled Dual-Band Transmission Response

This paper introduces a kind of frequency selective rasorber. By combining the upper lossy layer and the bottom lossless layer, one passband with two-sided absorption band is obtained. A 4×4 array is constructed to realize radar cross section (RCS) reduction.The 5dB RCS redction bandwidth is from 5GHz to 15GHz(relative bandwidth is 100%). It is also worth pointing out that the maximum RCSR is 29.7dB and 31.2dB around 8.8GHz for x- and y-polarized incident waves.

Wideband RCS Reduction Based on Dual-Polarization Frequency Selective Rasorber

Ship detection receives increasing concerns as an essential ocean mission. Recently, deep learning (DL) has greatly improved ship detection accuracy from traditional methods. However, most of exist methods only utilize single source data, there are still some challenges that influence the ship detection performance. Therefore, we propose a highlight foreground and local scale features network (HFL-Net) for cross-domain ship detection to solve the problems of complex inshore background interferences and multi-scale ship feature differences. It is evaluated on two datasets with three other state-of-the-art methods and the experimental results confirm the superiority ofHFL-Net.

IGARSS 2022 - 2022 IEEE International Geoscience and Remote Sensing Symposium

HFL-Net: Highlight Foreground and Local Scale Features Network for Cross-Domain Ship Detection

Vehicle object tracking is a research hotspot in computer vision. To solve the problem of single object extraction caused by the shadow effect and occlusion between vehicles, this paper presents a vehicle object tracking algorithm suitable for both dynamic and stationary states. First, the improved Canny algorithm is used to obtain the information in a video sequence, and the dynamic region of the object is extracted using the difference between the mean of the video sequence and the object frame. Secondly, the Gaussian mixture model is used for video object segmentation to obtain the foreground image and the background image, and the static object is identified through the intersection operation of the object dynamic region and the foreground image combined with the edge information. Then, chroma information is introduced into a statistical nonparametric model to eliminate the shadow of the foreground image, and the meanshift tracking algorithm is used for dynamic object tracking of the foreground image after eliminating the shadow. The experimental results show that the proposed tracking algorithm can identify and track vehicles effectively and quickly, providing new ideas for the future development of the sensor field.

Method of Unsupervised Static Recognition and Dynamic Tracking for Vehicles

In object detection in remote sensing images, owing to the complex background environment, there are problems of poor robustness to interference and low detection accuracy for small objects. The algorithm proposed in this paper combines the attention mechanism with the spatial pyramid structure to improve the You-only-look-once algorithm version 3 (YOLOv3), and it also includes the pyramid attention module to improve the performance of the detection model. The feature pyramid attention module is introduced into deep features, and the feature pyramid attention structure is combined with global context information to better learn object features. The global attention upsampling module is introduced into low-level features, and the global information provided by global pooling is used as a guide to select low-level features. The object detection model can more fully acquire the features of important information and selectively suppress irrelevant features, thereby improving the detection accuracy of the algorithm. To verify the performance of the proposed algorithm, it is used to detect airplanes, storage tanks, ships, baseball diamonds, and running tracks in remote sensing images, and its performance is compared with that of other algorithms. Experiments prove that the proposed algorithm has better detection performance and can improve the detection accuracy of each object in remote sensing images.

YOLOv3 Object Detection Algorithm with Feature Pyramid Attention for Remote Sensing Images

Activation of nuclear receptors, a family of ligand-dependent transcription factors, is used extensively in development of drug targets. We have previously shown that pioneer factor Foxa2 opens chromatin for binding of nuclear receptors FXR and LXRα during acute ligand activation. FXR is activated by bile acids and deletion of Foxa2 in the liver results in intrahepatic cholestasis. We hypothesized that Foxa2 also enables chromatin conformational changes during ligand activation. We performed Foxa2 HiChIP to assess Foxa2-dependent long-range interactions in mouse livers treated with either vehicle control or FXR agonist GW4064. HiChIP contact analysis shows that global chromatin interactions are dramatically increased during FXR activation. Ligand-treated livers exhibit extensive redistribution of topological associated domains (TAD and substantial increase in Foxa2-anchored loops, suggesting Foxa2 is involved in dynamic chromatin conformational changes. We demonstrate that chromatin conformation, including genome-wide interactions, TADs, intra-chromosomal and inter-chromosomal Foxa2-anchored loops, drastically changes upon addition of FXR agonist. Hence, we determine a novel role for Foxa2 in enabling these conformational changes, extending its function in bile acid metabolism.

Pioneer factor Foxa2 mediates chromatin conformation changes in ligand-dependent activation of nuclear receptor FXR

This paper explored the prosodic patterns of Chinese and English poetry reading as well as similarities and differences between them, based on the theory of Poetic Function and the Genre-specific Hypothesis. Duration, pitch and intensity patterns of a total of 110 poems read by 5 native English speakers and 6 Chinese native speakers were analyzed and the results demonstrated that both Chinese and English poetry reading realized the rhythm scheme through intensity range, but differed in the adoption of other acoustic cues for other properties respectively. Chinese native speakers applied duration to realize semantic rhythm while English native speakers adopted pitch to realize meter. This paper also has implications for the teaching of poetry reading, improving readers’ understanding and appreciation of Chinese and English poetry.

2020 Asia-Pacific Signal and Information Processing Association Annual Summit and Conference (APSIPA ASC)

Differentiated Prosodic Adaption of Chinese and English Poetry: An Acoustic Approach to Reading of Chinese Tang Poetry and Shakespearean Sonnets

CO2 utilization by reversible solid oxide cells towards carbon neutralization for long-term energy storage

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Enhancing durability of solid oxide cells for hydrogen production from seawater by designing nano-structured Sm0.5Sr0.5Co3-δ infiltrated air electrodes

This work investigated the durability of seawater electrolysis and degradation mechanism for hydrogen production under different seawater steam content using a flat-tube solid oxide electrolysis cell (SOEC). The results showed...

Effect of steam/hydrogen ratio on the performance of flat-tube solid oxide electrolysis cells for seawater

Properties of CuMn1.5Ni0.5O4 spinel as high-performance cathode for solid oxide fuel cells

Understanding thermal and redox cycling behaviors of flat-tube solid oxide fuel cells

Pulsed electrolysis of carbon dioxide by large‐scale solid oxide electrolytic cells for intermittent renewable energy storage

The properties of the fuel electrode of solid oxide cells under simulated seawater electrolysis

Effect of air addition to the air electrode on the stability and efficiency of carbon dioxide electrolysis by solid oxide cells

High reversible cycling performance of carbon dioxide electrolysis by flat-tube solid oxide cell

Electrochemical performance and durability of flat-tube solid oxide electrolysis cells for H2O/CO2 co-electrolysis

In-situ analysis of anode atmosphere in a flat-tube solid oxide fuel cell operated with dry reforming of methane

Mechanism of hydrogen generation from low melting point elements (Ga, In, Sn) on aluminum alloy hydrolysis

Red mold rice (RMR) generally contains gamma‐aminobutyric acid (GABA), which has several physiological functions. Monascus purpureus M162, with a high GABA production of 15.10 mg/g was generated by atmospheric and room temperature plasma mutation. Furthermore, we conducted a response surface methodology to produce a premium hongqu starter. The results revealed that under optimal conditions, that is, a substrate containing brown rice and bran in a brown rice: bran ratio of 9:1 (wt/wt), an inoculation size of 21.50 mL/100 g, a mixing frequency of one time/9 h, and a cultivation time of 7.20 days, the number of active spores, α‐amylase activity, and saccharification power activity was 4.15 × 107 spores/g, 155 U/g, and 3260 U/g in the high‐quality starter, respectively. These values were 224.32‐fold, 139.64%, and 141.74% higher than those obtained with M. purpureus M162 inoculated into steamed indica rice, respectively, and 153.70‐fold, 267.24%, and 151.63% higher than those obtained with the parent strain M. purpureus M1, respectively. The premium hongqu starter of M. purpureus M162 was inoculated into steamed indica rice to produce RMR with 15.93 mg/g of GABA. In conclusion, we proposed a novel strategy for functional RMR production with high GABA concentrations by solid‐state fermentation with Monascus spp.

Optimization of the hongqu starter preparation process for the manufacturing of red mold rice with high gamma‐aminobutyric acid production by solid‐state fermentation

ABSTRACT High efficiency conversion of CO2 can be realized in a solid oxide electrolysis cell. In this work, a flat-tube cell with symmetrical structure supported by Ni-YSZ fuel electrode was used to study the performance of high-temperature CO2 electrolysis under different reducing gas components in the fuel electrode. The results indicated that in the H2-CO2 fuel electrode atmosphere, the instantaneous performance of CO2 electrolysis is better, the polarization impedance is smaller, and the overpotential of CO2 electrolysis is lower under the same partial pressure of oxygen (i.e., with the same open-circuit voltage). Compared with CO as the protective gas, it is easier to achieve a stable electrolytic voltage for the electrolysis of CO2 under H2 protection. In the H2-CO2 reaction atmosphere, when the proportion of protective H2 increased from 25% to 75%, devastating irreversible degradation occurs at −300 mA/cm2, while in the CO-CO2 (71.7% CO-28.3% CO2) reaction atmosphere, the similar degradation occurs at – 200 mA/cm2. At – 200 mA/cm2 constant-current electrolysis, the highest energy conversion efficiency can reach 171% (disregarding energy consumption for heating the gas) and 81.6% (disregarding energy consumption for heating air). This work provides a useful reference for the selection of atmosphere protection in CO2 electrolysis based on Ni-YSZ electrode SOEC.

Performance of CO2 electrolysis using solid oxide electrolysis cell with Ni-YSZ as fuel electrode under different fuel atmospheres

Polymer substrate reshapes the microbial assemblage and metabolic patterns within a biofilm denitrification system

Denitrification performance and microbial diversity using starch-polycaprolactone blends as external solid carbon source and biofilm carriers for advanced treatment.

Efficient extraction and recovery of xylan and lignin from rice straw using a flow-through hydrothermal system

In the field of behavior-related brain computation, it is necessary to meaningfully align raw neural population activities against the drastic shift between them. However, the alignment is non-trivial since most neural population activities are in a multivariate time-series manner. An instrumental framework within neuroscience research posits that trial-based neural population activities rely on low-dimensional latent dynamics. Focusing on such latent dynamics greatly facilitates the alignment procedure. Despite the considerable progress we have reached, existing methods usually ignore the intrinsic spatio-temporal structures within latent dynamics. Thus, those solutions lead to poor quality in dynamics structures and overall performance after alignment. To tackle this problem, we propose a method leveraging the expressiveness of diffusion model to relieve such issues. Specifically, the latent dynamics structures of the source domain are first extracted by the diffusion model. Then, such structures are well-recovered through a maximum likelihood alignment procedure on the target domain. We first demonstrate the effectiveness of our proposed method on a synthetic dataset. Then, when applied to neural recordings from primate motor cortex, under both cross-day and inter-subject settings, our method consistently manifests its capability of preserving the spatio-temporal structure of latent dynamics and outperforms existing approaches in alignment quality.

Extraction and Recovery of Spatio-Temporal Structure in Latent Dynamics Alignment with Diffusion Model

We study the problem of Inverse Reinforcement Learning (IRL) with an average-reward criterion. The goal is to recover an unknown policy and a reward function when the agent only has samples of states and actions from an experienced agent. Previous IRL methods assume that the expert is trained in a discounted environment, and the discount factor is known. This work alleviates this assumption by proposing an average-reward framework with efficient learning algorithms. We develop novel stochastic first-order methods to solve the IRL problem under the average-reward setting, which requires solving an Average-reward Markov Decision Process (AMDP) as a subproblem. To solve the subproblem, we develop a Stochastic Policy Mirror Descent (SPMD) method under general state and action spaces that needs $\mathcal{{O}}(1/\varepsilon)$ steps of gradient computation. Equipped with SPMD, we propose the Inverse Policy Mirror Descent (IPMD) method for solving the IRL problem with a $\mathcal{O}(1/\varepsilon^2)$ complexity. To the best of our knowledge, the aforementioned complexity results are new in IRL. Finally, we corroborate our analysis with numerical experiments using the MuJoCo benchmark and additional control tasks.

Inverse Reinforcement Learning with the Average Reward Criterion

The decoding of brain neural networks has been an intriguing topic in neuroscience for a well-rounded understanding of different types of brain disorders and cognitive stimuli. Integrating different types of connectivity, e.g., Functional Connectivity (FC) and Structural Connectivity (SC), from multi-modal imaging techniques can take their complementary information into account and therefore have the potential to get better decoding capability. However, traditional approaches for integrating FC and SC overlook the dynamical variations, which stand a great chance to over-generalize the brain neural network. In this paper, we propose a Joint kernel Graph Attention Network (JGAT), which is a new multi-modal temporal graph attention network framework. It integrates the data from functional Magnetic Resonance Images (fMRI) and Diffusion Weighted Imaging (DWI) while preserving the dynamic information at the same time. We conduct brain-decoding tasks with our JGAT on four independent datasets: three of 7T fMRI datasets from the Human Connectome Project (HCP) and one from animal neural recordings. Furthermore, with Attention Scores (AS) and Frame Scores (FS) computed and learned from the model, we can locate several informative temporal segments and build meaningful dynamical pathways along the temporal domain for the HCP datasets. The URL to the code of JGAT model: https://github.com/BRAINML-GT/JGAT.

JGAT: a joint spatio-temporal graph attention model for brain decoding

The state-of-the-art dimensionality reduction approaches largely rely on complicated optimization procedures. On the other hand, closed-form approaches requiring merely eigen-decomposition do not have enough sophistication and nonlinearity. In this paper, we propose a novel nonlinear dimensionality reduction method—Inverse Kernel Decomposition (IKD)—based on an eigen-decomposition of the sample covariance matrix of data. The method is inspired by Gaussian process latent variable models (GPLVMs) and has comparable performance with GPLVMs. To deal with very noisy data with weak correlations, we propose two solutions—blockwise and geodesic—to make use of locally correlated data points and provide better and numerically more stable latent estima-tions. We use synthetic datasets and four real-world datasets to show that IKD is a better dimensionality reduction method than other eigen-decomposition-based methods, and achieves comparable performance against optimization-based methods with faster running speeds. Open-source IKD implementation in Python can be accessed at this https://github.com/JerrySoybean/ikd .

Researchers have been facing a difficult problem that data generation mechanisms could be influenced by internal or external factors leading to the training and test data with quite different distributions, consequently traditional classification or regression from the training set is unable to achieve satisfying results on test data. In this paper, we address this nontrivial domain generalization problem by finding a central subspace in which domain-based covariance is minimized while the functional relationship is simultaneously maximally preserved. We propose a novel variance measurement for multiple domains so as to minimize the difference between conditional distributions across domains with solid theoretical demonstration and supports, meanwhile, the algorithm preserves the functional relationship via maximizing the variance of conditional expectations given output. Furthermore, we also provide a fast implementation that requires much less computation and smaller memory for large-scale matrix operations, suitable for not only domain generalization but also other kernel-based eigenvalue decompositions. To show the practicality of the proposed method, we compare our methods against some well-known dimension reduction and domain generalization techniques on both synthetic data and real-world applications. We show that for small-scale datasets, we are able to achieve better quantitative results indicating better generalization performance over unseen test datasets. For large-scale problems, the proposed fast implementation maintains the quantitative performance but at a substantially lower computational cost.

Incorporating structured assumptions with probabilistic graphical models in fMRI data analysis

Latent dynamics discovery is challenging in extracting complex dynamics from high-dimensional noisy neural data. Many dimensionality reduction methods have been widely adopted to extract low-dimensional, smooth and time-evolving latent trajectories. However, simple state transition structures, linear embedding assumptions, or inflexible inference networks impede the accurate recovery of dynamic portraits. In this paper, we propose a novel latent dynamic model that is capable of capturing nonlinear, non-Markovian, long short-term time-dependent dynamics via recurrent neural networks and tackling complex nonlinear embedding via non-parametric Gaussian process. Due to the complexity and intractability of the model and its inference, we also provide a powerful inference network with bi-directional long short-term memory networks that encode both past and future information into posterior distributions. In the experiment, we show that our model outperforms other state-of-the-art methods in reconstructing insightful latent dynamics from both simulated and experimental neural datasets with either Gaussian or Poisson observations, especially in the low-sample scenario. Our codes and additional materials are available at this https URL.

Neural Dynamics Discovery via Gaussian Process Recurrent Neural Networks

Bayesian neural networks (BNNs) hold great promise as a flexible and principled solution to deal with uncertainty when learning from finite data. Among approaches to realize probabilistic inference in deep neural networks, variational Bayes (VB) is theoretically grounded, generally applicable, and computationally efficient. With wide recognition of potential advantages, why is it that variational Bayes has seen very limited practical use for BNNs in real applications? We argue that variational inference in neural networks is fragile: successful implementations require careful initialization and tuning of prior variances, as well as controlling the variance of Monte Carlo gradient estimates. We provide two innovations that aim to turn VB into a robust inference tool for Bayesian neural networks: first, we introduce a novel deterministic method to approximate moments in neural networks, eliminating gradient variance; second, we introduce a hierarchical prior for parameters and a novel Empirical Bayes procedure for automatically selecting prior variances. Combining these two innovations, the resulting method is highly efficient and robust. On the application of heteroscedastic regression we demonstrate good predictive performance over alternative approaches.

Bayesian neural networks (BNNs) hold great promise as a flexible and principled solution to deal with uncertainty when learning from finite data. Among approaches to realize probabilistic inference in deep neural networks, variational Bayes (VB) is theoretically grounded, generally applicable, and computationally efficient. With wide recognition of potential advantages, why is it that variational Bayes has seen very limited practical use for BNNs in real applications? We argue that variational inference in neural networks is fragile: successful implementations require careful initialization and tuning of prior variances, as well as controlling the variance of Monte Carlo gradient estimates. We fix VB and turn it into a robust inference tool for Bayesian neural networks. We achieve this with two innovations: first, we introduce a novel deterministic method to approximate moments in neural networks, eliminating gradient variance; second, we introduce a hierarchical prior for parameters and a novel empirical Bayes procedure for automatically selecting prior variances. Combining these two innovations, the resulting method is highly efficient and robust. On the application of heteroscedastic regression we demonstrate strong predictive performance over alternative approaches.

Fixing Variational Bayes: Deterministic Variational Inference for Bayesian Neural Networks

Deterministic Variational Inference for Robust Bayesian Neural Networks

TWIST1 induces proteasomal degradation of β-catenin during the differentiation of ovarian cancer stem-like cells

Poor chemotherapy response is the main obstacle of ovarian cancer (OC) treatment. Platinum‐refractory and ‐resistant patients are associated with a worse outcome than platinum‐sensitive and partially sensitive patients, but the comprehensive similarities and differences among them are not yet clear. In this study, we analyzed the data of patients with different chemotherapy response in The Cancer Genome Atlas. We found a minority of altered genes were overlapped in refractory and resistant groups, as did the enriched pathways and Gene Ontology terms. We noticed that the neural signaling and drug metabolism enzymes were more significantly enriched and the protein–protein interaction supported these results. The transcription analysis highlighted PDX1 as the common and central transcription factor in both refractory and resistant groups. The competing endogenous RNA (ceRNA) network shared no common ceRNA pairs, indicating a major difference in noncoding RNA post‐transcriptional regulation. In the end, we validated the expression, regulation, binding, and effect on chemotherapy response for selected MNX1‐AS1/hsa‐miR‐4697‐3p/HOXB13 in OC cell lines. Our study offered a novel and comprehensive insight into chemotherapy response, and potential targets for improving chemotherapy response in OC.

Comprehensive network analysis of dysregulated genes revealed MNX1‐AS1/hsa‐miR‐4697‐3p/HOXB13 axis in ovarian cancer chemotherapy response

Hotair promotes the migration and proliferation in ovarian cancer by miR-222-3p/CDK19 axis

Human integrin receptors are important for cell-cell and cell-matrix adhesion in normal epithelial cells. Emerging evidences have indicated integrin members are involved in cancer development and progression as well. However, the expression patterns and clinical significance of the whole integrin family in ovarian cancer (OC) have not yet been well understood. In the present study, we utilized the public datasets including GEPIA, GEO, ONCOMINE, cBioPortal, Kaplan-Meier Plotter, TIMER databases, to analyze the expression and prognostic value of integrin members in OC. We found ITGA3/B4/B6/B7/B8 were abnormally overexpressed in OC; ITGA6 was good prognosis predictor in OC; ITGA3/ B4/B8 were poor prognosis predictor specially in advanced OC patients; elevated ITGA3/B4 might promote metastasis and elevated ITGA3/B8 might promote platinum resistance of OC; ITGA3 and ITGB4 might synergistically or independently regulate cell adhesion and proliferation; ITGA4/AL/AM/AX/B2/B7 showed strong correlations with various tumor immune infiltrates (TILs), especially with pro-tumor immunes cell types like monocyte, M2 macrophage and exhaustion T cells infiltration; ITGAL/AM/B2/B7 and residing memory CD8+ T cells marker ITGAE were specially associated with early OC patients outcome. Our results implied that ITGA3/B4 were important prognostic markers of advanced OC, ITGAL/AM/ B2/B7 were immune associated prognosis markers of early OC, together they might render important therapeutic targets for OC.

Integrated Analysis of Prognostic and Immune Associated Integrin Family in Ovarian Cancer

The mortality rate of ovarian cancer is the highest among gynaecological cancers, primarily due to metastatic symptoms. Recent studies have shown that HOX genes are crucial in tumour progression, but the underlying mechanisms remain unclear. Here, HOXC10 expression was examined in ovarian cancer tissues. The function of HOXC10 in ovarian cancer metastasis was investigated in vitroand via intraperitoneal injection in vivo. A total of 158 ovarian cancer patients with adequate records were enrolled for analysis. HOXC10 was associated with metastasis and poor prognosis in ovarian cancer. In vitro, HOXC10 overexpression promoted ovarian cancer cell migration. Moreover, HOXC10 positively regulated Slug expression, altering the migration ability of cancer cells. Furthermore, our study showed that miR-222-3p was a suppressor of HOXC10. In vivo, a decrease in hepatic metastasis was seen in xenograft mice harbouring tumours with stable HOXC10 overexpression after miR-222-3p agomir (an overexpression reagent) injection. This study provides the first evidence that HOXC10 promotes ovarian cancer metastasis by regulating the transcription of the EMT-related gene Slug. Moreover, we found that HOXC10 is regulated by miR-222-3p. These data highlight the crucial role of HOXC10 in enhancing ovarian cancer metastasis and may provide a therapeutic target for ovarian cancer.

HOXC10 promotes tumour metastasis by regulating the EMT-related gene Slug in ovarian cancer

Correction: MiR-4524b-5p/WTX/β-catenin axis functions as a regulator of metastasis in cervical cancer

Cervical cancer is the second most deadly gynecological tumor worldwide. MicroRNAs (miRNAs) play very important roles in tumor oncogenesis and progression. The mechanism of post-transcription regulation of WTX gene is still unknown. A series of differential miRNAs were discovered by microarray analysis comparing three pairs of primary cervical cancer specimens and their relapsed tumors from three patients. Quantitative reverse transcriptase PCR (qRT-PCR), Western Blot (WB) and Immunohistochemistry (IHC) was used to detect the expression of miR-4524b-5p and WTX in cervical cell lines and tissues. The biological function of miR-4524b-5p and WTX was investigated through knockdown and overexpression with inhibitor/siRNA and mimic/plasmid in vitro and in vivo. In this study, we found that miR-4524b-5p is highly expressed in relapsed cervical cancer specimens. Combined in vitro and in vivo experiments, showed that miR-4524b-5p could regulate the migration and invasion ability of cervical cancer. Furthermore, we also found that miR-4524b-5p could regulate the migration and invasion of cervical cancer by targeting WTX and that WTX could regulate the expression of β-catenin. Taken together, our data identified a miR-4524b-5p/WTX/β-catenin regulatory axis for cervical cancer, and miR-4524b-5p may be a potential target for cervical cancer therapy.

MiR-4524b-5p/WTX/β-catenin axis functions as a regulator of metastasis in cervical cancer

Hsa_circ_0000098 is a novel therapeutic target that promotes hepatocellular carcinoma development and resistance to doxorubicin

Background Non-small-cell lung cancer (NSCLC) is a major component of lung cancer and is significantly correlated with poor prognosis. N6-methyladenosine (m6A) RNA methylation is closely related to the occurrence, progression, and prognosis of cancer. The potential biological functions and mechanisms of m6A RNA methylation in the immune microenvironment are still unclear. Methods We assessed m6A RNA methylation modification patterns in 1326 NSCLC patient samples based on 20 m6A regulators, linking these clusters to the tumor microenvironment and immune cell infiltration. The m6Ascore was created to quantify the m6A modification patterns of individual tumors. We then assessed the value of NSCLC patients in terms of clinical prognosis and immunotherapy response. Results According to different mRNA expression levels, two different m6A clusters were identified. m6A aggregation was significantly associated with clinical prognostic characteristics, the tumor microenvironment, and immune-related biological processes. Fifteen differential genes were screened based on these two m6A clusters, and to further investigate the mechanisms of action of these differential genes, they were subjected to unsupervised clustering analysis, which classified them into four different genomic isoforms. Prognostic analysis indicated that the survival advantage of the m6A gene cluster A modification mode was significantly prominent. We continued to construct the m6Ascore, which was used as a scoring tool to evaluate tumor typing, immunity, and prognosis. Patients with a low m6Ascore showed a significant survival advantage, and the group with a low m6Ascore had a better prognosis predicted by immunotherapy. The anti-PD-1/L1 immunotherapy cohort showed that a lower m6Ascore was associated with higher efficacy of immunotherapy. Conclusions The results suggest that m6A RNA methylation regulators make an important difference in the tumor immune microenvironment of patients with NSCLC. m6A gene characterization and the construction of the m6Ascore provide us with a richer understanding of m6A RNA methylation modification patterns in NSCLC patients and help to predict clinical prognosis and immunotherapeutic response.

Integrative Analysis of m6A RNA Methylation Regulators and the Tumor Immune Microenvironment in Non-Small-Cell Lung Cancer

Effects of ginkgo biloba powder (GBP) on the chemical, physicochemical properties and quality of dough and fresh wet noodles were investigated. Lower contents of gluten and starch, and higher contents of fibre, amylose and flavonoids in GBP than wheat flour, were detected. Water absorption of dough increased and the development time and stability time of dough were decreased with GBP addition. Meanwhile, the pasting properties results showed that the addition of GBP reduced the aging degree of starch and improved the thermal stability of dough. Scanning electron microscopy results showed that addition of GBP smoothed the surface of raw noodles while increasing the hole size of the cooked noodles. With increased GBP addition (0~40%), the chewiness and extensibility of the fresh wet noodles increased significantly (p < 0.05), and the sensory scores changed, ascending from 0~20% substitution, and then descending from 20~40% substitution. The digestibility and estimated glycemic index (eGI) values of the GBP fresh wet noodles decreased significantly (p < 0.05). In general, 20% GBP addition could improve the chewiness, extensibility, taste and nutrition of fresh wet noodles, and decrease the digestibility and eGI values of noodles. Thus, GBP has potential for application in the noodle industry.

Effect of Ginkgo Biloba Powder on the Physicochemical Properties and Quality Characteristics of Wheat Dough and Fresh Wet Noodles

Circular RNA hsa_circ_0016863 Regulates the Proliferation, Migration, Invasion and Apoptosis of Hepatocellular Carcinoma

Abstract Background Tripartite motif 28 (TRIM28) plays a role in multiple biological functions. The expression and function of TRIM28 in breast carcinoma (BC) remain unclear. The aim of this study was to explore potential association of TRIM28 with tumor features and survival. Materials and methods Specimens were collected from BC and adjacent normal tissues. Quantitative reverse transcription PCR (RT-qPCR) and immunohistochemistry (IHC) were performed to detect TRIM28 expression. The correlation of TRIM28 with clinicopathological features was evaluated by Chi-square test. The relationship between TRIM28 expression and survival was further analyzed by the Kaplan-Meier and Cox regression method. A receiver operating characteristic (ROC) curve was used to assess the value of TRIM28 in predicting BC. Results In this retrospective research, it was demonstrated that TRIM28 was overexpressed in BC tissues. TRIM28 overexpression was correlated with lymph node metastasis, advanced TNM stage, and poor molecular subtype. The survival analysis showed that overall survival (OS) and progression-free survival (PFS) were significantly shorter in TRIM28-positive group. Moreover, TRIM28 was an independent prognostic factor for BC. And ROC analysis verified the diagnostic role of TRIM28 in BC. Conclusions TRIM28 is overexpressed in BC and might be a promising prognostic and diagnostic biomarker of BC.

Prognostic significance of TRIM28 expression in patients with breast carcinoma

Triton X-100 supplementation regulates growth and secondary metabolite biosynthesis during in-depth extractive fermentation of Monascus purpureus.

Circular RNAs (circRNAs) are highly correlated with the progression and prognosis of hepatocellular carcinoma (HCC). In addition, mounting evidence has revealed that N6-methyladenosine (m6A) methylation, a common RNA modification, is involved in the progression of malignancies. In this research, a novel circRNA, hsa_circ_0058493, was proven to be upregulated in HCC, which was correlated with the prognosis of HCC patients. Experimentally, hsa_circ_0058493 knockdown suppressed the growth and metastasis of HCC cells in vivo and in vitro. On the contrary, the overexpression of hsa_circ_0058493 in HCC cells had the opposite effect in vitro. Mechanistic experiments revealed that hsa_circ_0058493 contained m6A methylation sites and that methyltransferase-like 3 (METTL3) mediated the degree of methylation modification of hsa_circ_0058493. Furthermore, YTH domain-containing protein 1 (YTHDC1) could bind to hsa_circ_0058493 and promote its intracellular localization from the nucleus to the cytoplasm. In addition, both si-METTL3 and si-YTHDC1 suppressed HCC cell growth and metastasis, whereas rescue experiments confirmed that overexpression of hsa_circ_0058493 inverted the inhibitory effects of si-METTL3 and si-YTHDC1 on HCC cells. Taken together, this study explored the oncogenic role of m6A-modified hsa_circ_0058493 and found to accelerate HCC progression via the METTL3-hsa_circ_0058493-YTHDC1 axis, indicating a potential therapeutic target for this deadly disease.

Methyltransferase-Like 3-Mediated m6A Methylation of Hsa_circ_0058493 Accelerates Hepatocellular Carcinoma Progression by Binding to YTH Domain-Containing Protein 1

Platelet membrane-camouflaged nanoparticles carry microRNA inhibitor against myocardial ischaemia‒reperfusion injury

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

An emerging role of the 5′ termini of mature tRNAs in human diseases: Current situation and prospects

Background: Mounting evidence has demonstrated that circular RNA (circRNA) plays crucial roles in the occurrence and development of hepatocellular carcinoma (HCC). However, the expression pattern and clinical application value of plasma circRNA in HCC are still largely unknown. Herein, we explored the role of plasma hsa_circ_0005397 in diagnosis and prognosis of HCC. Methods: The expression level of plasma hsa_circ_0005397 was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The identification and origin of plasma hsa_circ_0005397 were confirmed by RNase R assay, Sanger sequencing and HCC cell culture. In addition, its diagnostic value was assessed by receiver operating characteristic (ROC) curve and prognostic value was evaluated by dynamics monitoring and Kaplan–Meier curve analyses in HCC patients. Results: The expression of plasma hsa_circ_0005397 was higher in patients with HCC than that in patients with benign liver diseases and healthy controls (both p < 0.05). Moreover, it was closely correlated with tumor size (p = 0.020) and TNM stage (p = 0.006) of HCC patients. The area under the ROC curve of plasma hsa_circ_0005397 was 0.737 and 95% confidence interval was 0.671–0.795. Furthermore, the combination of plasma hsa_cic_0005397, serum AFP and AFP-L3 could improve the diagnostic sensitivity of HCC. Additionally, dynamic monitoring plasma hsa_cic_0005397 might help us predict recurrence or metastasis in HCC patients after surgical resection. Besides, the increased plasma hsa_cic_0005397 was closely correlated with shorter overall survival of HCC patients (p = 0.007). Conclusion: Plasma has_circ_0005397 represents a novel noninvasive biomarker for HCC. Moreover, the combination of plasma hsa_cic_0005397, serum AFP and AFP-L3 might improve the diagnostic value for HCC.

Identification of Plasma hsa_circ_0005397 and Combined With Serum AFP, AFP-L3 as Potential Biomarkers for Hepatocellular Carcinoma

Although accumulating documents have expounded the pivotal position of circular RNAs (circRNAs) in hepatocarcinogenesis and progression, the overwhelming majority of their functions and molecular mechanisms in hepatocellular carcinoma (HCC) are elusive. Herein, we explored the functions and potential mechanisms of hsa_circ_0005785 in HCC, which was aberrantly overexpressed in HCC and related to HCC patients' TNM stage and overall survival. Moreover, hsa_circ_0005785 depletion could repress proliferation and metastasis of the HCC cell in vitro, lead to cell apoptosis and cell-cycle arrest, and restrain HCC cell growth in vivo. Furthermore, mechanism analyses discovered that hsa_circ_0005785 adsorbed miR-578 by playing a miRNA sponge role, which resulted in the derepression of a proliferation-inducing ligand (APRIL) expression, miR-578's mRNA target. Besides, hsa_circ_0005785 reversed the suppressive influence of miR-578 on HCC and accelerated tumor malignant progression through the miR-578/APRIL axis. Taken together, our current study revealed an oncogenic role of hsa_circ_0005785 in the tumorigenesis of HCC. Moreover, targeting to the hsa_circ_0005785/miR-578/APRIL regulatory pathway might be a promising diagnostic and therapeutic strategy for HCC clinical practice.

Upregulated hsa_circ_0005785 Facilitates Cell Growth and Metastasis of Hepatocellular Carcinoma Through the miR-578/APRIL Axis

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences

Establishment of a direct quantitative method for measurement of microRNA-224 in serum by UHPLC/MS/MS.

Mechanical ventilation strategies for intensive care unit patients without acute lung injury or acute respiratory distress syndrome: a systematic review and network meta-analysis

Background: Although significant advances have been made toward understanding the molecular mechanisms underlying the effect of propofol on tumor cell metastasis, less is known regarding how cell membrane and cytoskeletal ultrastructure are affected in this process. Here, we investigated the relationship between cell morphology and cell size, which are features mainly defined by the cytoskeleton. Methods: To confirm the effects of propofol on the migratory ability of human cervical carcinoma cells, cell migration and invasion were examined through scratch wound healing and transwell membrane assays. Furthermore, HeLa cells cultivated with different concentrations of propofol were examined by confocal microscopy and atomic force microscopy (AFM), and the mean optical density and migration ability of these cells were also assessed. In addition, cell membrane morphology was inspected using AFM. Results: The results of the wound healing and transwell membrane assays indicated that propofol decreases the migratory ability of cervical carcinoma cells compared to control cells. A comparative analysis of the test results revealed that short-term (3 h) exposure to propofol induced marked changes in cell membrane microstructure and in the cytoskeleton in a dose-dependent manner. These morphological changes in the cell membrane were accompanied by cytoskeleton (F-actin) derangement. The present findings demonstrate a close relationship between changes in cell membrane ultrastructure and cytoskeletal alterations (F-actin) in propofol-treated HeLa cells. AFM scanning analysis showed that cell membrane ultrastructure was significantly changed, including a clear reduction in membrane roughness. Conclusion: The influence of propofol on the HeLa cell cytoskeleton can be directly reflected by changes in cellular morphology, as assessed by AFM. Moreover, the use of AFM is a good method for investigating propofol-mediated changes within cytoskeletal ultrastructure.

Effects of Propofol on Several Membrane Characteristics of Cervical Cancer Cell Lines

Data often occurs in groups, such as a set of noisy measurements or multiple samples collected from some organism. Classical machine learning tends to consider datasets that consist of individually labeled points, rather than datasets where sets of similarly-labeled points may be grouped together. First we introduce this problem formulation, and then propose a set of potential solutions, which we broadly call a Distribution-Based Approach (DBA). DBA leverages the structure of the problem, and we show that it achieves improved performance on a driver identification task and a map feature classification task.

Dynamic time warping constraint learning for large margin nearest neighbor classification

The effectiveness of nearest neighbor search heavily relies on the definition of distance function. Unfortunately, the meaningfulness of the frequently used distance, such as Euclidean distance, fractional distance and so on, will degrade with the increasing dimensionality. This problem, which is called distance concentration or instability, makes NN method perform poorly in a proximity query. The most popular distance function for time series, dynamic time warping(DTW), also concentrates when it is used in high-dimensional space. We learn the exponent p of the norm based on nearest neighbor large margin criterion for time series classification. The distance concentration is countered by maximum discrimination instead of maximum variance of distance distribution. The empirical results we presented demonstrate that the proposed approach shows a uniformly behavior, with results comparable to classic 1NN-Euclidean and 1NN-DTW.

Making the nearest neighbor meaningful for time series classification

Dimensionality reduction techniques are widely used in time series data mining. Dimensionality reduction can not only speed up the computation but also lead to improved performance. Most available techniques implement the reduction process without supervised information. This operation can be used to de-noise the insignificance detail, or blur the discriminative information which is important for supervised learning. To solve the problem, we design a framework of dimensionality reduction method, called the Large Margin Dimensionality Reduction (LMDR), based on large margin criterion. It is shown empirically that the LMDR significantly improves the performance in terms of time series data mining.

2010 First International Conference on Pervasive Computing, Signal Processing and Applications

Background Cuproptosis, one of the newest forms of cell death induction, is attracting mounting attention. However, the role of cuproptosis in lung cancer is currently unclear. In this study, we constructed a prognostic signature utilizing cuproptosis-related long noncoding RNAs (CRL) in lung adenocarcinoma (LUAD) and researched its clinical and molecular function. Methods RNA-related and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed CRLs were screened using the ‘limma’ package of R software. We used coexpression analysis and univariate Cox analysis to further identify prognostic CRLs. Applying least absolute shrinkage and selection operator (LASSO) regression and Cox regression models, a prognostic risk model based on 16 prognostic CRLs was constructed. To validate prognostic CRL function in LUAD, vitro experiments were conducted to explore the expression of GLIS2-AS1, LINC01230, and LINC00592 in LUAD. Subsequently, according to a formula, patients in the training, test, and overall groups were split into high- and low-risk groups. Kaplan-Meier and receiver operating characteristic (ROC) analyses were applied to assess the predictability of the risk model. Finally, the associations between risk signature and immunity-related analysis, somatic mutation, principal component analysis (PCA), enriched molecular pathways, and drug sensitivity was investigated. Results A cuproptosis-related long noncoding RNAs (lncRNAs) signature was constructed. Using quantitative polymerase chain reaction (qPCR) trial, we verified that the expressions of GLIS2-AS1, LINC01230, and LINC00592 in LUAD cell lines and tissues were consistent with the above screening results. Based on this signature, a total of 471 LUAD samples from TCGA data set were split into two risk groups based on the computed risk score. The risk model showed a better capacity in predicting prognosis than traditional clinicopathological features. Moreover, significant differences were found in immune cell infiltration, drug sensitivity, and immune checkpoint expression between the two risk groups. Conclusions The CRLs signature was shown to be a prospective biomarker to forecast prognosis in patients with LUAD and presents new insights for personalized treatment of LUAD.

A cuproptosis-related lncRNAs risk model to predict prognosis and guide immunotherapy for lung adenocarcinoma

The Prevalence and Determinants of Return to Work in Head and Neck Cancer Survivors: A Scoping Review

Tianyi Wang A liated Hospital of Nantong University Tingting Zhou A liated Hospital of Nantong University Mingming Xu A liated Hospital of Nantong University Xuechao Yang A liated Hospital of Nantong University Shuai He A liated Hospital of Nantong University Shuo Wang A liated Hospital of Nantong University Anqi Wu A liated Hospital of Nantong University Mingyang Zhang A liated Hospital of Nantong University You Lang Zhou A liated Hospital of Nantong University Jiahai Shi (  sjh@ntu.edu.cn ) A liated Hospital of Nantong University

Platelet Membrane-Camou aged Nanoparticles Carry microRNA inhibitor Against Myocardial Ischemia-Reperfusion Injury

Lysin cell-binding domain-functionalized magnetic beads for detection of Staphylococcus aureus via inhibition of fluorescence of Amplex Red/hydrogen peroxide assay by intracellular catalase

Abstract The Geneva Declaration on Human Rights at Sea was officially launched on 1 March 2022. The document was produced by the nongovernmental organization Human Rights at Sea, and responds to an undoubted need to prevent human rights violations at sea and to provide redress to victims of such abuses. Connecting the international human rights regime with the law of the sea has been one of many challenges to respond to this issue. This article explores the content of the Geneva Declaration and its alignment with existing law of the sea. Beyond the jurisdictional complexities presented, it is important to consider how this informal instrument holds relevance for international lawmaking. While there are obstacles, the Geneva Declaration creates a needed opportunity to bring attention to and clarity around the legal protections of human rights at sea.

Geneva Declaration on Human Rights at Sea: An Endeavor to Connect Law of the Sea and International Human Rights Law

China and International Dispute Resolution in the Context of the 'Belt and Road Initiative'

The Belt and Road Initiative and the Potential for Dispute Settlement under the UN Convention on the Law of the Sea

Maritime autonomous vehicles and international laws on boat migration: Lessons from the use of drones in the Mediterranean

The paper represents a starting point of a broader research project in strategic start-up communication. The main purpose of this study is to demonstrate the current state of research in this area and to compare those insights with an explorative study on the start-up ecosystem.,A neo-institutional framework is combined with the dual narrative framework of strategic communication and emergence to explain the emergence of strategic communication in this organizational field (start-up ecosystems). Research questions are derived from a systematic literature review and subjected to exploratory testing in two different qualitative surveys, with experts and investors, reflecting an external perspective, and with start-ups themselves.,Results from the literature review and the explorative interviews with expert external actors indicate eight areas in which start-ups face strategic communication challenges: the basic orientation of strategic communication, branding, external image, stakeholder relations, allocation of financial resources, owner centricity, human resources and internal communication. External consultants and funders recommend highly planned approaches like target group-oriented communication, well thought-out positioning with uniform messages and precisely applied communication channels. However, the internal perspective of start-ups presents a contrary picture based on emergent products of strategic communication.,The study indicates the importance of both the emergence in strategic start-up communication and the demonstration of planned strategic communication. Investigating a whole start-up ecosystem in a country regarding the emergence of strategic communication forms, practices and products offers potential for cross-country comparative research.,The findings indicate key challenges of strategic communication of start-ups. Bearing in mind these key challenges when founding a start-up can make a difference in the success of the start-up.,The article presents the first systematic literature review in the area of strategic start-up communication and a theoretical framework for further investigation. Moreover, the results of the explorative study demonstrate the importance of the different forms of planning and emergence in strategic start-up communication. Hence, this paper provides practical implications for practitioners working and investing in the start-up ecosystem.

The South China Sea Arbitration: Toward an International Legal Order in the Oceans, written by Yoshifumi Tanaka

Abstract The ongoing development of diverse maritime autonomous vehicles for varied ocean activities—ranging from scientific research, security surveillance, transportation of goods, military purposes and commission of crimes—is prompting greater consideration of how existing legal frameworks accommodate these vehicles. This article brings together the core legal issues, as well as current developments in relation to commercial shipping, the law of naval warfare, and maritime security. This article captures how these issues are now being addressed and what other legal questions will likely emerge as the newest technology impacts on one of the oldest bodies of international law.

MARITIME AUTONOMOUS VEHICLES: NEW FRONTIERS IN THE LAW OF THE SEA

Cruise ships have contributed to the spread of covid-19 around the world and State responses to the pandemic have needed to account for the presence of these ships in their ports and the medical treatment of both passengers and crew on board. This contribution outlines the key bodies of international law that must be brought to bear in deciding on State action in response to cruise ships and their covid-19 cases: the law of the sea, international health law, shipping conventions and especially treaties protecting the rights of seafarers, international human rights law and laws relating to consular assistance. While these laws tend to reinforce each other, it is argued that the need for humanitarian considerations to feature strongly in State decision-making is challenged by systemic weaknesses.

Stakeholders in Dispute Settlement Under the UN Convention on the Law of the Sea

The Timor Sea Conciliation and Lessons for Northeast Asia in Resolving Maritime Boundary Disputes

Dispute resolution and the law of the sea following the South China Sea arbitration

Maritime Autonomous Vehicles within the International Law Framework to Enhance Maritime Security

Abstract This article sets out two case studies to examine the evolving reality of ‘boat migration’ and the intersecting legal frameworks at play. Our analysis takes a systemic integration approach to reflect on the complex dynamics underpinning responses to the phenomenon in Australia and the Central Mediterranean. The regime that governments purport to act under in any given instance reflects the way they choose to frame incidents and possibly exploit legal gaps in, or contested interpretations of, the relevant rules. The ‘closed ports’ strategy adopted by Italy and Malta against the MV Lifeline and the detention-at-sea policy pursued by Australia are investigated from the competing perspectives of what we call the ‘security lens’ and the ‘humanitarian lens’ to demonstrate how a good faith interpretation of the applicable (if apparently conflicting and overlapping) norms can (and should) be mobilized to save lives, and how that goal is unduly undercut when security concerns trump humanitarian interests.

Between life, security and rights: Framing the interdiction of ‘boat migrants’ in the Central Mediterranean and Australia

Abstract This article compares the law and practice of the European Union and Australia in respect to the search and rescue (SAR) of boat migrants, concluding that the response to individuals in peril at sea in both jurisdictions is becoming increasingly securitized. This has led to the humanitarian purpose of SAR being compromised in the name of border security. Part I contrasts the unique challenge posed by SAR operations involving migrants and asylum seekers, as opposed to other people in distress at sea. Part II analyses the relevant international legal regime governing SAR activities and its operation among European States and in offshore Australia. Part III introduces the securitization framework as the explanatory paradigm for shifting State practice and its impact in Europe and Australia. It then examines the consequences of increasing securitization of SAR in both jurisdictions and identifies common trends, including an increase in militarization and criminalization, a lack of transparency and accountability, developments relating to disembarkation and non-refoulement, and challenges relating to cooperation and commodification.

SECURITIZATION OF SEARCH AND RESCUE AT SEA: THE RESPONSE TO BOAT MIGRATION IN THE MEDITERRANEAN AND OFFSHORE AUSTRALIA

Abstract The conservation and management of sharks is regulated under different international instruments of varying degrees of specificity and with different legal purposes. Two international instruments targeted at the conservation and management of sharks are the International Plan of Action for Sharks and the Sharks Memorandum of Understanding, which was adopted under the Convention on Migratory Species. This article examines and compares these two non-binding instruments, querying not only what was gained from the adoption of an additional non-binding instrument in the Sharks MoU just ten years after the IPOA Sharks but also how the accumulation of soft law instruments may operate within the framework of international environmental law. We show that such instruments do serve different purposes and can serve the ultimate goal of improving the conservation status of sharks, as well as thickening international environmental law to the benefit of species conservation.

From IPOA Sharks to Sharks MoU Under the Convention on Migratory Species: Progress or Clutter in International Environmental Law?

“This Is Your Wake-up Call”: Lea Brilmayer’s Impact as a Scholar and Teacher

Land and Sea: Resolving Contested Land and Disappearing Land Disputes under the UN Convention on the Law of the Sea

In International Law of Sharks, the authors critically analyse current legal frameworks for this important group of species. They explore obstacles, options and opportunities to improve the conservation status of sharks and draw out broader lessons for marine species.

The South China Sea Arbitration raises important questions about the potential operation of the dispute settlement system enshrined in Part XV of the United Nations Convention on the Law of the Sea (LOSC). This article explores the scope and different limitations that we are seeing in the interpretation of the LOSC dispute settlement regime with a particular focus on the South China Sea Arbitration. This examination questions the contours of the LOSC Part XV dispute settlement regime and its utility in resolving disputes relating to the South China Sea.

The Vicissitudes of Dispute Settlement under the Law of the Sea Convention

This chapter focuses on some distinct consequences for States where there is a land feature generating maritime zones over which sovereignty is disputed. The questions addressed are: What are the international legal consequences where a State is in occupation of an island (‘the occupying State’) but another State contests sovereignty (‘the disputing State’)? Can the State in occupation construct facilities on the island or in the waters surrounding that island? The constructions in the adjacent waters might include ports, or other docking facilities or other structures or installations outside the territorial sea for the purposes of research or resource exploration and exploitation. If the State in occupation proceeds with the exercise of its sovereignty over the disputed land, are there procedural steps or limits that should be taken into account to reduce the likelihood of legal challenge in the event of a dispute emerging under the UNCLOS dispute settlement procedure? A key lesson from the South China Sea arbitration is that the occupying State faces significant legal consequences if it is eventually determined not to be the coastal State with rights over the adjacent maritime area. The occupying State could expect that its actions may be challenged within the framework of the UNCLOS dispute settlement regime, even in the possible absence of a determination as to which State is the ‘coastal State’ or ‘user State’ under UNCLOS.

Resolving Disputes under UNCLOS when the Coastal and User States are Disputed

Can international litigation solve the India-Sri Lanka fishing dispute?

International Law of Sharks: Obstacles, Options and Opportunities

This panel examined the operation of International Mass Claims Commissions (IMCC), which are ad hoc international judicial institutions created to resolve specific international disputes. IMCCs generally involve a great variety and number of claims and claimants, thus providing a distinctive means to resolve international disputes. This panel seeks to evaluate the effectiveness and viability of IMCCs as international dispute resolution mechanisms. Looking in particular at the examples set by the Iran-U.S. Claims Tribunal, the UN Claims Commission, and the Eritrea-Ethiopia Claims Commission, the speakers assess strengths and weaknesses of these unique institutions. Panelists also considered the use of IMCCs in future situations, as an alternative to standing international tribunals.

Expansions and Restrictions in the UNCLOS Dispute Settlement Regime: Lessons from Recent Decisions

A Maritime Security Framework for the Legal Dimensions of Irregular Migration by Sea

The Philippines v China arbitration raises important questions about the potential operation of the UNCLOS dispute settlement system enshrined in Part XV of that Convention. This article explores the questions raised by this arbitration in relation to the place of negotiations as a dispute settlement process under UNCLOS and key questions concerning subject matter jurisdiction, especially where territorial disputes are mixed with law of the sea disputes. This examination questions the contours of the UNCLOS Part XV dispute settlement regime and its utility in resolving disputes relating to the South China Sea.

The Limitations of UNCLOS Part XV Dispute Settlement in Resolving South China Sea Disputes: The South China Sea – An International Law Perspective Conference

Abstract Maritime interceptions continue as a fundamental dimension to external border controls against irregular migration, as seen most recently in Australia's institution of Operation Sovereign Borders in late 2013. The practice of developed States has highlighted the varied application and interpretation of four bodies of international law: the law of the sea, search and rescue obligations, refugee obligations and international human rights law. This article assesses this practice and the use of laws, highlighting the fragmentation of international law that has resulted. A proposal is presented to harmonize these laws and reconcile the divergent policy perspectives of different stakeholders.

A CASE FOR HARMONIZING LAWS ON MARITIME INTERCEPTIONS OF IRREGULAR MIGRANTS

Litigating International Law Disputes: Dispute settlement options for the protection of nationals abroad

The Effectiveness of the UNCLOS Dispute Settlement Regime: Reaching for the Stars?

This chapter outlines the Whaling in the Antarctic case , highlighting the claims that Australia is asserting and setting out the broader issues that are at play, or may be brought into play. The example of the Whaling in the Antarctic case is used to examine more broadly the role for international litigation in pursuing claims that arise from activities in areas beyond national jurisdiction. Australia's standing refers to the requirement that a State seeking to enforce a legal right establish a sufficient link between itself and the legal rule that forms the subject matter of the enforcement action. The Whaling in the Antarctic case directly raises before the International Court of Justice (ICJ) fundamental questions concerning the capacity of international law to protect the marine environment beyond national jurisdiction and the organisms and ecosystems it supports. Keywords: Australia; international court of justice (ICJ); international litigation; legal rights; national jurisdiction; whaling in the Antarctic case

Chapter 23. Whaling in the Antarctic: Protecting Rights in Areas Beyond National Jurisdiction through International Litigation

Indonesia incursion report provides more questions than answers on turn-backs

Introduction Erika Techera and Natalie Klein Part 1: Governance Challenges 1. Approaches to Conservation and Governance of Marine Species Erika Techera 2. The Existing Global Legal Regimes Natalie Klein 3. Challenges for International Governance Mary Lack Part 2: Scientific Perspectives 4. The State of Knowledge on Sharks for Conservation and Management Michael Heithaus and Jeremy Kiszka 5. Shark Conservation, Governance and Management: The Science-Law Disconnect Paolo Momigliano and Robert Harcourt 6. Human Perceptions and Attitudes toward Sharks: Examining the Predator Policy Paradox Christopher Neff Part 3: Actors and Stakeholders 7. Collaborations for Conservation Anissa Lawrence 8. The Role of the Tourism Industry Christine Ward-Paige 9. Shark Conservation Efforts - as Diverse as Sharks Themselves Jill Hepp and Elizabeth Wilson Part 4: Risks and Rewards 10. Economic Rationale for Shark Conservation Andres Cisneros-Montemayor and Rashid Sumalia 11. Iconic Species: Great White Sharks, Basking Sharks and Whale Sharks Ryan Kempster and Shaun Collin 12. Species at the Intersection Charlie Huveneers and William Robbins Part 5: Tools and Techniques 13. The role of Marine Protected Areas and Sanctuaries Erich Hoyt 14. Fisheries Management and Regulations Boris Worm, Aurelie Cosandey-Godin and Brendal Davis 15. Synergies, Solutions and the Way Forward Natalie Klein and Erika Techera

Australia's Operation Sovereign Borders has significantly reduced the onshore arrival numbers of vessels carrying irregular migrants. The operational aspects of the Government's push back the boats policy has been shrouded in secrecy and prevented scrutiny, including scrutiny for Australia's compliance with international law. International law is one of the key frameworks for lawful maritime interceptions of irregular migrants. This article questions how the Australian Government may be conforming to international law standards in pushing back the boats under Operation Sovereign Borders. What legal arguments could possibly be raised to defend the policy? And how could the policy be legally challenged? It is shown that the Australian Government's legal bases are weak but potentially able to exploit a lack of short-term accountability in the international legal system.

Assessing Australia's push back the boats policy under international law: Legality and accountability for maritime interceptions of irregular migrants

Litigating International Law Disputes provides a fresh understanding of why states resort to international adjudication or arbitration to resolve international law disputes. A group of leading scholars and practitioners discern the reasons for the use of international litigation and other modes of dispute settlement by examining various substantive areas of international law (such as human rights, trade, environment, maritime boundaries, territorial sovereignty, and investment law), as well as considering case studies from particular countries and regions. The chapters also canvass the roles of international lawyers, non-governmental organizations, and private actors, as well as the political dynamics of disputes, and identify emergent trends in dispute settlement for different areas of international law.

This panel was convened at 2:30 pm, Friday, April 11, by its moderator, Cesare Romano of Loyola Law School Los Angeles, who introduced the panelists: Natalie Klein of Macquarie University; Coalter Lathrop of Sovereign Geographic; Joanna Mossop of Victoria University at Wellington; and Yoshifumi Tanaka of the University of Copenhagen. * THE EFFECTIVENESS OF THE UNCLOS DISPUTE SETTLEMENT REGIME: REACHING FOR THE STARS? By Natalie Klein ([dagger]) A good friend of mine told me the best thing she ever learned from a high school teacher was that they should always reach for the stars. That way, if they only reached the rooftops, at least they got off the ground. The dispute settlement regime in Part XV of the UN Convention on the Law of the Sea (UNCLOS) undoubtedly reached for the stars. It was to be "the pivot upon which the delicate equilibrium of the compromise must be balanced," (1) "the cement which should hold the whole structure together and guarantee its continued acceptability and endurance for all parties." (2) I was among the skeptics as to the promise that the UNCLOS dispute settlement regime held for all disputes arising from varied maritime activities. (3) In my earlier work, (4) I set out to consider whether the dispute settlement regime in UNCLOS was indeed indispensable to the overall operation of the many facets of the Convention. I concluded that compulsory procedures entailing binding decisions were indispensable in some (although not all) instances, but that the dispute settlement regime with its many limitations and exceptions was politically realistic. As we make an assessment of the effectiveness of the UNCLOS dispute settlement regime 20 years on, my purpose is twofold. First, I want to consider for what reasons the dispute settlement regime was needed and used. Second, I want to ask: What have been the unexpected uses of the UNCLOS dispute settlement regime, and how do those reflect on the effectiveness of Part XV to the law of the sea? Ultimately, to return to my earlier analogy, it is not possible to conclude that UNCLOS dispute settlement has reached the stars, but we can have a healthy debate as to what level rooftop has been reached. In assessing Part XV in the overall regime of UNCLOS, I had earlier taken the view that the dispute settlement regime was requisite for those parts of the Convention where a particularly delicate balance of interests had been achieved in the text and third-party adjudication or arbitration could be used to safeguard that balance. The most common balance of interests in this regard is between the exclusive interests of coastal states and the inclusive interests of all other states, often flag states, in seeking to protect their respective rights. This sort of balance is manifest in the transit passage regime, for example, as well as in Articles 56 and 58 pertaining to different interests within the exclusive economic zone. Another reason that the UNCLOS dispute settlement regime was needed was to flesh out some of the very broad or general obligations included in the Convention. Judicial decisionmaking would not, of course, be the only avenue available for this purpose, as UNCLOS anticipated further developments in organizations like the IMO, (5) or among concerned states under separate agreements, such as with regional fisheries management organizations or arrangements. (6) Yet if a dispute arose between states concerning the interpretation and application of provisions setting out general standards of conduct, it would inevitably fall to a court or tribunal to determine what would fall within those particular standards in the circumstances of the case. Part XV of UNCLOS has indeed been used, to greater and lesser extents, for these two reasons. In relation to safeguarding the balance of interests in the text, there are clear examples in the case law produced under UNCLOS. …

The Dispute Settlement System of the United Nations Convention on the Law of the Sea: An Assessment after 20 Years

Part I: 1. The place of international litigation in international law John Merrills 2. Litigation versus dispute resolution through political processes Shirley V. Scott 3. National and international litigation: partners or competitors? Christopher Ward Part II: 4. Australia's experience in international litigation Henry Burmester 5. Latin American states and the International Court of Justice Ximena Fuentes 6. The United States as an international litigant Mark Feldman 7. European perspectives on inter-state litigation Michael Wood 8. Asian perspectives on inter-state litigation Rodman R. Bundy 9. African perspectives on inter-state litigation Makane Moise Mbengue Part III: 10. Initiating territorial adjudication: the who, how, when and why of litigating contested sovereignty Lea Brilmayer and Adele Faure 11. Why litigate a maritime boundary? Some contributing factors Coalter Lathrop 12. Litigating law of the sea disputes using the UNCLOS dispute settlement system Md. Saiful Karim 13. International environmental disputes: to sue or not to sue? Tim Stephens 14. Why states resort to litigation in cases concerning the use of force? Christine Gray 15. Adjudicating armed conflict John R. Crook 16. Human rights as a subject of international litigation Ivan Shearer 17. The WTO dispute settlement system and underlying motivating factors for adjudication M. Rafiqul Islam 18. Resolving international investment disputes Chester Brown 19. Dispute settlement options for the protection of nationals abroad Natalie Klein Part IV: 20. Litigating international law disputes: whereto? Cesare P. R. Romano.

From eco-terrorism to eco-tourism: assessing effective regulatory tools and regimes in marine management

Law of the Sea Symposium : what responsibility over iconic marine living resources?

The role of law in shark-based eco-tourism : lessons from Australia

Book review : 'Maritime power and the law of the sea : expeditionary operations in world politics'

James Kraska, Maritime Power and the Law of the Sea: Expeditionary Operations in World Politics (New York: Oxford University Press), 2011, ISBN 978-0-19-977338, hardbound, US$95.00/£60.00, pp. xix + 464 incl. index.

Regulatory Tools for Shark Conservation and Management: Improving Legal Governance and Harnessing Eco-tourism

Foundations of International Migration Law: International migration by sea and air

1. Two Fundamental Concepts 2. Passage and Military Activities 3. Law Enforcement 4. Terrorism and Proliferation of Weapons of Mass Destruction 5. Intelligence Gathering and Information Sharing 6. Armed Conflict and Naval Warfare: Shifting Legal Regimes 7. International Law of Maritime Security - A Synopsis and Proposal for Change

Although Australia has adopted a firm stance opposing the death penalty within Australia, this position is complicated when Australian nationals are sentenced to death for crimes committed overseas. This article explores the legal avenues open to Australia, and to the individuals concerned, in seeking a lesser penalty so as to reduce inter-state disputes in these situations. The cases of Van Nguyen and members of the Bali Nine are used as focal points in this regard. It is argued that Australia needs to decide on a firm and consistent policy opposing the death penalty, and apply this approach globally and in its bilateral relationships. These steps are required if Australia is to minimise the likelihood of inter-state disputes and ameliorate the circumstances of Australians on death row.

Australians sentenced to death overseas: Promoting bilateral dialogues to avoid International law disputes

Global standards and specific needs: protection of the marine environment through particularly sensitive sea areas

International Law of Maritime Security: A Synopsis and Proposal for Change

The arrest and detention of Australians overseas continues to make headline news. What Australia is able and willing to do to assist one of its nationals imprisoned abroad is a complex issue steeped in legal questions and political considerations. Legal avenues for assisting Australians imprisoned abroad are explored in this article through an examination of the relatively high profile cases of David Hicks, Stern Hu, Scott Rush and Jock Palfreeman. In navigating the legal framework, three broad themes emerge: the bond of nationality, the protection of human rights, and the importance of reciprocity. It is argued here that, from both a legal and political perspective, greatest emphasis should be placed on reciprocity in order to best understand the decisions the Commonwealth government may make and the options available to the individuals concerned.

David Hicks, Stern Hu, Scott Rush, Jock Palfreeman and the legal parameters of Australia's protection of its citizens abroad

Fragmented governance : reconciling legal strategies for shark conservation

Achieving social and environmental justice through the many dimensions of globalisation: an elusive or achievable quest

Whaling, science and the role of the International Court of Justice

Globalisation and intellectual property rights: The struggle of developing countries to infl uence TRIPS

1. Australia, New Zealand and Maritime Security, Natalie Klein, Joanna Mossop, Donald R. Rothwell 2. Maritime Security and the Law of the Sea, Donald R. Rothwell, Natalie Klein 3. Australia's Traditional Maritime Security Concerns and Post 9/11 Perspectives, Donald R. Rothwell, Cameron Moore 4. Maritime Security in New Zealand, Joanna Mossop 5. Whose Security is it and How Much of it do We Want? The US Influence on the International Law against Maritime Terrorism, Shirley V. Scott 6. New Zealand and Australia's Role in Improving Maritime Security in the Pacific Region, Sam Bateman and Joanna Mossop 7. Maritime Security and Shipping Safety in the Southern Ocean, Karen N. Scott 8. Counter-Terrorism and the Security of Shipping in Southeast Asia, Caroline Foster 9. Maritime Security and Oceans Policy, Peter Cozens 10. Act of State Doctrine in the Antipodes: The Intersection of National and International Law in Naval Constabulary Operations, Cameron Moore 11. The Protection of Platforms, Pipelines and Submarine Cables under Australian and New Zealand Law, Stuart Kaye 12. Maritime Domain Awareness in Australia and New Zealand, Chris Rahman 13. Intelligence Gathering and Information Sharing for Maritime Security Purposes under International Law, Natalie Klein 14. Maritime Security in the Twenty-First Century: Contemporary and Anticipated Challenges for Australia and New Zealand, Donald R. Rothwell

Maritime security : international law and policy perspectives from Australia and New Zealand

[Australia’s efforts to protect certain marine resources have been challenged in recent litigation before Australian courts, potentially prompting repercussions for Australia’s standing within international legal regimes. In this article, the authors consider the extent to which Australian courts should not only be generally cognisant of the international law framework in which their decisions sit, but also take specific account of Australia’s international rights and duties in determining matters. This analysis contributes to wider discussions about the role of international law before national courts and, in particular, addresses the use made of non-justiciability doctrines as well as whether national courts should play a role in seeking institutional change in the international legal system.]

National litigation and international law: repercussions for Australia's protection of marine resources

Litigation over marine resources: lessons for law of the sea, international dispute settlement and international environmental law

Australia's relationship with Japan is of undeniable importance. Japan is Australia's largest trading partner, constituting Australia's top export market for more than forty years.' The economic links between Australia and Japan have solidified across the years through a series of treaties2 and may crystallize in the adoption of a Free Trade Agreement.3 In 2007, the relationship took a new direction with the adoption of a Joint Declaration on Security Cooperation,' providing an operational framework for Australian and Japanese defense forces to work together in certain situations and to "establish mechanisms to improve strategic alignment." 5 Japan also has considerable strategic interests in maintain-

Whales and tuna : the past and future of litigation between Australia and Japan

Book review : 'The Rules of the international tribunal for the law of the sea : a commentary'

The Rules of the International Tribunal for the Law of the Sea: A Commentary is a significant examination of the working of the International Tribunal for the Law of the Sea (‘ITLOS’ or ‘Tribunal’) by those who are most intimately familiar with its operation. The contributors to the volume are limited to the judges (past and present) of the Tribunal, as well as the Registrar, Philippe Gautier (also a co-editor), and a Legal Officer of the Tribunal (Ximena Hinrichs) (ix). Each contributor is responsible for the commentary for specific articles in the Rules. As the authors of the Commentary are those who were nearly all involved in the drafting of the Rules themselves and will be the primary interpreters of those provisions, the authoritative nature of this work cannot be doubted. In the Preface, the editors indicate that the task of the Tribunal in formulating the Rules has been to seek a balance between the well-accepted aspects of international judicial procedure and ensuring the efficient and speedy function of the Tribunal (vii). The importance of these key themes is highlighted throughout the Commentary. The Preface further acknowledges that the commentaries to the rules of the International Court of Justice (‘ICJ’) and the Permanent Court of International Justice (‘PCIJ’), as well as the rules of those institutions themselves, served as especially useful precedents (vii–viii).

The Rules of the International Tribunal for the Law of the Sea: A Commentary by P Chandrasekhara Rao and Ph. Gautier (eds) (Martinus Nijhoff Publishers, 2006; ISBN-13: 978-9004152403, 521 pp, hb)]

During Japan’s recent ‘scientifi c’ whaling expedition to Antarctica, the Australian government sent the Oceanic Viking vessel to collect evidence for possible use in any international court proceedings against Japan. It would not be the fi rst time that Australia had instituted a case against Japan to address the conservation and utilisation of marine life, having done so in relation to southern bluefi n tuna (‘SBT’) in the late 1990s. Given Australia’s experience in this regard, it is worth considering what lessons, if any, may be drawn from those proceedings in assessing whether Australia should commence international litigation against Japan in relation to its scientifi c whaling program. Equally, it should be asked whether the outcomes of that litigation foretell any comparable results in Australia and Japan’s relationship both with respect to whaling and more generally.

This paper was presented at the Annual Conference of the Australian and New Zealand Society of International Law. It examines the lessons learned from the Southern Bluefin Tuna litigation, the strategies and considerations for pursuing litigation against Japan to protect whale species and in doing so, considers the nature and place of litigation in resolving disputes for the protection of marine resources.

Protecting Australia's Marine Resources: Is Litigation the Answer?

The plight of David Hicks, an Australian imprisoned in Guantánamo Bay, raised widespread concern among the Australian community. One question frequently asked was why the Australian Government would not do more to secure his release. The lack of action by Australia during Hicks's five years of incarceration led his lawyers to consider what other avenues of protection may be available. The discovery and recognition of Hicks's entitlement to British nationality in addition to his Australian nationality opened up the possibility of Hicks being treated in a comparable manner to other British nationals held in Guantánamo Bay — namely, his release from that prison and repatriation to the United Kingdom. Hicks's acquisition of dual nationality raised many issues related to Australia and the United Kingdom taking action on his behalf against the United States through their right of diplomatic protection. This article explores why the nationality of David Hicks was significant in efforts to protect his rights and how he was reliant on the actions of Australia and the United Kingdom to exercise their right of diplomatic protection. Despite increasing recognition that the right of diplomatic protection is an important tool in the promotion and protection of human rights, the situation of David Hicks demonstrates that diplomatic protection remains bound in a state-centric construct. As a result, an important means of vindicating individuals’ human rights was denied.

A human rights perspective on diplomatic protection: David Hicks and his dual nationality

Editors' note : Globalisation and the quest for social and environmental justice : the relevance of international law in an evolving world order (Macquarie law journal)

The last sixty years has seen a tremendous growth in the role of non-state actors in the international legal system. It is easy to point to an array of examples : the emergence of a complex body of international human rights law for the protection of individuals; the recognition of the rights of peoples to self-determination; the increasing protections afforded to foreign investors; the plethora of intergovernmental and non-governmental organisations addressing a vast variety of issues; and, the escalating influence of multinational corporations in the world economy and world environment. In recent years, the actions of terrorists and the involvement of private contractors in armed conflicts have received greater attention in the development, application and interpretation of international law. There is no gainsaying that actors other than states have a vital role to play in the international legal system.

Non-state actors in inter-state litigation : beneficiaries or blameworthy? : conference papers

1. Achieving Social and Environmental Justice through the Many Dimensions of Globalisation: An Elusive or Achievable Quest? Shawkat Alam, Natalie Klein and Juliette Overland 2. 'Globalized Localisms': Three Phases of Environmental Governance for Biodiversity Protection, Lee Godden 3. Global Standards and Specific Needs: Protection of the Marine Environment Through Particularly Sensitive Sea Areas, Natalie Klein 4. Blue Oil: Water Resources, Social Justice and the International Law on Foreign Investment, Kate Miles 5. Economic Globalization: Rethinking Its Promises for Economic and Social Development from a Developing Country Perspective, Shawkat Alam 6. Standards in the WTO - Attitudes to Biotechnology, Joseph A. McMahon 7. Embedding the Neoliberal Transformation of Government Services through Trade in Services Agreements, Jane Kelsey 8. A Multi-Faceted Journey: Globalisation, Transnational Corporations and Corporate Social Responsibility, Juliette Overland 9. Globalisation and Intellectual Property Rights: The Struggle of Developing Countries to Influence TRIPS, Carlos M. Correa 10. Globalisation and Children's Rights: The Case of Child Labour, Sumaiya Khair 11. Gender and Globalisation: Engendering Social and Environmental Justice through Globalising Women's Human Rights, Erika George 12. ' "Why do they Hate us?" ... They Hate our freedoms': The Globalisation of Terrorism and Counter-Terrorism, Ben Saul 13. Harbingering a New Paradigm of Global Governance: The Role of NGOs in Shaping International Law and Relations in the 21st Century, M. Rafiqul Islam 14. The Challenges of Globalisation and International Law: The Way Forward, Ved P Nanda

Globalisation and the quest for social and environmental justice : the relevance of international law in an evolving world order

The Right of Visit and the 2005 Protocol on the Suppression of Unlawful Acts against the Safety of Maritime Navigation

This paper examines the different ways that individuals' interests have recently been represented in inter-state dispute settlement proceedings. In the past, the rights of individuals have most commonly been asserted through the state's right of diplomatic protection. The role of individuals in inter-state litigation merits reconsideration in view of the adoption in 2006 of the ILC's articles on Diplomatic Protection, which advocate a human rights perspective being brought to bear on states' decisions as to when to take up the claim of one of its nationals. What influence will this perspective have on states' decisions to initiate litigation or on how a court decides cases brought under the banner of diplomatic protection for the promotion of human rights? Individuals have also been found individually responsible for international crimes, and this approach has now been entrenched through the establishment of the International Criminal Court. The recognition of individual responsibility for certain international crimes now raises issues as to the intersection of individual responsibility with state responsibility. Will the actions of individuals in some way exculpate the state from a finding of responsibility, as was arguably the case in the recent Genocide judgement issued by the ICJ? The experience of the Eritrea-Ethiopia Claims Commission further brings to light the connections that exist between state and individual responsibility for international crimes, such as rape. The overall question to be considered is to what extent individuals will benefit from these developments in inter-state litigation or potentially become scapegoats and hence blameworthy for international law violations. This paper was presented at the South African Branch of the International Law Association Regional Conference in August, 2007.

Non-state actors in inter-state litigation : beneficiaries or blameworthy

The events of September 11, 2001, have brought a myriad of security concerns to international attention. Those events have already brought pressure to bear on the international rules concerning the use of force, international humanitarian law, and human rights law. The effect of these attacks has also initiated change in another traditional area of international law, notably the law of the sea. It is the purpose of this paper to outline what challenges are being posed by maritime security concerns to the traditional construct of the law of the sea, and to argue that not all security-driven challenges to legal regimes are detrimental to the rule of law. There are three particular avenues that states have pursued in order to reduce the likelihood of a terrorist attack against international shipping, or otherwise to hinder terrorist activity: (1) the unilateral initiative of Australia in instituting an 1,000 mile Maritime Identification System (AMIS); (2) the Proliferation Security Initiative (PSI), an informal arrangement instigated by the United States; and, (3) the adoption of a new multilateral treaty, the 2005 Protocol to the Convention for the Suppression of Unlawful Acts against the Safety of Maritime Navigation. In exploring these efforts, it is possible to discern how these regimes either violate existing international law or are stretching the usual interpretations of legal rules (particularly in relation to the AMIS and the PSI). The difficulty that states have faced in each endeavor to improve their maritime security is that the traditional construct of the law of the sea emphasizes the freedom of navigation and the exclusive authority of a state over vessels flying its flag. It is argued here that a small paradigm shift is necessary to enhance maritime security, and is viable without disrupting or nullifying the existing legal order.

Threats of Terrorism and Threats to International Legal Structures: A Law of the Sea Perspective

Abstract On 14 December 2004, Australia announced the institution of a ‘Maritime Identification Zone’, extending 1000 nautical miles from its coast and involving the identification of vessels seeking to enter Australian ports, as well as vessels transiting Australia' Exclusive Economic Zone. This Article analyses the legality of these security measures under the UN Convention on the Law of the Sea, new developments through the International Maritime Organization and the Proliferation Security Initiative. The implications of prescribing and enforcing identification requirements on the high seas and in the EEZ, the impact on maritime boundaries and avenues for dispute settlement are all explored.

Legal Implications Of Australia's Maritime Indentification System

[In the wake of September 11, 2001, efforts to protect against future terrorist attacks have affected many areas of international law, including the law of the sea. Australia's interests in improving its maritime security, were articulated at the end of 2004 with the adoption of the Australian Maritime Identification System, which is intended to identify vessels within 1000 nautical miles of Australia's coast. One difficulty faced is that the steps that Australia may take to ensure better protection of maritime assets' and shipping against terrorist attack are limited under international law. States have endeavoured to improve the existing legal framework through the adoption of the International Ship and Port Facility, Security, Code, the Proliferation Security Initiative, bilateral treaties to allow ship-boarding, and a new protocol to the Convention for the Suppression of Unlawful Acts against the Safety of Maritime Navigation. However, inadequacies remain because states are constantly constrained by the fundamental principles of the law of the sea, which emphasise the freedom of navigation and the exclusive authority of flag states. It is argued here that it is only when exclusive interests in flag state control and inclusive interests in the freedom of navigation are reconceived to account for a common interest in enhancing maritime security that weaknesses in the existing legal regime may be overcome.] CONTENTS I Introduction II The Balance of States' Interests in Different Maritime Zones A The Freedoms of the High Seas B Sovereignty over Territorial Seas C Sovereign Rights and Jurisdiction over the EEZ and the Continental Shelf III Post-September 11 Legal Developments to Enhance Maritime Security A The International Ship and Port Facility Security Code B The Proliferation Security Initiative C Protocol of 2005 to the Convention for the Suppression of Unlawful Acts against the Safety of Maritime Navigation D US Bilateral Ship-Boarding Agreements E Security Council Resolution 1540 IV The Need to Re-Balance States' Interests to Enhance Maritime Security V Conclusion I INTRODUCTION The events of September 11, 2001 brought myriad security concerns to international attention and provided the catalyst for significant changes in both national and international legal regimes. International rules concerning the use of force, international humanitarian law and human rights law have been adapted, or breached, in the face of perceived threats posed by al Qaeda and its associated organisations. Given the deadly use of aircraft on September 11, attention has subsequently been focused on the possibility of other modes of international transport being used for terrorist purposes. It is in this context that the maritime industry has been subjected to scrutiny, prompting modifications to existing legal regimes that deal with maritime security issues. Threats to maritime security may take various forms. Ships may be used for the transportation of terrorists, their supplies and their weapons. Of particular concern is the possibility of weapons of mass destruction being sent to terrorists or to states involved in the proliferation of these weapons. There is also the further risk of a large oil tanker, or a vessel shipping liquid natural gas, being hijacked and exploded in a narrow strait, or being rammed into a major port. Equally, small boats may be used to collide with an oil tanker or comparable vessel to similar effect, (1) In addition to the potential for loss of life and injury, the economic ramifications of a major terrorist attack against international shipping are significant, given that approximately 80 per cent of the world's goods are transported via the ocean. (2) Closure of a major port hub or vital shipping route could cause severe economic repercussions on a global scale. (4) The Australian Government is keenly aware of the dangers posed by maritime terrorism, including the proliferation of weapons of mass destruction among non-state actors. …

This article examines the interaction under LOSC of the powers of international courts and tribunals to order binding provisional measures and the obligation of states to make every effort to enter into provisional arrangements pending the delimitation of a maritime boundary. The importance of provisional measures or arrangements in delimiting maritime boundaries, previous state and judicial practice related to provisional arrangements and measures, and the relevant substantive and procedural rules under LOSC are all explored as a means of explaining how courts and tribunals should exercise their powers of ordering provisional measures when provisional arrangements are required. It is argued here that an international court or tribunal should exercise caution in order to ensure that the procedural mechanism complements, rather than conflicts with, the substantive obligation. To this end, provisional measures entailing recommendations, duties of cooperation and obligations of non-aggravation are to be preferred.

Provisional measures and provisional arrangements in maritime boundary disputes

The regulation of the uses of the oceans has demanded a high degree of cooperation between States in order to formulate a system that meets the needs and expectations of the greatest number of users. This regime requires an accommodation of both inclusive and exclusive interests – a balance between the freedoms of the high seas and certain economic rights inhering to coastal States. The far-reaching implications of oceans policies within the internal affairs of States have created a sufficient incentive for States to participate in an international regime and to transfer a certain degree of authority to the operation of the international system. Through participation, States may both control the interpretation and application of rules and standards as well as expect a certain degree of protection from the way that external control may be manipulated. This approach is manifest in the dispute settlement mechanism in Part XV. The dispute settlement procedures are intimately linked to the elaborate legal relationships set forth in UNCLOS, yet the necessity for dispute settlement procedures in relation to the normative framework of the Convention varies depending on the particular issue area in question. The complicated formulation of exceptions and limitations to the mandatory procedures established in the Convention indicates when dispute settlement is necessary for the functioning of the substantive rules. Also evident is when matters had to be left outside the purview of third-party adjudication and arbitration in favor of non-binding international processes, political settlement or unilateral decision-making.

Dispute Settlement in the UN Convention on the Law of the Sea: Limitations on Applicability of Compulsory Procedures Entailing Binding Decisions

Acknowledgements List of abbreviations Table of treaties and other international instruments Table of cases 1. Introduction 2. The dispute settlement procedure under UNCLOS 3. Limitations on applicability of compulsory procedures entailing binding decisions 4. Optional exceptions to applicability of compulsory procedures entailing binding decisions 5. Deep seabed mining 6. Conclusion Bibliography Index.

Dispute Settlement in the UN Convention on the Law of the Sea: Introduction

Dispute Settlement in the UN Convention on the Law of the Sea: CAMBRIDGE STUDIES IN INTERNATIONAL AND COMPARATIVE LAW

Dispute Settlement in the UN Convention on the Law of the Sea: The Dispute Settlement Procedure under UNCLOS

Introduction Article 298 of the Convention allows for States parties to exclude certain categories of disputes from compulsory procedures entailing binding decisions. States may declare when signing, ratifying, or acceding to the Convention, or at any time thereafter, that they do not accept the procedures available under Section for those disputes specified in Article 298. The declaration is without prejudice to the consent-based procedures set out in Section 1 of Part XV. While a State is entitled to withdraw its declaration, a State may not submit a dispute subject to a declaration to any procedure under the Convention without the consent of the other State. Declarations permitted under Article 298 relate, first, to maritime delimitation disputes in relation to the territorial sea, EEZ, or continental shelf of States with opposite or adjacent coasts, as well as disputes involving historic bays or title. Second, States may opt to exclude disputes relating to military activities, as well as law enforcement activities relating to marine scientific research and fishing in the EEZ. Finally, disputes in respect of which the Security Council is exercising its functions under the UN Charter may also be excluded from compulsory procedures entailing binding decisions at the election of States. This chapter explores these categories of disputes and the role that dispute settlement is expected to play and what justifications can be posited for the possible exclusion of these disputes.

Optional Exceptions to Applicability of Compulsory Procedures Entailing Binding Decisions

Dispute Settlement in the UN Convention on the Law of the Sea: Deep Seabed Mining

Case note: "Avena and other Mexican nationals (Mexico v. United States of America)"

State Responsibility for International Humanitarian Law Violations and the Work of the Eritrea Ethiopia Claims Commission So Far

This paper examines the reparations aspect of the Case Concerning Avena and Other Mexican Nationals (Mexico v. United States), and particularly the relevance of the International Court's decision for the Mexican nationals on death row in the United States. It first overviews the substantive obligations applying to the United States under the Vienna Convention on Consular Relations and then analyses the reparations decision of the Court. In respect of the latter, the intersection between international law and domestic law is brought to light. The paper concludes with views on enforcement of the ICJ's decision before US courts. This paper was presented at the 2004 Annual Meeting of the Australia and New Zealand Society of International Law.

Avena and Other Mexican Nationals: How the International Court of Justice Lost its Crown

GOVERNMENT OF ERITREA His Excellency Mr. Ali Said Abdella, Foreign Minister of the State of Eritrea, Agent Professor Lea Brilmayer, Co-Agent, Legal Advisor to the Office of the President of Eritrea, "Howard M. Holtzmann Professor of International Law," Yale University School of Law His Excellency Mr. Mohammed Suleiman Ahmed, Ambassador of the State of Eritrea to the Netherlands Mr. Habtom Gebremichael, Ministry of Foreign Affairs, State of Eritrea Ms. Megan Munzert, Associate Legal Advisor to the Office of the President of Eritrea

Eritrea-Ethiopia Boundary Commission (EEBC): Decision Regarding Delimitation of the Border between the State of Eritrea and the Federal Democratic Republic of Ethiopia *

The coastal State has inherent and primordial rights over the continental shelf, which, unlike other rights of a territorial nature, are not susceptible of being subverted by any of the recognized legal means, such as prescription .... No adverse interest is capable of derogating in any way from these rights. l The international legal regimes for allocation of sovereign rights to land and water areas are fundamentally different, both substantively and procedurally.2 As a substantive matter, rights to land territory are acquired by the fact of phys-

Land and Sea: Two Sovereignty Regimes In Search of a Common Denominator

IV. How THE INTERESTS OF STATES FORM THE 'VERY SUBJECT MATTER OF THE DISPUTE' . . 328 A. Provision of Evidence by a Necessary Party ......................... 329 B. Prior Determination of Responsibility ............................. 332 C. Apportionment of Responsibility ................................ 336 D. Determination of Responsibility at the Merits Stage .................... 337 E. Conclusion ............................................. 338

Multilateral Disputes and the Doctrine of Necessary Parties in the East Timor Case

Despite the centrality of empathy in human social life, there is no widely agreed definition or characterization of the concept of empathy. A common thread in many of the proposed definitions, however, is that empathy presupposes the discrimination of self and other on the grounds that, to empathize with another individual, the mental state of the target individual must first be distinguished from the empathizer's own mental state. The purpose of this study is to investigate this proposal empirically. We employed a paradigm in which participants rated the emotional valence and degree of arousal of 93 facial expressions of mental states. We asked participants to infer the mental state represented by each facial expression (the Other condition) as well as to describe the effect of the expression on their own mental state (the Self condition). An absolute difference score between the Other and the Self conditions was used as an index of a capacity for self-other discrimination. Empathy was measured using the Interpersonal Reactivity Index. Results show that individuals high in trait empathy discriminate between self and other to a significantly greater degree when judging mental states than individuals low in trait empathy. This suggests that the capacity for self-other discrimination may be a component of the capacity for empathy and that future investigations of the concept of empathy ought to retain it. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The discrimination of self from other as a component of empathy.

Machine learning approaches, such as deep neural networks, have shown recent success for target detection and identification problems in hyperspectral imagery. However, when deployed “in the wild,” there are no guarantees about the behavior of these black box algorithms when encountering new materials or environmental conditions that were not part of the training data. In addition, neural networks typically lack properties of linear identification methods in that their predictions tend to select a single class with high confidence even when there are multiple classes that could match a given input spectrum. To provide estimates of confidence in neural network predictions (i.e., target identifications) and to produce indicators of uncertainty, we apply stateof-the-art uncertainty quantification techniques to neural networks trained on hyperspectral data. Specifically, we assess recently proposed methods from the machine learning community including Monte Carlo dropout, ensembles of neural networks, and variational Bayesian neural networks. We report not only the accuracy of the resulting model-averaged networks on in-distribution data, but also the usefulness of uncertainty metrics on noisy or out-of-distribution data. We also compare ensemble neural network target identification results to a linear method on airborne long-wave infrared (LWIR) hyperspectral data with real targets. Finally, we offer some guidelines for applying these methods to hyperspectral target detection/identification problems.

Quantifying uncertainty in machine learning for hyperspectral target detection and identification

Among the new technologies being deployed at sea, maritime autonomous vehicles (MAV) are of increasing interest to States to enhance their intelligence, surveillance and reconnaissance capabilities to improve their maritime security. This article analyses the international law implications of this use of MAV to support maritime law enforcement efforts in response to drug trafficking and other crimes at sea. The use of MAV for criminal purposes, especially smuggling goods, also holds international law consequences. The article assesses how these different operations of MAV fit within existing legal regimes, highlighting emerging legal questions for resolution and setting out recommendations for law reform to enhance counter-smuggling operations at sea.

Maritime Autonomous Vehicles and Drug Trafficking by Sea: Some Legal Issues

ATOMIC Simulations and Experimental Data for Basalt-like Compounds

Strengthening International Fisheries Law in an Era of Changing Oceans

Strengthening Flag State Performance in Compliance and Enforcement

Litigation versus dispute resolution through political processes

1331: PREDICTORS OF DISCORDANCE IN EGFR USING SERUM CREATININE VERSUS CYSTATIN C

814: EVALUATION OF INPATIENT STAT ANTIEPILEPTIC DRUG ADMINISTRATION DELAYS

West Nile encephalitis relapse presenting with abducens and facial nerve palsies.

KIKUCHI'S DISEASE WITH LIVER DYSFUNCTION PRESENTING AS FEVER OF UNKNOWN ORIGIN

Reproductive dysfunction is a comorbidity that commonly occurs with temporal lobe epilepsy (TLE). Characterization of this comorbidity in various models of TLE in mice will greatly facilitate mechanistic investigations of the relationship between reproductive disorders and seizures initiated in the hippocampus. Here we investigate the impact on female reproductive estrous cyclicity in the intrahippocampal kainic acid mouse model of TLE and demonstrate the utility of using this model for future mechanistic studies.

Disrupted female estrous cyclicity in the intrahippocampal kainic acid mouse model of temporal lobe epilepsy

patient subsequently reported that her stuttering had ceased. A high degree of clinical suspicion for WNV infection should be considered in patients with a recent history of mosquito bites and an acute febrile illness associated with neurologic signs and symptoms (5). Typical CSF fi ndings of infection with WNV include lymphocytic pleocytosis, elevated protein level, reference glucose and lactic acid levels, and no erythrocytes (6). The clinical presentation of WNV infection varied widely from asymptomatic seroconversion to fatal encephalitis. It is possible, but unlikely, that the stuttering in the patient was an indication of a migraine aura. Initially, the patient reported that the headache might have been a migraine, but later reported that its associated symptoms, e.g., photophobia, were not as severe and did not last as long as her usual migraines. Further argument against migraine aura is the lack of response to her migraine medication and the fact that the stuttering continued after the headache resolved. Because WNV resembles JEV, it is interesting to note that a case of stuttering in a young adult infected with JEV has been reported (7). However, the mechanism of stuttering associated with WNV is unknown. One possible explanation is myoclonic contractions of the tongue, i.e., vocal myoclonus.

Background Hemophagocytic lymphohistiocytosis (HLH) is a rare condition associated with viral infections including HIV. Cases have been reported mainly in advanced HIV/AIDS. This is a rare case that reports HLH associated with human herpes virus-8 (HHV-8) associated multicentric Castleman disease in a stable HIV patient. Case Presentation A 70-year-old Asian male patient with history of stable HIV on medications with CD 4 cell count above 200 presented with cough and fever and was initially treated for pneumonia as an outpatient. Persisting symptoms prompted presentation to the hospital. The patient was found to have anemia which persisted despite repeated transfusion of packed red cells. A bone marrow biopsy to investigate anemia revealed hemophagocytosis. A CT scan revealed multiple enlarged lymph nodes and hepatosplenomegaly. An excisional lymph node biopsy revealed HHV-8 associated multicentric Castleman disease. The patient deteriorated despite initiation of treatment. Conclusion HLH can occur at any stage of HIV, rapid diagnosis to identify possible underlying reactive infectious etiology and prompt initiation of treatment is crucial to survival.

A Rare Case of HHV-8 Associated Hemophagocytic Lymphohistiocytosis in a Stable HIV Patient

Objective: The clinical effectiveness of tigecycline depends on appropriate use, and PK/PD (pharmacokinetic/pharmacodynamic) parameters related to dose and dosing interval. Methods: In our 600-bed university-affiliated teaching hospital, we conducted a tigecycline efficacy review over a three-month period in 34 evaluable patients. Parameters assessed included clinical response, cure or treatment failure, once daily as q12h dosing, maintenance dosing, high dose vs. standard loading regimens, adverse effects, and the effect of infectious disease consultation on outcomes. Results: We found once daily high dose tigecycline (HDT) was highly effective in treating serious systemic infections due to MDR Gram-positive/negative pathogens as well as C. difficile colitis. Adverse effects were infrequent and limited to mild nausea/vomiting. Once daily HDT was highly effective, and the few treatment failures were related to suboptimal/split dosing regimens. Conclusion: Once daily HDT was highly effective when used to treat susceptible pathogens and when optimally dosed, i.e., 200–400 mg (IV) loading dose ×1, followed by a once daily maintenance dose of 100–200 mg (IV) q24h.

Once Daily High Dose Tigecycline Is Optimal: Tigecycline PK/PD Parameters Predict Clinical Effectiveness

A Rare Cause of Biliary Obstruction: Intrabiliary Rupture of a Hepatic Hydatid Cyst

We present a case of severe adenoviral pneumonia in a 20-year-old immunocompetent host with persistently high fevers. The patient was needlessly given multiple empiric antibiotics for non-existent bacterial co-infection. This case has important antibiotic stewardship lessons for practitioners in approaching fevers in the ICU.

Severe Adenoviral Pneumonia in an Immunocompetent Host with Persistent Fevers Treated with Multiple Empiric Antibiotics for Presumed Bacterial Co-Infection: An Antibiotic Stewardship Perspective on De-Escalation Derailed

TO THE EDITOR—Clinical manifestations of Zika, dengue, and chikungunya infections have many features in common [1–7]. We report a case of Zika virus infection in a traveler returning from Puerto Rico, with fever, rash, myalgias/ arthralgias initially thought to be dengue fever because of her facial puffiness and palatal petechiae. A 41-year-old woman was admitted with fever, rash, headache, and myalgias/arthralgias for 4 days after returning to New York from Puerto Rico, where she reported multiple mosquito bites. One day before admission, a generalized nonpruritic maculopapular rash had developed. The patient reported fevers at home but she was afebrile on admission. Physical examination was remarkable for a generalized maculopapular rash that spared her palms and soles, conjunctival suffusion, facial puffiness, and palatal petechiae. No adenopathy or ankle edema was present on admission. Laboratory results included a white blood cell count of 2100/μL and 17% relative lymphopenia (normal, >21%), with

Facial Puffiness in a Returning Traveler From Puerto Rico: Chikungunya, Dengue Fever, or Zika Virus?

Dear Editor, 
 
We read the case of Chikungunya fever (CF) reported by doctors Hwang and Lee with interest [1]. We report a similar case, but from western South America. CF cases have been reported in western Europe, South America, Africa, and most recently in the Caribbean. Clinically, CF is characterized by persistent severe arthralgia [2]. 
 
In South America, CF, Mayaro fever (MF), and dengue fever (DF) share a similar geographic distribution and may resemble each other. CF, MF, and DF present with fever, chills, headache, myalgias/arthralgias, and rash. Arthralgias in CF typically persist for months, while those in MF and DF are usually transient and self-limited [3]. Serum transaminase and erythrocyte sedimentation rate (ESR) elevations are common in CF, MF, and DF [2,4,5,6]. 
 
A 37-year-old man travelled to western South America, including Ecuador, Colombia, Peru, Bolivia, and the Peruvian Amazon for 8 months (fall 2012 to spring 2013). He suffered many mosquito bites during his travels. Subsequently, he developed a fever of 39.5℃, chills, headache, myalgias, and severe arthralgias in June 2013. His fever abated within 6 days, but severe joint pains, involving the hands and wrists, persisted. Laboratory tests included a normal white blood cell count, platelet count, and ESR. Serum transaminases were unelevated. Leptospira spp., Rickettsia spp., and Brucella spp. titers were negative. Dengue immunoglobulin (Ig) G and IgM titers were negative. The mayaro virus (MV) IgM titer was negative and the MV IgG titer was positive (untitered enzyme-linked immunosorbent assay by US CDC). The chikungunya virus (CV) IgM titer was negative and the CV IgG titer was elevated to 1:320. Severe small joint arthralgias persisted for months. 
 
MF is endemic in South American countries (e.g., Peru and Brazil). Clinically, MF presents as a dengue-like illness with fever, myalgias, arthralgias, and rash, or may resemble CF. Arthralgias in MF are usually of short duration, i.e., 3-5 days, but may last weeks. Although our patient had elevated MV IgG and CV IgG titers, which are typically found in CF, severe arthralgias persisted for months [7,8,9,10]. Although MV IgG titers were positive, we believed that the patient's clinical course was characteristic of CF. CF had not been reported previously in western South America. 
 
We believe our patient contracted CF during his stay in western South America. Given the distribution of the Aedes aegypti and Aedes albopictus mosquito vectors, it is not surprising that CF was discovered in western South America. While the clinical presentation in our case is characteristic of CF, we cannot completely exclude MF, since MV titers may cross-react with CV titers. Although MV arthralgias may be prolonged in some cases, e.g., for weeks, the typical duration of severe CF arthralgias is months [7,9]. While a definitive diagnosis cannot be made from elevated CV IgG titers alone, the clinical presentation is typical of CF because of months of severe arthralgias. We believe that this is the first reported case of imported CF in a returned US traveler.

Fever and Prominent Arthralgia in a Traveler who Returned from Amazonia: Differentiating between Dengue Fever and Chikungunya Fever

Aerococcus christensenii native aortic valve subacute bacterial endocarditis (SBE) presenting as culture negative endocarditis (CNE) mimicking marantic endocarditis.

Mycoplasma pneumoniae preceding Lemierre's syndrome due to Fusobacterium nucleatum complicated by acute Epstein-Barr virus (EBV) infectious mononucleosis in an immunocompetent host.

To the Editor: West Nile virus (WNV), a mosquito-borne flavivirus, is closely related to St. Louis encephalitis virus and Japanese encephalitis virus (JEV). Most cases of WNV have been mild, but neuroinvasive disease has been observed, especially among older persons and immunocompromised persons (1,2). The most common neurologic manifestations of WNV are aseptic meningitis, meningoencephalitis, and encephalitis with or without acute flaccid paralysis (3). Other less common neurologic manifestations include Guillain-Barre syndrome, chorioretinitis, stroke-like symptoms, and unilateral brachial plexopathy (4,5). 
 
We report a case of WNV aseptic meningitis in a 39-year-old immunocompetent woman who had severe headache with new-onset stuttering. Her medical history included lumbar disc herniation and migraines, for which she was taking sumatriptan. Her symptoms started ≈2 weeks before hospitalization and included a severe generalized headache initially thought to be a migraine, but sumatriptan resulted in no improvement. A few days later, she had fever and was intermittently stuttering. She denied recent travel or animal exposure but admitted to having received multiple mosquito bites during the preceding weeks. 
 
At admission, she had a temperature of 101.3°F, pulse rate of 92 beats/min, blood pressure of 130/80 mm Hg, and respiratory rate of 16 breaths/min. She appeared mildly ill but was alert and oriented with no nuchal rigidity, photophobia, rash, or limb weakness. Results of a physical examination were unremarkable, and results of a neurologic examination were notable only for stuttering. Laboratory test results included a leukocyte count of 12,300 cells/mm3 (63% neutrophils, 29% lymphocytes, 7% monocytes, 1% basophils) and a platelet count of 204,000 cells/mm3. Other laboratory values were unremarkable, and levels of serum transaminases and creatinine phosphokinase were within reference ranges. Cerebrospinal fluid (CSF) was clear and contained 37 leukocytes/mm3 (2% neutrophils, 78% lymphocytes, 20% monocytes), 2 erythrocytes/mm3, a glucose level of 68 mg/dL, a protein level of 36 mg/dL, and a lactic acid level of 2.1 meq/L. No abnormalities were found on a cranial computed tomography scan. 
 
The patient began treatment with acyclovir, 10 mg/kg intravenously, every 8 hours for 3 days. On hospital day 2, she underwent magnetic resonance imaging of the brain; results were within reference limits. On hospital day 3, her headache began to improve and she became afebrile, but she still stuttered occasionally. Results of CSF tests for enterovirus, herpes simplex viruses 1 and 2, and varicella zoster virus and PCR for human herpesvirus 6 were negative, and acyclovir was discontinued. On hospital day 5, she was discharged. Three days later, serum and CSF ELISA results for WNV were positive. A WNV ELISA was performed at ViroMed Laboratories (Minnetonka, MN, USA) by using a Focus Test Kit (Focus Diagnostics, Cypress, CA, USA), and the result was positive. The patient subsequently reported that her stuttering had ceased. 
 
A high degree of clinical suspicion for WNV infection should be considered in patients with a recent history of mosquito bites and an acute febrile illness associated with neurologic signs and symptoms (5). Typical CSF findings of infection with WNV include lymphocytic pleocytosis, elevated protein level, reference glucose and lactic acid levels, and no erythrocytes (6). 
 
The clinical presentation of WNV infection varied widely from asymptomatic seroconversion to fatal encephalitis. It is possible, but unlikely, that the stuttering in the patient was an indication of a migraine aura. Initially, the patient reported that the headache might have been a migraine, but later reported that its associated symptoms, e.g., photophobia, were not as severe and did not last as long as her usual migraines. Further argument against migraine aura is the lack of response to her migraine medication and the fact that the stuttering continued after the headache resolved. 
 
Because WNV resembles JEV, it is interesting to note that a case of stuttering in a young adult infected with JEV has been reported (7). However, the mechanism of stuttering associated with WNV is unknown. One possible explanation is myoclonic contractions of the tongue, i.e., vocal myoclonus.

Abstract Varicella-zoster virus (VZV) is an unusual cause of meningoencephalitis in the immunocompetent patient. Most cases of VZV-associated aseptic meningitis or encephalitis are associated with the skin rash of primary varicella, localized herpes zoster, or disseminated zoster. We report a case of VZV meningoencephalitis without a rash occurring in a normal host.

Varicella-zoster virus meningoencephalitis in an immunocompetent patient without a rash

To the Editor: Pandemic (H1N1) 2009 virus first appeared in March 2009 in Mexico. In June 2009, a pandemic was declared by the World Health Organization (1). Influenza A virus (H1N1) caused a pandemic in 1918–1919; estimated deaths were ≈100 million worldwide (2). Symptoms of pandemic (H1N1) 2009 are similar to those of seasonal influenza (fever, cough, sore throat, body aches, headache, chills, and fatigue) (3). Pandemic (H1N1) 2009 should be considered in the differential diagnosis of patients with acute febrile respiratory illness who have been in contact with persons with confirmed influenza or reside in areas where influenza has been reported (2). 
 
Although most cases of pandemic (H1N1) 2009 in the United States have been mild, 2%–5% of infected persons have required hospitalization (2). Immunosuppressed persons, the elderly, persons with underlying lung or cardiac disease, pregnant women, persons with diabetes, obese persons, and children <5 years of age are at increased risk for this disease (4). 
 
We report pneumonia associated with pandemic (H1N1) 2009, which resulted in respiratory and renal failure and death, in a 39-year-old HIV-positive woman. She had type 1 diabetes and a diagnosis of AIDS 7 years ago and had received highly active antiretroviral therapy. She also had an ill child at home with an influenza-like illness. 
 
Her medical history included pleuropericardial Nocardia spp. infection, recurrent pleural effusions requiring thoracentesis, and hepatomegaly of unknown cause. Her most recent CD4 cell count was 166 cells/μL with undetectable viral load 1 month before admission. Medications prescribed included combivir, efavirenz, and trimethoprim/sulfamethoxazole but she was noncompliant. She had received the 2008–09 seasonal influenza vaccine and pneumococcal vaccine. 
 
The patient was admitted to Winthrop-University Hospital (Mineola, NY, USA) on June 5, 2009, for community-acquired pneumonia. She received empiric moxifloxacin and atovaquone. Because of concern for persistent Nocardia spp. infection, she was also treated with doxycycline. The result of a rapid influenza test (QuickVue; Quidel, San Diego, CA, USA) was negative for a nasal swab specimen on day 1 of hospitalization. Over the next 48 hours, her clinical status deteriorated, and she experienced worsening hypotension and respiratory distress. 
 
On admission, she had fever (101°F) for 3 days, pulse rate of 109 beats/min, blood pressure of 86/52 mm Hg, respiratory rate of 22 breaths/min (oxygen saturation of 88% on room air), generalized weakness, nonproductive cough, and increasing shortness of breath. She was alert and oriented. Physical examination showed decreased breath sounds at bases, hepatomegaly, and bilateral edema in the lower extremities. Laboratory tests showed 3,000 leukocytes/mm3 (93% neutrophils, 2% bands, and 3% lymphocytes), hemoglobin level of 12.7 g/dL, and 118,000 platelets/mm3. Other laboratory values were blood urea nitrogen 66 mg/dL, creatinine 2.9 mg/dL, creatinine phosphokinase 2,276 IU/L, and lactic acid 3.6 mmol/L (anion gap 13). A chest radiograph showed moderate pleural effusion in the right lung and retrocardiac air space disease. Test results for influenza virus, respiratory fluorescent antibodies (D3 Ultra DFA Respiratory Virus Screening and Infectious Disease Kit; Diagnostic Hybrids, Inc., Athens, OH, USA), and virus culture were negative. 
 
The patient was transferred to the intensive care unit and required intubation, pressor support, and continuous venovenous hemofiltration for fluid removal. Empiric oseltamivir (150 mg 2×/d) was started on hospital day 3; moxifloxicin was discontinued, and meropenem was given for pneumonia (5). Thoracentesis showed transudative fluid negative for acid-fast bacilli, bacteria, and fungi. 
 
Results of blood cultures and urine analysis for Legionella spp. antigen were negative. Repeat chest radiography showed a right-sided pneumothorax and worsening bilateral airspace disease. A chest tube was inserted in the right lung, and bronchoscopy was performed on hospital day 5. Results of bronchoalveolar lavage were negative for Pneumocystis jiroveci, virus inclusions, fungi, acid-fast bacilli, bacteria, and mycobacteria. However, clusters of filamentous organisms were seen. On hospital day 5, results of a second rapid influenza test, respiratory fluorescent antibody test, and nasopharyngeal virus culture were negative. Diagnosis was based on a positive result for pandemic (H1N1) 2009 by real-time reverse transcription–PCR (RT-PCR) for a nasopharyngeal swab specimen (New York State Department of Health). Despite empiric treatment with oseltamivir, the patient died on June 15, 2009 (day 11 of hospitalization). 
 
Symptoms of pandemic (H1N1) 2009 in HIV-infected persons are not known. However, these persons have a higher risk for complications. In previous seasonal influenza outbreaks, HIV-infected persons had more severe infections and increased hospitalization and mortality rates (6). 
 
Although a diagnosis of pandemic (H1N1) 2009 was first considered for our patient because of her ill child, she was not initially treated with oseltamivir because of the negative influenza test result and concern for opportunistic infections. Only the result of an RT-PCR for pandemic (H1N1) 2009 was positive. No other pathogens were detected in her blood, urine, sputum, bronchoalveolar lavage, or thoracenthesis fluid. 
 
Empiric treatment in patients with pandemic (H1N1) 2009 should be considered in those seeking treatment for influenza-like symptoms, especially in the setting of sick contacts with respiratory illnesses. Rapid influenza tests, respiratory fluorescent antibody tests, and viral cultures may not provide a diagnosis. An RT-PCR for pandemic (H1N1) 2009 may be needed to provide a diagnosis.

Fatal Case of Pneumonia Associated with Pandemic (H1N1) 2009 in HIV-Positive Patient

Legionnaires' disease mimicking swine influenza (H1N1) pneumonia during the “herald wave” of the pandemic

Although amebic liver abscesses are usually single, multiple abscesses may occur in up to 20% of patients. We present a case of multiple amebic liver abscesses occurring in a patient successfully treated for hepatitis C, who presented with a fever of unknown origin.

Fever of unknown origin (FUO) : Multiple amebic liver abscesses in a patient with hepatitis C

Abstract Bacteremias in inpatient chronic HD units have been described, but there is little information on bacteremias in ambulatory HD units. To determine the frequency of bacteremia and pathogen distribution in ambulatory chronic HD units, we retrospectively reviewed our experience with 107 bacteremias in 5 chronic ambulatory HD units over a 3 year period. The object of the study was twofold. The first objective was to determine if bacteremias in ambulatory HD setting were substantially different in frequency or type than in the inpatient HD setting. Secondly, febrile patients suspected of having bacteremia in chronic HD patients are often empirically treated with vancomycin and gentamicin. Chronic HD patients require repeated and frequent venous access for HD. Bacteremias are common in chronic HD patients and may be primary or secondary and are often related to venous access site infections. The distributions of bacteremia pathogens in chronic HD patients are predominantly reflective of skin flora, i.e., staphylococci and to lesser extent aerobic Gram-negative bacilli. After S. aureus (MSRA/MSSA) and coagulase-negative staphylococcus (CoNS), enterococci are the next most important Gram-positive pathogens in bacteremic HD patients. Most strains of E. faecalis are sensitive to vancomycin and for practical purposes should be considered as vancomycin sensitive enterococci (VSE). In contrast, most strains of E. faecium are resistant to vancomycin and should be considered as vancomycin resistant enterococci (VRE). We retrospectively reviewed 107 patients on chronic ambulatory HD to determine the adequacy of empiric vancomycin and gentamicin prophylaxis. We found amikacin is preferred to gentamicin and that meropenem is an effective alternate substitution for gentamicin and vancomycin combination therapy.

Appropriateness of Empiric Gentamicin and Vancomycin Therapy for Bacteremias in Chronic Dialysis Outpatient Units in the Era of Antibiotic Resistance

Falsely high antibiotic resistance in community-acquired E. coli UTIs requiring hospitalization.

The 5-Minute Infectious Diseases Consult Edited by Sherwood L. Gorbach and Matthew Falagas Philadelphia: Lippincott Williams & Wilkins, 2001. 527 pp. $79.95 (hardcover)

Infectious Common HIV/AIDS Typhoid fever Babesiosis Malaria Uncommon Viral hepatitis Tuberculosis Histoplasmosis Brucellosis Noninfectious Common Sarcoidosis Chronic corticosteroid use Antilymphocyte globulin Cancer chemotherapy Radiation therapy Rheumatoid arthritis Systemic lupus erythematosus Hodgkin’s disease Chronic alcohol abuse Uncommon CD4 lymphocytopenia Severe combined immunodeficiency Ataxia telangiectasia Wiskott-Aldridge syndrome Thoracic duct drainage Myasthenia gravis Idiopathic Profound and Prolonged Lymphocytopenia with West Nile Encephalitis

Profound and prolonged lymphocytopenia with West Nile encephalitis.

West Nile Virus in Nassau County, New York: the Long Island experience.

Erythromycin has been the most commonly used drug for the treatment of legionnaires' disease; however, failures have occurred and adverse effects are common. Doxycycline intravenously is preferred and is less expensive. The newer macrolides/azalides, clarithromycin and azithromycin, have excellent in vitro activity against Legionella and fewer adverse effects than erythromycin. The fluoroquinolones, particularly levofloxacin, are the most active anti-Legionella antibiotics available. Other agents with activity against Legionella pneumophila include minocycline, rifampin, and trimethoprim-sulfamethoxazole. The preferred therapy of legionellosis in immunocompromised patients are quinolone/macrolide combinations, eg, levofloxacin plus azithromycin.

ANTIBIOTIC APPROACHES TO THERAPY FOR LEGIONNAIRES' DISEASE : A REVIEW

UNUSUAL ORGANISMS CAUSING INTRAVENOUS LINE INFECTIONS IN COMPROMISED HOSTS: II. FUNGAL INFECTIONS

Cephalosporins are among the most frequently prescribed antibiotics as a result of their broad spectrum of microbiologic activity, favorable pharmacokinetics, low incidence of adverse reactions, and proven clinical efficacy for a wide variety of infections. Cephalosporins differ in their gram-positive, gram-negative, and anaerobic spectra, serum half-lives, penetration of the cerebrospinal fluid, and resistance to beta-lactamases. The first-generation and some second-generation agents maintain excellent activity against streptococci and staphylococci, while the third-generation agents have expanded gram-negative coverage. Two third-generation cephalosporins, ceftazidime and cefoperazone, are active against Pseudomonas. Ceftizoxime has become the workhorse third-generation cephalosporin. The fourth-generation agent cefepime provides excellent activity against gram-positive and gram-negative pathogens, including antibiotic-resistant Enterobacteriaceae. A major dilemma facing the practitioner is how to select the "right" cephalosporin for a particular patient, as no one drug will satisfy all clinical needs. This review describes a practical approach to selecting an appropriate cephalosporin for common infectious disease problems.

Endophthalmitis after ophthalmic surgery is a rare but serious complication. Postoperative endophthalmitis presents clinically with conjunctival erythema and lid edema with eye pain and decrease in visual acuity. Diagnosis requires invasive culture techniques because postoperative external eye cultures are not reflective of intraocular organisms. The most common pathogens causing postoperative endophthalmitis are staphylococci and streptococci. Less common organisms associated with exogenous endophthalmitis include gram-negative aerobic bacilli and fungi. We report a case of Serratia marcescens postoperative endophthalmitis in a normal host.

ObjectiveTo compare the clinical efficacy and safety of trimethoprim-sulfamethoxazole (TMP-SMX) with pentamidine in the therapy of Pneumocystis carinii pneumonia (PCP) in patients with AIDS. Patients, participantsTMP-SMX (TMP, 20 mg/kg/day plus SMX, 100 mg/kg/day) was compared with pentamidine (4 mg/kg/day), both administered intravenously for 21 days in a prospective randomized treatment trial of 163 patients diagnosed with PCP between November 1984 and May 1988. ResultsNinety-two evaluable patients received TMP-SMX as initial therapy; 68 received pentamidine. Failure to complete therapy was common. Of those receiving TMP-SMX, 39 (42%) required change in therapy because of failure to respond, and an additional 31 (34%) because of drug toxicity. This compared with 27 (40%; P = 0.733) and 17 (25%; P = 0.235), respectively, in the pentamidine-treated group. The overall survival rates were similar in the two groups, 62 out of 92 (67%) initially administered TMP-SMX versus 50 out of 68 (74%) initially administered pentamidine (P = 0.402). The survival rates for patients requiring a change in therapy because of failure to respond was 46% (18 out of 39) for the TMP-SMX group compared with 56% (15 out of 27) for the pentamidine group. When a change in therapy was made because of toxicity, survival rates were 97% (30 out of 31) for those receiving TMP-SMX versus 94% (16 out of 17) for those receiving pentamidine. ConclusionTMP-SMX and pentamidine are of equivalent efficacy as initial therapies for PCP in patients with AIDS.

Trimethoprim‐sulfamethoxazole versus pentamidine for Pneumocystis carinii pneumonia in AIDS patients: results of a large prospective randomized treatment trial

Infections with Listeria monocytogenes have been increasing in incidence over the last decade. Listeria species are found widely in the environment, frequently isolated from the soil, water, sewage, and from a variety of wild and domestic animals. Outbreaks of human listeriosis have been linked to contaminated coleslaw, milk, and other dairy products. Since Listeria is an intracellular pathogen, it is not surprising that the majority of symptomatic cases have occurred in individuals receiving immunosup pressive therapy, or with some defect in their cell-mediated immune system.

The fluoroquinolones have excellent activity against a number of respiratory pathogens, especially gram-negative bacteria, including beta-lactamase-producing Hemophilus influenzae and Moraxella catarrhalis. Several studies have shown ciprofloxacin to be effective in the treatment of acute exacerbations of chronic bronchitis, some community-acquired and nosocomial pneumonia, and acute exacerbations of bronchopulmonary infections in cystic fibrosis. The fluoroquinolones have less activity against Streptococcus pneumoniae and limited anaerobic activity, which should limit the use of these drugs in empiric therapy of community-acquired pneumonia where the pneumococcus or anaerobes play a predominant role.

Listeria monocytogenes bacteremia without meningitis has been reported in patients who have undergone long-term hemodialysis and have transfusional iron overload. On the other hand, cases of Listeria bacteremia without meningitis have occurred sporadically among the acquired immunodeficiency syndrome population, mostly homosexuals. There have been no reports of Listeria meningitis occurring among persons who are antibody positive to human immunodeficiency virus or are intravenous drug abusers having chronic renal failure and undergoing hemodialysis. This patient represents the first case of Listeria bacteremia and meningitis to occur in an intravenous drug abuser who is human immunodeficient antibody positive, is receiving hemodialysis, and has transfusional iron overload.

Listeria monocytogenes meningitis in a human immunodeficiency virus-positive patient undergoing hemodialysis.

Generalized tonic-clonic seizures in persons infected with the human immunodeficiency virus have usually occurred in the setting of space-occupying lesions in the brain. Seizures have also been known to occur in patients with acquired immunodeficiency syndrome-related dementia. Two patients, each with prior history of human immunodeficiency virus infection, had seizures early in the course of their illness. Neither patient had evidence of space-occupying lesions or dementia at the time of admission for the seizures. Patients with human immunodeficiency virus infection may present with seizures and may not have a clinically detectable focus for their seizures.

Early seizures in patients with acquired immunodeficiency syndrome without mass lesions.

Group B streptococci are the most frequent cause of life-threatening infections in newborn infants in the United States. The reservoir of this organism is thought to be the mother's vaginal or rectal microflora or both. Prevalence surveys have documented arriage rates ranging from 8% to 31%. Increased rates of vertical transmission are seen in infants born to women with dense vaginal colonization at delivery. In most cases, early onset group B streptococcal disease in neonates is diagnosed during the first day of life.' While the carrier rate may approach 30% in pregnant women, the incidence of serious disease in neonates is 0.2% to 0.4% with a mortality rate approaching 50% in some studies. Risk factors prominently associated with early onset group B streptococcal disease have been identified as premature labor, prolonged rupture of amniotic membranes and intrapartum fever.

We review our experience with brain abscesses presenting as primary brain tumor over a 5-year period (1983 to 1988). Four of 66 (6%) patients admitted with the diagnosis of primary brain tumor by computed tomographic scans were found at craniotomy to have brain abscesses. Periapical abscesses found after surgery were determined to be the cause of brain abscess in two of four patients. Our experience suggests that periapical abscess may be a more frequent cause of brain abscess than previously thought, and should be considered before surgery in patients with a suspected brain tumor.

Pulmonary tuberculosis in AIDS/ARC patients is an increasing problem. To assess the utility of acid-fast smears of pulmonary secretions in this patient population, we evaluated 38 AIDS/ARC patients with culture-positive pulmonary infection. A control group consisted of 57 non-AIDS/ARC patients, who also did not belong to an AIDS risk group, diagnosed during the same period. The number of culture-positive sputum samples evaluated per patient was similar in both groups (3.82 +/- 3.11 AIDS/ARC vs 4.47 +/- 2.83 control group). Significantly fewer AIDS/ARC patients, 45 percent, however, had a positive acid-fast smear compared with the control group, 81 percent (p less than 0.001). The initial sputum smear submitted was positive in only 29 percent of the AIDS/ARC group compared with 61 percent of control subjects (p less than 0.01). Further, greater than or equal to 5 negative smears were found in 60 percent of the evaluable AIDS/ARC patients compared with just 13 percent of control subjects (p less than 0.01). More extensive findings on chest roentgenograms were not associated with a significantly higher yield of smear positivity in the AIDS/ARC group. We conclude that acid-fast smears on sputum specimens are a relatively insensitive test for pulmonary tuberculosis in AIDS/ARC patients.

Use of mycobacterial smears in the diagnosis of pulmonary tuberculosis in AIDS/ARC patients.

Mycobacterium avium-intracellulare complex (MAI) is the most ubiquitous non-tuberculous mycobacterium in the environment. Until the onset of acquired immunodeficiency syndrome (AIDS) MAI infections were limited to the lungs of patients with underlying pulmonary disease. Pathogenesis of MAI infection is unknown however it is likely that colonization precedes the development of disease and occurs as a result of exposure to the pathogen in the environment. Postulated routes of acquisition include inhalation ingestion or through sexual contact. Infection requires a transient or permanent impairment of immune defenses and colonization with a large number of mycobacteria. Disseminated MAI infection occurs when an organism invades the bloodstream an event which occurs more commonly in immunocompromised hosts. In 1 series 77% of AIDS patients had disseminated infection in contrast to 5% prevalence of the same in non-AIDS patients. Disseminated infection is definitively diagnosed on the basis of isolation of MAI from blood or bone marrow. In 1 series of 47 AIDS patients with disseminated MAI 96% had positive blood cultures for MAI due to improved culturing techniques used in diagnosis. The pathological findings in AIDS patients are variable. Inflammatory reaction is often minimal. Acid fast staining reveals large number of bacilli in pathologic specimens. Weight loss can be dramatic with over 15% loss in a few weeks. Diarrhea is usually watery and non-bloody but can present as full blown colitis or malabsorption syndrome. In the past a combination of 5-6 antituberculous drugs were used in the treatment of pulmonary and disseminated MAI in non-AIDS patients. These agents have proved ineffective in AIDS patients infected with MAI. Of the currently available drugs the most active against MAI in vitro are ansamycin LM427 (rifabutin) and clofazimine both of which are investigational agents. Despite in vitro activity of some medications at present no effective therapy exists for disseminated MAI in AIDS patients.

Mycobacterial meningitis. Retrospective analysis from 1970 to 1983.

Experimental modulation of PRPP availability for ribonucleotide synthesis from hypoxanthine in human skin fibroblast cultures.

A glycerol auxotroph was isolated from Rhodopseudomonas capsulata for use as a system for studying membrane synthesis and function. When the mutant was deprived of glycerol, net phospholipid synthesis ceased immediately and a small amount of free fatty acids accumulated. A turnover of lipid occurred in both deprived and supplemented cultures. Deoxyribonucleic acid and protein synthesis continued for one doubling of cell massand then slowed down in deprived cells. Net ribonucleic acid synthesis slowed down more dramatically. Oxidative phosphorylation activity of membrane preparations from aerobically and semi-anaerobically grown cells appeared unaffected by glycerol deprivation, indicating that simultaneous lipid synthesis is not a requirement for new oxidative phosphorylating activity. In the absence of net phospholipid synthesis, bacteriochlorophyll and carotenoid syntheses were reduced to 30% of the activity of supplemented cultures. Delta-Aminolevulinic acid synthase, the first enzyme on the bacteriochlorophyll pathway that is subject to regulatory control, increased in activity in deprived cultures. Lascelles and Szilagyi (1965) showed an association between phospholipid synthesis and pigment production. They found an increased lipid content associated with pigmented cells. The present results indicate that not only is there an association between lipid and pigment synthesis, but also there is actually a dependence of bacteriochlorophyll synthesis on phospholipid synthesis.

Isolation and characterization of a glycerol auxotroph of Rhodopseudomonas capsulata: effect of lipid synthesis on the synthesis of photosynthetic pigments

Cultured fibroblasts from patients with partial or complete deficiencies of enzymes involved in purine metabolism provide a model for investigating the biosynthesis, interconversion, and excretion of purine metabolites at the cellular level. Skin fibroblast cultures were derived from five patients with hypoxanthineguanine phosphoribosyltransferase deficiency, from five subjects with idiopathic overproduction gout, from one patient with adenosine deaminase deficiency, and from four control subjects. Purine excretion was measured by recovering labeled purines from the incubation medium of cells grown in the presence of 14C-formate. In general the patterns of purine excretion by these cultured cells resembled the urinary excretion patterns of the patients from whom they were derived.

Purine excretion by cultured skin fibroblasts from patients with abnormal purine metabolism.

Therapy of the Pulmonary Fungal Mycoses Pulmonary Syndrome Therapy of Choice Aspergillosis Allergic bronchopulmonary aspergillosis Aspergilloma Chronic necrotizing pulmonary aspergillosis Invasive aspergillosis Blastomycosis Acute pulmonary disease Chronic pulmonary disease Coccidioidomycosis Acute 

Introduction Type 2 diabetes is prevalent among US adults. Lifestyle interventions that modify health behaviours prevent or delay progression to diabetes among individuals at high risk. Despite the well-documented influence of individuals’ social context on their health, evidence-based type 2 diabetes prevention interventions do not systematically incorporate participants’ romantic partners. Involving partners of individuals at high risk for type 2 diabetes in primary prevention may improve engagement and outcomes of programmes. The randomised pilot trial protocol described in this manuscript will evaluate a couple-based lifestyle intervention to prevent type 2 diabetes. The objective of the trial is to describe the feasibility of the couple-based intervention and the study protocol to guide planning of a definitive randomised clinical trial (RCT). Methods and analysis We used community-based participatory research principles to adapt an individual diabetes prevention curriculum for delivery to couples. This parallel two-arm pilot study will include 12 romantic couples in which at least one partner (ie, ‘target individual’) is at risk for type 2 diabetes. Couples will be randomised to either the 2021 version of the CDC’s PreventT2 curriculum designed for delivery to individuals (six couples), or PreventT2 Together, the adapted couple-based curriculum (six couples). Participants and interventionists will be unblinded, but research nurses collecting data will be blinded to treatment allocation. Feasibility of the couple-based intervention and the study protocol will be assessed using both quantitative and qualitative measures. Ethics and dissemination This study has been approved by the University of Utah IRB (#143079). Findings will be shared with researchers through publications and presentations. We will collaborate with community partners to determine the optimal strategy for communicating findings to community members. Results will inform a subsequent definitive RCT. Trial registration number NCT05695170

Couple-based lifestyle intervention to prevent type 2 diabetes: protocol for a randomised pilot trial

The Role of Advocacy in Adapting the Diabetes Prevention Program for Couple-Based Delivery That Reaches Marginalized Groups.

Glycated haemoglobin (HbA1c) is a sensitive marker of blood glucose in patients with diabetes. However, levels can vary considerably, even among individuals with similar mean blood glucose concentrations. Other glycated proteins, such as fructosamine, can also act as blood sugar markers, but estimating HbA1c and fructosamine via independent models may lead to errors of interpretation regarding disease severity. From a clinical standpoint, it would be of great interest to know the factors that aﬀect the mean concentration of both HbA1c and fructosamine, that inﬂuence the variability in the concentrations of these glycated markers, and that cause HbA1c/fructosamine discordance. Flexible models are required that illus-trate the behaviour of these variables as well as the association between them. The present work reviews existing models that might serve in this regard. Flexible copula regression models using P-splines, were used to provide a better understanding of the behaviour of both glycated proteins, and the relationship between them under the possible inﬂuence of diﬀerent covariates. This work shows the usefulness of this type of models in practice, and provides a basis for its clinical interpretation by means of an understandable case study. Ultimately, to better understand the eﬀects of each continuous covariate, they were represented at the true scale of the response variables.

Studying the relationship between markers of glycemic control (based on)/ (using) ﬂexible copula regression models // Assesing the relationship between markers of glycemic control through ﬂexible copula regresion models

Upon hearing a disfluent referring expression, listeners expect the speaker to refer to an object that is previously unmentioned, an object that does not have a straightforward label, or an object that requires a longer description. Two visual-world eye-tracking experiments examined whether listeners directly associate disfluency with these properties of objects, or whether disfluency attribution is more flexible and involves situation-specific inferences. Since in natural situations reference to objects that do not have a straightforward label or that require a longer description is correlated with both production difficulty and with disfluency, we used a mini-artificial lexicon to dissociate difficulty from these properties, building on the fact that recently learned names take longer to produce than existing words in one’s mental lexicon. The results demonstrate that disfluency attribution involves situation-specific inferences; we propose that in new situations listeners spontaneously infer what may cause production difficulty. However, the results show that these situation-specific inferences are limited in scope: listeners assessed difficulty relative to their own experience with the artificial names, and did not adapt to the assumed knowledge of the speaker.

Inferring Difficulty: Flexibility in the Real-time Processing of Disfluency

Pourquoi est-il plus naturel de dire « Jean ecoute la radio » plutot que « Jean ecoute une radio », ou « Jean attend sur le bord de la route » plutot que « Jean attend sur un bord de la route », et ce, non seulement en francais, mais dans des langues aussi differentes typologiquement que le francais, l’anglais ou l’hebreu ? Sont etudies ici les usages dits « faibles » de l’article defini, les contextes dans lesquels ce dernier est prefere a l’article indefini. Ce dossier reunit des etudes de linguistes, de philosophes et de psycholinguistes, et s’adresse a la fois aux chercheurs et aux etudiants qui travaillent sur la comparaison des langues.

Weak definites across languages: theoretical and experimental investigations

Definite noun phrases typically refer to entities that are uniquely identifiable in the speaker and addressee’s common ground. However, some definite noun phrases (e.g. the hospital in Mary had to go the hospital and John did too) seem to violate uniqueness. We discuss a series of experiments that seek to understand some of the properties of this class of definites. We consider most carefully the hypothesis that these “weak definite” interpretations arise in implicitly “incorporated” constructions, attempting to provide a sketch of this hypothesis’ motivation and potential consequences. In our experiments we found that compared to regular definites, the weak definites need not refer uniquely, and readily trigger semantically enriched readings that compete effectively with normal inferences one might draw from a sentence. Perhaps the most surprising finding in the experiments is that nouns that could occur as weak definites, also seemed to retain some of these “weak” properties even when expressed as indefinites. We try and make sense of this within the “incorporation” framework.

Weak definites as a form of definiteness: experimental investigations

Experimental investigations of weak definite and weak indefinite noun phrases

Classifying and massifying incrementally in Chinese language comprehension

“Some,” and possibly all, scalar inferences are not delayed: Evidence for immediate pragmatic enrichment

Understanding the role of mass and count classifiers in Chinese lexical access

As linguistic input arrives, listeners rapidly integrate that input with preceding context and generate expectations about the upcoming input. Some of the most striking evidence comes from studies using the visual world paradigm (Cooper, 1974, Tanenhaus, Spivey-Knowlton, Eberhard & Sedivy). For example, in a seminal study, Altmann & Kamide (1999) found that as listeners hear a verb,they generate anticipatory eye movements to a likely theme or patient (also see, Boland, 2000). Similarly, Chambers and colleagues have demonstrated anticipatory eye movements to to objects that contain the appropriate affordances for prepositions, for example making anticipatory eye movements to a container such as a can rather than a plate when the preposition “inside” is used (Chambers, Tanenhaus, Eberhard, Filip & Carlson, 2002). One surprising exception appears to be definite articles, such as “the,” where current comprehension data does not ostensibly capture the strength of offline judgments and theoretical analyses. It is widely accepted that definite noun phrases such as “the can” assume that the referent is uniquely identifiable. The definite article paradigmatically appears in noun phrases (NPs) that select a uniquely identifiable referent from the known world or discourse. The President of the United States of America (at present) refers exclusively to Barack Obama; the largest planet in our solar system refers exclusively to Jupiter. Instances in which the referent of an expression is semantically unique in fact require the definite article. For example, the use of an indefinite article with a superlative (such as a largest planet in our solar system) is infelicitous. By contrast, indefinite articles canonically introduce new referents into the discourse. A bald man with glasses introduces an individual meeting that description into the common ground as a discourse entity. Unlike a typical definite NP, an indefinite NP does not presuppose the unique identifiability of its referent. While the distinction we are drawing here between definite and indefinite NPs ignores important nuances, it nevertheless captures the way NPs are generally divided: definite NPs refer to specific, unique discourse referents, and indefinite NPs introduce new discourse referents, or refer to entities

David Restle University of München Underdetermination and enrichment in control constructions From a semantic point of view, infinitive constructions like [Peter asked/promised Mary] to come to the party and its German equivalent are underdetermined structures under more than one aspect. On the one hand, the lack of a syntactic subject calls for the reconstruction of a “logical” subject. In our example we need to reconstruct the reference of the person whose coming-to-the-party is the content of the request/promise. On the other hand, the semantic relation holding between the referential arguments of the control predicates and the referential arguments of the embedded infinitives is underdetermined: In the German nominal control construction die Freude zu gewinnen (literally ‘the joy to win’) either the context or intervening facultative pronominal adverbs darüber/daran/darauf determines if the event of winning is temporally located before, at, or after the event of joy (cf. Restle 2006). The discussion in this paper will be confined to the first case of underdetermination, the interpretation of PRO. Early research (cf. Rosenbaum 1967) was trying to get a grip on the problem of control interpretation with purely syntactic means (with the terms “subject/object control” stemming from this time), and failed. The options left nowadays are either semantic or pragmatic, as the dependencies of the control interpretation from context and stereotypes seem to suggest. Proponents of the semantic view of control interpretation (e.g. Culicover & Jackendoff 2005) use coercions in order to transform little John asked to go into little John asked to be allowed to go. This view is problematic in light of the fact that we can not predict exactly when coercion is necessary and when it is not. Proponents of more pragmatic views (e.g. Köpcke & Panther 2002) introduce special pragmatic roles and maxims in order to reconstruct logical subjects pragmatic roles that seem to be idiosyncratic for control phenomena. Besides the comparison of those general options we report on the results of a questionnaire which backs up the willingness for pragmatically induced control changes at least amongst younger speakers. Our new model will avoid the problems mentioned above in using an optimality theoretic device to enrich the conceptually underspecified semantic representation. This OT-account is also able to describe the differences in orientation strategy between

DGfS Annual Meeting , Bamberg 2008 AG 9 : ‘ Experimental Pragmatics / Semantics ’

The definite article paradigmatically appears in noun phrases (NPs) that select a uniquely identifiable referent from the known world or discourse. The President of the United States of America (at present) refers exclusively to George W. Bush; the Peter W. Stanley Professor of Linguistics and Philosophy at Pomona College is Jay Atlas; the largest planet in our solar system indicates Jupiter. Instances in which the referent of an expression is semantically unique in fact require the definite article. For example, the use of an indefinite article with a superlative (such as a largest planet in our solar system) is infelicitous. By contrast, indefinite articles canonically introduce new referents into the discourse. A bald man with glasses introduces an individual meeting that description into the common ground as a discourse entity. Unlike a typical definite NP, an indefinite NP does not presuppose the unique identifiability of its referent. While the distinction we are drawing here between definite and indefinite NPs ignores important nuances, it nevertheless captures the way NPs are generally divided: definite NPs refer to specific, unique discourse entities, and indefinite NPs introduce new discourse entities, or refer to entities that are not necessarily uniquely indentifiable. In this paper we focus on certain definite NPs that do not seem to behave like paradigmatic definite NPs. Carlson and Sussman (2005), inter alios, (e.g. Birner and Ward (1994); Barker (2005)) have noted that some definite NPs appear quite indefinite in nature, in that they (1) do not seem to presuppose unique identifiability and (2) do not appear to introduce individual entities into the discourse. These NPs, which we call weak definites following Poesio (1994), are the subject of the research we will present. Consider the following sentence from Carlson and Sussman (2005):

Weak definite noun phrases : rich , but not strong , special , but not unique ∗

Semantic accounts of the definite article have tended to fall into two general classes: ‘uniqueness’ accounts (Russell, 1905), and ‘familiarity’ accounts (Heim, 1982; see also Abbott, 2004, inter alia). It is also generally known that there are instances of definite descriptions that are resistant to such analyses, and are difficult to subsume under either treatment, or even a combination of both. Birner and Ward (1994), Poesio (1994), and Barker (in press) explicitly deal with what we are going to call “weak” interpretations of certain definite NP’s. Roberts (2003) is just one recent example of an attempt to integrate instances of this sort into a more general account.

In order to understand the spatial meaning of an utterance, comprehenders must integrate the spatial semantics of verbs and prepositions. For example, the spatial interpretation of at is typically non-directional, simply specifying a location in space: in the sentence Amy ran at the track, at only specifies the location of the running event. However, in the phrase threw at, the inherent directionality of the verb threw coerces the meaning of at into specifying a bounded path along which a thrown object traveled, e.g., Amy threw the ball at me. We report reading time data that show a processing cost for this semantic coercion. The results show coercion effects for both verbs and prepositions, and support semantic theories in which directionality is built from simpler spatial representations.

Integrating the Spatial Semantics of Verbs and Prepositions during Sentence Processing

Analyses of living and fossil taxa are crucial for understanding changes in biodiversity through time. The Total Evidence method allows living and fossil taxa to be combined in phylogenies, by using molecular data for living taxa and morphological data for both living and fossil taxa. With this method, substantial overlap of morphological data among living and fossil taxa is crucial for accurately inferring topology. However, although molecular data for living species is widely available, scientists using and generating morphological data mainly focus on fossils. Therefore, there is a gap in our knowledge of neontological morphological data even in well-studied groups such as mammals. We investigated the amount of morphological (cladistic) data available for living mammals and how this data was phylogenetically distributed across orders. 22 of 28 mammalian orders have < 25% species with available morphological data; this has implications for the accurate placement of fossil taxa, although the issue is less pronounced at higher taxonomic levels. In most orders, species with available data are randomly distributed across the phylogeny, which may reduce the impact of the problem. We suggest that increased morphological data collection efforts for living taxa are needed to produce accurate Total Evidence phylogenies.

Data used in the paper "Metabolic rate and body size are linked with perception of temporal information"

Cooper et al 2008 GEB Dataset - Frog macroecology and extinction risk

Dying without wings: ecological correlates of lifespan in mammals and birds

Unusual Organisms Causing Intravenous Line Infections in Compromised Hosts: I. Bacterial and Algal Infections

Using Immunohistochemistry to Determine FAM171B Expression in the Brain

The p16(INK4A)/pRb pathway and telomerase activity define a subgroup of Ph+ adult Acute Lymphoblastic Leukemia associated with inferior outcome.

Introduction The treatment of Adult Acute Lymphoblastic Leukemia (ALL) has improved by the use of pediatric-like approaches, erasing the poor prognostic impact of numerous variables. New markers are however still needed to identify poor prognosis patients in prospective trials. The p16INK4A/CDK4-6/pRb pathway and telomerase activity (TA), markers of cell activation and aging, were analyzed in 175 adult ALLs, treated between November 2003 and January 2007 according to the GRAALL/GRAAPH trials, to investigate their prognostic value in this context.

Methods The cohort comprised 105 males and 70 females aged between 16 and 59 years (median: 36). Immunophenotype by flow-cytometry allowed for the characterization of 123 B- and 52 T-lineage ALLs, 163 of them being subdivided according to EGIL criteria. Cytogenetic and/or molecular analyses allowed for the detection of BCR-ABL, MLL-AF4 or E2A-PBX1 fusion transcripts, NOTCH1 mutations in T-ALLs, and IKAROS deletions in BCR-ABL -negative B-ALLs. In all cases, cell samples were obtained at diagnosis, before any treatment, from bone marrow aspiration after the patients provided informed consent. Flow cytometric analysis of the DNA content was performed for evaluation of the percentages of cells in S/G2/M phases of the cell cycle. Cell cycle regulatory proteins were examined in 135 samples, by western blot. The TA assay was performed on 156 samples according to a telomeric repeat amplification protocol.

Furthermore, in vitro analyses of the p16INK4A/CDK4-6/pRb pathway and TA were carried out in normal peripheral blood lymphocytes before and after stimulation and during lymphocyte long-term culture.

Results The p16INK4A/CDK4-6/pRb pathway and TA were analyzed according to the immunological phenotype and molecular characteristics of ALLs. Leukocytosis (p<0.0001), proliferating blast cell percentage (p=0.004), CDK6 (p = 0.011), and pRb phosphorylation (p-pRb) (p = 0.003) were significantly higher in T-ALLs compared to B-ALLs, while p16INK4A expression was significantly higher in the latter (p = 0.002). Enhanced p16INK4A significantly correlated with B- and T-maturation (p = 0.03) and MLL rearrangement (p < 0.003).

Among sub-groups defined by clinical or biological data, the most significant relationships between the p16INK4A/CDK4-CDK6/pRb pathway or TA and prognosis were observed for BCR-ABL1+ ALLs (31 cases). An above median expression of CDK4 was related to shorter disease-free survival (DFS) (p = 0.031) and overall survival (OS) when taking into account either death due to any cause (p = 0.005), or only disease-related death (p = 0.018). In spite of the small size of this series, this prognostic value remained when the analysis was restricted to patients who did not receive allogeneic stem-cell transplantation (non-Allo SCT) for DFS (p = 0.034), OS (p = 0.019) or disease-related OS (p = 0.05). A shorter DFS was also associated with the CDK4/6 mediated-phosphorylation of pRb (p-pRb/pRb ratio > 0) (p = 0.042), paradoxically, with high expression levels of p16INK4A (p = 0.029), and also with above median TA (p=0.040). Patients with the highest TA (over quartile 75) showed a significantly shorter OS (p = 0.018) especially when considering only disease-related death (p = 0.007). The poor prognostic value of above median TA for OS (p = 0.026) and disease–related OS (p = 0.009) was also confirmed in the non-Allo SCT group.

Considering that IKAROS is deleted in most of BCR-ABL1+ ALLs and since survival was similar in BCR-ABL1+ ALLs and BCR-ABL1-/IKAROSdel B-ALLs, these two groups of patients were pooled for analysis (42 cases). A shorter DFS was linked to pRb phosphorylation (p = 0.036), while both a shorter DFS (p = 0.026) and OS (p = 0.055) were noted for patients with high TA.

In vitro analyses in normal lymphocytes demonstrated that increased expression of p16INK4A, CDK4, p-pRb and TA is related to cell activation, suggesting that ALL blasts with these criteria could be in an activated stage.

Conclusions These data bring new perspectives to the biological characterization of ALLs and associate a poor prognosis in BCR-ABL1 + ALLs with enhanced cell activation. Additional investigations could focus, in a prospective series, on the analysis of the cell activation markers described here and on the development of new therapeutic strategies by proposing the association of lymphocyte activation inhibitors.

Reappraisal Of The p16INK4A/Prb Pathway and Telomerase Activity, Markers Of Cell Activation and Aging, In Adult Acute Lymphoblastic Leukemia: A Graall Study

The role of platelet-derived growth factor production by tumor-associated macrophages in tumor stroma formation in lung cancer.

The question of whether bronchial squamous metaplasia is a true preneoplasia is important and demonstrated in animal for several carcinogens. We have now approached this problem in humans and in vivo.

Squamous metaplasia in the close vicinity of surgically resected lung tumors were evaluated for their mitotic index and screened for proto-oncogenes and P 53 protein expression by immunohistochemistry and/or in situ hybridization.

RESULTS
Among 16 patients, 4 had squamous metaplasia positive for either myc messages and/or for P 53 protein accumulation. In the same patients (3/4), the autologous bronchial tumors were also positive for the same markers. Squamous metaplasia positivity was observed essentially in patients with advanced diseases and only in squamous cell carcinomas. In addition, when evaluated with 5 iodo-2'-deoxyuridine systemic infusion, all patients presented hyperproliferative basal squamous metaplasic cells.

These results are reminiscent of the typical preneoplastic changes observed in familial colic adenomatosis, where genetic changes accumulate in hyperproliferative cells. They also suggest that bronchial squamous metaplasia could be an authentic preneoplasia in, at least, squamous cell carcinomas.

Squamous metaplasia expression of proto-oncogenes and P 53 in lung cancer patients.

Given two probability densities on related data spaces, we seek a map pushing one density to the other while satisfying application-dependent constraints. For maps to have utility in a broad application space (including domain translation, domain adaptation, and generative modeling), the map must be available to apply on out-of-sample data points and should correspond to a probabilistic model over the two spaces. Unfortunately, existing approaches, which are primarily based on optimal transport, do not address these needs. In this paper, we introduce a novel pushforward map learning algorithm that utilizes normalizing flows to parameterize the map. We first re-formulate the classical optimal transport problem to be map-focused and propose a learning algorithm to select from all possible maps under the constraint that the map minimizes a probability distance and application-specific regularizers; thus, our method can be seen as solving a modified optimal transport problem. Once the map is learned, it can be used to map samples from a source domain to a target domain. In addition, because the map is parameterized as a composition of normalizing flows, it models the empirical distributions over the two data spaces and allows both sampling and likelihood evaluation for both data sets. We compare our method (parOT) to related optimal transport approaches in the context of domain adaptation and domain translation on benchmark data sets. Finally, to illustrate the impact of our work on applied problems, we apply parOT to a real scientific application: spectral calibration for high-dimensional measurements from two vastly different environments

Semi-supervised Learning of Pushforwards For Domain Translation & Adaptation

In this work, we propose a novel generative model for map- ping inputs to structured, high-dimensional outputs using structured conditional normalizing ﬂows and Gaussian pro- cess regression. The model is motivated by the need to char-acterize uncertainty in the input/output relationship when making inferences on new data. In particular, in the physical sciences, limited training data may not adequately char- acterize future observed data; it is critical that models adequately indicate uncertainty, particularly when they may be asked to extrapolate. In our proposed model, structured conditional normalizing ﬂows provide parsimonious latent repre- sentations that relate to the inputs through a Gaussian process, providing exact likelihood calculations and uncertainty that naturally increases away from the training data inputs. We demonstrate the methodology on laser-induced breakdown spectroscopy data from the ChemCam instrument onboard the Mars rover Curiosity. ChemCam was designed to recover the chemical composition of rock and soil samples by mea-suring the spectral properties of plasma atomic emissions in- duced by a laser pulse. We show that our model can generate realistic spectra conditional on a given chemical composition and that we can use the model to perform uncertainty quantiﬁcation of chemical compositions for new observed spectra. Based on our results, we anticipate that our proposed modeling approach may be useful in other scientiﬁc domains with high-dimensional, complex structure where it is important to quantify predictive uncertainty.

Generative structured normalizing flow Gaussian processes applied to spectroscopic data

Selecting experiments to better inform predictive models for the Mars rover

In many scientiﬁc applications, measured time series are corrupted by noise or distortions. Traditional denoising techniques often fail to recover the signal of interest, particularly when the signal-to-noise ratio is low or when certain assump-tions on the signal and noise are violated. In this work, we demonstrate that deep learning-based denoising methods can outperform traditional techniques while exhibiting greater robustness to variation in noise and signal characteristics. Our motivating example is magnetic resonance spectroscopy, in which a primary goal is to detect the presence of short-duration, low-amplitude radio frequency signals that are often obscured by strong interference that can be difﬁcult to separate from the signal using traditional methods. We explore various deep learning architecture choices to capture the inherently complex-valued nature of magnetic resonance signals. On both synthetic and experimental data, we show that our deep learning-based approaches can exceed performance of traditional techniques, providing a powerful new class of methods for analysis of scientiﬁc time series data.

Constructing probability densities for inference in high-dimensional spectral data is often intractable. In this work, we use normalizing flows on structured spectral latent spaces to estimate such densities, enabling downstream inference tasks. In addition, we evaluate a method for uncertainty quantification when predicting unobserved state vectors associated with each spectrum. We demonstrate the capability of this approach on laser-induced breakdown spectroscopy data collected by the ChemCam instrument on the Mars rover Curiosity. Using our approach, we are able to generate realistic spectral samples and to accurately predict state vectors with associated well-calibrated uncertainties. We anticipate that this methodology will enable efficient probabilistic modeling of spectral data, leading to potential advances in several areas, including out-of-distribution detection and sensitivity analysis.

Neural density estimation and uncertainty quantification for laser induced breakdown spectroscopy spectra

The segmentation and temporal tracking of fast flow structures called bursty bulk flows is an integral part of space weather study. This paper presents the first known topological segmentation and tracking technique to analyze bursty bulk flows. We apply contour tree-based segmentation to identify regions of high plasma velocity from data output from space weather simulations. We then employ a Kuhn-Munkers assignment algorithm with a modified Wasserstein metric to match features in adjacent time steps. A newly implemented algorithm to determine splits and merges of segments results in a fully topological framework for feature detection and tracking of fast flow channels.

Topological Segmentation and Tracking for Space Weather Modeling

Computer simulations continue to grow in size and complexity and are moving towards exascale. Simulations at this scale can generate outputs that exceed both storage capacity and the bandwidth available for transferring to storage, making traditional offline statistical inference challenging. Therefore, it is desirable to embed statistical analyses in the simulation framework while the simulation is running - a strategy called in situ inference - to alleviate the burden of storage. In this work, we focus on adapting Principal Component Analysis (PCA) - a statistical method for reducing dimensionality of big data - to the in situ setting. We develop TributaryPCA: a distributed version of Oja's algorithm for streaming PCA that uses the Message Passing Interface (MPI) standard. Our approach significantly reduces data storage requirements of offline PCA and avoids excessive communication across compute nodes. We illustrate the method using data generated from the SHIELDS Framework for space weather simulation.

2021 7th International Workshop on Data Analysis and Reduction for Big Scientific Data (DRBSD-7)

TributaryPCA: Distributed, Streaming PCA for In Situ Dimension Reduction with Application to Space Weather Simulations

Because local field potentials (LFPs) arise from multiple sources in different spatial locations, they do not easily reveal coordinated activity across neural populations on a trial-to-trial basis. As we show here, however, once disparate source signals are decoupled, their trial-to-trial fluctuations become more accessible, and cross-population correlations become more apparent. To decouple sources we introduce a general framework for estimation of current source densities (CSDs). In this framework, the set of LFPs result from noise being added to the transform of the CSD by a biophysical forward model, while the CSD is considered to be the sum of a zero-mean, stationary, spatiotemporal Gaussian process, having fast and slow components, and a mean function, which is the sum of multiple time-varying functions distributed across space, each varying across trials. We derived biophysical forward models relevant to the data we analyzed. In simulation studies this approach improved identification of source signals compared to existing CSD estimation methods. Using data recorded from primate auditory cortex, we analyzed trial-to-trial fluctuations in both steady-state and task-evoked signals. We found cortical layer-specific phase coupling between two probes and showed that the same analysis applied directly to LFPs did not recover these patterns. We also found task-evoked CSDs to be correlated across probes, at specific cortical depths. Using data from Neuropixels probes in mouse visual areas, we again found evidence for depth-specific phase coupling of primary visual cortex and lateromedial area based on the CSDs.

Cross-population coupling of neural activity based on Gaussian process current source densities

Neural Density Estimation and Uncertainty Quantification for ChemCam Spectra

The study of many extreme weather events requires simulations with high spatiotemporal data that can grow in size quickly. Storing all the raw data from such a large-scale simulation for traditional post hoc analyses is soon going to be prohibitive as the data generation speed is outpacing the data storage capability in supercomputers. In situ analysis has emerged as a solution to this problem; data is analyzed when it is being produced, bypassing the slower disk input/output (I/O). In this work, we develop a new in situ analysis pathway for Energy Exascale Earth System Model (E3SM) and propose an algorithm for analyzing the impacts of sudden stratospheric warmings (SSWs), which can cause extreme cold temperature outbreaks at the surface, resulting in hazardous weather and disrupting many socioeconomic sectors. We detect SSWs and model the surface temperature data distributions in situ and show that post hoc analysis using the distribution models can predict the impact of SSWs in the continental United States.

ISAV'21: In Situ Infrastructures for Enabling Extreme-Scale Analysis and Visualization

Angular measurements are often modeled as circular random variables, where there are natural circular analogues of moments, including correlation. Because a product of circles is a torus, a d-dimensional vector of circular random variables lies on a d-dimensional torus. For such vectors we present here a class of graphical models, which we call torus graphs, based on the full exponential family with pairwise interactions. The topological distinction between a torus and Euclidean space has several important consequences. Our development was motivated by the problem of identifying phase coupling among oscillatory signals recorded from multiple electrodes in the brain: oscillatory phases across electrodes might tend to advance or recede together, indicating coordination across brain areas. The data analyzed here consisted of 24 phase angles measured repeatedly across 840 experimental trials (replications) during a memory task, where the electrodes were in 4 distinct brain regions, all known to be active while memories are being stored or retrieved. In realistic numerical simulations, we found that a standard pairwise assessment, known as phase locking value, is unable to describe multivariate phase interactions, but that torus graphs can accurately identify conditional associations. Torus graphs generalize several more restrictive approaches that have appeared in various scientific literatures, and produced intuitive results in the data we analyzed. Torus graphs thus unify multivariate analysis of circular data and present fertile territory for future research.

SUPPLEMENT TO “ TORUS GRAPHS FOR MULTIVARIATE PHASE COUPLING ANALYSIS

During adolescence, the integration of specialized functional brain networks related to cognitive control continues to increase. Slow frequency oscillations (4–10 Hz) have been shown to support cognitive control processes, especially within prefrontal regions. However, it is unclear how neural oscillations contribute to functional brain network development and improvements in cognitive control during adolescence. To bridge this gap, we employed magnetoencephalography (MEG) to explore changes in oscillatory power and phase coupling across cortical networks in a sample of 68 adolescents and young adults. We found a redistribution of power from lower to higher frequencies throughout adolescence, such that delta band (1–3 Hz) power decreased, whereas beta band power (14–16 and 22–26 Hz) increased. Delta band power decreased with age most strongly in association networks within the frontal lobe and operculum. Conversely, beta band power increased throughout development, most strongly in processing networks and the posterior cingulate cortex, a hub of the default mode (DM) network. In terms of phase, theta band (5–9 Hz) phase-locking robustly decreased with development, following an anterior-to-posterior gradient, with the greatest decoupling occurring between association networks. Additionally, decreased slow frequency phase-locking between frontolimbic regions was related to decreased impulsivity with age. Thus, greater decoupling of slow frequency oscillations may afford functional networks greater flexibility during the resting state to instantiate control when required.

Adolescent development of cortical oscillations: Power, phase, and support of cognitive maturation

Density estimation is one of the fundamental tasks in statistics and machine learning, as it often appears as a subroutine in tasks such as regression, classification, and clustering. However, density estimation in high dimensions remains a challenging problem due to the curse of dimensionality, which affects the convergence rates of many popular density estimation techniques. In addition, common density estimation techniques often lack in interpretability, adaptability, speed, accuracy, and reasonableness of assumptions. For instance, mixtures of Gaussians (MoGs) require parametric assumptions, fixed bandwidth kernel density estimators (KDEs) can’t adapt well to heterogeneous smoothness (even within even a single dimension), and adaptive bandwidth kernel density estimators (which seek to be more adaptable) are complex and expensive computationally.

CRISPR-Cas-Systeme der Klasse 1: Genome Engineering und Silencing

[Home treatment in geriatric psychiatry: an idea with a future?!]

This chapter examines how international environmental law (IEL) disputes are resolved before international courts and tribunals, addressing when parties will decide to litigate an IEL dispute as opposed to utilizing another form of dispute settlement. Assuming there is reason to pursue adjudication or arbitration, it looks at questions of jurisdiction. The chapter also considers preliminary matters that emerge in these cases, notably questions of standing and whether provisional measures are needed and may be secured before an international court or tribunal. It then turns to substantive matters, but only in the context of presentation of the case in terms of evidence and use of experts. Finally, the chapter assesses the available reparations in the resolution of IEL disputes before international courts and tribunals. Ultimately, considerable progress may be noted in respect of the use of international courts and tribunals for IEL disputes, but it is prudent to observe that in this area of international law, preventing the emergence of IEL disputes is ultimately more important than ex post facto responses to environmental damage.

Part VIII Compliance, Implementation, and Effectiveness, Ch.60 International Environmental Law Disputes Before International Courts and Tribunals

Abstract Ambitions to fulfil accountability demands in humanitarian action are high, including for protection activities in armed conflict settings. However, from a Dunantist position, meeting accountability demands is often not only unsatisfactory for practical reasons, but is also inappropriate in view of humanitarian principles and flawed from related ethical perspectives. Regarding accountability primarily as a technical exercise, rather than as being linked to ethical perspectives on humanitarianism and its principles, may thus inadvertently contribute to reduced acceptability of, and ultimately reduced access for, humanitarian actors. Dunantist actors wishing to stay true to their ethical approach need new ways of thinking about accountability, a reflection which can serve as an example for an ongoing need to consider differences between actors within the humanitarian–development nexus.

More humanitarian accountability, less humanitarian access? Alternative ideas on accountability for protection activities in conflict settings

Networks of coupled oscillators are a form of dynamical network originally inspired by various biological and physical systems. Much existing research focuses on simple, restricted models which are analytically tractable. In order to explore networks which do not fit into the existing models, we have programmed a flexible numerical simulation of oscillator networks. We have used the simulated network as an artificial neural network which uses a genetic algorithm for training. Preliminary results with the current neural network simulation suggest that the genetic algorithm is able to produce and optimize networks which perform differentiation between input frequencies. In future work, we hope to expand the existing numerical model, explore the role of noise during training on robustness, look at the effect of different network architectures, and explore optimization of neural networks for other tasks.

A Numerical Approach to Understanding Oscillator Neural Networks

Os sintagmas definidos denotam tipicamente entidades que sao identificaveis univocamente no fundo conversacional compartilhado pelo falante e pelo ouvinte. No entanto, alguns sintagmas nominais definidos (e.g. ‘o hospital’ em ‘Maria teve que ir pro hospital e Joao tambem’) parecem violar a unicidade. Discutimos uma serie de experimentos que procuram entender algumas das propriedades dessa classe de definidos. Consideramos, com mais cuidado, a hipotese de que essas interpretacoes de “definido fraco” surjam de construcoes implicitamente “incorporadas”, buscando fornecer um esquema da motivacao para essa hipotese e suas possiveis consequencias. Em nossos experimentos encontramos que, comparados aos definidos regulares, os definidos fracos nao denotam univocamente e disparam, de imediato, leituras semanticamente incorporadas que competem efetivamente com as inferencias que obtemos normalmente de uma sentenca. A descoberta mais surpreendente dos nossos experimentos e talvez que os nomes que podem ocorrer como definidos fracos, tambem parecem reter algumas de suas propriedades “fracas” quando sao expressos com indefinidos. Tentamos explicar isso dentro do quadro da incorporacao.

DEFINIDOS FRACOS, UMA FORMA DE DEFINITUDE: INVESTIGAÇÕES EXPERIMENTAIS

Abstract Social class is a major determining factor of people's life chances. Much sociology-based research shows that socio-economic position is still one of the best predictors of who will achieve success, prosperity and social status and, in particular, who will enjoy the highest levels of educational outcomes. Survey data and qualitative studies alike confirm that many people continue to see class as a feature of everyday life, in ways that are connected with their understanding of learning and its possibilities. However, despite its continued significance in people's lives, class has virtually disappeared from modern adult learning research. This paper concludes that in an era when governments across Europe are setting about the dismantling of social support and collective protection produced by social democracy and trade unionism, class analysis presents an important means of understanding change and changing understanding. The existence of persistent social class inequalities in access is a repeated theme of research into higher education (HE) participation. Moreover, socioeconomic inequalities persist in spite of the considerable enlargement of higher education systems that has taken place in many countries since the 1950s (Field, 2003; Alon, 2009; Boliver, 2011; Reay 2012). Moreover, survey data and qualitative accounts confirm that many people continue to see class as an everyday aspect of their lives, in ways that are connected with their understanding of learning and its possibilities. This paper looks at the ways in which experiences and constraints of social class were experienced and ‘storied’ by a group of non-traditional students in higher education. It starts out with reflections on the current status—or rather absence—of class as a key category of critical analysis in adult learning. We then examine briefly the question of class in the context of mass higher education. While much has changed in the social composition of the undergraduate population as a consequence of expansion, taken as a whole there seems to have been relatively little change in undergraduates' socio-economic status. While the overall number of students from broadly working class backgrounds has grown, their relative share of the undergraduate population has not greatly altered (Boliver, 2011). In England, it seems that the proportion of students from poorer families declined during the expansion period of the mid- to late-1990s and recovered to its original position during the early years of the current century (Chowdry et al., 2013). In Scotland, Ianelli concludes that similar fluctuations mean that ‘overall the relation between social class of origin and educational attainment has not significantly changed over time’ (Ianelli, 2011: 257). What does this mean for the experiences of students from working class backgrounds? We explore this question through a discussion of RANLHE interviews in Scottish higher education. We interviewed a sample of 83 students from three HEIs—one a highly selective institution, one a former central institution (roughly akin to a polytechnic) and one with a mixed mission emphasising both teaching and research. We recruited students through direct email contacts (both targeted and general), appeals in newsletters, intermediaries such as course leaders, and—once we had started—by snowballing; some also approached us, having heard about the project by word of mouth. All interviews were recorded and transcribed verbatim, with hesitations and repetitions included. We read and re-read the transcripts, which included responses to a standard question on class. Posed late on in the first or early in the second interview, the interviewer asked ‘How you would describe your background in terms of class?’ and the student's reply was then followed up. The interviewer did not provide a definition of class, though the follow-up discussion could explore definitional issues if the interviewee raised them (hardly anyone did, at least not explicitly). Responses during this initial discussion of class gave us a baseline for a preliminary thematic analysis which, in turn, provided a springboard for undertaking an iterative thematic and contextual examination of the ways in which different people spoke about class or—in some cases—deflected a discussion of class. We distinguished between how people spoke about membership of a particular class and how they talked about class as a phenomenon. The students in our sample spoke about class in relation to their own educational disadvantage and/or experiences/perceptions of HE. Often they discussed class obliquely, or in ways that can be understood through socio-cultural perspectives. One arts student, for example, talked of relating the circumstances of Tracey Emin's childhood (material disadvantage, abuse) to the context in which she grew up and being completely alienated during a class discussion by what she perceived as classist and misogynistic contempt shown towards Emin by fellow students. In addition, class affected student experiences in more material ways, both for mature students who had worked themselves and for young students who came from working-class families.

Reappraising the importance of class in higher education entry and persistence

The Importance of Social Support Structures for Retention and Success

This paper describes the key ﬁndings ofan NSPCC studyestimating need, in the UK, fortherapeutic services for children who have experienced sexual abuse. This is basedupon current estimates of the prevalence and impact of sexual abuse towards childrenand young people against the availability of therapeutic services in the UK. Data werecollected on service location, availability, scope and coverage across England, Wales,Northern Ireland and Scotland. Researchers: (1) mapped 508 services; (2) collecteddata from 195 services via a structured questionnaire; (3) followed up 21 servicemanagers and 11 service commissioners with a semi-structured interview; and (4)carried out two focus groups with young people.The overall level of specialist provision is low, with less than one service available per10 000 children and young people in the UK. Calculations of need indicate that 57 156children across the UK in the last year may have been unable to access a service.Findings from services support the view that need outstrips availability; that referralroutes are limited, leaving few options for young people who have been raped orseriouslysexuallyassaultedtodirectlyaccesssupport;thatsigniﬁcantwaitinglistsmeanservices must focus on reactive, rather than preventive, work; and that services are lessaccessible for certain groups, especially sexually abused teenagers, children withdisabilities and those from Black, Asian, Minority Ethnic and Refugee backgrounds.Copyright © 2012 John Wiley & Sons, Ltd.K

In Demand: Therapeutic Services for Children and Young People Who Have Experienced Sexual Abuse

Hitting the ground running: reflections on pre-entry student support and new students " academic preparedness for higher education This paper reports on experiences of non-traditional undergraduates who have entered university following a pre-entry preparatory programme. The evidence is drawn from a collaborative European research project on Access and Retention: Experiences of Non-traditional Learners in Higher Education. The project focuses on access, retention and drop-out in higher education institutions in relation to non-traditional students (younger and adults) and the factors which promote or inhibit this (for further details see www.ranlhe.dsw.edu.pl). By " non-traditional " we mean students who are under-represented in higher education and whose participation in HE is constrained by structural factors. This includes, for example, first generation entrants, students from low-income families, students from (particular) minority ethnic groups, mature age students, and students with disabilities. 2 We present here findings for the Scottish sample to date. We are particularly interested in looking at and understanding why some students from under-represented and disadvantaged backgrounds learn effectively, assume an undergraduate learner identity and complete their degree successfully, while others from similar backgrounds do not. We are also interested in identifying the learning, teaching and support processes which help non-traditional students to become effective and successful learners. Institutional cultures and structures can also impact on a learner " s identity so these aspects are also explored. In this paper, we examine the extent to which pre-entry preparation is a factor in helping non-traditional students to become effective and successful learners within higher education. The question of what support non-traditional students need to ensure successful transitions, and even whether they need support at all, is a controversial one and we discuss our findings in the light of some recent criticism of the idea of providing support to students experiencing educational transitions. Education (RANLHE), is being undertaken by a partnership of eight universities from across Europe. Each partner is undertaking fieldwork in three higher education institutions in their own country; in each country, these case study HEIs have been selected to represent a spread of highly selective institutions, moderately selective institutions and recruiting institutions. We are interviewing samples representing three groups of learners: those who drop-out, those who stay in and those who drop-out but later return and re-engage with learning. We are interviewing staff and students at 3 higher education institutions in Scotland; at each institution we are interviewing: o approximately 10 students …

Researching Retention and Non-Traditional Learners: evidence on pre-entry preparation

What does it mean to be a student in a period of mass higher education? A growing number of researchers in post-compulsory education and training have explored questions of identity as a significant dimension of the learning experience (Tedder and Biesta 2009; Merrill 2009). This paper provides a conceptual discussion of studenthood as a way of understanding the ways in which student identities are related to participation and retention. Studenthood refers here to the variety of different ways in which registering for an education programme is implicated in people’s sense of who they are.

Studenthood and identification: higher education as a liminal transitional space

Sexual abuse and therapeutic services for children and young people: The gap between provision and need (Full report)

Mapping therapeutic services to children and young people who have been sexually abused: Services in Scotland (Summary report)

This is a summary of research carried out by the NSPCC and the University of Edinburgh into the availability and accessibility of therapeutic services for children and young people who have experienced sexual abuse in England, Wales, Northern Ireland and Scotland. The research involved searches of local and national information resources on services; a survey of service providers; follow-up interviews with providers and commissioners of services; and focus groups with young people. The full research report can be downloaded from www.nspcc.org.uk/inform

Sexual abuse and therapeutic services for children and young people: The gap between provision and need (Executive summary)

4 Berlin Zoo, Hardenbergplatz 8, 10787 Berlin, GERMANY Abstract.—We established a primary skin cell culture of the Critically Endangered Chinese Giant Salamander, Andrias davidianus, from small biopsies using minimal invasive methodologies. Bi- opsies were taken from three animals simultaneously with assessment of two biopsy sampling techniques using samples from the tail tip. Cell culture was performed in a wet chamber at room temperature. Several culture media and supplementations were tested as well as culture contain- ers and surface coatings. The handling of A. davidianus in a landing net, without transfer out of the tank, allowed easier biopsy withdrawal. Best outgrowth of cells from explants was achieved in 60% DMEM/F12 medium with supplementation. Cells started to grow out as monolayer within the first 12 hours, and after three weeks formed pigmented multilayers, then died after 10 weeks. Primary cul- tures of Andrias skin cells, as well as other amphibian primary cell cultures, can be used in future studies to evaluate effects of disease, pollution, regeneration, wound healing, and could provide cells for use in reproduction technologies such as cryopreservation to preserve gene lines in this and other Critically Endangered species with minimal harm to the animals.

In vitro culture of skin cells from biopsies from the Critically Endangered Chinese giant salamander, Andrias davidianus (Blanchard, 1871) (Amphibia, Caudata, Cryptobranchidae)

A randomized controlled trial to determine whether a video presentation improves informed consent for hysterectomy

T rauma is devastating. It is the fourth leading cause of death for all age groups and the leading cause of death for those younger than 46 years old. Approximately 170,000 Americans died of traumatic injuries in 2013 alone, and the direct costs of trauma are nearly equal to those for cancer. But disease processes receive a larger portion of research funding from theNational Institutes of Health than does trauma. However, the Department of Defense (DoD) is inherently interested in trauma treatment, and in 2015, the Combat Casualty Care Research Program at the U.S. Army Medical Research and Materiel Command (USAMRMC) dedicated roughly $130 M to support trauma research in both military and civilian institutions. Trauma clinical research has unique requirements, as does DoD funding. Understanding both will make it easier to access funding for trauma research, and to develop and field technologies for trauma care. The medical product development process is a data-driven, multifactorial, time-intensive undertaking (Fig. 1), and Food and Drug Administration (FDA)–regulated clinical research can be a formidable undertaking. Successful efforts begin by focusing on the goal of product licensure and are managed by experienced teams with a wide range of expertise. It is prudent for a clinician principal investigator (PI) to be familiar with FDA regulations to conduct the clinical study according to Good Clinical Practices (GCPs), but it is also critical for PIs to know how, when, and whom to engage as resources. Some of these resources include clinical research and regulatory consultants, the institution’s office of technology transfer, seasoned clinical trial personnel, and sufficient research funding. This report will focus on this holistic approach to FDA–regulated medical product development, as such an approach represents the best chance for successfully achieving marketing approval for new medical products.

Transitioning trauma research: Navigating the regulatory requirements for medical product development.

As a policy goal, widening participation is increasingly associated with retention and completion. For those who are concerned with equity or social mobility, it makes little sense to recruit new types of student if they do not then qualify for a graduate profession. In its strategic plan, the Higher Education Funding Council for England (HEFCE) states that one of its main strategic aims is to promote ‘the opportunity of successful participation in HE to everyone who can benefit from it’ (HEFCE, 2009, p. 18). There has also been growing interest in retention among researchers, much of which has centred on the extent to which new students can be helped to integrate into the institution. In the UK, this focus has been increased through a major programme of research and development on retention, jointly funded by HEFCE and the Paul Hamlyn Foundation, much of which has been concerned with ‘promoting academic and social integration into the institution to promote a sense of belonging’ (Action on Access 2009). We are particularly interested here in the ways in which students feel themselves to be legitimate members of the ‘imagined community’ of higher education, a concept that we have adapted from Anderson’s treatment of nationalisms (Anderson, 1991; see also Quinn, 2010). Citation information

John Field and Natalie Morgan-Klein, ‘The Importance of Social Support Structures for Retention and Success’, in Tamsin Hinton- Smith (ed.), Widening Participation in Higher Education: Casting the net wide? London: Palgrave, 2012, pp. 178-92

The model single-stranded DNA binding protein of bacteriophage T4, gene 32 protein (gp32) has well-established roles in DNA replication, recombination, and repair. gp32 is a single-chain polypeptide consisting of three domains. Based on thermodynamics and kinetics measurements, we have proposed that gp32 can undergo a conformational change where the acidic C-terminal domain binds internally to or near the single-stranded (ss) DNA binding surface in the core (central) domain, blocking ssDNA interaction. To test this model, we have employed a variety of experimental approaches and gp32 variants to characterize this conformational change. Utilizing stopped-flow methods, the association kinetics of wild type and truncated forms of gp32 with ssDNA were measured. When the C-domain is present, the log-log plot of k vs. [NaCl] shows a positive slope, whereas when it is absent (*I protein), there is little rate change with salt concentration, as expected for this model.A gp32 variant lacking residues 292–296 within the C-domain, ΔPR201, displays kinetic properties intermediate between gp32 and *I. The single molecule force-induced DNA helix-destabilizing activitiesas well as the single- and double-stranded DNA affinities of ΔPR201 and gp32 truncated at residue 295 also fall between full-length protein and *I. Finally, chemical cross-linking of recombinant C-domain and gp32 lacking both N- and C-terminal domains is inhibited by increasing concentrations of a short single-stranded oligonucleotide, and the salt dependence of cross-linking mirrors that expected for the model. Taken together, these results provide the first evidence in support of this model that have been obtained through structural probes.

The role of the C-domain of bacteriophage T4 gene 32 protein in ssDNA binding and dsDNA helix-destabilization: Kinetic, single-molecule, and cross-linking studies

Binding of C-terminal domain to the core domain of T4 gene 32 protein: Competition with single-stranded DNA

Using fluorophore-labeled oligonucleotides to measure affinities of protein-DNA interactions.

In protein dynamics, allosteric regulation is a mechanism in which chemical interaction at an allosteric site, which is to say a site other than the catalytically active protein site, affects the conformation and subsequent function of the protein. Allosteric control is a fundamental control mechanism in cells, especially with regards to enzymes. We use mechanical forces applied to allosteric sites on proteins to mimic a conformational change typically attributed to chemical reactions. In this way, we control the function of the protein with mechanical forces instead of chemical forces. We have attached a semi-rigid DNA polymer to a kinase protein that performs a simple catalytic reaction. This DNA, which acts as a molecular spring, is attached on opposite sides of the soft protein and exerts an outward force on the protein that results in an “open” and functionally incapacitated conformation. This paper investigates how a DNA-binding agent, ethidium bromide, affects the rigidity of our DNA spring. Previous molecular spring experiments with our DNA-protein chimera recorded inhibition of the protein function by singlestranded (ss) DNA interaction with the protein active site. This inhibitory effect lessens our ability to investigate the relationship between mechanical stress and protein function. This paper also inspects the effect that histones have on removing this functional inhibition. Introduction—Since the advent of Koshland’s induced fit theory (1), understanding the relationship between protein form and function has been of fundamental importance to research scientists. We use mechanical stresses applied to guanylate kinase (GK) to deform the conformation of the protein, which affects its function. We are able to use mechanical stress to deform the geometry of proteins because their physical properties resemble soft condensed matter (2). By controlling the mechanical forces we exert on the protein, and using this method with a protein that performs a relatively simple catalytic reaction, we are able to better understand the complex relationship between form and function, while at the same time developing a method to “probe” molecules using mechanical forces. In the long run, the benefits of being able to, in essence, turn a protein on or off, has numerous applications and is of incalculable biological importance. Allosteric regulation is the regulation of a protein by an effector molecule at an allosteric site—that is, a site other than the catalytically active site. We implement a mechanical analog to traditional allosteric control. Previous experiments that used mechanical forces to change protein conformation and function have shown to be successful (3,4,5). Instead of a natural chemical reaction causing the protein’s conformational change, we use mechanical stress caused by the tension stored in a rigid polymer, in this case double-stranded (ds) DNA. We are able to use the energy stored in this molecular spring because of GK’s geometry. A simplified model of GK structure can be identified as three distinct parts—LID, CORE, and NMP-BD—that move with respect to one another (figure 1); this relative motion characterizes changes in the protein conformation. The three parts form a U-shaped structure with the active site located on the inside of the structure (6). Because GK is a soft macromolecule, it naturally fluctuates between different conformations; the forces we apply simply bias the probability of a particular conformation. We favor the open conformation, attaching the dsDNA to the outside of the protein, on opposite sides of the active site, and the dsDNA acts like a bent spring and exerts an outward force of the GK, which changes the GK’s conformation. This “open” conformation is functionally inactive, contrary to the functionally active “closed” conformation. Because GK has a relatively simple relationship between form and function, we are able to inspect how the application of different mechanical forces affects the conformation of the GK. GK catalyzes the reversible phosphoryl transfer from ATP to GMP, producing ADP and GDP. Activity of GK is associated with large conformational changes, about 1 nm. Substrate binding to the GK results in the conformational changes that move as rigid bodies connected by hinges (6). GMP binding induces a large change that brings the NMP-binding region and LID region closer together. Subsequent ATP binding increases the closure on a smaller scale (6). This is a good example of the induced fit mechanism that was mentioned previously. In previous experiments involving the allosteric mechanical control of GK, it was shown that GMP-binding is not necessary for ATP to bind; however, for the phosphoryl transfer to occur, GMP must certainly be bound (3). In this way, GMP controls the reaction of GK through an induced fit mechanism. Without GMP bound to bring the NMP-binding region and LID region closer together, without GMP changing the conformation of GK, the protein function is nonexistent. We control GK by counteracting the work performed by GMP chemically instigating an induced fit mechanism. As mentioned previously, GMP binding is coupled with a large conformational change that “closes” the U-shaped GK. Similarly, the binding affinity of GMP is drastically reduced when GK is in the open conformation (3). If we are able to control the geometry of GK, which is a soft protein that is structurally deformed by simple thermal agitation (2), and hold the GK in the open configuration, we will be able to directly control the reaction rate enzymatically controlled by the protein. Figure 2: (a) GK in the closed conformation with GMP(green) bound (PDB structure 1EX7). (b) GK in the open conformation (PDB structure 1S4Q) Figure 1: Cartoon of GK structure. The red structures indicate where the outward mechanical forces are applied (Cys mutations). Blue: GMPbinding site. Green: ATP binding site. PDB structure 1S4Q. Image from (3). We use dsDNA to apply mechanical forces to the GK to change its conformation. The dsDNA acts as a molecular spring attached to opposite sides of the GK. Previous experiments with a 60mer dsDNA attached to GK (figure 3) showed two-fold inhibition that resulted from the protein being held in the open configuration by the mechanical force exerted by the DNA. The force exerted by the DNA is calculated by the work required to bend it (7):

F Factor TraI Relaxase Domain bound to F oriT Single-stranded DNA

Inter- and intramolecular determinants of the specificity of single-stranded DNA binding and cleavage by the F factor relaxase.

Transfer of conjugative plasmids between bacteria requires the activity of relaxases or mobilization proteins. These proteins nick the plasmid in a site- and strand-specific manner prior to transfer of the cut strand from donor to recipient. TraI36, the relaxase domain of TraI from plasmid F factor, binds a single-stranded DNA (ssDNA) oligonucleotide containing an F factor sequence with high affinity and sequence specificity. To better understand the energetics of this interaction, we examined the temperature, salt, and pH dependence of TraI36 recognition. Binding is entropically driven below 25 °C and enthalpically driven at higher temperatures. van't Hoff analysis yields an estimated \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \({\Delta}C_{P}^{0}\) \end{document} of binding (–3300 cal mol–1 K–1) that is larger and more negative than that observed for most double-stranded DNA (dsDNA)-binding proteins. Based on analyses of circular dichroism data and the crystal structure of the unliganded protein, we attribute the \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \({\Delta}C_{P}^{0}\) \end{document} to both burial of hydrophobic surface area and coupled folding and binding of the protein. The salt dependence of the binding indicates that several ssDNA phosphates are buried in the complex, and the pH dependence of the binding suggests that some of these ssDNA phosphates form ionic interactions with basic residues of the protein. Although data are available for relatively few sequence-specific ssDNA-binding proteins, sufficient differences exist between TraI36 and other proteins to indicate that, like dsDNA-binding proteins, ssDNA-binding proteins use different motifs and combinations of forces to achieve specific recognition.

Energetics of the Sequence-specific Binding of Single-stranded DNA by the F Factor Relaxase Domain*

Agonistic behaviors of 14 groups of pigtail monkeys were monitored under 2 spatial conditions, normal living space and half that amount of space. Aggression occurred less frequently in the crowded than in the relatively less crowded condition. The results of this study resemble those of some analogous research on human children, and they suggest that nonhuman primate models of crowding stress and aggression may be especially appropriate.

Effects of short‐term crowding on aggression in captive groups of pigtail monkeys (macaca nemestrina)

To assess the influence of provision of “cover” on aggressive behavior in captive nonhuman primate groups, concrete cylinders were introduced into rooms in which six groups of pigtail monkeys resided. Basal incidence of aggression was measured prior to introduction of the cylinders and during their presence in the rooms. Four groups, which underwent little or no change in group composition during the study, exhibited substantially less aggression when cover was available than when it was not. Moderate and extreme changes in group composition occurred in two groups; these changes resulted in slight and dramatic increases in aggression, respectively, at the times when the changes occurred. Subjects frequently used the cylinders to avoid successfully the aggressive attacks of others. Cover of the sort provided by the concrete cylinders resulted in decreased aggression in stable groups but did not prevent aggression in groups which underwent moderate or extreme social change.

Aggression in Captive Pigtail Monkey Groups: Effects of Provision of Cover

15 pregnant female monkeys (Macaca nemestrina) were observed and the frequencies of 14 categories of agonistic behavior were recorded. Predictions of sex of fetus were based on relative frequencies of aggressive and submissive behaviors. Correct predictions were made in 11 of 15 cases (P < .06). The relative aggressiveness of females carrying male fetuses (by contrast with those carrying female fetuses) suggests that the secretion of androgens by male fetuses may masculinize the behavior of the female host.

Agonistic Behavior of Pregnant Female Monkeys (Macaca Nemestrina): Possible Influences of Fetal Gonadal Hormones

Nursing behavior of 56 singleton infant pigtail monkeys (Macaca nemestrina) was monitored. Infants over 1 mo. of age showed strong preferences for one of their mothers' nipples, while few infants less than 1 mo. old did so. The infants which had the lowest birthweights for each sex showed no clear preference even though they were older than 1 mo. A trend toward lateral preference (for the right nipple) was identical for male and female infants. Analysis of the development of preference for nipple may provide useful information for assessing developmental progress.

Nursing Behavior of Infant Pigtail Monkeys (Macaca Nemestrina): Preferences for Nipples

A comparison of two timed-mating strategies for breeding pigtail monkeys. (Macaca nemestrina)

Allele-Selective Knockdown of MYH7 Using Antisense Oligonucleotides

Missense single-nucleotide polymorphisms (mSNPs) in titin are emerging as a main causative factor of heart failure. However, distinguishing between benign and disease-causing mSNPs is a substantial challenge. Here, we research the question of whether a single mSNP in a generic domain of titin can affect heart function as a whole and, if so, how. For this, we studied the mSNP T2850I, seemingly linked to arrhythmogenic right ventricular cardiomyopathy (ARVC). We used structural biology, computational simulations and transgenic muscle in vivo methods to track the effect of the mutation from the molecular to the organismal level. The data show that the T2850I exchange is compatible with the domain three-dimensional fold, but that it strongly destabilizes it. Further, it induces a change in the conformational dynamics of the titin chain that alters its reactivity, causing the formation of aberrant interactions in the sarcomere. Echocardiography of knock-in mice indicated a mild diastolic dysfunction arising from increased myocardial stiffness. In conclusion, our data provide evidence that single mSNPs in titin's I-band can alter overall muscle behaviour. Our suggested mechanisms of disease are the development of non-native sarcomeric interactions and titin instability leading to a reduced I-band compliance. However, understanding the T2850I-induced ARVC pathology mechanistically remains a complex problem and will require a deeper understanding of the sarcomeric context of the titin region affected.

Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I

Exploration of the pathological potential of isolated mSNPs in titin: the cardiomyopathy-linked mutation T2580I

Phosphorylating Titin's Cardiac N2B Element by ERK2 or CaMKIIδ Lowers the Single Molecule and Cardiac Muscle Force.

Determining the Molecular Mechanisms that Link a Titin Mutation to Cardiomyopathy

Background: A mutation found in titin has been linked to arrhythmogenic cardiomyopathy (AC). Results: The mutation increases Ig10 instability and susceptibility to degradation. Conclusion: The mutation compromises the local structure of Ig10 and has a significant effect on Ig10 unfolding dynamics. Significance: Titin is the first sarcomeric protein to be implicated in AC pathology; a novel titin-based disease mechanism is suggested. Titin plays crucial roles in sarcomere organization and cardiac elasticity by acting as an intrasarcomeric molecular spring. A mutation in the tenth Ig-like domain of titin's spring region is associated with arrhythmogenic cardiomyopathy, a disease characterized by ventricular arrhythmias leading to cardiac arrest and sudden death. Titin is the first sarcomeric protein linked to arrhythmogenic cardiomyopathy. To characterize the disease mechanism, we have used atomic force microscopy to directly measure the effects that the disease-linked point mutation (T16I) has on the mechanical and kinetic stability of Ig10 at the single molecule level. The mutation decreases the force needed to unfold Ig10 and increases its rate of unfolding 4-fold. We also found that T16I Ig10 is more prone to degradation, presumably due to compromised local protein structure. Overall, the disease-linked mutation weakens the structural integrity of titin's Ig10 domain and suggests an Ig domain disease mechanism.

Single Molecule Force Spectroscopy on Titin Implicates Immunoglobulin Domain Stability as a Cardiac Disease Mechanism*

Single Molecule Force Spectroscopy on Titin Implicates Immunoglobulin Domain Stability as a Cardiac

Single Molecule Studies of a Titin Mutation Linked to Cardiac Disease

Titin-based tension in the cardiac sarcomere: molecular origin and physiological adaptations.

Background— Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited genetic myocardial disease characterized by fibrofatty replacement of the myocardium and a predisposition to cardiac arrhythmias and sudden death. We evaluated the cardiomyopathy gene titin (TTN) as a candidate ARVC gene because of its proximity to an ARVC locus at position 2q32 and the connection of the titin protein to the transitional junction at intercalated disks. Methods and Results— All 312 titin exons known to be expressed in human cardiac titin and the complete 3′ untranslated region were sequenced in 38 ARVC families. Eight unique TTN variants were detected in 7 families, including a prominent Thr2896Ile mutation that showed complete segregation with the ARVC phenotype in 1 large family. The Thr2896IIe mutation maps within a highly conserved immunoglobulin-like fold (Ig10 domain) located in the spring region of titin. Native gel electrophoresis, nuclear magnetic resonance, intrinsic fluorescence, and proteolysis assays of wild-type and mutant Ig10 domains revealed that the Thr2896IIe exchange reduces the structural stability and increases the propensity for degradation of the Ig10 domain. The phenotype of TTN variant carriers was characterized by a history of sudden death (5 of 7 families), progressive myocardial dysfunction causing death or heart transplantation (8 of 14 cases), frequent conduction disease (11 of 14), and incomplete penetrance (86%). Conclusions— Our data provide evidence that titin mutations can cause ARVC, a finding that further expands the origin of the disease beyond desmosomal proteins. Structural impairment of the titin spring is a likely cause of ARVC and constitutes a novel mechanism underlying myocardial remodeling and sudden cardiac death.

Genetic Variation in Titin in Arrhythmogenic Right Ventricular Cardiomyopathy–Overlap Syndromes

The effects of PKCalpha phosphorylation on the extensibility of titin's PEVK element.

Single Molecule Analysis of PKC Phosphorylation of Titin's PEVK Domain

Rationale: Protein kinase C (PKC) regulates contractility of cardiac muscle cells by phosphorylating thin- and thick- filament–based proteins. Myocardial sarcomeres also contain a third myofilament, titin, and it is unknown whether titin can be phosphorylated by PKC and whether it affects passive tension. Objective: The purpose of this study was to examine the effect of PKC on titin phosphorylation and titin-based passive tension. Methods and Results: Phosphorylation assays with PKC&agr; revealed that titin is phosphorylated in skinned myocardial tissues; this effect is exacerbated by pretreating with protein phosphatase 1. In vitro phosphorylation of recombinant protein representing titin’s spring elements showed that PKC&agr; targets the proline – glutamate – valine – lysine (PEVK) spring element. Furthermore, mass spectrometry in combination with site-directed mutagenesis identified 2 highly conserved sites in the PEVK region that are phosphorylated by PKC&agr; (S11878 and S12022); when these 2 sites are mutated to alanine, phosphorylation is effectively abolished. Mechanical experiments with skinned left ventricular myocardium revealed that PKC&agr; significantly increases titin-based passive tension, an effect that is reversed by protein phosphatase 1. Single molecule force-extension curves show that PKC&agr; decreases the PEVK persistence length (from 1.20 nm to 0.55 nm), without altering the contour length, and using a serially-linked wormlike chain model we show that this increases titin-based passive force with a sarcomere length dependence that is similar to that measured in skinned myocardium after PKC&agr; phosphorylation. Conclusions: PKC phosphorylation of titin is a novel and conserved pathway that links myocardial signaling and myocardial stiffness.

PKC Phosphorylation of Titin’s PEVK Element: A Novel and Conserved Pathway for Modulating Myocardial Stiffness

Polychromatic laser light can reduce speckle noise in many wavefront-sensing and imaging applications. To help quantify the achievable reduction in speckle noise, this study investigates the accuracy of three polychromatic wave-optics models under the specific conditions of an unresolved object. Because existing theory assumes a well-resolved object, laboratory experiments are used to evaluate model accuracy. The three models use Monte-Carlo averaging, depth slicing, and spectral slicing, respectively, to simulate the laser-object interaction. The experiments involve spoiling the temporal coherence of laser light via a fiber-based, electro-optic modulator. After the light scatters off of the rough object, speckle statistics are measured. The Monte-Carlo method is found to be highly inaccurate, while depth-slicing error peaks at 7.8% but is generally much lower in comparison. The spectral-slicing method is the most accurate, always producing results within the error bounds of the experiment.

Polychromatic wave-optics models for image-plane speckle. 2. Unresolved objects.

Polychromatic laser light can reduce speckle contrast in wavefront-sensing and imaging applications that use direct detection schemes. To help quantify the associated reduction in speckle contrast, this study investigates the accuracy and numerical efficiency of three separate wave-optics models that simulate the active illumination of extended objects with polychromatic laser light. The three separate models use spectral slicing, Monte Carlo averaging, and depth slicing, respectively, to simulate the laser-target interaction. The sampling requirements of all three models are discussed. Comparisons to analytical solutions and experimental data are made when possible. In general, the experiments and theory compare favorably with the models.

The fitting of Rigid Gas Permeable contact lenses is a process that is not complete without a final "lens on• evaluation of overall fit. For a great majority of practitioners, this evaluation involves observing fluorescein pooling patterns underneath the contact lens using cobalt blue light. To gain confidence in correctly interpreting these patterns, a great many lens fitting patterns need to be seen. We feel that there is a great need for a simple yet thorough compilation of fluorescein pattern photographs that can be used as a teaching supplement both in classroom and clinic to show how changing lens parameters

The use of fluorescein patterns as a guide in fitting rigid gas permeable contact lenses

Utilization of intranasal ipratropium bromide in the prevention of recurrent croup events: Is it effective?

A global initiative to refine acute inhalation studies through the use of 'evident toxicity' as an endpoint: Towards adoption of the fixed concentration procedure.

Evidence for the involvement of CYP1A2 in the metabolism of bromodichloromethane in rat liver.

OF TOWED BALLUTE INTERACTIONSPeter A. Gnoffo * Brian P. Anderson;p.a.gnoffo @ larc.nasa, gov b.p.anderson @ larc.nasa.govNASA Langley Research Center GWU- JIAFSHampton, VA 23681-0001AbstractA ballute (balloon-parachute) is an inflatable, aerodynamic drag device for application toplanetary entry vehicles. Ballutes may be directly attached to a vehicle, increasing its cross-sectional area upon inflation, or towed behind the vehicle as a semi-independent device that canbe quickly cut free when the requisite change in velocity is achieved. The aerothermodynamicsof spherical and toroidal towed ballutes are considered in the present study. A limiting case ofzero towline length (clamped system) is also considered. A toroidal system can be designed(ignoring influence of the tethers) such that all flow processed by the bow shock of the towingspacecraft passes through the hole in the toroid. For a spherical ballute, towline length is acritical parameter that affects aeroheating on the ballute being towed through the spacecraftwake. In both cases, complex and often unsteady interactions ensue in which the spacecraft andits wake resemble an aero spike situated in front of the ballute. The strength of the interactionsdepends upon system geometry and Reynolds number. We show how interactions may envelopethe base of the towing spacecraft or impinge on the ballute surface with adverse consequences toits thermal protection system. Geometric constraints to minimize or eliminate such adverseinteractions are discussed. The towed, toroidal system and the clamped, spherical system showgreatest potential for a baseline design approach.DLM,11qwrRcRIReNomenclature

In recent years, policymakers have proposed and implemented regulatory changes promoting the deprioritization, decriminalization, or state-level legalization of one or more psychedelic substances, usually referencing data from clinical trials as reasons to support liberalizing drug control policies. As psychedelic policies continue to be drafted, personal possession limits may be considered for inclusion in those regulations. If "allowable amount" limits are to be written into law to set personal possession limits, then such amounts should be more consistently related to psychedelic doses found to be safe and efficacious in clinical trials, existing data on moderate-high doses commonly used in various naturalistic settings, and the few studies that estimate psychedelic dose equivalence based on the intensity of subjective effects. In this commentary, we provide an evidence-informed table of typical moderate-high doses for seven commonly used psychedelic substances. These estimates of comparable moderate-high doses can be used to inform "allowable amount" values for psychedelic substances. When such limits are written into legislation, the adoption of evidence-informed comparable limits akin to those presented here would be an important first step toward ensuring greater parity and consistency in drug policy, relative to limits that have little or no scientific basis.

Commentary: Evidence-Informed Recommendation to Achieve Approximate Parity in the Allowed Number of Doses for Common Psychedelics.

Editor’s Note The Journal of Psychoactive Drugs published a case study reporting reduction of obsessive-compulsive disorder (OCD) symptoms after consumption of psilocybin-containing mushrooms (Lugo-Radillo and CortesLopez 2021). We subsequently received a letter suggesting that psychedelic research has progressed beyond case studies, and recommending that journals focus on publication of clinical trials rather than case reports. I found the both the letter and the reviewer comments thoughtful and informative concerning current issues in psychedelic research, and invited all authors to publish their comments in this section. Joseph Guydish, PhD Editor, Journal of Psychoactive Drugs Letter to the Editor: Prioritize Well-Controlled Randomized Trials in Psychedelic Medicine I read with interest the case report entitled “Longterm Amelioration of OCD Symptoms in a Patient with Chronic Consumption of Psilocybin containing Mushrooms,” published in Journal of Psychoactive Drugs (Lugo-Radillo and Cortes-Lopez 2021). While the topic is relevant and provides insights, this study underscores the need for well-controlled clinical trials when evaluating the potential therapeutic efficacy of psychedelics such as psilocybin and lysergic acid diethylamide (LSD). Psychedelic medicine is undergoing a renaissance, after many decades of limited research as a consequence of political forces. Despite being generally considered physically safe and non-addictive, these psychoactive substances significantly alter cognitive, mood, and perceptual processes (Nichols 2016). In this past decade, emerging clinical research has revealed positive effects of psychedelic-assisted psychotherapy on anxiety, addictive and depressive symptoms. Most noteworthy, London’s Center for Psychedelic Research demonstrated antidepressant effects of psilocybin equal to escitalopram in phase 2, double-blind, randomized controlled trial. Positive treatment outcomes favored psilocybin involving these patients with major depressive disorder (Carhart-Harris et al. 2021). What the psychedelic community needs are welldesigned clinical trials, not more case reports. James Allen Wilcox reported in this journal’s 2014 issue that psilocybin relieved core symptoms of OCD in one patient, but there was a future “need for further, legitimate research into the value of psilocybin in the treatment of anxiety disorders” (Wilcox 2014). That time for legitimate research is now, as jurisdictions loosen laws and there are 176 “recruiting and not yet recruiting studies” registered on ClinicalTrials.gov (2021). This plethora of ongoing psychedelic-based interventions is in stark contrast to other previously published cases (Leonard and Rapoport 1987; Moreno and Delgado 1997; Wilcox 2014), when funding and ethical approvals were hard to come by for researchers. The medical community does not need more cases reporting preventative or therapeutic interventions in small sample sizes, e.g. n = 1, as these require stronger evidence. Lugo-Radillo & Cortes-Lopez detailed a patient “who reported a significant decrease in his OCD symptoms after the consumption of psilocybincontaining mushrooms” (2021). This positive case may act as a guide for vulnerable patients wishing to re-create this outcome, and the variant and source of mushrooms are even identified here. The inclusion of such information may exert more harm than good, as the field awaits news of trustworthy and possible guideline-changing clinical trial data. Psilocybin has been once safely used in patients with OCD in a clinically controlled environment (Moreno et al. 2006), but nothing can be inferred to non-clinically controlled environments. Meanwhile, it is widely known

Comment and Response: (Lugo-Radillo & Cortez-Lopez, 2020) Long-Term Amelioration of OCD Symptoms in a Patient with Chronic Consumption of Psilocybin-Containing Mushrooms

If the doors of perception were cleansed, would chronic pain be relieved? Evaluating the benefits and risks of psychedelics.

Special considerations for evaluating psilocybin-facilitated psychotherapy in vulnerable populations

Policy considerations that support equitable access to responsible, accountable, safe, and ethical uses of psychedelic medicines

The primary objective of this qualitative study was to explore the therapeutic trajectories of individuals undergoing psilocybin-assisted group therapy. This interpretive phenomenological analysis ...

Participant Reports of Mindfulness, Posttraumatic Growth, and Social Connectedness in Psilocybin-Assisted Group Therapy: An Interpretive Phenomenological Analysis

The Potential of Psychedelics for End of Life and Palliative Care.

Attachment insecurity is determined early in life, is a risk factor for psychopathology, and can be measured on two separate continuous dimensions: attachment anxiety and attachment avoidance. Therapeutic changes toward more secure attachment correlate with reduction in psychiatric symptoms. Psilocybin-assisted psychotherapy has demonstrated promise in the treatment of psychopathology, such as treatment-resistant depression and substance use disorders. We hypothesized that psilocybin-assisted psychotherapy would reduce attachment anxiety and attachment avoidance, thus increasing attachment security. We also hypothesized that baseline measures of attachment insecurity, which can reflect a diminished capacity for trust and exploration, would inform the quality of the psilocybin session. Participants were male long-term AIDS survivors with moderate-severe demoralization (n = 18). Using the Experiences in Close Relationships scale, we measured attachment insecurity at baseline as well as immediately, and 3 months, after completion of a brief group therapy course, which included a single midtreatment open-label psilocybin session conducted individually. Clinically important aspects of the psilocybin session were assessed using the revised Mystical Experience Questionnaire and the Challenging Experience Questionnaire the day following psilocybin administration. Self-reported ratings of attachment anxiety decreased significantly from baseline to 3-months post-intervention, t(16) = -2.2; p = 0.045; d rm = 0.45; 95% CI 0.01, 0.87. Attachment avoidance did not change significantly. Baseline attachment anxiety was strongly correlated with psilocybin-occasioned mystical-type experiences, r(15) = 0.53, p = 0.029, and baseline attachment avoidance was strongly correlated with psilocybin-related challenging experiences, r(16) = 0.62, p = 0.006. These findings have important implications for the general treatment of psychopathology as well as optimizing psilocybin-assisted psychotherapy as a broadly applicable treatment modality.

Psilocybin-Assisted Group Therapy and Attachment: Observed Reduction in Attachment Anxiety and Influences of Attachment Insecurity on the Psilocybin Experience.

TPS778Background: Demoralization is a maladaptive coping response to stressful situations characterized by thoughts of hopelessness, helplessness, and loss of meaning and purpose. Psychometrically,...

Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study

T137. Psilocybin-Assisted Group Therapy for Demoralization in Long-Term AIDS Survivors

ABSTRACT Contemporary research with classic psychedelic drugs (e.g., lysergic acid diethylamide (LSD) and psilocybin) is indebted to the twentieth-century researchers and clinicians who generated valuable clinical knowledge of these substances through experimentation. Several recent reviews that highlight the contributions of this early literature have focused on psychedelic-assisted individual psychotherapy modalities. None have attempted to systematically identify and compile experimental studies of psychedelic-assisted group therapy. In therapeutic settings, psychedelics were often used to enhance group therapy for a variety of populations and clinical indications. We report on the results of a systematic review of the published literature in English and Spanish on psychedelic-assisted group therapies. Publications are characterized by their clinical approach, experimental method, and clinical outcomes. Given the renewed interest in the clinical use of psychedelic medicines, this review aims to stimulate hypotheses to be tested in future research on psychedelic-assisted psychotherapy, group process, and interpersonal functioning.

Informal, coercive residential centers for the treatment of addiction are widespread and growing throughout Latin America. In Mexico these centers are called “anexos” and they are run and utilized by low-income individuals and families with problems related to drugs and alcohol. This article draws on findings from a 3-year anthropological study of anexos in Mexico City. Participant observation and in-depth interviews were used to describe and analyze anexos, their therapeutic practices, and residents’ own accounts of addiction and recovery. Our findings indicate that poverty, addiction, and drug-related violence have fueled the proliferation of anexos. They also suggest that anexos offer valuable health, social, and practical support, but risk exacerbating the suffering of residents through coercive rehabilitation techniques. Emphasizing this tension, this article considers the complex relationship between coercion and care, and poses fundamental questions about what drug recovery consists of in settings of poverty and violence.

Violence, addiction, recovery: An anthropological study of Mexico’s anexos

Summary A previously unknown Spanish-language mutual aid resource for substance use and mental health concerns is available in Latino communities across the USA and much of Latin America. This kind of ‘4th and 5th step’ group is a ‘culturally adapted’ version of the 12-step programme and provides empirical grounds on which to re-theorise the importance of spirituality and culture in mutual aid recovery groups. This article presents ethnographic data on this organisation.

‘Spirituality’ and ‘cultural adaptation’ in a Latino mutual aid group for substance misuse and mental health

This article reports results from a preliminary ethnographic study of a new and largely unknown self-help organization for Latinos with substance use disorders, known as “4th and 5th Step Group” (in Spanish, Grupo de Cuarto y Quinto Paso, “CQ”). It describes the nature of CQ, aspects of group membership, and members' experiences of the organization. Although findings are preliminary, they provide critical information on a potentially important therapeutic resource. More rigorous research with larger and more diverse samples of Latinos participating in CQ is warranted.

Fourth and Fifth Step Groups: A New and Growing Self-Help Organization for Underserved Latinos with Substance Use Disorders

Healing with Yagé: An Interview with Taita Juan Bautista Agreda Chindoy

12. Efectos de la afiliación al Santo Daime sobre la dependencia a sustancias

There is a growing interest among scientists and the lay public alike in using the South American psychedelic brew, ayahuasca, to treat psychiatric disorders like depression and anxiety. Such a practice is controversial due to a style of reasoning within conventional psychiatry that sees psychedelic-induced modified states of consciousness as pathological. This article analyzes the academic literature on ayahuasca's psychological effects to determine how this style of reasoning is shaping formal scientific discourse on ayahuasca's therapeutic potential as a treatment for depression and anxiety. Findings from these publications suggest that different kinds of experiments are differentially affected by this style of reasoning but can nonetheless indicate some potential therapeutic utility of the ayahuasca-induced modified state of consciousness. The article concludes by suggesting ways in which conventional psychiatry's dominant style of reasoning about psychedelic modified states of consciousness could be reconsidered.

Ayahuasca as Antidepressant? Psychedelics and Styles of Reasoning in Psychiatry

Ritual Ayahuasca use and health: an interview with Jacques Mabit

Venous thromboembolism (VTE) is a major cause of morbidity and mortality for surgical patients. This article aims to determine factors that may have contributed to the development of VTE in patients undergoing lateral skull base surgery, to assess the validity of the Caprini Risk Assessment Model (RAM) score in this subset of patients, and to determine the efficacy of mechanical DVT prophylaxis alone in preventing VTE.

Rate of Development of Venous Thromboembolism in Lateral Skull Base Surgery

The NASA Orion Capsule Parachute Assembly System (CPAS) development and qualification testing was completed in September 2018. Over the course of the airdrop and ground testing campaign, the team benefited from the ability to design, test, and adjust the design based on observations and inspection results. While the design team used the best knowledge available and attempted to utilize best practices, a number of lessons were learned that should be documented for consideration by future designers. This paper describes these lessons learned including the use of textile reefing loops, the importance of performing joint tests, the impact of using bight sleeves on parachute deployment, and a surprising number of design changes required in the CPAS system after the decision was made to change the suspension line braid to save system mass.

Textile Material Lessons Learned During the Design and Qualification of the NASA Orion Capsule Parachute Assembly System

A two-week test campaign was conducted in the National Full-Scale Aerodynamics Complex 80 x 120-ft Wind Tunnel in support of Orion parachute pendulum mitigation activities. The test gathered static aerodynamic data using an instrumented, 3-tether system attached to the parachute vent in combination with an instrumented parachute riser. Dynamic data was also gathered by releasing the tether system and measuring canopy performance using photogrammetry. Several canopy configurations were tested and compared against the current Orion parachute design to understand changes in drag performance and aerodynamic stability. These configurations included canopies with varying levels and locations of geometric porosity as well as sails with increased levels of fullness. In total, 37 runs were completed for a total of 392 data points. Immediately after the end of the testing campaign a down-select decision was made based on preliminary data to support follow-on sub-scale air drop testing. A summary of a more rigorous analysis of the test data is also presented.

Sub-Scale Orion Parachute Test Results from the National Full-Scale Aerodynamics Complex 80- By 120-ft Wind Tunnel

Orion Multi-Purpose Crew Vehicle Solving and Mitigating the Two Main Parachute Pendulum Problem

Steel cable was chosen for the lower end of the drogue and main parachute risers on NASA's Orion Multi Purpose Crew Vehicle Parachute Assembly System (CPAS) to protect the risers from extreme temperatures and abrasion should they contact the crew module during deployment, as was done for Apollo. Due to the weight and deployment complexity inherent in steel, there was significant interest in the possibility of substituting textile for steel for the drogue and main parachute risers. However, textile risers could be damaged when subjected to high temperature and abrasion. Investigations were consequently performed by a subset of the authors to determine whether sacrificial, non-load-bearing textile riser covers could be developed to mitigate the thermal and abrasion concerns. Multiple material combinations were tested, resulting in a cover design capable of protecting the riser against severe riser/crew module contact interactions. A feasibility study was then conducted to evaluate the performance of the textile drogue riser cover in relevant abrasive environments. This paper describes the testing performed and documents the results of this feasibility study.

In support of the Boundary Layer Transition (BLT) Flight Experiment (FE) Project in which a manufactured protuberance tile was installed on the port wing of Space Shuttle Orbiter Discovery for STS-119, STS- 128, STS-131 and STS-133 as well as Space Shuttle Orbiter Endeavour for STS-134, a significant ground test campaign was completed. The primary goals of the test campaign were to provide ground test data to support the planning and safety certification efforts required to fly the flight experiment as well as validation for the collected flight data. These test included Arcjet testing of the tile protuberance, aerothermal testing to determine the boundary layer transition behavior and resultant surface heating and planar laser induced fluorescence (PLIF) testing in order to gain a better understanding of the flow field characteristics associated with the flight experiment. This paper provides an overview of the BLT FE Project ground testing. High-level overviews of the facilities, models, test techniques and data are presented, along with a summary of the insights gained from each test.

Space Shuttle Boundary Layer Transition Flight Experiment Ground Testing Overview

Deceleration of the Orion spacecraft following reentry is a process that demands precise timing and high confidence in the materials used. Among the most critical material parameters is the strength of the parachute risers. These risers can become damaged during deployment through contact with various edges and objects on the surface of the capsule. Previous investigations determined that, after the Forward Bay Cover (FBC) is jettisoned, the FBC Parachute (FBCP) riser will likely contact the FBC thermal tiles for several seconds. Most contact scenarios involve relative motion between the riser and tile, resulting in abrasive contact. An investigation was conducted to determine the effect of this abrasive contact on the strength of the riser and what, if any, protective materials and protection approaches would be required to reduce or eliminate the damage. The riser and tile test articles were designed to closely represent the current design of flight hardware. Testing consisted of subjecting the test articles to conditions approximating the worst-case abrasive contact experienced after jettison of the FBC. This paper describes the tests performed and documents the results of this investigation.

Evaluation of Abrasive Contact between Forward Bay Cover Textile Parachute Risers and Thermal Tiles

Hypersonic entry flight testing motivated by efforts seeking to characterize boundary layer transition on the Space Shuttle Orbiters have identified challenges in our ability to acquire high quality quantitative surface temperature measurements versus time. Five missions near the end of the Space Shuttle Program implemented a tile surface protuberance as a boundary layer trip together with tile surface thermocouples to capture temperature measurements during entry. Similar engineering implementations of these measurements on Discovery and Endeavor demonstrated unexpected measurement voltage response during the high heating portion of the entry trajectory. An assessment has been performed to characterize possible causes of the issues experienced during STS-119, STS-128, STS-131, STS-133 and STS-134 as well as similar issues encountered during other orbiter entries.

Tile Surface Thermocouple Measurement Challenges from the Orbiter Boundary Layer Transition Flight Experiment

Statistical BGK and Direct Simulation Monte Carlo (DSMC) flow simulations coupled with the material thermal response solution were performed to estimate the micro-crack growth in an AVCOAT coated heat shield of an Earth atmospheric re-entry vehicle. The after shock inlet boundary conditions for the localized BGK crack flow studies were obtained from large scale DSMC solutions of the re-entry flow over a vehicle at different altitudes along a projected Crew Exploration Vehicle (CEV) trajectory. The maximum material loss due to oxidation of the micro crack walls was observed at the initial portion of the vehicle trajectory where the pyrolysis processes are not yet fully developed. The shock layer produced active radicals, atomic oxygen and nitrogen, are able to reach the crack walls causing reactions at the flow-surface interface that lead to wall recession. The presented results draw conclusion regarding the vulnerability of AVCOAT charing ablator to the growth of the micro cracks that could occur because of gas-surface chemistry.

The newly developed reinforced-carbon―carbon damage assessment model is applied to a micrometeoroid crack at the stagnation point of a sphere for a space shuttle reentry trajectory. The model, which has been validated against arcjet tests (Titov, E., Zhong, J., Levin, D., and Picetti, D., "Simulation of Carbon―Carbon Crack Growth due to Carbon Oxidation in High Temperatures," Journal of Thermophysics and Heat Transfer, Vol. 23, No. 3, July― Sept. 2009, pp. 489―501.) (Titov, E., Levin, D., Picetti, D., and Anderson, B. P., "Thermal Protection System Crack Growth Simulation Using Advanced Grid Morphing Techniques," Journal of Thermophysics and Heat Transfer, Vol. 24, No. 4, 2010, pp. 708―720.), predicts the microhole wall material response to the high-energy, atomic oxygen rich flow to simulate a micrometeoroid impact of the space shuttle nose cap shield during the STS-5 mission reentry. The extent of the crack damage site hole diameter was found to grow by a factor of 2.7, which agrees within about 30% of the NASA Johnson Space Center reinforced-carbon―carbon damage growth tool, version 2, a semi-empirical approach developed through extensive arcjet testing.

Simulation of the Stagnation Region Microcrack Growth During Space Shuttle Reentry

CFD analyses were performed to estimate the ability of compression pads in a fore-body heat shield thermal protection system (TPS) to survive the high speed reentry heat loads. These analyses are necessary to estimate the heat load acting on the structural elements of the compression pads, such as the ones comprised of the metal alloy Inconel. The analyses included boundary conditions that took into account chemical processes occurring at the vehicle AVCOAT TPS surface. In particular oxidation of the TPS surface was modeled and the influence of the gases released from the TPS due to in-depth pyrolysis processes was considered.

Simulation of Heat Loads on the CEV Orion Compression Pads During Reentry

Development and Application of a Charring Ablator Thermal Response Model

In support of the Boundary Layer Transition Flight Experiment (BLT FE) Project, a manufactured protuberance tile was installed on the port wing of Space Shuttle Orbiter Discovery for STS-119, STS-128, STS-131 and STS-133 as well as Space Shuttle Endeavour for STS-134. Additional instrumentation was installed in order to obtain more spatially resolved measurements downstream of the protuberance. This paper provides an overview of the BLT FE Project with emphasis on the STS-131 and STS-133 results. A high-level overview of the in-situ flight data is presented, along with a summary of the comparisons between pre- and post-flight analysis predictions and flight data. Comparisons show that empirically correlated predictions for boundary layer transition onset time closely match the flight data, while predicted surface temperatures were significantly higher than observed flight temperatures. A thermocouple anomaly observed on a number of the missions is discussed as are a number of the mitigation actions that will be taken on the final flight, STS-134, including potential alterations of the flight trajectory and changes to the flight instrumentation.

In an experimental study to obtain detailed heating data over the Space Shuttle Orbiter, CUBRC has completed an extensive matrix of experiments using three distinct models and two unique hypervelocity wind tunnel facilities. This detailed data will be employed to assess heating augmentation due to boundary layer transition on the Orbiter wing leading edge and wind side acreage with comparisons to computational methods and flight data obtained during the Orbiter Entry Boundary Layer Flight Experiment 1 and HYTHIRM 2 during STS-119, -128, -131, -133, and -134 re-entries. These comparisons will facilitate critical updates to the engineering tools employed to make assessments about natural and tripped boundary layer transition during Orbiter re-entry and to guide the design of future re-entry configurations. To achieve the goals of this study data was obtained over a range of Mach numbers from 10 to 18, with flight scaled Reynolds numbers and model attitudes representing key points on the Orbiter re-entry trajectory. The first of these studies were performed as an integral part of Return to Flight activities following the accident that occurred during the re-entry of the Space Shuttle Columbia (STS-107) in February of 2003 3 . This accident was caused by debris, which originated from the foam covering the external tank bipod fitting ramps, striking and damaging critical wing leading edge thermal protection panels that reside in the Orbiter bow shock/wing interaction region. During investigation of the accident aeroheating team members discovered that only a limited amount of experimental wing leading edge data existed in this critical peak heating area and a need arose to acquire a detailed dataset of heating in this region. This new dataset was acquired in two phases consisting of a risk mitigation phase employing a 1.8% scale Orbiter model with special temperature sensitive paint covering the wing leading edge and the primary 1.8% scale Orbiter model with detailed thin- film resolution in both the span and chord direction in the area of peak heating. Additional objectives of this first study included: obtaining natural or tripped turbulent wing leading edge heating levels, assessing the effectiveness of protuberances and cavities placed at specified locations on the orbiter over a range of Mach numbers and Reynolds numbers to evaluate and compare to existing engineering and computational tools, obtaining cavity floor heating to aid in the verification of cavity heating correlations, acquiring control surface deflection heating data on both the main body flap and elevons, and obtain high speed schlieren videos of the interaction of the orbiter nose bow shock with the wing leading edge. To support these objectives, the stainless steel 1.8% scale orbiter model in addition to the sensors on the wing leading edge was instrumented down the windward centerline, over the wing acreage on the port side, and painted with

Experimental Studies of Space Shuttle Orbiter Boundary Layer Transition with Flight Representative Protuberances

In support of the Boundary Layer Transition Flight Experiment (BLT FE) Project, a manufactured protuberance tile was installed on the port wing of Space Shuttle Orbiter Discovery for the flight of STS-119. Additional instrumentation was also installed in order to obtain more spatially resolved measurements. This paper will provide an overview of the BLT FE Project, including the project history, organizations involved, and motivations for the flight experiment. Significant efforts were made to place the protuberance at an appropriate location on the Orbiter and to design the protuberance to withstand the expected environments. Efforts were also extended to understand the as-fabricated shape of the protuberance and the thermal protection system tile configuration surrounding the protuberance. A high level overview of the in-situ flight data will be presented, along with a summary of the comparisons between pre- and post-flight analysis predictions and flight data.

In support of the Boundary Layer Transition Flight Experiment (BLTFE) Project, a manufactured protuberance tile was installed on the port wing of Space Shuttle Orbiter Discovery for the flights of STS-119 and STS-128. Additional instrumentation was also installed in order to obtain more spatially resolved measurements downstream of the protuberance. This paper provides an overview of the BLTFE Project, including the project history, organizations involved, and motivations for the flight experiment. Significant efforts were made to place the protuberance at an appropriate location on the Orbiter and to design the protuberance to withstand the expected environments. Efforts were also extended to understand the as-fabricated shape of the protuberance and the thermal protection system tile configuration surrounding the protuberance. A high-level overview of the in-situ flight data is presented, along with a summary of the comparisons between pre- and post-flight analysis predictions and flight data. Comparisons show that predictions for boundary layer transition onset time closely match the flight data, while predicted temperatures were significantly higher than observed flight temperatures.

Boundary Layer Transition Flight Experiment Overview and In-Situ Measurements

Statistical BGK simulations coupled with the material response solution were performed to estimate the micro-crack growth in an arcjet AVCOAT coated specimen representing the Crew Exploration Vehicle thermal protection system. The after shock inlet boundary conditions for the BGK studies were obtained from a CFD (DPLR) solution of the arcjet flow. The solution of the arcjet case is followed by a 81 km CEV flow-material response study which represents a point along a CEV re-entry trajectory. Rarefied flow conditions at 81 km prompted using the baseline DSMC technique to solve the shock wave layer flow providing data for the inlet boundary conditions for the local crack-material response studies. The results draw a preliminary conclusion regarding the effectiveness of the AVCOAT protective mechanisms against the growth of the micro cracks during the Earth atmosphere re-entry of the vehicle.

Updates to an analytic tool developed for Shuttle support to predict the onset of boundary layer transition resulting from thermal protection system damage or repair are presented. The boundary layer transition tool is part of a suite of tools that analyze the local aerothermodynamic environment to enable informed disposition of damage for making recommendations to fly as is or to repair. Using mission specific trajectory information and details of each d agmea site or repair, the expected time (and thus Mach number) of transition onset is predicted to help define proper environments for use in subsequent thermal and stress analysis of the thermal protection system and structure. The boundary layer transition criteria utilized within the tool were updated based on new local boundary layer properties obtained from high fidelity computational solutions. Also, new ground-based measurements were obtained to allow for a wider parametric variation with both protuberances and cavities and then the resulting correlations were calibrated against updated flight data. The end result is to provide correlations that allow increased confidence with the resulting transition predictions. Recently, a new approach was adopted to remove conservatism in terms of sustained turbulence along the wing leading edge. Finally, some of the newer flight data are also discussed in terms of how these results reflect back on the updated correlations.

An extension of previous [Titov, E., Zhong, J., Levin, D., and Picetti, D., "Simulation of RCC Crack Growth Due to Carbon Oxidation in High-Temperature Gas Environments," Journal of Thermophysics and Heat Transfer, Vol. 23, No. 3, July-Sept. 2009, pp. 489-501.] modeling of crack damage growth in reinforced carbon-carbon specimens is presented in this work. The specimens were studied in an arcjet and represented a portion of the space shuttle wing [Lewis, R., "Quick Look Report," Atmospheric Reentry Materials and Structures, 2004.] and a high-velocity meteoroid impact [Curry, D. M., Pham, V. T., Norman, I., and Chao, D. C., "Oxidation of Reinforced Carbon-Carbon Subjected to Hypervelocity Impact," NASA TP 2000-209760, March 2000.]. The test geometry and flow conditions rendered the flow regime as transitional to continuum; therefore, a Navier-Stokes-based gas-dynamic approach with the temperature jump and velocity slip correction to the boundary conditions was used. The modeled mechanism for wall material loss was atomic oxygen reaction with the bare, exposed carbon surface. The purpose of this work is to improve the predictive modeling of crack growth damage assessment by developing procedures that use coupled, advanced topology-based surface and grid-meshing tools. A recessing three-dimensional surface morphing procedure was developed and tested by comparison with arcjet experimental results. A multiblock structured adaptive meshing was used to model the computational domain changes due to the wall recession. This approach made it possible to model full three-dimensional crack growth scenarios as well as to include the presence of realistic reinforced carbon-carbon material features such as delamination, both of which affect damage growth because they enable higher atomic oxygen penetration. Comparison with the arcjet data show that the inclusion of these two factors further improves the comparison between modeling and data. The predicted channel growth and shape change were found to agree with arcjet observations, and local gas flowfield results were found to affect the oxidation rate in a manner that cannot be predicted by previous mass loss correlations. The method holds promise for future modeling of materials gas-dynamic interactions for hypersonic flight.

Thermal Protection System Crack Growth Simulation Using Advanced Grid Morphing Techniques

A thermal math model for the Space Shuttle Reinforced Carbon-Carbon (RCC) Plug Repair was developed to increase the confidence in the repair entry performance and provide a real-time mission support tool. The thermal response of the plug cover plate, local RCC, and metallic attach hardware can be assessed with this model for any location on the wing leading edge. The geometry and spatial location of the thermal mesh also matches the structural mesh which allows for the direct mapping of temperature loads and computation of the thermoelastic stresses. The thermal model was correlated to a full scale plug repair radiant test. To utilize the thermal model for flight analyses, accurate predictions of protuberance heating were required. Wind tunnel testing was performed at CUBRC to characterize the heat flux in both the radial and angular directions. Due to the complexity of the implementation of the protuberance heating, an intermediate program was developed to output the heating per nodal location for all OML surfaces in SINDA format. Three Design Reference Cases (DRC) were evaluated with the correlated plug thermal math model to bound the environments which the plug repair would potentially be used.

Simulation of TPS crack growth due to carbon oxidation using advanced grid morphing techniques

The Hypersonic Thermodynamic Infrared Measurement (HYTHIRM) project is presently focused on near term support to the Shuttle program through the development of an infrared imaging capability of sufficient spatial and temporal resolution to augment existing on-board Orbiter instrumentation. Significant progress has been made with the identification and inventory of relevant existing optical imaging assets and the development, maturation, and validation of simulation and modeling tools for assessment and mission planning purposes, which were intended to lead to the best strategies and assets for successful acquisition of quantitative global surface temperature data on the Shuttle during entry. However, there are longer-term goals of providing global infrared imaging support to other flight projects as well. A status of HYTHIRM from the perspective of how two NASA-sponsored boundary layer transition flight experiments could benefit by infrared measurements is provided. Those two flight projects are the Hypersonic Boundary layer Transition (HyBoLT) flight experiment and the Shuttle Boundary Layer Transition Flight Experiment (BLT FE), which are both intended for reducing uncertainties associated with the extrapolation of wind tunnel derived transition correlations for flight application. Thus, the criticality of obtaining high quality flight data along with the impact it would provide to the Shuttle program damage assessment process are discussed. Two recent wind tunnel efforts that were intended as risk mitigation in terms of quantifying the transition process and resulting turbulent wedge locations are briefly reviewed. Progress is being made towards finalizing an imaging strategy in support of the Shuttle BLT FE, however there are no plans currently to image HyBoLT.

Infrared Imaging of Boundary Layer Transition Flight Experiments

The BLT Prediction Tool ("BLT" signifies "Boundary Layer Transition") is provided as part of the Damage Assessment Team analysis package, which is utilized for analyzing local aerothermodynamics environments of damaged or repaired space-shuttle thermal protection tiles. Such analyses are helpful in deciding whether to repair launch-induced damage before re-entering the terrestrial atmosphere.

The Columbia accident on February 1, 2003 began an unprecedented level of effort within the hypersonic aerothermodynamic community to support the Space Shuttle Program. During the approximately six month time frame of the primary Columbia Accident Investigation Board activity, many technical disciplines were involved in a concerted effort to reconstruct the last moments of the Columbia and her crew, and understand the critical events that led to that loss. Significant contributions to the CAIB activity were made by the hypersonic aerothermodynamic community(REF CAIB) in understanding the re-entry environments that led to the propagation of an ascent foam induced wing leading edge damage to a subsequent breech of the wing spar of Columbia, and the subsequent breakup of the vehicle. A core of the NASA hypersonic aerothermodynamics team that was involved in the CAIB investigation has been combined with the United Space Alliance and Boeing Orbiter engineering team in order to position the Space Shuttle Program with a process to perform in-flight Thermal Protection System damage assessments. This damage assessment process is now part of the baselined plan for Shuttle support, and is a direct out-growth of the Columbia accident and NASAs response. Multiple re-entry aeroheating tools are involved in this damage assessment process, many of which have been developed during the Return To Flight activity. In addition, because these aeroheating tools are part of an overall damage assessment process that also involves the thermal and stress analyses community, in addition to a much broader mission support team, an integrated process for performing the damage assessment activities has been developed by the Space Shuttle Program and the Orbiter engineering community. Several subsets of activity in the Orbiter aeroheating communities support to the Return To Flight effort have been described in previous publications (CFD?, Cavity Heating? Any BLT? Grid Generation?). This work will provide a description of the integrated process utilized to perform Orbiter tile damage assessment, and in particular will seek to provide a description of the integrated aeroheating tools utilized to perform these assessments. Individual aeroheating tools will be described which provide the nominal re-entry heating environment characterization for the Orbiter, the heating environments for tile damage, heating effects due to exposed Thermal Protection System substrates, the application of Computational Fluid Dynamics for the description of tile cavity heating, and boundary layer transition prediction. This paper is meant to provide an overall view of the integrated aeroheating assessment process for tile damage assessment as one of a sequence of papers on the development of the boundary layer transition prediction capability in support of Space Shuttle Return To Flight efforts.

Shuttle Orbiter Fuselage Global Temperature Measurements from Infrared Images at Hypersonic Speeds

The magnitude of tropical cooling during the Last Glacial Maximum (LGM; ∼19–26.5 ka) remains controversial, with sea‐surface temperatures cooling by several degrees less than most temperatures reconstructed at high elevations. To explain this discrepancy, past studies proposed a steeper (increased) lapse rate—the temperature decrease with elevation—during the LGM relative to today. For instance, LGM temperatures in East Africa reconstructed from branched GDGTs from multiple elevations support an ∼0.9°C/km increase in the lapse rate during the LGM relative to present day. Lapse rates are a critical part of the Earth's climate sensitivity and atmospheric energy transfer, and it is vital to know whether and by how much the tropical lapse rate steepened during the LGM. Here, we simulate LGM glacier extents in the Rwenzori Mountains of Uganda with and without a change in lapse rate using a range of temperature and precipitation estimates. We find that the lapse rate must have been steeper than present for glaciers to reach their LGM positions using available sea‐level temperature and precipitation estimates for East Africa.

Last Glacial Maximum Reconstructions of Rwenzori Mountain Glaciers

Modelled response of debris-covered and lake-calving glaciers to climate change, Kā Tiritiri o te Moana/Southern Alps, New Zealand

Local summer insolation and greenhouse gas forcing drove warming and glacier retreat in New Zealand during the Holocene

Measuring past glacier fluctuations from historic photographs geolocated using Structure from Motion

ABSTRACT Quantifying historic changes in glacier size and mass balance is important for understanding how the cryosphere responds to climate variability and change. Airborne photogrammetry enables glacier extent and equilibrium line altitudes (ELAs) to be monitored for more glaciers at lower cost than traditional mass-balance programs and other remote-sensing techniques. Since 1977, end-of-summer-snowlines, which are a proxy for annual ELAs, have been recorded for 50 glaciers in the Southern Alps of New Zealand using oblique aerial photographs. In this study, we use structure from motion photogrammetry to estimate the camera parameters, including position, for historic photographs, which we then use to measure glacier change. We apply this method to a small maritime New Zealand glacier (Brewster Glacier, 1670–2400 m a.s.l.) to derive annual ELA and length records between 1981 and 2017, and quantify the uncertainties associated with the method. Our length reconstruction shows largely continuous terminus retreat of 365 ± 12 m for Brewster Glacier since 1981. The ELA record, which compares well with glaciological mass-balance data measured between 2005 and 2015, shows pronounced interannual variability. Mean ELAs range from 1707 ± 6 to 2303 ± 5 m a.s.l., with the highest ELAs occurring in the last decade.

Using structure from motion photogrammetry to measure past glacier changes from historic aerial photographs

Regional cooling caused recent New Zealand glacier advances in a period of global warming

Geological records of mountain glacier fluctuations provide useful evidence for tracing the magnitude and rate of past temperature change. In this study, we present air temperature reconstructions for the last glacial termination in New Zealand derived using snowline reconstructions and numerical glacier modelling. We target the Arthur's Pass moraines in the Otira River catchment, which have previously been dated to the Lateglacial using cosmogenic 10Be. Recalculation of these exposure ages using a locally calibrated 10Be production rate indicates that these moraines formed ca. 16–14 ka. Our glacier modelling experiments and snowline reconstructions exhibit good agreement and show that the Arthur's Pass moraines formed in a climate that was 2.2–3.5 °C colder than present. Combining our results with other, proximal glacier records shows that ice in this catchment retreated ca. 50 km from the coastal plain to the main divide during the interval 17–15 ka, in response to a temperature increase of at least ca. 3 °C. Over half of this retreat occurred after the glacier had withdrawn from an overdeepened basin. Thus, we conclude that temperature increase was the primary driver of widespread and rapid glacier retreat in New Zealand at the onset of the last glacial termination.

Glacier‐based climate reconstructions for the last glacial–interglacial transition: Arthur's Pass, New Zealand (43°S)

ABSTRACT Recognising the scarcity of glacier mass-balance data in the Southern Hemisphere, a mass-balance measurement programme was started at Brewster Glacier in the Southern Alps of New Zealand in 2004. Evolution of the measurement regime over the 11 years of data recorded means there are differences in the spatial density of data obtained. To ensure the temporal integrity of the dataset a new geostatistical approach is developed to calculate mass balance. Spatial co-variance between elevation and snow depth allows a digital elevation model to be used in a co-kriging approach to develop a snow depth index (SDI). By capturing the observed spatial variability in snow depth, the SDI is a more reliable predictor than elevation and is used to adjust each year of measurements consistently despite variability in sampling spatial density. The SDI also resolves the spatial structure of summer balance better than elevation. Co-kriging is used again to spatially interpolate a derived mean summer balance index using SDI as a co-variate, which yields a spatial predictor for summer balance. The average glacier-wide surface winter, summer and annual balances over the period 2005–15 are 2484, −2586 and −102 mm w.e., respectively, with changes in summer balance explaining most of the variability in annual balance.

An 11-year record of mass balance of Brewster Glacier, New Zealand, determined using a geostatistical approach

During the period from November 1995 through October 1996, the Placement Service of the Human Factors and Ergonomics Society distributed announcements describing 195 positions available for human factors engineers and ergonomics professionals. This paper describes placement opportunities for HFE and ergonomics professionals in industry, government/military and consulting positions (N=162), while an overview of all advertised positions, and a description of academic (N=8) and internship positions (N=25) is provided in Part I (Moroney, Proulx & Parker, 1997). The attributes of the position descriptions examined include: degree requirements, major field of study, industrial sector, areas of expertise, required work experience, salary, geographic location, job description and skills required. Fifty-seven percent of the positions describe the masters degree as the minimum requirement, with 18% of the opportunities in the consulting sector. The area of expertise most frequently requested (69%) was HCI, with test and evaluation (specifically usability testing) being specified for 44% of the positions. The most frequently cited (35%) primary area of responsibility was interface design.

Proceedings of the Human Factors and Ergonomics Society Annual Meeting

Placement Opportunities for Human Factors Engineering and Ergonomics Professionals

ABSTRACT Youth with experience in the foster care system are often more susceptible to negative outcomes in adulthood due to higher levels of cumulative risk; however, there is little research on perceptions of resilience among this population. This mixed-method pilot study presents results from a modified prototype analysis that examined both qualitative and quantitative aspects of how emerging adults (ages 18–25; n = 18) with foster care backgrounds viewed the concept of “success.” Specifically, the approach involved a demographic questionnaire, modified prototype analysis, Developmental Assets® assessment, and focus group discussion providing valuable insight into the perceptions and experiences of emerging adults who have spent time in the care of foster families. Results share youth's perspectives of how their foster families contributed to resiliency and successful adult development. Findings indicate that the definition of “success” is complex and subjectively defined based on personal goals and that specific Developmental Assets® are important for foster families to promote youth resilience. This deeper insight into perspectives of former foster youth gained through the modified prototype analysis can guide agencies, advocates, and parents, permitting a more intentional promotion of success, and maximizing opportunities for resiliency.

Defining Success: The Perspective of Emerging Adults with Foster Care Experience

ABSTRACT Faculty scholarship at historically Black colleges and universities (HBCU) has in the past served as a blueprint for the Black masses. Even today, HBCU faculty scholarship continues to be an informative source to communicate accurate information regarding marginalized groups. This study examines h-index scores of 65 faculty members at five doctorate-granting schools of social work. The majority of calculated h-index scores were considered to be low in terms of productivity. We make the argument that these scores are not a good measure of productivity because of the problematic nature of their use to evaluate HBCU faculty. Implications for future research, practice, and teaching are presented.

Scholarly Productivity of Social Work Faculty at Historically Black Colleges and Universities: Are h-Index Scores a Suitable Measure?

ABSTRACT Internship placements located away from capital cities and metropolitan areas may lack opportunities for involvement in high-profile issues but they can uphold standards of “high-impact educational practice” (Kuh 2008). This study of 59 political science interns at the Mississippi University for Women demonstrates that high-impact outcomes may be generated in small-city placements that include administrative tasks if students are encouraged to reflect on their experiences and recommend improvements. Students not only extract information from their experiences for academic assignments, they also appraise the effectiveness of the work unit in attaining its goals and they formulate means by which it may improve procedures and outcomes. The scale of operations in small-city environments broadens the options for this type of analysis: exposure to a wide scope of decision processes and results is preferred to a focus on a specialized task.

High-Impact Political Science Internships in a “Low-Density Opportunity” Environment

The effect of an historical/cultural unit of study on the performance capabilities and knowledge of high school band students

Land subsidence is triggered by groundwater overexploitation in the Alto Guadalentín Basin (Spain) aquifer system. In this work, we propose a new commercial LiDAR differencing flow to detect land subsidence at basin scale, based on the multiscale model-to-model cloud comparison (M3C2) algorithm. This method is applied to two airborne LiDAR datasets acquired in 2009 and 2016, respectively. First the iterative closest point (ICP) algorithm is used for point cloud registration of both point clouds exhibiting a very stable and robust performance. LiDAR datasets capture information from ground and non-ground points. Therefore, a method combining gradient filtering and cloth simulation filtering (CSF) algorithm was applied to remove non-ground points. The internal edge connection errors in the different flight lines were also addressed by means of the smoothing point cloud method. The results show that vertical deformation rates are up to -12 cm/year in the basin from 2009 to 2016, in agreement with the displacement reported in previous studies. LiDAR results have been compared to the velocity measured by continuous GNSS stations and an InSAR dataset. The results show a good agreement between the vertical displacements obtained from the three different surveying techniques. Furthermore, LiDAR results were compared to the distribution of soft soil thickness showing a clear relationship. The study underlines the potential of LiDAR to monitor the distribution and magnitude of vertical deformations in areas prone to be affected by groundwater-withdrawal-induced land subsidence. Tropical climates provide a healthy ecosystem that favors rich biodiversity in atmospheric fauna, particularly insects. The insects play roles such as pollination, predation or as preys, pests, disease vectors, etc. In Ghana, conventional techniques such as sweep nets, pit falls, sticky traps continue to be used to study these insects. These conventional techniques are somewhat destructive, time consuming and laborious. Nowadays, complementary and alternatives to the conventional techniques are been offered by LIDAR techniques which can provide rapid, non-invasive, in-situ and remote measurement. Fortunately, relatively less costly systems for LIDAR operation are been developed and demonstrated by Brydegaard et al., [1, 2]. They (Brydegaard et al) have since 2009 organized regular workshops and training among some countries in Africa (Burkina Faso, Cameron, Cote D’ Ivoire, Ghana, Mali, Senegal, Togo and Kenya). Through this program the Laser and Fibre Optics Centre (LAFOC) in Ghana at the University of Cape Coast has been has been provided with a Fluorescence Lidar for remote studies. The LIDAR is equipped with a Diode laser of 100 mW power and a wavelength of 401 nm. It also has a home-built telescope system which has most of the optical components held by 3D printed parts. The Lidar is arranged in the Scheimpflug configuration providing elastic and fluorescence echo of insects traversing the path of the light within a range of six (6) to hundred (100) meters. The Scheimpflug configuration is very conducive to obtain high resolution, temporal and spatial data from flying insects [2]. Currently, the LIDAR system is being deployed for field studies of some insects, particularly Bees, House The Light imaging Detection And Ranging (LiDAR) system is a range-determining active imaging system [1-3]. An optical system projects a laser beam to enlarge it and aim it toward a subject to be recorded. LiDAR is an essential tool for autonomous driving. Autonomous driving is the future of transportation that uses cutting-edge technologies. It drives the massive potential for the latest application of high-end sophisticated devices and mythology. LiDAR is a powerful emerging autonomous driving technology, showing the direction and highest possible sensing technology. In this work, I am reporting an initial optical design for the LiDAR. This initial optical design aims to determine how the spot size at the target changes when the input laser's source angle to the optics system changes. The difference between the input and output angles after the laser travels through the lenses is also determined. A wavelength of 1550 nm is used, which is widely used for communication systems. laser inch radian divergence, entered into the Field Data LDE, tilt proper The historic forest fire raged in the third week of March 2014 over Seshachala forest range (13.7 o N, 79.35 o E) in the Southeastern India that last for several days devastating rare species of flora and fauna in around two thousand hectares of forest land has been analyzed using the Micro Pulse Lidar (MPL) observations made at S. V. University, Tirupati located at the foot hills of the forest range. Earlier studies [1,2] proved that Lidar observations are excellent tool to monitor the forest fire plumes to the surrounding regions. An intense thin smoke plume has been observed on 18 March at 3 km altitude in the lidar back scatter signal on which wide spread fire was identified. These fire has been extinguished using aerial water showers using choppers on 20 March and again the fire raged on 22 March. About 3.5km deep layer of intense lidar back scatter is noticed on 22 March after which it slowly dissipated till 27 March. In addition, the ground based in-situ observations of aerosol physical and optical properties and the Black Carbon (BC) concentrations measured at nearby station NARL, Gadanki (13.5 o N, 79.2 o E) is combined to investigate the environmental impact of this forest fire. MODIS observed total aerosol extinction and BC mass density show significant enhancement during 22-24 March coinciding with the lidar observations. The back ground wind circulation in the lower troposphere has been analyzed using the high resolution GPS based radiosonde data available at NARL during the fire event to understand the dispersion of the fire smoke. The effect of this fire smoke dispersion on the local environment has been investigated using the WRF-Chem simulations. Laser-induced autofluorescence (LIAF), combined with multivariate techniques, has been used to discriminate a cataractous lens from healthy lens tissues. In this study, 405 nm and 445 nm were used as excitation sources to induce the autofluorescence. Results show higher autofluorescence intensity in cataractous lens tissues than in healthy ones. Cataractous lens tissues show a red shift of 0.9 nm and 1.2 nm at 405 nm and 445 nm excitations, respectively. Using principal component analysis (PCA), three principal components (PCs) gave more than 99% variability for both 405 nm and 445 nm excitation sources. Based on the three PCs, Fisher’s linear discriminant model was developed. An accuracy of 100% was obtained in classifying the lens tissues using Fisher’s linear discriminant analysis (FLDA). The LIAF technique assisted by PCA and FLDA may be used for objective discrimination of cataractous lens from healthy lens tissues of Sprague – Dawley rats Thermal lens spectroscopy (TLS) is based on the energy absorbed by the sample, generating a temperature gradient in the sample and consequently a refractive index gradient that causes defocusing of the probe laser beam passing through a liquid pre- excited medium. We present a theoretical model that describes induced temperature and refractive index profiles generated by the Laguerre – Gaussian (LG) excitation beam. It indicates that there is a decrease or increase around the optical axis in the refractive index by LG modes, thus enabling an enhancement of the refractive index gradient along the radial direction, which could enhance the sensitivity in photothermal lens detection. A comparison with the fundamental Gaussian beam TEM00 indicates that the temperature gradient in the vicinity of the axis can be increased substantially when using higher-order Gaussian modes but only if the steady state condition is reached. However, for LG01 mode (having narrower Full Width Half Maxima), the refractive index gradient is higher than for TEM00 even at lower illumination times [1]. This fact can contribute to generate a high TL signal as well as high sensitivity in measurement. In perspective, this result can be used for further development of a TL model based on non-Gaussian excitation beams such as LG, which can be easily generated using different optical elements. This work is in progress along with the correspondent experimental procedure. Due to the high bandwidth and low energy consumption, polymer optical waveguides have been implemented in various optoelectronic devices and shown their potentials in a short-reach arena with low propagation loss. In this research, we present a directional coupler splitter realized with organic-inorganic hybrid polymer materials (core: NP-005 and Cladding: NP-211 correspond to refractive indices 1.575 and 1.567, respectively at 1550 nm) because of their cost-effective in manufacturing, and easy integration on printed circuit boards (PCBs). We introduce this polymer directional coupler as follows: two waveguides having two input and output straight cores and they are connected to two S-bend segments, and these two S-bend cores are connected to another two straight waveguides in the middle with a separation distance between them. The index profile of this coupler is a graded-index (GI) type, and the core diameter was controlled within 10 µm. We design and analyze this polymer coupler by utilizing the beam propagation method (BPM) at 1550 nm. The power efficiency of this SI directional coupler is approximately 96% at 1550 nm. We also investigate the insertion loss and polarization dependency for practical use. In this work we theoretically study Fraunhofer diffraction of a Laguerre-Gaussian (LG) laser beam with radial mode number n =0 and azimuthal mode number l , by a combination of fork-shaped grating with integer topological charge (TC) p and axicon. The axicon is attached with its bas

Analysis of large-gradient land subsidence in the Alto Guadalentín Basin (Spain) using LiDAR data

Data density has a crucial impact on the accuracy of Digital Elevation Models (DEMs). In this study, DEMs were created from a high point-density LIDAR dataset using the bare earth extraction module in Quick Terrain Modeler. Lower point-density LIDAR collects were simulated by randomly selecting points from the original dataset at a series of decreasing percentages. The DEMs created from the lower resolution datasets are compared to the original DEM. Results show a decrease in DEM accuracy as the resolution of the LIDAR dataset is reduced. Some analysis is made of the types of errors encountered in the lower resolution DEMs. It is also noted that the percentage of points classified as bare earth decreases as the resolution of the LIDAR dataset is reduced.

Effects of lidar point density on bare earth extraction and DEM creation

Abstract : This thesis discusses the production of Digital Elevation Maps (DEM) using varying density of data points from a Lidar (Laser or Light Detection And Ranging) collection. Additionally, this thesis contains information on the multiple space missions that use laser altimetry or Lidar to gather data about planet earth, the moon, asteroids, Mars and Mercury. The thesis covers the accuracy of different amounts of data used when generating a DEM in Quick Terrain Modeler software package and the ILAP Bare Earth Extraction Plug-In and discusses the error analysis when comparing the different DEMs built by randomly selecting 90%, 66%, 50%, 30%, 10%, 5%, 3%, 1%, 0.5%, 0.3%, 0.05%, 0.03% and 0.01% of the data from an airborne Lidar collection from Honduras in 2008. Analyzing surface DEMs created in QTM, the results of the point reduction experiment indicate that a collection cloud point density of 60,000 points per square kilometer are required for an accurate surface DEM in this environment.

Assessing Accuracy in Varying LIDAR Data Point Densities in Digital Elevation Maps

Three Patterns of Spinal Manipulative Therapy for Back Pain and Their Association With Imaging Studies, Injection Procedures, and Surgery: A Cohort Study of Insurance Claims.

Guideline-concordant utilization of magnetic resonance imaging in adults receiving chiropractic manipulative therapy vs other care for radicular low back pain: a retrospective cohort study

The Effect of Reduced Access to Chiropractic Care on Medical Service Use for Spine Conditions Among Older Adults.

Risk of Treatment Escalation in Recipients vs Nonrecipients of Spinal Manipulation for Musculoskeletal Cervical Spine Disorders: An Analysis of Insurance Claims.

The Relationship Between Healthcare Provider Availability and Conservative Versus Non-conservative Treatment for Back Pain Among Older Americans

Chronic pain (that is, pain lasting beyond the usual course of illness or injury, usually longer than 3 to 6 months) is widespread, challenging to treat, and a growing problem (13). Approximately 20% of physician visits and 10% of drug sales are attributed to pain (1, 2). More than 116 million Americans have chronic pain, costing $600 billion annually (1, 3). Chronic pain disproportionately affects economically disadvantaged persons, ethnic minority groups, women, and older adults (2, 4), who have higher rates of chronic pain, greater risk for pain-related disability, and higher rates of major chronic physical and psychological comorbid conditions (1, 58). Standard approaches to chronic pain focus on expensive biomedical interventions and analgesic medications that are fraught with undesirable side effects, as exemplified by the spiraling opioid epidemic. Recently published national clinical practice guidelines stress nonpharmacologic, evidence-based alternatives to pain medications (911). However, many providers are not familiar with such treatments as cognitive behavioral therapy (CBT), and access to CBT is limited, particularly in low-income communities. Although CBT for chronic pain is effective (1214), rigorous trials have not been conducted in populations with low socioeconomic status (1, 2). Pilot research showed that group-administered CBT and pain education (EDU), adapted to reduce cognitive demands, were efficacious in persons with low socioeconomic status who have chronic pain (15). That trial was underpowered to detect differences between treatment groups and lacked a usual care comparison group, precluding evaluation of whether the interventions could augment existing practices (16). The purpose of this study was to compare literacy-adapted CBT, EDU, and usual care for treating chronic pain in a larger sample of patients with chronic pain. We hypothesized that participants randomly assigned to receive CBT or EDU would show greater posttreatment improvements in pain intensity, physical function, and depression than those receiving usual care and that CBT would be superior to EDU and usual care in reducing depression. Because of the highly disadvantaged nature of the population and anticipated difficulty reaching participants for follow-up, we defined posttreatment as our primary end point and did not make hypotheses about maintenance of effects at 6 months. Supplement. Study Protocol Methods Design Overview The LAMP (Learning About My Pain) study was a 3-group, parallel-design (1:1:1 allocation ratio), randomized controlled trial comparing CBT, EDU, and usual care in treating chronic pain (17). Participants were recruited from 12 September 2013 to 1 December 2015, and follow-up visits were completed by 30 September 2016. Although the trial registration was submitted to ClinicalTrials.gov in June 2013, required revisions delayed its final publication. Sixteen of 290 patients (5.5% of the sample) were enrolled before trial registration on 21 October 2013, but no outcome data were collected. Procedures were approved by the University of Alabama Institutional Review Board (IRB); minor protocol changes during the study are described in Appendix Table 1. Informed consent was obtained at enrollment. Appendix Table 1. IRB Modifications Throughout the LAMP Trial Setting and Participants Participants were recruited from 4 clinic sites in 36 separate cohorts at community health centers administered by Whatley Health Services (WHS), a private nonprofit agency in western Alabama that predominantly serves members of ethnic minorities with low socioeconomic status. Two WHS employees served as paid participant coordinators. Together, they recruited and screened potential participants for eligibility, followed all participants (including those in usual care), and facilitated retention. All WHS patients with a chronic painrelated diagnosis were contacted to determine their interest in participating in the study. Eligible persons were at least 19 years of age; had a chronic painrelated diagnosis, with pain most days of the month for at least 3 months; were proficient in English; and provided a means of contact. Exclusion criteria were pain related to cancer, clinically significant cognitive impairment, current self-reported substance abuse, serious uncontrolled mental illness, a reading level below first grade, recent changes in pain or psychotropic medication (in the previous 4 weeks), and current psychosocial treatment for pain (Figure 1). Figure 1. Flow of participants through the trial with usual care, CBT, and EDU. CBT= cognitive behavioral therapy; EDU= pain education. Randomization and Interventions The study statistician used statistical software to generate a random-number table that stratified treatment assignments by site (n= 4, with intentional weighting toward the highest-volume site) and was balanced by treatment group (n= 3). At each site, participants were assigned to cohorts of 7 to 9 persons per group. Cognitive behavioral therapy and EDU were administered in group format by co-therapists. Both interventions were the result of adaptations begun in previous research to simplify treatment procedures and revise patient workbooks to a fifth grade reading level (15, 18). The patient workbooks and therapist supplements are copyrighted but freely available at pmt.ua.edu/publications.html. Each participant received a workbook and weekly audio CD with a summary of that week's material. For the CBT groups, CDs included instructions for skills practice and a relaxation exercise. Participants were compensated $20 per session for travel to the group sessions, with no additional compensation for attendance. CBT: LAMP Group The CBT treatment manual used in this study is standardized and supported by empirical studies (15, 19). Ten weekly 90-minute group sessions provided simplified cognitive behavioral techniques, including motivational reinforcement, pain education, and pain management skills training (such as cognitive restructuring, activity pacing, and relaxation). EDU: LAMP Group Ten weekly 90-minute group sessions provided relevant pain-related information aimed toward pain self-management and group discussion, but no specific skill-building exercises were taught. The EDU program was matched to the CBT intervention with regard to format, discussion, and therapist engagement; it is standardized and supported by empirical research (15, 18, 20). Both Groups All participants received usual medical care, which may have involved any nonpsychological pain management method, including medication, chiropractic, or physical therapy, through WHS or external providers. Those randomly assigned to usual care had parallel contact with participant coordinators and assessors, as well as intermittent phone contact to facilitate retention, but received no psychosocial treatment. Therapists worked in pairs of 1 doctorate-level psychologist and 1 predoctoral clinical psychology trainee (total of 10 therapists: 5 doctoral, 5 predoctoral). Training for the CBT and EDU therapists, as well as supervision of ongoing therapy, was provided by using the standardized CBT and EDU materials. All sessions were video recorded, and a study investigator uninvolved in treatment used a structured scale (21) to evaluate the therapists' adherence to the protocol and the quality of the intervention for 26.7% of the sessions (randomly selected) (Appendix Table 2). Appendix Table 2. Summary of Treatment Integrity Process for the LAMP Protocol* Blinding Study participants and patient coordinators were not blinded to treatment allocation but were unaware of the study hypotheses. Therapists were not blinded to participants' treatment assignment for the groups they led. Study outcomes were collected by blinded, trained assessors. Because the principal investigator supervised the therapists, she was not blinded to participants' assignment status; however, she did not conduct outcome assessments, nor was she one of the medical providers following the patients. Outcomes and Follow-up Assessors conducted face-to-face, 90-minute interviews, presenting assessment materials verbally. Assessment data were collected at baseline (before randomization), 5 weeks after the start of treatment (mid-treatment), at 10 weeks (posttreatment), and 6 months after treatment. Participants were compensated $45 for each assessment. Outcomes were prespecified as primarypain intensity, assessed by using the 4-item Brief Pain InventoryShort Form (BPI-SF) Pain Intensity subscaleand secondaryphysical function, measured by the BPI-SF Pain Interference subscale (22), and depression, measured by the Patient Health Questionnaire9, (PHQ-9) (23). Patient Global Impression of Change (24) was a secondary outcome evaluated in the study but not reported here. At baseline, sociodemographic and pain information was obtained, including self-reported methods to manage pain, and data regarding opioid prescriptions were collected from medical records. Primary literacy also was assessed with the Wide Range Achievement Test 4 Word Reading Subtest (25). Treatment adherence was defined as the number of CBT or EDU group sessions attended, and adequate dosage was defined as attendance at more than 6 sessions. Self-reported adverse events (emergency room visits, hospitalization, suicidal ideation) were queried weekly by therapists for participants in the CBT and EDU groups and by assessors at mid-treatment and posttreatment for all participants (including those receiving usual care). Identified adverse events were documented in compliance with IRB policies, and IRB staff ultimately determined whether each event was related to the study. An external data safety officer monitored all trial safety procedures and events, as did the IRB and principal investigator. Statistical Analysis Sample size was estimated by using the smallest expected between-group effect: the difference between groups across time in dep

Literacy-Adapted Cognitive Behavioral Therapy Versus Education for Chronic Pain at Low-Income Clinics

Factors associated with diabetes-specific health-related quality of life in youth with T1DM: the global TEENs study

The journal of pain : official journal of the American Pain Society

(511) Understanding factors related to enrollment and retention in psychosocial treatment for chronic pain: a qualitative analysis of patients' perspectives.

1. CLOSED SESSION. Pursuant to Minnesota Statutes, Section 13D.05, subdivision 3(b), to conduct a closed session pursuant to the attorney-client privilege to engage in confidential attorney-client communications and litigation strategy related to a pending litigation matter: Thelma Jones, Priyia Lacey, Faisa Abdi, Ali Ali, Rukiya Hussein, Lucia Porras, David Trotter-Ford, and Somali Community Resettlement Services, Inc. vs. City of Faribault.

CITY OF FARIBAULT FARIBAULT, MINNESOTA NOTICE OF SPECIAL CITY COUNCIL MEETING

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Ethics is the science of morality. Its purpose is to define a proper code of values to guide human choices and actions. Morality, in a simple form, is merely a collection of rules by which we live our lives. Generally, these rules prohibit harm or evil. These harms or evils are common to almost all cultures and comprise death, pain, disability, loss of freedom, and loss of pleasure. A well-known example of such rules is the 10 Commandments dictated to Moses by his God, and these affirmed a common morality within that society. Transgression of such rules by rational people is punishable. An early example of rules applicable to medicine is contained in the Hippocratic Oath (4th century BC). This oath defined the character of a good physician for centuries. This oath, applicable to medicine, is not separate from society s common morality, but rather a subpart of it. Rules aim to remove the need for complex case by case decision making. With rules, we can do what is right for the patient almost instinctively by simply following principles of common morality. Debate has existed about the medical rules since and probably before the ancient Greeks. However, revelation that human subjects were used in biomedical experiments during World War II brought the field of bioethics to public attention. Subsequent rapid technological developments for diagnosis (e.g. genetics, amniocentesis) and treatment of illness (e.g. organ transplantation, artificial ventilation) posed new dilemmas about prolongation of life or access to medical treatments. Innovations in pediatric anesthesia [Liverpool technique (1–3)], intensive care [extracorporeal membrane oxygenation (4), continuous positive airway pressure (5)], anencephalic organ donation (6), and analgesia or lack of analgesia (7,8) continued to fuel this debate (9). These debates, initially led by philosophers and religious leaders, spread to bioethics (the philosophical study of the ethical controversies brought about by advances in biology and medicine) academic programs. Frustratingly, for clinicians keen to do what is right for patients, bioethicists often come up with divergent opinions. There may be more than one right answer. Occasionally, some problems of bioethics are irresolvable. Continuing advances in technology introduce new dilemmas and further debate. The Hippocratic Oath has been modified over the years as a consequence of technological advances and social, religious, and political changes. The original version, for example, forbade the practice of surgery (and required practitioners to share their goods with their lecturers!), and current versions often do not address the complex ethical issues that face modern physicians. We have seen the advent of modern rules for our specialty such as the Declaration of Helsinki (10), revisions of which are continually debated (11). The lack of a single correct answer to modern medical moral issues can be frustrating; indeed any answer sometimes seems better than simply ruling out the amoral answer. Unfortunately, medicine is complicated by uncertainties. In our own field of pediatric anesthesia, there is a chance, albeit small, that children may suffer awareness during a general anesthetic, regional techniques may fail, anaphylaxis to drugs may occur, or central venous access attempts can cause pneumothoraces. The ED50 of a drug has variability. Quantification of uncertainties complicates decision making by introducing new variables that must be weighed to determine best outcome. Debate between staff, parents, and ⁄ or children in clinical practice sometimes reaches a stalemate and referral to the law courts is necessary to clarify the rule. The courts attempt to define common morality as they apply to individual circumstances. This Correspondence to: B.J. Anderson PhD FANZCA FJFICM, Paediatric Intensive Care Unit, Auckland Children s Hospital, Park Road, Auckland, New Zealand (email: briana@adhb.govt.nz). Pediatric Anesthesia 2009 19: 931–933 doi:10.1111/j.1460-9592.2009.03119.x

F.1.c. Response to Questions Posed by the Ambulance Governance Advisory Council - In Private H.1.a. City Manager's 2005 Performance Evaluation - In Private H.1.b. City Auditor's 2005 Performance Evaluation - In Private CARRIED

The following are the minutes of the City Council Meeting of the Herriman City Council. The meeting was held on Wednesday, April 18, 2018 at 5:00 p.m. in the Herriman City Hall Council Chambers, 5355 West Herriman Main Street, Herriman, Utah. Adequate notice of this meeting, as required by law, was posted in the City Hall, on the City’s website, and delivered to members of the Council, media, and interested citizens.

CIVIL PRACTICE Executions and Judicial Sales: Reduce the Continuously Published Period to Become the County's Official Organ Designated to Run Official or Legal Advertising

LAW ENFORCEMENT AND OTHER AGENCIES Employment and Training and Peace Officers; Restrict Public Access to Bomb Technicians' Training Materials

Tableau Visualizations Leveraging Predictive Analytics on Virtualized Structured and Unstructured Data.

Foundations 2015: Proc. Int’l Foundations Congress & Equipment (EXPO 2015, GSP 256)

Business Executives, Technologists, and Auditors Need Least Privilege

Applications, Databases, and Desktop Data Need Least Privilege, Too

Persistent LINDA: Design and implementation of a system to add transactions to LINDA

Objective: To examine the role of intensive care unit (ICU) management following lateral skull base surgery for vestibular schwannoma and identify risk factors for complications warranting admission to the ICU. Study Design: Retrospective review. Setting: Tertiary referral center. Patients: Two hundred consecutive patients undergoing lateral skull base surgery for vestibular schwannomas. Intervention: Lateral skull base approach for resection of vestibular schwannoma and postoperative monitoring. Main Outcome Measures: Patients were grouped if they sustained an ICU complication, a non-ICU complication, or no complication. Analysis was performed to determine patient or treatment factors that may be associated with ICU complications. Multivariate and three-way analysis of variance compared groups, and multivariate logistic regression determined adjusted odds ratios (aOR) for analyzed factors. Results: Seventeen of 200 patients sustained ICU complications (8.5%), most commonly hypertensive urgency (n = 15). Forty-six (23%) sustained non-ICU complications, and 137 (68.5%) had no complications. When controlling for age, sex, obesity, and other comorbidities, only hypertension (aOR 5.43, 95% confidence interval (CI) 1.35–21.73, p = 0.017) and tumor volume (aOR 3.29, 95% CI 1.09–9.96, p = 0.035) were independently associated with increased risk of ICU complications. Conclusions: The necessity of intensive care following lateral skull base surgery is rare, with the primary ICU complication being hypertensive urgency. Preoperative hypertension and large tumor volume (>4500 mm3) were independently associated with increased risk for ICU complications. These findings may allow for risk stratification of patients appropriate for admission to stepdown units following resection of vestibular schwannomas. Further prospective, multi-center, randomized studies are necessary to validate these findings before systematic changes to current postoperative care practices.

Risk Factors for Complications Following Lateral Skull Base Surgery and the Utility of ICU Monitoring

Proof of Principle Subjective Analysis of a New Deep-Learning Model for MRI Autocontouring in Clinical Practice

Extracranial Olfactory Ensheathing Cell Tumor: Case Report of a New Clinical Entity.

The effect of extent of resection on time to tumor progression and survival in patients with glioblastoma multiforme of the cerebral hemisphere.

A team at the University of Pennsylvania Health System devised the I-READI conceptual framework — for Integration, Root Cause Analysis, Evidence Review, Adaptation, Dissemination, and Implementation — to help health care organizations respond to quality and safety challenges during crises, such as emerging infectious diseases or periods of capacity strain.

The I-READI Quality and Safety Framework: A Health System’s Response to Airway Complications in Mechanically Ventilated Patients with Covid-19

100 years ago, there was a medical education revolution. Medicine became evidence based and the average human life span had doubled by the end of the 20th century. We have now arguably reached the limit of human capacity for such radical progress in the practice of medicine and we must now embed technology into the toolbox of each physician to sustain the rate of change in human health and the drive towards better diagnostic, treatment and prognostic outcomes. Whilst the demand for such skills is well documented, the provision of capacity has severely lagged behind. This paper will explore the skills and knowledge required to facilitate the next revolution in healthcare and examine the current state of education to meet this demand.

Proceedings of the Australasian Computer Science Week Multiconference

Educating for the next health revolution: are we failing the frontline?

Removing Care Barriers: Cross-Training HIV and Mental Health Peer Staff

The case for providing ethics training for your staff, and dangers that lie in failing to do so

The Public Health Context in Vietnam and the Potential for Informatics

Today, the Diversity Committee assists and informs department leadership in the recruitment and retention of students and faculty from underrepresented populations to better serve our diverse patient populations, with a member of the diversity committee serving on each search committee. The committee also sponsors and selects the recipient of the annual Dr. Evelyn Lee Visiting Scholar Lecture in Cultural Competence and Diversity.

"Quality improvement in health care: is the patient still left out?".

Exploiting manifolds of L1 halo orbits for end-to-end Earth–Moon low-thrust trajectory design

Across the boreal forest in North America, the black spruce (Picea mariana) cover type is ecologically and economically important, occupying roughly 10 percent of Minnesota’s, USA 17.4 million acres (7.0 million hectares) of forestland. Traditionally managed through clearcut regeneration harvests, alternative silvicultural systems are being increasingly used in Canada. Here, we examine the 10and 57-year effects of six silvicultural treatments (clearcut strips, clearcut patches, thinning, group selection, single-tree selection, shelterwood) on stand structure and dynamics in lowland black spruce. Treatments were installed in 1948 in northern Minnesota, and remeasured and re-treated 10 years later. A subset of the clearcut strips, clearcut patches, and shelterwood treatments were remeasured in 2017. After 10 years, diameter growth of residual stems varied by treatment, with the shelterwood experiencing the greatest growth, and basal area increased in all but the shelterwood treatment. Over the long term, the shelterwood exhibited larger diameters and heights and greater crown ratios, basal area, structural complexity, and compositional diversity than the clearcuts. Our results suggest that managers may consider using a shelterwood instead of traditional large clearcuts to achieve increased structural and compositional diversity, particularly when eastern spruce dwarf mistletoe (Arceuthobium pusillum) does not necessitate a traditional clearcut.

Short- and Long-Term Results of Alternative Silviculture in Peatland Black Spruce in Minnesota, USA

 Mountain glacier moraine sequences and their chronologies allow us to evaluate the timing and climate conditions that underpin changes in the equilibrium line altitudes (ELAs), which can provide valuable information on the paleoclimatology of understudied regions such as tropical East Africa. However, moraine sequences are inherently discontinuous, and the precise climate conditions that they represent can be ambiguous due to the sensitivity of mountain glaciers to temperature, precipitation, and other environmental variables. Here, we used a two-dimensional (2-D) ice-flow and mass-balance model to simulate glacier extents and ELAs in the Rwenzori Mountains in East Africa over the past 31,000 yr (31 k.y.), including the Last Glacial Maximum (LGM), late glacial period, and the Holocene Epoch. We drove the glacier model with two independent, continuous temperature reconstructions to simulate possible glacier length changes through time. Model input paleoclimate values came from branched glycerol dialkyl glycerol tetraether (brGDGT) temperature reconstructions from alpine lakes on Mount Kenya for the last ~31 k.y., and precipitation reconstructions for the LGM came from various East African locations. We then compared the simulated fluctuations with the positions and ages (where known) of the Rwenzori moraines. The simulated glacier extents reached within 1.1 km of the dated LGM moraines in one valley (93% of the full LGM extent) when forced by the brGDGT temperature reconstructions (maximum cooling of 6.1 °C) and a decrease in precipitation (−10% than modern amounts). These simulations suggest that the Rwenzori glaciers required a cooling of at least 6.1 °C to reach the dated LGM moraines. Based on the model output, we predict an age of 12–11 ka for moraines located halfway between the LGM and modern glacier extents. We also predict ice-free conditions in the Rwenzori Mountains for most of the early to middle Holocene, followed by a late Holocene glacier readvance within the last 2000 yr.

Modeling glacier extents and equilibrium line altitudes in the Rwenzori Mountains, Uganda, over the last 31,000 yr

Assessing and modeling total height and diameter increment of ponderosa pine planted in Minnesota, USA

University of Minnesota M.S. thesis. May 2018. Major: Natural Resources Science and Management. Advisors: Marcella Windmuller-Campione, Matthew Russell. 1 computer file (PDF); vii, 55 pages.

Short- and long-term effects of alternative silvicultural systems on stand development of lowland black spruce forests in northern Minnesota, USA

The black spruce cover type occupies roughly 10% of Minnesota’s 7 million hectares of forestland, and is an important species, both ecologically and economically. A clearcut regeneration harvest is the main silvicultural system in black spruce in this region. The effects of managing black spruce with alternative silvicultural methods in the Lake States remains largely understudied. Here, we examine a silviculture study in lowland black spruce to assess the performance of two diameter growth models fit to this data compared to a widely-used model. Six silvicultural treatments (clearcut strips, clearcut patches, thinning, group selection, single-tree selection, and shelterwood) and a control were treated and measured around 1950, with a follow-up measurement occurring 10 years later. Fixed- and mixed-effects growth-models were adapted from the previous work, and fit to 10,231 observations and compared to a recently released diameter growth model. The mixed-effects model using treatment, compartment, and plot as nested random effects outperformed the fixed-effects model, and outperformed a model proposed for use in the Lake States variant of the Forest Vegetation Simulator that was fit to this data. This modeling approach of localized growth models across a wide-range of diameters (9.1–32.1 cm) more accurately predicted the diameter growth in lowland black spruce than the conventional approach of using separate models for large (>12.7 cm) and small (≤12.7 cm) diameter trees.

Development and Evaluation of Black Spruce (Picea mariana (Miller) B.S.P.) Diameter Increment Models across Silvicultural Treatments in Northern Minnesota, USA

MODELING GLACIAL EXTENT DURING THE LAST GLACIAL MAXIMUM IN UGANDA

MODELING EAST AFRICAN TROPICAL GLACIERS DURING THE LAST GLACIAL MAXIMUM

Asteroid 2006 RH120 was the first natural object captured by the Earth to be observed called a Minimoon. In this work, we show that the invariant manifolds of the orbits around the L1 and L2 Lagrange points play a significant role in the capture of the asteroid around Earth and its eventual escape from the Earth approximately 1 year later. This is similar to the Temporary Capture of comets around Jupiter. We determined that the asteroid was in a 27:29 mean motion resonance with the Earth and approached the Earth through the stable manifold of an L1 Northern Halo Orbit. After the Temporary Capture, the asteroid escaped the Earth through the unstable manifold of an L2 Southern Halo orbit and into a 21:20 resonant orbit with the Earth. The asteroid travelled through a series of resonant orbits before and after the capture. These resonant transitions are similar to the orbits of Galileo and Cassini during their touring phase, using resonant orbits to reduce mission ∆V requirements.

( Preprint ) AAS 16-484 DYNAMICS OF ASTEROID 2006 RH 120 : PRE-CAPTURE AND ESCAPE PHASES

Over 300 stand and stock tables and summary of volume tables for Minnesota were restored from the first FIA Lake States forest survey conducted between 1930 and 1938. The level of detail of the data varied, but included area of forest cover types and stand size classes, and number of trees and volumes per acre by individual species. The data was presented in an Access database with a series of tables and queries. Definitions and further explanations about the restored historic data can be found in Staff Paper Series No. 241, Department of Forest Resources, University of Minnesota

Inferring Past Climate in Equatorial East Africa using Glacier Models

Magnetic Measurements on Mars: What Is in Work and What Could Be

A Fractionated Space Weather Base at L5 using CubeSats and Solar Sails

Science and Management Community Aquatic Habitat Connectivity Discussion – Background, Process and the Bigger Picture

Gaylord and Dorothy Donnelley Foundation, 35 East Wacker Drive, Suite 2600, Chicago, IL 60606 Grant/Contract No: 1-556283

Development of a Natural Areas Integrity and Restorability Index and Application to Lands of the Chicago Region

Survey of the distribution, size, and development of canebrakes in southern Illinois

The bluebreast darter Etheostoma camurum (Cope) has a disjunct distribution within the Ohio River drainage. I examined the distribution and life history characteristics of E. camurum in the Vermilion River basin (Wabash River drainage), Illinois, during the summer of 2007. The darter commonly was collected in areas of moderate to swift currents over cobble and boulder. It spawned in these areas during early summer, and consumed predominately aquatic insect larvae for its diet. Because of its small range, I recommend the species remain listed as state-endangered. Introduction The bluebreast darter Etheostoma camurum (Cope) is a diminutive (typically < 125 mm), shortlived (typically < 3 years) fish in the Family Percidae (Page, 1983). It is sporadically distributed in several streams in the Ohio River drainage, including the Allegheny River basin in New York and Pennsylvania, the Wabash River basin in Indiana and Illinois, and the Tennessee River basin in North Carolina and Tennessee (Zorach, 1972; Page, 1983). This range can be attributed to recent degradation and fragmentation of habitat following post-Pleistocene dispersal (Zorach, 1972). Etheostoma camurum is a habitat specialist usually found on the streambed in depths of 10 30 cm under boulder in fast riffles in large, clear streams (Page, 1983; Greenberg, 1991; Stauffer et al., 1996; Welsh and Perry, 1998). In Illinois, it is found only in the Vermilion River basin of the Wabash River drainage (Smith, 1979). No other Illinois streams contain the preferred habitat requirements of E. camurum, and earlier references (e.g., Large, 1903; Forbes and Richardson, 1920; O’Donnell, 1935) of the species having been collected elsewhere in central and southern Illinois were based on misidentifications (Smith, 1979). As with most benthic fishes, E. camurum is negatively affected by anthropogenic disturbances, including siltation and

Status Of Darters In The Wabash River Basin In Illinois, And Its Implications On Recovery Actions For Three Listed Freshwater Mussels

Afro-Cuban percussion, its roots and role in popular Cuban music

Abstract : The Joint Chiefs of Staff have commissioned a study through the Defense Intelligence Agency (DIA) to investigate both the background and personality characteristics of those individuals who proliferate weapons of mass destruction. The DIA is hopeful that some particular background traits will stand out and allow them advanced warning that the potential for proliferation exists in a suspect. This study will be limited to three individuals: Dr. Abdul Qadeer Khan who specializes in the proliferation of nuclear weapons, General Anatoly Kuntsevich who specializes in the proliferation of chemical weapons, and Dr. Rihab Taha who specializes in the proliferation of biological weapons. The study will provide extensive information regarding the history, education, political affiliation, and writings of each individual. The hypothesis of Weapons of mass destruction proliferants have common background traits will be tested via a traditional research methodology. The personality characteristics of these individuals will be analyzed in another study.

Abstract : In 1999, USCINCSPACE/J5 commissioned a study through the Institute for National Security Studies asking the question, How should the USCINCSPACE go about shaping the region of space in accordance with the National Military Strategy?" The research question went on to ask if there are any systematic approaches used by other CINCs to shape their AOR that can be used by USCINCSPACE to shape the region of space. This study analyzes one way in which the USCINSSPACE might best shape the medium of space. The 1997 National Military Strategy builds on the premise that the United States will remain globally engaged to shape the international environment and create conditions favorable to US interests and global security. Does this include shaping the region of space? Terms like shaping, region, AOR, and aerospace have different contextual meanings and often raise emotional responses. This paper places those terms in their proper context. Finally, this paper directly applies the geographic CINC model for shaping as it is described in the US National Military Strategy to the space medium and determines its applicability for the USCINCSPACE. This paper recommends that the USCINCSPACE adopt the use of the guidelines given by the geographic CINC model, as they are described in the US National Military Strategy, to shape the space medium.

Abstract : Tactical space support has earned a reputation as unresponsive and the Operationally Responsive Space Office was created in 2007 to address this for the military. The intent of this course project is to use an educational research approach to develop a future architecture that will make space responsive in 2025. This paper evaluates the shortcomings that hinder quick and effective space-based support to the U.S. Military and Intelligence Community. The current space community is fragmented, preventing quick, unified decisions, and does not have the executive clout necessary to lead effectively. Our group's solution creates a Department of Space at the cabinet level. The Department of Space will unify the space community, promoting quicker decisions with one common and consistent vision. This change would enable unified plans and policies as well as allow one organization to prioritize all of the space programs. The responsive culture would facilitate other needed changes to Space Operations, Launch, and Acquisition.

Operationally Responsive Space: Creating Responsive Space for America

OPERATION Desert Storm is often referred to as the United States' first "space war." At that time, there was no doctrine for centrally commanding and controlling space forces, and that remains true today. This dilemma has led to many debates on how to remedy the situation. After more than 11 years of development, Joint Publication (JP) 3-14, Space Operations, was published in August 2001, and the concept of joint force space operations authority (JFSOA) was introduced to the joint force commander (JFC). JFSOA's purpose is to provide theater command and control (C2) of space support. The JP outlines the JFSOA's role as belonging to one of the component commanders. This article suggests that the best answer is to give this support function to the Bs information operations cell. Few debate that when the United States has space-based weapons there will be a need for a joint force space component commander (JFSCC). Here, we will offer an interim command structure that not only serves the JFC today but also allows an easy transition to a JFSCC structure. Standards in Terminology Why are there so many differing opinions on how to lead and direct space forces? Is parochialism at the heart of the differences? Perhaps. We believe, however, the primary source of difference stems from how the military services think about space. At the root of differing space strategies and concepts lies a lack of standard terminology. For instance, U.S. Air Force (USAF) space terms do not align with Department of Defense (DOD) or joint terms. This is important because the USAF operates most of the unclassified space systems that support warfighters, and warfighters must clearly understand space terminology. Terminology affects the way people think and the way they are trained, organized, and equipped. Key terms with varying definitions within DOD are "space," "space forces," and "space operations." Differences in interpreting these terms have led to various misconceptions. A misconception in the USAF is that air and space form one seamless medium. Within this context, space is retained in its status as a force multiplier or support commodity. Another misconception is that space operations and support from space are exactly the same, which they are not. This misconception blurs the line between space operations and certain intelligence functions, particularly collection management. However, no matter what the misconception, the JFC has to deconflict the differences these misconceptions can cause before he can synchronize operations. Space defined. DOD's space policy states that "space is a separate medium like land, sea, and air within which military activities shall be conducted to achieve U.S. national security objectives. The ability to access and utilize space is a vital national interest because many of the activities conducted in the medium are critical to U.S. national security and economic well being."' Using this definition, some have proposed that the space medium warrants its own service.2 Other mediums have their own service, and space, after all, is a medium of vital national interest. Others have suggested space should have a component command within a joint force command structure. The JFSCC would coordinate space operations and forces for the JFC in a structure similar to the existing air, land, maritime, or special operations component. Most would agree that, although certainly a potential structure for the future, the JFSCC structure could not support the JFC today. JP 1-02, DOD Dictionary of Military and Associated Terms, does not define space. It does, however, define aerospace as "of, or pertaining to, Earth's envelope of atmosphere and the space above it; two separate entities considered as a single realm for launching, guidance, and control of vehicles that will travel in both entities."' The USAF has adopted this concept as the foundation for its aerospace and space warfare doctrine. …

Characterizing the degradation of [(UO2F2)(H2O)]7 4H2O under humid conditions

Opportunities for exascale in the characterization of uranium materials

We confirm that synthetic uranyl hydroxide hydrate metaschoepite [(UO)24O(OH)6]·5H2O is unstable against dehydration under dry conditions, and we present a structural and vibrational spectroscopic study of synthetic metaschoepite and its ambient temperature dehydration product. Complementary structural (X-ray diffraction and neutron diffraction) and vibrational spectroscopic techniques (Raman spectroscopy, infrared spectroscopy, and inelastic neutron scattering) are used to probe different components of these species. Analysis of the dehydration product suggests that it contains both pentagonally coordinated and hexagonally coordinated uranyl ions, necessitating that some uranyl ions undergo a coordination change during the dehydration of pentagonally coordinated metaschoepite. Vibrational spectra of metaschoepite and its dehydration product are interpreted with power spectra generated from ab initio molecular dynamics trajectories, allowing assignment of all major features. We identify the uranyl symmetric stretching modes of the four distinct uranyl ions in synthetic metaschoepite and clarify the assignment of lower energy Raman modes in both structures. The coanalysis of experimental and computational data reveals a strong coupling between the uranyl stretching modes and hydroxide bending modes in the anhydrous structure, leading to the presence of several high-energy combination bands in the inelastic neutron scattering data.

Elucidation of the Structure and Vibrational Spectroscopy of Synthetic Metaschoepite and Its Dehydration Product.

Amorphous uranium oxides are known to arise via industrial processes relevant to the nuclear fuel cycle yet evade rigorous structural characterization. A promising approach is to develop statistica...

The Impact of Coordination Environment on the Thermodynamic Stability of Uranium Oxides

Hydrated uranyl fluoride, [(UO2F2)(H2O)]7·4H2O, is not stable at elevated water vapor pressure, undergoing a complete loss of fluorine to form a uranyl hydroxide hydrate. Powder X-ray diffraction data of the resultant uranyl hydroxide species is presented for the first time, along with Raman and infrared (IR) spectra. The new uranyl hydroxide species is structurally similar to the layered uranyl hydroxide hydrate minerals schoepite and metaschoepite, but has a significantly expanded interlayer spacing (c = 15.12 vs. 14.73 Å), suggesting that additional H2O molecules may be present between the uranyl layers. Comparison of the Raman and IR spectra of this new uranyl hydroxide hydrate and synthetic metaschoepite ([(UO2)4O(OH)6]·5H2O) suggests that the equatorial environment of the uranyl ion may differ and that H2O molecules in the new species participate in stronger hydrogen bonds. In addition, the interlayer spacing of both this new uranyl hydroxide species and synthetic metaschoepite is shown to be sensitive to the environmental humidity, contracting and re-expanding with desiccation and rehydration. Structural distinction between the new uranyl hydroxide species and synthetic metaschoepite is confirmed by a comparison of the thermal behavior; unlike metaschoepite, the new hydrate does not form α-UO2(OH)2 upon dehydration.

Formation of a uranyl hydroxide hydrate via hydration of [(UO2F2)(H2O)]7·4H2O.

We have demonstrated the solid-state formation of a uranyl peroxide (UP) species from hydrated uranyl fluoride via a uranyl hydroxide intermediate, the first observation of a UP species formed in a solid-state reaction. Water vapor pressure is shown to be a driving factor of both the loss of fluorine and the subsequent formation of peroxo units. We have ruled out a photochemical mechanism for formation of the UP species by demonstrating that the same reaction occurs in the dark. A radiolytic mechanism is unlikely because of the low radioactivity of the sample material, suggesting the existence of a novel UP formation mechanism.

Evidence of a Nonphotochemical Mechanism for the Solid-State Formation of Uranyl Peroxide.

Genetic Algorithms and DFT in the Search for Novel Stable and Metastable Crystal Structures of the Uranium Oxides

A method for measuring the partially saturated fluid trans port properties of an absorbent. The steps of the method are generating a physical spatial map of Saturation of a fluid within an absorbent in a physical test environment, gener ating a virtual spatial map of Saturation of a fluid within an absorbent in a virtual test environment, and identifying the absorbent-fluid interaction properties for the absorbent such that the virtual spatial map of Saturation approximates the physical spatial map of Saturation.

Uranyl fluoride (UO2F2) is a hygroscopic powder with two main structural phases: an anhydrous crystal and a partially hydrated crystal of the same R3¯m symmetry. The formally closed-shell electron structure of anhydrous UO2F2 is amenable to density functional theory calculations. We use density functional perturbation theory (DFPT) to calculate the vibrational frequencies of the anhydrous crystal structure and employ complementary inelastic neutron scattering and temperature-dependent Raman scattering to validate those frequencies. As a model closed-shell actinide, we investigated the effect of LDA, GGA, and non-local vdW functionals as well as the spherically averaged Hubbard +U correction on vibrational frequencies, electronic structure, and geometry of anhydrous UO2F2. A particular choice of Ueff=5.5 eV yields the correct U-Oyl bond distance and vibrational frequencies for the characteristic Eg and A1g modes that are within the resolution of experiment. Inelastic neutron scattering and Raman scattering suggest a degree of water coupling to the lattice vibrations in the more experimentally accessible partially hydrated UO2F2 system, with the symmetric stretching vibration shifted approximately 47 cm-1 lower in energy compared to the anhydrous structure. Evidence of water interaction with the uranyl ion is present from a two-peak decomposition of the uranyl stretching vibration in the Raman spectra and anion-hydrogen stretching vibrations in the inelastic neutron scattering spectra. A first-order dehydration phase transition temperature is definitively identified to be 125 °C using temperature-dependent Raman scattering.

Vibrational properties of anhydrous and partially hydrated uranyl fluoride.

ABSTRACT Uranyl fluoride is a three-layer, hexagonal structure with significant stacking disorder in the c-direction. It supports a range of unsolved ‘thermodynamic’ hydrates with 0–2.5 water molecules per uranium atom, and perhaps more. However, the relationship between water, hydrate crystal structures, and thermodynamic results, collectively representing the chemical pathway through these hydrate structures, has not been sufficiently elucidated. We used high-resolution quasielastic neutron scattering to study the dynamics of water in partially hydrated uranyl fluoride powder over the course of 4 weeks under closed conditions. The spectra are composed of two quasielastic components: one is associated with translational diffusive motion of water that is approximately five to six times slower than bulk water, and the other is a slow (on the order of 2–300 ps), spatially bounded water motion. The translational component represents water diffusing between the weakly bonded layers in the crystal, while the bounded component may represent water trapped in subnanometre ‘pockets’ formed by the space between uranium-centred polymerisation units. Complementary neutron and X-ray diffraction measurements do not show any significant structural changes, suggesting that a chemical conversion of the material does not occur in the thermodynamically isolated system on this timescale.

The structural phase diagram of uranyl fluoride (UO2F2), while incomplete, contains at least one anhydrous crystal structure and a second, zeolite-like structure with the formula [(UO2F2)(H2O)]7 ⋅ (H2O)4 that can be produced by adding water to the anhydrous structure. While traditional diffraction measurements can easily differentiate these crystals, additional aqueous structures (in general of the form UO2F2 + xH2O) have been proposed as well. We present results using a novel sample environment setup to intercalate water during a quasielastic neutron scattering measurement over the course of 86 h. Our sample environment allows low-pressure (<2 atm) humid air flow across the sample coupled with a system to control the relative humidity of this air flow between 10% and 70%. The water dynamics in UO2F2 and [(UO2F2)(H2O)]7 ⋅ (H2O)4 are sufficiently different to distinguish them, with water in the latter executing a restricted diffusion (D = 2.7 × 10−6 cm2/s) within the structure's accessible pores (r = 3.17 ...

Quasielastic neutron scattering with in situ humidity control: Water dynamics in uranyl fluoride

We report a novel production method for uranium oxyfluoride [(UO2)7F14(H2O)7]·4H2O, referred to as structure D. Structure D is produced as a product of hydrating anhydrous uranyl fluoride, UO2F2, through the gas phase at ambient temperatures followed by desiccation by equilibration with a dry environment. We follow the structure of [(UO2)7F14(H2O)7]·4H2O through an intermediate, liquid-like phase, wherein the coordination number of the uranyl ion is reduced to 5 (from 6 in the anhydrous structure), and a water molecule binds as an equatorial ligand to the uranyl ion. Quasielastic neutron scattering results compare well with previous measurements of mineral hydrates. The two groups of structurally distinct water molecules in D perform restricted motion on a length scale commensurate with the O-H bond (r = 0.92 Å). The more tightly bound equatorial ligand waters rotate slower (Dr = 2.2 ps(-1)) than their hydrogen-bonded partners (Dr = 28.7 ps(-1)).

Structural Phase Transitions and Water Dynamics in Uranyl Fluoride Hydrates.

Comparison of active and passive environmental sampling for safeguards applications

Feasibility of a uniquely fabricated SERS-SEIRA substrate for uranyl detection

Computational Continuum and Rarefied Flow Results for Ballute Applications

Using surface excitations to detect bare vortices in a hose einstein condensate

Abstract This article focuses on first-year black female students at the University of KwaZulu-Natal who were exposed to and experienced sexual violence. The aim of the study was, broadly, to determine how female students experience and negotiate gender, sexuality and violence in campus residences. Semi-structured individual interviews were utilised to generate data. The findings show that violence was shaped by gender and power dynamics. These students were first years, and predominantly from poor backgrounds, and therefore particularly vulnerable to sexual violence and unequal relationships. Alcohol, substance abuse and dangerous masculinised spaces further exacerbated their vulnerability. Poverty, scarce resources and gender intersect to produce vulnerability and constrained forms of their agency that translate into transactional relationships. The findings also suggest that being first year female students have implications for how these young women negotiated their newfound freedom away from the parental gaze. The study highlights the ways in which these first-year students are aware that sexual violence is prevalent on campus particularly in certain spaces such as Dark City and residence rooms. Members of the SRC and DSRA are cited as likely perpetrators of sexually predatory behaviours. We therefore propose that the Gender Based Violence Policy at UKZN should be introduced to first year students by way of induction courses, and that these courses should also include gender and sexuality education to help ensure that awareness around gender violence permeates the lives of all students.

“Fresh meat”: First year female students negotiating sexual violence on campus residences

Gender and identity status differences in late adolescents' possible selves.

A review of the verbal aggression literature and findings of past studies reveals the importance of further inquiry into this construct. Verbal aggression has been studied by communication scholars for it's impact on interpersonal relationships. This paper is especially concerned with maternal verbal aggression and its effects on the adult‐children's romantic relationships later in life. Solidarity, emotional support, and relationship quality are introduced as relational outcomes and are used to evaluate the effects of maternal verbal aggression on relationships. Results of this study indicate that individuals who report receiving higher amounts of verbal aggression report lower levels of relationship solidarity and perceive their partners as less emotionally supportive. These findings are consistent with previous research by Vissing, Straus, Gelles, and Harrop (1991) which indicate that individuals who receive verbally aggressive messages from parents have difficulty forming and maintaining interpersonal...

The effects of maternal verbal aggression on the adult child's future romantic relationships

Jesus Christ: King or Messiah? the utilization of Psalm Two in the New Testament

Figure 3 accompanies the article, "A Population Study of the Benthonic Foraminiferida in Northern Biscayne Bay, Florida," by Brian L. Anderson.

Table 3: Percentage distribution of standing crop and total population

1) Background information from the SQO Staff Report; 2) A brief review of the 1999 – 2001 elutriate and SWI side-by-side test comparisons; 3) Description of a new study (by SCCWRP) to determine optimal equilibration time for homogenized sediment for the Sediment-Water Interface Exposure Method as an alternative to collecting intact sediment cores; and 4) General discussion points and suggestions for further evaluation of the SWI method.

Re: Selection of Sub-lethal Sediment Tests for the Rmp Annual Status and Trends Cruise

Speculations On Space: Urban interventions, Sibiu - European Capital of Culture 2007

Abstract : This study is part of a continuing assessment of the performance of the irondale DBCP control system in preventing the off-post migration of contaminated ground water. It covers the period of October, 1984, through September, 1986. The purposes of this study are to: Document the monitoring data collected since the FY 84 report; Incorporate the data collected by shell; data collected under other investigative programs conducted by the army during the report period; Document the continuing effectiveness of the system in preventing off-post migration of DBCP contaminated ground water

Evaluation of Shell Chemical Company's Ground-Water DBCP Control System at Rocky Mountain Arsenal. Volume 1

Abstract : Volume I discusses the history and placement of the system, geology, hydrology, containment distribution, and system effectiveness. It also contains sample collection protocol, plant operation log, water flow chart, chemical analyses of plant influent and effluent, and analyte concentrations in dewatering wells.

North Boundry Containment/Treatment System Performance Report. Rocky Mountain Arsenal, Denver, Colorado. Volume 1

Abstract : RMA and USATHAMA have been tasked with developing a preliminary conceptual design for the Northwest Boundary Contamination Control System. Specific tasks included in this program follow: (1) Provide a Concept Selection with supporting Rationale for the recommended control system. This design will include the number of dewatering and recharge wells, the type of treatment system, the monitoring well requirements, the spacing of wells, the location of the barrier and wells, and the expected performance of the system components; (2) Provide a buy versus lease analysis for the treatment system; and (3) Prepare a 1391C and PDB-1 Document for submission from the technical operations directorate to the installation service directorate at RMA

Concept Selection Northwest Boundary Containment System. Rocky Mountain Arsenal, Denver, Colorado

Background As many as 70% of veterans with chronic pain treated within the US Veterans Administration (VA) system may have posttraumatic stress disorder (PTSD), and conversely, up to 80% of those with PTSD may have pain. We describe pain experienced by US service members and veterans with symptoms of PTSD, and report on the effect of Accelerated Resolution Therapy (ART), a new, brief exposure-based therapy, on acute pain reduction secondary to treatment of symptoms of PTSD. Methods A randomized controlled trial of ART versus an attention control (AC) regimen was conducted among 45 US service members/veterans with symptoms of combat-related PTSD. Participants received a mean of 3.7 sessions of ART. Results Mean age was 41.0 + 12.4 years and 20% were female. Most veterans (93%) reported pain. The majority (78%) used descriptive terms indicative of neuropathic pain, with 29% reporting symptoms of a concussion or feeling dazed. Mean pre-/post-change on the Pain Outcomes Questionnaire (POQ) was −16.9±16.6 in the ART group versus −0.7±14.2 in the AC group (p=0.0006). Among POQ subscales, treatment effects with ART were reported for pain intensity (effect size = 1.81, p=0.006), pain-related impairment in mobility (effect size = 0.69, p=0.01), and negative affect (effect size = 1.01, p=0.001). Conclusions Veterans with symptoms of combat-related PTSD have a high prevalence of significant pain, including neuropathic pain. Brief treatment of symptoms of combat-related PTSD among veterans by use of ART appears to acutely reduce concomitant pain.

Accelerated Resolution Therapy for treatment of pain secondary to symptoms of combat-related posttraumatic stress disorder

Prospective Imaging of Mild Traumatic Brain Injury: Assessing Variability

P.5.110 Can ampakines reverse cognitivedeficits in healthy adults?

BACKGROUND AND PURPOSE
Although concussion is common among athletes, evidence-based methods for clinical evaluation, treatment, and recovery are lacking. We used a prospective, functional neuroimaging approach to assess sports-related concussion in which imaging was performed before injury so that brain changes resulting from concussion could be better understood.

METHODS
Neurophysiologic correlates of sports-related concussion were investigated in eight college football players by using functional MR imaging. Preseason baseline levels of blood oxygen level-dependent (BOLD) activity were acquired during the performance of a test battery that included mathematical, memory, and sensorimotor coordination tasks. Four players who had a concussion repeated these baseline procedures within 1 week of injury. The remaining control players were retested at the end of the season.

RESULTS
Specific neural signatures of concussion were detected in individual players by comparing postconcussion results to preconcussion baseline values. The validity of these indicators was confirmed by comparing them with the same measures in noninjured control subjects. When compared with control subjects, concussed players had marked within-subject increases in the amplitude and extent of BOLD activity during a finger-sequencing task. Effects were observed primarily in the parietal and lateral frontal and cerebellar regions.

Differences in neural functioning were observed in the absence of observed deficits in behavioral performance, suggesting that this approach may increase sensitivity to concussion compared with neuropsychological evaluation alone. Though preliminary, the proposed prospective neuroimaging approach may have great potential for understanding mild traumatic brain injury and identifying mechanisms underlying recovery.

A prospective functional MR imaging study of mild traumatic brain injury in college football players.

Background: Heparin anticoagulation has been used successfully for cardiopulmonary bypass (CPB). However, an alternative anticoagulant approach is desirable due to the cases of heparin-induced thrombocytopenia. Dabigatran provides anticoagulation for an in vitro model of simulated CPB. The current analysis tests the hypothesis that dabigatran provides sufficient anticoagulation for CPB in intact rabbits. Methods: Nonlinear mixed effects models were used to estimate dabigatran parameters for a two-compartment pharmacokinetic model in 10 New Zealand White rabbits. A dabigatran infusion designed to maintain a plasma concentration of 90 µg/ml was run throughout CPB based on the pharmacokinetics. Animals were subjected to sternotomy and anticoagulated with IV dabigatran (six animals) or heparin (four animals). Rabbits were cannulated centrally using the right atrium and ascending aorta and CPB was maintained for 120 min. Measurement of activated clotting time, thromboelastometric reaction time, and blood gases were performed during CPB. Then, the animals were euthanized, and the brain and one kidney were removed for histology. Sections of the arterial filters were inspected using electron microscopy. Results: The observed dabigatran concentrations during CPB were greater than the target concentration, ranging from 137 ± 40 μg/ml at 5 min of CPB to 428 ± 150 μg/ml at 60 min, and 295 ± 35 μg/ml at 120 min. All rabbits completed 2 h of CPB without visible thrombosis. In the two groups, reaction time values were elevated, reaching 10,262 ± 4,198 s (dabigatran group) and 354 ± 141 s (heparin group) at 120 min of CPB. Brains and kidneys showed no evidence of thrombosis or ultrastructural damage. Sections of the arterial line filter showed minimal or no fibrin. There was no significant difference in outcomes between dabigatran- and heparin-treated animals. Conclusions: In this first-use, proof-of-concept study, the authors have shown that dabigatran provides acceptable anticoagulation similar to heparin to prevent thrombosis using a rabbit CPB model. The hypothesis that dabigatran would provide sufficient anticoagulation for cardiopulmonary bypass was tested in a first-use, proof-of-concept study using a rabbit model of cardiopulmonary bypass that included a comparison group receiving heparin. The dabigatran loading dose and maintenance infusions were designed after first determining its pharmacokinetics in rabbits and the target concentration in an in vitro simulation of cardiopulmonary bypass. Dabigatran provided acceptable anticoagulation to prevent thrombosis during 2 h of cardiopulmonary bypass in rabbits that was similar to that provided by heparin and was well tolerated despite accumulating well above the target concentration during the period of anesthesia and cardiopulmonary bypass.

Intravenous Dabigatran Provides Adequate Anticoagulation for Cardiopulmonary Bypass Using a Rabbit Model

FACTORS ASSOCIATED WITH 30-DAY AMPUTATION IN PATIENTS WITH CRITICAL LIMB ISCHEMIA UNDERGOING ENDOVASCULAR INTERVENTION

The selective α2-adrenoreceptor agonist dexmedetomidine has shown neuroprotective, analgesic, anti-inflammatory, and sympatholytic properties that may be beneficial in neonatal encephalopathy (NE). As therapeutic hypothermia is only partially effective, adjunct therapies are needed to optimize outcomes. The aim was to assess whether hypothermia + dexmedetomidine treatment augments neuroprotection compared to routine treatment (hypothermia + fentanyl sedation) in a piglet model of NE using magnetic resonance spectroscopy (MRS) biomarkers, which predict outcomes in babies with NE, and immunohistochemistry. After hypoxia-ischaemia (HI), 20 large White male piglets were randomized to: (i) hypothermia + fentanyl with cooling to 33.5°C from 2 to 26 h, or (ii) hypothermia + dexmedetomidine (a loading dose of 2 μg/kg at 10 min followed by 0.028 μg/kg/h for 48 h). Whole-brain phosphorus-31 and regional proton MRS biomarkers were assessed at baseline, 24, and 48 h after HI. At 48 h, cell death was evaluated over 7 brain regions by means of transferase-mediated d-UTP nick end labeling (TUNEL). Dexmedetomidine plasma levels were mainly within the target sedative range of 1 μg/L. In the hypothermia + dexmedetomidine group, there were 6 cardiac arrests (3 fatal) versus 2 (non-fatal) in the hypothermia + fentanyl group. The hypothermia + dexmedetomidine group required more saline (p = 0.005) to maintain blood pressure. Thalamic and white-matter lactate/N-acetylaspartate did not differ between groups (p = 0.66 and p = 0.21, respectively); the whole-brain nucleotide triphosphate/exchangeable phosphate pool was similar (p = 0.73) over 48 h. Cell death (TUNEL-positive cells/mm2) was higher in the hypothermia + dexmedetomidine group than in the hypothermia + fentanyl group (mean 5.1 vs. 2.3, difference 2.8 [95% CI 0.6-4.9], p = 0.036). Hypothermia + dexmedetomidine treatment was associated with adverse cardiovascular events, even within the recommended clinical sedative plasma level; these may have been exacerbated by an interaction with either isoflurane or low body temperature. Hypothermia + dexmedetomidine treatment was neurotoxic following HI in our piglet NE model, suggesting that caution is vital if dexmedetomidine is combined with cooling following NE.

Dexmedetomidine Combined with Therapeutic Hypothermia Is Associated with Cardiovascular Instability and Neurotoxicity in a Piglet Model of Perinatal Asphyxia

Background: Antifibrinolytic medications such as &egr;-aminocaproic acid (EACA) are used in pediatric heart surgery to decrease surgical bleeding and transfusion. Dosing schemes for neonates are often based on adult regimens, or are simply empiric, in part due to the lack of neonatal pharmacokinetic information. The authors sought to determine the pharmacokinetics of EACA in neonates undergoing cardiac surgery and to devise a dosing regimen for this population. Methods: Ten neonates undergoing cardiac surgery with cardiopulmonary bypass were given EACA according to standard practice, and blood was drawn at 10 time points to determine drug concentrations. Time-concentration profiles were analyzed using nonlinear mixed effects models. Parameter estimates (standardized to a 70-kg person) were used to develop a dosing regimen intended to maintain a target concentration shown to inhibit fibrinolysis in neonatal plasma (50 mg/l). Results: Pharmacokinetics were described using a two-compartment model plus an additional compartment for the cardiopulmonary bypass pump. First-order elimination was described with a clearance of 5.07 l/h × (WT/70)0.75. Simulation showed a dosing regimen with a loading dose of 40 mg/kg and an infusion of 30 mg · kg−1 · h−1, with a pump prime concentration of 100 mg/l maintained plasma concentrations above 50 mg/l in 90% of neonates during cardiopulmonary bypass surgery. Conclusions: EACA clearance, expressed using allometry, is reduced in neonates compared with older children and adults. Loading dose and infusion dose are approximately half those required in children and adults.

Pharmacokinetics of &egr;-Aminocaproic Acid in Neonates Undergoing Cardiac Surgery with Cardiopulmonary Bypass

The highly selective α2‐adrenoreceptor agonist, dexmedetomidine, exerts neuroprotective, analgesic, anti‐inflammatory and sympatholytic properties that may be beneficial for perinatal asphyxia. The optimal safe dose for pre‐clinical newborn neuroprotection studies is unknown.

Pharmacokinetics of dexmedetomidine combined with therapeutic hypothermia in a piglet asphyxia model

Dorsal penile nerve blocking (DPNB) has been used with success in decreasing neonatal stress during circumcision. This study was designed to confirm the effectiveness of lidocaine in DPNB and to demonstrate that chloroprocaine, a shorter acting anesthetic, is as effective in blocking circumcision stress as lidocaine, but, because of its shorter plasma elimination half-life and time of onset of action, is safer. Five groups of 15 neonates were matched for weight, age, and Apgar scores and randomly assigned to a control group, one lidocaine group and three chloroprocaine groups with 2-, 3- and 5-minute postinjection waiting periods. Each neonate was subjected to six events during circumcision for which heart rate, tissue oxygenation, and cry duration were recorded. We found that, as in previous investigations, DPNB with lidocaine was effective in reducing neonatal stress, as was evident from decreased excursion from baseline heart rate, tissue oxygenation, and cry duration when compared with the control group (nonblocked). Furthermore, chloroprocaine DPNB approximates the effectiveness of lidocaine, as was evident from decreased change from baseline cry duration, tissue oxygenation, and heart rate during the most stressful events, particularly in the 3-minute wait chloroprocaine group. This more rapid onset of regional anesthesia decreases DPNB circumcision time and benefits patients, parents, and physicians.

Dorsal penile nerve block in neonatal circumcision: chloroprocaine versus lidocaine.

The depth dependence of the SO42−, Mg2+, and Ca2+ contents of interstitial waters extracted from sediments in 140 Deep Sea Drilling Project/Ocean Drilling Program/Integrated Ocean Drilling Program drill holes on oceanic crust has been fit using a model of transport (advection and diffusion) and reaction. These drill holes come from a range of crustal ages, sediment types, sediment thicknesses, and sediment accumulation rates. The best fitting specific discharge through the sediment at these locations is estimated to be generally <500 m Myr−1 (0.05 cm yr−1), where sediments are thicker than 100 m, although an order of magnitude faster seepage is estimated for some locations with sediment tens of meters thick. Assuming that the drill holes are globally representative, then seepage of fluids through marine sediments at specific discharges of a few hundred m Myr−1 is estimated to be only a few percent of the total ridge flank hydrothermal fluid flux. This is consistent with the previous suggestion that hydrothermal fluid exchange between the ocean and the crustal aquifer primarily occurs through basement outcrops. Chemical fluxes of SO42−, Mg2+, and Ca2+ across the sediment‐water interface globally (excluding continental margins) are estimated to be less than 10% of the riverine input to the ocean.

Fluid seepage velocities through marine sediments constrained by a global compilation of interstitial water SO42−, Mg2+, and Ca2+ profiles

Hydrologic models of the oceanic crust commonly assume that the uppermost igneous extrusive layer of the aquifer is thermally well mixed, although this assumption has not been rigorously tested. Here, the assumption of a thermally well‐mixed aquifer is tested against the geological record using O isotope‐derived crystallization temperatures of carbonates in the lavas as a record of the temperatures experienced by the aquifer. It is found that carbonate formation temperatures are higher than can be explained by a model of outcrop‐to‐outcrop flow in a well‐mixed aquifer at four of the seven drilling locations analyzed. A poorly mixed aquifer is developed to further explore the crustal hydrology at these locations. Relative to a well‐mixed aquifer, a poorly mixed aquifer can achieve higher average temperatures, develops larger lateral pressure gradients driving flow, and requires a lower permeability to achieve a given lateral fluid flux. O isotope data from most of the carbonate samples analyzed are consistent with temperatures achievable in a poorly mixed aquifer; those samples which are not consistent can be explained by plausible special circumstances (such as formation at a discharge zone, where ascending fluid may warm the uppermost aquifer).

A hydrologic model for the uppermost oceanic crust constrained by temperature estimates from carbonate minerals

Publisher's Note: “A subgrid-scale model for large-eddy simulation based on the physics of interscale energy transfer in turbulence” [Phys. Fluids 24, 065104 (2012)]

[1] It has been proposed that ridge flank hydrothermal circulation by outcrop-to-outcrop (lateral) flow may be the dominant mode of oceanic hydrothermal circulation globally. In this model, the upper igneous crust is an aquifer overlain by low permeability sediments, and aquifer-ocean fluid exchange occurs through basement outcrops. Thermally induced pressure gradients drive fluid laterally from recharge outcrops to discharge outcrops. To test the global applicability of outcrop-to-outcrop flow, models of synthetic basement bathymetry representative of crust formed at different spreading rates, pelagic sediment supply and post depositional transport, and sediment hydraulic impedance are used to quantify the time-varying distribution of sediment and basement outcrops globally. Results suggest that basement outcrops may be 40–50% closer together than previously estimated. The modeled sediment and outcrop results are coupled with a two-dimensional model of outcrop-to-outcrop fluid flow and heat exchange in a vertically isothermal crustal aquifer to predict the spatial distributions of seafloor heat flow within the simulation region under this mode of hydrothermal circulation. It is found that both the time-varying average and standard deviation of modeled seafloor heat flow required by outcrop-to-outcrop flow simultaneously fit the global heat flow data if the average aquifer permeability decreases from ∼10−9 m2 to ∼10−11 m2 over the duration of the global heat flow deficit (to ∼65 Myr). This permeability range is consistent with other estimates of upper crustal permeability on comparable spatial scales, and supports the proposition that outcrop-to-outcrop fluid flow may be the dominant mode of off-axis hydrothermal circulation globally.

The role of outcrop-to-outcrop fluid flow in off-axis oceanic hydrothermal systems under abyssal sedimentation conditions

The scale-similarity model in large-eddy simulation (LES) leads to an attractive, functionally simple expression for the subgrid-scale (SGS) stress tensor. It is well known, however, that the similarity model fails to accurately predict some of the most fundamental quantities in turbulent flows, perhaps the most important being the global energy transfer and the associated subgrid-scale dissipation. To address this, additional dissipative terms are usually added to the similarity model to improve its performance. In the present paper, considerations of interscale energy transfer have been used to identify sources of the observed deficiencies of the similarity model, specifically its inadequate balancing of terms contributing energy to the smallest scales and its duplication of terms producing effects in the largest scales. These considerations provide guidance in the development of a new model, which shows more favorable characteristics of energy transfer while preserving the functional simplicity of the ...

A subgrid-scale model for large-eddy simulation based on the physics of interscale energy transfer in turbulence

Submitted for the DFD10 Meeting of The American Physical Society Development of a subgrid-scale similarity model for LES based on the physics of interscale energy transfer in turbulence BRIAN W. ANDERSON, JULIAN A. DOMARADZKI, University of Southern California — It is well known that scale-similarity models suffer from an insufficient SGS dissipation which causes them to fail in actual, time evolving LES of turbulent flows. We determine that this failure is due to the representation of the interscale energy transfer among the resolved scales which is incorrect for purposes of LES. Alternatives to previous forms of similarity models have been evaluated with the intent of improving upon the deficiencies of these models in predicting subgrid-scale energy dissipation. Expressions describing interscale turbulence interactions have been constructed using test-filtered velocity fields and these terms have been used to formulate an alternative model that offers improvements on the predictions of global energy flux from resolved to subgrid scales. Results for wall-bounded flow simulations indicate that improved predictions of mean and RMS flow quantities are possible. Julian A. Domaradzki University of Southern California Date submitted: 04 Aug 2010 Electronic form version 1.4

Development of a subgrid-scale similarity model for LES based on the physics of interscale energy transfer in turbulence

The Role of Lateral Fluid Flow in Off-Axis, Oceanic Hydrothermal Systems Under Abyssal Sedimentation Conditions

Wind tunnel testing has long been an important component common to many introductory fluid mechanics and aerodynamics courses. Demonstrations of the basic physical mechanisms of viscous and pressure drag associated with the formation of drag forces on various aerodynamic shapes are readily conducted using standard electronic or mechanical balance hardware. Experimental measurements of lift, drag, pitching moment, and pressure distribution on smallscale models likewise play a significant role in supporting basic fluid mechanics theory in such introductory courses. Understanding these physical characteristics is very important to automotive aerodynamic design, for maximizing fuel economy, and in the teaching of basic principles of aerodynamic design as applied to aircraft. In addition to the more common use of the wind tunnel as a tool for investigation of the aerodynamics of sting-mounted test models, however, the wind tunnel as a whole provides the means to demonstrate several significant principles of fluid mechanics and the application of these principles to engineering design. One such recent application of the wind tunnel involved instrumenting the entire wind tunnel for pressure distribution measurements, to demonstrate ideal inviscid fluid flow behavior, as well to illustrate the relative importance of various sources of mechanical energy losses to wind tunnel design. This paper presents the authors experience with modifying an Aerolab educational wind tunnel test facility for experimental work associated with an Undergraduate Campus Internship (CSI) mentoring program project. The purpose of this laboratory activity was to demonstrate characteristics of variable area duct flow and diffuser boundary layer separation using flow visualization by smoke injection. A simple modification to the test section region of the wind tunnel was made to conform to a converging and/or diverging (diffuser) duct flow configuration. This setup was used in conjunction with a special-purpose smoke rake injection system of our own design, and a relatively inexpensive low-power laser-based lighting system, for visualization of the associated air flow. The paper describes various ways of constructing and testing simple duct flows for the wind tunnel test section region using inexpensive materials, as well as the requirements for obtaining good quality flow visualization using smoke injection. The smoke visualization tests can potentially reveal the details of inviscid streamline flow for converging ducts or channels and the onset of boundary layer separation, along with various flow instabilities associated with discharge from a low-speed diverging (diffuser) duct outlet. The connection between diffuser and nozzle head loss behavior and boundary layer separation phenomena are also brought out in these experiments, and they should be adaptable to most educational wind tunnel laboratory test facilities.

A Simple Educational Wind Tunnel Setup For Visualization Of Duct Flow Streamlines And Nozzle/Diffuser Boundary Layer Separation

Laboratories which make use of wind tunnel experimentation play an important role in many undergraduate courses in the fluid and thermal sciences area, including those associated with aerodynamics and fluid mechanics courses. Measurements of the lift, drag and pitching moment behavior of airfoils as a function of angle of attack are a common occurrence in such labs. The importance of reinforcing theoretical aerodynamic concepts is clear, but the challenge is to provide meaningful experiments that demonstrate the desired effects without either introducing numerous extraneous phenomena, or overly complicating the experimental procedure. This paper presents the authors experience with an Aerolab educational wind tunnel test facility as part of course-related work in both junior-level Fluid Mechanics (ME571) and senior-level Aerodynamics (ME628) courses. The simple addition of several special-purpose pressure taps, to complement existing built-in pressure taps normally associated with the standard test section region, provide the means to map the axial pressure distribution within the entire wind tunnel. This allows direct identification of the location(s) of significant mechanical energy losses, through comparison with ideal inviscid stream tube analysis associated with fluid mechanics principles. In particular, the losses associated with the diffuser section become very apparent, in contrast with the inlet convergent section. Pressure recovery in the diffuser section is modeled in a very simple manner and compared directly with wind tunnel measurements. Fan power requirements associated with wind tunnel design are also included as part of the experimentation. The connection between diffuser loss behavior and boundary layer separation phenomena associated with flow over a wing is also brought out in these experiments.

AC 2007-2821: THE WIND TUNNEL AS A PRACTICAL TOOL FOR THE DEMONSTRATION OF ENGINEERING FLUID MECHANICS AND PRINCIPLES OF AERODYNAMIC DESIGN

Abstract : This report is concerned with the relation of meteorological conditions to parameters and processes that influence the optical propagation properties of the turbulent atmosphere. The approach is centered around the use of aircraft and surface based remote sensors to investigate the relationship of the refractive index structure function parameter, Cn-sq, to various meteorological variables and to generally evaluate the accuracy of measurements of Cn-sq by in situ and remote means. the relationship of the atmospheric turbulence profile to the synoptic context and the use of physical models to predict the profile using standard meteorological profile data was also investigated. The study features two modes of data acquisition: (1) continuous archiving of 1 hr average wind profiles and turbulence levels with VHF doppler radar profiles, and (2) high time resolution aircraft measurements in association with other measurements (ground based optical scintillometers, thermosondes, radar profilers, and doppler sodar profilers). In one case all of the surface based systems were assembled in an intensive campaign given the acronym EWAK. The atmospheric turbulence profiles and resultant optical propagation parameters have been found to be strongly influenced by synoptic conditions. In particular, the turbulence is substantially affected by the strength and location of jet stream. A very strong correlation between wind shear (which is maximum above and below the core of the jet) and pilot reports of turbulence was found. Richardson number gave a much weaker indication possibly because of the poorer quality of the vertical temperature gradient data. (JHD)

Atmospheric Turbulence Measurements in Support of Adaptive Optics Technology

Comparison between field mill and corona point instrumentation at Kennedy Space Center - Use of these data with a model to determine cloudbase electric fields

Abstract : Experimental results from a two year aircraft investigation of the atmospheric electrical and meteorological properties of the unstable planetary boundary layer (PBL) are reported. The primary objectives of the research were to 1) examine the strength of the electrode effect charge source over land and sea, and 2) obtain simultaneous measurements of meteorological and charge fluxes under varying conditions of atmospheric stability to test predictions of a second order closure model of charge transport. Soundings of electric field, conductivity, temperature, condensation nuclei, dew point, and turbulence structure functions for velocity, temperature and humidity along with surface temperatures and wind speeds were obtained over the desert in southeastern New Mexico in May 1986, and over water in the Bahamas in March 1987. Our results indicate 1) strong electrode layers form over the ocean but are often inhibited over land by surface radioactivity and 2) the shape and intensity of convection current profiles are dependent on electrical relaxation and turbulence intensity as predicted by the charge transport model.

Aircraft Investigation of the Turbulent Transport of Electric Charge through the Unstable Planetary Boundary Layer

Cost Reduction in E&P, IMR, and Survey Operations Using Unmanned Surface Vehicles

Rapid autonomous marine 4D (RAM4D): Developing unmanned 4D seismic surveys

Hydrospheric mass changes create subsurface stress perturbations on a scale that can trigger seismic events or accelerate frequency of seismicity on proximal faults. For example, groundwater pumping has been implicated in the 2011 Mw 5.1 earthquake in Lorca, Spain and the 2010 Mw 7.1 El-Mayor Cucapah earthquake in northern Baja California. Previous work on effects of pumping on seismicity is retrospective. We propose a method to assess changes in rupture potential on faults near areas of large-scale groundwater withdrawal before pumping begins. Changes in potentiometric head due to pumping predicted by (MODFLOW) groundwater flow models can be used as the change in surface load input for analytical solutions from Boussinesq [1885] to resolve changes in the subsurface state of stress. Coulomb stress, which quantifies a fault’s tendency toward failure, is then resolved on proximal faults. These stress changes can be compared with a 10 kPa stress threshold developed in previous work from statistical correlation of aftershock occurrence with spatial patterns of post-seismic Coulomb stress change on surrounding faults. Stress changes on critical to near-critically stressed faults above the threshold represent a higher likelihood of seismic rupture. The method is applied to a proposed groundwater development project in Spring Valley, Nevada. Proposed pumping in excess of 50 years will result in stress change on the proximal normal fault exceeding the 10 kPa threshold. This change in Coulomb stress is in the realm of earthquake-inducing pumping. However, the low seismic hazard in the region determined from geodetic and paleoseismic analysis does not suggest imminent rupture.

Analysis of fault rupture potential resulting from large-scale groundwater withdrawal: Application to Spring Valley, Nevada

Autonomous Surface Vehicle Operations in the Arctic: Regional Baseline Data Acquisition

This TB presents some operational or potential anti- and deicing systems (AI/DI). However, for a better understanding and appropriate application of the recommended techniques, the TB also informs on some fundamental aspects of ice accretion and its mechanical and thermodynamic behaviour. The promising potential of new materials such as AI coatings and the role of modern meteorological forecasting models for reliable use of AI/DI techniques are also discussed.

Systems for prediction and monitoring of ice shedding, anti-icing and de-icing for power line conductors and ground wires

Time lapse (or 4D) seismic monitoring of producing oil fields is an accepted method for optimisation of field development and product recovery, providing significant improvements in recovery rates and saving in drilling cost.. This paper provides an overview of the concept and design of an autonomous seismic node recording system, and a comparative analysis of using nodes versus permanent sensor cable installations for 4D seismic analysis and monitoring of an oil field. The node approach has only recently been used by industry, but the development and testing of these systems has been in progress for nearly 20 years. This paper illustrates node seismic instrumentation and operation, description of directional sensitivity or vector fidelity, and the application of node seismic to the Cantarell Field in Mexico, a field with an extensive network of pipelines and surface platforms, all of which are serious obstacles in the path of an accurate and well-sampled seismic survey. A quantitative description of navigation accuracy vs. water depth is provided, along with a comparative commercial analysis of the permanent cable installation at BP’s Valhall Field with an equivalent array of autonomous nodes.

Autonomous nodes for time lapse reservoir seismic an alternative to permanent seabed arrays

Ten years ago, the argument for permanent ocean-bottom cables (OBC) seemed compelling. Permanent OBC deployment would provide the best possible receiver repeatability, while wide-azimuth geometry would provide improved illumination as well as fracture characterization. Hydrophone-geophone (PZ) combinations would improve demultiple. Finally, multicomponent receivers would also record shear waves that would unravel the combined effects of lithology, porosity, and fractures for reservoir characterization, as well as the combined effects of fluid replacement and pressure changes for monitoring.

Boff Anderson, Peter van Baaren, Mark Daly, Will Grace, John Quigley, and Denis Sweeney 
of WesternGeco explain how the ‘interleaving’ of seismic surveys provides benefits in terms 
of time saved between exploration and development as well as reduced investment in seismic 
data acquisition over the asset life cycle. 
 
The traditional cycle of land seismic exploration first employs a broad regional 2D seismic exploration survey with widely spaced seismic lines. After initial interpretation, a further 2D grid of intersecting lines is acquired over large areas of interest. This grid would normally 
have lines intersecting every few kilometers or closer. Following up on these programmes there is often a need for 3D surveys to image discovered structures of interest in greater detail to provide information for well planning. 3D surveys may subsequently be repeated several times through the life of the field to successively improve the subsurface image and, hence, help guide the reservoir management process. This article demonstrates a solution for two of the main drawbacks to this traditional cycle of acquiring land seismic data: the time taken to move through the seismic exploration cycle, and the inefficient use of seismic surveys through the life cycle of an asset. 
 
Shortening the asset development cycle time 
The time between starting a 2D exploration programme and receiving high-quality images from 3D surveys suitable to make business decisions, such as planning drilling locations or placing surface facilities, can be significant. Initial 2D seismic data must be recorded, tapes shipped to a processing centre (often out of country), then processed and interpreted. The cycle is then repeated with 3D seismic surveys acquired one or more times to generate images of sufficient quality over the right areas to enable the business decisions to be made. This cycle can take one or more years to complete. 
The ideal exploration seismic survey scenario would allow immediate pursuit of exploration leads to appraise structures of interest as they are identified. A crew’s acquisition plan could be adjusted to record infill seismic data over the identified lead. This idea can be compared to recording infill lines in a marine seismic survey. Rather than the marine case of infilling to improve fold that was ‘missed’ on the first pass, in land acquisition, infilling can be used to improve the resolution of an image through increasing the trace density over structures as they are identified. On land, rather than referring to infill, the term ‘interleaving’ is more descriptive. Two step changes in acquisition and processing methodology are required to make this possible: first, the initial data must be acquired in a sparse 3D mode rather than a closely spaced 2D programme, and second, the data must be processed through to an interpretable image within the time frame of the acquisition.

Point-receiver seismic data offers new approach to managing onshore E&P development cycle

Site Reconnaissance for the EarthScope/USArray Transportable Seismic Array

Detailed mapping of Moho relief, crustal thickness, detailed basement structure, and a tectonic framework for the deepwater Gulf of Mexico has recently been completed. Input data for this work includes a 100 deepwater well velocity database, 95,000 line miles of newly acquired high-resolution gravity and bathymetry data, and 268,000 line miles of detailed aeromagnetics. The interpretation includes over three man-years of effort by senior project geophysicists. This poster presents a review of input data, interpretation flowchart, and a statistical analysis of deepwater discovery locations versus basement structure as illustrated in figure 5.

Detailed basement mapping in the deepwater Gulf of Mexico from integrated modeling

Visualizing Seafloor, Seismic, Gravity and Magnetics Data in the Deepwater Gulf of Mexico Improves Understanding of Geohazards, Salt and Seeps

Abstract Seismic depth migration continues to be an important, but expensive, tool for reducing exploration risks. Newly acquired high-resolution gravity data provide a low-cost method to enhance the seismic depth migration process by providing an independently measured constraint to the seismic velocity model. State-of-the-art commercial software tools enable rapid integration of the gravity and seismic data. In many geologic settings, integrated density/velocity modeling yields a more accurate velocity model than can be derived from the seismic data alone. A case study is presented to illustrate both steps employed in the data integration process and the resulting improvement in depth-migrated seismic data. End_of_Record - Last_Page 241-------

Abstract: Use of Gravity Data to Enhance Seismic Depth Migration

Summary During a marine seismic survey in 1997, conducted offshore Oman for Triton Oman Inc., a marine magnetometer was used to collect a new magnetic data set which is compared with a previously flown high-resolution aeromagnetic survey. Profile analysis is provided for purposes of a comparison between the two data types.

Comparison of a New Marine Magnetometer System to High-Resolution Aeromagnetic Data - A Case Study from Offshore Oman

A Synergistic Combination of Technologies: Multibeam Bathymetry, Acoustic Reflectivity, Gravity, and Magnetics in the Deepwater Gulf of Mexico

Abstract There is presently a massive increase in the addition of high-resolution gravity to seismic surveys all over the world. The reason behind this increase is improvements in gravity data resolution, increasingly difficult seismic imaging challenges, and better tools and technologies for incorporating gravity into the seismic workstation interpretation environment. Using a project workflow outline and case studies from the Deep Water Gulf of Mexico, we present a generalized approach for state of the art gravity application for the Gulf of Mexico explorationist. We also demonstrate a quantitative estimate of the relationship between gravity data accuracy, and anticipated accuracy of the interpreted geology.

A Report on the Renaissance of Gravity in the Deep Water Gulf of Mexico: A Practical View of Integration Methods

ABSTRACT Along with the tremendous increase in seismic activity in deep water areas of the Gulf of Mexico, the use of high-resolution gravity and magnetic data has also increased dramatically. The proper application of these data can result in enhanced seismic velocities, truly integrated geologic models, and decreased exploration risk. Using new interpretation case studies from the TGS-CALIBRE Geophysical Company Deep Water Reconnaissance Program (TGS Phase 45), the utility of incorporating gravity constraints on deep water interpretations can be clearly demonstrated. Since the Phase 45 program is comprised of long regional lines, a clearer view of the deep regional structure may also be interpreted from the data. The acquisition of high-resolution gravity and magnetic data, in conjunction with both 2-D and 3-D seismic surveys, has now become a standard procedure in the Gulf of Mexico. Several hundred OCS blocks of high-resolution gravity and large areas of high-resolution aeromagnetic data have been recently acquired and more acquisition is in progress. The use of high-resolution gravity in seismic velocity analysis and the use of velocity grids for localized, focused density input to gravity models are now commonly used. A brief review of instrumentation, costs, and integrated workstation software applications is provided to set the framework for the interpretation case studies. A detailed example of an integrated interpretation of a localized salt feature is provided from the Phase 45 area. Workstation applications now in use facilitate the direct transfer of data and models between seismic and gravity/magnetic modeling software systems. A demonstration of these tools is included in the presentation.

Integrated Interpretation in the Deep Water Gulf of Mexico Examples from the TGS Phase 45 Deep Water Reconnaissance Program

Abstract Recent advances in the acquisition, processing, and interpretation of gravity and magnetics methods now enable the use of these data for solving a wide range of seismic problems. In the summer of 1995, LCT in conjunction with Robertson Research International, Kevron Ply Ltd. and Oil Search Plc. acquired a unique airborne gravity, magnetics, and seepfinder survey over the Erlend Basin in the North Sea. A review of the gravity data from this survey demonstrates an accuracy approaching that of 2D marine surveys. There is an increasing number of marine 3D seismic surveys being acquired with concurrently recorded high resolution gravity and magnetics data. Instrumentation, navigation, and processing advances have led to significantly increased gravity and magnetics data resolution. State of the art workstation software tools provide a means for the integration of seismic, gravity, and magnetic data. Integrated interpretations have aided in the delineation of complex imaging problems including the verification and enhancement of seismic velocity models. A review is given of technical developments, economic considerations, and case studies in support of integrated 3D marine surveys utilizing gravity, magnetics, and seismic data.

In parallel with advances in 3-D seismic technology, there have also been a number of giant steps forward in non-seismic 3-D geophysical applications. Non-seismic methods, when recorded in conjunction with a 3-D seismic program, offer the benefit of an independently measured geophysical property which can be effectively used to verify, refine and constrain a 3-D velocity model and/or seismic interpretation. This is a dramatic change from more classical gravity- and magnetic-data applications, such as mapping of magnetic or high-density basement, basin delineation, sedimentary sequence thicknesses and volcanic rocks. This paper reviews these advances in 3-D gravity and magnetic survey methods.

Islet encapsulation with polyphenol coatings decreases pro-inflammatory chemokine synthesis and T cell trafficking.

 Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic b-cell lysis via reactive oxygen species (ROS), pro-inflammatory cytokines, and islet-infiltrating leukocytes. One promising treatment for T1D is islet transplantation, but its clinical application is constrained due to islet availability, adverse effects of immunosuppressants on islet function, and declining graft survival. Islet encapsulation may provide an immunoprotective barrier to aid in preserving function and curbing immune-mediated rejection post transplantation. We previously demonstrated that a cytoprotective nanothin multilayer coating consisting of tannic acid (TA), an immunomodulatory antioxidant, and poly (N-vinylpyrrolidone) (PVPON), curtailed immune responses involved in transplant rejection. We hypothesized that (PVPON/TA) coating may hinder the synthesis of redox-sensitive chemokines that recruit immune cells to sites of islet engraftment and blunt ROS-dependent cues necessary for M1 macrophage differentiation. (PVPON/TA) coatings elicited a 7-fold decrease in M1 macrophage-derived pro-inflammatory chemokines CCL5 and CXCL10, blunted M1 macrophage activation markers, and curbed diabetogenic CD4 T cell migration approximately 2-fold. Importantly, murine islet encapsulation with (PVPON/TA) material restored euglycemia in immunodeficient-diabetic mice post transplantation. Our studies demonstrate that (PVPON/TA) multilayer coatings represent a promising immunomodulatory biomaterial for islet transplantation. Future studies will evaluate the efficiency of PVPON/TA coated islets in curbing hyperglycemia by allotransplantation into diabetic rodent models.

Islet encapsulation with tannic acid-containing nanothin coatings modulates immune responses and restores euglycemia upon islet transplantation

 In Type 1 diabetes (T1D), infiltrating leukocytes secrete reactive oxygen species (ROS) and pro-inflammatory cytokines that participate in β-cell destruction and enhance T cell autoreactivity. We previously demonstrated that superoxide-deficient Non-obese diabetic (NOD.Ncf1m1J) mice were T1D-resistant due, in part, to blunted Th1 CD4 and cytotoxic CD8 T cell responses. To dissect the role of ROS on autoreactive CD4 T cells, we created the NOD.BDC-2.5.Ncf1m1J (BDC-2.5.Ncf1m1J) mouse with diabetogenic, superoxide-deficient CD4 T cells and hypothesized that reducing ROS would diminish autoreactivity. BDC-2.5.Ncf1m1J splenocytes stimulated with the BDC-2.5 mimotope or islets displayed elevated IFN-γ and pro-inflammatory chemokine ligands CXCL10 and CCL5 (p<0.05). BDC-2.5.Ncf1m1J CD4 T cells were more diabetogenic (p=0.002), with only 26% of transferred NOD.Rag (n=45) mice euglycemic at 10 days post transfer, in contrast to 56% of BDC-2.5-transferred mice (n=24). In vivo suppression assays revealed that enhanced diabetogenicity was due to defective Treg activity, as BDC-2.5.Ncf1m1J Tregs curbed T1D in only 33% of BDC-2.5-transferred NOD.Rag mice (n=9), while BDC-2.5 Tregs induced 70% protection (n=10). Our results highlight the intricate role that ROS induce and restrict T1D autoreactivity. Future studies will dissect the TCR adaptor molecule oxidation status in BDC-2.5.Ncf1m1J CD4 T cells, as these targets may reveal novel biomarkers for T1D progression and prevention.

Loss of NAPDH oxidase-derived superoxide exacerbates diabetogenic CD4 T cell effector responses (BA11P.122)

Reactive oxygen species (ROS) play prominent roles in numerous biological systems. While classically expressed by neutrophils and macrophages, CD4 T cells also express NADPH oxidase (NOX), the superoxide-generating multisubunit enzyme. Our laboratory recently demonstrated that superoxide-deficient nonobese diabetic (NOD.Ncf1m1J) mice exhibited a delay in type 1 diabetes (T1D) partially due to blunted IFN-γ synthesis by CD4 T cells. For further investigation of the roles of superoxide on CD4 T-cell diabetogenicity, the NOD.BDC-2.5.Ncf1m1J (BDC-2.5.Ncf1m1J) mouse strain was generated, possessing autoreactive CD4 T cells deficient in NOX-derived superoxide. Unlike NOD.Ncf1m1J, stimulated BDC-2.5.Ncf1m1J CD4 T cells and splenocytes displayed elevated synthesis of Th1 cytokines and chemokines. Superoxide-deficient BDC-2.5 mice developed spontaneous T1D, and CD4 T cells were more diabetogenic upon adoptive transfer into NOD.Rag recipients due to a skewing toward impaired Treg suppression. Exogenous superoxide blunted exacerbated Th1 cytokines and proinflammatory chemokines to approximately wild-type levels, concomitant with reduced IL-12Rβ2 signaling and P-STAT4 (Y693) activation. These results highlight the importance of NOX-derived superoxide in curbing autoreactivity due, in part, to control of Treg function and as a redox-dependent checkpoint of effector T-cell responses. Ultimately, our studies reveal the complexities of free radicals in CD4 T-cell responses.

Loss of NOX-Derived Superoxide Exacerbates Diabetogenic CD4 T-Cell Effector Responses in Type 1 Diabetes

 In autoimmune Type 1 diabetes (T1D), islet-infiltrating leukocytes synthesize noxious free radicals to collectively mediate b-cell lysis and enhance diabetogenic T cell responses as a pro-inflammatory third signal. We recently demonstrated a crucial role for NADPH oxidase (NOX)-dependent superoxide in T1D, as NOX-deficient Non-obese diabetic (NOD.Ncf1m1J) mice were highly resistant to autoimmune diabetes due to an enhanced alternatively-activated M2 macrophage phenotype, diminished pro-inflammatory cytokine and Type I interferon synthesis upon Toll-like receptor stimulation, dampened Th1 cytokine responses, and blunted CD8 T cell cytotoxicity. To further define the synergy between free radicals and T1D, we employed a 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) immuno-spin trapping technique to identify the generation of free radicals upon T cell activation and infection with Coxsackie B4 (CB4) virus, a putative diabetogenic enterovirus and hypothesized that NOD.Ncf1m1J immune cells would exhibit severe reductions in DMPO adducts. In the absence of superoxide, NOD.Ncf1m1J macrophages and CD4 T cells exhibited a significant decrease in DMPO adducts upon CB4 infection and autoantigen stimulation, respectively, in contrast to wild type cells. Future studies will utilize this technique to visualize the interface between free radicals and immune cells during spontaneous T1D progression and determine if immuno-spin trapping can be used as a biomarker during spontaneous T1D progression.

Immuno-spin trapping to detect immune-derived free radicals in type 1 diabetes (TECH2P.903)

 Reactive oxygen species (ROS) induces Type-1 diabetes (T1D) by directly killing pancreatic β-cells, triggering pro-inflammatory cytokine production, and promoting autoreactive T cell maturation. We hypothesize that free radical synthesis in T1D can synergize and enhance autoimmune responses in T1D onset and progression. Free radicals can be identified by immuno-spin trapping with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and utilizing a DMPO-specific antibody to detect DMPO-radical adducts. We previously reported a delay in spontaneous T1D onset in Non-obese diabetic (NOD) mice impaired in NADPH Oxidase (NOX)-derived superoxide synthesis (NOD.Ncf1m1J). Bone marrow-derived macrophages (BM-Mϕ) from NOD.Ncf1m1J mice infected with Coxsackie virus CB3 strain displayed a significant decrease (p<0.0001) in fluorescence intensity of DMPO adducts at 4, 6,12 and 24 hours post-infection concomitant with a decrease (p=0.0027) in STAT1 phosphorylation compared to NOD BM-Mϕ. CB3 infected-NOD.Ncf1m1J BM-Mϕ also exhibited a decrease in Tnfa (p=0.0037) and Ifih1 (p=0.002) mRNA accumulation in contrast with NOD BM-Mϕ. These findings suggest that anti-viral responses in NOD.Ncf1m1J BM-Mϕ are redox-regulated and were compromised by ROS-deficiency. Our results further illustrate the importance of NOX-derived superoxide in modulating autoimmune responses in T1D. Future studies will utilize immuno-spin trapping to visualize the interface between free radicals and immune cells during T1D progression.

Macrophage anti-viral responses to diabetogenic Coxsackie virus infections are mediated by free radicals (BA6P.134)

PURPOSE
Cisplatin, mitolactol (dibromodulcitol), and ifosfamide have been the most active single agents in squamous carcinoma of the cervix identified so far by the Gynecologic Oncology Group (GOG). Combinations of cisplatin plus ifosfamide and cisplatin plus mitolactol are prospectively compared with cisplatin alone.

Patients were randomized to receive cisplatin 50 mg/m2 or the same dose of cisplatin plus mitolactol (C + M) 180 mg/m2 orally on days 2 to 6, or cisplatin plus ifosfamide (CIFX) 5 g/m2 given as a 24-hour infusion plus mesna 6 g/m2 during and for 12 hours after the ifosfamide infusion, every 3 weeks for up to six courses. Of 454 patients entered, 438 were eligible and analyzed for response and survival.

RESULTS
CIFX had a higher response rate (31.1% v 17.8%, p = .004) and longer progression-free survival (PFS) time (P = .003) compared with cisplatin alone. The median times to progression or death were 4.6 and 3.2 months, respectively. C + M showed no significant improvement in these parameters compared with cisplatin alone. Survival was associated with initial performance score (PS; 0 was more favorable; P < .001) and with age (younger was unfavorable, P = .025). There was no significant difference in overall survival between cisplatin and either of the combinations. Leukopenia, renal toxicity, peripheral neurotoxicity, and CNS toxicity were more frequent with CIFX (P < .05).

CIFX improved the response rate and PFS duration in advanced cervix cancer compared with cisplatin alone, but at the cost of greater toxicity and with no improvement in survival.

Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study.

A techno-economic study of geothermal energy utilization in biorefineries is conducted using ASPEN Plus and corresponding economic analysis tools. The biorefinery is based on a gasification platform to produce synthesis gas, which in turn is synthesized to produce liquid transportation fuels. The biorefinery uses 2,000 metric tonnes of corn stover per day, and the products include hydrogen, gasoline, diesel fuel, and electricity. In this study, various streams of purchased steam are replaced by steam at 150°C derived from geothermal resources. Geothermal steam is used in various ways including as a gasifying agent, for syngas reforming, and biomass drying. Results show that the price of transportation fuels produced from the present biorefinery utilizing geothermal energy is comparable to that using the purchased steam. The major benefit of utilizing geothermal steam is the reduction of greenhouse gas emissions resulting from combustion of petroleum fuels used to generate the purchased steam.

TECHNO-ECONOMIC ANALYSIS OF BIOREFINERY UTILIZING GEOTHERMAL ENERGY FOR PROCESSING

Predicting genotoxicity of aromatic and heteroaromatic amines using electrotopological state indices.

INEL has radiologically contaminated nitrate salt and soil waste stored above and below ground in Pad A and the Acid Pit at the Radioactive Waste Management Complex. Pad A contain uranium and transuranic contaminated potassium and sodium nitrate salts generated from dewatered waste solutions at the Rocky Flats Plant. The Acid Pit was used to dispose of liquids containing waste mineral acids, uranium, nitrate, chlorinated solvents, and some mercury. Ex situ vitrification is a high temperature destruction of nitrates and organics and immobilizes hazardous and radioactive metals. Laboratory scale melting of actual radionuclides containing INEL Pad A nitrate salts and Acid Pit soils was performed. The salt/soil/additive ratios were varied to determine the range of glass compositions (resulted from melting different wastes); maximize mass and volume reduction, durability, and immobilization of hazardous and radioactive metals; and minimize viscosity and offgas generation for wastes prevalent at INEL and other DOE sites. Some mixtures were spiked with additional hazardous and radioactive metals. Representative glasses were leach tested and showed none. Samples spiked with transuranic showed low nuclide leaching. Wasteforms were two to three times bulk densities of the salt and soil. Thermally co-processing soils and salts is an effective remediation method formore » destroying nitrate salts while stabilizing the radiological and hazardous metals they contain. The measured durability of these low-level waste glasses approached those of high-level waste glasses. Lab scale vitrification of actual INEL contaminated salts and soils was performed at General Atomics Laboratory as part of the INEL Waste Technology Development and Environmental Restoration within the Buried Waste Integrated Demonstration Program.« less

Laboratory scale vitrification of low-level radioactive nitrate salts and soils from the Idaho National Engineering Laboratory

Interlaboratory study of a thermospray-liquid chromatographic/mass spectrometric method for selected N-methyl carbamates, N-methyl carbamoyloximes, and substituted urea pesticides

Cladding-pumped Raman laser with M^2 of 1.3 and 400 µJ first Stokes energy

Individual fiber amplifiers with increased average power while maintaining a narrow spectrum and excellent beam quality, enable power scaling of beam combined systems. To accomplish this, fiber amplifiers must contend with two well-known deleterious processes: thermal modal instability (TMI) and stimulated Brillouin scattering (SBS). Changing the fiber host material from silica glass to crystalline Yttrium Aluminum Garnet (YAG) has been reported as a potential means to increase the SBS and TMI power thresholds due to favorable material properties, mainly increased thermal conductivity and decreased electrostrictive constants. In this report, the development of numerical models to examine nonlinear effects in crystalline YAG fiber is described. Fiber simulation code previously developed at the Air Force Research Laboratory (AFRL) for silica are leveraged for crystalline gain media. Results show TMI threshold for a Ytterbium doped YAG (Yb:YAG) fiber 28 times higher than the equivalent silica fiber, and an increase in SBS threshold by over 250 times in YAG compared to silica. The investigations also include thresholds for Holmium doped YAG (Ho:YAG) and Thulium doped (Tm:YAG), which compare well with published experimental data.

Recent advances in thulium doped fibers have significantly improved the optical conversion efficiencies, indicating their potential utility for a variety of applications. Recently, kilowatt-class fiber amplifiers have been demonstrated with narrow linewidth operation. However, their limitations in scaling to higher powers aren’t well understood. While thermal mode instability (TMI) is a well-known limitation in ytterbium doped fiber amplifiers, no experimental data exists for CW thulium doped fiber amplifiers. As such, it’s difficult to quantify or predict when this limitation is expected to impact TDFA’s. Here, we report on the first measurements of TMI in CW thulium doped fiber amplifiers. We characterize the TMI threshold of both 20μm and 25μm fibers by measuring the beam quality, relative intensity noise (RIN), and polarization extinction ratio (PER). In particular, a strong dependence on the TMI threshold with the fiber length is noted. Counter intuitively, measurements show that short fibers have significantly higher TMI thresholds than longer fiber lengths; indeed doubling the fiber length can reduce the TMI threshold by almost 50%. By optimizing the fiber length, a 20/400μm thulium doped fiber amplifier is scaled to 905W, with 57% optical conversion efficiency and a linewidth 5 GHz.

A 1.1 kW CW fiber amplifier emitting at 1.95µm and phase modulated at 5 GHz, with 51% optical conversion efficiency and near diffraction limited beam quality (M2<1.1) is demonstrated. The fiber amplifier consists of 9m of active 20/400um thulium doped fiber, and 2m of passive delivery fiber. Several limiting nonlinearities critical to maintaining coherence were analyzed, including stimulated Brillouin Scattering and modulation instability. To our knowledge, this is the first kw-class thulium doped fiber amplifier operating with narrow linewidth.

Stimulated Brillouin scattering (SBS) is typically the lowest order nonlinearity encountered in ytterbium doped fiber amplifiers (YDFA), and the simplest means of suppressing it is though linewidth broadening from phase modulation. However, to maintain compatibility with beam combining techniques critical to scaling to high output powers, narrow linewidths are needed, and bandwidth efficient means of suppressing SBS are key to scaling to high powers. Here, the scalability of novel phase modulation techniques in combination with laser gain competition are explored. Ultimately, LGC is shown to improve the TMI threshold by 15%, and reduce the linewidth by a factor of 2.1. A 1.8 kW fiber amplifier with 7 Ghz linewidth is demonstrated.

SBS suppression techniques in high-power, narrow-linewidth fiber amplifiers

We present an overview of fiber amplifier power-scaling and beam-combining at AFRL. Nonlinear mitigation and power-scaling results of kW amplifiers is discussed. Here nonlinear suppression is attained through phase modulation and laser gain competition. Subsequently, five kW amplifiers were coherently combined into one 5kW beam.

2019 IEEE Research and Applications of Photonics in Defense Conference (RAPID)

High Power All-Fiber Amplifiers at Air Force Research Laboratory (AFRL)

In this chapter, several beam combining architectures suitable for DE applications have been reported, and are divided into two distinct categories: incoherent beam combination (IBC) and coherent beam combination (CBC). The purpose of each method is to increase the far field intensity when brightness and power of a single fiber amplifier is limited. In IBC, an array of fiber lasers is superimposed in the far field without control of the relative spectra or phases of the different fibers. No brightness enhancement is obtained from this method, limiting the maximum intensity in the far field. Although such beam combining has been successfully demonstrated by the Navy [5], this approach is limited to propagation ranges on the order of a few kilometers. In spectral beam combining (SBC), a separate class of IBC, incoherent beams of different wavelengths are spatially overlapped to create a single output beam of multiple colors. The brightness of the propagating beam can be increased at the cost of increased spectral bandwidth. Similarly, SBC has the advantage of not requiring active phase control or mutual temporal coherence of the individual beams. Alternatively, coherent beam combining (CBC) schemes require proper phase, frequency, and polarization relationships for efficient beam combination. Overall, due to their brightness enhancements, for longer range and higher power/ intensity DE applications, SBC and CBC are potentially more appealing.

Beam combinable, kilowatt all-fiber amplifiers for directed energy

The scalability of dual wavelength laser gain competition for the design of beam combinable, high power fiber amplifiers is analyzed by characterizing the nonlinear phase accumulated due to self and cross-phase modulation.

Nonlinear Characterization of a Kilowatt-class Amplifier Based on Laser Gain Competition

Pseudo random phase modulation signals have been shown to provide considerable stimulated Brillouin scattering (SBS) suppression in narrow linewidth Yb-doped all-fiber amplifiers. In terms of coherent beam combining, however, pseudo random signals display a linear drop in visibility; leading to pronounced drops in combining efficiencies for small path length deviations. To that end, we report a novel filtered pseudo random modulation approach for enhanced combining efficiency and coherence length performance. Here a low pass radio frequency (RF) filter is used to mitigate the PRBS high frequency components, thereby suppressing the sidelobes in the optical spectrum. This leads to an approximate Gaussian visibility function and improved coherence lengths of up to 27% in a kW class fiber amplifier (954 W). In addition, the spectral sidelobe suppression leads to concurrent SBS threshold enhancement due to a reduction in the spectral overlap between the Rayleigh reflected light and the Stokes shifted light. This reduction in the SBS seeding phenomena leads to ~10% SBS threshold improvements in a kW class fiber amplifier. Theoretical and experimental data is presented to substantiate the improved coherence length and SBS suppression. More importantly, the simultaneous nonlinear SBS suppression and coherence length benefits of the filtered PRBS approach can have a significant impact for high power, narrow linewidth, all-fiber amplifiers.

Filtered pseudo random modulated fiber amplifier with enhanced coherence and nonlinear suppression.

In this paper we report the generation of flat top optical spectrum using an arbitrary waveform generator to increase the SBS threshold in high power optical fiber amplifiers. The optical spectrum consists of a number of discrete spectral lines, ranging from 16 to 380, within the bandwidth of 2GHz, corresponding to line spacing between 133 MHz and 5 MHz. These discrete spectral lines correspond to a PRBS pattern of n = 4 to n = 8. The SBS threshold and coherence properties of the flat top spectrum are measured and compared to that of the filtered PRBS in a kilowatt class fiber amplifier. It is experimentally demonstrated that for large frequency line spacing, the flat top spectrum significantly outperforms the corresponding filtered PRBS, but as the line spacing is decreased to less than the Brillouin bandwidth, the two modulation waveforms have similar enhancement factors in the SBS threshold due to the enhanced crosstalk between neighboring frequency components.

SBS suppression and coherence properties of a flat top optical spectrum in a high power fiber amplifier

A diode pumped (793nm), long-wavelength thulium-doped all-fiber amplifier was demonstrated. Laser gain competition was used to suppress parasitic lasing and an output power of 80 W was generated at 2130nm with 50% optical efficiency.

We report power scaling results of a highly efficient narrow-linewidth monolithic Yb-doped fiber amplifier seeded with two signals, operating at 1038 and 1064 nm. With the appropriate seed power ratio applied, this technique was shown to suppress stimulated Brillouin scattering in conjunction with phase modulation, while generating the output power in predominantly the longer wavelength signal. Notably, the integration of laser gain competition with pseudo-random bit sequence phase modulation, set at a clock rate of 2.5 GHz and utilizing an optimized pattern to match the shortened effective nonlinear length, yielded 1 kW of output power. The beam quality was measured to be near the diffraction limit with no sign of transverse mode instability. Furthermore, the coherent beam combination performance of the amplifier provided a 90% combining efficiency with no indication of spectral broadening when compared to the single-tone case. Overall, the power scaling results represent a significant reduction in spectral linewidth compared to that of commercially available narrow-linewidth Yb-doped fiber amplifiers.

Beam combinable, kilowatt, all-fiber amplifier based on phase-modulated laser gain competition.

The design of Q-switched lasers capable of producing pulse widths of 100’s of picoseconds necessitates the cavity length be shorter than a few centimeters. Increasing the amount of energy extracted per pulse requires increasing the mode area of the resonator that for the same cavity length causes exciting higher order transverse modes and decreasing the brightness of the output radiation. To suppress the higher order modes of these multimode resonators while maintaining the compact cavity requires the use of intra-cavity angular filters. A novel Q-switched laser design is presented using transmitting Bragg gratings (TBGs) as angular filters to suppress the higher order transverse modes. The laser consists of a 5 mm thick slab of Nd:YAG, a 3 mm thick slab of Cr:YAG with a 20% transmission, one TBG aligned to suppress the higher order modes along the x-axis, and a 40% output coupler. The gratings are recorded in photo-thermo-refractive (PTR) glass, which has a high damage threshold that can withstand both the high peak powers and high average powers present within the resonator. Using a 4.1 mrad TBG in a 10.8 mm long resonator with an 800μm x 400 μm pump beam, a nearly diffraction limited beam quality of M2 = 1.3 is obtained in a 0.76 mJ pulse with a pulse width of 614 ps.

High brightness sub-nanosecond Q-switched laser using volume Bragg gratings

A low-pass filter is used to suppress the high-frequency components of a PRBS signal and is used to modulate a fiber amplifier. Notably, the coherence length and SBS threshold of a kilowatt-class amplifier are increased.

Enhanced psuedo-random phase modulation for high power fiber amplifiers

Laser gain competition was used in conjunction with external phase modulation techniques in order to investigate power scaling of narrow-linewidth monolithic Ytterbium-doped fiber amplifiers. In this study, both pseudo-random bit sequence (PRBS) and filtered white noise source (WNS) modulation techniques were separately utilized to drive the external phase modulator for linewidth broadening. The final-stage amplifier was then seeded with the phase modulated narrow-linewidth 1064 nm signal along with a spectrally broader 1038 nm source. Consequently, integration of laser gain competition in conjunction with PRBS phase modulation yields a factor of ∼15 dB in stimulated Brillouin scattering (SBS) threshold enhancement at a clock rate of 2.5 GHz; leading to 1 kilowatt of output power with 85% optical efficiency at 1064 nm. Notably, the combination of PRBS phase modulation with laser gain competition provided superior enhancement in SBS threshold power when compared to the WNS modulated case. The beam quality at maximum power was near the diffraction limit (M2 <1.2) with no sign of modal instability. Overall, the power scaling results represent a significant reduction in spectral linewidth compared to that of commercially available narrowlinewidth Ytterbium-doped fiber amplifiers.

Kilowatt-level narrow-linewidth monolithic fiber amplifier based on laser gain competition

We present multi-kW power scaling results of narrow line Yb-doped fiber amplifiers. Nonlinear suppression is attained through pseudo-random modulation. Subsequently, 5 pseudorandom modulated kW amplifiers were coherently combined into a 5kW beam.

Coherent Beam Combining and Nonlinear Suppression of Multi-Kilowatt All-Fiber Amplifiers

Power scaling results of a phase modulated two-tone fiber amplifier at clock rate of 2.5GHz are presented. Coherent beam combination performance of the two-tone amplifier yielded ∼90% combining efficiency with no sign of linewidth broadening.

Power Scaling and Coherent Beam Combination of a Narrow-Linewidth, Monolithic Two-Tone Fiber amplifier

We report results from two ~1.5 kW Yb-doped fiber amplifiers with comparable optical to optical efficiencies and linewidths. One amplifier utilized a fiber with a core diameter of 25 μm while the core diameter of the fiber utilized in the other amplifier was 20 μm. Stimulated Brillouin scattering (SBS) suppression in both cases was achieved through pseudo-random bit sequence (PRBS) phase modulation. While the power generated in the larger core fiber was modal instability (MI) limited, no sign of MI was observed in the smaller core fiber. This may allow us to utilize the higher MI threshold fiber to scale further while maintaining sufficiently narrow linewidth for beam combining. Furthermore, in a demonstration of the utility of applying a thermal gradient in conjunction with phase modulation to suppress SBS further, we report on a 1 kW amplifier driven at a PRBS clock rate of 2 GHz. Finally, we compare the coherent beam combining properties of amplifiers seeded with PRBS phase modulated sources to those seeded with white noise sources.

Multi-kilowatt power scaling and coherent beam combining of narrow-linewidth fiber lasers

We report efficient coherent beam combining of five kilowatt-class fiber amplifiers with a diffractive optical element (DOE). Based on a master oscillator power amplifier (MOPA) configuration, the amplifiers were seeded with pseudo random phase modulated light. Each non-polarization maintaining fiber amplifier was optically path length matched and provides approximately 1.2 kW of near diffraction-limited output power (measured M2<1.1). Consequently, a low power sample of each laser was utilized for active linear polarization control. A low power sample of the combined beam after the DOE provided an error signal for active phase locking which was performed via Locking of Optical Coherence by Single-Detector Electronic-Frequency Tagging (LOCSET). After phase stabilization, the beams were coherently combined via the 1x5 DOE. A total combined output power of 4.9 kW was achieved with 82% combining efficiency and excellent beam quality (M2<1.1). The intrinsic DOE splitter loss was 5%. Similarly, losses due in part to non-ideal polarization, ASE content, uncorrelated wavefront errors, and misalignment errors contributed to the efficiency reduction.

Multi-kW coherent combining of fiber lasers seeded with pseudo random phase modulated light

Power scaling investigation of a narrow-linewidth, Ytterbium-doped all-fiber amplifier operating at 1034 nm is presented. Nonlinear stimulated Brillouin scattering (SBS) effects were suppressed through the utilization of an external phase modulation technique. Here, the power amplifier was seeded with a spectrally broadened master oscillator and the results were compared using both pseudo-random bit sequence (PRBS) and white noise source (WNS) phase modulation formats. By utilizing an optical band pass filter as well as optimizing the length of fiber used in the pre-amplifier stages, we were able to appreciably suppress unwanted amplified spontaneous emission (ASE). Notably, through PRBS phase modulation, greater than two-fold enhancement in threshold power was achieved when compared to the WNS modulated case. Consequently, by further optimizing both the power amplifier length and PRBS pattern at a clock rate of 3.5 GHz, we demonstrated 1 kilowatt of power with a slope efficiency of 81% and an overall ASE content of less than 1%. Beam quality measurements at 1 kilowatt provided near diffraction-limited operation (M2 < 1.2) with no sign of modal instability. To the best of our knowledge, the power scaling results achieved in this work represent the highest power reported for a spectrally narrow all-fiber amplifier operating at < 1040 nm in Yb-doped silica-based fiber.

Kilowatt high-efficiency narrow-linewidth monolithic fiber amplifier operating at 1034 nm

The design of high power lasers requires large mode areas to overcome various intensity driven nonlinear effects. Increasing the aperture size within the laser can overcome these effects, but typically result in multi-transverse mode output and reduced beam quality, limiting the brightness of the system. As one possible solution, the angular selectivity of a diffractive optical element is proposed as a spatial filter, allowing for the design of compact high brightness sources not possible with conventional methods of transverse mode selection. This thesis explores the angular selectivity of volume Bragg gratings (VBGs) and their use as spatial transverse mode filters in a laser resonator. 
Selection of the fundamental mode of a resonator is explored using transmission Bragg gratings (TBGs) as the spatial filter. Simulations and experimental measurements are made for a planar, 1 cm long resonator demonstrating near diffraction limited output (M2 < 1.4) for aperture sizes as large as 2.0 mm. Applications to novel fiber laser designs are explored. Single mode operation of a multi-mode Yb3+ doped ribbon fiber laser (core dimensions of 107.8 ?m x 8.3 ?m) is obtained using a single transmission VBG as the filter in an external cavity resonator.
Finally, a novel method of selecting a pure higher order mode to oscillate within the gain medium while simultaneously converting this higher order mode to a fundamental mode at an output coupler is proposed and demonstrated. A multiplexed transmission VBG is used as the mode converting element, selecting the 12th higher order mode for amplifications in an Yb3+ doped ribbon fiber laser, while converting the higher order mode of a laser resonator to a single lobed output beam with diffraction limited divergence.

Transverse mode selection and brightness enhancement in laser resonators by means of volume Bragg gratings

Power scaling using a higher order mode in a ribbon fiber has previously been proposed. However, methods of selecting the higher order mode and converting to a single lobe high brightness beam are needed. We propose using a multiplexed transmitting Bragg grating (MTBG) to convert a higher order mode into a single lobe beam. Using a ribbon fiber with core dimensions of 107.8 μm by 8.3 μm, we use the MTBG to select a higher order mode oscillating within the resonator with 51.4% efficiency, while simultaneously converting the higher order mode to a beam with diffraction limited divergence of 10.2 mrad containing 60% of the total power.

Higher order mode selection for power scaling in laser resonators using transmitting Bragg gratings

Optical linewidth broadening through both white noise (WNS) and pseudo-random binary sequence (PBRS) phase modulation are effective techniques for suppressing stimulated Brillouin scattering (SBS) in high- power fiber amplifiers. However, detailed studies comparing both coherent beam combining and SBS suppression of these phase modulation schemes have not been reported. In this study, a passive fiber cutback experiment is performed comparing the SBS threshold enhancement factor of a PRBS and WNS broadened seed as a function of linewidth and fiber length. Particularly, assuming an optimal PRBS pattern is chosen, pseudo-random modulation provides superior SBS suppression than WNS for a given fiber length and signal linewidth. Furthermore, two WNS and PRBS modulated 150 W fiber lasers are coherently combined to measure and compare the combining efficiency, beam quality, and coherence as a function of optical path length difference. Notably, the discrete spectral density of PRBS modulation provides a re-coherence effect where the lasers periodically come back into phase. Overall, this may reduce path length matching complexity in coherently combined fiber laser systems.

Comparison of phase modulation schemes for coherently combined fiber amplifiers.

Increasing the dimensions of a waveguide provides the simplest means of reducing detrimental nonlinear effects, but such systems are inherently multi-mode, reducing the brightness of the system. Furthermore, using rectangular dimensions allows for improved heat extraction, as well as uniform temperature profile within the core. We propose a method of using the angular acceptance of a transmitting Bragg grating (TBG) to filter the fundamental mode of a fiber laser resonator, and as a means to increase the brightness of multi-mode fiber laser. Numerical modeling is used to calculate the diffraction losses needed to suppress the higher order modes in a laser system with saturable gain. The model is tested by constructing an external cavity resonator using an ytterbium doped ribbon fiber with core dimensions of 107.8μm by 8.3μm as the active medium. We show that the TBG increases the beam quality of the system from M2 = 11.3 to M2 = 1.45, while reducing the slope efficiency from 76% to 53%, overall increasing the brightness by 5.1 times.

Brightness enhancement of a multi-mode ribbon fiber using transmitting Bragg gratings

White noise phase modulation (WNS) and pseudo-random binary sequence phase modulation (PRBS) are effective techniques for mitigation of nonlinear effects such as stimulated Brillouin scattering (SBS); thereby paving the way for higher power narrow linewidth fiber amplifiers. However, detailed studies comparing both coherent beam combination and the SBS suppression of these phase modulation schemes have not been reported. In this study an active fiber cutback experiment is performed comparing the enhancement factor of a PRBS and WNS broadened seed as a function of linewidth and fiber length. Furthermore, two WNS and PRBS modulated fiber lasers are coherently combined to measure and compare the fringe visibility and coherence length as a function of optical path length difference. Notably, the discrete frequency comb of PRBS modulation provides a beam combining re-coherence effect where the lasers periodically come back into phase. Significantly, this may reduce path length matching complexity in coherently combined fiber laser systems.

Beam combining and SBS suppression in white noise and pseudo-random modulated amplifiers

White noise phase modulation is an effective technique capable of increasing the SBS threshold in high power fiber amplifiers. Theoretical models predict the enhancement factor as a function of linewidth and fiber length, but have yet to be experimentally verified over wide ranges of these variables. We present results on a cut-back experiment performed on a passive fiber with a white-noise broadened laser, measuring the SBS enhancement factor as a function of fiber length and bandwidth. In addition, the experimental results will be compared to phase modulation models of the SBS process in optical fibers.

Experimental study of SBS suppression via white noise phase modulation

We propose to use transmitting volume Bragg gratings recorded in photo-thermo-refractive glass as high efficient intracavity angular filters in order to achieve high beam quality while using large aperture active medium. The paper describes implementation of novel compact cavity design for solid state lasers, laser diodes, fiber crystal lasers and others.

Novel laser cavity design by way of transmitting volume Bragg gratings

Power scaling of high power laser resonators is limited due to several nonlinear effects. Scaling to larger mode areas can offset these effects at the cost of decreased beam quality, limiting the brightness that can be achieved from the multi-mode system. In order to improve the brightness from such multi-mode systems, we present a method of transverse mode selection utilizing volume Bragg gratings (VBGs) as an angular filter, allowing for high beam quality from large mode area laser resonators. An overview of transverse mode selection using VBGs is given, with theoretical models showing the effect of the angular selectivity of transmitting VBGs on the resonator modes. Applications of this ideology to the design of laser resonators, with cavity designs and experimental results presented for three types of multimode solid state lasers: a Nd:YVO4 laser with 1 cm cavity length and 0.8 mm diameter beam with an M2 of 1.1, a multimode diode with diffraction limited far field divergence in the slow axis, and a ribbon fiber laser with 13 cores showing M2 improved from 11.3 to 1.5.

Transverse mode selection in laser resonators using volume Bragg gratings

Selection of the fundamental mode of an active large mode area "ribbon" fiber laser with core dimensions of 107.8 μm by 8.3 μm was produced by a transmitting Bragg grating (TBG) in a free-space resonator. The multimode performance of the original laser was characterized to have an M2 of 11.3 with an absorbed power slope efficiency of 76%. With the TBG aligned to provide maximum diffraction efficiency for the fundamental mode, the M2 improved to 1.45 at an absorbed power slope efficiency of 54% and enhanced the brightness by 5.1 times.

Fundamental mode operation of a ribbon fiber laser by way of volume Bragg gratings.

Volume Bragg gratings (VBG) recorded in photo-thermo refractive glass (PTR) have high stability, and high damage threshold, allowing for many applications to the design of high power lasers. Gratings recorded in the transmitting geometry (TBG) have narrow angular selectivity, and can be used as a spatial filter in a resonator. Such gratings have previously been useful for improving the brightness of high power diodes, and increasing the beam quality in rod geometry solid state lasers. As the gratings have narrow angular selectivity, losses for higher order modes in the resonator no longer depend on the cavity length, allowing for the construction of short cavities with large mode areas. In this paper, we explore the design of short 1cm cavities using two TBGs as a spatial filter and no aperture in the cavity. The M2 parameter as a function of pump size and angular selectivity of the TBG are explored, using pump diameters ranging from 800um to 2mm and angular selectivity ranging from 11mrad to 1.8mrad. An M2 parameter of 1.05 is reported for an 800μm pump diameter, a 6.2mrad TBG, and a 1cm long cavity.

Compact cavity design in solid state resonators by way of volume Bragg gratings

Volume Bragg Gratings (VBG) are holographic elements recorded in Photo-Thermo-Refractive (PTR) glass. They are relatively new invention of the last decade that has been successfully used for high power and high spectral density laser beam combining [1]. Main application of these beams include laser beam welding and cutting. Further demand for increased output power of these systems implies necessity for higher output powers of each separate laser. This in turn creates higher heat deposition in working optical elements such as VBG's, and leads to thermal deformation of PTR glass plates. These changes of shape or thickness of grating may cause substantial deterioration of output beam quality and even change of spectral transmission range. In this work we consider one of the cheapest and most efficient ways of reduction of these negative effects by means of cooling the system by forced airflow. This method was recently suggested by Venus et. al. [2]. A realistic model of the setup for this type of cooling is developed and studied using COMSOL Multiphysics®. The schematic of the setup is shown on Fig. 1 for one VBG and a copper holder with slits for air cooling. Geometric dimensions of the VBG were taken to be 2.2 x 2.2 x 0.274 cm which are typical for many applications. Modeling was conducted for four laser beam intensities of 4.5KW, 6.7KW, 8.9KW, 11KW and seven evenly incremented rates of cooling airflow. Temperature of the incoming flow was taken to be 20 degrees Celsius and corresponded to the ambient temperature in the system. Beam intensity distribution was taken as Gaussian, with beam width of 3mm (FWe^(-2)IM) and its axis perpendicular to face of VBG (Fig 2a). In our model, we obtained data for spatial mean temperature increase in the VBG along the axis of heating beam and compared it with data obtained from an experimental setup with the same parameters. These results are shown on Fig 3. They indicate that our model is adequate for prediction of behavior of real systems. Discrepancy between modeled and experimental temperature increase was around 15%, with the maximum reaching 27% for some combinations of laser power and rate of air flow. Calculations of the same type were conducted for a model, where airflow was limited by two transparent glass plates, presumably allowing for more efficient cooling at the same rates of airflow as before (Fig 2b). This assumption was proven to be correct both by our modeling and by the experiment (Fig 4). While measurement of each new parameter of the system in physical experiment requires special arrangements, in our model we obtained information about some of those parameters (airflow velocity distribution, non-axial temperature distribution, etc.) along with computation of main parameters. This substantially contributed to understanding of the system behavior. To conclude, forced air cooling of VBG proved to be efficient for reducing thermal deformations caused by laser heating. Results obtained within framework of our model are consistent with experiment.

Effects of Forced Airflow Cooling on Laser Beam Heating of Volume Bragg Gratings

Volume Bragg gratings have been successfully used in spectral beam combining of high power fiber lasers with narrow channel separation and in four channel passive coherent beam combining of fiber lasers. Future application of beam combining with kilowatt level lasers requires a more detailed understanding of how to cool the gratings without hurting beam quality. Forced air cooling blown across both surfaces of the grating is both easy and cheap, but has been avoided in the past due to concerns of how the air density fluctuations will hurt beam quality. It is now shown that forced air cooling has no adverse effect on the M2 parameter due to density fluctuations in the air, and can efficiently cool VBG’s such that no degradation in beam quality is seen due to thermal distortions.

Forced air cooling of volume Bragg gratings for spectral beam combination

A 1cm long cavity with 800um pump diameter is built using a thin slab of Nd:YVO4. The narrow angular selectivity of a transmitting VBG is used to produce an M2 of 1.05.

Transverse Mode Selection in Solid State Resonators by Way of Volume Bragg Gratings

In order to generate high power laser radiation it is often necessary to combine multiple lasers into a single beam. The recent advances in high power spectral beam combining using multiplexed volume Bragg gratings recorded in photo-thermo-refractive glass are presented. The focus is on using multiple gratings recorded within the same volume to lower the complexity of the combining system. Combining of 420 W with 96% efficiency using a monolithic, multiplexed double grating recorded in PTR glass is demonstrated. A multiplexed quadruple grating that maintains high efficiency and good beam quality is demonstrated to pave a way for further scaling of combining channels.

Scaling the spectral beam combining channels in a multiplexed volume Bragg grating.

The recent development of kW fiber laser sources makes the concept of laser systems operating at power levels from tens of kilowatts up to 100-kilowatt levels a reality. The use of volume Bragg gratings for spectral beam combining is one approach to achieve that goal. To make such systems compact, lower the complexity and minimize the induced thermal distortions we propose and demonstrate the use of special volume Bragg elements which have several Bragg gratings written inside as combining optical components. The multiplexed volume Bragg gratings (MVBGs) were recorded in photo-thermo refractive glass and three beams with total power of 420 W were successfully combined using one MVBG. The combining efficiency was 97% and there was no significant beam quality degradation. The results demonstrated that the approach of using multiplexed volume Bragg gratings for spectral beam combining is an excellent extension to the current state of the art combining techniques. Especially valuable is the capability to reduce the number of optical elements in the system and while being able to manage the expected thermal load when kilowatt level sources are used for beam combining.

Multiplexed volume Bragg gratings for spectral beam combining of high power fiber lasers

Little is known about the lipid composition of cold-adapted dinoflagellates. Here, we investigate Peridinium aciculiferum and Scrippsiella hangoei, two cold-adapted dinoflagellate morphospecies that present significant differences in general morphology, physiology and habitat, but which share identical ribosomal DNA (rDNA) sequences, indicating a recent evolutionary divergence between them. Despite their present taxonomic names, it is now known that these two genetically isolated morphospecies are evolutionarily related to the so-called Pfiesteria-like species. We have found that chloroplast-associated glycolipids from P. aciculiferum and S. hangoei contained a higher relative percentage of two polyunsaturated C18 fatty acids (octadecapentaenoic [18:5(n-3)] and octadecatetraenoic [18:4(n-3)] acids), and a lower relative percentage of hexadecanoic acid (16:0) than typically observed in previously examined warm-adapted dinoflagellate species. This suggests that these two fatty acids provided the requisite membrane fluidity for chloroplasts under a cold growth condition in these two organisms. A similar increase in 18:5(n-3) and 18:4(n-3) over warm-adapted species was also found in the phospholipids and triglycerides. P. aciculiferum and S. hangoei were also examined for the production of unique sterols that may serve as chemical biomarkers. Both were found to have a very similar sterol composition, consisting of two common dinoflagellate sterols, cholestanol and dinostanol, as dominant sterols, along with a number of other common dinoflagellate sterols as minor sterols. This demonstrated the absence of a specific steroidal biomarker but, more importantly, showed that these two morphospecies still produce very similar sterols despite having diverged in several other traits.

Fatty acid and sterol composition of two evolutionarily closely related dinoflagellate morphospecies from cold Scandinavian brackish and freshwaters

Fattening and fatty acid synthetase in juvenile richardson's ground squirrels

Whole-body lipids andfatty acid synthetase (FAS) activity of liver, white adipose tissue (WAT), and brown adipose tissue (BAT) infield-caught Richardson's ground squirrels were measured to determine the effects of reproduction on fattening. Whole-body lipids increased by 9 g and 8 g/wk, respectively, in males and nonparous females between April 1 and June 5 and by 10 g/wk between May 10 and July 1 inparous females. Males were always heavier than nonparous females, but thepercentage of body mass that was lipid was similar. The lipid mass accumulated by parous females by July 1 had been achieved by nonparousfemales 1 mo earlier. For both liver and WAT, FAS activity in males and nonparous females was similar throughout the active season. FAS activity of liver was depressed in late pregnancy. FAS activity of both liver and WAT was depressed during lactation, being 70 times greater in WAT of nonparous than of parous females. FAS activity in WAT and liver of postlactating females increased, but there was no compensatory increase in rate of fattening or FAS activity above that in males and nonparous females. Apparently, parous females hibernate later than other adults because reproduction causes them to initiate fattening later, and, once initiated, rate offat deposition is similar to that in other members of the population. WAT appears to be the principal tissue of fatty acid synthesis for prehibernation fattening.

Whole-Body Lipids and Fatty Acid Synthetase Activity in Richardson's Ground Squirrels, Spermophilus richardsonii

Comparative biochemistry and physiology. A, Comparative physiology

Fatty acid synthetase in control, starved and refed Richardson's ground squirrels.

Motional Dynamics of Fatty Acids: Advantages of 15N and Deuterium Substituted Fatty Acid Spin Labels for Studies of Lipid-Protein Interactions and Motion in Membrane Bilayers

A Study of a Population of Passer domesticus that has been Shown to the Carrying St. Louis Encephalitis

Risk Factors for and Rate of Development of Venous Thromboembolism in Lateral Skull Base Surgery

Risk Factors Associated with Necessity for Intensive Care Utilization in Lateral Skull Base Surgery

Pisa syndrome, defined as dystonia leading to lateral flexion of the spine, is an increasingly recognized complicating factor in the treatment of Parkinson’s disease (PD). Symptoms may persist despite medical therapy, or medical therapy may not be tolerated due to adverse effects. Here, we demonstrate the long-term efficacy of deep brain stimulation (DBS) at the globus pallidus internus (GPi) for the treatment of Pisa syndrome. One patient with Pisa syndrome and Parkinson disease underwent bilateral GPi DBS with computed tomography (CT)-and microelectrode-based guidance. Follow-up with neurosurgery and neurology was done over a four-year period. The patient’s axial deformity decreased from approximately 45 to 25 degrees, and he reported significant relief from back pain. Bilateral GPi DBS is a safe and effective option for Pisa syndrome in patients with PD.

Long-term Outcome of Globus Pallidus Internus Stimulation for Pisa Syndrome

Intracranial lipomas represent approximately 1% of intracranial lesions generally felt to represent the abnormal persistence of the meninx primitiva and are commonly accompanied by various developmental brain abnormalities. We report a case of midline intracranial lipoma and evolving frontal lobe fluid-attenuated inversion recovery (FLAIR) abnormality concerning for glial neoplasm in a patient with intractable epilepsy. Our case shows evolving magnetic resonance imaging (MRI) features over two decades raising suspicion for low-grade neoplasm which was ultimately found to represent cortical dysplasia.

Pericallosal Lipoma and Cortical Dysplasia Masquerading as a Glioma

W e read and reviewed the article “Outpatient Cervical and Lumbar Spine Surgery is Feasible and Safe: A Consecutive Single Center Series of 1449 Patients” by Helseth et al, published in Neurosurgery in June 2015. The authors of this study set out to show that, with careful patient selection and the correct circumstances, surgery for degenerative spine disease can be done safely at an outpatient facility. In the traditional PICO format (population, intervention, control, outcome), the authors studied patients undergoing anterior cervical discectomy and fusion (ACDF), posterior cervical foraminotomy, and lumbar microsurgical decompression in an outpatient setting. They compared their results with those of previously published studies and looked at multiple complications, including mortality, hematoma, hospital admission, and readmission. Because of the increasing demand for surgical management of degenerative spine disease and the limited health resources to meet these demands, the authors felt that showing that such surgery could be done safely in an outpatient setting was an important finding. It is easy to see why the use of outpatient facilities in this situation would certainly increase the resources available significantly.

Journal Club: Outpatient Cervical and Lumbar Spine Surgery Is Feasible and Safe: A Consecutive Single Center Series of 1449 Patients.

W e read with interest and were happy to review the article by Taylor, “Neurosurgical Practice Liability: Relative Risk by Procedure Type,” published in Neurosurgery in December 2014. In this study, the author examined the association between neurosurgical subspecialty and litigation using professional and liability insurance databases. “Exposure” (type of neurosurgical procedure) was measured using the 2006 American Association of Neurological Surgeons (AANS) practice survey and outcomes were taken from the Physician Insurance Association of America Data Sharing Project (PIAA DSP), a large database of medical professional liability carriers. The study question, summarized in PICO format (population, intervention, comparator, outcome), was whether the incidence and expense of claims after spine surgery differ compared with claims after cranial, cerebrospinal fluid shunting, peripheral nerve, functional, endovascular, and extracranial cerebrovascular cases. Additionally, indemnity, common alleged factors, and disposition of claims were explored. The author frames the studywithin the context of the challenge of litigation in neurosurgical practice, pointing out that neurosurgeons have the greatest exposure to litigation of all specialties. Improved understanding of factors responsible for this may allow neurosurgeons to minimize exposure and improve patient satisfaction. Furthermore, studies seem to indicate that litigation is most common after spine surgery. Because spine surgery is a common procedure in neurosurgical practice, the author questions whether the incidence of spine claims is truly greater than other subspecialties (eg, cranial). These are important questions with significant implications. Neurosurgeons spend nearly a third of their career with an openmalpractice claim. If risk factors for litigation can be identified, they can be studied carefully. Increased understanding of practice liability will allow neurosurgeons to minimize risk as well as improve patient care and the trust that is essential for effective physician-patient relationships.

Journal Club: Neurosurgical Practice Liability: Relative Risk by Procedure Type.

Summary Background Aneurysmal rupture accounts for the majority of nontraumatic subarachnoid hemorrhage (SAH). Increasingly recognized is the occurrence of nontraumatic convexity SAH unaccounted for by aneurysmal rupture. Case Report These presentations require consideration of rare but clinically significant sources of SAH. We report a patient presenting with prolonged mild headaches and acute onset of seizure like activity found to have diffuse subarachnoid hemorrhage and extensive dural venous sinus thrombosis involving the superior sagittal sinus and right transverse-sigmoid sinuses. Conclusions There are few reported cases of SAH secondary to dural sinus thrombosis; however most of these are convexity hemorrhage. Sinus thrombosis presenting as diffuse SAH is extremely rare, as is showcased in this report.

Diffuse Subarachnoid Hemorrhage Secondary to Cerebral Venous Sinus Thrombosis

Journal club: Magnetic resonance imaging-guided focused laser interstitial thermal therapy for intracranial lesions: single-institution series.

Journal club: national variability in intracranial pressure monitoring and craniotomy for children with moderate to severe traumatic brain injury.

BACKGROUND: Subarachnoid hemorrhage (SAH) is the cause of 5% to 10% of strokes annually in the United States. OBJECTIVE: To study the incidence and mortality trends of admissions of SAH from 1979 to 2008 using a nationally representative sample of all nonfederal acute-care hospitals in the United States: The National Hospital Discharge Survey. METHODS: The sample was obtained from the hospital discharge records according to the International Classification of Disease, 9th Revision, Clinical Modification code 430. RESULTS: We reviewed data on approximately 1 billion hospitalizations in the United States over a 30-year study period and identified 612 500 cases of SAH, which was more common in women (relative risk 1.71, 95% confidence interval 1.7-1.72) and nonwhite persons than white persons (relative risk 1.46, 95% confidence interval 1.4-1.5). The estimated incidence rate of admission after SAH was 7.2 to 9.0 per 100 000/year and did not significantly change over the study period. Overall, in-hospital mortality after SAH fell from 30% during the period from 1979 to 1983 to 20% during the subperiod from 2004 to 2008 ( P = .03) and was lower in larger treating hospitals. The average days of care for SAH hospitalizations decreased, but the rate of discharge to long-term care facilities increased. CONCLUSION: The incidence rate of admission after SAH has remained stable over the past 30 years. Total deaths and in-hospital mortality after SAH have decreased significantly. In-hospital mortality after SAH is lower in larger treating hospitals. the sample, these persons were excluded only from the calculations of race-adjusted specific estimates but were included in all other calculations. We used commercially available statistical software (JMP 9.0, SAS Institute, Cary, North Carolina). P -values are 2-sided, and statistical significance was judged when P , .05. at Jupiter in 2016 to study the giant planet from an elliptical, polar orbit. Juno will repeatedly dive between the planet and its intense belts of charged particle radiation, coming about 3000 miles from the cloud tops at closest approach. Juno ’ s primary goal is to improve our understanding of Jupiter ’ s formation and evolution. The spacecraft will spend a year investigating the planet ’ s origins, interior structure, deep atmosphere and magnetosphere.

The epidemiology of admissions of nontraumatic subarachnoid hemorrhage in the United States.

Journal club: the impact of body mass index on hospital stay and complications after spinal fusion.

An aneurysm by definition is a permanent localized arterial dilation with 50 percent or greater increase in size over the normal diameter of the affected artery. Aneurysms have been classified as true or false (pseudo) aneurysms. True aneurysms involve all three layers of the arterial wall (intima, media, & adventitia). A false or pseudo-aneurysm is a collection of blood or hematoma which had leaked from a defect in the wall of an artery to be later variably confined by the surrounding interstitial tissues. The varied presentations of six patients with false aneurysms admitted and treated on General Surgical wards are presented with the pertinent literature on the subject reviewed along with a review of the records of patients that presented at Gondar University Hospital (GUH) with the diagnosis of false aneurysm over a six years period.

Journal club: the impact of provider volume on the outcomes after surgery for lumbar spinal stenosis.

Cerebral amyloid angiopathy associated with massive intracerebral hemorrhage

The ultimate aim of most intensive care therapies is to improve tissue oxygen delivery; consequently, a detailed knowledge of this area of physiology is important to a wide range of Critical Care Staff. We describe a simple mathematical model of oxygen transport that was initially written as a training aid for extracorporeal oxygenation training. The model has subsequently proved useful for explaining the determinants of oxygen transport to a broader audience. It is based on simple linear equations and is easily displayed with a standard computer spreadsheet. Apart from its teaching value, the model can also generate a graph of oxygen saturation vs. inspired oxygen fraction for different degrees of pulmonary shunt. This provides a noninvasive method for determining the magnitude of pulmonary venous admixture and may also prove to have some clinical value.

Mathematical model of oxygen transport: a teaching aid for normal physiology adaptable to extracorporeal oxygenation circuits.

MODEL OF OXYGEN TRANSPORT: A TEACHING AID FOR NORMAL PHYSIOLOGY ADAPTABLE TO

When rats with desoxycorticosterone acetate (DOCA)-induced potassium chloride deficiency are given sodium chloride there is simultaneously a partial correction of metabolic alkalosis and a marked reduction in urinary citrate excretion and renal citrate content. To examine DOCA's role in this phenomenon and to determine how sodium chloride alters renal metabolism, rats were made KC1 deficient using furosemide and a KC1-deficient diet. Renal citrate and ammonia metabolism were then studied after chronic oral sodium chloride administration or acute volume expansion with isotonic mannitol. Although both maneuvers partially corrected metabolic alkalosis, sodium chloride raised serum chloride concentration while mannitol significantly decreased it. Urinary citrate excretion decreased to 10% of control in rats given NaCl and to 50% of control in rats infused with mannitol. The filtered load of citrate was constant or increased indicating increased tubular citrate reabsorption. Renal cortical citrate content also decreased approximately 50%. Renal cortical slices from KCl-deficient rats incubated in low or normal chloride media produced equal amounts of 14CO2 from (1, 5-14C) citrate. In addition, urinary ammonia excretion increased by over 300% in both groups. This occurred in the mannitol group despite increased urinary pH and flow rate indicating a rise in renal ammonia production. It seems that neither DOCA nor an increase in serum chloride concentration explains the experimental results. Rather, it appears that volume expansion is responsible for increased renal tubular citrate reabsorption and renal ammonia production. As these renal metabolic responses ordinarily occur in response to acidosis, the data are consistent with the hypothesis that volume expansion reduces renal cell pH in 3KCl-deficient rats.

Effect of volume expansion on renal citrate and ammonia metabolism in KCl-deficient rats.

To investigate the effect of altered extracellular osmolarity on cell pH, intact rat diaphragms were incubated in a Krebs-Ringer bicarbonate solution. Cell pH was measured simultaneously by weak-acid (pH DMO) or weak-base (ph nicotine) distribution. When osmolarity was raised by mannitol addition, cell water decreased 5-10% (P smaller than .01) while both pH DMO and pH nicotine increased (P smaller than .01) under acid, normal, and alkaline external pH conditions. Hyperosmolarity of identical degree caused by urea resulted in no changes in either cell water or cell pH. Identical amounts of mannitol added to the bath in the absence of external osmolar changes resulted in no changes in either cell water or cell pH. When extracellular osmolarity was lowered by decreasing sodium chloride concentration, cell water increased 10-12% (P smaller than .01). Despite this large change in cell water, no changes in pH DMO or pH nicotine occurred. These data indicate that osmolar induced alterations in cell water only partially explain cell pH changes found in abnormal osmolar states. Alterations in passive and active hydrogen ion transport must also play significant roles.

Effect of osmolarity on intracellular pH of rat diaphragm muscle.?22.

Renal citrate in the potassium-deficient rat: role of potassium and chloride ions.

Regulation of citrate metabolism by cell pH in potassium-depleted rat diaphragm.

The role of bicarbonate in determining pH heterogeneity in rat diaphragm.

The effect of acute potassium depletion on muscle cell pH in vitro.

Metabolic acid-base effects on tissue citrate content and metabolism in the rat.

Most lay people can correctly identify indigenous venomous snakes.

Effectiveness of a Constructed Wetland with Carbon Filtration in Reducing Pesticides Associated with Agricultural Runoff

The Salinas Valley in Monterey County, California, USA, is a highly productive agricultural region that produces much of the country’s salad greens, strawberries, artichokes, and cruciferous vegetables such as broccoli, cauliflower, and Brussels sprouts. Agricultural irrigation runoff containing pesticides at concentrations toxic to aquatic organisms poses a threat to aquatic ecosystems within local watersheds. This study was designed to monitor the effectiveness of a constructed wetland treatment system with a granulated activated carbon (GAC) filter installation at reducing pesticides associated with agricultural runoff. The addition of pennywort ( Hydrocotyle spp.) was evaluated in some trials. The Molera Road Experimental Treatment Wetland was supplied with water pumped from the Tembladero Slough, a 303(d) listed agricultural and urban drainage that eventually enters the Monterey Bay National Marine Sanctuary. Water samples collected throughout the wetland treatment system during five monitoring trials were analyzed for 170 fungicides, herbicides, and insecticides. The system’s average percent reduction in detected pesticide concentrations was 52%. The wetland channel and GAC filtration component each provided significant treatment, with the latter responsible for the majority. There was also a significant effect of pesticide solubility on changes in concentration within the wetland channel and the GAC filtration. The integrated treatment system reduced nitrate by 61%, phosphate by 73%, and turbidity by 90% on average. Additionally, the samples were analyzed for toxicity to the daphnid Ceriodaphnia dubia , the amphipod Hyalella azteca , and the midge Chironomus dilutus . Input water was significantly toxic to C. dubia and H. azteca in the first trial. Toxicity to C. dubia persisted throughout the treatment system, including post-GAC filtration, whereas toxicity to H. azteca was removed by the channel, but there was residual toxicity post-GAC. The last trial had significant input toxicity to H. azteca and C. dilutus . The channel reduced toxicity to H. azteca and removed it for C. dilutus . GAC filtration reduced amphipod toxicity to an insignificant level. There was no input toxicity in the other three trials. The results demonstrate that a wetland treatment system coupled with GAC filtration can reduce pesticide concentrations, nutrients, suspended particles, and toxicity associated with agricultural runoff. 96-h Tests conducted in five replicate 300-mL test 10, 9-d to 14-d-old amphipods YCT test following a 48-h renewal of 50% of the test Final survival in the water was compared with 96-h survival in laboratory well water. Toxicity tests with C. dilutus were conducted in four replicate 300-mL glass beakers test 12, 7-d-old larva. Five mL sand each larval tube Larvae were fed daily TetraMin™ days to 3, mL/d; 4 to 6, 1.0 1.5 mL/d. Tests were conducted for 10 d, and 50% of the test solution renewed every 48 h. Final survival in the water samples was compared with 10-d survival in laboratory well and growth of surviving animals was measured as ash-free dry weight. A positive control reference toxicant test conducted concurrently with every toxicity test to bracket test The reference tests

Effectiveness of an Integrated Wetland Treatment System in Reducing Pesticide Concentrations Associated with Agricultural Runoff

Size-specific responses of the amphipod Eohaustorius estuarius to clay in sediment toxicity testing

The management of pesticides to protect water quality remains a significant global challenge. Historically, despite regulatory frameworks intended to prevent, minimize, and manage off‐site movement of pesticides, multiple generations of pesticide active ingredients have created a seemingly unending cycle of pesticide water pollution in both agricultural and urban watersheds. In California, the most populous and most agricultural US state, pesticide and water quality regulators realized in the 1990s that working independently of each other was not an effective approach to address pesticide water pollution. Over the years, these California agencies have developed a joint vision and have continued to develop a unified approach that has the potential to minimize pesticide risks to aquatic life through a combination of prevention, monitoring, and management actions, while maintaining pesticide availability for effective pest control. Key elements of the current California pesticide/water quality effort include: 1) pesticide and toxicity monitoring, coupled with watershed modeling, to maximize information obtained from monitoring; 2) predictive fate and exposure modeling to identify potential risks to aquatic life for new pesticide products when used as allowed by the label or to identify effective mitigation measures; and 3) management approaches tailored to the different pesticide uses, discharge sources, physical environments, and regulatory environments that exist for agricultural runoff, urban runoff, and municipal wastewater. Lessons from this effort may inform pesticide management elsewhere in the world as well as other chemical regulatory programs, such as the recently reformed US Toxic Substances Control Act and California's Safer Consumer Products regulatory program. Environ Toxicol Chem 2020;39:953–966. © 2020 SETAC

Water Quality Impairments Due to Aquatic Life Pesticide Toxicity: Prevention and Mitigation in California, USA

Comparison of the Relative Efficacies of Granulated Activated Carbon and Biochar to Reduce Chlorpyrifos and Imidacloprid Loading and Toxicity Using Laboratory Bench Scale Experiments

Regulation of agriculture irrigation water discharges in California, USA, is assessed and controlled by its 9 Regional Water Quality Control Boards under the jurisdiction of the California State Water Resources Control Board. Each Regional Water Board has developed programs to control pesticides in runoff as part of the waste discharge requirements implemented through each region's Irrigated Lands Regulatory Program. The present study assessed how pesticide use patterns differ in the Imperial (Imperial County) and the Salinas and Santa Maria (Monterey County) valleys, which host 3 of California's prime agriculture areas. Surface‐water toxicity associated with current use pesticides was monitored at several sites in these areas in 2014 and 2015, and results were linked to changes in pesticide use patterns in these areas. Pesticide use patterns appeared to coincide with differences in the way agriculture programs were implemented by the 2 respective Regional Water Quality Control Boards, and these programs differed in the 2 Water Board Regions. Different pesticide use patterns affected the occurrence of pesticides in agriculture runoff, and this influenced toxicity test results. Greater detection frequency and higher concentrations of the organophosphate pesticide chlorpyrifos were detected in agriculture runoff in Imperial County compared to Monterey County, likely due to more rigorous monitoring requirements for growers using this pesticide in Monterey County. Monterey County agriculture runoff contained toxic concentrations of pyrethroid and neonicotinoid pesticides, which impacted amphipods (Hyalella azteca) and midge larvae (Chironomus dilutus) in toxicity tests. Study results illustrate how monitoring strategies need to evolve as regulatory actions affect change in pesticide use and demonstrate the importance of using toxicity test indicator species appropriate for the suite of contaminants in runoff in order to accurately assess environmental risk. Integr Environ Assess Manag 2018;14:270–281. © 2017 SETAC

Changing patterns in water toxicity associated with current use pesticides in three California agriculture regions

Toxin-producing cyanobacteria are increasing in rivers and streams globally, leading to growing concerns over their potential impacts on aquatic ecosystems. The present study was designed to culture field-collected Phormidium in the laboratory, identify individual species, conduct chemical analyses to identify cyanotoxins, and conduct toxicity tests to investigate the potential for this genera to impact stream health. Freshwater toxicity tests were conducted with standard US Environmental Protection Agency invertebrate test protocols with culture water used to grow 3 Phormidium strains isolated from the Russian River (CA, USA). Enzyme linked immunosorbent assays were used to measure total anatoxin concentrations. Culture waters from the 3 Phormidium strains were highly toxic to Ceriodaphnia dubia, Hyalella azteca, and Chironomus dilutus. The C. dubia 7-d survival median lethal concentrations were 0.71, 0.49, and 0.56 μg/L anatoxin for Phormidum strains 1, 2, and 3, respectively. The 7-d reproduction inhibitory concentrations, 25% were 0.55, 0.32, and 0.30 μg/L anatoxin for strains 1, 2, and 3, respectively. Chironomus dilutus survival was reduced at concentrations <2 μg/L anatoxin by all 3 strains, and the H. azteca 96-h lethal concentrations, 25% were 2.82, 1.26, and 5.30 μg/L for strains 1, 2, and 3, respectively. Additional liquid chromatography-mass spectrometry analyses demonstrated that the likely anatoxin variant in these cultures was dihydro-anatoxin-a. The results suggest that anatoxins produced by Phormidium have the potential to impact stream macroinvertebrates. Environ Toxicol Chem 2018;37:2851-2859. © 2018 SETAC.

Extracts from benthic anatoxin-producing Phormidium are toxic to 3 macroinvertebrate taxa at environmentally relevant concentrations.

Recent Advances in Toxicity Test Methods Using Kelp Gametophytes

Agricultural runoff containing toxic concentrations of the organophosphate pesticide chlorpyrifos has led to impaired water body listings and total maximum daily load restrictions in California's central coast watersheds. Chlorpyrifos use is now tightly regulated by the Central Coast Regional Water Quality Control Board. This study evaluated treatments designed to reduce chlorpyrifos in agricultural runoff. Initial trials evaluated the efficacy of 3 different drainage ditch installations individually: compost filters, granulated activated carbon (GAC) filters, and native grasses in a vegetated ditch. Treatments were compared to bare ditch controls, and experiments were conducted with simulated runoff spiked with chlorpyrifos at a 1.9 L/s flow rate. Chlorpyrifos concentrations and toxicity to Ceriodaphnia dubia were measured at the input and output of the system. Input concentrations of chlorpyrifos ranged from 858 ng/L to 2840 ng/L. Carbon filters and vegetation provided the greatest load reduction of chlorpyrifos (99% and 90%, respectively). Toxicity was completely removed in only one of the carbon filter trials. A second set of trials evaluated an integrated approach combining all 3 treatments. Three trials were conducted each at 3.2 L/s and 6.3 L/s flow rates at input concentrations ranging from 282 ng/L to 973 ng/L. Chlorpyrifos loadings were reduced by an average of 98% at the low flow rate and 94% at the high flow rate. Final chlorpyrifos concentrations ranged from nondetect (<50 ng/L) to 82 ng/L. Toxicity to C. dubia was eliminated in 3 of 6 integrated trials. Modeling of the ditch and its components informed design alterations that are intended to eventually remove up to 100% of pesticides and sediment. Future work includes investigating the adsorption capacity of GAC, costs associated with GAC disposal, and real‐world field trials to further reduce model uncertainties and confirm design optimization. Trials with more water‐soluble pesticides such as neonicotinoids are also recommended. Integr Environ Assess Manag 2017;13:423–430. © 2016 SETAC

An integrated vegetated ditch system reduces chlorpyrifos loading in agricultural runoff

Carbon Treatment as a Method to Remove Imidacloprid from Agriculture Runoff

Urban stormwater and agriculture irrigation runoff contain a complex mixture of contaminants that are often toxic to adjacent receiving waters. Runoff may be treated with simple systems designed to promote sorption of contaminants to vegetation and soils and promote infiltration. Two example systems are described: a bioswale treatment system for urban stormwater treatment, and a vegetated drainage ditch for treating agriculture irrigation runoff. Both have similar attributes that reduce contaminant loading in runoff: vegetation that results in sorption of the contaminants to the soil and plant surfaces, and water infiltration. These systems may also include the integration of granulated activated carbon as a polishing step to remove residual contaminants. Implementation of these systems in agriculture and urban watersheds requires system monitoring to verify treatment efficacy. This includes chemical monitoring for specific contaminants responsible for toxicity. The current paper emphasizes monitoring of current use pesticides since these are responsible for surface water toxicity to aquatic invertebrates.

Vegetated Treatment Systems for Removing Contaminants Associated with Surface Water Toxicity in Agriculture and Urban Runoff.

†University of California, Davis, Department of Environmental Toxicology 34500 Highway One, Monterey, CA 93940 (831) 624-0947 Phone, (831) 626-1518 Fax bmphillips@ucdavis.edu, anderson@ucdavis.edu, jpvoorhees@ucdavis.edu, csiegler@ucdavis.edu, rstjeerdema@ucdavis.edu ‡University of California Cooperative Extension Monterey County, 1432 Abbott Street, Salinas, CA 93901 mdcahn@ucanr.edu §California Department of Pesticide Regulation, 1001 I Street, Sacramento, CA 95814 Xuyang.Zhang@cdpr.ca.gov, rbudd@cdpr.ca.gov, kgoh@cdpr.ca.gov

A Integrated Vegetated Ditch System Reduces Chlorpyrifos Loading in Agricultural Runoff † Running Head : Strategies for Reducing Chlorpyrifos in Irrigation Runoff

Contamination and toxicity associated with urban storm water runoff are a growing concern because of the potential impacts on receiving systems. California water regulators are mandating implementation of green infrastructure as part of new urban development projects to treat storm water and increase infiltration. Parking lot bioswales are low impact development practices that promote filtering of runoff through plants and soil. Studies have demonstrated that bioswales reduce concentrations of suspended sediments, metals, and hydrocarbons. There have been no published studies evaluating how well these structures treat current‐use pesticides, and studies have largely ignored whether bioswales reduce toxicity in surface water. Three storms were monitored at 3 commercial and residential sites, and reductions of contaminants and associated toxicity were quantified. Toxicity testing showed that the majority of untreated storm water samples were toxic to amphipods (Hyalella azteca) and midges (Chironomus dilutus), and toxicity was reduced by the bioswales. No samples were toxic to daphnids (Ceriodaphnia dubia) or fish (Pimephales promelas). Contaminants were significantly reduced by the bioswales, including suspended solids (81% reduction), metals (81% reduction), hydrocarbons (82% reduction), and pyrethroid pesticides (74% reduction). The single exception was the phenypyrazole pesticide fipronil, which showed inconsistent treatment. The results demonstrate these systems effectively treat contaminated storm water associated with surface water toxicity but suggest that modifications of their construction may be required to treat some contaminant classes. Environ Toxicol Chem 2016;35:3124–3134. © 2016 SETAC

Bioswales reduce contaminants associated with toxicity in urban storm water

Mitigation Strategies for Reducing Aquatic Toxicity from Chlorpyrifos in Cole Crop Irrigation Runoff

Many watersheds in the Central Valley region of California are listed as impaired due to pyrethroid‐associated sediment toxicity. The Central Valley Regional Water Quality Control Board is developing numeric sediment quality criteria for pyrethroids, beginning with bifenthrin. Criteria are being developed using existing data, along with data from 10 d and 28 d toxicity tests with Hyalella azteca conducted as part of the current study. A single range‐finder and 2 definitive tests were conducted for each test duration. Median lethal concentrations (LC50s), as well as LC20s and inhibition concentrations (IC20s) were calculated based on measured whole sediment bifenthrin concentrations and interstitial water concentrations. Sediment LC50s were also corrected for organic C content. Average LC50s were not significantly different in 10 d versus 28 d tests with H. azteca: 9.1 and 9.6 ng/g bifenthrin for 10 d and 28 d tests, respectively. Average LC20 values were also similar with concentrations at 7.1 and 7.0 for 10 d and 28 d tests, respectively. Bifenthrin inhibition concentrations (IC20s) based on amphipod growth were variable, particularly in the 28 d tests, where a clear dose‐response relationship was observed in only 1 of the definitive experiments. Average amphipod growth IC20s were 3.9 and 9.0 ng/g for 10 d and 28 d tests, respectively. Amphipod growth calculated as biomass resulted in IC20s of 4.1 and 6.3 ng/g for the 10 d and 28 d tests, respectively. Lack of a clear growth effect in the longer term test may be related to the lack of food adjustment to account for amphipod mortality in whole sediment exposures. The average C‐corrected LC50s were 1.03 and 1.09 μg/g OC for the 10 d and 28 d tests, respectively. Interstitial water LC50s were determined as the measured dissolved concentration of bifenthrin relative to interstitial water dissolved organic carbon. The average LC50s for dissolved interstitial water bifenthrin were 4.23 and 4.28 ng/L for the 10 d and 28 d tests, respectively. In addition, a set of 10 d and 28 d tests were conducted at 15 °C to assess the relative toxicity of bifenthrin at a lower temperature than the standard 23 °C test temperature. These results showed that bifenthrin was more toxic at the lower temperature, with LC50s of 5.1 and 3.4 ng/g bifenthrin in 10 d and 28 d tests, respectively. Amphipod growth at 15 °C after a 28 d exposure resulted in the lowest effect concentration of all experiments conducted (IC20 = 0.61 ng/g). This article discusses how bifenthrin dose–response data from 10 d and 28 d exposures inform development of sediment quality criteria for this pesticide for California Central Valley watersheds. Integr Environ Assess Manag 2015;11:319–328. © 2015 SETAC

Relative toxicity of bifenthrin to Hyalella azteca in 10 day versus 28 day exposures

Funding for this report was provided by the Regional Monitoring Program for Water Quality in San Francisco Bay. The Program is a collaborative effort between the San Francisco Bay Regional Water Quality Control Board, the regulated discharger community, and the San Francisco Estuary Institute to support scientific investigations that inform management decisions for San Francisco Bay. CLEAN WATER / RMP

The Effects of Kaolin Clay on the Amphipod Eohaustorius estuarius

Temporal and spatial trends in sediment contaminants associated with toxicity in California watersheds.

The Effects of the Landguard™ A900 Enzyme on the Macroinvertebrate Community in the Salinas River, California, United States of America

Pesticides are applied to state and local waterways in California to control insects such as mosquitoes, which are known to serve as a vector for West Nile Virus infection of humans. The California State Water Resources Control Board adopted a National Pollutant Discharge Elimination System General Permit to address the discharge to waters of the United States of pesticides resulting from adult and larval mosquito control. Because pesticides used in spray activities have the potential to cause toxicity to nontarget organisms in receiving waters, the current study was designed to determine whether toxicity testing provides additional, useful environmental risk information beyond chemical analysis in monitoring spray pesticide applications. Monitoring included a combination of aquatic toxicity tests and chemical analyses of receiving waters from agricultural, urban, and wetland habitats. The active ingredients monitored included the organophosphate pesticides malathion and naled, the pyrethroid pesticides etofenprox, permethrin, and sumithrin, pyrethrins, and piperonyl butoxide (PBO). Approximately 15% of the postapplication water samples were significantly toxic. Toxicity of half of these samples was attributed to the naled breakdown product dichlorvos. Toxicity of 2 other water samples likely occurred when PBO synergized the effects of pyrethroid pesticides that were likely present in the receiving system. Four of 43 postapplication sediment samples were significantly more toxic than their corresponding pre‐application samples, but none of the observed toxicity was attributed to the application events. These results indicate that many of the spray pesticides used for adult mosquito control do not pose significant acute toxicity risk to invertebrates in receiving systems. In the case of naled in water, analysis of only the active ingredient underestimated potential impacts to the receiving system, because toxicity was attributed to the breakdown product, dichlorvos. Toxicity testing can provide useful risk information about unidentified, unmeasured toxicants or mixtures of toxicants. In this case, toxicity testing provided information that could lead to the inclusion of dichlorvos monitoring as a permit requirement. Integr Environ Assess Manag 2014;10:449–455. © 2014 SETAC

Monitoring the aquatic toxicity of mosquito vector control spray pesticides to freshwater receiving waters

Hypersalinity Toxicity Thresholds for Nine California Ocean Plan Toxicity Test Protocols

Environmental fate of fungicides and other current-use pesticides in a central California estuary.

Crude oil contamination remains a problem along coastal California and its impacts on pelagic organisms are of concern. Previous crude and dispersed oil studies showed a decrease in fish toxicity when Corexit 9500 dispersant was applied. However, observed sublethal metabolic effects were similar for both oil conditions, suggesting fish were accumulating similar dissolved hydrocarbons. This study aimed to characterize the bioavailable fraction of the water-accommodated fraction (WAF) and the chemically-enhanced WAF (CEWAF) of Prudhoe Bay Crude Oil (PBCO), using semi-permeable membrane devices (SPMDs) as fish models. Seven accumulated PAHs were identified (naphthalene, 2-methylnaphthalene, 1-methylnapthalene, biphenyl, fluorene, dibenzothiophene and phenanthrene) from 24 h static exposures. Although WAF and CEWAF oil loadings differed by eight-fold, accumulated dissolved concentrations among the seven PAHs differed by some three-fold. Overall, the use of SPMDs in characterizing the dissolved fraction of PBCO, has provided a better understanding of the bioavailability of crude and dispersed oil.

Use of semipermeable membrane devices (SPMDs) to characterize dissolved hydrocarbon fractions of both dispersed and undispersed oil.

General Pesticide Permit Toxicity Study: Monitoring Aquatic Toxicity of Spray Pesticides to Freshwater Organisms

Portions of the Santa Maria River and Oso Flaco Creek watersheds in central California, USA, are listed as impaired under section 303(d) of the Clean Water Act and require development of total maximum daily load (TMDL) allocations. These listings are for general pesticide contamination, but are largely based on historic monitoring of sediment and fish tissue samples that showed contamination by organochlorine pesticides. Recent studies have shown that toxicity in these watersheds is caused by organophosphate pesticides (water and sediment) and pyrethroid pesticides (sediment). The present study was designed to provide information on the temporal and spatial variability of toxicity associated with these pesticides to better inform the TMDL process. Ten stations were sampled in four study areas, one with urban influences, and the remaining in agriculture production areas. Water toxicity was assessed with the water flea Ceriodaphnia dubia, and sediment toxicity was assessed with the amphipod Hyalella azteca. Stations in the lower Santa Maria River had the highest incidence of toxicity, followed by stations influenced by urban inputs. Toxicity identification evaluations and chemical analysis demonstrated that the majority of the observed water toxicity was attributed to organophosphate pesticides, particularly chlorpyrifos, and that sediment toxicity was caused by mixtures of pyrethroid pesticides. The results demonstrate that both agriculture and urban land uses are contributing toxic concentrations of these pesticides to adjacent watersheds, and regional water quality regulators are now using this information to develop management objectives. Environ. Toxicol. Chem. 2012; 31: 1595–1603. © 2012 SETAC

Pyrethroid and organophosphate pesticide‐associated toxicity in two coastal watersheds (California, USA)

NMR-based characterization of the acute metabolic effects of weathered crude and dispersed oil in spawning topsmelt and their embryos.

2. Hyper‐Salinity Toxicity Thresholds for Nine California Ocean Plan Toxicity Test Protocols Final Report Prepared by: Bryn M. Phillips, Brian S. Anderson, Katie Siegler, Jennifer P. Voorhees, Scott Katz, Lydia Jennings, and Ron S. Tjeerdema University of California, Davis, Department of Environmental Toxicology Prepared for: California State Water Resources Control Board Agreement Number 11‐133‐250 July 2012

Hyper-Salinity Toxicity Thresholds for Nine California Ocean Plan Toxicity Test

The whole effluent toxicity (WET) program in the United States, Canada, and other countries typically requires multi concentration testing of effluents. While multiconcentration testing of chemicals is desirable for regulatory and scientific reasons, we believe this requirement is not as efficient for evaluating effluent compliance in a WET program. The key regulatory question of concern is whether an effluent is toxic or not, which is best answered statistically using a hypothesis approach, not a point estimate approach. However, the traditional hypothesis approach currently recommended does not reward high within‐test precision. This report describes the need for 3 specific changes in the analysis of WET compliance data that we believe would yield a more robust WET regulatory program: (1) restate the null hypothesis so that test power is associated with demonstrating that the effluent is not toxic, (2) use USEPA's Test of Significant Toxicity (based on the noninferiority approach) to identify unacceptable toxicity as well as acceptable effects with a high probability, and (3) evaluate only the test control and the critical concentration of concern (e.g., instream waste concentration). We demonstrate that instituting these 3 changes would provide: Positive incentives for permittees to produce high‐quality WET data, a transparent analysis approach in which the permittee could have greater control over regulatory decisions based on test results, and potentially a less expensive testing program because fewer effluent concentrations need to be examined within a test. As a result, WET test frequency could be increased for the same cost as current testing programs while providing greater representativeness of effluent quality. Integr Environ Assess Manag 2012; 8: 351–358. © 2011 SETAC

It is time for changes in the analysis of whole effluent toxicity data

Acknowledgements This report is the product of a collaborative project among regional, state, and federal agencies involved in reducing pesticide runoff in California. The Resource Conservation District (RCD) of Monterey County was the lead agency procuring and administering the United States Department of Agriculture (USDA) Conservation Innovation Grant which funded the majority of this work. The author's thank Paul Robins and Rami Shihadeh for administering the grant and organizing grower outreach meetings where results of this project were presented to central coast growers and local resource agencies. The California Department of Pesticide Regulation (DPR) provided matching funds used for field work and pesticide analyses of water samples. The authors thank Robert Budd and Kean Goh for their support and guidance, and Sue Peoples for coordinating the chemical analyses. conducted the toxicity tests and chemical analyses for this project, and their diligence and professionalism is much appreciated. This work could not have been completed without the cooperation of Salinas Valley growers concerned with improving surface water quality on the central coast; the author's appreciate their continuing participation in this research. The agricultural fields of Monterey County contain a $4 billion/year industry that produces much of the nation's lettuce, strawberries, crucifer crops and grapes. Runoff from irrigated agriculture contributes a significant amount of water to local stream flow, and several studies have measured significant pesticide concentrations and biological impacts in the Salinas River and its watersheds (Anderson et al., 2003b; Hunt et al., 2003; Phillips et al., 2004). Pesticides in runoff from irrigated vegetable production can also impact invertebrate communities (Anderson et al., 2003a; Liess and von der Ohe, 2005; Anderson et al., 2006b), have adverse impacts on salmonids (Scholz et al., 2000), and lead to food web magnification in fish and wildlife (Pereira et al., 1996). Results of studies conducted throughout California have demonstrated that surface water toxicity is caused by organophosphate and pyrethroid pesticides (Anderson et al., 2011). Developing effective systems for the treatment of runoff is necessary to reduce pesticide loading to aquatic habitats and is an integral requirement of recent Central Coast Water Quality Control Board regulations. The integrated vegetated treatment system (VTS) in the current study was constructed on a working farm in a narrow linear ditch. This system was previously evaluated by Anderson et al. (2011), and consisted of a short sediment settling basin followed by a vegetated portion, and treatment with Landguard™ OP-A enzyme, which …

Optimization of an Integrated Vegetated Treatment System Incorporating Landguard A 900 Enzyme : Reduction of Water Toxicity Caused by Organophosphate and Pyrethroid Pesticides

RMP Sediment Study 2009-2010 Determining Causes of Sediment Toxicity in the San Francisco Estuary

Sediment Toxicity Identification Evaluation: Advancing Procedures for Extracting and Recovering Chemicals of Concern from Sediment Interstitial Water FINAL REPORT

Treatment of Agriculture Runoff with Enzyme and Vegetation Removes Pesticides and Associated Toxicity

Large volume direct injection liquid chromatography with tandem mass spectrometry for the detection of the components of Corexit 9500 oil dispersant in real seawater samples

The California, USA, central coast is one of the most productive agricultural areas in the world, and numerous stakeholders are working there to implement conservation practices to reduce contaminated runoff. Practices include vegetated treatment systems (VTS) designed to promote contaminant reduction and breakdown. The current study evaluated the effectiveness of a vegetated drainage ditch incorporating a sedimentation basin, a vegetated section, and a Landguard organophosphate‐A (OP‐A) enzyme dosing system. The VTS was constructed on a working farm and was designed to remove organophosphate and pyrethroid pesticides, the primary pesticides causing toxicity in Salinas Valley watersheds. The present study was conducted during five separate irrigation events on tailwater runoff containing mixtures of pesticides and suspended sediments. Water samples were collected at four stations within the system, and these were subjected to chemical analyses and tested for toxicity to Ceriodaphnia dubia. All inflow samples were highly toxic to C. dubia, and this was largely because of diazinon. Treatment of diazinon‐contaminated runoff was only partially effective using aquatic vegetation. All diazinon remaining after vegetated treatment was effectively removed after treatment with the Landguard OP‐A enzyme. Chemical analysis of the VTS water samples showed that pyrethroid and organochlorine pesticide concentrations in water were greatly reduced in the sedimentation section of the ditch, and these pesticides were further reduced in the vegetated section of the ditch. The overall conclusion from these analyses is that the VTS was effective at reducing the more hydrophobic organochlorine and pyrethroid pesticides from water. The water‐soluble pesticide diazinon was not sufficiently removed during the VTS residence times observed in this study; however, residual diazinon was effectively removed using Landguard OP‐A. Environ. Toxicol. Chem. 2011; 30:1036–1043. © 2011 SETAC

Pesticide and toxicity reduction using an integrated vegetated treatment system

Evaluation of methods to determine causes of sediment toxicity in San Diego Bay, California, USA.

On April 24, 2010, the sinking of the Deepwater Horizon oil rig resulted in the release of oil into the Gulf of Mexico. As of July 19, 2010, the federal government’s Deepwater Horizon Incident Joint Information Center estimates the cumulative range of oil released is 3,067,000 to 5,258,000 barrels, with a relief well to be completed in early August. By comparison, the Exxon Valdez oil spill released a total of 260,000 barrels of crude oil into the environment. As of June 9, BP has used over 1 million gallons of Corexit oil dispersants to solubilize oil and help prevent the development of a surface oil slick (1). Oil dispersants are mixtures containing solvents and surfactants that can exhibit toxicity toward aquatic life and may enhance the toxicity of components of weathered crude oil. Detailed knowledge of the composition of both Corexit formulations and other dispersants applied in the Gulf will facilitate comprehensive monitoring programs for determining the occurrence, fate, and biological effects of the dispersant chemicals. The lack of information on the potential impacts of oil dispersants has caught industry, federal, and state officials off guard. Until compositions of Corexit 9500 and 9527 were released by the U.S. Environmental Protection Agency online, the only information available consisted of Material Safety Data Sheets (MSDS), patent documentation, and a National Research Council report on oil dispersants (2). Several trade and common names are used for the components of the Corexits. For example, Tween 80 and Tween 85 are oligomeric mixtures.

A role for analytical chemistry in advancing our understanding of the occurrence, fate, and effects of Corexit oil dispersants.

As part of a statewide assessment of pyrethroid pesticides and sediment toxicity in urban creeks, sites throughout California were screened, and thirty were chosen to evaluate the potential of pyrethroids to contribute to biological impacts. Sediment samples from four sites containing varied concentrations of pyrethroids were investigated using toxicity identification evaluations (TIEs) to determine causes of toxicity. Treatments were conducted on both whole sediment and interstitial water to determine the role of pyrethroids in the observed toxicity to the amphipod Hyalella azteca, and to evaluate TIE method performance. Whole sediment treatments included the addition of binding resins for organics and metals, and specific treatments designed to alter pyrethroid toxicity, including the addition of carboxylesterase enzyme, the addition of piperonyl butoxide (a pyrethroid synergist), and the testing of sediments at two temperatures. Interstitial water TIEs included solid-phase extraction (SPE) columns to reduce and return toxicity caused by organics and metals, as well as the treatments specific to pyrethroids. Resin and SPE column treatments characterized the causes of toxicity as organic compounds. Results of pyrethroid-specific treatments in whole sediment were variable, but similar treatments in interstitial water demonstrated pyrethroids were contributing to toxicity. Measured pyrethroid concentrations in whole sediment and interstitial water SPE extracts were high enough to have contributed to toxicity. Using both whole sediment and interstitial water TIEs and chemical analysis provided multiple lines of evidence that pyrethroids contributed to toxicity.

The contribution of pyrethroid pesticides to sediment toxicity in four urban creeks in California, USA.

Metabolic responses produced by crude versus dispersed oil in Chinook salmon pre-smolts via NMR-based metabolomics.

Preliminary investigation of the effects of dispersed Prudhoe Bay Crude Oil on developing topsmelt embryos, Atherinops affinis.

Evaluation of phase II toxicity identification evaluation methods for freshwater whole sediment and interstitial water.

Characterization of the metabolic actions of crude versus dispersed oil in salmon smolts via NMR-based metabolomics.

Recent monitoring in California has indicated that sediment toxicity associated with pyrethroid pesticides is of concern in urban and agriculture-dominated watersheds. In some cases, waterbodies that are listed as impaired due to sediment toxicity may require development of Total Maximum Daily Load (TMDL) allocations to regulate chemicals of concern. This process will require identification of specific chemicals causing toxicity, and sediment toxicity identification evaluation procedures (TIEs) are one of the primary tools used in this process. This paper provides an overview of sediment TIE methods with an emphasis on those which have been demonstrated to be useful in resolving toxicity caused by pyrethroid pesticides. These include use of media for extracting non-polar organic chemicals from sediment and interstitial water and use of a carboxylesterase enzyme for hydrolyzing pyrethroids. Additional methods that have proven useful for identifying pyrethroid toxicity include addition of the metabolic inhibitor piperonyl butoxide, and manipulations of sample toxicity test temperatures. Methods are described for both solid-phase and interstitial water TIEs. In addition to discussing specific TIE methods, examples of studies that have successfully used the different procedures are cited. Results of two sediment TIE case studies which incorporate the majority of these methods are also provided to illustrate the utility of using a weight-of-evidence in the TIE approach. Results from the case study experiments conducted using samples from Westley Wasteway Creek (WWNCR) and an agriculture tailwater pond in the Salinas Valley (SV03) demonstrate that sediment toxicity at WWNCR was likely due to L-cyhalothrin and bifenthrin, and that toxicity at SV03 was likely due to L-cyhalothrin and cypermethrin. The results suggest that current solid-phase and interstitial water TIE methods are adequate for identifying toxicity caused by pyrethroid pesticides. Refinement of these methods will improve our ability to resolve causes of toxicity in sediments contaminated by complex chemical mixtures.

Recent Advances in Sediment Toxicity Identification Evaluations Emphasizing Pyrethroid Pesticides

2 Executive Summary More than 25 years of monitoring studies have shown widespread sediment toxicity in the San Francisco Estuary. While toxicity is generally persistent, patterns of sediment toxicity demonstrate temporal and spatial variability, with greater toxicity observed in samples collected during the rainy winter season at sites near the mouths of tributaries. Samples collected as part of the Regional Monitoring Program's Status and Trends program consistently show significant but moderate levels of toxicity at many stations. A number of studies have shown that amphipod mortality in laboratory tests is correlated with several metal and organic chemical constituents in the Estuary's sediments. These studies have also demonstrated significant correlations between amphipod mortality and chemical mixtures. While correlative studies are useful, they do not provide direct evidence of the causes of sediment toxicity. Understanding the cause(s) of sediment toxicity is one of the primary goals of the RMP because management of contaminants entering the Estuary is most efficient when it targets the key chemicals responsible for biological impacts. One approach for determining the cause(s) of toxicity is the process known as Toxicity Identification Evaluation (TIE), which involves a series of procedures designed to decrease, increase, or transform the bioavailable fractions of sediment contaminants to assess their contributions to sample toxicity. TIEs have been used to show that divalent cations (e.g., copper) were responsible for toxicity to bivalves in sediment samples from the Estuary. To date, however, TIE methods have not been sufficiently developed to determine the causes of sediment toxicity to amphipods. With the recent development of new sediment TIE procedures, the RMP funded a TIE study designed to investigate causes of sediment toxicity in two samples collected during the rainy season from stations located near the margins of the Estuary. Based on historical data, twelve samples from previously toxic stations were selected for a screening survey, from which two stations were to be selected for TIEs. Toxicity of these sediments was tested with the amphipod Eohaustorius estuarius, the primary species used in the Status and Trends program, as well as the benchmark species used in the State of California's Sediment Quality Objectives program. Fourteen samples from twelve stations were surveyed, but only Mission Creek sediment was sufficiently toxic for use in a TIE (<50% survival). One station had poor sediment quality and could not be tested, and a thirteenth station was added in an effort to find another 3 significantly …

RMP Sediment TIE Study 2007-2008: Using Toxicity Identification Evaluation (TIE)Methods to Investigate Causes of Sediment Toxicity to Amphipods

Sublethal test methods are being used with increasing frequency to measure sediment toxicity, but little is known about the relative sensitivity of these tests compared to the more commonly used acute tests. The present study was conducted to compare the sensitivity of several acute and sublethal methods and to investigate their correlations with sediment chemistry and benthic community condition. Six sublethal methods (amphipod: Leptocheirus plumulosus survival, growth, and reproduction; polychaete: Neanthes arenaceodentata survival and growth; benthic copepod: Amphiascus tenuiremis life cycle; seed clam: Mercenaria mercenaria growth; oyster: Crassostrea virginica lysosome destabilization; and sediment–water interface testing with mussel embryos, Mytilus galloprovincialis) and two acute methods (amphipod survival with Eohaustorius estuarius and L. plumulosus) were used to test split sediment samples from stations in California. The test with Amphiascus proved to be the most sensitive sublethal test and the most sensitive overall, identifying 90% of the stations as toxic. The Leptocheirus 10‐d test was the most sensitive of the acute tests, identifying 60% of the stations as toxic. In general, the sublethal tests were not more sensitive to sediments than the acute tests, with the sublethal tests finding an average of 35% of the stations to be toxic while the acute found 44%. Of the sublethal tests, only the Amphiascus endpoints and Neanthes growth significantly (p ≤ 0.05) correlated with sediment chemical concentrations. Poor correspondence occurred between the toxicity endpoints and the indicators of benthic community condition. Differences in test characteristics such as mode of exposure, species‐specific contaminant sensitivity, changes in contaminant bioavailability, and influence of noncontaminant stressors on the benthos may have been responsible for variation in response among the tests and low correspondence with benthic community condition. The influence of these factors cannot be easily predicted, underscoring the need to use multiple toxicity methods, in combination with other lines of evidence, to provide an accurate and confident assessment of sediment toxicity.

Comparison of methods for evaluating acute and chronic toxicity in marine sediments

Use of toxicity identification evaluations to determine the pesticide mitigation effectiveness of on-farm vegetated treatment systems.

Relative sensitivities of toxicity test protocols with the amphipods Eohaustorius estuarius and Ampelisca abdita.

Applications of carboxylesterase activity in environmental monitoring and toxicity identification evaluations (TIEs).

Sampling in the Freshwater Reaches of the Lower Delta for the Sediment Quality Objectives Measures. UPDATED for CALFED meeting Oct 2008

A statewide investigation of urban creek sediment toxicity was conducted in California in recognition of increased incidences of toxicity linked to pyrethroid pesticides. The goals were to examine the spatial occurrence and magnitude of sediment toxicity in California urban creeks, and to examine the role of pyrethroids in toxic urban creek sediment samples. After a preliminary screening of 90 sites, 30 creeks were sampled in eight geographical regions. Sediment toxicity was assessed using 10 day bioassays with the resident amphipod Hyalella azteca. Bioassays were conducted at two test temperatures of 23 degrees C and at 15 degrees C to provide evidence of the cause of toxicity, and to more accurately reflect ambient environmental temperatures. Twenty-five of 30 samples were toxic when tested at 23 degrees C, and all 30 samples were toxic when tested at 15 degrees C. The magnitude of toxicity increased in samples tested at 15 degrees C suggesting the influence of pyrethroids, which are more toxic at colder temperatures. Pyrethroids were present in all sediment samples and were the only compounds detected at concentrations toxic to H. azteca. Bifenthrin was the pyrethroid of greatest toxicological concern, occurring in all 30 samples at concentrations up to 219 ng/g. Pyrethroid contamination of urban creeks was most severe in the Los Angeles, Central Valley, and San Diego regions, respectively. However, pyrethroids were also linked to urban creek aquatic toxicity in all regions sampled, including the less urbanized areas of the North Coast and Lake Tahoe.

Statewide investigation of the role of pyrethroid pesticides in sediment toxicity in California's urban waterways.

Quality Assurance Project Plan: Investigations of Sources and Effects of Pyrethroid Pesticides in Watersheds of the San Francisco Bay Estuary

Final Project Report: Investigations of Sources and Effects of Pyrethroid Pesticides in Watersheds of the San Francisco Estuary

............................................................................................. 2 Acknowledgements ................................................................................ 3 List of Figures ...................................................................................... 5 List of Tables ....................................................................................... 7 1.0 Introduction .................................................................................... 1 2.0 Objectives ....................................................................................... 1 3.0 Methods ......................................................................................... 2 3.1 Exposure Materials .................................................................. 2 3.2 Gas Chromatography ................................................................ 3 3.3 Toxicity Test Procedures ............................................................ 3 3.4 Statistics ............................................................................... 4 3.5 Animal and Experimental Design for Metabolomics studies .................. 4 3.6 Metabolite Extraction ................................................................ 5 3.7 1D H and 2D –J-Resolved NMR Spectroscopy ................................. 5 3.8 NMR Spectral Pre-Processing and Statistical Analyses ........................ 5 4.0 Results .......................................................................................... 6 4.1 System Performance ................................................................. 6 4.2 Acute Toxicity of WAF and CEWAF ............................................. 6 4.3 NMR Spectroscopy of Metabolites from Muscle Tissues ...................... 7 4.4 NMR Spectroscopy of Metabolites from Liver Tissues ......................... 7 4.5 Dose-Response of Metabolic Profiles in Muscles of Smolts Exposed to WAF or CEWAF .................................................................................... 7 4.6 Dose-Response of Metabolic Profiles in Livers of Smolts Exposed to WAF or CEWAF .................................................................................... 8 4.7 Specific Metabolic Changes in Muscles after Exposures ....................... 8 4.8 Specific Metabolite Changes in Livers after Exposures ........................ 9 4.9 Long-Term Growth .................................................................. 9 5.0 Discussion ..................................................................................... 10 5.1 Relative Toxicity of Dispersed and Non-Dispersed Oil ........................ 10 5.2 Application of Metabolomics ...................................................... 11 5.3 Dose-Dependent Metabolic Changes ............................................. 11 5.4 Role of Endogenous Metabolites .................................................. 12 5.5 Potential Biomarkers of WAF or CEWAF Exposures .......................... 13 5.6 Concluding Remarks ................................................................ 13 6.0 Technology Transfer ......................................................................... 13 7.0 Achievement and Dissemination ............................................................ 14 7.1 Publication ..................................................................................... 14 7.2 Presentation ........................................................................... 14 References .................................................................................................................. 15

I ACUTE AND CHRONIC EFFECTS OF CRUDE AND DISPERSED OIL ON CHINOOK SALMON SMOLTS (ONCORHYNCHUS TSHAWYTSCHA)

The New River (CA, USA) was created in 1905 to 1907 when the Colorado River washed out diversionary works and flowed into the Salton Basin, creating the Salton Sea. Approximately 70% of the river's current flow is agricultural wastewater from the Imperial Valley. The river is contaminated with pesticides, industrial organic chemicals, metals, nutrients, bacteria, and silt. Monitoring for the State of California Surface Water Ambient Monitoring Program has indicated persistent water column toxicity to the epibenthic amphipod Hyalella azteca. Four toxicity identification evaluations (TIEs), along with chemical analyses, were performed, and the results indicated multiple and varying causes of toxicity. The first two TIEs characterized the causes of toxicity as a combination of metals and organics, but only the second sample contained enough total copper to contribute to toxicity. The third TIE used an emerging method for characterizing and identifying toxicity caused by pyrethroid pesticides. This TIE characterized organics as the cause of toxicity, and a carboxylesterase enzyme treatment further identified the cause of toxicity as pyrethroids. The final TIE used the enzyme and Phase II procedures to identify cypermethrin as the cause of toxicity. The TIE results demonstrate the evolving causes of toxicity in the New River and should assist regulators with implementing the total maximum daily load process for pesticides, particularly pyrethroids. Further research will determine if pyrethroids and other New River contaminants are having an impact on the Salton Sea.

Causes of water toxicity to Hyalella azteca in the New River, California, USA

Patterns and trends in sediment toxicity in the San Francisco Estuary.

Sublethal test methods are being used with increasing frequency to measure sediment toxicity, but little is known about the relative sensitivity of these tests compared to the more commonly used acute tests. A study was conducted to compare the sensitivity of several acute and sublethal toxicity methods and investigate their correlations with sediment chemistry and benthic community condition. Six sublethal methods (amphipod: Leptocheirus plumulosus 28-day survival, growth and reproduction; polychaete: Neanthes arenaceodentata 28-day survival and growth; benthic copepod: Amphiascus tenuiremis, 14-day life-cycle; seed clam: Mercenaria mercenaria 7-day growth; oyster: Crassostrea virginica lysosome destabilization; and sediment-water interface testing with embryos of the mussel Mytilus galloprovincialis) and two acute methods (10-day amphipod survival with Eohaustorius estuarius and Leptocheirus plumulosus) were used to test split samples of sediment from stations in southern California and San Francisco Bay. The life-cycle test with the copepod, Amphiascus, proved to be the most sensitive sublethal test and the most sensitive test overall. The Leptocheirus 10-day survival test was the most sensitive of the acute tests. In general, the sublethal tests were not more sensitive to sediments than the acute tests. Of the sublethal tests, only the Amphiascus endpoints and polychaete growth correlated with sediment chemistry. There was poor correspondence between the toxicity endpoints and indicators of benthic community condition. Differences in test characteristics such as mode of exposure, species-specific contaminant sensitivity, changes in contaminant bioavailability, and the influence of noncontaminant stressors on the benthos may have been responsible for variation in response among the tests and low correspondence with benthic community condition. The influence of these factors cannot be easily predicted, underscoring the need to use multiple toxicity methods in combination with other lines of evidence to provide an accurate and confident assessment of sediment toxicity.

Comparison of methods for acute and chronic toxicity in marine sediments

Identifying primary stressors impacting macroinvertebrates in the Salinas River (California, USA): relative effects of pesticides and suspended particles.

Characterizing Sediment Contamination and Potential Ecological Effects in Six Tributaries of the San Francisco Bay Estuary

The Santa Maria River provides significant freshwater and coastal habitat in a semiarid region of central California, USA. We conducted a water and sediment quality assessment consisting of chemical analyses, toxicity tests, toxicity identification evaluations, and macroinvertebrate bioassessments of samples from six stations collected during four surveys conducted between July 2002 and May 2003. Santa Maria River water samples collected downstream of Orcutt Creek (Santa Maria, Santa Barbara County, CA, USA), which conveys agriculture drain water, were acutely toxic to cladocera (Ceriodaphnia dubia), as were samples from Orcutt Creek. Toxicity identification evaluations (TIEs) suggested that toxicity to C. dubia in Orcutt Creek and the Santa Maria River was due to chlorpyrifos. Sediments from these two stations also were acutely toxic to the amphipod Hyalella azteca, a resident invertebrate. The TIEs conducted on sediment suggested that toxicity to amphipods, in part, was due to organophosphate pesticides. Concentrations of chlorpyrifos in pore water sometimes exceeded the 10‐d median lethal concentration for H. azteca. Additional TIE and chemical evidence suggested sediment toxicity also partly could be due to pyrethroid pesticides. Relative to an upstream reference station, macroinvertebrate community structure was impacted in Orcutt Creek and in the Santa Maria River downstream of the Creek input. This study suggests that pesticide pollution likely is the cause of ecological damage in the Santa Maria River.

Evidence of pesticide impacts in the Santa Maria River watershed, California, USA

The lower Santa Maria River watershed provides important aquatic habitat on the central California coast and is influenced heavily by agricultural runoff. As part of a recently completed water quality assessment, we conducted a series of water column and sediment toxicity tests throughout this watershed. Sediment from Orcutt Creek, a tributary that drains agricultural land, consistently was toxic to the amphipod Hyalella azteca, which is a resident genus in this river. Toxicity identification evaluations (TIEs) were conducted to determine cause(s) of toxicity. We observed no toxicity in sediment interstitial water even though concentrations of chlorpyrifos exceeded published aqueous toxicity thresholds for H. azteca. In contrast to interstitial water, bulk sediment was toxic to H. azteca. In bulk‐phase sediment TIEs, the addition of 20% (by volume) coconut charcoal increased survival by 41%, implicating organic chemical(s). Addition of 5% (by volume) of the carbonaceous resin Ambersorb 563® increased survival by 88%, again suggesting toxicity due to organic chemicals. Toxicity was confirmed by isolating Ambersorb from the sediment, eluting the resin with methanol, and observing significant toxicity in control water spiked with the methanol eluate. A carboxylesterase enzyme that hydrolyzes synthetic pyrethroids was added to overlying water, and this significantly reduced toxicity to amphipods. Although the pesticides chlorpyrifos, DDT, permethrin, esfenvalerate, and fenvalerate were detected in this sediment, and their concentrations were below published toxicity thresholds for H. azteca, additivity or synergism may have occurred. The weight‐of‐evidence suggests toxicity of this sediment was caused by an organic contaminant, most likely a synthetic pyrethroid.

Solid‐phase sediment toxicity identification evaluation in an agricultural stream

Spatial Relationships Between Water Quality and Pesticide Application Rates in Agricultural Watersheds

A hydraulic braking system for an automotive vehicle having a power pressure source for generating a hydraulic power pressure, a master cylinder generating a hydraulic braking pressure in response to depression of a brake pedal, a dynamic hydraulic pressure generator for regulating the hydraulic power pressure in response to depression of the brake pedal and generating a regulated braking pressure, and a plurality of wheel brake cylinders for braking respective road wheels with one of the hydraulic braking pressure supplied from the master cylinder and the regulated braking pressure supplied from the dynamic hydraulic pressure generator. A power pressure changeover valve is provided and repeatedly changed over to be placed in one of a first operating position where a passage defining therein a closed space is communicated with a space under atmospheric pressure, and a second operating position where the passage is communicated with the power pressure source when the hydraulic power pressure exceeds a predetermined value, so that the hydraulic power pressure is reduced to a proper value.

Tolerance of Five West Coast Marine Toxicity Test Organisms to Ammonia

Conceptual Framework and Rationale for the Exposure and Effects Pilot Study

The Salinas River receives inputs from extensive farmlands before flowing into the Salinas River National Wildlife Refuge and the Monterey Bay National Marine Sanctuary (CA, USA). Previous monitoring using laboratory toxicity tests and chemical analyses identified toxic agricultural drain‐water inputs in this system. Using caged daphnids (Ceriodaphnia dubia) and amphipods (Hyalella azteca), we investigated in situ toxicity at stations downstream from an agricultural drain relative to a reference station. A flow sensor indicated highly variable inputs from irrigation, and daily synoptic chemical analyses using enzyme‐linked immunosorbent assay techniques demonstrated fluctuating concentrations of organophosphate pesticides. Test organism mortality in the field coincided with contaminant concentrations that exceeded chemical effect thresholds for the test species. Laboratory toxicity tests using C. dubia were comparable to results from field exposures, but tests with H. azteca were not. Laboratory exposures can be reasonable surrogates for field evaluations in this system, but they were less effective for assessing short‐term temporal variability. Results from the field toxicity studies corroborated results of bioassessment surveys conducted as part of a concurrent study. Toxicity identification evaluations indicated that organophosphate pesticides caused toxicity to daphnids and that effects of suspended solids were negligible.

In situ water and sediment toxicity in an agricultural watershed

A Comparison of In Situ and Laboratory Toxicity Tests with the Estuarine Amphipod Eohaustorius estuarius

The Salinas River is the largest of the three rivers that drain into the Monterey Bay National Marine Sanctuary in central California (USA). Large areas of this watershed are cultivated year‐round in row crops, and previous laboratory studies have demonstrated that acute toxicity of agricultural drain water to Ceriodaphnia dubia is caused by the organophosphate (OP) pesticides chlorpyrifos and diazinon. We investigated chemical contamination and toxicity in waters and sediments in the river downstream of an agricultural drain water input. Ecological impacts of drain water were investigated by using bioassessments of macroinvertebrate community structure. Toxicity identification evaluations were used to characterize chemicals responsible for toxicity. Salinas River water downstream of the agricultural drain was acutely toxic to the cladoceran Ceriodaphnia dubia, and toxicity to C. dubia was highly correlated with combined toxic units (TUs) of chlorpyrifos and diazinon. Laboratory tests were used to demonstrate that sediments in this system were acutely toxic to the amphipod Hyalella azteca, a resident invertebrate. Toxicity identification evaluations (TIEs) conducted on sediment pore water suggested that toxicity to amphipods was due in part to OP pesticides; concentrations of chlorpyrifos in pore water sometimes exceeded the 10‐d mean lethal concentration (LC50) for H. azteca. Potentiation of toxicity with addition of the metabolic inhibitor piperonyl butoxide suggested that sediment toxicity also was due to other non–metabolically activated compounds. Macroinvertebrate community structure was highly impacted downstream of the agricultural drain input, and a number of macroinvertebrate community metrics were negatively correlated with combined TUs of chlorpyrifos and diazinon, as well as turbidity associated with the drain water. Some macroinvertebrate metrics were also correlated with bank vegetation cover. This study suggests that pesticide pollution is the likely cause of ecological damage in the Salinas River, and this factor may interact with other stressors associated with agricultural drain water to impact the macroinvertebrate community in the system.

Ecotoxicologic impacts of agricultural drain water in the Salinas River, California, USA

Toxicity of Cadmium-Copper-Nickel-Zinc Mixtures to Larval Purple Sea Urchins (Strongylocentrotus purpuratus)

Summary of 10 years of sediment toxicity monitoring for the San Francisco Estuary RMP

Causes of Sediment Toxicity to Mytilus galloprovincialis in San Francisco Bay, California

Ambient Toxicity Due to Chlorpyrifos and Diazinon in a Central California Coastal Watershed

Integrated assessment of the impacts of agricultural drainwater in the Salinas River (California, USA).

Acute and chronic toxicity tests were conducted to determine the effects of nickel on three U.S. west coast marine species: a fish (the topsmelt, Atherinops affinis), a mollusk (the red abalone, Haliotis rufescens), and a crustacean (the mysid, Mysidopsis intii). The 96‐h median lethal concentration (LC50) for topsmelt was 26,560 mg/L, and the chronic value for the most sensitive endpoint in a 40‐d exposure was 4,270 mg/L. The median effective concentration (EC50) for 48‐h abalone larval development was 145.5 μg/L, and the chronic value for juvenile growth in a 22‐d exposure through larval metamorphosis was 26.43 mg/L. The mysid 96‐h LC50 was 148.6 μg/L, and the chronic value for the most sensitive endpoint in a 28‐d, whole life‐cycle exposure was 22.09 μg/L. The abalone and mysid acute values were lower than other values available in the literature. Acute‐tochronic ratios for nickel toxicity to the three species were 6.220, 5.505, and 6.727, respectively, which were similar to the only other available saltwater value of 5.478 (for Americamysis [Mysidopsis] bahia) and significantly lower than the existing values of 35.58 and 29.86 for freshwater organisms. Incorporation of data from the present study into calculations for water quality criteria would lower the criterion maximum concentration and raise the criterion continuous concentration for nickel.

Acute and chronic toxicity of nickel to marine organisms: Implications for water quality criteria

Causes of Ambient Toxicity in the Calleguas Creek Watershed of Southern California

A number of methods have been employed to determine the statistical significance of sediment toxicity test results. To allow consistency among comparisons, regardless of among‐replicate variability, a protocol‐specific approach has been used that considers protocol performance over a large number of comparisons. Ninetieth‐percentile minimum significant difference (MSD) values were calculated to determine a critical threshold for statistically significant sample toxicity. Significant toxicity threshold values (as a percentage of laboratory control values) are presented for six species and nine endpoints based on data from as many as 720 stations. These threshold values are useful for interpreting sediment toxicity data from large studies and in eliminating cases where statistical significance is assigned in individual cases because among‐replicate variability is small.

Statistical significance of sediment toxicity test results: Threshold values derived by the detectable significance approach

Sediment Toxicity Identification Evaluations San Francisco Bay RMP for Trace Substances - Progress Report

Influence of sample manipulation on contaminant flux and toxicity at the sediment-water interface.

Sediment reference sites were used to establish toxicity standards against which to compare results from sites investigated in San Francisco Bay (California, USA) monitoring programs. The reference sites were selected on the basis of low concentrations of anthropogenic chemicals, distance from active contaminant sources, location in representative hydrographic areas of the Bay, and physical features characteristic of depositional areas (e.g., fine grain size and medium total organic carbon [TOC]). Five field‐replicated sites in San Francisco Bay were evaluated over three seasons. Samples from each site were tested with nine toxicity test protocols and were analyzed for sediment grain size and concentrations of trace metals, trace organics, ammonia, hydrogen sulfide, and TOC. The candidate sites were found to have relatively low concentrations of measured chemicals and generally exhibited low toxicity. Toxicity data from the reference sites were then used to calculate numerical tolerance limits to be used as threshold values to determine which test sites had significantly higher toxicity than reference sites. Tolerance limits are presented for four standard test protocols, including solid‐phase sediment tests with the amphipods Ampelisca abdita and Eohaustorius estuarius and sea urchin Strong ylocentrotus purpuratus embryo/larval development tests in pore water and at the sediment‐water interface (SWI). Tolerance limits delineating the lowest 10th percentile (0.10 quantile) of the reference site data distribution were 71% of the control response for Ampelisca, 70% for Eohaustorius, 94% for sea urchin embryos in pore water, and 87% for sea urchins embryos exposed at the SWI. The tolerance limits are discussed in terms of the critical values governing their calculation and the management implications arising from their use in determining elevated toxicity relative to reference conditions.

Evaluation and use of sediment toxicity reference sites for statistical comparisons in regional assessments

Sediment quality in the Los Angeles and Long Beach Harbor area of southern California, USA, was assessed from 1992 to 1997 as part of the California State Water Resources Control Board's Bay Protection and Toxic Cleanup Program and the National Oceanic and Atmospheric Administration's National Status and Trends Program. The assessment strategy relied on application of various components of the sediment quality triad, combined with bioaccumulation measures, in a weight‐of‐evidence approach to sediment quality investigations. Results of bulk‐phase chemical measurements, solid‐phase amphipod toxicity tests, pore‐water toxicity tests with invertebrate embryos, benthic community analyses (presented as a relative benthic index), and bioaccumulation measures indicated that inner harbor areas of this system are polluted by high concentrations of a mixture of sediment‐associated contaminants and that this pollution is highly correlated with toxicity in laboratory experiments and degradation of benthic community structure. While 29% of sediment samples from this system were toxic to amphipods (Rhepoxynius abronius or Eohaustorius estuarius), 79% were toxic to abalone embryos (Haliotis rufescens) exposed to 100% pore‐water concentrations. Statistical analyses indicated that amphipod survival in laboratory toxicity tests was significantly correlated with the number of crustacean species and the total number of species measured in the benthos at these stations. Triad measures were incorporated into a decision matrix designed to classify stations based on degree of sediment pollution, toxicity, benthic community degradation, and, where applicable, tissue concentrations in laboratory‐exposed bivalves and feral fish.

Mean sediment quality guideline quotients (mean SQGQs) were developed to represent the presence of chemical mixtures in sediments and are derived by normalizing a suite of chemicals to their respective numerical sediment quality guidelines (SQGs). Mean SQGQs incorporate the number of SQGs exceeded and the degree to which they are exceeded and are used for comparison with observed biological effects in the laboratory or field. The current research makes it clear, however, that the number and type of SQGs used in the derivation of these mean quotients can influence the ability of mean SQGQ values to correctly predict acute toxicity to marine amphipods in laboratory toxicity tests. To determine the optimal predictive ability of mean SQGQs, a total of 18 different chemical combinations were developed and compared. The ability of each set of mean SQGQs to correctly predict the presence and absence of acute toxicity to amphipods was determined using three independent databases (n = 605, 2753, 226). Calculated mean SQGQ values for all chemical combinations ranged from 0.002 to 100. The mean SQGQ that was most predictive of acute toxicity to amphipods is calculated as SQGQ1 = ((γ ([cadmium]/4.21)([copper]/270)([lead]/112.18)([silver]/1.77)([zinc]/410)([total chlordane]/6)([dieldrin]/8)([total PAHoc]/1,800)([total PCB]/400))/9). Both the incidence and magnitude of acute toxicity to amphipods increased with increasing SQGQ1 values. To provide better comparability between regions and national surveys, SQGQ1 is recommended to serve as the standard method for combination of chemicals and respective SQGs when calculating mean SQGQs.

An evaluation of methods for calculating mean sediment quality guideline quotients as indicators of contamination and acute toxicity to amphipods by chemical mixtures

Sediment quality was assessed in San Francisco Bay, California, USA, using a two‐tiered approach in which 111 sites were initially screened for sediment toxicity. Sites exhibiting toxicity were then resampled and analyzed for chemical contamination, recurrent toxicity, and, in some cases, benthic community impacts. Resulting data were compared with newly derived threshold values for each of the metrics in a triad‐based weight‐of‐evidence evaluation. Sediment toxicity test results were compared with tolerance limits derived from reference site data, benthic community data were compared with threshold values for a relative benthic index based on the presence and abundance of pollution‐tolerant and ‐sensitive taxa, and concentrations of chemicals and chemical mixtures were compared with sediment quality guideline‐based thresholds. A total of 57 sites exceeded threshold values for at least one metric, and each site was categorized based on triad inferences. Nine sites were found to exhibit recurrent sediment toxicity associated with elevated contaminant concentrations, conditions that met program criteria for regulatory attention. Benthic community impacts were also observed at three of these sites, providing triad evidence of pollution‐induced degradation. Multi‐ and univariate correlations indicated that chemical mixtures, heavy metals, chlordanes, and other organic compounds were associated with measured biological impacts in the Bay. Toxicity identification evaluations indicated that metals were responsible for pore‐water toxicity to sea urchin larvae at two sites. Gradient studies indicated that the toxicity tests and benthic community metrics employed in the study predictably tracked concentrations of chemical mixtures in Bay sediments.

A large‐scale categorization of sites in San Francisco Bay, USA, based on the sediment quality triad, toxicity identification evaluations, and gradient studies

Investigations of Sediment Elutriate Toxicity at Three Estuarine Stations in San Francisco Bay, California

Lauritzen Channel is an industrial waterway adjacent to the former United Heckathorn facility in the inner Richmond Harbor area of San Francisco Bay, California, USA. Marine sediments at this Superfund site were dredged from late 1996 through early 1997 to remove the primary chemicals of concern: DDT, and dieldrin. This study assessed the Lauritzen Channel marine environment immediately before and approximately one year after the dredging of sediments. The study included chemical analysis of sediments, tissue concentrations of transplanted mussels, toxicity testing of sediment samples, and characterization of benthic community structure. Results indicated that sediment toxicity to bivalve larvae (Mytilus galloprovincialis) decreased in postre‐mediation samples, but that toxicity to the amphipod Eohaustorius estuarius increased significantly. Assessment of benthos at this site suggested a transitional benthic community structure. In addition, postremediation sediments remained contaminated by a variety of organic chemical compounds, including DDT, dieldrin, chlordane, polycyclic aromatic hydrocarbons, and polychlorinated bi‐phenyls. Tissue concentrations of DDT and dieldrin in mussels (M. galloprovincialis) were lower than those in preremediation samples, indicating that although sediment concentrations of organochlorine pesticides remained high, concentrations of these chemicals in the water column were reduced after dredging. This study demonstrates that the components of the site assessment were useful in determining effectiveness of the remediation activities.

Ecotoxicologic change at a remediated superfund site in San Francisco, California, USA

Abstract Field experiments at two sites assessed the effects of insolation and gastropod grazing on the distribution and abundance of Prasiola meridionalis Setchell et Gardner, a green alga that occurs in the upper splash zone (supralittoral) on guano-covered rocks. At site 1, a sun-exposed horizontal rock where the alga occurs seasonally and grazers were rare, blades appeared in the early spring and died back in early summer. Lack of gastropod grazers and persistence of blades in experimentally shaded plots showed that increased insolation or some associated factor (or factors) was responsible for temporal variation at this site. At site 2, the alga grew in a distinct, perennial band on a shaded vertical rock face with abundant gastropod grazers. These grazers were excluded from long vertical plots that extended from the lower portion of the P. meridionalis band down to a zone of the red alga Endocladia muricata (Postels et Ruprecht) J. Agardh more than 2 m below. The results showed that grazing set the ...

THE EFFECTS OF INSOLATION AND GRAZING ON POPULATIONS OF THE SPLASH ZONE ALGA PRASIOLA MERIDIONALIS (CHLOROPHYTA)

Relationships Between Sediment Toxicity and Contamination in San Francisco Bay

Relationship Between Sediment Toxicity and Contamination in San Francisco Bay (Abstract)

Relationships between sediment contamination and toxicity in San Francisco Bay

Patterns of aquatic toxicity in an agriculturally dominated coastal watershed in California

Chemistry, Toxicity and Benthic Community Conditions of Sediments from Selected Southern California Bays and Estuaries

The 10‐d amphipod survival toxicity test protocol using Rhepoxynius abronius was compared to the 20‐d polychaete worm growth and survival protocol using Nereis (Neanthes) arenaceodentata. Of the 341 sediment samples collected in California and tested over a 2‐year period, 78% significantly inhibited R. abronius survival, whereas 2 and 26% significantly inhibited N. arenaceodentata survival and biomass, respectively. Statistical power associated with each protocol endpoint was determined by calculating the minimum significant difference (MSD) for each test protocol for this data set. The 90th percentile MSDs for R. abronius survival and N. arenaceodentata survival and biomass were 16, 36, and 56%, respectively. Survival of R. abronius was significantly negatively correlated with a number of toxicants including metals, pesticides, polycyclic aromatic hydrocarbons, and polychlorinated biphenyls. No significant correlations were determined between N. arenaceodentata survival or biomass and contaminants measured. Amphipod survival was also negatively correlated with sediment total organic carbon and grain size, but when samples with a high percent fine grain size (>90% fines) were eliminated from consideration, the overall conclusions of the study were not altered. The 10‐d amphipod survival protocol using R. abronius was a more sensitive indicator of toxicity, but the results indicate that this was due to greater statistical power rather than greater sensitivity of the test organisms or endpoints.

Comparison of marine sediment toxicity test protocols for the amphipod Rhepoxynius abronius and the polychaete worm Nereis (Neanthes) arenaceodentata

Sediment quality within San Diego Bay, Mission Bay, and the Tijuana River Estuary of California was investigated as part of an ongoing statewide monitoring effort (Bay Protection and Toxic Cleanup Program). Study objectives were to determine the incidence, spatial patterns, and spatial extent of toxicity in sediments and porewater; the concentration and distribution of potentially toxic anthropogenic chemicals; and the relationships between toxicity and chemical concentrations. Rhepoxynius abronius survival bioassays, grain size, and total organic carbon analyses were performed on 350 sediment samples. Strongylocentrotus purpuratus development bioassays were performed on 164 pore‐water samples. Toxicity was demonstrated throughout the San Diego Bay region, with increased incidence and concordance occurring in areas of industrial and shipping activity. Trace metal and trace synthetic organic analyses were performed on 229 samples. Copper, zinc, mercury, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, and chlordane were found to exceed ERM (effects range median) or PEL (probable effects level) sediment quality guidelines and were considered the six major chemicals or chemical groups of concern. Statistical analysis of the relationships between amphipod toxicity, bulk phase sediment chemistry, and physical parameters demonstrated few significant linear relationships. Significant differences in chemical levels were found between toxic and nontoxic responses using multivariate and univariate statistics. Potential sources of anthropogenic chemicals were discussed.

Assessment of sediment toxicity and chemical concentrations in the San Diego Bay region, California, USA

Purple urchins (Strongylocentrotus purpuratus) were maintained in year‐round spawning condition in the laboratory for use in fertilization and larval development experiments designed to assess temporal variability in response to zinc. Results of these tests were compared to those from tests using gametes obtained from a field‐collected population. Fertilization and larval development tests were also conducted comparing field‐collected purple urchins from three geographically distinct groups on the West Coast of the United States. Fertilization tests conducted to assess temporal variability produced variable median effects concentrations (EC50s) ranging from 4.1 to >100 μg/L zinc. Larval development tests produced more consistent EC50s, which averaged 107.4 ± 21.9 μg/L zinc for laboratory purple urchins and 97.2 ± 19.2 μg/L zinc for field‐collected purple urchins. Larval development tests did not demonstrate significant differences in response to zinc between geographically distinct purple urchin populations. Fertilization test variability was examined in terms of sperm concentration and sperm collection method during two seasons. Reduced variability was found with dry sperm collection in tests conducted in March 1995 but increased again in tests conducted in June 1995, regardless of sperm collection method. Increased variability in response to zinc may be caused by seasonal temperature effects.

Spatial and temporal variation in results of purple urchin (Strongylocentrotus purpuratus) toxicity tests with zinc

MEASUREMENT AND DISTRIBUTION OF INTERSTITIAL AND OVERLYING WATER AMMONIA AND HYDROGEN SULFIDE IN SEDIMENT TOXICITY TESTS

A 7‐d growth and survival toxicity test using the west coast marine mysid crustacean Holmesimysis costata (Holmes) was evaluated to determine test precision and sensitivity. The intralaboratory coefficient of variation (CV) among six reference toxicant test median lethal concentrations (LC50s) was 25%, whereas the mean intralaboratory CV for side‐by‐side effluent test LC50s was 7%. The mean intralaboratory CV for the concentration at which growth was inhibited by 25% (IC25) was 19%. Interlaboratory CVs for effluent LC50s averaged 14%, whereas variation among growth IC25s averaged 15%. Test precision and sensitivity compared favorably with literature values for a number of commonly used toxicity tests and chemical methods. Toxicity increased slightly with increased mysid exposure from 4 to 7 d (mean effluent LC50s of 9.9% for 4 d of exposure and 7.5% for 7 d), and more significantly from 7 to 24 d (zinc LC50 values were 50 μg/L and 7.8 μg/L for concurrent 7‐d and 24‐d tests). Although growth was a less sensitive endpoint than survival in tests with individual chemicals (zinc and sodium azide), growth was the more sensitive endpoint in seven of nine tests with complex effluents. Seventy‐five percent of tests conducted at all participating laboratories met protocol test acceptability criteria (n = 40).

Precision and sensitivity of a seven‐day growth and survival toxicity test using the west coast marine mysid crustacean Holmesimysis costata

Experiments were conducted to compare a short-term 48-h aquatic toxicity test endpoint of abnormal larval shell development with other, more clearly adverse effects. In similar experiments conducted with two different toxicants, zinc sulfate and bleached-kraft mill effluent, red abalone (Haliotis rufescens) embryos were simultaneously exposed to identical dilution series and incubated for three different exposure periods: 48 h, 48 h followed by an 8-d recovery period in clean seawater, and 10 d of continuous exposure. Abnormal larval shell development was assessed in the 48-h short-term tests, and inhibition of metamorphosis was assessed in the exposure-recovery and continuous exposure experiments. For the zinc experiments, the median effective concentration (EC50) values for the 48-h exposure, the exposure-recovery experiment, and the continuous exposure experiment were 40, 34, and 32 {micro}g/L zinc, respectively. For the bleached-kraft mill effluent experiments, the EC50 values were 0.98, 0.76, and 0.69% effluent, respectively. Results indicate that toxicant concentrations causing abnormal larval shell development also inhibit metamorphosis and that larvae exposed to toxicant concentrations which inhibit larval shell development do not recover to metamorphose when transferred to clean seawater. None of the successfully metamorphosed postlarvae had deformed larval shells, indicating that shell deformity precludes survival past the planktonic stage.more » A longer (15-d) experiment allowed measurement of postlarval shell length in exposed postmetamorphic abalone. Insignificant differences in postlarval shell length indicated that the timing of larval metamorphosis was similar regardless of toxicant exposure and that the effects of the toxicant was to inhibit rather than to delay metamorphosis.« less

Validation of a short‐term toxicity test endpoint by comparison with longer‐term effects on larval red abalone Haliotis rufescens

Purple sea urchins (Strongylocentrotus purpuratus) are commonly used in toxicity tests on the west coast for permit monitoring and other applications. They have variable spawning seasons that usually peak in the winter months, but recent work suggests sea urchins can be kept in spawning condition year-round. In this study adult broodstock sea urchins were kept in spawning condition in the laboratory. The gametes from these animals were used in fertilization and larval development experiments designed to assess temporal variability in response to zinc sulfate over a year-long period. The results of these tests were compared to concurrent experiments using gametes from a wild population. Similar tests were conducted comparing urchins from three geographically isolated groups on the west coast. Fertilization tests for the temporal study produced variable EC50`s ranging from 4.1 mg/l to > 100 {micro}g/l zinc. Urchins demonstrated decreased sensitivity during summer months with lab animals showing a more dramatic trend. Larval development tests resulted in EC50`s averaging 107.4 {+-} 21.9 {micro}g/l zinc for laboratory urchins and 97.2 {+-} 19.2 {micro}g/l zinc for wild urchins. Interpopulation larval development results were not significantly different. EC50`s were 133.0 {+-} 19.2 {micro}g/l for Newport, Oregon urchins, 116.1 {+-} 16.8 {micro}g/l for Carmel,more » California, and 94.3 {+-} 28.8 {micro}g/l for San Diego, California. Similar variability was encountered in the interpopulation fertilization tests. Methods to reduce fertilization test variability have been investigated, and will be discussed in terms of sperm to egg ratios and sperm collection techniques.« less

Spatial and temporal sensitivity of purple sea urchins (Strongylocentrotus purpuratus) to zinc

Relatively uncontaminated sites in San Francisco Bay, Tomales Bay and Bolinas Lagoon were evaluated as reference sites for sediment quality assessment studies. Toxicity test results from reference sites can be used to characterize natural variation among sites in the absence of contaminant effects. This natural variation, which includes variation in space, time and sediment composition, can then be used as the variance component in a ``reference envelope`` statistical analysis to determine whether toxicity observed at potentially contaminated sites is statistically significant. In this study, the authors collected field-replicated sediment samples from seven potential reference sites and three contaminated sites. Solid phase sediment and pore water from each site were tested three separate times with protocols for Eohaustorius, Neanthes, Ampelisca, Nebalia, Strongylocentrotus, and Mytilus. Results indicated consistently low toxicity for many potential reference sites, unexplained toxicity at some uncontaminated sites (which are being investigated with TIES) , and high toxicity at two known contaminated sites. Of the protocols employed, the sea urchin larval development test gave the most consistent results, while the Neanthes growth and survival test did not respond at highly contaminated sites. Test performance and reference site selection are discussed in terms of their effects on sediment quality assessment.

Toxicity evaluation of sediments from potential reference sites in San Francisco Bay

Sediment toxicity is typically assessed using homogenized surficial sediment samples. It has been recognized that homogenization alters sediment integrity and may result in changes in chemical bioavailability through oxidation-reduction or other chemical processes. In this study, intact (unhomogenized) sediment cores were taken from a Van Veen grab sampler and tested concurrently with sediment homogenate from the same sample in order to investigate the effect of homogenization on toxicity. Two different solid-phase toxicity test protocols were used for these comparisons. Results of amphipod exposures to samples from San Francisco Bay indicated minimal difference between intact and homogenized samples. Mean amphipod survival in intact cores relative to homogenates was similar at two contaminated sites. Mean survival was 34 and 33% in intact and homogenized samples, respectively, at Castro Cove. Mean survival was 41% and 57%, respectively, in intact and homogenized samples from Islais Creek. Studies using the sea urchin development protocol, modified for testing at the sediment/water interface, indicated considerably more toxicity in intact samples relative to homogenized samples from San Diego Bay. Measures of metal flux into the overlying water demonstrated greater flux of metals from the intact samples. Zinc flux was five times greater, and copper flux was twice asmore » great in some intact samples relative to homogenates. Future experiments will compare flux of metals and organic compounds in intact and homogenized sediments to further evaluate the efficacy of using intact cores for solid phase toxicity assessment.« less

Effects of sample homogenization on solid phase sediment toxicity

Influence of salinity on copper and azide toxicity to larval topsmelt Atherinops affinis (Ayres)

Sulfide and ammonia are natural components of marine sediments which may occur in concentrations toxic to marine organisms. Because these compounds are toxic, it is important to measure them accurately to determine their influence on toxicity test results. Standard solid phase test protocols may not adequately address sampling methodology for ammonia and sulfide analysis. Samples are commonly taken from overlying water in test containers, which may not adequately characterize the medium to which test animals are exposed. As part of research conducted under the California State Water Resources Control Board`s Bay Protection and Toxic Cleanup Program, the authors are investigating alternative sampling methods to more accurately characterize sulfide and ammonia in sediments. Measurements taken from water overlying test sediment are compared to those taken from interstitial water in tests using Neanthes and Rhepoxynius. Pre-test interstitial samples are extracted from sediment using centrifugation. Final measurements are made on water centrifuged from sediment in an additional laboratory replicate. Oxidation can affect the measurement of both constituents, therefore efforts are made to reduce oxidation by centrifuging with no head space. Ammonia is analyzed immediately using an ion specific electrode, and sulfide samples are preserved for spectrophotometric analysis. In preliminary studies sulfide concentrations weremore » 13 times higher and ammonia concentrations 4 times higher in the interstitial water than in samples taken from overlying water. Results will be discussed in terms of sulfide and ammonia toxicity and possible ways of improving sampling methodology.« less

Effect of sampling method on measured concentrations of sulfide and ammonia in sediment toxicity tests

Three separate groups of adult topsmelt (Atherinops a/finis) were spawned in rotation in laboratory culture over a two-year period to provide larvae for toxicity tests. Size and viability of embryos and larvae produced during the normal summer spawning period (May-August) were compared to those produced during the off season (October-April). Mean embryo viability was relatively high throughout the study (82%), whereas size of larvae varied. Larval size was significantly larger during the summer spawning period than in winter. A 7-d growth and survival toxicity test protocol was developed for topsmelt larvae. Variability of the protocol was assessed over a 12-month period using copper chloride as a reference toxicant. Precision of 12 toxicity tests using copper was high; the intralaboratory C.V. for copper LC50s was 19%. The 7-d larval protocol also gave comparable results in two interlaboratory toxicity tests using copper and complex effluent. This study demonstrates that topsmelt may be spawned throughout the year to provide larvae for toxicity tests and that topsmelt larvae have comparable sensitivity to other larval fishes commonly used in toxicity testing.

Off-season spawning and factors influencing toxicity test development with topsmelt Atherinops Affinis

ABSTRACT Field and laboratory studies were made in Monterey Bay, California, on Holmesimysis costata, an ecologically important mysid crustacean in West Coast kelp forests that is currently being used as a water quality indicator organism. Nearly all the mysids were found in the upper portions of the kelp canopy. Relative abundance, size, and male/female/juvenile frequency of occurrence varied substantially throughout the 2-year study. Abundance, ranging monthly from 254-3,359 individuals per 300-1 sample, correlated with sea-water temperature the first year, but not the second. Laboratory growth rate, determined by measuring carapace length, was approximately linear for the first 37 days after hatching (16 µm day―1), after which it increased and became more variable until sexual maturity was reached at 62 days (females 41 µm day―1, males 35 µm day―1) Brooding females were collected thoughout 1 year, but highest fecundities (maximum 45 juveniles in 1 female) occurred between May and August. Mean field fecundities (27.4 ± 6.6 juveniles per female) were higher than those of laboratory-reared females (16.4 ± 4.3). These results indicate that there is high year-round production of these mysids, with peak production in summer when predation by recruiting rockfishes would be most intense.

Population Structure, Growth, and Fecundity of the Kelp Forest Mysid Holmesimysis Costata in Monterey Bay, California

The age-specific sensitivity of topsmelt (Atherinops affinis) larvae to copper was assessed. A series of 7-d growth and survival experiments were conducted using cohorts of larval fish isolated into different age groups of 0, 1, 3, 5, 7, 9, 11, 15, and 20 d post-hatch. Fish aged 0, 3, and 5 d were less sensitive to copper chloride than fish ≥7 d old. The median lethal concentration (LC50) for copper ranged from 365 μg L−1 in 0-d larvae, to 137 μg L−1 in 20-d larvae. NOECs remained relatively constant for all ages: 180 μg L−1 for 1- and 3-d-old fish, 100 μg L−1 for all other cohorts. Regression analysis indicated a significant negative correlation between LC50 and gill surface area (GSA; R2 = —0.793) and cutaneous surface area (CSA; R2 = —0.760. Although these correlations were expected because both morphometrics increase with age, the relationships between increasing respiratory surface area and LC50 may indicate that the increase in sensitivity with larval age is related to an increase in copper uptake, either cutaneously or branchially. GSA increased more than sevenfold between hatch and 20 d, whereas CSA increased only threefold throughout the same period.

Age-specific toxicity of copper to larval topsmelt Atherinops affinis

Sea otters (Enhydra lutris), well documented as "keystone" predators in rocky marine communities, were found to exert a strong influence on infaunal prey com- munities in soft-sedimnent habitats. Direct and indirect effects of sea otter predation on subtidal soft-bottom prey communities were evaluated along a temporal gradient of sea otter occupancy around the Kodiak Archipelago. The results indicate that Kodiak otters forage primarily on bivalve prey and dramatically reduce infaunal bivalve and green sea urchin (Strongylocentrotus droebachiensis) prey populations. Bivalve prey abundance, bio- mass, and size were inversely related to duration of sea otter occupancy. The relative conditions of shells discarded by otters in shallow ( 20 m) water at the same sites indicate that otters first exploited Saxidomus in shallow-water feeding areas, and later switched to Macoma spp. in deeper water. Otter-cracked shells of the deep- burrowing clam Tresus capax were rarely found, even at otter foraging sites where the clam accounted for the majority of available prey biomass, suggesting that it has a partial depth refuge from otter predation. The indirect effects of otter predation included substratum disturbance and the facili- tation of sea star predation on infaunal prey. Sea stars, Pycnopodia helianthoides, were attracted to experimentally dug excavations as well as natural sea otter foraging pits, where the sea stars foraged on smaller size classes of infaunal bivalves than those eaten by otters. Otters also discard clam shells on the sediment surface and expose old, buried shells during excavation. Surface shells were found to provide attachment sites for large anemones and kelp. Our study shows that sea otters can affect soft-sediment communities, not only through predation, as in rocky habitats, but also through disturbance, and thus retain a high degree of influence in two very different habitat types.

Changes in Alaskan soft-bottom prey communities along a gradient in sea otter predation

Topsmelt (Atherinops affinis) were spawned repeatedly in the laboratory from May to July 1989. A periodic “temperature spike” from the holding temperature of approximately 18 up to approximately 20.5°C, introduced at 7- to 9-d intervals, resulted in maximum production of viable embryos on the fourth morning after the spike. Examination of embryonic stages and comparison to known developmental rates for Atherinops affinis embryos revealed that spawning was generally nocturnal, occurring between 1900 and 0500 h. Survival of embryonic and larval Atherinops affinis cultured at 21 ± 1°C and 20 ± 2‰ salinity was excellent (>80%). A larval growth curve was developed for the first 24 d post-hatch.

Laboratory spawning of topsmelt, Atherinops affinis, with notes on culture and growth of larvae

Copper toxicity to sperm, embryos and larvae of topsmelt atherinops affinis, with notes on induced spawning

Experiments were conducted to evaluate temporal and geographic variation in sensitivity of microscopic stages of giant kelp Macrocystis pyrifera to copper. Spores from kelp sporophylls collected from different locations and at different times of the year were exposed to series of copper concentrations following a standard toxicity test procedure. After 48 h static exposures, toxicity was determined by measuring 2 test endpoints: germination success and growth of germination tubes. The sensitivity of these endpoints to copper was also compared with the sensitivity of longer-term reproductive endpoints: sporophyte production and sporophyte growth. No significant differences in response to copper were found among spores from different collection sites. Variability between 4 tests conducted quarterly throughout the year was greater than that between 3 tests done consecutively within 1 mo, indicating temporal variability in response to copper. Long-term reproductive endpoints were more sensitive to copper than were short-term vegetative endpoints, with No Observed Effect Concentrations of < 10 pg 1-' for sporophyte production, 10 yg 1-I for sporophyte growth, 10 yg 1-' for germ-tube growth, and 50 yg 1-I for germination inhibition.

Copper toxicity to microscopic stages of giant kelp Macrocystis pyrifera:interpopulation comparisons and temporal variability

Laboratory experiments were conducted to evaluate the mysid crustacean Holmesimysis costata as a test organism for routine complex effluent toxicity testing. Three-day-old juvenile mysids, hatched in the laboratory from field-collected gravid females, were used in repetitive 48-h and 96-h mortality tests. With zinc sulfate as a reference toxicant, mean 96-h LC50 and no observed effect concentration (NOEC) values for Holmesimysis were 97 and 56 μg/L, respectively, lower than previously reported values for other crustacea. Different laboratories conducting the 96-h mortality test with Holmesimysis produced significantly different results in one trial, but results from different laboratories were not significantly different in the second trial. Coefficients of variation between laboratories for LC50s and NOECs were 24 and 33%, respectively, in the first trial, and 25 and 1%, respectively, in the second trial. Juvenile mysids aged 3, 5, 7 and 9 d old responded similarly to zinc exposure, though control mortality differed among these groups. Gravid female mysids were less sensitive, and 1-d-old mysids had high control mortality; neither group was suitable for toxicity testing. The NOEC for zinc effects on growth was 18 μg/L in a 7-d experiment. LC50 and NOEC values for copper were 27 and <11 μg/L (the lowest concentration tested), respectively. Effluents from four municipal sewage treatment plants (primary through secondary) produced LC50s ranging from 4.5 to 64.0% effluent, and NOECs ranging from 1.0 to 32% effluent, depending on the level of effluent treatment.

Experimental evaluation of the mysid Holmesimysis costata as a test organism for effluent toxicity testing

Sublethal effects of zinc and municipal effluents on larvae of the red abalone Haliotis rufescens

Bioassay methods for evaluating the toxicity of heavy metals, biocides and sewage effluent using microscopic stages of giant kelp Macrocystis pyrifera (Agardh): A preliminary report

Sea otter foraging on deep-burrowing bivalves in a California coastal lagoon

The California sea otter population is gradually expanding in size and geographic range and is consequently invading new feeding grounds, including bays and estuaries that are home to extensive populations of bivalve prey. One such area is the Elkhorn Slough, where otters have apparently established a spring and summer communal feeding and resting area. In anticipation of future otter foraging in the slough, an extensive baseline database on bivalve densities, size distributions, biomasses, and burrow depths has been established for three potential bivalve prey species, Saxidomus nuttalli, Tresus nutallii, and Zirphaea pilsbryi. 
 
In 1986, the Elkhorn Slough otters were foraging predominately at two areas immediately east and west of the Highway 1 bridge (Skipper's and the PG&E Outfall). Extensive subtidal populations of Saxidomus nuttalli and Tresus nuttallii occur in these areas. Shell records collected at these study areas indicated that sea otters were foraging selectively on Saxidomus over Tresus. The reason for this apparent preference was not clear. At the Skipper's study site, 51% of the shell record was composed of Saxidomus, yet this species accounted for only 16% of the in situ biomass, and only 39% of the available clams. Tresus represented 49% of the shell record at Skipper's, yet this species accounted for 84% of the in situ biomass and 61% of the available clams. There was no difference in mean burrow depth between the two species at this site so availability does not explain the disparity in consumption. At the PG&E Outfall, Saxidomus represents 66% of the in situ biomass and 81% of the available clams, while Tresus accounts for 34% of the in situ biomass and 19% of the available clams. Saxidomus accounts for 96% of the shell record at this site vs. 4% for Tresus, again indicating that the otters were preying on Saxidomus out of proportion to their density or biomass. 
 
High densities and biomasses of a third species, Zirphaea pilsbryi, occur in areas where sea otters were observed to be foraging, yet no cast-off Zirphaea shells were found. Although it is possible this species was not represented in the shell record because the otters were simply chewing up the shells, it is more likely this species is avoided by sea otters. 
 
There were relatively few sea otters in the Elkhorn Slough in 1986 compared to the previous two years. This, coupled with high bivalve densities, precluded any quantitative comparison of bivalve densities before and after the 1986 sea otter occupation. Qualitative observations made during the course of this study, and quantitative observations from previous studies indicate that, after 3 years, sea otters are not yet significantly affecting bivalve densities in the Elkhorn Slough.

Sea otter predation and the distribution of bivalve prey in the Elkhorn Slough National Estuarine Research Reserve

Optically Nonlinear Films of Amphiphilic Polymers: Synthesis, Langmuir-Blodgett Deposition, and Optical Measurements

In acoustics, time reversal processing may be used to focus sound to a selected spatial location. Recently, the nonlinear characteristics of time-reversalfocusing at amplitudes as high as 200 dB have been reported [Patchett and Anderson, J. Acoust. Soc. Am., 151(6), (2022)]. These studies were experimental in nature and suggested that converging waves nonlinearly interact in the focusing of waves, leading to surprising observations of nonlinear amplification. This study investigates the nonlinear interactions and subsequent characteristics from a model-based approach. Utilizing both the k-Wave© package for MATLAB©, and COMSOL Multiphysics©, it is shown that nonlinear interactions between high-amplitude waves leads to free-space Mach-wave coalescence of the converging waves. The number of waves used in both models represents a small piece of the full aperture of converging waves experimentally. Limiting the number of waves limits the number of Mach-stem formations and reduces the nonlinear growth of thefocus amplitudes when compared to experiment. However, limiting the number of waves allows the identification of individual Mach waves. Mach wave coalescence leading to Mach-stem formation appears to be the mechanism behind nonlinear amplification of peak focus amplitudes observed in high amplitude time reversal focusing.

Modeling free space Mach stem formation in high-amplitude focusing of sound using time reversal

In acoustics, time-reversal processing is commonly used to exploit multiple scatterings in reverberant environments to focus sound to a specific location. Recently, the nonlinear characteristics of time-reversal focusing at amplitudes as high as 200 dB have been reported [Patchett and Anderson, J. Acoust. Soc. Am. 151(6), 3603-3614 (2022)]. These studies were experimental in nature and suggested that converging waves nonlinearly interact in the focusing of waves, leading to nonlinear amplification. This study investigates the nonlinear interactions and subsequent characteristics from a model-based approach. Utilizing both finite difference and finite-element models, it is shown that nonlinear interactions between high-amplitude waves lead to free-space Mach-wave coalescence of the converging waves. The number of waves used in both models represents a small piece of the full aperture of converging waves experimentally. Limiting the number of waves limits the number of Mach-stem formations and reduces the nonlinear growth of the focus amplitudes when compared to experiment. However, limiting the number of waves allows the identification of individual Mach waves. Mach wave coalescence leading to Mach-stem formation appears to be the mechanism behind nonlinear amplification of peak focus amplitudes observed in high-amplitude time-reversal focusing.

Numerical modeling of Mach-stem formation in high-amplitude time-reversal focusing.

Super resolution is possible using resonators placed in the near field of time reversal focusing. This presentation addresses the problem that a two-dimensional Helmholtz resonator array in a three-dimensional reverberant environment has limited ability to produce a high-resolution spatial focus in the time reversal focusing of audible sound. Acoustic waves propagating out-of-plane with the resonator array are not as strongly modified by the resonators, partially negating the effect of the resonators. The use of a two-dimensional waveguide limits the out-of-plane propagation, leading to improved resolution. It is also shown that post processing using an orthogonal particle velocity decomposition of a spatial scan of the focusing can limit out-of-plane particle motion in the near field of the array, which bypasses the effect of the unwanted third spatial dimension of propagation. Each of these techniques results in a pressure field focus reconstruction that has a higher spatial resolution.

Improving the super resolution focusing above a two-dimensional Helmholtz resonator array using particle velocity decomposition of time reversal focusing

Poor acoustics in a classroom can lead to vocal strain and heath challenges for teachers using these rooms over many years. In some cases, voice amplification can be used to help alleviate vocal strain. The acoustics of various types of elementary and secondary school (K–12) classrooms in Utah were assessed with speech parameters calculated from impulse response measurements for teacher to student interactions (using a dodecahedron loudspeaker and microphone) as well as oral binaural impulse responses for the teacher’s perception of the room (using a KEMAR mannequin with a mouth simulator). The use of and impact on speech intelligibility of voice amplification was also investigated. This study is part of an overall effort to better assess the degree to which rooms with poor acoustics may impact vocal strain.

Survey of the classroom acoustics in Utah elementary and secondary schools and voice amplification systems

Errata: The song of the singing rod [J. Acoust. Soc. Am. 131, 2435-2443 (2012)].

Super resolution, time reversal focusing using path extending properties of scatterers

Time reversal (TR) is a signal processing technique that can be used to focus high amplitude sound or vibration at a desired location. TR focusing can be done with sources placed far from the desired focal location and the technique excels in complex environments. The impulse response between each source and the desired focal location must be obtained prior to the focusing and the environment must remain relatively unchanged for successful focusing. Multiple scattering or reverberation of waves off of many reflecting surfaces in the environment can actually be used advantageously by exploiting those reflections as additional image sources. This talk will provide an introduction to TR and then focus on the use of TR to provide high amplitude focusing of sound and vibration. Applications of high amplitude TR include lithotripsy of kidney stones, histotripsy of lesions, and locating cracks and defects in structures such as in human teeth, spent nuclear fuel storage casks, airplane wings, and automotive bearing caps. Recently, high amplitude TR of airborne sound has been studied in a reverberation chamber to generate a focused difference frequency and to study the nonlinear acoustics of the peak sound levels of 200 dB that have been attained.

Exciting structures with a broadband noise signal is a method used to assess a structure’s health and how it responds to the noise. Past work has shown that time reversal (TR) acoustics has provided a robust method to focus impulses at high amplitudes. Maximization of the highest possible amplitude while maintaining the desired spectral shape can be challenging. This study explores the benefits of using TR with equalization methods to a steady state broadband noise signal to acoustically excite structures. Tradeoffs exist between the possible amplitude of the focused noise and the duration of the noise and the amount of equalization employed. The spatial extent of the focusing will also be discussed. The use of TR to generate high amplitude broadband noise is compared to standard point application of noise equalization with the overall goal to use this high amplitude noise to excite structures under test.

Exploring ways to maximize the amplitude of steady state broadband noise signals using time reversal in order to excite structures acoustically

Time reversal focusing above an array of resonators creates subwavelength features when compared to waves in free space. Previous work has shown the ability to focus acoustic waves near the resonators with and without time reversal with an array placed coplanar with acoustic sources. In this work, a two-dimensional array of resonators is studied with a full three-dimensional aperture of waves in a reverberation chamber. The full impulse response is recorded (including reverberation), and the spatial inverse filter is used to produce a focus among the resonators. Additionally, complex images are produced by extending the spatial inverse filter to create focal images such as dipoles and quadrupoles. Although waves at oblique angles would be expected to degrade the focal quality, it is shown that complex focal images can still be achieved.

Super resolution focusing of complex sources above a two-dimensional array of resonators in a three-dimensional environment

Time reversal is a technique that allows the focusing of sound from a source to a remote location causing an impulsive focusing event. Using more sources and other amplitude-increasing techniques, the focusing of audible sound can reach over 200 dB peak. This can extinguish the flame on a single candle without affecting nearby lit candles. Most methods used to extinguish a flame using sound involve the nearfield and nonlinear airflow effects. Because time reversal focusing can occur far from the sources, the mechanism is different. Using high-speed video footage of the focal event, we can see the finer details of this millisecond scale focus interacting with the flame. Measuring the sound field during the focus event at and near the focal location also sheds light on the mechanism. So far, it has been seen that the focus pushes the flame outward, separating the plasma from its fuel source. The known formation of shock waves provides a possible explanation. Further research is being done to explore the cause of the extinguishing of the flame. This talk will show that not only is it possible to focus high amplitude sound waves but targeted flows of air as well.

Blowing out a candle from a distance with high amplitude time reversal

School teachers’ voice problems are widespread and influence the learning process. Voice amplification systems in classrooms are a common response and a preventative strategy. The primary purpose of this study was to (1) determine the relationship between teacher vocal fatigue and use of classroom amplification; and (2) identify factors influencing amplification usage. Teachers throughout the US completed questionnaires regarding vocal health, classroom conditions, lifestyle habits, and access to and use of vocal amplification systems. Responses indicated that biological female teachers who used voice amplification or taught grades kindergarten to middle school were more likely to report higher levels of vocal fatigue. Further, teachers with access to amplification systems were more likely to use them if they were teachers in lower grade levels, who smoked occasionally, drank alcohol frequently, and taught in larger capacity classrooms. In conclusion, it maybe that those using the amplifications are using them because of pre-existing voice issues. Finally, the work-related factors associated with the use of amplification systems (e.g., grade level, classroom capacity) may be indicators of adjustments to reduce the occurrence of voice problems among teachers. Ongoing studies reviewing the available classroom amplification equipment and use from a school administrators perspective will be discussed.

Teacher’s vocal health: Voice application systems and other work-related factors

A phononic crystal acts as a dispersive medium with a phase speed that is lower than the bulk wave speed at frequencies below the resonance of a single resonator. Time reversal is used to compensate for the phase shifts caused by individual resonators as the waves enter the medium and enable focusing of acoustic waves among the crystal. An equivalent circuit, which can predict the dispersion and attenuation of the crystal model, is shown and compared to a full-wave finite-element simulation in frequency and time. The phase shift due to a single resonator is also depicted.

Time reversal in a phononic crystal using finite-element modeling and an equivalent circuit model.

At Brigham Young University, acoustic time reversal experiments are conducted in solids and fluid media. The experimental setup involves synchronized generation and acquisition hardware. The synchronized hardware allows for multi-channel generation, and in some cases, multi-channel acquisition of time reversal focusing. A LabVIEW application has been compiled to increase ease of use and repeatability for the students conducting experiments. Forward and backward steps of time reversal are conducted through this simple user interface. The software is also able to control a 2D positioning system that allows for the measurement of the spatial extent of a time reversal focus. Modifications to traditional time reversal processing, such as inverse filtering and one-bit processing, may be easily implemented in the software. This presentation describes the hardware and software that help to facilitate time reversal research. Ideas from this presentation may help others develop time reversal data acquisition systems.

Development of software for performing acoustic time reversal with multiple inputs and outputs

This presentation will discuss the time reversal focusing of audible sound over an array of Helmholtz resonators. The presence of the resonators modifies the phase speed of waves, thereby lowering the effective wavelength, in the near field of the focus. It is shown experimentally what conditions are necessary to obtain super resolution. Frequencies above the resonators’ resonance frequency do not result in super resolution. In order to achieve super resolution in the plane of the resonators, the focused waves must be confined to propagate only in the plane of the resonators. When waves converged in three dimensions, super-resolution was not observed but when a 2-D waveguide was used, and super-resolution was observed.

Exploring conditions required for the subwavelength focusing of sound in the near field of an array of resonators using time reversal

Time reversal (TR) is a method of focusing wave energy at a point in space. The optimization of a TR demonstration is described, which knocks over one selected LEGO minifigure among other minifigures by focusing the vibrations within an aluminum plate at the target minifigure. The aim is to achieve a high repeatability of the demonstration along with reduced costs to create a museum exhibit. By comparing the minifigure's motion to the plate's motion directly beneath its feet, it is determined that a major factor inhibiting the repeatability is that the smaller vibrations before the focal event cause the minifigure to bounce repeatedly and it ends up being in the air during the main vibrational focal event, which was intended to launch the minifigure. The deconvolution TR technique is determined to be optimal in providing the demonstration repeatability. The amplitude, frequency, and plate thickness are optimized in a laboratory setting. An eddy current sensor is then used to reduce the costs, and the impact on the repeatability is determined. A description is given of the implementation of the demonstration for a museum exhibit. This demonstration illustrates the power of the focusing acoustic waves, and the principles learned by optimizing this demonstration can be applied to other real-world applications.

The physics of knocking over LEGO minifigures with time reversal focused vibrations for use in a museum exhibit.

Time reversal (TR) is a signal processing technique that may be used to generate a focusing of waves at selected positions in reverberant environments. This study looks at the increase in the focal amplitude as the distance between the focal location and a boundary is decreased. Previous studies with audible sound in rooms have shown experimentally and numerically that there is a 3 dB increase in focal amplitude if the focal location is positioned 1 cm away from a wall; the numerical model used was a modal summation simulation. It has since been found that using an image source model simulation does not show any increase in focal amplitude as the focal location approaches boundaries. Experiments conducted in solid media with ultrasound showed that focal amplitudes increase by 6 dB at a free boundary. Experiments and modal summation modeling conducted with audible sound in a reverberation chamber also yielded similar results as the focal location reached the wall. The presentation will discuss why the image source model does not yield these results.

Time reversal focal amplitudes as the focal position approaches boundaries

Sounds to Astound is an acoustics demonstration show, produced for the community twice yearly by the Brigham Young University Student Chapter of the Acoustical Society of America. The free, interactive demonstration show explores the science of sound for a target audience of fifth- to eighth-grade students. Introductory acoustics concepts, such as longitudinal wave motion, wave properties, propagation effects, and standing waves, are taught with live demonstrations, animations, and videos. The goal of this paper is to inspire and encourage readers in their outreach efforts by describing the purposes of Sounds to Astound and technical details of several entertaining and educational demonstrations. Lessons learned from a decade of these student-produced shows serve as an aid for future efforts and highlight the benefits of outreach efforts, particularly for the students involved.

Guitar amplifiers comprise specialized powered loudspeakers with distinct configurations and directivity characteristics. Recently, the authors measured the directivities of six guitar amplifiers using a new measurement system. The system employs a rotating semicircular microphone array in an anechoic chamber, with 2522 unique microphone positions over a surrounding sphere (i.e., 5-deg resolution in both the polar and azimuthal angles). This presentation will describe the measurement and processing procedures and compare the measured results to those produced by theoretical directivity models. An online archival database provides easy access to the guitar amplifier data and other directivity data from the human voice, played musical instruments, and other sound sources. The data are available in several commonly used file formats and should provide valuable information for many applications, including spatial audio, architectural acoustics modeling, and microphone placement.

This presentation will discuss the possibility of using path-diverting scatterers in time reversal focusing to achieve super resolution. In particular, use of a one-dimensional pipe system with varying lengths of diverting pipes is shown to decrease the effective wave speed. This provides insight, albeit in an extreme case, of how scatterers can force sound to travel a longer path as the waves converge to the focal location. As the effective wave speed decreases, the spatial extent of the focusing decreases, creating an apparent super resolution when compared to the speed of sound in an unaltered pipe system. Previous work achieved super resolution with what they described as scatterers, but it is likely that their scatterers are better classified as resonators, and consequently, it has yet to be shown that scatterers can be used to obtain super resolution.

Super-resolution, time-reversal focusing using path-diverting scatterers

Time reversal (TR) is a process that can be used to generate high amplitude focusing of sound. It has been previously shown that using TR in reverberant environments to cause high amplitude foci will in fact have multiple nonlinear properties including waveform steepening and a nonlinear increase in peak pressure compressions. This study investigates the removal of one possible cause for these phenomena: free-space Mach stems. By isolating the focus into a 1-D system, the potential formation of Mach stems is eliminated so that remaining effects can be qualitatively observed. To achieve this, a system of pipes is used to restrict the focused waves to be planar in a 1-D reverberant environment. Preliminary results have shown that waveform steepening effects remain as expected but that the nonlinear increase in compression amplitudes disappears, which is consistent with the idea that free-space Mach stems cannot be formed in a 1-D system.

Nonlinear acoustic phenomena in high amplitude time reversal focusing of airborne sound in a 1-D system

This presentation will outline the physical and practical considerations for conducting a COMSOL simulation of time reversal focusing in air. Attempts to obtain sub-diffraction-limited time reversal focusing, along with physical and practical consideration, will be presented. Physical considerations include end-corrections, resonator shape and placement, computational domain and anechoic terminations. Practical considerations include mesh size and temporal length. While conducting a time domain study in COMSOL, mesh size is related to the highest frequency and the simulation length is related to the lowest frequency. To maximize computational resources, the simulation uses a restricted bandwidth. Extending the bandwidth is accomplished by combining multiple simulations. Comparison to previous super resolution studies as well as the authors’ equivalent circuit model will also be discussed.

COMSOL modeling of time reversal focusing in a periodic network of Helmholtz resonators

acoustic time reversal experiments are conducted in solids and fluid media. The experimental setup involves synchronized generation and acquisition hardware. The synchronized hardware allows for multi-channel generation, and in some cases, multi-channel acquisition of time reversal focusing. A LabVIEW application has been compiled to increase ease of use and repeatability for the students conducting experiments. Forward and backward steps of time reversal are conducted through this simple user interface. The software is also able to control a 2D positioning system that allows for the measurement of the spatial extent of a time reversal focus. Modifications to traditional time reversal processing, such as inverse filtering and one-bit processing, may be easily implemented in the software. This paper describes the hardware and software that facilitates time reversal research.

182nd Acoustical Signal Processing in Acoustics: Paper 3pSP1 Development of software for performing acoustic time reversal with multiple inputs and outputs

An equivalent circuit model has been developed to model a one-dimensional waveguide with many side-branch Helmholtz resonators. This waveguide constitutes a phononic crystal that has been shown to have decreased phase speed below the resonance frequency of an individual resonator. This decreased phase speed can be exploited to achieve super-resolution using broadband time reversal focusing techniques. It is shown that the equivalent circuit model is capable of quantifying this change in phase speed of the crystal and also the small-scale wave-resonator interactions within the crystal. The equivalent circuit model enables the parameterization of the physical variables and the optimization of the focusing bandwidth by balancing the combination of increasing resolution and decreasing amplitude near the resonance frequency. It is shown that the quality factor-in this case, the quality factor determined by the geometric shape of each resonator-controls the range of frequencies that are strongly affected by the Helmholtz resonators.

Super-resolution within a one-dimensional phononic crystal of resonators using time reversal in an equivalent circuit model.

Time reversal is a method often used to focus sound to a desired location within a reverberant environment. Recent high-amplitude focusing experiments have shown that when multiple sources are used simultaneously to generate a focus, the level reached (200 dB) is higher than if each source were focused individually with the signals being superposed computationally. An investigation into the temporal and spatial features and harmonic content of each method is presented in order to work toward an understanding of the mechanisms driving the nonlinear increases observed when the sources are combined acoustically as opposed to being summed in post-processing.

Comparison of high-amplitude focus creation methods with time reversal to help determine a mechanism of nonlinearity

Time reversal (TR) signal processing is an effective tool to exploit a reverberant environment for the intentional focusing of airborne, audible sound. A previous room acoustics TR study found preliminary evidence that above a certain focal amplitude the focal waveform begins to display signs of nonlinearity [Willardson, Anderson, Young, Denison, and Patchett, J. Acoust. Soc. Am. 143(2), 696-705 (2018)]. This study investigates that nonlinearity further by increasing the focal peak amplitudes beyond that previously observed. This increases the nonlinear characteristics, allowing for a closer inspection of their properties. An experiment is conducted using eight horn loudspeaker sources and a single receiver in a reverberation chamber. A maximum peak focal amplitude of 214.8 kPa (200.6 dBpk) is achieved. The focus signal waveforms are linearly scaled to observe and characterize the nonlinear amplification of the waveform. Frequency spectra of the peak focal amplitudes are plotted to observe changes in frequency content as the signals become nonlinear. A one-dimensional spatial scan of the focal region is conducted to observe properties of the converging and diverging waves. A proposal for a possible explanation involving free-space Mach stem formation is given.

Nonlinear characteristics of high amplitude focusing using time reversal in a reverberation chamber.

his article provides an historical overview of Time Reversal (TR), introduces its basic physics, addresses advantages and limitations, and describes some applications of this very active research area of acoustics. In the Geophysics Group at the Los Alamos National Laboratory, we conduct studies of TR of elastic waves in solids. Our work includes application of TR to nondestructive evaluation of materials, as well as to earthquake source characterization, and ground-based nuclear explo-sion monitoring. We emphasize the term elastic waves here to underscore that we include both compression and shear waves, in contrast to purely acoustic waves that are only compressional.

BYU ScholarsArchive BYU ScholarsArchive Time Reversal Time Reversal

Knocking over LEGO minifigures with time reversal focused vibrations: Understanding the physics and developing a museum demonstration

Time reversal is used as an energy-focusing technique in nondestructive evaluation applications. Here, it is often of interest to evaluate small samples or samples that do not lend themselves to the bonding of transducers to their surfaces. A reverberant cavity, called a chaotic cavity, attached to the sample of interest provides space for the attachment of transducers as well as an added reverberant environment, which reverberation is critical to the quality of time reversal focusing. The goal of this research is to explore the dependence of the quality of the time reversal focusing on the size and geometric shape of the chaotic cavity used. An optimal chaotic cavity will produce the largest focusing amplitude, best spatial resolution, and linear focusing of the time reversed signal. Ultrasonic elastic-wave experiments are performed on a rectangular, cylindrical, and three-dimensional Sinai billiard prism samples, and experiments are repeated each time these samples are successively cut down to smaller volumes. As the size of the cavity decreases, the peak amplitude may increase or decrease depending on the normalization scheme employed. The higher the degree of ergodicity of the cavity, the higher the amplitude and quality focusing achieved.

The performance of time reversal in elastic chaotic cavities as a function of volume and geometric shape of the cavity.

Active noise control using remotely placed sources: Application to magnetic resonance imaging noise and equivalence to the time reversal inverse filter

Time reversal (TR) focusing of airborne ultrasound in a room is demonstrated. Various methods are employed to increase the amplitude of the focus. These methods include creating a small wooden box (or chamber) to act as a miniature reverberation chamber, using multiple sources, and using the clipping processing method. The use of a beam blocker to make the sources more omnidirectional is also examined, and it is found that for most source/microphone orientations, the use of a beam blocker increases the amplitude of the focus. A high-amplitude focus of 134 dB peak re 20 μPa sound pressure level with a center frequency of about 38 kHz is generated using TR. Using four sources centered at 36.1 kHz and another four sources centered at 39.6 kHz, nonlinear difference frequency content centered at 3.5 kHz is observed in the focus signal. The difference frequency amplitude grows quadratically with increasing primary frequency amplitude. When using beam blockers, the difference frequency content propagates away from the focal location with higher amplitude than when beam blockers are not used. This is likely due to the differences in the directionality of the converging waves during TR focusing.

High-amplitude time reversal focusing of airborne ultrasound to generate a focused nonlinear difference frequency.

The natural frequency resonances and sound radiation from one-dimensional acoustic systems are of great interest in the study of musical instruments, human vocal tract effects on speech, automotive exhaust pipes, duct systems for temperature control in buildings, and more. The impedance translation theorem is an approach that may be used to solve for the input impedance and therefore the resonance frequencies of one-dimensional systems. Equivalent circuits offer another approach to solving one-dimensional systems, though with equivalent circuits you can also solve for the response at any location in the system, including the radiated sound pressure. At Brigham Young University, there are two graduate level courses that teach these two techniques. One of the most challenging and memorable homework assignments from these courses is based on using one of these techniques to analyze a particular acoustic system and compare its response with the real thing. This paper discusses the basics of these two techniques and applies them to an analysis of phonemes produced by altering the human vocal tract. Details about the homework assignments are also given.

Solving one-dimensional acoustic systems using the impedance translation theorem and equivalent circuits: A graduate level homework assignment.

Modeling time reversal focusing amplitudes in a reverberation chamber using a modal summation approach

One problem, two solution approaches: Using the impedance translation theorem and equivalent circuits for graduate level homework

Generation of a focused nonlinear difference frequency using high-amplitude time reversal focusing of airborne ultrasound

Quantifying nonlinear characteristics in time reversal focusing of airborne sound

Time reversal (TR) is a signal processing technique often used to generate focusing at selected positions within reverberant environments. This study investigates the effect of the location of the focusing, with respect to the room wall boundaries, on the amplitude of the focusing and the uniformity of this amplitude when focusing at various room locations. This is done experimentally with eight sources and two reverberation chambers. The chambers are of differing dimensions and were chosen to verify the findings in different volume environments. Multiple spatial positions for the TR focusing are explored within the rooms' diffuse field, against a single wall, along a two-wall edge, and in the corners (three walls). Measurements of TR focusing at various locations within the room show that for each region of study, the peak amplitude of the focusing is quite uniform, and there is a notable and consistent increase in amplitude for each additional wall that is adjacent to the focal location. A numerical model was created to simulate the TR process in the larger reverberation chamber. This model returned results similar to those of the experiments, with spatial uniformity of focusing within the room and increases when the focusing is near adjacent walls.

The impact of room location on time reversal focusing amplitudes.

Time reversal acoustics for communications, focusing, and source localization

Understanding Acoustics: An Experimentalist's View of Sound and Vibration, Second Edition.

Time reversal is used as an energy-focusing technique in nondestructive evaluation applications. Here, it is often of interest to evaluate small samples or samples that do not lend themselves to the bonding of transducers to their surfaces. A reverberant cavity, called a chaotic cavity, attached to the sample of interest provides space for the attachment of transducers as well as an added reverberant environment, which reverberation is critical to the quality of time reversal focusing. The goal of this research is to explore the dependence of the quality of the time reversal focusing on the size and geometric shape of the chaotic cavity used. An optimal chaotic cavity will produce the largest focusing amplitude, best spatial resolution, and linear focusing of the time reversed signal. Ultrasonic elastic-wave experiments are performed on a rectangular, cylindrical, and three-dimensional Sinai billiard prism samples, and experiments are repeated each time these samples are successively cut down to smaller volumes. As the size of the cavity decreases, the peak amplitude may increase or decrease depending on the normalization scheme employed. The higher the degree of ergodicity of the cavity, the higher the amplitude and quality focusing achieved. VC 2021 Acoustical Society of America. https://doi.org/10.1121/10.0005654 (Received 17 December 2020; revised 1 June 2021; accepted 30 June 2021; published online 21 July 2021) [Editor: Efren Fernandez-Grande] Pages: 526–539

The performance of time reversal in elastic chaotic cavities as a function of volume and geometric shape of the cavity

Detecting and imaging stress corrosion cracking in stainless steel, with application to inspecting storage canisters for spent nuclear fuel

Electromagnetic excitation technique for nonlinear resonant ultrasound spectroscopy

The effects of source placement on time reversal focusing in rooms

Moving-coil loudspeaker parameters are typically derived from electrical impedance measurements. Leishman and Anderson previously provided the theoretical foundations for extracting these parameters from sound transmission measurements conducted in a plane wave tube. This presentation will discuss experimental results of using this idea to extract the parameters of moving-coil drivers and those of passive radiators, the latter of which cannot be derived from electrical impedance measurements. The two-load method is used to account for the non-anechoic behavior of the tube to better enable accurate extraction of the sound transmission. Mechanical parameters are extracted from an open-circuit sound transmission measurement, and the electrical parameters are extracted by placing a wire across the loudspeaker’s terminals to provide a closed-circuit sound transmission measurement. Parameters extracted from measurements of electrical impedance, sound transmission, and destructive analysis of diaphragm assemblies will be compared.Moving-coil loudspeaker parameters are typically derived from electrical impedance measurements. Leishman and Anderson previously provided the theoretical foundations for extracting these parameters from sound transmission measurements conducted in a plane wave tube. This presentation will discuss experimental results of using this idea to extract the parameters of moving-coil drivers and those of passive radiators, the latter of which cannot be derived from electrical impedance measurements. The two-load method is used to account for the non-anechoic behavior of the tube to better enable accurate extraction of the sound transmission. Mechanical parameters are extracted from an open-circuit sound transmission measurement, and the electrical parameters are extracted by placing a wire across the loudspeaker’s terminals to provide a closed-circuit sound transmission measurement. Parameters extracted from measurements of electrical impedance, sound transmission, and destructive analysis of diaphragm assemblie...

Experimental extraction of loudspeaker parameters from sound transmission measurements in a plane wave tube for moving-coil drivers and passive radiators

Whether it is locating an enemy submarine, finding that annoying sound generated inside an airplane, optimizing the focusing of sound to destroy kidney stones, or learning how bats track their food...

Signal Processing: Data analysis, machine learning, and imaging sources

At Brigham Young University we offer a graduate level course on the fundamentals of acoustics. This course has traditionally covered the fundamentals of vibration in masses and springs, strings, bars, membranes and plates in the first half of the course. The second half of the course covers the derivation of the wave equation, wave propagation, reflection and transmission phenomena, and source radiation problems. For a couple decades, we used Kinsler and Frey’s “Fundamentals of Acoustics” book but the rising costs, lack of updates, and dissatisfaction with the rigor of the book motivated us to find a new text. For a few years, we used Kinsler and Frey for the first half of the course (vibrations) and also Blackstock’s “Fundamentals of Physical Acoustics” for the second half (fluids). Two books meant even higher costs, although the Kinsler and Frey text was also used in another class at that time. When we switched instructors for the course, Anderson was asked to review Garrett’s “Understanding Acoustics” text and he ended up adopting it for this course. This talk will review our experiences in switching textbooks and discuss our reasons for selecting our current text and how we are using it in class in conjunction with pre-class reading quizzes, which has helped increase classroom discussions.At Brigham Young University we offer a graduate level course on the fundamentals of acoustics. This course has traditionally covered the fundamentals of vibration in masses and springs, strings, bars, membranes and plates in the first half of the course. The second half of the course covers the derivation of the wave equation, wave propagation, reflection and transmission phenomena, and source radiation problems. For a couple decades, we used Kinsler and Frey’s “Fundamentals of Acoustics” book but the rising costs, lack of updates, and dissatisfaction with the rigor of the book motivated us to find a new text. For a few years, we used Kinsler and Frey for the first half of the course (vibrations) and also Blackstock’s “Fundamentals of Physical Acoustics” for the second half (fluids). Two books meant even higher costs, although the Kinsler and Frey text was also used in another class at that time. When we switched instructors for the course, Anderson was asked to review Garrett’s “Understanding Acoustics” ...

Selecting a new textbook for a graduate level course on vibration and fluid acoustics

Experimental analysis of the size and shape of time reversal chaotic cavities for nondestructive evaluation

Time reversal (TR) focusing used for nonlinear detection of cracks relies on the ability of the TR process to provide spatially localized, high-amplitude excitation. The high amplitude improves the ability to detect nonlinear features that are a signature of the motion of closed cracks. It follows that a higher peak focal amplitude than what can be generated with the traditional TR process will improve the detection capability. Modifying the time-reversed impulse response to increase the amplitude of later arrivals in the impulse response, while maintaining the phase information of all arrivals, increases the overall focal signal amplitude. A variety of existing techniques for increasing amplitude are discussed, and decay compensation TR, a technique wherein amplitude is increased according to the inverse of the amplitude envelope of the impulse response decay, is identified as the best modification technique for nonlinear crack detection. This technique increases the focal signal amplitude with a minor introduction of harmonic content, a drawback in two other methods studied, one-bit TR and clipping TR. A final study employs both decay compensation TR and traditional TR, focusing on a rod with stress corrosion cracking, and compares the merits of each in detecting nonlinearity from cracks in a real system.

A comparison of impulse response modification techniques for time reversal with application to crack detection.

In this study, time reversal (TR) signal processing methods are used to create a focus of airborne ultrasound (between approximately 30 kHz and 50 kHz) in a room. There are unique challenges presented by ultrasonic sources, such as the highly directional nature of the sources, and attenuation of ultrasound in air. The aim of this study is to create a TR focus whose amplitude is as high as possible using the clipping processing method. Because ultrasonic sources tend to be very directional, this study explores the impact of using methods to make the sources more omnidirectional, which increases the number of reflective paths that contribute to the TR focus. This study explores various configurations of source and microphone in the room to determine which configuration yields the highest amplitude. Because thermoviscous loses for ultrasound are higher than for audible frequencies, a smaller room is used in the experiments to increase focal amplitudes.In this study, time reversal (TR) signal processing methods are used to create a focus of airborne ultrasound (between approximately 30 kHz and 50 kHz) in a room. There are unique challenges presented by ultrasonic sources, such as the highly directional nature of the sources, and attenuation of ultrasound in air. The aim of this study is to create a TR focus whose amplitude is as high as possible using the clipping processing method. Because ultrasonic sources tend to be very directional, this study explores the impact of using methods to make the sources more omnidirectional, which increases the number of reflective paths that contribute to the TR focus. This study explores various configurations of source and microphone in the room to determine which configuration yields the highest amplitude. Because thermoviscous loses for ultrasound are higher than for audible frequencies, a smaller room is used in the experiments to increase focal amplitudes.

High-amplitude focusing of ultrasound in air using time reversal

Defects in a sample cause localized distortions of a wave. Focused waves at a defect create amplitude-dependent signatures that may be quantified in post processing, thereby offering a means of locating and characterizing the defect. Time reversal (TR) is a technique that allows intentional focusing of wave energy. TR has been developed for crack and defect detection in solid media. Because TR provides a localized focus of elastic energy, it can be used to study the local nonlinear properties at point(s) of interest that are indicative of the presence of cracks and defects. Source transducers may remain in place as a sample is scanned for defects. A laser Doppler vibrometer offers a noncontact means of selecting points at which to focus energy. TR applied to detect cracking in steel rods will be presented. The results demonstrate that cracks may be identified through their nonlinear signatures when TR is used to focus energy at various positions along the rods.

Nonlinearity in high amplitude focused waves in solids for crack detection using time reversal techniques

The Time Reversed Elastic Nonlinearity Diagnostic (TREND) has a long history of successful nondestructive detection of cracks in solids using nonlinear indicators. Recent research implemented TREND to find stress corrosion cracking (SCC) in the heat-affected zone adjacent to welds in stainless steel. SCC development around welds is likely to occur due to the temperature and chemical exposure of steel canisters housing spent nuclear fuel. The ideal SCC detection technique would quantify the size and extent of the SCC, rather than just locating it, as TREND has been used for in the past. The current paper explores TREND's ability to detect an assumed increase in SCC over time using 13 samples exposed to a magnesium chloride (MgCl2) bath for different lengths of time. The samples are then scanned with TREND and nonlinearity is quantified for each scan point and each sample. The results suggest that TREND can be used to not only locate SCC in the heat-affected zone, but also track an increase in nonlinearity, and thereby an increase in damage, in samples exposed to the MgCl2 solution for a longer duration.

Nonlinearity from stress corrosion cracking as a function of chloride exposure time using the time reversed elastic nonlinearity diagnostic.

Time reversal (TR) is a method of focusing wave energy at a single point in space. This project optimizes a TR demonstration designed to knock over one selected LEGO minifigure among other minifigures by focusing vibrations within an aluminum plate at the target minifigure. The goal is to achieve high repeatability of the demo along with making it possible to do at a lower cost. By comparing the motion of the minifigure and the plate directly beneath its feet, it was determined that a major factor inhibiting the repeatability of the demo was that smaller vibrations leading up to the focal event caused the minifigure to bounce repeatedly, losing contact with the plate and ending up in the air during the main focal event intended to knock over the minifigure. This project explores the effects of amplitude, frequency, TR technique, plate size, and vibration sensor type on the repeatability of the demonstration. This demonstration illustrates the power of TR focusing and the principles learned by optimizing this demonstration can be applied to other real-world applications.Time reversal (TR) is a method of focusing wave energy at a single point in space. This project optimizes a TR demonstration designed to knock over one selected LEGO minifigure among other minifigures by focusing vibrations within an aluminum plate at the target minifigure. The goal is to achieve high repeatability of the demo along with making it possible to do at a lower cost. By comparing the motion of the minifigure and the plate directly beneath its feet, it was determined that a major factor inhibiting the repeatability of the demo was that smaller vibrations leading up to the focal event caused the minifigure to bounce repeatedly, losing contact with the plate and ending up in the air during the main focal event intended to knock over the minifigure. This project explores the effects of amplitude, frequency, TR technique, plate size, and vibration sensor type on the repeatability of the demonstration. This demonstration illustrates the power of TR focusing and the principles learned by optimizing t...

The physics of knocking over LEGO minifigures with time reversal focused vibrations

Time reversal (TR) is a signal processing technique that may be used to intentionally generate high amplitude focusing of sound. The use of time reversal in room acoustics has been studied previously, but an analysis of the dependence of spatial positioning of the transducers in the room, and its effect on high amplitude focus signals has not previously been explored. Experiments are carried out in two reverberation chambers of differing size with eight compression drivers. Using these drivers, the impulse response is found and reversed in time. The spatial dependence of the transducers position is measured by calculating the time reversed impulse response at various transducer positions and then measuring the peak focal amplitude generated when the time reversed signal is broadcast to those positions. Multiple measurements suggest that the amplitude of the focus signal changes with both room size and proximity to a reflecting surface in the chambers.

Time reversal focusing of high amplitude sound in a reverberation chamber: Optimizing the placement of transducers

Nonlinear resonant ultrasound spectroscopy of stress corrosion cracking in stainless steel rods

The noise produced by a Magnetic Resonance Imaging (MRI) scan can cause discomfort to patients. Active Noise Control (ANC) systems have been developed to help reduce the amount of noise a patient experiences. However, due to the small enclosure of the MRI machine, ANC equipment can be cumbersome to use, and is limited to non-ferrous material. Time Reversal Acoustics (TRA) is a technique that can focus sound to a selected position in space that may be far from actual sound sources. We are exploring using TRA to deliver an ANC signal by broadcasting “anti-noise” signals that are focused to the patient’s ears through TRA to cancel the MRI noise. This presentation will explore the applicability of using TRA to deliver different types of ANC signals to determine limitations in this process and show some proof of concept results.

Using time reversal focusing for active control of magnetic resonance imaging noise

The Time Reversed Elastic Nonlinearity Diagnostic (TREND) is an inspection technique that enables one to locate damage in a structure using time reversal processing. TREND has been used to detect various types of damage in metals and rocks, but little has been done specific to stress corrosion cracking (SCC) other than the work of Anderson et al. J. Acoust. Soc. Am. 141, EL76–EL81 (2017). SCC in stainless steel, especially around welds, is produced as a result of elevated temperature and saline conditions, and so has different properties from fatigue cracking or delaminations, both of which have been studied with TREND. In current research, welded steel samples exposed to a magnesium chloride bath were created. A number of samples were exposed for successively longer durations in order to study the corrosion damage level versus exposure time. Using TREND, samples were scanned then evaluated for indicators of local cracking at each scan point. Specific changes in spectral characteristics that are indicator...

Time reversed elastic nonlinearity diagnostic applied to stress corrosion cracking in stainless steel

It is very common for students to struggle to grasp a conceptual understanding of acoustic radiation impedance and input impedance. Often graduate students need exposure to impedance concepts in more than one course before they start to understand its importance and meaning. Instructors commonly suggest that impedance can be thought of as a resistance, ignoring the imaginary part of the impedance (the reactance), and the word “sloshing” is sometimes used to describe what the radiation reactance represents. This presentation will show some animations that have been developed in MATLAB to help students visualize the motion of the air particles near a vibrating surface. These animations utilize the relevant physical equations to observe the ratio of the pressure to the particle velocity. While these animations are not directly interactive, the user can change things like the frequency, source size, and excitation amplitude and recreate a new animation. Thinking of the impedance as the ratio of a potential qu...

Time Reversal (TR) is a technique that may be used to focus an acoustic signal at a particular point in space. While many variables contribute to the quality of TR focusing of sound in a particular room, the most important have been shown to be the number of sound sources, signal bandwidth, and absorption properties of the medium as noted by Ribay, de Rosny, and Fink [J. Acoust. Soc. Am. 117(5), 2866-2872 (2005)]. However, the effect of room size on TR focusing has not been explored. Using the image source method algorithm proposed by Allen and Berkley [J. Acoust. Soc. Am. 65(4), 943-950 (1979)], TR focusing was simulated in a variety of rooms with different absorption and volume properties. Experiments are also conducted in a couple rooms to verify the simulations. The peak focal amplitude, the temporal focus quality, and the spatial focus clarity are defined and calculated for each simulation. The results are used to determine the effects of absorption and room volume on TR. Less absorption increases the amplitude of the focusing and spatial clarity while decreasing temporal quality. Dissimilarly, larger volumes decrease focal amplitude and spatial clarity while increasing temporal quality.

Time reversal acoustics applied to rooms of various reverberation times.

Nonlinear resonant ultrasound spectroscopy (NRUS) is a method that can be used for detecting microcracks in structures. NRUS detects shifts in resonance frequencies versus excitation amplitude. Excitation of the sample is typically done with a piezoelectric transducer. We have been applying an electromagnetic excitation developed for resonant ultrasound spectroscopy [S. Garrett, J. Acoust. Soc. Am. 88(1), 210–221 (1990)] as an alternative for NRUS excitation. It involves gluing a coil of wire onto the end of a rod-shaped sample and placing it in a magnetic field. By controlling which part of the coil is in the strongest part of the magnetic field, we can control the principle direction of the driven oscillations in the rod. This method allows us to selectively excite longitudinal, torsional, and bending vibrations and measure the nonlinear properties of the sample for each type of vibration. We have applied this electromagnetic method to measuring the nonlinear properties of Berea sandstone, and we plan t...

Nonlinear resonant ultrasound spectroscopy using electromagnetic excitation

Integrated Research Program Overview on the “Innovative Approaches to Marine Atmospheric Stress Corrosion Cracking Inspection, Evaluation And Modeling in Used‐Fuel Dry Storage Canisters”

During disposal, spent nuclear fuel rods are placed into stainless steel containers and may be stored this way for decades. In order to ensure there is as little radiation leakage as possible, the structure of the stainless steel needs to be evaluated and possible damage detected. In particular, one type of damage these containers are particularly susceptible to is stress corrosion cracking (SCC). Traditional (linear) evaluation methods can detect open cracks but often a closed portion of the crack extends further, compromising the air tight seal sooner. To this end, it has been proposed to use Nonlinear Resonant Ultrasound Spectroscopy (NRUS) to quantify the degree of cracking in a structure. In order to prove this concept, cylindrical 304L stainless steel rods were immersed in a heated 42% MgCl2 solution to induce SCC in an accelerated manner to simulate the damage that is likely to occur on the actual containers. The rods were removed after different lengths of exposure. NRUS measurements were then conducted for longitudinal modes in the rods.During disposal, spent nuclear fuel rods are placed into stainless steel containers and may be stored this way for decades. In order to ensure there is as little radiation leakage as possible, the structure of the stainless steel needs to be evaluated and possible damage detected. In particular, one type of damage these containers are particularly susceptible to is stress corrosion cracking (SCC). Traditional (linear) evaluation methods can detect open cracks but often a closed portion of the crack extends further, compromising the air tight seal sooner. To this end, it has been proposed to use Nonlinear Resonant Ultrasound Spectroscopy (NRUS) to quantify the degree of cracking in a structure. In order to prove this concept, cylindrical 304L stainless steel rods were immersed in a heated 42% MgCl2 solution to induce SCC in an accelerated manner to simulate the damage that is likely to occur on the actual containers. The rods were removed after different lengths of exposure. NRUS measurements were then con...

Characterizing stress corrosion cracking in stainless steel using nonlinear resonant ultrasound spectroscopy

Time reversal (TR) is a technique that may be used for intentional focusing of wave energy. TR has been developed for crack and defect detection in solid media. Because TR provides a localized focus of elastic energy, it can be used to study the local nonlinear properties at point(s) of interest that are indicative of the presence of cracks and defects. Source transducers may be bonded to the sample under test or to a chaotic cavity that is coupled to a sample under test. A receiver, such as a laser Doppler vibrometer, is placed at a location of interest. Impulse responses are obtained between each source and the receiver and then the impulse responses are reversed in time. The reversed impulse responses are then simultaneously broadcast from the respective source transducers and a focus of energy occurs at the receiver position. Since the largest amplitude is obtained at the receiver position, any amplitude-dependent (nonlinear) vibration that occurs at the receiver position dominates nonlinearities, such as harmonics, that are detected in the signal recorded at the receiver position during focusing. This presentation will review the progress made in the detection of cracks using time reversal and present some recent results.Time reversal (TR) is a technique that may be used for intentional focusing of wave energy. TR has been developed for crack and defect detection in solid media. Because TR provides a localized focus of elastic energy, it can be used to study the local nonlinear properties at point(s) of interest that are indicative of the presence of cracks and defects. Source transducers may be bonded to the sample under test or to a chaotic cavity that is coupled to a sample under test. A receiver, such as a laser Doppler vibrometer, is placed at a location of interest. Impulse responses are obtained between each source and the receiver and then the impulse responses are reversed in time. The reversed impulse responses are then simultaneously broadcast from the respective source transducers and a focus of energy occurs at the receiver position. Since the largest amplitude is obtained at the receiver position, any amplitude-dependent (nonlinear) vibration that occurs at the receiver position dominates nonlinearities, suc...

Nonlinear Ultrasonic and Vibro-Acoustical Techniques for Nondestructive Evaluation

Time Reversal (TR) is a technique used to focus an acoustic signal at a particular point in space. Of the many variables that contribute to the quality of TR focusing, the most important are the number of sound sources, signal bandwidth. and properties of the medium. Although much research has been done to quantify the effects that the number of sound sources and signal bandwidth have on the TR process, little has been done in regard to the effect that room parameters have on TR. This is largely due to the difficulty involved with changing room acoustic parameters to measure their effects. We use the image source method (using the algorithm proposed by Allen and Berkley) to simulate the TR process in a variety of rooms with different acoustic and geometric room parameters. We define and calculate the maximum focal amplitude, the temporal focus quality and the spatial focus quality for each simulation. We compare the results and determine the effects of absorption and room volume on TR. We find that less absorption improves max response and spatial quality while it decreases temporal quality and that larger volumes have decreased max response and spatial quality while having increased temporal quality.Time Reversal (TR) is a technique used to focus an acoustic signal at a particular point in space. Of the many variables that contribute to the quality of TR focusing, the most important are the number of sound sources, signal bandwidth. and properties of the medium. Although much research has been done to quantify the effects that the number of sound sources and signal bandwidth have on the TR process, little has been done in regard to the effect that room parameters have on TR. This is largely due to the difficulty involved with changing room acoustic parameters to measure their effects. We use the image source method (using the algorithm proposed by Allen and Berkley) to simulate the TR process in a variety of rooms with different acoustic and geometric room parameters. We define and calculate the maximum focal amplitude, the temporal focus quality and the spatial focus quality for each simulation. We compare the results and determine the effects of absorption and room volume on TR. We find that less a...

Understanding the effect of room parameters on acoustic time reversal

Time reversal (TR) is a signal processing technique that can be used for intentional sound focusing. While it has been studied in room acoustics, the application of TR to produce a high amplitude focus of sound in a room has not yet been explored. The purpose of this study is to create a virtual source of spherical waves with TR that are of sufficient intensity to study nonlinear acoustic propagation. A parameterization study of deconvolution, one-bit, clipping, and decay compensation TR methods is performed to optimize high amplitude focusing and temporal signal focus quality. Of all TR methods studied, clipping is shown to produce the highest amplitude focal signal. An experiment utilizing eight horn loudspeakers in a reverberation chamber is done with the clipping TR method. A peak focal amplitude of 9.05 kPa (173.1 dB peak re 20 μPa) is achieved. Results from this experiment indicate that this high amplitude focusing is a nonlinear process.

Time reversal focusing of high amplitude sound in a reverberation chamber.

Effects of simultaneous sound arrivals on direction-of-arrival estimates of the polar energy time curve

This letter explores the effect of the directivity of a source on time reversal acoustic focusing of energy. A single loudspeaker produces an airborne focus of sound in a reverberation chamber and in a classroom. Individual foci are created at microphone positions that surround the loudspeaker. The primary axis of the loudspeaker is then rotated and experiments are repeated to average out the room response. Focal amplitude, temporal quality of the foci, and spatial focusing quality are compared to determine the optimal angle to aim a directional source axis relative to the desired focal position.

Spent nuclear fuel is often stored in stainless steel canisters in the United States. Stainless steel is susceptible to Stress Corrosion Cracking (SCC). This presentation will discuss progress on the use of the Time Reversed Elastic Nonlinearity Diagnostic (TREND) and Nonlinear Resonant Ultrasound Spectroscopy (NRUS) to determine whether SCC is present and attempt to quantify the depth of the cracking. NRUS is the measurement of the amplitude dependence of a sample’s resonance frequency, which occurs because of a softening of the elastic modulus in damaged media. NRUS provides a global indication of damage in a sample. TREND employs time reversal acoustics, which focuses wave energy at various points of interest to excite localized high amplitude. The amplitude dependence of this localized energy allows pointwise inspection of a sample. [This work was funded by the Nuclear Energy University Program of the U.S. Department of Energy through a subcontract from Los Alamos National Laboratory.]

Stress corrosion crack imaging in stainless steel using the time reversed elastic nonlinearity diagnostic and nonlinear resonant ultrasound spectroscopy

The time reversed elastic nonlinearity diagnostic (TREND) is a nondestructive inspection technique based on the principle of time reversal and used to scan the surface of a sample to identify and characterize cracks and other defects. TREND utilizes a series of individual time reversal experiments conducted on a grid of points in a region of interest to map out the spatial extent of surficial expressions of cracks and subsurface features that are less than a wavelength below the surface. The focal signatures from each of these experiments can be used to determine not only the location but also the orientation of the crack. We will discuss how this technique can be applied to a stainless steel sample with stress corrosion cracking (SCC) using stationary piezoelectric transducers broadcasting ultrasonic waves and a scanning laser vibrometer setup used to detect the three dimensional vibration of the sample surface. The orientation of the crack is critical to estimate how soon a crack might penetrate through...

Directional information extracted from time reversal scanning to image stress corrosion crack orientation

This research optimizes a time reversal focus of energy in terms of amplitude and quality by exploring several signal processing techniques applied to the reversed impulse response. Techniques explored here include deconvolution or inverse filtering [M. Tanter et al., J. Acoust. Soc. Am. 108, 223-234 (2000)], one-bit time reversal [A. Derode et al., J. Appl. Phys. 85, 6343-6352 (1999)], and a new technique termed “clipping.” A parameterization study comparing the maximum focal amplitude and focal temporal quality of time reversal focal signals for these techniques with different settings will be presented. Focal signals are explored in two different systems. The first is a resonant system comprised of a steel sample with a piezoelectric transducer and a scanning laser Doppler vibrometer (SLDV). The second, nominally non-resonant system, comprises a studio monitor loudspeaker and a precision microphone in a reverberant space above the Schroeder frequency. Comparing the focal quality of various time reversa...

Optimization of time reversal focusing in resonant and non-resonant systems through various signal processing techniques

The purpose of this research is to develop a visual demonstration of time reversal focusing of vibrations in a thin plate. Various plate materials are tested to provide optimal conditions for time reversal focusing. Specifically, the reverberation time in each plate and the vibration coupling efficiency from a shaker to the plate are quantified to illustrate why a given plate provides the best spatially confined focus as well as the highest focal amplitude possible. A single vibration speaker and a scanning laser Doppler vibrometer (SLDV) are used to provide the time reversal focusing. Table salt is sprinkled onto the plate surface to allow visualization of the high amplitude, spatially localized time reversal focus; the salt is thrown upward only at the focal position. Spatial mapping of the vibration focusing on the plate using the SLDV is correlated to the visual salt jumping demonstration. The time reversal focusing is also used to knock over an object when the object is placed at the focal position; some discussion of optimal objects to use for this demonstration are given.

Time reversal focusing of elastic waves in plates for an educational demonstration.

Evidence of the ability to probe depth information of stress corrosion cracking (SCC) are presented using the time reversed elastic nonlinearity diagnostic (TREND). Depth estimation of SCC is important to determine when a stainless steel canister has been breached. TREND is a method to focus elastic energy to a point in space in order to probe that point for damage and its' depth penetration is used here to study depth information about SCC. High frequencies are used to probe near the surface, while low frequencies are used to probe deeper into a stainless steel section of a cylinder.

Stress corrosion crack depth investigation using the time reversed elastic nonlinearity diagnostic.

It has been shown experimentally that it is feasible to use time-reversal elastic nonlinearity diagnostics (TREND) to estimate the penetration depth of stress corrosion cracks (SCC) in steel samples. TREND is a method to focus elastic waves energy to a point in space in order to probe that point for damage. High frequencies are used to probe near the surface, while low frequencies are used to probe deeper into the material. Depth estimation of a crack is important to determine when a critical size of defect is reached. This paper aims at a parametric analysis of the time reversal focusing process by means of numerical simulations. The influence of excitation frequency and waveform on the focal spot size and penetration depth are analyzed. An in-house simulation framework based on a commercial Finite Element (FE) solver is used to perform a series of numerical simulations of time-reversal focusing in a steel sample with a curved crack. Results of this study could help to understand the relationship between...

Estimating the penetration depth of stress corrosion cracks using time-reversal acoustics—A Numerical Study

At Brigham Young University, a general education course introduces students to the basic descriptive acoustic principles of music, speech, and audio. A third of this course focuses on the physics of musical instrument families. Three of these families include bowed string, plucked string, and struck string instruments. The concepts of driven systems and freely vibrating systems are taught, including the consequences of these excitation conditions. A hands-on lab for the course enables students to explore how the length, density, and tension of the string change the fundamental frequency. An in-class demonstration highlights the role of inharmonicity on the partial frequency values for these string instrument families. The combination of hands-on activity and demonstration aids the students in comprehending the basic acoustic principles behind string instruments and the reason for varying levels of inharmonicity between these instrument families.

Teaching the descriptive physics of string instruments at the undergraduate level

The purpose of this research is to develop a visual demonstration of time reversal focusing in a thin plate to be used as a teaching tool. This presentation will discuss the various plate materials tested to provide the optimal conditions for time reversal focusing. Specifically, the reverberation time in each plate and the sensitivity of the source of vibrations are quantified to provide the best spatially confined focus as well as the highest focal amplitude possible. A vibration speaker and a scanning laser Doppler vibrometer (SLDV) are used to provide the time reversal focusing. A series of objects are placed on the plate in an attempt to knock over objects near the focal location and not elsewhere. Spatial mapping of the plate vibration using the SLDV will be shown to illustrate why some objects fall and others do not.

“Knocked Over!”: A visual demonstration of time reversal focusing using bending waves in a thin plate

At Brigham Young University, two of the acoustics courses taught in the Physics and Astronomy Department focus on resonance topics. One of the undergraduate courses is a general education, descriptive acoustics course on musical instruments, speech, hearing, and audio. One of the graduate level courses using a differential equations approach to wave motion and resonances on strings, bars, membranes, and plates. In both of these courses, taught at very different levels, the concept of resonance is explored and analyzed. This presentation will discuss various demonstrations used in these classrooms and discuss how they are used in the learning development of the students. Demonstrations include wine glasses, strings, and bars.

Using wine glasses, strings, and bars to teach resonance at the undergraduate and graduate levels

This letter presents a series of vibrational communication experiments, using time reversal, conducted on a set of cast iron pipes. Time reversal has been used to provide robust, private, and clean communications in many underwater acoustic applications. Here the use of time reversal to communicate along sections of pipes and through a wall is demonstrated to overcome the complications of dispersion and multiple scattering. These demonstrations utilize a single source transducer and a single sensor, a triaxial accelerometer, enabling multiple channels of simultaneous communication streams to a single location.

Three-dimensional time reversal communications in elastic media.

Over the last decades, nonlinear acoustic techniques have been developed to detect mechanical damage in solids. They have been proven to be far more sensitive to early damage than standard linear acoustic techniques. Unfortunately, they often require high amplitude waves to propagate within the sample. To be practical in industrial applications, signals have to be generated without contact. Here, we will present a novel non contact acoustic source that can produce higher amplitude than standard transducers and how it can be used to image defects into a carbon fiber reinforce plastic plate damaged by an impact. We will show that we can not only image cracks but also separate two overlapping defects according to their orientation. [This work was supported by the US Department of Energy via the used fuel disposition campaign of the nuclear energy program.]

This presentation explores the effect of transducer directivity on the focusing properties of time reversal acoustics. Time reversal is a signal processing technique that can be used to focus sound to a location in space for source reconstruction, communication, and intentional sound focusing. One loudspeaker and one microphone are used to produce a time reversal focus in a reverberation chamber. The primary axis of the loudspeaker is oriented in various different directions to produce a time reversal focus for each orientation. Since source directivity depends on the frequency of the sound emitted, these experiments are conducted for a low frequency band and a high frequency band such that these two frequency bands have fairly different directivities. Properties of these foci are compared to determine the overall effect of directivity on the time reversal focus.

The effect of transducer directivity on properties of time reversal focusing

This presentation will review research conducted to determine the effect of inharmonic partials on the pitch of piano tones [JASA, 117, 3268–3272 (2005)]. Synthetic piano tones were created based on recordings of an upright piano. One set of tones were made to have inharmonic partials that matched the partial frequencies of the piano tone recording, whereas another set of tones consisted of harmonic partials. Listeners compared a synthetic, inharmonic piano tone to a set of synthetic, harmonic piano tone with varying fundamental frequencies. They were asked to select the harmonic tone whose pitch best matched that of the inharmonic tone. The pitch of the inharmonic tones was perceived to be sharp relative to the harmonic tones (sharp in terms of the comparison of their respective fundamental frequencies).

The two microphone transfer function technique is used to measure sound transmission properties of porous screens or membranes in a plane wave tube. This paper will compare sound transmission of porous screens from several manufacturers. Measurements are made with two different plane wave tubes, one of diameter 10.2 cm to measure frequencies between 100 Hz and 2 kHz, and the other of diameter 1.3 cm to measure frequencies between 2 kHz and 16 kHz. Multiple methods of transmission loss measurement and analysis are presented. Special considerations are made to account for the intrinsic losses in the smaller diameter tube.

Time reversal is a technique that may be used to achieve intentional sound focusing. The purpose of this presentation is to explore how intense the focus of airborne sound energy can be using time reversal. Experiments utilize loudspeakers and a single microphone placed in a reverberation chamber. Various frequency ranges and loudspeaker orientations are explored along with different types of loudspeakers in order to experimentally determine the optimum conditions for generating the loudest focus possible. The overall purpose of this study is to create an acoustic focus at nonlinear sound pressure levels in order to create a controllable source of nonlinear acoustic sound.

Use of time reversal focusing to create a high amplitude focus of sound in air

At Brigham Young University, one of the acoustics courses taught in the Physics and Astronomy Department focuses on resonance topics. This course is a graduate level course that uses a differential equation approach to wave motion and resonances on strings, bars, membranes, and plates. This paper discusses the theory of flexural, or bending, waves in free-free rods and describes a laboratory experiment to test the rod thickness limits of the Bernoulli-Euler theory for rods. It is found that the fundamental frequency departs from Bernoulli-Euler theory as the thickness exceeds 6% of a flexural wavelength, however the mode shape above this limit remains unchanged (at least for the rods tested which included thicknesses up until the thickness equals 16% of a wavelength).

A laboratory experiment to test the limits of Bernoulli-Euler theory for flexural waves in bars

We demonstrate the possibility of selectively imaging the features of a barely visible impact damage in a laminated composite plate by using an air-coupled time reversal mirror. The mirror consists of a number of piezoelectric transducers affixed to wedges of power law profiles, which act as unconventional matching layers. The transducers are enclosed in a hollow reverberant cavity with an opening to allow progressive emission of the ultrasonic wave field towards the composite plate. The principle of time reversal is used to focus elastic waves at each point of a scanning grid spanning the surface of the plate, thus allowing localized inspection at each of these points. The proposed device and signal processing removes the need to be in direct contact with the plate and reveals the same features as vibrothermography and more features than a C-scan. More importantly, this device can decouple the features of the defect according to their orientation, by selectively focusing vector components of motion into the object, through air. For instance, a delamination can be imaged in one experiment using out-of-plane focusing, whereas a crack can be imaged in a separate experiment using in-plane focusing. This capability, inherited from the principle of time reversal, cannot be found in conventional air-coupled transducers.

Damage imaging in a laminated composite plate using an air-coupled time reversal mirror

We present the first set of experiments in which air-coupled ultrasonic emission is used for exhaustive and rapid imaging of a Barely Visible Impact Damage (BVID) introduced by an impact test on a laminated composite. Such experiments have been limited thus far by the impedance mismatch of nearly five orders of magnitude between the air and an elastic solid. This limitation was overcome by designing an ultrasonic source capable of generating a focused elastic wave field in the sample with an amplitude sufficiently large to allow the use of nonlinear elastic wave spectroscopy. The images of the damaged area obtained with the proposed apparatus and signal processing technique reveal the same features, namely a delamination and a crack, as with vibro-thermography and more features than with a C-scan, but remove the need to be in direct contact with the composite, thus reducing the test time by orders of magnitude. [This work was supported by the U.S. Department of Energy through the LANL/LDRD Program and the...

Imaging a barely visible impact damage in a laminated composite without contact using air-coupled nonlinear elastic wave spectroscopy

The bending stiffness in a homogeneous, isotropic, thin plate is experimentally derived from measurements of coincidence angles extracted from supercritical sound transmission versus frequency measurements. A computer controlled turn table rotates a plate sample and a receiver array, placed in the near field of the plate. The array is used to track the transmitted sound through the plate, generated by a far-field stationary source, using beam forming. The array technique enables measurement of plates measuring only one wavelength in width. Two examples are used for proof of concept, including an aluminum plate in air and an alumina plate under water.

Extraction of plate bending stiffness from coincidence angles of sound transmission measurements.

Improving spatio-temporal focusing and source reconstruction through deconvolution

In some Non-Destructive Evaluation techniques, detecting a crack is only the first step. Some applications like monitoring of used nuclear fuel canister also requires the characterization of the orientation of the cracks if any exist. Here, we show experimental results that expand the Time Reversal Elasticity Nonlinear Diagnostic method (TREND) to obtain the crack depth and orientation information. TREND is based on using time reversal to focus energy at a point of interest and then quantifying the nonlinearity at this point. By varying the frequency of the focal signal, one can interrogate different depth of the material, therefore getting access to information about the penetration depth of a crack. We will also show how Time Reversal can be used to select the orientation of the focus wave to any desired direction and how this, in turn, allows measuring different nonlinear responses according to this orientation and how this could be used to determine the orientation of cracks. [This work was supported ...

Elasticity Nonlinear Diagnostic method for crack detection and depth estimation

Time reversal provides an optimal prefilter matched signal to apply to a communication signal before signal transmission. Time reversal allows compensation for wave speed dispersion and can function well in reverberant environments. Time reversal can be used to focus elastic energy to each of the three components of motion independently. A pipe encased in concrete was used to demonstrate the ability to conduct communications of information using three component time reversal. The ability of time reversal to compensate for multi-path distortion (overcoming reverberation) will be demonstrated and the rate of signal communication will be presented. [The U.S. Department of Energy, through the LANL/LDRD Program, is gratefully acknowledged for supporting this work.]

This chapter provides a working knowledge of the basic acoustical or sound measurements and measurement techniques for the practicing engineer. It also provides a broad overview and introduction to more advanced acoustical measurement methods. The chapter discusses the acoustical quantities that are typically measured. It presents the definitions of the terms, measurement units, and weighting filters. The chapter also discusses the various types of microphones. It explains the hardware used to make the measurements along with principles of calibration and data acquisition. The chapter gives the detailed steps to the measurement of sound pressure. It also describes the acoustical measurements important in the areas of sound isolation and room acoustics. The chapter focuses on the measurements of sound intensity and sound power, which are the most advanced measures of a sound field. It concludes with a discussion of sound exposure and noise dosage measurements. 
 
Keywords: 
 
acoustical measurements; 
microphones; 
room acoustics measurements; 
sound exposure measurements; 
sound intensity measurements; 
sound isolation; 
sound power measurements

The purpose of this project was to explore the use of time reversal technologies as a means for communication to a targeted individual or location. The idea is to have the privacy of whispering in one’s ear, but to do this remotely from loudspeakers not located near the target. Applications of this work include communicating with hostages and survivors in rescue operations, communicating imaging and operational conditions in deep drilling operations, monitoring storage of spent nuclear fuel in storage casks without wires, or clandestine activities requiring signaling between specific points. This technology provides a solution in any application where wires and radio communications are not possible or not desired. It also may be configured to self calibrate on a regular basis to adjust for changing conditions. These communications allow two people to converse with one another in real time, converse in an inaudible frequency range or medium (i.e. using ultrasonic frequencies and/or sending vibrations through a structure), or send information for a system to interpret (even allowing remote control of a system using sound). The time reversal process allows one to focus energy to a specific location in space and to send a clean transmission of a selected signal onlymore » to that location. In order for the time reversal process to work, a calibration signal must be obtained. This signal may be obtained experimentally using an impulsive sound, a known chirp signal, or other known signals. It may also be determined from a numerical model of a known environment in which the focusing is desired or from passive listening over time to ambient noise.« less

This paper presents experimental results comparing the detected acceleration values from sensors measuring American football helmet impacts. The sensors used in the study include a laser vibrometer, a research grade accelerometer, an Impakt Protective, Inc. Shockbox® Football Helmet Sensor, a Reebok CHECKLIGHT™ sensor, and a Pressure Analysis Company, Inc. prototype sensor. A human head model was placed into a Riddell helmet and this helmet was then affixed to a pendulum. The helmet was pulled back and allowed to collide with a large granite block to create a frontal, forehead area impact on the helmet. A comparison is made of the detected accelerations from these sensors with a wide range of impact velocities, along with a repeatability determination of several measurements made for two selected impact velocities.

Comparison of acceleration sensors for American football helmet impacts

Ultrasonic radiation from wedges of cubic profile: Experimental results.

The source mechanisms of jet noise are not fully understood and different analysis methods can provide insight. Time reversal (TR) is a robust data processing method that has been used in myriad contexts to localize and characterize sources from measured data, but has not extensively been applied to jet noise. It is applied here in the context of an installed full-scale military jet engine. Recently, measurements of an F-22A were taken using linear and planar microphone arrays at various engine conditions near the jet plume [Wall et al., Noise Control Eng. J. 60, 421–434 (2012)]. TR provides source imaging information as broadband and narrowband jet noise recordings are reversed and back propagated to the source region. These reconstruction estimates provide information on dominant source regions as a function of frequency and highlight directional features attributed to large-scale structures in the downstream jet direction. They also highlight the utility of TR analysis as being complementary to beamfor...

Application of time reversal analysis to military jet aircraft noise

The far-field radiation originating from a finite-length pipe is well studied, especially for steady-state conditions. However, because all physical systems do not begin in steady state, these radiation characteristics are only valid after the transient portion of the solution has decayed. Understanding transient radiation characteristics may be important (particularly for systems transmitting very short-duration signals), as they can differ quite significantly. A numerical complication to this problem involves dealing with a sharp corner in the domain of interest. While many numerical studies have attempted to couple solutions from the domains inside and outside a pipe, the analysis presented in this work treats the computational domain as a single region by expressing the entire physical domain as a map from a simple rectangular domain in generalized curvilinear coordinates. This method will be introduced in detail and general results of transient radiation will be presented for an infinitely baffled, finite-length pipe using the finite-difference method expressed in generalized curvilinear coordinates. Comparison will be made to previous results [P. Stepanishen and R. A. Tougas, J. Acoust. Soc. Am. 93, 3074-3084 (1993)] that used a semi-analytic approach with certain assumptions.

Finite-difference simulations of transient radiation from a finite-length pipe.

The large impedance contrast between bulk piezoelectric disks and air does not allow for efficient coupling of sound radiation from the piezoelectric into air. Here, we present the idea of using wedges of power law profiles to more efficiently radiate sound into air. Wedges of power law profiles have been used to provide absorption of vibrational energy in plates, but their efficient radiation of sound into air has not been demonstrated. We present numerical modeling and experimental results to demonstrate the concept. The wedge shape provides a gradual impedance contrast as the wave travels down the tapering of the wedge, while the wave speed also continually slows down. For an ideal wedge that tapers down to zero thickness, the waves become trapped at the tip and the vibrational energy can only radiate into the surrounding air. [This work was supported by institutional support [Laboratory Directed Research and Development (LDRD)] at Los Alamos National Laboratory.]

Technical Report on the Status of Nonlinear Ultrasonic Techniques for Non-Destructive Inspection

A focus of elastic energy on the surface of a solid sample can be useful to nondestructively evaluate whether the surface or the near-surficial region is damaged. Time reversal techniques allow one to focus energy in this manner. In order to quantify the degree to which a time reversal focus can probe near-surficial features, the depth profile of a time reversal focus must be quantified. This presentation will discuss numerical modeling and experimental results used to quantify the depth profile. [This work was supported by the U.S. Dept. of Energy, Fuel Cycle R&D, Used Fuel Disposition (Storage) Campaign.]

Quantifying the depth profile of time reversal focusing in elastic media

Optimized Dynamic Acousto-elasticity Applied to Fatigue Damage and Stress Corrosion Cracking

Introduction Nondestructive testing (NDT) of structures and mechanical parts is increasingly receiving attention as the need to monitor the health of aging infrastructure and quality controls on the manufacturing of mechanical parts is becoming more apparent. NDT is defined as using various tools, whether they be acoustic, electromagnetic, or thermally based, to inspect the structural integrity of these objects without damaging the object as a result of testing it. In the case of acoustic NDT techniques, a source transducer emits sound/vibrational waves into the structure under test and various techniques are then used to detect signatures of damage (such as micro or macro cracking, etc.).

of Air-Coupled Transduction for nondestructive Testing and evaluation The future of nondestructive testing lies in the ability to efficiently generate waves in structures without contact

Modern Application of Time-Reversal to Seismic Source characterization

Improving the air coupling of bulk piezoelectric transducers with wedges of power-law profiles: a numerical study.

Linear acoustic techniques often are not able to locate closed cracks as the acoustic waves pass right through them. Fortunately, nonlinear acoustic techniques may be used in conjunction with time reversal techniques to not only locate a closed crack but also to image it. This presentation will discuss how cracks may be imaged using the three component time reversed nonlinearity diagnostic (3D-TREND). Specifically, the orientation of individual cracks in a 304L stainless steel plate, which resulted from controlled stress corrosion cracking (SCC) experiments, will be presented along with other imaging information about the crack. 3D-TREND is used to create an individual time reversal focus of energy at each inspection point of interest. The use of different frequencies and different excitation signals has been used in an attempt to extract more information about the crack. [This work was supported by the U.S. Dept. of Energy, Fuel Cycle R&D, Used Fuel Disposition (Storage) Campaign].

Imaging the orientation of stress corrosion cracking using the three component time reversed elastic nonlinearity diagnostic

Identifying cracks in stainless steel using time reversal techniques

This paper describes the principle behind a high amplitude non-contact acoustic source based on the principle of time reversal (TR), a process to focus energy at a point in space. By doing the TR in an air filled, hollow cavity and using a laser vibrometer in the calibration of the system, a non-contact source may be created. This source is proven to be more energetic than an off the shelf focused ultrasound transducer. A scaled up version of the proposed source has the potential to allow nondestructive evaluation processes that require high amplitude, such as nonlinear elastic wave spectroscopy (NEWS) techniques.

A high amplitude, time reversal acoustic non-contact excitation (trance).

This Letter presents a series of time reversal experiments conducted on the surface of a fused silica glass block. Four different time reversal techniques are compared using three different imaging conditions. The techniques include two classical time reversal experiments: one with a pulse waveform source and one with an impulse response generated from a chirp signal. The other two techniques utilize the deconvolution, or inverse filter, signal processing methods for obtaining the signals to back propagate using a pulse waveform and an impulse response from a chirp. The max-in-time, symmetry, and energy current imaging conditions are compared.

Comparison and visualization of focusing wave fields from various time reversal techniques in elastic media.

Simulations of a high amplitude air coupled source based on time reversal

Time reversal (TR) utilizes an array of transducers, a time reversal mirror (TRM), to locate sources. Here TR is applied to simple sources using steady-state waveforms in a numerical, point source model in a half-space environment. It is found that TR can effectively localize a simple source broadcasting a continuous wave, depending on the angular spacing. Furthermore, the angular spacing and the aperture of the TRM are the most important parameters when creating a setup of receivers for imaging a source. This work optimizes a TRM when the source's location is known within a region of certainty.

Optimization of the array mirror for time reversal techniques used in a half-space environment.

The parameters of moving-coil loudspeaker drivers are typically determined using direct electrical excitation and measurement. However, as electro-mechano-acoustical devices, their parameters should also follow from suitable mechanical or acoustical evaluations. This paper presents the theory of an acoustical method of excitation and measurement using normal-incidence sound transmission through a baffled driver as a plane-wave tube partition. Analogous circuits enable key parameters to be extracted from measurement results in terms of open and closed-circuit driver conditions. Associated tools are presented that facilitate adjacent field decompositions and derivations of sound transmission coefficients (in terms of driver parameters) directly from the circuits. The paper also clarifies the impact of nonanechoic receiving tube terminations and the specific benefits of downstream field decompositions.

Evaluation of moving-coil loudspeaker and passive radiator parameters using normal-incidence sound transmission measurements: theoretical developments.

The time reversed elastic nonlinearity diagnostic (TREND) is a method to allow one to nondestructively evaluate a sample by locating nonlinear scatterers. In the TREND method one creates a localized focus of energy using time reversal at each point of interest. The localized nature of the focus, which is at a higher energy level relative to the wave field nearby thereby amplifying the potential nonlinear signature of the focal location, allows one to image localized nonlinearities. It has also been shown that a focus of energy may be individually created in each of the three independent vector components of vibration using time reversal. Here we show that the use of TREND scans in each of the three vector component directions allows imaging of a crack’s orientation. This work is conducted on steel samples, each with cracks at known orientations that were created in a controlled manner. The scaling subtraction method is also used at each scan point to classify the nonlinearity. [Work supported by Instituti...

Imaging crack orientation using the time reversed elastic nonlinearity diagnostic with three component time reversal

Recently, the preliminary design of a high-amplitude, non-contact acoustic source was proposed for nondestructive testing applications [Le Bas et al., J. Acoust. Soc. Am. 134, EL52 (2013)]. The design is based on the principle of time reversal, a process to focus energy at a point in space. In the present work, the main physical mechanisms involved in the operation of this device are examined numerically using the finite-element (FE) method. First, a three-dimensional FE model of the device is validated in the frequency domain against experimental data. Subsequently, two-dimensional transient simulations are used to conduct a parametric study on the effect of wall thickness and transducer density on the efficiency of the device. Last, a time reversal numerical experiment is presented. Results from this study can be used to design a more efficient non-contact source. [Work supported by Institutional Support (LDRD) at the Los Alamos National Laboratory.]

A high amplitude non-contact acoustic source: from a proof of concept to the understanding of the mechanisms involved

The Udu drum, sometimes called the water pot drum, is a traditional Nigerian instrument. Musicians who play the Udu exploit its aerophone and idiophone resonances. This paper will discuss an electrical equivalent circuit model for the Udu Utar, a modern innovation of the traditional Udu, to predict the low frequency aerophone resonances and will also present scanning laser vibrometer measurements to determine the mode shapes of the dominant idiophone resonances. These analyses not only provide an understanding of the unique sound of the Udu instrument but may also be used by instrument designers to create instruments with resonance frequencies at traditional musical intervals for the various tones produced and to create musical harmonic ratios. The information, specifically the laser vibrometry measurements, may also be useful to musicians in knowing the best places to strike the Udu to excite musical tones.

Equivalent circuit modeling and vibrometry measurements of the Nigerian-origin Udu Utar drum.

The time reversal acoustic noncontact source (TRANS) utilizes time reversal (TR) from several transducers arranged in a cavity to focus energy onto a solid surface to allow inspection of that surface. The advantage of TRANS is that multiple transducers may be used to increase the amplitude of the focused energy onto the surface and potentially allow interrogation of nonlinear surficial features such as cracks and delaminations. TR is known to be a matched signal process and therefore is limited in the temporal fidelity and spatial compression of the focused energy. Fortunately, using a deconvolution operation in conjunction with TR (or inverse filter similar to Tanter et al. [JASA, 108, 223-234 (2000)]) can greatly improve the quality of the spatial focusing as well as increasing the temporal fidelity. Visualizations of the impact of the deconvolution operation will be presented to provide insight into the increased quality of the spatial focusing along with results from using the deconvolution operation ...

Improving the focal quality of the time reversal acoustic noncontact source using a deconvolution operation

Research in physics education has indicated that the traditional lecture-style class is not the most efficient way to teach introductory physical science courses at the university level. Current best teaching practices focus on creating an active-learning environment and emphasize the students' role in the learning process. Several of the recommended techniques have recently been applied to Brigham Young University's introductory acoustics course, which has been taught for more than 40 years. Adjustments have been built on a foundation of establishing student-based learning outcomes and attempting to align these objectives with assessments and course activities. Improvements have been made to nearly every aspect of the course including use of class time, assessment materials, and time the students spend out of the classroom. A description of the progress made in improving the course offers suggestions for those seeking to modernize or create a similar course at their institution. In addition, many of the principles can be similarly applied to acoustics education at other academic levels.

Creating an active-learning environment in an introductory acoustics course.

The coincidence effect is manifested by maximal sound transmission at angles at which trace wave number matching occurs. Coincidence effect theory is well-defined for unbounded thin plates using plane-wave excitation. However, experimental results for finite bars are known to diverge from theory near grazing angles. Prior experimental work has focused on pulse excitation. An experimental setup has been developed to observe coincidence using continuous- wave excitation and phased-array methods. Experimental results with an aluminum bar exhibit maxima at the predicted angles, showing that coincidence is observable using continuous waves. Transmission near grazing angles is seen to diverge from infinite plate theory.

On the measurement of airborne, angular-dependent sound transmission through supercritical bars.

Acoustic Imaging of Delaminations and Cracks Using Time Reversal and Nonlinear Spectroscopy Techniques

This paper presents a physical demonstration of an audio-range line array used to teach interference of multiple sources in a classroom or laboratory exercise setting. Software has been developed that permits real-time control and steering of the array. The graphical interface permits a user to vary the frequency, the angular response by phase shading, and reduce sidelobes through amplitude shading. An inexpensive, eight-element loudspeaker array has been constructed to test the control program. Directivity measurements of this array in an anechoic chamber and in a large classroom are presented. These measurements have good agreement with theoretical directivity predictions, thereby allowing its use as a quantitative learning tool for advanced students as well as a qualitative demonstration of arrays in other settings. Portions of this paper are directed toward educators who may wish to implement a similar demonstration for their advanced undergraduate or graduate level course in acoustics.

A method of measuring the angular dependence of sound transmission through supercritical bars in air is discussed. The coincidence effect occurs in a supercritical bar when the component of the acoustic wave number parallel to the bar matches the bending wave number in the bar. The transmission of sound is at a maximum at the angle where this trace wave number matching occurs. The theory of the coincidence effect is well-defined for unbounded thin plates using plane-wave excitation. An experimental setup has been developed in order to observe the coincidence effect using continuous-wave excitation and phased-array methods through finite bars. Experimental results through a 0.5 mm thick aluminum bar exhibit strong maxima at the predicted coincidence angles, showing that coincidence is observable using continuous waves. Measurements of the coincidence angle at frequencies spanning from the critical frequency up to nearly three times the critical frequency have been made. A curve fit to the frequency depende...

On the measurement of angular-dependent, airborne sound transmission through finite supercritical bars: Further results

Nonlinear acoustic techniques have proven to be extremely sensitive to early stage damage detection. However, the main issue preventing widespread use of these techniques is that they require high amplitude waves to induce the nonlinear response. As an alternative to transducers bonded to the test material, a more practical realization consists of developing non-contact ultrasonic transducers capable of generating high amplitude waves. Time reversal (TR) techniques are particularly suited to concentrate sound energy at a chosen location in space and at a specific instance in time. In this paper, it is numerically demonstrated how TR and a "candy can" (i.e. a highly scattering, contained medium) can be used to create a focused, high amplitude non-contact transducer. We developed and investigated the results of a finite element model of the "candy can" concept. The model allows to demonstrate the concept in different situations and illustrates the ability to pre-calibrate the non-contact source in air. The ...

First simulations of the "candy can" concept for high amplitude non-contact excitation

Time reversal is a proven technique for focusing wave energy in time and space. A known side effect of the process is the presence of temporal side lobes and spatial fringes, which can be undesirable depending upon the application. A deconvolution, also known as an inverse filter, technique has been developed to improve temporal compression of the focal signal. This presentation will explore the use of deconvolution in comparison to standard time reversal and provide insight into the process through visualizations of the wave-fields. Attention will also be given to the effect of the deconvolution technique upon nonlinear elasticity applications such as the time reversed nonlinear elasticity diagnostic (TREND).

Improving time reversal focusing through deconvolution: 20 questions

In this study a technique is demonstrated to optimize the ability of time reversal to both spatially and temporally focus, or compress, elastic wave energy. This method allows for optimization of time reversal focusing for any number of channels by calculating the required time reversed signal to be rebroadcast from the time reversal mirror element using only the original recorded scattered signal from that element. The speed, simplicity and robust nature of this process for any number of time reversal mirror elements, including only a single channel, provide the ability to enhance applications currently using time reversal for tasks such as communications, nondestructive evaluation, lithotripsy and imaging, among others. It is also demonstrated theoretically and numerically that good temporal focusing implies that the radius in the spherically symmetric part of the spatial focus is small.

The udu drum is both an aerophone and an idiophone played with both of the musician's hands. It originates from Nigeria where it began as a functional water pot made out of fired clay. At some point, a side hole was cut into the pot and it became a musical instrument, traditionally played by women, which had an important role in religious ceremonies. The udu is capable of producing deep tones that result from acoustic resonances similar to those of Helmholtz resonators, though with a second hole. It also may produce higher pitch sounds that result from the musician tapping the surface of the udu. This paper will discuss one-dimensional equivalent circuit modeling of the acoustic resonances of the udu. A comparison of the resonance frequencies in the equivalent circuit modeling to measured resonance frequencies will be given. Additionally, an analysis of the structural modes of the udu as measured by a scanning laser vibrometer will be given, along with some insights into the sound produced by striking the...

Equivalent circuit modeling and vibrometry analysis of the Udu Utar Nigerian drum

The sound radiation of the hammered dulcimer has been investigated. The dulcimer studied is a 16/15 fixed-top instrument of typical size with Baltic birch (laminated plywood) soundboard and back. To determine the instrument body resonances, the dulcimer was driven at the treble and bass bridges with a shaker. Accelerometers were used to obtain the resonance frequencies of the soundboard and back, and a microphone was placed inside the instrument to obtain the cavity resonances. The individual resonance peaks found were further investigated using near-field acoustical holography. Preliminary results show that there is little modal response of the instrument at the fundamental frequencies of the lowest notes of the dulcimer. In addition, the vibration coupling to the back plate through the internal bracing causes it to serve as a second soundboard. Lastly, the holography results indicate significant radiation from the sound holes at some frequencies, which may contradict the commonly held notion that the du...

Assessment of desirable reflections and control of undesirable reflections in rooms are best accomplished if the reflecting surfaces are properly localized. Several measurement techniques exist to identify the incident direction of reflected sound, including the useful polar energy time curve (Polar ETC), which requires six cardioid impulse response measurements along the Cartesian axes. The purpose of this investigation is to quantify the incidence angle estimation error introduced into the Polar ETC by non-cardioid microphone directivities. The results demonstrate that errors may be minimized with a cardioid-family microphone possessing a certain range of directivities and by maximizing the measurement signal-to-noise ratio.

The effects of non-cardioid directivity on incidence angle estimation using the polar energy time curve.

Over the last decades, nonlinear acoustic techniques have been developed to detect mechanical damage in solids. They have been proven to be far more sensitive to early damage than standard linear acoustic techniques. Unfortunately, they often require high amplitude waves to propagate within the sample. To be practical in industrial applications, signals have to be generated without contact. Currently available non-contact transducers are generally not powerful enough. A first step toward the creation of a high amplitude non-contact acoustic source will be described. This source is based on the principle of focusing energy on the surface of a sample using Time Reversal in a hollow cavity. By using a laser vibrometer for the necessary calibration of the system we are able to use a full non-contact process. New development in signal processing allows a much cleaner signal generation than usually achieve with time reversal. This source is proven to be much more energetic than current off the shelf non-contact...

Toward a high power non-contact acoustic source using time reversal

Time reversal (TR) is a technique of mapping acoustical sources using a time reversal mirror (TRM) and is especially useful in reverberant environments. Studies of using TRMs in chaotic, reverberant environments have shown that the mirror elements should be spaced with no smaller than a half‐wavelength spacing [IEEE Trans. Ultrason. Ferroelectr. Freq. Control 39(5), 555–566 (1992)]. In a half‐space environment, TR cannot exploit multiple reflections to enhance source localization. Thus the question arose as to whether half‐wavelength spacing of TRM elements was optimal or not when using TR in a half space. Using simple point source propagation theoretical computer modeling and experimental measurements, it is shown that the TRM elements need not be spaced as close as a half wavelength to optimize focusing. The purpose of this study is to optimize TR localization of an acoustical source using as few TRM elements as possible, thereby increasing the efficiency of the technique. [This work is supported by the...

Optimizing time reversal mirrors in a half‐space environment with application to localization of jet noise.

Time reversal (TR) has the potential to become a powerful tool in non‐destructive evaluation. Coupled with nonlinear properties of cracks in a group of techniques known as Time reverse nonlinear elastic wave spectroscopy, it provides the means to detect and image mechanical damage in complex solids. In this prototype experimental study, we show that we can excite a buried nonlinear feature applying TR. The feature scatters energy that is detected on the sample perimeter. The time signals are filtered about the nonlinear‐generated components and are broadcast back, focusing on their source, the buried nonlinear feature. The current challenge is introducing sufficient energy in order to excite the buried feature and produce nonlinear scattering that can be detected on the edges of the sample. This was achieved using a 30 channel system. Two features were localized: a part of the interface between two blocks submitted to a high amplitude signal, and a defect on the same interface (a cured drop of glue creati...

A nonlinear scatterer is simulated in the body of a sample and demonstrates a technique to locate and define the elastic nature of the scatterer. Using the principle of time reversal, elastic wave energy is focused at the interface between blocks of optical grade glass and aluminum. Focusing of energy at the interface creates nonlinear wave scattering that can be detected on the sample perimeter with time-reversal mirror elements. The nonlinearly generated scattered signal is bandpass filtered about the nonlinearly generated components, time reversed and broadcast from the same mirror elements, and the signal is focused at the scattering location on the interface.

Probing the interior of a solid volume with time reversal and nonlinear elastic wave spectroscopy.

This paper discusses the original time reversal experiments as conducted by Antares Parvulescu and Clarence Clay. The idea of conducting the first time reversal experiment came about from measurements of the reproducibility of sound transmissions in the ocean in the late 1950's and early 1960's. Then it was believed by many that long range acoustic signal transmissions in the ocean were not reproducible or stable. During a coffee hour in 1960, Parvulescu proposed a simple experiment to create an acoustic matched signal through the use of time reversal, in their coffee room/lab area. This represents the first known record of a time reversal experiment. The paper will then discuss a series of experiments that were conducted underwater to communicate between two ships through the use of this matched signal technique. Details are in the theoretical - experimental monograph of Ivan Tolstoy and Clay [Ocean Acoustics (Mcgraw-Hill 1966 and Acoust. Soc. Am. 1987), Sections 7.4-7.7]. This paper calls attention to t...

Reverse time migration (RTM) is a commonly employed imaging technique in seismic applications (e.g., to image reservoirs of oil). Its standard implementation cannot account for multiple scattering/reverberation. For this reason it has not yet found application in nondestructive evaluation (NDE). This paper applies RTM imaging to NDE applications in bounded samples, where reverberation is always present. This paper presents a fully experimental implementation of RTM, whereas in seismic applications, only part of the procedure is done experimentally. A modified RTM imaging condition is able to localize scatterers and locations of disbonding. Experiments are conducted on aluminum samples with controlled scatterers.

Experimental implementation of reverse time migration for nondestructive evaluation applications.

This paper discusses basic and advanced aspects of the sound radiated by the singing rod demonstration commonly used in physics courses to depict an example of longitudinal waves. Various methods of exciting these rods are discussed along with the issues associated with each method. Analysis of the sound radiated by various rods with small-signal and large-signal excitations is presented for four different rods. The small-signal sound radiation consists of a fundamental frequency and odd harmonics (each corresponding to a longitudinal mode) when the rod is held at its midpoint. Large-signal sound radiation is highly dependent on the rod's geometry. The large-signal sound can possess strong even harmonics and/or beating tones resulting from modal coupling of transverse bending modes and either subharmonic longitudinal modes or torsional modes. A detailed analysis of the sound radiation from a singing rod can provide excellent laboratory exercises or classroom demonstrations for advanced undergraduate or graduate level acoustics courses whose scope includes resonances of a bar.

Qualifying an anechoic chamber for frequencies that extend into the ultrasonic range is necessary for research work involving airborne ultrasonic sound. The ANSI S12.55/ISO 3745 standard which covers anechoic chamber qualification does not extend into the ultrasonic frequency range, nor have issues pertinent to this frequency range been fully discussed in the literature. An increasing number of technologies employ ultrasound; hence the need for an ultrasonic anechoic chamber. This paper will specifically discuss the need to account for atmospheric absorption and issues pertaining to source transducer directivity by presenting some results for qualification of a chamber at Brigham Young University.

Ultrasonic anechoic chamber qualification: accounting for atmospheric absorption and transducer directivity.

Angular dependence of sound transmission through airborne plates, at frequencies above their critical frequencies (supercritical), is discussed. Experimental measurements of this angular dependence have been conducted using phased array methods. Theory governing the sound transmission through supercritical plates is already well developed; however, experimental results are known to depart from theory near grazing incidence. The details of the measurement apparatus and issues involved in making this type of measurement will be discussed. The results of the measurements will be compared to theory, focusing on the departure of experiments from theory.

On the Measurement of Angular Dependent Sound Transmission through Airborne Supercritical Plates

The ability of the time reversal process to reconstruct sources of finite size relative to a wavelength is investigated. Specifically the quality of the spatial reconstruction of a finite sized source will be presented through the use of time reversal experiments conducted on an aluminum plate. The data presented in the paper show that time reversal can reconstruct a source equally well regarding less of its size, when the source is a half wavelength or less in size. The quality of spatial reconstruction when the source is larger than a half wavelength progressively decreases with the size of the source.

Time reversal reconstruction of finite sized sources in elastic media.

Time reversal (TR) is a technique of localizing acoustical sources using a time reversal mirror (TRM) and is especially useful in reverberant environments. TR is commonly used to find acoustically small sources and in many cases pulsed waveforms are used. Here TR is applied to distributed sources using long duration waveforms. This is done using a straightforward, theoretical, point source propagation computer modeling and data from experimental measurements of jet noise. The quality of the TR focusing versus using different numbers of microphones to constitute the TRM is determined. These results are compared to other imaging techniques and theories of sound radiation from jets.

Application of time reversal to sources in non-ideal environments

Measurements of ultrasonic noise emitted from manmade electrical devices have been made in an ultrasonic anechoic chamber. Until now, little has been published about the levels and frequency content of ultrasonic noise emitted from electronic devices such as laptops, cell phones, and other electronic devices. The most common source of ultrasonic noise in these devices is dc to dc power supplies. Measurements are made over the range of 20–200 kHz emitted by electronic devices (e.g., laptops). The results of these measurements and the challenges associated with making the measurements will be discussed (including anechoic chamber qualification in the ultrasonic frequency range). [This work has been funded by the Los Alamos National Laboratory.]

Transmission loss and insertion loss measurements of building materials at audible frequencies are commonly made using plane wave tubes or as a panel between reverberant rooms. These measurements provide information for noise isolation control in architectural acoustics and in product development. Airborne ultrasonic sound transmission through common building materials has not been fully explored. Technologies and products that utilize ultrasonic frequencies are becoming increasingly more common, hence the need to conduct such measurements. This letter presents preliminary measurements of the ultrasonic insertion loss levels for common building materials over a frequency range of 28-90 kHz using continuous-wave excitation.

Ultrasonic airborne insertion loss measurements at normal incidence (L).

Directivity is a convenient way to represent how sound radiates from some arbitrary object in steady-state. The steady-state condition is implied when time harmonicity is assumed. Because all physical systems do not begin in steady-state, this directivity measurement is only valid after the transient portion of the solution has decayed. Transient directivity—a measure of sound radiation versus angle at a given instant in time and before the system has reached steady-state—is presented. Understanding an object’s transient and steady-state radiation characteristics may be important in understanding the sound radiation from sources that are transient in nature. Results of transient directivity will be presented for pipes and horns from both numerical models and experimental measurements.

THURSDAY MORNING , 22 APRIL 2010 LAUREL A / B , 8 : 00 TO 11 : 45 A . M . Session 4 aEA Engineering Acoustics : Sound Projection and Transduction

Inherent limitations of the traditional time reversal process in the case of multiple sources or scatterers make it impossible to distinguish them individually. The selective source reduction (SSR) method employs a subtraction technique to selectively suppress in amplitude (and ideally eliminate) a time reversed focal signal that is masking another focus. In previous work, Scalerandi et al. and Anderson et al. successfully applied the SSR method to identify masked primary sources in a fully linear medium. Here, we extend the capabilities of the SSR method to deal with (i) secondary sources (for example, scattering caused by embedded defects) and (ii) nonlinear scattering generated during the ultrasonic wave propagation as well. We call this new method selective source reduction based on nonlinear time reversed acoustics (SSR‐NLTRA). In the extended approach, the contribution of all primary sources is first eliminated by means of the scaling subtraction method. Subsequently, the SSR‐TRA method is applied t...

Imaging multiple masked nonlinear scatterers applying a combination of time reversal principles and the selective source reduction method.

Crack Localization And Characterization In Solid Media Using Time Reversal Techniques

Directivity is a convenient way to represent how sound radiates from some arbitrary object in steady‐state. The steady‐state condition is implied when time harmonicity is assumed. Because all physical systems do not begin in steady‐state, this directivity measurement is only valid after the transient portion of the solution has decayed. Transient directivity—a measure of sound radiation versus angle at a given instant in time and before the system has reached steady‐state—is presented. Understanding an object’s transient and steady‐state radiation characteristics may be important in understanding the sound radiation from sources that are transient in nature. Results of transient directivity will be presented for pipes and horns from both numerical models and experimental measurements.

Vector component focusing in elastic solids using a scalar source in three component time reversal

The horns used in loudspeaker systems are well known for their ability to increase radiation efficiency and control directivity. Because of the horn’s ubiquitous nature, significant research efforts have been undertaken to explore both its directional and frequency response characteristics. The following research reported in this presentation incorporates several numerical methods (including finite difference and boundary element analysis) to better understand the nature of wave propagation through horns and the effects that geometrical and configurational changes have in better controlling directivity and improving frequency response.

An energy flux imaging method for use in locating sources of wave energy during the back propagation stage of the time reversal process will be presented. During the back propagation phase of an ideal time reversal experiment, wave energy coalesces from all angles of incidence to recreate the source event; after the recreation, wave energy diverges in every direction. An energy flux imaging method based on this convergence/divergence behavior has been developed. The energy flux imaging method yields better spatial resolution in source reconstruction than is possible with traditional imaging methods. [This work is supported by Institutional Support (LDRD) at Los Alamos National Laboratory.]

Transmission loss measurements of building materials at audible frequencies are commonly made using various techniques such as plane wave tubes. These measurements provide vital information for control of noise isolation in architectural acoustics. To our knowledge, however, not much has been done to explore airborne ultrasonic sound transmission through common building materials. This paper will present various measurements of the ultrasonic transmission loss for various building materials over a frequency range of 20–200 kHz. The materials include fir plywood, particle board, medium density fiberboard, styrofoam, galvanized steel, and acrylic and polycarbonate plastics. This presentation will also discuss the challenges involved in making such measurements.

Ultrasonic sound transmission through common building materials.

The time reversed elastic nonlinearity diagnostic (TREND) has been shown to have the ability to image near surface nonlinear scatterers (e.g., cracks and disbonds) using the normal (out of plane) component of motion. This technique has been advanced with the addition of three‐component vector wave field detection using laser vibrometry. This advancement provides the ability of TREND to detect and image features of various orientations, increasing its capability and decreasing the likelihood of overlooking features due to the inability to excite them. Furthermore, the ability to selectively focus each component of motion provides the means to investigate the mechanism of the nonlinear wave generation at the nonlinear scattering sites. Experimental data are presented from samples containing known defects (location and orientation) confirming the sensitivity of three‐component time reversal imaging in both linear and nonlinear ultrasonics to feature orientation.

Three Component Time Reversal Imaging using Nonlinear Elasticity

Pure sound piano wire is a stainless‐steel wire that has only recently entered the U.S. market. Because of its different composition, which makes the wire more malleable, it should have a considerably lower amount of inharmonicity compared to regular steel wire. Measurements were conducted on several pianos with regular piano wire (Rosslau and Mapes) and pure sound in order to assess their differences in inharmonicity and tonal qualities. The pure sound wire produced measurably less inharmonicity than regular wire on the same kind of piano. However, this difference is much smaller compared to the difference between small and large pianos. This presentation will explain the methods of measurement and analysis, as well as simulations that were implemented in order to analyze the effect that inharmonicity has on the temperament, octave stretching, and interval patterns. [The Brigham Young University Department of Physics is acknowledged for the funding it provided for this research.]

Experimental observations of spatial focusing of continuous-wave, steady-state elastic waves in a reverberant elastic cavity using time reversal are reported here. Spatially localized focusing is achieved when multiple channels are employed, while a single channel does not yield such focusing. The amplitude of the energy at the focal location increases as the square of the number of channels used, while the amplitude elsewhere in the medium increases proportionally with the number of channels used. The observation is important in the context of imaging in solid laboratory samples as well as problems involving continuous-wave signals in Earth.

Time reversal of continuous-wave, steady-state signals in elastic media

A set of experiments has been conducted to show that time reversal of steady state monochromatic signals can produce spatial focusing in a reverberant elastic cavity when multiple channels are used. The transient portion of the received signals is not used. A single channel does not produce spatial focusing as it only drives the system according to its modal distribution. The amplitude of the energy at the focal location increases as the square of the number of channels used, while the amplitude elsewhere in the medium increases proportionally with the number of channels used. This work has importance in the field of medical ultrasound where the use of a long duration monochromatic excitation may be used for lithotripsy or other ultrasonic therapy. [This work is supported by Institutional Support (LDRD) at Los Alamos National Laboratory.]

The success of the Girl Scouts of America (GSA) and the Optical Society of America’s “Project Lighten Up” and the proposed “Project Listen Up” have prompted a discussion of how Scouting can be used as an outreach vehicle to interest today’s youth in science and, more particularly, in acoustics. One possibility for this would be the drafting of a “Sound and Audio” merit badge for the Boy Scouts of America (BSA) or a similar activity award for the GSA. The BSA currently offers 121 merit badges for scouts, including varied topics such as archeology, rifle shooting, plumbing, truck transportation, and coin collecting. Although there are physical science‐related merit badges (e.g., composite materials, chemistry, nuclear science), there is not a badge that deals directly with acoustics. This talk will outline how an acoustics‐related merit badge may help engage youth interest in science and discuss ideas for possible badge requirements.

An energy current imaging method is presented for use in locating sources of wave energy during the back propagation stage of the time reversal process. During the back propagation phase of an ideal time reversal experiment, wave energy coalesces from all angles of incidence to recreate the source event; after the recreation, wave energy diverges in every direction. An energy current imaging method based on this convergence/divergence behavior has been developed. The energy current imaging method yields a smaller spatial distribution for source reconstruction than is possible with traditional energy imaging methods.

Energy current imaging method for time reversal in elastic media

This paper describes a time reversal (TR) method of spatially illuminating a source signal which has been masked by another source signal. This masking occurs as a result of inherent limitations in the traditional TR process. The selective source reduction (SSR) method employs a subtraction technique where one TR focus is selectively reduced to illuminate the masked focus. Experimental results and considerations are presented to demonstrate the SSR method for two elastic wave pulses emitted simultaneously from two spatially separated surficial sources and to examine the limitations of the method. A blind test was conducted to demonstrate that no a priori information about the source(s) is required. Spatial and/or temporal characteristics of multiple close-proximity sources can be resolved with the use of the illumination method. The measurements show that the SSR method’s limitations are chiefly due to imperfect temporal reconstruction of the source function in the time reversed focal signal, which consequently limits signal reduction.

Experimentally identifying masked sources applying time reversal with the selective source reduction method

In acoustics, it is known that, for a given response signal at an arbitrary location, reciprocity and time reversal (TR) can be used to focus high levels of acoustic energy at that position. In solid media, elastic waves generally induce different disturbances in three directions. In this paper, both experimental and numerical wave propagation results for solid materials demonstrate the ability to use a scalar source, a three component detector and the reciprocal TR process to selectively focus each of the different vector components, either individually or collectively. The principle is explained from an analytical point of view. The numerical and experimental study demonstrates excellent temporal and spatial focalization. Applications of the selective vector component focusing can be found in damage imaging techniques using both linear or nonlinear ultrasonic waves.

Three component time reversal: Focusing vector components using a scalar source

On the use of time reversal in the detection of buried nonlinear features

Time reversal acoustics (TRA) techniques can exploit the nonlinear processes emerging from the interaction between the incident waves and nonlinear scatterers in solid media in order to localize and characterize the scatterers themselves. When nonlinear scatterers are embedded, their localization can be obtained through a mixed experimental/numerical TRA procedure: the forward propagation is performed experimentally, while the time reversal (TR) backward propagation is simulated using computational codes and a reference model of the solid. The synergetic use of dedicated processing of the forward propagation signals collected at the time reversal mirror (TRM), for example with nonlinear elastic wave spectroscopy (NEWS) techniques, and the calculation of the backpropagated wave fields at each point within the specimen leads to imaging of the nonlinear scatterers. We show examples of nonlinear scatterer (macroscopic cracks, distributed microcracks) imaging by such a procedure, exploiting high performance (p...

Computational time reversal acoustics imaging of embedded defects in solid media

Time reversal has the potential to become a powerful tool in nondestructive evaluation. Coupled with nonlinear properties of cracks in a technique known as time reverse nonlinear elastic wave spectroscopy (TRNEWS), it provides the means to detect defects in complex structures. This experimental study explores the capabilities of TR to focus energy inside a 3D medium in order to activate nonlinear features or defects. Special attention is given to buried cracks. The current challenge is introducing sufficient energy in order to excite the buried feature and produce nonlinear scattering. We will provide an overview of the problem.

We investigate some of the limitations of time reversal acoustics (TRA) in solid media with transducers attached to the surface. In particular, we consider the limitations due to the finite size of the transducers and elastic wave propagation. Using a theoretical approach, numerical simulations and validation from laboratory ultrasound experiments, we find that finite size transducers and the existence of longitudinal and shear waves play significant roles in perturbing the time reversal process. Despite these limitations, we show that TRA in solids is very robust, providing the means to reconstruct the main features of the source signal. The analysis of TRA retro-focusing properties in solid specimens is of foremost importance for the development of new non-destructive evaluation techniques.

Investigation of the robustness of time reversal acoustics in solid media through the reconstruction of temporally symmetric sources

Time Reversal Acoustics (TRA) has been shown to be very robust not only in fluids but also in solid bounded media. The most relevant limitations to the Time Reversal Process (TRP) in solid specimens are the co‐existence of several propagation modes, mode conversion at each interface (inhomogeneities or boundaries), attenuation mechanisms and the multidimensional nature of the propagating wave fields. Additional limitations arise in practical applications, for example for Non Destructive Evaluation purposes, when the Time Reversal Mirror (TRM) piezoelectric transducers are usually attached to the surface of the solid. We have investigated the role of the finite size of the TRM transducers and their sensitivity to only certain components of the incident wave fields in the TRP when they are attached to the surface of the sample under study. We have developed a theoretical analysis and performed numerical simulations and laboratory experiments in order to examine the robustness of TRA in solid media, including where the TRM is composed of finite size elements attached to the specimen surface. The results lead to useful information about the efficiency of the TRP as well as the optimization of the TRM setup in terms of transducer size.

Numerical modeling of the effects of finite size transducers for time reversal acoustics in solid media

Time Reversal Acoustics (TRA) has been shown to be very robust not only in fluids but also in solid bounded media. The most relevant limitations to the Time Reversal Process (TRP) in solid specimens are the coexistence of several propagation modes, mode conversion at each interface (inhomogeneities or boundaries), attenuation mechanisms and the multidimensional nature of the propagating wave fields. Additional limitations arise in practical applications, for example for Non Destructive Evaluation purposes, when the Time Reversal Mirror (TRM) piezoelectric transducers are usually attached to the surface of the solid. We have investigated the role of the finite size of the TRM transducers and their sensitivity to only certain components of the incident wave fields in the TRP when they are attached to the surface of the sample under study. We have developed a theoretical analysis and performed numerical simulations and laboratory experiments in order to examine the robustness of TRA in solid media, including where the TRM is composed of finite size elements attached to the specimen surface. The results lead to useful information about the eciency of the TRP as well as the optimization of the TRM setup in terms of transducer size.

ACOUSTICS2008/939 Numerical modeling of the eects of finite size transducers for time reversal acoustics in solid media

Every experimental implementation of Time Reversal (TR) involves the use of transducers to convert wave motion, whether mechanical or acoustical, into electrical signals, and vice versa. Practical considerations of transducers are not included in the basic theory of time reversal, which is based on idealized point‐like sources. These considerations include temporal ring down at a narrowband transducer resonance, the finite size of the transducer giving rise to directivity, and the impedance contrast between the transducer and the medium. The effects of these considerations on the TR process will be characterized by presenting data from various TR experiments.

The effects of transducers on the time reversal process in solids

Introduced in this paper is a new method of determining and investigating focal positions of time reversed elastic wave fields. This method exploits the temporally symmetric nature of time reversed acoustics focused signals as they are akin to the autocorrelation function of the forward propagation received signals. Contrasting this symmetry with the degree of asymmetry at regions away from the focal location provides details about the original source that cannot be retrieved when using other standard imaging conditions.

Every experimental implementation of Time Reversal (TR) involves the use of transducers to convert wave motion, whether mechanical or acoustical, into electrical signals, and vice versa. Practical considerations of transducers are not included in the basic theory of time reversal, which is based on idealized point-like sources. These considerations include temporal ring down at a narrowband transducer resonance, the finite size of the transducer giving rise to directivity, and the impedance contrast between the transducer and the medium. The eects of these considerations on the TR process will be characterized by presenting data from various TR experiments.

ACOUSTICS2008/1594 The eects of transducers on the time reversal process in solids

This paper introduces a method to selectively reduce large time‐reversed focal events to provide the potential to illuminate smaller events which have been masked by the larger one. The method is demonstrated for two elastic wave pulses emitted simultaneously from two spatially separated sources. The method improves upon the spatial resolution abilities of time reversed acoustics in nondestructive evaluation applications to identify characteristics of a sample such as cracks (nonlinear elastic wave scattering sources).

Selective source reduction to identify masked smaller sources using Time Reversed Acoustics (TRA)

The ability to direct sound energy through the flexural vibrations of a submerged plate at various angles of incidence using a near-field transducer array is investigated. An alumina bar is placed in front of a one-dimensional, eight-element transducer array, between the array and the water. Operating in a receive mode, data were taken as a function of angle of incidence and compared to data taken without the presence of the alumina bar. The array was also operated in transmit mode and results were compared to corresponding receive mode data, showing that reciprocity holds. Results show that in fact sound energy can be steered through a plate, and that the measurement method used provides a convenient method of measuring the angular dependence of transmission through a plate, including measurements at frequencies above the plate's critical frequency. Experimental results of sound transmission versus angle of incidence of finite sized plates agree qualitatively with theoretical results from an analysis of the transmission through an unbounded flexible partition.

On the steering of sound energy through a supercritical plate by a near-field transducer array.

This article provides an historical overview of Time Reversal (TR), introduces its basic physics, addresses advantages and limitations, and describes some applications of this very active research area of acoustics. In the Geophysics Group at the Los Alamos National Laboratory, we conduct studies of TR of elastic waves in solids. Our work includes application of TR to nondestructive evaluation of materials, as well as to earthquake source characterization, and ground-based nuclear explosion monitoring. We emphasize the term elastic waves here to underscore that we include both compression and shear waves, in contrast to purely acoustic waves that are only compressional.

The degree family tree of Brian E. Anderson will be presented. The poster will display evidence of the strong connection between the Graduate Program in Acoustics at The Pennsylvania State University and the Acoustics Research Group of the Department of Physics and Astronomy at Brigham Young University. Currently Brian represents a branch with no fruit, but Brian hopes to someday bear much fruit (advise graduate students as a faculty member).

The presence of strong sources of elastic waves often makes it impossible to localize weaker ones, which are sometimes the most meaningful, e.g. in the characterization of complexity of active Earth faults or of microdamage in a composite structural material. To address this problem, a selective source reduction method is proposed here which, applied in conjunction with time reversal acoustics (TRA), provides the means to selectively reduce the contribution of strong sources allowing full illumination of the weak ones. The method is complementary to other methods based on TRA which aim at the selective illumination of scatterers in the propagation medium. In this paper, a description of the method is given along with presentation of a few numerical results to demonstrate its usefulness for localization of sources. Validation and some experimental results are also presented.

Selective source reduction to identify masked sources using time reversal acoustics

In the typical application of time reversed acoustics, the spatial resolution of a time‐reversed focus is set by the diffraction limit, i.e., a focal spot size cannot be made smaller than a half of a wavelength. A frequency‐domain signal processing method is introduced in which the information in the received signal of the forward propagation stage is shifted to higher frequency. The resulting time domain signal is time reversed and rebroadcast to form a focal spot size that is diffraction limited at the higher frequency (shorter) wavelength. This method requires neither a priori information about the original source location nor nearfield signal detection. A theoretical discussion of the problem, along with numerical and experimental results, will be presented. The limitations and potential applications will also be presented. [This work is supported by Institutional Support (LDRD) at Los Alamos National Laboratory.]

Improving spatial resolution of a time‐reversed focus using frequency‐domain signal processing

Large earthquakes are composed of a complex succession of slip events that are nearly indistinguishable on a seismogram. The question, how does an earthquake work? remains largely unsolved. The slip events on the fault plane(s) generally take place at different spatial locations and at different times. TR wave physics can be advantageously exploited to recreate, from measured signals, a spatially and/or temporally complex sound/seismic source. An experimental study is conducted to determine the spatial and temporal resolution limitations in imaging a complex source in solids, as part of our goal to understand earthquake source complexity. TR experiments are conducted on solid blocks of different materials, such as Berea sandstone and aluminum. Arrays of piezoelectric transducers are bonded to the samples for the creation of complex spatial‐temporal sources, as well as to record signals. The experimental spatial and temporal resolution limits for complex source imaging will be presented as a function of ma...

Complex source imaging using time‐reversal (TR): experimental studies of spatial and temporal resolution limits

Our ultimate goal is locating and imaging nonlinear scatterers in solids (e.g., cracks) without a priori knowledge of their existence. Toward that goal, two methods have been devised that combine the spatial and temporal focusing abilities of TRA with nonlinear elastic wave spectroscopy’s (NEWS) sensitivity to mechanical damage. The first method uses TRA to create large amplitude signals and induce a nonlinear response in a highly localized region on a sample surface. Repeating the process in a step‐scan approach provides the means to image the sample surface/near‐surface with high resolution, distinguishing nonlinear features (cracks) from the linear background (undamaged material). The second method takes advantage of TRA to focus acoustic energy from two input frequencies onto an unknown, but nonlinear, scattering source, creating nonlinear wave modulation. The time reversal mirror (TRM) array records the primary and scattering source waveforms. Filtering the recorded signals for a modulation sideband,...

Nonlinear dynamics and time reversed acoustic imaging in damaged solids

The effect of placing a structural acoustic filter between water and the transducer elements of an array to help reduce undesirable grating lobes is investigated. A supercritical plate is mounted to transducer elements with a thin decoupling polyurethane layer between the transducers and the plate. The plate acts as a radiation/incidence angle filter to pass energy at angles near normal incidence, but suppress energy at large incidence angles. Grating lobe reduction is achieved at the expense of limiting the available steering of the main lobe. Within this steer angle limitation, the main lobe can be steered as normal while the grating lobe level is reduced by the plate's angular filtering. The insertion of a plate structural filter provides, in principal, an inexpensive and easily implemented approach to extend usable frequency bandwidth with reduced level grating lobes, without increasing the number of array elements. Even though the data match theory well, a practical material has yet to be found that possesses optimal material properties to make the proposed idea practical. This work represents the first attempt to advantageously utilize a plate above its critical frequency to provide angular dependent sound transmission filtering.

Grating lobe reduction in transducer arrays through structural filtering of supercritical plates.

This presentation investigates the effect of placing a finite‐length bar between eight transducer elements and water in order to reduce undesirable grating lobes. The transducer elements are mounted to the bar, with a thin polyurethane layer between the elements and the bar, and force the bar to approximate the radiation of a continuous line source (i.e., no grating lobes). Reductions in the grating lobe with the insertion of a bar, compared to the unmodified array, have been found numerically and experimentally. In addition the transducer array can still be steered and amplitude shaded, and the bar geometry may be scaled according to the design frequency. Freely vibrating bending modes in the bar create undesirable additional radiation. The benefits and limitations of retrofitting existing array systems with a bar for grating lobe reduction, in frequency and steer angle, will be presented. The insertion of the bar provides a very inexpensive and easily implemented approach to reduce grating lobes without...

Grating lobe reduction in 1‐D transducer arrays by driving a bar

DERIVATION OF MOVING-COIL LOUDSPEAKER PARAMETERS USING PLANE WAVE TUBE TECHNIQUES Brian E. Anderson Department of Physics and Astronomy Master of Science Small-signal moving-coil loudspeaker driver parameters are traditionally derived through electrical impedance measurement techniques. These parameters are commonly called Thiele/Small parameters, after Neville Thiele and Richard Small who are credited with developing industry-standard loudspeaker modeling techniques. However, because loudspeaker drivers are electro-mechano-acoustical transducers, it should be possible to measure their parameters in physical domains other than the electrical domain. A method of measuring loudspeaker parameters from the acoustical domain will be developed. The technique uses a plane wave tube to measure acoustical properties of a baffled driver under test. Quantities such as the transmission loss through the driver are measured for a driver placed in the tube using the two-microphone transfer-function technique. Models have been developed to curve fit the resulting data, from which small-signal loudspeaker parameters are subsequently derived. This thesis discusses the acoustical measurement theory, apparatus, and system modeling methods (via equivalent circuits). It also compares measured parameters to those derived using electrical techniques. Parameters derived from both approaches are compared with reference values to establish bias errors. Sequential measurements are also compared to reveal random errors in the derivation processes.

Derivation of Moving-Coil Loudspeaker Parameters Using Plane Wave Tube Techniques

Complaints of perceived echoes at specific locations in a 21,000 seat fan‐shaped auditorium have prompted the measurement and analysis of numerous impulse responses. The responses were first processed using the echo criterion of Niese, then using the criterion of Dietsch and Kraak. This paper compares the two criteria and explores their abilities to assess whether peaks and anomalies of the measured responses were likely to produce audible echoes in the hall. The Niese criterion was found to better predict the perception of echoes produced by broad irregular decay trends. The Dietsch and Kraak criterion was able to better predict echoes produced by sufficiently strong specular reflections. Neither criterion alone was able to fully characterize these perceptions. Results obtained for both criteria at various seat locations will be presented and compared with subjective findings.

A unique acoustical method of measuring small‐signal moving‐coil loudspeaker parameters has recently been developed. This technique involves the use of a plane wave tube to measure acoustical properties (e.g., reflection and transmission coefficients) of a driver under test (DUT). From this data, small‐signal parameters are derived using curve‐fitting techniques. Electrical conditions are easily controlled and automated to allow for the derivation of additional parameters. Current parameter measurement techniques require measurement of the electrical impedance of the DUT. This paper will discuss the acoustical measurement apparatus, experimental measurement techniques, and compare its measured parameters to those derived using electrical techniques.

Derivation of moving‐coil loudspeaker parameters using acoustical testing techniques: Experiment results

Moving‐coil loudspeaker driver parameters are generally derived through the measurement of electrical impedances. Nevertheless, because these drivers are electro‐mechano‐acoustical transducers, their parameters may also be determined from measurements taken in other physical domains. This paper presents theoretical concepts that show how they may be determined acoustically using plane wave tube techniques. A driver is mounted in a baffle to form a composite partition between a source tube and a receiving tube. The frequency‐dependent transmission loss of the partition is determined using upstream and downstream sound field decompositions that compensate for possible nonanechoic receiving tube conditions. A transmission loss curve based on an equivalent circuit model of the system is then fit to the measured curve to extract specific driver parameters. Different electrical conditions are imposed at the driver terminals to modify the transmission loss in ways that allow the determination of additional param...

Derivation of moving‐coil loudspeaker parameters using acoustical testing techniques: Theoretical developments

Because loudspeaker drivers are electro-mechano-acoustical transducers, their parameters may be measured from physical domains other than the electrical domain. A method has been developed by the authors to determine moving-coil loudspeaker parameters through the use of acoustical measurements. The technique utilizes a plane wave tube and the two-microphone transfer function technique to measure acoustical properties of a baffled driver under test (DUT). Quantities such as the reflection and transmission coefficients of the DUT are first measured. Driver parameters are then extracted from the measurements using curve-fitting techniques and theoretical solutions to equivalent circuits of the composite system. This paper discusses the acoustical measurement apparatus, system modeling, and a comparison of acoustically measured parameters to those measured using common electrical techniques. Parameters derived from the various methods are also compared to reference parameters to establish bias errors. 0. GLOSSARY OF SYMBOLS B Magnetic flux density in the driver gap Bl Motor strength, the product of B and l c Speed of sound in air MS C Compliance of driver suspension c f Cutoff frequency for the first cross mode of the plane wave tube 0 f In vacuo resonance frequency of driver s f Free-air resonance frequency of driver l Length of voice coil in magnet air gap VC L Inductance of driver voice coil MD M Moving mass of driver diaphragm assembly ANDERSON AND LEISHMAN ACOUSTICAL MEASUREMENT OF LOUDSPEAKERS AES 115TH CONVENTION, NEW YORK, NEW YORK, 2003 OCTOBER 10-13 2 MS M Moving mass of driver diaphragm assembly including air load B p Blocked sound pressure from source driver i p Sound pressure incident upon driver t p Sound pressure transmitted through driver ES Q Electrical quality factor MS Q Mechanical quality factor TS Q Total system quality factor MS R Mechanical resistance of driver suspension VC R DC resistance of driver voice coil S Cross-sectional area of plane wave tube D S Effective radiating surface area of driver TL Transmission loss U Volume velocity, particle velocity multiplied by surface area AS V Volume of air having the same acoustic compliance as the driver suspension i W Sound power incident upon driver t W Sound power transmitted through driver E X Electrical reactance of driver’s electrical system M X Mechanical reactance of driver’s mechanical system MT X Mechanical reactance of termination impedance AR Z Acoustic radiation impedance seen by source driver AT Z Acoustic impedance of termination translated up to the back of the driver diamphram E Z Electrical impedance of the driver’s voice coil M Z Mechanical impedance of the driver’s mechanical system BB M Z , Mechanical impedance of a black box MT Z Mechanical termination impedance translated up to the back of the driver diaphragm 0 ρ Density of air τ Sound power transmission coefficient CC τ Closed circuit transmission coefficient of driver under test OC τ Open circuit transmission coefficient of driver under test ω Angular frequency, in rad/s

An Acoustical Measurement Method for the Derivation of Loudspeaker Parameters

Piano tones have partials whose frequencies are sharp relative to harmonic values. A listening test was conducted to determine the effect of inharmonicity on pitch for piano tones in the lowest three octaves of a piano. Nine real tones from the lowest three octaves of a piano were analyzed to obtain frequencies, relative amplitudes, and decay rates of their partials. Synthetic inharmonic tones were produced from these results. Synthetic harmonic tones, each with a twelfth of a semitone increase in the fundamental, were also produced. A jury of 21 listeners matched the pitch of each synthetic inharmonic tone to one of the synthetic harmonic tones. The effect of the inharmonicity on pitch was determined from an average of the listeners' results. For the nine synthetic piano tones studied, pitch increase ranged from approximately two and a half semitones at low fundamental frequencies to an eighth of a semitone at higher fundamental frequencies.

A novel acoustical method of measuring small‐signal moving‐coil loudspeaker parameters has recently been developed. This technique involves the use of a plane wave tube to measure acoustical properties (e.g., reflection and transmission coefficients) of a driver under test (DUT). From this data, small‐signal parameters are derived using curve‐fitting techniques. Current loudspeaker parameter measurement techniques require measurement of the electrical impedance of the DUT. This paper will discuss the acoustical measurement apparatus, system modeling (via equivalent circuits), and a comparison of measured parameters to those derived using electrical techniques.

Derivation of moving‐coil loudspeaker parameters using acoustical testing techniques

Investigation of geomagnetic reference models based on the Iridium
 
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 constellation

In this study, field‐aligned currents (FACs) obtained from the Active Magnetosphere and Planetary Electrodynamics Response Experiment data set have been used to specify the high‐latitude electric potential in the Global Ionosphere Thermosphere Model (GITM). The advantages and challenges of the FAC‐driven simulation are investigated based on a series of numerical experiments and data‐model comparisons for the 2013 St Patrick's Day geomagnetic storm. It is found that the cross‐track ion drift measured by the Defense Meteorological Satellite Program satellites can be well reproduced in the FAC‐driven simulation when the electron precipitation pattern obtained from Assimilative Mapping of Ionospheric Electrodynamics (AMIE) technique is used in GITM. It is also found that including the neutral wind dynamo properly is very important when using FACs to derive the high‐latitude electric field. Without the neutral wind dynamo, the cross‐polar‐cap potential and hemispheric integrated Joule heating could be underestimated by more than 20%. Moreover, the FAC‐driven simulation is able to well reproduce the ionospheric response to the geomagnetic storm in the American sector. However, the FAC‐driven simulation yields relatively larger data‐model discrepancies compared to the AMIE‐driven GITM simulation. This may result from inaccurate Joule heating estimations in the FAC‐driven simulation caused by the inconsistency between the FAC and electron precipitation patterns. This study indicates that the FAC‐driven technique could be a useful tool for studying the coupled ionosphere and thermosphere system provided that the FACs and electron precipitation patterns can be accurately specified.

Assessment of Using Field‐Aligned Currents to Drive the Global Ionosphere Thermosphere Model: A Case Study for the 2013 St Patrick’s Day Geomagnetic Storm

Investigation of geomagnetic reference models based on the Iridium®\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{\

Exploring a Lunar Magnetic Anomaly: The Lunar Vertex PRISM Mission

Data from the Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE) have been used to study electric fields and currents for multiple magnetic storms. The calculation uses a high latitude conductivity model based on the field-aligned currents measured by AMPERE compared to measurements from the Poker Flat Incoherent Scatter Radar. The derivation of conductivities from field-aligned currents ensures spatial and temporal consistency in the calculated electrodynamic parameters. For all of the magnetic storms studied, the combined energy input from precipitating particles exhibits sharply-peaked maxima for small scale structures at the times of local minima in DsT, suggesting a close coupling between magnetospheric and/or ring current energy content and the high latitude currents driven by field-aligned currents. We speculate that these relatively rapid increases and decreases of the high latitude energy deposition may be a result of the variation of ionospheric conductance with field-aligned current strength, leading to a nonlinear relation between current and voltage, and impulsive transfer of energy from the magnetosphere to the ionosphere. © 2018 BBSCS RN SWS. All rights reserved

Impulsive Energy Transfer from the Magnetosphere to the Ionosphere during Geomagnetic Storms

MISSION CONCEPT. David T. Blewett, Dana M. Hurley, Brett W. Denevi, Joshua T.S. Cahill, Rachel L. Klima, Lauren M. Jozwiak, Jeffrey B. Plescia, Christopher P. Paranicas, Benjamin T. Greenhagen, Charles A. Hibbitts, Brian A. Anderson, Haje Korth, George C. Ho, Jorge I. Núñez, Michael I. Zimmerman, and Pontus C. Brandt. Space Science Branch, Space Exploration Sector, Johns Hopkins University Applied Physics Laboratory, Laurel, Md., USA. (david.blewett@jhuapl.edu).

EXPLORATION OF A LUNAR CRUSTAL MAGNETIC ANOMALY : THE LUNAR COMPASS ROVER MISSION CONCEPT

Science from the Surface of the Moon: A Rover Traversing a Crustal Magnetic Anomaly

ANOMALY. David T. Blewett, Dana M. Hurley, Brett W. Denevi, Joshua T.S. Cahill, Rachel L. Klima, Jeffrey B. Plescia, Christopher P. Paranicas, Benjamin T. Greenhagen, Brian A. Anderson, Haje Korth, George C. Ho, Jorge I. Núñez, Michael I. Zimmerman, and Pontus C. Brandt. Space Science Branch, Space Exploration Sector, Johns Hopkins University Applied Physics Laboratory, Laurel, Md., USA. (david.blewett@jhuapl.edu).

Lunar Compass: A Rover Mission for Exploration of a Lunar Crustal Magnetic Anomaly

During the past decade engineering‐grade magnetic field measurements from the low Earth orbiting (LEO) Iridium constellation of communication satellites have been available to the geospace science community as a tool to map field‐aligned currents. The Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE) applied to Iridium measurements markedly improved the temporal and spatial resolution of these data. We developed new methods to compare data from the latest improvement to AMPERE with those from a constellation of four LEO Defense Meteorological Satellite Program (DMSP) spacecraft that carry high‐resolution magnetometers. To perform the comparisons, we transformed all data to a common coordinate frame and altitude (110 km) and developed a means of computing spacecraft magnetic conjunctions. These conjunctions yield discrepancies in the magnetic field perturbations measured at each proximate spacecraft. During the geomagnetic disturbance of 29–30 May 2010, the vector differences in the horizontal perturbations at closest approach (typically a few tens of kilometers) had mean, median, and standard deviation values of 132 nT, 112 nT, and 90 nT, respectively. The DMSP spacecraft tend to report larger perturbations in the northern polar cap and cusp regions, especially during active intervals. We attribute some of the differences to limitations of spacecraft‐attitude knowledge that propagate into AMPERE data. Overall, for the magnetic storm, we provide clear evidence that AMPERE data can provide high‐resolution auroral zone data in good agreement with DMSP data for use in data assimilation algorithms. Such dual‐use commercial data can provide important global augmentation to the nation's space weather monitoring capabilities.

Comparison of magnetic perturbation data from LEO satellite constellations: Statistics of DMSP and AMPERE

The Balloon Array for RBSP Relativistic Electron Losses (BARREL)

(1) The Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA (George.Ho@jhuapl.edu), (2) Academy of Athens, Office of Space Research and Technology, Soranou Efesiou 4, Athens 11527, Greece, (3) Laboratory for Atmospheric and Space Physics, University of Colorado, Boulder, CO 80303, USA, (4) Department of Atmospheric, Oceanic and Space Sciences, University of Michigan, Ann Arbor, MI 48109, USA, (5) Department of Terrestrial Magnetism, Carnegie Institution of Washington, Washington, DC 20015, USA

The paper compares two finite element time domain solvers for transient electromagnetic simulation of multiscale structures. The first solver is based on a dual-field implicit-explicit formulation. By limiting the number of implicit elements, the solver closely resembles nodal discontinuous Galerkin and has better scalability in memory requirement and multithreading for solving large-scale problems. However, when the structures and features to be solved are electrically small, the explicit part of the hybrid solver is limited by the stability condition and becomes inefficient in passing low-frequency signals through the structures. We will demonstrate that the second solver based on a single-variable fully implicit formulation can better handle low-frequency applications such as electrostatic discharge and lightning strikes. It is also immune to bad meshes with extremely small or ill-shaped elements.

Comparison of hybrid and fully implicit time domain finite element solvers for transient electromagnetic simulation

Topologies for ad-hoc networks utilizing directional antennas with restricted fields of view

Full-wave analysis is traditionally performed in the frequency domain, or in the time domain using specialized simulators (e.g., finite difference time domain). We describe here an approach that allows us to generate full-wave models for SPICE simulation. The advantage of this approach is that it allows us to easily consider the effects of arbitrary terminations. A frequency-domain finite-element method or method-of-moments solver is used to determine the frequency response of a three-dimensional structure, and then a SPICE model is constructed, which matches this frequency response across a specified frequency band. Some examples are presented to demonstrate the efficacy of the technique.

Abstract : Currently, most antenna array designs are mechanically steered. However, as demand for higher performance antennas increases, an electronic replacement for the mechanical system becomes necessary. An alternative that may prove to be more cost effective is to use ferrite patch antennas as the elements in the array. The antenna's radiation characteristics are controlled by the direction and magnitude of the imposed magnetic fields that bias the ferrite. This is accomplished without requiring additional circuitry in the signal path. An initial study of this type of device was performed. The advanced ferrite handling capability of Ansoft HFSS was used to simulate the radiation characteristics of ferrite patch antennas. The simulation capability of this finite element field simulation tool with its advanced absorbing boundary condition to simulate ferrite patch antennas was studied. The advantage of this type of solver is the ability to analyze ferrites with non-uniform bias fields. Through this investigation a better understanding of the operating characteristics of ferrite patch antennas was achieved.

Focused Application Software for Design of Ferrite Patch Antennas. Phase 1.

This paper presents a full wave vector finite element analysis of microwave devices that utilize gyrotropic ferrite materials. The ferrite permeability tensor's dependence upon the magnetostatic bias field is accounted for by determining the static fields using a three-dimensional finite element magnetostatic solver. This accounts for non-uniform demagnetization and the resulting spatial inhomogeneities in the full-wave high-frequency computations. Comparisons are made between the calculated S-parameters of a microstrip circulator and measured S-parameters.

IEEE Antennas and Propagation Society International Symposium. 1996 Digest

Three-dimensional finite element analysis of ferrite devices including spatial inhomogeneity of the permeability tensor

This paper describes a new method for computing the propagation constants of a ferrite loaded waveguide using, triangular vector finite elements. The method has been applied successfully to situations where the DC bias is parallel or is transverse to the direction of propagation. >

Solution of ferrite loaded waveguide using vector finite elements

Understanding regional as well as global spinal alignment is increasingly recognized as important for the spine surgeon. A novel software program for virtual preoperative measurement and surgical manipulation of sagittal spinal alignment was developed to provide a research and educational tool for spine surgeons. This first-generation software program provides tools to measure sagittal spinal alignment from the occiput to the pelvis, and to allow for virtual surgical manipulation of sagittal spinal alignment. The software was developed in conjunction with Clifton Labs, Inc. Photographs and radiographs were imported into the software program, and a 2D virtual spine was constructed from the images. The software then measured regional and global sagittal spinal alignment from the virtual spine construct, showing the user how to perform the measurements. After measuring alignment, the program allowed for virtual surgical manipulation, simulating surgical procedures such as interbody fusion, facet osteotomy, pedicle subtraction osteotomy, and reduction of spondylolisthesis, as well as allowing for rotation of the pelvis on the hip axis. Following virtual manipulation, the program remeasured regional and global sagittal spinal alignment. Computer software can be used to measure and manipulate sagittal spinal alignment virtually, providing a new research and educational tool. In the future, more comprehensive programs may allow for measurement and interaction in the coronal, axial, and sagittal planes.

Virtual preoperative measurement and surgical manipulation of sagittal spinal alignment using a novel research and educational software program.

The modeling and analysis of a USB storage device with a novel protection mechanism is described. The USB storage device contains an active monitoring subsystem that decodes and analyzes an encoded request stream has been developed by Clifton Labs. However, before moving to fabrication, there are several design parameters that need to be explored and better understood. In this manuscript we review our experiences in the modeling and analysis of our USB device using the Microsoft Windows Driver's kit. Initially we began this project with limited experience with the USB bus protocol and with no prior experience with the Microsoft device driver tools. In this paper we describe our work modeling and analyzing the new USB storage device and describe our the problems and complications we encountered using these modeling and analysis tools.

The Use of Device Simulation in Development of USB Storage Devices

Late glacial climate evolution in the Patagonian Andes (44–47° S) from alpine glacier modelling

 Due to adverse snow and cloud conditions, only a few inventories are available for the maritime glaciers in New Zealand. These are difficult to compare as different approaches and baseline data have been used to create them. In consequence, glacier fluctuations in New Zealand over the past two decades are only known for a few glaciers based on field observations. Here we present the results of a new inventory for the ‘year 2000’ (some scenes are from 2001 and 2002) that is based on glacier outlines from a recently published inventory for the year 2016 and allowed consistent change assessment for nearly 3000 glaciers over this period. The year 2000 inventory was created by manual on-screen digitizing using Landsat ETM+ satellite imagery (15 m panchromatic band) in the background and the year 2016 outlines as a starting point. Major challenges faced were late and early seasonal snow, clouds and shadow, the geo-location mismatch between Landsat and Sentinel-2 as well as the correct interpretation of ice patches and ice under debris cover. In total, we re-mapped 2967 glaciers covering an area of 885.5 km2 in 2000, which is 91.7 km2 (or 10.4%) more than the 793.8 km2 mapped in 2016. Area change rates (mean rate −0.65% a−1) increase towards smaller glaciers. Strongest area loss from 2000 to 2016 occurred at elevations ~1900 m but the highest relative loss was found below 800 m a.s.l. In total, 109 glaciers split into two or more entities and 264 had wasted away by 2016.

Deriving a year 2000 glacier inventory for New Zealand from the existing 2016 inventory

Abstract An end of summer snowline (EOSS) photographic dataset for Aotearoa New Zealand contains over four decades of equilibrium line altitude (ELA) observations for more than 50 index glaciers. This dataset provides an opportunity to create a climatological ELA reference series that has several applications. Our work screened out EOSS sites that had low temporal coverage and also removed limited observations when the official survey did not take place. Snowline data from 41 of 50 glaciers in the EOSS dataset were retained and included in a normalised master snowline series that spans 1977–2020. Application of the regionally representative normalised master snowline series in monthly and seasonally resolved climate response function analyses showed consistently strong relationships with austral warm-season temperatures for land-based stations west of the Southern Alps and the central Tasman Sea. There is a trend towards higher regional snowlines since the 1990s that has been steepening in recent decades. If contemporary decadal normalised master snowline series trends are maintained, the average Southern Alps snowline elevation will be displaced at least 200 m higher than normal by the 2025–2034 decade. More frequent extremely high snowlines are expected to drive more extreme cumulative mass-balance losses that will reduce the glacierised area of Aotearoa New Zealand.

Southern Alps equilibrium line altitudes: four decades of observations show coherent glacier–climate responses and a rising snowline trend

Projected land ice contributions to twenty-first-century sea level rise

Paraglacial adjustment of sediment slopes during and immediately after glacial debuttressing

Glacier mass loss is recognized as a major contributor to current sea level rise. However, large uncertainties remain in projections of glacier mass loss on global and regional scales. We present an ensemble of 288 glacier mass and area change projections for the 21st century based on 11 glacier models using up to 10 general circulation models and four Representative Concentration Pathways (RCPs) as boundary conditions. We partition the total uncertainty into the individual contributions caused by glacier models, general circulation models, RCPs, and natural variability. We find that emission scenario uncertainty is growing throughout the 21st century and is the largest source of uncertainty by 2100. The relative importance of glacier model uncertainty decreases over time, but it is the greatest source of uncertainty until the middle of this century. The projection uncertainty associated with natural variability is small on the global scale but can be large on regional scales. The projected global mass loss by 2100 relative to 2015 (79 ± 56 mm sea level equivalent for RCP2.6, 159 ± 86 mm sea level equivalent for RCP8.5) is lower than, but well within, the uncertainty range of previous projections.

Partitioning the Uncertainty of Ensemble Projections of Global Glacier Mass Change

ABSTRACT Fox Glacier/Te Moeka o Tuawe is a fast-responding maritime glacier that has undergone multiple advance and retreat phases during recent decades. Here we use a combination of repeat photography, Structure from Motion (SfM), and ice discharge measurement, to identify key morphological differences associated with these repeated phase changes, and assess how much of the current terminus is still dynamically active. Increasing surface-debris cover at the margins and topographic shading result in the asymmetry of the retreating terminus, with central portions receding faster than the margins. In 2019, the glacier is shorter than at any time in recorded history, and ice flux is insufficient to sustain the current glacier length, with a further ∼300 m of the glacier terminus region potentially vulnerable to retreat. However, due to the high climate sensitivity of this maritime glacier, even a slight shift towards increasing mass flux could see this trend reverse.

Morphological changes to the terminus of a maritime glacier during advance and retreat phases: Fox Glacier/Te Moeka o Tuawe, New Zealand

Abstract The only complete inventory of New Zealand glaciers was based on aerial photography starting in 1978. While there have been partial updates using 2002 and 2009 satellite data, most glaciers are still represented by the 1978 outlines in contemporary global glacier databases. The objective of this project is to establish an updated glacier inventory for New Zealand. We have used Landsat 8 OLI satellite imagery from February and March 2016 for delineating clean glaciers using a semi-automatic band ratio method and debris-covered glaciers using a maximum likelihood classification. The outlines have been checked against Sentinel-2 MSI data, which have a higher resolution. Manual post processing was necessary due to misclassifications (e.g. lakes, clouds), mapping in shadowed areas, and combining the clean and debris-covered parts into single glaciers. New Zealand glaciers cover an area of 794 ± 34 km2 in 2016 with a debris-covered area of 10%. Of the 2918 glaciers, seven glaciers are >10 km2 while 71% is <0.1 km2. The debris cover on those largest glaciers is >40%. Only 15 glaciers are located on the North Island. For a selection of glaciers, we were able to calculate the area reduction between the 1978 and 2016 inventories.

Updated inventory of glacier ice in New Zealand based on 2016 satellite imagery

Climate amelioration during the Last Glacial Maximum recorded by a sensitive mountain glacier in New Zealand

ABSTRACT Compilation of fragmented glaciological data, spanning more than a century at Haupapa/Tasman Glacier, provides new insight on how this glacier is changing over time. Despite consistency in high accumulation on the glacier, dramatic surface thinning and up-glacier expansion of supraglacial debris highlights that the glacier is currently in disequilibrium with climate. However, pauses in the rate of debris emergence indicate that despite ongoing terminus retreat at the proglacial lake, a subtle response to climate is still detectable mid-glacier. Analysis of surface velocity data at key locations reveals no trend over time at the Malte Brun site in the upper ablation area, but recent deceleration was recorded near the Ball Glacier confluence, located 5 km up-glacier from the current terminus. Near-terminus acceleration during a period of rapid lake expansion, followed by more recent deceleration, demonstrates that at this time, ice thinning at Haupapa/Tasman Glacier is likely being driven by negative surface mass balance as opposed to dynamic thinning associated with proglacial lake enlargement.

Revisiting glaciological measurements on Haupapa/Tasman Glacier, New Zealand, in a contemporary context

ABSTRACT The Darwin–Hatherton Glacial system (DHGS) connects the East Antarctic Ice Sheet (EAIS) with the Ross Ice Shelf and is a key area for understanding past variations in ice thickness of surrounding ice masses. Here we present the first detailed measurements of ice thickness and grounding zone characteristics of the DHGS as well as new measurements of ice velocity. The results illustrate the changes that occur in glacier geometry and ice flux as ice flows from the polar plateau and into the Ross Ice Shelf. The ice discharge and the mean basal ice shelf melt for the first 8.5 km downstream of the grounding line amount to 0.24 ± 0.05 km3 a−1 and 0.3 ± 0.1 m a−1, respectively. As the ice begins to float, ice thickness decreases rapidly and basal terraces develop. Constructed maps of glacier geometry suggest that ice drainage from the EAIS into the Darwin Glacier occurs primarily through a deep subglacial canyon. By contrast, ice thins to <200 m at the head of the much slower flowing Hatherton Glacier. The glaciological field study establishes an improved basis for the interpretation of glacial drift sheets at the link between the EAIS and the Ross Ice Sheet.

Geometry and ice dynamics of the Darwin–Hatherton glacial system, Transantarctic Mountains

Glaciers offer the potential to reconstruct past climate over timescales from decades to millennia. They are found on nearly every continent, and at the Last Glacial Maximum, glaciers were larger in all regions on Earth. The physics of glacier-climate interaction are relatively well understood, and glacier models can be used to reconstruct past climate from geological evidence of past glacier extent. This can lead to significant insights regarding past, present, and future climate. For example, glacier modeling has demonstrated that the near-ubiquitous global pattern of glacier retreat during the last few centuries resulted from a global-scale climate warming of ∼1°C, consistent with instrumental data and climate proxy records. Climate reconstructions from glaciers have also demonstrated that the tropics were colder at the Last Glacial Maximum than was originally inferred from sea surface temperature reconstructions. Future efforts to reconstruct climate from glaciers may provide new constraints on climat...

An exercise in glacier length modeling: Interannual climatic variability alone cannot explain Holocene glacier fluctuations in New Zealand

Hillslope failure and paraglacial reworking of sediments in response to glacier retreat, Fox Valley, New Zealand.

Alpine permafrost occurrence in maritime climates has received little attention, despite suggestions that permafrost may occur at lower elevations than in continental climates. To assess the spatial and altitudinal limits of permafrost in the maritime Southern Alps, we developed and tested a catchment-scale distributed permafrost estimate. We used logistic regression to identify the relationship between permafrost presence at 280 active and relict rock glacier sites and the independent variables a) mean annual air temperature and b) potential incoming solar radiation in snow free months. The statistical relationships were subsequently employed to calculate the spatially-distributed probability of permafrost occurrence, using a probability of ≥ 0.6 to delineate the potential permafrost extent. Our results suggest that topoclimatic conditions are favorable for permafrost occurrence in debris-mantled slopes above ~ 2000 m in the central Southern Alps and above ~ 2150 m in the more northern Kaikoura ranges. Considering the well-recognized latitudinal influence on global permafrost occurrences, these altitudinal limits are lower than the limits observed in other mountain regions. We argue that the Southern Alps’ lower distribution limits may exemplify an oceanic influence on global permafrost distribution. Reduced ice-loss due to moderate maritime summer temperature extremes may facilitate the existence of permafrost at lower altitudes than in continental regions at similar latitude. Empirical permafrost distribution models derived in continental climates may consequently be of limited applicability in maritime settings.

Estimating Permafrost Distribution in the Maritime Southern Alps, New Zealand, Based on Climatic Conditions at Rock Glacier Sites

Abstract. Knowledge of the ice thickness distribution of glaciers and ice caps is an important prerequisite for many glaciological and hydrological investigations. A wealth of approaches has recently been presented for inferring ice thickness from characteristics of the surface. With the Ice Thickness Models Intercomparison eXperiment (ITMIX) we performed the first coordinated assessment quantifying individual model performance. A set of 17 different models showed that individual ice thickness estimates can differ considerably – locally by a spread comparable to the observed thickness. Averaging the results of multiple models, however, significantly improved the results: on average over the 21 considered test cases, comparison against direct ice thickness measurements revealed deviations on the order of 10 ± 24 % of the mean ice thickness (1σ estimate). Models relying on multiple data sets – such as surface ice velocity fields, surface mass balance, or rates of ice thickness change – showed high sensitivity to input data quality. Together with the requirement of being able to handle large regions in an automated fashion, the capacity of better accounting for uncertainties in the input data will be a key for an improved next generation of ice thickness estimation approaches.

How accurate are estimates of glacier ice thickness? Results from ITMIX, the Ice Thickness Models Intercomparison eXperiment

© Author(s) 2016. Quantitative palaeoclimate reconstructions provide data for evaluating the mechanisms of past, natural climate variability. Geometries of former mountain glaciers, constrained by moraine mapping, afford the opportunity to reconstruct palaeoclimate, due to the close relationship between ice extent and local climate. In this study, we present results from a series of experiments using a 2-D coupled energy balance-ice flow model that investigate the palaeoclimate significance of Last Glacial Maximum moraines within nine catchments in the central North Island, New Zealand. We find that the former ice limits can be simulated when present-day temperatures are reduced by between 4 and 7°C, if precipitation remains unchanged from present. The spread in the results between the nine catchments is likely to represent the combination of chronological and model uncertainties. The majority of catchments targeted require temperature decreases of 5.1 to 6.3°C to simulate the former glaciers, which represents our best estimate of the temperature anomaly in the central North Island, New Zealand, during the Last Glacial Maximum. A decrease in precipitation of up to 25% from present, as suggested by proxy evidence and climate models, increases the magnitude of the required temperature changes by up to 0.8°C. Glacier model experiments using reconstructed topographies that exclude the volume of post-glacial (< 15 ka) volcanism generally increased the magnitude of cooling required to simulate the former ice limits by up to 0.5°C. Our palaeotemperature estimates expand the spatial coverage of proxy-based quantitative palaeoclimate reconstructions in New Zealand. Our results are also consistent with independent, proximal temperature reconstructions from fossil groundwater and pollen assemblages, as well as similar glacier modelling reconstructions from the central Southern Alps, which suggest air temperatures were ca. 6°C lower than present across New Zealand during the Last Glacial Maximum.

The Last Glacial Maximum in the central North Island, New Zealand: Palaeoclimate inferences from glacier modelling

Exploring the source-to-sink residence time of terrestrial pollen deposited offshore Westland, New Zealand

Short-term glacier velocity variations typically occur when a water input is accommodated by an increase in the subglacial water pressure. Although these velocity variations have been well documented on many glaciers, few studies have considered them on glaciers where heavy rain and glacier melt occur year-round. This study investigates the relationship between water inputs and glacier velocity on Franz Josef Glacier, New Zealand. We installed six GNSS stations across the lower glacier during austral summer 2010/11 and one station during summer 2012/13. Glacier velocity remained elevated at all stations for ∼7 days following large rain events. During diurnal melt events, we find velocity variations in the early afternoon (12:00–16:00) at 600 m a.s.l. and in the late evening (20:00–01:00) at 400 m a.s.l. We hypothesize that the late-evening velocity variations occurred as an upstream region of high subglacial water pressures and accelerated ice motion propagated downstream. This mechanism may also explain the increased longitudinal compression and transverse extension across the lower glacier during speed-up events. Our results indicate that the subglacial drainage system likely decreases in efficiency upstream and that the water input variability can still cause short-term velocity variations despite the large year-round water inputs.

Glacier velocity and water input variability in a maritime environment: Franz Josef Glacier, New Zealand

Abstract. Glacier behaviour during the mid-Holocene (MH, 6000 years BP) in the Southern Hemisphere provides observational data to constrain our understanding of the origin and propagation of palaeoclimate signals. In this study we examine the climatic forcing of glacier response in the MH by evaluating modelled glacier equilibrium line altitudes (ELAs) and climatic conditions during the MH compared with pre-industrial time (PI, year 1750). We focus on the middle latitudes of the Southern Hemisphere, specifically Patagonia and the South Island of New Zealand. Climate conditions for the MH were obtained from PMIP2 model simulations, which in turn were used to force a simple glacier mass balance model to simulate changes in ELA. In Patagonia, the models simulate colder conditions during the MH in austral summer (−0.2 °C), autumn (−0.5 °C), and winter (−0.4), and warmer temperatures (0.2 °C) during spring. In the Southern Alps the models show colder MH conditions in autumn (−0.7 °C) and winter (−0.4 °C), warmer conditions in spring (0.3 °C), and no significant change in summer temperature. Precipitation does not show significant changes but exhibits a seasonal shift, with less precipitation from April to September and more precipitation from October to April during the MH in both regions. The mass balance model simulates a climatic ELA that is 15–33 m lower during the MH compared with PI conditions. We suggest that the main causes of this difference are driven mainly by colder temperatures associated with the MH simulation. Differences in temperature have a dual effect on glacier mass balance: (i) less energy is available for ablation during summer and early autumn and (ii) lower temperatures cause more precipitation to fall as snow rather than rain in late autumn and winter, resulting in more accumulation and higher surface albedo. For these reasons, we postulate that the modelled ELA changes, although small, may help to explain larger glacier extents observed by 6000 years BP in South America and New Zealand.

Modelled glacier equilibrium line altitudes during the mid-Holocene in the southern mid-latitudes

Abstract Glacier mass balance is more sensitive to warming than cooling, but feedbacks related to the exposure of previously buried firn and ice in very warm years is not generally considered in sensitivity studies. A ground‐penetrating radar survey in the accumulation area of Rolleston Glacier, New Zealand shows that five years of previous net accumulation was removed by melt from parts of the glacier above the long‐term equilibrium line altitude during a single negative mass balance year. Rolleston Glacier receives a large amount of accumulation from snow avalanches, which may temporarily buffer it from climate warming by providing additional mass that has accumulated at higher elevations, effectively increasing the elevation range of the glacier. However, glaciers reliant on avalanche input may have high sensitivity to climatic variations because the extra mass is concentrated on a small part of the glacier, and small variations in avalanche input could have a large impact on overall glacier accumulation. Further research is needed to better estimate the amount and spatial distribution of accumulation by avalanche in order to quantify the climate sensitivity of small avalanche‐fed glaciers.

The impact of extreme summer melt on net accumulation of an avalanche fed glacier, as determined by ground‐penetrating radar

Glacier velocity variability due to rain-induced sliding and cavity formation

Observations show that glaciers around the world are in retreat and losing mass. Internationally coordinated for over a century, glacier monitoring activities provide an unprecedented dataset of glacier observations from ground, air and space. Glacier studies generally select specific parts of these datasets to obtain optimal assessments of the mass-balance data relating to the impact that glaciers exercise on global sea-level fluctuations or on regional runoff. In this study we provide an overview and analysis of the main observational datasets compiled by the World Glacier Monitoring Service (WGMS). The dataset on glacier front variations (�42000 since 1600) delivers clear evidence that centennial glacier retreat is a global phenomenon. Intermittent readvance periods at regional and decadal scale are normally restricted to a subsample of glaciers and have not come close to achieving the maximum positions of the Little Ice Age (or Holocene). Glaciological and geodetic observations (�5200since 1850) show that the rates of early 21st-century mass loss are without precedent on a global scale, at least for the time period observed and probably also for recorded history, as indicated also in reconstructions from written and illustrated documents. This strong imbalance implies that glaciers in many regions will very likely suffer further ice loss, even if climate remains stable.

Historically unprecedented global glacier decline in the early 21st century

Abstract Ka Roimata o Hine Hukatere (Franz Josef Glacier) is a fast-flowing maritime glacier and its climatological and hydrological drivers are different from those of many previously studied alpine glaciers. The glacier tongue has recently advanced as well as retreated, remains largely snow free, has significant volumes of melt and rainwater inputs throughout the year, and experiences small radiation and air temperature fluctuations over diurnal to seasonal time scales. We discuss measurements of surface velocity made between 2000 and 2012 at annual, seasonal, weekly, and daily time scales together with measurements of glacier geometry change, and calculations of surface water inputs and subglacial water pressure variations derived from a distributed surface mass balance model and a one-dimensional conduit hydrology model, respectively. Annual velocity variations are linked to changes in glacier geometry and advance/retreat cycles with accelerations during thickening and advance and decelerations during thinning and retreat. At seasonal, weekly and daily time scales, velocities are correlated with water input variations and with rates of water pressure fluctuation rather than absolute magnitudes of water pressure.

Annual to Daily Ice Velocity and Water Pressure Variations on Ka Roimata o Hine Hukatere (Franz Josef Glacier), New Zealand

Franz Josef and Fox Glaciers, New Zealand: Historic length records

Evaluation of Lateglacial temperatures in the Southern Alps of New Zealand based on glacier modelling at Irishman Stream, Ben Ohau Range

The influence of sub-glacial bed evolution on ice extent: a model-based evaluation of the Last Glacial Maximum Pukaki glacier, New Zealand

Glacier speed-up events and water inputs on the lower Franz Josef Glacier, New Zealand

[1] The “mass balance sensitivity” of a glacier provides a means for assessing its response to future warming and contribution to sea level rise. Many studies have concluded that the first-order control on mass balance sensitivity is climatic, where higher-precipitation (and less continental) glaciers are most sensitive while lower-precipitation (and more continental) glaciers are least sensitive. The Southern Alps in New Zealand experience a limited range of continentality (9–13 K) but strong gradients in precipitation (2.5–11 m a−1). Using an energy balance model applied on a regional scale we find that the central Southern Alps glaciers are very sensitive to temperature change (1.9 m w.e. a−1 K−1, with a range of −1.1 to −4.0 m w.e. a−1 K−1) and that an 82% increase in precipitation is required to offset a 1 K warming. Spatial variations in mass balance sensitivity cannot be simply explained as a function of precipitation. Topographic effects are important, and we find that debris cover reduces mass balance sensitivity. Mass balance amplitude, which takes into account debris cover, hypsometry and other topographic characteristics, is a better predictor of mass balance sensitivity than precipitation. The mass balance gradient is almost as good a predictor indicating that hypsometry is not a necessary component of sensitivity calculations. Estimating mass balance sensitivity as a function of mass balance gradient allows for parameterizations of mass balance sensitivity based on glacier inventory data. This provides a simple and robust way to assess glacier mass balance sensitivity on a global scale, which may refine future predictions of valley glacier melt and its contribution to sea level rise.

Controls on mass balance sensitivity of maritime glaciers in the Southern Alps, New Zealand: The role of debris cover

Last Glacial Maximum climate in New Zealand inferred from a modelled Southern Alps icefield

Sensitivity of turbulent fluxes to wind speed over snow surfaces in different climatic settings

Net accumulation measurements from two glaciers located on opposite sides of the New Zealand Southern Alps were used to explore processes controlling spatial variability. The degree of variability, as measured by the spatial variogram, differed in each of the three successive years, but the lowest variance occurred on both glaciers in March 2008, after a hot and dry summer. Strong relationships between net accumulation and elevation within the accumulation area were only found on Franz Josef Glacier (FJG), despite this being the primary control used in glacier mass balance modelling. Interaction between wind and topography was found to be important to the distribution of net accumulation on both glaciers. The crevasse stratigraphy method is an ideal way to gain good spatial coverage of net accumulation, and particularly suited to glaciers with high annual precipitation. Copyright © 2010 John Wiley & Sons, Ltd.

Controls on spatial variability in snow accumulation on glaciers in the Southern Alps, New Zealand; as revealed by crevasse stratigraphy

Interannual variability in net accumulation on Tasman Glacier and its relationship with climate

Abstract Understanding relationships between snow accumulation and synoptic climatology is important for assessing the way in which future climate variability will impact on glacier mass balance. However, few studies have as yet examined these relationships. Variability in snow accumulation on mid-latitude glaciers is strongly influenced by atmospheric circulation, orography, and redistribution of snow by wind. Very little is known about these processes in the New Zealand Southern Alps, where it is assumed that west-facing glaciers receive higher snow totals. However, few measurements are available to test this hypothesis. These processes were investigated over a 21-day period in winter 2008 on glaciers located west (Franz Josef Glacier) and east (Tasman Glacier) of the Main Divide of the Southern Alps. We directly measured snow accumulation and considered how it was affected by synoptic weather regime and location with respect to the Main Divide. Both glaciers received ∼75% of their snowfall during troughing regimes, which are characterized by strong westerly quadrant winds bringing humid air masses from the Tasman Sea over the Southern Alps. The Franz Josef Glacier site received ∼30% more snow than the Tasman Glacier site, but wind deflation meant that by the end of the study period, net snow accumulation was similar at both sites. Blocking synoptic regimes resulted in a reversal of prevailing westerly flow, generating strong downslope winds at Franz Josef Glacier and snow loss.

Synoptic Influences on Snow Accumulation on Glaciers East and West of a Topographic Divide: Southern Alps, New Zealand

This paper evaluates the use of field data on the spatial variability of snow water equivalent (SWE) to guide the design of distributed snow models. An extensive reanalysis of results from previous field studies in different snow environments around the world is presented, followed by an analysis of field data on spatial variability of snow collected in the headwaters of the Jollie River basin, a rugged mountain catchment in the Southern Alps of New Zealand. In addition, area‐averaged simulations of SWE based on different types of spatial discretization are evaluated. Spatial variability of SWE is shaped by a range of different processes that occur across a hierarchy of spatial scales. Spatial variability at the watershed‐scale is shaped by variability in near‐surface meteorological fields (e.g., elevation gradients in temperature) and, provided suitable meteorological data is available, can be explicitly resolved by spatial interpolation/extrapolation. On the other hand, spatial variability of SWE at the hillslope‐scale is governed by processes such as drifting, sloughing of snow off steep slopes, trapping of snow by shrubs, and the nonuniform unloading of snow by the forest canopy, which are more difficult to resolve explicitly. Subgrid probability distributions are often capable of representing the aggregate‐impact of unresolved processes at the hillslope‐scale, though they may not adequately capture the effects of elevation gradients. While the best modeling strategy is case‐specific, the analysis in this paper provides guidance on both the suitability of several common snow modeling approaches and on the choice of parameter values in subgrid probability distributions.

Representing spatial variability of snow water equivalent in hydrologic and land‐surface models: A review

Abstract Coverage of ice velocities in the central part of the Southern Alps, New Zealand, is obtained from feature tracking using repeat optical imagery in 2002 and 2006. Precise orthorectification, co-registration and correlation is carried out using the freely available software COSI-Corr. This analysis, combined with short times between image acquisitions, has enabled velocities to be captured even in the accumulation areas, where velocities are lowest and surface features ephemeral. The results indicate large velocities for mountain glaciers (i.e. up to ∼5 m d−1) as well as dynamic changes in some glaciers that have occurred between 2002 and 2006. For the steep and more responsive Fox and Franz Josef Glaciers the speed increased at the glacier snout during the advance period, while the low-angled and debris-covered Tasman Glacier showed no measurable velocity change. Velocity increases on the steeper glaciers are the result of an observed thickening and steepening of the glacier tongues as they moved from a retreat phase in 2002 to an advance phase in 2006. This contrasting behaviour is consistent with historic terminus position changes. The steeper glaciers have undergone several advance/retreat cycles during the observation period (1894 to present), while the low-angled glacier showed little terminus response until retreat resulting from the accelerating growth of a proglacial lake commenced in 1983.

Mountain glacier velocity variation during a retreat/advance cycle quantified using sub-pixel analysis of ASTER images

Abstract The sensitivity of glaciers to climatic change is key information in assessing the response and sea-level implications of projected future warming. New Zealand glaciers are important globally as an example of how maritime glaciers will contribute to sea-level rise. A spatially distributed energy-balance model is applied to Brewster Glacier, New Zealand, in order to calculate glacier mass balance, run-off and sensitivity to climate change. The model successfully simulates four annual mass-balance cycles. Close to half (52%) of the energy available for melt on the glacier is supplied by turbulent heat fluxes, with radiation less important, except during the winter. Model sensitivity to temperature change is one of the largest reported on Earth, at −2.0 m w.e. a−1 °C−1. In contrast, a 50% change in precipitation is required to offset the mass-balance change resulting from a 1 °C temperature change. Meltwater runoff sensitivity is also very high, increasing 60% with a 1°C warming. The extreme sensitivity of mass balance to temperature change suggests that significant ice loss will occur with even moderate climate warming.

Climate sensitivity of a high-precipitation glacier in New Zealand

BACKGROUND ANDRILL and earlier (Cape Roberts, CIROS 1 and 2) coring in the Ross Sea region of Antarctica (Barrett, 2009, Naish et al 2002, 2009), and associated ice sheet modelling (DeConto and Pollard 2003, Pollard and DeConto, 2009) have demonstrated East and West Antarctic ice sheet variability on orbital timescales since ice sheet inception at the Eocene/Oligocene boundary at around 35 Ma. Of direct societal relevance, interpretation of the ANDRILL 1B core suggests that repeated collapses of the West Antarctic Ice Sheet (WAIS) have occurred in the last 5 Ma, in both the Pliocene and during Pleistocene ‘super’ interglacials when temperatures and CO2 levels were slightly higher than today (Naish et al. 2009, Pollard and DeConto 2009). In apparent conflict with these findings, moraine dating, survival of extreme polar desert landforms, ancient buried ice, and extinction of local temperate biota in the adjacent Dry Valleys region indicate stability of the East Antarctic Ice Sheet since the mid Miocene (the last 13 ma) (Sugden et al. 1995, Sugden and Denton 2004, Lewis et al. 2008). At present, it is not possible to discriminate between these seemingly divergent hypotheses, nor assess whether they are compatible, because the interpretation of geological evidence (both cores and onshore geomorphology) involve substantial extrapolation in both space and time, and ice sheet modelling lacks the appropriate spatial resolution for direct comparison to field evidence. As a consequence of these and other uncertainties, numerical modelling and empirical reconstructions differ vastly in their interpretation of the former ice volumes which resulted from temperatures slightly warmer than today (c.f. Hill et al., 2007; Pollard & DeConto, 2009). The extent to which East Antarctic Ice Sheet (EAIS) outlet glaciers changed during such ice-sheet reconfiguration(s) is central to this uncertainty (Sugden 1996; Hall et al., 1997; Sugden & Denton 2004), and remains keenly debated, with evidence from the Dry Valleys region suggesting minor Pliocene ice advances (Marchant et al. 1993), whereas temperate glacier deposits of presumed but disputed Pliocene age (McKay 2008) adjacent to the Beardmore and Shackleton Glaciers at >80oS, may indicate conditions substantially warmer than present (Mercer 1972, Hambrey et al. 2003).

Response of Franz Josef Glacier Ka Roimata o Hine Hukatere to climate change

Despite their relatively small total ice volume, mid-latitude valley glaciers are expected to make a significant contribution to global sea-level rise over the next century due to the sensitivity of their mass-balance systems to small changes in climate. Here we use a degree-day model to reconstruct the past century of mass-balance variation at ‘Ka Roimata o Hine Hukatere’ Franz Josef Glacier, New Zealand, and to predict how mass balance may change over the next century. Analysis of the relationship between temperature, precipitation and mass balance indicates that temperature is a stronger control than precipitation on the mass balance of Franz Josef Glacier. The glacier’s mass balance, relative to its 1986 geometry, has decreased at a mean annual rate of 0.02maw.e. between 1894 and 2005. We compare this reduction to observations of terminus advance and retreat, of which Franz Josef Glacier has the best record in the Southern Hemisphere. For the years 2000–05 the relative mass balance ranged from –0.75 to +1.50maw.e., with 2000/01 the only year showing a negative mass balance. In a regionally downscaled Intergovernmental Panel on Climate Change mean warming scenario, the annual relative mass balance will continue to decrease at 0.02maw.e. through the next century.

Advance and retreat of temperate glaciers is largely controlled by changes in temperature and precipitation, but the relative importance of these drivers is debated. Numerical modeling of a New Zealand glacier reveals that temperature is the dominant control on glacier length. We find that a glacial advance, dated to ca. 13,000 yr B.P., requires a cooling event of 3–4 °C. This mid-latitude Southern Hemisphere cooling is similar in magnitude to the Antarctic Cold Reversal in the Vostok ice core record and likely to be a response to the same climate signal.

Temperature change is the major driver of late-glacial and Holocene glacier fluctuations in New Zealand

Despite their relatively small total ice volume, mid-latitude valley glaciers are expected to make a significant contribution to global sea-level rise over the next century due to the sensitivity of their mass-balance systems to small changes in climate. Here we use a degree-day model to reconstruct the past century of mass-balance variation at 'Ka Roimata o Hine Hukatere' Franz Josef Glacier, New Zealand, and to predict how mass balance may change over the next century. Analysis of the relationship between temperature, precipitation and mass balance indicates that temperature is a stronger control than precipitation on the mass balance of Franz Josef Glacier. The glacier's mass balance, relative to its 1986 geometry, has decreased at a mean annual rate of 0.02 m a -1 w.e. between 1894 and 2005. We compare this reduction to observations of terminus advance and retreat, of which Franz Josef Glacier has the best record in the Southern Hemisphere. For the years 2000-05 the relative mass balance ranged from -0.75 to +1.50 m a -1 w.e., with 2000/01 the only year showing a negative mass balance. In a regionally downscaled Intergovernmental Panel on Climate Change mean warming scenario, the annual relative mass balance will continue to decrease at 0.02 m a -1 w.e. through the next century.

Past and future mass balance of ‘Ka Roimata o Hine Hukatere’ Franz Josef Glacier, New Zealand

Abstract During February and March 2003, a series of unusual events involving supraglacial flooding and ice collapse affected an area of Franz Josef Glacier, South Westland, New Zealand. This paper describes these events and examines rainfall and river stage data in order to explain their occurrence. Relationships between rainfall events, supraglacial flooding, and stage of the Waiho River suggest that subglacial water was rerouted to a supraglacial position, most likely resulting from blockage of the subglacial route by ice collapse near the base of the main icefall on the lower part of the glacier. Review of previous literature reveals that a variety of flood and ice collapse events are frequent at Franz Josef Glacier. While this is only one of several natural hazards in the Franz Josef area, it is of considerable importance because of the large number and significant duration of tourist visits to the terminus and onto the lower part of the glacier.

Outburst flooding at Franz Josef Glacier, South Westland, New Zealand

Abstract Ice-penetrating radar and modelling data are presented suggesting the presence of a zone of temperate ice, water ponding or saturated sediment beneath the tongue of Taylor Glacier, Dry Valleys, Antarctica. The proposed subglacial zone lies 3–6 km up-glacier of the terminus and is 400– 1000m across. The zone coincides with an extensive topographic overdeepening to 80m below sea level. High values of residual bed reflective power across this zone compared to other regions and the margins of the glacier require a high dielectric contrast between the ice and the bed and are strongly indicative of the presence of basal water or saturated sediment. Analysis of the hydraulic equipotential surface also indicates strong convergence into this zone of subglacial water flow paths. However, thermodynamic modelling reveals that basal temperatures in this region could not exceed –7˚C relative to the pressure-melting point. Such a result is at odds with the radar observations unless the subglacial water is a hypersaline brine.

Evidence for subglacial ponding across Taylor Glacier, Dry Valleys, Antarctica

A modelling study of the response of Hatherton Glacier to Ross Ice Sheet grounding line retreat

Supraglacial routing of subglacial water at Franz Josef Glacier, South Westland, New Zealand

Measurement and modelling of the variable deformation of contrasting ice facies

I. Glacial-Marine Sediment in Space and Time.- Ancient Glacial-Marine Deposits: Their Spatial and Temporal Distribution.- II. Quaternary Glacial-Marine Sedimentation.- Alaska.- Subarctic Glacial-Marine Sedimentation: A Model.- Geotechnical Analyses of Submarine Landslides in Glacial-Marine Sediment, Northeast Gulf of Alaska.- Glacial-Marine Sedimentation Processes and Lithofacies of Temperate Tidewater Glaciers, Glacier Bay Alaska.- Antarctica.- Development of a Polar Glacial-Marine Sedimentation Model from Antarctic Quaternary Deposits and Glaciological Information.- Distribution and Association of Sediment Gravity Flow Deposits and Glacial/Glacial-Marine Sediments Around the Continental Margin of Antarctica.- Arctic Ocean.- Central Arctic Ocean Sediment Texture: A Key to Ice Transport Mechanisms.- A Late Cenozoic Stratigraphy for Glacial-Marine Sediments of The Eastern Alpha Cordillera, Central Arctic Ocean.- Stratigraphy and Sedimentology of Ice-Rafted and Turbidite Sediment, Canada Basin, Arctic Ocean.- Kane Basin.- Glacial and Glacial-Marine Sediment Lithofacies of the Kane Basin.- Baffin Island.- Changes in Glacial-Marine Sedimentation in Core HU77-159, Frobisher Bay, Baffin Island, N.W.T.: A Record of Proximal, Distal, and Ice-Rafting Glacial-Marine Environments.- A Facies Model of Quaternary Glacial-Marine Cyclic Sedimentation Along Eastern Baffin Island, Canada.- Puget Lowlands.- Facies of Late Pleistocene Glacial-Marine Sediments on Whidbey Island, Washington: An Isostatic Glacial-Marine Sequence.- Paleoecology of Late Pleistocene Glacial-Marine Sediments in Northwestern Washington and Southwestern British Columbia.- North Atlantic Ocean.- Distal Glacial-Marine Sedimentation: Abundance, Composition, and Distribution of North Atlantic Ocean Pleistocene Ice-Rafted Sediment.- III. Older Glacial-Marine Sedimentation.- Neogene.- Glacial Lithofacies of the Neogene Yakataga Formation, Robinson Mountains, Southern Alaska Coast Range, Alaska.- Paleozoic.- Glacial-Marine Sedimentation in the Late Paleozoic Karoo Basin, Southern Africa.- Precambrian.- Glacial-Marine and Subglacial Sedimentation, Upper Proterozoic Mineral Fork Formation, Utah.- List of Contributors.- Author Index.- Geographic Index.

European heritage breeds, such as the Blonde (B), Red (R), and Swallow-bellied (SB) Mangalica pig, display an extreme propensity to fatten and are reputed to produce superior quality pork. This suggests that Mangalica pork should command a higher price, and the Mangalica is a candidate breed to target niche markets within the United States. Our objectives were to test this hypothesis by (1) directly comparing growth performance and carcass merit of purebred Yorkshire (Y), B, R, and SB Mangalica pigs to identify the best breed for adoption, and (2) comparing indices of pork quality in purebred R, Y, and crossbred (R × Y) pigs to determine if crossbreeding represented a viable alternative to the adoption of purebred Mangalica. Daily feed intake, average daily gain (ADG), and feed efficiency were highest in Y and lowest in SB pigs with B and R ranked intermediately (p < 0.001). Backfat thickness was greatest in B and lowest in Y with R and SB ranked intermediately (p < 0.001). Marbling score was greatest in R pigs and lowest in Y pigs with B and SB ranked intermediately (p < 0.01). In contrast, loin eye area (LEA) was greatest in Y pigs compared to B, R, and SB (p < 0.001). Indices of meat quality were then compared in R, R × Y, and Y pigs. Backfat thickness and marbling scores were greater in R than R × Y and Y pigs (p < 0.001) while LEA was greater in Y than R × Y and R pigs (p < 0.001). Loin and ham ultimate pH, color, and firmness scores were significantly greater in R than R × Y or Y pigs (p < 0.05). Meanwhile, cook loss was significantly less in R than Y pigs (p < 0.007) while Warner-Bratzler Shear Force (WBS) was not different in chops between groups (p < 0.11). These data indicate that though Mangalica exhibit poorer growth performance, Mangalica pork exhibits superior pork quality attributes, suggesting that higher price points for Mangalica pork in niche markets are justified.

Characterization of Growth Performance, Pork Quality, and Body Composition in Mangalica Pigs

A randomized complete block design experiment was conducted to determine the safety and efficacy of supplementation of increasing concentrations of a novel, bacterial fermentation-derived vitamin D source on growth performance and tissue deposition of 25-hydroxycholecalciferol (25OHD3) in growing swine. Dietary treatments were as follows: commercial control with vitamin D3 (CON) at NRC recommended concentrations and 3 diets composed of CON + increasing inclusions (25, 50, and 250 µg/kg equivalent) of 25OHD3 from a novel source (CON+25; CON+50; and CON+250 respectively). Pigs (n = 144) were assigned to 24 pens which were allotted to 1 of the 4 dietary treatments and fed for 42 d. Blood samples were collected for 25OHD3 concentration determination and individual body weights were measured on experimental d 0, 39, and 63. On d 42, tissues from 48 pigs (12 pigs per dietary treatment) were analyzed for 25OHD3 concentration. No differences were observed in growth performance. Day 39 serum 25OHD3 concentrations were greatest in CON+250-fed pigs and linearly decreased as dietary 25OHD3 inclusion decreased (P < 0.0001). On d 42, tissue 25OHD3 concentrations increased linearly as 25OHD3 increased in the diet (P < 0.0001). On d 63, 21 d after dietary 25OHD3 withdrawal, serum 25OHD3 concentrations of all 25OHD3-fed pigs decreased to that of or within 2.76 ± 0.89 ng/mL of CON-fed pigs which demonstrates that feeding 250 µg/kg 25OHD3 is well tolerated by growing pigs and will clear the body within 21 d.

Efficacy and safety of a novel source of dietary 25-hydroxycholecalciferol in growing pigs.

Multimodal intravital microscopy and PET imaging of S. aureus endocarditis can monitor adjuvant immunotherapy in mice and pigs. Imaging infection Infection of the lining of the heart and valves (endocarditis) can be difficult to treat, and proper identification of the causal pathogen is very important. Panizzi et al. developed small-molecule imaging agents based on dabigatran, a thrombin inhibitor, to visualize Staphylococcus aureus endocarditis. Positron emission tomography and intravital microscopy using the imaging agents revealed that treatment with neutralizing antibodies reduced thrombin deposition and impeded S. aureus endocarditis growth in mice. The imaging agents could also be used to visualize infections in piglets. These imaging tools could help monitor disease progression and response to treatment. Acute bacterial endocarditis is a rapid, difficult to manage, and frequently lethal disease. Potent antibiotics often cannot efficiently kill Staphylococcus aureus that colonizes the heart’s valves. S. aureus relies on virulence factors to evade therapeutics and the host’s immune response, usurping the host’s clotting system by activating circulating prothrombin with staphylocoagulase and von Willebrand factor–binding protein. An insoluble fibrin barrier then forms around the bacterial colony, shielding the pathogen from immune cell clearance. Targeting virulence factors may provide previously unidentified avenues to better diagnose and treat endocarditis. To tap into this unused therapeutic opportunity, we codeveloped therapeutics and multimodal molecular imaging to probe the host-pathogen interface. We introduced and validated a family of small-molecule optical and positron emission tomography (PET) reporters targeting active thrombin in the fibrin-rich environment of bacterial colonies. The imaging agents, based on the clinical thrombin inhibitor dabigatran, are bound to heart valve vegetations in mice. Using optical imaging, we monitored therapy with antibodies neutralizing staphylocoagulase and von Willebrand factor–binding protein in mice with S. aureus endocarditis. This treatment deactivated bacterial defenses against innate immune cells, decreased in vivo imaging signal, and improved survival. Aortic or tricuspid S. aureus endocarditis in piglets was also successfully imaged with clinical PET/magnetic resonance imaging. Our data map a route toward adjuvant immunotherapy for endocarditis and provide efficient tools to monitor this drug class for infectious diseases.

Multimodal imaging of bacterial-host interface in mice and piglets with Staphylococcus aureus endocarditis

Chlamydia suis is an important, highly prevalent, and diverse obligate intracellular pathogen infecting pigs. In order to investigate the prevalence and diversity of C. suis in the U.S., 276 whole blood samples from feral swine were collected as well as 109 fecal swabs and 60 whole blood samples from domestic pigs. C. suis-specific peptide ELISA identified anti-C. suis antibodies in 13.0% of the blood of feral swine (26/276) and 80.0% of the domestic pigs (48/60). FRET-qPCR and DNA sequencing found C. suis DNA in 99.1% of the fecal swabs (108/109) and 21.7% of the whole blood (13/60) of the domestic pigs, but not in any of the assayed blood samples (0/267) in feral swine. Phylogenetic comparison of partial C. suis ompA gene sequences and C. suis-specific multilocus sequencing typing (MLST) revealed significant genetic diversity of the C. suis identified in this study. Highly genetically diverse C. suis strains are prevalent in domestic pigs in the USA. As crowding strongly enhances the frequency and intensity of highly prevalent Chlamydia infections in animals, less population density in feral swine than in domestic pigs may explain the significantly lower C. suis prevalence in feral swine. A future study is warranted to obtain C. suis DNA from feral swine to perform genetic diversity of C. suis between commercial and feral pigs.

Peptide ELISA and FRET-qPCR Identified a Significantly Higher Prevalence of Chlamydia suis in Domestic Pigs Than in Feral Swine from the State of Alabama, USA

We investigate experimentally the nonlocal phase modulation of multiple-frequency-mode, continuous-variable entangled twin beams. We use a pair of electro-optical phase modulators to modulate the entangled probe and conjugate light beams produced by four-wave mixing in hot Rb vapor. A single phase modulator in either one of the twin beams reduces the two-mode squeezing signal, and we find that the modulations interfere nonlocally to modify the beam correlations. The nonlocal modulation of the beams can produce quantum correlations among frequency modes of the multimode fields.

Nonlocal phase modulation of multimode, continuous-variable twin beams

We experimentally investigate the nonlocal phase modulation of multi-frequency-mode twin beams via a fourwave mixing process. Two separated phase modulators interfere nonlocally to modify the beam correlations, resulting in various covariance matrices.

Nonlocal phase modulation of multi-frequency-mode twin beams: toward networked quantum computing and sensing

We experimentally investigate the nonlocal phase modulation of spatially separate continuous-variable twin beams via a four-wave mixing process. Two separated phase modulators interfere nonlocally to modify the beam correlations, resulting in the various covariance matrices.

Phase conjugation is a unique phenomenon that readily mimics Stokes’s principle of time reversal. We report, for the first time, experimental observations of the formation of Kerr solitons in a phase-conjugate resonator.

Kerr soliton formation in nondegenerate phase-conjugate resonators

Dissipative Kerr solitons generated by four-wave mixing in hot rubidium atoms within a phase conjugate resonator are presented. The solitons are tunable with pump detuning and laser power and exhibit Turing rolls and dark-soliton formation.

Homodyne detection is often used for interferometers based on nonlinear optical gain media. For the configuration of a seeded, "truncated SU(1,1)" interferometer Anderson, et al. [ Phys. Rev. A95, 063843 (2017)] showed how to optimize the homodyne detection scheme and demonstrated theoretically that it can saturate the quantum Cramer-Rao bound for phase estimation. In this work we extend those results by taking into account loss in the truncated SU(1,1) interferometer and determining the optimized homodyne detection scheme for phase measurement. Further, we build a truncated SU(1,1) interferometer and experimentally demonstrate that this optimized scheme achieves a reduction in noise level, corresponding to an enhanced potential phase sensitivity, compared to a typical homodyne detection scheme for a two-mode squeezed state. In doing so, we also demonstrate an improvement in the degree to which we can beat the standard quantum limit with this device.

We demonstrate the ability of a phase-sensitive amplifier (PSA) to pre-amplify a selected quadrature of one mode of a two-mode squeezed state in order to improve the measurement of two-mode quantum correlations that exist before degradation due to optical and detection losses. We use four-wave mixing (4WM) in 85Rb vapor to generate bright beams in a two-mode squeezed state. One of these two modes then passes through a second 4WM interaction in a PSA configuration to noiselessly pre-amplify the desired quadrature of the mode before loss is intentionally introduced. We demonstrate an enhancement in the measured degree of intensity correlation and intensity-difference squeezing between the two modes.

Improved measurement of two-mode quantum correlations using a phase-sensitive amplifier.

Supplement 1: Phase sensing beyond the standard quantum limit with a variation on the SU(1,1) interferometer

Absolute Calibration of Analog Photodiodes with Correlated Twin Beams from Four-wave Mixing

Submitted for the DAMOP17 Meeting of The American Physical Society Improvement of Two-Mode Squeezing in the Presence of Loss with a Phase-Sensitive Amplifer TIAN LI, BRIAN ANDERSON, BONNIE SCHMITTBERGER, TRAVIS HORROM, Joint Quantum Institute, NIST and Univ. of Maryland, KEVIN JONES, Department of Physics, Williams College, PAUL LETT, Joint Quantum Institute, NIST and Univ. of Maryland and Quantum Measurement Division, National Institute of Standards and Technology — We demonstrate a phase-sensitive amplifier (PSA) to pre-amplify quantum correlations in twin light beams before degradation due to loss and detector efficiency. We use four-wave mixing (4WM) in Rb vapor to generate bright beams in a two-mode squeezed state. After which, a second 4WM interaction in a PSA configuration amplifies one half of the two-mode state before a loss is intentionally introduced. It is well known that, in the case of a PSA, no extra noise will be added given the correct relative phases (e.g. at the maximal amplification and the maximal deamplification) among the inputs. We thus lock our PSA phase at the phase where we are able to have the maximal, noiseless, amplification of one half of the two-mode squeezed state and compare with its twin beam. Due to this noiseless pre-amplification, we demonstrate that phase-sensitive amplification placed before losses can improve correlations between the beams, or squeezing. Tian Li Joint Quantum Institute, NIST and Univ. of Maryland Date submitted: 27 Jan 2017 Electronic form version 1.4

Improvement of Two-Mode Squeezing in the Presence of Loss with a Phase-Sensitive Amplifer

We present an SU(1,1) interferometer variation by replacing the second nonlinear interaction with the homodyne detection and demonstrate an improvement in phase sensitivity over the standard quantum limit.

A novel variation on the SU(1,1) interferometer for phase sensing beyond the standard quantum limit

The SU(1,1) interferometer can be thought of as a Mach-Zehnder interferometer with its linear beamsplitters replaced with parametric nonlinear optical processes. We consider the cases of bright and vacuum-seeded SU(1,1) interferometers using intensity or homodyne detectors. A simplified, truncated scheme with only one nonlinear interaction is introduced, which not only beats conventional intensity detection with a bright seed, but can saturate the phase sensitivity bound set by the quantum Fisher information. We also show that the truncated scheme achieves a sub-shot-noise phase sensitivity in the vacuum-seeded case, despite the phase-sensing optical beams having no well-defined phase.

Optimal phase measurements with bright- and vacuum-seeded SU(1,1) interferometers

Improving the Detection of Squeezed Light in the Presence of Loss

We present an SU(1,1) interferometer variation where the second nonlinear interaction is replaced with homodyne detection. Sensitivity measurements as a function of phase demonstrate that our device beats the standard quantum limit by 4dB.

Phase sensing beyond standard quantum limit with a truncated SU(1,1) interferometer

Nonlinear optical SU(1,1) interferometer using four-wave mixing in Rb

Many optical applications depend on amplitude modulating optical beams using devices such as acousto-optical modulators (AOMs) or optical choppers. Methods to add amplitude modulation (AM) often inadvertently impart phase modulation (PM) onto the light as well. While this PM is of no consequence to many phase-insensitive applications, phase-sensitive processes can be affected. Here we study the effects of input phase and amplitude modulation on the output of a quantum-noise limited phase-sensitive optical amplifier (PSA) realized in hot 85Rb vapor. We investigate the dependence of PM on AOM alignment and demonstrate a novel approach to quantifying PM by using the PSA as a diagnostic tool. We then use this method to measure the alignment-dependent PM of an optical chopper which arises due to diffraction effects as the chopper blade passes through the optical beam.

Effect of input phase modulation to a phase-sensitive optical amplifier.

Submitted for the DAMOP16 Meeting of The American Physical Society Toward perfect homodyne detection of twin vacuum beams TIAN LI, TRAVIS HORROM, BRIAN ANDERSON, Joint Quantum Institute, National Institute of Standards and Technology and the University of Maryland, College Park, MD 20742, USA, PAUL LETT, Quantum Measurement Division, National Institute of Standards and Technology and Joint Quantum Institute, NIST and UMD, Gaithersburg, MD 20899, USA — We demonstrate the use of an optical phase-sensitive amplifier to recover the quantum correlations in twin light beams after degradation due to optical loss and detector efficiency. We use four-wave mixing in hot 85Rb vapor cell to generate correlated twin beams in a two-mode squeezed vacuum state. We then use a second four-wave mixing cell as our optical phasesensitive amplifier to amplify one half of the two-mode state, which can compensate for downstream optical loss and restore the nonclassical correlations of the state. Tian Li Joint Quantum Institute, National Institute of Standards and Technology and the University of Maryland, College Park, MD 20742, USA Date submitted: 29 Jan 2016 Electronic form version 1.4

Quantum-enhanced precision measurements have emerged as one of the most useful applications of quantum optics. Exploiting quantum states of light and quantum processes, classical measurement limits can be surpassed, leading to improvements in areas including clocks, spectroscopy, magnetometry, and imaging. One measurement where straightforward quantum enhancements are possible is phase sensing with an interferometer. One can inject squeezed vacuum states into the dark port of the beamsplitter in a traditional interferometer to reduce the quantum noise and reach phase sensitivities beyond the shot noise limit. An alternate approach is to replace the beamsplitters of an interferometer with nonlinear parametric amplifiers, which produce nonclassical states of light that can be used to surpass classical performance. This so called SU(1,1) interferometer can theoretically approach sensitivities that scale as 1/n, the Heisenberg limit where n is the interior phase sensing photon number, compared to the shot noise limit of 1/ √ n for a traditional interferometer [1]. I will present our group’s experimental progress in testing a Mach-Zender SU(1,1) interferometer using four-wave mixers (4WMs) in hot Rb atoms as the parametric beamsplitters. The 4WM process generates entangled twin beams which serve as the two arms of the interferometer, and are then recombined in a second 4WM cell, resulting in a phase-sensitive output. We will extend the work done on this interferometer [2, 3] by performing a detailed analysis of the output signal to noise through homodyne measurements, and will attempt to observe the better-than-shot-noise scaling of the sensitivity. We will also consider the various difficulties of this optical interferometer such as the susceptibility to loss and imperfect mode-matching within the interferometer. Our group is also considering an analogous SU(1,1) interferometer in a cold atom system. Collisions in a spinor Bose-Einstein condensate of sodium atoms give rise to a 4WM process that produces spin states of the atoms which are entangled in atom number. These interactions can be controlled to set up an SU(1,1) atom interferometer, where the relevant measurements are now atomic population differences rather than photon intensities. These enhancements can lead to drastic improvements in atomic spin interferometry [3, 4].

Precision phase measurements with an SU(1,1) interferometer using 4-wave mixing in hot Rb85 vapors

Quantum correlations of an entangled state propagating through a phase-sensitive amplifier

Four-wave mixing in atomic vapor allows for the generation of multi-spatial-mode states of light containing many pairs of two-mode entangled vacuum beams. This in principle can be used to send independent secure keys to multiple parties simultaneously using a single light source. In our experiment, we demonstrate this spatial multiplexing of information by selecting three independent pairs of entangled modes and performing continuous-variable measurements to verify the correlations between entangled partners. In this way, we generate three independent pairs of correlated random bit streams that could be used as secure keys. We then demonstrate a classical four-party secret sharing scheme as an example for how this spatially multiplexed source could be used.

Multi-channel entanglement distribution using spatial multiplexing from four-wave mixing in atomic vapor

Unitary transformations are the most general input-output maps available in closed quantum systems. Good control protocols have been developed for qubits, but questions remain about the use of optimal control theory to design unitary maps in high-dimensional Hilbert spaces, and about the feasibility of their robust implementation in the laboratory. Here we design and implement unitary maps in a 16-dimensional Hilbert space associated with the 6S(1/2) ground state of (133)Cs, achieving fidelities >0.98 with built-in robustness to static and dynamic perturbations. Our work has relevance for quantum information processing and provides a template for similar advances on other physical platforms.

Accurate and Robust Unitary Transformations of a High-Dimensional Quantum System.

The emerging field of quantum engineering seeks to design and construct quantum devices for use in technological applications. To do so, one must learn to prepare a physical system in a well defined quantum state, drive it though a specified evolution, and access its final state through measurement. Historically, some of the most successful laboratory platforms with which to explore these challenges have originated in the field of quantum optics. This work reviews some of the recent advances in single- and many atom quantum control at the College of Optical Science, and their integration into a novel atom-light quantum interface.

We implement arbitrary maps between pure states in the 16-dimensional Hilbert space associated with the ground electronic manifold of ^{133}Cs. This is accomplished by driving atoms with phase modulated radio-frequency and microwave fields, using modulation waveforms found via numerical optimization and designed to work robustly in the presence of imperfections. We evaluate the performance of a sample of randomly chosen state maps by randomized benchmarking, obtaining an average fidelity >99%. Our protocol advances state-of-the-art quantum control and has immediate applications in quantum metrology and tomography.

Quantum control in the Cs 6S(1/2) ground manifold using radio-frequency and microwave magnetic fields.

Quantum state tomography by compressed sensing: Fast and robust decoding of a quantum fingerprint

The need to perform quantum state tomography on ever-larger systems has spurred a search for methods that yield good estimates from incomplete data. We study the performance of compressed sensing (CS) and least squares (LS) estimators in a fast protocol based on continuous measurement on an ensemble of cesium atomic spins. They both efficiently reconstruct nearly pure states in the 16-dimensional ground manifold, reaching average fidelities ¯ FCS = 0.92 and ¯ FLS = 0.88 using similar amounts of incomplete data. Surprisingly, the main

Quantum state tomography by continuous measurement and compressed sensing

— Quantum systems with Hilbert space dimension greater than two (qudits) provide an alternative to qubits as carri-ers of quantum information, and may prove advantageous for quantum information tasks if good laboratory tools for qudit manipulation and readout can be developed. We have successfully implemented a protocol for arbitrary quantum state-to-state mapping in the 16 dimensional hyperﬁne ground manifold of Cesium 133 atoms using only DC, rf and microwave magnetic ﬁelds to drive the atomic evolution. Exper-imentally we achieve a state-to-state average mapping ﬁdelity of better than 99%, averaged over a sample of randomly chosen initial and target states. Current work involves designing and implementing unitary transformations. We have successfully used the GRAPE algorithm to design unitary operators that can be implemented with the same experimental framework as state mapping.

State Mapping and Unitary Transformations in the Cesium Hyperfine Ground Manifold

Many experiments involving cold and ultracold atomic gases require very precise control of magnetic fields that couple to and drive the atomic spins. Examples include quantum control of atomic spins, quantum control and quantum simulation in optical lattices, and studies of spinor Bose condensates. This makes accurate cancellation of the (generally time dependent) background magnetic field a critical factor in such experiments. We describe a technique that uses the atomic spins themselves to measure dc and ac components of the background field independently along three orthogonal axes, with a resolution of a few tens of µG in a bandwidth of ∼1 kHz. Once measured, the background field can be cancelled with three pairs of compensating coils driven by arbitrary waveform generators. In our laboratory, the magnetic field environment is sufficiently stable for the procedure to reduce the field along each axis to less than ∼50 µG rms, corresponding to a suppression of the ac part by about one order of magnitude. This suggests that our approach can provide access to a new low-field regime in cold atom experiments.

Three-axis measurement and cancellation of background magnetic fields to less than 50 µG in a cold atom experiment

Submitted for the 4CF11 Meeting of The American Physical Society Quantum State Tomography via Continuous Measurement of Laser Cooled Cesium Atoms AARON SMITH, BRIAN ANDERSON, HECTOR SOSA, POUL JESSEN, University of Arizona, CARLOS RIOFRIO, IVAN DEUTSCH, University of New Mexico — Quantum State Tomography (QST) is the process of reconstructing an unknown quantum state from the outcomes of a sufficiently complete series of measurements. To improve the speed and accuracy of QST, we have developed and implemented a new protocol based on weak continuous measurement and dynamical control. In our experiment, an ensemble of Cs atoms are prepared in identical quantum states within the ground hyperfine manifold, driven by a combination of static, rf and μw magnetic fields, and simultaneously probed by coupling the atomic spin to the polarization of a near-resonant optical probe field. A continuous measurement of the probe polarization yields an informationally complete measurement record that can be inverted to obtain an estimate of the unknown hyperfine state. We have reconstructed the full density matrix for a number of randomly chosen test states, using computer algorithms based either on least squares fitting or compressed sensing. Both approaches perform similarly and reconstruct our test states with an average fidelity around 90%, limited primarily by errors in the applied drive fields. Aaron Smith University of Arizona Date submitted: 16 Sep 2011 Electronic form version 1.4

Quantum State Tomography via Continuous Measurement of Laser Cooled Cesium Atoms

Quantum Control and Measurement in the 133Cs Full Hyperfine Ground Manifold

Quantum state reconstruction of the 16 dimensional hyperfine manifold in cesium via continuous measurement and control

The large-scale expansion dynamics of quantum gases is a central tool for ultra-cold gas experiments and poses a signiﬁcant challenge for theory. In this work we provide an exact reformulation of the Gross-Pitaevskii equation for the ultra-cold Bose gas in a coordinate frame that adaptively scales with the system size during evolution, enabling simulations of long evolution times during expansion or similar large-scale manipulation. Our approach makes no hydrodynamic approximations, is not restricted to a scaling ansatz, harmonic potentials, or energy eigenstates, and can be generalized readily to non-contact interactions via the appropriate stress tensor of the quantum ﬂuid. As applications, we simulate the expansion of the ideal gas, a cigar-shaped condensate in the Thomas-Fermi regime, and a linear superposition of counter propagating Gaussian wavepackets. We recover known scaling for the ideal gas and Thomas-Fermi regimes, and identify a linear regime of aspect-ratio preserving free expansion; analysis of the scaling dynamics equations shows that an exact, aspect-ratio invariant, free expansion does not exist for nonlinear evolution. Our treatment enables exploration of nonlinear eﬀects in matter-wave dynamics over large scale-changing evolution.

We experimentally and numerically demonstrate a method to deterministically generate multiply-quantized superﬂuid circulation about an obstacle in highly oblate Bose-Einstein condensates (BECs). Our method involves spiraling a blue-detuned laser beam, which acts as a repulsive optical potential, around and towards the center of the BEC. This optical potential serves ﬁrst as a repulsive stirrer to initiate superﬂow within the BEC, and then as a pinning potential that transports the center of the superﬂuid circulation to the center of the condensate. By changing the rate at which the beam moves along the spiral trajectory, we selectively control the net circulation introduced into the BEC. We experimentally achieve pinned superﬂow with winding numbers as high as 11, which persists for at least 4 s. At the end of the spiral trajectory, with the pinning beam on at full power, the BEC has a toroidal geometry with a high winding-number persistent current. Alternatively, the beam power can be ramped oﬀ, allowing controlled placement of a cluster of singly-quantized vortices of the same circulation. This technique can serve as a building block in future experimental architectures to create on-demand vortex distributions and superﬂuid circulation in BECs.

Generation of high-winding-number superfluid circulation in Bose-Einstein condensates

We discuss the design of quantum hybrid inertial sensor that combines an optomechanical inertial sensor with the retroreflector of a cold atom interferometer. This sensor fusion approach provides absolute and high-accuracy measurements with cold atom interferometers, while utilizing the optomechanical inertial sensor at frequencies above the repetition rate of the atom interferometer. This improves the overall measurement bandwidth as well as the robustness and field deployment capabilities of these systems. We evaluate which parameters yield an optimal acceleration sensitivity, from which we anticipate a noise floor at nano-g levels from DC to 1 kHz.

In quantum mechanics, the state of a physical system at time t is associated with a symbol such as c placed within half-right-angled brackets: jci. This symbol is called a ket vector or a ket. A symbol within a ket may represent a physical quantity. For instance, if E1 is a possible energy of a particle, then jE1i indicates that the particle is in a state with an energy of precisely E1. Kets may contain multiple symbols that represent multiple physical quantities.

In the present work we examine the statics and dynamics of multiple parallel dark soliton stripes in a two-dimensional Bose-Einstein condensate. Our principal goal is to study the effect of the interaction between the stripes on the transverse instability of the individual stripes. We use a recently developed adiabatic invariant formulation to derive a quasi-analytical prediction for the stripe equilibrium position and for the Bogoliubov-de Gennes spectrum of excitations of stationary stripes. We subsequently test these predictions against numerical simulations of the full two-dimensional Gross-Pitaevskii equation. We find that the number of unstable eigenmodes increases as the number of stripes increases due to (unstable) relative motions between the stripes. Their corresponding growth rates do not significantly change, although for large chemical potentials, the larger the stripe number, the larger the maximal instability growth rate. In addition to examining the cases of three and four stripes, we explore for all of these cases the dynamical implications of the instability towards the formation of multi-vortex patterns.

P. G. Kevrekidis, ∗ Wenlong Wang, † G. Theocharis, D. J. Frantzeskakis, R. Carretero-González, and B. P. Anderson Department of Mathematics and Statistics, University of Massachusetts, Amherst, Massachusetts 01003-4515 USA Department of Theoretical Physics, Royal Institute of Technology, Stockholm, SE-106 91, Sweden Laboratoire d’Acoustique de l’Université du Maine, UMR-CNRS 6613, Av. Olivier Messiaen, Le Mans 72000, France Department of Physics, National and Kapodistrian University of Athens, Panepistimiopolis, Zografos, 15784 Athens, Greece Nonlinear Dynamical Systems Group, Computational Sciences Research Center, and Department of Mathematics and Statistics, San Diego State University, San Diego, California 92182-7720, USA College of Optical Sciences, University of Arizona, Tucson, AZ, 85721, USA.

Expectation Values Consider an ensemble of microscopic systems prepared in the same initial state \(\mid A \rangle\). Suppose a measurement of the observable \(\xi'\) is made on each system. We know that each measurement yields the value \(\xi'\) with probability \(P(\xi')\). What is the mean value of the measurement? This quantity, which is generally referred to as the expectation value of \(\xi'\), is given by \((58)\;\;\;\;\;\ \langle\xi\rangle = \displaystyle \sum^{}_{\xi'} \xi'P(\xi') = \displaystyle \sum^{}_{\xi'} \xi' \mid\langle A\mid\ xi\rangle\mid^{2}\) \( = \displaystyle \sum^{}_{\xi'} \xi' \langle A\mid\xi\rangle\langle \xi'\mid A\rangle = \displaystyle \sum^{}_{\xi'} \xi' \langle A\mid\xi\mid\xi'\rangle\langle \xi'\mid A\rangle\)

A quantum vortex dipole, comprised of a closely bound pair of
vortices of equal strength with opposite circulation, is a spatially
localized travelling excitation of a planar superfluid that carries
linear momentum, suggesting a possible analogy with ray optics. We
investigate numerically and analytically the motion of a quantum vortex
dipole incident upon a step-change in the background superfluid density
of an otherwise uniform two-dimensional Bose-Einstein condensate. Due to
the conservation of fluid momentum and energy, the incident and
refracted angles of the dipole satisfy a relation analogous to Snell’s
law, when crossing the interface between regions of different density.
The predictions of the analogue Snell’s law relation are confirmed for a
wide range of incident angles by systematic numerical simulations of the
Gross-Piteavskii equation. Near the critical angle for total internal
reflection, we identify a regime of anomalous Snell’s law behaviour
where the finite size of the dipole causes transient capture by the
interface. Remarkably, despite the extra complexity of the interface
interaction, the incoming and outgoing dipole paths obey Snell’s
law.

Fe b 20 14 Dynamic and Energetic Stabilization of Persistent Currents in Bose-Einstein Condensates

By modifying the geometry of the optical beam, we control the effective nonlocal interaction length of a nonlocal photon fluid. This allows us to access the superfluid flow regime, which would otherwise be unobservable.

European Research Council under the European Unions Seventh Framework Programme (FP)/ERC [GA 306559]; EPSRC (UK) [EP/J00443X/1]; ERC through the QGBE grant; EU-FET Proactive grant AQuS [640800]; Autonomous Province of Trento, through the SiQuro project ("On Silicon Chip Quantum Optics for Quantum Computing and Secure Communications")

Role of geometry in the superfluid flow of nonlocal photon fluids

We investigate superfluid behavior in a room-temperature photon fluid based on a thermal nonlinearity that mediates the photon-photon interactions. Placing an extended obstacle inside the flowing photon fluid leads to the nucleation of quantised vortices.

Superfluid flow and vortex nucleation in room temperature, nonlocal photon fluids

Stroboscopic \textit{in situ} detection of 2D superfluid dynamics in BECs

Submitted for the DAMOP15 Meeting of The American Physical Society Construction of a new apparatus to study 2D superfluid dynamics in BECs ZACH NEWMAN, JESSICA DOEHRMANN, BRIAN P. ANDERSON, University of Arizona — We are in the process of constructing a new apparatus at the University of Arizona with the intent of studying two-dimensional superfluid dynamics, quantum turbulence, and vortex dynamics in highly oblate Bose-Einstein condensates. The trap geometries used in such experiments enable the application of high resolution imaging methods that permit direct, in situ detection of vortices and wave phenomena in BECs. In this poster, we describe our design of a new apparatus aimed specifically at studying 2D superfluid phenomena, discuss technical challenges, and present progress towards the completion of our new apparatus. Zach Newman University of Arizona Date submitted: 28 Jan 2015 Electronic form version 1.4

Construction of a new apparatus to study 2D superfluid dynamics in BECs

We numerically investigate an experimentally viable method for generating and manipulating on-demand several vortices in a highly oblate atomic Bose-Einstein condensate (BEC) in order to initialize complex vortex distributions for studies of vortex dynamics. The method utilizes moving laser beams to generate, capture, and transport vortices inside and outside the BEC. We examine in detail this methodology and show a wide parameter range of applicability for the prototypical two-vortex case, as well as case examples of producing and manipulating several vortices for which there is no net circulation, corresponding to equal numbers of positive and negative circulation vortices, and cases for which there is one net quantum of circulation. We find that the presence of dissipation can help stabilize the pinning of the vortices on their respective laser beam pinning sites. Finally, we illustrate how to utilize laser beams as repositories that hold large numbers of vortices and how to deposit individual vortices in a sequential fashion in the repositories in order to construct superfluid flows about the repository beams with several quanta of circulation.

Generating and Manipulating Quantized Vortices On-Demand in a Bose-Einstein Condensate: a Numerical Study

Spring 4-2-2001 Using Surface-Wave Spectroscopy to Characterize Tilt Modes of a Vortex in a Bose-Einstein Condensate

We experimentally and numerically demonstrate deterministic creation and manipulation of a pair of oppositely charged singly quantized vortices in a highly oblate Bose-Einstein condensate (BEC). Two identical blue-detuned, focused Gaussian laser beams that pierce the BEC serve as repulsive obstacles for the superfluid atomic gas; by controlling the positions of the beams within the plane of the BEC, superfluid flow is deterministically established around each beam such that two vortices of opposite circulation are generated by the motion of the beams, with each vortex pinned to the \emph{in situ} position of a laser beam. We study the vortex creation process, and show that the vortices can be moved about within the BEC by translating the positions of the laser beams. This technique can serve as a building block in future experimental techniques to create, on-demand, deterministic arrangements of few or many vortices within a BEC for precise studies of vortex dynamics and vortex interactions.

Deterministic creation, pinning, and manipulation of quantized vortices in a Bose-Einstein condensate

Publisher's copyright statement: Reprinted with permission from the American Physical Society: Matthew T. Reeves, Thomas P. Billam, Brian P. Anderson, and Ashton S. Bradley (2014) 'Signatures of coherent vortex structures in a disordered two-dimensional quantum uid.'. Physical Review A, 89 (5), 053631. c © 2014 by the American Physical Society. Readers may view, browse, and/or download material for temporary copying purposes only, provided these uses are for noncommercial personal purposes. Except as provided by law, this material may not be further reproduced, distributed, transmitted, modi ed, adapted, performed, displayed, published, or sold in whole or part, without prior written permission from the American Physical Society.

Deposited in DRO : 19 September 2014 Version of attached le : Published Version Peer-review status of attached

The Reynolds number provides a characterization of the transition to turbulent flow, with wide application in classical fluid dynamics. Identifying such a parameter in superfluid systems is challenging due to their fundamentally inviscid nature. Performing a systematic study of superfluid cylinder wakes in two dimensions, we observe dynamical similarity of the frequency of vortex shedding by a cylindrical obstacle. The universality of the turbulent wake dynamics is revealed by expressing shedding frequencies in terms of an appropriately defined superfluid Reynolds number, Re(s), that accounts for the breakdown of superfluid flow through quantum vortex shedding. For large obstacles, the dimensionless shedding frequency exhibits a universal form that is well-fitted by a classical empirical relation. In this regime the transition to turbulence occurs at Re(s)≈0.7, irrespective of obstacle width.

Identifying a Superfluid Reynolds Number via Dynamical Similarity.

We study conditions under which vortices in a highly oblate harmonically trapped Bose-Einstein condensate (BEC) can be stabilized due to pinning by a blue-detuned Gaussian laser beam, with particular emphasis on the potentially destabilizing effects of laser beam positioning within the BEC. Our approach involves theoretical and numerical exploration of dynamically and energetically stable pinning of vortices with winding number up to $S=6$, in correspondence with experimental observations. Stable pinning is quantified theoretically via Bogoliubov-de Gennes excitation spectrum computations and confirmed via direct numerical simulations for a range of conditions similar to those of experimental observations. The theoretical and numerical results indicate that the pinned winding number, or equivalently the winding number of the superfluid current about the laser beam, decays as a laser beam of fixed intensity moves away from the BEC center. Our theoretical analysis helps explain previous experimental observations and helps define limits of stable vortex pinning for future experiments involving vortex manipulation by laser beams.

Dynamic and energetic stabilization of persistent currents in Bose-Einstein condensates

We have demonstrated in-situ detection of two-dimensional vortex distributions in a single-component Bose-Einstein condensate. We discuss development of the next generation quantum vortex microscope and implications for observations of superfluid dynamics.

Quantum vortex microscope for observing two-dimensional vortex dynamics in bose-einstein condensates

Laboratory observations of vortex dynamics in Bose-Einstein condensates (BECs) are essential for determination of many aspects of superfluid dynamics in these systems. We present a novel application of dark-field imaging that enables \texttt{\it in situ} detection of two-dimensional vortex distributions in single-component BECs, a step towards real-time measurements of complex two-dimensional vortex dynamics within a single BEC. By rotating a $^{87}$Rb BEC in a magnetic trap, we generate a triangular lattice of vortex cores in the BEC, with core diameters on the order of 400 nm and cores separated by approximately 9 $\mu$m. We have experimentally confirmed that the positions of the vortex cores can be determined without the need for ballistic expansion of the BEC.

Despite the prominence of Onsager's point-vortex model as a statistical description of 2D classical turbulence, a first-principles development of the model for a realistic superfluid has remained an open problem. Here we develop a mapping of a system of quantum vortices described by the homogeneous 2D Gross-Pitaevskii equation (GPE) to the point-vortex model, enabling Monte Carlo sampling of the vortex microcanonical ensemble. We use this approach to survey the full range of vortex states in a 2D superfluid, from the vortex-dipole gas at positive temperature to negative-temperature states exhibiting both macroscopic vortex clustering and kinetic energy condensation, which we term an Onsager-Kraichnan condensate (OKC). Damped GPE simulations reveal that such OKC states can emerge dynamically, via aggregation of small-scale clusters into giant OKC clusters, as the end states of decaying 2D quantum turbulence in a compressible, finite-temperature superfluid. These statistical equilibrium states should be accessible in atomic Bose-Einstein condensate experiments.

Onsager-Kraichnan condensation in decaying two-dimensional quantum turbulence.

The emergence of coherent rotating structures is a phenomenon characteristic of both classical and quantum two-dimensional (2D) turbulence. In this work we show theoretically that the coherent vortex structures that emerge in decaying 2D quantum turbulence can approach quasiclassical rigid-body rotation, obeying the Feynman rule of constant average areal vortex density while remaining spatially disordered. By developing a rigorous link between the velocity probability distribution and the quantum kinetic energy spectrum over wave number k, we show that the coherent vortex structures are associated with a k3 power law in the infrared region of the spectrum, and a well-defined spectral peak that is a physical manifestation of the largest structures. We discuss the possibility of realizing coherent structures in Bose-Einstein condensate experiments and present Gross-Pitaevskii simulations showing that this phenomenon, and its associated spectral signatures, can emerge dynamically from feasible initial vortex configurations.

Signatures of coherent vortex structures in a disordered two-dimensional quantum fluid

We show that topological vortex pumping can be implemented for a dilute Bose–Einstein condensate confined in a magnetic time-averaged orbiting potential trap with axial optical confinement. Contrary to earlier proposals for the vortex pump, we do not employ an additional optical potential to trap the condensate in the radial direction, but instead, the radial confinement is provided by the magnetic field throughout the pumping cycle. By performing numerical simulations based on the spin-1 Gross–Pitaevskii equation, we find that several pumping cycles can be carried out to produce a highly charged vortex before a majority of the particles escape from the trap or before the vortex splits into singly charged vortices. On the other hand, we observe that an additional, relatively weak optical plug potential is efficient in preventing splitting and reducing particle loss. With these results, we hope to bring the vortex pump closer to experimental realization.

Vortex pump for Bose-Einstein condensates utilizing a time-averaged orbiting potential trap

After more than a decade of experiments generating and studying the physics of quantized vortices in atomic gas Bose–Einstein condensates, research is beginning to focus on the roles of vortices in quantum turbulence, as well as other measures of quantum turbulence in atomic condensates. Such research directions have the potential to uncover new insights into quantum turbulence, vortices, and superfluidity and also explore the similarities and differences between quantum and classical turbulence in entirely new settings. Here we present a critical assessment of theoretical and experimental studies in this emerging field of quantum turbulence in atomic condensates.

Bose–Einstein condensates of dilute gases are well-suited for investigations of vortex dynamics and turbulence in quantum fluids, yet there has been little experimental research into the approaches that may be most promising for generating states of two-dimensional turbulence in these systems. Here we give an overview of techniques for generating the large and disordered vortex distributions associated with two-dimensional quantum turbulence. We focus on describing methods explored in our Bose–Einstein condensation laboratory, and discuss the suitability of these methods for studying various aspects of two-dimensional quantum turbulence. We also summarize some of the open questions regarding our own understanding of these mechanisms of two-dimensional quantum turbulence generation in condensates. We find that while these disordered distributions of vortices can be generated by a variety of techniques, further investigation is needed to identify methods for obtaining quasisteady-state quantum turbulence in condensates.

Experimental Methods for Generating Two-Dimensional Quantum Turbulence in Bose-Einstein Condensates

Pinning and manipulation of vortex cores in Bose-Einstein condensates

Energy Spectra of Vortex Distributions in Two-Dimensional Quantum Turbulence

Experimental stirring of a toroidally trapped Bose-Einstein condensate at high temperature generates a disordered array of quantum vortices that decays via thermal dissipation to form a macroscopic persistent current. We perform three-dimensional numerical simulations of the experimental sequence within the stochastic projected Gross-Pitaevskii equation using ab initio determined reservoir parameters. We find that both damping and noise are essential for describing the dynamics of the high-temperature Bose field. The theory gives a quantitative account of the formation of a persistent current, with no fitted parameters.

Persistent-current formation in a high-temperature Bose-Einstein condensate: An experimental test for classical-field theory

We demonstrate an inverse energy cascade in a minimal model of forced 2D quantum vortex turbulence. We simulate the Gross-Pitaevskii equation for a moving superfluid subject to forcing by a stationary grid of obstacle potentials, and damping by a stationary thermal cloud. The forcing injects large amounts of vortex energy into the system at the scale of a few healing lengths. A regime of forcing and damping is identified where vortex energy is efficiently transported to large length scales via an inverse energy cascade associated with the growth of clusters of same-circulation vortices, a Kolmogorov scaling law in the kinetic energy spectrum over a substantial inertial range, and spectral condensation of kinetic energy at the scale of the system size. Our results provide clear evidence that the inverse energy cascade phenomenon, previously observed in a diverse range of classical systems, can also occur in quantum fluids.

Inverse energy cascade in forced two-dimensional quantum turbulence.

Fluids subjected to suitable forcing will exhibit turbulence, with characteristics strongly affected by the fluid's physical properties and dimensionality. In this work, we explore two-dimensional (2D) quantum turbulence in an oblate Bose-Einstein condensate confined to an annular trapping potential. Experimentally, we find conditions for which small-scale stirring of the condensate generates disordered 2D vortex distributions that dissipatively evolve toward persistent currents, indicating energy transport from small to large length scales. Simulations of the experiment reveal spontaneous clustering of same-circulation vortices and an incompressible energy spectrum with k(-5/3) dependence for low wave numbers k. This work links experimentally observed vortex dynamics with signatures of 2D turbulence in a compressible superfluid.

Characteristics of two-dimensional quantum turbulence in a compressible superfluid.

We investigate two-dimensional turbulence in finite-temperature trapped Bose-Einstein condensates within damped Gross-Pitaevskii theory. Turbulence is produced via circular motion of a Gaussian potential barrier stirring the condensate. We systematically explore a range of stirring parameters and identify three regimes, characterized by the injection of distinct quantum vortex structures into the condensate: (A) periodic vortex dipole injection, (B) irregular injection of a mixture of vortex dipoles and co-rotating vortex clusters, and (C) continuous injection of oblique solitons that decay into vortex dipoles. Spectral analysis of the kinetic energy associated with vortices reveals that regime (B) can intermittently exhibit a Kolmogorov k 53 power law over almost a decade of length or wave-number (k) scales. The kinetic energy spectrum of regime (C) exhibits a clear k32 power law associated with an inertial range for weak-wave turbulence and a k72 power law for high wave numbers. We thus identify distinct regimes of forcing for generating either two-dimensional quantum turbulence or classical weak-wave turbulence that may be realizable experimentally.

Classical and quantum regimes of two-dimensional turbulence in trapped Bose-Einstein condensates

Imaging the 3D structure of vortex cores in Bose-Einstein condensates

We study the Kelvin mode excitations on a vortex line in a three-dimensional trapped Bose-Einstein condensate at finite temperature. Our stochastic Gross-Pitaevskii simulations show that the activation of these modes can be suppressed by tightening the confinement along the direction of the vortex line, leading to a strong suppression in the vortex decay rate as the system enters a regime of two dimensional vortex dynamics. As the system approached the transition temperature we find that the vortex decay rate is strongly sensitive to dimensionality and temperature, observing a large enhancement for quasi-two-dimensional traps.

Suppression of Kelvon-induced decay of quantized vortices in trapped Bose-Einstein Condensates

We study the Kelvin mode excitations on a vortex line in a three-dimensional trapped Bose-Einstein condensate at finite temperature. Our stochastic Gross-Pitaevskii simulations show that the activation of these modes can be suppressed by tightening the confinement along the direction of the vortex line, leading to a strong suppression in the vortex decay rate as the system enters a regime of two-dimensional vortex dynamics. As the system approaches the condensation transition temperature we find that the vortex decay rate is strongly sensitive to dimensionality and temperature, observing a large enhancement for quasi-two-dimensional traps. Three-dimensional simulations of the recent vortex dipole decay experiment of Neely et al. [Phys. Rev. Lett. 104, 160401 (2010)] confirm two-dimensional vortex dynamics, and predict a dipole lifetime consistent with experimental observations and suppression of Kelvon-induced vortex decay in highly oblate condensates.

Suppression of Kelvon-induced decay of quantized vortices in oblate Bose-Einstein condensates

Persistent currents from the decay of quantum turbulence: signatures of an inverse energy cascade in Bose-Einstein condensates

Generation and pinning of high winding-number vortices in Bose-Einstein condensates

Abstract : This report decribes the research and results of the activity on various projects over the period of the grant. The optics of study include atom optics and matter-wave quantum point contacts, theory of optical refrigeration of semiconductors and nonlinear optical response of quantum well Bragg structures, tuneable high-brightness vertical external cavity surface emitting lasers and generation of blue-green lasers by frequency doubling, quantum dots for cavity QED entanglement, near-field nonlinear optics, and optically bound matter. The project supports student research and generates opportunities for scientific publications. The projects involve interaction with colleagues and DOD laboratories and supports in-house Army and Air Force research efforts to develop optics technology relevant to military applications.

We report the experimental generation of two-dimensional quantum turbulence in dilute-gas Bose-Einstein condensates by stirring the condensate with a laser beam, and the decay of the turbulent state to a large-scale flow in the form of a persistent current in a toroidal trap geometry. From numerical simulations of the stirring process, we characterize the dynamics of the quantized vortices in the condensate, and analyze the kinetic energy spectrum. Our observations are consistent with basic features of two-dimensional turbulence in classical incompressible fluids.

2011 International Quantum Electronics Conference (IQEC) and Conference on Lasers and Electro-Optics (CLEO) Pacific Rim incorporating the Australasian Conference on Optics, Lasers and Spectroscopy and the Australian Conference on Optical Fibre Technology

Resource Article: Experiments with Vortices in Superfluid Atomic Gases

While quantized vortices and vortex lattices in Bose-Einstein condensates (BECs) have received much recent attention, the formation and dynamics of vortex dipoles have been nearly unexplored in experimental BECs. Vortex dipoles consist of a pair of vortices of opposite circulation moving under the influence of each other, and may be considered as metastable topological structures that carry linear momentum in a fluid. In this talk, a collaborative experimental and numerical study of the formation, dynamics, and lifetimes of vortex dipoles in BECs will be presented. In our work [1], single vortex dipoles were deterministically nucleated by causing highly oblate, harmonically trapped BECs to move past a repulsive obstacle above a supercritical flow velocity. Our measured critical velocity for vortex dipole shedding, and the subsequent dipole dynamics, are in good agreement with new numerical simulations. We find that vortex dipoles can survive for many seconds in the BEC without selfannihilation, and that multiply charged vortex dipoles can be formed with high enough flow velocities. References: 1. T.W. Neely, E.C. Samson, A.S. Bradley, M.J. Davis, and B.P. Anderson, preprint available at http://arxiv.org/abs/0912.3773.

M. C. Davis, R. Carretero-González, Z. Shi, K. J. H. Law, P. G. Kevrekidis, and B. P. Anderson Department of Mathematics and Statistics and Computational Science Research Center, Nonlinear Dynamical Systems Group, San Diego State University, San Diego, California 92182-7720, USA Department of Mathematics and Statistics, University of Massachusetts, Amherst, Massachusetts 01003, USA College of Optical Sciences and Department of Physics, University of Arizona, Tucson, Arizona 85721, USA Received 16 May 2009; published 6 August 2009

M ay 2 00 9 Manipulation of Vortices by Localized Impurities in Bose-Einstein Condensates

We consider the manipulation of Bose-Einstein condensate vortices by optical potentials generated by focused laser beams. It is shown that for appropriate choices of the laser strength and width it is possible to successfully transport vortices to various positions inside the trap confining the condensate atoms. Furthermore, the full bifurcation structure of possible stationary single-charge vortex solutions in a harmonic potential with this type of impurity is elucidated. The case when a moving vortex is captured by a stationary laser beam is also studied, as well as the possibility of dragging the vortex by means of periodic optical lattices.

Manipulation of vortices by localized impurities in Bose-Einstein condensates

Measuring the rates of spontaneous vortex formation in highly oblate Bose-Einstein condensates

We report experimental observations and numerical simulations of the formation, dynamics, and lifetimes of single and multiply charged quantized vortex dipoles in highly oblate dilute-gas Bose-Einstein condensates (BECs). We nucleate pairs of vortices of opposite charge (vortex dipoles) by forcing superfluid flow around a repulsive Gaussian obstacle within the BEC. By controlling the flow velocity we determine the critical velocity for the nucleation of a single vortex dipole, with excellent agreement between experimental and numerical results. We present measurements of vortex dipole dynamics, finding that the vortex cores of opposite charge can exist for many seconds and that annihilation is inhibited in our trap geometry. For sufficiently rapid flow velocities, clusters of like-charge vortices aggregate into long-lived multiply charged dipolar flow structures.

Observation of vortex dipoles in an oblate Bose-Einstein condensate.

Abstract : The Bose-Einstein condensation (BEC) laboratory at the University of Arizona has built a program of research that focuses on two areas of BEC physics. First, we developed techniques necessary to experimentally investigate dynamic quasi-condensed states. With our system, we have instituted new directions of experimental BEC physics: studying spontaneous formation of topological defects during the BEC phase transition, and studying transitions to superfluid turbulent states. As phase transitions and turbulence occur throughout natural phenomena, this work is further relevant to a wide range of subjects in physics. Our first published results have been enabled using the support of ARO award DAAD19-03-1-0368; our research in these areas is also ongoing. Our second main efforts have revolved around refining capabilities for studying and manipulating vortices and ultra-cold gases in disc-shaped and annular potentials using optical potentials, with a particular eye towards quantum engineering of vortex and persistent current states. These efforts involve often separate areas of investigation: manipulating condensates with laser light, two-dimensional physics, fluid dynamics and turbulence, phase-transition dynamics, and vortices and persistent currents. Our efforts are collaborative, with theoretical work at multiple universities and experimental work in Arizona progressing in tandem.

Coherent Atom Optics with Optical Potentials: A Summary of New Phenomena with Bose-Einstein Condensates at the University of Arizona

Studies of spontaneous vortex formation during Bose-Einstein condensation.

In this work, we study two-dimensional Bose–Einstein condensates confined by both a cylindrically symmetric harmonic potential and an optical lattice with equal periodicity in two orthogonal directions. We first identify the spectrum of the underlying two-dimensional linear problem through multiple-scale techniques. Then, we use the results obtained in the linear limit as a starting point for the existence and stability analysis of the lowest energy states, emanating from the linear ones, in the nonlinear problem. Two-parameter continuations of these states are performed for increasing nonlinearity and optical lattice strengths, and their instabilities and temporal evolution are investigated. It is found that the ground state as well as some of the excited states may be stable or weakly unstable for both attractive and repulsive interatomic interactions. Higher excited states are typically found to be increasingly more unstable.

Structure and stability of two-dimensional Bose–Einstein condensates under both harmonic and lattice confinement

Spontaneous vortices in the formation of Bose–Einstein condensates

Spontaneous vortices in Bose-Einstein condensate formation: comparison of experiment and theory

We study the formation of vortices in a Bose-Einstein condensate (BEC) that has been prepared by allowing isolated and independent condensed fragments to merge together. We focus on the experimental setup of Scherer et al. [Phys. Rev. Lett. 98, 110402 (2007)], where three BECs are created in a magnetic trap that is segmented into three regions by a repulsive optical potential; the BECs merge together as the optical potential is removed. First, we study the two-dimensional case; in particular, we examine the effects of the relative phases of the different fragments and the removal rate of the optical potential on the vortex formation. We find that many vortices are created by instant removal of the optical potential regardless of relative phases, and that fewer vortices are created if the intensity of the optical potential is gradually ramped down and the condensed fragments gradually merge. In all cases, self-annihilation of vortices of opposite charge is observed. We also find that for sufficiently long barrier ramp times, the initial relative phases between the fragments leave a clear imprint on the resulting topological configuration. Finally, we study the three-dimensional system and the formation of vortex lines and vortex rings due to the merger of the BEC fragments; our results illustrate how the relevant vorticity is manifested for appropriate phase differences, as well as how it may be masked by the planar projections observed experimentally.

Dynamics of vortex formation in merging Bose-Einstein condensate fragments

We report on experiments and simulations of the growth of a Bose-Einstein condensate in which vortices are observed to form spontaneously in a non-rotating potential. Between 10% and 50% of experiments result in between one and three unambiguous vortex cores. We simulate a temperature quench of a Bose gas through the critical point using the stochastic Gross-Pitaevskii equation and find remarkable agreement with the experimental data. Faster cooling results in a higher probability of vortex formation, and we interpret these results in light of the Kibble-Zurek scenario for the formation of topological defects in continuous phase transitions.

Spontaneous Vortex Formation During the Growth of a Bose-Einstein Condensate

Vortex formation during the creation of Bose-Einstein condensates

Spontaneous vortex formation during the creation of Bose-Einstein condensates

Fragmentation and Phase Manipulation Studies of Bose-Einstein Condensates using Computer-Generated Holograms

We report observations of vortex formation by merging and interfering multiple (87)Rb Bose-Einstein condensates (BECs) in a confining potential. In this experiment, a single harmonic potential well is partitioned into three sections by a barrier, enabling the simultaneous formation of three independent, uncorrelated BECs. The BECs may either automatically merge together during their growth, or for high-energy barriers, the BECs can be merged together by barrier removal after their formation. Either process may instigate vortex formation in the resulting BEC, depending on the initially indeterminate relative phases of the condensates and the merging rate.

Vortex formation by merging of multiple trapped Bose-Einstein condensates.

Using Computer-Generated Holograms and Optical Fields to Study Phase Dynamics and Phase Manipulation of Bose-Einstein Condensates

Coupled-ring atomic-phase interference devices using Bose-Einstein condensates

We examine the effect of the trapping potential on the critical temperature ${T}_{C}$ for the BCS transition to a superfluid state in trapped atomic gases of fermions. ${T}_{C}$ for an arbitrary power-law trap is calculated in the Thomas-Fermi approximation. For anharmonic traps, ${T}_{C}$ can be increased by several orders of magnitude in comparison to a harmonic trap. Our theoretical results indicate that, in practice, one could manipulate the critical temperature for the BCS phase transition by shaping the traps confining the atomic Fermi gases.

Manipulating the critical temperature for the superfluid phase transition in trapped atomic Fermi gases

We theoretically investigate the ground-state properties and quantum dynamics of a pair of adjacent ring-shaped Bose-Einstein condensates that are coupled via tunneling. This device, which is the analog of a symmetric superconducting quantum interference device, is the simplest version of what we term an atomic-phase interference device (APHID). The two-ring APHID is shown to be sensitive to rotation.

Atomic-phase interference devices based on ring-shaped Bose-Einstein condensates: Two-ring case

Solitons and vortex rings in a two-component Bose-Einstein condensate

Low-intensity white light was used to increase the loading rate of ${}^{87}\mathrm{Rb}$ atoms into a vapor-cell magneto-optic trap by inducing nonthermal desorption of Rb atoms from the stainless-steel walls of the vapor cell. An increased Rb partial pressure reached a new equilibrium value in fewer than 10 s after switching on the broadband light source. After the source was turned off, the partial pressure returned to its previous value in $1/e$ times as short as 10 s.

Loading a vapor-cell magneto-optic trap using light-induced atom desorption

We have created spatial dark solitons in two-component Bose-Einstein condensates in which the soliton exists in one of the condensate components and the soliton nodal plane is filled with the second component. The filled solitons are stable for hundreds of milliseconds. The filling can be selectively removed, making the soliton more susceptible to dynamical instabilities. For a condensate in a spherically symmetric potential, these instabilities cause the dark soliton to decay into stable vortex rings. We have imaged the resulting vortex rings.

Watching dark solitons decay into vortex rings in a Bose-Einstein condensate.

We have observed and characterized the dynamics of singly quantized vortices in dilute-gas Bose-Einstein condensates. Our condensates are produced in a superposition of two internal states of 87Rb, with one state supporting a vortex and the other filling the vortex core. Subsequently, the state filling the core can be partially or completely removed, reducing the radius of the core by as much as a factor of 13, all the way down to its bare value of the healing length. The corresponding superfluid rotation rates, evaluated at the core radius, vary by a factor of 150, but the precession frequency of the vortex core about the condensate axis changes by only a factor of 2.

Vortex precession in Bose-Einstein condensates: observations with filled and empty cores.

A vortex in a condensate in a nonspherical trapping potential will in general experience a torque. The torque will induce tilting of the direction of the vortex axis. We observe this behavior experimentally and show that by applying small distortions to the trapping potential, we can control the tilting behavior. By suppressing vortex tilt, we have been able to hold the vortex axis along the line of sight for up to 15 sec. Alternatively, we can induce a 180 degrees tilt, effectively reversing the charge on the vortex as observed in the lab frame. We characterize the vortex nondestructively with a surface-wave spectroscopic technique.

Use of surface-wave spectroscopy to characterize tilt modes of a vortex in a Bose-Einstein condensate.

Bose-Einstein condensation of ${}^{87}\mathrm{Rb}$ has been observed in a vapor cell time-averaged orbiting potential trap, and the trapped condensates have been studied using in situ absorption and dark-ground imaging methods. Condensates of $3\ifmmode\times\else\texttimes\fi{}{10}^{4}$ atoms were observed after 26 s of evaporative cooling. The evaporative cooling sequence consisted of a combination of cooling with ramping magnetic-field strengths and radio-frequency-induced cooling. The measured sizes, numbers of atoms, and transition temperatures of the condensates are consistent with theoretical predictions that include the effects of atomic interactions.

Spatial observation of Bose-Einstein condensation of 87Rb in a confining potential

Summary form only given. Since the first observations of Bose Einstein condensates (BEC) in dilute atomic gases, there has been considerable interest in observing effects in atomic BEC akin to the hallmark effects associated with a superfluid, in particular persistent, quantized circulation of the fluid. Using a method proposed by Williams and Holland' we have prepared vortices, macroscopic quantum states with quantized angular momentum, in a trapped BEC of /sup 87/Rb. The experimental realization of this method takes advantage of unique features of the time averaged orbiting potential (TOP) trap and builds on earlier work involving two-component condensates. The two components refer to two different internal hyperfine states of /sup 87/Rb, confined by identical and fully overlapping magnetic trap potentials in these experiments.

Bose-Einstein condensation in a dilute vapor of magnetically trapped Rb was achieved, and the condensed atoms were used to observe de Broglie-wave interference due to atom tunneling between the barriers of an array of traps. The condensed atoms were loaded into a vertically-oriented one-dimensional optical lattice formed by a retro-reflected laser beam, creating the trap array. In the limit of negligible interactions between atoms, the energy difference between adjacent array sites was determined by the gravitational potential energy shift between the sites. This energy difference initiated an oscillating atom mass current similar to an electric current in the ac Josephson effect for two coupled superconductors. In the optical lattice, de Broglie-wave interference occurred between atoms in localized lattice states, and the interference was observed as a train of falling pulses of atoms. In a separate experiment, using a dilute vapor of lithium, enhanced loading of a Li magneto-optic trap with spectrally-broadened cooling and trapping light was demonstrated. By placing the Li oven nozzle near the trap, the Li atoms could be efficiently captured from an atomic beam without using a pre-cooling stage. The trapped atoms were transferred into a three-dimensional optical lattice, formed by four intersecting and interfering beams of far-off-resonant laser light, and adiabatic cooling and velocity selection in three dimensions was demonstrated.

Bose-Einstein condensation and macroscopic interference with atomic tunnel arrays

The order parameter of a condensate with two internal states can continuously distort in such a way as to remove twists that have been imposed along its length. We observe this effect experimentally in the collapse and recurrence of Rabi oscillations in a magnetically trapped, two-component Bose-Einstein condensate of ${}^{87}\mathrm{Rb}$.

Watching a Superfluid Untwist Itself: Recurrence of Rabi Oscillations in a Bose-Einstein Condensate

The availability of coherent matter waves from Bose-Einstein condensates had led to the extension of atom optics from the linear to the nonlinear regime, in analogy with the developments in optics following the invention of the laser. We provide a tutorial introduction to this emerging field, emphasizing the role of collisions as a “nonlinear medium” in the focusing and defocusing of matter waves, the launching of atomic solitons, the generation of vortices, and the demonstration of four-wave mixing both among matter waves and between optical and matter waves.

The authors have designed and assembled an experiment to determine the rate of fine structure changing collisions between ultra-cold ({approximately} 1 mK) laser cooled Li atoms. The atoms are confined by a magneto-optical trap which consists of six polarized orthogonal laser beams tuned slightly below the 2S{sub 1/2}-2P{sub 3/2} resonance frequency of lithium. Measurements show that about 2 x 10{sup 7} atoms are confined to a roughly spherical region of about 1 mm in diameter. Fine structure changing collisions occur when an atom in the 2S{sub 1/2} state and an atom in the 2P{sub 3/2} state collide, and yield an atom in the 2S{sub 1/2} state and an atom in the 2P{sub 1/2} state, with an energy release corresponding to about 10 GHz. This energy adds kinetic energy to the atoms in the trap, and knocks atoms out of the trap. The authors have devised a method to measure the rate of this collisional loss mechanism. The method uses a laser diode and a dye laser to selectively photo-ionize the 2P{sub 1/2} atoms, and a channeltron particle multipiler measures the rate of ion formation. We will report the progress of this experiment.

Fine structure changing collisions between ultra-cold lithium atoms

A vortex in a condensate in a nonspherical trapping potential will in general experience a torque. The torque will induce tilting of the direction of the vortex axis. We observe this behavior experimentally and show that by applying small distortions to the trapping potential, we can control the tilting behaviour. By suppressing vortex tilt, we have been able to hold the vortex axis along the line of sight for up to 15 seconds. Alternatively, we can induce a 180◦ tilt, effectively reversing the charge on the vortex as observed in the lab frame. We characterize the vortex non-destructively with a surface-wave spectroscopic technique.

D ec 2 00 0 Using surface-wave spectroscopy to characterize tilt modes of a vortex in a Bose-Einstein Condensate

ec 2 00 0 Watching dark solitons decay into vortex rings in a Bose-Einstein condensate

Transactions of the American Climatological Association for the year ... American Climatological Association

Future missions to Enceladus would beneﬁt from multi-moon tours that leverage V ∞ on resonant orbits to progressively transfer between moons. Such “resonance family hopping” trajectories present a vast search space for global optimization due to the different combinations of available resonances and ﬂyby speeds. The proposed multi-objective tour design algorithm optimizes entire moon tours from Titan to Enceladus via grid-based dynamic programming, in which the computa- tion time is signiﬁcantly reduced by utilizing a database of V ∞ -leveraging transfers. The result unveils a complete trade space of the moon tour design to Ence- ladus in a tractable computation time and global optimality.

Velocity Variability of a Debris-Covered Glacier at Hourly to Annual Timescales

This study investigates causes behind correlations between snow and terrain properties in a 27 km2 mountain watershed. Whereas terrain correlations reveal where snow resides, the physical processes responsible for correlations can be ambiguous. We conducted biweekly snow surveys at small transect scales to provide insight into late‐season correlations at the basin scale. The evolving parameters of transect variograms reveal the interplay between differential accumulation and differential ablation that is responsible for correlations between snow and terrain properties including elevation, aspect, and canopy density. Elevation‐induced differential accumulation imposes a persistent source of varariabity at the basin scale, but is not sufficient to explain the elevational distribution of snow water equivalent (SWE) on the ground. Differential ablation, with earlier and more frequent ablation at lower elevations, steepens the SWE‐elevation gradient through the season. Correlations with aspect are primarily controlled by differences in solar loading. Aspect related redistribution of precipitation by wind, however, is important early in the season. Forested sites hold more snow than nonforested sites at the basin scale due to differences in ablation processes, while open areas within forested sites hold more snow than covered areas due to interception. However, as the season progresses energetic differences between open and covered areas within forested sites cause differences induced by interception to diminish. Results of this study can help determine which accumulation and ablation processes must be represented explicitly and which can be parameterized in models of snow dynamics.

Insights into the physical processes controlling correlations between snow distribution and terrain properties

Spatial Distribution and Evolution of a Seasonal Snowpack in Complex Terrain: An Evaluation of the SNODAS Modeling Product

As a critical unit of computer vision (CV) based applications, image segmentation is quite worth studying. Hybrid method of spatial credibilistic clustering and particle swarm optimization (SCCPSO) is a novel effective segmentation method. It's proved to produce better results than other common methods. In this paper, SCCPSO is further investigated by discussing several key points such as membership function, initialization, pre-selection, and boundary conditions. Then the modified SCCPSO is put forth and applied in a CV-based inspection system to show its effectivity and better performance. The proposed method can be also used in other CV-based applications.

2009 Sixth International Conference on Fuzzy Systems and Knowledge Discovery

Hybrid Method of Spatial Credibilistic Clustering and Particle Swarm Optimization: Discussion and Application

A survey is provided dealing with the formulation of modelling problems for dynamic factor models, and the various algorithm possibilities for solving these modelling problems. Emphasis is placed on understanding requirements for the handling of errors, noting the relevance of the proposed application of the model, be it for example prediction or business cycle determination. Mixed frequency problems are also considered, in which certain entries of an underlying vector process are only available for measurement at a submultiple frequency of the original process. Certain classes of processes are shown to be generically identifiable, and others not to have this property.

A study is presented on solutions of the Yule‐Walker equations for singular AR processes that are stationary outputs of a given AR system. If the Yule‐Walker equations admit more than one solution and the order of the AR system is no less than two, the solution set includes solutions which define unstable AR systems. The solution set also includes one solution, the minimal norm solution, which defines an AR system whose characteristic polynomial has either only stable zeros (implying that only one stationary output exists for this system and it is linearly regular) or has stable zeros as well as zeros of unit modulus, (implying that stationary solutions of this system are a sum of a linearly regular process and a linearly singular process). The numbers of stable and unit circle zeros of the characteristic polynomial of the defined AR system can be characterized in terms of the ranks of certain matrices, and the characteristic polynomial of the AR system defined by the minimal norm solution has the least number of unit circle zeros and the most number of stable zeros over all possible solutions.

The main contributions presented are (i) to widen the classes of model sets for which necessary and sufficient conditions for uncertainty model unfalsification can be obtained, and (ii) to display the effect of different assumptions concerning the modeling error on the curves defining the boundary of unfalsified models (the optimal uncertainty tradeoff curve) for the same underlying data set.

A major revision to the American Petroleum Institute's Publication 2519/sup 1/ provides a tool to accurately quantify evaporative losses and the resultant atmospheric emissions from petroleum stocks stored in internal floating-roof tanks (IFRTs). As a result of significant improvements in the loss calculation procedures included in the revised publication, entitled ''Evaporation Loss from Internal Floating Roof Tanks,'' more accurate stock inventory accounting and improved stock loss control can now be achieved. Also, cost-effectiveness of alternate floating-roof tank equipment can now be assessed for existing and new tanks. Environmental uses include the development of more accurate emission inventories for existing tankage and emission estimates required for permitting new tanks. Also, the environmental benefits of proposed emission controls can be evaluated to allow for informed regulatory development. Specifically, the effects of various generic equipment types, generic design details, and stock parameters on total evaporative loss can now be determined, and the three primary sources of loss from IFRTs (rim seals, deck fittings, and bolted deck seams) can be independently quantified. These loss calculation details, developed specifically for IFRTs, greatly enchance the accuracy and usefulness of the third edition over the second edition (1976), which it supersedes. The 1976 edition, which provided onlymore » a rough estimate of total loss based on a loss equation previously developed for external floating-roof tanks (EFRTs), had become inadequate for current industry needs.« less

Shining a light on amorphous U2O7: A computational approach to understanding amorphous uranium materials

CONTEXT
- Urinary tract infections are characterized by the presence of microbial pathogens within the urinary tract. They represent one of the most common infections in hospitalized and clinic patients.

- To model the parameters of the Sysmex UF-1000i to the gold standard, urine culture, and to compare the detection of dipstick leukocyte esterase and nitrates to urine cultures and UF-1000i results.

DESIGN
- Data were compared from urine samples collected in sterile containers for bacterial culture and microscopic analysis. One sample was used to inoculate a 5% sheep blood agar and MacConkey agar plate using a 0.001-mL calibrated loop. The second sample was analyzed by urinalysis-associated microscopy. The media plates were investigated for growth after 18 to 24 hours of aerobic incubation at 37°C. The second sample was analyzed for bacteria and leukocytes with the Sysmex UF-1000i according to the manufacturer's guidelines. Three definitions for culture results, sensitivity, and specificity at different cutoff values were calculated for the UF-1000i.

RESULTS
- The negative predictive value for any positive culture in the adult population included in the study was 95.5%, and the negative predictive value for positive cultures containing growth of 100 000 or more colony-forming units was 99.3% using the Sysmex UF-1000i.

- Sysmex UF-1000i showed 98% sensitivity and 93.7% specificity with a 95.5% negative predictive value. Thus, a negative screen with the UF-1000i using defined thresholds for white blood cell counts and bacteria was likely to be a true negative, decreasing the need for presumptive antibiotics.

The Accuracy of the Sysmex UF-1000i in Urine Bacterial Detection Compared With the Standard Urine Analysis and Culture.

Since the introduction of safeguards strengthening measures approved by the International Atomic Energy Agency (IAEA) Board of Governors (1992-1997), international nuclear safeguards inspectors have been able to utilize environmental sampling (ES) (e.g. deposited particulates, air, water, vegetation, sediments, soil and biota) in their safeguarding approaches at bulk uranium/plutonium handling facilities. Enhancements of environmental sampling techniques used by the IAEA in drawing conclusions concerning the absence of undeclared nuclear materials or activities will soon be able to take advantage of a recent step change improvement in the gathering and analysis of air samples at these facilities. Location specific air monitoring feasibility tests have been performed with excellent results in determining attribute and isotopic composition of chemical elements present in an actual test-bed sample. Isotopic analysis of collected particles from an Aerosol Contaminant Extractor (ACE) collection, was performed with the standard bulk sampling protocol used throughout the IAEA network of analytical laboratories (NWAL). The results yielded bulk isotopic values expected for the operations. Advanced designs of air monitoring instruments such as the ACE may be used in gas centrifuge enrichment plants (GCEP) to detect the production of highly enriched uranium (HEU) or enrichments not declared by a State. Researchers at Savannah Rivermore » National Laboratory in collaboration with Oak Ridge National Laboratory are developing the next generation of ES equipment for air grab and constant samples that could become an important addition to the international nuclear safeguards inspector's toolkit. Location specific air monitoring to be used to establish a baseline environmental signature of a particular facility employed for comparison of consistencies in declared operations will be described in this paper. Implementation of air monitoring will be contrasted against the use of smear ES when used during unannounced inspections, design information verification, limited frequency unannounced access, and complementary access visits at bulk handling facilities. Analysis of technical features required for tamper indication and resistance will demonstrate the viability of successful application of the system in taking ES within a bulk handling location. Further exploration of putting this technology into practice is planned to include mapping uranium enrichment facilities for the identification of optimal for installation of air monitoring devices.« less

ENVIRONMENTAL SAMPLING USING LOCATION SPECIFIC AIR MONITORING IN BULK HANDLING FACILITIES

The Analytical Development Section (ADS) of the Savannah River Technology Center (SRTC) developed a novel, monlithic surface plasmon resonance (SPR) probe for process monitoring as part of the Defense Programs Plant Directed Research and Development Program. The sensor incorporates multi-layer thin films on a fused-silica hemispherical lens. The simple optical design of the device increases robustness and fabrication precision and allows for sensitive SPR measurements to be made without complex polarizing and collimating optics. The utility of the probe is demonstrated for sensing moisture and hydrogen in process environments. This device is capable of optically detecting moisture from <1% (750ppb) to 100% and hydrogen concentrations from at least 0.1% to the explosive limit (4%) with a calculated limit of detection for H2 of 0.102% (signal-to-noise (S/N) = 3 criteria). Theoretical optical modeling of the SPR system and room temperature performance characteristics of the sensor are reported. WSRC-TR-2003-00290, Rev. 0 July 30, 2003 Page 5 of 26

Revision 0 Surface Plasmon Resonance Spectroscopy-Based Process Sensors

The Department of Energy must treat and dispose of large volumes of radioactive waste stored in underground storage tanks at five DOE sites. Technology development has been focused on the separation and removal of various radionuclides from the supernatant contained in the Hanford waste tanks.

Feasibility Study for the Development of a Surface Plasmon Resonance spectroscopy-based Sensor for the BNFL-Hanford

Calculation of transmitter concentration in individual PC12 cell vesicles with electrochemical data and a distribution of vesicle size obtained by electron microscopy

Chemical profiles and monitoring dynamics at an individual nerve cell in Planorbis corneus with electrochemical detection.

Demonstration of two distributions of vesicle radius in the dopamine neuron of Planorbis corneus from electrochemical data

A method is described for the direct identification of amino acids and amine-containing compounds from a fully developed neuron in Planorbis corneus as well as cultured pheochromocytoma cells by capillary electrophoresis with napthalene-2,3-dicarboxaldehyde (NDA) derivatization and electrochemical detection. Several compounds have been identified from the Planorbis neuron, including dopamine, glycine, dopa, glutamic acid, and aspartic acid. Quantitation was accomplished through the use of calibration curves. Cellular levels of the compounds ranged from 0.386 to 26.5 fmol. Voltammetry of the NDA products was also examined by scanning electrochemical detection in order to determine whether the technique could be used for peak identification. © 1998 John Wiley & Sons, Inc. J Micro Sep 10: 185–192, 1998

Capillary electrophoresis with NDA derivatization and electrochemical detection for the analysis of cellular amino acids

Dopamine levels of two classes of vesicles are differentially depleted by amphetamine

Electrochemical detection of reverse transport from Planorbis giant dopamine neuron.

The interaction of light with scattering matrixes, particularly particles suspended in a liquid, is described as it relates to the use of a technique known as grating light reflection spectroscopy (GLRS). Analysis of the singular behavior of light reflected from a transmission diffraction grating in contact with a scattering matrix has shown that the effective dielectric function of the medium in contact with the grating can be measured using a reflection method. The relative contributions of the real and imaginary components of the effective dielectric function are probed as mean particle radius increases, shifting the forward scattering regime from the Rayleigh limit to the Fraunhofer diffraction approximation. It is shown that GLRS provides substantial information regarding the characteristics of colloids and suspensions. Further investigations could, in theory, yield particle shape and density distribution information as well.

Grating Light Reflection Spectroscopy of Colloids and Suspensions

Several compounds were evaluated in a number of optical configurations in order to test the optical response of these compounds to changes in humidity. Reichardt`s betaine (Reichardt`s dye, ET-30 dye, 2,6-diphenyl-4-(2,4,6-triphenyl-N-pyridinio)phenolate), a solvatochromic molecule, and several vapochromic compounds were tested, and each responded to a wide range of humidity by exhibiting shifts in visible absorption. All compounds in the study suffered from some degree of hysteresis upon humidity cycling. It is unclear as to the mechanism for this hysteresis, but future work will attempt to either model or remove the hysteresis effects. In the case of the vapochromic compounds, the hysteresis may be due to structural changes in the crystal lattice of the solid state compound. A prototype sensor configuration was also developed involving an attenuated total reflectance probe. The future of the project will deal with elucidating the hysteresis mechanisms for each compound, evaluating several other vapochromic compounds, and testing different immobilization schemes for the compounds under study. In addition, several other optical technologies will be investigated for application in optical humidity sensing.

FY97 report on moisture sensors for enhanced surveillance program project LL-ESP96-13

An optical sensing technique is described and evaluated for sensitivity to changes in refractive index and absorbance of model sample matrices. A binary dielectric/metal transmission diffraction grating is placed in contact with a sample and utilized in reflection mode; thus, the light captured and analyzed does not pass through the sample. This particular condition creates thresholds at which a particular transmitted diffraction order is transformed from a traveling wave to an evanescent one. The positions of these thresholds depend upon the complex dielectric function of the sample, the period of the grating, and the wavelength and incident angle of light striking the grating. Experimental evidence directly supports the theoretical predictions regarding responses to both the real and imaginary portions of the refractive index:  the reflection coefficient derivative wavelength peak position shifts linearly with changes in the real part of the refractive index, and the derivative peak amplitudes exhibit a square-root dependence on absorbance. Refractive index sensitivity to a series of ethanol/water solutions is demonstrated with detectable changes in index as small as 2 × 10(-)(6). Absorbance sensitivity is shown via the differentiation of methylene blue samples having equivalent 1 cm path length absorbances between 0.459 and 244 AU. In a single reflection measurement, GLRS offers a large dynamic range for absorbance detection, allows simultaneous determination of bulk refractive index in optically dense media, and provides a platform for performing continuous process analysis.

Grating light reflection spectroscopy for determination of bulk refractive index and absorbance.

A new optical analytical chemical method for measuring concentrations in liquids and gases is described. The method is based on measurements of light reflection from diffraction gratings in contact with the sample. Features in the reflection spectrum are directly related to the complex dielectric constant of the sample solution.

Application of grating light reflection spectroscopy in analytical sensors

 The expansion of telehealth use during the COVID-19 pandemic increased access to health care services for many US residents. This is particularly true for provider-to-patient telehealth communication. In rural communities, telehealth can increase access to health care services that would otherwise be limited due to geographic and distance barriers. The adoption of telehealth in rural communities, however, has been hindered by technology barriers, lack of community awareness, and lack of provider buy-in. The purpose of this study was to explore community-identified approaches to improving telehealth access in rural North Central Washington.
 
 The aim of this study was to identify, group, and rate approaches to expanding and integrating telehealth in rural communities in North Central Washington.
 
 We used group concept mapping, a participant-engaged, mixed method approach, to explore participant perspectives and preferences. Purposively sampled participants were community leaders and stakeholders in rural North Central Washington. Participants brainstormed strategies for implementing and expanding community telehealth access in their community and sorted them into conceptually similar groups. Strategies were then rated by participants in terms of potential impact, feasibility, and the cost of implementation. Quantitative analyses included multidimensional scaling and hierarchical cluster analysis to produce a cluster map and pattern match graph for interpreting the community members’ ideas and preferences.
 
 Participant brainstorming yielded 70 strategies for implementing telehealth in rural North Central Washington. Strategies were individually sorted into groups (point map stress value 0.21), producing a 6-cluster solution. The clusters were “Community infrastructure,” “Ensuring access to telehealth technology,” “Technology infrastructure for telehealth,” “Training/awareness of telehealth,” “State- and policy-level considerations,” and “Health care systems engagement and delivery.” Participants rated “Training/awareness of telehealth” and “Health care systems engagement and delivery” to be highly impactful and feasible approaches. The “Training/awareness of telehealth” cluster included strategies such as educating community members that telehealth is an easy, reliable, convenient, and private way to access health care and providing community training on how to access health care remotely. The latter cluster, “Health care systems engagement and delivery,” included approaches that were ranked as highly feasible and impactful, such as engaging with clinics and providers on overcoming barriers to implementing telehealth services or ensuring that local health clinic staff is on board with telehealth as an alternative platform to provide services.
 
 Strategies identified and rated by participants incorporate the importance of community engagement in telehealth implementation, including educating community members about telehealth and engaging with community health clinics to facilitate use by providers. Community partners in North Central Washington will use these findings, along with additional community survey data, broadband speed test data, and provider input, to increase access to telehealth in their rural and remote communities.
 
 None declared.

Identifying Feasible and Impactful Approaches to Implementing Telehealth in Rural Washington Communities: Group Concept Mapping Study

Abstract Most adults report a preference for aging-in-place (AIP) – remaining safely in their own home and community as they age, even as they become more dependent on others. When attempting to determine options and feasibility for AIP, older adults and/or their families – especially those living in non-metropolitan rural areas and small towns, may turn to Extension educators for information and guidance. For the current study we interviewed seven family-focused Extension educators responsible for 25 counties throughout a Midwestern state to explore the challenges, supports, patterns of experience, and service/policy recommendations that these professionals find relevant to AIP in their regions. The principal investigator (PI) conducted each semi-structured interview by phone; each audio-recorded interview lasted approximately 60 minutes. Two trained research assistants and the PI applied combined deductive-inductive thematic analyses to the transcribed interview data following Braun and Clarke (2012), utilizing MAXQDA, and ensuring trustworthiness during the coding process. Five major categories with sub-themes emerged: Challenges to AIP (e.g., transportation), Supports to AIP (e.g., churches), Most-Challenged Populations (e.g., middle-income families who neither can afford in-home assistance nor are eligible for government aid), Attitudes Toward AIP (e.g., caution against social isolation), and Recommendations for Services/Policies to Facilitate AIP (e.g., government funding, in-home technology assistance). Some variation across counties was apparent with, for example, one county making concerted efforts to retain young adults in its communities (i.e., reducing out-migration), thus enhancing family presence making AIP more feasible, non-isolating. Our findings will be especially noteworthy to social service providers and aging-focused public policymakers.

ABSTRACT Historically Black colleges and universities (HBCUs) have a long-standing history of engaging the African-American community. In most instances, these institutions are located in predominantly African-American communities. This article intends to offer a discussion of a pedagogical approach used at an HBCU, located in a large mid-Atlantic city. The purpose of this macro-assignment was an effort designed to prepare BSW students for macro-practice with communities through participation in service-learning projects that involved community engagement with urban communities. Outcomes reflect that students have a vested interest in working with underserved communities, which exemplifies the School of Social Work’s mission; said mission is to fully prepare urban social work leaders who are committed to the alleviation of human suffering, social justice, and the improvement of the quality of life for diverse urban populations.

A partnership forged: BSW students and service learning at a historically Black college and university (HBCU) serving urban communities

Civic education and service learning aim to prepare competent and responsible citizens through active learning, workforce development and civic and political engagement that purposely connect students with their communities. Political efficacy is related to an individual’s belief, faith and trust in citizenship, government policies and practices.  This commentary argues there are connections between workforce readiness and college students who engage in service learning, social and political activism, and volunteerism.  The theoretical approach underscoring this argument is embedded in civic education structures that afford college students various opportunities to learn and be active citizens in their communities. This commentary explores different types of civically engaged experiences students are exposed to on college and university campuses, the surrounding communities, and their relationship to workforce readiness. Student experiences will be examined through civic education, service learning, and how these models of engagement are infused within higher education institutions. Thus, these experiences and others may influence college students’ perspectives and understanding of political affairs, social issues, global awareness, community development, and workplace readiness.  Colleges and universities are embedded in many communities that students reside and thus impact their choice to become or not become active citizens and workforce ready within their communities.

Enhancing Workforce Readiness Using Civic Education and Service Learning Experiences of College Students and Their Political Efficacy

ABSTRACT Depression is a major problem among African American older women; however, they also tend to be understudied as members of a multiple minority and oppressed group. As matriarchs and grandmothers in their families and communities, depression often emerges and becomes a detrimental problem for these older African American women. This study, a secondary data analysis, utilized the Health and Retirement Study (HRS) 2010 database to examine depression among older African American women. This article discusses the joint impact of age, social support, religion, caregiving, and physical health on depression among older community dwelling African American women. Findings indicate that age, physical health, and marital status as an aspect of social support were significant predictors of whether or not an older African American woman had ever had depression and whether or not she felt depressed in the past year. Receiving help from relatives as an aspect of social support also remained significant for participants who were feeling depressed in the past year. Implications for research, theory, and policy are offered.

What about African American older women and depressive symptoms?

Studies on aging have often focused on the medical and biological aspects of the aging process. This article presents an alternative perspective by providing a meaningful understanding of living well in an aging population with multiple chronic conditions. Our community-based qualitative study elaborates narratives from aging African Americans living in the Arkansas Delta and their perceptions of the links between social determinants and aging. Using purposeful sampling, we recruited and individually interviewed thirty one study participants, aged 50 years or older, with a self-reported chronic illness diagnosis. We analyzed data using grounded theory methodology. Results indicated that the personal meaning of aging, shaped by an individual’s socio-environmental contexts, affects one’s perception of living well. Findings highlighted that the personal definition of living well may vary in different stages of chronic conditions. Implications for a comprehensive approach integrating medical, biological, and psychosocial aspects to guide practice and policy are discussed.

Exploring the Links between Social Determinants and Perceptions of Living Well among Aging African Americans in the Arkansas Delta Region : A Qualitative Study

Using the Strong Interest Inventory Profile to Predict Satisfaction and Success in Student's College Experience

Research on mentoring has expanded from examination of traditional mentor-protege dyads to developmental mentoring networks. 20,37 In these network approaches, the emphasis is on a constellation of career developmental and personally supportive relationships to design career experiences for focal individuals and to respond to the issues that these focal individuals, or mentees, express. 1,15 To study engineering women faculty’ career experiences, we examine their egocentric mentoring networks, 29 that is, the individuals’ self-reported linkages between themselves (i.e., “ego” or hub of the network) and career developmental “nodes”/mentors. We use a mixed methodological approach including multi-dimensional network analysis to map out the configurations of women faculty’s mentoring network 11 and inductive analysis 6,7 to code our interview transcripts for mentoring relationships, women faculty’s feelings about such relationships, and their perceived outcomes. Female engineering faculty members generally express dissatisfaction with the formal mentoring programs but endorse their informal and spontaneous/episodic mentorships emerging from their egocentric mentoring network. These women’s mentoring networks are highly career-driven and consist of heterogeneous/diverse nodes, as well as multiplex ties that indicate multiple relationships between mentors and mentees. We provide theoretical and pragmatic implications of mentoring networks in the context of engineering faculty development. Mentoring is a dynamic process that is defined as “a communication relationship in which a senior person supports, tutors, guides, and facilitates a junior person’s career development” (p. 15). 23 It is traditionally characterized by reciprocity or mutuality of social exchange, developmental benefits linked to the mentees’ work and career, and consistent mentor-mentee interactions over some period of time 20 as opposed to a one-way short-term relationship. Research on mentoring has expanded from examination of traditional mentor-protege dyads to diverse situationally-based developmental mentoring networks. 20,37 In these more recent network approaches, the emphasis is on a constellation of career developmental and personally supportive relationships to design career experiences for individuals and to respond to the issues that these individuals, or mentees, express. 1,15 Developmental networks are valuable for achieving a variety of career outcomes ranging from promotion and career advancement 39 as well as clarity of professional identity, 16 to more variability of advice than a primary or sole mentor can achieve. 22 In addition, developmental networks are found to be gendered and racialized in the sense that women and individuals of color more often experience challenges in gaining access to and maintaining reliable and meaningful mentoring networks. Current research mainly focuses on mentoring in corporate settings. In academe, there is a growing body of research on undergraduate mentoring. However, few studies explore faculty mentoring processes in academic settings and none describe how faculty mentoring networks are enacted in ways that advantage and disadvantage particular group members such as women in engineering. 44 Our research expands the current literature by studying not only women faculty members’ mentoring relationships but also women engineers’ developmental mentoring network configurations. Furthermore, we explore an underresearched mentoring process known as episodic or spontaneous mentoring and mentoring moments. 1 As such, we contribute to muchneeded empirical research on women in STEM disciplines (science, technology, engineering, and math) that can help identify reasons for and strategies to combat women’s unequal participation in these occupations and careers. We do so through theoretical and methodological lenses unused previously in academic engineering contexts. Specifically, we examine women’s egocentric mentoring networks derived from qualitative interview data. Egocentric mentoring networks consist of individuals’ self-reported linkages between themselves (i.e., “ego” or hub of the network) and their career developmental “nodes”. 29 These network nodes can be resources, technology, and people that serve particular roles connected with departments, associations, institutions, agencies, and other organizations. 11 Guided by multiple network theories such as homophily, embeddedness, and social capital, our goal is twofold: to understand how women engineering faculty construct their mentoring networks; and to display and analyze women engineering faculty’s mentoring network configurations. To provide further context for these aims, we next supply an overview of mentoring research and social network constructs and theories that concludes with our two research questions. We follow this literature review with a detailed description of our research methods. We then present the findings based on the content and attributes of nodes as well as ties within the ego-centric mentoring networks. We conclude our paper by discussing our theoretical contributions and our findings’ pragmatic applications to women engineering faculty’s career development.

Novel dexamethasone-HPMA copolymer conjugate and its potential application in treatment of rheumatoid arthritis

Abstract Maternal skeletal mineral lost during lactation is rapidly restored after weaning. The purposes of this study were to determine when increases of bone formation occur after weaning, whether the expanding osteoblast population is derived from proliferating progenitors, and to relate these skeletal changes to known endocrine events at weaning. Female rats were allowed to complete one reproductive cycle. Half of these rats were mated a second time and allowed to lactate for 20 days. The other half served as an age-matched, normal estrus cycling comparison group. One day after weaning, the dams and their comparison group were given four injections of bromodeoxyuridine (BrdU) at 8-h intervals. Indices of bone formation and the kinetics of BrdU-labeled cells were measured in lumbar vertebral cancellous bone. At 2 days after weaning, cancellous bone formation rates were substantially greater than those in the nonmated rats. Indices of bone formation more than doubled from the second to seventh day after weaning. At 25 h after the first BrdU injection in the postweaned rats, considerable numbers of labeled cells were observed on or near the bone surface, with about 17% of the osteoblast population labeled. Labeled osteoblasts peaked at 20%–24% compared with 4% in the normal estrus cycling group. Immediately following weaning, there is a profound increase in the osteoblast population in maternal cancellous bone. Many, if not most of these newly formed osteoblasts were derived from proliferating progenitors. It is possible that the endocrine milieu of lactation expands or primes the osteoprogenitor pool for this rapid anabolic phase.

Weaning Initiates a Rapid and Powerful Anabolic Phase in the Rat Maternal Skeleton1

Background Confirming ablation completeness with sufficient ablative margin is critical for local tumor control following colorectal liver metastasis (CLM) ablation. An image-based confirmation method considering patient- and ablation-related biomechanical deformation is an unmet need. Purpose To evaluate a biomechanical deformable image registration (DIR) method for three-dimensional (3D) minimal ablative margin (MAM) quantification and the association with local disease progression following CT-guided CLM ablation. Materials and Methods This single-institution retrospective study included patients with CLM treated with CT-guided microwave or radiofrequency ablation from October 2015 to March 2020. A biomechanical DIR method with AI-based autosegmentation of liver, tumors, and ablation zones on CT images was applied for MAM quantification retrospectively. The per-tumor incidence of local disease progression was defined as residual tumor or local tumor progression. Factors associated with local disease progression were evaluated using the multivariable Fine-Gray subdistribution hazard model. Local disease progression sites were spatially localized with the tissue at risk for tumor progression (<5 mm) using a 3D ray-tracing method. Results Overall, 213 ablated CLMs (mean diameter, 1.4 cm) in 124 consecutive patients (mean age, 57 years ± 12 [SD]; 69 women) were evaluated, with a median follow-up interval of 25.8 months. In ablated CLMs, an MAM of 0 mm was depicted in 14.6% (31 of 213), from greater than 0 to less than 5 mm in 40.4% (86 of 213), and greater than or equal to 5 mm in 45.1% (96 of 213). The 2-year cumulative incidence of local disease progression was 72% for 0 mm and 12% for greater than 0 to less than 5 mm. No local disease progression was observed for an MAM greater than or equal to 5 mm. Among 117 tumors with an MAM less than 5 mm, 36 had local disease progression and 30 were spatially localized within the tissue at risk for tumor progression. On multivariable analysis, an MAM of 0 mm (subdistribution hazard ratio, 23.3; 95% CI: 10.8, 50.5; P < .001) was independently associated with local disease progression. Conclusion Biomechanical deformable image registration and autosegmentation on CT images enabled identification and spatial localization of colorectal liver metastases at risk for local disease progression following ablation, with a minimal ablative margin greater than or equal to 5 mm as the optimal end point. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Sofocleous in this issue.

Ablative Margins of Colorectal Liver Metastases Using Deformable CT Image Registration and Autosegmentation.

Purpose Discrepancies between planned and delivered dose to GI structures during radiation therapy (RT) of liver cancer may hamper the prediction of treatment outcomes. The purpose of this study is to develop a streamlined workflow for dose accumulation in a treatment planning system (TPS) during liver image-guided RT and to assess its accuracy when using different deformable image registration (DIR) algorithms. Materials and Methods Fifty-six patients with primary and metastatic liver cancer treated with external beam radiotherapy guided by daily CT-on-rails (CTOR) were retrospectively analyzed. The liver, stomach and duodenum contours were auto-segmented on all planning CTs and daily CTORs using deep-learning methods. Dose accumulation was performed for each patient using scripting functionalities of the TPS and considering three available DIR algorithms based on: (i) image intensities only; (ii) intensities + contours; (iii) a biomechanical model (contours only). Planned and accumulated doses were converted to equivalent dose in 2Gy (EQD2) and normal tissue complication probabilities (NTCP) were calculated for the stomach and duodenum. Dosimetric indexes for the normal liver, GTV, stomach and duodenum and the NTCP values were exported from the TPS for analysis of the discrepancies between planned and the different accumulated doses. Results Deep learning segmentation of the stomach and duodenum enabled considerable acceleration of the dose accumulation process for the 56 patients. Differences between accumulated and planned doses were analyzed considering the 3 DIR methods. For the normal liver, stomach and duodenum, the distribution of the 56 differences in maximum doses (D2%) presented a significantly higher variance when a contour-driven DIR method was used instead of the intensity only-based method. Comparing the two contour-driven DIR methods, differences in accumulated minimum doses (D98%) in the GTV were >2Gy for 15 (27%) of the patients. Considering accumulated dose instead of planned dose in standard NTCP models of the duodenum demonstrated a high sensitivity of the duodenum toxicity risk to these dose discrepancies, whereas smaller variations were observed for the stomach. Conclusion This study demonstrated a successful implementation of an automatic workflow for dose accumulation during liver cancer RT in a commercial TPS. The use of contour-driven DIR methods led to larger discrepancies between planned and accumulated doses in comparison to using an intensity only based DIR method, suggesting a better capability of these approaches in estimating complex deformations of the GI organs.

Leveraging deep learning-based segmentation and contours-driven deformable registration for dose accumulation in abdominal structures

Study Protocol COVER-ALL: Clinical Impact of a Volumetric Image Method for Confirming Tumour Coverage with Ablation on Patients with Malignant Liver Lesions

Simple Summary The DL model predictions in automated breast density assessment were independent of the imaging technologies, moderately or substantially agreed with the clinical reader density values, and had improved performance as compared to inclusion of commercial software values. Abstract Recently, convolutional neural network (CNN) models have been proposed to automate the assessment of breast density, breast cancer detection or risk stratification using single image modality. However, analysis of breast density using multiple mammographic types using clinical data has not been reported in the literature. In this study, we investigate pre-trained EfficientNetB0 deep learning (DL) models for automated assessment of breast density using multiple mammographic types with and without clinical information to improve reliability and versatility of reporting. 120,000 for-processing and for-presentation full-field digital mammograms (FFDM), digital breast tomosynthesis (DBT), and synthesized 2D images from 5032 women were retrospectively analyzed. Each participant underwent up to 3 screening examinations and completed a questionnaire at each screening encounter. Pre-trained EfficientNetB0 DL models with or without clinical history were optimized. The DL models were evaluated using BI-RADS (fatty, scattered fibroglandular densities, heterogeneously dense, or extremely dense) versus binary (non-dense or dense) density classification. Pre-trained EfficientNetB0 model performances were compared using inter-observer and commercial software (Volpara) variabilities. Results show that the average Fleiss’ Kappa score between-observers ranged from 0.31–0.50 and 0.55–0.69 for the BI-RADS and binary classifications, respectively, showing higher uncertainty among experts. Volpara-observer agreement was 0.33 and 0.54 for BI-RADS and binary classifications, respectively, showing fair to moderate agreement. However, our proposed pre-trained EfficientNetB0 DL models-observer agreement was 0.61–0.66 and 0.70–0.75 for BI-RADS and binary classifications, respectively, showing moderate to substantial agreement. Overall results show that the best breast density estimation was achieved using for-presentation FFDM and DBT images without added clinical information. Pre-trained EfficientNetB0 model can automatically assess breast density from any images modality type, with the best results obtained from for-presentation FFDM and DBT, which are the most common image archived in clinical practice.

Deep Learning Models for Automated Assessment of Breast Density Using Multiple Mammographic Image Types

Successful generation of biomechanical model-based deformable image registration (BM-DIR) relies on user-defined parameters that dictate surface mesh quality. The trial-and-error process to determine the optimal parameters can be labor intensive and hinder DIR efficiency and clinical workflow.

PURPOSE
To identify optimal parameters in surface mesh generation as boundary conditions for a BM-DIR in longitudinal liver and lung CT images to facilitate streamlined image registration processes.

METHODS
Contrast-enhanced CT images of 29 colorectal liver cancer patients and end-exhale 4DCT images of 26 locally advanced non-small cell lung cancer patients were collected. Different combinations of parameters that determine the triangle mesh quality (voxel side length and triangle edge length) were investigated. The quality of DIRs generated using these parameters was evaluated with metrics for geometric accuracy, robustness, and efficiency. Metrics for geometric accuracy included target registration error (TRE) of internal vessel bifurcations, dice similar coefficient (DSC), mean distance to agreement (MDA), Hausdorff Distance (HD) for organ contours, and number of vertices in the triangle mesh. AAPM Task Group 132 was used to ensure parameters met TRE, DSC, MDA recommendations before the comparison among the parameters. Robustness was evaluated as the success rate of DIR generation, and efficiency was evaluated as the total time to generate boundary conditions and compute finite element analysis.

RESULTS
Voxel side length of 0.2 cm and triangle edge length of 3 were found to be the optimal parameters for both liver and lung, with success rate of 1.00 and 0.98 and average DIR computation time of 100 and 143 seconds, respectively. For this combination, the average TRE, DSC, MDA, and HD were 0.38-0.40 mm, 0.96-0.97, 0.09-0.12 mm, and 0.87-1.17 mm, respectively.

The optimal parameters were found for the analyzed patients. The decision-making process described in this study serves as a recommendation for BM-DIR algorithms to be used for liver and lung. These parameters can facilitate consistence in the evaluation of published studies and more widespread utilization of BM-DIR in clinical practice. This article is protected by copyright. All rights reserved.

Optimization of mesh generation for geometric accuracy, robustness, and efficiency of biomechanical model-based deformable image registration.

Comparison of Machine-Learning and Deep-Learning Methods for the Prediction of Osteoradionecrosis Resulting From Head and Neck Cancer Radiation Therapy

Objectives Colorectal cancer (CRC), the third most common cancer in the USA, is a leading cause of cancer-related death worldwide. Up to 60% of patients develop liver metastasis (CRLM). Treatments like radiation and ablation therapies require disease segmentation for planning and therapy delivery. For ablation, ablation-zone segmentation is required to evaluate disease coverage. We hypothesize that fully convolutional (FC) neural networks, trained using novel methods, will provide rapid and accurate identification and segmentation of CRLM and ablation zones. Methods Four FC model styles were investigated: Standard 3D-UNet, Residual 3D-UNet, Dense 3D-UNet, and Hybrid-WNet. Models were trained on 92 patients from the liver tumor segmentation (LiTS) challenge. For the evaluation, we acquired 15 patients from the 3D-IRCADb database, 18 patients from our institution (CRLM = 24, ablation-zone = 19), and those submitted to the LiTS challenge (n = 70). Qualitative evaluations of our institutional data were performed by two board-certified radiologists (interventional and diagnostic) and a radiology-trained physician fellow, using a Likert scale of 1–5. Results The most accurate model was the Hybrid-WNet. On a patient-by-patient basis in the 3D-IRCADb dataset, the median (min–max) Dice similarity coefficient (DSC) was 0.73 (0.41–0.88), the median surface distance was 1.75 mm (0.57–7.63 mm), and the number of false positives was 1 (0–4). In the LiTS challenge (n = 70), the global DSC was 0.810. The model sensitivity was 98% (47/48) for sites ≥15 mm in diameter. Qualitatively, 100% (24/24; minority vote) of the CRLM and 84% (16/19; majority vote) of the ablation zones had Likert scores ≥4. Conclusion The Hybrid-WNet model provided fast (<30 s) and accurate segmentations of CRLM and ablation zones on contrast-enhanced CT scans, with positive physician reviews.

Automated segmentation of colorectal liver metastasis and liver ablation on contrast-enhanced CT images

IMPACT: This work aims to identify best practices for university-based asset development programs to improve commercialization throughput, which in turn will drive innovation in the biomedical space and directly contribute to improved human health. OBJECTIVES/GOALS: University technology transfer exhibits a high rate of failure, often due to a lack of researcher experience or early-stage financial capital. The LEAP program at Washington University (WUSTL) was created to address these needs. The goal of this study is to assess the performance of LEAP against similar gap funds and further improve program operations. METHODS/ STUDY POPULATION: The goals of LEAP are achieved by provid-ing university inventors with individualized consulting and feedback from industry experts, as well as awarding funding to the most prom-ising projects. To determine whether these activities are impactful, we distributed an awardee report form to collect data on all funded LEAP projects, and then combined the results with project registra-tion information. We also collected records Office of Technology Management, including invention disclosures, licenses, and startup creations. The resulting dataset was used to calculate program met-rics and then evaluated against comparable gap funds. Sentiment ABSTRACT IMPACT: This work will standardize necessary image pre-processing for diagnostic and prognostic clinical workflows dependent on quantitative analysis of conventional magnetic resonance imaging. OBJECTIVES/GOALS: Conventional magnetic resonance imaging (MRI) poses challenges for quantitative analysis due to a lack of uniform inter-scanner voxel intensity values. Head and neck cancer (HNC) applications in particular have not been well investigated. This project aims to systematically evaluate voxel intensity standardization (VIS) methods for HNC MRI. METHODS/ STUDY POPULATION: We utilize two separate cohorts of HNC patients, where T2-weighted (T2-w) MRI sequences were acquired

Translational Fellows as a mechanism to improve throughput of university technology commercialization Data Comparison of voxel intensity standardization methods in head and neck cancer magnetic resonance imaging

ABSTRACT IMPACT: This work will standardize necessary image pre-processing for diagnostic and prognostic clinical workflows dependent on quantitative analysis of conventional magnetic resonance imaging. OBJECTIVES/GOALS: Conventional magnetic resonance imaging (MRI) poses challenges for quantitative analysis due to a lack of uniform inter-scanner voxel intensity values. Head and neck cancer (HNC) applications in particular have not been well investigated. This project aims to systematically evaluate voxel intensity standardization (VIS) methods for HNC MRI. METHODS/STUDY POPULATION: We utilize two separate cohorts of HNC patients, where T2-weighted (T2-w) MRI sequences were acquired before beginning radiotherapy for five patients in each cohort. The first cohort corresponds to patients with images taken at various institutions with a variety of non-uniform acquisition scanners and parameters. The second cohort corresponds to patients from a prospective clinical trial with uniformity in both scanner and acquisition parameters. Regions of interest from a variety of healthy tissues assumed to have minimal interpatient variation were manually contoured for each image and used to compare differences between a variety of VIS methods for each cohort. Towards this end, we implement a new metric for cohort intensity distributional overlap to compare region of interest similarity in a given cohort. RESULTS/ANTICIPATED RESULTS: Using a simple and interpretable metric, we have systematically investigated the effects of various commonly implementable VIS methods on T2-w sequences for two independent cohorts of HNC patients based on region of interest intensity similarity. We demonstrate VIS has a substantial effect on T2-w images where non-uniform acquisition parameters and scanners are utilized. Oppositely, it has a modest to minimal impact on T2-w images generated from the same scanner with the same acquisition parameters. Moreover, with a few notable exceptions, there does not seem to be a clear advantage or disadvantage to using one VIS method over another for T2-w images with non-uniform acquisition parameters. DISCUSSION/SIGNIFICANCE OF FINDINGS: Our results inform which VIS methods should be favored in HNC MRI and may indicate VIS is not a critical factor to consider in circumstances where similar acquisition parameters can be utilized. Moreover, our results can help guide downstream quantitative imaging tasks that may one day be implemented in clinical workflows.

16461 Comparison of voxel intensity standardization methods in head and neck cancer magnetic resonance imaging

Intensity standardization methods in magnetic resonance imaging of head and neck cancer

Improving GI Toxicity Models Through Deep Learning-Based Segmentation and Biomechanical Model-Based Dose Accumulation.

Simple Python Module for Conversions between DICOM Images and Radiation Therapy Structures, Masks, and Prediction Arrays.

Abstract Purpose Re‐planning for four‐dimensional computed tomography (4DCT)‐based lung adaptive radiotherapy commonly requires deformable dose mapping between the planning average‐intensity image (AVG) and the newly acquired AVG. However, such AVG‐AVG deformable image registration (DIR) lacks accuracy assessment. The current work quantified and compared geometric accuracies of AVG‐AVG DIR and corresponding phase‐phase DIRs, and subsequently investigated the clinical impact of such AVG‐AVG DIR on deformable dose mapping. Methods and Materials Hybrid intensity‐based AVG‐AVG and phase‐phase DIRs were performed between the planning and mid‐treatment 4DCTs of 28 non‐small cell lung cancer patients. An automated landmark identification algorithm detected vessel bifurcation pairs in both lungs. Target registration error (TRE) of these landmark pairs was calculated for both DIR types. The correlation between TRE and respiratory‐induced landmark motion in the planning 4DCT was analyzed. Global and local dose metrics were used to assess the clinical implications of AVG‐AVG deformable dose mapping with both DIR types. Results TRE of AVG‐AVG and phase‐phase DIRs averaged 3.2 ± 1.0 and 2.6 ± 0.8 mm respectively (p < 0.001). Using AVG‐AVG DIR, TREs for landmarks with <10 mm motion averaged 2.9 ± 2.0 mm, compared to 3.1 ± 1.9 mm for the remaining landmarks (p < 0.01). Comparatively, no significant difference was demonstrated for phase‐phase DIRs. Dosimetrically, no significant difference in global dose metrics was observed between doses mapped with AVG‐AVG DIR and the phase‐phase DIR, but a positive linear relationship existed (p = 0.04) between the TRE of AVG‐AVG DIR and local dose difference. Conclusions When the region of interest experiences <10 mm respiratory‐induced motion, AVG‐AVG DIR may provide sufficient geometric accuracy; conversely, extra attention is warranted, and phase‐phase DIR is recommended. Dosimetrically, the differences in geometric accuracy between AVG‐AVG and phase‐phase DIRs did not impact global lung‐based metrics. However, as more localized dose metrics are needed for toxicity assessment, phase‐phase DIR may be required as its lower mean TRE improved voxel‐based dosimetry.

Geometric and dosimetric accuracy of deformable image registration between average‐intensity images for 4DCT‐based adaptive radiotherapy for non‐small cell lung cancer

PURPOSE
Objective assessment of deformable image registration (DIR) accuracy often relies on the identification of anatomical landmarks in image pairs, a manual process known to be extremely time-expensive. The goal of this study is to propose a method to automatically detect vessel bifurcations in images and assess their use for the computation of target registration errors (TRE).

Three image datasets were retrospectively analyzed. The first dataset included 10 pairs of inhale/exhale phases from lung 4DCTs and full inhale and exhale breath-hold CT scans from 10 patients presenting with chronic obstructive pulmonary disease, with 300 corresponding landmarks available for each case (DIR-Lab). The second dataset included 6 pairs of inhale/exhale phases from lung 4DCTs (POPI Dataset), with 100 pairs of landmarks for each case. The third dataset included 28 pairs of pre/post-radiotherapy liver contrast-enhanced CT scans, each with 5 manually picked vessel bifurcation correspondences. For all images, the vasculature was autosegmented by computing and thresholding a vesselness image. Images of the vasculature centerline were computed and bifurcations were detected based on centerline voxel neighbors' count. The vasculature segmentations were independently registered using a Demons algorithm between representations of their surface with distance maps. Detected bifurcations were considered as corresponding when distant by less than 5 mm after vasculature DIR. The selected pairs of bifurcations were used to calculate TRE after registration of the images considering three algorithms: rigid registration, Anaconda and a Demons algorithm. For comparison with the ground truth, TRE values calculated using the automatically detected correspondences were interpolated in the whole organs to generate TRE maps. The performance of the method in automatically calculating TRE after image registration was quantified by measuring the correlation with the TRE obtained when using the ground truth landmarks.

RESULTS
The median Pearson correlation coefficients between ground truth TRE and corresponding values in the generated TRE maps were r = 0.81 and r = 0.67 for the lung and liver cases, respectively. The correlation coefficients between mean TRE for each case were r = 0.99 and r = 0.64 for the lung and liver cases, respectively.

For lungs or liver CT scans DIR, a strong correlation was obtained between TRE calculated using manually picked or landmarks automatically detected with the proposed method. This tool should be particularly useful in studies requiring to assess the reliability of a high number of DIRs. This article is protected by copyright. All rights reserved.

Detection of vessel bifurcations in CT scans for automatic objective assessment of deformable image registration accuracy.

Purpose: Colorectal cancer is the third most common form of cancer in the United States, and up to 60% of these patients develop liver metastasis. While hepatic resection is the curative treatment of choice, only 20% of patients are candidates at the time of diagnosis. While percutaneous thermal ablation (PTA) has demonstrated 24%–51% overall 5-year survival rates, assurance of sufficient ablation margin delivery (5 mm) can be challenging, with current methods of 2D distance measurement not ensuring 3D minimum margin. We hypothesized that biomechanical model-based deformable image registration (DIR) can reduce spatial uncertainties and differentiate local tumor progression (LTP) patients from LTP-free patients. Methods: We retrospectively acquired 30 patients (16 LTP and 14 LTP-free) at our institution who had undergone PTA and had a contrast-enhanced pre-treatment and post-ablation CT scan. Liver, disease, and ablation zone were manually segmented. Biomechanical model-based DIR between the pre-treatment and post-ablation CT mapped the gross tumor volume onto the ablation zone and measured 3D minimum delivered margin (MDM). An in-house cone-tracing algorithm determined if progression qualitatively collocated with insufficient 5 mm margin achieved. Results: Mann–Whitney U test showed a significant difference (p < 0.01) in MDM from the LTP and LTP-free groups. A total of 93% (13/14) of patients with LTP had a correlation between progression and missing 5 mm of margin volume. Conclusions: Biomechanical DIR is able to reduce spatial uncertainty and allow measurement of delivered 3D MDM. This minimum margin can help ensure sufficient ablation delivery, and our workflow can provide valuable information in a clinically useful timeframe.

A novel use of biomechanical model-based deformable image registration (DIR) for assessing colorectal liver metastases ablation outcomes

Background: Conventional MRI poses unique challenges in quantitative analysis due to a lack of specific physical meaning for voxel intensity values. In recent years, intensity standardization methods to optimize MRI signal consistency have been developed to address this problem. However, the effects of standardization methods on the head and neck region have not been previously investigated. Purpose: This study proposes a workflow based on healthy tissue region of interest (ROI) analysis to determine intensity consistency within a patient cohort. Through this workflow, we systematically evaluate different intensity standardization methods for T2-weighted MRI of the head and neck region. Methods: Two image cohorts of five head and neck cancer patients, one with heterogeneous acquisition parameters (median age 59 years [range, 53-61]), and another with homogeneous acquisition parameters from a clinical trial (NCT04265430) (median age 61 years [range, 54-77]) were retrospectively analyzed. The standard deviation of cohort-level normalized mean intensity (SD NMIc), a metric of intensity consistency, was calculated across ROIs to determine the effect of five intensity standardization methods on T2-weighted images. For each cohort, the Friedman test with a subsequent post-hoc Bonferroni-corrected Wilcoxon signed-rank test was conducted to compare SD NMIc among methods. Results: Consistency (SD NMIc across ROIs) between T2-weighted images is substantially more impaired in the cohort with heterogeneous acquisition parameters (0.28 +- 0.04) than in the cohort with homogeneous acquisition parameters (0.15 +- 0.05). Consequently, intensity standardization methods more significantly improve consistency in the cohort with heterogeneous acquisition parameters (corrected p < 0.005 for all methods compared to no standardization) than in the cohort with homogeneous acquisition parameters (corrected p > 0.05 for all methods compared to no standardization). Conclusions: Our findings stress the importance of image acquisition parameter standardization, together with the need for testing intensity consistency before performing quantitative analysis of MRI.

MRI Intensity Standardization Evaluation Design for Head and Neck Quantitative Imaging Applications

Optimization of Normal Liver Radiation Avoidance to Promote Liver Preservation

Glioblastoma is an aggressive brain tumor with a propensity for intracranial recurrence. We hypothesized that tumors can be visualized with diffusion tensor imaging (DTI) before they are detected on anatomical magnetic resonance (MR) images. We retrospectively analyzed serial MR images from 30 patients, including the DTI and T1-weighted images at recurrence, at 2 months and 4 months before recurrence, and at 1 month after radiation therapy. The diffusion maps and T1 images were deformably registered longitudinally. The recurrent tumor was manually segmented on the T1-weighted image and then applied to the diffusion maps at each time point to collect mean FA, diffusivities, and neurite density index (NDI) values, respectively. Group analysis of variance showed significant changes in FA (p = 0.01) and NDI (p = 0.0015) over time. Pairwise t tests also revealed that FA and NDI at 2 months before recurrence were 11.2% and 6.4% lower than those at 1 month after radiation therapy (p < 0.05), respectively. Changes in FA and NDI were observed 2 months before recurrence, suggesting that progressive microstructural changes and neurite density loss may be detectable before tumor detection in anatomical MR images. FA and NDI may serve as non-contrast MR-based biomarkers for detecting subclinical tumors.

Detection of Glioblastoma Subclinical Recurrence Using Serial Diffusion Tensor Imaging

Automated Contouring of Contrast and Noncontrast Computed Tomography Liver Images With Fully Convolutional Networks

Automatic Segmentation Using Deep Learning for Online Dose Optimization During Adaptive Radiotherapy of Cervical Cancer

Automatic Verification of Beam Apertures for Cervical Cancer Radiation Therapy

Automatic segmentation using deep learning to enable online dose optimization during adaptive radiotherapy of cervical cancer.

PURPOSE
Response assessment of radiotherapy for the treatment of intrahepatic cholangiocarcinoma (IHCC) across longitudinal images is challenging due to anatomical changes. Advanced deformable image registration (DIR) techniques are required to correlate corresponding tissues across time. In this study, the accuracy of five commercially available DIR algorithms in four treatment planning systems (TPS) is investigated for the registration of planning images with post-treatment follow-up images for response assessment or re-treatment purposes.

METHODS
Twenty-nine IHCC patients treated with hypofractionated radiotherapy and with pre-treatment and post-treatment contrast-enhanced CT images were analyzed. Liver segmentations were semi-automatically generated on all CTs and the post-treatment CT was then registered to the pre-treatment CT using five commercially available algorithms (Demon's, B-splines, salient feature-based, anatomically-constrained and finite element-based) in four TPSs. This was followed by an in-depth analysis of ten DIR strategies (plus global and liver-focused rigid registration) in one of the TPSs. Eight of the strategies were variants of the anatomically-constrained DIR while the two were based on a finite element-based biomechanical registration. The anatomically constrained techniques were combinations of: (1) initializations with the two rigid registrations; (2) two similarity metrics - correlation coefficient (CC) and mutual information (MI); and (3) with and without a controlling ROI (liver). The finite element-based techniques were initialized by the two rigid registrations. The accuracy of each registration was evaluated using target registration error (TRE) based on identified vessel bifurcations. The results were statistically analyzed with a one-way ANOVA and pairwise comparison tests. Stratified analysis was conducted on the inter-TPS data (plus the liver-focused rigid registration) using treatment volume changes, slice thickness, time between scans and abnormal lab values as stratifying factors.

RESULTS
The complex deformation observed following treatment resulted in average TRE exceeding the image voxel size for all techniques. For the inter-TPS comparison, the Demon's algorithm had the lowest TRE, which was significantly superior to all the other algorithms. The respective mean (standard deviation) TRE (in mm) for the Demons's, B-splines, salient feature-based, anatomically-constrained and finite element-based algorithms were 4.6 (2.0), 7.4 (2.7), 7.2 (2.6), 6.3 (2.3) and 7.5 (4.0). In the follow-up comparison of the anatomically-constrained DIR, the strategy with liver-focused rigid registration initialization, CC as similarity metric and liver as a controlling ROI had the lowest mean TRE - 6.0 (2.0). The maximum TRE for all techniques exceeded 10 mm. Selection of DIR strategy was found to be a statistically significant factor for registration accuracy. Tumor volume change had a significant effect on TRE for finite element- based registration and B-splines DIR. Time between scans had a substantial effect on TRE for all registrations but was only significant for liver-focused rigid, finite element-based and salient feature-based DIRs.

This study demonstrates the limitations of commercially available DIR techniques in treatment planning systems for alignment of longitudinal images of liver cancer presenting complex anatomical changes including local hypertrophy and fibrosis/necrosis. DIR in this setting should be used with caution and careful evaluation.

Accuracy of deformable image registration techniques for alignment of longitudinal cholangiocarcinoma CT Images.

03:00 PM Abstract No. 363 Improving colorectal liver metastasis treatments with biomechanical modeling and deep learning

Radiomics studies require many patients in order to power them, thus patients are often combined from different institutions and using different imaging protocols. Various studies have shown that imaging protocols affect radiomics feature values. We examined whether using data from cohorts with controlled imaging protocols improved patient outcome models. We retrospectively reviewed 726 CT and 686 PET images from head and neck cancer patients, who were divided into training or independent testing cohorts. For each patient, radiomics features with different preprocessing were calculated and two clinical variables—HPV status and tumor volume—were also included. A Cox proportional hazards model was built on the training data by using bootstrapped Lasso regression to predict overall survival. The effect of controlled imaging protocols on model performance was evaluated by subsetting the original training and independent testing cohorts to include only patients whose images were obtained using the same imaging protocol and vendor. Tumor volume, HPV status, and two radiomics covariates were selected for the CT model, resulting in an AUC of 0.72. However, volume alone produced a higher AUC, whereas adding radiomics features reduced the AUC. HPV status and one radiomics feature were selected as covariates for the PET model, resulting in an AUC of 0.59, but neither covariate was significantly associated with survival. Limiting the training and independent testing to patients with the same imaging protocol reduced the AUC for CT patients to 0.55, and no covariates were selected for PET patients. Radiomics features were not consistently associated with survival in CT or PET images of head and neck patients, even within patients with the same imaging protocol.

Radiomics features of the primary tumor fail to improve prediction of overall survival in large cohorts of CT- and PET-imaged head and neck cancer patients

Vasculature-Driven Biomechanical Deformable Image Registration of Longitudinal Liver Cholangiocarcinoma Computed Tomographic Scans

Longitudinal and Dose Dependent Analysis on White Matter Injury in Glioblastoma Radiation Therapy

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology

Effect of setup and inter-fraction anatomical changes on the accumulated dose in CT-guided breath-hold intensity modulated proton therapy of liver malignancies.

Evaluation of Serial Diffusion Tensor Imaging to Reveal Subclinical Tumor Prior to Detection on Anatomical Imaging in Patients with Glioblastoma

During head and neck (HN) cancer radiation therapy, analysis of the dose-response relationship for the parotid glands (PG) relies on the ability to accurately align soft tissue organs between longitudinal images. In order to isolate the response of the salivary glands to delivered dose, from deformation due to patient position, it is important to resolve the patient postural changes, mainly due to neck flexion. In this study we evaluate the use of a biomechanical model-based deformable image registration (DIR) algorithm to estimate the displacements and deformations of the salivary glands due to postural changes. A total of 82 pairs of CT images of HN cancer patients with varying angles of neck flexion were retrospectively obtained. The pairs of CTs of each patient were aligned using bone-based rigid registration. The images were then deformed using biomechanical model-based DIR method that focused on the mandible, C1 vertebrae, C3 vertebrae, and external contour. For comparison, an intensity-based DIR was also performed. The accuracy of the biomechanical model-based DIR was assessed using Dice similarity coefficient (DSC) for all images and for the subset of images where the PGs had a volume change within 20%. The accuracy was compared to the intensity-based DIR. The PG mean  ±  STD DSC were 0.63  ±  0.18, 0.80  ±  0.08, and 0.82  ±  0.15 for the rigid registration, biomechanical model-based DIR, and intensity based DIR, respectively, for patients with a PG volume change up to 20%. For the entire cohort of patients, where the PG volume change was up to 57%, the PG mean  ±  STD DSC were 0.60  ±  0.18, 0.78  ±  0.09, and 0.81  ±  0.14 for the rigid registration, biomechanical model-based DIR, and intensity based DIR, respectively. The difference in DSC of the intensity and biomechanical model-based DIR methods was not statistically significant when the volume change was less than 20% (two-sided paired t-test, p   =  0.12). When all volume changes were considered, there was a significant difference between the two registration approaches, although the magnitude was small. These results demonstrate that the proposed biomechanical model with boundary conditions on the bony anatomy can serve to describe the varying angles of neck flexion appearing in images during radiation treatment and to align the salivary glands for proper analysis of dose-response relationships. It also motivates the need for dose response modeling following neck flexion for cases where parotid gland response is noted.

Biomechanical modeling of neck flexion for deformable alignment of the salivary glands in head and neck cancer images

Abstract A large number of surveys have been sent to the medical physics community addressing many clinical topics for which the medical physicist is, or may be, responsible. Each survey provides an insight into clinical practice relevant to the medical physics community. The goal of this study was to create a summary of these surveys giving a snapshot of clinical practice patterns. Surveys used in this study were created using SurveyMonkey and distributed between February 6, 2013 and January 2, 2018 via the MEDPHYS and MEDDOS listserv groups. The format of the surveys included questions that were multiple choice and free response. Surveys were included in this analysis if they met the following criteria: more than 20 responses, relevant to radiation therapy physics practice, not single‐vendor specific, and formatted as multiple‐choice questions (i.e., not exclusively free‐text responses). Although the results of free response questions were not explicitly reported, they were carefully reviewed, and the responses were considered in the discussion of each topic. Two‐hundred and fifty‐two surveys were available, of which 139 passed the inclusion criteria. The mean number of questions per survey was 4. The mean number of respondents per survey was 63. Summaries were made for the following topics: simulation, treatment planning, electron treatments, linac commissioning and quality assurance, setup and treatment verification, IMRT and VMAT treatments, SRS/SBRT, breast treatments, prostate treatments, brachytherapy, TBI, facial lesion treatments, clinical workflow, and after‐hours/emergent treatments. We have provided a coherent overview of medical physics practice according to surveys conducted over the last 5 yr, which will be instructive for medical physicists.

Biomechanical Model-Based Deformable Image Registration for Modeling Neck Flexion in Head and Neck Cancer Patients

Automated Contouring of Contrast and Non-Contrast CT Liver Images with Fully Convolutional Neural Networks

Accurate clinical target volume (CTV) delineation is essential to ensure proper tumor coverage in radiation therapy. This is a particularly difficult task for head-and-neck cancer patients where detailed knowledge of the pathways of microscopic tumor spread is necessary. This paper proposes a solution to auto-segment these volumes in oropharyngeal cancer patients using a two-channel 3D U-Net architecture. The first channel feeds the network with the patient’s CT image providing anatomical context, whereas the second channel provides the network with tumor location and morphological information. Radiation therapy simulation computer tomography scans and their corresponding manually delineated CTV and gross tumor volume (GTV) delineations from 285 oropharyngeal patients previously treated at MD Anderson Cancer Center were used in this study. CTV and GTV delineations underwent rigorous group peer-review prior to the start of treatment delivery. The convolutional network’s parameters were fine-tuned using a training set of 210 patients using 3-fold cross-validation. During hyper-parameter selection, we use a score based on the overlap (dice similarity coefficient (DSC)) and missed volumes (false negative dice (FND)) to minimize any possible under-treatment. Three auto-delineated models were created to estimate tight, moderate, and wide CTV margin delineations. Predictions on our test set (75 patients) resulted in auto-delineations with high overlap and close surface distance agreement (DSC  >  0.75 on 96% of cases for tight and moderate auto-delineation models and 97% of cases having mean surface distance  ⩽  5.0 mm) to the ground-truth. We found that applying a 5 mm uniform margin expansion to the auto-delineated CTVs would cover at least 90% of the physician CTV volumes for a large majority of patients; however, determination of appropriate margin expansions for auto-delineated CTVs merits further investigation.

Auto-delineation of oropharyngeal clinical target volumes using 3D convolutional neural networks

The purpose of this research is to improve treatment of colorectal liver metastases (CLM) in the clinic. It has been previously shown that an ablation margin of 5 mm or more for CLM greatly increases 5 year local tumor progression free survival, however it is often difficult to ensure proper ablation using intraprocedural imaging. CT images of 30 patients with CLM treated with ablation were retrospectively obtained from the MD Anderson Cancer Center. Contours defining the liver, ablation probes, CLM margins, and ablation margin were created from the pre-treatment contrast enhanced CTs and intra-interventional CT images. Using a biomechanical model-based deformable image registration these contours were deformed onto the contrast enhanced CT images obtained just after treatment. The propagated ablation region was then compared with the GTV, as defined before the procedure, to determine the ablation margin delivered. There was a statistically significant difference (p<0.01) in the achieved ablation margin between patients who did and did not have local recurrence. Results showed that patients without local recurrence received on average 3.19 mm of minimum ablation margin around the gross tumor volume(GTV), while those with local recurrence received an average of 1.14 mm. The model presented can assist in the treatment of CLM by identifying the minimum distance to agreement between the GTV and the ablation region directly after treatment. This metric can help determine if sufficient ablation has been delivered to the treat the disease.

Improvement of liver ablation treatment for colorectal liver metastases

Imaging Biomarker Explorer (IBEX) is an open-source tool for medical imaging radiomics work. The purpose of this paper is to describe how to use IBEX's graphical user interface (GUI) and to demonstrate how IBEX calculated features have been used in clinical studies. IBEX allows for the import of DICOM images with DICOM radiation therapy structure files or Pinnacle files. Once the images are imported, IBEX has tools within the Data Selection GUI to manipulate the viewing of the images, measure voxel values and distances, and create and edit contours. IBEX comes with 27 preprocessing and 132 feature choices to design feature sets. Each preprocessing and feature category has parameters that can be altered. The output from IBEX is a spreadsheet that contains: 1) each feature from the feature set calculated for each contour in a data set, 2) image information about each contour in a data set, and 3) a summary of the preprocessing and features used with their selected parameters. Features calculated from IBEX have been used in studies to test the variability of features under different imaging conditions and in survival models to improve current clinical models.

Guidelines and Experience Using Imaging Biomarker Explorer (IBEX) for Radiomics.

The Radiation Planning Assistant (RPA) is a system developed for the fully automated creation of radiotherapy treatment plans, including volume-modulated arc therapy (VMAT) plans for patients with head/neck cancer and 4-field box plans for patients with cervical cancer. It is a combination of specially developed in-house software that uses an application programming interface to communicate with a commercial radiotherapy treatment planning system. It also interfaces with a commercial secondary dose verification software. The necessary inputs to the system are a Treatment Plan Order, approved by the radiation oncologist, and a simulation computed tomography (CT) image, approved by the radiographer. The RPA then generates a complete radiotherapy treatment plan. For the cervical cancer treatment plans, no additional user intervention is necessary until the plan is complete. For head/neck treatment plans, after the normal tissue and some of the target structures are automatically delineated on the CT image, the radiation oncologist must review the contours, making edits if necessary. They also delineate the gross tumor volume. The RPA then completes the treatment planning process, creating a VMAT plan. Finally, the completed plan must be reviewed by qualified clinical staff.

Radiation Planning Assistant - A Streamlined, Fully Automated Radiotherapy Treatment Planning System

Recommended Citation Anderson, Brian M.; Court, Laurence E.; Klopp, Ann; Kry, Stephen F.; Johnson, Jennifer; Cressman, Erik; Rao, Arvind; and Yang, Jinzhong, "Computer-Aided Detection of Pathologically Enlarged Lymph Nodes On Non-Contrast CT In Cervical Cancer Patients For Low-Resource Settings" (2017). UT GSBS Dissertations and Theses (Open Access). 746. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/746

Computer-Aided Detection of Pathologically Enlarged Lymph Nodes On Non-Contrast CT In Cervical Cancer Patients For Low-Resource Settings

Abstract To investigate the inter‐ and intra‐fraction motion associated with the use of a low‐cost tape immobilization technique as an alternative to thermoplastic immobilization masks for whole‐brain treatments. The results of this study may be of interest to clinical staff with severely limited resources (e.g., in low‐income countries) and also when treating patients who cannot tolerate standard immobilization masks. Setup reproducibility of eight healthy volunteers was assessed for two different immobilization techniques. (a) One strip of tape was placed across the volunteer's forehead and attached to the sides of the treatment table. (b) A second strip was added to the first, under the chin, and secured to the table above the volunteer's head. After initial positioning, anterior and lateral photographs were acquired. Volunteers were positioned five times with each technique to allow calculation of inter‐fraction reproducibility measurements. To estimate intra‐fraction reproducibility, 5‐minute anterior and lateral videos were taken for each technique per volunteer. An in‐house software was used to analyze the photos and videos to assess setup reproducibility. The maximum intra‐fraction displacement for all volunteers was 2.8 mm. Intra‐fraction motion increased with time on table. The maximum inter‐fraction range of positions for all volunteers was 5.4 mm. The magnitude of inter‐fraction and intra‐fraction motion found using the “1‐strip” and “2‐strip” tape immobilization techniques was comparable to motion restrictions provided by a thermoplastic mask for whole‐brain radiotherapy. The results suggest that tape‐based immobilization techniques represent an economical and useful alternative to the thermoplastic mask.

This paper considers the classical Susceptible--Infected--Susceptible (SIS) network epidemic model, which describes a disease spreading through $n$ nodes, with the network links governing the possible transmission pathways of the disease between nodes. We consider feedback control to eliminate the disease in scenarios where the disease would otherwise persist in an uncontrolled network. We propose a family of decentralised adaptive-gain control algorithms, in which each node has a control gain that adaptively evolves according to a differential equation, independent of the gains of other nodes. The adaptive gain is applied multiplicatively to either decrease the infection rate or increase the recovery rate. To begin, we assume all nodes are controlled, and prove that both infection rate control and recovery rate control algorithms eliminate the disease with the limiting gains being positive and finite. Then, we consider the possibility of controlling a subset of the nodes, for both the infection rate control and recovery rate control. We first identify a necessary and sufficient condition for the existence of a subset of nodes, which if controlled would result in the elimination of the disease. For a given network, there may exist several such viable subsets, and we propose an iterative algorithm to identify such a subset. Simulations are provided to demonstrate the effectiveness of the various proposed controllers.

Decentralised adaptive-gain control for eliminating epidemic spreading on networks

—In the vector-ﬁeld guided path-following problem, a suf- ﬁciently smooth vector ﬁeld is designed such that its integral curves converge to and move along a one-dimensional geometric desired path. The existence of singular points where the vector ﬁeld vanishes creates a topological obstruction to global convergence to the desired path and some associated topological analysis has been conducted in [1]. In this paper, we strengthen the result in [1, Theorem 2] by showing that the domain of attraction of the desired path, which is a compact asymptotically stable one-dimensional embedded submanifold of an n -dimensional ambient manifold M , is homeomorphic to R n − 1 × S 1 , and not just homotopy equivalent to S 1 as shown in [1, Theorem 2]. This result is extended for a k -dimensional compact manifold for k ≥ 2 .

The Domain of Attraction of the Desired Path in Vector-field Guided Path Following

This paper investigates the problem of securing exponentially fast consensus (exponential consensus for short) for identical agents with finite-dimensional linear system dynamics over dynamic network topology. Our aim is to find the weakest possible conditions that guarantee exponentially fast consensus using a Lyapunov function consisting of a sum of terms of the same functional form. We first investigate necessary conditions, starting by examining the system (both agent and network) parameters. It is found that controllability of the linear agents is necessary for reaching consensus. Then, to work out necessary conditions incorporating the network topology, we construct a set of Laplacian matrix-valued functions. The precompactness of this set of functions is shown to be a significant generalization of existing assumptions on network topology, including the common assumption that the edge weights are bounded piecewise constant functions or continuous functions. With the aid of such a precompactness assumption and restricting the Lyapunov function to one consisting of a sum of terms of the same functional form, we prove that a joint $(\delta, T)$-connectivity condition on the network topology is necessary for exponential consensus. Finally, we investigate how the above two ``necessities'' work together to guarantee exponential consensus. To partially address this problem, we define a synchronization index to characterize the interplay between agent parameters and network topology. Based on this notion, it is shown that by designing a proper feedback matrix and under the precompactness assumption, exponential consensus can be reached globally and uniformly if the joint $(\delta,T)$-connectivity and controllability conditions are satisfied, and the synchronization index is not less than one.

Exponential Consensus of Multiple Agents over Dynamic Network Topology: Controllability, Connectivity, and Compactness

In this letter, we consider an epidemic model for two competitive viruses spreading over a metapopulation network, termed the ‘bivirus model’ for convenience. The dynamics are described by a networked continuous-time dynamical system, with each node representing a population and edges representing infection pathways for the viruses. We survey existing results on the bivirus model beginning with the nature of the equilibria, including whether they are isolated, and where they exist within the state space with the corresponding interpretation in the context of epidemics. We identify key convergence results, including the conclusion that for generic system parameters, global convergence occurs for almost all initial conditions. Conditions relating to the stability properties of various equilibria are also presented. In presenting these results, we also recall some of the key tools and theories used to secure them. We conclude by discussing the various open problems, ranging from control and network optimization, to further characterization of equilibria, and finally extensions such as modeling three or more viruses.

A new approach to solving the linear algebraic equation <inline-formula> <tex-math notation="LaTeX">$Ax=b$ </tex-math></inline-formula> is presented by introducing a leaderless clustered multi-agent system. Each agent is associated with a certain submatrix of <inline-formula> <tex-math notation="LaTeX">$A$ </tex-math></inline-formula> and a vector obtained from <inline-formula> <tex-math notation="LaTeX">$b$ </tex-math></inline-formula> by a certain decomposition process. A distributed algorithm has each agent processing information solely with its own information about <inline-formula> <tex-math notation="LaTeX">$A$ </tex-math></inline-formula> and <inline-formula> <tex-math notation="LaTeX">$b$ </tex-math></inline-formula>, but sharing a time-varying estimate of part of the solution of <inline-formula> <tex-math notation="LaTeX">$Ax=b$ </tex-math></inline-formula> with its neighbors, as defined by a graphical structure overlaying the agents. This graphical structure divides the agents into clusters, with agents in one cluster being associated with one block column of <inline-formula> <tex-math notation="LaTeX">$A$ </tex-math></inline-formula>, and different rows of that block column; with each intra-cluster graph being connected. The update law uses consensus within individual clusters, utilizing their estimated states together with a process of inter-cluster conservation to ensure that the concatenated sub-solutions reached by the clusters solve the overall system of linear equations. Unlike previous literature that uses clustered multi-agent systems or double-layered networks, this framework does not require the presence of an aggregator or central node in the network’s clusters. The algorithm demonstrates exponential convergence, evidenced by both theoretical proof and numerical simulations.

A Distributed Algorithm for Solving Linear Equations in Clustered Multi-Agent Systems

This paper investigates the problem of cooperative tuning of multi-agent optimal control systems, where a network of agents (i.e. multiple coupled optimal control systems) adjusts parameters in their dynamics, objective functions, or controllers in a coordinated way to minimize the sum of their loss functions. Different from classical techniques for tuning parameters in a controller, we allow tunable parameters appearing in both the system dynamics and the objective functions of each agent. A framework is developed to allow all agents to reach a consensus on the tunable parameter, which minimizes team loss. The key idea of the proposed algorithm rests on the integration of consensus-based distributed optimization for a multi-agent system and a gradient generator capturing the optimal performance as a function of the parameter in the feedback loop tuning the parameter for each agent. Both theoretical results and simulations for a synchronous multi-agent rendezvous problem are provided to validate the proposed method for cooperative tuning of multi-agent optimal control.

Graph matching, or the determination of the vertex correspondences between a pair of graphs, is a crucial task in various problems in different science and engineering disciplines. This article aims to propose a distributed optimization approach for graph matching (GM) between two isomorphic graphs over multiagent networks. For this, we first show that for a class of asymmetric graphs, GM of two isomorphic graphs is equivalent to a convex relaxation where the set of permutation matrices is replaced by the set of pseudostochastic matrices. Then, we formulate GM as a distributed convex optimization problem with equality constraints and a set constraint, over a network of multiple agents. For arbitrary labelings of the vertices, each agent only has information about just one vertex and its neighborhood, and can exchange information with its neighbors. A projected primal-dual gradient method is developed to solve the constrained optimization problem, and globally exponential convergence of the agents' states to the optimal permutation is achieved. Finally, we illustrate the effectiveness of the algorithm through simulation examples.

We consider the problem of cooperative motion coordination for multiple heterogeneous mobile vehicles subject to various constraints. These include nonholonomic motion constraints, constant speed constraints, holonomic coordination constraints, and equality/inequality geometric constraints. We develop a general framework involving differential-algebraic equations and viability theory to determine coordination feasibility for a coordinated motion control under heterogeneous vehicle dynamics and different types of coordination task constraints. If a coordinated motion solution exists for the derived differential-algebraic equations and/or inequalities, a constructive algorithm is proposed to derive an equivalent dynamical system that generates a set of feasible coordinated motions for each individual vehicle. In case studies on coordinating two vehicles, we derive analytical solutions to motion generation for two-vehicle groups consisting of car-like vehicles, unicycle vehicles, or vehicles with constant speeds, which serve as benchmark coordination tasks for more complex vehicle groups. The motion generation algorithm is well-backed by simulation data for a wide variety of coordination situations involving heterogeneous vehicles. We then extend the vehicle control framework to deal with the cooperative coordination problem with timevarying coordination tasks and leader-follower structure. We show several simulation experiments on multi-vehicle coordination under various constraints to validate the theory and the effectiveness of the proposed schemes.

Cooperative constrained motion coordination of networked heterogeneous vehicles

This paper studies a particular property of formation rigidity, which is termed infinitesimal sign rigidity, to specify multi-agent target formations using distance- and signed volume-constraints in 3-D space. In comparison with the conventional rigidity theory with distance constraints only, the concept of infinitesimal sign rigidity employs signed volume constraints to eliminate the possibility of formation ambiguity issues arising in 3-D space. Based on the property of infinitesimal sign rigidity, this paper explores a formation specification control law to achieve multi-agent formations with desired distances and signed volumes in 3-D space. It is shown that under the control law, agents close to a target formation can converge to a formation with desired distances and signed volumes exponentially fast.

Formation specification control based on infinitesimal sign rigidity in 3-D space*

Accurately following a geometric desired path in a two-dimensional (2-D) space is a fundamental task for many engineering systems, in particular mobile robots. When the desired path is occluded by obstacles, it is necessary and crucial to temporarily deviate from the path for obstacle/collision avoidance. In this article, we develop a composite guiding vector field via the use of smooth bump functions and provide theoretical guarantees that the integral curves of the vector field can follow an arbitrary sufficiently smooth desired path and avoid collision with obstacles of arbitrary shapes. These two behaviors are reactive since path (re)planning and global map construction are not involved. To deal with the common deadlock problem, we introduce a switching vector field, and the Zeno behavior is excluded. Simulations are conducted to support the theoretical results.

This paper studies a distributed state estimation problem for both continuous- and discrete-time linear systems. A simply structured distributed estimator is ﬁrst described for estimating the state of a continuous-time, jointly observable, input free, multi-channel linear system whose sensed outputs are distributed across a ﬁxed multi-agent network. The estimator is then extended to non-stationary networks whose graphs switch according to a switching signal with a ﬁxed dwell time or a variable but with ﬁxed average dwell time, or switch arbitrarily under appropriate assumptions. The estimator is guaranteed to solve the problem, provided a network-widely shared gain is suﬃciently large. As an alternative to sharing a common gain across the network, a fully distributed version of the estimator is thus studied in which each agent adaptively adjusts a local gain though the practicality of this approach is subject to a robustness issue common to adaptive control. A discrete-time version of the distributed state estimation problem is also studied, and a corresponding estimator is proposed for time-varying networks. For each scenario, it is explained how to construct the estimator so that its state estimation errors all converge to zero exponentially fast at a ﬁxed but arbitrarily chosen rate, provided the network’s graph is strongly connected for all time. This is accomplished by appealing to the “split-spectrum” approach and exploiting several well-known properties of invariant subspace. The proposed estimators are inherently resilient to abrupt changes in the number of agents and communication links in the inter-agent communication graph upon which the algorithms depend, provided the network is redundantly strongly connected and redundantly jointly observable.

A path-following control algorithm enables a system’s trajectories under its guidance to converge to and evolve along a given geometric desired path. There exist various such algorithms, but many of them can only guarantee local convergence to the desired path in its neighborhood. In contrast, the control algorithms using a well-designed guiding vector field can ensure almost global convergence of trajectories to the desired path; here, “almost” means that in some cases, a measure-zero set of trajectories converge to the singular set where the vector field becomes zero (with all other trajectories converging to the desired path). In this article, we first generalize the guiding vector field from the Euclidean space to a general smooth Riemannian manifold. This generalization can deal with path-following in some abstract configuration space (such as robot arm joint space). Then, we show several theoretical results from a topological viewpoint. Specifically, we are motivated by the observation that singular points of the guiding vector field exist in many examples where the desired path is homeomorphic to the unit circle, but it is unknown whether the existence of singular points always holds in general (i.e., is inherent in the topology of the desired path). In the <inline-formula><tex-math notation="LaTeX">$n$</tex-math></inline-formula>-dimensional Euclidean space, we provide an affirmative answer, and conclude that it is not possible to guarantee global convergence to desired paths that are homeomorphic to the unit circle. Furthermore, we show that there always exist nonpath-converging trajectories (i.e., trajectories that do not converge to the desired path) starting from the boundary of a ball containing the desired path in an <inline-formula><tex-math notation="LaTeX">$n$</tex-math></inline-formula>-dimensional Euclidean space where <inline-formula><tex-math notation="LaTeX">$n \geq 3$</tex-math></inline-formula>. Examples are provided to illustrate the theoretical results.

Topological Analysis of Vector-Field Guided Path Following on Manifolds

By the distributed averaging problem is meant the problem of computing the average value of a set of numbers possessed by the agents in a distributed network using only communication between neighboring agents. Gossiping is a well-known approach to the problem which seeks to iteratively arrive at a solution by allowing each agent to interchange information with at most one neighbor at each iterative step. Crafting a gossiping protocol which accomplishes this is challenging because gossiping is an inherently collaborative process which can lead to deadlocks unless careful precautions are taken to ensure that it does not. Many gossiping protocols are request-based which means simply that a gossip between two agents will occur whenever one of the two agents accepts a request to gossip placed by the other. In this paper, we present three deterministic request-based protocols. We show by example that the first can deadlock. The second is guaranteed to avoid deadlocks by exploiting the idea of local ordering together with the notion of an agent’s neighbor queue; the protocol requires the simplest queue updates, which provides an in-depth understanding of how local ordering and queue updates avoid deadlocks. It is shown that a third protocol which uses a slightly more complicated queue update rule can lead to significantly faster convergence; a worst case bound on convergence rate is provided.

According to the DeGroot-Friedkin model of a social network, an individual's social power evolves as the network discusses individual opinions over a sequence of issues. Under mild assumptions on the connectivity of the network, the social power of every individual converges to a constant nonnegative value as the number of issues discussed increases. If the network has a special topology, namely the “star topology”, then all social power accumulates with the individual at the centre of the star. This paper studies the strategic introduction of new individuals and/or interpersonal relationships into a social network with the star topology so as to reduce the social power of the centre individual. In fact, several strategies are proposed. For each strategy, we derive necessary and sufficient conditions on the strength of the new interpersonal relationships, based on local information, which ensures that the centre individual no longer has the greatest social power within the social network. Interpretations of these conditions reveal that the strategies are remarkably intuitive and that certain strategies are favourable compared to others, all of which is sociologically expected.

Modification of social dominance in social networks by selective adjustment of interpersonal weights

This paper proposes a distributed model‐independent algorithm to achieve leaderless consensus on a directed network where each fully‐actuated agent has self‐dynamics described by Euler–Lagrange equations of motion. Specifically, we aim to achieve consensus of the generalised coordinates with zero generalised velocity. We show that on a strongly connected graph, a model‐independent algorithm can achieve the consensus objective at an exponential rate if an upper bound on the initial conditions is known a priori. By model‐independent, we mean that each agent can execute the algorithm with no knowledge of the equations describing the self‐dynamics of any agent. For design of the control laws which achieve consensus, a control gain scalar and a control gain matrix are required to satisfy several inequalities involving bounds on the matrices of the agent dynamic model, bounds on the Laplacian matrix describing the network topology and the set of initial conditions; design of the algorithm therefore requires some knowledge on the bounds of the agent dynamical parameters. Because only bounds are required, the proposed algorithm offers robustness to uncertainty in the parameters of the multiagent system. We systematically show that additional relative velocity information improves the performance of the controller. Numerical simulations are provided to show the effectiveness of the algorithm. Copyright © 2016 John Wiley & Sons, Ltd.

Distributed model‐independent consensus of Euler–Lagrange agents on directed networks

Most of the existing results on distributed distance‐constrained rigid formation control establish asymptotic or exponential convergence. To further improve the convergence rate, we explain in this paper how to modify existing gradient controllers to obtain finite time stability. For point agents modeled by single integrators, the controllers proposed in this paper drive the whole formation to locally converge to a desired shape with finite settling time. We also show for undirected triangular formation shape control, if all the agents start with non‐collinear positions, then the formation will converge to the desired shape in finite time. For agents modeled by double integrators, the proposed controllers allow all agents to both achieve the same velocity and reach a desired shape in finite time. All controllers are totally distributed. Simulations are also provided to validate the proposed control strategies. Copyright © 2015 John Wiley & Sons, Ltd.

Finite time distributed distance‐constrained shape stabilization and flocking control for d‐dimensional undirected rigid formations

This paper considers the problem of localization and circumnavigation of a group of targets, which are either stationary or moving slowly with unknown speed, by a single agent. An estimator is proposed, initially for the stationary target case, to localize the targets and the center of mass of them as well as a control law that forces the agent to move on a circular trajectory around the center of mass of the targets such that both the estimator and the controller are exponentially stable. Then the case where the targets might experience slow but possibly steady movements is studied. The system inputs include the agent's position and the bearing angles to the targets. The performance of the proposed algorithms is verified through simulations. Copyright © 2014 John Wiley & Sons, Ltd.

Multi‐target localization and circumnavigation by a single agent using bearing measurements

Multi‐agent formations have been recently the subject of many studies. An important operational challenge, largely unaddressed in the literature, is to ensure that functionality of the formation is retained should agents be lost through misadventure, mission reassignment, and so on. In the context of sensor networks, it is also important to allow for the loss of multiple sensors as the low quality of sensor hardware, common unattended implementations, and so on makes it a common issue. In this paper, we address these issues by proposing information structures that are tolerant to the loss of multiple agents. Using graph theory (and more specifically rigidity theory), we characterize several properties of such formations/networks in a unified framework: We characterize the k‐vertex rigidity property of the underling graph of such formations. This is performed by deriving a set of useful conditions that can form a guideline for designing agent‐loss‐tolerant formations. We elaborate the study by characterizing robust formations with the optimal number of control links. We also propose a set of operations preserving the tolerance to multiple agent losses in such formations. These operations provide flexibility in designing the formations in terms of several designing parameters (e.g., geometry, diameter, and max degree). Especially in the case of formations, the ability to handle controller adjustments in a distributed way is important, and the paper addresses this issue for a number of the robustness problems considered. Copyright © 2014 John Wiley & Sons, Ltd.

On the robustness to multiple agent losses in 2D and 3D formations

Heterogeneous formation shape control with interagent bearing and distance constraints involves the design of a distributed control law that ensures the formation moves such that these interagent constraints are achieved and maintained. This paper looks at the design of a distributed control scheme to solve different formation shape control problems in an ambient two‐dimensional space with bearing, distance and mixed bearing and distance constraints. The proposed control law allows the agents in the formation to move in any direction on a half‐plane and guarantees that despite this freedom, the proposed shape control algorithm ensures convergence to a formation shape meeting the prescribed constraints. This work provides an interesting and novel contrast to much of the existing work in formation control where distance‐only constraints are typically maintained and where each agent's motion is typically restricted to follow a very particular path. A stability analysis is sketched, and a number of illustrative examples are also given. Copyright © 2014 John Wiley & Sons, Ltd.

Abstract Most of the existing results on distributed distance-based rigid formation control establish asymptotic and often exponentially asymptotic convergence. To further improve the convergence rate, we explain in this paper how to modify existing controllers to obtain finite time stability. For point agents modeled by single integrators, the controllers proposed in this paper drive the whole formation to converge to a desired shape with finite settling time. For agents modeled by double integrators, the proposed controllers allow all agents to both achieve the same velocity and reach a desired shape in finite time. All controllers are totally distributed. Simulations are also provided to validate the proposed control.

Finite Time Distance-based Rigid Formation Stabilization and Flocking

This paper presents an adaptive scheme for localization of a target from distance measurements and motion control of a mobile agent to pursue this target. The localization and motion control task of interest is approached within a parameter‐identifier‐based adaptive control framework, where the localization is formulated as a parameter identification problem and the motion control is achieved using an adaptive controller based on the produced location estimates of the target. First, a robust adaptive law is designed to generate location estimate of the target using distance measurements. Then, following the standard certainty equivalence approach, a motion control law is developed considering substitution of the estimate generated by the localization algorithm for the unknown location of the target. Noting that there is some incompatibility between the persistence of excitation requirements of the localization algorithm and the target pursuit goal of the motion control law, the base motion control law is (re)designed to eliminate the effects of this incompatibility. The novelty of this paper is in this motion control design eliminating the persistence of excitation incompatibility. Stability and convergence analysis for the overall adaptive control scheme is presented. The results are valid in both two and three dimensions of motion space. The applications of the adaptive scheme include rescue localization, surveillance of signal sources, and formation acquisition of autonomous multi‐robot/vehicle systems. Copyright © 2012 John Wiley & Sons, Ltd.

This manuscript considers the problem of close target reconnaissance by a group of autonomous agents. The overall close target reconnaissance (CTR) involves subtasks of avoiding inter‐agent collisions, reaching a close vicinity of a specific target position, and forming an equilateral polygon formation around the target. The agents performing the task fly at a constant speed to mimic the velocity behavior of small fixed‐wing unmanned aerial vehicles (UAV). A decentralized control scheme is developed for this overall task and the finite‐time convergence of the system under the proposed control law is established. Furthermore, it is guaranteed that no collision occurs among the agent. The relevant analysis and simulation test results are provided. Copyright © 2010 John Wiley & Sons, Ltd.

This paper proposes a systematic approach to solve the closing rank problem for a rigid multi‐agent formation, viz. restoring rigidity after loss of an agent. The approach is based on a particular graph operation, the edge contraction operation. It is proven that when an agent is lost in an arbitrary two‐dimensional rigid formation, rigidity can always be restored by transferring all links to which this agent was incident on to one of its neighbors, though not in general any arbitrary one of them. From a graph theoretical point of view, this corresponds to contraction of a certain edge incident to the vertex representing the agent being lost. It is established, for any two‐dimensional rigid formation (graph), that there exists at least two such edges that can be contracted to solve the closing ranks problem. Later, it is demonstrated that any potential decentralized algorithm to check if an arbitrary edge is contractible would need to use information on vertices and edges that can be at arbitrarily large distance from the edge considered; and a set of rigid graph theoretical results are established for several general settings, which can be used in selection of the edge to contract in these settings in order to solve the corresponding closing ranks problems. Partial results are also obtained for three‐dimensional formations, and it is shown that the two‐dimensional results do not generalize as such to higher dimension. Copyright © 2010 John Wiley & Sons, Ltd.

Closing ranks in rigid multi‐agent formations using edge contraction

In this paper, we address the problem of agent loss in vehicle formations and sensor networks via two separate approaches: (1) perform a ‘self‐repair’ operation in the event of agent loss to recover desirable information architecture properties or (2) introduce robustness into the information architecture a priori such that agent loss does not destroy desirable properties. We model the information architecture as a graph G(V, E), where V is a set of vertices representing the agents and E is a set of edges representing information flow amongst the agents. We focus on two properties of the graph called rigidity and global rigidity, which are required for formation shape maintenance and sensor network self‐localization, respectively. For the self‐repair approach, we show that while previous results permit local repair involving only neighbours of the lost agent, the repair cannot always be implemented using only local information. We present new results that can be applied to make the local repair using only local information. We describe implementation and illustrate with algorithms and examples. For the robustness approach, we investigate the structure of graphs with the property that rigidity or global rigidity is preserved after removing any single vertex (we call the property as 2‐vertex‐rigidity or 2‐vertex‐global‐rigidity, respectively). Information architectures with such properties would allow formation shape maintenance or self‐localization to be performed even in the event of agent failure. We review a characterization of a class of 2‐vertex‐rigidity and develop a separate class, making significant strides towards a complete characterization. We also present a characterization of a class of 2‐vertex‐global‐rigidity. Copyright © 2008 John Wiley & Sons, Ltd.

We examine the problem of optimal bearing-only localization of a single target using synchronous measurements from multiple sensors. We approach the problem by forming geometric relationships between the measured parameters and their corresponding errors in the relevant emitter localization scenarios. Specifically, we derive a geometric constraint equation on the measurement errors in such a scenario. Using this constraint, we formulate the localization task as a constrained optimization problem that can be performed on the measurements in order to provide the optimal values such that the solution is consistent with the underlying geometry. We illustrate and confirm the advantages of our approach through simulation, offering detailed comparison with traditional maximum likelihood (TML) estimation.

Bearing-Only Localization using Geometrically Constrained Optimization

This paper treats the problem of merging formations, where the underlying model of a formation is graphical. We first analyze the rigidity and persistence of meta‐formations, which are formations obtained by connecting several rigid or persistent formations. Persistence is a generalization to directed graphs of the undirected notion of rigidity. In the context of moving autonomous agent formations, persistence characterizes the efficacy of a directed structure of unilateral distance constraints seeking to preserve a formation shape. We derive then, for agents evolving in a two‐ or three‐dimensional space, the conditions under which a set of persistent formations can be merged into a persistent meta‐formation, and give the minimal number of interconnections needed for such a merging. We also give conditions for a meta‐formation obtained by merging several persistent formations to be persistent. Copyright © 2008 John Wiley and Sons Asia Pte Ltd and Chinese Automatic Control Society

Rigidity and persistence for ensuring shape maintenance of multi‐agent meta‐formations

This paper proposes a new type of algorithm aimed at finding the traditional maximum-likelihood (TML) estimate of the position of a target given time-difference-of-arrival (TDOA) information, contaminated by noise. The novelty lies in the fact that a performance index, akin to but not identical with that in maximum likelihood (ML), is a minimized subject to a number of constraints, which flow from geometric constraints inherent in the underlying problem. The minimization is in a higher dimensional space than for TML, and has the advantage that the algorithm can be very straightforwardly and systematically initialized. Simulation evidence shows that failure to converge to a solution of the localization problem near the true value is less likely to occur with this new algorithm than with TML. This makes it attractive to use in adverse geometric situations.

Optimal Range-Difference-Based Localization Considering Geometrical Constraints

This article sets out the rudiments of a theory for analyzing and creating architectures appropriate to the control of formations of autonomous vehicles. The theory rests on ideas of rigid graph theory, some but not all of which are old. The theory, however, has some gaps in it, and their elimination would help in applications. Some of the gaps in the relevant graph theory are as follows. First, there is as yet no analogue for three-dimensional graphs of Laman's theorem, which provides a combinatorial criterion for rigidity in two-dimensional graphs. Second, for three-dimensional graphs there is no analogue of the two-dimensional Henneberg construction for growing or deconstructing minimally rigid graphs although there are conjectures. Third, global rigidity can easily be characterized for two-dimensional graphs, but not for three-dimensional graphs.

In this paper we characterize the relative sensor-target geometry in R2 in terms of potential localization performance for time-of-arrival based localization. Our aim is to characterize those relative sensor-target geometries which minimize the relative Cramer-Rao lower bound.

2007 3rd International Conference on Intelligent Sensors, Sensor Networks and Information

Optimality Analysis of Sensor-Target Geometries in Passive Localization: Part 2 - Time-of-Arrival Based Localization

In this paper, we examine the geometric relations between various measured parameters and their corresponding errors in angle-measurement based emitter localization scenarios. We derive a geometric constraint formulating the relationship among the measurement errors in such a scenario. Using this constraint, we formulate the localization task as a constrained optimization problem that can be performed on the measurements in order to provide the optimal values such that the solution is consistent with the underlying geometry.

Passive Angle Measurement Based LocalizationConsistency via Geometric Constraints

In this paper, we analyze the problem of acquiring and maintaining desired inter-agent distances for non-hierarchical autonomous multi-agent platoons (1-dimensional formations), where the agents can be autonomous robots or vehicles, using only agent-wise relative position measurements. In our analysis, we consider the existence of measurement noises, which may cause the failure of controllers ignoring these noises in keeping the positions of the agents bounded. We design a switching control scheme that addresses the above problem, i.e., that acquires and maintains the desired inter-agent distances while guaranteeing that the agent positions are kept bounded.

Switching control for robust autonomous robot and vehicle platoon formation maintenance

Inspired by the recent "Robot Sheepdog Project" in the literature, in this paper a new method for coordination of multi-agent systems moving in a 2-dimensional region with the obstacles along a collision free trajectory is presented. A two level decentralized control scheme is proposed. At lower level, for the agents within the formation, "the sheep", the only concern is to keep that of their formation shape intact and avoid inter-agent collision. At the higher level, an intelligent agent, "the sheepdog", is responsible for determining a collision free trajectory for both the formation and itself, and then coordinating the formation motion along this computed path sequence. This sheepdog utilizes a repulsive vector (acting as a source of repulsive force) to drive the formation along the planned path. The effectiveness of the proposed scheme is demonstrated via simulation results in the presence of multiple obstacles.

In this paper we characterize the relative sensor-target geometry for bearing-only localization in R2. We analyze the geometry in terms of the Cramer-Rao inequality and the corresponding Fisher information matrix, aiming to characterize and state explicit results in terms of the potential localization performance. In particular, a number of interesting results are rigorously derived which highlight erroneous assumptions often made in the existing literature.

Optimality Analysis of Sensor-Target Geometries in Passive Localization: Part 1 - Bearing-Only Localization

Accurate self-localization capability is highly desirable in wireless sensor networks. A major problem in trilateration based wireless sensor network localization that may introduce large errors in the location estimates is flip ambiguity. Recently the notion of robust quadrilaterals has been introduced as a way to identify possible flip ambiguities that otherwise corrupt localization computations. In this paper, we provide a formal geometric analysis of flip ambiguity problems using similar notions. The two main objectives of the paper are filling some technical gaps in the recent relevant works and developing a generic formal method for quantifying the likelihood of suffering from flip ambiguities for arbitrary sensor neighborhood geometries.

Analysis of Flip Ambiguities in Distributed Network Localization

This paper treats the problem of the merging of formations, where the underlying model of a formation is graphical. We first analyze the persistence of meta-formations, which are formations obtained by connecting several persistent formations. Persistence is a generalization to directed graphs of the undirected notion of rigidity. In the context of moving autonomous agent formations, persistence characterizes the efficacy of a directed structure of unilateral distance constraints seeking to preserve a formation shape. We derive then, for agents evolving in a two- or three-dimensional space, the conditions under which a set of persistent formations can be merged into a persistent meta-formation, and give the minimal number of interconnections needed for such a merging. We also give conditions for a meta-formation obtained by merging several persistent formations to be persistent

The path loss exponent (PLE) is a parameter indicating the rate at which the received signal strength (RSS) decreases with distance, and its value depends on the specific propagation environment. Path loss exponent estimation plays an important role in distance-based wireless sensor network localization, where distance is estimated from the RSS measurements. Path loss exponent estimation is also useful for other purposes like sensor network dimensioning. Existing techniques on PLE estimation rely on both RSS measurements and distance measurements in the same environment to calibrate the PLE. However distance measurements can be difficult and expensive to obtain in some environments. In this paper we propose a novel technique for online calibration of the path loss exponent in wireless sensor networks without using distance measurements. The major contribution of this paper is to demonstrate that it is possible to estimate the PLE using only power measurements and the geometric constraints associated with planarity in a sensor network. This may have a significant impact on wireless sensor network localization.

WSN06-4: Online Calibration of Path Loss Exponent in Wireless Sensor Networks

The sensor network localization problem with distance information is to determine the positions of all sensors in a network given the positions of some sensors and the distances between some pairs of sensors. We present a specialized localization algorithm and identify the graph properties of some classes of networks that can be localized by the algorithm. We also give an important application of our algorithm in creating formations in multi-agent systems

This paper considers the problem of merging of more than two (minimally) rigid formations which do not have any common agent to obtain a single (minimally) rigid formation in Rfr2 and Rfr3. Following previously developed strategies for sequential merging of two rigid formations, a new set of enhanced merging operations is developed. They can be performed in a formalized meta-formation framework, where the individual rigid formations are considered as meta-vertices and they can be merged into a meta-formation. These operations for growing meta-formations offer a level of control to the merging quality and optimality, in the sense of minimizing the number of meta-edges (that is, edges between different meta-vertices) required. It is also proved that all minimally rigid meta-formations in Rfr2 can be obtained by successively merging two or more meta-vertices using the proposed set of meta-operations

The problem of source localization has assumed increased importance in recent years. Applications include locating the source of a cellular phone signal, sensor localization or satellite localization. In this paper we formulate a continuous time adaptive localization algorithm that permits a mobile agent to estimate the location of a stationary source using only the measured distance from the source. The algorithm is shown to be exponentially asymptotically stable, under a persistent excitation condition that has an intuitively appealing interpretation. Exponential asymptotic stability indicates the ability of the algorithm to track modest movements of the source

This paper reviews a number of concepts and results relevant to the design of architectures to maintain the shape of a formation of autonomous agents. The paper begins with motivating examples from nature and the manmade world, and emphasises the task of providing satisfactory sensing, communication and control architectures within a formation of autonomous agents. Then some technical tools for characterising and designing architectures are described, largely resting on graph theoretic considerations.

This paper is concerned with rigid formations of mobile autonomous agents that have leader-follower architecture. In a previous paper, Baillieul and Suri gave a proposition as a necessary condition for stable rigidity. They also gave a separate theorem as a sufficient condition for stable rigidity. This paper suggests an approach to analyze rigid formations that have leader-follower architecture. It proves that the third condition in the proposition given by Baillieul and Suri is redundant, and it proves that this proposition is a necessary and sufficient condition for stable rigidity. Simulation results are also presented to illustrate rigidity.

Information structures to secure control of rigid formations with leader-follower architecture

Motivated by [1], [2] and [3], we consider here formations of autonomous agents in a 2-dimensional space. Each agent tries to maintain its distances toward a pre-specified group of other agents constant, and the problem is to determine if one can guarantee that the structure of the formation will persist, i.e., if the distance between any pair of agents will remain constant. A natural way to represent such a formation is to use a directed graph. We provide a theoretical framework for this problem, and give a formal definition of persistent graphs (a graph is persistent if almost all corresponding agents formations persist). Note that although persistence is related to rigidity (concerning which much is known [4]), these are two distinct notions. We then derive various properties of persistent graphs, and give a combinatorial criterion to decide persistence. We also define the notion of minimal persistence (persistence with least number of edges), and eventually, we apply these notion to the interesting special case of cycle-free graphs.

An approach to formulate geometric relations among distances between nodes as equality constraints is introduced in this paper to study the localization problem with imprecise distance information in sensor networks. These constraints can be further used to formulate optimization problems for distance estimation. The optimization solutions correspond to a set of distances that are consistent with the fact that sensor nodes live in the same plane or 3D space as the anchor nodes. These techniques serve as the foundation for most of the existing localization algorithms that depend on the sensors' distances to anchors to compute each sensor’s location.

Localization with Imprecise Distance Information in Sensor Networks

Knowing the positions of the nodes in a network is essential to many next generation pervasive and sensor network functionalities. Although many network localization systems have recently been proposed and evaluated, there has been no systematic study of partially localizable networks, i.e., networks in which there exist nodes whose positions cannot be uniquely determined. There is no existing study which correctly identifies precisely which nodes in a network are uniquely localizable and which are not. This absence of a sufficient uniqueness condition permits the computation of erroneous positions that may in turn lead applications to produce flawed results. In this paper, in addition to demonstrating the relevance of networks that may not be fully localizable, we design the first framework for two dimensional network localization with an efficient component to correctly determine which nodes are localizable and which are not. Implementing this system, we conduct comprehensive evaluations of network localizability, providing guidelines for both network design and deployment. Furthermore, we study an integration of traditional geographic routing with geographic routing over virtual coordinates in the partially localizable network setting. We show that this novel cross-layer integration yields good performance, and argue that such optimizations will be likely be necessary to ensure acceptable application performance in partially localizable networks.

Proceedings IEEE 24th Annual Joint Conference of the IEEE Computer and Communications Societies.

This paper focuses on developing techniques and strategies for the analysis and design of sensor and network topologies required to achieve rigid formations of mobile autonomous agents for cooperative tasks. These strategies ensure minimum number of changes in the set of sensing and communication links between agents during splitting and merging operations. That is, in splitting, all the links between agents in the same post-split sub-formation are preserved and a minimum number of links are inserted into each post-split sub-formation to regain minimal rigidity. In merging, all the links in each pre-merged rigid sub-formation are preserved and a minimum number of links are inserted between sub-formations to create one single post-merged minimally rigid formation.

Information structures to control formation splitting and merging

This paper is concerned with the collective behavior of a group of n > 1 mobile autonomous agents, labelled 1 through n, which can all move in the plane. Each agent is able to continuously track the positions of all other agents currently within its "sensing region" where by an agent's sensing region is meant a closed disk of positive radius r centered at the agent's current position. The multi-agent rendezvous problem is to devise "local" control strategies, one for each agent, which without any active communication between agents, cause all members of the group to eventually rendezvous at single unspecified location. This paper describes a family of asynchronously functioning strategies for solving the problem. Correctness is established appealing to the concept of "analytic synchronization".

2004 43rd IEEE Conference on Decision and Control (CDC) (IEEE Cat. No.04CH37601)

This paper is concerned with the collective behavior of a group of n > 1 mobile autonomous agents, labelled 1 through n, which can all move in the plane. Each agent is able to continuously track the positions of all other agents currently within its "sensing region" where by an agent's sensing region is meant a closed disk of positive radius r centered at the agent's current position. The multi-agent rendezvous problem is to devise "local" control strategies, one for each agent, which without any active communication between agents, cause all members of the group to eventually rendezvous at single unspecified location. This paper describes two types of strategies for solving the problem. The first consists of agent strategies, which are mutually synchronized, in the sense that all depend on a common clock. The second consists of strategies, which can be implemented independent of each other, without reference to a common clock.

42nd IEEE International Conference on Decision and Control (IEEE Cat. No.03CH37475)

Two different methods have been proposed for performing asymptotically optimal simulation to obtain the statistics of buffer overflows in queueing networks, with both using large deviations and importance sampling. In the first, based on heuristic arguments, the distributions of interarrival and virtual service times are analyzed to find the simulation system. In the second, it is the distribution of jumps occurring in a Markov chain that is examined. The authors show that the approaches produce identical fast simulation systems for an arbitrary G1/G1/1 queue.<<ETX>>

[1991] Proceedings of the 30th IEEE Conference on Decision and Control

Importance sampling, jump distributions and event-time distributions

In the investigation of the robust stability of control systems with structured uncertainties, many results have been presented that lead to stability tests of the edges of a polytope. Some results are discussed where the stability of an edge can be guaranteed by the stability of the vertices of the edge. For two types of stability-the Schur and a rational D-stability-the conditions for the vertex property of an edge are obtained from the decomposition of the edge polynomials. The associated polynomial families, which can result by control of uncertain plants, are discussed.<<ETX>>

Robust stability of control systems: extreme point results for the stability of edges

The problem of finding a time-invariant controller for a given SISO (single-input, single output) plant so that the closed-loop system satisfies two tolerances for sensitivity and for complementary sensitivity simultaneously is considered. The solvability condition of the problem is derived in terms of an explicit inequality. It is also discovered that for a multivariable plant, there exists a very simple one-to-one correspondence between the sensitivity problem for r > 1 and the complementary sensitivity problem for the same r. Namely, a solution to either of the two problems can be obtained simply by multiplying a solution to the other problem by some certain constant. This indicates that sensitivity and complementary sensitivity have the same minimum for a plant if either minimum is greater than 1.<<ETX>>

The combined sensitivity and gain margin problem for single-input, single-output linear systems is formulated and solved using a complex function interpolation technique. It is proved that this problem always has a real rational solution provided it is solvable in the complex irrational sense. The sensitivity minimization problem subject to a gain margin constraint and its dual problem are also considered. In addition, the range of the gain margin constraint subject to which the optimal constrained sensitivity is identical to the optimal unconstrained sensitivity is given. It is shown that gain margin maximization conflicts with sensitivity minimization for a nonminimum phase plant.<<ETX>>

Proceedings of the 28th IEEE Conference on Decision and Control,

The simultaneous optimization problem for sensitivity and gain margin

When a decision feedback equalizer is used on a channel satisfying a simple constraint the error recovery time is bounded, and thus recovery is rapid, regardless of the initial conditions and the particular data sequence. The authors define the finite-error-recovery-time problem. The background passivity theory is then given along with the authors' main theorem. Four applications are presented, including an analysis of a real channel. Convergence rates and explicit bounds are established, given an exponential overbound on the channel impulse response. The result for M-ary data is presented, and the error-recovery-time bound is related back to the binary case. For high SNR channels satisfying a passivity constraint, a formula for error probability is given.<<ETX>>

Channels leading to rapid error recovery for decision feedback equalizers: passivity analysis

 This study was conducted to determine the efficacy and safety of a dietary vitamin D source on growth performance and tissue deposition of 25-hydroxycholecalciferol (25OHD3) in growing swine. Dietary treatments were a control with vitamin D3 at NRC recommended concentrations (C) and 3 diets composed of C + increasing inclusions (25, 50, and 250 µg/kg BioD, Huvepharma) of 25OHD3 (C+25; C+50; and C+250 respectively). Pigs (n = 144) were assigned to 24 pens which were allotted to 1 of 4 dietary treatments and fed for 42 d. On d 0, 39, and 63, serum was collected for 25OHD3 concentration determination and individual BW were measured. At d 42, tissues from 48 pigs (12 pigs per treatment) were analyzed for 25OHD3 concentration, blood chemistry and hematology (BCH) analysis was conducted, and 1 femur from each pig was collected for dual-energy X-ray absorptiometry scanning. Data were analyzed with SAS PROC GLIMMIX and means separated at P ≤ 0.05. No differences among treatments were observed for growth performance (P ≥ 0.2239). Serum and tissue 25OHD3 concentrations increased linearly as dietary 25OHD3 inclusion increased (P < 0.0001). Following a 21-d withdrawal period, 25OHD3 serum concentrations decreased to that of or within 2.76 ± 0.89 ng/mL of C-fed pigs (P > 0.0005). All BCH variables measured were similar among treatments (P = 0.0967). At day 42, femurs from C+50 and C+250-fed pigs had the greatest bone mineral content (BMC) and density (BMD; P < 0.0326). Concentrations of 25OHD3 in serum and tissue increased and BMC and BMD were improved as dietary vitamin D supplementation increased, but pig growth performance was unaltered. Absence of gross abnormalities and changes in BCH as well return of circulating 25OHD3 concentrations to that of C-fed pigs following withdrawal indicate this source can safely improve vitamin D status in growing pigs.

263 Efficacy and Safety of a Novel Source of 25-Hydroxycholecalciferol in Performance and Tissue Deposition in Growing Pigs

The identification of the endogenous ligands of natural killer T cells reveals the presence of mammalian α-linked glycosylceramides.

Natural killer T (NKT) cells are a subset of T cells that recognize glycolipid antigens presented by the CD1d protein. The initial discovery of immunostimulatory glycolipids from a marine sponge and the T cells that respond to the compounds has led to extensive research by chemists and immunologists to understand how glycolipids are recognized, possible responses by NKT cells, and the structural features of glycolipids necessary for stimulatory activity. The presence of this cell type in humans and most mammals suggests that it plays critical roles in antigen recognition and the interface between innate and adaptive immunity. Both endogenous and exogenous natural antigens for NKT cells have been identified, and it is likely that glycolipid antigens remain to be discovered. Multiple series of structurally varied glycolipids have been synthesized and tested for stimulatory activity. The structural features of glycolipids necessary for NKT cell stimulation are moderately well understood, and designed compounds have proven to be much more potent antigens than their natural counterparts. Nevertheless, control over NKT cell responses by designed glycolipids has not been optimized, and further research will be required to fully reveal the therapeutic potential of this cell type.

Synthesis and Immunological Evaluation of Type I, Type II, and γδ NKT Cell Antigens Brian L. Anderson Department of Chemistry and Biochemistry Doctor of Philosophy The purpose of the immune system is to protect our bodies from infection. One way it accomplishes this task is through the presentation of foreign pathogens to NKT cells. After an antigen is presented to the T cell receptor, activated NKT cells quickly release soluble chemical signals, termed chemokines and cytokines, that modulate the response of the immune system. Due to the immunological relevance of NKT cell activation, we developed and synthesised non-natural analogs of immunostimulatory type I, II, and γδ NKT cell antigens. The immunological evaluations of these analogs resulted in identification of sulfatide as a γδ NKT cell antigen, along with the characterization of these newly discovered sulfatide-reactive γδ NKT cell line. During sulfatide structure activity relationship studies, a novel azido-sulfatide analog was synthesized to traffick and image sulfatide in vivo. These studies demonstrated that sulfatide accumulated in the late endosome/lysosome. In conjunction with previous studies, this observation explains the persistence of CD1d-restricted T cells with high affinity for this antigen in healthy individuals. Finally, stimulatory assays were performed on a panel of synthesized lyso-glycosylceramides. This led to the discovery of stimulatory type I NKT cell antigens, α-psychosine and α-glucopsychosine.

Synthesis and Immunological Evaluation of Type I, Type II, and gammadelta NKT Cell Antigens

The dysfibrinogen γR275C can be a clinically silent mutation, with only two out of 17 cases in the literature reporting a hemorrhagic presentation and four cases reporting a thrombotic presentation. We describe here a particularly severe presentation in 54-year-old female patient who required a hysterectomy at 47 years of age due to heavy menstrual bleeding. Coagulation studies revealed a prolonged prothrombin time and thrombin time, a normal fibrinogen antigen level, and a low fibrinogen activity level. Molecular analysis of the patient's DNA revealed a γ chain gene mutation resulting in an amino acid substitution at residue 275 (γR275C). Protein sequencing of the fibrinogen γ chain confirmed this mutation, which was named Fibrinogen Portland I. This case demonstrates that the γR275C mutation can lead to a severe hemorrhagic phenotype.

Severe bleeding in a woman heterozygous for the fibrinogen γR275C mutation

The envelope glycoprotein G of rabies virus in vaccines induces the production of neutralizing antibodies important in the protection against the disease. The measurement of anti-envelope glycoprotein antibodies is a good predictor of the degree of humoral immunity in people during anti-rabies treatment or after vaccination. Several assays exist for the serological determination of antibody protection against rabies virus infection. Antibody neutralization by the rapid fluorescent focus inhibition test (RFFIT) or the fluorescent antibody virus neutralization (FAVN) test is currently the gold standard. Performance of the highly complex RFFIT and FAVN tests, however, requires specialized reference laboratories with expertise with this assay. Although not widely used, ELISA test kits are available and may be an additional option for testing that is more accessible. The aim of the present study was to evaluate available ELISA assays for the determination of anti-rabies antibodies. We compared the Bio-Rad Platelia Rabies II ELISA, DRG Rabies Virus IgG Ab ELISA and Focus Diagnostics Rabies Antibody Detection by ELISA to RFFIT. Bland-Altman plots comparing the Bio-Rad Platelia assay and the Focus Diagnostics assay to RFFIT showed a low degree of variability between the ELISA assays and RFFIT results except in samples with high RFFIT values. The agreement, sensitivity and specificity of Bio-Rad Platelia Rabies II ELISA when compared to RFFIT were 95.1 %, 94.1 % and 95.8 %, respectively. The DRG Rabies assay compared to RFFIT had an agreement of 77.7 %, a sensitivity of 86.7 % and a specificity of 69.4 %. The agreement, sensitivity and specificity of Focus Diagnostics Rabies Detection by ELISA when compared to RFFIT were 82.2 %, 91.7 % and 73.0 %, respectively. Overall, the Bio-Rad Platelia assay showed higher accuracy and specificity than either the DRG or Focus assays. All of these ELISAs, however, measure all antibody types and do not discriminate the neutralizing antibodies as measured by functional assays (RFFIT and FAVN) and cannot be relied upon to predict the neutralizing activity of the sera. The results of this study offer insight into the availability of alternative, less-complex methods to monitor rabies antibody titres in at-risk individuals following vaccination.

An evaluation of two commercially available ELISAs and one in-house reference laboratory ELISA for the determination of human anti-rabies virus antibodies.

ABSTRACT Tuberculosis (TB) caused by Mycobacterium tuberculosis remains a major world disease, with approximately 9 million new cases each year. Identification and treatment of active disease are essential for TB control. Serology may offer increased detection of active disease in patients with a positive tuberculin skin test (TST) or QuantiFERON-TB (QFT-G). The InBios Active TbDetect immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA), IBL M. tuberculosis IgG ELISA, and Anda Biologics TB ELISAs were evaluated for the ability to detect M. tuberculosis antibodies in patients with active disease. Agreement, sensitivity, and specificity for each ELISA were determined and compared to those for culture or amplified direct detection and M. tuberculosis low-risk control patients. The InBios Active TbDetect ELISA had an agreement of 96.2%, a sensitivity of 83.3%, and a specificity of 98.9%. The IBL M. tuberculosis ELISA had an agreement of 84.0%, a sensitivity of 5.6%, and a specificity of 100.0%. The agreement, sensitivity, and specificity of the Anda Biologics TB ELISA were 74.2%, 83.3%, and 72.0%, respectively. The sensitivity for detecting M. tuberculosis antibodies in human immunodeficiency virus-associated TB was 50% for both the InBios Active TbDetect ELISA and the Anda Biologics TB ELISA and 0% for the IBL M. tuberculosis ELISA. The positivity rates for InBios Active TbDetect ELISA, IBL M. tuberculosis ELISA, and Anda Biologics TB ELISA in latently infected individuals positive by TST and/or QFT-G were 5.1%, 0.0%, and 30.8%, respectively. It can be concluded that the InBios Active TbDetect IgG ELISA is superior to the other ELISAs in accurately detecting active TB.

Assessment of Three Commercially Available Serologic Assays for Detection of Antibodies to Mycobacterium tuberculosis and Identification of Active Tuberculosis

As West Nile virus (WNV) has become endemic in the United States, following the first reported cases in New York during the summer of 1999, the demand for specific serology has increased. Several IgM capture ELISA assays for the detection of WNV‐specific IgM have been approved by the Food and Drug Administration for in vitro diagnostic testing, including kits from Focus Diagnostics and InBios International, Inc. The Focus Diagnostics IgM capture ELISA has a background subtraction protocol and the InBios IgM capture ELISA implements a ratio method to detect nonspecific reactivity due to rheumatoid factor, heterophile antibodies, and other interfering substances. We compared the InBios IgM capture ELISA with the Focus Diagnostics capture ELISA. Agreement, sensitivity, and specificity of the InBios IgM capture ELISA were 99, 98, and 100%, respectively. Samples that originally tested positive on the Focus Diagnostics IgM capture ELISA without the subtraction protocol and were then determined negative following the subtraction protocol agreed 100% with the InBios IgM capture ELISA. We conclude that a method to eliminate background reactivity is a necessary portion of any anti‐WNV IgM assay in order to eliminate false‐positive results. J. Clin. Lab. Anal. 22:362–366, 2008. © 2008 Wiley‐Liss, Inc.

Evaluation of a new commercial enzyme immunoassay for the detection of IgM antibodies to West Nile virus using a ratio method to eliminate nonspecific reactivity

ABSTRACT InBios International has developed an immunochromatographic rapid strip for the detection of visceral leishmaniasis that requires minimal equipment and only a small amount of blood to run a test. We compared the InBios rapid strip test with the CDC immunofluorescent antibody assay, and the agreement, sensitivity, and specificity were 98%, 90%, and 100%, respectively.

Rapid Immunochromatographic Strip Test for Detection of Anti-K39 Immunoglobulin G Antibodies for Diagnosis of Visceral Leishmaniasis

Esterification of 9-fluorenylmethyloxycarbonyl α-amino acid N-carboxyanhydrides to hydroxyl-functionalized resins

Esterification of Fmoc amino acid N-carboxyanhydrides (UNCAs) to hydroxy resins

[DTrp6] LH-RH was prepared using urethane-protected alpha-amino and N-carboxyanhydrides (UNCAs) both in solution and by solid-phase methodologies. The yields and purities of the crude materials in both cases were high, as indicated by HPLC. The structures were confirmed by 1H NMR, FAB mass spectrometry and found to be identical to an authentic sample. Both synthetic samples were analytically pure by capillary zone electrophoresis.

A comparative synthesis of the [DTrp6] LH-RH analog by the UNCA method in solution and by solid phase.

Social science has an important role in aviation biofuels research, yet social science methods and approaches tend to be underdeveloped and under-utilized in the broader aviation biofuels literature and biofuels overall. Over the last 5 years, social science approaches in aviation biofuels research, particularly site-selection, have made several advances. Where early site-selection models either entirely excluded social science concepts or included only a few measurements using poor proxies, current models more accurately, and more comprehensively capture key social science concepts to better examine and predict project implementation success and long-term sustainability. Despite several studies published within the last 20 years noting the need for more empirical studies of social sustainability and improvement in incorporation of social criteria, progress has remained rather stagnant in several areas. To help move the field forward, we conduct a review of the current state of social science research in aviation biofuels with a focus on sustainability, site-selection, and public acceptance research, identifying key approaches, important developments, and research gaps and weaknesses of current approaches. While several review studies already exist, they tend to focus on a single area of biofuels such as public acceptance. By broadening our review to several areas, we are able to identify several common limitations across these areas that contribute to the continued underutilization of social science approaches in aviation biofuels. This includes the preference for practical and reliable indicators for social criteria that prioritize quantitative methods over other approaches. Based on these limitations, we make several recommendations to improve social science research in aviation biofuels, including ensuring that social scientists are key members of the research team, the adoption of a mixed-methods research designs that combines quantitative and qualitative approaches that better measure some criteria and local-level impacts, and adequate resources for social science research throughout biofuel development projects as these methods are often more time-consuming and costly to implement. We argue that implementing these recommendations in future aviation biofuel development projects will improve social science approaches utilized in aviation biofuels research and address a long-acknowledged gap in the field.

Social Science Applications in Sustainable Aviation Biofuels Research: Opportunities, Challenges, and Advancements

OBJECTIVES: COVID-19 is a heterogenous disease. Biomarker-based approaches may identify patients at risk for severe disease, who may be more likely to benefit from specific therapies. Our objective was to identify and validate a plasma protein signature for severe COVID-19. DESIGN: Prospective observational cohort study. SETTING: Two hospitals in the United States. PATIENTS: One hundred sixty-seven hospitalized adults with COVID-19. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We measured 713 plasma proteins in 167 hospitalized patients with COVID-19 using a high-throughput platform. We classified patients as nonsevere versus severe COVID-19, defined as the need for high-flow nasal cannula, mechanical ventilation, extracorporeal membrane oxygenation, or death, at study entry and in 7-day intervals thereafter. We compared proteins measured at baseline between these two groups by logistic regression adjusting for age, sex, symptom duration, and comorbidities. We used lead proteins from dysregulated pathways as inputs for elastic net logistic regression to identify a parsimonious signature of severe disease and validated this signature in an external COVID-19 dataset. We tested whether the association between corticosteroid use and mortality varied by protein signature. One hundred ninety-four proteins were associated with severe COVID-19 at the time of hospital admission. Pathway analysis identified multiple pathways associated with inflammatory response and tissue repair programs. Elastic net logistic regression yielded a 14-protein signature that discriminated 90-day mortality in an external cohort with an area under the receiver-operator characteristic curve of 0.92 (95% CI, 0.88–0.95). Classifying patients based on the predicted risk from the signature identified a heterogeneous response to treatment with corticosteroids (p = 0.006). CONCLUSIONS: Inpatients with COVID-19 express heterogeneous patterns of plasma proteins. We propose a 14-protein signature of disease severity that may have value in developing precision medicine approaches for COVID-19 pneumonia.

B23. CRITICAL CARE: STEP ACROSS THIS LINE - MICROBIOME, GENETICS, AND OTHER BIOMARKERS IN ACUTE CRITICAL ILLNESS

Plasma Mitochondrial DNA Is Associated with Acute Respiratory Distress Syndrome in Sepsis

Robin Hissam received her Bachelor’s and Master’s degrees in Materials Science and Engineering from Virginia Tech. The focus of her research as both an undergraduate and graduate at Virginia Tech was polymer physics, in particular, the crystallization of polymers. Robin joined the Materials Science and Engineering department at the University of Delaware as a PhD candidate in 2001, where her research under Dr. Kristi Kiick involved the design, synthesis and characterization of protein polymers for applications in toxin inhibition. Graduating in 2006, Robin joined the group of Dr. Kimberly Woodhouse in Chemical Engineering and Applied Chemistry at the University of Toronto for a two year postdoctoral fellowship. The research in Toronto looked at the possible application of elastin-based protein polymers for drug delivery vehicles. For her work in this area, Robin received a scholarship from the Advanced Regenerative Tissue Engineering Centre. At West Virginia University, Robin is continuing her work in production of protein polymers for application in tissue engineering, biomineralization, and biosensors.

The Dollar Bay Project is part of the North Dakota State University WWWIC (Worldwide Web Instructional Committee) Research effort. Dollar Bay is a fictitious seaside town simulated in an interactive, Web-based environment intended to teach the principles and practices of retailing. To begin the game, a player must first create a character and become a storeowner in Dollar Bay. The character is then assigned retail space and a starting budget. The player’s goal is simple: make more profit than the other store owners in Dollar Bay. However, the means by which a player obtains their profit represents a formidable, yet invigorating challenge. For instance, the game has the ability to simulate seasonal affects on consumer purchasing trends. Dollar Bay players must anticipate these and other trends along with socioeconomic factors in order to adjust inventory and pricing accordingly to keep their business thriving. Depending on the success of their business decisions, players may also be inducted into the Hall of Fame. Each semester, students are assigned to cross-functional teams, much like those in today’s progressive organizations, in order to facilitate improvements in various areas of Dollar Bay. The Dollar Bay Project is the anthology of ongoing collaboration of students taking Computer Science courses at NDSU.

After a two-year delay, the National Practitioner Data Bank, authorized by the Health Care Quality Improvement Act of 1986, has yet to begin its mission to collect and disseminate information concerning adverse actions affecting physicians' hospital privileges, licensure, and malpractice claims experience. This article discusses some of the problems that are likely to arise in the operation of the Data Bank.

Selection history contributes to suboptimal attention strategies

Reward learning has been shown to habitually guide overt spatial attention to specific regions of a scene. However, the neural mechanisms that support this bias are unknown. In the present study, participants learned to orient themselves to a particular quadrant of a scene (a high-value quadrant) to maximize monetary gains. This learning was scene-specific, with the high-value quadrant varying across different scenes. During a subsequent test phase, participants were faster at identifying a target if it appeared in the high-value quadrant (valid), and initial saccades were more likely to be made to the high-value quadrant. fMRI analyses during the test phase revealed learning-dependent priority signals in the caudate tail, superior colliculus, frontal eye field, anterior cingulate cortex, and insula, paralleling findings concerning feature-based, value-driven attention. In addition, ventral regions typically associated with scene selection and spatial information processing, including the hippocampus, parahippocampal gyrus, and temporo-occipital cortex, were also implicated. Taken together, our findings offer new insights into the neural architecture subserving value-driven attention, both extending our understanding of nodes in the attention network previously implicated in feature-based, value-driven attention and identifying a ventral network of brain regions implicated in reward's influence on scene-dependent spatial orienting.

Accumulating evidence demonstrates that selection history influences the allocation of attention. However, it is unclear how working memory (WM), which is tightly connected to attention, is influenced by selection history. The aim of present study was to investigate the influence of encoding history on WM encoding. By incorporating task switching into an attribute amnesia task, participants' encoding history for stimulus attributes was manipulated and its corresponding influence on WM performance was tested. The results revealed that encoding an attribute in one situation can enhance the working memory encoding process for this same attribute in a different situation. Subsequent experiments revealed that this facilitation in WM encoding cannot be explained by increased attentional demand to the probed feature caused by the need to task switch. In addition, verbal instruction does not have a crucial influence on memory performance, which is mainly driven by prior experience in the task. Collectively, our findings lend unique insights into how selection history influences the encoding of information into WM. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Encoding history enhances working memory encoding: Evidence from attribute amnesia.

Prioritizing attention to reward-predictive items is critical for survival, but challenging because these items rarely appear in the same feature or within the same environment. However, whether attention selection can be adaptively tuned to items that matched the context-dependent, relative feature of previously rewarded items remains largely unknown. In four experiments (N = 40 per experiment), we trained participants to learn the color-reward association and then adopted visual search tasks in which the color of a singleton distractor matched either the feature value (e.g., red or yellow) or feature relationship (i.e., redder or yellower) of previously rewarded colors. We consistently found enhanced attentional capture by a singleton distractor when it was relationally matched to the high reward compared with the low reward relationship, in addition to observing the typical effect of learned value on singletons matching the previously rewarded colors. Our findings provide novel evidence for the flexibility of value-driven attention via feature relationship, which is particularly useful given the changeable sensory inputs in real-world searches. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Reward history modulates attention based on feature relationship.

Road Construction Workers’ Boredom Susceptibility, Habituation to Warning Alarms, and Accident Proneness: Virtual Reality Experiment

A comparison of mental imagery and perceptual cueing across domains of attention.

Tasks that involve more demanding cognitive operations, such as working memory maintenance and rule switching, tend to be perceived as effortful. People will make choices that minimize the need to perform such tasks and will even accept some measure of physical pain in exchange for the ability to avoid them. Nearly all tasks require that people find and extract relevant perceptual information from their environment, but demands of this nature are often ignored in the study of mental effort. Visual search is sometimes described as "difficult" or "easy" on the basis of search slopes or other performance-based metrics, but how such performance differences map onto conceptions of cognitive demand is unclear. In the present study, we examined whether people would be willing to exert physical effort in exchange for the opportunity to minimize the number of items they needed to search through in a visual search task and whether they would be more willing to endure physical effort demands if it resulted in fewer items needing to be searched. Our results are broadly consistent with the idea that the performance of visual search constitutes effortful work that can trade-off with physical effort demands, which has broad implications for theories of visual information processing and practical considerations for professions that tax peoples' ability to search. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Reward learning and aversive conditioning have consequences for attentional selection, such that stimuli that come to signal reward and threat bias attention regardless of their valence. Appetitive and aversive stimuli have distinctive influences on response selection, such that they activate an approach and an avoidance response, respectively. However, whether the involuntary influence of reward- and threat-history-laden stimuli extends to the manner in which a response is directed remains unclear. Using a feedback-joystick task and a manikin task, which are common paradigms for examining valence-action bias, we demonstrate that reward- and threat-signalling stimuli do not modulate response selection. Stimuli that came to signal reward and threat via training biased attention and invigorated action in general, but they did not facilitate an approach and avoidance response, respectively. We conclude that attention can be biased towards a stimulus as a function of its prior association with reward or aversive outcomes without necessarily influencing approach vs. avoidance tendencies, such that the mechanisms underlying the involuntary control of attention and behaviour evoked by valent stimuli can be decoupled.

On the Relationship between Value- and Threat-Driven Attentional Capture and Approach-Avoidance Biases

Virtual accident curb risk habituation in workers by restoring sensory responses to real-world warning

Combined influence of valence and statistical learning on the control of attention II: Evidence from within-domain additivity

Attention is biased toward stimuli previously associated with reward. The same is true for aversive conditioning; stimuli previously associated with an aversive outcome also bias attention, suggesting that motivational salience guides attention. Most research that supports this conclusion has manipulated monetary gain-a secondary reinforcer-for reward learning, and electric shocks-a primary punisher-for aversive conditioning, making it difficult to directly compare their influence on attention. Therefore, in the present study, we matched for reinforcer dimensions by using primary taste as reinforcers/punishers and assessed their influence on attention. In a training phase, participants learned to associate three colors with sweet juice (reward), salt water (aversive), and no outcome (neutral), respectively. The two primary reinforcers were equated for valence based on choices made in a prior decision-making task. In a later test phase, these three colors were used for targets and distractors in a task in which participants oriented to a shape-defined target. An attentional bias in favor of the aversively conditioned and reward-associated colors was evident when comparing to the neutral color. Importantly, a direct comparison of rewarded and aversive stimuli revealed no significant differences. These results suggest that when matched for reinforcer dimensions and valence, reward and aversive outcomes bias attention in a similar manner and their effects are comparable, providing further evidence in support of the motivational salience account of learning-dependent attention. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Primary rewards and aversive outcomes have comparable effects on attentional bias.

Bicyclist-evoked arousal and greater attention to bicyclists independently promote safer driving

On the relationship between value-driven and stimulus-driven attentional capture

Selection history in context: Evidence for the role of reinforcement learning in biasing attention

Value-driven attentional capture is modulated by the contents of working memory: An EEG study

Correction to: Reduced Value-Driven Attentional Capture among Children with ADHD Compared to Typically Developing Controls

On t﻿he distinction between value-driven attention and selection history: Evidence from individuals with depressive symptoms

Reduced Value-Driven Attentional Capture Among Children with ADHD Compared to Typically Developing Controls

Controlled information processing, automaticity, and the burden of proof

Information Processing Biases in the Brain: Implications for Decision-Making and Self-Governance

Dissociating location-specific inhibition and attention shifts: Evidence against the disengagement account of contingent capture

Value-driven attentional and oculomotor capture during goal-directed, unconstrained viewing

We analyze probability distributions of Birkeland current densities measured by the Active Magnetosphere and Planetary Electrodynamics Response Experiment. We find that the distributions are leptokurtic rather than normal and they are sometimes heavy‐tailed. We fit q‐exponential functions to the distributions and use these to estimate where the largest currents are likely to occur. The shape and scale parameters of the fitted q‐exponential distribution vary with location: The scale parameter maximizes for current densities with the same polarity and in the same location as the average Region 1 current, whereas the shape parameter maximizes for current densities with the same polarity and in the same location as the average Region 2 current. We find that current densities |J| ≥ 0.2 μA m−2 are most likely to occur in the average Region 1 current region, and second most likely to occur in the average Region 2 current region. However, for extreme currents (|J| ≥ 4.0 μA m−2), we find that the most likely location is colocated with the average Region 2 current region on the dayside, at a colatitude of 18°−22°.

Distributions of Birkeland Current Density Observed by AMPERE are Heavy‐Tailed or Long‐Tailed

Mesoscale dynamics are a fundamental process in space physics, but fall within an observational gap of current and planned missions. Particularly in the solar wind, measurements at the mesoscales (100s RE to a few degrees heliographic longitude at 1 au) are crucial for understanding the connection between the corona and an observer anywhere within the heliosphere. Mesoscale dynamics may also be key to revealing the currently unresolved physics regulating particle acceleration and transport, magnetic field topology, and the causes of variability in the composition and acceleration of solar wind plasma. Studies using single-point observations do not allow for investigations into mesoscale solar wind dynamics and plasma variability, nor do they allow for the exploration of the sub-structuring of large-scale solar wind structures like coronal mass ejections (CMEs), co-rotating/stream interaction regions (CIR/SIRs), and the heliospheric plasma sheet. To address this fundamental gap in our knowledge of the heliosphere at these scales, the Interplanetary Mesoscale Observatory (InterMeso) concept employs a multi-point approach using four identical spacecraft in Earth-trailing orbits near 1 au. Varying drift speeds of the InterMeso spacecraft enable the mission to span a range of mesoscale separations in the solar wind, achieving significant and innovative science return. Simultaneous, longitudinally-separated measurements of structures co-rotating over the spacecraft also allow for disambiguation of spatiotemporal variability, tracking of the evolution of solar wind structures, and determination of how the transport of energetic particles is impacted by these variabilities.

Interplanetary mesoscale observatory (InterMeso): A mission to untangle dynamic mesoscale structures throughout the heliosphere

Investigation of the homogeneity of energy conversion processes at dipolarization fronts from MMS measurements

During geomagnetic storms a large amount of energy is transferred into the ionosphere-thermosphere (IT) system, leading to local and global changes in e.g., the dynamics, composition, and neutral density. The more steady energy from the lower atmosphere into the IT system is in general much smaller than the energy input from the magnetosphere, especially during geomagnetic storms, and therefore details of the lower atmosphere forcing are often neglected in storm time simulations. In this study we compare the neutral density observed by Swarm-C during the moderate geomagnetic storm of 31 January to 3 February 2016 with the Thermosphere-Ionosphere-Electrodynamics-GCM (TIEGCM) finding that the model can capture the observed large scale neutral density variations better in the southern than northern hemisphere. The importance of more realistic lower atmospheric (LB) variations as specified by the Whole Atmosphere Community Climate Model eXtended (WACCM-X) with specified dynamics (SD) is demonstrated by improving especially the northern hemisphere neutral density by up to 15% compared to using climatological LB forcing. Further analysis highlights the importance of the background atmospheric condition in facilitating hemispheric different neutral density changes in response to the LB perturbations. In comparison, employing observationally based field-aligned current (FAC) versus using an empirical model to describe magnetosphere-ionosphere (MI) coupling leads to an 7–20% improved northern hemisphere neutral density. The results highlight the importance of the lower atmospheric variations and high latitude forcing in simulating the absolute large scale neutral density especially the hemispheric differences. However, focusing on the storm time variation with respect to the quiescent time, the lower atmospheric influence is reduced to 1–1.5% improvement with respect to the total observed neutral density. The results provide some guidance on the importance of more realistic upper boundary forcing and lower atmospheric variations when modeling large scale, absolute and relative neutral density variations.

Importance of lower atmospheric forcing and magnetosphere-ionosphere coupling in simulating neutral density during the February 2016 geomagnetic storm

The role of diffuse electron precipitation in the formation of subauroral polarization streams (SAPS) is investigated with the Multiscale Atmosphere‐Geospace Environment (MAGE) model. Diffuse precipitation is derived from the distribution of drifting electrons. SAPS manifest themselves as a separate mesoscale flow channel in the duskside ionosphere, which gradually merges with the primary auroral convection toward dayside as the equatorward auroral boundary approaches the poleward Region‐2 field‐aligned currents (FACs) boundary. SAPS expand to lower latitudes and toward the nightside during the main phase of a geomagnetic storm, associated with magnetotail earthward plasma flows building up the ring current and intensifying Region‐2 FACs and electron precipitation. SAPS shrink poleward and sunward as the interplanetary magnetic field turns northward. When diffuse precipitation is turned off in a controlled MAGE simulation, ring current and duskside Region‐2 FACs become weaker, but subauroral zonal ion drifts are still comparable to auroral convection. However, subauroral and auroral convection manifest as a single broad flow channel without showing any mesoscale structure. SAPS overlap with the downward Region‐2 FACs equatorward of diffuse precipitation, where poleward electric fields are strong due to a low conductance in the subauroral ionosphere. The Region‐2 FACs extend to latitudes lower than the diffuse precipitation because the ring current protons penetrate closer to the Earth than the electrons do. This study reproduces the key physics of SAPS formation and their evolution in the coupled magnetosphere‐ionosphere during a geomagnetic storm. Diffuse electron precipitation is demonstrated to play a critical role in determining SAPS location and structure.

The Role of Diffuse Electron Precipitation in the Formation of Subauroral Polarization Streams

Characterization of Earth's magnetic field is key to understanding dynamics of the core. We assess whether Iridium Communications magnetometer data can be used for this purpose since. The 66 Iridium satellites are in 86° inclination, 780 km altitude, circular orbits, with 11 satellites in each of six orbit planes. In one day the constellation returns 300,000 measurements spanning the globe with <2° spacing. We used data from January 2010 through November 2015, and compared against International Geomagnetic Reference Field (IGRF‐11) to inter‐calibrate all data to the same model. Geomagnetically quiet 24‐h intervals were selected using the total Birkeland current, auroral electrojet, and ring current indices. The z‐scores for these quantities were combined and the quietest 16 intervals from each quarter selected for analysis. Residuals between the data and IGRF‐11 yield consistent patterns that evolve gradually from 2010 to 2015. Residuals for each day were binned in 9° latitude by 9° longitude and the distributions about the mean in each bin are Gaussian with 1‐sigma standard errors of ∼3 nT. Spherical harmonic coefficients for each quiet day were computed and time series of the coefficients used to identify artifacts at the orbit precession (8 months) and seasonal (12 months) periods and their harmonics which were then removed by notch filtering. This analysis yields time series at 800 virtual geomagnetic observatories each providing a global field map using a single day of data. The results and CHAOS 7.4 generally agree, but systematic differences larger than the statistical uncertainties are present that warrant further exploration.

Iridium Communications Satellite Constellation Data for Study of Earth's Magnetic Field

For over a decade, the Super Dual Auroral Radar Network and the Active Magnetosphere and Planetary Electrodynamics Response Experiment have been measuring ionospheric convection and field‐aligned currents in the high‐latitude regions, respectively. Using both, high‐latitude maps of the magnetosphere‐ionosphere energy transfer rate (the Poynting flux) have been generated with a time resolution of 2 min between 2010 and 2017. These data driven Poynting flux (PF) patterns are used in this study to perform a superposed epoch analysis of the northern hemisphere ionospheric response to transitions of the interplanetary magnetic field Bz component, upwards of 60° geomagnetic latitude. We discuss the difference in the distribution of PF between the magnetosphere‐ionosphere Dungey cycle “switching on” and “switching off” to solar wind driving, revealing that they are not symmetric temporally or spatially.

Ionospheric Energy Input in Response to Changes in Solar Wind Driving: Statistics From the SuperDARN and AMPERE Campaigns

We calculate high latitude electrodynamic parameters using global maps of field‐aligned currents from the Active Magnetosphere and Planetary Response Experiment (AMPERE). The model is based on previous studies that relate field‐aligned currents to auroral Pedersen and Hall conductances measured by incoherent scatter radar. The field‐aligned currents and conductances are used to solve for the electric potential at high latitudes from which electric fields are computed. The electric fields are then used with the conductances to calculate horizontal ionospheric currents. We validate the results by simulating the SuperMAG magnetic indices for 30 geomagnetically active days. The correlation coefficients between derived and actual magnetic indices were 0.68, 0.76, and 0.84 for the SMU, SML, and SME indices, respectively. We show examples of times when the simulations differ markedly from the measured indices and attribute them to either small‐scale, substorm‐related current structures or the effects of neutral winds. Overall, the performance of the model demonstrates that with few exceptions, auroral electrodynamic parameters can be accurately deduced from the global field‐aligned current distribution provided by AMPERE.

Determination of Auroral Electrodynamic Parameters From AMPERE Field‐Aligned Current Measurements

A new technique has been developed in which the high-latitude electric potential is determined from field-aligned current observations from the Active Magnetosphere and Planetary Electrodynamics Re...

High-latitude electrodynamics specified in SAMI3 using AMPERE field-aligned currents

We quantify the contributions of different convection states to the magnetic flux throughput of the magnetosphere during 2010. To do this we provide a continuous classification of convection state for the duration of 2010 based upon observations of the solar wind and interplanetary magnetic field, geomagnetic indices, and field‐aligned currents measured by the Active Magnetosphere and Planetary Electrodynamics Response Experiment. Convection states are defined as (1) quiet, (2) weak activity, substorm (3) growth, (4) expansion and (5) recovery phases, (6) substorm driven phase (when relatively steady magnetospheric convection occurs), (7) recovery bays (when recovery phase is accompanied by a negative excursion of the AL electrojet index), and (8) periods of multiple intensifications (storm‐time periods when continuous short‐period AL activity occur). The magnetosphere is quiet for 46% of the time, when very little convection takes place. The majority of convection occurs during growth and driven phases (21% and 38%, respectively, of open magnetic flux accumulation by dayside reconnection). We discuss these results in the context of the expanding/contracting polar cap model of convection, and describe a framework within which isolated substorms and disturbances during periods of more continuous solar wind‐magnetosphere driving can be understood.

Magnetospheric Flux Throughput in the Dungey Cycle: Identification of Convection State During 2010

Field-aligned current during an interval of $\rm B_{Y}$-dominated interplanetary-field; modeled-to-observed comparisons

The sub‐auroral polarization stream (SAPS) is a region of westward high velocity plasma convection equatorward of the auroral oval that plays an important role in mid‐latitude space weather dynamics. In this study, we present observations of SAPS flows extending across the North American sector observed during the recovery phase of a minor geomagnetic storm. A resurgence in substorm activity drove a new set of field‐aligned currents (FACs) into the ionosphere, initiating the SAPS. An upward FAC system is the most prominent feature spreading across most SAPS local times, except near dusk, where a downward current system is pronounced. The location of SAPS flows remained relatively constant, firmly inside the trough, independent of the variability in the location and intensity of the FACs. The SAPS flows were sustained even after the FACs weakened and retreated polewards with a decline in geomagnetic activity. The observations indicate that the mid‐latitude trough plays a crucial role in determining the location of the SAPS and that SAPS flows can be sustained even after the magnetospheric driver has weakened.

An Examination of Magnetosphere‐Ionosphere Influences During a SAPS Event

Large thermospheric neutral density enhancements in the cusp region have been examined for many years. The Challenging Minisatellite Payload (CHAMP) satellite for example has enabled many observations of the perturbation, showing that it is mesoscale in size and exists statistically over solar cycle timescales. Further studies examining the relationship with magnetospheric energy input have shown that fine‐scale Poynting fluxes are associated with the density perturbations on a case‐by‐case basis, whilst others have found that mesoscale downward fluxes also exist in the cusp region statistically. In this study, we use nearly 8 years of the overlapping Super Dual Auroral Radar Network and Active Magnetosphere and Planetary Electrodynamics Response Experiment datasets to generate global‐scale patterns of the high‐latitude and height‐integrated Poynting flux into the ionosphere, with a time resolution of 2 min. From these, average patterns are generated based on the interplanetary magnetic field orientation. We show the cusp is indeed an important feature in the Poynting flux maps, but the magnitude does not correlate well with statistical neutral mass density perturbations observed by the CHAMP satellite on similar spatial scales. Importantly, the lack of correlation between mesoscale height‐integrated Poynting fluxes and the cusp neutral mass density enhancement gives possible insight into other processes that may account for the discrepancy, such as energy deposition at finer scale sizes or at higher altitudes than captured.

The Relationship Between Large Scale Thermospheric Density Enhancements and the Spatial Distribution of Poynting Flux

<p>Auroral precipitation plays an important role in magnetosphere-ionosphere-thermosphere (MIT) coupling by enhancing ionospheric ionization and conductivity at high latitudes. Diffuse electron precipitation refers to scattered electrons from the plasma sheet that are lost in the ionosphere. Diffuse precipitation makes the largest contribution to the total precipitation energy flux and is expected to have substantial impacts on the ionospheric conductance and affect the electrodynamic coupling between the magnetosphere and ionosphere-thermosphere. Kinetic theory and observational analysis also demonstrate that diffuse precipitation is subject to multiple reflection effects, i.e. secondary electrons produced by the primary precipitation are reflected between the north and south hemispheres multiple times before they are fully lost in the atmosphere. In this study, we make use of the newly developed Multiscale Atmosphere-Geospace Environment (MAGE) model developed at the NASA DRIVE Science Center for Geospace Storms (CGS) to explore the role of diffuse electron precipitation in MIT coupling. Diffuse precipitation in MAGE is derived from the electron distribution in the Rice Convection Model (RCM), a ring current model that solves for energy dependent drifts of electrons and ions. Diffuse precipitation, together with mono-energetic electron precipitation based on parameterization of the magnetohydrodynamic (MHD) parameters from the Grid Agnostic MHD with Extended Research Applications (GAMERA) magnetosphere model, are input to the Thermosphere Ionosphere Electrodynamic General Circulation Model (TIEGCM) to calculate the ionospheric ionization rate and conductivity and height-integrated conductance. With controlled numerical experiments, we investigate 1. how the diffuse precipitation affects the location and structure of a mesoscale ionospheric convection process, i.e., subauroral polarization streams (SAPS); 2. How multiple reflection effects impact the ionosphere-thermosphere and their coupling with the magnetosphere. Our study demonstrates that diffuse electron precipitation plays a critical role in determining the location and structure of SAPS. The multiple reflection effects make diffuse precipitation number flux and energy flux a few times higher than the unmodified precipitation, resulting in a greatly enhanced auroral ionospheric conductance, lower cross polar cap potential, &#160;higher total field-aligned currents, and changes in global thermospheric winds and temperature. Therefore, diffuse electron precipitation has both local and global impacts on MIT coupling.</p>

Diffuse electron precipitation in magnetosphere-ionosphere-thermosphere coupling

Upstream solar wind measurements from near the L1 Lagrangian point are commonly used to investigate solar wind‐magnetosphere coupling. The off‐Sun‐Earth line distance of such solar wind monitors can be large, up to 100 RE. We investigate how the correlation between measurements of the interplanetary magnetic field and associated ionospheric responses deteriorates as the off‐Sun‐Earth line distance increases. Specifically, we use the magnitude and polarity of the dayside region 0 field‐aligned currents (R0 FACs) as a measure of interplanetary magnetic field (IMF) BY‐associated magnetic tension effects on newly‐reconnected field lines, related to the Svalgaard‐Mansurov effect. The R0 FACs are derived from Advanced Magnetosphere and Planetary Electrodynamics Response Experiment measurements by a principal component analysis, for the years 2010–2016. We perform cross‐correlation analyses between time‐series of IMF BY, measured by the Wind spacecraft and propagated to the nose of the bow shock by the OMNI technique, and these R0 FAC measurements. Typically, in the summer hemisphere, cross‐correlation coefficients between 0.6 and 0.9 are found. However, there is a reduction of order 0.1–0.15 in correlation coefficient between periods when Wind is close to (within 45 RE) and distant from (beyond 70 RE) the Sun‐Earth line. We find a time‐lag of around 17 min between predictions of the arrival of IMF features at the bow shock and their effect in the ionosphere, irrespective of the location of Wind.

Influence of Off‐Sun‐Earth Line Distance on the Accuracy of L1 Solar Wind Monitoring

We present latest results from the Conductance Model for Extreme Events (CMEE) and the Magnetosphere-Ionosphere-Thermosphere (MAGNIT) Conductance Model. Both models have been integrated into the Sp...

Global Driving of Auroral Conductance - Balance of Sources & Numerical Considerations

We present a multi‐instrumental study of ionospheric irregularities of different scales (from tens of centimeters to few kilometers) observed over the Central and East Siberia, Russia, during a moderate‐to‐strong geomagnetic storm on 27–28 May 2017. From high‐frequency (HF) and ultrahigh‐frequency (UHF) radar data, we observed an intense auroral backscatter developed right after the initial phase of the geomagnetic storm. Additionally, we examined variations of Global Positioning System (GPS)‐based ROT (rate of TEC changes, where TEC is total electron content) for available GPS receivers in the region. Ionosondes, HF, and UHF radar data exhibited a presence of intense multi‐scale ionospheric irregularities. We revealed a correlation between different‐scale Auroral/Farley‐Buneman ionospheric irregularities of the E layer during the geomagnetic storm. The combined analysis showed that an area of intense irregularities is well connected and located slightly equatorward to field‐aligned currents (FACs) and auroral oval at different stages of the geomagnetic storm. An increase and equatorward displacement of Region 1 (R1)/Region 2 (R2) FACs leads to appearance and equatorward expansion of ionospheric irregularities. During downward (upward) R1 FAC and upward (downward) R2 FAC, the eastward and upward (westward and downward) E × B drift of ionospheric irregularities occurred. Simultaneous disappearance of UHF/HF auroral backscatter and GPS ROT decrease occurred during a prolonged near noon reversal of R1 and R2 FAC directions that accompanied by R1/R2 FAC degradation and disappearance of high‐energy auroral precipitation.

Spatial and Temporal Evolution of Different‐Scale Ionospheric Irregularities in Central and East Siberia During the 27–28 May 2017 Geomagnetic Storm

The existence of Birkeland magnetic field‐aligned current (FAC) system was proposed more than a century ago, and it has been of immense interest for investigating the nature of solar wind‐magnetosphere‐ionosphere coupling ever since. In this paper, we present the first application of deep learning architecture for modeling the Birkeland currents using data from the Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE). The model uses a 1‐hr time history of several different parameters such as interplanetary magnetic field (IMF), solar wind, and geomagnetic and solar indices as inputs to determine the global distribution of Birkeland currents in the Northern Hemisphere. We present a comparison between our model and bin‐averaged statistical patterns under steady IMF conditions and also when the IMF is variable. Our deep learning model shows good agreement with the bin‐averaged patterns, capturing several prominent large‐scale features such as the Regions 1 and 2 FACs, the NBZ current system, and the cusp currents along with their seasonal variations. However, when IMF and solar wind conditions are not stable, our model provides a more accurate view of the time‐dependent evolution of Birkeland currents. The reconfiguration of the FACs following an abrupt change in IMF orientation can be traced in its details. The magnitude of FACs is found to evolve with e‐folding times that vary with season and MLT. When IMF Bz turns southward after a prolonged northward orientation, NBZ currents decay exponentially with an e‐folding time of ∼25 min, whereas Region 1 currents grow with an e‐folding time of 6–20 min depending on the MLT.

A Deep Learning‐Based Approach for Modeling the Dynamics of AMPERE Birkeland Currents

Rocket Investigation of Current Closure in the Ionosphere (RICCI): A novel application of CubeSats from a sounding rocket platform

Methodology 1. While the technical approach is largely (see below) well explained the methodology is questionable. When the authors organize their data by IMF, dipole tilt angle, F10.7 and so on the assumption is that these parameters are indeed controlling the ionospheric electrodynamics. There is a causality implied in the approach which opens two fundamental questions: is there a cause-and-effect and if so what is the delay?. I think this may work on the dayside where delays between SW conditions and the response of the ionospheric electrodynamics are likely on the order of minutes

Interactive comment on “Testing the Electrodynamic Method to Derive Height-Integrated Ionospheric Conductances” by

The formation of polar cap density enhancements, such as tongues‐of‐ionization (TOIs), are often attributed to enhanced dayside reconnection and convection due to solar wind changes. However, ionospheric poleward moving density enhancements can also form in the absence of changes in the solar wind. This study examines how TOI and patch events that are not triggered by solar wind changes relate to magnetospheric processes, specifically substorms. Based on total electron content and Super Dual Auroral Radar Network (SuperDARN) observations, we find substorms that occur at the same time as TOIs are associated with sudden enhancements in dayside poleward flows during the substorm expansion phase. Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE) observations also show enhanced field‐aligned currents (FACs) that extend into the dayside ionosphere during this period. We suggest that the global enhancement of FACs and convection during these substorms are the drivers of these TOIs by enhancing dayside convection and transporting high‐density lower‐latitude plasma into the polar cap. However, we also find that not all substorms are coincident with polar cap density enhancements. A superposed epoch study showed that the AL index for TOIs during substorms is not particularly stronger than substorms without TOIs, but epoch studies of AMPERE observations do show events with TOIs to have a higher total FAC on both the dayside and nightside. Our results show the importance of TOI formation during substorms when solar wind drivers are absent, and the importance of considering substorms in the global current system. This work also shows the need to incorporate substorms into models of high‐latitude global convection and currents.

We track a remarkably bright and persistent auroral cusp spot emission in the high‐latitude Northern Hemisphere polar cap, well inside the main auroral oval, for approximately 11 hr on 16 and 17 June 2012. The auroral emissions are presented in both the Lyman‐α and Lyman‐Birge‐Hopfield bands, as observed by the Special Sensor Ultraviolet Spectrographic Imager on board two of the Defense Meteorological Satellite Programme spacecraft, and supported by detections of precipitating particles by the same spacecraft. The auroral observations are accompanied by patterns of field aligned currents, obtained from the Active Magnetosphere and Planetary Electrodynamics Response Experiment, along with ionospheric convection patterns from the Super Dual Auroral Radar Network. These data provide unprecedented coverage of a cusp spot, unusually seen in both electron and proton aurora. The location and movement of the auroral emissions, current systems, and ionospheric convection patterns are extremely distorted under the northward to Y‐component‐dominated interplanetary magnetic field. The cusp spot emission region is associated with the sunward flow region of the ionosphere. Ion dispersion signatures are detected on traversal of the region of brightest proton auroral emissions. Proton‐excited Lyman‐α emissions are most evident following impulses of high solar wind density. The auroral emissions, field‐aligned current patterns, and ionospheric convection are consistent with a model of a compressed magnetosphere under strongly northward interplanetary magnetic field, following an impact of an Interplanetary Coronal Mass Ejection and associated magnetic cloud at the magnetopause, inducing high‐latitude lobe reconnection that progresses increasingly tailward during the presented interval.

The Evolution of Long‐Duration Cusp Spot Emission During Lobe Reconnection With Respect to Field‐Aligned Currents

Field‐aligned currents from the Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE) were combined with simultaneous and coincident observations of ionospheric conductivities made by the Poker Flat Incoherent Scatter Radar (PFISR) in Alaska for 20 geomagnetically active days. The height‐integrated conductivities (conductances) were determined from the electron densities measured by the radar between 80 and 200 km altitude. Binning and averaging the data by field‐aligned current density and magnetic local time, we find that the currents correlate with conductances in both upward and downward current regions over some magnetic local times. The strongest correlation is seen in the late evening and morning sectors, with the Hall conductances two to three times larger than the Pedersen conductances for the same values of the field‐aligned current. The observed correlations reflect the mean energy of auroral precipitation, the contributions from electrons and protons to producing enhanced conductances, and the availability of charge carriers on auroral field lines. We apply linear fitting and smoothing to the correlations to construct an empirical model for specifying auroral conductances globally from AMPERE field‐aligned current maps. The energy fluxes from precipitating particles derived from the model conductances compare well with those derived using AMPERE data combined with satellite‐based measurements of far ultraviolet emissions, suggesting the results obtained at Poker Flat may be applicable to all high latitude locations. The ability to estimate conductances from AMPERE field‐aligned current maps provides the means to develop a global conductance model for the auroral ionosphere.

Statistical Relations Between Auroral Electrical Conductances and Field‐Aligned Currents at High Latitudes

We present examples of high‐latitude field‐aligned current (FAC) and toroidal magnetic potential patterns in both hemispheres reconstructed at a 2‐min cadence using an updated optimal interpolation (OI) method that ingests magnetic perturbation data provided by the Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE) program. A solstice and an equinoctial event are studied to demonstrate the reconstructed patterns and to provide scientific insights into FAC response to different solar wind drivers. For the 14 June 2011 high‐speed stream event with mostly northward Bz driving, we found persistently stronger FACs in the Northern Hemisphere. Extreme interhemispheric asymmetry is associated with the interplanetary magnetic field (IMF) direction and large dipole tilt, consistent with earlier studies. FAC asymmetries seen during an isolated substorm can be attributed to dipole tilt. During relatively low geomagnetic activity, the FAC response to IMF Bx changes is identified. For the 17–18 March 2013 period, we provide global snapshots of rapid FAC changes related to an interplanetary shock passage. We further present comparisons between instantaneous and mean behaviors of FAC for the solar wind sheath passage and interplanetary coronal mass ejection southward Bz interval and northward Bz intervals. We show that (1) sheath passage results in strong FAC and high variation in the dayside polar cap region and pre‐midnight region, different from the typical R1/R2 currents during prolonged southward Bz; (2) four‐cell reverse patterns appear during northward Bz but are not stable; and (3) persistent dawn‐dusk asymmetry is seen throughout the storm, especially during an extreme substorm, likely associated with a dawnside current wedge.

Event Studies of High‐Latitude FACs With Inverse and Assimilative Analysis of AMPERE Magnetometer Data

Super Dual Auroral Radar Network (SuperDARN) ionospheric convection maps are a powerful tool for the study of solar wind‐magnetosphere‐ionosphere interactions. SuperDARN data have high temporal (approximately minutes) and spatial (∼45 km) resolution, meaning that the convection can be mapped on fine time scales that show more detail than the large‐scale changes in the pattern. The Heppner‐Maynard boundary (HMB) defines the low‐latitude limit of the convection region, and its identification is an essential component of the standard SuperDARN convection mapping technique. However, the estimation of the latitude of this boundary is dependent on ionospheric scatter availability. Consequentially it is susceptible to nonphysical variations as areas of scatter in different latitude and local time regions appear and disappear, often due to changing propagation conditions. In this paper, the HMB is compared to an independent field‐aligned current data set from the Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE). A linear trend is found between the HMB and the boundary between the AMPERE Region 1 and Region 2 field‐aligned currents in the Northern Hemisphere, at both solar minimum and solar maximum. The use of this trend and the AMPERE current data set to predict the latitude position of the HMB is found to improve the interpretation of the SuperDARN measurements in convection mapping.

An Improved Estimation of SuperDARN Heppner‐Maynard Boundaries Using AMPERE Data

Remote observations by the Mariner 10 and MErcury Surface, Space ENvironment, GEophysics, and Ranging (MESSENGER) spacecraft have shown the existence of hydrogen in the exosphere of Mercury. However, to date the hydrogen number densities could only be estimated indirectly from exospheric models, based on the remotely observed Lyman‐α radiances for atomic H, and the detection threshold of the Mariner 10 occultation experiment for molecular H2. Here, we show the first on‐site determined altitude‐density profile of atomic H, derived from in situ magnetic field observations by MESSENGER. The results reveal an extended H exosphere with densities that are ∼1–2 orders of magnitude larger than previously predicted. Using an exospheric model that reproduces the H altitude‐density profile allows us to constrain the so far unknown H2 density at the surface, which is ∼2–3 orders of magnitude smaller than previously assumed. These findings demonstrate the importance of (a) in situ measurements supporting remote observations of Mercury's exosphere that will be realized in the near future by the BepiColombo mission and (b) that dissociation processes play a crucial role in Mercury's exosphere.

Abstract. Recently the two-spacecraft mission BepiColombo launched to explore the plasma and magnetic field environment of Mercury. Both spacecraft, the Mercury Planetary Orbiter (MPO) and the Mercury Magnetospheric Orbiter (MMO, also referred to as Mio), are equipped with fluxgate magnetometers, which have proven to be well-suited to measure the magnetic field in space with high precision. Nevertheless, accurate magnetic field measurements require proper in-flight calibration. In particular the magnetometer offset, which relates relative fluxgate readings into an absolute value, needs to be determined with high accuracy.
Usually, the offsets are evaluated from observations of Alfvénic fluctuations in the pristine solar wind, if those are available. An alternative offset determination method, which is based on the observation of highly compressional fluctuations instead of incompressible Alfvénic fluctuations, is the so-called mirror mode technique. To evaluate the method performance in the Hermean environment, we analyze four years of MESSENGER (MErcury Surface, Space ENvironment, GEophysics and Ranging) magnetometer data, which are calibrated by the Alfvénic fluctuation method, and compare it with the accuracy and error of the offsets determined by the mirror mode method in different plasma environments around Mercury.
We show that the mirror mode method yields the same offset estimates and thereby confirms its applicability. Furthermore, we evaluate the spacecraft observation time within different regions necessary to obtain reliable offset estimates. Although the lowest percentage of strong compressional fluctuations are observed in the solar wind, this region is most suitable for an accurate offset determination with the mirror mode method. 132 h of solar wind data are sufficient to determine the offset to within 0.5 nT, while thousands of hours are necessary to reach this accuracy in the magnetosheath or within the magnetosphere.
We conclude that in the solar wind the mirror mode method might be a good complementary approach to the Alfvénic fluctuation method to determine the (spin-axis) offset of the Mio magnetometer.

Magnetometer in-flight offset accuracy for the BepiColombo spacecraft

The rapid changes of magnetic fields associated with nighttime magnetic perturbations with amplitudes |ΔB| of hundreds of nT and 5-10 min periods can induce bursts of geomagnetically-induced curren...

Nighttime magnetic perturbation events observed in Arctic Canada: Investigating their associations with localized field-aligned currents and with substorms

We propose a mechanism for the formation of the horse‐collar auroral configuration during periods of strongly northward interplanetary magnetic field (IMF), invoking the action of dual‐lobe reconnection (DLR). Auroral observations are provided by the Imager for Magnetopause‐to‐Aurora Global Exploration (IMAGE) satellite and spacecraft of the Defense Meteorological Satellite Program (DMSP). We also use ionospheric flow measurements from DMSP and polar maps of field‐aligned currents (FACs) derived from the Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE). Sunward convection is observed within the dark polar cap, with antisunward flows within the horse‐collar auroral region, together with the NBZ FAC distribution expected to be associated with DLR. We suggest that newly closed flux is transported antisunward and to dawn and dusk within the reverse lobe cell convection pattern associated with DLR, causing the polar cap to acquire a teardrop shape and weak auroras to form at high latitudes. Horse‐collar auroras are a common feature of the quiet magnetosphere, and this model provides a first understanding of their formation, resolving several outstanding questions regarding the nature of DLR and the magnetospheric structure and dynamics during northward IMF. The model can also provide insights into the trapping of solar wind plasma by the magnetosphere and the formation of a low‐latitude boundary layer and cold, dense plasma sheet. We speculate that prolonged DLR could lead to a fully closed magnetosphere, with the formation of horse‐collar auroras being an intermediate step.

We determine the primary modes of field‐aligned current (FAC) variability and their hemispheric asymmetry by nonlinear regression analysis of a multiyear global data set of Iridium constellation engineering‐grade magnetometer data from the Active Magnetosphere and Planetary Electrodynamics Response Experiment program. The spatial and temporal FAC variability associated with three major categories of solar wind drivers, (1) slow flow, (2) high‐speed streams (HSS), (3) transient flow related to coronal mass ejections (CMEs), and (4) a combination of these, is characterized as empirical orthogonal functions (EOFs) and their time‐varying amplitude. For the combined solar wind category, the order of the modes of variability are strengthening/weakening of (1) EOF1—all FACs; (2) EOF2—Region 2 (R2) FACs; and (3) EOF3—dayside/nightside FACs. The first two EOFs are associated with solar wind coupling; EOF3 is associated with the ecliptic components of the interplanetary magnetic field (IMF). We also find hemispheric asymmetry in FACs. Northern Hemisphere EOFs show clearer spatial features and higher correlation coefficients with solar wind drivers. The Northern Hemisphere also shows higher correlation coefficients in all seasons except winter. We find transient flow EOFs to be better correlated with solar wind drivers such as IMF Bz and coupling functions, while HSS EOFs are better correlated with solar wind plasma parameters. CME‐related transient flow EOFs also show R2 FAC variabilities that are not found in other separate wind drivers. Application of the EOF analysis to the Iridium magnetometer data shows significant promise for greater understanding of geoeffectiveness of solar wind interactions with geospace.

Modes of (FACs) Variability and Their Hemispheric Asymmetry Revealed by Inverse and Assimilative Analysis of Iridium Magnetometer Data

The MErcury Surface, Space Environment, GEochemistry, and Ranging (MESSENGER) spacecraft orbited Mercury between March 2011 and April 2015, typically passing through the magnetosphere, magnetosheath, and interplanetary magnetic field, on each orbit. Using data from the Magnetometer, we identify magnetopause crossings for the complete orbital mission and model the average boundary shape. We find that Mercury's average magnetopause is well modeled by both an axisymmetric shape and a three‐dimensional shape containing indentations in the cusp regions and a magnetotail that is wider in the north‐south versus east‐west direction. Examination of MESSENGER data and the use of simulated crossings show that coverage is very limited in the cusp region. Parameters describing the indentation are poorly constrained, and model fits may be biased due to the combination of orbital geometry and magnetospheric dynamics. The distribution of MESSENGER data inside the magnetopause, together with minimum variance analysis of a representative subset of magnetopause crossings, hints at the presence of a cusp indentation, though likely shallower than that estimated from the observed crossing positions. The BepiColombo spacecraft will arrive at Mercury in 2025. We simulate expected data coverage and magnetopause crossings using both axisymmetric and three‐dimensional magnetopause models. BepiColombo will improve our understanding of the magnetopause shape by providing data over the southern hemisphere and regions of the northern cusp indentation not covered by MESSENGER. There is also the potential for simultaneous measurements of the interplanetary magnetic field and magnetopause position.

The Shape of Mercury's Magnetopause: The Picture From MESSENGER Magnetometer Observations and Future Prospects for BepiColombo

Ionospheric conductance is a crucial factor in regulating the closure of magnetospheric field‐aligned currents through the ionosphere as Hall and Pedersen currents. Despite its importance in predictive investigations of the magnetosphere‐ionosphere coupling, the estimation of ionospheric conductance in the auroral region is precarious in most global first‐principles‐based models. This impreciseness in estimating the auroral conductance impedes both our understanding and predictive capabilities of the magnetosphere‐ionosphere system during extreme space weather events. In this article, we address this concern, with the development of an advanced Conductance Model for Extreme Events (CMEE) that estimates the auroral conductance from field‐aligned current values. CMEE has been developed using nonlinear regression over a year's worth of 1‐min resolution output from assimilative maps, specifically including times of extreme driving of the solar wind‐magnetosphere‐ionosphere system. The model also includes provisions to enhance the conductance in the aurora using additional adjustments to refine the auroral oval. CMEE has been incorporated within the Ridley Ionosphere Model (RIM) of the Space Weather Modeling Framework (SWMF) for usage in space weather simulations. This paper compares performance of CMEE against the existing conductance model in RIM, through a validation process for six space weather events. The performance analysis indicates overall improvement in the ionospheric feedback to ground‐based space weather forecasts. Specifically, the model is able to improve the prediction of ionospheric currents, which impact the simulated dB/dt and ΔB, resulting in substantial improvements in dB/dt predictive skill.

Conductance Model for Extreme Events: Impact of Auroral Conductance on Space Weather Forecasts

Rapid cadence estimation of Earth's magnetic field structure reflecting core processes from the Iridium constellation

Electromagnetic ion cyclotron (EMIC) waves at large L shells were observed away from the magnetic equator by the Magnetospheric MultiScale (MMS) mission nearly continuously for over four hours on 28 October 2015. During this event, the wave Poynting vector direction systematically changed from parallel to the magnetic field (toward the equator), to bidirectional, to antiparallel (away from the equator). These changes coincide with the shift in the location of the minimum in the magnetic field in the southern hemisphere from poleward to equatorward of MMS. The local plasma conditions measured with the EMIC waves also suggest that the outer magnetospheric region sampled during this event was generally unstable to EMIC wave growth. Together, these observations indicate that the bidirectionally propagating wave packets were not a result of reflection at high latitudes but that MMS passed through an off‐equator EMIC wave source region associated with the local minimum in the magnetic field.

EMIC Waves in the Outer Magnetosphere: Observations of an Off‐Equator Source Region

We present a continuing investigation of mass‐/charge‐dependent interactions between energetic ions (greater than tens of kiloelectron volts) and planetary magnetopauses and of the escape of the ions across the boundary. Previous studies at Earth using Magnetospheric Multiscale mission data are refined and advanced showing profound behavior differences between light (H, He) and singly charged heavy ions (O+). We highlight a distinctive feature of oxygen ions: an angular distribution bifurcation providing clear indication of entrainment along the magnetopause in Speiser‐like orbits during relatively stable magnetic conditions. This signature, interpreted using a simple kinetic model, suggests that these ions tend to be carried substantial distances along the boundary (even with boundary‐normal magnetic fields) in a fashion that impedes their full dayside escape. While large fluctuations and waves can likely sometimes disrupt the observed ordering, the following picture emerges. Energetic particles with gyroradii much smaller than the magnetopause thickness (e.g., electrons and absent boundary‐normal magnetic fields) and ions with gyroradii much larger than the thickness (e.g., O+) are impeded from fully escaping across the boundary. However, energetic ions with intermediate‐sized gyroradii commensurate with the thickness (e.g., H+, He++, and O6+) can be effectively scattered within the boundary causing them to escape much more readily, with and without boundary‐normal fields. This picture is supported by observations from the Juno spacecraft at the near‐dawn meridian side of Jupiter's magnetopause. There it is observed that energetic electrons and heavy ions are more strongly contained by the magnetopause than are the energetic protons and helium ions.

Investigation of Mass‐/Charge‐Dependent Escape of Energetic Ions Across the Magnetopauses of Earth and Jupiter

David T. Blewett1, Jasper Halekas2, Benjamin T. Greenhagen1, Brian J. Anderson1, Brett W. Denevi1, Dana M. Hurley1, Rachel L. Klima1, Joshua T.S. Cahill1, Jan Deca3, Mihir Desai4, Robert Ebert4, Shahab Fatemi5, George C. Ho1, Lon L. Hood6, Lauren M. Jozwiak1, Paul G. Lucey7, Kathleen Mandt1, Jorge I. Núñez1, Christopher P. Paranicas1, Jeffrey B. Plescia1, Thomas Sotirelis1, Sonia M. Tikoo8, Joseph H. Westlake1, and Mark Wieczorek9. 1Johns Hopkins University Applied Physics Laboratory, Laurel, MD, USA; 2University of Iowa, Iowa City, IA, USA; 3University of Colorado, Boulder, CO, USA; 4Southwest Research Institute, San Antonio, TX USA; 5Swedish Institute of Space Physics, Kiruna, Sweden; 6University of Arizona, Tucson, AZ, USA; 7University of Hawaii, Honolulu, HI, USA; 8Rutgers University, Piscataway, NJ, USA; 9Observatoire de la Côte d'Azur, Nice, France. (david.blewett@jhuapl.edu).

MAGNETIC ANOMALY AS NATURAL LABORATORY : THE LUNAR COMPASS MISSION CONCEPT

We present high‐latitude field‐aligned current (FAC) response to nearly frontal shocks (NFSs) and highly inclined shocks (HISs) through a superposed epoch analysis. The FACs are derived from magnetic perturbation data provided by the Active Magnetosphere and Planetary Electrodynamics Response Experiment program. Forty‐nine events for each group are used for the superposed epoch analysis. The 25%, 50%, and 75% quantiles of the FAC and total current distributions are studied. We found that NFSs are statistically stronger shocks in terms of solar wind parameters such as solar wind speed and interplanetary magnetic field.For the 50% quantiles, both groups of shocks produce rapid increases in total currents after shock arrival, but NFSs result in sharper increase in FACs and more intense FACs compared to HISs. At the 50% and 75% quantiles, NFSs trigger stronger auroral‐zone current disturbance for the first hour after shock arrival than do HISs. Spatially, the difference in FAC response is most notable in (1) the dayside noon region, (2) the duskside Region 2 current system, and (3) the dawnside prenoon Region 1 current system. Our results are consistent with previous numerical simulations that showed more symmetric and stronger compression of the magnetosphere for high‐speed and nearly frontal shocks. We observationally confirm the role of shock impact angle in controlling the subsequent shock geoeffectiveness for fast shocks. We assert that determining the shock impact angle via an upstream solar wind model could provide useful insight in forecasting the geoeffectiveness of a shock prior to its arrival at the magnetopause.

Effects of Nearly Frontal and Highly Inclined Interplanetary Shocks on High‐Latitude Field‐Aligned Currents (FACs)

We study the role of substorms and steady magnetospheric convection (SMC) in magnetic flux transport in the magnetosphere, using observations of field‐aligned currents by the Active Magnetosphere and Planetary Electrodynamics Response Experiment. We identify two classes of substorm, with onsets above and below 65° magnetic latitude, which display different nightside field‐aligned current morphologies. We show that the low‐latitude onsets develop a poleward‐expanding auroral bulge, and identify these as substorms that manifest ionospheric convection‐braking in the auroral bulge region as suggested by Grocott et al. (2009, https://doi.org/10.5194/angeo-27-591-2009). We show that the high‐latitude substorms, which do not experience braking, can evolve into SMC events if the interplanetary magnetic field remains southward for a prolonged period following onset. We conclude that during periods of ongoing driving, the magnetosphere displays repeated substorm activity or SMC depending on the rate of driving and the open magnetic flux content of the magnetosphere prior to onset. We speculate that sawtooth events are an extreme case of repeated onsets and that substorms triggered by northward‐turnings of the interplanetary magnetic field mark the cessation of periods of SMC. Our results provide a new explanation for the differing modes of response of the terrestrial system to solar wind‐magnetosphere‐ionosphere coupling by invoking friction between the ionosphere and atmosphere.

Substorm Onset Latitude and the Steadiness of Magnetospheric Convection

The Magnetospheric Multiscale (MMS) spacecraft obtained unprecedented high‐time resolution multipoint particle and field measurements of an interplanetary shock event on 8 January 2018. The spacecraft encountered the supercritical forward shock of a forward/reverse shock pair in the pristine solar wind upstream of the bow shock near the subsolar point as they neared apogee at ~25 RE. The high‐time resolution measurements from the four spacecraft, separated by only ~20 km, allowed direct measurement of particle distributions revealing evidence of electron heating and near specularly reflected ions. The cross‐shock potential is calculated directly from 3‐D electric field measurements. This is the first reported direct high temporal resolution (<1 s) observation at an interplanetary shock of near specularly reflected ions. Calculation of the cross‐shock potential yields a potential jump significant enough to reflect at least some of the protons from the incident solar wind beam. The cross‐shock potential calculated here is consistent with previous estimations based on particle measurements and numerical/analytical simulations. The ambipolar contribution to the cross‐shock potential calculated from the four‐spacecraft divergence of the electron pressure tensor is somewhat higher than that inferred form the Liouville‐mapped electron energy gain across the shock. Furthermore, the high‐time‐resolution 3‐D electric field measurements reported here reveal small‐scale nonlinear structures embedded in the shock layer that contribute to the nonmonotonic shock transition.

High‐Resolution Measurements of the Cross‐Shock Potential, Ion Reflection, and Electron Heating at an Interplanetary Shock by MMS

Conductance in the Aurora: Influence of Magnetospheric Contributors

Dayside Polar Cap Flows and Density Enhancements Triggered by Substorms

Abstract. The high-latitude atmosphere is a dynamic region with processes that respond to forcing from the Sun, magnetosphere, neutral atmosphere, and
ionosphere. Historically, the dominance of magnetosphere–ionosphere interactions has motivated upper atmospheric studies to use magnetic
coordinates when examining magnetosphere–ionosphere–thermosphere coupling processes. However, there are significant differences between the
dominant interactions within the polar cap, auroral oval, and equatorward of the auroral oval. Organising data relative to these boundaries has
been shown to improve climatological and statistical studies, but the process of doing so is complicated by the shifting nature of the auroral oval
and the difficulty in measuring its poleward and equatorward boundaries. This study presents a new set of open–closed magnetic field line boundaries (OCBs) obtained from Active Magnetosphere and Planetary Electrodynamics
Response Experiment (AMPERE) magnetic perturbation data. AMPERE observations of field-aligned currents (FACs) are used to determine the location of
the boundary between the Region 1 (R1) and Region 2 (R2) FAC systems. This current boundary is thought to typically lie a few degrees equatorward
of the OCB, making it a good candidate for obtaining OCB locations. The AMPERE R1–R2 boundaries are compared to the Defense Meteorological
Satellite Program Special Sensor J (DMSP SSJ) electron energy flux boundaries to test this hypothesis and determine the best estimate of the
systematic offset between the R1–R2 boundary and the OCB as a function of magnetic local time. These calibrated boundaries, as well as OCBs
obtained from the Imager for Magnetopause-to-Aurora Global Exploration (IMAGE) observations, are validated using simultaneous observations of the
convection reversal boundary measured by DMSP. The validation shows that the OCBs from IMAGE and AMPERE may be used together in statistical
studies, providing the basis of a long-term data set that can be used to separate observations originating inside and outside of the polar cap.

We obtain current densities from the Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE), alongside By and Bz from the Interplanetary Magnetic Field (IMF) for March 2010. For each AMPERE spatial coordinate, we cross‐correlate current density with By and Bz, finding the maximum correlation for lags up to 360 min. The patterns of maximum correlation contain large‐scale structures consistent with the literature. For the correlation with By, the lags on the dayside are 10 min at high latitudes but up to 240 min at lower latitudes. Lags on the nightside are 90–150 min. For Bz, the shortest lags on the dayside are 10–20 min; on the equatorward edge of the current oval, 60–90 min; and on the nightside, predominantly 90–150 min. This novel approach enables us to see statistically the timescales on which information is electrodynamically communicated to the ionosphere after magnetic field lines reconnect on the dayside and nightside.

The Relationship Between Bifurcations of Region 2 Field-Aligned Currents and the Occurrence of Sub-Auroral Polarization Streams

Mercury’s magnetosphere is known to be affected by the enhanced ram pressure and magnetic fields inside interplanetary coronal mass ejections (ICMEs). Here we report detailed observations of an ICME compressing Mercury’s dayside magnetosphere to the surface. A fast CME launched from the Sun on 2013 November 29 impacted first the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft, which was orbiting Mercury, on November 30 and later STEREO-A near 1 au on December 1. Following the ICME impact, MESSENGER remained in the solar wind as the spacecraft traveled inwards and northwards toward Mercury’s surface until it reached and passed its closest approach to the planet (at 371 km altitude) without crossing into the magnetosphere. The magnetospheric crossing finally occurred 1 minute before reaching the planet’s nightside at 400 km altitude and 84°N latitude, indicating the lack of dayside magnetosphere on this orbit. In addition, the peak magnetic field measured by MESSENGER at this time was 40% above the values measured in the orbits just prior to and after the ICME, a consequence of the magnetospheric compression. Using both a proxy method at Mercury and measurements at STEREO-A, we show that the extremely high ram pressure associated with this ICME was more than high enough to collapse Mercury’s weak magnetosphere. As a consequence, the ICME plasma likely interacted with Mercury’s surface, evidenced by enhanced sodium ions in the exosphere. The collapse of Mercury’s dayside magnetosphere has important implications for the habitability of close-in exoplanets around M dwarf stars, as such events may significantly contribute to planetary atmospheric loss in these systems.

Observations of Extreme ICME Ram Pressure Compressing Mercury’s Dayside Magnetosphere to the Surface

Nittler2, Brian J. Anderson3, and Paul K. Byrne4, 1Lamont-Doherty Earth Observatory, Columbia University, Palisades, NY 10964, USA (solomon@ldeo.columbia.edu), 2Department of Terrestrial Magnetism, Carnegie Institution of Washington, Washington, DC 20015, USA, 3The Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA, 4Department of Marine, Earth, and Atmospheric Sciences, North Carolina State University, Raleigh, NC 27695, USA.

W. Denevi, David T. Blewett, Dana M. Hurley, Joshua T.S. Cahill, Rachel L. Klima, Lauren M. Jozwiak, Jeffrey B. Plescia, Christopher P. Paranicas, Benjamin T. Greenhagen, Charles A. Hibbitts, Brian J. Anderson, Haje Korth, George C. Ho, Jorge I. Núñez, Michael I. Zimmerman, Pontus C. Brandt, Sabine Stanley, Joseph H. Westlake, Antonio Diaz-Calderon, and Jeffrey R. Johnson. Space Science Branch, Space Exploration Sector, Johns Hopkins University Applied Physics Laboratory, Laurel, Md., USA. (brett.denevi@jhuapl.edu).

THE LUNAR COMPASS ROVER MISSION CONCEPT : EXPLORING A MAGNETIC ANOMALY

We investigate the formation and development of a large‐scale current system in the dawn sector during intense geomagnetic storms. Four events are selected based on the historical ranking of the westward deflections of the morningside midlatitude magnetic field. For each event the polar distribution of equivalent currents indicates a significant intensification of the westward electrojet (WEJ), which initially takes place at postmidnight and then extends eastward covering the entire dawn sector. The longitudinal confinement of the enhanced WEJ suggests that it closes with downward and upward field‐aligned currents (FACs) at its eastern and western ends, respectively, and therefore, the entire system may be envisioned as a wedge current. It is noted, however, that the primary closure of FACs is meridional, and those upward and downward FACs are considered to be unbalanced parts of the R1 and R2 currents. In one event dipolarization was observed in the dawnside plasma sheet near the magnetic conjugate point of the enhanced WEJ, and in another event a major auroral expansion was observed in the entire dawn sector. It is therefore suggested that the formation of the wedge current system and the subsequent expansion toward dayside is an ionospheric projection of the tail current reduction extending toward the dawnside flank. This wedge current system is similar to the substorm wedge current system except that it is centered at dawn. The recurrent formation of this dawnside current wedge in intense storms suggests that this is another distinct constituent of the storm time current system.

Dawnside Wedge Current System Formed During Intense Geomagnetic Storms

The stimulation of electromagnetic ion cyclotron (EMIC) waves by a magnetospheric compression is perhaps the closest thing to a controlled experiment that is currently possible in magnetospheric physics, in that one prominent factor that can increase wave growth acts at a well‐defined time. We present a detailed analysis of EMIC waves observed in the outer dayside magnetosphere by the four Magnetosphere Multiscale (MMS) spacecraft, Van Allen Probe A, and GOES 13 and by four very high latitude ground magnetometer stations in the western hemisphere before, during, and after a modest interplanetary shock on 14 December 2015. Analysis shows several features consistent with current theory, as well as some unexpected features. During the most intense MMS wave burst, which began ~ 1 min after the end of a brief magnetosheath incursion, independent transverse EMIC waves with orthogonal linear polarizations appeared simultaneously at all four spacecraft. He++ band EMIC waves were observed by MMS inside the magnetosphere, whereas almost all previous studies of He++ band EMIC waves observed them only in the magnetosheath and magnetopause boundary layers. Transverse EMIC waves also appeared at Van Allen Probe A and GOES 13 very near the times when the magnetic field compression reached their locations, indicating that the compression lowered the instability threshold to allow for EMIC wave generation throughout the outer dayside magnetosphere. The timing of the EMIC waves at both MMS and Van Allen Probe A was consistent with theoretical expectations for EMIC instabilities based on characteristics of the proton distributions observed by instruments on these spacecraft.

MMS, Van Allen Probes, GOES 13, and Ground‐Based Magnetometer Observations of EMIC Wave Events Before, During, and After a Modest Interplanetary Shock

P33B-1929, San Francisco, CA, 3–7 December. Merkel, A. W., Cassidy, T. A., Vervack, R. J., Jr., McClintock, W. E., Sarantos, M., Burger, M. H. and Killen, R. M. (2017). Seasonal variations of Mercury’s magnesium dayside exosphere from MESSENGER observations. Icarus, 281, 46–54. Moses, J. I., Rawlins, K., Zahnle, K. and Dones, L. (1999). External sources of water for Mercury’s putative ice deposits. Icarus, 137, 197–221. Murchie, S. L., Klima, R. L., Denevi, B.W., Ernst, C.M., Keller, M. R., Domingue, D. L., Blewett, D. T., Chabot, N. L., Hash, C. D., Malaret, E., Izenberg, N. R., Vilas, F., Nittler, L. R., Gillis-Davis, J. J., Head, J. W. and Solomon, S. C. (2015). Orbital multispectral mapping of Mercury with the MESSENGER Mercury Dual Imaging System: Evidence for the origins of plains units and low-reflectance material. Icarus, 254, 287–305. Namur, O., Collinet, M., Charlier, B., Grove, T. L., Holtz, F. and McCammon, C. (2016). Melting processes and mantle sources of lavas on Mercury. Earth Planet. Sci. Lett., 439, 117–128. Ness, N. F., Behannon, K.W., Lepping, R. P. andWhang, Y. C. (1976). Observations of Mercury’s magnetic field. Icarus, 28, 479–488. Neumann, G. A., Cavanaugh, J. F., Sun, X., Mazarico, E. M., Smith, D. E., Zuber, M. T., Mao, D., Paige, D. A., Solomon, S. C., Ernst, C. M. and Barnouin, O. S. (2013). Bright and dark polar deposits on Mercury: Evidence for surface volatiles. Science, 339, 296–300. Nittler, L. R., Starr, R. D., Weider, S. Z., McCoy, T. J., Boynton, W. V., Ebel, D. S., Ernst, C.M., Evans, L. G., Goldsten, J. O., Hamara, D. K., Lawrence, D. J., McNutt, R. L., Jr., Schlemm, C. E., II, Solomon, S. C. and Sprague, A. L. (2011). The major-element composition of Mercury’s surface from MESSENGER X-ray spectrometry. Science, 333, 1847–1851. Paige, D. A., Wood, S. E. and Vasavada, A. R. (1992). The internal stability ofwater ice at the poles ofMercury. Science, 258, 643–646. Paige, D. A., Siegler, M. A., Harmon, J. K., Neumann, G. A., Mazarico, E. M., Smith, D. E., Zuber, M. T., Harju, E., Delitsky, M. L. and Solomon, S. C. (2013). Thermal stability of volatiles in the north polar region of Mercury. Science, 339, 300–303. Peale, S. J. (1976). Does Mercury have a molten core? Nature, 262, 765–766. Peale, S. J., Phillips, R. J., Solomon, S. C., Smith, D. E. and Zuber, M. T. (2002). A procedure for determining the nature of Mercury’s core. Meteorit. Planet. Sci., 37, 1269–1283. Peplowski, P. N., Evans, L. G., Hauck, S. A., II, McCoy, T. J., Boynton, W. V., Gillis-Davis, J. J., Ebel, D. S., Goldsten, J. O., Hamara, D. K., Lawrence, D. J., McNutt, R. L., Jr., Nittler, L. R., Solomon, S. C., Rhodes, E. A., Sprague, A. L., Starr, R. D. and StockstillCahill, K. R. (2011). Radioactive elements on Mercury’s surface from MESSENGER: Implications for the planet’s formation and evolution. Science, 333, 1850–1852. Peplowski, P. N., Lawrence, D. J., Rhodes, E. A., Sprague, A. L., McCoy, T. J., Denevi, B. W., Evans, L. G., Head, J. W., Nittler, L. R., Solomon, S. C., Stockstill-Cahill, K. R. and Weider, S. Z. (2012). Variations in the abundances of potassium and thorium on the surface of Mercury: Results from the MESSENGER GammaRay Spectrometer. J. Geophys. Res., 117, E00L04, doi:10.1029/ 2012JE004141. Peplowski, P. N., Lawrence, D. J., Feldman, W. C., Goldsten, J. O., Bazell, D., Evans, L. G., Head, J.W., Nittler, L. R., Solomon, S. C. and Weider, S. Z. (2015). Geochemical terranes of Mercury’s northern hemisphere as revealed by MESSENGER neutron measurements. Icarus, 253, 346–353. Peplowski, P. N., Klima, R. L., Lawrence, D. J., Ernst, C. M., Denevi, B. W., Frank, E. A., Goldsten, J. O., Murchie, S. L., Nittler, L. R. and Solomon, S. C. (2016). Remote sensing evidence for an ancient carbon-bearing crust on Mercury. Nature Geosci., 9, 273–276. Potter, A. and Morgan, T. (1985). Discovery of sodium in the atmosphere of Mercury. Science, 229, 651–653. Potter, A. E. and Morgan, T. H. (1986). Potassium in the atmosphere of Mercury. Icarus, 67, 336–340. Preusker, F., Oberst, J., Head, J. W., Watters, T. R., Robinson, M. S., Zuber, M. T. and Solomon, S. C. (2011). Stereo topographic models of Mercury after three MESSENGER flybys. Planet. Space Sci., 59, 1910–1917. Prockter, L. M., Ernst, C. M., Denevi, B. W., Chapman, C. R., Head, J. W., Fassett, C. I., Merline, W. J., Solomon, S. C., Watters, T. R., Strom, R. G., Cremonese, G., Marchi, S. and Massironi, M. (2010). Evidence for young volcanism on Mercury from the third MESSENGER flyby. Science, 329, 668–671. Raines, J. M., Gershman, D. J., Zurbuchen, T. H., Sarantos, M., Slavin, J. A., Gilbert, J. A., Korth, H., Anderson, B. J., Gloeckler, G., Krimigis, S. M., Baker, D. N., McNutt, R. L., Jr. and Solomon, S. C. (2013). Distribution and compositional variations of plasma ions in Mercury’s space environment: The first three Mercury years of MESSENGER observations. J. Geophys. Res. Space Physics, 118, 1604–1619. Raines, J. M., Gershman, D. J., Slavin, J. A., Zurbuchen, T. H., Korth, H., Anderson, B. J. and Solomon, S. C. (2014). Structure and dynamics of Mercury’s magnetospheric cusp: MESSENGER measurements of protons and planetary ions. J. Geophys. Res. Space Physics, 119, 6587–6602. Robinson, M. S., Murchie, S. L., Blewett, D. T., Domingue, D. L., Hawkins, S. E., III, Head, J. W., Holsclaw, G.M., McClintock,W. E., McCoy, T. J., McNutt, R. L., Jr., Prockter, L. M. Solomon, S. C. and T. R. Watters, T. R. (2008). Reflectance and color variations on Mercury: Regolith processes and compositional heterogeneity. Science, 321, 66–69. Santo, A. G., Gold, R. E., McNutt, R. L., Jr., Solomon, S. C., Ercol, C. J., Farquhar, R. W., Hartka, T. J., Jenkins, J. E., McAdams, J. V., Mosher, L. E., Persons, D. F., Artis, D. A., Bokulic, R. S., Conde, R. F., Dakermanji, G., Goss, M. E., Jr., Haley, D. R., Heeres, K. J., Maurer, R. H., Moore, R. C., Rodberg, E. H., Stern, T. G., Wiley, S. R., Williams, B. G., Yen, C. L. and Peterson, M. R. (2001). The MESSENGER mission to Mercury: Spacecraft and mission design. Planet. Space Sci., 49, 1481–1500. Schlemm, C. E., II, Starr, R. D., Ho, G. C., Bechtold, K. E., Hamilton, S. A., Boldt, J. D., Boynton, W. V., Bradley, W., Fraeman, M. E., Gold, R. E., Goldsten, J. O., Hayes, J. R., Jaskulek, S. E., Rossano, E., Rumpf, R. A., Schaefer, E. D., Strohbehn, K., Shelton, R. G., Thompson, R. E., Trombka, J. I. and Williams, B. D. (2007). The X-Ray Spectrometer on the MESSENGER spacecraft. Space Sci. Rev., 131, 393–415. Schubert, G., Ross, M. N., Stevenson, D. J. and Spohn, T. (1988). Mercury’s thermal history and the generation of its magnetic field. In Mercury, ed. F. Vilas, C. R. Chapman and M. S. Matthews. Tucson, AZ: University of Arizona Press, pp. 429–460. Siegfried, R. W., II and Solomon, S. C. (1974). Mercury: Internal structure and thermal evolution. Icarus, 23, 192–205. Slade, M. A., Butler, B. J. and Muhleman, D. O. (1992). Mercury radar imaging: Evidence for polar ice. Science, 258, 635–640. Slavin, J. A., Acuña, M. A., Anderson, B. J., Baker, D. N., Benna, M., Gloeckler, G., Gold, R. E., Ho, G. C., Killen, R. M., Korth, H., Krimigis, S. A., McNutt, R. L., Jr., Nittler, L. R., Raines, J. M., Schriver, D., Solomon, S. C., Starr, R. D., Trávníček, P. and Zurbuchen, T. H. (2008). Mercury’s magnetosphere after MESSENGER’s first flyby. Science, 321, 85–89. Slavin, J. A., Anderson, B. J., Baker, D. N., Benna, M., Boardsen, S. A., Gold, R. E., Ho, G. C., Imber, S. M., Korth, H., Krimigis, S. M., References 27

We present the first simultaneous in situ observation by the Arase satellite of the region-2 field-aligned currents (FACs) and the ring current during a storm main phase on 16 July 2017. The crossing of the postmidnight upward FAC with the maximum current density of 60 nA/m 2 at L~4.2 and MLAT~20 o was determined by a change in the azimuthal magnetic field. The peak of the FAC density was located in the inner part of the ring current derived from the plasma pressure. The current driven by the oxygen pressure significantly contributed to the ring current density, in particular in the inner part. The FAC density value and invariant latitude in the inner magnetosphere were consistent with the corresponding FAC on the ionosphere derived from the AMPERE (Active Magnetosphere and Planetary Electrodynamics Response Experiment), indicating a connection of FAC between these regions.

Region-2 field-aligned current and ring current ions during storm main phase: Arase and AMPERE observations

The development of large‐scale Birkeland currents is examined using the Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE), which measures global Birkeland currents continuously on 10‐min time scales. The integrated current was used to identify onsets of at least 1 MA preceded by periods of quiescence lasting at least 3 hr. The Region 1 currents do not fully form without Region 2. Rather, they develop together, first on the dayside, then on the nightside, and lastly, they fill in and intensify at all local times to form the nominal statistical pattern. The onsets are closely correlated with enhancements of magnetospheric forcing as indicated by the solar wind electric field and the orientation of the interplanetary magnetic field. Nightside onsets correspond to intensifications of the auroral electrojet as reflected in the AE index; they are delayed by ~40 min relative to the increase of the dayside current and are 2.8 times more rapid than the dayside current increase. After nightside onset, Birkeland currents expand toward dawn and dusk and merge with the dayside currents while also intensifying at all local times. The dayside current pattern depends on the sign of the interplanetary magnetic field BY. The nightside current distributions are the same for positive and negative BY and display a Harang discontinuity independent of the sign of BY. The predominant development and intensification of Birkeland currents occur after nightside onset at all local times with roughly 75% of the total current, both Regions 1 and 2, appearing after nightside onset.

Electromagnetic ion cyclotron (EMIC) waves play important roles in particle loss processes in the magnetosphere. Determining the evolution of EMIC waves as they propagate and how this evolution affects wave‐particle interactions requires accurate knowledge of the wave vector, k. We present a technique using the curl of the wave magnetic field to determine k observationally, enabled by the unique configuration and instrumentation of the Magnetospheric MultiScale (MMS) spacecraft. The wave curl analysis is demonstrated for synthetic arbitrary electromagnetic waves with varying properties typical of observed EMIC waves. The method is also applied to an EMIC wave interval observed by MMS on October 28, 2015. The derived wave properties and k from the wave curl analysis for the observed EMIC wave are compared with the Waves in Homogenous, Anisotropic, Multi‐component Plasma (WHAMP) wave dispersion solution and with results from other single‐ and multi‐spacecraft techniques. We find good agreement between k from the wave curl analysis, k determined from other observational techniques, and k determined from WHAMP. Additionally, the variation of k due to the time and frequency intervals used in the wave curl analysis is explored. This exploration demonstrates that the method is robust when applied to a wave containing at least 3–4 wave periods and over a rather wide frequency range encompassing the peak wave emission. These results provide confidence that we are able to directly determine the wave vector properties using this multi‐spacecraft method implementation, enabling systematic studies of EMIC wave k properties with MMS.

Determining EMIC Wave Vector Properties Through Multi‐Point Measurements: The Wave Curl Analysis

Principal component analysis is performed on Birkeland or field‐aligned current (FAC) measurements from the Active Magnetosphere and Planetary Electrodynamics Response Experiment, to determine the response of dayside and nightside FACs to reversals in the orientation of the interplanetary magnetic field (IMF) and the occurrence of substorms. Dayside FACs respond promptly to changes in IMF BY, but the nightside response is delayed by up to an hour and can take up to 4 hr to develop fully, especially during northward IMF. Nightside FAC asymmetries grow during substorm growth phase when the IMF has a significant BY component, and also promptly at substorm onset. Our findings suggest that magnetotail twisting and/or BY penetration into the magnetotail, due to subsolar reconnection with east‐west orientated IMF, are the main cause of these nightside FAC asymmetries and that asymmetries also arise due to magnetotail reconnection of these twisted field lines.

Timescales of Dayside and Nightside Field‐Aligned Current Response to Changes in Solar Wind‐Magnetosphere Coupling

New insight into energetic particle escape from the Energetic Particle Detector aboard MMS

Key Questions in Planetary Science to be Addressed by Exploration of a Lunar Magnetic Anomaly: The Lunar Compass Rover Discovery Mission Concept

Abstract. During the 14 November 2012 geomagnetic storm, the Van Allen Probes spacecraft observed a number of sharp decreases
(“dropouts”) in particle fluxes for ions and electrons of different energies. In this paper, we investigate the global
magnetosphere dynamics and magnetosphere–ionosphere (M–I) coupling during the dropout events using multipoint
measurements by Van Allen Probes, TWINS, and AMPERE together with the output of the two-way coupled global BATS-R-US–CRCM
model. We find different behavior for two pairs of dropouts. For one pair, the same pattern was repeated: (1) weak
nightside Region 1 and 2 Birkeland currents before and during the dropout; (2) intensification of Region 2 currents after
the dropout; and (3) a particle injection detected by TWINS after the dropout. The model predicted similar behavior of
Birkeland currents. TWINS low-altitude emissions demonstrated high variability during these intervals, indicating high
geomagnetic activity in the near-Earth tail region. For the second pair of dropouts, the structure of both Birkeland
currents and ENA emissions was relatively stable. The model also showed quasi-stationary behavior of Birkeland currents
and simulated ENA emissions with gradual ring current buildup. We confirm that the first pair of dropouts was caused by
large-scale motions of the OCB (open–closed boundary) during substorm activity. We show the new result that this OCB
motion was associated with global changes in Birkeland (M–I coupling) currents and strong modulation of low-altitude ion
precipitation. The second pair of dropouts is the result of smaller OCB disturbances not related to magnetospheric
substorms. The local observations of the first pair of dropouts result from a global magnetospheric reconfiguration, which
is manifested by ion injections and enhanced ion precipitation detected by TWINS and changes in the structure of Birkeland
currents detected by AMPERE. This study demonstrates that multipoint measurements along with the global model results
enable the reconstruction of a more complete system-level picture of the dropout events and provides insight into M–I
coupling aspects that have not previously been investigated. Keywords. Magnetospheric physics (magnetosphere–ionosphere interactions; magnetospheric configuration and dynamics); space plasma physics (numerical simulation studies)

Magnetosphere dynamics during the 14 November 2012 storm inferred from TWINS, AMPERE, Van Allen Probes, and BATS-R-US–CRCM

We review research into the Birkeland currents (also known as field-aligned currents) that has been conducted using the Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE). We open with a short review of the history of research into the Birkeland current systems, before describing the conception of AMPERE and its roots in Iridium telecommunications satellite engineering telemetry data. We describe the difference between Iridium engineering telemetry data and AMPERE data, and review the work that has been done using both datasets. We review research into Regions 1 and 2 Birkeland current during geomagnetic storms and consequently the ways in which the currents are driven by the solar wind, before moving onto the substorm current wedge and discussing the present controversy over this phenomenon in AMPERE data. Ways in which AMPERE data can be used to examine ionospheric conductivity are detailed alongside ways in which AMPERE has contributed to empirical models of the coupled solar wind-magnetosphere- ionosphere system. Finally, we look to the future and speculate on the manner in which AMPERE may yet unlock the secrets of the magnetosphere.

(1) Delft University of Technology, Faculty of Aerospace Engineering, Space Engineering, Delft, Netherlands (e.n.doornbos@tudelft.nl), (2) Faculty of Aerospace Engineering, TU Delft, Delft, The Netherlands (e.n.doornbos@tudelft.nl), (3) High Altitude Observatory, National Center for Atmospheric Research, Boulder, Colorado, USA, (4) The Johns Hopkins University Applied Physics Laboratory, Laurel, Maryland, USA, (5) ESA/ESRIN, Frascati, Italy, (6) ESA/ESTEC Noordwijk, The Netherlands

Increasing the contribution of satellite gravity field missions to the investigation of the thermosphere-ionosphere

Measurements of field‐aligned currents from the Active Magnetosphere and Planetary Electrodynamics Response Experiment are combined with measurements of far ultraviolet emissions from the Global Ultraviolet Imager on the Thermosphere‐Ionosphere‐Mesosphere Energetics and Dynamics satellite to examine the correlation between parallel currents and auroral electron energy flux. The energy flux is derived from the far ultraviolet emissions in the N2 Lyman‐Birge‐Hopfield bands. We find that energy flux correlates with field‐aligned currents in both upward and downward current regions. The correlations vary with magnetic local time with the strongest dependences near magnetic midnight. The data are binned and averaged to construct a model of precipitating particle energy flux as a function of field‐aligned current and magnetic local time. With Active Magnetosphere and Planetary Electrodynamics Response Experiment data as input, the model yields accurate estimates of the hemispheric power input from precipitating particles.

Statistical Relations Between Field‐Aligned Currents and Precipitating Electron Energy Flux

The strength of field‐aligned currents coupling the magnetosphere to the ionosphere was obtained by the Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE) using the network of Iridium® spacecraft. The distribution of current was integrated giving total current in and out of the ionosphere on the dayside and nightside of the Earth in both hemispheres. The onset of auroral zone negative bays and midlatitude positive bays corresponds to an increase in nightside upward current. The total outward current tends toward saturation with increasing solar wind driver strength. The optimum solar wind coupling function for AL index predicts ~73% of the variance in nightside upward current. The dayside and nightside predictors of upward current rise to a peak at 30–45 min and decay slowly over 2.5 hr. Nightside response is delayed relative to dayside.

Relation of Field‐Aligned Currents Measured by the Network of Iridium® Spacecraft to Solar Wind and Substorms

CHARGED: Understanding the Physics of Extreme Geomagnetically Induced Currents

Mirror mode waves are ubiquitous in the Earth's magnetosheath, in particular behind the quasi‐perpendicular shock. Embedded in these nonlinear structures, intense lion roars are often observed. Lion roars are characterized by whistler wave packets at a frequency ∼100 Hz, which are thought to be generated in the magnetic field minima. In this study, we make use of the high time resolution instruments on board the Magnetospheric MultiScale mission to investigate these waves and the associated electron dynamics in the quasi‐perpendicular magnetosheath on 22 January 2016. We show that despite a core electron parallel anisotropy, lion roars can be generated locally in the range 0.05–0.2fce by the perpendicular anisotropy of electrons in a particular energy range. We also show that intense lion roars can be observed up to higher frequencies due to the sharp nonlinear peaks of the signal, which appear as sharp spikes in the dynamic spectra. As a result, a high sampling rate is needed to estimate correctly their amplitude, and the latter might have been underestimated in previous studies using lower time resolution instruments. We also present for the first‐time 3‐D high time resolution electron velocity distribution functions in mirror modes. We demonstrate that the dynamics of electrons trapped in the mirror mode structures are consistent with the Kivelson and Southwood (1996) model. However, these electrons can also interact with the embedded lion roars: first signatures of electron quasi‐linear pitch angle diffusion and possible signatures of nonlinear interaction with high‐amplitude wave packets are presented. These processes can lead to electron untrapping from mirror modes.

The Properties of Lion Roars and Electron Dynamics in Mirror Mode Waves Observed by the Magnetospheric MultiScale Mission

An examination of inner-magnetosphere shielding by Region-2 Field-Aligned Currents

Acceleration, Jerks, and External Signals: Global Characterization of Earth's Field on Sub-Annual Time Scales with Space Constellation Measurements

MMS Observations of the Kinetic Processes within an Interplanetary Shock

Improving Global Ionospheric Electrodynamics Based on Low-Earth Orbiting Satellite Observations

We present characteristics of current layers in the off‐equatorial near‐Earth plasma sheet boundary observed with high time‐resolution measurements from the Magnetospheric Multiscale mission during an intense substorm associated with multiple dipolarizations. The four Magnetospheric Multiscale spacecraft, separated by distances of about 50 km, were located in the southern hemisphere in the dusk portion of a substorm current wedge. They observed fast flow disturbances (up to about 500 km/s), most intense in the dawn‐dusk direction. Field‐aligned currents were observed initially within the expanding plasma sheet, where the flow and field disturbances showed the distinct pattern expected in the braking region of localized flows. Subsequently, intense thin field‐aligned current layers were detected at the inner boundary of equatorward moving flux tubes together with Earthward streaming hot ions. Intense Hall current layers were found adjacent to the field‐aligned currents. In particular, we found a Hall current structure in the vicinity of the Earthward streaming ion jet that consisted of mixed ion components, that is, hot unmagnetized ions, cold E × B drifting ions, and magnetized electrons. Our observations show that both the near‐Earth plasma jet diversion and the thin Hall current layers formed around the reconnection jet boundary are the sites where diversion of the perpendicular currents take place that contribute to the observed field‐aligned current pattern as predicted by simulations of reconnection jets. Hence, multiscale structure of flow braking is preserved in the field‐aligned currents in the off‐equatorial plasma sheet and is also translated to ionosphere to become a part of the substorm field‐aligned current system.

Dawnside Wedge Current System: A distinct storm-time current system that has been widely overlooked

Geospace Specification and Prediction using Global Low Earth Orbit Observations of the Coupling Electric Currents

In this paper, we report global observations of high-m poloidal waves occurred during the recovery phase of the magnetic storm starting on 22 June 2015. The long lasting waves are observed by a constellation of widely spaced satellites from 5 missions including MMS, Van Allen Probes, THEMIS, Cluster, and GOES, covering L-values between 4 and 12 in a large range of local times. These observations have demonstrated that storm-time high-m poloidal waves can occur globally. High-resolution data from four MMS satellites enable us to detect the azimuthal phase shifts and determine the m number to be ∼100. The mode identification suggests that the observed poloidal waves are associated with the second harmonic of the field line resonance. The wave frequencies range from 8 to 22 mHz and decrease as the L-value increases. Detailed examinations of instantaneous wave frequency show discrete spatial structures with step-like changes along the radial direction. In each discrete structure the wave has a steady frequency and spans about 1 Re in the radial direction. Our observations suggest that storm-time high-m poloidal waves are different from the single-frequency global poloidal mode waves that are common during periods of low-level of geomagnetic activities.

Global Observations of High-m Poloidal Waves in the Magnetosphere during the Recovery Phase of the June 2015 Magnetic Storm

Previous observations have driven the prevailing assumption in the field that energetic ions measured by an instrument using a bare solid state detector (SSD) are predominantly protons. However, new near‐equatorial energetic particle observations obtained between 7 and 12 RE during Phase 1 of the Magnetospheric Multiscale mission challenge the validity of this assumption. In particular, measurements by the Energetic Ion Spectrometer (EIS) instruments have revealed that the intensities of heavy ion species (specifically oxygen and helium) dominate those of protons at energies ≳ 150–220 keV in the middle to outer (>7 RE) magnetosphere. Given that relative composition measurements can drift as sensors degrade in gain, quality cross‐calibration agreement between EIS observations and those from the SSD‐based Fly's Eye Energetic Particle Spectrometer (FEEPS) sensors provides critical support to the veracity of the measurement. Similar observations from the Radiation Belt Storm Probes Ion Composition Experiment (RBSPICE) instruments aboard the Van Allen Probes spacecraft extend the ion composition measurements into the middle magnetosphere and reveal a strongly proton‐dominated environment at L≲6 but decreasing proton intensities at L≳6 . It is concluded that the intensity dominance of the heavy ions at higher energies (>150 keV) arises from the existence of significant populations of multiply‐charged heavy ions, presumably of solar wind origin.

Dominance of high‐energy (>150 keV) heavy ion intensities in Earth's middle to outer magnetosphere

The magnetic storm that commenced on June 22, 2015 was one of the largest storms in the current solar cycle, resulting from an active region on the Sun that produced numerous coronal mass ejections (CMEs) and associated interplanetary shock waves. On June 22 at 18:36 UT the magnetosphere was impacted by the leading-edge shock wave and a sheath carrying a large and highly variable interplanetary magnetic field (IMF) Bz with values ranging from +25 to -40 nT. During the subsequent interval from 0000 to 0800 UT, there was a second intensification of the geomagnetic storm resulting from the impact of the CME. We present dramatic responses of near-simultaneous particle measurements with the FPI instrument [Pollock et al., 2016] from the high-altitude MMS mission [Burch et al., 2016] in the near-Earth equatorial plane in the magnetosphere (~9-12 Re), and from the low-altitude Fregion data from the Floating Potential Measurement Unit (FPMU, [Coffey et al., 2008; Wright et al., 2008]) on board the International Space Station (ISS), both in the evening local time sector. We analyze potential causes of the dramatic MMS particle flux dropouts and the ISS density depletions by putting them in the context of storm-time electrodynamics, and support our results with numerical simulations of the global magnetosphere and ionosphere. Additonally, we discuss the modeling results in comparison with observiations from the Meteorological Satellite Program (DMSP) at low latitudes and the Birkeland currents from the Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE).

Observations of Deep Ionospheric F-Region Density Depletions with FPMU Instrumentation and Their Relationship with the Global Dynamics of the June 22-23, 2015 Geomagnetic Storm

Transition from Meso-scale to Macro-scale Field-aligned Currents as Observed by Magnetospheric Multiscale

We use theory and simulations to study how the out‐of‐plane (guide) magnetic field strength modifies the location where the energy conversion rate between the electric field and the plasma is appreciable during asymmetric magnetic reconnection, motivated by observations (Genestreti et al., 2017). For weak guide fields, energy conversion is maximum on the magnetospheric side of the X line, midway between the X line and electron stagnation point. As the guide field increases, the electron stagnation point gets closer to the X line, and energy conversion occurs closer to the electron stagnation point. We motivate one possible nonrigorous approach to extend the theory of the stagnation point location to include a guide field. The predictions are compared to two‐dimensional particle‐in‐cell (PIC) simulations with vastly different guide fields. The simulations have upstream parameters corresponding to three events observed with Magnetospheric Multiscale (MMS). The predictions agree reasonably well with the simulation results, capturing trends with the guide field. The theory correctly predicts that the X line and stagnation points approach each other as the guide field increases. The results are compared to MMS observations, Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE) observations of each event, and a global resistive‐magnetohydrodynamics simulation of the 16 October 2015 event. The PIC simulation results agree well with the global observations and simulation but differ in the strong electric fields and energy conversion rates found in MMS observations. The observational, theoretical, and numerical results suggest that the strong electric fields observed by MMS do not represent a steady global reconnection rate.

The Effect of a Guide Field on Local Energy Conversion During Asymmetric Magnetic Reconnection: Particle‐in‐Cell Simulations

Spatial Structure and Asymmetries of Magnetospheric Currents Inferred from High‐Resolution Empirical Geomagnetic Field Models

We conduct a superposed epoch analysis of Birkeland current densities from AMPERE (Active Magnetosphere and Planetary Electrodynamics Response Experiment) using isolated substorm expansion phase onsets identified by an independently derived data set. In order to evaluate whether R1 and R2 currents contribute to the substorm current wedge, we rotate global maps of Birkeland currents into a common coordinate system centered on the magnetic local time of substorm onset. When the latitude of substorm is taken into account, it is clear that both R1 and R2 current systems play a role in substorm onset, contrary to previous studies which found that R2 current did not contribute. The latitude of substorm onset is colocated with the interface between R1 and R2 currents, allowing us to infer that R1 current closes just tailward and R2 current closes just earthward of the associated current disruption in the tail. AMPERE is the first data set to give near‐instantaneous measurements of Birkeland current across the whole polar cap, and this study addresses apparent discrepancies in previous studies which have used AMPERE to examine the morphology of the substorm current wedge. Finally, we present evidence for an extremely localized reduction in current density immediately prior to substorm onset, and we interpret this as the first statistical signature of auroral dimming in Birkeland current.

Birkeland currents during substorms: Statistical evidence for intensification of Regions 1 and 2 currents after onset and a localized signature of auroral dimming

Near-Earth plasma sheet boundary dynamics during substorm dipolarization

1. Earth Planetary and Space Sciences, University of California, Los Angeles, CA 90095, USA., 2. Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723-6099, USA, 3. Space Research Institute, Austrian Academy of Sciences, Graz, Austria, 4. NASA Goddard Space Flight Center, Greenbelt, MD 20771, USA, 5. University of Michigan, Climate and Space Sciences and Engineering, Ann Arbor, MI 48109-2143, USA, 6. University of New Hampshire, Durham, NH 03824, USA, 7. Southwest Research Institute, Boulder, CO 80302, USA.

The Earth’s Magnetopause: Force Balance and Topology Revealed by High Cadence Plasma Measurements

We present an advance toward accurately predicting the arrivals of coronal mass ejections (CMEs) at the terrestrial planets, including Earth. For the first time, we are able to assess a CME prediction model using data over two thirds of a solar cycle of observations with the Heliophysics System Observatory. We validate modeling results of 1337 CMEs observed with the Solar Terrestrial Relations Observatory (STEREO) heliospheric imagers (HI) (science data) from 8 years of observations by five in situ observing spacecraft. We use the self‐similar expansion model for CME fronts assuming 60° longitudinal width, constant speed, and constant propagation direction. With these assumptions we find that 23%–35% of all CMEs that were predicted to hit a certain spacecraft lead to clear in situ signatures, so that for one correct prediction, two to three false alarms would have been issued. In addition, we find that the prediction accuracy does not degrade with the HI longitudinal separation from Earth. Predicted arrival times are on average within 2.6 ± 16.6 h difference of the in situ arrival time, similar to analytical and numerical modeling, and a true skill statistic of 0.21. We also discuss various factors that may improve the accuracy of space weather forecasting using wide‐angle heliospheric imager observations. These results form a first‐order approximated baseline of the prediction accuracy that is possible with HI and other methods used for data by an operational space weather mission at the Sun‐Earth L5 point.

Modeling observations of solar coronal mass ejections with heliospheric imagers verified with the Heliophysics System Observatory

Mercury's solar wind and interplanetary magnetic field environment is highly dynamic, and variations in these external conditions directly control the current systems and magnetic fields inside the planetary magnetosphere. We update our previous static model of Mercury's magnetic field by incorporating variations in the magnetospheric current systems, parameterized as functions of Mercury's heliocentric distance and magnetic activity. The new, dynamic model reproduces the location of the magnetopause current system as a function of systematic pressure variations encountered during Mercury's eccentric orbit, as well as the increase in the cross‐tail current intensity with increasing magnetic activity. Despite the enhancements in the external field parameterization, the residuals between the observed and modeled magnetic field inside the magnetosphere indicate that the dynamic model achieves only a modest overall improvement over the previous static model. The spatial distribution of the residuals in the magnetic field components shows substantial improvement of the model accuracy near the dayside magnetopause. Elsewhere, the large‐scale distribution of the residuals is similar to those of the static model. This result implies either that magnetic activity varies much faster than can be determined from the spacecraft's passage through the magnetosphere or that the residual fields are due to additional external current systems not represented in the model or both. Birkeland currents flowing along magnetic field lines between the magnetosphere and planetary high‐latitude regions have been identified as one such contribution.

We report global observations of high‐m poloidal waves during the recovery phase of the 22 June 2015 magnetic storm from a constellation of widely spaced satellites of five missions including Magnetospheric Multiscale (MMS), Van Allen Probes, Time History of Events and Macroscale Interactions during Substorm (THEMIS), Cluster, and Geostationary Operational Environmental Satellites (GOES). The combined observations demonstrate the global spatial extent of storm time poloidal waves. MMS observations confirm high azimuthal wave numbers (m ~ 100). Mode identification indicates the waves are associated with the second harmonic of field line resonances. The wave frequencies exhibit a decreasing trend as L increases, distinguishing them from the single‐frequency global poloidal modes normally observed during quiet times. Detailed examination of the instantaneous frequency reveals discrete spatial structures with step‐like frequency changes along L. Each discrete L shell has a steady wave frequency and spans about 1 RE, suggesting that there exist a discrete number of drift‐bounce resonance regions across L shells during storm times.

Global observations of magnetospheric high‐m poloidal waves during the 22 June 2015 magnetic storm

Probing the structure of the magnetopause The magnetopause is the boundary in space that separates the region dominated by Earth’s magnetic field (the magnetosphere) from the surrounding solar wind. The four spacecraft of NASA’s Magnetospheric Multiscale (MMS) mission have repeatedly flown in formation through the magnetopause, measuring the properties of the plasma and magnetic fields in the region. Russell et al. used MMS measurements to study the magnetopause’s structure and force balance. They identified small-scale dynamic features that form a complex topology and evidence for magnetic flux ropes at the boundary. The results aid our understanding of Earth’s space environment and magnetospheres around other planets. Science, this issue p. 960 Flying through Earth’s magnetopause reveals small-scale dynamic structures and magnetic flux ropes. The magnetopause deflects the solar wind plasma and confines Earth’s magnetic field. We combine measurements made by the four spacecraft of the Magnetospheric Multiscale mission to demonstrate how the plasma and magnetic forces at the boundary affect the interaction between the shocked solar wind and Earth’s magnetosphere. We compare these forces with the plasma pressure and examine the electron distribution function. We find that the magnetopause has sublayers with thickness comparable to the ion scale. Small pockets of low magnetic field strength, small radius of curvature, and high electric current mark the electron diffusion region. The flow of electrons, parallel and antiparallel to the magnetic field, reveals a complex topology with the creation of magnetic ropes at the boundary.

We present an overview of the approach to in-flight calibration, which is a coordinated effort between the University of California Los Angeles (UCLA), Space Research Institute, Graz, Austria (IWF) and the NASA Goddard Space Flight Center (GSFC). We present details of the calibration effort at GSFC. During the first dayside season of the Magnetospheric Multiscale (MMS) mission, the in-flight calibration process for the Fluxgate magnetometers (FGM) implemented an algorithm that selected a constant offset (zero-level) for each sensor on each orbit. This method was generally able to reduce the amplitude of residual spin tone to less than 0.2 nT within the region of interest. However, there are times when the offsets do show significant short-term variations. These variations are most prominent in the nighttime season (phase 1X), when eclipses are accompanied by offset changes as large as 1 nT. Eclipses are followed by a recovery period as long as 12 hours where the offsets continue to change as temperatures stabilize. Understanding and compensating for these changes will become critical during Phase 2 of the mission in 2017, when the nightside will become the focus of MMS science. Although there is no direct correlation between offset and temperature, the offsets are seen for the period of any given week to be well-characterized as function of instrument temperature. Using this property, a new calibration method has been developed that has proven effective in compensating for temperature-dependent offsets during phase 1X of the MMS mission and also promises to further refine calibration quality during the dayside season.

Towards Effective Reconnection Rates: Estimating a Stable Magnetopause Normal

Predictions of solar coronal mass ejections with heliospheric imagers verified with the Heliophysics System Observatory

MMS Observations of the Evolution of Ion-Scale Flux Transfer Events

Two of the geomagnetic storms for the Space Weather Prediction Center Geospace Environment Modeling challenge occurred after data were first acquired by the Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE). We compare Birkeland currents from AMPERE with predictions from four models for the 4–5 April 2010 and 5–6 August 2011 storms. The four models are the Weimer (2005b) field‐aligned current statistical model, the Lyon‐Fedder‐Mobarry magnetohydrodynamic (MHD) simulation, the Open Global Geospace Circulation Model MHD simulation, and the Space Weather Modeling Framework MHD simulation. The MHD simulations were run as described in Pulkkinen et al. (2013) and the results obtained from the Community Coordinated Modeling Center. The total radial Birkeland current, ITotal, and the distribution of radial current density, Jr, for all models are compared with AMPERE results. While the total currents are well correlated, the quantitative agreement varies considerably. The Jr distributions reveal discrepancies between the models and observations related to the latitude distribution, morphologies, and lack of nightside current systems in the models. The results motivate enhancing the simulations first by increasing the simulation resolution and then by examining the relative merits of implementing more sophisticated ionospheric conductance models, including ionospheric outflows or other omitted physical processes. Some aspects of the system, including substorm timing and location, may remain challenging to simulate, implying a continuing need for real‐time specification.

Comparison of predictive estimates of high‐latitude electrodynamics with observations of global‐scale Birkeland currents

Spatial Variations of Poloidal and Toroidal Mode Field Line Resonances Observed by MMS

The Rocket Investigation of Current Closure in the Ionosphere (RICCI) mission: A novel application of CubeSats from a sounding rocket platform

Science Innovation Through Industry Partnership: Lessons from AMPERE in Bridging the Federal Sponsor/Private Corporation Divide

Magnetospheric Multiscale Observations of Field-Aligned Currents in the Magnetotail

Observations from the Energetic Particle Detector (EPD) instrument suite aboard the Magnetospheric Multiscale (MMS) spacecraft show that energetic (greater than tens of keV) magnetospheric particle escape into the magnetosheath occurs commonly across the dayside. This includes the surprisingly frequent observation of magnetospheric electrons in the duskside magnetosheath, an unexpected result given assumptions regarding magnetic drift shadowing. The 238 events identified in the 40 keV electron energy channel during the first MMS dayside season that exhibit strongly anisotropic pitch angle distributions indicating monohemispheric field‐aligned streaming away from the magnetopause. A review of the extremely rich literature of energetic electron observations beyond the magnetopause is provided to place these new observations into historical context. Despite the extensive history of such research, these new observations provide a more comprehensive data set that includes unprecedented magnetic local time (MLT) coverage of the dayside equatorial magnetopause/magnetosheath. These data clearly highlight the common escape of energetic electrons along magnetic field lines concluded to have been reconnected across the magnetopause. While these streaming escape events agree with prior studies which show strong correlation with geomagnetic activity (suggesting a magnetotail source) and occur most frequently during periods of southward IMF, the high number of duskside events is unexpected and previously unobserved. Although the lowest electron energy channel was the focus of this study, the events reported here exhibit pitch angle anisotropies indicative of streaming up to 200 keV, which could represent the magnetopause loss of >1 MeV electrons from the outer radiation belt.

Statistical analysis of MMS observations of energetic electron escape observed at/beyond the dayside magnetopause

Messenger Observations Inside 1 AU of Low-Frequency Magnetic Waves due to Inner Source Pickup Protons

Energy conversion and dissipation at dipolarization fronts: Theory, modeling and MMS observations

We report on the observations of an electron vortex magnetic hole corresponding to a new type of coherent structure in the turbulent magnetosheath plasma using the Magnetospheric Multiscale mission data. The magnetic hole is characterized by a magnetic depression, a density peak, a total electron temperature increase (with a parallel temperature decrease but a perpendicular temperature increase), and strong currents carried by the electrons. The current has a dip in the core region and a peak in the outer region of the magnetic hole. The estimated size of the magnetic hole is about 0.23 ρi (∼30 ρe) in the quasi-circular cross-section perpendicular to its axis, where ρi and ρe are respectively the proton and electron gyroradius. There are no clear enhancements seen in high-energy electron fluxes. However, there is an enhancement in the perpendicular electron fluxes at 90° pitch angle inside the magnetic hole, implying that the electrons are trapped within it. The variations of the electron velocity components Vem and Ven suggest that an electron vortex is formed by trapping electrons inside the magnetic hole in the cross-section in the M–N plane. These observations demonstrate the existence of a new type of coherent structures behaving as an electron vortex magnetic hole in turbulent space plasmas as predicted by recent kinetic simulations.

Magnetospheric Multiscale Observations of Electron Vortex Magnetic Hole in the Turbulent Magnetosheath Plasma

The FIELDS Instrument Suite on MMS: Scientific Objectives, Measurements, and Data Products

A longstanding puzzle is that the escape of magnetospheric energetic particles (greater than tens of keV) across Earth's magnetopause into the magnetosheath is common irrespective of conditions thought to engender magnetic reconnection and boundary normal magnetic fields. Multiple causes for escape have been invoked, including interactions with strong gradients, wave scattering, boundary dynamics, and boundary normal fields. Here we tackle only part of the problem by developing a relatively simple kinetic model including critical features not utilized in previous models. We find that particles can often completely escape without invoking waves or unmodeled magnetosheath structures for both northwardly and southwardly magnetosheath fields. Because multiple means of escape are found to be available, the particles are hard to completely contain, consistent with observations. The model also predicts specific pitch angle evolution signatures that uniquely identify boundary normal field‐enabled escape, now reported in a companion paper as observed by the Magnetospheric Multiscale (MMS) mission.

Modeling magnetospheric energetic particle escape across Earth's magnetopause as observed by the MMS mission

Orbital data from the Magnetometer on the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft allow investigation of magnetic fields induced at the top of Mercury's core by time‐varying magnetospheric fields. We used 15 Mercury years of observations of the magnetopause position as well as the magnetic field inside the magnetosphere to establish the presence and magnitude of an annual induction signal. Our results indicate an annual change in the internal axial dipole term, g10, of 7.5 to 9.5 nT. For negligible mantle conductivity, the average annual induction signal provides an estimate of Mercury's core radius to within ±90 km, independent of geodetic results. Larger induction signals during extreme events are expected but are challenging to identify because of reconnection‐driven erosion. Our results indicate that the magnetopause reaches the dayside planetary surface 1.5–4% of the time.

MESSENGER observations of induced magnetic fields in Mercury's core

Energetic (greater than tens of keV) magnetospheric particle escape into the magnetosheath occurs commonly, irrespective of conditions that engender reconnection and boundary‐normal magnetic fields. A signature observed by the Magnetospheric Multiscale (MMS) mission, simultaneous monohemispheric streaming of multiple species (electrons, H+, Hen+), is reported here as unexpectedly common in the dayside, dusk quadrant of the magnetosheath even though that region is thought to be drift‐shadowed from energetic electrons. This signature is sometimes part of a pitch angle distribution evolving from symmetric in the magnetosphere, to asymmetric approaching the magnetopause, to monohemispheric streaming in the magnetosheath. While monohemispheric streaming in the magnetosheath may be possible without a boundary‐normal magnetic field, the additional pitch angle depletion, particularly of electrons, on the magnetospheric side requires one. Observations of this signature in the dayside dusk sector imply that the static picture of magnetospheric drift‐shadowing is inappropriate for energetic particle dynamics in the outer magnetosphere.

Observations of energetic particle escape at the magnetopause: Early results from the MMS Energetic Ion Spectrometer (EIS)

Dipolarization fronts (DFs), embedded in bursty bulk flows, play a crucial role in Earth's plasma sheet dynamics because the energy input from the solar wind is partly dissipated in their vicinity. This dissipation is in the form of strong low‐frequency waves that can heat and accelerate energetic electrons up to the high‐latitude plasma sheet. However, the dynamics of DF propagation and associated low‐frequency waves in the magnetotail are still under debate due to instrumental limitations and spacecraft separation distances. In May 2015 the Magnetospheric Multiscale (MMS) mission was in a string‐of‐pearls configuration with an average intersatellite distance of 160 km, which allows us to study in detail the microphysics of DFs. Thus, in this letter we employ MMS data to investigate the properties of dipolarization fronts propagating earthward and associated whistler mode wave emissions. We show that the spatial dynamics of DFs are below the ion gyroradius scale in this region (∼500 km), which can modify the dynamics of ions in the vicinity of the DF (e.g., making their motion nonadiabatic). We also show that whistler wave dynamics have a temporal scale of the order of the ion gyroperiod (a few seconds), indicating that the perpendicular temperature anisotropy can vary on such time scales.

Multispacecraft analysis of dipolarization fronts and associated whistler wave emissions using MMS data

Surface waves at the magnetopause flanks typically feature steeper, i.e., more inclined leading (antisunward facing) than trailing (sunward facing) edges. This is expected for Kelvin‐Helmholtz instability (KHI) amplified waves. Very rarely, during northward interplanetary magnetic field (IMF) conditions, anomalous/inverse steepening has been observed. The small‐scale tetrahedral configuration of the Magnetospheric Multiscale spacecraft and their high time resolution measurements enable us to routinely ascertain magnetopause boundary inclinations during surface wave passage with high accuracy by four‐spacecraft timing analysis. At the dusk flank magnetopause, 77%/23% of the analyzed wave intervals exhibit regular/inverse steepening. Inverse steepening happens during northward IMF conditions, as previously reported and, in addition, during intervals of dominant equatorial IMF. Inverse steepening observed under the latter conditions may be due to the absence of KHI or due to instabilities arising from the alignment of flow and magnetic fields in the magnetosheath.

Multipoint measurements are a powerful method in studying wavefields in space plasmas. The wave telescope technique is tested against magnetic field fluctuations in the terrestrial magnetosheath measured by the four Magnetospheric Multiscale (MMS) spacecraft on a spatial scale of about 20 km. The dispersion relation diagram and the wave vector distribution are determined for the first time in the ion‐kinetic range. Moreover, the dispersion relation diagram is determined in a proxy plasma rest frame by regarding the low‐frequency dispersion relation as a Doppler relation and compensating for the apparent phase velocity. Fluctuations are highly compressible, and the wave vectors have an angle of about 60° from the mean magnetic field. We interpret that the measured fluctuations represent a kinetic‐drift mirror mode in the magnetosheath which is dispersive and in a turbulent state accompanied by a sideband formation.

The MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) mission to Mercury has provided a wealth of new data about energetic particle phenomena. With observations from MESSENGER's Energetic Particle Spectrometer, as well as data arising from energetic electrons recorded by the X‐Ray Spectrometer and Gamma‐Ray and Neutron Spectrometer (GRNS) instruments, recent work greatly extends our record of the acceleration, transport, and loss of energetic electrons at Mercury. The combined data sets include measurements from a few keV up to several hundred keV in electron kinetic energy and have permitted relatively good spatial and temporal resolution for many events. We focus here on the detailed nature of energetic electron bursts measured by the GRNS system, and we place these events in the context of solar wind and magnetospheric forcing at Mercury. Our examination of data at high temporal resolution (10 ms) during the period March 2013 through October 2014 supports strongly the view that energetic electrons are accelerated in the near‐tail region of Mercury's magnetosphere and are subsequently “injected” onto closed magnetic field lines on the planetary nightside. The electrons populate the plasma sheet and drift rapidly eastward toward the dawn and prenoon sectors, at times executing multiple complete drifts around the planet to form “quasi‐trapped” populations.

Intense energetic electron flux enhancements in Mercury's magnetosphere: An integrated view with high‐resolution observations from MESSENGER

(1) Rice Space Institute, Rice University, Houston, United States, (2) Marshall Space Flight Center, NASA, Huntsville, United States, (3) OEAW, Austrian Academy of Science, Wien, Austria, (4) Applied Physics Lab, Johns Hopkins University, Laurel, United States, (5) Space Science, University of Texas at Dallas, Richardson, United States, (6) IGPP, University of California at Los Angeles, Los Angeles, United States, (7) LASP, University of Colorado, Boulder, United States

Geomagnetically Induced Currents (GICs) are electric currents driven by activity in near-Earth outer space as our magnetic field interacts with that of the Sun’s. These currents can flow through any conducting path, including pipelines and high voltage electric power lines. When GICs become strong enough, these technological systems can be interrupted or damaged, drastically affecting those who depend on them. Developing systems to accurately monitor and predict GIC events has therefore become a critical task for national security. An initial effort to assess the performance of five operationally-promising GIC models was presented by Pulkkinen et al. [2013]. The results of this validation effort showed that the models can provide predictive value, but shortcomings exist. While this work represents a landmark first-step towards numerical space weather forecasting, many questions remain concerning each of the models’ capabilities. How do the models perform for different levels of geomagnetic activity? What is the range of activity for which the models have been validated? Based on the assumptions and input data for each model, what is the maximum driving for which the results can be considered valid? This study presents a reanalysis of the Pulkkinen et al. [2013] results to extend our understanding of the models’ capabilities and answer the questions posed above. Data-model errors between predicted and observed magnetometer dB/dt values are binned by activity (solar wind electric field or D ST ). The bins are arranged to yield error as a function of driving. Input data for empirical relationships, on which the models either rely or of which they comprise entirely, are binned by activity to determine the range of conditions over which each model is valid. A comparison of each model is presented to further illustrate previously published results. Additionally, because GICs are intimately linked to the electrojets which are in turn closely related to field-aligned currents, we also compare Birkeland currents

Exploring Predictive Performance of Ground dB/dt Models: A Reanalysis of the Geospace Model Transition Challenge

Dusk side magnetopause surface waves: boundary motion, thickness, and wave steepening

The Magnetospheric Multiscale mission (MMS) consists of four identical spacecraft forming a closely separated (≤10 km) and nearly regular tetrahedron. This configuration enables the decoupling of spatial and temporal variations and allows the calculation of the spatial gradients of plasma and electromagnetic field quantities. We make full use of the well cross‐calibrated MMS magnetometers and fast plasma instruments measurements to calculate both the magnetic and plasma forces in flux transfer events (FTEs) and evaluate the relative contributions of different forces to the magnetopause momentum variation. This analysis demonstrates that some but not all FTEs, consistent with previous studies, are indeed force‐free structures in which the magnetic pressure force balances the magnetic curvature force. Furthermore, we contrast these events with FTE events that have non‐force‐free signatures.

Force balance at the magnetopause determined with MMS: Application to flux transfer events

High Latitude Precipitating Energy Flux and Joule Heating During Geomagnetic Storms Determined from AMPERE Field-aligned Currents

The magnetic storm of 22–23 June 2015 was one of the largest in the current solar cycle. We present in situ observations from the Magnetospheric Multiscale Mission (MMS) and the Van Allen Probes (VAP) in the magnetotail, field‐aligned currents from AMPERE (Active Magnetosphere and Planetary Electrodynamics Response), and ionospheric flow data from Defense Meteorological Satellite Program (DMSP). Our real‐time space weather alert system sent out a “red alert,” correctly predicting Kp indices greater than 8. We show strong outflow of ionospheric oxygen, dipolarizations in the MMS magnetometer data, and dropouts in the particle fluxes seen by the MMS Fast Plasma Instrument suite. At ionospheric altitudes, the AMPERE data show highly variable currents exceeding 20 MA. We present numerical simulations with the Block Adaptive Tree‐Solarwind ‐ Roe ‐ Upwind Scheme (BATS‐R‐US) global magnetohydrodynamic model linked with the Rice Convection Model. The model predicted the magnitude of the dipolarizations, and varying polar cap convection patterns, which were confirmed by DMSP measurements.

Multispacecraft observations and modeling of the 22/23 June 2015 geomagnetic storm

The Extent to Which Dayside Reconnection Drives Field-Aligned Currents During Substorms

MMS observations of magnetic reconnection in small-scale current sheets in magnetosheath turbulence.

Temporal and Spatial Development of Birkeland and Electrojet Currents

Flux Transfer Events on the Magnetopause, Force-Free or Not: An MMS Multi-Instrument Study

Using AMIENext Patterns Derived from AMPERE Data to Explore Hemispheric Asymmetries in Field Aligned Currents and Magnetic Potential

Leakage of ions from the magnetosphere into the magnetosheath remains an important topic in understanding the plasma physics of Earth's magnetopause and the interaction of the solar wind with the magnetosphere. Here using sophisticated instrumentation from two spacecraft (Radiation Belt Storm Probes Ion Composition Experiment on the Van Allen Probes and Energetic Ion Spectrometer on the Magnetospheric Multiscale) spaced uniquely near and outside the dayside magnetopause, we are able to determine the escape mechanisms for large gyroradii oxygen ions and much smaller gyroradii hydrogen and helium ions. The oxygen ions are entrained on the magnetosphere boundary, while the hydrogen and helium ions appear to escape along reconnected field lines. These results have important implications for not only Earth's magnetosphere but also other solar system magnetospheres.

The permeability of the magnetopause to a multispecies substorm injection of energetic particles

We present a statistical study of dipolarization fronts (DFs), using magnetic field data from MMS and Cluster, at radial distances below 12 RE and 20 RE, respectively. Assuming that the DFs have a semicircular cross section and are propelled by the magnetic tension force, we used multispacecraft observations to determine the DF velocities. About three quarters of the DFs propagate earthward and about one quarter tailward. Generally, MMS is in a more dipolar magnetic field region and observes larger‐amplitude DFs than Cluster. The major findings obtained in this study are as follows: (1) At MMS ∼57 % of the DFs move faster than 150 km/s, while at Cluster only ∼35 %, indicating a variable flux transport rate inside the flow‐braking region. (2) Larger DF velocities correspond to higher Bz values directly ahead of the DFs. We interpret this as a snow plow‐like phenomenon, resulting from a higher magnetic flux pileup ahead of DFs with higher velocities.

Magnetopause Current Measurements Using the Magnetospheric Multiscale Mission: A Dynamic Current-Strength in Regions of Opposing Magnetic Forces

In this letter, first observations of ion‐scale magnetic island from the Magnetospheric Multiscale mission in the magnetosheath turbulent plasma are presented. The magnetic island is characterized by bipolar variation of magnetic fields with magnetic field compression, strong core field, density depletion, and strong currents dominated by the parallel component to the local magnetic field. The estimated size of magnetic island is about 8 di, where di is the ion inertial length. Distinct particle behaviors and wave activities inside and at the edges of the magnetic island are observed: parallel electron beam accompanied with electrostatic solitary waves and strong electromagnetic lower hybrid drift waves inside the magnetic island and bidirectional electron beams, whistler waves, weak electromagnetic lower hybrid drift waves, and strong broadband electrostatic noise at the edges of the magnetic island. Our observations demonstrate that highly dynamical, strong wave activities and electron‐scale physics occur within ion‐scale magnetic islands in the magnetosheath turbulent plasma.

MMS observations of ion‐scale magnetic island in the magnetosheath turbulent plasma

Relation of field-aligned currents measured by AMPERE project to solar wind and substorms

We report on field‐aligned current observations by the four Magnetospheric Multiscale (MMS) spacecraft near the plasma sheet boundary layer (PSBL) during two major substorms on 23 June 2015. Small‐scale field‐aligned currents were found embedded in fluctuating PSBL flux tubes near the separatrix region. We resolve, for the first time, short‐lived earthward (downward) intense field‐aligned current sheets with thicknesses of a few tens of kilometers, which are well below the ion scale, on flux tubes moving equatorward/earthward during outward plasma sheet expansion. They coincide with upward field‐aligned electron beams with energies of a few hundred eV. These electrons are most likely due to acceleration associated with a reconnection jet or high‐energy ion beam‐produced disturbances. The observations highlight coupling of multiscale processes in PSBL as a consequence of magnetotail reconnection.

Transient, small‐scale field‐aligned currents in the plasma sheet boundary layer during storm time substorms

CONDUCTIVITY OF THE CRUST AND MANTLE. Brian J. Anderson, Haje Korth, Catherine L. Johnson, Roger J. Phillips, Lydia C. Philpott and Sean C. Solomon, The Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA, brian.anderson@jhuapl.edu. Department of Earth, Ocean and Atmospheric Sciences, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada. Planetary Science Institute, Tucson, AZ 85719, USA. Planetary Science Directorate, Southwest Research Institute, Boulder, CO 80302, USA. Department of Earth and Planetary Sciences, Washington University, St Louis, MO 63130, USA. Lamont-Doherty Earth Observatory, Columbia University, Palisades, NY 10964, USA. Department of Terrestrial Magnetism, Carnegie Institution of Washington, Washington, DC 20015, USA.

Closure of Birkeland Currents at Mercury: Constraints on the Electrical Conductivity of the Crust and Mantle

Abstract. The Magnetospheric Multiscale mission (MMS) targets the characterization of fine-scale current structures in the Earth's tail and magnetopause. The high speed of these structures, when traversing one of the MMS spacecraft, creates magnetic field signatures that cross the sensitive frequency bands of both search coil and fluxgate magnetometers. Higher data quality for analysis of these events can be achieved by combining data from both instrument types and using the frequency bands with best sensitivity and signal-to-noise ratio from both sensors. This can be achieved by a model-based frequency compensation approach which requires the precise knowledge of instrument gain and phase properties. We discuss relevant aspects of the instrument design and the ground calibration activities, describe the model development and explain the application on in-flight data. Finally, we show the precision of this method by comparison of in-flight data. It confirms unity gain and a time difference of less than 100 µs between the different magnetometer instruments.

High latitude convection dynamics during Magnetospheric Multiscale magnetopause encounters and magnetic reconnection observations

Quantifying Hemispheric Asymmetry of Auroral Currents by Polar Region Interhemispheric Magnetic Observatories (PRIMO)

In-Flight Calibration Methods for Temperature-Dependent Offsets in the MMS Fluxgate Magnetometers

Magnetopause observations by Magnetospheric Multiscale (MMS) and Birkeland currents observed by the Active Magnetosphere and Planetary Electrodynamics Response Experiment are used to relate magnetopause encounters to ionospheric electrodynamics. MMS magnetopause crossings on 15 August and 19 September 2015 occurred earthward of expectations due to solar wind ram pressure alone and coincided with equatorward expansion of the Birkeland currents. Magnetopause erosion, consistent with expansion of the polar cap, contributed to the magnetopause crossings. The ionospheric projections of MMS during the events and at times of the magnetopause crossings indicate that MMS observations are related to the main path of flux transport in one case but not in a second. The analysis provides a way to routinely relate in situ observations to the context of in situ convection and flux transport.

Electrodynamic context of magnetopause dynamics observed by magnetospheric multiscale

The MMS mission was successfully launched on March 13, 2015 into an equatorial, highly elliptical orbit with a low altitude perigee and an apogee of 12 earth radii. Each satellite is equipped by a search-coil magnetometer (SCM) which measures the three components of the magnetic field fluctuations with a nominal frequency range from 1 Hz to 6 kHz. During the past months of the commissioning phase, the SCM waveforms have usually been gathered at 128 or 256 samples per second (S/s). Yet in a few cases, burst data corresponding to 8192 S/s were obtained. Since the launch, the orbit apogee has moved from dawn to dusk. These various conditions allow us to present high frequency wave measurements and wave polarization analysis in the dawn magnetosphere flank as well as associated with local and global dipolarization events in the night side. Furthermore, the SCM is not saturated due to a large amplitude spin modulation even at perigee since the MMS spin frequency is low (50 mHz). Thanks to the onboard spectra computed by the digital signal processor, we are able to continuously monitor the magnetic wave activity through the full SCM frequency range all along the orbit and notably in the radiation belt region. Thus some typical figures of the wave activity in the inner magnetosphere are also briefly described.

Observations by the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft in Mercury's magnetotail demonstrate for the first time that Na+ ions exert a dynamic influence on Mercury's magnetospheric system. Na+ ions are shown to contribute up to ~30% of the ion thermal pressure required to achieve pressure balance in the premidnight plasma sheet. High concentrations of planetary ions should lead to Na+ dominance of the plasma mass density in these regions. On orbits with northward‐oriented interplanetary magnetic field and high (i.e., >1 cm−3) Na+ concentrations, MESSENGER has often recorded magnetic field fluctuations near the Na+ gyrofrequency associated with the Kelvin‐Helmholtz (K‐H) instability. These nightside K‐H vortices are characteristically different from those observed on Mercury's dayside that have a nearly constant wave frequency of ~0.025 Hz. Collectively, these observations suggest that large spatial gradients in the hot planetary ion population at Mercury may result in a transition from a fluid description to a kinetic description of vortex formation across the dusk terminator, providing the first set of truly multiscale observations of the K‐H instability at any of the diverse magnetospheric environments explored in the solar system.

MESSENGER observations of multiscale Kelvin‐Helmholtz vortices at Mercury

MErcury Surface, Space ENviroment, GEochemistry, and Ranging (MESSENGER) magnetic field and plasma measurements taken during crossings of Mercury's magnetotail from 2011 to 2014 have been examined for evidence of substorms. A total of 26 events were found during which an Earth‐like growth phase was followed by clear near‐tail expansion phase signatures. During the growth phase, just as at Earth, the thinning of the plasma sheet and the increase of the magnetic field intensity in the lobe are observed, but the fractional increase in field intensity could be ∼3 to 5 times that at Earth. The average timescale of the growth phase is ∼1 min. The dipolarization that marks the initiation of the substorm expansion phase is only a few seconds in duration. During the expansion phase, lasting ∼1 min, the plasma sheet is observed to thicken and engulf the spacecraft. The duration of the substorm observed in this paper is consistent with previous observations of Mercury's Dungey cycle. The reconfiguration of the magnetotail during Mercury's substorm is very similar to that at Earth despite its very compressed timescale.

MESSENGER observations of magnetospheric substorm activity in Mercury's near magnetotail

Observing Dynamics in Large-Scale Birkeland Currents with the Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE)

Multi-point, multi-scale observation of the near-Earth current sheet reconfiguration during storm-time multi-onset substorms

Electrodynamic Context of Magnetotail Dynamics Signatures Observed by Magnetospheric Multi-Scal

Old minerals expose an ancient field Mercury is the only terrestrial planet other than Earth with an active, internally generated magnetic field. Results from the MESSENGER spacecraft indicate that the field is almost as old as the planet. Johnson et al. took advantage of close flybys to extract evidence of an ancient magnetic field. Certain minerals are able to “lock in” the signature of a field at the time they crystallize. This remnant magnetization was found in a region on Mercury believed to be 3.8 billion years old. Science, this issue p. 892 Magnetic field measurements of Mercury’s crust uncover a global magnetic field operating at least 3.8 billion years ago. Magnetized rocks can record the history of the magnetic field of a planet, a key constraint for understanding its evolution. From orbital vector magnetic field measurements of Mercury taken by the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft at altitudes below 150 kilometers, we have detected remanent magnetization in Mercury’s crust. We infer a lower bound on the average age of magnetization of 3.7 to 3.9 billion years. Our findings indicate that a global magnetic field driven by dynamo processes in the fluid outer core operated early in Mercury’s history. Ancient field strengths that range from those similar to Mercury’s present dipole field to Earth-like values are consistent with the magnetic field observations and with the low iron content of Mercury’s crust inferred from MESSENGER elemental composition data.

Low-altitude magnetic field measurements by MESSENGER reveal Mercury’s ancient crustal field

Magnetospheric Multiscale Observations of Ultra Low Frequency Waves in the Inner Magnetosphere

MMS Spacecraft Observation of Near Tail Thin Current Sheets: Their Locations, Conditions for Formation and Relation to Geomagnetic Activity

Dynamics of Global-Scale Birkeland Currents During Geomagnetic Storm

During solar energetic particle (SEP) events, the inner heliosphere is bathed in MeV electrons. Through magnetic reconnection, these relativistic electrons can enter the magnetosphere of Mercury, nearly instantaneously filling the regions of open field lines with precipitating particles. With energies sufficient to penetrate solid aluminum shielding more than 1 mm thick, these electrons were observable by a number of sensors on the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft. Because of its thin shielding, frequent sampling, and continuous temporal coverage, the Fast Imaging Plasma Spectrometer provided by far the most sensitive measurements of MeV electrons of all MESSENGER sensors. Sharp changes in energetic electron flux coincided with topological boundaries in the magnetosphere, including the magnetopause, polar cap, and central plasma sheet. Precipitating electrons with fluxes equal to ~40% of their corresponding upstream levels were measured over the entire polar cap, demonstrating that electron space weathering of Mercury's surface is not limited to the cusp region. We use these distinct precipitation signatures acquired over 33 orbits during 11 SEP events to map the full extent of Mercury's northern polar cap. We confirm a highly asymmetric polar cap, for which the dayside and nightside boundary latitudes range over ~50–70°N and ~30–60°N, respectively. These latitudinal ranges are consistent with average models of Mercury's magnetic field but exhibit a large variability indicative of active dayside and nightside magnetic reconnection processes. Finally, we observed enhanced electron fluxes within the central plasma sheet. Although these particles cannot form a stable ring current around the planet, their motion results in an apparent trapped electron population at low latitudes in the magnetotail.

MESSENGER observations of solar energetic electrons within Mercury's magnetosphere

We present the first observations of Mercury's plasma mantle, a primary region for solar wind entry into the planetary magnetosphere, located in the high‐latitude magnetotail. MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) observations from two orbits on 10 November 2012 have been analyzed. The main plasma mantle features are (1) a steady decrease in proton density as MESSENGER moved deeper into the magnetotail; (2) frequent flux transfer events throughout the magnetosheath and into the magnetotail, suggesting that these events are the primary source for solar wind plasma injection; (3) a diamagnetic depression, due to the presence of plasma, as pressure balance is maintained; and (4) a clear proton velocity dispersion, resulting from lower‐energy protons being transported deep into the magnetosphere as higher‐energy protons escape downtail. From these velocity dispersions we infer cross‐magnetosphere electric potentials of 23 kV and 29 kV, consistent with estimates determined from measurements of magnetopause reconnection rate and tail loading and unloading events.

Energetic electron flux enhancements in Mercury's magnetosphere: An integrated view with multi-instrument observations from MESSENGER

Mapping Mercury's magnetic topology with solar energetic electrons

First MMS Observations of High Time Resolution 3D Electric and Magnetic fields at the Dayside Magnetopause.

Electrodynamic Context of Magnetotail and Magnetopause Dynamics Observed by Magnetospheric Multiscal

Relationships between Geomagnetic Induced Currents and Field Aligned Currents

ALTITUDE CAMPAIGN. Catherine L. Johnson, Michael E. Purucker, Lydia C. Philpott, Haje Korth, Brian J. Anderson, Nikolai A. Tsyganenko, Steven A. Hauck, II, Brett W. Denevi, Paul K. Byrne, James W. Head III, Matthew A. Siegler, Roger J. Phillips and Sean C. Solomon, Department of Earth, Ocean and Atmospheric Sciences, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada, cjohnson@eos.ubc.ca. Planetary Science Institute, Tucson, AZ 85719, USA, cjohnson@psi.edu. NASA Goddard Space Flight Center, Greenbelt, MD 20771, USA. The Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA. Institute and Faculty of Physics, Saint Petersburg State University, Saint Petersburg, Russia. 7 Department of Earth, Environmental and Planetary Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA USA. Lunar and Planetary Institute, Houston, TX 77058, USA. Department of Earth, Environmental and Planetary Sciences, Brown University, Providence, RI 02912, USA. Department of Earth Sciences, Southern Methodist University, Dallas, TX 75205, USA. Planetary Science Directorate, Southwest Research Institute, Boulder, CO 80302, USA. LamontDoherty Earth Observatory, Columbia University, Palisades, NY 10964, USA. Department of Terrestrial Magnetism, Carnegie Institution of Washington, Washington, DC 20015, USA.

Evidence for Remanent Magnetic Fields on Mercury from MESSENGER'S Low-Altitude Campaign

The X‐Ray Spectrometer (XRS) on the MErcury Surface, Space ENvironment, GEochemistry, and Ranging spacecraft regularly detected fluorescent X‐rays near Mercury induced by low‐energy (1–10 keV) or suprathermal electrons. We devised an algorithm to select these events from XRS records between April 2011 and March 2015 on the basis of their duration, location, and spectral slope. We identified 3102 events during 3900 orbits around Mercury, sampling all Mercury longitudes multiple times over the 4 year period. These suprathermal electrons were present near the planet at all local times, but the majority were on the nightside of the planet, and a dawn‐dusk asymmetry is seen in the data. When the event locations are plotted in a coordinate system based on a simplified magnetic field model, several distinct clusters of events are evident. We infer that all are signatures of accelerated electrons that were injected from Mercury's tail region to form a quasi‐trapped electron population at Mercury.

MESSENGER observations of suprathermal electrons in Mercury's magnetosphere

Fine Scale Structure of the Afternoon Equatorial Magnetopause as Seen on the Magnetospheric Multiscale Mission

A Model of Mercury's Magnetospheric Magnetic Field with Dependence on Magnetic Activity

Low-Frequency Wave Activity Detected by MMS during Dusk Magnetopause Crossings and its Relation to Heating and Acceleration of Particles

Field-aligned currents connect the Earth's magnetosphere to the high latitude ionosphere, and provide a main channel for energy transfer from the magnetosphere to the ionosphere. They are driven by solar wind-magnetosphere interactions and respond dynamically to changes in the solar wind and interplanetary magnetic field. Enhanced interaction during geomagnetic storms significantly intensifies their strength and variability. In this paper, we review our recent observations of field-aligned currents (FACs) during geomagnetic storms using observations from polar orbiting Swarm constellation as well as the Active Magnetosphere and Polar Electrodynamics Response Experiment (AMPERE). Both temporal resolutions and spatial coverage of these observations provide new insights in understanding the FACs and the magnetosphere-ionosphere coupling. We will discuss their spatial and temporal evolutions, ionospheric closure currents, and hemispheric asymmetry during storms.

Swarm Observations of Field Aligned Currents during Geomagnetic Storms

Principal component analysis is performed on Birkeland or field‐aligned current (FAC) measurements from the Active Magnetosphere and Planetary Electrodynamics Response Experiment. Principal component analysis (PCA) identifies the patterns in the FACs that respond coherently to different aspects of geomagnetic activity. The regions 1 and 2 current system is shown to be the most reproducible feature of the currents, followed by cusp currents associated with magnetic tension forces on newly reconnected field lines. The cusp currents are strongly modulated by season, indicating that their strength is regulated by the ionospheric conductance at the foot of the field lines. PCA does not identify a pattern that is clearly characteristic of a substorm current wedge. Rather, a superposed epoch analysis of the currents associated with substorms demonstrates that there is not a single mode of response, but a complicated and subtle mixture of different patterns.

Principal component analysis of Birkeland currents determined by the Active Magnetosphere and Planetary Electrodynamics Response Experiment

The dynamics of region 1 field-aligned currents during periods of dayside and nightside reconnection

The calibration effort for the Magnetospheric Multiscale Mission (MMS) Analog Fluxgate (AFG) and DigitalFluxgate (DFG) magnetometers is a coordinated effort between three primary institutions: University of California, LosAngeles (UCLA); Space Research Institute, Graz, Austria (IWF); and Goddard Space Flight Center (GSFC). Since thesuccessful deployment of all 8 magnetometers on 17 March 2015, the effort to confirm and update the groundcalibrations has been underway during the MMS commissioning phase. The in-flight calibration processes evaluatetwelve parameters that determine the alignment, orthogonalization, offsets, and gains for all 8 magnetometers usingalgorithms originally developed by UCLA and the Technical University of Braunschweig and tailored to MMS by IWF,UCLA, and GSFC. We focus on the processes run at GSFC to determine the eight parameters associated with spin tonesand harmonics. We will also discuss the processing flow and interchange of parameters between GSFC, IWF, and UCLA.IWF determines the low range spin axis offsets using the Electron Drift Instrument (EDI). UCLA determines the absolutegains and sensor azimuth orientation using Earth field comparisons. We evaluate the performance achieved for MMS andgive examples of the quality of the resulting calibrations.

In-Flight Calibration Processes for the MMS Fluxgate Magnetometers

We show that ~1 Hz magnetic compressional waves observed in Mercury's inner magnetosphere could be interpreted as ion‐Bernstein waves in a moderate proton beta ~0.1 plasma. An observation of a proton distribution with a large planetary loss cone is presented, and we show that this type of distribution is highly unstable to the generation of ion‐Bernstein waves with low magnetic compression. Ray tracing shows that as these waves propagate back and forth about the magnetic equator; they cycle between a state of low and high magnetic compression. The group velocity decreases during the high‐compression state leading to a pileup of compressional wave energy, which could explain the observed dominance of the highly compressional waves. This bimodal nature is due to the complexity of the index of refraction surface in a warm plasma whose upper branch has high growth rate with low compression, and its lower branch has low growth/damping rate with strong compression. Two different cycles are found: one where the compression maximum occurs at the magnetic equator and one where the compression maximum straddles the magnetic equator. The later cycle could explain observations where the maximum in compression straddles the equator. Ray tracing shows that this mode is confined within ±12° magnetic latitude which can account for the bulk of the observations. We show that the Doppler shift can account for the difference between the observed and model wave frequency, if the wave vector direction is in opposition to the plasma flow direction. We note that the Wentzel‐Kramers‐Brillouin approximation breaks down during the pileup of compressional energy and that a study involving full wave solutions is required.

Interpreting ~1 Hz magnetic compressional waves in Mercury's inner magnetosphere in terms of propagating ion‐Bernstein waves

Energy Dissipation and Transport Associated with Whistler-wave Generation during Plasma Jet Events using MMS Data

! Small rubble pile asteroids exhibit a diverse range of evolutionary behaviors and morphologies, driven by an array of poorly understood geophysical effects. The complex ways that these bodies evolve belies their simple structure: gravitational aggregates of shattered primitive bodies. Their evolution can be dramatic, such as seen in the active asteroids P/2013 P5 and P/ 2013 R3, or may be subtly masked, such as in the tide-BYORP equilibria of singly-synchronous binary asteroids. Their evolutionary outcomes can defy the imagination, such as asteroid 1950 DA which is spinning faster than its gravitational attraction yet is held together by weak van der Waals forces (Rozitis et al. 2014), or present us with profound mysteries, such as how the Almahata Sitta meteorite could be comprised of such diverse components. ! ! Beyond these motivations, the study of rubble pile asteroid geophysics can shed insight into any solar system environment where gravitational aggregates interact in a micro-gravity setting, ranging from the protoplanetary disc to planetary ring systems. The broad study of the geophysics of aggregates in such micro-gravity environments is becoming both a unifying theme and emerging field of study. ! ! Out of the many diverse and complex forms that rubble pile asteroids take on, the study of NEA binary asteroids can in particular be used to expose the geophysics of micro-gravity aggregates. Binaries are an expression of micro-gravity geophysics due to the manner in which they form and their continuing evolution. Due to our ability to visit, probe and interact with NEA, we can also turn them into geophysical laboratories. ! ! This talk will introduce the science of the Binary Asteroid in-situ Explorer (BASiX) Discovery mission, which proposes to turn the primitive C-Type binary asteroid (175706) 1996 FG3 into such a geophysical laboratory. Exploring this body enables us to probe a broad range of rubble pile asteroid properties: internal tidal dissipation (through FG3's documented tide-BYORP equilibrium), the nature of surface heterogeneities on primitive bodies (well documented for FG3), the intrinsic seismic and strength properties of micro-gravity aggregates, and the processes that form and evolve such binaries.! Binary asteroid 1996 FG3 is one of the best characterized binaries known, enabling a detailed mission plan and design to be developed prior to launch.

A Geophysical Laboratory for Rubble Pile Asteroids: The BASiX Mission

We use observations from the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft, in orbit around Mercury, to investigate interplanetary coronal mass ejections (ICMEs) near 0.3 AU. MESSENGER is the first spacecraft since Helios 1 and 2 in the 1980s to make in situ measurements of the interplanetary medium at heliocentric distances < 0.5 AU. As such, it presents a unique opportunity for observing the innermost heliosphere. It also allows for observations of ICMEs well within 1 AU to study their evolution as they expand and propagate outward, interacting with the solar wind. We catalog ICME events observed by the MESSENGER Magnetometer between 2011 and 2014 and present statistical analyses of ICME properties at Mercury. In addition, using existing data sets of ICMEs at 1 AU, we investigate key ICME property changes from Mercury to 1 AU. We find good agreement with previous studies for the magnetic field strength dependence on distance, and we also find evidence that ICME deceleration continues past the orbit of Mercury. This paper describes the database of ICMEs from MESSENGER orbital observations around Mercury, which is publicly available through the supporting information (Table S1) associated with this manuscript and the Virtual Energetic Particle Observatory. Our ICME database will prove particularly useful for multipoint spacecraft studies of recent ICMEs, as well as for model validation of ICME properties.

Interplanetary coronal mass ejections from MESSENGER orbital observations at Mercury

This paper presents an analysis of data from the magnetometers on board the Defense Meteorological Satellite Program (DMSP) F‐15, F‐16, F‐17, and F‐18 satellites and the Iridium satellite constellation, using an inverse procedure for high‐latitude ionospheric electrodynamics, during the period of 29–30 May 2010. The Iridium magnetometer data are made available through the Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE) program. The method presented here is built upon the assimilative mapping of ionospheric electrodynamics procedure but with a more complete treatment of the prior model uncertainty to facilitate an optimal inference of complete polar maps of electrodynamic variables from irregularly distributed observational data. The procedure can provide an objective measure of uncertainty associated with the analysis. The cross‐validation analysis, in which the DMSP data are used as independent validation data sets, suggests that the procedure yields the spatial prediction of DMSP perturbation magnetic fields from AMPERE data alone with a median discrepancy of 30–50 nT. Discrepancies larger than 100 nT are seen in about 20% of total samples, whose location and magnitude are generally consistent with the previously identified discrepancy between DMSP and AMPERE data sets. Resulting field‐aligned current (FAC) patterns exhibit more distinct spatial patterns without spurious high‐frequency oscillatory features in comparison to the FAC products provided by AMPERE. Maps of the toroidal magnetic potential and FAC estimated from both AMPERE and DMSP data under four distinctive interplanetary magnetic field (IMF) conditions during a magnetic cloud event demonstrate the IMF control of high‐latitude electrodynamics and the opportunity for future scientific investigation.

Inverse procedure for high‐latitude ionospheric electrodynamics: Analysis of satellite‐borne magnetometer data

Data from the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) Gamma‐Ray and Neutron Spectrometer have been used to detect and characterize energetic electron (EE) events in Mercury's magnetosphere. This instrument detects EE events indirectly via bremsstrahlung photons that are emitted when instrument and spacecraft materials stop electrons having energies of tens to hundreds of keV. From Neutron Spectrometer data taken between 18 March 2011 and 31 December 2013 we have identified 2711 EE events. EE event amplitudes versus energy are distributed as a power law and have a dynamic range of a factor of 400. The duration of the EE events ranges from tens of seconds to nearly 20 min. EE events may be classified as bursty (large variation with time over an event) or smooth (small variation). Almost all EE events are detected inside Mercury's magnetosphere on closed field lines. The precise occurrence times of EE events are stochastic, but the events are located in well‐defined regions with clear boundaries that persist in time and form what we call “quasi‐permanent structures.” Bursty events occur closer to dawn and at higher latitudes than smooth events, which are seen near noon‐to‐dusk local times at lower latitudes. A subset of EE events shows strong periodicities that range from hundreds of seconds to tens of milliseconds. The few‐minute periodicities are consistent with the Dungey cycle timescale for the magnetosphere and the occurrence of substorm events in Mercury's magnetotail region. Shorter periods may be related to phenomena such as north‐south bounce processes for the energetic electrons.

Comprehensive survey of energetic electron events in Mercury's magnetosphere with data from the MESSENGER Gamma‐Ray and Neutron Spectrometer

Effect of electron ambient plasmas in reconnection jets and dipolarization fronts : MMS initial results

Accurate knowledge of Mercury's magnetospheric magnetic field is required to understand the sources of the planet's internal field. We present the first model of Mercury's magnetospheric magnetic field confined within a magnetopause shape derived from Magnetometer observations by the MErcury Surface, Space ENvironment, GEochemistry, and Ranging spacecraft. The field of internal origin is approximated by a dipole of magnitude 190 nT RM3, where RM is Mercury's radius, offset northward by 479 km along the spin axis. External field sources include currents flowing on the magnetopause boundary and in the cross‐tail current sheet. The cross‐tail current is described by a disk‐shaped current near the planet and a sheet current at larger (≳ 5 RM) antisunward distances. The tail currents are constrained by minimizing the root‐mean‐square (RMS) residual between the model and the magnetic field observed within the magnetosphere. The magnetopause current contributions are derived by shielding the field of each module external to the magnetopause by minimizing the RMS normal component of the magnetic field at the magnetopause. The new model yields improvements over the previously developed paraboloid model in regions that are close to the magnetopause and the nightside magnetic equatorial plane. Magnetic field residuals remain that are distributed systematically over large areas and vary monotonically with magnetic activity. Further advances in empirical descriptions of Mercury's magnetospheric external field will need to account for the dependence of the tail and magnetopause currents on magnetic activity and additional sources within the magnetosphere associated with Birkeland currents and plasma distributions near the dayside magnetopause.

Modular model for Mercury's magnetospheric magnetic field confined within the average observed magnetopause

MMS observations of small magnetic flux ropes in the near‐tail (X > ‐11 Re)

Mercury's Crustal Magnetic Field from Low-Altitude Measurements by MESSENGER.

Plasma precipitation on Mercury's nightside and its implications for magnetospheric convection and exosphere generation.

Response of High Latitude Birkeland Currents and Ionospheric Convection to Transitions in Solar Wind Forcing

MESSENGER Disappearing Dayside Magnetosphere Events: Evidence for Severe Dayside Erosion and/or Compression?

COMPARISON WITH MESSENGER DATA AND CONSTRAINTS ON SECULAR VARIATION. Lydia C. Philpott, Catherine L. Johnson, Reka M. Winslow, Brian J. Anderson, Haje Korth, Michael E. Purucker, Sean C. Solomon, Department of Earth, Ocean and Atmospheric Sciences, University of British Columbia, BC, V6T 1Z4, Canada, lphilpott@eos.ubc.ca. Planetary Science Institute, Tucson, AZ 85719, USA. The Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA. NASA Goddard Space Flight Center, Greenbelt, MD 20771, USA. Lamont-Doherty Earth Observatory, Columbia University, Palisades, NY 10964, USA.

Analysis of Magnetic Field Data from the Third Mariner 10 Flyby of Mercury: Comparison with MESSENGER Data and Constraints on Secular Variation

The MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft while in orbit about Mercury observed highly localized, ~3‐s‐long reductions in the dayside magnetospheric magnetic field, with amplitudes up to 90% of the ambient intensity. These magnetic field depressions are termed cusp filaments because they were observed from just poleward of the magnetospheric cusp to midlatitudes, i.e., ~55° to 85°N. We analyzed 345 high‐ and low‐altitude cusp filaments identified from MESSENGER magnetic field data to determine their physical properties. Minimum variance analysis indicates that most filaments resemble cylindrical flux tubes within which the magnetic field intensity decreases toward its central axis. If the filaments move over the spacecraft at an estimated magnetospheric convection speed of ~35 km/s, then they have a typical diameter of ~105 km or ~7 gyroradii for 1 keV H+ ions in a 300 nT magnetic field. During these events, MESSENGER's Fast Imaging Plasma Spectrometer observed H+ ions with magnetosheath‐like energies. MESSENGER observations during the spacecraft's final low‐altitude campaign revealed that these cusp filaments likely extend down to Mercury's surface. We calculated an occurrence‐rate‐normalized integrated particle precipitation rate onto the surface from all filaments of (2.70 ± 0.09) × 1025 s−1. This precipitation rate is comparable to published estimates of the total precipitation rate in the larger‐scale cusp. Overall, the MESSENGER observations analyzed here suggest that cusp filaments are the magnetospheric extensions of the flux transfer events that form at the magnetopause as a result of localized magnetic reconnection.

With data from the Fast Imaging Plasma Spectrometer sensor on the MErcury Surface, Space ENvironment, GEochemistry, and Ranging spacecraft, we demonstrate that the average distributions for both solar wind and planetary ions in Mercury's pre‐midnight plasma sheet are well‐described by hot Maxwell‐Boltzmann distributions. Temperatures and densities of the H+‐dominated plasma sheet, in the ranges ~1–10 cm−3 and ~5–30 MK, respectively, maintain thermal pressures of ~1 nPa. The dominant planetary ion, Na+, has number densities about 10% that of H+. Solar wind ions retain near‐solar‐wind abundances with respect to H+ and exhibit mass‐proportional ion temperatures, indicative of a reconnection‐dominated heating in the magnetosphere. Conversely, planetary ion species are accelerated to similar average energies greater by a factor of ~1.5 than that of H+. This energization is suggestive of acceleration in an electric potential, consistent with the presence of a strong centrifugal acceleration process in Mercury's magnetosphere.

The three‐dimensional “substorm current wedge” (SCW) was postulated by McPherron et al. (1973) to explain substorm magnetic perturbations. The origin and coherence as a physical system of this important paradigm of modern space physics remained unclear, however, with progress hindered by gross undersampling, and uniqueness problems in data inversion. Complementing AMPERE (Active Magnetosphere and Planetary Electrodynamics Response Experiment) space‐derived radial electric currents with ground magnetic data allowing us to determine currents from the ionosphere up, we overcome problems of uniqueness identified by Fukushima (1969, 1994). For a substorm on 24 February 2010, we quantify SCW development consistently from ground and space data. Its westward electrojet carries 0.5 MA in the more poleward part of the auroral oval, in Region 1 (R1) sense spanning midnight. The evening sector electrojet also feeds into its upward current. We thus validate the SCW concept and obtain parameters needed for quantitative study of substorms.

Electric currents of a substorm current wedge on 24 February 2010

Mercury’s Internal Magnetic Field: Results from MESSENGER’s Search for Remanent Crustal Magnetization Associated with Impact Basins

Magnetic field observations acquired in orbit about Mercury by the MESSENGER spacecraft demonstrate the presence in the planet's northern hemisphere of Birkeland currents that flow to low altitudes. Currents of density 10–30 nA/m2 flow downward at dawn and upward at dusk. Total currents are typically 20–40 kA and exceed 200 kA during disturbed conditions. The current density and total current are two orders of magnitude lower than at Earth. An electric potential of ~30 kV from dayside magnetopause magnetic reconnection implies a net electrical conductance of ~1 S. A spherical‐shell conductance model indicates closure of current radially through the low‐conductivity layers near the surface and by lateral flow from dawn to dusk through more conductive material at depth.

events (brown). Also shown are the three weathering epochs of ref. [11] (green, orange red). The uncertainty on the end of the Martian dynamo currently overlaps the Noachian-Hesperian and phyllosian-theiikian boundaries. The seven Mars 2020 SDT reference sites explore Noachian and Hesperian terranes. After refs. [12-16]. MARS COMPASS: A MAGNETOMETER FOR THE MARS 2020 ROVER. B. P. Weiss, C. T. Russell, B. J. Anderson, J. L. Kirschvink, M. P. Golombek, C. A. Raymond, N. Murphy, Department of Earth, Atmospheric and Planetary Sciences, Massachusetts Institute of Technology, Cambridge, MA, Institute of Geophysics and Planetary Physics, University of California, Los Angeles, CA, The Johns Hopkins University Applied Physics Laboratory, Laurel, MD, Division of Geological and Planetary Sciences, California Institute of Technology, Pasadena, CA, Jet Propulsion Laboratory, California Institute of Technology, Pasadena, CA

Mercury’s Internal Magnetic Field: Results from MESSENGER’s Low-altitude Campaign

Development with MESSENGER Data of a Model of Mercury's Magnetospheric Magnetic Field Confined within the Average Observed Magnetopause

Coronal mass ejections (CMEs) and other transient solar phenomena play important roles in magnetospheric and exospheric dynamics. Although a planet may interact only occasionally with the interplanetary consequences of these events, such transient phenomena can result in departures from the background solar wind that often involve more than an order of magnitude greater ram pressure and interplanetary electric field applied to the planetary magnetosphere. For Mercury, an order of magnitude greater ram pressure combined with high Alfvén speeds and reconnection rates can push the magnetopause essentially to the planet's surface, exposing the surface directly to the solar wind flow. In order to understand how the solar wind interacts with Mercury's magnetosphere and exosphere, previous studies have used the Wang‐Sheeley‐Arge (WSA)‐ENLIL solar wind modeling tool to calculate basic and composite solar wind parameters at Mercury's orbital location. This model forecasts only the background solar wind, however, and does not include major transient events. The Cone extension permits the inclusion of CMEs and related solar wind perturbations and thus enables characterization of the effects of strong solar wind disturbances on the Mercury system. The Cone extension is predicated on the assumption of constant angular and radial velocities of CMEs to integrate these phenomena into the WSA‐ENLIL coupled model. Comparisons of the model results with observations by the MESSENGER spacecraft indicate that the WSA‐ENLIL+Cone model more accurately forecasts total solar wind conditions at Mercury and has greater predictive power for magnetospheric and exospheric processes than the WSA‐ENLIL model alone.

Improving solar wind modeling at Mercury: Incorporating transient solar phenomena into the WSA‐ENLIL model with the Cone extension

Field-Aligned and Ionospheric Current Contributions to Ground Magnetic Perturbations

Multi-Scale Kelvin-Helmholtz Vortices Along Mercury's Magnetopause

We assess the statistical spatial distribution of plasma in Mercury's magnetosphere from observations of magnetic pressure deficits and plasma characteristics by the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft. The statistical distributions of proton flux and pressure were derived from 10 months of Fast Imaging Plasma Spectrometer (FIPS) observations obtained during the orbital phase of the MESSENGER mission. The Magnetometer‐derived pressure distributions compare favorably with those deduced from the FIPS observations at locations where depressions in the magnetic field associated with the presence of enhanced plasma pressures are discernible in the Magnetometer data. The magnitudes of the magnetic pressure deficit and the plasma pressure agree on average, although the two measures of plasma pressure may deviate for individual events by as much as a factor of ~3. The FIPS distributions provide better statistics in regions where the plasma is more tenuous and reveal an enhanced plasma population near the magnetopause flanks resulting from direct entry of magnetosheath plasma into the low‐latitude boundary layer of the magnetosphere. The plasma observations also exhibit a pronounced north‐south asymmetry on the nightside, with markedly lower fluxes at low altitudes in the northern hemisphere than at higher altitudes in the south on the same field line. This asymmetry is consistent with particle loss to the southern hemisphere surface during bounce motion in Mercury's offset dipole magnetic field.

Plasma distribution in Mercury's magnetosphere derived from MESSENGER Magnetometer and Fast Imaging Plasma Spectrometer observations

We report the observational results of upstream ULF waves in the Mercury's foreshock using high-time resolution magnetic field data, 20 samples per second, from the MESSENGER spacecraft. The Mercury's bow shock is unique in our solar system as it is produced by low Mach number solar wind blowing over a small magnetized body with a predominately radial interplanetary magnetic field. Our study has showed the existence of at least three types of upstream waves: 1) whistler waves at frequencies near 2 Hz, similar to the 1-Hz waves at the Earth; 2) waves with frequencies ~ 0.3 Hz, similar to the large-amplitude 30-s waves at the Earth; 3) fluctuations with spectral peaks centered at ~ 0.8 Hz. Unlike the Earth's foreshock where the most prominent upstream wave phenomenon is locally generated large-amplitude 30-s magnetosonic waves, the most common foreshock waves are whistler waves generated at the bow shock, with properties similar to the 1-Hz waves in the Earth's foreshock. Their occurrence characteristics show that the “1-Hz” wave generation is generic to the bow shock and not affected by the strength and size of the shock at Mercury. On the other hand, the “30-s” magnetosonic waves at Mercury occur only sporadically and with small amplitudes. The general lack of strong “30-s” magnetosonic waves at Mercury can be attributed to the lack of strong backstreaming ions due to a weak bow shock and not enough time for wave growth due to the small foreshock size. Superposed on the “1-Hz” whistler waves, there are short bursts of spectral peaks at ~ 0.8 Hz that are new and have not been reported previously in Mariner 10 data. The source of the ~ 0.8 Hz waves remains to be identified.

2014 XXXIth URSI General Assembly and Scientific Symposium (URSI GASS)

Observations of upstream ultra-low-frequency waves in the Mercury's foreshock

Solar wind protons observed by the MESSENGER spacecraft in orbit about Mercury exhibit signatures of precipitation loss to Mercury's surface. We apply proton‐reflection magnetometry to sense Mercury's surface magnetic field intensity in the planet's northern and southern hemispheres. The results are consistent with a dipole field offset to the north and show that the technique may be used to resolve regional‐scale fields at the surface. The proton loss cones indicate persistent ion precipitation to the surface in the northern magnetospheric cusp region and in the southern hemisphere at low nightside latitudes. The latter observation implies that most of the surface in Mercury's southern hemisphere is continuously bombarded by plasma, in contrast with the premise that the global magnetic field largely protects the planetary surface from the solar wind.

Mercury's surface magnetic field determined from proton‐reflection magnetometry

The MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft has observed the northern magnetospheric cusp of Mercury regularly since the probe was inserted into orbit about the innermost planet in March 2011. Observations from the Fast Imaging Plasma Spectrometer (FIPS) made at altitudes < 400 km in the planet's cusp have shown average proton densities (>10 cm−3) that are exceeded only by those observed in the magnetosheath. These high plasma densities are also associated with strong diamagnetic depressions observed by MESSENGER's Magnetometer. Plasma in the cusp may originate from several sources: (1) Direct inflow from the magnetosheath, (2) locally produced planetary photoions and ions sputtered off the surface from solar wind impact and then accelerated upward, and (3) flow of magnetosheath and magnetospheric plasma accelerated from dayside reconnection X‐lines. We surveyed 518 cusp passes by MESSENGER, focusing on the spatial distribution, energy spectra, and pitch‐angle distributions of protons and Na+‐group ions. Of those, we selected 77 cusp passes during which substantial Na+‐group ion populations were present for a more detailed analysis. We find that Mercury's cusp is a highly dynamic region, both in spatial extent and plasma composition and energies. From the three‐dimensional plasma distributions observed by FIPS, protons with mean energies of 1 keV were found flowing down into the cusp (i.e., source (1) above). The distribution of pitch angles of these protons showed a depletion in the direction away from the surface, indicating that ions within 40° of the magnetic field direction are in the loss cone, lost to the surface rather than being reflected by the magnetic field. In contrast, Na+‐group ions show two distinct behaviors depending on their energy. Low‐energy (100–300 eV) ions appear to be streaming out of the cusp, showing pitch‐angle distributions with a strong component antiparallel to the magnetic field (away from the surface). These ions appear to have been generated in the cusp and accelerated locally (i.e., source (2) above). Higher‐energy (≥1 keV) Na+‐group ions in the cusp exhibit much larger perpendicular components in their energy distributions. During active times, as judged by frequent, large‐amplitude magnetic field fluctuations, many more Na+‐group ions are measured at latitudes south of the cusp. In several cases, these Na+‐group ions in the dayside magnetosphere are flowing northward toward the cusp. The high mean energy, pitch‐angle distributions, and large number of Na+‐group ions on dayside magnetospheric field lines are inconsistent with direct transport into the cusp of sputtered ions from the surface or newly photoionized particles. Furthermore, the highest densities and mean energies often occur together with high‐amplitude magnetic fluctuations, attributed to flux transfer events along the magnetopause. These results indicate that high‐energy Na+‐group ions in the cusp are likely formed by ionization of escaping neutral Na in the outer dayside magnetosphere and the magnetosheath followed by acceleration and transport into the cusp by reconnection at the subsolar magnetopause (i.e., source 3 above).

Structure and dynamics of Mercury's magnetospheric cusp: MESSENGER measurements of protons and planetary ions

Sounding the Interior of Mars and Venus Using Existing Spacecraft and Future Landers

MESSENGER Observation on Reconnection and Structure of Mercury’s Magnetotail Lobes and Plasma Sheet

In this paper we present the first large‐scale statistical study of the influence of magnetic reconnection on the magnitude of the regions 1 and 2 Birkeland field‐aligned currents (FACs). While previous studies have employed single spacecraft measurements to construct a statistical picture of the location and density of the Birkeland currents, it has hitherto been difficult to compare in situ measurements of the solar wind with instantaneous global field‐aligned current measurements. To that end, we utilize the Active Magnetosphere Planetary Electrodynamics Response Experiment (AMPERE), which yields field‐aligned current density in both hemispheres at a cadence of 10 min. We quantify the amount of current flowing in the regions 1 (R1) and 2 (R2) FACs, and we compare these with the dayside reconnection rate ΦD deduced from interplanetary parameters from the OMNI data set and with the AL index to examine whether magnetic reconnection is responsible for driving currents in the coupled magnetosphere‐ionosphere system. We find that current magnitudes are strongly correlated with both ΦD and AL index. We also find that R1 currents tend to be higher than R2 currents during periods of magnetic reconnection, suggesting leakage of current across the polar cap or an association with the substorm current wedge.

The magnitudes of the regions 1 and 2 Birkeland currents observed by AMPERE and their role in solar wind‐magnetosphere‐ionosphere coupling

MESSENGER's low-altitude plasma observations in Mercury's northern magnetospheric cusp

The large‐scale dynamic behavior of Mercury's highly compressed magnetosphere is predominantly powered by magnetic reconnection, which transfers energy and momentum from the solar wind to the magnetosphere. The contribution of flux transfer events (FTEs) at the dayside magnetopause to the redistribution of magnetic flux in Mercury's magnetosphere is assessed with magnetic field data acquired in orbit about Mercury by the Magnetometer on the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft. FTEs with core fields greater than the planetary field just inside the magnetopause are prevalent at Mercury. Fifty‐eight such large‐amplitude FTEs were identified during February and May 2012, when MESSENGER sampled the subsolar magnetosheath. The orientation of each FTE was determined by minimum variance analysis, and the magnetic flux content of each was estimated using a force‐free flux rope model. The average flux content of the FTEs was 0.06 MWb, and their durations imply a transient increase in the cross‐polar cap potential of ~25 kV. For a substorm timescale of 2–3 min, as indicated by magnetotail flux loading and unloading, the FTE repetition rate (10 s) and average flux content (assumed to be 0.03 MWb) imply that FTEs contribute at least ~30% of the flux transport required to drive the Mercury substorm cycle. At Earth, in contrast, FTEs are estimated to contribute less than 2% of the substorm flux transport. This result implies that whereas at Earth, at which steady‐state dayside reconnection is prevalent, multiple X‐line dayside reconnection and associated FTEs at Mercury are a dominant forcing for magnetospheric dynamics.

MESSENGER observations of large dayside flux transfer events: Do they drive Mercury's substorm cycle?

Characteristics of Energetic Electron Events in Mercury's Magnetosphere at the 10-ms Timescale

Regional-Scale Surface Magnetic Fields and Proton Fluxes to Mercury’s Surface from Proton-Reflection Magnetometry

Simultaneous observations of Birkeland currents by the constellation of Iridium satellites and N2 Lyman‐Birge‐Hopfield (LBH) auroral emissions measured by the Global Ultraviolet Imager (GUVI) onboard the Thermosphere, Ionosphere, and Mesosphere Energetics and Dynamics (TIMED) satellite are used to establish relationships between large‐scale upward field‐aligned currents and electron precipitation during stable current configurations. The electron precipitation was inferred from GUVI data using a statistical relationship between LBH intensity and electron energy flux. LBH emissions with >5% contribution from protons, identified by Lyman‐alpha intensity, were excluded from the analysis. The Birkeland currents were derived with a spatial resolution of 3° in latitude and 2 h in local time. For southward interplanetary magnetic field (IMF), the electron precipitation occurred primarily within and near large‐scale upward currents. The correspondence was less evident for northward IMF, presumably because the spatial variability is large compared to the areas of interest so that the number of events identified is smaller and the derived statistical distributions are less reliable. At dusk, the correlation between upward current and precipitation was especially high, where a larger fraction of the electron precipitation is accelerated downward by a field‐aligned potential difference. Unaccelerated electron precipitation dominated in the morning sector, presumably induced by scattering of eastward‐drifting energetic electrons into the loss cone through interaction with whistler‐mode waves (diffuse precipitation) rather than by field‐aligned acceleration. In the upward Region 1 on the dayside, where the electron precipitation is almost exclusively due to field‐aligned acceleration, a quadratic relationship between current density and electron energy flux was observed, implying a linear current‐voltage relationship in this region. Current density and electron energy flux in the regions of the large‐scale upward currents from pre‐midnight through dawn to noon are essentially uncorrelated, consistent with diffuse electron precipitation dominating the incident energy flux.

Statistical relationship between large‐scale upward field‐aligned currents and electron precipitation

The structure of Mercury's dayside magnetosphere is investigated during three extreme solar wind dynamic pressure events. Two were the result of coronal mass ejections (CMEs), and one was from a high‐speed stream (HSS). The inferred pressures for these events are ~ 45 to 65 nPa. The CME events produced thick, low‐β (where β is the ratio of plasma thermal to magnetic pressure) plasma depletion layers and high reconnection rates of 0.1–0.2, despite small magnetic shear angles across the magnetopause of only 27 to 60°. For one of the CME events, brief, ~ 1–2 s long diamagnetic decreases, which we term cusp plasma filaments, were observed within and adjacent to the cusp. These filaments may map magnetically to flux transfer events at the magnetopause. The HSS event produced a high‐β magnetosheath with no plasma depletion layer and large magnetic shear angles of 148 to 166°, but low reconnection rates of 0.03 to 0.1. These results confirm that magnetic reconnection at Mercury is very intense, and its rate is primarily controlled by plasma β in the adjacent magnetosheath. The distance to the subsolar magnetopause is reduced during these events from its mean of 1.45 Mercury radii (RM) from the planetary magnetic dipole to between 1.03 and 1.12 RM. The shielding provided by induction currents in Mercury's interior, which temporarily increase Mercury's magnetic moment, was negated by reconnection‐driven magnetic flux erosion.

MESSENGER observations of Mercury's dayside magnetosphere under extreme solar wind conditions

Plasma Transport, Acceleration, and Loss in Mercury’s Magnetosphere and Comparison with Other Planetary Magnetospheres

Observations of Mercury's internal magnetic field from the Magnetometer on the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft have revealed a dipole moment of 190 nT RM3 offset about 480 km northward from the planetary equator, where RM is Mercury's radius. We have reanalyzed magnetic field observations acquired by the Mariner 10 spacecraft during its third flyby of Mercury (M10‐III) in 1975 to constrain the secular variation in the internal field over the past 40 years. With the application of techniques developed in the analysis of MESSENGER data, we find that the dipole moment that best fits the M10‐III data is 188 nT RM3 offset 475 km northward from the equator. Our results are consistent with no secular variation, although variations of up to 10%, 16%, and 35%, respectively, are permitted in the zonal coefficients g10, g20, and g30 in a spherical harmonic expansion of the internal field.

Constraints on the secular variation of Mercury's magnetic field from the combined analysis of MESSENGER and Mariner 10 data

First Observations of Mercury's Plasma Mantle As Seen By MESSENGER

The Active Magnetosphere and Planetary Electrodynamics Response Experiment uses magnetic field data from the Iridium constellation to derive the global Birkeland current distribution every 10 min. We examine cases in which the interplanetary magnetic field (IMF) rotated from northward to southward resulting in onsets of the Birkeland currents. Dayside Region 1/2 currents, totaling ~25% of the final current, appear within 20 min of the IMF southward turning and remain steady. Onset of nightside currents occurs 40 to 70 min after the dayside currents appear. Thereafter, the currents intensify at dawn, dusk, and on the dayside, yielding a fully formed Region 1/2 system ~30 min after the nightside onset. The results imply that the dayside Birkeland currents are driven by magnetopause reconnection, and the remainder of the system forms as magnetospheric return flows start and progress sunward, ultimately closing the Dungey convection cycle.

Development of large‐scale Birkeland currents determined from the Active Magnetosphere and Planetary Electrodynamics Response Experiment

We have analyzed measurements of planetary ions near Mercury made by the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) Fast Imaging Plasma Spectrometer (FIPS) over the first three Mercury years of orbital observations (25 March 2011 through 31 December 2011). We determined the composition and spatial distributions of the most abundant species in the regions sampled by the MESSENGER spacecraft during that period. In particular, we here focus on altitude dependence and relative abundances of species in a variety of spatial domains. We used observed density as a proxy for ambient plasma density, because of limitations to the FIPS field of view. We find that the average observed density is 3.9 × 10–2 cm–3 for He2+, 3.4 × 10–4 cm–3 for He+, 8.0 × 10–4 cm–3 for O+‐group ions, and 5.1 × 10–3 cm–3 for Na+‐group ions. Na+‐group ions are particularly enhanced over other planetary ions (He+ and O+ group) in the northern magnetospheric cusp (by a factor of ~2.0) and in the premidnight sector on the nightside (by a factor of ~1.6). Within 30° of the equator, the average densities of all planetary ions are depressed at the subsolar point relative to the dawn and dusk terminators. The effect is largest for Na+‐group ions, which are 49% lower in density at the subsolar point than at the terminators. This depression could be an effect of the FIPS energy threshold. The three planetary ion species considered show distinct dependences on altitude and local time. The Na+ group has the smallest e‐folding height at all dayside local times, whereas He+ has the largest. At the subsolar point, the e‐folding height for Na+‐group ions is 590 km, and that for the O+ group and He+ is 1100 km. On the nightside and within 750 km of the geographic equator, Na+‐group ions are enhanced in the premidnight sector. This enhancement is consistent with nonadiabatic motion and may be observational evidence that nonadiabatic effects are important in Mercury's magnetosphere.

Distribution and compositional variations of plasma ions in Mercury's space environment: The first three Mercury years of MESSENGER observations

The Ionospheric Convection and Birkeland Current Response to an Impulse in the Interplanetary Magnetic Field BY Component

An Investigation of Current Closure within an Auroral Arc: Modeling and Observations

We study the two most intense electron events observed by the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft during the rising phase of solar cycle 24. Both events occurred during intense periods of solar activity when sequences of coronal mass ejections (CMEs) emanated from the Sun. The first event occurred on 4 June 2011, when two successive CMEs, spaced by 15 h, were released from the same active region. A possible interpretation for this event is that the first CME, located beyond MESSENGER's heliocentric distance (R = 0.33 AU) at the time of the second CME, acted as a magnetic barrier for solar energetic particles (SEPs) accelerated during the second CME. Elevated electron intensities at MESSENGER resulted from particle confinement between the two CME‐driven shocks. This scenario is consistent with that proposed by Kallenrode and Cliver [2001a] to explain intense SEP events. The second event, observed by MESSENGER at R = 0.31 AU on 7 March 2012, belonged to a series of events generated by a single active region. A fast (>1500 km s−1) CME occurred 45 h before the onset of the main electron event. That implies that the prior CME‐driven shock was at such a distance that particle reflection from behind that shock might have not been sufficient to account for the initial onset of sunward‐directed electrons at MESSENGER, and additional mirroring and/or scattering processes closer to MESSENGER were necessary. Elevated intensities in this event are consistent with strong injection of SEPs from close to the Sun and particle reflection at some point in interplanetary space.

Recent studies of low frequency waves ({omega}{sub r} {le} {Omega}{sub p}, where {Omega}{sub p} is the proton gyrofrequency) observed by AMPTE/CCE in the plasma depletion layer and magnetosheath proper arereviewed. These waves are shown to be well identified with ion cyclotron and mirror mode waves. By statistically analyzing the transitions between the magnetopause and time intervals with ion cyclotron and mirror mode waves, it is established that the regions in which ion cyclotron waves occur are between the magnetopause and the regions where the mirror mode is observed. This result is shown to follow from the fact that the wave spectral properties are ordered with respect to the proton parallel beta, {beta}{sub {parallel}p}. The later result is predicted by linear Vlasov theory using a simple model for the magnetosheath and plasma depletion layer. Thus, the observed spectral type can be associated with relative distance from the magnetopause. The anisotropy-beta relation, A{sub p} {triple_bond} (T{perpendicular}/T{sub {parallel}}){sub p} {minus} 1 = 0.50{beta}{sub {parallel}p}{sup {minus}0.48} results from the fact that the waves pitch angle scatter the particles so that the plasma is near marginal stability, and is a fundamental constraint on the plasma.

Ion anisotropy driven waves in the earth`s magnetosheath and plasma depletion layer

WSA-ENLIL Cone Extension: Improving Solar Wind Forcing Parameter Estimates at Mercury

We here document with magnetic field observations a passage of the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft through Mercury's magnetosphere under conditions of a quasi‐parallel bow shock, i.e., when the direction of the upstream interplanetary magnetic field was within 45° of the bow shock normal. The spacecraft's fast transition of the magnetosheath and the steady solar wind conditions during the period analyzed allow both spatial and temporal properties of the shock crossing to be investigated. The observations show that the shock reformation process can be nearly periodic under stable solar wind conditions. Throughout the 25‐min‐long observation period, the pulsation duration deviated by at most ~10% from the average 10 s period measured. This quasiperiodicity allows us to study all aspects of the shock reconfiguration, including ultra‐low‐frequency waves in the upstream region and large‐amplitude magnetic structures observed in the vicinity of the magnetosheath‐solar wind transition region and inside the magnetosheath. We also show that bow shock reformation can be a substantial source of wave activity in the magnetosphere, on this occasion having given rise to oscillations in the magnetic field with peak‐to‐peak amplitudes of 40–50 nT over large parts of the dayside magnetosphere. The clean and cyclic behavior observed throughout the magnetosphere, the magnetosheath, and the upstream region indicates that the subsolar region was primarily influenced by a cyclic reformation of the shock front, rather than by a spatial and temporal patchwork of short large‐amplitude magnetic structures, as is generally the case at the terrestrial bow shock under quasi‐parallel conditions.

Cyclic reformation of a quasi‐parallel bow shock at Mercury: MESSENGER observations

Large electric fields in the sub-auroral, dusk side ionosphere have long been inferred from observations of fast (>1000m/s) sun ward ion drifts. Extreme Ultraviolet (EUV) images of the plasmasphere obtained by the EUV camera on board the IMAGE satellite, suggest that the dusk side plasmapause can be eroded by these strong sub-auroral electric fields. Ring current models, that self-consistently compute the electric field, can reproduce the observed phenomena qualitatively, and they indicate that the electric field is driven by the closure of the Region 2 (R2) pressure-driven field aligned currents (FAC) through the dusk side, sub-auroral low-conductance ionosphere. We investigate the temporal and spatial relation between global ring current images and the onset of sub-auroral electric fields by using data from the High Energetic Neutral Atom (HENA) imager on board the IMAGE satellite, Ion Drift Meter (IDM) data from the Defense Meteorological Satellite Program (DMSP), and field-aligned currents (FACs) derived from Iridium magnetometer data. We find that the ring current pressure is enhanced about 30 min before an erosion of the plasmapause is first observed. We compute the correlation between the Region 2 FAC obtained by Iridium multiplied by the size of the low-conductance gap and the sub-auroral potential drop (SAPD) and find that it is 0.79 for the period 16-23 April 2002. These results show that there is a correlation between the FAC, the size of the low-conductance gap and strength of the SAPD.

On the Relation Between Sub‐Auroral Electric Fields, the Ring Current and the Plasmasphere

MESSENGER observations of dayside flux transfer events: Do they drive Mercury's substorm cycle? (Invited)

We have established the average shape and location of Mercury's magnetopause and bow shock from orbital observations by the MESSENGER Magnetometer. We fit empirical models to midpoints of boundary crossings and probability density maps of the magnetopause and bow shock positions. The magnetopause was fit by a surface for which the position R from the planetary dipole varies as [1 + cos(θ)]−α, where θ is the angle between R and the dipole‐Sun line, the subsolar standoff distance Rss is 1.45 RM (where RM is Mercury's radius), and the flaring parameter α = 0.5. The average magnetopause shape and location were determined under a mean solar wind ram pressure PRam of 14.3 nPa. The best fit bow shock shape established under an average Alfvén Mach number (MA) of 6.6 is described by a hyperboloid having Rss = 1.96 RM and an eccentricity of 1.02. These boundaries move as PRam and MA vary, but their shapes remain unchanged. The magnetopause Rss varies from 1.55 to 1.35 RM for PRam in the range of 8.8–21.6 nPa. The bow shock Rss varies from 2.29 to 1.89 RM for MA in the range of 4.12–11.8. The boundaries are well approximated by figures of revolution. Additional quantifiable effects of the interplanetary magnetic field are masked by the large dynamic variability of these boundaries. The magnetotail surface is nearly cylindrical, with a radius of ~2.7 RM at a distance of 3 RM downstream of Mercury. By comparison, Earth's magnetotail flaring continues until a downstream distance of ~10 Rss.

Mercury's magnetopause and bow shock from MESSENGER Magnetometer observations

Wet Mercury Radar observations of Mercury's poles in the 1990s revealed regions of high backscatter that were interpreted as indicative of thick deposits of water ice; however, other explanations have also been proposed (see the Perspective by Lucey). MESSENGER neutron data reported by Lawrence et al. (p. 292, published online 29 November) in conjunction with thermal modeling by Paige et al. (p. 300, published online 29 November) now confirm that the primary component of radar-reflective material at Mercury's north pole is water ice. Neumann et al. (p. 296, published online 29 November) analyzed surface reflectance measurements from the Mercury Laser Altimeter onboard MESSENGER and found that while some areas of high radar backscatter coincide with optically bright regions, consistent with water ice exposed at the surface, some radar-reflective areas correlate with optically dark regions, indicative of organic sublimation lag deposits overlying the ice. Dark areas that fall outside regions of high radio backscatter suggest that water ice was once more widespread. Spacecraft data and a thermal model show that water ice and organic volatiles are present at Mercury’s north pole. [Also see Perspective by Lucey] Measurements by the Neutron Spectrometer on the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft show decreases in the flux of epithermal and fast neutrons from Mercury’s north polar region that are consistent with the presence of water ice in permanently shadowed regions. The neutron data indicate that Mercury’s radar-bright polar deposits contain, on average, a hydrogen-rich layer more than tens of centimeters thick beneath a surficial layer 10 to 30 cm thick that is less rich in hydrogen. Combined neutron and radar data are best matched if the buried layer consists of nearly pure water ice. The upper layer contains less than 25 weight % water-equivalent hydrogen. The total mass of water at Mercury’s poles is inferred to be 2 × 1016 to 1018 grams and is consistent with delivery by comets or volatile-rich asteroids.

Evidence for Water Ice Near Mercury’s North Pole from MESSENGER Neutron Spectrometer Measurements

Role of Magnetosphere-Ionosphere Coupling in Destabilisation of the Earth's Magnetotail

What Happened to the High-Energy (> 100 keV) Particles at Mercury?

Propagation of Compressional Pc 3 Pulsations from Space to the Ground: A Case Study Using Multipoint Measurements

Assessment of the auroral electrojet index performance under various geomagnetic conditions

In this paper we compare time‐dependent global ionospheric field‐aligned current (FAC) patterns on 10 min timescales inferred from the Active Magnetosphere and Polar Electrodynamics Response Experiment (AMPERE) with the high‐resolution Lyon‐Fedder‐Mobarry (LFM) global magnetohydrodynamic (MHD) model. The improved LFM model yields temporally varying FAC patterns with a fine structure on the sub‐100 km scale. The goal of the study is to explore the responses of observed and simulated FAC patterns and underlying magnetic perturbations to a succession of rapid transitions in the solar wind and Interplanetary Magnetic Field (IMF) parameters. To drive the simulations, we use the upstream Wind and Time History of Events and Macroscale Interactions during Substorms (THEMIS) spacecraft measurements recorded on 3 August 2010. For the time interval of interest (∼40 min following the impact of an interplanetary shock), the IMF is characterized by a BZ rotation from southward to northward direction under negative BY conditions. Through this case study analysis, it is found that the simulations have generally reproduced the salient characteristics of both the morphology and dynamics of the AMPERE FAC patterns. Due to the high resolution of the global model, the peak current densities are found to significantly (by a factor of 2–4) exceed those obtained from AMPERE. As a further quantitative analysis, the low‐altitude magnetic perturbations measured by Iridium spacecraft and used to derive the AMPERE 2‐D FAC patterns are also compared with the magnetic field variations calculated from the simulations. It is found that outside of localized regions of peak current densities, which mainly occur on the dayside and can fall between the Iridium tracks, the simulated magnetic perturbations closely follow the Iridium measurements. This demonstrates, in particular, that there is no systematic bias in the simulations to overestimate the magnetic perturbations and corresponding FAC densities. Overall, our results demonstrate that given sufficient resolution, contemporary global MHD models are capable of reproducing observed features of global ionospheric FAC distributions. This, in particular, suggests the feasibility of potential efforts to assimilate AMPERE observations in global magnetospheric models.

Global evolution of Birkeland currents on 10 min timescales: MHD simulations and observations

We present a magnetic disturbance measure for Mercury derived from MESSENGER Magnetometer data. Magnetic field fluctuations were computed in three period bands: 0.1–2 s, 2–20 s, and 20–300 s. From these, we determined log average magnetic variability versus latitude and local time in Mercury's magnetosphere. The quietest regions are the southern tail lobe and the nightside poleward of 30° magnetic latitude, and the most disturbed regions are near magnetopause boundaries and the magnetospheric cusp. We used ratios at each location between the mean disturbance and that observed on each pass to compute normalized measures of magnetic disturbance for each orbit. Composite disturbance indices incorporate disturbance levels in all three bands. Percentile ranking of the composite indices provides a quantitative basis for selecting data from quiet to disturbed conditions.

A magnetic disturbance index for Mercury's magnetic field derived from MESSENGER Magnetometer data

At around 19:30 UT on 17 April 2002, an undulative motion of the plasma-pause was observed by the Extreme Ultraviolet (EUV) camera on board the IMAGE satellite. The motion expanded westward into the duskside and at the same time a ring current pressure increase was observed by the High Energy Neutral Atom (HENA) imager on board IMAGE. The pressure increase was due to a substorm injection with a localized auroral onset at 19:05 UT. It has been shown that the motion of the plasmapause was caused by an electric field set up in the sub-auroral, duskside ionosphere, by the closure of the Region-2 currents, poleward to Region-1 as originally proposed by Anderson et al. (1993). In this paper we discuss the cause of the westward propagation of the motion of the plasmapause, and suggest that it may be caused by the westward expansion of the aurora.

On the Relation between Electric Fields in the Inner Magnetosphere, Ring Current, Auroral Conductance, and Plasmapause Motion

Johnson, Reka M. Winslow, Brian J. Anderson, Michael E. Purucker, Haje Korth, Steve A. Hauck, Daniel Heyner, Roger J. Phillips, James A, Slavin, Sean C. Solomon, Department of Earth, Ocean and Atmospheric Sciences, University of British Columbia, BC, V6T 1Z4, Canada, cjohnson@eos.ubc.ca. Planetary Science Institute, Tucson, AZ 85719, USA, cjohnson@psi.edu. The Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA. NASA Goddard Space Flight Center, Greenbelt, MD 20771, USA. Department of Earth, Environmental and Planetary Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA. Institut für Geophysik und extraterrestrische Physik, Technische Universität Braunschweig, Braunschweig, Germany. Planetary Science Directorate, Southwest Research Institute, Boulder, CO 80302, USA. Department of Atmospheric, Oceanic, and Space Sciences, University of Michigan, Ann Arbor, MI 48109, USA. Lamont-Doherty Earth Observatory, Columbia University, Palisades, NY 10964, USA.

(1) Space Sciences Laboratory, UC Berkeley, United States (pavel@ssl.berkeley.edu), (2) Astronomical Institute and Institute of Atmospherics physics, AS CR, Czech Republic, (4) Institute for Geophysics and Extraterrestrial Physics, TU-BS, Germany, (3) Institute of Geophysics and Planetary Physics, UCLA, Los Angeles, USA, (5) Johns Hopkins University Applied Physics Laboratory, Laurel, Maryland, USA, (6) Department of Atmospheric, Oceanic and Space Sciences, University of Michigan, Ann Arbor, Michigan, USA

Mercury's plasma belt under different Interplanetary Magnetic Field: hybrid simulations results compared to in-situ measurements

We present a comprehensive two‐dimensional view of the field‐aligned currents (FACs) during the late growth and expansion phases for three isolated substorms utilizing in situ observations from the Active Magnetosphere and Planetary Electrodynamics Response Experiment and from ground‐based magnetometer and optical instrumentation from the Canadian Array for Realtime Investigations of Magnetic Activity and Time History of Events and Macroscale Interactions during Substorms ground‐based arrays. We demonstrate that the structure of FACs formed during the expansion phase and associated with the substorm current wedge is significantly more complex than a simple equivalent line current model comprising a downward FAC in the east and upward FAC in the west. This two‐dimensional view demonstrates that azimuthal bands of upward and downward FACs with periodic structuring in latitude form across midnight and can span up to 8 h of magnetic local time. However, when averaged over latitude, the overall longitudinal structure of the net FACs resembles the simpler equivalent line current description of the substorm current wedge (SCW). In addition, we demonstrate that the upward FAC elements of the structured SCW are spatially very well correlated with discrete aurora during the substorm expansion phase and that discrete changes in the FAC topology are observed in the late growth phase prior to auroral substorm expansion phase onset. These observations have important implications for determining how the magnetosphere and ionosphere couple during the late growth phase and expansion phase, as well as providing important constraints on the magnetospheric generator of the FACs comprising the SCW.

The detailed spatial structure of field‐aligned currents comprising the substorm current wedge

Mercury's bow shock is unique in our solar system as it is produced by low Mach number solar wind blowing over a small magnetized body. The availability of MESSENGER orbiter data enables us for the first time to conduct an in‐depth study of upstream waves in Mercury's foreshock. This paper reports first results of an observational study of upstream ULF waves in Mercury's foreshock using high‐time resolution magnetic field data from the MESSENGER spacecraft to understand the general morphology of these waves. We find that the most common wave phenomenon in Mercury's foreshock has frequencies ~ 2 Hz, with properties similar to the 1 Hz whistler waves in the Earth's foreshock. Their generation appears to be generic to the shock and not affected by the weak strength and small size of Mercury's bow shock. On the other hand, the most common wave phenomenon in the Earth's foreshock is the large‐amplitude 30 second waves, identified as fast magnetosonic waves generated by backstreaming ions. Similar waves at Mercury have wave frequencies at ~ 0.3 Hz, but occur only sporadically. The general lack of strong “30 second” magnetosonic waves at Mercury can be attributed to the lack of strong backstreaming ions due to a weak bow shock and not enough time for wave growth due to the small foreshock size. Superposed on the “1 Hz” whistler waves, there are short bursts of spectral peaks at ~ 0.8 Hz that are new and have not been reported previously in Mariner 10 data.

Upstream ultra‐low frequency waves in Mercury's foreshock region: MESSENGER magnetic field observations

Measurements from the Fast Imaging Plasma Spectrometer (FIPS) and Magnetometer (MAG) on the MErcury Surface, Space ENvironment, GEochemistry, and Ranging spacecraft during 40 orbits about Mercury are used to characterize the plasma depletion layer just exterior to the planet's dayside magnetopause. A plasma depletion layer forms at Mercury as a result of piled‐up magnetic flux that is draped around the magnetosphere. The low average upstream Alfvénic Mach number (MA ~3–5) in the solar wind at Mercury often results in large‐scale plasma depletion in the magnetosheath between the subsolar magnetopause and the bow shock. Flux pileup is observed to occur downstream under both quasi‐perpendicular and quasi‐parallel shock geometries for all orientations of the interplanetary magnetic field (IMF). Furthermore, little to no plasma depletion is seen during some periods with stable northward IMF. The consistently low value of plasma β, the ratio of plasma pressure to magnetic pressure, at the magnetopause associated with the low average upstream MA is believed to be the cause for the high average reconnection rate at Mercury, reported to be nearly 3 times that observed at Earth. Finally, a characteristic depletion length outward from the subsolar magnetopause of ~300 km is found for Mercury. This value scales among planetary bodies as the average standoff distance of the magnetopause.

Magnetic flux pileup and plasma depletion in Mercury's subsolar magnetosheath

An Overview of Spacecraft Observations of 10 s to 600 s Period Magnetic Pulsations in the Earth's Magnetosphere

[1] When the interplanetary magnetic field (IMF) is dawnward or duskward, magnetic merging between the IMF and the geomagnetic field occurs near the cusp on the dayside flanks of the magnetosphere. During these intervals, flow channels in the ionosphere with velocities in excess of 2 km/s have been observed, which can deposit large amounts of energy into the high-latitude thermosphere. In this study, we analyze an interval on 5 April 2010 where there was a strong dawnward impulse in the IMF, followed by a gradual decay in IMF magnitude at constant clock angle. Data from the Sondrestrom incoherent scatter radar and the Defense Meteorological Satellite Program spacecraft were used to investigate ionospheric convection during this interval, and data from the Active Magnetospheric and Planetary Electrodynamics Response Experiment (AMPERE) were used to investigate the associated Field-Aligned Current (FAC) system. Additionally, data from AMPERE were used to investigate the time response of the dawnside FAC pair. We find there is a delay of approximately 1.25 h between the arrival of the dawnward IMF impulse at the magnetopause and strength of the dawnward FAC pair, which is comparable to substorm growth and expansion time scales under southward IMF. Additionally, we find at the time of the peak FAC, there is evidence of a reconfiguring four-sheet FAC system in the morning local time sector of the ionosphere. Additionally, we find an inverse correlation between the dawn FAC strength and both the solar wind Alfvenic Mach number and the SYM-H index. No statistically significant correlation between the FAC strength and the solar wind dynamic pressure was found.

Field‐aligned current reconfiguration and magnetospheric response to an impulse in the interplanetary magnetic field BY component

High-resolution magnetic field data from the Polar Magnetic Field Experiment (MFE) show that narrow band waves at frequencies approximately 0.2 to 3 Hz are a permanent feature in the vicinity of the polar cusp. The waves have been found in the magnetosphere adjacent to the cusp (both poleward and equatorward of the cusp) and in the cusp itself. The occurrence of waves is coincident with depression of magnetic field strength associated with enhanced plasma density, indicating the entry of magnetosheath plasma into the cusp region. The wave frequencies are generally scaled by the local proton cyclotron frequency, and vary between 0.2 and 1.7 times local proton cyclotron frequency. This suggests that the waves are generated in the cusp region by the precipitating magnetosheath plasma. The properties of the waves are highly variable. The waves exhibit both lefthanded and right-handed polarization in the spacecraft frame. The propagation angles vary from nearly parallel to nearly perpendicular to the magnetic field. We find no correlation among wave frequency, propagation angle and polarization. Combined magnetic field and electric field data for the waves indicate that the energy flux of the waves is guided by the background magnetic field and points downward toward the ionosphere.

Electromagnetic Ion Cyclotron Waves in the High Altitude Cusp: Polar Observations

Changes in Magnetosphere-Ionosphere Coupling and FACs Associated with Substorm Onset (Invited)

[1] Using the location of maximum region 1 current determined by the Active Magnetosphere and Planetary Electrodynamics Response Experiment as a proxy for the open/closed field line boundary, we monitor the evolution of the amount of open magnetic flux inside the magnetosphere during 772 substorms. We then divide all substorms into three classes, depending on the amount of open flux at expansion phase onset. Studying the temporal variations during the substorms of each class for a number of related geophysical parameters, we find that substorms occurring while the amount of open flux is large are generally more intense. By intense we mean that the auroral electrojet, region 1 current, auroral brightness, tail dipolarization and flow speed, ground magnetic signatures, Pi2 wave power, as well as the intensity and extent of the substorm current wedge (SCW) are all larger than during substorms that occur on a contracted polar cap. The SCW manifests itself as an intensification of the nightside R1 and R2 current system after onset. Our analysis shows that to dispose of large amounts of accumulated open magnetic flux, large substorms are triggered in the terrestrial magnetosphere.

Using the location of maximum region 1 current determined by the Active Magnetosphere and Planetary Electrodynamics Response Experiment as a proxy

We study the interplanetary conditions during the occurrence of the most intense solar energetic particle (SEP) event observed by the MESSENGER spacecraft during the rising phase of solar cycle 24. Elevated electron intensities at MESSENGER (at 0.33 AU from the Sun) resulted from the confinement of energetic particles by two CME-driven shocks. This scenario is consistent with that proposed by Kallenrode and Cliver [3] to explain the most intense SEP events of a solar cycle. In analogy to the rogue ocean waves having unusually large amplitudes due to the superposition of two wave fields, these events were referred to as rogue SEP events. We compare the interplanetary conditions in the most intense event at MESSENGER with those observed in other rogue SEP events.

A rogue solar energetic particle event at 0.33 AU: Importance of interplanetary structures in SEP events

On 18 March 2011, MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) became the first spacecraft to orbit Mercury, providing a new opportunity to study the outer boundary of the planet's magnetosphere—the magnetopause. Here we characterize Mercury's magnetopause using measurements collected by MESSENGER's Magnetometer and Fast Imaging Plasma Spectrometer. Analysis of measurements from two of MESSENGER's “hot seasons,” when the orbital periapsis is on Mercury's dayside and the magnetopause crossing takes place in the subsolar region, resulted in 43 events with well‐determined boundary normals. The typical duration of a magnetopause traversal was ~5 s. The average normal magnetic field component was ~20 nT, and the dimensionless reconnection rate, i.e., the ratio of the normal magnetic field component to the total field magnitude just inside the magnetopause, was 0.15 ± 0.02. This rate is a factor of ~3 larger than values found during the most extensive surveys at Earth. The ratio of the reconnection rate at Mercury to that of the Earth is comparable to the ratio of the solar wind Alfvén speeds at their respective orbits. We also find that the magnetopause reconnection rate at Mercury is independent of magnetic field shear angle, but it varies inversely with plasma β, the ratio of total thermal pressure to magnetic pressure, in the magnetosheath. These results suggest that reconnection at Mercury is not only more intense than at Earth but also that it occurs for nearly all orientations of the interplanetary magnetic field due to the low‐β nature of the solar wind in the inner heliosphere.

MESSENGER observations of magnetopause structure and dynamics at Mercury

In this tutorial and selective review, we define magnetosphere-ionosphere (M-I) coupling, present its basic properties, and summarize outstanding problems in the field. We compare M-I coupling processes at Earth and Jupiter. We use that comparison to argue that M-I coupling processes that generate the northern and southern auroral lights are fundamental to how some astrophysical systems behave and evolve throughout the universe, specifically those involving partially ionized gases connected by magnetic fields. Using the example of solar system formation, we finally speculate as to the importance of what we can learn about M-I coupling at Earth and Jupiter towards understanding these distant astrophysical systems.

Characterizing Energetic Electron Events within Mercury's Magnetosphere as Measured with MESSENGER's Neutron Spectrometer

The Auroral Current and Electrodynamics Structure (ACES) mission consisted of two sounding rockets launched nearly simultaneously from Poker Flat Research Range, AK on January 29, 2009 into a dynamic multiple-arc aurora. The ACES rocket mission was designed to observe electrodynamic and plasma parameters above and within the current closure region of the auroral ionosphere. Two well instrumented payloads were flown along very similar magnetic field footprints, at different altitudes, with small temporal separation between both payloads. The higher altitude payload (apogee 360 km), obtained in-situ measurements of electrodynamic and plasma parameters above the current closure region to determine the input signature. The low altitude payload (apogee 130 km), made similar observations within the current closure region. Results are presented comparing observations of the electric fields, magnetic components, and the differential electron energy flux at magnetic footpoints common to both payloads. In situ data is compared to the ground based all-sky imager data, which presents the evolution of the auroral event as the payloads traversed through magnetically similar regions. Current measurements derived from the magnetometers on the high altitude payload observed upward and downward field-aligned currents. The effect of collisions with the neutral atmosphere is investigated to determine if it is a significant mechanism to explain discrepancies in the low energy electron flux. The high altitude payload also observed time-dispersed arrivals in the electron flux and perturbations in the electric and magnetic field components, which are indicative of Alfven waves.

Current Closure in the Auroral Ionosphere: Results From the Auroral Current and Electrodynamics Structure Rocket Mission

[1] The structure of Mercury's internal magnetic field has been determined from analysis of orbital Magnetometer measurements by the MESSENGER spacecraft. We identified the magnetic equator on 531 low-altitude and 120 high-altitude equator crossings from the zero in the radial cylindrical magnetic field component,Bρ. The low-altitude crossings are offset 479 ± 6 km northward, indicating an offset of the planetary dipole. The tilt of the magnetic pole relative to the planetary spin axis is less than 0.8°. The high-altitude crossings yield a northward offset of the magnetic equator of 486 ± 74 km. A field with only nonzero dipole and octupole coefficients also matches the low-altitude observations but cannot yield off-equatorialBρ= 0 at radial distances greater than 3520 km. We compared offset dipole and other descriptions of the field with vector field observations below 600 km for 13 longitudinally distributed, magnetically quiet orbits. An offset dipole with southward directed moment of 190 nT-RM3yields root-mean-square (RMS) residuals below 14 nT, whereas a field with only dipole and octupole terms tuned to match the polar field and the low-altitude magnetic equator crossings yields RMS residuals up to 68 nT. Attributing the residuals from the offset-dipole field to axial degree 3 and 4 contributions we estimate that the Gauss coefficient magnitudes for the additional terms are less than 4% and 7%, respectively, relative to the dipole. The axial alignment and prominent quadrupole are consistent with a non-convecting layer above a deep dynamo in Mercury's fluid outer core.

Combining remote and in-situ observations to learn about CME evolution

MESSENGER observations of plasma signatures in Mercury's northern magnetospheric cusp

We examine the global field‐aligned current (FAC) topology associated with a clear substorm on the 16 February 2010. We show that for this particular substorm there is a clear and localised reduction in the FACs observed by AMPERE at least 6 minutes prior to auroral onset. A new auroral arc forms in the region of reduced FAC and on closed field lines which subsequently brightens and expands poleward, signifying the start of the substorm expansion phase. We argue that the change in FACs observed prior to onset is the result of a change in the magnetosphere‐ionosphere (M‐I) coupling in a region local to the subsequent auroral onset. Such a change implies an important role for M‐I coupling in destabilising the near‐Earth tail during magnetospheric substorms and perhaps more importantly in selecting the location in the ionosphere where auroral onset begins.

Reduction in field‐aligned currents preceding and local to auroral substorm onset

[1] Geomagnetic field-aligned currents from the Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE) satellite mission are used to drive the Thermosphere-Ionosphere-Electrodynamics General Circulation Model (TIEGCM). We present a comparison between ground magnetic signatures computed by the model and observations at four different geomagnetic observatories, for different magnetic disturbance levels. Results show the ability of the model to pick up the gross features of the magnetic variations, improving its performance with increasing disturbance level and from low to high latitudes. During geomagnetically quiescent conditions a baseline noise of about 5 nT is evident in reconstructed ground magnetic field signatures, which we attribute to the baseline noise level in the AMPERE currents. For variations shorter than about 30 min the modeled signals are often significantly lower than observed by a factor up to 3 to 4, possibly reflecting localized ionization structures not captured in the TIEGCM conductance modules, or missing small-scale and rapid temporal variations in auroral currents. While the observed horizontal field variations are reflected in the model, the vertical component is consistently underestimated, possibly indicating errors in the estimates for ground induction currents. Comparison with the standard version of the TIEGCM is also carried out, showing that time variations shorter than 6 h and down to the 10 min resolution of the AMPERE data (which do not appear in the standard version of TIEGCM) are now reflected in the AMPERE-driven model.

Forcing the TIEGCM model with Birkeland currents from the Active Magnetosphere and Planetary Electrodynamics Response Experiment

(1) University of Michigan, Dept. Atmospheric, Oceanic and Space Sciences, Ann Arbor, USA (jaslavin@umich.edu), (2) Heliophysics Science Division, NASA Goddard Space Flight Center, Greenbelt, USA, (3) Department of Astronomy, University of Maryland, College Park, USA, (4) Goddard Earth Science and Technology Center, University of Maryland, Baltimore County, USA, (5) The Johns Hopkins University Applied Physics Laboratory, Laurel, USA, (6) Academy of Athens, Greece, (7) Laboratory for Atmospheric and Space Physics, University of Colorado, Boulder, USA, (8) Department of Terrestrial Magnetism, Carnegie Institution of Washington, Washginton, D.C., USA

MESSENGER Observations of Magnetopause Reconnection and Its Effects on Mercury's Magnetosphere

A Rocket-Borne Study of Auroral Electrodynamics within the Current Closure Ionosphere: Modeling

Messenger observations of Mercury's bow shock and upstream ultra-low frequency waves below 1-Hz

Reka Moldovan (1), Brian J. Anderson (2), Catherine L. Johnson (1,3), James A. Slavin (4), Haje Korth (2), Michael E. Purucker (4), Sean C. Solomon (5) (1) University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z4; (2) The Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA, (3) Planetary Science Institute, Tucson, AZ 85719, USA (4) NASA Goddard Space Flight Center, Greenbelt, MD 20771, USA; (5) Department of Terrestrial Magnetism, Carnegie Institution of Washington, Washington DC 20015, USA (rmoldova@eos.ubc.ca).

Mercury's magnetopause and bow shock from MESSENGER observations

obstructed by the spacecraft sunshade, a data analysis technique has been developed that recovers both bulk and thermal speeds to 10% accuracy and provides the first measurements of solar wind heavy ions (mass per charge >2 amu/e) at heliocentric distances within 0.5 AU. Solar wind alpha particles and heavy ions appear to have similar mean flow speeds at values greater than that of the protons by approximately 70% of the Alfven speed. From an examination of the thermal properties of alpha particles and heavier solar wind ions, we find a ratio of the temperature of alpha particles to that of protons nearly twice that of previously reported Helios observations, though still within the limits of excessive heating of heavy ions observed spectroscopically close to the Sun. Furthermore, examination of typical magnetic power spectra at the orbits of MESSENGER and at 1 AU reveals the lack of a strong signature of local resonant ion heating, implying that a majority of heavy ion heating could occur close to the Sun. These results demonstrate that the solar wind at � 0.3 AU is a blend of the effects of wave–particle interactions occurring in both the solar corona and the heliosphere.

Solar wind alpha particles and heavy ions in the inner heliosphere observed with MESSENGER

Long-Term Variability of Precipitation of Charged Particles on Mercury's Surface

Survey of Coherent Approximately 1 Hz Waves in Mercury's Inner Magnetosphere from MESSENGER Observations

[1] During June 16–21, 2010, an Earth-directed coronal mass ejection (CME) event was observed by instruments onboard STEREO, SOHO, MESSENGER and Wind. This event was the first direct detection of a rotating CME in the middle and outer corona. Here, we carry out a comprehensive analysis of the evolution of the CME in the interplanetary medium comparing in situ and remote observations, with analytical models and three-dimensional reconstructions. In particular, we investigate the parallel and perpendicular cross section expansion of the CME from the corona through the heliosphere up to 1 AU. We use height-time measurements and the Gradual Cylindrical Shell (GCS) technique to model the imaging observations, remove the projection effects, and derive the 3-dimensional extent of the event. Then, we compare the results with in situ analytical Magnetic Cloud (MC) models, and with geometrical predictions from past works. We find that the parallel (along the propagation plane) cross section expansion agrees well with the in situ model and with the Bothmer and Schwenn (1998) empirical relationship based on in situ observations between 0.3 and 1 AU. Our results effectively extend this empirical relationship to about 5 solar radii. The expansion of the perpendicular diameter agrees very well with the in situ results at MESSENGER (∼0.5 AU) but not at 1 AU. We also find a slightly different, from Bothmer and Schwenn (1998), empirical relationship for the perpendicular expansion. More importantly, we find no evidence that the CME undergoes a significant latitudinal over-expansion as it is commonly assumed. Instead, we find evidence that effects due to CME rotation and expansion can be easily confused in the images leading to a severe overestimation of the proper 3D size of the event. Finally, we find that the reconstructions of the CME morphology from the in situ observations at 1 AU are in agreement with the remote sensing observations but they show a big discrepancy at MESSENGER. We attribute this discrepancy to the ambiguity of selecting the proper boundaries due to the lack of accompanying plasma measurements.

Remote and in situ observations of an unusual Earth‐directed coronal mass ejection from multiple viewpoints

The Radial Variation of Interplanetary Shocks in the Inner Heliosphere: Observations by Helios, MESSENGER, and STEREO

Dynamics of the AMPERE Region 1 Birkeland current oval during storms, substorms and steady magnetospheric convection

[1] When the interplanetary magnetic field (IMF) is northward, dawnward, or duskward, magnetic merging between the IMF and the geomagnetic field occurs near the cusp of the magnetosphere. While these periods are usually considered “quiet,” they can lead to intense, but highly localized, energy deposition into the dayside ionosphere. We identify such an occurrence during a series of two geomagnetic storms on 5 April 2010. Using data from the Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE) for the first time as an input to the Assimilative Mapping of Ionospheric Electrodynamics (AMIE) algorithm, we show that during the recovery phase of the first storm there is intense ionospheric Joule heating in the dayside polar regions. This is associated with an intense field-aligned current pair near the noon meridian that is associated with northward IMF and a strong IMF By component. AMIE outputs are used to drive the thermosphere-ionosphere-mesosphere electrodynamics general circulation model to demonstrate that the intense levels of Joule heating can lead to anomalous thermospheric density enhancements and traveling disturbances.

Intense dayside Joule heating during the 5 April 2010 geomagnetic storm recovery phase observed by AMIE and AMPERE

We present a survey of Kelvi\ n-Helmholtz (KH) waves at Mercury's magnetopause during MESSENGER's first Mercury year in orb it. The waves were identified on the basis of the well-established sawtooth wave signatures that are associated with non-linear KH vortices at the magnetopause. MESSENGER frequently observed such KH waves in the dayside region of the magnetosphere where the magnetosheath flow velocity is still sub -sonic, which implies that instability growth rates at Mercury's magnetopau~ are much larger than at Earth. We attribute these greater rates to the limited wave energy dissipation in Mercury's highly resistive regolith. The wave amplitude was often on the order of ' 00 nT or more, and the wave periods were - 10- 20 s. A clear dawn-dusk asymmetry is present in the data, in that all of the observed wave events occurred in the post-noon and dusk-side sectors of the magnetopause. This asymmetry is like ly related to finite Larmor-radius effects and is in agreement with results from particle-in-cell simulations of the instability. The waves were observed almost exclusively during periods when the north-south component of the magnetosheath magnetic field was northward, a pattern similar to that for most terrestrial KH wave events. Accompanying plasma measurements show that the waves were associated with the transport of magnetosheath plasma into the magnetosphere.

MESSENGER orbital observations of large‐amplitude Kelvin‐Helmholtz waves at Mercury's magnetopause

[1] Analysis of MESSENGER magnetic field observations taken in the southern lobe of Mercury's magnetotail and the adjacent magnetosheath on 11 April 2011 indicates that a total of 163 flux transfer events (FTEs) occurred within a 25 min interval. Each FTE had a duration of ∼2–3 s and was separated in time from the next by ∼8–10 s. A range of values have been reported at Earth, with mean values near ∼1–2 min and ∼8 min, respectively. We term these intervals of quasiperiodic flux transfer events “FTE showers.” The northward and sunward orientation of the interplanetary magnetic field during this shower strongly suggests that the FTEs observed during this event formed just tailward of Mercury's southern magnetic cusp. The point of origin for the shower was confirmed with the Cooling model of FTE motion. Modeling of the individual FTE-type flux ropes in the magnetosheath indicates that these flux ropes had elliptical cross sections, a mean semimajor axis of 0.15RM (where RM is Mercury's radius, or 2440 km), and a mean axial magnetic flux of 1.25 MWb. The lobe magnetic field was relatively constant until the onset of the FTE shower, but thereafter the field magnitude decreased steadily until the spacecraft crossed the magnetopause. This decrease in magnetic field intensity is frequently observed during FTE showers. Such a decrease may be due to the diamagnetism of the new magnetosheath plasma being injected into the tail by the FTEs.

MESSENGER observations of a flux‐transfer‐event shower at Mercury

[1] Several series of large dipolarization events are documented from magnetic field observations in Mercury's magnetotail made by the MESSENGER spacecraft. The dipolarizations are identified by a rapid (∼1 s) increase in the northward component of the magnetic field, followed by a slower return (∼10 s) to pre-onset values. The changes in field strength during an event frequently reach 40 nT or higher, equivalent to an increase in the total magnetic field magnitude by a factor of ∼4 or more. The presence of spatially constrained dipolarizations at Mercury provides a key to understanding the magnetic substorm process in a new parameter regime: the dipolarization timescale, which is shorter than at Earth, is suspected to lead to efficient non-adiabatic heating of the plasma sheet proton population, and the high recurrence rate of the structures is similar to that frequently observed for flux ropes and traveling compression regions in Mercury's magnetotail. The relatively short lifetime of the events is attributed to the lack of steady field-aligned current systems at Mercury.

MESSENGER observations of dipolarization events in Mercury's magnetotail

MESSENGER and Mariner 10 Flyby Observations of Magnetotail Structure and Dynamics at Mercury

[1] We present a baseline, time-averaged model for Mercury's magnetosphere, derived from MESSENGER Magnetometer data from 24 March to 12 December 2011, comprising the spacecraft's first three Mercury years in orbit around the innermost planet. The model, constructed under the approximation that the magnetospheric shape can be represented as a paraboloid of revolution, includes two external (magnetopause and magnetotail) current systems and an internal (dipole) field and allows for reconnection. We take advantage of the geometry of the orbital Magnetometer data to estimate all but one of the model parameters, and their ranges, directly from the observations. These parameters are then used as a priori constraints in the paraboloid magnetospheric model, and the sole remaining parameter, the dipole moment, is estimated as 190 nTRM3from a grid search. We verify that the best fit dipole moment is insensitive to changes in the other parameters within their determined ranges. The model provides an excellent first-order fit to the MESSENGER observations, with a root-mean-square misfit of less than 20 nT globally. The results show that the magnetopause field strength ranges from 10% to 50% of the dipole field strength at observation locations on the dayside and at nightside latitudes north of 60°N. Globally, the residual signatures observed to date are dominated by the results of magnetospheric processes, confirming the dynamic nature of Mercury's magnetosphere.

An Analysis of the Effect of Solar Wind Drivers on the Birkeland Current Ovals Observed by AMPERE

[1] We present a survey of Kelvin-Helmholtz (KH) waves at Mercury’s magnetopause during MESSENGER’s first Mercury year in orbit. The waves were identified on the basis of the well-established sawtooth wave signatures that are associated with nonlinear KH vortices at the magnetopause. MESSENGER frequently observed such KH waves in the dayside region of the magnetosphere where the magnetosheath flow velocity is still subsonic, which implies that instability growth rates at Mercury’s magnetopause are much larger than at Earth. We attribute these greater rates to the limited wave energy dissipation in Mercury’s highly resistive regolith. The wave amplitude was often on the order of 100 nT or more, and the wave periods were 10–20 s. A clear dawn-dusk asymmetry is present in the data, in that all of the observed wave events occurred in the postnoon and duskside sectors of the magnetopause. This asymmetry is likely related to finite Larmor-radius effects and is in agreement with results from particle-in-cell simulations of the instability. The waves were observed almost exclusively during periods when the north-south component of the magnetosheath magnetic field was northward, a pattern similar to that for most terrestrial KH wave events. Accompanying plasma measurements show that the waves were associated with the transport of magnetosheath plasma into the magnetosphere.

We present a survey of Kelvin-Helmholtz ( KH ) waves at Mercury ’ s magnetopause during MESSENGER ’ s first Mercury

[1] The Energetic Particle Spectrometer (EPS) on the MESSENGER spacecraft, in orbit about Mercury since March 2011, has detected bursts of low- and moderate-energy (tens to hundreds of keV) electrons during portions of most orbits. There have been periods when such bursts were observed regularly on every orbit over a span of several weeks, and other periods when electrons were not observed for several days at a time. We have systematically characterized these energetic events on the basis of particle intensity over the 12-month period since MESSENGER began orbital operations. Now that MESSENGER has sampled most Mercury longitudes and local times, it is evident that the largest burst events were either at high northern latitudes or near local midnight. Lower-energy events were also seen near the equator but were mostly absent in both the dawn and dusk local time sectors. The high-latitude and nightside events are similar in particle intensity, spectra, and pitch angle and are interpreted to be the result of acceleration by the same mechanism. Another group of events occurred upstream of Mercury's bow shock. For two examples of this group of upstream events with good pitch angle coverage, the particles were field-aligned and traveling away from the bow shock. This group of events is interpreted to be similar to upstream events found at Earth during which particles are accelerated at the bow shock and subsequently travel upstream into the solar wind.

Spatial Distribution and Spectral Characteristics of Energetic Electrons in Mercury's Magnetosphere

[1] Localized reductions in the magnetic field associated with plasma pressure in Mercury's magnetospheric cusp and nightside plasma sheet have been routinely observed by the Magnetometer on the MErcury Surface, Space ENvironment, GEochemistry and Ranging (MESSENGER) spacecraft. We present a statistical analysis of near-equatorial magnetic depressions to derive the structure of Mercury's plasma sheet pressure. Because the plasma pressure in the magnetosphere correlates with solar wind density, the pressures were normalized to a Mercury heliocentric distance of 0.39 AU. A model magnetic field was used to map observations obtained on the ascending and descending orbit nodes to the magnetic equator and revealed the presence of plasma in a toroidal section extending on the nightside from dusk to dawn. Mapping the data to invariant magnetic latitude shows that the pressure is symmetric about the magnetic equator. The average pressure normalized for heliocentric distance is 1.45 nPa and exhibits a weak, 0.05 nPa/h, dusk-to-dawn gradient with local time. The plasma sheet pressure can vary between successive orbits by an order of magnitude. Unlike the predictions of some global simulations of Mercury's magnetosphere, the plasma enhancements do not form a closed distribution around the planet. This difference may arise from the idealized solar wind and interplanetary magnetic field conditions used in the simulations, which maximize the size and stability of the magnetosphere, thus promoting the formation of drift paths that close around the planet. For typical plasma sheet energies, 5 keV, the first adiabatic invariant for protons fails to be conserved even within 500 km altitude at midnight, implying that stochastic processes must be considered in plasma sheet transport.

Characteristics of the plasma distribution in Mercury's equatorial magnetosphere derived from MESSENGER Magnetometer observations

Polar Electrodynamics During the 14-16 July 2012 Geomagnetic Storm

Active current sheets and hot flow anomalies in Mercury's bow shock

On Hydrogen at Mercury's North Pole: Analysis of MESSENGER Neutron Spectrometer Data

MESSENGER Observations of Upstream Whistler Waves in Mercury's Foreshock Region

[1] We summarize observations by the MESSENGER spacecraft of highly coherent waves at frequencies between 0.4 and 5 Hz in Mercury's inner magnetosphere. This survey covers the time period from 24 March to 25 September 2011, or 2.1 Mercury years. These waves typically exhibit banded harmonic structure that drifts in frequency as the spacecraft traverses the magnetic equator. The waves are seen at all magnetic local times, but their observed rate of occurrence is much less on the dayside, at least in part the result of MESSENGER's orbit. On the nightside, on average, wave power is maximum near the equator and decreases with increasing magnetic latitude, consistent with an equatorial source. When the spacecraft traverses the plasma sheet during its equatorial crossings, wave power is a factor of 2 larger than for equatorial crossings that do not cross the plasma sheet. The waves are highly transverse at large magnetic latitudes but are more compressional near the equator. However, at the equator the transverse component of these waves increases relative to the compressional component as the degree of polarization decreases. Also, there is a substantial minority of events that are transverse at all magnetic latitudes, including the equator. A few of these latter events could be interpreted as ion cyclotron waves. In general, the waves tend to be strongly linear and characterized by values of the ellipticity <0.3 and wave-normal angles peaked near 90°. Their maxima in wave power at the equator coupled with their narrow-band character suggests that these waves might be generated locally in loss cone plasma characterized by high values of the ratio β of plasma pressure to magnetic pressure. Presumably both electromagnetic ion cyclotron waves and electromagnetic ion Bernstein waves can be generated by ion loss cone distributions. If proton β decreases with increasing magnetic latitude along a field line, then electromagnetic ion Bernstein waves are predicted to transition from compressional to transverse, a pattern consistent with our observations. We hypothesize that these local instabilities can lead to enhanced ion precipitation and directly feed field-line resonances.

Survey of coherent 1 Hz waves in Mercury's inner magnetosphere from MESSENGER observations

[1] The region 1 (R1) and region 2 current systems typically form concentric rings of field-aligned currents in the polar ionospheres; we term the inner ring the R1 oval. We apply an automated fitting scheme to field-aligned current densities provided by the Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE) and identify the latitude of maximum R1 current at all magnetic local times to yield the size of the R1 oval. We investigate the dynamics of the R1 oval size in response to geomagnetic activity for two cases corresponding to: repeated substorm activations with a minimally enhanced ring current; a significant ring current enhancement with multiple substorms. During the first event the dynamics of the R1 oval size reflected an expanding-contracting polar cap: during substorm growth phase dayside reconnection added open magnetic flux to the polar cap, expanding the R1 oval equatorward. Tail reconnection during the substorm expansion phase converted open into closed magnetic flux and the polar cap contracts as reflected by the poleward retreat of the R1 oval. During the period of enhanced ring current intensity the R1 oval grew to larger sizes during each substorm growth phase than it did during the other event, consistent with the suggestion that a stronger ring current stabilizes the magnetospheric tail to the onset of magnetic reconnection. The presented methodology allows AMPERE data to be condensed into a single parameter, the R1 oval size, which reflects magnetospheric dynamics and provides a convenient measure of the instantaneous magnetospheric system state in both hemispheres.

Dynamics of the region 1 Birkeland current oval derived from the Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE)

We present multi-point in situ observations of a complex sequence of coronal mass ejections (CMEs) which may serve as a benchmark event for numerical and empirical space weather prediction models. On 2010 August 1, instruments on various space missions, Solar Dynamics Observatory/Solar and Heliospheric Observatory/Solar-TErrestrial-RElations-Observatory (SDO/SOHO/STEREO), monitored several CMEs originating within tens of degrees from the solar disk center. We compare their imprints on four widely separated locations, spanning 120° in heliospheric longitude, with radial distances from the Sun ranging from MESSENGER (0.38 AU) to Venus Express (VEX, at 0.72 AU) to Wind, ACE, and ARTEMIS near Earth and STEREO-B close to 1 AU. Calculating shock and flux rope parameters at each location points to a non-spherical shape of the shock, and shows the global configuration of the interplanetary coronal mass ejections (ICMEs), which have interacted, but do not seem to have merged. VEX and STEREO-B observed similar magnetic flux ropes (MFRs), in contrast to structures at Wind. The geomagnetic storm was intense, reaching two minima in the Dst index (≈ − 100 nT), and was caused by the sheath region behind the shock and one of two observed MFRs. MESSENGER received a glancing blow of the ICMEs, and the events missed STEREO-A entirely. The observations demonstrate how sympathetic solar eruptions may immerse at least 1/3 of the heliosphere in the ecliptic with their distinct plasma and magnetic field signatures. We also emphasize the difficulties in linking the local views derived from single-spacecraft observations to a consistent global picture, pointing to possible alterations from the classical picture of ICMEs.

MULTI-POINT SHOCK AND FLUX ROPE ANALYSIS OF MULTIPLE INTERPLANETARY CORONAL MASS EJECTIONS AROUND 2010 AUGUST 1 IN THE INNER HELIOSPHERE

MESSENGER observations of the plasma depletion layer in Mercury's magnetosphere

One of the major challenges for a mission to the Jovian system is the radiation tolerance of the spacecraft (S/C) and the payload. Moreover, being able to achieve science observations with high signal to noise ratios (SNR), while passing through the high flux radiation zones, requires additional ingenuity on the part of the instrument provider. Consequently, the radiation mitigation is closely intertwined with the payload, spacecraft and trajectory design, and requires a systems-level approach. This paper presents a design for the Io Volcano Observer (IVO), a Discovery mission concept that makes multiple close encounters with Io while orbiting Jupiter. The mission aims to answer key outstanding questions about Io, especially the nature of its intense active volcanism and the internal processes that drive it. The payload includes narrow-angle and wide-angle cameras (NAC and WAC), dual fluxgate magnetometers (FGM), a thermal mapper (ThM), dual ion and neutral mass spectrometers (INMS), and dual plasma ion analyzers (PIA). The radiation mitigation is implemented by drawing upon experiences from designs and studies for missions such as the Radiation Belt Storm Probes (RBSP) and Jupiter Europa Orbiter (JEO). At the core of the radiation mitigation is IVO's inclined and highly elliptical orbit, which leads to rapid passes through the most intense radiation near Io, minimizing the total ionizing dose (177 krads behind 100 mils of Aluminum with radiation design margin (RDM) of 2 after 7 encounters). The payload and the spacecraft are designed specifically to accommodate the fast flyby velocities (e.g. the spacecraft is radioisotope powered, remaining small and agile without any flexible appendages). The science instruments, which collect the majority of the high-priority data when close to Io and thus near the peak flux, also have to mitigate transient noise in their detectors. The cameras use a combination of shielding and CMOS detectors with extremely fast readout to minimize noise. INMS microchannel plate detectors and PIA channel electron multipliers require additional shielding. The FGM is not sensitive to noise induced by energetic particles and the ThM microbolometer detector is nearly insensitive. Detailed SNR calculations are presented. To facilitate targeting agility, all of the spacecraft components are shielded separately since this approach is more mass efficient than using a radiation vault. IVO uses proven radiation-hardened parts (rated at 100 krad behind equivalent shielding of 280 mils of Aluminum with RDM of 2) and is expected to have ample mass margin to increase shielding if needed.

Io Volcano Observer's (IVO) integrated approach to optimizing system design for radiation challenges

(1) Department of Atmospheric, Oceanic and Space Sciences, University of Michigan, Ann Arbor, MI 48109, USA, (2) Heliophysics Science Division, NASA Goddard Space Flight Center, Greenbelt, MD 20771, USA, (3) Goddard Earth Sciences and Technology Center, University of Maryland, Baltimore County, Baltimore, MD 21228, USA, (4) The Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA, (5) Office of Space Research and Technology, Academy of Athens, Athens 11527, Greece, (6) Laboratory for Atmospheric and Space Physics, University of Colorado, Boulder, CO 80303, USA, (7) Department of Terrestrial Magnetism, Carnegie Institution of Washington, DC 20015, USA

Compositional variations in the distribution of plasma ions in Mercury's magnetosphere: The first Mercury year of MESSENGER observations

Global and local signatures of magnetosphere-ionosphere coupling during the growth and expansion phases of a substorm

The MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft entered a ~12-hr orbit around Mercury on 18 March 2011. Following instrument turn-on, several instruments in the payload began detecting energetic electrons with energies from ~300 keV. In addition to direct measurements with the Energetic Particle Spectrometer (EPS) component of the Energetic Particle and Plasma Spectrometer (EPPS) [1], bursts of hard X-rays have been measured in the sensors of the Gamma-Ray and Neutron Spectrometer (GRNS) [2] and soft X-rays in the X-ray Spectrometer (XRS) [3], consistent with bremsstrahlung from in situ electrons [4]. Accumulated evidence to date corroborates the XRS data from the MESSENGER flybys, as well as the inference of bursts of energetic electrons identified during the first Mercury flyby of Mariner 10 [5-7].

Energetic electron detection in Mercury's magnetosphere with the MESSENGER Gamma-Ray Spectrometer

Sean C. Solomon, Ralph L. McNutt, Jr., Peter D. Bedini, Brian J. Anderson, David T. Blewett, Larry G. Evans, Robert E. Gold, Stamatios M. Krimigis, Scott L. Murchie, Larry R. Nittler, Roger J. Phillips, Louise M. Prockter, James A. Slavin, and Maria T. Zuber, Department of Terrestrial Magnetism, Carnegie Institution of Washington, 5241 Broad Branch Road, N.W., Washington, DC 20015, USA (scs@dtm.ciw.edu); Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA; Computer Sciences Corporation, Lanham-Seabrook, MD 20706, USA; Academy of Athens, Athens 11527, Greece; Southwest Research Institute, Boulder, CO 80302, USA; Heliophysics Science Division, NASA Goddard Space Flight Center, Greenbelt, MD 20771, USA; Department of Earth, Atmospheric and Planetary Sciences, MIT, Cambridge, MA 02129, USA.

(1) Heliophysics Science Division, NASA Goddard Space Flight Center, Greenbelt, MD 20771, USA (James.A.Slavin@nasa.gov); (2) Goddard Earth Sciences and Technology Center, University of Maryland, Baltimore County, Baltimore, MD 21228, USA; (3) Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA; (4) Department of Atmospheric, Oceanic and Space Sciences, University of Michigan, Ann Arbor, Michigan, USA; and (5) Department of Terrestrial Magnetism, Carnegie Institution of Washington, 5241 Broad Branch Road, N.W., Washington, DC 20015, USA.

MESSENGER Observations of Showers of Flux Transfer Events at Mercury

Magnetic fields of the solar system: A comparative planetology toolkit

Ring Current Pressure Profiles During Geomagnetic Storms as Observed by TWINS

Abstract. We present the first ever comprehensive statistical study of the spatiotemporal characteristics of field-aligned currents in the terrestrial magnetosphere-ionosphere system using multi point measurements. We determine how the FAC density, variability and scale size are coupled. The three ST 5 satellites were in a pearls-on-a-string formation making measurements of the magnetic field with variable inter-spacecraft separations ranging from a few seconds to about 10 min. More than 4700 sets of satellite passes are analyzed using a robust correlation analysis aimed at determining the variability of the FAC system as a function of scale size and satellite spacing. We find significant differences between the FAC characteristics on the dayside and on the nightside in terms of dynamics of the current systems. On the dayside the FAC characteristics are found to be independent of IMF Bz and geomagnetic activity while the nightside indicates increased variability during disturbed conditions. The boundary separating highly and poorly correlated FACs can be fitted by a linear line for satellite separations shorter than 60 s (dayside) and 160 s (nightside). We interpret this as the dayside and nightside magnetospheric reconfiguration times respectively. For times exceeding this the FAC characteristics are suggested to be controlled by the solar wind (dayside) and plasma sheet (nightside) dynamics. Finally, the characteristics of FAC system with scale sizes larger than ~200 km (at ionospheric altitude) appear to be stable and repeatable on time scales of the order of a minute (i.e. comparable to the low-altitude orbiting satellite's traverse time across the auroral belt). In this sense, our results effectively validate the Iijima and Potemra (1978) assumption that on average the large-scale currents with scale sizes of the Region1 and Region2 are quasi-persistently significant in the transport of energy and momentum between the magnetosphere and the ionosphere.

Mariner 10 and MESSENGER spacecraft observations have established that Mercury has an intrinsic magnetic field and magnetosphere. Following the March 2011 insertion of MESSENGER into orbit around Mercury, measurements show that ions and electrons with typical energies of about 1–10 keV form an equatorially centered distribution of plasma at 1.4 RM radial distance (where RMis Mercury's radius) around a substantial portion of the planet in local time from morning through night and into the afternoon sector. Coincident with the detection of plasma around Mercury, an observed drop in the total magnetic pressure is attributable to the ion and electron thermal pressure. Additionally, intense waves near the ion cyclotron frequency were observed at the same location as the quasi‐trapped particle population, which are likely a result of anisotropic distributions created by the large loss cone (>30o) at these radial distances.

We use a nonstationary generalization of the higher-order structure function technique to investigate statistical properties of the magnetic field fluctuations recorded by MESSENGER spacecraft during its first flyby (01/14/2008) through the near Mercury's space environment, with the emphasis on key boundary regions participating in the solar wind -- magnetosphere interaction. Our analysis shows, for the first time, that kinetic-scale fluctuations play a significant role in the Mercury's magnetosphere up to the largest resolvable time scale ~20 s imposed by the signal nonstationarity, suggesting that turbulence at this planet is largely controlled by finite Larmor radius effects. In particular, we report the presence of a highly turbulent and extended foreshock system filled with packets of ULF oscillations, broad-band intermittent fluctuations in the magnetosheath, ion-kinetic turbulence in the central plasma sheet of Mercury's magnetotail, and kinetic-scale fluctuations in the inner current sheet encountered at the outbound (dawn-side) magnetopause. Overall, our measurements indicate that the Hermean magnetosphere, as well as the surrounding region, are strongly affected by non-MHD effects introduced by finite sizes of cyclotron orbits of the constituting ion species. Physical mechanisms of these effects and their potentially critical impact on the structure and dynamics of Mercury's magnetic field remain to be understood.

Kinetic-scale magnetic turbulence and finite Larmor radius effects at Mercury

Detection of energetic electrons in Mercury's magnetosphere with the MESSENGER Gamma-Ray Spectrometer

George C. Ho, Richard D. Starr, Robert E. Gold, Stamatios M. Krimigis, James A. Slavin, 5 Daniel N. Baker, Brian J. Anderson, Ralph L. McNutt, Jr., Larry R. Nittler, Sean C. Solomon 6 7 8 9 The Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA 10 Physics Department, The Catholic University of America, Washington, DC 20064, USA 11 Academy of Athens, Office of Space Research and Technology, Soranou Efesiou 4, Athens 12 11527, Greece 13 Heliophysics Science Division, NASA Goddard Space Flight Center, Greenbelt, MD 20771, 14 USA 15 Laboratory for Atmospheric and Space Physics, University of Colorado, Boulder, CO 80303, 16 USA 17 Department of Terrestrial Magnetism, Carnegie Institution of Washington, Washington, DC 18 20015, USA 19 20 DRAFT 21

Observations of Suprathermal Electrons in Mercury ’ s 2 Magnetosphere during the Three MESSENGER

The polar regions of Mercury are important sources of material for its ionized exosphere. Global measurements by MESSENGER of the fluxes of heavy ions at Mercury, particularly sodium (Na+) and oxygen (O+), exhibit distinct maxima in the northern magnetic-cusp region, indicating that polar regions are important sources of Mercury’s ionized exosphere, presumably through solar-wind sputtering near the poles. The observed fluxes of helium (He+) are more evenly distributed, indicating a more uniform source such as that expected from evaporation from a helium-saturated surface. In some regions near Mercury, especially the nightside equatorial region, the Na+ pressure can be a substantial fraction of the proton pressure.

MESSENGER Observations of the Spatial Distribution of Planetary Ions Near Mercury

MESSENGER observations of plasma ion composition at Mercury through the first 150 days of orbital observations

The magnetic cusp of a planetary magnetosphere allows solar wind plasma to gain access to the planet's magnetosphere and, for Mercury, the surface. From measurements by the MESSENGER Magnetometer we have characterized the magnetic field in the northern cusp region of Mercury. The first six months of orbital measurements indicate a mean latitudinal extent of the cusp of ∼11°, and a mean local time extent of 4.5 hrs, at spacecraft altitudes. From the average magnetic pressure deficit in the cusp, we estimate that (1.1 ± 0.6) × 1024 protons s−1 bombard the surface over an area of (5.2 ± 1.6) × 1011 m2near the northern cusp. Plasma pressures in the cusp are 40% higher when the interplanetary magnetic field (IMF) is anti‐sunward than when it is sunward. The influence of the IMF direction does not overcome the north‐south asymmetry of Mercury's internal field, and particle flux to the surface near the southern cusp is predicted to be a factor of 4 greater than in the north. The higher particle flux impacting the surface in the south should lead to a greater exospheric source from the south and a higher rate of space weathering than in the area of the northern cusp.

Observations of Mercury's northern cusp region with MESSENGER's Magnetometer

Displacement of Mercury's magnetic dipole implies that the surface field has a north-south asymmetry. Magnetometer data acquired by the MESSENGER spacecraft in orbit about Mercury permit the separation of internal and external magnetic field contributions. The global planetary field is represented as a southward-directed, spin-aligned, offset dipole centered on the spin axis. Positions where the cylindrical radial magnetic field component vanishes were used to map the magnetic equator and reveal an offset of 484 ± 11 kilometers northward of the geographic equator. The magnetic axis is tilted by less than 3° from the rotation axis. A magnetopause and tail-current model was defined by using 332 magnetopause crossing locations. Residuals of the net external and offset-dipole fields from observations north of 30°N yield a best-fit planetary moment of 195 ± 10 nanotesla-RM3, where RM is Mercury’s mean radius.

The Global Magnetic Field of Mercury from MESSENGER Orbital Observations

Reconstruction of propagating Kelvin–Helmholtz vortices at Mercury's magnetopause

Brian J. Anderson (1), Catherine L. Johnson (2,3), Haje Korth (1), Michael E. Purucker (4), Reka Moldovan (2), Sean C. Solomon (5), and Ralph L. McNutt, Jr. (1) (1) The Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA; (2) University of British Columbia, Vancouver, BC, Canada V6T 1Z4; (3) Planetary Science Institute, Tucson, AZ 85719; (4) Goddard Space Flight Center, Greenbelt, MD 20771, USA; (5) Department of Terrestrial Magnetism, Carnegie Institution of Washington, Washington DC 20015, USA (brian.anderson@jhuapl.edu / Fax: +01-240-2280386).

Since insertion of the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft into orbit around Mercury on 18 March 2011, the probe's Magnetometer has routinely observed localized reductions of the magnetic field magnitude below the level predicted by a planetary dipole model corrected for magnetospheric magnetic fields. These magnetic depressions are observed on almost every orbit, and the latitude at which they are observed is local‐time dependent. The depression signatures are indicators of the presence of enhanced plasma pressures, which inflate the magnetic field locally to maintain pressure balance, thus lowering the magnetic flux density. Mapping the magnetic depressions in local time and latitude provides insight into the plasma distribution near the planet, which complements that provided by MESSENGER's Fast Imaging Plasma Spectrometer. The spatial distribution shows that magnetic depressions are concentrated in two distinct regions, one near the equator on the nightside and another at high latitudes principally on the dayside. Here we focus on the nightside, equatorial pressure signatures, which we attribute to the magnetotail plasma sheet. The plasma‐sheet pressures extend from dusk to dawn and are offset northward from the planetary geographic equator by about 10° in latitude, commensurate with the offset of the planetary dipole. The pressures associated with the plasma‐sheet depressions range from 0.1 to 3 nPa and are systematically higher at dawn than at dusk. Proton gradient‐curvature and convection drift in Mercury's dipole magnetic field with a dawn‐to‐dusk electric field result in low drift velocities near dawn, leading to systematically higher densities and pressures at dawn than at dusk, consistent with the observations.

Plasma pressure in Mercury's equatorial magnetosphere derived from MESSENGER Magnetometer observations

Structure of Mercury's magnetosphere during MESSENGER's first three months in orbit

On January 29, 2009, two identically instrumented sounding rockets were launched into a sub-storm auroral arc from Poker Flat Alaska. Labeled the Auroral Currents and Electrodynamics Structure (ACES) mission, the payloads were launched to different apogees (approx.350km and approx.120km) and staggered in time so as to optimize their magnetic conjunctions. The different altitudes provided simultaneous in-situ measurements of magnetospheric input and output to the ionosphere and the ionospheric response in the lower F and E region. Measurements included 3-axis magnetic field, 2-axis electric field nominally perpendicular to the magnetic field, energetic particles, electron and ion, up to 15keV, cold plasma temperature and density. In addition, PFISR was also operating in a special designed mode to measure electric field and density profiles in the plane defined by the rocket trajectories and laterally to either side of the trajectories. Observation of the measured currents and electrodynamics structure of the auroral form encountered are presented in the context of standard auroral models and the temporal/spatial limitations of mission designs.

Auroral Current and Electrodynamics Structure Measured by Two SOunding Rockets in Flight Simultaneously

George C. Ho (1), Stamatios M. Krimigis (1, 2), Ralph L. McNutt, Jr. (1), Robert E. Gold (1), James A. Slavin (3), Daniel N. Baker (4), Brian J. Anderson (1), Haje Korth (1), Richard D. Starr (5), and Sean C. Solomon (6), (1) The Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA; (2) Academy of Athens, Office of Space Research and Technology, Soranou Efesiou 4, Athens 11527, Greece; (3) Heliophysics Science Division, NASA Goddard Space Flight Center, Greenbelt, MD 20771, USA; (4) Laboratory for Atmospheric and Space Physics, University of Colorado, Boulder, CO 80303, USA; (5) Physics Department, The Catholic University of America, Washington, DC 20064, USA; (6) Department of Terrestrial Magnetism, Carnegie Institution of Washington, Washington, DC 20015, USA (george.ho@jhuapl.edu / Fax: +1-240-228-7083).

Kinetic-Scale Magnetic Fluctuations in the Near-Mercury Space Environment

Abstract. Spatial distributions of the large-scale Birkeland currents derived from magnetic field data acquired by the constellation of Iridium Communications satellites have been compared with global-magnetosphere magneto-hydrodynamic (MHD) simulations. The Iridium data, spanning the interval from February 1999 to December 2007, were first sorted into 45°-wide bins of the interplanetary magnetic field (IMF) clock angle, and the dependencies of the Birkeland currents on solar wind electric field magnitude, Eyz, ram pressure, psw, and Alfven Mach number, MA, were then examined within each bin. The simulations have been conducted at the publicly-accessible Community Coordinated Modeling Center using the University of Michigan Space Weather modeling Framework, which features a global magnetosphere model coupled to the Rice Convection Model. In excess of 120 simulations with steady-state conditions were executed to yield the dependencies of the Birkeland currents on the solar wind and IMF parameters of the coupled model. Averaged over all IMF orientations, the simulation reproduces the Iridium statistical Birkeland current distributions with a two-dimensional correlation coefficient of about 0.8, and the total current agrees with the climatology averages to within 10%. The total current for individual events regularly exceeds those computed from statistical distributions by factors of ≥2, resulting in larger disparities between observations and simulations. The simulation results also qualitatively reflect the observed increases in total current with increasing Eyz and psw, but the model underestimates the rate of increase by up to 50%. The equatorward expansion and shift of the large-scale currents toward noon observed for increasing Eyz are also evident in the simulation current patterns. Consistent with the observations, the simulation does not show a significant dependence of the total current on MA.

Comparison of the observed dependence of large-scale Birkeland currents on solar wind parameters with that obtained from global simulations

Sean C. Solomon, Ralph L. McNutt, Jr., Peter D. Bedini, Brian J. Anderson, David T. Blewett, Larry G. Evans, Robert E. Gold, Stamatios M. Krimigis, Scott L. Murchie, Larry R. Nittler, Roger J. Phillips, Louise M. Prockter, James A. Slavin, and Maria T. Zuber, Department of Terrestrial Magnetism, Carnegie Institution of Washington, 5241 Broad Branch Road, N.W., Washington, DC 20015, USA (scs@dtm.ciw.edu); Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA; Computer Sciences Corporation, Lanham-Seabrook, MD 20706, USA; Academy of Athens, Athens 11527, Greece; Southwest Research Institute, Boulder, CO 80302, USA; Heliophysics Science Division, NASA Goddard Space Flight Center, Greenbelt, MD 20771, USA; Department of Earth, Atmospheric, and Planetary Sciences, MIT, Cambridge, MA 02129, USA.

MESSENGER AT MERCURY: FLYBY ACCOMPLISHMENTS AND ORBITAL OBSERVING PLANS

Michael E. Purucker (1), Catherine L. Johnson (2,3), Reka Moldovan (2), Maria T. Zuber (4), Sean C. Solomon (5), Brian J. Anderson (6), Haje Korth (6), David A. Paige (7), James A. Slavin (1), Igor I. Alexeev (8), and Roger J. Phillips (9) (1) Goddard Space Flight Center, Greenbelt, MD 20771, USA; (2) University of British Columbia, Vancouver, BC, Canada V6T 1Z4; (3) Planetary Science Institute, Tucson, AZ 85719; (4) Department of Earth, Atmospheric, and Planetary Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; (5) Department of Terrestrial Magnetism, Carnegie Institution of Washington, Washington, DC 20015, USA; (6) The John Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA; (7) Dept. of Earth and Space Sciences, UCLA, Los Angeles, CA 90095, USA; (8) Lomonosov Moscow State University, Moscow, Russia; (9) Planetary Science Directorate, Southwest Research Institute, Boulder, CO 80302, USA (Michael.e.purucker@nasa.gov / Fax: +01-301-614-6522).

A search for a crustal magnetization signature of variations in insolation at Mercury

The interplanetary magnetic field environment at Mercury's orbit

Structure of Mercury's Global Magnetic Field Determined from MESSENGER Orbital Observations

Torbjörn Sundberg (1), Scott A. Boardsen (1,2), James A. Slavin (1), Brian J. Anderson (3), Haje Korth (3), Thomas H. Zurbuchen (4), Jim M. Raines (4), and Sean C. Solomon (5) (1) Heliophysics Science Division, NASA Goddard Space Flight Center, Greenbelt, MD 20771, USA; (2) Goddard Earth Sciences and Technology Center, University of Maryland, Baltimore County, MD 21228, USA; (3) Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA; (4) Department of Atmospheric, Oceanic and Space Sciences, University of Michigan, Ann Arbor, MI 48109, USA; (5) Department of Terrestrial Magnetism, Carnegie Institution of Washington, Washington, DC 20015, USA (torbjorn.sundberg@nasa.gov).

MESSENGER observations of large-amplitude Kelvin-Helmholtz waves at Mercury's magnetopause

Distribution of ~1 Hz ULF Waves in Mercury's Inner Magnetosphere

The space environment of Mercury at the times of the second and third MESSENGER flybys

Despite having an internal magnetic field, Mercury does not have a Van Allen–type radiation belt. The MESSENGER spacecraft began detecting energetic electrons with energies greater than 30 kilo–electron volts (keV) shortly after its insertion into orbit about Mercury. In contrast, no energetic protons were observed. The energetic electrons arrive as bursts lasting from seconds to hours and are most intense close to the planet, distributed in latitude from the equator to the north pole, and present at most local times. Energies can exceed 200 keV but often exhibit cutoffs near 100 keV. Angular distributions of the electrons about the magnetic field suggest that they do not execute complete drift paths around the planet. This set of characteristics demonstrates that Mercury’s weak magnetic field does not support Van Allen–type radiation belts, unlike all other planets in the solar system with internal magnetic fields.

MESSENGER Observations of Transient Bursts of Energetic Electrons in Mercury’s Magnetosphere

The Auroral Current and Electrodynamics Structure (ACES) mission consisted of two sounding rockets launched nearly simultaneously from Poker Flat Research Range, AK on January 29, 2009 into a dynamic multiple-arc aurora. The ACES rocket mission, in conjunction with the PFISR Radar, was designed to observe the three-dimensional current system of a stable auroral arc system. ACES utilized two well instrumented payloads flown along very similar magnetic field footprints, at various altitudes with small temporal separation between both payloads. ACES High, the higher altitude payload (apogee 360 km), took in-situ measurements of the plasma parameters above the current closure region to provide the input signature into the lower ionosphere. ACES Low, the low-altitude payload (apogee 130 km), took similar observations within the current closure region, where cross-field currents can flow. We present results comparing observations of the electric fields, magnetic fields, electron flux, and the electron temperature at similar magnetic footpoints between both payloads. We further present data from all-sky imagers and PFISR detailing the evolution of the auroral event as the payloads traversed regions connected by similar magnetic footpoints. Current measurements derived from the magnetometers on both payloads are further compared. We examine data from both PFISR and observations on the high-altitude payload which we interpreted as a signature of electron acceleration by means of Alfv n waves. We further examine all measurements to understand ionospheric conductivity and how energy is being deposited into the ionosphere through Joule heating. Data from ACES is compared against models of Joule heating to make inferences regarding the effect of collisions at various altitudes.

A Rocket-Base Study of Auroral Electrodynamics Within the Current Closure Ionosphere

Electron transport and precipitation at Mercury during the MESSENGER flybys: Implications for electron-stimulated desorption

Mercury is the least explored terrestrial planet, and the one subjected to the highest flux of solar radiation in the heliosphere. Its highly dynamic, miniature magnetosphere contains ions from the exosphere and solar wind, and at times may allow solar wind ions to directly impact the planet's surface. Together these features create a plasma environment that shares many features with, but is nonetheless very different from, that of Earth. The first in situ measurements of plasma ions in the Mercury space environment were made only recently, by the Fast Imaging Plasma Spectrometer (FIPS) during the MESSENGER spacecraft's three flybys of the planet in 2008-2009 as the probe was en route to insertion into orbit about Mercury earlier this year. Here. we present analysis of flyby and early orbital mission data with novel techniques that address the particular challenges inherent in these measurements. First. spacecraft structures and sensor orientation limit the FIPS field of view and allow only partial sampling of velocity distribution functions. We use a software model of FIPS sampling in velocity space to explore these effects and recover bulk parameters under certain assumptions. Second, the low densities found in the Mercury magnetosphere result in a relatively low signal-to-noise ratio for many ions. To address this issue, we apply a kernel density spread function to guide removal of background counts according to a background-signature probability map. We then assign individual counts to particular ion species with a time-of-flight forward model, taking into account energy losses in the carbon foil and other physical behavior of ions within the instrument. Using these methods, we have derived bulk plasma properties and heavy ion composition and evaluated them in the context of the Mercury magnetosphere.

[1] Using 2 Hz magnetic field data from the MESSENGER mission, we have investigated more than 300 strong narrowband ion cyclotron wave (ICW) events at a heliocentric distance of about 0.3 AU during 31 May to 9 June 2008. These nearly circularly polarized transverse waves are observed extensively and discretely in the solar wind, with a median duration of 21 s. They are preferentially observed when the magnetic field is more radial than the ambient solar wind. The waves appear both left-handed and right-handed in the spacecraft frame. Their wave frequencies in the spacecraft frame are generally larger than the local proton cyclotron frequency (fpc), with a median of 1.44 fpc. The wave power spectra do not cutoff at the local fpc. On the basis of their wave characteristics, we conclude that they are intrinsically left-handed in the solar wind frame and they are generated closer to the Sun and carried out to the spacecraft by the super Alfvenic solar wind. After removing the Doppler shift, the wave frequencies in the solar wind frame are all below the local fpc, with a median of 0.35 fpc. The ICWs propagate nearly parallel to the magnetic field, and the median wave amplitude is about 0.73 nT, 3% of the background magnetic field. We compare these observations with earlier Helios observations at 0.3 AU in 1976 and contemporary 1 AU observations.

Observations of ion cyclotron waves in the solar wind near 0.3 AU

Magnetic field investigation of Mercury's magnetosphere and the inner heliosphere by MMO/MGF

The fluxgate magnetometer of the BepiColombo Mercury Planetary Orbiter

. clicking here colleagues, clients, or customers by , you can order high-quality copies for your If you wish to distribute this article to others . here following the guidelines can be obtained by Permission to republish or repurpose articles or portions of articles (this information is current as of August 6, 2010 ): The following resources related to this article are available online at www.sciencemag.org http://www.sciencemag.org/cgi/content/full/329/5992/662 version of this article at: including high-resolution figures, can be found in the online Updated information and services, http://www.sciencemag.org/cgi/content/full/329/5992/662/DC1 can be found at: Supporting Online Material http://www.sciencemag.org/cgi/content/full/329/5992/662#otherarticles , 2 of which can be accessed for free: cites 37 articles This article http://www.sciencemag.org/cgi/collection/physics Physics : subject collections This article appears in the following

Angular Momentum Variables Quantum Correlations in Optical Angle Orbital

MESSENGER's Third Set of Messages MESSENGER, the spacecraft en route to insertion into orbit about Mercury in March 2011, completed its third flyby of the planet on 29 September 2009. Prockter et al. (p. 668, published online 15 July) present imaging data acquired during this flyby, showing that volcanism on Mercury has extended to much more recent times than previously assumed. The temporal extent of volcanic activity and, in particular, the timing of most recent activity had been missing ingredients in the understanding of Mercury's global thermal evolution. Slavin et al. (p. 665, published online 15 July) report on magnetic field measurements made during the 29 September flyby, when Mercury's magnetosphere underwent extremely strong coupling with the solar wind. The planet's tail magnetic field increased and then decreased by factors of 2 to 3.5 during periods lasting 2 to 3 minutes. These observations suggest that magnetic open flux loads the magnetosphere, which is subsequently unloaded by substorms—magnetic disturbances during which energy is rapidly released in the magnetotail. At Earth, changes in tail magnetic field intensity during the loading/unloading cycle are much smaller and occur on much longer time scales. Vervack et al. (p. 672, published online 15 July) used the Mercury Atmospheric and Surface Composition Spectrometer onboard MESSENGER to make measurements of Mercury's neutral and ion exospheres. Differences in the altitude profiles of magnesium, calcium, and sodium over the north and south poles of Mercury indicate that multiple processes are at play to create and maintain the exosphere. Mercury’s exosphere is more varied and more intertwined with its magnetospheric environment than previously thought. During MESSENGER’s third flyby of Mercury, the Mercury Atmospheric and Surface Composition Spectrometer detected emission from ionized calcium concentrated 1 to 2 Mercury radii tailward of the planet. This measurement provides evidence for tailward magnetospheric convection of photoions produced inside the magnetosphere. Observations of neutral sodium, calcium, and magnesium above the planet’s north and south poles reveal altitude distributions that are distinct for each species. A two-component sodium distribution and markedly different magnesium distributions above the two poles are direct indications that multiple processes control the distribution of even single species in Mercury’s exosphere.

Mercury’s Complex Exosphere: Results from MESSENGER’s Third Flyby

MESSENGER Observations of Mercury's Dynamic Magnetosphere During Three Flybys

MESSENGER's Third Set of Messages MESSENGER, the spacecraft en route to insertion into orbit about Mercury in March 2011, completed its third flyby of the planet on 29 September 2009. Prockter et al. (p. 668, published online 15 July) present imaging data acquired during this flyby, showing that volcanism on Mercury has extended to much more recent times than previously assumed. The temporal extent of volcanic activity and, in particular, the timing of most recent activity had been missing ingredients in the understanding of Mercury's global thermal evolution. Slavin et al. (p. 665, published online 15 July) report on magnetic field measurements made during the 29 September flyby, when Mercury's magnetosphere underwent extremely strong coupling with the solar wind. The planet's tail magnetic field increased and then decreased by factors of 2 to 3.5 during periods lasting 2 to 3 minutes. These observations suggest that magnetic open flux loads the magnetosphere, which is subsequently unloaded by substorms—magnetic disturbances during which energy is rapidly released in the magnetotail. At Earth, changes in tail magnetic field intensity during the loading/unloading cycle are much smaller and occur on much longer time scales. Vervack et al. (p. 672, published online 15 July) used the Mercury Atmospheric and Surface Composition Spectrometer onboard MESSENGER to make measurements of Mercury's neutral and ion exospheres. Differences in the altitude profiles of magnesium, calcium, and sodium over the north and south poles of Mercury indicate that multiple processes are at play to create and maintain the exosphere. Relative to Earth, Mercury’s magnetospheric substorms are more intense and occur on shorter time scales. During MESSENGER’s third flyby of Mercury, the magnetic field in the planet’s magnetic tail increased by factors of 2 to 3.5 over intervals of 2 to 3 minutes. Magnetospheric substorms at Earth are powered by similar tail loading, but the amplitude is lower by a factor of ~10 and typical durations are ~1 hour. The extreme tail loading observed at Mercury implies that the relative intensity of substorms must be much larger than at Earth. The correspondence between the duration of tail field enhancements and the characteristic time for the Dungey cycle, which describes plasma circulation through Mercury’s magnetosphere, suggests that such circulation determines the substorm time scale. A key aspect of tail unloading during terrestrial substorms is the acceleration of energetic charged particles, but no acceleration signatures were seen during the MESSENGER flyby.

MESSENGER Observations of Extreme Loading and Unloading of Mercury’s Magnetic Tail

Interplanetary Shocks in the Inner Solar System: Observations with STEREO and MESSENGER During the Deep Solar Minimum of 2008

Whole-disk spectrophotometric properties of Mercury: Synthesis of MESSENGER and ground-based observations

Mercury's interior dipole and magnetospheric current systems after the MESSENGER flybys

Observations of suprathermal electrons in Mercury's magnetosphere during the three MESSENGER flybys

Using MHD modeling to specify inner heliosphere conditions during the three MESSENGER Mercury flybys

Abstract. The spatial distributions of large-scale field-aligned Birkeland currents have been derived using magnetic field data obtained from the Iridium constellation of satellites from February 1999 to December 2007. From this database, we selected intervals that had at least 45% overlap in the large-scale currents between successive hours. The consistency in the current distributions is taken to indicate stability of the large-scale magnetosphere–ionosphere system to within the spatial and temporal resolution of the Iridium observations. The resulting data set of about 1500 two-hour intervals (4% of the data) was sorted first by the interplanetary magnetic field (IMF) GSM clock angle (arctan(By/Bz)) since this governs the spatial morphology of the currents. The Birkeland current densities were then corrected for variations in EUV-produced ionospheric conductance by normalizing the current densities to those occurring for 0° dipole tilt. To determine the dependence of the currents on other solar wind variables for a given IMF clock angle, the data were then sorted sequentially by the following parameters: the solar wind electric field in the plane normal to the Earth–Sun line, Eyz; the solar wind ram pressure; and the solar wind Alfven Mach number. The solar wind electric field is the dominant factor determining the Birkeland current intensities. The currents shift toward noon and expand equatorward with increasing solar wind electric field. The total current increases by 0.8 MA per mV m−1 increase in Eyz for southward IMF, while for northward IMF it is nearly independent of the electric field, increasing by only 0.1 MA per mV m−1 increase in Eyz. The dependence on solar wind pressure is comparatively modest. After correcting for the solar dynamo dependencies in intensity and distribution, the total current intensity increases with solar wind dynamic pressure by 0.4 MA/nPa for southward IMF. Normalizing the Birkeland current densities to both the median solar wind electric field and dynamic pressure effects, we find no significant dependence of the Birkeland currents on solar wind Alfven Mach number.

Statistical analysis of the dependence of large-scale Birkeland currents on solar wind parameters

Six flux transfer events (FTEs) were encountered during MESSENGER's first two flybys of Mercury (M1 and M2). For M1 the interplanetary magnetic field (IMF) was predominantly northward and four FTEs with durations of 1 to 6 s were observed in the magnetosheath following southward IMF turnings. The IMF was steadily southward during M2, and an FTE 4 s in duration was observed just inside the dawn magnetopause followed ∼32 s later by a 7‐s FTE in the magnetosheath. Flux rope models were fit to the magnetic field data to determine FTE dimensions and flux content. The largest FTE observed by MESSENGER had a diameter of ∼1 RM (where RM is Mercury's radius), and its open magnetic field increased the fraction of the surface exposed to the solar wind by 10–20 percent and contributed up to ∼30 kV to the cross‐magnetospheric electric potential.

PLANET. Sean C. Solomon, Ralph L. McNutt, Jr., Brian J. Anderson, David T. Blewett, Larry G. Evans, Robert E. Gold, Stamatios M. Krimigis, Scott L. Murchie, Larry R. Nittler, Roger J. Phillips, Louise M. Prockter, James A. Slavin, Maria T. Zuber, and the MESSENGER Team, Department of Terrestrial Magnetism, Carnegie Institution of Washington, 5241 Broad Branch Road, N.W., Washington, DC 20015, USA (scs@dtm.ciw.edu); Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA; Computer Sciences Corporation, Lanham-Seabrook, MD 20706, USA; Academy of Athens, Athens 11527, Greece; Southwest Research Institute, Boulder, CO 80302, USA; Heliophysics Science Division, NASA Goddard Space Flight Center, Greenbelt, MD 20771, USA; Department of Earth, Atmospheric, and Planetary Sciences, MIT, Cambridge, MA 02129, USA.

MESSENGER's Three Flybys of Mercury: An Emerging View of the Innermost Planet

Modeling of the magnetosphere of Mercury at the time of the first MESSENGER flyby

We report the in situ observations of the ion cyclotron waves in the solar wind from 0.3 to 1 AU, using the highresolution magnetometer data from STEREO, Helios, Venus Express, and MESSENGER missions. These waves are circularly-polarized transverse waves, propagating nearly parallel to the magnetic field, and below the local proton gyro-frequency in the solar wind frame. Since we avoid planetary flybys and interplanetary shocks in our investigation, these waves are unlikely to be generated by planets or shocks. Because these waves often occur when the field is close to the radial direction, the angles between the magnetic field and the solar wind velocity are small, these waves are unlikely to be generated by pickup ions. Although the waves appear both left-handed and right-handed in the spacecraft frame, their characteristics suggest they are all intrinsically left-handed waves in the solar wind frame. We propose these waves are all generated closer to the Sun and carried out by the super-Alfvenic solar wind, and the different handedness is due to inward or outward propagation with respect to the solar wind. We analyze the wave properties of each event to obtain the statistics of the wave power and wave frequency from 0.3 to 1 AU. By comparing these wave properties at different distances, we try to constrain further their evolution and their generation mechanism.

Observations of Ion Cyclotron Waves in the Solar Wind from 0.3 to 1 AU

AMPERE: Project Implementation Overview and Initial Results (Invited)

During the third MESSENGER flyby of Mercury on 29 September 2009, 15 crossings of the dusk‐side magnetopause were observed in the magnetic field data over a 2‐min period, during which the spacecraft traveled a distance of 0.2 RM (where RM is Mercury's radius). The quasi‐periodic nature of the magnetic field variations during the crossings, the characteristic time separations of ∼16 s between pairs of crossings, and the variations of the magnetopause normal directions indicate that the signals are likely the signature of surface waves highly steepened at their leading edge that arose from the Kelvin‐Helmholtz instability. At Earth, the Kelvin‐Helmholtz instability is believed to lead to the turbulent transport of solar wind plasma into Earth's plasma sheet. This solar wind entry mechanism could also be important at Mercury.

Observations of Kelvin‐Helmholtz waves along the dusk‐side boundary of Mercury's magnetosphere during MESSENGER's third flyby

Mercury’s magnetospheric magnetic field after the first two MESSENGER flybys

MESSENGER Observations of Reconnection and its Effects on Mercury's MagnetosphereJames A. Slavin (1), Brian J. Anderson (2), Daniel N. Baker (3), Mehdi Benna(4,5), Scott A.Boardsen (1,5), George GIoeckler (6,7), Robert E. Gold (2), George C. Ho (2), Suzanne M. Imber(1,5), Haje Korth (2), Stamatios M. Krimigis (2,8), Ralph L. McNutt, Jr. (2), Larry R. Nittler(9).Jim M. Raines (6), Menelaos Sarantos (1 5), David Schriver (10), Sean C. Solomon (9), RichardD. Starr (11), Pavel Travnicek (12), Thomas H. Zurbuchen (7)'Heliophysics Science Division, NASA Goddard Space Flight Center, Greenbelt, MD 20771,USA; 2The Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA;Laboratory for Atmospheric and Space Physics, University of Colorado Boulder, CO 80303,USA; ¢Solar System Exploration Division, NASA Goddard Space Flight Center, Greenbelt, MD20771, USA; 'Goddard Earth Science and Technology Center, University of Maryland,Baltimore County, Baltimore, MD 21228, USA; Department of Astronomy, University ofMaryland, College Park, MD 20742, USA; 'Department of Atmospheric, Oceanic and SpaceSciences, The University of Michigan, Ann Arbor, MI 48109, USA; 8Academy of Athens,Athens 11527, Greece; ')Department of Terrestrial Magnetism, Carnegie Institution ofWashington, Washington, DC 20015, USA; 1 °lnstitute of Geophysics and Planetary Physics,University of California, Los Angeles, CA 90024, USA; ' 'Department of Physics, CatholicUniversity of America, Washington, DC 20064, USA. 'ZAstronomical Institute, Academy ofSciences of the Czech Republic, 14131 Prague, Czech Republic.During MESSENGER's second and third flybys of Mercury on October 6, 2008 and September29, 2009, respectively, southward interplanetary magnetic fields produced very intensereconnection signatures in the dayside and nightside magnetosphere and very different system-level responses. The IMF during the second flyby was continuously southward and themagnetosphere appeared very active with very large magnetic fields normal to the magnetopauseand the generation of flux transfer events at the magnetopause and plasmoids in the tail currentsheet every 30 s to 90 s. However, the strength and direction of the tail magnetic field was verystable. In contrast the third flyby experienced a variable IMF with it varying from north to southon timescales of minutes. Although the MESSENGER measurements were limited this time tothe nightside magnetosphere, numerous examples of plasmoid release in the tail werc detected,but they were not periodic. Rather, plasmoid release was highly correlated with the four largeenhancements of the tail magnetic field (i.e. by factors > 2) with durations of — 2 — 3 min. Theincreased flaring of the magnetic field during these intervals indicates that the enhancementswere caused by loading of the tail with magnetic flux transferred from the daysidemagnetosphere. New analyses of the second and third flyby observations of reconnection and itssystem-level effects will be presented. The results will be examined in light of what is knownabout the response of the Earth's magnetosphere to variable versus steady southward IMF.

MESSENGER Observations of Reconnection and Its Effects on Mercury's Magnetosphere

[1] The empirical analysis of structure and evolution of the geomagnetic field and underlying electric currents during the 8–11 March 2008 magnetospheric storm, driven by a corotating interaction region, is presented. It is based on the high-resolution geomagnetic field model TS07D (http://geomag_field.jhuapl.edu/model/) and the low-altitude mapping of field-aligned currents obtained using Iridium satellites. Compared to storms, driven by coronal mass ejections, the equatorial currents are found to be overall more dawn-dusk symmetric. Only in the early main phase a moderate hook-like westward current flowing from the Region-2 inflow area on the dawn side to the dusk/afternoon magnetopause is detected, along with an eastward current near the pre-noon magnetopause. New tail-type currents are found to dominate the storm-time magnetosphere in early main and recovery phases at the moments of strong peaks of the solar wind dynamic pressure. Similar effects, found in CME-driven storms, coincide in time with the plasma sheet density bursts. A clear distinction between the periods dominated by the partial ring current and the tail-type currents seen in the model agrees with the Iridium data that indicate a significant reduction and contraction of the field-aligned current pattern in the latter case. Overall small magnitudes of the total field-aligned currents, with rather transient enhancements, appear to be the most distinctive feature of CIR-driven storms. Comparison between the model and observations made by five THEMIS probes shows good agreement on storm timescales. Moreover, every deviation arising during a substorm reveals characteristic signatures of the tail current sheet thinning and dipolarization.

Mercury’s magnetosphere–solar wind interaction for northward and southward interplanetary magnetic field: Hybrid simulation results

During MESSENGER's third flyby of Mercury on September 29, 2009, a variable interplanetary magnetic field produced a series of several minute enhancements of the tail magnetic field hy factors of approx. 2 to 3.5. The magnetic field flaring during these intervals indicates that they result from loading of the tail with magnetic flux transferred from the dayside magnetosphere. The unloading intervals were associated with plasmoids and traveling compression regions, signatures of tail reconnection. The peak tail magnetic flux during the smallest loading events equaled 30% of the magnetic flux emanating from Mercury, and may have reached 100% for the largest event. In this case the dayside magnetic shielding is reduced and solar wind flux impacting the surface may be greatly enhanced. Despite the intensity of these events and their similarity to terrestrial substorm magnetic flux dynamics, no energetic charged particles with energies greater than 36 keV were observed.

MESSENGER Observations of Extreme Magnetic Tail Loading and Unloading During its Third Flyby of Mercury: Substorms?

Johnson, Brian J. Anderson, Haje Korth, Hideharu Uno, David T. Blewett, Terence J. Sabaka, Sean C. Solomon, and James W. Head, Raytheon at Planetary Geodynamics Laboratory, Code 698, NASA Goddard Space Flight Center, Greenbelt, MD 20771, michael.e.purucker@nasa.gov; Department of Earth and Ocean Sciences, University of British Columbia, 6339 Stores Road, Vancouver, BC, V6T 1Z4, Canada; Scripps Institution of Oceanography, 9500 Gilman Drive, La Jolla, CA 92093-0225; The Johns Hopkins University Applied Physics Laboratory, 11100 John Hopkins Road, Laurel, MD 20723-6009; Department of Terrestrial Magnetism, Carnegie Institution of Washington, 5241 Broad Branch Road, N.W., Washington, DC 20015-1305; Dept of Geological Sciences, Brown University, Providence, RI 02912

INTERNAL FIELD MODELS. Catherine L. Johnson, Hideharu Uno, Michael E. Purucker, Brian J. Anderson, Haje Korth, James A. Slavin, and Sean C. Solomon, Department of Earth and Ocean Sciences, University of British Columbia, 6339 Stores Road, Vancouver, BC, V6T 1Z4, Canada, cjohnson@eos.ubc.ca; Scripps Institution of Oceanography, 9500 Gilman Drive, La Jolla, CA 92093-0225; Raytheon at Planetary Geodynamics Lab, Code 698, NASA Goddard Space Flight Center, Greenbelt, MD 20771; The Johns Hopkins University Applied Physics Laboratory, 11100 John Hopkins Road, Laurel, MD 20723-6009; Department of Terrestrial Magnetism, Carnegie Institution of Washington, 5241 Broad Branch Road, N.W., Washington, DC 20015-1305.

Mercury's Magnetic Field: Assessing the Effects of External Fields on Internal Field Models

[1] The first flyby of Mercury by the Mercury Surface, Space Environment, Geochemistry and Ranging (MESSENGER) spacecraft occurred on 14 January 2008. In order to provide contextual information about the solar wind (SW) properties and the interplanetary magnetic field near the planet, we have used an empirical modeling technique combined with a numerical physics-based SW model. The Wang-Sheeley-Arge (WSA) method uses solar photospheric magnetic field observations (from Earth-based instruments) in order to estimate inner heliospheric conditions out to 21.5 solar radii from the Sun. This information is then used as input to the global numerical magnetohydrodynamic model, ENLIL, which calculates SW velocity, density, temperature, and magnetic field strength and polarity throughout the inner heliosphere. The present paper shows WSA-ENLIL conditions computed for the several week period encompassing the first flyby. This information is used in conjunction with MESSENGER magnetometer data (and the only limited available MESSENGER SW plasma data) to help understand the Mercury flyby results. The in situ spacecraft data, in turn, can also be used iteratively to improve the model accuracy for inner heliospheric “space weather” purposes. Looking to the future, we discuss how with such modeling we can estimate relatively continuously the SW properties near Mercury and at the cruise location of MESSENGER now, for upcoming flybys, and toward the time of spacecraft orbit insertion in 2011.

Space environment of Mercury at the time of the first MESSENGER flyby: Solar wind and interplanetary magnetic field modeling of upstream conditions

MESSENGER from Mercury The spacecraft MESSENGER passed by Mercury in October 2008, in what was the second of three fly-bys before it settles into the planet's orbit in 2011. Another spacecraft visited Mercury in the mid-1970s, which mapped 45% of the planet's surface. Now, after MESSENGER, only 10% of Mercury's surface remains to be imaged up close. Denevi et al. (p. 613) use this near-global data to look at the mechanisms that shaped Mercury's crust, which likely formed by eruption of magmas of different compositions over a long period of time. Like the Moon, Mercury's surface is dotted with impact craters. Watters et al. (p. 618) describe a well-preserved impact basin, Rembrandt, which is second in size to the largest known basin, Caloris. Unlike Caloris, Rembrandt is not completely filled by material of volcanic origin, preserving clues to its formation and evolution. It displays unique patterns of tectonic deformation, some of which result from Mercury's contraction as its interior cooled over time. Mercury's exosphere and magnetosphere were also observed (see the Perspective by Glassmeier). Magnetic reconnection is a process whereby the interplanetary magnetic field lines join the magnetospheric field lines and transfer energy from the solar wind into the magnetosphere. Slavin et al. (p. 606) report observations of intense magnetic reconnection 10 times as intense as that of Earth. McClintock et al. (p. 610) describe simultaneous, high-resolution measurements of Mg, Ca, and Na in Mercury's exosphere, which may shed light on the processes that create and maintain the exosphere. Mercury’s magnetosphere responds more strongly to the influence of the Sun’s magnetic field than does Earth’s magnetosphere. Solar wind energy transfer to planetary magnetospheres and ionospheres is controlled by magnetic reconnection, a process that determines the degree of connectivity between the interplanetary magnetic field (IMF) and a planet’s magnetic field. During MESSENGER’s second flyby of Mercury, a steady southward IMF was observed and the magnetopause was threaded by a strong magnetic field, indicating a reconnection rate ~10 times that typical at Earth. Moreover, a large flux transfer event was observed in the magnetosheath, and a plasmoid and multiple traveling compression regions were observed in Mercury’s magnetotail, all products of reconnection. These observations indicate that Mercury’s magnetosphere is much more responsive to IMF direction and dominated by the effects of reconnection than that of Earth or the other magnetized planets.

MESSENGER Observations of Magnetic Reconnection in Mercury’s Magnetosphere

A self‐consistent global three‐dimensional kinetic study of Mercury's magnetosphere is carried out examining waves and instabilities generated by ion temperature anisotropy and plasma flow. The overall structure of Mercury's upstream bow shock and magnetosheath are qualitatively very similar to those of Earth. Beam‐generated long‐wavelength oscillations are present upstream of Mercury's quasi‐parallel bow shock, whereas large‐amplitude mirror waves develop downstream of the quasi‐parallel bow shock in the magnetosheath. A train of mirror waves forms also downstream of the quasi‐perpendicular bow shock. A velocity shear near the magnetopause can lead to formation of vortex‐like structures. The magnetospheric cavity close to the planet's equatorial plane is filled with ions much hotter than the solar wind protons. A drift‐driven plasma belt close to the equator is present in the model and contains plasma with high‐temperature anisotropy, and the loss cone for charged particles in this region is large. The belt may cause diamagnetic effects superimposed on the planet's internal magnetic field and can interact with Mercury's magnetopause.

Kinetic instabilities in Mercury's magnetosphere: Three‐dimensional simulation results

Narrow‐band ultra‐low‐frequency (ULF) waves at frequencies greater than the He+ cyclotron frequency (fcHe+) were detected during MESSENGER's first two Mercury flybys. The waves were observed primarily between closest approach (CA) and the outbound magnetopause. The magnetosphere was very quiet during the first flyby (M1) and highly disturbed during the second flyby (M2); that ULF waves were observed during both flybys despite these different magnetospheric conditions is remarkable. The wave frequency structure in the boundary layer (BL) was similar between M1 and M2. Between CA and the BL, for M1 the wave frequency rose systematically from fcHe+ to the proton cyclotron frequency (fcH+), while during M2 two frequency bands were observed, one near the He++ cyclotron frequency and one near fcH+. The main difference in the waves between the two flybys, apart from their frequency structure, was their power, which was 4 to 5 times larger during M2 than during M1.

Comparison of ultra‐low‐frequency waves at Mercury under northward and southward IMF

Modeling Mercury's internal magnetic field with smooth inversions

The second MESSENGER flyby of Venus on 5 June 2007 provided a new opportunity to study the response of the induced magnetosphere of the planet to changes in the direction of the interplanetary magnetic field (IMF). At the time of the MESSENGER flyby, the European Space Agency's Venus Express spacecraft was located outside the magnetosphere and provided a monitor of solar wind conditions. Measurements by the Venus Express magnetometer show that the IMF underwent four major changes in direction and magnitude while MESSENGER was traveling through the inner magnetosphere of Venus. The response of the magnetosphere to each of these IMF changes was determined with a semi‐time‐dependant global magnetohydrodynamic (MHD) model, and the results were compared with magnetic and compositional measurements by the Magnetometer (MAG) and the Energetic Particle and Plasma Spectrometer (EPPS) on MESSENGER. Our modeling results show that this semi‐time‐dependant MHD technique produces magnetic field profiles that can account for both of the field reversals seen by MAG and the peak in the pick‐up ion density measured by EPPS. Moreover, these results reveal that the plasma sheet that confines most of the pick‐up ions has a barred disk shape and continuously rotates along the Sun‐planet axis to align its smallest dimension with the transverse direction of the IMF.

Modeling the response of the induced magnetosphere of Venus to changing IMF direction using MESSENGER and Venus Express observations

MESSENGER X-Ray Spectrometer and Energetic Particle Spectrometer Observations of Energetic Electrons during the Mercury Flybys

MESSENGER's January 14, 2008, flyby of Mercury has provided new observations of the planet's magnetosphere for northward interplanetary magnetic field (IMF). The dusk magnetopause was located inward from the mean magnetopause surface, possibly due to reduced tail magnetic flux content for IMF Bz > 0 and/or the pressure of planetary pickup ions as they respond to the dawnward – v × B electric field in the magnetosheath. Within the plasma sheet rotations of the magnetic field are observed consistent with, Kelvin–Helmholtz vortices ∼1 RM in diameter (RM is Mercury's radius). MESSENGER exited through a 1,000 km‐wide boundary layer bordered by inner and outer current sheets that resemble rotational and tangential discontinuities, respectively. The total magnetic field change across this layer is consistent with the predicted solar wind ram pressure at Mercury during the MESSENGER flyby.

MESSENGER observations of Mercury's magnetosphere during northward IMF

MHD modeling of the interaction of the magnetosphere of Mercury with the solar wind during the MESSENGER flybys

Mercury's internal magnetic field: Constraints on large- and small-scale fields of crustal origin

The suite of SECCHI optical imaging instruments on the STEREO-A spacecraft is used to track a solar storm, consisting of several coronal mass ejections (CMEs) and other coronal loops, as it propagates from the Sun into the heliosphere during May 2007. The 3-D propagation path of the largest interplanetary CME (ICME) is determined from the observations made by the SECCHI Heliospheric Imager (HI) on STEREO-A (HI-1/2A). Two parts of the CME are tracked through the SECCHI images, a bright loop and a V-shaped feature located at the rear of the event. We show that these two structures could be the result of line-of-sight integration of the light scattered by electrons located on a single flux rope. In addition to being imaged by HI, the CME is observed simultaneously by the plasma and magnetic field experiments on the Venus Express and MESSENGER spacecraft. The imaged loop and V-shaped structure bound, as expected, the flux rope observed in situ. The SECCHI images reveal that the leading loop-like structure propagated faster than the V-shaped structure, and a decrease in in situ CME speed occurred during the passage of the flux rope. We interpret this as the result of the continuous radial expansion of the flux rope as it progressed outward through the interplanetary medium. An expansion speed in the radial direction of similar to 30 km s(-1) is obtained directly from the SECCHI-HI images and is in agreement with the difference in speed of the two structures observed in situ. This paper shows that the flux rope location can be determined from white light images, which could have important space weather applications.

A solar storm observed from the Sun to Venus using the STEREO, Venus Express, and MESSENGER spacecraft

Mercury's magnetosphere-solar wind interaction under northward and southward interplanetary magnetic field during the MESSENGER flybys

The primary goal of this paper is to provide estimates of upstream solar wind plasma conditions at Mercury during the January 2008 MESSENGER flyby, based on two completely independent solar wind models. The first is a steady‐state three‐dimensional (3‐D) magnetohydrodynamic (MHD) model of the solar corona and inner heliosphere, which simulates the solar wind propagation from the source surface outward to Mercury, using synoptic charts of the photospheric magnetic field as input. The second model is a time‐dependent 1‐D MHD model of solar wind propagation that employs actual solar wind data at 1 AU as boundary conditions and propagates the solar wind backward in time to Mercury. We compare and validate the two models with each other as well as with actual magnetic field data from the MESSENGER Magnetometer instrument. Our combined method can produce the most accurate results for the solar wind speed and the sector structure of the interplanetary magnetic field.

Upstream conditions at Mercury during the first MESSENGER flyby: Results from two independent solar wind models

Abstract. The configuration of the Earth's magnetosphere under various Interplanetary Magnetic Field (IMF) and solar wind conditions alters the global distribution of Field-Aligned Currents (FACs) at the high latitude ionospheres. We use magnetic field data obtained from the Iridium constellation to extend recent studies that infer the dependence of the global FAC configuration on IMF direction and magnitude, hemisphere and season. New results are a reduced IMF By influence on the FAC configuration for the winter hemisphere and a redistribution of FAC to the nightside for winter relative to the summer hemisphere. These effects are linked to the winter ionosphere conductance distribution being dominated by localised nightside enhancement associated with ionisation from energetic particle precipitation. A comparison of an estimated open-closed field line boundary (OCFLB) with the Region 1 FAC locations shows reasonable agreement for summer FAC configurations. However, the OCFLB location is decoupled from the Region 1 FACs in winter, especially for IMF Bz>0.

Seasonal and interplanetary magnetic field dependence of the field-aligned currents for both Northern and Southern Hemispheres

MESSENGER (MErcury Surface, Space ENvironment, GEochemistry, and Ranging) is the first spacecraft to visit Mercury since the Mariner 10 flybys in 1974 and 1975 and will be the first spacecraft to orbit the innermost planet, beginning in March 2011. The science payload is designed to study all aspects of Mercury and its environment and consists of seven instruments and a radio science experiment. During the primary orbital phase of the mission, the MESSENGER team faces the challenge of scheduling science observations to meet all measurement objectives while operating in a thermally harsh environment in geometrically challenging orbits. An efficient, automated science planning and commanding system called MESSENGER SciBox has been developed to support orbital analysis and strategic planning activities prior to orbital insertion, and to schedule and command the instrument and spacecraft operation during the orbital phase. In this paper we present the architecture of MESSENGER SciBox and its application to pre-orbital simulation and inorbit operational usage.

Abstract. During geomagnetic storms relativistic electron fluxes in the outer radiation belt exhibit dynamic variability over multiple orders of magnitude. This requires radial transport of electrons across their drift shells and implies violation of their third adiabatic invariant. Radial transport is induced by the interaction of the electron drift motion with electric and magnetic field fluctuations in the ULF frequency range. It was previously shown that solar-wind driven ULF waves have long azimuthal wave lengths and thus can violate the third invariant of trapped electrons in the process of resonant interaction with their gradient-curvature motion. However, the amplitude of solar-wind driven ULF waves rapidly decreases with decreasing L. It is therefore not clear what mechanisms are responsible for fast transport rates observed inside the geosynchronous orbit. In this paper we investigate wether stormtime Pc5 waves can contribute to this process. Stormtime Pc5s have short azimuthal wave lengths and therefore cannot exhibit resonance with the the electron drift motion. However we show that stormtime Pc5s can cause localized random scattering of electron drift motion that violates the third invariant. According to our results electron interaction with stormtime Pc5s can produce rapid radial transport even as low as L≃4. Numerical simulations show that electron transport can exhibit large deviations from radial diffusion. The diffusion approximation is not valid for individual storms but only applies to the statistically averaged response of the outer belt to stormtime Pc5 waves.

Radial transport of radiation belt electrons due to stormtime Pc5 waves

Displacement and changes in distribution of Birkeland currents during disturbed conditions relative to nominal activity

MESSENGER's third flyby of Mercury en route to orbit insertion about the innermost planet took place on 29 September 2009. The earlier 14 January and 6 October 2008 encounters revealed that Mercury's magnetic field is highly dipolar and stable over the 35 years since its discovery by Mariner 10; that a structured, temporally variable exosphere extends to great altitudes on the dayside and forms a long tail in the anti-sunward direction; a cloud of planetary ions encompasses the magnetosphere from the dayside bow shock to the downstream magnetosheath and magnetotail; and that the magnetosphere undergoes extremely intense magnetic reconnect ion in response to variations in the interplanetary magnetic field. Here we report on new results derived from observations from MESSENGER's Mercury Atmospheric and Surface Composition Spectrometer (MASCS), Magnetometer (MAG), and Energetic Particle and Plasma Spectrometer (EPPS) taken during the third flyby.

Mercury's Atmosphere and Magnetosphere: MESSENGER Third Flyby Observations

The Space Environment of Mercury at the Time of the Third MESSENGER Flyby: Solar Wind and IMF Modeling of Upstream Conditions

Overview of magnetic field observations from MESSENGER's third flyby of Mercury

Observations by MESSENGER show that Mercury's magnetosphere is immersed in a comet-like cloud of planetary ions. The most abundant, Na+, is broadly distributed but exhibits flux maxima in the magnetosheath, where the local plasma flow speed is high, and near the spacecraft's closest approach, where atmospheric density should peak. The magnetic field showed reconnection signatures in the form of flux transfer events, azimuthal rotations consistent with Kelvin-Helmholtz waves along the magnetopause, and extensive ultralow-frequency wave activity. Two outbound current sheet boundaries were observed, across which the magnetic field decreased in a manner suggestive of a double magnetopause. The separation of these current layers, comparable to the gyro-radius of a Na+ pickup ion entering the magnetosphere after being accelerated in the magnetosheath, may indicate a planetary ion boundary layer.

Narrow-Band Ultra-Low-Frequency Wave Observations During the October 6, 2008, Flyby of Mercury.

Overview of magnetosphere and magnetic field observations from MESSENGER's second flyby of Mercury

MESSENGER'S 14 January 2008 encounter with Mercury has provided new observations of the magnetopause of this small magnetosphere, particularly concerning the effect of the direction of the interplanetary magnetic field (IMF) on the structure and dynamics of this boundary. The IMF was northward immediately prior to and following the passage of the MESSENGER spacecraft through Mercury's magnetosphere. However, several-minute episodes of southward IMF were observed in the magnetosheath during the inbound portion of the encounter. Evidence for reconnection at the dayside magnetopause in the form of well-developed flux transfer events (FTEs) was observed in the magnetosheath following some of these southward-B, intervals. The inbound magnetopause crossing seen in the magnetic field measurements is consistent with a transition from the magnetosheath into the plasma sheet. Immediately following MESSENGER'S entry into the magnetosphere, rotational perturbations in the magnetic field similar to those seen at the Earth in association with large-scale plasma sheet vortices driven by Kelvin-Helmholtz waves along the magnetotail boundary at the Earth were observed. The outbound magnetopause occurred during northward IMF B(sub z) and had the characteristics of a tangential discontinuity. These new observations by MESSENGER may be combined and compared with the magnetopause measurements collected by Mariner 10 to derive new understanding of the response of Mercury's magnetopause to IMF direction and its effect on the rate of solar wind energy and mass input to this small magnetosphere.

MESSENGER Observation of Mercury's Magnetopause: Structure and Dynamics

Low altitude field-aligned current densities obtained from global magnetospheric simulations are compared with two-dimensional distributions of Birkeland currents at the topside ionosphere derived from magnetic field observations by the constellation of Iridium satellites. We present the analysis of two magnetic cloud events, 17–19 August 2003 and 19–21 March 2001, where the interplanetary magnetic field (IMF) rotates slowly (~10°/h) to avoid time-aliasing in the magnetic perturbations used to calculate the Birkeland currents. In the August 2003 event the IMF rotates from southward to northward while maintaining a negative IMF B y during much of the interval. During the March 2001 event the IMF direction varies from dawnward to southward to duskward. We find that the distributions of the Birkeland current densities in the simulations agree qualitatively with the observations for northward IMF. For southward IMF, the dayside Region-1 currents are reproduced in the simulation, but appear on average 5° further poleward of their observed location, while the nightside Region-1 currents and the Region-2 currents are largely under-represented. Comparison of the observed and simulated Birkeland current distributions, which are intimately related to the plasma drifts at the ionosphere, shows that the ionospheric convection pattern in the MHD model and its dependence on the IMF orientation is essentially correct. The Birkeland total currents in the simulations are about a factor of 2 larger than observed during southward IMF. For B z >0 the disparity in the total current is reduced and the simulations for purely northward IMF agree with the observations to within 10%. The disparities in the magnitudes of the Birkeland currents between the observations and the simulation results are a combined effect of the simulation overestimating the ionospheric electric field and of the Iridium fits underestimating the magnetic perturbations. The marginal difference in the latitude resolution of the ionospheric grids in the simulations and the observations is shown to have only secondary effect on the magnitudes of the Birkeland currents. The electric potentials in the simulation for southward IMF periods are twice as large as those obtained from measurements of the plasma drift velocities by DMSP, implying that the reconnection rates in the simulation are too large.

Comparison of Birkeland current observations during two magnetic cloud events with MHD simulations

Interplanetary magnetic field measurements made as NEAR approached Earth in December 1997 have allowed us to compare a magnetic cloud like event seen by the NEAR and WIND spacecraft. The magnetic cloud seen by WIND and NEAR has temporal signatures both in magnitude and direction that indicate a similar geometry and orientation. The magnetic helicity of the cloud structure seen at NEAR is the same as at WIND. The magnitude of the field in the cloud event is consistently lower at NEAR than at WIND as expected for radial convection plus expansion. We model the field of this cloud structure at each spacecraft, obtain fits to the cloud axis as well as rates of expansion, and find that the predicted spacecraft separation distance is consistent with observations.

Flux rope modeling of an interplanetary coronal mass ejection observed at WIND and NEAR

(1) Heliophysics Science Division, NASA GSFC, Greenbelt, MD 20771, USA, (2) Solar System Exploration Division, NASA GSFC, Greenbelt, MD 20771, USA, (3) The Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA, (4) Swedish Institute of Space Physics, Kiruna, Sweden, (5) Max Planck Institute for Solar System Research, Katlenburg-Lindau, Germany, (6) Department of Atmospheric, Oceanic, and Space Sciences, University of Michigan, Ann Arbor, MI 48109, USA, (7) Department of Terrestrial Magnetism, Carnegie Institution of Washington, DC 20015, USA, and (8) Space Research Institute, Austrian Academy of Sciences, Graz, Austria

MESSENGER and Venus Express Observations of the Near-tail of Venus: Magnetic Flux Transport, Current Sheet Structure, and Flux Rope Formation

MESSENGER's First Flyby The Structure of Mercury's Magnetic Field from

Kinetic simulation of Mercury's magnetosphere compared with observations during MESSENGER's first Mercury flyby on 14 January 2008

Observations by the MESSENGER spacecraft on 14 January 2008 have revealed new features of the solar system's smallest planetary magnetosphere. The interplanetary magnetic field orientation was unfavorable for large inputs of energy from the solar wind and no evidence of magnetic substorms, internal magnetic reconnection, or energetic particle acceleration was detected. Large-scale rotations of the magnetic field were measured along the dusk flank of the magnetosphere and ultra-tow frequency waves were frequently observed beginning near closest approach. Outbound the spacecraft encountered two current-sheet boundaries across which the magnetic field intensity decreased in a step-like manner. The outer current sheet is the magnetopause boundary. The inner current sheet is similar in structure, but weaker and -1000 km closer to the planet. Between these two current sheets the magnetic field intensity is depressed by the diamagnetic effect of planetary ions created by the photo-ionization of Mercury's exosphere.

New Understanding of Mercury's Magnetosphere from MESSENGER'S First Flyby

The Space Environment of Mercury: Solar Wind and IMF Modeling of Upstream Conditions

During its first flyby of Mercury, the MESSENGER spacecraft measured the planet's near-equatorial magnetic field. The field strength is consistent to within an estimated uncertainty of 10% with that observed near the equator by Mariner 10. Centered dipole solutions yield a southward planetary moment of 230 to 290 nanotesla RM3 (where RM is Mercury's mean radius) tilted between 5° and 12° from the rotation axis. Multipole solutions yield non-dipolar contributions of 22% to 52% of the dipole field magnitude. Magnetopause and tail currents account for part of the high-order field, and plasma pressure effects may explain the remainder, so that a pure centered dipole cannot be ruled out.

The Structure of Mercury's Magnetic Field from MESSENGER's First Flyby

Validation of southern hemisphere field-aligned currents calculated from iridium magnetic field data

We present a statistical analysis of Birkeland currents derived from Iridium magnetometer data acquired in the Northern Hemisphere to determine the dependence of large-scale currents on the interplanetary magnetic field (IMF) direction. Because the Iridium data span nearly seven years, we can restrict analysis to only those intervals with sta- ble currents. We used image comparison to quantify the con- sistency between successive one-hour current distributions and selected 1550 two-hour intervals, 5% of the data, for analysis. Results include: no statistically significant aver- age currents are present poleward of 80 during southward IMF; Region-2 currents are weak and confined to latitudes >65 during northward IMF; there is marked contrast be- tween currents for northward and southward IMF but the evo- lution of the patterns is continuous with IMF rotation. The directions of flows inferred from the most poleward currents are more consistent with theoretical expectations of transport away from magnetopause reconnection than previous results. We attribute the differences to the restriction in this analysis to intervals having relatively stable distributions of current so that the data set corresponds more nearly to pure states of the system. the dynamic state of the system. The M-I system and hence the distribution and intensity of the large-scale Birkeland cur- rents is largely governed by the magnitude and direction of the interplanetary magnetic field (IMF), the solar wind speed and density, and the ionospheric conductivity. Characteriz- ing these dependencies is central to understanding driven M- I electrodynamics. Previous studies have determined global distributions of the large-scale Birkeland currents and their relationship to solar wind and IMF parameters by statistical analysis of single-satellite observations ( Iijima and Potemra, 1978; Weimer, 2001, 2005; Papitashvili et al., 2002). These studies significantly advanced our understanding of M-I cou- pling and may represent the most comprehensive analyses possible with these data. From this body of work we know that the IMF orientation is the dominant factor controlling the distribution of the currents and that while the IMF magnitude and the solar wind speed and density affect the intensity of the currents, they do not to first order alter the pattern of the

Statistical Birkeland current distributions from magnetic field observations by the Iridium constellation

(1) Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA, (2) Institut für Geophysik und Extraterrestrische Physik, Technische Universität Braunschweig, 38106 Braunschweig, Germany, (3) NASA Goddard Space Flight Center, Greenbelt, MD 20771, USA, (4) Department of Earth and Ocean Sciences, University of British Columbia, Vancouver, BC V6T 1Z4, Canada, (5) Institute of Geophysics and Planetary Physics, Scripps Institution of Oceanography, University of California, La Jolla, CA 92093, USA, (6) Department of Atmospheric, Oceanic, and Space Sciences, University of Michigan, Ann Arbor, MI 48109, USA, (7) Institute of Geophysics and Planetary Physics, University of California, Los Angeles, CA 90024, USA, (8) Astronomical Institute, Academy of Sciences of the Czech Republic, Prague, Czech Republic, (9) Department of Terrestrial Magnetism, Carnegie Institution of Washington, Washington, DC 20015, USA (haje.korth@jhuapl.edu / Fax: +1-240-228-0386)

Toward an Improved Understanding of the Magnetic Field of Mercury: Results Using Data from the First MESSENGER Flyby

(1) Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA, (2) Department of Atmospheric, Oceanic and Space Sciences, University of Michigan, Ann Arbor, MI 48109, USA, (3) Academy of Athens, Athens 11527, Greece, (4) NASA Goddard Space Flight Center, Greenbelt, MD 20771, USA, (5) Department of Physics and Astronomy, Eastern Michigan University, 303 Strong Hall, Ypsilanti, MI 48197, USA (6) Department of Astronomy, University of Maryland, College Park, MD 20742, USA, (7) Department of Terrestrial Magnetism, Carnegie Institution of Washington, Washington, DC 20015, USA (Ralph.mcnutt@jhuapl.edu / Fax: +1-443-778-0386)

Temperature of Mercury's plasma electron environment: limits from the first MESSENGER flyby

On 14 January 2008 the MESSENGER spacecraft will encounter Mercury for the first time. Depending upon the solar wind conditions, this initial flyby will return Magnetometer measurements of Mercury's magnetic field over a time interval lasting between - 30 md 60 min. Closest approach for MESSENGER is targeted for an altitude of 200 km as compared with the 707 krn and 327 km attained by Mariner 10 on 29 March 1974 and 16 March 1975, respectively. Furthermore, the differences in the MESSENGER and Mariner 10 encounter trajectories, with respect both to magnetospheric and body-fixed coordinates are highly complementary and expected to lead to significant improvements in our knowledge of Mercury's magnetic field. We present an overview of the MESSENGER magnetic field observations, an initial subtraction of the magnetic fields attributable to magnetospheric current systems from the total measured magnetic field, and an improved model of Mercury's intrinsic magnetic field. We also discuss the expected advances afforded by the two additional MESSENGER flybys, which occur in October 2008 and September 2009, as well as the orbital phase that will begin in March 201 1.

MESSENGER Measurements of Mercury's Magnetic Field during the First Flyby

During MESSENGER's first flyby of Mercury, numerous narrow‐band ultra‐low‐frequency (ULF) waves and their harmonics were detected between closest approach (CA) and the outbound magnetopause (MP) crossing. The fundamental mode was at frequencies between the He+ (fcHe+) and the H+ (fcH+) cyclotron frequencies. A boundary layer (BL) was detected before the MP crossing. The ULF frequency and amplitude increased from CA to the edge of the BL. In the BL the frequency dropped by a factor of 2, and the amplitude increased by an order of magnitude. There was a large variation in the wave‐normal angle (Ψ), with a slight tendency for Ψ to be perpendicular to the ambient magnetic field near CA and parallel away from CA. Near CA the parallel power tended to be larger than the perpendicular power, while away from CA the perpendicular power dominated. Large variations in wave polarization properties were observed.

Narrow‐band ultra‐low‐frequency wave observations by MESSENGER during its January 2008 flyby through Mercury's magnetosphere

[1] The high-latitude response of sunward E × B flow and Birkeland field-aligned currents (FAC) is analyzed for the 15 May 2005 magnetic cloud that generated a great magnetic storm (SYM-H = −305 nT at 0820 UT). The interplanetary magnetic field (IMF) clock angle, θ = arctan(By/Bz), gradually rotated from 65° to −80° during the 10-h long northward IMF period and the recovery of this storm. DMSP observations confirm a dawnward migration of a Northern Hemisphere sunward E × B flow channel (FC) between a downward and upward FAC pair. This FAC system developed during southward IMF (θ = 109°) at the poleward edge of the duskside auroral oval as part of a four-sheet FAC system 23 min before the IMF became northward. TIMED/GUVI observations show that the dawnward migration of the upward FAC coincides with a drifting transpolar auroral arc (TPA). IMAGE/WIC did not observe a TPA in the southern (winter) hemisphere. DMSP and Iridium observations are in good agreement with MHD simulation predictions of a northward IMF reorientation of high-latitude FACs. The northern FC migration was likely due to summer hemisphere conductances, a strong average IMF Bx = −35 nT and the sunward dipole tilt angle that favor a northern high-latitude reconnection mechanism for a well-organized sunward FC and FAC system migration. The storm recovery rate appeared to be related with the region 2 FAC. A fast 11.4 nT/h rate was observed for a weak or nonexistent region 2 system during the high-latitude FAC redistribution. The SYM-H recovery slowed significantly to 0.9 nT/h following the 1800 UT region 2 system recovery.

High‐latitude ionosphere convection and Birkeland current response for the 15 May 2005 magnetic storm recovery phase

[1] We study magnetic field line curvature (FLC) pitch angle scattering as a detrapping mechanism in the inner magnetosphere. In this region, changes in pitch angle from individual scattering events are usually small which allows us to use the diffusion approximation. Previous studies that have used the diffusion approximation simply calculated rough decay rates which were based either on inverse diffusion coefficients or the strong diffusion limit. Here we calculate FLC diffusion coefficients for a dipole field and use eigenfunction analysis to model the long-term behavior of particle distributions in a quiet time inner magnetosphere. The resulting pitch angle distributions are given and their decay periods are used to explore energy thresholds. Our calculations predict that the long-term pitch angle distributions are sharply peaked near 90° when the adiabaticity parameter e ≲ 1/3, but they broaden as e increases. This dependence is consistent with the expectation that at large e the pitch angle distribution will become isotropic. Because the change in pitch angle for individual particles depends strongly on e, a threshold in e is often used to demarcate the onset of nonadiabatic single particle motion. Although the distribution decay rates calculated here are also strongly dependent on e, we find that a realistic description of the division between static and diffusive regimes must account for the local bounce frequency.

Magnetic field line curvature induced pitch angle diffusion in the inner magnetosphere

MESSENGER'S 14 January 2008 encounter with Mercury will provide the first new observations of the solar wind interaction with this planet since the Mariner 10 flybys that took place over 30 years ago. The closest approach distance for this first MESSENGER flyby is targeted for an altitude of 200 km as compared with the 707 km and 327 km attained by Mariner 10 on 29 March 1974 and 16 March 1975, respectively. The locations of the bow shock and magnetopause boundaries observed by MESSENGER will be examined and compared against those found in the earlier Mariner 10 measurements and the predictions of theoretical models and numerical simulations. The structure of the magnetopause will be investigated for the presence of flux transfer events or other evidence of magnetic reconnection as will the more general implications of these new MESSENGER bow shock and magnetopause observations for the global solar wind interaction with Mercury.

J. Anderson, Mario H. Acuna, James A. Slavin, Haje Korth, Michael E. Purucker, Mehdi Benna, Catherine L. Johnson, David Schriver, Scott A. Boardsen, Sean C. Solomon, and the MESSENGER Team. Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723 (brian.anderson@jhuapl.edu); NASA Goddard Space Flight Center, Greenbelt MD, 20771; Department of Earth and Ocean Sciences, University of British Columbia, Vancouver, Canada; Institute of Geophysics and Planetary Physics, UCLA, Los Angeles, CA 90095; Department of Terrestrial Magnetism, Carnegie Institution of Washington, Washington, DC 20015.

THE MAGNETIC FIELD OF MERCURY: INSIGHTS AFTER THE FIRST MESSENGER FLYBY

Statistical Dependence of the Large-Scale Birkeland Currents on Solar Wind Parameters

Mercury's Internal Magnetic Field: Modeling Core Fields with Smooth Inversions

The response of the polar ionosphere- thermosphere (I-T) system to electromagnetic (EM) energy input is fundamentally different to that from particle precip- itation. To understand the I-T response to polar energy in- put one must know the intensities and spatial distributions of both EM and precipitation energy deposition. Moreover, since individual events typically display behavior different from statistical models, it is important to observe the global system state for specific events. We present an analysis of an event in Northern Hemisphere winter for sustained south- ward interplanetary magnetic field (IMF), 10 January 2002, 10:00-12:00 UT, for which excellent observations are avail- able from the constellation of Iridium satellites, the Super- DARN radar network, and the Far-Ultraviolet (FUV) instru- ment on the IMAGE satellite. Using data from these assets we determine the EM and particle precipitation energy fluxes to the Northern Hemisphere poleward of 60 MLAT and ex- amine their spatial distributions and intensities. The accu- racy of the global estimates are assessed quantitatively using comparisons with in-situ observations by DMSP along two orbit planes. While the location of EM power input evalu- ated from Iridium and SuperDARN data is in good agree- ment with DMSP, the magnitude estimated from DMSP ob- servations is approximately four times larger. Corrected for this underestimate, the total EM power input to the North- ern Hemisphere is 188 GW. Comparison of IMAGE FUV- derived distributions of the particle energy flux with DMSP plasma data indicates that the IMAGE FUV results similarly locate the precipitation accurately while underestimating the precipitation input somewhat. The total particle input is es- timated to be 20 GW, nearly a factor of ten lower than the EM input. We therefore expect the thermosphere response to be determined primarily by the EM input even under winter conditions, and accurate assessment of the EM energy input is therefore key to achieving a comprehensive understanding of the I-T system, particularly during active times when the energy input increases markedly and expands well equator- ward of nominal auroral latitudes.

Global observations of electromagnetic and particle energy flux for an event during northern winter with southward interplanetary magnetic field

At 23:08 UTC on 5 June 2007 the MESSENGER spacecraft reached its closest approach altitude of 338 km during its final flyby of Venus en route to its 2011 orbit insertion at Mercury. The availability of the simultaneous Venus Express solar wind and interplanetary magnetic field measurements provides a rare opportunity to examine the influence of upstream conditions on this planet's solar wind interaction. We present MESSENGER observations of new features of the Venus ‐ solar wind interaction including hot flow anomalies upstream of the bow shock, a flux rope in the near‐tail and a two‐point determination of the timescale for magnetic flux transport through this induced magnetosphere.

MESSENGER and Venus Express observations of the solar wind interaction with Venus

Stand-alone WIreless Magnetometer System: Concept Design and Development Status

[1] A technique for estimating the large-scale spatial distribution of the height-integrated electrical conductivity (conductance) of the Earth’s high-latitude ionosphere is presented. By combining satellite magnetic perturbation data with ground-based magnetometer and HF radar observations the Hall (SH) and Pedersen (SP) conductances are independently calculated. Magnetic perturbations observed at the Earth’s surface are combined with those recorded by satellites to calculate the horizontal ionospheric current (~ ?). Combined HF radar and satellite ion drift data give the ionospheric electric field ( ~?), which combined with ~ J ? allows SH and SP to be estimated from Ohm’s law. Conductance results from preliminary application of the technique to an event with a 1 hour integration time are presented. Significant uncertainties arise due to sparse ground magnetometer and electric field coverage. The resulting conductance distribution shows an enhancement in the auroral regions as expected from a statistical model conductance. However, the calculated conductance enhancement is located between the region 1 and region 2 Birkeland currents. This agrees with the statistical model data in the morning sector but disagrees in the evening sector. Comparison of the conductance results with conductance data inferred from in situ precipitating particle observations shows colocated enhancements. The calculated data also show a low (<1) Hall to Pedersen conductance ratio in regions near downward Birkeland current.

Technique: Large-scale ionospheric conductance estimated from combined satellite and ground-based electromagnetic data

Saturation of global field aligned currents observed during storms by the Iridium satellite constellation

Sean C. Solomon, Brian J. Anderson, Deborah L. Domingue, Robert E. Gold, Noam R. Izenberg, James C. Leary, James V. McAdams, William E. McClintock, Ralph L. McNutt, Jr., Gregory A. Neumann, Louise M. Prockter, Mark S. Robinson, Richard D. Starr, Tony H. Taylor, and Bobby G. Williams. Department of Terrestrial Magnetism, Carnegie Institution of Washington, Washington, DC 20015; Space Department, The Johns Hopkins University Applied Physics Laboratory, 11100 Johns Hopkins Road, Laurel, MD 20723; Laboratory for Atmospheric and Space Physics, University of Colorado, Boulder, CO 80303; NASA Goddard Space Flight Center, Greenbelt, MD 20771; Department of Geological Sciences, Northwestern University, Evanston, IL 60208; Space Navigation and Flight Dynamics Practice, KinetX, Inc., Simi Valley, CA 93065.

THE MESSENGER VENUS FLYBYS: OPPORTUNITIES FOR NEW VENUS OBSERVATIONS

Comparing OpenGGCM event simulations to observed ionospheric electrodynamics.

Numerical results on the relationship of region 2 field-aligned current and the ring current

[1] During geomagnetic storms the magnetic field of the inner magnetosphere exhibits large-scale variations over timescales from minutes to days. Being mainly controlled by the magnetic field the motion of relativistic electrons of the outer radiation belt can be highly susceptible to its variations. This paper investigates evolution of the outer belt during the 7 September 2002 storm. Evolution of electron phase space density is calculated with the use of a test-particle simulation in storm time magnetic and electric fields. The results show that storm time intensification of the ring current produces a large impact on the belt. In contrast to the conventional Dst effect the dominant effects are nonadiabatic and lead to profound and irreversible transformations of the belt. The diamagnetic influence of the partial ring current leads to expansion of electron drift orbits such that their paths intersect the magnetopause leading to rapid electron losses. About 2.5 hr after the storm onset most of the electrons outside L = 5 are lost. The partial ring current pressure also leads to an electron trap in the dayside magnetosphere where electrons stay on closed dayside drift orbits for as long as 11 hours. These sequestered electrons are reinjected into the outer belt due to partial recovery of the ring current. The third adiabatic invariant of these electrons exhibits rapid jumps and changes sign. These jumps produce localized peaks in the L*-profile of electron phase space density which have previously been considered as an observable indication of local electron acceleration.

Storm time evolution of the outer radiation belt: Transport and losses

Controlling factors of Region 2 field-aligned current and its relationship to the ring current: Model results

[1] Detailed investigations on the relationship between the ring current and Region 2 field-aligned currents (FACs) have been tenuous. Using the Comprehensive Ring Current Model (CRCM), we first studied their relationship for two GEM storm events (22 April 2001 and 21 October 2001) through model and data comparison. The simulated Region 2 FACs for two different magnetic storm events capture major characteristics of the Iridium measurements, and the simulated ENA flux has a reasonable agreement with the IMAGE/HENA data. We then examined the effects of polar cap potential drop, ionospheric conductivity, plasma sheet density and different magnetic field models on the development of Region 2 FACs, and the relationship between Region 2 FACs and the ring current, either through one of the two GEM events or the 12 August 2000 storm. It is shown that an increase in polar cap potential, ionospheric conductivity, or plasma sheet density generally results in an increase in Region 2 FACs' intensity, but Region 2 FACs display different local time and latitudinal distributions for changes in each parameter due to the different mechanisms involved. The CRCM run in the Tsyganenko 2004 magnetic field model for storm times (T04S), which includes a partial ring current, produces the dawn-dusk asymmetry in Region 2 FACs during geomagnetically active times, as reported by Anderson et al. (2005): more intense currents flow into the ionosphere around dusk, compared to those that flow out of the ionosphere around dawn, and the dusk currents shift further equatorward than do the dawn currents.

Relationship between Region 2 field‐aligned current and the ring current: Model results

Global Measurement of Birkeland Currents with Iridium: How it Works and Future Prospects

Abstract. The Birkeland currents, J||, electrically couple the high latitude ionosphere with the near Earth space environment. Approximating the spatial distribution of the Birkeland currents may be achieved using the divergence of the ionospheric electric field, , assuming zero conductance gradients such that . In this paper, electric field data derived from the Super Dual Auroral Radar Network (SuperDARN) are used to calculate , which is compared with the Birkeland current distribution derived globally from the constellation of Iridium satellites poleward of 60° magnetic latitude. We find that the assumption of zero conductance gradients is often a poor approximation. On the dayside, in regions where the SuperDARN electric field is constrained by radar returns, the agreement in the locations of regions of upward and downward current between and J|| obtained from Iridium data is reasonable with differences of less than 3° in the latitudinal location of major current features. It is also shown that away from noon, currents arising from conductance gradients can be larger than the component. By combining the estimate in regions of radar coverage with in-situ estimates of conductance gradients from DMSP satellite particle data, the agreement with the Iridium derived J|| is considerably improved. However, using an empirical model of ionospheric conductance did not account for the conductance gradient current terms. In regions where radar data are sparse or non-existent and therefore constrained by the statistical potential model the approximation does not agree with J|| calculated from Iridium data.

Comparison of large-scale Birkeland currents determined from Iridium and SuperDARN data

Comparison of Global Electromagnetic and Particle Energy Flux Distributions in the High-Latitude Ionosphere

Abstract. We present a case study of a prolonged interval of strongly northward orientation of the interplanetary magnetic field on 16 July 2000, 16:00-19:00 UT to characterize the energy exchange between the magnetosphere and ionosphere for conditions associated with minimum solar wind-magnetosphere coupling. With reconnection occurring tailward of the cusp under northward IMF conditions, the reconnection dynamo should be separated from the viscous dynamo, presumably driven by the Kelvin-Helmholtz (KH) instability. Thus, these conditions are also ideal for evaluating the contribution of a viscous interaction to the coupling process. We derive the two-dimensional distribution of the Poynting vector radial component in the northern sunlit polar ionosphere from magnetic field observations by the constellation of Iridium satellites together with drift meter and magnetometer observations from the Defense Meteorological Satellite Program (DMSP) F13 and F15 satellites. The electromagnetic energy flux is then compared with the particle energy flux obtained from auroral images taken by the far-ultraviolet (FUV) instrument on the Imager for Magnetopause to Aurora Global Exploration (IMAGE) spacecraft. The electromagnetic energy input to the ionosphere of 51 GW calculated from the Iridium/DMSP observations is eight times larger than the 6 GW due to particle precipitation all poleward of 78° MLAT. This result indicates that the energy transport is significant, particularly as it is concentrated in a small region near the magnetic pole, even under conditions traditionally considered to be quiet and is dominated by the electromagnetic flux. We estimate the contributions of the high and mid-latitude dynamos to both the Birkeland currents and electric potentials finding that high-latitude reconnection accounts for 0.8 MA and 45kV while we attribute

High-latitude electromagnetic and particle energy flux during an event with sustained strongly northward IMF

[1] Relativistic electron fluxes in the outer radiation belt exhibit highly variable complex behavior. Previous studies have established a strong correlation of electron fluxes and the inner magnetospheric ULF waves in the Pc 3–5 frequency range. Resonant interaction of ULF waves with the drift motion of radiation belt electrons violates their third adiabatic invariant and consequently leads to their radial transport. If the wave-particle interaction has a stochastic character, then the electron transport is diffusive. The goal of this paper is to analyze the impact of toroidal ULF waves on radiation belt electrons. The study is based on direct measurements of ULF electric fields on the CRRES spacecraft. We show that the electric fields of inner magnetospheric toroidal ULF waves exhibit high asymmetry in magnetic local time and have narrow-band frequency spectra. Such narrow-band waves can induce radial diffusion of energetic electrons, if an extrinsic stochasticity is introduced in the system. The quasi-periodic variations in the solar wind dynamic pressure are identified as a possible source of extrinsic stochasticity. In the asymmetric magnetic field, drifting electrons can interact with both azimuthal and radial electric field components. We derive analytically and then calculate numerically the diffusion rates associated with azimuthal and radial electric field components of the waves. It is shown that even under highly disturbed geomagnetic conditions, when the background field asymmetry is large, the diffusion rates due to the radial field component are small. At the same time, the resonant scattering of energetic electrons by the azimuthal electric field of the waves provides an efficient form of radial diffusion and therefore can play an important role in the dynamics of the outer radiation belt.

Impact of toroidal ULF waves on the outer radiation belt electrons

[1] Magnetometer data from the Iridium constellation of satellites are used to characterize storm-time global Birkeland currents. The geomagnetic storm of 1 October 2002 was driven by a slowly rotating interplanetary magnetic field (IMF) and the currents display a 3° latitude equatorward shift at dusk relative to dawn and have higher intensity at dusk. The asymmetry develops during the storm main phase and lasts to the early recovery phase, corresponding to the time of strongest ASY-H. A survey of 37 large storms, Dst minimum below −100 nT, from February 1999 through December 2004 yielded 62 two-hour intervals from 22 storms for which the Iridium data indicated sufficiently steady conditions to warrant calculation of the Birkeland currents. Statistical analysis shows that the storm-time dusk currents are shifted equatorward relative to dawn by 2.4° on average with a range of to −2.9° to 6.9°. The latitude asymmetry depends on two independent factors. First, the latitude asymmetry correlates with the maximum magnetic perturbation at noon, indicating a shift of high-latitude convection toward dawn (dusk) for positive (negative) IMF By. Second, the dusk currents shift ∼1° further equatorward and intensify ∼0.06 MA/° per 100 nT in ASY-H more than the currents at dawn. We suggest that the ion pressure associated with the partial ring current leads to stronger duskside currents and an asymmetric inflation of the magnetosphere, shifting the ionospheric projection of currents at dusk to lower latitudes.

Storm time dawn‐dusk asymmetry of the large‐scale Birkeland currents

[1] Several ground-based observational studies have reported unstructured Pc1-2 waves near and poleward of the dayside cusp. Dyrud et al. (1997) were the first to suggest that these waves originated in the high-altitude plasma mantle. We report here on simultaneous field and particle observations from the Polar satellite and from ground magnetometer data that confirm the presence of these “mantle” waves and characterize the ion distributions associated with them. Unstructured Pc1-2 waves were found to occur during 45% of the available passes of Polar across the mantle during the interval March–May 2000, during which time the orbit of Polar was near local noon as it crossed these latitudes. Poynting vector calculations using Polar electric and magnetic field data show a mixture of upward and downward energy flux in the cusp but consistently downward flux when mantle waves are observed. This is consistent with earlier observations that ground-based magnetometers can detect such mantle waves but not the more intense wave activity observed by spacecraft in the middle- and low-altitude cusp. In situ particle observations from the Hydra instrument appear to confirm the generation mechanism suggested by Dyrud et al. that cusp particles mirroring at low altitudes and then traveling outward in the plasma mantle poleward of the cusp are the source of the free energy for these waves. Quantitative estimates of ion cyclotron instability of the observed ion distributions suggest they are stable at the ≤9 RE altitudes traversed by Polar but may be reasonably inferred to be unstable in the exterior mantle, a location consistent with their observed frequency.

[1] The two-dimensional structure of thermospheric neutral composition, specifically, the atomic oxygen to molecular nitrogen column density ratio, [O/N2], is studied during the 17–24 April 2002 geomagnetic storms to understand the cause of ionospheric storms in regions equatorward of the auroral oval on an instantaneous large scale. The [O/N2] ratio is derived from the dayglow emission ratio of O I 1356 A to N2 Lyman-Birge-Hopfield (1600–1800 A) acquired from the Polar ultraviolet imager (UVI) and the total electron content (TEC), which is used to infer ionospheric storms, is derived from the phase delays of dual-band global positioning satellite (GPS) accumulated around the globe. It is found that the regions of decreasing [O/N2] generally coincided with the regions of depleted TEC during and after the development of the storms. This is consistent with previous theoretical and experimental analysis in which composition changes play a major role in the negative ionospheric storm effects. At lower latitudes, long-lived positive storm effects predicted by empirical and general circulation models were not observed. In fact, there was no noticeable change in [O/N2]. The TEC data also showed no noticeable change, except a few “short-lived,” localized positive TEC perturbations. For this particular event, the equatorward expansion of the decreased [O/N2] at the onset of the first storms was estimated to be more than 600 m/s, much faster than the typical thermospheric wind, and reached ∼30°N in 2 hours much equatorward (>25° MLAT) beyond the auroral electrojets. This result suggests that midlatitude (negative) ionospheric storms are caused by direct equatorward penetration of a reduced thermospheric [O/N2], at least during the first few hours of storms.

Neutral composition effects on ionospheric storms at middle and low latitudes

Abstract. We show results of the Lyon-Fedder-Mobarry (LFM) global MHD simulations of an event previously examined using Iridium spacecraft observations as well as DMSP and IMAGE FUV data. The event is chosen for the steady northward IMF sustained over a three-hour period during 16 July 2000. The Iridium observations showed very weak or absent Region 2 currents in the ionosphere, which makes the event favorable for global MHD modeling. Here we are interested in examining the model's performace during weak magnetospheric forcing, in particular, its ability to reproduce gross signatures of the ionospheric currents and convection pattern and energy deposition in the ionosphere both due to the Poynting flux and particle precipitation. We compare the ionospheric field-aligned current and electric potential patterns with those recovered from Iridium and DMSP observations, respectively. In addition, DMSP magnetometer data are used for comparisons of ionospheric magnetic perturbations. The electromagnetic energy flux is compared with Iridium-inferred values, while IMAGE FUV observations are utilized to verify the simulated particle energy flux.

A global MHD simulation of an event with a quasi-steady northward IMF

[1] Global magnetospheric simulation results of the field-aligned current (FAC) density at low altitudes are compared with global two-dimensional distributions of Birkeland currents at the topside ionosphere derived from magnetic field data of the Iridium satellite constellation. We present two events with opposite direction of the interplanetary magnetic field By, 23 November 1999 1400–1700 UT, By > 0, and 31 March 2000 1500–1800 UT, By < 0. In both observations and simulations the configuration of the FACs near noon displays the expected reversal of sense with latitude corresponding to the sign of By. The total Region-1 current in the simulations (2–3 MA) is larger than that derived from Iridium (1–1.5 MA), consistent with known underestimates from Iridium, but there is a deficit of Region 2 in the simulations. The poleward limit of the simulated Region-1 currents is significantly, ∼5°, poleward of the observed currents for standard resolution simulations (∼6° per grid point at 70° magnetic latitude). Doubling the simulation resolution leads to a marked improvement in the agreement with the observed spatial distribution of Region-1 FACs. Moreover, the higher resolution leads to the appearance of some Region-2 FACs in the 23 November event. The location of the inner simulation boundary, 2 RE or 3 RE, is found to have negligible effect on the distribution of Region-1 currents, but positioning the inner boundary at 3 RE can be inadequate for capturing Region-2 FACs. Nightside currents in the simulation underestimate the observed FACs. Separating FACs associated with ∇ · E, ∇ΣP, and ∇ΣH terms in the ionosphere, we find that the observed nightside currents agree well with the ∇ · E FACs and that the ∇ΣH term cancels some of the ∇ · E currents on the nightside, resulting in the discrepancy with the observations. The results imply that in addition to including a ring current module to properly account for the particle drift physics, a high simulation resolution and improved nighttime ionospheric conductivities are two factors that also need to be addressed to obtain reliable simulation results.

Intercomparison of ionospheric electrodynamics from the Iridium constellation with global MHD simulations

In a recent study of IMAGE FUV data, Frey et al. [2003] examined cases of high‐latitude dayside aurora (HiLDA) caused by precipitating electrons predominantly during northward IMF with a strongly positive IMF By component. To determine the conditions that control these auroral emissions, we examine field‐aligned currents observed by the Iridium constellation for 25 events of prolonged steady IMF orientation with both Bz and By positive. We find that localized FACs are sustained under all observed solar wind conditions, but that the occurrence of HiLDA is generally restricted to solar wind proton densities below 4 cm−3 and peak current densities higher than 0.7 μA/m2. That the solar wind density orders the occurrence of the auroral emissions indicates that magnetosheath plasma has ready access to the field lines carrying the upward current. Assuming that the magnetosheath plasma density and temperature govern the high‐altitude conditions on these field lines, we find that the intensity of the HiLDA emissions correlates with an estimate for the particle precipitation energy density based on the Knight relation, using the measured current density and the magnetosheath temperature and density.

Coupling Processes in the Inner Magnetosphere Associated with Midlatitude Red Auroras during Superstorms

Abstract. Field-aligned currents convey stress between the magnetosphere and ionosphere, and the associated low altitude magnetic and electric fields reflect the flow of electromagnetic energy to the polar ionosphere. We introduce a new technique to measure the global distribution of high latitude Poynting flux, S || , by combining electric field estimates from the Super Dual Auroral Radar Network (SuperDARN) with magnetic perturbations derived using magnetometer data from the Iridium satellite constellation. Spherical harmonic methods are used to merge the data sets and calculate S || for any magnetic local time (MLT) from the pole to 60° magnetic latitude (MLAT). The effective spatial resolutions are 2° MLAT, 2h MLT, and the time resolution is about one hour due to the telemetry rate of the Iridium magnetometer data. The technique allows for the assessment of high-latitude net S || and its spatial distribution on one hour time scales with two key advantages: (1) it yields the net S || including the contribution of neutral winds; and (2) the results are obtained without recourse to estimates of ionosphere conductivity. We present two examples, 23 November 1999, 14:00-15:00 UT, and 11 March 2000, 16:00-17:00 UT, to test the accuracy of the technique and to illustrate the distributions of S || that it gives. Comparisons with in-situ S || estimates from DMSP satellites show agreement to a few mW/m 2 and in the locations of S || enhancements to within the technique's resolution. The total electromagnetic energy flux was 50GW for these events. At auroral latitudes, S || tends to maximize in the morning and afternoon in regions less than 5° in MLAT by two hours in MLT having S || =10 to 20mW/m 2 and total power up to 10GW. The power poleward of the Region 1 currents is about one-third of the total power, indicating significant energy flux over the polar cap.

High-latitude poynting flux from combined Iridium and SuperDARN data

An interstellar "precursor" mission has been under discussion in the scientific community for at least 30 years. Fundamental scientific questions about the interaction of the Sun with the interstellar medium can only be answered with in situ measurements that such a mission can provide. The Innovative Interstellar Explorer (IIE) and its use of Radioisotope Electric Propulsion (REP) is being studied under a NASA "Vision Mission" grant. Speed is provided by a combination of a high-energy launch, using current launch vehicle technology, a Jupiter gravity assist, and long-term, low-thrust, continuous acceleration provided by an ion thruster running off electricity provided by advanced radioisotope electric generators. A payload of ten instruments with an aggregate mass of ~35 kg and requiring ~30 W has been carefully chosen to address the compelling science questions. The nominal 20-day launch window opens on 22 October 2014 followed by a Jupiter gravity assist on 5 February 2016. The REP system accelerates the spacecraft to a "burnout" speed of 7.8 AU per year at 104 AU on 13 October 2032 (Voyager 1's current speed is ~3.6 AU/yr). The spacecraft will return at least 500 bits per second from at least 200 AU ~30 years after launch. Additional (backup) launch opportunities occur every 13 months to early 2018. In addition to addressing basic heliospheric science, the mission will ensure continued information on the far-heliospheric galactic cosmic ray population after the Voyagers have fallen silent and as the era of human Mars exploration begins.

IMAGE/HENA: pressure and current distributions during the 1 October 2002 storm

Global Proton Pressure Distributions in the Inner Magnetosphere Derived by IMAGE/HENA Using Realistic Magnetic Fields and Their Relation to Birkeland Currents Measured by Iridium

In this paper we present a data‐derived model of relativistic electron flux at geosynchronous orbit. The model is driven by multiple solar wind and magnetospheric inputs and combines the deterministic approach of nonlinear dynamics with conditional probability consideration. The model is used for one‐day predictions of daily flux maxima for the years 1995–2000. The deterministic part of the model yields average prediction efficiency of 0.77 and linear correlation coefficient of 0.89. It identifies solar wind velocity and SymH index as most relevant input parameters. The probabilistic part of the model quantifies the risks of deviations from deterministic predictions as a function of average solar wind and magnetosphere conditions.

Data‐derived forecasting model for relativistic electron intensity at geosynchronous orbit

Determination of the properties of Mercury's magnetic field by the MESSENGER mission

Multiple spacecraft observations are used to examine the spatial variation of magnetic flux ropes in the interplanetary medium near 1 AU. When the observing spacecraft are close and radially aligned they observe nearly the same structure. When they are radially aligned and far apart they reveal the expansion of the ropes with heliocentric distance. When the spacecraft are azimuthally separated and the separation vector is along the rope axis, this axis is shown to be bent. The observed radial expansion is consistent with earlier Helios results.

Radial Variation of Magnetic Flux Ropes: Case Studies with ACE and NEAR

Magnetometer data from the Iridium constellation are used to study hemispheric differences in Birkeland currents. The Iridium constellation consists of 70 satellites in 780 km circular polar orbits configured in six orbit planes spaced equally in longitude. The constellation provides global coverage in both the northern and southern hemispheres. By comparing globally distributed data in the north and south obtained for exactly the same times, the effects of variability in the solar wind and magnetospheric dynamos can be removed to study inter-hemispheric differences with unprecedented accuracy. Using data for all of 2000, 2001 and 2002 we study the seasonal and diurnal variation of currents by comparing the ratio of perturbations between the north and south. These results show seasonal and diurnal variations in the relative current with approximately equal magnitude, amounting to a variation in relative current of a factor of two for each of seasonal and diurnal effects. The seasonal and diurnal amplitude as well as the seasonal variation of the diurnal currents are explained by variations in Pedersen conductivity due to solar EUV, auroral precipitation, and structure in Earth's main field at auroral latitudes. The success of ionospheric conductivity in explaining the observations shows that the impedance of solar wind/magnetosphere dynamos on large scales is much smaller than the ionospheric impedance. A systematic bias for 10 percent larger magnetic perturbations in the north than in the south is attributed to hemispheric differences in the auroral oval geometry and magnetic field. The results imply that there is strong diurnal and seasonal variation in thermospheric heating and that there is systematically more thermospheric heating in the north than in the south. For free parking please park in lot DD or anywhere on levels 1-2 in lot B (the big parking garage) after 4.00 pm. Make sure that you park in a spot WITHOUT a parking meter.

Simultaneous Inter-hemisphere Comparison of Birkeland Current Magnetic Perturbations: Quantitative Tests of Conductivity Control

Comparison of Iridium determined field-aligned current patterns with IMAGE FUV observations

An Iridium Based Model of Low Altitude Field Aligned Currents with Extension to Storm-Time Conditions

Abstract The magnetometer investigation aboard the NEAR-Shoemaker spacecraft has obtained extensive magnetic field observations throughout the 433 Eros environment, from distances in excess of 100,000 km to those conducted after landing on 12 February 2001. We report the apparent absence of global scale magnetization at this asteroid ( H −1 ; natural remanent magnetization per kilogram −6 A·m 2 ·kg −1 ), orders of magnitude less than the intense magnetization attributed to S-class asteroids Gaspra and Braille. The extremely low magnetization state of 433 Eros places this object significantly below the levels generally associated with LL chondrites and undifferentiated primitive bodies, challenging our current understanding of the meteorite–asteroid connection.

NEAR Magnetic Field Observations at 433 Eros: First Measurements from the Surface of an Asteroid

Validation Tests of an Iridium Based Model of Low Altitude Field Aligned Currents

[1] Analysis of high time resolution magnetometer data from the Polar satellite and from an array of high-latitude ground stations in Antarctica has identified 20 simultaneously observed Pc 1–2 wave events in the outer dayside magnetosphere during the first 17 months of Polar operations. In contrast to most earlier satellite studies of Pc 1–2 waves, based on data from equatorial satellites near apogee which moved only slowly across L shells if at all, the initial orbit of Polar allowed it to rapidly cross outer magnetospheric L shells, but significantly away from the magnetic equator. Consistent with several previous studies of outer magnetospheric Pc 1–2 waves, the majority of these events (75%) were associated with significant compressions of the magnetosphere. Seven of the events occurred simultaneously in satellite and ground data, with wave bursts temporally associated with compressions. These events, most at L values > 9, confirm the suggestion of Anderson and Hamilton [1993] that the outer dayside magnetosphere is often near marginal stability for electromagnetic ion cyclotron (EMIC) wave generation, so waves can be stimulated by even modest magnetospheric compressions. However, 10 of the wave events (five associated with compressions, and five not) were highly localized in L shell. In these “spatially localized” cases, continuous wave emissions were seen on the ground for extended periods of time, while in space waves were observed for only a few minutes and occurred only in radially narrow regions. The noncompressional events, all spatially localized, appear to be the first examples identified in space of the class of wave events known as Pc 1–2, sustained narrowband emissions which have durations at high-latitude ground stations of the order of 10 hours in the day and dusk local time sectors. All 10 of the spatially localized events, whether compressional or not, followed intervals of at least 12 hours of sustained very quiet magnetospheric conditions. Energetic ion observations from Polar confirm earlier suggestions that drifting plasma sheet ions are the source of dayside Pc 1–2 waves in the outer dayside magnetosphere, but they also show different particle configurations for the spatially localized and temporally ordered event categories. Events in both categories occurred within radially extended regions with ring-like, moderately anisotropic distributions of ≥5 keV protons and with deep minima in the flux distributions at energies <5 keV. However, spatially localized wave events occurred only in association with radially localized regions that also contained highly anisotropic fluxes of ∼0.5–3 keV protons, at a considerable distance from the magnetospheric boundary. In contrast, no such radial structure was evident in any of the temporally ordered events, or in three “uncertain” events. The association of the spatially localized events with highly structured populations of plasma sheet protons of keV and higher energies indicates an important but unanticipated role for these protons in destabilizing plasma in the outer dayside magnetosphere, possibly through increasing the local plasma beta near the magnetic equator.

Observations of two types of Pc 1-2 pulsations in the outer dayside magnetosphere

Comparison of Iridium Determined Field-Aligned Current Patterns with MHD Simulations

IMAGE/HENA has imaged about 30 main phases of geomagnetic storms since its launch in March 2000. All of main phases show that the proton pressure preferentially builds up in the midnight to post-midnight sector, rather than the evening sector as previously expected. The most extreme skewing of the proton distributions occured when the IMF By was more than 20 nT it is probably related to the skewing of the merging lines on the dayside magnetopause, which in turn skews the ionospheric potential pattern. However, for small By the proton pressure peaks around midnight. Model results from a self consistent kinetic model agrees well with the data. This morphology is seen throughout the 10-200 keV range, which means that protons even in the 100s keV range is governed by electric field drifts. If the magnetic drift velocity of a 100 keV proton at dipole L=4 equals the electric drift velocity, the electric field has to be ∼10 mV/m. This electric field is consistent with measurement by e.g. CRRES and is probably produced by the closure of the region 2 current system through the mid-latitude ionosphere where the conductivity is low. We will show examples of the skewing and its effects on the ionosphere as measured by the Millstone Hill Radar and as inferred by field-aligned current (FAC) measured by the Irridium satellites. A method for deriving the current distribution from the global pressure distribution from HENA is currently being developed. We will compare the results of this method to the global FAC maps inferred by the Irridium measurements.

Global pressure distributions and electric fields in the inner magnetosphere inferred from IMAGE/HENA

[1] The cold, magnetized plasma in the Earth's magnetosphere supports two ultralow- frequency plasma wave modes. Both these modes may exhibit resonant oscillations in the magnetosphere cavity. Theoretical and numerical studies have predicted the existence of cavity/waveguide resonance modes, yet experimental evidence is sparse. In this paper we detail the expected structure of these modes using both one dimensional (1-D) and three-dimensional (3-D) magnetohydrodynamic (MHD) numerical models. The cavity/waveguide mode structures are examined in order to develop experimental detection methods suitable for spacecraft electric and magnetic field perturbation data. Cavity mode resonances in the 1-D model suggest a detection method based on wave polarization using the radial (bx) and field-aligned (bz) magnetic perturbations. However, when implemented, this method failed to identify cavity/waveguide modes in the magnetic field data recorded by Active Magnetospheric Particle Tracer Explorers/CCE for events that showed pronounced field line resonances in the azimuthal (by) channel. An examination of data from a 3-D MHD numerical simulation showed that the cavity/waveguide resonant signature was identified best in bz component data. Consequently, a wave mode detection method using the bz data from two spatially separated satellites is discussed. Magnetometer data examples from the ISEE 1 and 2 spacecraft show that field line resonances appear in the by data even when the coherence length of the bz data is less than 0.4 RE.

Detection of ultralow‐frequency cavity modes using spacecraft data

[1] The Iridium satellites in 780 km altitude, circular polar orbits provide continuous global monitoring of the Birkeland current system via engineering magnetometer data. These data have been used to characterize basic features of the global field-aligned currents (FACs) with a time window of 45 min and a time step of 15 min. The three sigma magnetometer data noise threshold is 93 nT on average. The fraction of measurements above the noise is used to provide one measure of the location of the auroral FACs. Measures are also presented for the mean latitude and equatorward/poleward extent of the region 1/region 2 FAC system. The equatorward latitude of region 1/region 2 FACs is anticorrelated with Kp, r = 0.68. Indices are presented for the net FAC intensity in terms of the eastward (westward) magnetic perturbation in the northern (southern) hemisphere by analogy with the AE, AU, and AL indices. The Iridium system indices show high correlation with the quick look auroral electrojet indices both in individual cases and statistically, r = +0.73 between their logarithms. Results are presented for two storms, 22–23 September 1999, Dst minimum approximately 160 nT, and 21–22 October 1999, Dst minimum approximately 230 nT, reflecting that intensification and equatorward expansion of the global FACs occur in response to southward IMF. Enhanced dynamic pressure promotes more rapid equatorial expansion, 10� in 1.5 hours for the September storm, for which the dynamic pressure was enhanced, 15–20 nPa, at southward IMF turning, as opposed to the October case, 13� over 8 hours, for which the southward turning occurred during nominal dynamic pressure, 5 nPa. In both storms the current intensity decreases to prestorm levels within an hour when the IMF turns northward or nearly horizontal, at the beginning of storm recovery. The key parameters are a useful means of accessing the Iridium system data for preliminary analyses, and the initial results provide motivation for future analyses to quantify the accuracy and reliability of products derived from the Iridium system data. INDEX TERMS: 2708 Magnetospheric Physics: Current systems (2409); 2736 Magnetospheric Physics: Magnetosphere/ionosphere interactions; 2407 Ionosphere: Auroral ionosphere (2704); 2794 Magnetospheric Physics: Instruments and techniques; 2788 Magnetospheric Physics: Storms and substorms; KEYWORDS: Iridium constellation, Birkeland field-aligned currents

Birkeland current system key parameters derived from Iridium observations: Method and initial validation results

[1] The combination of magnetic field line curvature (FLC) and weak magnetic field strength affects charged particle motion in a magnetic field by causing changes of the particle's first adiabatic invariant, μ. In this paper we refer to these changes as FLC induced μ scattering or simply μ scattering. Both large single scatterings and the cumulative effects of many small scatterings (Δμ/μ ≪ 1) influence particle populations in the Earth's magnetosphere. Because FLC-induced μ scattering is strongly dependent on the magnetic field geometry and strength, realistic magnetospheric models must be employed in order to gain a quantitative understanding of how μ scattering affects the evolution of these populations. This requires a μ-scattering model that is accurate for many different magnetic field geometries. Though several μ-scattering models have been developed previously, we demonstrate that their accuracy is limited to the simple field geometries for which they were derived. In realistic magnetic fields, there are regions where these μ-scattering models depart from Lorentz integration results by a factor of 2 or greater. The source of these discrepancies is attributed to the fact that the only magnetic field information used is the field line curvature RC and magnetic field strength B both evaluated at a single point, the magnetic equator. To generalize the analytical representation of μ scattering to a range of magnetic field geometries, we have developed a new μ-scattering model that uses two additional parameters. These are proportional to the second derivatives of the field line curvature, ∂2RC/∂S2, and the field intensity, ∂2B /∂S2, where S is the distance along the field line and the derivatives are evaluated at the magnetic equator. We have defined an error parameter that measures the fit between the model and Lorentz integration results. Using this parameter, we show that the difference between our model Δμ values and those based on Lorentz integration is, on average, only 4%; this is at least a factor of 5 less than the difference using previous analytical models. Our new model will greatly facilitate quantitative analysis of μ scattering for realistic magnetospheric magnetic field geometries including active as well as quiet conditions.

Empirical model for μ scattering caused by field line curvature in a realistic magnetosphere

The Iridium® System satellite constellation consists of 66 satellites in circular, polar, 780 km altitude orbits in six equally spaced planes. Each satellite carries an engineering magnetometer which has sufficient resolution to sense the Birkeland currents. This paper presents a spherical harmonic fitting (SHF) technique for estimating field aligned currents (FACs) using the cross track component of the magnetic field measurements from the Iridium satellites. The SHF magnetic field perturbations along with Ampere's law are used to derive the global FACs from 40° MLAT to the pole in either hemisphere. Data for 10–11 UT, 23 August, 1999 were obtained from Iridium, Defense Meteorology Satellite Program (DMSP) Fl3 and the Ultraviolet Imager (UVI) onboard the POLAR satellite. The SHF data were evaluated along the DMSP F13 track. The range of east‐west component, SHF magnetic perturbations from Iridium was (−530,465) nT compared with ( −630,634) nT from DMSP F13. The derived upward FACs ranged from −0.8 to 0.9 µAm−2. Upward FACs were co‐located with bright dayside UVI emissions.

Estimation of global field aligned currents using the iridium® System magnetometer data

The science objectives for the Near Earth Asteroid Rendezvous (NEAR) Magnetometer Experiment (MAG) are to measure a possible magnetic field of 433 Eros to 5 nT accuracy and secondarily to detect asteroid-solar wind interaction signatures. Because the MAG sensor is body mounted, achieving this accuracy required detailed analysis of spacecraft magnetic fields during cruise. Sources of magnetic contamination identified prior to launch and during cruise are: propulsion latch valves, fixed 190 nT residual held, solar arrays and power harness, variable 15 to 60 nT field, power distribution terminal board, /spl sim/30 nT field with 5 nT variations, power shunting circuitry, 1-5 nT variations, the MAG sensor survival heater, 6 nT steps and attitude control momentum wheels, and 1 nT amplitude at 0.5 to 10 Hz from each of four wheels. Analysis of cruise data was used to create accurate /spl plusmn/1 nT models for the fixed and variable fields with signals below 0.5 Hz to provide correction of the raw data. The spacecraft field corrections and MAG calibration were validated with data from the Earth swing-by of January 1997. Comparison of solar wind magnetic held measurements from the WIND spacecraft and NEAR from January 22-24, 1997, before and after the Earth swing-by maneuver, confirm that the resulting NEAR magnetic field measurements are accurate to 1-2 nT.

The Iridium system consists of >70 satellites in low altitude, 780km, polar orbits in six equally spaced orbit planes with at least eleven satellites in each plane. Each satellite carries an engineering magnetometer with 48nT resolution. Techniques have been developed at JHU/APL to process Iridium magnetic field data and obtain global maps of magnetic perturbations due to field aligned currents (FACs). The noise level in the processed data is typically 70 to 100 nT and readings above the noise level occur at high magnetic latitudes consistent with an auroral signature. Time series also display well known features characteristic of FACs. Synoptic maps derived using three hours of data from 17 February, 2000, AE ∼100–300nT, show patterns consistent with the Region 1/2 currents previously determined statistically. The Indium data set provides new global measurements of the Birkeland currents in both hemispheres on time scales of a few hours or less.

Sensing global Birkeland currents with iridium® engineering magnetometer data

in These indicate that variations in may be one of the important in explaining the strong local time variation in the thermospheric NO con-centration observed by the instrument.

Reply [to “Comment on ‘The diffuse aurora: A significant source of ionization in the middle atmosphere’ by R. A. Frahm et al.”]

Substorm-injected particles are time dispersed with pitch angle such that low pitch angle particles arrive earliest on the dayside at geosynchronous orbit, opposite the sense predicted by drift in a dipole field. In contrast to energy dispersion which is well understood, pitch angle dispersion of particle injections has not been quantitatively explained. We present a statistical analysis of energetic ion injections observed by the Active Magnetospheric Particle Tracer Explorers/Charge Composition Explorer (AMPTE/CCE) satellite, and we compare the results with model calculations of single-particle drift in realistic model magnetospheric electric and magnetic fields. The data analysis is based on observations made from August 1984 to February 1986, which cover all local times, radial distances between 5.5 and 8.8 RE, and dipole latitudes between −16° and 16° and includes over 400 events mostly beyond 8 RE. Using events observed between L = 8 and L = 9, where the effects of the satellite radial motion are minimal, we study the local time dependence of the injection delay time between different energies and pitch angles. We find that high pitch angle injection is delayed from low pitch angle injection and that the delay increases westward from the evening sector reaching ∼2 min (67° versus 23° pitch angles) at 1200 magnetic local time (MLT) at 120–220 keV. The observations are compared to proton drift calculations in static magnetic (T89c) and electric (Volland-Stern) field models. The calculations reproduce the observed drift times, pitch angle dispersion, and local time dependences, showing for the first time that sufficiently realistic magnetospheric magnetic field models can account for reverse pitch angle dispersion. Detailed examination of the curvature and gradient drift terms shows that the pitch angle dispersion is due principally to compression of the dayside magnetosphere, which preferentially suppresses the gradient and curvature drifts of near equatorially mirroring particles.

Booster concepts and liquid propulsion options for Space Shuttle upgrades

Nearly 4 months of continuous interplanetary magnetic field measurements September 1997 through December 1997 have allowed us to compare four interplanetary coronal mass ejection (ICME) events seen by the NEAR and Wind spacecraft. When the spacecraft are in close proximity (separated by 1° in azimuth relative to the sun) the ICMEs seen by Wind and NEAR have similar signatures as expected for structures with dimensions along the solar wind flow of ∼0.2 AU. When the NEAR spacecraft is separated by ∼5.4° in azimuth from the Earth the vector signature of ICMEs seen at NEAR begins to differ from those seen at Wind even though the magnitude of the field in the events and the background solar wind show similarities at the two spacecraft. When the spacecraft are separated by 11.3° the magnetic signatures are quite different and sometimes ICMEs are seen only at one of the two locations. Nevertheless, in all cases the magnetic helicity of the cloud structures seen at NEAR is the same as at Wind. The radial speeds of the shock and ICME leading edge as they cross Wind and the time delays of those events, for which we have some assurance that they also arrived at NEAR, indicate that the ICMEs decelerate measurably as they travel near 1 AU.

Intercomparison of NEAR and Wind interplanetary coronal mass ejection observations

Satellites in low-altitude orbits provide unique opportunities to study the ionospheric screening effects on ULF waves propagating from the magnetosphere. This paper presents the first report of observation of a Pi2 pulsation from the Upper Atmosphere Research Satellite (UARS) at an altitude of ∼580 km. The Pi2 pulsation occurred on November 18, 1993, when the satellite was over the Pacific near the three ground magnetometer sites, Chichijima (L = 1.14, MLT = 23), Ewa Beach (L = 1.17, MLT = 03), and Guam (L = 1.07, MLT = 23). On the ground the Pi2 was visible in the H (northward) component from 1337 to 1343 UT at all locations with the same period of 43 s but with an amplitude ranging from 2.1 nT (Guam) to 0.6 nT (Ewa Beach). At the satellite the same pulsation was detected in the H component with an amplitude of 1.7 nT. The transverse radial component and the parallel component at the satellite oscillated in phase, consistent with previous Active Magnetospheric Particle Tracer Explorers Charge Composition Explorer observations at L > 2. When the ground signals are linearly interpolated to the geographic longitude and latitude of UARS, the orientation of the major axis of polarization agreed well with that observed by UARS, as is expected for a fast-mode wave propagating through the ionosphere.

Upper Atmosphere Research Satellite observation of a Pi2 pulsation

We present data from a number of ground stations and satellites that reveal an example of a previously unreported type of global event. The event is characterized by the occurrence of monochromatic pulsations of widely varying frequencies in different regions of local times and L shells. The pulsations appear to be modulated with a ∼45 min periodicity. Simultaneously, energetic particle fluxes observed at geosynchronous orbit (with energies resulting in a drift period of ∼45 min) appear to become phase bunched and the pulsations are observed to occur coincident with minima in the particle bunching. Corresponding data from GOES 5 show an increase in the compressional component of the magnetic field with this period. Data from South Pole Station show fluctuations in the east–west component of the magnetic field at half this period, along with a weak auroral signature and riometer absorptions. We conclude that the data show the existence of a global disturbance with a compressional magnetic field signature, and we suggest that this compression induces a radial electric field, based on Faraday's law. Phase bunching of energetic electrons (due to the induction electric field) and monochromatic pulsations are consequences of the global disturbance, although the mechanism responsible for exciting the pulsations is not clear.

Evidence for a global disturbance with monochromatic pulsations and energetic electron bunching

Robust system design is the best protection against meteoroid damage. Impacts by small meteoroids are common on satellite surfaces, but impacts by meteoroids large enough to damage well designed systems are very rare. Estimating the threat from the normal meteoroid environment is difficult. Estimates for the occasional "storm" are even more uncertain. Common sense precautions are in order for the 1999 Leonids, but wide-spread catastrophic damage is highly unlikely. Strong Leonid showers are also expected in 2000 and 2001, but these pose much less threat than 1999.

T he primary objective of the Magnetic Field Instrument on the Near Earth Asteroid Rendezvous (NEAR) spacecraft is to search for and characterize the magnetic field of the asteroid Eros to better understand the origin and evolution of this planetary body. The instrument consists of a three-axis fluxgate magnetometer with a sensor mounted on the high-gain antenna feed structure of the NEAR spacecraft. It is currently operating in space and is providing measurements of the interplanetary magnetic field with a resolution of better than 1 nT. The Magnetic Field Instrument is capable of detecting a surface field at Eros of 10 nT at the 35-km altitude that will be the eventual orbit of NEAR.

Magnetic field and particle observations from the Upper Atmosphere Research Satellite particle environment monitor (UARS/PEM) are used to estimate field-aligned currents, electron precipitation energy flux, ionospheric conductivities, and Joule heating rates during the main phase of the November 4, 1993, geomagnetic storm. From 0300 to 1200 UT on November 4 the auroral oval expanded equatorward of 65° magnetic latitude (MLAT), and UARS encountered the polar cap on seven consecutive passes during the storm main phase. These passes provide data appropriate to determine field-aligned currents and estimate ionospheric Joule heating. For this storm, UARS sampled the midnight to dawn sector in the northern hemisphere and the noon to dusk sector in the southern hemisphere. The maximum net currents on the day side and nightside are comparable and reach 1 A/m for several hours. The average Joule heating rates are comparable at midnight, early morning, and noon, where they are 9.2, 6.6, and 7.7 GW/h, respectively, but have a strong peak in the late afternoon, where they are 25.6 GW/h. In contrast, the electron precipitation energy deposition is highest near midnight at 5.6 GW/h but drops to less than half this level to 2.4 GW/h and 1.9 GW/h in the early morning and at dusk, respectively, but is very small near noon, only 0.24 GW/h. The Joule to particle energy deposition rate ratio thus varies by roughly an order of magnitude with local time, being over 40 near noon, about 20 at dusk, 3 near dawn, and 2 at midnight. The hemispherical Joule and electron precipitation heating rates, HJ and Helec, are estimated to have been 290 GW and 50 GW, respectively, giving HJ/Helec = 4.5 and HJ + Helec = 340 GW. Differences between these averages and assimilative mapping of ionospheric dynamics (AMIE) results, HJ = 200 GW and Helec = 80 GW, reflect time variability during the storm and are largely resolved when AMIE results only at the times of UARS passes are considered.

Coordinated observations were made between the South Pole Station 630-nm all-sky imager and the Active Magnetospheric Particle Tracer Explorer (AMPTE) CCE satellite when it was at 9 RE apogee in the midday sector in an effort to understand the variety of dynamical changes at the magnetopause that map to the dayside aurora. On June 18, 1988, three events were observed. The first, at 1150 MLT, was a local event showing a rotation of the magnetic field and the sudden appearance of low-energy electrons indicating the satellite entering the magnetosheath or low-altitude boundary layer. This event was preceded by a type of poleward expansion of the aurora which had been previously interpreted as a possible signature/footprint of a flux transfer event (FTE). Although the magnetic field signatures at the satellite are not characteristic of an FTE, the event could be a magnetic field change produced by an FTE, which after some delay propagated to the vicinity of the satellite. The foot of the field line containing the satellite was at some distance from the south pole meridian. The second event, starting at 1610 UT (1240 MLT), was a clear case of field erosion during which the satellite entered the magnetosheath characterized by a reduction in energetic electrons, an increase in soft electrons, and a decrease in the magnetic field strength accompanied by an equatorward motion of the aurora. The third event, in the afternoon at about 1900 UT (1530 MLT), showed similar changes in the electron fluxes and similar equatorward motion of the aurora. However, this event was associated with an increase in the magnetic field at the satellite. Such a field increase could be characteristic of a pressure pulse. However, there was a corresponding equatorward motion of the aurora, which suggests that the event was also a flux erosion event in which the fringing fields of the region 1 current system, which normally cause a field depression at the subsolar region, created ah increase in the field at the CCE satellite near the late afternoon side. The latitudinal (equatorward) movements of the aurora for all three events were strongly correlated with the global AE index which was dominated by stations in the dawn/dusk sectors.

We have conducted an investigation into the relationship between magnetic field fluctuations below 100 Hz observed with the UARS and Freja magnetic field experiments and concluded that increases in this “ac” activity serve as an excellent indicator of the boundaries of large-scale field-aligned current systems. Magnetic field fluctuations in these regions generally correspond to increased electron fluxes at energies below roughly 2 keV. Using a single equatorward boundary crossing as a reference point, the statistical field-aligned current pattern of Iijima and Potemra [1978] for disturbed magnetic conditions can be extrapolated to provide an estimate of the global position of the auroral oval. Real-time in situ magnetic field measurements from high-latitude spacecraft can be used to provide a quick, simple, locator of the equatorward boundaries of the large-scale field-aligned currents, accurate to within ± 2° in latitude. A proof-of-concept implementation of this technique has been performed using magnetic field data acquired by the Freja spacecraft. Development of the automated detection algorithm, essentially a measurement of the standard deviation of the low-frequency magnetic field measurements, was aided by using UARS magnetic field data. The UARS data were binned by MLT and magnetic latitude for varying Kp conditions and demonstrated observable ac boundaries at all local times and all Kp levels. In a separate statistical study consisting of 96 UARS high-latitude observations, we determined the differences between the observed and estimated equatorward boundaries of the large-scale field-aligned current system for each high-latitude pass. This difference was within 2 deg of latitude in 53 of 96 cases, with 84 of 96 cases within 5 deg.

Identification of auroral oval boundaries from in situ magnetic field measurements

We have analyzed accounts of Leonid storms and showers occurring near the 33 year resonance to derive probabilities of the occurrence of Leonid storms as a function of time since comet nodal passage and distance to the orbit of the particle stream. Based on this analysis, we have obtained the following storm probabilities for the coming apparition: 1997 - 33%, 1998 - 60%, 1999 - 100%, and 2000 - 25%. 95% confidence bands are also computed for these years. An expression for the Leonid storm flux is derived using a simple velocity-corrected ZHR scaling to the sporadic flux, which is then compared to that obtained from observations of the 1966 Leonid storm. The two results agree to within a factor of five, provided the Kessler meteor mass-magnitude relation is used. If the Jenniskens mass-magnitude relation is adopted, then the results are more disparate, disagreeing by a full order of magnitude. From the standpoint of spacecraft risk, it would make sense to choose the more conservative of the two relations, so the expression for the Leonid storm flux is F(sub storm) = 3x 10(exp 19) ZHR m(exp -1.3), where m, the meteoroid mass, is in grams, and the flux is in units of # /m2s. Based on the historical record, we are expecting Leonid ZHR's somewhere between 1000 and 5000 in 1998 and 1999.

Estimates of Leonid Storm Probabilities and Fluxes from Historical Information

Abstract : Long-term goals include understanding the basic physics of magnetospheric and ionospheric currents and waves for the purpose of developing predictive models of magnetospheric dynamics. This requires characterizing the magnetic signatures of currents and waves detected by spaceborne magnetometers at low Earth orbit and higher altitudes.

Investigation of Disturbance Magnetic Fields from Satellite Data Due to Magnetospheric/Ionospheric Currents and Waves

Simple Monte Carlo methods have been applied to the calculation of meteoroid penetration of spacecraft surfaces to account for the distributions of impact angle and velocity on the impact mechanics. Both single sheet and double sheet surfaces have been modeled. The model has been applied to several spacecraft and spacecraft concepts to evaluate light leakage into optical instruments or through sunshades. Results indicate that surfaces are less likely to be penetrated - or will be penetrated less often - than indicated by simply assuming an "average" velocity and normal impact. The reduction is typically about 40 percent. This effect is caused by the angular dependence of the penetration mechanics. However, the probability distribution of penetrating particles is relatively broad and indicates a peak above the ballistic limit particle size associated with the average velocity case.

During the major storm of November 3–11, 1993, the UARS particle environment monitor (PEM), in a 57° inclination, 585-km circular orbit, made measurements of energetic particles, X rays, and magnetic field perturbations in the midnight-dawn magnetic local time sector of the northern hemisphere and in the noon-evening sector of the southern hemisphere. X-ray images provide a global picture (∼20-min resolution) of the electron precipitation regions twice per 90-min orbit, which were used to study morphology during the main and recovery phases of the storm. Detailed examination of the precipitating electrons measured between 5 eV and 5 MeV show that in the several hundred eV to several MeV energy range the spectra may often be represented by the kappa distribution, which has a thermal character in the keV range and a power law distribution at higher energies. Selected spectral measurements were used to calculate ionization production rates as functions of altitude. The profiles peak between 95 and 120 km, each having a secondary ledge at lower altitudes produced by the bremsstrahlung X rays. We show that the ionization thus produced can be significant at altitudes as low as the upper stratosphere. Because of the length of time over which this ionization is produced globally, it is expected to have a substantial impact on atmospheric chemistry. Global power inputs to the auroral regions due to precipitating particles have been computed for each day of the storm using PEM X-ray and particle observations. On November 4, 1993, the day that includes the main and early recovery phases of the storm, the northern hemispheric power calculated by in situ measurement of the electron fluxes was 56.8 GW; that determined by using the X-ray images was 47.4 GW, These values may be compared with the northern hemisphere Joule heating rate of 290 GW on the same day computed using the PEM magnetometer and electron flux measurements.

UARS particle environment monitor observations during the November 1993 storm: Auroral morphology, spectral characterization, and energy deposition

Although Pc3 magnetic pulsations are commonly observed in the dayside magnetosphere and are believed to propagate into the inner magnetosphere and to the ground, how and where they establish themselves as a regular oscillation are not completely understood. In particular, it is not clear whether the cavity mode plays a significant role in determining the spectral properties of Pc3 pulsations. The mode, in principle, can be identified by multipoint observations of the spatial variation of the amplitude and phase of magnetic field perturbations, with at least one satellite providing evidence of compressional magnetic field oscillation in the magnetosphere. Motivated by these requirements for detection of the cavity mode, we surveyed combined magnetic field data from the Active Magnetospheric Particle Tracer Explorers Charge Composition Explorer (AMPTE CCE) satellite and the Kakioka ground station. We identified an interval on November 4–5, 1984, during which both the satellite (dipole L = 3–6) and ground station (L = 1.25) were on the morningside (near 8-hour local time) with a small local time separation (within 0.9 hour) and observed Pc3 magnetic pulsations exhibiting a compressional component in space. Unlike previous studies, which used satellites located at L > 6, we observed high coherence in the Pc3 band between the compressional component (bz)in space and the horizontal component (H) on the ground. A cross-phase analysis of the merged bz and H time series indicates that these components oscillated in antiphase over a range of satellite radial distance. We discuss whether the observations can be taken as evidence of a cavity mode oscillation in the magnetosphere.

The Near Earth Asteroid Rendezvous spacecraft (NEAR) conducted a swingby of Earth on January 23, 1998, en route to its final destination, the asteroid 433 Eros. The spacecraft, built and managed by the Applied Physics Laboratory of Johns Hopkins University in Laurel, Maryland, and launched February 17, 1996, aboard a Delta II-7925-8 rocket from Cape Canaveral, is on a mission to further our understanding of the nature of asteroids and their role in the formation of the solar system. The spacecraft is three-axis stabilized, passively cooled, and uses four fixed solar panels to power five scientific instruments and transmit data to Earth through a 1.5 m, fixed, high-gain antenna. 
 
As the first NASA Discovery-class mission, NEAR was designed to return the maximum amount of information on a timely basis with minimal cost. Aside from the transponder that will be used to determine Eros' mass and gravity field, the science instruments are focused on understanding the geology, chemistry, and history of the target asteroid. The seven-band Multi-Spectral Imager (MSI), covering wavelengths of 0.5 to 1.1 microns, will image the entire surface of the 40 x 14 x 14 km (25 x 9 x 9 mi) asteroid, mapping its morphology and color [Hawkins et al., 1997]. The Near Infrared Spectrometer (NIS) will map out Eros' surface mineralogy using reflected sunlight in the 0.8 to 2.5 micron range [Warren et al., 1997], while the X ray/Gamma ray Spectrometers (XGRS) will determine surface elemental composition of key rock-forming species such as Mg, Al, Si, S, Ca, Fe, Ti, and K [Goldsten et al., 1997]. The NEAR magnetometer will characterize the intensity and structure of any intrinsic magnetization of Eros [Lohr et al., 1997]. Finally, the NEAR Laser Rangefinder (NLR) altimeter will measure the asteroid's topography and shape to 1 m vertical resolution with its infrared 15 mJ pulsed beam [Cole et al., 1997].

Energetic electrons can penetrate into the middle atmosphere causing excitation, dissociation, and ionization of neutral constituents, resulting in chemical changes. In this paper, representative electron spectra measured by the Upper Atmosphere Research Satellite particle environment monitor are used to determine the relative contributions of bremsstrahlung X rays and direct electron impact on the energy deposition and ionization production rates for altitudes between 20 and 150 km. Above 50 km most of the ionization comes from direct electron impact. However, in the stratosphere the energy contributed below 50 km is mostly due to bremsstrahlung X rays. In the diffuse aurora the ionization from the bremsstrahlung component exceeds that due to the galactic cosmic ray background to altitudes as low as 30 km during geomagnetically active periods. This paper demonstrates that a diffuse auroral source can input as much or more energy into the upper portion of the lower and middle atmosphere as previously reported for relativistic electron events. The effects of the diffuse aurora (including both the direct electron and the bremsstrahlung contributions) on atmospheric chemistry may be significant.

The diffuse aurora: A significant source of ionization in the middle atmosphere

The NEAR magnetic field investigation is an integrated technical, scientific, and management undertaking that was selected by NASA to achieve the following goals: to coordinate and support the development, calibration, and integration aboard the NEAR spacecraft of the magnetometer facility instrument (MAG), to provide technical assistance to the NEAR project in the area of magnetic cleanliness, and to ensure maximum science data quality. The prime objective of the MAG investigation is to establish the nature of the magnetic field of 433 Eros and any detectable effects of its interaction with the solar wind. The detection of an intrinsic magnetic field would place a strong constraint on the composition and structure of the asteroid's interior and thermal evolution. NEAR magnetometer data will be primarily available through the Johns Hopkins University Applied Physics Laboratory (APL) Science Data Center, http://sd-www.jhuapl.edu/NEAR. The basic building block of the MAG investigation is the facility-class magnetometer instrument flown aboard the NEAR spacecraft [Lohr et al., 1997]. The NEAR MAG was built as a cooperative undertaking between the Laboratory for Extraterrestrial Physics of the Goddard Space Flight Center (GSFC) and APL. GSFC provided the sensors and analog systems, and APL provided the digital processing unit and power converter as well as oversight for test and integration activities on the spacecraft. No booms or appendages were used to place the MAG sensor away from the spacecraft; instead and in analogous fashion to ESA's Giotto spacecraft, the sensor assembly was mounted on the high-gain antenna feed structure. This arrangement results in a minimum detectable magnetic signature of 2-5 nT.

The NEAR magnetic field investigation: Science objectives at asteroid Eros 433 and experimental approach

The onset of nonadiabatic proton motion is studied using direct integration of the Lorentz force equation of motion in the T89c magnetic field model with no electric field. Irreversible changes in the magnetic moment μ occur on traversals of the equator and give the gyrophase dependence predicted by Birmingham [1984]. Birmingham's expression δB and the semiemipirical centrifugal impulse model of Delcourt et al. [1996] δCIM2 nave linear regression coefficients with Δμ/μ of 0.99 and 0.95, respectively, for Δμ/μ ≤ 1. By contrast, e = 1/κ2, where κ is the kappa parameter, has a linear regression coefficient with Δμ/μ of only 0.5. To reliably estimate the onset of nonadiabatic behavior, one must therefore use δB or δCIM2 rather than κ. Using isocontours of constant δB we map the regions of nonadiabatic ion motion. For a given energy the transition to nonadiabatic motion occurs over a radial distance of ∼2 RE on the nightside and is closest to the Earth at midnight. At midnight the nonadiabatic regime for protons extends inward to ∼11 RE (∼7.5 RE) for 1 keV and to ∼6 RE (∼4.5 RE) for 1 MeV with the Kp = 0 (Kp = 6) model. For O+ the nonadiabatic regime is 1.5 to 2 RE closer to the Earth than for protons. Drift trajectory calculations and analytical estimates show that particles drifting through regions with δB > 0.01 suffer net Δμ ∼ μ. The net Δμ is extremely sensitive to initial gyrophase and it is shown that for δB 50 keV, whose adiabatic drift paths are closed in the presence of a convection electric field. The implications of nonadiabatic effects for ring current modeling based on Liouville's theorem apply equally well in the zero and finite electric field cases.

Onset of nonadiabatic particle motion in the near‐Earth magnetotail

One feature of a magnetospheric substorm is the injection of energetic particles into closed drift orbits. Injections are routinely observed by geosynchronous satellites and have been used to identify the occurrence of substorms and the local time of particle energization. In this study we examine pitch angle distributions of ion injections in the 50-to 300-keV energy range observed by the Active Magnetospheric Particle Tracer Explorers Charge Composition Explorer (AMPTE/CCE) satellite, hereinafter CCE. In a dipole field, all pitch angles follow the same drift shell, but the day{endash}night asymmetry of the magnetospheric magnetic field introduces a pitch angle dependence in particle drift orbits, so that particles with different pitch angles disperse radially as they drift. The effect is known as drift-shell splitting. For satellite observations near noon at a fixed geocentric distance, the guiding center orbits of ions detected at small pitch angles intersect the midnight meridian at larger geocentric distances than do ions with near-90{degree} pitch angles. The ion pitch angle distributions detected on the dayside therefore provide information about the radial distance of the nightside acceleration region. We apply this principle to study ion injection events observed on September 17{endash}18, 1984, in association with pseudo-substorm onsets. CCE was atmore » 13 hours local time near its apogee (8.8R{sub E}) and observed a series of ion flux enhancements. Energy dispersion of the timing of the flux increases assures that they are due to injections on the nightside. The flux increases were observed only at pitch angles from 0{degree} to 60{degree}. We calculate drift orbits of protons using the Tsyganenko 89c magnetic field model and find that the drift orbits for 60{degree} pitch angle protons observed at the satellite pass through midnight at 9R{sub E}, well outside of geostationary orbit, indicating that the ion injections occurred tailward of 9R{sub E}. Energetic ion data from geostationary satellites for the same time interval show no evidence of injections at 6.6R{sub E}, consistent with the calculated inner boundary of the injections. Model calculations are presented demonstrating that dispersive injections observed near noon outside geosynchronous orbit provide the greatest sensitivity to drift-shell splitting effects and are therefore most suitable for remote sensing the radial boundaries of substorm injections. {copyright} 1997 American Geophysical Union« less

Drift‐shell splitting of energetic ions injected at pseudo‐substorm onsets

Electrons above 50 eV are a sensitive indicator of field line topology at the magnetopause, particularly when the solar wind dynamic pressure is high and the shear across the boundary is low. AMPTE/CCE electron observations under conditions when these criteria are fulfilled indicate a clear topological transition from the magnetosheath to open field lines threading the magnetopause in the magnetosheath boundary layer (MSBL). Once across the magnetopause and in the low latitude boundary layer (LLBL), the fast moving electrons are no longer a good indicator of magnetic field topology. In particular, the counterstreaming electron observations in this region are not an indicator of a closed magnetic topology. Rather, the field topology continues to be open, and the counterstreaming occurs because electrons from the magnetopause region move rapidly enough along the LLBL magnetic field to make it to the ionosphere, mirror, and return to the observation point Slower moving ions provide important additional information on magnetic field topology in the LLBL. CCE observations discussed here indicate that two types of solar wind ion distributions are observed in this layer. One type consists of a single, heated distribution which resembles somewhat the electron distribution in the layer. The field-aligned velocity of this distribution is near zero. The other type consists of a unidirectional streaming distribution. The field-aligned velocity of this distribution is higher than in the adjacent magnetosheath. Combining these observations with magnetospheric ion observations (e.g., O+) in the LLBL and with electron observations in the MSBL, two distinct magnetic field topologies emerge for the low-shear magnetopause. The first, which gives rise to single, low-parallel-velocity and heated solar wind ion distributions in the LLBL, is magnetic reconnection poleward of the cusp. The second, which gives rise to unidirectional streaming solar wind ion distributions in the LLBL, is magnetic reconnection equatorward of the cusp. This type of component reconnection may not be sustained in a quasi-steady fashion.

Electron and ion signatures of field line topology at the low-shear magnetopause

Observations in the subsolar magnetosheath show that the plasma depletion layer (PDL) is less pronounced for southward than for northward IMF. Since subsolar plasma depletion indicates pile-up of magnetic flux, the degree of plasma depletion should depend on the relative rates of flux transport via subsolar reconnection and flux advection by the solar wind flow. To identify the factors affecting plasma depletion, we consider the ratio D = Er/Esw where Er is the reconnection electric field and Esw is the imposed solar wind electric field. For a quasi-perpendicular subsolar bow shock D can be expressed in terms of magnetosheath parameters. Since PDL formation is suppressed when the subsolar bow shock is quasi-parallel, we restrict attention to quasi-perpendicular conditions. We show that D increases with increasing reconnection efficiency, magnetic shear at the magnetopause, and the magnetosheath magnetic field but decreases with increasing total perpendicular pressure (particle plus magnetic field) in the magnetosheath. By combining observations of the subsolar quasi-perpendicular magnetosheath from AMPTE/IRM and AMPTE/CCE we verify that the degree of plasma depletion is inversely correlated with D. Furthermore, we show that the greater prevalence of plasma depletion in the CCE data implies that the reconnection efficiency is lower for the CCE events and specifically that the reconnection efficiency depends roughly inversely on magnetosheath β, for β > 1. Finally, the results show that all of the changes brought about by plasma depletion act to increase Er so that some subsolar reconnection is likely to occur even for low magnetic shear. Thus the percentage of the magnetosheath magnetic field that participates in reconnection near the subsolar region does not act as a rectifier but remains positive for all shear angles, decreasing monotonically as the magnetic shear at the subsolar magnetopause changes from high to low shear. This implies that the equatorward polar cap convection cells observed during northward IMF and conventionally thought to be driven by a viscous interaction may be due at least in part if not wholly to subsolar low shear reconnection.

Relationships between plasma depletion and subsolar reconnection

Transverse magnetic pulsations polarized in the east-west direction (toroidal waves) are a common feature in the dayside magnetosphere, but they are also observed in the nightside magnetosphere in the form of transient oscillations typically lasting 10–20 min. Until now, little attention has been paid to these transient toroidal waves (TTWs). To get insight into the propagation mode and generation mechanism of TTWs, we have examined magnetic field records from the elliptically orbiting AMPTE CCE, geostationary GOES 5 (located at a geographic longitude of ∼75° W), and GOES 6 (∼ 100°W) satellites. We find that TTW onset times are often simultaneous among the satellites within an accuracy of 1–2 min, but that the wave periods differ from one satellite to another. The latter feature is evidence that TTWs are due to standing Alfven waves on individual magnetic field lines. Additional evidence of the standing waves is provided from the phase relationship between oscillations in magnetic field and ion flux anisotropy. We show by a numerical calculation of the ionospheric damping rate that toroidal mode standing waves can last for a few wave periods once they are excited. Thus, the general lack of continuous toroidal waves on the nightside can be attributed to the absence of sources rather than to strong ionospheric damping. Using CCE data and ground magnetic field data, we confirm that TTWs can be observed immediately following ∼30% (∼2%) of substorm onsets when the satellite is on the nightside (dayside) at 4 < L < 7. Substorms and pseudo substorm onsets produce magnetohydrodynamic disturbances in the near-Earth magnetotail, and these disturbances appear to be a major source of TTWs.

Characteristics of low energy (∼10 to 50 eV) H+ and He+ distributions in the afternoon magnetosphere from L = 4 to 9 are studied using Active Magnetospheric Particle Tracer Explorers/Charge Composition Explorer (AMPTE/CCE) data. He+ distributions in this study routinely display features indicating resonant heating by proton cyclotron waves in the outer magnetosphere (L > 7) whereas protons exhibit minimal evidence of heating. Low energy H+ distributions have T⊥ ≫ T‖ for L < 5 but T⊥ ≪ T‖ for L >7. The change is due to a decrease in T⊥ with increasing L and is consistent with adiabatic cooling in the perpendicular direction as the ions convect sunward. By contrast, low‐energy He+ distributions have T⊥ ≫ T‖ independent of L. The failure of the He+ to cool adiabatically indicates that He+ experiences transverse heating as it convects sunward through the outer magnetosphere. The occurrence of proton cyclotron waves in the afternoon magnetosphere is evaluated using AMPTE/CCE magnetometer data and shows that low energy ions convecting sunward from the afternoon plasmasphere have a 20% chance of being exposed to cyclotron waves by the time they reach L = 5, 50% by L = 6 and > 95% by L = 7. The majority of cyclotron waves in the early afternoon outer magnetosphere occur above the local He+ gyrofrequency and will interact resonantly with He+ but nonresonantly with H+. The combined effects of adiabatic sunward convection and interactions between the low‐energy ions and proton cyclotron waves therefore account for the observed characteristics of both the H+ and He+ distributions in the afternoon magnetosphere.

Low‐energy He+ and H+ distributions and proton cyclotron waves in the afternoon equatorial magnetosphere

Ground measurements of bursts of Pc 1 pulsations (minutes duration) are a common dayside phenomenon at high latitudes. For the past several years, dayside ground measurements of similar-duration bursts of Pc 5 period pulsations, magnetic impulse events (MIE), have attracted a great deal of interest concerning their role in dayside reconnection. From an analysis of several years of induction antenna data from southern and northern hemisphere sites in the Antarctic, Greenland, and Canada, it is found that about 70% of all isolated MIE events are associated with Pc 1 bursts, and about half of all events are conjugate between hemispheres. There appears to be no definitive phase relationship between the onset of the Pc 1 bursts and the MIE, suggesting that both might be produced by the same event on the dayside but have different source locations. Correlative data from ground and spacecraft measurements suggest this to be the case and also show that the Pc 1 are waves inside the magnetosphere propagating into the ionosphere. Finally, a timing study between ground sites separated by 2 hours local time shows that the isolated MIEs are measured first near the subsolar point and at later times down both flanks of the magnetosphere. This suggests that the source mechanism for these events has an E–W component of motion which when projected to the equatorial plane is of the order of the antisunward flow velocity in the magnetosheath. As this source moves down the magnetospheric flanks it creates well within the magnetosphere conditions (pressure pulses?) ripe for the ion cyclotron generation of the Pc 1 bursts associated with the MIE.

Magnetic impulse events and associated Pc 1 bursts at dayside high latitudes

We present a study of the proton cyclotron instability in the Earth's outer magnetosphere, L > 7, using Active Magnetosphere Particle Tracer Explorers/Charge Composition Explorer (AMPTE/CCE) magnetic field, ion, and plasma wave data. The analysis addresses the energy of protons that generate the waves, the ability of linear theory to predict both instability and stability, comparison of the predicted wave properties with the observed wave polarization and frequency, and the temperature anisotropy/parallel beta relation. The data were obtained during 24 intervals of electromagnetic ion cyclotron (EMIC) wave activity (active) and 24 intervals from orbits without EMIC waves (quiet). This is the same set of events used by Anderson and Fuselier [1994]. The active events are drawn from noon and dawn local times for which the wave properties are significantly different. For instability analysis, magnetospheric hot proton distributions required the use of multiple populations to analytically represent the data. Cyclotron waves are expected to limit the proton temperature anisotropy, Ap = T⊥p/T‖p − 1, according to Ap < aβ‖pc with a ∼ 1 and c ∼ 0.5, where T⊥p, T‖p, and β‖p are the perpendicular and parallel proton temperatures and the proton parallel beta, respectively. During cyclotron wave events, Ap should be close to aβ‖pc whereas in the absence of waves Ap should be below aβ‖pc. The active dawn cases yielded instability in 9 of 12 cases using the measured plasma data with an average growth rate γ/Ωp = 0.025 and followed the relation Ap = 0.85β‖p−0.52. The active noon events gave instability in 10 of 12 cases, but only when an additional ∼2 cm−3 cold plasma was assumed. The noon wave events fell well below the dawn events in Ap-β‖p space, slightly above the Ap = 0.2β‖p−0.5 curve. The lower Ap limit for the noon cases is attributed to the presence of unmeasured cold plasma. The quiet events were all stable even for additional assumed cold ion densities of up to 10 cm−3, the upper limit implied by the plasma wave data. The quiet events gave Ap < 0.2β‖p−0.5. At noon, the unstable component has T⊥p ∼ 20 keV and Ap ∼0.8. At dawn the unstable component has T⊥p ∼ 4 keV and Ap ∼ 2.3. Observed wave frequencies agree with the frequencies of positive growth, and the difference in frequency between noon and dawn is attributable to the combined effects of the different hot proton T⊥p and Ap and the inferred higher cold plasma density at noon. The dawn events had significant growth for highly oblique waves, suggesting that the linear polarization of the dawn waves may be due to domination of the wave spectrum by waves generated with oblique wave vectors.

Observational test of local proton cyclotron instability in the Earth's magnetosphere

Geomagnetic pulsations from 0.2 to 5.0 Hz (Pc 1) observed on the ground could be used to monitor the magnetospheric processes generating them if their source regions were known. We report simultaneous observations of Pc 1 bursts at South Pole Station and in space at 9 Re geocentric distance near the magnetic equator showing that the subsolar outer magnetosphere, earthward of the low latitude boundary layer, is the source region of Pc 1 bursts. The source extends 1 to 2 hours azimuthally and 1 to 2 Re radially. Correlation of magnetopause displacements and bursts at South Pole indicates that the bursts are stimulated by compressions of the dayside magnetosphere. In space the bursts occur above the He+ gyrofrequency implying that the H+-He+ bi-ion resonance does not prevent the signals from reaching the ionosphere.

Solar cycle change of Pc1 waves observed by an equatorial satellite and on the ground

Polarization characteristics of magnetospheric proton cyclotron waves should provide definitive tests of mechanisms for wave propagation and growth. Previous studies used Fourier spectral analysis to determine the ellipticity ε and the minimum variance direction êmin, which gives θmin, the angle between êmin and the background field B0. Comparison with theoretical models depends critically on accurate determination of ε and θmin. However, observed fluctuations might not be sets of phase‐coherent sine waves, as implicitly assumed in Fourier analysis, but may consist of series of packets whose phase and azimuthal orientation vary randomly. By constructing synthetic nonstationary signals, we find that spectral analysis of data intervals containing several wave packets systematically underestimates θmin, often by 45° or more, and overestimates |ε|. The problem is caused by fluctuations in the polarization ellipse azimuth orientation. We present a minimum variance analysis technique, called wave‐step analysis, which requires only a few wave cycles of data. Tests of the wave‐step procedure show that it is valid for signals with bandwidths up to ∼30% full width at half maximum and is therefore applicable to the majority of proton cyclotron wave events. Comparison of the wave‐step and Fourier analyses for cyclotron wave events confirms that cyclotron wave fluctuations display features characteristic of nonstationary signals. Relative to the wave‐step results, the Fourier results underestimate θmin, overestimate |ε|, and display the predicted variations of these parameters with each other and with azimuth angle fluctuations. The opposite relationship between Fourier and wave‐step θmin should result if the signals were too broadbanded for the wave‐step algorithm. Thus the θmin results provide an unambiguous indication of nonstationarity. Time windows of 30 s proved to be too long for analysis of ∼0.5 Hz signals, indicating that analysis needs to be carried out on timescales shorter than tens of wave periods. Previous analyses reported θmin ≤ 30°, but the wavestep results for one linearly polarized event analyzed here show that θmin can be larger than 70°.

On determining polarization characteristics of ion cyclotron wave magnetic field fluctuations

Using data from the Active Magnetospheric Particle Tracer Explorers/Charge Composition Explorer spacecraft, we make a detailed comparison between the observed polarization properties of electromagnetic ion cyclotron (EMIC) waves and those predicted by theory. The polarization can be described by three parameters: the ellipticity e, the ratio of parallel (to the background magnetic field B0) magnetic fluctuations δBz to the major axis component of the elliptical perturbation in the perpendicular plane δBmajor, and the phase angle between δBz and δBmajor. On the basis of the plasma parameters observed during EMIC events, we have calculated the linear properties of the theoretical modes and compared these to the observations. The result is that two and in some cases, three of the observed polarization properties are inconsistent with the assumption that the waves result from a single linear mode. We use a simple model with two constituent waves in various azimuthal orientations (around B0) and temporal phase relations and show that the distribution of observed polarization properties can be understood as resulting from the superposition of more than one mode. When there is superposition, the instantaneous polarization characteristics of the fluctuations do not reliably reflect the constituent wave properties and the minimum variance direction cannot be associated with a wave vector direction. Nonetheless, we have shown that the constituent wave properties can be inferred from the distribution of observed properties. For superposition of two waves with only slightly dissimilar characteristics, the constituent wave e is approximately the median observed e, e, and the constituent θkB (angle between the wave vector k and B0) is approximately given by tan θkB = δBz/δBmajor/e, with the overbar on δBz/δBmajor again indicating a median value.

Effects of wave superposition on the polarization of electromagnetic ion cyclotron waves

Recent observations of electromagnetic ion cyclotron waves in space

A statistical study of Pc 1 waves has been performed using electric field data recorded in the ionosphere by the Dynamics Explorer 2 satellite. The study was performed by applying an automated wave detection algorithm to over 900 hours of data recorded at invariant latitudes (INV) greater than 40° from December 6, 1981, to February 16, 1983. A total of 390 Pc 1 waves in the electric field were identified using a selection technique based on spectral peak detection in the frequency range from 0.2 to 6.0 Hz. Most events were observed at frequencies between 0.4 and 2.0 Hz and in the dawn (0400–0600 MLT) and noon (1000–1500 MLT) sectors from 50° to 62° INV. Detection of events at high latitudes (INV > 65°) was limited by noise associated with auroral zone electric fields. Significant differences in the properties of ionospheric Pc 1 waves were observed in the dawn and noon sectors. First, noon sector waves were clearly ordered by the equatorial gyrofrequencies (ƒ 10 (mV/m)2/Hz, in the noon sector compared with just 23% in the dawn sector. Third, for events with a magnetic field component, the median value of ΔE/ΔB was 410 km/s in the dawn and 330 km/s in the noon sector, although the median value of the ratio between (ΔE/ΔB) and the Alfven velocity was similar in both sectors. Fourth, more short-duration events (2–8 s) were observed in the noon than in the dawn sector. We conclude that the source of noon sector ionospheric Pc 1 waves is electromagnetic ion cyclotron waves generated in the equatorial magnetosphere. The source of the dawn sector waves is less certain, as many waves were observed only in the electric field.

There are four low-frequency modes which may propagate in a high-beta nearly bi-Maxwellian plasma. These are the magnetosonic, Alfven, ion acoustic, and mirror modes. This manuscript defines a procedure based on linear Vlasov theory for the unique identification of these modes by use of transport ratios, dimensionless ratios of the fluctuating field and plasma quantities. A single parameter, the mode deviation, is defined which characterizes the difference between the theoretical transport ratios of a particular mode and the observed ratios. The mode deviation is calculated using the plasma and magnetic field data gathered by the Active Magnetospheric Particle Tracer Explorers/Ion Release Module spacecraft to identify the modes observed in the terrestrial magnetosheath near the magnetopause. As well as determining the mode which best describes the observed fluctuations, it gives us a measure of whether or not the resulting identification is unique. Using 17 time periods temporally close to a magnetopause crossing, and confining our study to the frequency range from 0.01 to 0.04 Hz, we find that the only clearly identified mode in this frequency range is the mirror mode. Most commonly, the quasi-perpendicular mirror mode (with wave vector k roughly perpendicular to the background magnetic field B0) is observed. In two events the quasi-parallel mirror mode (k ∥ B0) was identified.

Low-frequency fluctuations in the magnetosheath near the magnetopause

Electron distributions at energies above 50 eV have been found to be a sensitive indicator of magnetic topology for magnetopause crossings of the AMPTE/CCE spacecraft. Progressing from the magnetosheath to the magnetosphere two abrupt transitions occur. First, the magnetosheath electron population directed either parallel or antiparallel to the magnetic field is replaced by a streaming, heated magnetosheath electron population. The other half of the distribution is unchanged. The region with unidirectional, heated magnetosheath electrons is identified as the magnetosheath boundary layer (MSBL). Second, the unheated magnetosheath electron population is replaced by a heated population nearly identical to the population encountered in the MSBL, resulting in a symmetric counterstreaming distribution. The region populated by the bidirectional heated magnetosheath electrons is identified as the low-latitude boundary layer (LLBL). The MSBL and LLBL identified by the electron transitions are the same as the regions identified using ion composition measurements. The magnetosheath-MSBL transition reflects a change in magnetic topology from a solar wind field line to one that threads the magnetopause, and the existence of a magnetosheath-MSBL transition implies that the magnetopause is open. When the current layer is easily identified, the MSBL-LLBL transition coincides with the magnetopause current layer, indicating that the magnetosheath electrons are heated in the current layer. Both magnetosheath-MSBL and MSBL-LLBL transitions are observed for low as well as high magnetic shears. Moreover, the transitions are particularly clear for low shear implying that magnetic topology boundaries are sharp even when abrupt changes in the field and other plasma parameters are absent. Furthermore, for low magnetic shear, solar wind ions with low parallel drift speeds make up the majority of the LLBL population indicating that the magnetosheath plasma has convected directly across the magnetopause. These observations are consistent with quasi-steady, high-latitude reconnection and indicate that the signatures of this reconnection geometry are commonly present in the subsolar region.

Particle signatures of magnetic topology at the magnetopause: AMPTE/CCE observations

Compressional magnetic pulsations with irregular waveforms and periods longer than 150 s (here termed Pi 3) have been studied by using data from Active Magnetospheric Particle Tracer Explorers Charge Composition Explorer (AMPTE/CCE) and GOES 5 and 6 in the dayside magnetosphere and compared with signatures on the ground at low latitudes by using data from Kakioka station (L = 1.25). On the ground, the pulsations appear in the horizontal component. A study of 17 such concurrent events during a 2-month period in 1986 reveals the following pulsation characteristics. (1) The peak-to-peak amplitudes in space (δBT) and on the ground (δH) are comparable and are in the range of 0.5–7 nT. (2) On the ground the pulsations can be seen at all local times, even at midnight, while at geostationary orbit they are observed only on the dayside with a clear amplitude maximum at noon. (3) The pulsations on the ground lag those observed by CCE near local noon, and the lag increases as the local time separation between CCE and the ground station increases. The time lag is 1–2 min longer when the ground station is on the nightside than when it is on the dayside. (4) The time lag between pulsations observed at geostationary orbit and near noon by CCE varies systematically with local time and is about 2 min per 6 hours of local time separation. These observations indicate that some nightside pulsations in the Pi 3 band have dayside origins. The position dependence of the pulsation amplitude can be explained well by changes in the magnetopause current, which are in turn presumably caused by changes in the solar wind dynamic pressure. The time lags observed in space are consistent with signal propagation in the MHD fast mode, but the variation in space-ground time lags with ground station local time must be attributed to another mechanism.

Observation and modeling of compressional Pi 3 magnetic pulsations

The spatial variation of the properties of magnetospheric Pi 2 pulsations is studied using magnetic field records acquired simultaneously by the Active Magnetospheric Particle Tracer Explorers Charge Composition Explorer (AMPTE CCE) satellite at radial distances less than 6.6 Earth radii and at geomagnetic latitudes from −16° to 16° and at the Kakioka ground station located at magnetic shell of L = 1.23. Pi 2 magnetic pulsations are identified from the Kakioka data acquired within 3 hours of midnight, but no restriction is imposed on the local time of CCE. An automated Pi 2 selection procedure resulted in 249 events from the Kakioka data. We have characterized magnetic field variations in the radial Bx, azimuthal By, and compressional Bz components at CCE in terms of their spectral density, coherence, and phase relative to those of the Pi 2 pulsation in the horizontal H component of the Kakioka data and then examined how these parameters depend on the location of CCE. It is found that high-coherence events (coherence between CCE and Kakioka > 0.6) are observed primarily when CCE is on the nightside and at L < 4. For these events the magnetic field perturbations at CCE are dominated by the poloidal components Bx and Bz, and these components exhibit a ground-to-satellite cross phase of either ∼0 or ∼180°, depending on the location of the satellite. The spatial phase structure is consistent with the eigenmode structure of a compressional cavity-mode-type resonance excited between two reflecting boundaries. We find no evidence supporting the view that ground Pi 2 are midlatitude toroidal field line resonances excited in response to source waves on auroral zone field lines. Rather, the results imply that midlatitude (2 <L< 5) Pi 2 pulsations observed on the ground originate from a cavity-mode-type resonance excited in the inner magnetosphere bounded below by the ionosphere and at high altitudes by an Alfven velocity gradient. The cavity resonance is probably excited by earthward propagating fast mode waves launched at substorm onset by the large-scale magnetic reconfiguration associated with cross-tail current disruption.

Statistical analysis of Pi 2 pulsations observed by the AMPTE CCE Spacecraft in the inner magnetosphere

The Johns Hopkins University Applied Physics Laboratory (JHU/APL) Magnetic Field Experiment Data Analysis System (MFEDAS) has been developed to process and analyze satellite magnetic field experiment data from the TRIAD, MAGSAT, AMPTE/CCE, Viking, Polar BEAR, DMSP, HILAT, UARS, and Freja satellites. The MFEDAS provides extensive data management and analysis capabilities. The system is based on standard data structures and a standard user interface. The MFEDAS has two major elements: (1) a set of satellite unique telemetry processing programs for uniform and rapid conversion of the raw data to a standard format and (2) the program Magplot which has file handling, data analysis, and data display sections. This system is an example of software reuse, allowing new data sets and software extensions to be added in a cost effective and timely manner. Future additions to the system will include the addition of standard format file import routines, modification of the display routines to use a commercial graphics package based on X-Window protocols, and a generic utility for telemetry data access and conversion.

Active Magnetosphere Particle Tracer Explorers/Charge Composition Explorer (AMPTE/CCE) magnetic field data are used to study the excitation mechanism of local toroidal harmonic field line resonances (MRs). Enhanced toroidal fluctuations can exhibit either clear harmonic resonance signatures or broadband power enhancements. This may indicate that two different processes are operating. To assess the differences between toroidal harmonic and broadband events statistically, we examined data from 56 dayside orbits and selected intervals that displayed either clear toroidal harmonics (Harmonic) or primarily broadband (Broadband) toroidal power. The resulting database consisted of 878 intervals, each 26.5 min long. Spectral power was integrated from 10 to 50 mHz to obtain radial, PR, toroidal (eastward), PE, and compressional (northward), PN, power levels. Absolute toroidal power levels were comparable for both Harmonic and Broadband events, ranging from 0.1 to 20 nT 2 for both categories. To minimize the influence of activity variations in power level, we examined power ratios, for example, PE/PN, rather than the absolute power levels. The Harmonic events have an average PE/PN of 2.28±0.07, whereas PE/PN averages 1.51±0.05 for the Broadband events. The average radial power is essentially equal to the compressional power: average PR/PN is 1.04±0.04 for Harmonic and 1.00±0.04 for Broadband events. That toroidal power is enhanced for the Broadband as well as Harmonic events suggests that resonance effects occur in the Broadband events but that the resonances are not sufficiently developed to be apparent as harmonics in power spectra. For the Harmonic events PE/PN decreases with L, whereas for Broadband events PE/PN is constant or rises with L, also suggesting that their sources are different. There are three ways to interpret these results. First, one can attribute the Harmonic events to coupling of compressional modes to local MRs. Since the observed MRs occur over a continuous range in frequency, one must assume, however, that the cavity eigenfrequency spectrum is also nearly continuous, that is, the number of eigenmodes is very large. The Broadband events are not readily accounted for in the cavity mode picture, however. Alternately, if the magnetospheric system is considered to be a relatively poor global resonator, low Q, due to Joule dissipation and/or a Poynting flux directed out of the cavity, there are two possible explanations. In the first low-Q scenario, harmonic toroidal fluctuations are driven by the high-latitude entry mechanism of Engebretson et al. (1991), whereas the Broadband events are due to coupling of propagating compressional waves with the shear Alfven mode. The second low-Q scenario attributes both Harmonic and Broadband events to local MR excitation by propagating compressional waves, but the Harmonic events correspond to local MRs excited by longer wavelength perturbations at the magnetopause, yielding better coupling to the local MRs and hence more fully developed resonance signatures

Relative intensity of toroidal and compressional Pc 3‐4 wave power in the dayside outer magnetosphere

Correlations between plasma properties and magnetic fluctuations in the sub-solar magnetosheath downstream of a quasi-perpendicular shock have been found and indicate that mirror and ion cyclotronlike fluctuations correlate with the magnetosheath proper and plasma depletion layer, respectively (Anderson and Fueselier, 1993). We explore the entire range of magnetic spectral signatures observed from the Active Magnetospheric Particle Tracer Explorers/Charge Composition Explorer (AMPTE/CCE)spacecraft in the magnetosheath downstream of a quasi-perpendicular shock. The magnetic spectral signatures typically progress from predominantly compressional fluctuations,delta B(sub parallel)/delta B perpendicular to approximately 3, with F/F (sub p) less than 0.2 (F and F (sub p) are the wave frequency and proton gyrofrequency, respectively) to predominantly transverse fluctuations, delta B(sub parallel)/delta B perpendicular to approximately 0.3, extending up to F(sub p). The compressional fluctuations are characterized by anticorrelation between the field magnitude and electron density, n(sub e), and by a small compressibility, C(sub e) identically equal to (delta n(sub e)/n(sub e)) (exp 2) (B/delta B(sub parallel)) (exp 2) approximately 0.13, indicative of mirror waves. The spectral characteristics of the transverse fluctuations are in agreement with predictions of linear Vlasov theory for the H(+) and He(2+) cyclotron modes. The power spectra and local plasma parameters are found to vary in concert: mirror waves occur for beta(s ub parallel p) (beta (sub parallel p) identically = 2 mu(sub zero) n(sub p) kT (sub parallel p) / B(exp 2) approximately = 2, A(sub p) indentically = T(sub perpendicular to p)/T(sub parallel p) - 1 approximately = 0.4, whereas cyclotron waves occur for beta (sub parallel p) approximately = 0.2 and A(sub p) approximately = 2. The transition from mirror to cyclotron modes is predicted by linear theory. The spectral characteristics overlap for intermediate plasma parameters. The plasma observations are described by A(sub p) = 0.85 beta(sub parallel P) (exp - 0.48) with a log regression coefficient of -0.74. This inverse A(sub p) - beta(sub parallel p) correlation corresponds closely to the isocontours of maximum ion anisotropy instability growth, gamma (sub m)/omega(sub p) = 0.01, for the mirror and cyclotron modes. The agreement of observed properties and predictions of local theory suggests that the spectral signatures reflect the local plasma environment and that the anisotropy instabilities regulate A(sub p). We suggest that the spectral characteristics may provide a useful basis for ordering observations in the magnetosheath and that the A(sub p) - beta(sub parallel p) inverse correlation may be used as a beta-dependent upper limit on the proton anisotropy to represent kinetic effects.

Magnetic spectral signatures in the Earth's magnetosheath and plasma depletion layer

A unique arrangement of satellites and ground-based magnetometers has provided the opportunity to study the distortion of the magnetosphere by conditions of elevated solar wind dynamic pressure and high geomagnetic activity on October 27, 1992. Data were acquired by the near-Earth satellites Freja, UARS, DMSP-F8 and DMSP-F11, and by IMP-8. This study will focus on patterns of large-scale Birkeland currents deduced from the APL magnetic field experiments on Freja and UARS. Because of the relatively low inclinations of their orbits (63° for Freja and 57° for UARS) these satellites skim the current systems over a wide range of local time and provide a kind of “global image” of the Birkeland currents. Energetic particle data from the DMSP satellites are used in an attempt to complete the image of the auroral region. The principal findings of this study include the following. The dayside Birkeland current system is displaced 6° to 9° equatorward of the statistical pattern determined by Iijima and Potemra [1978] for undisturbed conditions (|AL|< 100 nT) and 3° equatorward of their disturbed statistical pattern (|AL|≥ 100 nT). The densities of these daytime Birkeland currents are estimated to be 1 to 2 µA/m², comparable to, but not larger than the statistical values determined by Iijima and Potemra for disturbed conditions. The nightside Birkeland currents are located close to the Iijima and Potemra disturbed statistical pattern and they are less intense than the dayside currents.

Freja's contribution to the ISTP event of October 27, 1992. A distorted magnetosphere

Erratum: ``Magnetic pulsations from 0.1 to 4.0 Hz and associated plasma properties in the Earth's subsolar magnetosheath and plasma depletion layer'' [J. Geophys. Res. 98, 1461-1479 (1993)]

During an intense geomagnetic storm (Kp 7+) that began at {approximately} 1830 UT on October 1, 1991, the UARS satellite encountered the dayside postnoon auroral oval. On two consecutive crossings of the northern hemisphere between 2040 and 2240 UT, the vector magnetometer detected region 1 and 2 Birkeland and ionospheric currents in the postnoon sector. Low-energy electron events were observed near 1400 MLT within a narrow portion of the region 1 current system. Simultaneous magnetic field measurements revealed the presence of intense ({approximately} 20 {mu}A/m{sup 2}) bipolar filament current structures embedded in the auroral oval. The upward-directed currents were associated with the more concentrated region of precipitating electrons. Ions associated with the more intense flux of low-energy electrons exhibited a dispersion signature typical of an ion velocity filter. The dispersion, aligned along the orbit, exhibited higher-energy ions at lower latitudes and earlier local times. The colocation of filament currents and ion dispersion signatures at such late postnoon local times is not consistent with typical E x B {open_quotes}cusp{close_quotes} dispersions. These features more likely result from dayside boundary wave phenomena. 34 refs., 9 figs.

Filamentary current structures in the postnoon sector: Observations from UARS

Recent observations have delineated several different kinds of enhanced magnetic fluctuation spectra below the proton cyclotron frequency in the terrestrial magnetosheath. A model is presented that represents the variation of plasma parameters across the plasma depletion layer and into the magnetosheath proper. Using this model, we find that many of the properties of the observed spectra follow directly from the predictions of linear Vlasov instability theory. The observed progression of spectral features is a natural progression from mirror mode to merged (in frequency range) proton and He2+ cyclotron modes to bifurcated (in frequency range) cyclotron modes as plasma convects earthward in the magnetosheath. The necessary change in dispersion surface topology from separated proton and He2+ cyclotron surfaces at low beta to merged surfaces at high beta is described.

Low-frequency magnetic fluctuation spectra in the magnetosheath and plasma depletion layer

Electromagnetic ion cyclotron waves generated by 10-50 keV protons in the Earth`s equatorial magnetosphere will interact with the ambient low-energy ions also found in this region. The authors examine H{sup +} and He{sup +} distribution functions from {approx} 1 to 160 eV using the Hot Plasma Composition Experiment instrument on AMPTE/CCE to investigate the thermal ion response to the waves. A total of 48 intervals were chosen on the basis of electromagnetic ion cyclotron (EMIC) wave activity: 24 with prevalent EMIC waves and 24 with no EMIC waves observed on the orbit. There is a close correlation between EMIC waves and perpendicularly heated ion distributions. For protons the perpendicular temperature increase is modest, about 5 eV, and is always observed at 90{degrees} pitch angles. This is consistent with a nonresonant interaction near the equator. By contrast, He{sup +} temperatures during EMIC wave events averaged 35 eV and sometimes exceeded 100 eV, indicating stronger interaction with the waves. Furthermore, heated He{sup +} ions have X-type distributions with maximum fluxes occurring at pitch angles intermediate between field-aligned and perpendicular directions. The X-type He{sup +} distributions are consistent with a gyroresonant interaction off the equator. The concentration of He{sup +} relative to H{supmore » +} is found to correlate with EMIC wave activity, but it is suggested that the preferential heating of He{sup +} accounts for the apparent increase in relative He{sup +} concentration by increasing the proportion of He{sup +} detected by the ion instrument. 35 refs., 8 figs., 1 tab.« less

Average proton parameters in the magnetosheath downstream from the quasi-perpendicular shock (the quasi-perpendicular magnetosheath) for high solar wind dynamic pressure conditions are observed to vary continuously from high-beta, low-temperature anisotropy to low-beta, high-temperature anisotropy. Observations and theory have shown that this inverse correlation is a direct consequence of pitch angle scattering by electromagnetic ion cyclotron (EMIC) waves, which regulate the anisotropy, restoring the plasma toward marginal stability. Although the previously documented spectral characteristics of EMIC waves are not evident downstream of the quasi-parallel bow shock, the inverse anisotropy-beta relation found in the quasi-perpendicular magnetosheath also holds in the quasi-parallel magnetosheath. This indicates that the EMIC instability regulates the ion anisotropy regardless of the shock geometry.

Inverse correlations between the ion temperature anisotropy and plasma beta in the Earth's quasi-parallel magnetosheath

Spacecraft observations in the strongly compressed subsolar magnetosheath show an inverse correlation between the proton temperature anisotropy (T{sub {perpendicular}p}/T{sub {parallel}p} > 1 where {perpendicular} and {parallel} denote directions perpendicular and parallel to the background magnetic field) and the parallel proton {beta}({beta}{sub {parallel}p}). This manuscript uses one-dimensional hybrid simulations of the proton cyclotron anisotropy instability in homogeneous electron-proton plasmas to study this correlation which may represent a limited closure relation for fluid theories of anisotropic space plasmas. The emphasis is on driven simulations which increase the temperature anisotropy by periodically reducing the magnetic-field-aligned velocities of the protons. The late-time states from ensembles of both initial value and driven simulations yield very similar expressions for the proton anisotropy/{beta}{sub {parallel}p} inverse correlation, and provide a basis for explaining differences between sheath observations from different spacecraft. The driven simulations also yield expressions for the maximum instability growth rate and the fluctuating field energy as functions of {beta}{sub {parallel}p} and a parameter characterizing the anisotropy driver. 50 refs., 5 figs.

The proton cyclotron instability and the anisotropy/β inverse correlation

Temporal and spatial fluctuations of large-scale electric currents totaling millions of amperes in the ionosphere have long been known to induce current and voltage in the Earth's surface and on large manmade conductive structures. A strong, persistent solar wind can interact with the geomagnetic environment and produce auroral zone currents at mid latitudes. Presented here is a specific correlation of ionospheric auroral currents inferred from magnetic field measurements from the Swedish Freja satellite and induced current in the electric power distribution system on the east coast of the United States, in particular the Chalk Point, Maryland, transformer station. The event discussed here registered a Kp level of 6 to 8 and occurred on April 4–5, 1993. An important aspect is that information from both of these space- and ground-based monitoring systems is available automatically and in real time. In addition, satellite data from earlier local times, e.g., data monitored from European ground stations, can give precursor information of later North American geomagnetic activity.

Ionospheric currents correlated with geomagnetic induced currents; Freja magnetic field measurements and the Sunburst Monitor System

A bounded anisotropy fluid model is developed which describes the temperature evolution of a collisionless plasma including the effect of pitch angle scattering due to ion cyclotron waves. The model equations accurately describe the proton temperature evolution in the plasma depletion layer, a magnetosheath regime of decreasing plasma density near the magnetopause. As in double adiabatic theory, changes in T⊥ are driven by changes in flux tube area A (∝ 1/B), while changes in T∥ are driven by changes in field line scale length L. In the bounded anisotropy model, if the proton temperature ratio T⊥/T∥ rises above the value 1 + 0.85 β∥p−0.48 (Anderson et al., 1994), where β∥p is the proton parallel beta, energy is transferred from the perpendicular to parallel temperature until this equation is satisfied. This energy exchange represents the effect of ion cyclotron wave pitch angle scattering, which keeps the plasma state near to marginal stability. Equations of the same form, employing bounded anisotropy expressions appropriate to different species, are also applied to He2+ and to electrons. These equations well describe the evolution of the He2+ but do not describe the evolution of the electron temperature, apparently due to the high electron thermal conduction which the model does not include. These results indicate that an energy exchange term may be incorporated into anisotropic fluid equations to simulate the effect of ion cyclotron wave pitch angle scattering in global fluid equations.

Boundary determinations from low frequency magnetic field measurements

Boundary conditions for magnetopause processes such as reconnection can be understood by studying the properties of magnetosheath plasma as it flows toward this transition. This manuscript reviews the role of electromagnetic ion cyclotron instabilities in constraining ion temperature anisotropies in the magnetosheath. Linear Vlasov theory and hybrid computer simulations have demonstrated that the inverse correlation between the proton anisotropy and the parallel proton {beta} observed from AMPTE/CCE in the subsolar sheath is due to wave-particle scattering by ion cyclotron anisotropy instabilities. Recent research on this topic is reviewed and the application of this inverse correlation to a successful bounded anisotropy model of proton temperatures in the sheath is described.

The ions of the terrestrial magnetosheath are typically observed to have bi‐Maxwellian velocity distributions with T⊥≳T∥, where ⊥ and ∥ denote directions perpendicular and parallel to the background magnetic field. Observations of the highly compressed magnetosheath have demonstrated an inverse correlation between the proton temperature anisotropy and the proton parallel β. Hybrid computer simulations have shown that wave–particle scattering by the proton cyclotron anisotropy instability can yield similar correlations between these two parameters. Although these correlations are due to nonlinear plasma processes, they correspond to a threshold of this instability that can be determined from linear Vlasov theory. This proton anisotropy/β correlation represents a limited closure relation for anisotropic magnetohydrodynamic plasma models.

A limited closure relation for anisotropic plasmas from the Earth’s magnetosheath*

Both the protons and the helium ions of the terrestrial magnetosheath typically display T⊥ > T∥, where ⊥ and ∥ denote directions perpendicular and parallel to the background magnetic field. Observations of the highly compressed magnetosheath show an inverse correlation between these ion temperature anisotropies and the parallel proton β. Computer simulations have demonstrated that these correlations are due to wave-particle scattering by electromagnetic ion cyclotron anisotropy instabilities. These correlations correspond to linear theory thresholds of the proton cyclotron and the helium cyclotron instabilities. This paper uses linear Vlasov theory and the assumption of a constant maximum growth rate to obtain closed-form expressions for these thresholds as a function of the relative helium density and the parallel proton β in a parameter model of the magnetosheath.

Proton and helium cyclotron anisotropy instability thresholds in the magnetosheath

A number of statistical studies using spacecraft data have been made of ULF waves in the magnetosphere. These studies provide an overview of ULF pulsation activity for r = 5-15 R(E) and allow an assessment of likely source mechanisms. In this review pulsations are categorized into five general types: compressional Pc 5, poloidal Pc 4, toroidal harmonics, toroidal Pc 5 (fundamental mode), and incoherent noise. The occurrence distributions and/or distributions of wave power of the different types suggest that compressional Pc 5 and poloidal Pc 4 derive their energy locally, most likely from energetic protons. The toroidal pulsations, both harmonic and fundamental mode, appear to be driven by an energy source outside the magnetopause - directly upstream in the sheath and solar wind for harmonics and the flanks for fundamentals. Incoherent pulsations are a prominent pulsation type but from their occurrence distribution alone it is unclear what their dominant energy source may be.

Statistical studies of Pc 3-5 pulsations and their relevance for possible source mechanisms of ULF waves

The magnetic storm of November 8 and 9, 1991, lead to expansion of the auroral oval below 45° magnetic latitude (MLAT) and auroral phenomena were sampled by the Upper Atmosphere Research Satellite (UARS). The attitude precision and stability of UARS allow monitoring of Birkeland and ionospheric currents via magnetic field measurements from the Particle Environment Monitor (PEM) magnetometer. This paper reports the development of the intensity and location of Birkeland currents associated with this storm. Two principle results are obtained: (1) total Birkeland currents exceed 30 MA, more than 6 times nominal values, indicating Joule heating of about 3×1012 W; (2) Birkeland currents below 50°, polar cap currents indicative of anti-sunward convection, and cusp particle signatures of southward IMF all persist at least eight hours into recovery phase of the storm.

Auroral currents during the magnetic storm of November 8 and 9, 1991: Observations from the Upper Atmosphere Research Satellite Particle Environment Monitor

The relationship between sudden impulses and enhancements or onset of Pc 1 at high-latitude ground stations is well established. It has been proposed that increased hot proton temperature anisotropy resulting from convection during magnetospheric compression is responsible for the enhancement in Pc 1 emissions via generation of electromagnetic ion cyclotron (EMIC) waves in the dayside outer equatorial magnetosphere (e.g., Olson and Lee, 1983). We use AMPTE/CCE magnetic field and particle data to test this suggestion. Compression-induced Pc 1 events are very common in the AMPTE/CCE data set: among isolated sudden ( 6 region, 47% are associated with EMIC wave onset at the satellite. Compressions energize particles via earthward convection, so the association of local Pc 1 onsets with compressions may be either a temporal effect or merely the result of inward transport to the spacecraft of plasma previously unstable to EMIC waves. EMIC waves occur 10-20% of the time in the outer magnetosphere, which is considerably less than the occurrence rate of Pc 1 with compressions, suggesting that convection alone does not account for compression Pc 1 onset. To test whether the plasma is more unstable to EMIC waves after compressions than before, the proton distribution (1-300 keV) measured at the peak of the compression is used together with an image dipole model to calculate the distribution that would result from adiabatic expansion back to the precompression state. Comparison of the EMIC wave growth rates from the measured compression and extrapolated expansion distributions provide an indication of the compression-induced enhancement of EMIC wave activity. Differences in wave growth of several orders of magnitude are found, indicating significant increases in EMIC wave activity. The results suggest that enhancements in dynamic pressure pump the energetic proton distributions in the outer magnetosphere, driving EMIC waves. Waves are expected to be generated most readily close to the magnetopause, and transient pressure pulses may be associated with bursts of EMIC waves, which would be observed on the ground in association with ionospheric transient signatures.

Electromagnetic ion cyclotron waves stimulated by modest magnetospheric compressions

We have studied the theoretical properties of electromagnetic ion cyclotron (EMIC) waves which occur in the plasma depletion layer. Our analysis assumes a homogeneous plasma with the characteristics which were measured by the AMPTE/CCE satellite at 1450-1501 UT on October 5, 1984. During this time, waves were observed in the Pc 1 frequency range (0.2-5 Hz) below the hydrogen gyrofrequency, and we identify these waves as EMIC waves. In agreement with observations, the theory predicts two frequency bands of waves, above and below about 0.4 ΩH, where ΩH is the hydrogen gyrofrequency. The higher-frequency instability is driven by the temperature anisotropy of the H+ ions, while the lower-frequency instability is driven by the temperature anisotropy of the He2+ ions. These two frequency bands occur on the same dispersion surface. The EMIC waves tend to quasi-linearly control the value of the proton temperature ratio T⊥/T∥ by an increase in T∥ due to scattering so that the bulk plasma stays near marginal stability. Here, T∥ (T⊥) is the temperature parallel (perpendicular) to B0. Without convective effects, the nonlinear wave amplitude tends to be large over the entire angular range 0 ≤ θkB ≤ 75°, where θkB is the angle between the wave vector and the background magnetic field (B0). However, waves for which the perpendicular (to B0) group velocity υg⊥ is large, are likely to be convectively limited in growth. Within the higher-frequency band, υg⊥ is small only for wave vectors k which are close to parallel to B0. Within the lower-frequency band, υg⊥ is small only for oblique k. Therefore, it is likely that the higher-frequency waves will have k roughly parallel to B0 and will be left-hand polarized, while the lower-frequency wave band will have k oblique to B0 and will be linearly polarized, in agreement with observations.

Electromagnetic ion cyclotron waves in the plasma depletion layer

This paper reports the multisatellite and ground observations of two pseudo-substorm onset events that occurred successively at 0747 UT and 0811 UT, May 30, 1985, with more attention to the 0747 UT onset. The distinguishing features of the 0747 UT event are as follows. (1) The substorm-associated tail reconfiguration started in a very localized region in the near-Earth magnetotail. (2) The magnitude of the current disruption decreased markedly as the disruption region expanded tailward. (3) On the ground the onset of a very small negative bay (∼ 40 nT) was observed simultaneously with the onset of the current disruption, but over a much wider local time sector than the near-Earth tail reconfiguration. Positive bay onsets at mid-latitudes also had a longitudinally wide distribution. From these features we infer that in the present event the current disruption took place filamentarily near AMPTE/CCE at ∼8.8 RE. It is also inferred that pseudo-substorm onsets are distinguished from standard substorm onsets by the absence of a global expansion of the current disruption, and that the spatial scale of the onset region in the magnetosphere is not a major difference between the two. The present study suggests that the spatial distribution of the magnetic distortion before onsets is an important factor to determine the expansion scale of the current disruption. It is also suggested that the current disruption is basically an internal process of the magnetosphere.

A multisatellite study of a Pseudo-substorm onset in the near-earth magnetotail

The overall objective of the particle environment monitor (PEM) is to provide comprehensive measurements of both local and global energy inputs into the Earth's atmosphere by charged particles and Joule dissipation using a carefully integrated set of instruments. PEM consists of four instruments: the atmospheric X ray imaging spectrometer (AXIS), the high-energy particle spectrometer (HEPS), the medium-energy particle spectrometer (MEPS), and the vector magnetometer (VMAG). AXIS provides global scale images and energy spectra of 3- to 100-keV bremsstrahlung X rays produced by electron precipitation into the atmosphere. HEPS and MEPS provide in situ measurements of precipitating electrons in the energy range from 1 eV to 5 MeV and protons in the energy range from 1 eV to 150 MeV. Particles in this energy range deposit their energy in the atmosphere at altitudes extending from several hundred kilometers down to as low as ∼30 km. VMAG provides the magnetic field direction needed to indicate and interpret the locations and intensities of ionospheric and field-aligned currents as well as providing a reference for the particle measurements. This paper describes each instrument separately and also in the context of the PEM objectives which include the determination of energy deposition and ionization production rates as functions of altitude. Examples of data acquired early in the Upper Atmosphere Research Satellite (UARS) mission are presented.

Recent observations in Earth's magnetosheath have delineated several different kinds of magnetic fluctuation spectra below the proton cyclotron frequency. This paper provides a theoretical interpretation for some of these observations, describing solutions of the linear Vlasov dispersion equation for fully electromagnetic instabilities for particle distributions which model those observed in the magnetosheath. The model assumes a high-[beta], homogeneous plasma with bi-Maxwellian, anisotropic (T[sub [perpendicular]p]/T[sub [parallel]p]) protons; a similarly anisotropic, tenuous, doubly ionized helium component; and isotropic cool electrons. This model also assumes a uniform magnetic field and no relative average drifts among the components. This model yields three growing modes: the proton cyclotron anisotropy, the helium cyclotron anisotropy, and the mirror instabilities. The regimes in [beta][sub p] versus T[sub [perpendicular]p]/T[sub [parallel]p] space which correspond to maximum growth rates of the mirror and proton cyclotron anisotropy instabilities are computed, including helium densities appropriate for the magnetosheath; the results show very good agreement with the observations of mirror-like and proton-cyclotron-like events. This agreement with observations implies that the transition between cyclotron and mirror fluctuation dominance is consistent with linear theory. 33 refs., 7 figs., 1 tab.

Dynamic spectral analysis covering frequencies 0.1 to 4.0 Hz has been applied to analyze Active Magnetospheric Particle Tracer Explorers CCE magnetic field data during periods of magnetospheric compressions when the spacecraft sampled the magnetosheath. Ion (H+, He2+) and electron data are used to identify regions, to monitor the upstream shock geometry, and to evaluate moments of the proton distribution. A total of 14 encounters representing 46 hours of observations are analyzed. For quasi-perpendicular shock conditions, two distinctive band limited spectral types are found to characterize the majority of magnetosheath observations: (1) purely compressional fluctuations with F 5 and T⊥p/T∥p of 1.5 whereas EMIC waves occur for βp≤1 and T⊥p/T∥p = 2.5 - 5 (the subscript p denotes quantities evaluated for protons). EMIC waves also occur for higher field strength and lower plasma densities than mirror waves, indicative of EMIC wave occurrence in the plasma depletion layer (PDL). The increased T⊥p/T∥p during EMIC waves relative to periods of mirror waves is due to a decrease in T∥p suggesting that the EMIC wave region has suffered a loss of particles in the parallel direction. A compilation of the temporal sequence of spectral structures shows that EMIC waves occur next to the magnetopause while mirror waves occur outside the region of EMIC waves. We conclude that there is a close relationship between EMIC waves in the sheath and the PDL. Both the density depletion and the increase in temperature anisotropy, Ap = T⊥p/T∥p - 1, are attributed to extrusion of plasma along the draped field lines as plasma flows into the PDL. For quasi-parallel upstream conditions, the magnetic field power spectra often exhibit no band limited structures but only broadband noise. The absence of EMIC wave emissions during quasi-parallel conditions is consistent with predictions that the PDL does not form for radial IMF conditions.

Magnetic pulsations from 0.1 to 4.0 Hz and associated plasma properties in the Earth's subsolar magnetosheath and plasma depletion layer

One- and two-dimensional initial value hybrid computer simulations are used with a magnetosheath parameter model to study the consequences of the growth of the mirror and ion cyclotron anisotropy instabilities. Magnetosheath observations have demonstrated inverse correlations between the proton and helium ion temperature anisotropies and the proton parallel β. Using the maximum growth rate as a fitting parameter, linear Vlasov instability theory for the proton cyclotron and helium cyclotron anisotropy instabilities reproduces both observed correlations. Furthermore, results from the asymptotic states of simulations of the ion cyclotron instabilities qualitatively reproduce both observations.

A study of AMPTE CCE magnetic field data covering the frequency range 0.1-4.0 Hz using all data obtained during the first complete local time precession of the satellite orbit major axis (7,500 hours of observations) has been made to evaluate the occurrence of transverse, narrowband Pc 1-2 emissions, identified as electromagnetic ion cyclotron (EMIC) waves, in the equatorial magnetosphere from L = 3.5 to L = 9 at all local times. A set of example events illustrates the pattern of Pc 1-2 occurrence: events occur primarily for L > 7, and a radial separation of several R{sub E} between low ( 6) pulsations is observed. Statistically, the highest concentration of events occurred near apogee in the afternoon. The L>6 and L,6 event populations appear to be radially separated in the morning but merge together in the afternoon. The authors construct a normalized occurrence distribution throughout the equatorial plane from L = 3.5 to L = 9 of Pc 1-2 with peak to peak amplitudes greater than 0.8 nT. The occurrence distribution exhibits a number of properties: for L > 7, Pc 1-2 occur at any given place in the early afternoon (1200-1500 MLT) with 10-20% probability and inmore » the morning (0300-0900 MLT) with {approx} 3% probability; the L = 6-7 local time distribution reproduces results obtained previously from data at geostationary orbit; L 7 events implies that plasma sheet ion develop sufficient temperature anisotropy to generate EMIC waves on a routine basis in their drift from the nightside to the dayside and that plasma sheet ions on open drift paths rather than ring current ions on closed drift paths present the greatest source of equatorially generated EMIC waves.« less

A statistical study of Pc 1–2 magnetic pulsations in the equatorial magnetosphere: 1. Equatorial occurrence distributions

Pearl pulsations, with an average repetition period of 60 s, were recorded using the magnetic and electric field experiments on the polar-orbiting Viking satellite. The wave event occurred on September 30, 1986, during Viking orbit 1212 at 1030 MLT, from L = 3.6 to L = 4.1, and at an altitude of 13,500 km. Electron density observations obtained from Viking show that the waves were generated at the plasmapause and at lower amplitudes in the plasmasphere. The wave Poynting flux, calculated using the magnetic and electric field, indicated that the waves generally were propagating downward toward the ionosphere, although upward Poynting fluxes were observed. Clear evidence of upward propagating waves, associated with downward propagating waves reflected at the ionosphere, was not observed. Linear convective growth rates suggest that the anisotropic ions which provide the free energy have a perpendicular temperature around 15 keV. The repetition period, calculated using the measured electron density and magnetic field strength at Viking, is consistent with the double-hop transit time for ion cyclotron waves which propagate along field lines from one hemisphere to the other. However, the absence of upward propagating wave packets implies that the upper limit of the wave ionospheric reflection coefficient is on the order of 10 to 20%. Alternative mechanisms for producing the observed repetition are also investigated and include a periodic generation model of pearl pulsations at the ion bounce period.

Viking magnetic and electric field observations of periodic Pc 1 waves: Pearl pulsations

AMPTE CCE magnetic field data from a period spanning a complete local time revolution of the satellite orbit major axis are used to examine the occurrence distribution of transverse narrowband Pc 1-2 emissions in the equatorial magnetosphere from L = 3.5 to L = 9 at all local times. Three examples are presented to illustrate the properties of events occurring at dawn, noon, and dusk. The early afternoon outer magnetosphere is found to be the dominant site for electromagnetic ion cyclotron wave occurrence. Pc 1-2 exhibited a radial structure with a gap between high- and low-L events. The example intervals indicate that a significant local time variation of wave properties may exist. Distributions are presented of narrowband Pc 1-2 frequency, ellipticity, normalized frequency and spectral power vs local time, L, and magnetic latitude, using the data base of more than 9000 events obtained from AMPTE CCE magnetometer data. Events occurring in the region 0300-0900 MLT, L greater than 7 are distinctly different from the remainder of Pc 1-2. The unique features of this population are linear polarization at all latitudes and high normalized frequency, 0.4 to 0.5 on average.

A statistical study of Pc 1-2 magnetic pulsations in the equatorial magnetosphere. I - Equatorial occurrence distributions. II - Wave properties

A statistical study of narrowband transverse 0.1- to 4.0-Hz magnetic pulsations, essentially Pc 1–2 (0.1–5.0 Hz), occurring from L=3.5 to L=9, |MLAT| 7 have not previously been discussed and are found to exhibit remarkable polarization behavior. The A.M. events have the highest X observed in the data base, with X averaging 0.4 to 0.5, but most remarkably, they are linearly polarized at all magnetic latitudes sampled. Given the high normalized frequency, the equatorial linear polarization of the A.M. events cannot be explained in terms of a crossover from left- to right-hand polarization occurring during propagation from low to high magnetic field strengths. Oblique propagation or the effects of multiple reflection through the wave growth region might lead to linear polarizations. The results suggest that a new examination of EMIC wave generation specifically addressing the properties of this A.M. population may be needed.

A statistical study of Pc 1–2 magnetic pulsations in the equatorial magnetosphere: 2. Wave properties

Observations from the Charge Composition Explorerin 1985 and 1986 revealed fifteen current disruption events in which the magnetic field fluctuations were large and their onsets coincided well with ground onsets of substorm expansion or intensification. These events are of short durations locally (∼1–5 min). They are mostly confined to within ∼0.5 RE of the neutral sheet and 1 hour local time from the magnetic midnight. Over the disruption interval, the local magnetic field can change by as much as a factor of ∼7. In general, the stronger the current buildup and the closer to the neutral sheet, the larger the resultant field change. There is also a tendency for a larger subsequent enhancement in the AE index with a stronger current buildup prior to current disruption. For events with good pitch angle coverage and extended observation in the neutral sheet region we find that the particle pressure increases toward the disruption onset and decreases afterward. Just prior to disruption, either the total particle pressure is isotropic, or the perpendicular component (P⊥) dominates the parallel comment (P∥), the plasma beta is seen to be as high as ∼70, and the observed plasma pressure gradient at the neutral sheet is large along the tail axis. The deduced local current density associated with pressure gradient is ∼27–80 nA/m² and is ∼85–105 mA/m when integrated over the sheet thickness. We infer from these results that just prior to the onset of current disruption, (1) an extremely thin current sheet requiring P∥ > P⊥ for stress balance does not develop at these distances, (2) the thermal ion orbits are in the chaotic or Speiser regime while the thermal electrons are in the adiabatic regime and, in one case, exhibit peaked fluxes perpendicular to the magnetic field, thus implying no electron orbit chaotization to possibly initiate ion tearing instability, and (3) the neutral sheet is in the unstable regime specified by the cross-field current instability. Subsequent to the disruption onset, enhancement of magnetic noise over a broad frequency range, magnetic field aligned counterstreaming electron beams, ion energization perpendicular to the magnetic field, and current reduction in the amount similar to that of current buildup during the growth phase are observed. These features seem to be compatible with the predicted development of the cross-field current instability.

The distribution of ULF energy (frequency < 80 mHz) in the inner magnetosphere (L = 2.5-6.5) has been studied using magnetic field measurements made with the Active Magnetospheric Particle Tracers Explorers Charge Composition Explorer (AMPTE CCE) spacecraft during its whole mission of over 4 years. The magnetic field time series was split into consecutive 10-min segments and subjected to fast Fourier transform (FFT), and the spectral data were achieved along with the Kp index and the satellite location. This data base was then used to examine the spatial distribution of ULF energy. Overall, the oscillation energy is localized to the dayside except for compressional oscillations associated with substorms. From the spatial distributions of wave power and spectral structures the authors identify several pulsation types, including multiharmonic toroidal oscillations; equatorial compressional Pc 3 oscillations; second harmonic poloidal oscillations; and nightside compressional oscillations; equatorial compressional Pc 3 oscillations; second harmonic poloidal oscillations; and nightside compressional oscillations. The toroidal oscillations are observable even in the plasmasphere, and using their frequencies they can determine the statistical radial profile of the plasma mass density and Alfven velocity. They find a clear signature of the plasmapause in the profiles of these average parameters. Of particular interestmore » among the other oscillation types are the equatorial compressional Pc 3 oscillations that have an average spectral peak around 30 mHz and are present in the prenoon sector and from L{approximately}3 to {approximately}5. The oscillations are similar to the compressional Pc3 previously observed at and near geostationary orbit and might represent magnetohydrodynamic waves propagating from the parallel portion of the bow shock.« less

Distribution of ULF energy (ƒ < 80 mHz) in the inner magnetosphere: A statistical analysis of AMPTE CCE magnetic field data

“Upstream waves,” generated in the solar wind upstream of a quasi-parallel bow shook, are believed to be a major source of the Pc 3-4 pulsation activity observed in the dayside magnetosphere. In an attempt to better understand the means by which “upstream wave” energy is transmitted from the solar wind into the magnetosphere, we compared simultaneous data from ISEE 1 and 2 in the upstream solar wind, AMPTE IRM in the subsolar magnetosheath, and AMPTE CCE in the dayside magnetosphere. Our observations indicate that dayside magnetospheric Pc 3-4 pulsation activity and low IMF cone angles are associated with increased turbulence in the subsolar magnetosheath magnetic field (with large amplitude fluctuations both parallel and transverse to the average field direction), and with increased and highly variable levels of energetic magnetosheath particles. Fourier analysis of the magnetic field fluctuations shows broadband increases in wave power from 0.01 Hz to at least 0.5 Hz, but with peak power at Pc 3-4 frequencies; there is no evidence in our data set of narrow-band magnetic field variations in the magnetosheath at these times. Purely compressional waves, which are at times observed in the subsolar magnetosheath, have a somewhat narrower frequency distribution, but are associated with neither upstream wave activity nor magnetospheric pulsations.

A comparison of ULF fluctuations in the solar wind, magnetosheath, and dayside magnetosphere: 1. Magnetosheath morphology

A series of recent studies of Pc 3 magnetic pulsations in the dayside outer magnetosphere has given new insights into the possible mechanisms of entry of ULF wave power into the magnetosphere from a bow shock related upstream source. In this paper we first review many of these new observational results by presenting a comparison of data from two 10-hour intervals on successive days in April 1986 and then present a possible model for transmission of pulsation signals from the magnetosheath into the dayside magnetosphere. Simultaneous multi-instrument observations at South Pole Station, located below the cusp/cleft ionosphere near local noon, magnetic field observations by the AMPTE CCE satellite in the dayside outer magnetosphere, and upstream magnetic field observations by the IMP 8 satellite show clear interplanetary magnetic field field magnitude control of dayside resonant harmonic pulsations and band-limited very high latitude pulsations, as well as pulsation-modulated precipitation of what appear to be magnetosheath/boundary layer electrons. We believe that this modulated precipitation may be responsible for the propagation of upstream wave power in the Pc 3 frequency band into the high-latitude ionosphere, from whence it may be transported throughout the dayside outer magnetosphere by means of an “ionospheric transistor.” In this model, modulations in ionospheric conductivity caused by cusp/cleft precipitation cause varying ionospheric currents with frequency spectra determined by the upstream waves; these modulations will be superimposed on the Birkeland currents, which close via these ionospheric currents. Modulated region 2 Birkeland currents will in turn provide a narrow-band source of wave energy to a wide range of dayside local times in the outer magnetosphere.

The role of the ionosphere in coupling upstream ULF wave power into the dayside magnetosphere

H. LUEI-IR, ' T. A. POTEMRA; B. J. ANDERSON,  AND L. J. ZANETrI  Data from three spacecraft (AMPTE IRM, ACCE, and ISEE 1 or 2) are used to study the correlation among the field and plasma conditions in the subsolar magnetosheath region, ULF wave activity in the magneto- sphere, and the cone angle of the IMF. A disturbance parameter, R, which is the magnitude of the normalized resultant of unit vectors (calculated from measurements of the magnetic field or the plasma bulk velocity in a time interval), is used to describe the disturbance of the magnetosheath region. A "quiet" state has R values close to unity. We have studied five time intervals and found that when the R values of the magnetosheath magnetic field were below 0.8, indicative of a disturbed magnetosheath near local noon, transverse harmonic oscillations of magnetic field lines in the Pc 3, 4 range were observed in the magnetosphere and small cone angles were observed in the solar wind. We have also investigated the variation of other magnetosheath parameters (such as the magnetic pressure, the thermal pressure, the dynamic pressure, and the pelurbation energy, etc.) under various magnetosheath conditions by comparing them with the disturbance parameter. It is found that the thermal beta (the ratio of the thermal pressure to the magnetic pressure) and the pelurbation energy increase greatly as R decreases (i.e., as the magnetosheath region becomes more disturbed). The total pressure, which is the sum of the magnetic, thermal, and dynamic pressure of the subsolar magnetosheath region, decreases as the region becomes more disturbed. The dynamic pressure and the dynamic beta (the ratio of the dynamic pressure to the magnetic pressure) measured in the magnetosheath are poorly correlated with R, indicating that the changes in magnitude of the plasma bulk velocity in the subsolar magnetosheath have little effect on the occurrence of Pc 3-4 waves in the outer magnetosphere. All magnetosheath parameters we examined became more variable during disturbed periods than during quiet ones. The implication of the above results to the transport of wave energy from the solar wind to the magneto sphere is discussed.

A comparison of ULF fluctuations in the solar wind, magnetosheath, and dayside magnetosphere: 2. Field and plasma conditions in the magnetosheath

Active Magnetospheric Particle Tracer Explorer (AMPTE)/Charge Composition Explorer observations downstream from the quasi-perpendicular bow shock are combined with upstream observations from the AMPTE/UKS and IRM spacecraft to distinguish intrinsic changes in the solar wind H+ and He2+ plasma and magnetic field from changes inherent in the magnetosheath and near magnetopause region. Using these spacecraft, a plasma depletion layer and an external accelerated flow layer (on the magnetosheath side, sunward of the magnetopause) are identified in the magnetosheath near the magnetopause. Compared to the upstream region, the magnetosheath plasma has higher densities and temperatures and the same He2+/H+ density and average temperature ratios. Compared to the magnetosheath, the plasma depletion layer has decreased solar wind ion densities, increased magnetic field magnitude, lower and more anisotropic ion temperatures, a higher He2+/H+ density and temperature ratio, and an energetic H+ population leaked from the magnetosphere. Compared to the depletion layer, plasma the accelerated flow layer on the magnetosheath side of the magnetopause has an increased flux of energetic electrons and the addition of magnetosheath ions reflected off the magnetopause. The density, temperature, and magnetic field changes and the presence of leaked magnetospheric protons in the plasma depletion layer are consistent with the draping and pileup of the magnetic field sunward of but near the dayside magnetopause. Changes in the ion distributions in the accelerated flow layer are consistent with dayside magnetic reconnection. These results indicate that at times the plasma adjacent to the dayside magnetopause has significantly different characteristics from the magnetosheath or upstream solar wind plasma.

He2+ and H+ dynamics in the subsolar magnetosheath and plasma depletion layer

Simultaneous data from ISEE 1 and 2 in the upstream solar wind, from AMPTE IRM in the subsolar magnetosheath, and from AMPTE CCE in the dayside magnetosphere are used to investigate the properties of the magnetosheath responsible for the transmission into the magnetosphere the ULF waves generated in the solar wind upstream of a quasi-parallel bow shock. The data are used to characterize the magnetosheath both during the periods when azimuthally polarized resonant harmonic ULF magnetic pulsations were observed in the dayside outer maagnetosphere, and when they were not. In addition, a detailed analysis is carried out of magnetic field and plasma conditions in the subsolar magnetosheath during these and other periods.

A comparison of ULF fluctuations in the solar wind, magnetosheath, and dayside magnetosphere. I - Magnetosheath morphology. II - Field and plasma conditions in the magnetosheath

Observations from AMPTE/CCE in the Earth's magnetosheath on October 5, 1984 are presented to illustrate 0.1–4.0 Hz magnetic field pulsations in the subsolar plasma depletion layer (PDL) for northward sheath field during a magnetospheric compression. The PDL is unambiguously identified by comparing CCE data with data from IRM in the upstream solar wind. Pulsations in the PDL are dominated by transverse waves with F/FH+ ≤ 1.0 and a slot in spectral power at F/FH+ = 0.5. The upper branch is left hand polarized while the lower branch is linearly polarized. In the sheath the proton temperature anisotropy, A = T⟂/T∥ − 1, is ≈ 0.6 but it is ≈ 1.7 in the PDL during wave occurrence. The properties and correlation of waves with increased anisotropy indicate that they are electromagnetic ion cyclotron waves.

Electromagnetic ion cyclotron waves observed in the plasma depletion layer

Viking magnetic field, electric field, and image data have been used to assess polar region phenomena for steady state northward interplanetary magnetic field (IMF) conditions. Regions of polar Birkeland current (NBZ currents) and convection and their extent from the vicinity of the magnetic pole are determined. Also discussed are mechanisms that could produce polar aurora in general; two suggestions are (1) converging electric fields from convection patterns alone and (2) the bifurcation of the magnetotail with its associated plasma transport and convection patterns. Macroscopic (> 1° latitude) systems of Birkeland currents and convection in the polar regions have been established for a case on April 9,1986, from Viking spacecraft data. The current systems were confined to the highest latitudes of the polar regions and occurred during strongly northward IMF with a significantly negative Bx. An arc extends across the polar region within the dawn cell of Birkeland current. The arc is located at a sunward to antisunward convection reversal that corresponds to a converging electric field. A converging electric field (▽ · E < 0) alone is suggested as the cause of this polar arc. The signature of both transverse disturbance vectors indicates that the polar region dawn NBZ Birkeland current does not connect to the dayside auroral region. It is inferred that the dawn polar region convection cell associated with this Birkeland current is also limited in the sunward direction and does not connect to the dayside auroral region convection.

Polar region Birkeland current, convection, and aurora for northward interplanetary magnetic field

Electromagnetic ion cyclotron waves in the Pc1-2 frequency range (0.1-5 Hz) have been observed in Earth's equatorial magnetosphere over the range L=3 to 9 by the AMPTE/CCE magnetic fields experiment. The authors report detailed analysis of data from two orbits together with preliminary occurrences statistics from 31 days. One example occurred during disturbed geomagnetic conditions (maximum AE>1,000 nT) and exhibited intense Pc1 from L=5 to the magnetopause (L{approx}7.5). The second example occurred during moderate to quiet conditions (average AE{approx}300 nT) and displayed Pc1 in two distinct L ranges: low (L{approx}4) and high (L>7.5). Statistical results show that Pc1 are {approx}4 times more common for L>7 than for L<6 and occur primarily in the afternoon. The discovery of a statistically dominant outer magnetospheric source region implies that ring current interaction with the plasmasphere is not the primary source of Pc1 excitation but suggests that plasma sheet ions may be a significant energy source for Pc1. This result is consistent with the strong dependence of the linear convective growth rate on magnetic field strength.

Pc1 pulsations observed by AMPTE/CCE in the Earth's outer magnetosphere

Spacecraft observations have shown that geomagnetic pulsations originating in magnetospheric processes, in spite of their small amplitude on the ground, have amplitudes in space relative to the local magnetic field of 5-10 percent and occasionally up to about 50 percent. It is noted that by studying geomagnetic pulsations, a detailed comparison can be made between plasma physics theory and observations that are not possible in laboratory experiments. Also geomagnetic pulsations play a role in magnetospheric dynamics and energy transport, and their study forms an integral part of enhancing the knowledge of the magnetosphere. The importance of spacecraft observations are discussed and attention is given to such topics as waves in the magnetosphere, field-line resonances, the quantitative analysis of a dipole field, plasma instabilities, and energy flow. 28 refs.

Ultra-low-frequency magnetic pulsations in the earth's magnetosphere

In this paper the authors present multipoint observations of a small substorm which occurred just after 0110 UT on April 25, 1985. The observations were made by spacecraft (AMPTE CCE, AMPTE IRM, DMSP F6, and DMSP F7), ground auroral stations (EISCAT magnetometer cross, Syowa, Narssarssuaq, Great Whale River, and Fort Churchill), and mid-latitude stations (Furstenfeldbruck, Toledo, and Argentine Island). These data provide them with a broad range of observations, including the latitudinal extent of the polar cap, visual identification of substorm aurorae and the magnetic perturbations produced directly beneath them, in situ magnetic field and energetic particle observations of the disruption of the cross-tail current sheet, and observations concerning the spatial expansion of the current disruption region from two radially aligned spacecraft. The DMSP data indicate that the event took place during a period when the polar cap was relatively contracted, yet the disruption of the current sheet was observed by CCE at 8.56 R{sub E}. They have been able to infer a considerable amount of detail concerning the structure and westward expansion of the auroral features associated with the event, and they show that those auroral surges were located more than 10{degree} equatorward of the boundary between open andmore » closed field lines. Moreover, they present evidence that the current sheet disruption observed by CCE in the neutral sheet was located on field lines which mapped to the westward traveling surge observed directly overhead of the ground station at Syowa. Furthermore, the observations strongly imply that disruption of the cross-tail current began in the near-Earth region and that it had a component of expansion which was radially antisunward.« less

Three-component dynamic spectrograms (0–80 mHz) of AMPTE/CCE magnetic field data from August 24, 1984, through December 7, 1985, have been used to survey ULF pulsation activity occurring from L = 5 to 9 in the equatorial magnetosphere (±16° magnetic latitude) at all local times. The data were scanned visually, and each half-hour interval was categorized by spectral type, approximate polarization, spectral intensity, and spacecraft location to produce a data base representing 7231 hours of observations. Coherent pulsations are divided into nine categories which fall into four basic classes: (1) harmonic toroidal resonances (17.9% of the data), (2) fundamental mode toroidal resonances (11.0%), (3) radially polarized pulsations (5.2%), and (4) compressional low-frequency pulsations (10.6%). Classes (1) and (2) are not mutually exclusive. Intervals devoid of coherent pulsations are divided into five levels according to noise intensity and account for 56.8% of the observations. Uncategorized events represented 4.2% of the data. The spatial occurrence distributions of each pulsation category and the latitude distribution of selected categories have been examined. The basic conclusions of the study are as follows: (1) Harmonic toroidal resonances are found to be the dominant coherent activity on the dayside, particularly in the prenoon hours, where they occur 60% of the time. Their region of excitation is uniformly distributed in radial distance and extends in local time from 0600 to 1600 but cuts off sharply at the local time boundaries. The pattern is consistent with excitation by a dayside energy source, possibly upstream waves, but the spatial distribution places constraints on models of energy transmission. (2) Fundamental toroidal resonances are observed with an occurrence rate of 40% to 50% for L > 8 at dawn but were observed less than 10% of the time at dusk for L > 8. Dusk is also the site of several types of pulsations of sufficient average intensity to obscure fundamental mode resonances, so this trend may be exaggerated by masking effects. Nonetheless, the dawn/dusk asymmetry is sufficiently remarkable to warrant further study. The occurrence distribution exhibits a pronounced node at the magnetic equator, and the occurrence rate for MLAT > 13° at dawn is ≈80%, suggesting that the fundamental mode resonances are present continually at the dawn flank. The preference for occurrence at the flank suggests that the Kelvin-Helmholtz instability is ultimately responsible for driving the resonances. (3) Radially polarized pulsations are observed ≈10% of the time except in the 0400–1100 MLT, sector where their occurrence rate is less than 5%. The occurrence distribution of radially polarized waves suggests that they are driven by wave-particle interactions but not by freshly injected particles. (4) Storm time Pc 5 type waves were observed most often at dusk for L > 8 where they occurred ≈30% of the time. A secondary maximum in storm time Pc 5 type occurrence near dawn was also found. The spatial distribution of storm time Pc 5 type waves suggests a relationship to substorm injections, although the secondary maximum at dawn may not be explained by this mechanism alone. (5) Quiet periods represent 30% to 50% of nighttime but less than 10% of daytime observations, while noisy periods represent ≈20% of the data at night and 40% to 50% during the day.

A statistical study of Pc 3–5 pulsations observed by the AMPTE/CCE Magnetic Fields Experiment, 1. Occurrence distributions

The UV images obtained with the Viking satellite often show bright features which resemble “beads” or “pearls” aligned in the east–west direction between noon and 1800 MLT (Lui et al., 1989). Viking acquired a series of 25 UV images during a 28-min period on July 29, 1986, which showed a distinctive series of periodic bright features in this region. Magnetic field and hot plasma measurements obtained by Viking confirm that the UV emissions are colocated with the field line projection of an upward-flowing region 1 Birkeland current and precipitating energetic (∼200 eV) electrons. These observations support previous work (see the review by Evans, 1985), which concludes that this region is the ionospheric projection of the cusp and low-latitude boundary layer. The magnetic field and electric field measurements show transverse oscillations (predominantly in the westward and southward components, respectively) with a nearly constant period of about 3.5 min from 67° invariant latitude equatorward up to the location of the large-scale Birkeland current system near 76° invariant latitude. The electric field oscillations lead the magnetic field oscillations by about a quarter-period. We interpret the observed oscillations as standing Alfven waves driven at a frequency near the local resonance frequency by a large-scale wave in the boundary layer. We propose that the energy flux of the precipitating low-energy electrons in this afternoon region is modulated by this boundary wave and produces the periodic UV emission features. These observations may be interpreted in terms of a boundary wave drifting tailward with a speed of about 0.12 MLT hour/min (1.8° longitude/min or about 800 m/s in the ionosphere) and with a wavelength of about 0.35 MLT hour (5.3° of longitude or about 160 km in the ionosphere). The results of this study support the view that large-scale oscillations of magnetospheric boundaries, possibly associated with the Kelvin-Helmholtz instability, can modulate currents, particles, and auroral forms.

Periodic auroral forms and geomagnetic field oscillations in the 1400 MLT region

Studies of ULF waves with AMPTE CCE spacecraft: Review of spacecraft observations and outlook on ground/space studies

Very few spacecraft observations of magnetic Pc 3-4 pulsations at L {lt} 4 have been reported in the past despite the fact that Pc 3-4 pulsations are a common occurrence on the ground at L {lt} 4. In order to fill this observational gap in the magnetosphere, the authors have initiated an analysis of magnetic field data acquired by the AMPTE CCE spacecraft. A procedure has been developed to reduce the artificial modulation and noise in magnetic field measurements, with the resultant data useful for studying magnetic pulsations with amplitude less that 1 nT in the 1,000 nT (L {approximately} 3) background and periods longer than 12 s. From a survey of 41 CCE passes in L = 2-6 and in the postnoon sector, they find that the most commonly observed pulsations in this region are the east-west oscillations of magnetic field with clearly L-dependent frequencies. These are identified to be the toroidal mode standing Alfven waves. From a comparison of CCE and GOES 5 magnetic field measurements there is evidence that the resonances can be excited by the same mechanism as those previously found at geostationary orbit or beyond. Abrupt changes is resonance frequency, as a function of L,more » are not usually seen, supporting previous reports that the mass or number density profile on the dayside does not have a steep plasmapause structure.« less

Studies of Pc 1-Pc3 Geomagnetic Pulsations at High Southern Latitudes: Implications for origin and Transmission

We use a multipoint case study approach to delineate significant morphological differences between, and distinct sources for, two kinds of high-latitude dayside ULF wave activity in the Pc 3 to Pi 1 frequency range. Ground data obtained during April 26 and 27, 1986, from search coil magnetometers at South Pole Station (invariant latitude −74°) and McMurdo (invariant latitude −79°), located at nominal dayside auroral oval/polar cleft latitude and in the polar cap, respectively, are compared with interplanetary magnetic field data from IMP 8 in the upstream solar wind, magnetic field data from Active Magnetosphere Partice Tracer Explorers (AMPTE) CCE in the prenoon equatorial outer magnetosphere, and precipitating energetic particle data from Defense Meteorological Satellite Program (DMSP) F7 satellite in the dayside ionosphere. Large-amplitude, broad-band Pi 1 activity (which was shown in an earlier study to be statistically dominant at South Pole) is usually weaker or not detectable at McMurdo or at AMPTE CCE. Its occurrence is shown to be related to precipitation of energetic plasma sheet electrons, as established earlier for auroral and subauroral Pi 1 activity. In the cases shown, cusp/cleft latitude Pi 1 activity appears in response to southward turnings of the IMF, with a time delay characteristic of substorm processes. On the other hand, narrow-band Pc 3 activity on the ground occurred at the same time it was observed at AMPTE CCE, and was controlled by the cone angle of the IMF. The intensity of Pc 3 activity decreased roughly with the distance of each ground station from the nominal dayside cleft position, but was clearly evident at McMurdo even in predawn local times. Observed amplitude and local time variations of Pc 3 activity at these very high latitude stations and at AMPTE CCE support recent suggestions of a cusp/cleft-related entry mechanism for these pulsations.

A theoretical model is developed which shows that measurements of ULF wave frequencies from spacecraft may be distorted due to the combined effects of spacecraft motion and spatial gradients in wave frequency, phase velocity, and the oscillation onset time. Spectral broadening and frequency shifts due to sampling biases caused by spacecraft acceleration and nonlinear variations in wave frequency with position are also considered. For toroidal field line resonances observed from AMPTE/CCE, distortions due to spatial gradients in wave frequency are the most important. For commonly observed standing Alfven waves, the measured frequency is lower than the true frequency on the outbound leg of the orbit while it is anomalously high on the inbound pass. The predicted frequency error for the AMPTE/CCE orbit ranges from {approx} 15% for L = 5 to {approx}4% for L = 8. Comparison of fundamental mode frequency measurements made on 10 inbound and 9 outbound passes during low to moderate Kp (2 - to 4+) in the morning sector (0500 to 0900 MLT) confirms the predictions of the model. The average effective ringing time is estimated to be 1000{plus minus}300s. The agreement of this result with theoretical calculations of damping rates due to ionospheric Joule dissipationmore » (Newton et al., 1978) indicates that phase mixing between adjacent toroidal oscillations is not the dominant damping mechanism. The variation of pulsation frequency with L is also used to examine the dependence of plasma mass density on r. The form {rho} {proportional to} r{sup {minus}q} is found to fit the data reasonably well in the outer magnetosphere with q ranging from 3.0 to 5.5 for individual passes and q=4.0 determined from the combinations of all measurements.« less

Distortion effects in spacecraft observations of MHD toroidal standing waves: Theory and observations

The Fusion Plasma Propulsion System scoping study was performed to investigate the possibilities of a fusion powered plasma propulsion system for space applications. Specifically, it was to be compared against existing electric propulsion concepts for a manned Mars mission. Design parameters consist of 1000 N thrust for 500 days, and the minimum mass possible. This investigation is briefly presented and conclusions drawn.

Purpose. To assess the effect of a sustained-release preparation of bone morphogenetic protein-4 (BMP-4) on EOM force generation and muscle size. Methods. Sustained-release pellets, releasing 500 nanograms/day of BMP-4 for a maximum of 3 months, were implanted beneath the superior rectus muscle (SR) belly in anesthetized adult rabbits. The contralateral side received a placebo pellet as a control. After 1, 3, and 6 months, SRs were removed, and force generation at twitch and tetanic frequencies as well as fatigue resistance were determined in vitro. Myofiber size, myosin heavy chain isoform expression, and satellite cell density were assessed histologically. Results. SR force generation was significantly decreased by BMP-4 compared with the contralateral controls. Force generation was decreased by 25-30% by 1 month, 31-50% by 3 months, and at 6 months, after 3 BMP-4-free months, force was still decreased by 20-31%. No change in fatigue was seen. Significant decreases in muscle size were seen, greatest at 3 months. At all time points Pax7- and MyoD-positive satellite cell densities were significantly decreased. Conclusions. The decreased force generation and muscle size caused by sustained release of BMP-4 suggests that myogenic signaling factors may provide a more biological method of decreasing muscle strength in vivo than exogenously administered toxins. Treating antagonist-agonist pairs of EOM with titratable, naturally occurring myogenic signaling and growth factors may provide safe, efficacious, nonsurgical treatment options for patients with strabismus.

Sustained release of bone morphogenetic protein-4 in adult rabbit extraocular muscle results in decreased force and muscle size: potential for strabismus treatment.

PURPOSE
Botulinum toxin A is the most commonly used treatment for blepharospasm, hemifacial spasm, and other focal dystonias. Its main drawback is its relatively short duration of effect. The goal of this study was to examine the ability of corticotropin releasing factor (CRF) or antibody to insulin growth factor I-receptor (anti-IGFIR) to reduce the up-regulation of neuromuscular junctions that are associated with return of muscle function after botulinum toxin treatment.

METHODS
Eyelids of adult rabbits were locally injected with either botulinum toxin alone or botulinum toxin treatment followed by injection of either CRF or anti-IGFIR. After one, two, or four weeks, the orbicularis oculi muscles within the treated eyelids were examined for density of neuromuscular junctions histologically.

RESULTS
Injection of botulinum toxin into rabbit eyelids resulted in a significant increase in the density of neuromuscular junctions at one and two weeks, and an even greater increase in neuromuscular junction density by four weeks after treatment. Treatment with either CRF or anti-IGFIR completely prevented this increase in neuromuscular junction density.

The return of function after botulinum toxin-induced muscle paralysis is due to terminal sprouting and formation of new neuromuscular junctions within the paralyzed muscles. Injection with CRF or anti-IGFIR after botulinum toxin treatment prevents this sprouting, which in turn should increase the duration of effectiveness of single botulinum toxin treatments. Future physiology studies will address this. Prolonging botulinum toxin's clinical efficacy should decrease the number of injections needed for patient muscle spasm relief, decreasing the risk of negative side effects and changes in drug effectiveness that often occurs over a lifetime of botulinum toxin exposure.

Modulating neuromuscular junction density changes in botulinum toxin-treated orbicularis oculi muscle.

Long-Term Application of Bone Morphogenetic Protein-4 Results in Significant Decreases in Muscle Force Generation in Rabbit Extraocular Muscle

PURPOSE
Future pharmacologic treatment of strabismus may be optimized if drugs that are less potentially toxic to patients can be developed. Prior studies have shown that direct injection of extraocular muscles (EOMs) with insulin growth factor or fibroblast growth factor results in significant increases in the generation of EOM force. The purpose of this study was to examine the morphometric and physiological effects of direct EOM injection with the growth factors BMP4, TGFbeta1, Shh, and Wnt3A.

METHODS
One superior rectus muscle of normal adult rabbits was injected with BMP4, TGFbeta1, Shh, or Wnt3A. The contralateral muscle was injected with an equal volume of saline to serve as a control. After 1 week, the animals were euthanatized, and both superior rectus muscles were removed and assayed physiologically. The muscles were stimulated at increasing frequencies to determine force generation. A separate group of treated and control superior rectus muscles were examined histologically for alterations in total muscle cross-sectional area and myosin heavy chain isoform (MyHC) composition.

RESULTS
One week after a single injection of BMP4, TGFbeta1, Shh, or Wnt3A, all treated muscles showed significant decreases in generation of force compared with control muscles. BMP4, TGFbeta1, Shh, and Wnt3A significantly decreased the mean myofiber cross-sectional area of fast MyHC-positive myofibers. BMP4 resulted in a conversion of fast-to-slow myofibers and a significant decrease in the percentage of developmental and neonatal MyHC-positive myofibers. Alterations in mean cross-sectional area and proportion of MyHCs were seen after injection with TGFbeta1, Shh, and Wnt3A. TGFbeta1 and BMP4 injections resulted in increased Pax7-positive satellite cells, whereas BMP4, TGFbeta1, and Wnt3A resulted in a decrease in MyoD-positive satellite cells.

These results suggest that, rather than using toxins or immunotoxins, a more biological approach to decrease muscle strength is possible and demonstrate the potential utility of myogenic signaling factors for decreasing EOM strength. Ongoing drug-delivery studies will elucidate means of extending treatment effect to make such agents clinically useful.

Myogenic growth factors can decrease extraocular muscle force generation: a potential biological approach to the treatment of strabismus.

Localization and Effect of Botulinum Toxin on Neuromuscular Junction Density in Rabbit Orbicularis Muscle

Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus

Botulinum toxin pretreatment augments the weakening effect of injection with ricin-mAb35 in rabbit extraocular muscle.

PURPOSE
The density and three-dimensional localization of neuromuscular junctions (NMJs) of normal and botulinum toxin-treated normal adult rabbit and monkey extraocular muscles (EOMs) were analyzed. To demonstrate average myofiber length, randomly selected individual myofibers were reconstructed and compared with total muscle length.

METHODS
Normal adult rabbit and monkey EOM and normal adult rabbit tibialis anterior were dissected in their entirety, frozen, sectioned longitudinally, and immunostained for NMJ localization. In addition, adult rabbit EOMs were injected with 5 U botulinum toxin, and NMJ density was determined after 2 weeks. NMJ locations for the three groups of EOM were reconstructed, and density of NMJ was determined. Individual myofibers were reconstructed from the orbital and global layers to determine mean fiber length.

RESULTS
NMJs were dispersed throughout the entire length of all EOMs examined from adult rabbits and monkeys and were visualized by alpha-bungarotoxin staining and three-dimensional reconstruction of serial sections. In leg muscle, two relatively tight bands of NMJs were seen. Botulinum toxin significantly increased total NMJ density. Mean fiber lengths were 1.9 and 4.83 mm in the orbital and global layers, respectively, approximately 10% and 24% of the total origin-to-insertion muscle lengths. In addition, individual myofibers continuously changed their intrafascicular relationships over their lengths.

The density and distribution of NMJs in normal EOMs are more extensive than previously described. Individual myofibers are significantly shorter than the tendon-to-tendon muscle length in both muscle layers. Botulinum toxin results in a doubling of NMJ density. NMJ localization in normal EOMs has ramifications for understanding eye movement control, but it is also important when surgical or pharmacologic intervention is used for the treatment of strabismus, nystagmus, or other eye muscle disorders.

Myofiber length and three-dimensional localization of NMJs in normal and botulinum toxin treated adult extraocular muscles.

Effect of Basic Fibroblast Growth Factor (FGF2) on Force Generation in Rabbit Extraocular Muscle

Neuromuscular Junction Localization in Normal and Botox–Treated Extraocular Muscles of Rabbits

PURPOSE
Previous work has demonstrated the effectiveness of insulin-like growth factor (IGF)-II in increasing force generation in extraocular muscle (EOM). Studies in the literature have suggested that IGF-I would be even more effective than IGF-II. This study was performed to assess the effects on muscle mass and force generation of IGF-I injection in adult rabbit superior rectus muscle.

METHODS
Adult rabbits received a single injection of IGF-I at one of several doses into one superior rectus muscle. One week after treatment, the rabbits were euthanatized, and the superior rectus muscle from each orbit was removed. Force generation was measured using an in vitro apparatus, and injected muscles were compared with the contralateral control. A second group of animals were injected similarly, and the muscles were examined at 1 week for changes in cross-sectional area of individual myofibers.

RESULTS
EOMs demonstrate significant numbers of cells expressing the IGF receptor. After the EOMs were injected with IGF-I, there were significant increases both in muscle force generation and cross-sectional area at all doses tested in this study. Doses of 10 and 25 microg IGF-I were most effective.

Direct muscular injection of IGF-I effectively increases EOM force generation without the potential biomechanical hazards of surgery such as permanently altered muscle length or insertional position on the globe.

Increased extraocular muscle strength with direct injection of insulin-like growth factor-I.

Increasing muscle strength as a treatment for strabismus: sustained release of insulin-like growth factor-1 in rabbit extraocular muscle.

Combining Ricin–mAb35 and Botulinum Toxin to Weaken Extraocular Muscle

Sustained Release of Insulin-like Growth Factor Results in Stronger Extraocular Muscle

Histological Assessment of a Rat Model of Anterior Ischemic Optic Neuropathy

SUMMARY Broiler chickens are routinely fed diets containing the growth promotant 3-nitro-4hydroxyphenylarsonic acid (roxarsone; ROX). Four trials were conducted to determine the amount of arsenic present in broiler excreta and broiler litter when broilers were fed a diet containing ROX. Two experimental diets were utilized in all four experiments: the control diet (CON) that contained no added ROX and the ROX diet that contained 45.4 g of ROX per ton. The CON and ROX diets were fed from 1 d of age until 42 d of age. From 42 to 47 d of age, both treatments received a withdrawal diet that contained no ROX. Weekly fecal samples were taken during Experiment 1. In Experiments 2, 3, and 4, litter samples were collected prior to each chick placement and at the end of each growout. All fecal and litter samples were analyzed for total arsenic content. In Trial 1, the total arsenic level in the feces of birds receiving the ROX diet increased from 1 to 4 wk; the total arsenic level decreased from 4 to 6 wk, and continued to decrease through the withdrawal period (42 to 47 d). In addition, the ROX birds exhibited a greater level of total arsenic in the feces than the CON birds during each week of Trial 1. The total arsenic level in the feces of the birds receiving the CON diet remained constant throughout Trial 1. In Trials 2, 3, and 4, the total arsenic level in ROX built-up litter did not exhibit a continuous increase with multiple growouts and remained constant in the CON built-up litter.

THE EFFECT OF DIETARY 3-NITRO- 4-HYDROXYPHENYLARSONIC ACID (ROXARSONE) ON THE TOTAL ARSENIC LEVEL IN BROILER EXCRETA

Determination of bis(2-ethylhexyl) phthalate in cow's milk and infant formula by high-performance liquid chromatography

Arachis oil was added to heavily wilted ryegrass at a mean level of 4 · 16 % of the total ensiled dry matter. Gas-liquid chromatography of the lipid extract was used to investigate possible chemical changes in the ensiled oil. The data obtained suggest that little degradation of the acids occurred. The percentage of linolenic acid increased and this was accompanied by a decrease in the percentage of linoleic acid and oleic acid. The presence of the oil decreased the volatile fatty acid content of the silage. There were no significant differences in the pH or the proportion of volatile fatty acids present in the rumen liquor of sheep fed the oil-treated silage compared with those in the rumen liquor of sheep fed control silage.

Effect of arachis oil on the conservation of heavily wilted herbage ensiled in plastic containers. II. Fate of the arachis oil and its effect on the rumen volatile fatty acids of sheep.

SUMMARY Experiments were carried out to assess the effect of the following diets: unwilted and wilted silage, barn-dried hay and wilted silage and ensiled mixtures of grass and barley on the ruminal VFA patterns in sheep. There was a tendency for the unwilted silage to result in a slightly higher level of rumen acetate and a lower level of propionate than grass, wilted silage or barn-dried hay. In two of the experiments (Exps. 2 and 4) significant direct relationships were found between rumen acetate and the crude-fibre content of the diets and significant inverse relationships were found between the rumen propionate and the crude-fibre content of the diets. Significant relationships were also found between the rumen acids and the metabolizable energy content of the diets and in Exp. 2 there was a significant relationship between the rumen acetate and the water-soluble carbohydrate content of the diet. The addition of barley meal to grass produced different ruminal VFA patterns in sheep fed the ensiled material and the resulting silage.

Volatile fatty acids in the ruemen of sheep fed grass, unwilted and wilted silage, and barn-dried hay

Conservation of heavily wilted herbage at 4 stages of growth in experimental air-tight tower silos.

Two experiments are described in which ground harley meal was added to freshly-cut grass hefore ensiling it in small air-tight metal containers and polythene containers. The mean DM loss from the air-tight metal containers was 1 % and from the polythene containers 18.8%. The silages were all of satisfactory fermentation quality, as assessed hy pH, voladle acids, lactic-acid and Tolatile-hase content. The addition of the harley meal significantly improved the nutritive content of the ensiled material, and the resulting silage in the air-tight metal containers. Sheep were used to measure the voluntary intakes of the silages conserved in the polythene containers.

THE CONSERVATION OF GRASS IN SEALED METAL AND PLASTIC CONTAINERS, WITH AND WITHOUT GROUND BARLEY MEAL

Italian ryegrass was ensiled in gas-tight silos in unwilted (21% dry matter) and wilted (42% dry matter) conditions without an additive and with the addition of molasses at a mean level of 8% in the dry matter. The total dry matter losses were 8·7, 7·2, 4·5 and 5·0% for unwilted, molassed unwilted, wilted, and molassed wilted grass silages respectively. The silages were all well preserved but the extent of fermentation had been reduced in the wilted silages. The losses of individual sugars during the silage process and the products of fermentation were used to assess the pathways of fermentation. The dominant pathway of fructose utilisation was by heterolactic fermentation. The addition of molasses reduced the ratio of fructose: glucose in the ensiled material and reduced the amount of mannitol produced during the ensilage process.

Conservation of wilted and unwilted grass ensiled in air-tight metal containers with and without the addition of molasses

Herbage at four different dry matter levels, 19·8, 28·0, 37·5 and 45·0%, was ensiled in air-tight metal containers. There was no loss as inedible waste and this together with the low losses of constituents demonstrated the efficiency of this system of conservation. The mean dry matter loss from the silos was 6%. There was no discernible trend in the dry matter losses with increasing dryness of the ensiled material. 
 
The presence of butyric acid and the low levels of volatile nitrogen indicated a saccharolytic type of clostridial activity. 
 
Arabinose, galactose and xylose arising from the breakdown of hemicellulose were detected in the silages but the loss of the hemicellulose fraction was low. 
 
The presence of mannitol, which was most prevalent in the wilted-grass silages, indicated a substantial degree of a heterolactic fermentation of fructose. In the material of low dry matter concentration a homolactic fermentation was predominant.

Conservation of herbage of varying dry matter content in air‐tight metal containers with reference to the carbohydrate fraction

Timothy-meadow fescue grass was wilted to 27.7–33.9% dry matter content and two silos were filled with the wilted material alone and two with the wilted herbage to which urea, at a level of 1.38% of the dry matter ensiled, was added. The mean dry matter loss from the control silages was 16.7% and from the urea-treated silages 11.4%. No urea could be detected in the silage made from the urea-treated herbage. There was no evidence for any major differences in the fermentation pathways between the control and urea-treated silage. Voluntary intake of control and urea-treated silage by sheep was similar (1.7 times the maintenance metabolisable energy requirement) so that nitrogen intake was higher when the urea-silage was fed. No toxic effects of the treated silage were observed when assessed by blood urea and ammonia levels.

Conservation of wilted herbage ensiled in sealed plastic containers, with and without the addition of urea, and its intake by sheep.

Fresh and wilted timothy-meadow fescue herbage of 19 and 46.6° dry matter content, respectively, was ensiled in rubber-sealed steel cylinders 5 ft deep and 3 ft in diameter. Mean dry matter losses from all silos were about 6%. All silages were well preserved, the wilted material containing less lactic acid and volatile acids and having a higher pH. The dry matter digestibility coefficients from fresh and wilted grass silages were 71.5 and 70.2%, respectively, and were slightly higher than for the grass before ensilage. Ensilage resulted in a fall in metabolisable energy of the wilted grass. Intake of wilted silage by sheep was higher than that of silage from fresh grass.

Conservation of fresh and wilted grass in air-tight metal containers.

The conservation of fresh and wilted grass in evacuated and non-evacuated polythene containers.

DRY MILLING AND EXTRUSION OF PROSO MILLET AND THE ROLE OF MILLET LIPIDS ON EXTRUDATE SENSORY PROPERTIES Brian J. Anderson Co-advisor: University of Guelph, 2014 Dr. Massimo Marcone Co-advisor: Dr. Lisa Duizer Structurally, millet is a small grain, composed of an outer fibrous pericarp, a starchy endosperm and a germ body. The traditional milling method of millet is labor intensive, time consuming, and yields a poor endosperm fraction. Modern millet dry milling is a technique that has been used on a limited basis, but is not well understood. The purpose of this study, using abrasive dry milling, was to establish a laboratory process flow that will enhance baseline research and advance the commercial milling of millet. A commercial short flow abrasive dry milling system was developed for the production of low fat and fiber millet grits. The process is defined in two major steps; abrasive decortification and endosperm grit aspiration. The endosperm grit produced averaged a yield of 83.5 % with fat and fiber levels of 1.9 % and .61 %. In addition, this research was designed to focus on millet lipids and their role in off flavor formation in single screw extrudates. The design was created to compare refined millet and corn oil addition at increasing levels in a corn meal control to understand if millet lipids cause a higher rate of oxidation leading to off flavors and odors in extruded extrudates. This is important to understand if millet usage is to be increased using single screw extrusion to make snack foods and cereals. In this research, analysis by lipid chemistry, human sensory and direct ionization it was found that millet lipid addition to a base corn meal formula did not create abnormal concentrations of off flavors and odors in extrudates.

Dry Milling and Extrusion of Proso Millet and the Role of Millet Lipids on Extrudate Sensory Properties

Characterization of microbial protein expression provides information necessary to better understand the unique biological pathways that occur within soil microbial communities that contribute to atmospheric CO2 levels and the earth's changing climate. A significant challenge in studying the soil microbial community proteome is the initial dissociation of bacterial proteins from the complex mixture of particles found in natural soil. The differential extraction of intact bacterial cells limits the characterization of the complete representation of a microbial community. However, in situ lysis of bacterial cells in soil can lead to potentially high levels of protein adsorption to soil particles. Here, we investigated various amino acids for their ability to block soil protein adsorption sites prior to in situ lysis of bacterial cells, as well as their compatibility with both tryptic digestion and mass spectrometric analysis. The treatments were tested by adding proteins from lysed Escherichia coli cells to representative treated and untreated soil samples. The results show that it is possible to significantly increase protein identifications through blockage of binding sites on a variety of soil and sediment textures; use of an optimized desorption buffer further increases the number of identifications.

Amino acid treatment enhances protein recovery from sediment and soils for metaproteomic studies

Barriers to the implementation of coal syngas/polygeneration (CSP) in China

ABSTRACT Commercial and food-type sorghum hybrids with differing kernel and endosperm characteristics were grown under comparable conditions and steam flaked in each of three years. The raw-grain kernel characteristics and proximate analyses were homogenous over the three-year period. The waxy hybrid produced large, translucent, durable flakes that had significantly higher enzyme-susceptible starch values for all years compared to the other varieties. Flakes with lower amylose contents (waxy endosperm) were positively correlated with percent whole flakes (r2 = 0.509), flake diameter (r2 = 0.846), and enzyme-susceptible starches (r2 = 0.564) and negatively correlated with higher flake fragility (r2 = -0.647), test weight (r2 = -0.626), and flake breakage (r2 = -0.560). The heterowaxy flakes had a good appearance and were generally comparable in quality to the nonwaxy commercial and experimental hybrids. Heterowaxy sorghum hybrids with good grain yields can provide improved quality grain and flakes without ...

Steam Flaking Characteristics of Sorghum Hybrids and Lines with Differing Endosperm Characteristics

Apparatus and process for the production of pasta filata cheese with a reduced fat content

ABSTRACT Tempering agents affect the pericarp of steamed grain and the endosperm of steam-flaked sorghum. Examination by environmental scanning electron microscopy (ESEM) clearly showed that β-mercaptoethanol (BME), sulfurous acid (SA), phosphoric acid, and cellulase significantly altered the structure of the pericarp and endosperm during tempering. Lime and protease had a lesser effect on the pericarp structure of the kernels, and had little effect on the endosperm. Steamed flakes from the SA treatment were more translucent and durable than all other treatments. Flakes with BME were translucent and high in quality, but were more fragile than the SA flakes. Nontempered, water only, and commercial conditioner treatments produced flakes with the lowest quality. Peak, final, and breakdown Rapid Visco Analyzer (RVA) viscosities were lowest for the SA flakes due to disruption of the starch chains by the weak acid. BME viscosity values were higher than SA, but lower than the water and commercial tempering treat...

Effect of Conditioning Agents on the Structure of Tempered and Steam-Flaked Sorghum

The present invention relates to a method and a device for cheese and soft cheese with rennet plastic, high quality and low fat content. Where appropriate substitute cheese is introduced rice based on the newly processed cheese. It is used for this procedure kneading and spray preserves the integrity of the fiber structure of the cheese.

Apparatus and method for the manufacture of pasta filata cheese low fat.

ABSTRACT Sorghum undergoes structural changes during tempering, steam cooking, and flaking at various tempering moisture levels. Physical properties of flakes, digestibility, birefringence, scanning electron microscopy (SEM), and environmental SEM (ESEM) were used to evaluate the quality of steam-flaked sorghum from grain containing 11–23% water. As moisture levels increased, the flakes became stronger (57–69% whole flakes) and less dusty (9–4% fines). The diameter of the flakes varied among moisture levels, but preflake and final flake moisture contents increased as the temper level increased. Starch birefringence remained unchanged after tempering, and decreased only slightly after steam cooking; gelatinization occurred primarily during the flaking process. The steaming process prepared the grain for flaking by heating and softening the kernels. Tempering allowed extra water to penetrate inside the kernel endosperm. More starch granules had the opportunity to reach the glass transition temperature (T g)...

Second harmonic generation in Langmuir-Blodgett multilayers of stilbazolium chloride polyethers

CHARACTERIZATION OF MODULATED SPIN-COATED AND LANGMUIR-BLODGETT THIN FILM ETALONS

Quadratically enhanced second harmonic generation in polymer-dye Langmuir-Blodgett films: A new bilayer architecture

Second-harmonic generation in Langmuir-Blodgett films of hemicyanine-poly(octadecyl methacrylate) and hemicyanine-behenic acid☆

Highly oriented dye-containing polymer films are a promising class of nonlinear optical materials. We have prepared a poly(epicholorohydrin) derivative suitable for fabrication of noncentrosymmetric Langmuir-Blodgett (L/B) multilayer films. The synthesis, L/B deposition, and second harmonic generation measurements of these polymer films are reported.

New Hemicyanine Dye-Substituted Polyethers As Nonlinear Optical Materials

Publisher's copyright statement: Reprinted with permission from the American Physical Society: Physical Review Letters 114, 155302 c © 2015 by the American Physical Society. Readers may view, browse, and/or download material for temporary copying purposes only, provided these uses are for noncommercial personal purposes. Except as provided by law, this material may not be further reproduced, distributed, transmitted, modi ed, adapted, performed, displayed, published, or sold in whole or part, without prior written permission from the American Physical Society.

Deposited in DRO : 30 June 2015 Version of attached le : Published Version Peer-review status of attached

What executives get wrong about statistics: Moving from statistical significance to effect sizes and practical impact

Future Research Opportunities in the Strategic Leadership-EO Space

Contextual and Industry Considerations in Strategic Leadership-EO Research

We posit that environmental hostility exhibits an inverse U-shaped relationship with a firm’s entrepreneurial orientation. We suggest a nuanced perspective on the threat rigidity argument that firms generally retrench from entrepreneurial capital allocation behaviors as hostility increases. We argue that firms are likely to act opportunistically and increase EO, but only to the point where the marginal costs of such activity outweigh the marginal benefits, at which point EO drops precipitously. Analyzing 60,440 observations from 6,481 firms across 373 industries from 1998 through 2017, our results indicate that EO exhibits a generally negative relationship with environmental hostility. Further, we examine a potential moderating influence of recoverable slack on the hostility–EO relationship, arguing that recoverable slack represents a meaningful buffer on behavioral change stemming from changing environmental hostility.

Entrepreneurial Orientation and Environmental Hostility: A Threat Rigidity Perspective

Editorial: Enhancing the exploration and communication of quantitative entrepreneurship research

The temptation of exaggeration: Exploring the line between preparedness and misrepresentation in entrepreneurial pitches

While entrepreneurial orientation (EO) correlates with many organizational phenomena, we lack convincing evidence of causal relationships within EO’s nomological network. We explore the challenges to establishing causal relationships with a systematic review of EO–performance research. We then use a simulation to illustrate how popular research designs in EO research limit our ability to make causal claims. We conclude by outlining the research design considerations to move from associational to causal EO–performance research. Our message is that while experiments may not be practical or feasible in many areas of organizational research, including EO, scholars can nevertheless move towards causal understanding.

The Chicken or the Egg? Causal Inference in Entrepreneurial Orientation–Performance Research

Editorial: Enhancing quantitative theory-testing entrepreneurship research

The purpose of this editorial is to discuss methodological advancements to enhance quantitative theory-testing entrepreneurship research. As the impact of entrepreneurship scholarship accelerates and deepens, our methods must keep pace to continue shaping theory, policy, and practice. Like our sister fields in business, entrepreneurship is coming to terms with the replication and credibility crisis in the social sciences, forcing the field to revisit commonly-held assumptions that limit the promise and prospect of our scholarship. Thus, we provide suggestions for reviewers and editors to identify concerns in empirical work, and to guide authors in improving their analyses and research designs. We hope that our editorial provides useful and actionable guidance for entrepreneurship researchers submitting theory-testing papers to Journal of Business Venturing.

2 Editorial: Enhancing Quantitative Theory-Testing Entrepreneurship Research

The Chicken or the Egg: Causal Inference in the Entrepreneurial Orientation-Performance Relationship

Research Summary Delineating between conservative and entrepreneurial firms to discern the causes, consequences, and benefits of entrepreneurial behavior is a key conversation in strategic entrepreneurship research. We introduce to this conversation a new construct, Strategic Entrepreneurship Behaviors, which we argue provides several theoretical and practical benefits to scholars exploring strategic entrepreneurship phenomenon. We develop and validate a measurement model for the Strategic Entrepreneurship Behaviors construct using a three-study design in Japan and in the United States. To facilitate reproducibility and replication of our results, we posted all data, R code, and Supporting Information on the Open Science Framework website available at . Managerial Summary The driving question in strategic entrepreneurship research is the impact of an organization's entrepreneurial activity on its performance. Answering this and related questions requires careful measurement of entrepreneurial activity. Existing measures and scales served the field well, but to answer questions establishing causal relationships, we need new constructs and measures robust to causal research designs. We introduce a new construct and scale, Strategic Entrepreneurial Behaviors, to capture the firm's exploitation of new product-market opportunities through the intended commercialization of its product innovations. We hope this new measure for a firm's entrepreneurial activity allows researchers to build more predictive theory, and to ask-and answer-new research questions that move the strategic entrepreneurship conversation forward.

Strategic entrepreneurial behaviors: Construct and scale development

Under the table: Exploring the type and communication of corruption on opportunity pursuit

Corporate venture capital (CVC) is a valuable strategic tool associated with numerous innovative outcomes. However, less is known about whether CVC investing creates value for the investing (or parent) firm. Drawing from the attention–based view and contingency theory, we suggest that an increase in firm value from CVC investing is contingent on attentional mechanisms that discipline the selection of new investment opportunities. We posit that increases in firm value associated with CVC investing accrues to firms adopting specific operational structures and operating in particular environmental contexts. We find support for our research model in a sample of 95 companies between 2000 and 2008.

Firm Structure and Environment as Contingencies to the Corporate Venture Capital-Parent Firm Value Relationship

Research summary: This paper posits adaptive capability as a mechanism through which a firm's prior growth influences the exhibition of future entrepreneurial action. Defined as the firm's proficiency in altering its understanding of market expectations, increased adaptive capability is a consequence of the new resource combinations that result from expanding organizational boundaries. Increased adaptive capability in turn corresponds to expansion of entrepreneurial activity, as firms increase their entrepreneurial orientation as the strategic mechanism to capitalize on their improved understanding of market conditions. We find support for our research model in a two-study series conducted in South Korea and the United Kingdom. 
 
Managerial summary: Most would agree that entrepreneurially oriented firms—being innovative, entering new markets, and taking risk—grow faster. But how a firm becomes entrepreneurial is a complicated question. In this study, we flipped the growth relationship around and found support for growth contributing to a firm's entrepreneurial orientation. But between growth and being more entrepreneurial is the firm's ability to recognize changes in market expectations. We argue that as a firm grows, it acquires new resources and new knowledge of how to use those resources. These new resource combinations increase its ability to recognize changes in market expectations—its adaptive capability. This capability uncovers new entrepreneurial opportunities for value creation. To capture this potential value, firms expand their entrepreneurial orientation. Copyright © 2016 John Wiley & Sons, Ltd.

Firm growth, adaptive capability, and entrepreneurial orientation

Entrepreneurial orientation (EO)—a firm's strategic posture towards entrepreneurship—has become the predominant construct of interest in strategic entrepreneurship research. Despite the ever-increasing volume of nomological research on EO, there remain ongoing conversations regarding its ontology. Drawing from measurement theory, we outline an EO reconceptualization addressing the likely prevalence of Type II nomological error in the EO literature stemming from measurement model misspecification. Focusing on the question of whether EO is an attitudinal construct, a behavioral construct, or both, we propose a formative construction of EO viewing the exhibition of entrepreneurial behaviors and of managerial attitude towards risk as jointly necessary dimensions that collectively form the higher-order EO construct. We present an empirical illustration of our reconceptualization followed by a discussion of future research opportunities

This paper posits that strategic adaptability is the mechanism through which a firm’s prior growth influences the exhibition of future entrepreneurial strategies. Defined as the firm’s ability to recognize opportunistic changes to its product offerings based on evolving market demand, strategic adaptability is an outcome of a firm’s prior growth and the corresponding impetus to respond to changing market conditions in order to maintain the firm’s growth trajectory. Firms then exploit these opportunities by increasing their entrepreneurial orientation. We find support for our research model in a two-study series conducted in South Korea and the United Kingdom.

FIRM GROWTH, STRATEGIC ADAPTABILITY, AND ENTREPRENEURIAL ORIENTATION

Firms faced with the introduction of an innovation by a competitor face a difficult decision. Does the firm imitate the innovation in a bid to ward off any competitive advantage accruing to the competitor; or does the firm forgo imitation, believing that the competitor has misjudged the market receptiveness of the innovation? The risk of following – hoping that the competitor has judged the market correctly and warrants resource expenditure – must be weighed against the risk of not following – potentially missing out on a critical market opportunity. We offer a theoretical framework for firms contemplating imitation using signals embedded at the innovation-level and at the organizational-level of the competitor to better guide imitation decision making. 
 
Keywords: 
 
innovation; 
imitation; 
signaling theory; 
multilevel decision making; 
information asymmetry; 
competitive dynamics

A GLOBAL INVESTIGATION OF THE INFLUENCE OF INSTITUTIONAL RISK FACTORS ON THE ENTREPRENEURIAL ORIENTATION-FIRM GROWTH RELATIONSHIP (SUMMARY)

DOES VENTURING CREATE FIRM VALUE? A CONFIGURATIONAL APPROACH TO UNDERSTANDING THE VENTURING-FIRM VALUE RELATIONSHIP (INTERACTIVE PAPER)

This study compares the persistence and start-up speed of intrapreneurs and entrepreneurs in creating new ventures. Against the theoretical backdrop of differences in initial resource endowments, i...

While external corporate venturing—investing in or creating new businesses outside of the firm’s boundaries—is an arguably valuable strategic mechanism, there is little empirical evidence to suggest that venturing is a meaningful driver of firm value. Drawing from the attention based view, we suggest that an increase in firm value from adopting an external corporate venturing strategy is contingent on attentional mechanisms endogenous and exogenous to the firm that frame managerial attention on venturing opportunities that closely compliment the firm’s core business. Further, we recast the contingencies into a configurational perspective to demonstrate that maximum value from an external corporate venturing strategy occurs when there is alignment between strategy, organizational structure, and environmental exigencies. We find support for our research model in a longitudinal sample of 358 companies between 1998-2008 across 12 industries.

Increasing Firm Value Through External Corporate Venturing Strategy: A Configurational Model

Substantial research explores how firms engage in behaviors to intentionally signal information to encourage a specific reaction, but studies identifying behaviors that unintentionally signal information are comparatively scarce. This study examines whether a firm’s entrepreneurial orientation (EO) is an unintended signal influencing market performance. Using an objective measure of the EO of U.S. publicly traded companies from 2001-2010, we find that EO unintentionally sends an observable and consistent signal resulting in market performance non-monotonically increasing at an increasing rate. We also find that environmental dynamism and hostility influence the EO-market performance relationship, supporting signaling theory’s assertion that signal environment influences signal quality.

Entrepreneurial Orientation as an Unintended Market Signal (WITHDRAWN)

Previous research examining the relationship between environmental hostility and a firm’s entrepreneurial orientation (EO) has been plagued by inconsistent results. The current study draws upon theories of constrained strategic choice and threat rigidity to shed light on the complex nature of the hostility-EO relationship. Utilizing data consisting of 21,129 observations taken from 3,075 firms during 1999-2010. Using objective measures of EO, our results suggest that EO exhibits an inverse U-shaped relationship with environmental hostility. Further, the results suggest that recoverable slack moderates this inverse U-shaped relationship by attenuating the relationship at high levels of recoverable slack, while accentuating the relationship at low levels of recoverable slack. Taken together, these findings lend support to theoretical arguments suggesting that a firm’s environmental context has an identifiable impact on its willingness to display an EO, and that the unencumbered structural resources embedded...

The influence of firm age and intangible resources on the relationship between entrepreneurial orientation and firm growth among Japanese SMEs

This study adopts a signaling theory perspective to test the relationship between entrepreneurial orientation (EO) and market performance, and to further test theoretically meaningful boundary conditions of that relationship. We estimate our research model using an objective measure of EO among publicly traded companies from 2001-2010. Our results suggest that EO and market performance are non-monotonically related (U-shaped), and that environmental dynamism, and environmental hostility, individually and jointly influence the EO-market performance relationship.

A CONFIGURATIONAL MODEL OF FIRM GROWTH: OPPORTUNITY RECOGNITION MODE, ENTREPRENEURIAL ORIENTATION, AND INTANGIBLE RESOURCE ADVANTAGE AMONG JAPANESE SMES (INTERACTIVE PAPER)

Entrepreneurial orientation (EO) has rapidly established itself as the predominant construct of interest in corporate entrepreneurship research—a field of inquiry at the intersection of strategic management and entrepreneurship. Despite the burgeoning volume of research exploring the nomological network of EO, there remain ongoing debates regarding its epistemology and measurement. We contend that these scholarly disputes may be unnecessarily hampering knowledge creation around EO—a construct of importance to scholars and to practitioners. Thus, we develop a revised course for EO research based on a reconceptualization of EO drawing upon EO’s conceptual roots. This reconceptualization addresses the most common theoretical and measurement challenges associated with current conceptualizations of EO and provides practical guidance to EO scholars regarding research design and measurement. We conclude with a discussion of the implications and contributions of this reconceptualization, and an outline of future ...

Reconceptualizing Entrepreneurial Orientation: Revisiting a Vital but Troublesome Construct

Entrepreneurial orientation—the decision-making practices, managerial philosophies, and strategic behaviors that are entrepreneurial in nature—is a ‘troublesome’ construct, or so it is argued to be...

While individual-level entrepreneurship flourishes in emerging economies, it is unclear whether the same pattern holds true for entrepreneurial strategies pursued by organizations. Utilizing an ins...

ATTITUDE, BEHAVIOR, OR BOTH? AN EMPIRICAL INVESTIGATION OF THE ENTREPRENEURIAL ORIENTATION CONSTRUCT (INTERACTIVE PAPER)

Resource knowledge, organizational slack, and entrepreneurial orientation

This research explores the relationship between strategic learning capability—a firm's proficiency at generating, and then acting on, strategic knowledge—and entrepreneurial orientation (EO). While theory posits the inevitably of building strategic learning capability from behaving entrepreneurially, there is little empirical research to validate this proposition and even less understanding of how and why EO contributes to strategic learning capability. Empirical results from 110 manufacturing firms confirm the direct effect of EO on strategic learning capability, and support is found for three constructs—structural organicity, market responsiveness, and strategy formation mode—that fully mediate the EO-strategic learning capability relationship. Copyright © 2009 Strategic Management Society.

Understanding the relationship between entrepreneurial orientation and strategic learning capability: an empirical investigation

The article presents the results of research on entrepreneurial orientation (EO), a term which indicates a corporate culture of innovation and risk tolerance. The focus is on the relationship between EO and strategic learning. An overview of related previous studies is provided, along with details of the research protocol, which involved U.S. manufacturing firms. It was found that EO improves a firm's strategic learning capability, and mechanisms which might account for a causal relationship between EO and strategic learning are described.

UNDERSTANDING THE RELATIONSHIP BETWEEN ENTREPRENEURIAL ORIENTATION AND STRATEGIC LEARNING.

Firm decision makers contemplating imitation of a competitor's innovation face a dilemma: Imitate a new, unproven offering, or forgo imitation and perhaps miss out on the “next big thing”? Approach...

The Follower's Dilemma: Innovation and Imitation in the Professional Services Industry

Market Outlook For Athabasca Bitumen -- The Economics of Location

Understanding the dynamic nature of a leisure experience: personal schema as an explanatory context

Acetaminophen is a commonly used perioperative analgesic drug in children. The use of a preoperative loading dose achieves a target concentration of 10 mg/L associated with a target analgesic effect that is 2.6 pain units (visual analogue scale 1–10). Postoperative maintenance dosing is used to keep this effect at a steady-state concentration. The loading dose in children is commonly prescribed per kilogram. That dose is consistent with the linear relationship between the volume of distribution and total body weight. Total body weight is made up of both fat and fat-free mass. The fat mass has little influence on the volume of distribution of acetaminophen but fat mass should be considered for maintenance dosing that is determined by clearance. The relationship between the pharmacokinetic parameter, clearance, and size is not linear. A number of size metrics (e.g., fat-free and normal fat mass, ideal body weight and lean body weight) have been proposed to scale clearance and all consequent dosing schedules recognize curvilinear relationships between clearance and size. This relationship can be described using allometric theory. Fat mass also has an indirect influence on clearance that is independent of its effects due to increased body mass. Normal fat mass, used in conjunction with allometry, has proven a useful size metric for acetaminophen; it is calculated using fat-free mass and a fraction (Ffat) of the additional mass contributing to total body weight. However, the Ffat for acetaminophen is large (Ffat = 0.82), pharmacokinetic and pharmacodynamic parameter variability high, and the concentration–response slope gentle at the target concentration. Consequently, total body weight with allometry is acceptable for the calculation of maintenance dose. The dose of acetaminophen is tempered by concerns about adverse effects, notably hepatotoxicity associated with use after 2–3 days at doses greater than 90 mg/kg/day.

Background: Sleep and circadian disruption (SCD) is common and severe in the ICU. On the basis of rigorous evidence in non-ICU populations and emerging evidence in ICU populations, SCD is likely to have a profound negative impact on patient outcomes. Thus, it is urgent that we establish research priorities to advance understanding of ICU SCD. Methods: We convened a multidisciplinary group with relevant expertise to participate in an American Thoracic Society Workshop. Workshop objectives included identifying ICU SCD subtopics of interest, key knowledge gaps, and research priorities. Members attended remote sessions from March to November 2021. Recorded presentations were prepared and viewed by members before Workshop sessions. Workshop discussion focused on key gaps and related research priorities. The priorities listed herein were selected on the basis of rank as established by a series of anonymous surveys. Results: We identified the following research priorities: establish an ICU SCD definition, further develop rigorous and feasible ICU SCD measures, test associations between ICU SCD domains and outcomes, promote the inclusion of mechanistic and patient-centered outcomes within large clinical studies, leverage implementation science strategies to maximize intervention fidelity and sustainability, and collaborate among investigators to harmonize methods and promote multisite investigation. Conclusions: ICU SCD is a complex and compelling potential target for improving ICU outcomes. Given the influence on all other research priorities, further development of rigorous, feasible ICU SCD measurement is a key next step in advancing the field.

Causes, Consequences, and Treatments of Sleep and Circadian Disruption in the ICU: An Official American Thoracic Society Research Statement.

The intravenous induction or loading dose in children is commonly prescribed per kilogram. That dose recognizes the linear relationship between volume of distribution and total body weight. Total body weight comprises both fat and fat-free mass. Fat mass influences the volume of distribution and the use of total body weight fails to recognize the impact of fat mass on pharmacokinetics in children. Size metrics alternative to total body mass (e.g., fat-free and normal fat mass, ideal body weight and lean body weight) have been proposed to scale pharmacokinetic parameters (clearance, volume of distribution) for size. Clearance is the key parameter used to calculate infusion rates or maintenance dosing at steady state. Dosing schedules recognize the curvilinear relationship, described using allometric theory, between clearance and size. Fat mass also has an indirect influence on clearance through both metabolic and renal function that is independent of its effects due to increased body mass. Fat-free mass, lean body mass and ideal body mass are not drug specific and fail to recognize the variable impact of fat mass contributing to body composition in children, both lean and obese. Normal fat mass, used in conjunction with allometry, may prove a useful size metric but computation by clinicians for the individual child is not facile. Dosing is further complicated by the need for multicompartment models to describe intravenous drug pharmacokinetics and the concentration effect relationship, both beneficial and adverse, is often poorly understood. Obesity is also associated with other morbidity that may also influence pharmacokinetics. Dose is best determined using pharmacokinetic–pharmacodynamic (PKPD) models that account for these varied factors. These models, along with covariates (age, weight, body composition), can be incorporated into programmable target-controlled infusion pumps. The use of target-controlled infusion pumps, assuming practitioners have a sound understanding of the PKPD within programs, provide the best available guide to intravenous dose in obese children.

Considerations for Intravenous Anesthesia Dose in Obese Children: Understanding PKPD

Objective The β2-agonists such as salbutamol are the mainstay of asthma management. Pharmacokinetic–pharmacodynamic (PKPD) models to guide paediatric dosing are lacking. We explored the relationship between salbutamol dose, serum concentration, effectiveness and adverse effects in children by developing a PKPD model. Design A prospective cohort study of children admitted to hospital with acute asthma, who received intravenous salbutamol. Setting Children were recruited in two cohorts: the emergency departments of two London hospitals or those retrieved by the Children’s Acute Transport Service to three London paediatric intensive care units. Patients Patients were eligible if aged 1–15 years, admitted for acute asthma and about to receive or receiving intravenous salbutamol. Interventions Treatment was according to local policy. Serial salbutamol plasma levels were taken. Effectiveness measurements were recorded using the Paediatric Asthma Severity Score (PASS). Toxicity measurements included lactate, pH, glucose, heart rate, blood pressure and arrhythmias. PKPD modelling was performed with non-linear mixed-effect models. Main outcomes Fifty-eight children were recruited with 221 salbutamol concentration measurements from 54 children. Median (range) age was 2.9 (1.1–15.2) years, and weight was 13.6 (8–57.3) kg. Ninety-five PASS measurements and 2078 toxicity measurements were obtained. Results A two-compartment PK model adequately described the time course of salbutamol–plasma concentrations. An EMAX (maximum drug effect) concentration–effect relationship described PASS and toxicity measures. PKPD simulations showed an infusion of 0.5 µg/kg/min (maximum 20 µg/min) for 4 hours after bolus achieves >90% maximal bronchodilation for 12 hours. Conclusions A paediatric PKPD model for salbutamol is described. An infusion of 0.5 µg/kg/min after bolus achieves effective bronchodilation. Higher rates are associated with greater tachycardia and hyperglycaemia.

Pharmacokinetic‐pharmacodynamic modeling and simulation can facilitate understanding and prediction of exposure‐response relationships in children with acute or chronic pain. The pharmacokinetics of diamorphine (diacetylmorphine, heroin), a strong opioid, remain poorly quantified in children and dose is often guided by clinical acumen. This tutorial demonstrates how a model to describe intranasal and intravenous diamorphine pharmacokinetics can be fashioned from a model for diamorphine disposition in adults and a model describing morphine disposition in children. Allometric scaling and maturation models were applied to clearances and volumes to account for differences in size and age between children and adults. The utility of modeling and simulation to gain insight into the analgesic exposure‐response relationship is demonstrated. The model explains reported observations, can be used for interrogation, interpolated to determine equianalgesia and inform future clinical studies. Simulation was used to illustrate how diamorphine is rapidly metabolized to morphine via its active metabolite 6‐monoacetylmorphine, which mediates an early dopaminergic response accountable for early euphoria. Morphine formation is then responsible for the slower, prolonged analgesic response. Time‐concentration profiles of diamorphine and its metabolites reflected disposition changes with age and were used to describe intravenous and intranasal dosing regimens. These indicated that morphine exposure in children after intranasal diamorphine 0.1 mg.kg−1 was similar to that after intranasal diamorphine 5 mg in adults. A target concentration of morphine 30 μg.L−1 can be achieved by a diamorphine intravenous infusion in neonates 14 μg.kg−1.h−1, in a 5‐year‐old child 42 μg.kg−1.h−1 and in an 15 year‐old‐adolescent 33 μg.kg−1.h−1.

Pharmacokinetic modeling and simulation to understand diamorphine dose‐response in neonates, children, and adolescents

The protease inhibitor, ritonavir, is a strong inhibitor of CYP 3A. The drug is used for management of the human immunovirus and is currently part of an oral antiviral drug combination (nirmatrelvir–ritonavir) for the early treatment of SARS‐2 COVID‐19‐positive patients aged 12 years and over who have recognized comorbidities. The CYP 3A enzyme system is responsible for clearance of numerous drugs used in anesthesia (e.g., alfentanil, fentanyl, methadone, rocuronium, bupivacaine, midazolam, ketamine). Ritonavir will have an impact on drug clearances that are dependent on ritonavir concentration, anesthesia drug intrinsic hepatic clearance, metabolic pathways, concentration‐response relationship, and route of administration. Drugs with a steep concentration‐response relationship (ketamine, midazolam, rocuronium) are mostly affected because small changes in concentration have major changes in effect response. An increase in midazolam concentration is observed after oral administration because CYP 3A in the gastrointestinal wall is inhibited, causing a large increase in relative bioavailability. Fentanyl infusion may be associated with a modest increase in plasma concentration and effect, but the large between subject variability of pharmacokinetic and pharmacodynamic concentration changes suggests it will have little impact on an individual patient, especially when used with adverse effect monitoring. It has been proposed that drugs that have no or only a small metabolic pathway involving the CYP 3A enzyme be used during anesthesia, for example, propofol, atracurium, remifentanil, and the volatile agents. That anesthesia approach denies children of drugs with considerable value. It is better that the inhibitory changes in clearance of these drugs are understood so that rational drug choices can be made to tailor drug use to the individual patient. Altered drug dose, anticipation of duration of effect, timing of administration, use of reversal agents and perioperative monitoring would better behoove children undergoing anesthesia.

Interactions of the protease inhibitor, ritonavir, with common anesthesia drugs

ARDS Mediates the Association Between Early Plasma sRAGE Concentrations and Mortality in Sepsis.

Hysteresis is reported between plasma concentration and analgesic effect from nonsteroidal anti‐inflammatory drugs. It is possible that the temporal delay between plasma and CSF nonsteroidal anti‐inflammatory drugs mirrors this hysteresis. The temporal relationship between plasma and CSF concentrations of COX‐inhibitors (celecoxib, rofecoxib, valdecoxib) has been described. The purpose of this secondary data analysis was to develop a compartmental model for plasma and CSF disposition of these COX‐2 inhibitors.

Modeling adult COX‐2 cerebrospinal fluid pharmacokinetics to inform pediatric investigation

Acetaminophen is routinely used for perioperative analgesia in children undergoing major surgical procedures. There are few estimates of acetaminophen pharmacokinetic parameters in children with congenital heart disease, especially those with cyanotic heart disease.

Acetaminophen pharmacokinetics in infants and children with congenital heart disease

Dabigatran is an anticoagulant with potential use during cardiopulmonary bypass in children and adults. The pharmacokinetic–pharmacodynamic relationship for dabigatran anticoagulation effect was investigated in an intact animal model using rabbits.

Delayed concentration effect models for dabigatran anticoagulation

The use of pharmacokinetic-pharmacodynamic models has improved anaesthesia practice in children through a better understanding of dose-concentration-response relationships, developmental pharmacokinetic changes, quantification of drug interactions and insights into how covariates (e.g., age, size, organ dysfunction, pharmacogenomics) impact drug prescription. Simulation using information from these models has enabled the prediction and learning of beneficial and adverse effects and decision-making around clinical scenarios. Covariate information, including the use of allometric size scaling, age and consideration of fat mass, has reduced population parameter variability. The target concentration approach has rationalised dose calculation. Paediatric pharmacokinetic-pharmacodynamic insights have led to better drug delivery systems for total intravenous anaesthesia and an expectation about drug offset when delivery is stopped. Understanding concentration-dependent adverse effects have tempered dose regimens. Quantification of drug interactions has improved the understanding of the effects of drug combinations. Repurposed drugs (e.g., antiviral drugs used for COVID-19) within the community can have important effects on drugs used in paediatric anaesthesia, and the use of simulation educates about these drug vagaries.

Pharmacokinetic Pharmacodynamic Modelling Contributions to Improve Paediatric Anaesthesia Practice

Population Pharmacokinetic Modelling of Acetaminophen and Ibuprofen: the Influence of Body Composition, Formulation and Feeding in Healthy Adult Volunteers

Association of vancomycin plus piperacillin–tazobactam with early changes in creatinine versus cystatin C in critically ill adults: a prospective cohort study

Background Intranasal diamorphine is a potential treatment for breakthrough pain but few paediatric data are available to assist dose estimation. Aim To determine an intranasal diamorphine dose in children through an understanding of pharmacokinetics. Design A systematic review of the literature was undertaken to seek diamorphine pharmacokinetic parameters in neonates, children and adults. Parenteral and enteral diamorphine bioavailability were reviewed with respect to formation of the major metabolite, morphine. Clinical data quantifying equianalgesic effects of diamorphine and morphine were reviewed. Review sources PubMed (1960–2020); EMBASE (1980–2020); IPA (1973–2020) and original human research studies that reported diacetylmorphine and metabolite after any dose or route of administration. Results The systematic review identified 19 studies: 16 in adults and 1 in children and 2 neonatal reports. Details of study participants were extracted. Age ranged from premature neonates to 67 years and weight 1.4–88 kg. Intranasal diamorphine bioavailability was predicted as 50%. The equianalgesic intravenous conversion ratio of morphine:diamorphine was 2:1. There was heterogeneity between pharmacokinetic parameter estimates attributed to routes of administration, lack of size standardisation, methodology and pharmacokinetic analysis. Estimates of the pharmacokinetic parameters clearance and volume of distribution were reduced in neonates. There were insufficient paediatric data to characterise clearance or volume maturation of either diamorphine or its metabolites. Conclusions We estimate equianalgesic ratios of intravenous morphine:diamorphine 2:1, intravenous morphine:intranasal diamorphine 1:1 and oral morphine:intranasal diamorphine of 1:3. These ratios are based on adult literature, but are reasonable for deciding on an initial dose of 0.1 mg/kg in children 4–13 years.

Diamorphine pharmacokinetics and conversion factor estimates for intranasal diamorphine in paediatric breakthrough pain:systematic review

Dear Sir, Three antiviral agents (remdesivir, molnupiravir, and nirmatrelvir) have gained prominence for communitybased early management of proven COVID19 infection.1 Nirmatrelvir acts via inhibition of the SARSCoV2 main protease (Mpro), also referred to as 3Clike protease (3CLpro) or nsp5 protease, which is essential for viral replication. Nirmatrelvir is combined with a protease inhibitor, ritonavir, that slows the metabolism of nirmatrelvir via cytochrome enzyme inhibition. Ritonavir is a strong inhibitor of CYP3A but has lesser effect on other CYP isoenzymes, for example, 2D6, 2B6, and 2C9. A large number of medicines are metabolized by CYP3A, and therefore, that the inclusion of ritonavir in the drug combination is likely to create complexities and restrictions in its use.2 Future widespread community use of oral nirmatrelvir/ritonavir (Paxlovid®) has implications for those responsible for anesthesia delivery to children. The inhibition of CYP3A enzyme by ritonavir may impair the metabolism of frequently used anesthetic and analgesic drugs such as midazolam, fentanyl, alfentanil, ketamine, rocuronium, and bupivacaine.3 Clearance will be reduced and plasma concentration slow to decrease. Clinical implications will depend on how the anesthetic drug is administered (single bolus only or via infusion or repeated boluses); infusion, for example, will result in a higher steadystate concentration when clearance is reduced, plasma concentration decreases may be dictated more by redistribution than metabolism. The activity of alternative clearance pathways beside CYP3A and the concentrationresponse relationship for any particular drug will also have impact on any observed effect. It currently remains unclear whether the use of this antiviral drug will lead to a clinically significant change in response to an individual drug; however, coadministration of these anesthetic drugs with nirmatrelvir/ritonavir may require dosage adjustment and monitoring of therapeutic and adverse effects, particularly in highrisk cases. Children who present for anesthesia are often taking medications for concomitant pathology. For example, coadministration of ritonavir with medications such as carbamazepine can lead to both a risk of toxicity from an increased concentration of the anticonvulsant, as well as a potential loss of virological response because of a competitive interaction. The inhibitory effect of ritonavir on the CYP3A4 enzyme is predicted to mostly disappear approximately 3 days after stopping the drug. Indications for the future use of nirmatrelvir/ritonavir remain uncertain. If it is used to treat children that are unvaccinated, then anesthetic practitioners are likely to encounter them as patients, either as part of their treatment for COVID19 infection or coincidentally during treatment or investigation of other illnesses. We would urge caution in their management and encourage colleagues to review possible drug interactions.3,4 Consideration should be given to delaying any interventions until at least 3 days after stopping the antiviral agent.

A single caudal anesthetic at the start of lower abdominal surgery is unlikely to provide prolonged analgesia. A second caudal at the end of the procedure extends the analgesia duration but total plasma concentrations may be associated with toxicity. Our aim was to measure total plasma levobupivacaine concentrations after repeat caudal anesthesia in infants and to generate a pharmacokinetic model for prediction of plasma concentrations after repeat caudal anesthesia in neonates, infants and children.

Levobupivacaine plasma concentrations following repeat caudal anesthetics

Dexmedetomidine is the sedative agent administered in combination with remifentanil and low dose of sevoflurane in the interventional arm of the ongoing TREX trial (Trial Remifentanil DExmedetomidine). The TREX pilot study (published in Paediatr Anaesth 2019;29:59–67) established infusion rates higher than those initially proposed. This could be attributed to an inappropriate target concentration for sedation or incorrect initial pharmacokinetic parameter estimates.

Justification of empiric methodology to determine dexmedetomidine dose for the TREX study

A typical adult‐based bivalirudin regimen during cardiopulmonary bypass uses a loading dose of 1 mg kg−1 and a circuit prime (volume L × 13 mg) with a subsequent intravenous infusion 2.5 mg h−1 kg−1. Dose in children remains unknown. We wished to determine a practical bivalirudin dosing schedule for children undergoing surgery with cardiopulmonary bypass.

Dose estimation for bivalirudin during pediatric cardiopulmonary bypass

Endothelial-Derived Highly-Sulfated Chondroitin Sulfate Deposition in the Hippocampus as a Driver of Sepsis-Induced Delirium

Oxycodone is used in children and adults for the control of acute postoperative pain. Covariate influences such as age, size, and fat mass on oxycodone pharmacokinetic parameters over the human lifespan are poorly quantified.

Population pharmacokinetics of oxycodone: Premature neonates to adults

Plasma drug concentration is the variable linking dose to effect. The decrement time required for plasma concentration of anesthetic agents to decrease by 50% (context‐sensitive half‐time) correlates with the time taken to regain consciousness. However, the decrement time to consciousness may not be 50%. An effect compartment concentration is associated more closely with return of consciousness than plasma concentration. An alternative decrement time, the time required for propofol to decrease to a predetermined effect compartment concentration associated with movement (eg, 2 µg.ml−1), was used to simulate time for the concentration to decrease from steady state at a typical targeted effect compartment concentration 3.5 µg.ml−1 in children. These times were short and reflected a decrement time to consciousness (CSTAWAKE) increase that was small with longer infusion time. CSTAWAKE ranged from 7.5 min in 1‐year‐old infant given propofol for 15 min to 13.5 min in a 15‐year‐old adolescent given a 2‐hour infusion. Changes in decrement time with age reflect maturation of drug clearance. Neonates had prolonged increment times, 10 min after 15 min infusion and 18 min after 120 min infusion using a target concentration of 3.5 µg.ml−1. Decrement times to a targeted arousal concentration are context‐sensitive. Use of a higher target concentration of 6 µg.ml−1 doubled decrement times. Decrement times are associated with variability: delayed recovery beyond these simulated times is likely more attributable to the use of adjuvant drugs or the child's clinical status. An understanding of propofol decrement times can be used to guide recovery after anesthesia.

The parameters for a three-compartment model described by Morse and colleagues [...].

Estimation of the Loading Dose for Target-Controlled Infusion of Dexmedetomidine. Reply to Eleveld et al. Comment on “Morse et al. A Universal Pharmacokinetic Model for Dexmedetomidine in Children and Adults. J. Clin. Med. 2020, 9, 3480”

Impact of COVID-19 on inpatient clinical emergencies: A single-center experience

Interaction Between Severity of Organ Failure and Number of Injured Organs in Sepsis Mortality

Pharmacokinetics and Pharmacodynamics in the Pediatric Population

Supplemental Digital Content is available in the text ABSTRACT Background: Matrix Metalloproteinases (MMP) respond to tissue damage during sepsis. Higher plasma concentrations of MMPs and the tissue-inhibitor of matrix metalloproteinases (TIMP) have been reported in sepsis compared with healthy controls. The objective of this study was to examine if plasma levels of MMP-3, MMP-9, and TIMP-1 associate with mortality and organ dysfunction during sepsis. Methods: We conducted a prospective cohort study of critically ill patients with sepsis adjudicated per Sepsis-3 criteria at a tertiary academic medical center. We measured plasma concentrations of MMP-3, MMP-9, and TIMP-1 on intensive care unit admission. We phenotyped the subjects for shock, acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), and mortality at 30 days. We used logistic regression to test the associations between the MMPs and TIMP-1 with shock, ARDS, AKI, and mortality. Results: Higher plasma TIMP-1 levels were associated with shock (odds ratio [OR] 1.51 per log increase [95% CI 1.25, 1.83]), ARDS (OR 1.24 [95% CI 1.05, 1.46]), AKI (OR 1.18 [95% CI 1.01, 1.38]), and mortality (OR 1.20 [95% CI 1.05, 1.46]. Higher plasma MMP-3 concentrations were associated with shock (OR 1.40 [95% CI 1.12, 1.75]) and mortality (OR 1.24 [95% CI 1.03, 1.48]) whereas MMP-9 levels were not associated with outcomes. Higher plasma TIMP-1 to MMP-3 ratios were associated with shock (OR 1.41 [95% CI 1.15, 1.72], P = 0.02). Conclusion: Elevated plasma concentrations of TIMP-1 associate with organ dysfunction and mortality in sepsis. Higher plasma levels of MMP-3 associate with shock and mortality. Plasma MMP and TIMP-1 may warrant further investigation as emerging sepsis theragnostic biomarkers.

Elevated Plasma Levels of Matrix Metalloproteinase-3 and Tissue-Inhibitor of Matrix Metalloproteinases-1 Associate With Organ Dysfunction and Mortality in Sepsis

A Whole Blood Transcriptome Signature Implicates Dysregulation of Both Innate and Adaptive Immunity in Septic Shock

Respiratory depression, an adverse effect of opioids, is feared by anesthesia practitioners. Naloxone is a competitive μopioid receptor antagonist, used for many years in children and adults to reverse opioidrelated respiratory depression. There are limited data on the pharmacokinetics and pharmacodynamics (PKPD) of naloxone in children; most information comes from case reports.1 In the current issue of Pediatric Anesthesia, MalmrosOlsson and colleagues2 investigated the absorption profile of intranasal naloxone (0.4 mg ml−1) in children (n = 20; 6 months to 10 years) given 20 μg kg−1 (maximum 0.4 mg). The investigators used noncompartment pharmacokinetics to describe maximum concentration (CMAX) and time to maximum concentration (TMAX) and report an observed CMAX between 2 and 6 ng ml−1 reached in more than half of children within 20 min. This is useful and novel clinical information that help guide the use of intranasal naloxone in children. Intranasal administration of naloxone has been shown to be an effective and safe enteral option in children and adults.3 The study by MalmrosOlsson and colleagues2 assists understanding of naloxone absorption after intranasal administration in children. Unfortunately, since naloxone plasma concentrations were measured only during the first 20 minutes after its administration in the study, uncertainty around the estimation of CMAX and TMAX remains. Other relevant pharmacokinetic parameters such as absorption halftime (TABS), intranasal relative bioavailability (FIN), clearance (CL), and volume of distribution (V) remain unquantified. In addition, current estimates of CMAX and TMAX could have been compromised by protocol design factors, such as the total amount of fractional doses given in each nostril, the time elapsed for completing the total dose, the relatively sparse sampling design, differences in sampling times between subjects, and missing measured concentrations. Complementary information of naloxone intranasal absorption is required and should include the fraction of the dose that enters the systemic circulation (relative bioavailability, FIN) and the speed of this absorption process. Bioavailability can only be estimated if data after intravenous route and intranasal route administration are obtained. In adults, intranasal naloxone has a relative bioavailability of not more than 0.5 with a duration of action of generally less than 1 h.3 Anesthesia practitioners commonly use compartment models to describe drug disposition. Absorption across the nasal mucosa can be described with a firstorder rate constant (ka) using compartment analysis methods. Alternatively, the speed of absorption can be also expressed as an absorption halftime (TABS ~ 0.7/ka), which is a more clinically meaningful parameter (i.e., in 4 halflives more than 90% of absorption has been completed). Although TMAX is a surrogate for absorption halftime (TABS ~ 1/3 TMAX), TMAX and CMAX can be estimated with compartment model equations. Equations 1 and 2 are example equations for a 1compartment model with firstorder absorption and elimination:

Information gleaned from naloxone non‐compartment pharmacokinetic estimates

Improving the Safety of Pediatric Sedation: Human Error, Technology, and Clinical Microsystems

Deep learning to detect acute respiratory distress syndrome on chest radiographs: a retrospective study with external validation

Correction to: Improving the Safety of Pediatric Sedation: Human Error, Technology, and Clinical Microsystems

Pediatric preoxygenation and inhalation induction of anesthesia can include a mixture of gases. In children, the clinical impact on oxygenation while using other gases with oxygen during an inhalation induction is unknown.

Incidence of post‐induction hypoxemia in children and the effect of induction gas composition

In a large health system in the United States, investigators examined whether mortality, receipt of mechanical ventilation, and patient acuity changed over time among adult patients with COVID-19–related critical illness admitted to intensive care units.

Characteristics, Outcomes, and Trends of Patients With COVID-19–Related Critical Illness at a Learning Health System in the United States

Pharmacokinetic simulation was used to characterize levobupivacaine disposition after regional anesthetic rescue for failed spinal anesthesia in neonates and infants.

Prediction of levobupivacaine concentrations in neonates and infants following neuraxial rescue blocks

Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (N-acetyl-p-aminophenol (APAP; paracetamol)) are the commonest analgesic drugs used in childhood. Though both drugs act through inhibition of prostaglandin H2 synthetase, acetaminophen lacks the anti-inflammatory effects of the NSAIDs. Neonatal acetaminophen hepatic clearance is reduced in premature neonates (5–10% adult rates) and increases to 30% adult rates in neonates born at term; adult rates (approximately 16–20 l/h/70 kg) are reached within the first year of life. NSAID clearance maturation, mostly through cytochrome P450 mixed oxidases, is more rapid. Concentration–response relationships suggest a maximum pain reduction of 5 or 6 on a 10-point scale for both drugs. Combination therapy does not increase this maximum effect but does prolong duration of analgesia. Whilst both drugs have good safety profiles, dosing of both drug groups is tempered by concerns about toxicity. Acetaminophen hepatotoxicity is associated with single doses (>250 mg/kg in preschool children, >150 mg/kg in adults) and therapy duration longer than 3–5 days (>90 mg/kg/day).The most common minor adverse events in NSAID recipients are nausea, dizziness, and headache. More concerning is the potential of NSAIDs to cause gastrointestinal irritation, blood clotting disorders, renal impairment, neutrophil dysfunction, and bronchoconstriction. These adverse effects are uncommon provided care is taken with drug dose, duration of therapy, and recognition of contraindications.

Self-reported poor quality of sleep in solid organ transplant: A systematic review.

Oxycodone pharmacokinetics have been described in premature neonates through to obese adults. Covariate influences have been accounted for using allometry (size) and maturation of oxycodone clearance with age. The target concentration is dependent on pain intensity that may differ over pain duration or between individuals.

Oxycodone target concentration dosing for acute pain in children

Short and Long Term Exposure to Ambient Air Pollutants and Increased Risk of Acute Respiratory Distress Syndrome in Sepsis

Rationale: Respiratory viruses are commonly detected pathogens in pulmonary sepsis. Prior studies have demonstrated that patients with respiratory viral infections may have transient lymphocytopenia and thrombocytopenia. Leukocyte parameters including lymphocyte to monocyte ratio (LMR) and neutrophil to lymphocyte ratio (NLR) have been reported as screening tools for viral infections. Platelet counts and dynamics have been described as quantitative traits for ARDS risk and mortality. Therefore, we hypothesized that early hematologic parameters including lymphocyte count, monocyte count, platelet count, NLR, and LMR may distinguish viral from bacterial pulmonary sepsis. Methods: We enrolled 1,158 critically ill patients with pulmonary sepsis from 2009 to 2020 and measured lymphocyte count, monocyte count, platelet count, NLR, and LMR on ICU admission and at 24-hrs. Respiratory viruses were detected via PCR panel on nasopharyngeal swabs. Pulmonary sepsis was adjudicated by a physician panel. APACHE III scores were collected during the first 24-hrs. Shock was assessed by vasopressor use or mean arterial pressure &lt;65mmHg despite 30cc/kg fluid resuscitation. ARDS was defined per Berlin criteria. We assessed mortality at 30 days. We used multivariable linear regression to test the association between each of the laboratory studies and a positive respiratory pathogen panel (RVP) adjusting for APACHE III score, age, sex, malignancy, and race. We used multivariable logistic regression to assess for associations between a positive RVP and outcomes. Results: The incidence of respiratory virus detection was 33.9%. The incidence of ARDS and mortality were 52.7% and 49.0%, respectively. The most commonly detected pathogens were SARS-CoV-2 and rhinovirus (Table 1). Lower platelet counts at 24-hrs were significantly associated with respiratory virus detection (β-41.59 × 109/L [95%CI-79.03,-4.15], p=0.03), whereas admission platelet counts were not significantly associated (β-22.38 × 109/L [95%CI-63.26, 20.49], p=0.32). The significant association at 24-hrs was also present on sensitivity analyses excluding patients with SARS-CoV-2. There were no statistically significant differences between the populations with respect to lymphocyte count, monocyte count, NLR, LMR, ARDS, shock, and mortality. Conclusion: Lower early platelet counts were identified in patients with viral pulmonary sepsis. Although LMR and NLR have been reported as screening tools for viral infections in non-critically ill populations, we did not detect significant associations between lymphocyte count, monocyte count, NLR or LMR and viral detection in pulmonary sepsis. Our findings suggest that platelet counts in combination with other validated parameters may warrant further investigation for the early discrimination of viral versus bacterial pulmonary sepsis.

Early Platelet Counts Distinguish Viral and Bacterial Pulmonary Sepsis

Pharmacokinetic parameter estimates are used in mathematical equations (pharmacokinetic models) to describe concentration changes with time in a population and are specific to that population. Simulation using these models and their parameter estimates can enrich understanding of drug behavior and serve as a basis for study design. Pharmacokinetic concepts are presented pertaining to future designs of dexmedetomidine target‐controlled infusion pumps in children. This manuscript provides the pediatric anesthesiologist with an understanding of the nuances that should be considered when using target‐controlled infusion pumps; how the central volume may differ between populations, how clearance changes with age, and the impact of adverse effects on dose. In addition, the ideal loading dose and rate of delivery to achieve target concentration without adverse cardiovascular effects are reviewed, and finally, dose considerations for obese children, based on contact‐sensitive half‐time, are introduced. An understanding of context‐sensitive half‐time changes with age enables anesthetic practitioners to better estimate duration of effect after cessation of dexmedetomidine infusion. Use of these known pharmacokinetic parameters and covariate information for the pediatric patient could readily be incorporated into commercial target‐controlled infusion pumps to allow effective and safe open‐loop administration of dexmedetomidine in children.

Pharmacokinetic concepts for dexmedetomidine target‐controlled infusion pumps in children

Intranasal Fentanyl for Intervention-Associated Breakthrough Pain After Cardiac Surgery

ABSTRACT Introduction: The target concentration strategy uses PKPD information for dose determination. Models have also quantified exposure-response relationships, improved understanding of developmental pharmacokinetics, rationalized dose prescription, provided insight into the importance of covariate information, explained drug interactions and driven decision-making and learning during drug development. Areas covered: The prime PKPD consideration is parameter estimation and quantification of variability. The main sources of variability in children are age (maturation) and weight (size). Model use is mostly confined to pharmacokinetics, partly because anesthesia effect models in the young are imprecise. Exploration of PK and PD covariates and their variability hold potential to better individualize treatment. Expert opinion: The ability to model drugs using computer-based technology is hindered because covariate data required to individualize treatment using these programs remain lacking. Target concentration intervention strategies remain incomplete because covariate information that might better predict individualization of dose is absent. Pharmacogenomics appear a valuable area for investigation for pharmacodynamics and pharmacodynamics. Effect measures in the very young are imprecise. Assessment of the analgesic component of anesthesia is crude. While neuromuscular monitoring is satisfactory, depth of anaesthesia EEG interpretation is inadequate. Closed loop anesthesia is possible with better understanding of EEG changes.

Pharmacokinetic and pharmacodynamic considerations of general anesthesia in pediatric subjects

Abstract Objective Pain after coronary artery by-pass (CAB) surgery is severe. Analgesic administration by mouth is unreliable until after gastrointestinal function has recovered. We evaluated the bioavailability of oxycodone co-administered with naloxone by mouth in patients after CAB surgery using either a conventional extracorporeal circulation (CECC) or off-pump surgery (OPCAB). Methods Twenty-four patients, 50–73 years, 12 with CECC and 12 with OPCAB, were administered a 10/5 mg oxycodone-naloxone controlled-release tablet by mouth on the preoperative day and for the first seven postoperative days (PODs) thereafter. Blood samples were collected up to 24 h after the preoperative administration, and then randomly either on POD1 and POD3 or on POD2 and POD4. The oxycodone concentration in plasma was analyzed using liquid chromatography-mass spectrometry. Results On POD1 oxycodone absorption was markedly delayed in five of six patients after CECC and in all six patients after OPCAB surgery; median of tmax after CECC 630 [range 270–1420] minutes and after OPCAB 1020 [720–1410] minutes, compared to median of 120–315 min preoperatively and on POD2-POD4. The carry-over corrected AUC0–24 values on the PODs did not differ from the preoperative values, but were higher on POD3 compared with POD1 in both CECC and OPCAB groups. The rate and extent of oxycodone absorption equaled preoperative values on POD2 and onwards in patients with CAB surgery. Conclusions Bioavailability of oxycodone by mouth was similar after CAB surgery via CECC or having OPCAB. Data indicate that POD2 is an appropriate time to start oxycodone administration by mouth after CAB surgery.

Bioavailability of oxycodone by mouth in coronary artery bypass surgery patients – a randomized trial

Supplemental Digital Content is available in the text. Background: After critical illness, new or worsening impairments in physical, cognitive, and/or mental health function are common among patients who have survived. Who should be screened for long-term impairments, what tools to use, and when remain unclear. Objectives: Provide pragmatic recommendations to clinicians caring for adult survivors of critical illness related to screening for postdischarge impairments. Participants: Thirty-one international experts in risk-stratification and assessment of survivors of critical illness, including practitioners involved in the Society of Critical Care Medicine’s Thrive Post-ICU Collaboratives, survivors of critical illness, and clinical researchers. Design: Society of Critical Care Medicine consensus conference on post-intensive care syndrome prediction and assessment, held in Dallas, in May 2019. A systematic search of PubMed and the Cochrane Library was conducted in 2018 and updated in 2019 to complete an original systematic review and to identify pre-existing systematic reviews. Meeting Outcomes: We concluded that existing tools are insufficient to reliably predict post-intensive care syndrome. We identified factors before (e.g., frailty, preexisting functional impairments), during (e.g., duration of delirium, sepsis, acute respiratory distress syndrome), and after (e.g., early symptoms of anxiety, depression, or post-traumatic stress disorder) critical illness that can be used to identify patients at high-risk for cognitive, mental health, and physical impairments after critical illness in whom screening is recommended. We recommend serial assessments, beginning within 2–4 weeks of hospital discharge, using the following screening tools: Montreal Cognitive Assessment test; Hospital Anxiety and Depression Scale; Impact of Event Scale-Revised (post-traumatic stress disorder); 6-minute walk; and/or the EuroQol-5D-5L, a health-related quality of life measure (physical function). Conclusions: Beginning with an assessment of a patient’s pre-ICU functional abilities at ICU admission, clinicians have a care coordination strategy to identify and manage impairments across the continuum. As hospital discharge approaches, clinicians should use brief, standardized assessments and compare these results to patient’s pre-ICU functional abilities (“functional reconciliation”). We recommend serial assessments for post-intensive care syndrome-related problems continue within 2–4 weeks of hospital discharge, be prioritized among high-risk patients, using the identified screening tools to prompt referrals for services and/or more detailed assessments.

Society of Critical Care Medicine’s International Consensus Conference on Prediction and Identification of Long-Term Impairments After Critical Illness

Supplemental Digital Content is available in the text. Objectives: Examine well-being, measured as burnout and professional fulfillment, across critical care healthcare professionals, ICUs, and hospitals within a health system; examine the impact of the coronavirus disease 2019 pandemic. Design: To complement a longitudinal survey administered to medical critical care physicians at the end of an ICU rotation, which began in May 2018, we conducted a cross-sectional survey among critical care professionals across four hospitals in December 2018 to January 2019. We report the results of the cross-sectional survey and, to examine the impact of the coronavirus disease 2019 pandemic, the longitudinal survey results from July 2019 to May 2020. Setting: Academic medical center. Subjects: Four-hundred eighty-one critical care professionals, including 353 critical care nurses, 58 advanced practice providers, 57 physicians, and 13 pharmacists, participated in the cross-sectional survey; 15 medical critical care physicians participated in the longitudinal survey through the coronavirus disease 2019 pandemic. Interventions: None. Measurements and Main Results: Burnout was present in 50% of ICU clinicians, ranging from 42% for critical care physicians to 55% for advanced practice providers. Professional fulfillment was less common at 37%, with significant variability across provider (p = 0.04), with a low of 23% among critical care pharmacists and a high of 53% among physicians. Well-being varied significantly at the hospital and ICU level. Workload and job demand were identified as drivers of burnout and meaning in work, culture and values of work community, control and flexibility, and social support and community at work were each identified as drivers of well-being. Between July 2019 and March 2020, burnout and professional fulfillment were present in 35% (15/43) and 58% (25/43) of medical critical care physician responses, respectively. In comparison, during the coronavirus disease 2019 pandemic, burnout and professional fulfillment were present in 57% (12/21) and 38% (8/21), respectively. Conclusions: Burnout was common across roles, yet differed across ICUs and hospitals. Professional fulfillment varied by provider role. We identified potentially modifiable factors related to clinician well-being that can inform organizational strategies at the ICU and hospital level. Longitudinal studies, designed to assess the long-term impact of the coronavirus disease 2019 pandemic on the well-being of the critical care workforce, are urgently needed.

Benchmarking Critical Care Well-Being: Before and After the Coronavirus Disease 2019 Pandemic

INTRODUCTION: To describe the epidemiology of Coronavirus Disease 2019 (COVID-19)-related critical illness at a diverse academic health system METHODS: We performed a single-health system, multihospital retrospective cohort study of patients with COVID- 19-related critical illness who were admitted to an intensive care unit (ICU) at any of five hospitals within the University of Pennsylvania Health System We report descriptive statistics for patient demographics, comorbidities, acute physiology parameters, receipt of ICU therapies, hospital outcomes, and survivorship Using multivariable linear and logistic regression, we evaluated trends over time in all-cause 28-day in-hospital mortality, the primary outcome, and in patient acuity, and we evaluated candidate prognostic risk factors for association with mortality RESULTS: 468 patients with COVID-19-related critical illness had a median age of 65 years (interquartile range [IQR] 54-74), were more likely male (57 7%), were more likely Black race (52 8%), and had a high co-morbidity burden (71 8% with ≥ 2 points on the Charlson Comorbidity Index) At least once during their hospitalization, 319 (68 2%) patients were treated with mechanical ventilation and 121 (25 9%) with vasopressors Outcomes were notable for 29 9% all-cause 28-day in-hospital mortality (37 0% among those who received mechanical ventilation and 14 8% among those who did not receive mechanical ventilation), 8-day (IQR 3-17) median ICU length of stay, 13-day (IQR 7-25) median hospital length of stay, and 10 8% all-cause 30-day readmission rate Mortality decreased over time from 43 5% (95% confidence interval 31 3%-53 8%) to 19 2% (11 6%- 26 7%) between the first and last 15-day periods in the fully adjusted model Risk factors at ICU admission prognostic for mortality included increasing age, peripheral vascular disease, low or high body mass index, abnormal mental status, hypoxemia, tachypnea, and thrombocytopenia CONCLUSIONS: Among patients with COVID-19-related critical illness admitted to the ICU at an academic health system in the U S , a finite set of patient-level factors were prognostic for mortality and mortality decreased over time

134: Characteristics and Outcomes of Patients With COVID-19-Related Critical Illness

Clonidine is used off‐label in children but only limited pediatric pharmacokinetic data are available for intravenously administered clonidine.

Pharmacokinetics of an intravenous bolus dose of clonidine in children undergoing surgery

Objectives: To review interventions required by children admitted for intensive care management following tonsillectomy or adenotonsillectomy either as elective or unplanned admission in a tertiary children’s hospital. Methods: A retrospective chart review over a 10-year period between April 2007 and March 2017 was performed. Charts were interrogated for treatments that were administered in the paediatric intensive care unit. Respiratory support therapies such as supplemental oxygen administration, high-flow nasal oxygen, positive pressure ventilation, continuous positive airway pressure, airway interventions and tracheal intubation were reviewed. Results: There were 103 children admitted to the paediatric intensive care unit following tonsillectomy or adenotonsillectomy. The average age was 6.2 years (range 7 months–17 years). The main indications for the procedure were sleep disordered breathing or obstructive sleep apnoea syndrome. In all, 53 children had syndromes with medical comorbidities, 31 were current continuous positive airway pressure users and 5 had a tracheostomy in situ. Forty children admitted to paediatric intensive care unit did not require any high-level care. Ten children who had an unplanned admission had their respiratory interventions started in the theatre or in the post-anaesthetic care unit, before paediatric intensive care unit admission, and did not require escalation of care. Conclusion: Children may not require admission for intensive care after tonsillectomy if they have had an incident-free period in the post-anaesthetic care unit. Some of those who required high-flow nasal oxygen could have been managed on the ward provided with adequate training and monitoring facilities. The level of care they require in post-anaesthetic care unit reflected the level of care for the immediate postoperative period in the paediatric intensive care unit.

Postoperative admission to paediatric intensive care after tonsillectomy

Supplemental Digital Content is available in the text. Objectives: To assess the feasibility, safety, and efficacy of a sedation protocol using dexmedetomidine as the primary sedative in mechanically ventilated critically ill children. Design: Open-label, pilot, prospective, multicenter, randomized, controlled trial. The primary outcome was the proportion of sedation scores in the target sedation range in the first 48 hours. Safety outcomes included device removal, adverse events, and vasopressor use. Feasibility outcomes included time to randomization and protocol fidelity. Setting: Six tertiary PICUs in Australia and New Zealand. Patients: Critically ill children, younger than 16 years old, requiring intubation and mechanical ventilation and expected to be mechanically ventilated for at least 24 hours. Interventions: Children randomized to dexmedetomidine received a dexmedetomidine-based algorithm targeted to light sedation (State Behavioral Scale –1 to +1). Children randomized to usual care received sedation as determined by the treating clinician (but not dexmedetomidine), also targeted to light sedation. Measurements and Main Results: Sedation with dexmedetomidine as the primary sedative resulted in a greater proportion of sedation measurements in the light sedation range (State Behavioral Scale –1 to +1) over the first 48 hours (229/325 [71%] vs 181/331 [58%]; p = 0.04) and the first 24 hours (66/103 [64%] vs 48/116 [41%]; p < 0.001) compared with usual care. Cumulative midazolam dosage was significantly reduced in the dexmedetomidine arm compared with usual care (p = 0.002).There were more episodes of hypotension and bradycardia with dexmedetomidine (including one serious adverse event) but no difference in vasopressor requirements. Median time to randomization after intubation was 6.0 hours (interquartile range, 2.0–9.0 hr) in the dexmedetomidine arm compared with 3.0 hours (interquartile range, 1.0–7.0 hr) in the usual care arm (p = 0.24). Conclusions: A sedation protocol using dexmedetomidine as the primary sedative was feasible, appeared safe, achieved early, light sedation, and reduced midazolam requirements. The findings of this pilot study justify further studies of sedative agents in critically ill children.

Dexmedetomidine Sedation in Mechanically Ventilated Critically Ill Children: A Pilot Randomized Controlled Trial

A universal pharmacokinetic model was developed from pooled paediatric and adult data (40.6 postmenstrual weeks, 70.8 years, 3.1–152 kg). A three-compartment pharmacokinetic model with first-order elimination was superior to a two-compartment model to describe these pooled dexmedetomidine data. Population parameter estimates (population parameter variability%) were clearance (CL) 0.9 L/min/70 kg (36); intercompartmental clearances (Q2) 1.68 L/min/70 kg (63); Q3 0.62 L/min/70 kg (90); volume of distribution in the central compartment (V1) 25.2 L/70 kg (103.9); rapidly equilibrating peripheral compartment (V2) 34.4 L/70 kg (41.8); slow equilibrating peripheral compartment (V3) 65.4 L/70 kg (62). Obesity was best described by fat-free mass for clearances and normal fat mass for volumes with a factor for fat mass (FfatV) of 0.293. Models describing dexmedetomidine pharmacokinetics in adults can be applied to children by accounting for size (allometry) and age (maturation). This universal dexmedetomidine model is applicable to a broad range of ages and weights: neonates through to obese adults. Lean body weight is a better size descriptor for dexmedetomidine clearance than total body weight. This parameter set could be programmed into target-controlled infusion pumps for use in a broad population.

A Universal Pharmacokinetic Model for Dexmedetomidine in Children and Adults

BACKGROUND: Previous formulations of alfaxalone have shown it to be a fast-acting intravenous anesthetic with high therapeutic index. Alfaxalone has been reformulated for human use as Phaxan, an aqueous solution of 10 mg/mL of alfaxalone and 13% betadex. This study assessed the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of alfaxalone given as a bolus intravenous injection of this formulation to human male volunteers. METHODS: A dose of 0.5 mg/kg (0.42–0.55 mg/kg) of alfaxalone [mean (range)] was given by single intravenous bolus injection to 12 healthy subjects. Plasma alfaxalone concentrations and bispectral index (BIS) values were analyzed using an integrated pharmacokinetic–pharmacodynamic (PKPD) model using nonlinear mixed-effects models. Effect (BIS) was described using a sigmoidal fractional maximum effect (EMAX) model. All parameters were scaled using allometry and standardized to a 70-kg person using exponents of 0.75 for clearance parameters (CL, Q2, and Q3), 1.0 for volumes (V1, V2, and V3), and 0.25 for time-related parameters half-time keo (t1/2keo). RESULTS: A 3-compartment model used to fit PK data with an additional compartment, linked by t1/2keo to describe the effect compartment, yielded alfaxalone PK parameter estimates: CL: 1.08 L/min; 0.87–1.34 L/min (median; 95% confidence interval [CI]); central volume of distribution (V1): 0.99 L; 0.53–2.05 L (median; 95% CI); intercompartment CLs (Q2): 0.87 L/min; 0.32–1.71 L/min (median; 95% CI) and Q3: 0.46 L/min; 0.19–1.03 L/min (median; 95% CI); and peripheral volumes of distribution (V2): 6.36 L; 2.79–10.7 L (median; 95% CI) and V3: 19.1 L; 8.61–37.4 L (median; 95% CI). PD interrogation assumed a baseline BIS of 96, with an estimated EMAX: 0.94; 0.71–0.99 (median; 95% CI), a plasma concentration (Cp) for 50% effect (C50): 0.98 mg/L; 0.83–1.09 mg/L (median; 95% CI), and a Hill coefficient (γ): 12.1; 6.7–15 (median; 95% CI). The t1/2keo was 8 minutes; 4.70–12.8 minutes (median; 95% CI). The mean time to a BIS 50 was 0.94 minutes (standard deviation [SD] = 0.2 minutes). CONCLUSIONS: After a single bolus intravenous injection, alfaxalone has a high plasma CL equal to hepatic blood flow as reported for earlier studies of bolus injections of a previous formulation of alfaxalone. The plasma levels associated with BIS values of <60 are comparable to those previously reported in patients anesthetized with alfaxalone. The t1/2keo is relatively high, but the large Hill coefficient contributes to rapid onset and offset of action. This information can inform future studies of this formulation.

Pharmacokinetic and Pharmacodynamic Analysis of Alfaxalone Administered as a Bolus Intravenous Injection of Phaxan in a Phase 1 Randomized Trial

The ABO histo-blood group is defined by carbohydrate modifications and is associated with risk for multiple diseases including Acute Respiratory Distress Syndrome (ARDS). We hypothesized that genetically determined blood subtype A1 is associated with increased risk of ARDS and markers of microvascular dysfunction and coagulation.

METHODS
We conducted analyses in three cohorts of critically ill trauma and sepsis patients (n = 3,710) genotyped on genome-wide platforms to determine the association of the A1 blood type genotype with ARDS risk. We subsequently determined if associations were present in FUT2 defined non-secretors who lack ABO antigens on epithelium, but not endothelium. In a patient subgroup, we determined the associations of blood type with plasma levels of endothelial glycoproteins and disseminated intravascular coagulation (DIC). Lastly, we tested if blood type A was associated with less donor lung injury recovery during human ex vivo lung perfusion (EVLP).

RESULTS
The A1 genotype was associated with a higher risk of moderate to severe ARDS relative to type O in all three populations. In sepsis, this relationship was strongest in non-pulmonary infections. The association persisted in non-secretors, suggesting a vascular mechanism. The A1 genotype was also associated with higher DIC risk as well as concentrations of thrombomodulin and von Willebrand Factor, which in turn were associated with ARDS risk. Blood type A was also associated with less lung injury recovery during EVLP.

We identified a replicable association between ABO blood type A1 and risk of ARDS among the critically ill possibly mediated through microvascular dysfunction and coagulation.

The ABO Histo-Blood Group, endothelial activation, and acute respiratory distress syndrome risk in critical illness.

Viral Pulmonary Sepsis Is Inversely Associated with Shock and Circulating Matrix Metalloproteinases

Delivering transformative action in paediatric pain: a Lancet Child & Adolescent Health Commission.

Absolute Lymphopenia Associates with Plasma Markers of Hyperinflammation

Christopher Eccleston (Ph.D.), Emma Fisher (Ph.D.), Richard F. Howard (FFPMRCA), Rebeccah Slater (Ph.D.), Paula Forgeron (Ph.D.) , Tonya M. Palermo (Ph.D.) , Kathryn A. Birnie (Ph.D.), Brian J. Anderson (Ph.D.), Christine T. Chambers (Ph.D.) , Geert Crombez (Ph.D.), Gustaf Ljungman (Ph.D.), Isabel Jordan, Zachary Jordan, Caitriona Roberts (LLM), Neil Schechter (M.D.), Christine B. Sieberg (Ph.D.), Dick Tibboel (M.D.), Suellen M. Walker (Ph.D) , Dominic Wilkinson (DPhil) 20, 21, , Chantal Wood (M.D)

Delivering transformative change in paediatric pain: A Lancet Child & Adolescent Health Commission

30: IMPROVING TIME TO URGENT ANTIBIOTIC ADMINISTRATION IN CRITICALLY ILL PATIENTS WITH SUSPECTED SEPSIS

Postoperative tonsillectomy pain is problematic with 75% of children reportingsevere pain on swallowing in the first 3 days of surgery.1 This pain decreases over time and while 86% of children 2-12 years might report noteworthy pain on day one at home, 67% of children were rated by parents as experiencing significant overall pain on day 3.2 However, 41% of those children were given only one or no analgesic on day 3.2 Although similar pain resolution profiles, with mirrored analgesic intake, have been reported during the first week after surgery, these patterns are not consistent.3 Some have reported increases in pain on day 2-3.4 Althoughinadequately treated postoperative pain is multifactorial, the combination of acetaminophen and a nonsteroidal anti-inflammatory drug alone appears inadequate for 30% of children for the first few postoperative days.

1360: MICU ADVANCED PRACTICE PROVIDERS: DELIVER QUALITY CARE AND REDUCED BED STRAIN AND PHYSICIAN BURNOUT

Prediction Models for Physical, Cognitive, and Mental Health Impairments After Critical Illness: A Systematic Review and Critical Appraisal

1 Professor, Department of Anaesthesiology, University of Auckland, 2 Paediatric Allergist andClinical Immunologist, StarshipChildren’s Hospital, Auckland, New Zealand ............................................................................................................................................................................................................................................................................................................ Correspondenc to: B. Anderson Email:briana@adhb.govt.nz Accepted: 4 June 2019

Clinical Impact of an Electronic Dashboard and Alert System for Sedation Minimization and Ventilator Liberation: A Before-After Study

We know little about the safety or efficacy of pharmacological medicines for children and adolescents with chronic pain, despite their common use. Our aim was to conduct an overview review of systematic reviews of pharmacological interventions that purport to reduce pain in children with chronic noncancer pain (CNCP) or chronic cancer-related pain (CCRP). We searched the Cochrane Database of Systematic Reviews, Medline, EMBASE, and DARE for systematic reviews from inception to March 2018. We conducted reference and citation searches of included reviews. We included children (0-18 years of age) with CNCP or CCRP. We extracted the review characteristics and primary outcomes of ≥30% participant-reported pain relief and patient global impression of change. We sifted 704 abstracts and included 23 systematic reviews investigating children with CNCP or CCRP. Seven of those 23 reviews included 6 trials that involved children with CNCP. There were no randomised controlled trials in reviews relating to reducing pain in CCRP. We were unable to combine data in a meta-analysis. Overall, the quality of evidence was very low, and we have very little confidence in the effect estimates. The state of evidence of randomized controlled trials in this field is poor; we have no evidence from randomised controlled trials for pharmacological interventions in children with cancer-related pain, yet cannot deny individual children access to potential pain relief. Prospero ID: CRD42018086900.

Pharmacological interventions for chronic pain in children: an overview of systematic reviews.

Innovative, Multidisciplinary Central Line Assessments in the Medical ICU (MICU): Utilizing Technology to Provide Real-time Feedback

Plasma receptor interacting protein kinase-3 levels are associated with acute respiratory distress syndrome in sepsis and trauma: a cohort study

D104. CRITICAL CARE: A FINE BALANCE - SEPSIS DEFINITIONS, OUTCOMES AND EPIDEMIOLOGY

ABO Blood Type as a Risk Factor for Disseminated Intravascular Coagulation (DIC) in Sepsis

30: GENETIC REGULATION OF LACTATE DURING SEPSIS IMPLICATES PHOSPHODIESTERASE 4D IN SEPSIS OUTCOME

Thank you for your comments regarding our article “Hemodynamic and Pharmacokinetic Analysis of Oxymetazoline Use During Nasal Surgery in Children”. The authors are grateful that you found our study informative, as your work has been the motivation for our interest in this subject. Currently, the United States Food and Drug Administration (FDA) approves oxymetazoline use in patients who are ≥6 years of age. Unfortunately, pharmacokinetic studies that define the appropriate dosing of this medication in children, especially infants and toddlers, are lacking. These data are needed because it appears that oxymetazoline offers some clinical superiority over other agents. Similar to the case reported by Latham and Jardine, we reported significant hemodynamic effects following the placement of oxymetazoline-soaked pledgets into the nasal cavity of a 4-year-old child during a bilateral inferior turbinate reduction. Subsequently, we had additional anecdotal experience with an adolescent who developed hypertension, left ventricular strain, and pulmonary edema following the unrestricted intraoperative administration of oxymetazoline during closed reduction of a nasal fracture. Latham and Jardine demonstrated that when the bottle is inverted, as may occur when a patient is supine on the operating room table, the volume delivered is 15 to 80 times that delivered in the upright position. These results were independently verified by our group. The current study demonstrates that, despite the volumetric increase of oxymetazoline when administered by nasal pledgets, the serum concentration achieved was not excessive. Importantly, it does not lead to significant hemodynamic changes when used as described. Given the concerns outlined above, we agree wholeheartedly with Dr. Latham that some standardized method is needed for the administration of oxymetazoline. This can be accomplished by measuring out a specific volume of the liquid prior to administration and avoiding the use of an inverted over-the-counter bottle for administration. When oxymetazoline-soaked pledgets are used, the total volume of oxymetazoline should be limited and placement should minimize the potential for absorption from nonsurgical areas. Despite the widespread use of oxymetazoline in a variety of clinical settings, the reports of adverse effects remain rare, sporadic, and anecdotal. Although it may be that underreporting of serious adverse events is present, it may also be that these reports demonstrate that the life-threatening hemodynamic effects require a combination of factors to be present, which are yet to be elucidated. Additional research is needed to more clearly define the safe use of oxymetazoline in pediatric patients in various clinical settings.

In Response to Hemodynamic and Pharmacokinetic Analysis of Oxymetazoline Use During Nasal Surgery in Children

Septic patients frequently develop cognitive impairment that persists beyond hospital discharge. The impact of sepsis on electrophysiological and molecular determinants of learning is underexplored. We observed that mice that survived sepsis or endotoxemia experienced loss of hippocampal long-term potentiation (LTP), a brain-derived neurotrophic factor–mediated (BDNF-mediated) process responsible for spatial memory formation. Memory impairment occurred despite preserved hippocampal BDNF content and could be reversed by stimulation of BDNF signaling, suggesting the presence of a local BDNF inhibitor. Sepsis is associated with degradation of the endothelial glycocalyx, releasing heparan sulfate fragments (of sufficient size and sulfation to bind BDNF) into the circulation. Heparan sulfate fragments penetrated the hippocampal blood-brain barrier during sepsis and inhibited BDNF-mediated LTP. Glycoarray approaches demonstrated that the avidity of heparan sulfate for BDNF increased with sulfation at the 2-O position of iduronic acid and the N position of glucosamine. Circulating heparan sulfate in endotoxemic mice and septic humans was enriched in 2-O– and N-sulfated disaccharides; furthermore, the presence of these sulfation patterns in the plasma of septic patients at intensive care unit (ICU) admission predicted persistent cognitive impairment 14 days after ICU discharge or at hospital discharge. Our findings indicate that circulating 2-O– and N-sulfated heparan sulfate fragments contribute to septic cognitive impairment.

Circulating heparan sulfate fragments mediate septic cognitive dysfunction

Plasma sTNFR1 and IL8 for prognostic enrichment in sepsis trials: a prospective cohort study

Early pain after laparoscopy is often severe. Oxycodone is a feasible analgesic option after laparoscopy, but there are sparse data on epidural administration. The aim was to evaluate the analgesic efficacy and pharmacokinetics of a single dose of epidural oxycodone as a part of multimodal analgesia after gynaecological laparoscopy.

Analgesic efficacy and pharmacokinetics of epidural oxycodone in pain management after gynaecological laparoscopy—A randomised, double blind, active control, double‐dummy clinical comparison with intravenous administration

Oxymetazoline is an α‐adrenergic agonist that is commonly used as a topical hemostatic agent in the operating room during ear, nose, and throat surgery. There are limited data on oxymetazoline pharmacokinetics in children who undergo general anesthesia. We assessed the hemodynamic effects and systemic absorption of topically applied oxymetazoline in children undergoing various nasal procedures.

Hemodynamic and pharmacokinetic analysis of oxymetazoline use during nasal surgery in children

Propofol administered in conjunction with an opioid such as remifentanil is used to provide total intravenous anesthesia for children. Drugs can be given as infusion controlled manually by the physician or as automated target-controlled infusion that targets plasma or effect site. Smart pumps programmed with pharmacokinetic parameter estimates administer drugs to a preset plasma concentration. A linking rate constant parameter (keo) allows estimation of effect site concentration. There are two parameter sets, named after the first author describing them, that are commonly used in pediatric target-controlled infusion for propofol (Absalom and Kataria) and one for remifentanil (Minto). Propofol validation studies suggest that these parameter estimates are satisfactory for the majority of children. Recommended target concentrations for both propofol and remifentanil depend on the type of surgery, the degree of surgical stimulation, the use of local anesthetic blocks, and the ventilatory status of the patient. The use of processed electroencephalographic monitoring is helpful in pediatric total intravenous anesthesia and target-controlled infusion anesthesia, particularly in the presence of neuromuscular blockade.

Practicalities of Total Intravenous Anesthesia and Target-controlled Infusion in Children.

Purpose of review Pharmacokinetic–pharmacodynamic (PKPD) population modelling has advanced adult anaesthesia. Current literature was reviewed to discern use of this analytic technique for benefit in the perioperative management of children. Recent findings Variability in drug response, selection of a dose that achieves a desired target concentration and optimizing sampling protocols for further studies are all facets of paediatric anaesthesia that have benefitted from modelling approaches. PKPD models have driven the maintenance dose rate in target-controlled infusion pumps used for total intravenous anaesthesia. Although many of the models used in these pumps were developed in adults, translation for paediatric use has followed, including subgroups, such as neonates and obese children. The use of drug effect measures (e.g. bispectral index) has improved the predictive performance of pharmacodynamic models. Simulation studies have facilitated an increase in safety by quantifying drug variability, and identifying where possible adverse drug events may occur. Summary Modelling and simulation continue to have an important role optimizing drug use during anaesthesia. Models incorporating influential covariates that better describe drug pharmacokinetics and pharmacodynamics improve anaesthetic treatments and safety in diverse populations and clarify drug role and impact. Their use developing paediatric clinical studies improves trial conduct, often with fewer subjects required for study.

Pharmacokinetic–pharmacodynamic population modelling in paediatric anaesthesia and its clinical translation

Manual propofol infusion regimens for neonates and infants have been determined from clinical observations in children under the age of 3 years undergoing anesthesia. We assessed the performance of these regimens using reported age‐specific pharmacokinetic parameters for propofol. Where performance was poor, we propose alternative dosing regimens.

Burnout, and Fulfillment, in the Profession of Critical Care Medicine.

METHODS: Plasma mtDNA concentrations were measured at ED presentation and approximately 48 h later in separate prospective cohorts of critically ill patients with trauma and sepsis. ARDS was classified according to the Berlin definition. The association of mtDNA with ARDS was tested by using multivariable logistic regression, adjusted for covariates previously shown to contribute to ARDS risk in each population.

Plasma Mitochondrial DNA Levels Are Associated With ARDS in Trauma and Sepsis Patients

Rationale: Acute respiratory distress syndrome (ARDS) lacks known causal biomarkers. Plasma concentrations of sRAGE (soluble receptorforadvancedglycationendproducts)stronglyassociatewithARDSrisk.However,whetherplasmasRAGEcontributescausallytoARDSremainsunknown. Objectives: Evaluate plasma sRAGE as a causal intermediate in ARDS by Mendelian randomization (MR), a statistical method to infer causality using observational data. Methods: We measured early plasma sRAGE in two critically ill populations with sepsis. The cohorts were whole-genome genotyped and phenotyped for ARDS. To select validated genetic instruments for MR, we regressed plasma sRAGE on genome-wide genotypes in both cohorts. The causal effect of plasma sRAGE on ARDS was inferred using the top variants with signi ﬁ cant associations in both populations ( P , 0.01, R 2 . 0.02). We applied the inverse variance – weighted method to obtain consistent estimates of the causal effect of plasma sRAGE on ARDS risk. Measurements and Main Results: There were 393 European and 266 African ancestry patients in the ﬁ rst cohort and 843 European ancestry patients in the second cohort. Plasma sRAGE was strongly associated with ARDS risk in both populations (odds ratio, 1.86; 95% con ﬁ dence interval [1.54 – 2.25]; 2.56 [2.14 – 3.06] per log increase). Using genetic instruments common to both populations, plasma sRAGE had a consistent causal effect on ARDS risk with a b estimate of 0.50 (95% con ﬁ dence interval [0.09 – 0.91] per log increase). Conclusions: Plasma sRAGE is genetically regulated during sepsis, and MR analysis indicates that increased plasma sRAGE leads to increased ARDS risk, suggesting plasma sRAGE acts as a causal intermediate in sepsis-related ARDS. of SNPs Predisposing to Altered ALI Risk; MESSI=Molecular Epidemiology of Sepsis in the ICU; OR=odds ratio; sRAGE=soluble receptor for advanced glycation end products. Among 393 subjects with European ancestry and 266 subjects with African ancestry in the MESSI population, there was a signiﬁcant positive association between higher plasma concentrations of sRAGE and increased odds of acute respiratory distress syndrome. The logistic regression analyses in MESSI were adjusted for pulmonary source of infection and Acute Physiology and Chronic Health Evaluation III score, which possessed independent associations with acute respiratory distress syndrome on univariate analyses. The same association was observed within the 843 iSPAAR subjects.

Plasma sRAGE Acts as a Genetically Regulated Causal Intermediate in Sepsis-associated Acute Respiratory Distress Syndrome : Plasma sRAGE as a Causal Intermediate in ARDS Risk

Ibuprofen is widely used for ductus arteriosus closure in premature neonates and for analgesia in children and adults. There are no maturation descriptors of clearance. This lack of maturation understanding limits dosing recommendations from premature neonates to adulthood.

A target concentration strategy to determine ibuprofen dosing in children

OBJECTIVE
This study aims to determine the prevalence of functional and psychological impairment in survivors of extracorporeal life support (ECLS) and assess the needs of survivors to guide development of an effective follow-up program.

DESIGN
This mixed-methods outcomes study used quantitative assessment via standardized instruments (Katz Index of Independence of Activities of Daily Living [Katz ADL], the Lawton Instrumental Activities of Daily Living [Lawton IADL], Hospital Anxiety and Depression Scale, and the Post Traumatic Growth Inventory) and qualitative interview to identify challenges experienced by survivors.

SETTING
A single institutional experience in an academic medical center in the United States.

PATIENTS
Patient selection targeted patients who underwent veno-venous ECLS for acute respiratory failure between January 1, 2015, and April 1, 2017. Forty-two patients (21 male, 21 female; median age of 49 years; interquartile range 36-57 years) completed the interview a median of 14.6 (interquartile range 7.7-21.1) months after ECLS decannulation.

This was an observational follow-up study for which no intervention was made.

MEASUREMENTS AND MAIN RESULTS
The Katz ADL and Lawton IADL revealed high independence and functionality in 62% of patients (26 of 42). Clinically significant anxiety was present in 48% (20 of 42) of patients and depression in 26% (11 of 42). There was a correlation between the number of ADL and IADL deficiencies and depression (rho 0.61, p < 0.001) and anxiety (rho 0.29, p = 0.033) subscales of the Hospital Anxiety and Depression Scale. High levels of posttraumatic growth were noted in 50% (21 of 42) of patients. Nearly all survivors noted that a clinic designed for post-ECLS follow-up would be beneficial. Patients desired access to education, improved coordination of care, and additional mental health resources.

This study demonstrated persistent physical and psychological impairments in survivors of ECLS. Patients consistently expressed a desire to debrief on their hospital course and receive education on possible long-term effects. Study findings suggest that structured follow-up may allow for early identification of psychological and physical impairments to improve outcomes. Future studies should focus on investigating the effect of rehabilitation and follow-up clinics in preventing these issues.

Long-Term Outcomes After Extracorporeal Life Support for Acute Respiratory Failure.

RATIONALE
Acute respiratory distress syndrome (ARDS) lacks known causal biomarkers. Plasma concentrations of the soluble receptor for advanced glycation end products (sRAGE) strongly associate with ARDS risk. However, whether plasma sRAGE contributes causally to ARDS remains unknown.

Evaluate plasma sRAGE as a causal intermediate in ARDS by Mendelian Randomization (MR), a statistical method to infer causality using observational data.

METHODS
We measured early plasma sRAGE in two critically ill populations with sepsis. The cohorts were whole genome-genotyped and phenotyped for ARDS. To select validated genetic instruments for MR, we regressed plasma sRAGE on genome-wide genotypes in both cohorts. The causal effect of plasma sRAGE on ARDS was inferred using the top variants with significant associations in both populations (p<0.01, R^2>0.02). We applied the inverse-variance weighted method to obtain consistent estimates of the causal effect of plasma sRAGE on ARDS risk.

There were 393 European and 266 African ancestry patients in the first cohort and 843 European ancestry patients in the second cohort. Plasma sRAGE was strongly associated with ARDS risk in both populations (OR 1.86; 95% CI [1.54, 2.25]; 2.56 [2.14-3.06] per log increase). Using genetic instruments common to both populations, plasma sRAGE had a consistent causal effect on ARDS risk with a β estimate of 0.50 95% CI [0.09, 0.91] per log increase.

Plasma sRAGE is genetically regulated during sepsis, and MR analysis indicates that increased plasma sRAGE leads to increased ARDS risk suggesting plasma sRAGE acts a causal intermediate in sepsis-related ARDS.

Plasma sRAGE Acts as Genetically Regulated Causal Intermediate in Sepsis-Associated ARDS.

Plasma Mitochondrial DNA Levels are Associated with Acute Respiratory Distress Syndrome in Trauma and Sepsis Patients.

Concern over potential neurotoxicity of anesthetics has led to growing interest in prospective clinical trials using potentially less toxic anesthetic regimens, especially for prolonged anesthesia in infants. Preclinical studies suggest that dexmedetomidine may have a reduced neurotoxic profile compared to other conventional anesthetic regimens; however, coadministration with either anesthetic drugs (eg, remifentanil) and/or regional blockade is required to achieve adequate anesthesia for surgery. The feasibility of this pharmacological approach is unknown. The aim of this study was to determine the feasibility of a remifentanil/dexmedetomidine/neuraxial block technique in infants scheduled for surgery lasting longer than 2 hours.

An open label pilot study of a dexmedetomidine‐remifentanil‐caudal anesthetic for infant lower abdominal/lower extremity surgery: The T REX pilot study

Background— Delirium significantly affects postoperative outcomes, but the incidence, risk factors and the long-term impact of delirium in lung transplant recipients have not been well studied. Methods— We analyzed 155 lung transplant recipients enrolled in the Lung Transplant Outcomes Group (LTOG) cohort at a single center. We determined delirium incidence by structured chart review, identified risk factors for delirium, determined if plasma concentrations of two cerebral injury markers (neuron specific enolase [NSE] and glial fibrillary acidic protein [GFAP]) were associated with delirium, and determined the association of postoperative delirium with 1-year survival. Results— Fifty-seven (36.8%) patients developed postoperative delirium. Independent risk factors for delirium included pre-transplant benzodiazepine prescription (relative risk [RR] 1.82; 95% confidence interval [CI]: 1.08, 3.07; p = 0.025), total ischemic time (RR 1.10 per 30 minute increase; 95% CI: 1.01, 1.21; p = 0.027), duration of time with intraoperative mean arterial pressure <60 mmHg (RR 1.07 per 15 minute increase; 95% CI: 1.00, 1.14; p = 0.041) and grade 3 primary graft dysfunction (RR 2.13; 95% CI: 1.27, 3.58; p = 0.004). Ninety-one (58.7%) patients had available plasma 24 hours. Plasma GFAP was inconsistently detected, whereas NSE was universally detectable, with higher NSE concentrations associated with delirium (risk difference 15.1% comparing 75 th and 25 th percentiles; 95% CI: 2.5, 27.7; p = 0.026). One year mortality appeared higher among delirious patients, 12.3% compared to 7.1%, but was not significant (p = 0.28). Conclusions— Postoperative delirium is common in lung transplant recipients, and several potentially modifiable risk factors deserve further study to determine their associated mechanisms and predictive values.

INCIDENCE, RISK FACTORS AND CLINICAL IMPLICATIONS OF POSTOPERATIVE DELIRIUM IN LUNG TRANSPLANT RECIPIENTS

Intravenous acetaminophen is commonly administered as an adjunctive to opioids during major surgical procedures, but neither the correct pharmacokinetic size descriptor nor the dose is certain in severely obese adolescents undergoing bariatric surgery.

Acetaminophen pharmacokinetics in severely obese adolescents and young adults

The impact of tramadol in children given acetaminophen‐ibuprofen combination therapy is uncertain in acute pediatric pain management. A model describing the interaction between these three drugs would be useful to understand the role of supplemental analgesic therapy.

Acetaminophen, ibuprofen, and tramadol analgesic interactions after adenotonsillectomy

Plasma angiopoietin-2 as a potential causal marker in sepsis-associated ARDS development: evidence from Mendelian randomization and mediation analysis

Intravenous ketorolac is commonly administered to children for the control of postoperative pain. An effect site EC50 for analgesia of 0.37 mg.L−1 is described in adults.

The pharmacokinetics of intravenous ketorolac in children aged 2 months to 16 years: A population analysis

Quantitative peripheral muscle ultrasound in sepsis: Muscle area superior to thickness

Dexmedetomidine metabolic clearance is not affected by fat mass in obese patients

BACKGROUND: The aim of this study is to derive a propofol pharmacokinetic (PK) pharmacodynamic (PD) model to perform effect-site target-controlled infusion (TCI) in obese patients, and to analyze its performance along with that of other available PK models. METHODS: In the first step of the study, a 3-compartment PK model linked to a sigmoidal inhibitory Emax PD model by a first-order rate constant (keo) was used to fit propofol concentration–bispectral index (BIS) data. Population modeling analysis was performed by nonlinear mixed effects regression in NONMEM (ICON, Dublin, Ireland). PK data from 3 previous studies in obese adult patients (n = 47), including PD (BIS) data from 1 of these studies (n = 20), were pooled and simultaneously analyzed. A decrease in NONMEM objective function (&Dgr;OBJ) of 3.84 points, for an added parameter, was considered significant at the 0.05 level. In the second step of the study, we analyzed the predictive performance (median predictive errors [MDPE] and median absolute predictive errors [MDAPE]) of the current model and of other available models using an independent data set (n = 14). RESULTS: Step 1: The selected PKPD model produced an adequate fit of the data. Total body weight resulted in the best size scalar for volumes and clearances (&Dgr;OBJ, −18.173). Empirical allometric total body weight relationships did not improve model fit (&Dgr;OBJ, 0.309). A lag time parameter for BIS response improved the fit (&Dgr;OBJ, 89.593). No effect of age or gender was observed. Step 2: Current model MDPE and MDAPE were 11.5% (3.7–25.0) and 26.8% (20.7–32.6) in the PK part and 0.4% (−10.39 to 3.85) and 11.9% (20.7–32.6) in the PD part. The PK model developed by Eleveld et al resulted in the lowest PK predictive errors (MDPE = <10% and MDAPE = <25%). CONCLUSIONS: We derived and validated a propofol PKPD model to perform effect-site TCI in obese patients. This model, derived exclusively from obese patient’s data, is not recommended for TCI in lean patients because it carries the risk of underdosing.

Effect-Site Target-Controlled Infusion in the Obese: Model Derivation and Performance Assessment

Tramadol has recently fallen under the same scrutiny as codeine because both drugs have an active metabolite formed by the hepatic liver enzyme cytochrome P450 (CYP)-2D6 that is subject to genetic polymorphism.1 This article considers the important differences between these two drugs. We discuss why tramadol should not have the same contraindication applied to it as codeine in the settings of breastfeeding mothers (with subsequent low newborn or infant exposure) or hospitalised neonates.

A publication in 2006 reported a death of a breastfed neonate whose mother was taking codeine in the puerperium.2 The mother was a CYP2D6 ultrarapid metaboliser, which resulted in documented high morphine (codeine’s active metabolite) transferral through the breast milk. The Food and Drug Administration (FDA), the European Medicines Agency, and the Medicines and Healthcare products Regulatory Agency subsequently published advisories. In 2012–2013, these bodies warned that codeine use was contraindicated in breastfeeding mothers. The FDA report provides references of several reports of respiratory depression in neonates as further basis for this warning.3 In 2016, the National Library of Medicine created a Drugs and Lactation metadata base (LactMed) as a subset of the Toxicology Data Network. For codeine, this cites articles and scientific meeting abstracts about plasma concentrations in a small number of breastfeeding mothers, from the same author group that reported the neonatal death.4 LactMed also references a scientific poster, where breastfeeding women who reported central nervous system depression were more likely to have CYP2D6 gene duplication.4

During the same period, deaths were reported in toddlers, and obese older children, who were using codeine as a cough suppressant or for analgesia after tonsillectomy. This led to a 2012 FDA investigation documenting 13 paediatric cases of mortality or serious morbidity.5 Some of these children were ultrarapid metabolisers, while others were extensive (normal) metabolisers, with higher …

Transition from the intrauterine to the extrauterine environment in neonates is associated with major changes in blood flow and oxygenation with consequent increases in metabolic functions. The additional impact of birth on renal function and drug metabolism above that predicted by postmenstrual age and allometry is uncertain. Increased clearance at birth could reduce analgesic effect attributable to a lowering of plasma concentration. These elimination processes can be described using the clearance concept.

Negligible impact of birth on renal function and drug metabolism

Pain following tonsillectomy is often poorly managed in the home setting. Multimodal analgesia with acetaminophen (paracetamol) and nonsteroidal anti‐inflammatory drugs offers superior analgesia over monotherapy but may be difficult for caregivers to manage. A fixed‐dose combination oral suspension product containing paracetamol and ibuprofen has been developed to facilitate pediatric dosing.

Analgesic effectiveness, pharmacokinetics, and safety of a paracetamol/ibuprofen fixed‐dose combination in children undergoing adenotonsillectomy: A randomized, single‐blind, parallel group trial

Propofol and remifentanil are commonly combined during total intravenous anesthesia. The impact of remifentanil in this relationship is poorly quantified in children. Derivation of an integrated pharmacokinetic and pharmacodynamic propofol model, containing remifentanil pharmacodynamic interaction information, enables propofol effect‐site target‐controlled infusion in children with a better prediction of its hypnotic effect when both drugs are combined.

Propofol pharmacokinetic and pharmacodynamic profile and its electroencephalographic interaction with remifentanil in children

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation

Incidence, risk factors, and clinical implications of post-operative delirium in lung transplant recipients.

Postoperative wound infections represent an important source of morbidity and mortality in children. Perioperative antibiotic prophylaxis has been shown to decrease the risk of developing infections and hospital guidelines surrounding antibiotic use exist to standardize patient care. Despite supporting evidence, rates of compliance with guidelines vary. Quality improvement initiatives have been introduced to improve compliance with intraoperative antibiotic guidelines. Thorough infection surveillance, including antibiotic provision in presurgical checklists, computerized voice antibiotic administration prompts, and national feedback systems are now increasingly common. Few studies have been conducted investigating the effectiveness of prophylactic antibiotics in children. Outcome measures such as morbidity and mortality and return to the operating room can be used to examine the relationship between antibiotic use and patient outcome but these measures are limited in that they occur infrequently or are subjective and difficult to measure. Metrics such as days alive out of hospital and length of hospital stay may be useful alternatives for ongoing monitoring of infections and identifying improvements in patient outcomes. Guidelines on antibiotic prophylaxis have facilitated an increase in the correct provision of perioperative antibiotics and a reduction in the incidence of postoperative infection. Measures of patient outcome such as days alive out of hospital and length of hospital stay are easy to collect and calculate but further work is needed to confirm the utility of these measures for monitoring infection rates.

Compliance with perioperative prophylaxis guidelines and the use of novel outcome measures

Comment on “Effect of Age-Related Factors on the Pharmacokinetics of Lamotrigine and Potential Implications for Maintenance Dose Optimisation in Future Clinical Trials”

Purpose of review Medication errors in paediatric anaesthesia and the perioperative setting continue to occur despite widespread recognition of the problem and published advice for reduction of this predicament at international, national, local and individual levels. Current literature was reviewed to ascertain drug error rates and to appraise causes and proposed solutions to reduce these errors. Recent findings The medication error incidence remains high. There is documentation of reduction through identification of causes with consequent education and application of safety analytics and quality improvement programs in anaesthesia departments. Children remain at higher risk than adults because of additional complexities such as drug dose calculations, increased susceptibility to some adverse effects and changes associated with growth and maturation. Major improvements are best made through institutional system changes rather than a commitment to do better on the part of each practitioner. Summary Medication errors in paediatric anaesthesia represent an important risk to children and most are avoidable. There is now an understanding of the genesis of adverse drug events and this understanding should facilitate the implementation of known effective countermeasures. An institution-wide commitment and strategy are the basis for a worthwhile and sustained improvement in medication safety.

Drug error in paediatric anaesthesia: current status and where to go now

Reply: A New Direction: Sleep and Neuropsychological Impairment after Critical Illness.

Purpose of review The use of conventional pharmacokinetic parameters sets ‘models’ derived from nonobese patients has proven inadequate to administer intravenous anesthetics in the obese population and is commonly associated with higher than anticipated plasma propofol concentrations when used with target (plasma or effect site) controlled infusion pumps. In this review we will describe recent modeling strategies to characterize the disposition of intravenous anesthetics in the obese patient and will show clinically relevant aspects of new model's performance in the obese population. Recent findings Because clearance of a drug increases in a nonlinear manner with weight, nonlinear relationships better scale infusion rates between lean and obese individuals. Allometric concepts have been successfully used to describe size-related nonlinear changes in clearances. Other nonlinear scaling options include the use of descriptors such as body surface area, lean body weight, fat-free mass, and normal fat mass. Newer pharmacokinetic models, determined from obese patient data, have been developed for propofol and remifentanil using allometric concepts and comprehensive size descriptors. Summary Pharmacokinetic models to perform target-controlled infusion in the obese population should incorporate descriptors that reflect with greater precision the influence of body composition in volumes and clearances of each drug. It is our hope that commercially available pumps will soon incorporate these new models to improve the performance of this technique in the obese population.

Advances in pharmacokinetic modeling: target controlled infusions in the obese

Alpha‐2 agonists are direct peripheral vasoconstrictors, which achieve these effects by activating vascular smooth muscle alpha‐2 adrenoceptors. The impact of this response during dexmedetomidine infusion remains poorly quantified. Our goal was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD, vasoconstriction) effects of a computer‐controlled dexmedetomidine infusion in healthy volunteers.

Pharmacokinetics and pharmacodynamics of dexmedetomidine‐induced vasoconstriction in healthy volunteers

Sevoflurane pharmacokinetics have been traditionally described using physiological models, while pharmacodynamics employed the use of minimal alveolar concentration.

Modeling the pharmacokinetics and pharmacodynamics of sevoflurane using compartment models in children and adults

Objective: Plasma interleukin-1 beta may influence sepsis mortality, yet recombinant human interleukin-1 receptor antagonist did not reduce mortality in randomized trials. We tested for heterogeneity in the treatment effect of recombinant human interleukin-1 receptor antagonist by baseline plasma interleukin-1 beta or interleukin-1 receptor antagonist concentration. Design: Retrospective subgroup analysis of randomized controlled trial. Setting: Multicenter North American and European clinical trial. Patients: Five hundred twenty-nine subjects with sepsis and hypotension or hypoperfusion, representing 59% of the original trial population. Interventions: Random assignment of placebo or recombinant human interleukin-1 receptor antagonist × 72 hours. Measurements and Main Results: We measured prerandomization plasma interleukin-1 beta and interleukin-1 receptor antagonist and tested for statistical interaction between recombinant human interleukin-1 receptor antagonist treatment and baseline plasma interleukin-1 receptor antagonist or interleukin-1 beta concentration on 28-day mortality. There was significant heterogeneity in the effect of recombinant human interleukin-1 receptor antagonist treatment by plasma interleukin-1 receptor antagonist concentration whether plasma interleukin-1 receptor antagonist was divided into deciles (interaction p = 0.046) or dichotomized (interaction p = 0.028). Interaction remained present across different predicted mortality levels. Among subjects with baseline plasma interleukin-1 receptor antagonist above 2,071 pg/mL (n = 283), recombinant human interleukin-1 receptor antagonist therapy reduced adjusted mortality from 45.4% to 34.3% (adjusted risk difference, –0.12; 95% CI, –0.23 to –0.01), p = 0.044. Mortality in subjects with plasma interleukin-1 receptor antagonist below 2,071 pg/mL was not reduced by recombinant human interleukin-1 receptor antagonist (adjusted risk difference, +0.07; 95% CI, –0.04 to +0.17), p = 0.230. Interaction between plasma interleukin-1 beta concentration and recombinant human interleukin-1 receptor antagonist treatment was not statistically significant. Conclusions: We report a heterogeneous effect of recombinant human interleukin-1 receptor antagonist on 28-day sepsis mortality that is potentially predictable by plasma interleukin-1 receptor antagonist in one trial. A precision clinical trial of recombinant human interleukin-1 receptor antagonist targeted to septic patients with high plasma interleukin-1 receptor antagonist may be worthy of consideration.

Mortality Benefit of Recombinant Human Interleukin-1 Receptor Antagonist for Sepsis Varies by Initial Interleukin-1 Receptor Antagonist Plasma Concentration*

Organ Dysfunction in Sepsis: Brain, Neuromuscular, Cardiovascular, and Gastrointestinal

Bringing the ABCDEF Bundle to Life and Saving Lives Through the Process.

Objective The mainstay of pain treatment after paediatric cardiac surgery is the use of opioids. Current guidelines for its optimal use are based on small, non-randomised clinical trials, and data on the pharmacokinetics (PK) and pharmacodynamics (PD) of opioids are lacking. This study aims at providing an overview of international hospital practices on the treatment of pain and sedation after paediatric cardiac surgery. Design A multicentre survey study assessed the management of pain and sedation in children aged 0–18 years after cardiac surgery. Setting Pediatric intensive care units (PICU)of 19 tertiary children’s hospitals worldwide were invited to participate. The focus of the survey was on type and dose of analgesic and sedative drugs and the tools used for their pharmacodynamic assessment. Results Fifteen hospitals (response rate 79%) filled out the survey. Morphine was the primary analgesic in most hospitals, and its doses for continuous infusion ranged from 10 to 60 mcg kg-1 h-1 in children aged 0–36 months. Benzodiazepines were the first choice for sedation, with midazolam used in all study hospitals. Eight hospitals (53%) reported routine use of sedatives with pain treatment. Overall, type and dosing of analgesic and sedative drugs differed substantially between hospitals. All participating hospitals used validated pain and sedation assessment tools. Conclusion There was a large variation in the type and dosing of drugs employed in the treatment of pain and sedation after paediatric cardiac surgery. As a consequence, there is a need to rationalise pain and sedation management for this vulnerable patient group.

An international survey of management of pain and sedation after paediatric cardiac surgery

Lean body mass is commonly proposed for anesthesia maintenance drug dosing calculations. However, total body mass used with allometric scaling has been shown to be better for propofol in obese adults and children. Fat‐free mass has also been used instead of lean body mass. Fat‐free mass is essentially the same as lean body mass but excludes a small percentage of mass of lipids in cell membranes, CNS, and bone marrow. Normal fat mass is a size descriptor that partitions total body mass into fat‐free mass and fat mass calculated from total body mass minus fat‐free mass. The relative influence of fat mass compared with fat‐free mass is described by the fraction of fat mass that makes fat equivalent to fat‐free mass in terms of allometric size. This fraction (Ffat) will differ for each drug and each parameter affected by body size (eg, clearance and volume of distribution). This fraction is based on the concept of theory‐based allometric size. The normal fat mass based on allometric theory and partition of body mass into fat and fat‐free components provides a principle‐based approach explaining size and body composition effects on pharmacokinetics of all drugs in children and in adults.

Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as important.We designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol) in order to review the evidence for children's pain utilising pharmacological interventions.As the leading cause of morbidity in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (that is pain lasting three months or longer) can arise in the paediatric population in a variety of pathophysiological classifications (nociceptive, neuropathic, or idiopathic) from genetic conditions, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, as well as for other unknown reasons.Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat pain, reduce fever, and for their anti-inflammation properties. They are commonly used within paediatric pain management. Non-steroidal anti-inflammatory drugs are currently licensed for use in Western countries, however they are not approved for infants under three months old. The main adverse effects include renal impairment and gastrointestinal issues. Common side effects in children include diarrhoea, headache, nausea, constipation, rash, dizziness, and abdominal pain.

To assess the analgesic efficacy and adverse events of NSAIDs used to treat chronic non-cancer pain in children and adolescents aged between birth and 17 years, in any setting.

SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, and Embase via Ovid from inception to 6 September 2016. We also searched the reference lists of retrieved studies and reviews, as well as online clinical trial registries.

SELECTION CRITERIA
Randomised controlled trials, with or without blinding, of any dose and any route, treating chronic non-cancer pain in children and adolescents, comparing any NSAID with placebo or an active comparator.

DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods. We assessed GRADE and created three 'Summary of findings' tables.

MAIN RESULTS
We included seven studies with a total of 1074 participants (aged 2 to 18 years) with chronic juvenile polyarthritis or chronic juvenile rheumatoid arthritis. All seven studies compared an NSAID with an active comparator. None of the studies were placebo controlled. No two studies investigated the same type of NSAID compared with another. We were unable to perform a meta-analysis.Risk of bias varied. For randomisation and allocation concealment, one study was low risk and six studies were unclear risk. For blinding of participants and personnel, three studies were low risk and four studies were unclear to high risk. For blinding of outcome assessors, all studies were unclear risk. For attrition, four studies were low risk and three studies were unclear risk. For selective reporting, four studies were low risk, two studies were unclear risk, and one study was high risk. For size, three studies were unclear risk and four studies were high risk. For other potential sources of bias, seven studies were low risk. Primary outcomesThree studies reported participant-reported pain relief of 30% or greater, showing no statistically significant difference in pain scores between meloxicam and naproxen, celecoxib and naproxen, or rofecoxib and naproxen (P > 0.05) (low-quality evidence).One study reported participant-reported pain relief of 50% or greater, showing no statistically significant difference in pain scores between low-dose meloxicam (0.125 mg/kg) and high-dose meloxicam (0.25 mg/kg) when compared to naproxen 10 mg/kg (P > 0.05) (low-quality evidence).One study reported Patient Global Impression of Change, showing 'very much improved' in 85% of ibuprofen and 90% of aspirin participants (low-quality evidence). Secondary outcomesAll seven studies reported adverse events. Participants reporting an adverse event (one or more per person) by drug were: aspirin 85/202; fenoprofen 28/49; ibuprofen 40/45; indomethacin 9/30; ketoprofen 9/30; meloxicam 18/47; naproxen 44/202; and rofecoxib 47/209 (very low-quality evidence).All seven studies reported withdrawals due to adverse events. Participants withdrawn due to an adverse event by drug were: aspirin 16/120; celecoxib 10/159; fenoprofen 0/49; ibuprofen 0/45; indomethacin 0/30; ketoprofen 0/30; meloxicam 10/147; naproxen 17/285; and rofecoxib 3/209 (very low-quality evidence).All seven studies reported serious adverse events. Participants experiencing a serious adverse event by drug were: aspirin 13/120; celecoxib 5/159; fenoprofen 0/79; ketoprofen 0/30; ibuprofen 4/45; indomethacin 0/30; meloxicam 11/147; naproxen 10/285; and rofecoxib 0/209 (very low-quality evidence).There were few or no data for our remaining secondary outcomes: Carer Global Impression of Change; requirement for rescue analgesia; sleep duration and quality; acceptability of treatment; physical functioning as defined by validated scales; and quality of life as defined by validated scales (very low-quality evidence).We rated the overall quality of the evidence (GRADE rating) for our primary and secondary outcomes as very low because there were limited data from studies and no opportunity for a meta-analysis.

AUTHORS' CONCLUSIONS
We identified only a small number of studies, with insufficient data for analysis.As we could undertake no meta-analysis, we are unable to comment about efficacy or harm from the use of NSAIDs to treat chronic non-cancer pain in children and adolescents. Similarly, we cannot comment on our remaining secondary outcomes: Carer Global Impression of Change; requirement for rescue analgesia; sleep duration and quality; acceptability of treatment; physical functioning; and quality of life.We know from adult randomised controlled trials that some NSAIDs, such as ibuprofen, naproxen, and aspirin, can be effective in certain chronic pain conditions.

Non-steroidal anti-inflammatory drugs (NSAIDs) for chronic non-cancer pain in children and adolescents.

Tramadol is a weak opioid that is structurally related to morphine and codeine. Two enantiomers provide analgesia; one is an opioid l-receptor agonist, and the other inhibits neuronal reuptake of serotonin and norepinephrine, thus producing “multimodal antinociception.” It is widely used in children as a second-line analgesic or rescue medication when paracetamol and NSAIDs prove inadequate. An important metabolic pathway is that provided by CYP2D6 to form O-desmethyltramadol; the active M1 metabolite. This active M1 metabolite has a l-receptor affinity approximately 200 times greater than tramadol. CYP2D6 is the same enzyme responsible for the production of codeine’s major active metabolite, morphine. Tramadol has come under increasing scrutiny ever since codeine was identified as a contributing factor to death in children suffering obstructive sleep apnea who underwent tonsillectomy. The USA Food and Drug Administration (FDA) issued a warning in 2013 concerning the use of codeine in children after adenotonsillectomy surgery following a number of deaths that were attributed to overdoses associated with undiagnosed ultra-rapid polymorphisms of CYP2D6.

Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past, pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as important.We designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol as priority areas) in order to review the evidence for children's pain utilising pharmacological interventions in children and adolescents.As the leading cause of morbidity in children and adolescents in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (lasting three months or longer) can arise in the paediatric population in a variety of pathophysiological classifications: nociceptive, neuropathic, idiopathic, visceral, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, and other unknown reasons.Paracetamol (acetaminophen) is one of the most widely used analgesics in both adults and children. The recommended dosage in the UK, Europe, Australia, and the USA for children and adolescents is generally 10 to 15 mg/kg every four to six hours, with specific age ranges from 60 mg (6 to 12 months old) up to 500 to 1000 mg (over 12 years old). Paracetamol is the only recommended analgesic for children under 3 months of age. Paracetamol has been proven to be safe in appropriate and controlled dosages, however potential adverse effects of paracetamol if overdosed or overused in children include liver and kidney failure.

To assess the analgesic efficacy and adverse events of paracetamol (acetaminophen) used to treat chronic non-cancer pain in children and adolescents aged between birth and 17 years, in any setting.

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, and Embase via Ovid from inception to 6 September 2016. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries.

Randomised controlled trials, with or without blinding, of any dose and any route, treating chronic non-cancer pain in children and adolescents, comparing paracetamol with placebo or an active comparator.

Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and numbers needed to treat, using standard methods where data were available. We assessed GRADE (Grading of Recommendations Assessment, Development and Evaluation) and planned to create a 'Summary of findings' table.

No studies were eligible for inclusion in this review. We rated the quality of the evidence as very low. We downgraded the quality of evidence by three levels due to the lack of data reported for any outcome.

There was no evidence from randomised controlled trials to support or refute the use of paracetamol (acetaminophen) to treat chronic non-cancer pain in children and adolescents. We are unable to comment about efficacy or harm from the use of paracetamol to treat chronic non-cancer pain in children and adolescents.We know from adult randomised controlled trials that paracetamol, can be effective, in certain doses, and in certain pain conditions (not always chronic).This means that no conclusions could be made about efficacy or harm in the use of paracetamol (acetaminophen) to treat chronic non-cancer pain in children and adolescents.

Paracetamol (acetaminophen) for chronic non-cancer pain in children and adolescents.

Purpose of review Dexmedetomidine is a drug with sedative, anxiolytic, sympatholytic and analgesic properties, which is finding widespread practice in paediatric anaesthesia and related practices. The present review summarizes its pharmacology and current experience with the drug. Recent findings Dexmedetomidine is proving useful in many diverse areas in paediatric anaesthesia where its sedative properties are useful for premedication, fibreoptic intubation and radiologic procedures. Its use as an adjunct for balanced anaesthesia where it can decrease the use of other drugs, reduce emergence delirium, postoperative shivering and vomiting. Muted apoptotic neuroprotective effects may realize benefits in neonates. Cardiac conduction delay, an adverse effect, may prove beneficial for arrhythmias after congenital cardiac surgery. Summary Most of the paediatric published studies concerning dexmedetomidine are observational in nature, with limited control groups or comparators. Adverse effects (e.g. bradycardia) still require greater scrutiny in the paediatric population and particularly with respect to different age groups. Dexmedetomidine currently has a firm position in the armamentarium of anaesthesia pharmacology. It is not the new all-in-one drug, but it is shaping up as a valuable adjunct for diverse indications within paediatric anaesthesia. Video abstract http://links.lww.com/COAN/A44.

Dexmedetomidine: the new all-in-one drug in paediatric anaesthesia?

Germovsek and colleagues have recently concluded that a standard approach to modelling pharmacokinetics is not wrong and appears to be at least as useful as other ad hoc methods for describing drug concentrations. There are other advantages of this approach including learning about biology, comparing different studies, detecting errors and rationalizing dose prediction. A standard approach to size and maturation is not a panacea but provides the framework for challenging new ideas and supports a consistent method of dosing in patients of all ages.

We present a case of subtotal cavernous sinus thrombosis secondary to Panton-Valentine leukocidin–associated Staphylococcus aureus pyomyositis of the muscles of mastication in a previously healthy child, who was successfully managed with no residual disease. He was found to have a factor V Leiden heterozygous mutation. We highlight the propensity of Panton-Valentine leukocidin Staphylococcus aureus to induce venous thrombosis at any site but with potential for more severe consequences in the head. We highlight pyomyositis as a differential for periorbital cellulitis and discuss the significance of the factor V Leiden mutation.

The Neutrophil-to-Lymphocyte Ratio in Bordetella Pertussis Infection.

Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization (WHO) guidelines for pharmacological treatments for persisting pain in children acknowledge that pain in children is a major public health concern of high significance in most parts of the world. Views on children's pain have changed over time and relief of pain is now seen as important. In the past, pain was largely dismissed and was frequently left untreated, and it was assumed that children quickly forgot about painful experiences.We designed a suite of seven reviews in chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol as priority areas) to review the evidence for children's pain using pharmacological interventions.As one of the leading causes of mortality and morbidity for children and adolescents in the world today, childhood cancer (and its associated pain) is a major health concern. Specific mortality and morbidity data relating to children are not currently identified. All childhood cancer rates are on the rise; for example, in the USA approximately 10,380 children aged under 15 years were expected to be diagnosed with cancer by the end of 2016. However, with survival rates also increasing, over 80% of paediatric cancer patients are expected to survive for five years or more, thus identifying the need to address pain management in this population.Cancer pain in infants, children, and adolescents is primarily nociceptive pain with negative long term effects. Cancer-related pain is generally caused directly by the tumour itself such as compressing on the nerve or inflammation of the organs. Cancer-related pain generally occurs as a result of perioperative procedures, nerve damage caused by radiation or chemotherapy treatments, or mucositis. However, this review focused on pain caused directly by the tumour itself such as nerve infiltration, external nerve compression, and other inflammatory events.Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat pain, reduce fever, and for their anti-inflammatory properties. They are commonly used within paediatric pain management. NSAIDs are currently licensed for use in western countries, however not approved for infants aged under three months. Primary adverse effects include gastrointestinal issues and possible renal impairment with long term use. Other adverse effects in children include diarrhoea, headache, nausea, constipation, rash, dizziness, and abdominal pain.

To assess the analgesic efficacy, and adverse events, of non-steroidal anti-inflammatory drugs (NSAIDs) used to treat cancer-related pain in children and adolescents aged from birth and 17 years, in any setting.

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, and Embase via Ovid from inception to 21 February 2017. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries.

Randomised, double-blind trials of any dose, and any route, treating cancer-related pain in children and adolescents, comparing NSAIDs with placebo or an active comparator.

Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods. We assessed GRADE (Grading of Recommendations Assessment, Development and Evaluation) and planned to create a 'Summary of findings' table.

No studies were eligible for inclusion in this review (very low quality evidence). We downgraded the quality of evidence by three levels due to the lack of data reported for any outcome.

There is no evidence from randomised controlled trials that non-steroidal anti-inflammatory drugs (NSAIDs) reduce cancer-related pain in children and adolescents. This means that no reliance or conclusions can be made about efficacy or harm in the use of NSAIDs to treat chronic cancer-related pain in children and adolescents.

Non-steroidal anti-inflammatory drugs (NSAIDs) for cancer-related pain in children and adolescents.

Intranasal phenylephrine is commonly used to vasoconstrict the nasal mucosa, reducing bleeding associated with nasotracheal intubation or endoscopic sinus surgery. There are few data quantifying either absorption pharmacokinetics or phenylephrine concentration effect on blood pressure in children.

The phenylephrine concentration‐response relationship for blood pressure after nasal delivery in children

Oral morphine has been proposed as an effective and safe alternative to codeine for after‐discharge pain in children following surgery but there are few data guiding an optimum safe oral dose.

Oral morphine dosing predictions based on single dose in healthy children undergoing surgery

Stressing the Brain: The Immune System, Hypothalamic–Pituitary– Adrenal Axis, and Psychiatric Symptoms in Acute Respiratory Distress Syndrome Survivors Brian J. Anderson and Mark E. Mikkelsen Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; and Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania

Stressing the Brain: The Immune System, Hypothalamic-Pituitary-Adrenal Axis, and Psychiatric Symptoms in Acute Respiratory Distress Syndrome Survivors.

Allometric size: The scientific theory and extension to normal fat mass

A survey conducted by Collier et al 1 highlights the problem of drug dosing in obese children. The authors identify two aspects that require greater attention from paediatric practitioners: the identification of the obese child and the lack of use of ideal body weight (IBW) for drug calculation in that obese child. Both involve effort from prescribers to go beyond simply measuring total body weight (TBW). There remains a question about the benefits of using IBW compared with using TBW or any other measure of body mass. The lack of enthusiasm to calculate IBW obvious from the Collier et al survey is reflective of uncertainty concerning dose calculation in the obese child.

Collier et al propose anecdotally that using IBW rather than TBW would have avoided toxicity from an overdose of aminophylline. While we agree that aminophylline maintenance doses using TBW may be over-predicted in obesity, initial dosing based on either IBW or TBW for a target concentration (TC) of 10 mg/L is unlikely to be toxic.2 While the use of TBW to calculate initial doses may not be ideal for the maintenance dose, the problem could have been avoided by measuring …

Tonsillectomy as a day‐stay procedure remains controversial, although it is an established procedure in New Zealand. We reviewed our last 10 years' experience.

The starship children's hospital tonsillectomy: A further 10 years of experience

An optimal sampling schedule for neonates, infants & children receiving cefazolin +/- vancomycin for cardiopulmonary bypass

Critical Care Medicine www.ccmjournal.org 2111 Survivors of critical illness experience profound loss. The loss manifests in myriad ways, including declines in cognitive function (1, 2), physical function (2, 3), and mental health (4, 5). These impairments define the post–intensive care syndrome, represent a major barrier to recovery, and often result in a loss of independence (6). The ripple effect incurred by caregivers of survivors is similarly profound. Collectively, the loss experienced by survivors and their loved ones has a significant public health impact (7). The study by Norman et al (8) in this issue of Critical Care Medicine examines a different kind of loss. Return to employment is an important component of recovery after critical illness, one associated with improved quality of life and fewer depressive symptoms (9). Unfortunately, return to employment is a major challenge for ICU survivors, as only 43–63% return to any form of employment (9–11). Among those who return to work, many return to reduced employment (11). Although gender, level of education, and nonsurgical ICU admission have been shown to be associated with return to employment after critical illness (9), potentially modifiable factors, including delirium and long-term neuropsychologic and physical function, have not been well studied. Given prior work that suggested a potential relationship between cognitive function and employment status (12), Norman et al (8) designed their study to examine the relationship between delirium and post-ICU cognitive function and return to employment in survivors of critical illness. Within the larger Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors study, the authors identified a nested cohort of 113 critically ill patients with shock or respiratory failure who were employed prior to ICU admission. Leveraging the robust study design of the parent study, delirium was assessed during the hospital stay using the Confusion Assessment Method for the ICU and cognitive function was assessed at 3 and 12 months using the Repeatable Battery for the Assessment of Neuropsychological Status (1). Employment status was determined by patient or proxy self-report. In this important work, the authors confirmed yet another loss that we need to prepare survivors and their loved ones– for the inability to return to one’s prior employment status. At 3 months, only 42% of survivors reported returning to any form of employment and only a modest number returned to their pre-ICU level of employment. At 3 months, level of education, illness severity, and physical function, but not duration of delirium or cognitive function 3 months post discharge, were identified as risk factors for loss of employment. At 12 months, the situation was similarly bleak. Older survivors appeared to be more likely to experience a loss of employment. Potentially related, worse cognitive function also appeared to be, although the association was not statistically significant (odds ratio, 0.49; 95% CI, 0.23–1.05; p = 0.07). Given the association between aging, level of education, and cognitive function, future studies should examine these relationships, including testing whether cognitive impairment after critical illness mediates the relationship between age and loss of employment, especially in those approaching retirement. Several potential limitations of the study should be noted to guide future investigations. A common limitation of the longitudinal cohort study design is loss to follow-up, and 19 patients were lost to follow-up between 3 and 12 months, which could have introduced bias. Although this study is one of the largest to investigate factors associated with return to work after critical illness, larger studies, powered to detect a multitude of risk factors mapped to a conceptual framework that accounts more fully for the domains involved (e.g., social support), are required. The primary outcome was a self-reported decrease in employment, which may have introduced recall bias. In the future, a mixed-methods study, designed to understand the demands of one’s work before and after critical illness and one’s ability to perform the previously required tasks, would complement the existing literature well. In addition, employment characteristics, such as the type of position and salary, may also be potential determinants of return to employment. For example, some survivors may be able to delay return to employment because of job or financial stability, benefits, or Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000001925 *See also p. 2003.

The Road to Recovery: Turning the Tide on Losses Incurred After Critical Illness.

The aim of this study was to characterize the dose–effect relationship of rocuronium at the adductor pollicis and masseter muscles.

Rocuronium pharmacokinetics and pharmacodynamics in the adductor pollicis and masseter muscles

The rising incidence of sepsis and improvements in critical care medicine have led to a growing number of sepsis survivors (1). Unfortunately, many intensive care unit (ICU) survivors suffer impairments in cognitive function, physical function and mental health (2-5).

From self-awareness to self-actualization: empowering sepsis survivors to a meaningful and enduring recovery.

Salbutamol is a selective beta-2 adrenoreceptor agonist widely used for the treatment of bronchospasm. While the pharmacodynamics of other bronchodilators such as theophylline have been reported, the pharmacodymamics of salbutamol are poorly characterised. An understanding of pharmacodynamics allows use of target concentration strategies to determine dose and the poor understanding of salbutamol pharmacodynamics is reflected in current infusion rate recommendations that range from 3 to 20 mcg/ min in those suffering status asthmaticus. The time to onset of action after inhaled salbutamol administration is believed to be less than 15 min, while that of oral administration is less than 30 min. Salbutamol is commonly given intravenously to patients suffering from bronchospasm but the onset time has not been reported. Such information could guide practitioners towards management if the response appears to be delayed. Is a delayed response due to distribution, receptor activation and bronchial muscle relaxation or is there a problem with IV administration or incorrect diagnosis of reversible bronchospasm?

Crit Care Med 2016 • Volume 44 • Number 12 (Suppl.) Methods: Institutional review board approved, single-center prospective observational study. All adolescents (age 13-18 years) admitted to a tertiary-care, freestanding children’s hospital were screened over a 1-year period (June 2014 June 2015). Alert-identified patients were verified for CRS in real-time by an ICU physician and all charts were reviewed by an ICU trained nurse. Results: Over the study period, 2546 adolescent inpatients were electronically screened and their data analyzed for CRS. The average patient age was 15.2 years with 48% males. Two hundred patients triggered 435 alerts for CRS with 91 patients generating 234 true positive alerts. Algorithm sensitivity was 90.4%, Specificity 96.2%, Positive Predictive Value (PPV) 36.5%, and Negative Predictive Value (NPV) 99.7%. There were 6 false negative alerts. Alerts were distributed across various units: Pediatric ICU (n=197), Cardiac ICU (n=17), Emergency Department (n=24), Clinical Teaching Units (n=136). Using mixed logistic regression on 15 alert indicators, Pulse (p=0.004), Temperature (p=0.008), ALT (p=0.015) and BUN/Creatinine ratio (p=0.013) were found to be key independent determinants of CRS. Conclusions: An EMR-integrated screening tool for real-time surveillance can be successfully employed with high sensitivity and specificity to identify adolescent CRS. Longitudinal studies using this EMR-integrated screening algorithm are required to improve algorithm PPV and further characterize adolescent CRS.

1344: PLASMA RIP3, A REGULATOR OF NECROPTOSIS, IS ASSOCIATED WITH MORTALITY & ORGAN DYSFUNCTION IN SEPSIS

Admission plasma levels of the neuronal injury marker neuron-specific enolase are associated with mortality and delirium in sepsis.

Dead poets are venerated; not so the occasional author of a scientific article who did not live to see submission of his or her work. The current issue of Pediatric Anesthesia includes a retrospective report that was planned and performed circa 1995–2002 by a single investigator (1). The work was completed by his colleagues after his demise. Despite this individual researcher’s large contribution to the work, he was not granted authorship, only an acknowledgment. Should he have been granted authorship? The International Committee of Medical Journal Editors (ICMJE) has developed criteria to differentiate authors from other contributors for a scientific paper. Four criteria are suggested for authorship (http:// www.icmje.org/recommendations/browse/roles-andresponsibilities/defining-the-role-of-authors-and-contributors.html):

An unimmunised 5-week-old, term male infant presented to the intensive care unit with cardiorespiratory failure and peripheral lymphocytosis. The infant deteriorated despite intubation, ventilation, vasoactive drug infusions and exchange transfusion. Venoarterial extracorporeal membrane oxygenation (ECMO) was started. Infection with Bordetella pertussis was subsequently confirmed. The lungs remained radiologically opacified and tidal volumes were poor despite lung recruitment manoeuvres, resulting in a prolonged …

Porcelain lung: calcification in severe Bordetella pertussis infection

Delirium is common in the intensive care unit (ICU) (1) and is particularly common in patients recovering from lung transplantation (2, 3). The emergence of delirium is frightening to patients and family members. Delirium complicates patient care and is associated with prolonged mechanical ventilation (4, 5), longer hospital stays (3–6), and increased mortality (5–7). In addition, delirium is associated with significant long-term morbidity in ICU survivors, including long-term cognitive impairment (1, 2, 8). Importantly, growing evidence also suggests delirium is associated with potentially permanent brain injury. Imaging studies comparing ICU survivors with matched controls reveal significant volume loss in the frontal lobes and hippocampus, the severity of which is closely linked to the duration of delirium and the degree of long-term cognitive impairment (9, 10). The pathophysiology of delirium and how it may lead to subsequent cognitive impairment remains poorly understood. Few studies have investigated hypoperfusion as a mechanism leading delirium. One study by Wijdicks and colleagues demonstrated that cardiovascular failure was a risk factor for septic encephalopathy in 84 postoperative patients (11), but to our knowledge, the study in this month’s issue of AnnalsATS by Smith and colleagues (pp. 180–187) is the only human study linking hypoperfusion to delirium (12). Using a prospective cohort design, the authors obtained detailed hemodynamic measurements on 63 patients who underwent lung transplantation. They defined cerebral perfusion pressure (CPP) as the difference between mean arterial pressure (MAP), measured by a femoral or radial arterial catheter, and central venous pressure (CVP), measured by a pulmonary artery catheter (CPP =MAP –CVP). Patients were assessed daily for delirium, using the Confusion Assessment Method, and were also assessed for delirium severity, using the Delirium Rating Scale. Using logistic regression adjusting for native lung disease and primary graft dysfunction, the authors demonstrated that every 10 mm Hg decrease in CPP was associated with a doubling of the odds of developing postoperative delirium (odds ratio, 2.08; 95% confidence interval, 1.08–4.24; P = 0.043). Next, in a negative binomial regression model adjusting for native lung disease and primary graft dysfunction, they showed that lower CPP was associated with longer duration of delirium (b =20.54; 95% confidence interval, 21.00 to 20.08; P = 0.22), such that every 10 mmHg decrease in CPP was associated with a 1.7-day increase in delirium duration. Finally, they identified an association of lower CPP with higher delirium severity, as well as associations of primary graft dysfunction with both odds of delirium and delirium duration. The study by Smith and colleagues has several strengths. First, the authors rigorously investigated an important topic that continues to challenge the critical care community. Second, the authors employed sound methodology, including a welldefined exposure variable and use of a wellvalidated screening tool for delirium. Third, the statistical techniques were appropriately chosen and the authors assessed their models for overfitting, given the small number of outcomes relative to the potential numbers of covariates. Several potential limitations of the study should be noted. The study was performed at a single center and thus may not be generalizable. This remains the primary limitation to the majority of studies evaluating delirium and neurocognition in lung transplant recipients. Although the authors adjusted for native lung disease and subsequent development of primary graft dysfunction, the association of CPP with delirium may be subject to residual confounding by additional covariates such as pretransplant cognitive function, severity of illness (e.g., mechanical ventilation and/ or extracorporeal membrane oxygenation as a bridge to transplant), age, chronic history of hypertension, and benzodiazepine or opiate use (3, 13). One prior study identified graft ischemic time as an independent risk factor of worse posttransplant cognitive function (14); thus, it would be interesting to investigate graft ischemic time as a potential confounder. A particular challenge in investigating mechanisms of delirium in patients with end-stage lung disease who undergo lung transplantation is accounting for the effects of hypoxemia on cognitive function. The authors note that reduced cerebral oxygenation has been associated with postoperative neurocognitive dysfunction (12), and additional studies have shown

Under Pressure: Reduced Cerebral Perfusion as a Risk Factor for Postoperative Delirium in Lung Transplant Recipients.

Tolerance to sedative drugs in PICU: can it be moderated or is it immutable?

Low Plasma Levels of Adiponectin Do Not Explain Acute Respiratory Distress Syndrome Risk: a Prospective Cohort Study of Patients with Severe Sepsis

An acceptable systolic or mean arterial blood pressure for children 0–6 years during anesthesia is unknown. Accepted blood pressures reported in standard charts for healthy awake children may not apply to those undergoing anesthesia.

Blood pressure and heart rates in neonates and preschool children: an analysis from 10 years of electronic recording

Neutropenic sepsis is associated with distinct clinical and biological characteristics: a cohort study of severe sepsis

Few pharmacokinetic (PK) and pharmacodynamic (PD) data exist for COX‐2 selective inhibitors in children. We wished to characterize the PKPD of parecoxib and its active metabolite, valdecoxib, in this population.

Pharmacokinetics and analgesic effectiveness of intravenous parecoxib for tonsillectomy ± adenoidectomy

Introduction: Assessment of analgesic drugs includes comparative studies to other analgesics and local anesthesia blockade, number needed to treat estimates and opioid sparing descriptions. An additional methodology is to define the concentration–response relationship using pharmacokinetic/pharmacodynamic (PK/PD) modeling. Areas covered: A concentration–response relationship allows analgesic effect comparison between drugs for different acute pain types. Covariates such as size, age and organ function impact greatly on PK in children. The cumulative effect of confounding factors (e.g., pharmacogenetics, placebo and changes in baseline pain over time) complicates PD. Other factors (outcome measures, method of measurement, failure to account for study attrition) impact on outcome. Population PK/PD modeling approaches allow us to account for these various factors to some extent. Expert opinion: Nonlinear mixed effects models help interpret analgesic data and their use is increasing. The PK is relatively well understood. The next investigative step will involve investigation into covariate effects for PD. Mathematical functions for both placebo models and dropout models are well described and should be incorporated into analgesic effectiveness studies that investigate a range of doses. Improvements in pain assessment tools and a greater understanding of pharmacogenomics factors will help individualize analgesic therapy.

Considerations when using pharmacokinetic/pharmacodynamic modeling to determine the effectiveness of simple analgesics in children

Sodium nitroprusside (SNP) has been widely used to control blood pressure in infants and children. The goals of this analysis were to develop models that describe the hemodynamic response to SNP dosing in pediatric patients; examine sources of variation in dose-response, defining age, and size dependencies; and determine vulnerable populations or patient subtypes that may elicit dosing modifications. A multi-center, randomized, double-blinded, parallel-group, dose-ranging, effect-controlled study, followed by an open-label dose titration of an intravenous infusion of SNP was undertaken in 203 pediatric subjects, who required deliberate hypotension or controlled normotension during anesthesia. A total of 3464 MAP measurements collected from 202 patients during the study's blinded phase, including baseline measurements up to 6 min prior to the blinded were available for analysis. A population K-PD model was developed with a one-compartment model assumed for SNP. Size differences in CL and V of the effect compartment were described using theory-based allometry. An inhibitory sigmoidal Emax model was used to describe the effect of SNP. A power function of age was used to describe age-related differences in baseline MAP. A mixture model of two groups with low and high EC50 was used to explain variability in MAP response. Change in MAP was characterized by a linear disease progression slope during the blinded phase. In the final population model, CL and V increased with weight, and baseline MAP increased with age. The effect compartment half-life of SNP was 13.4 min. The infusion rate producing 50% of Emax (ER50) at steady state for high EC50, was 0.34 μg/kg/min and for low EC50 0.103 μg/kg/min. The K-PD model well-describes initial dosing of SNP under controlled circumstances; model-based dosing guidance agrees with current practice. An initial titration strategy supported via algorithm-based feedback should improve maintenance of target MAP.

A hemodynamic model to guide blood pressure control during deliberate hypotension with sodium nitroprusside in children

Increased bioavailability of phenylephrine by co-administration of acetaminophen: results of four open-label, crossover pharmacokinetic trials in healthy volunteers

Improving the safety of pediatric sedation? Human error, technology, and clinical microsystems

Erratum to: Increased bioavailability of phenylephrine by co-administration of acetaminophen: results of four open-label, crossover pharmacokinetic trials in healthy volunteers

Pharmacokinetic (PK) and pharmacodynamic (PD) models are important tools for summarizing drug dose, concentration, and effect relationships. Co‐administration of drugs may alter PK and PD relationships. Traditional methods of evaluating PD interactions include using isoboles, shifts in dose–response curves, or interaction indices based on parameters of potency derived from separate monotherapy and combination therapy analyses. These methods provide an estimation of the magnitude of effect for dose or concentration combinations, but they do not inform us on the time course of that effect, or its associated variability. A better way to investigate PD interactions is to use modeling, and to take advantage of the benefits of population analyses. A population analysis is a statistical method in which a model describing the typical (or population) response, and the variability between individuals within that population, is developed. Models for monotherapy, derived using a population approach, can be combined and extended to incorporate PD interactions between two or more drugs. The purpose of this article was to provide a general road map for understanding and interpreting PD interaction models, including the ‘response surface’ models. Several types of response surface models exist, and here we review these with examples taken from the literature. We also consider current and future applications for this type of analysis for clinical anesthesia and pediatrics.

an 80-fold range in concentrations 1 h after three 500-mg tablets. Even larger variability has been described after rectal administration in children (8). Pharmacodynamic variability is also large. The coefficient of variability for the EC50 is reported as 94% (6). The response of any one individual to rectal acetaminophen is unpredictable. Supplementation with nonsteroidal antiinflammatory drugs to improve analgesia, rather than increasing acetaminophen dose, might prove a safer option. Titrated IV opioids provide superior analgesia.

TEE Diagnosis of Mechanical AVR Dysfunction Associated With Biological Glue

Potential cardiovascular adverse events when phenylephrine is combined with paracetamol: simulation and narrative review

Intravenous racemic ketamine is commonly administered for procedural sedation, although few pharmacokinetic studies have been conducted among children. Moreover, an optimal sampling schedule has not been derived to enable the conduct of pharmacokinetic studies that minimally inconvenience study participants.

Development of an optimal sampling schedule for children receiving ketamine for short‐term procedural sedation and analgesia

Tramadol and O-Desmethyl Tramadol Clearance Maturation and Disposition in Humans: A Pooled Pharmacokinetic Study

ABO blood types are determined by antigen modifications on glycoproteins and glycolipids and associated with altered plasma levels of inflammatory and endothelial injury markers implicated in AKI pathogenesis. We sought to determine the association of ABO blood types with AKI risk in critically ill patients with trauma or sepsis.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
We conducted two prospective cohort studies at an urban, academic, level I trauma center and tertiary referral center; 497 patients with trauma admitted to the surgical intensive care unit between 2005 and 2010 with an injury severity score >15 and 759 patients with severe sepsis admitted to the medical intensive care unit between 2008 and 2013 were followed for 6 days for the development of incident AKI. AKI was defined by Acute Kidney Injury Network creatinine and dialysis criteria.

RESULTS
Of 497 patients with trauma, 134 developed AKI (27%). In multivariable analysis, blood type A was associated with higher AKI risk relative to type O among patients of European descent (n=229; adjusted risk, 0.28 versus 0.14; risk difference, 0.14; 95% confidence interval, 0.03 to 0.24; P=0.02). Of 759 patients with sepsis, AKI developed in 326 (43%). Blood type A again conferred higher AKI risk relative to type O among patients of European descent (n=437; adjusted risk, 0.53 versus 0.40; risk difference, 0.14; 95% confidence interval, 0.04 to 0.23; P=0.01). Findings were similar when analysis was restricted to those patients who did not develop acute respiratory distress syndrome or were not transfused. We did not detect a significant association between blood type and AKI risk among individuals of African descent in either cohort.

Blood type A is independently associated with AKI risk in critically ill patients with trauma or severe sepsis of European descent, suggesting a role for ABO glycans in AKI susceptibility.

The ABO Histo-Blood Group and AKI in Critically Ill Patients with Trauma or Sepsis.

Demonstrably accurate records facilitate clinical decision making, improve patient safety, provide better defense against frivolous lawsuits, and enable better medical policy decisions. Anesthesia Information Management Systems (AIMS) have the potential to improve on the accuracy and reliability of handwritten records. Interfaces with electronic recording systems within the hospital or wider community allow correlation of anesthesia relevant data with biochemistry laboratory results, billing sections, radiological units, pharmacy, earlier patient records, and other systems. Electronic storage of large and accurate datasets has lent itself to quality assurance, enhancement of patient safety, research, cost containment, scheduling, anesthesia training initiatives, and has even stimulated organizational change. The time for record making may be increased by AIMS, but in some cases has been reduced. The question of impact on vigilance is not entirely settled, but substantial negative effects seem to be unlikely. The usefulness of these large databases depends on the accuracy of data and they may be incorrect or incomplete. Consequent biases are threats to the validity of research results. Data mining of biomedical databases makes it easier for individuals with political, social, or economic agendas to generate misleading research findings for the purpose of manipulating public opinion and swaying policymakers. There remains a fear that accessibility of data may have undesirable regulatory or legal consequences. Increasing regulation of treatment options during the perioperative period through regulated policies could reduce autonomy for clinicians. These fears are as yet unsubstantiated.

Comment on Pharmacokinetic Studies in Neonates: The Utility of an Opportunistic Sampling Design

Dexmedetomidine has established a firm position in the armamentarium of anesthesia pharmacology. However, it is still a relatively new drug and its application is based on early evidence that is intriguing but far from conclusive. Based on experience with previous cure-alls, anesthesia clinicians and researchers must insist on more information and formulate appropriate science that will allow us to truly understand the role of this dexmedetomidine in our specialty—as wonder drug or also-ran.

Clinical pharmacologists have contributed greatly to our understanding of drugs used in anesthesia and the perioperative period. Anesthesiologists, as practicing clinical pharmacologists, have readily adopted many of the techniques used by these scientists to further our specialty. Population pharmacokinetics and pharmacodynamics, modeling, and simulation are now common in our literature. This is particularly true for the intravenous anesthetic combination of propofol and remifentanil. We incorporate pharmacokinetic parameters (e.g., Marsh (1), Kataria (2), Paedfusor (3)) into our target controlled infusion pumps and make use of display screens to demonstrate drug concentration in the plasma and effect site for a typical child. Complex pharmacodynamic interactions between propofol and remifentanil are understood and used clinically (4). And yet, there still remains a divide between what the pharmacologists suggest based on science and what the clinician does, often based on empirical beliefs. We clinicians seem to believe that our field is special and sometimes separated from what the pharmacologist studies and reports. This is true even of common drugs such as acetaminophen (paracetamol); this analgesic/antipyretic has come under increased scrutiny since the introduction of the intravenous preparation. The basic pharmacokinetic parameters (clearance and volume of distribution) are unchanged no matter what formulation is used. The only parameters that might change are those describing enteral formulation absorption and bioavailability. The basic pharmacodynamic parameters (EC50, Emax) have been described in both children (5) and adults (6). Future studies should be planned to simply confirm what is known or explore differences in other populations, rather than re-learning what is known. This principle has been espoused for clinical drug development (7). Modeling and simulation are now integral parts of drug development (8), and yet we continue to design simple clinical studies without using this valuable resource. Adults and children are subjected to bloodletting for studies where the results could be predicted or where available knowledge could be used to improve study design or lessen patient numbers. Children are unnecessarily allocated to placebo groups in order to demonstrate drug effectiveness (9,10). Newly reported acetaminophen time-concentration profiles conform to known pharmacokinetic parameter estimates (11). Simulation will readily demonstrate that there will be differences in plasma concentrations in the immediate postoperative period between those given enteral and those given parental formulations, and yet there continue to be clinical studies demonstrating this (e.g., (12,13)). Although these studies may claim that ‘therapeutic plasma concentrations’ are achieved in the postoperative period, they often fail to recognize that it is the concentration in the effect site, rather than plasma that relates to analgesia (5). Plasma and effect site concentrations may be equivalent at steady state after regular dosing, but this is not so after a single dose. There is an equilibration delay between the central and effect compartments of 30–50 min (5,6). This delay has been demonstrated clinically in both children after inguinal hernia repair (14) and adults after third molar tooth surgery (15). Analgesic onset is more rapid after intravenous than after oral administration. These studies simply confirm what is already known. It is possible to use the different formulations to children’s benefit. Rectal absorption of acetaminophen is slow. Consequently, we might anticipate rectal administration to be associated with delayed onset of analgesia, but with an increased duration of effect. A simulation, based on known PK and PD, demonstrates this prolonged analgesic effect after a suppository in Figure 1. Analgesic duration in children 2–5 years presenting for adenotonsillectomy given either 15 mg kg 1 IV or 40 mg kg 1 PR intraoperatively have been compared in a clinical study (16). Kaplan–Meier survival curves show that the time to first analgesic request was longer in children receiving rectal acetaminophen (median 10 h, interquartile range 9–11 h) compared with those receiving intravenous acetaminophen (7.6–10 h). This prolonged duration of effect after rectal acetaminophen 40 or 60 mg kg 1 in day-case pediatric surgery has been demonstrated by others (17). However, those studies could have been undertaken with fewer pediatric patients by using those children to confirm known characteristics of formulation differences rather than using randomized controlled trials that require high patient numbers to generate the magic P < 0.05 (18). The potential usefulness of the learning versus confirming principle is highlighted by investigations into the analgesic effectiveness of acetaminophen after cleft palate surgery. Acetaminophen is a mild analgesic with efficacy (Emax) of 5.2/10 (visual analogue scale 0–10). A concentration in the effect site compartment of 10 mg L 1 is associated with pain reduction in 2.6/10 in both neonates and children (5,19). If pain is scored at 6/ 10 after surgery, then this effect site concentration of

portion of the PLM was once again tightly approximated to the shaft and gently introduced into the oral cavity from the right side by railroading over the suction catheter (Fig. 1). With minimal manipulation, the laryngeal mask airway could be introduced. Suction catheter was removed and breathing circuit was attached (Figure S2). With just 3-ml air to inflate the laryngeal mask airway cuff, adequate spontaneous respiration was noted by the movement of the reservoir bag and capnographic curves. Subsequently, the patient was maintained on 1–3% sevoflurane in a mixture of 50% nitrous oxide in oxygen on spontaneous breathing. The attending anesthesiologist attempted fiberscopy through the laryngeal mask airway but failed as the laryngeal mask airway was noted to be poorly positioned, a finding noted by others also (4). Throughout this period, patient had been breathing spontaneously receiving sevoflurane in oxygen via face mask between attempts. Oxygen saturation remained between 98 and 100% and heart rate ranged between 113 and 146/min. As the patient has to come for multiple surgeries over the next few weeks, it was decided to perform surgical tracheostomy prior to the release of various contractures in stages (Figure S3). Since then, the patient has been anesthetized uneventfully several times using tracheostomy as an airway. This case report highlights the fact that a distorted airway anatomy secondary to scarring may impair both mask ventilation and much advocated fiberoptic tracheal intubation. In addition, traditional rescue methods such as the laryngeal mask airway may fail using the conventional approach. The key to success is adequate planning, preparation, and the ability to improvise to suit the occasion as demonstrated by successful catheterguided placement of the laryngeal mask airway in this patient.

of 7.5 mg kg of paracetamol be used in term neonates ,10 daysoldbasedonobservedplasmaparacetamolconcentrations. The problem of extending this recommendation up to a body weight of 10 kg has already been discussed in 2008. More comprehensive data analyses have subsequently been undertaken that consider body size, clearance maturation, effect, and safety of i.v. paracetamol during the neonatal period. On the basis of these studies, the dose of i.v. paracetamol in neonates and infants, when postmenstrual age is between 32 and 44 weeks, should be a loading dose of 20 mg kg (or 2 ml kg) followed with a maintenance dose of 10 mg kg (or 1 ml kg) every 6 h, which would achieve steady-state plasma concentrations associated with reasonable analgesia. In older infants and children, the dose should be 15 mg kg (or 1.5 ml kg) every 6 h. The interval between two maintenance doses should be increased up to 12 h if the neonate’s postmenstrual age is between 28 and 31 weeks. In order to avoid underdosage and insufficient painrelieving effect, we strongly believe that the above-mentioned dosage be adopted in neonates and small infants.

Comparison of postoperative redness of eyes after sub-Tenon ’ s block and topical anaesthesia following phacoemulsification cataract surgery

RATIONALE
Cognitive and psychiatric impairments are threats to functional independence, general health, and quality of life. Evidence regarding these outcomes after lung transplantation is limited.

Determine the frequency of cognitive and psychiatric impairment after lung transplantation and identify potential factors associated with cognitive impairment after lung transplantation.

METHODS
In a retrospective cohort study, we assessed cognitive function, mental health, and health-related quality of life using a validated battery of standardized tests in 42 subjects post-transplantation. The battery assessed cognition, depression, anxiety, resilience, and post-traumatic stress disorder (PTSD). Cognitive function was assessed using the Montreal Cognitive Assessment, a validated screening test with a range of 0 to 30. We hypothesized that cognitive function post-transplantation would be associated with type of transplant, cardiopulmonary bypass, primary graft dysfunction, allograft ischemic time, and physical therapy post-transplantation. We used multivariable linear regression to examine the relationship between candidate risk factors and cognitive function post-transplantation.

Mild cognitive impairment (score, 18-25) was observed in 67% of post-transplant subjects (95% confidence interval [CI]: 50-80%) and moderate cognitive impairment (score, 10-17) was observed in 5% (95% CI, 1-16%) of post-transplant subjects. Symptoms of moderate to severe anxiety and depression were observed in 21 and 3% of post-transplant subjects, respectively. No transplant recipients reported symptoms of PTSD. Higher resilience correlated with less psychological distress in the domains of depression (P < 0.001) and PTSD (P = 0.02). Prolonged graft ischemic time was independently associated with worse cognitive performance after lung transplantation (P = 0.001). The functional gain in 6-minute-walk distance achieved at the end of post-transplant physical rehabilitation (P = 0.04) was independently associated with improved cognitive performance post-transplantation.

Mild cognitive impairment was present in the majority of patients after lung transplantation. Prolonged allograft ischemic time may be associated with cognitive impairment. Poor physical performance and cognitive impairment are linked, and physical rehabilitation post-transplant and psychological resilience may be protective against the development of long-term impairment. Further study is warranted to confirm these potential associations and to examine the trajectory of cognitive function after lung transplantation.

Cognitive function, mental health, and health-related quality of life after lung transplantation.

The lack of methadone pharmacokinetic data in children and neonates restrains dosing to achieve the target concentration in these populations. A minimum effective analgesic concentration of methadone in opioid naïve adults is 0.058 mg·l−1, while no withdrawal symptoms were observed in neonates suffering opioid withdrawal if plasma concentrations of methadone were above 0.06 mg·l−1. The racemate of methadone which is commonly used in pediatric and anesthetic care is metabolized to 2‐ethylidine‐1,5‐dimethyl‐3,3‐diphenylpyrrolidine (EDDP) and 2‐ethyl‐5‐methyl‐3,3‐diphenylpyrroline (EMDP).

The pharmacokinetics of methadone and its metabolites in neonates, infants, and children

Clonidine may be used intraoperatively to decrease emergence delirium in children, but the drug's impact on postoperative sedation is poorly quantified.

The impact of clonidine on sedation after adenotonsillectomy: a prospective audit

Propofol mixed with racemic ketamine (or ‘ketofol’) is popular for short procedural sedation and analgesia. Use is creeping into anesthesia, yet neither the optimal combination nor infusion rate is known. The EC50 of propofol's antiemetic effect is reported to be 0.343 mg·l−1, while ketamine analgesia is thought to persist with concentrations above 0.2 mg·l−1. We aimed to determine a ketofol dosing regimen for anesthesia 30‐min and 1.5‐h duration in a healthy child that did not unduly compromise recovery.

Delirium has been described in medical writings as early as the first century (1), yet it remains a challenge for modern-day physicians and its pathophysiology remains poorly understood. The concept resonates within the critical care community because it is common in the critically ill (2-4) and because delirium is associated with increased short- and long-term mortality (2-4). Moreover, delirium has been associated with long-term cognitive and functional impairment in survivors of critical illness (5-8). From a patient and family centered care perspective, its development matters deeply to the loved ones at the bedside, as eloquently detailed in a recent account of one family's frightening encounter with delirium (9). Delirium undermines our rational self, it challenges the Cartesian principle “Cogito ergo sum” (I Think, Therefore I am), and in its wake, it leaves the patient and their family vulnerable and potentially, forever changed (5-10). 
 
To combat the deleterious consequences of delirium, intense efforts have been directed at reducing the duration of delirium. A critical question, addressed in this issue of the journal by Al-Qadheeb and colleagues, is whether the myriad treatments that have been evaluated to reduce the duration of delirium have an effect on short-term mortality (11). Through a rigorous systematic search, the authors identified 17 randomized trials conducted between 2001-2012 that enrolled 2,849 subjects. The trials examined the effects of pharmacologic and non-pharmacologic interventions hypothesized to reduce the duration of delirium. The trials enrolled diverse populations at varying stages of delirium. Similarly, the methodology for delirium assessment varied in terms of frequency, personnel performing the assessment, and the assessment tool used. 
 
Using a random effects model meta-regression, Al-Qadheeb et al. found that delirium duration was significantly reduced by the interventions, although the effect size was modest (0.64 days less, p=0.01) and significant heterogeneity (p<0.001) existed across studies. In the 13 trials that reported short-term mortality, there was no significant survival difference between the intervention and control groups (15.6% vs. 16.5%, p=0.54). Consistent with the direct comparison, the meta-regression analyses demonstrated that delirium duration was not associated with a reduction in short-term mortality (slope of the ln(RR mortality) = -0.17; 95% CI -0.39 to 0.04; p = 0.11), nor was the relationship substantially different in the extensive sensitivity analyses conducted. 
 
The strengths of the present study are numerous. First, the authors have tackled an important, and challenging, question in critical care medicine. Second, the methodology employed was rigorous and comprehensive, beginning with their extensive literature search and carefully selected eligibility criteria, and as demonstrated in their systematic data abstraction and bias assessment. Third, after their attempt to use a random effects model meta-analyses was thwarted, they expertly utilized a random effects model meta-regression to answer the questions at hand. Further, their use of multiple sensitivity analyses provide the reader with an additional level of confidence that the results were not due to an analytical decision. 
 
Several potential limitations of the study should be noted. First, the 17 trials included a heterogeneous group of pharmacologic (antipsychotics, alpha-2 receptor agonists, and acetylcholinesterase inhibitors) and mixed/non-pharmacologic (daily sedative interruption, early mobilization, and protocolized peri-operative perfusion pressure) interventions. The studies enrolled medical and surgical ICU patients, with varied severity of illness. While interventions that benefit a broad group of patients would be generalizeable, delirium varies by patient population, the underlying illness, and sedation practice. As such, the heterogeneity observed, while appealing in some ways, makes interpretation of the results challenging. Second, because the relationship described by a meta-regression is an observational one, confounding is an important potential bias (12). Despite conducting a number of important subgroup analyses, the potential for residual confounding of observed (e.g., illness severity) and unobserved (e.g., duration of coma) covariates exists (13-14). Future studies exploring the relationship between delirium duration and its outcomes will need to account for variations in illness severity and sedation use over time, incorporate the complete spectrum of acute brain dysfunction given the independent association between coma and mortality (13-14), and assess the short- and long-term consequences of delirium. Last, given the number of trials included in the meta-analysis, it is plausible that the study was underpowered to detect whether interventions that reduce delirium duration result in short-term survival benefit. 
 
Despite its potential limitations, there are two important findings in the present study by Al-Qadheeb and colleagues. First, a diverse group of pharmacologic and nonpharmacologic interventions do appear to reduce the duration of delirium. Second, interventions employed to reduce the duration of delirium may not result in a similar reduction in short-term mortality. Several interpretations exist to reconcile the present findings with a recent systematic review of observational studies that found that delirium was independently associated with increased mortality (15). First, these findings may signal that interventions that reduce delirium do not actually impact short-term mortality. This explanation, which requires confirmation given pathophysiologic rationale (2) and prior observational studies (2-4), would suggest that the prior association, at least in the short-term, was not causal. Alternative explanations, which also require further investigation, include: the effect size seen across these heterogeneous studies was too small to see a mortality reduction, the means to reduce delirium and the method of delirium assessment are critical factors in the relationship which could not be adequately analyzed given the sample size and last, the ability to impact mortality may be mediated by delirium prevention to a significantly greater degree than reducing delirium duration once delirium has begun. 
 
In summary, this rigorous systematic review and meta-regression leads us to conclude that heterogeneous “delirium-reducing interventions” across diverse patient populations can, in fact, reduce the duration of delirium. And yet, the achieved benefit in reducing the duration of delirium may not result in an effect on short-term mortality. While further research is required to confirm these findings, the opportunity to improve the lives of patients and their families, by reducing the incidence and duration of delirium experienced in the ICU with an eye on the short- and long-term perspective, remains a viable and important objective for our field and for those that we serve.

Duration of delirium and patient-centered outcomes: embracing the short- and long-term perspective.

Background Propofol mixed with racemic ketamine (or “ketofol”) is popular for short procedural sedation and analgesia, yet the optimal combination is unknown. We aimed to determine a ketofol dosing regimen for short procedural sedation and analgesia of 5- to 20-minute duration in healthy patients (2–20 y). Methods Pharmacokinetic-pharmacodynamic parameters were used to simulate drug concentration and effect profiles over time for different ketamine-to-propofol ratios (1:1–1:10). The target effect was a Children’s Hospital of Wisconsin Sedation Scale score of less than 2. Combined effects were additive, with a propofol EC50 of 1.54 &mgr;g/mL (concentration required to produce hypnosis in 50% of patients), a ketamine EC50 of 0.44 &mgr;g/mL, and a slope of 5.3. Emergence threshold concentrations for propofol were 2.0 &mgr;g/mL in children and 1.8 &mgr;g/mL in adults as well as 0.5 &mgr;g/mL for ketamine (children and adults). The EC50 for propofol antiemesis was 0.343 &mgr;g/mL. Results A ketamine-to-propofol ratio of 1:3 was the best combination for intermittent dosing, achieving a rapid onset of a Children’s Hospital of Wisconsin Sedation Scale score of less than 2 within 1 minute and a time to emergence of 9 to 19 minutes in all ages after a 10-minute sedation. The optimal ketofol dosing in children (2–11 y) was 0.1 mL/kg initially followed by 0.05 mL/kg at 2 minutes and then 0.025 mL/kg for the subsequent doses. The adults (12–20 y) received 0.05 mL/kg of ketofol initially followed by 0.025 mL/kg for the subsequent doses. These regimens maintain a propofol antiemesis for 30 to 40 minutes after the last dose. Conclusions We suggest an optimal ratio of racemic ketamine to propofol of 1:3 for boluses during short procedures (5–20 minutes). A short ketofol infusion, ratio 1:4, is a suitable alternative to intermittent boluses. Ratios greater than 1:3 result in delayed recovery after 20 minutes.

Allometric principles were used to discern cross-species differences in (±)-tramadol disposition and formation of its primary analgesic metabolite, (±)-O-desmethyl-tramadol (M1). Species differences in formation of M1 may help predict the analgesic effectiveness of tramadol. Tramadol was administered intravenously by a zero-order (constant infusion) process or rapid bolus dose and racemic concentrations of tramadol and M1 measured. Data were pooled to define differences between species (human, rat, cat, dog, goat, donkey and horse). A two-compartment linear disposition model with first-order elimination was used to describe tramadol and M1 disposition. Slow metabolizers were detected in 6% of the population and tramadol clearance to M1 was 16.2% that of extensive metabolizers. Tramadol clearance to M1 was slower and tramadol clearance by other pathways was faster in rats, dogs, and horses compared to humans. There are substantial differences between species in the pharmacokinetics of tramadol and its M1 metabolite, which are not explained by differences in body weight. The hypothesis that volumes of distribution are similar across species was shown not to be true. M1 exposure in the goat, donkey and cat was comparable to humans, which indicates it is likely to be an effective analgesic at typically used doses in these species but not in dogs or horses.

Parent-Metabolite Pharmacokinetic Models for Tramadol - Tests of Assumptions and Predictions

The goal of any treatment is a desired response, known as the target effect. This effect might be pain reduction to a score <4 on a visual analog scale (VAS 0-10). An understanding of the concentration–response relationship (i.e., pharmacodynamics, PD) can be used to predict the target concentration required to achieve this target effect in a typical child (1). Pharmacokinetic (PK) knowledge (defined by parameters such as clearance and volume of distribution) can be used to predict the dose that will achieve the target concentration. This principle can, and is, applied to many of the drugs used in anesthesia. We commonly target a steady-state concentration of 10 mg L 1 for paracetamol (2), 3 mg L 1 for propofol (3), 3 lg L 1 for remifentanil (4), or a minimal alveolar concentration value of 2.5% in children given sevoflurane (5). Concentration–response relationships for these drugs have been published (2,6–8), and these assist dosing in the perioperative period. The target concentration may vary depending on the magnitude of desired effect. A remifentanil target of 2–3 lg L 1 is adequate for laryngoscopy and 6–8 lg L 1 for laparotomy, and 10-12 lg L 1 might be sought to ablate the stress response associated with cardiac surgery (4). And yet there is no concentration–response relationship published for the most common opioid used for acute pain in children, morphine. Empiric studies have taught us that a concentration range (10–20 lg L ) has analgesic effect (9) without associated adverse effects such as the respiratory depression observed with higher concentrations (10) or postoperative nausea and vomiting reported with higher doses (11). We continue to titrate morphine dose to gain satisfactory analgesia (12,13), despite use of this drug in one formulation or another for over 2000 years. A further observational study on morphine titration in the postanesthetic care unit in children is presented in the current issue of Pediatric Anesthesia (14). We recognize that increased pain severity may require increased dose, but still, we approach drug delivery cautiously, giving small increments rather than the larger increment required for severe pain. Despite this lack of knowledge concerning the concentration– response relationship, the drug remains remarkably safe when used as an infusion in hospital practice. The overall incidence of serious harm was only 1 : 10 000 with opioid infusion techniques, and those predisposed to harm can be identified (e.g., young infants, those with neurodevelopmental, respiratory, or cardiac comorbidities) (15). We propose two questions: 1. Why is there no concentration–response relationship described for children? 2. Would knowledge of a concentration–response relationship improve current therapy?

Why is there no morphine concentration–response curve for acute pain?

New data suggest that use of acetaminophen with phenylephrine results in twice the expected plasma levels of phenylephrine. Not all assumptions about over-the-counter drug combinations have been tested.

Increased phenylephrine plasma levels with administration of acetaminophen.

Since its original description in 1967, acute respiratory distress syndrome (ARDS) has been recognized as a devastating condition associated with significant morbidity and mortality. Advances in critical care medicine and ARDS management have led to a substantial increase in the number of ARDS survivors. Long-term cognitive impairment after critical illness is a significant public health concern. ARDS survivors frequently experience long-term cognitive impairment, as well as physical impairment, psychiatric morbidity, and reduced health-related quality of life. At present, no intensive care unit-based intervention has been proven to reduce the risk of long-term cognitive impairment after ARDS. To address the urgent need to identify strategies to preserve long-term health, investigators have advocated the measurement of short- and long-term outcomes in clinical trials. Maintaining adequate oxygen delivery to preserve organ function is of vital importance in ARDS management. The optimal target range for arterial oxygenation in ARDS remains unknown, due in part to the challenge to maintain adequate tissue oxygenation and to minimize harm, such as oxygen toxicity. An approach targeted to subnormal oxygenation values (partial pressure of arterial oxygen, 55-80 mm Hg) has emerged as a means to accomplish these aims. In this perspective, we critically evaluate this strategy from short- and long-term perspectives, with a focus on the potential long-term cognitive effects of the strategy. We conclude with a proposal to consider resetting the target range for arterial oxygenation higher (85-110 mm Hg) as a potential strategy to improve the long-term outcomes of ARDS survivors.

Can we optimize long-term outcomes in acute respiratory distress syndrome by targeting normoxemia?

The management of procedural pain in children ranges from physical restraint to pharmacological interventions. Pediatric formulations that permit accurate dosing, are accepted by children and a have a rapid onset of analgesia are lacking.

macokinet 2006; 45: 1051–1060. 8 Malviya S, Voepel-Lewis T, Ludomirsky A et al. Can we improve the assessment of discharge readiness?: A comparative study of observational and objective measures of depth of sedation in children. Anesthesiology 2004; 100: 218–224. 9 Pasero C. Assessment of sedation during opioid administration for pain management. J Perianesth Nurs 2009; 24: 186–190. 10 Joint Commission. Safe Use of Opioids in Hospitals. Chicago: Joint Commission, 2012.

Diclofenac dosing in children for analgesia is currently extrapolated from adult data. Oral diclofenac 1.0 mg·kg−1 is recommended for children aged 1–12 years. Analgesic effect from combination diclofenac/acetaminophen is unknown.

Postoperative analgesia using diclofenac and acetaminophen in children

Covariates of intravenous paracetamol pharmacokinetics in adults

Cote and Lerman's a practice of anesthesia for infants and children / , Cote and Lerman's a practice of anesthesia for infants and children / , کتابخانه دیجیتال جندی شاپور اهواز

Cote and Lerman's a practice of anesthesia for infants and children /

The pharmacokinetic behavior of medicines used in humans follows largely predictable patterns across the human age range from premature babies to elderly adults. Most of the differences associated with age are in fact due to differences in size. Additional considerations are required to describe the processes of maturation of clearance processes and postnatal changes in body composition. Application of standard approaches to reporting pharmacokinetic parameters is essential for comparative human pharmacokinetic studies from babies to adults. A standardized comparison of pharmacokinetic parameters obtained in children and adults is shown for 46 drugs. Appropriate size scaling shows that children (over 2 years old) are similar to adults. Maturation changes are generally completed within the first 2 years of postnatal life; consequently babies may be considered as immature children, whereas children are just small adults.

Pharmacology of paediatric total intravenous anaesthesia☆ La farmacología de la anestesia total intravenosa en pediatría

To determine if the addition of adrenaline, clonidine, or their combination altered the pharmacokinetic profile of levobupivacaine administered via the caudal epidural route in children.

Absorption characteristics of epidural levobupivacaine with adrenaline and clonidine in children

The optimal methadone dosing regimen for children undergoing spinal surgery is uncertain because of sparse pediatric pharmacokinetic data and a paucity of analgesic effect data. The minimum effective analgesic concentration of methadone in opioid naïve adults is 58 mcg·L−1.

The pharmacokinetics of methadone in adolescents undergoing posterior spinal fusion

We suggested a loading dose (20 mg·kg−1) followed by 10 mg·kg−1 q6h of intravenous (IV) paracetamol to achieve an effect compartment concentration of 11 mg·l−1 in neonates. Since there are no pharmacodynamic data to support such an effect compartment concentration, pain scores collected in neonates treated with an IV paracetamol loading dose (20 mg·kg−1) were used to validate this effect compartment concentration.

Unraveling Pharmacokinetics and Pharmacodynamics in Infants and Children

There remains a need for alternative medical treatments for patent ductus arteriosus (PDA) closure in extreme preterm neonates because of therapeutic failure and adverse effects associated with non-selective cyclo-oxygenase inhibitors. Reports of an association between paracetamol exposure and PDA closure in a limited number of extreme preterm neonates have been published. However, causality cannot be taken for granted because a link between the current knowledge of the clinical pharmacology of paracetamol and (patho)physiology of ductal closure is not known. In contrast to non-selective cyclo-oxygenase inhibitors, paracetamol has limited effects at peripheral sites, is a poor antithrombotic and anti-inflammatory drug and exerts its effects primarily within the central nervous system. Although paracetamol appears an effective and safe analgesic in term and near term neonates, its effectiveness and safety for PDA closure are uncertain because the drug is administered in high doses and there remain a limited number of observations in this specific subpopulation so far. Prospective comparative trials are reasonable and are urgently needed to establish both the effectiveness and safety data of paracetamol when used for this indication.

Aim:  We performed a retrospective audit of intravenous morphine infusion administered to children in an effort to characterize the relationship between dose and age.

The relationship between age and morphine infusion rate in children

By and large, children hate needles. Children in pain have a sympathetic response causing vasoconstriction rendering venous access somewhat more technically challenging than usual. Venous access in children presenting for anaesthesia is not always easy; nor is it always necessary for simple short procedures using inhalational anaesthesic agents. Similarly, children presenting to an emergency department with pain from a damaged limb require effective analgesia, and this can be delivered without resort to an immediate intravenous injection. Alternative routes for early analgesic administration are available. After all, adults commonly self-administer drugs with analgesic properties using mucous surfaces or the nasal cavity for recreational purposes. Neri and colleagues1 describe their own positive experience using sublingual tramadol and ketorolac.

The oral route of drug administration is a stalwart for elective procedural sedation. There are often time delays before the drug is absorbed in the small intestine, and further delays before the drug in plasma reaches its site of action. The latter is commonly known as the effect compartment, and it is drug concentration in this effect compartment that correlates with response rather than drug concentration in the plasma. Sedative and analgesic administration can be timed to take advantage of absorption characteristics, therapeutic effect compartment concentrations or metabolites. Ketamine, for example, is reported satisfactory for dressing changes in children suffering burns. Formation of its metabolite norketamine after oral absorption is advantageous because it also has analgesic properties, but for many drugs, the oral route is less than ideal in the emergency room. Pain relief is desired reasonably quickly. Trauma may cause delayed gastric emptying, slowing delivery and …

Paediatric dose cannot be scaled down directly from an adult using weight (eg, mg/kg). This results in a dose too small in infants and children because elimination does not change in direct proportion to weight, and a dose too large in neonates whose drug elimination pathways are immature. The goal of treatment is a desired response (the target effect). An understanding of the concentration–response relationship (pharmacodynamics) can be used to predict the target concentration required to achieve this target effect. Pharmacokinetic knowledge then determines the target dose that will achieve the target concentration. Variability associated with both pharmacokinetics and pharmacodynamics can be reduced by demographic information (covariates), which can be used to help predict the target dose in a specific child. The covariates of size, maturation and organ function are the three principle contributors to pharmacokinetic variability. Children (2 years postnatal age or older) are essentially similar to adults (ie, mature) and differ only in size. Maturation processes are only important in neonates and infants, therefore, this cohort can be viewed as immature children. Paediatric pharmacodynamic studies are fewer than pharmacokinetic studies, but are required to elucidate the target concentration and consequent dose. The lack of pharmacodynamic studies is a serious challenge for rational dosing.

Understanding dosing: children are small adults, neonates are immature children

A case is presented of a 
serious, potentially life-threatening intravenous acetaminophen overdose in a 
3-month-old (40 weeks’ post menstrual age),2.3 kgbaby girl. The 
neonate was scheduled for urgent laser therapy for retinopathy of prematurity. 
Instead of an intended intravenous Hartmann’s solution bolus of 10 ml·kgˉ1, 
the neonate received a 17 ml bolus of correctly labelled intravenous 1% 
acetaminophen. The National Poisons Bureau was immediately contacted for advice 
and in the absence of data suggested a treatment with N-acetylcysteine for a 
24-hour period. Baseline blood samples for clotting, liver function, urea and 
electrolytes, full blood count and plasma acetaminophen concentration were 
taken 30 min, 8.25 h, 12.5 h, 18.5 h and 120 h after the overdose. Acetaminophen 
concentration was 78 mg·Lˉ1 at 
30 min, but it was undetectable at any other time. Using a recent and complete 
PK-PD dataset we are able to show that the measured plasma acetaminophen concentration 
fits well on PK estimates for acetaminophen in this neonate. The 
non-detectable (low) plasma acetaminophen concentration at >8 h is also 
consistent with this model, especially if clearance is slightly increased in 
the premature nursery graduate. Medical errors are rarely the fault of an individual and 
they are often due to a combination of factors. Contributing factors, in this 
case, are described under the following headings: Catalyst event, system fault, 
loss of situational awareness, and human error.

Potentially life-threatening intravenous acetaminophen overdose in a 3-month-old (40 weeks’ post-menstrual age), 2.3 kg baby girl

Aspirin‐exacerbated respiratory disease (AERD) has been recognized in adults with chronic asthma. Samter's triad is a subset of AERD where adult patients develop nasal polyps, asthma, and sensitivity to aspirin. This condition is thought not to occur before the third decade of life. We report a 13‐year‐old boy with nasal polyps who suffered a life‐threatening exacerbation of asthma during a graded aspirin challenge. Resuscitation required positive pressure ventilation and inotropic support. Our observations confirm that classical Samter's triad can occur in children. We suggest that graded aspirin challenges in children are undertaken in a facility with equipment and staff trained for resuscitation. Consideration should be given to this rare complication when prescribing nonsteroidal anti‐inflammatory drugs in the perioperative period. Suspicion of this condition merits referral to an immunologist for desensitization to aspirin.

Samter's triad in childhood: a warning for those prescribing NSAIDs

This journal has reported numerous efforts to improve acute pain management in children. For example, guidelines from the Association of Pediatric Anesthetists of Great Britain and Ireland concerning good practice in postoperative procedural pain management were published in Pediatric Anesthesia last year (1). While the management of children with persistent (chronic) pain has lagged behind such acute pain endeavors, considerable efforts have been made to improve the management of pain in children with cancer. The evidence for treatment options, however, has been slow to surface (2,3). Guidelines published by the World Health Organization (WHO) in 1998 (4) provided a useful framework for healthcare workers to improve pain relief in children with cancer, and they were extended to the management of pain in children with other life-limiting conditions. These guidelines were not without criticism, which included the lack of an evidence-based approach to the recommendations. After considerable delay, the WHO updated the guidelines in 2012 (5), partly in response to this criticism, and widened the mandate to address the pharmacological management of persisting pain in children with medical illnesses. These are now based on evidence, which brings its own disquiet, but they still inadequately address all facets of care that children with persistent pain require.

Managing persisting pain in children with medical illnesses: another frontier unexplored

Codeine was considered a suitable analgesic for children after adenotonsillectomy. It has been used extensively in the UK1 for over 40 years and appeared effective.2 It was listed in the WHO as the second step on the Analgesic Ladder for the treatment of cancer pain. Adult data suggest the combination paracetamol 1000 mg/codeine 60 mg provides better analgesia (number needed to treat, (NNT) 1.9) than codeine 60 mg (NNT 17), or paracetamol 1000 mg (NNT 4.6), illustrating the synergistic effect of analgesic combinations.3 The addition of codeine to paracetamol increased duration of analgesia by about 1 hour, and reduced the need for rescue medication.4 Consequently, many clinicians have expressed surprise at moves by regulatory bodies (US Food and Drug Administration (FDA), European Medicines Agency, Medicines and Healthcare Products Regulatory Agency) to impose restrictions on its use in children, particularly after adenotonsillectomy.

Children suffer considerable pain with severe functional limitation for at least 7 days after this common procedure.5 Although part of the problem may be inadequate parent education and information concerning analgesia,6 there are also gaps in our pharmacologic armamentarium. Non-steroidal anti-inflammatory drugs (NSAID) have been frowned upon because of fears concerning their effects on platelet function and subsequent postoperative bleeding despite studies demonstrating that NSAIDs did not cause any increase in bleeding requiring a return to operating room.7 Paracetamol dosing recommendations have been lowered in recent years; these recommendations are not based on pharmacokinetic or pharmacodynamic knowledge,8 but rather on fears of potential hepatotoxicity due to paracetamol's oxidative metabolite (N -acetyl- p -benzoquinone imine).9 This adverse effect is rare but devastating when the drug is routinely given, and the reason why some children are so afflicted remains unknown. Opioid use at home is generally discouraged because of dispensing regulations and the knowledge that these drugs can cause …

Thiopentone Elimination in Newborn Infants: Exploring Michaelis-Menten Kinetics

Background:  Morphine is widely used throughout the human life span. Several pharmacokinetic models have been proposed to predict how morphine clearance changes with weight and age. This study uses a large external data set to evaluate the ability of pharmacokinetic models to predict morphine doses.

The strategies used to manage children exposed to long‐term opioids are extrapolated from adult literature. Opioid consumption during the perioperative period is more than three times that observed in patients not taking chronic opioids. A sparing use of opioids in the perioperative period results in both poor pain management and withdrawal phenomena. The child’s pre‐existing opioid requirement should be maintained, and acute pain associated with operative procedures should be managed with additional analgesia. This usually comprises short‐acting opioids, regional or local anesthesia, and adjuvant therapies. Long‐acting opioids, transdermal opioid patches, and implantable pumps can be used to maintain the regular opioid requirement. Intravenous infusion, nurse controlled analgesia, patient‐controlled analgesia, or oral formulations are invaluable for supplemental requirements postoperatively. Effective management requires more than simply increasing opioid dose during this time. Collaboration of the child, family, and all teams involved is necessary. While chronic pain or palliative care teams and other staff experienced with the care of children suffering chronic pain may have helpful input, many pediatric hospitals do not have chronic pain teams, and many patients receiving long‐term opioids are not palliative. Acute pain services are appropriate to deal with those on long‐term opioids in the perioperative setting and do so successfully in many centers. Staff caring for such children in the perioperative period should be aware of the challenges these children face and be educated before surgery about strategies for postoperative management and discharge planning.

The pharmacokinetic (PK) parameters that are important for dosing (e.g., clearance and volume) are well known. They are used in universal mathematical formulae that describe the time course of drug concentration. Additional formulae can be used to describe major covariate effects in children, such as size and maturation. PK parameters describing the time–concentration profile of a drug after administration are those for a typical individual in a population. These parameters are associated with variability. Further, any one individual may not be typical of the population studied. While size and maturation are two important considerations in children and assist with dosing estimation, there are also a number of additional PK covariates (e.g., organ function, disease, drug interactions, pharmacogenetics), and identifying these sources of variability allows us to individualize drug dose. Pharmacology is not simply an application of PK, and determinants of drug dose also require an understanding of the variability associated with pharmacodynamic response and a balancing of beneficial effects against unwanted effects. Each child is unique in this respect.

Background:  Accidental puncture of the vertebral arteries (VAs) can occur through the internal jugular veins (IJVs) during central venous catheterization (CVC). We evaluated the anatomic relation of the VAs to the IJVs in children undergoing IJV cannulation.

Ultrasonic analysis of the anatomical relationships between vertebral arteries and internal jugular veins in children

BACKGROUND: Ketorolac tromethamine (ketorolac) administration reduces postoperative opioid requirements. The pharmacokinetic characteristics of intranasal ketorolac tromethamine in children have not been characterized. Our objective of this study was to determine the pharmacokinetics of a single intranasal dose of ketorolac in adolescent patients. METHODS: Twenty surgical patients, ages 12 to 17 years, were enrolled. After surgery, subjects received intranasal ketorolac 15 mg (weight ⩽50 kg) or 30 mg (weight >50 kg) using a proprietary administration system. Blood samples were obtained for ketorolac assay at baseline (within 15 minutes before the dose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after the dose. A population analysis was undertaken using nonlinear mixed-effects models. Parameter estimates were standardized to a 70-kg person. RESULTS: The intranasal dosing in adolescents was well tolerated with minimal adverse effects. A 1-compartment model with first-order absorption and elimination was satisfactory to describe time-concentration profiles. Population parameter estimates (between subject variability) were clearance (CL/F) 2.05 L/h (60.5%), volume of distribution (V/F) 15.2 L (32.4%), absorption half-life (t1/2abs) 0.173 hour (25.0%). Time to peak concentration (Tmax) was 52 minutes (SD 6 minutes). CONCLUSION: Administration of ketorolac by the intranasal route resulted in a rapid increase in plasma concentration and may be a useful therapeutic alternative to IV injection in adolescents because plasma concentrations attained with the device are likely to be analgesic (investigational new drug no. 62,829).

The Pharmacokinetics of Ketorolac After Single Postoperative Intranasal Administration in Adolescent Patients

SIR—The need to limit the volume of blood required for drug assays in pharmacokinetic/pharmacodynamics studies and clinical monitoring can hinder pediatric utility. Millership’s recent review article of micro assays outlined some of the advances in the sample preparation and analytical methods that are of particular benefit for studies involving neonates and small children (1). However Millership makes no distinction between plasma and serum samples. And in both this journal and the wider literature, these terms are sometimes used inaccurately and often interchangeably (2). Most commonly, plasma concentration is misused when serum samples have been taken. We would like to draw attention to the important differences between plasma and serum sampling. These differences are summarized in Table 1 and explained in more detail by Uges in his 1988 review paper (3). Plasma is the cell-free supernatant that results after centrifuge of a whole blood sample collected in a tube containing an anticoagulant; whereas serum is obtained by first allowing complete clotting of a sample, followed by centrifuge. Both serum and plasma contain albumin and globulins, but serum contains no fibrinogen and no anticoagulants. Most importantly, there is a larger volume yield from collected blood sample if plasma is used, which therefore results in a greater amount of drug, and fewer problems with the sensitivity of assay. Plasma yield is typically 50% of the total blood collected, while serum yields 15–20% less. So the use of plasma for drug assays helps to minimize the amount of blood required for sampling. Volume aside, does it matter? Serum and plasma specimens often result in similar analyte concentrations, but drug concentrations can sometimes be affected by either the process of in-tube coagulation or additive anticoagulant, respectively. Although plasma samples have the advantage of avoiding coagulation-induced changes or interferences in drug assays, the addition of anticoagulant may cause problems in addition to those resulting from under-filling or inadequate mixing of blood in collection tubes. Various forms of heparin are commonly used as the anticoagulant, but there is a confusing array of alternatives, including citrate and EDTA. Uges (3) gives several examples of drugs where anticoagulants in tubes for plasma analysis may interfere with drug analysis in varying ways. Examples include the following: gentamicin (where high heparin concentrations interfere); ibuprofen and lignocaine (where increased free fractions are present in heparinized plasma); and phenytoin and amitriptyline (where free drug concentrations were reduced in heparinized plasma). Serum samples may be preferred where the determination of free fraction is important. There may be other unknown effects from the anticoagulant used or associated additives/impurities on the sample stability, protein binding, or other aspects of the assay affecting concentration. Indeed even in the much wider field of biochemical analysis, there is a lack of consensus on the extent of differences in the results of plasma and serum samples (4,5). In the past, plasma sampling tubes have been more expensive than serum sampling tubes. However, another advantage of

A morphine plasma concentration/respiratory rate relationship has been described for both adults and children although that of its metabolite, morphine-6-glucuronide, remains uncertain. We describe this relationship in a child with end-stage renal failure who received repeat morphine administration over two days. An EMAX model for additive morphine and morphine-6-glucuronide respiratory effects described respiratory rate better than models describing either alone. Failure to clear morphine-6-glucuronide renally led to respiratory depression episodes occurring later than those predicted by modelling morphine levels only. These findings support the use of alternative analgesics (e.g. fentanyl) that are cleared by non-renal pathways and have no active metabolites in patients with end-stage renal disease.

Contribution of Morphine and Morphine-6-Glucuronide to Respiratory Depression in a Child

1 Lent CM, Fliegner KH, Freedman E et al. Ingestive behaviour and physiology of the medicinal leech. J Exp Biol 1988; 137: 513– 527. 2 Uygur K, Yasan H, Yavuz L et al. Removal of a laryngeal leech: a safe and effective method. Am J Otolaryngol 2003; 24: 338–340. 3 Mohammad Y, Rostum M, Dubaybo BA. Laryngeal hirudiniasis: an unusual cause of airway obstruction and hemoptysis. Pediatr Pulmonol 2002; 33: 224–226. 4 Iynen I, Sogut O, San I et al. A Rare Cause of Epistaxis, Hemoptysis and Anemia: leech in the Nasopharynx. J Med Cases 2010; 1: 71–73. 5 Cundall DB, Whitehead SM, Hechtel FO. Severe anaemia and death due to the pharyngeal leech Myxobdella africana. Trans R Soc Trop Med Hyg 1986; 80: 940–944. 6 Al-Hadrani A, Debry C, Faucon F et al. Hoarseness due to leech ingestion. J Laryngol Otol 2000; 114: 145–146. 7 Pandey CK, Sharma R, Baronia A et al. An unusual cause of respiratory distress: live leech in the larynx. Anesth Analg 2000; 90: 1227–1228.

Myocarditis Associated with 2009 Influenza A (H1N1) Pandemic in Japan organized by Japanese Circulation Society. A national survey on myocarditis associated with the 2009 influenza A (H1N1) pandemic in Japan. Circ J 2010; 74: 2193–9 3 Schultz JC, Hilliard AA, Cooper LT Jr, Rihal CS. Diagnosis and treatment of viral myocarditis. Mayo Clin Proc 2009; 84: 1001–9 4 Oda T, Yasunaga H, Tsutsumi Y, et al. A child with influenza A (H1N1)-associated myocarditis rescued by extracorporeal membrane oxygenation. J Artif Organs 2010; 13: 232–4 5 Latva-Hirvelä J, Kytö V, Saraste A, Vuorinen T, Levijoki J, Saukko P. Effects of levosimendan in experimental acute coxsackievirus myocarditis. Eur J Clin Invest 2009; 39: 876–82 6 Maytin M, Colucci WS. Cardioprotection: a new paradigm in the management of acute heart failure syndromes. Am J Cardiol 2005; 96: 26G–31G

Anaesthesia dosing in infants (0–2 years) should be based on pharmacokinetic–pharmacodynamic considerations and adverse effects profiles. Disease processes and treatments in this group are distinct from those in adults. Absorption, distribution and clearance change dramatically during this period because of maturation of anatomical and physiological processes as well as behavioural changes. Pharmacogenomic expression also matures in this period. Population-based and physiological-based pharmacokinetic modelling has improved the understanding of maturation and subsequent dose approximation. Postmenstrual, rather than postnatal, age is a reasonable measure for maturation. There remains a need for clinically applicable tools to assess pharmacodynamics which can provide response feedback; this has been achieved for neuromuscular monitoring, but not yet fully for depth of anaesthesia, sedation or pain. Morbidity and mortality associated with paediatric anaesthesia have historically been highest in this age group and continue to be so. Some of this morbidity was attributable to a poor understanding of developmental pharmacology; this facet continues to plague the specialty.

Neonates and infants include those from birth up to the age of 2 years of life. Consequently, postmenstrual age (PMA) may range from extreme preterm birth at 22 weeks up to 780 weeks PMA with a corresponding weight range from 0.5 to 20kg. Maturation of anatomical and physiological systems distinguishes this group as a specific population with major pharmacological differences from their older counterparts. Morbidity and mortality associated with anaesthesia is highest in this age group, attributable in part, to a poor understanding of developmental pharmacology

- 1-10 RC 1-Anderson Pharmacology in the Very Young : Anaesthetic Implications

Background:  Physiological‐based pharmacokinetic models have been used to describe midazolam clearance (CL) maturation. There are no maturation descriptors of CL from neonate to adulthood based on reported estimates at different ages.

The primary objective in the Mahmood paper [1] is to evaluate the predictions of a model for morphine clearance reported by Anand et al. [2]. It should be noted that the Anand paper did not claim to predict morphine clearance in individual subjects. A model was developed to describe the pattern of size and maturation changes of morphine clearance and its variability. These patterns are clearly confirmed from external data sources including those proposed by Mahmood [1]. The primary descriptive features of the model are clearly evident over three orders of magnitude of clearance i.e. very low clearance in premature infants, size adjusted maturation being reached around 50 weeks post-menstrual age (PMA) and a mature clearance value close to adult values. 
 
Acceptable prediction bias is proposed to be 10% but this is an unrealistic figure in clinical practice. The typical bioequivalence criteria of 80–125% show that a bias of up to 25% in the delivered dose from an equivalent formulation is widely acceptable while up to two-fold differences in clearance may also be acceptable for regulatory purposes [3]. 
 
Acceptable precision of the prediction is proposed to be 15%. However, as shown in Sheiner & Beal [4] (reference 20 in Mahmood's paper) the mean square error is the sum of the squared bias and mean square deviation from the mean. In this context the mean squared deviation from the mean is the between subject random variance around the typical clearance value. The square root of this variance was estimated to be 48% by Anand et al. [2]. Thus even if the bias was zero, the root mean square error would be 48% and so a precision target of 15% is unattainable even if the prediction model is perfect. 
 
The percentage mean prediction error (%MPE), used to estimate bias, is calculated by Mahmood [1] relative to the average observed clearance. This is not an appropriate way to calculate MPE when there is a wide range of values being compared. It minimizes the MPE at low clearance values and exaggerates it at higher values. The prediction error in clearance is important relative to the observed value not relative to a value that may be an order of magnitude or more different. 
 
The text and figures include coefficients of determination to support the assertion that the model makes poor predictions. Yet Mahmood acknowledges ‘Correlation coefficient (r2) (sic) is however, not a good measure for the assessment of he predictive power of a model’. The coefficients of determination add nothing to the evaluation of the data and should be ignored. The use of a regression line rather than a line of identity and unequal axis sizes distort the comparison of predictions with observations (e.g. Figure 2). These figures are more informative about the predictions when they show the line of identity (e.g. Figure 1). 
 
Figure 1 
 
Predicted and observed clearance in 75 neonates (GA < 37 weeks) based on literature cited by Mahmood [1] 
 
Figure 2 
 
Mahmood [1]Figure 1 showing predicted and observed clearances in 75 neonates. There seem to be points missing at observed clearances around 8–11 ml min−1 
 
Mahmood challenges the definition of the age at which the clearance in a child is 50% of an adult value (page 11). He proposes a definition which uses an adult size standardized value (70 kg) but then fails to apply a similar size standard before comparing clearances in children and adults. We believe a major strength of our approach using size standardized values is that it allows a meaningful description of maturation independent of size. He goes on to say that our prediction that morphine clearance approaches adult size standardized values around 1 year is incorrect because physiological development continues past this age. However he offers no evidence to show that morphine metabolism continues to mature independently of size after 1 year. 
 
We retrieved the individual clearance estimates from the 10 original publications used by Mahmood. A comparison of the plots of clearance values shows that some data points appear to be missing (Figures 1 and ​and2).2). He reports more observations (147 vs. 144) but appears to have omitted two of the subjects with ‘divergent kinetics’ (Figure 3) reported by Dahlstrom et al. [5]. Clearance estimates above 400 ml min-1 appear to be missing from Figure 1 of Mahmood's manuscript (Figure 4). We believe there may be errors in the data used by Mahmood and these discrepancies should be resolved. 
 
Figure 3 
 
Predicted and observed clearance in 144 neonates and children (age ≤ 5 PNA years) found in the literature cited by Mahmood [1]. Circled symbols refer to clearance estimates in the original publication that the original authors identified as being ... 
 
Figure 4 
 
Mahmood [1]Figure 2 showing predicted and observed clearances in 147 neonates and children. There seem to be points missing at observed clearances greater than 400 ml min−1 
 
Individual predictions of morphine clearance (and thus dose) may be guided initially by the model predictions but of course should be refined by direct observation of clinical response. Clearance, and thus the appropriate dose rate, changes rapidly in the first few weeks of life and is determined by both age and weight. We would assert that initial dosing, based on typical subject clearances of morphine, is of practical value. This is directly opposed by Mahmood who states ‘… the prediction of morphine clearance … and the magnitude of prediction error was too high to be acceptable for any practical use’. We also cannot agree with the conclusion that the maturation model in the abstract ‘may not be of any practical value for the prediction of morphine clearance in this age group.’ This assertion is presented without any justification or evidence that it would not be of practical value. 
 
The ‘secondary objective’ of Mahmood is to evaluate the allometric exponent of 0.75. Mahmood provides no justification for claiming that the allometric model with an exponent of 0.75 is erroneous. Predictions from Method II (using just this allometric model) are applied to all subjects and ignore age. Necessarily the predictions are bad for the neonates when neither maturation nor prematurity are included. He acknowledges that including maturation makes the predictions much better but still wants to claim that 0.75 ‘introduces substantial error’ (bottom of page 12). 
 
This claim about ‘introducing substantial error’ is perhaps the most unacceptable part of the paper because it is not supported by what is presented. There is nothing in this paper to show that the use of the allometric exponent of 0.75 introduces error in the predictions. Indeed, Mahmood demonstrates that in children who are predicted to be mature, the clearance is adequately predicted from weight using the allometric model with an exponent of 0.75. The only ‘substantial error’ is when he uses allometric scaling alone but that is exactly why we have proposed additional biologically based models for describing why size alone is not adequate.

Evaluation of a morphine maturation model for the prediction of morphine clearance in children.

Background:  The value of acetaminophen–ibuprofen combination therapy over single therapy is uncertain in acute pediatric pain management. A model describing the interaction between these two drugs would be useful both for understanding current literature and for future study design.

Explaining the acetaminophen–ibuprofen analgesic interaction using a response surface model

The report that chronic therapy with phenobarbital shortens the duration of effectiveness of ketamine by Eker et al. (1) is not unexpected, given that phenobarbital is a drug that is known to induce a multitude of hepatic enzymes. What is surprising is that there is a paucity of reports in the anesthesia literature about this drug interaction. Phenobarbital is an old drug, first introduced in 1912 by Bayer. It remains a very effective management therapy for epilepsy, although use for its sedative and hypnotic properties has diminished since the introduction of the benzodiazepines 30 years ago. The popularity of this drug is driven, in part, by its long half-life of 79 h (range 53–120 h) in adults. Clearance is reduced in neonates and increases with age, attaining mature rates within 6–12 months of life (2); dosing can be daily or even less frequently. Metabolism is mostly through hepatic pathways, and the P450 cytochrome (CYP) 2C19 is the dominant hepatic clearance enzyme. However, enzyme induction of a number of other pathways responsible for drug clearances occurs (3), e.g., CYP1A2, CYP2C9, CYP2C19, CYP3A4, and UDP-glucuronosyltransferase (UGT) (4–6). These isoenzymes are responsible for the clearance of a great many drugs, including many drugs used in anesthesia and intensive care practice.

Intravenous paracetamol pharmacokinetics in neonates: a pooled analysis

Is Hyperbilirubinaemia a Clinical Useful Indicator of Reduced Drug Clearance Capacity in Neonates?

Background The aim was to describe intravenous paracetamol pharmacokinetics, determine major covariates and suggest a dosing regimen for (pre)term neonates. Methods A population pharmacokinetic analysis of 943 paracetamol observations from 158 neonates (27–45 weeks' postmenstrual age (PMA)) was undertaken using non-linear mixed effects models. Data from three published studies were pooled with newly collected time–concentration points during repeated intravenous paracetamol administration. Results A two-compartment (central, peripheral) linear disposition model was used. Population parameter estimates (between-subject variability, %) were central volume 51.9 l/70 kg (21.6%), peripheral volume of distribution 22.7 l/70 kg, clearance 5 l/h/70 kg (40%) and intercompartment clearance 16.2 l/h/70 kg. Covariate information predicts 60.9% of clearance variance. Weight was used to predict patient size and was the major covariate contributing 57.5% of variance. Clearance expressed as mg/kg/h increases only slightly with PMA (0.138 l/kg/h at 28 weeks' PMA to 0.167 l/kg/h at 44 weeks' PMA) and contributes only 2.2% of variance. High unconjugated bilirubin levels contributed an additional 1.2%. Conclusions Patient size (predicted by weight) is the major covariate of clearance variance in neonates. Using these estimates, a mean paracetamol serum concentration of 11 mg/l is predicted in neonates of 32–44 weeks' PMA given a standard dose of intravenous paracetamol of 10 mg/kg every 6 h. Safety data for this drug are limited in neonates. Continued surveillance therefore remains essential.

The pharmacokinetics of intravenous paracetamol in neonates: size matters most

Medication errors in pediatric anesthesia represent an important risk to children. Concerted action to reduce harm from this cause is overdue. An understanding of the genesis of avoidable adverse drug events may facilitate the development of effective countermeasures to the events or their effects. Errors include those involving the automatic system of cognition and those involving the reflective system. Errors and violations are distinct, but violations often predispose to error. The system of medication administration is complex, and many aspects of it are conducive to error. Evidence‐based practices to reduce the risk of medication error in general include those encompassed by the following recommendations: systematic countermeasures should be used to decrease the number of drug administration errors in anesthesia; the label on any drug ampoule or syringe should be read carefully before a drug is drawn up or injected; the legibility and contents of labels on ampoules and syringes should be optimized according to agreed standards; syringes should always be labeled; formal organization of drug drawers and workspaces should be used; labels should be checked with a second person or a device before a drug is drawn up or administered. Dosage errors are particularly common in pediatric patients. Causes that should be addressed include a lack of pediatric formulations and/or presentations of medication that necessitates dilution before administration or the use of intravenous formulations for oral administration in children, a frequent failure to obtain accurate weights for patients and a paucity of pharmacokinetic and pharmacodynamic data. Technological innovations, including the use of bar codes and various cognitive aids, may facilitate compliance with these recommendations. Improved medication safety requires a system‐wide strategy standardized at least to the level of the institution; it is the responsibility of institutional leadership to introduce such strategies and of individual practitioners to engage in them.

Objective:  The transdermal therapeutic system (TTS) with buprenorphine is currently being used ‘off‐label’ to treat chronic pediatric pain. We compiled available pharmacokinetic (PK), pharmacodynamic (PD), and clinical pediatric data on buprenorphine to rationalize treatment regimens.

Buprenorphine TTS for children – a review of the drug’s clinical pharmacology

Aims:  The aim of this study was to describe ketamine pharmacokinetics when administered orally to children suffering from burn injury in >10% body surface area.

Exploring the pharmacokinetics of oral ketamine in children undergoing burns procedures

Tramadol and O-demethyltramadol disposition in humans: a pooled study

Background:  Oral clonidine is used as premedication in children. The bioavailability of clonidine given orally in adults is 75–100% but is unknown in children.

Concentration at the effect site determines response. The desired effect is known as the target effect (TE), and the concentration that achieves this TE is the target concentration (TC). The goal of treatment is the TE. The PD model is used to predict the TC given a TE. Population estimates of maximum effect (Emax) and the concentration that achieves half this maximum effect (EC50) and covariate information are used to predict typical Emax and EC50 values in a specific patient. Population estimates of volume of distribution (V) and clearance (CL) and covariate information are then used to predict typical V and CL values in a specific patient (2). It is then possible to predict the TC to achieve the TE, e.g.,

Developmental pharmacology; filling one knowledge gap in pediatric anesthesiology

extraction, and congenital cardiac septal defect correction (4,5). Incidence of cardiac defects in CRS with eye involvement could be as high as 95% (6). This mandates cardiac evaluation by pediatric cardiologist for the structural abnormalities and may include echocardiography and Doppler studies. Even though the child initially was referred for cataract surgery, it was decided to do PDA ligation as well to give a better prognosis and improve her life expectancy. In addition to inherent concerns of management of neonatae, additional concerns include airway management because of congenital defects like cleft lip/palate, micrognathia, and episodes of transient pneumonitis. So we arranged the difficult airway cart for this patient and administered muscle relaxant only after ensuring adequate bag mask ventilation. Such combined procedures required change of position intraoperatively and care should be taken during positioning because of association of bone abnormalities. The anesthetic drugs should be cautiously used because of associated liver abnormalities and hypothyroidism. The analgesic management should avoid drugs having affect on platelets as these patients are prone for thrombocytopenia. De-airing of the intravenous line is also an important consideration. The concerns related to ductal ligation including effects on blood pressure need to be monitored during the surgical procedure. During the ductal ligation, injury to recurrent laryngeal nerve or accidental ligation of the vessels like pulmonary aorta may occur. To conclude, child of CRS required thorough evaluation of associated systemic abnormalities and great vigilance in the perioperative period. The airway difficulty needs to be anticipated. The drug metabolism may be deranged and thus careful use of anesthetic drugs.

Pharmacokinetic (PK) and pharmacodynamic (PD) modeling has elucidated aspects of developmental pharmacology of value to the anesthetic community. The increasing sophistication of modeling techniques is associated with pitfalls that may not be readily apparent to readers or investigators. While size and age are considered primary covariates for PK models, the impact of birth on clearance maturation is poorly documented, dose in obese children is poorly investigated, pharmacologic implications of physiologic changes poorly portrayed, disease progression on drug response poorly depicted and the impact of metabolites on effect poorly illustrated. This review identifies some of these pitfalls and suggests ideas to circumvent or investigate these hazards.

Intravenous paracetamol pharmacokinetics in neonates: weight outweights age

Background: Thiopentone elimination has been described using Michaelis–Menten pharmacokinetics in adults after prolonged infusion or overdose, but there are few reports of elimination in neonates.

Thiopentone elimination in newborn infants: exploring Michaelis–Menten kinetics

Purpose of review Target controlled infusion (TCI) devices are gaining popularity among paediatric anaesthesia practitioners because propofol and short-acting opioids allow rapid onset and offset of action, reduce postoperative nausea and vomiting, reduce emergence delirium, lessen exposure to atmospheric pollutants and can be used in peripheral locations. Widespread use remains limited and this review examines reasons why children do not yet enjoy such benefits. Recent findings There is no integrated pharmacokinetic/pharmacodynamic analysis that can supply parameter estimates to be programmed into pumps for either plasma or effect-site concentration determination over the broad paediatric age range. The six pharmacokinetic parameter sets available for children out of infancy all differ. Validation studies are few. Estimates in neonates and infants are dependent on maturation and size considerations that have not yet been elucidated. There remains a need for specific neonate-derived algorithms if electroencephalogram (EEG)-derived anaesthesia depth monitors are to be used for neonates or infants. End-tidal breath analysis of propofol offers a useful tool for central compartment monitoring. Summary Hardware limitations, a lack of integrated pharmacokinetic/pharmacodynamic studies and target monitoring issues restrict use. Intravenous induction remains a hurdle, but increasing familiarity with the technique guarantees continued use for maintenance anaesthesia.

Are there still limitations for the use of target-controlled infusion in children?

The objective of this study was to develop a pharmacokinetic (PK) model to characterize the influence of obesity on propofol PK parameters.

METHODS
Nineteen obese ASA II patients undergoing bariatric surgery were studied. Patients received propofol 2 mg kg(-1) bolus dose followed by a 5-20-40-120 min, 10-8-6-5 mg kg(-1) h(-1) infusion. Arterial blood samples were withdrawn at 1, 3, 5 min after induction, every 10-20 min during propofol infusion, and every 10-30 min for 2 h after stopping the propofol infusion. Arterial samples were processed by high-performance liquid chromatography. Time-concentration data profiles from this study were pooled with data from two other propofol PK studies available at http://www.opentci.org. Population PK modelling was performed using non-linear mixed effects model.

RESULTS
The study involved 19 obese adults who contributed 163 observations. The pooled analysis involved 51 patients (weight 93 sd 24 kg, range 44-160 kg; age 46 sd 16 yr, range 25-81 yr; BMI 33 sd 9 kg m(-2), range 16-52 kg m(-2)). A three-compartment model was used to investigate propofol PK. An allometric size model using total body weight (TBW) was superior to all other models investigated (linear TBW, free fat mass, lean body weight, normal fat mass) for all clearance parameters. Variability in V2 and Q2 was reduced by a function showing a decrease in both parameters with age.

We have derived a population PK model using obese and non-obese data to characterize propofol PK over a wide range of body weights. An allometric model using TBW as the size descriptor of volumes and clearances was superior to other size descriptors to characterize propofol PK in obese patients.

Influence of obesity on propofol pharmacokinetics: derivation of a pharmacokinetic model.

Background:  Dexmedetomidine has opposing effects on the cardiovascular system. Action in the central nervous system produces sympatholysis and a reduction in blood pressure, while peripherally it causes vasoconstriction leading to an increase in blood pressure. The purpose of our study is to define the concentration–response profile for these hemodynamic effects in children after cardiac surgery.

Background Acetaminophen is often used with a non-steriodal anti-inflammatory drug for acute pain. Hitherto, these drugs have had to be given separately, typically at different time intervals. Maxigesic® tablets combine acetaminophen and ibuprofen in clinically appropriate doses to simplify administration and dosage regimen. We compared this combination with each of the constituent drugs for the relief of pain after extraction of third molar teeth. Methods Adults (more than 16 yr) having one or more wisdom teeth removed under general or local anaesthesia were instructed to take two tablets before operation, then two tablets every 6 h for up to 48 h of: (i) a combination of acetaminophen 500 mg and ibuprofen 150 mg per tablet (Maxigesic®); (ii) acetaminophen 500 mg per tablet alone; or (iii) ibuprofen 150 mg per tablet alone. The primary outcome measure was the area under the curve (AUC) of the 100 mm visual analogue scale pain measurements taken for up to 48 h after surgery, divided by time, at rest and on activity. Pharmacokinetic data were collected in a subset of patients. Results The mean (sem) time-corrected AUC on rest and activity, respectively, were: combination group 22.3 (3.2) and 28.4 (3.4); acetaminophen group 33.0 (3.1) and 40.4 (3.3); and ibuprofen group 34.8 (3.2) and 40.2 (3.4); P<0.01 for each of the four comparisons of combination vs constituent drug. There was no pharmacokinetic interaction between acetaminophen and ibuprofen administered together. Conclusions Maxigesic® tablets provide superior pain relief after oral surgery to acetaminophen or ibuprofen alone.

Combined acetaminophen and ibuprofen for pain relief after oral surgery in adults: a randomized controlled trial

Models describe systems in simple terms, although some models may be quite sophisticated. They are used to describe, predict, and explain observations. Pharmacokinetic (PK) and pharmacodynamic (PD) models are used to improve pediatric anesthetic management. They quantify the exposure–response relationship, often providing clarity and insight into complex systems as well as a mechanistic understanding of the drug effect. Dosing can be rationalized. Models may enable extrapolation beyond observed data. Modeling is a knowledge management tool; it captures and integrates data from all studies. Models can also be used for hypothesis testing and can drive decisions about the best way to interpret observations in clinical practice. A population approach, achieved through nonlinear mixed effects models, is now an established method for investigating PK and PD data. This population approach has implications beyond pharmacology and can be used to describe physiology (1) and has also been advocated for interpreting analgesia trials (2). The approach was used by Standing et al. (3) in the current issue of Pediatric Anesthesia to examine the PK–PD relationship between remifentanil and blood pressure changes. The authors used complex modeling to rend this relationship from only five subjects. Can we really believe such results or are they taking things too far?

Background: The widespread use of codeine in children has been questioned in recent years because of concerns about unpredictable analgesia and side effects compared to other agents. Objective: To debate the advantages and disadvantages of the use of codeine as an analgesic for children. Design/Participants: 2 debaters (a pediatrician from the United Kingdom and a pharmacist from New Zealand) present arguments for and against the use of codeine. The pharmacist lays out his objections against codeine, which has been used for its analgesic, anti-tussive, and anti-diarrheal properties. Codeine's analgesic action is mediated through its metabolite, morphine. Clinicians have long noted variability and lack of analgesia in the response to codeine among certain patients, which is likely due to variations in a particular gene—CYP 2D6—that governs the metabolism of codeine to morphine. Metabolizers can be poor, intermediate, or extensive; 7% to 10% of whites are slow metabolizers, so codeine's conversion to morphine is limited, and this would partly explain the lack of efficacy. Only 2% of Asians are slow metabolizers. Neonates have enzymatic immaturity, and codeine is an impractical drug in this age group. Codeine has 1/10 the potency of morphine, so 60 mg of codeine has a morphine equivalence of 6 mg. The pharmacist makes a pitch for the use of oral morphine, compared to codeine, in hospital settings. This is not common in the United States, in part because of its taste as well as greater familiarity with intravenous use. The pediatrician argues that codeine has a long history of clinical usage with effective dose regimens and is available in liquid formulations for children. He concedes, however, that there are no large randomized trials involving codeine in discrete age-specific clinical situations. He argues that it should not be the drug of choice for acute severe pain in cases in which morphine, in particular, is a drug of choice. Until medications such as Tramadol, hydromorphone, or oxycodone are better studied in children, he believes codeine remains the main oral medication if acetaminophen and nonsteroidal anti-inflammatory medications are ineffective. Regarding safety, he notes that the use of codeine for many years and in many patients suggests a good safety record. Conclusions: Both discussants note that experience with codeine is extensive and that alternatives for moderate pain currently are limited. They agree that codeine is likely to remain a popular drug in pediatric medicine for the foreseeable future. Reviewer's Comments: The fact of slow versus fast metabolizers of codeine is likely under-appreciated by clinicians. It is something to consider if you have a patient on codeine who is not responding to standard dosing. Also, be sure to think about adding acetaminophen in some combination for the synergistic effects. (Reviewer-Mark F. Ditmar, MD).

Pro–con debate: is codeine a drug that still has a useful role in pediatric practice?

Target‐controlled infusion (TCI) pumps currently do not satisfactorily cater for the pediatric population, particularly for those under 5 years. Growth and development are two major aspects of children not readily apparent in adults, and these two aspects influence clearance (CL) and volume of distribution (V). In simple terms, V determines initial dose, and CL determines infusion rate at steady state. Three major covariates (size, age, and organ function) contribute to parameter variability in children. Size can be standardized for clearance in a 70‐kg person using the allometric ¾ power model. Remifentanil, a drug cleared by hydrolysis, can be modeled in all age groups by simple application of this model using a standardized clearance of 2790 ml·min−1 for a 70‐kg person. Allometry alone is insufficient to predict clearance in neonates and infants from adult parameters for most drugs used in anesthesia. The addition of a model describing maturation is required. The sigmoid Emax or Hill model has been found useful for describing this maturation process. Propofol maturation has been described with a mature clearance of 1.83 l·min−1·70kg−1, a maturation half‐time (TM50) of 44 weeks and a Hill coefficient of 4.9. Organ function also affects clearance, and propofol clearance is reduced in neonates and infants after cardiac surgery. Although pharmacokinetics (PK) in children is receiving increasing attention and is eminently programmable into a TCI device, pharmacodynamic (PD) measures in children remain poorly defined, partly because the depth of anesthesia monitoring are inadequate. Both PK and PD are necessary for safe use of TCI pumps.

Background:  Published dexmedetomidine pharmacokinetic studies in children are limited by participant numbers and restricted pathology. Pooling the available studies allows investigation of covariate effects.

Dexmedetomidine pharmacokinetics in pediatric intensive care – a pooled analysis

Maturational tramadol clearance throughout childhood: a pooled analysis

Quantification of the impact of indomethacin or ibuprofen administration on vancomycin clearance in neonates

Human renal function maturation: a quantitative description using weight and postmenstrual age

Pooling data from different pediatric studies can provide a single robust pharmacokinetic analysis that allows covariate analysis and hypothesis testing. Data sharing should be driven by the altruistic purpose of improving drug understanding to the clinical benefit of children. Electronic communications have rendered the sharing of data relatively easy, and data sharing within the wider scientific community has become commonplace. Data sharing allows verification of results, save costs and time, allows new interpretation of old data, and can fulfill teaching benefits. It may stimulate cooperative competition between researchers and allow individual researchers to concentrate on unique aspects of the scientific puzzle. However, there is occasionally a reluctance to share, in part because of fear of others stealing the hard work of a research group, which may not be recognized in subsequent publications that reuse data. Providing data may require additional effort for presentation in a suitable format. Data may be abused or used for purposes other than those for which they were collected. Propriety claims may limit access to industry‐sponsored drug research. The question of who has ownership of data is contentious. Investigators often consider data they have collected to be their own property. Reputations and grants may be hinge on ownership of a data set. However, other team members, institutions, funding agencies, and the public also have a stake. The difficulties identified in the general scientific community also apply to data sharing for pediatric pharmacokinetic studies. There are few clearly established rules at present, and consideration of the issues hinges on ethical and philosophical arguments. The development of databases will depend on collaboration and cooperation and greater clarity and consensus over appropriate processes and procedures.

Purpose of review Toxicity concerns and awareness during anesthesia issues continue to concern pediatric anesthesiologists. Most developmental pharmacokinetic, pharmacodynamic and pharmacogenomic changes occur within the first year of life. Understanding these early changes can improve drug use in this cohort. Recent findings Growth and development are two major aspects of children not readily apparent in adults. Clearance in the pediatric population should be investigated using models that describe size, maturation and organ function influences. Glucuronide conjugation (hepatic phase II process) mirrors glomerular filtration maturation over the first year of life. Phase 1 processes appear more rapid, and differences attributable to single nuclear polymorphisms may be obvious by the end of the 4-week neonatal period in term infants. Pharmacodynamic differences in infancy remain poorly defined, and neonatal pharmacokinetic-pharmacodynamic analyses that might elucidate such differences are few, partly because of a paucity of effective pharmacodynamic measures. Summary Mechanistic models create a framework for the study of pharmacokinetic changes in infancy. Understanding these changes allows a target concentration approach to therapy and potential for reduced toxicity. The target concentration may be undefined because of a paucity of effect measures.

Cefazolin pharmacokinetics in maternal plasma and amniotic fluid during pregnancy.

Pharmacokinetics of tramadol in human neonates, children and adults and in adult rats, cats, goats and horses

Thyroid hormone and cortisol concentrations after congenital heart surgery in infants younger than 3 months of age

Intravenous (i.v.) paracetamol (acetaminophen) is gaining increasing use in neonates (1–3), despite an off-label status in some countries. Product information for i.v. paracetamol does not consider the clearance maturation with age in neonates in its dosing recommendations. In Australasia the same dose of 15 mgAEkg 6 h is suggested for neonates over 10 days of age and for infants and children up to 33 kg. A reduced dose of 7.5 mgAEkg 6 h is proposed in term neonates <10 days of age. In Europe there is no labeled use for neonates <10 days of age. The registered dose is 7.5 mgAEkg 6 h for neonates after 10 days of age through to infants of 10 kg. A dose of 15 mgAEkg 6 h (max daily dose 60 mgAEkg) is recommended between 10 and 40 kg. These dosing regimens suggest something magic about 10 days. There are data concerning the pharmacokinetics of this formulation in neonates. Population pharmacokinetics of the i.v. prodrug (propacetamol) have been studied in neonates following single (4,5) and repeat dose administration (6). Parameter estimates from neonates given repeat doses of i.v. paracetamol over a median of 4 days duration are consistent with those estimated using propacetamol (7). Dosing regimens used in some institutions for neonates have been published in Pediatric Anesthesia (2,8), but there are few data validating the safety or effectiveness of these regimens. The idea that a target effect and associated target concentration can be used to make rational individual dose decisions has acceptance (9). A knowledge of neonatal pharmacokinetics assists with dose prediction to achieve the target concentration. There are, however, flaws and constraints of current knowledge that limit implementation of this approach to dosing.

Growth and development are two major aspects of children not readily apparent in adults. Clearance in the paediatric population should be investigated using models that describe size, maturation and organ function influences. Size is the primary covariate and although lean body weight is argued as a better measure than total body weight, the use of different fractions of fat mass to explain how pharmacokinetic parameters vary with body composition has been proposed. Allometric scaling using an empiric power exponent of 3/4 is superior to scaling using body surface area. The sigmoid hyperbolic model has proven useful to describe maturation. An extra parameter that describes asymmetry can be incorporated into this model. These descriptors are used to illustrate creatinine, morphine and paracetamol clearance in children. Simultaneous investigation of pooled GFR, paracetamol and morphine data enabled testing for shared common features of maturation processes. Results suggest that GFR matures before paracetamol or morphine clearance, consistent with phase II conjugation processes that convert xenobiotics to water soluble forms that can subsequently be eliminated from the body through the renal system. The use of such mechanistic approaches improves understanding of paediatric pharmacokinetics; improving dosing predictions and allowing projection in exploratory drug development.

Mechanistic basis of using body size and maturation to predict clearance in humans.

Growth and development can be investigated using readily observable demographic factors such as weight and age. Size is the primary covariate and can be referenced to a 70-kg person with allometry using a coefficient of 0.75 for clearance and 1 for volume. The use of these coefficients is supported by fractal geometric concepts and observations from diverse areas in biology. Fat free mass (FFM) might be expected to do better than total body weight when there are wide variations in fat affecting body composition. Clearance pathways develop in the fetus before birth. The use of postnatal age as a descriptor of maturation is unsatisfactory because birth may occur prematurely; therefore postmenstrual age is a superior predictor of elimination function. A sigmoid E(max) model (Hill equation) describes gradual maturation of clearance in early life leading to a mature adult clearance achieved at a later age.

Mechanism-based concepts of size and maturity in pharmacokinetics.

Background:  There are few data describing dexmedetomidine population pharmacokinetics (PK) in children (0–15 years) despite increasing use.

Objective: To alert readers to the possibility of rebound hyperkalemia following pancreatic resection for neonatal hyperinsulinism. Design: Case report. Setting: Intensive care unit of tertiary pediatric hospital. Patient: A term neonate with severe hyperinsulinism complicated by hypokalemia, fluid overload, and necrotizing enterocolitis. Interventions: Preoperative management consisted of glucose 20.8 mg/kg/min, diazoxide 15 mg/kg/day, octreotide 27 &mgr;g/kg/day, and potassium (>10 mmol/kg/day) to maintain normoglycemia and normokalemia. The large glucose requirement, administered as 20% glucose, contributed to congestive heart failure, which was treated with frusemide. Attempts to feed enterally were abandoned because of necrotizing enterocolitis. Partial colectomy and subtotal pancreatectomy were performed on day 20. Measurements and Main Results: Serum potassium rose rapidly within 2 hrs of surgery to reach 12.3 mmol/L, causing ventricular tachycardia (240 beats/min) on electrocardiogram. There was no evidence of renal failure or adrenal insufficiency. Management consisted of insulin 0.1 units/kg intravenously, 10% calcium gluconate 0.1 mmol/kg intravenously, sodium bicarbonate 3 mmol/kg intravenously, frusemide 2 mg/kg intravenously, and resonium 0.6 g/kg per rectum with good outcome. Conclusions: This report highlights the rapid electrolyte shifts possible after sudden cessation of hormones regulating Na+/K+-ATPase activity.

Life-threatening hyperkalemia following partial pancreatectomy for neonatal hyperinsulinism

Objective: To describe intravenous ketamine dosing regimens for children requiring brief procedural sedation. Methods: Time-concentration and sedation profiles were simulated in children (2, 6, and 12 years old) using published pediatric pharmacokinetic and pharmacodynamic parameter estimates. Single-dose, repeat-dosing, and infusion regimens to achieve sedation level of less than 2 (arouses slowly to consciousness, with sustained painful stimulus) for 15 minutes were investigated. Results: A single bolus dose of 1.5 and 1.75, 2, and 2.125 mg/kg (for adult and 12-, 6-, and 2-year-olds, respectively) was required to achieve the desired sedation. Anticipated recovery would be slow, and a sedation level of 4 (drowsy, eyes open or closed but easily arouses to consciousness with verbal stimulus) was reached only after 70 minutes. The use of a smaller initial bolus with a subsequent half-dose "top-up" at 8 minutes achieves the same sedation level but with earlier recovery. A smaller initial dose of 0.25 and 0.275, 0.3, and 0.35 mg/kg followed by an infusion 2.5 and 2.75, 3, and 3.5 mg/kg per hour (for adult and 12-, 6-, and 2-year-olds, respectively) for 15 minutes gives a more even sedation level and rapid recovery (20 minutes to sedation level 4). Conclusions: Dosing increases with decreasing age. A large single dose is associated with deep sedation, possible adverse effects, and delayed recovery. Between-subjects variability is large, and dose should be tailored to clinical monitoring and requirement. Intermittent pain insult is better suited to a top-up technique, whereas continuous pain is better suited to an infusion technique.

Dosing Ketamine for Pediatric Procedural Sedation in the Emergency Department

Objective. Postoperative urinary retention (PUR) is associated with overdistension of the bladder. The prevention of PUR by routine catheterization may increase the risk of urinary tract infection. Postoperative monitoring of the bladder volume by ultrasound to prevent PUR is reliable in adults, but has not been evaluated in children. Material and methods. The BladderScan® BVI 6200, an ultrasound device specifically designed for children, was assessed. Forty patients who required urinary catheter placement during surgery or during intensive care unit stay were entered into this blinded calibration study. An assessment of bladder urine volume by ultrasound was performed before and after catheterization in surgical patients. In these patients and intensive care patients 0, 2.5 or 5 ml/kg sterile normal NaCl was injected through the bladder catheter and the catheter was clamped. Volumes estimated with ultrasound were compared with measured catheter drainage or/and injected volume after the scan. Results. The mean relative difference (bias) between the ultrasound estimate and the injected volume was −20% (95% confidence interval 140 to −180%). Precision, estimated using the Wilcoxon signed ranks test, showed a significant difference (Z=−3.25, p=0.001) between the ultrasound-estimated volumes and the injected volumes. Conclusions. This study could not confirm good agreement between the ultrasound-estimated volumes and the injected volumes at volumes below 5 ml/kg. Bladder volumes were underestimated with a very broad 95% confidence interval. The ultrasound device should not replace current clinical assessment.

Evaluation of a non-invasive bladder volume measurement in children

Contributors to between-individual variabilityof amikacin clearance in neonates

Pharmacokinetics of an i.v. prodrug of acetaminophen (propacetamol) in neonates after repeat dosing are reported, with scant data for i.v. acetaminophen formulation.

METHODS
Neonates from an intensive care unit received 6-hourly prn i.v. acetaminophen dosed according to postmenstrual age (PMA): 28-32 weeks, 10 mg kg(-1); 32-36 weeks, 12.5 mg kg(-1); and > or =36 weeks, 15 mg kg(-1). A maximum of five blood samples for assay and liver function tests (LFTs) were collected. A one-compartment linear disposition model (zero-order input; first-order elimination) was used to describe time-concentration profiles using population modelling (NONMEM).

RESULTS
Fifty neonates, median (range) PMA 38.6 (32-45) weeks, mean (SD) weight 2.9 (0.7) kg, received a mean of 15 doses over a median 4 days with 189 serum acetaminophen and 231 LFT measurements. Standardized population parameter estimates for a term neonate were clearance (CL) 5.24 (CV 30.5%) litre h(-1) 70 kg(-1) and volume of distribution (V) 76 (29.6%) litre 70 kg(-1). CL increased with PMA from 4.4 litre h(-1) 70 kg(-1) at 34 weeks to 6.3 litre h(-1) 70 kg(-1) at 46 weeks. The presence of unconjugated hyperbilirubinaemia was associated with reduced CL: 150 micromol litre(-1) associated with 40% CL reduction. Acetaminophen concentrations between 10 and 23 mg litre(-1) at steady state are predicted after 15 mg kg(-1) 6-hourly for a neonate of PMA 40 weeks. Hepatic enzyme analysis of daily samples changed significantly for one patient whose alanine aminotransferase concentration tripled.

The parameter estimates are similar to those described for propacetamol. There was no evidence of hepatotoxicity. Unconjugated hyperbilirubinaemia impacts upon CL, dictating dose reduction.

I.V. acetaminophen pharmacokinetics in neonates after multiple doses.

Methods. Neonates from an intensive care unit received 6-hourly prn i.v. acetaminophen dosed according to postmenstrual age (PMA): 28–32 weeks, 10 mg kg; 32–36 weeks, 12.5 mg kg; and 36 weeks, 15 mg kg. A maximum of five blood samples for assay and liver function tests (LFTs) were collected. A one-compartment linear disposition model (zero-order input; first-order elimination) was used to describe time–concentration profiles using population modelling (NONMEM).

Paracetamol has a central analgesic effect that is mediated through activation of descending serotonergic pathways. Debate exists about its primary site of action, which may be inhibition of prostaglandin (PG) synthesis or through an active metabolite influencing cannabinoid receptors. Prostaglandin H2 synthetase (PGHS) is the enzyme responsible for metabolism of arachidonic acid to the unstable PGH2. The two major forms of this enzyme are the constitutive PGHS‐1 and the inducible PGHS‐2. PGHS comprises of two sites: a cyclooxygenase (COX) site and a peroxidase (POX) site. The conversion of arachidonic acid to PGG2 is dependent on a tyrosine‐385 radical at the COX site. Formation of a ferryl protoporphyrin IX radical cation from the reducing agent Fe3+ at the POX site is essential for conversion of tyrosine‐385 to its radical form. Paracetamol acts as a reducing cosubstrate on the POX site and lessens availability of the ferryl protoporphyrin IX radical cation. This effect can be reduced in the presence of hydroperoxide‐generating lipoxygenase enzymes within the cell (peroxide tone) or by swamping the POX site with substrate such as PGG2. Peroxide tone and swamping explain lack of peripheral analgesic effect, platelet effect, and anti‐inflammatory effect by paracetamol. Alternatively, paracetamol effects may be mediated by an active metabolite (p‐aminophenol). p‐Aminophenol is conjugated with arachidonic acid by fatty acid amide hydrolase to form AM404. AM404 exerts effect through cannabinoid receptors. It may also work through PGHS, particularly in areas of the brain with high concentrations of fatty acid amide hydrolase.

Contributors to interindividual variability of tramadol disposition in the first months of life: 9AP9-1

CYP2D6 polymorphisms contribute to M1 formation clearance but not to overall tramadol clearance in early life

Relationships between plasma morphine concentrations and neonatal responses to endotracheal tube (ETT) suctioning are unknown in preterm neonates.

METHODS
Ventilated preterm neonates (n=898) from 16 centres were randomly assigned to placebo (n=449) or morphine (n=449). After an i.v. loading dose (100 microg kg(-1)), morphine infusions [23-26 weeks postmenstrual age (PMA) 10 microg kg(-1) h(-1); 27-29 weeks 20 microg kg(-1) h(-1); and 30-32 weeks 30 microg kg(-1) h(-1)] were established for a maximum of 14 days. Open-label morphine (20-100 microg kg(-1)) was given for pain or agitation. Morphine assay and neonatal response to ETT suctioning was measured at 20-28 and 70-76 h after starting the drug infusion and at 10-14 h after discontinuation of the study drug. The concentration-effect response was investigated using non-linear mixed effects models.

RESULTS
A total of 5119 data points (1598 measured morphine concentrations and 3521 effect measures) were available from 875 neonates for analysis. Clearance was 50% that of the mature value at 54.2 weeks PMA (CLmat(50)) and increased from 2.05 litre h(-1) 70 kg(-1) at 24 weeks PMA to 6.04 litre h(-1) 70 kg(-1) at 32 weeks PMA. The volume of distribution in preterm neonates was 190 litre 70 kg(-1) (CV 51%) and did not change with age. There was no relationship between morphine concentrations (range 0-440 microg litre(-1)) and heart rate changes associated with ETT suctioning or with the Premature Infant Pain Profile.

A sigmoid curve describing maturation of morphine clearance is moved to the right in preterm neonates and volume of distribution is increased compared with term neonates. Morphine does not alter the neonatal response to ETT suctioning.

Morphine pharmacokinetics and pharmacodynamics in preterm and term neonates: secondary results from the NEOPAIN trial.

An earlier reported population pharmacokinetic study documented limited predictability of amikacin clearance (65%) at birth. An exercise in the first month of life resulted in extended predictability (92%) with similar clearance estimates after the first postnatal days, reflecting the impact of postnatal age on clearance predictability.

Covariates of amikacin clearance in neonates: the impact of postnatal age on predictability.

CYP2D6 contributes to M1 formation clearance but not to overall tramadol clearance in early neonatal life

ABSTRACT To describe and investigate the covariate effects of cerebrospinal fluid (CSF) amikacin pharmacokinetics in neonates, CSF samples were prospectively collected from neonates in whom amikacin had been initiated before a diagnostic lumbar puncture was performed. CSF analysis (amikacin concentration, white blood count [WBC], glucose content, and protein concentration) and amikacin therapeutic drug monitoring results (peak and trough concentrations) in serum were recorded. Correlations (Spearman rank) between the CSF amikacin concentration and the CSF WBC and glucose and protein concentration were investigated. There were 44 CSF amikacin concentrations and 83 serum samples available from 43 neonates (mean postmenstrual age, 36 weeks [range, 26 to 41 weeks]; mean weight, 2.43 kg [range, 0.87 to 3.86 kg]). The median time interval between initiation of amikacin administration and CSF sampling was 25 h (range, 2.5 to 93.7 h). The median amikacin concentration in the CSF was 1.08 mg/liter (range, 0.34 to 2.65 mg/liter), and the mean trough and peak amikacin concentrations in serum were 3.8 ± 2.5 mg/liter and 35.7 ± 5.9 mg/liter, respectively. A correlation between CSF amikacin and CSF protein contents (P < 0.01, r = 0.41, 95% confidence interval = 0.13 to 0.63) but not between CSF WBC and CSF glucose was documented. A two-compartment (central and CSF) linear disposition model was used to estimate population pharmacokinetics. The half time for equilibration (Teq) between serum and CSF compartments was used as a measure of blood-brain barrier permeability. The Teq was 7.58 h (coefficient of variation [CV] = 49.1%) with a partition coefficient of 0.103 (CV = 26.4%). There was no relationship between the Teq and CSF WBC, CSF glucose content, or CSF protein content.

Cerebrospinal Fluid Compartmental Pharmacokinetics of Amikacin in Neonates

Aim:  We aimed to produce a racemic ketamine manual infusion regimen capable of maintaining a steady‐state blood concentration associated with anesthesia in children aged 1.5–12 years.

Background:  The pharmacokinetics and analgesic effects of intravenous and rectal paracetamol were compared in nonventilated infants after craniofacial surgery in a double‐blind placebo controlled study.

Pharmacokinetics and analgesic effects of intravenous propacetamol vs rectal paracetamol in children after major craniofacial surgery

Data on contributors to between-individual variability in overall tramadol clearance and O-demethyl tramadol (M1) formation in preterm neonates and young infants are limited.

METHODS
A population pharmacokinetic analysis of tramadol and M1 was undertaken using non-linear mixed effects model. Covariate analysis included weight, postmenstrual age (PMA), postnatal age (PNA), creatinaemia, (cardiac) surgery, cardiac defect, and cytochrome (CYP)2D6 polymorphisms, classified by CYP2D6 activity score.

RESULTS
In 57 patients (25-54 weeks PMA), 593 observations were collected. Tramadol clearance was described using a two-compartment, zero-order input, first-order elimination linear model. An additional compartment was used to characterize M1. Tramadol clearance at term age was 17.1 litre h(-1) (70 kg)(-1) (CV, 37.2%). Size (37.8%) and PMA (27.3%) contribute to this variability. M1 formation clearance (CL2M1, i.e. the contribution of M1 synthesis to M clearance) was 4.11 litre h(-1) (70 kg)(-1) (CV, 110.9%) at term age. Size and PMA were the major contributors to the variability (52.7%); the CYP2D6 activity score contributes 6.4% to this variability.

Overall tramadol clearance estimates confirm earlier reports while CL2M1 variability is explained by size, PMA, and CYP2D6 polymorphisms. The CL2M1 is very low in preterm neonates, irrespective of the CYP2D6 polymorphism with subsequent rapid maturation. The slope of this increase depends on the CYP2D6 activity score. The current pharmacokinetic observations suggest a limited micro-opioid receptor-mediated analgesic effect of M1 in preterm neonates and a potential CYP2D6 polymorphism-dependent effect beyond term age.

Background:  The aim of this study was to describe ketamine pharmacodynamics (PD) in children. Adult ketamine concentrations during recovery are reported as 0.74 mg·l−1 (sd 0.24 mg·l−1) with an EC50 for anesthesia of 2 mg·l−1 (sd 0.5 mg·l−1), but pediatric data are few.

Background:  The aim of this study was to describe ketamine pharmacokinetics in children to simulate time–concentration profiles to predict duration of concentrations associated with anesthesia, arousal and analgesia.

Ketamine disposition in children presenting for procedural sedation and analgesia in a children's emergency department

Problems and pitfalls performing pharmacokinetic studies in children

Transdermal fentanyl in childhood and adolescence: a comprehensive literature review.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
*Effects of size, renal function, age (postnatal age, gestational age and postmenstrual age) as predictors of vancomycin clearance in premature neonates are established, but the relative contribution of each component remains poorly quantified, largely because these variables are closely correlated. *We have quantified the covariates contributing to vancomycin clearance population parameter variability in order to establish the major covariates required for dosing predictions. Size, standardized using allometric models, was the primary covariate used in our analysis.

WHAT THIS STUDY ADDS
*Size explained 49.8%, postmenstrual age 18.2% and renal function 14.1% of clearance variability. *Descriptors of the relationship between age and clearance in premature neonates vary. *The use of a variable slope sigmoidal model to describe the relationship between clearance and postmenstrual age predicted an adult clearance of 3.79 l h(-1) 70 kg(-1) (95% confidence interval 2.76, 4.98) from premature neonatal data.

AIM
To identify and quantify factors describing the variability of vancomycin clearance in premature neonates.

METHODS
Population pharmacokinetics were estimated (NONMEM) in 214 neonates [postmenstrual age (PMA) 30.4 weeks, range 24-34 weeks; postnatal age 11.9 days, range 1-27 days; weight 1.30 kg, range 0.42-2.6 kg] using therapeutic drug monitoring data. Covariate analysis included weight, PMA, serum creatinine, use of inotropes or ibuprofen, positive blood culture and respiratory support. A one-compartment linear disposition model with zero order input and first-order elimination was used to describe the data (604 observations).

RESULTS
The population estimate for volume of distribution (V) was 39 l 70 kg(-1) (coefficient of variation 19.4%). Clearance (CL) increased from 0.897 l h(-1) 70 kg(-1) at 24 weeks PMA to 2.02 l h(-1) 70 kg(-1) by 34 weeks PMA. The between-subject variability for CL was 18.6% and the between-occasion variability was 12.2%. The use of ibuprofen reduced clearance, but this effect was attributable to reduced renal function. Overall, 82% of the variability of CL was predictable. Size explained 49.8%, PMA 18.2% and renal function 14.1%. The use of a variable slope sigmoidal model to describe the relationship between clearance and PMA predicted an adult clearance of 3.79 l h(-1) 70 kg(-1) (95% confidence interval 2.76, 4.98).

Size, renal function and PMA are the major contributors to clearance variability in premature neonates. The small (18%) unexplained variability in clearance suggests target concentration intervention is unnecessary if size, age and renal function are used to predict the dose. Extrapolation to an adult clearance from neonatal data is possible using allometric size models and a function describing clearance maturation.

Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance.

Therapeutic catastrophes in neonates such as the grey baby syndrome attributable to chloramphenicol and phocomelia due to thalidomide have shaped modern drug development. Unmonitored off-label use of medicines in neonates and infants, extrapolated from adult data, has resulted in significant morbidity that could have been avoided or minimized by investigation in this population. A surge of interest in developmental pharmacology, methods for scaling paediatric pharmacokinetic (PK) parameters from adult and individual drug studies in children of all ages is improving current drug management in the first year of life. This chapter examines pharmacokinetic and pharmacodynamic (PD) changes after birth, explores common size models and reviews the pharmacology of analgesic drugs commonly used in early infancy.

Background:  Norketamine, a metabolite of ketamine, is an analgesic with a potency one‐third that of ketamine. The aim of this study was to describe norketamine pharmacokinetics in children in order to predict time–concentration profiles for this metabolite after racemic ketamine single dose and infusion administration. The possible analgesic potential resulting from norketamine concentration may then be predicted using simulation.

Modeling the norketamine metabolite in children and the implications for analgesia

Practicality of dose prescriptions in a paediatric intensive care unit

Does growth restriction at birth contribute to the interindividual variability of renal drug clearance in the first month of life

Difficult airway equipment containers are commonly found in operating rooms, but the availability of airway equipment beyond that environment is unknown. Using the Difficult Airway Society (U.K.) and American Society of Anesthesiologists’ guidelines, we conducted an inspection audit of airway equipment at all anaesthetic sites in our region. Staff knowledge about the equipment was assessed and feedback was provided to each site. Eighteen of the 42 sites had an airway container. Equipment for an unexpected difficult intubation, according to the guidelines, was deficient at all sites. Equipment to detect oesophageal intubation was inadequate. Locations remote from the operating suite lacked emergency invasive airway equipment and were, on average, a 4.3 minute walk from the nearest appropriate equipment. Two clinics had no emergency invasive airway equipment. Half of the airway containers with check lists had items missing. One third of the items with an expiry date were expired. Quality control and implementation of airway guidelines could rectify these deficiencies. Anaesthesia organisations should be encouraged to publish detailed equipment guidelines.

Lack of pharmacokinetic information in children leads clinicians to use experience and trial-and-error to determine how best to administer ketamine.

Notwithstanding the prolonged induction time, inability to ventilate the patient in case of apnea ⁄ worsening obstruction was a major concern. The severe cicatrization did not permit the introduction of a nasopharyngeal or oropharyngeal airway. Forceful introduction of a nasopharyngeal airway could result in catastrophic bleeding or entry into a false passage. As we were unsure of the nature ⁄ extent of the intraoral lesion the effectiveness of a jaw thrust maneuver to open a collapsed airway remained at best, unpredictable. We considered the possibility of transtracheal jet ventilation to maintain the oxygenation together with a propofol ⁄ fentanyl infusion while the surgeon released the oral scar sufficiently to allow laryngoscopy and intubation or introduction of an LMA. Jet ventilation in a setting of upper airway obstruction may be risky. Commissurotomy under ketamine anesthesia was an option. Because of uncertainty about the nature ⁄ extent of intraoral scarring and fear of soiling an unprotected airway, we eliminated these options. With the oral and nasal routes inaccessible a surgical airway was the only alternative. Tracheostomy under local anesthesia permits spontaneous ventilation and acceptable oxygenation while a definitive surgical airway is secured. We did not think that this situation warranted an awake tracheostomy. An agitated and combative child could aggravate the obstruction and interfere with surgery. Attempts at venous access may upset the child. However, in the hypercarbic, obtunded child with a hyperdynamic circulation, establishing venous access is relatively simple and appropriate. We chose ketamine because of its minimal effects on the central respiratory drive and airway reflexes (1). Through this case report, we highlight the role of ketamine as a sedative-analgesic in difficult airway situations where spontaneous respiration is to be preserved. We also want to emphasize that speed and safety should be the overriding concerns for a difficult pediatric airway emergency. Rani A Sunder M D , D N B Kumud K Handa M S All India Institute of Medical Sciences, New Delhi, India (email: rani_kannan2000@yahoo.com)

Renal drug clearance in the first month of life: further evidence in support of the Barker hypothesis

Interpretation of analgesic and antipyretic responses documented after paracetamol administration is confused because response is not directly related to concentration in the blood, but rather to an effect compartment. The effect compartment does not have real measurable concentrations, but concentrations equate approximately to those observed in the cerebrospinal fluid. A time delay exists before drug reaches the effect compartment, and the equilibration half-time between the central and effect compartment is described by a single first-order parameter (Teq or T1/2keo), reported to be ∼1 h for paracetamol. Paediatric analgesic studies are limited because they have only explored postoperative pain after tonsillectomy or day-stay surgery. Other pain types and pain confounders have not been investigated. Adult studies are also similarly limited. Studies investigating antipyresis have not explored the maximum response, limiting the precision of any EC50 estimate. The influence of the cyclical nature of fever or initial temperature is seldom accounted for in antipyretic studies. Target effect compartment concentrations of 5 mg/l for fever and 10 mg/l for pain do not seem unreasonable on the basis of current literature. Speed of onset may be shortened by giving a larger initial dose or improving absorption characteristics. Consequent plasma concentration achieved, differences in effect compartment equilibration times, and the shape of the effect compartment concentration–response curve help to explain differences between common analgesic/antipyretic drugs.

Paracetamol (acetaminophen) pharmacodynamics: interpreting the plasma concentration

Background:  There are few data describing clonidine population pharmacokinetics in children (0–15 years) despite common use. Current pediatric data, described in terms of elimination half‐life or Cmax and Tmax, poorly explain variability in drug responses among individuals representative of those in whom the drug will be used clinically.

34th Annual Scientific Meeting of the Association of Paediatric Anaesthetists of Great Britain and Ireland, 8?10 March 2007, Manchester. Clonidine disposition in children: a population analysis

Abstracts: Aminoglycosides and glycopeptides are almost exclusively eliminated by renal excretion. Postmenstrual age (PMA) is the best predictor of their clearance, presumably because it predicts the time course of development of the glomerular filtration rate (GFR). Intrauterine growth restriction has an impact on the normalized weight of the kidney, on the number of nephrons, on GFR, and on tubular function in human perinatal life. We investigated whether prenatal growth also affects clearance of drugs such as aminoglycosides or glycopeptides that are eliminated through the kidney. Observations collected in two population pharmacokinetic studies involving preterm neonates and investigating amikacin and vancomycin in the first month of postnatal life were used to estimate the impact of prenatal growth (as judged by birth weight for gestational age) on the clearance of these drugs. Data from 1212 drug measurements (vancomycin, 648; amikacin, 564) in 531 subjects (vancomycin, 249; amikacin, 282) were available for study. Neonates born small for gestational age (SGA) were found to have a 16.2% (coefficient of variation, 12.2%) reduction in drug clearance. This effect was present from birth up to the postnatal age of 4 weeks. The covariate size (weight0.75) explained 47.3% of drug clearance; PMA, 25.2%; coadministration of a nonselective cyclo-oxygenase inhibitor, 3.5%; renal function, 7.6%; and SGA, 1.7%. Renal drug clearance is significantly lower in preterm neonates born SGA than in appropriate-for-gestational-age (AGA) controls. This reduced clearance was observed not only at birth but also up to the postnatal age of 4 weeks.

Renal Drug Clearance in Preterm Neonates: Relation to Prenatal Growth

Population clinical pharmacology of children: general principles

Antenatal betamethasone and renal drug clearance in preterm neonates

A prospective randomised single blinded study comparing harmonic scalpel tonsillectomy with bipolar tonsillectomy.

Morphine Metabolite Pharmacokinetics during Venoarterial Extra Corporeal Membrane Oxygenation in Neonates

We read with great interest the paper of Dimitriou et al on the impact of antenatal steroids and fluid balance in very low birth weight infants.1 The authors nicely documented the impact of prenatal steroids on insensible water loss and on urine output. However, one should be aware that diuresis, glomerular filtration …

Background : We aimed to identify and quantify major factors describing the variability of levobupivacaine clearance in children.

Age and size are the major covariates for prediction of levobupivacaine clearance in children

Interindividual variability of aminoglycoside pharmacokinetics in preterm neonates at birth

Purpose of review This review explores progress in developmental pharmacokinetics, pharmacogenomics and formulations of analgesic agents, and discusses potential implications for pain therapy. Recent findings Characterization of the developmental pharmacokinetics of morphine, tramadol, paracetamol and nonsteroidal anti-inflammatory drugs has improved dosing in children. Oral sugar solutions have replaced the brandy/sugar pacifier and are effective for single painful events in neonates. Intravenous paracetamol offers increased dosing accuracy, and avoids absorption and bioavailability variability. New nitric-oxide-releasing versions of paracetamol and nonsteroidal anti-inflammatory drugs offer safer alternatives to their parent drugs with enhanced potency. Ketamine has come under a cloud for its possible effects on the neonatal developing brain, but it is being used increasingly in children to supplement opioids for pain after major surgery. Hopes that morphine analgesia may improve neurological outcome in premature babies have not materialized. Reports concerning chronic pain are generally case series and controlled trials are rare and nearly nonexistent in children. Summary Unlicensed drug use in the very young will increase as familiarity increases. Pharmacogenomic studies have the potential to tailor drug therapy to the individual and decrease between-patient variability. Unfortunately, the pharmacodynamic knowledge in children of analgesic agents remains neglected and is usually extrapolated from adult data.

Recent developments in the pharmacological management of pain in children

Population clinical pharmacology of children: modelling covariate effects

Policies and Philosophies Related to Risk Management in the Athletic Setting

The administration of ibuprofen or any other nonselective cyclooxygenase (COX) inhibitor drug in early neonatal life is associated with a reduction of glomerular filtration, which reduces the elimination of drugs dependent on renal function for clearance. However, the relationship between COX inhibitor drug indication (prophylactic or therapeutic) and the magnitude of this effect remains unclear. Observations collected in two population pharmacokinetic studies, in preterm neonates, investigating amikacin and vancomycin were used to estimate: i) the impact of ibuprofen administration on the clearance of these drugs; and ii) the difference between prophylactic and therapeutic administration of ibuprofen on this clearance. Prophylactic administration of ibuprofen to preterm neonates on the first day of life to enhance closure of an asymptomatic patent ductus arteriosus (PDA) reduced amikacin clearance by 21% while coadministration of ibuprofen to induce closure of a symptomatic PDA resulted in an 18% reduction in vancomycin clearance in the first month of postnatal life. A significant and clinically relevant reduction in drug clearance is observed when ibuprofen is coadministered independent of indication, postmenstrual or postnatal age. Population modeling with covariate analyses can provide us with the tools to further disentangle the impact of nonselective COX-inhibitors on renal drug clearance.

Impact of ibuprofen administration on renal drug clearance in the first weeks of life.

Impact of a paediatric vial on the magnitude of systematic medication errors in neonates

Predictability of renal drug clearance of aminoglycosides and glycopeptides in preterm neonates.

AIM
Identify and quantify factors describing variability of amikacin clearance in preterm neonates at birth.

METHODS
Population pharmacokinetics of amikacin were estimated in a cohort of 205 extreme preterm neonates [post conception age (PCA) 27.8, SD 1.8, range 24-30 weeks; weight 1.07, SD 0.34, range 0.45-1.98 kg, postnatal age < 72 h]. Covariate analysis included weight, PCA, Apgar score, prophylactic administration of a nonsteroidal anti-inflammatory drug (NSAID) to the neonate, maternal indomethacin and betamethasone administration, and chorioamnionitis.

RESULTS
A one-compartment linear disposition model with zero order input (0.3 h i.v. infusion) and first-order elimination was used. The population parameter estimate for volume of distribution (V) was 40.2 l per 70 kg. Clearance (CL) increased from 0.486 l h(-1) per 70 kg at 24 weeks PCA to 0.940 l h(-1) per 70 kg by 30 weeks PCA. The population parameter variability (PPV) for CL and V was 0.336 and 0.451. The use of a NSAID (either aspirin or ibuprofen) in the first day of life reduced amikacin clearance by 22%. Overall 65% of the variability of CL was predictable. Weight explained 48%, PCA 15% and NSAIDs 2%.

Size and post-conception age are the major contributors to clearance variability in extreme premature neonates (<31 weeks PCA). The large (35% of total) unexplained variability in clearance reinforces the need for target concentration intervention to reduce variability in exposure to a safe and effective range.

Limited predictability of amikacin clearance in extreme premature neonates at birth.

Do we still need therapeutic drug monitoring for amikacin in preterm neonates

Maturational pharmacokinetics of intravenous tramadol during childhood

Contributors to the variability in amikacin clearance in preterm neonates

Maturational pharmacokinetics of intravenous tramadol: pharmacodynamic relevance

Clinical pharmacologic studies in the neonatal intensive care unit: intravenous paracetamol as a model drug

The history of drug regulation reveals that major advances in legislation within the USA have followed pharmacological disasters in children. After 13 children died in 1901 following exposure to diphtheria toxoid contaminated with tetanus bacilli, the Food and Drug Administration (FDA) introduced legislation to ensure purity and quality of medicines. In 1937, 107 persons, many of whom were children, died from renal failure after ingesting sulfanilamide diluted in diethylene glycol, and subsequently, legislation was enacted to ensure safety testing of medicines. Finally in 1961, thalidomide was recognized as a potent teratogen after many hundreds of children were born with phocomelia. After this, the Kefauver–Harris amendments required that medicines to be tested for efficacy as well as safety.

Tramadol disposition: in vivo assessment of CYP2D6 ontogeny in neonates and children

Background:  The aim of this study was to describe propacetamol pharmacokinetics in children in order to predict concentrations after a standard dosing regimen of propacetamol 30 mg·kg−1 (15 mg·kg−1 paracetamol) 6 h.

Pediatric intravenous paracetamol (propacetamol) pharmacokinetics: a population analysis 1

There are few data describing levobupivacaine pharmacokinetics in infants (<3 months) after caudal administration.

METHODS
An open-label study was undertaken to examine the pharmacokinetics of levobupivacaine 2.5 mg ml(-1), 2 mg kg(-1) in children aged less than 3 months after single-shot caudal epidural administration. Plasma concentrations were determined at intervals from 0.5 to 4 h after injection. A population pharmacokinetic analysis of levobupivacaine time-concentration profiles (84 observations) from 22 infants with mean postnatal age (PNA) 2.0 (range 0.6-2.9) months was undertaken using non-linear mixed effects models (NONMEM). Time-concentration profiles were analysed using a one-compartment model with first-order input and first-order elimination. Estimates were standardized to a 70 kg adult using allometric size models.

RESULTS
Population parameter estimates (between-subject variability) for total levobupivacaine were clearance (CLt) 12.8 [coefficient of variation (CV) 50.6%] litre h(-1) 70 kg(-1), volume of distribution (Vt) 202 (CV 31.6%) litre 70 kg(-1), absorption half-life (Tabs) 0.323 (CV 18.6%) h 70 kg(-1). Estimates for the unbound drug were clearance (CLfree) 104 (CV 43.5%) litre h(-1) 70 kg(-1), volume of distribution (Vfree) 1700 (CV 44.9%) litre 70 kg(-1), absorption half-life (Tabsfree) 0.175 (CV 83.7%) h 70 kg(-1). There was no effect attributable to PNA on CL or V. Time to peak plasma concentration (Tmax) was 0.82 (CV 18%) h. Peak plasma concentration (Cmax) was 0.69 (CV 25%) microg ml(-1) for total levobupivacaine and 0.09 (CV 37%) microg ml(-1) for unbound levobupivacaine.

Clearance in infants is approximately half that described in adults, suggesting immaturity of P450 CYP3A4 and CYP1A2 enzyme isoforms that metabolize levobupivacaine in infants. This lower clearance delays Tmax, which was noted to occur approximately 50 min after administration of caudal epidural levobupivacaine.

Pharmacokinetics of levobupivacaine after caudal epidural administration in infants less than 3 months of age.

Methods. An open-label study was undertaken to examine the pharmacokinetics of levobupivacaine 2.5 mg ml , 2 mg kg 1 in children aged less than 3 months after single-shot caudal epidural administration. Plasma concentrations were determined at intervals from 0.5 to 4 h after injection. A population pharmacokinetic analysis of levobupivacaine time–concentration profiles (84 observations) from 22 infants with mean postnatal age (PNA) 2.0 (range 0.6–2.9) months was undertaken using non-linear mixed effects models (NONMEM). Time–concentration profiles were analysed using a one-compartment model with first-order input and first-order elimination. Estimates were standardized to a 70 kg adult using allometric size models.

REGIONAL ANAESTHESIA Pharmacokinetics of levobupivacaine after caudal epidural administration in infants less than 3 months of age

The aim of this study was to investigate methods of practice, assess skill level, and evaluate attitudes towards fibreoptic intubation in the anaesthetic community of New Zealand. A postal survey questionnaire was sent to all vocationally registered anaesthetists in New Zealand and to all New Zealand anaesthetic trainees registered with the Australian and New Zealand College of Anaesthetists. There were 611 survey questionnaires posted and 386 (63%) respondents. Almost all respondents (98% of specialists, 100% of trainees) had access to fibreoptic equipment in public and 92% of respondents performed fibreoptic intubation. The median number of fibreoptic intubations performed per year was 3 for consultants and 4 for trainees. Respondents were either self taught or colleague taught (82%). Most learnt the technique on patients (92%). There were 14% who considered themselves experienced, 30% competent, 34% adequate and 20% novice. Skills were maintained by clinical patient mix in 73%. Fibreoptic intubation was considered a skill required by all anaesthetists in 87%, and 66% considered it the gold standard for expected difficult airways. Lack of clinical cases requiring the skill and lack of practice were identified as the primary barriers to skill development. Consultants had greater opportunity to learn fibreoptic intubation skills during daily practice than trainees. Only 18% of trainees had a formal airway management program available to them at their place of work. There appears to be a need to increase available opportunities to perform fibreoptic intubation to enable maintenance and improvement of fibreoptic skills in our community. A formalized program of teaching fibreoptic intubation may offer greater opportunity for learning and skill development.

Aims: To review clinical features and outcome of children with severe Staphylococcus aureus sepsis (SAS) presenting to a paediatric intensive care unit (PICU) with particular focus on ethnicity, clinical presentation, cardiac involvement, and outcome. Methods: Retrospective chart review of patients coded for SAS over 10 years (October 1993 to April 2004). Results: There were 58 patients identified with SAS over the 10 year study period; 55 were community acquired. This accounted for 4% of hospital admissions for SAS over this time; children with staphylococcal illness comprised 1% of all admissions to the PICU. Maori and Pacific children with SAS were overly represented in the PICU (81%) from a paediatric population where they contribute 21.6%. Musculoskeletal symptoms (79%) dominated presentation rather than isolated pneumonia (10%). An aggressive search for foci and surgical drainage of infective foci was required in 50% of children. Most children had multifocal disease (67%) and normal cardiac valves (95%); the few children (12%) presenting with methicillin resistant S aureus (MRSA) had community acquired infection. The median length of stay in the PICU was 3 (mean 5.8, SD 7.6, range 1–44) days. The median length of stay in hospital was 15 (mean 21, SD 22.7, range 2–149) days. Mortality due to SAS was 8.6% (95% CI 1.4–15.8%) compared with the overall mortality for the PICU of 6% (95% CI 5.3–6.7%). Ten children had significant morbidity after discharge. Conclusions: Community acquired SAS affects healthy children, is multifocal, and has high morbidity and mortality, in keeping with the high severity of illness scores on admission. It is imperative to look for sites of dissemination and to drain and debride foci. Routine echocardiography had low yield in the absence of pre-existing cardiac lesions, persisting fever, or persisting bacteraemia.

Review of Staphylococcus aureus infections requiring admission to a paediatric intensive care unit

A 4‐month‐old ex‐premature infant with severe airway obstruction from subglottic cysts presented for surgical cyst removal. Laryngeal and tracheal surgical procedures in children may present difficulties for the anesthetist because the airway is shared with the surgeon. We report the use of high‐frequency jet ventilation (HFJV) to maintain ventilation and provide adequate surgical access. Anesthesia was induced using sevoflurane in oxygen and was maintained with intravenous infusions of propofol 7.5 mg·kg−1·h−1 and remifentanil 0.4 μg·kg−1·min−1. The suction channel of the ENT laryngoscope was used to introduce an 8‐FG ureteric drainage catheter into the larynx and this catheter was used to provide HFJV. Obstruction to expiratory flow was a major concern and was dependent on good positioning of the rigid laryngoscope. Complications such as barotrauma, pneumopericardium, CO2‐retention, necrotizing tracheobronchitis, and gastric rupture dictate a fastidious technique.

Jet ventilation for laryngotracheal surgery in an ex‐premature infant

Tramadol is potentially a very useful pain relief medication in neonates and infants. It is primarily metabolized into O-demethyl tramadol (M1) by CYP2D6. Data concerning tramadol disposition and CYP2D6 activity in young infants are not available.

METHODS
A population pharmacokinetic analysis of tramadol and M1 time-concentration profiles was undertaken using non-linear mixed-effects models (NONMEM), based on newly collected data on tramadol and M1 time-concentration profiles in neonates and young infants (n=20) and published studies on intravenous tramadol in children and adults. M1 formation served as a surrogate for CYP2D6 activity.

RESULTS
Tramadol clearance was described using a two-compartment linear model with zero-order input and first-order elimination. Clearance increased from 25 weeks post-conception age (PCA) (5.52 litre h(-1) [70 kg](-1)) to reach 84% of the mature value by 44 weeks PCA (standardized to a 70 kg adult using allometric '1/4 power' models). The central volume of distribution decreased from 25 weeks PCA (256 litre [70 kg](-1)) to reach 120% of its mature value by 87 weeks PCA. Formation clearance to M1 contributed 43% of tramadol clearance, but had no relationship with PCA. There was a weak non-linear relationship between PCA and M1 metabolite clearance.

Maturational clearance of tramadol is almost complete by 44 weeks PCA. A target concentration of 300 microg litre(-1) is achieved after a bolus of tramadol hydrochloride 1 mg kg(-1) and can be maintained by infusion of tramadol hydrochloride 0.09 mg kg(-1) h(-1) at 25 weeks PCA, 0.14 mg kg(-1) h(-1) at 30 weeks PCA, 0.17 mg kg(-1) h(-1) at 35 weeks PCA, 0.18 mg kg(-1) h(-1) at 40 weeks, 0.19 mg kg(-1) h(-1) at 50 weeks PCA to 1 yr, 0.18 mg kg(-1) h(-1) at 3 yr and 0.12 mg kg(-1) h(-1) in adulthood. CYP2D6 activity was observed as early as 25 weeks PCA, but the impact of CYP2D6 polymorphism on the variability in pharmacokinetics, metabolism and pharmacodynamics of tramadol remains to be established.

Tramadol disposition in the very young: an attempt to assess in vivo cytochrome P-450 2D6 activity.

Morphine pharmacokinetics during venoarterial extracorporeal membrane oxygenation in neonates

Descriptions of the pharmacokinetics and metabolism of morphine and its metabolites in young children are scant. Previous studies have not differentiated the effects of size from those related to age during infancy.

METHODS
Postoperative children 0-3 yr old were given an intravenous loading dose of morphine hydrochloride (100 micro g kg(-1) in 2 min) followed by either an intravenous morphine infusion of 10 micro g h(-1) kg(-1) (n=92) or 3-hourly intravenous morphine boluses of 30 micro g kg(-1) (n=92). Additional morphine (5 micro g kg(-1)) every 10 min was given if the visual analogue (VAS, 0-10) pain score was >/=4. Arterial blood (1.4 ml) was sampled within 5 min of the loading dose and at 6, 12 and 24 h for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). The disposition of morphine and formation clearances of morphine base to its glucuronide metabolites and their elimination clearances were estimated using non-linear mixed effects models.

RESULTS
The analysis used 1856 concentration observations from 184 subjects. Population parameter estimates and their variability (%) for a one-compartment, first-order elimination model were as follows: volume of distribution 136 (59.3) litres, formation clearance to M3G 64.3 (58.8) litres h(-1), formation clearance to M6G 3.63 (82.2) litres h(-1), morphine clearance by other routes 3.12 litres h(-1) per 70 kg, elimination clearance of M3G 17.4 (43.0) litres h(-1), elimination clearance of M6G 5.8 (73.8) litres h(-1). All parameters are standardized to a 70 kg person using allometric 3/4 power models and reflect fully mature adult values. The volume of distribution increased exponentially with a maturation half-life of 26 days from 83 litres per 70 kg at birth; formation clearance to M3G and M6G increased with a maturation half-life of 88.3 days from 10.8 and 0.61 litres h(-1) per 70 kg respectively at birth. Metabolite formation decreased with increased serum bilirubin concentration. Metabolite clearance increased with age (maturation half-life 129 days), and appeared to be similar to that described for glomerular filtration rate maturation in infants.

M3G is the predominant metabolite of morphine in young children and total body morphine clearance is 80% that of adult values by 6 months. A mean steady-state serum concentration of 10 ng ml(-1) can be achieved in children after non-cardiac surgery in an intensive care unit with a morphine hydrochloride infusion of 5 micro g h(-1) kg(-1) at birth (term neonates), 8.5 micro g h(-1) kg(-1) at 1 month, 13.5 micro g h(-1) kg(-1) at 3 months and 18 micro g h(-1) kg(-1) at 1 year and 16 micro g h(-1) kg(-1) for 1- to 3-yr-old children.

Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children.

Paracetamol (acetaminophen) and the nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in children for antipyresis and analgesia. The anti-inflammatory properties of the NSAIDs have, in addition, been used in such diverse disorders as juvenile idiopathic arthritis, Kawasaki disease and cystic fibrosis (1–4). The NSAIDs indomethacin and ibuprofen are also used to treat delayed closure of patent ductus arteriosus (PDA) in premature infants (5). Paracetamol and NSAIDs are often given together for the management of pain or fever. Despite the widespread use of these medications there are few data comparing efficacy of these drugs. The combined effectiveness of paracetamol and a NSAID is insufficiently documented in children and it is unknown if there is synergy or additivity of effect when the two drugs are used together. Litalien and Jacqz-Aigrain (6) have recently reviewed the risks and benefits of NSAIDs and paracetamol in children. Knowledge of individual drug pharmacokinetics (PK) and pharmacodynamics (PD) is essential to compare effectiveness. Pharmacokinetic age-related changes and covariate effects are poorly documented for many of the NSAIDs. Pharmacodynamic data are often a simple comparison of one drug to another without quantifying effect. There is a paucity of analgesia concentration–effect relationship data in children, although fever control (7–10) and PDA closure (11) relationships are emerging. In order to use these drugs properly, effectiveness data must be balanced against the drugs safety profiles. Currently this is not carried out and often the safety profile of one NSAID is extrapolated to another. This current review examines the methods used to compare NSAIDs with paracetamol, the difficulties associated with such comparisons and the impact of drug side effects on dosing regimens in children.

Background : Data concerning metabolism of diclofenac in children are limited to intravenous and enteric coated oral formulations. There are no data examining diclofenac or its hydroxyl metabolite pharmacokinetics after rectal administration in children.

Infants are at risk of apnea in the postoperative period and during respiratory illnesses such as bronchiolitis, because of immature respiratory control. The methylxanthines, caffeine and theophylline, have been used to manage apnea of prematurity in neonatal intensive care units and to manage some term infants with idiopathic apnea. The use of these drugs has extended into pediatric intensive care and postanesthetic care. In this review, we discuss the evidence for the use of methylxanthines in premature infants, ex-premature infants, and infants born at term, and how this applies to both postanesthetic care and the management of apnea associated with bronchiolitis in intensive care units. The pharmacokinetic profile of the methylxanthines changes with age and we also discuss the clinical and dosing implications of maturing renal and hepatic clearance.

Methylxanthines for the treatment of apnea associated with bronchiolitis and anesthesia

A commentary on the paper by Allegaert et al 

Neonatal analgesia is a humane consideration, and paracetamol offers a reasonable alternative for mild to moderate pain. The investigation of propacetamol, an intravenous prodrug of paracetamol (acetaminophen), in premature neonates after intravenous administration has received scant attention. We might expect propacetamol to offer advantages clinically because a plasma target concentration can be rapidly attained and variability due to absorption kinetics and relative bioavailability is reduced. In addition, an intravenous drug offers a cleaner pharmacokinetic study that can further our knowledge of paracetamol pharmacokinetics in premature and term neonates.1–5 Allegaert et al are to be congratulated for investigating propacetamol use in premature neonates. Neonatal pharmacokinetic studies are fraught with pitfalls.

Clearance often increases rapidly after birth (postnatal age) no matter what the gestational age at birth. This study gets around this …

Pharmacokinetic (PK) studies in neonates and young children have sometimes been assumed less relevant than clinical studies for pediatric anesthetists; this, despite the earlier disasters of circulatory collapse associated with chloramphenicol and kernicterus after sulphonamides in premature neonates. More recently, acknowledgement of the rapid development of withdrawal symptoms following prolonged administration of fentanyl in infants (1) and bupivacaine toxicity in this age group has spurred renewed interest in PK studies. Safe continuous bupivacaine epidural infusion rates 0.2–0.25 mg kg 1 h 1 in neonates and 0.4–0.5 mg kg 1 h 1 in children were empirically derived in 1992 (2) following analysis of 10 case reports of young children suffering convulsions during continuous epidural infusion (3,4). These empirically derived rates in children and neonates result in steady state concentrations of about 1 mg l 1 and follow age-related clearance changes (5). There was increased interest in neonatal total and unbound bupivacaine clearance determinations after these neonatal toxicity reports (6–8). In contrast, ropivacaine PK studies in children and neonates (9–16) swiftly followed ropivacaine’s introduction into pediatric clinical practice, reflecting lessons learned from our experience with bupivacaine. Rapp et al. (17) report neonatal unbound ropivacaine PK using a complex PK population analysis technique in this current issue of Pediatric Anesthesia. The purpose of any PK study is to gain data, which can guide safe and efficient dosing of drugs for future patients. The usual way to do this is by studying discrete groups of patients who differ from each other in one particular aspect. In traditional PK studies an empirical mathematical model is defined to describe the plasma concentration time course after drug administration for each particular individual. The individual structural parameters are then treated as variables and subsequently summarized across individuals using statistical parameters (usually sample mean and standard deviation). However, models such as this ‘standard two-stage’ approach may be flawed because they imply that interindividual variability does not occur. Size and age may account for a large portion of this interindividual variability in children, with important implications for dosing. In an effort to improve parameter and covariate estimates, PK and PD (pharmacodynamic) population analyses have acquired increased sophistication that have also allowed us to interpret complex multicompartment PK models and concentration– response relationships (18). Nonlinear mixed effects modeling is one method for interpreting such data. These mixed effects models can be approached through a variety of statistical and computational techniques. The method that has been around the longest and has been implemented in the most flexible software program to date is NONMEM (19); the method used by Rapp et al. (17) It must be remembered that PK models are mathematical constructions that try to mimic reality. They do not necessarily reflect true physiology and consequently do have limitations. Mixed effects models are ‘mixed’ because they describe the data using a mixture of fixed and random effects. Fixed effects are under the control of the investigator (e.g. the time of measurement) while random effects describe the variability in the measurements within or between subjects. The power of Correspondence to: Brian J. Anderson PhD FANZCA FJFICM, Department of Anaesthesiology, University of Auckland, New Zealand (email: briana@adhb.govt.nz). Pediatric Anesthesia 2004 14: 713–715

Intravenous paracetamol (propacetamol) pharmacokinetics in term and preterm neonates

Nonsyndromal dysgnathia is a rare disorder with a probable genetic basis characterized by a hypoplastic or absent mandible (agnathia), microstomia, microglossia, and ear anomalies secondary to a defect in the ventral portion of the first branchial arch caused by defective neural crest migration or proliferation. Dysgnathic newborn infants often suffer fatal respiratory failure from airway obstruction. Nineteen children with isolated dysgnathia complex are described in the literature – six were stillborn, eight died shortly after birth, and only five survived infancy. All survivors required tracheostomy to maintain an airway. It is difficult to intubate the trachea of these children and early airway management planning is important. We report a neonate who presented with a prenatal ultrasound diagnosis of severe micrognathia, polyhydramnios and a family history of severe micrognathia. Airway management was achieved with fiberoptic intubation through a laryngeal mask airway (LMATM) during an ex utero intrapartum treatment procedure. Fiberoptic intubation was hampered by copious amounts of amniotic fluid. This child and her sibling are the first two siblings with isolated dysgnathia complex to have survived infancy and provide further support for a genetic basis to this condition.

Airway management during an EXIT procedure for a fetus with dysgnathia complex

BACKGROUND/PURPOSE
There are few reports describing the surgical management and outcome of children suffering purpura fulminans secondary to meningococcal sepsis. New Zealand is in the grips of a meningococcal epidemic, and, with the attendant sequalae of the disease process, the authors sought to formally review the children who have required surgical involvement.

METHODS
A retrospective case review of children with the sequalae of meningococcal disease presenting to the Orthopedic and Plastic Surgical Units in a university teaching hospital was undertaken.

RESULTS
There were 117 procedures in 21 children performed over a 12-year period. Surgical management was separated into 2 phases-early and late. The mean delay from admission with acute sepsis to the first surgical procedure (ie, early intervention) was 15.9 days. Debridement and autologous skin grafting was the mainstay of managing the necrotic defects; however, allograft skin proved a useful adjunct as a physiologic dressing. Local flaps were used with deep defects down to bone, but in the extremities amputation to viable tissue was required once gangrene was demarcated. Amputations were carried out in 9 of 21 children. Late interventions were related to relief of contractures or fibula overgrowth causing stump ulceration. Clinical follow-up showed that all children interviewed over 5 years of age (9 children) attend ordinary regular school classes and were physically active within the context of their physical disabilities.

The data would suggest that children requiring surgery for purpura fulminans achieve age-appropriate milestones and are primarily limited by their physical disability related to amputations, scarring, and abnormal bone growth.

Surgical interventions in children with meningococcal purpura fulminans--a review of 117 procedures in 21 children.

Acetaminophen developmental pharmacokinetics in premature neonates were described through infancy to suggest age-appropriate dosing regimens. A population pharmacokinetic analysis was made of acetaminophen time–concentration profiles in 283 children (124 aged 6 mo or less) reported in 6 studies that were undertaken using nonlinear mixed-effects models. Neonates and infants were given either mixed or multiple doses of four different formulations: oral elixir, rectal solution, or triglyceride or capsular suppository. The median postnatal age of children younger than 6 mo was 1 day (range, birth to 6 mo), median postconception age was 40 wk (range, 28–64 wk), and the median weight was 3.1 kg (range, 1.9–9.0 kg). Population pharmacokinetic parameter estimates and their percentage of variability for a one-compartment model with first-order input, lag time, and first-order elimination were as follows: volume of distribution, 66.6 L (20%); clearance, 12.5 L/hr (44%); standardized to a 70-kg person using allometric “1/4 power” models. The volume of distribution decreased exponentially with a maturation half-life of 11.5 wk from 109.7 L/70 kg at 28 wk after conception to 72.9 L/kg by 60 wk. Clearance increased from 28 wk after conception to 72.9 L/hr/70 kg by 60 wk. Clearance increased from 28 wk after conception (0.74 L/hr/70 kg) with a maturation half-life of 11.3 wk to reach 10.8 L/hr/70 kg by 60 wk. The absorption half-life for the oral elixir preparation was 0.21 hr (120%) with a lag time of 0.42 hr (70%), but absorption was further delayed (2 hr) in premature neonates during the first few days of life. Absorption half-life parameters for the triglyceride base and capsule suppositories were 0.80 hr (100%) and 1.4 hr (57%), respectively. The absorption half-life for the rectal solution was 0.33 hr. Absorption lag time was negligible by the rectal route for all three formulations. The bioavailability of the capsule suppository relative to elixir decreased with age from 0.92 (22%) at 28 wk after conception to 0.86 (35%) at 2 yr of age, whereas the triglyceride base decreased from 0.86 (35%) at 28 wk after conception to 0.5 at 2 yr of age. The relative bioavailability of the rectal route was 0.66. A mean steady-state target concentration greater than 10 mg/L at trough can be attained with an oral dose of 25 mg/ kg/day in premature neonates at 30 wk after conception, 45 mg/kg/day at 34 wk’ gestation, 60 mg/kg/day at term, and 90 mg/kg/ day at 6 mo. of age. The relative rectal bioavailability is formulation dependent and decreases with age. Similar concentrations can be attained with maintenance rectal doses of 25 (capsule suppository) or 30 (triglyceride suppository) mg/kg/day in premature neonates at 30 wk’ gestation, increasing to 90 (capsule suppository) or 120 (triglyceride suppository) mg/kg/day at 6 mo. These regimens may cause hepatotoxicity in some persons if used for longer than 2 to 3 days.

Summary Single‐lung anaesthesia for thoracotomy is usually achieved with endobronchial intubation, a double‐lumen tube or an endobronchial blocker. High‐frequency jet ventilation (HFJV) is seldom described for thoracotomy in children, although it is used for both laryngology procedures in the operating room and as a ventilation mode in intensive care. HFJV was used in three children, aged 10–12 years, who presented for scoliosis correction involving thoracotomy. The jet ventilation catheter was passed through a tracheal tube to reduce the risk of outflow obstruction and allow a smooth conversion to intermittent positive‐pressure ventilation when required. Mean airway pressures measured at the tip of the HFJV catheter were at or below 4 cmH2O. Surgical opening of the nondependent lung pleura resulted in sufficient collapse of the pulmonary parenchyma with the patient in the lateral decubitus position for the surgical procedure. Arterial blood gas analyses performed during thoracotomy were within normal limits, with no CO2 retention. HFJV is an alternative ventilation strategy for thoracotomy in children because of its unique ability to deliver small tidal volumes at low mean airway pressures via a narrow catheter.

The effects of analgesia in the vulnerable infant during the perinatal period.

Children remain therapeutic orphans (3±6) and the lack of well-conducted pharmacokinetic±pharmacodynamic studies is often replaced by extrapolation from adult or animal data. Size models play a signi®cant role in determining drug doses for young children, but it is important to appreciate their limitations. This review examines three size models in an attempt to improve understanding of their role, the pharmacokinetic interpretations they have generated and the pitfalls associated with their use. Boxenbaum (7) claims that, generally speaking, there are two extremes of scienti®c personality types: sharpeners and levellers. Sharpeners, highly attuned to system differences and nuances, and always alert to distinctions, try hard to let nothing slip by them unnoticed. Levellers, on the other hand, attempt to submerge system differences, reveal uniform patterns, and condense disparate elements (7). In this review, we have assumed the role of the leveller. More in depth reviews of these size models are available in the literature (8±11).

Scaling for size: some implications for paediatric anaesthesia dosing

Introduction  Glucuronidation is immature in neonates and sulphation is the dominant metabolic pathway (glucuronide/sulphate 0.34). Adult glucuronide/sulphate ratios (+2) are believed to occur at 12 years (1). Different UDP-glucuronosyltransferases, the rate-limiting enzyme in neonates, mature at different rates: that responsible for bilirubin metabolism, for example, within the first 3 months of life. These enzymes are regulated not only by ontogenic, but also by genetic processes. Paracetamol clearance approaches adult rates at 1 year, when standardised to an allometric 3/4 power model (2). Urinary metabolites in 11-month-old children were investigated to determine metabolic pathway predominance at this age for paracetamol. 
 
Methods  Ethical committee approval was granted and informed consent from parents/caregivers was obtained for each study child. Children (n = 158) nursed in PICU after craniosyntosis surgery were given regular paracetamol (LD 40 mg/kg, MD 20 mg·kg−1 6–8 h over 24 h). Serial serum concentrations were measured in 150 children (3). Urine was collected at 3 h intervals for 24 h and assayed for paracetamol, paracetamol glucuronide and paracetamol sulphate in 15 children. 
 
Data were analysed using differential equations for a 7 compartment model with the first order conditional estimate method using ADVAN 6, Tol = 5 of NONMEM V. Data were pooled with another study (2) to characterise oral bioavailability. 
 
Results  Children had a mean age 11.8 SD 2.6 months and weight 9.1 SD 1.9 kg. Oral paracetamol bioavailability was low compared to rectal. due to nasogastric loss and vomiting. Sulphate metabolite clearance was 2.85 l·h−1·70kg−1 while glueuronide metabolite clearance was 6.07 l·h−1·70kg−1. Unmetabolised paracetamol urinary clearance (3.65 l·h−1·70kg−1) was unexpectedly large and was related to urine production with an exponential function. We were unable to estimate other metabolite (e.g. mercaptopurine/cysteine metabolites from glutathione) clearances. 
 
Discussion  The glucuronide/sulphate ratio of approximately 2 that is described in children aged 12 years (1) was reached by the age of 1 year. Earlier reports suggested that this ratio be attained slowly during childhood. Our data suggests that maturation of the glucuronide system for paracetamol is more rapid during the first year than previously assumed.

Summary Urinary retention occurring after caudal anaesthesia in children has a low incidence. Most children will void within 12 h of surgery, although the incidence of retention is higher after hypospadias repair. However, overdistention causing bladder atony that is temporary, or may become permanent, is described in adults. Long‐term effects of overdistention in children have not been described. Urine volume, used to describe overdistention, is traditionally measured after catheterization.

Use of ultrasound bladder monitoring in children after caudal anaesthesia

Background The aim of this study was to describe acetaminophen developmental pharmacokinetics in premature neonates through infancy to suggest age-appropriate dosing regimens. Methods A population pharmacokinetic analysis of acetaminophen time–concentration profiles in 283 children (124 aged ≤ 6 months) reported in six studies was undertaken using nonlinear mixed-effects models. Neonates and infants were given either single or multiple doses of four different formulations: oral elixir, rectal solution, or triglyceride or capsular suppository. The median postnatal age of children younger than 6 months was 1 day (range, birth to 6 months), median postconception age was 40 weeks (range, 28–64 weeks), and median weight was 3.1 kg (range, 1.2–9.0 kg). Results Population pharmacokinetic parameter estimates and their variability (percent) for a one-compartment model with first-order input, lag time, and first-order elimination were as follows: volume of distribution, 66.6 l (20%); clearance, 12.5 l/h (44%); standardized to a 70-kg person using allometric “1/4 power” models. The volume of distribution decreased exponentially with a maturation half-life of 11.5 weeks from 109.7 l/70 kg at 28 weeks after conception to 72.9 l/70 kg by 60 weeks. Clearance increased from 28 weeks after conception (0.74 l · h−1 · 70 kg−1) with a maturation half-life of 11.3 weeks to reach 10.8 l · h−1 · 70 kg−1 by 60 weeks. The absorption half-life for the oral elixir preparation was 0.21 h (120%) with a lag time of 0.42 h (70%), but absorption was further delayed (2 h) in premature neonates in the first few days of life. Absorption half-life parameters for the triglyceride base and capsule suppositories were 0.80 h (100%) and 1.4 h (57%), respectively. The absorption half-life for the rectal solution was 0.33 h. Absorption lag time was negligible by the rectal route for all three formulations. The bioavailability of the capsule suppository relative to elixir decreased with age from 0.92 (22%) at 28 weeks after conception to 0.86 at 2 yr of age, whereas the triglyceride base decreased from 0.86 (35%) at 28 weeks postconception to 0.5 at 2 yr of age. The relative bioavailability of the rectal solution was 0.66. Conclusions A mean steady state target concentration greater than 10 mg/l at trough can be achieved by an oral dose of 25 mg · kg−1 · d−1 in premature neonates at 30 weeks’ postconception, 45 mg · kg−1 · d−1 at 34 weeks’ gestation, 60 mg · kg−1 · d−1 at term, and 90 mg · kg−1 · d−1 at 6 months of age. The relative rectal bioavailability is formulation dependent and decreases with age. Similar concentrations can be achieved with maintenance rectal doses of 25 (capsule suppository) or 30 (triglyceride suppository) mg · kg−1 · d−1 in premature neonates at 30 weeks’ gestation, increasing to 90 (capsule suppository) or 120 (triglyceride suppository) mg · kg−1 · d−1 at 6 months. These regimens may cause hepatotoxicity in some individuals if used for longer than 2–3 days.

Acetaminophen Developmental Pharmacokinetics in Premature Neonates and Infants: A Pooled Population Analysis

The objective of the study was to demonstrate a decreased incidence of postoperative nausea and vomiting (PONV) in children through the use of an antiemetic protocol. PONV was recorded in children (1.5–15 years) after inpatient surgery under general anaesthesia in a prospective, interview based survey. Group 1 consisted of children having surgery 1 month before the introduction of a formalized antiemetic protocol and group 2, 2 months after its introduction. Data were collected over a 1‐month period in each group. Outcome measures of nausea, emesis, antiemetic requirement and patient satisfaction were monitored for the first 24‐h postoperative period. There were 272 children enrolled: 138 in group 1 and 134 in group 2. There was a difference between the two groups for gender (P=0.03), type of surgery (P=0.017), perioperative opioid (P=0.003) and perioperative antiemetic use (P=0.024). However, multivariate analysis did not demonstrate an impact on outcome from these factors. The incidence of postoperative nausea (PON) and postoperative vomiting (POV) following the introduction of the protocol was 36% and 34%, respectively. Moderate to severe nausea was decreased after introduction of the protocol (18% versus 9%, P=0.028) but moderate to severe vomiting failed to reach significance (19% versus 11%, P=0.078). The proportion of children who had repeated nausea decreased after the introduction of the protocol (17% versus 8%, P=0.02) but repeated episodes of vomiting remained unchanged (19% versus 14%). This was attributed to a significant increase in antiemetic prescribing by protocol in group 2 (10% versus 59%, P < 0.001). Patient satisfaction was high in both groups (85% versus 90%). The introduction of a postoperative antiemetic protocol improved prescribing frequency. This resulted in a decreased incidence of moderate to severe PON and a reduction in the number of patients with repeated nausea.

Impact of an antiemetic protocol on postoperative nausea and vomiting in children

Acetaminophen analgesia in children: placebo effect and pain resolution after tonsillectomy

The effect of intraoperative airway management on postoperative vomiting after tonsillectomy is unknown. Logistic regression was used in a retrospective study to investigate the effect of the laryngeal mask airway (LMA) on a morphine dose–vomiting response curve. Charts were reviewed in 351 children in whom the airway was managed with either a LMA (n=177) or a tracheal tube (n=174). A mean perioperative morphine dose of 0.10 mg·kg−1 (SD 0.09) was used in 248 children and a further 103 children were given no opioid. One hundred and eighteen of these 248 children vomited (47.6%) compared to 14 of 103 children given no morphine (13.6%). The probability of vomiting was related to morphine dose using logistic regression with both a linear and an Emax model. Both the calibration (Hosmer–Lemishow goodness of fit chi‐squared test λ2, P=0.81) and discrimination (area under the receiver operating characteristic plot, AUC ROC=0.67) of the Emax model were better than the linear model (λ2, P=0.49; AUC ROC=0.64). Pharmacodynamic parameter estimates for the Emax model were P0 (the baseline probability of vomiting) 0.139, Pmax (the maximal probability of vomiting due to morphine) 0.96, ED50 (morphine dose that induces an effect equivalent to 50% of the logit Pmax) 0.09 mg·kg−1. The probability of vomiting was 50% after morphine 0.125 mg·kg−1. The use of the LMA had no effect on this dose–response curve. A covariate analysis investigating propofol for induction or isoflurane for the intraoperative maintenance of anaesthesia, however, showed that both drugs shifted the curve to the right. The probability of vomiting was 50% after morphine 0.17 mg·kg−1 and 0.21 mg·kg−1 for the isoflurane and propofol use curves, respectively. The concomitant use of propofol and isoflurane, but not the use of the LMA, decreases the probability of vomiting due to morphine.

Investigations using logistic regression models on the effect of the LMA on morphine induced vomiting after tonsillectomy

A dose-response curve for intravenous morphine and vomiting was investigated in children having day-stay tonsillectomy. A retrospective chart review was performed for the 164 children fulfilling the inclusion criteria. Morphine (mean 0.09 mg/kg SD 0.05) was used in 108 children in the perioperative period and a further 56 children were given no opioid. Fifty-five of these 164 children vomited and 20 children required an overnight stay in hospital because of vomiting. The probability of vomiting or overnight stay in hospital was related to morphine dose (by logistic regression). The overall probability of vomiting after morphine 0.1 mg/kg was 50% and the probability of admission for vomiting with this dose was 10%. Pharmacodynamic parameter estimates for postoperative vomiting were P0 (the baseline probability of vomiting, with no opioid) 0.115, Pmax (the maximal probability of vomiting due to morphine) 0.997, ED50 (morphine dose that induces an effect equivalent to 50% of the logit Pmax) 0.18 mg/kg. Parameter estimates for overnight stay because of vomiting after morphine administration were P0 0.038, Pmax 0.999, ED50 0.369 mg/kg. Satisfactory postoperative analgesia in children has been reported with morphine 0.05 to 0.15 mg/kg. Doses above 0.1 mg/kg are associated with a greater than 50% incidence of vomiting. Our data suggests that lower doses of morphine are associated with a decreased incidence of emesis after tonsillectomy in children.

The Dose-Effect Relationship for Morphine and Vomiting after Day-Stay Tonsillectomy in Children

AIMS
The aims of this study were to describe paracetamol pharmacokinetics in neonates and infants.

METHODS
Infants in their first 3 months of life (n = 30) were randomised to sequentially receive one of three paracetamol formulations (dose 30-40 mg kg-1) over a 2 day period. The formulations were (a) elixir, (b) glycogelatin capsule suppository and (c) triglyceride base suppository. Approximately six blood samples were taken after each dose over the subsequent 10-16 h. Data were analysed using a nonlinear mixed effect model. These neonatal and infant data were then included with data from four published studies of paracetamol pharmacokinetics (n = 221) and age-related pharmacokinetic changes investigated.

RESULTS
Population pharmacokinetic parameter estimates and their coefficients of variation (CV%) for a one compartment model with first order input, lag time and first order elimination were volume of distribution 69.9 (18%) l and clearance 13.0 (41%) l h-1 (standardized to a 70 kg person). The volume of distribution decreased exponentially with a half-life of 1.9 days from 120 l 70 kg-1 at birth to 69.9 l 70 kg-1 by 14 days. Clearance increased from birth (4.9 l h-1 70 kg-1) with a half-life of 3.25 months to reach 12.4 l h-1 70 kg-1 by 12 months. The absorption half-life (tabs) for the oral preparation was 0.13 (154%) h with a lag time (tlag) of 0.39 h (31%). Absorption parameters for the triglyceride base and capsule suppositories were tabs 1.34 (90%) h, tlag 0.14 h (31%) and tabs 0.65 (63%) h, tlag 0.54 h (31%), respectively. The tabs for elixir and capsule suppository in children under 3 months were 3.68 and 1.51 times greater than children over 3 months. The relative bioavailability of rectal formulations compared with elixir were 0.67 (30%) and 0.61 (23%) for the triglyceride base and capsule suppositories, respectively.

Total body clearance of paracetamol at birth is 62% and volume of distribution 174% that of older children. A target concentration above 10 mg l-1 in approximately 50% subjects can be achieved by a dose from 45 mg kg-1 day-1 at birth and up to 90 mg kg-1 day-1 in 5-year-old children. A reduced dose of 75 mg kg-1 day-1 in an 8-year-old child is sufficient because clearance is a nonlinear function of weight.

A model for size and age changes in the pharmacokinetics of paracetamol in neonates, infants and children.

The effect preoperative paracetamol elixir has on gastric contents is unknown. Children presenting for elective adenotonsillectomy were randomized to receive either paracetamol elixir (40 mg·kg−1) 90 min before surgery or paracetamol suppositories (40 mg·kg−1) intraoperatively. Following induction of anaesthesia a 16 Fr multiple‐oriface orogastric tube was passed into the stomach and measure taken of the residual gastric volume and pH. The children had a mean age of 8.5 years ( SD 3.2) with a weight of 35 kg ( SD 16.5). Children given elixir (n=41) had a mean residual gastric volume of 0.083 ml·kg−1 (95% CI; 0.006, 1.24) and a pH of 1.83 (95% CI; 0.75, 4.49), while those given suppositories (n=40) had a mean residual gastric volume of 0.083 ml·kg−1 (95% CI; 0.008, 0.9) and a pH of 2.07 (95% CI; 0.84, 5.12). There was no significant difference between these two groups. Paracetamol elixir is rapidly absorbed in the gastrointestinal system of children and preoperative administration has no effect on gastric contents. Given paracetamol's slow equilibration rate constant from the central to the effect compartment, children may be given this medication preoperatively for routine surgical procedures.

Effect of preoperative paracetamol on gastric volumes and pH in children

Predicting concentrations in children presenting with acetaminophen overdose.

Pharmacokinetics and the drugs used in pediatric regional anesthesia

BackgroundThere are no adequate pharmacodynamic data relating concentrations of acetaminophen in serum to analgesia.MethodsChildren undergoing outpatient tonsillectomy were administered acetaminophen either orally, 0.5-1.0 h preoperatively (n = 20), or per rectum at induction of anesthesia (n = 100)

Perioperative Pharmacodynamics of Acetaminophen Analgesia in Children

Drug administration errors are common in infants. Although the infant population has a high exposure to drugs, there are few data concerning pharmacokinetics or pharmacodynamics, or the influence of paediatric diseases on these processes. Children remain therapeutic orphans. Formulations are often suitable only for adults; in addition, the lack of maturation of drug elimination processes, alteration of body composition and influence of size render the calculation of drug doses complex in infants. The commonest drug administration error in infants is one of dose, and the commonest hospital site for this error is the intensive care unit. Drug errors are a consequence of system error, and preventive strategies are possible through system analysis. The goal of a zero drug error rate should be aggressively sought, with systems in place that aim to eliminate the effects of inevitable human error. This involves review of the entire system from drug manufacture to drug administration. The nuclear industry, telecommunications and air traffic control services all practise error reduction policies with zero error as a clear goal, not by finding fault in the individual, but by identifying faults in the system and building into that system mechanisms for picking up faults before they occur. Such policies could be adapted to medicine using interventions both specific (the production of formulations which are for children only and clearly labelled, regular audit by pharmacists, legible prescriptions, standardised dose tables) and general (paediatric drug trials, education programmes, nonpunitive error reporting) to reduce the number of errors made in giving medication to infants.

Common errors of drug administration in infants: causes and avoidance.

A 37-year-old 91 kg man presented with features of Ludwig's angina. Anaesthesia for incision and drainage of his submandibular abscess was undertaken by two specialist anaesthetists with an otorhinolaryngological surgeon prepared for immediate tracheostomy. After preoxygenation, gas induction with sevoflurane in oxygen was followed by a gush of pus into the oral cavity and laryngospam causing acute upper airway obstruction. This resolved with 25 mg of suxamethonium and an endotracheal tube was passed into the trachea with difficulty. Options for management of the difficult airway in Ludwig's angina are discussed.

The elimination of caffeine was investigated in a 1860 g, 31 week gestation neonate, following the accidental administration of a 160 mg.kg−1 dose. The first serum concentration measured was 217.5 mg.l−1 at 36.5 h after dosing. Fitting of time-concentration data was performed using non-linear regression with MKMODEL. A first order elimination model was superior to a mixed order model. Parameter estimates were: clearance 0.01 l.h−1, volume of distribution 1.17 litres, elimination half-life 81 h. Toxic manifestations included hypertonia, sweating, tachycardia, cardiac failure, pulmonary oedema and metabolic disturbances (metabolic acidosis, hyperglycaemia and creatine kinase elevation). An unusual feature of this infant's illness course was gastric dilatation. These signs resolved by day 7 at a serum concentration of 60–70 mg.l−1. Caffeine clearance has traditionally been reported as either an absolute value or as directly proportional to body weight. The per kilogram model gives an erroneous impression that clearance is greatest in early childhood and then decreases with age until adult rates are reached in late adolescence. Age-related clearance values reported in the literature were reviewed using an allometric 3/4 power model. This size model demonstrates that clearance increases in infancy and reaches adult rates within the first three months of life.

Caffeine Overdose in a Premature Infant: Clinical Course and Pharmacokinetics

The pharmacokinetics of paracetamol in adults after cardiac surgery have not been described. Twenty patients were randomized to receive either paracetamol 2 g through a nasogastric tube and as a suppository eight hours later or vice versa. Arterial blood samples were taken at 0.5, one, two, four, six and eight hours after dosing. Each patient was studied for 16 h. There were 16 males and three females. One patient was excluded because of sampling errors. The mean age was 59 (SD 8) years and the mean weight 84kg (16). The time-concentration profiles for each individual were used to estimate pharmacokinetic parameters using a non-linear mixed effects model (NONMEM). Population parameter estimates with coefficient of variation (CV%), standardized to a 70 kg person, for a one-compartment model with first order input, lag time and first order elimination were volume of distribution 127 l (28) and clearance 26.4 l/h (29) Rectal paracetamol had an absorption half-life (Tabs) of 2.02 h (31) with a lag time of 0.28h. The absorption half-life for the oral preparation was 1.49h (81) with a lag time of 0.17h. The relative bioavailability of the rectal compared to the oral formulation was 0.98 (18). Concentrations after either nasogastric or rectal paracetamol 2g were below a target concentration of 10 mg/l, which is associated with analgesia. Absorption after nasogastric administration was slow compared to healthy adults (Tabs 0.06 to 0.7h) and the bioavailability was half that expected, due to nasogastric loss. Parameter estimates had large variability. Paracetamol is unlikely to have useful clinical impact in the majority of patients when standard doses (6 g/day) are given on day 1 after cardiac surgery.

Children require higher infusion rates of propofol than adults to maintain clinical anaesthesia. We aimed to produce a manual infusion regimen capable of maintaining a steady‐state blood concentration of 3 μg ml−1 in children aged 3–11 years. Pharmacokinetic parameter estimates were taken from published studies of infusion data in children and used in a pharmacokinetic simulation programme to predict likely propofol blood concentrations during infusions. A variability of 5% was allowed about the target concentration of 3 μg ml−1. A loading dose of 2.5 mg·kg−1 followed by an infusion rate of 15 mg·kg−1·h−1 for the first 15 min, 13 mg·kg−1·h−1 from 15 to 30 min, 11 mg·kg−1·h−1 from 30 to 60 min, 10 mg·kg−1·h−1 from 1 to 2 h and 9 mg·kg−1·h−1 from 2 to 4 h resulted in a pseudo‐steady state target concentration of 3 μg·ml−1 in children 3–11 years. We were unable to predict similar rates by applying size models to adult data. The context sensitive half‐time in children was longer than in adults, rising from 10.4 min at 1 h to 19.6 min at 4 h compared to adult estimates of 6.7 min and 9.5 min, respectively. Children require higher infusion rates than adults to maintain steady state concentrations of 3 μg·ml−1 and have longer context sensitive half‐times than adults. These differences can be attributed to altered pharmacokinetics in this age group.

The use of propofol infusions in paediatric anaesthesia: a practical guide

There are no adequate pharmacodynamic data relating concentrations of acetaminophen in serum to analgesia.

METHODS
Children undergoing outpatient tonsillectomy were administered acetaminophen either orally, 0.5-1.0 h preoperatively (n = 20), or per rectum at induction of anesthesia (n = 100). No other analgesic agents were administered. Individual concentrations of acetaminophen in serum and pain scores (0-10) measured over a 4-h postoperative period were analyzed using a nonlinear mixed-effects model (NONMEM).

RESULTS
Mean (% CV) estimates of population pharmacokinetic parameters with percent coefficient of variation, standardized to a 70-kg person, for a one-compartment model with first-order input, lag time, and first order-elimination were a volume of distribution of 60 (21) 1 and a clearance of 13.5 (46) 1/h. Rectally administered acetaminophen had an absorption half-life of 35 (63) min with a lag time of 40 min. The absorption half-life for the oral preparation was 4.5 (63) min without a detectable lag time. The relative bioavailability of the rectal compared with the oral formulation was 0.54. The equilibration half-time of an effect compartment was 1.6 (131) h. Pharmacodynamic population parameter estimates (percent coefficient of variation) for a fractional sigmoidal Emax model, in which the greatest possible pain relief equates to an Emax of 1, were Emax = 1, EC50 (the concentration producing 50% of Emax) = 3.4 (94) mg/l, and Hill coefficient = 0.54 (42).

The pharmacodynamics of acetaminophen can be described using a sigmoidal Emax model with a low Hill coefficient. To achieve a mean posttonsillectomy pain score of 3.6 of 10, an effect compartment concentration of 10 mg/l is necessary.

Perioperative pharmacodynamics of acetaminophen analgesia in children.

This article describes the use of rapid cycle improvement in a community hospital adult cardiac surgery program. The hospital participated in the Breakthrough Series: collaborative adult cardiac surgery sponsored by the Institute of Healthcare Improvement (IHI). As a result of this 1-year project, median length of stay for diagnosis-related groups 104 through 108 was decreased 30 percent from 8.62 days to 6.0 days; percentage of patients extubated within 6 hours postoperatively rose from 5 percent to 75 percent; median cost per case declined $19 percent; and pain and anxiety, service, and satisfaction scores all improved. There was no adverse impact on the clinical indicators 30-day readmission rate, reintubation, return to operating room, and mortality.

Breakthrough Change for Adult Cardiac Surgery in a Community‐Based Cardiovascular Program

AIMS
Paracetamol has a central action for both antipyresis and analgesia. Maximum temperature decrease and peak analgesia are reported at 1-2 h after peak plasma paracetamol concentration. We wished to determine the relationship between plasma and cerebrospinal fluid (CSF) pharmacokinetics in children.

METHODS
Concentration-time profiles in plasma and CSF after nasogastric paracetamol 40 mg kg(-1) were measured in nine children who had indwelling ventricular drains. Estimation of population pharmacokinetic parameters was made using both a standard two-stage population approach (MKMODEL) and a nonlinear mixed effect model (NONMEM). Results were standardized to a 70 kg person using an allometric power model.

RESULTS
Both approaches gave similar estimates. NONMEM parameter estimates were clearance 10.21 h(-1) (CV 47%), volume of distribution 67.11 (CV 58%) and absorption rate constant 0.77 h(-1) (CV 49%). Cerebrospinal fluid concentrations lagged behind those of plasma. The equilibration half time was 0.72 h (CV 117%). The CSF/plasma partition coefficient was 1.18 (CV 8%).

Higher concentrations in the CSF probably reflect the lower free water volume of plasma. The CSF equilibration half time suggests that CSF kinetics approximate more closely to the effect compartment than plasma, but further time is required for paracetamol to exert its effects. Effect site concentrations equilibrate slowly with plasma. Paracetamol should be given 1-2 h before anticipated pain or fever in children.

Paracetamol plasma and cerebrospinal fluid pharmacokinetics in children.

Paracetamol pharmacokinetics in the premature neonate; the problem with limited data.

Size, Myths and the Clinical Pharmacokinetics of Analgesia in Paediatric Patients

A pharmacokinetic dynamic simulation model was used to predict rectal paracetamol dosing schedules which would maintain steady state plasma concentrations of 10–20 mg·l−1. These plasma concentrations of paracetamol are known to reduce fever. The conventional dosing schedule of 15 mg·kg−1 four hourly was unsatisfactory. Steady state concentrations of 8–12 mg·l−1 were only reached after 16 h. A loading dose of 50 mg·kg−1 followed by 30 mg·kg−1 six hourly achieved plasma concentrations of 9–18 mg·l−1. Paracetamol is a mild analgesic. A higher plasma paracetamol concentration of 25 mg·l−1 is known to give satisfactory analgesia to 60% of children after tonsillectomy. This concentration can be reached after a loading dose of 70 mg·kg−1 and a maintenance dose of 50 mg·kg−1 8 hourly. Doses above 150 mg·kg−1·day−1 have been reported to cause reversible liver toxicity after 2–8 days and should not be sustained.

Rectal paracetamol dosing regimens: determination by computer simulation

A nine-month infant, weighing 9.8 kg, presented with hypotonia secondary to acute hypokalaemia (1.0 mmol/l). Muscle strength improved as the serum potassium was increased. Muscle strength was assessed by the pressure generated inside a saline-filled endotracheal tube cuff during a grasp reflex. Potassium concentration and hand grip strength were related using a sigmoidal Emax model. Zero effect was assumed when the potassium concentration was zero. The Emax, EC50 and Hill coefficient values were determined by non-linear regression using the MKMODEL program. Parameter estimates (SE) were EC50 1.79 (0.15) mmol/l, Hill coefficient 3.79 (0.92), Emax 114.4 (8.9) mmHg.

Relationship of Muscle Strength to Potassium Concentration in a Hypokalaemic Infant

Michaelis-Menten pharmacokinetic parameters for theophylline were estimated in a three-month infant following an accidental overdose of intravenous aminophylline. Fitting of time-concentration data was performed using nonlinear regression with MKMODEL. A mixed order elimination model was superior to a first order model. Parameter estimates were standardized to a 70 kg human using an allometric power model. Parameter estimates (SE) were: maximum rate of metabolism (Vmax) 71(42) mg.h–1, Michaelis-Menten constant (Km) 32.3 (33.5) mg.l–1, volume of distribution (Vd) 46.9 (2.6) l. This Michaelis-Menten constant is lower than that reported for adults and consequently non-linear elimination will occur at lower plasma concentrations in infants than in adults. Theophylline clearance has traditionally been reported as directly proportional to body weight. This per kilogram model gives an erroneous impression that clearance is greatest in early childhood and then decreases with age until adult rates are reached in late adolescence. Age-related clearance values reported in the literature were reviewed using an allometric 3/4 power model. This size model demonstrates that clearance increases in infancy and reaches adult rates in the first one to two years of life.

The analgesic efficacy of paracetamol was assessed in a prospective, randomized, double-blinded study of 100 children undergoing tonsillectomy with or without adenoidectomy. Fifty children were given paracetamol elixir 40 mg/kg 40 minutes preoperatively (Group A); the remaining 50 children were given an oral placebo 40 minutes pre-operatively and paracetamol suppositories 40 mg/kg after induction of anaesthesia (Group B). Paracetamol was the only analgesic given and was given either orally or rectally in order to produce high variations in plasma paracetamol concentrations postoperatively. At 30 minutes after the end of surgery a pain score (0–10) was obtained and a venous blood sample was taken for serum paracetamol concentration analysis. Children given paracetamol elixir had a higher mean paracetamol concentration (0.15 [SD 0.06] mmol/l vs 0.05 [SD 0.03] mmol/l, P < 0.001) and a lower median pain score (5 vs 7, P < 0.02) than those who were given suppositories. The use of rescue morphine was higher (10 vs 23, P < 0.001) in the latter group. The incidence of nausea and vomiting was the same in both groups (20%) during the 24 hour postoperative period. Plasma paracetamol concentrations of 0.066–0.132 mmol/l are known to reduce temperature; plasma paracetamol concentrations which provide analgesia are unknown. Children with plasma paracetamol concentrations above 0.07 mmol/l had superior analgesia to those with concentrations below this level (P < 0.05).

Analgesic Efficacy of Paracetamol in Children Using Tonsillectomy as a Pain Model

AIM
Paracetamol is an analgesic/antipyretic widely used in children. The drug can cause hepatic and renal damage due to cumulative toxicity when used in excess of 90 mg/kg@day. There are no dosing guidelines for paracetamol use in children under 1 month of age. We wished to discern current paracetamol prescribing habits in order to establish safety of current practices and offer recommendations towards rational use.

METHODS
An anonymous questionnaire was sent to all medical staff working in a university childrenís hospital. We sought information about paracetamol prescribing regimes for children 4 months and over, 3 months and under and neonates in the first 2 weeks of life. Pharmacists audited daily prescription charts of inpatients without hepatic or renal disease over a 2 month period. The maximum possible daily dose was calculated for each child and note was made if a dose in excess of 95 mg/kg was given.

RESULTS
There were 53 respondents to the 80 questionnaires posted. There was a trend to use lower daily doses in the younger age group. Similarly, more practitioners either did not use or did not know safe dosing schedules in children 3 months and younger. During the 2 month period there were 823 prescriptions for children 4 months and over, 85 for infants 3 months and under and seven for under 2 week old neonates. In the children 4 months and over 25 of 140 prescriptions exceeding 95 mg/kg/day were given and two of six were given in infants 3 months and younger.

Many medical staff were unsure of current safe dosing regimens, particularly in the younger age groups. Seventeen percent of prescriptions were above 95 mg/kg/day although only 3% of children were given these doses due to on demand charting and due to audit by pharmacy and nursing staff. There are few guidelines for children 3 months and under. The literature suggests 60-65 mg/kg/day in infants 1-3 months, although this dose was only charted in 16% of prescriptions and phamacokinetic data favours a higher dose. In neonates 30 mg/kg/day achieves effective therapeutic concentrations but further studies are needed.

Glycogelatin capsular suppositories containing a paracetamol slurry 40 mg·kg‐1 were given PR to 20 children (12 months‐17 yrs) after major orthopaedic surgery and plasma concentrations of paracetamol measured for up to 18 h. The mean maximum concentration (Cmax) was 0.115 (SD 0.049) mmol·l‐1. Peak concentration occurred (Tmax) at 2.3 (SD 1.2) h. Mean concentration was 0.07 (SD 0.03) mmol·l‐1 at six h. Apparent paracetamol clearance was 5.8 ml·min‐1·kg‐1. The plasma concentration of paracetamol associated with analgesic effectiveness in children is unknown, but antipyretic effects are seen in the range 0.066–0.130 mmol·l‐1. Paracetamol suppositories 40 mg·kg‐1 given perioperatively achieve effective therapeutic antipyretic plasma concentrations within 1–2 h. The timing is coincident with the recovery phase of short duration paediatric surgery. The coefficient of variance of Cmax was 43%. Some individual patients may not achieve a Cmax which is therapeutic.

Pharmacokinetics of rectal paracetamol after major surgery in children

A double-blind study consisting of 339 randomly selected children investigated the effects of several premedicants on the preoperative and postoperative behaviour of children who underwent day-stay surgery. Patients were allocated into two groups. Group 1 consisted of 165 children aged between 6 and 4 7 months. Group 2 consisted of 174 children aged four years and older to a body weight of 50 kg. Each child received one premedicant. Both groups included alprazolam 0.005 mg/kg, midazolam 0.3 mg/kg and placebo. In addition Group 1 included chloral hydrate 40 mg/kg and Group 2 diazepam 0.25 mg/kg. Chloral hydrate produced superior conditions (more patients calm or asleep) at induction of anaesthesia. Postoperative behaviour and incidence of vomiting were similar for all drugs. No premedicant reduced anxiety in the older group. The time to awaken postoperatively with diazepam was longer than with placebo. Alprazolam and midazolam were unpalatable for children over four years and conferred no advantage over placebo.

Oral Premedication in Children: A Comparison of Chloral Hydrate, Diazepam, Alprazolam, Midazolam and Placebo for Day Surgery

A prospective, randomized, double-blind trial was conducted to compare the analgesic actions and side effects of sufentanil continuously infused (5 μg/h) into the lumbar epidural space (L2–3) with those of an infusion of lumbar epidural morphine (0.5 mq/h). Forty patients admitted to an intensive care unit after elective major abdominal surgery participated over a varying period of 24–40 h. Post-operative pain was treated with an epidural bolus of either sufentanil (50 μg) or morphine (5 mg), followed by a continuous infusion of the same opiate. The quality of pain relief was similar in each group. The sufentanil group had a more rapid onset of analgesia. The incidence of nausea and vomiting, pruritus, and drowsiness was similar in the two groups. In spontaneously breathing patients there were no respiratory complications requiring treatment. Forced vital capacities were statistically significantly better during the first 1–4 h with sufentanil.

Postoperative Pain Control With a Continuous Infusion of Epidural Sufentanil in the Intensive Care Unit: A Comparison With Epidural Morphine

A review of the anaesthetic management of children with congenital myotonic dystrophy anaesthetised at the Royal Children's Hospital over the past ten years is presented. Seven children underwent a total of fourteen anaesthetics. Anaesthetic considerations must include the degree of muscle weakness and hypotonia altering muscle relaxant requirements, aspiration risk due to palatopharyngeal dysfunction, and cardiomyopathy. Succinylcholine caused muscle contracture in a patient without clinical myotonia. This drug should be avoided. Although a low threshold to institute postoperative respiratory support must exist when treating neonates and infants, the older children did not clinically exhibit increased sensitivity to respiratory depressant drugs.

Congenital Myotonic Dystrophy in Children — A Review of Ten Years’ Experience

Congenital myotonic dystrophy is a rare disorder with a reported incidence of six per 100,000. Although anaesthetic problems in adults with myotonic dystrophy are well recognised, anaesthesia for children with congenital myotonic dystrophy is rarely described in the literature

Ten volunteers were given varying ratios of oxygen and nitrous oxide at 4,6 and 8 litres per minute using a Hudson mask delivery system. Maximum and minimum inspired oxygen concentrations, maximum inspired nitrous oxide concentrations and end tidal carbon dioxide concentrations were measured using the Datex Cardiocap CCI-104 monitor. Although pharyngeal oxygen fraction varies with the Hudson mask because the inspiratory flow exceeds the entrainment of the mask by a variable amount during much of the cycle, at 8 litres/minute flow with a ratio of 3 to 5, oxygen to nitrous oxide, safe levels of oxygen were delivered (range of means 26–31%) with basal nitrous oxide levels (mean maximum inspired N 2 O, 34%). When nitrous oxide sedation is used clinically, nitrous oxide must be used with consideration of safe oxygen levels. This study did not detect unsafe pharyngeal oxygen levels in the ratios investigated, where the maximum delivered nitrous oxide concentration was 75%.

Inspired Oxygen and Nitrous Oxide Concentrations in Volunteers during Nitrous Oxide Sedation with a Hudson Mask

SUMMARY 
 
METATROPIC DYSPLASIA is a spondylo-epi-metaphyseal dysplasia with characteristic clinical and radiographic features. 37 cases of the disorder were reported up to 1983 accordingly to Beck et al. 
 
14 cases of spondylo-epi-metaphyseal dysplasia of metatropic variety from 9 paediatrk institutions have been analysed. 
 
Radiologically and clinically we discern four groups of patients with features of metatropic dysplasia. 1. A lethal, pen-natal type, 2. An autosomal recessive type with diagnostic radiographic findings and often fatal outcome in the first few years of life, 3. A rare dominant type, 4. A mild type consistent probably of different spondylo-epi-metaphyseal dysplasias which show mild metatropic changes. (Metatropic Dysplasia Variants).

A child with influenza A (H1N1)-associated myocarditis rescued by extracorporeal membrane oxygenation. Do old pharmacokinetic parameter estimates predict new data? Editor—Investigators may report different parameter estimates to describe the pharmacokinetics of a drug used in children. A number of parameter sets exist for describing pro-pofol time–concentration data in children, often predicting quite different profiles in a typical child. 1 These differences may be attributed to different patient populations, administration (single dose vs infusion), study duration, and differing analysis methodologies. Similarly, parameter sets for i.v. paracetamol are reported that differ. An alternative to comparing predicted time–concentra-tion profiles using differing parameter sets for a typical child is to ascertain if parameter estimates from an earlier study can predict concentrations similar to those reported in a new study is to use a modelling tool known as the visual predictive check. 4 Concentration prediction intervals from an earlier study 5 are graphically superimposed on those intervals determined from observed concentrations in the new study. 2 Simulation is performed with parameter estimates from the earlier study using 1000 subjects with characteristics taken from new patients. For data such as these where covariates such as dose, weight, and height are different for each patient, a prediction-corrected visual predictive check 4 is used; observations and simulations are multiplied by the population baseline value divided by the individual-estimated baseline. Figure 1 shows a graphical representation. The median predictions and observations graphically lie on top of each other. Observed concentration intervals are narrower than predictions, reflecting limited subjects (n¼33) in the new study. The earlier study (n¼144) was performed using a prodrug of paracetamol (procetamol) that is rapidly metabolized to paracetamol (F¼0.5) by plasma esterases. This graphical validation supports parameter estimates for i.v. paracetamol determined using the prodrug.

Lymphoblastic lymphoma is a rare and aggressive form of non-Hodgkin lymphoma (NHL). The tumor can derive from T-cell or B-cell and is clinically similar to acute lymphoblastic leukemia with minimal to no bone marrow involvement distinguishing the two. We present a rare case of lymphoblastic lymphoma originating from the paranasal sinuses. A 40-year-old male presented to the emergency department and was diagnosed with right-sided acute sinusitis complicated by pre-septal cellulitis. After failing medical management, he underwent endoscopic sinus surgery. Pathologic analysis of nasal contents stained for CD79a, CD34, and PAX5, suggesting a B-cell lymphoblastic lymphoma (B-LBL). He was referred to hematology-oncology and was treated with hyperfractionated cyclophosphamide, vincristine, Adriamycin, dexamethasone (Hyper-CVAD). Short-term follow-up has thus far demonstrated near-complete resolution of the tumor. Non-Hodgkin lymphomas of the paranasal sinuses are rare, and B-cell lymphoblastic lymphomas comprise just 0.3% of adults with NHL. Immunohistochemical phenotyping for B-LBL is typically positive for B-cell markers CD19, CD20, CD22 and CD79a. Classic treatment involves a chemotherapy regimen of Hyper-CVAD with an overall survival rate of 66%. B-cell lymphoblastic lymphoma is rarely reported in the paranasal sinuses. A thorough history and physical exam along with a complete workup, including biopsies with histopathological and immunohistochemical analysis, needs to be obtained. Little is known about its prognosis when the primary site is within the paranasal sinuses, and therefore, patients need prompt and aggressive treatment when the diagnosis is made.

B-cell Lymphoblastic Lymphoma of the Paranasal Sinuses: A Case Study of a Rare Clinical Entity

. A set A of nonnegative integers is an asymptotic basis of order h if every suﬃciently large integer can be represented as the sum of h not nec- essarily distinct elements of A . An asymptotic basis A is minimal if removing any element of A destroys every representation of inﬁnitely many integers. In this paper, a new class of minimal asymptotic bases is constructed.

Seed production in subtropical environments is commonly used by soybean [Glycine max (L.) Merr.] breeders to reduce the number of years for cultivar development. Low-phytate (LP) soybean lines with the mips allele had substantially reduced fi eld emergence when planted with seed from a subtropical source. The objective of this study was to determine if seed source also would impact the fi eld emergence of lowphytate lines with the pha1 and pha2 alleles. Seed of six BC 3 F 4 -derived LP lines, the LP donor parent CX1834-1-6 (CX1834), and the normal-phytate (NP) recurrent parent B01769B019 (B019), was harvested from the fi eld at Ames, IA, in 2005 (IA-2005), at Ponce, PR, in January 2007 (PR-Jan), and at Ponce, PR, in May 2007 (PR-May). The three seed sources of the eight lines were evaluated at three Iowa locations in 2007. The mean fi eld emergence of LP lines was 77.6% for the IA-2005 source, 70.1% for the PRJan source, and 25.4% for the PR-May source while that of B019 ranged from 80.3 to 82.0% for the three sources. The seed source used to plant lines with the pha1 and pha2 alleles can have a signifi cant infl uence on their fi eld emergence, which can impact the development and evaluation of LP lines and on seed increases for commercial production.

Seed Source Affects Field Emergence of Low‐Phytate Soybean Lines

In this paper, we present a modiication of a closed-loop identiication scheme known as the \Hansen scheme". The advantage of the alternative procedure is that the order of the resulting model is tunable by the user.

Author's reply to Comments on 'Analysis and Synthesis of Nonlinear Reciprocal Networks containing two Element Types and Transformers'

A synthesis procedure is presented for a lossless positive real impedance matrix Z(s) . The procedure, based on a choice of a suitable state-space representation for Z(s) , uses the minimum possible number of reactive elements and, simultaneously, the minimum possible number of gyrators.

A new proof of the Lienard-Chipart criterion is given that is based on the reduced Hermite criterion. It is proved from first principles.

The reduced hermite criterion with application to proof of the Liénard-Chipart criterion

A recent paper (see abstr. B3611 of 1968) is extended to show the existence of a quantity associated with a noisy two-port that is invariant under lossless transformation. The transforming network may be reciprocal or nonreciprocal.

In this correspondence, we show that it is impossible to redize a gyrator using time-variable transformers, and passive time-invariant resistors and capacitors. We point out that it has earlier been demonstrated that a gyrator realization is possible which uses time-varying transformers, together with positive and negative time-invariant ~ ~ ~ a c i t a r s . ' Thus here it is demonstrated that i t is impossible to improve on this realieation, in the sense that it is impossible to dispense with the negative capacitors. In other words, it is both impossible to rudise a gyrator with time-varying transformers alone, or a combination of timevarying transformers and positive capilcitors. I t is eRsy to observe that if a realization exists using time-varying transformers, and passive time-iivariant rmistors and capacitors, then the resistors can be removed and renlaced bv anen circuits . . without altering the port behavior. This is true because the gyrator is a lossless device, and if the resistors in an all-~assive-element realization carried current, the lossless property would be destroyed. Since then any resistors in the realization carry no ourrent, they may evidently be removed. Conseqoently, we are led to hypothesizing a realization of the type shorn in Fig. 1, where, it will benoticed, transformer nomalbations allow us to as$ume all the capacitors are one farad. Gyrator behavior is assumed at ports 1 and 2.

Objective: To identify factors associated with malignant pertussis. Design: A retrospective case notes review from January 2003 to August 2013. Area under the receiver-operator characteristic curve was used to determine how well vital sign and white cell characteristics within 48 hours of hospital presentation identified children with malignant pertussis. Setting: The national children’s hospital in Auckland, New Zealand. Patients: One hundred fifty-two children with pertussis. Measurements and Main Results: There were 152 children with confirmed pertussis identified, including 11 children with malignant pertussis. The area under the receiver-operator characteristic curve was 0.88 (95% CI, 0.78–0.97) for maximum heart rate. The optimal cut-point was 180 beats/min, which predicted malignant pertussis with a sensitivity of 73% and a specificity of 91%. The area under the receiver-operator characteristic curve was 0.92 (95% CI, 0.81–1.0) for absolute neutrophil count, 0.85 (95% CI, 0.71–0.99) for total WBC count, 0.80 (95% CI, 0.63–0.96) for neutrophil-to-lymphocyte ratio, and 0.77 (95% CI, 0.58–0.92) for absolute lymphocyte count. All children with malignant pertussis had one or more of heart rate greater than 180 beats/min, total WBC count greater than 25 × 109/L, and neutrophil-to-lymphocyte ratio greater than 1.0 with an area under the receiver-operator characteristic curve of 0.96 (95% CI, 0.91–1.0) for a multivariate model that included these three variables. Conclusions: Clinical predictors of malignant pertussis are identifiable within 48 hours of hospital presentation. Early recognition of children at risk of malignant pertussis may facilitate early referral to a PICU for advanced life support and selection for trials of investigational therapies.

Identifying Children at Risk of Malignant Bordetella pertussis Infection

AIM
To estimate hospitalisation costs for children with pertussis in New Zealand.

METHOD
All children less than 16 years of age and hospitalised with pertussis between 01/01/2003 and 31/12/2013 were identified from the National Minimum Data Set and the National Paediatric Intensive Care Unit database. The cost of hospital care was estimated by multiplying the diagnosis-related group cost-weight by the national price and inflating to 2013/2014 values.

RESULTS
There were 1,456 children with pertussis admitted to hospital including 65 admissions to the paediatric intensive care unit. Infants (<1 year) accounted for 78% of hospital admissions, 98% of paediatric intensive care admissions and 87% of hospitalisation costs. The total inflation-adjusted cost of the 11-year cohort was estimated at $8.3 million and the mean cost of hospital ward and paediatric intensive care was $4,242 and $42,016 respectively, per child. The 2011-2013 epidemic accounted for 39% of all hospital admissions and the cost estimated at $4.2 million. Peak annual hospitalisation costs during epidemic years increased from under $800,000 in 2004 and 2009 to over $2 million in 2012.

Infants with pertussis are more likely than older children to be admitted to hospital and to the paediatric intensive care unit and generate the majority of hospitalisation costs. A revised focus on protecting vulnerable newborns and infants has the potential to both improve health outcomes for infants with pertussis and reduce medical costs.

Attention is biased toward features aligning with task goals and stimuli previously allocated attentional priority (selection history). The relationship between selection history and the strategic control of attention has scarcely been explored. In the present study, we utilized a modified version of the Adaptive Choice Visual Search (ACVS) task to determine whether the choice of visual search strategy varies with the strategies participants have elected to use in the past. Participants were tasked with searching through stimuli presented in two task-relevant colors on each trial to find one of two targets. The distribution of stimuli rendered in these two colors was manipulated between subjects, with one group receiving more imbalanced displays during learning. Participants who experienced the more imbalanced displays quickly learned the optimal visual search strategy of searching through the less abundant color, which maximized performance. Critically, these participants retained their tendency toward this learned strategy in a subsequent test phase in which displays were less imbalanced, in contrast to participants who completed the same test phase but had only experienced the less imbalanced displays. Our results demonstrate that, without explicit instruction, the choice of visual search strategy is to some degree dependent upon selection history. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Journal of experimental psychology. Learning, memory, and cognition

Correction to: Cross-modal generalization of value-based attentional priority

Statistical Learning Facilitates the Strategic Use of Attentional Control

Learning from rewarding and aversive outcomes shapes how sensory signals are processed by the attention system, reflecting a consequence of selection history. Substantial evidence points to Pavlovian associative learning as the mechanism by which previously reward-associated and aversively conditioned stimulus features gain attentional priority. On the basis of differences between reward-dependent feature-based and space-based attentional biases, it has been suggested that reinforcement learning underlies the influence of selection history on spatial attention. By pairing the orienting of overt spatial attention with aversive electric shock, we provide direct evidence that Pavlovian learning between locations and outcomes can shape spatial attention. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Pavlovian learning in the selection history-dependent control of overt spatial attention.

This is a test: Oculomotor capture when the experiment keeps score

Statistical learning of distractor shape modulates attentional capture

AbstractRepeated exposure to hazards in road construction work zones often generates worker habituation to risks associated with those hazards, a key causal factor in workplace accidents. Understan...

Reducing Risk Habituation to Struck-By Hazards in a Road Construction Environment Using Virtual Reality Behavioral Intervention

ABSTRACT In the target article, Luck et al. [2020. Progress toward resolving the attentional capture debate. Visual Cognition. doi:10.1080/13506285.2020.1848949] argue for progress that has been made in the attentional capture debate, offering points of agreement in addition to highlighting specific outstanding issues that could contribute to further resolution. This commentary questions the most fundamental assumption on which the debate rests: namely that the computation of attentional priority can culminate in a quantal event in which attention can be said to have been captured. The notion of attention-as-capturable leads to a forced dichotomy with respect to the occurrence of capture that undergirds the arguments forwarded by Luck et al. (2020), a dichotomy predicated on arbitrary lines of demarcation over a continuous and temporally-unfolding mental process distributed over multiple regions of the brain. These lines of demarcation serve to perpetuate claims that one type of stimulus either does or does not qualify as capturing attention under particular experiment conditions, on which this entire debate rests. I argue that it is more productive to conceptualize issues surrounding the control of attention in terms of the computation of attentional priority, which naturally links together goal-directed and stimulus-driven influences in a richer and more coherent way.

Time to stop calling it attentional “capture” and embrace a mechanistic understanding of attentional priority

Previously reward-associated stimuli have consistently been shown to involuntarily capture attention in the visual domain. Although previously reward-associated but currently task-irrelevant sounds have also been shown to interfere with visual processing, it remains unclear whether such stimuli can interfere with the processing of task-relevant auditory information. To address this question, we modified a dichotic listening task to measure interference from task-irrelevant but previously reward-associated sounds. In a training phase, participants were simultaneously presented with a spoken letter and number in different auditory streams and learned to associate the correct identification of each of three letters with high, low, and no monetary reward, respectively. In a subsequent test phase, participants were again presented with the same auditory stimuli but were instead instructed to report the number while ignoring spoken letters. In both the training and test phases, response time measures demonstrated that attention was biased in favour of the auditory stimulus associated with high value. Our findings demonstrate that attention can be biased towards learned reward cues in the auditory domain, interfering with goal-directed auditory processing.

Previously reward-associated sounds interfere with goal-directed auditory processing

Rewarding and aversive outcomes have opposing effects on behaviour, facilitating approach and avoidance, although we need to accurately anticipate each type of outcome in order to behave effectively. Attention is biased toward stimuli that have been learned to predict either type of outcome, and it remains an open question whether such orienting is driven by separate systems for value- and threat-based orienting or whether there exists a common underlying mechanism of attentional control driven by motivational salience. Here we provide a direct comparison of the neural correlates of value- and threat-based attentional capture following associative learning. Across multiple measures of behaviour and brain activation, our findings overwhelmingly support a motivational salience account of the control of attention. We conclude that there exists a core mechanism of experience-dependent attentional control driven by motivational salience, and that prior characterisations of attention as being value-driven or supporting threat monitoring need to be revisited.

Motivational salience guides attention to valuable and threatening stimuli: Evidence from behaviour and fMRI

Abstract Rewarding and aversive outcomes have opposing effects on behavior, facilitating approach and avoidance, although we need to accurately anticipate each type of outcome to behave effectively. Attention is biased toward stimuli that have been learned to predict either type of outcome, and it remains an open question whether such orienting is driven by separate systems for value- and threat-based orienting or whether there exists a common underlying mechanism of attentional control driven by motivational salience. Here, we provide a direct comparison of the neural correlates of value- and threat-based attentional capture after associative learning. Across multiple measures of behavior and brain activation, our findings overwhelmingly support a motivational salience account of the control of attention. We conclude that there exists a core mechanism of experience-dependent attentional control driven by motivational salience and that prior characterizations of attention as being value driven or supporting threat monitoring need to be revisited.

Motivational Salience Guides Attention to Valuable and Threatening Stimuli: Evidence from Behavior and Functional Magnetic Resonance Imaging

ABSTRACT The present study aimed to determine whether attentional prioritization of visual stimuli associated with punishment transfers across conceptual knowledge independently of physical features. Participants performed a Stroop task in which words were presented individually. These stimuli consisted of four pairs of synonyms selected such that the two words of each pair have both a strong semantic association and no perceptual similarity. In the learning phase, two words (from two different pairs) were associated with shock independently of performance; all the other words were never paired with shock. In the subsequent test phase, no shock was delivered. Results are consistent with semantic generalization of punishment-related attentional priority; synonyms of words paired with shock produced a Stroop interference effect (i.e., slower response times) in learning and test phases, relative to synonyms of words not paired with shock, suggesting they were prioritized by attention.

Semantic generalization of punishment-related attentional priority

jsPsych is a useful open-source library for building browser-based behavioral experiments over the internet. However, vision science experiments involve unique considerations that are not well-accommodated by existing resources within jsPsych. In the present article, we provide a brief overview of our solutions to challenges such as response-dependent stimulus displays and accurate and flexible stimulus presentation within a web browser. Our solutions, which include freely-available functions and code accessible to other researchers, will focus on the jsPsych-JATOS workflow. The implementation of these solutions will allow vision scientists to make better use of jsPsych-JATOS and the benefits that it offers, including significant flexibility in hosting browser-based experiments in-house (i.e., without relying on a fee-for-service model) with broad compatibility across recruitment services (e.g., Amazon MTurk, SONA, and Prolific).

Studies on attentional bias have overwhelmingly focused on the priority of different stimuli and have rarely manipulated the state of the observer. Recently, the threat of unpredictable shock has been utilized to experimentally induce anxiety and investigate how negative arousal modulates attentional control. Experimentally induced anxiety has been shown to reduce the attentional priority afforded to reward-related stimuli while enhancing the efficiency of goal-directed attentional control. It is unclear which of these two influences might dominate when attending to reward-related stimuli is consistent with task goals and by extension what the scope of the modulatory influence of threat on attention is. In contrast to paradigms in the visual domain, a novel auditory identification task has demonstrated a robust influence of target-value associations on selective attention. In the present study, we examined how the threat of shock modulates the influence of learned value on voluntary attention. In both threat and no-threat conditions, we replicate prior findings of voluntary prioritization of reward-associated sounds. However, unlike in studies measuring involuntary attentional capture, threat did not modulate the influence of reward on attention. Our findings highlight important limitations to when and how threat modulates the control of attention, contextualizing prior findings.

How Does Threat Modulate the Motivational Effects of Reward on Attention?

Matter over mind: Effects of imagery and perceptual priming on visual attention

Recent research has demonstrated a counterproductive attentional bias toward threat-related stimuli: under conditions in which fixating on a color distractor stimulus sometimes resulted in an immediate shock, participants were nevertheless more likely to look at this threat-related distractor than a neutral distractor matched for physical salience. However, participants in that prior research may not have realized that their own actions caused delivery of aversive outcomes, such that monitoring for the threat-related distractor may not have been counterproductive from participants' perspective. In Experiment 1 of the current study, we demonstrate that the attentional bias to the threat-related distractor persists (and indeed, becomes stronger) when participants are made explicitly aware that looking at this stimulus is the sole cause of aversive events, which are otherwise avoidable. In Experiment 2 we replicate the bias in informed participants under conditions in which there is additional (reward-driven) motivation to avoid attending to distractors. Taken together with prior findings, the observation of an attentional bias toward the threat-related distractor under these explicitly counterproductive conditions provides strong support for the idea that threat-related stimuli are automatically prioritized by our attentional system. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

You do it to yourself: Attentional capture by threat-signaling stimuli persists even when entirely counterproductive.

Abstract Attentional capture by previously reward-associated stimuli has predominantly been measured in the visual domain. Recently, behavioral studies of value-driven attention have demonstrated involuntary attentional capture by previously reward-associated sounds, emulating behavioral findings within the visual domain and suggesting a common mechanism of attentional capture by value across sensory modalities. However, the neural correlates of the modulatory role of learned value on the processing of auditory information has not been examined. Here, we conducted a neuroimaging study on human participants using a previously established behavioral paradigm that measures value-driven attention in an auditory target identification task. We replicate behavioral findings of both voluntary prioritization and involuntary attentional capture by previously reward-associated sounds. When task-relevant, the selective processing of high-value sounds is supported by reduced activation in the dorsal attention network of the visual system (FEF, intraparietal sulcus, right middle frontal gyrus), implicating cross-modal processes of biased competition. When task-irrelevant, in contrast, high-value sounds evoke elevated activation in posterior parietal cortex and are represented with greater fidelity in the auditory cortex. Our findings reveal two distinct mechanisms of prioritizing reward-related auditory signals, with voluntary and involuntary modes of orienting that are differently manifested in biased competition.

Although humans can voluntarily direct their attention to particular stimuli, attention can at times be involuntarily allocated to stimuli and such attentional capture can result in unproductive distraction. A challenge to any comprehensive theory of attention is to explain how involuntary mechanisms of attentional control and their potential to produce distraction are ultimately reflective of an adaptation. Traditional arguments on this topic have appealed to a generalized cost-benefit accounting. Specifically, the cost of misallocating attention to the kinds of stimuli prioritized by involuntary mechanisms of attentional control over the long run is argued to be small in comparison with the potentially life-altering cost of failing to attend to such stimuli, which involuntary mechanisms of attentional control guard against. Our understanding of these mechanisms has undergone a revolution in recent years, findings from which point to a much more sophisticated adaptation that systematically maximizes benefits associated with automating the control of attention while minimizing unwanted distraction. In this review, I provide an updated model of the adaptive nature of involuntary mechanisms of attentional control, outlining concrete principles governing the management of specific costs and benefits. I conclude that distraction does not in general constitute a failure of attentional control but rather reflects the joint product of these adaptive principles. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Direct Comparison of the Neural Correlates of Value- and Punishment-Driven Attentional Capture

The effect of concurrent reward on aversive information processing in the brain

Previously reward-associated stimuli persistently capture attention. We attempted to extinguish this attentional bias through a reversal learning procedure where the high-value color changed unexpectedly. Attentional priority shifted during training in favor of the currently high-value color, although a residual bias toward the original high-value color was still evident. Importantly, during a subsequent test phase, attention was initially more strongly biased toward the original high-value color, counter to the attentional priorities evident at the end of training. Our results show that value-based attentional biases do not quickly update with new learning and lag behind the reshaping of strategic attentional priorities by reward.

Attention prioritizes stimuli previously associated with reward or punishment. The present study examined whether this attentional bias, widely considered to be involuntary and automatic, could be suppressed with sufficient motivation. Participants performed visual search for a shape-defined target. One color-singleton distractor predicted the possibility of receiving a reward and another an electric shock, with each outcome occurring infrequently. Participants were informed that the likelihood to earn a reward or avert punishment depended on fast and accurate performance, thus providing strong motivation to resist distraction by reward- and shock-related stimuli. Results revealed a reduction in the magnitude of attentional capture by reward- and threat-associated distractors, relative to neutral distractors, that persisted into extinction. In a second experiment, we replicated the suppression of value-modulated attentional capture in the absence of the shock condition, thus confirming that the suppression did not result from the presence of threat. Finally, in a third experiment, we replicated the typical pattern of attentional capture by reward cues using a more conventional procedure in which the motivation to suppress valent stimuli was low (the likelihood to be rewarded was high and not contingent on fast performance). This study demonstrates that signals for reward and threat can be actively suppressed with sufficient motivation. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Motivated suppression of value- and threat-modulated attentional capture.

Combined influence of valence and statistical learning on the control of attention: Evidence for independent sources of bias

What we direct our attention to is strongly influenced by both bottom-up and top-down processes. Moreover, the control of attention is biased by prior learning, such that attention is automatically captured by stimuli previously associated with either reward or threat. It is unknown whether value-oriented and threat-oriented mechanisms of selective information processing function independently of one another, or whether they interact with each other in the selection process. Here, we introduced the threat of electric shock into the value-driven attentional capture paradigm to examine whether the experience of threat influences the attention capturing quality of previously reward-associated stimuli. The results showed that value-driven attentional capture was blunted by the experience of threat. This contrasts with previous reports of threat potentiating attentional capture by physically salient stimuli, which we replicate here. Our findings demonstrate that threat selectively interferes with value-based but not salience-based attentional priority, consistent with a competitive relationship between value-based and threat-based information processing. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Threat reduces value-driven but not salience-driven attentional capture.

Abstract Anxiety is an adaptive neural state that promotes rapid responses under heightened vigilance when survival is threatened. Anxiety has consistently been found to potentiate the attentional processing of physically salient stimuli. However, a recent study demonstrated that a threat manipulation reduces attentional capture by reward-associated stimuli, suggesting a more complex relationship between anxiety and the control of attention. The mechanisms by which threat can reduce the distracting quality of stimuli are unknown. In this study, using functional magnetic resonance imaging (fMRI) on human subjects, we examined the neural correlates of attention to previously reward-associated stimuli with and without the threat of unpredictable electric shock. We replicate enhanced distractor-evoked activity throughout the value-driven attention network (VDAN) in addition to enhanced stimulus-evoked activity generally under threat. Importantly, these two factors interacted such that the representation of previously reward-associated distractors was particularly pronounced under threat. Our results from neuroimaging fit well with the principle of arousal-biased competition (ABC), although such effects are typically associated with behavioral measures of increased attention to stimuli that already possess elevated attentional priority. The findings of our study suggest that ABC can be leveraged to support more efficient ignoring of reward cues, revealing new insights into the functional significance of ABC as a mechanism of attentional control, and provide a mechanistic explanation of how threat reduces attention to irrelevant reward information.

Arousal-Biased Competition Explains Reduced Distraction by Reward Cues under Threat

Using aversive conditioning with near-real-time feedback to shape eye movements during naturalistic viewing

Reward learning has been shown to habitually guide spatial attention to regions of a scene. However, the neural mechanisms that support this bias in spatial orienting are unknown. In the present study, participants learned to orient to a particular quadrant of a scene (high-value quadrant) to maximize monetary gains. This learning was scene-specific, with the high-value quadrant varying across different scenes. During a subsequent test phase, participants were faster at identifying a target if it appeared in the high-value quadrant (valid), and initial saccades were more likely to be made to the high-value quadrant. fMRI analyses during the test phase revealed learning-dependent priority signals in the bilateral caudate tail and superior colliculus, frontal eye field, substantia nigra, and insula, paralleling findings concerning feature-based value-driven attention. In addition, ventral regions typically associated with scene selective and spatial information processing, including the hippocampus, parahippocampal gyrus, and temporo-occipital cortex, were also implicated. Taken together, our findings offer new insights into the neural architecture subserving value-driven attention, both extending our understanding of nodes in the attention network previously implicated in feature-based value-driven attention and identifying a ventral network of brain regions implicated in reward’s influence on scene-dependent spatial orienting.

The influence of threat on the efficiency of goal-directed attentional control

ABSTRACT The control of attention is influenced by current goals, physical salience, and selection history. Under certain conditions, physically salient stimuli can be strategically suppressed below baseline levels, facilitating visual search for a target. It is unclear whether such signal suppression is a broad mechanism of selective information processing that extends to other sources of attentional priority evoked by task-irrelevant stimuli, or whether it is particular to physically salient perceptual signals. Using eye movements, in the present study we highlight a case where a former-target-colour distractor facilitates search for a target on a large percentage of trials. Our findings provide evidence that the principle of signal suppression extends to other sources of attentional priority beyond physical salience, and that selection history can be leveraged to strategically guide attention away from a stimulus.

Attention prioritizes stimuli previously associated with punishment. Despite the importance of this process for survival and adaptation, the potential generalization of punishment-related attentional biases has been largely ignored in the literature. This study aimed to determine whether stimulus-punishment associations learned in a specific context bias attention in another context (in which the stimulus was never paired with punishment). We examined this issue using an antisaccade task in which participants had to shift their gaze in the opposite direction of a colored square during stimulus-outcome learning. Two contexts and three colors were employed. One color was associated with punishment (i.e., electrical shock) in one context and never paired with punishment in the other context. For a second color, the punishment-context relationship was reversed. A third color never paired with shock in either context (neutral) was included in Experiment 1 but absent in Experiment 2. Participants then performed search for a shape-defined target in an extinction phase (in which no shock was delivered) in which attentional bias for the colors was assessed. Context was manipulated via the background image upon which the stimuli were presented. In each of the two experiments, a bias to selectively orient toward the color that had been associated with punishment in the current context was observed, suggesting that punishment-modulated attentional priority is context specific.

Learning about aversive outcomes plays a role in the guidance of attention. Classical conditioning generates a bias to predictors of aversive outcomes, whereas instrumental learning potentiates a negatively reinforced avoidance behavior, which can be difficult to dissociate in the case of attention to aversively conditioned stimuli. The present study examined the relative contribution from these two learning processes to the control of attention. Participants were first provided an opportunity to avoid an electric shock by generating a saccade in the direction opposite one of two stimuli. In contradiction to the practiced avoidance behavior, such training resulted in a bias to orient toward the shock-associated stimulus, indicative of a more dominant role of classical conditioning in the control of attention. The findings are in parallel with the influence of positive reinforcement on attention, suggesting that the attention system may be guided by motivational relevance rather than a particular emotional valence. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Attention is biased toward stimuli that have been associated with aversive outcomes in the past. This bias has previously been interpreted as reflecting automatic orienting toward threat signals. However, in many prior studies, either the threatening stimulus provided valuable predictive information, signaling the possibility of an otherwise unavoidable punishment and thereby allowing participants to brace themselves, or the aversive event could be avoided with fast and accurate task performance. Under these conditions, monitoring for threat could be viewed as an adaptive strategy. In the present study, fixating a color stimulus immediately resulted in a shock on some trials, providing a direct incentive not to look at the stimulus. Nevertheless, this contingency resulted in participants fixating the shock-associated stimulus more frequently than a neutral distractor matched for physical salience. Our findings demonstrate that threatening stimuli are automatically attended even when attending such stimuli is actually responsible for triggering the aversive event, providing compelling evidence for automaticity. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

On the automaticity of attentional orienting to threatening stimuli.

ABSTRACT Our attention is strongly influenced by reward learning. Stimuli previously associated with monetary reward have been shown to automatically capture attention in both behavioral and neurophysiological studies. Stimuli previously associated with positive social feedback similarly capture attention; however, it is unknown whether such social facilitation of attention relies on similar or dissociable neural systems. Here, we used the value-driven attentional capture paradigm in an fMRI study to identify the neural correlates of attention to stimuli previously associated with social reward. The results reveal learning-dependent priority signals in the contralateral visual cortex, posterior parietal cortex, and caudate tail, similar to studies using monetary reward. An additional priority signal was consistently evident in the right middle frontal gyrus (MFG). Our findings support the notion of a common neural mechanism for directing attention on the basis of selection history that generalizes across different types of reward.

Neural correlates of attentional capture by stimuli previously associated with social reward

The influence of threat and aversive motivation on conflict processing in the Stroop task

This study aimed to determine whether attentional prioritization of stimuli associated with reward transfers across conceptual knowledge independently of physical features. Participants successively performed two color-word Stroop tasks. In the learning phase, neutral words were associated with high, low, or no monetary reward. In the generalization phase (in which no reward was delivered), synonyms of words previously paired with reward served as Stroop stimuli. Results are consistent with semantic generalization of stimulus–reward associations, with synonyms of high-value words impairing color-naming performance, although this effect was particular to participants who were unaware of the reward contingencies.

Dissociable neural mechanisms underlie value-driven and selection-driven attentional capture

Measuring attention to reward as an individual trait: the value-driven attention questionnaire (VDAQ)

Neural evidence for automatic value-modulated approach behaviour

Distinguishing Between Punishment vs Negative Reinforcement in the Control of Attention

Dissociable Effects of Salience on Attention and Goal-Directed Action

Reward learning biases the direction of saccades in visual search

Statistical regularities in distractor location trigger suppression of high-probability distractor locations during visual search. The degree to which such suppression reflects generalizable, persistent changes in a spatial priority map has not been examined. We demonstrate that suppression of high-probability distractor locations persists after location probabilities are equalized and likely reflects a genuine reshaping of the priority map rather than more transient effects of selection history. Statistically learned suppression generalizes across contexts within a task during learning but does not generalize between task paradigms using unrelated stimuli in identical spatial locations. These findings suggest that stimulus features do play a role in learned spatial suppression, potentially gating the weights applied to a spatial priority map. However, the binding of location to context during learning is not automatic, in contrast to the previously reported interaction of location-based statistical learning and stimulus features. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Specificity and persistence of statistical learning in distractor suppression.

Neural Mechanisms of Attentional Bias Following Aversive Conditioning

Mechanisms of value-learning in the guidance of spatial attention

Evidence for impaired attention to social stimuli in autism has been mixed. The role of social feedback in shaping attention to other, non-social stimuli that are predictive of such feedback has not been examined in the context of autism. In the present study, participants searched for a color-defined target during a training phase, with the color of the target predicting the emotional reaction of a face that appeared after each trial. Then, participants performed visual search for a shape-defined target while trying to ignore the color of stimuli. On a subset of trials, one of the non-targets was rendered in the color of a former target from training. Autistic traits were measured for each participant using the Autism Quotient (AQ). Our findings replicate robust attentional capture by stimuli learned to predict valenced social feedback. There was no evidence that autistic traits are associated with blunted attention to predictors of social outcomes. Consistent with an emerging body of literature, our findings cast doubt on strong versions of the claim that autistic traits can be explained by a blunted influence of social information on the attention system. We extend these findings to non-social stimuli that predict socially relevant information.

Relating Attentional Biases for Stimuli Associated with Social Reward and Punishment to Autistic Traits

Reward learning biases attention toward both reward-associated objects and reward-associated regions of space. The relationship between objects and space in the value-based control of attention, as well as the contextual specificity of space-reward pairings, remains unclear. In the present study, using a free-viewing task, we provide evidence of overt attentional biases toward previously rewarded regions of texture scenes that lack objects. When scrutinizing a texture scene, participants look more frequently toward, and spend a longer amount of time looking at, regions that they have repeatedly oriented to in the past as a result of performance feedback. These biases were scene specific, such that different spatial contexts produced different patterns of habitual spatial orienting. Our findings indicate that reinforcement learning can modify looking behavior via a representation that is purely spatial in nature in a context-specific manner. NEW & NOTEWORTHY The representational nature of space in the value-driven control of attention remains unclear. Here, we provide evidence for scene-specific overt spatial attentional biases following reinforcement learning, even though the scenes contained no objects. Our findings indicate that reinforcement learning can modify looking behavior via a representation that is purely spatial in nature in a context-specific manner.

On the representational nature of value-driven spatial attentional biases.

Linking dopaminergic reward signals to the development of attentional bias: A positron emission tomographic study

Neural Basis of Cognitive Control over Movement Inhibition: Human fMRI and Primate Electrophysiology Evidence

What we pay attention to is influenced by reward learning. Previously reward-associated stimuli are difficult to ignore, automatically drawing our attention even when we know they are no longer beneficial to us. Recent research has suggested that these value-dependent attentional biases affect more than just perception, biasing an individual to act in such a way as to pursue the attended stimulus. Here, I review this evidence and argue for a direct link between attentional biases and shifts in action-related priorities. Given this link, abnormal or otherwise inappropriate reward-related attentional biases are hypothesized to contribute to undesired habits and poor economic choices.

The density (measured at binding potential) of available striatal D2/D3 receptors has been shown to predict trait impulsiveness. This relationship is highly robust and well replicated. In each case, however, the availability of dopamine receptors was measured at rest. More broadly, the extent to which relationships between dopamine receptor availability and behavioral traits hold when participants perform a cognitive task is unclear. Furthermore, the performance of a cognitive task engages fundamentally different neural networks than are maximally engaged during the resting state. This complicates interpretation of previously observed correlations, which could be influenced by two distinct factors. The first is variation in available receptor density, which reflects a stable trait of the individual. The second is variation in context-specific dopamine release, which differentially displaces some dopamine radiotracers (such as raclopride) across individuals. Using an existing data set, we related trait impulsiveness, as measured using the Barratt Impulsiveness Scale (BIS-11), to the density (binding potential) of available striatal D2/D3 receptors as measured using positron emission tomography (PET) with [11C]raclopride. Importantly, the PET scan was completed while participants performed an attention-demanding visual search task. We replicate robust correlations between this measure of receptor availability and trait impulsiveness previously demonstrated during the resting state, extending this relationship to periods of active task engagement. Our results support the idea that this relationship depends on striatal D2/D3 receptor density and not on context-dependent dopamine release.NEW & NOTEWORTHY Several studies have demonstrated a relationship between the density of available striatal D2/D3 receptors and trait impulsiveness. However, in each case, the availability of dopamine receptors was measured during the resting state. This complicates interpretation of previously observed correlations, which could be influenced by either stable variation in receptor density or context-dependent dopamine release. We present evidence uniquely consistent with the former interpretation, providing clarity to the nature of this brain-behavior relationship.

Density of available striatal dopamine receptors predicts trait impulsiveness during performance of an attention-demanding task.

When an otherwise inconspicuous stimulus is learned to predict a reward, this stimulus will automatically capture visual attention. This learned attentional bias is not specific to the precise object previously associated with reward, but can be observed for different stimuli that share a defining feature with the reward cue. Under certain circumstances, value-driven attentional biases can even transfer to new contexts in which the reward cues were not previously experienced, and can also be evident for different exemplars of a stimulus category, suggesting some degree of tolerance in the scope of the underlying bias. Whether a match to a reward-predictive feature is necessary to support value-driven attention, or whether similar-looking features also receive some degree of elevated priority following associative reward learning, remains an open question. Here, I examine the impact of learned associations between reward and red- and green-colored stimuli on the processing of other colors. The findings show that even though other colors experienced during training were non-predictive with respect to reward, the speed with which targets possessing these colors were identified in a subsequent test phase was affected by their similarity to the high-value color. Thus, value-driven attentional biases for stimulus features are imprecise, as would be predicted by a sensory gain model of value-driven attention.

ABSTRACT Which stimuli we pay attention to is strongly influenced by learning. Stimuli previously associated with reward outcomes, such as money and food, and stimuli previously associated with aversive outcomes, such as monetary loss and electric shock, automatically capture attention. Social reward (happy expressions) can bias attention towards associated stimuli, but the role of negative social feedback in biasing attentional selection remains unexplored. On the one hand, negative social feedback often serves to discourage particular behaviours. If attentional selection can be curbed much like any other behavioural preference, we might expect stimuli associated with negative social feedback to be more readily ignored. On the other hand, if negative social feedback influences attention in the same way that other aversive outcomes do, such feedback might ironically bias attention towards the stimuli it is intended to discourage selection of. In the present study, participants first completed a training phase in which colour targets were associated with negative social feedback. Then, in a subsequent test phase, these same colour stimuli served as task-irrelevant distractors during a visual search task. The results strongly support the latter interpretation in that stimuli previously associated with negative social feedback impaired search performance.

Counterintuitive effects of negative social feedback on attention

Reward learning has a powerful influence on the attention system, causing previously reward-associated stimuli to automatically capture attention. Difficulty ignoring stimuli associated with drug reward has been linked to addiction relapse, and the attention system of drug-dependent patients seems especially influenced by reward history. This and other evidence suggests that value-driven attention has consequences for behavior and decision-making, facilitating a bias to approach and consume the previously reward-associated stimulus even when doing so runs counter to current goals and priorities. Yet, a mechanism linking value-driven attention to behavioral responding and a general approach bias is lacking. Here we show that previously reward-associated stimuli escape inhibitory processing in a go/no-go task. Control experiments confirmed that this value-dependent failure of goal-directed inhibition could not be explained by search history or residual motivation, but depended specifically on the learned association between particular stimuli and reward outcome. When a previously high-value stimulus is encountered, the response codes generated by that stimulus are automatically afforded high priority, bypassing goal-directed cognitive processes involved in suppressing task-irrelevant behavior. (PsycINFO Database Record

Mechanisms of habitual approach: Failure to suppress irrelevant responses evoked by previously reward-associated stimuli.

Relating value-driven attentional capture to striatal dopamine: A positron emission tomography study

Neural mechanisms of goal-contingent task disengagement: Response-irrelevant stimuli activate the default mode network

There is growing consensus that reward plays an important role in the control of attention. Until recently, reward was thought to influence attention indirectly by modulating task‐specific motivation and its effects on voluntary control over selection. Such an account was consistent with the goal‐directed (endogenous) versus stimulus‐driven (exogenous) framework that had long dominated the field of attention research. Now, a different perspective is emerging. Demonstrations that previously reward‐associated stimuli can automatically capture attention even when physically inconspicuous and task‐irrelevant challenge previously held assumptions about attentional control. The idea that attentional selection can be value driven, reflecting a distinct and previously unrecognized control mechanism, has gained traction. Since these early demonstrations, the influence of reward learning on attention has rapidly become an area of intense investigation, sparking many new insights. The result is an emerging picture of how the reward system of the brain automatically biases information processing. Here, I review the progress that has been made in this area, synthesizing a wealth of recent evidence to provide an integrated, up‐to‐date account of value‐driven attention and some of its broader implications.

The attention habit: how reward learning shapes attentional selection

Abstract Through associative reward learning, arbitrary cues acquire the ability to automatically capture visual attention. Previous studies have examined the neural correlates of value-driven attentional orienting, revealing elevated activity within a network of brain regions encompassing the visual corticostriatal loop [caudate tail, lateral occipital complex (LOC) and early visual cortex] and intraparietal sulcus (IPS). Such attentional priority signals raise a broader question concerning how visual signals are combined with reward signals during learning to create a representation that is sensitive to the confluence of the two. This study examines reward signals during the cued reward training phase commonly used to generate value-driven attentional biases. High, compared with low, reward feedback preferentially activated the value-driven attention network, in addition to regions typically implicated in reward processing. Further examination of these reward signals within the visual system revealed information about the identity of the preceding cue in the caudate tail and LOC, and information about the location of the preceding cue in IPS, while early visual cortex represented both location and identity. The results reveal teaching signals within the value-driven attention network during associative reward learning, and further suggest functional specialization within different regions of this network during the acquisition of an integrated representation of stimulus value.

Reward processing in the value-driven attention network: reward signals tracking cue identity and location

Paying attention to stimuli that predict a reward outcome is important for an organism to survive and thrive. When visual stimuli are associated with tangible, extrinsic rewards such as money or food, these stimuli acquire high attentional priority and come to automatically capture attention. In humans and other primates, however, many behaviors are not motivated directly by such extrinsic rewards, but rather by the social feedback that results from performing those behaviors. In the present study, I examine whether positive social feedback can similarly influence attentional bias. The results show that stimuli previously associated with a high probability of positive social feedback elicit value-driven attentional capture, much like stimuli associated with extrinsic rewards. Unlike with extrinsic rewards, however, such stimuli also influence task-specific motivation. My findings offer a potential mechanism by which social reward shapes the information that we prioritize when perceiving the world around us.

Individuals regularly experience fluctuations in the ability to perform cognitive operations. Although previous research has focused on predicting cognitive flexibility from persistent individual traits, as well as from spontaneous fluctuations in neural activity, the role of learning in shaping preparatory attentional control remains poorly understood. Across 3 experiments, we manipulated the statistical regularities of an attentional orienting paradigm to examine whether individuals modulated attentional flexibility, the readiness to perform a spatial shift of attention, across learned contexts. We found evidence of learning-based modulations in preparatory attentional control settings when the probability of shifting the focus of attention differed based on temporally or color-defined contexts. Furthermore, in the case of color-defined contexts, these modulations in preparatory control persisted even after a change in the underlying statistical properties. Our results indicate that dynamic adjustments in preparatory attentional control are sensitive to the underlying statistical regularities of an environment. This finding has implications for understanding disordered patterns of attentional control and how these patterns might be modified with training.

When visual features are learned to predict a reward outcome, stimuli possessing these reward-associated features automatically capture attention. This consequence of reward learning on attention has only been examined under conditions in which visual features (e.g., color, orientation) are associated with tangible, extrinsic rewards such as money and food. In the present set of experiments, I examine how an irrelevant reward-associated sound affects visual processing and whether positive social feedback produces attentional biases for associated visual stimuli. In one experiment, participants first performed a training phase comprising a sound identification task in which certain sounds were associated with a monetary reward outcome. In a subsequent test phase, participants completed a visual search task while trying to ignore task-irrelevant sounds, certain of which were previously associated with reward. Visual search performance was impaired in the presence of the previously high-value sound, demonstrating cross-modal attentional capture. In another experiment, participants first performed a training phase comprising visual search for a color-defined target. Trial-by-trial feedback consisted of a face exhibiting either a positive (smile) or neutral expression. Participants were told that these faces would "react to what happened on that trial." One color target was more likely than the other to be followed by a positive expression; the feedback participants received was unrelated to their actual performance. Then, in a subsequent test phase, former-target-color stimuli were presented as distractors in a visual search task for a shape-defined target. Distractors rendered in the color previously associated with a high probability of positive social feedback impaired search. The findings support the domain generality of value-driven attention, with a range of positive outcomes biasing information processing across and between different sensory systems. Meeting abstract presented at VSS 2015.

Exploring Value-Driven Attention: Evidence for a Domain-General Mechanism of Selection.

When stimuli are associated with reward outcome, their visual features acquire high attentional priority such that stimuli possessing those features involuntarily capture attention. Whether a particular feature is predictive of reward, however, will vary with a number of contextual factors. One such factor is spatial location: for example, red berries are likely to be found in low-lying bushes, whereas yellow bananas are likely to be found on treetops. In the present study, I explore whether the attentional priority afforded to reward-associated features is modulated by such location-based contingencies. The results demonstrate that when a stimulus feature is associated with a reward outcome in one spatial location but not another, attentional capture by that feature is selective to when it appears in the rewarded location. This finding provides insight into how reward learning effectively modulates attention in an environment with complex stimulus–reward contingencies, thereby supporting efficient foraging.

Value-driven attentional capture is modulated by spatial context

Neural recording studies in monkeys have shown that shape representation in high-level ventral pathway cortex (including inferotemporal cortex or IT) is structural: ensembles of neurons encode shapes as spatial configurations of structural fragments. The putative homologue for IT in the human brain is the lateral occipital complex (LOC), which is defined by differential responses to intact and scrambled object photographs. Here, we used fMRI to test whether shape representation in human LOC is similarly structural, or is better explained by spatial frequency tuning, which has been the standard quantitative model for shape sensitivity in human cortex. Our stimuli were letter-like combinations of medial axis fragments (straight and curved line segments). Stimuli were presented in random order while subjects performed a one-back shape-matching task. We used a generalized linear model (GLM) to estimate the response pattern of each LOC voxel across stimuli. We parameterized the stimuli as combinations of medial axis fragments, defined by their curvatures, orientations, and object-relative positions. For each voxel, we used stepwise regression to fit a structural tuning model that explained stimulus responses in terms of sensitivity to component fragments. Model complexity was limited to components that explained at least 5% additional variance. Typical models comprised 3-6 components and explained 45-65% of the response variance across stimuli. In contrast, comparable spectral models, based on components from a Gabor wavelet pyramid decomposition of the stimuli, typically explained only 5-15% of the response variance. The explanatory power of the structural models suggests that LOC represents shapes as configurations of structural components. These results also support the homology between human LOC and monkey IT, where neural mechanisms of shape coding can be studied in detail. Meeting abstract presented at VSS 2015.

Structural, not spectral, representation of shape in lateral occipital complex.

Visual attention has long been known to be drawn to stimuli that are physically salient or congruent with task-specific goals. Several recent studies have shown that attention is also captured by stimuli that are neither salient nor task relevant, but that are rendered in a colour that has previously been associated with reward. We investigated whether another feature dimension—orientation—can be associated with reward via learning and thereby elicit value-driven attentional capture. In a training phase, participants received a monetary reward for identifying the colour of Gabor patches exhibiting one of two target orientations. A subsequent test phase in which no reward was delivered required participants to search for Gabor patches exhibiting one of two spatial frequencies (orientation was now irrelevant to the task). Previously rewarded orientations robustly captured attention. We conclude that reward learning can imbue features other than colour—in this case, specific orientations—with persistent value.

Several recent studies have reported an inter-individual correlation between regional GABA concentration, as measured by MRS, and the amplitude of the functional blood oxygenation level dependent (BOLD) response in the same region. In this study, we set out to investigate whether this coupling generalizes across cortex. In 18 healthy participants, we performed edited MRS measurements of GABA and BOLD-fMRI experiments using regionally related activation paradigms. Regions and tasks were the: occipital cortex with a visual grating stimulus; auditory cortex with a white noise stimulus; sensorimotor cortex with a finger-tapping task; frontal eye field with a saccade task; and dorsolateral prefrontal cortex with a working memory task. In contrast to the prior literature, no correlation between GABA concentration and BOLD activation was detected in any region. The origin of this discrepancy is not clear. Subtle differences in study design or insufficient power may cause differing results; these and other potential reasons for the discrepant results are discussed. This negative result, although it should be interpreted with caution, has a larger sample size than prior positive results, and suggests that the relationship between GABA and the BOLD response may be more complex than previously thought.

Multi-Regional Investigation of the Relationship between Functional MRI Blood Oxygenation Level Dependent (BOLD) Activation and GABA Concentration

Previously rewarded stimuli involuntarily capture attention. The learning mechanisms underlying this value-driven attentional capture remain less understood. We tested whether theories of prediction-based associative reward learning explain the conditions under which reward feedback leads to value-based modulations of attentional priority. Across 4 experiments, we manipulated whether stimulus features served as unique predictors of reward outcomes. Participants received monetary rewards for correctly identifying a color-defined target in an initial search task (training phase) and then immediately completed a second, unrewarded visual search task in which color was irrelevant (test phase). In Experiments 1-3, monetary reward followed correct target selection during training, but critically, no target-defining features carried uniquely predictive information about reward outcomes. Under these conditions, we found no evidence of attentional capture by the previous target colors in the subsequent test phase. Conversely, when target colors in the training phase of Experiment 4 carried uniquely predictive information about reward magnitude, we observed significant attentional capture by the previously rewarded color. Our findings show that value-based attentional priority only develops for stimulus features that carry uniquely predictive information about reward, ruling out a purely motivational account and suggesting that mechanisms of reward prediction play an important role in shaping attentional priorities.

Value-driven attentional priority signals in human basal ganglia and visual cortex

The attribution of value-based attentional priority in individuals with depressive symptoms

One aspect of effective cognitive control is the ability to withhold contextually inappropriate responses. The inhibition of a response can be elicited by a goal-relevant stop signal, which has been characterized as a voluntary cognitive process. Cases in which inhibition is triggered automatically by a stimulus have been reported but are limited to instances in which the withholding of a response is associated with the same stimulus over repeated trials, which reflects the gradual emergence of automaticity through associative learning. Findings such as these suggest that inhibitory control is driven by two dissociable mechanisms, one that is flexible but deliberate and another that is automatic but inflexibly learned. In the present study, we showed that response inhibition can be involuntarily triggered when stimulus-response mapping varies unpredictably, without contributions from associative learning. Our findings demonstrate that automatic response inhibition can be flexibly conditioned on top-down goals, which has broad implications for theories of cognitive control.

Attentional capture by non-drug reward is magnified in addiction

ii Acknowledgements iii Dedication iv Chapter I: Introduction and Theoretical Framework 1 1. Attentional Priority as a Function of Stimulus Value 1 2. Evidence that Attentional Selection is Shaped by Rewards 6 3. Exploring the Role of Reward History in Involuntary Attentional Selection 11 Chapter II: Salience-driven Attentional Capture is Modulated by Reward History 13 1. Experiment 1 14 2. Experiment 2 20 3. Summary and General Discussion 23 Chapter III: Attentional Capture Driven by Learned Value 25 1. Experiment 3 26 2. Experiment 4 28 3. Summary and General Discussion 29 Chapter IV: Spatial Specificity of Value-driven Attentional Capture 31 1. Experiment 5 31 2. Experiment 6 33 3. Summary and General Discussion 41 Chapter V: Persistence of Value-driven Attentional Capture 43 1. Experiment 7 43

Value-driven attentional capture: Exploring the influence of reward history on involuntary attentional selection

Attention selects objects in a scene for cognitive processing. A growing body of evidence has been used to argue that observers are able to narrowly restrict attentional selection to stimuli that match a feature-based target template while ignoring similar-looking distractors. For example, visual search for a target among feature-similar nontargets is highly efficient. Here, I demonstrate that observers are substantially impaired at selecting a target among feature-similar nontargets when stimuli are compared with a target template serially in time. The results argue that goal-directed attentional selection is distinctly imprecise, and that comparing stimuli with a target template reflects an inefficient mechanism of selection that cannot fully explain visual search performance under demanding conditions.

Statistical Learning Modulates the Flexible Control of Spatial Attention

Involuntary Inhibition of Motor Responses Contingent on Top-Down Goals

Attention selects stimuli for perceptual and cognitive processing according to an adaptive selection schedule. It has long been known that attention selects stimuli that are task relevant or perceptually salient. Recent evidence has shown that stimuli previously associated with reward persistently capture attention involuntarily, even when they are no longer associated with reward. Here we examine whether the capture of attention by previously reward-associated stimuli is modulated by the processing of current but unrelated rewards. Participants learned to associate two color stimuli with different amounts of reward during a training phase. In a subsequent test phase, these previously rewarded color stimuli were occasionally presented as to-be-ignored distractors while participants performed visual search for each of two differentially rewarded shape-defined targets. The results reveal that attentional capture by formerly rewarded distractors was the largest when both recently received and currently expected reward were the highest in the test phase, even though such rewards were unrelated to the color distractors. Our findings support a model in which value-driven attentional biases acquired through reward learning are maintained via the cognitive mechanisms involved in predicting future rewards.

Cognitive flexibility reflects both a trait that reliably differs between individuals and a state that can fluctuate moment-to-moment. Whether individuals can undergo persistent changes in cognitive flexibility as a result of reward learning is less understood. Here, we investigated whether reinforcing a periodic shift in an object selection strategy can make an individual more prone to switch strategies in a subsequent unrelated task. Participants completed two different choice tasks in which they selected one of four objects in an attempt to obtain a hidden reward on each trial. During a training phase, objects were defined by color. Participants received either consistent reward contingencies in which one color was more often rewarded, or contingencies in which the color that was more often rewarded changed periodically and without warning. Following the training phase, all participants completed a test phase in which reward contingencies were defined by spatial location and the location that was more often rewarded remained constant across the entire task. Those participants who received inconsistent contingencies during training continued to make more variable selections during the test phase in comparison to those who received the consistent training. Furthermore, a difference in the likelihood to switch selections on a trial-by-trial basis emerged between training groups: participants who received consistent contingencies during training were less likely to switch object selections following an unrewarded trial and more likely to repeat a selection following reward. Our findings provide evidence that the extent to which priority shifting is reinforced modulates the stability of cognitive control settings in a persistent manner, such that individuals become generally more or less prone to shifting priorities in the future.

Reinforcement learning modulates the stability of cognitive control settings for object selection

The Role of Predictable and Unpredictable Reward in the Control of Attention

Attentional biases for drug-related stimuli play a prominent role in addiction, predicting treatment outcomes. Attentional biases also develop for stimuli that have been paired with nondrug rewards in adults without a history of addiction, the magnitude of which is predicted by visual working-memory capacity and impulsiveness. We tested the hypothesis that addiction is associated with an increased attentional bias for nondrug (monetary) reward relative to that of healthy controls, and that this bias is related to working-memory impairments and increased impulsiveness. Seventeen patients receiving methadone-maintenance treatment for opioid dependence and 17 healthy controls participated. Impulsiveness was measured using the Barratt Impulsiveness Scale (BIS-11; Patton, Stanford, & Barratt, 1995), visual working-memory capacity was measured as the ability to recognize briefly presented color stimuli, and attentional bias was measured as the magnitude of response time slowing caused by irrelevant but previously reward-associated distractors in a visual-search task. The results showed that attention was biased toward the distractors across all participants, replicating previous findings. It is important to note, this bias was significantly greater in the patients than in the controls and was negatively correlated with visual working-memory capacity. Patients were also significantly more impulsive than controls as a group. Our findings demonstrate that patients in treatment for addiction experience greater difficulty ignoring stimuli associated with nondrug reward. This nonspecific reward-related bias could mediate the distracting quality of drug-related stimuli previously observed in addiction.

Attention selects stimuli for cognitive processing, and the mechanisms that underlie the process of attentional selection have been a major topic of psychological research for over 30 years. From this research, it has been well documented that attentional selection can proceed both voluntarily, driven by visual search goals, and involuntarily, driven by the physical salience of stimuli. In this review, I provide a conceptual framework for attentional control that emphasizes the need for stimulus selection to promote the survival and wellbeing of an organism. I argue that although goal-driven and salience-driven mechanisms of attentional selection fit within this framework, a central component that is missing is a mechanism of attentional selection that is uniquely driven by learned associations between stimuli and rewards. I go on to review recent evidence for such a value-driven mechanism of attentional selection, and describe how this mechanism functions independently of the well-documented salience-driven and goal-driven mechanisms. I conclude by arguing that reward learning modifies the attentional priority of stimuli, allowing them to compete more effectively for selection even when nonsalient and task-irrelevant.

Stimuli that have previously been associated with the delivery of reward involuntarily capture attention when presented as unrewarded and task-irrelevant distractors in a subsequent visual search task. It is unknown how long such effects of reward learning on attention persist. One possibility is that value-driven attentional biases are plastic and constantly evolve to reflect only recent reward history. According to such a mechanism of attentional control, only consistently reinforced patterns of attention allocation persist for extended periods of time. Another possibility is that reward learning creates enduring changes in attentional priority that can persist indefinitely without further learning. Here we provide evidence for an enduring effect of reward learning on attentional priority: stimuli previously associated with reward in a training phase capture attention when presented as irrelevant distractors over half a year later, without the need for further reward learning.

Nebraska Symposium on Motivation. Nebraska Symposium on Motivation

Effective motor control involves both the execution of appropriate responses and the inhibition of inappropriate responses that are evoked by response-associated stimuli. The inhibition of a motor response has traditionally been characterized as either a voluntary act of cognitive control or a low-level perceptual bias arising from processes such as inhibition of return and priming. Involuntary effects of top-down goals on motoric inhibition have been reported, but involve the perseveration of an inhibitory strategy. It is unknown whether the inhibition of a motor response can be selectively triggered by a goal-relevant stimulus, reflecting the automatic activation of a top-down inhibitory strategy. Here we show that irrelevant flankers that share the color of a no-go target elicit the inhibition of their associated motor response while other-colored flankers do not, even when participants have sufficient time to prepare for the upcoming target while ignoring the flankers. Our results demonstrate contingent involuntary motoric inhibition: motoric inhibition can be automatically triggered by a stimulus based on top-down goals.

Contingent involuntary motoric inhibition: the involuntary inhibition of a motor response contingent on top-down goals.

Third, our results demonstrate that failures of colour cued spatial memory consist almost entirely of binding failures, not guesses, unlike spatially cued colour memory. This asymmetry suggests that location information may be uniquely maintained after a colour location binding is lost. Overall, these results favour a structured feature storage account of VSTM (Brady, Konkle, & Alvarez, 2011) and draw attention to the need to characterize retrieval processes in VSTM.

Reinforcement learning modulates preparatory states of cognitive flexibility

Attention is the mechanism by which important or salient stimuli are selected for perceptual and cognitive processing. Which stimuli are attended has important implications for effective goal-directed behaviour, survival, and well-being. A growing body of evidence suggests that reward-predicting stimuli capture attention involuntarily. In previous studies, value-based attentional priority has been observed only when the formerly reward-related stimuli themselves were presented as targets or distractors. Here we show that stimulus–reward associations learned in one task generalize to different stimuli that share a defining feature (colour) in another task. Our results reveal a broad and flexible role for reward learning in modulating attentional priority.

Persistent Changes in Attentional Bias Following Brief Reward Learning: (502412013-863)

Visual attention is captured by physically salient stimuli (termed salience-based attentional capture), and by otherwise task-irrelevant stimuli that contain goal-related features (termed contingent attentional capture). Recently, we reported that physically nonsalient stimuli associated with value through reward learning also capture attention involuntarily (Anderson, Laurent, & Yantis, PNAS, 2011). Although it is known that physical salience and goal-relatedness both influence attentional priority, it is unknown whether or how attentional capture by a salient stimulus is modulated by its associated value. Here we show that a physically salient, task-irrelevant distractor previously associated with a large reward slows visual search more than an equally salient distractor previously associated with a smaller reward. This magnification of salience-based attentional capture by learned value extinguishes over several hundred trials. These findings reveal a broad influence of learned value on involuntary attentional capture.

Attention selects which aspects of sensory input are brought to awareness. To promote survival and well-being, attention prioritizes stimuli both voluntarily, according to context-specific goals (e.g., searching for car keys), and involuntarily, through attentional capture driven by physical salience (e.g., looking toward a sudden noise). Valuable stimuli strongly modulate voluntary attention allocation, but there is little evidence that high-value but contextually irrelevant stimuli capture attention as a consequence of reward learning. Here we show that visual search for a salient target is slowed by the presence of an inconspicuous, task-irrelevant item that was previously associated with monetary reward during a brief training session. Thus, arbitrary and otherwise neutral stimuli imbued with value via associative learning capture attention powerfully and persistently during extinction, independently of goals and salience. Vulnerability to such value-driven attentional capture covaries across individuals with working memory capacity and trait impulsivity. This unique form of attentional capture may provide a useful model for investigating failures of cognitive control in clinical syndromes in which value assigned to stimuli conflicts with behavioral goals (e.g., addiction, obesity).

Target-uncertainty effects in attentional capture: Color-singleton set or multiple attentional control settings?

Variations in the magnitude of attentional capture: Testing a two-process model

Explaining variations in the magnitude of attentional capture: New tests of a two-process model

Cognitive deficits have long been recognized in the phenomenology of schizophrenia, but only recently have these deficits been explored as a potential factor contributing to psychotic symptoms. One such deficit that has risen to the forefront of this research concerns reality monitoring, which refers to the ability to maintain a distinction between internally and externally generated information. The present review summarizes the findings from this exciting new direction in the field of psychopathology, and argues that research concerning deficits in reality monitoring holds promise in unlocking some of the mysteries of how schizophrenia develops. Current gaps in the literature on reality monitoring in schizophrenia are also discussed, and future research directions targeted at filling in these gaps are explored. Generalized cognitive deficits have long been identified as a critical component of schizophrenia (Weinberger, Aloia, Goldberg, & Berman, 1994). Impaired reasoning skills often become manifest when schizophrenics are asked to perform a task, such as the Wisconsin Card Sorting Test (WCST), that requires the application of higher order processes associated with the prefrontal cortex (PFC) (Weinberger & Berman, 1996). Indeed, this disparity between the cognitive reasoning ability of schizophrenics and that of healthy individuals is so great and consistent that some clinical researchers believe it should be reflected in the diagnostic criteria for the disorder (Stip, 2006). A number of theories of schizophrenia have arisen from research into this generalized impairment, the most prominent of which has been the theory of

Converging Evidence for Reality Monitoring Deficits as a Critical Component in Understanding Schizophrenia Symptomatology

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A 31-year-old man with no previous pertinent medical or surgical history presented with seizures and a progressive cognitive decline. He became tremulous, and he had a variable but constant fine action tremor. There were saccadic eye movements on voluntary gaze to either side. He developed myoclonus superimposed on psychomotor slowing with periods of agitation, followed by incoordination, suggesting mild cerebellar dysfunction. There were no other abnormal neurological findings. Laboratory investigation included an elevated protein level in the cerebrospinal fluid and nonspecific slowing in an electroencephalogram. Computed tomography and magnetic resonance imaging of brain and spinal cord were normal, and brain scan showed no indication of cerebral blood flow changes; an extensive metabolic workup was negative. The dementia seemed to progress more rapidly than expected from most metabolic or other dementing diseases; 8 months into his course, a left frontal lobe biopsy was performed, revealing rare microvascular endothelial cell nuclear clusters (Fig. A).

FIGURE 
(A) Frontal lobe biopsy blood vessel has clusters of atypical vascular endothelial cell nuclei and a widened lumen. …

Correspondence regarding: a novel cerebral microangiopathy with endothelial cell atypia and multifocal white matter lesions: a direct mycoplasmal infection? J Neuropathol Exp Neurol 2007;66: 1100-17.

Prolonged eosinophilia ofunknown cause has generally been described as the hypereosinophilic syndrome, and is characterised by peripheral blood and bone marrow infiltration and frequent multisystem disease. The nature of this disorder has been questioned, and the clinical features are quite variable, suggesting its heterogeneity and probable neoplastic aetiology. A patient with severe eosinophilia, karyotype abnormalities, serum gammopathy and massive organ disease is reported. The clinical course was aggressive despite cytoreduction of eosinophils and terminated in multisystem failure. These findings are consistent with a diagnosis of eosinophilic leukaemia, and it is suggested that chromosome and cell culture studies might be useful in the early diagnosis of this controversial

High-dose thiopentone for open-chamber cardiac surgery: a retrospective review

Prolonged eosinophilia of unknown cause has generally been described as the hypereosinophilic syndrome, and is characterised by peripheral blood and bone marrow infiltration and frequent multisystem disease. The nature of this disorder has been questioned, and the clinical features are quite variable, suggesting its heterogeneity and probable neoplastic aetiology. A patient with severe eosinophilia, karyotype abnormalities, serum gammopathy and massive organ disease is reported. The clinical course was aggressive despite cytoreduction of eosinophils and terminated in multisystem failure. These findings are consistent with a diagnosis of eosinophilic leukaemia, and it is suggested that chromosome and cell culture studies might be useful in the early diagnosis of this controversial entity.

(July 1986 through June 1989). Our purpose was to determine the therapeutic equivalence (or lack thereof) of cefotetan and cefoxitin with regard to a specific spectrum of activity (gram-negative rods and Bacteroides jragilis), clinical outcome, and comparative toxicities.' Age, sex, allergies, diagnosis, dose, schedule, duration of therapy, culture and sensitivity tests, and prothrombin time (PT) were evaluated based on preset criteria.P A total of 2135 patientswere reviewed.Of these, 1325patients (62 percent) receivedcefotetanand 810(38 percent)weregivencefoxitin. Bothagents were used for surgical prophylaxis in clean-contaminated surgery (i.e., colorectal andgastroduodenal surgery)and in the treatmentofclinicallyproveninfections (i.e., intraabdominal infection). Cefotetan was administered to 714 patients (54 percent) for surgical prophylaxis; the remaining 611 patients (46 percent) were treated for clinically documented infections. Cefoxitin was administeredto 810patients. Of these 194(20 percent) were dosed for surgical prophylaxis and the remaining 616 patients (76 percent) were treated for clinically documented infections. See Table I for a listing of all dosage regimens. It should be noted that both in surgical prophylaxis and treatment of documented infections cefotetan and cefoxitin were deemed therapeutically equivalent based on the established criteria.' Of the 611 patients receiving cefotetan, only 9 patients (1.47 percent) developed an increase in PT. In those patients treated with cefoxitin, only 7 of 616 patients (1.13 percent) developed an increase in PT (defined as a 30 percent rise from baseline at the completion of three days of therapy). Prophylaxis patients were not included in the hypoprothrombinemia evaluation. There wasnot a statistically significant difference found by the chi-square method of analysis between the two agents relative to hypoprothrombinemia. Bleeding episodes were not documented in any of the evaluable patients. It should be noted that some of the patients had underlying risk factors that may have predisposed them to develop a prolonged PT (e.g., critical illness, renal impairment). These elevations in PT were reversed by the administration of vitamin K. This drug-use review demonstrated clinically insignificant differences between cefotetan and cefoxitin in terms ofclinical effectiveness and drug toxicity. The two antibiotics proved to be comparable when used in the prophylaxis ofclean-contaminated surgery and in the treatment of infection due to susceptible organisms. Although cefotetan is slightly more expensive than cefoxitin on a per-gram basis (Table 2), the longer half-life allows for a twice-daily dosing regimen and a single preoperative dose for surgical prophylaxis. As a result of this study, the pharmacy department realized a costavoidance savings of $11 500 during the first year of this OUR, $20 825 during the second year, and $22 645 during the third year. REFERENCES

Abstract: Although carotid endarterectomy is a common surgical procedure in North America, controversies exist regarding the type of anesthesia, the use of indwelling shunts and the need for intraoperative cerebral monitoring. We present a prospective study of 100 carotid endarterectomies performed over a three year period by a single surgeon without the use of indwelling shunts, patch grafts, or EEG monitoring. The combined stroke and mortality rate was 1%. Our results confirm those of other authors; that indwelling shunts and EEG monitoring are not absolutely essential for a satisfactory outcome in carotid endarterectomies.

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques

Carotid Endarterectomy Without Indwelling Shunts and Intraoperative Electrophysiologic Monitoring

Abstract: Pineal tumours are commonly of germ cell origin. The endodermal sinus tumour is a rare histologic subtype that is highly malignant and radioresistant. A single case is described and compared to six reported intracranial cases in which chemotherapy was used in addition to surgery and/or radiation. Although a beneficial effect of chemotherapy cannot be proven, the probable benefit in non-CNS cases requires that it be strongly considered. A uniform approach to diagnosis, investigation and treatment for intracranial tumours of this type is suggested.

ABSTRACT: We describe eight cases of primary cerebral lymphoma seen in Manitoba from 1980 to 1985. The clinical presentation is similar to other primary brain tumors. The diagnosis should be considered when single or multiple, often deep lesions, show dense enhancement on computerized tomographic (CT) scan, but are avascular at angiography. These tumors are histologically indistinguishable from non-Hodgkins lymphomas arising outside the CNS. The prognosis is poor. However, radiotherapy with or without surgery may offer significant palliation. Although there is no consensus on the value of chemotherapy, corticosteroids alone or multiagent chemotherapy have shown promise in a few cases. For these reasons, histologic diagnosis should be sought in all cases and surgery, radiotherapy, and chemotherapy should be considered, as prolonged survival is possible.

Primary Lymphoma of the Central Nervous System: Manitoba Experience and Literature Review

Intrathecal Synthesis of Autoantibodies to Myelin Basic Protein in Multiple Sclerosis Ingrid Catz and Kenneth C. Warren 21 Effect of Methylprednisolone on CSF IgC Parameters, Myelin Basic Protein and Anti-Myelin Basic Protein in Multiple Sclerosis Exacerbations Kenneth C. Warren, Ingrid Catz, Verona M. leffrey and Dorothy I. Carroll 25 Cytoplasmic RNA in Nervous System Tumours in Children: A Fluorochromic Histochemical Study using Acridine Orange Harvey B. Sarnat, Bernadette Curry, N.B. Rewcastle and Cynthia L. Trevenen 31 High Dose Anticholinergic Therapy in Adult Dystonia Anthony E. Lang 42 Prevalence of Multiple Sclerosis in British Columbia Vincent P. Sweeney, Adele D. Sadovnick and Vilma Brandejs 47 Nitrazepam for Periodic Movements in Sleep (Sleep-related Myoclonus) Harvey Moldofsky, Carole Tullis, Grace Quance and Franklin A. Lue 52 Primary Lymphoma of the Central Nervous System: Manitoba Experience and Literature Review Douglas E. Hobson, Brian A. Anderson, Ian Carr and Michael West 55 Dorsal Midbrain Syndrome in Multiple Sclerosis with Magnetic Resonance Imaging Correlation A. Costantino, S.E. Black, T. Carr, R.i. Nicholson and I.H. Noseworthy 62 The Concurrence of Multiple Sclerosis and Amyotrophic Lateral Sclerosis Walter I. Hader, Bohdan Rozdilsky and Cheranada P. Nair 66 Hypopituitarism Resulting from an Intrasellar Carotid Aneurysm T.C. Ooi and N.A. Russell 70 Rapid Reversal of Ergotamine-induced Vasospasm P. leffrey Lewis, Thomas W. Noseworthy, Avril A. Fitzgerald, George C. Andrews and Albert I. Ceeraert 72 Correspondence 75 Book Reviews 75 Books Received 77 Notes and Announcements 78 Calendar of Events 79

ABSTRACT: The literature contains a single description of sensory perineuritis (Asbury et al 1972). These patients demonstrated a painful, distal, sensory neuropathy, and examination of peripheral nerve biopsies revealed focal thickening and inflammatory infiltrates of the perineurium. We report a patient with sensorimotor peripheral nerve dysfunction, accompanied by progressive slowing of nerve conduction velocity. Examination of a sural nerve biopsy demonstrated focal thickening of the perineurium, inflammatory infiltrates, and necrosis of perineurial cells. Immunohistology revealed a patchy precipitation of IgG and IgM on perineurial cells. Ultrastructurally, mononuclear cells were found adjacent to perineurial cells undergoing necrosis. The patient showed gradual improvement partially coinciding with a course of steroid therapy. We suggest that this neuropathy is caused by damage to the perineurial barrier possibly by an immune-mediated destruction of perineurial cells and subsequent compression of the endoneurial content by perineurial scarring.

Focal neurologic signs developed in a 75-year-old woman who had presented with encephalitis. A diagnosis of western equine encephalitis was made from serologic findings. Although she was improving clinically the patient died from acute dissection of an aortic aneurysm 11 days after admission to hospital. The pathological findings--perivascular infiltrates and multifocal necrosis in the deep grey matter--were consistent with the diagnosis of western equine encephalitis. Similar findings in the basal ganglia and spinal cord corresponded to the focal clinical signs.

• A child, three years after bone marrow transplantation for aplastic anemia, had polymyositis develop as part of chronic graft vs host disease (GVHD). Previous reports have alluded to nonspecific musculoskeletal complaints during life and the occasional finding of necrotizing myositis at autopsy. This report describes the recognition during life, biopsy findings, and response to treatment of inflammatory myopathy during the course of GVHD.

Mitogenic response of lymphocytes in the presence of serum from rats bearing allogenic tissue implants in the anterior chamber of the eye

Summary This case report describes a melanin-containing neurofibroma involving a spinal nerve root. Electron microscopy of the tumor shows that neoplastic Schwann cells are capable of melanogene-sis. Although this capability is suggested in the literature, few reports provide ultra-structural confirmation. The likely identity between reported “cellular blue nevi of spinal nerve roots” and nerve sheath tumors is discussed. It is possible that pigmented nerve sheath tumors behave more aggressively than nonpigmented ones, although it is debatable.

Melanin Containing Neurofibroma: Case Report with evidence of Schwann Cell Origin of Melanin

Trusting LTE Communications for Over-the-Air Updates in Automobiles

Abstract : Overview: Why did we develop a Space Control Strategy? Goal; Threats; Shaping the environment Respond; Preparing now for an uncertain future End State; Status.

Prognostic Factors Associated With Survival In Melanoma Of The Vulva And Vagina

Is Childhood Leukemia Incidence in Florida Linked to Pesticide Exposure

Lichen planus (LP) is an inflammatory disease of autoimmune origin affecting the skin and mucosa with a population prevalence of 0.5%-1.5%. Esophageal involvement with LP is very rare. Oral LP has been associated with chronic liver disease, particularly Hepatitis C virus (HCV) infection. The treatment of hepatitis C, at present, is based on pegylated interferon (Peg-INF) and ribavirin. The relationship between LP and treat- ment of HCV remains uncertain. Some case series have indicated a worsening of oral lichen planus lesions during interferon based treatment but this association is not clear. In this paper, we report the first case in the literature of a patient with esophageal lichen planus related to HCV infection and provide a review of the pertinent world's literature.

Esophageal Lichen Planus and Hepatitis C: Review of the Literature

34 – Recurrent Laryngeal Neuropathy: Clinical Aspects and Endoscopic Diagnosis

During a 20-year period, we treated 26 patients with radiation after total laryngectomy because of laryngeal cancer with subglottic extension (LCSE). The paratracheal lymph nodes superior (and inferior in two cases) to the suprasternal notch were irradiated in addition to the primary tumour bed. With a follow-up period ranging from 5 to 185 months, the occurrence of neoplastic disease in the upper mediastinum was not observed in a single case. The rates of recurrent tumour in the neck and distant metastasis were both 8%. The 6-year survival rate was 67%. The observed results lead us to the conclusion that even with non-irradiation of the superior mediastinal paratracheal lymph nodes, postoperative radiotherapy can achieve reasonable long-term disease-free survival in patients with LCSE.

Is the extent of paratracheal nodal irradiation in laryngeal cancer with subglottic extension related to outcome?

1158 sentinel lymph nodes (SLNs), excised from patients with primary cutaneous melanoma, were assessed pathologically using histology with immunohistochemistry (IHC) on all nodes, and RT‐PCR for Mart‐1 and tyrosinase on 55 nodes. RT‐PCR was compared with the histology and IHC assessed on the same nodes. The evaluation of progressively more detailed protocols for histology and IHC modulated by the RT‐PCR results led to a procedure that consistently detects metastases in 34% of patients submitted to SLN biopsy for cutaneous melanomas with a vertical growth phase and a mean thickness of 2.02 mm (range 0.25, with regression, to 19 mm). As this technique is virtually free of false positives and produces only a marginally lower detection rate than RT‐PCR, which was subject to false positives of 7% in our study, it is suggested that this extended protocol should be the basis on which further evaluation of the place of RT‐PCR in SLN assessment takes place. The evolved protocol described here has been adopted by the EORTC as the standard procedure for pathological handling of sentinel lymph nodes for melanoma when SLN status is a criterion in their clinical trials or studies. Copyright © 2003 John Wiley & Sons, Ltd.

The development of optimal pathological assessment of sentinel lymph nodes for melanoma

The earliest or patch stage of mycosis fungoides may present diagnostic difficulty both clinically and pathologically. The present study of the polymerase chain reaction (PCR) as a diagnostic tool in early mycosis fungoides was therefore undertaken, using a rapid PCR method for the detection of γ‐ and β‐chain T‐cell receptor (TCR) gene rearrangements in routine formalin‐fixed, paraffin‐embedded histological sections. Forty‐two biopsies were studied from 26 patients with mycosis fungoides. Twenty‐three skin biopsies with a clinicopathological diagnosis of early, or patch stage, mycosis fungoides were investigated. Of these, 18 (78 per cent) showed TCR‐γ or both β‐ and γ‐chain TCR gene rearrangements. TCR gene rearrangements were shown in seven of the 14 plaque stage lesions (50 per cent) and also in the single case of tumour stage disease. Where gene rearrangements were identified, these were identical in all biopsies from an individual patient, irrespective of the site of the lesion, the disease stage, or the time lapse between the biopsies. The PCR is therefore a highly sensitive technique, which can be performed on routine pathological material, in cases where the diagnosis of early mycosis fungoides cannot be made with certainty on conventional histopathological and immunohistochemical grounds. © 1997 John Wiley & Sons, Ltd.

The polymerase chain reaction in the diagnosis of early mycosis fungoides

An elderly Caucasian woman with a 2-year-history of hypothyroidism, treated with thyroxine, presented with a rapidly growing mass in the thyroid. The morphological and immunological features of this thyroid tumour were those of a peripheral T-cell lymphoma with an immunophenotype commonly associated with HTLV-1 positive-adult T-cell leukaemia/lymphoma, although serology for HTLV1 antibody was negative. Monoclonal gene rearrangements were demonstrated with T-cell receptor beta- and gamma-specific primers. There are several interesting features in this case (i): although primary B-cell lymphomas (MALT-associated lymphomas) of thyroid are a well-recognized sequel to thyroiditis, primary T-cell lymphomas are rare, even in areas of the world where adult T-cell lymphomas predominate; (ii) the tumour showed the typical immunophenotype of an HTLV-1 positive T-cell lymphoma but the patient is English, has not visited endemic areas, and is serologically negative for HTLV-1; (iii) the residual thyroid gland showed a florid lymphocytic thyroiditis with Hürthle cell change, typical of Hashimoto's thyroiditis; (iv) unlike other reports of thyroid T-cell lymphoma, which have presented with stage III-IV disease, this tumour presented in the favourable clinical stage of IE.

Carcinomas arising in choledochal cysts are well recognized; however, small cell carcinomas have not been reported to arise in choledochal cysts. Extrapulmonary small cell carcinomas have been recognized as unique clinicopathologic entities for decades, and have been found arising in numerous sites. Recently there have been several reviews of the subject (Remick et al.: Medicine 66:457-71, 1987; Richardson and Weiland: Seminars in Oncology 9:484-496, 1982; Levenson et al.: Journal of the National Cancer Institute 67:607-612, 1981). Small cell carcinoma of the pancreas has only rarely been described (Reyes and Wang: Cancer 47:2500-2502, 1981; Corrin et al.: Cancer 31:1523-1527, 1973). These tumors must be distinguished from carcinoid tumors and islet cell tumors, which can often lead to histochemical and histologic confusion (Richardson and Weiland: Seminars in Oncology 9:484-496, 1982). Their response to therapy has not been well documented. We report here a small cell carcinoma of the pancreas that arose within a choledochal cyst and that had immunohistochemical characteristics supporting a neuroendocrine origin but that lacked evidence of islet cell differentiation. A complete response to chemotherapy is also described.

Small cell carcinoma of the pancreas in association with a choledochal cyst: immunohistochemical characterization and complete response to combination chemotherapy.

Screening and initial diagnosis of endometrial cancer can be accomplished by cytologic or histologic sampling techniques when these are positive for malignant cells. When they are negative, the evaluation of the symptomatic patient requires further diagnostic procedures. Fractional dilatation and curettage remains the most reliable method and can begin to establish extent of disease. When dilatation and curettage results are negative in the symptomatic patient, hysterography or hysteroscopy can help identify lesions missed by curettage. Once the diagnosis has been established, a careful search for metastatic disease begins with careful pelvic examination and chest X-ray. When the endocervical curettage contains tumor cells, tracheloscopy and contact hysteroscopy can identify those patients with true endocervical involvement. Preoperative computed axial tomography (CT) or magnetic resonance imaging can direct a thin needle biopsy to prove metastatic disease when enlarged nodes are seen. These imaging techniques can also identify and localize highly suspicious nodes to be biopsied at surgery. Because of a high rate of false negativity, neither of these imaging techniques can exclude the presence of metastatic disease. If CT scanning is done, liver-spleen scan and intravenous pyelography may not be necessary as additional studies. In the absence of CT scanning, intravenous pyelography should be done as a routine, and liver-spleen scanning if liver function tests or physical examination indicate abnormalities. Magnetic resonance imaging and isotope scanning may be useful in the future but are not readily available yet. Surgical evaluation must include removal of the uterus, tubes and ovaries, sampling of the pelvic and para-aortic lymph nodes, and cytology on washings of the pelvic cavity for determination of the extent of disease and of factors placing the patient at high risk for disseminated metastases. Histopathologic evaluation of depth of myometrial invasion, presence of occult cervical involvement and lymph node metastasis and grade of tumor complete the identification of high-risk disease. Speedy and accurate evaluation and diagnosis of endometrial carcinoma and extent of disease can direct timely treatment and offer the patient the best chance for survival.

Summary A study of 16 malignant melanomas of the vulva was undertaken to identify the histologic variants found on the vulva and to evaluate the use of microstaging as a predictor of behavior. Ten of 16 cases were melanoma of mucous membrane (MMM) type of acral lentiginous melanoma. This percentage (63%) is notably higher than in previous reports. Three cases were nodular melanoma (NM). All lesions of MMM and NM type occurred on mucous membranes. Three cases were superficial spreading melanoma and all occurred on skin. Neurotropism was observed in 5 of the 10 MMM. Neuro-tropic melanoma has been reported only once previously in the vulva. Depth of the melanomas was greater than 1.0 mm in 13 of the 16 cases. This correlated with Clark and Chung levels of 3 or higher in the same 13 cases. A poor outcome with an overall 5 year survival of 20% of cases with invasive disease was found. The poor outcome and large number of thick lesions would suggest a correlation, but the distribution is skewed and number of cases too small for statistical documentation.

Malignant Melanoma of the Vulva: A Clinical‐Pathologic Review of 16 Cases

Vulvar lymphangioma circumscriptum: a rare complication of therapy for squamous cell carcinoma of the cervix.

1. Adenomyosis and cancer of the body of the uterus are frequently associated. In 249 cases of endometrial carcinoma, adenomyosis was present in greater or less degree in 96 or 38.5 per cent.

Australian and New Zealand Journal of Obstetrics and Gynaecology

Abstract : The subject matter of the grant was robust behavior of sensor networks. The questions to be addressed included: given a sensor network, to characterize its ability to retain a discrete-valued property in the event of loss of p nodes and q communication links; determine where a further communication link or sensor should be introduced to achieve the best improvement; and address solvability under the constraint that any sensor can communicate with only a limited number of its neighbors. Research results included (1) how sensor networks retain localizability property in the event of loss of p nodes and q communication links, and; (2) characterization of "giant" component in large scale random networks.

Measuring and Ensuring Performance and Information Quality in Multi-Agent Sensor Network Systems

Effect of the number of users on the performance of a local area network

Dissolved organic matter in hand-dug well water as groundwater quality indicator: assessment using laser-induced fluorescence spectroscopy and multivariate statistical techniques

Microbes may play a key role in the mobilization of arsenic present in elevated concentrations within the aquifers extensively exploited for irrigation and drinking water in West Bengal, Bangladesh, and in other regions of South‐East Asia. Microcosm experiments using Cambodian sediments (which are also representative of other similar reducing aquifers containing arsenic‐rich waters) show that arsenic release and iron reduction are microbially mediated and demonstrate that the type of organic matter present, not necessarily the total abundance of organic matter, is important in controlling the rate and magnitude of microbially mediated arsenic release from these aquifer sediments. The possible role of naturally occurring petroleum in stimulating this process is also demonstrated. In addition to acting as an electron donor, certain types of organic matter may accelerate arsenic release by acting as an electron shuttle, indicating a dual role for organic matter in the process. The results also suggest that the fine‐grained sediment regions of these aquifers are particularly vulnerable to accelerated arsenic release following the introduction of labile organic carbon.

The control of organic matter on microbially mediated iron reduction and arsenic release in shallow alluvial aquifers, Cambodia

Stable carbon isotope variations in sediment from Baffin Bay, Texas, U.S.A.: Evidence for cyclic changes in organic matter source

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

Enhanced Sensitivity of the MRL/MpJ Mouse to the Neuroplastic and Behavioral Effects of Chronic Antidepressant Treatments

Chronic pretreatment of mice with the monoamine oxidase type B inhibitor (–) deprenly resulted in an increase in the density of cerebral cortical 3H‐imipramine binding sites and a decrease in the density of cerebral cortical beta‐adrenergic receptors. In contrast, pretreatment of mice with the tricyclie antidepresents imipramine and desipramine did not alter the density of cerebral cortical 3‐Himipramine binding sites. Imipramine and desipramine treatment decreased the density of beta‐adrenergic receptors. Haloperidol pretreatment resulted in an increase in the density of striatal D‐2 dopamine receptors, but did not alter the density of cerebral cortical 3H‐imipramine binding sites or beta‐adrenergic receptors. These data suggest that brain 3H‐imipramine binding sites can be regulated by pharmacological pretreatment, but that this regulation may not occur for all antidepresents.

Chronic antidepressant treatment and mouse brain 3H‐imipramine binding

Dynamical Networks of Social Influence: Modern Trends and Perspectives

This article describes and proposes the Success in Transition Model as a guiding framework for a reconceptualized Transition Assistance Program (TAP) to support U.S. military members as they leave the service. Key groups of veterans have ongoing difficulties adjusting to civilian settings after their time in the service. Even with recent changes, the current TAP has a narrow focus of primarily aiding members to prepare for finding post-military employment, education, and benefits. Little attention is given to other key areas of their functioning such as adjusting to their new work/educational/cultural settings, meeting family transition needs, financial management issues, procuring housing, dealing with trauma responses, or assuring that veterans truly obtain the benefits and support they need. This new model addresses key flaws with the current TAP and is grounded in human and military transition theories and research into optimal ways to foster improved outcomes for transitioning military members.

Reconceptualizing the U.S. Military’s Transition Assistance Program: The Success in Transition Model

Recent Advances in the Modelling and Analysis of Opinion Dynamics on Influence Networks

______________________________________________________________________________________________________________________ The Prairie Research Institute at the University of Illinois at Urbana-Champaign comprises the Illinois Natural History Survey, Illinois State Archaeological Survey, Illinois State Geological Survey, Illinois State Water Survey, and Illinois Sustainable Technology Center. Zika Virus Background

Most international governmental and non-governmental organizations agree that the access to information—and notably access to legal information—is critical to enhancing and promoting the rule of law. Meaningful access to legal information has also been held out as a fundamental right, even declared by some as an international human right. While law libraries are designed to help citizens access legal information, in many societies, especially in developing states, public libraries may be better suited to promote citizens’ access to legal information for a variety of reasons. Public libraries can help uphold and promote the rule of law by providing this access to legal information through outreach programs, partnerships with law library counterparts, and by using other tools to train staff and create physical and digital collections to enhance access.

Meaningful Access to Information as a Critical Element of the Rule of Law: How Law Libraries and Public Libraries Can Work Together to Promote Access

More than satisfying intellectual curiosity, surveys of law libraries can show how they support justice sector institutions, provide access to legal information, and give guidance for future development of libraries. This article investigates Rwanda’s law libraries, and their potential to contribute to the justice sector and overall society in Rwanda.

Examining the relationship between law libraries and democracy in transitional states — a case study of the republic of Rwanda

Contemporary Iraq is facing the full range of challenges that come with post-conflict transitional justice, including “paving the road toward peace and reconciliation” and establishing a functional state, characterized by the Rule of Law. Prospects for the establishment of an independent judiciary in Iraq are obstructed by a number of factors, including (1) how to apply the explicit recognition of the law of Islam in the Iraqi Constitution, (2) the inability to pass legislation on the Federal Courts of Iraq, leaving several provisions of the Iraqi Constitution unimplemented, and other critical elements of judicial independence unaddressed, including provisions for tenure, reappointment and removal of judges, and (3) the impact of the de-Ba’athification authority in Iraq, which has sweeping power to remove judges, and other officials, from office based on allegations that they were too closely tied to the prior regime. Serious concerns about security for judges in Iraq further complicate the picture.Hopes for the Rule of Law in post-conflict Iraq depend heavily on Iraq’s ability to address these deficiencies in judicial independence, setting the stage for effective anti-corruption, reconciliation, peace-building and justice among a people who desperately need it, and who have lived without it for far too long.

Judicial Independence in Post-Conflict Iraq: Establishing the Rule of Law in an Islamic Constitutional Democracy

The Internet has the potential to play a key role in the way civil society organizations promote the rule of law in transitional states. In many states several barriers stand in the way of utilizing the Internet for this purpose. Challenges that arise include technological deficits and poor infrastructure, socio-economic barriers, government hostility to open information, and civil society organizations unable to reach populations. With the development of new technologies, and increased openness of information, civil society organizations will be better positioned to embrace the use of the Internet to promote the rule of law by helping citizens receive information, and facilitating communication between citizens and government.

Internet Enhancement of the Role of Civil Society in Promoting the Rule of Law in Transitional States

In transitional states, especially those developing systems of democratic governance, the creation of online, reliable, and accessible legal information systems is a critical component of good governance. When these databases are created, however, there are significant challenges that may arise to achieving a working and sustainable database. Once created, additional opportunities exist for creating better content, educating users, and enhancing the rule of law through open access to laws. This article will address some of the particular challenges and opportunities presented to transitional states when creating an online legal information system, specifically those involving political and social issues from gaining government commitment, the sustainability of databases, surveying users, and developing added and enhanced content for sites.

Compiling Online Legal Information in Transitional States: Challenges and Opportunities

An Analysis of Hourly Employees Fears of the "Into the Future" Testing Program

Abstract : Our senior leadership is placing renewed emphasis on Air Force core values and recognizes the internalization of these values are critical to the long-term success of our professional officer corps. If we are going to foster these values into the 21st century then we must measure the current health of Air Force core values among our company grade officers and determine where we should focus our efforts to ensure internalization of these values. Therefore, Chapter One of this paper will focus on what makes the military unique from society, provide a brief review of the articulated core values from our senior leadership, and illustrate why our junior officer corps holds the key to sustained change. Next, Chapter Two will address the current trends concerning core values, from a company grade officer perspective, based upon a survey of SOS students. Then, Chapter Three will analyze various Uniform Code of Military Justice (UCMJ) statistics to determine any linkages they may have to the health of company grade officer core values. Based upon my assessment of the survey and UCMJ statistics, Chapter Four will make specific recommendations concerning the role of the consider and the mentoring process to help achieve successful results. Chapter Five will address core values alignment opportunities in our organizations, system, and processes. Finally, my conclusion will recommend a comprehensive needs assessment be instituted to determine the scope and effectiveness of the our core values program and make a call for action on the part of all officers to embrace and live the values.

Internalization of Air Force Core Values Among Company Grade Officers: Where are We and Where are We Going?

The locus and effect of divine revelation among non-Christian religions : a critical analysis of the views of Karl Barth, Karl Rahner and Wilfred Cantwell Smith

We have measured the transverse asymmetry A T (cid:2) in the quasielastic 3 (cid:3) He( (cid:3) e,e (cid:2) ) process with high precision at Q 2 values from 0.1 to 0 . 6(GeV /c ) 2 . The neutron magnetic form factor G nM was extracted at Q 2 values of 0.1 and 0 . 2(GeV /c ) 2 using a nonrelativistic Faddeev calculation which includes both ﬁnal-state interactions (FSI) and meson-exchange currents (MEC). Theoretical uncertainties due to the FSI and MEC effects were constrained with a precision measurement of the spin-dependent asymmetry in the threshold region of 3 (cid:3) He( (cid:3) e,e (cid:2) ). We also extracted the neutron magnetic form factor G nM at Q 2 values of 0.3 to 0 . 6(GeV /c ) 2 based on plane wave impulse approximation calculations.

Extraction of the neutron magnetic form factor from quasielastic 3 (cid:1) He( (cid:1) e , e ) at

A high precision measurement of the transverse spin-dependent asymmetry A T 8 in 3 He W ( e W , e 8 ) quasielastic scattering was performed in Hall A at Jefferson Lab at values of the squared four-momentum transfer, Q 2 , between 0.1 and 0.6 (GeV/ c ) 2 . A T 8 is sensitive to the neutron magnetic form factor, G Mn . Values of G Mn at Q 2 5 0.1 and 0.2 (GeV/ c ) 2 , extracted using Faddeev calculations, were reported previously. Here, we report the extraction of G Mn for the remaining Q 2 values in the range from 0.3 to 0.6 (GeV/ c ) 2 using a plane-wave impulse approximation calculation. The results are in good agreement with recent precision data from experiments using a deuterium target.

Plane-wave impulse approximation extraction of the neutron magnetic form factor from quasielastic 3He(e,e′) at Q2=0.3 to 0.6 (GeV/c)2

We have measured the transverse asymmetry A(T') in 3He(e,e(')) quasielastic scattering in Hall A at Jefferson Laboratory with high precision for Q2 values from 0.1 to 0.6 (GeV/c)(2). The neutron magnetic form factor G(n)(M) was extracted based on Faddeev calculations for Q2 = 0.1 and 0.2 (GeV/c)(2) with an experimental uncertainty of less than 2%.

Transverse asymmetry AT' from the quasielastic 3He(e,e') process and the neutron magnetic form factor.

We have measured the transverse asymmetry from inclusive scattering of longitudinally polarized electrons from polarized {sup 3}He nuclei at quasi-elastic kinematics in Hall A at Jefferson Lab with high statistical and systematic precision. The neutron magnetic form factor was extracted based on Faddeev calculations with an experimental uncertainty of less than 2%.

The Transverse Asymmetry A{sub T}, from Quasi-elastic {sup 3}{ovr He}({rvec e}, e{prime}) Process and the Neutron Magnetic Form Factor

A ug 2 00 2 PW IA Extraction ofthe N eutron M agnetic Form Factor from Q uasi-Elastic

Evaluation of Methods for Early Growth Stage Identification of Corn Genotypes With Stalk Lodging and Rot Resistance

Electron micrographs of a silver resistant strain of Pseudomonas aeruginosa grown in the presence of 50 micrograms/ml Ag+ indicate that the surviving cells are resistant at the level of the cytoplasmic membrane. Spheroplasts of the resistant strain were not lysed by 1 h contact with 8 micrograms/ml Ag+, but were 36% and 22% lysed by 1 h contact with 20 micrograms/ml chlorhexidine and 40 micrograms/ml polysorbate 80, respectively. Spheroplasts of a silver sensitive strain of P. aeruginosa were lysed by 22% on contact with 1 microgram/ml Ag+ for 1 h.

Effect of silver on whole cells and spheroplasts of a silver resistant Pseudomonas aeruginosa.

P.aeruginosa samples were harvested washed twice in 0.9?6 sterile saline and challenged with sterile RZK (25, 50 and 100 ~g/ml). The control was treated similarly except there was no challenge with RZK. All tests were carried out at 37OC in a shaking water bath. Aliquots, removed from the reaction mixtures at intervals, were diluted through inactivating medium and sterile saline and counted by surface plating. The results are illustrated in Figures 1 and 2.

EFFECT OF GROWTH RATE ON THE RESISTANCE OF PSEUDOMONAS AERUGINOSA TO BELZALKONIUM CHLORIDE

Investigation into the Euglena method of assay of vitamin B12 : the results obtained in human serum and liver using an improved method of assay

We use a deterministic model to study two competing viruses spreading over a two-layer network in the Susceptible– Infected–Susceptible (SIS) framework, and address a central problem of identifying the winning virus in a “survival-of-the-ﬁttest” battle. Existing suﬃcient conditions ensure that the same virus always wins regardless of initial states. For networks with an arbitrary but ﬁnite number of nodes, there exists a necessary and suﬃcient condition that guarantees local exponential stability of the two equilibria corresponding to each virus winning the battle, meaning that either of the viruses can win, depending on the initial states. However, establishing existence and ﬁnding examples of networks with more than three nodes that satisfy such a condition has remained unaddressed. In this paper, we address both issues for networks with an arbitrary but ﬁnite number of nodes. We do this by proving that given almost any network layer of one virus, there exists a network layer for the other virus such that the resulting two-layer network satisﬁes the aforementioned condition. To operationalize our ﬁndings, a four-step procedure is developed to reliably and consistently design one of the network layers, when given the other layer. Conclusions from numerical case studies, including a real-world mobility network that captures the commuting patterns for people between 107 provinces in Italy, extend on the theoretical result and its consequences.

Competitive epidemic networks with multiple survival-of-the-fittest outcomes

All modern web browsers - Internet Explorer, Firefox, Chrome, Opera, and Safari - have a core rendering engine written in C++. This language choice was made because it affords the systems programmer complete control of the underlying hardware features and memory in use, and it provides a transparent compilation model. Unfortunately, this language is complex (especially to new contributors!), challenging to write correct parallel code in, and highly susceptible to memory safety issues that potentially lead to security holes. Servo is a project started at Mozilla Research to build a new web browser engine that preserves the capabilities of these other browser engines but also both takes advantage of the recent trends in parallel hardware and is more memory-safe. We use a new language, Rust, that provides us a similar level of control of the underlying system to C++ but which statically prevents many memory safety issues and provides direct support for parallelism and concurrency. In this paper, we show how a language with an advanced type system can address many of the most common security issues and software engineering challenges in other browser engines, while still producing code that has the same performance and memory profile. This language is also quite accessible to new open source contributors and employees, even those without a background in C++ or systems programming. We also outline several pitfalls encountered along the way and describe some potential areas for future improvement.

2016 IEEE/ACM 38th International Conference on Software Engineering Companion (ICSE-C)

All modern web browsers - Internet Explorer, Firefox, Chrome, Opera, and Safari - have a core rendering engine written in C++. This language choice was made because it affords the systems programmer complete control of the underlying hardware features and memory in use, and it provides a transparent compilation model. 
Servo is a project started at Mozilla Research to build a new web browser engine that preserves the capabilities of these other browser engines but also both takes advantage of the recent trends in parallel hardware and is more memory-safe. We use a new language, Rust, that provides us a similar level of control of the underlying system to C++ but which builds on many concepts familiar to the functional programming community, forming a novelty - a useful, safe systems programming language. 
In this paper, we show how a language with an affine type system, regions, and many syntactic features familiar to functional language programmers can be successfully used to build state-of-the-art systems software. We also outline several pitfalls encountered along the way and describe some potential areas for future research.

Experience Report: Developing the Servo Web Browser Engine using Rust

Log simulation is critical for understanding and interpreting logging-tool responses. Simulation helps the log analyst understand near-wellbore measurements in complex environments, particularly in anomalous situations. Simulated logs also can be used in what-if scenarios or as part of an iterative scheme to determine the formation's geometry and material properties. A forward-modeling and inversion environment with a multitier Web-based architecture was developed to provide universal access from the user's desktop, through a common Web browser, to the simulator engine running on a high-performance compute server.

The paper deals with the synthesis of passive networks and relies on general systems theory and control concepts. The network-synthesis problem is first interpreted in state-variable terminology, solved as a control problem and the solution is then translated back into network-theory terms. After a review of state-space formulations, an algebraic theory of synthesis is developed, beginning with a minimal state-space realisation, perhaps obtained through control-theory procedures, from which a synthesis of rational positive-real impedance matrices is obtained through a transformation on the state. The method rests upon an appropriate basis change, in the state-space, obtained by factoring the Pmatrix of the control-theory positive real lemma. The minimum number of resistors and reactive elements is used. The paper also serves as a review of the ‘state-of-the-art’ for formal nport synthesis; the results lead to new methods of attacking open problems, as well as to methods of analysis and synthesis via digital computers.

Detection of latent tuberculosis infection among migrant farmworkers along the US-Mexico border

Preventing tuberculosis among the homeless has emerged as an especially difficult challenge.

We assessed a 2008-2009 tuberculosis (TB) outbreak ad subsequent prevention strategies among homeless persons in metropolitan Jackson, Hinds County, Mississippi.

DESIGN, SETTING AND PARTICIPANTS
We compared data about cases and subclinical TB infections (LTBI) among homeless persons during the outbreak and post-outbreak years, interviewed involved homeless persons, compiled observations from visits to Jackson homeless shelters and conducted literature reviews on homelessness and infectious diseases. We reviewed homeless shelter TB prevention methods adopted by other municipalities, guidelines developed by the Centers for Disease Control and Prevention (CDC), and recommendations from other official and ad hoc groups and considered their applicability to metropolitan Jackson.

The Mississippi State Department of Health TB Program assisted by the CDC and other agencies, contained the Jackson-area outbreak by the end of 2009 as reflected by progressively lower TB rates among homeless persons thereafter. However, some follow-up activities and enforcement of shelter preventive measures have not been consistently maintained. Resources to prevent further outbreaks continue to be inadequate, and over-reliance on private organizations has continued. In the process, appreciation of the dynamic interaction enhancing TB risk among the homeless and incarcerated persons has emerged.

RESULTS
Major outbreak contributors were lack of periodic TB screening among homeless shelter clients, preventive treatment compliance and follow-up difficulties among those with subclinical tuberculosis infections, interrupted preventive measures among infected persons incarcerated in local correctional facilities who disproportionately re-join Jackson's homeless community when released, inadequate attention to shelter environmental preventive strategies such as ultraviolet light germicidal irradiators and proper air-exchange/ventilation, costs of isolation housing for homeless people with full-blown tuberculosis (especially those co-infected with HIV and other infections and those with alcohol and/or other chemical dependencies), lack of adequate transportation which impacts access to evaluation and care, lack of mandated ongoing training among shelter and correctional facility staff, and inadequate attention to the societal problem of homelessness itself.

Sustained adherence to local shelter and correctional facility TB prevention measures based on standards and policies proved effective in other settings is most crucial. These include requirements for periodic tuberculosis prevention and awareness training for shelter and correctional facility staff, ongoing tuberculosis screening and follow-up among homeless shelter clients and inmates of local correctional facilities, and attention to shelter and correctional facility environmental sanitation, proper ventilation, ultraviolet light fixtures and capacity/bed alignment standards.

Tuberculosis Containment among the Homeless in Metropolitan Jackson, Mississippi.

Objective. To investigate the epidemiology of multidrug-resistant Enterobacteriaceae (MDRE) in hospitalized infants. Methods. From 2000 through 2005, active surveillance cultures for MDRE were performed for patients admitted to a 40-bed neonatal intensive care unit (NICU) that provides care for critically ill infants 6 months of age or younger. MDRE epidemiology and the genetic relatedness of MDRE strains determined by repetitive-sequence polymerase chain reaction were analyzed. Results. Active surveillance cultures revealed that 759 (23%) of 3,370 NICU infants (or approximately 1 in 5) developed MDRE colonization or infection and that 613 (72%) of the 853 isolates with epidemiologic data available were healthcare acquired. MDRE colonization occurred more frequently (in 653 infants [86%]) than did MDRE infection (in 106 [14%]). Of the 653 infants with MDRE colonization, 119 (18%) eventually became infected, with 29 (4%) acquiring sterile site infections. The most commonly isolated organisms were the Enterobacter species, accounting for 612 (71%) of the 862 isolates. Molecular epidemiologic analysis revealed that genetic-relatedness clustering (related clusters defined as having a genetic similarity coefficient greater than 95%) varied depending on microbial species. Clustering was detected for 36 (78%) of the 46 Enterobacter aerogenes isolates, 22 (45%) of the 49 Enterobacter cloacae isolates, and 13 (59%) of the 22 Klebsiella pneumoniae isolates. Conclusion. Hospitalized infants are at significant risk of acquiring MDRE, specifically Enterobacter species, at the study institution. Active surveillance cultures identified colonized patients who likely contributed to the institutional reservoir of MDRE. Molecular epidemiologic studies suggest that both patient-to-patient transmission and de novo acquisition of resistance play a role in the acquisition of these organisms, and that the clinical significance of such acquisition varies by species. The high percentage of E. aerogenes isolates that demonstrated genetic clustering suggests that monitoring the prevalence of this organism could serve as a useful measure of compliance with infection control procedures.

Molecular and Descriptive Epidemiology of Multidrug-Resistant Enterobacteriaceae in Hospitalized Infants

We conducted a case-control study of 93 mesothelioma cases and 281 cancer controls to determine whether sugarcane workers exposed to biogenic silica fibers were at increased risk of mesothelioma. We found no important excess risk of mesothelioma in sugarcane workers [odds ratio (OR) = 1.3; 95% confidence interval (CI) = 0.4-3.8] when we excluded all control subjects with cancer of sites suspected of being associated with asbestos exposure. We could not identify any sugarcane workers who developed mesothelioma and worked in jobs where high exposure levels of biogenic silica fibers have been measured. We did confirm that mesothelioma risk in Hawaii is associated with probable occupational asbestos exposure. Work at the Pearl Harbor Naval Shipyard was associated with a 10-fold increase in mesothelioma when we excluded controls with cancer of sites related to asbestos exposure (OR = 10.1; 95% CI = 2.6-56.6). Work in the medical industry was also associated with an unexpected increased risk for mesothelioma (OR = 4.2; 95% CI = 1.2-15.5).

A case-control study of mesothelioma and employment in the Hawaii sugarcane industry.

Giardiasis is the most frequently reported diarrheal disease in northern New England. A case-control study of endemic giardiasis and environmental risk factors among residents of New Hampshire involved 273 cases from the state's 1984 disease registry and 375 controls. Giardiasis was associated with a shallow dug well as a residential water source (odds ratio [OR] = 2.4; 95% confidence interval [CI], 1.3-47.0), a recent history of drinking untreated surface water (OR = 3.4; CI, 2.1-5.5), a history of swimming in a lake or pond (OR = 4.6; CI, 2.4-86.0) or swimming in any natural body of fresh water (OR = 4.0; CI, 2.3-70.0), contact with a person thought to have giardiasis (OR = 2.3; CI, 1.4-36.0), and recent contact with a child in day care (OR = 1.5; CI, 1.0-2.1). Multivariate modeling supported these associations. Shallow wells, relatively common in New Hampshire, have not previously been established as important sources of giardiasis.

Endemic giardiasis in New Hampshire: a case-control study of environmental risks.

Staphylococcus aureus clonal complex (СС) 30 are associated with hospital-acquired and community-associated invasive infections and may cause outbreaks of staphylococcal food-borne infections (SFI). In recent years, severe SFI outbreaks caused by S. aureus CC30 in cohorts not linked to high-risk groups have been detected in Russia. Aim : The aim of the study is to conduct a comparative genomic analysis of S. aureus strains B-7778 and B-7779 isolated during widespread SFI outbreak at the International Youth Forum Seliger in 2014, and S. aureus strains B-7738 and B-7739 isolated during widespread SFI outbreak among construction personnel in Saint Petersburg in 2013. Methods : Seliger-2014 S. aureus cultures were screened by PCR and sequence typing. S. aureus strains B-7778 and B-7779 were isolated from clinic material and from food handlers, respectively. Draft genome sequencing and phylogenetic analysis of S. aureus strains B-7778 and B-7779 were carried out. The production of enterotoxin A was determined by the enzyme immunoassay. Results : S. aureus strain B-7778 isolated from 38 patients and S. aureus strain B-7779 isolated from two food handlers at the Forum Seliger-2014 have identical nucleotide sequences, belong to spa-type t122 and sequence-type 30, and carry a set of toxin genes being responsible for SFI manifestations. The core-genome SNP typing has shown that S. aureus B-7738/ B-7739 (St. Petersburg, 2013) and S. aureus B-7778/ B-7779 (Seliger, 2014) belong to different clusters of S. aureus СС30 clade 3. S. aureus B-7778/ B-7779 not closely related with major clusters of S. aureus СС30. The production of enterotoxin A, SFI etiological factor, by S. aureus strains B-7738, B-7739, B-7778, and B-7779 has been confirmed. Conclusion : The genomic analysis of SFI-associated S. aureus strains isolated in Russia has been conducted for the first time. Two different genetic clones of S. aureus СС30 which are able to cause severe SFI outbreaks in cohorts not linked to high-risk groups have been identified and characterized. SNP typing of Seliger-2014 S. aureus genomes has revealed their genetic specificity among known strains of S. aureus CC30. Identified genome sequences of SFI-associated strains will be used for further studies S. aureus clones circulating through the food chain in Russia.

(PO-033) UCSF End of Life Option Act 2016-2020: A Retrospective Chart Review

UCSF End-of-Life Option Act 2016–2019: A Retrospective Chart Review Pilot (SCI923)

Allina Hospitals and Clinics is implementing an enterprise-wide information system with inpatient and ambulatory clinical documentation and orders, clinical decision support, and revenue cycle applications. Allina has adopted a rigorous approach to planning for and realizing the expected clinical and financial benefits from this investment. Allina's strategies include: Forming a benefits realization team with formal responsibility for analysis, education, facilitation, and measurement; Studying system design to consider requirements for benefits realization; Integrating cultural, organizational and process change plans with system implementation plans; Measuring benefits using a measurement framework that matches organizational reporting, enables multi-level sequential analysis and adjusts for bias in quantifying benefits; Assigning accountability for achieving benefits by matching every benefit with an individual and an operational group; system executives, hospital executives, and department managers are held accountable for benefits within their scope of responsibility, and expected financial benefits are part of their yearly budgets. This article describes Allina's approach for benefits planning, contrasting it with the typical provider's approach to benefits realization. It argues that this approach may greatly increase the likelihood of realizing the value of investments in integrated clinical and business IT

Benefits planning for advanced clinical information systems implementation at Allina hospitals and clinics.

Clinical laboratory management review : official publication of the Clinical Laboratory Management Association

Following an era of "do more, earn more," the health-care industry, including physicians and hospitals, has been faced with cost-containment measures. With this in mind, the Detroit Medical Center (DMC) embarked on a laboratory consolidation initiative to achieve this objective in 1985. The DMC entered into a partnership with Damon Clinical Laboratories, forming Damon Clinical Laboratories at the Detroit Medical Center. This partnership resulted in the consolidation of laboratory services within the DMC and the establishment of an outreach activity. In December 1992, it was decided that the partnership would be dissolved, with the DMC assuming full ownership and responsibility for the management of laboratory services. Thus, DMC University Laboratories was created and is currently in its third year of operation. This article presents how the decision to consolidate laboratory services within the DMC was made, along with the process and outcomes of consolidating the operations of seven hospital laboratories.

Restructuring of laboratory services at the Detroit Medical Center. Process and outcomes.

Mountain glaciers are highly sensitive to climate change. However, the extent to which glaciers capture regional to hemisphere‐scale atmospheric processes remains uncertain, hindering paleoclimatic interpretations derived from moraine‐based glacier reconstructions. Here, we evaluate how mid‐latitude glacier systems monitor climate by comparing climate reanalysis products with glacier annual equilibrium line altitude (ELA) elevations from the antipodal Southern Alps of New Zealand and European Alps. We find significant regional and hemispheric correlations between glacier annual ELA and summer tropospheric temperatures. Annual ELA also exhibit positive correlations with the latitude of the westerly jets in both hemispheres. These results indicate that westerly wind‐belt latitude modulates the proportion of cold versus warm air masses influencing these glacier systems. These results highlight the sensitivity of mid‐latitude glaciers to atmospheric temperatures and circulation, with implications for interpreting moraine‐based paleoclimate reconstructions. Combined impacts of ongoing tropospheric warming and poleward‐shifting westerlies will likely accelerate recession of mid‐latitude glaciers.

Correspondence Among Mid‐Latitude Glacier Equilibrium Line Altitudes, Atmospheric Temperatures, and Westerly Wind Fields

Uniform summer cooling drove glacier re-advance across New Zealand during the late-glacial climate reversal

The timing and magnitude of postglacial climatic changes around the globe provide insights into the underlying drivers of natural climate change. Using geomorphologic mapping of moraines, 10 Be surface-exposure dating, snowline reconstructions, and numerical modeling, we quantified glacier behavior during Late Glacial (15–11.5 ka) and Holocene (the past ∼11.5 k.y.) time in the Ben Ohau Range, New Zealand. Glaciers were more extensive during the Antarctic Cold Reversal (ACR), than subsequently, and the margins underwent a punctuated net withdrawal over the Holocene. Numerical modeling experiments that achieve the best fit to the moraines suggest that air temperature during the ACR was between 1.8 °C and 2.6 °C cooler than today, with similar (±20%) prescribed precipitation. After the ACR, a net snowline rise of ∼100 m through the Younger Dryas stadial (12.9–11.7 ka) was succeeded by a further "long-term," or net, rise of ∼100 m between ∼11 k.y. and ∼500 yr ago. Glacier snowline records in New Zealand show generally coherent Late Glacial and Holocene climate trends. However, the paleoclimate record in the southwest Pacific region shows important differences from that in the Northern Hemisphere.

The anatomy of long-term warming since 15 ka in New Zealand based on net glacier snowline rise

Interhemispheric correlation of glacial terminations using in-situ Be-10

Structure of the Last Glacial Maximum in New Zealand -Terrestrial and Marine Evidence from Southern mid-latitudes

Autobiographical accounts of historical violence and trauma in comics form have gained widespread recognition as valuable pedagogical tools, particularly in the wake of Art Spiegelman’s groundbreaking Maus (1980–91). These comics often draw from the conventions of text-based autobiographies to provide first-person, non-fiction narratives of historical events, contributing to their perceived legitimacy as ‘serious’ texts worthy of inclusion in the classroom. However, this narrow focus on autobiographical comics as authentic windows to history has led educators to largely overlook the unique pedagogical possibilities offered by historical fiction comics, which can use both their fictionality and the comics medium to teach young readers to critically engage with history in different and deeper ways than traditional history textbooks and single-narrator autobiographical comics. This article remedies this gap by analysing how Nathan Hale’s middle-grade historical fiction comic One Dead Spy enacts a critical pedagogy approach to teach children to challenge hegemonic historical discourses and ways of thinking. The comic centres on the Revolutionary spy Nathan Hale (no relation to the comics creator) as he attempts to delay his hanging by narrating the American Revolution to his executioners. Nathan’s purportedly true account hinders children’s critical engagement with history by perpetuating dominant historical discourses, providing readers with a whitewashed, male-centric narrative of the Revolution. By contrast, the backmatter complicates Nathan’s one-sided representation of history by featuring a mini-comic narrated by the former slave Crispus Attucks and by attributing the comic’s non-fiction bibliography to fictional Research Babies. This blending of academic citational practices with absurd metafiction, as well as the introduction of marginalized counter-narrators, teaches middle-grade readers to question the authority of history writers and destabilizes all historical narratives as artificial constructs. However, the paratext also reinforces racist and sexist paradigms by displacing black and female voices to the comic’s supplemental endpapers, underwriting the comic’s well-intentioned attempts to educate readers about important voices excluded from white-centric narratives. Thus, while One Dead Spy demonstrates how historical fiction comics can provoke much-needed discussions about the inherent biases and erasures of dominant historical discourses, it also reveals the dangers of relegating opportunities for children to learn about marginalized perspectives in history to the literal margins.

Revolutionary paratext and critical pedagogy in Nathan Hale’s One Dead Spy

Guide to print and electronic resources for rule of law research at the Taggart Law Library

Print and electronic sources for comparative administrative law research at the Taggart Law Library

Labour relations and Indian self-determination : a Fort Alexander case study

Providing treatment to people with severe mental illnesses on an inpatient unit is fraught with challenges. Many patients are acutely ill and may be experiencing very severe symptoms that coexist with poor insight, emotional dysregulation, impulsivity, aggression, and severe disability. Moreover, many patients are involuntarily hospitalized and may be less cooperative with inpatient treatment. Some civilly committed patients may view their hospital tenure as needlessly lengthy and forced medications as impinging on their civil rights, while longing for less restrictive environments. For many practitioners, these are clinical challenges that adversely impact treatment adherence and ultimately positive treatment outcomes. There is accumulating evidence that the traditional model of decision making is insufficient in psychiatric care and may play a significant role in the reluctance of individuals who need mental health care to seek it and sustain their efforts in it. Shared decision-making, in contrast, provides a viable system of enhancing the engagement of care recipients in treatment and is an essential component of recovery-oriented practice. Inasmuch as it represents a change from the paternalistic model of traditional care, shared decision-making requires a shift in perspective and skill for both the provider and for the individual receiving mental health services. This chapter presents the concept of shared decision-making, explores provider attitudes, expectations and beliefs that may serve as barriers to its implementation, and provides practical strategies to facilitate effective shared decision-making in clinical care.

Drug Treatment Courts and the Elderly: An Examination of the Risks and Needs of Geriatric Drug Offenders

Futile treatment. Do not resuscitate (DNR). These terms and the thoughts they evoke may be unfamiliar to families with ill children. Similarly, laws, such as the Americans with Disabilities Act or the Emergency Medical Treatment and Active Labor Act, are probably unfamiliar. Yet these terms and laws, and, more important, their implications, are part of a new world of health care into which more families are thrust—the world of wrenching and complicated decisions. Although the number of these situations is increasing and even predictable, the infrastructure of support services for families dealing with these medical decisions for seriously ill children has not been adequately addressed or developed. Parents know that some children are born with or develop serious illnesses and die. Amid absorbing large amounts of new information and interpreting the parameters and implications of what they are learning about their child's condition, families are forced by circumstances to assess—and to act on—their most critical, and perhaps previously unexamined, values.

Little knowledge exists concerning long-term sequelae in children born of pregnancies complicated by chronic uteroplacental insufficiency. This follow-up study evaluates 12 children with positive contraction stress tests (CSTs) 5.5 months to 4.75 years following birth. Subsequent physical growth was uniformly normal in the four infants classified as appropriate for gestational age at birth; however, continued postnatal growth deficiency was present in 50% of the eight infants who suffered from intrauterine growth retardation. No major neurologic abnormalities were detected, and 10 of the 12 displayed normal mental and motor function, as determined by the Denver Developmental Screening Test, Bayley Scales of Infant Development and Wechsler Preschool and Primary Scale of Intelligence. Two of the 12 infants were depressed at birth and had serious neonatal complications. These were the only two children who scored poorly on the Bayley test. Although no conclusions regarding minimal brain dysfunction can be made, the majority of infants with positive CSTs demonstrate grossly normal neurologic and psychologic development.

Subsequent physical and mental development in infants with positive contraction stress tests.

Solar Storms around Earth and the terrestrial planets from 2007-2015

Abstract : The MERLIN telescope, based at Jodrell Bank, achieves coherent operation using a frequency standard transmitted over microwave links. This system is locally known as the "Lband Link" (LBL). The LBL uses pulses of RF carrier waves to transmit bi-directionally between two locations in a time-division-multiplexed system (TDM). Tests in the laboratory and astronomical observations have confirmed that the LBL detects changes of delay at approximately the 1-picosecond level over periods of time extending to many hours. The legacy, radio-based, LBL terminal equipment was adapted to transmit, using thermally controlled externally modulated lasers at 1550 nanometers, over an installed fiber network of up to 110 km. The TDM operation of the LBL means that the system lasers may have very close wavelengths and are transmitted over a single fiber. Phase errors due to chromatic dispersion, circulator leakage, and differences in fiber path length are, therefore, reduced or eliminated. The round-trip delay value, halved, and the one-way path delay were measured. Any differences between the two values will indicate the error in the delay measurement, or stability, of the LBL. The objective was to establish if, in an LBL over-fiber system, an rms error close to the 1-picosecond level could be achieved. The measured rms error of the LBL over-fiber system is 1 picosecond, over sampling intervals of between 1 second and 1 minute, irrespective of fiber length. This suggests that the short-term instability seen in the results is due to terminal equipment and measurement error, rather than a fiber effect. Over a 2-hour sampling interval, an LBL over 110-km fiber system has an rms error of 4 picoseconds, compared to the legacy terminal equipment that has an rms error of 3 picoseconds, over the same period.

Phase Transfer for Radio Astronomy Interferometers, Over Installed Fiber Networks, Using a Round-Trip Correction System

VizieR Online Data Catalog: Radio sources in HDF and HFF (Muxlow+, 2005)

18 days of MERLIN data and 42 h of A-array VLA data at 1.4 GHz have been combined to image a 10-arcmin field centred on the Hubble Deep Field (HDF). This area also includes the Hubble Flanking Fields (HFF). A complete sample of 92 radio sources with S 1.4 > 40 μJy was detected using the VLA data alone and then imaged with the MERLIN+VLA combination. The combined images offer (i) higher angular resolution (synthesized beams of diameter 0.2-0.5 arcsec), (ii) improved astrometric accuracy, and (iii) improved sensitivity compared with VLA-only data. The images are amongst the most sensitive yet made at 1.4GHz, with rms noise levels of 3.3 μJy beam -1 in the 0.2-arcsec images. Virtually all the sources are resolved, with angular sizes in the range 0.2 to 3 arcsec. The central 3-arcmin square was imaged separately to search for sources down to 27 μJy. No additional sources were detected, indicating that sources fainter than 40 μJy are heavily resolved with MERLIN and must have typical angular sizes > 0.5 arcsec. Radio sources associated with compact galaxies have been used to align the HDF, the HFF and a larger CFHT optical field to the radio-based International Celestial Reference Frame. The HST optical fields have been registered to 70 per cent of the sources are starburst-type systems associated with major disc galaxies in the redshift range 0.3-1.3. Chandra detections are associated with 55 of the 92 radio sources, but their X-ray flux densities do not appear to be correlated with the radio flux densities or morphologies. The most recent submillimetre results on the HDF and HFF do not provide any unambiguous identifications with these latest radio data, except for HDF8550.1, but suggest at least three strong candidates.

High-resolution studies of radio sources in the Hubble Deep and Flanking Fields

The Mark 4 VLBI correlator is a station‐based system designed to process data from up to 16 stations at an aggregate data rate of 1 Gbps/station. It is compatible with data recorded on Mark 3A, Mark 4, and VLBA tape‐based data‐acquisition systems, as well as the new disc‐based Mark 5 system which also supports both real‐time and quasi‐real‐time data‐transmission over high‐speed networks. The system incorporates an XF algorithm implemented in a custom‐VLSI chip that can be flexibly configured to cross‐correlate VLBI data from one to four baselines of a single 2‐bits/sample channel at 64 Mbps/channel/station. Each chip also incorporates integral phase generators, rotators and vernier‐delay management circuitry. Each of the sixteen Correlator Boards in the system contains 32 correlator chips and can process up to 8192 complex lags that can be flexibly traded off between baselines, lags and channels. Innovative algorithms allow station‐model information to be injected periodically into the data stream from each channel of each station to drive the correlation process. The correlator control software allows up to four independent multistation scans to be processed simultaneously to significantly improve processing efficiency.

Abstract The low loss and ease of use of optical fibres for data transmission offers a number of advantages over traditional methods of bringing signals from radio telescopes together. Aperture synthesis techniques involve the correlation of signals from each pair of telescopes in the array. The requirements of radio astronomy systems, where the broad-band noise-like signals from each telescope have to be brought together coherently over distances as large as hundreds of km or greater in some cases, are discussed in this paper. A number of arrays around the world currently use fibres for data transmission and also for the coherent transfer of local oscillator signals. Further developments in the use of optical fibres in radio astronomy are described as well as new instruments planned for the next millennium, where fibre interconnections will be an essential part of their design.

. We report on a project to determine the proper motions of a sample of 13 young pulsars. Sky positions are measured with phase referencing using two elements of the MERLIN array, giving a baseline of 198km. This technique involves the concurrent observation of each pulsar with one or more extra-galactic reference sources located in the same primary beam. At an observing wavelength of 21 cm, this allows the measurement of pulsar positions to an accuracy greater than 1 mas.

A programme of observations to measure the proper motions of 44 pulsars has been carried out at Jodrell Bank over a four-year period, yielding 31 determinations of proper motion and 13 upper limits. Observations were carried out with two interferometers of the MERLIN radio synthesis instrument at 408 MHz. By wide-field phase referencing to multiple sources with the primary beam of the instrument, accurate positions of each pulsar relative to its reference sources have been determined for a number of epochs. The change in the measured position with epoch results in the determination of the proper motion of the pulsar, using a method similar to that of Lyne, Anderson & Salter.

We present hybrid maps of two quasars, 3C 147 and 3C 286, made at 329 MHz from VLBI observations. Both objects consist of an unresolved core; an extended, asymmetric jet; and an even larger, completely resolved, halo. For 3C 147 it is possible to decompose the spectrum into individual component spectra; at 329 MHz the core of 3C 147 is found to be strongly self-adsorbed. For both sources, the spectral index decreases monotonically from core to jet to halo.

Very long baseline interferometry observations of 3C 147 and 3C 286 at 329 megahertz

Statistical investigation of compact emitting regions in extragalactic radio sources

Radio structure of 3C147 determined by multi-element very long baseline interferometry

Very-long-baseline interferometry (v. l. b. i.) experiments can determine the separation between antennae many thousands of kilometres apart and can also determine the orientation of a baseline with respect to an extragalactic frame of reference. Shapiro et al. (1974) have used v. l. b. i. to determine the length of a 3900 km baseline with an accuracy of approximately 20 cm, and to estimate changes of universal time and the x; component of polar motion which are in agreement with conventional optical determinations to within 3 ms and 1.3 m respectively. A significant improvement in accuracy is expected shortly. The technique and the limitations are reviewed.

Philosophical Transactions of the Royal Society of London. Series A, Mathematical and Physical Sciences

Applications of very-long-baseline interferometry to geodesy and geodynamics

Gold pointed out in 1967 that as some quasars have components smaller than 0.01, radio interferometers might allow distances on Earth of the order of 104 km to be measured to a precision of a few centimetres. He envisaged radio interferometers employing video tape recorders and atomic time standards. The difficulties and probable costs of such measurements are reviewed.

A Discussion on the measurement and interpretation of changes of strain in the Earth - Useful geodetic measurements with radio interferometers?

Radio Diameter Measurements with Interferometer Baselines of One Million and Two Million Wavelengths

Observations of Twelve Radio Sources at A Wavelength of 0.73 m with A Tracking Interferometer Having A Baseline of 180,000 Wavelengths

Observations of the Quasi-stellar and Other Radio Sources with an Interferometer of Resolving Power 0.4 sec of Arc

Observations of 384 Radio Sources at a Frequency of 158 Mc/s with a Long Baseline Interferometer

Crosslinked hyaluronic acid hydrogels: a strategy to functionalize and pattern.

Substrate-mediated delivery from self-assembled monolayers: effect of surface ionization, hydrophilicity, and patterning.

Efficient gene delivery is a fundamental goal of biotechnology and has numerous applications in both basic and applied science. Substrate-mediated delivery and reverse transfection enhance gene transfer by increasing the concentration of DNA in the cellular microenvironment through immobilizing a plasmid to a cell culture substrate prior to cell seeding. In this report, we examine gene delivery of plasmids that were complexed with cationic polymers (polyplexes) or lipids (lipoplexes) and subsequently immobilized to cell culture or biomaterial substrates by adsorption. Polyplexes and lipoplexes were adsorbed to either tissue culture polystyrene or serum-adsorbed tissue culture polystyrene. The quantity of DNA immobilized increased with time of exposure, and the deposition rate and final amount deposited depended upon the properties of the substrate and complex. For polyplexes, serum modification enhanced reporter gene expression up to 1500-fold relative to unmodified substrates and yielded equivalent or greater expression compared to bolus delivery. For lipoplexes, serum modification significantly increased the number of transfected cells relative to unmodified substrates yet provided similar levels of expression. Immobilized complexes transfect primary cells with improved cellular viability relative to bolus delivery. Finally, this substrate-mediated delivery approach was extended to a widely used biomaterial, poly(lactide-co-glycolide). Immobilization of DNA complexes to tissue culture polystyrene substrates can be a useful tool for enhancing gene delivery for in vitro studies. Additionally, adapting this system to biomaterials may facilitate application to fields such as tissue engineering.

Gene delivery through cell culture substrate adsorbed DNA complexes.

Novel pH-sensitive gel-forming pentablock copolymers based on commercially available Pluronic (poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide), PEO-b-PPO-b-PEO) triblock copolymers and cationic diblock copolymers based on poly(ethylene glycol) methyl ether (PEGME) were synthesized by oxyanionic polymerization. Polymerization of the cationic moiety, poly((diethylamino)ethyl methacrylate), PDEAEM, was initiated by a difunctional potassium alcoholate of the triblock Pluronic copolymer F127 (PEO106−PPO69−PEO106) or PEGME. The difunctionality of the initiation using the triblock macroinitiator, indicating formation of a pentablock copolymer rather than a tetrablock copolymer, was verified by functionalized termination of the living polymer chains. Critical micellization temperatures (cmt) of the synthesized polymers were obtained from differential scanning calorimetry for the pentablock materials. The pentablock copolymers retained the thermoreversible gel-forming properties of Pluronic F12...

Synthesis and characterization of diblock and gel-forming pentablock copolymers of tertiary amine methacrylates, poly(ethylene glycol), and poly(propylene glycol)

Studies were performed to examine the effect of ionic salts on phase transitions, dissolution rates, and diffusion coefficients of water in gels of poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) with polymer concentrations ranging from 22 to 32% w/w and salt concentrations ranging from 0 to 1.5% w/w. Salts tested include Na(3)PO(4), Na(2)SO(4), Na(2)HPO(4), NaH(2)PO(4), NaCH(3)CO(2), NaCl, and KI. Micellization transition temperatures were obtained using differential scanning calorimetry. The dissolution rates were obtained by measurement of the surface erosion rates, and diffusion coefficients were obtained by using a method to analyze the intrusion of water into the aqueous gels. It was found that salts had no effect on the dissolution rate of the polymer gels into deionized water. However, when the salt concentration in the aqueous dissolution media was adjusted to match the concentration in the gels, the dissolution rate of the polymer gel decreased with increasing salt concentration. The salts also had a profound effect on the critical micellization temperature (CMT) and the diffusion coefficient of water within the gel. The diffusion coefficient and CMT decreased in the presence of salts. The magnitude of these effects was comparable to their placement on the Hofmeister, or lyotropic series for salts. The effects of polymer and salt concentrations on the CMT were quantified, and a single correlation was proposed to predict the micellization temperatures for a wide range of salt and polymer concentrations.

The effect of salts on the micellization temperature of aqueous poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) solutions and the dissolution rate and water diffusion coefficient in their corresponding gels.

The underlying theme of this thesis is the use of polymeric materials in bioapplications. Chapters 2-5 either develop a fundamental understanding of current materials used for bioapplications or establish protocols and procedures used in characterizing and synthesizing novel materials. In chapters 6 and 7 these principles and procedures are applied to the development of materials to be used for gene therapy and drug delivery. Chapter one is an introduction to the ideas that will be necessary to understand the subsequent chapters, as well as a literature review of these topics. Chapter two is a paper that has been published in the ''Journal of Controlled Release'' that examines the mechanism of drug release from a polymer gel, as well as experimental design suggestions for the evaluation of water soluble drug delivery systems. Chapter three is a paper that has been published in the ''Journal of Pharmaceutical Sciences'' that discusses the effect ionic salts have on properties of the polymer systems examined in chapter two. Chapter four is a paper published in the Materials Research Society Fall 2000 Symposium Series dealing with the design and synthesis of a pH-sensitive polymeric drug delivery device. Chapter five is a paper that has been published in the journal ''Biomaterials'' proposing a novel polymer/metal composite for use as a biomaterial in hip arthroplasty surgery. Chapter six is a paper that will appear in an upcoming volume of the Journal ''Biomaterials'' dealing with the synthesis of a novel water soluble cationic polymer with possible applications in non-viral gene therapy. Chapter seven is a paper that has been submitted to ''Macromolecules'' discussing several novel block copolymers based on poly(ethylene glycol) and poly(diethylamino ethyl methacrylate) that possess both pH-sensitive and temperature sensitive properties. Chapter eight contains a summary of the research contained in chapters 2-7 and proposes future research for the gene therapy and drug delivery projects.

Development of Novel Polymeric Materials for Gene Therapy and pH-Sensitive Drug Delivery: Modeling, Synthesis, Characterization, and Analysis

We have developed methods to synthesize a family of novel self-assembling, pH and temperature sensitive water-soluble multiblock copolymers based on poly(ethylene oxide) (PEO) and poly(diethylaminoethylmethacrylate) (PDEAEM) with a variety of nanoarchitectures.. We have developed oxyanionic polymerization techniques to synthesize di-, tri-, and pentablock copolymers of PEO, poly(propylene oxide) (PPO) and PDEAEM, and also random copolymers of poly(ethylene glycol) methyl ether methacrylate and PDEAEM. The pentablock copolymers self-assemble to form nanometer scale micelles in aqueous solutions and above a critical gelation temperature, the micelles entangle and self-assemble to form macroscale thermoreversible water-soluble physical gels. Aqueous solutions of these polymers at room temperatures can be injected into the body where they form physical gels for controlled delivery that eventually dissolve and release the entrapped molecules. They also possess the ability to undergo swelling/syneresis in response to changes in pH. These polymers were characterized by a number of techniques such as NMR, gel permeation chromatography, infrared spectroscopy, etc. Such smart injectable systems could be very useful for insulin in response to glucose changes. These cationic polymers also exhibit complexation with DNA at physiological pH values and are potential as gene therapy vectors.

Proceedings of the Second Joint 24th Annual Conference and the Annual Fall Meeting of the Biomedical Engineering Society] [Engineering in Medicine and Biology

Design and synthesis of novel pH and temperature sensitive copolymers for injectable delivery

Al-Cu-Fe quasicrystal/ultra-high molecular weight polyethylene composites as biomaterials for acetabular cup prosthetics.

Synthesis and characterization of injectable, water-soluble copolymers of tertiary amine methacrylates and poly(ethylene glycol) containing methacrylates.

Journal of controlled release : official journal of the Controlled Release Society

Understanding drug release from poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) gels.

Synthesis and Characterization of Water Soluble Block Copolymers for pH-Sensitive Delivery

The permeation-controlled transport (or lack of transport) of cations of various size through thin films of the molecular square compound, [Re(CO)3(Cl))(μ-pyrazine)]4, was studied using cyclic voltammetry. Cations smaller than the available cavity in the square molecules were found to permeate the film, while cations larger than the cavity showed no appreciable permeation. The permeation by the redox-silent cations was indirectly observed by monitoring the oxidation of iodide or chloride counter ions. These results indicate that the available cavity size in the title compound is between 4. 1 and 6.1 A, which, as expected, is smaller than the ca. 7.2 A Re…Re distance observed by X-ray crystallography.

Preliminary electrochemical studies of the permeation of mesoporous films of the molecular square compound, [Re(Co)3(Cl)(μ-pyrazine)]4 by redox-silent cations : Redox-active counter anions as reporters on the cation size dependence of the permeation process

Study of monolayers formed from n-alkanethiols chemisorbed on gold and synthesis of a photo-responsive poly(gamma-benzyl-L-glutamate) monolayer

Digital Radiographic Pixel Measurement for On-line Piping Integrity

Hybrid microstructured fibers, utilizing both air holes and high index cladding structures, provide important advantages over conventional fiber including robust fundamental mode operation with large core diameters (>30μm) and spectral filtering (i.e. amplified spontaneous emission and Raman suppression). This work investigates the capabilities of a hybrid fiber designed to suppress stimulated Brillouin scattering (SBS) and modal instability (MI) by characterizing these effects in a counter-pumped amplifier configuration as well as interrogating SBS using a pump-probe Brillouin gain spectrum (BGS) diagnostic suite. The fiber has a 35 μm annularly gain tailored core, the center doped with Yb and the second annulus comprised of un-doped fused silica, designed to optimize gain in the fundamental mode while limiting gain to higher order modes. A narrow-linewidth seed was amplified to an MI-limited 820 W, with near-diffraction-limited beam quality, an effective linewidth ~ 1 GHz, and a pump conversion efficiency of 78%. Via a BGS pump-probe measurement system a high resolution spectra and corresponding gain coefficient were obtained. The primary gain peak, corresponding to the Yb doped region of the core, occurred at 15.9 GHz and had a gain coefficient of 1.92×10-11 m/W. A much weaker BGS response, due to the pure silica annulus, occurred at 16.3 GHz. This result demonstrates the feasibility of power scaling hybrid microstructured fiber amplifiers

Power scaling of a hybrid microstructured Yb-doped fiber amplifier

The development of high-power fiber lasers is of great interest due to the advantages they offer relative to other laser technologies. Currently, the maximum power from a reportedly single-mode fiber amplifier stands at 10 kW. Though impressive, this power level was achieved at the cost of a large spectral linewidth, making the laser unsuitable for coherent or spectral beam combination techniques required to reach power levels necessary for airborne tactical applications. An effective approach in limiting the SBS effect is to insert an electro-optic phase modulator at the low-power end of a master oscillator power amplifier (MOPA) system. As a result, the optical power is spread among spectral sidebands; thus raising the overall SBS threshold of the amplifier. It is the purpose of this work to present a comprehensive numerical scheme that is based on the extended nonlinear Schrodinger equations that allows for accurate analysis of phase modulated fiber amplifier systems in relation to the group velocity dispersion and Kerr nonlinearities and their effect on the coherent beam combining efficiency. As such, we have simulated a high-power MOPA system modulated via filtered pseudo-random bit sequence format for different clock rates and power levels. We show that at clock rates of ≥30 GHz, the combination of GVD and self-phase modulation may lead to a drastic drop in beam combining efficiency at the multi-kW level. Furthermore, we extend our work to study the effect of cross-phase modulation where an amplifier is seeded with two laser sources.

Numerical investigations of self- and cross-phase modulation effects in high-power fiber amplifiers (Conference Presentation)

Abstract. We report efficient coherent beam combining of five kW-class fiber amplifiers seeded with pseudorandom phase-modulated light, using a 1×5 diffractive optical element (DOE). Each fiber amplifier channel was path length matched, actively polarized, and provided approximately 1.2 kW of near diffraction-limited output power (M2<1.1). A low-power sample of the combined beam after the DOE provided an error signal for active phase stabilization. After phase stabilization, the beams were coherently combined via the DOE. Notably, a total output power of ∼5  kW was achieved with 82% combining efficiency and excellent beam quality (M2<1.1). The intrinsic DOE splitter loss was 5%. Additional losses due in part to nonideal polarization, amplified spontaneous emission content, uncorrelated wavefront errors, and fractional beam misalignments contributed to the efficiency reduction. Overall, multi-kW beam combining of pseudorandom-modulated fiber amplifiers was demonstrated for the first time.

Multi-kilowatt diffractive coherent combining of pseudorandom-modulated fiber amplifiers

Gain between the I(2P3/2) and I*(2P1/2) states of atomic iodine at 1.315 μm was detected in a transverse subsonic flow reactor that produced electronically excited I*(2P1/2) atoms from the efficient energy transfer reaction between NCl(a1Δ) metastables and ground state I(2P3/2) atoms. The population inversion was directly observed using a 1.315 μm tunable diode laser that scanned across the entire I(2P3/2)−I*(2P1/2) hyperfine transition with complete resolution.

The direct observation of gain on the 1.315 μm transition of atomic iodine produced by the energy transfer from NCl(a1Δ) to I(2P3/2)

High-resolution diode laser spectroscopy has been used to probe the gain in the active medium formed by an advanced supersonic chemical oxygen iodine laser (COIL), ejector nozzle bank. The probe beam was directed through the medium at 90/spl deg/ (normal) to the flow velocity and at an angle of 27.5/spl deg/ away from normal incidence. Analysis of the small-signal gain spectrum allowed for the determination of the gain, average gas velocity, static pressure, and temperature. The dependence of gain, temperature, and gas velocity on the primary nitrogen molar flow rate and basic hydrogen peroxide temperature was obtained. A maximum small-signal gain of 7 /spl times/ 10/sup -3/ cm/sup -1/, average gas velocity of 575 m/s, static temperature of 172 K were measured for flow rates of 270 mmole/s of primary nitrogen, 39.2 mmole/s of chlorine, 11 mmole/s of secondary nitrogen, and 0.8 mmole/s of iodine. Estimation of the static pressure in the flow core from spectroscopic data is very close to the static sidewall pressure. The role of transverse velocity components in the gas flow and their effect on the interpretation of gain profiles is discussed.

Results of small-signal gain measurements on a supersonic chemical oxygen iodine laser with an advanced nozzle bank

A novel high sensitivity diagnostic for magnetic fields using a high Verdet constant ZnSe crystal is demonstrated. It was thought that x-ray effects might render this particular diagnostic realization suspect for fast rise time magnetic fields. Tests with x-ray fluxes up to 180 millirad at photon-energies up to 200 keV indicate immunity from these effects.

High sensitivity Faraday rotation technique for measurements of magnetic fields with immunity to x-ray effects

The gain, the temperature, and the absolute velocity of the supersonic active oxygen—iodine medium produced by an ejector nozzle unit were determined by the technique of high-resolution diode laser spectroscopy. The gain in the active medium is formed at less than 44 mm from the nozzle unit for an absolute flow velocity ν ≈ 600 m s-1. Upon dilution of oxygen by primary nitrogen in the ratio of 1 : 6.9, the gain of the active medium amounts to 7×10-3 cm-1, the temperature of the active medium to 200 K, the absolute flow velocity to 580 m s-1, and the pressure to 58 Torr. As the dilution is increased to 1 : 13.5, the gain reduces to 4.5×10-3 cm-1, the temperature lowers to 180 K, the velocity of the active medium increases to 615 m s-1, and the pressure increases to 88 Torr. The increase in the initial content of water vapour in the oxygen flow results in an increase in the temperature and a decrease in the gain of the active medium.

ACTIVE MEDIA: Amplification and gas-dynamic parameters of the active oxygen---iodine medium produced by an ejector nozzle unit

A compact, short pulse photolytic iodine laser (PIL) system designed for use as a source in Raman conversion experiments is described. The single-shot, flashlamp-pumped laser outputs 10 Joules in a 3 microsecond(s) FWHM pulse at a wavelength of 1.315 micrometer and uses n-C3F7I as the renewable laser fuel. Laser design and performance characteristics are presented.

The Zeeman spectra of atomic iodine in the presence of a magnetic field ranging from 0 to 400 G has been directly observed with a high-resolution 1.3-µm diode laser tuned across the I(2P1/2)→I(2P3/2) hyperfine transitions in a heated I2 cell. Experimental results for both σ(ΔMF=0) and π(ΔMF=±1) transitions are presented and compared with a theoretical model with good agreement. A Gaussian fit to zero-field spectral lines gives a measure of gas temperature and peak absorption in agreement with calculated values based on experimental conditions.

This paper summarizes recent progress that has occurred in several research areas related to the development of a repetitively-pulsed, frequency-shifted chemical oxygen iodine laser (COIL). COIL gain- switch experiments at 10 kHz pulse rates are described using a novel solid state pulsed magnetic field system. Raman conversion experiments in hydrogen using a pulsed photolytic iodine laser as a COIL surrogate are also described.

Progress report on the development of a repetitively pulsed frequency-shifted COIL laser

Recent experimental results in the development of an all gas phase iodine laser

A direct measurement of gain on the electronic I (2P3/2) - I*(2Pi/2) transition of atomic iodine at 1.315 jam using tunable diode laser is demonstrated. The population inversion results from the efficient energy transfer between NCI (alA) metastables and I (2P3/2) atoms. Ground state iodine atoms and NCI (a1 A) metastables are produced in a transverse subsonic flow device from the stepwise reaction of Cl atoms with HI followed by the reaction of Cl with azide (N3) radicals, respectively. Under current experimental conditions, a gain of 0.020%/cm is obtained and appears to be limited by reagent number density. A kinetic model was constructed to simulate the experimental gain profile using a mechanism consisting of fully coupled finite rate chemistry and 1-D fluid dynamics. Good agreement with experimental and theoretical calculations are obtained. Keywords: Gain, population inversion, atomic iodine, NCI (a*A) metastables, azides, energy transfer

Measurement of gain on the 1.315-μm transition of atomic iodine as produced from the NCl(a1Δ) + I(2P3/2) energy transfer reaction

The measurement of gain on the 1.315 μm transition of atomic iodine in a subsonic flow of chemically generated NCl(a1Δ)

A high-resolution, continuously tunable 1.3 micrometers diode laser is used as a small signal probe to investigate the Zeeman spectra of atomic iodine. A heated quartz cell containing a small amount of I2 is placed in a 0 to 400 gauss B field transverse to the axis of the laser probe. Hyperfine spectral scans are recorded as a function of B- field strength and laser polarization and are compared to theory with very good agreement.

This paper describes the results from a combined experimental theoretical investigation of a coaxial pumped photolytic bromine laser. A 532-nm pump was used to photodissociate IBr and produce Br*(/sup 2/P/sub 1/2/) with subsequent lasing on the (/sup 2/P/sub 1/2/)/spl rarr/(/sup 2/P/sub 3/2/) transition. Experimental results are presented for output energy, mode buildup time and small-signal gain as a function of pump energy and mirror outcoupling fraction. A simplified rate equation model was developed to predict the laser performance parameters and shows good agreement with the laser output energy and small-signal gain.

Experimental and theoretical investigation of a coaxial pumped photolytic atomic bromine laser

Results of parametric studies on a high efficiency, 2.7 micrometers atomic bromine laser, produced by photolyzing IBr with 532 nm radiation, are presented. Concurrently, the results of a rate equation computer model show excellent agreement with experimental measurements.

Experimental and theoretical investigation of a coaxial-pumped photolytic atomic bromine laser

For pt.I, see ibid., vol.29, no.3, p.933-43 (1993). Results are presented from an experimental/theoretical investigation of the frequency shifting and tuning behavior of a chemical oxygen-iodine laser in the presence of an applied magnetic field. Frequency shifting measurements are presented for both P and S polarization over a range of magnetic field strength from 0 to 3000 G, in a pressure regime (3 torr) where the line shape is Doppler broadened. Theoretical predictions of the location and magnitude of the frequency shifts are shown to be in good agreement with both the present measurements and a previous investigation in the pressure broadened regime. >

The chemical oxygen iodine laser in the presence of a magnetic field. II. Frequency tuning behavior

For pt.II, see ibid., vol.29, no.3, p.944-53 (1993). The results from a combined experimental/theoretical investigation of the influence of a magnetic field on the gain and polarization in a supersonic chemical oxygen laser are described. Theoretical calculations are presented for the normalized gain as a function of magnetic field strength and are shown to be in good agreement with the experimental data. Experimental results are given for the gain suppression for P and S polarization over the range 0-1000 G. Without polarizing elements internal to the laser cavity the degree of P polarization was measured for field strength from 0 to 200 G, and a qualitative explanation is offered for the observed behavior. >

The chemical oxygen iodine laser in the presence of a magnetic field. I. Gain measurements and polarization effects

The Chemical Oxygen Iodine Laser in the presence of a magnetic field. I - Gain measurements and polarization effects

We report on a fast framing camera designed to image imploding foils driven by inductive storage drivers. The camera has several front ends which are disposable, they allow for imaging in either the visible, UV, or x‐ray regions; it also has very large dynamic range which allows it to record sequences of events where the brightness changes by many orders of magnitude.

Optical and UV/x‐ray imaging diagnostics for imploding plasma experiments

We report the first observation to our knowledge of self-pumped phase conjugation in BaTiO(3) at 1.06 microm. An essential feature is the lower threshold external ring configuration rather than total internal reflection geometry. Although the product of incident power (1 W/cm(2)) and formation time (600 sec) is much larger than the corresponding values at 0.80 microm (0.15 W/cm(2); 120 sec), the effect was observed in two crystals purchased more than a year apart and poled at separate facilities.

Several possibilities for plasma diagnostics provided by optical phase conjugation and, in particular, self‐pumped phase conjugation in barium titanate (BaTiO3) are discussed. These include placing a plasma within a dye laser cavity equipped with a phase conjugate mirror for intracavity absorption measurements, time differential refractometry with high spatial resolution, and simplified real‐time holographic interferometry. The principles of phase conjugation with particular reference to photorefractive media and the special advantages of self‐pumped phase conjugation are reviewed prior to the discussion of the applications. Distinctions are made in the applications between those for which photorefractive conjugators are essential and those for which they only offer experimental simplification relative to other types of phase conjugators.

Application of optical phase conjugation to plasma diagnostics (invited)

Short-lived effect of (des-tyr)-gamma-endorphin in schizophrenia

Since the discovery of endorphins, a number of hypotheses relating these substances to' mental illness have been formulated; these hypotheses are discussed in other papers in this volume. The administration of opioid antagonists has been used as a tool to test some of these hypotheses. This strategy is based on the displacement of endorphins from the receptors; the functions that are affected by endorphins are thus altered. Unfortunately, opioid antagonists have many other effects besides the displacement of endorphins. These confounding effects will be discussed later.

NALOXONE AND NALTREXONE IN MENTAL ILLNESS AND TARDIVE DYSKINESIA *

The safety of lecithin diet supplementation in schizophrenic patients.

A novel methodology is proposed for designing low-thrust trajectories to quasi-periodic, near-rectilinear Halo orbits that leverages ephemeris-driven, “invariant manifold analogs” as long-duration ...

Eclipse-Conscious Transfer to Lunar Gateway Using Ephemeris-Driven Terminal Coast Arcs

Orbital Communications Adaptor (OCA) Flight Controllers, in NASA's International Space Station Mission Control Center, use different computer systems to uplink, downlink, mirror, archive, and deliver files to and from the International Space Station (ISS) in real time. The OCA Mirroring System (OCAMS) is a multiagent software system (MAS) that is operational in NASA's Mission Control Center. This paper presents OCAMS and its workings in an operational setting where flight controllers rely on the system 24x7. We also discuss the return on investment, based on a simulation baseline, six months of 24x7 operations at NASA Johnson Space Center in Houston, Texas, and a projection of future capabilities. This paper ends with a discussion of the value of MAS and future planned functionality and capabilities.

NASA's OCA Mirroring System: An Application of Multiagent Systems in Mission Control

Sponsored by the Central Test and Evaluation Investment Program (CTEIP), the integrated Network Enhanced Telemetry (iNET) project has created a proposed architecture for network enhancing aeronautical telemetry. Given the static nature of the current aeronautical telemetry architecture (it has not significantly changed in over 50 years), it is recognized that iNET must be carefully deployed to avoid test disruptions and safety issues. In support of a smooth transition to this new architecture, the Naval Air Warfare Division Aircraft (NAWCAD) conducted an extensive continuous process improvement project. This paper will describe the process, defined and launched by this study, to assure the safe deployment of iNET.

Abstract : Recognizing the inability of current telemetry technology to meet emergent needs within the Major Range and Test Facility Base, the Central Test and Evaluation Investment Program launched the integrated Network Enhanced Telemetry (iNET) Project. iNET is taking a systems engineering approach to defining a new architecture for flight test telemetry. The iNET architecture is the first major change to the underlying architecture of flight test telemetry in over 50 years! Changing an architecture that has been in place this long could have unforeseen impacts. Across Navy ranges, processes, procedures, and systems have characteristics of the traditional telemetry architecture inherent in their design. A careful, defined, and disciplined process is required for assuring that these processes, procedures, and systems are ready to accept iNET technology. As one of the initial deployment sites for iNET, NAVAIR Pax River has conducted a continuous process improvement project to study the potential disruptions and mitigations of deploying this revolutionary and potentially disruptive technology. This article describes the study process, the potential disruptions identified, the results of the risk/failure mode effect analysis, and useful end products developed to facilitate the safe deployment of iNET at the Naval Air Warfare Center Aircraft Division at Patuxent River, MD.

iNET Deployment at Pax River: Identifying and Mitigating the Disruptions

Results of the 2005 Enhancing Space Operations Workshop Held by the AIAA Space Operations and Support Technical Committee

The X-38 Project consists of a series of experimental vehicles designed to provide the technical "blueprint" for the International Space Station's (ISS) Crew Return Vehicle (CRV). There are three atmospheric vehicles and one space flight vehicle in the program. Each vehicle is designed as a technical stepping stone for the next vehicle, with each new vehicle being more complex and advanced than it's predecessor. The X-38 project began in 1995 at the Johnson Space Center (JSC) in Houston, Texas at the direction of the NASA administrator. From the beginning, the project has had the CRY design validation as its ultimate goal. The CRY has three basic missions that drive the design that must be proven during the course of the X-38 Project: a) Emergency return of an ill or injured crew member. b) Emergency return of an entire ISS crew due to the inability of ISS to sustain life c) Planned return of an entire ISS crew due to the inability to re-supply the ISS or return the crew. The X-38 project must provide the blueprint for a vehicle that provides the capability for human return from space for all three of these design missions.

Control center operators fulfil a critical role in the delivery of transit services with today's continued trend towards automated driverless transit systems. This paper describes a systems engineering approach that helps define the requirements of the new control center workstations. Two case studies, the Vancouver SkyTrain extension and the JFK International Airport AIRTRAIN, are presented as examples of an approach that was used to capture the functionality of and necessary enhancements to the existing control centers. These examples offer many lessons for the successful delivery of transit systems.

OPERATIONS CONTROL CENTERS INTEGRATED WORKSTATIONS: TWO CASE STUDIES

The latter half of the last decade was witness to significant changes in the regulatory environment in Bangladesh. Various forms of competition have been allowed into the telecommunications landscape, most notably involving wireless technology. Bangladesh has taken a unique road in deregulation of telecommunications. Bangladesh has competition only in the local loop internal and international long distance remains a monopoly. Using the lens of GrameenPhone, we view the regulatory innovations in Bangladesh and conclude that such regulatory experiments are certainly worthwhile, if not always optimal, and thereby implicitly oppose the economic orthodoxy of complete deregulation and immediate privatisation as supported by the World Trade Organization (WTO) and the International Telecommunication Union (ITU). In 1996, the wireline network in Bangladesh was in dismal shape. The same year, wireless licensing was expanded. One of the wireless providers to surface soon thereafter was a subsidiary of Grameen Bank, the premier development organisation in the region. This paper will discuss how regulatory changes in Bangladesh enabled GrameenPhone (the cellular provider under Grameen Bank) to offer a development program for the explicit purpose of expanding access to POTS (Plain Old Telephone Service). The GrameenPhone Village Program, Grameen's telecommunications for development initiative, offers a potentially sustainable solution to poor connectivity in rural Bangladesh. The programme achieves this end by combining the use of new technology with a unique entrepreneurial approach to marketing and financing their service. Is that because of or despite the regulation? This is the question we explore. A previous version of this paper was presented at the Internet Society Annual Meeting INET 2000.

Deregulating the local loop: the telecommunications regulation path less chosen as taken by Bangladesh

The X-38 is an experimental NASA project developing a core human capable spacecraft at a fraction of the cost of any previous human rated vehicle. The first operational derivative developed from the X-38 program will be the International Space Station (ISS) Crew Return Vehicle (CRV). Although the current X-38 vehicles are designed as re-entry vehicles only, the option exists to modify the vehicle for uses as an upward vehicle launched from an expendable launch vehicle or from the X-33 operational derivative. The Operational CRV, that will be derived from the X-38 spaceflight vehicle, will provide an emergency return capability from the International Space Station (ISS). The spacecraft can hold a crew of up to seven inside a pressurized cabin. The CRV is passively delivered to ISS, stays up to three year on-orbit attached to ISS in a passive mode with periodic functional checkout, before separation from ISS, de-orbit, entry and landing. The X-38 Vehicle 201 (V201) is being developed at NASA/JSC to demonstrate key technologies associated with the development of the CRV design. The X-38 flight test will validate the low cost development concept by demonstrating the entire station departure, re-entry, guidance and landing portions of the CRV mission. All new technologies and subsystems proposed for CRV will be validated during either the on orbit checkout or flight phases of the X-38 space flight test. The X-38 subsystems are required to be similar to those subsystems required for the CRV to the greatest extent possible. In many cases, the subsystems are identical to those that will be utilized on the Operational CRV.

A Space Shuttle Main Engine (SSME) test program was conducted between August 1995 and May 1996 using the Technology Test Bed (TTB) Engine. SSTO vehicle studies have indicated that increases in the propulsion system operating range can save significant weight and cost at the vehicle level. This test program demonstrated the ability of the SSME to accommodate a wide variation in safe operating ranges and therefore its applicability to the SSTO mission. A total of eight tests were completed with four at Marshall Space Flight Center's Advanced Engine Test Facility and four at the Stennis Space Center (SSC) A-2 attitude test stand. Key demonstration objectives were: 1) Mainstage operation at 5.4 to 6.9 mixture ratio; 2) Nominal engine start with significantly reduced engine inlet pressures of 50 psia LOX and 38 psia fuel; and 3) Low power level operation at 17%, 22%, 27%, 40%, 45%, and 50% of Rated Power Level. Use of the highly instrumented TTB engine for this test series has afforded the opportunity to study in great detail engine system operation not possible with a standard SSME and has significantly contributed to a greater understanding of the capabilities of the SSME and liquid rocket engines in general.

System capabilities began to appear in electrical distribution gear some 6 to 8 years ago. However, it is only in the last 1 to 2 years that this technology has begun to take off. Today, the majority of larger switchgear and motor control center jobs contain some form of system requirement (metering and trip unit networking, supervisory system software, etc). This paper discusses what goes into deploying a modern power management system including integration into other plant systems such as DCS, cell control and building automation. The open system technologies that are relevant to achieving this will be briefly discussed. Secondly, a quantitative evaluation of the return on investment based on a more detailed look at savings and operational improvements associated with a power management control system will be presented. This will be based on one or more specific customer installations within the process industries. The value of deploying a power management control system can be objectively measured in terms of energy management/conservation and reduced unscheduled downtime due to power distribution and load related problems. The first step to managing energy consumption is to known which departments, buildings, or process steps use the energy and to correlate that information withmore » utility rate structures. Peak demand charges often account for a major portion of a customer`s energy bill. As for downtime reduction, the goal is to use the system to achieve improved remedial and predictive maintenance, improved power quality, and to re-deploy resources away from routine manual tasks such as meter readings.« less

Operational experiences and economic benefits from implementing a power management control system

The development of the Control Center Complex (CCC), a synergistic control center supporting both the Space Station Freedom and the Space Shuttle Program, is described. To provide maximum growth and flexibility, the CCC uses commercial off-the-shelf technology and industry standards. The discussion covers the development philosophy, CCC architecture, data distribution, the software platform concept, workstation platform, commercial tools for the CCC, and benefits of synergy.

Synergistic control center development utilizing commercial technology and industry standards. [NASA space programs]

有向ネットワーク上のEuler‐Lagrangeエージェントのランデブーのための可変利得モデルに依存しないアルゴリズム【Powered by NICT】

Crystal Structure of V delta 1 T Cell Receptor in Complex with CD1d-Sulfatide Shows MHC-like Recognition of a Self-Lipid by Human gamma delta T Cells.

Crystal structure of Vδ1 T cell receptor in complex with CD1d-sulfatide shows MHC-like recognition of a self-lipid by human γδ T cells.

αβ T‐cell lines specific for sulfatide, an abundant myelin glycosphingolipid presented by various CD1 molecules, have been previously derived from PBMCs of patients with demyelinating diseases such as multiple sclerosis (MS) but also from healthy subjects. Using an unbiased tetramer‐based MACS enrichment method to enrich for rare antigen‐specific cells, we confirmed the presence of CD1d‐sulfatide‐specific T cells in all healthy individuals examined. Surprisingly, the great majority of fresh sulfatide‐specific T cells belonged to the γδ lineage. Furthermore, these cells used the Vδ1 TCR variable segment, which is uncommon in the blood but predominates in tissues such as the gut and specifically accumulates in MS lesions. Recombinant Vδ1 TCRs from different individuals were shown to bind recombinant CD1d‐sulfatide complexes in a sulfatide‐specific manner. These results provide the first direct demonstration of MHC‐like‐restricted, antigen‐specific recognition by γδ TCRs. Together with previous reports, they support the notion that human Vδ1 T cells are enriched in CD1‐specific T cells and suggest that the Vδ1 T‐cell population that accumulates in MS lesions might be enriched in CD1‐sulfatide‐specific cells.

The majority of CD1d‐sulfatide‐specific T cells in human blood use a semiinvariant Vδ1 TCR

ABSTRACT Some inborn errors of metabolism due to deficiencies of soluble lysosomal enzymes cause global neurodegenerative disease. Representative examples include the infantile and late infantile forms of the ceroid lipofuscinoses (CLN1 or CLN2 deficiency, respectively) and mucopolysaccharidoses type VII (MPS VII), a deficiency of β-glucuronidase. Treatment of the central nervous system component of these disorders will require widespread protein or enzyme replacement, either through dissemination of the protein or through dissemination of a gene encoding it. We hypothesize that transduction of brain microcapillary endothelium (BME) with recombinant viral vectors, with secretion of enzyme product basolaterally, could allow for widespread enzyme dissemination. To achieve this, viruses should be modified to target the BME. This requires (i) identification of a BME-resident target receptor, (ii) identification of motifs targeted to that molecule, (iii) the construction of modified viruses to allow for binding to the target receptor, and (iv) demonstrated transduction of receptor-expressing cells. In proof of principal experiments, we chose the human transferrin receptor (hTfR), a molecule found at high density on human BME. A nonamer phage display library was panned for motifs which could bind hTfR. Forty-three clones were sequenced, most of which contained an AKxxK/R, KxKxPK/R, or KxK motif. Ten peptides representative of the three motifs were cloned into the HI loop of adenovirus type 5 fiber. All motifs tested retained their ability to trimerize and bind transferrin receptor, and seven allowed for recombinant adenovirus production. Importantly, the fiber-modified viruses facilitated increased gene transfer (2- to 34-fold) to hTfR expressing cell lines and human brain microcapillary endothelia expressing high levels of endogenous receptor. Our data indicate that adenoviruses can be modified in the HI loop for expanded tropism to the hTfR.

Recombinant Human Adenovirus: Targeting to the Human Transferrin Receptor Improves Gene Transfer to Brain Microcapillary Endothelium

Palavras-chave: Democracia; Política; Sistema Eleitoral; Processo de Mercado; Escola Austríaca. RESUMO Em 2018, o brasileiro se depara com um importante processo democrático na Nova República representado pelas eleições, que irão definir os rumos do Brasil para os próximos anos. Este artigo tem por objetivo propor soluções para resolver ou atenuar os problemas teóricos e práticos encontrados em um regime democrático. Para tal, foram utilizadas as ferramentas metodológicas do núcleo de pesquisa da Escola Austríaca, incorporando nas instituições democráticas aqueles elementos presentes no processo de livre mercado que o tornam desejável. Ficou demonstrado como as soluções propostas tornam o sistema democrático mais adequado para atender aos interesses dos cidadãos.

Making sense of student learning objectives within teacher evaluations: A case study of Illinois principals as implementing agents

ACKNOWLEDGMENTS PREFACE TO THE SECOND EDITION THE STRATEGIC APPROACH TO CLASS ACTION LITIGATION 1. WHAT CLASS ACTIONS ARE AND WHY THEY EXIST 2. CLASS CERTIFICATION REQUIREMENTS 3. CONSTRUCTING A CLASS ACTION LAWSUIT 4. PRE-CERTIFICATION STEPS 5. THE CLASS CERTIFICATION MOTION 6. POST-CERTIFICATION STEPS 7. TRIAL PREPARATION 8. SETTLING CLASS ACTIONS 9. CLASS ACTION JUDGMENTS 10. CLASS ACTIONS OUTSIDE THE UNITED STATES TABLE OF CASES INDEX

For the better part of 30 years, liberal bias has dominated mainstream media. But author and political journalist Brian Anderson reveals in his new book that the era of liberal dominance is going the way of the dodo bird.

BERNARD-HENRI LEVY. Sartre: The Philosopher of the Twentieth Century. POLITY PRESS. 536 PAGES. $29.95 BACK IN the 1960s, or even early seventies, if you asked the average intelligent person to name a philosopher, the answer would as likely have been Jean-Paul Sartre as it would have been Aristotle or Plato. "The Pope of Existentialism," as people called him, enjoyed household-name status. By the time of his death in 1980, however, Sartre's star had already darkened; the 50,000 mourners who shuffled after his casket to Montparnasse cemetery in Paris represented a last flare from his vanishing fame, not a sign of real influence. Structuralism, post-structuralism, feminism, colonial studies--as new radical enthusiasms swept through Paris and through the Western academy, existentialism came for many to seem a mere footnote in the history of twentieth-century thought. Who still took seriously The Critique of Dialectical Reason or even Being and Nothingness and Nausea? For Bernard-Henri Levy, contemporary France's leading public intellectual and a major media star, this neglect of Sartre's thought and literature is a significant mistake. In fact, he argues in Sartre: The Philosopher of the Twentieth Century (first published to acclaim in France in 2000 and now translated in this English-language edition by Andrew Brown), Sartre's work is "the meeting point of all the ways of getting through the twentieth century, getting lost in it, avoiding its dark and slippery slopes--and all the ways of setting it off, now, into the new century." Plunging into that work once again, Levy claims, will help protect us against future threats to human liberty. Levy's thick book--a kind of intellectual biography cum philosophical meditation--vigorously defends the man he calls "the absolute intellectual." Levy is right about the need to read Sartre, but his admiration is misplaced. What Sartre actually offers us is a paradigmatic example of the leftist mind, in all its dodgy enthusiasms. Sartre's early existentialism presents a nihilistic conception of human freedom that still informs some forms of liberal thought; his later political writings seethe with the pathologies of the far left, including an admiration for bloodletting, so long as it targets democrats and capitalists and Westerners generally. Sartre may indeed have been "the absolute intellectual," but only in a negative sense: His oeuvre stands as an absolute warning about the wrong turns that moral and political thought can take when untethered from nature or any sense of reality. Were Sartre alive today, he doubtless would place the blame for September 11 and Palestinian suicide bombings on their victims--defending, as he frequently did, the indefensible. JEAN-PAUL SARTRE was born in Paris in June 1905 into a bourgeois family. His mother, born Anne Marie Schweitzer, was a relative of the Christian missionary, theologian, and musician Albert Schweitzer; his father, Jean-Baptiste, was a military officer who died in 1906. After Jean-Baptiste's death, Sartre's mother returned to live with the Schweitzers. Her father, Charles, became Sartre's nominal pere. In his 1963 autobiography Words, Sartre described his childhood as introverted and lonely, blaming Charles Schweitzer for keeping him away from other kids--though he never lacked for love. Revealingly, Words ends at Sartre's twelfth year, when his mother remarried an engineer, Joseph Mancy. Sartre revered his mother, and Levy--rightly, I believe--suggests that her remarriage was a trauma from which he never fully recovered. Sartre and his followers would later toss around the word "engineer" as a term of ultimate opprobrium. When Mancy later died, Sartre took in his mother, and they shared an apartment for much of his adult life. Sartre may have been a lonely mama's boy, but he dazzled academically and won entry in 1924 to the Ecole Normale Superieure, France's premier institute of higher learning for literature and philosophy. …

Chapter 1 Introduction Part 2 Part One: Liberty: The Virtue and the Institutions Chapter 3 Truth and Liberty Chapter 4 Seven Whig Amendments Chapter 5 How to Make a Republic Work Chapter 6 Boredom, Virtue and Democratic Capitalism (or) The End of History? Chapter 7 Civil Society and Self-Government Chapter 8 The Crisis of the Welfare State Chapter 9 In Praise of Bourgeois Virtues Part 10 Part Two: Liberty: The Tradition and Some of Its Heroes Chapter 11 The Catholic Whig Revisited Chapter 12 Thomas Aquinas v. Heretics Chapter 13 The Achievement of Jacques Maritain Chapter 14 Maritain and the Jews Chapter 15 Needing Niebuhr Again Chapter 16 Reinhold Niebuhr, Father of Neoconservatives Chapter 17 Twice Chosen: Irving Kristol as American Chapter 18 The Christian Philosophy of John Paul II Part 19 Part Three: Afterword Chapter 20 Errand into the Wilderness Chapter 21 A Reader's Guide

Christian Social Ethics in a Global Era Edited by Max Stackhouse Nashville: Abingdon Press, 1995 (135 pages)

Review of "Christian Social Ethics in a Global Era" edited by Max Stockhouse

This concise and penetrating analysis introduces students to the life and thought of one of the giants of twentieth-century French intellectual life. Portraying Raymond Aron as a great defender of reason, moderation, and political sobriety in an era dominated by ideological fervor and philosophical fashion, Brian Anderson demonstrates the centrality of political reason to Aron's philosophy of history, his critique of ideological thinking, his meditations on the perennial problems of peace and war, and the nature of conservative liberalism.

A Comprehensive Statute of Limitations for Litigation Arising from Defective Custom Computer Systems

MA-[D-Leu-4)-OB3, a Small Molecule Synthetic Peptide Leptin Mimetic, Improves Serum Lipid Profiles in Mouse Models of Type 1 and Type 2 Diabetes Mellitus

Abstract Adult hippocampal neurogenesis (AHN) is suppressed by high-fat (HF) diet and metabolic disease, including obesity and type 2 diabetes. Deficits in AHN may contribute to cognitive decline and increased risk of dementia and mood disorders, which have higher prevalence in women. However, sex differences in the effects of HF diet/metabolic disease on AHN have yet to be thoroughly investigated. Herein, male and female C57BL/6J mice were fed an HF or control (CON) diet from ∼2 to 6 months of age. After 3 months on the diet, mice were injected with 5-ethynyl-2′-deoxyuridine (EdU) then killed 4 weeks later. Cell proliferation, differentiation/maturation, and survival of new neurons in the dentate gyrus were assessed with immunofluorescence for EdU, Ki67, doublecortin (DCX), and NeuN. CON females had more proliferating cells (Ki67+) and neuroblasts/immature neurons (DCX+) compared with CON males; however, HF diet reduced these cells in females to the levels of males. Diet did not affect neurogenesis in males. Further, the numbers of proliferating cells and immature neurons were inversely correlated with both weight gain and glucose intolerance in females only. These effects were robust in the dorsal hippocampus, which supports cognitive processes. Assessment of microglia in the dentate gyrus using immunofluorescence for Iba1 and CD68 uncovered sex-specific effects of diet, which may contribute to observed differences in neurogenesis. These findings demonstrate sex-specific effects of HF diet/metabolic disease on AHN, and highlight the potential for targeting neurogenic deficits to treat cognitive decline and reduce the risk of dementia associated with these conditions, particularly in females.

High-Fat Diet-Induced Obesity Causes Sex-Specific Deficits in Adult Hippocampal Neurogenesis in Mice

Abstract Glucose dysregulation and disruption of insulin signaling in the brain have been suggested as a possible etiology of Alzheimer’s Disease. In the present study, we show that oral delivery of MA-[D-Leu-4]-OB3 to young male Swiss Webster (SW) mice rendered hyperglycemic by intraperitoneal injection of streptozotocin (STZ), prevented insulin-induced increase in body weight gain and enhanced the effects of insulin alone on fasting blood glucose to levels approaching those of normal SW mice of the same age and sex. Novel object testing indicated that insulin treatment improved working memory in STZ-induced hyperglycemic mice, and that MA-[D-Leu-4]-OB3 given in combination with insulin significantly accelerated the time course of this improvement. Although positive results in an animal model may not be recapitulated in human pathology, our data suggest that MA-[D-Leu-4]-OB3, when added to an insulin regimen, may have application to the treatment of Alzheimer’s Disease by improving insulin sensitivity and glycemic control, thus slowing or preventing the progression of memory disruption associated with this disease.

MON-481 MA-[D-Leu-4]-OB3, a Small Molecule Synthetic Peptide Leptin Mimetic, Enhances the Effects of Insulin on Glycemic Control and Cognitive Function in Streptozotocin-Induced Hyperglycemic Swiss Webster Mice

MA-[d-Leu-4]-OB3, a Small Molecule Synthetic Peptide Leptin Mimetic, Mirrors the Cognitive Enhancing Action of Leptin in a Mouse Model of Type 1 Diabetes Mellitus and Alzheimer’s Disease-Like Cognitive Impairment

[D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, small molecule synthetic peptide leptin mimetics, improve glycemic control in diet-induced obese (DIO) mice

METABOLIC AND COGNITIVE EFFECTS OF HIGH FAT DIET IN MALE AND FEMALE MICE

Sex differences in the metabolic effects of diet-induced obesity vary by age of onset

Oral delivery of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, synthetic peptide leptin mimetics: Immunofluorescent localization in the mouse hypothalamus

Intrahippocampal administration of a domain antibody that binds aggregated amyloid-β reverses cognitive deficits produced by diet-induced obesity.

Context-dependent memory following recurrent hypoglycaemia in non-diabetic rats is mediated via glucocorticoid signalling in the dorsal hippocampus

Myristic acid conjugation of [D-Leu-4]-OB3, a biologically active leptin-related synthetic peptide amide, significantly improves its pharmacokinetic profile and efficacy

Chapter 62 – Examination of the equine athlete prior to purchase

Abstract : The Mobility Triad of airlift, sealift, and prepositioning is a successful strategic concept, but lacks depth in its structure to accomplish the mobility mission down to the operational level. The structure is designed for strategic employment, but does not integrate well into theater requirements, without operational trade-off. This paper will discuss the significant advantages and disadvantages the operational commander must address in order to fulfill their deployment requirements.

C.L. Hartley, V.E.R. Anderson, B.H. Anderson & J. Robertson (1997) Neuropathology and Applied Neurobiology23, 364–372

Acrylamide and 2,5‐hexanedione induce collapse of neurofilaments in SH‐SY5Y human neuroblastoma cells to form perikaryal inclusion bodies

The rate of lactate production from glucose in hearts is not altered by per-deuteration of glucose.

Measuring glucose cerebral metabolism in the healthy mouse using hyperpolarized 13C magnetic resonance

An enzyme-electrode sensor designed specifically for pocket-portable self-monitoring of blood glucose is described. The sensing device in this instrument is unique because it is reusable for at least 30 days, at which time it is easily replaced by placing a new enzyme-membrane cartridge over the electrode. As little as 7 μl of undiluted whole blood, plasma, or serum is applied directly to the sensor, and glucose is automatically determined in 30 s. No manual timing or wiping step is required after sample application. On eight production instruments, plasma glucose concentration was determined (n = 20) at 57, 125, 246, and 347 mg/dl. The average coefficient of variation for the 80 determinations for each instrument ranged from 2 to 5%, averaging 3.7%. The instrument is inherently linear, independent of hematocrit, and without oxygen limitation when dissolved oxygen concentration is >35 mmHg. No interferences were found from plasma constituents, heparin, or acetaminophen.

Procédé de distribution de publications numériques incorporant un contenu généré par l'utilisateur et chiffré, à empreintes digitales uniques

L'invention porte sur des systemes et des procedes qui analysent la structure physique de rangees de texte dans une image de document (21800), comprenant les positions d'un ou de plusieurs alignements d'un ou de plusieurs blocs de caracteres (132) dans une ou plusieurs rangees de texte de l'image de document (21800). Les systemes et procedes determinent un ou plusieurs groupes de rangees de texte placees dans une classe en fonction des structures des rangees de texte, telles que les positions du ou des alignements du ou des blocs de caracteres (132) dans chaque rangee de texte. Un systeme de correspondance de motif (211) determine alors si une ou plusieurs classes devraient etre davantage combinees en une classe combinee.

La presente invention concerne un procede et un dispositif de fabrication de fromage a pâte molle et a caille plastique, de haute qualite et a faible teneur en matieres grasses. En l'occurrence, on introduit un substitut de fromage a base de riz dans le fromage fraichement elabore. On utilise pour cela un procede de malaxage et de pulverisation qui preserve l'integrite de la structure en fibres du fromage.

Procede et dispositif de fabrication de fromage a pate molle et a caille plastique a faible teneur en matieres grasses

Polycyclic Aromatic Hydrocarbon Release from Pavement Rejuvenators Due to Rolling Wheel Contact: An Investigation Using a Model Mobile Load Simulator

Film cooling can have a significant effect on the heat transfer coefficient (HTC) between the overflowing freestream gas and the underlying surface. This study investigated the influence of approach flow characteristics, including the boundary layer thickness and character (laminar and turbulent), as well as the approach flow Reynolds number, on the HTC. The figure of merit for this study was the HTC augmentation, that is, the ratio of HTCs for a cooled versus uncooled surface. A heated foil surface provided a known heat flux, allowing direct measurement of HTC and augmentation. The foil was placed both upstream and downstream of the film cooling holes, in order to generate an approaching thermal boundary layer, as representative of actual engine conditions. High-resolution IR thermography provided spatially resolved HTC augmentation data. An open-literature shaped-hole design was used, known as the 7-7-7 hole, in order to compare with existing results in the literature. A variety of blowing conditions were tested from M = 0.5 to 3.0. Two elevated density ratios of DR = 1.20 and DR = 1.80 were used. The results indicated that turbulent boundary layer thickness had a modest effect on HTC augmentation, whereas a very high level of augmentation was observed for a laminar approach boundary layer. The presence of upstream heating greatly increased the HTC augmentation in the near-hole region, although these effects died out by 10–15 diameters from the holes.

Direct Experimental Measurements of Heat Transfer Coefficient Augmentation Due to Approach Flow Effects

Effect of Internal Crossflow Velocity on Film Cooling Effectiveness—Part II: Compound Angle Shaped Holes

Effect of Internal Crossflow Velocity on Film Cooling Effectiveness—Part I: Axial Shaped Holes

The effect of feeding shaped film cooling holes with an internal crossflow is not well understood. Previous studies have shown internal crossflow reduces film cooling effectiveness from axial shaped holes, but little is known about the mechanisms governing this effect. It was recently shown that the crossflow-to-mainstream velocity ratio is important, but only a few of these crossflow velocity ratios have been studied. This effect is of concern because gas turbine blades typically feature internal passages that feed film cooling holes in this manner. In this study, film cooling effectiveness was measured for a single row of axial shaped cooling holes fed by an internal crossflow with crossflow-to-mainstream velocity ratio varying from 0.2–0.6 and jet-to-mainstream velocity ratios varying from 0.3–1.7. Experiments were conducted in a low speed flat plate facility at coolant-to-mainstream density ratios of 1.2 and 1.8. It was found that film cooling effectiveness was highly sensitive to crossflow velocity at higher injection rates, while it was much less sensitive at lower injection rates. Analysis of the jet shape and lateral spreading found that certain jet characteristic parameters scale well with the crossflow-to-coolant jet velocity ratio, demonstrating that the crossflow effect is governed by how coolant enters the film cooling holes.Copyright © 2017 by ASME

Effect of Internal Crossflow Velocity on Film Cooling Effectiveness: Part I — Axial Shaped Holes

Freestream Flow Effects on Film Effectiveness and Heat Transfer Coefficient Augmentation for Compound Angle Shaped Holes

Investigation of approach flow parameters, scaling factors, and measurement accuracy for film cooling effectiveness and heat transfer coefficient measurements

In gas turbine engines, film cooling holes are commonly fed with an internal crossflow, the magnitude of which has been shown to have a notable effect on film cooling effectiveness. In Part I of this study, as well as in a few previous studies, the magnitude of internal crossflow velocity was shown to have a substantial effect on film cooling effectiveness of axial shaped holes. There is, however, almost no data available in the literature that shows how internal crossflow affects compound angle shaped film cooling holes. In Part II, film cooling effectiveness, heat transfer coefficient augmentation, and discharge coefficients were measured for a single row of compound angle shaped film cooling holes fed by internal crossflow flowing both in-line and counter to the span-wise direction of coolant injection. The crossflow-to-mainstream velocity ratio was varied from 0.2–0.6 and the injection velocity ratio was varied from 0.2–1.7. It was found that increasing the magnitude of the crossflow velocity generally caused degradation of the film cooling effectiveness, especially for in-line crossflow. An analysis of jet characteristic parameters demonstrated the importance of crossflow effects relative to the effect of varying the film cooling injection rate. Heat transfer coefficient augmentation was found to be primarily dependent on injection rate, although for in-line crossflow, increasing crossflow velocity significantly increased augmentation for certain conditions.Copyright © 2017 by ASME

Effect of Internal Crossflow Velocity on Film Cooling Effectiveness: Part II — Compound Angle Shaped Holes

An Investigation of Turbine Film Cooling Effectiveness With Shaped Holes and Internal Cross-Flow With Varying Operational Parameters

Effects of Freestream Mach Number, Reynolds Number, and Boundary Layer Thickness on Film Cooling Effectiveness of Shaped Holes

The performance of film cooling designs is typically quantified by the adiabatic effectiveness, with results presented in terms of non-dimensional parameters such as the blowing ratio, momentum flux ratio, or velocity ratio of the coolant to the overflowing mainstream gas. In order to appropriately model experimental film cooling designs, the correct coolant flow parameter should be selected. In this work, a single row of axial round holes and shaped holes were placed in a flat plate and tested within a recirculating wind tunnel at low speeds and temperatures. Mainstream turbulence intensity and boundary layer thickness were set similar to expected engine conditions. The density ratio of the coolant was varied from 1.2 to 1.6 in order to independently vary the parameters listed above, which were tested at six different conditions for each density ratio. High-resolution IR thermography was used to measure adiabatic effectiveness downstream of the single row of cooling holes. The results indicate that adiabatic effectiveness performance of cylindrical and shaped holes are scaled most effectively using velocity ratio, providing much more accurate results then when the blowing ratio is used.© 2015 ASME

Experimental Investigation of Coolant-to-Mainstream Scaling Parameters With Cylindrical and Shaped Film Cooling Holes

In gas turbine engines, film cooling holes are often fed by an internal crossflow, with flow normal to the direction of the external flow around the airfoil. Many experimental studies have used a quiescent plenum to feed model film cooling holes and thus do not account for the effects of internal crossflow. In this study, an experimental flat plate facility was constructed to study the effects of internal crossflow on a row of cylindrical compound angle film cooling holes. There are relatively few studies available in literature that focus on the effects of crossflow on film cooling performance, with no studies examining the effects of internal crossflow on film cooling with round, compound angled holes. A crossflow channel allowed for coolant to flow alternately in either direction perpendicular to the mainstream flow. Experimental conditions were scaled to match realistic turbine engine conditions at low speeds. Cylindrical compound angle film cooling holes were operated at blowing ratios ranging from 0.5 to 2.0 and at a density ratio (DR) of 1.5. The results from the crossflow experiments were compared to a baseline plenum-fed configuration. This study showed that significantly greater adiabatic effectiveness was achieved for crossflow counter to the direction of coolant injection.

The Effect of Internal Crossflow on the Adiabatic Effectiveness of Compound Angle Film Cooling Holes

Reduction of Wind Erosion Potential Using Microbial Calcite and Soil Fibers

In gas turbine engines, film cooling holes are often fed by an internal cross-flow, with flow normal to the direction of the external flow around the airfoil. Many experimental studies have used a quiescent plenum to feed model film cooling holes and thus do not account for the effects of internal cross-flow. In this study, an experimental flat plate facility was constructed to study the effects of internal cross-flow on a row of cylindrical compound angle film cooling holes. Operating conditions were scaled, based on coolant hole Reynolds number and turbulence level, to match realistic turbine engine conditions. A cross-flow channel allowed for coolant to flow alternately in either direction perpendicular to the mainstream flow. Film cooling holes were operated at blowing ratios ranging from 0.5 to 2.0 at a density ratio of 1.5. There are relatively few studies available in literature that focus on the effects of cross-flow on film cooling performance, with no studies examining the effects of internal cross-flow on film cooling with round, compound angled holes. This study showed that significantly greater adiabatic effectiveness was achieved for cross-flow in the opposite direction of the span-wise direction of the coolant holes and provides possible explanations for this result.Copyright © 2014 by ASME

The Effect of Internal Cross-Flow on the Adiabatic Effectiveness of Compound Angle Film Cooling Holes

The leading edge of a turbine vane is subject to some of the highest temperature loading within an engine, and an accurate understanding of leading edge film coolant behavior is essential for modern engine design. Although there have been many investigations of the adiabatic effectiveness for showerhead film cooling of a vane leading edge region, there have been no previous studies in which individual rows of the showerhead were tested with the explicit intent of validating superposition models. For the current investigation, a series of adiabatic effectiveness experiments were performed with a five-row and three-row showerhead. The experiments were repeated separately with each individual row of holes active. This allowed evaluation of superposition methods on both the suction side of the vane, which was moderately convex, and the pressure side of the vane, which was mildly concave. Superposition was found to accurately predict performance on the suction side of the vane at lower momentum flux ratios, but not at higher momentum flux ratios. On the pressure side of the vane the superposition predictions were consistently lower than measured values, with significant errors occurring at the higher momentum flux ratios. Reasons for the under-prediction by superposition analysis are presented.Copyright © 2014 by Siemens Energy, Inc.

Evaluation of Superposition Predictions for Showerhead Film Cooling on a Vane

Surface curvature is known to have significant effects on film cooling performance, with convex curvature inducing increased film effectiveness and concave curvature causing decreased film effectiveness. Generally, these curvature effects have been presumed to scale with 2r/d at the film cooling hole location, where r is the radius of curvature and d is coolant hole diameter. In this study, the validity of this scaling of curvature effects are examined by performing experiments in regions of large and low curvature on a model vane. Single rows of cylindrical holes were placed at various locations along the high curvature section of the suction side of the vane. For the first series of experiments, a single row of holes was placed at two locations with different local surface curvature. The coolant hole diameters were then adjusted to match 2r/d values. Results from these experiments showed that there was better correspondence of film performance when using the 2r/d scaling, but there was not an exact matching of performance. A second series of experiments focused on evaluating the effects of curvature downstream of the coolant holes. One row of holes was placed at a position upstream of the highest curvature, while another row was placed at a downstream position such that the radius of curvature was equivalent for the two rows of holes. Results indicated that the local radius of curvature is not sufficient in understanding the performance of film cooling. Instead, the curvature envelope downstream of the coolant holes plays a significant role on the performance of film cooling for cylindrical holes.Copyright © 2013 by Siemens Energy, Inc.

Convex curvature effects on film cooling adiabatic effectiveness

Superposition in the leading edge region of a film cooled gas turbine vane

This study involves helping Manufacturing Company reduce overall production time, starting from concept through production, by finding and correlating the parameters of drag force, lift force, side force, pitching moment, yawing moment, and rolling moment of an Ahmed body, representative of a vehicle. The correlation parameters for the Ahmed body are between the computational fluid dynamics software Star-CCM+ and actual wind tunnel testing at the University of Wisconsin-Milwaukee?s (UWM) wind tunnel at a 0.3 scale prototype made from SOS rapid prototyping material. This small scale Ahmed body will be compared to the correlation parameters gathered from a full scale testing of an Ahmed body in the Wichita State wind tunnel also. The results of all three tests will be compared to see if they are in agreement with each other. The wind tunnel testing at UWM will utilize a 6-axis force/torque sensor having the capability to measure all the parameters. If the CFD results are within 5% of the actual wind tunnel testing, the project will validate the accuracy and reliability of CFD and further allow its usage to replace wind tunnel testing with confidence.

Determination of Aerodynamic Correlation Parameters of a Vehicle

A systems level analysis is presented for a solar organic Rankine cycle (S-ORC) for assessing the feasibility of the cycle to be used in small scale rural/residential power generation. A thermodynamic model was generated for a system composed of the collector, the heat transfer fluid, the pump, the expander, and the heat exchangers, using five different working fluids. Based on the collector efficiency and incident radiation, the thermodynamic efficiency of the system was evaluated. For flat panel solar collectors, the highest system efficiency was found to be 6.2% when using R-134a as a working fluid. R-134a also required the least boiler heat transfer area, although its operation required relatively higher pressures. The performance of the solar-ORC system is compared with that of photovoltaic systems and the practicality of these solar thermal systems are discussed in terms of system size and end use.Copyright © 2012 by ASME

Test-Time Adaptation (TTA) allows to update pretrained models to changing data distributions at deployment time. While early work tested these algorithms for individual fixed distribution shifts, recent work proposed and applied methods for continual adaptation over long timescales. To examine the reported progress in the field, we propose the Continuously Changing Corruptions (CCC) benchmark to measure asymptotic performance of TTA techniques. We find that eventually all but one state-of-the-art methods collapse and perform worse than a non-adapting model, including models specifically proposed to be robust to performance collapse. In addition, we introduce a simple baseline,"RDumb", that periodically resets the model to its pretrained state. RDumb performs better or on par with the previously proposed state-of-the-art in all considered benchmarks. Our results show that previous TTA approaches are neither effective at regularizing adaptation to avoid collapse nor able to outperform a simplistic resetting strategy.

RDumb: A simple approach that questions our progress in continual test-time adaptation

DeepGaze vs SceneWalk: what can DNNs and biological scan path models teach each other?

Using the DeepGaze III model to decompose spatial and dynamic contributions to fixation placement over time

Abstract Humans typically move their eyes in “scanpaths” of fixations linked by saccades. Here we present DeepGaze III, a new model that predicts the spatial location of consecutive fixations in a free-viewing scanpath over static images. DeepGaze III is a deep learning–based model that combines image information with information about the previous fixation history to predict where a participant might fixate next. As a high-capacity and flexible model, DeepGaze III captures many relevant patterns in the human scanpath data, setting a new state of the art in the MIT300 dataset and thereby providing insight into how much information in scanpaths across observers exists in the first place. We use this insight to assess the importance of mechanisms implemented in simpler, interpretable models for fixation selection. Due to its architecture, DeepGaze III allows us to disentangle several factors that play an important role in fixation selection, such as the interplay of scene content and scanpath history. The modular nature of DeepGaze III allows us to conduct ablation studies, which show that scene content has a stronger effect on fixation selection than previous scanpath history in our main dataset. In addition, we can use the model to identify scenes for which the relative importance of these sources of information differs most. These data-driven insights would be difficult to accomplish with simpler models that do not have the computational capacity to capture such patterns, demonstrating an example of how deep learning advances can be used to contribute to scientific understanding.

DeepGaze III: Modeling free-viewing human scanpaths with deep learning

The last years have seen a surge in models predicting the scanpaths of fixations made by humans when viewing images. However, the field is lacking a principled comparison of those models with respect to their predictive power. In the past, models have usually been evaluated based on comparing human scanpaths to scanpaths generated from the model. Here, instead we evaluate models based on how well they predict each fixation in a scanpath given the previous scanpath history. This makes model evaluation closely aligned with the biological processes thought to underly scanpath generation and allows to apply established saliency metrics like AUC and NSS in an intuitive and interpretable way. We evaluate many existing models of scanpath prediction on the datasets MIT1003, MIT300, CAT2000 train and CAT200 test, for the first time giving a detailed picture of the current state of the art of human scanpath prediction. We also show that the discussed method of model benchmarking allows for more detailed analyses leading to interesting insights about where and when models fail to predict human behaviour. The MIT/Tuebingen Saliency Benchmark will implement the evaluation of scanpath models as detailed here, allowing researchers to score their models on the established benchmark datasets MIT300 and CAT2000.

New enhancements to the DeepGaze models for a better understanding of human scanpaths

There is no evidence that meaning maps capture semantic information relevant to gaze guidance: Reply to Henderson, Hayes, Peacock, and Rehrig (2021)

Object-context inconsistencies affect gaze behavior differently than predicted by contextualized meaning maps

Semantic information is important in eye-movement control. An important semantic influence on gaze guidance relates to object-scene relationships: objects that are semantically inconsistent with the scene attract more fixations than consistent objects. One interpretation of this effect is that fixations are driven towards inconsistent objects because they are semantically more informative. We tested this explanation using contextualized meaning maps, a method that is based on crowd-sourced ratings to quantify the spatial distribution of context-sensitive ‘meaning’ in images. In Experiment 1, we compared gaze data and contextualized meaning maps for images, in which objects-scene consistency was manipulated. Observers fixated more on inconsistent vs. consistent objects. However, contextualized meaning maps did not assigned higher meaning to image regions that contained semantic inconsistencies. In Experiment 2, a large number of raters evaluated the meaningfulness of a set of carefully selected image-regions. The results suggest that the same scene locations were experienced as slightly less meaningful when they contained inconsistent compared to consistent objects. In summary, we demonstrated that – in the context of our rating task – semantically inconsistent objects are experienced as less meaningful than their consistent counterparts, and that contextualized meaning maps do not capture prototypical influences of image meaning on gaze guidance.

Semantic object-scene inconsistencies affect eye movements, but not in the way predicted by contextualized meaning maps

Since 2014 transfer learning has become the key driver for the improvement of spatial saliency prediction—however, with stagnant progress in the last 3-5 years. We conduct a large-scale transfer learning study which tests different ImageNet backbones, always using the same read out architecture and learning protocol adopted from DeepGaze II. By replacing the VGG19 backbone of DeepGaze II with ResNet50 features we improve the performance on saliency prediction from 78% to 85%. However, as we continue to test better ImageNet models as backbones—such as EfficientNetB5—we observe no additional improvement on saliency prediction. By analyzing the backbones further, we find that generalization to other datasets differs substantially, with models being consistently overconfident in their fixation predictions. We show that by combining multiple backbones in a principled manner a good confidence calibration on unseen datasets can be achieved. This new model "DeepGaze IIE" yields a significant leap in benchmark performance in and out-of-domain with a 15 percent point improvement over DeepGaze II to 93% on MIT1003, marking a new state of the art on the MIT/Tuebingen Saliency Benchmark in all available metrics (AUC: 88.3%, sAUC: 79.4%, CC: 82.4%).

2021 IEEE/CVF International Conference on Computer Vision (ICCV)

DeepGaze IIE: Calibrated prediction in and out-of-domain for state-of-the-art saliency modeling

Correlations between factors of variation are prevalent in real-world data. Exploiting such correlations may increase predictive performance on noisy data; however, often correlations are not robust (e.g., they may change between domains, datasets, or applications) and models that exploit them do not generalize when correlations shift. Disentanglement methods aim to learn representations which capture different factors of variation in latent subspaces. A common approach involves minimizing the mutual information between latent subspaces, such that each encodes a single underlying attribute. However, this fails when attributes are correlated. We solve this problem by enforcing independence between subspaces conditioned on the available attributes, which allows us to remove only dependencies that are not due to the correlation structure present in the training data. We achieve this via an adversarial approach to minimize the conditional mutual information (CMI) between subspaces with respect to categorical variables. We first show theoretically that CMI minimization is a good objective for robust disentanglement on linear problems. We then apply our method on real-world datasets based on MNIST and CelebA, and show that it yields models that are disentangled and robust under correlation shift, including in weakly supervised settings.

Author Correction: SciPy 1.0: fundamental algorithms for scientific computing in Python

Where people look when watching videos is believed to be heavily influenced by temporal patterns. In this work, we test this assumption by quantifying to which extent gaze on recent video saliency benchmarks can be predicted by a static baseline model. On the recent LEDOV dataset, we find that at least 75% of the explainable information as defined by a gold standard model can be explained using static features. Our baseline model “DeepGaze MR” even outperforms state-ofthe-art video saliency models, despite deliberately ignoring all temporal patterns. Visual inspection of our static baseline’s failure cases shows that clear temporal effects on human gaze placement exist, but are both rare in the dataset and not captured by any of the recent video saliency models. To focus the development of video saliency models on better capturing temporal effects we construct a meta-dataset consisting of those examples requiring temporal information.

Throughout the past five years, the susceptibility of neural networks to minimal adversarial perturbations has moved from a peculiar phenomenon to a core issue in Deep Learning. Despite much attention, however, progress towards more robust models is significantly impaired by the difficulty of evaluating the robustness of neural network models. Today's methods are either fast but brittle (gradient-based attacks), or they are fairly reliable but slow (score- and decision-based attacks). We here develop a new set of gradient-based adversarial attacks which (a) are more reliable in the face of gradient-masking than other gradient-based attacks, (b) perform better and are more query efficient than current state-of-the-art gradient-based attacks, (c) can be flexibly adapted to a wide range of adversarial criteria and (d) require virtually no hyperparameter tuning. These findings are carefully validated across a diverse set of six different models and hold for L0, L1, L2 and Linf in both targeted as well as untargeted scenarios. Implementations will soon be available in all major toolboxes (Foolbox, CleverHans and ART). We hope that this class of attacks will make robustness evaluations easier and more reliable, thus contributing to more signal in the search for more robust machine learning models.

Many animals make eye movements to gather relevant visual information about the environment. How fixation locations are selected has been debated for decades in neuroscience and psychology. One hypothesis states that “priority” or “saliency” values are assigned locally to image locations, independent of saccade history, and are only later combined with saccade history and other constraints to select the next fixation location. A second hypothesis is that there are interactions between saccade history and image content that cannot be summarised by a single value. Here we discriminate between these possibilities in a data-driven manner. Using transfer learning from the VGG deep neural network, we train a model of scanpath prediction “DeepGaze III” on human free-viewing eye scanpath data. DeepGaze III can either be forced to use a single saliency map or can be allowed to learn complex interactions via multiple saliency maps. We find that using multiple saliency maps gives no advantage in scanpath prediction compared to a single saliency map. This suggesest that – at least for free-viewing – no complex interactions between scene content and scanpath history exist and a single saliency map may exist that does not depend on either current or previous gaze locations.

DeepGaze III: Using Deep Learning to Probe Interactions Between Scene Content and Scanpath History in Fixation Selection

Behavioural evidence for the existence of a spatiotopic free-viewing saliency map

Meaning maps and deep neural networks are insensitive to meaning when predicting human fixations

Selecting Maximally-Predictive Deep Features to Explain What Drives Fixations in Free-Viewing

SciPy 1.0: fundamental algorithms for scientific computing in Python

Eye movements are vital for human vision, and it is therefore important to understand how observers decide where to look. Meaning maps (MMs), a technique to capture the distribution of semantic importance across an image, have recently been proposed to support the hypothesis that meaning rather than image features guide human gaze. MMs have the potential to be an important tool far beyond eye-movements research. Here, we examine central assumptions underlying MMs. First, we compared the performance of MMs in predicting fixations to saliency models, showing that DeepGaze II – a deep neural network trained to predict fixations based on high-level features rather than meaning – outperforms MMs. Second, we show that whereas human observers respond to changes in meaning induced by manipulating object-context relationships, MMs and DeepGaze II do not. Together, these findings challenge central assumptions underlying the use of MMs to measure the distribution of meaning in images.

Meaning maps and saliency models based on deep convolutional neural networks are insensitive to image meaning when predicting human fixations

Recent results suggest that state-of-the-art saliency models perform far from optimal in predicting fixations. This lack in performance has been attributed to an inability to model the influence of high-level image features such as objects. Recent seminal advances in applying deep neural networks to tasks like object recognition suggests that they are able to capture this kind of structure. However, the enormous amount of training data necessary to train these networks makes them difficult to apply directly to saliency prediction. We present a novel way of reusing existing neural networks that have been pretrained on the task of object recognition in models of fixation prediction. Using the well-known network of Krizhevsky et al. (2012), we come up with a new saliency model that significantly outperforms all state-of-the-art models on the MIT Saliency Benchmark. The structure of this network allows new insights in the psychophysics of fixation selection and potentially their neural implementation. To train our network, we build on recent work on the modeling of saliency as point processes. By understanding how humans choose eye fixations, we can hope to understand and explain human behaviour in a number of vision-related tasks. For this reason human eye movements have been studied for more than 80 years (e. g. Buswell, 1935). During the last 20 years, many models have been developed trying to explain fixations in terms of so called “saliency maps”. Recently, it has been suggested to model saliency maps probabilistically using point processes (Barthelmé et al., 2013) and to evaluate them using log-likelihood (Kümmerer et al., 2014). This evaluation revealed that state-of-the-art models of saliency explain only one third of the explainable information in the spatial fixation structure (Kümmerer et al., 2014). Most of the existing models use low-level cues like edge-detectors and color filters (Itti et al., 1998) or local image statistics (Zhang et al., 2008; Bruce & Tsotsos, 2009). However, human fixations are largely clustered around objects (see Figure 1 for examples). This has led to some models trying to incorporate more high level features: Cerf et al. (2008) combined existing saliency map models with a face detector, while Judd et al. (2009) included detectors for faces, people, cars and horizon. Nevertheless, current saliency models mostly fail to capture these high-level influences which might be the main reason for the poor overall performance of state-of-the-art models. This analysis raises the question whether there are any computational systems capable of capturing such high-level influences. Independent of these developments, the last two years have seen the rise of deep neural networks to solve multifarious tasks like object detection, speech recognition or automatic translation. Provided with enough training data, deep neural networks show impressive results, often outperforming all competing methods. It has also been shown that deep convolutional networks that have been optimized for object classification can be used to predict neuron responses in higher brain areas of the visual system (Yamins et al., 2014; Razavian et al., 2014). Deep neural networks have also proven to generalize well over tasks (Donahue et al., 2013): a network trained for some task like object detection can often be easily retrained to achieve state-of-the-art performance in some other only loosely related task like scene recognition. Motivated by these developments, we here try to use pretrained deep neural networks to model fixation selection. The results of Yamins et al. (2014) connect neural network representations with IT 1 ar X iv :1 41 1. 10 45 v4 [ cs .C V ] 9 A pr 2 01 5 Accepted as a workshop contribution at ICLR 2015 Im ag e w ith fix at io ns

OOSTING SALIENCY PREDICTION WITH FEATURE MAPS TRAINED ON I MAGE N ET

Understanding how humans place their gaze is important for understanding how humans exlore their environment and for computer vision applications and has attracted research for many decades. So called “saliency models” compute a “saliency map” to predict fixations for an image. Many different saliency models have been proposed, from low-level feature integration to complex deep-learning based models, and more are added every year. However the field is facing a fundamental problem: there is no agreed-upon metric for assessing the quality of a saliency map. Instead, e.g. the most commonly used MIT saliency benchmark evaluates a total of eight metrics which yield highly inconsistent model rankings. This has led to contradicting conclusions about which algorithms are most predictive. We have previously shown that treating models probabilistically and evaluating log-density saliency maps removes most of the disagreement, but at the price of performing suboptimally in most metrics. Here we apply Bayesian utility theory to the problem: the metric is the utility function and the saliency map represents the particular choice one must make given the predicted fixation density and the utility function. We can show that it is impossible for one saliency map to perform well in all saliency metrics (Figure 1c). Instead we propose a principled way to derive different metricdependent saliency maps from a model’s predicted fixation density by maximizing the expected metric performance of a saliency map under the predicted fixation density (Figure 1b). By converting several influential saliency map models to probabilistic models, we show that our approach indeed improves benchmarking on real data. We demonstrate that this allows models to compete with state-of-the-art for each metric (Figure 2). Furthermore, by using the right saliency maps for different metrics, the model ranking is consistent over different metrics. This indicates that the existing saliency metrics are in fact not measuring different properties of the predicted fixation densities – they just interpret saliency maps in different ways. This simple yet meaningful way to compare saliency models should allow a better understanding of which mechanisms work and which don’t work and provide a better guide to future research.

Consistent Saliency Benchmarking: How One Model Can Win on All Metrics

The eye fixation patterns of human observers are a fundamental indicator of the aspects of an image to which humans attend. Thus, manipulating fixation patterns to guide human attention is an exciting challenge in digital image processing. Here, we present a new model for manipulating images to change the distribution of human fixations in a controlled fashion. We use the state-of-the-art model for fixation prediction to train a convolutional neural network to transform images so that they satisfy a given fixation distribution. For network training, we carefully design a loss function to achieve a perceptual effect while preserving naturalness of the transformed images. Finally, we evaluate the success of our model by measuring human fixations for a set of manipulated images. On our test images we can in-/decrease the probability to fixate on selected objects on average by 43/22% but show that the effectiveness of the model depends on the semantic content of the manipulated images.

DeepGaze II: Predicting fixations from deep features over time and tasks

Understanding where people look in images is an important problem in computer vision. Despite significant research, it remains unclear to what extent human fixations can be predicted by low-level (contrast) compared to highlevel (presence of objects) image features. Here we address this problem by introducing two novel models that use different feature spaces but the same readout architecture. The first model predicts human fixations based on deep neural network features trained on object recognition. This model sets a new state-of-the art in fixation prediction by achieving top performance in area under the curve metrics on the MIT300 hold-out benchmark (AUC = 88%, sAUC = 77%, NSS = 2.34). The second model uses purely low-level (isotropic contrast) features. This model achieves better performance than all models not using features pretrained on object recognition, making it a strong baseline to assess the utility of high-level features. We then evaluate and visualize which fixations are better explained by lowlevel compared to high-level image features. Surprisingly we find that a substantial proportion of fixations are better explained by the simple low-level model than the stateof- the-art model. Comparing different features within the same powerful readout architecture allows us to better understand the relevance of low- versus high-level features in predicting fixation locations, while simultaneously achieving state-of-the-art saliency prediction.

Understanding Low- and High-Level Contributions to Fixation Prediction

Saliency Benchmarking Made Easy: Separating Models, Maps and Metrics

The field of fixation prediction is heavily model-driven, with dozens of new models published every year. However, progress in the field can be difficult to judge because models are compared using a variety of inconsistent metrics. As soon as a saliency map is optimized for a certain metric, it is penalized by other metrics. Here we propose a principled approach to solve the benchmarking problem: we separate the notions of saliency models and saliency maps. We define a saliency model to be a probabilistic model of fixation density prediction and, inspired by Bayesian decision theory, a saliency map to be a metric-specific prediction derived from the model density which maximizes the expected performance on that metric. We derive the optimal saliency map for the most commonly used saliency metrics (AUC, sAUC, NSS, CC, SIM, KL-Div) and show that they can be computed analytically or approximated with high precision using the model density. We show that this leads to consistent rankings in all metrics and avoids the penalties of using one saliency map for all metrics. Under this framework, "good" models will perform well in all metrics.

Learning what properties of an image are associated with human gaze placement is important both for understanding how biological systems explore the environment and for computer vision applications. Recent advances in deep learning for the first time enable us to explain a significant portion of the information expressed in the spatial fixation structure. Our saliency model DeepGaze II uses the VGG network (trained on object recognition in the ImageNet challenge) to convert an image into a high-dimensional feature space which is then readout by a second very simple network to yield a density prediction. DeepGaze II is right now the best performing model for predicting fixations when freeviewing still images (MIT Saliency Benchmark, AUC and sAUC). By retraining on other datasets, we can explore how the features driving fixations change over different tasks or over presentation time. Additionally, the modular architecture of DeepGaze II allows us to quantify how predictive certain features are for fixations. We demonstrate this by replacing the VGG network with very simple isotropic mean-luminance-contrast features and end up with a network that outperforms all previous saliency models before the models that used pretrained deep networks (including models with high-level features like Judd or eDN; Figure 2). Using DeepGaze and the Mean-Luminance-Contrast model (MLC), we can separate how much low-level and high-level features contribute to fixation selection in different situations (Figure 3).

DeepGaze II: A big step towards explaining all information in image-based saliency

DeepGaze II: Explaining nearly all information in image-based saliency using features trained on object detection

When free-viewing scenes, the first few fixations of human observers are driven in part by bottom-up attention. We seek to characterize this process by extracting all information from images that can be used to predict fixation densities (Kuemmerer et al, PNAS, 2015). If we ignore time and observer identity, the average amount of information is slightly larger than 2 bits per image for the MIT 1003 dataset. The minimum amount of information is 0.3 bits and the maximum 5.2 bits. Before the rise of deep neural networks the best models were able to capture 1/3 of this information on average. We developed new saliency algorithms based on highperforming convolutional neural networks such as AlexNet or VGG-19 that have been shown to provide generally useful representations of natural images. Using a transfer learning paradigm we first developed DeepGaze I based on AlexNet that captures 56% of the total information. Subsequently, we developed DeepGaze II based on VGG-19 that captures 88% and is state-of-theart on the MIT 300 benchmark dataset. I will show best case and worst case examples as well as feature selection methods to visualize which structures in the image are critical for predicting fixation densities.

Here we present DeepGaze II, a model that predicts where people look in images. The model uses the features from the VGG-19 deep neural network trained to identify objects in images. Contrary to other saliency models that use deep features, here we use the VGG features for saliency prediction with no additional fine-tuning (rather, a few readout layers are trained on top of the VGG features to predict saliency). The model is therefore a strong test of transfer learning. After conservative cross-validation, DeepGaze II explains about 87% of the explainable information gain in the patterns of fixations and achieves top performance in area under the curve metrics on the MIT300 hold-out benchmark. These results corroborate the finding from DeepGaze I (which explained 56% of the explainable information gain), that deep features trained on object recognition provide a versatile feature space for performing related visual tasks. We explore the factors that contribute to this success and present several informative image examples. A web service is available to compute model predictions at this http URL.

DeepGaze II: Reading fixations from deep features trained on object recognition

Significance Where do people look in images? Predicting eye movements from images is an active field of study, with more than 50 quantitative prediction models competing to explain scene viewing behavior. Yet the rules for this competition are unclear. Using a principled metric for model comparison (information gain), we quantify progress in the field and show how formulating the models probabilistically resolves discrepancies in other metrics. We have also developed model assessment tools to reveal where models fail on the database, image, and pixel levels. These tools will facilitate future advances in saliency modeling and are made freely available in an open source software framework (www.bethgelab.org/code/pysaliency). Learning the properties of an image associated with human gaze placement is important both for understanding how biological systems explore the environment and for computer vision applications. There is a large literature on quantitative eye movement models that seeks to predict fixations from images (sometimes termed “saliency” prediction). A major problem known to the field is that existing model comparison metrics give inconsistent results, causing confusion. We argue that the primary reason for these inconsistencies is because different metrics and models use different definitions of what a “saliency map” entails. For example, some metrics expect a model to account for image-independent central fixation bias whereas others will penalize a model that does. Here we bring saliency evaluation into the domain of information by framing fixation prediction models probabilistically and calculating information gain. We jointly optimize the scale, the center bias, and spatial blurring of all models within this framework. Evaluating existing metrics on these rephrased models produces almost perfect agreement in model rankings across the metrics. Model performance is separated from center bias and spatial blurring, avoiding the confounding of these factors in model comparison. We additionally provide a method to show where and how models fail to capture information in the fixations on the pixel level. These methods are readily extended to spatiotemporal models of fixation scanpaths, and we provide a software package to facilitate their use.

Among the wide range of complex factors driving where people look, the properties of an image that are predictive for fixations under free viewing conditions have been studied most extensively. Here we frame saliency models probabilistically as point processes, allowing the calculation of log-likelihoods and bringing saliency evaluation into the domain of information theory. We compare the information gain of all highperforming state-of-the-art models to a gold standard and find that only one third of the explainable spatial information is captured. Thus, contrary to previous assertions, purely spatial saliency remains a significant challenge. Our probabilistic approach also offers a principled way of understanding and reconciling much of the disagreement between existing saliency metrics. Finally, we present a novel way of reusing existing neural networks that have been pre-trained on the task of object recognition in models of fixation prediction. Using the well-known network "AlexNet" developed by Krizhevsky et al., 2012, we come up with a new saliency model, "Deep Gaze I", that accounts for high-level features like objects and popout. It significantly outperforms previous state-of-the-art models on the MIT Saliency Benchmark and explains more than half of the explainable information. Joint work with Tomas Wallis, Lucas Theis, and Matthias Bethge Organized by: Sponsored by: Institute for Neural Computation: http://inc.ucsd.edu Qualcomm: http://www.qualcomm.com University of California San Diego Brain Corporation: http://www.braincorporation.com

Jumping ahead from 1/3 to 1/2 of understanding image based saliency

Recent results suggest that state-of-the-art saliency models perform far from optimal in predicting fixations. This lack in performance has been attributed to an inability to model the influence of high-level image features such as objects. Recent seminal advances in applying deep neural networks to tasks like object recognition suggests that they are able to capture this kind of structure. However, the enormous amount of training data necessary to train these networks makes them difficult to apply directly to saliency prediction. We present a novel way of reusing existing neural networks that have been pretrained on the task of object recognition in models of fixation prediction. Using the well-known network of Krizhevsky et al. (2012), we come up with a new saliency model that significantly outperforms all state-of-the-art models on the MIT Saliency Benchmark. We show that the structure of this network allows new insights in the psychophysics of fixation selection and potentially their neural implementation. To train our network, we build on recent work on the modeling of saliency as point processes.

Deep Gaze I: Boosting Saliency Prediction with Feature Maps Trained on ImageNet

Within the set of the many complex factors driving gaze placement, the properities of an image that are associated with fixations under free viewing conditions have been studied extensively. There is a general impression that the field is close to understanding this particular association. Here we frame saliency models probabilistically as point processes, allowing the calculation of log-likelihoods and bringing saliency evaluation into the domain of information. We compared the information gain of state-of-the-art models to a gold standard and find that only one third of the explainable spatial information is captured. We additionally provide a principled method to show where and how models fail to capture information in the fixations. Thus, contrary to previous assertions, purely spatial saliency remains a significant challenge.

Acoustics research involving human participants typically takes place in specialized laboratory settings. Listening studies, for example, may present controlled sounds using calibrated transducers in sound-attenuating or anechoic chambers. In contrast, remote testing takes place outside of the laboratory in everyday settings (e.g., participants' homes). Remote testing could provide greater access to participants, larger sample sizes, and opportunities to characterize performance in typical listening environments at the cost of reduced control of environmental conditions, less precise calibration, and inconsistency in attentional state and/or response behaviors from relatively smaller sample sizes and unintuitive experimental tasks. The Acoustical Society of America Technical Committee on Psychological and Physiological Acoustics launched the Task Force on Remote Testing (https://tcppasa.org/remotetesting/) in May 2020 with goals of surveying approaches and platforms available to support remote testing and identifying challenges and considerations for prospective investigators. The results of this task force survey were made available online in the form of a set of Wiki pages and summarized in this report. This report outlines the state-of-the-art of remote testing in auditory-related research as of August 2021, which is based on the Wiki and a literature search of papers published in this area since 2020, and provides three case studies to demonstrate feasibility during practice.

FORUM: Remote testing for psychological and physiological acoustics

In recent years, temporal response function (TRF) analyses of non-invasive recordings of neural activity evoked by continuous naturalistic stimuli have become increasingly popular for characterizing response properties within the auditory hierarchy. However, despite this rise in TRF usage, relatively few educational resources for these tools exist. Here we use a dual-talker continuous speech paradigm to demonstrate how a key parameter of experimental design, the quantity of acquired data, influences TRF analyses fit to either individual data (subject-specific analyses), or group data (generic analyses). We show that although model performance monotonically increases with data quantity, the amount of data required to achieve significant prediction accuracies can vary substantially based on whether the fitted model contains densely (e.g., acoustic envelope) or sparsely (e.g., lexical surprisal) spaced features, especially when the goal of the analyses is to capture the aspect of neural responses uniquely explained by specific features. Moreover, we demonstrate that generic models can exhibit high performance on small amounts of test data (2-8 min), if they are trained on a sufficiently large data set. As such, they may be particularly useful for clinical and multi-task study designs with limited recording time. Finally, we show that the regularization procedure used in fitting TRF models can interact with the quantity of data used to fit the models, with larger training quantities resulting in systematically larger TRF amplitudes. Together, demonstrations in this work should aid the learning process of new users of TRF analyses, and in combination with other tools, such as piloting and power analyses, may serve as a detailed reference for choosing acquisition duration in future studies.

The effects of data quantity on performance of temporal response function analyses of natural speech processing

Speech-in-noise comprehension difficulties are common among the elderly population, yet traditional objective measures of speech perception are largely insensitive to this deficit, particularly in the absence of clinical hearing loss. In recent years, a growing body of research in young normal-hearing adults has demonstrated that high-level features related to speech semantics and lexical predictability elicit strong centro-parietal negativity in the EEG signal around 400 ms following the word onset. Here we investigate effects of age on cortical tracking of these word-level features within a two-talker speech mixture, and their relationship with self-reported difficulties with speech-in-noise understanding. While undergoing EEG recordings, younger and older adult participants listened to a continuous narrative story in the presence of a distractor story. We then utilized forward encoding models to estimate cortical tracking of four speech features: (1) word onsets, (2) “semantic” dissimilarity of each word relative to the preceding context, (3) lexical surprisal for each word, and (4) overall word audibility. Our results revealed robust tracking of all features for attended speech, with surprisal and word audibility showing significantly stronger contributions to neural activity than dissimilarity. Additionally, older adults exhibited significantly stronger tracking of word-level features than younger adults, especially over frontal electrode sites, potentially reflecting increased listening effort. Finally, neuro-behavioral analyses revealed trends of a negative relationship between subjective speech-in-noise perception difficulties and the model goodness-of-fit for attended speech, as well as a positive relationship between task performance and the goodness-of-fit, indicating behavioral relevance of these measures. Together, our results demonstrate the utility of modeling cortical responses to multi-talker speech using complex, word-level features and the potential for their use to study changes in speech processing due to aging and hearing loss.

Effects of Age on Cortical Tracking of Word-Level Features of Continuous Competing Speech

Frequency-to-place mapping, or tonotopy, is a fundamental organizing principle throughout the auditory system, from the earliest stages of auditory processing in the cochlea to subcortical and cortical regions. Although cortical maps are referred to as tonotopic, it is unclear whether they simply reflect a mapping of physical frequency inherited from the cochlea, a computation of pitch based on the fundamental frequency, or a mixture of these two features. We used high-resolution functional magnetic resonance imaging (fMRI) to measure BOLD responses as male and female human participants listened to pure tones that varied in frequency or complex tones that varied in either spectral content (brightness) or fundamental frequency (pitch). Our results reveal evidence for pitch tuning in bilateral regions that partially overlap with the traditional tonotopic maps of spectral content. In general, primary regions within Heschl's gyri (HGs) exhibited more tuning to spectral content, whereas areas surrounding HGs exhibited more tuning to pitch. SIGNIFICANCE STATEMENT Tonotopy, an orderly mapping of frequency, is observed throughout the auditory system. However, it is not known whether the tonotopy observed in the cortex simply reflects the frequency spectrum (as in the ear) or instead represents the higher-level feature of fundamental frequency, or pitch. Using carefully controlled stimuli and high-resolution functional magnetic resonance imaging (fMRI), we separated these features to study their cortical representations. Our results suggest that tonotopy in primary cortical regions is driven predominantly by frequency, but also reveal evidence for tuning to pitch in regions that partially overlap with the tonotopic gradients but extend into nonprimary cortical areas. In addition to resolving ambiguities surrounding cortical tonotopy, our findings provide evidence that selectivity for pitch is distributed bilaterally throughout auditory cortex.

Distinct Representations of Tonotopy and Pitch in Human Auditory Cortex

Frequency-to-place mapping, or tonotopy, is a fundamental organizing principle from the earliest stages of auditory processing in the cochlea to subcortical and cortical regions. Although cortical maps are referred to as tonotopic, previous studies employed sounds that covary in spectral content and higher-level perceptual features such as pitch, making it unclear whether these maps are inherited from cochlear organization and are indeed tonotopic, or instead reflect transformations based on higher-level features. We used high-resolution fMRI to measure BOLD responses in 10 participants as they listened to pure tones that varied in frequency or complex tones that independently varied in either spectral content or fundamental frequency (pitch). We show that auditory cortical gradients are in fact a mixture of maps organized both by spectral content and pitch. Consistent with hierarchical organization, primary regions were tuned predominantly to spectral content, whereas higher-level pitch tuning was observed bilaterally in surrounding non-primary regions.

Acoustics research involving human participants typically takes place in specialized laboratory settings. Lis-tening studies, for example, may present controlled sounds using calibrated transducers in sound-attenuating or anechoic chambers. In contrast, remote testing takes place away from the lab, in natural settings or in participants’ homes. Remote testing could provide greater access to participants, larger sample sizes, and enhanced ecological validity, at the cost of reduced acoustical control, less precise calibration, and incon-sistency of participant experiences. The ASA Technical Committee on Psychological and Physiological Acoustics (P&P) launched the Task Force on Remote Testing in May 2020, with goals of (1) surveying ap-proaches and platforms available to support remote testing by ASA members, (2) identifying challenges and considerations for prospective investigators, and (3) communicating this information via online resources, papers, and presentations. Longer-term goals include identifying best practices and providing resources for evaluating outcomes of remote testing, e.g. via peer review.

Remote testing for psychological and physiological acoustics: Initial report of the P&P Task Force on Remote Testing

Recent studies on amplitude modulation (AM) detection for tones in noise reported that AM-detection thresholds improve when the AM stimulus is preceded by a noise precursor. The physiological mechanisms underlying this AM unmasking are unknown. One possibility is that adaptation to the level of the noise precursor facilitates AM encoding by causing a shift in neural rate-level functions to optimize level encoding around the precursor level. The aims of this study were to investigate whether such a dynamic-range adaptation is a plausible mechanism for the AM unmasking and whether frequency modulation (FM), thought to be encoded via AM, also exhibits the unmasking effect. Detection thresholds for AM and FM of tones in noise were measured with and without a fixed-level precursor. Listeners showing the unmasking effect were then tested with the precursor level roved over a wide range to modulate the effect of adaptation to the precursor level on the detection of the subsequent AM. It was found that FM detection benefits from a precursor and the magnitude of FM unmasking correlates with that of AM unmasking. Moreover, consistent with dynamic-range adaptation, the unmasking magnitude weakens as the level difference between the precursor and simultaneous masker of the tone increases.

Effects of noise precursors on the detection of amplitude and frequency modulation for tones in noise.

Remote testing for psychological and physiological acoustics: Initial report of the ASA P&P Task Force on Remote Testing

Speech-in-noise comprehension difficulties are common among the elderly population, yet traditional objective measures of speech perception are largely insensitive to this deficit, particularly in the absence of clinical hearing loss. In recent years, a growing body of research in young normal-hearing adults has demonstrated that high-level features related to speech semantics and lexical predictability elicit strong centro-parietal negativity in the EEG signal around 400 ms following the word onset. Here we investigate effects of age on cortical tracking of these word-level features within a two-talker speech mixture, and their relationship with self-reported difficulties with speech-in-noise understanding. While undergoing EEG recordings, younger and older adult participants listened to a continuous narrative story in the presence of a distractor story. We then utilized forward encoding models to estimate cortical tracking of three speech features: 1) “semantic” dissimilarity of each word relative to the preceding context, 2) lexical surprisal for each word, and 3) overall word audibility. Our results revealed robust tracking of all three features for attended speech, with surprisal and word audibility showing significantly stronger contributions to neural activity than dissimilarity. Additionally, older adults exhibited significantly stronger tracking of surprisal and audibility than younger adults, especially over frontal electrode sites, potentially reflecting increased listening effort. Finally, neuro-behavioral analyses revealed trends of a negative relationship between subjective speech-in-noise perception difficulties and the model goodness-of-fit for attended speech, as well as a positive relationship between task performance and the goodness-of-fit, indicating behavioral relevance of these measures. Together, our results demonstrate the utility of modeling cortical responses to multi-talker speech using complex, word-level features and the potential for their use to study changes in speech processing due to aging and hearing loss.

Amplified cortical tracking of word-level features of continuous competing speech in older adults

Underlying mechanisms of temporal dynamics in bistable perception

Pitch and timbre are two primary features of auditory perception that are generally considered independent. However, an increase in pitch (produced by a change in fundamental frequency) can be confused with an increase in brightness (an attribute of timbre related to spectral centroid) and vice versa. Previous work indicates that pitch and timbre are processed in overlapping regions of the auditory cortex, but are separable to some extent via multivoxel pattern analysis. Here, we tested whether attention to one or other feature increases the spatial separation of their cortical representations and if attention can enhance the cortical representation of these features in the absence of any physical change in the stimulus. Ten human subjects (four female, six male) listened to pairs of tone triplets varying in pitch, timbre, or both and judged which tone triplet had the higher pitch or brighter timbre. Variations in each feature engaged common auditory regions with no clear distinctions at a univariate level. Attending to one did not improve the separability of the neural representations of pitch and timbre at the univariate level. At the multivariate level, the classifier performed above chance in distinguishing between conditions in which pitch or timbre was discriminated. The results confirm that the computations underlying pitch and timbre perception are subserved by strongly overlapping cortical regions, but reveal that attention to one or other feature leads to distinguishable activation patterns even in the absence of physical differences in the stimuli. SIGNIFICANCE STATEMENT Although pitch and timbre are generally thought of as independent auditory features of a sound, pitch height and timbral brightness can be confused for one another. This study shows that pitch and timbre variations are represented in overlapping regions of auditory cortex, but that they produce distinguishable patterns of activation. Most importantly, the patterns of activation can be distinguished based on whether subjects attended to pitch or timbre even when the stimuli remained physically identical. The results therefore show that variations in pitch and timbre are represented by overlapping neural networks, but that attention to different features of the same sound can lead to distinguishable patterns of activation.

Association of musical training with auditory and speech neural coding and perception

Later visual areas can adapt to adapted input from earlier visual areas.

Exposure to oriented luminance contrast patterns causes a reduction in visual sensitivity specifically for the adapter orientation. This orientation selectivity is probably the most studied aspect of contrast adaptation, but it has rarely been measured with steady-state visually evoked potentials (SSVEPs), despite their becoming one of the more popular methods of human neuroscience. Here, we measured orientation selective adaptation by presenting a plaid stimulus of which the horizontal and vertical grating reversed contrast at different temporal frequencies, while recording EEG signals from occipital visual areas. In three experiments, we compared SSVEP responses to the plaid before and after adaptation. All experiments showed a significant decrease in SSVEP response at the frequency of the adapter orientation, whereas such an effect was absent for the frequency of the orthogonal orientation. Adaptation also led to robust phase delays, selectively for the SSVEP frequency corresponding to the adapter orientation. These results demonstrate the efficiency of SSVEPs for measuring orientation selective adaptation; the method can measure changes in both amplitude and phase, simultaneously for two orientations.

Purpose People with central field loss (CFL) lose information in the scotomatous region. Remapping is a method to modify images to present the missing information outside the scotoma. This study tested the hypothesis that remapping improves reading performance for subjects with simulated CFL. Methods Circular central scotomas, with diameters ranging from 4° to 16°, were simulated in normally sighted subjects using an eye tracker on either a head-mounted display (HMD) (experiments 1, 2) or a traditional monitor (experiment 3). In the three experiments, reading speed was measured for groups of 7, 11, and 13 subjects with and without remapping of text. Results Remapping increased reading speed in all three experiments. On the traditional monitor, it increased reading speed by 34% (8°), 38% (12°), and 35% (16°). In the two HMD experiments, remapping increased reading speed only for the largest scotoma size, possibly due to latency of updating of the simulated scotoma. Conclusions Remapping significantly increased reading speed in simulated CFL subjects. Additional testing should examine the efficacy of remapping for reading and other visual tasks for patients with advanced CFL.

Beneficial Effects of Spatial Remapping for Reading With Simulated Central Field Loss

Long-term contrast deprivation increases neural gain in early visual cortex

Three Years after the Paris Agreement: More Disturbing Science Data, Some Rhetoric and Too Little Action

Phase analysis of SSVEP reveals that masking delays neural response in human cortex

University of Minnesota Ph.D. dissertation. December 2017. Major: Psychology. Advisors: Stephen Engel, Sheng He. 1 computer file (PDF); vii, 131 pages.

If we stare at a waterfall for a while and then shift our gaze away, our visual environment will appear to move upward. First reported by Aristotle ∼330 BC, this phenomenon is known as the waterfall illusion or the motion aftereffect ([Anstis et al., 1998][1]). The motion aftereffect is a

Adaptation, the Coding Catastrophe and Disaster Management in Natural Vision

Repeated adaptation to natural images with biased orientation statistics does not alter adaptation dynamics

"I'm not a fan of hyperbole, but it would be churlish to say the adoption of the Paris Agreement was anything other than a globally, historic moment," wrote respected BBC environment correspondent Matt McGrath, on December 12, 2015.1 McGrath's statement was far from being the only one: quite the contrary, the results of the Paris Conference of Parties (COP 21) fostered a satisfaction bordering on excitement that was almost universal and univocal - with just a few, albeit notable individuals, dissenting from the general feeling of relief and satisfaction.The Paris Agreement was adopted by 195 countries and became the first-ever universal, legally binding climate deal. The key elements of the agreement can be found, inter alia, on the European Commission's website on climate action2. An absolutely crucial part of the agreement is the declared goal to limit the increase in the average global temperature to below 2°C, preferably to just 1.5°C. This goal is in line with the recommendations made by the Intergovernmental Panel for Climate Change;3 however, it is questionable whether it is still physically possible. In addition to this key question, there is doubt as to whether the wording of the agreement sufficiently operationalizes the path towards the stated goal.The Paris Agreement is without doubt the diplomatic triumph of the European Union and in particular French diplomacy and Laurent Fabius, French foreign minister and chair of the Paris conference. The Paris Agreement is the highest common denominator on which the global polity could agree in 2015; however, this denominator may prove to be too low to achieve aspirations. Since the first United Nations Framework Convention on Climate Change conference of Parties (COP) in Berlin in 1995, politicians and experts have met 21 times on an annual basis4 and agreed a variety of documents and approaches to be taken to tackle advancing climate change, most notably that on the Kyoto Protocol.5 Despite this diplomatic effort, the Earth's climate system took no notice and there has been no visible change in the dynamics of CO2 emissions and climate change. Fifteen of the sixteen warmest years since systematic record-keeping began have been recorded since 2001 - the only exception is 1998 (Figure 1). No noticeable slowdown in human CO2 emissions has been recorded over the past three decades (Figure2).tiationsIn the meantime the concentration of atmospheric CO2 has grown from around 360 ppm in 1995 - when COP1 was held - to its current level of over 400 parts per million: such a concentration has not been seen in the whole history of the human species. Similar concentrations of atmospheric CO2 were present on Earth in the Pliocene Epoch, when the average global temperature was 3 to 4°C higher than today and sea levels were 5 to 40 meters above recent levels.6 The year 2014 was the warmest year on record - but only till 2015, when it was surpassed by a large margin. Data published by American NASA and NOAA show that the average global temperature in 2015 was 0.13°C higher than in the previous record warm year of 2014. This is the largest margin by which the previous temperature record has been broken since global instrumental measurements were first taken.7 To put the figures in context, 2015 was 0.75°C warmer than the 1961-1990 average or, using the time framework used in the Paris Agreement, 2015 was the first year when the average global temperature surpassed the global pre-industrial temperature by 1°C.Can we really stop temperature growth?Already in December 2015 the authoritative British Met Office published a forecast suggesting that the year 2016 could be 1.1°C above preindustrial levels or 0.84°C above the 1961-1990 average global temperature. Professor Adam Scaife of the Met Office commentedIn 2014 we had 0.6 which was nominally a record, 2015 so far we've had 0.7 which is also nominally a record, and next year we are talking about 0.8 - so you can see that very rapid rise over three years and by the end of 2016 we may be looking at three record years in a row. …

Contrast adaptation adjusts sensitivity to match the statistical structure of the world. Does the visual system adapt faster to statistics with which it has prior experience? To answer this question, we repeatedly adapted subjects (n=6), over the course of 4 days, to three distinct sets of contrast statistics, and measured the growth and decay of the tilt-aftereffect. Subjects viewed 2 min sequences comprised of rapidly presented sinusoidal gratings of 12 different orientations (33 ms/grating, 85% contrast). The sequences were either uniform across orientation, or biased, with one orientation much more likely than the others (66% vs 3% probability). The biased sequences have been shown to induce contrast adaptation to the high probability orientation. "Adapter" and unbiased "test" sequences were presented simultaneously on opposite sides of fixation at 2.5 deg eccentricity. To measure the tilt-aftereffect, every 1 sec a pair of 2.5 deg, 50% contrast gratings were inserted in the sequences for 250 msec. Using a mouse, subjects adjusted the tilt of the grating in the test sequence to match its apparent orientation in the adapter sequence. The test was oriented 13, 15, or 17 deg away from the biased orientation, offsets at which robust tilt-aftereffects are observable. Every day, subjects completed 4 task runs, each containing 5 blocks that alternated between biased adapters and unbiased "baseline" adapters. The biased adapters induced a strong tilt-aftereffect (on average ~2 deg). However, we observed no change in adaptation dynamics across the 4 days. Adaptation growth and decay time constants and peak tilt-aftereffect levels did not reliably change across the 4 days p>0.05). Our results suggest that the visual system cannot learn to adapt more quickly to statistical regularities in low-level visual features, at least over the timescales tested here. Meeting abstract presented at VSS 2015.

Repeatedly adapting to orientation ensembles does not change contrast adaptation dynamics.

Since the first part of this essay was published in the DEF, the mighty, formally educated, yet future-naive Europe has received her wake-up call from the future. By the end of 2015, 800,000 asylum seekers are expected to have arrived in Germany (Guardian 2015 A). This is four times more than one year before. By August 2015, more than 125,000 migrants reached the Greek islands – a 750% increase over the whole of 2014 (Business 2015). Globally in three years, from 2011 to 2014, the number of people displaced by war grew from 42.5 million to 59.5 million (UNHCR 2015).

Oil, climate, denial and the future capacity of development assistance—Part II

Investigating the Effects of Experience on the Dynamics of Visual Adaptation

Repeated days of 2 hr visual adaptation create effects that are faster but weaker.

There are many theories on the purpose of neural adaptation, but evidence remains elusive. Here, we discuss the recent work by Benucci et al. (Nat Neurosci 16: 724-729, 2013), who measured for the first time the immediate effects of adaptation on the overall activity of a neuronal population. These measurements confirm two long-standing hypotheses about the purpose of adaptation, namely that adaptation counteracts biases in the statistics of the environment, and that it maintains decorrelation in neuronal stimulus selectivity.

Repeated days of 2 hr visual adaptation create effects that are faster

Detection reveals multiple temporally tuned mechanisms controlling contrast adaptation

Changes to the visual environment can happen at many timescales, from very transient to semi-permanent. To adapt optimally, the visual system also adjusts at different timescales, with longer-lasting environmental changes producing longer-lasting effects, but how the visual system adapts in this way remains unknown. Here, we show that contrast adaptation-the most-studied form of visual adaptation-has multiple controllers, each operating over a different time scale. In a series of experiments, subjects completed either a contrast matching, contrast detection, or tilt adjustment task, while adapting to contrast at one orientation. Following a relatively longer period (5 min) of adaptation to high contrast, subjects were "deadapted" for a shorter period (e.g., 40 s) to a lower contrast. Deadaptation eliminated perceptual aftereffects of adaptation, but continued testing in a neutral environment revealed their striking recovery. These results suggest the following account: Adaptation was controlled by at least two mechanisms, with initial adaptation affecting a longer-term one and deadaptation affecting a shorter-term one in the opposite direction. Immediately following deadaptation, the effects of the two mechanisms cancelled each other, but the short-term effects rapidly decayed, revealing ongoing longer-term adaptation. A single controlling mechanism cannot account for the observed recovery of effects, since once deadaptation cancels the initial longer-term adaptation, no trace of it remains. Combined with previous results at very long adaptation durations, the present results suggest that contrast adaptation is possibly controlled by a continuum of mechanisms acting over a large range of timescales.

Distinct mechanisms control contrast adaptation over different timescales.

Spontaneous recovery of the motion aftereffect (and face adaptation)

We effortlessly and seemingly instantaneously recognize thousands of objects, although we rarely--if ever--see the same image of an object twice. The retinal image of an object can vary by context, size, viewpoint, illumination, and location. The present study examined how the visual system abstracts object category across variations in retinal location. In three experiments, participants viewed images of objects presented to different retinal locations while brain activity was recorded using magnetoencephalography (MEG). A pattern classifier was trained to recover the stimulus position (Experiments 1, 2, and 3) and category (Experiment 3) from the recordings. Using this decoding approach, we show that an object's location in the visual field can be recovered in high temporal resolution (5 ms) and with sufficient fidelity to capture topographic organization in visual areas. Experiment 3 showed that an object's category could be recovered from the recordings as early as 135 ms after the onset of the stimulus and that category decoding generalized across retinal location (i.e., position invariance). Our experiments thus show that the visual system rapidly constructs a category representation for objects that is invariant to position.

High temporal resolution decoding of object position and category.

Community foundations are locally based grant making foundations that mobilize local philanthropic contributions to support variety of development projects. They are becoming increasingly important in mobilizing local resources and development expertise. These foundations play a particularly valuable role in assisting local development, strengthening resourcefulness and capacities, attracting new resources and cultivating philanthropy from local donors for community-based and Community-Driven Development (CDD). This note provides guidance to those considering community foundations as an element of a larger CDD or Social Investment Fund (SIF) project.

Community Foundations How To Series : Getting Started with a Community Foundation

This newsletter concerns the relevance for social funds in Urban Areas. Social funds face a common challenge of sustaining the community capacities that are built and investments that are supported beyond the relatively short lifespan of external funding. For long-term sustainability, external funding needs to be replaced by a steady flow of domestic revenue. The Community foundation (CF) approach offers a number of advantages for urban work. Community foundations are independent organizations that provide grants to support a variety of projects identified and implemented by local residents. A CF does not replace the scale of resources and national reach achieved by social funds. But it can provide a partial answer to the sustainability challenge in some large and medium-size urban areas, where it can mobilize local resources and sustain social dynamism and participation in broad areas of development work.

Community Foundations - The Relevance for Social Funds in Urban Areas: The Tanzania Social Action Fund Experience

Community Driven Development (CDD) approaches present an effective means to involve young people in local development decision-making, giving them voice and influencing power, with benefits for themselves and their communities. This note highlights a range of key learning points emerging from years of international experience with youth banks, and youth advisory committees, an innovative tool for engaging youth in their communities. Community foundations hosting, youth advisory committees, or youth banks see youth in the community as a resource to be tapped into, not a problem to be solved. They see the best way for utilizing the energy and creativity of young people in giving them a large share of responsibility for the identification of youth needs and opportunities for youth engagement, selection of priority projects, grant making, implementation of projects, their monitoring as well as raising funds needed for the work.

Community Foundations: A Tool for Engaging Youth in Community Driven Development

Europe/Plan B – For a Carbon-Free Economy Independent of Arabic Oil, Russian Gas or Chinese Coal

Tracking the emergence of meaning in the brain during natural story comprehension

An International Inquire on the Opinions of Practising Physics Teachers on Initial Teacher Training in the Frame of Eupen Activities

Neurophysiological markers of ADHD symptoms in typically-developing children

To characterize the left-ventral occipito-temporal cortex (lvOT) role during reading in a quantitatively explicit and testable manner, we propose the lexical categorization model (LCM). The LCM assumes that lvOT optimizes linguistic processing by allowing fast meaning access when words are familiar and filter out orthographic strings without meaning. The LCM successfully simulates benchmark results from functional brain imaging. Empirically, using functional magnetic resonance imaging, we demonstrate that quantitative LCM simulations predict lvOT activation across three studies better than alternative models. Besides, we found that word-likeness, which is assumed as input to LCM, is represented posterior to lvOT. In contrast, a dichotomous word/non-word contrast, which is assumed as the LCM’s output, could be localized to upstream frontal brain regions. Finally, we found that training lexical categorization results in more efficient reading. Thus, we propose a ventral-visual-stream processing framework for reading involving word-likeness extraction followed by lexical categorization, before meaning extraction.

The lexical categorization model: A computational model of left ventral occipito-temporal cortex activation in visual word recognition

Improving free-viewing fixation-related EEG potentials with continuous-time regression

Cluster-based permutation tests are gaining an almost universal acceptance as inferential procedures in cognitive neuroscience. They elegantly handle the multiple comparisons problem in high-dimensional magnetoencephalographic and EEG data. Unfortunately, the power of this procedure comes hand in hand with the allure for unwarranted interpretations of the inferential output, the most prominent of which is the overestimation of the temporal, spatial, and frequency precision of statistical claims. This leads researchers to statements about the onset or offset of a certain effect that is not supported by the permutation test. In this article, we outline problems and common pitfalls of using and interpreting cluster-based permutation tests. We illustrate these with simulated data in order to promote a more intuitive understanding of the method. We hope that raising awareness about these issues will be beneficial to common scientific practices, while at the same time increasing the popularity of cluster-based permutation procedures.

Cluster-based permutation tests of MEG/EEG data do not establish significance of effect latency or location.

Scientific Methods for Open Behavioral, Social and Cognitive Sciences

How is semantic information stored in the human mind and brain? Some philosophers and cognitive scientists argue for vectorial representations of concepts, where the meaning of a word is represented as its position in a high-dimensional neural state space. At the intersection of natural language processing and artificial intelligence, a class of very successful distributional word vector models has developed that can account for classic EEG findings of language, i.e., the ease vs. difficulty of integrating a word with its sentence context. However, models of semantics have to account not only for context-based word processing, but should also describe how word meaning is represented. Here, we investigate whether distributional vector representations of word meaning can model brain activity induced by words presented without context. Using EEG activity (event-related brain potentials) collected while participants in two experiments (English, German) read isolated words, we encode and decode word vectors taken from the family of prediction-based word2vec algorithms. We find that, first, the position of a word in vector space allows the prediction of the pattern of corresponding neural activity over time, in particular during a time window of 300 to 500 ms after word onset. Second, distributional models perform better than a human-created taxonomic baseline model (WordNet), and this holds for several distinct vector-based models. Third, multiple latent semantic dimensions of word meaning can be decoded from brain activity. Combined, these results suggest that empiricist, prediction-based vectorial representations of meaning are a viable candidate for the representational architecture of human semantic knowledge.

Traces of Meaning Itself: Encoding Distributional Word Vectors in Brain Activity

Finding the P3 in the P600: Decoding shared neural mechanisms of responses to syntactic violations and oddball targets

Event-related brain potentials have a strong impact on neurocognitive models, as they inform about the temporal sequence of cognitive processes. Nevertheless, their value for deciding among alternative cognitive architectures is partly limited by component overlap and the possibility of ambiguity regarding component identity. Here, we apply temporally-generalized multivariate pattern analysis – a recently-proposed machine learning method capable of tracking the evolution of neurocognitive processes over time – to constrain possible alternative architectures underlying the processing of semantic incongruency in sentences. In a spoken sentence paradigm, we replicate established N400/P600 correlates of semantic mismatch. Time-generalized decoding indicates that early vs. late mismatch-sensitive processes are (i) distinct in their neural substrate, arguing against recurrent or latency-shifted single process architectures, and (ii) partially overlapping in time, inconsistent with predictions of strictly serial models. These results are in accordance with an incremental-cascading neurocognitive organization of semantic mismatch processing. We propose time-generalized multivariate decoding as a valuable tool for neurocognitive language studies.

Eye movements during text reading align with the rate of speech production

The oddball effect on P3 disappears when feature relevance or feature-response mappings are unknown

ABSTRACT Naturalistic language processing cannot be approached with the analysis methods constructed to handle well-controlled experiments. Language is a multi- and cross-level phenomenon, with sequential interdependencies and correlations between various lexical dimensions. A recently-developed method allows the analysis of neural time series during natural story comprehension: time-resolved multiple regression. It consists in modelling continuous brain recordings with multiple regression after embedding linguistic features in a temporal-extension matrix (a distributed-lags model). It identifies neural correlates of linguistic processes, accounting for temporal interdependencies – simultaneously for, e.g. acoustics, phonology and semantics. This has resulted in impactful discoveries about how brains process coherent speech, potentially broadening the class of phenomena that can be studied. I discuss the method conceptually, highlight caveats, and relate it to similar as well as to traditional methods, all with a particular consideration for analysing the processing of coherent narratives. In a practical example, the word frequency-dependent N400 effect is estimated from a half-hour continuous narrative.

How to analyse electrophysiological responses to naturalistic language with time-resolved multiple regression

Across languages, the speech signal is characterized by a ~4-5 Hz rhythm of the amplitude modulation spectrum, reflecting the processing of linguistic information chunks approximately every 200 ms. Interestingly, ~200 ms is also the typical eye-fixation duration during reading. Prompted by this observation, we estimated the frequency at which readers sample text, and demonstrate that they read sentences at a rate of ~5 Hz. We then examined the generality of this finding in a meta analysis. While replicating the experimentally measured 5 Hz sampling rate in the language in which it was obtained, i.e., German, we observe that fixation-based sampling frequencies vary across languages between 3.1 and 5.2 Hz, with the majority of languages lying between 4 and 5 Hz. Remarkably, we identify a systematic rate reduction from easy to difficult writing systems. Reading in easy-to-process writing systems thus is aligned with the rhythm of speech, which may constitute an upper boundary for reading. We argue that reading is likely tuned to supply information to linguistic processes at an optimal rate, coincident with the typical rate of speech.

Reading at the speed of speech: the rate of eye movements aligns with auditory language processing

Time-generalized multivariate analysis of EEG responses reveals a cascading architecture of semantic mismatch processing

Current cognitive models of reading assume that word recognition involves the 9bottom-up9 assembly of perceived low-level visual features into letters, letter combinations, and words. This rather inefficient strategy, however, is incompatible with neurophysiological theories of Bayesian-like predictive neural computations during perception. Here we propose that prior knowledge of the words in a language is used to 9explain away9 redundant and highly expected parts of the percept. As a result, subsequent processing stages operate upon an optimized representation highlighting information relevant for word identification, i.e., the orthographic prediction error. We demonstrate empirically that the orthographic prediction error accounts for word recognition behavior. We then report neurophysiological data showing that this informationally optimized orthographic prediction error is processed around 200 ms after word-onset in the occipital cortex. The remarkable efficiency of reading, thus, is achieved by optimizing the mental representation of the visual percept, based on prior visual-orthographic knowledge.

Visual word recognition relies on an orthographic prediction error signal

Time-generalized multivariate analysis of EEG responses reveals a cascading 1 architecture of semantic mismatch processing 2 3 4 5

How are verb-argument structure preferences acquired? Children typically receive very little negative evidence, raising the question of how they come to understand the restrictions on grammatical constructions. Statistical learning theories propose stochastic patterns in the input contain sufficient clues. For example, if a verb is very common, but never observed in transitive constructions, this would indicate that transitive usage of that verb is illegal. Ambridge et al. (2008) have shown that in offline grammaticality judgements of intransitive verbs used in transitive constructions, low-frequency verbs elicit higher acceptability ratings than high-frequency verbs, as predicted if relative frequency is a cue during statistical learning. Here, we investigate if the same pattern also emerges in on-line processing of English sentences. EEG was recorded while healthy adults listened to sentences featuring transitive uses of semantically matched verb pairs of differing frequencies. We replicate the finding of higher acceptabilities of transitive uses of low- vs. high-frequency intransitive verbs. Event-Related Potentials indicate a similar result: early electrophysiological signals distinguish between misuse of high- vs low-frequency verbs. This indicates online processing shows a similar sensitivity to frequency as off-line judgements, consistent with a parser that reflects an original acquisition of grammatical constructions via statistical cues. However, the nature of the observed neural responses was not of the expected, or an easily interpretable, form, motivating further work into neural correlates of online processing of syntactic constructions.

Frequency Sensitivity of Neural Responses to English Verb Argument Structure Violations

Free-viewing fixation related EEG-potentials with continuous-time regression

ABSTRACT The outstanding speed of language comprehension necessitates a highly efficient implementation of cognitive-linguistic processes. The domain-general theory of Predictive Coding suggests that our brain solves this problem by continuously forming linguistic predictions about expected upcoming input. The neurophysiological implementation of these predictive linguistic processes, however, is not yet understood. Here, we use EEG (human participants, both sexes) to investigate the existence and nature of online-generated, category-level semantic representations during sentence processing. We conducted two experiments in which some nouns – embedded in a predictive spoken sentence context – were unexpectedly delayed by 1 second. Target nouns were either abstract/concrete (Experiment 1) or animate/inanimate (Experiment 2). We hypothesized that if neural prediction error signals following (temporary) omissions carry specific information about the stimulus, the semantic category of the upcoming target word is encoded in brain activity prior to its presentation. Using time-generalized multivariate pattern analysis, we demonstrate significant decoding of word category from silent periods directly preceding the target word, in both experiments. This provides direct evidence for predictive coding during sentence processing, i.e., that information about a word can be encoded in brain activity before it is perceived. While the same semantic contrast could also be decoded from EEG activity elicited by isolated words (Experiment 1), the identified neural patterns did not generalize to pre-stimulus delay period activity in sentences. Our results not only indicate that the brain processes language predictively, but also demonstrate the nature and sentence-specificity of category-level semantic predictions preactivated during sentence comprehension. STATEMENT OF SIGNIFICANCE The speed of language comprehension necessitates a highly efficient implementation of cognitive-linguistic processes. Predictive processing has been suggested as a solution to this problem, but the underlying neural mechanisms and linguistic content of such predictions are only poorly understood. Inspired by Predictive Coding theory, we investigate whether the meaning of expected, but not-yet heard words can be decoded from brain activity. Using EEG, we can predict if a word is, e.g., abstract (as opposed to concrete), or animate (vs. inanimate), from brain signals preceding the word itself. This strengthens predictive coding theory as a likely candidate for the principled neural mechanisms underlying online processing of language and indicates that predictive processing applies to highly abstract categories like semantics.

Investigating the temporal dynamics of object-scene integration using MVPA: The role of the N300/N400 complex in object perception

An orthographic prediction error as the basis for efficient visual word recognition

Here, first, some statistical patterns in normal language are discussed, and how they demostrate the need for a multivariate, time-resolved analysis such as time-resolved multiple regression. Then, some background regarding multiple linear regression are laid out with the intent of helping understand important aspects of solving rERP/mTRF analyses. 1 Demonstration of confounds from statistical patterns in natural language Methods A part of speech tagger (ParZu; Sennrich, Volk, & Schneider, 2013) was applied to a large selection of continuous narratives: the entire text of the German Projekt Gutenberg corpus at www.gutenberg.org. Some non-prose texts, e.g. lexica, were excluded, leaving 925 texts. First, corpus frequencies for all words were retrieved (Brysbaert et al., 2011). The autocorrelation of the resulting time series was calculated; i.e., the correlation between the series of frequencies with itself was calculated, then the correlation between the series as-is vs. the series shifted by one word forward, then two words forwards . . . up to four; this was repeated with backwards shifts. Then, this was repeated after shuffling all words randomly to create a baseline measure. If there were no pattern in the occurence of frequent vs. infrequent words, the empirical and the permuted autocorrelations should be identical; otherwise, discrepancies will become observable. Then, for all of the texts, the lengths of all continuous sequences of function words was counted; e.g., the text “The fox ate the hen and left” would have been counted as (2, 1, 1), for an uninterrupted sequence of two content words (‘fox ate’) and two single content words. This was repeated for function words; e.g., for the example, (1, 1, 1). Then, to estimate with which regularity content and function words alternate, it was counted how often each sequence length occured; e.g., in this case, for content words, this would have resulted in two counts of sequences of of one, and one count of sequences of two. Then, to establish a baseline, the sequences of function and content words were shuffled randomly times, and the procedure was

Supplement – Basic mathematical background to time-resolved regression analysis and examples for statistical patterns in normal language

No evidence from MVPA for different processes underlying the N300 and N400 incongruity effects in object-scene processing

Abstract Across languages, the speech signal is characterized by a predominant modulation of the amplitude spectrum at ~4-5 Hz, reflecting the processing of linguistic information chunks (i.e., syllables or words) approximately every 200 ms. Interestingly, ~200 ms is also the typical duration of eye fixations during reading. Prompted by this observation, we estimated the frequency at which German readers sample text, and demonstrate that they read sentences at a rate of ~5 Hz. We then examined the generality of this finding in a meta-analysis including 14 languages. We replicated the empirical result for German and observed that fixation-based sampling frequencies vary across languages between 3.9 and 5.2 Hz. Remarkably, we identified a systematic rate reduction from easy to difficult writing systems. Finally, we directly investigated in a new experiment the association between speech spectrum and eye-movement sampling frequency at a person-specific level and found a significant correlation. Based on this evidence, we argue that during reading, the rate of our eye movements is tuned to supply information to language comprehension processes at a preferred rate, coincident with the typical rate of speech. Significance Statement Across languages, speech is produced and perceived at a rate of ~4-5Hz. When listening to speech, our brain capitalizes this temporal structure to segment speech. We show empirically that while reading our eyes sample text at the same rate, and generalize this finding in a meta-analysis to 14 languages. Reading rates vary between 3.9 and 5.2Hz – i.e., within the typical range of the speech signal. We demonstrate that the difficulty of writing systems underpins this variance. Lastly, we also demonstrate that the speech rate between persons is correlated with the rate at which their eyes sample text. The speech rate of spoken language appears to act as a driving force for the voluntary control of eye movements during reading.

Reading at the speed of speech: Alignment of eye-movement sampling in reading with the speech production rate

The P600 Event-Related Brain Potential, elicited by syntactic violations in sentences, is generally interpreted as indicating language-specific structural/combinatorial processing, with far-reaching implications for models of language. P600 effects are also often taken as evidence for language-like grammars in non-linguistic domains like music or arithmetic. An alternative account, however, interprets the P600 as a P3, a domain-general brain response to salience. Using time-generalized multivariate pattern analysis, we demonstrate that P3 EEG patterns, elicited in a visual Oddball experiment, account for the P600 effect elicited in a syntactic violation experiment: P3 pattern-trained MVPA can classify P600 trials just as well as P600-trained ones. A second study replicates and generalizes this finding, and demonstrates its specificity by comparing it to face- and semantic mismatch-associated EEG responses. These results indicate that P3 and P600 share neural patterns to a substantial degree, calling into question the interpretation of P600 as a language-specific brain response and instead strengthening its association with the P3. More generally, our data indicate that observing P600-like brain responses provides no direct evidence for the presence of language-like grammars, in language or elsewhere.

Finding the P3 in the P600: Decoding shared neural mechanisms of responses to syntactic violations and oddball target detection

A central challenge to cognitive neuroscience consists in decomposing complex brain signals into an interpretable sequence of operations-an algorithm-which ultimately accounts for intelligent behaviors. Over the past decades, a variety of analytical tools have been developed to (i) isolate each algorithmic step and (ii) track their ordering from neuronal activity. In the present chapter, we briefly review the main methods to encode and decode temporally-resolved neural recordings, show how these approaches relate to one-another, and summarize their main premises and challenges. Finally we highlight, through a series of recent findings, the increasing role of machine learning both as i) a method to extract convoluted patterns of neural activity, and as ii) an operational framework to formalize the computational bases of cognition. Overall, we discuss how modern analyses of neural time series can identify the algorithmic organization of cognition.

Encoding and Decoding Neuronal Dynamics: Methodological Framework to Uncover the Algorithms of Cognition

Domain-general neural correlates of dependency formation: Using complex tones to simulate language

, © Sassenhagen This article is distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and redistribution in any medium, provided that the original author and source are credited. There is a fundamental problem of imprecise theories in many scientific disciplines. Trying to follow the gravitational wave detection recently reported by the LIGO consortium, it appears that in physics, none of the problems well-known from e.g. psychology and medicine seem to come up as problems. Consider this section from one of the papers reporting on LIGO:

Precise, predictive theories without wiggle room: Lessons from Physics

A common misapplication of statistical inference: Nuisance control with null-hypothesis significance tests

Much experimental research on behavior and cognition rests on stimulus or subject selection where not all parameters can be fully controlled, even when attempting strict matching. For example, when contrasting patients to controls, factors such as intelligence or socioeconomic status are often correlated with patient status. Similarly, when presenting word stimuli, factors such as word frequency are often correlated with primary variables of interest. One procedure very commonly employed to control for such nuisance parameter effects is conducting inferential tests on confounding stimulus or subject characteristics. For example, if word length is not significantly different for two stimulus sets, they are considered as matched for word length. Such a test has high failure rates and is conceptually misguided. It stems from a common misunderstanding of statistical tests. We show inferential testing to be inappropriate both pragmatically and philosophically, present a survey showing its high prevalence, and briefly discuss an alternative in the form of regression including nuisance parameters.

A common misapplication of statistical inference: nuisance parameter control with null-hypothesis rejection tests

The P600 as a correlate of ventral attention network reorientation

Cross-linguistic variation in the neurophysiological response to semantic processing: Evidence from anomalies at the borderline of awareness

The P600-as-P3 hypothesis revisited: Single-trial analyses reveal that the late EEG positivity following linguistically deviant material is reaction time aligned

Working memory (WM) requires encoding stimulus identity and context (e.g., where or when stimuli were encountered). To explore the neural bases of the strategic control of context binding in WM, we acquired fMRI while subjects performed delayed recognition of three orientation patches presented serially and at different locations. The recognition probe was an orientation patch with a superimposed digit, and pretrial instructions directed subjects to respond according to its location (location-relevant), to the ordinal position corresponding to its digit (order-relevant), or to just its orientation (relative to all three samples; context-irrelevant). Delay-period signal in PPC was greater for context-relevant than for context-irrelevant trials, and multivariate decoding revealed strong sensitivity to context binding requirements (relevant vs. irrelevant) and to context domain (location- vs. order-relevant) in both occipital cortex and PPC. At recognition, multivariate inverted encoding modeling revealed markedly different patterns in these two regions, suggesting different context-processing functions. In occipital cortex, an active representation of the location of each of the three samples was reinstated, regardless of trial type. The pattern in PPC, in contrast, suggested a trial type-dependent filtering of sample information. These results indicate that PPC exerts strategic control over the representation of stimulus context in visual WM.

Strategic control of location and ordinal context in visual working memory

Four percent of individuals who undergo research brain MR imaging have an incidental, potentially clinically significant finding. Routine neuroradiologist review of all scans yields a much higher rate of significant lesion detection than selective referral from nonradiologists who perform the examinations. BACKGROUND AND PURPOSE: Incidental findings are discovered in neuroimaging research, ranging from trivial to life-threatening. We describe the prevalence and characteristics of incidental findings from 16,400 research brain MRIs, comparing spontaneous detection by nonradiology scanning staff versus formal neuroradiologist interpretation. MATERIALS AND METHODS: We prospectively collected 16,400 brain MRIs (7782 males, 8618 females; younger than 1 to 94 years of age; median age, 38 years) under an institutional review board directive intended to identify clinically relevant incidental findings. The study population included 13,150 presumed healthy volunteers and 3250 individuals with known neurologic diagnoses. Scanning staff were asked to flag concerning imaging findings seen during the scan session, and neuroradiologists produced structured reports after reviewing every scan. RESULTS: Neuroradiologists reported 13,593/16,400 (83%) scans as having normal findings, 2193/16,400 (13.3%) with abnormal findings without follow-up recommended, and 614/16,400 (3.7%) with “abnormal findings with follow-up recommended.” The most common abnormalities prompting follow-up were vascular (263/614, 43%), neoplastic (130/614, 21%), and congenital (92/614, 15%). Volunteers older than 65 years of age were significantly more likely to have scans with abnormal findings (P < .001); however, among all volunteers with incidental findings, those younger than 65 years of age were more likely to be recommended for follow-up. Nonradiologists flagged <1% of MRIs containing at least 1 abnormality reported by the neuroradiologists to be concerning enough to warrant further evaluation. CONCLUSIONS: Four percent of individuals who undergo research brain MRIs have an incidental, potentially clinically significant finding. Routine neuroradiologist review of all scans yields a much higher rate of significant lesion detection than selective referral from nonradiologists who perform the examinations. Workflow and scan review processes need to be carefully considered when designing research protocols.

Incidental Findings from 16,400 Brain MRI Examinations of Research Volunteers

Successful goal-directed behavior often requires continuous sensory processing while simultaneously maintaining task-related information in working memory (WM). Although WM and perception are known to interact, little is known about how their interactions are controlled. Here, we tested the hypothesis that WM perception interactions engage two distinct modes of control – proactive and reactive – in a manner similar to classic conflict-adaptation tasks (e.g. Stroop, flanker, and Simon). Participants performed a delayed recall-of-orientation WM task, plus a standalone visual discrimination-of-orientation task the occurred during the delay period, and with the congruity in orientation between the tasks manipulated. Proactive control was seen in the sensitivity of task performance to the previous trial's congruity (i.e. a Gratton effect). Reactive control was observed in a repulsive serial-dependence produced by incongruent discriminanda. Quantitatively, these effects were explained by parameters from a reinforcement learning-based model that tracks trial-to-trial fluctuations in control demand: reactive control by a phasic control prediction error (control PE), and proactive control by a tonic level of predicted conflict updated each trial by the control PE. Thus, WM-perception interactions may be controlled by the same mechanisms that govern conflict in other domains of cognition, such as response selection.

Flexible top-down control in the interaction between working memory and perception

For the past 20 years, Mark Stokes has had a remarkably outsized influence on many areas of research within cognitive neuroscience. As an undergraduate at the University of Melbourne, in the laboratory of Jason Mattingley, he contributed to several studies pioneering the use of TMS for the study of human cognition (cf. Feredoes, 2023). Althoughmany of these addressed fundamental questions about attention, arguably the most enduring of his contributions from that time was methodological, 2005’s “Simple metric for scaling motor threshold based on scalp-cortex distance: Application to studies using transcranial magnetic stimulation” (Stokes et al., 2005). Google Scholar shows that although the citation count for this introduction of “the Stokes method” initially peaked in 2011, its year-by-year histogram has remained stubbornly elevated, achieving additional modes in 2017, in 2019, and now again in 2022 (for which, already by the 9-month mark, it has already eclipsed the previously most highly cited calendar year). For his PhD, Mark Stokes moved to Cambridge University where, in the laboratory of JohnDuncan, he was among the first to applymultivariate decoding analyses to neuroimaging studies of high-level cognition (cf. Duncan, 2023). Subsequently, he moved to Oxford University, initially to work with Kia Nobre as a research fellow and later establishing his own independent group and mentoring an impressive cohort of trainees (cf. Pike et al., 2023). Across his time at Oxford, he played a major role in bridging research on memory and attention, promoting a functional account of working memory in which forward-looking memory traces are informationally and computationally tuned for interacting with incoming sensory signals to guide adaptive behavior (Nobre& Stokes, 2019; cf. Myers, 2023; Nobre, 2023). In addition, and perhaps most influentially, soon after his arrival at Oxford, Mark Stokes turned his analytic acumen to developing a then-novel approach for the “retrospectively multivariate” analysis of data from single-unit extracellular recordings from awake, behaving animals. As recently as the decade of the 2000s, the preponderance of neurophysiological studies of nonhuman primates used the approach, during chronic recording sessions, of first isolating a single neuron, then recording from that neuron while the animal engaged in the behavior of interest, repeating this process across hundreds of recording sessions, then averaging the results across similarly tuned neurons. Stokes’ insight was that one might learn more from such data sets by, rather than approaching them as a collection of univariate observations, treating them as a single multivariate observation by, in effect, pretending that these hundreds of units had all been recorded simultaneously. The results have been breathtakingly revealing. The first, and perhaps most impactful, of publications to come out of Mark Stokes’ “retrospectively multivariate” enterprise was a product of his enduring collaborative relationship with John Duncan—a reanalysis of recordings from the pFC of nonhuman primates performing a working memory task (Sigala, Kusunoki, Nimmo-Smith, Gaffan, & Duncan, 2008). It reported the discovery that the population-level representation of stimulus information in pFCunderwent a dynamic trajectory of state transitions that reflected taskand trial-specific context (Stokes et al., 2013; cf. Adam, Rademaker, & Serences, 2023). (For example, when a new stimulus appeared, its representation in pFC transitioned, over the course of just a few hundredmilliseconds, from one primarily reflecting stimulus identity to one primarily reflecting whether it was a “target” [that would require a response] or a distractor [that would not].) Critically, because this information could be read out even during periods when the average firing rate in pFC did not differ frombaseline, this finding implied that these dynamic transformations were occurring at the level of changing patterns of connectivity between neurons, rather than at the level of firing rates. It may well turn out that the most enduringly consequential impact to arise from thisworkwill have been an insight that Stokes himself derived from it: There may be an “activity-silent” basis for the representation of information in working memory (Stokes, 2015). The wide-ranging implications of this proposal are being seen, seemingly every day, in newmodels and experimental results in disciplines ranging from experimental psychology to computational neuroscience to cellular neurobiology (cf. Buschman & Miller, 2023; Manohar, 2023). Sadly for our field, personal circumstances have led to Dr. Stokes moving away from his role as Head of Attention group at Oxford’s Department of Experimental Psychology. During the Summer of 2022, the contributions of this remarkable, and remarkably influential, cognitive neuroscientist were highlighted by an international gathering for a Stokes Fest[schrift] hosted on the grounds of New College (Figure 1). The articles collected in this Special Focus capture some of the spirit and ferment (cf. Wu & Buckley, 2023) that pervaded this celebration of the career of a dearly valued and admired colleague/mentor/teacher. University of Wisconsin–Madison

Flexible control of the contents of working memory (WM) includes removing no-longer-relevant information. Although simply withdrawing attention offers a “passive” mechanism, empirical findings suggest that it is also possible to actively remove information from WM. In this Registered Report we tested evidence that the bias (serial dependence) that an item exerts on the subsequent trial will be opposite in sign—attraction vs. repulsion — depending on whether it was passively or actively removed, respectively. A repulsive bias would be consistent with a specific mechanism for active removal: a rapid adaptation-like modification of perceptual circuitry. In a preliminary study, trials of two types were administered in pairs, multi-item WM followed by 1-item delayed recall, and we evaluated serial dependence of the latter on items from the former. In the first trial of each pair, two memoranda were presented, then one was designated irrelevant, then a third memorandum was presented. The critical manipulation was whether the third item was presented at the same location as the now “irrelevant memory item” (IMI). Overlap between the two should prompt the active removal of the IMI, whereas nonoverlap might prompt just the withdrawal of attention. Whereas the IMI exerted the expected attractive bias on 1-item recall in the no-overlap condition, we found an (unexpected) repulsive bias in the overlap condition. Because repulsive biases have been attributed to the adaptation-like modification of perceptual circuitry, replication of this result in this Registered Report would provide independent evidence for this mechanism for active removal from WM. Interpretation of the Stage 2 results are complicated by the fact that the approved Registered Report, carried out online, generated data that failed to meet a basic sanity check, and were therefore uninterpretable. Consequently, a follow-up lab-based experiment using procedures similar to the Registered Report generated results consistent with the hypothesis of principal theoretical interest: The IMI in the overlap condition exerted a repulsive bias on the subsequent trial.

The Influence of Active Removal from Working Memory on Serial Dependence

How does the brain prioritize among the contents of working memory (WM) to appropriately guide behavior? Using inverted encoding modeling (IEM), previous work (Wan et al., 2020) showed that unprioritized memory items (UMI) are actively represented in the brain but in a “flipped”, or opposite, format compared to prioritized memory items (PMI). To gain insight into the mechanisms underlying the UMI-to-PMI representational transformation, we trained recurrent neural networks (RNNs) with an LSTM (long short-term memory) architecture to perform a 2-back working memory task. Although visualization of LSTM hidden layer activity using Principal Component Analysis (PCA) suggested that stimulus representations undergo a smooth rotational transformation across the trial, demixed (d)PCA of the same data decomposed this pattern into a cascade of multiple trajectories, each with a different time course, unfolding within UMI and PMI subspaces. The application of the same analyses to the EEG dataset of Wan et al. (2020) indicated that an item’s trajectory through the UMI subspace closely mirrored that of the RNN, but that its trajectory through the PMI subspace differed markedly from the RNN. It may be a general principle that, at the level of the representational code, information held in WM undergoes priority-based transformations that allow for its retention while preventing it from interfering with concurrent behavior. Implementational details of this process may vary across model systems. Author Summary How is information held in working memory (WM) but outside the current focus of attention? Motivated by previous neuroimaging studies, we trained recurrent neural networks (RNNs) to perform a 2-back WM task that entails shifts of an item’s priority status. Dimensionality reduction of the resultant activity in the hidden layer of the RNN allowed us to characterize how a stimulus item’s representation follows a transformational trajectory through high-dimensional representational space as its priority status changes from memory probe to unprioritized to prioritized. This work illustrates the value of artificial neural networks for assessing and refining hypotheses about mechanisms for information processing in the brain.

Priority-based transformations of stimulus representation in visual working memory

Visual Abstract Successful retrieval of a specific item from visual working memory (VWM) depends on the binding of that item to its unique context. Recent functional magnetic resonance imaging studies of VWM manipulating memory set homogeneity have identified an important role for the intraparietal sulcus in context binding, independent of any role in representing stimulus identity. The current study explored whether the contralateral delay activity (CDA), which is an event-related potential (ERP) component derived from posterior electrodes that tracks the amount of information held in VWM, might also be sensitive to context-binding demands. In experiment 1, human participants performed lateralized delayed recognition with memory sets containing one, three, or five items that were drawn from the same category (orientations: “homogeneous”) or from different categories (orientation, color, and luminance: “heterogeneous”). Because the location and identity of the memory probe indicated the item to be retrieved, homogeneous trials placed higher context-binding demands. VWM capacity was higher in heterogeneous trials. ERPs contralateral (contra) and ipsilateral (ipsi) to the remembered stimuli were higher for homogeneous trials, but these differences were removed in the contra – ipsi subtraction that produced the CDA. In experiment 2, human participants performed lateralized delayed recall with memory sets of one or three items (homogeneous or heterogeneous). Behavior was superior for three-item heterogeneous trials than for homogeneous trials, with modeling revealing context-binding errors in the latter. Bilateral ERPs and CDA results replicated experiment 1. These results support that the CDA tracks the number of object files engaged by VWM and establish that it is not sensitive to context-binding demands.

Context Binding in Visual Working Memory Is Reflected in Bilateral Event-Related Potentials, But Not in Contralateral Delay Activity

Abstract What mechanisms underlie the prioritization of neural representations of visually perceived information to guide behavior? We assessed the dynamics whereby attention biases competition for representation of visual stimuli by enhancing representations of relevant information and suppressing the irrelevant. Multivariate pattern analysis (MVPA) classifiers were trained to discriminate patterns of fMRI activity associated with each of three stimuli, within several predefined ROIs. Participants performed a change-detection task wherein two of three presented items flashed at 1 Hz, one to each side of central fixation. Both flashing stimuli would unpredictably change state, but participants covertly counted the number of changes only for the cued item. In the ventral occipito-temporal ROI, MVPA evidence (a proxy for representational fidelity) was dynamically enhanced for attended stimuli and suppressed for unattended stimuli, consistent with a mechanism of biased competition between stimulus representations. Frontal and parietal ROIs displayed a qualitatively distinct, more “source-like” profile, wherein MVPA evidence for only the attended stimulus could be observed above baseline levels. To assess how attentional modulation of ventral occipito-temporal representations might relate to signals originating in the frontal and/or parietal ROIs, we analyzed informational connectivity (IC), which indexes time-varying covariation between regional levels of MVPA evidence. Parietal-posterior IC was elevated during the task, but did not differ for cued versus uncued items. Frontal-posterior IC, in contrast, was sensitive to an item's priority status. Thus, although regions of frontal and parietal cortex act as sources of top–down attentional control, their precise functions likely differ.

Attention Biases Competition for Visual Representation via Dissociable Influences from Frontal and Parietal Cortex

How does the brain prioritize among the contents of working memory to appropriately guide behavior? Using inverted encoding modeling (IEM), previous work (Wan et al., 2020) showed that unprioritized memory items (UMI) are actively represented in the brain but in a “flipped”, or opposite, format compared to prioritized memory items (PMI). To gain insight into the mechanisms underlying the UMI-to-PMI representational transformation, we trained recurrent neural networks (RNNs) with an LSTM architecture to perform a 2-back working memory task. Visualization of the LSTM hidden layer activity using Principle Component Analysis (PCA) revealed that the UMI representation is rotationally remapped to that of PMI, and this was quantified and confirmed via demixed PCA. The application of the same analyses to the EEG dataset of Wan et al. (2020) revealed similar rotational remapping between the UMI and PMI representations. These results identify rotational remapping as a candidate neural computation employed in the dynamic prioritization within contents of working memory.Our flexible behavior relies on the successful prioritization among the many pieces of information that may be held in working memory (WM). However, the computations underlying prioritization remain poorly understood. The current work investigated computational bases of prioritization by training recurrent neural networks (RNNs) to perform a 2-back WM task. Dimensionality reduction techniques revealed that a remembered item undergoes a rotational transformation in multi-dimensional representational space as its priority status changes. Prompted by this finding, we next asked if a similar mechanism might be applied by the human brain. Applying analogous analyses to an empirical EEG dataset of 2-back WM performance, we found a similar pattern of priority-based rotational remapping of working memory representations. This work highlights the power of artificial neural networks in generating mechanistic hypotheses for empirical work in understanding brain and cognition.

Rotational remapping between differently prioritized representations in visual working memory

Visual working memory interacts with ongoing visual processing in a stimulus-specific manner, potentially through a common neural substrate supporting visual perception and working memory maintenance. The spatial specificity of this effect, however, remains unknown. The current study tested whether features in working memory influence perception in a spatially specific or global fashion. Across four experiments, subjects performed perceptual discrimination tasks on orientation or on contrast while concurrently holding an orientation in working memory. Experiments 1 and 2 revealed that memory content boosted the perceived contrast of the discrimination stimulus when the two matched in orientation, but only when the locations of the memorandum and the discriminandum also matched. In turn, feature-based influence on memory precision was also greater when locations matched. Experiments 3 and 4 demonstrated that the spatial specificity of this interaction was influenced by task demands. When encoding of location was discouraged in Experiment 3, memory interacted with perception in a global fashion, whereas when location was task-relevant in otherwise very similar Experiment 4, the feature-based enhancement was again modulated by location. These results suggest that context-binding demand is an important determinant of the spatial specificity of memory-perception interaction and highlight the flexible configurability of working memory representations. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Spatial specificity of feature-based interaction between working memory and visual processing.

Humans can construct rich subjective experience even when no information is available in the external world. Here, we investigated the neural representation of purely internally generated stimulus-like information during visual working memory. Participants performed delayed recall of oriented gratings embedded in noise with varying contrast during fMRI scanning. Their trialwise behavioral responses provided an estimate of their mental representation of the to-be-reported orientation. We used multivariate inverted encoding models to reconstruct the neural representations of orientation in reference to the response. We found that response orientation could be successfully reconstructed from activity in early visual cortex, even on 0% contrast trials when no orientation information was actually presented, suggesting the existence of a purely internally generated neural code in early visual cortex. In addition, cross-generalization and multidimensional scaling analyses demonstrated that information derived from internal sources was represented differently from typical working memory representations, which receive influences from both external and internal sources. Similar results were also observed in intraparietal sulcus, with slightly different cross-generalization patterns. These results suggest a potential mechanism for how externally driven and internally generated information is maintained in working memory.

The Neural Codes Underlying Internally Generated Representations in Visual Working Memory.

Abstract Humans can construct rich subjective experience even when no information is available in the external world. Here, we investigated the neural representation of purely internally generated stimulus-like information during visual working memory. Participants performed delayed recall of oriented gratings embedded in noise with varying contrast during fMRI scanning. Their trialwise behavioral responses provided an estimate of their mental representation of the to-be-reported orientation. We used multivariate inverted encoding models to reconstruct the neural representations of orientation in reference to the response. We found that response orientation could be successfully reconstructed from activity in early visual cortex, even on 0% contrast trials when no orientation information was actually presented, suggesting the existence of a purely internally generated neural code in early visual cortex. In addition, cross-generalization and multidimensional scaling analyses demonstrated that information derived from internal sources was represented differently from typical working memory representations, which receive influences from both external and internal sources. Similar results were also observed in intraparietal sulcus, with slightly different cross-generalization patterns. These results suggest a potential mechanism for how externally driven and internally generated information is maintained in working memory.

The Neural Codes Underlying Internally Generated Representations in Visual Working Memory

ABSTRACT In her commentary, Xu [2020. Revisit once more the sensory storage account of visual working memory. Visual Cognition, 28(5–8), 433–446] admonishes the reader that “To have a full understanding of the cognitive mechanisms underlying VWM [visual working memory], both behavioral and neural evidence needs to be taken into account. This is a must, and not a choice, for any study that attempts to capture the nature of VWM” (p. 11). Although we don’t disagree with this statement, our overall assessment of this commentary is that it, itself, fails to satisfy several “musts” and, consequently, does not pose a serious challenge for the sensory recruitment framework for understanding visual working memory. These “musts” include accurately characterizing the framework being critiqued, not favouring verbal models and intuition at the expense of formal quantitative models, and providing even-handed interpretation of the work of others. We’ll conclude with a summary of how the sensory recruitment framework can be incorporated into a broader working model of visual working memory.

Understanding occipital and parietal contributions to visual working memory: Commentary on Xu (2020)

Anticipatory covert spatial attention improves performance on tests of visual detection and discrimination, and shifts are accompanied by decreases and increases of α band power at electroencephalography (EEG) electrodes corresponding to the attended and unattended location, respectively. Although the increase at the unattended location is often interpreted as an active mechanism (e.g., inhibiting processing at the unattended location), most experiments cannot rule out the alternative possibility that it is a secondary consequence of selection elsewhere. To adjudicate between these accounts, we designed a Posner-style visual cueing task in which male and female human participants made orientation judgments of targets appearing at one of four locations: up, down, right, or left. Critically, trials were blocked such that within a block the locations along one meridian alternated in status between attended and unattended, and targets never appeared at the other two, making them irrelevant. Analyses of the concurrently measured EEG signal were conducted on “traditional” narrowband α (8–14 Hz), as well as on two components resulting from the decomposition of this signal: “periodic” α; and the slope of the aperiodic 1/f-like component. Although data from right-left blocks replicated the familiar pattern of lateralized asymmetry in narrowband α power, with neither α signal could we find evidence for any difference in the time course at unattended versus irrelevant locations, an outcome consistent with the secondary-consequence interpretation of attention-related dynamics in the α band. Additionally, 1/f slope was shallower at attended and unattended locations, relative to irrelevant, suggesting a tonic adjustment of physiological state. SIGNIFICANCE STATEMENT Visual spatial attention, the prioritization of one location in the visual field, is critical for guiding behavior in cluttered environments. Although influential theories posit an important role for α band oscillations in the inhibition of processing at unattended locations, we used a novel procedure to find evidence for an alternative interpretation: selection of one location may simply result in a return to physiological baseline at all others. In addition to determining one way that attention does not work (important for future progress in this field), we also discovered novel evidence for one way that it does work: by modifying the tonic physiological state (indexed by an aperiodic component of the electroencephalography (EEG)] at locations where spatial selection is likely to occur.

Spectral Distribution Dynamics across Different Attentional Priority States

Decision letter: Modality-specific tracking of attention and sensory statistics in the human electrophysiological spectral exponent

These modifications to our practices have worked well. Indeed, 2020 and 2021 have seen an uptick in the number of editorial rejections that we have issued, relative to “the Beforetimes”, perhaps in part because 18months of global pandemic-related lockdown led stuck-at-home scientists to write up and submit articles that, for whatever reason, hadn’t until then been of high priority? Whatever the reasons, we are grateful to our newly assembled team of Consulting Editors for helping us work through this uptick in difficult decisions. Importantly, the fact that onmany occasions a Consulting Editor has overruled an initial decision to editorially reject an article means that the decisionmaking process for editorial rejection has become fairer.

This chapter provides a broad overview of research focused on the use of transcranial magnetic stimulation (TMS), both alone and together with neural recording modalities such as magnetic resonance imaging (MRI) and electroencephalography (EEG), to elucidate the cognitive and neural underpinnings of working memory. It first considers research using TMS to create “virtual lesions” in targeted brain areas, with the goal of establishing the causal role, and sometimes the timing, of the targeted area in specific working memory component processes. Next, it highlights research adopting a “perturb-and-measure” approach, in which TMS is used in conjunction with simultaneous neural recording (e.g., functional MRI or EEG) to assess the role of brain excitability and inter-area connectivity in working memory. Finally, research using TMS to assess the role of neural oscillations in working memory is reviewed. Throughout, the chapter highlights how different TMS modalities can be used profitably to clarify the neural bases of working memory and to effect strong tests of predictions derived from psychological models.

The ability to frequently update the contents working memory (WM) is vital for the flexible control of behavior. Whether there even exists a mechanism for the active removal of information from working memory, however, remains poorly understood. In this Registered Report we will test the predictions of models for two different (and not mutually exclusive) mechanisms of active removal: adaptation-hijacking and mental-context shifting. We will collect functional magnetic resonance imaging (fMRI) data while subjects perform a novel “ABC-retrocuing” task designed to elicit two modes of removal, active or passive (Shan & Postle, Registered Report). The adaptation-hijacking model posits an adaptation-like modification of perceptual circuits combined with a weak activation of the to-be-removed item. Its predictions will be assessed by using multivariate inverted encoding modeling (IEM) and photic “pings” to assay the state of feature-selective encoding channels and of activity-silent representations under active-removal versus passive-removal conditions. A second model – “working memory episodic memory” (WMEM) – posits that interference from no-longer-relevant information is minimized by making the mental context associated with new information dissimilar from that associated with the to-be-“removed” information. This will be tested by using representational similarity analysis (RSA) to compare the rate of contextual drift under active-removal versus passive-removal conditions.

Perceptual metacognition of human faces is causally supported by function of the lateral prefrontal cortex

We used functional magnetic resonance imaging (fMRI) to investigate the neural codes for representing stimulus information held in different states of priority in working memory. Human participants (male and female) performed delayed recall for 2 oriented gratings that could appear in any of several locations. Priority status was manipulated by a retrocue, such that one became the prioritized memory item (PMI) and another the unprioritized memory item (UMI). Using inverted encoding models (IEMs), we found that, in early visual cortex, the orientation of the UMI was represented in a neural representation that was rotated relative to the PMI. In intraparietal sulcus (IPS), we observed the analogous effect for the representation of the location of the UMI. Taken together, these results provide evidence for a common remapping mechanism that may be responsible for representing stimulus identity and stimulus context with different levels of priority in working memory.

Different states of priority recruit different neural representations in visual working memory

In the field of neuroscience, despite the fact that the proportion of peer-reviewed publications authored by women has increased in recent decades, the proportion of citations of women-led publications has not seen a commensurate increase: In five broad-scope journals, citations of papers first- and/or last-authored by women have been shown to be fewer than would be expected if gender was not a factor in citation decisions (Dworkin et al., 2020). Given the important implications that such underrepresentation may have on the careers of women researchers, it is important to determine whether this same trend is true in subdisciplines of the field, where interventions might be more effective. Here, we report the results of an extension of the analyses carried out by Dworkin et al. (2020) to citation patterns in the Journal of Cognitive Neuroscience (JoCN). The results indicate that the underrepresentation of women-led publications in reference sections is also characteristic of papers published in JoCN over the past decade. Furthermore, this pattern of citation imbalances is present for all gender classes of authors, implicating systemic factors. These results contribute to the growing body of evidence that intentional action is needed to address inequities in the way that we carry out and communicate our science.

Gender (im)balance in citation practices in cognitive neuroscience

Supplementary material from "Tracking stimulus representation across a 2-back visual working memory task"

Preface xvi Acknowledgments xix Methodology Boxes xxi Walkthrough of Pedagogical Features xxii Companion Website xxiv SECTION I: THE NEUROBIOLOGY OF THINKING 1 1 Introduction and History 4 2 The Brain 22 SECTION II: SENSATION, PERCEPTION, ATTENTION, AND ACTION 51 3 Sensation and Perception of Visual Signals 54 4 Audition and Somatosensation 85 5 The Visual System 120 6 Spatial Cognition and Attention 153 7 Skeletomotor Control 196 8 Oculomotor Control and the Control of Attention 229 SECTION III: MENTAL REPRESENTATION 259 9 Visual Object Recognition and Knowledge 262 10 Neural Bases of Memory 286 11 Declarative Long?]Term Memory 312 12 Semantic Long?]Term Memory 336 13 Short?]Term and Working Memory 360 SECTION IV: HIGH-LEVEL COGNITION 395 14 Cognitive Control 397 15 Decision Making 422 16 Social Behavior 449 17 Emotion 476 18 Language 502 19 Consciousness 531 Glossary 562 Index 571

One important neural hallmark of working memory is persistent elevated delay-period activity in frontal and parietal cortex. In human fMRI, delay-period BOLD activity in frontal and parietal cortex increases monotonically with memory load and asymptotes at an individual’s capacity. Previous work has demonstrated that frontal and parietal delay-period activity correlates with the decline in behavioral memory precision observed with increasing memory load. However, because memory precision can be influenced by a variety of factors, it remains unclear what cognitive processes underlie persistent activity in frontal and parietal cortex. Recent psychophysical work has shown that attractor dynamics bias memory representations toward a few stable representations and reduce the effects of internal noise. From this perspective, imprecision in memory results from both drift towards stable attractor states and random diffusion. Here we asked whether delay-period BOLD activity in frontal and parietal cortex might be explained, in part, by these attractor dynamics. We analyzed data from an existing experiment in which subjects performed delayed recall for line orientation, at different loads, during fMRI scanning. We modeled subjects’ behavior using a discrete attractor model, and calculated within-subject correlation between frontal and parietal delay-period activity and estimated sources of memory error (drift and diffusion). We found that although increases in frontal and parietal activity were associated with increases in both diffusion and drift, diffusion explained the most variance in frontal and parietal delay-period activity. In comparison, a subsequent whole-brain regression analysis showed that drift rather than diffusion explained the most variance in delay-period activity in lateral occipital cortex. These results provide a new interpretation for the function of frontal, parietal, and occipital delay-period activity in working memory.

Delay-period activity in frontal, parietal, and occipital cortex tracks different attractor dynamics in visual working memory

Working memory is imprecise, and these imprecisions can be explained by the combined influences of random diffusive error and systematic drift toward a set of stable states (“attractors”). However, the neural correlates of diffusion and drift remain unknown. Here, we investigated how delay-period activity in frontal and parietal cortex, which is known to correlate with the decline in behavioral memory precision observed with increasing memory load, might relate to diffusion and drift. We analyzed data from an existing experiment in which subjects performed delayed recall for line orientation, at different loads, during functional magnetic resonance imaging (fMRI) scanning. To quantify the influence of drift and diffusion, we modeled subjects’ behavior using a discrete attractor model and calculated within-subject correlation between frontal and parietal delay-period activity and whole-trial estimates of drift and diffusion. We found that although increases in frontal and parietal activity were associated with increases in both diffusion and drift, diffusion explained the most variance in frontal and parietal delay-period activity. In comparison, a subsequent whole-brain regression analysis showed that drift, rather than diffusion, explained the most variance in delay-period activity in lateral occipital cortex. These results are consistent with a model of the differential recruitment of general frontoparietal mechanisms in response to diffusive noise and of stimulus-specific biases in occipital cortex.

Delay-period activity in frontal, parietal, and occipital cortex tracks noise and biases in visual working memory

Spontaneous alpha-band amplitude predicts subjective visibility but not discrimination accuracy during high-level perception

Content in working memory (WM) has been shown to interact with attentional selection (e.g., Olivers, Meijer, Theeuwes, 2006) and alter perceptual processing (Teng & Kravitz, 2019) in a stimulus-specific way, potentially through the shared recruitment of sensory cortices for perception and WM maintenance (sensory recruitment model; D’Esposito & Postle, 2015; Postle, 2015). Here, we directly tested the spatially specificity of the interaction between WM and perception with a psychophysical task. We predict that if a feature maintained in WM is retinotopically organized, its influence on perception would be spatially specific; alternatively, if WM activates feature channels globally in a similar manner as feature-based attention, its influence would not be constrained by location. In a dual-task paradigm, participants were first presented with two orientations on each side of the display and were instructed to memorize one of them. While holding the orientation in mind, they performed a secondary orientation discrimination task on another orientated stimulus and then reported the memorized orientation at the end. The discrimination stimuli in the secondary task could either match or mismatch the location and orientation of the memory stimuli. The contrast of the discrimination stimuli was systematically manipulated to derive the contrast threshold. We found that WM boosted the perceived contrast of the orientation-matching discrimination stimuli only when their locations also matched. The threshold was significantly lower in the location-match and orientation-match condition than the other conditions. Further, shifting attention away from the memory location had a detrimental effect on memory precision, indicating that location mismatch might disrupted the context-binding process in WM. These results suggest that 1) there is a spatially specific representation of WM that influences early stage perceptual processing; 2) spatial context is an important determinant of the strength of WM.

Spatial modulation of feature-based interaction between working memory and perception

ABSTRACT Several recent studies have interpreted multivariate evidence for stimulus-specific patterns of activity in parietal and/or frontal cortex as evidence for a representational function in those regions that is qualitatively similar to the representational functions of the visual system. Here we argue that although evidence that a brain system takes on a different configuration for each stimulus in a stimulus set is a necessary property for that system having a role in perceptual representation, such evidence is not specific for this function. Drawing on several examples from the recent literature, we offer alternative accounts for understanding stimulus-specificity in parietal and frontal cortex that are consistent with longstanding ideas that activity in these regions is best understood as implementing control-related, rather than inherently representational, functions.

Neuroimaging and the localization of function in visual cognition

How does the neural representation of visual working memory content vary with behavioural priority? To address this, we recorded electroencephalography (EEG) while subjects performed a continuous-performance 2-back working memory task with oriented-grating stimuli. We tracked the transition of the neural representation of an item (n) from its initial encoding, to the status of ‘unprioritized memory item' (UMI), and back to ‘prioritized memory item', with multivariate inverted encoding modelling. Results showed that the representational format was remapped from its initially encoded format into a distinctive ‘opposite' representational format when it became a UMI and then mapped back into its initial format when subsequently prioritized in anticipation of its comparison with item n + 2. Thus, contrary to the default assumption that the activity representing an item in working memory might simply get weaker when it is deprioritized, it may be that a process of priority-based remapping helps to protect remembered information when it is not in the focus of attention.

Tracking stimulus representation across a 2-back visual working memory task

After 18 years (sic), Mark D’Esposito has stepped down as Editor-in-Chief (EIC) of the Journal of Cognitive Neuroscience ( JoCN). Our community owes a large debt of gratitude to Mark and, before him, to Mike Gazzaniga, for creating and shepherding this journal that has played such a vital role in the growth and success of our field. By the time you’re reading this, I will have fully transitioned into the EIC role and am grateful that many of the journal’s highly talented and dedicated Associate Editors will be staying on and are helping to smooth the transition: Jeff Binder, Randy McIntosh, Earl Miller, and Jordan Taylor. We will miss the expert contributions of the departing Roshan Cools and Kia Nobre but are thrilled that Morgan Barense, Heleen Slagter, and Virginie van Wassenhove have joined our ranks! Although we don’t have grand ambitions to “fix what ain’t broken” at the journal, we are planning some modifications to how it operates, in the hopes of accommodating the increased importance that our field is putting on robustness in our science and on transparency and equity in our practices. Our decisions about what to keep at JoCN, and what to change, are guided by the fundamental conviction that there is a special role in our science for the society journal. Society journals, like JoCN, are run by us, for us. Editorial policy is guided by what’s best for the field, with minimal influence from commercial considerations. Editorial decisions are made by colleagues who are, like us, active members of our community. At JoCN, there are no layers of professional staff between authors and reviewers as well as no staff generating surveys or promotional messages to clog our inboxes. Along with this special status comes a special responsibility to lead by example, and we hope that the changes that I’ll summarize here will be welcomed in that spirit.

Despite the fact that multiple items can be held in working memory (WM), it is often the case that only one of these is relevant for guiding in-the-moment behavior. Therefore, understanding how priority is established and controlled in WM is an important problem. Data from Rose et al. (2016) have provided evidence that although neuroimaging evidence for an active trace of an “unprioritized memory item” (UMI) held in WM drops to baseline levels, evidence for its retention in WM can be “reactivated” by a single pulse of transcranial magnetic stimulation (TMS). Critically, this TMS-reactivation effect was specific to the first delay period of a dual serial retrocue (DSR) task, when the UMI could be needed for the trial’s second memory probe, and was not observed during the second delay period, when the uncued item was no longer needed (i.e., when it is an “irrelevant memory item” [IMI]). A problem for the interpretation of these results, however, is that the status of the UMI/IMI was confounded with time spent in WM, as well as with the number of intervening cognitive operations. Here, we report data from a follow-up study designed to replicate the findings Rose et al. (2016) and to add a condition that unconfounds time-since-sample-presentation and UMI/IMI status. The results indicate that the TMS-reactivation effect is, indeed, an index of status in WM (UMI vs. IMI), and not a mere consequence of time elapsed since sample presentation.

Cognitive Control, Not Time, Determines the Status of Items in Working Memory

This chapter takes the perspective that ‘working memory’ refers to a class of behaviours that can be accomplished by the coordinated recruitment of sensory-, representational-, action-, and control-related mechanisms and representations. There is no working memory system, per se. This idea is illustrated with findings from cognitive neuroscience, with an emphasis on studies of human working memory with functional magnetic resonance imaging and electroencephalography, and on simulations of human behaviour with recurrent neural network modelling. Understanding principles of attention and oculomotor control are central to understanding the selection of stimulus information and its retention ‘in’ working memory, as well as for the moment-to-moment prioritization of subsets of the contents of working memory. Recent research from a dynamical systems perspective suggests a principled framework for understanding how, and under what circumstances, knowledge from long-term memory is recruited to support working memory performance. An important challenge for contemporary cognitive neuroscience is to develop an accepted procedure for assessing when multiple regions can be shown to represent stimulus-specific information, whether these regions are all supporting the same function, or perhaps different functions that nonetheless all entail the active representation of the same information.

Investigating the effects of attentional prioritization in visual working memory

Stimulus location is not always informative during visual short-term memory (VSTM) for nonspatial features. Nevertheless, there is considerable evidence for the automatic encoding and retention of location information, regardless of its task relevance. To explore the functional and neural bases of the representation of spatial context in VSTM for nonspatial information, functional magnetic resonance imaging was performed while subjects performed delayed recall for the orientation of individual stimuli. Stimulus location varied across trials, and although this information was irrelevant for task performance, multivariate pattern analysis decoding of stimulus location sustained across trials, and also the decoding strength, predicted the precision of the recall of orientation. The influence of spatial context on the representation of orientation was operationalized by comparing the orientation reconstructions with multivariate inverted encoding models (IEM) trained in location context-dependent vs. -independent data. Although orientation reconstructions were robust for both location-dependent and location-independent IEMs, they were markedly stronger for the former. Furthermore, the functional relevance of location context was demonstrated by the fact that only the location-dependent neural representations of stimulus orientation predicted recall precision. NEW & NOTEWORTHY Neural representation strength of stimulus location predicts the precision of visual short-term memory (VSTM) recall of nonspatial stimulus, even when this information is task irrelevant. Neural representations of nonspatial stimuli that incorporate location context are stronger than those that do not, and only the former representations are strongly linked to behavior. The contributions to nonspatial VSTM performance of the representation of location context are at least partly distinct from those of the representation of stimulus content.

Overlapping and distinct contributions of stimulus location and of spatial context to nonspatial visual short-term memory.

Connectivity differences between consciousness and unconsciousness in non-rapid eye movement sleep: a TMS–EEG study

Although humans can hold multiple items in mind simultaneously, the contents of working memory (WM) can be selectively prioritized to effectively guide behavior in response to rapidly changing exigencies in the environment. Neural evidence for this is seen in studies of dual serial retrocuing of two items held concurrently in visual WM, in which evidence in occipital cortex for the active neural representation of the cued item increases, and evidence for the uncued item decreases, often to levels indistinguishable from empirical baseline. Although this pattern is reminiscent of the effects of selective attention on visual perception, the extent to which more subtle principles of visual attention may also apply to visual working memory remains uncertain. In the present study we explored whether the well-characterized “same-object” benefit in visual target detection, attributed to object-based attention (e.g., Duncan, 1984; Egly, Driver, & Rafal, 1994), may also be observed for information held in visual WM. fMRI data were collected while human subjects (male and female) performed a multi-step serial retrocuing task in which they first viewed two two-dimensional sample stimuli comprised of colored moving dots. After stimulus . CC-BY 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint . http://dx.doi.org/10.1101/606665 doi: bioRxiv preprint first posted online Apr. 12, 2019;

Although humans can hold multiple items in mind simultaneously, the contents of working memory (WM) can be selectively prioritized to effectively guide behavior in response to rapidly changing exigencies in the environment. Neural evidence for this is seen in studies of dual serial retrocuing of two items held concurrently in visual WM, in which evidence in occipital cortex for the active neural representation of the cued item increases, and evidence for the uncued item decreases, often to levels indistinguishable from empirical baseline. Although this pattern is reminiscent of the effects of selective attention on visual perception, the extent to which more subtle principles of visual attention may also apply to visual working memory remains uncertain. In the present study we explored whether the well-characterized “same-object” benefit in visual target detection, attributed to object-based attention (e.g., Duncan, 1984; Egly, Driver, & Rafal, 1994), may also be observed for information held in visual WM. fMRI data were collected while human subjects (male and female) performed a multi-step serial retrocuing task in which they first viewed two two-dimensional sample stimuli comprised of colored moving dots. After stimulus offset, an initial relevance cue then indicated whether both dimensions of only the first or only the second object, or only the color or only the direction-of-motion of both objects, would be relevant for the remainder of the trial, which then proceeded with the standard dual serial retrocuing procedure. Thus, on “object-relevant” trials, the ensuing priority cues prompted the selection of one from among two features (“color” or “direction”) bound to the same object, whereas on “feature-relevant” trials the priority cues prompted the selection of one from among two features each belonging to a different object. Results of analyses with multivariate inverted encoding models (IEM) revealed a same-object benefit on object-relevant trials: Whereas, on feature-relevant trials, the first priority cue triggered a strengthening of the neural representation of the cued feature and a concomitant weakening-to-baseline of the uncued feature; on object-relevant trials the cued item remained active but did not increase in strength, and the uncued item weakened, but remained significantly elevated throughout the delay period. Of additional interest, on both types of trials the second priority cue prompted an active recoding of the uncued item into a different neural representation, perhaps to minimize its ability to interfere with recall of the cued item. Finally, although stimulus-specific representation in parietal and frontal cortex was weak and uneven, these regions closely tracked the higher-order information of which stimulus category was relevant for behavior at all points during the trial, indicating an important role in controlling the prioritization of information in visual working memory.

The Neural Consequences of Attentional Prioritization of Internal Representations in Visual Working Memory

X Ying Cai, Andrew D. Sheldon, Qing Yu, and Bradley R. Postle State Key Laboratory of Cognitive Neuroscience and Learning, and IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, People’s Republic of China; Department of Psychiatry, University of Wisconsin–Madison, Madison, Wisconsin; Medical Scientist Training Program and Neuroscience Training Program, University of Wisconsin– Madison, Madison, Wisconsin; and Department of Psychology, University of Wisconsin–Madison, Madison, Wisconsin

Higher Neural Functions and Behavior Overlapping and distinct contributions of stimulus location and of spatial context to nonspatial visual short-term memory

Neural oscillatory processes underlying context binding in visual working memory

Effects of meaningfulness on perception: Alpha-band oscillations carry perceptual expectations and influence early visual responses

In the absence of external feedback, a decision maker must rely on a subjective estimate of their decision accuracy in order to appropriately guide behavior. Normative models of perceptual decision making relate subjective estimates of internal signal quality (e.g. confidence) directly to the internal signal quality itself, thereby making it unknowable whether the subjective estimate or the underlying signal is what drives behavior. We constructed stimuli that dissociated human observer’s performance on a visual estimation task from their subjective estimates of confidence in their performance, thus violating normative principles. To understand whether confidence influences future decision making, we examined serial dependence in observer’s responses, a phenomenon whereby the estimate of a stimulus on the current trial can be biased towards the stimulus from the previous trial. We found that when decisions were made with high confidence, they conferred stronger biases upon the following trial, suggesting that confidence may enhance serial dependence. Critically, this finding was true also when confidence was experimentally dissociated from task performance, indicating that subjective confidence, independent of signal quality, can amplify serial dependence. These findings demonstrate an effect of confidence on future behavior, independent of task performance, and suggest that perceptual decisions incorporate recent history in an uncertainty-weighted manner, but where the uncertainty carried forward is a subjectively estimated and possibly suboptimal readout of objective sensory uncertainty.

We tracked the neural representation of the orientation and the location of stimuli held in working memory at different levels of priority (“attended” and “unattended” memory items -- AMI and UMI), using multivariate inverted encoding models of human fMRI. Although representation of the orientation of the AMI and of the UMI could be reconstructed in several brain regions, including in early visual and parietal regions, the identity of the UMI was actively represented in early visual cortex in a distinct “reversed” code, suggesting this region as a site of the focus of attention to nonspatial stimulus information. The location of stimuli was also broadly represented, although only in parietal cortex was the location of the UMI represented in a reversed code. Our results suggest that a common recoding operation may be engaged, across stimulus dimensions and brain areas, to retain information in working memory while outside the focus of attention.

Different states of priority recruit different neural codes in visual working memory

Abstract Successful retrieval of an item from visual working memory (VWM) often requires an associated representation of the trial-unique context in which that item was presented. In experiment 1, fMRI of 16 male and female humans replicated a previous dissociation of the effects of manipulating memory load in comparison to the effects of manipulating context binding, by comparing VWM for one oriented line versus for three lines individuated by their location versus for three “heterogeneous” items drawn from different categories (orientation, color, and luminance): delay-period fMRI signal in frontal cortex and intraparietal sulcus (IPS) was sensitive to stimulus homogeneity rather than to memory load per se. Additionally, inspection of behavioral performance revealed a broad range of individual differences in the probability of responses to nontargets (also known as “swap errors”), and a post hoc comparison of high swap-error versus low swap-error groups generated several intriguing results: at recall, high swap-error subjects were seen to represent both the orientation and the location of the probed item less strongly, and with less differentiation from nonprobed items, and delay-period signal in IPS predicted behavioral and neural correlates of context binding at recall. In experiment 2, which was a preregistered replication, the 27 male and female humans were grouped into low and high swap-error groups by median split, and the results were broadly consistent with experiment 1. These results present a neural correlate of swap errors, and suggest that delay-period activity of the IPS may be more important for the operation of context binding than for representation per se of stimulus identity.

The Role of Location-Context Binding in Nonspatial Visual Working Memory

Retraction Note: Unexpected events disrupt visuomotor working memory and increase guessing

The brain stores information that is needed immediately and information that will be needed in the future in different ways.

Although the manipulation of load is popular in visual working memory research, many studies confound general attentional demands with context binding by drawing memoranda from the same stimulus category. In this fMRI study of human observers (both sexes), we created high- versus low-binding conditions, while holding load constant, by comparing trials requiring memory for the direction of motion of one random dot kinematogram (RDK; 1M trials) versus for three RDKs (3M), or versus one RDK and two color patches (1M2C). Memory precision was highest for 1M trials and comparable for 3M and 1M2C trials. And although delay-period activity in occipital cortex did not differ between the three conditions, returning to baseline for all three, multivariate pattern analysis decoding of a remembered RDK from occipital cortex was also highest for 1M trials and comparable for 3M and 1M2C trials. Delay-period activity in intraparietal sulcus (IPS), although elevated for all three conditions, displayed more sensitivity to demands on context binding than to load per se. The 1M-to-3M increase in IPS signal predicted the 1M-to-3M declines in both behavioral and neural estimates of working memory precision. These effects strengthened along a caudal-to-rostral gradient, from IPS0 to IPS5. Context binding-independent load sensitivity was observed when analyses were lateralized and extended into PFC, with trend-level effects evident in left IPS and strong effects in left lateral PFC. These findings illustrate how visual working memory capacity limitations arise from multiple factors that each recruit dissociable brain systems. SIGNIFICANCE STATEMENT Visual working memory capacity predicts performance on a wide array of cognitive and real-world outcomes. At least two theoretically distinct factors are proposed to influence visual working memory capacity limitations: an amodal attentional resource that must be shared across remembered items; and the demands on context binding. We unconfounded these two factors by varying load with items drawn from the same stimulus category (“high demands on context binding”) versus items drawn from different stimulus categories (“low demands on context binding”). The results provide evidence for the dissociability, and the neural bases, of these two theorized factors, and they specify that the functions of intraparietal sulcus may relate more strongly to the control of representations than to the general allocation of attention.

Parietal-Occipital Interactions Underlying Control- and Representation-Related Processes in Working Memory for Nonspatial Visual Features

& Understanding the contributions of the prefrontal cortex (PFC) to working memory is central to understanding the neural bases of high-level cognition. One question that remains controversial is whether the same areas of the dorsolateral PFC (dlPFC) that participate in the manipulation of information in working memory also contribute to its short-term retention (STR). We evaluated this question by first identifying, with functional magnetic resonance imaging (fMRI), brain areas involved in manipulation. Next, these areas were targeted with repetitive transcranial magnetic stimulation (rTMS) while subjects performed tasks requiring only the STR or the STR plus manipulation of information in working memory. fMRI indicated that manipulation-related activity was independent of retention-related activity in both the PFC and superior parietal lobule (SPL). rTMS, however, yielded a different pattern of results. Although rTMS of the dlPFC selectively disrupted manipulation, rTMS of the SPL disrupted manipulation and STR to the same extent. rTMS of the postcentral gyrus (a control region) had no effect on performance. The implications of these results are twofold. In the PFC, they are consistent with the view that this region contributes more importantly to the control of information in working memory than to its STR. In the SPL, they illustrate the importance of supplementing the fundamentally correlational data from neuroimaging with a disruptive method, which affords stronger inference about structure–function relations. &

Repetitive transcranial magnetic stimulation dissociates working memory manipulation from retention functions in the prefrontal , but not posterior parietal

![Graphic][1] Howard B. Eichenbaum, a Distinguished Professor in the Department of Psychological and Brain Sciences at Boston University, and a leading figure in Neuroscience died in Boston on July 21, 2017. He was 69. He was also the director of BU’s Center for Memory …

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Announcement: A Memory Researcher of the Hippocampus Has Gone, but Left His Mark

Adaptive behavior depends on the ability to accurately introspect about one’s own performance. Whether this metacognitive ability is supported by the same mechanisms across different tasks has thus far been investigated with a focus on correlating metacognitive accuracy between perception and long-term memory paradigms. Here, we investigated the relationship between metacognition of visual perception and metacognition of visual short-term memory (VSTM), a cognitive function thought to be more intimately related to visual processing. Experiments 1 and 2 required subjects to estimate the perceived or remembered orientation of a grating stimulus and rate their confidence. We observed strong positive correlations between individual differences in metacognitive accuracy between the two tasks. This relationship was not accounted for by individual differences in task performance or average confidence, and was present across two different metrics of metacognition and in both experiments. A model-based analysis of data from a third experiment showed that a cross-domain correlation only emerged when both tasks shared the same task-relevant stimulus feature. That is, metacognition for perception and VSTM were correlated when both tasks required orientation judgments, but not when the perceptual task was switched to require contrast judgments. In contrast to previous results comparing perception and long-term memory, which have largely provided evidence for domain-specific metacognitive processes, the current findings suggest that metacognition of visual perception and VSTM is supported by a domain-general metacognitive architecture, but only when both domains share the same task-relevant stimulus feature.

Correlated individual differences suggest a common mechanism underlying metacognition in visual perception and visual short-term memory

RETRACTED ARTICLE: Unexpected events disrupt visuomotor working memory and increase guessing

Numerous studies have demonstrated that visual STM (VSTM) and attention are tightly linked processes that share a number of neuroanatomical substrates. Here, we used repetitive TMS (rTMS) along with simultaneous EEG to examine the causal relationship between intraparietal sulcus functioning and performance on tasks of attention and VSTM. Participants performed two tasks in which they were required to attend to or remember colored items over a brief interval, with 10-Hz rTMS applied on some of the trials. Although no overall behavioral changes were observed across either task, rTMS did affect individual performance on both the attention and VSTM tasks in a manner that was predicted by individual differences in baseline performance. Furthermore, rTMS also affected ongoing oscillations in the alpha and beta bands, and these changes were related to the observed change in behavioral performance. The results reveal a causal relationship between intraparietal sulcus activity and tasks measuring both visual attention and VSTM.

Comparing the Effects of 10-Hz Repetitive TMS on Tasks of Visual STM and Attention

Supplementary material from "Correlated individual differences suggest a common mechanism underlying metacognition in visual perception and visual short-term memory"

Optimal functioning in everyday life requires the ability to override reflexive emotional responses and prevent affective spillover to situations or people unrelated to the source of emotion. In the current study, we investigated whether the lateral prefrontal cortex (lPFC) causally regulates the influence of emotional information on subsequent judgments. We disrupted left lPFC function using transcranial magnetic stimulation (TMS) and recorded electroencephalography (EEG) before and after. Subjects evaluated the likeability of novel neutral faces after a brief exposure to a happy or fearful face. We found that lPFC inhibition biased evaluations of novel faces according to the previously processed emotional expression. Greater frontal EEG alpha power, reflecting increased inhibition by TMS, predicted increased behavioral bias. TMS-induced affective misattribution was long-lasting: Emotionally biased first impressions formed during lPFC inhibition were still detectable outside of the laboratory 3 days later. These findings indicate that lPFC serves an important emotion-regulation function by preventing incidental emotional encoding from automatically biasing subsequent appraisals.

Inhibition of Lateral Prefrontal Cortex Produces Emotionally Biased First Impressions: A Transcranial Magnetic Stimulation and Electroencephalography Study

The role of the frontal cortex in consciousness remains a matter of debate. In this Perspective, we will critically review the clinical and neuroimaging evidence for the involvement of the front versus the back of the cortex in specifying conscious contents and discuss promising research avenues. Dual Perspectives Companion Paper: Should a Few Null Findings Falsify Prefrontal Theories of Conscious Perception?, by Brian Odegaard, Robert T. Knight, and Hakwan Lau

Are the Neural Correlates of Consciousness in the Front or in the Back of the Cerebral Cortex? Clinical and Neuroimaging Evidence

What are the effects of attentional prioritization on multifeature objects in WM

Magnetic stimulation (TMS) of human occipital and posterior parietal cortex can give rise to visual sensations called phosphenes, but neural correlates preceding and succeeding stimulation of both areas are unknown. Using near-threshold TMS with concurrent electroencephalography (EEG) recordings, we uncover oscillatory brain dynamics that covary, on single trials, with the perception of phosphenes following occipital and parietal TMS. Prestimulus power and phase predominantly in the alpha-band (8-13 Hz) predicted occipital TMS phosphenes, whereas higher frequency beta-band (13-20 Hz) power (but not phase) predicted parietal TMS phosphenes. TMS evoked responses related to phosphene perception were similar across stimulation sites and were characterized by an early (200 ms) posterior negativity and a later (>300 ms) parietal positivity in the time domain and an increase in low-frequency (~5-7 Hz) power followed by a broadband decrease in alpha/beta power in the time-frequency domain. These correlates of phosphene perception closely resemble know electrophysiological correlates of conscious perception using near-threshold visual stimuli and speak to the possible early onset of visual consciousness. The differential pattern of prestimulus predictors of phosphene perception suggest that distinct frequencies reflect cortical excitability within different cortical regions, and that the alpha-band rhythm, long thought of as a general index of cortical inhibition, may not reflect excitability of the posterior parietal cortex.

Electrophysiological correlates of phosphene perception induced by stimulation of human occipital and parietal cortex

Visual awareness is hypothesized to be intimately related to visual working memory (WM), such that information present in WM is thought to have necessarily been represented consciously. Recent work has challenged this longstanding view by demonstrating that visual stimuli rated by observers as unseen can nevertheless be maintained over a delay period. These experiments have been criticized, however, on the basis that subjective awareness ratings may contain response bias (e.g., an observer may report no awareness when in fact they had partial awareness). We mitigated this issue by investigating WM for visual stimuli that were matched for perceptual discrimination capacity (d′), yet which varied in subjective confidence ratings (so-called relative blindsight). If the degree of initial subjective awareness of a stimulus facilitates later maintenance of that information, WM performance should improve for stimuli encoded with higher confidence. In contrast, we found that WM performance did not benefit from higher visual discrimination confidence. This relationship was observed regardless of WM load (1 or 3). Insofar as metacognitive ratings (e.g., confidence, visibility) reflect visual awareness, these results challenge a strong relationship between conscious perception and WM using a paradigm that controls for discrimination accuracy and is less subject to response bias (since confidence is manipulated within subjects). Methodologically, we replicate prior efforts to induce relative blindsight using similar stimulus displays, providing a general framework for isolating metacognitive awareness in order to examine the function of consciousness.

Dissociating Perceptual Confidence from Discrimination Accuracy Reveals No Influence of Metacognitive Awareness on Working Memory

A pulse of random activity is sufficient for a brain network to retrieve a dormant activity state. How to reactivate forgotten memories Sophisticated techniques can decode stimulus representations for items held in a person's working memory. However, when subjects shift their attention toward something else, the neural representation of the now unattended item drops to baseline, as though the item has been forgotten. Rose et al. used single-pulse transcranial magnetic stimulation (TMS) to briefly reactivate the representation of an unattended item. A short pulse of TMS enhanced recognition of “forgotten” stimuli, bringing an unattended item back into focal attention. Science, this issue p. 1136 The ability to hold information in working memory is fundamental for cognition. Contrary to the long-standing view that working memory depends on sustained, elevated activity, we present evidence suggesting that humans can hold information in working memory via “activity-silent” synaptic mechanisms. Using multivariate pattern analyses to decode brain activity patterns, we found that the active representation of an item in working memory drops to baseline when attention shifts away. A targeted pulse of transcranial magnetic stimulation produced a brief reemergence of the item in concurrently measured brain activity. This reactivation effect occurred and influenced memory performance only when the item was potentially relevant later in the trial, which suggests that the representation is dynamic and modifiable via cognitive control. The results support a synaptic theory of working memory.

Reactivation of latent working memories with transcranial magnetic stimulation

Oscillations in the alpha-band (8-13 Hz) of human electroencephalographic (EEG) recordings are thought to reflect cortical excitability. As such, the magnitude of alpha power prior to the onset of a near threshold visual stimulus has been shown to predict stimulus detectability. Mechanistically, however, non-specific increases in visual-cortical excitability should result in amplified signal as well as amplified noise, leaving actual discriminability unchanged. Using a two-choice orientation discrimination task with equally probable stimuli, we found that discrimination accuracy was unaffected by fluctuations in prestimulus alpha-band power. Decision confidence, on the other hand, was strongly negatively correlated with prestimulus alpha power. This finding constitutes a clear dissociation between objective and subjective measures of visual perception as a function of prestimulus cortical excitability. This dissociation is predicted by models of perceptual confidence under which the balance of evidence in favor of each choice drives objective performance but only the magnitude of evidence in favor of the chosen stimulus drives subjective reports, suggesting that human perceptual confidence can be suboptimal.

Prestimulus alpha-band power biases visual discrimination confidence, but not accuracy

Over the course of the past half century, Suzanne Hammond Corkin (1937–2016) has made a remarkable number of contributions to our understanding of the neural bases of human cognition. She is, of course, best known for her career-long association with the amnesic patient H.M., eloquently summarized in her book Permanent Present Tense: The Unforgettable Life of the Amnesic Patient, H.M. (Corkin, 2013). From this association have come foundational insights into the functions of the hippocampus and surrounding tissue of the medial temporal lobe (MTL), and into the organization of memory. In addition to these contributions, her wide-ranging research has also explored the neural bases of perception and working memory, the interaction of emotion and memory, and the effects of aging and of age-related neurodegenerative disease on cognition. Throughout her celebrated career, she set a pioneering example for how to be successful as a woman in science. Suzanne Hammond grew up in the Hartford, Connecticut. As circumstance would have it, she was a childhood friend of the daughter of the neurosurgeon, William Beecher Scoville. She was of high-school age, and perhaps just a few miles distant, when Scoville performed the fateful bilateral medial temporal lobectomy on Henry Molaison, a 27-year-old with intractable epilepsy. She was pursing her B.A. at Smith College when Scoville and Milner published their initial report of H.M.’s case (Scoville and Milner, 1957). Shortly thereafter, she enrolled in the Clinical Psychology graduate program at McGill University, where she learned from and worked with some of the giants of neuroscience, including D.O. Hebb, Wilder Penfield, Herbert Jasper, Theodore Rasmussen, Robert Malmo, and her mentor Brenda Milner. She initially came to Milner with an interest in somesthesis, a topic on which she was to publish work carried out at the Montreal Neurological Institute (Corkin et al., 1964, 1970), as well as, several years later, with collaborators in Boston (Moore et al., 2000a,b). Most famously, however, it was also at this time that she began her work with H.M. The 1957 report from Scoville and Milner had established “a special importance to the anterior hippocampus and hippocampal gyrus in the retention of new experience” (p. 21). This was a revolutionary breakthrough in memory research. (Consider that, just a few years earlier, Lashley (1950) had noted that “I sometimes feel, in reviewing the evidence on the localization of the memory trace, that the necessary conclusion is that learning just is not possible. . . It is not possible to demonstrate the isolated localization of a memory trace anywhere within the nervous system” (p. 477–478).) Critically, H.M.’s profound memory impairment coexisted with an above-normal IQ, indicating that memory could be understood as dissociable from other high-level mental functions. Shortly thereafter, a second important conceptual breakthrough came with Milner’s demonstration that H.M. could retain learning of a sensorimotor skill (mirror tracing) despite no consciously accessible memory of his prior experience with the testing apparatus (Milner, 1962). Corkin followed up on this finding, demonstrating preserved learning in H.M. when navigating a tactually guided maze (Corkin, 1965), performing motor skills (Corkin, 1968), and recognizing degraded visual images (Milner et al., 1968). The implication of these findings was that memory, itself, was not a unitary entity, but could be neurally dissociated into different classes. One—which came to be known as declarative or explicit—was dependent on the hippocampus and MTL, and others—which became known as nondeclarative, procedural, or implicit—were not (e.g., Cohen and Squire, 1980; Schacter, 1987). After receiving her PhD in 1964, Suzanne Corkin moved to the laboratory of Hans-Lukas Teuber at MIT. During her first 15 years at MIT, she was the engine behind the Department of Psychology’s Clinical Research Center, where brain-injured subjects were studied. Years later, it was noted that this facility was “so original [for a department of psychology] that even today it is more admired than emulated” (Gross, 1994) (p. 453). During this time, Corkin also played a critical role in the editing of Neuropsychologia, the era’s leading journal of the neuroscientific study of human behavior. In 1977, Teuber’s untimely death led to two developments that were without precedent at MIT. First, although she held a research staff (i.e., not faculty) position, Corkin became director of the human neuropsychology lab. Second, in 1981, 1 Departments of Psychology and Psychiatry, University of Wisconsin– Madison, Madison, Wisconsin; 2 Department of Psychology, Boston College, Massachusetts *Correspondence to: Bradley R. Postle, Departments of Psychology and Psychiatry, University of Wisconsin–Madison, Madison, WI, USA. E-mail: postle@wisc.edu Received 11 July 2016; Accepted for publication 19 July 2016. DOI 10.1002/hipo.22618 Published online 20 July 2016 in Wiley Online Library (wileyonlinelibrary.com).

A long-standing assumption of cognitive neuroscience has been that working memory (WM) is accomplished by sustained, elevated neural activity. More recently, theories of WM have expanded this view by describing different attentional states in WM with differing activation levels. Several studies have used multivariate pattern analysis (MVPA) of functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) data to study neural activity corresponding to these WM states. Intriguingly, no evidence was found for active neural representations for information held in WM outside the focus of attention ("unattended memory items," UMIs), suggesting that only attended memory items (AMIs) are accompanied by an active trace. However, these results depended on category-level decoding, which lacks sensitivity to neural representations of individual items. Therefore, we employed a WM task in which subjects remembered the directions of motion of two dot arrays, with a retrocue indicating which was relevant for an imminent memory probe (the AMI). This design allowed MVPA decoding of delay-period fMRI signal at the stimulus-item level, affording a more sensitive test of the neural representation of UMIs. Whereas evidence for the AMI was reliably high, evidence for the UMI dropped to baseline, consistent with the notion that different WM attentional states may have qualitatively different mechanisms of retention.

Within-Category Decoding of Information in Different Attentional States in Short-Term Memory

Consciousness and cortical responsiveness: a within-state study during non-rapid eye movement sleep

For decades, theoreticians and experimentalists have worked under the assumption that the short-term retention of information depends on elevated activity in the neural elements that represent this information. This was reinforced by the observation of elevated activity in the prefrontal cortex (PFC) during the performance of working memory tasks. Increasingly, however, researchers are realizing that the face-value interpretation of regional patterns of elevated activity, including in the PFC, is constrained, a priori, to the principle that brain functions (like working memory) are organized in a modular manner. This is at odds with our current understanding of the brain as a highly distributed, dynamical system capable of multiplexed processing. An alternative empirical approach, the application of multivariate pattern analysis to neural data sets, has led to two important developments in our conceptualization of working memory. First, it has shown that sustained delay-period activity in the PFC (and elsewhere) often does not correspond to the active retention, per se, of information. Second, it has provided strong empirical evidence for two mechanisms that may underlie our ability to keep in mind small amounts of information with which we can guide our behavior: sensorimotor recruitment, and the temporary activation of long-term memory representations.

Transcranial magnetic stimulation (TMS) of human occipital and posterior parietal cortex can give rise to visual sensations called phosphenes. We used near-threshold TMS with concurrent EEG recordings to measure how oscillatory brain dynamics covary, on single trials, with the perception of phosphenes after occipital and parietal TMS. Prestimulus power and phase, predominantly in the alpha band (8–13 Hz), predicted occipital TMS phosphenes, whereas higher-frequency beta-band (13–20 Hz) power (but not phase) predicted parietal TMS phosphenes. TMS-evoked responses related to phosphene perception were similar across stimulation sites and were characterized by an early (200 ms) posterior negativity and a later (>300 ms) parietal positivity in the time domain and an increase in low-frequency (∼5–7 Hz) power followed by a broadband decrease in alpha/beta power in the time–frequency domain. These correlates of phosphene perception closely resemble known electrophysiological correlates of conscious perception of near-threshold visual stimuli. The regionally differential pattern of prestimulus predictors of phosphene perception suggests that distinct frequencies may reflect cortical excitability in occipital versus posterior parietal cortex, calling into question the broader assumption that the alpha rhythm may serve as a general index of cortical excitability. SIGNIFICANCE STATEMENT Alpha-band oscillations are thought to reflect cortical excitability and are therefore ascribed an important role in gating information transmission across cortex. We probed cortical excitability directly in human occipital and parietal cortex and observed that, whereas alpha-band dynamics indeed reflect excitability of occipital areas, beta-band activity was most predictive of parietal cortex excitability. Differences in the state of cortical excitability predicted perceptual outcomes (phosphenes), which were manifest in both early and late patterns of evoked activity, revealing the time course of phosphene perception. Our findings prompt revision of the notion that alpha activity reflects excitability across all of cortex and suggest instead that excitability in different regions is reflected in distinct frequency bands.

Distinct Oscillatory Frequencies Underlie Excitability of Human Occipital and Parietal Cortex

Many aspects of perception and cognition are supported by activity in neural populations that are tuned to different stimulus features (e.g., orientation, spatial location, color). Goal-directed behavior, such as sustained attention, requires a mechanism for the selective prioritization of contextually appropriate representations. A candidate mechanism of sustained spatial attention is neural activity in the alpha band (8–13 Hz), whose power in the human EEG covaries with the focus of covert attention. Here, we applied an inverted encoding model to assess whether spatially selective neural responses could be recovered from the topography of alpha-band oscillations during spatial attention. Participants were cued to covertly attend to one of six spatial locations arranged concentrically around fixation while EEG was recorded. A linear classifier applied to EEG data during sustained attention demonstrated successful classification of the attended location from the topography of alpha power, although not from other frequency bands. We next sought to reconstruct the focus of spatial attention over time by applying inverted encoding models to the topography of alpha power and phase. Alpha power, but not phase, allowed for robust reconstructions of the specific attended location beginning around 450 msec postcue, an onset earlier than previous reports. These results demonstrate that posterior alpha-band oscillations can be used to track activity in feature-selective neural populations with high temporal precision during the deployment of covert spatial attention.

Decoding and Reconstructing the Focus of Spatial Attention from the Topography of Alpha-band Oscillations

Cortical responses to transcranial magnetic stimulation during Non-Rapid Eye Movement Sleep

Recent studies applying multivariate pattern analysis (MVPA) to functional magnetic resonance imaging (fMRI) data sets have called into question long-held assumptions about the importance of sustained, elevated activity for the short-term retention of information (i.e., short-term and working memory). Findings from these studies include the fact that delay-period activity in frontal and parietal cortex may not correspond to information storage, per se, and that information that is in short-term memory, but outside the focus of attention, may be retained in a transient structural code.

The Speed of Alpha-Band Oscillations Predicts the Temporal Resolution of Visual Perception

This study was designed to explore neural evidence for the simultaneous engagement of multiple mental codes while retaining a visual object in short-term memory (STM) and, if successful, to explore the neural bases of strategic prioritization among these codes. We used multivariate pattern analysis of fMRI data to track patterns of brain activity associated with three common mental codes: visual, verbal, and semantic. When participants did not know which dimension of a sample stimulus would be tested, patterns of brain activity during the memory delay indicated that a visual representation was quickly augmented with both verbal and semantic re-representations of the stimulus. The verbal code emerged as most highly activated, consistent with a canonical visual-to-phonological recoding operation in STM. If participants knew which dimension of a sample stimulus would be tested, brain activity patterns were biased toward the probe-relevant stimulus dimension. Interestingly, probe-irrelevant neural states persisted at an intermediate level of activation when they were potentially relevant later in the trial, but dropped to baseline when cued to be irrelevant. These results reveal the neural dynamics underlying the creation and retention of mental codes, and they illustrate the flexible control that humans can exert over these representations.

Neural Evidence for the Flexible Control of Mental Representations.

Evidence for a Synaptic Theory of Working Memory: An fMRI/EEG/TMS Study: (528942014-149)

Context-specific differences in fronto-parieto-occipital effective connectivity during short-term memory maintenance

The short- and long-term fates of memory items retained outside the focus of attention

Working-Memory Task Motion Information Is Spatially Localized in a Visual

Significance In contrast to canonical, stimulus-driven models of perception, recent proposals argue that perceptual experiences are constructed in an active manner in which top-down influences play a key role. In particular, predictions that the brain makes about the world are incorporated into each perceptual experience. Because forming the appropriate sensory predictions can have a large impact on our visual experiences and visually guided behaviors, a mechanism thought to be disrupted in certain neurological conditions like autism and schizophrenia, an understanding of the neural basis of these predictions is critical. Here, we provide evidence that perceptual expectations about when a stimulus will appear are instantiated in the brain by optimally configuring prestimulus alpha-band oscillations so as to make subsequent processing most efficacious. The physiological state of the brain before an incoming stimulus has substantial consequences for subsequent behavior and neural processing. For example, the phase of ongoing posterior alpha-band oscillations (8–14 Hz) immediately before visual stimulation has been shown to predict perceptual outcomes and downstream neural activity. Although this phenomenon suggests that these oscillations may phasically route information through functional networks, many accounts treat these periodic effects as a consequence of ongoing activity that is independent of behavioral strategy. Here, we investigated whether alpha-band phase can be guided by top-down control in a temporal cueing task. When participants were provided with cues predictive of the moment of visual target onset, discrimination accuracy improved and targets were more frequently reported as consciously seen, relative to unpredictive cues. This effect was accompanied by a significant shift in the phase of alpha-band oscillations, before target onset, toward each participant’s optimal phase for stimulus discrimination. These findings provide direct evidence that forming predictions about when a stimulus will appear can bias the phase of ongoing alpha-band oscillations toward an optimal phase for visual processing, and may thus serve as a mechanism for the top-down control of visual processing guided by temporal predictions.

Top-down control of the phase of alpha-band oscillations as a mechanism for temporal prediction

1 RUNNING HEAD: Pre-stimulation phase predicts the TMS-evoked response 2 3 4 5 6 7 8 9 10 11 Pre-stimulation phase predicts the TMS-evoked response 12 13 Bornali Kundu, Jeffrey S. Johnson, Bradley R. Postle 14 15 16 1. Medical Scientist Training Program and the Neuroscience Training 17 Program, University of Wisconsin—Madison, USA 18 2. Department of Psychiatry, University of Wisconsin—Madison, USA 19 3. Department of Psychology, University of Wisconsin—Madison, USA 20 21 22 23 24 Corresponding Author: 25 26 Bornali Kundu 27 Department of Psychiatry 28 University of Wisconsin-Madison 29 6001 Research Park Blvd. 30 Madison, WI 53719 31 32 Phone: 1-608-265-8961 33 Email: bkundu@wisc.edu 34 35 36 37 38 Articles in PresS. J Neurophysiol (July 9, 2014). doi:10.1152/jn.00390.2013

Pre-stimulation phase predicts the TMS-evoked response 2 3 4 5 6 7 8 9 10 11 Pre-stimulation phase predicts the TMS-evoked response 12 13

Pre-stimulation phase predicts the TMS-evoked response Pre-stimulation phase predicts the TMS-evoked response

Mapping the spatial distribution of short-term memory representations for visual motion

Jones GE, Tanteles GA, Vasudevan PC, et al. A novel mutation in NIPBL3 in a case of Cornelia de Lange syndrome confirmed with genetic testing following intrauterine fetal death. J Clin Pathol 2014;67:283–4. The title was published wrong. The correct title should be A novel mutation in NIPBL in a case of Cornelia de Lange syndrome confirmed with genetic testing following intrauterine fetal death. In Discussion, one sentence in the last paragraph was also published with mistake. The correct sentence reads as follows ‘The mutation identified in the NIPBL gene has not previously been reported.’

Prestimulation oscillatory phase and power in particular frequency bands predict perception of at-threshold visual stimuli and of transcranial magnetic stimulation (TMS)-induced phosphenes. These effects may be due to changes in cortical excitability, such that certain ranges of power and/or phase values result in a state in which a particular brain area is more receptive to input, thereby biasing behavior. However, the effects of trial-by-trial fluctuations in phase and power of ongoing oscillations on the brain's electrical response to TMS itself have thus far not been addressed. The present study adopts a combined TMS and electroencepalography (EEG) approach to determine whether the TMS-evoked response is sensitive to momentary fluctuations in prestimulation phase and/or power in different frequency bands. Specifically, TMS was applied to superior parietal lobule while subjects performed a short-term memory task. Results showed that the prestimulation phase, particularly within the beta (15-25 Hz) band, predicted pulse-by-pulse variations in the global mean field amplitude. No such relationship was observed between prestimulation power and the global mean field amplitude. Furthermore, TMS-evoked power in the beta band fluctuated with prestimulation phase in the beta band in a manner that differed from spontaneous brain activity. These effects were observed in areas at and distal to the stimulation site. Together, these results confirm the idea that fluctuating phase of ongoing neuronal oscillations create "windows of excitability" in the brain, and they give insight into how TMS interacts with ongoing brain activity on a pulse-by-pulse basis.

Trait-like Differences in Underlying Oscillatory State Predict Individual Differences in the TMS-evoked Response

Short-term memory (STM) refers to the capacity-limited retention of information over a brief period of time, and working memory (WM) refers to the manipulation and use of that information to guide behavior. In recent years it has become apparent that STM and WM interact and overlap with other cognitive processes, including attention (the selection of a subset of information for further processing) and long-term memory (LTM—the encoding and retention of an effectively unlimited amount of information for a much longer period of time). Broadly speaking, there have been two classes of memory models: systems models, which posit distinct stores for STM and LTM (Atkinson and Shiffrin, 1968; Baddeley and Hitch, 1974); and state-based models, which posit a common store with different activation states corresponding to STM and LTM (Cowan, 1995; McElree, 1996; Oberauer, 2002). In this paper, we will focus on state-based accounts of STM. First, we will consider several theoretical models that postulate, based on considerable behavioral evidence, that information in STM can exist in multiple representational states. We will then consider how neural data from recent studies of STM can inform and constrain these theoretical models. In the process we will highlight the inferential advantage of multivariate, information-based analyses of neuroimaging data (fMRI and electroencephalography (EEG)) over conventional activation-based analysis approaches (Postle, in press). We will conclude by addressing lingering questions regarding the fractionation of STM, highlighting differences between the attention to information vs. the retention of information during brief memory delays.

Multiple neural states of representation in short-term memory? It’s a matter of attention

What are the neural correlates of consciousness? Studies that have addressed this question in the past either compared neural activity during tasks in which subjects report perceiving a stimulus or not, or have contrasted conscious wakefulness with unconscious sleep or anesthesia. However, such contrasts may include correlates of stimulus processing, response preparation or of changes in behavioral state, rather than of consciousness per se. To overcome these limitations, we developed a no-task, within-state paradigm in which sleeping subjects recorded with high density-EEG reported retrospectively whether they had been conscious or not. We identified specific frontal and parieto-occipital regions showing EEG changes several seconds preceding awakenings that distinguished between reports of consciousness and unconsciousness. While decreased parieto-occipital low-frequency activity was associated with highly perceptual experiences, increased frontal high-frequency activity was associated with highly thought-like experiences. Finally, we identified localized, content-specific activations for faces, spatial setting, movement and speech experienced in dreams.

The neural correlates of consciousness in sleep: a no-task, within-state paradigm

Although long considered a natively endowed and fixed trait, working memory (WM) ability has recently been shown to improve with intensive training. What remains controversial and poorly understood, however, are the neural bases of these training effects and the extent to which WM training gains transfer to other cognitive tasks. Here we present evidence from human electrophysiology (EEG) and simultaneous transcranial magnetic stimulation and EEG that the transfer of WM training to other cognitive tasks is supported by changes in task-related effective connectivity in frontoparietal and parieto-occipital networks that are engaged by both the trained and transfer tasks. One consequence of this effect is greater efficiency of stimulus processing, as evidenced by changes in EEG indices of individual differences in short-term memory capacity and in visual search performance. Transfer to search-related activity provides evidence that something more fundamental than task-specific strategy or stimulus-specific representations has been learned. Furthermore, these patterns of training and transfer highlight the role of common neural systems in determining individual differences in aspects of visuospatial cognition.

Strengthened Effective Connectivity Underlies Transfer of Working Memory Training to Tests of Short-Term Memory and Attention

Dreaming—a particular form of consciousness that occurs during sleep—undergoes major changes in the course of the night. We aimed to outline state-dependent features of consciousness using a paradigm with multiple serial awakenings/questionings that allowed for within as well as between subject comparisons. Seven healthy participants who spent 44 experimental study nights in the laboratory were awakened by a computerized sound at 15–30 min intervals, regardless of sleep stage, and questioned for the presence or absence of sleep consciousness. Recall without content (“I was experiencing something but do not remember what”) was considered separately. Subjects had to indicate the content of the most recent conscious experience prior to the alarm sound and to estimate its duration and richness. We also assessed the degree of thinking and perceiving, self- and environment-relatedness and reflective consciousness of the experiences. Of the 778 questionings, 5% were performed during wakefulness, 2% in stage N1, 42% in N2, 33% in N3, and 17% in rapid eye movement (REM) sleep. Recall with content was reported in 34% of non-REM and in 77% of REM sleep awakenings. Sleep fragmentation inherent to the study design appeared to only minimally affect the recall of conscious experiences. Each stage displayed a unique combination of characteristic features of sleep consciousness. In conclusion, our serial awakening paradigm allowed us to collect a large and representative sample of conscious experiences across states of being. It represents a time-efficient method for the study of sleep consciousness that may prove particularly advantageous when combined with techniques such as functional MRI and high-density EEG.

Assessing sleep consciousness within subjects using a serial awakening paradigm

For decades it has been assumed that sustained, elevated neural activity—the so-called active trace—is the neural correlate of the short-term retention of information. However, a recent fMRI study has suggested that this activity may be more related to attention than to retention. Specifically, a multivariate pattern analysis failed to find evidence that information that was outside the focus of attention, but nonetheless in STM, was retained in an active state. Here, we replicate and extend this finding by querying the neural signatures of attended versus unattended information within STM with electroencephalograpy (EEG), a method sensitive to oscillatory neural activity to which the previous fMRI study was insensitive. We demonstrate that in the delay-period EEG activity, there is information only about memory items that are also in the focus of attention. Information about items outside the focus of attention is not detectable. This result converges with the fMRI findings to suggest that, contrary to conventional wisdom, an active memory trace may be unnecessary for the short-term retention of information.

Decoding Attended Information in Short-term Memory: An EEG Study

Whole brain images were acquired with the 3T scanner (Discovery MR750; GE Healthcare) at the Lane Neuroimaging Laboratory at the University of Wisconsin–Madison. High-resolution T1-weighted images were acquired for all subjects with an FSPGR sequence (8.132 ms TR, 3.18 ms TE, 12° flip angle, 156 axial slices, 256 ϫ 256 in-plane, 1.0 mm isotropic). BOLD-sensitive data were acquired using a gradient-echo, echoplanar sequence (2 s TR, 25 ms TE) within a 64 ϫ 64 matrix (39 sagittal slices, 3.5 mm isotropic). Six runs, each lasting 13 min (390 volumes), were obtained for each subject. The first three TRs from each run were removed before analysis to achieve a steady state of tissue magnetization.

Correction: Emrich et al., Distributed Patterns of Activity in Sensory Cortex Reflect the Precision of Multiple Items Maintained in Visual Short-Term Memory

Volume 4, Issue 2 of the Journal of Transport and Land Use focuses on coevolution: how transport drives changes in land use, and vice versa. e issue contains four research articles, examining different geographies, eras, and technologies. ese papers present new ndings, but as good science should, raise new questions, and help us set a research agenda to better understand the coevolution of transport and land use.

Traditionally, load sensitivity of sustained, elevated activity has been taken as an index of storage for a limited number of items in visual short-term memory (VSTM). Recently, studies have demonstrated that the contents of a single item held in VSTM can be decoded from early visual cortex, despite the fact that these areas do not exhibit elevated, sustained activity. It is unknown, however, whether the patterns of neural activity decoded from sensory cortex change as a function of load, as one would expect from a region storing multiple representations. Here, we use multivoxel pattern analysis to examine the neural representations of VSTM in humans across multiple memory loads. In an important extension of previous findings, our results demonstrate that the contents of VSTM can be decoded from areas that exhibit a transient response to visual stimuli, but not from regions that exhibit elevated, sustained load-sensitive delay-period activity. Moreover, the neural information present in these transiently activated areas decreases significantly with increasing load, indicating load sensitivity of the patterns of activity that support VSTM maintenance. Importantly, the decrease in classification performance as a function of load is correlated with within-subject changes in mnemonic resolution. These findings indicate that distributed patterns of neural activity in putatively sensory visual cortex support the representation and precision of information in VSTM.

Distributed Patterns of Activity in Sensory Cortex Reflect the Precision of Multiple Items Maintained in Visual Short-Term Memory

The positional-specificity effect refers to enhanced performance in visual short-term memory (VSTM) when the recognition probe is presented at the same location as had been the sample, even though location is irrelevant to the match/nonmatch decision. We investigated the mechanisms underlying this effect with behavioral and fMRI studies of object change-detection performance. To test whether the positional-specificity effect is a direct consequence of active storage in VSTM, we varied memory load, reasoning that it should be observed for all objects presented in a sub-span array of items. The results, however, indicated that although robust with a memory load of 1, the positional-specificity effect was restricted to the second of two sequentially presented sample stimuli in a load-of-2 experiment. An additional behavioral experiment showed that this disruption wasn’t due to the increased load per se, because actively processing a second object – in the absence of a storage requirement – also eliminated the effect. These behavioral findings suggest that, during tests of object memory, position-related information is not actively stored in VSTM, but may be retained in a passive tag that marks the most recent site of selection. The fMRI data were consistent with this interpretation, failing to find location-specific bias in sustained delay-period activity, but revealing an enhanced response to recognition probes that matched the location of that trial’s sample stimulus.

The Positional-Specificity Effect Reveals a Passive-Trace Contribution to Visual Short-Term Memory

Does the sustained, elevated neural activity observed during working memory tasks reflect the short-term retention of information? Functional magnetic resonance imaging (fMRI) data of delayed recognition of visual motion in human participants were analyzed with two methods: a general linear model (GLM) and multivoxel pattern analysis. Although the GLM identified sustained, elevated delay-period activity in superior and lateral frontal cortex and in intraparietal sulcus, pattern classifiers were unable to recover trial-specific stimulus information from these delay-active regions. The converse—no sustained, elevated delay-period activity but successful classification of trial-specific stimulus information—was true of posterior visual regions, including area MT+ (which contains both middle temporal area and medial superior temporal area) and calcarine and pericalcarine cortex. In contrast to stimulus information, pattern classifiers were able to extract trial-specific task instruction-related information from frontal and parietal areas showing elevated delay-period activity. Thus, the elevated delay-period activity that is measured with fMRI may reflect processes other than the storage, per se, of trial-specific stimulus information. It may be that the short-term storage of stimulus information is represented in patterns of (statistically) “subthreshold” activity distributed across regions of low-level sensory cortex that univariate methods cannot detect.

The Relationship between Working Memory Storage and Elevated Activity as Measured with Functional Magnetic Resonance Imaging

The concept of the “mnemonic scotoma,” a spatially circumscribed region of working memory impairment produced by unilateral lesions of the PFC, is central to the view that PFC is critical for the short-term retention of information. Presented here, however, are previously unpublished data that offer an alternative, nonmnemonic interpretation of this pattern of deficit. In their study, Wajima and Sawaguchi [Wajima, K., & Sawaguchi, T. The role of GABAergic inhibiton in suppressing perseverative responses in the monkey prefrontal cortex. Neuroscience Research, 50(Suppl. 1), P3–P317, 2004] applied the GABAA antagonist bicuculline methiodide unilaterally to the PFC of two monkeys while they performed an oculomotor delayed-response task. Consistent with previous studies, errors for the initial memory-guided saccade were markedly higher when the cued location fell into the region of the visual field affected by the infusion. These erroneous saccades tended to select an alternative target location (out of a possible 16) that had not been cued on that trial. By extending the analysis window, however, it was observed that the second, “corrective” saccade often acquired the location that had been cued on that trial. Further analysis of the erroneous initial saccades indicated that they tended to be directed to a location that had been relevant on the previous trial. Thus, the deficit was not one of “forgetting” the cued location. Rather, it was one of selecting between currently and previously relevant locations. These findings suggest a need for a reconsideration of the concept of the mnemonic scotoma, which in turn invites a reconsideration of functional interpretations of sustained neuronal activity in PFC.

The Prefrontal Cortex and Oculomotor Delayed Response: A Reconsideration of the “Mnemonic Scotoma”

The brain's electrical response to transcranial magnetic stimulation (TMS) is known to be influenced by exogenous factors such as the frequency and intensity of stimulation and the orientation and positioning of the stimulating coil. Less understood, however, is the influence of endogenous neural factors, such as global brain state, on the TMS-evoked response (TMS-ER). In the present study, we explored how changes in behavioral state affect the TMS-ER by perturbing the superior parietal lobule (SPL) with single pulses of TMS and measuring consequent differences in the frequency, strength, and spatial spread of TMS-evoked currents during the delay period of a spatial short-term memory task and during a period of passive fixation. Results revealed that task performance increased the overall strength of electrical currents induced by TMS, increased the spatial spread of TMS-evoked activity to distal brain regions, and increased the ability of TMS to reset the phase of ongoing broadband cortical oscillations. By contrast, task performance had little effect on the dominant frequency of the TMS-ER, both locally and at distal brain areas. These findings contribute to a growing body of work using combined TMS and neuroimaging methods to explore task-dependent changes in the functional organization of cortical networks implicated in task performance.

Task-dependent changes in cortical excitability and effective connectivity: a combined TMS-EEG study.

CONTEXT
Schizophrenia is a devastating illness with an indeterminate pathophysiology. Several lines of evidence implicate dysfunction in the thalamus, a key node in the distributed neural networks underlying perception, emotion, and cognition. Existing evidence of aberrant thalamic function is based on indirect measures of thalamic activity, but dysfunction has not yet been demonstrated with a causal method.

OBJECTIVE
To test the hypothesis that direct physiological stimulation of the cortex will produce an abnormal thalamic response in individuals with schizophrenia.

DESIGN
We stimulated the precentral gyrus with single-pulse transcranial magnetic stimulation (spTMS) and measured the response to this pulse in synaptically connected regions (thalamus, medial superior frontal cortex, insula) using concurrent functional magnetic resonance imaging. The mean hemodynamic response from these regions was fit with the sum of 2 gamma functions, and response parameters were compared across groups.

SETTING
Academic research laboratory.

Patients with schizophrenia and sex- and age-matched psychiatrically healthy subjects were recruited from the community.

Peak amplitude of the thalamic hemodynamic response to spTMS of the precentral gyrus.

RESULTS
The spTMS-evoked responses did not differ between groups at the cortical stimulation site. Compared with healthy subjects, patients with schizophrenia showed a reduced response to spTMS in the thalamus (P=1.86 × 10(-9)) and medial superior frontal cortex (P=.02). Similar results were observed in the insula. Sham TMS indicated that these results could not be attributed to indirect effects of TMS coil discharge. Functional connectivity analyses revealed weaker thalamus-medial superior frontal cortex and thalamus-insula connectivity in patients with schizophrenia compared with control subjects.

Individuals with schizophrenia showed reduced thalamic activation in response to direct perturbation delivered to the cortex. These results extend prior work implicating the thalamus in the pathophysiology of schizophrenia and suggest that the thalamus contributes to the patterns of aberrant connectivity characteristic of this disease.

Probing thalamic integrity in schizophrenia using concurrent transcranial magnetic stimulation and functional magnetic resonance imaging.

The Representation of Stimulus Identity for Multiple Items in Short-Term Memory Revealed Using fMRI Classification

Schizophrenia is a severe mental illness with neurobiological bases that remain elusive. One hypothesis emphasizes disordered thalamic function. We previously used concurrent single pulse transcranial magnetic stimulation (spTMS) and functional magnetic resonance imaging (fMRI) to show that individuals with schizophrenia have a decreased spTMS-evoked response in the thalamus, and decreased effective connectivity between thalamus and insula and thalamus and superior frontal gyrus. To better understand the factors that may accompany or account for these findings, we investigated, in the same participants, resting state functional connectivity, white matter structural connectivity, and grey matter integrity. Patients with schizophrenia did not differ from healthy control subjects in resting state functional- or white matter structural connectivity, although they did show decreased measures of grey matter integrity in the insula. However, in this region, the spTMS-evoked response did not differ between groups. In a region of the thalamus that also had grey matter intensity abnormalities, although not at a level that survived correction for multiple comparisons, the spTMS-evoked response in patients was deficient. These results suggest that measures of structure and function are not necessarily complementary. Further, given its sensitivity for identifying deficits not evident with traditional imaging methods, these results highlight the utility of spTMS-fMRI, a method that directly and causally probes effective connectivity, as a tool for studying brain-based disorders.

Conserved Functional Connectivity but Impaired Effective Connectivity of Thalamocortical Circuitry in Schizophrenia

It is widely assumed that the short-term retention of information is accomplished via maintenance of an active neural trace. However, we demonstrate that memory can be preserved across a brief delay despite the apparent loss of sustained representations. Delay period activity may, in fact, reflect the focus of attention, rather than STM. We unconfounded attention and memory by causing external and internal shifts of attention away from items that were being actively retained. Multivariate pattern analysis of fMRI indicated that only items within the focus of attention elicited an active neural trace. Activity corresponding to representations of items outside the focus quickly dropped to baseline. Nevertheless, this information was remembered after a brief delay. Our data also show that refocusing attention toward a previously unattended memory item can reactivate its neural signature. The loss of sustained activity has long been thought to indicate a disruption of STM, but our results suggest that, even for small memory loads not exceeding the capacity limits of STM, the active maintenance of a stimulus representation may not be necessary for its short-term retention.

Neural Evidence for a Distinction between Short-term Memory and the Focus of Attention

CONTEXT
Converging evidence from electrophysiological studies suggests that in individuals with schizophrenia, electroencephalographic frontal fast oscillations are reduced. It is still unclear whether this reduction reflects an intrinsic deficit of underlying cortical/thalamocortical circuits and whether this deficit is specific for frontal regions. Recent electrophysiological studies in healthy individuals have established that, when perturbed, different brain regions oscillate at a specific, intrinsically generated dominant frequency, the natural frequency.

OBJECTIVE
To assess the natural frequency of the posterior parietal, motor, premotor, and prefrontal cortices in patients with schizophrenia and healthy control subjects.

DESIGN
High-density electroencephalographic recordings during transcranial magnetic stimulation of 4 cortical areas were performed. Several transcranial magnetic stimulation–evoked electroencephalographic oscillation parameters, including synchronization, amplitude, and natural frequency, were compared across the schizophrenia and healthy control groups.

SETTING
Wisconsin Psychiatric Institute and Clinic, University of Wisconsin–Madison.

Twenty patients with schizophrenia and 20 age-matched healthy control subjects.

High-density electroencephalographic measurements of transcranial magnetic stimulation–evoked activity in 4 cortical areas, scores on the Positive and Negative Syndrome Scale, and performance scores (reaction time, accuracy) on 2 computerized tasks (word memory [Penn Word Recognition Test] and facial memory [Penn Facial Memory Test]).

RESULTS
Patients with schizophrenia showed a slowing in the natural frequency of the frontal/prefrontal regions compared with healthy control subjects (from an average of a 2-Hz decrease for the motor area to an almost 10-Hz decrease for the prefrontal cortex). The prefrontal natural frequency of individuals with schizophrenia was slower than in any healthy comparison subject and correlated with both positive Positive and Negative Syndrome Scale scores and reaction time on the Penn Word Recognition Test.

These findings suggest that patients with schizophrenia have an intrinsic slowing in the natural frequency of frontal cortical/thalamocortical circuits, that this slowing is not present in parietal areas, and that the prefrontal natural frequency can predict some of the symptoms as well as the cognitive dysfunctions of schizophrenia.

Reduced natural oscillatory frequency of frontal thalamocortical circuits in schizophrenia.

Verbal working memory (VWM), the ability to maintain and manipulate representations of speech sounds over short periods, is held by some influential models to be independent from the systems responsible for language production and comprehension [e.g., Baddeley, A. D. Working memory, thought, and action. New York, NY: Oxford University Press, 2007]. We explore the alternative hypothesis that maintenance in VWM is subserved by temporary activation of the language production system [Acheson, D. J., & MacDonald, M. C. Verbal working memory and language production: Common approaches to the serial ordering of verbal information. Psychological Bulletin, 135, 50–68, 2009b]. Specifically, we hypothesized that for stimuli lacking a semantic representation (e.g., nonwords such as mun), maintenance in VWM can be achieved by cycling information back and forth between the stages of phonological encoding and articulatory planning. First, fMRI was used to identify regions associated with two different stages of language production planning: the posterior superior temporal gyrus (pSTG) for phonological encoding (critical for VWM of nonwords) and the middle temporal gyrus (MTG) for lexical–semantic retrieval (not critical for VWM of nonwords). Next, in the same subjects, these regions were targeted with repetitive transcranial magnetic stimulation (rTMS) during language production and VWM task performance. Results showed that rTMS to the pSTG, but not the MTG, increased error rates on paced reading (a language production task) and on delayed serial recall of nonwords (a test of VWM). Performance on a lexical–semantic retrieval task (picture naming), in contrast, was significantly sensitive to rTMS of the MTG. Because rTMS was guided by language production-related activity, these results provide the first causal evidence that maintenance in VWM directly depends on the long-term representations and processes used in speech production.

A Common Neural Substrate for Language Production and Verbal Working Memory

Areas of left perisylvian cortex mediate auditory–verbal short-term memory

The influence of semantic processing on the serial ordering of items in short-term memory was explored using a novel dual-task paradigm. Participants engaged in 2 picture-judgment tasks while simultaneously performing delayed serial recall. List material varied in the presence of phonological overlap (Experiments 1 and 2) and in semantic content (concrete words in Experiment 1 and 3; nonwords in Experiments 2 and 3). Picture judgments varied in the extent to which they required accessing visual semantic information (i.e., semantic categorization and line orientation judgments). Results showed that, relative to line-orientation judgments, engaging in semantic categorization judgments increased the proportion of item-ordering errors for concrete lists but did not affect error proportions for nonword lists. Furthermore, although more ordering errors were observed for phonologically similar relative to dissimilar lists, no interactions were observed between the phonological overlap and picture-judgment task manipulations. These results demonstrate that lexical-semantic representations can affect the serial ordering of items in short-term memory. Furthermore, the dual-task paradigm provides a new method for examining when and how semantic representations affect memory performance.

The effect of concurrent semantic categorization on delayed serial recall.

Disrupted TMS-evoked response in the thalamus of patients with schizophrenia as measured with fMRI

Studies exploring the role of neural oscillations in cognition have revealed sustained increases in alpha-band (~8–14 Hz) power during the delay period of delayed-recognition short-term memory tasks. These increases have been proposed to reflect the inhibition, for example, of cortical areas representing task-irrelevant information, or of potentially interfering representations from previous trials. Another possibility, however, is that elevated delay-period alpha-band power (DPABP) reflects the selection and maintenance of information, rather than, or in addition to, the inhibition of task-irrelevant information. In the present study, we explored these possibilities using a delayed-recognition paradigm in which the presence and task relevance of shape information was systematically manipulated across trial blocks and electroencephalographic was used to measure alpha-band power. In the first trial block, participants remembered locations marked by identical black circles. The second block featured the same instructions, but locations were marked by unique shapes. The third block featured the same stimulus presentation as the second, but with pretrial instructions indicating, on a trial-by-trial basis, whether memory for shape or location was required, the other dimension being irrelevant. In the final block, participants remembered the unique pairing of shape and location for each stimulus. Results revealed minimal DPABP in each of the location-memory conditions, whether locations were marked with identical circles or with unique task-irrelevant shapes. In contrast, alpha-band power increases were observed in both the shape-memory condition, in which location was task irrelevant, and in the critical final condition, in which both shape and location were task relevant. These results provide support for the proposal that alpha-band oscillations reflect the retention of shape information and/or shape–location associations in short-term memory.

Increased Alpha-Band Power during the Retention of Shapes and Shape-Location Associations in Visual Short-Term Memory

Brain responses evoked by high-frequency repetitive transcranial magnetic stimulation: An event-related potential study

Although phonological representations have been a primary focus of verbal working memory research, lexical-semantic manipulations also influence performance. In the present study, the authors investigated whether a classic phenomenon in verbal working memory, the phonological similarity effect (PSE), is modulated by a lexical-semantic variable, word concreteness. Phonological overlap and concreteness were factorially manipulated in each of four experiments across which presentation modality (Experiments 1 and 2: visual presentation; Experiments 3 and 4: auditory presentation) and concurrent articulation (present in Experiments 2 and 4) were manipulated. In addition to main effects of each variable, results show a Phonological Overlap x Concreteness interaction whereby the magnitude of the PSE is greater for concrete word lists relative to abstract word lists. This effect is driven by superior item memory for nonoverlapping, concrete lists and is robust to the modality of presentation and concurrent articulation. These results demonstrate that in verbal working memory tasks, there are multiple routes to the phonological form of a word and that maintenance and retrieval occur over more than just a phonological level. (PsycINFO Database Record (c) 2009 APA, all rights reserved).

The interaction of concreteness and phonological similarity in verbal working memory.

Left inferior frontal gyrus (IFG) is a critical neural substrate for the resolution of proactive interference (PI) in working memory. We hypothesized that left IFG achieves this by controlling the influence of familiarity- versus recollection-based information about memory probes. Consistent with this idea, we observed evidence for an early (200 msec)-peaking signal corresponding to memory probe familiarity and a late (500 msec)-resolving signal corresponding to full accrual of trial-related contextual (“recollection-based”) information. Next, we applied brief trains of repetitive transcranial magnetic stimulation (rTMS) time locked to these mnemonic signals, to left IFG and to a control region. Only early rTMS of left IFG produced a modulation of the false alarm rate for high-PI probes. Additionally, the magnitude of this effect was predicted by individual differences in susceptibility to PI. These results suggest that left IFG-based control may bias the influence of familiarity- and recollection-based signals on recognition decisions.

Prefrontal Control of Familiarity and Recollection in Working Memory

Does High-Frequency Repetitive Transcranial Magnetic Stimulation Produce Residual and/or Cumulative Effects Within an Experimental Session?

A governing assumption about repetitive transcranial magnetic stimulation (rTMS) has been that it interferes with task-related neuronal activity – in effect, by “injecting noise” into the brain – and thereby disrupts behavior. Recent reports of rTMS-produced behavioral enhancement, however, call this assumption into question. We investigated the neurophysiological effects of rTMS delivered during the delay period of a visual working memory task by simultaneously recording brain activity with electroencephalography (EEG). Subjects performed visual working memory for locations or for shapes, and in half the trials a 10-Hz train of rTMS was delivered to the superior parietal lobule (SPL) or a control brain area. The wide range of individual differences in the effects of rTMS on task accuracy, from improvement to impairment, was predicted by individual differences in the effect of rTMS on power in the alpha-band of the EEG (∼10 Hz): a decrease in alpha-band power corresponded to improved performance, whereas an increase in alpha-band power corresponded to the opposite. The EEG effect was localized to cortical sources encompassing the frontal eye fields and the intraparietal sulcus, and was specific to task (location, but not object memory) and to rTMS target (SPL, not control area). Furthermore, for the same task condition, rTMS-induced changes in cross-frequency phase synchrony between alpha- and gamma-band (>40 Hz) oscillations predicted changes in behavior. These results suggest that alpha-band oscillations play an active role cognitive processes and do not simply reflect absence of processing. Furthermore, this study shows that the complex effects of rTMS on behavior can result from biasing endogenous patterns of network-level oscillations.

Repetitive Transcranial Magnetic Stimulation Affects behavior by Biasing Endogenous Cortical Oscillations

Background: Many recent studies have employed repetitive transcranial magnetic stimulation (rTMS) to study brain-behavior relationships. However, the pulse-to-pulse neural effects of rapid delivery of multiple TMS pulses are unknown largely because of TMS-evoked electrical artifacts limiting recording of brain activity. Objective: In this study, TMS-related artifacts were removed with independent component analysis (ICA), which allowed for the investigation of the neurophysiological effects of rTMS with simultaneous electroencephalographic (EEG) recordings. Methods: 10-Hz, 3-sec rTMS trains (110% of motor threshold) were delivered to the postcentral gyrus and superior parietal lobule in 16 young adults. Simultaneous EEG recordings were made with a TMS-compatible system. The stereotypical pattern of TMS-related electrical artifacts was identified by ICA. Results: Removal of artifacts allowed for identification of a series of five evoked brain potentials occurring within 100 ms of each TMS pulse. With the exception of the first potential, for both areas targeted, there was a quadratic relationship between potential peak amplitude and pulse number within the TMS train. This was characterized by a decrease followed by a rise in amplitude. Conclusions: ICA is an effective method for removal of TMS-evoked electrical artifacts in EEG data. With the use of this procedure we found that the physiological responses to rTMS-evoked potentials, 3 TMS pulses delivered in a high-frequency train of pulses are not independent. The sensitivity of the magnitude of these responses to recent stimulation history suggests a complex recruitment of multiple neuronal events with different temporal dynamics. rTMS-evoked potentials, 4

Brain responses evoked by high-frequency repetitive TMS : An ERP study

In recent years, theoretical perspectives on posterior parietal function have evolved beyond the traditional visuospatial processing models to include more diverse cognitive operations, such as long-term and working memory. However, definitive neuropsychological evidence supporting the superior parietal lobule's purported role in working memory has been lacking. Here, we studied human brain lesion patients to determine whether the superior parietal lobule is indeed necessary for working memory. We assessed a wide range of memory functions in three participant groups: superior parietal lesions (n = 19), lesions not involving superior parietal cortex (n = 146), and no brain lesions (n = 55). Superior parietal damage was reliably associated with deficits on tests involving the manipulation and rearrangement of information in working memory, but not on working memory tests requiring only rehearsal and retrieval processes, nor on tests of long-term memory. These results indicate that superior parietal cortex is critically important for the manipulation of information in working memory.

Superior Parietal Cortex Is Critical for the Manipulation of Information in Working Memory

Evaluating the role of prefrontal and parietal cortices in memory-guided response with repetitive transcranial magnetic stimulation

5 seconds 2 sconds Prodcedure: On 90% of trials, one of the directions selected from three orientations (7°, 127°, 247°) Non-target and catch-trial directions selected randomly Perform 180 trials balanced for load x direction x probe order fMRI Scanning Parameters: Gradient-echo, echo-planar pulse sequence (2 s TR, 25 ms TE) acquired with a whole-brain 64 x 64 matrix (39 sagital slices, 3.5 mm isotropic) Analysis: Behavioral performance assessed using 3-component model (Bays et al., 2009) Univariate GLM used to identify parametric sampleand delay-evoked activity MVPC performed using using L2-regularized logistic regression Training of classifiers for direction and load performed on one volume (late delay or ITI [control]), then swept across remainder of time series Evidence, taken from the classifier estimate (from 0 to 1) that the pattern of BOLD activity matched the category (e.g., direction), used to index performance How is information retained in STM? Traditionally, load-sensitivity of (univariate) signal intensity, often observed in intraparietal sulcus (IPS) and prefrontal cortex (PFC), has been taken as a hallmark of STM storage. Multivariate patternclassification (MVPC), however, indicates that information can be decoded during the delay from areas supporting sensory encoding (e.g., in extrastriate cortex; Harrison & Tong, 2009). Here, we address this discrepancy by applying MVPC to fMRI data from a task manipulating STM load.

The Representation of Stimulus Identity for Multiple Items in STM Revealed Using fMRI Classificaiton

Assessment of long-term, within-session effects of high-frequency repetitive transcranial magnetic stimulation on a cognitive task

This study describes a functional magnetic resonance imaging study of humans engaged in long-term memory (LTM) and working memory tasks. A pattern classifier learned to identify patterns of brain activity associated with viewing and making judgments about three categories of pictures (famous people, famous locations, and common objects). The evaluation of these stimuli relied on perception and long-term semantic and/or episodic memories. We investigated whether this classifier could successfully decode brain activity from a subsequent delayed paired-associate recognition working memory task that required the short-term retention of the same stimuli. We reasoned that the LTM-trained classifier would be able to decode delay-period activity only if that activity reflected, to some extent, the temporary activation of LTM. Our results demonstrated successful decoding: delay-period activity from a distributed network of brain regions matched learned patterns of activity for task-relevant stimuli to a greater extent than for task-irrelevant stimuli. In varying degrees throughout the delay, activity reflected the target (a retrospective code) and its associate (a prospective code) with considerable variability among subjects. Although prefrontal cortex (PFC) demonstrated category-specific patterns of activity during the LTM task, these patterns were not reinstated in PFC during the working memory task. We conclude that the short-term retention of information can be supported by the temporary reactivation of LTM representations.

Temporary Activation of Long-Term Memory Supports Working Memory

Evaluating frontal and parietal contributions to spatial working memory with repetitive transcranial magnetic stimulation

NEUROSCIENCE, PSYCHOLOGICAL AND COGNITIVE SCIENCES Correction for “Top-down control of the phase of alpha-band oscillations as a mechanism for temporal prediction,” by Jason Samaha, Phoebe Bauer, Sawyer Cimaroli, and Bradley R. Postle, which appeared in issue 27, July 7, 2015, of Proc Natl Acad Sci USA (112:8439–8444; first published June 22, 2015; 10.1073/ pnas.1503686112). The authors note that on page 8442, right column, second full paragraph, line 18, “(30)” should instead appear as “(29);” in the same paragraph, line 22, “(reviewed in 31)” should instead appear as “(reviewed in 30);” on the same page, third full paragraph, line 6, “(32)” should instead appear as “(31);” in the same paragraph, line 9, “[as did Bonnefond et al. (30)]” should instead appear as “[as did Bonnefond et al. (29)];” and on page 8443, left column, first full paragraph, line 7, “(32)” should instead appear as “(33).”

Localization of load sensitivity of working memory storage: Quantitatively and qualitatively discrepant results yielded by single-subject and group-averaged approaches to fMRI group analysis

Context-dependent interpretation of words: Evidence for interactive neural processes

Systems models hold working memory to depend on specialized, domain-specific storage buffers. Here, however, we demonstrate that short-term retention of the identity or location of visually presented stimuli is disrupted by nonvisual secondary tasks performed in the dark-passive listening to nouns or endogenous generation of saccades, respectively. This indicates that the short-term retention of visual information relies on multiple mental codes, some of them nonvisual. Event-related functional magnetic resonance imaging (fMRI) reveals the neural correlates of these interference effects to be more complex and more regionally specific than previously described. Although nonspecific dual-task effects produce a generalized decrease of task-evoked fMRI response across many brain regions, the interference-specific effect is a relative increase of activity localized to regions associated with the secondary task in question: left hemisphere perisylvian cortex in the case of passive listening distraction and frontal oculomotor regions in the case of saccadic distraction. Within these regions, the neural interference effects are specific to voxels that show delay-period activity on unfilled memory trials. They also predict individual differences in the magnitude of the behavioral interference effect. These results indicate that nonvisual processes supported by nonvisual brain areas contribute importantly to "visual" working memory performance.

Nonvisual codes and nonvisual brain areas support visual working memory.

For more than 50 years, psychologists and neuroscientists have recognized the importance of a working memory to coordinate processing when multiple goals are active and to guide behavior with information that is not present in the immediate environment. In recent years, psychological theory and cognitive neuroscience data have converged on the idea that information is encoded into working memory by allocating attention to internal representations, whether semantic long-term memory (e.g., letters, digits, words), sensory, or motoric. Thus, information-based multivariate analyses of human functional MRI data typically find evidence for the temporary representation of stimuli in regions that also process this information in nonworking memory contexts. The prefrontal cortex (PFC), on the other hand, exerts control over behavior by biasing the salience of mnemonic representations and adjudicating among competing, context-dependent rules. The "control of the controller" emerges from a complex interplay between PFC and striatal circuits and ascending dopaminergic neuromodulatory signals.

Corrigendum to “Localization of load sensitivity of working memory storage: Quantitatively and qualitatively discrepant results yielded by single-subject and group-averaged approaches to fMRI group analysis” [NeuroImage 35 (2007) 881–903]

What are the precise brain regions supporting the short-term retention of verbal information? A previous functional magnetic resonance imaging (fMRI) study suggested that they may be topographically variable across individuals, occurring, in most, in regions posterior to prefrontal cortex (PFC), and that detection of these regions may be best suited to a single-subject (SS) approach to fMRI analysis (Feredoes and Postle, 2007). In contrast, other studies using spatially normalized group-averaged (SNGA) analyses have localized storage-related activity to PFC. To evaluate the necessity of the regions identified by these two methods, we applied repetitive transcranial magnetic stimulation (rTMS) to SS- and SNGA-identified regions throughout the retention period of a delayed letter-recognition task. Results indicated that rTMS targeting SS analysis-identified regions of left perisylvian and sensorimotor cortex impaired performance, whereas rTMS targeting the SNGA-identified region of left caudal PFC had no effect on performance. Our results support the view that the short-term retention of verbal information can be supported by regions associated with acoustic, lexical, phonological, and speech-based representation of information. They also suggest that the brain bases of some cognitive functions may be better detected by SS than by SNGA approaches to fMRI data analysis.

The Neural Bases of the Short-Term Storage of Verbal Information Are Anatomically Variable across Individuals

Distraction-spanning sustained activity during delayed recognition of locations

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verbal working memory Direct evidence for a prefrontal contribution to the control of proactive interference in

Understanding the contributions of the prefrontal cortex (PFC) to working memory is central to understanding the neural bases of high-level cognition. One question that remains controversial is whether the same areas of the dorsolateral PFC (dlPFC) that participate in the manipulation of information in working memory also contribute to its short-term retention (STR). We evaluated this question by first identifying, with functional magnetic resonance imaging (fMRI), brain areas involved in manipulation. Next, these areas were targeted with repetitive transcranial magnetic stimulation (rTMS) while subjects performed tasks requiring only the STR or the STR plus manipulation of information in working memory. fMRI indicated that manipulation-related activity was independent of retention-related activity in both the PFC and superior parietal lobule (SPL). rTMS, however, yielded a different pattern of results. Although rTMS of the dlPFC selectively disrupted manipulation, rTMS of the SPL disrupted manipulation and STR to the same extent. rTMS of the postcentral gyrus (a control region) had no effect on performance. The implications of these results are twofold. In the PFC, they are consistent with the view that this region contributes more importantly to the control of information in working memory than to its STR. In the SPL, they illustrate the importance of supplementing the fundamentally correlational data from neuroimaging with a disruptive method, which affords stronger inference about structure-function relations.

Repetitive Transcranial Magnetic Stimulation Dissociates Working Memory Manipulation from Retention Functions in the Prefrontal, but not Posterior Parietal, Cortex

Controlling the effects of proactive interference (PI), the deleterious effect of prior mental activity on current memory representations, is believed to be a key function of the prefrontal cortex. This view is supported by neuroimaging evidence for a correlation between the longer reaction times caused by high PI conditions of a working memory task and increased activity in left inferior frontal gyrus (IFG) of the prefrontal cortex. An alternative that has never been ruled out, however, is that this left IFG effect may merely reflect sensitivity to such nonspecific factors as difficulty and/or time on task. To resolve this confound, we applied the interference methodology of repetitive transcranial magnetic stimulation (rTMS) to the left IFG and two control regions while subjects performed delayed letter recognition. rTMS was guided with high-resolution magnetic resonance images and was time-locked to the onset of the memory probe. The effect of rTMS, a disruption of accuracy restricted to high-PI probes, was specific to the left IFG. These results demonstrate that unpredictable, phasic disruption of the left IFG selectively disrupts control of responses to high-conflict verbal working memory probes, and they conclusively reject nonspecific alternative accounts.

Direct evidence for a prefrontal contribution to the control of proactive interference in verbal working memory

In the late 1970s/early 1980s, Baddeley and colleagues conducted a series of experiments investigating the role of eye movements in visual working memory. Although only described briefly in a book (Baddeley, 1986), these studies have influenced a remarkable number of empirical and theoretical developments in fields ranging from experimental psychology to human neuropsychology to nonhuman primate electrophysiology. This paper presents, in full detail, three critical studies from this series, together with a recently performed study that includes a level of eye movement measurement and control that was not available for the older studies. Together, the results demonstrate several facts about the sensitivity of visuospatial working memory to eye movements. First, it is eye movement control, not movement per se, that produces the disruptive effects. Second, these effects are limited to working memory for locations and do not generalize to visual working memory for shapes. Third, they can be isolated to the storage/maintenance components of working memory (e.g., to the delay period of the delayed-recognition task). These facts have important implications for models of visual working memory.

The selective disruption of spatial working memory by eye movements

Although the prefrontal cortex (PFC) is consistently found to be associated with various working memory processes, the necessity of the PFC for such processes remains unclear. To elucidate PFC contributions to storage and rehearsal/maintenance processes engaged during verbal working memory function, we assessed behavior of patients with lesions to the left or right lateral PFC, and neural activity of healthy young subjects during fMRI scanning, during performance of working memory tasks. We found that PFC lesions did not affect storage processes—which is consistent with the notion that posterior cortical networks can support simple retention of information. We also found that PFC lesions did not affect rehearsal/maintenance processes, which was in contrast to our finding that healthy subjects performing a verbal delayed recognition task showed bilateral PFC activation. These combined imaging and behavioral data suggest that working memory rehearsal/maintenance processes may depend on both hemispheres, which may have implications for recovery of function and development of rehabilitation therapies after frontal injury. (JINS, 2006, 12, 248–260.)

Is the Prefrontal Cortex Necessary for Delay Task Performance? Evidence from Lesion and fMRI Data

The prefrontal cortex (PFC) contributes to working memory functions via executive control processes that do not entail the storage, per se, of mnemonic representations. One of these control processes may be a sensory gating mechanism that facilitates retention of representations in working memory by down-regulating the gain of the sensory processing of intervening irrelevant stimuli. This idea was tested by scanning healthy young adults with functional magnetic resonance imaging while they performed a delayed face-recognition task. The 2 2 factorial design varied the factors of Memory (present, absent) and Distraction (present, absent). During memory-present trials, target and probe stimuli were individual gray-scale male faces. Memory-absent trials were identical, except that they employed the same recurring female faces (denoting a no memory trial). Distraction-present trials featured rapid serial visual presentation of bespectacled male faces during the two middle seconds of the delay. The first step of the analyses identified dorsolateral PFC (dlPFC) and inferior occipitotemporal cortex (IOTC) voxels exhibiting delay-period activity in memory-present/distraction-absent trials, that is, the unfilled delay. Within these voxels, distraction-evoked activity in the dlPFC was markedly higher during trials that required the concurrent short-term retention of information than on those that did not, whereas the opposite effect was seen in the IOTC. These results are consistent with the view that processes related to sensory gating account for a portion of the delay-period activity that is routinely observed in the dlPFC.

Delay-period Activity in the Prefrontal Cortex: One Function Is Sensory Gating

The conclusion drawn by Slotnick (2005), that the “timecourse analysis” employed in his reanalysis of data from Postle, Berger, Taich, and D’Esposito (2000a) yields evidence consistent with a labeled line model of the functional organisation of frontal cortex, can not be supported with the analyses that he describes. This is because his method does not take into account the temporal dependencies of the theoretically discrete processes engaged by the behavioural task that produced the data. That Slotnick’s analysis may not be appropriate for a reanalysis of the data from Postle et al. (2000a) is foreshadowed by his statement in the Introduction, that fMRI time courses “are analogous to event-related potential scalp voltage timecourses” (Slotnick, 2005, p. 908). This would seem to overlook a critical difference between the two; the latter arises directly from neural activity whereas the former is a lowpass-filtered (i.e., “smeared out”) transform of this activity. One consequence of this difference is that simply plucking a time point from an fMRI time course does not yield a “clean,” or “process-pure” datum. Rather, it yields an observation whose value reflects an uneven integration across neural events that occurred during the 10-to-20 s preceding the time point in question. (This is because, even though the modal haemodynamic response function [HRF] peaks at between 4 and 6 s, it takes an additional 10 s or more for it to finally return to baseline.) This aspect of fMRI data means that the approach used by Slotnick will only yield interpretable results if the two time points being contrasted are each preceded by precisely the same events. (In such a case, the variance attributable to these preceding events would be expected to cancel out.) This requirement was not met in Slotnick’s reanalysis of the Postle et al. (2000a) data. The Postle et al. (2000a) task comprised four trial types—free saccades, guided saccades, forward memory, and reordered memory—each featuring the same multi-epoch structure (as reviewed by Slotnick, 2005). This is a task in which each epoch is temporally dependent on the others (i.e., preliminary instructions always precede encoding/saccades, which always precede delay/fixation, etc.), and as such is not amenable to, for example, the linear deconvolution approach employed with “fast” event-related analysis methods. Nor is it amenable to the analysis to which Slotnick submits it. This is because his analysis does not take into account the fact that the signal intensity value of the “2-D saccade” time point that he selects for his analysis also incorporates variance deriving from the ITI and preliminary instructions epochs that precede it— epochs during which relatively little activity would be expected—whereas the “working memory” time point that he selects is confounded with variance deriving from the encoding/saccades epoch

Analysis of fMRI data from tasks containing temporal dependencies: An evaluation of Slotnick (2005)

Effects of verbal and nonverbal interference on spatial and object visual working memory

Prefrontal cortex and the mediation of proactive interference in working memory

In this course we will consider issues and data associated with many of the central ideas in this field. Our readings and discussion will reach from decades-old foundational papers to reports that appeared this past summer.

The where and how of attention-based rehearsal in spatial working memory.

The neural bases of the effects of item-nonspecific proactive interference in working memory

Spatial working memory activity of the caudate nucleus is sensitive to frame of reference

or at least diminishing puzzles about intentionality and representation, and it is for perhaps this reason that so much philosophical attention has recently focused on the problem of consciousness. Lloyd’s (2002) study suggests an approach to consciousness that, to our knowledge, marks a promising departure from the status quo. In the first place, Lloyd takes seriously work in phenomenology with which most philosophers in the analytic tradition are unfamiliar. This, by itself, is no reason to endorse such work, but if, as Lloyd suggests, phenomenology might be usefully integrated with functional brain imaging, then it is time for the analytic philosopher to think more carefully about phenomenological investigations of consciousness. Perhaps even more significantly, Lloyd’s work gives the philosopher, whether of phenomenological or analytical bent, a working example of how philosophical speculations about consciousness might usefully be married to functional brain imaging.

The role of lateral prefrontal cortex in working memory: evidence from event-related fMRI studies

Behavioral and neurophysiological correlates of episodic coding, proactive interference, and list length effects in a running span verbal working memory task

We examined, with event-related fMRI, two hypotheses about the organization of human working memory function in frontal cortex: (1) that a region immediately anterior to the frontal eye fields (FEF) (superior frontal cortex, SFC) is specialized for spatial working memory (Courtney, et al., 1998); and (2) that dorsolateral prefrontal cortex (PFC) plays a privileged role in the manipulation of spatial stimuli held in working memory (Owen, et al., 1996; Petrides 1994). Our delayed-response task featured 2-D arrays of irregularly arranged squares that were highlighted serially in a random sequence. The Forward Memory condition required maintenance of the spatio-temporal sequence, the Manipulate Memory condition required reordering this sequence into a new spatially defined order, the Guided Saccade condition required saccades to highlighted squares in the array, but no memory, and the Free Saccade condition required self-paced, horizontal saccades. The comparison of fMRI signal intensity associated with 2-D saccade generation (Guided Saccades) versus fMRI signal intensity associated with the delay period of the working memorials condition revealed no evidence for greater working memory-related activity than saccade-related activity in SFC in any individual subject, nor at the level of the group, and greater 2-D saccade than delay-period activity in three of five subjects. These results fail to support the hypothesis that spatial working memory-related activity is represented preferentially in a region of SFC anterior to the FEF (Courtney, et al., 1998). The comparison of maintenance versus manipulation of spatio-temporal information in working memory revealed significantly greater activity associated with the latter in dorsolateral PFC, but not in ventrolateral PFC or in SFC. These results suggest that the delay-related function of SFC is limited to the maintenance of spatial information, and that this region does not support the nonmnemonic executive control functions supported by dorsolateral PFC. These results also indicate that the preferential recruitment of dorsolateral PFC for the manipulation of information held in working memory applies to tasks employing spatial stimuli, as well as to tasks employing verbal stimuli (D'Esposito, et al., 1999); Petrides et al., 1993; Postle et al., 1999).

Activity in Human Frontal Cortex Associated with Spatial Working Memory and Saccadic Behavior

Prefrontal cortical contributions to working memory: evidence from event-related fMRI studies

Evaluating models of the topographical organization of working memory function in frontal cortex with event-related fMRI

The experiments presented in this report were designed to test the hypothesis that visual working memory for spatial stimuli and for object stimuli recruits separate neuronal networks in prefrontal cortex. We acquired BOLD fMRI data from subjects while they compared each serially presented stimulus to the one that had appeared two or three stimuli previously. Three experiments failed to reject the null hypothesis that prefrontal cortical activity associated with spatial working memory performance cannot be dissociated from prefrontal cortical activity associated with nonspatial working memory performance. Polymodal regions of parietal cortex (inferior and superior parietal lobules), as well as cortex surrounding the superior frontal sulcus (and encompassing the frontal eye fields), also demonstrated equivalent levels of activation in the spatial and object conditions. Posterior cortical regions associated with the ventral visual processing stream (portions of lingual, fusiform, and inferior temporal gyri), however, demonstrated greater object than spatial working memory-related activity, particularly when stimuli varied only along spatial or featural dimensions. These experiments, representing fMRI studies of spatial and object working memory in which the testing procedure and the stimuli were identical in the two conditions, suggest that domain-specific visual working memory processing may be mediated by posterior regions associated with domain-specific sensory processing.

An fMRI Investigation of Cortical Contributions to Spatial and Nonspatial Visual Working Memory

Using event-related fMRI to assess delay-period activity during performance of spatial and nonspatial working memory tasks.

Manipulation of familiarity reveals a necessary lexical component of the word-stem completion priming effect

Behavioral studies indicate that spatial and object working memory are computed by dissociable subsystems. We investigated the neural bases of this dissociation with a whole-brain fMRI design and analysis technique that permitted direct assessment of delay-period activity, uncontaminated by other components of the trial. The task employed a "what"-then-"where" design, with an object and a spatial delay period incorporated in each trial; within-trial order of delay conditions was balanced across each scan. Our experiment failed to find evidence, at the single-subject level and at the group level, for anatomical segregation of spatial and object working memory function in the frontal cortex. Delay-period activity in the caudate nucleus revealed a sensitivity to position in the trial in the spatial, but not the object, condition. In posterior regions, spatial delay-period activity was associated with preferential recruitment of extrastriate areas falling within Brodmann's area 19 and, less reliably, the superior parietal lobule. Object-specific delay-period activity was found predominantly in ventral regions of the posterior cortex and demonstrated more topographic variability across subjects than did spatial working memory activity.

"What"-Then-Where" in visual working memory: an event-related fMRI study.

Behavioral studies indicate that spatial and object working memory are computed by dissociable subsystems. We investigated the neural bases of this dissociation with a whole-brain fMRI design and analysis technique that permitted direct assessment of delay-period activity, uncontaminated by other components of the trial. The task employed a what-then-where design, with an object and a spatial delay period incorporated in each trial; within-trial order of delay conditions was balanced across each scan. Our experiment failed to find evidence, at the single-subject level and at the group level, for anatomical segregation of spatial and object working memory function in the frontal cortex. Delay-period activity in the caudate nucleus revealed a sensitivity to position in the trial in the spatial, but not the object, condition. In posterior regions, spatial delay-period activity was associated with preferential recruitment of extrastriate areas falling within Brodmann's area 19 and, less reliably, the superior parietal lobule. Object-specific delay-period activity was found predominantly in ventral regions of the posterior cortex and demonstrated more topographic variability across subjects than did spatial working memory activity.

WhatThenWhere in Visual Working Memory: An Event-Related fMRI Study

We used event-related functional MRI to investigate the neural bases of two categories of mental processes believed to contribute to performance of an alphabetization working memory task: memory storage and memory manipulation. Our delayed-response tasks required memory for the identity and position-in-the-display of items in two- or five-letter memory sets (to identify load-sensitive regions) or memory for the identity and relative position-in-the-alphabet of items in five-letter memory sets (to identify manipulation-sensitive regions). Results revealed voxels in the left perisylvian cortex of five of five subjects showing load sensitivity (as contrasted with alphabetization-sensitive voxels in this region in only one subject) and voxels of dorsolateral prefrontal cortex in all subjects showing alphabetization sensitivity (as contrasted with load-sensitive voxels in this region in two subjects). This double dissociation was reliable at the group level. These data are consistent with the hypothesis that the nonmnemonic executive control processes that can contribute to working memory function are primarily prefrontal cortex-mediated whereas mnemonic processes necessary for working memory storage are primarily posteriorly mediated. More broadly, they support the view that working memory is a faculty that arises from the coordinated interaction of computationally and neuroanatomically dissociable processes.

Functional neuroanatomical double dissociation of mnemonic and executive control processes contributing to working memory performance.

Research on the prefrontal cortex (PFC) of monkeys and humans indicates that this region supports a heterogeneous repertoire of mental processes that contribute to many complex behaviors, such as working memory. Anatomical evidence for some of these processes derives from functional neuroimaging experiments using blocked experimental designs, which average signal across all components of many trials and therefore cannot dissociate distinct processes with different time courses. Using event-related functional MRI, we were able to isolate temporally the neural correlates of processes contributing to the target presentation, delay, and probe portions of an item-recognition task. Two types of trials were of greatest interest: those with Recent Negative probes that matched an item from the target set of the previous, but not the present, two trials, and those with Nonrecent Negative probes that did not match a target item from either the present or the two previous trials. There was no difference between the two trial types in target presentation (i.e., encoding) or delay-period (i.e., active maintenance) PFC activation, but there was significantly greater activation for Recent Negatives than Nonrecent Negative activation associated with the probe period within left ventrolateral PFC. These findings characterize spatially and temporally a proactive interference effect that may reflect the operation of a PFC-mediated response-inhibition mechanism that contributes to working memory performance.

The neural substrate and temporal dynamics of interference effects in working memory as revealed by event-related functional MRI.

An evaluation of the concurrent discrimination task as a measure of habit learning: performance of amnesic subjects

One model of the functional organization of lateral prefrontal cortex (PFC) in primates posits that this region is organized in a dorsal/ventral fashion subserving spatial and object working memory, respectively. Alternatively, it has been proposed that a dorsal/ventral subdivision of lateral PFC instead reflects the type of processing performed upon information held in working memory. We tested this hypothesis using an event-related fMRI method that can discriminate among functional changes occurring during temporally separated behavioral subcomponents of a single trial. Subjects performed a delayed-response task with two types of trials in which they were required to: (1) retain a sequence of letters across the delay period (maintenance) or (2) reorder the sequence into alphabetical order across the delay period (manipulation). In each subject, activity during the delay period was found in both dorsolateral and ventrolateral PFC in both types of trials. However, dorsolateral PFC activity was greater in manipulation trials. These findings are consistent with the processing model of the functional organization of working memory in PFC.

Maintenance versus Manipulation of Information Held in Working Memory: An Event-Related fMRI Study

Dissociation of human caudate nucleus activity in spatial and nonspatial working memory: an event-related fMRI study.

The dependence of span and delayed-response performance on prefrontal cortex

Impaired word-stem completion priming but intact perceptual identification priming with novel words: evidence from the amnesic patient H.M.

The time course of spatial and object learning in Parkinson's disease

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 1997.

The cognitive mechanisms and neural substrates underlying repetition priming

The authors hypothesized that the pathophysiology of early Parkinson's disease (PD) may selectively target structures that support visual working memory for spatial relations but leave structures that support working memory for featural characteristics of objects relatively intact. Fifteen PD and 15 normal control participants took a visual delayed-response test with a spatial condition and a (nonspatial) object condition, equating the perceptual difficulty of the tests for each participant. The stimuli were irregular polygons presented at different locations on a computer screen. Results revealed a selective impairment of spatial delayed response in PD, indicating a disruption of spatial working memory unconfounded by sensory processing difficulties. The selectivity of this deficit may reflect the circumscribed nature of pathophysiological change affecting the caudate nucleus in early PD.

Spatial, but not object, delayed response is impaired in early Parkinson's disease.

Repetition priming is a kind of implicit memory (learning without awareness) that does not depend on the medial temporal-lobe system. For example, the amnesic patient H.M., who underwent bilateral medial temporal-lobe resection, shows intact priming with novel patterns, suggesting that perceptual priming with nonverbal material does not depend on areas critical for explicit memory. A logical candidate for the neural substrate that supports this kind of priming is the peristriate cortex, an area that is relatively spared in Alzheimer's disease (AD). We therefore predicted that AD subjects would be unimpaired on pattern priming. Subjects copied each of six target figures onto dot patterns. After performing a 3-min distractor task, they were given the same dot patterns (without lines) and asked to draw the first figure that came to mind by connecting the dots with straight lines. Subsequently, in a test of recognition (explicit) memory, subjects viewed each of the six patterns of dots that they had copied previously and were asked to indicate which of four possible completions corresponded to the figure that they had copied 3 min earlier. The AD and control groups achieved comparable priming scores, but AD subjects were significantly impaired in recognizing the patterns explicitly. Our finding of intact pattern priming in AD provides, for the first time, evidence that pattern priming depends on the peristriate cortex.

Intact implicit memory for novel patterns in Alzheimer's disease.

(1995). Eighth Meeting of the International Study Group on the Pharmacology of Memory Disorders Associated with Aging, Zurich, Switzerland. February 17-19, 1995: The Neurobiology of Alzheimer's Disease. Amyloid: Vol. 2, No. 3, pp. 204-212.

Eighth Meeting of the International Study Group on the Pharmacology of Memory Disorders Associated with Aging, Zurich, Switzerland. February 17-19, 1995: The Neurobiology of Alzheimer's Disease

Rontgenographische Untersuchungsmethoden konnen nicht nur zur Charakterisierung technischer kristalliner Zusatzstoffe fur Plaste herangezogen werden. Im Falle der Stabilisatoren zweibasisches Bleistearat und dreibasisches Bleisulfat im PVC wird gezeigt, das man den Abbau dieser Stoffe bei thermischer Beanspruchung des Materials durch Anfertigung von Diffraktogrammen erfassen kann, wobei basische Bleioxichloride als kristalline Zwischenstufen erkennbar werden. Als Endprodukt der Reaktion der Bleistabilisatoren mit dem bei der Spaltung des PVC freigesetzten HCl entsteht Bleichlorid, wobei auch die Umsetzung des Sulfatanteils des dreibasischen Bleisulfats in dieser Verbindung in Betracht gezogen werden mus. Die Intensitaten der Interferenzen des dreibasischen Bleisulfats und des Bleichlorids auf den Rontgendiffraktogrammen gestatten den Abbauzustand des Werkstoffes nach einem mit einer thermischen Beanspruchung verbundenen Verarbeitungsprozes einzuschatzen. Es besteht auch die Moglichkeit, die thermische Stabilitat verschiedener bleistabilisierter PVC-Materialien miteinander zu vergleichen. 
 
Investigation methods of X-ray diffraction cannot only be used for characterizing technical crystalline admixtures of plastic material. In the case of stabilizers „dibasic lead stearate” and „three-basic lead sulphate” in PVC, there has been shown that the degradation of these substances at thermal stress of the material can be illustrated by diffractograms proving basic lead oxichlorides in cristalline intermediate stages. As final product of the reaction of lead stabilizers with HCl liberated when PVC decomposes, lead chloride appears, and in this connection the conversion of the sulphate part of th three-basic lead sulfate in this compound must also be taken into account. The intensities of the interferences of the three-basic lead sulphate and of the lead chloride on the X-ray diffractograms show the degree of degradation of the material after a processing operation due to the thermal stress. There is also the possibility of comparing the thermal stability of various lead stabilized PVC materials.

Röntgenographische Untersuchungen zum Abbau von bleihaltigen Stabilisatoren im PVC

Zur Ermittlung der Lokalkonzentrationen von Ga, Al und As in Ga1−xAlxAs-Epitaxieschichten aus den Rontgenstrahlintensitaten bei der ESMA wurden mehrere Korrekturverfahren uberpruft. Die genauesten Ergebnisse werden durch Kombination der Methode von BIRKS fur die Al-Korrektur mit der Methode nach DUNCUMB/REED/SPRINGER fur die Ga-Korrektur erhalten. Dabei betragt die relative mittlere Abweichung von 50% fur die Summe der Gallium- und Aluminium-Atomprozente nur −0,1%. In einem Anhang werden fur den praktischen Gebrauch erforderliche Gleichungen zur gegenseitigen Umrechnung von Gewichts- und Konzentrationsangaben in dem betrachteten System angegeben. 
 
Several methods of correcting the X-ray intensity in the electron probe microanalysis were examined for getting the local concentrations of Ga, Al and As in Ga1−xAlxAs epitaxial layers. Most correct results were obtained by combining the method of BIRKS for the Al-determination with that of DUNCUMB/REED/SPRINGER for the Ga-determination. In this case the mean departure from 50% for the sum of the Ga and Al atom-percents is only −0.1%. Equations for the mutual conversion of concentrations into masses, necessary for the practical use, are given in an appendix.

Quantitative Bestimmung der Zusammensetzung von Ga1−xAlxAs-Epitaxieschichten mit der Elektronenstrahl-Mikroanalyse (ESMA)†

Vorbeugung angebracht erscheint, daß sich der Täter einer Periode der Disziplin unterzieht (§ 18); es ist nicht mehr erforderlich, vorhergehende Verurteilungen oder verbrecherische Gewohnheiten oder Neigungen festzustellen **). Die Borstal Institutions werden als Plätze bezeichnet, in denen Straffällige von nicht weniger als 16, aber unter 21Jahren untergebracht werden, und wo ihnen eine Erziehung und Belehrung gegeben wird, die zu ihrer Besserung und zur Verhinderung eines Kticfcfailes führt. Die Vorlage von 1938 hatte als Ersatz für Gefängnis noch die Schaffung verschiedener anderer Atistaltstypeto, unter anderen sog. attendance centres, vorgeschlagen*); in der neuen Bill sind diese Vorschläge nicht mehr enthalten. VT. Das gemeinsame Ziel aller Vorschläge dieser Vorlage isit es, zu erreichen, daß die strafrechtliche Reaktion nicht so sehr auf die Tat, sondern auf den Täter) abgestellt wird. Es ist wichtig und lehrreich zu studieren, wie man diese auch in anderen Ländern aufgestellte Forderung in England erreichen will.

Electrical resistance tomography (ERT) can be used to create large-scale soft tactile sensors that are flexible and robust. Good performance requires a fast and accurate mapping from the sensor’s sequential voltage measurements to the distribution of force across its surface. However, particularly with multiple contacts, this task is challenging for both previously developed approaches: physics-based modeling and end-to-end data-driven learning. Some promising results were recently achieved using sim-to-real transfer learning, but estimating multiple contact locations and accurate contact forces remains difficult because simulations tend to be less accurate with a high number of contact locations and/or high force. This paper introduces a modular hybrid method that combines simulation data synthesized from an electromechanical finite element model with real measurements collected from a new ERT-based tactile sensor. We use about 290 000 simulated and 90000 real measurements to train two deep neural networks: the first (Transfer-Net) captures the inevitable gap between simulation and reality, and the second (Recon-Net) reconstructs contact forces from voltage measurements. The number of contacts, contact locations, force magnitudes, and contact diameters are evaluated for a manually collected multi-contact dataset of 150 measurements. Our modular pipeline’s results outperform predictions by both a physics-based model and end-to-end learning. Note to Practitioners–ERT-based tactile sensors use high-speed voltage measurements from electrodes distributed over a piezoresistive area to output a force map that shows where contact is occurring, and how strong each contact is. Such sensors hold promise for giving robots and other devices a sense of touch over large surfaces with low hardware complexity. However, the software problem of converting voltages to an accurate force map has not previously been solved well, requiring either extensive model calibration or extensive contact data collection. This paper suggests a hybrid approach where a straightforward physics model simulates multi-contact experiments that are too costly to acquire in reality and a practical automatic indentation setup acquires real but geometrically limited multi-contact data. Although the number of real measurements required to learn the discrepancy between the sensor and the model is still large due to the inherent inverse nature of ERT-based tactile sensors, our combination of simulation and deep networks achieves better performance than either physical modeling or learning alone. This approach can advance practical large-area tactile sensing for industrial automation systems where multiple contacts occur, such as in manufacturing and assistive robotics. It could also likely be adapted to other nonlinear inverse problems.

Predicting the Force Map of an ERT-Based Tactile Sensor Using Simulation and Deep Networks

The essential ingredient for studying the phenomena of emergence is the ability to generate and manipulate emergent systems that span large scales. Cellular automata are the model class particularly known for their effective scalability but are also typically constrained by fixed local rules. In this paper, we propose a new model class of adaptive cellular automata that allows for the generation of scalable and expressive models. We show how to implement computation-effective adaptation by coupling the update rule of the cellular automaton with itself and the system state in a localized way. To demonstrate the applications of this approach, we implement two different emergent models: a self-organizing Ising model and two types of plastic neural networks, a rate and spiking model. With the Ising model, we show how coupling local/global temperatures to local/global measurements can tune the model to stay in the vicinity of the critical temperature. With the neural models, we reproduce a classical balanced state in large recurrent neuronal networks with excitatory and inhibitory neurons and various plasticity mechanisms. Our study opens multiple directions for studying collective behavior and emergence.

Locally adaptive cellular automata for goal-oriented self-organization

Physics is a field of science that has traditionally used the scientific method to answer questions about why natural phenomena occur and to make testable models that explain the phenomena. Discovering equations, laws and principles that are invariant, robust and causal explanations of the world has been fundamental in physical sciences throughout the centuries. Discoveries emerge from observing the world and, when possible, performing interventional studies in the system under study. With the advent of big data and the use of data-driven methods, causal and equation discovery fields have grown and made progress in computer science, physics, statistics, philosophy, and many applied fields. All these domains are intertwined and can be used to discover causal relations, physical laws, and equations from observational data. This paper reviews the concepts, methods, and relevant works on causal and equation discovery in the broad field of Physics and outlines the most important challenges and promising future lines of research. We also provide a taxonomy for observational causal and equation discovery, point out connections, and showcase a complete set of case studies in Earth and climate sciences, fluid dynamics and mechanics, and the neurosciences. This review demonstrates that discovering fundamental laws and causal relations by observing natural phenomena is being revolutionised with the efficient exploitation of observational data, modern machine learning algorithms and the interaction with domain knowledge. Exciting times are ahead with many challenges and opportunities to improve our understanding of complex systems.

In many applications, learning systems are required to process continuous non-stationary data streams. We study this problem in an online learning framework and propose an algorithm that can deal with adversarial time-varying and nonlinear constraints. As we show in our work, the algorithm called Constraint Violation Velocity Projection (CVV-Pro) achieves $\sqrt{T}$ regret and converges to the feasible set at a rate of $1/\sqrt{T}$, despite the fact that the feasible set is slowly time-varying and a priori unknown to the learner. CVV-Pro only relies on local sparse linear approximations of the feasible set and therefore avoids optimizing over the entire set at each iteration, which is in sharp contrast to projected gradients or Frank-Wolfe methods. We also empirically evaluate our algorithm on two-player games, where the players are subjected to a shared constraint.

Deep learning has recently gained immense popularity in the Earth sciences as it enables us to formulate purely data-driven models of complex Earth system processes. Deep learning-based weather prediction (DLWP) models have made significant progress in the last few years, achieving forecast skills comparable to established numerical weather prediction (NWP) models with comparatively lesser computational costs. In order to train accurate, reliable, and tractable DLWP models with several millions of parameters, the model design needs to incorporate suitable inductive biases that encode structural assumptions about the data and modelled processes. When chosen appropriately, these biases enable faster learning and better generalisation to unseen data. Although inductive biases play a crucial role in successful DLWP models, they are often not stated explicitly and how they contribute to model performance remains unclear. Here, we review and analyse the inductive biases of six state-of-the-art DLWP models, involving a deeper look at five key design elements: input data, forecasting objective, loss components, layered design of the deep learning architectures, and optimisation methods. We show how the design choices made in each of the five design elements relate to structural assumptions. Given recent developments in the broader DL community, we anticipate that the future of DLWP will likely see a wider use of foundation models -- large models pre-trained on big databases with self-supervised learning -- combined with explicit physics-informed inductive biases that allow the models to provide competitive forecasts even at the more challenging subseasonal-to-seasonal scales.

Intelligent interaction with the physical world requires perceptual abilities beyond vision and hearing; vibrant tactile sensing is essential for autonomous robots to dexterously manipulate unfamiliar objects or safely contact humans. Therefore, robotic manipulators need high-resolution touch sensors that are compact, robust, inexpensive, and efficient. The soft vision-based haptic sensor presented herein is a miniaturized and optimized version of the previously published sensor Insight. Minsight has the size and shape of a human fingertip and uses machine learning methods to output high-resolution maps of 3D contact force vectors at 60 Hz. Experiments confirm its excellent sensing performance, with a mean absolute force error of 0.07 N and contact location error of 0.6 mm across its surface area. Minsight's utility is shown in two robotic tasks on a 3-DoF manipulator. First, closed-loop force control enables the robot to track the movements of a human finger based only on tactile data. Second, the informative value of the sensor output is shown by detecting whether a hard lump is embedded within a soft elastomer with an accuracy of 98%. These findings indicate that Minsight can give robots the detailed fingertip touch sensing needed for dexterous manipulation and physical human-robot interaction.

Minsight: A Fingertip-Sized Vision-Based Tactile Sensor for Robotic Manipulation

To characterize the dynamical behavior of many-body quantum systems, one is usually interested in the evolution of so-called order-parameters rather than in characterizing the full quantum state. In many situations, these quantities coincide with the expectation value of local observables, such as the magnetization or the particle density. In experiment, however, these expectation values can only be obtained with a finite degree of accuracy due to the effects of the projection noise. Here, we utilize a machine-learning approach to infer the dynamical generator governing the evolution of local observables in a many-body system from noisy data. To benchmark our method, we consider a variant of the quantum Ising model and generate synthetic experimental data, containing the results of $N$ projective measurements at $M$ sampling points in time, using the time-evolving block-decimation algorithm. As we show, across a wide range of parameters the dynamical generator of local observables can be approximated by a Markovian quantum master equation. Our method is not only useful for extracting effective dynamical generators from many-body systems, but may also be applied for inferring decoherence mechanisms of quantum simulation and computing platforms.

Inferring interpretable dynamical generators of local quantum observables from projective measurements through machine learning

Unsupervised video-based object-centric learning is a promising avenue to learn structured representations from large, unlabeled video collections, but previous approaches have only managed to scale to real-world datasets in restricted domains. Recently, it was shown that the reconstruction of pre-trained self-supervised features leads to object-centric representations on unconstrained real-world image datasets. Building on this approach, we propose a novel way to use such pre-trained features in the form of a temporal feature similarity loss. This loss encodes temporal correlations between image patches and is a natural way to introduce a motion bias for object discovery. We demonstrate that this loss leads to state-of-the-art performance on the challenging synthetic MOVi datasets. When used in combination with the feature reconstruction loss, our model is the first object-centric video model that scales to unconstrained video datasets such as YouTube-VIS.

Object-Centric Learning for Real-World Videos by Predicting Temporal Feature Similarities

Real-world robotic manipulation tasks remain an elusive challenge, since they involve both fine-grained environment interaction, as well as the ability to plan for long-horizon goals. Although deep reinforcement learning (RL) methods have shown encouraging results when planning end-to-end in high-dimensional environments, they remain fundamentally limited by poor sample efficiency due to inefficient exploration, and by the complexity of credit assignment over long horizons. In this work, we present Efficient Learning of High-Level Plans from Play (ELF-P), a framework for robotic learning that bridges motion planning and deep RL to achieve long-horizon complex manipulation tasks. We leverage task-agnostic play data to learn a discrete behavioral prior over object-centric primitives, modeling their feasibility given the current context. We then design a high-level goal-conditioned policy which (1) uses primitives as building blocks to scaffold complex long-horizon tasks and (2) leverages the behavioral prior to accelerate learning. We demonstrate that ELF-P has significantly better sample efficiency than relevant baselines over multiple realistic manipulation tasks and learns policies that can be easily transferred to physical hardware.

Muscle-actuated organisms are capable of learning an unparalleled diversity of dexterous movements despite their vast amount of muscles. Reinforcement learning (RL) on large musculoskeletal models, however, has not been able to show similar performance. We conjecture that ineffective exploration in large overactuated action spaces is a key problem. This is supported by the finding that common exploration noise strategies are inadequate in synthetic examples of overactuated systems. We identify differential extrinsic plasticity (DEP), a method from the domain of self-organization, as being able to induce state-space covering exploration within seconds of interaction. By integrating DEP into RL, we achieve fast learning of reaching and locomotion in musculoskeletal systems, outperforming current approaches in all considered tasks in sample efficiency and robustness.

DEP-RL: Embodied Exploration for Reinforcement Learning in Overactuated and Musculoskeletal Systems

Learning agile skills is one of the main challenges in robotics. To this end, reinforcement learning approaches have achieved impressive results. These methods require explicit task information in terms of a reward function or an expert that can be queried in simulation to provide a target control output, which limits their applicability. In this work, we propose a generative adversarial method for inferring reward functions from partial and potentially physically incompatible demonstrations for successful skill acquirement where reference or expert demonstrations are not easily accessible. Moreover, we show that by using a Wasserstein GAN formulation and transitions from demonstrations with rough and partial information as input, we are able to extract policies that are robust and capable of imitating demonstrated behaviors. Finally, the obtained skills such as a backflip are tested on an agile quadruped robot called Solo 8 and present faithful replication of hand-held human demonstrations.

Learning Agile Skills via Adversarial Imitation of Rough Partial Demonstrations

Full information about a many-body quantum system is usually out-ofreach due to the exponential growth — with the size of the system — of the number of parameters needed to encode its state. Nonetheless, in order to understand the complex phenomenology that can be observed in these systems, it is often sufficient to consider dynamical or stationary properties of local observables or, at most, of fewbody correlation functions. These quantities are typically studied by singling out a specific subsystem of interest and regarding the remainder of the many-body system as an effective bath. In the simplest scenario, the subsystem dynamics, which is in fact an open quantum dynamics, can be approximated through Markovian quantum master equations. Here, we show how the generator of such a dynamics can be efficiently learned by means of a fully interpretable neural network which provides the relevant dynamical parameters for the subsystem of interest. Importantly, the neural network is constructed such that the learned generator implements a physically consistent open quantum time-evolution. We exploit our method to learn the generator of the dynamics of a subsystem of a many-body system subject to a unitary quantum dynamics. We explore the capability of the network to predict the time-evolution of a two-body subsystem and exploit the physical consistency of the generator to make predictions on the stationary state of the subsystem dynamics.

Machine learning Markovian quantum master equations of few-body observables in interacting spin chains

Capturing aleatoric uncertainty is a critical part of many machine learning systems. In deep learning, a common approach to this end is to train a neural network to estimate the parameters of a heteroscedastic Gaussian distribution by maximizing the logarithm of the likelihood function under the observed data. In this work, we examine this approach and identify potential hazards associated with the use of log-likelihood in conjunction with gradient-based optimizers. First, we present a synthetic example illustrating how this approach can lead to very poor but stable parameter estimates. Second, we identify the culprit to be the log-likelihood loss, along with certain conditions that exacerbate the issue. Third, we present an alternative formulation, termed $\beta$-NLL, in which each data point's contribution to the loss is weighted by the $\beta$-exponentiated variance estimate. We show that using an appropriate $\beta$ largely mitigates the issue in our illustrative example. Fourth, we evaluate this approach on a range of domains and tasks and show that it achieves considerable improvements and performs more robustly concerning hyperparameters, both in predictive RMSE and log-likelihood criteria.

On the Pitfalls of Heteroscedastic Uncertainty Estimation with Probabilistic Neural Networks

A soft thumb-sized vision-based sensor with accurate all-round force perception

Variational autoencoders (VAEs) are a popular framework for modeling complex data distributions; they can be efficiently trained via variational inference by maximizing the evidence lower bound (ELBO), at the expense of a gap to the exact (log-)marginal likelihood. While VAEs are commonly used for representation learning, it is unclear why ELBO maximization would yield useful representations, since unregularized maximum likelihood estimation cannot invert the data-generating process. Yet, VAEs often succeed at this task. We seek to elucidate this apparent paradox by studying nonlinear VAEs in the limit of near-deterministic decoders. We first prove that, in this regime, the optimal encoder approximately inverts the decoder -- a commonly used but unproven conjecture -- which we refer to as {\em self-consistency}. Leveraging self-consistency, we show that the ELBO converges to a regularized log-likelihood. This allows VAEs to perform what has recently been termed independent mechanism analysis (IMA): it adds an inductive bias towards decoders with column-orthogonal Jacobians, which helps recovering the true latent factors. The gap between ELBO and log-likelihood is therefore welcome, since it bears unanticipated benefits for nonlinear representation learning. In experiments on synthetic and image data, we show that VAEs uncover the true latent factors when the data generating process satisfies the IMA assumption.

Abstract It has long been hypothesized that operating close to the critical state is beneficial for natural and artificial evolutionary systems. We put this hypothesis to test in a system of evolving foraging agents controlled by neural networks that can adapt the agents’ dynamical regime throughout evolution. Surprisingly, we find that all populations that discover solutions evolve to be subcritical. By a resilience analysis, we find that there are still benefits of starting the evolution in the critical regime. Namely, initially critical agents maintain their fitness level under environmental changes (for example, in the lifespan) and degrade gracefully when their genome is perturbed. At the same time, initially subcritical agents, even when evolved to the same fitness, are often inadequate to withstand the changes in the lifespan and degrade catastrophically with genetic perturbations. Furthermore, we find the optimal distance to criticality depends on the task complexity. To test it we introduce a hard task and a simple task: For the hard task, agents evolve closer to criticality, whereas more subcritical solutions are found for the simple task. We verify that our results are independent of the selected evolutionary mechanisms by testing them on two principally different approaches: a genetic algorithm and an evolutionary strategy. In summary, our study suggests that although optimal behaviour in the simple task is obtained in a subcritical regime, initializing near criticality is important to be efficient at finding optimal solutions for new tasks of unknown complexity.

When to Be Critical? Performance and Evolvability in Different Regimes of Neural Ising Agents

Full information about a many-body quantum system is usually out-of-reach due to the exponential growth—with the size of the system—of the number of parameters needed to encode its state. Nonetheless, in order to understand the complex phenomenology that can be observed in these systems, it is often sufficient to consider dynamical or stationary properties of local observables or, at most, of few-body correlation functions. These quantities are typically studied by singling out a specific subsystem of interest and regarding the remainder of the many-body system as an effective bath. In the simplest scenario, the subsystem dynamics, which is in fact an open quantum dynamics, can be approximated through Markovian quantum master equations. Here, we formulate the problem of finding the generator of the subsystem dynamics as a variational problem, which we solve using the standard toolbox of machine learning for optimization. This dynamical or ‘Lindblad’ generator provides the relevant dynamical parameters for the subsystem of interest. Importantly, the algorithm we develop is constructed such that the learned generator implements a physically consistent open quantum time-evolution. We exploit this to learn the generator of the dynamics of a subsystem of a many-body system subject to a unitary quantum dynamics. We explore the capability of our method to recover the time-evolution of a two-body subsystem and exploit the physical consistency of the generator to make predictions on the stationary state of the subsystem dynamics.

Inferring Markovian quantum master equations of few-body observables in interacting spin chains

Capturing aleatoric uncertainty is a critical part of many machine learning systems. In deep learning, a common approach to this end is to train a neural network to estimate the parameters of a heteroscedastic Gaussian distribution by maximizing the logarithm of the likelihood function under the observed data. In this work, we examine this approach and identify potential hazards associated with the use of log-likelihood in conjunction with gradient-based optimizers. First, we present a synthetic example illustrating how this approach can lead to very poor but stable parameter estimates. Second, we identify the culprit to be the log-likelihood loss, along with certain conditions that exacerbate the issue. Third, we present an alternative formulation, termed β − NLL , in which each data point’s contribution to the loss is weighted by the β -exponentiated variance estimate. We show that using an appropriate β largely mitigates the issue in our illustrative example. Fourth, we evaluate this approach on a range of domains and tasks and show that it achieves considerable improvements and performs more robustly concerning hyperparameters, both in predictive RMSE and log-likelihood criteria.

O N THE P ITFALLS OF H ETEROSCEDASTIC U NCERTAINTY E STIMATION WITH P ROBABILISTIC N EURAL N ETWORKS

Tactile feedback is essential to make robots more agile and effective in unstructured environments. However, high-resolution tactile skins are not widely available; this is due to the large size of robust sensing units and because many units typically lead to fragility in wiring and to high costs. One route toward high-resolution and robust tactile skins involves the embedding of a few sensor units (taxels) into a flexible surface material and the use of signal processing to achieve sensing with superresolution accuracy. Here, we propose a theory for geometric superresolution to guide the development of tactile sensors of this kind and link it to machine learning techniques for signal processing. This theory is based on sensor isolines and allows us to compute the possible force sensitivity and accuracy in contact position and force magnitude as a spatial quantity before building a sensor. We evaluate the influence of different factors, such as elastic properties of the material, structure design, and transduction methods, using finite element simulations and by implementing real sensors. We empirically determine sensor isolines and validate the theory in two custom-built sensors with 1D and 2D measurement surfaces that use barometric units. Using machine learning methods to infer contact information, our sensors obtain an average superresolution factor of over 100 and 1200, respectively. Our theory can guide future tactile sensor designs and inform various design choices. Description We propose a theory using taxel value isolines to guide superresolution tactile sensor design and evaluate it empirically.

Guiding the design of superresolution tactile skins with taxel value isolines theory

Equation learning is a deep learning framework for explainable machine learning in regression settings, with applications in engineering and the natural sciences. Equation learners typically do not capture uncertainty about the model or its predictions, although uncertainty is often highly structured and particularly relevant for these kinds of applications. We show how simple, yet effective forms of Bayesian deep learning can be used to build structure and explainable uncertainty over a set of found equations. Specifically, we use a mixture of Laplace approximations, where each mixture component captures a different equation structure, and the local Laplace approximations capture parametric uncertainty within one family of equations. We present results on both synthetic and real world examples.

Proceedings of the Genetic and Evolutionary Computation Conference Companion

Learning diverse skills is one of the main challenges in robotics. To this end, imitation learning approaches have achieved impressive results. These methods require explicitly labeled datasets or assume consistent skill execution to enable learning and active control of individual behaviors, which limits their applicability. In this work, we propose a cooperative adversarial method for obtaining single versatile policies with controllable skill sets from unlabeled datasets containing diverse state transition patterns by maximizing their discriminability. Moreover, we show that by utilizing unsupervised skill discovery in the generative adversarial imitation learning framework, novel and useful skills emerge with successful task fulfillment. Finally, the obtained versatile policies are tested on an agile quadruped robot called Solo 8 and present faithful replications of diverse skills encoded in the demonstrations.

Versatile Skill Control via Self-supervised Adversarial Imitation of Unlabeled Mixed Motions

Humans are able to outperform robots in terms of robustness, versatility, and learning of new tasks in a wide variety of movements. We hypothesize that highly nonlinear muscle dynamics play a large role in providing inherent stability, which is favorable to learning. While recent advances have been made in applying modern learning techniques to muscle-actuated systems both in simulation as well as in robotics, so far, no detailed analysis has been performed to show the benefits of muscles when learning from scratch. Our study closes this gap and showcases the potential of muscle actuators for core robotics challenges in terms of data-efficiency, hyperparameter sensitivity, and robustness.

Learning with Muscles: Benefits for Data-Efficiency and Robustness in Anthropomorphic Tasks

Humans can make predictions on various time scales and hierarchical levels. Thereby, the learning of event encodings seems to play a crucial role. In this work we model the development of hierarchical predictions via autonomously learned latent event codes. We present a hierarchical recurrent neural network architecture, whose inductive learning biases foster the development of sparsely changing latent state that compress sensorimotor sequences. A higher level network learns to predict the situations in which the latent states tend to change. Using a simulated robotic manipulator, we demonstrate that the system (i) learns latent states that accurately reflect the event structure of the data, (ii) develops meaningful temporal abstract predictions on the higher level, and (iii) generates goal-anticipatory behavior similar to gaze behavior found in eye-tracking studies with infants. The architecture offers a step towards the autonomous learning of compressed hierarchical encodings of gathered experiences and the exploitation of these encodings to generate adaptive behavior.

2022 IEEE International Conference on Development and Learning (ICDL)

Developing hierarchical anticipations via neural network-based event segmentation

Embedding discrete solvers as differentiable layers has given modern deep learning architectures combinatorial expressivity and discrete reasoning capabilities. The derivative of these solvers is zero or undefined, therefore a meaningful replacement is crucial for effective gradient-based learning. Prior works rely on smoothing the solver with input perturbations, relaxing the solver to continuous problems, or interpolating the loss landscape with techniques that typically require additional solver calls, introduce extra hyper-parameters, or compromise performance. We propose a principled approach to exploit the geometry of the discrete solution space to treat the solver as a negative identity on the backward pass and further provide a theoretical justification. Our experiments demonstrate that such a straightforward hyper-parameter-free approach is able to compete with previous more complex methods on numerous experiments such as backpropagation through discrete samplers, deep graph matching, and image retrieval. Furthermore, we substitute the previously proposed problem-specific and label-dependent margin with a generic regularization procedure that prevents cost collapse and increases robustness.

Gradient Backpropagation Through Combinatorial Algorithms: Identity with Projection Works

It has been a long-standing dream to design artificial agents that explore their environment efficiently via intrinsic motivation, similar to how children perform curious free play. Despite recent advances in intrinsically motivated reinforcement learning (RL), sample-efficient exploration in object manipulation scenarios remains a significant challenge as most of the relevant information lies in the sparse agent-object and object-object interactions. In this paper, we propose to use structured world models to incorporate relational inductive biases in the control loop to achieve sample-efficient and interaction-rich exploration in compositional multi-object environments. By planning for future novelty inside structured world models, our method generates free-play behavior that starts to interact with objects early on and develops more complex behavior over time. Instead of using models only to compute intrinsic rewards, as commonly done, our method showcases that the self-reinforcing cycle between good models and good exploration also opens up another avenue: zero-shot generalization to downstream tasks via model-based planning. After the entirely intrinsic task-agnostic exploration phase, our method solves challenging downstream tasks such as stacking, flipping, pick&place, and throwing that generalizes to unseen numbers and arrangements of objects without any additional training.

Curious Exploration via Structured World Models Yields Zero-Shot Object Manipulation

Manual inspection of workpieces in highly flexible production facilities with small lot sizes is costly and less reliable compared to automated inspection systems. Reinforcement Learning (RL) offers promising, intelligent solutions for robotic inspection and manufacturing tasks. This paper presents an RL-based approach to determine a high-quality set of sensor view poses for arbitrary workpieces based on their 3D computer-aided design (CAD). The framework extends available open-source libraries and provides an interface to the Robot Operating System (ROS) for deploying any supported robot and sensor. The integration into commonly used OpenAI Gym and Baselines leads to an expandable and comparable benchmark for RL algorithms. We give a comprehensive overview of related work in the field of view planning and RL. A comparison of different RL algorithms provides a proof of concept for the framework’s functionality in experimental scenarios. The obtained results exhibit a coverage ratio of up to 0.8 illustrating its potential impact and expandability. The project will be made publicly available along with this article.

A Reinforcement Learning Approach to View Planning for Automated Inspection Tasks

Falsification of hybrid systems with symbolic reachability analysis and trajectory splicing

To successfully tackle challenging manipulation tasks, autonomous agents must learn a diverse set of skills and how to combine them. Recently, self-supervised agents that set their own abstract goals by exploiting the discovered structure in the environment were shown to perform well on many different tasks. In particular, some of them were applied to learn basic manipulation skills in compositional multi-object environments. However, these methods learn skills without taking the dependencies between objects into account. Thus, the learned skills are difficult to combine in realistic environments. We propose a novel self-supervised agent that estimates relations between environment components and uses them to independently control different parts of the environment state. In addition, the estimated relations between objects can be used to decompose a complex goal into a compatible sequence of subgoals. We show that, by using this framework, an agent can efficiently and automatically learn manipulation tasks in multi-object environments with different relations between objects.

Self-supervised Reinforcement Learning with Independently Controllable Subgoals

Bridging logical and algorithmic reasoning with modern machine learning techniques is a funda-mental challenge with potentially transformative impact. On the algorithmic side, many NP- HARD problems can be expressed as integer programs, in which the constraints play the role of their “com-binatorial specification.” In this work, we aim to integrate integer programming solvers into neural network architectures as layers capable of learning both the cost terms and the constraints. The resulting end-to-end trainable architectures jointly extract features from raw data and solve a suitable (learned) combinatorial problem with state-of-the-art integer programming solvers. We demonstrate the potential of such layers with an extensive performance analysis on synthetic data and with a demonstration on a competitive computer vision keypoint matching benchmark.

CombOptNet: Fit the Right NP-Hard Problem by Learning Integer Programming Constraints

Many reinforcement learning (RL) environments consist of independent entities that interact sparsely. In such environments, RL agents have only limited influence over other entities in any particular situation. Our idea in this work is that learning can be efficiently guided by knowing when and what the agent can influence with its actions. To achieve this, we introduce a measure of situation-dependent causal influence based on conditional mutual information and show that it can reliably detect states of influence. We then propose several ways to integrate this measure into RL algorithms to improve exploration and off-policy learning. All modified algorithms show strong increases in data efficiency on robotic manipulation tasks.

Causal Influence Detection for Improving Efficiency in Reinforcement Learning

Paolo P. Mazza, Dominik Zietlow, Federico Carollo, Sabine Andergassen, Georg Martius, and Igor Lesanovsky 3, 4 Institut für Theoretische Physik and Center for Quantum Science, Universität Tübingen, Auf der Morgenstelle 14, 72076 Tübingen, Germany Max Planck Institute for Intelligent Systems, Max-Planck-Ring 4, 72076 Tübingen, Germany School of Physics and Astronomy, University of Nottingham, Nottingham, NG7 2RD, UK Centre for the Mathematics and Theoretical Physics of Quantum Non-Equilibrium Systems, University of Nottingham, Nottingham, NG7 2RD, UK

Distilling data into compact and interpretable analytic equations is one of the goals of science. Instead, contemporary supervised machine learning methods mostly produce unstructured and dense maps from input to output. Particularly in deep learning, this property is owed to the generic nature of simple standard link functions. To learn equations rather than maps, standard non-linearities can be replaced with structured building blocks of atomic functions. However, without strong priors on sparsity and structure, representational complexity and numerical conditioning limit this direct approach. To scale to realistic settings in science and engineering, we propose an informed equation learning system. It provides a way to incorporate expert knowledge about what are permitted or prohibited equation components, as well as a domain-dependent structured sparsity prior. Our system then utilizes a robust method to learn equations with atomic functions exhibiting singularities, as e.g. logarithm and division. We demonstrate several artificial and real-world experiments from the engineering domain, in which our system learns interpretable models of high predictive power.

We introduce a simple but effective method for managing risk in zero1 order trajectory optimization that involves probabilistic safety constraints and 2 balancing of optimism in the face of epistemic uncertainty and pessimism in the 3 face of aleatoric uncertainty of an ensemble of stochastic neural networks. Various 4 experiments indicate that the separation of uncertainties is essential to performing 5 well with data-driven MPC approaches in uncertain and safety-critical control 6 environments. 7

Hierarchical reinforcement learning (HRL) holds great potential for sample-efficient learning on challenging long-horizon tasks. In particular, letting a higher level assign subgoals to a lower level has been shown to enable fast learning on difficult problems. However, such subgoal-based methods have been designed with static reinforcement learning environments in mind and consequently struggle with dynamic elements beyond the immediate control of the agent even though they are ubiquitous in real-world problems. In this paper, we introduce Hierarchical reinforcement learning with Timed Subgoals (HiTS), an HRL algorithm that enables the agent to adapt its timing to a dynamic environment by not only specifying what goal state is to be reached but also when. We discuss how communicating with a lower level in terms of such timed subgoals results in a more stable learning problem for the higher level. Our experiments on a range of standard benchmarks and three new challenging dynamic reinforcement learning environments show that our method is capable of sample-efficient learning where an existing state-of-the-art subgoal-based HRL method fails to learn stable solutions.

A common approach to prediction and planning in partially observable domains is to use recurrent neural networks (RNNs), which ideally develop and maintain a latent memory about hidden, task-relevant factors. We hypothesize that many of these hidden factors in the physical world are constant over time, changing only sparsely. To study this hypothesis, we propose Gated L 0 Regularized Dynamics (GateL0RD), a novel recurrent architecture that incorporates the inductive bias to maintain stable, sparsely changing latent states. The bias is implemented by means of a novel internal gating function and a penalty on the L 0 norm of latent state changes. We demonstrate that GateL0RD can compete with or outperform state-of-the-art RNNs in a variety of partially observable prediction and control tasks. GateL0RD tends to encode the underlying generative factors of the environment, ignores spurious temporal dependencies, and generalizes better, improving sampling efﬁciency and overall performance in model-based planning and reinforcement learning tasks. Moreover, we show that the developing latent states can be easily interpreted, which is a step towards better explainability in RNNs.

Sparsely Changing Latent States for Prediction and Planning in Partially Observable Domains

Solving high-dimensional, continuous robotic tasks is a challenging optimization problem. Model-based methods that rely on zero-order optimizers like the crossentropy method (CEM) have so far shown strong performance and are considered state-of-the-art in the model-based reinforcement learning community. However, this success comes at the cost of high computational complexity, being therefore not suitable for real-time control. In this paper, we propose a technique to jointly optimize the trajectory and distill a policy, which is essential for fast execution in real robotic systems. Our method builds upon standard approaches, like guidance cost and dataset aggregation, and introduces a novel adaptive factor which prevents the optimizer from collapsing to the learner’s behavior at the beginning of the training. The extracted policies reach unprecedented performance on challenging tasks like making a humanoid stand up and opening a door without reward shaping. Figure 1: Environments and exemplary behaviors of the learned policy using APEX. From left to right: FETCH PICK&PLACE (sparse reward), DOOR (sparse reward), and HUMANOID STANDUP.

Extracting Strong Policies for Robotics Tasks from Zero-Order Trajectory Optimizers

Haptic feedback is important to make robots more dexterous and effective. High-resolution haptic sensors are still not widely available, and their application is often bound by robustness issues. A route towards high-resolution and robust sensors is to embed a few sensor units (taxels) into a flexible surface material and use signal processing to achieve sensing with superresolution accuracy. We propose a theory for geometric superresolution to guide the development of haptic sensors of this kind. This theory is based on sensor isolines and allows us to predict force sensitivity and accuracy in force magnitude and contact position as a spatial quantity. We evaluate the influence of different factors, such as the elastic properties of the material, using finite element simulations. We compare three representative real sensor unit types, empirically determine their isolines, and validate the theory in a custom-built sensor. Using machine learning techniques, we obtain an average super-resolution factor of 300. As we illustrate, our theory can guide future haptic sensor designs and inform various design choices.

Although model-based and model-free approaches to learning the control of systems have achieved impressive results on standard benchmarks, generalization to task variations is still lacking. Recent results suggest that generalization for standard architectures improves only after obtaining exhaustive amounts of data. We give evidence that generalization capabilities are in many cases bottlenecked by the inability to generalize on the combinatorial aspects of the problem. Furthermore, we show that for a certain subclass of the MDP framework, this can be alleviated by neuro-algorithmic architectures. Many control problems require long-term planning that is hard to solve generically with neural networks alone. We introduce a neuro-algorithmic policy architecture consisting of a neural network and an embedded time-dependant shortest path solver. These policies can be trained end-to-end by blackbox differentiation. We show that this type of architecture generalizes well to unseen variations in the environment already after seeing a few examples.

Neuro-algorithmic Policies enable Fast Combinatorial Generalization

Haptic feedback is important to make robots more dexterous and effective in unstructured environments. High-resolution haptic sensors are still not widely available, and their application is often bound by the resolution-robustness dilemma. A route towards high-resolution and robust skin embeds a few sensor units (taxels) into a flexible surface material and uses signal processing to achieve sensing with super-resolution accuracy. We propose a theory for geometric super-resolution to guide the development of haptic sensors of this kind and link it to machine learning techniques for signal processing. This theory is based on sensor isolines and allows us to predict force sensitivity and accuracy in contact position and force magnitude as a spatial quantity. We evaluate the influence of different factors, such as elastic properties of the material, structure design, and transduction methods, using finite element simulations and by implementing real sensors. We empirically determine sensor isolines and validate the theory in two custom-built sensors with barometric units for 1D and 2D measurement surfaces. Using machine learning methods for the inference of contact information, our sensors obtain an unparalleled average super-resolution factor of over 100 and 1200, respectively. Our theory can guide future haptic sensor designs and inform various design choices.

The performance of β-Variational-Autoencoders (β-VAEs) and their variants on learning semantically meaningful, disentangled representations is unparalleled. On the other hand, there are theoretical arguments suggesting the impossibility of unsupervised disentanglement. In this work, we shed light on the inductive bias responsible for the success of VAE-based architectures. We show that in classical datasets the structure of variance, induced by the generating factors, is conveniently aligned with the latent directions fostered by the VAE objective. This builds the pivotal bias on which the disentangling abilities of VAEs rely. By small, elaborate perturbations of existing datasets, we hide the convenient correlation structure that is easily exploited by a variety of architectures. To demonstrate this, we construct modified versions of standard datasets in which (i) the generative factors are perfectly preserved; (ii) each image undergoes a mild transformation causing a small change of variance; (iii) the leading VAE-based disentanglement architectures fail to produce disentangled representations whilst the performance of a nonvariational method remains unchanged. The construction of our modifications is nontrivial and relies on recent progress on mechanistic understanding of β-VAEs and their connection to PCA. We strengthen that connection by providing additional insights that are of stand-alone interest.

It has long been hypothesized that operating close to the critical state is beneﬁcial for natural and artiﬁcial systems. We test this hypothesis by evolving foraging agents controlled by neural networks that can change the system’s dynamical regime throughout evolution. Surprisingly, we ﬁnd that all populations, regardless of their initial regime, evolve to be subcritical in simple tasks and even strongly subcritical populations can reach comparable performance. We hypoth-esize that the moderately subcritical regime combines the beneﬁts of generalizability and adaptability brought by closeness to criticality with the stability of the dynamics characteristic for subcritical systems. By a re-silience analysis, we ﬁnd that initially critical agents maintain their ﬁtness level even under environmental changes and degrade slowly with increasing perturbation strength. On the other hand, subcritical agents originally evolved to the same ﬁtness, were often ren-dered utterly inadequate and degraded faster. We con-clude that although the subcritical regime is preferable for a simple task, the optimal deviation from criticality depends on the task difﬁculty: for harder tasks, agents evolve closer to criticality. Furthermore, subcritical populations cannot ﬁnd the path to decrease their distance to criticality. In summary, our study suggests that initializing models near criticality is important to ﬁnd an optimal and ﬂexible solution.

The dynamical regime and its importance for evolvability, task performance and generalization

The ability to form complex plans based on raw visual input is a litmus test for current capabilities of artificial intelligence, as it requires a seamless combination of visual processing and abstract algorithmic execution, two traditionally separate areas of computer science. A recent surge of interest in this field brought advances that yield good performance in tasks ranging from arcade games to continuous control; these methods however do not come without significant issues, such as limited generalization capabilities and difficulties when dealing with combinatorially hard planning instances. Our contribution is two-fold: (i) we present a method that learns to represent its environment as a latent graph and leverages state reidentification to reduce the complexity of finding a good policy from exponential to linear (ii) we introduce a set of lightweight environments with an underlying discrete combinatorial structure in which planning is challenging even for humans. Moreover, we show that our methods achieves strong empirical generalization to variations in the environment, even across highly disadvantaged regimes, such as “one-shot” planning, or in an offline RL paradigm which only provides low-quality trajectories. breadth first search (with reidentification) latent graph space

Planning from Pixels in Environments with Combinatorially Hard Search Spaces

Since the environments become deterministic for a fixed random seed, we first unrolled their dynamics for each level. After obtaining the underlying grid structure and entities, we labeled them with costs and constructed a graph that reflects the grid structure. An expert trajectory is constructed by applying Dijkstra’s algorithm on this graph and the humanlabeled costs and then executing in simulation.

Supplementary for Neuro-algorithmic Policies Enable Fast Combinatorial Generalization

Departamento de Ciencias de la Computación, Instituto de Investigaciones en Matemáticas Aplicadas y en Sistemas, Universidad Nacional Autónoma de Mexico, Mexico, Mexico, Centro de Ciencias de la Complejidad, Universidad Nacional Autónoma de Mexico, Mexico, Mexico, 3 Lakeside Labs GmbH, Klagenfurt, Austria, 4 School of Engineering and Computer Science, University of Hertfordshire, Hatfield, United Kingdom, 5 Autonomous Learning Group, Max Planck Institute for

The performance of β-Variational-Autoencoders (β-VAEs) and their variants on learning semantically meaningful, disentangled representations is unparalleled. On the other hand, there are theoretical arguments suggesting the impossibility of unsupervised disentanglement. In this work, we shed light on the inductive bias responsible for the success of VAE-based architectures. We show that in classical datasets the structure of variance induced by the generating factors is conveniently aligned with the latent directions fostered by the VAE objective. This builds the pivotal bias on which the disentangling abilities of VAEs rely. By small, elaborate perturbations of existing datasets, we hide the convenient correlation structure that is easily exploited by a variety of architectures. To demonstrate this, we construct modified versions of standard datasets in which (i) the generative factors are perfectly preserved; (ii) each image undergoes a mild transformation causing a small change of variance; (iii) the leading VAE-based disentanglement architectures fail to produce disentangled representations while the performance of a non-variational method remains unchanged.

Demystifying Inductive Biases for (Beta-)VAE Based Architectures

Fast Non-Parametric Learning to Accelerate Mixed-Integer Programming for Hybrid Model Predictive Control

Trajectory optimizers for model-based reinforcement learning, such as the Cross-Entropy Method (CEM), can yield compelling results even in high-dimensional control tasks and sparse-reward environments. However, their sampling inefficiency prevents them from being used for real-time planning and control. We propose an improved version of the CEM algorithm for fast planning, with novel additions including temporally-correlated actions and memory, requiring 2.7-22x less samples and yielding a performance increase of 1.2-10x in high-dimensional control problems.

Although model-based and model-free approaches to learning the control of systems have achieved impressive results on standard benchmarks, most have been shown to be lacking in their generalization capabilities. These methods usually require sampling an exhaustive amount of data from different environment configurations. We propose a hybrid policy architecture with a deep network and a shortest path planner working in unison. The model can be trained end-toend via blackbox-differentiation. The deep network learns to predict time-dependent way-costs such that internal plans match expert trajectories. These neuro-algorithmic policies generalize well to unseen environment configurations.

Discrete Planning with End-to-end Trained Neuro-algorithmic Policies

Deep Graph Matching via Blackbox Differentiation of Combinatorial Solvers

Autonomous agents need large repertoires of skills to act reasonably on new tasks that they have not seen before. However, acquiring these skills using only a stream of high-dimensional, unstructured, and unlabeled observations is a tricky challenge for any autonomous agent. Previous methods have used variational autoencoders to encode a scene into a low-dimensional vector that can be used as a goal for an agent to discover new skills. Nevertheless, in compositional/multi-object environments it is difficult to disentangle all the factors of variation into such a fixed-length representation of the whole scene. We propose to use object-centric representations as a modular and structured observation space, which is learned with a compositional generative world model. We show that the structure in the representations in combination with goal-conditioned attention policies helps the autonomous agent to discover and learn useful skills. These skills can be further combined to address compositional tasks like the manipulation of several different objects.

Self-supervised Visual Reinforcement Learning with Object-centric Representations

Bridging logical and algorithmic reasoning with modern machine learning techniques is a fundamental challenge with potentially transformative impact. On the algorithmic side, many NP-Hard problems can be expressed as integer programs, in which the constraints play the role of their “combinatorial specification”. In this work, we aim to integrate integer programming solvers into neural network architectures by providing loss functions for both the objective and the constraints. The resulting end-to-end trainable architectures have the power of jointly extracting features from raw data and of solving a suitable (learned) combinatorial problem with state-of-the-art integer programming solvers. We experimentally validate our approach on artificial datasets created from random constraints, and on solving KNAPSACK instances from their description in natural language.

Fit The Right NP-Hard Problem: End-to-end Learning of Integer Programming Constraints

In the context of model-based reinforcement learning and control, a large number of methods for learning system dynamics have been proposed in recent years. The purpose of these learned models is to synthesize new control policies. An important open question is how robust current dynamics-learning methods are to shifts in the data distribution due to changes in the control policy. We present a real-robot dataset which allows to systematically investigate this question. This dataset contains trajectories of a 3 degrees-of-freedom (DOF) robot being controlled by a diverse set of policies. For comparison, we also provide a simulated version of the dataset. Finally, we benchmark a few widely-used dynamics-learning methods using the proposed dataset. Our results show that the iid test error of a learned model is not necessarily a good indicator of its accuracy under control policies different from the one which generated the training data. This suggests that it may be important to evaluate dynamics-learning methods in terms of their transfer performance, rather than only their iid error.

2020 IEEE International Conference on Robotics and Automation (ICRA)

A Real-Robot Dataset for Assessing Transferability of Learned Dynamics Models

Jumping over baselines with new methods to predict activation maps from resting-state fMRI

Autonomous agents need large repertoires of skills to act reasonably on new tasks that they have not seen before. However, acquiring these skills using only a stream of high-dimensional, unstructured, and unlabeled observations is a tricky challenge for any autonomous agent. Previous methods have used variational autoencoders to encode a scene into a low-dimensional vector that can be used as a goal for an agent to discover new skills. Nevertheless, in compositional/multiobject environments it is difficult to disentangle all the factors of variation into such a fixed-length representation of the whole scene. We propose to use object-centric representations as a modular and structured observation space, which is learned with a compositional generative world model. We show that the structure in the representations in combination with goal-conditioned attention policies helps the autonomous agent to discover and learn useful skills. These skills can be further combined to address compositional tasks like the manipulation of several different objects. https://sites.google.com/view/smorl-iclr2021

The falsification of a hybrid system aims at finding trajectories that violate a given safety property. This is a challenging problem, and the practical applicability of current falsification algorithms still suffers from their high time complexity. In contrast to falsification, verification algorithms aim at providing guarantees that no such trajectories exist. Recent symbolic reachability techniques are capable of efficiently computing linear constraints that enclose all trajectories of the system with reasonable precision. In this paper, we leverage the power of symbolic reachability algorithms to improve the scalability of falsification techniques. Recent approaches to falsification reduce the problem to a nonlinear optimization problem. We propose to reduce the search space of the optimization problem by adding linear state constraints obtained with a reachability algorithm. We showcase the efficiency of our approach on a number of standard hybrid systems benchmarks demonstrating the performance increase in speed and number of falsifyable instances.

Proceedings of the 22nd ACM International Conference on Hybrid Systems: Computation and Control

Falsification of hybrid systems using symbolic reachability and trajectory splicing

Achieving fusion of deep learning with combinatorial algorithms promises transformative changes to artificial intelligence. One possible approach is to introduce combinatorial building blocks into neural networks. Such end-to-end architectures have the potential to tackle combinatorial problems on raw input data such as ensuring global consistency in multi-object tracking or route planning on maps in robotics. In this work, we present a method that implements an efficient backward pass through blackbox implementations of combinatorial solvers with linear objective functions. We provide both theoretical and experimental backing. In particular, we incorporate the Gurobi MIP solver, Blossom V algorithm, and Dijkstra's algorithm into architectures that extract suitable features from raw inputs for the traveling salesman problem, the min-cost perfect matching problem and the shortest path problem.

We explore the feasibility of using machine learning methods to obtain an analytic form of the classical free energy functional for two model fluids, hard rods and Lennard-Jones, in one dimension. The equation learning network proposed by Martius and Lampert [e-print arXiv:1610.02995 (2016)] is suitably modified to construct free energy densities which are functions of a set of weighted densities and which are built from a small number of basis functions with flexible combination rules. This setup considerably enlarges the functional space used in the machine learning optimization as compared to the previous work [S.-C. Lin and M. Oettel, SciPost Phys. 6, 025 (2019)] where the functional is limited to a simple polynomial form. As a result, we find a good approximation for the exact hard rod functional and its direct correlation function. For the Lennard-Jones fluid, we let the network learn (i) the full excess free energy functional and (ii) the excess free energy functional related to interparticle attractions. Both functionals show a good agreement with simulated density profiles for thermodynamic parameters inside and outside the training region.

Analytical classical density functionals from an equation learning network

Voluntary behavior of humans appears to be composed of small, elementary building blocks, or behavioral primitives. While this modular organization seems crucial for the learning of complex motor skills and the flexible adaption of behavior to new circumstances, the problem of learning meaningful, compositional abstractions from sensorimotor experiences remains an open challenge. Here, we introduce a computational learning architecture, termed as surprise-based behavioral modularization into event-predictive structures (SUBMODES) that explores behavior and identifies the underlying behavioral units completely from scratch. The SUBMODES architecture bootstraps sensorimotor exploration using a self-organizing neural controller. While exploring the behavioral capabilities of its own body, the system learns modular structures that predict the sensorimotor dynamics and generate the associated behavior. In line with recent theories of event perception, the system uses unexpected prediction error signals, i.e., surprise, to detect transitions between successive behavioral primitives. We show that, when applied to two robotic systems with completely different body kinematics, the system manages to learn a variety of complex behavioral primitives. Moreover, after initial self exploration the system can use its learned predictive models progressively more effectively for invoking model predictive planning and goal-directed control in different tasks and environments.

Autonomous Identification and Goal-Directed Invocation of Event-Predictive Behavioral Primitives

Can we generate abstract aesthetic images without bias from natural or human selected image corpi? Are aesthetic images singled out in their correlation functions? In this paper we give answers to these and more questions. We generate images using compositional pattern-producing networks with random weights and varying architecture. We demonstrate that even with the randomly selected weights the correlation functions remain largely determined by the network architecture. In a controlled experiment, human subjects picked aesthetic images out of a large dataset of all generated images. Statistical analysis reveals that the correlation function is indeed different for aesthetic images.

Assessing Aesthetics of Generated Abstract Images Using Correlation Structure

Robust haptic sensation systems are essential for obtaining dexterous robots. Currently, we have solutions for small surface areas, such as fingers, but affordable and robust techniques for covering large areas of an arbitrary 3D surface are still missing. Here, we introduce a general machine learning framework to infer multi-contact haptic forces on a 3D robot's limb surface from internal deformation measured by only a few physical sensors. The general idea of this framework is to predict first the whole surface deformation pattern from the sparsely placed sensors and then to infer number, locations, and force magnitudes of unknown contact points. We show how this can be done even if training data can only be obtained for single-contact points using transfer learning at the example of a modified limb of the Poppy robot. With only 10 strain-gauge sensors we obtain a high accuracy also for multiple-contact points. The method can be applied to arbitrarily shaped surfaces and physical sensor types, as long as training data can be obtained.

Machine Learning for Haptics: Inferring Multi-Contact Stimulation From Sparse Sensor Configuration

Today's fast linear algebra and numerical optimization tools have pushed the frontier of model predictive control (MPC) forward, to the efficient control of highly nonlinear and hybrid systems. The field of hybrid MPC has demonstrated that exact optimal control law can be computed, e.g., by mixed-integer programming (MIP) under piecewise-affine (PWA) system models. Despite the elegant theory, online solving hybrid MPC is still out of reach for many applications. We aim to speed up MIP by combining geometric insights from hybrid MPC, a simple-yet-effective learning algorithm, and MIP warm start techniques. Following a line of work in approximate explicit MPC, the proposed learning-control algorithm, LNMS, gains computational advantage over MIP at little cost and is straightforward for practitioners to implement.

Fast Non-Parametric Learning to Accelerate Mixed-Integer Programming for Online Hybrid Model Predictive Control

Rank-based metrics are some of the most widely used criteria for performance evaluation of computer vision models. Despite years of effort, direct optimization for these metrics remains a challenge due to their non-differentiable and non-decomposable nature. We present an efficient, theoretically sound, and general method for differentiating rank-based metrics with mini-batch gradient descent. In addition, we address optimization instability and sparsity of the supervision signal that both arise from using rank-based metrics as optimization targets. Resulting losses based on recall and Average Precision are applied to image retrieval and object detection tasks. We obtain performance that is competitive with state-of-the-art on standard image retrieval datasets and consistently improve performance of near state-of-the-art object detectors.

2020 IEEE/CVF Conference on Computer Vision and Pattern Recognition (CVPR)

We present a novel intrinsically motivated agent that learns how to control the environment in the fastest possible manner by optimizing learning progress. It learns what can be controlled, how to allocate time and attention, and the relations between objects using surprise based motivation. The effectiveness of our method is demonstrated in a synthetic as well as a robotic manipulation environment yielding considerably improved performance and smaller sample complexity. In a nutshell, our work combines several task-level planning agent structures (backtracking search on task graph, probabilistic road-maps, allocation of search efforts) with intrinsic motivation to achieve learning from scratch.

Control What You Can: Intrinsically Motivated Task-Planning Agent

We present an approach to identify concise equations from data using a shallow neural network approach. In contrast to ordinary black-box regression, this approach allows understanding functional relations and generalizing them from observed data to unseen parts of the parameter space. We show how to extend the class of learnable equations for a recently proposed equation learning network to include divisions, and we improve the learning and model selection strategy to be useful for challenging real-world data. For systems governed by analytical expressions, our method can in many cases identify the true underlying equation and extrapolate to unseen domains. We demonstrate its effectiveness by experiments on a cart-pendulum system, where only 2 random rollouts are required to learn the forward dynamics and successfully achieve the swing-up task.

One of the challenges of this century is to understand the neural mechanisms behind cognitive control and learning. Recent investigations propose biologically plausible synaptic mechanisms for self...

Systematic self-exploration of behaviors for robots in a dynamical systems framework

The Variational Autoencoder (VAE) is a powerful architecture capable of representation learning and generative modeling. When it comes to learning interpretable (disentangled) representations, VAE and its variants show unparalleled performance. However, the reasons for this are unclear, since a very particular alignment of the latent embedding is needed but the design of the VAE does not encourage it in any explicit way. We address this matter and offer the following explanation: the diagonal approximation in the encoder together with the inherent stochasticity force local orthogonality of the decoder. The local behavior of promoting both reconstruction and orthogonality matches closely how the PCA embedding is chosen. Alongside providing an intuitive understanding, we justify the statement with full theoretical analysis as well as with experiments.

2019 IEEE/CVF Conference on Computer Vision and Pattern Recognition (CVPR)

Haptic sensation is an important modality for interacting with the real world. This paper proposes a general framework of inferring haptic forces on the surface of a 3D structure from internal deformations using a small number of physical sensors instead of employing dense sensor arrays. Using machine learning techniques, we optimize the sensor number and their placement and are able to obtain high-precision force inference for a robotic limb using as few as 9 sensors. For the optimal and sparse placement of the measurement units (strain gauges), we employ data-driven methods based on data obtained by finite element simulation. We compare data-driven approaches with model-based methods relying on geometric distance and information criteria such as Entropy and Mutual Information. We validate our approach on a modified limb of the “Poppy” robot [1] and obtain 8 mm localization precision.

2018 IEEE-RAS 18th International Conference on Humanoid Robots (Humanoids)

Robust Affordable 3D Haptic Sensation via Learning Deformation Patterns

We propose a stepsize adaptation scheme for stochastic gradient descent. It operates directly with the loss function and rescales the gradient in order to make fixed predicted progress on the loss. We demonstrate its capabilities by strongly improving the performance of Adam and Momentum optimizers. The enhanced optimizers with default hyperparameters consistently outperform their constant stepsize counterparts, even the best ones, without a measurable increase in computational cost. The performance is validated on multiple architectures including ResNets and the Differential Neural Computer. A prototype implementation as a TensorFlow optimizer is released.

Event-triggered control (ETC) methods can achieve high-performance control with a significantly lower number of samples compared to usual, time-triggered methods. These frameworks are often based on a mathematical model of the system and specific designs of controller and event trigger. In this paper, we show how deep reinforcement learning (DRL) algorithms can be leveraged to simultaneously learn control and communication behavior from scratch, and present a DRL approach that is particularly suitable for ETC. To our knowledge, this is the first work to apply DRL to ETC. We validate the approach on multiple control tasks and compare it to model-based event-triggering frameworks. In particular, we demonstrate that it can, other than many model-based ETC designs, be straightforwardly applied to nonlinear systems.

Self-organizing (SO) systems have the capabilities to induce low-dimensional global behavior in a high-dimensional system, for instance in bird flocks or ant colonies. These systems tend to be resilient under changeable conditions or to malfunction of individual parts. In the case of agents’ behavior, the self-organization relies on the embodied interaction with the environment and exploits physical effects. These properties make it natural to aim for the application of a self-organizing method to robot development. A difference between the prominent SO systems and a robot is that it consists of a single component instead of many largely independent components. In order to obtain a self-organized behavioral development, a guiding principle is required. One of the prominent principles is Homeokinesis – balancing activity and predictability. The maximization of the predictive information (PI) [1] is another such principle that was also cast into a online algorithm [3]. Although these methods lead to self-organization of behavior in a large variety of robots, the principle has an inherent disadvantage of constantly increasing the complexity of the behavior. As an effect the system aims for behaviors with maximal attractor dimension, see [5]. However, natural behavior such as walking, crawling, reaching, etc. are low-dimensional. Conceptually, it might be a question of timescales. If a succession of low-dimensional behaviors is generated then on a longer time-scale the predictive information can potentially also be maximized. Nevertheless, for direct behavior generation, it may ultimately not be suitable. Recently the differential extrinsic plasticity (DEP) [2] learning rule was proposed, which originated from a simplification of the PI rule. It leads to the emergence of low-dimensional behaviors in different systems. Examples are a humanoid robot starting to crawling, turn a wheel or a hexapod robot to locomote [2]. Applied to a real tendon driven anthropomorphic arm the learning rule led to the SO development of bottle swinging, and shaking, table wiping and wheel turning, just due to the brain-body-environment coupling [4]. The DEP rule creates a dynamics with a multitude of attractors. Depending on the body and environmental conditions different attractor behaviors are reached. These can be switched by perturbations. However, a systematic understanding is still missing. In this contribution we provide a first analysis of DEP rule and propose a method to obtain a systematic sweep through the behavior landscape.

With the accelerated development of robot technologies, control becomes one of the central themes of research. In traditional approaches, the controller, by its internal functionality, finds appropriate actions on the basis of specific objectives for the task at hand. While very successful in many applications, self-organized control schemes seem to be favored in large complex systems with unknown dynamics or which are difficult to model. Reasons are the expected scalability, robustness, and resilience of self-organizing systems. The paper presents a self-learning neurocontroller based on extrinsic differential plasticity introduced recently, applying it to an anthropomorphic musculoskeletal robot arm with attached objects of unknown physical dynamics. The central finding of the paper is the following effect: by the mere feedback through the internal dynamics of the object, the robot is learning to relate each of the objects with a very specific sensorimotor pattern. Specifically, an attached pendulum pilots the arm into a circular motion, a half-filled bottle produces axis oriented shaking behavior, a wheel is getting rotated, and wiping patterns emerge automatically in a table-plus-brush setting. By these object-specific dynamical patterns, the robot may be said to recognize the object's identity, or in other words, it discovers dynamical affordances of objects. Furthermore, when including hand coordinates obtained from a camera, a dedicated hand-eye coordination self-organizes spontaneously. These phenomena are discussed from a specific dynamical system perspective. Central is the dedicated working regime at the border to instability with its potentially infinite reservoir of (limit cycle) attractors “waiting” to be excited. Besides converging toward one of these attractors, variate behavior is also arising from a self-induced attractor morphing driven by the learning rule. We claim that experimental investigations with this anthropomorphic, self-learning robot not only generate interesting and potentially useful behaviors, but may also help to better understand what subjective human muscle feelings are, how they can be rooted in sensorimotor patterns, and how these concepts may feed back on robotics.

We present an approach that enables robots to self-organize their sensorimotor behavior from scratch without providing specific information about neither the robot nor its environment. This is achieved by a simple neural control law that increases the consistency between external sensor dynamics and internal neural dynamics of the utterly simple controller. In this way, the embodiment and the agent-environment coupling are the only source of individual development. We show how an anthropomorphic tendon driven arm-shoulder system develops different behaviors depending on that coupling. For instance: given a bottle half-filled with water, the arm starts to shake it, driven by the physical response of the water. When attaching a brush, the arm can be manipulated into wiping a table, and when connected to a revolvable wheel it finds out how to rotate it. Thus, the robot may be said to discover the affordances of the world. When allowing two (simulated) humanoid robots to interact physically, they engage into a joint behavior development leading to, for instance, spontaneous cooperation. More social effects are observed if the robots can visually perceive each other. Although, as an observer, it is tempting to attribute an apparent intentionality, there is nothing of the kind put in. As a conclusion, we argue that emergent behavior may be much less rooted in explicit intentions, internal motivations, or specific reward systems than is commonly believed.

2016 Joint IEEE International Conference on Development and Learning and Epigenetic Robotics (ICDL-EpiRob)

Dynamical self-consistency leads to behavioral development and emergent social interactions in robots

With the accelerated development of robot technologies, optimal control becomes one of the central themes of research. In traditional approaches, the controller, by its internal functionality, finds appropriate actions on the basis of the history of sensor values, guided by the goals, intentions, objectives, learning schemes, and so on planted into it. The idea is that the controller controls the world---the body plus its environment---as reliably as possible. This paper advocates for a new paradigm of control, obtained by making the world control its controller in the first place. The paper presents a solution with a controller that is devoid of any functionalities of its own, given by a fixed, explicit and context-free function of the recent history of the sensor values. When applying this controller to a muscle-tendon driven arm-shoulder system from the Myorobotics toolkit, we observe a vast variety of self-organized behavior patterns: when left alone, the arm realizes pseudo-random sequences of different poses but one can also manipulate the system into definite motion patterns. But most interestingly, after attaching an object, the controller gets in a functional resonance with the object's internal dynamics: when given a half-filled bottle, the system spontaneously starts shaking the bottle so that maximum response from the dynamics of the water is being generated. After attaching a pendulum to the arm, the controller drives the pendulum into a circular mode. In this way, the robot discovers affordances of objects its body is interacting with. We also discuss perspectives for using this controller paradigm for intention driven behavior generation.

The world as its own best controller: a case study with anthropomimetic robots

With the accelerated development of robot technologies, optimal control becomes one of the central themes of research. In traditional approaches, the controller, by its internal functionality, find...

Self-organized control of an tendon driven arm by differential extrinsic plasticity

With the accelerated development of robot technologies, optimal control becomes one of the central themes of research. In traditional approaches, the controller, by its internal functionality, finds appropriate actions on the basis of the history of sensor values, guided by the goals, intentions, objectives, learning schemes, and so on planted into it. The idea is that the controller controls the world---the body plus its environment---as reliably as possible. However, in elastically actuated robots this approach faces severe difficulties. This paper advocates for a new paradigm of self-organized control. The paper presents a solution with a controller that is devoid of any functionalities of its own, given by a fixed, explicit and context-free function of the recent history of the sensor values. When applying this controller to a muscle-tendon driven arm-shoulder system from the Myorobotics toolkit, we observe a vast variety of self-organized behavior patterns: when left alone, the arm realizes pseudo-random sequences of different poses but one can also manipulate the system into definite motion patterns. But most interestingly, after attaching an object, the controller gets in a functional resonance with the object's internal dynamics: when given a half-filled bottle, the system spontaneously starts shaking the bottle so that maximum response from the dynamics of the water is being generated. After attaching a pendulum to the arm, the controller drives the pendulum into a circular mode. In this way, the robot discovers dynamical affordances of objects its body is interacting with. We also discuss perspectives for using this controller paradigm for intention driven behavior generation.

In classical machine learning, regression is treated as a black box process of identifying a suitable function from a hypothesis set without attempting to gain insight into the mechanism connecting inputs and outputs. In the natural sciences, however, finding an interpretable function for a phenomenon is the prime goal as it allows to understand and generalize results. This paper proposes a new type of function learning network, called equation learner (EQL), that can learn analytical expressions and is able to extrapolate to unseen domains. It is implemented as an end-to-end differentiable feed-forward network and allows for efficient gradient based training. Due to sparsity regularization concise interpretable expressions can be obtained. We also devise a model selection strategy tailored to the function learning setting, such that often the true underlying source expression can be identified. In this way the behavior of physical systems can be learned and effectively predicted even in new situations. A full description of the method can be found in Martius and Lampert [2].

With the accelerated development of robot technologies, optimal control becomes one of the central themes of research. In traditional approaches, the controller, by its internal functionality, finds appropriate actions on the basis of the history of sensor values, guided by the goals, intentions, objectives, learning schemes, and so forth. While very successful with classical robots, these methods run into severe difficulties when applied to soft robots, a new field of robotics with large interest for human-robot interaction. We claim that a novel controller paradigm opens new perspective for this field. This paper applies a recently developed neuro controller with differential extrinsic synaptic plasticity to a muscle-tendon driven arm-shoulder system from the Myorobotics toolkit. In the experiments, we observe a vast variety of self-organized behavior patterns: when left alone, the arm realizes pseudo-random sequences of different poses. By applying physical forces, the system can be entrained into definite motion patterns like wiping a table. Most interestingly, after attaching an object, the controller gets in a functional resonance with the object's internal dynamics, starting to shake spontaneously bottles half-filled with water or sensitively driving an attached pendulum into a circular mode. When attached to the crank of a wheel the neural system independently develops to rotate it. In this way, the robot discovers affordances of objects its body is interacting with.

2016 IEEE/RSJ International Conference on Intelligent Robots and Systems (IROS)

Compliant control for soft robots: Emergent behavior of a tendon driven anthropomorphic arm

In classical machine learning, regression is treated as a black box process of identifying a suitable function from a hypothesis set without attempting to gain insight into the mechanism connecting inputs and outputs. In the natural sciences, however, finding an interpretable function for a phenomenon is the prime goal as it allows to understand and generalize results. This paper proposes a novel type of function learning network, called equation learner (EQL), that can learn analytical expressions and is able to extrapolate to unseen domains. It is implemented as an end-to-end differentiable feed-forward network and allows for efficient gradient based training. Due to sparsity regularization concise interpretable expressions can be obtained. Often the true underlying source expression is identified.

Retina is a paradigmatic system for studying sensory encoding: the transformation of light into spiking activity of ganglion cells. The inverse problem, where stimulus is reconstructed from spikes, has received less attention, especially for complex stimuli that should be reconstructed “pixel-by-pixel”. We recorded around a hundred neurons from a dense patch in a rat retina and decoded movies of multiple small randomly-moving discs. We constructed nonlinear (kernelized and neural network) decoders that improved significantly over linear results. An important contribution to this was the ability of nonlinear decoders to reliably separate between neural responses driven by locally fluctuating light signals, and responses at locally constant light driven by spontaneous-like activity. This improvement crucially depended on the precise, non-Poisson temporal structure of individual spike trains, which originated in the spike-history dependence of neural responses. We propose a general principle by which downstream circuitry could discriminate between spontaneous and stimulus-driven activity based solely on higher-order statistical structure in the incoming spike trains.

Significance To find how autonomous behavior and its development can be realized by a brain or an artificial neural network is a fundamental challenge for neuroscience and robotics. Commonly, the self-organized unfolding of behavior is explained by postulating special concepts like internal drives, curiosity, specific reward systems, or selective pressures. We propose a simple, local, and biologically plausible synaptic mechanism that enables an embodied agent to self-organize its individual sensorimotor development without recourse to such higher-level constructs. When applied to robotic systems, a rich spectrum of rhythmic behaviors emerges, ranging from locomotion patterns to spontaneous cooperation between partners. A possible utilization of our novel mechanism in nature would lead to a new understanding of the early stages of sensorimotor development and of saltations in evolution. Grounding autonomous behavior in the nervous system is a fundamental challenge for neuroscience. In particular, self-organized behavioral development provides more questions than answers. Are there special functional units for curiosity, motivation, and creativity? This paper argues that these features can be grounded in synaptic plasticity itself, without requiring any higher-level constructs. We propose differential extrinsic plasticity (DEP) as a new synaptic rule for self-learning systems and apply it to a number of complex robotic systems as a test case. Without specifying any purpose or goal, seemingly purposeful and adaptive rhythmic behavior is developed, displaying a certain level of sensorimotor intelligence. These surprising results require no system-specific modifications of the DEP rule. They rather arise from the underlying mechanism of spontaneous symmetry breaking, which is due to the tight brain body environment coupling. The new synaptic rule is biologically plausible and would be an interesting target for neurobiological investigation. We also argue that this neuronal mechanism may have been a catalyst in natural evolution.

Novel plasticity rule can explain the development of sensorimotor intelligence

Quantifying behaviors of robots which were generated autonomously from task-independent objective functions is an important prerequisite for objective comparisons of algorithms and movements of animals. The temporal sequence of such a behavior can be considered as a time series and hence complexity measures developed for time series are natural candidates for its quantification. The predictive information and the excess entropy are such complexity measures. They measure the amount of information the past contains about the future and thus quantify the nonrandom structure in the temporal sequence. However, when using these measures for systems with continuous states one has to deal with the fact that their values will depend on the resolution with which the systems states are observed. For deterministic systems both measures will diverge with increasing resolution. We therefore propose a new decomposition of the excess entropy in resolution dependent and resolution independent parts and discuss how they depend on the dimensionality of the dynamics, correlations and the noise level. For the practical estimation we propose to use estimates based on the correlation integral instead of the direct estimation of the mutual information using the algorithm by Kraskov et al. (2004) which is based on next neighbor statistics because the latter allows less control of the scale dependencies. Using our algorithm we are able to show how autonomous learning generates behavior of increasing complexity with increasing learning duration.

Introduction In recent years research in autonomous robots has been more and more successful in developing algorithms for generating behavior from a generic taskindependent objective. Examples are intrinsic motivations for artificial curiosity, empowerment, homeokinesis, and maximizing predictive information. Independently of its origin, it would be useful to quantify behavior, in order to objectively compare algorithms with each other or even with human or animal movements. We investigate different methods for extracting characteristic measures based on information theoretic quantities. Example Behaviors We consider behaviors from a hexapod robot with 18DoF and from a snake robot with 14DoF when controlled by a simplified predictive information maximizing controller (Der and Martius, 2013). The behavior is generated by an adaptive coupling between sensors and motors in a purely reactive manner ‐ without a central pattern generator nor internal recurrences. In Fig 1 two example behaviors of the snake are shown which we uses here as a brief illustration. The data consists of 10 6 steps of joint position sensors.

Self-exploration of the Stumpy Robot with Predictive Information Maximization

One of the main challenges in the eld of embodied articial intelligence is the open-ended autonomous learning of complex behaviours. Our approach is to use task-independent, information-driven intrinsic motivation(s) to support task-dependent learning. The work presented here is a preliminary step in which we investigate the predictive information (the mutual information of the past and future of the sensor stream) as an intrinsic drive, ideally supporting any kind of task acquisition. Previous experiments have shown that the predictive information (PI) is a good candidate to support autonomous, open-ended learning of complex behaviours, because a maximisation of the PI corresponds to an exploration of morphology- and environment-dependent behavioural regularities. The idea is that these regularities can then be exploited in order to solve any given task. Three dierent experiments are presented and their results lead to the conclusion that the linear combination of the one-step PI with an external reward function is not generally recommended in an episodic policy gradient setting. Only for hard tasks a great speed-up can be achieved at the cost of an asymptotic performance lost.

Information-driven intrinsic motivation in reinforcement learning

Information theory is a powerful tool to express principles to drive autonomous systems because it is domain invariant and allows for an intuitive interpretation. This paper studies the use of the predictive information (PI), also called excess entropy or effective measure complexity, of the sensorimotor process as a driving force to generate behavior. We study nonlinear and nonstationary systems and introduce the time-local predicting information (TiPI) which allows us to derive exact results together with explicit update rules for the parameters of the controller in the dynamical systems framework. In this way the information principle, formulated at the level of behavior, is translated to the dynamics of the synapses. We underpin our results with a number of case studies with high-dimensional robotic systems. We show the spontaneous cooperativity in a complex physical system with decentralized control. Moreover, a jointly controlled humanoid robot develops a high behavioral variety depending on its physics and the environment it is dynamically embedded into. The behavior can be decomposed into a succession of low-dimensional modes that increasingly explore the behavior space. This is a promising way to avoid the curse of dimensionality which hinders learning systems to scale well.

Information Driven Self-Organization of Complex Robotic Behaviors

One of the main challenges in the field of embodied artificial intelligence is the open-ended autonomous learning of complex behaviors. Our approach is to use task-independent, information-driven intrinsic motivation(s) to support task-dependent learning. The work presented here is a preliminary step in which we investigate the predictive information (the mutual information of the past and future of the sensor stream) as an intrinsic drive, ideally supporting any kind of task acquisition. Previous experiments have shown that the predictive information (PI) is a good candidate to support autonomous, open-ended learning of complex behaviors, because a maximization of the PI corresponds to an exploration of morphology- and environment-dependent behavioral regularities. The idea is that these regularities can then be exploited in order to solve any given task. Three different experiments are presented and their results lead to the conclusion that the linear combination of the one-step PI with an external reward function is not generally recommended in an episodic policy gradient setting. Only for hard tasks a great speed-up can be achieved at the cost of an asymptotic performance lost.

Linear combination of one-step predictive information with an external reward in an episodic policy gradient setting: a critical analysis

Self-organization—ubiquitous in nature—is a major challenge for both artificial life and modern robotics offering intriguing perspectives for practical applications utilized so far only incipiently. There is some progress, though, in formulating general objective functions for driving systems into selforganization (SO). Based on general principles like information maximization, these approaches are domain invariant and free of arbitrariness. However, and this seems to be a major source of concerns, if nothing is specified from outside, will SO simply make the robot an arbitrary subject that is completely unpredictable in its behaviors and thus rather a thread than a hope. The aim of this paper is to show that this attitude is not justified. Instead, we develop an understanding of what happens if the system is self-organizing, what the role of the embodiment is and how we can find clues for predicting and shaping the behavior patterns emerging in a genuine SO scenario. The approach is based on a new unsupervised learning rule staging two antagonistic activities—driving systems towards instability while preserving the physical symmetries of the system as much as possible. This leads to spontaneous symmetry breaking, the leading phenomenon of SO known from nature that has been overlooked by the robotics community so far. It is shown by a number of examples that the unsupervised learning rule induces an amazing variety of behaviors—patterns in space and time that can be interpreted as broken symmetries.

Self-organizing processes are crucial for the development of living beings. Practical applications in robots may benefit from the self-organization of behavior, e.g., to increase fault tolerance and enhance flexibility, provided that external goals can also be achieved. We present results on the guidance of self-organizing control by visual target stimuli and show a remarkable robustness to sensorimotor disruptions. In a proof of concept study an autonomous wheeled robot is learning an object finding and ball-pushing task from scratch within a few minutes in continuous domains. The robustness is demonstrated by the rapid recovery of the performance after severe changes of the sensor configuration.

Robustness of Guided Self-Organization against Sensorimotor disruptions

The Playful Machine - Theoretical Foundation and Practical Realization of Self-Organizing Robots

We propose a novel approach to learning in autonomous robots that relies on the dynamical maintenance of an actively sensitized sensorimotor loop. Very weak learning cues are sufficient to orient a robot towards the desired behavior which is then selected from the intrinsic exploratory movements rather than imposed by a control command. The learning paradigm is a form of guided self-organization and is complementary to both active and intrinsically motivated learning. We present a systematic analysis of the learning algorithm in a robot control task and demonstrate its remarkable scalability with respect to the degrees of freedom of the system.

Tipping the scales: guidance and intrinsically motivated behavior

Taming the Beast: Guided Self-organization of Behavior in Autonomous Robots

We study adaptive control algorithms within a dynamical systems approach for autonomous robots that cause the self-organization of coordinated behaviors without specific goals or particular information about the physical body. A self-exploration is achieved that causes different body- and environment-related behaviors to emerge and to change during the learning process. We propose several methods to guide the self-organization towards specific behaviors, which is particularly useful in high-dimensional systems. An unsupervised extraction of behavioral primitives is achieved with a set of competing neural networks, where each network develops to a controller for one behavior. Finally we combine classical reinforcement learning with the behavioral primitives to obtain goal-oriented behaviors. The algorithms are verified with realistically simulated robots using our own simulator LpzRobots, which is briefly described.

Goal-Oriented Control of Self-Organizing Behavior in Autonomous Robots

Animals process sensory information in order to generate behavior that matches the affordances of their environment. The statistical properties of an environment, however, appear substantially different to an inexperienced individual and to its more skilled fellow. On the one hand, appropriate learning opportunities may rarely occur by chance, while on the other hand a concentration on well-learned behaviors tends to reduce the frequency of errors although these are important indicators of the environmental dynamics. In order to extract the currently relevant aspects of the sensory world, the agent should thus aim at performing coherent behavior based on incident regularities as well as maintain a constant excitation of the controlled systems in order to escape from suboptimal behaviors and track the environmental dynamics. The strategies for departing from either of these uninformative situations requires the agent to engage actively in the learning process [1]. In the present contribution we will show that homeokinetic learning [2] is an expedient method to achieve this goal and that it presents a viable approach to active learning. This method comprises the simultaneous maximization of the sensitivity of an agent with respect to its stimuli and the predictability of these stimuli. Sensitization leads to exploratory behavior which is counterbalanced by the requirement of predictability by means of an internal model. As a theoretically provable consequence, the motor activity becomes distributed over many degrees of freedom of a robotic system. Homeokinetic learning leads to flexible, versatile and body-specific behaviors [3] that can be characterized by their controllability.

Author to whom correspondence should be addressed.Received: 30 November 2008 / Accepted: 26 February 2009 / Published: 4 March 2009Abstract: Ideally, sensory information forms the only source of information to a robot. Weconsider an algorithm for the self-organization of a controller. At short time scales the con-troller is merely reactive but the parameter dynamics and the acquisition of knowledge by aninternal model lead to seemingly purposeful behavior on longer time scales. As a paradigmaticexample, we study the simulation of an underactuated snake-like robot. By interacting withthe real physical system formed by the robotic hardware and the environment, the controllerachieves a sensitive and body-speciﬁc actuation of the robot.Keywords: Self-Organization; Autonomous Robot Control; Neural Networks; Homeokine-sis.

A Sensor-Based Learning Algorithm for the Self-Organization of Robot Behavior

Emergence of behavioral primitives in self-organizing control and composition of behavior for autonomous robots

Alignments are part of the most important data type in the field of comparative genomics. They can be abstracted to a character matrix derived from aligned sequences. A variety of biological questions forces the researcher to inspect these alignments. Our tool, called COMPOSALIGN, was developed to sonify large scale genomic data. The resulting musical composition is based on COMMON MUSIC and allows the mapping of genes to motifs and species to instruments. It enables the researcher to listen to the musical representation of the genome-wide alignment and contrasts a bioinformatician’s sight-oriented work at the computer.

We describe a learning algorithm that generates behaviors by self-organization of sensorimotor loops in an autonomous robot. The behavior of the robot is analyzed by a multi-expert architecture, where a number of controllers compete for the data from the physical robot. Each expert stabilizes the representation of the acquired sensorimotor mapping in dependence of the achieved prediction error and forms eventually a behavioral primitive. The experts provide a discrete representation of the behavioral manifold of the robot and are suited to form building blocks for complex behaviors.

2008 IEEE/RSJ International Conference on Intelligent Robots and Systems

Self-organization and the phenomenon of emergence play an essential role in living systems and form a challenge to artificial life systems. This is not only because systems become more life like but also since self-organization may help in reducing the design efforts in creating complex behavior systems. The present paper exemplifies a general approach to the self-organization of behavior which has been developed and tested in various examples in recent years. We apply this approach to a spherical robot driven by shifting internal masses. The complex physics of this robotic object is completely unknown to the controller. Nevertheless after a short time the robot develops systematic rolling movements covering large distances with high velocity. In a hilly landscape it is capable of maneuvering out of the wells and in landscapes with a fixed rotational geometry the robot more or less adapts its movements to this geometry – the controller so to say develops a kind of feeling for its environment although there are no sensors for measuring the positions or the velocity of the robot. We argue that this behavior is a result of the spontaneous symmetry breaking effects which are responsible for the emergence of behavior in our approach.

Let it roll - Emerging Sensorimotor Coordination in a Spherical Robot

From Motor Babbling to Purposive Actions: Emerging Self-exploration in a Dynamical Systems Approach to Early Robot Development

Dynamical systems offer intriguing possibilities as a substrate for the generation of behavior because of their rich behavioral complexity. However this complexity together with the largely covert relation between the parameters and the behavior of the agent is also the main hindrance in the goal oriented design of a behavior system. This paper presents a general approach to the self-regulation of dynamical systems so that the design problem is circumvented. We consider the controller (a neural net work) as the mediator for changes in the sensor values over time and define a dynamics for the parameters of the controller by maximizing the dynamical complexity of the sensorimotor loop under the condition that the consequences of the actions taken are still predictable. This very general principle is given a concrete mathematical formulation and is implemented in an extremely robust and versatile algorithm for the parameter dynamics of the controller. We consider two different applications, a mechanical device called the rocking stamper and the ODE simulations of a “snake” with five degrees of freedom. In these and many other examples studied we observed various behavior modes of high dynamical complexity

Rocking Stamper and Jumping Snakes from a Dynamical Systems Approach to Artificial Life

Despite the tremendous progress in robotic hardware and in both sensorial and computing efficiencies the performance of contemporary autonomous robots is still far below that of simple animals. This has triggered an intensive search for alternative approaches to the control of robots. The present paper exemplifies a general approach to the self-organization of behavior which has been developed and tested in various examples in recent years. We apply this approach to an underactuated "snake" like artifact with a complex physical behavior which is not known to the controller. Due to the weak forces available, the controller so to say has to develop a kind of feeling for the body which is seen to emerge from our approach in a natural way with meandering and rotational collective modes being observed in computer simulation experiments

International Conference on Computational Intelligence for Modelling, Control and Automation and International Conference on Intelligent Agents, Web Technologies and Internet Commerce (CIMCA-IAWTIC'06)

The patient was a 32-year-old para 2 who developed within a few hours after the first symptoms a lethal HELLP-syndrome. Despite initially normal blood pressure an hepatic failure, hemolysis and cerebral bleeding appeared. The autopsy revealed an eclamptic liver and symptoms of a disseminated intravasal coagulation (DIC). As a consequence a quick delivery instead of a conservative-expectant management because of fetal prematurity is recommended.

[Comments on the survey in "Zentralblatt für Gynäkologie" 111 (1989) issue 20, p. 1390 on delivery of the second twin].

[On the overcoming of detaching difficulties in frank breech presentation with "extended legs"].

Gynaecologia. International monthly review of obstetrics and gynecology. Revue internationale mensuelle d'obstetrique et de gynecologie. Monatsschrift fur Geburtshilfe und Gynakologie

[HEAD SIZE AND HEAD SHAPE OF THE NEWBORN INFANT IN ITS RELATION TO THE MECHANISM OF LABOR. II. OBSERVATIONS IN STRETCH POSITION AND OCCIPITO-POSTERIOR PRESENTATION].

[DISTURBANCES OF THE MICROMOTOR TONUS REGULATION IN PROLONGED PREGNANCY].

[ON DELIVERY IN BREECH PRESENTATION. SOME SURGICAL TECHNICAL AND DIDACTIC REMARKS].

[HEAD MEASUREMENTS AND HEAD SHAPE OF THE NEWBORN IN THEIR RELATION TO THE MECHANISM OF LABOR. OBSERVATIONS IN OCCIPUT ANTERIOR PRESENTATION. I].

[ANIMAL EXPERIMENTAL STUDIES ON THE PROBLEM OF FETAL DAMAGE BY PYRIMETHAMINE].

[Chloroquine in serological conflict in pregnancy. A contribution to the prevention of hemolytic disease of the newborn].

[New possibilities in labor prognosis with the aid of a study of intensification of fine motor tone].

[Dosage and indications in the combined use of analgesics and opiate antagonists in obstetrics].

[On the relations between distal tonus regulations and labor activity].

[Histological examination of the placenta in study of the pathogenesis of hemolytic disease of the newborn].

[Surgical correction of a congenital uterine prolapse in a newborn infant].

A m e r ic a n B a b A s s o c i a t i o n J o u r n a l , October, 1948 (Vol. 34, No. 10). Accomplish­ ments of United Nations: Specific Gains for Peace and Law Give Hope (pp. 866-869, 964-966), Orie L. Phillips; Declaration on Human Rights: Canadian, American Bars Ask Delay of Action (pp. 881-885); Charles Evans Hughes, 1862-1948: America’s Great Diplomat-Jurist Dies (pp. 902-903); The Development of International Law (pp. 910-912), Louis B . Sohn. ------, November, 1948 (Vol. 34, No. 11). Agreements with Russia: Analysis of Factors That May Bring War or Peace (pp. 979-981, 1077-1078), James B. Byrnes; An “ International Bill of Bights” : Proposals Have Dangerous Implications for V. S. (pp. 984-986, 1078-1079), Frank E. Holman; The Development of International Law (pp. 1040-1042), Louis B. Sohn. A m e r ic a n F o r e ig n S e r v ic e J o u r n a l , November, 1948 (Vol. 25, No. 11). The Brookings Institution’s New Program of Research and Education in International Relations (pp. 10-12, 36), Joseph W. Ballantine; American Policy in Respect to China (pp. 14-15, 38), O. Edmund Clubb. A r b i t r a t i o n J o u r n a l , Fall, 1948 (Vol. 3, No. 3). World Arbitration Promise and Achievement (pp. 130-133), Frances Kellor; Enforcement of Arbitral Awards in International Agencies (pp. 134-146), F. Blaine Sloan; The Pact of Bogota (pp. 147­ 155), Josef L. Kunz. A r c h i v d e s V o l k e r r e c h t s (Vol. I, No. 1). Vom Volkerbund mu den Vereinten Nationen (pp. 3-25), Walter Schatzel; Volkerrecht und Welt organisation im Atomzeitalter (pp. 26-47), Georg Sehwarzenberger; Tatigkeit der Vereinten Nationen in volkerrechtlichen Fragen (pp. 48-67), Hans-Jiirgen Sehlochauer; Volkerrechtliche Fragen von europaischer Bedeutung (pp. 68-88), Hans-Jiirgen Schlochauer. -----Vol. I, No. 2). Die Mitgliedschaft in den Vereinten Nationen (pp. 147-187), Friedrich Klein; Zur Frage eines Besatzungsstatuts fur Deutschland (pp. 188-215), Hans-Jiirgen Schlochauer; Die Vorarbeiten der Vereinten Nationen zur Frage des inter­ n ationa l Schutzes des Individuums (pp. 219-231), Berthold Mosheim; Die Entwicklung des zwischenstaatlichen Donauschiffahrtsrechts (pp. 237-242), Georg Martius. B o l e t i n d e l I n s t i t u t o d e D e r e c h o C o m p a ra d o d e M e x i c o , May-August, 1948 (Vol. I, No. 1). Estatuto juridico y fiscal de las sociedades extranjeras en Mexico (pp. 9-26), Joaquin Eodriguez y R.; Ley de Organization Judicial y Cddigo de Procedimiento Civil de la Ciudad del Vaticano (pp. 27-37), Niceto Alcala-Zamora y C. C a n a d ia n B a r R e v ie w , October, 1948 (Vol. XXVI, No. 8). Ireland in International Affairs (pp. 1195-1211), A. Costello. C o lu m b ia L a w R e v ie w , November, 1948 (Vol. 48, No. 7). Extraterritorial Criminal Jurisdiction of a Sovereign over its Nationals ( Coumas v. Superior Court, Cal. 1948) (pp. 1103-1105). La C o h u n it A I n t e r n a t i o n a l® , January, 1948 (Vol. I l l , No. 1). II Quarantotto e I’unitd, europea (pp. 3-9), Luigi Salvatorelli; La dotrina di Truman (pp. 38-44), Rolando Quadri; La Cina dopo la guerra (pp. 61-69), Giuliano Cora. -----, April, 1948 (Vol. I l l , No. 2). La conferenza mondiale del commercio (pp. 189-202), Francesco Coppola D ’Anna; L ’intervento collettivo per la soluzione dei conflitti internazionali nelle triplici dell’Aia (1659-1668) (pp. 203-239), Basilio Cialdea; Sistemi economici supernazionali e commercio internazionale (pp. 240-249), Francesco Milani; I nuovi compiti dell’organizzazione internazionale del lavoro nel campo delle migrazioni (pp. 250-263), Attilio Oblath.

Working memory allows us to hold specific pieces of information in an active and easily retrieved state, but what happens to that information during an unexpected interruption between study and test? To answer this question, we used a surprise trial paradigm in which an unexpected event precedes a probe of the observer's memory for a search target. In the first set of experiments, participants were tasked to report the identity of the target letter before unexpectedly being asked to read a task-irrelevant passage. We observed that the introduction of this passage interfered with the observer's memory of the target letter, but this interference only occurred after participants had experience completing the task without interruption. However, a remember cue placed just prior to the reading prompt reduced this cost, suggesting that participants can rapidly reinforce information about the target in working memory to resist the interference. We then used this same cuing manipulation to test whether information in an attribute amnesia paradigm, which unexpectedly probes an attribute relevant to target selection but irrelevant to participant's response expectations, could also be protected against unexpected interference. Using this paradigm, we observed that a remember cue did not improve performance following the surprising event, which supports theories that attribute amnesia is not caused solely by interference. These results reveal both the vulnerability and flexibility of working memory and demonstrate the importance of understanding how task experience establishes expectations that impact the underlying cognitive representations formed by the observer. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Slipping through the cracks: The peril of unexpected interruption on the contents of working memory.

The influence of category representativeness on the low prevalence effect in visual search

It has been debated whether salient distractors in visual search can be proactively suppressed to completely prevent attentional capture, as the occurrence of proactive suppression implies that the initial shift of attention is not entirely driven by physical salience. While the presence of a Pd component in the EEG (associated with suppression) without a preceding N2pc component (associated with selection) has been used as evidence for proactive suppression, the link between these ERPs and the underlying mechanisms is not always clear. This is exemplified in two recent papers that observed the same waveform pattern, where an early Pd-like component flipped to a N2pc-like component, but provided very different interpretations (Drisdelle & Eimer, Psychophysiology, 58(9), 1-12, 2021; Kerzel & Burra, Journal of Cognitive Neuroscience, 32(6), 1170-1183, 2020). Using RAGNAROC (Wyble et al., Psychological Review, 127(6), 1163-1198, 2020), a computational model of reflexive attention, we successfully simulated this ERP pattern with minimal changes to its existing architecture, providing a parsimonious and mechanistic explanation for this flip in the EEG that is unique from both of the previous interpretations. Our account supports the occurrence of proactive suppression and demonstrates the benefits of incorporating computational modelling into theory building.

What the flip? What the P-N flip can tell us about proactive suppression

The early attentional pancake: Minimal selection in depth for rapid attentional cueing

Is attribute amnesia really just forgetting?: Assessing the influence of reading on surprise trial performance

And like that, they were gone: A failure to remember recently attended unique faces

We investigated the extents of automaticity in location and orientation encoding in visual working memory (VWM) by manipulating their task relevance and assessing the amount of resource recruited by their encoding. Across five experiments, participants were surprised with a location report trial (Experiment 1A, 2A, and 3) or an orientation report trial (Experiment 2A and 2B) at a point when only the item's color had been task-relevant. This was followed by control trials to assess the memory quality of color when location or orientation had become task-relevant. We found the surprise trial performance to be significantly worse than the first control trial for both location and orientation, although to a greater extent for orientation for which there was virtually no measurable information from the subjects' reports. This was the case even when encoding was the only incidental memory process before the control trials (Experiment 2A and 2B), and the surprise memory costs cannot be attributed to the unexpectedness inherent to the surprise question (Experiment 3). The control trials revealed a consistent reduction of color memory only in the orientation experiments. These results suggest that although location encoding is more automatic than orientation, neither is encoded in a fully automatic manner. Our results show that incidentally encoded location is only coarse-grained, constraining the spatial precision of space-based indexing systems. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Location has a privilege, but it is limited: Evidence from probing task-irrelevant location.

Abstract In this critical review, we examine the application of predictive models, for example, classifiers, trained using machine learning (ML) to assist in interpretation of functional neuroimaging data. Our primary goal is to summarize how ML is being applied and critically assess common practices. Our review covers 250 studies published using ML and resting-state functional MRI (fMRI) to infer various dimensions of the human functional connectome. Results for holdout (“lockbox”) performance was, on average, ∼13% less accurate than performance measured through cross-validation alone, highlighting the importance of lockbox data, which was included in only 16% of the studies. There was also a concerning lack of transparency across the key steps in training and evaluating predictive models. The summary of this literature underscores the importance of the use of a lockbox and highlights several methodological pitfalls that can be addressed by the imaging community. We argue that, ideally, studies are motivated both by the reproducibility and generalizability of findings as well as the potential clinical significance of the insights. We offer recommendations for principled integration of machine learning into the clinical neurosciences with the goal of advancing imaging biomarkers of brain disorders, understanding causative determinants for health risks, and parsing heterogeneous patient outcomes.

Feeding the machine: Challenges to reproducible predictive modeling in resting-state connectomics

Perceiving what is not there: Distractor intrusions accounted for by a computational model.

Location Encoding in Visual Working Memory is not Completely Automatic

Accumulating evidence suggests that many findings in psychological science and cognitive neuroscience may prove difficult to reproduce; statistical power in brain imaging studies is low and has not improved recently; software errors in analysis tools are common and can go undetected for many years; and, a few large‐scale studies notwithstanding, open sharing of data, code, and materials remain the rare exception. At the same time, there is a renewed focus on reproducibility, transparency, and openness as essential core values in cognitive neuroscience. The emergence and rapid growth of data archives, meta‐analytic tools, software pipelines, and research groups devoted to improved methodology reflect this new sensibility. We review evidence that the field has begun to embrace new open research practices and illustrate how these can begin to address problems of reproducibility, statistical power, and transparency in ways that will ultimately accelerate discovery.

Progress toward openness, transparency, and reproducibility in cognitive neuroscience

With the increasing use of technology in the field of cognitive science there has been a need for software that can accomplish the tasks needed to further research. Many experiments require high levels of precision in spatial and temporal presentation of stimuli as well as the ability to collect data from participants. Many toolkits have been created for this purpose ranging different platforms and purposes. However, most psychologists lack the knowledge required to use these different toolkits, since they require substantial experience with programming languages like Python or MATLAB. Acquiring the necessary skills to use these toolkits is often practically impossible since the learning curve can be quite steep before one gets to the point of being able to use these tools effectively. The Stream Toolkit was created to bridge this gap. Stream simplifies the programming side of the experimental design process and allows people with a relatively basic level of programming knowledge to create complex experiments. Stream provides user-friendly scripts as well as many tutorials that will walk researchers through various aspects of experiment design, such as creating stimuli, displaying them, collecting responses, and analyzing data. It is still necessary to understand basic MATLAB functions and syntax in order to begin using Stream. The documentation provides a list of basic commands and topics that should be learned prior to beginning. Stream can be downloaded at: [https://bitbucket.org/streamtoolbox/stream_official_toolbo x/downloads].

Stream: A toolkit for rapidly developing high precision experiments

Children learn to build a visual representation of the world from unsupervised exploration and we hypothesize that a key part of this learning ability is the use of self-generated navigational information as a similarity label to drive a learning objective for selfsupervised learning. The goal of this work is to exploit navigational information in a visual environment to provide performance in training that exceeds the stateof-the-art self-supervised training. Here, we show that using spatial and temporal information in the pretraining stage of contrastive learning can improve the performance of downstream classification relative to conventional contrastive learning approaches that use instance discrimination to discriminate between two alterations of the same image or two different images. We designed a pipeline to generate egocentric-vision images from a photorealistic ray-tracing environment (ThreeDWorld) and record relevant navigational information for each image. Modifying the Momentum Contrast (MoCo) model, we introduced spatial and temporal information to evaluate the similarity of two views in the pretraining stage instead of instance discrimination. This work reveals the effectiveness and efficiency of contextual information for improving representation learning. The work informs our understanding of the means by which children might learn to see the world without external supervision.

Abstract In this issue, Pessoa emphasizes the importance of viewing neural activity from a perspective that functional networks form dynamically in a way that dramatically changes the functional contribution of individual brain areas. In this response, I argue that we should strive toward pluralism in understanding neural activity at both the emergent network and modular levels, on the bases that a purely emergent understanding would be incomplete, and that there are computational advantages to anatomically stable modularity.

Machine learning offers a promising set of prediction tools that have enjoyed more recent application in network neuroscience. In this NETN Perspectives, we examine the current application of predictive models, e.g., classifiers trained using machine learning (ML), within the clinical network neurosciences. Our review covers 118 studies published using ML and functional MRI (fMRI) to infer various dimensions of the human functional connectome. We identify several important methodological challenges in this literature. For example, more than half of the studies focused almost exclusively on maximizing the accuracy of classifying brain functional connectomes into one of several predetermined categories (e.g., disease versus healthy), with significantly less emphasis on reproducibility and generalizability of the findings.. . There was also a concerning lack of transparency across many of the key steps in training and evaluating predictive models using machine learning. The summary of this literature underscores the importance of external validation (i.e., lockbox or test-set data) and highlights several methodological pitfalls that can be addressed by the imaging community. We offer recommendations for the principled application of machine learning in the clinical neurosciences to advance imaging biomarkers, understand causative determinants for health risks and track the trajectory of heterogeneous patient outcomes.

Feeding the machine: challenges to reproducible predictive modeling in network neuroscience

Visual knowledge obtained from our lifelong experience of the world plays a critical role in our ability to build short-term memories. We propose a mechanistic explanation of how working memories are built from the latent representations of visual knowledge and can then be reconstructed. The proposed model, Memory for Latent Representations (MLR), features a variational autoencoder with an architecture that corresponds broadly to the human visual system and an activation-based binding pool of neurons that binds items’ attributes to tokenized representations. The simulation results revealed that the shapes of familiar items can be encoded and retrieved efficiently from latents in higher levels of the visual hierarchy. On the other hand, novel patterns that are completely outside the training set can be stored from a single exposure using only latents from early layers of the visual system. Moreover, a given stimulus in working memory can have multiple codes, representing specific visual features such as shape or color, in addition to categorical information. Finally, we validated our model by testing a series of predictions against behavioral results obtained from WM tasks. The model provides a compelling demonstration of how visual knowledge yields compact visual representation for efficient memory encoding.

Memory for Latent Representations: An Account of Working Memory that Builds on Visual Knowledge for Efficient and Detailed Visual Representations

How do we imagine visual objects and combine them to create new forms? To answer this question, we need to explore the cognitive, computational and neural mechanisms underlying imagery and creativity. The body of research on deep learning models with creative behaviors is growing. However, in this paper we suggest that the complexity of such models and their training sets is an impediment to using them as tools to understand human aspects of creativity. We propose using simpler models, inspired by neural and cognitive mechanisms, that are trained with smaller data sets. We show that a standard deep learning architecture can demonstrate imagery by generating shape/color combinations using only symbolic codes as input. However, generating a new combination that was not experienced by the model was not possible. We discuss the limitations of such models, and explain how creativity could be embedded by incorporating memory mechanisms to combine the network’s output into new combinations and use that as new training data.

Seeking the Building Blocks of Visual Imagery and Creativity in a Cognitively Inspired Neural Network

Previous research has shown that Attentional blink (AB) data can differ between tasks, or subjects and it can be challenging to interpret these differences. In this paper, we provided a ready-to-use tool that allows researchers to map their data onto the episodic Simultaneous Type, Serial Token (eSTST) model. This tool uses the Markov Chain Monte Carlo algorithm to find the best set of 3 model parameters to simulate a given AB pattern. These 3 parameters have cognitive interpretations, such that differences in these parameters between different paradigms can be used for inferences about the timing of attentional deployment or the encoding of memory. Additionally, our tool allows for a combination of quantitative fitting against the overall pattern of data points, and qualitative fitting for theoretically important features. We demonstrate the algorithm using several data sets, showing that it can find cognitively interpretable parameter sets for some of them, but fails to find a good fit for one data set. This indicates an explanatory boundary of the eSTST model. Finally, we provide a feature to avoid overfitting of individual data points with high uncertainty, such as in the case of individual participant data.

How to interpret attentional blink findings? A practical MCMC tool to assess the attentional blink with the eSTST model

There have been conflicting findings on the degree to which exogenous/reflexive visual attention is selective for depth, and this issue has important implications for attention models. Previous findings have attempted to find depth-based cueing effects on such attention using reaction time measures for stimuli presented in stereo goggles with a display screen. Results stemming from such approaches have been mixed, depending on whether target/distractor discrimination was required. To help clarify the existence of such depth effects, we have developed a paradigm that measures accuracy rather than reaction time in an immersive virtual-reality environment, providing a more appropriate context of depth. Four modified Posner Cueing paradigms were run to test for depth-specific attentional selectivity. Participants fixated a cross while attempting to identify a rapidly masked letter that was preceded by a cue that could be valid in depth and side, depth only, or side only. In Experiment 1, a potent cueing effect was found for side validity and a weak effect was found for depth. Experiment 2 controlled for differences in cue and target sizes when presented at different depths, which caused the depth validity effect to disappear entirely even though participants were explicitly asked to report depth and the difference in virtual depth was extreme (20 vs 300 meters). Experiments 3a and 3b brought the front depth plane even closer (1 m) to maximize effects of binocular disparity, but no reliable depth cueing validity was observed. Thus, it seems that rapid/exogenous attention pancakes 3-dimensional space into a 2-dimensional reference frame.

The early attentional pancake: Lack of selection in depth for rapid exogenous cueing

No explicit memory for individual trial display configurations in a visual search task

Transforming Latent Descriptors into memory Representations: The TLDR model of working memory

To what extent does specific spatiotopic location accompany the remembered representation of a visual event? Feature integration theory suggests that identifying a multi-feature object requires focusing on its spatial location to integrate those features. Moreover, single unit data from anterior ventral stream neurons that fire preferentially to complex objects indicates that they have retinotopic receptive fields. It can, therefore, be predicted that location information of features of a complex stimulus is inherent in the memory of a perceived visual stimulus’ representation. To evaluate this prediction, we presented participants with a brief array of characters with instructions to identify and locate the solitary letter among a set of digits. Surprisingly, analysis of trials in which the target identity was accurately reported indicated that in more than 15% of trials (i.e., in Experiments 2b & 2c) participants were almost completely uninformed about the location of the letter that they had just identified. Further analysis showed that there were two main sources of these location errors; misbinding the target to the distractors’ locations and extremely poor spatial representation of the target’s location to an extent that was indistinguishable from guessing. The latter finding indicates that consciously accessible representations of visual events can form despite being untethered to robust and spatially-specific representations, implying that the specific location was either not quite encoded into working memory, or was rapidly forgotten. However, when the target was marked by a single feature (color), there was no evidence of remembering the target identity without remembering its location even with strong masking.

Memories of Visual Events Can Be Formed Without Specific Spatial Coordinates

Finding the Explanatory Limits of the eSTST Model of the Attentional Blink

Developing an OATS (Operationalized Attentional Task Set): Assessing how attentional sets update with task experience

A quintessential challenge for any perceptual system is the need to focus on task-relevant information without being blindsided by unexpected, yet important information. The human visual system incorporates several solutions to this challenge, 1 of which is a reflexive covert attention system that is rapidly responsive to both the physical salience and the task-relevance of new information. This article presents a model that simulates behavioral and neural correlates of reflexive attention as the product of brief neural attractor states that are formed across the visual hierarchy when attention is engaged. Such attractors emerge from an attentional gradient distributed over a population of topographically organized neurons and serve to focus processing at 1 or more locations in the visual field, while inhibiting the processing of lower priority information. The model moves toward a resolution of key debates about the nature of reflexive attention, such as whether it is parallel or serial, and whether suppression effects are distributed in a spatial surround, or selectively at the location of distractors. The model also develops a framework for understanding the neural mechanisms of visual attention as a spatiotopic decision process within a hierarchy and links them to observable correlates such as accuracy, reaction time (RT), and the N2pc and PD components of the electroencephalogram (EEG). This last contribution is the most crucial for repairing the disconnect that exists between our understanding of behavioral and neural correlates of attention. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Understanding visual attention with RAGNAROC: A reflexive attention gradient through neural AttRactOr competition.

A delay in sampling information from temporally autocorrelated visual stimuli

It is well-known that in free recall participants tend to recall words presented close together in time in sequence, reflecting a form of temporal binding in memory. This contiguity effect is robust, having been observed across many different experimental manipulations. In order to explore a potential boundary on the contiguity effect, participants performed a free recall task in which items were presented at rates ranging from 2 Hz to 8 Hz. Participants were still able to recall items even at the fastest presentation rate, though accuracy decreased. Importantly, the contiguity effect flattened as presentation rates increased. These findings illuminate possible constraints on the temporal encoding of episodic memories.

Rapid Presentation Rate Negatively Impacts the Contiguity Effect in Free Recall

The human visual system faces an extraordinary challenge in building memories from a continuous stream of visual data without the opportunity to store it and process offline. This suggests a crucial role for visual attention in attending to specific moments in time. This project outlines key data and theories related to human temporal attention. The focus of this submission is on bridging the divide between the human visual system and artificial models by explicating segmentation mechanisms that accelerate the ability to learn the structure of the world through continuous vision. A computational model that simulates the temporal dynamics of visual attention in humans indicates a role for attention in on-demand temporal segmentation of incoming information at the sub-second scale. We predict that in humans this segmentation plays a key role in 1) simplifying visual information for learning about object kinds through compression 2) segmenting information from neighboring fixations and 3) encoding the temporal sequence of events. Such segmentation is likely to also play a key role in allowing artificial systems to learn from visual input in an online fashion, even though their specific temporal constraints are not shared with biology.

As our environment is frequently changing, it is common that our expectations are violated by unexpected stimuli or events, which leaves us uncertain about which pieces of information will be useful in the future. It is unclear how an expectation violation affects the subsequent control settings for processing of information. The current study directly addressed this issue by employing a double-surprise-trial paradigm based on the attribute amnesia task (Chen & Wyble, 2015a). In Experiment 1, participants were asked to report the location of a target letter presented among distractor digits on several trials and were then unexpectedly asked to report a different attribute (color or identity) of the target letter. In the next trial, participants were asked another unexpected question about the other attribute (identity or color respectively). The results show that, despite participants’ poor performance in the first surprise trial, which replicated the attribute amnesia effect, their memory performance in the second surprise trial was dramatically improved, even when the probed attribute was different from that of the first surprise trial. This was also true in Experiment 2, where 15 trials were inserted between the two surprise trials. Experiment 3 further clarified that this effect is not triggered by the mere presence of a surprise test, but rather the violation of expectation about the nature of a surprise test. These results suggest the operation of an adaptive control mechanism that reduces the selectivity of processing in the face of unexpected events.

Journal of Experimental Psychology: Human Perception and Performance

Expecting the Unexpected: Violation of Expectation Shifts Strategies Toward Information Exploration

On the limits of evidence accumulation of the preconscious percept

A quintessential challenge for any perceptual system is the need to focus on task-relevant information without being blindsided by unexpected, yet important information. The human visual system incorporates several solutions to this challenge, one of which is a reflexive covert attention system that is rapidly responsive to both the physical salience and the task-relevance of new information. Decades of research have outlined the capabilities of such attentional effects using both behavioral and neural correlates. This paper presents a comprehensive model for explaining both kinds of data as the product of brief neural attractor states that are distributed across the visual hierarchy at the moment when attention is engaged at a location in the visual field. Such attractors emerge from a competitive attentional gradient distributed over a population of topographically organized neurons. The model helps to resolve key debates about the nature of reflexive attention, such as whether it is parallel or serial, and whether suppression effects are distributed in a spatial surround, or selectively at the location of distractors. Most importantly, the model develops a framework for understanding the neural mechanisms of visual attention, and links those mechanisms to observable behavioral and neural correlates such as accuracy, reaction time, and ERPs such as the N2pc and Pd. This last contribution is the most crucial for repairing the disconnect that exists between our understanding of behavioral and neural correlates of attention.

Understanding visual attention with RAGNAROC: A Reflexive Attention Gradient through Neural AttRactOr Competition

We often remember information without its source (e.g., word or picture format). This phenomenon has been studied extensively in long-term memory but rarely in the context of short-term working memory (WM), which leaves open the question of whether source amnesia can result from a lack of memory encoding rather than forgetting. This study provided a series of striking and novel demonstrations showing participants’ inability to report the source of a color representation immediately after that color was used in a task and stored in memory. These counterintuitive findings occurred when participants repeatedly judged the congruency between two color representations from one single object (i.e., color and identity of a color word) or two distinct objects (i.e., color of a square and identity of a color word) and then were unexpectedly asked to report the source of one color representation. These discoveries suggest that source information is often not stored in WM.

Is Source Information Automatically Available in Working Memory?

The visual system can use conceptual information to search for targets even in the absence of clear featural signifiers1, and visual saccades are often directed at target objects defined by conceptual content2. These abilities are a core component of our facility with the visual world. Here, we evaluate whether contingent mechanisms of visual attention, known to trigger in response to target features such as motion, color or luminance3, are also triggered by visual patterns that match conceptually specified categories. These pre-registered experiments provide convergent behavioral and electrophysiological support that attention is rapidly triggered by natural image exemplars from superordinate conceptually described target sets such as dinner food or four-legged animal, causing a rapid, spatially selective, covert enhancement of visual input, even though images were never repeated within a given experiment. In the behavioral experiment, two such targets presented in sequence elicited higher accuracy for reporting the second when it appeared in the same spatial location as the first. In the EEC experiment, target images elicited clear N2pcand P3 components only when those images matched the conceptually specified target set. The same images elicited no comparable waveforms when they were not of the target set. The latency of the N2pc peaked at roughly 250ms, which is comparable to that commonly found in other N2pc studies for simpler stimulus types. These results suggest that vision is able to quickly decode conceptual information from natural images and selectively deploy spatial attention to locations containing information that matches current search goals.

Conceptual content in images triggers rapid shifts of covert attention

The visual system deploys attention reflexively in response to important stimuli to facilitate rapid selection. To better understand how a system that is distributed across a hierarchy of brain areas coordinates this rapid response, we have developed a computational model that simulates reflexive attention as a recurrent lock-on state between topographically aligned cortical areas. This model provokes key questions about reflexive attention that we study through the N2pc, an EEG component that indexes the timing and lateralization of stimulus-driven attention. A key finding from such research is that for two sequential targets sharing a location, the second elicits no N2pc, despite being easily perceivable. This suggests that attention locks-on to a target’s location and carries forward in time to a second target without being redeployed. Here, we assess key properties of reflexive attention in four EEG experiments. First, the lock-on N2pc effect generalizes to feature target types. Second, the lock-on state is specific to a location, not just a visual hemifield. Third, reflexive attention decays as the interval between two targets increases, such that a second target will once-again elicit an N2pc at longer intervals. Finally, the lock-on state is not specific to a particular target type, which implies that reflexive attention is mediated using representations that are not stimulus-specific. These results provide important constraints on our understanding of visual attention. We incorporate those constraints in a formalized model of attention that elucidates the link between neural mechanisms and a key neural correlate of attention.

A Hierarchical Model of Visual Processing Simulates Neural Mechanisms Underlying Reflexive Attention

The attentional blink (AB) is thought to help the visual system parse and categorize rapidly changing information by segmenting it into temporal chunks, and is elicited using Rapid Serial Visual Presentation. It is reflected in a decrease in accuracy at detecting the second of two targets presented within 200-500 ms of the first, and its development appears to be protracted on tasks that require set-shifting. Here, younger (M = 8.5 years) and older (M = 12.8 years) children and adults (M = 19.13 years) completed a simple AB task with no set-shift requirement in which participants detected two letters in a stream of numbers presented at a rate of 135 ms/item. In addition to assessing the developmental course of the AB on this simple task, we also assessed temporal order errors, or swaps. The AB and its associated characteristics are present in both groups but developmental differences were noted in the depth of the AB, and the presence or absence of lag-1 sparing. These developmental changes were explained by changes in a single parameter, inhibition, using the eTST model, which suggests that the AB is an adaptive function of the visual system.

Adults blink more deeply: a comparative study of the attentional blink across different age groups.

Previous work has shown mixed evidence regarding age-related deficits for binding in working memory. The current study used the newly developed attribute amnesia effect (H. Chen & Wyble, 2015a) to test the associative-deficit hypothesis during working memory and to probe whether hyper-binding extends to include binding of de-selected information. In studies of attribute amnesia, participants use target attributes (e.g., identity, color) to demonstrate near ceiling levels of reporting of a second target attribute (e.g., location) across a series of trials (H. Chen & Wyble, 2015a, 2016). Yet, despite having just processed the target-defining attribute, they have difficulty reporting it on a surprise trial. This effect provides several predictions for associative binding in aging. The associative-deficit hypothesis predicts age-related decline on the surprise trial, whereas an extension of hyper-binding predicts age-related increase in performance in older adults. In Experiment 1, when working memory load was low, older adults demonstrated attribute amnesia equal to that found in younger adults. When load increased in Experiment 2, older adults again demonstrated attribute amnesia as well as an age deficit for reporting target attributes. In lieu of spontaneous binding, results suggest that expectancy plays a critical role in older adults’ propensity to encode and bind target attributes in working memory. Results further suggest that expectancy alone is not enough for older adults to form bound representations when task demands are high. Taken together results revealed a boundary condition of hyper-binding and further provided conditional support for the associative-deficit hypothesis in working memory.

Using Attribute Amnesia to Test the Limits of Hyper-Binding and Associative Deficits in Working Memory

The Neglected Contribution of Memory Encoding in Spatial Cueing effects: A New Theory of Costs and Benefits

From location to configuration: Does the Structure of a Display stick in memory as strongly as target location?

Modeling the neural underpinnings of attentional suppression as constrained by EEG and behavioral data

Spatial cueing is thought to indicate the resource limits of visual attention because invalidly cued items are reported more slowly and less accurately than validly cued items. However, limited resource accounts cannot explain certain findings, such as dividing attention without costs, or attentional benefits without invalidity costs. The current study presents a new account of exogenous cueing, namely the memory encoding cost (MEC) theory, which integrates attention and memory encoding to explain costs and benefits evoked by a spatial cue. Unlike conventional theories that focus on the role of attention in yielding spatial cueing effects, the MEC theory argues that some cueing effects are caused by a combination of attentional facilitation evoked by the cue, but also the cost of encoding the cue into memory. The crucial implication of this theory is that limitations in attentional deployment may not necessarily be the cause of invalidity costs. MEC generates a number of predictions that we test here, providing five convergent lines of evidence that cue encoding plays a key role in producing cueing effects. Furthermore, the MEC suggests a common mechanism underlying cueing costs and the attentional blink, and we simulate the core empirical findings of the current study with an existing attentional blink model. The model was able to simulate these effects primarily through manipulation of a single parameter that corresponds to memory encoding. The MEC theory thus simplifies our theoretical understanding of attentional effects by linking the attentional blink and some varieties of spatial cueing costs to a common mechanism.

The Neglected Contribution of Memory Encoding in Spatial Cueing: A New Theory of Costs and Benefits

To what extent does spatiotopic location accompany the representation of a visual event? Feature integration theory suggests that identifying a multi-feature object requires focus on its spatial location to integrate those features. Moreover, single unit data from neurons preferring complex objects, indicates that they have retinotopic receptive fields. It can therefore be predicted that identification of complex stimuli is contingent upon localization of their features by attention. To evaluate this, we presented participants with a brief array of characters with instructions to identify and locate the solitary letter. Surprisingly, subjects sometimes identified the target without knowing where it had been presented. However, when targets were marked by a single feature (color), there was no evidence of identifying the target without locating it also. These results indicate that consciously accessible representations of visual events can form despite being untethered to spatially specific neural activity in early visual areas.

Awareness of visual events without concomitant spatiotopic information

Attribute amnesia is a phenomenon in which information about a stimulus that was just recently used to perform a task is poorly remembered in a surprise test (Chen & Wyble, 2015a). In a recent article by Jiang, Shupe, Swallow, and Tan (2016), this effect was replicated but with an additional priming measure that revealed some carryover memory for the information that participants had trouble explicitly reporting on the surprise trial. Their work invites a discussion of the underlying cause of attribute amnesia by suggesting that the surprise question caused an overwriting of working memory contents. Although we agree that overwriting may be partially responsible for the inability to report, data from other experiments have suggested that a failure to consolidate a robust memory of the attended information is a major cause of the amnesia. We discuss experimental evidence supporting the theory that memory consolidation of attended information is an optional process that can be selectively evoked by task requirements. (PsycINFO Database Record

Memory consolidation of attended information is optional: Comment on Jiang et al. (2016).

Presentation Abstract Summary One of the most challenging aspects of perception for any agent is the decision of what to attend. What makes information “important” is often thought to be a combination of goal-defined top-down control (e.g. searching for the exit sign while driving down the highway), and stimulus driven bottom-up salience (e.g. a deer suddenly appearing in front of your car). Mediating between these two competing requirements is a major challenge that the brain meets by allowing stimuli to compete for the control of attention. We present a model of this competition that allows information to be either enhanced or suppressed depending on the outcome of the competition. This Reactive-Convergent Gradient Field (R-CGF) model is a unique approach to modeling spatial attention in that it links neural mechanisms to EEG data. This model was developed with the aim of explaining different, sometimes conflicting, findings in the attention literature, such as whether attention is serial or parallel, and the spatial distribution of suppression. By fitting a large number of behavioral and neural correlates of attention, the R-CGF offers useful insight into a general solution to the stimulus competition problem.

Modeling the neural circuitry underlying the behavioral and EEG correlates of attentional capture

Developmental changes in feature detection across time: Evidence from the attentional blink.

Preprint:The neglected contribution of memory encoding in spatial cueing: A new theory of costs and benefits

Competitive interactions affect working memory performance for both simultaneous and sequential stimulus presentation

Measuring the speed of attentional selection for two features concurrently from a single object reveals a foveal speed advantage for color

A system level model of visual attention: Targets and distractors are figments of your experimental design

Non-singleton colors are not attended faster than categories, but they are encoded faster: A combined approach of behavior, modeling and ERPs

Working memory representations persist in the face of unexpected task alterations

Expecting the unexpected: expecting to be surprised reduces attribute amnesia

Does an unexpected task reset the contents of visual working memory

Children with Autism Detect Targets at Very Rapid Presentation Rates with Similar Accuracy as Adults

When does visual attention need to be retargeted? A study of the neural correlates of attentional deployment to two sequential targets

Towards a unified multiresolution vision model for autonomous ground robots

Measuring attentional deployment and sampling of multiple dynamic features within the same object

Competitive interactions occur during working memory encoding and iconic memory but not during working memory maintenance.

Accessing without remembering: memory consolidation of information at the focus of awareness is optional

Prolonged focal attention without binding: Tracking a ball for half a minute without remembering its color

For the most part, visual working memory research uses simple shapes, such as colored squares, precisely because there are few prelearned bindings of feature values for such stimuli; one colored square is almost as likely as another for most of us. These artificial stimuli give the researcher greater control over the amount of information to be stored, since the visual system of the participant will be limited in its ability to chunk or compress the information.

Smeets et al. (2016) suggested that motor adjustments may be quick because they don’t require stimulus detection. We agree that these rapid adjustments probably reflect rapid perceptual processing rather than rapid motor execution, but we question whether the absence of detection is the best way to explain the effect. We suggest that it is unclear what mechanisms would be involved in detection and why detection would be required in some of the cases discussed by Smeets et al. Instead, we suggest that ultra-fast motor adjustments require very little competition among possible stimuli or responses. We suggest that escaping competition rather than avoiding detection may be the cause of the very short reaction times that Smeets et al. identified.

Are Motor Adjustments Quick Because They Don't Require Detection or Because They Escape Competition?

Working memory is a limited resource. To further characterize its limitations, it is vital to understand exactly what is encoded about a visual object beyond the "relevant" features probed in a particular task. We measured the memory quality of a task-irrelevant feature of an attended object by coupling a delayed estimation task with a surprise test. Participants were presented with a single colored arrow and were asked to retrieve just its color for the first half of the experiment before unexpectedly being asked to report its direction. Mixture modeling of the data revealed that participants had highly variable precision on the surprise test, indicating a coarse-grained memory for the irrelevant feature. Following the surprise test, all participants could precisely recall the arrow's direction; however, this improvement in direction memory came at a cost in precision for color memory even though only a single object was being remembered. We attribute these findings to varying levels of attention to different features during memory encoding.

Memory for a single object has differently variable precisions for relevant and irrelevant features.

Machine learning is a powerful set of techniques that has enhanced the abilities of neuroscientists to interpret information collected through EEG, fMRI, MEG, and PET data. With these new techniques come new dangers of overfitting that are not well understood by the neuroscience community. In this article, we use Support Vector Machine (SVM) classifiers, and genetic algorithms to demonstrate the ease by which overfitting can occur, despite the use of cross validation. We demonstrate that comparable and non-generalizable results can be obtained on informative and non-informative (i.e. random) data by iteratively modifying hyperparameters in seemingly innocuous ways. We recommend a number of techniques for limiting overfitting, such as lock boxes, blind analyses, and pre-registrations. These techniques, although uncommon in neuroscience applications, are common in many other fields that use machine learning, including computer science and physics. Adopting similar safeguards is critical for ensuring the robustness of machine-learning techniques.

I tried a bunch of things: The dangers of unexpected overfitting in classification of brain data

A recently reported phenomenon, termed attribute amnesia, challenged the commonly held belief that attention plays the determining role in controlling how information is remembered, by showing that participants fail to remember a specific attended attribute (e.g., the target-defining color), even when they had just used that attribute to perform a task (Chen & Wyble, 2015a). The main purpose of the present study sought to better understand the mechanism underlying this phenomenon. The results revealed that attribute amnesia was nearly eliminated once participants were forced to store and hold attended information for a brief time, suggesting that this amnesia effect most likely reflects a lack of memory consolidation for an attended attribute that had been processed to some certain level. In addition, we demonstrated that the effect is not particular to the use of location report or the repetition of targets. One additional finding is that amnesia was markedly absent for location memory, indicating an important difference between memories for locations and attributes such as color or identity. (PsycINFO Database Record

Attribute amnesia reflects a lack of memory consolidation for attended information.

We have a good understanding of how well people can remember a relevant feature of an attended object (e.g. color of a color patch; Bays et al., 2009), but we know relatively little about how an attended object's task irrelevant features are encoded (e.g. shape of a color patch). Previous research suggests that we have some categorical knowledge of irrelevant features (Eitam et al., 2013), but knowing the precision with which this information is stored is essential for understanding the capacity of working memory. To better understand the memory of irrelevant features, we presented participants with a colored arrow, and for the first 25 trials, consistently asked participants about its color using a color wheel. On trial 26, we cued participants to recall the direction of the arrow in a surprise test (i.e. the critical trial). To determine how participants are responding on the critical trial, we compared the log likelihood of different combinations of von Mises distributions' fit to the behavioral data, with the distributions varying from precise to guessing (i.e. uniform distribution). From this comparison process, we find that some participants remember the irrelevant information imprecisely, relative to a relevant feature response distribution, while other participants are simply guessing. Importantly, after the surprise test, all participants could easily recall the arrow's direction but this improvement in direction memory came at a significant cost in precision for color memory. We attribute these findings to varying levels of attention to different features during memory encoding. To understand how these tradeoffs occur at a mechanistic level, we simulated featural attention in the Binding Pool model of visual Working Memory (Swan & Wyble 2014) according to findings from monkey neurophysiology (McAdams et al., 1999). The model accurately simulates imprecise retrieval for irrelevant features and the cost of adding features to a memory. Meeting abstract presented at VSS 2015.

Measuring the memory quality of a task irrelevant feature of an attended object.

Theories of human cognition generally agree in assuming the existence of a fundamental limit in information processing, but these theories are challenged by findings that appear to circumvent these limitations. We argue that theories are needed that offer a principled account of why the limitations

On the interplay between working memory consolidation and attentional selection in controlling conscious access: parallel processing at a cost—a comment on ‘The interplay of attention and consciousness in visual search, attentional blink and working memory consolidation’

Competing theories regarding the neural mechanism underlying the N2pc suggest that it reflects target enhancement or distractor suppression, but we suggest a different theory. In our study, participants viewed a bilateral dual-stream rapid serial visual presentation (RSVP). Each trial had either one or two targets (T1, T2) presented either in the same or different streams. We found that the N2pc elicited by T1 was not affected by an immediately following T2 at the same location. However, if T2 was on the opposite hemifield, a second N2pc was elicited. These results suggest that the N2pc reflects neural processes involved in localizing a target to initiate the deployment of attention, rather than the sustained enhancement of processing at that location or distractor inhibition. We have created a computational model of a convergent gradient-filter model of attention that reproduces the observed event-related potential traces and makes five testable predictions to be addressed in future work.

Understanding how visual attention locks on to a location: Toward a computational model of the N2pc component.

This article explores the time course of the functional interplay between detection and encoding stages of information processing in the brain and the role they play in conscious visual perception. We employed a multitarget rapid serial visual presentation (RSVP) approach and examined the electrophysiological P3 component elicited by a target terminating an RSVP sequence. Target-locked P3 activity was detected both at frontal and parietal recording sites and an independent component analysis confirmed the presence of two distinct P3 components. The posterior P3b varied with intertarget lag, with diminished amplitude and postponed latency at short relative to long lags—an electroencephalographic signature of the attentional blink (AB). Under analogous conditions, the anterior P3a was also reduced in amplitude but did not vary in latency. Collectively, the results provide an electrophysiological record of the interaction between frontal and posterior components linked to detection (P3a) and encoding (P3b) of visual information. Our findings suggest that, although the AB delays target encoding into working memory, it does not slow down detection of a target but instead reduces the efficacy of this process. A functional characterization of P3a in attentive tasks is discussed with reference to current models of the AB phenomenon.

The Attentional Blink Impairs Detection and Delays Encoding of Visual Information: Evidence from Human Electrophysiology

When spatial attention is directed by a target towards one side of the visual field, electrodes on the scalp record an asymmetrical electrophysiological potential over parietal cortex called the N2pc. This EEG component has recently been shown to reflect the engagement of attention at a location, but not sustained attentional deployment (Tan & Wyble, In Press). A computational model has interpreted this component as the attentional system "locking-on" to the location of a target (Tan & Wyble, In Press). The Pd is another lateralized component, thought to reflect suppression of distracting information. In contrast to this interpretation, we have run an EEG experiment using four RSVP streams which reveals a Pd elicited by two simultaneously presented targets, when the targets are separated by one degree of visual angle, but not when separated by four degrees. To provide a neural intuition for the mechanisms underlying the Pd component, we have revised our previous neurocomputational model of attentional dynamics so that it simulates both the N2pc and the Pd as suggested by a variety of experimental findings. The new model simulates the Pd as a laterally asymmetric imbalance in the inhibition of attentional control neurons in posterior parietal cortex. This imbalance can have multiple causes, which explains how the Pd is elicited both with and without distractors. Critical to this account is strategic regulation of the attentional focus, such that it is tighter when stimuli are spatially proximal, whether they are targets or distractors. Furthermore, since the Pd can be elicited by distractors without a leading N2pc, the model includes a reactive form of inhibition that can, in some cases, suppress distracting information before it can elicit an attentional response. Meeting abstract presented at VSS 2015.

Understanding the PD and the N2pc: modeling the neural mechanisms underlying spatial attention shifts.

When a target is presented on one side of a visual display, EEG will record a brief negativity from posterior locations on the contralateral scalp about 200ms after target onset. This component, called the N2pc, is thought to reflect the deployment of attention towards the target. The present study contrasted the N2pcs produced by targets defined by feature or by category. Participants viewed two RSVP streams with a 150ms SOA. The distractors were black letters and the targets were either red letters (differing from distractors in feature) or black digits (differing in category). Trials either had one target or two (T1 and T2), with T2 always presented immediately after and on the same side as T1 in all possible combinations of target types. The presentation of the target(s) was followed by another string of distractors and subsequently participants were asked to report what targets they had seen. We found that the N2pc onset was later when T1 was defined by category (digit) versus feature (red letter). From this we predicted that the delay in the localization of attention from a category target would delay the subsequent encoding of that target, such that participants would swap the T1 and T2 in their report more often whenever the first target was specified by category rather than feature. The behavioral data confirmed this prediction. Additionally, in an unexpected finding, the lowest accuracy in reporting both targets involved a categorical T1 (slow localization) followed by a featural T2 (fast localization). This arrangement may have caused the attentional processes evoked by the two attentional sets to collide, thus producing less efficient encoding of the targets from the RSVP stream. The reverse order (feature followed by digit) produced much higher accuracy. Meeting abstract presented at VSS 2015.

Using the N2pc to compare the timing of attentional shifts to categorical and featural targets.

Mapping the spatiotemporal dynamics of interference between two visual targets

Temporal perception deficits in schizophrenia: integration is the problem, not deployment of attentions

Stimulus-stimulus compatibility effects, such as Stroop interference, have been studied for many years as differences in reaction times when stimuli have varying levels of compatibility. However, it is not known whether such interference can be observed in the absence of a response, which would definitively answer questions about whether such interference can exist in a purely perceptual task. To answer this question we measured the difference in the attentional blink of a neutral word caused by a preceding word that was a congruent, incongruent or neutral Stroop stimulus. During the experiment, a fixation cross was presented at the beginning of each trial that was followed by the first target (T1) which was a congruent, neutral or incongruent word presented for 80 msec. On half of the trials, a mask was presented immediately after T1 for 80 msec. The second target (T2) was a neutral word that appeared at one of several latencies following T1 and was always masked. Participants reported the color of both words and always ignored the words themselves. Analyzing accuracy of the T2 on trials when the T1 was accurately reported, we observed a main effect of T1 congruence and an interaction between T1 congruence and inter-target lag. This revealed that the attentional blink was deeper for incongruent T1s. Surprisingly, omitting the first target mask did not reduce the effect of congruence. These results provide the clearest evidence yet that incompatible stimulus attributes reduce the speed of processing during stimulus identification, even in the complete absence of the need to generate a speeded motor response. These results also strongly support computational models in which the identification or encoding of a stimulus can be slowed by the presence of stimulus-stimulus conflict (Kornblum, Stevens, Whipple and Requin 1999; Wyble, Sharma, and Bowman 2008). Meeting abstract presented at VSS 2015.

Measuring Stroop interference in the absence of response generation using the attentional blink.

People intuitively believe that when they become consciously aware of a visual stimulus, they will be able to remember it and immediately report it. The present study provides a series of striking demonstrations of behavior that is inconsistent with such an intuition. Four experiments showed that in certain conditions, participants could not report an attribute (e.g., letter identity) of a stimulus even when that attribute had been attended and had reached a full state of conscious awareness just prior to being questioned about it. We term this effect attribute amnesia, and it occurs when participants repeatedly locate a target using one attribute and are then unexpectedly asked to report that attribute. This discovery suggests that attention to and awareness of a stimulus attribute are insufficient to ensure its immediate reportability. These results imply that when attention is configured by using an attribute for target selection, that attribute will not necessarily be remembered.

We intuitively believe that when we attend to an attribute (e.g., color or identity) of a highly visible stimulus, we will be able to report it immediately afterwards. Conventional theories of cognition also suggest attention as a gateway to working memory (e.g., Awh, Vogel, & Oh, 2006), or regard working memory as an interface in which attention can operate in the absence of visual input (Chun, 2011). Despite extensive evidence showing the crucial contribution of attention in the storage and maintenance of information, recent experiments have revealed striking demonstrations that a more important determinant of robust memory storage is the expectation of the observer that the attended information needs to be remembered (Chen & Wyble, in press at Psychological Science; Eitam et al., 2013). In our experiments, participants were asked to locate a target among distractors by using one particular attribute (e.g., letter identity) for several repetitions and were then surprisingly asked to report that attribute. The results showed that participants could not report the attribute of the target, even though that attribute had been attended and used by participants to perform the primary task (e.g., localized a target letter among digits) just prior to the surprise question. Followup control trials ensure that this effect is not a failure of perception. We term this effect attribute amnesia. In an extension, participants counted passes of a colored ball in a video recorded from a real-world context. In a surprise trial, 35% of participants could not report the color of the ball they had just been tracking for 40 seconds. These results change our understanding of the link between attention and memory. Instead of memory being a record of attended information, we must view memory storage as a resource that is used sparingly in strict accordance with the goals of the observer. Meeting abstract presented at VSS 2015.

Attribute Amnesia: Failure to report attended, task-relevant attributes of a highly visible object.

The location but not the attributes of visual cues are automatically encoded into working memory

The benefit of attention is not diminished when distributed over two simultaneous cues

The binding pool: A model of shared neural resources for distinct items in visual working memory

While studies on visual memory commonly assume that the consolidation of a visual stimulus into working memory is interrupted by a trailing mask, studies on dual-task interference suggest that the consolidation of a stimulus can continue for several hundred milliseconds after a mask. As a result, estimates of the time course of working memory consolidation differ more than an order of magnitude. Here, we contrasted these opposing views by examining if and for how long the processing of a masked display of visual stimuli can be disturbed by a trailing 2-alternative forced choice task (2-AFC; a color discrimination task or a visual or auditory parity judgment task). The results showed that the presence of the 2-AFC task produced a pronounced retroactive interference effect that dissipated across stimulus onset asynchronies of 250-1,000 ms, indicating that the processing elicited by the 2-AFC task interfered with the gradual consolidation of the earlier shown stimuli. Furthermore, this interference effect occurred regardless of whether the to-be-remembered stimuli comprised a string of letters or an unfamiliar complex visual shape, and it occurred regardless of whether these stimuli were masked. Conversely, the interference effect was reduced when the memory load for the 1st task was reduced, or when the 2nd task was a color detection task that did not require decision making. Taken together, these findings show that the formation of a durable and consciously accessible working memory trace for a briefly shown visual stimulus can be disturbed by a trailing 2-AFC task for up to several hundred milliseconds after the stimulus has been masked. By implication, the current findings challenge the common view that working memory consolidation involves an immutable central processing bottleneck, and they also make clear that consolidation does not stop when a stimulus is masked.

Beyond a mask and against the bottleneck: retroactive dual-task interference during working memory consolidation of a masked visual target.

The Binding Pool model of VWM: A model for storing individuated objects in a shared resource pool

Semantic priming produces contingent attentional capture by conceptual content

Encoding suppression: Linking spatial cueing costs to the attentional blink

The attentional blink (AB) is a dual-target, rapid serial visual presentation (RSVP) deficit thought to represent a failure of perceptual awareness that reflects the dynamics of temporal attention. However, second target (T2) report is typically unimpaired when the targets appear within 150 ms of one another (i.e., lag-1 sparing). In addition, this sparing can be extended if more targets appear sequentially. It is thought that sequential targets are processed in the same attentional window. Here, we investigated the fate of targets processed in these windows and, specifically, the consequence for subsequent targets when an item at lag-1 is reported versus missed. The results demonstrated that target encoding in attentional windows has an all-or-none influence on subsequent item report: When comparing two- and three-target (T1 and T2 not separated by distractors) RSVP streams, there was no difference in AB magnitude for the final target when either T2 or T1 was missed in the three-target condition, but both of these conditions had significantly smaller blinks than those observed when T1 and T2 were accurately reported. A comparison of our results to a computational model of temporal attention demonstrates how structural limitations on the rate of encoding affect perception, even during sparing.

Simultaneous cueing at two discrete locations and lag-0 sparing: breaking the attentional spotlight

We propose a novel deception detection system based on Rapid Serial Visual Presentation (RSVP). One motivation for the new method is to present stimuli on the fringe of awareness, such that it is more difficult for deceivers to confound the deception test using countermeasures. The proposed system is able to detect identity deception (by using the first names of participants) with a 100% hit rate (at an alpha level of 0.05). To achieve this, we extended the classic Event-Related Potential (ERP) techniques (such as peak-to-peak) by applying Randomisation, a form of Monte Carlo resampling, which we used to detect deception at an individual level. In order to make the deployment of the system simple and rapid, we utilised data from three electrodes only: Fz, Cz and Pz. We then combined data from the three electrodes using Fisher's method so that each participant was assigned a single p-value, which represents the combined probability that a specific participant was being deceptive. We also present subliminal salience search as a general method to determine what participants find salient by detecting breakthrough into conscious awareness using EEG.

Subliminal Salience Search Illustrated: EEG Identity and Deception Detection on the Fringe of Awareness

A cornerstone of the target article is that, in a predictive coding framework, attention can be modelled by weighting prediction error with a measure of precision. We argue that this is not a complete explanation, especially in the light of ERP (event-related potentials) data showing large evoked responses for frequently presented target stimuli, which thus are predicted.

Twelve-picture RSVP sequences support feed-forward models of detection at 75 Hz

Working memory consolidation does not necessarily delay response selection: Disentangling the costs of task initiation and execution

Attentional capture is an unintentional shift of visuospatial attention to the location of a distractor that is either highly salient, or relevant to the current task set. The latter situation is referred to as contingent capture, in that the effect is contingent on a match between characteristics of the stimuli and the task-defined attentional-control settings of the viewer. Contingent capture has been demonstrated for low-level features, such as color, motion, and orientation. In the present paper we show that contingent capture can also occur for conceptual information at the superordinate level (e.g., sports equipment, marine animal, dessert food). This effect occurs rapidly (i.e., within 200 ms), is a spatial form of attention, and is contingent on attentional-control settings that change on each trial, suggesting that natural images can be decoded into their conceptual meaning to drive shifts of attention within the time course of a single fixation.

Future work will generate predictions to be tested empirically. Model architecture: • Tokens index stored representations • Types represent stimulus features • The Binding pool is a shared resource pool of distributed representations in which multiple stimuli are stored A property of this model is that simultaneously presented stimuli are encoded serially. Thus, a prediction is that encoding of simultaneous and sequential stimuli should produce similar patterns of errors.

Simultaneously and sequentially presented colors exhibit similar within-task interference for working memory representations.

Sparing from the attentional blink is not spared from structural limitations

Theories of the attentional blink (AB) – an impairment in perceiving the second of two targets shown within less than 500 ms of each other – generally assume that this effect reflects the time required to consolidate the first target in memory. In this view, the fact that the AB is strongly increased when the first target is masked suggests that masking prolongs the time needed for first-target consolidation. It is also possible, however, that the presence of a mask could elicit additional processing mechanisms that cause an increased blink without prolonging the duration of T1 processing. To answer this question, we examined reaction times for masked and unmasked targets embedded in rapid serial visual presentation. The results showed an increase in median reaction times for targets followed by immediate or delayed masks relative to targets followed by blanks. This was true for both target detection (spot any letter among numbers) and target discrimination (2AFC vowel vs consonant) tasks. These results corroborate theories of the AB in which the depth of the AB is related to the duration of T1 processing (Bowman & Wyble 2007; Wyble, Bowman & Nieuwenstein 2009).

Testing models of the attentional blink : Does masking increase processing duration in RSVP?

Working memory consolidation denotes the process that enables sensory information to be stored in short-term memory. What is currently unclear is how long this process takes and whether it continues after a stimulus has been masked. Here, we address these matters by examining whether the consolidation of visual stimuli can still be disturbed even after they have been masked. Participants viewed brief and masked displays of letters or Kanji characters that had to be memorized and that could be followed at varying stimulus onset asynchronies (SOA) by a visual or auditory discrimination task. Memory performance improved as SOA increased from 100 to 1000 ms, revealing what may be called a “cognitive backward masking effect” caused by the discrimination tasks. Taken together, the results show that working memory consolidation is a time-consuming but volatile process that continues after a stimulus has been masked and that can be disrupted by executing another task.

Cognitive Backward Masking: A Window Into the Formation of a Short-Term Memory Trace

"Attention blinks for selection, not perception or memory: Reading sentences and reporting targets": Correction to Potter et al. (2011).

Attentional capture by images that match a conceptual target set

The root cause of the attentional blink: First-target processing or disruption of input control?

RSVP in orbit: Identification of single and dual targets in motion

Is one's temporal perception of the world truly as seamless as it appears? This article presents a computationally motivated theory suggesting that visual attention samples information from temporal episodes (episodic simultaneous type/serial token model; Wyble, Bowman, & Nieuwenstein, 2009). Breaks between these episodes are punctuated by periods of suppressed attention, better known as the attentional blink (Raymond, Shapiro, & Arnell, 1992). We test predictions from this model and demonstrate that participants were able to report more letters from a sequence of 4 targets presented in a dense temporal cluster than from a sequence of 4 targets interleaved with nontargets. However, this superior report accuracy comes at a cost in impaired temporal order perception. Further experiments explore the dynamics of multiple episodes and the boundary conditions that trigger episodic breaks. Finally, we contrast the importance of attentional control, limited resources, and memory capacity constructs in the model.

In whole report, a sentence presented sequentially at the rate of about 10 words/s can be recalled accurately, whereas if the task is to report only two target words (e.g., red words), the second target suffers an attentional blink if it appears shortly after the first target. If these two tasks are carried out simultaneously, is there an attentional blink, and does it affect both tasks? Here, sentence report was combined with report of two target words (Experiments 1 and 2) or two inserted target digits, Arabic numerals or word digits (Experiments 3 and 4). When participants reported only the targets an attentional blink was always observed. When they reported both the sentence and targets, sentence report was quite accurate but there was an attentional blink in picking out the targets when they were part of the sentence. When targets were extra digits inserted in the sentence there was no blink when viewers also reported the sentence. These results challenge some theories of the attentional blink: Blinks result from online selection, not perception or memory.

Attention blinks for selection, not perception or memory: reading sentences and reporting targets.

Temporal feature binding in vision refers to the process by which features of objects presented one after the other at the same spatial location are correctly bound together. In this paper, we describe a computational model of putative neural mechanisms that would produce this behaviour. These simulations highlight the role of transient attentional enhancement in mediating the temporal binding of features into working memory. This model builds upon previous approaches, and explains a range of behavioural findings relating to the patterns of illusory conjunctions observed in experiments. Further, it provides a parsimonious account of a counter-intuitive pattern of reaction time data.

Fortunate Conjunctions Revived: Feature Binding with the 2f-ST2 Model

Identification of point light walkers exhibits an attentional blink

A pictured object can be readily detected in an RSVP sequence when the target is specified by a superordinate category name such as animal or vehicle. Are category features the initial basis for detection, with identification of the specific object occurring in a second stage (Evans & Treisman, 2005), or is identification of the object the basis for detection? When two targets in the same superordinate category are presented successively (lag 1), only the identification-first hypothesis predicts lag 1 sparing of the second target. The results of two experiments with novel pictures and a wide range of categories supported the identification-first hypothesis and a transient-attention model of lag 1 sparing and the attentional blink (Wyble, Bowman, & Potter, 2009).

A pictured object can be readily detected in a rapid serial visual presentation sequence when the target is specified by a superordinate category name such as animal or vehicle. Are category features the initial basis for detection, with identification of the specific object occurring in a second stage (Evans & Treisman, 2005), or is identification of the object the basis for detection? When 2 targets in the same superordinate category are presented successively (lag 1), only the identification-first hypothesis predicts lag 1 sparing of the second target. The results of 2 experiments with novel pictures and a wide range of categories supported the identification-first hypothesis and a transient-attention model of lag 1 sparing and the attentional blink (Wyble, Bowman, & Potter, 2009).

Picture detection in rapid serial visual presentation: features or identity?

Reporting two simultaneous targets: Competition, bias, and temporal displacement

A neural network account of binding discrete items into working memory using a distributed pool of flexible resources

Background Most people show a remarkable deficit in reporting the second of two targets (T2) when presented 200–500 ms after the first (T1), reflecting an ‘attentional blink’ (AB). However, there are large individual differences in the magnitude of the effect, with some people, referred to as ‘non-blinkers’, showing no such attentional restrictions. Methodology/Principal Findings Here we replicate these individual differences in a task requiring identification of two letters amongst digits, and show that the observed differences in T2 performance cannot be attributed to individual differences in T1 performance. In a second experiment, the generality of the non-blinkers' superior performance was tested using a task containing novel pictures rather than alphanumeric stimuli. A substantial AB was obtained in non-blinkers that was equivalent to that of ‘blinkers’. Conclusion/Significance The results suggest that non-blinkers employ an efficient target selection strategy that relies on well-learned alphabetic and numeric category sets.

A Quick Mind with Letters Can Be a Slow Mind with Natural Scenes: Individual Differences in Attentional Selection

Cooccurrence binding errors: Are people bound to the chairs they are sitting on?

Background: Most people show a remarkable deficit in reporting the second of two targets (T2) when presented 200– 500 ms after the first (T1), reflecting an ‘attentional blink’ (AB). However, there are large individual differences in the magnitude of the effect, with some people, referred to as ‘non-blinkers’, showing no such attentional restrictions. Methodology/Principal Findings: Here we replicate these individual differences in a task requiring identification of two letters amongst digits, and show that the observed differences in T2 performance cannot be attributed to individual differences in T1 performance. In a second experiment, the generality of the non-blinkers’ superior performance was tested using a task containing novel pictures rather than alphanumeric stimuli. A substantial AB was obtained in non-blinkers that was equivalent to that of ‘blinkers’. Conclusion/Significance: The results suggest that non-blinkers employ an efficient target selection strategy that relies on well-learned alphabetic and numeric category sets. Citation: Martens S, Dun M, Wyble B, Potter MC (2010) A Quick Mind with Letters Can Be a Slow Mind with Natural Scenes: Individual Differences in Attentional Selection. PLoS ONE 5(10): e13562. doi:10.1371/journal.pone.0013562 Editor: Mark W. Greenlee, University of Regensburg, Germany Received June 11, 2010; Accepted October 1, 2010; Published October 27, 2010 This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. Funding: This research was supported by a grant of the Behavioural and Cognitive Neurosciences (BCN) Research School (http://www.rug.nl/bcn/index). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: s.martens@med.umcg.nl

University of Groningen A Quick Mind with Letters Can Be a Slow Mind with Natural Scenes

A previously published computational model of the Attentional Blink (Wyble and Bowman, 2004) has given rise to predictions about the time course of the U-shaped T2 performance curve that is characteristic of the AB. Specifically, we posit that the blink curve is a hallmark of limitations in the temporal resolution of the binding of working memory tokens to types. In our model, lag-1 sparing results from a temporal window approximately 150 msec in length during which multiple items can be bound to the same token. Recovery of the blink occurs when a second token becomes available for binding. In testing these predictions, we have performed two AB experiments. The first experiment compared the shape of AB curves for RSVP streams in the style of Chun and Potter (1995), presented at either 10 or 20 items/sec. If the AB is the result of temporal processes, the shape of the curve should be constant with respect to time. In our data, the blink curves had the same shape with respect to the time lag between T1 and T2, not the number of items. Specifically, in the faster presentation stream, we observed lag-2 sparing, maximal depth at lag 6 and recovery by lag 12. Our second experiment involved presenting subjects with a letter pair for each of T1 and T2. If sparing involves binding T1 and T2 into a single conglomerate token, there should be a high percentage of binding errors at lag 1, in which one element of T1 is swapped with one element of T2. This prediction was confirmed, subjects made many binding errors at lag-1, and returned to baseline levels of error by lag-2. This work details our continuing efforts to use the AB paradigm to explore the temporal structure of working memory. These data support our theoretical position that the AB stems from limitations in the consolidation of working memory tokens. We present these data in the context of a previously published connectionist model of the AB.

The attentional blink reflects the time course of token binding, computational modeling and empirical data

Sparing at a Cost: The attentional blink serves to enhance episodic distinctiveness

Targets in RSVP sentences: Attentional blinks in whole versus partial report

The attentional blink: Past, present, and future of a blind spot in perceptual awareness

Transient attention to a visually salient cue enhances processing of a subsequent target in the same spatial location between 50 to 150 ms after cue onset (K. Nakayama & M. Mackeben, 1989). Do stimuli from a categorically defined target set, such as letters or digits, also generate transient attention? Participants reported digit targets among keyboard symbols in a changing array of 8 items. When 1 target preceded a second target in the same location at a stimulus onset asynchrony of 107 ms (but not 213 ms), the second target was reported more often than in a condition in which there was no leading target. When the 2 targets were at different locations, report of the second target was impaired. With both letters and digits as targets, the enhancement effect was shown not to be due to category priming. Critically, the attentional benefit was present whether or not participants reported the leading target. Transient attention, contingent attentional capture, popout, and Lag 1 sparing in the attentional blink may involve a common mechanism for orienting processing resources towards salient and task relevant stimuli.

Categorically defined targets trigger spatiotemporal visual attention.

The delayed consolidation hypothesis of all-or-none conscious perception during the attentional blink, applying the ST 2 framework H. Bowman 1 , P. Craston 1 , S. Chennu 1 , B. Wyble 2 Centre for Cognitive Neuroscience and Cognitive Systems, University of Kent, UK Department of Brain and Cognitive Sciences, MIT, USA Abstract There is evidence that conscious perception during the attentional blink is all-or-none, which contrasts with the finding of a continuum of perceptual strength in masking experiments. This seems to reveal the underlying representation of strength that can be found in the brain in the absence of attentional enhancement. We provide electrophysiological support for this all-or-none theory. Then, using principles from the ST 2 model of temporal attention and working memory, we show how this all-or-none pattern can be explained by the delayed target consolidation that is known to arise during the attentional blink. Keywords: Attentional Blink, P300, ST 2 Introduction Intuitively, it would seem that conscious perception is all- or-none. For example, bistable visual stimuli, e.g. the Necker cube or binocular rivalry, exhibit a dichotomy in perception: one or other stable percept is perceived in its entirety, without access to intermediate images. In other words, we either see all of a particular stable percept or none of it. Consistent with this perspective, (Sergent & Dehaene, 2004; Sergent, Baillet & Dehaene, 2005) have argued that conscious perception during the attentional blink (AB) is all-or-none; that is, targets presented during the attentional blink deficit are either completely perceived or completely missed, as revealed by subject visibility ratings. However, masking experiments in which strength is systematically varied suggest a continuous (although probably non-linear) gradation of visibility (Sergent & Dehaene, 2004, Del Cul, Baillet & Dehaene, 2007). This paper seeks to explain this seeming inconsistency in experimental findings, by arguing that all-or-none conscious perception during the attentional blink (AB) arises because of the delayed consolidation that is known to occur during the AB (Sessa et al., 2006; Vogel & Luck, 2002; Bowman et al., 2008). We do this by presenting a neural model of all-or- none consolidation during the AB, which reuses principles from the simultaneous type, serial token (ST 2 ) model of temporal attention (Bowman & Wyble, 2007; Wyble et al., Why, though, should we be interested in the attentional blink? The AB is the deficit in reporting a second target (T2) if it is presented between 100 and 500 ms after a reported first target (T1), when a rapid serial visual presentation (RSVP) format is employed. The first reason is that the AB reflects a late stage deficit; that is, T2s that are missed during the AB are processed for visual and semantic features (Vogel et al., 1998). Thus, the AB seems to isolate the extra processing step that is required to encode an otherwise preconscious representation into working memory, i.e. to consciously perceive it. A second reason for being interested in the AB, is that it enables bottom-up strength and attention to be independently manipulated. A first requirement for an item to be consciously perceived is sufficient bottom-up strength. Under normal viewing conditions, most stimuli are strong enough to be consciously perceived. However, if stimulus representations are fleeting, as in RSVP, they will sometimes be too weak to enter consciousness. Hence, the weaker a neural representation of a stimulus, the less the likelihood it will enter awareness (Kanwisher, 2001). However, this cannot be the sole requirement for conscious perception, as stimuli that are equally strong in perceptual terms, in some cases succeed but in others fail to enter consciousness (Luck et al., 1996, Rees et al., 2000). In particular, the neural representation of a stimulus also needs to be attended to before it can enter awareness. Koch & Tsuchiya (2007) have argued that attention and consciousness ‘are distinct phenomena that need not occur together and can be manipulated using distinct paradigms.’ To investigate the influence of target strength and attention on conscious perception, we thus require an experimental paradigm where the availability of attention and bottom-up strength can be manipulated independently (Kim & Blake, 2005); the AB is such a paradigm. A key aspect of modern cognitive neuroscience is the identification of neurophysiological correlates of conscious perception. Within the context of the AB, the P3 component of the event-related potential (ERP) is viewed as such a correlate. A P3 component is only evoked by those targets in RSVP that can be correctly reported (e.g. Kranczioch et al., 2003). Target items that are missed do not evoke a P3. The P3 is thus generally seen as an EEG correlate of encoding items into working memory (Vogel et al., 1998) and, by the same logic, a number of studies have proposed that the P3 serves as an index of conscious perception (e.g. Sergent et al., 2005, Kranczioch et al., 2007). In line with these previous studies, we use the P3 component as a correlate of conscious perception for targets in RSVP. We present EEG data investigating how bottom-up target strength and the availability of attention modulate conscious perception of targets in RSVP. We compare the EEG signatures (specifically, the P3 components) of targets presented outside and during the AB. We find that bottom up strength of targets affects the P3 for targets presented outside the AB, but does not influence the P3 evoked by

The delayed consolidation hypothesis of all-or-none conscious perception during the attentional blink, applying the ST2 framework

A wealth of neurophysiological data has demonstrated that visual attention can selectively enhance target representations early in the visual processing pathway. In conjunction, behavioural evidence tells us that the extent to which irrelevant items interfere with target processing depends on their featural similarity to the target. In this context, how does target discriminability influence temporal selection? We present results from an electrophysiology study that addresses this question by investigating the time course of the neural processes involved in target selection as target distinctiveness is varied. The results suggest that, in line with previous findings, making discrimination harder reduces the accuracy of target identification. We find that there are significant differences in the perceptual processing of the target in the two conditions, as indexed by early visual ERPs and the P3 ERP. We ground this and previous empirical evidence within a theoretical framework for understanding the mechanism of attentional selection represented in the ST2 model, a neural network model of temporal attention and working memory. By simulating both experimental conditions, we show that the model provides a convincing explanation of the pattern of experimental results, in addition to informing questions about the nature and time course of attentional selection.

The influence of target discriminability on the time course of attentional selection

What role does attention play in ensuring the temporal precision of visual perception? Behavioural studies have investigated feature selection and binding in time using fleeting sequences of stimuli in the Rapid Serial Visual Presentation (RSVP) paradigm, and found that temporal accuracy is reduced when attentional control is diminished. To reduce the efficacy of attentional deployment, these studies have employed the Attentional Blink (AB) phenomenon. In this article, we use electroencephalography (EEG) to directly investigate the temporal dynamics of conscious perception. Specifically, employing a combination of experimental analysis and neural network modelling, we test the hypothesis that the availability of attention reduces temporal jitter in the latency between a target's visual onset and its consolidation into working memory. We perform time-frequency analysis on data from an AB study to compare the EEG trials underlying the P3 ERPs (Event-related Potential) evoked by targets seen outside vs. inside the AB time window. We find visual differences in phase-sorted ERPimages and statistical differences in the variance of the P3 phase distributions. These results argue for increased variation in the latency of conscious perception during the AB. This experimental analysis is complemented by a theoretical exploration of temporal attention and target processing. Using activation traces from the Neural-ST2 model, we generate virtual ERPs and virtual ERPimages. These are compared to their human counterparts to propose an explanation of how target consolidation in the context of the AB influences the temporal variability of selective attention. The AB provides us with a suitable phenomenon with which to investigate the interplay between attention and perception. The combination of experimental and theoretical elucidation in this article contributes to converging evidence for the notion that the AB reflects a reduction in the temporal acuity of selective attention and the timeliness of perception.

Attention Increases the Temporal Precision of Conscious Perception: Verifying the Neural-ST2 Model

Observers often miss a second target (T2) if it follows an identified first target item (T1) within half a second in rapid serial visual presentation (RSVP), a finding termed the attentional blink. If two targets are presented in immediate succession, however, accuracy is excellent (Lag 1 sparing). The resource sharing hypothesis proposes a dynamic distribution of resources over a time span of up to 600 msec during the attentional blink. In contrast, the ST2 model argues that working memory encoding is serial during the attentional blink and that, due to joint consolidation, Lag 1 is the only case where resources are shared. Experiment 1 investigates the P3 ERP component evoked by targets in RSVP. The results suggest that, in this context, P3 amplitude is an indication of bottom–up strength rather than a measure of cognitive resource allocation. Experiment 2, employing a two-target paradigm, suggests that T1 consolidation is not affected by the presentation of T2 during the attentional blink. However, if targets are presented in immediate succession (Lag 1 sparing), they are jointly encoded into working memory. We use the ST2 model's neural network implementation, which replicates a range of behavioral results related to the attentional blink, to generate “virtual ERPs” by summing across activation traces. We compare virtual to human ERPs and show how the results suggest a serial nature of working memory encoding as implied by the ST2 model.

The Attentional Blink Reveals Serial Working Memory Encoding: Evidence from Virtual and Human Event-related Potentials

Process algebraic modelling of attentional capture and human electrophysiology in interactive systems

Humans are very good at prioritising competing processing demands. In particular, perception of a salient environmental event can interrupt ongoing processing, causing attention, and accompanying processing resources, to be redirected to the new event. A classic example of this is the well-known Cocktail Party Effect (Cherry, 1953). Not only are we easily able to follow just one conversation when several people are speaking, but the occurrence of a salient phrase in a peripheral conversation stream, such as somebody mentioning our name, causes auditory attention to be redirected. It is also clear that emotion s, motivation and physiological state in general, play a key role in such prioritisation, e.g. Oatley and Johnson-Laird suggest that:

Human Attention in Digital Environments: Salience sensitive control, temporal attention and stimulus-rich reactive interfaces

The attentional blink (J. E. Raymond, K. L. Shapiro, & K. M. Arnell, 1992) refers to an apparent gap in perception observed when a second target follows a first within several hundred milliseconds. Theoretical and computational work have provided explanations for early sets of blink data, but more recent data have challenged these accounts by showing that the blink is attenuated when subjects encode strings of stimuli (J. Kawahara, T. Kumada, & V. Di Lollo, 2006; M. R. Nieuwenstein & M. C. Potter, 2006; C. N. Olivers, 2007) or are distracted (C. N. Olivers & S. Nieuwenhuis, 2005) while viewing the rapid serial visual presentation stream. The authors describe the episodic simultaneous type, serial token model, a computational account of encoding visual stimuli into working memory that suggests that the attentional blink is a cognitive strategy rather than a resource limitation. This model is composed of neurobiologically plausible elements and simulates the attentional blink with a competitive attentional mechanism that facilitates the formation of episodically distinct representations within working memory. In addition to addressing the blink, the model addresses the phenomena of repetition blindness and whole report superiority, producing predictions that are supported by experimental work.

The attentional blink provides episodic distinctiveness: sparing at a cost.

The attentional blink (AB) refers to the finding that observers often miss the second of two masked visual targets (T1 and T2, e.g., letters) appearing within 200-500 ms. Although the presence of a T1 mask is thought to be required for this effect, we recently found that an AB deficit can be observed even in the absence of a T1 mask if T2 is shown very briefly and followed by a pattern mask (M. R. Nieuwenstein, M. C. Potter, & J. Theeuwes, 2009). Using such a sensitive T2 task, the present study sought to determine the minimum requirements for eliciting an AB deficit. To this end, we examined if the occurrence of an AB depends on T1 exposure duration, the requirement to perform a task for T1, and awareness of T1. The results showed that an AB deficit occurs regardless of the presentation duration of T1, and regardless of whether there is a T1 task. A boundary condition for the occurrence of an AB was found in conscious awareness of T1. With a near-threshold detection task for T1, attention blinked when T1 was seen, but not when T1 was missed. Accordingly, we conclude that the minimum requirement for an AB deficit is T1 awareness.

Temporal constraints on conscious vision: on the ubiquitous nature of the attentional blink.

The Attentional Blink (AB) is a well studied temporal attention phenomenon, and is particularly suitable for investigating the nature and limits of conscious perception. The AB employs Rapid Serial Visual Presentation (RSVP), in which a sequence of items is presented at the same spatial location at a rate of around 10 items per second, with each item rapidly replacing the previous one. At such speeds, the items presented, some of which are targets to be detected and others are irrelevant distractors, yield only fleeting mental representations, resulting in targets often being missed. In the AB, detection of a second target (T2) following a correctly identified first target (T1) is significantly impaired if T2 follows T1 within 200-600 ms. There has been considerable recent interest in the identification of neural correlates of the AB, and the development of neurally explicit explanations of it, a prominent one being the Simultaneous Type Serial Token (ST 2 ) [1] neural model. In addition to incorporating computationally explicit accounts of visual processing, item identification, attentional selection and working memory encoding, the model proposes the episodic distinctiveness hypothesis, i.e., that the AB reflects a system attempting to allocate unique episodic contexts to targets. Importantly, it suggests that when the visual system detects an item that may be task relevant, a spatially specific Transient Attentional Enhancement (TAE), called the ‘blaster’ is triggered. For a fleeting stimulus such as that arising in RSVP, the contribution of this enhancement is critical in enabling the stimulus to be encoded into working memory. This paper reports on our investigations into EEG activity during the AB, and a hypothesized correlation between the blaster and the N2pc ERP component [2]. The N2pc describes a negative deflection of the ERP at around 190-300 ms after the presentation of a laterally offset target, and is most strongly visible at posterior electrodes contralateral to the position of the target. Previous research has associated the N2pc with the selection of a target in the presence of competing distractors. We discuss findings that, in the context of the AB, suggest a correspondence between blaster activity and manifestation of the N2pc. Specifically, we demonstrate that the temporal firing pattern of the blaster in the model matches the N2pc component in human ERP recordings, for T1s and T2s that are seen and missed during the AB. Such a correlation between a computational account of the AB and ERP data provides useful insights into the processes underlying selectivity in temporal attention.

TRANSIENT ATTENTIONAL ENHANCEMENT DURING THE ATTENTIONAL BLINK: EEG CORRELATES OF THE ST 2 MODEL

Transient attention to a visually salient cue enhances processing of a subsequent target in the same spatial location between 50 to 150 ms after cue onset (Nakayama & Mackeben, 1989). Do stimuli from a categorically defined target set, such as letters or digits, also generate transient attention? Participants reported digit targets among keyboard symbols in a changing array of 8 items. When one target preceded a second target in the same location at an SOA of 107 ms (but not 213 ms), the second target was reported more often than in a condition in which there was no leading target. When the two targets were at different locations, report of the second target was impaired. With both letters and digits as targets, the enhancement effect was shown not to be due to category priming. Critically, the attentional benefit was present whether or not participants reported the leading target. Transient attention, contingent attentional capture, popout, and lag 1 sparing in the attentional blink may involve a common mechanism for directing processing resources towards salient and task relevant stimuli.

There is considerable current interest in neural modeling of the attentional blink phenomenon. Two prominent models of this task are the Simultaneous Type Serial Token (ST(2)) model and the Locus Coeruleus-Norepinephrine (LC-NE) model. The former of these generates a broad spectrum of behavioral data, while the latter provides a neurophysiologically detailed account. This paper explores the relationship between these two approaches. Specifically, we consider the spectrum of empirical phenomena that the two models generate, particularly emphasizing the need to generate a reciprocal relationship between bottom-up trace strength and the blink bottleneck. Then we discuss the implications of using ST(2) token mechanisms in the LC-NE setting.

A reciprocal relationship between bottom-up trace strength and the attentional blink bottleneck: relating the LC-NE and ST(2) models.

A reciprocal relationship between bottom-up trace strength and the attentional blink bottleneck: Relating the LC–NE and ST2 models

Modelling the formation of attentional episodes: it's about time

The attentional blink in reverse: Retroactive interference in encoding masked visual targets.

We present a neural network model of stimulus processing, which uses a mechanism of adaptive attentional control to regulate the moment to moment deployment of attention according to both the demands of the current task, and the demands of emotionally salient information. This mechanism allows negative emotional information to reduce cognitive control to aid in the detection of threats, which produces a momentary withdrawal from the current task set to allow unbiased processing of available information. The combination of cognitive and emotional regulation of task set allows this model to address inter-trial aspects of emotional interference in colour naming. In particular, we focus on the nature of the emotional interference in colour naming (McKenna & Sharma, 2004) as well as in word reading (Algom, Chajut, & Lev, 2004) and show how this form of interference is functionally distinct from the classic Stroop effect. Our model addresses a range of findings in colour naming and word reading tasks and is informed by recent neuroimaging data concerning the interaction between the anterior cingulate and prefrontal cortices. The model is used to explore the interface between cognition and emotion with a series of predictions, including a qualitative distinction between state and trait forms of anxiety.

Strategic regulation of cognitive control by emotional salience: A neural network model

Modulation of Cognitive Control by Negative Affect. Experimental Verification of a Connectionist Model of the Emotional Stroop

A detailed description of the simultaneous type, serial token (ST2) model is presented. ST2 is a model of temporal attention and working memory that encapsulates 5 principles: (a) M. M. Chun and M. C. Potter's (1995) 2-stage model, (b) a Stage 1 salience filter, (c) N. G. Kanwisher's (1987, 1991) types-tokens distinction, (d) a transient attentional enhancement, and (e) a mechanism for associating types with tokens called the binding pool. The authors instantiate this theoretical position in a connectionist implementation, called neural-ST2, which they illustrate by modeling temporal attention results focused on the attentional blink (AB). They demonstrate that the ST2 model explains a spectrum of AB findings. Furthermore, they highlight a number of new temporal attention predictions arising from the ST2 theory, which are tested in a series of behavioral experiments. Finally, the authors review major AB models and theories and compare them with ST2.

The simultaneous type, serial token model of temporal attention and working memory.

Previous theoretical work has identified a set of attentional mechanisms. This paper explores the practical implications of these mechanisms. Two findings that have particularly inspired this practical work are, 1) the existence of a very rapid (first phase) of attention, called Transient Attentional Enhancement (TAE), which acts within 150ms of stimulus presentation; and 2) that even such rapid attentional deployment is modulated by task set, e.g. it could be initiated by detection of an item in a target category. Such mechanisms have great relevance for the development of Stimulus Rich Reactive Interfaces (SRRIs). In particular, in interfaces with rapidly arriving streams of information, it is important to understand how stimuli capture attention. To explore this issue, this paper presents a prototype SRRI test system. This comprises a central task involving driving through a virtual maze and the presentation of an intermittent stream of competing stimuli of varying levels of salience. Centrally presented arrows are followed in the driving task and the stream of competing stimuli is presented via a head mounted display. The colour relationship between the central arrows and stimuli in the competing stream is varied. How this ''task prescribed'' colour relationship impinges upon attentional capture by stimuli in the competing stream is investigated.

Final Report for Project, Salience Sensitive Control in Humans and Artificial Systems (funded under the AIBACS programme) H Bowman (PI), B Wyble (RA), CG Johnson (I), PJ Barnard (External Collab), D Sharma (Internal Collab), Su Li (Contributing PhD Student) & P Craston (Contributing PhD Student) 1 Comp Lab, Univ of Kent; 2 MRC Cognition & Brain Sci Unit, Cambridge; & 3 Psych Dept, Univ of Kent

- 1-Final Report for Project , Salience Sensitive Control in Humans and Artificial Systems ( funded under the AIBACS programme )

To explore the degree which attentional set in one task interferes with performance in a secondary task, we have developed a prototype SRRI test system. This comprises a central task involving driving through a virtual maze and the presentation of an intermittent stream of competing stimuli of varying levels of salience. Centrally presented arrows are followed in the driving task and the stream of competing stimuli is presented via a head mounted display. The colour relationship between the central arrows and stimuli in the competing stream is varied. How this "task prescribed" colour relationship impinges upon attentional capture by stimuli in the competing stream is investigated. This experiment has revealed no discernible carryover effect of attentional set from one task to the other in either accuracy or reaction time for detecting the targets in the stream. Thus, the attention system seems to be adept at allocating feature based attention in a way that does not spontaneously migrate from one task to another. Introduction The visual world contains more information than can be processed by any real-time cognitive system. The human brain uses a multi-stage attention mechanism to deal with this problem. At the input level, the eyes can be moved around, selecting parts of the visual world around us with saccades. This visual input from the retina is then subject to a spatial form of attention, which selectively amplifies some regions of the visual field (Posner 1980). Beyond the spatial filter, the attention system can select items for processing based on certain features, such as a particular shape or color. All of these mechanisms are under the control of top-down volitional control, allowing a person to tune their attentional filters as necessary to detect targets that are relevant to their current goals. These mechanisms are clearly critical in allowing us to function in situations of information overload. If a user is aware of the salience of a red light in a cockpit display, attention can be configured to enhance the probability that red stimuli will be selected for further processing by the attentional system. 1 The full reference for this article is, B. Wyble, H. Bowman, and P. Craston. "Attentional capture in stimulus rich computer interfaces." Technical Report 7-06, Computing Lab, University of Kent at Canterbury, September 2006. Transient Attention and Contingent Capture In addition to relatively static spatial and feature based filters, the visual system also has a reactive method of deploying attention. Within just 50 ms of the onset of a salient visual cue, target detection is enhanced at the cued location, indicating a rapid and reactive deployment of attention (Nakayama & Mackeben 1989). This may be related to the phenomenon of attentional capture (Theeuwes 1994), the theory that a window of attention can be deployed in response to salient visual objects, which makes concurrent target detection more difficult at other spatial locations because this reactive mechanism is already occupied. A debate has centered around the degree to which this reactive attention mechanism is under top-down control. Recent work has demonstrated that the attention settings of the subject, for a particular color, makes it more likely that distractors of that color will be able to capture attention, a phenomenon known as contingent capture (Folk, Leber & Egeth 2002, Serences et al 2005). Recent computational work has demonstrated that this form of attention plays a critical role in our ability to perceive rapidly presented stimuli, especially in the context of Rapid Serial Visual Presentation (Bowman & Wyble 2007; Wyble, Bowman & Potter, submitted). What this work suggests is that the attentional settings of the subject (e.g. in search of a particular colour or shape) affect the ability of stimuli with those features to capture attention. This idea is critical in the present work, in which we test the ability of the attentional set specified in one task, to affect the ability to detect rapidly presented targets in another task. Dual-Task Research There is a large literature on the ability of subjects to switch from one task to another and the delays imposed by the switch (e.g. Arrington & Logan, 2004). The ability of the attentional system to mediate two different tasks at the same time is less well studied, as these paradigms make it difficult to isolate a single cognitive function. However, simultaneous performance is of critical importance for complex interfaces, such as in cockpits. One critical question that arises in such research is how flexible the attentional system truly is. For example, if a subject is looking for a certain color in one task, does that affect their ability to perceive targets in a second task for which that color distinction is irrelevant or reversed? In other words, is there a single attentional filter mechanism that needs to be shared across multiple tasks? Or can each task utilize its own dedicated filter? It is well known that there are fundamental limitations in our ability to do multiple things concurrently. For example, ideas such as central capacity theory (Kahneman 1973, Tombu & Jolicoeur 2003) are firmly established theoretical frameworks. Many of the experimental paradigms that study such central limitations report differences in response times that exist between performing two unrelated tasks. It is consistently found that doing two things at the same time results in slower performance, decreased accuracy, or both. For example, the psychological refractory period (PRP) refers to the increased time to respond to a second stimulus after having responded to a first one (Ruthruff, Pashler, & Hazeltine 2003), a cost which can be observed even for two tasks in different modalities. What is less well studied is the specific pattern of interference between tasks that use the same perceptual system. The question we ask here is to what degree do filters in one perceptual system (e.g. vision) cross tasks that rely on the same system; see Figure 1. This question is of vital importance for the design of any complex interface. If one display requires users to attend to red and ignore green, while another requires the opposite, what costs do these conflicting instructions incur if the user is to process both of these displays simultaneously? Some work has been done that is relevant to this question. Olivers & Watson (In Press) had subjects monitor an RSVP stream of characters for letters of a particular colour. Immediately following this task, subjects had to rapidly count the number of dots of a particular colour in a display. It was found that if the colour of the dots to be counted matched the colour of the distractors in the RSVP task, performance was impaired, indicating that the colour filter established for one task had carry over effects onto a secondary task, even though that distinction was entirely irrelevant. However these two tasks were performed sequentially, not simultaneously. Most & Astur (Under Revision) addressed this question directly, by having subjects maneuver a virtual car through a city, attending to signposted arrows of one colour, while ignoring arrows of another colour. While driving, subjects would occasionally have to break to avoid hitting a motorcyclist, appearing suddenly in front of the car. It was found that subjects were faster at braking in response to cyclists of the same color as the arrows to which they were attending. These results are suggestive of cross-task interference although it could be argued that this is not a true case of dual-task performance, as steering and braking could be considered parts of the same task. What we address here is the degree to which the visual system exhibits interference between concurrent, and unrelated tasks fed from the same modality. The question proposed is whether the same kind of interference demonstrated by Most & Astur will be found for independent tasks. Combining Rapid Presentation and Driving Tasks To test the interference between independent tasks that use a common sensory modality, we combine a colored-arrow guided navigation task, as in Most & Astur, with a task requiring rapid identification of digits presented concurrently in a heads-up display. The colour of each digit is randomly chosen, but subjects are to ignore the color. If the interaction between the colors of the arrows and the motorcyles in the Most & Astur task was due to the fact that subjects were sharing the same visual input between the tasks, we should expect to observe the same effect here. On the other hand, it is possible that if the visual system is being used for two distinct tasks, that a visual filter can be applied to the visual input to one of the tasks without strongly affecting the other. In our experiment, one group of subjects navigate the maze guided by black arrows and the other guided by white. Meanwhile, in a secondary display, they attempt to detect digits that are white, black or coloured. A critical aspect of the current task is that, on average, subjects in both the black and the white arrow groups are seeing the same visual stimulus. The only difference between them is the instructions that they are given at the start of the experiment (e.g. to attend to white or to black arrows). Thus, any differences observed would necessarily be the result of top-down task set.

Computer Science at Kent Attentional capture in stimulus rich computer interfaces

This paper illustrates a framework for applying formal methods techniques, which are symbolic in nature, to specifying and verifying neural networks, which are subsymbolic in nature. The paper describes a communicating automata [Bowman & Gomez, 2006] model of neural networks. We also implement the model using timed automata [Alur & Dill, 1994] and then undertake a verification of these models using the model checker Uppaal [Pettersson, 2000] in order to evaluate the performance of learning algorithms. This paper also presents discussion of a number of broad issues concerning cognitive neuroscience and the debate as to whether symbolic processing or connectionism is a suitable representation of cognitive systems. Additionally, the issue of integrating symbolic techniques, such as formal methods, with complex neural networks is discussed. We then argue that symbolic verifications may give theoretically well-founded ways to evaluate and justify neural learning systems in the field of both theoretical research and real world applications.

Formal Modeling of Connectionism using Concurrency Theory , an Approach Based on Automata and Model Checking *

We present an EEG study that investigates how target items are processed when presented in Rapid Serial Visual Presentation (RSVP). The RSVP task was similar to the well-known Attentional Blink experiment [Chun and Potter, 1995], however, the stream contained only one target. To increase task difficulty, the presentation rate was doubled to 47ms SOA. Half the targets were followed by a blank to test the effects of backward masking. A skeletal task [Ward et al., 1997] allowed study of targets presented without surrounding distractors (except a following mask). Subjects' EEG waves were recorded at 20 electrode sites. The study was motivated by predictions made on the basis of the ST2 model of temporal attention and visual working memory [Wyble and Bowman, 2005] concerning the influence of masking and task difficulty on target processing. In line with our predictions, the following results are observed: We find delayed processing of targets in RSVP streams compared to targets that are presented stand-alone (skeletal). In RSVP streams we do not observe accelerated processing of masked compared to unmasked targets as suggested by Kessler et al. (2005). A categorisation of target letters based on subject performance ('hard' or 'easy') modulates target ERPs, in particular the P3 component. Finally, we investigate the 'all-or-none' issue of conscious perception [Sergent et al., 2005] by correlating subjects' task performance and P3 amplitude using EEG single-trial analysis.

This paper explores the feasibility of using EEG in the context of Stimulus Rich Reactive Interfaces (SRRI), as a source of feedback on the cognitive state of the user. We have run experiments to evaluate the utility of two potential EEG measures of whether a stimulus has been perceived: 1) reduced EEG power in the alpha band at posterior brain areas and 2) a P3-like positive deflection over parietal areas. Such measures would enable re-presentation of a critical stimulus that has been missed. This paper considers whether, in the context of SRRIs, these measures can be reliably extracted online, i.e. in real-time. To determine this, we have investigated the extent to which online extraction of these measures predicts target report. Our results are positive, particularly with respect to the second approach. we also discuss possible ways in which such a system could be implemented and integrated into a pilot's helmet.

Electrophysiological Feedback in Adaptive Human Computer Interfaces

This paper explores the feasibility of using EEG in the context of Stimulus Rich Reactive Interfaces (SRRI’s), as a source of feedback on the cognitive state of the user. We have run experiments to evaluate the utility of two potential EEG measures of whether a stimulus has been perceived: 1) reduced EEG power in the alpha band at posterior brain areas and 2) a P3-like positive deflection over parietal areas. Such measures would enable re-presentation of a critical stimulus that has been missed. This paper considers whether, in the context of SRRIs, these measures can be reliably extracted online, i.e. in real-time. To determine this, we have investigated the extent to which online extraction of these measures predicts target report. Our results are positive, and suggest that a combination of multiple approaches can be used to improve the reliability of single trial discrimination. We also discuss possible ways in which such a system could be implemented and integrated into a head-mounted wearable display that is electrically isolated from the surroundings by optical input and output. Introduction One of the fundamental problems involved in real-time processing is information overload. A system has to pick and choose which stimuli to attend, before it has expended the resources to process them. The human brain has evolved a sophisticated attentional mechanism to pick and choose what information is selected for further processing. As a consequence, the designer of a computer interface is not always able to ensure that what the interface knows is important (such as a low altitude warning on an aircraft) is selected by the human user’s attention system. HCI design has learned a great deal of tricks to increase the inherent salience of input signals to a human user (using warning lights and sounds, for example), but accidents still occur due to critical information that is ignored. If described using computer networking as a metaphor, this situation is akin to transmitting information over a communication channel without acknowledgement of receipt. The computer is transmitting information to the user with the intent that it be received, but the system has no way of verifying that this transmission was successfully completed. No well-designed computer-computer interface operates in this way. Acknowledgement of packet receipt is a core element of any modern networking technology. The goal of this research is to record an acknowledgement signal from scalp recorded brain waves. Electrophysiological neuroscience has identified a number of electrical signals produced by the brain when information is encoded into working memory that could serve this role. In this paper, we explore a novel use of recorded brain signals, to enhance the reliability of information transmission from computer to user. Brain Computer Interface: The direct brain to computer interface (e.g. Vidal 1973, Levine, et al 2000, Beverina, Palmas, Silvoni, Piccione, & Giove 2000) has been one of the most useful applications to have arisen from electrophysiological neuroscience. By recording brain waves from human subjects with motor impairments, it has been possible to give the severely disabled a means of communication with the world (e.g. Cilliers & Van Der Kouwe 1993) Using these techniques, a subject can passively view a matrix of characters and guide a computer interface that is recording and analyzing EEG signals to the intended words he or she wishes to communicate. For some people, the electrical signal produced by their brain is 1 The full reference for this article is, B. Wyble, P. Craston and H. Bowman. "Electrophysiological feedback in adaptive human computer interfaces." Technical Report 8-06, Computing Lab, University of Kent at Canterbury, September 2006. the only means by which they can consciously communicate with the world. The Brain-ComputerInterface (BCI) field is now quite mature, using cutting edge technology to maximize the accuracy and speed of the information that can be read from the disabled subject’s brain (Meinicke, Kasper, Hoppe, Heumann & Ritter 2003; Hochberg, et al 2006) Work in the BCI field has almost exclusively focused on human-to-computer information transfer. However, recording brain signals can also serve to enhance the reliability of information flow in the opposite direction, an application that is virtually unexplored. We will describe a system that can use brainwaves to warn a computer that its user may have missed a critical piece of information. This warning will allow the computer to re-present missed information until it is perceived. The algorithms described in this report are simpler than those commonly used in BCI research. The intent of our approach is to develop a device with has the following characteristics: o Implementable with currently available electrical components o Small enough to be enclosed within a helmet o Easily shielded from nearby interference o Power consumption sufficiently low to run on lightweight battery power o Extremely rapid response (response within less than 1 second of target onset) o Easy to set up These restrictions presently rule out both sophisticated waveform analyses and multi-electrode arrays. This paper focuses on whether an uncomplicated analysis of data recorded from a single pair of electrodes can provide useful information to the computer about whether a target was detected. We will focus on two elements of the human EEG signal as indicators of target perception: the P3 component of the Event Related Potential (ERP) and changes in the power of oscillations near 10 hz, known as the Alpha power band. The P3 Component: When one records EEG from the human scalp, the signal measured is deflected by ongoing cognitive operations. In the EEG literature, these deflections are referred to as components, which are observed in the Event Related Potential (ERP) that emerges from averaging together a large number of trials, time locked to the onset of a salient stimulus. ERP components can be manipulated experimentally; hence, they have been associated with particular cognitive processes. Whereas the early part of the waveform is associated with sensory processing of target stimuli, the later part is associated with high-level processing of a stimulus. This component is typically called the P3 (i.e., the third positive peak of the ERP, also referred to as the P300 due to its typical latency of 300ms post-stimulus). Although some researchers have identified a frontally located P3a component, which is elicited by infrequent but task-irrelevant stimuli, we focus on the P3b, which has its maximum over parietal electrode sites. The P3b (called P3 from here on) is present for stimuli that are both infrequent and relevant to the task (Squires et al. 1975), As the P3 is only observed in the ERP for target stimuli that are detected by the subject (Vogel et al. 1998), it can be assumed to be an indication of an item being encoded into working memory (Donchin, 1981). Depending on the amount of noise in the signal, one normally has to average across a considerable number of trials to obtain a clean ERP waveform. However, the P3 component is often large enough to be detected even in the raw EEG. Of course, one cannot draw conclusions about P3 latency and shape from raw P3s; however, they are often clear enough to be detected on a trial-by-trial basis. The algorithm used in our approach focuses on these raw P3s. Alpha Waves: During scalp EEG recording, alpha oscillations (in the 8-12 hz band) are prominent in posterior areas of the brain and this is especially true when the subject’s eyes are closed. Alpha activity is so large that it can easily be discerned in the raw, unfiltered signal and is generally much larger than the P3 component, within an individual trial. However, because alpha activity is poorly phase locked to external events, it is not visible in most event triggered average plots, as employed in ERPs. However, if alpha activity is computed within individual waveforms, using FFT’s, strong changes in this oscillation can be observed in relation to cognitive events. One prominent relationship between oscillations and mental activity is that alpha power tends to diminish at the onset of a cognitive event, such as detecting a target, encoding something into memory, or initiating a movement. This is called an ERD or Event Related Desynchronization (see Pfurtshellter & da Silva 1999 for a review). It is thought that alpha activity may reflect an area of cortex that is being held in idling state. Experiments and Data: To test our ideas, we used data from another experiment, which presented targets embedded in a stream of distractors. We were able to record prominent P3 ERP’s as well as alpha waves. This EEG data serves as a test of the ability of online algorithms to determine wether a target was seen or missed. The experiment involved Rapid Serial Visual Presentation (RSVP), a presentation method commonly used in the visual attention field (Weichselgartner & Sperling 1987). In RSVP, a subject fixates on the center of the screen and views a stream of constantly changing stimuli, which contains one or more targets. In the experiments reported here, subjects viewed a stream of digits in search for any uppercase letter, which was reported at the end of a trial. The subjects did not know when the letter would appear, and stimuli changed every 47 ms. EEG data were compared with target detection on corresponding trials, to gauge the ability of EEG to discriminate between target seen and target missed trials for a random group of 12 subjects. Method Participants: Twelve underand postgraduate university students (mean age 24.1, Std. Dev. 2.9; 6 male and 6 female; 11 rightand 1 left-handed) provided written consent and received 10 GBP for participation. Participants were free from neurological disorders and had normal or corrected-to-normal vision. The study was approved by the local ethics c

Computer Science at Kent Electrophysiological Feedback in Adaptive Human Computer Interfaces

This paper illustrates a way for applying formal methods techniques to specifying and verifying neural networks, with applications in the area of neural network based controllers. Formal methods have some of the characteristics of symbolic models. We describe a communicating automata [Bowman and Gomez, 2005] model of neural networks, where the standard Backpropagation (BP) algorithm [Rumelhart et al., 1986] is applied. Then we undertake a verification of this model using the model checker Uppaal [Behrmann et al., 2004], in order to predict the performance of the learning process. We discuss broad issues of integrating symbolic techniques with complex neural systems. We also argue that symbolic verifications may give theoretically well-founded ways to evaluate and justify neural learning systems.

Symbolic Encoding of Neural Networks using Communicating Automata with Applications to Verification of Neural Network Based Controllers

Using 2-greedy reinforcement learning methods to further understand ventromedial prefrontal patients ’ deficits on the Iowa Gambling Task

This paper describes a computational model of the Attentional Blink constructed using the dual-stage model proposed by [1] and also incorporating a token based account of working memory [2]. This model reproduces data from a number of blink paradigms and makes predictions that lag-1 sparing is temporal and not sequential in origin. A further prediction is that enhancing the distinctiveness of T2 can impair T1 performance and also provoke order inversions of T1 and T2. Experiments from our lab examined the validity of these predictions. Implications and results are discussed.

For many years there have been lay people, philosophers and scientists who have made the distinction between affect and cold cognition. This paper examines the potential value of this dichotomy in relation to understanding ventromedial lesion (VMF) patients behaviour in general and on the Iowa Gambling Task (IGT). We use a combination of dual-process and somatic-marker theories and infer-ences based on simulations of normal controls and VMF patients on the IGT.

A consideration of decision-making, motivation and emotions within Dual Process theory: supporting evidence from Somatic-Marker theory and simulations of the Iowa Gambling task

If you believe this document infringes copyright then please contact the KAR admin team with the take-down information provided at http://kar.kent.ac.uk/contact.html Citation for published version Kalidindi, Kiran and Bowman, Howard and Wyble, Brad (2005) Using e-greedy reinforcement learning methods to further understand ventromedial prefrontal patients' deficits on the Iowa Gambling Task. Technical report. , Canterbury, Kent, CT2 7NF, UK

Using ǫ-greedy reinforcement learning methods to further understand ventromedial prefrontal patients’ deficits on the Iowa Gambling Task

Computational and Experimental Evaluation of the Attentional Blink: Testing The Simultaneous Type Serial Token Model Bradley Wyble (B.Wyble@kent.ac.uk) and Howard Bowman (H.Bowman@kent.ac.uk) Computing Laboratory, University of Kent, Canterbury, Kent, CT2 7NF UK Abstract The Full ST 2 model: Basic Principles A reduced version of the Simultaneous Type Serial Token Model is presented. This model embraces two theories of temporal attention: Chun and Potter’s two-stage theory and Kanwisher’s types-tokens theory. We explain the proposed model and show how it reproduces key data from the Attentional Blink phenomenon. In addition, we verify experimentally predictions arising from the model. Introduction Rapid Serial Visual Presentation (RSVP) has been used extensively to explore how humans deploy attention over time (Chun & Potter, 1995; Kanwisher, 1987; Raymond, Shapiro, & Arnell, 1992; Weighelsgartner & Sperling 1987) Prominent amongst RSVP tasks is the Attentional Blink (AB), in which a decline in performance on a 2 nd target (hereafter the T2) is observed when it is presented within between 100 and 500ms of the offset of a 1 st target (hereafter the T1) (Chun & Potter, 1995; Raymond et al., 1992). Until recently, theoretical debates centred on informal explanations of the blink, which included the 2- stage model (Chun & Potter, 1995) and the Interference theory (Shapiro et al., 1997). These informal explanations have proved valuable in focusing formulation of experimental questions. However, the maturity of the field now makes it ripe for computational modelling. Accordingly, a number of models have recently been proposed (review: Bowman & Wyble, submitted). The current paper focuses on the STST (Simultaneous Type Serial Token) model (Bowman & Wyble, submitted; Bowman, Wyble, & Barnard, 2004), for which we also use the shorthand ST 2 . This paper reports the development of a reduced version of the approach (called the reduced ST 2 model), which abstracts from some of the implementation details of the full model. Importantly though, the new model remains consistent with the theoretical principles that underlie the earlier ST 2 incarnation. The focus of both ST 2 models is the letters-in-digits paradigm (Chun & Potter, 1995), in which the subject’s task is to report the two letter targets placed in a stream of digit distractors. This experiment can be viewed as a canonical AB methodology since no task switch is involved between T1 and T2. The task originally used in (Raymond et al., 1992) involved a task switch, and is therefore more complex. This paper serves to describe the reduced ST 2 model, its predictions, and, finally experimental verification of these predictions. Before introducing the new model, we briefly review necessary elements of the full ST 2 model. The full ST 2 model began as a rate-coded neural network elaboration of the theoretical two-stage model (Chun, 1997; Chun & Potter, 1995). The central idea behind their conception of RSVP processing is that the 1 st stage can represent multiple items in parallel, but only for a short time (several hundred milliseconds). The 2 nd stage is required for consolidation into a memory store that can persist until the end of the trial. However the 2 nd stage is limited in its ability to process multiple items concurrently. Therefore, in order to limit interference in the 2 nd stage, a gate is shut that denies entry to subsequent items. While waiting to be processed, these items are vulnerable to decay if they have been masked. We agree with Chun (1997) that this model can be well implemented using the types and tokens framework described by Kanwisher (1987). In her theory, types represent possible kinds of items, devoid of context. In contrast, tokens represent memories that a given item was encountered, i.e. episodic (instance specific) information about the occurrence of an item. A token can be bound to any combination of types within its domain. In the case of the letters-in-digits task, types would include all of the letters and digits, and one or more tokens would be assigned to represent the occurrence of the targets within an RSVP stream. The other key difference between types and tokens is that the latter are strictly sequential in nature, in that only one token may be in the process of binding at any one time. Hence, the name of our approach: Simultaneous Type, Serial Token. Types can be considered analogous to stage 1 of the two stage theoretical model, while our token implementation is the analogue of stage 2. Stage 1. The full ST 2 model represented each potential item (i.e. each type) in an RSVP stream with a unique node that would be re-activated if the item occurred twice. We implemented a series of layers that represented steps of visual processing. At the 1 st layer, distractors backward masked targets via inhibitory connections. Remaining activation from these masked traces reached the task- selective layer, at which the task demand system emphasized targets. Stage 2. Target(s) in stage-1 could activate a token gate in stage-2, while strong lateral inhibition ensured only one token could be active at any time. The remainder of the token layer implemented dynamics, which insured, that after being active for a sufficient amount of time (approximately 200-300 msec), a token gate would be

Computational and Experimental Evaluation of the Attentional Blink: Testing the Simultaneous Type Serial Token Model

Somatic marker theory proposes that body states act as a valence associated with potential choices based on prior outcomes; and thus aid decision-making. The main supporting evidence for this theory arose from clinical interviews of subjects with ventromedial prefrontal cortex (VMF) lesions and their performance on the Iowa Gambling Task (IGT). VMF patient behaviour has been described as myopia about future consequences. The aim of this paper is to investigate the implications of this description using an abstract simulation of the neural mechanisms that could underlie decision-making in this type of reinforcement learning task.

AN INVESTIGATION OF THE MYOPIA FOR FUTURE CONSEQUENCES THEORY OF VMF PATIENT BEHAVIOUR ON THE IOWA GAMBLING TASK: AN ABSTRACT NEURAL NETWORK SIMULATION

Our connectionist model provides a theoretical explanation for the existence of slow and fast emotional Stroop effects, and depicts them as independent but interacting phenomena. We build upon previous modelling work by Cohen et a] (1990) and Botvinick et al (2001) among others, and incorporate data that suggest a functional division of the Anterior Cingulate Cortex (ACC) into Cognitive and Affective Divisions. This work suggests that slow emotional Stroop effects are caused by activation of the affective portion of the ACC, which inhibits the Cognitive division, reducing top-down cognitive control on the subsequent trial.

MODELLING THE SLOW EMOTIONAL STROOP EFFECT: SUPPRESSION OF COGNITIVE CONTROL

Centre for Cognitive Neuroscience and Cog- nitive Systems, Computer Science at Kent

These experiments examine changes in theta power as measured by wavelet analysis in five rats performing a conditional visual discrimination task and a simple running task. In the conditional task, rats were trained to press one lever to initiate a trial and then to press one of two choice levers, each corresponding to one of two cue lights. Analysis of theta power in this operant task found a large decrease in theta power during the choice bar presses, in contrast to the increase in theta power during trial initiation bar presses. This result seems to stand counter to results that propose consistent relationships between motor actions and theta power (Vanderwolf, EEG Clin Neurophys 26:407–418, 1969 ), as well as studies suggesting that the lack of bar‐press theta is the result of habituation. However, these data can be seen as being in broad agreement with the theoretical framework of sensorimotor integration (Bland and Oddie, Behav Brain Res 127:119–136, 2001 ). To investigate further the power of theta observed at the termination of type 1 motor activity, a runway task was devised in which rats ran back and forth between two ends of a linear track, one of which was always rewarded and the other never rewarded. Theta power decreased sharply 240 ms before movement ended at the rewarded end, but not at the unrewarded end of the track. These data extend the current scope of theory in demonstrating that hippocampal theta activity can end abruptly 200–400 ms prior to the end of type 1 motor movement when approaching the end of a motor sequence. © 2004 Wiley‐Liss, Inc.

Analysis of theta power in hippocampal EEG during bar pressing and running behavior in rats during distinct behavioral contexts

The Attentional Blink (AB) paradigm uses a Rapid Serial Visual Presentation (RSVP) stream, with two targets (denoted T1 and T2). There is a period of approximately 500 msec during which processing of T1 seems to impair the ability to detect and report T2 (Raymond, Shapiro and Arnell 1992). This suggests that the deployment of attention to processing T1 has a temporal window of a little over half a second. This interpretation is complicated by lag 1 sparing, which is the robust finding of almost unimpaired performance on T2 when it immediately follows T1. Early theories of the AB have posited that the blink is the result of interference between the T1, T1+1, T2 and T2+1 items (Raymond, Shapiro and Arnell 1992). In this formulation, the existence of distractors is key to producing the particular U shape of the AB curve. Specifically, it is the T1+1 distractor that reduces the accuracy of a lag-2 T2 by entering the visual buffer along with the T1. Another theoretical account posits the AB as the result of the interaction of two stages of processing (Chun and Potter 1995). Consolidation of the T1 in the second stage prevents the processing of T2. T1+1 items are important in causing the blink in that they make T1 processing more difficult We have implemented a model of the AB, which combines this two-stage architecture with a token-based account of working memory (Kanwisher, 1987). This model makes explicit the prediction that it is the temporal characteristics of the token binding process that determines the shape and time course of the blink, and not the sequential arrangement of targets. Specifically, our model predicts that the shape of the blink curve will be constant with respect to time, such that at a presentation rate of 20 items/sec, the maximal depth of the blink will be obtained at lags 4-6, recovery will occur by lags 10-12, and there will be strong lag-2 sparing. This paper will then describe an experiment that confirms these results empirically. These results are generally incompatible with the intereference theory of Raymond, Shapiro, and Arnell (1992).

The Attentional Blink at 20 items/sec, Model Prediction and Empirical Validation of Lag-2 Sparing

Stimulus specific type II theta rhythm elicited in fear conditioning paradigm

Experimental evidence suggests that the hippocampal theta rhythm plays a critical role in learning. Previous studies have shown long-term potentiation (LTP) to be preferentially induced with stimulation on the peak of local theta rhythm in region CA1 in anesthetized rats and with stimulation of the perforant path at the peak of theta in both anesthetized and behaving animals. We set out to determine the effects of tetanic burst stimulation in stratum radiatum of region CA1 in awake behaving animals, delivered during either the peak or the trough of the theta rhythm in the EEG. Bursts delivered to the peak resulted in an increase of 17.9 ± 0.94% in potential slope. When identical stimulation bursts were delivered to the trough of local theta waves, the potential slope decreased 12.9 ± 1.03%. This is the first report of LTP being preferentially induced at the peak of local theta rhythm in behaving animals in region CA1 and that LTD was found in response to tetanic stimulation at the trough of the local theta wave. The results are discussed within the framework of a recent theory that proposes that the theta rhythm sets the dynamics for alternating phases of encoding and retrieval (Hasselmo et al., 20021).

Stimulation in Hippocampal Region CA1 in Behaving Rats Yields Long-Term Potentiation when Delivered to the Peak of Theta and Long-Term Depression when Delivered to the Trough

The theta rhythm appears in the rat hippocampal electroencephalogram during exploration and shows phase locking to stimulus acquisition. Lesions that block theta rhythm impair performance in tasks requiring reversalofpriorlearning, includingreversalinaT-maze, whereassociations between one arm location and food reward need to be extinguished in favor of associations between the opposite arm location and food reward. Here, a hippocampal model shows how theta rhythm could be important for reversal in this task by providing separate functional phases during each 100-300 msec cycle, consistent with physiological data. In the model, effective encoding of new associations occurs in the phase when synaptic input from entorhinal cortex is strong and long-term potentiation (LTP) of excitatory connections arising from hippocampal region CA3 is strong, but synaptic currents arising from region CA3 input are weak (to prevent interference from prior learned associations). Retrieval of old associations occurs in the phase when entorhinal input is weak and synaptic input from region CA3 is strong, but when depotentiation occurs at synapses from CA3 (to allow extinction of prior learned associations that do not match current input). These phasic changes require that LTP at synapses arising from region CA3 should be strongest at the phase when synaptic transmission at these synapses is weakest. Consistent with these requirements, our recent data show that synaptic transmission in stratum radiatum is weakest at the positive peak of local theta, which is when previous data show that induction of LTP is strongest in this layer.

A Proposed Function for Hippocampal Theta Rhythm: Separate Phases of Encoding and Retrieval Enhance Reversal of Prior Learning

Theta rhythm oscillations and sequence encoding in the hippocampus

Cholinergic and GABAergic neurons projecting to the hippocampus fire with specific phase relations to theta rhythm oscillations in the electroencephalogram (EEG). To determine if this phasic input has an impact on synaptic transmission within the hippocampus, we recorded evoked population excitatory postsynaptic potential (EPSPs) during different phases of theta rhythm by using techniques similar to those described in Rudell and Fox. Synaptic potentials elicited by stimulation of region CA3 of the contralateral hippocampus were recorded in region CA1 and CA3. In these experiments, the initial slope of evoked potentials showed a change in magnitude during different phases of the theta rhythm recorded in the dentate fissure, with individual trials showing an average of 9.5% change in slope of potentials, and the average across all experiments showing a change of 7.8%. Evoked potentials were maximal 18 degrees after the positive peak of the dentate fissure theta EEG. These potentials were also smaller by 18.2% during theta as opposed to non-theta states. Phasic changes in modulation of synaptic transmission could contribute to phase precession of hippocampal place cells and could enhance storage of new sequences of activity as demonstrated by computational models.

Size of CA1-evoked synaptic potentials is related to theta rhythm phase in rat hippocampus.

Electrical stimulation of the horizontal limb of the diagonal band of Broca (HDB) was coupled with recording of evoked potentials in the piriform cortex. Stimulation of the HDB caused an enhancement of the late, disynaptic component of the evoked potential elicited by stimulation of the lateral olfactory tract but caused a suppression of the synaptic potential elicited by stimulation of the posterior piriform cortex. The muscarinic antagonist scopolamine blocked both effects of HDB stimulation. The enhancement of disynaptic potentials could be due to cholinergic depolarization of pyramidal cells, whereas the suppression of potentials evoked by posterior piriform stimulation could be due to presynaptic inhibition of intrinsic fiber synaptic transmission by acetylcholine.

Electrical stimulation of the horizontal limb of the diagonal band of broca modulates population EPSPs in piriform cortex.

This research focuses on linking episodic memory function to the cellular physiology of hippocampal neurons, with a particular emphasis on modulatory effects at cholinergic and γ‐aminobutyric acid B receptors. Drugs which block acetylcholine receptors (e.g., scopolamine) have been shown to impair encoding of new information in humans, nonhuman primates, and rodents. Extensive data have been gathered about the cellular effects of acetylcholine in the hippocampus. In this research, models of individual hippocampal subregions have been utilized to understand the significance of particular features of modulation, and these hippocampal subregions have been combined in a network simulation which can replicate the selective encoding impairment produced by scopolamine in human subjects. © 1997 Wiley‐Liss, Inc.

Encoding and retrieval of episodic memories: Role of cholinergic and GABAergic modulation in the hippocampus

A model of the effects of scopolamine on human memory performance

Free recall and recognition in a network model of the hippocampus: simulating effects of scopolamine on human memory function

DOES THE SPREAD OF ALZHEIMER'S DISEASE NEUROPATHOLOGY INVOLVE THE MECHANISMS OF CONSOLIDATION?

If you believe this document infringes copyright then please contact the KAR admin team with the take-down information provided at http://kar.kent.ac.uk/contact.html Citation for published version Bowman, Howard and Wyble, Brad and Chennu, Srivas and Craston, Patrick (2008) A Reciprocal Relationship Between Bottom-up Trace Strength and the Attentional Blink Bottleneck: Relating the LC-NE and ST2 Models. Brain Research, 1202 . pp. 25-42. ISSN 0006-8993.

A reciprocal relationship between bottom-up trace strength and the attentional blink bottleneck: Relating the LC–NE and ST models

From spike frequency to free recall : How neural circuits perform encoding and retrieval

When people learn to make decisions from experience, a reasonable intuition is that additional relevant information should improve their performance. In contrast, we find that additional information about foregone rewards (i.e., what could have gained at each point by making a different choice) severely hinders participants’ ability to repeatedly make choices that maximize long-term gains. We conclude that foregone reward information accentuates the local superiority of short-term options (e.g., consumption) and consequently biases choice away from productive long-term options (e.g., exercise). These conclusions are consistent with a standard reinforcement-learning mechanism that processes information about experienced and forgone rewards. In contrast to related contributions using delay-of-gratification paradigms, we do not posit separate top-down and emotion-driven systems to explain performance. We find that individual and group data are well characterized by a single reinforcement-learning mechanism that combines information about experienced and foregone rewards.

You Don't Want To Know What You're Missing: When Information about Forgone Rewards Impedes Dynamic Decision Making

Modeling the hydrological significance of wetland restoration scenarios.

Effects on aquatic and human health due to large scale bioenergy crop expansion.

Water quality impact assessment of large-scale biofuel crops expansion in agricultural regions of Michigan

Environmental Impact Analysis of Biofuel Crops Expansion in the Saginaw River Watershed

ABSTRACT This study assesses how the largest daily newspapers in states with female US Senate candidates in 2004 used non-partisan male and female expert and non-expert sources in covering campaigns. Using content analysis, it found that male, non-partisan sources appeared more frequently and prominently than did female sources. That difference was more than four times greater for expert sources who provided “horse race” or “issue” commentary than for non-expert sources. It also found that reporters of both genders cited female sources equally rarely. There was a negative correlation between gender diversity in story sourcing and newsroom racial diversity. The relative scarcity of female sources may have a significant effect on potential readership and the campaign-related news they receive.

Male and Female Sources in Newspaper Coverage of Male and Female Candidates in US Senate Races in 2004

A complete neuroscience requires multi-level theories that address phenomena ranging from higher-level cognitive behaviors to activities within a cell. A levels-of-mechanism approach that decomposes a higher-level model of cognition and behavior into component mechanisms provides a coherent and richer understanding of the system than any level alone. Toward this end, we decomposed a cognitive model into neuron-like units using a neural flocking approach that parallels recurrent hippocampal activity. Neural flocking coordinates units that collectively form higher-level mental constructs. The decomposed model suggested how brain-scale neural populations coordinate to form assemblies encoding concept and spatial representations, and why so many neurons are needed for robust performance at the cognitive level. This multi-level explanation provides a way to understand how cognition and symbol-like representations are supported by coordinated neural populations (assemblies) formed through learning.

A multi-level account of hippocampal function from behaviour to neurons

Dorsomedial striatum, but not dorsolateral striatum, is necessary for rat category learning

Complex behavior is supported by the coordination of multiple brain regions. We propose coordination is achieved by a controller-peripheral architecture in which peripherals (e.g., the ventral visual stream) aim to supply needed inputs to their controllers (e.g., the hippocampus and prefrontal cortex) while expending minimal resources. We developed a formal model within this frame-work to address how multiple brain regions coordinate to support rapid learning from a few example images. The model captured how higher-level activity in the controller shaped lower-level visual representations, affecting their precision and sparsity in a manner that paralleled brain measures. Alternative models optimized by gradient descent irrespective of architectural constraints could not account for human behavior or brain responses, and, typical of standard deep learning approaches, were unstable trial-by-trial learners.

A controller-peripheral architecture and costly energy principle for learning

Synthetic data is proliferating on the web and powering many advances in machine learning. However, it is not always clear if synthetic labels are perceptually sensible to humans. The web provides us with a platform to take a step towards addressing this question through online elicitation. We design a series of elicitation interfaces, which we release as HILL MixE Suite , and recruit 159 participants, to provide perceptual judgments over the kinds of synthetic data constructed during mixup training: a powerful regularizer shown to improve model robustness, generalization, and calibration. We ﬁnd that human perception does not consistently align with the labels traditionally used for synthetic points and begin to demonstrate the applicability of these ﬁndings to potentially increase the reliability of downstream models. We release all elicited judgments in a new data hub we call H-Mix .

A multi-level account of the hippocampus from behavior to neurons

Confound-leakage: Confound Removal in Machine Learning Leads to Leakage

Aligning model representations to humans has been found to improve robustness and generalization. However, such methods often focus on standard observational data. Synthetic data is proliferating and powering many advances in machine learning; yet, it is not always clear whether synthetic labels are perceptually aligned to humans -- rendering it likely model representations are not human aligned. We focus on the synthetic data used in mixup: a powerful regularizer shown to improve model robustness, generalization, and calibration. We design a comprehensive series of elicitation interfaces, which we release as HILL MixE Suite, and recruit 159 participants to provide perceptual judgments along with their uncertainties, over mixup examples. We find that human perceptions do not consistently align with the labels traditionally used for synthetic points, and begin to demonstrate the applicability of these findings to potentially increase the reliability of downstream models, particularly when incorporating human uncertainty. We release all elicited judgments in a new data hub we call H-Mix.

Functional correspondences between deep convolutional neural networks (DCNNs) and the mammalian visual system support a hierarchical account in which successive stages of processing contain ever higher-level information. However, these correspondences between brain and model activity involve shared, not task-relevant, variance. We propose a stricter account of correspondence: If a DCNN layer corresponds to a brain region, then replacing model activity with brain activity should successfully drive the DCNN’s object recognition decision. Using this approach on three datasets, we found that all regions along the ventral visual stream best corresponded with later model layers, indicating that all stages of processing contained higher-level information about object category. Time course analyses suggest that long-range recurrent connections transmit object class information from late to early visual areas.

Reassessing hierarchical correspondences between brain and deep networks through direct interface

We contribute to the study of the quality of learned representations. In many domains, an important evaluation criterion for safe and trustworthy deep learning is how well the invariances captured by representations of deep neural networks (DNNs) are shared with humans. We identify challenges in measuring these invariances. Prior works used gradient-based methods to generate identically represented inputs (IRI), i.e. , inputs which have similar representations (on a given layer) of a neural network. If these IRIs look ‘similar’ to humans then a neural network’s learned invariances are said to align with human perception. However, we show that prior studies on the alignment of invariances between DNNs and humans are ‘biased’ by the speciﬁc loss function used to generate IRI. We show how different loss functions can lead to different takeaways about a model’s shared invariances with humans. We show that under an adversarial IRI generation process all models appear to have very little shared invariance with humans. We conduct an in-depth investigation of how different components of the deep learning pipeline contribute to learning models that have good alignment with human’s invariances. We ﬁnd that architectures with residual connections trained using a self-supervised contrastive loss with (cid:96) p ball adversarial data augmentation tend to learn the most human-like invariances. of DNNs’ representations and human perception using IRI generation methods from these three categories, we arrive at very different conclusions. Speciﬁcally, compared to the regularizer-free IRI generation approach, the human-leaning IRI generation approach over-estimates a model’s alignment with human perception, while the adversarial approach under-estimates a model’s alignment with human perception. We also show how the alignment can be quantiﬁed reliably by designing simple visual perception tests that can be crowdsourced, i.e. used in human surveys.

Exploring Representational Alignment with Human Perception Using Identically Represented Inputs

The Costs and Benefits of Goal-Directed Attention in Deep Convolutional Neural Networks

We argue that a valuable perspective on when a model learns good representations is that inputs that are mapped to similar representations by the model should be perceived similarly by humans. We use representation inversion to generate multiple inputs that map to the same model representation, then quantify the perceptual similarity of these inputs via human surveys. Our approach yields a measure of the extent to which a model is aligned with human perception. Using this measure of alignment, we evaluate models trained with various learning paradigms ( e.g. supervised and self-supervised learning) and different training losses (standard and robust training). Our results suggest that the alignment of representations with human perception provides useful additional insights into the qualities of a model. For example, we ﬁnd that alignment with human perception can be used as a measure of trust in a model’s prediction on inputs where different models have conﬂicting outputs. We also ﬁnd that various properties of a model like its architecture, training paradigm, training loss, and data augmentation play a signiﬁcant role in learning representations that are aligned with human perception.

An evaluation criterion for safe and trustworthy deep learn- ing is how well the invariances captured by representations of deep neural networks (DNNs) are shared with humans. We identify challenges in measuring these invariances. Prior works used gradient-based methods to generate identically represented inputs (IRIs), i.e. , inputs which have identical representations (on a given layer) of a neural network, and thus capture invariances of a given network. One necessary criterion for a network’s invariances to align with human per- ception is for its IRIs look “similar” to humans. Prior works, however, have mixed takeaways; some argue that later layers of DNNs do not learn human-like invariances ([12]) yet oth-ers seem to indicate otherwise ([36]). We argue that the loss function used to generate IRIs can heavily affect takeaways about invariances of the network and is the primary reason for these conﬂicting ﬁndings. We propose an adversarial regularizer on the IRI-generation loss that ﬁnds IRIs that make any model appear to have very little shared invariance with humans. Based on this evidence, we argue that there is scope for improving models to have human-like invariances, and further, to have meaningful comparisons between models one should use IRIs generated using the regularizer-free loss. We then conduct an in-depth investigation of how different compo- nents ( e.g. architectures, training losses, data augmentations) of the deep learning pipeline contribute to learning models that have good alignment with humans. We ﬁnd that architectures with residual connections trained using a (self-supervised) contrastive loss with (cid:96) p ball adversarial data augmentation tend to learn invariances that are most aligned with humans.

Do Invariances in Deep Neural Networks Align with Human Perception?

Replay can consolidate memories through offline neural reactivation related to past experiences. Category knowledge is learned across multiple experiences, and its subsequent generalisation is promoted by consolidation and replay during rest and sleep. However, aspects of replay are difficult to determine from neuroimaging studies. We provided insights into category knowledge replay by simulating these processes in a neural network which approximated the roles of the human ventral visual stream and hippocampus. Generative replay, akin to imagining new category instances, facilitated generalisation to new experiences. Consolidation-related replay may therefore help to prepare us for the future as much as remember the past. Generative replay was more effective in later network layers functionally similar to the lateral occipital cortex than layers corresponding to early visual cortex, drawing a distinction between neural replay and its relevance to consolidation. Category replay was most beneficial for newly acquired knowledge, suggesting replay helps us adapt to changes in our environment. Finally, we present a novel mechanism for the observation that the brain selectively consolidates weaker information; a reinforcement learning process in which categories were replayed according to their contribution to network performance. This reinforces the idea of consolidation-related replay as an active rather than passive process.

A neural network account of memory replay and knowledge consolidation

One reason the mammalian visual system is viewed as hierarchical, such that successive stages of processing contain ever higher-level information, is because of functional correspondences with deep convolutional neural networks (DCNNs). However, these correspondences between brain and model activity involve shared, not task-relevant, variance. We propose a stricter test of correspondence: If a DCNN layer corresponds to a brain region, then replacing model activity with brain activity should successfully drive the DCNN’s object recognition decision. Using this approach on three datasets, we found all regions along the ventral visual stream best corresponded with later model layers, indicating all stages of processing contained higher-level information about object category. Time course analyses suggest long-range recurrent connections transmit object class information from late to early visual areas.

Directly interfacing brain and deep networks exposes non-hierarchical visual processing

Prelimbic cortex maintains attention to category-relevant information and flexibly updates category representations

Whether adding songs to a playlist or groceries during an online shop, how do we decide what to choose next? We develop a model that predicts such open-ended, sequential choices using a process of cued retrieval from long-term memory. Using the past choice to cue subsequent retrievals, this model predicts the sequential purchases and response times of nearly 5 million grocery purchases made by more than 100,000 online shoppers. Products can be associated in different ways, such as by their episodic association or semantic overlap, and we find that consumers query multiple forms of associative knowledge when retrieving options. Attending to certain knowledge sources, as estimated by our model, predicts important retrieval errors, such as the propensity to forget or add unwanted products. Our results demonstrate how basic memory retrieval mechanisms shape choices in real-world, goal-directed tasks.

ABSTRACT How can words shape meaning? Shared labels highlight commonalities between concepts whereas contrasting labels make differences apparent. To address such findings, we propose a deep learning account that spans perception to decision (i.e. labelling). The model takes photographs as input, transforms them to semantic representations through computations that parallel the ventral visual stream, and finally determines the appropriate linguistic label. The underlying theory is that minimising error on two prediction tasks (predicting the meaning and label of a stimulus) requires a compromise in the network's semantic representations. Thus, differences in label use, whether across languages or levels of expertise, manifest in differences in the semantic representations that support label discrimination. We confirm these predictions in simulations involving fine-grained and coarse-grained labels. We hope these and allied efforts which model perception, semantics, and labelling at scale will advance developmental and neurocomputational accounts of concept and language learning.

Artificial neural networks (ANNs) have achieved near human-level performance on many tasks and can account for human behavioural and brain measures in a number of domains. Although a principal strength of ANNs is learning representations from experience, only a handful of contributions have evaluated this process to ask whether ANN learning dynamics provide a good model of human learning. We investigated whether humans learn similarly to an ANN, which adjusts its representations through gradient descent. Gradient descent learning is steep at first and initially ignores covariance between features. ANNs can theoretically display a non-monotonic behaviour in which early in learning, multiple weak predictors determine the ANN’s decision whereas late in learning a single strong predictor can dominate. This initial behaviour was confirmed in a simple ANN and in half of human participants performing a comparable task. Later in gradient descent learning, the ANN changed to placing a greater weight on the stronger predictor, and humans also shifted their preferences in the same way. Hidden Markov modelling of the behaviour of ANNs and humans predicted similar transitions from weak-feature to strong-feature states. Our results suggest a significant proportion of people learn about categories in a manner analogous to ANNs, possibly by updating their mental representations by a process akin to gradient descent. Our findings demonstrate how ANNs can be used to not only explain the products of human learning but also the process.

System alignment supports cross-domain learning and zero-shot generalisation

Top-down attention allows neural networks, both artificial and biological, to focus on the information most relevant for a given task. This is known to enhance performance in visual perception. But it remains unclear how attention brings about its perceptual boost, especially when it comes to naturalistic settings like recognising an object in an everyday scene. What aspects of a visual task does attention help to deal with? We aim to answer this with a computational experiment based on a general framework called task-oriented ablation design. First we define a broad range of visual tasks and identify six factors that underlie task variability. Then on each task we compare the performance of two neural networks, one with top-down attention and one without. These comparisons reveal the task-dependence of attention’s perceptual boost, giving a clearer idea of the role attention plays. Whereas many existing cognitive accounts link attention to stimulus-level variables, such as visual clutter and object scale, we find greater explanatory power in systemlevel variables that capture the interaction between the model, the distribution of training data and the task format. This finding suggests a shift in how attention is studied could be fruitful. We make publicly available our code and results, along with statistics relevant to ImageNet-based experiments beyond this one. Our contribution serves to support the development of more human-like vision models and the design of more informative machine-learning experiments.

Understanding top-down attention using task-oriented ablation design

Subjective value and decision entropy are jointly encoded by aligned gradients across the human brain

Variability in the analysis of a single neuroimaging dataset by many teams

Categorization is a fundamental cognitive function that organizes our experiences into meaningful “chunks.” This category knowledge can then be generalized to novel stimuli and situations. Multiple clinical populations, including people with Parkinson's disease, amnesia, autism, ADHD and schizophrenia, have impairments in the acquisition and use of categories. Although rodent research is well suited for examining the neural mechanisms underlying cognitive functions, many rodent cognitive tasks have limited translational value. To bridge this gap, we use touchscreens to permit greater flexibility in stimulus presentation and task design, track key dependent measures, and minimize experimenter involvement. Touchscreens offer a valuable tool for creating rodent cognitive tasks that are directly comparable to tasks used with humans. Touchscreen tasks are also readily used with cutting‐edge neuroscientific methods that are difficult to do in humans such as optogenetics, chemogenetics, neurophysiology and calcium imaging (using miniscopes). In this review, we show advantages of touchscreen‐based tasks for studying category learning in rats. We also address multiple factors for consideration when designing category learning tasks, including the limitations of the rodent visual system, experimental design, and analysis strategies.

S Abiteboul M Adiba A Albano P Apers I Balbin F Bancilhon D Batory C Beeri D Bell P Bernstein B Bhargava H Biller J Biskup A Borgida J Bubenko M Brodie R Brown P Buneman M Carey S Ceri 0 Chen W Chen D Choy S Christodoulakis W Chu J Clifford U Dayal C Delobel R Demolombe S Demurjian K Dittrich H D Ehrich A Fekete G Gardarin H D Gerhardt G Gottlob J Gray P Gray T Haerder I Hawryszkiewycz P Hawthorne S Ho M Hsu R Hull T Jaervi Y Kambayashi W Kent R King M Kitsuregawa C Landwehr G Lausen R Lee S Lee 0 Li W Litwin J Liu France France Italy Netherlands Australia France USA Israel Ireland USA USA W Germany W Germany USA Sweden USA USA USA USA Italy China Taiwan USA USA USA USA USA France France USA Switzerland W Germany Australia France E Germany Austria USA UK W Germany Australia USA Hong Kong USA USA Finland Japan USA USA Japan USA W Germany Taiwan Korea Australia France USA F Lochovsky P Lockemann V Lum P Lyngbaek F Manola Y Masunaga K McDonell R Meersman T Merrett K Meyer-Wegener J Minker A Motro J Mylopoulos S Navathe S Nishio A Olive M Orlowska z 0zs0y0glu M Papazoglou J Paradaens P Pistor F Rabitti K Ramamohanarao D Reiner I Restrepo-Lince A Reuter N Roussopoulos K van Rijsbergen H Sakai F Saltor P Scheuermann G Schlageter M Scholl Z Shi A Shoshani H W Six J Smith S Spaccapietra A Solvberg N Spyratos P Stocker s su K Tan K Tanaka C Thanos R Topor D Tsichritzis Y Vassiliou B Wah B Walter R Wang G Weikum TWu B Yao K Yokota S Zdonik R Zicari Canada W Germany USA USA USA Japan Australia Netherlands Canada W Germany USA USA USA USA Japan Spain Australia USA Australia Belgium W Germany Italy Australia USA Colombia W Germany USA UK Japan Spain USA W Germany France China USA W Germany Australia Switzerland Norway France UK USA Singapore Japan Italy Australia Switzerland Greece USA W Germany USA Switzerland USA USA Japan USA Italy

2011 8th International ISC Conference on Information Security and Cryptology

We evaluated whether the brain organises value and confidence signals in a systematic fashion that reflects the overall desirability of decision options. If so, regions that respond positively to increases in value should also respond positively to increases in confidence. Likewise, regions that respond negatively to both value and confidence should be widespread. We strongly confirmed these predictions through a model-based fMRI analysis of a mixed gambles task that assessed subjective value (SV) and inverse decision entropy (iDE), which is related to confidence. Purported value areas more strongly signalled iDE than SV, underscoring how intertwined value and confidence are. A gradient tied to the desirability of actions transitioned from positive SV and iDE in ventromedial prefrontal cortex to negative SV and iDE in dorsal medial prefrontal cortex. This non-accidental organisation of SV and iDE signals was found across the brain and was strongest in purported value areas.

Linking models and brain measures offers a number of advantages over standard analyses. Models that have been evaluated on previous datasets can provide theoretical constraints and assist in integrating findings across studies. Model-based analyses can be more sensitive and allow for evaluation of hypotheses that would not otherwise be addressable. For example, a cognitive model that is informed from several behavioural studies could be used to examine how multiple cognitive processes unfold across time in the brain. Models can be linked to brain measures in a number of ways. The information flow and constraints can be from model to brain, brain to model, or reciprocal. Likewise, the linkage from model and brain can be univariate or multivariate, as in studies that relate patterns of brain activity with model states. Models have multiple aspects that can be related to different facets of brain activity. This is well illustrated by deep learning models that have multiple layers or representations that can be aligned with different brain regions. Model-based approaches offer a lens on brain data that is complementary to popular multivariate decoding and representational similarity analysis approaches. Indeed, these approaches can realise greater theoretical significance when situated within a model-based approach.

Advances in supervised learning approaches to object recognition flourished in part because of the availability of high-quality datasets and associated benchmarks. However, these benchmarks—such as ILSVRC—are relatively task-specific, focusing predominately on predicting class labels. We introduce a publicly-available dataset that embodies the task-general capabilities of human perception and reasoning. The Human Similarity Judgments extension to ImageNet (ImageNet-HSJ) is composed of a large set of human similarity judgments that supplements the existing ILSVRC validation set. The new dataset supports a range of task and performance metrics, including evaluation of unsupervised algorithms. We demonstrate two methods of assessment: using the similarity judgments directly and using a psychological embedding trained on the similarity judgments. This embedding space contains an order of magnitude more points (i.e., images) than previous efforts based on human judgments. We were able to scale to the full 50,000 image ILSVRC validation set through a selective sampling process that used variational Bayesian inference and model ensembles to sample aspects of the embedding space that were most uncertain. To demonstrate the utility of ImageNet-HSJ, we used the similarity ratings and the embedding space to evaluate how well several popular models conform to human similarity judgments. One finding is that the more complex models that perform better on task-specific benchmarks do not better conform to human semantic judgments. In addition to the human similarity judgments, pre-trained psychological embeddings and code for inferring variational embeddings are made publicly available. ImageNet-HSJ supports the appraisal of internal representations and the development of more humanlike models.

2021 IEEE/CVF Conference on Computer Vision and Pattern Recognition (CVPR)

Enriching ImageNet with Human Similarity Judgments and Psychological Embeddings

Top-down attention allows people to focus on task-relevant visual information. Is the resulting perceptual boost task-dependent in naturalistic settings? We aim to answer this with a large-scale computational experiment. First, we design a collection of visual tasks, each consisting of classifying images from a chosen task set (subset of ImageNet categories). The nature of a task is determined by which categories are included in the task set. Second, on each task we train an attention-augmented neural network and then compare its accuracy to that of a baseline network. We show that the perceptual boost of attention is stronger with increasing task-set difficulty, weaker with increasing task-set size and weaker with increasing perceptual similarity within a task set.

The perceptual boost of visual attention is task-dependent in naturalistic settings

Similarity as a Window on the Dimensions of Object Representation

For decades, researchers have debated whether mental representations are symbolic or grounded in sensory inputs and motor programs. Certainly, aspects of mental representations are grounded. However, does the brain also contain abstract concept representations that mediate between perception and action in a flexible manner not tied to the details of sensory inputs and motor programs? Such conceptual pointers would be useful when concept remain constant despite changes in appearance and associated actions. We evaluated whether human participants acquire such representations using functional magnetic resonance imaging (fMRI). Participants completed a probabilistic concept learning task in which sensory, motor, and category variables were not perfectly coupled nor entirely independent, making it possible to observe evidence for abstract representations or purely grounded representations. To assess how the learned concept structure is represented in the brain, we examined brain regions implicated in flexible cognition (e.g., prefrontal and parietal cortex) that are most likely to encode an abstract representation removed from sensory-motor details. We also examined sensory-motor regions that might encode grounded sensory-motor based representations tuned for categorization. Using a cognitive model to estimate participants’ category rule and multivariate pattern analysis of fMRI data, we found left prefrontal cortex and MT coded for category in absence of information coding for stimulus or response. Because category was based on the stimulus, finding an abstract representation of category was not inevitable. Our results suggest that certain brain areas support categorization behaviour by constructing concept representations in a format akin to a symbol that differs from stimulus-motor codes.

Abstract neural representations of category membership beyond information coding stimulus or response

Ventromedial prefrontal cortex compression during concept learning

Who says models can only do what you tell them? Unsupervised category learning data, fits, and predictions Todd M. Gureckis (gureckis@love.psy.utexas.edu) Department of Psychology; The University of Texas at Austin Austin, TX 78712 USA Bradley C. Love (love@psy.utexas.edu) Department of Psychology; The University of Texas at Austin Austin, TX 78712 USA Abstract How do people learn and organize examples in the absence of a teacher? This paper explores this ques- tion through a examination of human data and com- putational modeling results. The SUSTAIN (Super- vised and Unsupervised STratified Incremental Net- work) model successfully fits human learning data drawn from two published studies. The first study examines how correlations between features can fa- cilitate unsupervised learning. The second set of studies examines the role that similarity and at- tention play in unsupervised category construction (i.e., sorting) tasks. Importantly, SUSTAIN sug- gests two novel behavioral predictions that are con- firmed. Introduction The study of human category learning has focused on supervised learning. Researchers typically utilize a experimental procedure in which the participant must learn to classify a set of stimuli while receiving corrective feedback on every trial. Certainly, there are many other ways to learn about the world. Our environment does not always provide us with explicit feedback and thus, some learning is better charac- terized as unsupervised. For example, we routinely categorize incoming email as “junk mail” in the ab- sence of a teacher. A great deal of human learning may be unsupervised. The goal of this paper is to expand our understanding of how humans learn from examples without supervision. To achieve this goal, we fit the SUSTAIN model of category learning to Billman and Knutson’s (1996) studies concerning how humans learn correlations through observation and to Medin, Wattenmaker, and Hampson’s (1987) data on unsupervised cate- gory construction (i.e., sorting) behavior. SUSTAIN successfully accounts for human performance in both of these studies with one set of parameters. Impor- tantly, SUSTAIN’s account of these studies suggests novel predictions which are subsequently tested (and confirmed) with human subjects. The Modeling Approach SUSTAIN has been successfully applied to an array of challenging human data sets spanning a variety of category learning paradigms including supervised classification (Love & Medin, 1998), inference learn- ing (Love, Markman, & Yamauchi, 2000), and un- supervised learning (Gureckis & Love, 2002). One primary goal of our modeling approach is to address multiple forms of category learning (both supervised and unsupervised) with one consistent set of princi- ples. After a brief introduction to the operation of SUSTAIN, these core principles will be discussed. Introduction to SUSTAIN SUSTAIN is a clustering model of human category learning. The internal representation of the model consists of a set of clusters. Category representations consist of one or more associated clusters. At the start of learning, the network has a single cluster that is centered in this representational space upon the first input pattern. When a new stimulus item is presented, SUSTAIN attempts to assign the item to the most similar ex- isting cluster. This assignment is unsupervised since it is based only on the similarity between item and cluster. If a surprising event occurs, such as a mis- prediction in supervised learning or a stimulus is en- countered in unsupervised learning that is not simi- lar to any existing cluster, SUSTAIN creates a new cluster to encode the current stimulus. This new cluster is centered in the representational space on the misclassified item. When a stimulus is not surprising, the item is as- signed to the most similar existing cluster and this cluster updates its internal representation to become more similar to the current item (a process some- what analogous to prototype formation). Classifica- tion decisions are based on the cluster to which a stimulus instance is assigned. Like other models of category learning (e.g., Kruschke, 1992), SUSTAIN’s selective attention mechanism learns to selectively weight stimulus feature dimensions that are most useful for categorization. The Principles of SUSTAIN With this general understanding of the operation of the model, we now examine the six key principles that underly SUSTAIN.

Proceedings of the Twenty-Fourth Annual Conference of the Cognitive Science Society

Who says models can only do what you tell them? Unsupervised category learning data, fits, and predictions

Deep convolutional neural networks (DCNNs) rival humans in object recognition. The layers (or levels of representation) in DCNNs have been successfully aligned with processing stages along the ventral stream for visual processing. Here, we propose a model of concept learning that uses visual representations from these networks to build memory representations of novel categories, which may rely on the medial temporal lobe (MTL) and medial prefrontal cortex (mPFC). Our approach opens up two possibilities: a) formal investigations can involve photographic stimuli as opposed to stimuli handcrafted and coded by the experimenter; b) model comparison can determine which level of representation within a DCNN a learner is using during categorization decisions. Pursuing the latter point, DCNNs suggest that the shape bias in children relies on representations at more advanced network layers whereas a learner that relied on lower network layers would display a color bias. These results confirm the role of natural statistics in the shape bias (i.e., shape is predictive of category membership) while highlighting that the type of statistics matter, i.e., those from lower or higher levels of representation. We use the same approach to provide evidence that pigeons performing seemingly sophisticated categorization of complex imagery may in fact be relying on representations that are very low-level (i.e., retinotopic). Although complex features, such as shape, relatively predominate at more advanced network layers, even simple features, such as spatial frequency and orientation, are better represented at the more advanced layers, contrary to a standard hierarchical view.

Levels of Representation in a Deep Learning Model of Categorization

A prominent theory of category learning, COVIS, posits that new categories are learned with either a declarative or procedural system, depending on the task. The declarative system uses the prefrontal cortex (PFC) to learn rule-based (RB) category tasks in which there is one relevant sensory dimension that can be used to establish a rule for solving the task, whereas the procedural system uses corticostriatal circuits for information integration (II) tasks in which there are multiple relevant dimensions, precluding use of explicit rules. Previous studies have found faster learning of RB versus II tasks in humans and monkeys but not in pigeons. The absence of a learning rate difference in pigeons has been attributed to their lacking a PFC. A major gap in this comparative analysis, however, is the lack of data from a nonprimate mammalian species, such as rats, that have a PFC but a less differentiated PFC than primates. Here, we investigated RB and II category learning in rats. Similar to pigeons, RB and II tasks were learned at the same rate. After reaching a learning criterion, wider distributions of stimuli were presented to examine generalization. A second experiment found equivalent RB and II learning with wider category distributions. Computational modeling revealed that rats extract and selectively attend to category-relevant information but do not consistently use rules to solve the RB task. These findings suggest rats are on a continuum of PFC function between birds and primates, with selective attention but limited ability to utilize rules relative to primates.

Notions of mechanism, emergence, reduction and explanation are all tied to levels of analysis. I cover the relationship between lower and higher levels, suggest a level of mechanism approach for neuroscience in which the components of a mechanism can themselves be further decomposed and argue that scientists' goals are best realized by focusing on pragmatic concerns rather than on metaphysical claims about what is ‘real'. Inexplicably, neuroscientists are enchanted by both reduction and emergence. A fascination with reduction is misplaced given that theory is neither sufficiently developed nor formal to allow it, whereas metaphysical claims of emergence bring physicalism into question. Moreover, neuroscience's existence as a discipline is owed to higher-level concepts that prove useful in practice. Claims of biological plausibility are shown to be incoherent from a level of mechanism view and more generally are vacuous. Instead, the relevant findings to address should be specified so that model selection procedures can adjudicate between competing accounts. Model selection can help reduce theoretical confusions and direct empirical investigations. Although measures themselves, such as behaviour, blood-oxygen-level-dependent (BOLD) and single-unit recordings, are not levels of analysis, like levels, no measure is fundamental and understanding how measures relate can hasten scientific progress. This article is part of the theme issue ‘Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity'.

Conceptual Organization is Revealed by Consumer Activity Patterns

How decisions and the desire for coherency shape subjective preferences over time

Concept induction requires the extraction and naming of concepts from noisy perceptual experience. For supervised approaches, as the number of concepts grows, so does the number of required training examples. Philosophers, psychologists, and computer scientists, have long recognized that children can learn to label objects without being explicitly taught. In a series of computational experiments, we highlight how information in the environment can be used to build and align conceptual systems. Unlike supervised learning, the learning problem becomes easier the more concepts and systems there are to master. The key insight is that each concept has a unique signature within one conceptual system (e.g., images) that is recapitulated in other systems (e.g., text or audio). As predicted, children’s early concepts form readily aligned systems. A typical person can correctly recognize and name thousands of objects. By 24 months, children already exhibit an average vocabulary of 200-300 words (Fenson et al., 1994). However, it remains unclear what mechanism makes this feat possible. Here, we conduct an information analysis and demonstrate that it is theoretically possible to learn the labels for objects through purely unsupervised means. Our key insight is that objects embedded within a conceptual system (e.g., text, audio, images) have a unique signature that allows for entire conceptual systems to be aligned (e.g., images with text) absent any instruction. 1 ar X iv :1 90 6. 09 01 2v 1 [ cs .L G ] 2 1 Ju n 20 19 A common assumption is that some degree of explicit instruction is necessary for word learning. For example, a child might be told that a particular object is called a compass, or by reading a caption in a book, learn that a particular photograph depicts a ladybug. However, as V. W. Quine argued, even supervised instruction contains a substantial amount of ambiguity (Quine, 1960). If someone utters the word gavagai while pointing to a rabbit, the word may refer to the whole animal, its long ears, the color of its fur, or the grass it’s eating. Quine suggested that meaning may derive from something’s place within a conceptual system. The meaning of gavagai could include all of these attributes as well as more macroscopic relationships such as the fact that rabbits are prey for other animals. Across multiple supervised learning episodes, it is possible for an individual to extrapolate the appropriate meaning of gavagai (McMurray, Horst, & Samuelson, 2012; Yu & Smith, 2012). However, a long-standing challenge of both cognitive science and machine learning is understanding how humans manage to learn concepts with relatively little supervised instruction. Although the world is a noisy, bustling place with an indefinite number of learnable concepts, it is also trellised with statistical regularities. Given appropriate learning mechanisms, an agent can discover these statistical regularities through unsupervised learning (Bell & Sejnowski, 1995; Chambers, Onishi, & Fisher, 2003; Olshausen & Field, 1996; Younger & Cohen, 1986). Unsupervised learning algorithms provide a means to construct rich feature representations–or embeddings–of the corresponding inputs that capture meaningful semantic relationships (Caron, Bojanowski, Joulin, & Douze, 2018; Pennington, Socher, & Manning, 2014). For example, an unsupervised learning system working with text documents would place cats and dogs near one another within a multidimensional embedding space because cats and dogs appear in similar linguistic contexts. However, such unsupervised approaches are siloed in that insights from one system (e.g., text) do not transfer to another (e.g., images). In contrast, work studying human memory indicates an ability to link the distributional statistics of different systems (Tyler & Moss, 2001). Traditional unsupervised learning fails to address Quine’s challenge. Arguably, supervised learning is so powerful because it explicitly links two distinct conceptual systems (e.g., images and words). In this work, we tap into this power by linking multiple unsupervised embeddings. In order to solve Quinne’s problem, we align a system of word labels and a system of visual semantics that both refer to the same underlying reality and therefore have related structure that can be discovered by unsupervised means (Figure 1). Different sources of input should produce similar conceptual systems because sources are different viewpoints of the same underlying reality. For example, the concepts of grass, rabbit, mouse, fox, and owl are likely to have similar co-occurrence statistics in visual media (images and videos) and communicative media (text and speech). In other words, functionally similar things tend to look alike, and we tend to talk in similar ways about things that are alike. If structural idiosyncrasies present in one embedding are qualitatively mirrored in the other embedding, then it is possible to align the two conceptual systems. In machine learning, a number of techniques referred to as manifold alignment exploit similar assumptions in order to identify mappings between different conceptual systems (Ham, Lee, & Saul, 2005; Wang & Mahadevan, 2008, 2011). Aligning conceptual systems provides a means for an agent to continuously harvest information from everyday experience. Unlike supervised visual category learning–which requires images

Rabbit Fox Mouse Squirrel Owl Vole Supervised Learning Unsupervised Learning From Text Unsupervised Learning From Images

The development and application of concepts is a critical component of cognition. Although concepts can be formed on the basis of simple perceptual or semantic features, conceptual representations can also capitalize on similarities across feature relationships. By representing these types of higher-order relationships, concepts can simplify the learning problem and facilitate decisions. Despite this, little is known about the neural mechanisms that support the construction and deployment of these kinds of higher-order concepts during learning. To address this question, we combined a carefully designed associative learning task with computational model-based functional magnetic resonance imaging (fMRI). Participants were scanned as they learned and made decisions about sixteen pairs of cues and associated outcomes. Associations were structured such that individual cues shared feature relationships, operationalized as shared patterns of cue pair-outcome associations. In order to capture the large number of possible conceptual representational structures that participants might employ and to evaluate how conceptual representations are used during learning, we leveraged a well-specified Bayesian computational model of category learning [1]. Behavioral and model-based results revealed that participants who displayed a tendency to link experiences in memory benefitted from faster learning rates, suggesting that the use of the conceptual structure in the task facilitated decisions about cue pair-outcome associations. Model-based fMRI analyses revealed that trial-by-trial integration of cue information into higher-order conceptual representations was supported by an anterior temporal (AT) network of regions previously implicated in representing complex conjunctions of features and meaning-based information.

Abstract Systematically comparing models that vary across components can be more informative and explanatory than determining whether behaviour is optimal, however defined. The process of model comparison has a number of benefits, including the possibility of integrating seemingly disparate empirical findings, understanding individual and group differences, and drawing theoretical connections between model proposals.

Through selective attention, decision-makers can learn to ignore behaviorally-irrelevant stimulus dimensions. This can improve learning and increase the perceptual discriminability of relevant stimulus information. To account for this effect, popular contemporary cognitive models of categorization typically include of attentional parameters, which provide information about the importance of each stimulus dimension in decision-making. The effect of these parameters on psychological representation is often described geometrically, such that perceptual differences over relevant psychological dimensions are accentuated (or stretched), and differences over irrelevant dimensions are down-weighted (or compressed). In sensory and association cortex, representations of stimulus features are known to covary with their behavioral relevance. Although this implies that neural representational space might closely resemble that hypothesized by formal categorization theory, to date, attentional effects in the brain have been demonstrated through powerful experimental manipulations (e.g., contrasts between relevant and irrelevant features). This approach sidesteps the role of idiosyncratic conceptual knowledge in guiding attention to useful information sources. To bridge this divide, we used formal categorization models, which were fit to behavioral data, to make inferences about the concepts and strategies used by individual participants during decision-making. We found that when greater attentional weight was devoted to a particular visual feature (e.g., “color”), its value (e.g., “red”) was more accurately decoded from occipitotemporal cortex. We additionally found that this effect was sufficiently sensitive to reflect individual differences in conceptual knowledge. The results indicate that occipitotemporal stimulus representations are embedded within a space closely resembling that proposed by classic categorization models.

Occipitotemporal Representations Reflect Individual Differences in Conceptual Knowledge

Contemporary models of categorization typically tend to sidestep the problem of how information is initially encoded during decision making. Instead, a focus of this work has been to investigate how, through selective attention, stimulus representations are “contorted” such that behaviorally relevant dimensions are accentuated (or “stretched”), and the representations of irrelevant dimensions are ignored (or “compressed”). In high-dimensional real-world environments, it is computationally infeasible to sample all available information, and human decision makers selectively sample information from sources expected to provide relevant information. To address these and other shortcomings, we develop an active sampling model, Sampling Emergent Attention (SEA), which sequentially and strategically samples information sources until the expected cost of information exceeds the expected benefit. The model specifies the interplay of two components, one involved in determining the expected utility of different information sources and the other in representing knowledge and beliefs about the environment. These two components interact such that knowledge of the world guides information sampling, and what is sampled updates knowledge. Like human decision makers, the model displays strategic sampling behavior, such as terminating information search when sufficient information has been sampled and adaptively adjusting the search path in response to previously sampled information. The model also shows human-like failure modes. For example, when information exploitation is prioritized over exploration, the bidirectional influences between information sampling and learning can lead to the development of beliefs that systematically differ from reality.

Bidirectional Influences of Information Sampling and Concept Learning

A non-spatial account of place and grid cells based on clustering models of concept learning

Heuristics are simple, yet effective, strategies that people use to make decisions. Because heuristics do not require all available information, they are thought to be easy to implement and to not tax limited cognitive resources, which has led heuristics to be characterized as fast-and-frugal. We question this monolithic conception of heuristics by contrasting the cognitive demands of two popular heuristics, Tallying and Take-the-Best. We contend that heuristics that are frugal in terms of information usage may not always be fast because of the attentional control required to implement this focus in certain contexts. In support of this hypothesis, we find that Take-the-Best, while being more frugal in terms of information usage, is slower to implement and fares worse under time pressure manipulations than Tallying. This effect is then reversed when search costs for Take-the-Best are reduced by changing the format of the stimuli. These findings suggest that heuristics are heterogeneous and should be unpacked according to their cognitive demands to determine the circumstances a heuristic best applies.

Journal of Experimental Psychology. Learning, Memory, and Cognition

Fast or Frugal, but Not Both: Decision Heuristics Under Time Pressure

How much we like something, whether it be a bottle of wine or a new film, is affected by the opinions of others. However, the social information that we receive can be contradictory and vary in its reliability. Here, we tested whether the brain incorporates these statistics when judging value and confidence. Participants provided value judgments about consumer goods in the presence of online reviews. We found that participants updated their initial value and confidence judgments in a Bayesian fashion, taking into account both the uncertainty of their initial beliefs and the reliability of the social information. Activity in dorsomedial prefrontal cortex tracked the degree of belief update. Analogous to how lower-level perceptual information is integrated, we found that the human brain integrates social information according to its reliability when judging value and confidence. SIGNIFICANCE STATEMENT The field of perceptual decision making has shown that the sensory system integrates different sources of information according to their respective reliability, as predicted by a Bayesian inference scheme. In this work, we hypothesized that a similar coding scheme is implemented by the human brain to process social signals and guide complex, value-based decisions. We provide experimental evidence that the human prefrontal cortex's activity is consistent with a Bayesian computation that integrates social information that differs in reliability and that this integration affects the neural representation of value and confidence.

Social Information Is Integrated into Value and Confidence Judgments According to Its Reliability

Partisan gerrymandering poses a threat to democracy. Moreover, the complexity of the districting task may exceed human capacities. One potential solution is using computational models to automate the districting process by optimizing objective and open criteria, such as how spatially compact districts are. We formulated one such model that minimized pairwise distance between voters within a district. Using US Census Bureau data, we confirmed our prediction that the difference in compactness between the computed and actual districts would be greatest for states that are large and therefore difficult for humans to properly district given their limited capacities. The computed solutions highlighted differences in how humans and machines solve this task with machine solutions more fully optimized and displaying emergent properties not evident in human solutions. These results suggest a division of labour in which humans debate and formulate districting criteria whereas machines optimize the criteria to draw the district boundaries. We discuss how criteria can be expanded beyond notions of compactness to include other factors, such as respecting municipal boundaries, historic communities, relevant legislation, etc.

Estimating the functional dimensionality of neural representations

One key question is whether people rely on frugal heuristics or full-information strategies when making preference decisions. We propose a novel method, model-based active learning, to answer whether people conform more to a rank-based heuristic (Take-The-Best) or a weight-based full-information strategy (logistic regression). Our method eclipses traditional model comparison techniques by using information theory to characterize model predictions for how decision makers should actively sample information. These analyses capture how sampling affects learning and how learning affects decisions on subsequent trials. We develop and test model-based active learning algorithms for both Take-The-Best and logistic regression. Our findings reveal that people largely follow a weight-based learning strategy rather than a rank-based strategy, even in cases where their preference decisions are better predicted by the Take-The-Best heuristic. This finding suggests that people may have more refined knowledge than is revealed by their preference decisions, but which can be revealed by their information sampling behavior. We argue that model-based active learning is an effective and sensitive method for model selection that expands the basis for model comparison.

Building concepts one episode at a time: The hippocampus and concept formation

Introduction Convolutional neural networks (CNNs) trained as classifiers learn by associating visual inputs (e.g., photographs of objects) with appropriate output labels (e.g., “crow”, “dog”, “car”). These complex models, which contain millions of weights, are the state-of-the art in machine vision, rivaling humans in object recognition tasks (LeCun, Bengio, & Hinton, 2015; Krizhevsky, Sutskever, & Hinton, 2012). What these networks learn displays some commonalities with human learning (Kubilius, Bracci, & de Beeck, 2016; Lake, Zaremba, Fergus, & Gureckis, 2015). Furthermore, the layers in these networks have been related to neural activity along the ventral stream (Khaligh-Razavi & Kriegeskorte, 2014; Yamins & DiCarlo, 2016) The similarity spaces created by these models at various network layers allow us to draw parallels with the brain’s neural coding schemes (Guest & Love, 2017). At earlier layers, networks display similarity spaces that reflect the high-level categories found in the input space, e.g., lions and tigers are more similar to one another than to mopeds. At the more advanced layers, similarity structure tends to break down such that representations of different object categories become orthogonal. Can these networks also shed light on how non-human animals categorize? CNNs can be used to determine at what level of representation (i.e., what network layer) animals are coding similarities between images. For example, are animals learning regularities at a very low level, close to the pixels in the image, or are they seizing upon more abstract shape features? In this contribution, we address this question by examining data from pigeons trained to categorize images of cardiograms as normal or abnormal. Pigeons are excellent at classifying visual stimuli (Bhatt, Wasserman, Reynolds, & Knauss, 1988). For example, pigeons trained to discriminate between medical images of nora) b)

Despite advances in understanding the brain structures involved in the expression of stereotypes and prejudice, little is known about the brain structures involved in their acquisition. Here, we combined fMRI, a task involving learning the valence of different social groups, and modeling of the learning process involved in the development of biases in thinking about social groups that support prejudice. Participants read descriptions of valenced behaviors performed by members of novel social groups, with majority groups being more frequently encountered during learning than minority groups. A model-based fMRI analysis revealed that the anterior temporal lobe tracked the trial-by-trial changes in the valence associated with each group encountered in the task. Descriptions of behavior by group members that deviated from the group average (i.e., prediction errors) were associated with activity in the left lateral PFC, dorsomedial PFC, and lateral anterior temporal cortex. Minority social groups were associated with slower acquisition rates and more activity in the ventral striatum and ACC/dorsomedial PFC compared with majority groups. These findings provide new insights into the brain regions that (a) support the acquisition of prejudice and (b) detect situations in which an individual's behavior deviates from the prejudicial attitude held toward their group.

Prefrontal cortex (PFC) is thought to support the ability to focus on goal-relevant information by filtering out irrelevant information, a process akin to dimensionality reduction. Here, we test this dimensionality reduction hypothesis by combining a data-driven approach to characterizing the complexity of neural representation with a theoretically-supported computational model of learning. We find direct evidence of goal-directed dimensionality reduction within human medial PFC during learning. Importantly, by using model predictions of each participant’s attentional strategies during learning, we find that that the degree of neural compression predicts an individual’s ability to selectively attend to concept-specific information. These findings suggest a domain-general mechanism of learning through compression in mPFC.

Medial prefrontal cortex compresses concept representations through learning

The success of fMRI places constraints on the nature of the neural code. The fact that researchers can infer similarities between neural representations, despite limitations in what fMRI measures, implies that certain neural coding schemes are more likely than others. For fMRI to be successful given its low temporal and spatial resolution, the neural code must be smooth at the sub-voxel and functional level such that similar stimuli engender similar internal representations. Through proof and simulation, we evaluate a number of reasonable coding schemes and demonstrate that only a subset are plausible given both fMRI’s successes and its limitations in measuring neural activity. Deep neural network approaches, which have been forwarded as computational accounts of the ventral stream, are consistent with the success of fMRI, though functional smoothness breaks down in the later network layers. These results have implications for the nature of neural code and ventral stream, as well as what can be successfully investigated with fMRI.

Older adults perform worse than younger adults in some complex decision-making scenarios, which is commonly attributed to age-related declines in striatal and frontostriatal processing. Recently, this popular account has been challenged by work that considered how older adults’ performance may differ as a function of greater knowledge and experience, and by work showing that, in some cases, older adults outperform younger adults in complex decision-making tasks. In light of this controversy, we examined the performance of older and younger adults in an exploratory choice task that is amenable to model-based analyses and ostensibly not reliant on prior knowledge. Exploration is a critical aspect of decision-making poorly understood across the life span. Across 2 experiments, we addressed (a) how older and younger adults differ in exploratory choice and (b) to what extent observed differences reflect processing capacity declines. Model-based analyses suggested that the strategies used by the 2 groups were qualitatively different, resulting in relatively worse performance for older adults in 1 decision-making environment but equal performance in another. Little evidence was found that differences in processing capacity drove performance differences. Rather the results suggested that older adults’ performance might result from applying a strategy that may have been shaped by their wealth of real-word decision-making experience. While this strategy is likely to be effective in the real world, it is ill suited to some decision environments. These results underscore the importance of taking into account effects of experience in aging studies, even for tasks that do not obviously tap past experiences.

Exploratory Decision-Making as a Function of Lifelong Experience, Not Cognitive Decline

Significance A cosmopolitan couple looking for a home may focus on trendy features. However, with news of a baby on the way, they must quickly learn which features make for a child-friendly home to conceptually reorganize their set of potential homes. We investigate how conceptual knowledge is updated in the brain when goals change and attention shifts to new information. By combining functional MRI with computational modeling, we find that object representations in the human hippocampus are dynamically updated with concept-relevant information during learning. We also demonstrate that when concept updating is most consequential, the hippocampus is functionally coupled with neocortex. Our findings suggest that the brain reorganizes when concepts change and provide support for a neurocomputational theory of concept formation. Concepts organize the relationship among individual stimuli or events by highlighting shared features. Often, new goals require updating conceptual knowledge to reflect relationships based on different goal-relevant features. Here, our aim is to determine how hippocampal (HPC) object representations are organized and updated to reflect changing conceptual knowledge. Participants learned two classification tasks in which successful learning required attention to different stimulus features, thus providing a means to index how representations of individual stimuli are reorganized according to changing task goals. We used a computational learning model to capture how people attended to goal-relevant features and organized object representations based on those features during learning. Using representational similarity analyses of functional magnetic resonance imaging data, we demonstrate that neural representations in left anterior HPC correspond with model predictions of concept organization. Moreover, we show that during early learning, when concept updating is most consequential, HPC is functionally coupled with prefrontal regions. Based on these findings, we propose that when task goals change, object representations in HPC can be organized in new ways, resulting in updated concepts that highlight the features most critical to the new goal.

Dynamic updating of hippocampal object representations reflects new conceptual knowledge

Investors significantly reduce their future returns by selecting mutual funds with higher fees, allured by higher past returns that do not predict future performance. This suboptimal behavior, which can roughly halve an investor’s retirement savings, is driven by 2 psychological factors. One factor is difficulty comprehending rate information, which is critical given that mutual fund fees and returns are typically communicated in percentages. A second factor is devaluing small differences in returns or fees (i.e., a peanuts effect). These 2 factors interact such that large investors benefit when fees are stated in currency (as opposed to percentages), whereas small investors benefit from returns stated in currency. These striking results suggest behavioral interventions that are tailored specifically for small and large investors.

Despite all the differences offered in theories of utility formation and decisions from experience/ 
descriptions, they share common assumption – decision makers have stable and coherent preferences, informed by consistent use of psychological strategy/processing (computational or sampling) that guide their choices between 
alternatives varying in risk and reward. In contrast, we argue for the non-existence of stable risk preferences; we propose that risk preferences are constructed dynamically based on strategy selection as a reinforcement-learning model. Accordingly, we found that decision context and 
associative learning predict strategy selection and govern risky preferences; rather having fixed preferences for risk, people select decision strategies from current context and learn to select decision strategies that are most successful (in terms of effort and reward) for a given context

Decision Context, Associative Learning and Preference Formation in Risky Choice

People are optimistic about their prospects relative to others. However, existing studies can be difficult to interpret because outcomes are not zero-sum. For example, one person avoiding cancer does not necessitate that another person develops cancer. Ideally, optimism bias would be evaluated within a closed formal system to establish with certainty the extent of the bias and the associated environmental factors, such that optimism bias is demonstrated when a population is internally inconsistent. Accordingly, we asked NFL fans to predict how many games teams they liked and disliked would win in the 2015 season. Fans, like ESPN reporters assigned to cover a team, were overly optimistic about their team’s prospects. The opposite pattern was found for teams that fans disliked. Optimism may flourish because year-to-year team results are marked by auto-correlation and regression to the group mean (i.e., good teams stay good, but bad teams improve).

A long-standing debate in decision making has been whether people rely on very little information for making choices, or weigh and add all available information. We propose a new method to determine whether a non-compensatory (Take-The-Best) or compensatory strategy (Logistic Regression) is more psychologically plausible: by looking at people’s active learning queries. This method goes beyond traditional model selection techniques as it reveals the information people choose to learn early on, which subsequently drives their decisions. We developed active learning algorithms for both Take-The-Best and logistic regression and designed an active learning experiment to psychologically distinguish between these two models. Letting both models and humans actively learn and then comparing their queries, we found that people follow a rank-based learning strategy in non-compensatory environments and prefer more certainty-based queries in compensatory environments. The potential for active learning studies to further tease apart different models of decision making will be discussed.

Active learning as a means to distinguish among prominent decision strategies

People in a changing environment must decide between exploiting options they currently favor and exploring alternative options that provide additional information about the state of the environment. For example, drivers must decide between purchasing gas at their currently favored station ( i.e. , exploit) or risk a fruitless trip to another station to evaluate whether the price has been lowered since the last visit. Previous laboratory studies on exploratory choice have found that people choose strategically and explore alternative options when it is more likely that the relative value of competing options has changed. Our study extends this work by considering how global trends (which affect all options equally) influence exploratory choice. For example, during an economic crisis, global gas prices may increase or decrease at all stations, yet consumers should still explore strategically to find the best option. Our research question is whether people can maintain effective exploration strategies in the presence of global trends that are irrelevant in that they do not affect the relative value of choice options. We find that people explore effectively irrespective of global trends.

Unfazed by Both the Bull and Bear: Strategic Exploration in Dynamic Environments

Reflective Exploratory Decision-Making in Older Adults: (528942014-513)

Category membership shapes perceptions of beauty and value for works of art: (527772014-580)

How Network Complexity Affects Our Understanding of Cognitive Processing Across the Lifespan: (528942014-308)

One popular distinction in machine learning is between discriminative and generative models (Ng & Jordan, 2001). Given the cross fertilization between research in human and machine learning, the time is ripe to ask whether the mind is a generative or discriminative learning device. This symposium tackles this question from a variety of perspectives. The aim is to explore the explanatory value of these two basic views of learning, which cut across existing distinctions in cognitive science (e.g., connectionist vs. Bayesian approaches). In brief, generative and discriminative models characterize the task of the learner differently. Generative models attempt to learn an internal model of each class (i.e., category). In contrast, discriminative models attempt to find a boundary that separates classes. Generative models are typically Bayesian in form, whereas discriminative models include decision trees, SVMs, regression approaches, and some (but not all) connectionist models. In generative models, the learning task is to estimate the joint probabilities between all variables. These models assume a hidden or latent variable (e.g., category label) generates observed features. In contrast, discriminative models perform a conditional estimation. For example, logistic regression only estimates the probability of a class (i.e., category) as a function of the predictive features. In this sense, discriminative models are more focused by the task, whereas generative models address a broader estimation problem, though models of all types have an inductive bias to make learning tractable.

Every scientist chooses a preferred level of analysis and this choice shapes the research program, even determining what counts as evidence. This contribution revisits Marr's (1982) three levels of analysis (implementation, algorithmic, and computational) and evaluates the prospect of making progress at each individual level. After reviewing limitations of theorizing within a level, two strategies for integration across levels are considered. One is top-down in that it attempts to build a bridge from the computational to algorithmic level. Limitations of this approach include insufficient theoretical constraint at the computation level to provide a foundation for integration, and that people are suboptimal for reasons other than capacity limitations. Instead, an inside-out approach is forwarded in which all three levels of analysis are integrated via the algorithmic level. This approach maximally leverages mutual data constraints at all levels. For example, algorithmic models can be used to interpret brain imaging data, and brain imaging data can be used to select among competing models. Examples of this approach to integration are provided. This merging of levels raises questions about the relevance of Marr's tripartite view.

The Algorithmic Level Is the Bridge Between Computation and Brain

Structural development of hippocampal sub fi elds is related to statistical learning and inference

Reinforcement learning (RL) refers to the scientific study of how animals and machines adapt their behavior in order to maximize reward. e history of RL research can be traced to early work in psychology on instrumental learning behavior. However, the modern field of RL is a highly interdisciplinary area which lies that the intersection of ideas in computer science, machine learning, psychology, and neuroscience. is chapter summarizes the key mathematical ideas underlying this field including the exploration/exploitation dilemma, temporal-difference (TD) learning, Q-learning, andmodelbased versus model-free learning. In addition, a broad survey of open questions in psychology and neuroscience are reviewed.

Thirty years after the publication of Marr's seminal book Vision (Marr, 1982) the papers in this topic consider the contemporary status of his influential conception of three distinct levels of analysis for information-processing systems, and in particular the role of the algorithmic and representational level with its cognitive-level concepts. This level has (either implicitly or explicitly) been downplayed or eliminated both by reductionist neuroscience approaches from below that seek to account for behavior from the implementation level and by Bayesian approaches from above that seek to account for behavior in purely computational-level terms.

Thirty years of Marr's Vision: Levels of Analysis in Cognitive Science

Familiarity, or memory strength, is a central construct in models of cognition. In previous categorization and long-term memory research, correlations have been found between psychological measures of memory strength and activation in the medial temporal lobes (MTLs), which suggests a common neural locus for memory strength. However, activation alone is insufficient for determining whether the same mechanisms underlie neural function across domains. Guided by mathematical models of categorization and long-term memory, we develop a theory and a method to test whether memory strength arises from the global similarity among neural representations. In human subjects, we find significant correlations between global similarity among activation patterns in the MTLs and both subsequent memory confidence in a recognition memory task and model-based measures of memory strength in a category learning task. Our work bridges formal cognitive theories and neuroscientific models by illustrating that the same global similarity computations underlie processing in multiple cognitive domains. Moreover, by establishing a link between neural similarity and psychological memory strength, our findings suggest that there may be an isomorphism between psychological and neural representational spaces that can be exploited to test cognitive theories at both the neural and behavioral levels.

Global Neural Pattern Similarity as a Common Basis for Categorization and Recognition Memory

Physiological and behavioral signatures of reflective exploratory choice

Heuristics as a special case of Bayesian Inference Paula Parpart University College London Matt Jones University of Colorado Boulder Brad Love University College London Keywords: ; ; ; ; ; ; ; Abstract: Probabilistic inference models (e.g. Bayesian models) are often cast as being rational and at odds with simple heuristic approaches. We show that prominent decision heuristics, take-the-best and tallying, are special cases of Bayesian inference. We developed two Bayesian learning models by extending two popular regularized regression approaches, lasso and ridge regression. The priors of these Bayesian models match the environmental structures necessary for tallying and take-the- best to succeed. Provably, the Bayesian models become equivalent to the heuristics as their priors become more extreme; hence they subsume heuristics and standard linear regression. In a re-analysis of datasets favouring heuristic approaches, we show that our Bayesian extension of ridge regression outperforms tallying and linear regression. A similar result holds for our Bayesian extension of lasso regression and the take-the-best heuristic. This indicates that true environmental structure and potentially psychological processing often lie somewhere between the assumptions of heuristic and standard regression approaches.

Model-Based fMRI Reveals Influence of Attention on Neural Representations of Categories: (505772014-250)

Improved Classification of Mammograms Following Idealized Training.

Decision-Network Context: Dynamics and Learning in Preference Formation: (633262013-325)

Choice exploration and exploitation in purchase decisions: a longitudinal study of customers’ exploration and exploitation of supermarket products. Peter S. Riefer University College London, London, City of London, United Kingdom Bradley C. Love University College London, London, City of London, United Kingdom Abstract: In non-stationary environments, the outcomes of certain choices may change over time. Therefore, people need to balance between the exploitation of presumably superior choices in order to maximize their outcomes and the exploration of seemingly inferior alternatives in order to observe environmental changes. Recent research suggests that people actually follow this principle and exploit choices they currently prefer while once in a while systematically exploring alternatives in order to update their beliefs about the environment. The present study follows up on this by extending the scope to the numerous choice options that people face in a retail store. We investigate choices from over 10,000 customers of a major UK supermarket chain over five years and find evidence that people systematically exploit and explore product choices. Furthermore, we are able to describe how their explorative behavior varies across different product categories.

Choice exploration and exploitation in purchase decisions: a longitudinal study of customers' exploration and exploitation of supermarket products

Neuroscience Perspectives for Science and Mathematics Learning in Technology-Enhanced Learning Environments

Basic decisions, such as judging a person as a friend or foe, involve categorizing novel stimuli. Recent work finds that people's category judgments are guided by a small set of examples that are retrieved from memory at decision time. This limited and stochastic retrieval places limits on human performance for probabilistic classification decisions. In light of this capacity limitation, recent work finds that idealizing training items, such that the saliency of ambiguous cases is reduced, improves human performance on novel test items. One shortcoming of previous work in idealization is that category distributions were idealized in an ad hoc or heuristic fashion. In this contribution, we take a first principles approach to constructing idealized training sets. We apply a machine teaching procedure to a cognitive model that is either limited capacity (as humans are) or unlimited capacity (as most machine learning systems are). As predicted, we find that the machine teacher recommends idealized training sets. We also find that human learners perform best when training recommendations from the machine teacher are based on a limited-capacity model. As predicted, to the extent that the learning model used by the machine teacher conforms to the true nature of human learners, the recommendations of the machine teacher prove effective. Our results provide a normative basis (given capacity constraints) for idealization procedures and offer a novel selection procedure for models of human learning.

People often make decisions by stochastically retrieving a small set of relevant memories. This limited retrieval implies that human performance can be improved by training on idealized category distributions (Giguère & Love, 2013). Here, we evaluate whether the benefits of idealized training extend to categorization of real-world stimuli, namely classifying mammograms as normal or tumorous. Participants in the idealized condition were trained exclusively on items that, according to a norming study, were relatively unambiguous. Participants in the actual condition were trained on a representative range of items. Despite being exclusively trained on easy items, idealized-condition participants were more emory retrieval ecision making

mproved classification of mammograms following idealized training

Most explanations of health risks are presented as “fear appeals,” messages that attempt to arouse fear to modify personal behavior. The central goal of this research is to assess fear appeal performance in online news while examining several research-design issues. Looking at digital news content as fear appeals will expand the scope of research into a new area, and more effective measurement and induction will avoid some common pitfalls. An online experiment produced data indicating that perceived threat and efficacy relationships developed as expected in online news and that improvements in research-design artifacts strongly affect observed variable relationships. Fear appeal and efficacy messages included in digital media content seem to be effective means to altering individual behavioral intentions.

"You may have a cancer-causing virus and not even know it" Fear appeals in online news

Bradley C. Love (b.love@ucl.ac.uk) University College London Niels A. Taatgen (n.a.taatgen@rug.nl) University of Groningen Jana Jarecki (jarecki@mpib-berlin.mpg.de) Max Planck Institute for Human Development Berlin Thomas L. Griffiths (tom_griffiths@berkeley.edu) University of California, Berkeley Jerome R. Busemeyer (jbusemey@indiana.edu) Indiana University Mirjam Jenny (jenny@mpib-berlin.mpg.de) Max Planck Institute for Human Development Berlin The Moot Point Cognitive science aims to understand how humans and animals process information and to build models of these processes – often referred to as process models. However, there seems to be no consensus about what constitutes a process model or which process models are useful (see e.g., Pohl, 2011 for the Recognition Heuristic Model). This symposium will discuss the moot point process models from various perspectives. It brings together researchers who develop and work with different types of models, such as ACT-R, probabilistic computational models, quantum probability, or fMRI data. Focusing on models of judgment and decision making, they will present and discuss the level and scope of their models, which are all seen as candidates for a “process model”. Relevance A discussion about this topic is timely: many formal models of human memory, attention, reasoning, or decision making carry the label “process model” and publications, which include the term process model, have been cited increasingly within the last decade even when controlling for a general positive citation trend (see Figure 1). Proportion of Citations Jana Jarecki (jarecki@mpib-berlin.mpg.de) Max Planck Institute for Human Development Berlin cognitive events unfolding over time (Townsend & Torii, 2005); one written in algorithmic and not analytic language (Gregg & Simon, 1967); one that predicts process data (Schulte-Mecklenbeck, Kuhberger & Raynard, 2011); or a model which is intended to describe processes. Aims This symposium has four aims: First, the methodological debate about whether a process model or a different kind of model is “correct” is recurrent in the field. This debate centers mostly around the general relevance of investigating processes, how to model particular effects, and fitting vs. predicting specific data. Therefore, our first goal is to step back and try to understand what kinds of process models may exist for different classes of data and tasks. Second, some researchers argue that process models are superior to other models. The debate might remain circular if different experts disagree about the features of the process model. This needs to be resolved. Third, we want to find common dimensions of process models of attention, working memory, or decision making. By discussing them we hope to shed light on similarities of process models, such as a temporal order, and constraints between these models, such as working memory limitations. Fourth and foremost: an overview about different types of process models will hopefully set the stage for theory integration through model integration. References Gregg, L. W., & Simon, H. A. (1967). Process models and stochastic theories of simple concept formation. Journal of Mathematical Psychology, 4, 246- Pohl, R. F. (2011). On the use of recognition in inferential decision making: An overview of the debate. Judgment and Decision Making, 6, 423–438. Year Figure 1 Increasing discussion of process models in cognitive science from 2004 to 2013. Number of citations of papers including the terms process model AND (judgment and decision making OR decision making) AND psychology AND cognitive) in relation to the number of citations of papers including only the terms (judgment and decision making OR decision making) AND psychology AND cognitive). Source: internet database Web of Knowledge. If we asked what coins a process model in cognitive science, we might likely get multiple answers: A model that includes Schulte-Mecklenbeck, M., Kuhberger, A., & Raynard, R. (2011). The role of process data in the development and testing of process models of judgment and decision making. Judgment and Decision Making, 6, 733-739 Townsend, J. T., & Torii, K. (2005). Information processing. In L. Nade (Ed.), Encyclopedia of Cognitive Science online, John Wiley and Sons., doi:10.1002/0470018860.s00554. Process Models as the Bridge Between Computation and Brain Bradley C. Love Theorizing in cognitive science occurs at multiple levels of analysis. For example, Marr proposed three levels of analysis: Page 1

The Role of Relational Information in Similarity and Semantic Representations: (537052012-819)

As otherwise healthy adults age, their performance on cognitive tests tends to decline. This change is traditionally taken as evidence that cognitive processing is subject to significant declines in healthy aging. We examine this claim, showing current theories over-estimate the evidence in support of it, and demonstrating that when properly evaluated, the empirical record often indicates that the opposite is true. To explain the disparity between the evidence and current theories, we show how the models of learning assumed in aging research are incapable of capturing even the most basic of empirical facts of “associative” learning, and lend themselves to spurious discoveries of “cognitive decline.” Once a more accurate model of learning is introduced, we demonstrate that far from declining, the accuracy of older adults lexical processing appears to improve continuously across the lifespan. We further identify other measures on which performance does not decline with age, and show how these different patterns of performance fit within an overall framework of learning. Finally, we consider the implications of our demonstrations of continuous and consistent learning performance throughout adulthood for our understanding of the changes in underlying brain morphology that occur during the course of cognitive development across the lifespan.

Learning is not decline: The mental lexicon as a window into cognition across the lifespan

Is better beautiful or is beautiful better? Exploring the relationship between beauty and category structure

Training in action video games can increase the speed of perceptual processing. However, it is unknown whether video-game training can lead to broad-based changes in higher-level competencies such as cognitive flexibility, a core and neurally distributed component of cognition. To determine whether video gaming can enhance cognitive flexibility and, if so, why these changes occur, the current study compares two versions of a real-time strategy (RTS) game. Using a meta-analytic Bayes factor approach, we found that the gaming condition that emphasized maintenance and rapid switching between multiple information and action sources led to a large increase in cognitive flexibility as measured by a wide array of non-video gaming tasks. Theoretically, the results suggest that the distributed brain networks supporting cognitive flexibility can be tuned by engrossing video game experience that stresses maintenance and rapid manipulation of multiple information sources. Practically, these results suggest avenues for increasing cognitive function.

Real-Time Strategy Game Training: Emergence of a Cognitive Flexibility Trait

21 Training in action video games can increase the speed of perceptual processing. However, it is 22 unknown whether video-game training can lead to broad-based changes in higher-level 23 competencies such as cognitive flexibility, a core and neurally distributed component of 24 cognition. To determine whether video gaming can enhance cognitive flexibility and, if so, why 25 these changes occur, the current study compares two versions of a real-time strategy (RTS) 26 game. Using a meta-analytic Bayes factor approach, we found that the gaming condition that 27 emphasized maintenance and rapid switching between multiple information and action sources 28 led to a large increase in cognitive flexibility as measured by a wide array of non-video gaming 29 tasks. Theoretically, the results suggest that the distributed brain networks supporting cognitive 30 flexibility can be tuned by engrossing video game experience that stresses maintenance and rapid 31 manipulation of multiple information sources. Practically, these results suggest avenues for 32 increasing cognitive function. 33

Running head : COGNITIVE FLEXIBILITY AND VIDEO GAME PLAY 1 1 2 3 4 Real-Time Strategy Game Training : Emergence of a Cognitive Flexibility Trait 5

Experiments in dynamic group action and decision making: How crowds of people can walk a tightrope together and survive a zombie attack Daniel C. Richardson (dcr@eyethink.org) Peter Riefer (peter.riefer.11@ucl.ac.uk) Bradley Love (b.love@ucl.ac.uk) Cognitive, Perceptual & Brain sciences, University College London Gower Street, London WC1E 6BT, United Kingdom Beau Lotto (lotto@ucl.ac.uk) Richard C. Clarke (richard.clarke@ucl.ac.uk) Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, United Kingdom Rick Dale (rdale@ucmerced.edu) Cognitive & Information Sciences University of California, Merced, CA 95343, USA John Rogers (john@delosis.com) James Ireland (james@delosis.com) Delosis, 8 Grosvenor Road, Twickenham, Middlesex TW1 4AE, United Kingdom Keywords: joint action; wisdom of crowds; group behaviour, situated cognition; decision making; public goods games Tightrope walking: a cooperative action game Proportion anticipation responses In our first, action-based game participants saw on a projection screen a picture of a man holding a pole, balanced on rope (Figure 1). Each participant held a handset and pressed one of two buttons. A laptop computer collected the responses and controlled the movements of the tightrope walker. Each time one of the participants pressed a button, it sent a small nudge to the tightrope walker, sending him left or right. A game ended when the tightrope walker fell. Analysing the time he stayed aloft and tracking individual responses, we found that on successful games participants were able to anticipate and compensate for the behaviour of the group. This conclusion was supported by agent based simulations. In later conditions we instructed the participants to vocalise their button presses as they made them. The evidence is that they made use of this information, and were better able to predict and compensate for each others’ actions. We present results from a new paradigm: mass participation games. In our experiments, hundreds of people can play a computer game simultaneously using audience response handsets. We can collect responses from a lecture hall full of people with the precision of a laboratory cubicle. We have studied two games: continuous, action games where participants cooperate to achieve a goal; and decision- making paradigms in which participants make repeated choices to maximise their own or the group’s rewards. We address a range of theoretical questions with experimental manipulations and computer modelling. Do participants play as if they were alone, or as a group? If so, do they represent the group as a single entity, or a collection of other agents? What are the dynamics of these behaviours, with learning across many trials? Lastly, what does it feel like to act in concert, or in competition, with a room full of people? There is wisdom in a crowd. The averaged response of a crowd usually betters any of the individual guesses, whether they are guessing the weight of a cow (Galton, 1907), predicting the stock market or making bets about geopolitical events (Surowiecki, 2004). But is the superiority of crowds restricted to single, static decisions? There may be wisdom in a crowd but what happens when they have to act together? What happens when they have to make decisions - pervasive in society - that trade off their own interests with those of the group? For these actions and decisions to be made, how do they learn to predict the behaviour of the group? We addressed these questions by developing mass participation games, in which participants cooperate or compete, maximising their own rewards or those of the group 1 . Figure 1. The tightrope walker game, the participants and the correlation between performance and anticipations If this paper is presented as a talk at the Cognitive Science conference, then the audience will of course be invited to play these games Trial time (s)

Experiments in dynamic group action and decision making: How crowds of people can walk a tightrope together and survive a zombie attack

Recently, there has been a debate in decision-making about whether people integrate 
attributes such as money and probabilities into subjective values or they employ somewhat different psychological processing, without integration of attributes and decision 
trade-offs. In the latter decision-making is accounted for by experience with sequential events, simple binary comparisons 
and a threshold mechanism. Despite all the differences offered in these theories of utility formation and decisions from experience/descriptions, they share common assumption - decision makers have stable and coherent preferences, informed by consistent use of psychological processing(computational or sampling) that guide their choices between 
alternatives varying in risk and reward. In this research we pursued the opposite idea: people do not have underlying preferences for risk; decision-makers gate strategy selection 
from current context (decision-network context) and learn to select decision strategies that are most successful (effort and reward) for a given context.

Decision-Network Context: Dynamics and Learning inPreference Formation.

Pothos & Busemeyer (P&B) provide a compelling case that quantum probability (QP) theory is a better match to human judgment than is classical probability (CP) theory. However, any theory (QP, CP, or other) phrased solely at the computational level runs the risk of being underconstrained. One suggestion is to ground QP accounts in mechanism, to leverage a wide range of process-level data.

Some decisions, such as predicting the winner of a baseball game, are challenging in part because outcomes are probabilistic. When making such decisions, one view is that humans stochastically and selectively retrieve a small set of relevant memories that provides evidence for competing options. We show that optimal performance at test is impossible when retrieving information in this fashion, no matter how extensive training is, because limited retrieval introduces noise into the decision process that cannot be overcome. One implication is that people should be more accurate in predicting future events when trained on idealized rather than on the actual distributions of items. In other words, we predict the best way to convey information to people is to present it in a distorted, idealized form. Idealization of training distributions is predicted to reduce the harmful noise induced by immutable bottlenecks in people’s memory retrieval processes. In contrast, machine learning systems that selectively weight (i.e., retrieve) all training examples at test should not benefit from idealization. These conjectures are strongly supported by several studies and supporting analyses. Unlike machine systems, people’s test performance on a target distribution is higher when they are trained on an idealized version of the distribution rather than on the actual target distribution. Optimal machine classifiers modified to selectively and stochastically sample from memory match the pattern of human performance. These results suggest firm limits on human rationality and have broad implications for how to train humans tasked with important classification decisions, such as radiologists, baggage screeners, intelligence analysts, and gamblers.

Acts of cognition can be described at different levels of analysis: what behavior should characterize the act, what algorithms and representations underlie the behavior, and how the algorithms are physically realized in neural activity [1]. Theories that bridge levels of analysis offer more complete explanations by leveraging the constraints present at each level [2–4]. Despite the great potential for theoretical advances, few studies of cognition bridge levels of analysis. For example, formal cognitive models of category decisions accurately predict human decision making [5, 6], but whether model algorithms and representations supporting category decisions are consistent with underlying neural implementation remains unknown. This uncertainty is largely due to the hurdle of forging links between theory and brain [7–9]. Here, we tackle this critical problem by using brain response to characterize the nature of mental computations that support category decisions to evaluate two dominant, and opposing, models of categorization.We found that brain states during category decisions were significantly more consistent with latent model representations from exemplar [5] rather than prototype theory [10, 11]. Representations of individual experiences, not the abstraction of experiences, are critical for category decision making. Holding models accountable for behavior and neural implementation provides a means for advancing more complete descriptions of the algorithms of cognition.

The influence of depression symptoms on exploratory decision-making

Abstract : Given that people can process only so many pieces of information, one key aspect of learning is learning which stimulus aspects are goal relevant in the current context. In addition to injecting noise into the decision process, gathering unnecessary information can have costs in terms of time, effort, dollars, fuel, and perhaps lives. In light of these considerations, many category learning models employ selective attention mechanisms that learn which stimulus dimensions are most critical to performance. However, attention in category learning models does not direct what is encoded, but instead establishes decision weights on stimulus dimensions. Likewise, machine learning approaches to feature selection sample features not included in the final subset, and these models do not contextually determine feature relevancy. To address these shortcomings, we develop a model that selectively encodes information during learning as a function of the learner's goals, task demands, and knowledge state. The model consists of two components that are both normative, but lead to apparent non-normative behaviors when linked. One component determines the value of potential sources of information. The value of a piece of information depends on the decision maker's goals and assumptions about (i.e., knowledge of) the world, as well as the cost of the information. The second component of the model reflects the decision maker's knowledge of the world, which is used by the first component to direct information gathering. This learning component of the model is updated by the information samples selected by the first component, completing the cycle of mutual influence. We develop sub-ideal models to both capture human performance and to inform related research in machine learning. Several existing datasets are considered and novel experiments are proposed.

Decoding the Brain’s Algorithm for Categorization from Its Neural Implementation

Category learning is a complex phenomenon that engages multiple cognitive processes, many of which occur simultaneously and unfold dynamically over time. For example, as people encounter objects in the world, they simultaneously engage processes to determine their fit with current knowledge structures, gather new information about the objects, and adjust their representations to support behavior in future encounters. Many techniques that are available to understand the neural basis of category learning assume that the multiple processes that subserve it can be neatly separated between different trials of an experiment. Model-based functional magnetic resonance imaging offers a promising tool to separate multiple, simultaneously occurring processes and bring the analysis of neuroimaging data more in line with category learning's dynamic and multifaceted nature. We use model-based imaging to explore the neural basis of recognition and entropy signals in the medial temporal lobe and striatum that are engaged while participants learn to categorize novel stimuli. Consistent with theories suggesting a role for the anterior hippocampus and ventral striatum in motivated learning in response to uncertainty, we find that activation in both regions correlates with a model-based measure of entropy. Simultaneously, separate subregions of the hippocampus and striatum exhibit activation correlated with a model-based recognition strength measure. Our results suggest that model-based analyses are exceptionally useful for extracting information about cognitive processes from neuroimaging data. Models provide a basis for identifying the multiple neural processes that contribute to behavior, and neuroimaging data can provide a powerful test bed for constraining and testing model predictions.

Striatal and hippocampal entropy and recognition signals in category learning: simultaneous processes revealed by model-based fMRI.

The increased usage of online cancer support groups as a resource for health-related information and social support has sparked numerous discussions about the role of online support in healthcare. However, little is known about the role of social-networking groups focused on supporting adolescents and young adults (AYAs) dealing with cancer. The current investigation report findings from a content analysis designed to explore how AYAs use an online support group to meet their psychosocial needs. Overall, members of the community focused on exchanging emotional and informational support, coping with difficult emotions through expression, describing experiences of being an AYA dealing with cancer through language (metaphors), enacting identity through evaluations of the new normal (life with and after cancer), and communicating membership as an AYA with cancer. This study highlights the unique needs of the AYA cancer community and offers a preliminary roadmap for practitioners, and network members, such as family and friends, to attempt to meet the needs of this unique community.

Exploring Psychosocial Support Online: A Content Analysis of Messages in an Adolescent and Young Adult Cancer Community

representationsdeclines in the fidelity of newly acquired category

We present a theory suggesting that the ability to build category representations that reflect the nuances of category structures in the environment depends upon clustering mechanisms instantiated in an MTL-PFC-based circuit. Because function in this circuit declines with age, we predict that the ability to build category representations will be impaired in older adults. Consistent with this prediction, we find that older adults are impaired relative to younger adults at learning nuanced category structures that contain exceptions to the rule. Model-based analysis reveals that this deficit arises from older adults' failure to engage clustering mechanisms to separate exception and rule-following items in memory.

Age-related declines in the fidelity of newly acquired category representations.

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Todd Maddox representations Age-related declines in the fidelity of newly acquired category Material

Special thanks to Alex Kline, Seth Koslov, and Marissa Gorlick for their help with this project. For more information, please visit: http://homepage.psy.utexas.edu/homepage/Group/MaddoxLAB/index.htm This research was supported by the NIDA grant DA032457 to W. Todd Maddox and NIH Diversity Supplement Award R01DA032457-01A1S1 to NJB. Decision-making requires balancing competing demands of exploiting options that have previously been successful, and exploring to gain more information1.

Dopamine-Related Genetic Influences on Exploratory Decision-making

Impulsivity is a stable personality trait associated with myopic choice behavior that favors immediate rewards over larger, delayed rewards and is often characterized as maladaptive inside and outside of the laboratory. An alternative view suggests that the consequences of trait impulsivity depend on the nature of the task environment. On this view, the optimal level of impulsivity varies across task payoff structures. This hypothesis is tested in two dynamic decision-making tasks that differ in the relative payoffs of delayed and immediate rewards. In a task that favors delayed rewards to immediate rewards, high-impulsive participants perform worse than low-impulsive participants. In contrast, in a task that favors immediate rewards over delayed rewards, high-impulsive participants outperform low-impulsive participants. These results suggest a more nuanced conceptualization of trait impulsivity as it applies to rewards-related decision making that may help explain the variability observed in this trait across individuals.

Human beings are a largely untapped source of in-the-loop knowledge and guidance for computational learning agents, including robots. To effectively design agents that leverage available human expertise, we need to understand how people naturally teach. In this paper, we describe two experiments that ask how differing conditions affect a human teacher's feedback frequency and the com- putational agent's learned performance. The first experiment considers the impact of a self-perceived teaching role in con- trast to believing one is merely critiquing a recording. The second considers whether a human trainer will give more frequent feedback if the agent acts less greedily (i.e., choos- ing actions believed to be worse) when the trainer's recent feedback frequency decreases. From the results of these ex- periments, we draw three main conclusions that inform the design of agents. More broadly, these two studies stand as early examples of a nascent technique of using agents as

representations Age-related declines in the fidelity of newly acquired category Material Supplemental

Category knowledge can be explicit, yet not conform to a perfect rule. For example, a child may acquire the rule "If it has wings, then it is a bird," but then must account for exceptions to this rule, such as bats. The current study explored the neurobiological basis of rule-plus-exception learning by using quantitative predictions from a category learning model, SUSTAIN, to analyze behavioral and functional magnetic resonance imaging (fMRI) data. SUSTAIN predicts that exceptions require formation of specialized representations to distinguish exceptions from rule-following items in memory. By incorporating quantitative trial-by-trial predictions from SUSTAIN directly into fMRI analyses, we observed medial temporal lobe (MTL) activation consistent with 2 predicted psychological processes that enable exception learning: item recognition and error correction. SUSTAIN explains how these processes vary in the MTL across learning trials as category knowledge is acquired. Importantly, MTL engagement during exception learning was not captured by an alternate exemplar-based model of category learning or by standard contrasts comparing exception and rule-following items. The current findings thus provide a well-specified theory for the role of the MTL in category learning, where the MTL plays an important role in forming specialized category representations appropriate for the learning context.

Learning the exception to the rule: model-based FMRI reveals specialized representations for surprising category members.

Abstract The prominence of Bayesian modeling of cognition has increased recently largely because of mathematical advances in specifying and deriving predictions from complex probabilistic models. Much of this research aims to demonstrate that cognitive behavior can be explained from rational principles alone, without recourse to psychological or neurological processes and representations. We note commonalities between this rational approach and other movements in psychology – namely, Behaviorism and evolutionary psychology – that set aside mechanistic explanations or make use of optimality assumptions. Through these comparisons, we identify a number of challenges that limit the rational program's potential contribution to psychological theory. Specifically, rational Bayesian models are significantly unconstrained, both because they are uninformed by a wide range of process-level data and because their assumptions about the environment are generally not grounded in empirical measurement. The psychological implications of most Bayesian models are also unclear. Bayesian inference itself is conceptually trivial, but strong assumptions are often embedded in the hypothesis sets and the approximation algorithms used to derive model predictions, without a clear delineation between psychological commitments and implementational details. Comparing multiple Bayesian models of the same task is rare, as is the realization that many Bayesian models recapitulate existing (mechanistic level) theories. Despite the expressive power of current Bayesian models, we argue they must be developed in conjunction with mechanistic considerations to offer substantive explanations of cognition. We lay out several means for such an integration, which take into account the representations on which Bayesian inference operates, as well as the algorithms and heuristics that carry it out. We argue this unification will better facilitate lasting contributions to psychological theory, avoiding the pitfalls that have plagued previous theoretical movements.

Bayesian Fundamentalism or Enlightenment? On the explanatory status and theoretical contributions of Bayesian models of cognition

Determinants of learning difficulty and boundary uncertainty in unidimensional category learning Gyslain Gigu` ere The University of Texas at Austin Bradley C. Love The University of Texas at Austin Abstract: Many real-world learning and classification problems involve mastering subtle and noisy distinctions. For example, predicting the winner of a baseball game is challenging due to numerous interactions and inherent noise in outcomes. One common approach in machine learning to reduce overfitting and boost performance (i.e., generalization) on novel test items is to use regularization methods that effectively smooth the training data. One research question is whether human performance can be boosted by effectively regularizing (i.e., idealizing) the training set. In the first two studies, participants learned and were tested on perceptual categories. Idealization was manipulated across conditions in terms of distribution variance and feedback type. In the third study, participants predicted the outcome of actual baseball games after training on either actual or idealized game results. In all three studies, participants performed better on generalization tests (involving actual items) when trained on idealized items than on actual items.

Determinants of learning difficulty and boundary uncertainty in unidimensional category learning

What mechanisms underlie children's language production? Structural priming--the repetition of sentence structure across utterances--is an important measure of the developing production system. We propose its mechanism in children is the same as may underlie analogical reasoning: structure-mapping. Under this view, structural priming is the result of making an analogy between utterances, such that children map semantic and syntactic structure from previous to future utterances. Because the ability to map relationally complex structures develops with age, younger children are less successful than older children at mapping both semantic and syntactic relations. Consistent with this account, 4-year-old children showed priming only of semantic relations when surface similarity across utterances was limited, whereas 5-year-olds showed priming of both semantic and syntactic structure regardless of shared surface similarity. The priming of semantic structure without syntactic structure is uniquely predicted by the structure-mapping account because others have interpreted structural priming as a reflection of developing syntactic knowledge.

Structural Priming as Structure-Mapping: Children Use Analogies From Previous Utterances to Guide Sentence Production

Abstract Mathematical developments in probabilistic inference have led to optimism over the prospects for Bayesian models of cognition. Our target article calls for better differentiation of these technical developments from theoretical contributions. It distinguishes between Bayesian Fundamentalism, which is theoretically limited because of its neglect of psychological mechanism, and Bayesian Enlightenment, which integrates rational and mechanistic considerations and is thus better positioned to advance psychological theory. The commentaries almost uniformly agree that mechanistic grounding is critical to the success of the Bayesian program. Some commentaries raise additional challenges, which we address here. Other commentaries claim that all Bayesian models are mechanistically grounded, while at the same time holding that they should be evaluated only on a computational level. We argue this contradictory stance makes it difficult to evaluate a model's scientific contribution, and that the psychological commitments of Bayesian models need to be made more explicit.

Pinning down the theoretical commitments of Bayesian cognitive models

In non-stationary environments, there is a conflict between exploiting currently favored options and gaining information by exploring lesser-known options that in the past have proven less rewarding. Optimal decision-making in such tasks requires considering future states of the environment (i.e., planning) and properly updating beliefs about the state of the environment after observing outcomes associated with choices. Optimal belief-updating is reflective in that beliefs can change without directly observing environmental change. For example, after 10 s elapse, one might correctly believe that a traffic light last observed to be red is now more likely to be green. To understand human decision-making when rewards associated with choice options change over time, we develop a variant of the classic “bandit” task that is both rich enough to encompass relevant phenomena and sufficiently tractable to allow for ideal actor analysis of sequential choice behavior. We evaluate whether people update beliefs about the state of environment in a reflexive (i.e., only in response to observed changes in reward structure) or reflective manner. In contrast to purely “random” accounts of exploratory behavior, model-based analyses of the subjects’ choices and latencies indicate that people are reflective belief updaters. However, unlike the Ideal Actor model, our analyses indicate that people’s choice behavior does not reflect consideration of future environmental states. Thus, although people update beliefs in a reflective manner consistent with the Ideal Actor, they do not engage in optimal long-term planning, but instead myopically choose the option on every trial that is believed to have the highest immediate payoff.

The Nature of Belief-Directed Exploratory Choice in Human Decision-Making

Becoming a Gamer: Cognitive Effects of Real-Time Strategy Gaming Brian D. Glass Department of Psychology, University of Texas at Austin Marc T. Tomlinson Department of Psychology, University of Texas at Austin W. Todd Maddox Department of Psychology, University of Texas at Austin Institute for Neuroscience, University of Texas at Austin Bradley C. Love Department of Psychology, University of Texas at Austin Abstract: Video games are rich, dynamic, and fast-paced virtual environments that tap a number of cognitive processes. Prior work reveals that experienced video game players (and novices who become experienced) demonstrate enhanced cognitive and perceptual performance in a range of tasks. It is not clear why video gaming leads to these enhancements. To address this, we use real-time strategy games which require dynamic attention and multitasking skills. We employ a variety of novel methods to capture which game features are associated with various cognitive enhancements. Specifically, we use model-based analysis of empirical feature selection priorities, tests of generation via multiple game maps, and a map manipulation of centered versus bimodal attentional load. Novice participants engaged in 40 hours of game-training, with cognitive testing occurring before, during, and after training. We consider the plasticity of cognitive abilities over training in light of these well controlled factors.

Becoming a Gamer: Cognitive Effects of Real-Time Strategy Gaming

Moving Beyond Where and What to How: Using Models and fMRI to Understand Brain-Behavior Relations Bradley C. Love (brad_love@mail.utexas.edu) Department of Psychology Austin, TX 78712 USA John P. Spencer (john-spencer@uiowa.edu) Department of Psychology and Delta Center, E11 Seashore Hall Iowa City, IA 52242 USA of model-based analysis of brain data. At the same time, the particularly challenges faced in each domain will be informative and raise discussion topics. Symposium Overview One central goal of cognitive science is to understand how the brain supports cognition. Toward this end, a great deal of effort is devoted toward computational modeling and brain imaging. The former effort is well represented at the Annual Conference, whereas the latter effort is neglected. One common criticism of brain imaging research from the cognitive science community is that it is overly focused on the where of cognition, as opposed to the how (i.e., process-level questions linking brain and behavior). Model-based analysis of fMRI data links models to the interpretation of imaging data, allowing process-level questions to be asked. The basic approach involves fitting models to behavioral data and then using internal quantities from the models as regressors in the imaging analysis. In this symposium, a broad assortment of leading researchers demonstrate the value of this approach in several domains. Testing a dynamic neural field model of visual working memory with fMRI (Spencer, Buss & Magnotta) Keywords: Computational models, reinforcement learning, categorization, working memory, social cognition, fMRI. Speakers We have assembled top speakers with extensive expertise in computational modeling of behavioral and neural data: Nathaniel Daw, Assistant Professor, New York University. Dr. Daw’s research concerns reinforcement learning and decision making from a computational approach, and particularly the application of computational models to the analysis of behavioral and neural data. Bradley C. Love, Professor of Psychology, University of Texas. Dr. Love is expert in experimental and computational explorations of learning and decision making. John O'Doherty, Professor, Caltech. His main research focus is on the neural mechanisms underpinning reinforcement-learning and value-based decision making. John P. Spencer (Panel Moderator), Professor, University of Iowa. Dr. Spencer is an expert in the use of dynamic neural fields to capture behavioral and neural data. Speaker Abstracts The abstracts provide broad coverage of topics, including working memory, reinforcement learning, category learning, and social inference. This diversity of problem domains will make clear the commonalities and general applicability Efficient visually-guided behavior depends on our ability to form, retain, and compare visual representations that may be separated in space and time. This ability relies on visual working memory (VWM). Although research has begun to shed light on the neuro-cognitive systems subserving this form of memory, few theories have addressed these processes in a neurally-grounded framework. Here, we describe a layered neural architecture that captures the cortical population dynamics that underlie VWM, including the encoding, maintenance and comparisons operations involved in change detection. We then test this model using functional neuroimaging. Recent work has shown that the BOLD response is strongly correlated with local field potentials (LFPs). An analog of LFPs can be estimated from dynamic neural field models. This estimate can be convolved with an impulse response function to yield time-dependent hemodynamic predictions. Using this approach, we show that the DFN model quantitatively captures fMRI data from recent studies probing changes in the BOLD response in the intraparietal sulcus (IPS) as set size increases in change detection, as well as data showing stronger activation on change trials versus same trials. We also test a novel prediction of the model that BOLD responses should be greater on false alarms versus misses. These data run counter to common explanations of the origin of errors in change detection. Computational models as neural hypotheses: Reinforcement learning (Daw) The predominant methods for analyzing neuroimaging data center on assessing explicit statistical models of the neural response. I consider how this approach can be extended to test more psychological or functional level models of neural computation. The function I focus on is learned trial-and- error decision making. Computational algorithms for this function – known in computer science as reinforcement learning -- can be viewed as explicit hypotheses about how

Moving Beyond Where and What to How: Using Models and fMRI to Understand Brain-Behavior Relations

Selective Attention by Structural Alignment: An Eyetracking Study Aaron B. Hoffman (aaron.hoffman@mail.utexas.edu) Department of Psychology, 1 University Station A8000 Austin, Texas 78712-0187 Bradley C. Love (brad_love@mail.utexas.edu) Department of Psychology, 1 University Station A8000 Austin, Texas 78712-0187 Arthur B. Markman (markman@psy.utexas.edu) Department of Psychology, 1 University Station A8000 Austin, Texas 78712-0187 Colner, & Hoffman, 2009) and in natural scene perception (e.g., Hayhoe, Shrivastava, Mruczek, & Pelz, 2003) proposes that the information demands of the task are the biggest influences on what people selectively attend. In the present study we test the idea that yet another determinant of people’s selective attention is the comparisons they make. We will first review comparison processes and then evidence from Markman and Gentner (1997) showing that people have better recall when they are cued by elements from scenes that are part of structural alignment. Then, by replicating Markman and Gentner (1997) with an eyetracker, we provide an online test of the idea that structural alignment can drive selective attention. Abstract A potential determinant of people’s selective attention is offered by the structural-alignment view of comparison. This view holds that objects are compared via structured representations that align sets of features that share relational roles. A central claim of this account is that the comparison process directs attention towards alignable features. This prediction has been supported by offline measures by Markman and Gentner (1997), who showed that alignable features serve as better cues for recall than nonalignable features. The present study provides the first online test of the structure-alignment theory’s claim that alignability drives selective attention. Consistent with this, we show that in addition to serving as better cues for recall, alignable differences are attended more than nonalignable differences. Within-trial attention dynamics revealed that attention to alignable differences increases over the course of the comparison process. Comparison Keywords: comparison, alignment, attention, recall, eye movements, eye tracking Introduction The amount of information that inundates people’s perceptual systems creates a significant challenge. As people move through their environment, they are faced with thousands of decisions about which information they should selectively attend and which they should filter out. They must decide that certain things are worth remembering and that others are not. How are such decisions made? There are a variety of factors that influence selection of parts of the stimulus stream. Early work examining how people attend to complex visual scenes showed that people will fixate the most informative elements (Buswell, 1935; Mackworth & Morandi, 1967; see Henderson & Hollingworth, 1999 for review). Subsequent work explored people’s tendency to attend to the most perceptually salient features (e.g., Henderson, Weeks, & Hollingworth, 1999; Parkhurst, Law, & Niebur, 2002). Work on schemata and memory suggests that semantic consistency with a schema determines what is later recalled (Bransford & Johnson, 1972; 1973; Brewer & Dupree, 1983; Rummelhart, 1980). Finally, recent eye tracking work in categorization (Rehder, The ability to compare is an integral part of human cognition. Category membership is determined by the degree of similarity to category representations (Medin & Schaffer, 1978; Nosofsky, 1984). In problem solving, people find solutions by comparing new problems to previously solved problems (Chi, Feltovich, & Glaser, 1981; Ross, 1987). In episodic memory, probes are compared to memory traces (Hintzman, 1986). In analogy people compare base and target domains. (Falkenhainer, Forbus, & Gentner, 1989; Gentner, 1983; Hummel & Holyoak, 1997) There have been a few approaches to modeling the comparison process, including computing distances in multidimensional space using feature vectors, (Shepard, 1962) or comparing features using set operations, Tversky (1977). And yet to account for human comparison of complex stimuli with relational structure, a third approach has been used. Borrowing from models of analogy (Falkenhainer et al., 1989), the structure-alignment account (Gentner, 1983) represents objects as features inside structures of relations. For example, structure-alignment theory posits that people will encode features (e.g., the people and objects in Figure 1A) as arguments to relational predicates: smokes(man, cigar) or paints(painter, model). On this account, significant processing is applied to building a representation of the relations between features in a scene

Selective Attention by Structural Alignment: An Eyetracking Study

Work in category learning addresses how humans acquire knowledge and, thus, should inform classroom practices. In two experiments, we apply and evaluate intuitions garnered from laboratory-based research in category learning to learning tasks situated in an educational context. In Experiment 1, learning through predictive inference and classification were compared for fifth-grade students using class-related materials. Making inferences about properties of category members and receiving feedback led to the acquisition of both queried (i.e., tested) properties and nonqueried properties that were correlated with a queried property (e.g., even if not queried, students learned about a species' habitat because it correlated with a queried property, like the species' size). In contrast, classifying items according to their species and receiving feedback led to knowledge of only the property most diagnostic of category membership. After multiple-day delay, the fifth-graders who learned through inference selectively retained information about the queried properties, and the fifth-graders who learned through classification retained information about the diagnostic property, indicating a role for explicit evaluation in establishing memories. Overall, inference learning resulted in fewer errors, better retention, and more liking of the categories than did classification learning. Experiment 2 revealed that querying a property only a few times was enough to manifest the full benefits of inference learning in undergraduate students. These results suggest that classroom teaching should emphasize reasoning from the category to multiple properties rather than from a set of properties to the category.

Learning and retention through predictive inference and classification.

This work explores the influence of motivation on choice behavior in a dynamic decision-making environment, where the payoffs from each choice depend on one's recent choice history. Previous research reveals that participants in a regulatory fit exhibit increased levels of exploratory choice and flexible use of multiple strategies over the course of an experiment. The present study placed promotion and prevention-focused participants in a dynamic environment for which optimal performance is facilitated by systematic exploration of the decision space. These participants either gained or lost points with each choice. Our experiment revealed that participants in a regulatory fit were more likely to engage in systematic exploration of the task environment than were participants in a regulatory mismatch and performed more optimally as a result. Implications for contemporary models of human reinforcement learning are discussed.

Regulatory fit and systematic exploration in a dynamic decision-making environment.

Abstract : This project focuses on how humans master new categories by learning from examples with extension to dynamic environments. Decision making tends to take place in dynamic environments in which successive decisions are contingent on one another, and in which the rewards associated with actions can be delayed, yet most tasks that have been studied in the laboratory are broken up into brief, independent trials (e.g., classification of a stimulus) in which responses are determined only by the immediate context and have no bearing on future states of the task environment. Thus, this project narrows the gap between the range of mental processes typically addressed by cognitive scientists and the mental processes that underlie performance in Air Force relevant activities. We find that people's performance profiles are generally consistent with modern reinforcement learning models.

Category Learning by Clustering with Extension to Dynamic Environments

Symposium: Dynamic Decision Making Todd M. Gureckis (Moderator ) and Douglas Markant Department of Psychology, New York University Jared M. Hotaling, Eric Dimperio, and Jerome R. Busemeyer Department of Psychological and Brain Sciences, Indiana University Michael D. Lee, Shunan Zhang, and Mark Steyvers Department of Cognitive Sciences, University of California at Irvine Bradley C. Love and A. Ross Otto Department of Psychology, University of Texas at Austin Dylan A. Simon and Nathaniel Daw Center for Neural Science, New York University Keywords: sequential decision making, computa- tional modeling, cognitive neuroscience The experimental study of decision making has his- torically focused on simple single-trial judgement or rea- soning tasks. However, real world behavior often necessi- tates online decision making, planning, and sequentially organized behavior. The goal of the proposed sympo- sium is to bring together researchers who are working to understand the cognitive processes underlying this kind of “dynamic decision making” (defined as tasks or con- texts that are structured as a sequence of interdependent decisions). A symposium on this topic is particularly timely since research in the area of dynamic decision making is hav- ing a tremendous impact on the field of psychology as a whole. First, researchers are converging on a set of novel computational modeling approaches that explain how decision makers plan sequences of multiple actions, take into account future contingencies, and react in real time to continually changing environmental dynamics. Second, many of the proposed algorithms and models are closely linked to neurobiological correlates (e.g., the recent explosion of research on neurobiology of reinforce- ment learning). Third, many of the tasks that are be- ing developed for evaluating these models also appear to relate to important individual differences in real-world decision-making. The goal in the symposium is to 1) highlight some of the best work in this area, 2) to fa- cilitate communication between researchers working on these problems from varying perspectives, and 3) to pro- vide an excellent showcase of this area for members of the cognitive science community who may not yet be familiar with this work. The speakers who agreed to participate are all accom- plished researchers in this area but each approach the set of problems involved in sequential decision making and learning from a slightly different perspective. The key topics covered include 1) how people plan sequences of actions to accomplish goals (Hotaling, Dimperio, & Busemeyer, Simon & Daw), 2) the underlying neurobi- ology of sequential decision making and planning (Simon & Daw), 3) how cognitive representations of the task or environment supporting planning and decision-making (Gureckis & Markant, Love & Otto, and Simon & Daw), and 4) how people balance exploration and exploitation in order to arrive at effective decision strategies in an unknown environment (Lee, Zhang, and Steyvers and Gureckis & Markant). In addition to these overlapping psychological themes, the researchers all share a core ap- proach of applying sophisticated computational models to understand human behavior (including Bayesian ap- proaches, reinforcement learning, and Markov Decision Processes). Todd Gureckis & Douglas Markant (New York University) Exploring to Exploit: Modeling the Process of Information Search and Planning Effective learning often involves actively querying the environment for information that can be exploited at a later point in time. However, the space of observations available in any situation can vary greatly in potential “informativeness” and relative cost. How do people de- cide which observations to make at any point in time given their future goals? We describe a series of stud- ies looking at how people plan sequences of information collection actions in a cognitive search task based on the children’s game Battleship. Participants made sequences of observations to disambiguate between a large number of potential game configurations subject to information- collection costs. Computational models are developed which predict which observations people will make on any given trial and when they should stop collecting in- formation and exploit their current knowledge. In partic- ular, the models measure the degree to which individu- als take into account future consequences when planning immediate actions. In our second study, we explore how people generate hypotheses consistent with their prior

© Oxford University Press, 2010. All rights reserved. This chapter reviews the relative merits of a variety of category learning models. These include rule-based models, prototype-based models, exemplar-based models, hybrid models, and multiple systems models. All of these models have played a critical role in driving advances in theory and in the design of key experiments. The development of new models is informed by the failings of preceding models.

Mechanistic models of associative and rule-based category learning

You don’t want to know what you’re missing: When information about forgone rewards impedes dynamic decision making

Relational reasoning is often considered more resource intensive than feature-based reasoning. This view implies that learning categories defined by relational regularities should be more difficult than learning categories defined by featural regularities. Unfortunately previous studies do not ground featural and relational information in a common perceptual substrate. After addressing this concern, a series of experiments compare learning performance for relation- and feature-based categories. Under certain circumstances we find faster learning for relation-based categories. The results suggest that mechanisms rooted in relational processes (e.g., relative stimulus judgement, analogical comparison) facilitate or hinder learning depending on whether the relational processes highlight or obscure the underlying category structure. Conversely, category learning affects relational processes by promoting relational comparisons that increase the coherence of acquired categories. In contrast to the largely independent research efforts in category learning and analogy research, our findings suggest that learning and comparison processes are deeply intertwined.

When learning to classify by relations is easier than by features

We suggest that human category formation relies on contrastive learning mechanisms that seek to reduce prediction error. In keeping with this view, manipulating category contrast leads to systematic distortions in people’s memory for category information. Simply by changing the basis of comparison (i.e., the available response options), we can systematically distort people’s perceptions of novel, energy-source, and political categories. Our proposal explains perceived variations in category members’ typicality, including cases in which average items are judged as highly typical and cases in which extreme or ideal members are judged as highly typical of the category. Although straightforward, our account spans findings from studies in goal-derived, cross-cultural, and object-based categorization and suggests ways in which society’s perception of key issues is distorted by political discourse.

Memory for Category Information Is Idealized Through Contrast With Competing Options

We discuss the problem of assessing and aiding user performance in dynamic tasks that require rapid selection among multiple information sources. Motivated by research in human sequential learning, we develop a system that learns by observation to predict the information a user desires in different contexts. The model decides when the display should be updated, which is akin to the problem of scene segmentation, and then selects the situationally relevant information display. The model reduces the cognitive burden of selecting situation-relevant displays. We evaluate the system in a tank video game environment and find that the system boosts user performance. The fit of the model to user data provides a quantitative assessment of user behavior, which is useful in assessing individual differences and the progression from novice- to expert-level proficiency. We discuss the relative benefits of adopting a learning approach to predicting information preferences and possible avenues to reduce the negative consequences of automation.

Proceedings of the SIGCHI Conference on Human Factors in Computing Systems

Learning to predict information needs: context-aware display as a cognitive aid and an assessment tool

We evaluate two broad classes of cognitive mechanisms that might support the learning of sequential patterns. According to the first, learning is based on the gradual accumulation of direct associations between events based on simple conditioning principles. The other view describes learning as the process of inducing the transformational structure that defines the material. Each of these learning mechanisms predict differences in the rate of acquisition for differently organized sequences. Across a set of empirical studies, we compare the predictions of each class of model with the behavior of human subjects. We find that learning mechanisms based on transformations of an internal state, such as recurrent network architectures (e.g., Elman, 1990), have difficulty accounting for the pattern of human results relative to a simpler (but more limited) learning mechanism based on learning direct associations. Our results suggest new constraints on the cognitive mechanisms supporting sequential learning behavior.

Direct Associations or Internal Transformations? Exploring the Mechanisms Underlying Sequential Learning Behavior

When Things Get Worse before they Get Better: Regulatory Fit and Average- Reward Learning in a Dynamic Decision-Making Environment A. Ross Otto, Arthur B. Markman, and Bradley C. Love Department of Psychology, University of Texas, Austin, TX 78712 USA [rotto@mail.utexas.edu, markman@psy.utexas.edu, love@psy.utexas.edu] Todd M. Gureckis Department of Psychology, New York University, 6 Washington Place, New York, NY 10003 [todd.gureckis@nyu.edu] Abstract This work explores the influence of motivation on choice behavior in a dynamic decision-making environment, where the payoffs from each choice depend on one’s recent choice history. Previous research reveals increased levels of exploratory choice among participants in a regulatory fit. The present study placed promotion and prevention-focused participants in a dynamic environment for which optimal performance requires that participants sustain a single choice strategy in the face of temporary payoff decreases. These participants either gained or lost points with each choice. Our behavioral results and model-based analysis, using the average-reward reinforcement learning framework, revealed differential levels of reactivity to local changes in payoffs— specifically, participants in a regulatory fit were less reactive to local perturbations in payoffs than participants in a regulatory mismatch and performed more optimally as a result. Keywords: Decision making; motivation; reinforcement learning Introduction Motivation is essential to action (e.g., Carver & Scheier, 1998; Yerkes & Dodson, 1908). Social psychology makes the distinction between two general motivational orientations (or regulatory foci), a promotion focus and a prevention focus, which accentuate potential gains and losses in the environment, respectively (Higgins, 1997). Recent research reveals that an interaction occurs between one’s regulatory focus and the reward structure of the task being performed, affecting peoples’ use of flexible strategies in a number of tasks. In one study (Worthy, Maddox, & Markman, 2007) utilizing a two-armed bandit task for which optimal choice behavior required exploratory choices as opposed to exploitative choices (c.f. Daw et al., 2006), participants attempting to earn a prize (inducing a promotion focus) exhibited more optimal choice behavior when the task environment had a gains reward structure (i.e., participants were maximizing gains of points) than when the task environment had a losses reward structure (i.e. participants were minimizing loss of points). Likewise, participants attempting to avoid losing a prize (a prevention focus) performed more optimally when the task involved a losses reward structure than when the task involved a gains reward structure. In n-armed bandit tasks where which the decision-maker learns to maximize his or her payoffs by making choices and experiencing the consequences of those choices (e.g. Daw et al., 2006; Bechara, A.R. Damasio, H. Damasio, & Anderson, 1994), optimal performance depends on balancing the demands of gathering and exploiting information about choice payoffs. Worthy et al.’s (2007) study demonstrated that participants in a regulatory fit, for whom their situational regulatory focus matches the reward structure of the task environment, exhibit more exploratory choice strategies than do participants in a regulatory mismatch, who exhibit more exploitative choice strategies. Through continued exploration of choices—with the consequence of occasionally taking decreases in payoffs— participants in a regulatory fit display behavior that is adaptive for the overall long-term pursuit of rewards. Further, their model-based analyses suggested that participants in a regulatory fit place less weight on outcomes from recent choices than do participants in a regulatory mismatch. While this class of tasks is well suited for investigating exploratory versus exploitative choice behavior, we seek to understand how motivational factors affect the degree to which recent changes in payoffs drive choice behavior. In this report, we examine the effects of regulatory fit in a two-option, repeated-choice decision making task in which payoff-maximizing, long-term optimal behavior requires that participants persevere with one choice strategy, sustaining temporary decreases in payoffs in order to maximize long-term gain. Our experiment placed participants in a version of the “rising optimum” task, previously used to investigate temporal-difference accounts of learning (Eagelman, Person, & Berns, 1998; Montague & Berns, 2002) and the problem of temporal credit assignment in human sequential decision-making (Bogacz, McClure, Li, Cohen, & Montague, 2007). Unlike other bandit tasks in which payoff contingencies remain invariant to participants’ behavior (e.g., Bechara et al., 1994; Daw et al., 2006; Worthy et al., 2007; Yechaim & Busemeyer; 2005), in this task, the state of the task environment changes as a function of a participant’s recent choices, which in turn governs the payoffs associated with each action. Consider the two payoff curves depicted in Figure 1, which correspond to the possible payoffs for two choices A and B in Egelman et al.’s (1998) “rising optimum” task. The payoff received from a choice depends on the proportion of A choices made over the last 20 trials, represented by the

When Things Get Worse before they Get Better: Regulatory Fit and Average-Reward Learning in a Dynamic Decision-Making Environment

Seeing the World through an Expert's Eyes: Context-Aware Display as a Training Companion

Short-term gains, long-term pains: How cues about state aid learning in dynamic environments

Anticipatory emotions in decision tasks: Covert markers of value or attentional processes?

Learning in Noise: Dynamic Decision-Making in a Variable Environment.

You Only Had to Ask Me Once: Long-term Retention Requires Direct Queries During Learning Yasuaki Sakamoto (ysakamot@stevens.edu) School of Technology Management, Stevens Institute of Technology Hoboken, NJ 07030 USA Bradley C. Love (brad_love@mail.utexas.edu) Department of Psychology, The University of Texas at Austin Austin, TX 78712 USA Abstract instead a missing feature value is inferred, followed by corrective feedback. What is the key to retaining learned study materials? We examine the role that direct queries play in the retention of category information acquired through inference learning. In inference learning, learners predict an unknown property of an item given its other properties and category membership. We manipulated query frequency across properties during inference learning and found that properties that were queried less often were remembered as well as properties that were queried more frequently. These effects extended from minutes to multiple day delays. Thus, asking about properties during inference training only a few times can immediately promote learning and greatly enhance the long-term retention of category knowledge. We situate our results in the broader memory and education literatures and consider how these findings constrain the development of category learning models. Keywords: Retention; category learning; inference; direct query; explicit evaluation. Introduction Figure 1: An inference learning trial in the current experiment is shown, in which the learner predicts an unknown property. The stimulus on the left differs from the stimulus on the right only on the values of the queried dimension (in this case, smaller vs. larger body size). What is the key to long-term retention of studied materials? In the present work, we investigate the role that direct queries play in category learning and recognition memory. The present work is unique in measuring retention over multiple day delays in category learning tasks. Retention has obvious importance in education and other everyday activities. However, the importance of consolidation to memory performance has been underappreciated by cognitive psychologists in general (Wixted, 2005) and grossly neglected by category learning researchers in particular. For instance, category learning studies that examine retention often impose delays of only a few minutes (e.g., Palmeri & Nosofsky, 1995; Sakamoto & Love, 2004). In addition to examining the role that direct query plays in consolidation, the current work advances our understanding of how category learning works using inference as the induction method. Typically, the classification induction method is used in category learning tasks. In classification learning, the learner is shown a stimulus and classifies it as belonging to one of a number of categories and then is supplied with corrective feedback. Like classification learning, inference learning is also a supervised learning method, but differs in that the category label is known and In category learning experiments using the inference method, the learner’s goal is to correctly predict an unknown property of an item given the item’s remaining properties and its category membership. Figure 1 displays an inference learning trial from the present experiment, in which the learner predicts whether the Tiger shark is small or large by guessing whether the left or right side describes the shark correctly. The left side of Figure 1 conveys the same information as the right side except for the queried dimension, size – the learner predicts the unknown property. The property that is queried in inference learning varies across trials. On the next inference learning trial, whether the Tiger shark has darker or lighter shade may be queried given the other properties and the category membership. Inference learning can lead to more efficient learning of the categories and greater knowledge about the categories than classification learning (Sakamoto & Love, 2006; Yamauchi & Markman, 1998). In classification learning, the learner’s goal is to successfully predict the category

You Only Had to Ask Me Once: Long-term Retention Requires Direct Queries During Learning

Navigating through abstract decision spaces: Evaluating the role of state generalization in a dynamic decision-making task

Providing health information to low health literate audiences remains a challenge. Beyond message design, realistic delivery models are needed for delivering information to a traditionally hard-to-reach audience. This study investigated two e-health interventions to provide health information on mobile devices — one providing diabetes information and one offering childcare information. Both were well-received, and most of the subjects' usability issues related to the translation of these interventions to the mobile device's smaller screen. The diabetes website was effective in providing information to study participants (as measured by pre- and post-tests of knowledge), while the childcare website was not. Continued work in this area could explore improved design strategies for mobile devices — a delivery model that could be used in doctors' offices, for example. Effective delivery of health information to low health literate audiences is an important issue, and this research highlights a critical element by targeting another potential delivery model.

Patient education on mobile devices: an e-health intervention for low health literate audiences

During unmoderated discussions it is commonly observed that some people end up having more influence than seems justified by the actual quality of their contributions. In this paper, we propose and illustrate a spreading-activation architecture for modeling such differential influence. In our model, each participant’s level of influence vis-a-vis others in a discussion emerges out of the interplay of the following four negotiated factors, (1) the relative quality of each person’s contributions; (2) their degree of authority as credible sources of information; (3) their level of access to the conversational floor; and (4) their level of access to the interactional space. We demonstrate the empirical viability of our model by showing how it can account for the dynamics of a heated student science argument. In particular, we show how shifts in the interaction that would perturb specific nodes in a model later affected other nodes in ways consistent with the model.

Toward a model of differential influence in discussions: Negotiating quality, authority, and access within a heated classroom argument

Abstract Penn et al. argue that the complexity of relational learning is beyond animals. We discuss a model that demonstrates relational learning need not involve complex processes. Novel stimuli are compared to previous experiences stored in memory. As learning shifts attention from featural to relational cues, the comparison process becomes more analogical in nature, successfully accounting for performance across species and development.

Monkey see, monkey do: Learning relations through concrete examples

How Goals Shape Category Acquisition: The Role of Contrasting Categories Tyler Davis (thdavis@mail.utexas.edu) Bradley C. Love (brad_love@mail.utexas.edu) Department of Psychology, The University of Texas at Austin Austin, TX 78712 USA Abstract category ideal (Barsalou, 1985). For example, the goal derived category foods to eat on a diet will have a graded structure near 0 calories (e.g., celery). Ideals have also been shown to influence the graded structure of taxonomic categories when groups or other cultures that have goals associated with the category are tested (e.g., Atran, 1999). For example, tree experts have been shown to view trees as more typical to the extent that they minimize weediness (Lynch, Coley, & Medin, 2000). The majority of explanations for how this idealization occurs suggest that these effects depend upon real-world and cultural influences that are not present in artificial categories commonly used in the laboratory. Thus, these findings are often depicted as being at odds with approaches to categorization that rely on laboratory techniques such as mathematical modeling. It is our perspective, however, that these methods are continuous with one another, and that they can be mutually informative. Further, we’ll argue that lower level learning mechanisms described by e.g., error-driven clustering models, provide at least a partial explanation for how goals affect graded structure, whilst making predictions for how these effects may be demonstrated in the laboratory. Categories associated with goals are often organized around ideals rather than central tendencies. In such real- world categories, items that are extreme are often perceived as being the most typical. Here, we demonstrate similar effects with artificial categories learned in the laboratory. Our experiment and simulations suggest that low-level learning mechanisms that seek to minimize prediction error may be responsible for aspects of category idealization. To minimize error, category centroids are adjusted to both increase similarity to their members, as well as to minimize similarity to members of contrasting categories. This learning dynamic distorts category representations away from contrasting categories, leading to idealization. Keywords: Category learning, category use, goals. Introduction Increasingly, research suggests that a learner’s goals within an environment place substantial constraints on the content of their category representations (for review see Markman & Ross, 2003). For example, categories learned by classification lead to important differences between those learned from inference, even though the two tasks are formally equivalent. These effects that goals have on category representations provide a critical challenge for formal approaches to category learning, as many models do not contain ways in which a learner’s goals can exert any influence over their representations (cf. Love, 2005). At the same time, because of this challenge, goals offer a substantial opportunity for cross- fertilization between fields such as those studying expertise/cultural psychology and those studying formal modeling/laboratory experimentation. In the following, we discuss ways in which goal related influences on representations can be studied using formal models, and design a novel experiment using predictions from the model and previous results from the cultural/expertise literatures. One finding in the cultural, expertise, and goal-derived category literatures is that categories associated with goals have a graded structure determined by ideals. Graded structure refers to the notion that members of a category differ in terms of how typical they are for the category to which they belong. Whereas many categories have a graded structure determined by the category’s statistical central tendency (Rosch, 1975), goal-derived categories have a graded structure centered around the A Formal Model Clustering models can be used to place a different perspective on how idealization occurs in categories defined by goals. To illustrate, in the diet food example above, a clustering model would have separate clusters representing diet foods and non-diet foods that would initially be centered on the mean number of calories in their respective categories. However, since the distributions of calories in these two categories are continuous, and even somewhat overlapping, sometimes food from one category will highly activate the cluster of the other category leading to error. Error-driven clustering models will compensate for this error by moving the cluster means on the calorie dimension further away from each other. After some trials, the clusters will tend to move further apart than the actual category means, producing a marked shift in the graded structure of the categories. Whereas at the outset of learning category members that are near the statistical central tendency of the category will produce the strongest activation, at the end of learning, items that are more extreme (i.e., ideal) on the goal dimension will.

How Goals Shape Category Acquisition: The Role of Contrasting Categories

Abstract : One major accomplishment in this project was the development of the CLUSTer Error Reduction (CLUSTER) model's formalism. The updated equations can be downloaded at http://love.psy.utexas.edu/~love/cluster.pdf. One popular approach to modeling human category learning in the face of challenging data has been to propose models containing multiple systems. These systems could include prototype, exemplar, or rule-based components, as well as gating mechanisms that determine how to combine the outputs from these systems or components. CLUSTER takes a complex systems approach in which "systems" emerge out of the learners interactions with their environment. One claim is that what appears as separate cognitive systems are all based on cluster representations that follow from CLUSTER's recruitment and learning rules.

Maximizing the Benefits of Training by Example and Direct Instruction

Predicting Information Needs: Adaptive Display in Dynamic Environments Bradley C. Love (brad love@mail.utexas.edu) Matt Jones (mcj@colorado.edu) Department of Psychology Austin, TX 78712 USA Department of Psychology Boulder, CO 80309 USA Marc T. Tomlinson (mtomlinson@love.psy.utexas.edu) Michael Howe (michael.howe@mail.utexas.edu) Department of Psychology Austin, TX 78712 USA Department of Psychology Austin, TX 78712 USA Abstract canny ability to deliver information to his commander mo- ments before the commander formulated his request, much like how RADAR learns to anticipate the information needs of the user to reduce cognitive load. Before presenting RADAR and empirically evaluating it in a well-controlled ex- periment, we briefly review related work. Although the information available to human operators can in- crease without obvious bound, human information processing capacities remain fixed. Finding and selecting the relevant in- formation to display in this deluge of options imposes a burden on the user. We describe a domain-general system, Responsive Adaptive Display Anticipates Requests (RADAR), that learns to highlight the information a user would select if the user searched through all possible options. By offloading this se- lection process to RADAR, the user can concentrate on the pri- mary task. Tests with human subjects in a tank video game en- vironment that required monitoring several information chan- nels while maintaining situation awareness revealed that play- ers performed better with RADAR selecting which channel to display. RADAR can customize its predictions to a user to take into account individual differences and changes within a user over time. RADAR’s emphasis on learning by observing minimizes the need for explicit guidance from subject matter experts. Related Efforts The topic of plan recognition in AI is concerned with cor- rectly attributing intentions, beliefs, and goals to the user. Plan recognition models tend to subscribe to the Belief- Desires-Intention framework (McTear, 1993). This line of work relies on knowledge-based approaches for user mod- eling and encoding insights from domain-specific experts (Goodman & Litman, 1992). These approaches can involve identifying a user’s subgoals through task-analysis (Yi & Bal- lard, 2006). Once a user’s beliefs, intentions, and goals are understood, display can be adapted appropriately (Goodman & Litman, 1992). Instead of focusing on identifying the internal state of the user, other approaches rely on input from domain experts to adapt display to emphasize the information to which the user should attend. For example human experts can label episodes and these episodes can serve as training instances for machine learning models that prioritize display elements (St. John, Smallman, & Manes, 2005). Alternatively, input from hu- man experts can be used to build expert systems or Bayesian models to prioritize display (Horvitz & Barry, 1995). Our approach diverges from the aforementioned work. Rather than prescribe which information source a user should prioritize, we attempt to highlight the information a user would select if the user searched through all possible options. Unlike work in plan recognition, we sidestep the problem of ascribing and ascertaining the user’s internal mental state. In- stead, RADAR learns to directly predict a user’s desired dis- play from contextual (i.e., situational) features. Our approach emphasizes learning as opposed to preprogrammed interfaces (M¨antyj¨arvi & Sepp¨anen, 2002). Adopting a learning ap- proach to adaptive display has a number of positive conse- quences, including the ability to take into account individ- ual differences across users (Schneider-Hufschmidt, K¨uhme, & Malinowski, 1993). Another positive consequence is that minimal input from subject matter experts is required to build a system. Like other keyhole approaches (Albrecht, Zuker- man, & Nicholson, 1998), our approach is based on observ- Introduction We increasingly find ourselves in information-rich environ- ments. Often, many information sources are potentially use- ful for completing a task. For example, in coordinating dis- aster relief, sources of potentially useful information include video feeds, weather forecasts, inventories of relief supplies, GPS tracking of support vehicles, etc. Likewise, the many sensors, gauges, and navigation systems in a modern auto- mobile are potentially useful to the driver. One key challenge people face is identifying which source of information is desired at the current moment. Although the information available to a human operator can increase with- out obvious bound, our basic information processing capaci- ties remain fixed. Each additional information source incurs a cost to the human operator by increasing the complexity of the selection process. As informational channels are added, at some point, the marginal costs (in terms of cognitive load) eclipse the marginal benefits. In this report, we propose and evaluate a system that eases this selection process by highlighting the information chan- nel desired by the user. The system, Responsive Adaptive Display Anticipates Requests (RADAR), learns to approxi- mate the selection process of the human operator by observ- ing the user’s selection behavior. In cases where RADAR successfully approximates the human’s selection process, the cognitive cost of information selection can be offloaded to RADAR. RADAR is named after the character Radar O’Reilly from the television series M*A*S*H. Radar O’Reilly had an un-

Predicting Information Needs: Adaptive Display in Dynamic Environments

Previous studies have suggested that relational concepts are more mutable—more prone to change meaning in context— than entity concepts even when both relational and entity concepts are denoted by nouns (Asmuth & Gentner, 2005; Feist & Férez, 2007). However, relationality is a complex dimension, and is highly correlated with other factors such as imageability and abstractness. In the current research, we compared the mutability of entity nouns and relational nouns while controlling for imageability (as well as frequency). People read these nouns in a given context and then had to recognize them in either the same or different context. We found that (1) participants showed greater recognition sensitivity for entity nouns than for relational nouns; and (2) recognition of relational nouns was more impaired by a change in context than was recognition of entity nouns. We conclude that the encoding of relational nouns is more influenced by context than the encoding of entity nouns and discuss parallels with encoding patterns for verbs and nouns.

Can Relationality be Distinguished from Abstractness in Noun Mutability ?

Proceedings of the 30th Annual Conference of the Cognitive Science Society.

Putting the psychology back into psychological models: Mechanistic versus rational approaches

When more is less: Feedback effects in perceptual category learning

Developing categorization schemes involves discovering structures in the world that support a learner's goals. Existing models of category learning, such as ex emplar and prototype models, neglect the role of goals in shaping conceptual organization. Here, a clustering ap proach is discussed that reflects the joint influences of the environment and goals in directing category acquisition. Clusters are a flexible representational medium that ex hibits properties of exemplar, prototype, and rule-based models. Clusters reflect the natural bundles of correlated features present in our environment. The clustering model Supervised and Unsupervised Stratified Incremental Adaptive Network (SUSTAIN) operates by assuming the world has a simple structure and adding complexity (i.e., clusters) when existing clusters fail to satisfy the learner's goals and thus elicit surprise. Although simple, this oper ation is sufficient to address findings from numerous lab oratory and cross-cultural categorization studies. KEYWORDS?-categories; clusters; goals; learning; stereo

CURRENT DIRECTIONS IN PSYCHOLOGICAL SCIENCE Environment and Goals Jointly Direct Category Acquisition

One of the problems encountered in Philosophy of Mind is that cognitive theories have a nontrivial dependence on the context of specific neurological makeups or mechanisms of individuals and species. Due to this context-dependency, for example, regularities or relationships between cognitive states are not considered genuine laws and cannot be directly related to neurological laws. The classical approaches to reduction such as bridge law reduction, functional reduction and interpretation mappings do not explicitly address this context-dependency. In this paper it is shown how these reduction approaches can be refined to incorporate the context-dependency. It is shown how the context-dependent reduction approaches obtained make explicit in which sense laws or regularities in a cognitive theory on the one hand relate to neurological laws and on the other hand to specific makeups.

Our work explores the assistance dilemma: when should instruction provide or withhold assistance? In three separate but very similar studies, we have investigated whether worked examples, a high-assistance approach, studied in conjunction with tutored problems to be solved, a mid-level assistance approach, can lead to better learning. Contrary to prior results with untutored problem solving, a low-assistance approach, we found that worked examples alternating with isomorphic tutored problems did not produce more learning gains than tutored problems alone. On the other hand, the examples group across the three studies learned more efficiently than the tutored-alone group; the students spent 21% less time learning the same amount of material. Practically, if these results were to scale across a 20-week course, students could save 4 weeks of time – yet learn just as much. Scientifically, we provide an analysis of a key dimension of assistance: when and how often should problem solutions be given to students versus elicited from them? Our studies, in conjunction with past studies, suggest that on this exampleproblem dimension mid-level assistance may lead to better learning than either lower or higher level assistance. While representing a step toward resolving the assistance dilemma for this dimension, more studies are required to confirm that mid-level assistance is best and further analysis is needed to develop predictive theory for what combinations of assistance yield the most effective and efficient learning.

When and How Often Should Worked Examples be Given to Students ? New Results and a Summary of the Current State of Research

A Fully Analytical Model of the Visual Lexical Decision Task Ferm´in Moscoso del Prado Mart´in (fermin.moscoso-del-prado@univ-provence.fr) Laboratoire de Psychologie Cognitive (UMR 6146) Aix-Marseille Universit´e & Centre National de la Recherche Scientifique Marseilles, France where the additional conditionings on ( H ) represent the set of modeling assumptions and previous knowledge under which we provide the estimates of the posteriors. The input I corresponds to a sequence of samples I = {x 1 , . . . , x T } from a noisy distribution. Therefore we can view the OR in (1) as a function of time, whose value changes with each new sample that is received. In this way, W would be chosen over NW at the first time T when the value of the OR between them exceeds some threshold value Θ W > 1: Abstract This study describes an analytical model of the visual lex- ical decision (VLD) task. The task is modeled as a prob- lem of hypothesis testing given noisy evidence using a gen- eral Bayesian framework, similar to several previously pub- lished models. The Bayesian formulation is then shown to reduce to a Geometric Brownian Motion with a drift and an infinitesimal variance (a Drift-Diffusion Model). In turn, this reduction enables the use of direct analytical techniques – in- stead of simulations – to understand the different factors that influence response latencies. We demonstrate the power of this technique by analyzing the individual response latencies to a realistic size vocabulary covering virtually the full English lexicon. The model achieves an accurate prediction of the re- sponse latencies and error scores to thousands of individual words in relation to previously published VLD data. Crucially, this approach enables a direct explanation of several known non-linear effects, directly addressing their underlying math- ematical explanation in a level of detail that is not attainable using traditional simulation-based approaches. B(T ) = Keywords: Visual Lexical Decision; Bayesian; Analytical; Brownian Motion; English; Distributed Representations A Bayesian Model of Lexical Decision In line with some current models of the VLD task (e.g., Adel- man & Brown, 2008; Norris, 2006; Ratcliff, G´omez, & McK- oon, 2004; Wagenmakers, Steyvers, Raaijmakers, Shiffrin, van Rijn, & Zeelenberg, 2004) we can view lexical decision as a problem of optimally taking a decision by accummulat- ing evidence coming from a noisy input. In VLD the input corresponds to the visual information provided by the eyes as time passes. As more samples of the input are accumulated the evidence supporting a ‘yes’ or a ‘no’ response grows until a certain level of certainty is attained. As noted by Adel- man and Brown (2008), Norris (2006), or Wagenmakers et al. (2004), from a Bayesian perspective, the problem of de- ciding whether a certain visual input corresponds to a word or not can be characterized as a general problem of hypoth- esis choice. We can view word versus non-word decision as two hypotheses from which participants have to choose one, and assume that the participants respond as soon as they have gathered a certain level of evidence in favor of either. Odds Ratios The Odds Ratio (OR) between two hypotheses is the ratio of their posterior probabilities given the available information. In our case the two hypotheses being word (W ) and non-word (NW ), the decision on presentation of a certain visual input (I) could be made using the OR: B = P(W |I, H ) P(NW |I, H ) P(W |x 1 , . . . , x T , H ) ≥ Θ W . P(NW |x 1 , . . . , x T , H ) This amounts to ensuring that the probability of W given the stimulus (and our assumptions) is at least Θ W times greater than the probability of NW given the stimulus. Symmet- rically, we can use another threshold 0 < Θ NW < Θ W that would enable us to choose to respond that the input corre- sponds to a non-word, whenever B(T ) ≤ Θ NW . These thresh- old parameters could take very different values, depending on how much easier we would expect one hypothesis to be recognized over another. However, for simplicity we will work under the assumptions that the thresholds are symmet- rical (Θ W = Θ, Θ NW = Θ 1 ). The calculation of the OR’s is simplified when one works in a logarithmic scale, the Log Odds Ratio (LOR). If we de- fine θ = log Θ, then the condition to choose a word over a non-word stated in (2) is fully equivalent to: b(T ) = log P(W |x 1 , . . . , x T , H ) P(NW |x 1 , . . . , x T , H ) The time T at which the condition in (2) is first satisfied is the same at which (3) becomes true. By applying Bayes’ Theorem on both terms of this ratio, we obtain the ratio of the likelihoods times the ratio of the prior probabilities. However, in a typical lexical decision experiment, the prior probability of observing a word or a pseudo-word are balanced and would normally cancel out. Thus we are left with the ratio between the likelihoods of the input sample {x 1 , . . . , x t } under a word or non-word hypoth- esis: P(x 1 , . . . , x t |W, H ) b(t) = log P(x 1 , . . . , x t |NW, H ) As in most models of this task, we assume that the samples from the visual input are independent of each other. Thus, we can expand this log-likelihood as the sum of the log- likelihoods of the independent samples (x t ) from the input: t b(t) = k=1 t ∑ log P(x k |W, H ) − ∑ log P(x k |NW, H ). k=1

Many decisions refer to actions that have a causal impact on other events. Such actions allow for mere learning of expected values, but also for causal learning about the structure of the decision context. Whereas most theories of decision making neglect causal knowledge, causal learning theories emphasize the importance of causal beliefs and assume that people represent decision problems in terms of their causal structure. In three studies we investigated the representations people acquire when repeatedly making decisions to maximize a certain payoff. Our results show that (i) initial causal hypotheses guide the interpretation of decision feedback, (ii) consequences of interventions are used to revise existing causal beliefs, (iii) decision makers use the experienced feedback to induce a causal model of the choice situation, which (iv) enables them to adapt their choices to changes of the decision problem.

Feature Relations and Feature Salience in Natural Categories Jonathan R. Rein (jrein@mail.utexas.edu) Bradley C. Love (brad_love@psy.utexas.edu) Arthur B. Markman (markman@psy.utexas.edu) Department of Psychology, 1 University Station A8000 Austin, TX 78712 USA instance, the bird example above would be represented as [1,1,1]. This is the preferred format for artificial categories and mathematical models, with the features and their corresponding values usually being defined by the experimenter (e.g. Love, Medin, & Gureckis, 2004; Medin & Shaffer, 1978; Nosofsky, 1986; see McRae, de Sa, & Seidenberg, 1997 for a model employing spatial representations derived from feature lists). Features and dimensions may be differentially weighted in these formats, but weights are generally not influenced by the relationships among features. In the next section, we describe ways that features’ salience can differ when those features are represented strictly independently. We then review previous research that has employed structured representations in categorization. From these findings, we suggest a relationship between features’ salience and connectivity in a structure of feature relations, which will motivate the current study. Abstract Feature salience is a poorly understood construct in the study of category knowledge. Independent-feature representations are limited in potential explanations, compared to more complex structured representations. We explore the relationship between features’ connectivity in a network of relational knowledge and those features’ relative salience, along with their potential for inference. Comparing values of individual features, we illustrate a unique relationship between features’ salience, inferential potency, and structural connectivity. We argue that these results provide evidence for the explanatory power of structured representation beyond independent-feature representation. Keywords: concepts representation and categories, memory, Introduction Cognitive scientists often invoke salience as an explanatory construct. When responses are biased toward some items or features over others, differential salience provides a fairly simple account. While such explanations may match intuition, they are not theoretically powerful unless one can further explicate why this difference exists. One area in which salience has a powerful impact is categorization. For example, more salient dimensions have greater initial weights or biases in mathematical models of category learning (e.g. Kruschke, 1992; Nosofsky, Palmeri, & McKinley, 1994). These weights are assigned according to arbitrary intuition or existing similarity data. The determinants of salience are generally left to mystery. We suggest that this explanatory limitation is partially the result of assumptions about the representational form of categories. The majority of published work assumes (explicitly or implicitly) that categories are sets of unstructured, unrelated features. These independent-feature representations are instantiated in two main ways. One is as a list of verbally described features, such as “has feathers”, “has wings”, and “flies” for the category bird. Feature lists are generally obtained for natural categories by querying semantic knowledge of normal participants (e.g. McRae, Cree, Seidenberg, & McNorgan, in press; Rosch & Mervis, 1975; Tversky, 1977). The other type of independent-feature representation is a spatial one, in which features are numerical values in a vector. For Independent Features and Salience There is a limited number of ways in which one can explain salience differences among features, given an independent-feature category representation. Tversky first suggested some of these in his seminal work on features and similarity (1977). One determinant of salience is our natural predisposition toward intensity, a contingent result of the design of our cognitive systems. This is most obviously the case for perceptual dimensions of stimuli, such as bright lights and loud sounds. Salience may also be influenced by the statistics of the environment. Two statistical properties of features that could have a straightforward relationship with salience are diagnosticity and frequency. A common measure of diagnosticity in categorization is cue validity, the conditional probability of category membership given a particular feature, or P(bird|”feathers”). A common measure of frequency is category validity, the conditional probability of the presence of a feature given category membership, or P(“feathers”|bird). One can obtain these statistics through simple arithmetic on tallies of independent features. Critically, both of these measures only involve the relationship between the feature and category label. More complex statistics could incorporate information across features and dimensions. Features may also differ in salience according to the

Translating From Perceptual to Cognitive Coding Tyler Davis (thdavis@mail.utexas.edu) Bradley C. Love (brad_love@mail.utexas.edu) W. Todd Maddox (maddox@psy.utexas.edu) Department of Psychology, The University of Texas at Austin Austin, TX 78712 USA features typical to a certain class of objects or a particular individual (Gauthier & Tarr, 1997; Tanaka & Gauthier, 1997). While these representational changes have been shown to facilitate the learning of new similar classes or new individuals within a class (Gauthier, et al., 1998; Tanaka, Curran, & Sheinberg, 2005), they likely do not generalize beyond a given basic level category. Thus, perceptual expertise is extremely useful for developing an automatic, stable, and permanent reidentification capacity for a class or an individual object, but it is too slow and specific to subserve all of the occasions where people need to be able to engage in subordinate level identification. Another capacity, which may bootstrap reidentification performance while perceptual expertise is developing, is a process we will refer to as translation. Translation will be defined as the mapping of sensory information onto a compositional alphabet of symbols that refer to sensory qualities or featural characteristics of objects. As with perceptual expertise, we argue that many of these symbols are learned, but instead of being fused configural entities, they refer to independent features, and can be applied across a wider variety of domains. These symbols may be acquired from a variety of sources, most particularly through the learning of a language (e.g. Quine, 1960), explicit instruction (Experiment 2), or the learning of task specific invariants (e.g Schyns, Goldstone, & Thiabut, 1998). For these symbols to be useful for object reidentification, a person must be able to use them systematically, and productively. That is, if an individual possesses a set of feature labels that they are able to attach to one object, they should at the very least be able to identify those qualities in any of their combinations in any other object. Another further constraint on the success of translation in a given context is that the symbols must stand in a one to one relationship with the sensory qualities to which they refer. For example, the term green may be sufficient for identifying a particular object when the only colors in the environment are green or blue, but when the colors of the objects vary more continuously the term green will quickly lose its utility. Though we are treating translation and the development of expertise as distinct, in many cases they may be intertwined in a manner similar to the algorithmic and automatic processes that operate in tasks like mental math (e.g. Logan, 1988; see Figure 1 for summary of proposed pathways). To this end, translation may not only be well suited for bootstrapping reidentification during the early stages of perceptual expertise, but it might continue to operate Abstract An important question in cognitive science is how conceptual knowledge interacts with perception. For example, how does knowing that trucks have wheels and windshields impact a person's recognition of a truck? Through a series of categorization tasks, we explore two pathways by which humans can learn to identify objects. One pathway involves the acquisition of perceptual expertise through extensive task- relevant experience, and leads to the rapid identification of individual stimuli. A second pathway involves a translation process in which percepts of objects are encoded into symbolic descriptions. The use of this pathway results in a similar ability to identify individual stimuli, but requires more time to operate due to the demands of the online translation process. These results are discussed in terms of related work in categorization, perceptual expertise, and influence of language on thought. Keywords: expertise; object identification; symbolic coding; translation; categorization; language and thought Introduction One of the most fundamental psychological capacities is the ability to recognize sameness. In categorization and object recognition this capacity is typically studied in terms of the formation and use of equivalence classes, however there are numerous occasions where a person’s goals require going beyond category membership to the level of individual identity. Whether it be taking the right car home from work, or the right dog home from the dog park, many times getting things exact makes all of the difference. This ability to recognize that something is the same as or equivalent to something seen on a previous occasion, termed reidentification (cf. Millikan, 1998), is fundamental to our everyday survival. The present study investigates two capacities, perceptual expertise and translation that interact to allow humans to maximize their ability to track objects across time. Perceptual expertise refers to a variety of representational changes that occur due to experience with a particular object or within a particular domain. These changes alter the way in which people process the objects for which they have expertise such that they become as efficient at recognizing them and as knowledgeable about their unique characteristics at subordinate levels (e.g. as an individual or a species) as they are at naming and discussing them as members of a basic level category (Tanaka & Taylor, 1991). However, perceptual expertise is acquired rather slowly, with the representations formed being largely configural, and thus specific to the metric relationships between

Relation-Based Categories are Easier to Learn than Feature-Based Categories Marc T. Tomlinson (mtomlinson@love.psy.utexas.edu) Bradley C. Love (Love@love.psy.utexas.edu) University of Texas At Austin 1 University Station, A8000 Austin, TX 78712 USA Abstract to grasping more complex relational matches (Gentner, 1988; Gentner & Ratterman, 1991; Richland, Morrison, & Holyoak, 2006), how far does this shift go? Perhaps when confounding factors are equated, adults will more readily master relation- based concepts than feature-based ones. The current study finds that certain relation-based cate- gories are more readily acquired and explores the basis for this advantage. All four experiments made use of stimuli in which featural and relational information supervenes on the same perceptual information. Experiment 1 establishes that certain relation-based categories are more readily acquired than comparable feature-based categories. Experiment 2 rules out that this advantage arises from a greater difficulty in encoding absolute stimulus information compared to relative stimulus information. Experiment 3 suggests that relation- based categories are acquired faster when the flexibility af- forded by aligning relations during the comparison process is useful for completing the task. Experiment 4 further tests this hypothesis using a category structure that should not benefit from the power of analogical alignment. In this case, feature- and relation-based categories are acquired at the same rate. Relational reasoning is often viewed as the pinnacle of hu- man intelligence. Accordingly, one common viewpoint is that learning categories defined by relational regularities is more difficult than learning categories defined by featural regulari- ties. This view is supported by developmental trends in learn- ing. Studies comparing featural and relational category learn- ing in adults also find a feature advantage, but these studies do not ground featural and relational information in a common perceptual substrate. The current study offers an appropri- ate comparison between feature- and relation-based category learning. Contrary to previous studies, we show how relational learning can be easier. The advantage is attributable to the flexibility of online relational comparisons between a stimulus and a memory representation of a category. Alternative expla- nations based on difficulties in processing absolute vs. relative stimulus information are ruled out. Keywords: Analogy; Category Learning; Relations Introduction The ability to grasp complex relations is a hallmark of human intelligence (Thompson & Oden, 2000). Evaluative tests such as the SAT, GRE, or Raven’s Progressive Matrices stress the importance of relational thinking. Most research comparing relational and featural performance supports the view that re- lational processing is a more advanced competency. Children learn concepts defined by features earlier than those defined by relations (Gentner, 1978). Experts differ from novices by organizing knowledge within their domain along relational lines (Chi, Feltovich, & Glaser, 1981). Despite this work comparing featural and relational pro- cessing, studies comparing the ability to learn novel concepts defined by features or relations under comparable conditions is absent. It is possible that when numerous factors are bal- anced, relational learning could prove easier than featural learning. For example, feature- and relation-based tasks of- ten differ in their information demands (Kittur, Hummel, & Holyoak, 2004; Waltz, Lau, Grewal, & Holyoak, 2000). Furthermore, no study comparing feature- and relation- based learning has used stimuli that rely on the same percep- tual substrate. In all cases, the perceptual features carrying relational and featural information are different. In other do- mains, such as same/different discrimination (Love, Rouder, & Wisniewski, 1999) and change detection (Kroger, Holyoak, & Hummel, 2004), this concordance has been achieved, but never in a learning study. Although many would agree that the developmental trajec- tory follows a progression from appreciating feature matches Stimulus Design The simple scenes used for the experiments were designed specifically to address the issue of whether it is harder for adults to learn categories defined by the relationships between objects or to learn categories defined by the general features of those same objects. To avoid confounding factors and pro- vide an informative comparison, the relations and features were both defined over the same perceptual factors. To cor- rectly classify a scene based on its features, participants had to observe the brightness and size of each object. To correctly classify the scene based on the relations within it, the par- ticipants had to make a relational judgement about the same perceptual factors of brightness and size. Each scene consisted of two circles appearing side-by-side. Across trials, these two circles varied in their size (small, medium, large) and brightness (light, moderate, dark). These circles were combined to give two overall relation attributes (which side was bigger and which was brighter) and two over- all feature attributes (size and brightness). The medium and moderate values were always manifested once in a scene (See Figure 1). Experiment 1 The purpose of Experiment 1 was to investigate the relative difficulty of learning to classify a scene based on either the

Relation-Based Categories are Easier to Learn than Feature-Based Categories

Behaviorism Reborn? Statistical Learning as Simple Conditioning Todd M. Gureckis (tgurecki@indiana.edu) Department of Psychology, Indiana University, 1101 E. 10th Street, Bloomington, IN 47405 USA Bradley C. Love (brad love@mail.utexas.edu) Consortium for Cognition and Computation, University of Texas at Austin, Austin, TX 78712 USA Abstract behaviorist tradition (Rescorla & Wagner, 1972). Cen- tral to our analysis is a detailed comparison between human learning and two computational models of sta- tistical sequence learning. While closely related, these models differ in the types of associative learning pro- cesses they utilize. The first model we consider, the sim- ple recurrent network (SRN, Elman, 1990), is a recurrent network architecture which learns via back-propagation to predict successive sequence elements on the basis of the last known element and a representation of the cur- rent context. This mechanism has been shown to posses a number of powerful computational properties. For ex- ample, the SRN can act as a “universal approximator” of arbitrary finite state machines (Cleeremans, Servan- Schreiber, & McClelland, 1989). We compare the SRN to a simple conditioning model based on direct stimulus-response mappings: the lin- ear associative-shift register (LASR) model of sequence learning (Gureckis & Love, 2005). Like the SRN, LASR is an associative model of sequential processing. How- ever, instead of relying on recurrent patterns of activa- tion, memory in the model takes the form of a simple shift-register memory (similar to the Buffer network of Cleeremans, 1993). Unlike the SRN or the Buffer net- work, this memory is directly associated with output re- sponses without mediation by an internal abstraction or recoding using hidden units. In this way LASR repre- sents a variant of Rescorla-Wagner which learns statis- tical relationships through time. Due to limited space we refer the reader to Gureckis & Love (2005) for the mathematical details of the model. A critical difference between these two models concerns their assumptions about the stages of processing that mediate stimulus and response. In LASR, sequence learning is driven through direct stimulus-stimulus or stimulus-response associa- tions while the SRN includes a set of internal “trans- formative” representations which mediate behavior. In this paper, we focus our analysis on two empirical studies of SL behavior in a standard serial reaction time (SRT) task. On each trial of our experiments, subjects were presented with a set of six response options, one of these options was cued, and subjects were instructed to quickly and accurately press a corresponding button. Unknown to the subject, the pattern of cued-responses followed simple sequential patterns which we manipu- lated. The primary variable of interest was the time be- tween presentation of the cued stimulus and the subject’s In recent years, statistical learning (SL) has emerged as a compelling alternative to nativist theories of language acquisition (i.e., Chomsky, 1980). However, in many ways the framework of statistical learning echoes aspects of classic behaviorism by stressing the role of associative learning processes and the environment in shaping be- havior. How far backwards has the needle swung? In this paper, we show how a subset of behaviors studied under the rubric of SL are in fact entirely consistent with a simple form of conditioned priming inspired by models from the behaviorist tradition (i.e. a variant of Rescola- Wagner which learns associative relationships through time). Keywords: Statistical Learning; Simple Recur- rent Network; Behaviorism; Language; Serial-Reaction Time Task In recent years, statistical learning (SL) has emerged as a compelling alternative to nativist theories of lan- guage acquisition (e.g., Chomsky, 1980). For example, young infants are able to learn the statistical patterns in short segments of artificial speech and to use these dependencies to isolate word-like units (Saffran, Aslin, & Newport, 1996). Results such as these appear to chal- lenge arguments concerning the “poverty of the stimu- lus” by demonstrating how the environment may provide subtle sources of structure which language learners can use to bootstrap into adult capabilities. The implications of this work revisit the tension in Chomsky’s (1959) attack on the behaviorist research pro- gram. Much like current SL research, Skinner’s (1957) research program placed a strong emphasis on the role of the environment and associative learning processes in shaping behavior. Interestingly, many experimental in- quiries into SL have relied on simple tasks which share much in common with stimulus-response or stimulus- stimulus conditioning. For example, in tasks such as the serial reaction time (SRT) task (Nissen & Bulle- mer, 1987), the syllable task (Saffran et al., 1996), and artificial grammar learning (A. Reber, 1967) subjects are presented with cued response sequences, auditory sequences, or letter strings with the goal of assessing learned associations between stimulus elements. Given these aspects of common theoretical alignment between SL literature and classic behaviorism, we reasonably might wonder the degree to which SL research reflects a return to behaviorist principles. In this paper, we will argue that an important sub- set of the learning behaviors studied under the rubric of SL are, in fact, consistent with a simple form of condi- tioned priming well captured by models inheriting from

Beyond common features: The role of roles in determining similarity

The Emergence of Multiple Learning Systems Bradley C. Love (love@psy.utexas.edu) Matt Jones (mattj@psy.utexas.edu) Consortium for Cognition and Computation, The University of Texas at Austin Austin, TX 78712 USA Abstract cumstances. For example, ATRIUM (Erickson & Kr- uschke, 1998) contains a rule and exemplar learning sys- tem. Which system is operable is determined by a gat- ing system, allowing different classification procedures to be applied to different parts of the stimulus space. For example, familiar items could be classified by the exem- plar system whereas rules could be applied to unfamiliar items. The power to apply qualitatively different pro- cedures to different stimuli is the hallmark of multiple systems models. Proposing multiple systems begs the questions of how many systems are present and how do they interact. Are there two, three, or thirty-four systems? Do some sys- tems combine outputs whereas others shunt each other? These questions are not trivial to answer. For example, a two system model may suffice for one data set, but a new manipulation could provide evidence for a third system. As systems propagate, the complexity of the overall system dramatically increases. Building in this degree of complexity complicates model evaluation. Instead of proposing a complex model of category learning containing multiple systems, we advocate a complex systems approach to category learning model- ing in which multiple learning systems emerge from a flexible and adaptive clustering mechanism’s interactions with the environment. We evaluate the hypothesis that a relatively small set of learning principles can effectively “grow” knowledge structures that satisfy the needs that multiple systems models are intended to address. Multiple learning systems models hold that separate learning systems, often organized around discrepant principles, combine their outputs to support human cat- egorization. Rather than propose a complex model, we adopt a complex systems’ viewpoint and propose that multiple learning systems emerge from a flexible and adaptive clustering mechanism’s interactions with the environment. The model, CLUSTer Error Reduc- tion (CLUSTER), retains the flexibility characteristic of human learning by building knowledge structures as needed to support a learner’s goals. Importantly, CLUS- TER can apply ostensibly different procedures to dif- ferent parts of the stimulus space, a hallmark of mul- tiple systems models. We describe a simulation of a human learning study in which CLUSTER develops dif- ferent cluster representations for different item types. Rule-following items are captured by clusters that are broadly tuned and focused on rule-relevant stimulus as- pects, whereas exceptions (especially those that violate high-frequency rules) are captured by narrowly tuned clusters that focus on item-specific stimulus qualities. We end by considering the relation between CLUSTER and findings from the cognitive neuroscience of category learning. Introduction Proposals for category representation are diverse, ranging from exemplar- (Medin & Schaffer, 1978) to prototype-based (Smith & Minda, 1998) and include proposals between these two extremes (Love, Medin, & Gureckis, 2004). Determining the best psychological model can be difficult as one model may perform well in one situation but be bested by a competing model in a different situation. One possibility is that there is not a single “true” model. In category learning, this line of reasoning has led to the development of models containing multiple learning systems. These more complex models hold that category learning behavior reflects the contributions of different systems organized around discrepant principles that uti- lize qualitatively distinct representations. The idea that multiple learning systems support category learning be- havior enjoys widespread support in the cognitive neu- roscience of category learning (see Ashby and O’Brien, 2005, for a review and Nosofsky and Zaki, 1998, for a dissenting opinion). Multiple system models of category learning detail the relative contributions of the component learning sys- tems. The relative contributions can depend on the cir- Past Work and Current Challenges Previous work with the SUSTAIN model, which is the precursor to the model that we introduce here, has par- tially delivered on the promise of flexibly building needed knowledge structures. SUSTAIN is a clustering model that starts simple and recruits clusters in response to surprising events, such as encountering an unfamiliar stimulus in unsupervised learning or making an error in supervised learning (cf. Carpenter & Grossberg, 2003). Surprising events are indicative that the existing clus- ters do not satisfy the learner’s current goals and that the model should grow new knowledge structures (i.e., clusters). These clusters are modified by learning rules that adjust their position to center them amidst their members. Dimension-wide attention is also adjusted to accentuate stimulus properties that are most predictive across clusters.

Accounts of learning and generalization typically focus on factors related to lasting changes in representation (i.e., long-term memory). The authors present evidence that shorter term effects also play a critical role in determining performance and that these recency effects can be subdivided into perceptual and decisional components. Experimental results based on a probabilistic category structure show that the previous stimulus exerts a contrastive effect on the current percept (perceptual recency) and that responses are biased toward or away from the previous feedback, depending on the similarity between successive stimuli (decisional recency). A method for assessing these recency effects is presented that clarifies open questions regarding stimulus generalization and perceptual contrast effects in categorization and in other domains.

Recency effects as a window to generalization: separating decisional and perceptual sequential effects in category learning.

Sizable Sharks Swim Swiftly: Learning Correlations through Inference in a Classroom Setting Yasuaki Sakamoto (yasu@psy.utexas.edu) Bradley C. Love (love@psy.utexas.edu) Department of Psychology, The University of Texas at Austin Austin, TX 78712 USA Abstract Fifth-graders’ results from a category learning experiment suggest that inferring stimulus properties given the category membership leads to better acquisition of category knowl- edge than classifying stimulus items. Fifth-graders liked better and learned more properties of the shark categories acquired through inference than those acquired through classification. Classification promoted learning of only the property that was most diagnostic in discriminating among categories. Inference facilitated learning of all properties associated with each cate- gory, including properties not queried during training. Seven to 33 days after training, fifth-graders who inferred still had more information about properties of each category than fifth- graders who classified. Classroom teaching should emphasize reasoning from the category to multiple properties rather than from a set of properties to the category. Category learning researchers seek to understand better how humans encode, organize, and use knowledge. Given these objectives, research in category learning should have impor- tant implications for education. However, the link between the two fields is not as solid as one might expect in part be- cause category learning research has focused mostly on clas- sification learning (e.g., Shepard, Hovland, & Jenkins, 1961) despite the fact that humans learn through a variety of in- teractions with their environment. As shown in Figure 1, in classification learning, participants predict the category mem- bership of a given stimulus item and then receive corrective feedback. The focus on classification learning has advanced the development of theories that predict how people classify stimulus items in the laboratory. Unfortunately, many of these theories do not generalize to category learning in the real world, such as in a classroom. More recent work has began to address the limitation of focusing on a single learning task by comparing learning and transfer performances for different category learning tasks, such as inference and classification learning (see Markman & Ross, 2003 for a review). Inference learning is closely related to classification learning. As shown in Figure 2, in inference learning, participants predict a single unknown property of an item given the remaining properties and the item’s cate- gory membership. Different properties are queried on differ- ent inference learning trials. Inference learners receive the same corrective feedback as classification learners consisting of the category label and all perceptual properties. In the present work, findings from category learning re- search with adults comparing classification and inference learning are extended to fifth-grade children with class re- lated materials. Many classroom exercises can take the forms of classification and inference learning. For instance, chil- dren may learn about different animals in a science class by Figure 1: A classification learning trial is shown. The de- scription on the left differs from the description on the right only on the category label (in this case, Tiger vs. Sixgill shark). classifying a series of animals presented to them. In the next class session, children may infer properties associated with the animals whose category memberships they already know. Consideration of related work in category learning leads us to advance that inference learning should result in better acquisition of category knowledge in a classroom than clas- sification learning. To foreshadow our results, children liked better and learned more properties of the shark categories ac- quired through inference than those acquired through classi- fication. Whereas children acquired only the most diagnostic property discriminating among categories when they learned through classification, they acquired all properties associated with each category, including properties not queried during training, when they learned through inference. Related Work in Category Learning The basic finding from work with adults is that the difference between classification and inference (see Figure 1 and Fig- ure 2) leads participants to focus on different sources of infor- mation (e.g., Chin-Parker & Ross, 2004; Yamauchi & Mark- man, 1998). Whereas classification learners focus mostly on diagnostic information that discriminates among categories, inference learners focus on each category’s prototype. For example, Chin-Parker and Ross (2004) asked classi-

Sizable Sharks Swim Swiftly: Learning Correlations through Inference in a Classroom Setting

The Role of Similarity in Generalization Matt Jones, W. Todd Maddox, and Bradley C. Love [mattj,maddox,love]@psy.utexas.edu University of Texas, Department of Psychology, 1 University Station A8000 Austin, TX 78712 USA Abstract between stimulus differences and category differences, in making category judgments. Similarity is often regarded as a fundamental construct underlying stimulus generalization in category learning and many other domains. The key assumption of this approach is that multidimensional differences between stimuli are summarized by a single value before entering the decision process. The present study challenges this assumption by showing that category judgments depend on the full relationship between present and past stimuli, in a way that cannot be mediated by a unidimensional similarity measure. Approaches based on response generalization, knowledge partitioning, and distributional representations are also shown to be insufficient to account for our findings. Recency approach to generalization Jones, Love, and Maddox (2006) demonstrate how stimulus generalization can be directly measured during a probabilistic classification task through analysis of decisional recency effects. Specifically, they found that responses are biased towards the feedback given on the previous trial, and that the strength of this bias is directly determined by the difference between present and previous stimuli. The effect of the previous feedback thus represents generalization from the previous stimulus to the current one. Jones, Maddox, and Love (2005) found that when one stimulus dimension is predictive of the category label and another dimension is irrelevant, generalization becomes selectively dependent on the diagnostic dimension (Fig. 1). This finding is consistent with accounts of selective attention that assume similarity adapts to weight tas k- relevant dimensions more heavily (Kruschke, 1992; Nosofsky, 1986). In other words, stimuli differing along the diagnostic dimension become less similar than stimuli differing along the irrelevant dimension. This adaptation of generalization is directly observable through analysis of recency effects, as elaborated below. Introduction Generalization Similarity has long been held to underlie a wide range of cognitive processes. Seminal work by Shepard (1957) showed that stimulus generalization in conditioning and identification tasks can be explained in terms of similarity between stimuli. This approach has since been extended to many other tasks, including categorization (Medin & Schaffer, 1978) and inductive reasoning (Osherson, Smith, Wilkie, Lopez, & Shafir, 1990). An important finding has been that similarity is not constant; rather, it changes systematically as a function of which stimulus attributes are relevant to the task (Heit & Rubinstein, 1994; Nosofsky, 1986). However, it is still generally assumed that similarity is well defined for any one judgment, context, and attentional set. This critical assumption holds not only for spatial models of similarity, but also for feature-set models (Tversky, 1977) and approaches based on internal relational structure (Markman & Gentner, 1993). The present study challenges the assumption that generalization is based directly on similarity. We describe an experiment using a four-category classification task in which subjects must attend to two dimensions simultaneously, but must use these sources of information in different ways. The principal finding is that multiple generalization gradients are simultaneously active for different aspects of the category judgment. Thus performance in this task cannot be explained in terms of a single similarity function (even one that changes from trial to trial). We argue that the failing of the similarity approach is that it assumes the relationships between multidimensional stimuli are reduced to a single value before this information is passed to the decision process. That is, similarity acts as a mediator or sufficient statistic. Instead, it appears that people use the full multidimensional relationship between stimuli, and in particular the alignment D ia gno stic d iff ere nce ce ren iffe d t an lev Irre Figure 1: Selective generalization in a 2-category classification task (Jones et al., 2005, Expt. 1, Condition F). Horizontal axes indicate the difference between successive stimuli. Vertical axis shows strength of generalization, defined as the effect (in log-odds) of the previous feedback on the response to the present stimulus.

Vancouver, Toronto, Montreal, Austin: Enhanced oddball memory through differentiation, not isolation

Learning Abstract Relations Through Analogy to Concrete Exemplars Marc T. Tomlinson and Bradley C. Love [mtomlinson,love]@love.psy.utexas.edu University of Texas At Austin 1 University Station, A8000 Austin, TX 78712-0187 USA Category Learning Abstract Proposals for category representation are diverse, rang- ing from exemplar-based (Medin & Schaffer, 1978) to prototype-based (Smith & Minda, 1998) and include proposals between these two extremes (Love, Medin, & Gureckis, 2004). In the present work, we focus on exemplar-based proposals. Exemplar-models of category learning hold that all abstraction or generalization occurs through similarity-based activations of concrete examples. In ex- emplar models, each experienced instance is stored in memory. When a new item is encountered, the similar- ity between the item and each exemplar in memory is calculated. The stimulus is predicted to belong in the category with the greatest sum of pairwise similarity. Thus, exemplar models clearly link experienced events to later generalization. The model of relational learning that we will de- velop here, BRIDGES, is an extension of Kruschke’s (1992) ALCOVE connectionist exemplar model of cate- gory learning. BRIDGES’s exemplar representation will support the notion that analogy to stored experiences is sufficient to appreciate abstract relationships. Further- more, by incorporating ALCOVE’s attentional shifting mechanisms into BRIDGES, we forward an explanation of how perceived similarity can change over the course of learning as more predictive stimulus properties are ac- centuated. Such attentional shifts will prove useful in demonstrating how seemingly abstract understandings can arise from concrete experiences. Finally, ALCOVE has been a very successful model of category learning and provides a strong foundation for bridging the category learning and analogy litera- tures. By virtue of containing ALCOVE as a special case, BRIDGES accounts for a wide variety of prior hu- man learning studies examining how people acquire cat- egories determined by featural regularities. We present a model that bridges work in analogy and category learning. The model, Building Rela- tions through Instance Driven Gradient Error Shift- ing (BRIDGES), extends ALCOVE, an exemplar-based connectionist model of category learning (Kruschke, 1992). Unlike ALCOVE which is limited to featu- ral or spatial representations, BRIDGES can appreci- ate analogical relationships between stimuli and stored predicate representations of exemplars. Like ALCOVE, BRIDGES learns to shift attention over the course of learning to reduce error and, in the process, alters its notion of similarity. A shift toward relational sources of similarity allows BRIDGES to display what appears to be an understanding of abstract domains, when in fact performance is driven by similarity-based structural alignment (i.e., analogy) to stored exemplars. Support- ive simulations of animal, infant, and adult learning are provided. Introduction We live in a world of concrete experiences, yet we appre- ciate seemingly abstract concepts. Category contrasts like “same” or “different” and “predator” or “prey” are not based on featural regularities. Instead, these con- cepts are relational in nature (e.g., two identical objects of any size, color, or shape are the same). How do we acquire concepts that are not based on featural regular- ities? The category learning literature has focused on how we acquire new concepts, but largely in domains in which the regularities are defined by distributions of features (e.g., red objects are in one category, whereas blue ob- jects are in the other category). In contrast, the analogy literature has considered how people appreciate regulari- ties defined by common relational structures, but has not leveraged work in category learning detailing how people integrate knowledge across examples and shift attention. Here, we extend an existing model of category learning to include a more sophisticated notion of similarity that is sensitive to both featural and relational match. We propose that in many domains where performance ap- pears to be governed by mental rules, it is actually driven by similarity-based activation of stored exemplars. This account is supported by simulations of how young infants learn seemingly abstract grammars and how animals and people learn the distinction between same and different. Analogy Analogical comparison can reveal non-obvious similar- ities. For example, people can appreciate that the Rutherford atom is similar to the solar system because the planets revolve around the sun much like how the electrons revolve around the atom’s nucleus (Gentner, 1983). The perceived similarity between the atom and the solar system is not based on feature overlap, but on common relational structure.

Learning Abstract Relations Through Analogy to Concrete Exemplars

We present a cognitive model that bridges work in analogy and category learning. The model, Building Relations through Instance Driven Gradient Error Shifting (BRIDGES), extends ALCOVE, an exemplar-based connectionist model of human category learning (Kruschke, 1992). Unlike ALCOVE which is limited to featural or spatial representations, BRIDGES can appreciate analogical relationships between stimuli and stored predicate representations of exemplars. Like ALCOVE, BRIDGES learns to shift attention over the course of learning to reduce error and, in the process, alters its notion of similarity. A shift toward relational sources of similarity allows BRIDGES to display what appears to be an understanding of abstract domains, when in fact performance is driven by similarity-based structural alignment (i.e., analogy) to stored exemplars. Supportive simulations of animal, infant, and adult learning are provided. We end by considering possible extensions of BRIDGES suitable for computationally demanding applications.

From Pigeons to Humans: Grounding Relational Learning in Concrete Examples

Bridging Levels: Using a Cognitive Model to Connect Brain and Behavior in Category Learning Todd M. Gureckis (tgurecki@indiana.edu) Department of Psychology, Indiana University 1101 E. 10th Street, Bloomington, IN 47405 USA Bradley C. Love (love@psy.utexas.edu) Consortium for Cognition and Computation, University of Texas at Austin Austin, TX 78712 USA Abstract to predict how degraded function along this circuit af- fects category learning performance for these (and other) groups. In particular, SUSTAIN relates the degree of preserved function to how readily members of a group can individuate events, as opposed to collapsing experi- ences together into a common gestalt (see Figure 1). After introducing the model, we explain the close cor- respondence between aspects of the model and the cur- rently understood function of a learning circuit involving PFC, the hippocampus, and perirhinal cortex. We then review a number of simulations which support our the- ory. In doing so, we provide a novel framework for under- standing the role this circuit plays in category learning ability. In addition, our analysis suggests a recasting of several dichotomies popular in the field, such as the distinction between categorization and recognition, rec- ollective and familiarity-driven responding, and episodic and semantic memory. Mental localization efforts tend to stress the where more than the what. We argue that the proper targets for lo- calization are well-specified cognitive models. We make this case by relating an existing cognitive model of cat- egory learning to a learning circuit involving the hip- pocampus, perirhinal, and prefrontal cortex. Results from groups varying in function along this circuit (e.g., infants, amnesics, older adults) are successfully simu- lated by reducing the model’s ability to form new clus- ters in response to surprising events, such as an error in supervised learning or an unfamiliar stimulus in un- supervised learning. Reported task dissociations (e.g., categorization vs. recognition) are explained in terms of cluster recruitment demands. A major goal of cognitive psychology has been to de- velop an understanding of behavior in terms of compu- tational principles. However, we are often left with the question of what these models tell us about the brain. The answer is certainly not clear. The growing area of cognitive neuroscience offers an endless source of new embers for this debate, as more and more cognitive func- tion is localized and described in terms of specific brain processes. However, by focusing on the localization of mental function (i.e., where is processes X in the brain?), we run the risk of amassing a list of brain areas associ- ated with certain tasks in the absence of useful linking theories reflecting how those regions interact to control behavior in our daily lives. In this paper, we argue that well-specified, process models of cognitive functions are the appropriate targets for localization. Successful process models offer a num- ber advantages over folk psychological, ad hoc, or tra- ditional psychological theories. For example, model de- veloped in cognitive psychology make predictions, have mechanisms and dynamics which can be related to brain measures, and offer a simple and clear starting point for developing theories of brain function. To support our conjecture, we focus on relating a process model of hu- man category learning to a learning circuit involving the hippocampus, perirhinal cortext, and prefrontal cortex (PFC). The model we consider, Supervised and Unsupervised STratified Adaptive Incremental Network (SUSTAIN), is applied to human data from a number of populations (infants, amnesics, and older adults) who differ in their category learning ability. Armed with its computational principles and the proposed mapping, SUSTAIN is able SUSTAIN and the Proposed Mapping We begin by introducing the computational theory (SUSTAIN) and the bridge theory linking SUSTAIN to functional components in the brain. Due to lim- ited space, readers interested in the mathematical de- tails of the model are directed elsewhere (Love, Medin, & Gureckis, 2004). SUSTAIN The basis for representing category knowledge has been proposed to be rule-based, exemplar-based, or prototype-based. SUSTAIN proposes that clusters, which display characteristics of all three of the afore- mentioned approaches, underlie our category represen- tations. A cluster is a bundle of features that captures conjunctive relationships across dimensions. For exam- ple, a cluster can capture the fact that having wings, flying, and having feathers tend to co-occur. In SUSTAIN, categories are represented by one or more clusters. For example, the category of birds might be represented by multiple clusters which capture natu- ral patterns of regularity within the category (e.g., song birds, birds of prey, penguins, and ostriches each might be represented by separate clusters which all belong to the super-ordinate). A cluster can also belong to mul- tiple categories at once because they are linked to cat- egories by association weights that are adjusted during learning.

Bridging levels: Using a cognitive model to connect brain and behavior in category learning

Enhanced memory for oddball items has been long established, but the basis for these effects is not well understood. The present work offers a novel way to think about novelty that clarifies the roles of isolation and differentiation in establishing new memories. According to the isolation account, items that are highly dissimilar to other items are better remembered. In contrast, recent category learning studies suggest that oddball items are better remembered because they must be differentiated from other similar items. The current work pits the isolation and differentiation accounts against each other. The results suggest that differentiation, not isolation, leads to more accurate memory for deviant items. In contrast, gains for isolated items are attributable to reduced confusion with other items, as opposed to preferential storage.

A Critical Look at the Mechanisms Underlying Implicit Sequence Learning Todd M. Gureckis (gureckis@psy.utexas.edu) Bradley C. Love (love@psy.utexas.edu) Department of Psychology; The University of Texas at Austin Austin, TX 78712 USA Second, we explore the ability of this simple model to account for sequential learning phenomena in a va- riety of implicit learning situations including the serial reaction time (SRT) task and statistical word learning paradigms. LASR provides a similar account of the type of processing which underlies performance in both kinds of tasks, suggesting that they may rely on similar under- lying mechanisms. We begin by introducing the LASR model and the principles upon which it is based. Next, we consider a study conducted by Lee (1997) assessing implicit learn- ing of sequentially structured material. Finally, we ex- plore the ability of LASR to account for statistical word learning in infants as reported by Saffran, Aslin, and Newport (1996). Abstract In this report, a model of human sequence learning is developed called the linear associative shift register (LASR). LASR uses a simple error-driven associative learning rule to incrementally acquire information about the structure of event sequences. In contrast to recent modeling approaches, LASR describes learning as a sim- ple and limited process. We argue that this simplicity is a virtue in that the complexity of the model is better matched to the demonstrated complexity of human pro- cessing. The model is applied in a variety of situations including implicit learning via the serial reaction time (SRT) task and statistical word learning. The results of these simulations highlight commonalities between dif- ferent tasks and learning modalities which suggest sim- ilar underlying learning mechanisms. Introduction The Linear Associative Shift-Register (LASR) Model One of the most striking aspects of human behavior is the ease with which we can acquire new skills with little conscious effort. In order to better understand this phe- nomena, a large literature has developed exploring the ability of participants to implicitly learn about the se- quential structure of a series of events (see Cleeremans, Destrebecqz, Boyer, 1998, for a review). However, the type of memory and learning mechanisms which might support such learning are not well understood (see Keele, Ivry, Mayr, Hazeltine, & Heuer, 2004 or Sun, Sluzarz, & Terry, 2005 for some recent proposals). In this paper, we develop a simple model of se- quence learning behavior called the linear associative shift-register (LASR). The model is unique from past ap- proaches in that it describes implicit sequence learning as a simple and limited process which operates on a small temporary buffer of past events. This contrasts with other models of sequence learning which have described learning as a more complex and flexible process (Cleere- mans & McClelland, 1991; Cleeremans, 1993; Lebiere & Wallach, 2000). There are two main goals of this report. First, we demonstrate how a very simple learning mechanism such as LASR can provide a detailed account of a number of findings from the implicit sequence learning literature. A key criticism we develop is that in previous modeling accounts (such as the simple recurrent network (SRN) of Cleeremans, 1993), the complexity of the model is not well matched to the demonstrated complexity of the learner. While LASR cannot explain all aspects of our rich sequential behavior, we believe the model provides a unique baseline against which to test more complex theories and experiments. LASR is a mechanistic model of implicit sequence learn- ing. The model describes implicit sequence learning as the task of appreciating the associative relationship be- tween past events and future ones. LASR assumes that subjects maintain a limited memory for the sequential order of past events and that they use a simple error- driven associative learning rule (Widrow & Hoff, 1960; Rescorla & Wagner, 1972) to incrementally acquire in- formation about sequential structure. Despite its sim- plicity, the model can very quickly learn to appreciate rather complex dependencies between events which are structured in time. The model is organized around 3 principles: 1. Past events are stored in a temporary buffer The model begins by assuming a simple shift-register memory for past events. Individual elements of the reg- ister are referred to as slots. New events encountered in time are inserted at one end of the register and all past events are accordingly shifted one time slot. Thus, the most recent event is always located in the right-most slot of the register (see Figure 1). This form of mem- ory maintains the sequential order of recent events us- ing spatial position (similar to many other models, see Sejnowski and Rosenberg (1987) or Cleereman’s (1993) buffer network). 2. Learning to predict what comes next This simple memory mechanism forms the basis of a detector (see Figure 1). A detector is a simple, single-layer linear network or perceptron (Rosenblatt, 1958) which learns to predict the occurrence of a single future event based

A Critical Look at the Mechanisms Underlying Implicit Sequence Learning

Stimulus Generalization in Category Learning Matt Jones, W. Todd Maddox, and Bradley C. Love [mattj,maddox,love]@psy.utexas.edu University of Texas, Department of Psychology, 1 University Station A8000 Austin, TX 78712 USA representations and the distinction between integral and separable dimensions. We conclude by discussing the broader applicability of this new methodology as well as its implications for the nature of perceptual and category representations, attentional learning, and the roles of short- and long-term memory in categorization. Abstract Stimulus generalization is often regarded as a fundamental component of category learning, yet it has not been directly studied in this context. Here we develop a technique for measuring generalization based on sequential effects in subjects’ responses. We find that patterns of generalization can adapt to global properties of the task, but only when the category structure is defined by perceptually primitive and separable dimensions. Implications are discussed for attentional learning and the nature of both perceptual and category representations. Recency effects and stimulus generalization Perhaps the most fundamental task facing the brain is to use past experience to determine useful behavior in novel situations. For example, in deciding whether a particular snake is poisonous, one might draw on knowledge of other, similar snakes whose toxicity was known. The details of this process can be critical: Basing one’s response on other snakes of similar color and markings may be effective, but relying on irrelevant properties such as length could have disastrous consequences. In other words, successful generalization depends critically on knowledge of which variables are relevant to the current prediction. One task in which stimulus generalization is believed to play an important role is category learning (Medin & Schaffer, 1978). However, in contrast to the rich body of data in conditioning (see Shepard, 1987), stimulus generalization in category learning has yet to be directly investigated. Often it is assumed that generalization operates the same in these two tasks, and generalization functions that have been empirically supported in conditioning studies are incorporated into the similarity functions of categorization models (Kruschke, 1992; Love, Medin, & Gureckis, 2004; Nosofsky, 1986). However, the richer nature of representations involved in category learning (e.g., Maddox & Ashby, 1993; Rosch et al., 1976; Sloman, Love, & Ahn, 1998) suggests that generalization in this domain may be far more complex than is currently assumed. The primary aim of this paper is to develop and explore a method for directly assessing stimulus generalization in category learning. The technique, described in more detail below, is based on a close connection between generalization and recency effects (Jones & Sieck, 2003). Here we present two experiments designed to validate this approach and to relate it to previous findings on attentional learning. Our results show good support for the approach and illustrate how it can provide insight into perceptual Proportion “A” responses Introduction Recency effects are a robust phenomenon in repeated judgment tasks. For example, in studies of probability learning (repeated uncued forced-choice tasks), it has been regularly found that subjects are biased to select whichever response was reinforced on the previous trial (see Myers, 1970, for a review). Jones and Sieck (2003) found that this same effect occurs in cued categorization: Once the identity of the current stimulus is controlled for, subjects tend to choose the category that was correct on the previous trial. This marginal effect of learning from the previous trial can be interpreted as generalization from one stimulus to the next, because it reflects the belief that the current stimulus is likely to belong to the same category as the previous stimulus. Consistent with this interpretation, Jones and Sieck found that the magnitude of the recency effect depends on the similarity between the present and previous stimuli, as shown in Figure 1. Stimuli in these experiments were hypothetical medical patients varying in the presence or absence of three symptoms. The recency effect was greatest when successive stimuli were identical and decreased with each cue mismatch, fully disappearing for cases of complete mismatch. The approximately exponential decrease is similar to the functional form of generalization commonly found in conditioning (Shepard, 1987). Previous Category A B Number of M ismatching Cues Figure 1: Recency effects as a function of number of mismatching cues between present and previous stimuli. (From Jones and Sieck, 2003, Expt. 2, control condition.)

Developing categorization schemes involves discovering structures in the world that support a learner's goals. Existing models of category learning, such as exemplar and prototype models, neglect the role of goals in shaping conceptual organization. Here, a clustering approach is discussed that reflects the joint influences of the environment and goals in directing category acquisition. Clusters are a flexible representational medium that exhibits properties of exemplar, prototype, and rule-based models. Clusters reflect the natural bundles of correlated features present in our environment. The clustering model Supervised and Unsupervised Stratified Incremental Adaptive Network (SUSTAIN) operates by assuming the world has a simple structure and adding complexity (i.e., clusters) when existing clusters fail to satisfy the learner's goals and thus elicit surprise. Although simple, this operation is sufficient to address findings from numerous laboratory and cross-cultural categorization studies.

Our ability to learn about sequences of events allows us to perceive melody in music, to coordinate the movement of our bodies, and to understand spoken language. Much of this sequential behavior proceeds outside of our conscious awareness. In this dissertation, I consider two questions: (1) What is the nature of the processes underlying our implicit sequence learning behavior? (2) To what degree does sequential behavior in different domains and tasks rely on similar underlying mechanisms? A cross section of current theories of sequential learning are evaluated in their ability to account for human learning studies drawn from both serial reaction time (SRT) and statistical word learning tasks. Five novel experiments are reported which differentiate between competing theories concerning the mechanisms underlying implicit sequence learning. A view emerges which describes implicit sequence learning as a relatively simple and limited process with a memory substrate utilizing distinct spatial codes for events in time as opposed to aggregate context.

Mechanisms and constraints underlying implicit sequence learning

Why Adaptationist Explanations are so Seductive Tania Lombrozo (lombrozo@wjh.harvard.edu) Department of Psychology, Harvard University 33 Kirkland St., Cambridge, MA 02138 USA Introduction Adaptationist explanations – evolutionary explanations in terms of a function, like “eyes are for seeing” – are increasingly common in the media. The popularity of such explanations is surprising in light of the finding that most people, including university students, have a poor understanding of natural selection (e.g. Brumby, 1979). Why would people favor explanations that implicate a process they don’t understand? The literature provides two possible answers. First, it could be that most people’s naive biology involves an evolutionary process distinct from natural selection, but that warrants such explanations. People seem to understand natural selection as a quasi-Lamarckian, goal-directed process at an individual rather than a population level. Second, teleological (e.g. adaptationist) explanations may reflect a basic mode of understanding consistent with implicit creationist assumptions (Kelemen, 2004). I suggest a third possibility: that people know enough about natural selection to believe it warrants adaptationist explanations (see Lombrozo & Carey, in press), but not enough to understand the mechanisms by which it operates. As a result, adaptationist explanations induce a sense of understanding that goes unchallenged: without appreciating how natural selection operates, people fail to recognize what could falsify the explanation. The experiment reported below tests two predictions: (a) that people find adaptationist explanations as satisfying as other teleological explanations, despite a poor grasp of natural selection, and (b) that people are selectively bad at identifying what falsifies an adaptationist explanation, despite recognizing that natural selection is involved. There was a main effect of explanation type (artifact vs adaptation, p < .05), a marginally significant effect of task (implication vs falsification, p = .081), and a significant interaction between explanation type and task (p < .05). Of participants in the adaptation/implication condition, 85% correctly recognized that the explanation implied the involvement of natural selection. Although participants rated the adaptationist and artifact explanations equally satisfying (4.5 vs. 5.3, ns), they were worse at identifying statements that falsify the adaptationist explanation. Table 1: Sample “adaptation” stimulus and statements A Spirk is a kind of bird that forages at dawn and dusk. Suppose someone asks the following question, and the answer below is offered: Question: Why do Spirks have large eyes? Answer: Because large eyes are better for seeing in dim light. Im plications Adaptation Falsifiers Figure 1: Average number of statements correctly identified a. Having large eyes is the result of natural selection. b. In the past, Spirks with larger eyes had more offspring. c. At some point in the past, Spirks varied somewhat in the size of their eyes. d. If larger eyes weren’t better for seeing in dim light, Spirks might not have had large eyes. e. Larger eyes are better for seeing in dim light. a. Large eyes resulted from a genetic mutation that came to dominate the population by chance. b. In the past, spirks with larger eyes didn’t produce more offspring than spirks with smaller eyes. c. All Spirks’ eyes are and always have been exactly the same size. d. The fact that larger eyes are better for seeing in dim light didn’t have any influence on Spirks’s evolving large eyes. e. Larger eyes are not better for seeing in dim light. Participants found adaptationist explanations satisfying despite a poor grasp of natural selection (as reflected in the inability to identifying falsifiers). Nonetheless, most participants recognized that the adaptationist explanations implied the operation of natural selection. These data suggest that naive theories involve skeletal knowledge (Keil, 2003). Possessing a “placeholder mechanisms,” the details of which are poorly understood, may be sufficient to accept explanations that rely on that mechanism. Each of 64 Harvard summer school students saw a single adaptationist explanation or a teleological explanation of an artifact, and was asked to identify which statements were either implied by or would falsify the explanation (Table 1). Figure 1 indicates the average number of such statements (out of 5) that were correctly selected for the 53 participants who professed belief in natural selection. Artifact Falsifying Statements Conclusions Experiment: Artifacts versus Adaptations Implied Statements References Brumby, M. (1979). Problems in learning the concept of natural selection. Journal of Biological Ed, 2, 119-122. Keil, F. C. (2003). Folkscience: course interpretations of a complex reality. Trends in Cognitive Science, 8, 368-373. Kelemen, D. (2004). Are children “intuitive theists”? Reasoning about purpose and design in nature. Psych Science, 5, 295-301. Lombrozo, T. & Carey, S. (in press). Functional Explanation and the Function of Explanation. Cognition.

This exploratory study applies and extends a new model of media attendance to examine factors that determine current levels of sharing files through peer-to-peer networks among college students, and to predict downloaders’ intentions to discontinue the behavior in the future. In a multiple regression analysis, downloading activity was found to be positively related to deficient self-regulation and the expected social outcomes of downloading behavior. Downloading activity was lessened by dissatisfaction with poor quality downloads. Those who are willing to discontinue downloading are motivated by fear of punishment, but skilled and habitual downloaders were unlikely to discontinue. Normative beliefs also affected downloading. The perception that downloading was morally unacceptable was positively related to intentions to discontinue downloading, while beliefs that the behavior was morally acceptable were positively related to current downloading activity.

This volume raises key questions about the nature and universality of naturally occurring concepts in human thinking. The work showcased in this book suggests that categories can differ significantly across cultures with respect to fundamental human concepts such as space, time, and objecthood. The building of bridges across communities that do not frequently interact has been inspired by the pioneering work of cognitive psychologist Douglas L. Medin, to whom this book is dedicated.

Categorization inside and outside the laboratory : essays in honor of Douglas L. Medin

Items that violate a category rule are remembered better than items that follow the rule. This finding cannot be predicted by exemplar models when all exemplars share the same attention along a dimension. With dimension-wide attention, violating and rule-following items are treated equally. When each exemplar selects which dimensions to attend to, exemplar models can predict the memory advantage for violating items. With exemplar-specific attention, attention is distributed uniformly for exemplars encoding violating items but is allocated to the rule dimension of exemplars encoding rulefollowing items. This differential attention makes violating items distinctive in memory. In addition to exemplar-specific attention, exemplar models need the ability to distinguish important errors from negligible ones to predict better memory for items that violate a stronger than a weaker rule. Humans are confronted with more information than they can process. Consequently, the ability to selectively attend to salient information is fundamental to our cognitive behavior. Many category learning models utilize the same attention at all locations along a dimension in the representational space (e.g., Kruschke, 1992; Love, Medin, & Gureckis, 2004; Nosofsky, 1986). The dimension-wide attention is well suited for many artificial category learning studies, in which categories are symmetric and category members are differentiated by the values on the same dimensions. For example, category A members may be large on the size dimension, whereas category B members may be small. In natural categories, however, there are inconsistent items that do not follow the structure. For example, penguins do not fly but are members of category birds, whereas bats fly but belong to category mammals. Dimension-wide attention may not fare as well when categories contain inconsistent members. Some laboratory work does suggest that attention is specific to the region along a dimension in the representational space (e.g., Aha & Goldstone, 1992; Barsalou & Medin, 1986; Lewandowsky, Kalish, & Ngang, 2002). Humans attend to different dimensions of an item depending on the context the item is in. For example, humans may attend to the color dimension when shopping for clothing but not as much when shopping for a computer. Exemplar models have a long history of explaining key psychological phenomena in the category learning research (Kruschke, 1992; Medin & Schaffer, 1978; Nosofsky, 1986). However, one finding that is problematic for exemplar models is that people better remember items that violate a structure (e.g., rule) than structure-consistent (e.g., rule-following) items (Palmeri & Nosofsky, 1995; Sakamoto & Love, in press). By storing every studied item as a separate trace and using the dimension-wide attention, current exemplar models treat consistent and inconsistent items in the same fashion and cannot predict the memory advantage for inconsistent items. In this paper, we show that an exemplar model with exemplar-specific attention (see Kruschke, 2001 for a related model with exemplar-specific “specificity”) can differentiate violating items from rulefollowing items and predict the memory advantage for violating items. While exemplars encoding rulefollowing items result in attention allocated to the rule dimension, exemplars encoding violating items result in attention distributed to the non-rule dimensions. This differential attention makes violating items distinctive in memory. We further show that in addition to the exemplarspecific attention, exemplar models need a mechanism that accentuates larger errors and minimizes the impact of smaller ones to predict a better memory for items that violate a stronger rule than items that violate a weaker rule (e.g., Sakamoto & Love, in press). In the remainder of the paper, we review previous category learning work that examines recognition memory for violating items, introduce the models, present model fits to previous findings, and discuss our modeling results. Memory Advantage for Exceptions Palmeri and Nosofsky (1995) found that humans remember exceptions to the category rule better than items that follow the rule. In their study, subjects learned to classify geometric stimuli into two contrasting categories. An imperfect rule successfully classified the majority of study items (e.g., most small items were in category A, whereas most large items were in category B), but two exceptions violated the rule (e.g., a large item that was a member of category A). Following learning, subjects completed a recognition test consisting of studied items and novel items that served as foils. The basic finding was that people recognized the exceptions better than the studied rule-following items. The special status of violating items is also suggested by the schema (e.g., Rojahn & Pettigrew, 1992) research and is not specific to category learning studies. Exemplar models with dimension-wide attention, such as ALCOVE (Kruschke, 1992) and the context model (Medin & Schaffer, 1978), cannot predict the memory advantage of exceptions. Exemplar models store every studied item as a separate trace. The likelihood of recognizing an item is determined by the item’s absolute similarity to all exemplars from both categories A and B. Exemplar models cannot predict the enhanced memory for exceptions because the exceptions share the same similarity relations with other items in memory as rule-following items do. Exceptions are distinguished from rule-following items because the exceptions’ category assignment runs counter to the rule. According to exemplar models, this reversal is not germane to recognition. In contrast, a rule-based model, such as RULEX (Nosofsky, Palmeri, & McKinley, 1994), can predict the memory advantage for exceptions. RULEX constructs rules and stores exceptions to the rules. Rule-following items are not individually stored but rather are captured by the rule. Information about exceptions is explicitly stored. The likelihood of recognizing an item is determined by the items in the exception store. The separate storage of exception information allows RULEX to predict the memory advantage of exceptions. However, RULEX cannot predict the entire pattern of Palmeri and Nosofsky’s results. In addition to the memory advantage for exceptions, they found better recognition for studied rule-following over novel items. RULEX cannot predict the memory advantage for rule-following over novel items, which the context model can predict, because rules encode very little information about rule-following items. Thus, Palmeri and Nosofsky combined RULEX and the context model (see Erikson & Kruschke, 1998 for a similar approach involving knowledge gating). The combined model was able to predict the entire pattern of their recognition data. The inability of RULEX to predict the memory advantage of rule-following over novel items suggests that humans encode more than just rules to represent rule-following items. In support of this idea, Allen and Brooks (1991) found that even when a rule is explicitly applied to a novel item, humans are still somewhat sensitive to the similarity between the novel item and previously encountered examples. This line of work argues that humans have both rule and exemplar systems for learning and recognition. An alternative approach is clustering as in SUSTAIN (Love, Medin, & Gureckis, 2004). SUSTAIN has aspects of both rule violation and exemplar memory and can predict better memory for exceptions than studied rule-following items as well as better memory for studied rule-following items than novel items. We predict that introducing exemplarspecific attention to exemplar models will allow those models to be sensitive to rule violation. Exemplar-Specific Attention An exemplar model, such as ALCOVE (Kruschke, 1992), treats exceptions and rule-following items in the same manner because all exemplars share the same attention along a dimension. Consequently, ALCOVE cannot predict the memory advantage of exceptions. In contrast, ALCOVE with exemplarspecific attention (ES-ALCOVE) should be able to predict the memory advantage for exceptions. ESALCOVE shifts attention to the rule dimension. To classify an exception in the correct category, ESALCOVE will distribute attention to the non-rule dimensions so that the exception is distinguished from the rule-following items from the opposing category. While attention will be distributed to the non-rule dimensions for the exceptions, the rulefollowing items will receive attention on the rule dimension. ES-ALCOVE could predict a memory advantage for exceptions because the exceptions will be “differentiated” from the rule-following items. We simulate ES-ALCOVE to Palmeri and Nosofsky’s results to test this intuition. In the next section, we formalize ES-ALCOVE.

Dimension-Wide vs. Exemplar-Specific Attention in Category Learning and Recognition

The results from 3 category learning experiments suggest that items are better remembered when they violate a salient knowledge structure such as a rule. The more salient the knowledge structure, the stronger the memory for deviant items. The effect of learning errors on subsequent recognition appears to be mediated through the imposed knowledge structure. The recognition advantage for deviant items extends to unsupervised learning situations. Exemplar-based and hypothesis-testing models cannot account for these results. The authors propose a clustering account in which deviant items are better remembered because they are differentiated from clusters that capture regularities. The function of clusters is akin to that of schemas. Their results and analyses expose connections among research in category learning, schemas, stereotypes, and analogy.

Schematic influences on category learning and recognition memory.

Computational models of infant categorization often fail to elaborate the transitional mechanisms that allow infants to achieve adult performance. In this article, we apply a successful connectionist model of adult category learning to developmental data. The Supervised and Unsupervised Stratified Adaptive Incremental Network (SUSTAIN) model is able to account for the emergence of infants' sensitivity to correlated attributes (e.g., has wings and can fly). SUSTAIN offers 2 complimentary explanations of the developmental trend. One explanation centers on memory storage limitations, whereas the other focuses on limitations in perceptual systems. Both explanations parallel published findings concerning the cognitive and sensory limitations of infants. SUSTAIN's simulations suggest that conceptual development follows a continuous and smooth trajectory despite qualitative changes in behavior and that the mechanisms that underlie infant and adult categorization might not differ significantly.

Infancy : the official journal of the International Society on Infant Studies

Type/Token Information in Category Learning and Recognition Yasuaki Sakamoto (yasu@psy.utexas.edu) Bradley C. Love (love@psy.utexas.edu) Department of Psychology, The University of Texas at Austin Austin, TX 78712 USA Items that violate a salient category regularity are remembered better than items that follow the reg- ularity (Palmeri & Nosofsky, 1995). A memory advantage for violating items is also found in the schema research (e.g., Rojahn & Pettigrew, 1992). Furthermore, work in the schema and category learning research suggests that the memory for in- consistent items is stronger when the violated reg- ularity is more salient (e.g., Rojahn & Pettigrew, 1992; Sakamoto & Love, in press). In Sakamoto and Love (in press), the salience of a regularity was manipulated by varying the num- ber of items that conformed to it. Category A contained eight items that followed the regularity, whereas category B contained only four. The clas- sification learning procedure encouraged subjects to entertain the rules “If value 1 on the first dimen- sion, then category A” and “If value 2 on the first dimension, then category B.” Each category con- tained an exception item that violated the rule (i.e., the regularity). The category B exception violated the category A rule, whereas the category A excep- tion violated the category B rule. After learning, these exceptions were remembered better than the rule-following items, replicating Palmeri and Nosof- sky (1995). Furthermore, following findings from the schema research, memory for the category B excep- tion, which violated the more frequent category A rule, was enhanced (cf., Rojahn & Pettigrew, 1992). While SUSTAIN (Love, Medin, & Gureckis, 2004), a clustering model, correctly predicted these find- ings, current exemplar and hypothesis-testing mod- els could not. Type vs. Token The category A rule-following items were more nu- merous in two ways. There were not only more rule-following tokens (i.e., instances of the rule) but also more rule-following types (i.e., distinct stimuli) in category A (cf., Barsalou, Huttenlocher, & Lam- berts, 1998). Thus, the strength of the category A’s regularity was attributable to both more tokens and more types. These two notions of “more” have per- fectly co-occurred in the schema literature. The goal of the current research is to test the contributions of types and tokens independently of each other. When repeating rule-following items from the cat- egory containing fewer types equated tokens, the exception that violated a regularity consisting of more rule-following types was remembered better (.86 vs. .65) than the exception that violated a regularity consisting of fewer rule-following types, t(51) = 3.27, p < .01. Preliminary results from experiments examining the effect of tokens indepen- dently of types are mixed across manipulations. Discussion The current results demonstrate that when tokens are held constant, items that violate a regularity consisting of many item types are remembered bet- ter than items that violate a regularity consisting of only a few item types. Future research will re- solve the effect of tokens on recognition of violating items when types are equated. Stronger manipula- tions are currently being examined that avoid con- trastive categories often used in category learning research. Work along these lines will illuminate fu- ture schema and category learning research and will advance our understanding of how humans represent rules, exceptions, and type/token information. References Barsalou, L. W., Huttenlocher, J., & Lamberts, K. (1998). Basing categorization on individuals and events. Cognitive Psychology, 36, 203–272. Love, B. C., Medin, D. L., & Gureckis, T. M. (2004). SUSTAIN: A Network Model of Human Category Learning. Psychological Review 111, 309–332. Palmeri, T. J., & Nosofsky, R. M. (1995). Recogni- tion memory for exceptions to the category rule. Journal of Experimental Psychology: Learning, Memory, & Cognition, 21, 548–568. Rojahn, K., & Pettigrew, T. F. (1992). Memory for schema-relevant information: A meta-analytic resolution. British Journal of Social Psychology, Sakamoto, Y., & Love, B. C. (in press). Schematic influences on category learning and recognition memory. Journal of Experimental Psychology: General.

The Hippocampus: Where a Cognitive Model meets Cognitive Neuroscience Bradley C. Love (love@psy.utexas.edu) and Todd M. Gureckis (gureckis@love.psy.utexas.edu) Department of Psychology, The University of Texas at Austin; 1 University Station A8000; Austin, TX 78712 USA Models and Cognitive Neuroscience The goal of the present work is explore possible mappings between an existing model from cognitive psychology and functional brain regions. There are numerous possible mappings between these somewhat different levels of analysis. For the the Supervised and Unsupervised STratified Incremental Network (SUSTAIN; Love, Medin, & Gureckis, 2004; Sakamoto & Love, in press) model, the mapping is straightforward: aspects of the model appear to map onto functional structures in the brain. SUSTAIN holds that humans represent category information in terms of natural bundles of information, referred to as clusters. For example, knowledge of mammals might be represented by several clusters (e.g., primates, four-legged mammals, whales, bats, etc.). SUSTAIN posits that learners form new clusters in response to surprising events, such as when a child is first told that a whale is a mammal and not a fish. In this poster, we will focus on SUSTAIN’s cluster formation process. Our hypothesis is that a healthy and intact hippocampus is necessary for forming new clusters to support cortical learning in the temporal lobe (cf., Gluck & Myers, 1993). Forming new clusters can be seen as constructing conjunctive codes. A wide variety of tasks rely on the formation of conjunctive codes such as episodic memory (a conjunction of item and context), sequence memory (item and position), list discrimination (item and list), and item relations (item and item). All of these tasks appear to rely heavily on the hippocampus (see Brown and Aggleton, 2001, for a review). Assuming reduced ability to form new clusters, SUSTAIN has been able to model developmental trends in infant learning (hippocampus not fully developed) and performance by amnesiacs with hippocampal lesions (Gureckis & Love, 2003). Rules and Exceptions: An Aging Study Our account of hippocampal function predicts that normal aging will disproportionately affect performance for exception items in rule-plus-exception classification studies. To master an exception, a cluster must be recruited to encode it, despite the fact that similar clusters or conjunctive codes likely already exist in memory. As we age, an accumulation of cortisol released in response to stressful events differentially leads to atrophy and reduceas the functioning of the hippocampus (Lupien et al., 1998). In the study design, three items from category A and three items from category B followed a simple rule (e.g., if large, then category A. if small, then category B.). The exception items ran counter to these rules. SUSTAIN predicts that older adults will form one cluster for category A and B, leading to increasing rule application and insensitivity to old vs. novel rule-following items with increasing age. In contrast, SUSTAIN predicts younger adults will recruit one cluster for each exception, storing them apart from rule- following items, which leads to predictions counter to those of the older population. Human Results Thirty-seven University of Texas undergraduates and thirty- seven healthy older adults (51-84 years-old, mean=67.9) recruited from the Austin VA outpatient clinic participated in the study. All of SUSTAIN’S predictions held. Only a subset of results are reported here. In the learning phase, item type (rule vs. exception) and population interacted such that the younger population exhibited a smaller difference in accuracy (.27 vs. .61) for exception and rule-following items than did the older population, F(1, 72) = 35.39, MSe = 1.09, p < .001. For the older population, performance on rule- following and exception items for the learning and test phase negatively correlated (r=-.38 and -.72, respectively), whereas these correlations were positive for the younger population (r=.52 and .49, respectively). In transfer, subjects from the older population made rule consistent responses to studied rule-following items and all novel items at about the same rate, .70 vs. .69, t < 1, whereas the younger population applied the rule more frequently (.88 vs. .77) to the studied examples, t(36) = 4.99, p < .001. References Brown, M. P., & Aggleton, J. P. (2001). Recognition memory: What are the roles of perirhinal cortex and hippocampus? Nature Neuroscience, 2, 51-61. Gluck, M. A., & Myers, C. (1993). Hippocampal mediation of stimulus representation: a computational theory. Hippocampus, 3, 491-516. Gureckis, T.M., & Love, B.C. (2004). Common Mechanisms in Infant and Adult Category Learning. Infancy, 5, 173-198. Love, B.C., Medin, D.L, & Gureckis, T.M (2004). SUSTAIN: A Network Model of Category Learning. Psychological Review, 111, 309-332. Lupien, S.J., DeLeon, M, DeSanti S, Convit A, Tarshish, C., Nair, NPV, McEwen, B.S., Hauger, R.L., & Meaney, M. (1998). Longitudinal increase in cortisol during human aging predicts hippocampal atrophy and memory deficits. Nature Neuroscience, 1, 69-73. Sakamoto, Y., & Love, B. C. (in press) Schematic Influences on Category Learning and Recognition Memory. Journal of Experimental Psychology: General.

The Hippocampus: Where a Cognitive Model meets Cognitive Neuroscience

Why do some observations lead to broad generalizations whereas other observations do not have as much influence on people's beliefs? One principle of evaluating evidence is the diversity principle, which states that more diverse evidence should lead to stronger inferences than a narrow sample of evidence. For example, if you see someone repeatedly acting aggressively while giving lectures, you might infer that this behavior is simply the person's lecturing style and not draw broad inferences about the person in general. On the other hand, ifyou observe someone acting aggressively in diverse contexts, such as in a lecture, at a restaurant, and at a party, you might infer that this is indeed an aggressive person overall. There are two views on the diversity principle. The first is the normative view. The emphasis in this view is on why people ought to reason in accord with the diversity principle-that is, why it will lead to successful reasoning. The normative view encompasses historical evidence of expert scientific practice following the diversity principle, as well as various arguments and proofs intended to show that the diversity principle leads to useful inferences. The second view is descriptive. The descriptive view emphasizes showing the many situations in which ordinary reasoning does indeed follow the diversity principle. Typically, the descriptive view has relied on experimental evidence investigating various subject populations. This chapter is organized in terms of these views. The first two sections briefly summarize the positive cases for the normative view and the descriptive view. The following two sections describe some of the challenges to these views and offer some responses in defense of the diversity principle.

SUSTAIN (Supervised and Unsupervised STratified Adaptive Incremental Network) is a model of how humans learn categories from examples. SUSTAIN initially assumes a simple category structure. If simple solutions prove inadequate and SUSTAIN is confronted with a surprising event (e.g., it is told that a bat is a mammal instead of a bird), SUSTAIN recruits an additional cluster to represent the surprising event. Newly recruited clusters are available to explain future events and can themselves evolve into prototypes-attractors-rules. SUSTAIN's discovery of category substructure is affected not only by the structure of the world but by the nature of the learning task and the learner's goals. SUSTAIN successfully extends category learning models to studies of inference learning, unsupervised learning, category construction, and contexts in which identification learning is faster than classification learning.

Abstract : The major accomplishment of this project was increasing the range of situations in which experimental results and models are informative for making predictions about how to best train personnel. In concert with a series of empirical investigations, the SUSTAIN (Supervised and Unsupervised Stratified Adaptive Incremental Network) model of how humans learn categories from examples was developed. SUSTAIN initially assumes a simple category structure. If simple solutions prove inadequate and SUSTAIN is confronted with a surprising event (e.g., it is told that a bat is a mammal instead of a bird), SUSTAIN recruits an additional cluster to represent the surprising event. Newly recruited clusters are available to explain future events and can themselves evolve into prototypes-attractors-rules. SUSTAIN's discovery of category substructure is affected not only by the structure of the world but by the nature of the learning task and the learner's goals. SUSTAIN successfully extends category learning models to studies of inference learning, unsupervised learning, category construction, and contexts in which identification learning is faster than classification learning. SUSTAIN brings the field closer to making a priori predictions about learning and performance under a variety of conditions.

The nonindependence of stimulus properties in human category learning

(Supervised and Unsupervised STratified Adaptive IncrementalNetwork) is a network model of human category learning. SUSTAIN initially assumes a simple category structure. If simple solutions prove inadequate and SUSTAIN is confronted with a surprising event (e.g. it is told that a bat is a mammal instead of a bird), SUSTAIN recruits an additional cluster to represent the surprising event. Newly recruited clusters are available to explain future events and can themselves evolve into prototypes/attractors/rules. SUSTAIN has expanded the scope of findings that models of human category learning can address. This paper extends SUSTAIN so that it can be used to account for both supervised and unsupervised learning data through a common mechanism. A modified recruitment rule is introduced that creates new conceptual clusters in response to surprising events during learning. The new formulation of the model is called uSUSTAIN for ‘unified SUSTAIN.’ The implications of using a unified recruitment method for both supervised and unsupervised learning are discussed.

Towards a unified account of supervised and unsupervised category learning

SUSTAIN (Supervised and Unsupervised STratified Adaptive Incremental Network) is a network model of human category learning. SUSTAIN initially assumes a simple category structure. If simple solutions prove inadequate and SUSTAIN is confronted with a surprising event (e.g. it is told that a bat is a mammal instead of a bird), SUSTAIN recruits an additional cluster to represent the surprising event. Newly recruited clusters are available to explain future events and can themselves evolve into prototypes/attractors/rules. SUSTAIN has expanded the scope of findings that models of human category learning can address. This paper extends SUSTAIN to account for both supervised and unsupervised learning data through a common mechanism. The modified model, uSUSTAIN (unified SUSTAIN), is successfully applied to human learning data that compares unsupervised and supervised learning performances.

Human Unsupervised and Supervised Learning as a Quantitative Distinction

Current models of human category learning and subsequent recognition are either exemplar-based, rule-based, or some combination of both approaches. We present learning and recognition data that cannot be accounted for by current approaches. The data suggest that the degree to which an item is remembered is determined by the strength of the expectation it violates. In our study, expectations take the form of simple, imperfect rules where the strength of the rules are determined by the number of items that follow the rules in training. Exemplarbased models cannot account for the results because they do not posit organizing knowledge structures that can be violated. The frequency insensitivity of rule-based accounts leads to their failure. We propose a cluster-based approach that is consistent with our findings, as well as findings from schema, stereotype, and basic memory research.

researchers are adopting richer and more well-developed similarity-based approaches. These second-wave similarity-based approaches address some of the shortcomings of previous approaches. The 13 chapters that form this volume are broad in scope but can be characterized as couching categorization in terms of more sophisticated and precise notions of similarity. This work shows promise in elucidat

SUSTAIN (Supervised and Unsupervised STratified Adaptive Incremental Network) is a network model of human category learning. This paper extends SUSTAIN so that it can be used to model unsupervised learning data. A modified recruitment mechanism is introduced that creates new conceptual clusters in response to surprising events during learning. Two seemingly contradictory unsupervised learning data sets are modeled using this new recruitment method. In addition, the feasibility of using a unified recruitment method for both supervised and unsupervised learning is discussed.

Previous research suggests that learning categories by classifying new instances highlights information that is useful for discriminating between categories. In contrast, learning categories by making predictive inferences focuses learners on an abstract summary of each category (e.g., the prototype). To test this characterization of classification and inference learning further, the authors evaluated the two learning procedures with nonlinearly separable categories. In contrast to previous research involving cohesive, linearly separable categories, the authors found that it is more difficult to learn nonlinearly separable categories by making inferences about features than it is to learn them by classifying instances. This finding reflects that the prototype of a nonlinearly separable category does not provide a good summary of the category members. The results from this study suggest that having a cohesive category structure is more important for inference than it is for classification.

Learning nonlinearly separable categories by inference and classification.

SUSTAIN (Supervised and Unsupervised STrati ed Adaptive Incremental Network) is a model of how humans learn categories from examples. SUSTAIN initially assumes a simple category structure. If simple solutions prove inadequate and SUSTAIN is confronted with a surprising event (e.g., it is told that a bat is a mammal instead of a bird), SUSTAIN recruits an additional cluster to represent the surprising event. Newly recruited clusters are available to explain future events and can themselves evolve into prototypes/attractors/rules. Importantly, SUSTAIN's discovery of category substructure is a ected not only by the structure of the world, but by the nature of the learning task and the learner's goals. SUSTAIN successfully extends category learning models to studies of inference learning, unsupervised learning, category construction, and contexts where identi cation learning is faster than classi cation learning.

Category Learning 1 Running head: A MODEL OF CATEGORY LEARNING SUSTAIN: A Network Model of Category Learning

Features differ in their mutability. For example, a robin could still be a robin even if it lacked a red breast; but it would probably not count as one if it lacked bones. I have hypothesized (Love & Sloman, 1995) that features are immutable to the extent other features depend on them. We can view a feature's mutability as a measure of transformational difficulty. In deriving new concepts, we often transform existing concepts (e.g. we can go from thinking about a robin to thinking about a robin without a red breast). The difficulty of this transformation, as measured by reaction time, increases with the immutability of the feature transformed. Conceptual transformations are strongly affected by context, but in a principled manner, also explained by feature dependency structure. A detailed account of context's effect on mutability is given, as well as corroborating data. I conclude by addressing how mutability-dependency theory can be applied to the study of similarity, categorization, conceptual combination, and

Tenenbaum and Griffiths's article continues three disturbing trends that typify category learning modeling: (1) modelers tend to focus on a single induction task; (2) the drive to create models that are formally elegant has resulted in a gross simplification of the phenomena of interest; (3) related research is generally ignored when doing so is expedient.

A Computational Level Theory of Similarity Bradley C. Love Department of Psychology The University of Texas at Austin MEZ 330 Austin, TX 78712 USA love@psy.utexas.edu Abstract Why are some pairs of objects (or events) perceived to be more similar to each other than other pairs? A computational level theory of perceived similarity is presented that extends previ- ous geometric and set-theoretic formulations. Like previous approaches, the current account posits that the similarity of two objects is a function of the common and distinctive fea- tures of the two objects. Unlike previous approaches, simi- larity is also a function of higher-order compatibility relations among features (as it is in models of analogy). Objects (or con- cepts) are represented as directed feature graphs as opposed to feature vectors or sets. Like current accounts of human analogical processing, the approach presented here holds that representational elements are put into correspondence during the comparison processes. Correspondences are chosen in or- der to maximize an objective function. The function contains four terms that are motivated by theories of human compari- son. The maximum of the function is monotonically related to perceived similarity. Thus, similarity is characterized as the byproduct of comparison and structural alignment. The objec- tive function serves as a quantitative computational level the- ory of human comparison. Introduction Since William James (1890/1950), psychologists have held that detecting the “sameness” or similarity of objects is at the backbone of cognition. Clearly, detecting similarities be- tween novel events and previous experiences is crucial in rea- soning, analogy, and object recognition. Many theories of category learning hold that similarity is the basis for catego- rization (see [7]). A fundamental question then is what makes two objects similar? Almost all accounts of perceived similarity hold that sim- ilarity increases as the number of feature matches increases and decreases as the number of feature mismatches increases. In geometric models of similarity, such as multidimensional scaling (MDS) models of similarity, concepts or objects are represented as points in a multidimensional space and sim- ilarity is inversely related to the distance between points in the space [20]. Objects that match on many features will be closer together in the space than objects that mismatch on a number of features. Unfortunately, the axioms of metric spaces (e.g., minimality, symmetry, and the triangle inequal- ity) appear to be violated by human similarity judgments (see [22]). More recently, Medin, Goldstone, and Gentner (1993) have demonstrated that an object can be rated as both more similar and more dissimilar to the same object in an object pair, which seems problematic for distance models. Tversky’s (1977) contrast model is a non-metric set- theoretic account of perceived similarity that aims to address some of the shortcoming of the distance models. Tversky’s model is based on evaluating sets of matching and mismatch- ing features: sim ( x; y ) = 1 F ( X \ Y ) sim 2 F ( X Y ) 3 F ( Y X ) where 1 ; 2 ; 3 0 where ( x; y ) reads “the similarity of x to y ,” X is the set of features that represents x , Y is the set of features that represents y , X \ Y is the set of features common to x and y , X Y is the set of features uniquely possessed by x , Y X is the set of features uniquely possessed by y , 1 , 2 , and 3 are free parameters, and F is a function over sets of features related to the features’ saliency. For simplicity and without loss of generalization, we assume here that all features are equally salient: ( X ) = j X j F where j X j denotes the cardinality of the set X . Of course, in many situations certain features will weigh more heavily on the evaluation of similarity than other features. Tversky’s contrast model can account for asymmetries that occur in similarity judgments. For example, “North Korea” is rated as being more similar to “China” than vice versa. The contrast model can explain such asymmetries by setting 2 > 3 . Ostensibly, when comparing x and y , the focus is on first term x , which I will refer to as the target, and not on the second term, which I will refer to as the base. Both x and y will be referred to as analogs. In the example above, most people know more about China than North Korea. Accord- ingly, when evaluating how similar China is to North Korea j X Y j will be larger than j Y X j . Another comparison related explanation for asymmetries is that subjects prefer the base to be the object out of an object pair that allows for more analogical inferences to be projected [1]. Such asymmetries may be attributable to the similarity predicate in particular. Another alternative is that asymmetries arise from general principles related to sentence interpretation such as the fig- ure/ground relationship between the target and base [21] or from general syntactic properties [6]. Although the contrast model can address a wide range of data, it cannot account for judgments of similarity that are re- lational or analogical in nature. Two analogs can be similar

Learning at Different Levels of Abstraction Bradley C. Love Department of Psychology The University of Texas at Austin Austin, TX 78712 USA love@psy.utexas.edu Abstract Previous category learning research and the SUSTAIN (Super- vised and Unsupervised STratified Adaptive Incremental Net- work) model of category learning suggest that preferred cate- gory level (in a hierarchy of categories) shifts towards lower- level (i.e., more specific) categories when stimuli are perceived to be more distinctive. This shift is in accord with work in ex- pertise. In their domain of expertise, experts excel (relative to novices) at classifying stimuli at lower category levels, but their advantage is attenuated with higher-level categories. The work described here directly tests (within a single study) this predicted interaction between category level and stimulus dis- tinctiveness using well controlled artificial stimuli. The results are consistent with prior work utilizing natural stimuli. The results are also informative for evaluating whether attention is dimension-wide (i.e., all items are represented in a common multi-dimensional space of the same extent) or cluster specific (i.e., different conceptual clusters can stress different stimu- lus dimensions so that different aspects of different stimuli are stressed). The results suggest that attention is not dimension- wide. Instead, attention can stress different aspects of different stimuli. The implications of these findings for models of cate- gory learning are discussed. Introduction Humans frequently utilize and acquire category knowledge at multiple levels of abstraction. For example, the same ob- ject can be classified as a vehicle, as a car, or as a 1978 Lin- coln Continental. Rosch, Mervis, Gray, Johnson, and Boyes- Braem (1976) argue that objects are most easily classified at the intermediate category level which most effectively parti- tions the world into informative clusters. However, Tanaka and Taylor (1991) have found that different groups of people tend to prefer different levels of abstraction with experts pre- ferring lower-level categories (i.e., narrower or finer grained categories) compared to novices who prefer higher-level cat- egories (i.e., broader or more abstract categories). One domain in which all adult humans are experts is the domain of face perception. Medin, Dewey, and Murphy (1983) found that people are faster to associate unique names to photographs of nine female faces than they are to catego- rize the photographs into two categories. The logical struc- ture of the two categories is shown in Table 1. One possible explanation for the relative ease of identification learning is that the stimuli used in Medin et al. (1983) were rich and distinct, varying along many dimensions not listed in Table 1, such as the shape of the face, the type of nose, etc.. This id- iosyncratic information makes each stimulus item more dis- Table 1: The logical structure of the two categories used in the category learning condition. The four dimensions were hair color, smile type, hair length, and shirt color. Category A Category B tinct. Experts may be more sensitive to idiosyncratic informa- tion than novices. In the absence of idiosyncratic information, common wisdom holds that identification learning should be harder than category learning. In other words, the ease of cat- egory acquisition interacts with the nature of the stimuli such that learning at lower levels of abstraction (with identification learning being the lowest level of abstraction) becomes easier relative to learning at higher levels of abstraction as stimuli become more distinct. Results from the category learning literature support this conclusion. Shepard, Hovland, and Jenkins (1961) trained subjects on the six category learning problems listed in Ta- ble 2 and found that Type I was the easiest to master, fol- lowed by Type II, followed by Types III-V, followed by Type VI. The Type IV problem has a family resemblance struc- ture that resembles the category structure used in Medin et al. (1983). In the Type IV problem, each category consists of an underlying prototype (111 for category “A” and 222 for category “B”) and any item that matches a prototype on two out of three dimensions is a member of the correspond- ing category. The more difficult to master Type VI problem, while not an identification learning problem, requires subjects to memorize all eight stimulus items because no regularities exist across any pair of dimensions. This data, along with Medin et al.’s (1983) data, suggest that preferred category level and stimulus distinctiveness interact with learning be- ing facilitated more at lower category levels with distinctive stimuli. One category learning model can capture this interaction. SUSTAIN (Supervised and Unsupervised STratified Adap- tive Incremental Network) has successfully fit Shepard et al.’s (1961) and Medin et al.’s (1983) data using the same set of

Human categorization research is dominated by work in classification learning. The field may be in danger of equating the classification learning paradigm with the more general phenomenon of category learning. This paper compares classification and inference learning and finds that different patterns of behavior emerge depending on which learning mode is engaged. Inference learning tends to focus subjects on the internal structure of each category, while classification learning highlights information that discriminates between the categories. The data suggest that different learning modes lead to the formation of different internal representations. SUSTAIN successfully models inference and classification learning by developing different internal representations for different learning modes. Other models do not fare as well.

SUSTAIN (Supervised and Unsupervised STratified Adaptive Incremental Network) is motivated by the intuition that people initially search for simple solutions to category learning problems. When simple solutions prove inadequate, more complex solutions are entertained. SUSTAIN is a three layer model where learning between the first two layers is unsupervised, while learning between the top two layers is supervised. SUSTAIN clusters inputs in an unsupervised fashion until it groups input patterns inappropriately (as signaled by the supervised portion of the network). When such an error occurs, SUSTAIN alters its architecture, recruiting a new unit that is tuned to correctly classify the exception. Units recruited to capture exceptions can evolve into prototypes/attractors/rules. With one setting of its parameters, SUSTAIN fits three diverse data sets. In the first two studies, SUSTAIN captures a complex interaction between category structures and stimulus properties. In particular, SUSTAIN predicts that acquiring lower-level (i.e., more subordinate) categories should become easier as the stimuli become more distinctive. In the third, SUSTAIN is applied to unsupervised learning data. Two behavioral studies of my own design support SUSTAIN while also suggesting points where SUSTAIN could be extended.

The order of processing, whether global forms are processed prior to local forms or vice versa, has been of considerable interest. Many current theories hold that the more perceptually conspicuous form is identified first. An alternative view is presented here in which the stuctural relations among elements are an important factor in explaining the relative speeds of global and local processing. We equated the conspicuity of the global and local forms in three experiments and still found advantages in the processing of global forms. Subjects were able to process the relations among the elements quickly, even before the elements themselves were identified. According to our alternative view, subjects created equivalence classes of similar and proximate local elements before identifying the constituent elements. The experiments required subjects to decide whether two displays were the same or different, and consequently, the results are relevant to work in higher-level cognition that stresses the importance of comparison processes (e.g., analogy and conceptual combination). We conclude by evaluating related work in higher-level cognition in light of our findings.

SUSTAIN (Supervised and Unsupervised STratified Adaptive Incremental Network) is a network model of human category learning. SUSTAIN is a three layer model where learning between the first two layers is unsupervised, while learning between the top two layers is supervised. SUSTAIN clusters inputs in an unsupervised fashion until it groups input patterns inappropriately (as signaled by the supervised portion of the network). When such an error occurs, SUSTAIN alters its architecture, recruiting a new unit that is tuned to correctly classify the exception. Units recruited to capture exceptions can evolve into prototypes/attractors/rules in their own right. SUSTAIN’s adaptive architecture allows it to master simple classification problems quickly, while still retaining the capacity to learn difficult mappings. SUSTAIN also adjusts its sensitivity to input dimensions during the course of learning, paying more attention to dimensions relevant to the classification task. SUSTAIN successfully fits item and category learning data from Medin, Dewey, and Murphy (1983). SUSTAIN’s performance on other data sets is discussed. SUSTAIN is compared with other models of category learning.

SUSTAIN (Supervised and Unsupervised STratified Adaptive Incremental Network) is a network model of human category learning. SUSTAIN is a three layer model where learning between the first two layers is unsupervised, while learning between the top two layers is supervised. SUSTAIN clusters inputs in an unsupervised fashion until it groups input patterns inappropriately (as signaled by the supervised portion of the network). When such an error occurs, SUSTAIN alters its architecture, recruiting a new unit that is tuned to correctly classify the exception. Units recruited to capture exceptions can evolve into prototypes/attractor/rules in their own right. SUSTAIN's adaptive architecture allows it to master simple classification problems quickly, while still retaining the capacity to learn difficult mappings. SUSTAIN also adjusts its sensitivity to input dimensions during the course of learning, paying more attention to dimensions relevant to the classification task. Shepard, Hovland, and Jenkins's (1961) challenging category learning data is fit successfully by SUSTAIN. Other applications of SUSTAIN are discussed. SUSTAIN is compared to other classification models.

Historically, connectionist systems have not excelled at representing and manipulating complex structures. How can a system composed of simple neuron-like computing elements encode complex relations? Recently, researchers have begun to appreciate that representations can extend in both time and space. Many researchers have proposed that the synchronous firing of units can encode complex representations. I identify the limitations of this approach and present an asynchronous model of binding that effectively represents complex structures. The asynchronous model extends the synchronous approach. I argue that our cognitive architecture utilizes a similar mechanism.

We evaluate the hypothesis that people interpret noun-noun combinations by first attempting to find a plausible relation in which the constituents play different functional roles (as in ‘‘a hawk that preys on robins’’ for robin hawk). If they do not succeed, they then attempt as a last resort to derive an interpretation based on properties of the modifier (‘‘hawk with a red breast’’). In one study, combinations with plausible relations were more often interpreted with properties when their constituents were highly similar. In a second study, property and relation interpretations of the same combination were selectively primed. In a final study, we show that property interpretations characterize the meanings of a number of familiar combinations in the English language. Taken together, the results of these studies run counter to the view that concepts are combined by first attempting to link them by a relation. We describe other reasons to doubt this view and discuss the implications of our findings for models of conceptual combination. q 1998 Academic Press

Conceptual features differ in how mentally tranformable they are. A robin that does not eat is harder to imagine than a robin that does not chirp. We argue that features are immutable to the extent that they are central in a network of dependency relations. The immutability of a feature reflects how much the internal structure of a concept depends on that feature; i.e., how much the feature contributes to the concept's coherence. Complementarily, mutability reflects the aspects in which a concept is flexible. We show that features can be reliably ordered according to their mutability using tasks that require people to conceive of objects missing a feature, and that mutability (conceptual centrality) can be distinguished from category centrality and from diagnosticity and salience. We test a model of mutability based on asymmetric, unlabeled, pairwise dependency relations. With no free parameters, the model provides reasonable fits to data. Qualitative tests of the model show that mutability judgments are unaffected by the type of dependency relation and that dependency structure influences judgments of variability.

Features differ in their mutability. For example, a robin could still be a robin even if it lacked a red breast; but i t would probably not count as one if it lacked bones. One hypothesis to explain this differential transformability is that having bones is more critical to a biological theory than having a red breast is. We reject this hypothesis in favor of a theory of mutability based solely on local dependency links and expressed in the form of an iterative equation. We hypothesize that features are immutable to the extent other features depend on them and offer supporting data.

Concept learning is the process of acquiring knowledge structures that enable an agent to make pre-dictive inferences. INTRODUCTION The human species evolves to meet challenges in the environment. Unfortunately, evolution is a slowìearning' process. Evolution can only help us address aspects of our environment that are not very variable and that are stable over a long period of time. Of course, many aspects of our environment are constantly undergoing change. Accordingly, many concepts have to be learned de novo by each individual. For example, a radiolo-gist is not born knowing how to interpret x-ray images. It is hard to imagine how that particular skill could evolve. Concept learning is integral to the survival of any agent (e.g. a human, an animal, a robot, etc.) operating in a complex and changing environment. A concept is a mental representation that is often derived from experiences with specific instances. We often develop concepts of categories (i.e. collections of objects) in the world. Without acquired concepts, we would be unable to make sense of the world around us. Every new object encountered would appear completely novel and we would not know how to interact with it. For example, the first time a child encounters a hot stove he may get burned. When the child visits a friend's house and encounters another stove, it is unlikely the child will touch it, even though the new stove may differ in a number of ways from the original stove (e.g. size, color, design, etc.). If the child did not generalize from his experiences

Paleodemography: A solution to the problem of obtaining a mortality schedule for paleodemographic data

This paper addresses the problem of estimating an age-at-death distribution or paleodemographic profile from osteological data. It is demonstrated that the classical two-stage procedure whereby one first constructs estimates of age-at-death of individual skeletons and then uses these age estimates to obtain a paleodemographic profile is not a correct approach. This is a consequence of Bayes' theorem. Instead, we demonstrate a valid approach that proceeds from the opposite starting point: given skeletal age-at-death, one first estimates the probability of assigning the skeleton into a specific osteological age-indicator stage. We show that this leads to a statistically valid method for obtaining a paleodemographic profile, and moreover, that valid individual age estimation itself requires a demographic profile and therefore is done subsequent to its construction. Individual age estimation thus becomes the last rather than the first step in the estimation procedure. A central concept of our statistical approach is that of a weight function. A weight function is associated with each osteological age-indicator stage or category, and provides the probability that a specific age indicator stage is observed, given age-at-death of the individual. We recommend that weight functions be estimated nonparametrically from a reference data set. In their entirety, the weight functions characterize the relevant stochastic properties of a chosen age indicator. For actual estimation of the paleodemographic profile, a parametric age distribution in the target sample is assumed. The maximum likelihood method is used to identify the unknown parameters of this distribution. As some components are estimated nonparametrically, one then has a semiparametric model. We show how to obtain valid estimates of individual age-at-death, confidence regions, and goodness-of-fit tests. The methods are illustrated with both real and simulated data.

Semiparametric method for estimating paleodemographic profiles from age indicator data.

Large-scale experiments on medflies that were subjected to sterilizing doses of ionizing radiation (plus intact controls) and maintained on either sugar-only or full, protein-enriched diets revealed that, whereas the mortality trajectories of both intact and irradiated male cohorts maintained on both diets are similar, the mortality patterns of females are highly variable. Mean mortality rates at 35 days in male cohorts ranged from 0.2 to 0.3 but in female cohorts ranged from 0.09 to 0.35, depending on treatment. The study reports three main influences: (a) qualitative differences exist in the sex-mortality response of medflies subjected to dietary manipulations and irradiation; (b) the female mortality response is linked to increased vulnerability due to the nutritional demands of reproduction; and (c) female sensitivity to environmental changes underlies the dynamics of the sex-mortality differential.

The journals of gerontology. Series A, Biological sciences and medical sciences

Female sensitivity to diet and irradiation treatments underlies sex-mortality differentials in the Mediterranean fruit fly.

Breast tumors from African American women have less favorable pathological characteristics and higher mortality rates than those of Caucasian women. Although socioeconomic status may influence prognosis, biological factors are also likely to contribute to tumor behavior.

Identification of differentially expressed genes in breast tumors from African American compared with Caucasian women

Abstract 3741: Identification of differentially expressed genes in breast tumors from African American compared with Caucasian women

Lymph node status remains one of the most useful prognostic indicators in breast cancer; however, current methods to assess nodal status disrupt the lymphatic system and may lead to secondary complications. Identification of molecular signatures discriminating lymph node-positive from lymph node-negative primary tumors would allow for stratification of patients requiring surgical assesment of lymph nodes. Primary breast tumors from women with negative (n = 41) and positive (n = 35) lymph node status matched for possible confounding factors were subjected to laser microdissection and gene expression data generated. Although ANOVA analysis (P < .001, fold-change >1.5) revealed 13 differentially expressed genes, hierarchical clustering classified 90% of node-negative but only 66% of node-positive tumors correctly. The inability to derive molecular profiles of metastasis in primary tumors may reflect tumor heterogeneity, paucity of cells within the primary tumor with metastatic potential, influence of the microenvironment, or inherited host susceptibility to metastasis.

Differential Gene Expression in Primary Breast Tumors Associated with Lymph Node Metastasis

1075 Background: Lymph node status remains one of the most useful prognostic indicators in breast cancer, however, current methods to assess nodal status disrupt the lymphatic system, lead to secondary complications, and 10-33% of women diagnosed with negative lymph nodes will develop metastases. Identification of molecular signatures discriminating primary tumors from patients with the propensity to metastasize from those without would allow for stratification of patients requiring surgical assessment of lymph node status and identification of node negative patients at high-risk of developing metastatic disease. Methods: Frozen breast specimens were collected from women with negative (n=39) and positive (n=35) lymph node status. Patients with positive BRCA1/BRCA2 status, neoadjuvant therapy or negative lymph node status who later developed distant metastasis were not included in this study. RNA was isolated from pure tumor cell populations after laser microdissection and gene expression data generated us...

Breast cancer metastasis gene signature: The search for the holy grail.

Background: The widespread use of mammographic screening resulted in increased diagnosis of small ( Methods: Frozen breast specimens were collected from women with T1 tumors and either negative (n=29) or positive (n=15) lymph node status. RNA was isolated from pure tumor cell populations after laser microdissection. Gene expression data was generated using HG U133A 2.0 arrays (Affymetrix). Differential expression was determined using Mann-Whitney testing using a P-value Results: Tumor characteristics did not differ significantly between groups in terms of age at diagnosis, grade, HER2 or PR status; however, tumors from patients with positive lymph nodes (47%) were significantly (P 4X higher levels in tumors without metastasis, in agreement with IHC findings. Conclusions: Small metastatic tumors differ in gene expression from those without metastasis. EPHX2 has been implicated as a metastasis suppressor while AURKA has been implicated as a metastasis promoter. These results suggest that small tumors have different propensities to metastasize and the genetic signature may serve as a new molecular tool to discriminate metastatic and non-metastatic small tumors, allowing appropriate treatment and risk assessment to be performed. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-06-09.

Abstract P4-06-09: Genetic Signature Discriminating Metastatic from Non-Metastatic Small Tumors

Abstract #1059 Background: Sentinel lymph node (SLN) status is a key prognostic factor for breast cancer patients. The SLN hypothesis postulates that cancer cells initially spread from the primary tumor to the first-draining (sentinel) node(s) before reaching higher echelon nodes. Although SLN biopsy is clinically useful for staging patients, little is known about the genomic heritage of cells that define the genetic makeup and clinical behavior of nodal metastases. We used allelic imbalance (AI) coupled with high-density SNP genotyping to examine the extent of genetic heterogeneity in primary tumors and relationships among metastases in sentinel and non-sentinel axillary lymph nodes in 30 patients with node positive breast cancer.  Material and Methods: Pathologically positive nodes were identified by HE genome-wide copy number variation was examined using Affymetrix GeneChip Human Mapping 500K arrays and the Genotyping Consol. The genomic heritage of sentinel and non-sentinel nodal metastases in relation to multiple areas of the primary tumor was assessed by hierarchical clustering and phylogenetic analyses.  Results: Extensive genomic heterogeneity was observed in primary tumors and among nodal metastases (0-44% in primaries, 0-36% in metastases). Overall levels of variation were significantly higher (P Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1059.

Fingerprinting genomic heterogeneity in primary breast carcinomas and among sentinel lymph node metastases: implications for clinical management of breast cancer patients.

Abstract #2095 Background: Although breast cancer incidence is higher among Caucasian women (CW), mortality is higher in African American women (AAW). AAW also tend to be diagnosed at a younger age and with larger and more aggressive tumors. Previously, we have found that gene expression patterns in AAW and CW differ in both breast tissues from women without breast disease as well as those from women with invasive breast cancer. Characterization of these differentially expressed genes is critical to understanding breast pathogenesis in AAW.  Methods: Total RNA was isolated from breast tissue from 29 AAW and 26 CW without evidence of breast disease using the RNeasy Lipid Tissue Midi kit (Qiagen) and from laser microdissected primary breast tumors from 23 AAW and 24 CW using the RNAqueous Micro kit (Ambion). Based on earlier microarray results, genes were selected for validation by quantitative real-time PCR using TaqMan Gene Expression Assays (Applied Biosystems). All TaqMan assays were performed on duplicate samples using the iCycler Real-Time Detection System (Bio-Rad). Relative expression levels were determined using the Comparative C t Method. A Wilcoxon test was used to determine significance.  Results: Among those genes that were confirmed to be differentially expressed in breast tissues from AAW and CW was phosphoserine phosphatase-like, or PSPHL. PSPHL showed significantly higher expression in both disease-free samples as well as primary tumors from AAW when compared to the same sample type from CW. In tissues from disease-free women, the relative level of PSPHL expression was significantly higher in AAW (median = 17.15) compared to CW (median = 0; P P Discussion: The current study has confirmed that expression of PSPHL is significantly higher in both disease-free and invasive breast tissues from AAW than those from CW. Recently, PSPHL has also been shown to have higher expression in prostate tumors from African American men than those from Caucasian men. The function of PSPHL is unknown; however, its increased expression has been associated with aberrant cellular proliferation and cell cycle progression in Fanconi anemia. Higher expression of PSPHL in both normal and diseased breast tissues may, therefore, increase cellular proliferation, contributing to the initial development and/or aggressiveness of breast tumors in AAW. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2095.

Role of phosphoserine phosphatase-like in breast disease in African American women.

Molecular Changes in Primary Breast Tumors and the Nottingham Histologic Score

The therapeutic benefits of adult adherent stem cells are currently being investigated in clinical trials for a variety of diseases. Data from initial clinical studies are promising and as a consequence of moving to later stage clinical studies, have resulted in larger scale clinical-grade cell production strategies. Therefore it becomes imperative to examine the epigenetic flux and genomic stability of stem cells in long-term culture to determine that minimal risk is associated with these therapies. Multipotent adult progenitor cells (MAPC) are an adherent adult stem cell population that can be derived from bone marrow and was the first of a class of adult stem cells that have broad developmental potential both in vitro and in vivo. Here, we report a panel of tests to characterize MultiStem, a multipotent adult stem cell type based on MAPC, and establish its genomic stability during culture expansion. A variety of techniques were employed that consisted of miRNA expression to characterize and define the cell population; chromosomal SNP analysis and G-banding to determine karyotypic stability; and methylation pattern and telomerase expression to examine potential changes in epigenetic and chromosomal stability with prolonged in vitro culture of cells. This panel of test was applied to cultures at early isolation stages and compared to cultures harvested at population doublings greater than those reached in current MultiStem clinical trials. These tests also provide a baseline for quality control of cells prepared from various biological donor sources for subsequent large scale propagation and preparation of cell banks for downstream applications.

Global Characterization and Genomic Stability of Human MultiStem, A Multipotent Adult Progenitor Cell.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts

Abstract #2049 

Background: Metastasis involves processes such as invasion, angiogenesis, intravasation, extravasation and eventual proliferation in the target organ. Metastasis initiation genes are those involved in dissemination of cells from the primary tumor while metastasis virulence genes contribute to metastatic colonization, specifically at the secondary site. Identification of metastasis initiation and virulence genes is critical to improve our understanding of and the ability to effectively treat metastatic breast cancer. Methods: A 51-gene signature was previously identified using RNA from 20 primary breast and matched metastatic lymph node tumors using the U133 2.0 microarrays (Affymetrix). Real-time PCR was performed for each assay using TaqMan assays (Applied Biosystems) using RNA from 25 pairs of primary breast and matched metastatic lymph node tumors. Data was evaluated using Mann-Whitney testing. Results: Gene expression levels were significantly different for 40 genes including 25 with P 50-fold difference in expression including WNT2, KRT14, TAC1, COL11A1, MMP13, GRP, and KERA with higher expression in primary tumors and EPHA3, PAX5 and NTS with higher expression in the metastasis. Discussion: A breast cancer metastasis signature involving 40 genes has been identified and validated. Genes expressed at higher levels in primary breast tumors are largely involved in degradation of the extracellular matrix (ECM), likely enabling cells with metastatic potential to disseminate. Decreased expression of these genes in the metastatic tumors suggests that once tumor cells have disseminated, invasion into foreign tissues does not require active tissue remodeling. Rather, cells that have successfully metastasized are characterized by the expression of genes involved in transcription, metabolism and immune response, potentially blocking cellular differentiation and providing cells with proliferation and survival advantages. These data not only improve our understanding of the biological processes involved in successful metastatic but provide new targets to arrest tumor cells dissemination and metastatic colonization.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2049.

Identification of breast cancer metastasis initiation and virulence genes.

A26 Autoantibody profiling using custom, disease-focused protein-arrays provides an accelerated approach to identify diagnostic-quality biomarkers for cancer. A custom prostate-cancer-targeted protein microarray (96 proteins) was screened for the presence of autoantibodies using sera from prostate cancer (PCa) patients and benign prostatic hyperplasia (BPH) patients. The goal of the study was to discover prostate-cancer tumor-associated antigens (biomarkers) that could clearly discriminate PCa from BPH. Biomarkers found in this manner, would be stable in blood, easily measured using ~ 1 uL of serum (or plasma) and could differentiate true prostate cancer from the closely-related benign prostatic hyperplasia, the major weakness in the current, clinically used, PSA-based prostate cancer diagnostic test. Autoantibody profiling on two pooled samples from thirty-two prostate cancer patients and thirty-two benign prostatic hyperplasia patients revealed twenty tumor associated antigens, including KDR and PIM-1, that induced significant humoral autoantibody response. Additional experiments using all 64 non-pooled serum samples applied to a low content protein chip showed that autoantibodies against KDR and PIM-1 differentiated prostate cancer from benign prostatic hyperplasia with 90.6% sensitivity and 84.4% specificity. Protein array signals were specific, and could be competed away by spiking pure antigen into the sera in a dose dependent manner. Additionally, fluorescence immunohistochemistry of prostate cancer tissue arrays showed that KDR and PIM-1 were differentially expressed in prostate cancer tissues with reduced expression in benign prostatic hyperplasia tissues, suggesting over expression of KDR and PIM-1 tumor antigens lead to the aberrant humoral response.

Accelerated discovery of biomarkers by protein chips: Autoantibodies to KDR and PIM-1 differentiate prostate cancer from benign prostatic hyperplasia

A gene expression signature that defines breast cancer metastases

Background: Incidence of breast cancer varies across ethnic groups. Overall incidence is highest among Caucasian women (CW); however, incidence in women younger than 40 as well as mortality is highest among African American women (AAW). Although socioeconomic disparities are often blamed for these differences, AAW are more likely than CW to present with large, aggressive tumors with poor prognostic features such as estrogen receptor negativity, triple negative phenotype, and lymph node involvement, suggesting that molecular factors may also contribute to the younger age of onset and worse outcomes in AAW. In the present study, we have compared primary breast tumors from AAW and CW by gene expression profiling to identify differentially expressed genes that may explain why diagnosis at a young age, aggressive tumor biology and lower survival are more prevalent in AAW than CW with breast cancer. Materials and Methods: Breast tumor specimens were obtained from 26 pairs of age and stage-matched AAW and CW enrolled in the Clinical Breast Care Project (CBCP). Tumor cells were isolated by laser microdissection (Leica) and RNA isolated using the RNAqueous Micro kit (Ambion). RNA was amplified and labeled with biotin-11-UTP using two rounds of amplification with the MessageAmp II aRNA Amplification kit (Ambion). Fragmented aRNA was hybridized to the HG U133A 2.0 array (Affymetrix). A Mann-Whitney U test was used to identify differentially expressed genes (p ≤ 0.001). Results: Sixty-five genes were differentially expressed between AAW and CW. Twenty-eight genes were more highly expressed in AAW, including SOS1, TSPO, and PSPH, while 37genes had lower expression in AAW, including ZNF228, SCAMP4, and PSD3. Discussion: These results support a model in which molecular factors influence breast cancer onset, progression and prognosis in AAW. Genes with higher expression in tumors from AAW function in steroid, fatty acid, and serine biosynthesis, signal transduction, cell proliferation and adhesion, and cytoskeleton organization and biogenesis. Functions of genes with lower expression in AAW tumors include regulation of transcription, vesicular transport, iron metabolism, signal transduction, and extracellular matrix organization and biogenesis. These results suggest that breast tumors from AAW and CW differ at the gene expression level and that these differences may be responsible for the more aggressive clinical features of breast tumors in AAW compared to CW.

Abstract 555: Gene expression differences in primary breast tumors from African American and Caucasian women.

Chromosomal Alterations Associated with the Transition from In Situ to Invasive Breast Cancer

1022 Background: The most important predictor of prognosis in breast cancer is pathologic status of the lymph nodes. Despite current knowledge about the various subtypes of breast carcinomas, little is known about genes responsible for invasion into the lymphatic system or the ability of the tumor cell to survive and multiply in the lymph node. Here, gene expression analysis was performed on primary breast and matched metastatic lymph node tumors to identify molecular profiles associated with nodal metastasis. Methods: OCT embedded primary breast and lymph node tumors were selected from 20 patients with positive lymph nodes. Pure tumor populations were isolated using laser microdissection. RNA was isolated and amplified using the MessageAmp II aRNA Amplification Kit (Ambion). The biotin-labeled aRNA product was hybridized to a GeneChip Human Genome U133A 2.0 array (Affymetrix). Differential expression was determined using Mann-Whitney testing; Bonferroni corrected p values of 0.05 and 0.001 were calculate...

Identification of a gene expression breast cancer nodal metastasis profile

Amplification of HER2 is a marker for global genomic instability

Genomic Alterations Associated with Early Stages of Breast Tumor Metastasis

Many of the currently established human embryonic stem (hES) cell lines have been characterized extensively in terms of their gene expression profiles and genetic stability in culture. Recent studies have indicated that microRNAs (miRNAs), a class of noncoding small RNAs that participate in the regulation of gene expression, may play a key role in stem cell self-renewal and differentiation. Using both microarrays and quantitative PCR, we report here the differences in miRNA expression between undifferentiated hES cells and their corresponding differentiated cells that underwent differentiation in vitro over a period of 2 weeks. Our results confirm the identity of a signature miRNA profile in pluripotent cells, comprising a small subset of differentially expressed miRNAs in hES cells. Examining both mRNA and miRNA profiles under multiple conditions using cross-correlation, we find clusters of miRNAs grouped with specific, biologically interpretable mRNAs. We identify patterns of expression in the progression from hES cells to differentiated cells that suggest a role for selected miRNAs in maintenance of the undifferentiated, pluripotent state. Profiling of the hES cell "miRNA-ome" provides an insight into molecules that control cellular differentiation and maintenance of the pluripotent state, findings that have broad implications in development, homeostasis, and human disease states.

MicroRNA expression pattern of undifferentiated and differentiated human embryonic stem cells.

Correlation of Levels and Patterns of Genomic Instability With Histological Grading of DCIS

As the number of human embryonic stem cell (hESC) lines increases, so does the need for systematic evaluation of each line's characteristics and potential. Comparisons between lines are complicated by variations in culture conditions, feeders, spontaneous differentiation, and the absence of standardized assays. These difficulties, combined with the inability of most labs to maintain more than a few lines simultaneously, compel the development of reference standards to which hESC lines can be compared. The use of a stable cell line as a reference standard offers many advantages. A line with a relatively unchanging hESC‐like gene and protein expression pattern could be a positive control for developing assays. It can be used as a reference for genomics or proteomics studies, especially for normalizing results obtained in separate laboratories. Such a cell line should be widely available without intellectual property restraints, easily cultured without feeders, and resistant to spontaneous changes in phenotype. We propose that the embryonal carcinoma (EC) line 2102Ep meets these requirements. We compared the protein, gene, and microRNA expression of this cell line with those of hESC lines and alternative reference lines such as the EC line NTERA‐2 and the karyotypically abnormal hESC line BG01V. The overall expression profiles of all these lines were similar, with exceptions reflecting the germ cell origins of EC. On the basis of global gene and microRNA expression, 2102Ep is somewhat less similar to hESC than the alternatives; however, 2102Ep expresses more hESC‐associated microRNAs than NTERA‐2 does, and fewer markers of differentiated fates.

Qualification of Embryonal Carcinoma 2102Ep As a Reference for Human Embryonic Stem Cell Research

Correlation of levels and patterns of genomic instability with histological grading of invasive breast tumors

Micro RNA profiling: an easy and rapid method to screen and characterize stem cell populations.

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

43 

Background: Breast cancer incidence in the United States varies among ethnic groups. Overall incidence is highest among Caucasian women (CW); however, when stratified by age, the highest incidence of breast cancer occurs among African American women (AAW) under the age of 40. Mortality rates are also highest among AAW. The poor outcomes observed in AAW are frequently attributed to disparities in socioeconomic status, healthcare access, and cultural beliefs. However, tumor biology also differs among AAW and CW. Tumors from AAW share many characteristics with tumors from women with hereditary BRCA1 mutations including large size, aggressiveness, poor differentiation, high-grade nuclear atypia, frequent lymph node involvement, and estrogen receptor negativity. Therefore, biological and molecular factors may also contribute to the poor prognosis of AAW with breast cancer. In the present study, we have identified gene expression differences in normal breast tissue from disease-free AAW and CW that may predispose AAW to aggressive tumors and poor clinical prognoses.

Methods: Normal breast tissue (reductive mammoplasty and/or disease-free biopsy specimens) was obtained from AAW (n=26) and CW (n=22) enrolled in the Clinical Breast Care Project (CBCP). RNA was isolated using the Qiagen RNeasy Lipid Tissue Midi kit, amplified using the MessageAmp II aRNA Amplification kit (Ambion) and hybridized to the Affymetrix GeneChip Human Genome U133A 2.0 expression array. Differentially expressed genes were identified using Mann-Whitney testing ( p ≤ 0.001).

Results: Eighty-nine genes were found to be differentially expressed in normal breast tissue from AAW and CW. Eighty-seven genes had lower expression in AAW compared to CW while two genes, PSPH and ACSM1, were more highly expressed in breast tissue from AAW. PSPH, encoding phoshoserine phosphatase, catalyzes the last step in L-serine biosynthesis. ACSM1, acyl-CoA synthetase medium chain family member 1, is involved in fatty acid oxidation.

Discussion: The CBCP provides us with a unique resource to study breast cancer in AAW. Because all women enrolled in the CBCP receive standardized treatment and care regardless of ethnicity, differences observed in gene expression are not confounded by differences in the quality of healthcare received. The increased expression of PSPH could potentially increase the amount of serine synthesized in the cell. As serine is used as an intermediate in the synthesis of other amino acids, phospholipids, and purines, this could have a profound impact on protein, lipid, and DNA metabolism. Likewise, increased expression of ACSM1 could increase the rate of fatty acid oxidation in the cell, resulting in a large increase in the amount of energy or ATP produced. Both conditions could promote cell growth and proliferation that would confer a growth advantage to breast cells in AAW that may increase their potential towards malignant transformation.

Differential gene expression in normal breast tissue from African American and Caucasian women.

10018 Background: Despite improved survival rates for women with breast cancer mainly from improved screening, aggressive therapies may result in the over treatment of many with undesirable physical and economic costs. Identification of molecular profiles in breast tumors that differentiate patients with poor prognosis from those with favorable outcomes would allow for development of effective, individualized treatment regimens with less overall morbidity.

METHODS
DNA was extracted from primary breast tumors representing stage I (n=75), stage II (n=42), stage III (n=24), and stage IV (n=9) after laser microdissection to isolate pure tumor cell populations. Genomic instability was detected using 52 microsatellite markers representing 26 chromosomal regions frequently altered in breast cancer. Statistical analyses were performed using Fisher's exact tests and Student t-tests.

RESULTS
Patients with poor prognosis (15% of sample population) were defined as those dead of disease (DOD) or alive with disease (AWD), either metastatic disease or disease recurrence; all others had no evidence of disease (NED). Overall levels of genomic instability were significantly higher in tumors from patients with poor prognosis (P<0.0005). At the chromosomal level, chromosome 17p13.3 (P<0.001), 3p13 (P<0.05), and 13q14 (P<0.05) were altered significantly more frequently in patients with poor prognosis compared to NED patients.

Chromosomes 3p13, 13q14, and 17p13.3 harbor the fragile histadine triad (FHIT), retinoblastoma 1 (RB1), and hypermethylated in cancer 1 (HIC1) genes, respectively. Alteration of the FHIT gene may promote overall genomic instability while alterations in RB1 and HIC1 has been associated with poor prognosis in patients with breast cancer. Assessment of genomic instability at these three regions may prove useful for stratifying patients by tumor aggressiveness, thus allowing more effective, customized treatment options to be developed. No significant financial relationships to disclose.

Patterns of genomic instability differentiate clinical outcomes in patients with invasive breast cancer.

Combining diverse data streams across different levels of biological observation, such as molecular, cellular, and clinical chemistry responses, support a system‐wide diagnostic approach. Recent progress in slide‐based cytometry contributes to the development of tissomics, a high‐throughput and high‐content phenotyping methodology that provides data‐rich profiles of cellular heterogeneity in tissues enabling correlative statistical treatments over multiple scales of biological hierarchies.

System‐wide analysis of hepatotoxicological responses: Tissomics is key

OR.65. Melanoma Biomarker Discovery Through Serum Antibody Profiling On Protein Microarrays

A major research objective of NIH is to discover novel biomarkers that can improve cancer detection assays. Many biomarker candidates with apparent differential expression identified by high throughput genomic and proteomic experiments have been reported as candidates for novel cancer detection assays. Despite these many discoveries, few biomarkers have been validated and successfully translated into clinical tests, a situation that may be attributable to the extensive and costly experimental evaluation required to fully develop a candidate biomarker into a clinically useful assay. The use of information in addition to disease-state expression data may help to focus biomarker assay development projects more selectively and facilitate successful assay development and translation. We describe a bioinformatics and data mining method for evaluating diagnostic serum biomarker candidates by selecting genes and gene products that possess intrinsic protein localization and tissue expression properties.

The bioinformatics methods we describe are based on the assumption that candidate markers with diagnostic value have been identified previously. We defined diagnostic value as differential up-regulation or high expression of the biomarker in cancer tissue compared with benign tissue. Our experience (unpublished) has shown that detection of differentially down-regulated serum biomarker candidates is problematic because the serum biomarker candidates are usually present in low concentrations at which it is difficult to detect the absence of signal under the normal tissue background. Regardless of the definition of diagnostic value, the bioinformatics methods we describe are not contingent on discovering or confirming the informative value of the candidate biomarkers for differentiating healthy vs diseased states. These methods are designed to select candidate biomarkers with properties that make them more readily detectable in the biologically complex serum environment, in which …

Bioinformatics methods for prioritizing serum biomarker candidates.

Immunoassays for prostate-specific antigen (PSA) are used routinely as an aid to detect prostate cancer (PCa). PSA permits early detection of PCa but lacks specificity (1)(2). In a typical screening population of African American men ≥40 years of age and other men ≥50 years of age, ∼4% of the men with a PSA concentration >4 μg/L, which is the upper reference limit for PSA, will have prostate cancer (1). Most of these cancers can be detected using PSA. At issue, however, is the comorbidity of men with benign prostatic hyperplasia whose age and PSA concentrations are within these ranges. For example, 50% of men >60 years of age have benign prostatic hyperplasia (3), and many will have PSA >4 μg/L. The low specificity of PSA measurement as a test for PCa necessitates many prostate biopsies, of which ∼75% are negative and theoretically unnecessary. Additional biomarkers may improve sensitivity and specificity of PSA. We theorized that bioinformatics and analysis of the existing scientific literature could identify promising protein biomarker candidates that, if combined with PSA, might improve clinical sensitivity and especially specificity.

The work flow we used to select candidate biomarkers is diagramed in the flow chart in Fig. 1⇓ . We searched Medline and other relevant databases from Nerac Corporation (Tolland, CT) for publications that appeared in 1999–2004 with the terms prostate cancer and markers or biomarkers or early detection or aggressiveness or staging or grading. We also used prostate-specific genes, prostate-specific proteins, and several well-known institutions and investigators in the field of prostate cancer research as search terms. Once compiled, the titles and abstracts were read to find proteins or genes documented to be differentially regulated in tissue or serum or plasma PCa samples compared with normal or benign samples. A list of >2700 citations was …

A systematic method for selection of promising serum protein biomarkers to improve prostate cancer (PCa1) detection.

Comprehensive evaluation of the association between prostate cancer and genotypes/haplotypes in CYP17A1, CYP3A4, and SRD5A2

Outer breast quadrants demonstrate increased patterns of DNA genomic instability

Outer Breast Quadrants Demonstrate Increased Levels of Genomic Instability

Genomic patterns of allelic imbalance in disease free tissue adjacent to primary breast carcinomas

Combined histomorphometric and gene-expression profiling applied to toxicology

MOTIVATION
In many microarray experiments, relatively few intra- and inter-array replicate measurements are made due to significant cost limitations and sample availability. Compounding this problem is a lack of robust statistical methods for analyzing gene expression data with limited experimental replicates. As a result, the interpretation of the results of these experiments are difficult with little understanding of the probability of type I and type II errors.

RESULTS
The variability in a series of replicate microarray measurements was modelled using a combination of parametric and non-parametric methods. A 3-dimensional surface was created for the conditional distribution of the variability given the mean signal intensity in both the Cy3 and Cy5 channels. The results were used as the basis for developing statistical methods for analyzing gene expression data with limited experimental replicates.

The statistical analysis scripts are available upon request.

A conditional density error model for the statistical analysis of microarray data

PSA group compared with the 0 – 4 ␮g/L group (Dunnet test P Ͻ0.05). There was no significant difference between the 0 – 4 ␮g/L and the 4 –10 ␮g/L group for HGF or ACPP, nor were there any substantial differences in the other 7 candidates between the 0 – 4 ␮g/L and the 4 –10 or Ͼ10 ␮g/L PSA groups. The Western blot analyses of the biomarker candidate anterior gradient 2 homolog (AGR2) showed a 3.8-fold median increase in signal at the expected molecular mass in cancer tissues vs the normal tissues of the 10 patients (Table 1). Expression of the other 6 candidate genes did not show a consistent difference in cancer and healthy tissue. Two of the 5 candidate genes subjected to qRTPCR showed very low expression in prostate tissue. Three candidates showed expression but no significant (Wil-coxon P Ͼ0.05) difference in expression between cancer and normal tissue. A lack of differential in gene expression between cancerous and normal tissue may not exclude the possibility of finding different protein concentrations in serum or other biological fluids of persons with PCa compared with those without PCa. We found that existing scientific literature can be specifically analyzed to select promising PCa biomarker candidates. These data can be reduced to a reasonable number of promising candidates by use of multiple, predetermined, clinically relevant criteria. Use of HUGO-approved gene symbols is crucial for reducing confusion caused by multiple aliases that exist for most genes and the proteins they express. Bioinformatics and publicly available databases can be used to select specific criteria that theoretically are crucial to the success of biomarkers, such as probability of secretion or tissue-and cancer-specific gene expression profiles. Once markers were selected we found a multitude of commercially available reagents such as ELISAs and antibodies that can be used to rapidly assess the validity of candidate biomarkers on relevant patient samples. Therefore, we have formulated an iterative process (Fig. 1) through which we can use all available scientific literature and bioinformatic information to select and then evaluate, in the laboratory, potential serum markers for prostate cancer. As new literature for prostate cancer marker candidates becomes available, we can continually assess the new data and evaluate new candidates through our iterative process. We hope that some of these promising candidates can be combined with PSA to produce a multianalyte test that decreases unnecessary prostate biopsies. Furthermore, this approach will …

A noninvasive, wearable continuous glucose monitor would be a major advancement in diabetes therapy. This trial investigated a novel noninvasive glucose monitor which analyzes spectral variations in radio frequency/microwave signals reflected from the wrist.

METHODS
A single-arm, open-label, experimental study compared glucose values from a prototype investigational device with laboratory glucose measurements from venous blood samples (Super GL Glucose Analyzer, Dr. Müller Gerätebau GmbH) at varying levels of glycemia. The study included 29 male participants with type 1 diabetes (age range = 19-56 years). The study comprised three stages with the following aims: (1) demonstrate initial proof-of-principle, (2) test an improved device design, and (3) test performance on two consecutive days without device recalibration. The co-primary endpoints in all trial stages were median and mean absolute relative difference (ARD) calculated across all data points.

RESULTS
In stage 1, the median and mean ARDs were 30% and 46%, respectively. Stage 2 produced marked performance improvements with a median and mean ARD of 22% and 28%, respectively. Stage 3 showed that, without recalibration, the device performed as well as the initial prototype (stage 1) with a median and mean ARD of 35% and 44%, respectively.

This proof-of-concept study shows that a novel noninvasive continuous glucose monitor was capable of detecting glucose levels. Furthermore, the ARD results are comparable to first models of commercially available minimally invasive products without the need to insert a needle. The prototype has been further developed and is being tested in subsequent studies.

TRIAL REGISTRATION NUMBER
NCT05023798.

Noninvasive Continuous Glucose Monitoring With a Novel Wearable Dial Resonating Sensor: A Clinical Proof-of-Concept Study.

The Indiana Department of Highways (IDOH) has been undersealing concrete pavements with bituminous materials since the late 1940s. Most early rigid pavements were constructed directly on soil subgrades and were subject to severe pumping. Thus early undersealing operations involved treating entire sections of roadway. As pavement designs improved, severe pumping became less prevalent and a method of identifying only those areas that required undersealing became necessary. The approach taken by IDOH personnel was global in nature. Because it was impractical to locate and treat specific voids, a method was developed to identify and treat the most severely distressed areas. The method of void detection presented herein uses Dynaflect deflections measured at regular (100-ft) intervals within each contract section. Decision criteria based on midslab deflections are established for each contract; Sensor 5 is the primary indicator variable. Because decision criteria are obtained independently for each contract section, the method is applicable to both jointed and continuously reinforced concrete sections and to previously overlaid sections. When the areas that require undersealing have been identified, all cracks and joints within each area are treated. The procedure involves carefully monitoring slab motion during material injection with a sensitive deflection gauge developed specifically for that purpose. Furthermore, injection time limits are observed to minimize material losses due to blowouts. Data are presented that demonstrate both the validity of the void detection method and the joint deflection improvements that can be expected from the undersealing procedure. The economic feasibility of the method is discussed in terms of the savings that have been realized since the implementation of the method.

VOID DETECTION AND RIGID PAVEMENT UNDERSEALING IN INDIANA: A COMPREHENSIVE APPROACH

Attempts to synthesize new k-phase superconductors have concentrated on ET salts with complex anions composed of Cu(I) or Ag(I) metal ions and pseudohalide anions. The targeted anion approach', by use of a preformed anion found in KCu{sub 2}(CN){sub 3}.H{sub 2}O and the presence of trace amounts of water, led to the discovery of the first copper-cyanide containing superconductor, K-(ET){sub 2}Cu{sub 2}(CN){sub 3}. The crystal structure, superconducting properties, and band electronic structure are described in this article. The complex k-(ET){sub 2}Cu{sub 2}(CN){sub 3} is in many ways similar to the superconductor K-(ET){sub 2}Cu(N(CN){sub 2})Cl, the superconductor with the highest T{sub c} reported to date. 28 refs., 3 figs.

Superconductivity at 2.8 K and 1.5 kbar in .kappa.-(BEDT-TTF)2Cu2(CN)3: the first organic superconductor containing a polymeric copper cyanide anion

Primates can recognize objects despite 3D geometric variations such as in-depth rotations. The computational mechanisms that give rise to such invariances are yet to be fully understood. A curious case of partial invariance occurs in the macaque face-patch AL and in fully connected layers of deep convolutional networks in which neurons respond similarly to mirror-symmetric views (e.g., left and right profiles). Why does this tuning develop? Here, we propose a simple learning-driven explanation for mirror-symmetric viewpoint tuning. We show that mirror-symmetric viewpoint tuning for faces emerges in the fully connected layers of convolutional deep neural networks trained on object recognition tasks, even when the training dataset does not include faces. First, using 3D objects rendered from multiple views as test stimuli, we demonstrate that mirror-symmetric viewpoint tuning in convolutional neural network models is not unique to faces: it emerges for multiple object categories with bilateral symmetry. Second, we show why this invariance emerges in the models. Learning to discriminate among bilaterally symmetric object categories induces reflection-equivariant intermediate representations. AL-like mirror-symmetric tuning is achieved when such equivariant responses are spatially pooled by downstream units with sufficiently large receptive fields. These results explain how mirror-symmetric viewpoint tuning can emerge in neural networks, providing a theory of how they might emerge in the primate brain. Our theory predicts that mirror-symmetric viewpoint tuning can emerge as a consequence of exposure to bilaterally symmetric objects beyond the category of faces, and that it can generalize beyond previously experienced object categories.

Emergence of brain-like mirror-symmetric viewpoint tuning in convolutional neural networks

The spreading of attention has been proposed as a mechanism for how humans group features to segment objects. However, such a mechanism has not yet been implemented and tested in naturalistic images. Here, we leverage the feature maps from self-supervised vision Transformers and propose a model of human object-based attention spreading and segmentation. Attention spreads within an object through the feature affinity signal between different patches of the image. We also collected behavioral data on people grouping objects in natural images by judging whether two dots are on the same object or on two different objects. We found that our models of affinity spread that were built on feature maps from the self-supervised Transformers showed significant improvement over baseline and CNN based models on predicting reaction time patterns of humans, despite not being trained on the task or with any other object labels. Our work provides new benchmarks for evaluating models of visual representation learning including Transformers.

Affinity-based Attention in Self-supervised Transformers Predicts Dynamics of Object Grouping in Humans

Deep neural network models (DNNs) are essential to modern AI and provide powerful models of information processing in biological neural networks. Researchers in both neuroscience and engineering are pursuing a better understanding of the internal representations and operations that undergird the successes and failures of DNNs. Neuroscientists additionally evaluate DNNs as models of brain computation by comparing their internal representations to those found in brains. It is therefore essential to have a method to easily and exhaustively extract and characterize the results of the internal operations of any DNN. Many models are implemented in PyTorch, the leading framework for building DNN models. Here we introduce TorchLens, a new open-source Python package for extracting and characterizing hidden-layer activations in PyTorch models. Uniquely among existing approaches to this problem, TorchLens has the following features: (1) it exhaustively extracts the results of all intermediate operations, not just those associated with PyTorch module objects, yielding a full record of every step in the model’s computational graph, (2) it provides an intuitive visualization of the model’s complete computational graph along with metadata about each computational step in a model’s forward pass for further analysis, (3) it contains a built-in validation procedure to algorithmically verify the accuracy of all saved hidden-layer activations, and (4) the approach it uses can be automatically applied to any PyTorch model with no modifications, including models with conditional (if-then) logic in their forward pass, recurrent models, branching models where layer outputs are fed into multiple subsequent layers in parallel, and models with internally generated tensors (e.g., injections of noise). Furthermore, using TorchLens requires minimal additional code, making it easy to incorporate into existing pipelines for model development and analysis, and useful as a pedagogical aid when teaching deep learning concepts. We hope this contribution will help researchers in AI and neuroscience understand the internal representations of DNNs.

TorchLens: A Python package for extracting and visualizing hidden activations of PyTorch models

Neural network language models can serve as computational hypotheses about how humans process language. We compared the model-human consistency of diverse language models using a novel experimental approach: controversial sentence pairs. For each controversial sentence pair, two language models disagree about which sentence is more likely to occur in natural text. Considering nine language models (including n-gram, recurrent neural networks, and transformer models), we created hundreds of such controversial sentence pairs by either selecting sentences from a corpus or synthetically optimizing sentence pairs to be highly controversial. Human subjects then provided judgments indicating for each pair which of the two sentences is more likely. Controversial sentence pairs proved highly effective at revealing model failures and identifying models that aligned most closely with human judgments. The most human-consistent model tested was GPT-2, although experiments also revealed significant shortcomings of its alignment with human perception.

Testing the limits of natural language models for predicting human language judgments

Comparing representations of complex stimuli in neural network layers to human brain representations or behavioral judgments can guide model development. However, even qualitatively distinct neural network models often predict similar representational geometries of typical stimulus sets. We propose a Bayesian experimental design approach to synthesizing stimulus sets for adjudicating among representational models efficiently. We apply our method to discriminate among candidate neural network models of behavioral face dissimilarity judgments. Our results indicate that a neural network trained to invert a 3D-face-model graphics renderer is more human-aligned than the same architecture trained on identification, classification, or autoencoding. Our proposed stimulus synthesis objective is generally applicable to designing experiments to be analyzed by representational similarity analysis for model comparison.

Distinguishing representational geometries with controversial stimuli: Bayesian experimental design and its application to face dissimilarity judgments

A neural network family for systematic analysis of RF size and computational-path-length distribution as determinants of neural predictivity and behavioral performance

Flying Objects: Challenging humans and machines in dynamic object vision

Neuronal populations code similar concepts by similar activity patterns across the human brain’s networks supporting language comprehension. However, it is unclear to what extent such meaning-to-symbol mapping reflects statistical distributions of symbol meanings in language use, as quantified by word co-occurrence frequencies, or, rather, experiential information thought to be necessary for grounding symbols in sensorimotor knowledge. Here we asked whether integrating distributional semantics with human judgments of grounded sensorimotor semantics better approximates the representational similarity of conceptual categories in the brain, as compared with each of these methods used separately. We examined the similarity structure of activation patterns elicited by action- and object-related concepts using multivariate representational similarity analysis (RSA) of fMRI data. The results suggested that a semantic vector integrating both sensorimotor and distributional information yields best category discrimination on the cognitive-linguistic level, and explains the corresponding activation patterns in left posterior inferior temporal cortex. In turn, semantic vectors based on detailed visual and motor information uncovered category-specific similarity patterns in fusiform and angular gyrus for object-related concepts, and in motor cortex, left inferior frontal cortex (BA 44), and supramarginal gyrus for action-related concepts.

Category-specific representational patterns in left inferior frontal and temporal cortex reflect similarities and differences in the sensorimotor and distributional properties of concepts

Despite the importance of face perception in human and computer vision, no quantitative model of perceived face dissimilarity exists. 1 We designed an efficient behavioural task to collect dissimilarity and same/different identity judgements for 232 pairs of realistic faces 2 that densely sampled geometric relationships in a face space derived from principal components of 3D shape and texture (Basel Face 3 Model, BFM). In a comparison of 15 models, we found that representational distances in deep neural networks (DNNs) and Euclidean 4 distances within BFM space predicted human judgements best. A face-trained DNN explained unique variance over simpler models 5 and was statistically indistinguishable from the noise ceiling. Sigmoidal transformation of distances improved performance for all 6 models. Identity judgements were better predicted by Euclidean than angular or radial distances in BFM space. DNNs provide 7 the best available image-computable models of perceived face dissimilarity. The success of BFM space suggests that human face 8 perception is attuned to the natural distribution of faces. 9

Face dissimilarity judgements are predicted by representational distance in deep neural networks and principal-component face space

Note: This is a reply to the Generative Adversarial Collaboration "Is perception probabilistic? Clarifying the definitions" by Rahnev, Block, Denison, and Jehee (DOI 10.31234/osf.io/f8v5r). Probabilistic representations promise to shed light on how humans and other organisms cope with uncertainty, but debates about them have been hindered by unclear definitions and a lack of testable predictions. We argue that neither camp in this GAC has offered a plausible way out of this situation. We describe problems with their attempts to define probabilistic representations and sketch an alternative view, in which the defining feature of a probabilistic representation is how it is used.

Probabilistic representations should be defined by their computational role: reply to Rahnev et al. 2021

Abstract Research into representation learning models of lexical semantics usually utilizes some form of intrinsic evaluation to ensure that the learned representations reflect human semantic judgments. Lexical semantic similarity estimation is a widely used evaluation method, but efforts have typically focused on pairwise judgments of words in isolation, or are limited to specific contexts and lexical stimuli. There are limitations with these approaches that either do not provide any context for judgments, and thereby ignore ambiguity, or provide very specific sentential contexts that cannot then be used to generate a larger lexical resource. Furthermore, similarity between more than two items is not considered. We provide a full description and analysis of our recently proposed methodology for large-scale data set construction that produces a semantic classification of a large sample of verbs in the first phase, as well as multi-way similarity judgments made within the resultant semantic classes in the second phase. The methodology uses a spatial multi-arrangement approach proposed in the field of cognitive neuroscience for capturing multi-way similarity judgments of visual stimuli. We have adapted this method to handle polysemous linguistic stimuli and much larger samples than previous work. We specifically target verbs, but the method can equally be applied to other parts of speech. We perform cluster analysis on the data from the first phase and demonstrate how this might be useful in the construction of a comprehensive verb resource. We also analyze the semantic information captured by the second phase and discuss the potential of the spatially induced similarity judgments to better reflect human notions of word similarity. We demonstrate how the resultant data set can be used for fine-grained analyses and evaluation of representation learning models on the intrinsic tasks of semantic clustering and semantic similarity. In particular, we find that stronger static word embedding methods still outperform lexical representations emerging from more recent pre-training methods, both on word-level similarity and clustering. Moreover, thanks to the data set’s vast coverage, we are able to compare the benefits of specializing vector representations for a particular type of external knowledge by evaluating FrameNet- and VerbNet-retrofitted models on specific semantic domains such as “Heat” or “Motion.”

Semantic Data Set Construction from Human Clustering and Spatial Arrangement

Despite the widespread use of principal-components-based 3D models to generate stimuli in face perception research, it is not clear how well these statistical “face spaces” explain human perception. We designed an efficient behavioural task to collect dissimilarity and same/different identity judgements for 232 pairs of realistic faces. The stimuli densely sampled geometric relationships in a face space derived from principal components of 3D shape and texture (Basel Face Model, BFM). Euclidean distance in the BFM explained both similarity and identity judgements surprisingly well, despite capturing no image-level information about faces. In a comparison against 11 alternative models, we found that BFM distance was competitive with representational distances in state-of-the-art image-computable deep neural networks. Models describing the distribution of facial features across individuals are not only useful tools for stimulus generation. They also capture important information about how faces are perceived, underscoring the statistically-tuned nature of face encoding.

Face dissimilarity judgments are predicted by representational distance in morphable and image-computable models

The Representational Dynamics of Perceived Voice Emotions Evolve from Categories to Dimensions

Significance Inspired by core principles of information processing in the brain, deep neural networks (DNNs) have demonstrated remarkable success in computer vision applications. At the same time, networks trained on the task of object classification exhibit similarities to representations found in the primate visual system. This result is surprising because the datasets commonly used for training are designed to be engineering challenges. Here, we use linguistic corpus statistics and human concreteness ratings as guiding principles to design a resource that more closely mirrors categories that are relevant to humans. The result is ecoset, a collection of 1.5 million images from 565 basic-level categories. We show that ecoset-trained DNNs yield better models of human higher-level visual cortex and human behavior. Deep neural networks provide the current best models of visual information processing in the primate brain. Drawing on work from computer vision, the most commonly used networks are pretrained on data from the ImageNet Large Scale Visual Recognition Challenge. This dataset comprises images from 1,000 categories, selected to provide a challenging testbed for automated visual object recognition systems. Moving beyond this common practice, we here introduce ecoset, a collection of >1.5 million images from 565 basic-level categories selected to better capture the distribution of objects relevant to humans. Ecoset categories were chosen to be both frequent in linguistic usage and concrete, thereby mirroring important physical objects in the world. We test the effects of training on this ecologically more valid dataset using multiple instances of two neural network architectures: AlexNet and vNet, a novel architecture designed to mimic the progressive increase in receptive field sizes along the human ventral stream. We show that training on ecoset leads to significant improvements in predicting representations in human higher-level visual cortex and perceptual judgments, surpassing the previous state of the art. Significant and highly consistent benefits are demonstrated for both architectures on two separate functional magnetic resonance imaging (fMRI) datasets and behavioral data, jointly covering responses to 1,292 visual stimuli from a wide variety of object categories. These results suggest that computational visual neuroscience may take better advantage of the deep learning framework by using image sets that reflect the human perceptual and cognitive experience. Ecoset and trained network models are openly available to the research community.

An ecologically motivated image dataset for deep learning yields better models of human vision

Social behavior is coordinated by a network of brain regions, including those involved in the perception of social stimuli and those involved in complex functions, such as inferring perceptual and mental states and controlling social interactions. The properties and function of many of these regions in isolation are relatively well understood, but less is known about how these regions interact while processing dynamic social interactions. To investigate whether the functional connectivity between brain regions is modulated by social context, we collected fMRI data from male monkeys (Macaca mulatta) viewing videos of social interactions labeled as “affiliative,” “aggressive,” or “ambiguous.” We show activation related to the perception of social interactions along both banks of the superior temporal sulcus, parietal cortex, medial and lateral frontal cortex, and the caudate nucleus. Within this network, we show that fronto-temporal functional connectivity is significantly modulated by social context. Crucially, we link the observation of specific behaviors to changes in functional connectivity within our network. Viewing aggressive behavior was associated with a limited increase in temporo-temporal and a weak increase in cingulate-temporal connectivity. By contrast, viewing interactions where the outcome was uncertain was associated with a pronounced increase in temporo-temporal, and cingulate-temporal functional connectivity. We hypothesize that this widespread network synchronization occurs when cingulate and temporal areas coordinate their activity when more difficult social inferences are being made. SIGNIFICANCE STATEMENT Processing social information from our environment requires the activation of several brain regions, which are concentrated within the frontal and temporal lobes. However, little is known about how these areas interact to facilitate the processing of different social interactions. Here we show that functional connectivity within and between the frontal and temporal lobes is modulated by social context. Specifically, we demonstrate that viewing social interactions where the outcome was unclear is associated with increased synchrony within and between the cingulate cortex and temporal cortices. These findings suggest that the coordination between the cingulate and temporal cortices is enhanced when more difficult social inferences are being made.

Viewing Ambiguous Social Interactions Increases Functional Connectivity between Frontal and Temporal Nodes of the Social Brain

Abstract Deep neural networks (DNNs) trained on object recognition provide the best current models of high-level visual cortex. What remains unclear is how strongly experimental choices, such as network architecture, training, and fitting to brain data, contribute to the observed similarities. Here, we compare a diverse set of nine DNN architectures on their ability to explain the representational geometry of 62 object images in human inferior temporal cortex (hIT), as measured with fMRI. We compare untrained networks to their task-trained counterparts and assess the effect of cross-validated fitting to hIT, by taking a weighted combination of the principal components of features within each layer and, subsequently, a weighted combination of layers. For each combination of training and fitting, we test all models for their correlation with the hIT representational dissimilarity matrix, using independent images and subjects. Trained models outperform untrained models (accounting for 57% more of the explainable variance), suggesting that structured visual features are important for explaining hIT. Model fitting further improves the alignment of DNN and hIT representations (by 124%), suggesting that the relative prevalence of different features in hIT does not readily emerge from the Imagenet object-recognition task used to train the networks. The same models can also explain the disparate representations in primary visual cortex (V1), where stronger weights are given to earlier layers. In each region, all architectures achieved equivalently high performance once trained and fitted. The models' shared properties—deep feedforward hierarchies of spatially restricted nonlinear filters—seem more important than their differences, when modeling human visual representations.

Diverse Deep Neural Networks All Predict Human Inferior Temporal Cortex Well, After Training and Fitting

Data visualizations summarize high-dimensional distributions in two or three dimensions. Dimensionality reduction entails a loss of information, and what is preserved differs between methods. Existing methods preserve the local or the global geometry of the points, and most techniques do not consider labels. Here we introduce “hypersphere2sphere” (H2S), a new method that aims to visualize not the points, but the relationships between the labeled distributions. H2S fits a hypersphere to each labeled set of points in a high-dimensional space and visualizes each hypersphere as a sphere in 3D (or circle in 2D). H2S perfectly captures the geometry of up to 4 hyperspheres in 3D (or 3 in 2D), and approximates the geometry for larger numbers of distributions, matching the sizes (radii), and the pairwise separations (between-center distances) and overlaps (along the center-connection line). The resulting visualizations are robust to sampling imbalances. Leveraging labels and the sphere as the simplest geometrical primitive, H2S provides an important addition to the toolbox of visualization techniques. Introduction Data visualization engages our visual system’s capacity for parallel processing, enabling us to understand a complex set of relationships at a glance. Visualization of high-dimensional data typically involves embedding the data in a 2or 3-dimensional space, such that every high-dimensional data point is displayed in the visualization. The embedding, however, requires dimensionality reduction, which inevitably entails a loss of information. Different methods make different trade-offs in terms of what information to preserve and what to discard. The most commonly used visualization methods reduce dimensionality without making use of data labels. Several popular dimensionality reduction techniques attempt to preserve the geometry of the data (Figure 1a). Principal Component Analysis (PCA) preserves the geometry of the high-dimensional data exactly, but only for the two or three dimen-

Visualizing the geometry of labeled high-dimensional data with spheres

Deep neural networks (DNNs) are promising models of the cortical computations supporting human object recognition. However, despite their ability to explain a significant portion of variance in neural data, the agreement between models and brain representational dynamics is far from perfect. We address this issue by asking which representational features are currently unaccounted for in neural time series data, estimated for multiple areas of the ventral stream via source-reconstructed magnetoencephalography data acquired in human participants (nine females, six males) during object viewing. We focus on the ability of visuo-semantic models, consisting of human-generated labels of object features and categories, to explain variance beyond the explanatory power of DNNs alone. We report a gradual reversal in the relative importance of DNN versus visuo-semantic features as ventral-stream object representations unfold over space and time. Although lower-level visual areas are better explained by DNN features starting early in time (at 66 ms after stimulus onset), higher-level cortical dynamics are best accounted for by visuo-semantic features starting later in time (at 146 ms after stimulus onset). Among the visuo-semantic features, object parts and basic categories drive the advantage over DNNs. These results show that a significant component of the variance unexplained by DNNs in higher-level cortical dynamics is structured and can be explained by readily nameable aspects of the objects. We conclude that current DNNs fail to fully capture dynamic representations in higher-level human visual cortex and suggest a path toward more accurate models of ventral-stream computations. SIGNIFICANCE STATEMENT When we view objects such as faces and cars in our visual environment, their neural representations dynamically unfold over time at a millisecond scale. These dynamics reflect the cortical computations that support fast and robust object recognition. DNNs have emerged as a promising framework for modeling these computations but cannot yet fully account for the neural dynamics. Using magnetoencephalography data acquired in human observers during object viewing, we show that readily nameable aspects of objects, such as 'eye', 'wheel', and 'face', can account for variance in the neural dynamics over and above DNNs. These findings suggest that DNNs and humans may in part rely on different object features for visual recognition and provide guidelines for model improvement.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Deep neural networks and visuo-semantic models explain complementary components of human ventral-stream representational dynamics

Correction: Inferring exemplar discriminability in brain representations

Facial similarity judgements are well predicted by image-computable DNNs and a statistical face distribution model

Rapid event-related, BOLD fMRI, non-human primates (NHP): choose two out of three

Deep neural networks (DNNs) trained on object recognition provide the best current models of high-level visual areas in the brain. What remains unclear is how strongly network design choices, such as architecture, task training, and subsequent fitting to brain data contribute to the observed similarities. Here we compare a diverse set of nine DNN architectures on their ability to explain the representational geometry of 62 isolated object images in human inferior temporal (hIT) cortex, as measured with functional magnetic resonance imaging. We compare untrained networks to their task-trained counterparts, and assess the effect of fitting them to hIT using a cross-validation procedure. To best explain hIT, we fit a weighted combination of the principal components of the features within each layer, and subsequently a weighted combination of layers. We test all models across all stages of training and fitting for their correlation with the hIT representational dissimilarity matrix (RDM) using an independent set of images and subjects. We find that trained models significantly outperform untrained models (accounting for 57% more of the explainable variance), suggesting that features representing natural images are important for explaining hIT. Model fitting further improves the alignment of DNN and hIT representations (by 124%), suggesting that the relative prevalence of different features in hIT does not readily emerge from the particular ImageNet object-recognition task used to train the networks. Finally, all DNN architectures tested achieved equivalent high performance once trained and fitted. Similar ability to explain hIT representations appears to be shared among deep feedforward hierarchies of nonlinear features with spatially restricted receptive fields.

Diverse deep neural networks all predict human IT well, after training and fitting

Going in circles is the way forward: the role of recurrence in visual inference

Social behaviour is coordinated by a network of brain regions, including those involved in the perception of social stimuli and those involved in complex functions like inferring perceptual and mental states and controlling social interactions. The properties and function of many of these regions in isolation is relatively well understood but little is known about how these regions interact whilst processing dynamic social interactions. To investigate whether social network connectivity is modulated by social context we collected fMRI data from monkeys viewing “affiliative”, “aggressive”, or “ambiguous” social interactions. We show activation relating to the perception of social interactions along both banks of the superior temporal sulcus, parietal, medial and lateral PFC and caudate nucleus. Within this network we demonstrate that fronto-temporal connectivity are significantly modulated by social context. Crucially, we link the observation of specific behaviours to changes in connectivity within our network. Viewing aggressive or affiliative behaviour was associated with a limited increase in temporo-temporal and premotor-temporal connectivity respectively. By contrast, viewing ambiguous interactions was associated with a pronounced increase in cingulate-cingulate, temporo-temporal, and cingulate-temporal connectivity. We hypothesise that this widespread network synchronisation occurs when cingulate and temporal areas coordinate their activity when more difficult social inferences are made.

Perceived ambiguity of social interactions increases coupling between frontal and temporal nodes of the social brain

 Scientists debate where, when, and how different visual, orthographic, lexical, and semantic features are involved in visual word recognition. In this study, we investigate intracranial neurophysiology data from 151 patients engaged in reading single words. Using representational similarity analysis, we characterize the neural representation of a hierarchy of word features across the entire cerebral cortex. We find evidence of both feed-forward and feedback processing, with early representation of visual and lexical information in lingual gyrus followed by lexical representation in fusiform gyrus and semantic sensitivity in inferior frontal gyrus, with letter representation emerging later in fusiform gyrus. Furthermore, we observed a variety of anatomically heterogeneous temporal response shapes, and these functional populations had significant feature sensitivity. Taken together, our results demonstrate the early influence of lexical, phonological, and semantic features in visual word recognition and reveal feed-forward, feed-back, and anatomically distributed processing mechanisms that contribute to visual word recognition.

Feed-forward, feed-back, and distributed feature representation during visual word recognition revealed by human intracranial neurophysiology

Human functional magnetic resonance imaging (fMRI) typically employs the blood-oxygen-level-dependent (BOLD) contrast mechanism. In non-human primates (NHP), contrast enhancement is possible using monocrystalline iron-oxide nanoparticles (MION) contrast agent, which has a more temporally extended response function. However, using BOLD fMRI in NHP is desirable for interspecies comparison, and the faster response of the BOLD signal promises to be beneficial to rapid event-related (rER) designs. Here, we used rER BOLD fMRI in macaque monkeys while viewing real-world images, and found visual responses and category-selectivity consistent with previous studies. However, activity estimates were very noisy, suggesting that the lower contrast-to-noise ratio of BOLD, suboptimal behavioural performance, and motion artefacts, in combination, render rER BOLD fMRI challenging in NHP. Previous studies have shown that rER monkey fMRI is possible with MION, despite its prolonged response function. To understand this, we conducted simulations of the BOLD and MION response during rER designs, and found that no matter how fast the design, the greater amplitude of the MION response outweighs the contrast loss caused by greater temporal smoothing. We conclude that although any two of the three elements (rER, BOLD, NHP) have been shown to work well, the combination of all three is particularly challenging.

The connection of brain and mind has been a source of intense speculation at least since humanity became aware that the brain was the source of our behavior. Brain refers to the neurons, cells, and chemicals that govern activities of the organism. Mind is often considered consciously aware perceptions and thoughts. However, there is a gradient from unconscious to conscious, demonstrated by enormous amounts of research, such as the effects upon behavior of subliminal primes, so that mind is best considered to be the conscious and unconscious processes that act as an intermediate stage between the organism’s biology and its behavior, or a translation from one to the other.

The National Academy of Sciences Colloquium “Brain Produces Mind by Modeling” was held May 1–3, 2019 at the Arnold and Mabel Beckman Center of the National Academy of Sciences in Irvine, CA. It was organized by Richard M. Shiffrin, Danielle S. Bassett, Nikolaus Kriegeskorte, and Joshua B. Tenenbaum. The theme of the colloquium and the foundation for the set of articles in this issue of PNAS is that the “mind” consists of a model formed by the “brain”: This would be a model of the entire environment, including the self, the body, the physical environment, other agents, and the social environment. Furthermore, the model would be a best guess about the most likely state of this environment. It uses this model to learn, decide, attend, remember, perceive, predict, and produce action. This model develops as the brain matures, rapidly during infancy and more slowly later. It has structural components that remain stable over long times. It has labile elements that change at multiple time scales, adapting to the current environment and goals. The mind’s formation through modeling of the world might be likened to the way scientists build models: through a … 

[↵][1]1To whom correspondence may be addressed. Email: shiffrin{at}indiana.edu.

 [1]: #xref-corresp-1-1

Distinct fronto-temporal substrates of distributional and taxonomic similarity among words: evidence from RSA of BOLD signals

We present a novel methodology for fast bottom-up creation of large-scale semantic similarity resources to support development and evaluation of NLP systems. Our work targets verb similarity, but the methodology is equally applicable to other parts of speech. Our approach circumvents the bottleneck of slow and expensive manual development of lexical resources by leveraging semantic intuitions of native speakers and adapting a spatial multi-arrangement approach from cognitive neuroscience, used before only with visual stimuli, to lexical stimuli. Our approach critically obtains judgments of word similarity in the context of a set of related words, rather than of word pairs in isolation. We also handle lexical ambiguity as a natural consequence of a two-phase process where verbs are placed in broad semantic classes prior to the fine-grained spatial similarity judgments. Our proposed design produces a large-scale verb resource comprising 17 relatedness-based classes and a verb similarity dataset containing similarity scores for 29,721 unique verb pairs and 825 target verbs, which we release with this paper.

Spatial Multi-Arrangement for Clustering and Multi-way Similarity Dataset Construction

Controversial stimuli: adjudicating between deep neural network models of biological vision with synthetic images

An error was made in including noise ceilings for human data in Khaligh-Razavi and Kriegeskorte (2014). For comparability with the macaque data, human data were averaged across participants before analysis. Therefore the noise ceilings indicating variability across human participants do not accurately depict the upper bounds of possible model performance and should not have been shown. Creating noise ceilings appropriate for the fitted models is not trivial. Below we present a method for doing this, and the results obtained with this new method. The corrected results differ from the original results in that the best-performing model (weighted combination of AlexNet layers and category readouts) does not reach the lower bound of the noise ceiling. However, the best-performing model is not significantly below the lower bound of the noise ceiling. The claim that the model “fully explains” the human IT data appears overstated. All other claims of the paper are unaffected.

Noise ceiling on the crossvalidated performance of reweighted models of representational dissimilarity: Addendum to Khaligh-Razavi & Kriegeskorte (2014)

Faces of different people elicit distinct fMRI patterns in several face-selective regions of the human brain. Here we used representational similarity analysis to investigate what type of identity-distinguishing information is encoded in three face-selective regions: fusiform face area (FFA), occipital face area (OFA), and posterior superior temporal sulcus (pSTS). In a sample of 30 human participants (22 females, 8 males), we used fMRI to measure brain activity patterns elicited by naturalistic videos of famous face identities, and compared their representational distances in each region with models of the differences between identities. We built diverse candidate models, ranging from low-level image-computable properties (pixel-wise, GIST, and Gabor-Jet dissimilarities), through higher-level image-computable descriptions (OpenFace deep neural network, trained to cluster faces by identity), to complex human-rated properties (perceived similarity, social traits, and gender). We found marked differences in the information represented by the FFA and OFA. Dissimilarities between face identities in FFA were accounted for by differences in perceived similarity, Social Traits, Gender, and by the OpenFace network. In contrast, representational distances in OFA were mainly driven by differences in low-level image-based properties (pixel-wise and Gabor-Jet dissimilarities). Our results suggest that, although FFA and OFA can both discriminate between identities, the FFA representation is further removed from the image, encoding higher-level perceptual and social face information. SIGNIFICANCE STATEMENT Recent studies using fMRI have shown that several face-responsive brain regions can distinguish between different face identities. It is however unclear whether these different face-responsive regions distinguish between identities in similar or different ways. We used representational similarity analysis to investigate the computations within three brain regions in response to naturalistically varying videos of face identities. Our results revealed that two regions, the fusiform face area and the occipital face area, encode distinct identity information about faces. Although identity can be decoded from both regions, identity representations in fusiform face area primarily contained information about social traits, gender, and high-level visual features, whereas occipital face area primarily represented lower-level image features.

A unifying framework for understanding neural tuning and representational geometry

Deep feedforward neural network models of vision dominate in both computational neuroscience and engineering. However, the primate visual system contains abundant recurrent connections. Recurrent signal flow enables recycling of limited computational resources over time, and so might boost the performance of a physically finite brain. In particular, recurrence could improve performance in vision tasks. Here we find that recurrent convolutional networks outperform feedforward convolutional networks matched in their number of parameters in large-scale visual recognition tasks. Moreover, recurrent networks can trade off accuracy for speed, balancing the cost of error against the cost of a delayed response (and the cost of greater energy consumption). We terminate recurrent computation once the output probability distribution has concentrated beyond a predefined entropy threshold. Trained by backpropagation through time, recurrent convolutional networks resemble the primate visual system in terms of their speed-accuracy trade-off behaviour. Moreover, their learned lateral connectivity patterns are consistent with those observed in primate early visual cortex. These results suggest that recurrent models are preferable to feedforward models of vision, both in terms of their performance at vision tasks and their ability to explain biological vision.

Recurrent networks can recycle neural resources to flexibly trade speed for accuracy in visual recognition

Distinct representations of basic taste qualities in human gustatory cortex

Representation of scene layout in human OPA is fast and invariant to surface-texture

Distinct scientific theories can make similar predictions. To adjudicate between theories, we must design experiments for which the theories make distinct predictions. Here we consider the problem of comparing deep neural networks as models of human visual recognition. To efficiently compare models’ ability to predict human responses, we synthesize controversial stimuli: images for which different models produce distinct responses. We applied this approach to two visual recognition tasks, handwritten digits (MNIST) and objects in small natural images (CIFAR-10). For each task, we synthesized controversial stimuli to maximize the disagreement among models which employed different architectures and recognition algorithms. Human subjects viewed hundreds of these stimuli, as well as natural examples, and judged the probability of presence of each digit/object category in each image. We quantified how accurately each model predicted the human judgments. The best-performing models were a generative analysis-by-synthesis model (based on variational autoencoders) for MNIST and a hybrid discriminative–generative joint energy model for CIFAR-10. These deep neural networks (DNNs), which model the distribution of images, performed better than purely discriminative DNNs, which learn only to map images to labels. None of the candidate models fully explained the human responses. Controversial stimuli generalize the concept of adversarial examples, obviating the need to assume a ground-truth model. Unlike natural images, controversial stimuli are not constrained to the stimulus distribution models are trained on, thus providing severe out-of-distribution tests that reveal the models’ inductive biases. Controversial stimuli therefore provide powerful probes of discrepancies between models and human perception.

Controversial stimuli: Pitting neural networks against each other as models of human cognition

Do responses in nonhuman primate inferior temporal cortex reflect external variables or internal dynamics?

Significance Understanding the computational principles that underlie human vision is a key challenge for neuroscience and could help improve machine vision. Feedforward neural network models process their input through a deep cascade of computations. These models can recognize objects in images and explain aspects of human rapid recognition. However, the human brain contains recurrent connections within and between stages of the cascade, which are missing from the models that dominate both engineering and neuroscience. Here, we measure and model the dynamics of human brain activity during visual perception. We compare feedforward and recurrent neural network models and find that only recurrent models can account for the dynamic transformations of representations among multiple regions of visual cortex. The human visual system is an intricate network of brain regions that enables us to recognize the world around us. Despite its abundant lateral and feedback connections, object processing is commonly viewed and studied as a feedforward process. Here, we measure and model the rapid representational dynamics across multiple stages of the human ventral stream using time-resolved brain imaging and deep learning. We observe substantial representational transformations during the first 300 ms of processing within and across ventral-stream regions. Categorical divisions emerge in sequence, cascading forward and in reverse across regions, and Granger causality analysis suggests bidirectional information flow between regions. Finally, recurrent deep neural network models clearly outperform parameter-matched feedforward models in terms of their ability to capture the multiregion cortical dynamics. Targeted virtual cooling experiments on the recurrent deep network models further substantiate the importance of their lateral and top-down connections. These results establish that recurrent models are required to understand information processing in the human ventral stream.

Recurrence is required to capture the representational dynamics of the human visual system

Successful visual navigation requires a sense of the geometry of the local environment. How do our brains extract this information from retinal images? Here we visually presented scenes with all possible combinations of five scene-bounding elements (left, right and back wall, ceiling, floor) to human subjects during functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG). The fMRI response patterns in the scene-responsive occipital place area (OPA) reflected scene layout with invariance to changes in surface texture. This result contrasted sharply with the primary visual cortex (V1), which reflected low-level image features of the stimuli, and parahippocampal place area (PPA), which showed better texture than layout decoding. MEG indicated that the texture-invariant scene-layout representation is computed from visual input within ~100 ms, suggesting a rapid computational mechanism. Taken together, these results suggest that the cortical representation underlying our instant sense of the environmental geometry is located in OPA.

The visual system is an intricate network of brain regions that enables us to recognize the world around us. Despite its abundant lateral and feedback connections, human object processing is commonly viewed and studied as a feedforward process. Here, we measure and model the rapid representational dynamics across multiple stages of the human ventral stream using time-resolved brain imaging and deep learning. We observe substantial representational transformations during the first 300 ms of processing within and across ventral-stream regions. Categorical divisions emerge in sequence, cascading forward and in reverse across regions, and Granger causality analysis suggests bidirectional information flow between regions. Finally, recurrent deep neural network models clearly outperform feedforward models in terms of their ability to jointly capture the multi-region cortical dynamics. These results establish that recurrent models are required to understand information processing in the human ventral stream.

Recurrence required to capture the dynamic computations of the human ventral visual stream

Human perception decomposes the world into represented objects that are selectively attended, tracked, and predicted as we engage our surroundings. Object representations emancipate perception from the senses, enabling us to keep in mind whats out of sight, and provide a stepping stone toward more abstract symbolic cognition. Human behavioral studies have captured cognitive objects by documenting empirical phenomena including object permanence, proto-objects, and object files. Current deep neural network (DNN) models of visual object recognition, by contrast, remain largely tethered to the sensory input — despite achieving human-level performance at labeling objects in images. Here, we review the key behavioral phenomena and cognitive concepts related to perceptual objects. We then link them to early-stage neural network mechanisms that capture certain aspects of these phenomena. We argue that the human behavioral and cognitive literature provides a starting point for experimental paradigms that can not only reveal mechanisms of human cognition, but also serve as benchmarks driving development of a new class of deep neural network models of vision that will put the object into object recognition.

What is a perceptual object? Human behavioral challenges for deep neural network modeling

Neural network models and deep learning - a primer for biologists

Neural network models can now recognise images, understand text, translate languages, and play many human games at human or superhuman levels. These systems are highly abstracted, but are inspired by biological brains and use only biologically plausible computations. In the coming years, neural networks are likely to become less reliant on learning from massive labelled datasets, and more robust and generalisable in their task performance. From their successes and failures, we can learn about the computational requirements of the different tasks at which brains excel. Deep learning also provides the tools for testing cognitive theories. In order to test a theory, we need to realise the proposed information-processing system at scale, so as to be able to assess its feasibility and emergent behaviours. Deep learning allows us to scale up from principles and circuit models to end-to-end trainable models capable of performing complex tasks. There are many levels at which cognitive neuroscientists can use deep learning in their work, from inspiring theories to serving as full computational models. Ongoing advances in deep learning bring us closer to understanding how cognition and perception may be implemented in the brain -- the grand challenge at the core of cognitive neuroscience.

Representational similarity analysis (RSA) has been shown to be an effective framework to characterize brain-activity profiles and deep neural network activations as representational geometry by computing the pairwise distances of the response patterns as a representational dissimilarity matrix (RDM). However, how to properly analyze and visualize the representational geometry as dynamics over the time course from stimulus onset to offset is not well understood. In this work, we formulated the pipeline to understand representational dynamics with RDM movies and Procrustes-aligned Multidimensional Scaling (pMDS), and applied it to neural recording of monkey IT cortex. Our results suggest that the the multidimensional scaling alignment can genuinely capture the dynamics of the category-specific representation spaces with multiple visualization possibilities, and that object categorization may be hierarchical, multi-staged, and oscillatory (or recurrent).

Visualizing Representational Dynamics with Multidimensional Scaling Alignment

The goal of computational neuroscience is to find mechanistic explanations of how the nervous system processes information to give rise to cognitive function and behaviour. At the heart of the field are its models, i.e. mathematical and computational descriptions of the system being studied, which map sensory stimuli to neural responses and/or neural to behavioural responses. These models range from simple to complex. Recently, deep neural networks (DNNs) have come to dominate several domains of artificial intelligence (AI). As the term “neural network” suggests, these models are inspired by biological brains. However, current DNNs neglect many details of biological neural networks. These simplifications contribute to their computational efficiency, enabling them to perform complex feats of intelligence, ranging from perceptual (e.g. visual object and auditory speech recognition) to cognitive tasks (e.g. machine translation), and on to motor control (e.g. playing computer games or controlling a robot arm). In addition to their ability to model complex intelligent behaviours, DNNs excel at predicting neural responses to novel sensory stimuli with accuracies well beyond any other currently available model type. DNNs can have millions of parameters, which are required to capture the domain knowledge needed for successful task performance. Contrary to the intuition that this renders them into impenetrable black boxes, the computational properties of the network units are the result of four directly manipulable elements: input statistics, network structure, functional objective, and learning algorithm. With full access to the activity and connectivity of all units, advanced visualization techniques, and analytic tools to map network representations to neural data, DNNs represent a powerful framework for building task-performing models and will drive substantial insights in computational neuroscience.

Deep neural networks (DNNs) excel at complex visual recognition tasks and have successfully been used as models of visual processing in the primate brain. Because network training is computationally expensive, many computational neuroscientists rely on pre-trained networks. Yet, it is unclear in how far the obtained results will generalize, as different weight initializations might shape the learned features (despite reaching similar testing performance). Here we estimate the effects of such initialization while keeping the network architecture and training sequence identical. To investigate the learned representations, we use representational similarity analysis (RSA), a technique borrowed from neuroscience. RSA characterizes a network’s internal representations by estimating all pairwise distances across a large set of input conditions – an approach that is invariant to rotations of the underlying highdimensional activation space. Our results indicate that differently initialized DNNs trained on the same task converged on indistinguishable performance levels, but substantially differed in their intermediate and higherlevel representations. This poses a potential problem for comparing representations across networks and neural data. As a path forward, we show that biologically motivated constraints, such as Gaussian noise and ratelimited tanh activation functions can substantially improve the reliability of learned representations.

Beware of the beginnings: intermediate and higher-level representations in deep neural networks are strongly affected by weight initialization

This work was funded by a Sir Henry Wellcome Postdoctoral Fellowship (206521/Z/17/Z) to KMJ, a DFG grant CI 241-1/1 (Emmy Noether Programme) to RMC and a British Academy Postdoctoral Fellowship (PS 140117) to MM.

Deep convolutional neural networks, features, and categories perform similarly at explaining primate high-level visual representations

Feedforward models of visual processing provide human-level object-recognition performance and stateof-the-art predictions of temporally averaged neural responses. However, the primate visual system processes information through dynamic recurrent signaling. Here we characterize and model the representational dynamics of visual processing along multiple areas of the human ventral stream by combining source-reconstructed magnetoencephalography data and deep learning. Our analyses of the empirical data revealed neural responses that traverse distinct encoding schemes across time and space, in line with signatures of recurrent signaling. Next, we estimated the ability of different deep network architectures to capture the neural dynamics by using neural representational trajectories as spaceand time-varying target functions. Feedforward models, with units that ramp-up their activity over time, predicted nonlinear representational dynamics, but failed to account for the neural effects. Recurrent models of matched parametric complexity significantly better explained the held-out data. We next optimised the recurrent networks for a classification objective only. While performing significantly better than random networks, the variance explained fell short of the architecture’s capacity. This paves the way for the search for additional objectives that the ventral stream may optimize, including category-orthogonal objectives, noise, occlusion, manipulability, and semantics.

Representational dynamics in the human ventral stream captured in deep recurrent neural nets

Corrigendum: Recurrent Convolutional Neural Networks: A Better Model of Biological Object Recognition

Modern artificial neural networks have been shown to learn representations comparable to the human visual cortex. However, the degree of representational similarity greatly differs between network architectures, training data sets and other factors. Understanding what makes a deep neural network learn representations closer to the human brain and subsequently developing models that reduce the gap helps computational neuroscientists investigate the underlying mechanisms that shape neural representations. Furthermore, understanding information processing in the brain paves the way for better artificial intelligence algorithms, as human vision is known to be highly robust. In this work, we investigate the relationship between augmentation of training data and the representational similarity of convolutional neural networks with high-level visual representations in human inferior temporal cortex. Our results suggest that networks trained with heavier augmentation yield representations that are more similar between deep neural networks and the brain.

Deep neural networks trained with heavier data augmentation learn features closer to representations in hIT

Faces and voices in the brain: RSA reveals modality-general person-identity representations in the STS

Whether the human brain represents emotional stimuli as discrete categories or continuous dimensions is still widely debated. Here we directly contrasted the power of categorical and dimensional models at explaining behavior and cerebral activity in the context of perceived emotion in the voice. We combined functional magnetic resonance imaging (fMRI) and magneto-encephalography (MEG) to measure with high spatiotemporal precision the dynamics of cerebral activity in participants who listened to voice stimuli expressing a range of emotions. The participants also provided a detailed perceptual assessment of the stimuli. By using representational similarity analysis (RSA), we show that the participants’ perceptual representation of the stimuli was initially dominated by discrete categories and an early (<200ms) cerebral response. These responses showed significant associations between brain activity and the categorical model in the auditory cortex starting as early as 77ms. Furthermore, we observed strong associations between the arousal and valence dimensions and activity in several cortical and subcortical areas at later latencies (>500ms). Our results thus show that both categorical and dimensional models account for patterns of cerebral responses to emotions in voices but with a different timeline and detail as to how these patterns evolve from discrete categories to progressively refined continuous dimensions. One Sentence Summary: Emotions expressed in the voice are instantly categorized in cortical processing and their distinct qualities are refined dimensionally only later on.

From categories to dimensions: spatio-temporal dynamics of the cerebral representations of emotion in voice

Faces and voices in the brain: A modality-general person-identity representation in superior temporal sulcus

Dealing with sensory uncertainty is necessary for humans to operate in the world. Often, multiple interpretations of an event are possible given the sensory evidence, even if one interpretation is most likely. The exact neurobiological mechanism used for representing uncertainty is unknown, but there is increasing evidence that the human brain could use stochasticity to code for uncertainty. However, the convolutional neural networks (CNNs) currently used to model human vision implement deterministic mappings from input to output. We seek to use stochasticity to improve CNNs as both computer vision models and models of human visual perception. We used Gaussian unit noise and sampling to approximate Bayesian CNNs for Ecoset, a large-scale object recognition dataset. We found that sampling during both training and testing improved a CNN’s accuracy and ability to represent its own uncertainty for large-scale object recognition. We also found that sampling during both training and testing improved the ability of linear classifiers trained on internal CNN representations to predict human confidence scores for image classification. These results add to the evidence that Bayesian models predict key aspects of human object categorisation behaviour and that sampling in biological neural networks could be a means of representing uncertainty for visual perception in the human brain.

Modelling Human Visual Uncertainty using Bayesian Deep Neural Networks

We evaluated the effectiveness of prospective motion correction (PMC) on a simple visual task when no deliberate subject motion was present. The PMC system utilizes an in-bore optical camera to track an external marker attached to the participant via a custom-moulded mouthpiece. The study was conducted at two resolutions (1.5mm vs 3mm) and under three conditions (PMC On and Mouthpiece On vs PMC Off and Mouthpiece On vs PMC Off and Mouthpiece Off). Multiple data analysis methods were conducted, including univariate and multivariate approaches, and we demonstrated that the benefit of PMC is most apparent for multi-voxel pattern decoding at higher resolutions. Additional testing on two participants showed that our inexpensive, commercially available mouthpiece solution produced comparable results to a dentist-moulded mouthpiece. Our results showed that PMC is increasingly important at higher resolutions for analyses that require accurate voxel registration across time.

Prospective motion correction improves the sensitivity of fMRI pattern decoding

Testing two potentially multivariate variables for statistical dependence on the basis finite samples is a fundamental statistical challenge. Here we explore a family of tests that adapt to the complexity of the relationship between the variables, promising robust power across scenarios. Building on the distance correlation, we introduce a family of adaptive independence criteria based on nonlinear monotonic transformations of distances. We show that these criteria, like the distance correlation and RKHS-based criteria, provide dependence indicators. We propose a class of adaptive (multi-threshold) test statistics, which form the basis for permutation tests. These tests empirically outperform some of the established tests in average and worst-case statistical sensitivity across a range of univariate and multivariate relationships, offer useful insights to the data and may deserve further exploration.

Brain computation can be understood as the transformation of representations across stages of processing. The content and format of a representation is reflected in the geometry of stimulus-related response patterns. Here we characterize the representations along the human ventral visual pathway with a new visualization technique called “hypersphere2sphere” (H2S). It takes as input a labeled set of points in a high-dimensional space (the multivariate response space of each cortical region) and fits a hypersphere to represent each category. It visualizes these high-dimensional hyperspheres as a set of spheres in 3D (or circles in 2D), revealing their relative sizes, separations, and overlaps. Using functional magnetic resonance imaging (fMRI), we measured response patterns to 48 images from four categories (faces, bodies, inanimate objects, and scenes). We computed unbiased distance estimates in representational space using crossvalidation. With H2S, we observed the emergence of response pattern clustering, based on category, at the level of the lateral occipital complex. Categories also occupy nonoverlapping hyperspheres in faceand place-selective areas, with faces most spread in the former and scenes in the latter. H2S provides a useful perspective on highdimensional representational geometries that promises new insights on the basis of hemodynamic and electrophysiological brain-activity measurements.

Visualizing the global geometry of population representations of multiple visual object categories with spheres

Testing two potentially multivariate variables for statistical dependence on the basis finite samples is a fundamental statistical challenge. Here we explore a family of tests that adapt to the complexity of the relationship between the variables, promising robust power across scenarios. Building on the distance correlation, we introduce a family of adaptive independence criteria based on nonlinear monotonic transformations of distances. We show that these criteria, like the distance correlation and RKHS-based criteria, provide dependence indicators. We propose a class of adaptive (multi-threshold) test statistics, which form the basis for permutation tests. These tests empirically outperform some of the established tests in average and worst-case statistical sensitivity across a range of univariate and multivariate relationships and might deserve further exploration.

Most connectivity metrics in neuroimaging research reduce multivariate activity patterns in regions-of-interests (ROIs) to one dimension, which leads to a loss of information. Importantly, it prevents us from investigating the transformations between patterns in different ROIs. Here, we applied linear estimation theory in order to robustly estimate the linear transformations between multivariate fMRI patterns with a cross-validated Tikhonov regularisation approach. We derived three novel metrics that describe different features of these voxel-by-voxel mappings: goodness-of-fit, sparsity and pattern deformation. The goodness-of-fit describes the degree to which the patterns in an input region can be described as a linear transformation of patterns in an output region. The sparsity metric, which relies on a Monte Carlo procedure, was introduced in order to test whether the transformation mostly consists of one-to-one mappings between voxels in different regions. Furthermore, we defined a metric for pattern deformation, i.e. the degree to which the transformation rotates or rescales the input patterns. As a proof of concept, we applied these metrics to an event-related fMRI data set consisting of four subjects that has been used in previous studies. We focused on the transformations from early visual cortex (EVC) to inferior temporal cortex (ITC), fusiform face area (FFA) and parahippocampal place area (PPA). Our results suggest that the estimated linear mappings are able to explain a significant amount of variance of the three output ROIs. The transformation from EVC to ITC shows the highest goodness-of-fit, and those from EVC to FFA and PPA show the expected preference for faces and places as well as animate and inanimate objects, respectively. The pattern transformations are sparse, but sparsity is lower than would have been expected for one-to-one mappings, thus suggesting the presence of one-to-few voxel mappings. ITC, FFA and PPA patterns are not simple rotations of an EVC pattern, indicating that the corresponding transformations amplify or dampen certain dimensions of the input patterns. While our results are only based on a small number of subjects, they show that our pattern transformation metrics can describe novel aspects of multivariate functional connectivity in neuroimaging data.

Analysing linear multivariate pattern transformations in neuroimaging data

Feedforward neural networks provide the dominant model of how the brain performs visual object recognition. However, these networks lack the lateral and feedback connections, and the resulting recurrent neuronal dynamics, of the ventral visual pathway in the human and nonhuman primate brain. Here we investigate recurrent convolutional neural networks with bottom-up (B), lateral (L), and top-down (T) connections. Combining these types of connections yields four architectures (B, BT, BL, and BLT), which we systematically test and compare. We hypothesized that recurrent dynamics might improve recognition performance in the challenging scenario of partial occlusion. We introduce two novel occluded object recognition tasks to test the efficacy of the models, digit clutter (where multiple target digits occlude one another) and digit debris (where target digits are occluded by digit fragments). We find that recurrent neural networks outperform feedforward control models (approximately matched in parametric complexity) at recognising objects, both in the absence of occlusion and in all occlusion conditions. Recurrent networks were also found to be more robust to the inclusion of additive Gaussian noise. Recurrent neural networks are better in two respects: (1) they are more neurobiologically realistic than their feedforward counterparts; (2) they are better in terms of their ability to recognise objects, especially under challenging conditions. This work shows that computer vision can benefit from using recurrent convolutional architectures and suggests that the ubiquitous recurrent connections in biological brains are essential for task performance.

Recurrent Convolutional Neural Networks: A Better Model of Biological Object Recognition

As deep neural networks (DNNs) are applied to increasingly challenging problems, they will need to be able to represent their own uncertainty. Modeling uncertainty is one of the key features of Bayesian methods. Using Bernoulli dropout with sampling at prediction time has recently been proposed as an efficient and well performing variational inference method for DNNs. However, sampling from other multiplicative noise based variational distributions has not been investigated in depth. We evaluated Bayesian DNNs trained with Bernoulli or Gaussian multiplicative masking of either the units (dropout) or the weights (dropconnect). We tested the calibration of the probabilistic predictions of Bayesian convolutional neural networks (CNNs) on MNIST and CIFAR-10. Sampling at prediction time increased the calibration of the DNNs’ probabalistic predictions. Sampling weights, whether Gaussian or Bernoulli, led to more robust representation of uncertainty compared to sampling of units. However, using either Gaussian or Bernoulli dropout led to increased test set classification accuracy. Based on these findings we used both Bernoulli dropout and Gaussian dropconnect concurrently, which we show approximates the use of a spike-and-slab variational distribution without increasing the number of learned parameters. We found that spike-and-slab sampling had higher test set performance than Gaussian dropconnect and more robustly represented its uncertainty compared to Bernoulli dropout.

Robustly representing uncertainty through sampling in deep neural networks

This record contains all presentations, recordings, programme and notes from the event "Helping Reseachers Publish in Sciences, Technology, Engineering and Mathematics", held at the University of Cambridge, Betty and Gordon Moore Library on 8 February 2017.

Presentations and notes from the Helping STEM Researchers Publish event on 8 February 2017

Functional readout analysis reveals nonlinear representational transformation from early visual to category-selective regions

Abstract Building machines that learn and think like humans is essential not only for cognitive science, but also for computational neuroscience, whose ultimate goal is to understand how cognition is implemented in biological brains. A new cognitive computational neuroscience should build cognitive-level and neural-level models, understand their relationships, and test both types of models with both brain and behavioral data.

Local opposite orientation preferences in V1: fMRI sensitivity to fine-grained pattern information

Categorical selectivity in the visual pathway revealed by fMRI in awake macaques

Recent advances in Deep convolutional Neural Networks (DNNs) have enabled unprecedentedly accurate computational models of brain representations, and present an exciting opportunity to model diverse cognitive functions. State-of-the-art DNNs achieve human-level performance on object categorisation, but it is unclear how well they capture human behavior on complex cognitive tasks. Recent reports suggest that DNNs can explain significant variance in one such task, judging object similarity. Here, we extend these findings by replicating them for a rich set of object images, comparing performance across layers within two DNNs of different depths, and examining how the DNNs’ performance compares to that of non-computational “conceptual” models. Human observers performed similarity judgments for a set of 92 images of real-world objects. Representations of the same images were obtained in each of the layers of two DNNs of different depths (8-layer AlexNet and 16-layer VGG-16). To create conceptual models, other human observers generated visual-feature labels (e.g., “eye”) and category labels (e.g., “animal”) for the same image set. Feature labels were divided into parts, colors, textures and contours, while category labels were divided into subordinate, basic, and superordinate categories. We fitted models derived from the features, categories, and from each layer of each DNN to the similarity judgments, using representational similarity analysis to evaluate model performance. In both DNNs, similarity within the last layer explains most of the explainable variance in human similarity judgments. The last layer outperforms almost all feature-based models. Late and mid-level layers outperform some but not all feature-based models. Importantly, categorical models predict similarity judgments significantly better than any DNN layer. Our results provide further evidence for commonalities between DNNs and brain representations. Models derived from visual features other than object parts perform relatively poorly, perhaps because DNNs more comprehensively capture the colors, textures and contours which matter to human object perception. However, categorical models outperform DNNs, suggesting that further work may be needed to bring high-level semantic representations in DNNs closer to those extracted by humans. Modern DNNs explain similarity judgments remarkably well considering they were not trained on this task, and are promising models for many aspects of human cognition.

Deep Convolutional Neural Networks Outperform Feature-Based But Not Categorical Models in Explaining Object Similarity Judgments

Abstract Language comprehension engages a distributed network of frontotemporal, parietal, and sensorimotor regions, but it is still unclear how meaning of words and their semantic relationships are represented and processed within these regions and to which degrees lexico‐semantic representations differ between regions and semantic types. We used fMRI and representational similarity analysis to relate word‐elicited multivoxel patterns to semantic similarity between action and object words. In left inferior frontal (BA 44‐45‐47), left posterior middle temporal and left precentral cortex, the similarity of brain response patterns reflected semantic similarity among action‐related verbs, as well as across lexical classes‐between action verbs and tool‐related nouns and, to a degree, between action verbs and food nouns, but not between action verbs and animal nouns. Instead, posterior inferior temporal cortex exhibited a reverse response pattern, which reflected the semantic similarity among object‐related nouns, but not action‐related words. These results show that semantic similarity is encoded by a range of cortical areas, including multimodal association (e.g., anterior inferior frontal, posterior middle temporal) and modality‐preferential (premotor) cortex and that the representational geometries in these regions are partly dependent on semantic type, with semantic similarity among action‐related words crossing lexical‐semantic category boundaries.

Representational Similarity Mapping of Distributional Semantics in Left Inferior Frontal, Middle Temporal, and Motor Cortex

Faces are salient social stimuli whose features attract a stereotypical pattern of fixations. The implications of this gaze behavior for perception and brain activity are largely unknown. Here, we characterize and quantify a retinotopic bias implied by typical gaze behavior toward faces, which leads to eyes and mouth appearing most often in the upper and lower visual field, respectively. We found that the adult human visual system is tuned to these contingencies. In two recognition experiments, recognition performance for isolated face parts was better when they were presented at typical, rather than reversed, visual field locations. The recognition cost of reversed locations was equal to ∼60% of that for whole face inversion in the same sample. Similarly, an fMRI experiment showed that patterns of activity evoked by eye and mouth stimuli in the right inferior occipital gyrus could be separated with significantly higher accuracy when these features were presented at typical, rather than reversed, visual field locations. Our findings demonstrate that human face perception is determined not only by the local position of features within a face context, but by whether features appear at the typical retinotopic location given normal gaze behavior. Such location sensitivity may reflect fine-tuning of category-specific visual processing to retinal input statistics. Our findings further suggest that retinotopic heterogeneity might play a role for face inversion effects and for the understanding of conditions affecting gaze behavior toward faces, such as autism spectrum disorders and congenital prosopagnosia. SIGNIFICANCE STATEMENT Faces attract our attention and trigger stereotypical patterns of visual fixations, concentrating on inner features, like eyes and mouth. Here we show that the visual system represents face features better when they are shown at retinal positions where they typically fall during natural vision. When facial features were shown at typical (rather than reversed) visual field locations, they were discriminated better by humans and could be decoded with higher accuracy from brain activity patterns in the right occipital face area. This suggests that brain representations of face features do not cover the visual field uniformly. It may help us understand the well-known face-inversion effect and conditions affecting gaze behavior toward faces, such as prosopagnosia and autism spectrum disorders.

Perception and Processing of Faces in the Human Brain Is Tuned to Typical Feature Locations

Fixed versus mixed RSA: Explaining visual representations by fixed and mixed feature sets from shallow and deep computational models

As deep neural networks (DNNs) are applied to increasingly challenging problems, they will need to be able to represent their own uncertainty. Modeling uncertainty is one of the key features of Bayesian methods. Scalable Bayesian DNNs that use dropout-based variational distributions have recently been proposed. Here we evaluate the ability of Bayesian DNNs trained with Bernoulli or Gaussian distributions over units (dropout) or weights (dropconnect) to represent their own uncertainty at the time of inference through sampling. We tested how well Bayesian fully connected and convolutional DNNs represented their own uncertainty in classifying the MNIST handwritten digits. By adding different levels of Gaussian noise to the test images, we assessed how DNNs represented their uncertainty about regions of input space not covered by the training set. Bayesian DNNs estimated their own uncertainty more accurately than traditional DNNs with a softmax output. These results are important for building better deep learning systems and for investigating the hypothesis that biological neural networks use sampling to represent uncertainty.

Representation of uncertainty in deep neural networks through sampling

Visual features versus categories: Explaining object representations in primate IT and deep neural networks with weighted representational modeling

Mixing deep neural network features to explain brain representations

Given concerns about the reproducibility of scientific findings, neuroimaging must define best practices for data analysis, results reporting, and algorithm and data sharing to promote transparency, reliability and collaboration. We describe insights from developing a set of recommendations on behalf of the Organization for Human Brain Mapping and identify barriers that impede these practices, including how the discipline must change to fully exploit the potential of the world's neuroimaging data.

Best practices in data analysis and sharing in neuroimaging using MRI

Representational distinctions within categories are important in all perceptual modalities and also in cognitive and motor representations. Recent pattern-information studies of brain activity have used condition-rich designs to sample the stimulus space more densely. To test whether brain response patterns discriminate among a set of stimuli (e.g. exemplars within a category) with good sensitivity, we can pool statistical evidence over all pairwise comparisons. A popular test statistic reflecting exemplar information is the exemplar discriminability index (EDI), which is defined as the average of the pattern dissimilarity estimates between different exemplars minus the average of the pattern dissimilarity estimates between repetitions of identical exemplars. The EDI is commonly tested with a t test (H0: population mean EDI = 0) across subjects (subject as random effect). However, it is unclear whether this approach is either valid or optimal. Here we describe a wide range of statistical tests of exemplar discriminability and assess the validity (specificity) and power (sensitivity) of each test. The tests include previously used and novel, parametric and nonparametric tests, which treat subject as a random or fixed effect, and are based on different dissimilarity measures, different test statistics, and different inference procedures. We use simulated and real data to determine which tests are valid and which are most sensitive. The popular across-subject t test of the EDI (typically using correlation distance as the pattern dissimilarity measure) requires the assumption that the EDI is 0-mean normal under H0, which is not strictly true. Reassuringly, our simulations suggest that the test controls the false-positives rate at the nominal level and is thus valid in practice. However, test statistics based on average Mahalanobis distances or average linear-discriminant t values (both accounting for the multivariate error covariance among responses) are substantially more powerful for both random- and fixed-effects inference. We suggest preferred procedures for safely and sensitively detecting subtle pattern differences between exemplars.

© Kriegeskorte This article is distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and redistribution in any medium, provided that the original author and source are credited. Preprint posting is the right thing to do for science and society. It enables us to share our results earlier, speeding up the pace of science. It also enables us to catch errors earlier, minimising the risk of alerting the world to our findings (through a high-impact publication) before the science is solid. Importantly, preprints ensure long-term open access to our results for scientists and for the public. Preprints can be rapidly posted for free on arXiv and bioRxiv, enabling instant open access.

As deep neural networks (DNNs) are applied to increasingly challenging problems, they will need to be able to represent their own uncertainty. Modeling uncertainty is one of the key features of Bayesian methods. Using Bernoulli dropout with sampling at prediction time has recently been proposed as an efficient and well performing variational inference method for DNNs. However, sampling from other multiplicative noise based variational distributions has not been investigated in depth. We evaluated Bayesian DNNs trained with Bernoulli or Gaussian multiplicative masking of either the units (dropout) or the weights (dropconnect). We tested the calibration of the probabilistic predictions of Bayesian convolutional neural networks (CNNs) on MNIST and CIFAR-10. Sampling at prediction time increased the calibration of the DNNs' probabalistic predictions. Sampling weights, whether Gaussian or Bernoulli, led to more robust representation of uncertainty compared to sampling of units. However, using either Gaussian or Bernoulli dropout led to increased test set classification accuracy. Based on these findings we used both Bernoulli dropout and Gaussian dropconnect concurrently, which we show approximates the use of a spike-and-slab variational distribution without increasing the number of learned parameters. We found that spike-and-slab sampling had higher test set performance than Gaussian dropconnect and more robustly represented its uncertainty compared to Bernoulli dropout.

Robustly representing uncertainty in deep neural networks through sampling

Robustly representing inferential uncertainty in deep neural networks through sampling

SUBMISSION DETAILS Presentation Type Oral Presentation Presentation Abstract Summary The primate visual system can be understood as a hierarchical feedforward system that transforms visual input into meaning via a range of linear and nonlinear transformations. The feedforward framework is very successful; however, it ignores temporal dynamics. Temporal dynamics might be highly relevant for object recognition. Here, we analyze single-unit recordings from monkey high-level visual cortex, i.e. inferior temporal cortex, to examine the temporal dynamics of neural population coding of object images. We show that both withinand between category distinctions arise early (80 ms after stimulus onset). Within-category distinctions can be explained by low-level features computed from the input image, while between-category distinctions cannot, especially at later time points after stimulus onset (> 125 ms). These results suggest that the IT code reflects both visual similarity and category distinctions and that the latter might require some recurrent processing to emerge. Paper Upload (PDF) CNN2017.pdf Co-author Information

Representational dynamics: the temporal evolution of neural population coding in nonhuman primate inferior temporal cortex

The perceptual representation of individual faces is often explained with reference to a norm-based face space. In such spaces, individuals are encoded as vectors where identity is primarily conveyed by direction and distinctiveness by eccentricity. Here we measured human fMRI responses and psychophysical similarity judgments of individual face exemplars, which were generated as realistic 3D animations using a computer-graphics model. We developed and evaluated multiple neurobiologically plausible computational models, each of which predicts a representational distance matrix and a regional-mean activation profile for 24 face stimuli. In the fusiform face area, a face-space coding model with sigmoidal ramp tuning provided a better account of the data than one based on exemplar tuning. However, an image-processing model with weighted banks of Gabor filters performed similarly. Accounting for the data required the inclusion of a measurement-level population averaging mechanism that approximates how fMRI voxels locally average distinct neuronal tunings. Our study demonstrates the importance of comparing multiple models and of modeling the measurement process in computational neuroimaging. Author Summary Humans recognize conspecifics by their faces. Understanding how faces are recognized is an open computational problem with relevance to theories of perception, social cognition, and the engineering of computer vision systems. Here we measured brain activity with functional MRI while human participants viewed individual faces. We developed multiple computational models inspired by known response preferences of single neurons in the primate visual cortex. We then compared these neuronal models to patterns of brain activity corresponding to individual faces. The data were consistent with a model where neurons respond to directions in a high-dimensional space of faces. It also proved essential to model how functional MRI voxels locally average the responses of tens of thousands of neurons. The study highlights the challenges in adjudicating between alternative computational theories of visual information processing.

Adjudicating between face-coding models with individual-face fMRI responses

Meaningful feedback to occluded V1 is improved by increasing local information in the surround

Perceptual similarity of visual patterns predicts dynamic neural activation patterns measured with MEG

Crossvalidation is a method for estimating predictive performance and adjudicating between multiple models. On each of k folds of the process, k-1 of k independent subsets of the data (training set) are used to fit the parameters of each model and the left-out subset (test set) is used to estimate predictive performance. The method is statistically efficient, because training data are reused for testing and performance estimates combined across folds. The method requires no assumptions, provides nearly unbiased (slightly conservative) estimates of predictive performance, and is generally applicable because it amounts to a direct empirical test of each model.

Visual processing involves feedforward and recurrent signals. Understanding which computations are performed in the feedforward sweep and which require recurrent processing has been challenging. We used fMRI and MEG to characterize the spatial and temporal components of human visual object representations. In the fMRI experiment, we used brief stimulus presentation (16.7ms) and a backward masking paradigm with short and long interstimulus intervals (ISI) to distinguish the contributions of feedforward and recurrent processing. In the short-ISI trials, the mask was presented 37ms after stimulus onset (ISI=20ms), interfering with recurrent processing. In the long-ISI trials, the mask appears only 1017ms after stimulus onset (ISI=1000ms), leaving time for recurrent processing. Representations of a set of animate/inanimate object photos were characterised by their representational dissimilarity matrices (RDMs). We observed no change of the representational geometry with recurrent processing in early visual cortex (EVC). In human inferior temporal (hIT) cortex, however, the representation was transformed as a result of recurrent processing. Long-ISI trials (enabling more extended recurrent processing) were associated with stronger clustering of artificial inanimate objects and more prominent human-body clusters. By contrast, human faces were more clustered in the short-ISI trials. We also compared the fMRI RDMs with RDM movies computed from MEG sensor patterns. The MEG-to-fMRI RDM correlations for the long-ISI fMRI data peaked later (126ms) than for the short-ISI fMRI data (75ms), suggesting that computations occurring at longer latencies after stimulus onset actually contribute to the representational geometry observed with fMRI in long-ISI trials. The MEG results further suggested that the categorical divisions observed in hIT (e.g. animate vs. inanimate) emerge dynamically, with the latency of categoricality peaks suggesting a role for recurrent processing. Our study demonstrates that object representations in hIT evolve with recurrent processing in a way that strengthens categorical divisions in the representational geometry. Meeting abstract presented at VSS 2015.

The effects of recurrent dynamics on ventral-stream representational geometry.

Real-world time-continuous stimuli such as video promise greater naturalism for studies of brain function. However, modeling the stimulus variation is challenging and introduces a bias in favor of particular descriptive dimensions. Alternatively, we can look for brain regions whose signal is correlated between subjects, essentially using one subject to model another. Intersubject correlation mapping (ICM) allows us to find brain regions driven in a canonical manner across subjects by a complex natural stimulus. However, it requires a direct voxel-to-voxel match between the spatiotemporal activity patterns and is thus only sensitive to common activations sufficiently extended to match up in Talairach space (or in an alternative, e.g. cortical-surface-based, common brain space). Here we introduce the more general approach of intersubject information mapping (IIM). For each brain region, IIM determines how much information is shared between the subjects' local spatiotemporal activity patterns. We estimate the intersubject mutual information using canonical correlation analysis applied to voxels within a spherical searchlight centered on each voxel in turn. The intersubject information estimate is invariant to linear transforms including spatial rearrangement of the voxels within the searchlight. This invariance to local encoding will be crucial in exploring fine-grained brain representations, which cannot be matched up in a common space and, more fundamentally, might be unique to each individual – like fingerprints. IIM yields a continuous brain map, which reflects intersubject information in fine-grained patterns. Performed on data from functional magnetic resonance imaging (fMRI) of subjects viewing the same television show, IIM and ICM both highlighted sensory representations, including primary visual and auditory cortices. However, IIM revealed additional regions in higher association cortices, namely temporal pole and orbitofrontal cortex. These regions appear to encode the same information across subjects in their fine-grained patterns, although their spatial-average activation was not significantly correlated between subjects.

Intersubject information mapping: revealing canonical representations of complex natural stimuli

Analyzing functional magnetic resonance imaging (fMRI) pattern similarity is becoming increasingly popular because it allows one to relate distributed patterns of voxel activity to continuous perceptual and cognitive states of the human brain. Here we show that fMRI pattern similarity estimates are severely affected by temporal pattern drifts in fMRI data – even after voxel-wise detrending. For this particular dataset, the drift effect obscures orientation information as measured by fMRI pattern dissimilarities. We demonstrate that orientation information can be recovered using three different methods: 1. Regressing out the drift component through linear modeling; 2. Computing representational distances between conditions measured in independent imaging runs; 3. Crossvalidation of pattern distance estimates. One possible source of temporal pattern drift could be random walk like fluctuations — physiological or scanner related — occurring within single voxel timecourses. This explanation is consistent with voxel-wise detrending not alleviating pattern drift effects. In addition, this would explain why crossvalidated pattern distances are robust to temporal drift because a random walk process is expected to give rise to non-replicable drift directions. Given these findings, we recommend that future fMRI studies take pattern drift into account when analyzing pattern similarity as this can greatly enhance the sensitivity to experimental effects of interest.

Mind the drift - improving sensitivity to fMRI pattern information by accounting for temporal pattern drift

Visual representations are dominated by intrinsic fluctuations correlated between areas

Face space provides a popular metaphor for the representation of individual faces. Although computer-graphics models of face space have a long history, their relationship to the cortical code for individual faces remains unclear. We used such a model to generate animations of faces with realistic 3D shape and texture and analyzed fMRI responses to each individual face. We developed and evaluated multiple neurobiologically plausible computational models of face-space coding, each of which predicts a representational geometry and a regional-mean activation profile. A population code of units with sigmoidal ramp tuning over the face-space dimensions explained both pattern and regional-mean fMRI effects better than alternative models, but only in conjunction with a readout-level population averaging mechanism. This model also accounted for perceptual similarity judgments. Our study demonstrates the importance of modeling readout-level population averaging and provides a computational account of the cortical representation underlying human face processing.

Ramp coding with population averaging predicts human cortical face-space representations and perception

A number of studies have shown that visual working memory (WM) is poorer for complex versus simple items, traditionally accounted for by higher information load placing greater demands on encoding and storage capacity limits. Other research suggests that it may not be complexity that determines WM performance per se, but rather increased perceptual similarity between complex items as a result of a large amount of overlapping information. Increased similarity is thought to lead to greater comparison errors between items encoded into WM and the test item(s) presented at retrieval. However, previous studies have used different object categories to manipulate complexity and similarity, raising questions as to whether these effects are simply due to cross-category differences. For the first time, here the relationship between complexity and similarity in WM using the same stimulus category (abstract polygons) are investigated. The authors used a delayed discrimination task to measure WM for 1-4 complex versus simple simultaneously presented items and manipulated the similarity between the single test item at retrieval and the sample items at encoding. WM was poorer for complex than simple items only when the test item was similar to 1 of the encoding items, and not when it was dissimilar or identical. The results provide clear support for reinterpretation of the complexity effect in WM as a similarity effect and highlight the importance of the retrieval stage in governing WM performance. The authors discuss how these findings can be reconciled with current models of WM capacity limits.

Similarity, not complexity, determines visual working memory performance.

Recent advances in neural network modelling have enabled major strides in computer vision and other artificial intelligence applications. Human-level visual recognition abilities are coming within reach of artificial systems. Artificial neural networks are inspired by the brain and their computations could be implemented in biological neurons. Convolutional feedforward networks, which now dominate computer vision, take further inspiration from the architecture of the primate visual hierarchy. However, the current models are designed with engineering goals and not to model brain computations. Nevertheless, initial studies comparing internal representations between these models and primate brains find surprisingly similar representational spaces. With human-level performance no longer out of reach, we are entering an exciting new era, in which we will be able to build neurobiologically faithful feedforward and recurrent computational models of how biological brains perform high-level feats of intelligence, including vision.

Deep neural networks: a new framework for modelling biological vision and brain information processing

We previously demonstrated an fMRI protocol for estimating population receptive fields (pRFs) of individual voxels in face-selective regions of ventral temporal cortex (Kay VSS 2014). Moreover, we demonstrated that pRF properties depend substantially on the attentional task performed by the subject. However, it is unknown how pRF properties might relate to behavior. We conducted a psychophysical experiment in which subjects judged the gender of faces presented at different visual field locations (1 central location + 8 angles x 5 eccentricities up to 12° = 41 locations) while maintaining central fixation. Each trial consisted of an 800-ms cue indicating the location of the upcoming face, a 500-ms gap, and an 800-ms face. As expected, as the eccentricity of the face increased, accuracy levels decreased and reaction times increased. Next, we attempted to predict the reaction times based on the pRFs estimated from the fMRI experiment. For each face location, we computed the predicted BOLD activity in each voxel based on its pRF and averaged activity across voxels in each region of interest (ROI). We then correlated the predicted activity for different face locations against the median reaction time observed for each location. We found near-perfect prediction of reaction time using activity in mFus-faces/FFA-2 (subject 1: r = -0.96, noise ceiling = -0.99; subject 2: r = -0.75, noise ceiling = -0.82). Furthermore, predictions were best when using (i) pRFs from the same subject (subject specificity), (ii) pRFs in mFus-faces/FFA2 as opposed to pRFs in pFus-faces/FFA1 or IOG-faces/OFA (ROI specificity), and (iii) pRFs estimated while subjects performed a face-related task (task specificity). These results suggest that neural activity in mFus provides critical information for face-related judgments and that this information is linearly accumulated over time. Consequently, low activity levels in mFus lead to long integration times and produce long reaction times. Meeting abstract presented at VSS 2015.

Near-perfect prediction of reaction time for face gender judgments based on activity in ventral temporal cortex.

*contributed equally What makes two faces appear similar to each other? We examined how the dissimilarity of pairs of faces depend upon the faces' features. We used the Basel Face Space (BFS), a high dimensional coordinate system where axes control facial features and each point is an individual face, to synthesize photorealistic faces. We generated pairs of faces that varied systematically in the angle separating them in the space (θ), and in their distances from the average face (r1 and r2). We used a novel method to collect dissimilarity judgments, in which subjects (n=26) placed each pair of faces vertically on a large touch screen to indicate how dissimilar the two faces appeared. The vertical axis was anchored by reference points denoting identicality and total dissimilarity: pairs of identical face at the bottom of the screen, and pairs of BFS antifaces at the top. We asked to what extent different functions of the BFS coordinates of two faces can predict face dissimilarity judgements. Candidate functions for predicting perceived dissimilarity included (a) linear and (b) sigmoid functions of (1) the BFS Euclidean distance between two faces and (2) linear combinations of the polar angle between faces (θ), and the two eccentricities (r1, r2) of the faces. We fitted models with half the data and compared their predictive performance on the other half. A sigmoid function of Euclidean distance in BFS provided a reasonable approximation to dissimilarity judgments. However, preliminary evidence suggests that similarity does not fall off exactly isotropically in face space as we move away from a reference face in different directions. We relate the results to predictions of alternative models of neuronal coding, including norm-based and exemplar-tuning models. Our results show that BFS provides a useful quantitative model for investigating the representation of faces and predicting perceptual judgments. Meeting abstract presented at VSS 2015.

Perceptual similarity is a cognitive judgment that represents the end-stage of a complex cascade of hierarchical processing throughout visual cortex. Previous studies have shown a correspondence between the similarity of coarse-scale fMRI activation patterns and the perceived similarity of visual stimuli, suggesting that visual objects that appear similar also share similar underlying patterns of neural activation. Here we explore the temporal relationship between the human brain's time-varying representation of visual patterns and behavioral judgments of perceptual similarity. The visual stimuli were abstract patterns constructed from identical perceptual units (oriented Gabor patches) so that each pattern had a unique global form or perceptual 'Gestalt'. The visual stimuli were decodable from evoked neural activation patterns measured with magnetoencephalography (MEG), however, stimuli differed in the similarity of their neural representation as estimated by differences in decodability. Early after stimulus onset (from 50ms), a model based on retinotopic organization predicted the representational similarity of the visual stimuli. Following the peak correlation between the retinotopic model and neural data at 80ms, the neural representations quickly evolved so that retinotopy no longer provided a sufficient account of the brain's time-varying representation of the stimuli. Overall the strongest predictor of the brain's representation was a model based on human judgments of perceptual similarity, which reached the limits of the maximum correlation with the neural data defined by the 'noise ceiling'. Our results show that large-scale brain activation patterns contain a neural signature for the perceptual Gestalt of composite visual features, and demonstrate a strong correspondence between perception and complex patterns of brain activity.

Perceptual similarity of visual patterns predicts the similarity of their dynamic neural activation patterns measured with MEG

Deep neural networks (DNNs) provide useful models of visual representational transformations. We present a method that enables a DNN (student) to learn from the internal representational spaces of a reference model (teacher), which could be another DNN or, in the future, a biological brain. Representational spaces of the student and the teacher are characterized by representational distance matrices (RDMs). We propose representational distance learning (RDL), a stochastic gradient descent method that drives the RDMs of the student to approximate the RDMs of the teacher. We demonstrate that RDL is competitive with other transfer learning techniques for two publicly available benchmark computer vision datasets (MNIST and CIFAR-100), while allowing for architectural differences between student and teacher. By pulling the student's RDMs toward those of the teacher, RDL significantly improved visual classification performance when compared to baseline networks that did not use transfer learning. In the future, RDL may enable combined supervised training of deep neural networks using task constraints (e.g., images and category labels) and constraints from brain-activity measurements, so as to build models that replicate the internal representational spaces of biological brains.

Visual features as stepping stones toward semantics: Explaining object similarity in IT and perception with non-negative least squares

Faciotopy—A face-feature map with face-like topology in the human occipital face area

Retinotopic priors for eyes and mouth in face perception and face sensitive cortex

How does the brain translate an internal representation of an object into a decision about the object's category? Recent studies have uncovered the structure of object representations in inferior temporal cortex (IT) using multivariate pattern analysis methods. These studies have shown that representations of individual object exemplars in IT occupy distinct locations in a high-dimensional activation space, with object exemplar representations clustering into distinguishable regions based on category (e.g., animate vs. inanimate objects). In this study, we hypothesized that a representational boundary between category representations in this activation space also constitutes a decision boundary for categorization. We show that behavioral RTs for categorizing objects are well described by our activation space hypothesis. Interpreted in terms of classical and contemporary models of decision-making, our results suggest that the process of settling on an internal representation of a stimulus is itself partially constitutive of decision-making for object categorization.

Reaction Time for Object Categorization Is Predicted by Representational Distance

Visual processing in cortex happens through a hierarchy of increasingly sophisticated representations. Here we explore a very wide range of model representations (29 models), testing their categorization performance (animate/inanimate) and their ability to account for the representational geometry of brain regions along the visual hierarchy (V1, V2, V3, V4, and LO). We also created new model instantiations (85 model instantiations in total) by reweighting and remixing of the model features. Reweighting and remixing was based on brain responses to an independent training set of 1750 images. We assessed the models with representational similarity analysis (RSA), which characterizes the geometry of a representation by a representational dissimilarity matrix (RDM). In this study, the RDM is either computed on the basis of the model features or on the basis of predicted voxel responses. Voxel responses are predicted by linear combinations of the model features. The model features are linearly remixed so as to best explain the voxel responses (as in voxel/population receptive-field modelling). This new approach of combining RSA with voxel receptive field modelling may help bridge the gap between the two methods. We found that early visual areas are best accounted for by a Gabor wavelet pyramid (GWP) model. The GWP implementations we used performed similarly with and without remixing, suggesting that the original features already approximate the representational space, obviating the need for remixing or reweighting. The lateral occipital region (LO), a higher visual representation, was best explained by the higher layers of a deep convolutional network (Krizhevsky et al., 2012). However, this model could explain the LO representation only after appropriate remixing of its feature set. Remixed RSA takes a step in an important direction, where each computational model representation is explored more broadly by considering not only its representational geometry, but the set of all geometries within reach of a linear transform. The exploration of many models and many brain areas may lead to a better understanding of the processing stages in the visual hierarchy, from low-level image representations in V1 to visuo-semantic representations in higher-level visual areas.

Explaining the hierarchy of visual representational geometries by remixing of features from many computational vision models

Intrinsic cortical dynamics are thought to underlie trial-to-trial variability of visually evoked responses in animal models. Understanding their function in the context of sensory processing and representation is a major current challenge. Here we report that intrinsic cortical dynamics strongly affect the representational geometry of a brain region, as reflected in response-pattern dissimilarities, and exaggerate the similarity of representations between brain regions. We characterized the representations in several human visual areas by representational dissimilarity matrices (RDMs) constructed from fMRI response-patterns for natural image stimuli. The RDMs of different visual areas were highly similar when the response-patterns were estimated on the basis of the same trials (sharing intrinsic cortical dynamics), and quite distinct when patterns were estimated on the basis of separate trials (sharing only the stimulus-driven component). We show that the greater similarity of the representational geometries can be explained by the coherent fluctuations of regional-mean activation within visual cortex, reflecting intrinsic dynamics. Using separate trials to study stimulus-driven representations revealed clearer distinctions between the representational geometries: a Gabor wavelet pyramid model explained representational geometry in visual areas V1–3 and a categorical animate– inanimate model in the object-responsive lateral occipital cortex.

Intrinsic cortical dynamics dominate population responses to natural images across human visual cortex

What is the nature of the decodable neuromagnetic signal? MEG, Models, and Perception.

In the ventral visual pathway, early visual areas encode light patterns on the retina in terms of image properties, for example, edges and color, whereas higher areas encode visual information in terms of objects and categories. At what point does semantic knowledge, as instantiated in human language, emerge? We examined this question by studying whether semantic similarity in language relates to the brain's organization of object representations in inferior temporal cortex (ITC), an area of the brain at the crux of several proposals describing how the brain might represent conceptual knowledge. Semantic relationships among words can be viewed as a geometrical structure with some pairs of words close in their meaning (e.g., man and boy) and other pairs more distant (e.g., man and tomato). ITC's representation of objects similarly can be viewed as a complex structure with some pairs of stimuli evoking similar patterns of activation (e.g., man and boy) and other pairs evoking very different patterns (e.g., man and tomato). In this study, we examined whether the geometry of visual object representations in ITC bears a correspondence to the geometry of semantic relationships between word labels used to describe the objects. We compared ITC's representation to semantic structure, evaluated by explicit ratings of semantic similarity and by five computational measures of semantic similarity. We show that the representational geometry of ITC—but not of earlier visual areas (V1)—is reflected both in explicit behavioral ratings of semantic similarity and also in measures of semantic similarity derived from word usage patterns in natural language. Our findings show that patterns of brain activity in ITC not only reflect the organization of visual information into objects but also represent objects in a format compatible with conceptual thought and language.

The Emergence of Semantic Meaning in the Ventral Temporal Pathway

RDM correlations between brain regions and not-strongly-supervised models.

Neuronal population codes are increasingly being investigated with multivariate pattern-information analyses. A key challenge is to use measured brain-activity patterns to test computational models of brain information processing. One approach to this problem is representational similarity analysis (RSA), which characterizes a representation in a brain or computational model by the distance matrix of the response patterns elicited by a set of stimuli. The representational distance matrix encapsulates what distinctions between stimuli are emphasized and what distinctions are de-emphasized in the representation. A model is tested by comparing the representational distance matrix it predicts to that of a measured brain region. RSA also enables us to compare representations between stages of processing within a given brain or model, between brain and behavioral data, and between individuals and species. Here, we introduce a Matlab toolbox for RSA. The toolbox supports an analysis approach that is simultaneously data- and hypothesis-driven. It is designed to help integrate a wide range of computational models into the analysis of multichannel brain-activity measurements as provided by modern functional imaging and neuronal recording techniques. Tools for visualization and inference enable the user to relate sets of models to sets of brain regions and to statistically test and compare the models using nonparametric inference methods. The toolbox supports searchlight-based RSA, to continuously map a measured brain volume in search of a neuronal population code with a specific geometry. Finally, we introduce the linear-discriminant t value as a measure of representational discriminability that bridges the gap between linear decoding analyses and RSA. In order to demonstrate the capabilities of the toolbox, we apply it to both simulated and real fMRI data. The key functions are equally applicable to other modalities of brain-activity measurement. The toolbox is freely available to the community under an open-source license agreement (http://www.mrc-cbu.cam.ac.uk/methods-and-resources/toolboxes/license/).

Population coding of affect across stimuli, modalities and individuals

Inferior temporal (IT) cortex in human and nonhuman primates serves visual object recognition. Computational object-vision models, although continually improving, do not yet reach human performance. It is unclear to what extent the internal representations of computational models can explain the IT representation. Here we investigate a wide range of computational model representations (37 in total), testing their categorization performance and their ability to account for the IT representational geometry. The models include well-known neuroscientific object-recognition models (e.g. HMAX, VisNet) along with several models from computer vision (e.g. SIFT, GIST, self-similarity features, and a deep convolutional neural network). We compared the representational dissimilarity matrices (RDMs) of the model representations with the RDMs obtained from human IT (measured with fMRI) and monkey IT (measured with cell recording) for the same set of stimuli (not used in training the models). Better performing models were more similar to IT in that they showed greater clustering of representational patterns by category. In addition, better performing models also more strongly resembled IT in terms of their within-category representational dissimilarities. Representational geometries were significantly correlated between IT and many of the models. However, the categorical clustering observed in IT was largely unexplained by the unsupervised models. The deep convolutional network, which was trained by supervision with over a million category-labeled images, reached the highest categorization performance and also best explained IT, although it did not fully explain the IT data. Combining the features of this model with appropriate weights and adding linear combinations that maximize the margin between animate and inanimate objects and between faces and other objects yielded a representation that fully explained our IT data. Overall, our results suggest that explaining IT requires computational features trained through supervised learning to emphasize the behaviorally important categorical divisions prominently reflected in IT.

Deep Supervised, but Not Unsupervised, Models May Explain IT Cortical Representation

Behavior is governed by rules that associate stimuli with responses and outcomes. Human and monkey studies have shown that rule-specific information is widely represented in the frontoparietal cortex. However, it is not known how establishing a rule under different contexts affects its neural representation. Here, we use event-related functional MRI (fMRI) and multivoxel pattern classification methods to investigate the human brain's mechanisms of establishing and maintaining rules for multiple perceptual decision tasks. Rules were either chosen by participants or specifically instructed to them, and the fMRI activation patterns representing rule-specific information were compared between these contexts. We show that frontoparietal regions differ in the properties of their rule representations during active maintenance before execution. First, rule-specific information maintained in the dorsolateral and medial frontal cortex depends on the context in which it was established (chosen vs specified). Second, rule representations maintained in the ventrolateral frontal and parietal cortex are independent of the context in which they were established. Furthermore, we found that the rule-specific coding maintained in anticipation of stimuli may change with execution of the rule: representations in context-independent regions remain invariant from maintenance to execution stages, whereas rule representations in context-dependent regions do not generalize to execution stage. The identification of distinct frontoparietal systems with context-independent and context-dependent task rule representations, and the distinction between anticipatory and executive rule representations, provide new insights into the functional architecture of goal-directed behavior.

Choosing the Rules: Distinct and Overlapping Frontoparietal Representations of Task Rules for Perceptual Decisions

One of the most remarkable properties of the visual system is the ability to identify and categorize a wide variety of objects effortlessly. However, the underlying neural mechanisms remain elusive. Specifically, the question of how individual object information is represented and intrinsically organized is still poorly understood. To address this question, we presented images of isolated real-world objects spanning a wide range of categories to awake monkeys using a rapid event-related functional magnetic resonance imaging (fMRI) design and analyzed the responses of multiple areas involved in object processing. We found that the multivoxel response patterns to individual exemplars in the inferior temporal (IT) cortex, especially area TE, encoded the animate-inanimate categorical division, with a subordinate cluster of faces within the animate category. In contrast, the individual exemplar representations in V4, the amygdala, and prefrontal cortex showed either no categorical structure, or a categorical structure different from that in IT cortex. Moreover, in the IT face-selective regions (“face patches”), especially the anterior face patches, (1) the multivoxel response patterns to individual exemplars showed a categorical distinction between faces and nonface objects (i.e., body parts and inanimate objects), and (2) the regionally averaged activations to individual exemplars showed face-selectivity and within-face exemplar-selectivity. Our findings demonstrate that, at both the single-exemplar and the population level, intrinsic object representation and categorization are organized hierarchically as one moves anteriorly along the ventral pathway, reflecting both modular and distributed processing.

Intrinsic Structure of Visual Exemplar and Category Representations in Macaque Brain

Population-code representations of natural images across human visual areas

Purpose: Typical fMRI studies use voxel sizes of approximately 3x3x3mm. Higher resolution fMRI has the potential to reveal brain activity patterns in greater spatial detail, which promises more precise localisation and the elucidation of population-code information residing in fine-grained columnar patterns of neuronal activity. At ultra-high field strengths (7T), it has been demonstrated that fMRI can reveal columnar level neuronal organisations such as ocular dominance columns [1]. However, several arguments question the practical utility of acquiring at high-resolution at 3T, for example, higher resolution comes at the price of a lower signal-to-noise ratio (SNR) and, from a neurovascular perspective, fMRI at 3T reflects signals in venules and veins, which might limit the effective resolution. This raises the question of which resolution best balances functional contrast and spatial detail for a given neuronal representation, so as to maximise the decodability of neuronal information from the fMRI patterns. Here we address this question empirically by eliciting checkerboard-like response patterns in early visual cortex at different spatial scales.

5000 Comparing Functional Contrast and Pattern Information across fMRI Resolutions

■ How does the brain translate an internal representation of an object into a decision about the objectʼs category? Recent studies have uncovered the structure of object representations in inferior temporal cortex (IT) using multivariate pattern analysis methods. These studies have shown that representations of individual object exemplars in IT occupy distinct locations in a high-dimensional activation space, with object exemplar representations clustering into distinguishable regions based on category (e.g., animate vs. inanimate objects). In this study, we hypothesized that a representational boundary between category representations in this activation space also constitutes a decision boundary for categorization. We show that behavioral RTs for categorizing objects are well described by our activation space hypothesis. Interpreted in terms of classical and contemporary models of decision-making, our results suggest that the process of settling on an internal representation of a stimulus is itself partially constitutive of decisionmaking for object categorization. ■

Un co rre cte d Pr oo f RT for Object Categorization Is Predicted by Representational Distance

Reaction Time for Rapid Object Categorization is Predicted by a Representational Decision-Boundary in Inferior Temporal Cortex (IT)

Intrinsic Structure of Visual Exemplars and Category Representations in Macaque Brain

Significance How is new information converted into a memory trace? Here, we used functional neuroimaging to assess what happens to representations of new events after we first experience them. We found that a particular part of the medial temporal lobe, a brain region known to be critical for intact memory, spontaneously reactivates these events even when we are engaged in unrelated activities. Indeed, the extent to which such automatic reactivation occurs seems directly related to later memory performance. This finding shows that we can now study the dynamics of memory processes for specific experiences during the “offline” periods that follow the initial learning phase. How are new experiences transformed into memories? Recent findings have shown that activation in brain regions involved in the initial task performance reemerges during postlearning rest, suggesting that “offline activity” might be important for this transformation. It is unclear, however, whether such offline activity indeed reflects reactivation of individual learning experiences, whether the amount of event-specific reactivation is directly related to later memory performance, and what brain regions support such event-specific reactivation. Here, we used functional magnetic resonance imaging to assess whether event-specific reactivation occurs spontaneously during an active, postlearning delay period in the human brain. Applying representational similarity analysis, we found that successful recall of individual study events was predicted by the degree of their endogenous reactivation during the delay period. Within the medial temporal lobe, this reactivation was observed in the entorhinal cortex. Beyond the medial temporal lobe, event-specific reactivation was found in the retrosplenial cortex. Controlling for the levels of blood oxygen level-dependent activation and the serial position during encoding, the data suggest that offline reactivation might be a key mechanism for bolstering episodic memory beyond initial study processes. These results open a unique avenue for the systematic investigation of reactivation and consolidation of episodic memories in humans.

Primate inferior temporal (IT) cortex is thought to contain a high-level representation of objects at the interface between vision and semantics. This suggests that the perceived similarity of real-world objects might be predicted from the IT representation. Here we show that objects that elicit similar activity patterns in human IT (hIT) tend to be judged as similar by humans. The IT representation explained the human judgments better than early visual cortex, other ventral-stream regions, and a range of computational models. Human similarity judgments exhibited category clusters that reflected several categorical divisions that are prevalent in the IT representation of both human and monkey, including the animate/inanimate and the face/body division. Human judgments also reflected the within-category representation of IT. However, the judgments transcended the IT representation in that they introduced additional categorical divisions. In particular, human judgments emphasized human-related additional divisions between human and non-human animals and between man-made and natural objects. hIT was more similar to monkey IT than to human judgments. One interpretation is that IT has evolved visual-feature detectors that distinguish between animates and inanimates and between faces and bodies because these divisions are fundamental to survival and reproduction for all primate species, and that other brain systems serve to more flexibly introduce species-dependent and evolutionarily more recent divisions.

Human Object-Similarity Judgments Reflect and Transcend the Primate-IT Object Representation

Representational geometry: integrating cognition, computation, and the brain

Human object recognition is remarkably efficient. In recent years, significant advancements have been made in our understanding of how the brain represents visual objects and organizes them into categories. Recent studies using pattern analyses methods have characterized a representational space of objects in human and primate inferior temporal cortex in which object exemplars are discriminable and cluster according to category (e.g., faces and bodies). In the present study we examined how category structure in object representations emerges in the first 1000 ms of visual processing. In the study, participants viewed 24 object exemplars with a planned categorical structure comprised of four levels ranging from highly specific (individual exemplars) to highly abstract (animate vs. inanimate), while their brain activity was recorded with magnetoencephalography (MEG). We used a sliding time window decoding approach to decode the exemplar and the exemplar's category that participants were viewing on a moment-to-moment basis. We found exemplar and category membership could be decoded from the neuromagnetic recordings shortly after stimulus onset (<100 ms) with peak decodability following thereafter. Latencies for peak decodability varied systematically with the level of category abstraction with more abstract categories emerging later, indicating that the brain hierarchically constructs category representations. In addition, we examined the stationarity of patterns of activity in the brain that encode object category information and show these patterns vary over time, suggesting the brain might use flexible time varying codes to represent visual object categories.

The human brain is thought to process auditory objects along a hierarchical temporal "what" stream that progressively abstracts object information from the low-level structure (e.g., loudness) as processing proceeds along the middle-to-anterior direction. Empirical demonstrations of abstract object encoding, independent of low-level structure, have relied on speech stimuli, and non-speech studies of object-category encoding (e.g., human vocalizations) often lack a systematic assessment of low-level information (e.g., vocalizations are highly harmonic). It is currently unknown whether abstract encoding constitutes a general functional principle that operates for auditory objects other than speech. We combined multivariate analyses of functional imaging data with an accurate analysis of the low-level acoustical information to examine the abstract encoding of non-speech categories. We observed abstract encoding of the living and human-action sound categories in the fine-grained spatial distribution of activity in the middle-to-posterior temporal cortex (e.g., planum temporale). Abstract encoding of auditory objects appears to extend to non-speech biological sounds and to operate in regions other than the anterior temporal lobe. Neural processes for the abstract encoding of auditory objects might have facilitated the emergence of speech categories in our ancestors.

Abstract encoding of auditory objects in cortical activity patterns.

Faciotopy – a face-feature map with face-like topology in the occipital face area

A scientific publication system needs to provide two basic services: access and evaluation. The traditional publication system restricts the access to papers by requiring payment, and it restricts the evaluation of papers by relying on just 2–4 pre-publication peer reviews and by keeping the reviews secret. As a result, the current system suffers from a lack of quality and transparency of the peer review process, and the only immediately available indication of a new paper's quality is the prestige of the journal it appeared in. 
 
Open access (OA) is now widely accepted as desirable and is beginning to become a reality. However, the second essential element, evaluation, has received less attention. Open evaluation (OE), an ongoing post-publication process of transparent peer review and rating of papers, promises to address the problems of the current system and bring scientific publishing into the twenty-first century. 
 
Evaluation steers the attention of the scientific community, and thus the very course of science. For better or worse, the most visible papers determine the direction of each field, and guide funding and public policy decisions. Evaluation, therefore, is at the heart of the entire endeavor of science. As the number of scientific publications explodes, evaluation, and selection will only gain importance. A grand challenge of our time, therefore, is to design the future system, by which we evaluate papers and decide which ones deserve broad attention and deep reading. However, it is unclear how exactly OE and the future system for scientific publishing should work. This motivated us to edit the Research Topic “Beyond open access: visions for open evaluation of scientific papers by post-publication peer review” in Frontiers in Computational Neuroscience. The Research Topic includes 18 papers, each going beyond mere criticism of the status quo and laying out a detailed vision for the ideal future system. The authors are from a wide variety of disciplines, including neuroscience, psychology, computer science, artificial intelligence, medicine, molecular biology, chemistry, and economics. 
 
The proposals could easily have turned out to contradict each other, with some authors favoring solutions that others advise against. However, our contributors' visions are largely compatible. While each paper elaborates on particular challenges, the solutions proposed have much overlap, and where distinct solutions are proposed, these are generally compatible. This puts us in a position to present our synopsis here as a coherent blueprint for the future system that reflects the consensus among the contributors.1 Each section heading below refers to a design feature of the future system that was a prevalent theme in the collection. If the feature was overwhelmingly endorsed, the section heading below is phrased as a statement. If at least two papers strongly advised against the feature, the section heading is phrased as a question. Figure ​Figure11 visualizes to what extent each paper encourages or discourages the inclusion of each design feature in the future system. The ratings used in Figure ​Figure11 have been agreed upon with the authors of the original papers.2 
 
Figure 1 
 
Overview of key design features across the 18 visions. The design features on the left capture major recurrent themes that were addressed (positively or negatively) in the Research Topic on OE. The columns indicate to what extent each design feature is ...

An emerging consensus for open evaluation: 18 visions for the future of scientific publishing

Human inferior temporal cortex contains category-selective visual regions, including the fusiform face area (FFA) and the parahippocampal place area (PPA). These regions are defined by their greater category-average activation to the preferred category (faces and places, respectively) relative to nonpreferred categories. The approach of investigating category-average activation has left unclear to what extent category selectivity holds for individual object images. Here we investigate single-image activation profiles to address (1) whether each image from the preferred category elicits greater activation than any image outside the preferred category (categorical ranking), (2) whether there are activation differences within and outside the preferred category (gradedness), and (3) whether the activation profile falls off continuously across the category boundary or exhibits a discontinuity at the boundary (category step). We used functional magnetic resonance imaging to measure the activation elicited in the FFA and PPA by each of 96 object images from a wide range of categories, including faces and places, but also humans and animals, and natural and manmade objects. Results suggest that responses in FFA and PPA exhibit almost perfect categorical ranking, are graded within and outside the preferred category, and exhibit a category step. The gradedness within the preferred category was more pronounced in FFA; the category step was more pronounced in PPA. These findings support the idea that these regions have category-specific functions, but are also consistent with a distributed object representation emphasizing categories while still distinguishing individual images.

Categorical, Yet Graded – Single-Image Activation Profiles of Human Category-Selective Cortical Regions

The essence of episodic memory is our ability to reexperience past events in great detail, even in the absence of external stimulus cues. Does the phenomenological reinstatement of past experiences go along with reinstating unique neural representations in the brain? And if so, how is this accomplished by the medial temporal lobe (MTL), a brain region intimately linked to episodic memory? Computational models suggest that such reinstatement (also termed “pattern completion”) in cortical regions is mediated by the hippocampus, a key region of the MTL. Although recent functional magnetic resonance imaging studies demonstrated reinstatement of coarse item properties like stimulus category or task context across different brain regions, it has not yet been shown whether reinstatement can be observed at the level of individual, discrete events—arguably the defining feature of episodic memory—nor whether MTL structures like the hippocampus support this “true episodic” reinstatement. Here we show that neural activity patterns for unique word-scene combinations encountered during encoding are reinstated in human parahippocampal cortex (PhC) during retrieval. Critically, this reinstatement occurs when word-scene combinations are successfully recollected (even though the original scene is not visually presented) and does not encompass other stimulus domains (such as word-color associations). Finally, the degree of PhC reinstatement across retrieval events correlated with hippocampal activity, consistent with a role of the hippocampus in coordinating pattern completion in cortical regions.

Time resolved imaging techniques, such as MEG and EEG, are unique in their ability to reveal the rich dynamic spatiotemporal patterning of neural activities. Here we propose a technique based on spatiotemporal searchlight Representational Similarity Analysis (RSA) of combined MEG and EEG (EMEG) data to directly analyze the multivariate pattern of information flow across the brain. This novel technique can recognize fine-grained dynamic neural computations both in space and in time. A prime example of such neural computations is our ability to understand spoken words in real time. A computational approach to these processes is suggested by the Cohort Model of spoken-word recognition. Here we show how spatiotemporal searchlight RSA applied to source estimations of EMEG data can provide insights into the neural correlates of the cohort model within bilateral front temporal brain regions.

2012 Second International Workshop on Pattern Recognition in NeuroImaging

Spatiotemporal Searchlight Representational Similarity Analysis in EMEG Source Space

The orientation of a large grating can be decoded from V1 functional magnetic resonance imaging (fMRI) data, even at low resolution (3-mm isotropic voxels). This finding has suggested that columnar-level neuronal information might be accessible to fMRI at 3T. However, orientation decodability might alternatively arise from global orientation-preference maps. Such global maps across V1 could result from bottom-up processing, if the preferences of V1 neurons were biased toward particular orientations (e.g., radial from fixation, or cardinal, i.e., vertical or horizontal). Global maps could also arise from local recurrent or top-down processing, reflecting pre-attentive perceptual grouping, attention spreading, or predictive coding of global form. Here we investigate whether fMRI orientation decoding with 2-mm voxels requires (a) globally coherent orientation stimuli and/or (b) global-scale patterns of V1 activity. We used opposite-orientation gratings (balanced about the cardinal orientations) and spirals (balanced about the radial orientation), along with novel patch-swapped variants of these stimuli. The two stimuli of a patch-swapped pair have opposite orientations everywhere (like their globally coherent parent stimuli). However, the two stimuli appear globally similar, a patchwork of opposite orientations. We find that all stimulus pairs are robustly decodable, demonstrating that fMRI orientation decoding does not require globally coherent orientation stimuli. Furthermore, decoding remained robust after spatial high-pass filtering for all stimuli, showing that fine-grained components of the fMRI patterns reflect visual orientations. Consistent with previous studies, we found evidence for global radial and vertical preference maps in V1. However, these were weak or absent for patch-swapped stimuli, suggesting that global preference maps depend on globally coherent orientations and might arise through recurrent or top-down processes related to the perception of global form.

fMRI orientation decoding in V1 does not require global maps or globally coherent orientation stimuli

The aim of this functional magnetic resonance imaging (fMRI) study was to identify human brain areas that are sensitive to the direction of auditory motion. Such directional sensitivity was assessed in a hypothesis‐free manner by analyzing fMRI response patterns across the entire brain volume using a spherical‐searchlight approach. In addition, we assessed directional sensitivity in three predefined brain areas that have been associated with auditory motion perception in previous neuroimaging studies. These were the primary auditory cortex, the planum temporale and the visual motion complex (hMT/V5+). Our whole‐brain analysis revealed that the direction of sound‐source movement could be decoded from fMRI response patterns in the right auditory cortex and in a high‐level visual area located in the right lateral occipital cortex. Our region‐of‐interest‐based analysis showed that the decoding of the direction of auditory motion was most reliable with activation patterns of the left and right planum temporale. Auditory motion direction could not be decoded from activation patterns in hMT/V5+. These findings provide further evidence for the planum temporale playing a central role in supporting auditory motion perception. In addition, our findings suggest a cross‐modal transfer of directional information to high‐level visual cortex in healthy humans. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.

Auditory motion direction encoding in auditory cortex and high‐level visual cortex

Vision is a massively parallel computational process, in which the retinal image is transformed over a sequence of stages so as to emphasize behaviorally relevant information (such as object category and identity) and deemphasize other information (such as viewpoint and lighting). The processes behind vision operate by concurrent computation and message passing among neurons within a visual area and between different areas. The theoretical concept of "population code" encapsulates the idea that visual content is represented at each stage by the pattern of activity across the local population of neurons. Understanding visual population codes ultimately requires multichannel measurement and multivariate analysis of activity patterns. Over the past decade, the multivariate approach has gained significant momentum in vision research. Functional imaging and cell recording measure brain activity in fundamentally different ways, but they now use similar theoretical concepts and mathematical tools in their modeling and analyses. With a focus on the ventral processing stream thought to underlie object recognition, this book presents recent advances in our understanding of visual population codes, novel multivariate pattern-information analysis techniques, and the beginnings of a unified perspective for cell recording and functional imaging. It serves as an introduction, overview, and reference for scientists and students across disciplines who are interested in human and primate vision and, more generally, in understanding how the brain represents and processes information.

Visual population codes : toward a common multivariate framework for cell recording and functional imaging

The two major functions of a scientific publishing system are to provide access to and evaluation of scientific papers. While open access (OA) is becoming a reality, open evaluation (OE), the other side of the coin, has received less attention. Evaluation steers the attention of the scientific community and thus the very course of science. It also influences the use of scientific findings in public policy. The current system of scientific publishing provides only journal prestige as an indication of the quality of new papers and relies on a non-transparent and noisy pre-publication peer-review process, which delays publication by many months on average. Here I propose an OE system, in which papers are evaluated post-publication in an ongoing fashion by means of open peer review and rating. Through signed ratings and reviews, scientists steer the attention of their field and build their reputation. Reviewers are motivated to be objective, because low-quality or self-serving signed evaluations will negatively impact their reputation. A core feature of this proposal is a division of powers between the accumulation of evaluative evidence and the analysis of this evidence by paper evaluation functions (PEFs). PEFs can be freely defined by individuals or groups (e.g., scientific societies) and provide a plurality of perspectives on the scientific literature. Simple PEFs will use averages of ratings, weighting reviewers (e.g., by H-index), and rating scales (e.g., by relevance to a decision process) in different ways. Complex PEFs will use advanced statistical techniques to infer the quality of a paper. Papers with initially promising ratings will be more deeply evaluated. The continual refinement of PEFs in response to attempts by individuals to influence evaluations in their own favor will make the system ungameable. OA and OE together have the power to revolutionize scientific publishing and usher in a new culture of transparency, constructive criticism, and collaboration.

Open Evaluation: A Vision for Entirely Transparent Post-Publication Peer Review and Rating for Science

Seeing patterns through the hemodynamic veil — The future of pattern-information fMRI

The pairwise dissimilarities of a set of items can be intuitively visualized by a 2D arrangement of the items, in which the distances reflect the dissimilarities. Such an arrangement can be obtained by multidimensional scaling (MDS). We propose a method for the inverse process: inferring the pairwise dissimilarities from multiple 2D arrangements of items. Perceptual dissimilarities are classically measured using pairwise dissimilarity judgments. However, alternative methods including free sorting and 2D arrangements have previously been proposed. The present proposal is novel (a) in that the dissimilarity matrix is estimated by “inverse MDS” based on multiple arrangements of item subsets, and (b) in that the subsets are designed by an adaptive algorithm that aims to provide optimal evidence for the dissimilarity estimates. The subject arranges the items (represented as icons on a computer screen) by means of mouse drag-and-drop operations. The multi-arrangement method can be construed as a generalization of simpler methods: It reduces to pairwise dissimilarity judgments if each arrangement contains only two items, and to free sorting if the items are categorically arranged into discrete piles. Multi-arrangement combines the advantages of these methods. It is efficient (because the subject communicates many dissimilarity judgments with each mouse drag), psychologically attractive (because dissimilarities are judged in context), and can characterize continuous high-dimensional dissimilarity structures. We present two procedures for estimating the dissimilarity matrix: a simple weighted-aligned-average of the partial dissimilarity matrices and a computationally intensive algorithm, which estimates the dissimilarity matrix by iteratively minimizing the error of MDS-predictions of the subject’s arrangements. The Matlab code for interactive arrangement and dissimilarity estimation is available from the authors upon request.

Inverse MDS: Inferring Dissimilarity Structure from Multiple Item Arrangements

Beyond open access: visions for open evaluation of scientific papers by post-publication peer review

Testing within-category exemplar discriminability in pattern-information analysis

Pattern-information analysis: From stimulus decoding to computational-model testing

Utilizing temporal information in fMRI decoding: Classifier using kernel regression methods

Gaze Direction Representations in Human Superior Temporal Sulcus are Invariant to Head View

A Head View-Invariant Representation of Gaze Direction in Anterior Superior Temporal Sulcus

Humans and other primates are adept at using the direction of another's gaze or head turn to infer where that individual is attending. Research in macaque neurophysiology suggests that anterior superior temporal sulcus (STS) contains a direction-sensitive code for such social attention cues. By contrast, most human functional Magnetic resonance imaging (fMRI) studies report that posterior STS is responsive to social attention cues. It is unclear whether this functional discrepancy is caused by a species difference or by experimental design differences. Furthermore, social attention cues are dynamic in naturalistic social interaction, but most studies to date have been restricted to static displays. In order to address these issues, we used multivariate pattern analysis of fMRI data to test whether response patterns in human right STS distinguish between leftward and rightward dynamic head turns. Such head turn discrimination was observed in right anterior STS/superior temporal gyrus (STG). Response patterns in this region were also significantly more discriminable for head turn direction than for rotation direction in physically matched ellipsoid control stimuli. Our findings suggest a role for right anterior STS/STG in coding the direction of motion in dynamic social attention cues.

Direction-Sensitive Codes for Observed Head Turns in Human Superior Temporal Sulcus

Recognizing a person by face: Dissociating brain regions involved in perceptual and conceptual components of person identification

Comparison of multivariate classifiers and response normalizations for pattern-information fMRI

Categorical neural processing of environmental sounds: activation- and information-based mapping

It is widely assumed that high-level visual object representations are position-independent (or invariant). While there is sensitivity to position in high-level object-selective cortex, position and object identity are thought to be encoded independently in the population response such that position information is available across objects and object information is available across positions. Contrary to this view, we show, with both behavior and neuroimaging, that visual object representations are position-dependent (tied to limited portions of the visual field). Behaviorally, we show that the effect of priming an object was greatly reduced with any change in position (within- or between-hemifields), indicating nonoverlapping representations of the same object across different positions. Furthermore, using neuroimaging, we show that object-selective cortex is not only highly sensitive to object position but also the ability to differentiate objects based on its response is greatly reduced across different positions, consistent with the observed behavior and the receptive field properties observed in macaque object-selective neurons. Thus, even at the population level, the object information available in response of object-selective cortex is constrained by position. We conclude that even high-level visual object representations are position-dependent.

High-level visual object representations are constrained by position.

Circular inference in neuroscience: The dangers of double dipping

The pervasive influence of position on object processing: From brain to behavior

Everything You Never Wanted to Know about Circular Analysis, but Were Afraid to Ask

Recent years have seen a strong growth of interest in multivariate approaches for analysing brain activity patterns. The primary goal of these approaches is to reveal the information represented in neuronal population codes. Here, we review how these methods have been used to relate neural activity patterns both to stimulus input and to behavioural output and how they might help to explain individual differences in behavioural performance. We examine the neuroscientific interpretation of different types of pattern-information analysis and highlight current challenges and promising future directions for this emerging field. The open challenges that we discuss are as follows: inferring the causal role of pattern information, seeking diagnostic power for functional Magnetic Resonance Imaging (fMRI) at the level of individuals, determining whether observed patterns have real functional significance, finding the structure underlying high-dimensional activation spaces and relating one person's neural patterns to another's. © 2010 Wiley Periodicals, Inc. Int J Imaging Syst Technol, 20, 31–41, 2010

Pattern-information fMRI: New questions which it opens up and challenges which face it

Recent years have seen a strong growth of interest in multivariate approaches for analysing brain activity patterns. The primary goal of these approaches is to reveal the information represented in neuronal population codes. Here, we review how these methods have been used to relate neural activity patterns both to stimulus input and to behavioural output and how they might help to explain individual differences in behavioural performance. We examine the neuroscientific interpretation of different types of pattern‐information analysis and highlight current challenges and promising future directions for this emerging field. The open challenges that we discuss are as follows: inferring the causal role of pattern information, seeking diagnostic power for functional Magnetic Resonance Imaging (fMRI) at the level of individuals, determining whether observed patterns have real functional significance, finding the structure underlying high‐dimensional activation spaces and relating one person's neural patterns to another's. © 2010 Wiley Periodicals, Inc. Int J Imaging Syst Technol, 20, 31–41, 2010

Pattern‐information fMRI: New questions which it opens up and challenges which face it

Relating neural object representations to perceptual judgments with representational similarity analysis

How does an fMRI voxel sample the neuronal activity pattern: Compact-kernel or complex spatiotemporal filter?

Representational similarity analysis — relating hi-res fMRI to other modalities and to computational models

Face recognition is a complex cognitive process that requires distinguishable neuronal representations of individual faces. Previous functional magnetic resonance imaging (fMRI) studies using the "fMRI-adaptation" technique have suggested the existence of face-identity representations in face-selective regions, including the fusiform face area (FFA). Here, we present face-identity adaptation findings that are not well explained in terms of face-identity representations. We performed blood-oxygen level-dependent (BOLD) fMRI measurements, while participants viewed familiar faces that were shown repeatedly throughout the experiment. We found decreased activation for repeated faces in face-selective regions, as expected based on previous studies. However, we found similar effects in regions that are not face-selective, including the parahippocampal place area (PPA) and early visual cortex (EVC). These effects were present for exact-image (same view and lighting) as well as different-image (different view and/or lighting) repetition, but more widespread for exact-image repetition. Given the known functional properties of PPA and EVC, it appears unlikely that they contain domain-specific face-identity representations. Alternative interpretations include general attentional effects and carryover of activation from connected regions. These results remind us that fMRI stimulus-change effects can have a range of causes and do not provide conclusive evidence for a neuronal representation of the changed stimulus property.

Face-identity change activation outside the face system: "release from adaptation" may not always indicate neuronal selectivity.

Response patterns in human Superior Temporal Sulcus discriminate the direction of observed head turns

Interpreting brain images: reflections on an adolescent field 
               
                        Stephen José
                        Hanson
                     
                        Martin
                        Bunzl
       
Category specificities in the neural processing of environmental sounds: information-based mapping

Circular analysis in systems neuroscience: the dangers of double dipping

Perceptual and cognitive content is thought to be represented in the brain by patterns of activity across populations of neurons. In order to test whether a computational model can explain a given population code and whether corresponding codes in man and monkey convey the same information, we need to quantitatively relate population-code representations. Here I give a brief introduction to representational similarity analysis, a particular approach to this problem. A population code is characterized by a representational dissimilarity matrix (RDM), which contains a dissimilarity for each pair of activity patterns elicited by a given stimulus set. The RDM encapsulates which distinctions the representation emphasizes and which it deemphasizes. By analyzing correlations between RDMs we can test models and compare different species. Moreover, we can study how representations are transformed across stages of processing and how they relate to behavioral measures of object similarity. We use an example from object vision to illustrate the method's potential to bridge major divides that have hampered progress in systems neuroscience.

Relating Population-Code Representations between Man, Monkey, and Computational Models

Conventional statistical analysis methods for functional magnetic resonance imaging (fMRI) data are very successful at detecting brain regions that are activated as a whole during specific mental activities. The overall activation of a region is usually taken to indicate involvement of the region in the task. However, such activation analysis does not consider the multivoxel patterns of activity within a brain region. These patterns of activity, which are thought to reflect neuronal population codes, can be investigated by pattern-information analysis. In this framework, a region's multivariate pattern information is taken to indicate representational content. This tutorial introduction motivates pattern-information analysis, explains its underlying assumptions, introduces the most widespread methods in an intuitive way, and outlines the basic sequence of analysis steps.

Revealing representational content with pattern-information fMRI--an introductory guide.

Brain function is widely investigated with functional magnetic resonance imaging (fMRI) in humans and animals. In fMRI, the time courses of voxels typically reflect the local blood-oxygen level, which is taken as an indicator of neuronal activity. Voxel time-course correlations are often explicitly modeled and interpreted in terms of neuronal interactions. They also affect standard analyses that do not explicitly target neuronal interactions. As a consequence, time-course correlations between voxels influence conclusions about cognitive and physiological brain processes in many studies. However, voxel correlations are known to arise not only from cognitive and physiological processes, but also as artifacts of fMRI techniques such as the commonly used echoplanar imaging. We empirically demonstrate this phenomenon by plotting time-course correlation as a function of voxel separation for a human brain in resting state and for a water-filled sphere (called a “phantom”). The phantom served as a test object known not to contain any interacting neuronal systems. The plots for brain and phantom are surprisingly similar. The correlational structure found in the phantom must be artifactual. Artifactual correlations spanning many centimeters occur within and between different imaging slices. Correlations between voxel time courses do not necessarily reflect brain processes. Instead, fMRI is affected by artifactual correlations, which are very strong for neighboring voxels and clearly present even at large distances. This needs to be taken into account in the neuroscientific interpretation of voxel correlations. © 2008 Wiley Periodicals, Inc. Int J Imaging Syst Technol, 18, 345–349, 2008

Artifactual time-course correlations in echo-planar fMRI with implications for studies of brain function

There is an extensive literature about the neuronal processes in the visual system that enable us to appreciate spatial structure at different scales. Basically, spatial receptive fields increase in size and complexity from early- to high-level visual areas. But what about our sense of temporal

The Arrow of Time: How Does the Brain Represent Natural Temporal Structure?

ACKNOWLEDGMENTS. Phil Nguyen provided invaluable assistance with literature review and management of the survey of researchers reported here, and Shirley Leong provided capable assistance with data management and analysis. We thank all the researchers who responded to our questionnaire. This work was supported by the National Institute of Mental Health (grant P50 MH0662286-01A1), Institute of Education Sciences (Grants R305H020061 and R305H040108 to H. Pashler), the National Science Foundation (Grant BCS-0720375 to H. Pashler; Grant SBE-0542013 to G. Cottrell), and a collaborative activity grant from the James S. McDonnell Foundation.

A fundamental challenge for systems neuroscience is to quantitatively relate its three major branches of research: brain-activity measurement, behavioral measurement, and computational modeling. Using measured brain-activity patterns to evaluate computational network models is complicated by the need to define the correspondency between the units of the model and the channels of the brain-activity data, e.g., single-cell recordings or voxels from functional magnetic resonance imaging (fMRI). Similar correspondency problems complicate relating activity patterns between different modalities of brain-activity measurement (e.g., fMRI and invasive or scalp electrophysiology), and between subjects and species. In order to bridge these divides, we suggest abstracting from the activity patterns themselves and computing representational dissimilarity matrices (RDMs), which characterize the information carried by a given representation in a brain or model. Building on a rich psychological and mathematical literature on similarity analysis, we propose a new experimental and data-analytical framework called representational similarity analysis (RSA), in which multi-channel measures of neural activity are quantitatively related to each other and to computational theory and behavior by comparing RDMs. We demonstrate RSA by relating representations of visual objects as measured with fMRI in early visual cortex and the fusiform face area to computational models spanning a wide range of complexities. The RDMs are simultaneously related via second-level application of multidimensional scaling and tested using randomization and bootstrap techniques. We discuss the broad potential of RSA, including novel approaches to experimental design, and argue that these ideas, which have deep roots in psychology and neuroscience, will allow the integrated quantitative analysis of data from all three branches, thus contributing to a more unified systems neuroscience.

Representational Similarity Analysis – Connecting the Branches of Systems Neuroscience

Patterns of fMRI activity representing perceived direction in apparent motion

Brain function is widely investigated with functional magnetic resonance imaging (fMRI) in humans and animals. In fMRI, the time courses of voxels typically reflect the local blood‐oxygen level, which is taken as an indicator of neuronal activity. Voxel time‐course correlations are often explicitly modeled and interpreted in terms of neuronal interactions. They also affect standard analyses that do not explicitly target neuronal interactions. As a consequence, time‐course correlations between voxels influence conclusions about cognitive and physiological brain processes in many studies. However, voxel correlations are known to arise not only from cognitive and physiological processes, but also as artifacts of fMRI techniques such as the commonly used echoplanar imaging. We empirically demonstrate this phenomenon by plotting time‐course correlation as a function of voxel separation for a human brain in resting state and for a water‐filled sphere (called a “phantom”). The phantom served as a test object known not to contain any interacting neuronal systems. The plots for brain and phantom are surprisingly similar. The correlational structure found in the phantom must be artifactual. Artifactual correlations spanning many centimeters occur within and between different imaging slices. Correlations between voxel time courses do not necessarily reflect brain processes. Instead, fMRI is affected by artifactual correlations, which are very strong for neighboring voxels and clearly present even at large distances. This needs to be taken into account in the neuroscientific interpretation of voxel correlations. © 2008 Wiley Periodicals, Inc. Int J Imaging Syst Technol, 18, 345–349, 2008

Artifactual time‐course correlations in echo‐planar fMRI with implications for studies of brain function

Trust is a critical social process that helps us to cooperate with others and is present to some degree in all human interaction. However, the underlying brain mechanisms of conditional and unconditional trust in social reciprocal exchange are still obscure. Here, we used hyperfunctional magnetic resonance imaging, in which two strangers interacted online with one another in a sequential reciprocal trust game while their brains were simultaneously scanned. By designing a nonanonymous, alternating multiround game, trust became bidirectional, and we were able to quantify partnership building and maintenance. Using within- and between-brain analyses, an examination of functional brain activity supports the hypothesis that the preferential activation of different neuronal systems implements these two trust strategies. We show that the paracingulate cortex is critically involved in building a trust relationship by inferring another person's intentions to predict subsequent behavior. This more recently evolved brain region can be differently engaged to interact with more primitive neural systems in maintaining conditional and unconditional trust in a partnership. Conditional trust selectively activated the ventral tegmental area, a region linked to the evaluation of expected and realized reward, whereas unconditional trust selectively activated the septal area, a region linked to social attachment behavior. The interplay of these neural systems supports reciprocal exchange that operates beyond the immediate spheres of kinship, one of the distinguishing features of the human species.

Analyzing for information, not activation, to exploit high-resolution fMRI

Visual face identification requires distinguishing between thousands of faces we know. This computational feat involves a network of brain regions including the fusiform face area (FFA) and anterior inferotemporal cortex (aIT), whose roles in the process are not well understood. Here, we provide the first demonstration that it is possible to discriminate cortical response patterns elicited by individual face images with high-resolution functional magnetic resonance imaging (fMRI). Response patterns elicited by the face images were distinct in aIT but not in the FFA. Individual-level face information is likely to be present in both regions, but our data suggest that it is more pronounced in aIT. One interpretation is that the FFA detects faces and engages aIT for identification.

Individual faces elicit distinct response patterns in human anterior temporal cortex

Combining the tools: Activation- and information-based fMRI analysis

The development of high-resolution neuroimaging and multielectrode electrophysiological recording provides neuroscientists with huge amounts of multivariate data. The complexity of the data creates a need for statistical summary, but the local averaging standardly applied to this end may obscure the effects of greatest neuroscientific interest. In neuroimaging, for example, brain mapping analysis has focused on the discovery of activation, i.e., of extended brain regions whose average activity changes across experimental conditions. Here we propose to ask a more general question of the data: Where in the brain does the activity pattern contain information about the experimental condition? To address this question, we propose scanning the imaged volume with a "searchlight," whose contents are analyzed multivariately at each location in the brain.

High-resolution functional magnetic resonance imaging (hi-res fMRI) promises to bridge the gap between the macro- and the microview of brain function afforded by conventional neuroimaging and invasive cell recording, respectively. Hi-res fMRI (nominal voxel sizes les(2 mm) 3) is robustly achievable in human studies today using widely available clinical 3-Tesla scanners. However, the neuroscientific exploitation of the greater spatial detail poses three challenges: (1) Fine-scale neuronal activity patterns are inaccurately depicted in the hemodynamic images obtained. (2) Single small voxels yield very noisy measurements. (3) For groups of subjects, the interindividual correspondency mapping is unknown at the fine scale of millimeters. Here we argue that these challenges can be met by abstracting from the regional fine-scale activity patterns themselves and instead asking how well they distinguish the experimental conditions

The neuroscientific exploitation of high-resolution functional magnetic resonance imaging

The illusion of apparent motion can be induced when visual stimuli are successively presented at different locations. It has been shown in previous studies that motion-sensitive regions in extrastriate cortex are relevant for the processing of apparent motion, but it is unclear whether primary visual cortex (V1) is also involved in the representation of the illusory motion path. We investigated, in human subjects, apparent-motion-related activity in patches of V1 representing locations along the path of illusory stimulus motion using functional magnetic resonance imaging. Here we show that apparent motion caused a blood-oxygenation-level-dependent response along the V1 representations of the apparent-motion path, including regions that were not directly activated by the apparent-motion-inducing stimuli. This response was unaltered when participants had to perform an attention-demanding task that diverted their attention away from the stimulus. With a bistable motion quartet, we confirmed that the activity was related to the conscious perception of movement. Our data suggest that V1 is part of the network that represents the illusory path of apparent motion. The activation in V1 can be explained either by lateral interactions within V1 or by feedback mechanisms from higher visual areas, especially the motion-sensitive human MT/V5 complex.

Primary Visual Cortex Activity along the Apparent-Motion Trace Reflects Illusory Perception

Functional magnetic resonance imaging of the human object-vision system : methodological and empirical contributions

Moving dots can evoke a percept of the spatial structure of a three-dimensional object in the absence of other visual cues. This phenomenon, called structure from motion (SFM), suggests that the motion flowfield represented in the dorsal stream can form the basis of object recognition performed in the ventral stream. SFM processing is likely to contribute to object perception whenever there is relative motion between the observer and the object viewed. Here we investigate the motion flowfield component of object recognition with functional magnetic resonance imaging. Our SFM stimuli encoded face surfaces and random three-dimensional control shapes with matched curvature properties. We used two different types of an SFM stimulus with the dots either fixed to the surface of the object or moving on it. Despite the radically different encoding of surface structure in the two types of SFM, both elicited strong surface percepts and involved the same network of cortical regions. From early visual areas, this network extends dorsally into the human motion complex and parietal regions and ventrally into object-related cortex. The SFM stimuli elicited a face-selective response in the fusiform face area. The human motion complex appears to have a central role in SFM object recognition, not merely representing the motion flowfield but also the surface structure of the motion-defined object. The motion complex and a region in the intraparietal sulcus reflected the motion state of the SFM-implicit object, responding more strongly when the implicit object was in motion than when it was stationary.

Human Cortical Object Recognition from a Visual Motion Flowfield

Cortical capacity constraints for visual working memory: dissociation of fMRI load effects in a fronto-parietal network

Spatial independent component analysis of functional magnetic resonance imaging time-series: characterization of the cortical components

When spatially segregated visual stimuli are presented in alternation, subjects may perceive a single stimulus moving between the two positions (apparent motion). By adjusting spatial and temporal parameters, an ambiguous condition can be created in which perception of back-and-forth motion alternates with the perception of two stationary blinking stimuli. We presented subjects with such ambiguous stimuli, asked them to signal periods of perceived motion and blinking, and measured brain activity with functional magnetic resonance imaging. Multiple regression analysis revealed that early visual areas responded with equal strength during both perceptual conditions, whereas hMT+(V5) (the human motion complex that includes the human homolog of MT and its satellites) was more active during the perception of apparent motion. These results indicate that neurons in hMT+ participate in the constructive process that creates a continuous motion percept from a discontinuous visual input.

Apparent Motion: Event-Related Functional Magnetic Resonance Imaging of Perceptual Switches and States

3D structure from motion and structure from on-surface motion of human faces and simple objects — psychophysics and fMRI

Polygon-mesh representations of the cortices of individual subjects are of anatomical interest, aid visualization of functional imaging data and provide important constraints for their statistical analysis. Due to noise and partial volume sampling, however, conventional segmentation methods rarely yield a voxel object whose outer boundary represents the folded cortical sheet without topological errors. These errors, called handles, have particularly deleterious effects when the polygon mesh constructed from the segmented voxel representation is inflated or flattened. So far handles had to be removed by cumbersome manual editing, or the computationally more expensive method of reconstruction by morphing had to be used, incorporating the a priori constraint of simple topology into the polygon-mesh model. Here we describe a linear time complexity algorithm that automatically detects and removes handles in presegmentations of the cortex obtained by conventional methods. The algorithm's modifications reflect the true structure of the cortical sheet. The core component of our method is a region growing process that starts deep inside the object, is prioritized by the distance-to-surface of the voxels considered for inclusion and is selftouching-sensitive, i.e., voxels whose inclusion would add a handle are never included. The result is a binary voxel object identical to the initial object except for "cuts" located in the thinnest part of each handle. By applying the same method to the inverse object, an alternative set of solutions is determined, correcting the errors by addition instead of deletion of voxels. For each handle separately, the solution more consistent with the intensities of the original anatomical MR scan is chosen. The accuracy of the resulting polygon-mesh reconstructions has been validated by visual inspection, by quantitative comparison to an expert's manual corrections, and by crossvalidation between reconstructions from different scans of the same subject's cortex.

An Efficient Algorithm for Topologically Correct Segmentation of the Cortical Sheet in Anatomical MR Volumes

RDM correlations between brain regions and layers of the deep convolutional network.

Remixing and reweighting features of the not-strongly supervised models does not explain IT.

RDMs of all layers of the strongly supervised deep convolutional network.

Simulated representation – inferential comparisons of multiple model representations.

Visualizing representations as RDMs, 2D arrangements, and clustering dendrograms.

Model representations resembling IT afford better categorization accuracy.

The strongly supervised deep network, with features remixed and reweighted, fully explains the IT data.

Remixing and reweighting features of the deep supervised network achieves an IT-like representational geometry.

Distinct reinstatement of multi-voxel patterns predicts memory for complex audio-visual stimuli

Effects of Noninvasive Ventilation: The Highest PEEP May Not Be Best Letter: Acute Hypoxemic Respiratory Failure in Acquired Immune Deficiency Syndrome:

Influence of the renal artery ostium flow diverter on hemodynamics and atherogenesis.

Renal hemodynamics: the influence of the renal artery ostium flow diverter

The tendency of atherosclerotic plaques to develop at arterial branch points is likely due to both the hemodynamics and macromolecular environment associated with these branch points. Arterial branches experience flow separation, which results in regions of low shear stress[1–3], and contributes to longer residence times that may allow for deposition of pro-atherogenic material in the vessel wall [2]. In addition, low shear stress itself may provide cellular signals that alter the tissue microenvironment in favor of atherogenesis [3, e.g.].Copyright © 2013 by ASME

Numerical Simulation of Blood Flow in the Renal Arteries: Influence of the Ostium Flow Diverter

prolonged breathing in porcine lung injury Dynamics of lung collapse and recruitment during

Transverse sinus thrombosis after internal jugular vein ligation.

Experimental pharmacotherapies for the acute respiratory distress syndrome (ARDS) have not met with success in the clinical realm. We hypothesized that chemically modified tetracycline 3 (CMT-3), an anti-inflammatory agent that blocks multiple proteases and cytokines, would prevent ARDS and injury in other organs in a clinically applicable, porcine model of inflammation-induced lung injury. Pigs (n = 15) were anesthetized and instrumented for monitoring. A “2-hit” injury was induced: (a) peritoneal sepsis—by placement of a fecal clot in the peritoneum, and (b) ischemia/reperfusion—by clamping the superior mesenteric artery for 30 min. Animals were randomized into two groups: CMT-3 group (n = 7) received CMT-3 (200 mg/kg); placebo group (n = 9) received the same dose of a CMT-3 vehicle (carboxymethylcellulose). Experiment duration was 48 h or until early mortality. Animals in both groups developed polymicrobial bacteremia. Chemically modified tetracycline 3 treatment prevented ARDS as indicated by PaO2/FIO2 ratio, static compliance, and plateau airway pressure (P < 0.05 vs. placebo). It improved all histological lesions of ARDS (P < 0.05 vs. placebo). The placebo group developed severe ARDS, coagulopathy, and histological injury to the bowel. Chemically modified tetracycline 3 treatment prevented coagulopathy and protected against bowel injury. It significantly lowered plasma concentrations of interleukin 1&bgr; (IL-1&bgr;), tumor necrosis factor &agr;, IL-6, IL-8, and IL-10. This study presents a clinically relevant model of lung injury in which CMT-3 treatment prevented the development of ARDS due in part to reduction of multiple plasma cytokines. Treatment of sepsis patients with CMT-3 could significantly reduce progression from sepsis into ARDS. ABBREVIATIONS ARDS—acute respiratory distress syndrome BALF—bronchoalveolar lavage fluid MMP—matrix metalloproteinase CMT-3—chemically modified tetracycline 3 TNF-&agr;—tumor necrosis factor &agr; IL—interleukin RM ANOVA—repeated-measures analysis of variance

Chemically Modified Tetracycline 3 Prevents Acute Respiratory Distress Syndrome in a Porcine Model of Sepsis + Ischemia/Reperfusion–Induced Lung Injury

Comparison of "open lung" modes with low tidal volumes in a porcine lung injury model.

A clinically applicable porcine model of septic and ischemia/reperfusion-induced shock and multiple organ injury.

Loss of airway pressure during HFOV results in an extended loss of oxygenation: a retrospective animal study.

Sepsis and hemorrhage can result in injury to multiple organs and is associated with an extremely high rate of mortality. We hypothesized that peritoneal negative pressure therapy (NPT) would reduce systemic inflammation and organ damage. Pigs (n = 12) were anesthetized and surgically instrumented for hemodynamic monitoring. Through a laparotomy, the superior mesenteric artery was clamped for 30 min. Feces was mixed with blood to form a fecal clot that was placed into the peritoneum, and the abdomen was closed. All subjects were treated with standard isotonic fluid resuscitation, wide spectrum antibiotics, and mechanical ventilation, and were monitored for 48 h. Animals were separated into two groups 12 h (T12) after injury: for NPT (n = 6), an abdominal wound vacuum dressing was placed in the laparotomy, and negative pressure (−125 mmHg) was applied (T12 - T48), whereas passive drainage (n = 6) was identical to the NPT group except the abdomen was allowed to passively drain. Negative pressure therapy removed a significantly greater volume of ascites (860 ± 134 mL) than did passive drainage (88 ± 56 mL). Systemic inflammation (e.g. TNF-&agr;, IL-1&bgr;, IL-6) was significantly reduced in the NPT group and was associated with significant improvement in intestine, lung, kidney, and liver histopathology. Our data suggest NPT efficacy is partially due to an attenuation of peritoneal inflammation by the removal of ascites. However, the exact mechanism needs further elucidation. The clinical implication of this study is that sepsis/trauma can result in an inflammatory ascites that may perpetuate organ injury; removal of the ascites can break the cycle and reduce organ damage.

Peritoneal Negative Pressure Therapy Prevents Multiple Organ Injury in a Chronic Porcine Sepsis and Ischemia/Reperfusion Model

Titration of mean airway pressure and FiO2 during high frequency oscillatory ventilation in a porcine model of acute lung injury.

Inappropriate mechanical ventilation in patients with acute respiratory distress syndrome can lead to ventilator-induced lung injury (VILI) and increase the morbidity and mortality. Reopening collapsed lung units may significantly reduce VILI, but the mechanisms governing lung recruitment are unclear. We thus investigated the dynamics of lung recruitment at the alveolar level. Rats (n = 6) were anesthetized and mechanically ventilated. The lungs were then lavaged with saline to simulate acute respiratory distress syndrome (ARDS). A left thoracotomy was performed, and an in vivo microscope was placed on the lung surface. The lung was recruited to three recruitment pressures (RP) of 20, 30, or 40 cmH(2)O for 40 s while subpleural alveoli were continuously filmed. Following measurement of microscopic alveolar recruitment, the lungs were excised, and macroscopic gross lung recruitment was digitally filmed. Recruitment was quantified by computer image analysis, and data were interpreted using a mathematical model. The majority of alveolar recruitment (78.3 +/- 7.4 and 84.6 +/- 5.1%) occurred in the first 2 s (T2) following application of RP 30 and 40, respectively. Only 51.9 +/- 5.4% of the microscopic field was recruited by T2 with RP 20. There was limited recruitment from T2 to T40 at all RPs. The majority of gross lung recruitment also occurred by T2 with gradual recruitment to T40. The data were accurately predicted by a mathematical model incorporating the effects of both pressure and time. Alveolar recruitment is determined by the magnitude of recruiting pressure and length of time pressure is applied, a concept supported by our mathematical model. Such a temporal dependence of alveolar recruitment needs to be considered when recruitment maneuvers for clinical application are designed.

Negative pressure therapy improved outcome in a clinically applicable abdominal compartment syndrome porcine model

Reduced intra-peritoneal inflammation by negative pressure therapy moderates systemic inflammation in a porcine model of the Abdominal Compartment Syndrome (ACS)

Protective Mechanical Ventilation: Lessons Learned From Alveolar Mechanics

Clinically applicable porcine model of abdominal compartment syndrome

P109: Late application of protective mechanical ventilation does not reduce lung injury in a porcine ARDS model

Effect of positive end-expiratory pressure and tidal volume on lung injury induced by alveolar instability

Alveolar instability caused by mechanical ventilation initially damages the nondependent normal lung

Injurious mechanical ventilation in the normal lung causes a progressive pathologic change in dynamic alveolar mechanics

Sensorimotor adaptation is supported by at least two parallel learning systems: an intentionally controlled explicit strategy, and an involuntary implicit learning system. To investigate the error sources driving these two systems, past work focused on constrained reaches or finger movements in laboratory environments has shown subconscious learning systems to be driven in part by sensory prediction error (SPE), i.e., the mismatch between the realized and expected outcome of an action. We designed a ball rolling task to explore whether SPEs can drive implicit motor adaptation during complex whole-body movements that impart physical motion on external objects. After applying a visual shift, participants rapidly adapted their rolling angles to reduce the error between the ball and target. We removed all visual feedback and told participants to aim their throw directly toward the primary target, revealing an unintentional 5.06° implicit adjustment to reach angles that decayed over time. To determine whether this implicit adaptation was driven by SPE, we gave participants a second aiming target that would ‘solve’ the visual shift, as in Mazzoni and Krakauer (2006). Remarkably, after rapidly reducing ball rolling error to zero (due to enhancements in strategic aiming), the additional aiming target caused rolling angles to deviate beyond the primary target by 3.15°. This involuntary overcompensation, which worsened task performance, is a hallmark of SPE-driven implicit learning. These results show that SPE-driven implicit processes, previously observed within simplified finger or planar reaching movements, actively contribute to motor adaptation in more complex naturalistic skill-based tasks. New and Noteworthy Implicit and explicit learning systems have been detected using simple, constrained movements inside the laboratory. How these systems impact movements during complex whole-body, skill-based tasks has not been established. Here we demonstrate that sensory prediction errors significantly impact how a person updates their movements, replicating findings from the laboratory in an unconstrained ball-rolling task. This real-world validation is an important step towards explaining how subconscious learning helps humans execute common motor skills in dynamic environments.

Sensory prediction error drives subconscious motor learning outside of the laboratory

When the same perturbation is experienced consecutively, learning is accelerated on the second attempt. This savings is a central property of sensorimotor adaptation. Current models suggest that these improvements in learning are due to changes in the brain’s sensitivity to error. Here, we tested whether these increases in error sensitivity could be facilitated by passive movement experiences. In each experimental group, the robot moved the arm passively in the direction that solved the upcoming rotation, but no visual feedback was provided. Then, following a break in time, participants adapted to a visuomotor rotation. Prior passive movements substantially improved motor learning, increasing total compensation in each group by approximately 30%. Similar to savings, a state-space model suggested that this improvement in learning was due to an increase in error sensitivity, but not memory retention. Thus, passive memories appeared to increase the motor learning system’s sensitivity to error. However, some features in the observed behavior were not captured by this model, nor by similar empirical models, which assumed that learning was due a single exponential process. When we considered the possibility that learning was supported by parallel fast and slow adaptive processes, a striking pattern emerged; whereas initial improvements in learning were driven by a slower adaptive state, increases in error sensitivity gradually transferred to a faster learning system with the passage of time.

A conversion from slow to fast memory in response to passive motion

In the article “The Neural Feedback Response to Error As a Teaching Signal for the Motor Learning System” by Scott T. Albert and Reza Shadmehr, which appeared on pages 4832– 4845 of the April 27, 2016 issue, the authors wish to correct an issue with the purple perpendicular displacement traces in Figure 2A, labeled “Error 2”. In the original figure, these traces mistakenly show the average error to the first and second perturbations of quartet trial progressions, rather than solely the second error as indicated by the figure caption. In conjunction with this issue, the authors would like to report that the statistically significant reduction in peak displacement from Error 1 to Error 2 reported on pg. 4837 is still correct, though the corresponding p values are in fact p 10 28 (CW perturbations) and p 10 26 (CCW perturbations) as opposed to p 10 23 which is reported in the original article. This correction is in line with the trend already reported in the original manuscript and therefore does not affect any of the results, interpretations, or conclusions of the article. All of the electromyographic data in Figure 2B are unaffected by this error, and all other figures in the original article remain correct. The corrected Figure 2 is shown below and has also been corrected on the online PDF version.

Correction: Albert and Shadmehr, “The Neural Feedback Response to Error As a Teaching Signal for the Motor Learning System”

N2O, NO, and NH3 Emissions from Soil after the Application of Organic Fertilizers, Urea and Water

Abstract. Grassland is a major source of nitrous oxide (N2O) and methane (CH4) emissions in the UK, resulting from high rates of fertilizer application. We studied the effects of substituting mineral fertilizer by organic manures and a slow‐release fertilizer in silage grass production on greenhouse gas emissions and soil mineral N content in a three‐year field experiment. The organic manures investigated were sewage sludge pellets and composted sewage sludge (dry materials), and digested sewage sludge and cattle slurry (liquid materials). The organic manures produced N2O and carbon dioxide (CO2) consistently from time of application up to harvest. However, they mitigated N2O emissions by around 90% when aggregate emissions of 15.7 kg N ha−1 from NPK fertilizer were caused by a flux of up to 4.9 kg N ha−1 d−1 during the first 4 days after heavy rainfall subsequent to the NPK fertilizer application. CH4 was emitted only for 2 or 3 days after application of the liquid manures. CH4 and CO2 fluxes were not significantly mitigated. Composting and dried pellets were useful methods of conserving nutrients in organic wastes, enabling slow and sustained release of nitrogen. NPK slow‐release fertilizer also maintained grass yields and was the most effective substitute for the conventional NPK fertilizer for mitigation of N2O fluxes.

Mitigation of greenhouse gas emissions from soil under silage production by use of organic manures or slow‐release fertilizer

This report was presented at the UK Organic Research 2002 Conference. 
Land emissions of N2O, CO2 and NH3 have been subject to little study under organic systems, yet form important aspects of sustainability of such systems. We describe innovative methods developed at SAC to assess trace gas emission using both automatic closed chamber systems (intensive, short term monitoring) and manually-operated closed chamber systems (occasional, long term monitoring). Long-term data were collected from organic ley-arable rotation trials in North-east of Scotland. Short term data were collected to show the effect of timing and depth of ploughing-out of the ley phase on gas emissions. Ploughing gave a shortterm stimulation of CO2 and, more markedly, of N2O emission. Emissions of N2O from organic grass-clover leys were considerably lower than from conventional grass. However, some N2O emissions from organic arable are higher than from conventional systems, particularly in the first year after ploughing out ley. Ammonia emissions after spreading manure on grass were significant in the summer, though only short-lived.

Abstract. Land disposal of sewage sludge in the UK is set to increase markedly in the next few years and much of this will be applied to grassland. Here we applied high rates of digested sludge cake (1–1.5×103 kg total N ha−1) to grassland and incorporated it prior to reseeding. Using automated chambers, nitrous oxide (N2O) and carbon dioxide (CO2) fluxes from the soil were monitored 2–4 times per day, for 6 months after sludge incorporation. Peaks of N2O emission were up to 1.4 kg N ha−1 d−1 soon after incorporation, and thereafter were regularly detected following significant rainfalls. Gas emissions reflected diurnal temperature variations, though N2O emissions were also strongly affected by rainfall. Although emissions decreased in the winter, temperatures below 4 °C stimulated short, sharp fluxes of both CO2 and N2O as temperature increased. The aggregate loss of nitrogen and carbon over the measurement period was up to 23 kg N ha−1 and 5.1 t C ha−1. Losses of N2O in the sludge‐amended soil were associated with good microbial conditions for N mineralization, and with high carbon and water contents. Since grassland is an important source of greenhouse gases, application of sewage sludge can be at least as significant as fertilizer in enhancing these emissions.

Nitrous oxide and carbon dioxide emissions from grassland amended with sewage sludge

Field N2O, CO2 and CH4 fluxes in relation to tillage, compaction and soil quality in Scotland

Soil and residue management effects on cropping conditions and nitrous oxide fluxes under controlled traffic in Scotland

Tillage practices and weather affect the release of greenhouse gases but there have been few integrated studies of the quantities released or the mechanisms involved. No-tillage may increase emissions of nitrous oxide (N2O) and the ®xation of carbon by decreasing carbon dioxide (CO2) emissions. Tillage may also decrease the oxidation rate of atmospheric methane (CH4) in aerobic soil. These effects are partly due to compaction and to the lack of both soil disturbance and residue incorporation. Our objective was to investigate how tillage practices, soil conditions and weather interact to in ̄uence greenhouse gas emissions. Here we present early measurements of N2O and CO2 emission and CH4 oxidation in two ®eld experiments in Scotland under a cool moist climate, one involving soil compaction plus residue incorporation and the other involving no-tillage and two depths of mouldboard ploughing of a former grass sward. The experiments were located 10± 15 km south of Edinburgh on a cambisol and a gleysol. In order to monitor emissions regularly, at short intervals and over long periods, a novel automatic gas sampling system which allows subsequent automated determination of both N2O and CO2 ̄uxes was used. Both N2O and CO2  ̄uxes were episodic and strongly dependent on rainfall. Peak N2O emissions were mainly associated with heavy rainfalls after fertilisation, particularly with no-tilled and compact soils. In the tillage experiment, N2O ̄uxes and treatment differences were greater under spring barley (Hordeum vulgare L.) (up to 600 g N haÿ1 per day) than under winter barley. CO2 emissions in the few weeks after sowing were not strongly in ̄uenced by tillage and diurnal variations were related to soil temperature. However, periods of low or zero CO2  ̄uxes and very high N2O  ̄uxes under notillage were associated with reduced gas diffusivity and air-®lled porosity, both caused by heavy rainfall. Early results show that CH4 oxidation rates may best be preserved by no-tillage. The quality of the loam/clay-loams and the climate in these experiments makes ploughing, preferably to 300 mm depth, and the control of compaction necessary to minimise soil N2O and CO2 losses. The gas exchange response of different soil types to tillage, particularly methane oxidation rate which is affected by long-term soil structural damage, is a potentially useful aspect of soil quality when taken in conjunction with other qualities. # 1999 Elsevier Science B.V. All rights reserved.

Field N 2 O , CO 2 and CH 4 ̄ uxes in relation to tillage , compaction and soil quality in Scotland

The authors describe two gas sample collection techniques, each of which is used in conjunction with custom made automated or manually operated closed chambers. The automated system allows automatic collection of gas samples for simultaneous analysis of multiple trace gas efflux from soils, permitting long-term monitoring. Since the manual system is cheaper to produce, it can be replicated more than the automated and used to estimate spatial variability of soil fluxes. The automated chamber covers a soil area of 0.5 m{sup 2} and has a motor driven lid that remains operational throughout a range of weather conditions. Both systems use gas-tight containers of robust metal construction, which give good sample retention, thereby allowing long-term storage and convenience of transport from remote locations. The containers in the automated system are filled by pumping gas from the closed chamber via a multiway rotary valve. Stored samples from both systems are analyzed simultaneously for N{sub 2}O and CO{sub 2} using automated injection into laboratory-based gas chromatographs. The use of both collection systems is illustrated by results from a field experiment on sewage sludge disposal to land where N{sub 2}O fluxes were high. The automated gas sampling system permitted quantification of the marked temporalmore » variability of concurrent N{sub 2}O and CO{sub 2} fluxes and allowed improved estimation of cumulative fluxes. The automated measurement approach yielded higher estimates of cumulative flux because integration of manual point-in-time observations missed a number of transient high-flux events.« less

Long term monitoring of soil gas fluxes with closed chambers using automated and manual systems

he recent special issue of this journal on 'Soils and the T Greenhouse Effect: indicated how nitrous oxide (N20) emissions from soil increase after incorporation of organic residues (Oenema et al., 1997). However, to date, very little work has been carried out on how sewage sludge amendment influences N20 emissions from soils. The ban on sea dumping and the need for additional waste water treatment could increase the amount of sludge for disposal 111 the UK to 1.5 million tonnes dry solid (tds) per annum by 2005 (Houghton, 1996). Much of this will be applied to grasslmd, hence our objective was to measure N20 emissions from a medium-textured soil in a typical area likely to receive sewage sludge. Digested sludge cake was incorporated into '1 grass sward at a rate of 185 tds/ha as part of an experiment investigating heavy metal accumulation at Auchincruive, Ayr. The total-N applied was 1000 kg/ha, 30% ofwhich was considered available (Aitken, 1997). For comparison, a similar rate of available-N (480 kg N/ha) was broadcast as ammonium nitrate fertilizer in four 120 kg increments on the control plot. Samples of N20 were collected at regular intervals (6/day) using a novel automated sample collection and storage sjstem, and from two manual chambers (2/week); samples were analysed using gas chromatography and fluxes calculated (Scott et al., 1998). Rainfall was recorded at hourly intervals During the first 4 days of assessment, large diurnal N20 fluxes (Fig. 1) were emitted from the sludge-amended plot. These fluxes are characteristic of denitrificarion processes

Nitrous oxide emissions from grassland amended with sewage sludge

Nitrous oxide emission from an agricultural field: Comparison between measurements by flux chamber and micrometerological techniques

Small flux chambers are widely used to measure emissions of nitrous oxide, N2O , from soil, the gas being determined by gas chromatography with an electron capture detector. The technique is relatively cheap, and is adaptable to a wide range of site conditions and emission rates: from the order of 1 µg m-2 h-1 to more than 10 mg m-2 h-1. Increasingly, systems are being automated, to get more information on short-term temporal variability and to collect data over long periods to improve estimates of total annual emissions. Such systems are being used in the field and with soil monoliths installed in a greenhouse. Large chambers 50-60 m2 in area, with gas analysis by long-path infrared spectrometry, offer a way of overcoming small-scale spatial variability, and are useful in conditions where micrometeorological methods may not be applicable, or when long runs of data are needed from the same site. In studies with small closed chambers, we have measured N20 emissions from grassland ranging from negligible values to about 4 mg N2O -N m-2 h-1 (nearly 1 kg N2O-N ha-1 d-1), with total losses in the range 0.14-5.1% of the nitrogen applied as fertilizer, depending on factors such as soil structure, water potential and temperature, and the chemical form of the fertilizer. Reasonable agreement can be obtained between chamber and micrometeorological flux measurements on homogeneous sites.

Philosophical Transactions of the Royal Society of London. Series A: Physical and Engineering Sciences

The measurement of nitrous oxide emissions from soil by using chambers

The Siemens-Plessey, Hawk long-path infrared gas monitor, an instrument originally designed for identification of leaks of pollutant gases from industrial sources, has been applied successfully to the measurement of nitrous oxide, N2O, fluxes from soil. The Hawk system was tuned to the 2180–2200 cm−1 region of the IR spectrum and thus dedicated to the measurement of N2O alone. The response to increasing concentrations of N2O in the absorption path was linear over the range measured, from ambient (0.31 parts per million by volume (ppmv)) up to 4.3 ppmv. The system was compared with a Bomem Fourier transform infrared (FTIR) spectrometer within an ultralarge chamber (60 m2). The responses of the two instruments were very closely correlated, and the FTIR was used to provide an absolute calibration of the Hawk. Flux measurements by the Hawk/ultralarge chamber system, on a fertilized grassland site on a clay soil in central Scotland, were compared with those measured by conventional small-chamber/gas chromatography methods, using small chambers both within the ultralarge chamber and elsewhere on the experimental site. The results obtained by the different methods were compatible, taking into account the high degree of spatial variability observed at this site. We conclude that the Hawk/large chamber combination shows considerable potential for measuring fluxes from areas 102–103 times larger than those covered by conventional small chambers and from sites where the heterogeneity (including the presence of experimental plots with different treatments) precludes the use of micrometeorological methods.

Use of a long-path infrared gas monitor for measurement of nitrous oxide flux from soil

This study aims to identify factors influencing corporate social responsibility reporting (CSRR) practices of international oil companies (IOCs) in Nigeria. It aims at distinguishing CSRR levels by examining both the quantity and quality of reporting.,The paper analyses annual reports through content analysis. CSRR extent and type are measured by the number of sentences. CSRR are further classified into three subcategories according to whether they are negative, neutral or positive reports and then their proportions compared through descriptive analysis.,For the extent and quality of CSRR, community was the most reported category. The majority of the total CSRR in the IOCs is positive with little evidence of negative news. None of the IOCs in the sample reported on the environment in their annual reports.,The measurement of CSRR focuses only on annual reports, without consideration of other reporting media such as standalone reports and corporate websites. CSRR are assumed to be voluntary for the companies and they may choose not to report any information in annual reports, as there are no regulations or reporting guidelines in Nigeria to be followed.,The results reveal the absence of environmental reporting in the CSRR of IOCs in Nigeria suggests that they are less concerned with meeting local demands for accountability. The study recommends the need for regulatory intervention on the part of the Nigerian Government.,The findings of study indicate that predominant existence of positive CSRR news among all the IOCs suggests there’s an attempt to encourage stakeholders and the public to believe that they are conscious of society and the environment.,The main contribution of this study lies in identifying the factors that have led to diversity and uniqueness in CSRR in IOCs. As such, this study seeks to contribute to the development of understanding multiple factors that could give rise to changing patterns of CSRR.

Corporate social responsibility reporting of international oil companies in Nigeria

Purpose 
 
This paper aims to identify factors influencing and shaping community perceptions of oil companies which present fertile ground for a better understanding of their actions. 
 
A qualitative methodology is adopted where primary data were collected through semi-structured interviews from members of three communities in the Niger Delta: Ogbunabali community in Port Harcourt (Rivers State), Biogbolo community in Yenagoa (Bayelsa State) and Ogunu community in Warri (Delta State). The interview data were recorded, transcribed and qualitatively analysed using content analysis with NVivo software. 
 
Findings 
 
Perceptions regarding negative and positive aspects of the oil companies were identified. These included environmental concerns; lack of compensation; health effects; lack of social development; neglect of communities; not creating employment opportunities; and providing community and educational support. 
 
A major limitation regards the small number of respondents selected from the communities. The sample of the interviewees was constrained by their availability and accessibility, which might have injected some bias. Gathering data from other stakeholders such as non-governmental organisations, consumers, investors and creditors may provide a deeper understanding of social and environmental practices. Another approach would be to extend this study by examining the perceptions of relevant government officials towards social and environmental concerns in developing countries. 
 
The qualitative research methodology utilised in this study uses content analysis to examine views of communities about oil companies’ commitments to their social and environmental concerns. An understanding of social and environmental commitments allows diverse stakeholders such as communities to become more engaged with issues affecting them.

Community perceptions of Nigerian oil companies commitment to social and environmental concerns

Purpose 
 
This study aims to identify the differences between local and foreign companies’ social and environmental disclosures (SEDs) practices operating in the Nigerian oil sector. It aims at distinguishing SED levels by comparing local and foreign companies operating in the oil sector. 
 
The paper analyses annual reports through content analysis. SED extent and type are measured by the number of sentences. SEDs are further classified into three subcategories according to whether they are negative, neutral or positive disclosures and then their proportions are compared through descriptive analysis. To better understand SED differences, the Kruskal–Wallis and Mann–Whitney–Wilcoxon tests are used. 
 
Findings 
 
Local companies are found to provide more content and a wider variety of SED than foreign companies. The majority of the total SEDs in both local and foreign companies are positive with very little evidence of negative news. 
 
The measurement of SEDs focuses on only annual reports, without consideration of other disclosure media such as standalone reports and corporate websites. SEDs are assumed to be voluntary for the companies and they may choose not to disclose any information in annual reports, as there are no regulations or disclosure guidelines in Nigeria to be followed. 
 
The main contribution of this study lies in identifying the factors that have led to diversity and uniqueness in SED between local and foreign oil companies. As such, this study seeks to contribute to the development of understanding multiple factors that could give rise to changing patterns of SED.

Differential reporting of social and environmental disclosures between local and foreign oil companies in Nigeria

Purpose 
 
This study seeks to examine the quantity and quality of social and environmental disclosures (SEDs) of Nigerian oil companies. The study aims to analyse SED activities as reported by the oil companies in their annual reports. 
 
The study analyses annual reports through content analysis. SED quantity is measured by alternative two units: number of sentences and number of pages. A two-point scale system to assess SED quality is used as follows: 1 = if SED is quantitative and reports specific activities of a company concerning its social and environmental responsibility; 0 = otherwise. Correlation analysis is performed among the different SED categories to identify the relationships among them. Kolmongrov–Smirnov and Shapiro–Wilk tests for normality are utilised. 
 
Findings 
 
SED activities are reported by most of the companies, and by quantity, employee information is found to be the most common type of disclosure. SED quantity and quality in the environment category is found to be overwhelmingly low despite the large-scale public concern expressed about the levels of the environmental degradation caused by oil company operations. 
 
The data collected for this study are based on one country, which controls diversity but limits the generalizability of the findings. The study is limited by the sample which includes mainly quoted companies, as they are believed to make improved disclosures because of their investor orientation and statutory obligations. 
 
The study extends SED research by focusing on social disclosures such as employee-, community- and health- and safety-related disclosures. The study also investigates the motivations of SED providers and establishes a link between stakeholder demands/engagement and the level of disclosure.

An examination of the quality of social and environmental disclosures by Nigerian oil companies

This study reviews the literature which attempts to analyse factors influencing corporate social and environmental disclosure (SED). Of particular interest are two questions: 1) Which companies are motivated to provide information on their SED responsibilities?; 2) Why are companies interested in SED? The review was carried out by primarily consulting leading corporate management and accounting journals over the past 30 years. An analysis of the factors affecting SED reporting was undertaken. The motivations of companies for SED vary widely, yet the literature strongly suggests there is inconsistency in motives. So why are companies interested in SED? This was explained primarily as a function of corporate image making and to avoid scrutiny by government which could lead to adverse publicity. There is wide variation in both the quantity and quality of disclosures. There are also noticeable differences in SED between developed, transition and developing country companies.

Factors influencing corporate social and environmental disclosures: a systematic review

Abstract: The paper reviews the history of water management policies in the Jefara Plain Region (JPR) of Libya in light of water scarcity. The paper also examines the theoretical considerations and current consensus of opinion concerning the issues of water scarcity, conservation and management to determine any gaps. The research design and method is a literature review of both academic publications and governmental and NGO reports relating to water scarcity and management in JPR Libya. While the country has been subjected to a variety of water management policies, those dealing with water issues in the JPR have been characterized by mismanagement and substandard practice. The JPR is an arid region and its meagre run-off water supplies are complemented by groundwater sources from fossil aquifers. These underground sources contribute more than 2,400 million cubic metres per year against an annual recharge of only 650 million cubic metres, and clearly will eventually run out. It indicates a failure of water management institutions to consider the three core considerations of water conservation: nature, the current generation, and future generations. This is a very early scholarly paper to examine in a rigorous fashion the literature and viewpoints relating to water scarcity and management in JPR Libya. It comes at an important time because the new Libyan government and citizens need to manage water issues satisfactorily in the near future.

Water scarcity and history of water management policy in agriculture in the Jefara Plain Region of Libya: theoretical considerations and the current consensus

Information about the current state of water institutional frameworks, water infrastructure and water management policies in Libya enable the identification and evaluation of a range of options for improving water use efficiency in agriculture and the potential role of water pricing in achieving sustainability of water sources. This paper begins with an overview of the agricultural sector. In order to assess the current water situation in Libya, the water infrastructure will be examined through a review of water legislation, its institutional framework and the infrastructure surrounding the various water resources. The national strategy for the management of water resources and the suggested plans to address the inefficient use of water in the Jefara Plain Region (JPR) will be discussed. The last section will be devoted to the Great Man-made River Project (GMRP) and water investment in JPR's agriculture, and conclude by identifying the problems and obstacles facing the outcomes for these investments.

Water infrastructure in Libya and the water situation in agriculture in the Jefara region of Libya

This study compares the contextual factors (culture, political, legal, economic system, and stock exchanges) in three North Africa countries (Egypt, Morocco, and Tunisia). The contextual factors of these countries are very similar being Islamic culture and French law. These countries have similarities in their recent histories. They were occupied by European countries which resulted in English and French languages being spoken in this region. Dictatorial governments (regardless of the types of governments - socialist or otherwise) have also controlled these countries for considerable periods of time since independence. In line with international society, an openness policy has been adopted and many reforms have been made in the stock exchange of these countries. However, much work remains to be done. Although contextual factors are similar, each country is in a slightly different place today in regards to economic and capital markets' development. Policy-makers can learn from the experiences of these three NA countries as the obstacles and backgrounds of these three countries are similar. This is the first accounting paper of which we are aware that studies these three NA countries.

A review of the contextual factors associated with the North African business environment - descriptive historical study

Organisations have developed collaborative alliances with the enterprises they interact with in the virtual environment. This paper explores the impact and the possible impact on virtual team members engaged in a collaborative network. A literature review was conducted on virtualization in organizations to ascertain the degree of attention given to the impact on individual team members in collaborative networks.

This paper explores the current debate about water management policies and the factors affecting their formulation and implementation in the arid and semi-arid zones of the Near East and North African Region (NENAR). In this context, relevant and significant experiences of other countries in the world facing similar challenges are also considered (Sachdeva, 2009). The literature pertaining to water management policies is examined to better understand the processes and the experiences of water management reform in these countries and the variables affecting them. Review of different water management policies should provide insights into the parameters and scope of research into improving water use efficiency in agriculture and the effect of water price on farmers' viability. This review will allow both an identification of, and an investigation into, the challenges faced by policymakers in framing water policies linked to water scarcity and water use efficiency in irrigation (Laamrani and Salih, 2010).

Review of agricultural water management policies in Near East and North African Region in light of water scarcity

Organizations have developed collaborative alliances with the enterprises they interact with in the virtual environment. This paper explores virtualization, collaborative networks and virtual teams. The current status of collaborative practices and recent research activities in virtualization are reviewed to determine what further developments and research is anticipated.

The purpose of this paper is to provide empirical evidence of an examined model of purchase intentions on business to consumer e-commerce transactions in developing countries using Indonesia as a case study. Adopting the theory of planned behavior, data from an Indonesia Internet discussion group was analyzed using structural equation modeling. The main finding is that purchase intention of business to consumer e-commerce transactions in developing countries such as Indonesia is able to be predicted by theory of planned behavior. Limited numbers of previous studies accommodate some proof of the theory of planned behavior and its application to explain consumers' purchase intentions in developing countries. This empirical study has provided evidence that the model is applicable in this context.

Purchase Intention to Undertake e-Commerce Transactions in Developing Countries: Application of Theory of Planned Behavior in Indonesia

This paper discusses the differences between a traditional organization and a virtual organization. Different forms of virtual organizations are described to illustrate the nature of a virtual organization. The concept of a virtual supply chain is proposed and defined as a hybrid of the existing forms of virtual organizations. A virtual supply chain is then explored from an information systems viewpoint. This exploration reveals contextual factors associated with information systems in a virtual supply chain. These issues are further explored to determine how they might be addressed. Finally further research that could be conducted is proposed.

2009 Fourth International Conference on Cooperation and Promotion of Information Resources in Science and Technology

Contextual Factors Associated with Information Systems in a Virtual Supply Chain

The quasi-integration of information systems of different organizations is made possible by Internet technology but the implications for management information systems has received scant attention in the literature. This paper explores the concept of management information systems in a virtual organization. The exploration revealed contextual factors associated with management information systems in a virtual organization. These contextual factors were further explored to determine how they might be addressed. Finally further research that could be conducted is proposed.

Contextual factors associated with management information systems in a virtual organization

Organizations are developing alliances with the 
enterprises they interact with in a virtual environment. The key factor in such virtual organizations is information systems. Concerns about quality of information systems may be 
compounded within the virtual organization. This paper considers possible issues that might affect the quality of information systems within the virtual organization.

There is evidence of a paradigm shift in organizational structures as organizations utilize the internet technology to add a virtual dimension to their activities. Virtuality in the manufacturing domain is referred to as Virtual Enterprises (VE) or Extended Enterprises and within the commercial domain is referred to as the Virtual Organization. 
The key factor in virtuality is the information flows across enterprises. The quasi-integration of information systems is made possible by the technology but the implications for information management has received scant attention in the literature. This paper explores the concept of virtuality to identify the possible challenges for information management. This exploration identifies a preliminary set of prerequisites associated with information management in the virtual organization. Further research to help meet this challenge is identified.

Implications for information management in the virtual organization

A student's perception of a software development process model appears to be a series of milestones when documentation is produced to satisfy academic requirements. Certain academic and industrial practices may influence students to place more emphasis on the software product than the process model. The proposal presented is to establish a more structured approach to project supervision to ensure a student performs quality planning, which includes the identification of appropriate software product quality attributes. Such an approach may ensure that sufficient attention is given to the software development process model to ensure that desired software product quality attributes are achieved.

Efforts to determine the suitability of low-grade pancreatic injuries for nonoperative management have been hindered by the inaccuracy of older computed tomography (CT) technology for detecting pancreatic injury (PI). This retrospective, multicenter American Association for the Surgery of Trauma-sponsored trial examined the sensitivity of newer 16- and 64-multidetector CT (MDCT) for detecting PI, and sensitivity/specificity for the identification of pancreatic ductal injury (PDI).

METHODS
Patients who received a preoperative 16- or 64-MDCT followed by laparotomy with a documented PI were enrolled. Preoperative MDCT scans were classified as indicating the presence (+) or absence (-) of PI and PDI. Operative notes were reviewed and all patients were confirmed as PI (+), and then classified as PDI (+) or (-). As all patients had PI, an analysis of PI specificity was not possible. PI patients formed the pool for further PDI analysis. As sensitivity and specificity data were available for PDI, multivariate logistic regression was performed for PDI patients using the presence or absence of agreement between CT and operative note findings as an independent variable. Covariates were age, gender, Injury Severity Score, mechanism of injury, presence of oral contrast, presence of other abdominal injuries, performance of the scan as part of a dedicated pancreas protocol, and image thickness < or =3 mm or > or =5 mm.

RESULTS
Twenty centers enrolled 206 PI patients, including 71 PDI (+) patients. Intravenous contrast was used in 203 studies; 69 studies used presence of oral contrast. Eight-nine percent were blunt mechanisms, and 96% were able to have their duct status operatively classified as PDI (+) or (-). The sensitivity of 16-MDCT for all PI was 60.1%, whereas 64-MDCT was 47.2%. For PDI, the sensitivities of 16- and 64-MDCT were 54.0% and 52.4%, respectively, with specificities of 94.8% for 16-MDCT scanners and 90.3% for 64-MDCT scanners. Logistic regression showed that no covariates were associated with an increased likelihood of detecting PDI for either 16- or 64-MDCT scanners. The area under the curve was 0.66 for the 16-MDCT PDI analysis and 0.77 for the 64-MDCT PDI analysis.

Sixteen and 64-MDCT have low sensitivity for detecting PI and PDI, while exhibiting a high specificity for PDI. Their use as decision-making tools for the nonoperative management of PI are, therefore, limited.

An evaluation of multidetector computed tomography in detecting pancreatic injury: results of a multicenter AAST study.

Meckel's diverticulum is the most common congenital abnormality of the gastrointestinal tract. Complications most frequently arise in children younger than 2 years who present with gastrointestinal bleeding. The diagnosis is usually made via radionuclide scintigraphy or intraoperatively. The authors report a 71-year-old man who developed a sudden onset of right lower quadrant abdominal pain, without bleeding, and was diagnosed as having Meckel's diverticulitis via computed tomography. The presence of Meckel' s diverticulitis was confirmed at surgery. Complications of a Meckel's diverticulum must be considered at any age. Computed tomography is another modality that may be helpful in the preoperative diagnosis.

Meckel's diverticulitis in an elderly man diagnosed by computed tomography.

According to the 2000 Report of the Surgeon General's Conference on Children's Mental Health, a significant percentage of children and adolescents have emotional or behavioral problems serious enough to merit a mental health diagnosis. The No Child Left Behind Act of 2001 and the Individuals With Disabilities Education Improvement Act of 2004 reemphasized the schools' importance in supporting cognitive and behavioral development in students, particularly those identified with learning problems. In this article, we examine the growing specialty of clinical neuropsychology and provide suggestions for integrating this field into school-based psychological services.

METHODS
This article provides a review of the neuropsychological bases for many childhood learning disorders and addresses how school psychologists can work with clinical neuropsychologists to better address the needs of exceptional children through neuropsychological testing.

RESULTS
There is substantial neurological evidence for attention-deficit hyperactivity disorder as well as disorders of reading, language, and mathematics. Close collaborative partnerships between clinical neuropsychologists and school psychologists will help develop assessment protocols that are likely to result in more effective intervention services for students with neuropsychological conditions.

Schools are being asked to support the physical, cognitive, and emotional development in students, particularly those identified with chronic physical and mental health challenges. Dissatisfaction with minimal screenings, the growing awareness of the neurology of learning disorders, and the passage of the Individuals With Disabilities Education Improvement Act of 2004 obliges all school-based mental health providers to consider how to fully integrate the tools of clinical neuropsychology into school-based psychological services.

Developments in clinical neuropsychology: implications for school psychological services.

This article describes a case study in which a 7-year-old first grade boy (Phil) underwent neuropsychological assessment to determine the possible existence of attention deficit hyperactivity disorder. Subsequent performances on tests of attention and executive functioning were quite variable. Specifically, there were indicators of inattention, erratic response style, and executive dysfunction evidenced by a large number of commission errors. In addition, there were difficulties maintaining attentional focus in the presence of distracters, weaknesses in working memory, information processing speed, and difficulties with planning and inhibition. Treatment implications are subsequently described, particularly the growing use of computer-assisted cognitive training to address working memory and executive functioning. Finally, the article concludes with a discussion about how to employ neuropsychological results in an effort to meaningfully engage the family of an attention deficit hyperactivity disorder child in long-term therapy.

Utilizing Neuropsychological Testing to Inform ADHD Diagnosis and Treatment

This article describes a case study in which neuropsychological assessment was carried out on a 30-year-old, previously diagnosed, bipolar female to determine existence of specific deficits in cognitive function. The patient, whose mood cycles were 12 hours to 24 hours, was subsequently evaluated 8 hours per day for 5 consecutive days (a complete work week of neuropsychological assessment). Neuropsychological results showed motor slowing, right hemispheric dysfunctioning, and memory problems during depressive periods and attentional and executive problems during hypomanic and manic periods. The most normal performance was found during euthymic periods. In addition, left and right hemi visual neglect, aphasia, and sensorimotor problems were present across all mood states. Treatment implications are subsequently described.

A Patient With Bipolar Illness and Her Neuropsychological Signature

The effect of involvement on the reading attitude-behavior relationship

Hedonic product design and its role in online marketing communications

Leisure reading and genre category preferences : Identifying discriminating product attributes

This study examined the relationship between the assertiveness, conformity, and drug use of sixteen (n = 16) university students. Subjects were exposed to a series of ten conformity tasks based on Asch's classic paradigm. The College Self-Expression Scale and the Tentative Drug Use Scale were administered. Assertiveness and conformity scores were blocked on alcohol-marijuana and “hard” drug-use. One-way analyses of variance revealed that alcohol-marijuana users were less assertive and more compliant than “hard” drug users.

The Relationship between Assertiveness, Conformity, and Drug Use

This study investigated the efficacy of covert other modeling, covert self-modeling, and written material on the acquisition of a counseling strategy that involved developing goals. Thirty-six student counselors were assigned randomly to the following four treatment conditions: covert other model, covert self-model, written material, and delayed-treatment control. Written pretest, posttest, retention test measures, and role-play pre- and posttest measures were obtained. A repeated measures ANOVA revealed that performance on the written measures for the three treatment groups increased significantly from pre- to post- testing and from pre- to retention testing. On the role-play measure, the performance of the three treatment groups also increased significantly from pre- to posttesting. The performance of the control group on pre- and posttesting for the written and role-play measures did not increase significantly.

Effects of Covert Modeling and Written Material on the Acquisition of a Counseling Strategy.

An unconventional path towards integration: A study of low-income community college students' career decision-making self-efficacy beliefs

This study investigated the morphology of the mesiobuccal root of the maxillary first molar. One hundred ten extracted maxillary first molars were accessed. The first and second mesiobuccal canals were exposed, soaked in black India ink, decalcified, dehydrated, and made transparent. The configurations of the root canals in the mesiobuccal root were studied under magnification (2.6x) and classified according to Weine's four types of root canal configurations. Under the conditions of this study, a high percentage of second mesiobuccal canals were revealed.

Canal configuration in the mesiobuccal root of the maxillary first molar: a descriptive study.

Sea and water imagery in Byron's Childe Harold's pilgrimage and Don Juan.

Surveillance imaging often shows indeterminate lesions in the cirrhotic liver, which may represent early hepatocellular carcinoma (HCC), dysplastic or regenerative nodules, or vascular shunts. The risk of HCC after identification of an indeterminate nodule is not well described.

An indeterminate nodule in the cirrhotic liver discovered by surveillance imaging is a prelude to malignancy

Outcomes in Patients with Obstructive Jaundice from Metastatic Colorectal Cancer and Implications for Management

Classification of Indeterminate Melanocytic Lesions by MicroRNA Profiling

An obstacle to China’s WWTPs: the COD and BOD standards for discharge into municipal sewers

The Appellate Body report in January 2012 had supported the decision of Panel in the “China-measures related to the exportation of various raw materials” case (WT/DS394,395,398) and affirmed that China’s restrictions (such as tariffs and quota measures) on the exportation of raw materials violated rules put forth by the WTO, which were required to be modified. In this case China’s right to invoke Article 20 of GATT1994 (“general exception”) to justify its exemption from the guidelines in Article 11.3 of the WTO Accession Protocol was denied by the Panel and the Appellate Body. This was due to the fact that the phrasing in Article 11.3 of Protocol failed to mention “GATT.” This was the consequence of the two interpretation approaches the Dispute Settlement Body (DSB) adopted – a narrow textual interpretation and a subjective presumption of “legislative silence.” The inappropriate use of the two methods of interpretation lead to an imbalance between the right and obligation of China under the additional obligations that were imposed upon China by the WTO, which create a negative impact on China’s rare earth case and the protection of domestic natural resources.

On “China-measures related to the exportation of various raw materials” case in terms of DSB’s interpretations

The purposes of this research are to understand contractor and customer motivations for participating in the Home Performance with ENERGY STAR (HPwES) Program; to assess the extent to which HPwES contractors are delivering whole house energy services; and to examine whether participating and nonparticipating contractors report using HPwES standards when installing measures outside the program. The study makes use of information developed for NYSERDA’s HPwES Market Characterization and Assessment Study completed in 2009, including analysis of program databases, telephone surveys with participating and nonparticipating contractors, and telephone surveys with homeowners.

New York Home Performance with ENERGY STAR Program (HPwES) Contractor and Customer Reports on Market Transformation 1

Applying APPA Guidelines for Custodial Staffing: The Case of Slippery Rock University.

Approximately 17 state-level, public benefit charge-funded clean energy programs across the country are in various stages of program design and maturation. These programs have many ambitious objectives that typically include: expanding renewable energy generating capacity, resulting in the displacement of fossil-fuel generation; developing sustainable markets for renewable energy based on voluntary purchases and private investment decisions; and increasing public support for renewable energy, manifested by consumer purchases, and citizen and corporate actions. Funding for measuring success and evaluating progress is not unlimited; administrators often seek maximum learning about their maturing programs on limited budgets. Staff time dedicated to evaluation is also scarce. This paper describes a methodology used to swiftly establish evaluation parameters, and the results from the ensuing evaluation, using a state-funded clean energy initiative as a sample case. This evaluation showed that the short time spent initially to identify and map the key program activities to outputs and long-term outcomes (through a simplified program logic modeling approach), can yield significant benefit in terms of providing managers with needed information for program optimization and strategies for maximizing achievements towards strategic objectives. In addition, using this type of evaluation approach can help renewable energy program administrators: document progress toward key short-term and intermediate goals; verify prudent expenditures of public funds; and lay the groundwork for subsequent intermediate- and long-term evaluation activities.

Using Program Logic Models to Guide Evaluation of Public Benefit Charge-Funded Clean Energy Programs Methodologies and Sample Results from a Recent Massachusetts Technology Collaborative Evaluation

Portfolio-level and program-specific theory and logic modeling activities are currently being performed within the New York State Research and Development Authority (NYSERDA) for their New York Energy-$martK Program. This paper provides details on the theory and logic efforts that have evolved during an ongoing assessment of over 30 interrelated energy-efficiency and renewable-resource programs. These activities are helping NYSERDA to describe critical program activities within a broader context of the markets it is targeting. They help describe how the portfolio of programs works together to achieve overarching goals and confirm and identify logic elements and underlying theories. In addition they can identify high priority measurement indicators and researchable issues for tracking performance, market changes, and assessing causality. Results from these activities are also providing NYSERDAs implementation staff with real-time insights and feedback on the effectiveness of their programs, recommendations for modifications to better align activities with desired goals (given current driving and restraining forces), and an improved performance story to explain their programs to partners and stakeholders. Samples of the methods used, logic-diagrams created, logic-elements identified (i.e., target markets, barriers, program activities, outputs, short, intermediate and long-term outcomes, external influences), potential measurement indicators, and researchable issues are provided. Finally, the paper summarizes results and lessons learned about logic modeling in general, and more practically with a focus on describing how these theory-related activities are being used to help develop energy-efficiency policies, program designs, market assessments and implementation improvements that will maximize abilities to achieve lasting change. Summary of the New York Energy $mart SM Program The New York Energy $mart SM Program was established through a regulatory Order issued by the New York State Public Service Commission (PSC) in January 1998 and commenced implementation on July 1, 1998. 1 In total program consists of over 30 separate initiatives, and multiple sub-components, working in four major program areas as follows: (1) Commercial and Industrial Energy Efficiency; (2) Residential Energy Affordability; (3) Low1 PSC Case No. 94-E-0952, Opinion and Order Concerning System Benefits Charge Issues, Issued and Effective January 30, 1998. The Program is currently scheduled to run through June 30, 2006.

Using program theory and logic to improve design and likelihood of real market change : experience with a state public benefits program.

A STUDY OF THE ANTIMONY TRICHLORIDE COLOR REACTION FOR VITAMIN A II. THE DILUTION CURVE OF COD LIVER OIL WITH ANTIMONY TRICHLORIDE REAGENT

PURE ARSENOBENZENE AND THE MOLECULAR COMPLEXITY OF ARSENOBENZENE AND ARSENOMETHANE

Additions and Corrections - The Arsonation of Aromatic Aldehydes

North American Racer (Coluber constrictor) on Grand Bahama, The Bahamas

Rulers without Borders:: The Difficulty of Identifying Polity Boundaries in Terminal Classic Yucatan and Beyond

Abstract The Sotuta pottery complex has been used in the archaeology of the northern Maya lowlands to identify the Terminal Classic period and cultural association with Chichen Itza. The Sotuta complex, however, is made up of many pottery types, the majority of which are inappropriate markers of elite sociopolitical history. It is argued here that Sotuta-complex slate wares developed out of previous local slate wares regardless of the elite sociopolitical changes taking place with the arrival of the Itza. The wares produced and distributed by commoners were independent of elites and have been artificially chained to questions of elite political expansion for which they are inappropriate correlates.

Abstract Surface collections are commonly used by archaeologists to sample artifact assemblages, but the correlation of surface and subsurface artifacts is not fully understood. Cultural, taphonomic, and research-design factors that can affect the relationship of surface and subsurface deposits are reviewed and the correlation of surface and subsurface deposits is tested statistically with data from the site of Popola, Yucatan, Mexico, a Late and Terminal Classic period (a.d. 600–1100) village in the northern Maya lowlands. This study suggests that surface artifact density is not correlated with subsurface artifact density. Large-scale surface collections can characterize the overall assemblage of a site, but not any small area in particular. In shallow bioturbated soils there is no significant variation between surface and subsurface assemblages at any depth. Surface artifacts may be used to identify the presence of subsurface artifacts, but should not be used to suggest their absence.

The correlation of surface and subsurface artifacts: A test case from Late and Terminal Classic Popola, Yucatan, Mexico

A Discussion and Description of Pottery Types Identified at Popolá, Yucatán, Mexico

Late and Terminal Classic power shifts in Yucatan: The view from Popola

The latest murals at Mayapan are painted on the Sala de los Simbolos Solares (Structure Q.161), an addition to the Castillo that dates to the last decades of Mayapan’s occupation (Milbrath and Peraza 2003:19, Table 1; Peraza et al. 2001) (Figure 1). The solar disks on Mayapan’s Structure Q.161 can be compared to Late Postclassic Aztec sculptures and to Mixteca-Puebla codices and murals at sites such as Mitla and Santa Rita (Figures 2–3). The Mayapan solar disks with only four rays seem simplified when compared to the more complex Aztec and Mixteca-Puebla forms, but this is not a significant stylistic difference because there is considerable variety in Mixteca-Puebla and Aztec solar disks (Miller 1982:Figure 109; Nuttal 1975:9, 10, 19, 21; Pasztory 1983:Plates 36, 85, 90, 234; Taube 1992:Figure 77).1 More Religious Imagery in Mayapan’s Murals ThePARI Journal

Splenius is a structurally complex muscle that is supplied by nerves from four cervical segments. We have examined the architectural organization of extrafusal fibers in splenius by microdissecting muscles stained "en bloc" with gold chloride. We also analyzed the distribution of motor units supplied from different cervical segments using the glycogen-depletion technique. Microdissections show that the fiber architecture of splenius is different in medial and lateral muscle parts. In medial splenius, muscle fascicles run uninterrupted from the muscle origin to insertion, while in lateral splenius, separate compartments of muscle fascicles are linked in series by two tendinous inscriptions. In muscle fascicles longer than 2.0 cm, many extrafusal fibers do not run the whole length of the fascicle. Instead, these fibers end intramuscularly by tapering to a fine strand that is closely adherent to adjacent extrafusal fibers. Less than 1% of extrafusal fibers in splenius exceeds 3.0 cm in length. Experiments using glycogen depletion showed that nerves from different spinal segments innervate different muscle regions. Nerves from C1 supply muscle fibers in a small rostromedial zone. Nerves from C2-C4 have motor domains that extend from the medial to the lateral muscle edge and are arranged in series. In lateral splenius, the motor domains are separated by tendinous inscriptions. In medial splenius, where no inscriptions are present, the motor domains of adjacent segmental nerves have overlapping boundaries due to the extensive interdigitation of motor units supplied from different segmental nerves. A single muscle fascicle in medial splenius is commonly composed of two sets of fibers supplied by adjacent segments that are distributed at opposite ends of the fascicle and interdigitate in midregions of the fascicle. The in-series compartmentalization of splenius has important implications for its motor control. To secure effective muscle shortening or tension development, central mechanisms may be required to coordinate the recruitment of in-series motor units. The presence of many short fibers with intramuscular insertions leads us to question how contractile forces are developed and transmitted in splenius and other mammalian muscles that are composed of short, in-series fibers.

The distribution of motoneurones to the cat dorsal neck muscles biventer cervicis, splenius and complexus has been examined using the technique of retrograde horseradish peroxidase transport. A comparison was initially made of HRP uptake into motoneurones produced either by injecting HRP solution directly into a singly neck muscle or by exposing the cut ends of motor nerves to an HRP solution. The injection of HRP into single neck muscles was found to produce widespread labelling of motoneurones presumably due to diffusion of HRP into adjacent muscles. For the examination of individual motoneurone pools the technique of cut nerve exposure was therefore used.

Distribution of motoneurones to the neck muscles, biventer cervicis, splenius and complexus in the cat

The antennal sensory appendix of Ctenicera destructor (Brown) appears to be a compound sensillum basiconicum formed by a union of about 12 individual sensilla. It is innervated by about 36 bipolar sense cells of type I, which occur usually in 12 groups of three neurons each. The sensory cuticle is large, cone-shaped, and abundantly perforated by a slit-tubule system. The dendrites of each group of neurons are enclosed distally by a single tubular cuticular sheath attached to the base of the cone by a suspensory fiber system. The ensheathed portion of the dendrites lies in a receptor-lymph cavity formed by the tormogen and accessory trophic cells. Distal dendritic branches pass below and occasionally enter inner pockets in the sensory cuticle, but no connections were seen between the slit-tubule system and the dendritic surfaces. About 12 of each of four types of cells are associated with the neurons in this sensillum: tormogen, trichogen, accessory trophic, and neurilemma. The ultrastructure and probable ...

Fine structure of the antennal sensory appendix in the larva of Ctenicera destructor (Brown) (Elateridae: Coleoptera).

The component ciliary collar, basal body, ciliary rootlets, trichogen–dendrite secretory junctions and secretory inclusions of the junction body region of dendrites in the wireworm antennal sensory cone are described. The primary function ascribed to the junction body region, based on the ultrastructural evidence presented, is one of secretion. The hypothesis that the secretory products produced in the junction body region are transported to the dendritic terminations in the sense organ is discussed and supported.

Fine structure of the dendritic junction body region of the antennal sensory cone in a larval elaterid (Coleoptera).

Aspects of the fine structure of symbiotes and related host tissues in nephridia of Allolobophora caliginosa typica (Annelida: Lumbricidae).

The isolation and analysis of hemicelluloses from rind of corn stalks, Zea mays.

The size and distribution of surplus in markets where credence quality attributes of goods are conveyed through some informational mechanism (typically labels) crucially depend on 1) how information changes consumers’ perception of quality and 2) producers’ strategic choice of quality provision in response to changes in consumers’ perception of quality. While there is a growing empirical literature on consumers’ perception of quality, there is a dearth of empirical studies regarding firms’ reactions to changes in consumers’ perception of quality. A major reason underlying this dearth of empirical studies is that consumers’ perceived, as opposed to actual–quality, is unobservable to the researcher. Based on previously derived theoretical predictions, I design an experiment in the laboratory where I emulate changes in consumers’ perception of quality and examine their effects on producers’ provision of quality and market surplus. The experiment indicates that overvaluation of high-quality products relative to their lower-quality competitors (e.g., 100% organic relative to organic or made with organic) and undervaluation of low-quality products (e.g., presence of GM inputs relative to GM-free) result in a significant increase in quality and prices at the higher end of the spectrum, increase in profit for the high-quality seller, and increase in total welfare. Misperception produces ambiguous changes at the lower quality end. Efficiency measures show that effective informational-based policies should focus on high-quality products, but distributional measures show that efficiency gains are at the expense of the low-quality segment of the market. Information-based mechanisms identifying unobserved credence attributes (e.g., labels) have proliferated in the markets of food products. Their increasing popularity is based on the assumption that they help consumers making better choices by eliminating informational asymmetries (Roe and Sheldon, 2007; Bonroy and Constantatos, 2015; Lusk et al., 2018). However, evidence provided by choice experiments reveals that consumers often fail to understand the information conceived in labels (Kiesel and Villas-Boas, 2013; Lee et al., 2013; Liaukonyte et al., 2015; McFadden and Lusk, 2018), which implies that consumers can miss-perceive (overor undervalue) the true quality of labeled products. Economic intuition suggests that misperception can distort consumers’ choices and change sellers’ strategic responses (e.g. quality choice, price charged), impacting the size and distribution of welfare in the market. However, there is a dearth of empirical studies examining sellers’ strategic reactions to consumers’ misperception. This is partly explained by the unobserved nature of consumers’ misperception and the difficulty of finding data with observational variation to misperception (Dranove and Jin, 2010). To circumvent these limitations, I report a laboratory experiment that analyzes the degree to which the intensity of consumers’ misperception alters sellers’ strategic responses. In this paper, I manipulate the intensity of consumer misperception in a laboratory experiment to test the direction and magnitude of the effects of misperception of quality on market outcomes (qualities and prices), and welfare outcomes (consumer surplus, profits, and total welfare). My experimental design is based on the comparative statics from Scott and Sesmero (2020) which modifies the canonical model of competition by vertical differentiation to include the effects of consumers’ misperception of quality. They consider a market where two single-product sellers— one serving the high-quality segment of the market and the other the low-quality segment— imperfectly compete on quality and prices. The authors assume quality is determined by credence attributes that can be conveyed by some costly informational mechanism to be adopted by sellers (e.g., labels), but consumers may misperceive the

Market and welfare effects of quality misperception in food labels

Credit plays a critical role in the agricultural sector, but many studies suggest that farmers are credit constrained. We examine the degree to which changes in non-real-estate agricultural loans at commercial banks are driven by changes in supply and demand, using information provided by agricultural lending surveys conducted by the Federal Reserve Banks of Chicago, Kansas City, and Minneapolis. Building on recent studies of loan officer opinion surveys, we estimate the changes in agricultural loan supply and demand using an unbalanced panel of 1,024 banks across 191 quarters (2002:Q1–2021:Q2). The survey responses provide instruments of “pure” supply and demand changes that allow us to examine fluctuations in bank-level agricultural loan volumes. We find that changes in the volume of non-real-estate farm loans at commercial banks are principally driven by changes in excess demand for loans. In addition, we demonstrate that excess loan demand is countercyclical to aggregate farm income.

Optimal quality gradation in organic labels: evidence from a structural econometrics model

This dissertation expands on the economics of labeling products with credence quality attributes. Specifically, it aims at incorporating recent discussions in the food markets regarding 1) consumers' difficulty of perceiving the exact quality that labels try to communicate and 2) imperfect competition on quality and price between firms providing these labeled products. These items are important because consumers and firms have to navigate a market environment in which there exist many quality labels competing for consumers' preferences (e.g., nonGMO, USDA organic, Bioengineered label, local) with many of these labels offering different grades of quality (e.g., 100\% organic, organic, made with organic ingredients). While more quality label may match consumers' heterogeneous preferences, they may cause confusion and misperception among buyers, ultimately impacting efficiency and distribution of surplus in the market. More quality labels also may impact firms' decisions as firms can select themselves into different poles of the quality spectrum and avoid price competition by doing so. Finally, governmental policies that aim at educating consumers or provide them with more options (e.g., informational-based policies, graded USDA organic certification program) can have unintended consequences under an environment in which there exist market failures related to information or competition.My goal is to evaluate this complex environment in three interconnected studies. The first study is an applied theory paper in which I show how curbing consumers' misperception about quality in a market of labeled credence attributes may decrease welfare if firms imperfectly compete in quality and prices. I show that this is true if consumers' misperception offers incentives for firms to either expand the size of the market or increase the average quality of products offered. The second essay empirically tests these insights in controlled laboratory experiments in which subjects act as sellers that compete along quality and price dimensions. I show that the insights of the theory paper hold particularly when consumers overvalue a high-quality product that holds a large market share. Finally, in the last study of this dissertation, I show that the rank-order of the USDA organic certification program may not hold in all markets, as consumers may not have a high willingness to pay for 100\% organic products. In the study, I show that consumers in the market of organic ground coffee market could be better off if USDA ditched the quality grade \textbf{100\% organic} of its program. Doing so would also benefit the most profitable firms in the market and increase welfare.This dissertation shows that label programs and food policies that tackle quality in credence attributes must be designed with two main market characteristics in sight. The first is how well consumers understand the information in labels. The second is what is the degree of competition in the market and how firms can use the certification program to extract further rents from consumers.

The economics of labeling credence goods: theory and measurement

Consumers’ shifting tastes have made sustainable growth for firms in the food industry increasingly difficult. Scholars and industry practitioners constantly try to develop business strategies to d...

Scott, Francisco A. MS, Purdue University, August 2016. Firm Demography and Location Decisions in the United States after 1990. Major Professor: Raymond J.G.M. Florax. This thesis deals with firm formation and location choice of firms in the manufacturing (and commercial service) sector in the United States after 1990. The topics of firm formation and location choice are part of a wider field that is usually referred to as “firm demography.” We start off with a description of the size structure of firms by looking at the evolution of the average size of manufacturing firms in counties in the USA between 1990 and 2011. We hypothesize that the size of manufacturing firms depends on the firm sizes in proximate regions as well as on the region’s own average firm size in previous years. Three Markov chain models are proposed to test this hypothesis, a first-order process, a second-order process and a spatially lagged Markov chain models. By means of Likelihood Ratio tests we show that the firstorder Markov chain does not suffice to describe average firm size. We recommend the use of more elaborate space-time modeling to explain the distribution of firm sizes across counties in the US. Exploratory space-time regressions confirm the relevance of spatio-temporal processes in the evolution of average size of manufacturing firms in the US. The analysis of the second topic is concerned with the location choice of firms, in particular of new firms (or start-ups). We address the question whether the location choice of start-ups over their life cycle follows a theoretical framework that is known as the “nursery city hypothesis.” This hypothesis suggests that firms are initially best located in highly diversified cities, because in their process of innovation towards finding their ideal product specification they benefit substantially from externalities

Firm demography and location decisions in the United States after 1990

This study examines the relationship between trade and potential determinants: GDP, FDI, unemployment rate in Spanish provinces while incorporting spatial dependence. This methodological paper contributes to the literature because it evaluates trade at a more disaggregated level and includes FDI to explain the trade pattern. The research concludes that: (1) Only considering GDP and unemployment rate; increase in economic growth or a decrease in unemployment rate could motivate trade in the province; likewise trade of the neighbors will increase the competition, which could decrease the province sales. (2) If FDI is included, FDI received by the neighbor provinces could decrease the exports of the province because it makes its rivals more productive and competitive.

THE ANALYSIS OF INTER-REGIONAL TRADE AND INVESTMENT FLOWS: THE AGGREGATED NET TRADE LEVEL IN THE SPANISH PROVINCES

F. Abe, H. Akimoto, A. Akopian, M. G. Albrow, S. R. Amendolia, D. Amidei, J. Antos, S. Aota, G. Apollinari, T. Arisawa, T. Asakawa, W. Ashmanskas, M. Atac, F. Azfar, P. Azzi-Bacchetta, N. Bacchetta, W. Badgett, S. Bagdasarov, M. W. Bailey, J. Bao, P. de Barbaro, A. Barbaro-Galtieri, V. E. Barnes, B. A. Barnett, M. Barone, E. Barzi, G. Bauer, T. Baumann, F. Bedeschi, S. Behrends, S. Belforte, G. Bellettini, J. Bellinger, D. Benjamin, J. Benlloch, J. Bensinger, D. Benton, A. Beretvas, J. P. Berge, J. Berryhill, S. Bertolucci, S. Bettelli, B. Bevensee, A. Bhatti, K. Biery, M. Binkley, D. Bisello, R. E. Blair, C. Blocker, S. Blusk, A. Bodek, W. Bokhari, G. Bolla, V. Bolognesi, Y. Bonushkin, D. Bortoletto, J. Boudreau, L. Breccia, C. Bromberg, N. Bruner, E. Buckley-Geer, H. S. Budd, K. Burkett, G. Busetto, A. Byon-Wagner, K. L. Byrum, C. Campagnari, M. Campbell, A. Caner, W. Carithers, D. Carlsmith, J. Cassada, A. Castro, D. Cauz, Y. Cen, A. Cerri, F. Cervelli, P. S. Chang, P. T. Chang, H. Y. Chao, J. Chapman, M. -T. Cheng, M. Chertok, G. Chiarelli, T. Chikamatsu, C. N. Chiou, L. Christofek, S. Cihangir, A. G. Clark, M. Cobal, E. Cocca, M. Contreras, J. Conway, J. Cooper, M. Cordelli, C. Couyoumtzelis, D. Crane, D. Cronin-Hennessy, R. Culbertson, T. Daniels, F. DeJongh, S. Delchamps, S. Dell’Agnello, M. Dell’Orso, R. Demina, L. Demortier, M. Deninno, P. F. Derwent, T. Devlin, J. R. Dittmann, S. Donati, J. Done, T. Dorigo, A. Dunn, N. Eddy, K. Einsweiler, J. E. Elias, R. Ely, E. Engels, Jr., D. Errede, S. Errede, Q. Fan, G. Feild, Z. Feng, C. Ferretti, I. Fiori, B. Flaugher, G. W. Foster, M. Franklin, M. Frautschi, J. Freeman, J. Friedman, H. Frisch, Y. Fukui, S. Funaki, S. Galeotti, M. Gallinaro, O. Ganel, M. Garcia-Sciveres, A. F. Garfinkel, C. Gay, S. Geer, D. W. Gerdes, P. Giannetti, N. Giokaris, P. Giromini, G. Giusti, L. Gladney, M. Gold, J. Gonzalez, A. Gordon, A. T. Goshaw, Y. Gotra, K. Goulianos, H. Grassmann, L. Groer, C. Grosso-Pilcher, G. Guillian, J. Guimarães, R. S. Guo, C. Haber, E. Hafen, S. R. Hahn, R. Hamilton, R. Handler, R. M. Hans, F. Happacher, K. Hara, A. D. Hardman, B. Harral, R. M. Harris, S. A. Hauger, J. Hauser, C. Hawk, E. Hayashi, J. Heinrich, B. Hinrichsen, K. D. Hoffman, M. Hohlmann, C. Holck, R. Hollebeek, L. Holloway, S. Hong, G. Houk, P. Hu, B. T. Huffman, R. Hughes, J. Huston, J. Huth, J. Hylen, H. Ikeda, M. Incagli, J. Incandela, G. Introzzi, J. Iwai, Y. Iwata, H. Jensen, U. Joshi, R. W. Kadel, E. Kajfasz, H. Kambara, T. Kamon, T. Kaneko, K. Karr, H. Kasha, Y. Kato, T. A. Keaffaber, K. Kelley, R. D. Kennedy, R. Kephart, P. Kesten, D. Kestenbaum, H. Keutelian, F. Keyvan, B. Kharadia, B. J. Kim, D. H. Kim, H. S. Kim, S. B. Kim, S. H. Kim, Y. K. Kim, L. Kirsch, P. Koehn, A. Köngeter, K. Kondo, J. Konigsberg, S. Kopp, K. Kordas, A. Korytov, W. Koska, E. Kovacs, W. Kowald, M. Krasberg, J. Kroll, M. Kruse, S. E. Kuhlmann, E. Kuns, T. Kuwabara, A. T. Laasanen, S. Lami, S. Lammel, J. I. Lamoureux, M. Lancaster, M. Lanzoni, G. Latino, T. LeCompte, S. Leone, J. D. Lewis, P. Limon, M. Lindgren, T. M. Liss, J. B. Liu, Y. C. Liu, N. Lockyer, O. Long, C. Loomis, M. Loreti, J. Lu, D. Lucchesi, P. Lukens, S. Lusin, J. Lys, K. Maeshima, A. Maghakian, P. Maksimovic, M. Mangano, M. Mariotti, J. P. Marriner, A. Martin, J. A. J. Matthews, R. Mattingly, P. Mazzanti, P. McIntyre, P. Melese, A. Menzione, E. Meschi, S. Metzler, C. Miao, T. Miao, G. Michail, R. Miller, H. Minato, S. Miscetti, M. Mishina, H. Mitsushio, T. Miyamoto, S. Miyashita, N. Moggi, Y. Morita, A. Mukherjee, T. Muller, P. Murat, S. Murgia, H. Nakada, I. Nakano, C. Nelson, D. Neuberger, C. Newman-Holmes, C.-Y. P. Ngan, M. Ninomiya, L. Nodulman, S. H. Oh, K. E. Ohl, T. Ohmoto, T. Ohsugi, R. Oishi, M. Okabe, T. Okusawa, R. Oliveira, J. Olsen, C. Pagliarone, R. Paoletti, V. Papadimitriou, S. P. Pappas, N. Parashar, S. Park, A. Parri, J. Patrick, G. Pauletta, M. Paulini, A. Perazzo, L. Pescara, M. D. Peters, T. J. Phillips, G. Piacentino, M. Pillai, K. T. Pitts, R. Plunkett, L. Pondrom, J. Proudfoot, F. Ptohos, G. Punzi, K. Ragan, D. Reher, A. Ribon, F. Rimondi, L. Ristori, W. J. Robertson, T. Rodrigo, S. Rolli, J. Romano, L. Rosenson, R. Roser, T. Saab, W. K. Sakumoto, D. Saltzberg, A. Sansoni, L. Santi, H. Sato, P. Schlabach, E. E. Schmidt, M. P. Schmidt, A. Scott, A. Scribano, S. Segler, S. Seidel, Y. Seiya, F. Semeria, G. Sganos, T. Shah, M. D. Shapiro, N. M. Shaw, Q. Shen, P. F. Shepard, M. Shimojima, M. Shochet, J. Siegrist, A. Sill, P. Sinervo, P. Singh, K. Sliwa, C. Smith, F. D. Snider, T. Song, J. Spalding, T. Speer, P. Sphicas, F. Spinella, M. Spiropulu, L. Spiegel, L. Stanco, J. Steele, A. Stefanini, J. Strait, R. Ströhmer, D. Stuart, G. Sullivan, K. Sumorok, J. Suzuki, T. Takada, T. Takahashi, T. Takano, K. Takikawa, N. Tamura, B. Tannenbaum, F. Tartarelli, W. Taylor, P. K. Teng, Y. Teramoto, S. Tether, D. Theriot, T. L. Thomas, R. Thun, R. Thurman-Keup, M. Timko, P. Tipton,

97 09 01 6 v 1 1 6 Se p 19 97 Properties of Jets in W Boson Events from 1 . 8 TeV pp Collisions

Ja n 20 02 Search for New Heavy Particles in the WZ 0 Final State in pp̄ Collisions at √ s = 1 . 8 TeV

Cross section and heavy quark composition of γ+μ events produced in pp ̅ collisions

Search for new physics in photon-lepton events in pp ̅ collisions at √s =1.8 1.8 TeV

Measurement of the B+ total cross section and B+ differential cross section dÏ.../dpT in ppÌ– collisions at â‹ıs=1.8 TeV

Search for Quark-Lepton Compositeness and a Heavy W′ Boson Using the eν Channel in pp ̅ Collisions at √s = 1.8 TeV

Measurement of ZT0 and Drell-Yan production cross sections using dimuons in pÌ–p collisions at â‹ıs =1.8 TeV

Measurement of the average time-integrated mixing probability of b-flavored hadrons produced at the Fermilab Tevatron

Study of the heavy flavor content of jets produced in association with W bosons in ppÌ– collisions at â‹ıs =1.8 TeV

Measurement of B0-B ̅0 flavor oscillations using jet-charge and lepton flavor tagging in pp ̅ collisions at √s =1.8 TeV

T. Affolder, H. Akimoto, A. Akopian, M. G. Albrow, P. Amaral, D. Amidei, K. Anikeev, J. Antos, G. Apollinari, T. Arisawa, A. Artikov, T. Asakawa, W. Ashmanskas, F. Azfar, P. Azzi-Bacchetta, N. Bacchetta, H. Bachacou, S. Bailey, P. de Barbaro, A. Barbaro-Galtieri, V. E. Barnes, B. A. Barnett, S. Baroiant, M. Barone, G. Bauer, F. Bedeschi, S. Belforte, W. H. Bell, G. Bellettini, J. Bellinger, D. Benjamin, J. Bensinger, A. Beretvas, J. P. Berge, J. Berryhill, A. Bhatti, M. Binkley, D. Bisello, M. Bishai, R. E. Blair, C. Blocker, K. Bloom, B. Blumenfeld, S. R. Blusk, A. Bocci, A. Bodek, W. Bokhari, G. Bolla, Y. Bonushkin, D. Bortoletto, J. Boudreau, A. Brandl, S. van den Brink, C. Bromberg, M. Brozovic, E. Brubaker, N. Bruner, E. Buckley-Geer, J. Budagov, H. S. Budd, K. Burkett, G. Busetto, A. Byon-Wagner, K. L. Byrum, S. Cabrera, P. Calafiura, M. Campbell, W. Carithers, J. Carlson, D. Carlsmith, W. Caskey, A. Castro, D. Cauz, A. Cerri, A. W. Chan, P. S. Chang, P. T. Chang, J. Chapman, C. Chen, Y. C. Chen, M. -T. Cheng, M. Chertok, G. Chiarelli, I. Chirikov-Zorin, G. Chlachidze, F. Chlebana, L. Christofek, M. L. Chu, Y. S. Chung, C. I. Ciobanu, A. G. Clark, A. Connolly, J. Conway, M. Cordelli, J. Cranshaw, R. Cropp, R. Culbertson, D. Dagenhart, S. D’Auria, F. DeJongh, S. Dell’Agnello, M. Dell’Orso, L. Demortier, M. Deninno, P. F. Derwent, T. Devlin, J. R. Dittmann, A. Dominguez, S. Donati, J. Done, M. D’Onofrio, T. Dorigo, N. Eddy, K. Einsweiler, J. E. Elias, E. Engels, Jr., R. Erbacher, D. Errede, S. Errede, Q. Fan, R. G. Feild, J. P. Fernandez, C. Ferretti, R. D. Field, I. Fiori, B. Flaugher, G. W. Foster, M. Franklin, J. Freeman, J. Friedman, Y. Fukui, I. Furic, S. Galeotti, A. Gallas, 16 M. Gallinaro, T. Gao, M. Garcia-Sciveres, A. F. Garfinkel, P. Gatti, C. Gay, D. W. Gerdes, P. Giannetti, P. Giromini, V. Glagolev, D. Glenzinski, M. Gold, J. Goldstein, I. Gorelov, A. T. Goshaw, Y. Gotra, K. Goulianos, C. Green, G. Grim, P. Gris, L. Groer, C. Grosso-Pilcher, M. Guenther, G. Guillian, J. Guimaraes da Costa, R. M. Haas, C. Haber, S. R. Hahn, C. Hall, T. Handa, R. Handler, W. Hao, F. Happacher, K. Hara, A. D. Hardman, R. M. Harris, F. Hartmann, K. Hatakeyama, J. Hauser, J. Heinrich, A. Heiss, M. Herndon, C. Hill, K. D. Hoffman, C. Holck, R. Hollebeek, L. Holloway, R. Hughes, J. Huston, J. Huth, H. Ikeda, J. Incandela, G. Introzzi, J. Iwai, Y. Iwata, E. James, M. Jones, U. Joshi, H. Kambara, T. Kamon, T. Kaneko, K. Karr, H. Kasha, Y. Kato, T. A. Keaffaber, K. Kelley, M. Kelly, R. D. Kennedy, R. Kephart, D. Khazins, T. Kikuchi, B. Kilminster, B. J. Kim, D. H. Kim, H. S. Kim, M. J. Kim, S. B. Kim, S. H. Kim, Y. K. Kim, M. Kirby, M. Kirk, L. Kirsch, S. Klimenko, P. Koehn, K. Kondo, J. Konigsberg, A. Korn, A. Korytov, E. Kovacs, J. Kroll, M. Kruse, S. E. Kuhlmann, K. Kurino, T. Kuwabara, A. T. Laasanen, N. Lai, S. Lami, S. Lammel, J. Lancaster, M. Lancaster, R. Lander, A. Lath, G. Latino, T. LeCompte, A. M. Lee IV, K. Lee, S. Leone, J. D. Lewis, M. Lindgren, T. M. Liss, J. B. Liu, Y. C. Liu, D. O. Litvintsev, O. Lobban, N. Lockyer, J. Loken, M. Loreti, D. Lucchesi, P. Lukens, S. Lusin, L. Lyons, J. Lys, R. Madrak, K. Maeshima, P. Maksimovic, L. Malferrari, M. Mangano, M. Mariotti, G. Martignon, A. Martin, J. A. J. Matthews, J. Mayer, P. Mazzanti, K. S. McFarland, P. McIntyre, E. McKigney, M. Menguzzato, A. Menzione, C. Mesropian, A. Meyer, T. Miao, R. Miller, J. S. Miller, H. Minato, S. Miscetti, M. Mishina, G. Mitselmakher, N. Moggi, E. Moore, R. Moore, Y. Morita, T. Moulik, M. Mulhearn, A. Mukherjee, T. Muller, A. Munar, P. Murat, S. Murgia, J. Nachtman, V. Nagaslaev, S. Nahn, H. Nakada, I. Nakano, C. Nelson, T. Nelson, C. Neu, D. Neuberger, C. Newman-Holmes, C.-Y. P. Ngan, H. Niu, L. Nodulman, A. Nomerotski, S. H. Oh, Y. D. Oh, T. Ohmoto, T. Ohsugi, R. Oishi, T. Okusawa, J. Olsen, W. Orejudos, C. Pagliarone, F. Palmonari, R. Paoletti, V. Papadimitriou, D. Partos, J. Patrick, G. Pauletta, M. Paulini, 23 C. Paus, D. Pellett, L. Pescara, T. J. Phillips, G. Piacentino, K. T. Pitts, A. Pompos, L. Pondrom, G. Pope, M. Popovic, F. Prokoshin, J. Proudfoot, F. Ptohos, O. Pukhov, G. Punzi, A. Rakitine, F. Ratnikov, D. Reher, A. Reichold, A. Ribon, W. Riegler, F. Rimondi, L. Ristori, M. Riveline, W. J. Robertson, A. Robinson, T. Rodrigo, S. Rolli, L. Rosenson, R. Roser, R. Rossin, A. Roy, A. Ruiz, A. Safonov, R. St. Denis, W. K. Sakumoto, D. Saltzberg, C. Sanchez, A. Sansoni, L. Santi, H. Sato, P. Savard, P. Schlabach, E. E. Schmidt, M. P. Schmidt, M. Schmitt, 16 L. Scodellaro, A. Scott, A. Scribano, S. Segler, S. Seidel, Y. Seiya, A. Semenov, F. Semeria, T. Shah, M. D. Shapiro, P. F. Shepard, T. Shibayama, M. Shimojima, M. Shochet, A. Sidoti, J. Siegrist, A. Sill, P. Sinervo, P. Singh, A. J. Slaughter, K. Sliwa, C. Smith, F. D. Snider, A. Solodsky, J. Spalding, T. Speer, P. Sphicas, F. Spinella, M. Spiropulu, L. Spiegel, J. Steele, A. Stefanini, J. Strologas, F. Strumia, 14 D. Stuart, K. Sumorok, T. Suzuki, T. Takano, R. Takashima, K. Takikawa, P. Tamburello, M. Tanaka,

1 1 1 Ju n 20 01 Measurement of dσ / dM and Forward-Backward Charge Asymmetry for High Mass

Measurement of the top quark mass using template methods on dilepton events in p ( p ) over-bar collisions at root s = 1 . 96 TeV

Measurement of the cross section for t ( t ) over-bar production in p ( p ) over-bar collisions using the kinematics of lepton plus jets events

Measurement of the top quark mass in p ( p ) over-bar collisions at root s = 1 . 96 TeV using the decay length technique

Search for lepton flavor violating decays of a heavy neutral particle in p ( p ) over-bar collisions at root s = 1 . 8 TeV

Measurement of the top quark mass with the dynamical likelihood method using lepton plus jets events with b-tags in ( p ) over-barp collisions at root s = 1 . 96

Observation of exclusive dijet production at the Fermilab Tevatron ( p ) over-bar-p collider

Erratum: Measurement of the inclusive jet cross section at the Fermilab Tevatronpp¯collider using a cone-based jet algorithm [Phys. Rev. D78, 052006 (2008)]

We report on a search for the standard-model Higgs boson in pp collisions at square root(s) = 1.96 TeV using an integrated luminosity of 2.0 fb(-1). We look for production of the Higgs boson decaying to a pair of bottom quarks in association with a vector boson V (W or Z) decaying to quarks, resulting in a four-jet final state. Two of the jets are required to have secondary vertices consistent with B-hadron decays. We set the first 95% confidence level upper limit on the VH production cross section with V(--> qq/qq')H(--> bb) decay for Higgs boson masses of 100-150 GeV/c2 using data from run II at the Fermilab Tevatron. For m(H) = 120 GeV/c2, we exclude cross sections larger than 38 times the standard-model prediction.

Search for the associated production of the standard-model Higgs Boson in the all-hadronic channel.

We search for b → sμ + μ - transitions in B meson (B + , B°, or B 0 s ) decays with 924 pb -1 of pp collisions at s = 1.96 TeV collected with the CDF II detector at the Fermilab Tevatron. We find excesses with significances of 4.5, 2.9, and 2.4 standard deviations in the B + → μ + μ - K + , B 0 → μ + μ - K*(892) 0 , and B 0 s → μ + μ - Φ decay modes, respectively. Using B → J/ψh (h = K + , K*(892) 0 , Φ) decays as normalization channels, we report branching fractions for the previously observed B + and B° decays, B(B + → μ + μ - K + ) = (0.59 ± 0.15 ± 0.04) X 10 -6 , and B(B 0 → μ + μ - K*(892) 0 ) = (0.81 ± 0.30 ± 0.10) × 10 -6 , where the first uncertainty is statistical, and the second is systematic. We set an upper limit on the relative branching fraction B(B 0 s → μ + μ - Φ)/Β(Β 0 s → J/ψΦ) < 2.6(2.3) X 10 -3 at the 95(90)% confidence level, which is the most stringent to date.

Search for the rare decays B+→μ+μ-K+, B0→μ+μ- K*(892)0, and Bs0→μ+μ- at CDF

Publisher's Note: Search for hadronic decays of W and Z bosons in photon events in pp collisions at {radical}(s)=1.96 TeV[Phys. Rev. D 80, 052011 (2009)]

We search for b ! s(cid:1) þ (cid:1) (cid:1) transitions in B meson ( B þ , B 0 , or B 0 s ) decays with 924 pb (cid:1) 1 of p (cid:1) p collisions at ﬃﬃﬃ s p ¼ 1 : 96 TeV collected with the CDF II detector at the Fermilab Tevatron. We ﬁnd excesses with signiﬁcances of 4.5, 2.9, and 2.4 standard deviations in the B þ ! (cid:1) þ (cid:1) (cid:1) K þ , B 0 ! (cid:1) þ (cid:1) (cid:1) K (cid:2) ð 892 Þ 0 , and B 0 s ! (cid:1) þ (cid:1) (cid:1) (cid:2) decay modes, respectively. Using B ! J= c h ( h ¼ K þ , K (cid:2) ð 892 Þ 0 , (cid:2) ) decays as normalization channels, we report branching fractions for the previously observed B þ and B 0 decays, B ð B þ ! (cid:1) þ (cid:1) (cid:1) K þ Þ ¼ ð 0 : 59 (cid:3) 0 : 15 (cid:3) 0 : 04 Þ (cid:4) 10 (cid:1) 6 , and B ð B 0 ! (cid:1) þ (cid:1) (cid:1) K (cid:2) ð 892 Þ 0 Þ ¼ ð 0 : 81 (cid:3) 0 : 30 (cid:3) 0 : 10 Þ (cid:4) 10 (cid:1) 6 , where the ﬁrst uncertainty is statistical, and the second is systematic. We set an upper limit on the relative branching fraction B ð B 0 s ! (cid:1) þ (cid:1) (cid:1) (cid:2) Þ = B ð B 0 s ! J= c (cid:2) Þ < 2 : 6 ð 2 : 3 Þ (cid:4) 10 (cid:1) 3 at the 95(90)% conﬁdence level, which is the most stringent to date.

Search for the rare decays B+-->mu+mu-K+, B-->mu+mu-K*(892), and Bs-->mu+mu- phi at CDF

We report the observation of the exclusive decay Bs0-->Ds-Ds+ at the 7.5 standard deviation level using 355 pb(-1) of data collected by the CDF II detector in pp collisions at sqrt[s]=1.96 TeV at the Fermilab Tevatron. We measure the relative branching ratio B(Bs0-->Ds-Ds+)/B(B0-->D-Ds+)=1.44(-0.44)(+0.48). Using the world average value for B(B0-->D-Ds+), we find B(Bs0-->Ds-Ds+)=(9.4(-4.2)(+4.4))x10(-3). This provides a lower bound DeltaGammasCP/Gammas>or=2B(Bs0-->Ds-Ds+)>1.2x10(-2) at 95% C.L.

First observation of the decay Bs0-->Ds-Ds+ and measurement of its branching ratio.

Forward-Backward Asymmetry in Top-Quark Production in p(p)over-bar Collisions at root s=1.96 TeV RID G-1087-2011 RID E-4473-2011

Search for standard model Higgs boson production in association with a W boson at CDF RID G-1087-2011 RID E-4473-2011

We have performed a search for B-s(0)->mu(+)mu(-) and B-0 ->mu(+)mu(-) decays in p (p) over bar collisions at root s = 1.96 TeV using 2 fb(-1) of integrated luminosity collected by the CDF II detector at the Fermilab Tevatron Collider. The observed number of B-s(0) and B-0 candidates is consistent with background expectations. The resulting upper limits on the branching fractions are B(B-s(0)->mu(+)mu(-)) mu(+)mu(-)) < 1.8 x 10(-8) at 95% C.L.

Search for B-s(0)->mu(+)mu(-) and B-0 ->mu(+)mu(-) Decays with 2 fb(-1) of p(p)over-bar Collisions

Recommended Citation Aaltonen, T., Abulencia, A., Adelman, J., Affolder, T., Akimoto, T., Albrow, M., Amerio, S., Amidei, D., Anastassov, A., Anikeev, K., Annovi, A., Antos, J., Aoki, M., Apollinari, G., Arisawa, T., Artikov, A., Ashmanskas, W., Attal, A., Aurisano, A., Azfar, F., Azzi-Bacchetta, P., Azzurri, P., Bacchetta, N., Badgett, W., Barbaro-Galtieri, A., Barnes, V., Barnett, B., & Baroiant, S. (2008). Measurement of correlated bb ̄ production in pp ̄ collisions at s=1960GeV. Physical Review D Particles, Fields, Gravitation and Cosmology, 77 (7) https://doi.org/10.1103/PhysRevD.77.072004

Measurement of correlated b(b)over-bar production in p(p)over-bar collisions at root s=1960 GeV RID G-1087-2011 RID E-4473-2011

Search for pair production of scalar top quarks decaying to a tau lepton and a b quark in p(p)over-bar collisions at root s=1.96 TeV RID G-1087-2011 RID E-4473-2011

We present the results of searches for large extra dimensions in samples of events with large missing transverse energy E_{T} and either a photon or a jet produced in pp[over ] collisions at sqrt[s]=1.96 TeV collected with the Collider Detector at Fermilab II. For gamma+E_{T} and jet+E_{T} candidate samples corresponding to 2.0 and 1.1 fb;{-1} of integrated luminosity, respectively, we observe good agreement with standard model expectations and obtain a combined lower limit on the fundamental parameter of the large extra dimensions model M_{D} as a function of the number of extra dimensions in the model.

Search for large extra dimensions in final states containing one photon or jet and large missing transverse energy produced in pp collisions at square root[s]=1.96 TeV.

Evidence for D(0)-(D)over-bar(0) mixing using the CDF II detector RID G-1087-2011 RID E-4473-2011

We search for the standard model Higgs boson produced in association with an electroweak vector boson in events with no identified charged leptons, large imbalance in transverse momentum, and two jets where at least one contains a secondary vertex consistent with the decay of b hadrons. We use approximately 1 fb(-1) integrated luminosity of pp collisions at square root(s)=1.96 TeV recorded by the Collider Detector at Fermilab II experiment at the Tevatron. We find 268 (16) single (double) b-tagged candidate events, where 248+/-43 (14.4+/-2.7) are expected from standard model background processes. We observe no significant excess over the expected background and thus set 95% confidence level upper limits on the Higgs boson production cross section for several Higgs boson masses ranging from 110 to 140 GeV/c(2). For a mass of 115 GeV/c(2), the observed (expected) limit is 20.4 (14.2) times the standard model prediction.

Search for the Higgs boson in events with missing transverse energy and b quark jets produced in pp collisions at square root(s)=1.96 TeV.

We search for pair production of doubly charged Higgs particles (H+/- +/-) followed by decays into electron-tau (etau) and muon-tau (mutau) pairs using data (350 pb(-1) collected from [over]pp collisions at sqrt[s]=1.96 TeV by the CDF II experiment. We search separately for cases where three or four final-state leptons are detected, and combine results for exclusive decays to left-handed etau (mutau) pairs. We set an H+/- +/- lower mass limit of 114(112) GeV/c(2) at the 95% confidence level.

Search for doubly charged Higgs bosons with lepton-flavor-violating decays involving tau leptons.

We report on a search for narrow-width particles decaying to a top and antitop quark pair. The data set used in the analysis corresponds to an integrated luminosity of 680 pb(-1) collected with the Collider Detector at Fermilab in run II. We present 95% confidence level upper limits on the cross section times branching ratio. Assuming a specific top-color-assisted technicolor production model, the leptophobic Z' with width Gamma(Z')=0.012M(Z'), we exclude the mass range M(Z')<725 GeV/c(2) at the 95% confidence level.

Search for resonant tt[overline] production in pp[overline] collisions at sqrt[s]=1.96 TeV.

We present the results of a search for pair production of scalar top quarks ({tilde t}{sub 1}) in an R-parity violating supersymmetric scenario using 322 pb{sup -1} of p{bar p} collisions at {radical}s = 1.96 TeV collected by the upgraded Collider Detector at Fermilab. We assume each {tilde t}{sub 1} decays into a {tau} lepton and a b quark with a branching ratio {beta}, and that the final state contains either an electron or a muon from a leptonic {tau} decay, a hadronically decaying {tau} lepton, and two or more jets. Two candidate events pass our final selection criteria, consistent with the expectation from standard model processes. We present upper limits on the cross section times branching ratio squared {sigma}({tilde t}{sub 1}{bar {tilde t}}{sub 1}) x {beta}{sup 2} as a function of the stop mass m({tilde t}{sub 1}). Assuming {beta} = 1, we set a 95% confidence level limit m({tilde t}{sub 1}) > 153 GeV=c{sup 2} obtained using a next-to-leading order cross section. These limits are also fully applicable to the case of a pair produced third generation scalar leptoquark decaying into a {tau} lepton and a b quark.

Search for pair production of scalar top quarks decaying to a τ lepton and a b quark in pp̄ collisions at s=1.96TeV

Limits on the production of narrow t(t)over-bar resonances in p(p)over-bar collisions at root s=1.96 TeV RID G-1087-2011 RID E-4473-2011

We report the first evidence of Z boson pair production at a hadron collider with a significance exceeding 4 standard deviations. This result is based on a data sample corresponding to 1.9 fb(-1) of integrated luminosity from pp[over] collisions at sqrt[s]=1.96 TeV collected with the Collider Detector at Fermilab II detector. In the lll'l' channel, we observe three ZZ candidates with an expected background of 0.096(-0.063)+0.092 events. In the llnunu channel, we use a leading-order calculation of the relative ZZ and WW event probabilities to discriminate between signal and background. In the combination of lll'l' and llnunu channels, we observe an excess of events with a probability of 5.1 x 10(-6) to be due to the expected background. This corresponds to a significance of 4.4 standard deviations. The measured cross section is sigma(pp[over]-->ZZ)=1.4(-0.6)+0.7(stat+syst) pb, consistent with the standard model expectation.

Strong evidence for ZZ production in pp[over] collisions at sqrt[s]=1.96 TeV.

A direct measurement of the total decay width of the W boson Gamma(W) is presented using 350 pb(-1) of data from pp[over ] collisions at square root s = 1.96 TeV collected with the CDF II detector at the Fermilab Tevatron. The width is determined by normalizing predicted signal and background distributions to 230 185 W candidates decaying to enu and micronu in the transverse-mass region 50<M(T)<90 GeV and then fitting the predicted shape to 6055 events in the high-M(T) region, 90<M(T)<200 GeV. The result is Gamma(W)=2032 +/- 45(stat)+/-57(syst) MeV, consistent with the standard model expectation.

Direct measurement of the W Boson width in ppover collisions at square roots = 1.96 TeV.

We present a measurement of the shapes of b-jets using 300 pb(-1) of data obtained with the upgraded Collider Detector at Fermilab (CDF II) in p(p)overbar collisions at center-of-mass energy root s=1.96 TeV. This measurement covers a wide transverse momentum range, from 52 to 300 GeV/c. Samples of heavy-flavor enhanced jets together with inclusive jets are used to extract the average shapes of b-jets. The b-jets are expected to be broader than inclusive jets. Moreover, b-jets containing a single b-quark are expected to be narrower than those containing a b(b)overbar pair from gluon splitting. The measured b-jet shapes are found to be significantly broader than expected from the PYTHIA and HERWIG Monte Carlo simulations. This effect may arise from an underestimation of the fraction of b-jets originating from gluon splitting in these simulations. The jet shape distributions provided in this paper could be compared to any full Monte Carlo simulation and could be used to further constrain the various parameters.

Measurement of b-jet shapes in inclusive jet production in pp̄ collisions at s=1.96TeV

B0 d-B 0 d oscillations are observed in “self-tagged” samples of partially reconstructed B mesons decaying into a lepton and a charmed meson collected in pp̄ collisions at √ s = 1.8 TeV. A flavor tagging technique is employed which relies upon the correlation between the flavor of B mesons and the charge of nearby particles. We measure the flavor oscillation frequency to be ∆md = 0.471 +0.078 −0.068 ± 0.034 ps−1. The tagging method is also demonstrated in exclusive samples of B+ u → J/ψK+ and B0 d → J/ψK∗0(892), where similar flavor-charge correlations are observed. The tagging characteristics of the various samples are compared with each other, and with Monte Carlo simulations. PACS numbers: 14.40.Nd, 13.20He, 13.25Hw Typeset using REVTEX

Measurement of the B 0 dB 0 d flavor oscillation frequency and study of same side flavor tagging of B mesons in pp̄ collisions

We search for pair production of supersymmetric top quarks (t over1), followed by R-parity violating decay t over1-->taub with a branching ratio beta, using 322 pb(-1) of pp over collisions at sqrt s=1.96 TeV collected by the upgraded Collider Detector at Fermilab. Two candidate events pass our final selection criteria, consistent with the standard model expectation. We set upper limits on the cross section sigma(t over1t over1) x beta2 as a function of the top-squark mass m(t over1). Assuming beta=1, we set a 95% confidence level limit m(t over1)>153 GeV/c2. The limits are also applicable to the case of a third-generation scalar leptoquark (LQ3) decaying LQ3-->taub.

Search for pair production of scalar top quarks decaying to a tau lepton and a b quark in pp over collisions at sqrt s=1.96 TeV.

This paper describes the first measurement of b-quark fragmentation fractions into bottom hadrons in Run II of the Tevatron Collider at Fermilab. The result is based on a 360 pb(-1) sample of data collected with the CDF II detector in p (p) over bar collisions at root s = 1.96 TeV. Semileptonic decays of (B) over bar (0), B-, and (B) over bar (0)(s) mesons, as well as Lambda(0)(b) baryons, are reconstructed. For an effective bottom hadron p(T) threshold of 7 GeV/c, the fragmentation fractions are measured to be f(u)/f(d)=1.054 +/- 0.018(stat)(-0.045)(+0.025)(sys)+/- 0.058(B), f(s)/(f(u)+f(d))=0.160 +/- 0.005(stat)(-0.010)(+0.011)(sys)(-0.034)(+0.057)(B), and f(Lambda b)/(f(u)+f(d))=0.281 +/- 0.012(stat)(-0.056)(+0.058)(sys)(-0.087)(+0.128)(B), where the uncertainty B is due to uncertainties on measured branching ratios. The value of f(s)/(f(u)+f(d)) agrees within one standard deviation with previous CDF measurements and the world average of this quantity, which is dominated by LEP measurements. However, the ratio f(Lambda b)/(f(u)+f(d)) is approximately twice the value previously measured at LEP. The approximately 2 sigma discrepancy is examined in terms of kinematic differences between the two production environments.

Measurement of ratios of fragmentation fractions for bottom hadrons in p(p)over-bar collisions at root s=1.96 TeV

We report the first evidence of Z boson pair production at a hadron collider with a significance exceeding 4 standard deviations. This result is based on a data sample corresponding to 1.9fb-1 of integrated luminosity from pp collisions at s=1.96TeV collected with the Collider Detector at Fermilab II detector. In the ′ ′ channel, we observe three ZZ candidates with an expected background of 0.096-0.063+0.092 events. In the νν channel, we use a leading-order calculation of the relative ZZ and WW event probabilities to discriminate between signal and background. In the combination of ′ ′ and νν channels, we observe an excess of events with a probability of 5.1×10-6 to be due to the expected background. This corresponds to a significance of 4.4 standard deviations. The measured cross section is σ(pp→ZZ)=1.4-0.6+0.7(stat+syst)pb, consistent with the standard model expectation. © 2008 The American Physical Society.

Strong evidence for ZZ production in pp̄ collisions at s=1.96TeV

The authors present the results of the first hadron collider search for heavy, long-lived neutralinos that decay via {tilde {chi}}{sub 1}{sup 0} {yields} {gamma}{tilde G} in gauge-mediated supersymmetry breaking models. Using an integrated luminosity of 570 {+-} 34 pb{sup -1} of p{bar p} collisions at {radical}s = 1.96 TeV, they select {gamma}+jet+missing transverse energy candidate events based on the arrival time of a high-energy photon at the electromagnetic calorimeter as measured with a timing system that was recently installed on the CDF II detector. They find 2 events, consistent with the background estimate of 1.3 {+-} 0.7 events. While the search strategy does not rely on model-specific dynamics, they set cross section limits and place the world-best 95% C.L. lower limit on the {tilde {chi}}{sub 1}{sup 0} mass of 101 GeV/c{sup 2} at {tau}{sub {tilde {chi}}{sub 1}{sup 0}} = 5 ns.

Search for heavy, long-lived neutralinos that decay to photons at CDF II using photon timing

A combined mass and particle identification fit is used to make the first observation of the decay B(s)(0) --> D(s)(+/-)K(-/+) and measure the branching fraction of B(s)(0) --> D(s)(+/-)K(-/+) relative to B(s)(0) --> D(s)(+)pi(-). This analysis uses 1.2 fb(-1) integrated luminosity of pp collisions at square root(s) = 1.96 TeV collected with the CDF II detector at the Fermilab Tevatron collider. We observe a B(s)(0) --> D(s)(+/-)K(-/+) signal with a statistical significance of 8.1 sigma and measure B(B(s)(0) --> D(s)(+/-)K(-/+) /B(B(s)(0) --> D(s)(+)pi(-) 0.097+/-0.018(stat) +/- 0.009(syst).

First observation of B(s)(0) --> D(s)(+/-)K(-/+) and measurement of the ratio of branching fractions B(B(s)(0) --> D(s)(+/-)K(-/+)/B(B(s)(0) --> D(s)(+)pi(-)).

Inclusive jet cross sections in Z/gamma* events, with Z/gamma* decaying into an electron-positron pair, are measured as a function of jet transverse momentum and jet multiplicity in pp[over ] collisions at square root s = 1.96 TeV with the upgraded Collider Detector at Fermilab in run II, based on an integrated luminosity of 1.7 fb(-1). The measurements cover the rapidity region |y(jet)|<2.1 and the transverse momentum range p(T)(jet)>30 GeV/c. Next-to-leading order perturbative QCD predictions are in good agreement with the measured cross sections.

Measurement of inclusive jet cross sections in Z/gamma*(-->e+e-) + jets production in pp[over ] collisions at square root s = 1.96 TeV.

Search for heavy toplike quarks using lepton plus jets events in 1.96 TeV p(p)over-bar collisions RID G-1087-2011 RID E-4473-2011

We present the first measurement of the production cross section of a W boson with a single charm quark (c) in pp collisions at sqrt(s)=1.96 TeV, using soft muon tagging of c jets. In a data sample of approximately 1.8 fb(-1), recorded with the Collider Detector at Fermilab II detector at the Fermilab Tevatron, we select events with W+1 or 2 jets. We use the charge correlation between the W and the muon from the semileptonic decay of a charm hadron to extract the Wc signal. We measure sigma Wc(PTc >20 GeV/c,|eta c|<1.5) x BR(W-->l nu)=9.8+/-3.2 pb, in agreement with theoretical expectations.

First measurement of W boson production in association with a single Charm quark in pp collisions at sqrt(s)=1.96 TeV.

Measurement of inclusive jet cross sections in Z/gamma*(-> e(+)e(-))+jets production in p(p)over-bar collisions at root s=1.96 TeV RID G-1087-2011 RID E-4473-2011

Search for new heavy particles decaying to Z(0)Z(0)-> eeee in p(p)over-bar collisions at root s=1.96 TeV RID G-1087-2011 RID E-4473-2011

Measurement of lifetime and decay-width difference in B(S)(0)-> J/psi phi decays RID G-1087-2011 RID E-4473-2011

We present measurements of the forward-backward charge asymmetry in top pair production using 1.9 fb;{-1} of pp[over ] collisions at sqrt[s]=1.96 TeV recorded with the Collider Detector at Fermilab II. Correcting for acceptance and measurement dilutions we obtain parton-level asymmetries of A_{FB};{pp[over ]}=0.17+/-0.08 in the pp[over ] frame and A_{FB};{tt[over ]}=0.24+/-0.14 in the tt[over ] frame. The values are consistent with the standard model expectation and disfavor exotic production mechanisms with significant negative values.

Forward-backward asymmetry in top-quark production in pp[over] collisions at sqrt[s]=1.96 TeV.

We report a measurement of the single-top-quark production cross section in 2.2 fb;{-1} of pp collision data collected by the Collider Detector at Fermilab at sqrt[s]=1.96 TeV. Candidate events are classified as signal-like by three parallel analyses which use likelihood, matrix element, and neural network discriminants. These results are combined in order to improve the sensitivity. We observe a signal consistent with the standard model prediction, but inconsistent with the background-only model by 3.7 standard deviations with a median expected sensitivity of 4.9 standard deviations. We measure a cross section of 2.2(-0.6)(+0.7)(stat+syst) pb, extract the Cabibbo-Kobayashi-Maskawa matrix-element value |V(tb)|=0.88(-0.12)(+0.13)(stat+syst)+/-0.07(theory), and set the limit |V(tb)|>0.66 at the 95% C.L.

Measurement of the single-top-quark production cross section at CDF.

We report a search for the flavor-changing neutral-current decay of the top quark t-->Zq (q=u, c) in pp collisions at sqrt[s]=1.96 TeV using a data sample corresponding to an integrated luminosity of 1.9 fb(-1) collected by the CDF II detector. This decay is strongly suppressed in the standard model and an observation of a signal at the Fermilab Tevatron would be an indication of physics beyond the standard model. Using Z+ > or = 4 jet final state candidate events, with and without an identified bottom quark jet, we obtain an upper limit of B(t-->Zq) < 3.7% at 95% C.L.

Search for the flavor-changing neutral-current decay t-->Zq in pp collisions at sqrt[s] = 1.96 TeV.

Erratum: Search for pair production of scalar top quarks decaying to a τ Lepton and a b quark in pp̄ collisions at s=1.96TeV (Physical Review Letters (2008) 101 (071802))

Two-particle momentum correlations in jets produced in p(p)over-barcollisions at root s=1.96 TeV RID G-1087-2011 RID E-4473-2011

Models of maximal flavor violation (MxFV) in elementary particle physics may contain at least one new scalar SU(2) doublet field Phi(FV)=(eta(0),eta(+)) that couples the first and third generation quarks (q_(1), q_(3)) via a Lagrangian term L(FV)=xi(13)Phi(FV)q(1)q(3). These models have a distinctive signature of same-charge top-quark pairs and evade flavor-changing limits from meson mixing measurements. Data corresponding to 2 fb(-1) collected by the Collider Dectector at Fermilab II detector in pp[over ] collisions at sqrt[s]=1.96 TeV are analyzed for evidence of the MxFV signature. For a neutral scalar eta(0) with m_(eta;(0))=200 GeV/c(2) and coupling xi(13)=1, approximately 11 signal events are expected over a background of 2.1+/-1.8 events. Three events are observed in the data, consistent with background expectations, and limits are set on the coupling xi(13) for m(eta(0)=180-300 GeV/c(2).

Search for maximal flavor violating scalars in same-charge lepton pairs in pp collisions at sqrt[s]=1.96 TeV.

Strong evidence for ZZ production in pp collisions at root s=1.96 TeV RID G-1087-2011 RID E-4473-2011

Data collected in run II of the Fermilab Tevatron are searched for indications of new electroweak scale physics. Rather than focusing on particular new physics scenarios, CDF data are analyzed for discrepancies with respect to the standard model prediction. A model-independent approach (Vista) considers the gross features of the data and is sensitive to new large cross section physics. A quasi-model-independent approach (Sleuth) searches for a significant excess of events with large summed transverse momentum and is particularly sensitive to new electroweak scale physics that appears predominantly in one final state. This global search for new physics in over 300 exclusive final states in 927pb-1 of pp collisions at s=1.96TeV reveals no such significant indication of physics beyond the standard model. © 2008 The American Physical Society.

Model-independent and quasi-model-independent search for new physics at CDF

We use the three lepton and missing energy trilepton signature to search for chargino-neutralino production with 2.0 fb;{-1} of integrated luminosity collected by the CDF II experiment at the Tevatron pp[over ] collider. We expect an excess of approximately 11 supersymmetric events for a choice of parameters of the mSUGRA model, but our observation of 7 events is consistent with the standard model expectation of 6.4 events. We constrain the mSUGRA model of supersymmetry and rule out chargino masses up to 145 GeV/c;{2} for a specific choice of parameters.

Search for supersymmetry in pp collisions at sqrt[s]=1.96 TeV Using the trilepton signature for chargino-neutralino production.

Observation of the decay B(c)(+/-) -> J/psi pi(+/-) and measurement of the B(c)(+/-) mass RID G-1087-2011 RID E-4473-2011

We present the first direct experimental bound on the total decay width of the top quark, Gamma(t), using 955 pb(-1) of the Tevatron's pp collisions recorded by the Collider Detector at Fermilab. We identify 253 top-antitop pair candidate events. The distribution of reconstructed top quark mass from these events is fitted to templates representing different values of the top quark width. Using a confidence interval based on likelihood-ratio ordering, we extract an upper limit at 95% C.L. of Gamma(t)<13.1 GeV for an assumed top quark mass of 175 GeV/c(2).

Direct bound on the total decay width of the top quark in pp collisions at sqrt[s]=1.96 TeV.

We present a measurement of the correlated bb production cross section. The data used in this analysis were taken with the upgraded CDF detector (CDF II) at the Fermilab Tevatron collider, and correspond to an integrated luminosity of 742 pb{sup -1}. We utilize muon pairs with invariant mass 5{ =}3 GeV/c and |{eta}|{ =}2 GeV/c and |y|{<=}1.3, we measure {sigma}{sub b{r_reversible}}{sub {mu}}{sub ,b{r_reversible}}{sub {mu}}=1549{+-}133 pb. We compare this result with theoretical predictions and previous measurements. We also report the measurement of {sigma}{sub c{r_reversible}}{sub {mu}}{sub ,c{r_reversible}}{sub {mu}}, a by-product of the study of the background to bb production.

Measurement of correlated bb̄ production in pp̄ collisions at s=1960GeV

Measurement of b-jet shapes in inclusive jet production in p overline p collisions at sqrt(s)=1.96 TeV RID G-1087-2011 RID E-4473-2011

We present a search for the Higgs boson in the process qq-->ZH-->l;{+}l;{-}bb[over ]. The analysis uses an integrated luminosity of 1 fb;{-1} of pp[over ] collisions produced at sqrt[s]=1.96 TeV and accumulated by the upgraded Collider Detector at Fermilab (CDF II). We employ artificial neural networks both to correct jets mismeasured in the calorimeter and to distinguish the signal kinematic distributions from those of the background. We see no evidence for Higgs boson production, and set 95% C.L. upper limits on sigma{ZH}B(H-->bb[over ]), ranging from 1.5 to 1.2 pb for a Higgs boson mass (m{H}) of 110 to 150 GeV/c(2).

Search for the Higgs boson produced in association with Z-->l+l in pp collisions at sqrt[s]=1.96 TeV.

We present the results of a search for pair production of a new heavy toplike quark t' decaying to a W boson and another quark using the Collider Detector at Fermilab II detector in run II of the Tevatron pp collider. Using a data sample corresponding to 760 pb(-1) of integrated luminosity, we fit the observed spectrum of total transverse energy and reconstructed t' quark mass to a combination of standard model processes and t' pair production. We see no evidence for t't' production, and we infer a lower limit of 256 GeV/c(2) on the mass of the t' at 95% C.L. assuming standard strong couplings for the t'.

Search for heavy toplike quarks using lepton plus jets events in 1.96 TeV pp collisions.

We have performed a search for Bs0→μ+μ- and B0→μ+μ- decays in pp¯ collisions at √s=1.96  TeV using 2  fb-1 of integrated luminosity collected by the CDF II detector at the Fermilab Tevatron Collider. The observed number of Bs0 and B0 candidates is consistent with background expectations. The resulting upper limits on the branching fractions are B(Bs0→μ+μ-)<5.8×10-8 and B(B0→μ+μ-)<1.8×10-8 at 95% C.L.

Search for Lepton Flavor Violation in Upsilon Decays Forward-Backward Asymmetry in Top-Quark Production in p(p)over-bar Collisions at root s=1.96 TeV

We report a measurement of the top-quark mass M_{t} in the dilepton decay channel tt[over ] --> bl;{'+} nu_{l};{'}b[over ]l;{-}nu[over ]_{l}. Events are selected with a neural network which has been directly optimized for statistical precision in top-quark mass using neuroevolution, a technique modeled on biological evolution. The top-quark mass is extracted from per-event probability densities that are formed by the convolution of leading order matrix elements and detector resolution functions. The joint probability is the product of the probability densities from 344 candidate events in 2.0 fb;{-1} of pp[over ] collisions collected with the CDF II detector, yielding a measurement of M_{t} = 171.2 +/- 2.7(stat) +/- 2.9(syst) GeV / c;{2}.

Measurement of the top-quark mass with dilepton events selected using neuroevolution at CDF.

Measurement of σχc2B(χc2→J/ψγ)/ σχc1B(χc1→J/ψγ) in pp̄ Collisions at s=1.96TeV

The Bc+/- meson is observed through the decay Bc+/--->J/psipi+/-, in data corresponding to an integrated luminosity of 2.4 fb(-1) recorded by the Collider Detector at Fermilab II detector at the Fermilab Tevatron. A signal of 108+/-15 candidates is observed, with a significance that exceeds 8sigma. The mass of the Bc+/- meson is measured to be 6275.6+/-2.9(stat)+/-2.5(syst) MeV/c2.

Observation of the decay Bc+/--->J/psipi+/- and measurement of the Bc+/- mass.

Polarizations of J/psi and psi(2S) mesons produced in p(p)over-bar collisins at root s-1.96 TeV RID G-1087-2011 RID E-4473-2011

Search for new particles leading to Z plus jets final states in p(p)over-bar collisions at root s=1.96 TeV RID G-1087-2011 RID E-4473-2011

The authors report on measurements of the inclusive jet production cross section as a function of the jet transverse momentum in p{bar p} collisions at {radical}s = 1.96 TeV, using the k{sub T} algorithm and a data sample corresponding to 1.0 fb{sup -1} collected with the Collider Detector at Fermilab in Run II. The measurements are carried out in five different jet rapidity regions with |y{sup jet}| < 2.1 and transverse momentum in the range 54 < p{sub T}{sup jet} < 700 GeV/c. Next-to-leading order perturbative QCD predictions are in good agreement with the measured cross sections.

Measurement of the inclusive jet cross section using the k(T) algorithm in p(p)over-bar collisions at root s=1.96 TeV with the CDF II detector

We have searched for exclusive gammagamma production in proton-antiproton collisions at sqrt[s]=1.96 TeV, using 532 pb(-1) of integrated luminosity taken by the run II Collider Detector at Fermilab. The event signature requires two electromagnetic showers, each with transverse energy E(T)>5 GeV and pseudorapidity |eta|<1.0, with no other particles detected in the event. Three candidate events are observed. We discuss the consistency of the three events with gammagamma, pi(0)pi(0), or eta eta production. The probability that other processes fluctuate to >or=3 events is 1.7x10(-4). An upper limit on the cross section of pp-->p + gammagamma + p production is set at 410 fb with 95% confidence level.

Search for exclusive gammagamma production in Hadron-Hadron collisions.

We measure the mean lifetime tau=2/(Gamma_{L}+Gamma_{H}) and the decay-width difference DeltaGamma=Gamma_{L}-Gamma_{H} of the light and heavy mass eigenstates of the B_{s}{0} meson, B_{sL}{0} and B_{sH}{0}, in B_{s}{0}-->J/psivarphi decays using 1.7 fb;{-1} of data collected with the CDF II detector at the Fermilab Tevatron pp[over ] collider. Assuming CP conservation, a good approximation for the B_{s}{0} system in the standard model, we obtain DeltaGamma=0.076_{-0.063}{+0.059}(stat)+/-0.006(syst) ps{-1} and tau=1.52+/-0.04(stat)+/-0.02(syst) ps, the most precise measurements to date. Our constraints on the weak phase and DeltaGamma are consistent with CP conservation.

Measurement of Lifetime and Decay-Width Difference in B_{s};{0}-->J/psivarphi Decays.

We report the first measurements of inclusive W and Z boson cross-sections times the corresponding leptonic branching ratios for collisions at TeV based on the decays of the W and Z bosons into electrons and muons. The data were recorded with the CDF II detector at the Fermilab Tevatron and correspond to an integrated luminosity of 72.0 ± 4.3 pb−1. We test e-μ lepton universality in W decays by measuring the ratio of the W → μν to W → eν cross sections and determine a value of 0.991 ± 0.004(stat.) ± 0.011(syst.) for the ratio of W − l − ν couplings (gμ/ge). Since there is no sign of non-universality, we combine our cross-section measurements in the different lepton decay modes and obtain nb and pb for dilepton pairs in the mass range between 66 GeV/c2 and 116 GeV/c2. We compute the ratio R of the W → lν to Z → ll cross sections taking all correlations among channels into account and obtain R = 10.84 ± 0.15(stat.) ± 0.14(syst.) including a correction for the virtual photon exchange component in our measured γ*/Z → ll cross section. Based on the measured value of R, we extract values for the W leptonic branching ratio, Br(W → lν)= 0.1082 ± 0.0022; the total width of the W boson, Γ(W)= 2092 ± 42 MeV; and the ratio of W and Z boson total widths, Γ(W)/Γ(Z)= 0.838 ± 0.017. In addition, we use our extracted value of Γ(W) whose value depends on various electroweak parameters and certain CKM matrix elements to constrain the Vcs CKM matrix element, |Vcs| = 0.976 ± 0.030.

Measurements of inclusive W and Z cross sections in collisions at

We report on a search for narrow-width particles decaying to a top and antitop quark pair. The data set used in the analysis corresponds to an integrated luminosity of 680 pb^{-1} collected with the Collider Detector at Fermilab in Run II. We present 95% confidence level upper limits on the cross section times branching ratio. Assuming a specific topcolor-assisted technicolor production model, the leptophobic Z' with width \Gamma_{Z'}=0.012M_{Z'}, we exclude the mass range M_{Z'} < 725 GeV/c^2 at the 95% confidence level.

Search for resonant $t\bart$ production in $p\barp$ collisions at $\sqrt{s}$=1.96 TeV

Observation and mass measurement of the baryon Xi(-)(b) RID G-1087-2011 RID E-4473-2011

We describe a search for anomalous production of events with two leptons (e or mu) of the same electric charge in pp[over ] collisions at a center-of-mass energy of 1.96 TeV. Many extensions to the standard model predict the production of two leptons of the same electric charge. This search has a significant increase in sensitivity compared to earlier searches. Using a data sample corresponding to 1 fb(-1) of integrated luminosity recorded by the CDF II detector, we observe no significant excess in an inclusive selection (expect 33.2+/-4.7 events, observe 44) or in a supersymmetry-optimized selection (expect 7.8+/-1.1 events, observe 13.).

Inclusive search for new physics with like-sign dilepton events in pp collisions at square root of s =1.96 TeV.

Measurement of the top quark mass in p(p)over-bar collisions at root s=1.96 TeV using the decay length technique RID G-1087-2011 RID E-4473-2011

We present a measurement of sigma(pp[over] --> W) x B(W --> e nu) at (square root)s = 1.96 TeV, using electrons identified in the forward region (1.2 < |eta| < 2.8) of the CDF II detector, in 223 pb(-1) of data. We measure sigma x B = 2796 +/- 13(stat)(-90)(+95)(syst) +/- 162(lum) pb. Combining this result with a previous CDF measurement obtained using electrons in the central region (|eta| approximately < 1), we present the first measurement of the ratio of central-electron to forward-electron W partial cross sections R(exp) = 0.925 +/- 0.006(stat) +/- 0.032(syst), consistent with theoretical predictions using Coordinated Theoretical-Experimental Project on QCD (CTEQ) and Martin-Roberts-Stirling-Thorne (MRST) parton distribution functions.

First measurement of the ratio of central-electron to forward-electron W partial cross sections in pp[over] collisions at (square root)s =1.96 TeV.

Measurement of theΛb0Lifetime inΛb0→J/ψΛ0inpp¯Collisions ats=1.96TeV

We report the first observation of the associated production of a W boson and a Z boson. This result is based on 1.1 fb;-1 of integrated luminosity from pp collisions at sqrt[s]=1.96 TeV collected with the CDF II detector at the Fermilab Tevatron. We observe 16 WZ candidates passing our event selection with an expected background of 2.7+/-0.4 events. A fit to the missing transverse energy distribution indicates an excess of events compared to the background expectation corresponding to a significance equivalent to 6 standard deviations. The measured cross section is sigma(pp-->WZ)=5.0(-1.6)(+1.8) pb, consistent with the standard model expectation.

Using 355 pb;{-1} of data collected by the CDF II detector in pp[over ] collisions at sqrt[s]=1.96 TeV at the Fermilab Tevatron, we study the fully reconstructed hadronic decays B_{(s)};{0}-->D_{(s)};{-}pi;{+} and B_{(s)};{0}-->D_{(s)};{-}pi;{+}pi;{+}pi;{-}. We present the first measurement of the ratio of branching fractions B(B_{s};{0}-->D_{s};{-}pi;{+}pi;{+}pi;{-})/B(B;{0}-->D;{-}pi;{+}pi;{+}pi;{-})=1.05+/-0.10(stat)+/-0.22(syst). We also update our measurement of B(B_{s};{0}-->D_{s};{-}pi;{+})/B(B;{0}-->D;{-}pi;{+}) to 1.13+/-0.08(stat)+/-0.23(syst), improving the statistical uncertainty by more than a factor of 2. We find B(B_{s};{0}-->D_{s};{-}pi;{+})=[3.8+/-0.3(stat)+/-1.3(syst)]x10;{-3} and B(B_{s};{0}-->D_{s};{-}pi;{+}pi;{+}pi;{-})=[8.4+/-0.8(stat)+/-3.2(syst)]x10;{-3}.

Measurement of the ratios of branching fractions B (B-s(0)-> D-s(-) pi(+) pi(+) pi(-))/B(B-0 -> D- pi(+) pi(+) pi(-)) and B(B-s(0) -> D-s(-) pi(+))/B(B-0 -> D- pi(+))

We have performed a search for B(s)(0) --> micro(+) micro(-) and B(0) --> micro(+) micro(-) decays in pp collisions at square root s = 1.96 TeV using 2 fb(-1) of integrated luminosity collected by the CDF II detector at the Fermilab Tevatron Collider. The observed number of B(s)(0) and B0 candidates is consistent with background expectations. The resulting upper limits on the branching fractions are B(B(s)0) --> micro(+) micro(-)) <5.8 x 10(-8) and B(B(0) --> micro(+) micro(-))<1.8 x 10(-8) at 95% C.L.

Search for Bs0 --> micro+ micro- and B0 --> micro+ micro- decays with 2 fb-1 of pp collisions.

We report on the results of a search for standard model Higgs bosons produced in association with W bosons from pp[over] collisions at sqrt[s]=1.96 TeV. The search uses a data sample corresponding to approximately 1 fb(-1) of integrated luminosity. Events consistent with the W-->lnu and H-->bb[over] signature are selected by triggering on a high-p(T) electron or muon candidate and tagging one or two of the jet candidates as having originated from b quarks. A neural network filter rejects a fraction of tagged charm and light-flavor jets, increasing the b-jet purity in the sample. We observe no excess lnubb[over] production beyond the background expectation, and we set 95% confidence level upper limits on the production cross section times branching fraction sigma(pp[over]-->WH)Br(H-->bb[over]) ranging from 3.9 to 1.3 pb, for specific Higgs boson mass hypotheses in the range 110 to 150 GeV/c2, respectively.

Search for standard model Higgs bosons produced in association with W bosons.

Measurement of sigma(0)(Lambda B)/sigma(0) x B(Lambda(0)(b)->Lambda(+)(c)pi(-))/B(B)over-bar(0)-> D(+)pi(-)) in p(p)over-bar collisions at root s=1.96 TeV RID G-1087-2011 RID E-4473-2011

Erratum: Measurement of the inclusive jet cross section using the kT algorithm in pp̄ collisions at s=1.96TeV with the CDF II detector (Physical Review D - Particles, Fields, Gravitation and Cosmology (2007) 75, (092006))

We present a measurement of the top-quark mass in p (p) over bar ollisions at root s = 1.96 TeV which uses events with an inclusive signature of missing transverse energy and jets. The event selection is sensitive to t (t) over bar -> W(+)bW(-)(b) over bar -> l nu bqq(') (b) over bar independent of the lepton flavor and results in a large acceptance for W -> tau nu decays. All-hadronic t (t) over bar decays and events with identified electrons or muons are vetoed to provide a statistically independent sample with respect to all previous measurements. The top-quark mass is inferred from the distribution of the scalar sum of all jet transverse energies and the missing transverse energy. Using 311 pb(-1) of integrated luminosity recorded by the Collider Detector at Fermilab, we measure a top-quark mass m(t) = 172.3(-9.6)(+10.8)(stat) +/- 10.8(syst) GeV/c(2). While the uncertainty on m(t) is larger than that of other measurements, the result is statistically uncorrelated with those of other methods and thus can help to reduce the overall m(t) uncertainty when combined with other existing measurements.

Measurement of the top-quark mass using missing E(T) plus jets events with secondary vertex b-tagging at CDF II

We present the results of a search for new particles that lead to a Z boson plus jets in pp collisions at s=1.96TeV using the Collider Detector at Fermilab (CDF II). A data sample with a luminosity of 1.06fb-1 collected using Z boson decays to ee and μμ is used. We describe a completely data-based method to predict the dominant background from standard model Z+jet events. This method can be similarly applied to other analyses requiring background predictions in multijet environments, as shown when validating the method by predicting the background from W+jets in tt production. No significant excess above the background prediction is observed, and a limit is set using a fourth generation quark model to quantify the acceptance. Assuming BR(b′→bZ)=100% and using a leading-order calculation of the b′ cross section, b′ quark masses below 268GeV/c2 are excluded at 95% confidence level. © 2007 The American Physical Society.

Search for new particles leading to Z+jets final states in pp̄ collisions at s=1.96TeV

We measure the ratio of cross section times branching fraction, Rp=sigma chi c2 B(chi c2-->J/psi gamma)/sigma chi c1 B(chi c1-->J/psi gamma), in 1.1 fb(-1) of pp collisions at square root s=1.96 TeV. This measurement covers the kinematic range pT(J/psi)>4.0 GeV/c, |eta(J/psi)<1.0, and pT(gamma)>1.0 GeV/c. For events due to prompt processes, we find Rp=0.395+/-0.016(stat)+/-0.015(syst). This result represents a significant improvement in precision over previous measurements of prompt chi c1,2 hadro production.

Measurement of sigma chi c2 B(chi c2-->J/psi gamma)/sigma chi c1 B(chi c1 -->J/psi gamma) in pp collisions at square root s=1.96 TeV.

We report an observation of new bottom baryons produced in pp collisions at the Tevatron. Using 1.1 fb(-1) of data collected by the CDF II detector, we observe four Lambda b 0 pi+/- resonances in the fully reconstructed decay mode Lambda b 0-->Lambda c + pi-, where Lambda c+-->pK* pi+. We interpret these states as the Sigma b(*)+/- baryons and measure the following masses: m Sigma b+=5807.8 -2.2 +2.0(stat.)+/-1.7(syst.) MeV/c2, m Sigma b- =5815.2+/-1.0(stat.)+/-1.7(syst.) MeV/c2, and m(Sigma b*)-m(Sigma b)=21.2-1.9 +2.0(stat.)-0.3+0.4(syst.) MeV/c2.

We present the first observation of the baryon decay Lambda b0-->Lambda c+pi- followed by Lambda c+-->pK-pi+ in 106 pb-1 pp collisions at square root s=1.96 TeV in the CDF experiment. In order to reduce systematic error, the measured rate for Lambda b0 decay is normalized to the kinematically similar meson decay B0-->D+pi- followed by D+-->pi+K-pi+. We report the ratio of production cross sections (sigma) times the ratio of branching fractions (B) for the momentum region integrated above pT>6 GeV/c and pseudorapidity range |eta|<1.3: sigma(pp-->Lambda b0X)/sigma(pp-->B0X)xB(Lambda b0-->Lambda c+pi-)/B(B0-->D+pi-)=0.82+/-0.08(stat)+/-0.11(syst)+/-0.22[B(Lambda c+-->pK-pi+)].

Measurement of sigma Lambda b0/sigma B0 x B(Lambda b0-->Lambda c+pi-)/B(B0-->D+pi-) in pp collisions at square root s=1.96 TeV.

Search for anomalous production of multilepton events in p$(p)over-bar-$ collisions at root s=1.96 TeV RID G-1087-2011 RID E-4473-2011

We present a search for anomalous triple gauge couplings (ATGC) in WW and WZ boson production. The boson pairs are produced in p (p) over bar collisions at root s = 1.96 TeV, and the data sample corresponds to 350 pb(-1) of integrated luminosity collected with the CDF II detector at the Fermilab Tevatron. In this search one W decays to leptons, and the other boson (W or Z) decays hadronically. Combining with a previously published CDF measurement of W gamma boson production yields ATGC limits of -0.18 <lambda < 0.17 and -0.46 <Delta kappa < 0.39 at the 95% confidence level, using a cutoff scale Lambda=1.5 TeV.

Limits on anomalous triple gauge couplings in p(p)over-bar collisions at root s=1.96 TeV

We present a measurement of the inclusive production cross section for Z bosons decaying to tau leptons in p (p) over bar collisions at root s=1.96 TeV. We use a channel with one hadronically-decaying and one electronically-decaying tau. This measurement is based on 350 pb(-1) of CDF Run II data. Using a sample of 504 opposite sign e tau events with a total expected background of 190 events, we obtain sigma(p (p) over bar -> 4Z)center dot B(Z ->tau tau)=264 +/- 23(stat)+/- 14(syst)+/- 15(lumi) pb, in agreement with the next-to-next-to-leading order QCD prediction. This is the first CDF cross section measurement using hadronically-decaying taus in Run II.

Measurement of sigma(p(p)over-bar -> Z) center dot B(Z -> tau tau) in p(p)over-bar collisions at root s=1.96 TeV

The authors present a measurement of the fractions F{sub 0} and F{sub +} of longitudinally polarized and right-handed W bosons in top quark decays using data collected with the CDF II detector. The data set used in the analysis corresponds to an integrated luminosity of approximately 318 pb{sup -1}. They select t{bar t} candidate events with one lepton, at least four jets, and missing transverse energy. The helicity measurement uses the decay angle {theta}*, which is defined as the angle between the momentum of the charged lepton in the W boson rest frame and the W momentum in the top quark rest frame. The cos {theta}* distribution in the data is determined by full kinematic reconstruction of the t{bar t} candidates. They find F{sub 0} = 0.85{sub -0.22}{sup +0.15}(stat){+-}0.06(syst) and F{sub +} = 0.05{sub -0.05}{sup +0.11}(stat) {+-} 0.03(syst), which is consistent with the standard model prediction. They set an upper limit on the fraction of right-handed W bosons of F{sub +} < 0.26 at the 95% confidence level.

Measurement of the helicity fractions of W bosons from top quark decays using fully reconstructed tt events with CDF II

We present the first measurement of {sigma}(gG {yields} t{bar t})/{sigma}(p{bar p} {yields} t{bar t}). We use 0.96 fb{sup -1} of {radical}s = 1.96 TeV p{bar p} collision data recorded with the CDF II detector at Fermilab. We identify the candidate t{bar t} events with a high-energy charged lepton, a neutrino candidate, and four or more jets with at least one identified as originating from a b quark. Using charged particles with low transverse momentum in t{bar t} events, we find {sigma}(gg {yields} t{bar t})/{sigma}(p{bar p} {yields} t{bar t}) = 0.07 {+-} 0.14(stat) {+-} 0.07(syst), in agreement with the standard model NLO prediction of 0.15 {+-} 0.05.

First measurement of the fraction of top-quark pair production through gluon-gluon fusion

Precise measurement of the top-quark mass in the Lepton plus Jets topology at CDF II RID C-3493-2011 RID G-1087-2011 RID E-4473-2011

This Letter describes the first determination of bounds on the CP-violation parameter 2beta(s) using B(s)(0) decays in which the flavor of the bottom meson at production is identified. The result is based on approximately 2000 B(s)(0)-->J/psiphi decays reconstructed in a 1.35 fb(-1) data sample collected with the CDF II detector using pp collisions produced at the Fermilab Tevatron. We report confidence regions in the two-dimensional space of 2beta(s) and the decay-width difference DeltaGamma. Assuming the standard model predictions of 2beta(s) and DeltaGamma, the probability of a deviation as large as the level of the observed data is 15%, corresponding to 1.5 Gaussian standard deviations.

First flavor-tagged determination of bounds on mixing-induced CP violation in Bs0 --> J/psiphi decays.

We report the first top-quark mass measurement that uses a cross-section constraint to improve the mass determination. This measurement is made with a dilepton tt event candidate sample collected with the Collider Detector II at Fermilab. From a data sample corresponding to an integrated luminosity of 1.2 fb(-1), we measure a top-quark mass of 170.7(-3.9)(+4.2)(stat)+/-2.6(syst)+/-2.4(theory) GeV/c(2). The measurement without the cross-section constraint is 169.7(-4.9)(+5.2)(stat)+/-3.1(syst) GeV/c(2).

Cross-section-constrained top-quark mass measurement from dilepton events at the Tevatron.

We have performed a search for new particles which decay to two photons using 1.2 fb(-1) of integrated luminosity from pp[over] collisions at square root s = 1.96 TeV collected using the CDF II detector at the Fermilab Tevatron. We find the diphoton mass spectrum to be in agreement with the standard model expectation, and set limits on the cross section times branching ratio for the Randall-Sundrum graviton, as a function of diphoton mass. We subsequently derive lower limits for the graviton mass of 230 GeV/c(2) and 850 GeV/c(2), at the 95% confidence level, for coupling parameters (k/M[over](Pl)) of 0.01 and 0.1, respectively.

Search for high-mass diphoton states and limits on Randall-Sundrum gravitons at CDF.

We present a measurement of the inclusive production cross section for Z bosons decaying to tau leptons in pp collisions at s=1.96TeV. We use a channel with one hadronically-decaying and one electronically-decaying tau. This measurement is based on 350pb-1 of CDF Run II data. Using a sample of 504 opposite sign eτ events with a total expected background of 190 events, we obtain σ(pp→4Z)•B(Z→ττ)=264±23(stat) ±14(syst)±15(lumi)pb, in agreement with the next-to-next-to- leading order QCD prediction. This is the first CDF cross section measurement using hadronically-decaying taus in Run II. © 2007 The American Physical Society.

We present a measurement of the mass of the top quark from proton-antiproton collisions recorded at the CDF experiment in Run II of the Fermilab Tevatron. We analyze events from the single lepton plus jets final state (tt-->W(+)bW(-)b-->lnubqq'b). The top-quark mass is extracted using a direct calculation of the probability density that each event corresponds to the tt final state. The probability is a function of both the mass of the top quark and the energy scale of the calorimeter jets, which is constrained in situ by the hadronic W boson mass. Using 167 events observed in 955 pb(-1) of integrated luminosity, we achieve the single most precise measurement of the top-quark mass, 170.8+/-2.2(stat.)+/-1.4(syst.) GeV/c(2).

Precise measurement of the top-quark mass in the lepton+jets topology at CDF II.

Measurement of the B(+) production cross section in pp(-) collisions at root s=1960 GeV RID G-1087-2011 RID E-4473-2011

We present an analysis of angular distributions and correlations of the X(3872) particle in the exclusive decay mode X(3872)-->J/psipi+ pi- with J/psi-->mu+ mu-. We use 780 pb-1 of data from pp[over ] collisions at sqrt[s]=1.96 TeV collected with the CDF II detector at the Fermilab Tevatron. We derive constraints on spin, parity, and charge conjugation parity of the X(3872) particle by comparing measured angular distributions of the decay products with predictions for different J(PC) hypotheses. The assignments J(PC)=1++ and 2-+ are the only ones consistent with the data.

We report a measurement of the top quark mass, M{sub t}, in the dilepton decay channel of t{bar t} {yields} b{ell}{prime}{sup +} {nu}{sub {ell}}, {bar b}{ell}{sup -}{bar {nu}}{sub {ell}} using an integrated luminosity of 1.0 fb{sup -1} of p{bar p} collisions collected with the CDF II detector. We apply a method that convolutes a leading-order matrix element with detector resolution functions to form event-by-event likelihoods; we have enhanced the leading-order description to describe the effects of initial-state radiation. The joint likelihood is the product of the likelihoods from 78 candidate events in this sample, which yields a measurement of M{sub t} = 164.5 {+-} 3.9(stat.) {+-} 3.9(syst.) GeV/c{sup 2}, the most precise measurement of M{sub t} in the dilepton channel.

Precision measurement of the top-quark mass from dilepton events at CDF II

Measurement of sigma(chi c2)B(chi(c2)-> J/psi gamma)/sigma(chi c1)B(chi(c1)-> J/psi gamma) in p(p)over-bar collisions at root s=1.96 TeV RID G-1087-2011 RID E-4473-2011

We report an upper limit on the fraction of V+A current, fV+A, in top-quark decays, using approximately 700 pb-1 of pp[over ] collisions at sqrts=1.96 TeV acquired by the upgraded Collider Detector at Fermilab. For the decay t-->Wb-->lnub (where l=e or micro), the invariant mass of the charged lepton and the bottom quark jet is sensitive to the polarization of the W boson. We determine fV+A=-0.06+/-0.25 given a top-quark mass of 175 GeV/c2. We set an upper limit on fV+A of 0.29 at the 95% confidence level, an improvement by a factor of 2 on the previous best direct limit.

Search for V+A current in top-quark decays in pp collisions at sqrts=1.96 TeV.

We present a measurement of {sigma}(pp{yields}W)xB(W{yields}e{nu}) at {radical}(s)=1.96 TeV, using electrons identified in the forward region (1.2< vertical bar {eta} vertical bar <2.8) of the CDF II detector, in 223 pb{sup -1} of data. We measure {sigma}xB=2796{+-}13(stat){sub -90}{sup +95}(syst){+-}162(lum) pb. Combining this result with a previous CDF measurement obtained using electrons in the central region ( vertical bar {eta} vertical bar < or approx. 1), we present the first measurement of the ratio of central-electron to forward-electron W partial cross sections R{sub exp}=0.925{+-}0.006(stat){+-}0.032(syst), consistent with theoretical predictions using Coordinated Theoretical-Experimental Project on QCD (CTEQ) and Martin-Roberts-Stirling-Thorne (MRST) parton distribution functions.

First measurement of the ratio of central-electron to forward-electron W partial cross sections in pp̄ collisions at s=1.96TeV

We report the observation and measurement of the mass of the bottom, strange baryon Xi(b)- through the decay chain Xi(b)- -->J/psiXi-, where J/psi-->mu+mu-, Xi- -->Lambdapi-, and Lambda-->ppi-. A signal is observed whose probability of arising from a background fluctuation is 6.6 x 10(-15), or 7.7 Gaussian standard deviations. The Xi(b)- mass is measured to be 5792.9+/-2.5(stat) +/- 1.7(syst) MeV/c2.

Measurement of σΛb0/ σB̄0×B(Λb0→Λc+π-)/B(B̄0→D+π- ) in pp̄ Collisions at s=1.96TeV

Measurement of $\sigma(p \bar{p} \to Z) . {\rm Br}(Z \to 2\tau)$ in $p\bar{p}$ collisions at $sqrt{s}=1.96$ TeV

We report the results of a search for a narrow resonance in electron-positron events in the invariant mass range of 150-950 GeV/c(2) using 1.3 fb(-1) of pp[over] collision data at square root s = 1.96 TeV collected by the CDF II detector at Fermilab. No significant evidence of such a resonance is observed and we interpret the results to exclude the standard-model-like Z' with a mass below 923 GeV/c(2) and the Randall-Sundrum graviton with a mass below 807 GeV/c(2) for k/M[over](pl) = 0.1, both at the 95% confidence level. Combining with diphoton data excludes the Randall-Sundrum graviton for masses below 889 GeV/c(2) for k/M[over](pl) = 0.1.

Search for new physics in high-mass electron-positron events in pp[over] collisions at square root s = 1.96 TeV.

We report an upper limit on the fraction of V+A current, f{sub V+A}, in top-quark decays, using approximately 700 pb{sup -1} of pp collisions at {radical}(s)=1.96 TeV acquired by the upgraded Collider Detector at Fermilab. For the decay t{yields}Wb{yields}l{nu}b (where l=e or {mu}), the invariant mass of the charged lepton and the bottom quark jet is sensitive to the polarization of the W boson. We determine f{sub V+A}=-0.06{+-}0.25 given a top-quark mass of 175 GeV/c{sup 2}. We set an upper limit on f{sub V+A} of 0.29 at the 95% confidence level, an improvement by a factor of 2 on the previous best direct limit.

Search for V plus A current in top-quark decays in p(p)over-bar collisions root s=1.96 TeV

Measurements of inclusive W and Z cross sections in p\overline{p} collisions at \sqrt{s} = 1\hbox{.}96\, {{\rm TeV}}

We report the first measurement of the top quark mass using the decay length technique in p{bar p} collisions at a center-of-mass energy of 1.96 TeV. This technique uses the measured flight distance of the b hadron to infer the mass of the top quark in lepton plus jets events with missing transverse energy. It relies solely on tracking and avoids the jet energy scale uncertainty that is common to all other methods used so far. We apply our novel method to a 695 pb{sup -1} data sample recorded by the CDF II detector at Fermilab and extract a measurement of m{sub t} = 180.7{sub -13.4}{sup +15.5}(stat.) {+-} 8.6 (syst.) GeV/c{sup 2}. While the uncertainty of this result is larger than that of other measurements, the dominant uncertainties in the decay length technique are uncorrelated with those in other methods. This result can help reduce the overall uncertainty when combined with other existing measurements of the top quark mass.

Measurement of the top quark mass in pp̄ collisions at s=1.96TeV using the decay length technique

We describe a search for anomalous production of events with two leptons (e or mu) of the same electric charge in p(p) over bar collisions at a center-of-mass energy of 1.96 TeV. Many extensions to the standard model predict the production of two leptons of the same electric charge. This search has a significant increase in sensitivity compared to earlier searches. Using a data sample corresponding to 1 fb(-1) of integrated luminosity recorded by the CDF II detector, we observe no significant excess in an inclusive selection (expect 33.2 +/- 4.7 events, observe 44) or in a supersymmetry-optimized selection (expect 7.8 +/- 1.1 events, observe 13.).

Inclusive search for new physics with like-sign dilepton events in p(p)over-bar collisions at root s=1.96 TeV

Search for new physics in lepton plus photon plus X events with 929 pb(-1) of pp collisions at root s=1.96 TeV

We measure the time dependence of the ratio of decay rates for the rare decay D{0}-->K{+}pi{-} to the Cabibbo-favored decay D{0}-->K{-}pi;{+}. A signal of 12.7x10;{3} D{0}-->K{+}pi{-} decays was obtained using the Collider Detector at Fermilab II detector at the Fermilab Tevatron with an integrated luminosity of 1.5 fb;{-1}. We measure the D0-D[over ]{0} mixing parameters (R_{D},y{'},x{'2}), and find that the data are inconsistent with the no-mixing hypothesis with a probability equivalent to 3.8 Gaussian standard deviations.

We present results of a search at CDF in 929±56pb-1 of pp collisions at 1.96 TeV for the anomalous production of events containing a high-transverse momentum charged lepton (l, either e or μ) and photon (γ), accompanied by missing transverse energy (E T), and/or additional leptons and photons, and jets (X). We use the same selection criteria as in a previous CDF Run I search, but with an order-magnitude larger data set, a higher pp collision energy, and the CDF II detector. We find 163 lγE T+X events, compared to an expectation of 150.6±13.0 events. We observe 74 lγ+X events, compared to an expectation of 65.1±7.7 events. We find no events similar to the Run I eeγγE T event. © 2007 The American Physical Society.

Search for new physics in lepton+photon+X events with 929pb-1 of pp̄ collisions at s=1.96TeV

Measurement of the Lambda(0)(b) lifetime in Lambda(0)(b)-> J/psi Lambda(0) in p(p)over-bar collisions at root s=1.96 TeV RID G-1087-2011 RID E-4473-2011

We present a measurement of the W-boson mass using 200 pb{-1} of data collected in pp[over ] collisions at sqrt[s]=1.96 TeV by the CDF II detector at run II of the Fermilab Tevatron. With a sample of 63 964 W-->enu candidates and 51 128 W-->munu candidates, we measure M_{W}=80 413+/-34{stat}+/-34{syst}=80,413+/-48 MeV/c;{2}. This is the most precise single measurement of the W-boson mass to date.

First measurement of the W-boson mass in run II of the Tevatron.

We have measured the polarizations of J/psi and psi(2S) mesons as functions of their transverse momentum p(T) when they are produced promptly in the rapidity range |y| < 0.6 with p(T) > or =5 GeV/c. The analysis is performed using a data sample with an integrated luminosity of about 800 pb(-1) collected by the CDF II detector. For both vector mesons, we find that the polarizations become increasingly longitudinal as p(T) increases from 5 to 30 GeV/c. These results are compared to the predictions of nonrelativistic quantum chromodynamics and other contemporary models. The effective polarizations of J/psi and psi(2S) mesons from B-hadron decays are also reported.

Polarizations of J/psi and psi(2S) mesons produced in pp collisions at square root s = 1.96 TeV.

We present a search for anomalous semileptonic decays of heavy flavor hadrons produced in association with a $W$ boson, in proton-antiproton collisions at sqrt{s}=1.96 TeV. We use 162 pb-1 of data collected with the CDF II detector at the Fermilab Tevatron Collider. We select events with one W boson and at least one jet with an identified secondary vertex. In the jets with a secondary vertex we look for a semileptonic decay to a muon. We compare the number of jets with both a secondary vertex and a semileptonic decay, and the kinematic properties of these jets, with the standard model expectation of W plus heavy flavor production and decay. No discrepancy is seen between the observation and the expectation, and we set limits on the production cross section of a B-like hadron with an anomalously high semileptonic branching ratio.

Search for anomalous semileptonic decay of heavy flavor hadrons produced in association with a W boson at CDF II

We report two measurements of the top-quark mass M-top using the CDF II detector at the Fermilab Tevatron in a 318 pb(-1) data sample of t (t) over bar events in the lepton+jets final state. One method uses an event-based likelihood technique resulting in M-top=173.2(-2.4)(+2.6)(stat)+/- 3.2(syst) GeV/c(2) or 173.2(-4.0)(+4.1) GeV/c(2). The second method reconstructs a top-quark mass in each event using the measured invariant mass of the hadronically decaying W boson to constrain the jet energy scale to obtain a value for M-top of 173.5(-3.6)(+3.7)(stat)+/- 1.3(syst) GeV/c(2) or 173.5(-3.8)(+3.9) GeV/c(2). We take the latter, which is more precise, as our result.

Precision top-quark mass measurement in the lepton plus jets topology in p(p)over-bar collisions at root s=1.96 TeV

This paper describes a measurement of the mass and of the width of two neutral narrow resonances D{sub 1}{sup 0} and D*{sub 2}{sup 0}, both composed of a charm quark and an up antiquark. The difference with respect to the well-known resonance D{sup 0}, also neutral and with the same quark composition, is that the two quarks have an orbital momentum 1, which increases their binding energy. Therefore the mass is larger than that of the D{sup 0}. Since the relative orientation of the spin is the same, in the limit of very large charm mass, the masses of these resonances should be the same; their small difference is predicted by theory and therefore important to measurement to distinguish the different models. These states have been observed in their decay into a kaon and three pions; two of these particles are required to originate from a displaced vertex with respect to the primary interaction vertex, to account for the longer lifetime of the charmed mesons. The resonances parameters have been extracted using a fitting procedure accounting for the expected resonance shape, including effects from detector resolution and background, providing a new best single measurement of the D{sub 1}{sup 0} andmore » D*{sub 2}{sup 0} masses and a competitive measurement of their widths.« less

Measurement of mass and width of the excited charmed meson states D10 and D2*0 at CDF

We present the first observation of exclusive e(+)e(-) production in hadron-hadron collisions, using pp[over] collision data at (square root) s = 1.96 TeV taken by the run II Collider Detector at Fermilab, and corresponding to an integrated luminosity of 532 pb(-1). We require the absence of any particle signatures in the detector except for an electron and a positron candidate, each with transverse energy E(T) > 5 GeV and pseudorapidity |eta| < 2. With these criteria, 16 events are observed compared to a background expectation of 1.9+/-0.3 events. These events are consistent in cross section and properties with the QED process pp[over] --> p + e(+)e(-) + p[over] through two-photon exchange. The measured cross section is 1.6(-0.3)(+0.5)(stat) +/- 0.3(syst) pb. This agrees with the theoretical prediction of 1.71+/-0.01 pb.

Observation of exclusive electron-positron production in hadron-hadron collisions.

Search for Higgs bosons decaying to b(b)over-bar and produced in association with W Bosons in p(p)over-bar collisions at root s = 1.96 TeV RID C-1693-2008 RID G-1087-2011 RID E-4473-2011

We present a measurement of the top-quark mass Mtop in the all-hadronic decay channel tt-->W+bW-b-->q1q2bq3q4b. The analysis is performed using 310 pb-1 of sqrt[s]=1.96 TeV pp[over ] collisions collected with the CDF II detector using a multijet trigger. The mass measurement is based on an event-by-event likelihood which depends on both the sample purity and the value of the top-quark mass, using 90 possible jet-to-parton assignments in the six-jet final state. The joint likelihood of 290 selected events yields a value of Mtop=177.1+/-4.9(stat)+/-4.7(syst) GeV/c2.

Measurement of the top-quark mass in all-hadronic decays in pp collisions at CDF II.

We report on a measurement of the inclusive jet production cross section as a function of the jet transverse momentum in pp collisions at (square root s)=1.96 TeV using data collected with the upgraded Collider Detector at Fermilab in run II, corresponding to an integrated luminosity of 385 pb-1. The measurement is carried out for jets with rapidity 0.1</yjet/<0.7 and transverse momentum in the range 54<pjetT<700 GeV/c. Next-to-leading order perturbative QCD predictions are in good agreement with the measured cross section after the necessary nonperturbative parton-to-hadron corrections are included.

Measurement of the inclusive jet cross section using the kT algorithm in pp collisions at (square root s)=1.96 TeV.

We search for excited and exotic muon states mu* using an integrated luminosity of 371 pb(-1) of p[over]p collision data at sqrt[s]=1.96 TeV. We search for associated production of mumu* followed by the decay mu*-->mugamma. We compare the data to model predictions as a function of the mass of the excited muon M(mu*), the compositeness energy scale Lambda, and the gauge coupling factor f. No signal above the standard model expectation is observed. We exclude 107<M(mu*)<853 GeV/c(2) for Lambda=M(mu*) in the contact interaction model, and 100<M(mu*)<410 GeV/c(2) for f/Lambda=10(-2) GeV-1 in the gauge-mediated model, both at the 95% confidence level.

Search for excited and exotic muons in the mugamma decay channel in p-p collisions at sqrt s =1.96 TeV.

We present a search for neutral supersymmetric Higgs bosons decaying to tau pairs produced in pp collisions at square root of s = 1.96 TeV. The data, corresponding to 310 pb(-1) integrated luminosity, were collected with the Collider Detector at Fermilab in run II of the Tevatron. No significant excess above the standard model backgrounds is observed. We set exclusion limits on the production cross section times branching fraction to tau pairs for Higgs boson masses in the range from 90 to 250 GeV/c2.

Search for neutral Higgs bosons of the minimal supersymmetric standard model decaying to tau pairs in pp collisions at square root of s = 1.96 TeV.

Measurement of the top quark mass using template methods on dilepton events in p(p)over-bar collisions at root s=1.96 TeV RID C-3493-2011 RID G-1087-2011 RID E-4473-2011

We search for Z' bosons in dielectron events produced in pp collisions at square root of s = 1.96 TeV, using 0.45 fb(-1) of data accumulated with the Collider Detector at Fermilab II detector at the Fermilab Tevatron. To identify the Z' --> e+ e- signal, both the dielectron invariant mass distribution and the angular distribution of the electron pair are used. No evidence of a signal is found, and 95% confidence level lower limits are set on the Z' mass for several models. Limits are also placed on the mass and gauge coupling of a generic Z', as well as on the contact-interaction mass scales for different helicity structure scenarios.

Search for Z' --> e+ e- using dielectron mass and angular distribution.

We report a measurement of the Lambda b0 lifetime in the exclusive decay Lambda b0-->J/psi Lambda 0 in pp collisions at square root s=1.96 TeV using an integrated luminosity of 1.0 fb-1 of data collected by the CDF II detector at the Fermilab Tevatron. Using fully reconstructed decays, we measure tau(Lambda b0)=1.593(-0.078)(+0.083)(stat)+/-0.033(syst) ps. This is the single most precise measurement of tau(Lambda b0) and is 3.2sigma higher than the current world average.

Measurement of the Lambda b0 lifetime in Lambda b0-->J/psi Lambda 0 in pp collisions at square root s=1.96 TeV.

Top quark mass measurement using the template method in the<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"><mml:mi>lepton</mml:mi><mml:mo>+</mml:mo><mml:mi>jets</mml:mi></mml:math>channel at CDF II

We present results of a search for anomalous production of events containing a charged lepton (l, either e or mu) and a photon (gamma), both with high transverse momentum, accompanied by additional signatures X, including missing transverse energy (ET) and additional leptons and photons. We use the same selection criteria as in a previous CDF search but with a substantially larger data set, 305 pb(-1), a pp collision energy of 1.96 TeV, and the CDF II detector. We find 42 lgammaET events versus an expectation of 37.3+/-5.4 events. We observe 31 llgamma+X events versus an expectation of 23.0+/-2.7 events. We find no events similar to the run I eegammagammaET event.

Search for new physics in lepton plus photon plus X events with 305 pb(-1) of p(p)over-bar collisions at root s=1.96 TeV

We measure the dipion mass spectrum in X(3872)--> J/psipi(+) pi(-) decays using 360 pb(-1) of pp collisions at square root s= 1.96 TeV collected with the CDF II detector. The spectrum is fit with predictions for odd C-parity ((3)S(1), (1)P(1), and (3)D(J)) charmonia decaying to J/psipi(+) pi(-), as well as even C-parity states in which the pions are from rho(0) decay. The latter case also encompasses exotic interpretations, such as a D(0)D(*0) molecule. Only the (3)S(1) and J/psirho hypotheses are compatible with our data. Since (3)S(1) is untenable on other grounds, decay via J/psirho is favored, which implies C= +1 for the X(3872). Models for J/psi - rho different angular momenta L are considered. Flexibility in the models, especially the introduction of rho - omega interference, enables good descriptions of our data for both L = 0 and 1.

A. Abulencia, D. Acosta, J. Adelman, T. Affolder, T. Akimoto, M. G. Albrow, D. Ambrose, S. Amerio, D. Amidei, A. Anastassov, K. Anikeev, A. Annovi, J. Antos, M. Aoki, G. Apollinari, J.-F. Arguin, T. Arisawa, A. Artikov, W. Ashmanskas, A. Attal, F. Azfar, P. Azzi-Bacchetta, P. Azzurri, N. Bacchetta, H. Bachacou, W. Badgett, A. Barbaro-Galtieri, V. E. Barnes, B. A. Barnett, S. Baroiant, V. Bartsch, G. Bauer, F. Bedeschi, S. Behari, S. Belforte, G. Bellettini, J. Bellinger, A. Belloni, E. Ben Haim, D. Benjamin, A. Beretvas, J. Beringer, T. Berry, A. Bhatti, M. Binkley, D. Bisello, R. E. Blair, C. Blocker, B. Blumenfeld, A. Bocci, A. Bodek, V. Boisvert, G. Bolla, A. Bolshov, D. Bortoletto, J. Boudreau, A. Boveia, B. Brau, C. Bromberg, E. Brubaker, J. Budagov, H. S. Budd, S. Budd, K. Burkett, G. Busetto, P. Bussey, K. L. Byrum, S. Cabrera, M. Campanelli, M. Campbell, F. Canelli, A. Canepa, D. Carlsmith, R. Carosi, S. Carron, M. Casarsa, A. Castro, P. Catastini, D. Cauz, M. Cavalli-Sforza, A. Cerri, L. Cerrito, S. H. Chang, J. Chapman, Y. C. Chen, M. Chertok, G. Chiarelli, G. Chlachidze, F. Chlebana, I. Cho, K. Cho, D. Chokheli, J. P. Chou, P. H. Chu, S. H. Chuang, K. Chung, W. H. Chung, Y. S. Chung, M. Ciljak, C. I. Ciobanu, M. A. Ciocci, A. Clark, D. Clark, M. Coca, G. Compostella, M. E. Convery, J. Conway, B. Cooper, K. Copic, M. Cordelli, G. Cortiana, F. Cresciolo, A. Cruz, C. Cuenca Almenar, J. Cuevas, R. Culbertson, D. Cyr, S. DaRonco, S. D’Auria, M. D’Onofrio, D. Dagenhart, P. de Barbaro, S. De Cecco, A. Deisher, G. De Lentdecker, M. Dell’Orso, F. Delli Paoli, S. Demers, L. Demortier, J. Deng, M. Deninno, D. De Pedis, P. F. Derwent, C. Dionisi, J. R. Dittmann, P. DiTuro, C. Dörr, S. Donati, M. Donega, P. Dong, J. Donini, T. Dorigo, S. Dube, K. Ebina, J. Efron, J. Ehlers, R. Erbacher, D. Errede, S. Errede, R. Eusebi, H. C. Fang, S. Farrington, I. Fedorko, W. T. Fedorko, R. G. Feild, M. Feindt, J. P. Fernandez, R. Field, G. Flanagan, L. R. Flores-Castillo, A. Foland, S. Forrester, G. W. Foster, M. Franklin, J. C. Freeman, I. Furic, M. Gallinaro, J. Galyardt, J. E. Garcia, M. Garcia Sciveres, A. F. Garfinkel, C. Gay, H. Gerberich, D. Gerdes, S. Giagu, P. Giannetti, A. Gibson, K. Gibson, C. Ginsburg, N. Giokaris, K. Giolo, M. Giordani, P. Giromini, M. Giunta, G. Giurgiu, V. Glagolev, D. Glenzinski, M. Gold, N. Goldschmidt, J. Goldstein, G. Gomez, G. Gomez-Ceballos, M. Goncharov, O. González, I. Gorelov, A. T. Goshaw, Y. Gotra, K. Goulianos, A. Gresele, M. Griffiths, S. Grinstein, C. Grosso-Pilcher, R. C. Group, U. Grundler, J. Guimaraes da Costa, Z. Gunay-Unalan, C. Haber, S. R. Hahn, K. Hahn, E. Halkiadakis, A. Hamilton, B.-Y. Han, J. Y. Han, R. Handler, F. Happacher, K. Hara, M. Hare, S. Harper, R. F. Harr, R. M. Harris, K. Hatakeyama, J. Hauser, C. Hays, A. Heijboer, B. Heinemann, J. Heinrich, M. Herndon, D. Hidas, C. S. Hill, D. Hirschbuehl, A. Hocker, A. Holloway, S. Hou, M. Houlden, S.-C. Hsu, B. T. Huffman, R. E. Hughes, J. Huston, J. Incandela, G. Introzzi, M. Iori, Y. Ishizawa, A. Ivanov, B. Iyutin, E. James, D. Jang, B. Jayatilaka, D. Jeans, H. Jensen, E. J. Jeon, S. Jindariani, M. Jones, K. K. Joo, S. Y. Jun, T. R. Junk, T. Kamon, J. Kang, P. E. Karchin, Y. Kato, Y. Kemp, R. Kephart, U. Kerzel, V. Khotilovich, B. Kilminster, D. H. Kim, H. S. Kim, J. E. Kim, M. J. Kim, S. B. Kim, S. H. Kim, Y. K. Kim, L. Kirsch, S. Klimenko, M. Klute, B. Knuteson, B. R. Ko, H. Kobayashi, K. Kondo, D. J. Kong, J. Konigsberg, A. Korytov, A. V. Kotwal, A. Kovalev, A. Kraan, J. Kraus, I. Kravchenko, M. Kreps, J. Kroll, N. Krumnack, M. Kruse, V. Krutelyov, S. E. Kuhlmann, Y. Kusakabe, S. Kwang, A. T. Laasanen, S. Lai, S. Lami, S. Lammel, M. Lancaster, R. L. Lander, K. Lannon, A. Lath, G. Latino, I. Lazzizzera, T. LeCompte, J. Lee, J. Lee, Y. J. Lee, S. W. Lee, R. Lefèvre, N. Leonardo, S. Leone, S. Levy, J. D. Lewis, C. Lin, C. S. Lin, M. Lindgren, E. Lipeles, A. Lister, D. O. Litvintsev, T. Liu, N. S. Lockyer, A. Loginov, M. Loreti, P. Loverre, R.-S. Lu, D. Lucchesi, P. Lujan, P. Lukens, G. Lungu, L. Lyons, J. Lys, R. Lysak, E. Lytken, P. Mack, D. MacQueen, R. Madrak, K. Maeshima, T. Maki, P. Maksimovic, S. Malde, G. Manca, F. Margaroli, R. Marginean, C. Marino, A. Martin, V. Martin, M. Martı́nez, T. Maruyama, H. Matsunaga, M. E. Mattson, R. Mazini, P. Mazzanti, K. S. McFarland, P. McIntyre, R. McNulty, A. Mehta, S. Menzemer, A. Menzione, P. Merkel, C. Mesropian, A. Messina, M. von der Mey, T. Miao, N. Miladinovic, J. Miles, R. Miller, J. S. Miller, C. Mills, M. Milnik, R. Miquel, A. Mitra, G. Mitselmakher, A. Miyamoto, N. Moggi, B. Mohr, R. Moore, M. Morello, P. Movilla Fernandez, J. Mülmenstädt, A. Mukherjee, Th. Muller, R. Mumford, P. Murat, J. Nachtman, J. Naganoma, S. Nahn, I. Nakano, A. Napier, D. Naumov, V. Necula,

Observation ofBs0→ψ(2S)ϕand Measurement of the Ratio of Branching FractionsB(Bs0→ψ(2S)ϕ)/B(Bs0→J/ψϕ)

The authors present the results of a search for new physics in the jets plus missing transverse energy data sample collected from 368 pb{sup -1} of p{bar p} collisions at {radical}s = 1.96 TeV recorded by the Collider Detector at Fermilab. They compare the number of events observed in the data with a data-based estimate of the standard model backgrounds contributing to this signature. They observe no significant excess of events, and they interpret this null result in terms of lower limits on the fundamental Planck scale for a large extra dimensions scenario.

Search for large extra dimensions in the production of jets and missing transverse energy in pp̄ collisions at s=1.96TeV

A search for a manifestly exotic S=-2 baryon state decaying to Ξ-π-, and its neutral partner decaying to Ξ-π+, has been performed using 220pb-1 of pp collisions at s=1.96TeV collected by the Collider Detector at Fermilab. The Ξ- trajectories were measured in a silicon tracker before their decay, resulting in a sample with low background and excellent position resolution. No evidence was found for S=-2 pentaquark candidates in the invariant mass range of 1600-2100MeV/c2. Upper limits on the product of pentaquark production cross section times its branching fraction to Ξ-π+,-, relative to the cross section of the well-established Ξ(1530) resonance, are presented for neutral and doubly negative candidates with pT>2GeV/c and

Search for exotic S =-2 baryons in p(p)over-bar collisions at root s=1.96 TeV

A measurement of the inclusive bottom jet cross section is presented for events containing a Z boson in pp collisions at {radical}(s)=1.96 TeV using the Collider Detector at Fermilab. Z bosons are identified in their electron and muon decay modes, and b jets with E{sub T}>20 GeV and {eta}<1.5 are identified by reconstructing a secondary decay vertex. The measurement is based on an integrated luminosity of about 330 pb{sup -1}. A cross section times branching ratio of {sigma}(Z+b jets)xB(Z{yields}l{sup +}l{sup -})=0.93{+-}0.36 pb is found, where B(Z{yields}l{sup +}l{sup -}) is the branching ratio of the Z boson or {gamma}* into a single flavor dilepton pair (e or {mu}) in the mass range between 66 and 116 GeV/c{sup 2}. The ratio of b jets to the total number of jets of any flavor in the Z sample, within the same kinematic range as the b jets, is 2.36{+-}0.92%. Here, the uncertainties are the quadratic sum of statistical and systematic uncertainties. Predictions made with next-to-leading order QCD agree, within experimental and theoretical uncertainties, with these measurements.

Measurement of the b jet cross section in events with a Z boson in pp(-) collisions at root s 1. 96 TeV

We report the first observation of B(0)(s)-->Psi(2S)Phi decay in p(p_) collisions at square root of 8=1.96 TeV using 360 pb(-1) of data collected by the CDF II detector at the Fermilab Tevatron. We observe 20.2 +/- 5.0 and 12.3 +/- 4.1 B(0)(s)-->Psi(2S)Phi candidates, in Psi(2S)-->mu(+)mu(-) and Phi(2S)-->J/Phipi(+)pi(-) decay modes, respectively. We present a measurement of the relative branching fraction Beta(B(0)(s)-->Psi(2S)Phi)/Beta(B(0)(s)-->J/PsiPhi)=0.52 +/- 0.13(stat) +/- 0.04(syst) +/- 0.06(BR) using the Psi(2S)-->mu(+)mu(-) decay mode.

Observation of B(0)(s)-->Psi(2S)Phi and measurement of the ratio of branching fractions Beta(B(0)(s)-->Psi(2S)Phi)/Beta(B(0)(s)-->J/PsiPhi).

Measurement of the ratios of branching fractions B(B0s --> Ds- pi+ pi+ pi-)/B(B0-->D- pi+ pi+ pi-) and B(B0s --> Ds- pi+)/B(B0-->D- pi+).

We report two measurements of the top-quark mass M(top) using the CDF II detector at the Fermilab Tevatron in a 318 pb(-1) data sample of tt events in the lepton+jets final state. One method uses an event-based likelihood technique resulting in M(top) = 173.2(-2.4)(+2.6)(stat) +/- 3.2(syst) GeV/c2 or 173.2(-4.0)(+4.1) GeV/c2. The second method reconstructs a top-quark mass in each event using the measured invariant mass of the hadronically decaying W boson to constrain the jet energy scale to obtain a value for M(top)of 173.5(-3.6)(+3.7)(stat) +/- 1.3(syst) GeV/c2 or 173.5(-3.8)(+3.9) GeV/c2 . We take the latter, which is more precise, as our result.

Precision top-quark mass measurement in the lepton+jets topology in p p collisions at square root s=1.96 TeV.

Search for excited and exotic muons in the mu gamma decay channel in p(p)over-bar collisions root s=1.96 TeV RID G-1087-2011 RID E-4473-2011

The authors search Z{prime} bosons in dielectron events produced in p{bar p} collisions at {radical}s = 1.96 TeV, using a 0.45 fb{sup -1} dataset accumulated with the CDF II detector at the Fermilab Tevatron. To identify the Z{prime} {yields} e{sup +}e{sup -} signal, both the dielectron invariant mass distribution and the angular distribution of the electron pair are used. No evidence of a signal is found, and 95% confidence level lower limits are set on the Z{prime} mass for several models. Limits are also placed on the mass and gauge coupling of a generic Z{prime}, as well as on the contact interaction mass scales for different helicity structure scenarios.

Search for Z??e+e- Using Dielectron Mass and Angular Distribution

Search for scalar bottom quarks from gluino decays in (p)over-barp collisions at root s=1.96 TeV RID G-1087-2011 RID E-4473-2011

Measurement of the inclusive jet cross section using the k(T) algorithm in p(p)over-bar collisions at root s=1.96 TeV RID G-1087-2011 RID E-4473-2011

We report an observation of the decay B(O)(S) --> D(-)(s)pi(+) in pp collisions at radical S = 1.96 TeV using 115 pb(-1) of data collected by the CDF II detector at the Fermilab Tevatron. We observe 83 +/- 11(stat) B(O)(s) --> D(-)(s)pi(+) candidates, representing a large increase in statistics over previous measurements and the first observation of this decay at a pp collider. We present the first measurement of the relative branching fraction Beta(B(O)(s) --> D(-)(s)pi(+))/Beta(B(0) --> D(-)(pi)(+)) = 1.32 +/- 0.18(stat) +/- 0.38(syst). We also measure Beta(B(+) --> D(0)pi(+))/Beta(B(0) -->D(-)pi(+)) = 1.97 +/- 0.10(stat) +/- 0.21(syst), which is consistent with previous measurements.

We search for decays of the type B(s)0-->h+ h'- (where h,h' = K or pi) in 180 pb(-1) of pp collisions collected at the Tevatron by the upgraded Collider Detector at Fermilab. We report the first observation of the new mode B(s)0-->K+ K- with a yield of 236+/-32 events, corresponding to (fs/fd) x B(B(s)0-->K+ K-)/B(B0-->K+ pi-) = 0.46+/-0.08stat+/-0.07syst, where fs/fd is the ratio of production fractions of B(s)0 and B0. We find results in agreement with world averages for the B0 modes, and set the following new limits at 90% C.L.: B(B(s)0-->K- pi+) < 5.6 x 10(-6) and B(B(s)0-->pi+ pi-) < 1.7 x 10(-6).

Observation of B(s)0-->K+ K- and measurements of branching fractions of charmless two-body decays of B0 and B(s)0 mesons in pp collisions at square root of s = 1.96 TeV.

Search for high-mass resonances decaying to e mu in pp- collisions at root s = 1.96 TeV RID G-1087-2011 RID E-4473-2011

Measurement of the ratios of branching fractions B(B(s)(0)-> D(s)(-)pi(+))/B(B(0)-> D(-)pi(+)) and B(B(+)->(D)over-bar(0)pi(+))/B(B(0)-> D(-)pi(+)) RID G-1087-2011 RID E-4473-2011

This report describes a measurement of the top quark mass, M{sub top}, with the dynamical likelihood method (DLM) using the CDF II detector at the Fermilab Tevatron. The Tevatron produces top/anti-top (t{bar t}) pairs in p{bar p} collisions at a center-of-mass energy of 1.96 TeV. The data sample used in this analysis was accumulated from March 2002 through August 2004, which corresponds to an integrated luminosity of 318 pb{sup -1}. They use the t{bar t} candidates in the ''lepton+jets'' decay channel, requiring at least one jet identified as a b quark by finding an displaced secondary vertex. The DLM defines a likelihood for each event based on the differential cross section as a function of M{sub top} per unit phase space volume of the final partons, multiplied by the transfer functions from jet to parton energies. The method takes into account all possible jet combinations in an event, and the likelihood is multiplied event by event to derive the top quark mass by the maximum likelihood method. Using 63 t{bar t} candidates observed in the data, with 9.2 events expected from background, they measure the top quark mass to be 173.2{sub -2.4}{sup +2.6}(stat.) {+-} 3.2(syst.) GeV/c{sup 2}, or 173.2{sub -4.0}{sup +4.1} GeV/c{sup 2}.

Measurement of the top quark mass with the dynamical likelihood method using lepton plus jets events with b-tags in pp̄ collisions at s=1.96TeV

We present a measurement of the Bc+ meson lifetime in the decay mode Bc+ --> J/Psie+nue using the Collider Detector at Fermilab II detector at the Fermilab Tevatron Collider. From a sample of about of 360 pb(-1) of pp collisions at square root of s = 1.96 TeV, we reconstruct J/Psie+ pairs with invariant mass in the kinematically allowed range 4< M(J/Psie) < 6 GeV/c2. A fit to the decay-length distribution of 238 signal events yields a measured Bc+ meson lifetime of 0.463(-0.065)(+0.073)(stat) +/- 0.036(syst) ps.

Measurement of the Bc+ meson lifetime using the decay mode Bc+ --> J/Psie+nue.

Measurement of the dipion mass spectrum in X(3872)-> J/psi pi(+)pi(-) decays RID C-1693-2008 RID G-1087-2011 RID E-4473-2011

We present the results of a search for standard model Higgs boson production with decay to WW*, identified through the leptonic final states e+ e- nu nu,+/-mu -/+nu nu and mu+ mu- nu nu. This search uses 360 pb -1 of data collected from pp collisions at square root of s =1.96 TeV by the upgraded Collider Detector at Fermilab (CDF II). We observe no signal excess and set 95% confidence level upper limits on the production cross section times branching ratio for the Higgs boson to WW* or any new scalar particle with similar decay products. These upper limits range from 5.5 to 3.2 pb for Higgs boson masses between 120 and 200 GeV/c2.

Search for a neutral Higgs boson decaying to a W boson pair in pp collisions at square root of s = 1.96 TeV.

Direct search for dirac magnetic monopoles in p(p)over-bar collisions at root s=1.96 TeV RID G-1087-2011 RID E-4473-2011

We report the first evidence of a fully reconstructed decay mode of the B{sub c}{sup {+-}} meson in the channel B{sub c}{sup {+-}} {yields} J/{psi}{sup {+-}}, with J/{psi} {yields} {mu}{sup +}{mu}{sup -}. The analysis is based on an integrated luminosity of 360 pb{sup -1} in p{bar p} collisions collected by the Collider Detector at Fermilab. We observe 18.9 {+-} 5.7 signal events on a background of 10.0 {+-} 1.4 events and the fit to the J/{psi}{pi}{sup {+-}} mass spectrum yields a B{sub c}{sup {+-}} mass of 6287.0 {+-} 4.8(stat) {+-} 1.1(syst) MeV/c{sup 2}.

Evidence for the exclusive decay Bc±→J/ψπ± and measurement of the mass of the Bc± meson

Search for charged Higgs bosons from top quark decays in p(p)over-barcollisions at root s=1.96 TeV RID C-1693-2008 RID C-3493-2011 RID G-1087-2011 RID E-4473-2011

We present the first precise measurement of the Bs0-Bs0 oscillation frequency Deltams. We use 1 fb-1 of data from pp collisions at sqrts=1.96 TeV collected with the CDF II detector at the Fermilab Tevatron. The sample contains signals of 3600 fully reconstructed hadronic Bs decays and 37,000 partially reconstructed semileptonic Bs decays. We measure the probability as a function of proper decay time that the Bs decays with the same, or opposite, flavor as the flavor at production, and we find a signal consistent with Bs0-Bs0 oscillations. The probability that random fluctuations could produce a comparable signal is 0.2%. Under the hypothesis that the signal is due to Bs0-Bs0 oscillations, we measure Deltams=17.31(-0.18)+0.33(stat)+/-0.07(syst) ps-1 and determine |Vtd/Vts|=0.208(-0.002)+0.001(expt)-0.006(+0.008)(theor).

Observation of B(s)(0)B(s)(0) oscillations RID G-1087-2011 RID E-4473-2011

We present a measurement of the tt production cross section in pp collisions at square root s = 1.96 TeV which uses events with an inclusive signature of significant missing transverse energy and jets. This is the first measurement which makes no explicit lepton identification requirements, so that sensitivity to W --> tau nu decays is maintained. Heavy flavor jets from top quark decay are identified with a secondary vertex tagging algorithm. From 311 pb(-1) of data collected by the Collider Detector at Fermilab, we measure a production cross section of 5.8 +/- 1.2(stat)(-0.7)(+0.9)(syst) pb for a top quark mass of 178 GeV/c2, in agreement with previous determinations and standard model predictions.

Measurement of the tt production cross section in pp collisions at square root s = 1.96 TeV using missing E(T) + jets events with secondary vertex b tagging.

This article presents a measurement of the top quark mass using the CDF II detector at Fermilab. Colliding beams of protons and antiprotons at Fermilab's Tevatron ({radical}(s)=1.96 TeV) produce top/antitop pairs, which decay to W{sup +}W{sup -}bb; events are selected where one W decays to hadrons and the other W decays to either e or {mu} plus a neutrino. The data sample corresponds to an integrated luminosity of approximately 318 pb{sup -1}. A total of 165 tt events are separated into four subsamples based on jet transverse energy thresholds and the number of b jets identified by reconstructing a displaced vertex. In each event, the reconstructed top quark invariant mass is determined by minimizing a {chi}{sup 2} for the overconstrained kinematic system. At the same time, the mass of the hadronically decaying W boson is measured in the same event sample. The observed W boson mass provides an in situ improvement in the determination of the hadronic jet energy scale. A simultaneous likelihood fit of the reconstructed top quark masses and the W boson invariant masses in the data sample to distributions from simulated signal and background events gives a top quark mass of 173.5{sub -3.8}{sup +3.9} GeV/c{sup 2}.

Top quark mass measurement using the template method in the lepton + jets channel at CDF II

Search for a Neutral Higgs Boson Decaying to a<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"><mml:mi>W</mml:mi></mml:math>Boson Pair in<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"><mml:mi>p</mml:mi><mml:mover accent="true"><mml:mi>p</mml:mi><mm

We present the first search for heavy, long-lived particles that decay to photons at a hadron collider. We use a sample of gamma + jet + missing transverse energy events in pp[over] collisions at square root[s] = 1.96 TeV taken with the CDF II detector. Candidate events are selected based on the arrival time of the photon at the detector. Using an integrated luminosity of 570 pb(-1) of collision data, we observe 2 events, consistent with the background estimate of 1.3+/-0.7 events. While our search strategy does not rely on model-specific dynamics, we set cross section limits in a supersymmetric model with [Formula: see text] and place the world-best 95% C.L. lower limit on the [Formula: see text] mass of 101 GeV/c(2) at [Formula: see text].

Search for heavy long-lived particles that decay to photons at CDF II.

We report the observation of Bs(0)-Bs(0) oscillations from a time-dependent measurement of the Bs(0)-Bs(0) oscillation frequency Deltams. Using a data sample of 1 fb(-1) of pp collisions at square root of s=1.96 TeV collected with the CDF II detector at the Fermilab Tevatron, we find signals of 5600 fully reconstructed hadronic Bs decays, 3100 partially reconstructed hadronic Bs decays, and 61,500 partially reconstructed semileptonic Bs decays. We measure the probability as a function of proper decay time that the Bs decays with the same, or opposite, flavor as the flavor at production, and we find a signal for Bs(0)-Bs(0) oscillations. The probability that random fluctuations could produce a comparable signal is 8 x 10(-8), which exceeds 5sigma significance. We measure Deltams=17.77 +/- 0.10(stat) +/- 0.07(syst) ps(-1) and extract /V(td)/V(ts)/=0.2060+/-0.0007(Deltams)(-0.0060)(+0.008)(Deltamd+theor).

Measurement of the B-c(+) meson lifetime using the decay mode B-c(+)-> J/psi e(+)nu(e)

Measurement of the B(c)(+) meson lifetime using the decay mode B(c)(+)-> J/psi e(+)nu(e) RID G-1087-2011 RID E-4473-2011

Search for neutral Higgs bosons of the minimal supersymmetric standard model decaying to tau pairs in p(p)over-bar collisions at root s=1.96 TeV RID C-1693-2008 RID G-1087-2011 RID E-4473-2011

Evidence for the exclusive decay B(c)(+/-)-> J/psi pi(+/-) and measurement of the mass of the B(c)(+/-) meson RID C-1693-2008 RID G-1087-2011 RID E-4473-2011

Search for new physics in lepton+photon+X events with 305 pb(-1) of pp collisions at [square root of s] = 1.96 TeV.

We present the results of a search for new physics in the jets plus missing transverse energy data sample collected from 368 pb(-1) of pp collisions at square root of s = 1.96 TeV recorded by the Collider Detector at Fermilab. We compare the number of events observed in the data with a data-based estimate of the standard model backgrounds contributing to this signature. We observe no significant excess of events, and we interpret this null result in terms of lower limits on the fundamental Planck scale for a large extra dimensions scenario.

Search for large extra dimensions in the production of jets and missing transverse energy in pp collisions at square root of s = 1.96 TeV.

We searched for scalar bottom quarks 156 pb(-1) of pp collisions at radicalS = 1.96 recorded by the Collider Detector at Fermilab II experiment at the Tevatron. Scalar bottom quarks can be produced from gluino decays in -parity conserving models of supersymmetry when the mass of the gluino exceeds that of the scalar bottom quark. Then, a scalar bottom quark can decay into a bottom quark and a neutralino. To search for this scenario, we investigated events with large missing transverse energy and at least three jets, two or more of which were identified as containing a secondary vertex from the hadronization of quarks. We found four candidate events, where 2.6 +/- 0.7 are expected from standard model processes, and placed 95% confidence level lower limits on gluino and scalar bottom quark masses of up to 280 and 240 GeV/c(2), respectively.

Search for scalar bottom quarks from gluino decays in collisions at.

We describe a general search for resonances decaying to a neutral emu final state in pp collisions at a center-of-mass energy of 1.96 TeV. Using a data sample representing 344 pb(-1) of integrated luminosity recorded by the Collider Detector at Fermilab II experiment, we compare standard model predictions with the number of observed events for invariant masses between 50 and 800 GeV/c2. Finding no significant excess (5 events observed vs 7.7 +/- 0.8 expected for M(emu) > 100 GeV/c2 ), we set limits on sneutrino and Z' masses as functions of lepton family number violating couplings.

Search for high-mass resonances decaying to emu in pp collisions at square root = 1.69 TeV.

We measure the masses of b hadrons in exclusively reconstructed final states containing a J/psi --> mu-mu+ decay using 220 pb(-1) of data collected by the CDF II experiment. We find: m(B+) = 5279.10 +/- 0.41(stat.) +/- 0.36(sys.) MeV/c2, m(B0) = 5279.63 +/- 0.53(stat.) +/- 0.33(sys.) MeV/c2, m(B(s)0) = 5366.01 +/- 0.73(stat.) +/- 0.33(sys.) MeV/c2, m(lambda(b)0) = 5619.7 +/- 1.2(stat.) +/- 1.2(sys.) MeV/c2. m(B+) - m(B0) = -0.53 +/- 0.67(stat.) +/- 0.14(sys.) MeV/c2, m(B(s)0) - m(B0) = 86.38 +/- 0.90(stat.) +/- 0.06(sys.) MeV/c2, m(lambda(b)0) - m(B0) = 339.2 +/- 1.4(stat.) +/- 0.1(sys.) MeV/c2. The measurements of the B(s)0, lambda(b)0 mass, m(B(s)0) - m(B0) and m(lambda(b)0) - m(B0) mass difference are of better precision than the current world averages.

Measurement of bottom-quark hadron masses in exclusive J/psi decays with the CDF detector.

A search for new particles (X) that decay to electron or muon pairs has been performed using approximately 200 pb(-1) of pp collision data at (square root) s = 1.96 TeV collected by the CDF II experiment at the Fermilab Tevatron. Limits on sigma(pp --> X)BR (X --> ll) are presented as a function of dilepton invariant mass m(ll) > 150 GeV/c2, for different spin hypotheses (0, 1, or 2). The limits are approximately 25 fb for m(ll) > GeV/c2. Lower mass bounds for X from representative models beyond the standard model including heavy neutral gauge bosons are presented.

Search for new high-mass particles decaying to Lepton pairs in pp collisions at square root s = 1.96 TeV.

Search for first-generation scalar leptoquarks in p(p)over-bar collisions at root s=1.96 TeV RID C-1693-2008 RID G-1087-2011 RID E-4473-2011

We present a search for long-lived doubly charged Higgs bosons (H(+/- +/-)), with signatures of high ionization energy loss and muonlike penetration. We use 292 pb(-1) of data collected in pp collisions at sqrt[s] = 1.96 TeV by the CDF II detector at the Fermilab Tevatron. Observing no evidence of long-lived doubly charged particle production, we exclude H(+/- +/-)(L) and H(+/- +/-)(R) bosons with masses below 133 GeV/c(2) and 109 GeV/c(2), respectively. In the degenerate case we exclude H(+/- +/-) mass below 146 GeV/c(2). All limits are quoted at the 95% confidence level.

Search for long-lived doubly charged Higgs bosons in pp collisions at sqrt[s] = 1.96 TeV.

Results on a search for pair production of second-generation scalar leptoquark in p (p) over bar collisions at root s=1.96 TeV are reported. The data analyzed were collected by the CDF detector during the 2002-2003 Tevatron Run II and correspond to an integrated luminosity of 198 pb(-1). Leptoquarks (LQ) are sought through their decay into (charged) leptons and quarks, with final state signatures represented by two muons and jets and one muon, large transverse missing energy and jets. We observe no evidence for LQ production and derive 95% C.L. upper limits on the LQ production cross sections as well as lower limits on their mass as a function of beta, where beta is the branching fraction for LQ ->mu q.

Search for second-generation scalar leptoquarks in p(p)over-bar collisions at root s=1.96 TeV

We report on a search for B0(s) --> mu+ mu- and B0(d) --> mu + mu- decays in pp collisions at square root(s) = 1.96 TeV using 364 pb(-1) of data collected by the CDF II detector at the Fermilab Tevatron Collider. After applying all selection requirements, we observe no candidates inside the B0(s) or B0(d) mass windows. The resulting upper limits on the branching fractions are B(B0(s) --> mu+ mu-) < 1.5 x 10(-7) and B(B0(d) --> mu+ mu-) < 3.9 x 10(-8) at 90% confidence level.

Search for [corrected] B0(s) --> mu+ mu- and B0(d) [corrected] --> mu + mu- decays in pp collisions with CDF II.

We present a search for Higgs bosons decaying into bb and produced in association with W bosons in pp collisions at square root of s = 1.96 TeV. This search uses 320 pb(-1) of the data set accumulated by the upgraded Collider Detector at Fermilab. Events are selected that have a high-transverse momentum electron or muon, missing transverse energy, and two jets, at least one of which is consistent with the hadronization of a b quark. Both the number of events and the dijet mass distribution are consistent with standard model background expectations, and we set 95% confidence level upper limits on the production cross section times branching ratio for the Higgs boson or any new particle with similar decay kinematics. These upper limits range from 10 pb for mH = 110 GeV/c2 to 3 pb for mH = 150 GeV/c2.

Search for Higgs bosons decaying to bb and produced in association with W bosons in pp collisions at square root of s = 1.96 TeV.

We report on a search for the pair production of scalar leptoquarks (LQ), using 191pb-1 of proton-antiproton collision data recorded by the CDF experiment during Run II of the Tevatron. The leptoquarks are sought via their decay into a neutrino and quark yielding missing transverse energy and several jets of large transverse energy. No evidence for LQ production is observed, and limits are set on σ(pp→LQLQX→ννqqX). Using a next-to-leading order theoretical prediction of the cross section for LQ production, we exclude first-generation LQ in the mass interval 78 to 117GeV/c2 at the 95% confidence level for BR(LQ→νq)=100%. © 2005 The American Physical Society.

Search for scalar leptoquark pairs decaying to νν̄qq̄ in pp̄ collisions at s=1.96TeV

We report the first evidence for a fully reconstructed decay mode of the B(c)+- meson in the channel B(c)+- --> J/psi pi+-, with J/psi --> mu+ mu-. The analysis is based on an integrated luminosity of 360 pb(-1) in pp collisions at 1.96 TeV center of mass energy collected by the Collider Detector at Fermilab. We observe 14.6 +/- 4.6 signal events with a background of 7.1 +/- 0.9 events, and a fit to the J/psi pi+-mass spectrum yields a B(c)+- mass of 6285.7 +/- 5.3(stat) +/- 1.2(syst) MeV/c2. The probability of a peak of this magnitude occurring by random fluctuation in the search region is estimated as 0.012%.

Evidence for the exclusive decay B(c)+- --> J/psi pi+- and measurement of the mass of the B(c)+- meson.

We report on a search for Λb0→pπ- and Λb0→pK- (and charge conjugate) decays in pp collisions at s=1.96TeV using 193pb-1 of data collected by the CDF II experiment at the Fermilab Tevatron Collider. Data were collected using a track trigger that has been optimized to select tracks belonging to a secondary vertex that is typical of two-body charmless decays of b-flavored hadrons, including Λb0 baryons. As no Λb0 signal was observed, we set the upper limits on the branching fraction B(Λb0→ph-), where h is K or π, of 2.3×10-5 at 90% C.L. and 2.9×10-5 at 95% C.L. © 2005 The American Physical Society.

Search for Λb0→pπ and Λb0→pK decays in pp̄ collisions at s=1.96 TeV

Search for new high-mass particles decaying to Lepton pairs in p(p)over-bar collisions at root s=1.96 TeV RID C-1693-2008 RID G-1087-2011 RID E-4473-2011

We report a measurement of the top-quark mass using events collected by the CDF II detector from pp collisions at square root of s = 1.96 TeV at the Fermilab Tevatron. We calculate a likelihood function for the top-quark mass in events that are consistent with tt --> bl(-)nu(l)bl'+ nu'(l) decays. The likelihood is formed as the convolution of the leading-order matrix element and detector resolution functions. The joint likelihood is the product of likelihoods for each of 33 events collected in 340 pb(-1) of integrated luminosity, yielding a top-quark mass M(t) = 165.2 +/- 6.1(stat) +/- 3.4(syst) GeV/c2. This first application of a matrix-element technique to tt --> bl+ nu(l)bl'- nu(l') decays gives the most precise single measurement of M(t) in dilepton events. Combined with other CDF run II measurements using dilepton events, we measure M(t) = 167.9 +/- 5.2(stat) +/- 3.7(syst) GeV/c2.

We present the results of a search for anomalous resonant production of tau lepton pairs with large invariant mass, the first such search using the CDF II Detector in Run II of the Tevatron pp collider. Such anomalous production could arise from various new physics processes. In a data sample corresponding to 195 pb(-1) of integrated luminosity we predict 2.8+/-0.5 events from standard model background processes and observe 4. We use this result to set limits on the production of heavy scalar and vector particles decaying to tau lepton pairs.

Search for new physics using high-mass tau pairs from 1.96 TeV pp collisions.

We report on a search for the pair production of scalar leptoquarks (LQ), using 191 pb(-1) of proton-antiproton collision data recorded by the CDF experiment during Run II of the Tevatron. The leptoquarks are sought via their decay into a neutrino and quark yielding missing transverse energy and several jets of large transverse energy. No evidence for LQ production is observed, and limits are set on sigma(p (p) over bar -> LQ (LQ) over barX -> v (v) over barq (q) over barX). Using a next-to-leading order theoretical prediction of the cross section for LQ production, we exclude first-generation LQ in the mass interval 78 to 117 GeV/c(2) at the 95% confidence level for BR(LQ -> vq)=100%.

Search for scalar leptoquark pairs decaying to v(v)over-barq(q)over-bar in p(p)over-bar collisions at root s=1.96 TeV

We present the first evidence of charmless decays of the B(0)(s) meson, the decay B(0)(s)--> phiphi, and a measurement of the branching ratio BR(B(0)(s)--> phiphi) using 180 pb(-1) of data collected by the CDF II experiment at the Fermilab Tevatron collider. In addition, the BR and direct CP asymmetry for the B+-->phiK+ decay are measured. We obtain BR(B(0)(s)--> phiphi)=[14(+6)(-5)(stat)+/-6(syst)] x 10(-6), BR(B+-->phiK+)=[7.6+/-1.3(stat)+/-0.6(syst)] x 10(-6), and A(CP)(B+-->phiK+)= -0.07+/-0.17(stat)+0.03 / -0.02(syst). Both decays are governed in the standard model by second order (penguin) b-->s(-)ss amplitudes.

Evidence for B0 s-->phiphi decay and measurements of branching ratio and A(CP) for B+ -->phiK+.

We report the results of a search for a charged Higgs boson in the decays of top quarks produced in pp collisions at a center-of-mass energy of 1.96 TeV. We use a data sample corresponding to an integrated luminosity of 193 pb-1 collected by the upgraded Collider Detector at Fermilab. No evidence for charged Higgs production is found, allowing 95% C.L. upper limits to be placed on BR(t-->H+b) for different charged Higgs decay scenarios. In addition, we present in the minimal supersymmetric standard model (mH+/-, tanbeta) plane the first exclusion regions with radiative and Yukawa coupling corrections.

Search for charged Higgs bosons from top quark decays in pp collisions at square root s=1.96 TeV.

Measurement of the W+ W− production cross section in pbar p collisions at sqrt(s) = 1.96 TeV using dilepton events.

Search for B(s)(0)->mu(+)mu(-) and B(s)(0)->mu(+)mu(-) decays in p(p)over-bar collisions with CDF II RID C-1693-2008 RID G-1087-2011 RID E-4473-2011

We present a measurement of the ratio of top-quark branching fractions R = B(t --> Wb)/B(t --> Wq), where q can be a b, s, or a d quark, using lepton-plus-jets and dilepton data sets with an integrated luminosity of approximately 162 pb(-1) collected with the Collider Detector at Fermilab during Run II of the Tevatron. The measurement is derived from the relative numbers of tt events with different multiplicity of identified secondary vertices. We set a lower limit of R > 0.61 at 95% confidence level.

Measurement of B(t --> Wb)/B(t--> Wq) at the collider detector at fermilab.

Search for new physics using high-mass tau pairs from 1.96 TeV p(p)over-bar collisions RID C-1693-2008 RID G-1087-2011 RID E-4473-2011

Search for first-generation scalar leptoquarks inpp¯collisions ats=1.96TeV

We present a measurement of the W(+)W(-) production cross section using 184 pb(-1) of p(p) collisions at a center-of-mass energy of 1.96 TeV collected with the Collider Detector at Fermilab. Using the dilepton decay channel W(+)W(-)-->l(+)nul(-), where the charged leptons can be either electrons or muons, we find 17 candidate events compared to an expected background of 5.0(+2.2)(-0.8) events. The resulting W(+)W(-) production cross-section measurement of sigma(pp-->W(+)W(-))=14.6(+5.8)(-5.1)(stat)(+1.8)(-3.0)(syst) +/- 0.9(lum) pb agrees well with the standard model expectation.

Measurement of the W(+)W(-) production cross section in pp collisions at square root[s]=1.96 TeV using dilepton events.

We search for pair-produced Dirac magnetic monopoles in 35.7 pb(-1) of proton-antiproton collisions at square root s = 1.96 TeV with the Collider Detector at Fermilab (CDF). We find no monopole candidates corresponding to a 95% confidence-level cross-section limit sigma < 0.2 pb for a monopole with mass between 200 and 700 GeV/c2. Assuming a Drell-Yan pair-production mechanism, we set a mass limit m > 360 GeV/c2.

Direct search for Dirac magnetic monopoles in pp collisions at square root s = 1.96 TeV.

Erratum: Search for Bs0 → μ+μ and Bd0 → μ+μ decays in pp_ collisions with CDF II (Phys. Rev. Lett. (2005) 95 (221805))

Search for Radiative B-Hadron Decays in $p\bar{p}$ Collisions at $\sqrt{s}$ = 1.8 TeV

Comparison of the isolated direct photon cross sections in [Formula Presented] collisions at [Formula Presented] and [Formula Presented]

We present a detailed examination of the heavy flavor content of the W+jet data sample collected with the Collider Detector at Fermilab during the 1992-1995 collider run at the Fermilab Tevatron. Jets containing heavy flavor quarks are selected via the identification of secondary vertices or semileptonic decays of b and c quarks. There is generally good agreement between the rates of secondary vertices and soft leptons in the data and in the standard model simulation including single and pair production of top quarks. An exception is the number of events in which a single jet has both a soft lepton and a secondary vertex tag. In W+2,3 jet data, we find 13 such events where we expected 4.4+/-0.6 events. The kinematic properties of this small sample of events are statistically difficult to reconcile with the simulation of standard model processes.

Study of the heavy flavor content of jets produced in association with W bosons in p(p)over-bar collisions at root s=1.8 TeV

Limits on extra dimensions and new particle production in the exclusive photon and missing energy signature in p(p)over-bar collisions at root s=1.8 TeV RID C-1693-2008 RID A-5169-2010 RID E-4473-2011 RID C-2406-2008

Comparison of the isolated direct photon cross sections in p(p)over-bar collisions at root s=1.8 TeV and root s=0.63 TeV RID C-1693-2008 RID A-5169-2010 RID E-4473-2011 RID C-2406-2008

Measurement of [Formula Presented]-meson lifetimes using fully reconstructed [Formula Presented] decays produced in [Formula Presented] collisions at [Formula Presented]

We present the results of a search in pp collisions at sqrt[s] = 1.8 TeV for anomalous production of events containing a photon and a lepton (e or mu), both with large transverse energy, using 86 pb(-1) of data collected with the Collider Detector at Fermilab during the 1994-1995 collider run at the Fermilab Tevatron. The presence of large missing transverse energy (E(T)), additional photons, or additional leptons in these events is also analyzed. The results are consistent with standard model expectations, with the possible exception of photon-lepton events with large E(T), for which the observed total is 16 events and the expected mean total is 7.6+/-0.7 events.

Search for new physics in photon-lepton events in pp collisions at sqrt[s] = 1.8 TeV.

Measurement ofB-meson lifetimes using fully reconstructedBdecays produced inpp¯collisions ats=1.8TeV

Measurement of d sigma/dy for high mass Drell-Yan e(+)e(-) pairs from p(p)over-bar collisions at root s=1.8 TeV

We update the measurement of the top production cross section using the CDF detector at the Fermilab Tevatron. This measurement uses $t\bar{t}$ decays to the final states $e+\nu$+jets and $\mu+\nu$+jets. We search for $b$ quarks from $t$ decays via secondary-vertex identification or the identification of semileptonic decays of the $b$ and cascade $c$ quarks. The background to the $t\bar{t}$ production is determined primarily through a Monte Carlo simulation. However, we calibrate the simulation and evaluate its uncertainty using several independent data samples. For a top mass of 175 $GeV/c^2$, we measure $\sigma_{t\bar{t}}=5.1 \pm 1.5$ pb and $\sigma_{t\bar{t}}=9.2 \pm 4.3$ pb using the secondary vertex and the lepton tagging algorithms, respectively. Finally, we combine these results with those from other $t\bar{t}$ decay channels and obtain $\sigma_{t\bar{t}} = 6.5^{+1.7}_{-1.4}$ pb.

Measurement of the $t\bar{t}$ production cross section in $p\bar{p}$ collisions at $\sqrt{s} = 1.8$ TeV

Comparison of the isolated direct photon cross sections in p anti-p collisions at s**(1/2) = 1.8 TeV and s**(1/2) = 0.63 Tev

We present searches for quark-lepton compositeness and a heavy W' boson at high electron-neutrino transverse mass. We use ~110/pb of data collected in p-pbar collisions at sqrt(s) = 1.8 TeV by the CDF collaboration during 1992--95. 
The data are consistent with standard model expectations. 
Limits are set on the quark-lepton compositeness scale Lambda and the ratio of partial cross sections sigma (W' -> e nu) / sigma (W -> e nu). The cross section ratio is used to obtain a lower limit on the mass of a W' boson with standard model couplings. 
We exclude Lambda < 2.81 TeV and a W' boson with mass below 754 GeV/c^2 at the 95% confidence level. We combine the W' mass limit with our previously published limit obtained using the muon channel, to exclude a W' boson with mass below 786 GeV/c^2 at the 95% confidence level.

Search for quark lepton compositeness and a heavy $W^\prime$ boson using the $e \nu$ channel in $p\bar{p}$ collisions at $\sqrt{s} = 1.8$ TeV

We have measured the polarization of J/psi and psi(2S) mesons produced in p (p) over bar collisions at root s = 1.8 TeV. using data collected at the Collider Detector at Fermilab during 1992-1995. The polarization of promptly produced J/psi [psi(2S)] mesons is isolated from those produced in B-hadron decay, and measured over the kinematic range 4 [5.5] < P-T < 20 GeV/c and \y\ < 0.6. For P-T greater than or similar to 12 GeV/c we do not observe significant polarization in the prompt component.

Measurement of J/psi and psi(2S) polarization in p(p)over-bar collisions at root s=1.8 TeV RID C-1693-2008 RID A-5169-2010 RID C-2406-2008

Measurement of de sigma / de y for high mass Drell-Yan e+ e- pairs from p bar p collisions at sqrt s = 1.8 TeV

We report on a search for the supersymmetric partner of the top quark (top squark) produced in t (t) over bar events using 110 ph(-1) of p (p) over bar collisions at roots = 1.8 TeV recorded with the Collider Detector at Fermilab. In the case of a light top squark, the decay of-the top quark into a top squark plus the lightest supersymmetric particle (LSP) could have a significant branching ratio. The observed events are consistent with standard model t (t) over bar production and decay. Hence, we set limits on the branching ratio of the top quark decaying into a top squark plus LSP, excluding branching ratios above 45% for a LSP mass up to 30 GeV/c(2)

Search for supersymmetric partner of the top-quark in p anti-p collisions at s**(1/2) = 1.8 TeV

Measurement of the differential dijet mass cross section in p(p)over-bar collisions at root s=1.8 TeV RID C-1693-2008 RID A-5169-2010 RID C-2406-2008

Measurement ofbb¯rapidity correlations inpp¯collisions ats=1.8TeV

We present a detailed description of a search for anomalous production of missing E T (Slashed E sign T ), jets, leptons (e, μ, τ), b quarks, or additional photons in events containing two isolated, central (|η| 12 GeV. The results are consistent with standard model expectations, with the possible exception of one event that has, in addition to the two photons, a central electron, a high-E T electromagnetic cluster, and large Slashed E sign T . We set limits using two specific SUSY scenarios for production of diphoton events with Slashed E sign T . ©1999 The American Physical Society.

Searches for new physics in diphoton events in pp̄ collisions at √s = 1.8 TeV

We present a measurement of the W boson mass using data collected with the CDF detector during the 1994-1995 collider run at the Fermilab Tevatron. A fit to the transverse mass spectrum of a sample of 30115 W --> ev events recorded in an integrated luminosity of 84 pb(-1) gives a mass M-W=80.473 +/-0.065(stat) +/-0.092(syst) GeV/c(2). A fit to the transverse mass spectrum of a sample of 14740 W --> muv events from 80 pb(-1) gives a mass M-W=80,465 +/-0.100(stat)+/-0.103(syst) Ge V/c(2) The dominant contributions to the systematic uncertainties are the uncertainties in the electron energy scale and the muon momentum scale, 0.075 GeV/c(2) and 0.085 GeV/c(2), respectively. The combined value for the electron and muon channel is M-W=80.470 +/-0.089-GeV/c(2). When combined with previously published CDF measurements, we obtain M-W=80.433 +/-0.079 GeV/c(2).

Measurement of the W Boson Mass with the Collider Detector at Fermilab

Search for long-lived parents of Z(0) bosons in p(p)over-bar collisions at root s=1.8 TeV

We present a measurement of the top quark pair production cross section in pp collisions at square root of s = 1.96 TeV using 318 pb(-1) of data collected with the Collider Detector at Fermilab. We select tt[over ] decays into the final states enu+jets and mu nu+ jets, in which at least one b quark from the t-quark decays is identified using a secondary vertex-finding algorithm. Assuming a top quark mass of 178 GeV/c2, we measure a cross section of 8.7 +/- 0.9(stat)(-0.9)+1.1(syst) pb. We also report the first observation of tt[over ] with significance greater than 5sigma in the subsample in which both b quarks are identified, corresponding to a cross section of 10.1(-1.4)+1.6(stat)(-1.3)+2.0(syst) pb.

Measurement of the tt production cross section in pp collisions at square root of s = 1.96 TeV.

Search for the decaysBd0→μ+μ−andBs0→μ+μ−inpp¯collisions ats=1.8TeV

We report the observation of two narrow resonances consistent with states of orbitally excited (L=1) B_(s) mesons using 1 fb;(-1) of pp[over ] collisions at sqrt[s]=1.96 TeV collected with the Collider Detector at Fermilab II detector at the Fermilab Tevatron. We use two-body decays into K- and B+ mesons reconstructed as B(+)-->J/psiK(+), J/psi-->mu(+)mu(-) or B(+)-->D[over ](0)pi(+), D[over ](0)-->K(+)pi(-). We deduce the masses of the two states to be m(B_(s1))=5829.4+/-0.7 MeV/c(2) and m(B_(s2);(*))=5839.6+/-0.7 MeV/c;(2).

A study of the effects of computer assisted instruction on proficiency test performance of high school students enrolled in mandatory proficiency intervention courses

The primary purpose of this report is to consolidate information on the agricultural research system. The report attempts to describe the agricultural research system as it currently exists, discuss successes and failures of previous reform efforts, review the framework proposed for the next reform steps and assess associated costs, and identify structural and financial options that might be elements of future reforms. In addition, the report identifies sub-sectors closely linked to agricultural research that must be reformed in parallel with agricultural research if agricultural research is to be successful.

The overall goal of our paper is to begin the task of laying out the current facts and to describe systematically the organization and utilization of China’s cultivated land resources. Currently, we observe enormous heterogeneity at the village level in the property rights that households enjoy. In some villages, farmers seem to enjoy relatively long-term security and most of the rights typically associated with a private property regime, short of being able to buy or sell the land. In other villages, on the other hand, tenure is insecure, and farmers’ use of the land appears to be constrained in a variety of ways. From a policy perspective the critical question is how effective these alternative regimes have been in providing households the necessary incentives to ensure rational land use and investment, while simultaneously helping local communities meet distributive objectives. One of the most important messages to take away from this essay is that a solid empirical basis does not currently exist for making an assessment of the impact of the land system on efficiency, equity, and overall development of China’s rural sector. On the basis of the work that has been done, the record of China’s land system is mixed. Over the past two decades, reallocations by village leaders may have facilitated access to land and the food it produces for a majority of China’s households and overcome some of the imperfections in land rental markets. No work has found a large effect of the land management system on agricultural production. Nonetheless, in many parts of China there are significant and growing costs of the current property right regime in terms of short and long-run productivity that are not being offset by lower income inequality. Land Rights In China: Facts, Fictions, and Issues China’s rural economic reform, widely regarded as one of the most successful transitions of the last two decades years (Johnson, 1996; Perkins, 1992; Lin, 1992), radically altered land tenure in rural China. With the introduction of the Household Responsibility System (HRS) and the extension of land-use rights and residual income rights to households, agriculture shifted from a collective-based to a family-based farming system. Land was not privatized, however. Ownership remained “collective”, with local governing bodies and officials at the village level exercising a major influence over household land use and allocation. The initial reforms triggered an unprecedented acceleration of agricultural growth in China. From 1979 to 1984, the gross value of agricultural output increased in real terms at an annual rate of 7.6 percent, and grain production rose by 4.9 percent annually (ZGTJNJ, 1989). Empirical studies (McMillan, Whalley, and Zhu,1989; Lin, 1992; and Huang and Rozelle,1996) attribute a significant part of this increase to the incentives associated with better residual income rights. Growth slackened after 1984, however, especially for grain production. From 1985 to 1994, grain output rose only 0.9 percent per year (ZGTJNJ, 1996), despite expanded efforts to further liberalize rural input and output markets. This deceleration has generated considerable debate about the reasons for the slowdown. Some observers have focused attention on China’s land management system, the one dimension of the farm economy that has been least altered since the initial reforms. Some suggest that weaknesses in these institutional arrangements are the fundamental source of the problem. Poor incentives related to tenure insecurity, for example, has reportedly discouraged investment in agriculture and lowered growth (Prosterman, Hansted, and Li, 1996). The perceived incentive problems have sparked calls for either land privatization or for extending land contracts to 30 or more years. (Chen, 1999). The need for privatization or extended tenure has not gone uncontested. Low farm-gate prices, not land rights arrangements, has alternatively been blamed for the sagging productivity. In many areas a majority of farmers reportedly oppose privatization (or even extended tenure) because their households enjoy better overall income security under the current form of 1 The growth rate was so fast that some policy makers even began to worry about how to deal with the problem of surplus grain in China.

This report aims to identify and consolidate information on crucial issues that impact on rural development in China. China's rural economic achievements of the past two decades - rapid growth and declining poverty - have been remarkable. However, replicating these achievements and improving sustainability during the next two decades will be difficult as many underlying conditions have changed. Economic reforms were initiated when supply shortages constrained growth, but currently, weak demand is more constraining. Furthermore, the productivity gains are largely exhausted from transition policies and institutions; future productivity gains will come from efficiencies, stimulated by market forces, and improved productivity of scarce water and land resources, through resource conservation and new technologies. The rural-agricultural sector will remain dependent on a robust urban-industrial sector to create jobs and absorb surplus rural and agricultural labor - thereby permitting the remaining farmers access to additional land resources. An effective fiscal system, a more efficient financial system, a workable land tenure arrangement with marketable land-use rights, and improved agricultural investment incentives need to be fostered. Continued reform will entail further liberalization of production, pricing, and marketing policies. It will also entail strong government promotion of a market environment and investments in public services and infrastructure.

The organic remains, traces, or imprint of seeds and fruits. Seeds, ovules containing a fertilized e…

Again available: Evolution and classification of flowering plants

I am sure that every avian breeder has had their share of experiences of breeding exotic species of birds. You have also had your share of broken eggs, addled eggs and for no apparent reason the parent abandoned the clutch. If you haven't then you are one of the lucky few. I really don't need to describe the joy and anticipation of a new clutch of eggs progressing very well nor the sorrow when the hen jumps out of the nest screaming and has broken her eggs. For several years I have been breeding exotic species and been puzzled at the low survival rate and the broken eggs problem. One morning I found the answer. I was eagerly watching my Moluccan Cockatoo's progress with her clutch. I had talked to her every morning when I fed her and was doing everything I could think of to keep her happy. Then a military C-130 aircraft over flew our aviary at approximately 400 feet above ground level and she came out of the nest screaming. I checked and her eggs were broken. To say I was upset is putting it mildly. I knew there had been low flying aircraft before but I just didn't put it together. I personally had been used to low flying aircraft and but it didn't occur to me that it would cause breeding problems. Boy, was I wrong. The Government has a Fly Neighborly Program which recognizes aircraft do bother people and livestock. The Government has provisions to compensate for damages. It is very easy to request the forms from the closest military legal office and they are very helpful in filing your damage claims. Believe me it stops there. For more than two and one half years I have recorded overflights and video record- ed aircraft. I have communicated with Army and Air Force Officials. I have requested Congressional help. I have communicated with The Dept of Justice and I have obtained, through the Freedom of Information Act, flight records of the offending aircraft. One would expect that this would be sufficient. But guess again. There are two claims procedures to follow. One is through the Tort Claims Court and the other is through the Damage Claims Court. The Tort Court requires you to prove the government is negligent and has violated their regulations therefore being negligent. In addition, you must prove damages. The Tort Court investigative procedure has no time limit. In effect, they can sit on the claim as long as they want to. You have no recourse until they act. Then you can file in Federal Court. The Damage Claims route does have a time limit. Should no action be taken within six months, you then have the right to file in Federal Court. You must be represented by an attorney. His fee is set by the court and is usually taken on contingency basis. Now what do you need to support your claim? The first is egg production records for the last five years. Then proof of value, sales receipts of your birds, price lists from other breeders. You need witnesses of the over flights or flight records. Be aware, there is no central repository for flight records and they are destroyed once the holding period expires. You will need to know the origin of flight. This usually is the closest military air base. Usually the military Public Affairs office can verify the flights or refer you to the flight source. My first claim was denied with the statement that "the Air Force Sound Assessment Reports indicate aircraft noise would not cause the startle response to damage eggs and that avian experts agreed that helicopters would not cause a problem." There was no such report. Their avian expert is a part time breeder or a part time lawyer (I don't know which) that stated to me that you "cannot stop the overflights." To the contrary, I discovered over 403 studies of aircraft disturbances to wildlife, horses, raptors, swans, sheep, fish, owls, sooty terns, brown pelicans, ostriches, and emus. The Endangered Species Act 16 Section, 1531 - 1544 prohibits the destruction of endangered species. I conferred with avian professionals who wrote in the avian medical publications and who conducted research on overflight disturbances to turkey and pheasant production. I have corresponded with avian medical authorities on the effects of noise induced stress. Each and every one of these publications, medical authorities and avian scientists are consistent in that low flying aircraft do disrupt the breeding cycle, will startle nesting birds and can cause nest abandonment. Heck, it wouldn't take a scientist to tell me that to bust in unannounced to my bedroom would be stressful and would disrupt us. Or, as one avian vet said "lying in bed fearful the kids might. .. " I suppose you would think the FAA would be responsible and assist in eliminating low flying aircraft. That too is a myth. Federal Aviation Regulation 91.119 para. b does prohibit aircraft from flying lower than 1000 ft. above the highest structure or within 2000 ft. of populated areas, settlements, or open air assembly of people. That seems pretty cut and dried. Guess again. The FAA has no jurisdiction over aircraft outside of a controlled air space. The pilot in command is solely responsible for the operation of the aircraft. FAA regulations do not require a flight plan to be filed on each flight. But when one is filed then it must be closed out within a time period.

Chester A. Arnold (1901–1977): Portrait of an American paleobotanist

Eleven species of fossil wood from the Eocene Clamo Formation of eastem Oregon, U.S.A. are described. Six are assigned to extant genera as their anatomy does not differ significantly from present-day species of that genus. Three belong to families in which the anatomy of modern day genera overlap and, consequentIy, it is not possible to determine the generic affinities of the fossil. Two woods are assigned to extinct genera as they differ significantly from any extant genus. This assemblage of fossil woods indicates that by the Eocene wood in some taxa had reached present-day levels of specialisation, while in others it was more 'primitive' than at present. These woods provide additional documentation from the fossil record for the validity of some of the generalisations about xylem evolution. Scalariform perforation plates are more common and have more bars in these Eocene woods than in their nearest living counterparts. Ring porosity, long believed to be a derived feature, apparently appears postEocene in the oaks.

Aspects of the palynology of the Chinle Formation (Upper Triassic), Colorado Plateau, Arizona, Utah, and New Mexico

Locomotory energetics in a marsupial (Antechinomys spenceri) and a rodent (Notomys alexis)

.--'Reconnaissance investigations of the heretofore l i t t l e known volcanic assemblage on St. Matthew Island provide significant information on the tectonic history of the Bering Sea shelf. Island i s made up of approximately 500 m of subaerial calc-alkaline volcanic rocks ranging i n composition from high-alumina basalt t o rhyolite. Four K-Ar analyses of samples from t h i s volcanic sequence give Late Cretaceous ages of 65-77 m.y., and intercalated carbonaceous tuff layers yield Cretaceous pollen assemblages. northeast coast St. volcanic rocks a r e intruded by granodiorite t h a t gives an early Tertiary K-Ar

Age and tectonic significance of volcanic rocks on St. Matthew Island, Bering Sea, Alaska

Variation in coastal plant species. 1. A method for studying the somatic chromosomes of plants using a Feulgen staining technique

“PRE‐CRETACEOUS” ANGIOSPERMS FROM UTAH: EVIDENCE FOR TERTIARY AGE OF THE PALM WOODS AND ROOTS

Availability of palynological material from Naval Petroleum Reserve No.4, XX: Arcon Barrow Core Test No. 1, Grandstand Test Well No. 1, Simpson Core Test No. 25, Titaluk Test Well No. 1, Umiat Test Wells Nos. 8, 9

Availability of palynological material from Naval Petroleum Reserve No.4, XIX: Umiat Test Wells Nos. 3 and 11, Simpson Core Tests 21, 27, 30, 30A

Availability of palynological material from Naval Petroleum Reserve No.4, XIV: Wolf Creek Test Wells Nos. 1, 2, 3; South Barrow Test Wells Nos. 1, 2

Availability of palynological material from Naval Petroleum Reserve No.4, XV: Skull Cliff Core Test No. 1

Availability of palynological material from Naval Petroleum Reserve No.4, XVIII: Umiat Test Wells Nos. 1 and 2, East Topagoruk Test Well No. 1

Availability of palynological material from Naval Petroleum Reserve No.4, XII: Square Lake Test Well No. 1

Availability of palynological material from Naval Petroleum Reserve No.4, XVI: Fish Creek Test Well No. 1

Availability of palynological material from Naval Petroleum Reserve No.4, XVII: Sentinel Hill Core Test No. 1

Availability of palynological material from Naval Petroleum Reserve No.4, XIII: South Barrow Test Well No. 4, Knifeblade Test Wells Nos. 1, 2, 2A

Availability of palynological material from Naval Petroleum Reserve No.4, X: Avak Test Well No. 1

Availability of palynological material from Naval Petroleum Reserve No.4, XI: Meade Test Well No. 1

Availability of palynological material from Naval Petroleum Reserve No.4, VIII: Gubik Test Well No. 2

Availability of palynological material from Naval Petroleum Reserve No.4, IX: Gubik Test Well No. 1

Availability of palynological material from Naval Petroleum Reserve No. 4, VI: South Barrow test well No. 3

Availability of palynological material from Naval Petroleum Reserve No.4, III: East Oumalik Test Well No. 1

Availability of palynological material from Naval Petroleum Reserve No. 4, VII: Topogorak Test Well No. 1

1. Platinum deposits of Alaska, by John B. Hertie, Jr. 65 p., 2 black-andwhite plates, 6 tables. Brooks Bldg., College, Alaska 99701; 100 Skyline Bldg., 508 2nd Ave., Anchorage, Alaska 99501; 441 Federal Bldg., Juneau, Alaska 99801; 504 Custom House, San Francisco, Calif. 94H1; 7638 Federal Bldg., Los Angeles, Calif. 90012. Reproducible material for the two plates from which copy can be made at private expense is available in the San Francisco office shown above.

Availability of palynological material from Naval Petroleum Reserve No.4, IV: North Simpson Test Well No. 1

Clostridium botulinum type F has been identified during the summer months in mud samples from a small stream. Its absence during the period from October to April in these mud samples is attributed to the presence of Bacillus

Clostridium botulinum Type F: Seasonal Inhibition by Bacillus licheniformis

Availability of palynological material from Naval Petroleum Reserve No.4, I: Simpson Test Well No. 1 and Simpson Core Tests Nos. 13 and 14

Availability of palynological material from Naval Petroleum Reserve No. 4, II: Kaolak Test Well No. 1

PRAKASH, U., E. S. BARGHOORN, and R. A. SCOTT. (Harvard U., Cambridge, Mass.) Fossil wood of Robinia and Gleditsia from the Tertiary of Montana. Amer. Jour. Bot. 49(7): 692-696. Illus. 1962.-Fossil woods representing 2 genera of the Leguminosae, Robinia Linnaeus and Gledit8ia Clayton, have been identified from Tertiary beds in southern Montana. These woods are noteworthy owing to their exceptionally fine structural preservation and from the standpoint of their paleogeographical distribution. Neither genus now lives in the region of Montana.

FOSSIL WOOD OF ROBINIA AND GLEDITSIA FROM THE TERTIARY OF MONTANA

Recently discovered pollen grains with asymmetrically ridged ektexines from the Chinle formation (Upper Triassic) represent the extant genus Ephedra. The holotype specimen of Equisetosporites chinleana Daugherty is also a conspecific Ephedra pollen grain, and the species is transferred to form the new combination Ephedra chinleana (Daugherty) R. A. Scott. Since this species was its genotype, the genus Equisetosporites Daugherty should be abandoned.

Pollen of Ephedra from the Chinle Formation (Upper Triassic) [Arizona] and the genus Equisetosporites

DEGRADATION OF THE PLANT CELL WALL AND ITS RELATION TO CERTAIN TRACHEARY FEATURES OF THE LEPIDODENDRALES

Fossil dicotyledonous fruits from the lower Upper Cretaceous Raritan formation at Kreischerville, New York, are indentified as the endocarps of Phytoecrene Wall. (tribe Phytocreneae, lcacinaceae). Modern species of Phytocrene arc climbing vines from tropical Asia and Africa. The Raritan species here described as P. micrccarpa n. sp. is the first Cretaceous record of the genus, which has also been identified from fossil leaves of Eocene age in California. The fossil endocarps of P. microcarpa constitute one of the common Mesozoic occurrences of reproductive structures referable to a modern genus of the angiosperms.

Phytocrene microcarpa - A new species of Icacinaceae based on Cretaceous fruits from Kreischerville, New York

THE CLARNO FORMATION of Eocene age in northcentral Oregon contains a varied assortment of fossil plant remains. These include leaves (Chaney, 1948) and structurally preserved ferns (Arnold, 1952); fruits and seeds (Scott, 1954), and wood (Scott and Barghoorn, 1955). The fruits and seeds, from an outcrop in Wheeler County near the type locality of the formation, are accompanied by logs and numerous pieces of silicified wood. The fruit and seed assemblage is unusual among American early Tertiary floras in showing a marked relationship to the London Clay flora from the Eocene of England (Reid and Chandler, 1933). In order to evaluate the significance of this relationship on a broader basis than that furnished by the fruits alone, an investigation of the fossil woods from the Clarno formation has been undertaken by the writer. Preliminary examination of the fossil woods has revealed that over 25 distinct entities are represented. Although most of the woods are well preserved, there is ample evidence of the ubiquitous presence of fungi in the form of hyphae penetrating the tracheary elements. The fungal remains thus far found in the woods from the Clarno formation consist chiefly of vegetative hyphae. However, several specimens of the wood of one species belonging to the Fagaceae (Castanop,sis?) contain a fungus whose septate hyphae bear both asexual spores and non-ostiolate sexual reproductive structures. These cleistothecia contain numerous ascospores. Another wood specimen representing a species of the Magnoliaceae (Magnolia?) also has similar cleistothecia within its vessels. The fungi, Ascomycetes assignable to the family Aspergillaceae (Eurotiaceae) , are unusual in that their sexual stages are preserved and in that their cleistothecia are borne in the lumina of the vessels. Although exceptions are known among modern forms, the ascocarps of most Ascomycetes are borne superficially rather than within the substrate. The recent discovery by Tyler and Barghoorn (1954) of fungal remains, together with algae, in Precambrian chert from Canada establishes for the fungi a fossil record as long as that of any other group of plants. Fossil fungi have been reported from a wide range of geologic horizons and in association with diverse plant groups (Seward, 1898; Pia, 1927). Most of the occurrences are

CRYPTOCOLAX—A NEW GENUS OF FUNGI (ASPERGILLACEAE) FROM THE EOCENE OF OREGON

The geological record of the angiosperms is conspicuously deficient in specific information regarding the nature and direction of morphological changes in time within the various taxa. Our present knowledge of such changes is based almost exclusively upon comparative data derived from the study of modern plants. There is no well documented sequence among the flowering plants comparable, for example, to the Cenozoic record of the Equidae among the vertebrates. That such evidence is lacking for the higher plants is due in large part to the fact that, while the relationships of the angiosperms have been established chiefly on the basis of their reproductive structures, their known fossil record consists for the most part of leaves (Chaney, 1949). The most notable exception to this situation is the large assemblage of fruits and seeds constituting the Eocene London Clay flora of England (Reid and Chandler, 1933). Some of the London Clay forms represent previous stages in the evolution of the reproductive structures borne by modern members of their respective groups. An unique assemblage of fossil dicotyledonous fruits showing distinct affinities with the London Clay flora has recently been described from a single locality in the Eocene Clarno formation of north central Oregon (Scott, 1954 and mss.). The Clarno fossils are preserved as chalcedony locule casts surrounded by the carbonized or silicified remains of the

EVOLUTION OF SOME ENDOCARPAL FEATURES IN THE TRIBE TINOSPOREAE (MENISPERMACEAE)

The occurrence of Euptelea in the Cenozoic of Western North America

Fossil fruits and seeds from the eocene clarno formation of Oregon

Observations on the Iodo-Amino-Acids of Marine Algae using Iodine-131

STATUS OF AN ASIATIC MEMBER OF THE JUGLANDACEAE REGARDED AS A ‘LIVING FOSSIL'

Solid Phase Determinations in the System Aluminium Sulphate/Sulphuric Acid/Water using Tracer Technique

A study of variation in leaf anatomy with reference to habitat in two species of Polypodiwm

Is this heaven? No, it's Iowa. -or- The avant-garde in a cornfield cures what ails you

Subcutaneous and Transvenous ICDs: an Update on Contemporary Questions and Controversies

Hair removal practices have changed in frequency and location on the body. Previous research on hair removal injuries has focused on a specific body region, age, or gender.

Hypothesis / aims of study Persistent stress urinary incontinence is a well documented potential complication of radical prostatectomy. Reduction in quality of life secondary to urinary incontinence in these men is also well known. The AdVance transobturator male sling (American Medical Systems) has been shown to be an efficacious and safe treatment option in the patient with mild-tomoderate post-prostatectomy stress incontinence (1). The authors hypothesized that placement of an AdVance transobturator sling at the time of a robotic assisted, laparoscopic radical prostatectomy would positively effect continence outcomes with little risk of increased complications.

Transobturator male sling at the time of robotic assisted, laparoscopic radical prostatectomy yields improved continence outcomes: data from a randomized clinical trial demonstrating safety and efficacy.

PURPOSE
The introduction of robotic assistance has the potential to improve surgical outcomes and reduce the steep learning curve associated with conventional laparoscopic radical prostatectomy. We report on our experience with robotic radical prostatectomy in the community setting.

A total of 200 patients underwent robotic radical prostatectomy during 18 months. Prospective data collection included a quality of life (Expanded Prostate Cancer Index Composite) questionnaire, basic demographics, prostate specific antigen (PSA), clinical stage and Gleason grade. Operative outcome measures included operative time, estimated blood loss and complications. Postoperative outcome measures included hospital stay, catheter time, pathology, PSA and return of continence.

RESULTS
Average operative time was 141 minutes with an estimated blood loss of 75 cc. The intraoperative complication rate was 1% with no mortality, reexploration or transfusion. Of the patients 95% were discharged home on postoperative day 1 (1 to 3) with hematocrit averaging 34.5 (range 25 to 45). The average difference in preoperative and postoperative hematocrit was 3 points (range -2 to 15). Average catheter time was 7.2 days (range 5 to 15). The positive margin rate was 10.5% for the entire series, 5.7% for T2 tumors, 28.5% (T3a), 20% (T3b) and 33% (T4a). Of the patients 95% had undetectable PSA (less than 0.1 ng/ml) at average followup of 9.7 months. Continence at 1, 3, 6, 9 and 12 months was 47%, 78%, 89%, 92% and 98%, respectively.

Our initial experience with robotic radical prostatectomy is promising. The learning curve was approximately 20 to 25 cases. With a structured methodical approach we were able to implement robotics safely and effectively into our community practice with minimal patient morbidity, and good oncological and functional outcomes.

Robotic radical prostatectomy in the community setting--the learning curve and beyond: initial 200 cases.

SUSCEPTIBILITY OF INTERLAYER POTASSIUM IN MICAS TO EXCHANGE WITH SODIUM * by

Zones 8 and 9 furnished carotenoids showing absorption maxima at 485 and 465mFt and at 455 and 429mjL in carbon disulphide respectively. The carotene zone furnished a mixture of a- and - carotenes whose dextrorotation in benzene indicated the presence of 28% of the former isomer (see Hunter & Scott, 194). The ether-soluble unsaponifiable matter was dissolved in light petroleum and the solution was extracted ten times with 90 % methanol. The residue obtained from the united extracts was chromatographed on 'Birlec' alumina and thereafter on calcium oxide. The broad orange-yellow upper zone furnished a carotenoid which showed absorption maxima at 500 and 473A474m,u in carbon disulphide. isomerization racemization

Recent methodological developments for determining potassium quantity–intensity (Q/I) relationships employing ion-selective electrodes offer a rapid means of carrying out such measurements for routine soil testing. In this investigation, various experimental factors in rapid measurements and their relevance to surface and subsurface soils are considered. Increasing the equilibration period generally enhanced the degree to which K+ was released or adsorbed by surface soil samples. Most of the gain or loss of K (ΔK) in the soil solution occurred within the first 10 min of the equilibration period. Also, regression analysis for 32 Iowa soils demonstrated that the Q/I results were highly correlated between short (e.g., 10 min) and long (e.g., 18 hr) equilibration periods. The correlations were even better when the results for surface and subsurface soils were considered separately. Increasing soil sampling depth generally increased the potential buffering capacity but had no consistent effect on other Q/I parameters. The depth of the soil samples also modified the effects of equilibration periods on the Q/I results. For subsurface soils, the 18-hr equilibration period usually induced less K+ release in low concentration ratio (CR) values in contrast to what occurs in surface soils. Such a distinction in Q/I status was attributed to the difference in the degree of reversion of released K+ between surface and subsurface soils during air-drying and re-wetting of samples. Overall, the results suggest that soil potassium Q/I relationships can be assessed with short equilibration periods but the interpretations for fertility status of surface and subsurface soils should be evaluated separately.

Effect of experimental relevance on potassium Q/I relationships and its implications for surface and subsurface soils

Determination of exchangeable potassium in soil using ion‐selective electrodes in soil suspensions

The use of proton-transfer reactions to detect low levels of impurities in bulk oxygen using an atmospheric pressure ionization mass spectrometer

Atmospheric pressure ionization mass spectrometry (APIMS) is being routinely used to quantify trace impurities in bulk gases used in the manufacture of semiconductor devices. APIMS has been successfully applied for the quantification of ppt levels of O(2), H(2)O, CO(2), and CH(4) in Ar, N(2), and He. However, it has not been successfully used to quantify trace impurities in bulk O(2) due to the low ionization potential of O(2). APIMS relies on charge-transfer reaction between the ions of the bulk gas molecules and impurity molecules. Since all the relevant impurity molecules have ionization potentials higher than that of O(2), APIMS has not been used to analyze for impurities in O(2). We report here the detection of sub-ppb levels of H(2)O in O(2) by making use of the clustering reaction between O(2)(+) and H(2)O. The declustering region in an APIMS, which is normally used to break apart unwanted and interfering clusters, has to be carefully adjusted to keep intact the weakly bound cluster O(2)(+)·H(2)O. Our results indicate a statistical detection limit of less than 300 ppt for the detection of H(2)O in O(2).

Use of a clustering reaction to detect low levels of moisture in bulk oxygen using an atmospheric pressure ionization mass spectrometer.

An XAFS study of the oxidation of structural iron in biotite mica by solutions containing Br2 or H2O2

X-ray absorption fine structure (XAFS) measurements were made on the Fe edge for a series of biotite micas oxidized to different extents by solutions containing either Br{sub 2} or H{sub 2}O{sub 2}. The Fe in the Br{sub 2}-treated sample was nearly completely oxidized to Fe(III), while the H{sub 2}O{sub 2}-treated samples showed an intermediate degree of oxidation. Both the near-edge and XAFS for the H{sub 2}O{sub 2} samples could have been fit well by a linear combination of the untreated and Br{sub 2}-treated samples. This indicates that the partially oxidized samples had the two forms of Fe in distinct sites. Detailed analysis for the oxidized site gave a coordination of 5.7 {+-} 0.5 with a Fe-O distance of 1.99 {angstrom}.

An XAFS study of the oxidation of structural iron in biotite mica by solutions containing Br{sub 2} or H{sub 2}O{sub 2}

A dynamic dilution system, utilizing single dilution, is described that generates sub ppb concentration of impurities in bulk nitrogen. An atmosphere pressure ionization mass spectrometer (APIMS) is used to verify the linearity of the dilution system. This system is used to obtain limits of detection of a commercially available single quadrupole APIMS for detecting methane, moisture, oxygen, and carbon dioxide in high purity nitrogen.

Dynamic Dilution Calibration System for Calibrating Analytical Instruments Used in Gas Analysis

Determination of ferrous iron in non-refractory silicate minerals

Methods of characterizing the K + status of soils in terms of quantity-intensity (Q/I) relationships usually entail lengthy equilibration periods, filtrations, and multiple analyses of the filtrates. It has been established, however, that simpler and less time-consuming methods of determining Q/I parameters can be devised with ion-selective electrodes (ISEs). To this end, different ISE methods were developed and evaluated with suspensions of three Iowa soils and a successive-additions method of varying the added K+. The ISE methods, which were categorized on the basis of the electrochemical cell involved, were tested for their applicability to soil suspensions. Specifically, single-ISE (K- and Ca-ISEs vs. a double-junction reference electrode assembly with a 10 M LiOAc salt bridge), dual-ISE (K-ISE vs. Ca-ISE), and triple-ISE (K- and Ca-ISEs vs. Cl-ISE) methods were compared to ascertain the best means of determining the ΔK (gain or loss of dissolved K) and CR [concentration ratio: CK/(CCa+Mg)1/2] terms o...

Comparison of ion-selective electrode methods for determining potassium Q/I relationships.

The layer charge of five smectites, one vermiculitic material, and five reduced-charge clays was determined by the alkylammonium and structural formula methods. The two sets of results were found to be linearly correlated (r =.961 ); however, the values that were determined by the alkylammonium method were 20 to 30% lower than those determined by the structural formula method, and the regression slope for their linear relationship was 1.67. The fact that the structural formula method includes the effects of cations on the lateral edges of the clay particles probably accounted for some of the differences in the magnitude of the results but should not have caused the regression slope to deviate substantially from 1.00. Therefore, inaccurate estimates of the packing density of alkylammonium cations in the interlayer space of 2:1 phyllosilicates were deemed responsible for the systematic divergence of the results of the two methods. To satisfy the need for a relationship between the two methods of determining layer charge, an empirical means of adjusting the alkylammonium values has been proposed and shown to yield values of layer charge that are comparable to those determined by the structural formula method.

Evaluation of the Alkylammonium Method of Determining Layer Charge

Techniques invo lv ing Xray powder dif f ract ion (XRD) and high-resolution transmission electron microscopy (HRTEM) are often used to characterize claysize phyllosilicates. The X R D approach is particularly well suited for determining the distinctive basal spacings o f clay minerals. The information provided by XRD analyses, however, can be complicated by interstratification, because the combined effects of various basal spacings are not easily distinguished from those due to particle size, morphology, and orientation (Brindley, 1980). On the other hand, H R T E M is an excellent method for studying the arrangement of both the particles within clay specimens and the layers within clay panicles. Clearly, a combinat ion of the two methods can provide a better understanding of the fabric of clay specimens than either method alone. The various techniques, however, of preparing clay specimens for HRTEM and X R D analyses (Jackson, 1985; McKee and Brown, 1977; Rich and Barnhisel, 1977) are substantially different, and it is not clear to what extent these techniques influence the fabric of the clay specimens. The following procedure was therefore developed to obtain X R D and H R T E M results for the same clay mineral specimen.

Technique for Transmission Electron Microscopy and X-Ray Powder Diffraction Analyses of the Same Clay Mineral Specimen

Ion-selective Electrode Determinations of Exchangeable Potassium in Soils1

The alkylammonium method of characterizing the charge of layer silicates has recently been applied to soil clays containing mixed mineral assemblages. Various sharp, low-angle x-ray diffraction (XRD) peaks (e.g., 2.5 nm for tetradecylammonium-treated samples) have been attributed to vermiculite or high-charge smectite. To the degree that alkylammonium cations can replace interlayer K, however, the observed low-angle peaks may represent K-depleted soil illite as well as vermiculite. This hypothesis was tested by treating two reference illites with alkylamine hydrochlorides. The treated illites exhibited low-angle XRD peaks similar to those observed in the soil clays. Moreover, the occurrence of these low-angle peaks coincided with the release of K from the illites. Similarly, the alkylamine hydrochloride treatments for layer-charge determinations released as much as 49% of the K from a soil clay. These data clearly show that the alkylammonium method can expand soil illites to give low-angle XRD peaks, which may be misinterpreted as evidence of soil vermiculite. Additional Index Words: layer charge, K release, illite. View complete article To view this complete article, insert Disc 5 then click button8

Oxidation of Iron in Biotite by Different Oxidizing Solutions at Room Temperature1

Construction and evaluation of a potassium-selective tube-mounted membrane electrode.

Laboratory experiments were carried out to establish a comprehensive understanding of the processes and factors governing the sorption and release of interlayer cations in micaceous minerals. A diverse approach with several lines of work was used to delineate the effects of different procedures, solution compositions and mineral properties. It was soon clear that the major factors controlling the exchange of interlayer cations are the blocking effects of dissolved fixable cations and the limiting effects of small particles. By using sodium tetraphenylboron to reduce the blocking effects and by excluding particles that were smaller than 2 ..mu..m, however, the subtle effects of many other factors were brought out. The redox status of structural iron, the hydroxyl groups, the interlayer spacing and the layer charge of the minerals are indicative of the type of factors involved and the fact that they are mainly interactive in nature. One conclusion from this work is that most experimental results for interlayer cation exchange are bound to reflect some combination of the controlling factors. More important, however, was the observation that proper management of interlayer cation exchange can make micaceous minerals a good sink for cesium and source of potassium.

Exchange of interlayer cations in micaceous minerals. Final report, February 1, 1967--August 31, 1976

Exchange of interlayer cations in micaceous minerals. Progress report, August 1, 1974--July 31, 1975

Exchange of interlayer cations in micaceous minerals. Progress report, August 1, 1973--July 31, 1974

Exchange of interlayer cations in micaceous minerals. Summary report, February 1, 1970--July 31, 1973

Temperature Effects on Interlayer Potassium Exchange in Micaceous Minerals1

Samples of several natural micas and a synthetic fluorphlogopite were heated at temperatures up to 850°C and then placed in NaCl.­NaTPB solutions at 25°C to determine the effect of various heat treatments on the exchange­ ability of their interlayer K. The maximum degree of K exchange was generally unaltered when the samples were heated but major changes in the rate of ex­ change occurred. The K in muscovite was released much faster if the.samples were preheated at temperatures above 350°C and even faster if the temperature were raised to 725°C or the time of heating were increased. As a result, nearly complete exchange of K in <50/*muscovite particles was achieved in 1 week in­ stead of 2 years. On the other hand, the release of K by biotite and lepido­ melane was retarded by similar heat treatments. Lepidomelane was affected by temperatures as low as 250°C and to such an extent that samples heated at 450°C for 24 hours released only 65% of its K in 2 years instead of all its K in 1 week. Phlogopite was relatively unaffected by temperatures up to 650°C whereas fluorphlogopite exhibited a decrease in rate and degree of K exchange when heated at 450°C. The K release behavior of the heated mica samples was evaluated in terms of Fe4"1" oxidation, dehydroxylation and structural adjustments in heated mieas. The significance of dehydroxylation was not clearly defined but a relationship with Fe"^ oxidation was observed. Fluorphlogopite (no Fe + + or OH") was altered by heat; hydrobiotites that contained Fe + + were not. Structural adjustments seem to be a major factor. ■ , rosnaauTOti OF THIS DOCUMENT IS \MM \

CHANGES IN INTERLAYER POTASSIUM EXCHANGEABILITY INDUCED BY HEATING MICAS.

EXTRACTABLE POTASSIUM IN GRUNDITE ILLITE. II. EFFECTS OF PARTICLE SIZE AND GRINDING.

EXCHANGE OF INTERLAYER CATIONS IN MICACEOUS MINERALS. Progress Report, September 30, 1969--September 30, 1970.

Control of Potassium Release and Reversion Associated with Changes in Soil Moisture1

EXCHANGE OF INTERLAYER CATIONS IN MICACEOUS MINERALS. Progress Report, February 1, 1967--September 30, 1967.

Mica particles approximately 10 or 25 mm square and 0.5 mm thick were placed in NaCl-NaTPB solutions to make visual observations of the changes that occur in micas when the interlayer K is replaced by Na. Samples of muscovite, biotite, phlogopite, lepidolite, and lepidomelane were used, and the effects of different degradation periods were photographed. An increase in the thickness of the particles due to basal planes splitting apart was observed with all micas. This exfoliation released interlayer K and in some cases caused the particles to cleave into separate flakes. Lepidomelane particles remained intact despite a 20-fold increase in thickness in 7 days. Even muscovite and lepidolite exfoliated and cleaved, but much longer degradation periods were needed. There was a distinct change in the color of the dark biotite, phlogopite and lepidomelane particles when K was removed. Therefore, the initial stages of K depletion at holes, scratches, and edges of the particles were easily followed. As the degradation of the mica particles progressed, however, the color of the mica became a less reliable index of the stage of K depletion. Visual evidence of K depletion at the edges of particles was also obtained with muscovite, but not with lepidolite. Transverse sections of 25-mm particles of K-depleted biotite were photographed to show the edge expansion that occurred when interlayer K was replaced by Na.

Visible Changes in Macro Mica Particles That Occur with Potassium Depletion

EXTRACTABLE POTASSIUM IN GRUNDITE ILLITE: I. METHOD OF EXTRACTION

ABSTRACT INTERLAYER, K in muscovite, biotite, phlogopite, illite and vermiculite-hydrobiotite samples was replaced by cation exchange with Na. The rate and amount of exchange varied with the mineral and the level of K in solution. Essentially, all the K in muscovite, biotite, phlogopite and vermiculite was exchangeable when the mass-action effect of the replaced K was reduced by maintaining a very low level of K in solution. The time required for this exchange varied from 45 weeks with muscovite. Only 66% of the K in the illite was exchangeable under these conditions. When the replaced K was allowed to accumulate in the solution, the amount of exchange was determined by the level of K in solution required for equilibrium. These levels decreased with the degree of K-depletion and with the selectivity of the mica for K. The order of selectivity was muscovite > illite > biotite > phlogopite > vermiculite. Decreasing the K in solution from 10 to 7 ppm increased the exchangeable K in biotite from 30 to 100%. A K level of only 0.1 ppm restricted the exchange of K in muscovite to 17%. A decrease in layer charge was not required for K exchange, but a decrease did occur in K-depleted biotite and vermiculite. Muscovite with the highest layer charge (247 meq/100 g), least expansion with Na (12.3 a), and least sensitivity to solution pH had the highest selectivity for K and the slowest rate of exchange. The K in vermiculite was the most readily exchangeable.

SUSCEPTIBILITY OF INTERLAYER POTASSIUM IN MICAS TO EXCHANGE WITH SODIUM

Soil Moisture Effects on Poteassium Release Observed on Drying Soils with Organic Additives 1

When Marshall subsoil samples were dried in an oven at 110°C. for 48 hours, the NH₄OAc extractable K increased from 27 to 210 ppm. This release of K was reduced to varying degrees by adding a wide variety of organic compounds to the soil samples before they were dried. The effect of these additives was not related to their solubility in water, dielectric constant or dipole moment. On the other hand, compounds with a high molecular weight and high boiling point were particularly effective in preventing K release. All alcohols tested reduced K release. Their effect increased with the amount added and their boiling point. Thus, the effect of normal primary alcohols increased with chain length and the effect of butyl alcohols decreased with chain branching. K release was eliminated by adding normal alcohol with a molecular weight equal to or greater than butanol. Glycerol, dextrose, sucrose, and n-octanol additions were particularly effective in preventing K release. The relative effect of these additives was related to the volume of each added, not the number of moles or hydroxyl groups involved. The addition of less than 2 ml. of these compounds per 10 g. soil eliminated K release entirely.

Changes in Exchangeable Potassium Observed on Drying Soils after Treatment with Organic Compounds: I. Release1

Muscovite samples were K-depleted with NaCl-NaTPB solutions. By varying the extraction period, samples that varied in total K from 219 to 15 meq per 100 g. were prepared. This treatment did not change the layer charge in the mineral, but it did increase the basal spacing of the mineral from 10 to 12.3 A. The changes in basal spacing that occurred when increasing amounts of interlayer K were replaced by Na and the effects of subsequent treatments for the removal of KTPB were determined with two size fractions. In each case, the interlayer K at the periphery of the muscovite particles was replaced by Na, and a fringe of K-depleted mineral with a basal spacing of 12.3 A developed. In a <50µ sample the particles retained an inner core of 10 A mineral as the weathered fringe increased. There was no evidence of interstratification. With this sample there was considerable Na trapping when the KTPB was removed with NH4Cl-acetone-water solutions. On the other hand, with a <2µ sample, mixed-layer structures developed as K was removed, and less Na trapping occurred. Na trapping was reduced by removing the KTPB with boiling NH4Cl. Undried Na-degraded muscovite with only 15 meq K per 100 g did not expand beyond 12.3 A. The NH4-degraded muscovite samples had a basal spacing of 10.4 A.

Chemical extraction of potassium from soils and micaceous minerals with solutions containing sodium tetraphenylboron : II. Biotite , Chemical extraction of potassium from soils and micaceous minerals with solutions containing sodium ... , مرکز فناوری اطلاعات و اطلاع رسانی کشاورزی

Chemical Extraction of Potassium from Soils and Micaceous Minerals With Solutions Containing Sodium Tetraphenylboron: II. Biotite1

GAS SORPTION BY SOILS AND CLAY MINERALS: 1. SOLUBILITY OF OXYGEN IN MOIST MATERIALS

Effect of Organic Additions on the Changes in Exchangeable Potassium Observed on Drying Soils 1

Kinetics of Potassium Release from Biotite and Muscovite in Sodium Tetraphenylboron Solutions1

Influence of Diverse Ions on the Determination of Manganese. A Study of the Lingane-Karplus Method

Undried soils were cropped in the greenhouse to determine the short-term release of nonexchangeable K under intensive cropping conditions. Using corn root mats with plants intact, it was found that 218, 59, 50 and −1 ppm. nonexchangeable K was released in 10 days by Marshall surface and subsoil and Clarion surface and subsoil samples, respectively, that had received no NH₄ or K additions. It was concluded that this short-term cropping method could be used to study factors that affect the availability of nonexchangeable soil K to plants. Nonexchangeable K was also extracted from the undried soils by two chemical methods that tend to reduce the blocking effect of replaced K. Single extractions with a NaOAc-NaBPh₄ solution removed more nonexchangeable K than five successive NaCl-HCl extractions or 5-day cropping periods. The corn plants and the NaCl-HCl solution, however, continued to remove K when the extraction period was increased whereas the NaOAc-NaBPh₄ solution did not.

Release of Nonexchangeable Soil Potassium During Short Periods of Cropping and Sodium Tetraphenylboron Extraction1

Availability of Nonexchangeable Soil Potassium to Plants as Affected by Added Potassium and Ammonium1

Factors influencing the change in exchangeable soil K observed on drying.

NITRIFICATION OF FIXED AMMONIUM IN CLAY MINERALS AS AFFECTED BY ADDED POTASSIUM

DETERMINATION OF THE PRECIPITATED POTASSIUM IN SODIUM TETRAPHENYLBORON— MICACEOUS MINERAL SYSTEMS THE CHEMICAL EXTRACTION of the nonexchangeable interlayer potassium in soils and micaceous minerals by exchange methods is blocked by relatively small amounts of potassium or ammonium in the extracting solution. Thus, to study the potassium-release characteristics of these materials and to make possible the removal of large amounts of potassium by mild exchange methods of extraction, these cations must be continuously removed from the solution. This can be accomplished by adding sodium tetraphenylboron (NaBPh4) to the aqueous extracting solution to precipitate the soluble potassium and ammonium.

Determination of the Precipitated Potassium in Sodium Tetraphenylboron—Micaceous Mineral Systems1

Removal of Fixed Ammonium from Clay Minerals by Cation Exchange Resins

Chemical Extraction of Potassium from Soils and Micaceous Minerals With Solutions Containing Sodium Tetraphenylboron. I. Preliminary Experiments

Soil Potassium-Moisture Relations: III. Determining the Increase in Exchangeable Soil Potassium on Drying Soils1

An active culture of nitrifying bacteria was established by adding moist garden soil to a high-K nutrient solution and incubating the system at room temperature with adequate aeration. By a success...

Nitrification in nutrient solutions with low levels of potassium.

NH₄-saturated samples of Montana vermiculite were extracted with 1N Na, 1N K, and 0.1N acid solutions that varied in pH. In some cases, successive and continuous extractions with boiling solutions were used. In others, the vermiculite samples were leached or distilled with solutions at room temperature. More NH₄ was removed by the Na solutions as the pH of the extracting solution increased or decreased from neutrality. When the accumulation of replaced NH₄ in the extracting solution was reduced by using alkaline solutions or by using the successive extraction method with the acid solutions there was an increase in the amount of NH₄ removed. In a given extraction period the amount of NH₄ removed by acid Na solutions increased linearily as the solution pH decreased. More NH₄ was removed by the K solutions as the pH of the extracting solution decreased. In the presence of a high concentration of a nonvolatile fixable cation (K) the alkaline solutions removed the least amount of NH₄. There was little effect of pH on the amount of NH₄ removed by 0.1N acid solutions when the solution pH was above 3. When the pH of the acid solutions was decreased below 3, there was a rapid increase in the amount of NH₄ removed.

Increments of salts or HCl were added to field-moist samples of selected Iowa soils. The soils were then dried and extracted with neutral 1N NH₄Ac to determine the K released under these conditions. When no salt or HCl was added, there was a continuous increase in K release when the moist soils were first dried at room temperature and then at progressively higher temperatures. The release of K at elevated temperatures appears to be part of the same extractable K-moisture relationship that has been observed when soils are airdried. Soils that normally released K on drying showed a continuous net fixation of K on drying when enough KCl was added to the moist soil. When lesser amounts of KCl were added both fixation and release were observed in the same drying sequence. The release of K was reduced when NH₄Cl, NaCl, or HCl was added to the soil prior to drying. The NH₄Cl additions were particularly effective. CaCl₂ additions had little or no effect on the K released by drying.

Soil Potassium-Moisture Relations: I. Potassium Release Observed on Drying Iowa Soils With Added Salts or HCl1

Fixed NH4 in vermiculite and bentonite was completely released by distillation in NaOH solutions. Small amounts of K in the solutions, however, blocked this release of NH4. If the amount of K was in excess of 2 K ions per 100 Na ions, no fixed NH4 was released from vermiculite. With smaller amounts of K present, the amount of fixed NH4 released decreased as the K/Na ratio in solution was increased. In an equilibrium NaCl extraction, small amounts of either fixable ion, NH4 or K, in the solution prevented the release of fixed NH4. There was no blocking from the NH4 in the NaOH distillations since it was lost from the alkaline systems. In the salt solutions, NH4 was more effective than K in blocking the release of fixed NH4. The blocking effect of a gixen fixable/nonfixable ion ratio in the neutral salt solutions increased as the amount of salt extractant per gram of mineral was increased. This is due to the preferential adsorption of the fixable cations. Higher K/Na ratios were required to block the release of fixed NH4 in neutral salt solutions than in alkaline solutions. Ten K ions per 100 Na ions in NaCl were not as effective as 2 K ions per 100 Na ions in NaOH. Higher K/Na or NH4/Na ratios were required to block the release of fixed NH4 from bentonite than from vermiculite. The NH4/Na ratio required to completely prevent the release of fixed NH4 from bentonite by NaCl was 0.04 as compared to 0.02 for vermiculite. View complete article To view this complete article, insert Disc 2 then click button8

Replaceability of Ammonium Fixed in Clay Minerals as Influenced by Ammonium or Potassium in the Extracting Solution1

Soil Potassium-Moisture Relations: II. Profile Distribution of Exchangeable K in Iowa Soils as Influenced by Drying and Rewetting 1

A laboratory technique is described which allows the continuous measurement of dissolved oxygen in saturated soil. The soil is flooded in a specially designed glass cylinder. A dropping mercury electrode is placed in contact with the soil solution of the saturated soil. The electrode is located so that the drops of mercury fall through the soil solution into a reservoir without coming in contact with the soil. A polarograph is used in conjunction with this dropping mercury electrode and a saturated calomel electrode to measure the dissolved oxygen content of the soil solution. Consideration is given to such factors as the interference of other constituents in the soil solution, the need of a maximum suppressor and the suitability of the soil solution as a supporting electrolyte. The limiting current at an applied voltage of 0.6 volts is shown to be a linear function of the dissolved oxygen in the soil solution. A time lag, which may exist in the method, is discussed and a limiting case is evaluated.

A Polarographic Method of Measuring Dissolved Oxygen in Saturated Soil

K of the ion activities in soil-water systems is essential to the proper understanding of the physico-chemical behavior of soils and the ionic environment of plant roots in the soil (4, 7). Prior to development of the clay membrane electrode by Marshall (4) little was known concerning the activities of exchangeable cations in soils although the "suspension effect" first demonstrated potentiometrically by Bradfield (1) with electrodialyzed clays constituted direct evidence of the dissociation of H+ ions in colloidal clay suspensions. Marshall (4, 5, 6) has successfully employed the clay membrane electrode to measure the activities of NH4+, Na+, K+, Ca++, and Mg++ ions in clay suspensions and has shown that the activities of the monovalent cations are much higher than those of the divalent cations at the same degree of base saturation. Unfortunately the clay membrane electrode lacks the desired specificity, and its use is therefore limited primarily to the measurement of cation activities in homoionic clay or soil suspensions, even though under favorable conditions Marshall (5) has extended this method to the determination of the activities of two coexisting cations in clay suspensions. In an effort to make possible simultaneous determination of the activities of any number of coexisting cations in soil water systems, a method based on the Donnan membrane equilibrium has been developed, and sufficient data have been obtained with clay suspensions to establish the validity of the method. In this paper, which is intended only as a preliminary report, a brief description of the method is presented together with some data on montmorillonite suspensions to illustrate the accuracy of the method as well as its utility in studies of ionic equilibria in clay or soil water systems.

Determination of Ionic Activities in Soil-Water Systems by Means of the Donnan Membrane Equilibrium 1

The library collection failure quotient: the ratio of interlibrary borrowing to collection size

E mboldened by the proliferation of photocopiers and by success in getting “fair use” recognized by the 1976 Copyright Act, U.S. research universities have banked on the potential for technology to reduce library costs. Institutions that spent 6 cents of their dollar on libraries in 1968 now

Book Reviews of An Introduction to Publishing Management, Directory of Books and Authors, Another Life, Technology and Scholarly Communication

Indicators that match the conservation and dissemination of information with its production may improve management of research investments. Constant dollar spending on research is compared with constant dollar spending on libraries 1960-1995. Price's exponential growth constant is compared with constant dollars spent on academic research and on libraries. An evaluation of the indirect cost policy by which library costs are reimbursed as a function of science grant management suggests that it has failed to promote cost-effective research. An evaluation of the impact of various information technologies finds enhancements to dissemination but misconceptions of their potential for savings.

Information Science and Information Policy: The Use of Constant Dollars and other Indicators to Manage Research Investments

An ideal vision of science requires goals and strategies to deal directly with the growth of new information. "Information Age" science policy fails to do this. By ignoring the study of science communications, it fosters a policy vacuum on information. By forgetting the economic value of libraries it fails to maximize the effective return on investments in research. Libraries are unable to meet the needs of their patrons. Publishers are discouraged from investing in markets dependent on academic libraries. The practice of neglecting information also scoffs at the law. Ending the neglect of science libraries means reforming the "indirect cost" policies by which government agencies support university libraries used for research.
In late 1997, House Speaker Newt Gingrich acknowledged that science and technology, "is now so inundated with its own technical knowledge, that it's almost impossible for it to become coherent." [Online] [October 23, 1997] He requested a "vision statement." I responded with an articulation that is embellished and expanded in the first part of this article. Two letters to Congress follow, expanding on goals and strategies, including an annotated list of references and a graphic analysis of the relationship of science and research libraries.

Science in the Twilight Zone; or, Are Science Libraries Related to Science?

Librarians have met the challenge of reduced funding by seeking "cost-effective" methods of collection management analysis: new ways to decide which subscriptions to cancel. Such methods are faulty and will eventually put researchers at a great disadvantage compared to those using libraries that have adequate funding. Library resources are essential to progress. Librarians are encouraged to advocate better funding based on libraries' importance to research and development and their place in the economy.

Abstract : The DOD Computer-aided Acquisition and Logistic Support (CALS) Test Network (CTN) is conducting tests of the military standard for the Automated Interchange of Technical Information (MIL-STD-1840A) and its companion suite of military specifications. The CTN is a DoD-sponsored confederation of voluntary participants from industry and government, managed jointly by a technical staff at Air Force Logistics Command (AFLC) and Lawrence Liver-more National Laboratory (LLNL). The objective of CTN tests is to demonstrate and evaluate the interchange and functional use of digital technical information between industry and government using the CALS standards. Publishing Systems Structured Test No. 1 was devised by the CALS Test Network staff and several representatives of SGML-oriented publishing vendors at TechDoc XIII in August, 1988. The objective of the test was to help settle some of the issues that arose during the attempt to formulate an Output Specification to accompany the conforming Document Type Definition of Specification MIL-M-38784B ('MIL-B'). The approach was to obtain consensus on interpretation of MIL-B by having several vendors compose the same Standard Generalized Markup Language (SGML) text file, and then comparing the results. The consensus might then speed the process of developing the Output Specification (OS).

Highlights from the 30th Annual Meeting of the Society for the Neural Control of Movement.

L'invention concerne des techniques de desinfection de stethoscope. Dans un mode de realisation particulier, les techniques peuvent etre realisees sous la forme d'un systeme de desinfection de stethoscope comprenant une premiere buse de distribution positionnee de facon a distribuer un fluide de desinfection sur une premiere surface d'un stethoscope, une seconde buse de distribution positionnee de facon a distribuer le fluide de desinfection sur une seconde surface d'un stethoscope, un premier capteur configure pour detecter la presence du stethoscope dans une zone a proximite etroite de la premiere buse de distribution et pour detecter la presence du stethoscope dans une zone a proximite etroite de la seconde buse de distribution, et une pompe configuree pour recevoir le fluide de desinfection a partir d'un receptacle de fluide de desinfection et pour envoyer le fluide de desinfection a la premiere buse de distribution et a la seconde buse de distribution. Les techniques peuvent comprendre un microcontroleur configure pour recevoir un signal provenant du premier capteur et declencher une operation de pompage en reaction a la reception du signal.

Procédés et systèmes pour la stérilisation d'instruments médicaux

Adherent-invasive Escherichia coli (AIEC) has been implicated as a microbiological factor in the pathogenesis of inflammatory bowel disease (IBD). We evaluated the ability of six live biotherapeutic products (LBPs) to inhibit the interaction of an AIEC strain to three cell lines representing human gut epithelium. Co-inoculation of LBPs with AIEC showed a reduction in adhesion (up to 73%) and invasion of AIEC (up to 89%). Pre-inoculation of LBPs in HT-29-MTX and Caco-2 cells before challenging with AIEC further reduced the adhesion and invasion of the AIEC, with three LBPs showing significantly (p < 0.0001) higher efficiency in reducing the adhesion of AIEC. In co-inoculation experiments, the highest reduction in adhesion (73%) of AIEC was observed in HT-29-MTX cells, whereas the highest reduction in invasion (89%) was seen in HT-29-MTX and the co-culture of cells. Pre-inoculation of LBPs further reduced the invasion of AIEC with highest reduction (97%) observed in co-culture of cells. Our results indicated that whilst there were differences in the efficacy of LBPs, they all reduced interaction of AIEC with cell lines representing gut epithelium. Their efficiency was higher when they were pre-inoculated onto the cells, suggesting their potential as candidates for alleviating pathogenesis of AIEC in patients with IBD.

Efficacy of Selected Live Biotherapeutic Candidates to Inhibit the Interaction of an Adhesive-Invasive Escherichia coli Strain with Caco-2, HT29-MTX Cells and Their Co-Culture

Traitements pour composante de sonde atomique. Par exemple, sous certains aspects, on decrit des procedes de traitement qui consistent a eliminer du materiau sur une surface de composante (par exemple au faisceau ionique, au plasma, a l'attaque chimique et/ou a l'energie photonique). Sous un autre aspect, on decrit un procede qui consiste a utiliser un dispositif de calcul pour controler automatiquement une tension utilisee dans un procede de pulverisation ionique. Selon d'autres aspects encore, on decrit des procedes qui consistent a rapprocher une energie photonique de la surface de composante, a effectuer un recuit d'au moins une partie de surface de composante, a revetir au moins une partie de surface de composante et/ou a refroidir au moins une partie de surface de composante.

La presente invention a trait a une sonde atomique comportant un support d'echantillons apte au maintien d'un echantillon a analyser. Un detecteur est espace du support d'echantillons. Entre le detecteur et le support d'echantillons est prevue une electrode locale avec une ouverture. Un laser est oriente pour l'emission d'un faisceau laser vers le support d'echantillons a un angle non nul par rapport au plan de l'ouverture, le plan de l'ouverture etant oriente perpendiculaire au trajet de deplacement d'ions defini a travers l'ouverture entre le support d'echantillons et le detecteur.

Abstract Due to the decreased cost and increased availability of digital camera technology, digital image analyses are rapidly replacing traditional caliper-based approaches to wildlife morphometry. The substitution of image-based measurement methods over those utilizing calipers is based on the assumption that both methods are comparable with respect to accuracy, precision, time required and inter-observer variation, yet this hypothesis has not been explicitly tested. In this article, we evaluate these aspects of each method using three life stages of the marbled salamander Ambystoma opacum. We found that digital image-based measurements were significantly more accurate, faster to obtain, and resulted in reduced inter-observer measurement variation relative to caliper measurements, yet the former was associated with reduced precision among repeated measurements relative to the latter. Based on our observations, we recommend that digital image-based measurements represent a useful alternative to caliper measurements and are particularly useful for organisms that pose risks to investigators, normally maintain non-linear body orientations, or cannot easily be removed from their habitat.

Assessment of digital image analyses for use in wildlife research

The work of Humphreys and Meleney (1928) and of Hall, Rymer and Jungherr (1929) firmly established the identity of Bacillus Sordellii and Clostridium oedematoides on the basis of cultural and morphologic comparisons and toxin-antitoxin cross protection tests. Hall (1929) later identified two cultures of unknown anaerobic bacilli sent to him by Dr. L. R. Vawter of Reno, Nevada as B. Sordellii in the same manner. In none of the preceding comparative studies, however, was the possibility of serologic identification by means of the agglutination reaction satisfactorily demonstrated. Sordelli (1923) evidently tried agglutination, for he said, "l'agglutination n'a pas permis d'etablir ni difference, ni analogie," but he gave no experimental results. Humphreys and Meleney (1928) stated that, "Agglutination reactions in this group" (the pathogenic clostridia) "are notoriously unreliable, owing, on the one hand, to the indefinite number of subgroups likely to be encountered, and on the other, to their frequent tendency to spontaneous agglutination." The work reported in this paper is a continuation of the comparative studies reported by Hall, Rymer and Jungherr in 1929, and deals with cross agglutination studies on the eight available strains of B. Sordellii and C. oedematoides. The following cultures were investigated:

The Serologic Agglutination of Bacillus Sordellii and Clostridium oedematoides

La presente invention porte sur un processeur d'affichage comprenant une unite d'interface, un processeur d'instructions, une unite de synchronisation, au moins une unite de traitement et une memoire tampon de dispositif. L'unite d'interface recoit des donnees image d'entree (par exemple d'une memoire principale) et produit des donnees image de sortie pour une memoire tampon d'image. Le processeur d'instructions recoit des instructions (par exemple dans un script ou une liste) et commande le fonctionnement de la ou des unites de traitement. L'unite de synchronisation determine l'emplacement d'un pointeur de lecture pour la memoire tampon d'image et commande l'ecriture de donnees image de sortie dans la memoire tampon d'image afin d'eviter que des artefacts ne soient generes sur un ecran a cristaux liquides. La ou les unites de traitement peuvent effectuer diverses fonctions de post-traitement telles que l'inversion de zone, la rotation de zone, la conversion couleur entre deux formats video (par exemple de l'espace couleur YCrCb a l'espace couleur RVB), l'augmentation/reduction de la taille de l'image, le melange alpha, la transparence, la superposition de texte, etc.

L'architecture de dispositif virtuel de l'invention fournit des peripheriques physique et logique qui permettent d'interfacer des logiciels tournant dans un microprocesseur du telephone mobile d'un systeme de communication sans fil avec l'un quelconque de divers peripheriques materiels connectables dans le telephone mobile. Les pilotes du peripherique logique convertissent des commandes recues des applications logicielles en commandes appropriees pouvant etre utilisees par des peripheriques materiels choisis. Les pilotes du peripherique physique recoivent les commandes converties des pilotes du peripherique logique et, en reponse auxdites commandes recues, prennent directement en main les peripheriques materiels choisis. Dans un exemple de l'invention, les pilotes du peripherique logique fournissent une traduction de commandes de base necessaires pour prendre en main les peripheriques materiels choisis, et une traduction de commandes etendues pour assurer un controle ameliore des peripheriques materiels.

Principal Sir James Donaldson : education and political patronage in Victorian Scotland

Physical and chemical properties of the petroleums of California

A look at past events that have helped aviation technologies and procedures progress is presented.

This paper covers several subjects of immediate concern to the pilot including emergencies, pilot furnishings, cockpit arrangement, accelerations, and landing characteristics. (author)

A flight evaluation of the stability and control of the X-4 swept-wing semitailless airplane

Report discussing some new requirements for satisfactory handling qualities due to the drastic changes in the speed range and configuration of airplanes. Longitudinal characteristics, lateral and directional stability and control characteristics, dynamic lateral and directional stability, and control effectiveness are described. Four categories of characteristics that may affect pilot control are included and ranked by level of severity.

Report discusses the need of uniform methods of determining the flash point and recommends certain forms of testers.

Flash point of oils; methods and apparatus for its determination

Investigations with the U. S. Bureau of Mines Modification of the Abel-Pensky and Pensky-Martens Flash-Point Testers

Abstract : This monograph addresses the question, Is the 1999 edition of FM 100-25, Doctrine for Army Special Operations Forces, adequate to integrate the actions of special operations forces (SOF) and conventional forces on the contemporary battlefield? Operations in Afghanistan in 2001 and operations in Iraq in 1991 showed two different degrees of physical integration between SOF and conventional forces on the battlefield. Forces in Afghanistan routinely conducted operations in close proximity to each other, measured in meters. This proximity required close, tactical-level cooperation between SOF and conventional forces. Forces in Iraq in 1991 however, rarely operated in close proximity to each other. Instead, SOF forces supported operational objectives, operating in areas physically separated from conventional forces by hundreds of kilometers. Evidence presented in this monograph shows that although the degree of physical integration was different, the method used to integrate the C2 functions of the two forces was similar, emphasizing a SOF centric approach to command and control of SOF forces. This monograph examines the integration of command and control (C2) functions of SOF and conventional forces in two case studies. Focus is placed on describing the relationships between physical integration of SOF and conventional forces on the battlefield, the command structure used to control the respective forces, and the methods used to integrate the C2 functions between SOF and conventional forces. This monograph concludes that effective integration between SOF and conventional force C2 was not observed in Afghanistan. A root cause of this ineffectiveness was that the doctrine that governs SOF and conventional force C2 integration, FM 100-25 dated 1999, was inadequate.

Tactical Integration of Special Operations and Conventional Forces Command and Control Functions

Cubist paintings 1910-1912 and Piaget's theory of the development of object permanence: On the existence of abstract and imaginary sense data

One device used to measure rate constants is the IAsys, and the flow in such a device can be modeled as stagnation point flow. Due to the special nature of the flow, the effects of transport on a surface reaction near a stagnation point may be incorporated exactly as long as the initial concentration of bound state is uniform. However, if the bound state is nonuniform initially, a complicated integrodifferential equation arises for the evolution of the bound state. Such a form is inconvenient for data analysis. The averaged approximation replaces the nonuniform initial state with its average, thus simplifying the analysis. This approximation is correct to O(Da) as the Damkohler number Da → 0. A numerical simulation of the integrodifferential equation is performed which shows that the averaged approximation is useful even outside this regime. Keywords—Surface-volume reactions, integrodifferential equations, numerical simulation, surface plasmon resonance, IAsys. § This work was supported by the University of Delaware Research Foundation. ∗ To whom correspondence should be addressed. E-mail address: edwards@math.udel.edu. This work was supported by the University of Delaware Research Foundation. † Current address: Federal Sector/Defense Group, Computer Sciences Corporation, Moorestown, NJ 08057-0902. Email address: sethajackson@hotmail.com. UD Technical Report 2002-3.2

Testing the Validity of the Averaged Approximation for the IAsys

A multiscale region detector for low-level image analysis is described. The basis of the detector is a set of filters similar to the Laplacian of an elliptical Gaussian. The responses of these filters to ideal ellipses are derived, and equations for determining the parameters of detected ellipses from the filter responses are found. The use of scale-space techniques to eliminate false ellipse sites in real images is described.

Proceedings of 13th International Conference on Pattern Recognition

THE root locus method for analyzing feedback control systems has become increasingly popular over the last few years. However, the great potentialities of the method have yet to be realized. The method has had the drawback of presenting only the transient response of the system under study. An ideal method of analysis and synthesis would allow the engineer to arrive at both the transient and the steady-state sinusoidal response without any large amount of extra work involved for either. The work would progress in two stages. The first stage would take a relatively short time to complete and would yield approximations to both the closed-loop transient response and the frequency response. At this point, various design features could be compared. The second stage would be an extension of the work done in the first stage - not a more detailed rework of the problem. This second stage of the problem would yield exact and complete transient and sinusoidal solutions.

Transactions of the American Institute of Electrical Engineers, Part II: Applications and Industry

An extension of the root locus method to obtain closed-loop frequency response of feedback control systems

Temperature induced atypical morphogenesis of the obligately psychrophilic yeast, Leucosporidium stokesii

Factors influencing hydrocarbon degradation in three freshwater lakes

Effect ofPseudomonas aeruginosa rhamnolipid on human neutrophil migration

Cells of the obligately psychrophilic yeast Leucosporidium stokesii were subjected to permissive (15 and 20 degrees C) and restrictive (23 and 25 degrees C) temperatures to determine the event(s) responsible for the low maximum growth temperature of this organism. An investigation of subcellular morphology by nuclear staining revealed that buds formed at 20 degrees C were anucleate but showed nuclear migration within the parent cell. Cells incubated initially at 23 degrees C and then shifted down to a permissive growth temperature of 15 degrees C in the presence of a deoxyribonucleic acid (DNA) synthesis inhibitor, hydroxyurea, confirmed the observation that the anucleate condition of atypical buds was the result of temperature-sensitive DNA synthesis. Concomitantly, the incorporation of labeled adenine into DNA was inhibited at 23 and 25 degrees C. The synthesis of ribonucleic acid, however, was enhanced at 23 degrees C but impaired at 25 degres C. Similarly, protein synthesis was unaffected at either restrictive temperature.

Molecular basis for the maximum growth temperature of an obligately psychrophilic yeast, Leucosporidium stokesii

GROWTH AND MACROMOLECULAR SYNTHESIS IN THE OBLIGATELY PSYCHROPHILIC YEAST, LEUCOSPORIDIUM STOKESII, AT PERMISSIVE AND RESTRICTIVE GROWTH TEMPERATURES

Responsiveness of lymphocytes from Mengovirus treated mice to phytohaemagglutinin stimulation, in vitro.

Spleen cells from Swiss-Webster mice inoculated with viruses were tested for their ability to respond; in•vitro to phytohemagglutinininduced DNA synthesis as measured by the amount of tritiated thymidine incorporated into DNA. Application of this response was utilized as a means of detecting a virus infection in vivo. ( A preliminary study indicated that splenic lymphocytes obtained from mice infected with Sendai virus, Reovirus, and Mengovirus-L demon­ strated a depression of PEA--induced DNA synthesis over a six-day post­ infection period. Mice inoculated with an LD^q concentration of Mengovirus-L for a 20-day postinfection period demonstrated an impaired ability of lym­ phocytes to respond to PHA stimulation, and this coincided with a time when the clinical signs of the disease were'apparent. Once signs of hyperactivity and paralysis declined, lymphocyte responsiveness to PHA stimulation returned to normal. These observations suggest that the responsiveness to PHA stimulation may reflect a direct virus-lymphocyte interaction or indicate, a more complex physiological relationship in vivo. Additional examinations of Mengovirus-L infectivity in relation to morphological changes in vivo, such as spleen and body weight changes and altered leukocyte profiles",, were not successful in establishing a positive correlation that was consistent with the impaired lymphocyte

Viral-induced unresponsiveness of mouse lumphocytes to phytohemagglutinin stimulation

Extended abstract of a paper presented at Microscopy and Microanalysis 2006 in Chicago, Illinois, USA, July 30 – August 3, 2005

An Automatic Electropolishing System for Needle-Shaped Specimens

This paper proposes obtaining structural information by directly imaging offsets between neighboring atom positions after reconstruction. This technique requires much less memory and CPU processing time than either FT implementation described above. Additionally, in certain situations position-dependent reconstruction aberrations can be estimated across much of the field of view by direct examination of peak shapes in the resulting 3D spatial distribution functions

Extended abstract of a paper presented at Microscopy and Microanalysis 2005 in Honolulu, Hawaii, USA, July 31--August 4, 2005

Three Dimensional Local Electrode Atom Probe Analysis of Microtips Fabricated on a Planar Specimen Utilizing a Broad Ion Beam

Imago Scientific Instruments is developing its Local Electrode Atom Probe (LEAP®) microscope for use in semiconductor, data storage, and other nanotechnology industries to provide 3-D atomic-scale metrology. The LEAP microscope achieves true 3-D atomic-scale analysis by using a high electric field to remove individual atoms from material surfaces and a position-sensitive detector to record information that reveals the atoms’ position and identity. The LEAP microscope represents a new class of tool for atomic-scale characterization whose analytical capabilities surpass those of currently employed metrology tools. The LEAP microscope’s atom-by-atom analysis achieves higher spatial resolution and greater sensitivity than TEM, and provides lateral spatial resolution that is not available by SIMS. Specific industry needs that may be addressed by the LEAP microscope are quantitative analysis of dopant distributions in ultra-shallow junctions, purity/interface structures of ultra-thin dielectrics, and multilayer thin film structure in read/write head and storage media technology. This paper presents results of LEAP analysis of buried interfaces in electronic materials to show the unique nature of the analytical information provided by the technique and the potential benefit to industry of developing a metrology tool based on LEAP technology.

The first dedicated local electrode atom probes (LEAP [a trademark of Imago Scientific Instruments Corporation]) have been built and tested as commercial prototypes. Several key performance parameters have been markedly improved relative to conventional three-dimensional atom probe (3DAP) designs. The Imago LEAP can operate at a sustained data collection rate of 1 million atoms/minute. This is some 600 times faster than the next fastest atom probe and large images can be collected in less than 1 h that otherwise would take many days. The field of view of the Imago LEAP is about 40 times larger than conventional 3DAPs. This makes it possible to analyze regions that are about 100 nm diameter by 100 nm deep containing on the order of 50 to 100 million atoms with this instrument. Several example applications that illustrate the advantages of the LEAP for materials analysis are presented.

An ultrasonic instrument employs a digital architecture to provide improved stability to sound speed measurements of human bone in vivo. A digitization of the received ultrasonic signal allows numerical analyses to be applied in determining precise arrival time of the waveform. The microprocessor may initiate the ultrasonic signal transmission and detect its arrival and may control the strength of the transmitted signal and the amplification of the received signal to optimize the signal path.

These prototype LEAPs are ultrahigh vacuum (UHV) systems with a three stage vacuum system. This dry vacuum system uses titanium sublimation pumping with a large ion pump on the main chamber to achieve 3 x 10 Pa after a bake at 150°C. An intermediate chamber achieves 10 Pa with a magnetically-levitated turbopump. Eighteen specimens may be inserted at one time through the airlock and it takes less than ten minutes to complete insertion of a specimen into the main chamber. The specimen stage has 10 nm or smaller steps with 8 mm travel using an inchworm actuator on each of three axes. A vibration-isolated two stage helium refrigerator system cools the specimen to 27K or lower.

Monday, August 5, 2002: Platform Sessions (AM) Monday, August 5, 2002: Poster Presentations, 1:00–3:00PM, Exhibit Hall Monday, August 5, 2002: Platform Sessions (PM) Monday, August 5, 2002: Presidential Happenings 5:00PM Tuesday, August 6, 2002: Platform Sessions (AM) Tuesday, August 6, 2002: Poster Presentations, 1:00–3:00PM, Exhibit Hall Tuesday, August 6, 2002: Platform Sessions (PM) Tuesday, August 6, 2002: Presidential Happenings 5:00PM Wednesday, August 7, 2002: Platform Sessions (AM) Wednesday, August 7, 2002: Poster Presentations, 1:00–3:00PM, Exhibit Hall Wednesday, August 7, 2002: Platform Sessions (PM) Thursday, August 8, 2002: Platform Sessions (AM) Thursday, August 8, 2002: Platform Sessions (PM)

The concept of a local electrode atom probe (LEAP) has its roots in the work of Nishikawa [1,2] in the early 1990’s who invented the concept of a counter electrode proximal to a field evaporation specimen. Subsequent work by Kelly et al. [3,4] identified many advantages that accrue from operation of an atom probe with such a counter electrode. Various efforts in academic settings have been made by Nishikawa et al. [2], Kelly et al. [4], and Cerezo et al. [5] to demonstrate operational feasibility of such instruments. These experimental efforts have demonstrated that the key concepts of a LEAP work. However, there has heretofore not been a single instrument that integrates all of the potential functionality in a single instrument.

Prevalence of Oral Human Papilloma Virus in a Urban Minority Population in the Washington, DC Metropolitan Area

Tales from the grave: Opposing autopsy reports from a body exhumed.

The Safety and Feasibility of Intraoperative Ultrasound to Aid Intrinsic Tumour Resection: A Retrospective Case-Control Series

Milton Abramowitz, M. I. Aissen, E. J. Akutowicz, C. B. Allendoerfer, R. D. Anderson, T. W. Anderson, R. G. Archibald, L. A. Aroian, Frederick Bagemihl, Joshua Barlaz, P. T. Bateman, F. P. Beer, E. G. Begle, Stefan Bergman, Lipman Bers, Garrett Birkhoff, D. W. Blackett, A. L. Blakers, A. A. Blank, S. G. Bourne, C. B. Boyer, Paul Brock, A. B. Brown, F. H. Brownell, L. J. Burton, Jewell H. Bushey, J. H. Bushey, W. R. Callahan, H. E. Campbell, P. G. Carlson, Jeremiah Certaine, K. T. Chen, Y. W. Chen, W. L. Chow, L. W. Cohen, A. J. Coleman, T. F. Cope, Natalie Coplan, L. M. Court, M. D. Darkow, Martin Davis, B. V. Dean, H. F. DeBaggis, J. L. Doob, Arnold Dresden, Aryeh Dvoretzky, Samuel Eilenberg, M. P. Epstein, R. M. Exner, J. M. Feld, F. A. Ficken, N. J. Fine, R. S. Finn, A. D. Fleshier, R. M. Foster, R. H. Fox, Gerald Freilich, Orrin Frink, G. N. Garrison, Hilda Geiringer, H. A. Giddings, J. B. Giever, B. P. Gill, G. H. Gleissner, H. E. Goheen, W. H. Gottschalk, Bernard Greenspan, Harriet Griffin, Emil Grosswald, E. J. Gumbel, V. H, Haefeli, F. C. Hall, F. S. Hawthorne, G. A. Hedlund, M. H. Heins, Alex Heller, Erik Hemmingsen, A. H. Henry, L. H. Herbach, A. A. Herschfeld, Einar Hille, Abraham Hillman, Joseph Hilsenrath, Banesh Hoffmann, T. R. Hollcroft, L. A. Hostinsky, E. M. Hull, Witold Hurewicz, L. C. Hutchinson, M. A. Hyman, Eugene Isaacson, Nathan Jacobson, Wenceslas Jardetzky, B^rge Jessen, S. A. Joffe, Fritz John, R. A. Johnson, F. E. Johnston, Shizuo Kakutani, Edward Kasner, W. H. Keen, M. E. Kellar, L. S. Kennison, J. F. Kiefer, H. S. Kieval, S. C. Kleene, J. R. Kline, E. G. Kogbetliantz, E. R. Kolchin, Horace Komm, B. O. Koopman, Jack Laderman, A. W. Landers, J. P. LaSalle, V. V. Latshaw, Solomon Lefschetz, Marguerite Lehr, Benjamin Lepson, Howard Levi, D. C. Lewis, M. A. Lipschutz, S. R. Lipsey, L. H. Loomis, E. R. Lorch, Lee Lorch, Janet McDonald, Brockway McMillan, L. A. MacColl, H, M. MacNeille, Irwin Mann, A. J. Maria, M. H. Maria, W. T. Martin, W. S. Massey, A. E. Meder, Paul Meier, A. N. Milgram, K. S. Miller, W. H. Mills, Don Mittleman, E. E. Moise, Deane Montgomery, Marston Morse, H. H. Mostafa, G. D. Mostow, T. S. Motzkin, F. J. Murray, David Nelson, C. V. Newsom, A. V. Newton, P. B. Norman, I. L. Novak, C. O. Oakley, J. C. Oxtoby, T. E. Peacock, A. J. Penico, I. D. Peters, B. J. Pettis, Everett Pitcher, E. L. Post, Walter Prenowitz, M. H. Protter, Hans Rademacher, Hans Râdstrom, G. N. Raney, H. E. Rauch, G. E. Raynor, M. S. Rees, Helene Reschovsky, Moses Richardson, J. F. Ritt, I. F. Ritter, J. E. Robinson, P. C. Rosenbloom, H. D. Ruderman, Raphael Salem, H. E. Salzer, Arthur Sard, Samuel Schecter, Henry Scheffé, Eugene Schenkman, M. M. Schiffer, Pincus Schub, Abraham Schwartz, G. E. Schweigert, Wladimir Seidel, Atle Selberg, D. B. Shaffer, Daniel Shanks, C. E. Shannon, H. N, Shapiro, LM. Sheffer, Seymour Sherman, James Singer, M. H. Slud, L. L. Smail, Ernst Snapper, Andrew Sobczyk, D. C. Spencer, George Springer, Fritz Steinhardt, Wolfgang Sternberg, J. J. Stoker, R R. Stoll, M. M. Sullivan, Olga Taussky, D. L. Thomsen, John Todd, P. M. Treuenfels, H. C. Tsang, Oswald Veblen, S. L Vrooman, H. V. Waldinger, J. L. Walsh, Alan Wayne, Alexander Weinstein, Louis Weisner, M. E. White, P. M. Whitman, D. V. Widder, Albert Wilansky, W. G. Wolfgang, Jacob Wolfowitz, Y. K. Wong,

THE OCTOBER MEETING IN NEW YORK The four hundred fiftieth meeting of the American Mathematical

particularly on the left. It had lost its line of demarcation. The patient's condition deteinorated. He lost weight, and became paler in spite of repeated transfusions. He complained of aches and pains in the thighs, chest, and more or less throughout his body. He gradually became cachectic and passed into a semicomatose state, and expired on February 15, approximately five weeks after admission. Necropsy was performed shortly after death with the following findings: (1) sarcoma of the prostateround and spindle cell type (Fig. 4); (2) metastases to the penis, bladder, pelvic bones, sacral plexus, rectum, vertebrw, para-aortic, mediastinal, and bronchial lymph nodes, lungs and pleurae; (3) bilateral bronchopneumonia.

Cortisone, together with a specific antibiotic, is being used more and more in the managemett of severe infections and as early as 1952 Conrad Collins and his associates in New Orleans' as well as Abraham Hurtig of Ottawa2 reported that they had successfully treated pelvic inflammatory disease with this therapeutic agent. Since that time, several similar publications have appeared in the literature. However, to date the number of patients with pelvic inflammatory disease who have received cortisone therapy is relatively small. It is not difficult to understand why cortisone would have a beneficial effect upon pelvic infection. It is known to have an anti-inflammatory effect, locally by minimizing or reducing the vascular and exudative response to infection and systemically by a non-specific antipyretic and antitoxic type of action. Also, it is generally accepted that cortisone inhibits the proliferation of scar tissue. Part of the beneficial effect of cortisone in an infection is perhaps due to its action on the arterioles, producing better tone. Another effect on the blood vessels is to maintain the integrity of the capillaries. The net result of these vascular effects is to help maintain a normal circulatory bed. Cortisone has proved to be of great value in the treatment of catastrophic forms of disease perhaps due to hypoadrenalism which may be associated with such an illness. However, the use of cortisone in the management of infection is not without danger. Cortisone has proved to increase the invasiveness of a wide variety of organisms and therefore it must be used together with a specific antibiotic. In pelvic inflammatory disease it is often difficult to determine the specific antibiotic. Another danger encountered in cortisone therapy is that it often masks the signs of infection such as might occur following rupture of a tubo-ovarian abscess. Other contraindications to cortisone therapy include peptic ulcer, borderline psychotic states, cardiac disease and pulmonary tuberculosis. It is the writer's belief that cortisone therapy should be reserved for those few cases of resistant or recurrent pelvic inflammatory disease where an acute or exudative element is present, where the causative organism and specific antibiotic is known, and where there is no other contraindication to cortisone therapy. The treatment schedule generally used is modified after Hurtig.3 4 The antibiotic is started 24 to 48 hours before beginning cortisone therapy and continued for 48 to 72 hours after the completion of cortisone administration. Cortisone is given in doses of 300 mg. the first day, 200 mg. the second day and 100 mg. each successive day for about 10 to 16 days. It is then reduced to 25 mg. per day before being discontinued altogether. A. B. BROWN

PELVIC INFLAMMATORY DISEASE Cortisone , together with a specific antibiotic , is being used more and more in the managemett of severe infections and as early as 1952

During the 1983-84 school year, 3,618 students under age 18 years with hearing impairments caused by meningitis were reported to the Gallaudet Research Institute Annual Survey, accounting for 8.7 per cent of children in the survey under 18 years. This research suggests that universal vaccination at age 18 months could prevent at least 115 cases of hearing loss annually in the United States. Reported prevalence rates of hearing loss from meningitis are higher for blacks (.98 per 105 than for all hearing impaired students (.58 per 105) and higher for males (.68 per 105) than females (.48 per 105). Geographic differences are also observed. Among those students with hearing losses from meningitis, 86.7 percent lose their hearing prior to age 3 years, 62.6 percent has profound hearing loss and 22.7 percent manifested additional sequelae, most of which were neurological.

Demographics of Meningitis-Induced Hearing Impairment: Implications for Immunization of Children Against Hemophilus Influenzae Type B

This symposium on the clinical and pathological significance of renal biopsy lives up to the high standard that we have come to expect from such occasions. Under the distinguished chairmanship of Professor Arnold Rich of Johns Hopkins Hospital a unique collection of data was presented to a critical and experienced audience. The ultra-structure of the glomerulus is more informative of the relation of structure to function than in most other organs and all who are interested in renal pathophysiology will welcome these authoritative pronouncements. The electron-micrographs of normal and diseased glomeruli and their correlation with light microscopic pictures are most informative, even if at times it is difficult to know whether the fine changes are the cause of the renal functional disturbance or the result. The contents range from fine ultra-structure in a variety of disorders through post-streptococcal and focal glomerulonephritis, lupus nephritis, pyelonephritis in various aspects, to quantitative histochemistry by ultra-micro methods and observations on acute anuria. A very valuable feature is the general discussion after each topic and also the general discussion at the end in which the company pooled their experience (amounting to 5,120 biopsies) of the dangers and catastrophies that may be encountered in renal biopsy. Altogether this is a most stimulating and instructive publication and if the procedures advocated are not always to the advantage of the individual patient there is no doubt that the cumulative knowledge will advance the accuracy of diagnosis and thus of treatment.

Book Review: New Books: Proceedings of a Symposium on Immunization in Childhood

Peripheral blood proteomic profiling of idiopathic pulmonary fibrosis biomarkers in the multicentre IPF-PRO Registry

Circulating matrix metalloproteinases and tissue metalloproteinase inhibitors in patients with idiopathic pulmonary fibrosis in the multicenter IPF-PRO Registry cohort

Visual systems of primates are the gold standard of robust perception. There is thus a general belief that mimicking the neural representations that underlie those systems will yield artificial visual systems that are adversarially robust. In this work, we develop a method for performing adversarial visual attacks directly on primate brain activ-ity. We then leverage this method to demonstrate that the above-mentioned belief might not be well founded. Specifically, we report that the biological neurons that make up visual systems of primates exhibit susceptibility to adversarial perturbations that is comparable in magnitude to existing (robustly trained) artificial neural networks.

Adversarially trained neural representations may already be as robust as corresponding biological neural representations

While some state-of-the-art artificial neural network systems in computer vision are strikingly accurate models of the corresponding primate visual processing, there are still many discrepancies between these models and the behavior of primates on object recognition tasks. Many current models suffer from extreme sensitivity to adversarial attacks and often do not align well with the image-by-image behavioral error patterns observed in humans. Previous research has provided strong evidence that primate object recognition behavior can be very accurately predicted by neural population activity in the inferior temporal (IT) cortex, a brain area in the late stages of the visual processing hierarchy. Therefore, here we directly test whether making the late stage representations of models more similar to that of macaque IT produces new models that exhibit more robust, primate-like behavior. We conducted chronic, large-scale multi-electrode recordings across the IT cortex in six non-human primates (rhesus macaques). We then use these data to fine-tune (end-to-end) the model “IT” representations such that they are more aligned with the biological IT representations, while preserving accuracy on object recognition tasks. We generate a cohort of models with a range of IT similarity scores validated on held-out animals across two image sets with distinct statistics. Across a battery of optimization conditions, we observed a strong correlation between the models’ IT-likeness and alignment with human behavior, as well as an increase in its adversarial robustness. We further assessed the limitations of this approach and find that the improvements in behavioral alignment and adversarial robustness generalize across different image statistics, but not to object categories outside of those covered in our IT training set. Taken together, our results demonstrate that building models that are more aligned with the primate brain leads to more robust and human-like behavior, and call for larger neural data-sets to further augment these gains.

Aligning Model and Macaque Inferior Temporal Cortex Representations Improves Model-to-Human Behavioral Alignment and Adversarial Robustness

Adversarially trained neural representations are already as robust as biological neural representations

Adversarial examples are often cited by neuroscientists and machine learning researchers as an example of how computational models diverge from biological sensory systems. Recent work has proposed adding biologically-inspired components to visual neural networks as a way to improve their adversarial robustness. One surprisingly effective component for reducing adversarial vulnerability is response stochasticity, like that exhibited by biological neurons. Here, using recently developed geometrical techniques from computational neuroscience, we investigate how adversarial perturbations influence the internal representations of standard, adversarially trained, and biologically-inspired stochastic networks. We find distinct geometric signatures for each type of network, revealing different mechanisms for achieving robust representations. Next, we generalize these results to the auditory domain, showing that neural stochasticity also makes auditory models more robust to adversarial perturbations. Geometric analysis of the stochastic networks reveals overlap between representations of clean and adversarially perturbed stimuli, and quantitatively demonstrates that competing geometric effects of stochasticity mediate a tradeoff between adversarial and clean performance. Our results shed light on the strategies of robust perception utilized by adversarially trained and stochastic networks, and help explain how stochasticity may be beneficial to machine and biological computation.1

Neural Population Geometry Reveals the Role of Stochasticity in Robust Perception

While some convolutional neural networks (CNNs) have surpassed human visual abilities in object classiﬁcation, they often struggle to recognize objects in images corrupted with different types of common noise patterns, highlighting a major limitation of this family of models. Recently, it has been shown that simulating a primary visual cortex (V1) at the front of CNNs leads to small improvements in robustness to these image perturbations. In this study, we start with the observation that different variants of the V1 model show gains for speciﬁc corruption types. We then build a new model using an ensembling technique, which combines multiple individual models with different V1 front-end variants. The model ensemble lever-ages the strengths of each individual model, leading to signiﬁcant improvements in robustness across all corruption categories and outperforming the base model by 38% on average. Finally, we show that using distillation it is possible to partially compress the knowledge in the ensemble model into a single model with a V1 front-end. While the ensembling and distillation techniques used here are hardly biologically-plausible, the results presented here demonstrate that by combining the speciﬁc strengths of different neuronal circuits in V1 it is possible to improve the robustness of CNNs for a wide range of perturbations.

Combining Different V1 Brain Model Variants to Improve Robustness to Image Corruptions in CNNs

Current state-of-the-art object recognition models are largely based on convolutional neural network (CNN) architectures, which are loosely inspired by the primate visual system. However, these CNNs can be fooled by imperceptibly small, explicitly crafted perturbations, and struggle to recognize objects in corrupted images that are easily recognized by humans. Here, by making comparisons with primate neural data, we first observed that CNN models with a neural hidden layer that better matches primate primary visual cortex (V1) are also more robust to adversarial attacks. Inspired by this observation, we developed VOneNets, a new class of hybrid CNN vision models. Each VOneNet contains a fixed weight neural network front-end that simulates primate V1, called the VOneBlock, followed by a neural network back-end adapted from current CNN vision models. The VOneBlock is based on a classical neuroscientific model of V1: the linear-nonlinear-Poisson model, consisting of a biologically-constrained Gabor filter bank, simple and complex cell nonlinearities, and a V1 neuronal stochasticity generator. After training, VOneNets retain high ImageNet performance, but each is substantially more robust, outperforming the base CNNs and state-of-the-art methods by 18% and 3%, respectively, on a conglomerate benchmark of perturbations comprised of white box adversarial attacks and common image corruptions. Finally, we show that all components of the VOneBlock work in synergy to improve robustness. While current CNN architectures are arguably brain-inspired, the results presented here demonstrate that more precisely mimicking just one stage of the primate visual system leads to new gains in ImageNet-level computer vision applications.

Simulating a Primary Visual Cortex at the Front of CNNs Improves Robustness to Image Perturbations

Visual signals influence the brain’s computation of spatial position and orientation. Accordingly, the primary visual cortex (V1) is extensively interconnected with areas involved in computing head direction (HD) information. Predictive coding theories posit that higher cortical areas send sensory or motor predictions to lower areas, but whether this includes cognitive variables like the HD signal—and whether HD information is present in V1—is unknown. Here we show that V1 encodes the yaw, roll, and pitch of the head in freely behaving rats, either in the presence or absence of visual cues. HD tuning was modulated by lighting and movement state, but was stable on a population level for over a week. These results demonstrate the presence of a critical spatial orientation signal in a primary cortical sensory area and support predictive coding theories of brain function.

The practical successes of deep neural networks have not been matched by theoretical progress that satisfyingly explains their behavior. In this work, we study the information bottleneck (IB) theory of deep learning, which makes three specific claims: first, that deep networks undergo two distinct phases consisting of an initial fitting phase and a subsequent compression phase; second, that the compression phase is causally related to the excellent generalization performance of deep networks; and third, that the compression phase occurs due to the diffusion-like behavior of stochastic gradient descent. Here we show that none of these claims hold true in the general case, and instead reflect assumptions made to compute a finite mutual information metric in deterministic networks. When computed using simple binning, we demonstrate through a combination of analytical results and simulation that the information plane trajectory observed in prior work is predominantly a function of the neural nonlinearity employed: double-sided saturating nonlinearities like yield a compression phase as neural activations enter the saturation regime, but linear activation functions and single-sided saturating nonlinearities like the widely used ReLU in fact do not. Moreover, we find that there is no evident causal connection between compression and generalization: networks that do not compress are still capable of generalization, and vice versa. Next, we show that the compression phase, when it exists, does not arise from stochasticity in training by demonstrating that we can replicate the IB findings using full batch gradient descent rather than stochastic gradient descent. Finally, we show that when an input domain consists of a subset of task-relevant and task-irrelevant information, hidden representations do compress the task-irrelevant information, although the overall information about the input may monotonically increase with training time, and that this compression happens concurrently with the fitting process rather than during a subsequent compression period.

Abstract. We introduce the design and theoretical analysis of a fiber-optic architecture for neural recording without contrast agents, which transduces neural electrical signals into a multiplexed optical readout. Our sensor design is inspired by electro-optic modulators, which modulate the refractive index of a waveguide by applying a voltage across an electro-optic core material. We estimate that this design would allow recording of the activities of individual neurons located at points along a 10-cm length of optical fiber with 40-μm axial resolution and sensitivity down to 100  μV using commercially available optical reflectometers as readout devices. Neural recording sites detect a potential difference against a reference and apply this potential to a capacitor. The waveguide serves as one of the plates of the capacitor, so charge accumulation across the capacitor results in an optical effect. A key concept of the design is that the sensitivity can be improved by increasing the capacitance. To maximize the capacitance, we utilize a microscopic layer of material with high relative permittivity. If suitable materials can be found—possessing high capacitance per unit area as well as favorable properties with respect to toxicity, optical attenuation, ohmic junctions, and surface capacitance—then such sensing fibers could, in principle, be scaled down to few-micron cross-sections for minimally invasive neural interfacing. We study these material requirements and propose potential material choices. Custom-designed multimaterial optical fibers, probed using a reflectometric readout, may, therefore, provide a powerful platform for neural sensing.

Multiplexed neural recording along a single optical fiber via optical reflectometry

Patterned illumination using a digital micromirror device (DMD) is a powerful tool for optogenetics. Compared to a scanning laser, DMDs are inexpensive and can easily create complex illumination patterns. Combining these complex spatiotemporal illumination patterns with optogenetics allows DMD-equipped microscopes to probe neural circuits by selectively manipulating the activity of many individual cells or many subcellular regions at the same time. To use DMDs to study neural activity, scientists must develop specialized software to coordinate optical stimulation patterns with the acquisition of electrophysiological and fluorescence data. To meet this growing need we have developed an open source optical pattern generation software for neuroscience—NeuroPG—that combines, DMD control, sample visualization, and data acquisition in one application. Built on a MATLAB platform, NeuroPG can also process, analyze, and visualize data. The software is designed specifically for the Mightex Polygon400; however, as an open source package, NeuroPG can be modified to incorporate any data acquisition, imaging, or illumination equipment that is compatible with MATLAB’s Data Acquisition and Image Acquisition toolboxes.

NeuroPG: open source software for optical pattern generation and data acquisition

A brain–computer interface (BCI) allows users to control external devices through brain activity. Portable neuroimaging techniques, such as near-infrared (NIR) imaging, are suitable for this goal. NIR imaging has been used to measure rapid changes in brain optical properties associated with neuronal activation, namely fast optical signals (FOS) with good spatiotemporal resolution. However, FOS have a low signal-to-noise ratio, limiting their BCI application. Here FOS were acquired with a frequency-domain optical system from the visual cortex during visual stimulation consisting of a rotating checkerboard wedge, flickering at 5 Hz. We used measures of photon count (Direct Current, DC light intensity) and time of flight (phase) at two NIR wavelengths (690 nm and 830 nm) combined with a machine learning approach for fast estimation of visual-field quadrant stimulation. The input features of a cross-validated support vector machine classifier were computed as the average modulus of the wavelet coherence between each channel and the average response among all channels in 512 ms time windows. An above chance performance was obtained when differentiating visual stimulation quadrants (left vs. right or top vs. bottom) with the best classification accuracy of ~63% (information transfer rate of ~6 bits/min) when classifying the superior and inferior stimulation quadrants using DC at 830 nm. The method is the first attempt to provide generalizable retinotopy classification relying on FOS, paving the way for the use of FOS in real-time BCI.

Fast Optical Signals for Real-Time Retinotopy and Brain Computer Interface

Numerous existing full-spectrum cannabis extract products have been used in clinical trials for the treatment of various diseases. Despite their efficacy, the clinical use of some of these full-spectrum cannabis extracts is limited by behavioral side effects such as cognitive dysfunction and impaired motor skills. To better understand what constitutes cannabis-induced behavioral effects, our objective was to identify a novel panel of blood-based metabolites that are predictive, diagnostic, and/or prognostic of behavioral effects. At 8 weeks of age, male rats were randomly assigned to groups and were gavage fed with full-spectrum cannabis extract (tetrahydrocannabinol/cannabidiol (THC/CBD) along with all other cannabis compounds, 15 mg/kg), broad-spectrum cannabis extract (CBD along with all other cannabis compounds, 15 mg/kg), or vehicle oil. Four hours after being gavage fed, behavioral assessments were determined using the open field test and the elevated plus maze. Following these assessments, serum was collected from all rats and the serum metabolites were identified and quantified by LC–MS/MS and 1H NMR spectroscopy. We found that only rats treated with full-spectrum cannabis extract exhibited behavioral changes. Compared to vehicle-treated and broad-spectrum extract–treated rats, full-spectrum extract–treated rats demonstrated higher serum concentrations of the amino acid phenylalanine and long-chain acylcarnitines, as well as lower serum concentrations of butyric acid and lysophosphatidylcholines. This unique metabolomic fingerprint in response to cannabis extract administration is linked to behavioral effects and may represent a biomarker profile of cannabis-induced behavioral changes. If validated, this work may allow a metabolomics-based decision tree that would aid in the rapid diagnosis of cannabis-induced behavioral changes including cognitive impairment.

Metabolomic Fingerprint of Behavioral Changes in Response to Full-Spectrum Cannabis Extracts

Accurate and timely prehospital stroke diagnosis and detection of large vessel occlusion (LVO) are essential to ensure stroke patients are transported to hospitals that offer emergent reperfusion therapies. However, symptom based prehospital stroke scales often fail to identify LVO. Thus, a need exists for cost-effective and portable diagnostic tools, such as portable electroencephalography (EEG) to improve the accuracy of prehospital stroke diagnosis.
 Hypotheses: 1) Quantitative EEG measures will differ between LVO and non-LVO stroke patients, particularly in regards to brain slowing (ratio of low to high frequency oscillatory brain power) and brain asymmetry (ratio between oscillations in the affected and unaffected hemisphere) 2) Combining EEG with prehospital stroke scales will improve the accuracy of LVO detection.
 We enrolled patients with acute suspected stroke on presentation to an emergency department at a comprehensive stroke centre. Patients were rapidly evaluated with the Los Angeles Motor Scale followed by a 3-minute resting-state EEG recording using a modified Muse EEG headband (InteraXon). The LVO diagnosis and the extent of cerebral blood flow abnormalities were determined from CT angiography and CT perfusion imaging performed in close temporal proximity to the EEG recording.
 The study enrolled 74 patients (n= 8 LVO, n=66 non-LVO, including stroke mimics). Initial analysis suggests that LVO patients have trends towards brain slowing, as measured by the delta alpha ratio (LVO: mean = 1.21, SEM = 0.03; non-LVO: mean = 1.19, SEM = 0.01; p-value = 0.34). Additionally, LVO patients showed a trend towards increased brain asymmetry from 6-8 Hz, suggesting physiological differences between hemispheres specific to the theta frequency (LVO: mean = 0.02, SEM = 0.006; non-LVO: mean = 0.01, SEM = 0.002; p-value = 0.13). Quantitative measures will be assessed using classification trees to determine which combination of EEG and clinical features is most predictive of LVO.
 In conclusion, acute differences in brain activity between LVO and non-LVO patients can be detected with portable EEG, which when combined with clinical stroke scales, have the potential to improve the diagnosis and triage of suspected stroke patients in a prehospital setting.

Abstract TP56: Low Cost, Portable Electroencephalograph May Improve The Accuracy Of Prehospital Stroke Diagnosis And Detection Of Large Vessel Occlusion

In this study, we used an oddball EEG bicycle paradigm to study how changes in urban environments elicit changes in EEG markers. Participants completed an auditory oddball task while riding in three different cycling lane environments. A low traffic condition where participants rode in a fully separated bike lane alongside a quiet residential street, an intermediate traffic condition where participants rode alongside a busy residential street in a painted lane, and a heavy traffic condition where participants rode alongside fast/heavy traffic on a shared-use path. Relative to the low traffic, heavy traffic was associated with faster reaction time and a trend towards reduced accuracy, and increased N1 amplitude evoked by the standard tones. We attribute this difference in N1 amplitude to different attentional demands evoked by the different traffic conditions. In this fashion, heavy traffic requires greater auditory filtering. Furthermore, we found no differences in P3 amplitude associated with the traffic conditions. We discuss the implications of mobile paradigms to study attention in real-world settings.

Surrounding Traffic Matters: Increases in Traffic Volume Are Related to Changes in EEG Rhythms in Urban Cyclists

Some evidence suggests that alpha activity is directly related to the baseline firing rate of sensory neurons which alters the probability of responding to a stimulus. Other evidence points to alpha indirectly modulating cortical excitability through its interactions with gamma oscillations. A third possibility is that alpha-based functional connectivity better explains attentional modulation and perceptual responses. To test this, alpha amplitude, CFC, and functional connectivity measures were extracted from EEG data recorded while participants performed a cued orientation perception task. Using pre-target data, the spatiotemporal activity of each metric was submitted to a SVM classifier to determine which activity pattern best distinguished trials with covert attention from trials without. The same metrics were submitted to SVR to find the activity that best predicted task performance. Results indicate the best metric for classifying trials with and without covert attention was alpha amplitude. This indicates that, prior to target onset, alpha amplitude alone is most sensitive to the presence of covert attention. In contrast, none of the metrics were strong predictors of task performance. Overall, our results support the idea that alpha activity is directly related to changes in the baseline firing rate of sensory neurons which changes responsiveness but not performance.

Connecting Covert Attention and Visual Perception to the Spatiotemporal Dynamics of Alpha Band Activity, Cross-Frequency Coupling (CFC), and Functional Connectivity using Multivariate Pattern Analysis (MVPA)

Since its beginnings in the early 20th century, the psychophysiological study of human brain function has included research into the spectral properties of electrical and magnetic brain signals. Now, dramatic advances in digital signal processing, biophysics, and computer science have enabled increasingly sophisticated methodology for neural time series analysis. Innovations in hardware and recording techniques have further expanded the range of tools available to researchers interested in measuring, quantifying, modeling, and altering the spectral properties of neural time series. These tools are increasingly used in the field, by a growing number of researchers who vary in their training, background, and research interests. Implementation and reporting standards also vary greatly in the published literature, causing challenges for authors, readers, reviewers, and editors alike. The present report addresses this issue by providing recommendations for the use of these methods, with a focus on foundational aspects of frequency domain and time-frequency analyses. It also provides publication guidelines, which aim to (1) foster replication and scientific rigor, (2) assist new researchers who wish to enter the field of brain oscillations, and (3) facilitate communication among authors, reviewers, and editors.

Recommendations and publication guidelines for studies using frequency domain and time-frequency domain analyses of neural time series.

Detection of visual stimuli fluctuates over time, and these fluctuations have been shown to correlate with time-domain evoked activity and frequency-domain periodic activity. However, it is unclear if these fluctuations are related to a change in guess rate, perceptual quality, or both. Here we determined whether the quality of perception randomly varies across trials or is fixed so that the variability is the same. Then we estimated how perceptual quality and guess rate on an orientation perception task relates to EEG activity. Response errors were fitted to variable precision models and the standard mixture model to determine whether perceptual quality is from a varying or fixed distribution. Overall, the best fit was the standard mixture model that assumes response variability can be defined by a fixed distribution. The power and phase of 2-7 Hz post-target activities were found to vary along with task performance in that more accurate trials had greater power, and the preferred phase differed significantly between accurate and guess trials. Guess rate and σ were significantly lower on trials with high 2-3 Hz power than low and the difference started around 250 ms post-target. These effects coincide with changes in the P3 ERP: there was a more positive deflection in the accurate trials vs guesses. These results suggest that the spread of errors (perceptual quality) can be characterized by a fixed range of values. Where the errors fall within that range is modulated by the post-target power in the lower frequency bands and their analogous ERPs.

To See, Not to See, or to See Poorly: Perceptual Quality and Guess Rate as a Function of Electroencephalography (EEG) Brain Activity in an Orientation Perception Task

Recent advancements in portable computer devices have opened new avenues in the study of human cognition outside research laboratories. This flexibility in methodology has led to the publication of several Electroencephalography (EEG) studies recording brain responses in real world scenarios such as cycling and walking outside. In the present study, we tested the classic auditory oddball task while participants moved around a running track using an electric skateboard. This novel approach allows for the study of attention in motion while virtually removing body movement. Using the skateboard auditory oddball paradigm, we found reliable and expected standard-target differences in the P3 and MMN/N2b event-related potentials (ERPs). We also recorded baseline EEG activity and found that, compared to this baseline, alpha power is attenuated in frontal and parietal regions during skateboarding. We also tested for the effect of stance preference to understand how changes in task difficulty modulate the P3 and alpha magnitude but found no differences in either.

EEG in Motion: Using an Oddball Task to Explore Motor Interference in Active Skateboarding

13 Detection of visual stimuli fluctuates over time, and these fluctuations have been shown 14 to correlate with time-domain evoked activity and frequency-domain periodic activity. However, 15 it is unclear if these fluctuations are related to a change in guess rate, perceptual quality, or both. 16 Here we determined whether the quality of perception randomly varies across trials or is fixed so 17 that the variability is the same. Then we estimated how perceptual quality and guess rate on an 18 orientation perception task relates to EEG activity. Response errors were fitted to variable 19 precision models and the standard mixture model to determine whether perceptual quality is 20 from a varying or fixed distribution. Overall, the best fit was the standard mixture model that 21 assumes response variability can be defined by a fixed distribution. 22 The power and phase of 2-7 Hz post-target activities were found to vary along with task 23 performance in that more accurate trials had greater power, and the preferred phase differed 24 significantly between accurate and guess trials. Guess rate and σ were significantly lower on 25 trials with high 2-3 Hz power than low and the difference started around 250 ms post-target. 26 These effects coincide with changes in the P3 ERP: there was a more positive deflection in the 27 accurate trials vs guesses. These results suggest that the spread of errors (perceptual quality) can 28 be characterized by a fixed range of values. Where the errors fall within that range is modulated 29 by the post-target power in the lower frequency bands and their analogous ERPs. 30

The time-course of moral perception: An ERP investigation of the moral pop-out effect Ana Gantman1, Sayeed Devraj-Kizuk2, Peter Mende-Siedlecki3, Jay J. Van Bavel4, Kyle E. Mathewson2,5 1Department of Psychology, Brooklyn College (CUNY) 2Neuroscience and Mental Health Institute, University of Alberta 3 Department of Psychological and Brain Sciences, University of Delaware 4Department of Psychology, New York University 5Department of Psychology, University of Alberta

The time-course of moral perception: An ERP investigation of the moral pop-out effect

Abstract Humans are highly attuned to perceptual cues about their values. A growing body of evidence suggests that people selectively attend to moral stimuli. However, it is unknown whether morality is prioritized early in perception or much later in cognitive processing. We use a combination of behavioral methods and electroencephalography to investigate how early in perception moral words are prioritized relative to non-moral words. The behavioral data replicate previous research indicating that people are more likely to correctly identify moral than non-moral words in a modified lexical decision task. The electroencephalography data reveal that words are distinguished from non-words as early as 200 ms after onset over frontal brain areas and moral words are distinguished from non-moral words 100 ms later over left-posterior cortex. Further analyses reveal that differences in brain activity to moral vs non-moral words cannot be explained by differences in arousal associated with the words. These results suggest that moral content might be prioritized in conscious awareness after an initial perceptual encoding but before subsequent memory processing or action preparation. This work offers a more precise theoretical framework for understanding how morality impacts vision and behavior.

The time course of moral perception: an ERP investigation of the moral pop-out effect

Objective In this pilot study, we investigated using portable electroencephalography (EEG) as a potential prehospital stroke diagnostic method. Methods We used a portable EEG system to record data from 25 participants, 16 had acute ischemic stroke events, and compared the results of age-matched controls that included stroke mimics. Delta/alpha ratio (DAR), (delta+theta)/(alpha+beta) ratio (DBATR) and pairwise-derived Brain Symmetry Index (pdBSI) were investigated, as well as accelerometer and gyroscope trends. We then made classification trees using TreeBagger to distinguish between different subgroups. Results DAR and DBATR showed an increase in ischemic stroke patients that correlates with stroke severity (p<0.01). pdBSI decreased in low frequencies and increased in high frequencies in patients who had a stroke (p<0.05). All quantitative EEG measures were significant between stroke patients and controls. Using classification trees, we were able to distinguish between subgroups of stroke patients and controls. Conclusions There are significant differences in DAR, DBATR, and pdBSI between patients with ischemic stroke when compared to controls; results relate to severity. Significance With significant differences between patients with strokes and controls, we have shown the feasibility and utility for the Muse EEG system to aid in patient triage and diagnosis as an early detection tool.

Application of the Muse portable EEG system to aid in rapid diagnosis of stroke

A ride in the park: Cycling in different outdoor environments modulates the auditory evoked potentials.

Recent advancements in portable technology have opened new avenues in the study of human cognition outside research laboratories. This flexibility in methodology has led to the publication of several Electroencephalography (EEG) studies recording brain responses in real world scenarios such as cycling and walking outside. In the present study, we wanted to test the classic oddball task event related potentials (ERPs) while participants moved around a running track using an electric skateboard. This novel approach allows for the study of attention in motion while virtually removing body movement. Using the auditory oddball paradigm, we were able to measure the P3 and MMN-N2b components elicited by this task. We also found that compared to resting state, alpha power is attenuated in frontal and parietal regions during skateboarding. We also tested for the effect of stance preference in terms of P3 and alpha magnitude and found no differences in for either of these. By replicating the findings of the classic oddball task under such a novel environment this study extends our knowledge of brain function in highly ecologically valid scenarios.

Attention in Motion: Using an Oddball Task to Record Brain Activity in Skateboarders

Predicting stroke severity with a 3-min recording from the Muse portable EEG system for rapid diagnosis of stroke

While compelling evidence indicates that poorer aerobic fitness relates to impairments in retrieving information from hippocampal-dependent memory, there is a paucity of research on how aerobic fitness relates to the acquisition of such relational information. Accordingly, the present investigation examined the association between aerobic fitness and the rate of encoding spatial relational memory-assessed using a maximal oxygen consumption test and a spatial configuration task-in a sample of 152 college-aged adults. The findings from this investigation revealed no association between aerobic fitness and the acquisition of spatial relational memory. These findings have implications for how aerobic fitness is characterized with regard to memory, such that aerobic fitness does not appear to relate to the rate of learning spatial-relational information; however, given previously reported evidence, aerobic fitness may be associated with a greater ability to recall relational information from memory.

Aerobic Fitness Unrelated to Acquisition of Spatial Relational Memory in College-Aged Adults.

Humans are highly attuned to perceptual cues about their values. A growing body of evidence suggests that people selectively attend to moral stimuli. However, it is unknown whether morality is prioritized early in perception or much later in cognitive processing. We use a combination of behavioral methods and electroencephalography to investigate how early in perception moral words are prioritized relative to non-moral words. The behavioral data replicate previous research indicating that people are more likely to correctly identify moral than non-moral words in a modified lexical decision task. The electroencephalography data reveal that words are distinguished from non-words as early as 200 milliseconds after onset over frontal brain areas, and moral words are distinguished from non-moral words 100 milliseconds later over left-posterior cortex. Further analyses reveal that differences in brain activity to moral vs. non-moral words cannot be explained by differences in arousal associated with the words. These results suggest that moral content might be prioritized in conscious awareness after an initial perceptual encoding but before subsequent memory processing or action preparation. This work offers a more precise theoretical framework for understanding how morality impacts vision and behavior.

The time-course of moral perception: An electroencephalography investigation

Publisher Correction: Large-area MRI-compatible epidermal electronic interfaces for prosthetic control and cognitive monitoring

We propose the use of SSVEP (Steady State Visual Evoked Potentials) in such a way as to cause the eye itself to function as a camera. By recording brainwaves in response to flickering visual stimuli, we read the “mind’s eye” and are able to successfully reconstruct a visual image of subject matter that a person is looking at. In addition to causing the eye itself to function as a camera (see Fig 1), we also propose a new way to visualize and photograph human vision and human perception, i.e. a new way to see and understand human vision. This new “meta-vision” (vision of vision) has many applications in healthcare, from testing human vision to furthering our understanding of the brain.

2019 IEEE International Conference on E-health Networking, Application & Services (HealthCom)

Mobile EEG allows the investigation of brain activity outside of the lab and in increasingly complex environments. In this study, EEG equipment was adapted for use and transportation in a backpack while cycling. Participants performed an auditory oddball task while cycling outside either in a quiet park or near a noisy roadway. In both conditions, we were able to accurately measure reliable event related potentials (ERP). The P2 and P3 were similar in topography, and morphology, with no differences in amplitude between conditions. When biking near the roadway, an increased N1 amplitude was observed when evoked by both standards and targets compared with biking in the quiet park. This may be due to attentional processes filtering the overlapping sounds between the tones used and similar environmental frequencies. No behavioural differences were found. This study established methods for mobile recording of ERP signals. Future directions include investigating auditory ERPs in more realistic studies outside of laboratory.

A ride in the park: Cycling in different outdoor environments modulates the auditory evoked potentials

Effects of random fluctuations in alpha oscillations on orientation detection: an EEG study

Large-area MRI-compatible epidermal electronic interfaces for prosthetic control and cognitive monitoring

Recreational use of concentrated oxygen has increased. Claims have been made that hyperoxic breathing can help reduce fatigue, increase alertness, and improve attentional capacities; however, few systematic studies of these potential benefits exist. Here, we examined the effects of short-term (15 min) hyperoxia on resting states in awake human subjects by measuring spontaneous EEG activity between normoxic and hyperoxic situations, using a within-subject design for both eyes-opened and eyes-closed conditions. We also measured respiration rate, heart rate, and blood oxygen saturation levels to correlate basic physiological changes due to the hyperoxic challenge with any brain activity changes. Our results show that breathing short-term 100% oxygen led to increased blood oxygen saturation levels, decreased heart rate, and a slight, but nonsignificant, decrease in breathing rate. Changes of brain activity were apparent, including decreases in low-alpha (7-10 Hz), high-alpha (10-14 Hz), beta (14-30 Hz), and gamma (30-50 Hz) frequency ranges during eyes-opened hyperoxic conditions. During eyes-closed hyperoxia, increases in the delta (0.5-3.5 Hz) and theta (3.5-7 Hz) frequency range were apparent together with decreases in the beta range. Hyperoxia appeared to accentuate the decrease of low alpha and gamma ranges across the eyes-opened and eyes-closed conditions, suggesting that it modulated brain state itself. As decreased alpha during eyes-opened conditions has been associated with increased attentional processing and selective attention, and increased delta and theta during eyes-closed condition are typically associated with the initiation of sleep, our results suggest a state-specific and perhaps opposing influence of short-term hyperoxia.

Electrophysiological correlates of hyperoxia during resting-state EEG in awake human subjects.

Magicians can often hide their method for a trick in plain sight by effecting a phenomenon known as change blindness. The purpose of this study was to find the reason for why an individual is induced with change blindness. Alpha oscillations are known to impair detection of visual stimuli, but it is unclear if this is due to increased guess rate or decreased fidelity of the mental representation. Here we estimated fidelity and guess rate as a function of pre-stimulus alpha oscillations using a change blindness task. In this study, each trial began with an array of 6 Gabor patches with a fixated dot that subjects were instructed to keep their eyes on. As the array traveled to the center of the screen, it either changed direction vertically at 90 degrees or continued horizontally. When the array switched direction, one of the Gabor patches rotated 30 degrees simultaneously. Subjects were then asked to identify which patch rotated. EEG (electroencephalography) data was simultaneously recorded with eye-tracking as subjects performed the task. Twenty-eight participants performed this task, which included six blocks of forty-eight trials. There were two different types of trials: flexion, in which the array changed direction, and control, in which the array did not change direction. Reaction time tended to be slower in flexion trials, and we found that the change in direction affected the subject’s ability to see the Gabor patch rotation. Based on the event-related potential results, which are an average of EEG signals aligned to the start of a trial, we could see that the P300 differed between correct flexion, incorrect flexion, and control trials. The P300 can be interpreted as a marker of consciousness. This difference demonstrates that the subject’s attention is automatically drawn to a larger change in stimuli.

Blinded by magic: Electrophysiological correlates of change blindness

Electroencephalography (EEG) research is typically conducted in controlled laboratory settings. This limits the generalizability to real-world situations. Virtual reality (VR) sits as a transitional tool that provides tight experimental control with more realistic stimuli. To test the validity of using VR for event-related potential (ERP) research, we used a well-established paradigm, the oddball task. Standard stimuli were presented 80% of the time and target stimuli which were responded to, 20% of the time. For our first study, we compared traditional to VR stimulus presentation using standard visual and auditory oddball tasks. We found that ERPs collected using VR head mounted displays and typical monitors were comparable on measures of latency, amplitude, and spectral composition. In a second study, we implemented a novel depth-based oddball task. We demonstrated that typical oddball ERPs elicited by the presentation of near and far stimuli. Interestingly, we observed significant differences in early ERPs components between near and far stimuli, even after controlling for the effects of the oddball task. Current results suggest that VR can serve as a valid means of stimulus presentation in novel or otherwise inaccessible environments for EEG experimentation. We demonstrated the capability of the depth-based oddball to reliably elicit P3 responses. We also found an interaction between the depth at which objects are presented and early ERP responses. Further research is warranted to better explain this influence of depth on the ERP components.

Real brains in virtual worlds: Validating a novel oddball paradigm in virtual reality

Most experiments using EEG recordings take place in highly isolated and restricted environments, limiting their applicability to real-life scenarios. New technologies for mobile EEG are changing this by allowing EEG recording to take place outside of the laboratory. However, before results from experiments performed outside the laboratory can be fully understood, the effects of ecological stimuli on brain activity during cognitive tasks must be examined. In this experiment, participants performed an auditory oddball task while also listening to concurrent background noises of silence, white noise, and outdoor ecological sounds, as well as a condition in which the tones themselves were at a low volume. We found a significantly increased N1 and decreased P2 when participants performed the task with outdoor sounds and white noise in the background, with the largest differences in the outdoor sound condition. This modulation in the N1 and P2 replicates what we have previously found outside while people rode bicycles. No behavioral differences were found in response to the target tones. We interpret these modulations in early ERPs as indicative of sensory filtering of background sounds and that ecologically valid sounds require more filtering than simple synthetic sounds. Our results reveal that much of what we understand about the brain will need to be updated as cognitive neuroscience research begins to step outside of the lab.

The ecological cocktail party: Measuring brain activity during an auditory oddball task with background noise.

Most experiments using EEG recordings take place in highly isolated and restricted environments, limiting their applicability to real-life scenarios. New technologies for mobile EEG are changing this by allowing EEG recording to take place outside of the laboratory. However, before results from experiments performed outside the laboratory can be fully understood, the effects of ecological stimuli on brain activity during cognitive tasks must be examined. In this experiment, participants performed an auditory oddball task while also listening to concurrent background noises of silence, white noise and outdoor ecological sounds, as well as a condition in which the tones themselves were at a low volume. We found a significantly increased N1 and decreased P2 when participants performed the task with outdoor sounds and white noise in the background, with the largest differences in the outdoor sound condition. This modulation in the N1 and P2 replicates what we have previously found outside while people ride bicycles (Scanlon et al., 2017). No behavioural differences were found in response to the target tones. We interpret these modulations in early ERPs as indicative of sensory filtering of background sounds, and that ecologically valid sounds require more filtering than synthetic sounds. Our results reveal that much of what we understand about the brain will need to be updated as we step outside the lab.

The ecological cocktail party: Measuring brain activity during an auditory oddball task with background noise

Many individuals cannot at first see two ambiguous figures as different interpretations simultaneously, even with effort. Here in a large sample replication, we find that the phrase “duck eats rabbit” allows those who could not see a duck and rabbit side by side to do so. In a second experiment, we show that a relational phrase “next to” that does not disambiguate the spatial position interpretation does not similarly allow the duck to be seen next to the rabbit, supporting the proposal that top-down semantic-framing can influence perception of ambiguous figures.

Duck Eats Rabbit: Exactly Which Type of Relational Phrase Can Disambiguate the Perception of Identical Side by Side Ambiguous Figures?

Erratum: “Power and Phase of Alpha Oscillations Reveal an Interaction between Spatial and Temporal Visual Attention by Sayeed A. D. Kizuk and Kyle E. Mathewson” in 30:7

Heart rate, measured in beats per minute, can be used as an index of an individual's physiological state. Each time the heart beats, blood is expelled and travels through the body. This blood flow can be detected in the face using a standard webcam that is able to pick up subtle changes in color that cannot be seen by the naked eye. Due to the light absorption spectrum of blood, we are able to detect differences in the amount of light absorbed by the blood traveling just below the skin (i.e., photoplethysmography). By modulating emotional and physiological stress-that is, viewing arousing images and sitting versus standing, respectively-to elicit changes in heart rate, we explored the feasibility of using a webcam as a psychophysiological measurement of autonomic activity. We found a high level of agreement between established physiological measures, electrocardiogram, and blood pulse oximetry, and heart rate estimates obtained from the webcam. We thus suggest webcams can be used as a noninvasive and readily available method for measuring psychophysiological changes, easily integrated into existing stimulus presentation software and hardware setups.

Noncontact measurement of emotional and physiological changes in heart rate from a webcam.

Entrainment of theta, not alpha, oscillations is predictive of the brightness enhancement of a flickering stimulus

Wearable healthcare systems require skin‐adhering electrodes that allow maximal comfort for patients as well as an electronics system to enable signal processing and transmittance. Textile‐based electronics, known as “e‐textiles,” is a platform technology that allows comfort for patients. Here, two‐layered e‐textile patches are designed by controlled permeation of Ag‐particle/fluoropolymer composite ink into a porous textile. The permeated ink forms a cladding onto the nanofibers in the textile substrate, which is beneficial for mechanical and electrical properties of the e‐textile. The printed e‐textile features conductivity of ≈3200 S cm−1, whereas 1000 cycles of 30% uniaxial stretching causes the resistance to increase only by a factor of ≈5, which is acceptable in many applications. Controlling over the penetration depth enables a two‐layer design of the e‐textile, where the sensing electrodes and the conducting traces are printed in the opposite sides of the substrate. The formation of vertical interconnected access is remarkably simple as an injection from a syringe. With the custom‐developed electronic circuits, a surface electromyography system with wireless data transmission is demonstrated. Furthermore, the dry e‐textile patch collects electroencephalography with comparable signal quality to commercial gel electrodes. It is anticipated that the two‐layered e‐textiles will be effective in healthcare and sports applications.

Two‐Layered and Stretchable e‐Textile Patches for Wearable Healthcare Electronics

Recreational use of concentrated oxygen has increased over the past decade. Claims have been made that hyperoxic breathing can reduce fatigue, increase alertness, and improve attentional capacities; however, few systematic studies of these potential benefits exist. Here we examined the effects of short-term (15 minutes) hyperoxia on resting-states in awake human subjects by measuring spontaneous EEG activity between normoxic and hyperoxic situations, using a within-subjects design for both eyes-opened and eyes-closed conditions. We also measured respiration rate, heart rate, and blood oxygen saturation levels to correlate basic physiological changes due to the hyperoxic challenge with any brain activity changes. Breathing short term 100% oxygen led to expected physiological changes including increased blood-oxygen saturation levels, decreased heart rate, and a slight, non-significant, decrease in breathing rate. Changes of brain activity were apparent, including decreases in low-alpha (7-10 Hz), high-alpha (10-14 Hz), beta (14 – 30 Hz), and gamma (30 – 50 Hz) frequency ranges during eyes-opened hyperoxic conditions. During eyes-closed hyperoxia, increases in the delta (0.5 – 3.5 Hz) and theta (3.5-7 Hz) frequency range were apparent together with decreases in the beta range. Hyperoxia appeared to accentuate the decrease of low alpha and gamma ranges across the eyes-opened and closed conditions suggesting that it modulated brain state itself. As decreased alpha during eyes-opened conditions has been associated with increased attentional processing and selective attention, and increased delta and theta during eyes-closed condition associated with the initiation of sleep, our results suggest a state-specific and perhaps opposing influence of shortterm hyperoxia.

Electrophysiological correlates of hyperoxia during resting-state EEG in awake human subjects

Background Electroencephalography (EEG) experiments often require several computers to ensure accurate stimulus presentation and data collection. However, this requirement can make it more difficult to perform such experiments in mobile settings within, or outside, the laboratory New Method Computer miniaturisation and increasing processing power allow for EEG experiments to become more portable. Our goal is to show that a Latte Panda, a small Windows 10 computer, can be used to accurately collect EEG data in a similar manner to a laptop. Using a stationary bike, we also demonstrate that the Latte Panda will allow for more portable EEG experiments. Results Significant and reliable MMN and P3 responses, event-related potentials (ERPs) typically associated with auditory oddball tasks, were observed and were consistent when using either the laptop or Latte Panda for EEG data collection. Similar MMN and P3 ERPs were also measured in the sitting and stationary biking conditions while using a Latte Panda for data collection. Comparison with Existing Method Data recorded by the Latte Panda computer produced comparable and equally reliable results to the laptop. As well, similar ERPs during sitting and biking would suggest that EEG experiments can be conducted in more mobile situations despite the increased noise and artefacts associated with muscle movement. Conclusions Our results show that the Latte Panda is a low-cost, more portable alternative to a laptop computer for recording EEG data. Such a device will further allow for more portable and mobile EEG experimentation in a wider variety of environments.

Increasing the mobility of EEG data collection using a Latte Panda computer

Mobile EEG allows the investigation of brain activity in increasingly complex environments. In this study, EEG equipment was adapted for use and transportation in a backpack while cycling. Participants performed an auditory oddball task while cycling outside and sitting in an isolated chamber inside the lab. Cycling increased EEG noise and marginally diminished alpha amplitude. However, this increased noise did not influence the ability to measure reliable event related potentials (ERP). The P3 was similar in topography, and morphology when outside on the bike, with a lower amplitude in the outside cycling condition. There was only a minor decrease in the statistical power to measure reliable ERP effects. Unexpectedly, when biking outside significantly decreased P2 and increased N1 amplitude were observed when evoked by both standards and targets compared with sitting in the lab. This may be due to attentional processes filtering the overlapping sounds between the tones used and similar environmental frequencies. This study established methods for mobile recording of ERP signals. Future directions include investigating auditory P2 filtering inside the laboratory. Highlights A backpack containing all the equipment necessary to record ERP and EEG was worn by participants as they rode a bicycle outside along a street EEG and ERP data from an auditory oddball task is compared with data acquired within subject inside the lab Reliable MMN/N2b and P3 responses were measured during bicycle riding outside equal in magnitude to those obtained inside the lab A surprising decrease in the P2 component of the ERP evoked by targets and standards was observed when doing the task outside on a bicycle, which we attribute to increased auditory filtering

Taking off the training wheels: Measuring auditory P3 during outdoor cycling using an active wet EEG system

Transitioning EEG experiments away from the laboratory using a Raspberry Pi 2

Research on the neural correlates of consciousness (NCC) has implicated an assortment of brain regions, ERP components, and network properties associated with visual awareness. Recently, the P3b ERP component has emerged as a leading NCC candidate. However, typical P3b paradigms depend on the detection of some stimulus change, making it difficult to separate brain processes elicited by the stimulus itself from those associated with updates or changes in visual awareness. Here we used binocular rivalry to ask whether the P3b is associated with changes in awareness even in the absence of changes in the object of awareness. We recorded ERPs during a probe-mediated binocular rivalry paradigm in which brief probes were presented over the image in either the suppressed or dominant eye to determine whether the elicited P3b activity is probe or reversal related. We found that the timing of P3b (but not its amplitude) was closely related to the timing of the report of a perceptual change rather than to the onset of the probe. This is consistent with the proposal that P3b indexes updates in conscious awareness, rather than being related to stimulus processing per se. Conversely, the probe-related P1 amplitude (but not its latency) was associated with reversal latency, suggesting that the degree to which the probe is processed increases the likelihood of a fast perceptual reversal. Finally, the response-locked P3b amplitude (but not its latency) was associated with the duration of an intermediate stage between reversals in which parts of both percepts coexist (piecemeal period). Together, the data suggest that the P3b reflects an update in consciousness and that the intensity of that process (as indexed by P3b amplitude) predicts how immediate that update is.

Regulating the Access to Awareness: Brain Activity Related to Probe-related and Spontaneous Reversals in Binocular Rivalry

The phase of alpha (8-12 Hz) brain oscillations have been associated with moment to moment changes in visual attention and awareness. Previous work has demonstrated that endogenous oscillations and subsequent behavior can be modulated by oscillating transcranial current stimulation (otCS). The purpose of the current study is to establish the efficacy of cathodal otCS for modulation of the ongoing alpha brain oscillations, allowing for modulation of individual’s visual perception. Thirty-six participants performed a target detection with sham and 10-Hz cathodal otCS. Each participant had two practice and two experimental sets composed of three blocks of 128 trials per block. Stimulating electrodes were small square sponges (20 cm2) placed on the participant’s head with the anode electrode at Cz and the cathode electrode at Oz. A 0.5 mA current was applied at the cathode electrode every 100 ms (10 Hz frequency) during the otCS condition. The same current and frequency was applied for the first 10-20 s of the sham condition, after which the current was turned off. Target detection rates were separated into ten 10-ms bins based on the latency between the stimulation/sham pulse and target onset. Target detection rates were then compared between the sham and otCS experimental conditions across the ten bins in order to test for effects of otCS phase on target detection. We found no significant difference in target detection rates between the sham and otCS conditions, and discuss potential reasons for the apparent inability of cathodal otCS to effectively modulate visual perception.

Does 10-Hz Cathodal Oscillating Current of the Parieto-Occipital Lobe Modulate Target Detection?

Increasingly, there is a trend to measure brain activity in more ecologically realistic scenarios. Normally, the confines of the laboratory and sedentary tasks mitigate sources of electrical noise on EEG measurement. Moving EEG outside of the lab requires understanding of the impact of complex movements and activities on traditional EEG and ERP measures. Here, we recorded EEG with active electrodes while participants were either riding or sitting on a stationary bike in an electrical and sound-attenuated chamber in the lab. Participants performed an auditory oddball task, pressing a button when they detected rare target tones in a series of standard frequent tones. We quantified both the levels of spectral, single-trial baseline, and ERP baseline noise, as well as classic MMN/N2b and P3 ERP components measured during both biking and sitting still. We observed slight increases in posterior high frequency noise in the spectra, and increased noise in the baseline period during biking. However, morphologically and topographically similar MMN/N2b and P3 components were measured reliably while both biking and sitting. A quantification of the power to reliably measure ERPs as a function of the number of trials revealed slight increases in the number of trials needed during biking to achieve the same level of power. Taken in sum, our results confirm that classic ERPs can be measured reliably during biking activities in the lab. Future directions will employ these techniques outside the lab in ecologically valid situations.

Your brain on bikes: P3, MMN/N2b, and baseline noise while pedaling a stationary bike.

Reorganization of neural systems mediating peripheral visual selective attention in the deaf: An optical imaging study

Increasingly there is a trend to measure brain activity in more ecologically realistic scenarios. Normally the confines of the laboratory and sedentary tasks mitigate sources of electrical noise on electroencephalography (EEG) measurement. Moving EEG outside of the lab requires understanding of the impact of complex movements and activities on traditional EEG and ERP measures. Here we recorded EEG with active electrodes while participants were either riding or sitting on a stationary bike in an electrical and sound attenuated chamber in the lab. Participants performed an auditory oddball task, pressing a button when they detected rare target tones in a series of standard frequent tones. We quantified both the levels of spectral, single-trial baseline, and ERP baseline noise, as well as classic MMN/N2b and P3 ERP components measured during both biking and sitting still. We observed slight increases in posterior high frequency noise in the spectra, and increased noise in the baseline period during biking. However, morphologically and topographically similar MMN/N2b and P3 components were measured reliably while both biking and sitting. A quantification of the power to reliably measure ERPs as a function of the number of trials revealed slight increases in the number of trials needed during biking to achieve the same level of power. Taken in sum our results confirm that classic ERPs can be measured reliably during biking activities in the lab. Future directions will employ these techniques outside the lab in ecologically valid situations. Page 2 of 42 Psychophysiology

RUNNING HEAD : Cycling and Auditory ERPs Your brain on bikes : P 3 , MMN / N 2 b , and baseline noise while pedalling a stationary bike

Dry electrodes are becoming popular for both lab-based and consumer-level electrophysiological-recording technologies because they better afford the ability to move traditional lab-based research into the real world. It is unclear, however, how dry electrodes compare in data quality to traditional electrodes. The current study compared three EEG electrode types: (a) passive-wet electrodes with no onboard amplification, (b) actively amplified, wet electrodes with moderate impedance levels, and low impedance levels, and (c) active-dry electrodes with very high impedance. Participants completed a classic P3 auditory oddball task to elicit characteristic EEG signatures and event-related potentials (ERPs). Across the three electrode types, we compared single-trial noise, average ERPs, scalp topographies, ERP noise, and ERP statistical power as a function of number of trials. We extended past work showing active electrodes' insensitivity to moderate levels of interelectrode impedance when compared to passive electrodes in the same amplifier. Importantly, the new dry electrode system could reliably measure EEG spectra and ERP components comparable to traditional electrode types. As expected, however, dry active electrodes with very high interelectrode impedance exhibited marked increases in single-trial and average noise levels, which decreased statistical power, requiring more trials to detect significant effects. This power decrease must be considered as a trade-off with the ease of application and long-term use. The current results help set constraints on experimental design with novel dry electrodes, and provide important evidence needed to measure brain activity in novel settings and situations.

High and dry? Comparing active dry EEG electrodes to active and passive wet electrodes.

Oscillatory brain rhythms can bias attention via phase and amplitude changes, which modulate sensory activity, biasing information to be processed or ignored. Alpha band (7–14 Hz) oscillations lateralize with spatial attention and rhythmically inhibit visual activity and awareness through pulses of inhibition. Here we show that human observers' awareness of spatially unattended targets is dependent on both alpha power and alpha phase at target onset. Following a predictive directional cue, alpha oscillations were entrained bilaterally using repetitive visual stimuli. Subsequently, we presented either spatially cued or uncued targets at SOAs either validly or invalidly predicted in time by the entrainers. Temporal validity maximally modulated perceptual performance outside the spatial focus of attention and was associated with both increased alpha power and increased neural entrainment of phase in the hemisphere processing spatially unattended information. The results demonstrate that alpha oscillations represent a pulsating inhibition, which impedes visual processing for unattended space.

Power and Phase of Alpha Oscillations Reveal an Interaction between Spatial and Temporal Visual Attention

28 Heart rate, measured in beats per minute (BPM), can be used as an index of an 29 individual’s physiological state. Each time the heart beats, blood is expelled and travels 30 through the body. This blood flow can be detected in the face using a standard webcam 31 that is able to pick up subtle changes in color that cannot be seen by the naked eye. Due 32 to the light absorption spectrum of blood, we are able to detect differences in the amount 33 of light absorbed by the blood traveling just below the skin (i.e., photoplethysmography). 34 By modulating emotional and physiological stress—i.e., viewing arousing images and 35 sitting vs. standing, respectively—to elicit changes in heart rate, we explored the 36 feasibility of using a webcam as a psychophysiological measurement of autonomic 37 activity. We found a high level of agreement between established physiological 38 measures, electrocardiogram (ECG), and blood pulse oximetry, and heart rate estimates 39 obtained from the webcam. We thus suggest webcams can be used as a non-invasive and 40 readily available method for measuring psychophysiological changes, easily integrated 41 into existing stimulus presentation software and hardware setups. 42 43

Task-related heart rate estimates from a webcam 1 1 2 3 4 5 6 Non-contact measurement of emotional and physiological changes 7 in heart rate from a webcam 8 9

Heart rate, measured in beats per minute (BPM), can be used as an index of an individual’s physiological state. Each time the heart beats, blood is expelled and travels through the body. This blood flow can be detected in the face using a standard webcam that is able to pick up subtle changes in color that cannot be seen by the naked eye. Due to the light absorption spectrum of blood, we are able to detect differences in the amount of light absorbed by the blood traveling just below the skin (i.e., photoplethysmography). By modulating emotional and physiological stress—i.e., viewing arousing images and sitting vs. standing, respectively—to elicit changes in heart rate, we explored the feasibility of using a webcam as a psychophysiological measurement of autonomic activity. We found a high level of agreement between established physiological measures, electrocardiogram (ECG), and blood pulse oximetry, and heart rate estimates obtained from the webcam. We thus suggest webcams can be used as a non-invasive and readily available method for measuring psychophysiological changes, easily integrated into existing stimulus presentation software and hardware setups.

Non-contact measurement of emotional and physiological changes in heart rate from a webcam

Abstract. Diffuse optical tomography (DOT) provides data about brain function using surface recordings. Despite recent advancements, an unbiased method for estimating the depth of absorption changes and for providing an accurate three-dimensional (3-D) reconstruction remains elusive. DOT involves solving an ill-posed inverse problem, requiring additional criteria for finding unique solutions. The most commonly used criterion is energy minimization (energy constraint). However, as measurements are taken from only one side of the medium (the scalp) and sensitivity is greater at shallow depths, the energy constraint leads to solutions that tend to be small and superficial. To correct for this bias, we combine the energy constraint with another criterion, minimization of spatial derivatives (Laplacian constraint, also used in low resolution electromagnetic tomography, LORETA). Used in isolation, the Laplacian constraint leads to solutions that tend to be large and deep. Using simulated, phantom, and actual brain activation data, we show that combining these two criteria results in accurate (error <2  mm) absorption depth estimates, while maintaining a two-point spatial resolution of <24  mm up to a depth of 30 mm. This indicates that accurate 3-D reconstruction of brain activity up to 30 mm from the scalp can be obtained with DOT.

Combining energy and Laplacian regularization to accurately retrieve the depth of brain activity of diffuse optical tomographic data

Mobile Multimedia Effects on Cognitive Engagement: Association between App Format, Learning and Cognitive Load

Introduction and Speakers S1 Panel Discussion Abstracts Wednesday, September 30, 2015 Panel Discussion 1: Altered States: Undergraduate-Driven EEG/ERP Research on Attention, Cognition, and Emotion S2 Friday, October 2, 2015 Panel Discussion 2: Psychophysiology Measures in Women’s Health Research: Challenges and Creative Solutions S3 Flash Talks Friday, October 2, 2015 A Focus on Early-to Mid-Career Psychophysiologists S4

Fifty-Fifth Annual Meeting of the Society for Psychophysiological Research: Westin Hotel, Seattle, Washington, USA September 30-October 4, 2015 Website: www.sprweb.org.

NON-CONTACT MEASUREMENT OF COGNITIVE, EMOTIONAL, AND PHYSIOLOGICAL CHANGES IN HEART RATE WITH A WEBCAM

Wearable Monitors Advances in microelectronics have yielded high-quality devices that allow for intensive signal collection or transmission. S. Xu et al. (p. 70) show how to make a soft wearable system that is constructed like a stretchable circuit board, where the electronic components are bridged electrically by thin, meandering conducting traces that float in a highly visco-elastic polymer. A complete soft circuit capable of multisignal physiological sensing on skin was created, with potential for use in health monitoring or neonatal care. Flexible skin-integrated electronic sensors enable continuous, wireless health monitoring. When mounted on the skin, modern sensors, circuits, radios, and power supply systems have the potential to provide clinical-quality health monitoring capabilities for continuous use, beyond the confines of traditional hospital or laboratory facilities. The most well-developed component technologies are, however, broadly available only in hard, planar formats. As a result, existing options in system design are unable to effectively accommodate integration with the soft, textured, curvilinear, and time-dynamic surfaces of the skin. Here, we describe experimental and theoretical approaches for using ideas in soft microfluidics, structured adhesive surfaces, and controlled mechanical buckling to achieve ultralow modulus, highly stretchable systems that incorporate assemblies of high-modulus, rigid, state-of-the-art functional elements. The outcome is a thin, conformable device technology that can softly laminate onto the surface of the skin to enable advanced, multifunctional operation for physiological monitoring in a wireless mode.

Soft Microfluidic Assemblies of Sensors, Circuits, and Radios for the Skin

Rugged and breathable forms of stretchable electronics with adherent composite substrates for transcutaneous monitoring

Retinotopic visual mapping of brain oxygenation and neuronal activity using simultaneous fast and slow near-infrared optical brain imaging in humans.

Molecular mechanisms of HIV infection (1.1) 10:30 – 10:45 Sarah Erickson-­‐Bhatt In vivo intra-­‐operative breast tumor margin detection using a portable OCT system with a handheld surgical imaging probe (1.2) 10:45 – 11:00 Sheng Xu Hard-­‐soft integrated multifunctional devices for mobile healthcare systems (1.3) 11:00 – 11:15 Venkatraman Srinivasan Fewer not more leaves-­‐ Key to obtaining the needed jump in crop yield potential (1.4) 11:15 – 11:30 Craig Yendrek Exploiting inter-­‐specific variation to improve abiotic stress tolerance in crops (1.5) 11:45 – 12:00 Mostafa Elag Data network (2.1) 12:00 – 12:15 Catello Di Martino Lessons learned from the failure analysis of Blue Waters (2.2) 12:15 – 12:30 Robin Berthier Challenges and solutions for a resilient power grid (2.3) 12:30 – 12:45 Yukako Komaki Analyses of cell cycle alteration induced by haloacetonitriles: Toxicity of drinking water disinfection by-­‐products (2.4)

4 Th Annual Postdoctoral Research Symposium Beckman Foyer near Auditorium and Room 1005: Registration Auditorium: Opening Remarks and Keynote Beckman Foyer near Auditorium and Room 1005: Break Beckman Foyer near Auditorium and Room 1005: Break

Not all probes are created equal: Suppressed probes presented during binocular rivalry draw attention to the suppressed image

We investigated the dynamics of brain processes facilitating conscious experience of external stimuli. Previously, we proposed that alpha (8–12 Hz) oscillations, which fluctuate with both sustained and directed attention, represent a pulsed inhibition of ongoing sensory brain activity. Here we tested the prediction that inhibitory alpha oscillations in visual cortex are modulated by top–down signals from frontoparietal attention networks. We measured modulations in phase-coherent alpha oscillations from superficial frontal, parietal, and occipital cortices using the event-related optical signal (EROS), a measure of neuronal activity affording high spatiotemporal resolution, along with concurrently recorded EEG, while participants performed a visual target detection task. The pretarget alpha oscillations measured with EEG and EROS from posterior areas were larger for subsequently undetected targets, supporting alpha's inhibitory role. Using EROS, we localized brain correlates of these awareness-related alpha oscillations measured at the scalp to the cuneus and precuneus. Crucially, EROS alpha suppression correlated with posterior EEG alpha power across participants. Sorting the EROS data based on EEG alpha power quartiles to investigate alpha modulators revealed that suppression of posterior alpha was preceded by increased activity in regions of the dorsal attention network and decreased activity in regions of the cingulo-opercular network. Cross-correlations revealed the temporal dynamics of activity within these preparatory networks before posterior alpha modulation. The novel combination of EEG and EROS afforded localization of the sources and correlates of alpha oscillations and their temporal relationships, supporting our proposal that top–down control from attention networks modulates both posterior alpha and awareness of visual stimuli.

Dynamics of Alpha Control: Preparatory Suppression of Posterior Alpha Oscillations by Frontal Modulators Revealed with Combined EEG and Event-related Optical Signal

Keep your mind on the road: Predicting mind-wandering while driving using classification of pre-probe oscillatory brain activity and driving performance

Cell-phone use impairs driving safety and performance. This impairment may stem from the remote partner’s lack of awareness about the driving situation. In this study, pairs of participants completed a driving simulator task while conversing naturally in the car and while talking on a hands-free cell phone. In a third condition, the driver drove while the remote conversation partner could see video of both the road ahead and the driver’s face. We tested the extent to which this additional visual information diminished the negative effects of cell-phone distraction and increased situational awareness. Collision rates for unexpected merging events were high when participants drove in a cell-phone condition but were reduced when they were in a videophone condition, reaching a level equal to that observed when they drove with an in-car passenger or drove alone. Drivers and their partners made shorter utterances and made longer, more frequent traffic references when they spoke in the videophone rather than the cell-phone condition. Providing a view of the driving scene allows remote partners to help drivers by modulating their conversation and referring to traffic more often.

Providing Views of the Driving Scene to Drivers’ Conversation Partners Mitigates Cell-Phone-Related Distraction

Fabrication Procedure for Rugged and Breathable Forms of Stretchable Electronics with Adherent and Composite Substrates

Cognitively demanding cell phone conversations impair driving performance. In some situations, conversations with a passenger are less disruptive than cell phone conversations, in theory because of heightened situational awareness. Here, drivers completed challenging freeway drives in a high-fidelity simulator while conversing with a partner. The pairs engaged in naturalistic conversations in three different conditions: remotely on a hands-free phone, as a passenger in the vehicle, and in a videophone condition where the hands-free phone experience was enhanced by a live video the driving scene and the driver’s face. This condition was designed to increase the conversation partner’s awareness of the driving situation to a level similar to that of an in-vehicle passenger, to test our hypothesis that this cognizance leads to less distracted driving. We compared these conversation conditions to a driving-alone condition. Drivers were involved in more collisions with merging vehicles in the phone condition compared to drive-alone, passenger or videophone conditions, and crucially there was no difference in collisions between the passenger and videophone conditions. Providing remote conversation partner information about the driver and driving scene reduces the detrimental effect of cell phone conversations, possibly by increasing shared situational awareness.

Providing conversation partners views of the driving scene mitigates cell phone-related distraction

We hypothesized that control processes, as measured using electrophysiological (EEG) variables, influence the rate of learning of complex tasks. Specifically, we measured alpha power, event-related spectral perturbations (ERSPs), and event-related brain potentials during early training of the Space Fortress task, and correlated these measures with subsequent learning rate and performance in transfer tasks. Once initial score was partialled out, the best predictors were frontal alpha power and alpha and delta ERSPs, but not P300. By combining these predictors, we could explain about 50% of the learning rate variance and 10%-20% of the variance in transfer to other tasks using only pretraining EEG measures. Thus, control processes, as indexed by alpha and delta EEG oscillations, can predict learning and skill improvements. The results are of potential use to optimize training regimes.

Different slopes for different folks: alpha and delta EEG power predict subsequent video game learning rate and improvements in cognitive control tasks.

Rhythmic events are common in our sensory world. Temporal regularities could be used to predict the timing of upcoming events, thus facilitating their processing. Indeed, cognitive theories have long posited the existence of internal oscillators whose timing can be entrained to ongoing periodic stimuli in the environment as a mechanism of temporal attention. Recently, recordings from primate brains have shown electrophysiological evidence for these hypothesized internal oscillations. We hypothesized that rhythmic visual stimuli can entrain ongoing neural oscillations in humans, locking the timing of the excitability cycles they represent and thus enhancing processing of subsequently predictable stimuli. Here we report evidence for entrainment of neural oscillations by predictable periodic stimuli in the alpha frequency band and show for the first time that the phase of existing brain oscillations cannot only be modified in response to rhythmic visual stimulation but that the resulting phase-locked fluctuations in excitability lead to concomitant fluctuations in visual awareness in humans. This entrainment effect was dependent on both the amount of spontaneous alpha power before the experiment and the level of 12-Hz oscillation before each trial and could not be explained by evoked activity. Rhythmic fluctuations in awareness elicited by entrainment of ongoing neural excitability cycles support a proposed role for alpha oscillations as a pulsed inhibition of cortical activity. Furthermore, these data provide evidence for the quantized nature of our conscious experience and reveal a powerful mechanism by which temporal attention as well as perceptual snapshots can be manipulated and controlled.

Making Waves in the Stream of Consciousness: Entraining Oscillations in EEG Alpha and Fluctuations in Visual Awareness with Rhythmic Visual Stimulation

Decision-making in the presence of other competitive intelligent agents is fundamental for social and economic behavior. Such decisions require agents to behave strategically, where in addition to learning about the rewards and punishments available in the environment, they also need to anticipate and respond to actions of others competing for the same rewards. However, whereas we know much about strategic learning at both theoretical and behavioral levels, we know relatively little about the underlying neural mechanisms. Here, we show using a multi-strategy competitive learning paradigm that strategic choices can be characterized by extending the reinforcement learning (RL) framework to incorporate agents’ beliefs about the actions of their opponents. Furthermore, using this characterization to generate putative internal values, we used model-based functional magnetic resonance imaging to investigate neural computations underlying strategic learning. We found that the distinct notions of prediction errors derived from our computational model are processed in a partially overlapping but distinct set of brain regions. Specifically, we found that the RL prediction error was correlated with activity in the ventral striatum. In contrast, activity in the ventral striatum, as well as the rostral anterior cingulate (rACC), was correlated with a previously uncharacterized belief-based prediction error. Furthermore, activity in rACC reflected individual differences in degree of engagement in belief learning. These results suggest a model of strategic behavior where learning arises from interaction of dissociable reinforcement and belief-based inputs.

Dissociable neural representations of reinforcement and belief prediction errors underlie strategic learning

. Aim: To identify neural predictors of target detection. Methods: EROS and EEG were simultaneously recorded from 10 participants in two session. Each trial began with a fixation cross. • On 50% of trials, a target was presented, followed by a nonoverlapping metacontrast mask; • 25% of trials were target only. • 25% of trials were mask only. Participants indicated on each trial if they detected the target. Behavioral Results: 68% detection rate. 9% False Alarm rate. Who’s controlling the brakes? Pulsed inhibitory alpha EEG is linked to preparatory activity in the fronto-parietal network measured concurrently with the event-related optical signal (EROS). Kyle E. Mathewson1, Alejandro Lleras1, Diane M. Beck1, Tony Ro2, Monica Fabiani1, Gabriele Gratton1 1 Beckman Institute and Department of Psychology, University of Illinois at Urbana-Champaign 2 The City College of the City University of New York

Who's controlling the brakes? Pulsed inhibitory alpha EEG is linked to preparatory activity in the fronto-parietal network measured concurrently with the event-related optical signal (EROS)

Alpha oscillations are ubiquitous in the brain, but their role in cortical processing remains a matter of debate. Recently, evidence has begun to accumulate in support of a role for alpha oscillations in attention selection and control. Here we first review evidence that 8–12 Hz oscillations in the brain have a general inhibitory role in cognitive processing, with an emphasis on their role in visual processing. Then, we summarize the evidence in support of our recent proposal that alpha represents a pulsed-inhibition of ongoing neural activity. The phase of the ongoing electroencephalography can influence evoked activity and subsequent processing, and we propose that alpha exerts its inhibitory role through alternating microstates of inhibition and excitation. Finally, we discuss evidence that this pulsed-inhibition can be entrained to rhythmic stimuli in the environment, such that preferential processing occurs for stimuli at predictable moments. The entrainment of preferential phase may provide a mechanism for temporal attention in the brain. This pulsed inhibitory account of alpha has important implications for many common cognitive phenomena, such as the attentional blink, and seems to indicate that our visual experience may at least some times be coming through in waves.

Pulsed Out of Awareness: EEG Alpha Oscillations Represent a Pulsed-Inhibition of Ongoing Cortical Processing

When viewing ambiguous figures like the classic duck/rabbit, people alternately perceive one interpretation and then the other, but not both interpretations at once. When two identical ambiguous figures appear together, the majority of observers perceive them as identical, and they typically alternate in unison. Just as most observers cannot see a single figure as both a duck and a rabbit, most cannot see one figure in a pair as a duck and the other as a rabbit even though the two figures and their features are spatially distinct. Is this inability to see both interpretations an inherent limitation of the visual system or is it just due to differences in top–down processing? We show that a simple prompt immediately allows people to see both interpretations, to their own surprise.

Simultaneous Perception of Both Interpretations of Ambiguous Figures

Changes in attention allocation with complex task learning reflect processing automatization and more efficient control. We studied these changes using ERP and EEG spectral analyses in subjects playing Space Fortress, a complex video game comprising standard cognitive task components. We hypothesized that training would free up attentional resources for a secondary auditory oddball task. Both P3 and delta EEG showed a processing trade-off between game and oddball tasks, but only some game events showed reduced attention requirements with practice. Training magnified a transient increase in alpha power following both primary and secondary task events. This contrasted with alpha suppression observed when the oddball task was performed alone, suggesting that alpha may be related to attention switching. Hence, P3 and EEG spectral data are differentially sensitive to changes in attentional processing occurring with complex task training.

Learning to multitask: effects of video game practice on electrophysiological indices of attention and resource allocation.

Controlling the timing of oscillations in neural activity and consciousness with rhythmic visual stimulation

Rescuing stimuli from invisibility: Inducing a momentary release from visual masking with pre-target entrainment

Pre-stimulus activity predicts subsequent target detection in meta-contrast masking

Illuminating awareness: Investigating the temporal and spatial neural dynamics of metacontrast masking using the event-related optical signal

We often fail to see something that at other times is readily detectable. Because the visual stimulus itself is unchanged, this variability in conscious awareness is likely related to changes in the brain. Here we show that the phase of EEG α rhythm measured over posterior brain regions can reliably predict both subsequent visual detection and stimulus-elicited cortical activation levels in a metacontrast masking paradigm. When a visual target presentation coincides with the trough of an α wave, cortical activation is suppressed as early as 100 ms after stimulus onset, and observers are less likely to detect the target. Thus, during one α cycle lasting 100 ms, the human brain goes through a rapid oscillation in excitability, which directly influences the probability that an environmental stimulus will reach conscious awareness. Moreover, ERPs to the appearance of a fixation cross before the target predict its detection, further suggesting that cortical excitability level may mediate target detection. A novel theory of cortical inhibition is proposed in which increased α power represents a “pulsed inhibition” of cortical activity that affects visual awareness.

To See or Not to See: Prestimulus α Phase Predicts Visual Awareness

What effect does working memory load have on attentional processes? The effect of performing a working memory task on a sustained attention 'Posner paradigm' was examined. Participants were cued to one side of visual space and indicated as quickly as possible the side on which targets appeared via a key press response. The task was performed with and without a dual-task of mental math. The mental math task led to an overall slowing of responses and the elimination of the cueing effect observed in the no-task condition. Thus, reaction time advantages afforded by attention are negated by working memory load.

The Detrimental Effects of Working Memory Load on a Sustained Attention Task: The Elimination of a Cueing Effect with Distraction.

Dopamanergic temporal difference (TD) reinforcement learning signals are believed crucial for the shaping of situationally appropriate behaviour. As a window into these neural signals, the error-related negativity (ERN) was examined during the shaping of motor sequences, and during their subsequent execution. During learning, the ERN elicited by feedback (fERN) is expected to diminish while the ERN following erroneous responses (rERN) is expected to increase. This predicted shift in ERN timing was obtained, mirroring the shift in timing of the dopamine signals to the earliest indicator of event outcomes, and elucidating the role of these TD signals in sequence learning. 
 
EXTENDED ABSTRACT 
 
The error-related negativity (ERN) is a component of the human-event-related potential that is sensitive to error feedback (fERN) and erroneous responses (rERN). The ERN proposedly reflects a dopamanergic temporal difference reinforcement learning signal used at the ACC to adjust future actions, and is shown to occur at the earliest indication that events deviate from expectations. Dopamanergic temporal difference (TD) reinforcement learning signals are believed crucial for the shaping of situationally appropriate behaviour. As a window into these neural signals, the error-related negativity (ERN) was examined during the shaping of motor sequences, and during their subsequent execution. During learning, the ERN elicited by feedback (fERN) is expected to diminish while the ERN following erroneous responses (rERN) is expected to increase. This predicted shift in ERN timing was obtained, mirroring the shift in timing of the dopamine signals to the earliest indicator of event outcomes, and elucidating the role of these TD signals in sequence learning. These findings lend support to a unifying theory of the ERN that implicates both the fERN and rERN as homologous parts of a general high-level error detection system, and elucidate the important role of the ACC in motor sequence learning.

The Error-Related Negativity as a Reinforcement Learning Signal in Motor Sequence Acquisition

 Persistent neurovascular uncoupling may be associated with poor outcome in patients with ischemic stroke after successful recanalization. Quantitative electroencephalography (EEG) can be used to assess neuronal function. We assessed relation between degree of recanalization post-endovascular thrombectomy (EVT), quantitative EEG based parameters and severity of neurological deficits.
 
 Methods:
 Patients with acute ischemic stroke with large vessel occlusion in anterior circulation were enrolled. EEG was recorded using a modified Muse headband (InteraXon) before, immediately after and at 24 hours post-EVT. Pairwise-derived brain symmetry index (pdBSI) and delta-to-alpha ratio (DAR) were computed using Fitting Oscillation & one-over F (FOOOF) MATLAB wrapper.
 
 Results:
 A total of six patients with mean age 73.6±11.6 years and baseline median (IQR) NIHSS of 13.5 (11-15) were included. Expanded thrombolysis in cerebral infarction (eTICI) scores were 2b67 in one, 2c in two and 3 in three cases. Baseline EEG was recorded at 75 minutes (60-100) from arrival, second at 255 minutes (90-420) after recanalization and third at 28.5 hours (27-31) after recanalization. Four patients with improvement in NIHSS of >10 had 46.6±31.7% change in pdBSI at 24 h. One patient with NIHSS <10 improvement had -25.3% change in pdBSI. One patient with low baseline NIHSS (9) had 90.9% change in pdBSI. There was linear correlation between baseline infarct volume on perfusion studies and change in pdBSI at 24 h (r=0.86, p<0.0001, Figure 1). There was no difference in the DAR in the ipsilateral hemisphere pre-EVT, immediately post-EVT (p=0.6) and 24 h post-EVT (p=0.8).
 
 Conclusion:
 Preliminary data suggest return of neuronal function and clinical recovery may lag after successful recanalization, due to persistent neurovascular uncoupling. Higher baseline infarct volume may predict lower pdBSI change. Portable EEG may help characterise this novel treatment target.
 
Abstract WMP46: Quantitative Electroencephalogram To Assess Neurovascular Coupling Post Endovascular Thrombectomy

This study investigated whether people can develop a global representation of local environments by path integration. Participants learned objects’ locations in two misaligned rectangular rooms in an immersive virtual environment. After learning, they adopted a local view in one room and judged directions of objects inside the same room; the views in two consecutive trials were from different rooms and locally or globally consistent (priming task). Participants were either teleported (Experiment 1) or they locomoted (Experiment 2) between the rooms during learning and then finished the priming task. In Experiment 3, participants learned directions of five buildings before locomoting within and between the two rooms. During testing, after the priming task, participants pointed to the buildings while adopting local views inside rooms (across-boundary pointing task). Participants’ estimated global headings were calculated from their responses to the buildings. Experiments 4 and 5 replicated Experiments 3 and 2 respectively except that participants locomoted between the rooms through a hallway, which minimized piloting cues. Results showed only a local priming effect in Experiments 1, 2 and 5, only a global priming effect in Experiment 4, and both local and global priming effects in Experiment 3. Consistent with the global priming effect, participants’ estimated global headings were also accurate in Experiments 3 and 4. These results suggest that people can develop a global cognitive map of two local environments by path integration; prior global representation may be important to integrating local spaces into a global map; both the global and local representations can be separately developed to multiscale cognitive maps, although this may require significant cognitive resources.

Author response for "To See, Not to See, or to See Poorly: Perceptual Quality and Guess Rate as a Function of Electroencephalography (EEG) Brain Activity in an Orientation Perception Task"

Neuro-Cloud's An Introduction to Neuroscience Sample Chapter and Story

Author response for "EEG in Motion: Using an Oddball Task to Explore Motor Interference in Active Skateboarding"

In this column we describe two courses that focus on the role of statistics in understanding social issues. The first is an introductory statistics course developed by Dr. Kendra Burbank at the University of Chicago where students learn statistical methods as they explore different aspects of the water crisis in Flint, Michigan. Then, we describe an intermediate-level service learning course taught by Dr. Judith Canner and Dr. Alana Unfried at California State University Monterey Bay University where students use statistics to consult with local nonprofits and learn how to take a data-driven approach to affect change. We conclude with resources for instructors interested in incorporating social issues in their courses.

The autoencoder algorithm is a simple but powerful unsupervised method for training neural networks. Autoencoder networks can learn sparse distributed codes similar to those seen in cortical sensory areas such as visual area V1, but they can also be stacked to learn increasingly abstract representations. Several computational neuroscience models of sensory areas, including Olshausen & Field’s Sparse Coding algorithm, can be seen as autoencoder variants, and autoencoders have seen extensive use in the machine learning community. Despite their power and versatility, autoencoders have been difficult to implement in a biologically realistic fashion. The challenges include their need to calculate differences between two neuronal activities and their requirement for learning rules which lead to identical changes at feedforward and feedback connections. Here, we study a biologically realistic network of integrate-and-fire neurons with anatomical connectivity and synaptic plasticity that closely matches that observed in cortical sensory areas. Our choice of synaptic plasticity rules is inspired by recent experimental and theoretical results suggesting that learning at feedback connections may have a different form from learning at feedforward connections, and our results depend critically on this novel choice of plasticity rules. Specifically, we propose that plasticity rules at feedforward versus feedback connections are temporally opposed versions of spike-timing dependent plasticity (STDP), leading to a symmetric combined rule we call Mirrored STDP (mSTDP). We show that with mSTDP, our network follows a learning rule that approximately minimizes an autoencoder loss function. When trained with whitened natural image patches, the learned synaptic weights resemble the receptive fields seen in V1. Our results use realistic synaptic plasticity rules to show that the powerful autoencoder learning algorithm could be within the reach of real biological networks.

Mirrored STDP Implements Autoencoder Learning in a Network of Spiking Neurons

Top-down synapses are ubiquitous throughout neocortex and play a central role in cognition, yet little is known about their development and specificity. During sensory experience, lower neocortical areas are activated before higher ones, causing top-down synapses to experience a preponderance of post-synaptic activity preceding pre-synaptic activity. This timing pattern is the opposite of that experienced by bottom-up synapses, which suggests that different versions of spike-timing dependent synaptic plasticity (STDP) rules may be required at top-down synapses. We consider a two-layer neural network model and investigate which STDP rules can lead to a distribution of top-down synaptic weights that is stable, diverse and avoids strong loops. We introduce a temporally reversed rule (rSTDP) where top-down synapses are potentiated if post-synaptic activity precedes pre-synaptic activity. Combining analytical work and integrate-and-fire simulations, we show that only depression-biased rSTDP (and not classical STDP) produces stable and diverse top-down weights. The conclusions did not change upon addition of homeostatic mechanisms, multiplicative STDP rules or weak external input to the top neurons. Our prediction for rSTDP at top-down synapses, which are distally located, is supported by recent neurophysiological evidence showing the existence of temporally reversed STDP in synapses that are distal to the post-synaptic cell body.

Depression-Biased Reverse Plasticity Rule Is Required for Stable Learning at Top-Down Connections

Self-organization mechanisms in the assembly and maintenance of bipolar spindles

Nonredundant Functions of Kinesin-13s during Meiotic Spindle Assembly

Anastral meiotic spindles are thought to be organized differently from astral mitotic spindles, but the field lacks the basic structural information required to describe and model them, including the location of microtubule-nucleating sites and minus ends. We measured the distributions of oriented microtubules in metaphase anastral spindles in Xenopus laevis extracts by fluorescence speckle microscopy and cross-correlation analysis. We localized plus ends by tubulin incorporation and combined this with the orientation data to infer the localization of minus ends. We found that minus ends are localized throughout the spindle, sparsely at the equator and at higher concentrations near the poles. Based on these data, we propose a model for maintenance of the metaphase steady-state that depends on continuous nucleation of microtubules near chromatin, followed by sorting and outward transport of stabilized minus ends, and, eventually, their loss near poles.

A new method reveals microtubule minus ends throughout the meiotic spindle

Senior projects are common requirements in engineering technology programs. Seniors are challenged to integrate in one project the knowledge, skills and abilities learned over three plus years. Recently, the projects at Western Carolina University have ranged from wireless car alarms to three-phase motor test stations to back up energy sources for aquariums. An integral part of the Department’s mission is external engagement, so the Electrical and Computer Engineering Technology faculty look for projects that can connect the WCU seniors to the community. Recently, faculty from the College of Education and Allied Professions and the Department of Engineering and Technology identified several special needs cases where a technical innovation could improve a student’s quality of life in the classroom. The initial project was the addition of a navigation system to a wheelchair. In this case, a child who is deaf-blind was given a motorized wheelchair, and a method was needed to prevent the student from running into objects in the classroom. A system was designed using four ultrasonic sensors controlled by a microcontroller board. Depending on the returned signal from the sensors, an alarm was activated to warn the student. In this design, a vibrating motor from a cell phone provided the alarm. The classroom teacher had the responsibility to teach the student to associate the vibration with the closeness to an obstacle. In the future, this classroom teacher hopes to expand the student’s abilities such that the student can sense each of the four directional sensors individually. As an electrical engineering technology senior project, the wheelchair navigation system required the WCU senior to integrate microcontrollers, sensors, programming, and power supplies and to consider the packaging issues. In addition, the collaboration required the senior to communicate with grade school teachers and the Special Education Program faculty. More importantly, this collaboration helped the senior connect his technical expertise with the needs of others and this sense of purpose energized the senior and his classmates. Introduction Western Carolina University (WCU) includes a College of Education and Allied Professions. Within this College’s Department of Human Services, there is a Special Education Program whose mission is to prepare educators who understand child development and who use that knowledge to implement educational programs based on individual student needs. This group of educators works with student teachers and also with practicing teachers in the regional schools. Page 10110.1 Proceedings of the 2005 American Society for Engineering Education Annual Conference & Exposition Copyright © 2005, American Society for Engineering Education The Western Carolina University Teacher Support Program, through offering an array of direct support services to all educators who serve students with disabilities, has led to the identification of several special needs cases where a technical innovation could improve a student’s quality of life in the classroom. Seeking help with the technical solutions, the Special Education Program faculty approached the Department of Engineering and Technology and several collaborative projects were defined. Many of the projects involve modifying existing commercial equipment for classroom use by grade school aged children. The modifications include adaptations for the smallness of the children and then further adaptations for a variety of disabilities. Two overall goals are to increase the amount of time children with disabilities can spend with their school peers, and to increase their independent learning. Preference is given to projects where the adaptations can be readily configured to additional users. The initial project was the addition of a navigation warning system to a motorized wheelchair. A student who is deaf-blind and wheelchair bound was given a motorized wheelchair for a trial period in a classroom. The student’s delight in independent movement led parents and teachers to extend the trial period. However, a method was needed to prevent the student from running into objects in the classroom. The classroom teacher concentrated on the basic go/no go instructions with the student, which required constant close supervision and feedback through physical contact. The Department of Engineering and Technology was approached to develop a feedback system to help the classroom teacher monitor and control the student’s wheelchair movements. The initial design is a system using four ultrasonic sensors controlled by a microcontroller board. The ultrasonic sensors generate a signal proportional to the distance, and, depending on the magnitude of the returned signal from the sensors, an alarm was activated to warn the student. After much discussion with the teachers, a vibrating motor from a cell phone was chosen to act as the alarm. In parallel with the electronic system development, the classroom teacher had the responsibility to teach the student to associate the vibration with closeness to an obstacle and to stop the wheelchair. Currently, the feedback is go/stop, but in the future, this teacher hopes to expand the student’s abilities such that the student can sense each of the four directional sensors individually. Relevance to Electrical Engineering Technology The criteria for the accreditation of Electrical and Computer Engineering Technology (ECET) programs are well defined by the Technology Accreditation Commission of ABET (TAC of ABET). Indeed, graduates of baccalaureate degree programs must be able to demonstrate the ability to analyze, design, and implement electronic systems. 1 For most ECET seniors, a project based on an electronic system is easy, and little effort is required to motivate them to build circuits. However, seniors consistently have trouble initially defining a project, and then have trouble finishing the documentation. These two aspects of systems are also discussed in the TAC of ABET criteria, under Program Outcomes “a through k”. In particular, programs must demonstrate that graduates have the ability to apply creativity Page 10110.2 in the design of systems (d), an ability to function effectively on teams (e), an ability to communicate effectively (g), and an ability to understand professional, ethical and social responsibilities (i) . As an ECET senior project, the wheelchair navigation system required the senior to integrate microcontrollers, sensors, programming, and power supplies and to consider the packaging issues. As at most universities, these components are studied in separate courses, and the senior project is the first opportunity for the integration of these topics and the synthesis of a system. The collaborative nature of this project required the WCU senior to communicate with grade school teachers and the Special Education Program faculty. Communicating with nonengineering types required the senior to more fully develop his thoughts and avoid quick instantmessaging style responses. More importantly, this collaboration helped the senior connect his technical expertise with the needs of others and this sense of purpose energized the senior and his classmates. The advantages of this type of project have been well described. Wheelchair Navigation System The overall system is shown in Figure 1. This system is a separate unit, added to an existing wheelchair, with the only interconnection being the 24V battery source. The main computing engine is an 8-bit microcontroller, programmed using C-language. The microcontroller board has one analog-to-digital channel hardwired to a potentiometer, and most of the ports are available to the user through connectors. Programming of the microcontroller was done using a PC connected through a USB interface, and debugging was done using this same interface. Once the program was finalized, the microcontroller can be disconnected from the PC and act as a stand-alone unit. Figure 1. Wheelchair Navigation System Proceedings of the 2005 American Society for Engineering Education Annual Conference & Exposition Copyright © 2005, American Society for Engineering Education P ge 10110.3 Circuit Operation The ultrasonic sensors generate a short audio pulse when triggered by the microcontroller. The time to echo reception is recorded by the microcontroller. The digital event time is then compared to a setpoint, and the result of the comparison controls the vibration motors. The flowchart for this control software is shown in Figure 2. The four sensors are pulsed at 5 Hz. The digital event time is related to the distance from the sensor to an object; closer objects reflect the sound waves back to the sensor quicker than far objects. The sensors here have a useful range of 15 feet. A setpoint is generated from the one A-D channel connected to a potentiometer, which allows an equivalent distance threshold to be established. When the wheelchair is “close” to an object, then a vibration motor is activated. Figure 3 shows the ultrasonic sensor and a motor, both mounted in telephone jack boxes. Using these boxes and RJ-11 connectors is a cheap and quick interconnection scheme. Proceedings of the 2005 American Society for Engineering Education Annual Conference & Exposition Copyright © 2005, American Society for Engineering Education The wheelchair itself is powered by two 12V batteries in series. To minimize any possible effects on the wheelchair, the designed system uses the 24V source as is. A simple connector and in-line fuse are used to connect to the wheelchair, and all voltage regulation is done on the new board. Figure 2. Flowchart for the control software. Initially, four ultrasonic sensors were used, with each sensor controlling a vibration motor. The goal was to provide four quadrants of detection, so the student in the wheelchair could detect an object in front, back, left, and right. However, this was too complicated for the stu

A Wheelchair Navigation System As A Collaborative Senior Project

Although mitotic and meiotic spindles maintain a steady-state length during metaphase, their antiparallel microtubules slide toward spindle poles at a constant rate. This “poleward flux” of microtubules occurs in many organisms and may provide part of the force for chromosome segregation. We use quantitative image analysis to examine the role of the kinesin Eg5 in poleward flux in metaphase Xenopus laevis egg extract spindles. Pharmacological inhibition of Eg5 results in a dose–responsive slowing of flux, and biochemical depletion of Eg5 significantly decreases the flux rate. Our results suggest that ensembles of nonprocessive Eg5 motors drive flux in metaphase Xenopus extract spindles.

The kinesin Eg5 drives poleward microtubule flux in Xenopus laevis egg extract spindles

Solid state proton spin–lattice relaxation in four structurally related organic molecules

Quaternary Phase Shift Keying (QPSK) is a fundamental method of encoding digital data in the phase of an analog carrier. This technique was used by early modems using the public telephone network. While the technology is no longer economically valid, the components of the modem span the coursework of most EET curricula; i.e. both analog and digital circuits, within a communications framework. A directed design project approach was used. The instructor defined the objectives of the project, and directed the sequence and tools used in the design. The class was given a QPSK modulator constructed from TTL 7400 series gates and 741 op amps. From this circuit, the students had to identify parts and create a schematic. The linear circuits included an oscillator and a band pass filter, and both were analyzed using PSpice. The digital circuits were split into combinational and sequential sections, and timing diagrams were developed. The digital circuits were then divided into sections suitable for implementation using programmable logic devices. The signal waveforms were observed in both the timeand frequency-domains, and the concept of bit rate vs. baud rate was introduced. This design project was first implemented in a sequential digital circuits course, after the students had taken a linear circuits course, both at the junior level. For most students, this was their first exposure to mixed digital-linear circuits, and the first circuit that they had to reverse engineer. The directed design approach is used as a prelude to the senior design projects. While the circuit is straightforward, it serves to reinforce the students’ knowledge of linear and digital circuits, their ability to analyze and design simple state machines, and their schematic capture and laboratory skills. Introduction A key tenet for engineering technology is hands-on experiential learning. For Electrical Engineering Technology (EET), this most often translates into building, testing, and troubleshooting electronic circuits. Most commercial designs are mixed analog and digital circuits. For our curriculum linear and digital circuits are covered in separate courses. This means that portions of the digital circuits class must be combined with previously studied analog op amp circuitry. The design example described here is a modem, which is then covered in a later class in digital communications. The goal of this project is to incorporate analog and digital circuit elements in a practical design that mimics a commercial device. Most students at least know that a modem is used between a computer and the Internet. From this fundamental knowledge, a modulator can be built using circuits already covered in the junior year. This design can be simulated using PSpice and Altera P ge 859.1 Proceedings of the 2003 American Society for Engineering Education Annual Conference & Exposition Copyright © 2003, American Society for Engineering Education MAX+PLUS II software, with these two modeling programs providing complementary views. The circuit can also be assembled in the lab and tested using conventional test instruments. In both cases, the students can verify the bandwidth requirements for transmitting an input data stream. Overview of Phase Shift Keying The Public Telephone Network (PTN) is a well-established and characterized analog transmission system. The existence of the PTN to nearly every home and business made it an obvious first choice for data transfer between computers. However, to transmit and receive digital data on an analog line requires a modulator/ demodulator pair, or modem. For the modulator portion, the input is a digital bit stream, with appropriate control and header bits. The modulator output is a sinusoid, with a frequency within the 300 – 3300 Hz pass band of the PTN. The receiver is the obvious counterpart. As in general communications systems, a modem can encode data on a sinusoid by modulating its amplitude, frequency, phase, or a combination of these three attributes. Phase Shift Keying (PSK) is the name given to the technique of encoding a digital bit in the phase of a constantamplitude, fixed-frequency sine wave. Binary PSK describes systems where one bit selects one of two phases. Quaternary PSK (QPSK) relies on two bits (a dibit) to select 1-of-4 phase angles. This process can be extended to include 8-PSK and 16-PSK, where 3 or 4 bits are grouped to select 1-of-8 or 1-of-16 phase angles. We can expand the discussion of QPSK by using Table 1. For a half-duplex modem, the entire transmission line bandwidth is dedicated to one channel, and the carrier frequency, fc, is set to 1800 Hz, the pass band center. The serial bit stream is “read” two bits at a time, with each dibit selecting a unique phase angle. This can be re-stated by claiming that QPSK has 2 bits/baud, where a baud is a change on the analog output. It is the baud rate that determines the bandwidth required for transmission. The bandwidth required to transmit a quaternary phase shift keyed signal is fc ±fb/4, where fb is the input data rate. By associating two bits with each baud, the data throughput is doubled for a given bandwidth. Getting the most bits through a given channel bandwidth is the driving force for modem revisions in all communications systems. The design example presented here includes a digital portion used to create the serial bit stream through the 1-of-4 phase angle selection. A separate analog section is presented which contains a band pass circuit, generating an output suitable for spectrum analysis. Relevance to EET program The junior level curriculum at WCU includes a course in digital electronics, covering sequential and combinational circuits. While some lab work is done with TTL devices, many of the labs are performed using the Altera MAX+PLUS II software, and the Complex Programmable Logic Table 1: QPSK Modulated Waveforms 2-bits Analog waveform 00 Asin(2πfct + 0°) 01 Asin(2πfct + 90°) 10 Asin(2πfct + 270°) 11 Asin(2πfct + 180°)

Polymorphism, the presence of structurally distinct solid phases of the same chemical species, affords a unique opportunity to evaluate the structural consequences of intermolecular forces. The study of two polymorphs of 2,6-di-tert-butylnaphthalene by single-crystal x-ray diffraction, differential scanning calorimetry (DSC), 13C magic-angle-spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy, and 1H NMR spin-lattice relaxation provides a picture of the differences in structure and dynamics in these materials. The subtle differences in structure, observed with x-ray diffraction and chemical shifts, strikingly affect the dynamics, as reflected in the relaxation measurements. We analyze the dynamics in terms of both discrete sums and continuous distributions of Poisson processes.

1H nuclear magnetic resonance spin-lattice relaxation, 13C magic-angle-spinning nuclear magnetic resonance spectroscopy, differential scanning calorimetry, and x-ray diffraction of two polymorphs of 2,6-di-tert-butylnaphthalene

—Why does the Adam optimizer work so well in deep- learning applications? Adam’s originators, Kingma and Ba, presented a mathematical argument that was meant to help explain its success, but Bock and colleagues have since reported that a key piece is missing from that argument — an unproven lemma which we will call Bock’s conjecture. Here we show that this conjecture is false, but we prove a modiﬁed version of it — a generalization of a result of Reddi and colleagues — which can take its place in analyses of Adam.

In 2014, Kingma and Ba published their Adam optimizer algorithm (Kingma & Ba, 2014), together with a mathematical argument that was meant to help justify it. In 2018, Bock and colleagues (Bock et al., 2018) reported that a key piece was missing from that argument — an unproven lemma which we will call Bock’s conjecture. Here we show that this conjecture is false, but a modified version of it does hold, and fills the gap in Bock’s proof of convergence for Adam.

Velocity-To-Position Transformations in the VOR and the Saccadic System

Interaction of Smooth Pursuit and the Vestibulo-Ocular Reflex in Three Dimensions

Current algorithms for deep learning probably cannot run in the brain because they rely on weight transport, in which forward-path neurons transmit their synaptic weights to a feedback path, in a way that is likely impossible biologically. An algorithm called feedback alignment achieves deep learning without weight transport by using random feedback weights, but it performs poorly on hard visual-recognition tasks. Here we describe a neural circuit called a weight mirror, which lets the feedback path learn appropriate synaptic weights quickly and accurately even in large networks, without weight transport or complex wiring, and with a Hebbian learning rule. Tested on the ImageNet visual-recognition task, networks with weight mirrors outperform both plain feedback alignment and the newer sign-symmetry method, and nearly match the error-backpropagation algorithm, which uses weight transport.

Current algorithms for deep learning probably cannot run in the brain because they rely on weight transport, where forward-path neurons transmit their synaptic weights to a feedback path, in a way that is likely impossible biologically. An algorithm called feedback alignment achieves deep learning without weight transport by using random feedback weights, but it performs poorly on hard visual-recognition tasks. Here we describe two mechanisms - a neural circuit called a weight mirror and a modification of an algorithm proposed by Kolen and Pollack in 1994 - both of which let the feedback path learn appropriate synaptic weights quickly and accurately even in large networks, without weight transport or complex wiring.Tested on the ImageNet visual-recognition task, these mechanisms outperform both feedback alignment and the newer sign-symmetry method, and nearly match backprop, the standard algorithm of deep learning, which uses weight transport.

Most algorithms for reinforcement learning work by estimating action-value functions. Here we present a method that uses Lagrange multipliers, the costate equation, and multilayer neural networks to compute policy gradients. We show that this method can find solutions to time-optimal control problems, driving linear mechanical systems quickly to a target configuration. On these tasks its performance is comparable to that of deep deterministic policy gradient, a recent action-value method.

Recent work in computer science has shown the power of deep learning driven by the backpropagation algorithm in networks of artificial neurons. But real neurons in the brain are different from most of these artificial ones in at least three crucial ways: they emit spikes rather than graded outputs, their inputs and outputs are related dynamically rather than by piecewise-smooth functions, and they have no known way to coordinate arrays of synapses in separate forward and feedback pathways so that they change simultaneously and identically, as they do in backpropagation. Given these differences, it is unlikely that current deep learning algorithms can operate in the brain, but we that show these problems can be solved by two simple devices: learning rules can approximate dynamic input-output relations with piecewise-smooth functions, and a variation on the feedback alignment algorithm can train deep networks without having to coordinate forward and feedback synapses. Our results also show that deep spiking networks learn much better if each neuron computes an intracellular teaching signal that reflects that cell’s nonlinearity. With this mechanism, networks of spiking neurons show useful learning in synapses at least nine layers upstream from the output cells and perform well compared to other spiking networks in the literature on the MNIST digit recognition task.

Deep Learning with Dynamic Spiking Neurons and Fixed Feedback Weights

Many recent algorithms for reinforcement learning are model-free and founded on the Bellman equation. Here we present a method founded on the costate equation and models of the state dynamics. We use the costate -- the gradient of cost with respect to state -- to improve the policy and also to "focus" the model, training it to detect and mimic those features of the environment that are most relevant to its task. We show that this method can handle difficult time-optimal control problems, driving deterministic or stochastic mechanical systems quickly to a target. On these tasks it works well compared to deep deterministic policy gradient, a recent Bellman method. And because it creates a model, the costate method can also learn from mental practice.

Random synaptic feedback weights support error backpropagation for deep learning

The brain processes information through many layers of neurons. This deep architecture is representationally powerful, but it complicates learning by making it hard to identify the responsible neurons when a mistake is made. In machine learning, the backpropagation algorithm assigns blame to a neuron by computing exactly how it contributed to an error. To do this, it multiplies error signals by matrices consisting of all the synaptic weights on the neuron's axon and farther downstream. This operation requires a precisely choreographed transport of synaptic weight information, which is thought to be impossible in the brain. Here we present a surprisingly simple algorithm for deep learning, which assigns blame by multiplying error signals by random synaptic weights. We show that a network can learn to extract useful information from signals sent through these random feedback connections. In essence, the network learns to learn. We demonstrate that this new mechanism performs as quickly and accurately as backpropagation on a variety of problems and describe the principles which underlie its function. Our demonstration provides a plausible basis for how a neuron can be adapted using error signals generated at distal locations in the brain, and thus dispels long-held assumptions about the algorithmic constraints on learning in neural circuits.

Random feedback weights support learning in deep neural networks

Adapting to inversion of the visual field: a new twist on an old problem

The control problem studied here is schematized in Supplementary Figure 1 and works as follows: the agent is presented with a visual target presented on a fixed 2D plane. Given the perceived location of the target the agent must then try to touch it. To keep the simulations simple, the attempt to strike the target is open loop (i.e. the agent is not able to modify their choice in mid-flight) and happens in a single time step or trial. Let, x(t) ∈ R and x(t) ∈ R, be the real and perceived location of the target on trial t. Here we will denote the elements of a vector using subscripts, e.g. x1(t) is the first element of x at trial t, and for convenience we will often drop the trial index, e.g. we may just write x or x. The target is viewed through one of three transformations, which are induced by prisms in the experimental setup,

Supplementary materials for : “ Adaptation to inversion of the visual field : a new twist on an old problem . ”

Optimal Control by Direct Approximation of the Gradient of the Cost-to-Go

When we learn something new, our brain may store the information in synapses or in reverberating loops of electrical activity, but current theories of motor learning focus almost entirely on the synapses. Here we show that loops could also play a role and would bring advantages: loop-based algorithms can learn complex control tasks faster, with exponentially fewer neurons, and avoid the problem of weight transport. They do all this at a cost: in the presence of long feedback delays, loop algorithms cannot control very fast movements, but in this case, loop and synaptic mechanisms can complement each other—mixed systems quickly learn to make accurate but not very fast motions and then gradually speed up. Loop algorithms explain aspects of consolidation, the role of attention, and the relapses that are sometimes seen after a task has apparently been learned, and they make further predictions.

Computational Advantages of Reverberating Loops for Sensorimotor Learning

Many neural control systems are at least roughly optimized, but how is optimal control learned? There are algorithms for this purpose, but in their current forms, they are not suited for biological neural networks because they rely on a type of communication that is not available in the brain, namely, weight transport—transmitting the strengths, or “weights,” of individual synapses to other synapses and neurons. Here we show how optimal control can be learned without weight transport. Our method involves a set of simple mechanisms that can compensate for the absence of weight transport in the brain and so may be useful for neural computation generally.

Computing Near-Optimal Controllers by Learning the Gradient of the Cost-To-Go

As good as it gets — testing a bayesian model of transsaccadic change blindness

Learning course adjustments during arm movements with reversed sensitivity derivatives

Afterimages and pursuit: refining Helmholtz's theory of visual motion perception

The method of generalized Hamilton-Jacobi-Bellman equations (GHJB) is a powerful way of creating near-optimal controllers by learning. It is based on the fact that if we have a feedback controller, and we learn to compute the gradient grad-J of its cost-to-go function, then we can use that gradient to define a better controller. We can then use the new controller's grad-J to define a still-better controller, and so on. Here I point out that GHJB works indirectly in the sense that it doesn't learn the best approximation to grad-J but instead learns the time derivative dJ/dt, and infers grad-J from that. I show that we can get simpler and lower-cost controllers by learning grad-J directly. To do this, we need teaching signals that report grad-J(x) for a varied set of states x. I show how to obtain these signals, using the GHJB equation to calculate one component of grad-J(x) -- the one parallel with dx/dt -- and computing all the other components by backward-in-time integration, using a formula similar to the Euler-Lagrange equation. I then compare this direct algorithm with GHJB on 2 test problems.

To learn effectively, an adaptive controller needs to know its sensitivity derivativesthe variables that quantify how system performance depends on the commands from the controller. In the case of biological sensorimotor control, no one has explained how those derivatives themselves might be learned, and some authors suggest they are not learned at all but are known innately. Here we show that this knowledge cannot be solely innate, given the adaptive flexibility of neural systems. And we show how it could be learned using forms of information transport that are available in the brain. The mechanism, which we call implicit supervision, helps explain the flexibility and speed of sensorimotor learning and our ability to cope with high-dimensional work spaces and tools.

PURPOSE
Skew deviation is a vertical strabismus caused by damage to the otolithic-ocular reflex pathway and is associated with abnormal ocular torsion. This study was conducted to determine whether patients with skew deviation show the normal pattern of three-dimensional eye control called Listing's law, which specifies the eye's torsional angle as a function of its horizontal and vertical position.

METHODS
Ten patients with skew deviation caused by brain stem or cerebellar lesions and nine normal control subjects were studied. Patients with diplopia and neurologic symptoms less than 1 month in duration were designated as acute (n = 4) and those with longer duration were classified as chronic (n = 10). Serial recordings were made in the four patients with acute skew deviation. With the head immobile, subjects made saccades to a target that moved between straight ahead and eight eccentric positions, while wearing search coils. At each target position, fixation was maintained for 3 seconds before the next saccade. From the eye position data, the plane of best fit, referred to as Listing's plane, was fitted. Violations of Listing's law were quantified by computing the "thickness" of this plane, defined as the SD of the distances to the plane from the data points.

RESULTS
Both the hypertropic and hypotropic eyes in patients with acute skew deviation violated Listing's and Donders' laws-that is, the eyes did not show one consistent angle of torsion in any given gaze direction, but rather an abnormally wide range of torsional angles. In contrast, each eye in patients with chronic skew deviation obeyed the laws. However, in chronic skew deviation, Listing's planes in both eyes had abnormal orientations.

Patients with acute skew deviation violated Listing's law, whereas those with chronic skew deviation obeyed it, indicating that despite brain lesions, neural adaptation can restore Listing's law so that the neural linkage between horizontal, vertical, and torsional eye position remains intact. Violation of Listing's and Donders' laws during fixation arises primarily from torsional drifts, indicating that patients with acute skew deviation have unstable torsional gaze holding that is independent of their horizontal-vertical eye positions.

Adaptive neural mechanism for Listing's law revealed in patients with skew deviation caused by brainstem or cerebellar lesion.

Optimal inference explains dimension-specific contractions of spatial perception

The theoretical horopter is an interesting qualitative tool for conceptualizing binocular correspondence, but its quantitative applications have been limited because they have ignored ocular kinematics and vertical binocular sensory fusion. Here we extend the mathematical definition of the horopter to a full surface over visual space, and we use this extended horopter to quantify binocular alignment and visualize its dependence on eye position. We reproduce the deformation of the theoretical horopter into a spiral shape in tertiary gaze as first described by Helmholtz (1867). We also describe a new effect of ocular torsion, where the Vieth-Müller circle rotates out of the visual plane for symmetric vergence conditions in elevated or depressed gaze. We demonstrate how these deformations are reduced or abolished when the eyes follow the modification of Listing's law during convergence called L2, which enlarges the extended horopter and keeps its location and shape constant across gaze directions.

The extended horopter: quantifying retinal correspondence across changes of 3D eye position.

Patients With Skew Deviation Have Abnormal Torsion but Obey Listing’s Law

Here we examined the level of the lateral occipital (LO) area within the processing stream of the ventral visual cortex. An important determinant of an area's level of processing is whether it codes visual elements on both sides of the visual field, as do higher visual areas, or prefers those in the contralateral visual field, as do early visual areas. The former would suggest that LO, on one side, combines bilateral visual elements into a whole, while the latter suggests that it codes only the parts of forms. We showed that LO has a relative preference for visual objects in the contralateral visual field. LO responses were influenced by attention. However, relative changes in LO activity caused by changes in object location were preserved even when attention was shifted away from the objects to moving random dot patterns on the opposite side. Our data offer a new view on LO as an intermediate, but not a high-level, visual area in which neurons are driven by visual input and spatial attention in a multiplicative fashion.

A contralateral preference in the lateral occipital area: sensory and attentional mechanisms.

The influence of head position and head reorientation on the axis of eye rotation and the vestibular time constant during postrotatory nystagmus

Interaction of Retinal Image and Eye Velocity in Motion Perception

Optimal transsaccadic integration explains distorted spatial perception

Palsy of a nerve might be expected to lower vestibulo‐ocular reflex (VOR) responses in its fields of motion, but effects of peripheral neuromuscular disease were unknown. We recorded the VOR during sinusoidal head rotations in yaw, pitch, and roll at 0.5‐2 Hz and static torsional gain in 43 patients with unilateral nerve palsies. Sixth nerve palsy (n= 21) reduced both abduction and adduction VOR gains in darkness. In light, horizontal visually enhanced VOR (VVOR) gains were normal in moderate and mild palsy. In severe palsy, horizontal VVOR gains remained low in the paretic eye when it was fixating, whereas gains in the nonparetic eye became higher than normal. Third nerve palsy (n= 10) decreased VOR and VVOR gains during abduction, adduction, elevation, depression, extorsion, and intorsion. Fourth nerve palsy (n= 13) reduced VOR gains of the paretic eye during intorsion, extorsion, elevation, depression, abduction, and adduction, but in light vertical and horizontal VVOR gains were normal. In the nonparetic eye, all gains were normal. Reduced VOR gains in the direction of paretic muscles and also in the direction of their antagonists, together with normal gains in the nonparetic eye, indicate a selective adjustment to the antagonists of paretic muscles. Increase of VVOR gains to normal in the paretic eye, when used for fixation, without conjugate increase in gains in the occluded nonparetic eye, provides further evidence of selective adaptation for the paretic eye. Motions of the eyes after nerve palsies indicate monocular VOR adaptation in three dimensions.

Adaptations and Deficits in the Vestibulo‐Ocular Reflex after Peripheral Ocular Motor Palsies

In animals with binocular depth vision, or stereopsis, the visual fields of the two eyes overlap, shrinking the overall field of view. Eye movements increase the field of view, but they also complicate the first stage of stereopsis: the search for corresponding images on the two retinas. If the eyes were stationary in the head, corresponding images would always lie on retina-fixed bands called epipolar lines. Because the eyes rotate, the epipolar lines move on the retinas. Therefore, the stereoptic system has a choice: it may monitor eye position to keep track of the epipolar lines, or it may give up on tracking epipolar lines and instead search for matches over retina-fixed regions, but in that case the search regions must be 2-D patches, large enough to encompass all possible locations of the epipolar lines in all usual eye positions. We use a new type of random-dot stereogram to show that human stereopsis uses large, retina-fixed search zones. We show that the brain somewhat reduces the size of these search zones by rotating the eyes about their lines of sight in a way that reduces the motion of the epipolar lines. These findings show the link between sensory and motor processes: by considering eye motion we can understand why the brain searches for matching images over 2-D retinal regions rather than along epipolar lines; and by considering retinal correspondence we appreciate why the eyes rotate as they do about their lines of sight.

Static head roll about the naso-occipital axis is known to produce an opposite ocular counterroll with a gain of approximately 10%, but the purpose and neural mechanism of this response remain obscure. In theory counterroll could be maintained either by direct tonic vestibular inputs to motoneurons, or by a neurally integrated pulse, as observed in the saccade generator and vestibulo-ocular reflex. When simulated together with ocular drift related to torsional integrator failure, the direct tonic input model predicted that the pattern of drift would shift torsionally as in ordinary counterroll, but the integrated pulse model predicted that the equilibrium position of torsional drift would be unaffected by head roll. This was tested experimentally by measuring ocular counterroll in 2 monkeys after injection of muscimol into the mesencephalic interstitial nucleus of Cajal. Whereas 90 degrees head roll produced a mean ocular counterroll of 8.5 degrees (+/-0.7 degrees SE) in control experiments, the torsional equilibrium position observed during integrator failure failed to counterroll, showing a torsional shift of only 0.3 degrees (+/-0.6 degrees SE). This result contradicted the direct tonic input model, but was consistent with models that implement counterroll by a neurally integrated pulse.

Static ocular counterroll is implemented through the 3-D neural integrator.

As we move through space, stationary objects around us show motion parallax: their directions relative to us change at different rates, depending on their distance. Does the brain incorporate parallax when it updates its stored representations of space? We had subjects fixate a distant target and then we flashed lights, at different distances, onto the retinal periphery. Subjects translated sideways while keeping their gaze on the distant target, and then they looked to the remembered location of the flash. Their responses corrected almost perfectly for parallax: they turned their eyes farther for nearer targets, in the predicted nonlinear patterns. Computer simulations suggest a neural mechanism in which feedback about self-motion updates remembered locations of objects within an internal map of three-dimensional visual space.

Motion Parallax Is Computed in the Updating of Human Spatial Memory

1. Brain of darkness 2. Guide to the interior 3. On the shoulders of computers 4. Genome for a network 5. The adaptive brain 6. Unfolding in time 7. Brains and brawn 8. Thoughts running in circles 9. Degrees of freedom 10. The flow of information 11. Inference 12. The search for intelligent life in the brain

Microcosms of the Brain: What Sensorimotor Systems Reveal about the Mind

Twenty-seven patients with unilateral sixth nerve palsy and ten normal subjects were studied. The range of ductions was examined and the degree of abduction defect was recorded. The amount of horizontal and vertical deviations was measured in nine diagnostic positions by the prism and cover test, Maddox rod and prism test, and magnetic scleral search coils. MRI with enhancement was performed for patients under 50 years of age and those with neurologic signs. CT with contrast was obtained in patients with ischemic risk factors and those over 50 years of age. If CT was normal, patients were followed at about 3 months. Those without improvement at 3 months and those with an abnormal CT were further investigated with MRI. We report here the primary deviations in our subjects; the results for secondary deviations were similar. ANOVA was used for statistical analysis.

Hyperdeviation and Static Ocular Counterroll in Unilateral Abducens Nerve Palsy

PURPOSE
During fixation and saccades, human eye movements obey Listing's law, which specifies the torsional eye position for each combination of horizontal and vertical eye positions. To study the mechanisms that implement Listing's law, the authors measured whether the law was violated in peripheral and central unilateral sixth nerve palsy.

METHODS
Twenty patients with peripheral (13 chronic, 7 acute) sixth nerve palsy, 7 patients with central sixth nerve palsy caused by brainstem lesions, and 10 normal subjects were studied with scleral search coils. With the head immobile, subjects made saccades to a target that moved between straight ahead and eight eccentric positions. At each target position, fixation was maintained for 3 seconds before the next saccade. To quantify violations of Listing's law, we measured ocular torsion during fixation and during saccades, and compared it with the torsion predicted by the law. The SD of the differences between the predicted and measured torsion was called Listing deviation.

RESULTS
Patients with central sixth nerve palsy had abnormal ocular torsion in both the paretic and nonparetic eyes, which violated Listing's law. During fixation, Listing deviation averaged 2.4 degrees in the paretic eye and 1.7 degrees in the nonparetic eye, compared with 0.8 degrees in normal control subjects (P < 0.05). During saccades, the Listing deviation averaged 2.7 degrees in the paretic eye, and 1.6 degrees in the nonparetic eye, compared with 0.8 degrees in normal control eyes (P < 0.05). Donders' law was also violated in both eyes of patients with central sixth nerve palsy. They showed an abnormally wide range of ocular torsion in any given gaze direction. In contrast, patients with acute peripheral palsy had abnormal ocular torsion only in the paretic eye. Listing deviation of the paretic eye averaged 2.3 degrees during fixation and 3.2 degrees during saccades (P < 0.05). Donders' law was obeyed in acute peripheral palsy. Patients with chronic peripheral sixth nerve palsy obeyed Listing's and Donders' laws during both fixation and saccades.

Patients with central unilateral sixth nerve palsy have abnormal ocular torsion in both eyes, demonstrating that brainstem circuits normally participate in the maintenance of Listing's law. Eye movements in patients with acute peripheral sixth nerve palsy violate Listing's law, whereas those in patients with chronic peripheral palsy obey it, indicating that neural adaptation can restore Listing's law, even when the eye muscle remains abnormal.

Adaptive neural mechanism for Listing's law revealed in patients with sixth nerve palsy.

PURPOSE
During fixation and saccades, human eye movements obey Listing's law, which specifies the eye's torsional angle as a function of its horizontal and vertical position. Torsion of the eye is in part controlled by the fourth nerve. This study investigates whether the brain adapts to defective torsional control after fourth nerve palsy.

METHODS
Thirteen patients with fourth nerve palsy (11 chronic, 2 acute), and 10 normal subjects were studied with scleral search coils. With the head immobile, subjects made saccades to a target that moved between straight ahead and eight eccentric positions. At each target position, fixation was maintained for 3 seconds before the next saccade. From the eye position data, we computed the plane of best fit, referred to as Listing's plane. Violations of Listing's law were quantified by computing the "thickness" of this plane, defined as the SD of the distances to the plane from the data points.

RESULTS
Both the paretic and nonparetic eyes in patients with chronic fourth nerve palsy obeyed Listing's law during fixation and saccades. However, Listing's planes in both eyes had abnormal orientations, being rotated temporally, meaning the eye excyclotorted during downgaze and incyclotorted during upgaze. In contrast, the paretic eye of patients with acute fourth nerve palsy violated Listing's law during saccades. During downward saccades, transient torsional deviations moved the paretic eye out of Listing's plane. Torsional drifts returned the paretic eye to Listing's plane during subsequent fixation.

During saccades, acute fourth nerve palsy violates Listing's law, whereas chronic palsy obeys it, indicating that neural adaptation can restore Listing's law by adjusting the innervations to the remaining extraocular muscles, even when one eye muscle remains paretic. The transient torsional deviations during downward saccades in acute palsy are attributed to pulse-step mismatch, as a result of lesions in the trochlear nerve that lead to an imbalance of phasic and tonic signals reaching the muscles.

Adaptive neural mechanism for listing's law revealed in patients with fourth nerve palsy.

Twenty-seven patients with unilateral sixth nerve palsy and 10 normal subjects were studied. Informed consent was obtained from each subject. Patients with diplopia of less than 4 weeks’ duration were classified as having acute palsy; all others were designated here as having chronic palsy. MRI with enhancement was performed for patients under 50 years of age and for those with neurologic signs. CT with contrast was obtained in patients with ischemic risk factors and those over 50 years of age. If the CT was normal, patients were followed at about 3 months. Those without improvement at 3 months and those with an abnormal CT were further investigated with MRI. Eye positions were measured with magnetic search coils while patients followed a laser target at 1 m with one eye covered. The laser was programmed to appear in nine different target positions, arranged in a 3 × 3 square. With head immobile, subjects made saccades to a target that moved between straight ahead and 8 eccentric positions. At each target position, fixation was maintained for 3 seconds before the next saccade. Using fitted functions, we quantified violations of Listing’s law by comparing the ocular torsion in each recorded eye position to the torsion predicted by the law. The standard deviation of the differences between the predicted and measured torsion was called Listing deviation.

Implementation of Listing's Law in Patients with Unilateral Sixth Nerve Palsy

We use rapid eye movements called saccades to direct our foveae to different parts of our surroundings. But how do we combine information from successive fixations? Surprisingly, we are blind even to large changes in the visual display occurring during saccades.1,2 For example, we are poor at recognizing shifts of a visual target when the shift coincides with the eye movement. This transsaccadic change blindness for displacement is commonly taken as evidence that our ability to integrate quantitative spatial information from successive fixations is poor. However, other studies suggest that under some conditions quantitative presaccadic information is still available after a saccade.3,4 Here we argue for a new interpretation of change blindness. We suggest that the integration of information across saccades relies on principles of optimal—or Bayesian—inference, and that change blindness is a consequence of this strategy. To interpret changes in the retinal image, the brain could employ visual and nonvisual information. From proprioceptive or motor information (e.g. efference copy), it could learn which changes in the retinal image might be due to eye motion rather than allocentric shifts, that is, movements of objects in the world. Visually it could identify common features in the retinal images before and after the saccade to try to deduce eye movements and allocentric shifts. Finally, the brain has sensitive visual motion detectors that respond to most allocentric motion, but that are switched off during saccades.5 We trained an artificial neural network to detect allocentric stimulus motion based on these three information sources: eye-movement signals, retinal position, and visual motion detectors. We took into account that (a) in normal life allocentric shifts seldom coincide precisely with saccades and (b) motion detection is quite accurate compared to the other two signals. Using a backprop algorithm with momentum, the network learned to combine its three input signals into a statistically optimal estimate of the allocentric motion. As

The vestibulo-ocular reflex in fourth nerve palsy: deficits and adaptation

Visual perception of impossible geometries: local and global constraints in stereopsis

The brain uses vision and other senses to compute the locations of objects relative to the body, and then must update these locations when the body moves. How geometrically sophisticated is this internal updating? It has been suggested that updating simply shifts the stored locations of all objects uniformly, by a common vector, when the eye or head turns. For horizontal and vertical turns, a uniform shift would often approximate the real changes in location of objects in front of the subject. But for torsional rotations, a shift would be inadequate: accurate updating would call for a more geometrically exact remapping, not shifting but rotating the stored locations through the inverse of the rotation of the eye in space. Here we asked human subjects to make eye saccades to remembered targets after torsional head rotations. Their accuracy showed that spatial updating works in the torsional dimension and operates by rotation rather than shifting.

Rotational Remapping in Human Spatial Memory during Eye and Head Motion

PURPOSE
The effects of paralytic strabismus on the vestibulo-ocular reflex (VOR) have not been systematically investigated in humans. The purpose of this study was to analyze the VOR in patients with unilateral peripheral sixth nerve palsy.

METHODS
Twenty-one patients with unilateral peripheral sixth nerve palsy (6 severe, 7 moderate, 8 mild) and 15 normal subjects were studied. Subjects made sinusoidal +/-10 degrees head-on-body rotations in yaw and pitch at approximately 0.5 and 2 Hz, and in roll at approximately 0.5, 1, and 2 Hz. Eye movement recordings were obtained using magnetic scleral search coils in each eye in darkness and during monocular viewing in light. Static torsional VOR gains, defined as change in torsional eye position divided by change in head position during sustained head roll, were also measured.

RESULTS
In all patients, horizontal VOR gains in darkness were decreased in the paretic eye in both abduction and adduction, but remained normal in the nonparetic eye in both directions. In light, horizontal visually enhanced VOR (VVOR) gains were normal in both eyes in moderate and mild palsy. In severe palsy, horizontal VVOR gains remained low in the paretic eye during viewing with either eye, whereas those in the nonparetic eye were higher than normal when the paretic eye viewed. Vertical VOR and VVOR were normal, but dynamic and static torsional VOR and VVOR gains were reduced in both eyes in all patients.

In darkness, horizontal VOR gains were reduced during abduction of the paretic eye in all patients, as anticipated in sixth nerve palsy. Gains were also reduced during adduction of the paretic eye, suggesting that innervation to the medial rectus has changed. After severe palsy, vision did not increase abducting or adducting horizontal VVOR gains to normal in the paretic eye, but caused secondary increase in VVOR gains to values above unity in the nonparetic eye, when the paretic eye fixated. In mild and moderate palsy, vision enhanced the VOR in the paretic eye but caused no change in the nonparetic eye, suggesting a monocular readjustment of innervation selectively to the paretic eye. Vertical VOR and VVOR gains were normal, indicating that the lateral rectus did not have significant vertical actions through the excursions that we tested (+/-10 degrees ). Reduced torsional VOR gains in the paretic eye can be explained by the esotropia in sixth nerve palsy. Torsional VOR gain normally varies with vergence. We attribute the reduced torsional gains in the paretic eye to the mechanism that normally lowers it during convergence. The low torsional gains in the nonparetic eye may be an adaptation to reduce torsional disparity between the two eyes.

Adaptations and deficits in the vestibulo-ocular reflex after sixth nerve palsy.

Soft tissue "pulleys" in the orbit alter the paths of the eye muscles in a way that may simplify the brain's work in implementing Listing's law, i.e., in holding ocular torsion at zero. But Listing's law does not apply to some oculomotor systems, such as the vestibuloocular reflex (VOR), which shows a different kinematic pattern. To explain this different pattern, some authors have assumed that the pulleys must adopt a different configuration, retracting along their muscles when the eye switches from Listing's law to VOR mode. The proposed retraction has not so far been observed, although the pulleys do move in other ways. We show that the hypothetical retraction of the pulleys would not in fact explain the full kinematic pattern seen in the VOR. But this pattern can be explained entirely on the basis of pulley positions and motions that have actually been observed. If one takes into account the neural processing within the VOR, specifically the fact that the reflex is weak in the torsional dimension, then a single mode of pulley action can serve both vestibuloocular kinematics and Listing's law.

The eyes are controlled by multiple brain circuits, some phylogenetically old and some new, whose aims may conflict. Old otolith reflexes counterroll the eyes when the head tilts relative to gravity. Newer vergence mechanisms coordinate the eyes to aid stereoptic vision. We show that counterroll hinders stereopsis, weakly when you look into the distance but strongly when you look near. The resolution of this conflict is that counterroll virtually vanishes when monkeys look close, i.e., stereopsis overrides gravity-driven reflexes but only on near gaze. This balance between gyroscopic and stereoptic mechanisms explains many other puzzling features of primate gaze control, such as the weakness of our otolith-ocular reflexes even during far viewing and the strange geometry of the primate counterpitch reflex, which rolls the eyes clockwise when monkeys look leftward while their heads are tipped nose up, but rolls them counterclockwise when the monkeys look rightward, and reverses this pattern when the head is tipped nose down.

In the 19th century, Donders observed that only one three-dimensional eye orientation is used for each gaze direction. Listing's law further specifies that the full set of eye orientation vectors forms a plane, whereas the equivalent Donders' law for the head, the Fick strategy, specifies a twisted two-dimensional range. Surprisingly, despite considerable research and speculation, the biological reasons for choosing one such range over another remain obscure. In the current study, human subjects performed head-free gaze shifts between visual targets while wearing pinhole goggles. During fixations, the head orientation range still obeyed Donders' law, but in most subjects, it immediately changed from the twisted Fick-like range to a flattened Listing-like range. Further controls showed that this was not attributable to loss of binocular vision or increased range of head motion, nor was it attributable to blocked peripheral vision; when subjects pointed a helmet-mounted laser toward targets (a task with goggle-like motor demands but normal vision), the head followed Listing's law even more closely. Donders' law of the head only broke down (in favor of a “minimum-rotation strategy”) when head motion was dissociated from gaze. These behaviors could not be modeled using current “Donders' operators” but were readily simulated nonholonomically, i.e., by modulating head velocity commands as a function of position and task. We conclude that the gaze control system uses such velocity rules to shape Donders' law on a moment-to-moment basis, not primarily to satisfy perceptual or anatomic demands, but rather for motor optimization; the Fick strategy optimizes the role of the head as a platform for eye movement, whereas Listing's law optimizes rapid control of the eye (or head) as a gaze pointer.

Task-Dependent Constraints in Motor Control: Pinhole Goggles Make the Head Move Like an Eye

Six subjects fixated an imagined space-fixed target in darkness, or a visible target against a structured visual background, while rotating their heads actively in yaw, pitch and roll at four different frequencies, from 0.3 to 2.4 Hz. We used search coils to measure the 3-dimensional rotations of the head and eye, and described the relation between them--the input-output function of the rotational vestibulo-ocular reflex (VOR)--using gain matrices. We found consistent cross-coupling in which torsional head rotation evoked horizontal eye rotation. The reason may be that the eyes are above the axis of torsional head rotation, and therefore may translate horizontally during the head motion, so the VOR rotates them horizontally to compensate. Torsional gain was lower than horizontal or vertical, more variable from subject to subject and decreased at low frequencies. One reason for the low gain may be that torsional head rotation produces little retinal slip near the fovea; hence little compensatory eye motion is needed, and so the VOR reduces its torsional gain to save energy or to approximate Listing's law by keeping ocular torsion near zero. In addition, the human VOR has little experience with purely torsional head rotations and so its adaptive networks may be poorly trained for such stimuli. The drop in torsional gain at low frequencies can be explained based on the leak in the neural integrator that helps convert torsional eye-velocity commands into eye-position commands.

Torsional dynamics and cross-coupling in the human vestibulo-ocular reflex during active head rotation.

Previous studies have indicated that timing of finger opening in an overarm throw is likely controlled centrally, possibly by means of an internal model of hand trajectory. The present objective was to extend the study of throwing to an examination of the dynamics of finger opening. Throwing a heavy ball and throwing a light ball presumably require different neural commands, because the weight of the ball affects the mechanics of the arm, and particularly, the mechanics of the finger. Yet finger control is critical to the accuracy of an overarm throw. We hypothesized that finger opening in an overarm throw is controlled by a central mechanism that uses an internal model to predict and compensate for movement-dependent back forces on the fingers. To test this idea we determined whether finger motion is affected by back forces, i.e., whether larger back forces cause larger finger extensions. Back forces were varied by having subjects throw, at the same fast speed, tennis-sized balls of different weights (14, 55, and 196 g). Arm- and finger-joint rotations were recorded with the search-coil technique; forces on the middle finger were measured with force transducers. Recordings showed that during ball release, the middle finger experienced larger back forces in throws with heavier balls. Nevertheless, most subjects showed proximal interphalangeal joint extensions that were unchanged or actually smaller with the heavier balls. This was the case for the first throw and for all subsequent throws with a ball of a new weight. This suggests that the finger flexors compensated for the larger back forces by exerting larger torques during finger extension. Supporting this view, at the moment of ball release, all finger joints flexed abruptly due to the now unopposed torques of the finger flexors, and the amplitude of this flexion was proportional to ball weight. We conclude that in overarm throws made with balls of different weights, the CNS predicts the different back forces from the balls and adjusts finger flexor torques accordingly. This is consistent with the view that finger opening in overarm throws is controlled by means of an internal model of the motor apparatus and the external load.

Prediction and compensation by an internal model for back forces during finger opening in an overarm throw.

Horizontal and vertical movements of the human eye bring new objects to the center of the visual field, but torsional movements rotate the visual world about its center. Ocular torsion stays near zero during head-fixed gaze shifts, and eye movements to visual targets are thought to be driven by purely horizontal and vertical commands. Here, analysis of eye-head gaze shifts revealed that gaze commands were three-dimensional, with a separate neural control system for torsion. Active torsion optimized gaze control as no two-dimensional system could have, stabilizing the retinal image as quickly as possible when it would otherwise have spun around the fixation point.

Using a synoptophore to test Listing's law during vergence in normal subjects and strabismic patients

We examined two ways in which the neural control system for eye-head saccades constrains the motion of the eye in the head. The first constraint involves Listing's law, which holds ocular torsion at zero during head-fixed saccades. During eye-head saccades, does this law govern the eye's motion in space or in the head? Our subjects, instructed to saccade between space-fixed targets with the head held still in different positions, systematically violated Listing's law of the eye in space in a way that approximately, but not perfectly, preserved Listing's law of the eye in head. This finding implies that the brain does not compute desired eye position based on the desired gaze direction alone but also considers head position. The second constraint we studied was saturation, the process where desired-eye-position commands in the brain are "clipped" to keep them within an effective oculomotor range (EOMR), which is smaller than the mechanical range of eye motion. We studied the adaptability of the EOMR by asking subjects to make head-only saccades. As predicted by current eye-head models, subjects failed to hold their eyes still in their orbits. Unexpectedly, though, the range of eye-in-head motion in the horizontal-vertical plane was on average 31% smaller in area than during normal eye-head saccades, suggesting that the EOMR had been reduced by effort of will. Larger reductions were possible with altered visual input: when subjects donned pinhole glasses, the EOMR immediately shrank by 80%. But even with its reduced EOMR, the eye still moved into the "blind" region beyond the pinhole aperture during eye-head saccades. Then, as the head movement brought the saccade target toward the pinhole, the eyes reversed their motion, anticipating or roughly matching the target's motion even though it was still outside the pinhole and therefore invisible. This finding shows that the backward rotation of the eye is timed by internal computations, not by vision. When subjects wore slit glasses, their EOMRs shrank mostly in the direction perpendicular to the slit, showing that altered vision can change the shape as well as the size of the EOMR. A recent, three-dimensional model of eye-head coordination can explain all these findings if we add to it a mechanism for adjusting the EOMR.

Current theories of eye-head gaze shifts deal only with one-dimensional motion, and do not touch on three-dimensional (3-D) issues such as curvature and Donders' laws. I show that recent 3-D data can be explained by a model based on ideas that are well established from one-dimensional studies, with just one new assumption: that the eye is driven toward a 3-D orientation in space that has been chosen so that Listing's law of the eye in head will hold when the eye-head movement is complete. As in previous, one-dimensional models, the eye and head are feedback-guided and the commands specifying desired eye position eye pass through a neural "saturation" so as to stay within the effective oculomotor range. The model correctly predicts the complex, 3-D trajectories of the head, eye in space, and eye in head in a variety of saccade tasks. And when it moves repeatedly to the same target, varying the contributions of eye and head, the model lands in different eye-in-space positions, but these positions differ only in their cyclotorsion about the line of sight, so they all point that line at the target-a behavior also seen in real eye-head saccades. Between movements the model obeys Listing's law of the eye in head and Donders' law of the head on torso, but during certain gaze shifts involving large torsional head movements, it shows marked, 8 degrees deviations from Listing's law. These deviations are the most important untested predictions of the theory. Their experimental refutation would sink the model, whereas confirmation would strongly support its central claim that the eye moves toward a 3-D position in space chosen to obey Listing's law and, therefore, that a Listing operator exists upstream from the eye pulse generator.

1. Accurate overarm throwing requires precise control of joint rotations so that the ball is released at the appropriate time on the appropriate hand trajectory. Inaccuracy in throws, in turn, must result from errors in the control of joint rotations. But do high and low throws result from disorders in the joint rotations that produce the hand trajectory or in those that cause ball release? Are they due to error at a particular joint or to accumulation of errors across a number of joints? The objective was to answer these questions and thereby to gain insight into the CNS control of joint rotations in a skilled arm movement task. 2. Ten subjects--male, right-handed recreational ball players, all accurate throwers--sat with a fixed trunk and threw tennis balls at a 9 x 9 grid of 6-cm target squares 1.5 or 3 m away. Rotations of five arm segments in three dimensions were measured at 1,000 Hz with the magnetic-field search-coil technique. Hand trajectory (translation) was computed from these rotations. 3. The cause of ball high-low inaccuracy was investigated by determining its relation with hand kinematic parameters that could potentially affect it. No statistically significant relation was found between height of ball impact on the target and height of the hand trajectory. In contrast, statistically significant relations appeared between height of ball impact on the target and both hand trajectory length at ball release (for 8 of 10 subjects) and finger and hand orientation in space at ball release (for all 10 subjects). 4. Three hypotheses were proposed to explain the variable finger and hand orientations in space at ball release, i.e., that they resulted from errors in velocity of rotation at one or more proximal joints (wrist, elbow, shoulder), timing of onset of rotation at one or more proximal joints, or timing of ball release (due to incorrect velocity or timing of onset of finger opening). All three mechanisms could result in inappropriate finger and hand orientations in space at ball release, but the pattern of joint space trajectories would be different in each case. 5. High and low throws did not follow the joint space paths predicted by the first two hypotheses. Instead, as predicted by the third hypothesis, a separation of traces occurred when finger extension was plotted against wrist flexion or against elbow extension, e.g., for a given amplitude of wrist flexion, finger extension was large for the high throws and small for the low throws. 6. In agreement, when all throws were considered, a statistically significant (P < 0.005) relation was found between ball impact height on the target and the amplitude of finger extension, for a fixed amplitude of wrist flexion (10 subjects), and for a fixed amplitude of elbow extension (8 subjects). Only two subjects showed a statistically significant relation between ball impact height and the amplitude of wrist flexion, for a fixed amplitude of elbow extension. 7. The separation of finger extension-wrist flexion traces in joint space for high and low throws was due to a difference in the timing of onset of finger rotation with respect to the wrist rather than to an inappropriate velocity of the finger (or the wrist). 8. As expected, all 10 subjects showed statistically significant relations between the time of onset of finger extension and both finger orientation in space at ball release and height of ball impact on the target. 9. It is concluded that in fast arm-only throws made by male recreational ball players, high and low throws do not primarily result from variability in the height of the hand trajectory or from variability in the amplitude of one or more proximal joints due to errors in the velocity or timing of onset of these joint rotations. Instead, in most cases, they result from inappropriate timing of onset of rotation of the fingers with respect to the rotations of the other joints and thus to inappropriate timing of ball release. These findings emphasize the im

Errors in the control of joint rotations associated with inaccuracies in overarm throws.

1. What is the neural mechanism of vestibuloocular reflex (VOR) cancellation when a subject fixates a target moving with the head? One theory is that the moving target evokes pursuit eye movements that add to and cancel the VOR. A recent finding with implications for this theory is that eye velocity vectors of both pursuit and the VOR vary with eye position, but in different ways, because pursuit follows Listing's law whereas the VOR obeys a "half-Listing" strategy. As a result, pursuit cannot exactly cancel the VOR in most eye positions, and so the pursuit superposition theory predicts an eye-position-dependent pattern of residual eye velocities during cancellation. To test these predictions, we measured eye velocity vectors in humans during VOR, pursuit, and cancellation in response to torsional, vertical, and horizontal stimuli with the eyes in different positions. 2. For example, if a subject is rolling clockwise (CW, frequency 0.3 Hz, maximum speed 37.5 deg/s) while looking 20 deg up, the VOR generates an eye velocity that is mainly counterclockwise (CCW), but also leftward. If we then turn on a small target light, located 20 deg up and moving with the subject, then pursuit superposition predicts that the CCW component of eye velocity will shrink and the horizontal component will reverse, from leftward to rightward. This pattern was seen in all subjects. 3. Velocities depended on eye position in the predicted way; e.g., when subjects looked 20 deg down, instead of 20 deg up, during CW roll, the reversal of horizontal eye velocity went the other way, from rightward to leftward. And when gaze was 20 deg right or left, analogous reversals occurred in the vertical eye velocity, again as predicted. 4. Analogous predictions for horizontal and vertical stimulation were also borne out by the data. For example, when subjects rotated rightward while looking 20 deg up, the VOR response was leftward and CCW. When the target light switched on, the torsional component of the response reversed, becoming CW. And analogous predictions for other eye positions and for vertical stimulation also held. 5. For all axes of stimulation and all eye positions, eye velocity during cancellation was roughly parallel with the gaze line. This alignment is predicted by pursuit superposition and has the effect of reducing retinal image slip over the fovea. 6. The fact that the complex dependence of eye velocity on the stimulation axis and eye position predicted by pursuit superposition was seen in all subjects and conditions suggests strongly that the VOR indeed is canceled additively by pursuit. However, eye velocities during cancellation were consistently smaller than predicted. This shrinkage indicates that a second mechanism, besides pursuit superposition, attenuates eye velocities during cancellation. The results can be explained if VOR gain is reduced by approximately 30%, and if, in addition, pursuit is driven by retinal slip rather than reconstructed target velocity in space.

Interaction of smooth pursuit and the vestibuloocular reflex in three dimensions.

1. Overarm throws made with the nondominant arm are usually less accurate than those made with the dominant arm. The objective was to determine the errors in the joint rotations associated with this inaccuracy, and thereby to gain insight into the neural mechanisms that contribute to skill in overarm throwing. 2. Overarm throws from both left and right arms were recorded on different occasions as six right-handed subjects sat with a fixed trunk and threw 150 tennis balls at about the same speed at a 6-cm square on a target grid 3 m away. Joint rotations at the shoulder, elbow, wrist, and finger, and arm translations, were computed from recordings of arm segment orientations made with the magnetic-field search-coil technique. 3. All subjects threw less accurately in this task with the left (nondominant) arm. For throws made with the left arm, the height of ball impact on the target grid was related to hand trajectory length and to hand orientation in space at ball release, but not to hand trajectory height. 4. Two hypotheses were proposed to explain the decreased ball accuracy in the high-low direction during throwing with the nondominant arm: that it was caused by increased variability in the velocity or timing of onset of rotations at proximal joints (which determine the path of the hand through space) or increased variability in the velocity or timing of onset of finger extension (which determine the moment of ball release). 5. A prediction of the first hypothesis was that proximal joint rotations should be more variable in throws with the left arm. This was the case for the majority of proximal joint rotations in the six subjects when variability was examined in joint space. However, some proximal joint rotations were more variable in the right arm. 6. The first hypothesis was directly tested by determining whether hand angular position in space (which represents the sum of all proximal joint rotations) was related to ball impact height on the target grid at a fixed translational position in the throw. No relation was found between these variables for throws with the left arm in four subjects, whereas a weak relation was found for two subjects. It was concluded that, considering all subjects, the first hypothesis could not explain the results. 7. In contrast, in agreement with the second hypothesis, a strong relation (P < 0.001) was found in all subjects between ball impact height on the target grid and time of ball release for throws with the left arm, and with time of onset of finger extension. 8. Across all six subjects the timing precision (windows) for 95% of the throws was (for ball release) right arm, 9.3 ms; left arm, 22.5 ms; (for onset of finger extension) right arm, 13.7 ms; left arm, 26.7 ms. 9. Timing of onset of finger extension was no less accurate than timing of onset of other joint rotations for both left and right arms. However, simulations of throws showed that, for the same error in timing, finger extension had twice as large an effect on ball direction as any other joint rotation. Timing errors at the fingers have a greater effect than errors at other joints because finger errors are scaled by the higher angular velocity of the hand in space rather than by the smaller angular velocities of the individual joints. 10. It is concluded that although rotations were in general more variable at both proximal and distal joints of the nondominant (left) arm, the major cause of its decreased throwing accuracy was increased variability at the distal joints, i.e., in the timing of onset of finger extension. This may be due to a lack of precision in the commands from the right hemisphere to the left fingers in right-handed throwers.

Overarm throws with the nondominant arm: kinematics of accuracy.

1. Three-dimensional (3D) eye and head rotations were measured with the use of the magnetic search coil technique in six healthy human subjects as they made large gaze shifts. The aims of this study were 1) to see whether the kinematic rules that constrain eye and head orientations to two degrees of freedom between saccades also hold during movements; 2) to chart the curvature and looping in eye and head trajectories; and 3) to assess whether the timing and paths of eye and head movements are more compatible with a single gaze error command driving both movements, or with two different feedback loops. 2. Static orientations of the eye and head relative to space are known to resemble the distribution that would be generated by a Fick gimbal (a horizontal axis moving on a fixed vertical axis). We show that gaze point trajectories during eye-head gaze shifts fit the Fick gimbal pattern, with horizontal movements following straight "line of latitude" paths and vertical movements curving like lines of longitude. However, horizontal (and to a lesser extent vertical) movements showed direction-dependent looping, with rightward and leftward (and up and down) saccades tracing slightly different paths. Plots of facing direction (the analogue of gaze direction for the head) also showed the latitude/longitude pattern, without looping. In radial saccades, the gaze point initially moved more vertically than the target direction and then curved; head trajectories were straight. 3. The eye and head components of randomly sequenced gaze shifts were not time locked to one another. The head could start moving at any time from slightly before the eye until 200 ms after, and the standard deviation of this interval could be as large as 80 ms. The head continued moving for a long (up to 400 ms) and highly variable time after the gaze error had fallen to zero. For repeated saccades between the same targets, peak eye and head velocities were directly, but very weakly, correlated; fast eye movements could accompany slow head movements and vice versa. Peak head acceleration and deceleration were also very weakly correlated with eye velocity. Further, the head rotated about an essentially fixed axis, with a smooth bell-shaped velocity profile, whereas the axis of eye rotation relative to the head varied throughout the movement and the velocity profiles were more ragged. 4. Plots of 3D eye orientation revealed strong and consistent looping in eye trajectories relative to space.(ABSTRACT TRUNCATED AT 400 WORDS)

The three-dimensional (3-D) properties if the vestibuloocular reflex (VOR) were studied in six normal human subjects during passive whole-body rotations in darkness and with full-field visual input in light. Subjects were asked to fixate a point target stationary in space straight ahead or to imagine such a target in darkness. Using a 3-D rotating chair, subjects were rotated sinusoidally (frequency .3 Hz, maximum speed 37.5 degrees/s) about an earth-vertical axis for horizontal stimulation and about an earth-horizontal axis for vertical and torsional stimulation. The subject faced forward for vertical stimulation, 90 degrees to the side for torsional stimulation, or 15 degrees to the right or left side for combined vertical and torsional stimulation. Left eye position was measured using 3-D search coils. The VOR response was quantified using the 3-D analogue of gain, a 3 x 3 matrix where each element describes the dependence of one component--torsional, vertical, or horizontal--of eye velocity on one component of head velocity. Average gain matrices were calculated for three cycles of rotation (10 s). Major findings were: (1) Gain values for the VOR were higher in light than in darkness for all directions. In light, vertical and horizontal responses were fully compensatory in both magnitude and direction, whereas the torsional responses were still weak. (2) Intersubject variability, large in the dark, was very small in the light for the vertical and horizontal responses but still considerable for the torsional.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of full-field visual input on the three-dimensional properties of the human vestibuloocular reflex.

Three-dimensional (3-D) eye movements during steady fixa- tion, saccades and smooth pursuit are governed by a powerful strategy re- stricting eye position to 2 degrees of freedom by keeping the torsional com- ponent close too (Listing's law). To test if Listing's law is also obeyed dur- ing optokinetic and vestibular stimulation, the study compares 3-D eye movements in humans during pursuit, optokinetic and vestibular activation using similar gaze trajectories. The optokinetic and vestibuloocular reflexes deviate from Listing's law showing a strategy lying about halfway between optimal full-field retinal image stabilization and Listing's law. The fact that for similar gaze trajectories the brain can choose between different 3-D movement strategies depending on the oculomotor subsystem currently in action (supposedly to optimize for the specific requirements of a particular oculomotor subsystem) suggests that Listing's law is due to a neurally-im- posed constraint on the oculomotor output.

Three-dimensional human eye movements are organized differently for the different

1. This series of three papers aims to describe the three-dimensional, kinematic input-output relations of the rotational vestibuloocular reflex (VOR) in humans, and to identify the functional advantages of these relations. In this first paper the response to sinusoidal rotation in darkness at 0.3 Hz, maximum speed 37.5%/s, was quantified by the use of the three-dimensional analogue of VOR gain: a 3 x 3 matrix where each element describes the dependence of one component (torsional, vertical, or horizontal) of eye velocity on one component of head velocity. 2. The three matrix elements indicating collinear gains (i.e., dependence of torsional eye velocity on torsional head velocity, vertical on vertical, and horizontal on horizontal) were smaller than the -1's required for optimal retinal image stabilization. Of these three the torsional gain was weakest: -0.37 for rotation about an earth-vertical axis, versus -0.73 and -0.64 for vertical and horizontal gains. Matrix elements indicating cross talk were mostly negligible. There was a tendency to leftward eye rotation in response to clockwise head motion, but this was not statistically significant. 3. VOR responses were compared for rotation about earth-vertical and earth-horizontal axes. The varying otolith input due to the rotation of the gravity vector relative to the head during earth-horizontal axis rotation made no difference to the collinear gains. 4. There were no consistent phase leads or lags except for a torsional phase lead of up to 10 degrees, usually more marked for clock-wise head rotation versus counterclockwise, and for oblique axis rotations versus purely torsional. 5. Torsional gain was magnified, averaging -0.52, when the torsional component of head rotation was only a small part of a predominantly vertical or horizontal rotation, i.e., when the axis of head rotation was near the frontal plane. Because most natural head rotations occur about such axes, the torsional VOR is probably somewhat stronger than the response to pure torsion would suggest. 6. The speed of eye rotation in response to a given stimulus varied widely among subjects, but the direction of rotation was much more uniform. For head rotations about oblique axes out of the frontal plane, there was a systematic misalignment of eye and head axes, with eye axes tilted toward the frontal plane. These findings can be explained on the basis of a strategy where the VOR balances the muscular effort of rotating the eyes against the cost of retinal slip.

Rotational kinematics of the human vestibuloocular reflex. I. Gain matrices.

1. Do neural computations in premotor circuits mirror the physical properties of the systems they control? In 1987, Tweed and Vilis showed that oculomotor theories where a neural integrator converts eye angular velocity commands into position commands cannot be correct, because angular position is not the integral of angular velocity. Recently Schnabolk and Raphan proposed that an angular velocity integrator is nevertheless used to generate tonic commands in the oculomotor system. Here we test the Schnabolk-Raphan (S-R) model against Tweed and Vilis's quaternion (Q) model of the velocity to position transformation. 2. The S-R model predicts large (up to 7 degrees) transient (approximately 700 ms) deviations ("blips") in torsional eye position during attempted horizontal and vertical saccades. The Q model predicts no blips. Search coil recordings of saccades by 7 normal human subjects showed no large blips. 3. For approximately 200 saccades by each subject, we plotted the area under the torsional blip versus the product of saccade eccentricity and magnitude. According to the S-R model, this graph should form a straight line with slope 1.00. According to the Q model, the slope should be zero. Measured slopes averaged 0.016 (range -0.073 to 0.061) for saccade targets at 20 degrees eccentricity and 0.040 (range 0.004-0.076) for targets at 40 degrees. 4. No parameter change can significantly improve the S-R model, but lowering one parameter eradicates the tiny inaccuracy in the Q model. We show that the fundamental reason for the S-R model's failure is its use of a commutative controller to steer a noncommutative plant.

Testing models of the oculomotor velocity-to-position transformation.

Three-dimensional (3-D) eye movements during steady fixation, saccades and smooth pursuit are governed by a powerful strategy restricting eye position to 2 degrees of freedom by keeping the torsional component close to o (Listing's law). To test if Listing's law is also obeyed during optokinetic and vestibular stimulation, the study compares 3-D eye movements in humans during pursuit, optokinetic and vestibular activation using similar gaze trajectories. The optokinetic and vestibuloocular reflexes deviate from Listing's law showing a strategy lying about halfway between optimal full-field retinal image stabilization and Listing's law. The fact that for similar gaze trajectories the brain can choose between different 3-D movement strategies depending on the oculomotor subsystem currently in action (supposedly to optimize for the specific requirements of a particular oculomotor subsystem) suggests that Listing's law is due to a neurally-im-posed constraint on the oculomotor output.

Three-dimensional human eye movements are organized differently for the different oculomotor subsystems

1. Gain matrices were used to quantify the three-dimensional vestibuloocular reflex (VOR) in five human subjects who were accelerated over 1 s and then spun at a constant 150 degrees/s for 29 s in darkness. Rotations were torsional, vertical and horizontal, about earth-vertical and earth-horizontal axes. 2. Elements on the main diagonal of the gain matrices were much smaller than the optimal value of -1, and torsional gain was weaker than vertical or horizontal. Off-diagonal elements, indicating cross talk, were minimal except for a small but consistent horizontal response to torsional head rotation. 3. Downward slow phases were more than twice as fast as upward at the start of rotation about both earth-vertical and earth-horizontal axes, but the asymmetry vanished later in the rotation. 4. During earth-vertical-axis rotation, all matrix elements decayed to zero. The main-diagonal torsional and vertical gains waned with time constants close to that of the cupula (6.7 and 7.3 s). Velocity storage prolonged the horizontal response to horizontal head rotation (time constant 14.2 s) but not the horizontal response to torsion (7.7 s). A simple explanation is that velocity storage acts on a central estimate of head motion that accurately distinguishes horizontal from torsional and that the inappropriate horizontal eye velocity response to torsion occurs because of cross talk downstream from velocity storage. 5. During earth-horizontal-axis rotation, the torsional, vertical, and horizontal main-diagonal elements declined, with time constants of 7.6, 8.2, and 7.9 s, to maintained nonzero values, all equal to about -0.1. Off-diagonal elements, including the horizontal response to torsion, decayed to zero, so that the otolith-driven reflex, late in the rotation, was equally strong in all dimensions and almost free of detectable cross talk. 6. The difference between gain curves over the course of earth-vertical- and earth-horizontal-axis rotations was not constant but increased with time, suggesting that the VOR response to earth-horizontal-axis rotation is not a simple sum of canal and otolith reflexes.

Rotational kinematics of the human vestibuloocular reflex. II. Velocity steps.

We studied the influence of static head position relative to the rotation axis on the three-dimensional (3-D) vestibuloocular reflex (VOR). By means of a 3-D rotating chair and a 3-D magnetic search-coil system, eye movements were recorded in 6 normal human subjects during sinusoidal rotation about an earth-vertical axis (yaw) with the head positioned at different pitch angles and about an earth-horizontal axis (pitch) with the head positioned at different yaw angles. We confirmed that torsional VOR gain is about 2/3 of horizontal and vertical VOR gain leading to non-collinear axes of eye and head rotation whenever torsional head movement components were present with eye movement axes tilting away from the torsional direction. Despite this non-collinearity of stimulus and eye movement rotation axes there was close to perfect adjustment of the different VOR components depending on the angle between gaze direction and stimulation axis, indicating a vectorial summation of gains obtained for rotations in the major body axes (roll, pitch and yaw). The horizontal and vertical eye movement components followed a cosine function of the angle between the plane of rotation and gaze direction. The torsional component followed a sine function.

Head position dependent adjustment of the three-dimensional human vestibuloocular reflex.

1. The fixation orientations adopted by the eye, head, and chest were examined when all three were allowed to participate in gaze shifts to visual targets. The objective was to discover whether there are invariant, neurally determined laws governing these orientations that might provide clues to the processes of perception and motor control. This is an extension of the classical studies of eye-only saccades that determined that there is only one eye orientation for each gaze direction (Donders' law) and that the rotations necessary to take the eye from a reference orientation to all other orientations adopted are about axes that lie in a plane (Listing's law). 2. The three-dimensional orientations of the static eyes, head, and chest were measured after each gaze shift to a visual target, the targets having been fixed at positions ranging from 0 to 135 degrees to the left and right of center and 45 degrees up and down. These measurements were taken of seven human subjects by means of the search coil technique with coils attached to the sternum, head, and right eye. Orientations were plotted as quaternion vectors so that those orientations obeying Donders' law formed a surface and those obeying Listing's law formed a plane. 3. The orientations adopted by the eye, head, and chest were found to be a small subset of those possible under the biomechanical and task-imposed constraints. Thus there is a neurally implemented restriction, specifically of the rotation of the eye relative to space (i.e., the orientation variable es) and to the head (eh); also of the rotation of the head relative to space (hs) and to the chest (hc), and the rotation of the chest relative to space (cs). Plotted as quaternion vectors, the data for each orientation variable formed a characteristic surfacelike shape. In the case of es, hs, and hc these were twisted surfaces, whereas for eh the surface was planar and for cs it was nearly linear. Thus to a first approximation each of the orientation variables conformed to Donders' law. 4. The eye adopted a pointing (gaze) direction that has the ratio of vertical to horizontal components generally greater than one when fixating each of the corner targets. The chest, by contrast, moved almost entirely in the horizontal direction, whereas the head performed an intermediate role. 5. The es-, hs-, and hc-fitted surfaces and cs-fitted lines were titled remarkably little from the vertical axis (i.e., the gravity direction) despite larger tilts being possible.(ABSTRACT TRUNCATED AT 400 WORDS)

Three-dimensional eye, head, and chest orientations after large gaze shifts and the underlying neural strategies.

1. Do slow phase eye velocities generated by the vestibuloocular reflex (VOR) depend on eye position? If the purpose of the VOR is simply to stabilize the retinal image, there can be no such dependence, because eye velocity must always be equal and opposite to head velocity. But if the VOR tolerates some retinal slip to achieve other goals, such as reducing eye velocity or following Listing's law, then one should see specific patterns of dependence. We examined VOR responses of human subjects to yaw, pitch, and roll rotation looking in various directions to quantify how the input-output properties of the VOR vary with eye position. 2. Eye rotation axes during yaw and pitch tilted in the same direction as the gaze line but only one-quarter as far on average. Thus, during yaw head rotation, the axis of eye rotation was roughly aligned with the head axis when the subject looked straight ahead, but tilted up when the gaze direction was up, and down when gaze was down. The amount of tilt varied between subjects, but on average a 30 degrees change in eye position caused a 7.5 degrees tilt in the eye rotation axis. During pitch, the eye axis tilted right when gaze was right and left when gaze was left, also moving 7.5 degrees on average for a 30 degrees change in the gaze direction. 3. During roll stimulation, the axis of eye rotation tilted in the opposite direction to the gaze line, and about one-half as far. On average, when the gaze line moved 30 degrees down, the eye rotation axis tilted 12.0 degrees up; when the gaze moved 30 degrees left, the eye axis tilted 15.3 degrees right. 4. It is often argued that the torsional VOR is weak because head rotation about the line of sight causes little image displacement on the fovea. But the line of sight is collinear with the torsional axis only when the subject looks straight ahead. Does the "weak axis" of the VOR stay collinear with the gaze line when the subject looks eccentrically? We calculated the axis of head rotation for which the VOR response is weakest and found that it does vary with eye position, but does not stay parallel with the gaze direction. When subjects looked straight ahead, the weak axis was roughly collinear with the gaze line; when gaze shifted eccentrically, the weak axis shifted in the same direction but only about one-half as far.(ABSTRACT TRUNCATED AT 400 WORDS)

Rotational kinematics of the human vestibuloocular reflex. III. Listing's law.

1. Overarm throwing is a skilled multijoint movement with potentially many degrees of freedom. Considering only the arm > or = 7 degrees of freedom are involved (shoulder 3, elbow 2, wrist 2). For each arm segment 3 degrees of freedom are potentially required to specify its angular position (orientation) at any moment during a throw. Simplification of the control problem for the CNS would occur if there were constraints on these degrees of freedom. The objective was to determine whether such constraints exist at ball release when throwing at targets in different directions using only the arm. 2. The angular positions in three dimensions of the distal phalanx of the middle finger, the hand, the forearm, and the upper arm were simultaneously recorded with search coils as subjects sat with a fixed trunk and threw balls at nine targets in an approximate +/- 40 degree work space. Ball release was signaled by microswitches on the proximal and distal phalanges of the middle finger (proximal and distal triggers). 3. On throwing at any one target the hand at ball release adopted a similar orientation for each throw, i.e., for a particular vertical and horizontal angular position the hand adopted a similar torsional position. On throwing at targets throughout the work space, angular position (rotation) vectors describing hand positions in space at ball release were confined to a two-dimensional surface rather than a three-dimensional volume. This constraint in hand torsion occurred near and at ball release but not throughout the entire throw. It was not due to mechanical factors because such a surface was not obtained when subjects deliberately twisted their arms when throwing. Thus at ball release during a "natural" throw the hand was constrained to 2 of its possible 3 angular degrees of freedom. 4. The same constraint was also found for finger, forearm, and upper arm angular positions in space at ball release as determined at both the proximal and distal triggers. A consequence is that at ball release the entire arm was constrained to 2 of its possible 7 degrees of freedom. 5. The two-dimensional position vector surface for each arm segment was similar to that obtained when pointing with a straight arm at the same targets. In both cases they showed torsion and were twisted like the surface obtained by rotations around the horizontal and vertical axes of a Fick gimbal. However, in some subjects the throwing surfaces were tilted from the vertical.(ABSTRACT TRUNCATED AT 400 WORDS)

The Effect of Head Reorientation on the Direction of Postrotatory Nystagmus in Humans

Traditionally the human vestibular system is tested by accelerations and decelerations in a rotating chair, stimulating the horizontal semicircular canals. This kind of testing provides no information about the performance or the two pairs of vertical (anterior and posterior) canals and the two pairs of otoliths. Testing the vestibulo-ocular reflex (VOR) in its entirety requires rotations around the 3 axis of the head (yaw, pitch and roll) as well as rotations where the axis is not aligned with gravity. The data presented here are, to our knowledge, the first measurements of the VOR in normal humans obtained with 3-dimensional high resolution recording techniques.

The vestibuloocular and optokinetic reflexes (VOR and OKR) help to stabilize the retinal image by rotating the eyes to compensate for movements of the head or visual field. In the past both reflexes have been studied one-dimensionally and characterized by their gain, which is output (eye velocity) divided by input (head or visual field velocity). The 3-D generalization of gain is a 3 x 3 matrix whose 9 components describe the dependence of all 3 components of the output vector on all 3 components of the input. But this description ignores the dependence of eye velocity on eye position, which should theoretically be negligible for OKR and VOR; e.g., for the VOR, eye velocity should be equal and opposite to head velocity, regardless of eye position. In this study we used linear fitting to describe the 3 x 3 matrix of VOR and OKR and examined both reflexes for any eye position dependence. For OKR, 3-D eye motion was recorded using the magnetic field-search coil technique in 3 normal human subjects as they tracked a field of light spots rotating about various axes (horizontal, vertical, torsional) with a constant velocity of 60"/second. For VOR, 3 normal subjects were rotated about body-vertical, nasooccipital, and interaural axes in complete darkness with a constant velocity of 150"/second by means of a computer-controlled rotating chair. TABLE 1 shows the gain matrix of the OKR averaged over the 3 subjects. To see whether slow phases follow Listing's law, we used an analysis program that assigned scores to periods of horizontal tracking: 0 when eye velocity was independent of eye position (as required for optimal tracking of a full-field stimulus), 0.5 for a Listing's law strategy (pursuit and saccades)."' For full-field tracking (stare), scores averaged 0.35 (range 0.25-0.40) showing a smaller but still strong dependence on eye position. TABLE 2 shows the gain matrices of the VOR averaged over the 3 subjects separate

Multidimensional Descriptions of the Optokinetic and Vestibuloocular Reflexes

The Influence of Head Reorientation on the Axis of Eye Rotation and the Vestibular Time Constant during Postrotatory Nystagmus

Computing three-dimensional eye position quaternions and eye velocity from search coil signals

Geometric relations of eye position and velocity vectors during saccades

The superior colliculus and spatiotemporal translation in the saccadic system

If you plot eye velocity in three dimensions during a rapid gaze shift, or saccade, you get a closed loop in space beginning and ending a t zero velocity. Each point in the loop is the angular velocity vector of the eye a t some instant. This angular velocity vector, usually called w, is defined as shown in FIGURE 1. The vector lies along the axis about which the eye is currently rotating. It is oriented to accord with the right hand rule; that is, if you point your right thumb in the direction of w, your fingers curl round in the direction the eye is turning. The length of the vector represents how fast the eye is turning about the axis. In what follows, we shall be looking at the direction of the angular velocity vector, or, in other words, the instantaneous axis of eye rotation, during visually elicited, head-fixed saccades made by human subjects. The question we shall ask is: how are the rotation axes of different saccades oriented in space? This question has implications for the neural circuitry that generates saccades. For example, we shall see that saccade axes are widely and systematically distributed in all three dimensions. It follows that the eye velocity vector for visually elicited saccades with the head fixed has three degrees of freedom. This in turn has implications for the short-lead burst neurons that code the saccadic eye velocity command. In addition, rotation axes provide a test for the quaternion model of the saccadic system recently put forward by us.' This model uses a multiplicative computation of motor error where other models have used subtraction. We shall compare the saccade axes predicted by multiplicative and subtractive models to the actual axes of head-fixed saccades. We shall need a representation for three-dimensional eye position. We have argued elsewhere' that because of their computational efficiency, especially for questions involving rotation axes, the four-component rotational operators called quaternions are the best representation of eye position for oculomotor modeling. In this paper we show that quaternion vectors (made up of the last three components of these quaternions) are a useful way to present experimental data. The quaternion representation of eye position is described in METHODS. We conclude this introduction by reviewing Listing's law, which turns up repeatedly later in the paper. The law states that, given an eye position, e, the eye assumes only those orientations that can be reached from e by a single rotation about an axis in a particular plane: which we call the displacement plane associated with e. Primary position is the unique eye position in which the fixation line is orthogonal to the displacement plane; the displacement plane of primary position is called Listing's

1. This paper develops three-dimensional models for the vestibuloocular reflex (VOR) and the internal feedback loop of the saccadic system. The models differ qualitatively from previous, one-dimensional versions, because the commutative algebra used in previous models does not apply to the three-dimensional rotations of the eye. 2. The hypothesis that eye position signals are generated by an eye velocity integrator in the indirect path of the VOR must be rejected because in three dimensions the integral of angular velocity does not specify angular position. Computer simulations using eye velocity integrators show large, cumulative gaze errors and post-VOR drift. We describe a simple velocity to position transformation that works in three dimensions. 3. In the feedback control of saccades, eye position error is not the vector difference between actual and desired eye positions. Subtractive feedback models must continuously adjust the axis of rotation throughout a saccade, and they generate meandering, dysmetric gaze saccades. We describe a multiplicative feedback system that solves these problems and generates fixed-axis saccades that accord with Listing's law. 4. We show that Listing's law requires that most saccades have their axes out of Listing's plane. A corollary is that if three pools of short-lead burst neurons code the eye velocity command during saccades, the three pools are not yoked, but function independently during visually triggered saccades. 5. In our three-dimensional models, we represent eye position using four-component rotational operators called quaternions. This is not the only algebraic system for describing rotations, but it is the one that best fits the needs of the oculomotor system, and it yields much simpler models than do rotation matrix or other representations. 6. Quaternion models predict that eye position is represented on four channels in the oculomotor system: three for the vector components of eye position and one inversely related to gaze eccentricity and torsion. 7. Many testable predictions made by quaternion models also turn up in models based on other mathematics. These predictions are therefore more fundamental than the specific models that generate them. Among these predictions are 1) to compute eye position in the indirect path of the VOR, eye or head velocity signals are multiplied by eye position feedback and then integrated; consequently 2) eye position signals and eye or head velocity signals converge on vestibular neurons, and their interaction is multiplicative.(ABSTRACT TRUNCATED AT 400 WORDS)

Implications of rotational kinematics for the oculomotor system in three dimensions.

The properties of the vestibuloocular reflex (VOR) when the axis of rotation is behind the eyes and fixation of a near target is required were studied in the monkey. The magnitude of VOR gain in each eye was found to be above 1.0 and near the ideal value for stabilizing a retinal image. Evidence that this large VOR gain was not visually mediated was provided by the observations that no reduction in gain and no phase lag were observed at high frequencies of head rotation (2 Hz), large gain was observed in the dark, and large gain was observed within 10-20 ms of the start of head rotation. The magnitude of VOR gain was found to increase with increasing radius of head rotation and also to increase with decreasing target distance. When the distances from the two eyes to the target were different the instantaneous velocities and VOR gains of the eyes were also different. The dependence on radius of rotation indicates that the VOR is mediated by a combination of otolith and canal inputs. A general model for otolith-canal interaction is proposed in which VOR gain is based on a computation of target location relative to the head. This model simplifies to the classical VOR reflex when a cyclopean eye is subjected only to angular displacement.

Neurons coordinate their activity to produce an astonishing variety of motor behaviors. Our present understanding of motor control has grown rapidly thanks to new methods for recording and analyzing populations of many individual neurons over time. In contrast, current methods for recording the nervous system’s actual motor output – the activation of muscle fibers by motor neurons – typically cannot detect the individual electrical events produced by muscle fibers during natural behaviors and scale poorly across species and muscle groups. Here we present a novel class of electrode devices (“Myomatrix arrays”) that record muscle activity at cellular resolution across muscles and behaviors. High-density, flexible electrode arrays allow for stable recordings from the muscle fibers activated by a single motor neuron, called a “motor unit”, during natural behaviors in many species, including mice, rats, primates, songbirds, frogs, and insects. This technology therefore allows the nervous system’s motor output to be monitored in unprecedented detail during complex behaviors across species and muscle morphologies. We anticipate that this technology will allow rapid advances in understanding the neural control of behavior and in identifying pathologies of the motor system.

High-performance neural population dynamics modeling enabled by scalable computational infrastructure

Artificial neural networks that can recover latent dynamics from recorded neural activity may provide a powerful avenue for identifying and interpreting the dynamical motifs underlying biological computation. Given that neural variance alone does not uniquely determine a latent dynamical system, interpretable architectures should prioritize accurate and low-dimensional latent dynamics. In this work, we evaluated the performance of sequential autoencoders (SAEs) in recovering latent chaotic attractors from simulated neural datasets. We found that SAEs with widely-used recurrent neural network (RNN)-based dynamics were unable to infer accurate firing rates at the true latent state dimensionality, and that larger RNNs relied upon dynamical features not present in the data. On the other hand, SAEs with neural ordinary differential equation (NODE)-based dynamics inferred accurate rates at the true latent state dimensionality, while also recovering latent trajectories and fixed point structure. Ablations reveal that this is mainly because NODEs (1) allow use of higher-capacity multi-layer perceptrons (MLPs) to model the vector field and (2) predict the derivative rather than the next state. Decoupling the capacity of the dynamics model from its latent dimensionality enables NODEs to learn the requisite low-D dynamics where RNN cells fail. Additionally, the fact that the NODE predicts derivatives imposes a useful autoregressive prior on the latent states. The suboptimal interpretability of widely-used RNN based dynamics may motivate substitution for alternative architectures, such as NODE, that enable learning of accurate dynamics in low-dimensional latent spaces.

Expressive architectures enhance interpretability of dynamics-based neural population models

A deep learning framework for inference of single-trial neural population dynamics from calcium imaging with subframe temporal resolution

Intracortical brain-computer interfaces (iBCIs) restore motor function to people with paralysis by translating brain activity into control signals for external devices. In current iBCIs, instabilities at the neural interface result in a degradation of decoding performance, which necessitates frequent supervised recalibration using new labeled data. One potential solution is to use the latent manifold structure that underlies neural population activity to facilitate a stable mapping between brain activity and behavior. Recent efforts using unsupervised approaches have improved iBCI stability using this principle; however, existing methods treat each time step as an independent sample and do not account for latent dynamics. Dynamics have been used to enable high performance prediction of movement intention, and may also help improve stabilization. Here, we present a platform for Nonlinear Manifold Alignment with Dynamics (NoMAD), which stabilizes iBCI decoding using recurrent neural network models of dynamics. NoMAD uses unsupervised distribution alignment to update the mapping of nonstationary neural data to a consistent set of neural dynamics, thereby providing stable input to the iBCI decoder. In applications to data from monkey motor cortex collected during motor tasks, NoMAD enables accurate behavioral decoding with unparalleled stability over weeks-to months-long timescales without any supervised recalibration.

Stabilizing brain-computer interfaces through alignment of latent dynamics

In many brain areas, neural populations act as a coordinated network whose state is tied to behavior on a moment-by-moment basis and millisecond timescale. Two-photon (2p) calcium imaging is a powerful tool to probe network-scale computation, as it can measure the activity of many individual neurons, monitor multiple cortical layers simultaneously, and sample from identified cell types. However, estimating network state and dynamics from 2p measurements has proven challenging because of noise, inherent nonlinearities, and limitations on temporal resolution. Here we describe RADICaL, a deep learning method to overcome these limitations at the population level. RADICaL extends methods that exploit dynamics in spiking activity for application to deconvolved calcium signals, whose statistics and temporal dynamics are quite distinct from electrophysiologically-recorded spikes. It incorporates a novel network training strategy that capitalizes on the timing of 2p sampling to recover network dynamics with high temporal precision. In synthetic tests, RADICaL infers network state more accurately than previous methods, particularly for high-frequency components. In real 2p recordings from sensorimotor areas in mice performing a “water grab” task, RADICaL infers network state with close correspondence to single-trial variations in behavior, and maintains high-quality inference even when neuronal populations are substantially reduced.

A deep learning framework for inference of single-trial neural population dynamics from calcium imaging with sub-frame temporal resolution

Objective. To study the neural control of movement, it is often necessary to estimate how muscles are activated across a variety of behavioral conditions. One approach is to try extracting the underlying neural command signal to muscles by applying latent variable modeling methods to electromyographic (EMG) recordings. However, estimating the latent command signal that underlies muscle activation is challenging due to its complex relation with recorded EMG signals. Common approaches estimate each muscle’s activation independently or require manual tuning of model hyperparameters to preserve behaviorally-relevant features. Approach. Here, we adapted AutoLFADS, a large-scale, unsupervised deep learning approach originally designed to de-noise cortical spiking data, to estimate muscle activation from multi-muscle EMG signals. AutoLFADS uses recurrent neural networks to model the spatial and temporal regularities that underlie multi-muscle activation. Main results. We first tested AutoLFADS on muscle activity from the rat hindlimb during locomotion and found that it dynamically adjusts its frequency response characteristics across different phases of behavior. The model produced single-trial estimates of muscle activation that improved prediction of joint kinematics as compared to low-pass or Bayesian filtering. We also applied AutoLFADS to monkey forearm muscle activity recorded during an isometric wrist force task. AutoLFADS uncovered previously uncharacterized high-frequency oscillations in the EMG that enhanced the correlation with measured force. The AutoLFADS-inferred estimates of muscle activation were also more closely correlated with simultaneously-recorded motor cortical activity than were other tested approaches. Significance. This method leverages dynamical systems modeling and artificial neural networks to provide estimates of muscle activation for multiple muscles. Ultimately, the approach can be used for further studies of multi-muscle coordination and its control by upstream brain areas, and for improving brain-machine interfaces that rely on myoelectric control signals.

Estimating muscle activation from EMG using deep learning-based dynamical systems models

Advances in our understanding of brain function, along with the development of neural interfaces that allow for the monitoring and activation of neurons, have paved the way for brain machine interfaces (BMI), which harness neural signals to reanimate the limbs via electrical activation of the muscles, or to control extra-corporeal devices, thereby bypassing the muscles and senses altogether. BMIs consist of reading out motor intent from the neuronal responses monitored in motor regions of the brain and executing intended movements using bionic limbs, reanimated limbs, or exoskeletons. BMIs also allow for the restoration of the sense of touch by electrically activating neurons in somatosensory regions of the brain, thereby evoking vivid tactile sensations and conveying feedback about object interactions. In this review, we discuss the neural mechanisms of motor control and somatosensation in able-bodied individuals and describe approaches to use neuronal responses as control signals for movement restoration and to activate residual sensory pathways to restore touch. While the focus of the review is on intracortical approaches, we also describe alternative signal sources for control and non-invasive strategies for sensory restoration.

The science and engineering behind sensitized brain-controlled bionic hands.

Modern neural interfaces allow access to the activity of up to a million neurons within brain circuits. However, bandwidth limits often create a trade-off between greater spatial sampling (more channels or pixels) and the temporal frequency of sampling. Here we demonstrate that it is possible to obtain spatio-temporal super-resolution in neuronal time series by exploiting relationships among neurons, embedded in latent low-dimensional population dynamics. Our novel neural network training strategy, selective backpropagation through time (SBTT), enables learning of deep generative models of latent dynamics from data in which the set of observed variables changes at each time step. The resulting models are able to infer activity for missing samples by combining observations with learned latent dynamics. We test SBTT applied to sequential autoencoders and demonstrate more efﬁcient and higher-ﬁdelity characterization of neural population dynamics in electrophysiological and calcium imaging data. In electrophysiology, SBTT enables accurate inference of neuronal population dynamics with lower interface bandwidths, providing an avenue to signiﬁcant power savings for implanted neu-roelectronic interfaces. In applications to two-photon calcium imaging, SBTT accurately uncovers high-frequency temporal structure underlying neural population activity, substantially outperforming the current

Deep inference of latent dynamics with spatio-temporal super-resolution using selective backpropagation through time

Neural population activity is theorized to reflect an underlying dynamical structure. This structure can be accurately captured using state space models with explicit dynamics, such as those based on recurrent neural networks (RNNs). However, using recurrence to explicitly model dynamics necessitates sequential processing of data, slowing real-time applications such as brain-computer interfaces. Here we introduce the Neural Data Transformer (NDT), a non-recurrent alternative. We test the NDT’s ability to capture autonomous dynamical systems by applying it to synthetic datasets with known dynamics and data from monkey motor cortex during a reaching task well-modeled by RNNs. The NDT models these datasets as well as state-of-the-art recurrent models. Further, its non-recurrence enables 3.9ms inference, well within the loop time of real-time applications and more than 6 times faster than recurrent baselines on the monkey reaching dataset. These results suggest that an explicit dynamics model is not necessary to model autonomous neural population dynamics. Code github.com/snel-repo/neural-data-transformers.

Representation learning for neural population activity with Neural Data Transformers

A large-scale neural network training framework for generalized estimation of single-trial population dynamics

The ability to grasp and manipulate objects requires controlling both finger movement kinematics and isometric force. Previous work suggests that these behavioral modes are controlled separately, but it is unknown whether the cerebral cortex represents them differently. Here, we investigated this question by recording high-density electrocorticography from the motor and premotor cortices of seven human subjects performing a sequential movement-force motor task. We decoded finger movement (0.7±0.3 fractional variance account for; FVAF) and force (0.7±0.2 FVAF) with high accuracy, yet found different spatial representations. We also found clear distinctions in electrocorticographic activity by using deep learning methods to uncover state-space representations, and by developing a new metric, the neural vector angle. Thus, state-space techniques can help to investigate broad cortical networks. Finally, we were able to classify the behavioral mode from neural signals with high accuracy (90±6%). Thus, finger movement and force have distinct representations in motor/premotor cortices. This will inform our understanding of the neural control of movement as well as the design of grasp brain-machine interfaces.

Distinct representations of finger movement and force in human motor and premotor cortices

Abstract The ability to grasp and manipulate objects requires controlling both finger movement kinematics and isometric force in rapid succession. Previous work suggests that these behavioral modes are controlled separately, but it is unknown whether the cerebral cortex represents them differently. Here, we asked the question of how movement and force were represented cortically, when executed sequentially with the same finger. We recorded high-density electrocorticography (ECoG) from the motor and premotor cortices of seven human subjects performing a movement-force motor task. We decoded finger movement [0.7 ± 0.3 fractional variance accounted for (FVAF)] and force (0.7 ± 0.2 FVAF) with high accuracy, yet found different spatial representations. In addition, we used a state-of-the-art deep learning method to uncover smooth, repeatable trajectories through ECoG state space during the movement-force task. We also summarized ECoG across trials and participants by developing a new metric, the neural vector angle (NVA). Thus, state-space techniques can help to investigate broad cortical networks. Finally, we were able to classify the behavioral mode from neural signals with high accuracy (90 ± 6%). Thus, finger movement and force appear to have distinct representations in motor/premotor cortices. These results inform our understanding of the neural control of movement, as well as the design of grasp brain-machine interfaces (BMIs).

The Representation of Finger Movement and Force in Human Motor and Premotor Cortices

Publisher Correction: Brain-machine interface cursor position only weakly affects monkey and human motor cortical activity in the absence of arm movements

Principled BCI Decoder Design and Parameter Selection Using a Feedback Control Model

Intracortical brain-computer interfaces (BCIs) can enable individuals to control effectors, such as a computer cursor, by directly decoding the user's movement intentions from action potentials and local field potentials (LFPs) recorded within the motor cortex. However, the accuracy and complexity of effector control achieved with such "biomimetic" BCIs will depend on the degree to which the intended movements used to elicit control modulate the neural activity. In particular, channels that do not record distinguishable action potentials and only record LFP modulations may be of limited use for BCI control. In contrast, a biofeedback approach may surpass these limitations by letting the participants generate new control signals and learn strategies that improve the volitional control of signals used for effector control. Here, we show that, by using a biofeedback paradigm, three individuals with tetraplegia achieved volitional control of gamma LFPs (40-400 Hz) recorded by a single microelectrode implanted in the precentral gyrus. Control was improved over a pair of consecutive sessions up to 3 days apart. In all but one session, the channel used to achieve control lacked distinguishable action potentials. Our results indicate that biofeedback LFP-based BCIs may potentially contribute to the neural modulation necessary to obtain reliable and useful control of effectors. NEW & NOTEWORTHY Our study demonstrates that people with tetraplegia can volitionally control individual high-gamma local-field potential (LFP) channels recorded from the motor cortex, and that this control can be improved using biofeedback. Motor cortical LFP signals are thought to be both informative and stable intracortical signals and, thus, of importance for future brain-computer interfaces.

Volitional control of single-electrode high gamma local field potentials by people with paralysis.

Continuing advances in neural interfaces have enabled simultaneous monitoring of spiking activity from hundreds to thousands of neurons. To interpret these large-scale data, several methods have been proposed to infer latent dynamic structure from high-dimensional datasets. One recent line of work uses recurrent neural networks in a sequential autoencoder (SAE) framework to uncover dynamics. SAEs are an appealing option for modeling nonlinear dynamical systems, and enable a precise link between neural activity and behavior on a single-trial basis. However, the very large parameter count and complexity of SAEs relative to other models has caused concern that SAEs may only perform well on very large training sets. We hypothesized that with a method to systematically optimize hyperparameters (HPs), SAEs might perform well even in cases of limited training data. Such a breakthrough would greatly extend their applicability. However, we find that SAEs applied to spiking neural data are prone to a particular form of overfitting that cannot be detected using standard validation metrics, which prevents standard HP searches. We develop and test two potential solutions: an alternate validation method ("sample validation") and a novel regularization method ("coordinated dropout"). These innovations prevent overfitting quite effectively, and allow us to test whether SAEs can achieve good performance on limited data through large-scale HP optimization. When applied to data from motor cortex recorded while monkeys made reaches in various directions, large-scale HP optimization allowed SAEs to better maintain performance for small dataset sizes. Our results should greatly extend the applicability of SAEs in extracting latent dynamics from sparse, multidimensional data, such as neural population spiking activity.

Enabling hyperparameter optimization in sequential autoencoders for spiking neural data

Objective. Brain–computer interfaces (BCIs) can enable individuals with tetraplegia to communicate and control external devices. Though much progress has been made in improving the speed and robustness of neural control provided by intracortical BCIs, little research has been devoted to minimizing the amount of time spent on decoder calibration. Approach. We investigated the amount of time users needed to calibrate decoders and achieve performance saturation using two markedly different decoding algorithms: the steady-state Kalman filter, and a novel technique using Gaussian process regression (GP-DKF). Main results. Three people with tetraplegia gained rapid closed-loop neural cursor control and peak, plateaued decoder performance within 3 min of initializing calibration. We also show that a BCI-naïve user (T5) was able to rapidly attain closed-loop neural cursor control with the GP-DKF using self-selected movement imagery on his first-ever day of closed-loop BCI use, acquiring a target 37 s after initiating calibration. Significance. These results demonstrate the potential for an intracortical BCI to be used immediately after deployment by people with paralysis, without the need for user learning or extensive system calibration.

Rapid calibration of an intracortical brain–computer interface for people with tetraplegia

Brain-machine interface cursor position only weakly affects monkey and human motor cortical activity in the absence of arm movements

In the 1960s, Evarts first recorded the activity of single neurons in motor cortex of behaving monkeys (Evarts, 1968). In the 50 years since, great effort has been devoted to understanding how single neuron activity relates to movement. Yet these single neurons exist within a vast network, the nature of which has been largely inaccessible. With advances in recording technologies, algorithms, and computational power, the ability to study these networks is increasing exponentially. Recent experimental results suggest that the dynamical properties of these networks are critical to movement planning and execution. Here we discuss this dynamical systems perspective and how it is reshaping our understanding of the motor cortices. Following an overview of key studies in motor cortex, we discuss techniques to uncover the “latent factors” underlying observed neural population activity. Finally, we discuss efforts to use these factors to improve the performance of brain–machine interfaces, promising to make these findings broadly relevant to neuroengineering as well as systems neuroscience.

Latent Factors and Dynamics in Motor Cortex and Their Application to Brain–Machine Interfaces

Objective: Brain–computer interfaces (BCIs) aim to help people with impaired movement ability by directly translating their movement intentions into command signals for assistive technologies. Despite large performance improvements over the last two decades, BCI systems still make errors that need to be corrected manually by the user. This decreases system performance and is also frustrating for the user. The deleterious effects of errors could be mitigated if the system automatically detected when the user perceives that an error was made and automatically intervened with a corrective action; thus, sparing users from having to make the correction themselves. Our previous preclinical work with monkeys demonstrated that task-outcome correlates exist in motor cortical spiking activity and can be utilized to improve BCI performance. Here, we asked if these signals also exist in the human hand area of motor cortex, and whether they can be decoded with high accuracy. Methods: We analyzed posthoc the intracortical neural activity of two BrainGate2 clinical trial participants who were neurally controlling a computer cursor to perform a grid target selection task and a keyboard-typing task. Results: Our key findings are that: 1) there exists a putative outcome error signal reflected in both the action potentials and local field potentials of the human hand area of motor cortex, and 2) target selection outcomes can be classified with high accuracy (70–85%) of errors successfully detected with minimal (0–3%) misclassifications of success trials, based on neural activity alone. Significance: These offline results suggest that it will be possible to improve the performance of clinical intracortical BCIs by incorporating a real-time error detect-and-undo system alongside the decoding of movement intention.

Feasibility of Automatic Error Detect-and-Undo System in Human Intracortical Brain–Computer Interfaces

Augmenting intracortical brain-computer interfaces in monkeys and humans with neurally driven error detectors

<italic>Objective</italic>: Recent reports indicate that making better assumptions about the user's intended movement can improve decoder calibration for intracortical brain–computer interfaces. Several methods now exist for estimating user intent, including an optimal feedback control model, a piecewise-linear feedback control model, ReFIT, and other heuristics. Which of these methods yields the best decoding performance? <italic>Methods </italic>: Using data from the BrainGate2 pilot clinical trial, we measured how a steady-state velocity Kalman filter decoder was affected by the choice of intention estimation method. We examined three separate components of the Kalman filter: dimensionality reduction, temporal smoothing, and output gain (speed scaling). <italic>Results</italic>: The decoder's dimensionality reduction properties were largely unaffected by the intention estimation method (the unsmoothed velocity vectors differed by <inline-formula><tex-math notation="LaTeX">$< \text{5}\% $</tex-math> </inline-formula> in terms of how accurately they pointed at the target and how their speeds decreased near the target). In contrast, the smoothing and gain properties of the decoder were greatly affected (<inline-formula> <tex-math notation="LaTeX">$> \text{50}\% $</tex-math></inline-formula> difference in average values). Surprisingly, simulation results show that these differences in gain and smoothing values were largely arbitrary, as all methods failed to optimize the gain and smoothing values to match the task parameters. <italic>Conclusion</italic>: Our results show that, gain and smoothing differences aside, current intention estimation methods yield nearly equivalent decoders and that simple models of user intent, such as a position error vector (target position minus cursor position), perform comparably to more elaborate models. Our results also highlight that current calibration methods yield arbitrary differences in gain and smoothing properties that can confound decoder comparisons.

A Comparison of Intention Estimation Methods for Decoder Calibration in Intracortical Brain–Computer Interfaces

Inferring single-trial neural population dynamics using sequential auto-encoders

Restoring communication for people with locked-in syndrome remains a challenging clinical problem without a reliable solution. Recent studies have shown that people with paralysis can use brain-computer interfaces (BCIs) based on intracortical spiking activity to efficiently type messages. However, due to neuronal signal instability, most intracortical BCIs have required frequent calibration and continuous assistance of skilled engineers to maintain performance. Here, an individual with locked-in syndrome due to brain stem stroke and an individual with tetraplegia secondary to amyotrophic lateral sclerosis (ALS) used a simple communication BCI based on intracortical local field potentials (LFPs) for 76 and 138 days, respectively, without recalibration and without significant loss of performance. BCI spelling rates of 3.07 and 6.88 correct characters/minute allowed the participants to type messages and write emails. Our results indicate that people with locked-in syndrome could soon use a slow but reliable LFP-based BCI for everyday communication without ongoing intervention from a technician or caregiver. NEW & NOTEWORTHY This study demonstrates, for the first time, stable repeated use of an intracortical brain-computer interface by people with tetraplegia over up to four and a half months. The approach uses local field potentials (LFPs), signals that may be more stable than neuronal action potentials, to decode participants' commands. Throughout the several months of evaluation, the decoder remained unchanged; thus no technical interventions were required to maintain consistent brain-computer interface operation.

Stable long-term BCI-enabled communication in ALS and locked-in syndrome using LFP signals.

General-purpose computers have become ubiquitous and important for everyday life, but they are difficult for people with paralysis to use. Specialized software and personalized input devices can improve access, but often provide only limited functionality. In this study, three research participants with tetraplegia who had multielectrode arrays implanted in motor cortex as part of the BrainGate2 clinical trial used an intracortical brain-computer interface (iBCI) to control an unmodified commercial tablet computer. Neural activity was decoded in real time as a point-and-click wireless Bluetooth mouse, allowing participants to use common and recreational applications (web browsing, email, chatting, playing music on a piano application, sending text messages, etc.). Two of the participants also used the iBCI to “chat” with each other in real time. This study demonstrates, for the first time, high-performance iBCI control of an unmodified, commercially available, general-purpose mobile computing device by people with tetraplegia.

Objective. When using an intracortical BCI (iBCI), users modulate their neural population activity to move an effector towards a target, stop accurately, and correct for movement errors. We call the rules that govern this modulation a ‘feedback control policy’. A better understanding of these policies may inform the design of higher-performing neural decoders. Approach. We studied how three participants in the BrainGate2 pilot clinical trial used an iBCI to control a cursor in a 2D target acquisition task. Participants used a velocity decoder with exponential smoothing dynamics. Through offline analyses, we characterized the users’ feedback control policies by modeling their neural activity as a function of cursor state and target position. We also tested whether users could adapt their policy to different decoder dynamics by varying the gain (speed scaling) and temporal smoothing parameters of the iBCI. Main results. We demonstrate that control policy assumptions made in previous studies do not fully describe the policies of our participants. To account for these discrepancies, we propose a new model that captures (1) how the user’s neural population activity gradually declines as the cursor approaches the target from afar, then decreases more sharply as the cursor comes into contact with the target, (2) how the user makes constant feedback corrections even when the cursor is on top of the target, and (3) how the user actively accounts for the cursor’s current velocity to avoid overshooting the target. Further, we show that users can adapt their control policy to decoder dynamics by attenuating neural modulation when the cursor gain is high and by damping the cursor velocity more strongly when the smoothing dynamics are high. Significance. Our control policy model may help to build better decoders, understand how neural activity varies during active iBCI control, and produce better simulations of closed-loop iBCI movements.

Feedback control policies employed by people using intracortical brain–computer interfaces

Objective. Do movements made with an intracortical BCI (iBCI) have the same movement time properties as able-bodied movements? Able-bodied movement times typically obey Fitts’ law: MT=a+blog2(D/R) (where MT is movement time, D is target distance, R is target radius, and a, b are parameters). Fitts’ law expresses two properties of natural movement that would be ideal for iBCIs to restore: (1) that movement times are insensitive to the absolute scale of the task (since movement time depends only on the ratio D/R) and (2) that movements have a large dynamic range of accuracy (since movement time is logarithmically proportional to D/R). Approach. Two participants in the BrainGate2 pilot clinical trial made cortically controlled cursor movements with a linear velocity decoder and acquired targets by dwelling on them. We investigated whether the movement times were well described by Fitts’ law. Main results. We found that movement times were better described by the equation MT=a+bD+cR−2, which captures how movement time increases sharply as the target radius becomes smaller, independently of distance. In contrast to able-bodied movements, the iBCI movements we studied had a low dynamic range of accuracy (absence of logarithmic proportionality) and were sensitive to the absolute scale of the task (small targets had long movement times regardless of the D/R ratio). We argue that this relationship emerges due to noise in the decoder output whose magnitude is largely independent of the user’s motor command (signal-independent noise). Signal-independent noise creates a baseline level of variability that cannot be decreased by trying to move slowly or hold still, making targets below a certain size very hard to acquire with a standard decoder. Significance. The results give new insight into how iBCI movements currently differ from able-bodied movements and suggest that restoring a Fitts’ law-like relationship to iBCI movements may require non-linear decoding strategies.

Signal-independent noise in intracortical brain–computer interfaces causes movement time properties inconsistent with Fitts’ law

Brain-computer interfaces (BCIs) have the potential to restore communication for people with tetraplegia and anarthria by translating neural activity into control signals for assistive communication devices. While previous pre-clinical and clinical studies have demonstrated promising proofs-of-concept (Serruya et al., 2002; Simeral et al., 2011; Bacher et al., 2015; Nuyujukian et al., 2015; Aflalo et al., 2015; Gilja et al., 2015; Jarosiewicz et al., 2015; Wolpaw et al., 1998; Hwang et al., 2012; Spüler et al., 2012; Leuthardt et al., 2004; Taylor et al., 2002; Schalk et al., 2008; Moran, 2010; Brunner et al., 2011; Wang et al., 2013; Townsend and Platsko, 2016; Vansteensel et al., 2016; Nuyujukian et al., 2016; Carmena et al., 2003; Musallam et al., 2004; Santhanam et al., 2006; Hochberg et al., 2006; Ganguly et al., 2011; O’Doherty et al., 2011; Gilja et al., 2012), the performance of human clinical BCI systems is not yet high enough to support widespread adoption by people with physical limitations of speech. Here we report a high-performance intracortical BCI (iBCI) for communication, which was tested by three clinical trial participants with paralysis. The system leveraged advances in decoder design developed in prior pre-clinical and clinical studies (Gilja et al., 2015; Kao et al., 2016; Gilja et al., 2012). For all three participants, performance exceeded previous iBCIs (Bacher et al., 2015; Jarosiewicz et al., 2015) as measured by typing rate (by a factor of 1.4–4.2) and information throughput (by a factor of 2.2–4.0). This high level of performance demonstrates the potential utility of iBCIs as powerful assistive communication devices for people with limited motor function. Clinical Trial No: NCT00912041 DOI: http://dx.doi.org/10.7554/eLife.18554.001

High performance communication by people with paralysis using an intracortical brain-computer interface

Precise Estimates of Single-Trial Dynamics in Motor Cortex using Deep Learning Techniques

Neuroscience is experiencing a data revolution in which many hundreds or thousands of neurons are recorded simultaneously. Currently, there is little consensus on how such data should be analyzed. Here we introduce LFADS (Latent Factor Analysis via Dynamical Systems), a method to infer latent dynamics from simultaneously recorded, single-trial, high-dimensional neural spiking data. LFADS is a sequential model based on a variational auto-encoder. By making a dynamical systems hypothesis regarding the generation of the observed data, LFADS reduces observed spiking to a set of low-dimensional temporal factors, per-trial initial conditions, and inferred inputs. We compare LFADS to existing methods on synthetic data and show that it significantly out-performs them in inferring neural firing rates and latent dynamics.

Author response: High performance communication by people with paralysis using an intracortical brain-computer interface

Individuals with tetraplegia are able to type self-paced for hours across multiple days using a self-calibrating point-and-click intracortical brain-computer interface. Prolonged typing with refined BCI The fact that the brain can be hooked up to a computer to allow paralyzed individuals to type is already a technological feat. But, these so-called brain-computer interface technologies can be tiring and burdensome for users, requiring frequent disruptions for recalibration when the decoded neural signals change. Jarosiewicz and colleagues therefore combined three calibration methods—retrospective target interference, velocity bias correction, and adaptive tracking of neural features—for seamless typing and stable neural control. This combination allowed two individuals with tetraplegia and with cortical microelectrode arrays to compose long texts at their own paces, with no need to interrupt typing for recalibration. Brain-computer interfaces (BCIs) promise to restore independence for people with severe motor disabilities by translating decoded neural activity directly into the control of a computer. However, recorded neural signals are not stationary (that is, can change over time), degrading the quality of decoding. Requiring users to pause what they are doing whenever signals change to perform decoder recalibration routines is time-consuming and impractical for everyday use of BCIs. We demonstrate that signal nonstationarity in an intracortical BCI can be mitigated automatically in software, enabling long periods (hours to days) of self-paced point-and-click typing by people with tetraplegia, without degradation in neural control. Three key innovations were included in our approach: tracking the statistics of the neural activity during self-timed pauses in neural control, velocity bias correction during neural control, and periodically recalibrating the decoder using data acquired during typing by mapping neural activity to movement intentions that are inferred retrospectively based on the user’s self-selected targets. These methods, which can be extended to a variety of neurally controlled applications, advance the potential for intracortical BCIs to help restore independent communication and assistive device control for people with paralysis.

Virtual typing by people with tetraplegia using a self-calibrating intracortical brain-computer interface

The prevailing view of motor cortex holds that motor cortical neural activity represents muscle or movement parameters. However, recent studies in non-human primates have shown that neural activity does not simply represent muscle or movement parameters; instead, its temporal structure is well-described by a dynamical system where activity during movement evolves lawfully from an initial pre-movement state. In this study, we analyze neuronal ensemble activity in motor cortex in two clinical trial participants diagnosed with Amyotrophic Lateral Sclerosis (ALS). We find that activity in human motor cortex has similar dynamical structure to that of non-human primates, indicating that human motor cortex contains a similar underlying dynamical system for movement generation. Clinical trial registration: NCT00912041. DOI: http://dx.doi.org/10.7554/eLife.07436.001

Neural population dynamics in human motor cortex during movements in people with ALS

Histone modifications are important regulators of gene expression in all eukaryotes. In Plasmodium falciparum, these epigenetic marks regulate expression of genes involved in several aspects of host-parasite interactions, including antigenic variation. While the identities and genomic positions of many histone modifications have now been cataloged, how they are targeted to defined genomic regions remains poorly understood. For example, how variant antigen encoding loci (var) are targeted for deposition of unique histone marks is a mystery that continues to perplex the field. Here we describe the recruitment of an ortholog of the histone modifier SET2 to var genes through direct interactions with the C-terminal domain (CTD) of RNA polymerase II. In higher eukaryotes, SET2 is a histone methyltransferase recruited by RNA pol II during mRNA transcription; however, the ortholog in P. falciparum (PfSET2) has an atypical architecture and its role in regulating transcription is unknown. Here we show that PfSET2 binds to the unphosphorylated form of the CTD, a property inconsistent with its recruitment during mRNA synthesis. Further, we show that H3K36me3, the epigenetic mark deposited by PfSET2, is enriched at both active and silent var gene loci, providing additional evidence that its recruitment is not associated with mRNA production. Over-expression of a dominant negative form of PfSET2 designed to disrupt binding to RNA pol II induced rapid var gene expression switching, confirming both the importance of PfSET2 in var gene regulation and a role for RNA pol II in its recruitment. RNA pol II is known to transcribe non-coding RNAs from both active and silent var genes, providing a possible mechanism by which it could recruit PfSET2 to var loci. This work unifies previous reports of histone modifications, the production of ncRNAs, and the promoter activity of var introns into a mechanism that contributes to antigenic variation by malaria parasites.

Recruitment of PfSET2 by RNA Polymerase II to Variant Antigen Encoding Loci Contributes to Antigenic Variation in P. falciparum

194 High Performance Computer Cursor Control Using Neuronal Ensemble Recordings From the Motor Cortex of a Person With ALS

Optogenetics offers a powerful new approach for controlling neural circuits. It has a vast array of applications in both basic and clinical science. For basic science, it opens the door to unraveling circuit operations, since one can perturb specific circuit components with high spatial (single cell) and high temporal (millisecond) resolution. For clinical applications, it allows new kinds of selective treatments, because it provides a method to inactivate or activate specific components in a malfunctioning circuit and bring it back into a normal operating range [1-3]. To harness the power of optogenetics, though, one needs stimulating tools that work with the same high spatial and temporal resolution as the molecules themselves, the channelrhodopsins. To date, most stimulating tools require a tradeoff between spatial and temporal precision and are prohibitively expensive to integrate into a stimulating/recording setup in a laboratory or a device in a clinical setting [4, 5]. Here we describe a Digital Light Processing (DLP)-based system capable of extremely high temporal resolution (sub-millisecond), without sacrificing spatial resolution. Furthermore, it is constructed using off-the-shelf components, making it feasible for a broad range of biology and bioengineering labs. Using transgenic mice that express channelrhodopsin-2 (ChR2), we demonstrate the system's capability for stimulating channelrhodopsin-expressing neurons in tissue with single cell and sub-millisecond precision.

13th IEEE International Conference on BioInformatics and BioEngineering

A system for optically controlling neural circuits with very high spatial and temporal resolution

Retinal prosthetics offer hope for patients with retinal degenerative diseases. There are 20–25 million people worldwide who are blind or facing blindness due to these diseases, and they have few treatment options. Drug therapies are able to help a small fraction of the population, but for the vast majority, their best hope is through prosthetic devices [reviewed in Chader et al. (2009) Prog Brain Res 175:317–332]. Current prosthetics, however, are still very limited in the vision that they provide: for example, they allow for perception of spots of light and high-contrast edges, but not natural images. Efforts to improve prosthetic capabilities have focused largely on increasing the resolution of the device’s stimulators (either electrodes or optogenetic transducers). Here, we show that a second factor is also critical: driving the stimulators with the retina’s neural code. Using the mouse as a model system, we generated a prosthetic system that incorporates the code. This dramatically increased the system’s capabilities—well beyond what can be achieved just by increasing resolution. Furthermore, the results show, using 9,800 optogenetically stimulated ganglion cell responses, that the combined effect of using the code and high-resolution stimulation is able to bring prosthetic capabilities into the realm of normal image representation.

Retinal prosthetic strategy with the capacity to restore normal vision

A Retinal Prosthetic Approach with the Capacity to Restore Normal Vision

Several recent studies have shown that the ON and OFF channels of the visual system are not simple mirror images of each other, that their response characteristics are asymmetric (Chichilnisky and Kalmar, 2002; Sagdullaev and McCall, 2005). How the asymmetries bear on visual processing is not well understood. Here, we show that ON and OFF ganglion cells show a strong asymmetry in their temporal adaptation to photopic (day) and scotopic (night) conditions and that the asymmetry confers a functional advantage. Under photopic conditions, the ON and OFF ganglion cells show similar temporal characteristics. Under scotopic conditions, the two cell classes diverge—ON cells shift their tuning to low temporal frequencies, whereas OFF cells continue to respond to high. This difference in processing corresponds to an asymmetry in the natural world, one produced by the Poisson nature of photon capture and persists over a broad range of light levels. This work characterizes a previously unknown divergence in the ON and OFF pathways and its utility to visual processing. Furthermore, the results have implications for downstream circuitry and thus offer new constraints for models of downstream processing, since ganglion cells serve as building blocks for circuits in higher brain areas. For example, if simple cells in visual cortex rely on complementary interactions between the two pathways, such as push–pull interactions (Alonso et al., 2001; Hirsch, 2003), their receptive fields may be radically different under scotopic conditions, when the ON and OFF pathways are out of sync.

Symmetry Breakdown in the ON and OFF Pathways of the Retina at Night: Functional Implications

An animal's ability to rapidly adjust to new conditions is essential to its survival. The nervous system, then, must be built with the flexibility to adjust, or shift, its processing capabilities on the fly. To understand how this flexibility comes about, we tracked a well-known behavioral shift, a visual integration shift, down to its underlying circuitry, and found that it is produced by a novel mechanism – a change in gap junction coupling that can turn a cell class on and off. The results showed that the turning on and off of a cell class shifted the circuit's behavior from one state to another, and, likewise, the animal's behavior. The widespread presence of similar gap junction-coupled networks in the brain suggests that this mechanism may underlie other behavioral shifts as well.

A Novel Mechanism for Switching a Neural System from One State to Another

How neural systems adjust to different environments: an intriguing role for gap junction coupling

Background The visual system can adjust itself to different visual environments. One of the most well known examples of this is the shift in spatial tuning that occurs in retinal ganglion cells with the change from night to day vision. This shift is thought to be produced by a change in the ganglion cell receptive field surround, mediated by a decrease in the coupling of horizontal cells. Methodology/Principal Findings To test this hypothesis, we used a transgenic mouse line, a connexin57-deficient line, in which horizontal cell coupling was abolished. Measurements, both at the ganglion cell level and the level of behavioral performance, showed no differences between wild-type retinas and retinas with decoupled horizontal cells from connexin57-deficient mice. Conclusion/Significance This analysis showed that the coupling and uncoupling of horizontal cells does not play a dominant role in spatial tuning and its adjustability to night and day light conditions. Instead, our data suggest that another mechanism, likely arising in the inner retina, must be responsible.

Ganglion Cell Adaptability: Does the Coupling of Horizontal Cells Play a Role?

Current–voltage measurements of Au contacts deposited on ex situ cleaned, n-type ZnO(0001) [(0001¯)] surfaces showed reverse bias leakage current densities of ∼0.01(∼0.1)A∕cm2 at 4.6 (3.75) V reverse bias and ideality factors >2 (both surfaces) before sharp, permanent breakdown (soft breakdown). This behavior was due primarily to the presence of (1.6–2.0)±0.1[(0.7–2.6)±0.1] monolayers (ML) of hydroxide, which forms an electron accumulation layer and increases the surface conductivity. In situ remote plasma cleaning of the (0001) [(0001¯)] surfaces using a 20vol%O2∕80vol%He mixture for the optimized temperatures, times, and pressure of 550±20°C(525±20°C), 60 (30) min, and 0.050 Torr reduced the thickness of the hydroxide layer to ∼0.4±0.1ML and completely eliminated all detectable hydrocarbon contamination. Subsequent cooling of both surfaces in the plasma ambient resulted in the chemisorption of oxygen and a change from 0.2 eV of downward band bending for samples cooled in vacuum to 0.3 eV of upward band ...

Structural, microstructural, and electrical properties of gold films and Schottky contacts on remote plasma-cleaned, n-type ZnO{0001} surfaces

In situ exposure of the (0001) surface of AlN thin films to flowing ammonia at 1120 °C and 10−4Torr removes oxygen∕hydroxide and hydrocarbon species below the detectable limits of x-ray photoelectron spectroscopy and decreases the Al∕N ratio from 1.3 to 1.0. The positions of the Al2p and the N1s core level peaks acquired from the cleaned surfaces were 75.0±0.1eV and 398.2±0.1eV, respectively, which were similar to the values determined for the as-loaded samples. The cleaning process left unchanged the (1×1) low energy electron diffraction pattern, the step-and-terrace microstructure, and the root mean square roughness values observed for the surfaces of the as-loaded samples; i.e., the surface structure and microstructure were not changed by the high-temperature exposure to ammonia at low pressures. Vacuum annealing under 10−7Torr at 1175 °C for 15 min removed all detectable hydrocarbons; however, it did not remove the oxygen∕hydroxide species.

Preparation and characterization of atomically clean, stoichiometric surfaces of AIN(0001)

Task Outcome Error Signals in Human Primary Motor Cortex and Their Use in Brain-Computer Interfaces

Title : A novel role for gap junction coupling : A mechanism for allowing neural networks to change states Location : South Hall A Presentation Time : Sunday

Towards high performance communication using intracortical brain-computer interfaces

Haptic feedback, which provides surgeons with interaction force information between instrument and tissue, is limited in handheld laparoscopic tissue graspers. Surgeons report difficulties to maintain precise control of the applied tissue forces when using state-of-the-art instrumentation, which is linked to accidental tissue trauma. Research describes the mechanical limitations of the conventional rigid-body mechanism tooltip design as culprit. This work replaces the conventional tooltip with a monolithic compliant mechanism that exhibits multi-modal stiffness properties to enhance haptic feedback and safety. Using experimental methods, the force transmission and input displacements are measured for the compliant tooltip and conventional tooltip. The authors compare representative metrics of grasping performance to demonstrate the transformation of the prior force-based control task into a position-based control task with amplified kinesthetic and cutaneous cues. As a prelude to user testing, the authors hypothesize several user benefits including the prevention of overloading and the enhancement of force sensitivity during tissue manipulation tasks.

Multi-Modal Mechanism for Enhancing Haptics and Safety in Handheld Surgical Grasping

 This work studies the feasibility of using Reinforcement Learning and Policy Based Optimization, on a continuous action space, for straight line path generation of four bar linkages. Based on the path radius of curvature, an optimization method introduces a reward function that is calculated by the inflection circle and the Euler-Savary equation to train policy based agents. Two experiments are defined, which run 200 agents in each setting. Results are compared to demonstrate the process and outcome of using this design method. In experiment one the starting point is fixed at the center of the design space. In experiment two the agents start from a random point in the design space. We conclude that agents trained in both experimental settings are capable of creating linkages that generate quasi-straight line segments (high radii of curvature). The results across 400 distinct agents show that more than 50% of the generated designs are reasonably straight, such that the linkages are suitable in applications for quasi-straight line path generation.

Design of Fourbar Linkages Using a Reinforcement Learning Optimization Method

 A design approach for the quasi-static balancing of four-bar linkages with torsion springs is proposed. Such approach is useful on the design of statically balanced compliant mechanisms by setting the stiffness of the Pseudo-Rigid-Body-Model. Here the positive stiffness exhibited by torsion springs at the R-joints is compensated by a negative stiffness function. The negative stiffness is created by a non-zero-free-length linear spring connected between the coupler link and the ground, and where both connecting points trace a line directed to the coupler link’s instant center of rotation. An example of the static balancing of the Burmester’s linkage for straight path generation is developed, where actuation energy is reduced in 94% for a range of motion of 80 degrees for the input link.

Static Balancing of Four-Bar Linkages With Torsion Springs by Exerting Negative Stiffness Using Linear Spring at the Instant Center of Rotation

 A design approach for the quasi-static balancing of four-bar linkages with torsion springs is proposed. Such an approach is useful in the design of quasi-statically balanced fully compliant mechanisms by tuning the stiffness of the pseudo-rigid-body-model. Here, the positive stiffness exhibited by torsion springs at the R-joints is compensated by a negative stiffness function. The negative stiffness is created by a non-zero-free-length linear spring connected between the coupler link and the ground, and where both connecting points trace a line directed to the coupler link’s instant center of rotation. A full example of the static balancing of two compliant linkages for approximate straight path generation is developed, where actuation energy of the compliant designs is reduced in 66% and 54%, respectively.

Static Balancing of Four-Bar Compliant Mechanisms With Torsion Springs by Exerting Negative Stiffness Using Linear Spring At the Instant Center of Rotation

The present invention provides a calibration set of rail dynamometric shafts, comprising a vertical positioning system, with at least one set of vertical guidance, a linear hoisting unit and a foot; a useful application of forces, with at least four calibration triaxial transducers arranged on a plate; a pedestal, which rigidly connects the upper ends of the triaxial transducers calibration; and a stretch of railway rail mounted on the stand; and a monitoring system; wherein the set vertical guide restricts lateral movement of the tool force application during the vertical movement providing linear hoisting unit to the plate, which is displaceable between an initial position and a final vertical stroke vertical stroke position; the initial and final positions of vertical stroke defined by the set of vertical guidance; the set of linear vertical guidance and hoisting unit being arranged on the foot.

Static balance can be applied to improve energy efficiency of mechanisms. In the field of static balancing, a lack of knowledge and design methods exists that are capable of dealing with torsional stiffness. This paper presents a design approach for statically balanced mechanisms, with the focus on mechanisms with torsional stiffness. The approach is graphical of nature and it is based on the requirement of constant potential energy. The first achievements of the presented approach are presented as five conceptual designs of four different types of mechanisms. One of them is developed further into a prototype, which has been tested. The prototype has a correlation coefficient of 0.96 and a normalized mean squared error of 0.12 with respect to the mechanical model of the conceptual design.© 2010 ASME

An Energy Approach to Static Balancing of Systems With Torsion Stiffness

The key behind the theory on static balanc- ing of mechanisms is the fact that the potential energy must remain constant along the range of motion of the system. Most of the design approaches for static balancing are based on this fact and the use of the effects of this on the first and second derivative of the potential energy respect to the DOF's, (meaning the force and stiffness of the system), but almost no consideration is given to the effects derived from the force and stiffness, like the natural frequency of the system, the speed on the solution of the equation of motion or buckling effects. Due to this fact the use of static bal- ancing is constrained in most cases to gravity compensa- tion of linkages and parallel manipulators through the use of counter-masses and longitudinal springs excluding ap- plications involving continuum structures or compensation through the use of other sources of potential energy. Here it is proposed a new perspective for the static balancing of mechanisms based on the buckling phenomena and one of its consequence which is the linearization of the potential energy function. Statically balanced mechanisms (SBM's) also known as energy free systems, are those mechanisms where the acting forces are balanced or in static equilibrium for all the points of a given range of motion, hence making the operation of the mechanisms effortless. This state is characterized by a constant potential energy along the given range of motion which is a necessary and sufficient condition to ensure such a state. From the analysis of the first and second derivative of the potential respect to the DOF's describing the motion (i.e. the force and stiffness) it is obtained that the resultant force is zero and that the stiffness along the range of motion is zero. Zero force or continuous equilibrium is also a nec- essary and sufficient condition to guaranty a state of static balancing whilst zero stiffness or neutral stability is only a necessary but no sufficient condition because it is also a condition for systems with constant resultant force. Applications of static balancing are mainly gravity com- pensation of linkages and parallel mechanisms. Most of the

Compliant mechanisms achieve their mobility through the deformation of their members, this means that part of the energy transmitted from the input to the output of the mechanisms will be stored in the mechanisms as strain energy. This energy storage in some cases is not a desired characteristic and a way to solve this problem is by static balancing the behavior of the mechanisms. Here five criteria are presented that can be used in the static balancing of compliant mechanisms. The criteria are combined in a systematic way with design methods for compliant mechanisms as an exercise to find feasible combinations for the development of design methods for statically balanced compliant mechanisms. The feasibility of the combination between criteria and design methods for compliant mechanisms is demonstrated by using rigid body mechanisms with torsion springs, roughly emulating their compliant counterpart.Copyright © 2010 by ASME

Compliant mechanisms are rapidly gaining importance, yet their design remains challenging. A great variety of methods are being developed as it is reported in a growing stream of publications. However, so far no review of this body of literature is available. This paper provides a comprehensive and conceptual overview of the main notions behind the most relevant design methods for compliant mechanisms. Rigid-Body-Replacement methods including the Pseudo-Rigid-Body model and the FACT approach are covered, as well as Building Block approaches. In addition an introduction and explanation on Topology Optimization and Shape Optimization is provided, including their most common parameterizations and formulations. This work aims to serve as an introduction into compliant mechanism design methods and as a reference work for more experienced scholars and professionals. It is intended to be a starting point for the exploration of the literature, as well as a guide to specific papers about a particular design problem one may have. For this reason, the paper presents the methods in a wide perspective, emphasizing the conceptual ideas behind every method and refers to literature for details and advanced features.Copyright © 2009 by ASME

In the last 20 years the interest in compliant mechanisms has experienced a rebirth with a continuous growth in research with the consequently increase of literature in this area. This work presents a classification scheme to organize literature on compliant mechanisms. The literature classification is based on the design methodology for conventional mechanisms; which is proposed as a compatible design process also for compliant mechanisms by assuming some limitations and extensions in the employed terms. As an example, 120 relevant research documents in compliant mechanisms have been classified. The work done on topology optimization was excluded due to its extension.Copyright © 2009 by ASME

Classification for Literature on Compliant Mechanisms: A Design Methodology Based Approach

Animals can quickly adapt learned movements in response to external perturbations. Motor adaptation is likely influenced by an animal’s existing movement repertoire, but the nature of this influence is unclear. Long-term learning causes lasting changes in neural connectivity which determine the activity patterns that can be produced. Here, we sought to understand how a neural population’s activity repertoire, acquired through long-term learning, affects short-term adaptation by modeling motor cortical neural population dynamics during de novo learning and subsequent adaptation using recurrent neural networks. We trained these networks on different motor repertoires comprising varying numbers of movements. Networks with multiple movements had more constrained and robust dynamics, which were associated with more defined neural ‘structure’—organization created by the neural population activity patterns corresponding to each movement. This structure facilitated adaptation, but only when small changes in motor output were required, and when the structure of the network inputs, the neural activity space, and the perturbation were congruent. These results highlight trade-offs in skill acquisition and demonstrate how prior experience and external cues during learning can shape the geometrical properties of neural population activity as well as subsequent adaptation.

De novo motor learning creates structure in neural activity space that shapes adaptation

Animals of the same species often exhibit similar behaviours that are advantageously adapted to their body and their environment. These behaviours are shaped by selection pressures over evolutionary timescales at the species level, yet each individual produces these behaviours using a different, uniquely constructed brain. It remains unclear how these common behavioural adaptations emerge from the idiosyncratic neural circuitry of a given individual. Here, we hypothesised that the adaptive behaviour of a species requires specific neural population ‘latent dynamics’. These latent dynamics should thus be preserved and identifiable across individuals within a species, regardless of the idiosyncratic aspects of each individual’s brain. Using recordings of neural populations from monkey and mouse motor cortex, we show that individuals from the same species share surprisingly similar neural dynamics when they perform the same behaviour. The similarity in neural population dynamics extends beyond cortical regions to the dorsal striatum, an evolutionarily older structure, and also holds when animals con-sciously plan future movements without overt behaviour. These preserved dynamics are behaviourally-relevant, allowing decoding of intended and ongoing movements across individuals. We posit that these emergent neural population dynamics result from evolutionarily-imposed constraints on brain development, and reflect a fundamental property of the neural basis of behaviour.

Preserved neural population dynamics across animals performing similar behaviour

Going beyond primary motor cortex to improve brain–computer interfaces

Animals use afferent feedback to rapidly correct ongoing movements in the presence of a perturbation. Repeated exposure to a predictable perturbation leads to behavioural adaptation that counteracts its effects. Primary motor cortex (M1) is intimately involved in both processes, integrating inputs from various sensorimotor brain regions to update the motor output. Here, we investigate whether feedback-based motor control and motor adaptation may share a common implementation in M1 circuits. We trained a recurrent neural network to control its own output through an error feedback signal, which allowed it to recover rapidly from external perturbations. Implementing a biologically plausible plasticity rule based on this same feedback signal also enabled the network to learn to counteract persistent perturbations through a trial-by-trial process, in a manner that reproduced several key aspects of human adaptation. Moreover, the resultant network activity changes were also present in neural population recordings from monkey M1. Online movement correction and longer-term motor adaptation may thus share a common implementation in neural circuits.

Feedback-based motor control can guide plasticity and drive rapid learning

Small, correlated changes in synaptic connectivity may facilitate rapid motor learning

The spiking activity of populations of cortical neurons is well described by a small number of population-wide covariance patterns, the “latent dynamics”. These latent dynamics are largely driven by the same correlated synaptic currents across the circuit that determine the generation of local field potentials (LFP). Yet, the relationship between latent dynamics and LFPs remains largely unexplored. Here, we characterised this relationship for three different regions of primate sensorimotor cortex during reaching. The correlation between latent dynamics and LFPs was frequency-dependent and varied across regions. However, for any given region, this relationship remained stable across behaviour: in each of primary motor and premotor cortices, the LFP-latent dynamics correlation profile was remarkably similar between movement planning and execution. These robust associations between LFPs and neural population latent dynamics help bridge the wealth of studies reporting neural correlates of behaviour using either type of recordings.

Local field potentials reflect cortical population dynamics in a region-specific and frequency-dependent manner

Decision letter: Neural ensemble dynamics in dorsal motor cortex during speech in people with paralysis

Pathological tremor is an oscillation of body parts at 3–10 Hz, determined by the output of spinal motor neurons (MNs), which receive synaptic inputs from supraspinal centers and muscle afferents. The behavior of spinal MNs during tremor is not well understood, especially in relation to the activation of the multiple muscles involved. Recent studies on patients with essential tremor have shown that antagonist MN pools receive shared input at the tremor frequency. In this study, we investigated the synaptic inputs related to tremor and voluntary movement, and their coordination across antagonist muscles. We analyzed the spike trains of motor units (MUs) identified from high-density surface electromyography from the forearm extensor and flexor muscles in 15 patients with essential tremor during postural tremor. The shared synaptic input was quantified by coherence and phase difference analysis of the spike trains. All pairs of spike trains in each muscle showed coherence peaks at the voluntary drive frequency (1–3 Hz, 0.2 ± 0.2, mean ± SD) and tremor frequency (3–10 Hz, 0.6 ± 0.3) and were synchronized with small phase differences (3.3 ± 25.2° and 3.9 ± 22.0° for the voluntary drive and tremor frequencies, respectively). The coherence between MN spike trains of antagonist muscle groups at the tremor frequency was significantly smaller than intramuscular coherence. We predominantly observed in-phase activation of MUs between agonist/antagonist muscles at the voluntary frequency band (0.6 ± 48.8°) and out-of-phase activation at the tremor frequency band (126.9 ± 75.6°). Thus MNs innervating agonist/antagonist muscles concurrently receive synaptic inputs with different phase shifts in the voluntary and tremor frequency bands. NEW & NOTEWORTHY Although the mechanical characteristics of tremor have been widely studied, the activation of the affected muscles is still poorly understood. We analyzed the behavior of motor units of pairs of antagonistic wrist muscle groups in patients with essential tremor and studied their activity at voluntary movement- and tremor-related frequencies. We found that the phase relation between inputs to antagonistic muscles is different at the voluntary and tremor frequency bands.

Voluntary and tremorogenic inputs to motor neuron pools of agonist/antagonist muscles in essential tremor patients

Background: Traditional studies on the neural mechanisms of tremor use coherence analysis to investigate the relationship between cortical and muscle activity, measured by electroencephalograms (EEG) and electromyograms (EMG). This methodology is limited by the need of relatively long signal recordings, and it is sensitive to EEG artifacts. Here, we analytically derive and experimentally validate a new method for automatic extraction of the tremor-related EEG component in pathological tremor patients that aims to overcome these limitations. Methods: We exploit the coupling between the tremor-related cortical activity and motor unit population firings to build a linear minimum mean square error estimator of the tremor component in EEG. We estimated the motor unit population activity by decomposing surface EMG signals into constituent motor unit spike trains, which we summed up into a cumulative spike train (CST). We used this CST to initialize our tremor-related EEG component estimate, which we optimized using a novel approach proposed here. Results: Tests on simulated signals demonstrate that our new method is robust to both noise and motor unit firing variability, and that it performs well across a wide range of spectral characteristics of the tremor. Results on 9 essential (ET) and 9 Parkinson's disease (PD) patients show a ~2-fold increase in amplitude of the coherence between the estimated EEG component and the CST, compared to the classical EEG-EMG coherence analysis. Conclusions: We have developed a novel method that allows for more precise and robust estimation of the tremor-related EEG component. This method does not require artifact removal, provides reliable results in relatively short datasets, and tracks changes in the tremor-related cortical activity over time.

Motor Unit-Driven Identification of Pathological Tremor in Electroencephalograms

Mechanical vibration does not systematically reduce the tremor in essential tremor patients

The impact of severity of pathological tremor on surface EMG decomposition was systematically assessed on eight essential tremor patients. The inertial data and surface EMG signals were concurrently recorded from wrist extensor and flexor muscles of both patients’ arms. The inertial recordings were segmented into different tremor cycles and the tremor amplitude was assessed in each tremor cycle. Surface EMG was decomposed by Convolution Kernel Compensation (CKC) technique in order to yield individual motor unit discharge patterns in each tremor cycle. Accuracy of EMG decomposition was assessed for each identified motor unit and was largely uncorrelated with tremor amplitude. In all the patients, the percentage of EMG energy identified by decomposition and the number of identified motor units were found to be positively correlated with tremor amplitude, though the correlation was relatively weak and not always significant. The results demonstrate that the CKC decomposition not only copes with moderate and severe tremor but also improves its performance with tremor intensity.

On the Impact of Pathological Tremor Intensity on Noninvasive Characterization of Motor Unit Discharge Properties

Pathological tremor is a common but highly complex movement disorder, affecting ~5% of population older than 65 years. Different methodologies have been proposed for its quantification. Nevertheless, the discrimination between Parkinson’s disease tremor and essential tremor remains a daunting clinical challenge, greatly impacting patient treatment and basic research. Here, we propose and compare several movement-based and electromyography-based tremor quantification metrics. For the latter, we identified individual motor unit discharge patterns from high-density surface electromyograms and characterized the neural drive to a single muscle and how it relates to other affected muscles in 27 Parkinson’s disease and 27 essential tremor patients. We also computed several metrics from the literature. The most discriminative metrics were the symmetry of the neural drive to muscles, motor unit synchronization, and the mean log power of the tremor harmonics in movement recordings. Noteworthily, the first two most discriminative metrics were proposed in this study. We then used decision tree modelling to find the most discriminative combinations of individual metrics, which increased the accuracy of tremor type discrimination to 94%. In summary, the proposed neural drive-based metrics were the most accurate at discriminating and characterizing the two most common pathological tremor types.

New Perspectives for Computer-Aided Discrimination of Parkinson's Disease and Essential Tremor

Juan Alvaro Gallego,* Robert M. Hardwick* and Emily R. Oby* Neural and Cognitive Engineering Group, Centre for Automation and Robotics CSIC-UPM, Madrid, Spain Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Department of Neurology, Johns Hopkins University, Baltimore, MD, USA Movement Control and Neuroplasticity Research Group, KU Leuven, Leuven, Belgium Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA 15213, USA

Highlights from the 2017 meeting of the Society for Neural Control of Movement (Dublin, Ireland)

J. L. Dideriksen, J. A. Gallego, F. Negro, A. Holobar and Dario Farina Department of Neurorehabilitation Engineering, Bernstein Focus Neurotechnology Göttingen, Bernstein Center for Computational Neuroscience, University Medical Center Göttingen, Georg-August University, Göttingen, Germany Bioengineering Group, Spanish National Research Council (CSIC), Arganda del Rey, Spain Faculty of Electrical Engineering and Computer Science, University of Maribor, Maribor, Slovenia

A Review of Methods to Characterize Motor Unit Firing Properties and Underlying Determinants

Standing Input to Bilateral Leg Muscles During Quiet Low-Alcohol Doses Reduce Common 10- to 15-Hz

Tremor in essential tremor (ET) is generated by pathological oscillations at 4-12 Hz, likely originating at cerebello-thalamo-cortical pathways. However, the way in which tremor is represented in the output of the spinal cord circuitries is largely unknown because of the difficulties in identifying the behavior of individual motor units from tremulous muscles. By using novel methods for the decomposition of multichannel surface EMG, we provide a systematic analysis of the discharge properties of motor units in nine ET patients, with concurrent recordings of EEG activity. This analysis allowed us to infer the contribution of common synaptic inputs to motor neurons in ET. Motor unit short-term synchronization was significantly greater in ET patients than in healthy subjects. Furthermore, the strong association between the degree of synchronization and the peak in coherence between motor unit spike trains at the tremor frequency indicated that the high synchronization levels were generated mainly by common synaptic inputs specifically at the tremor frequency. The coherence between EEG and motor unit spike trains demonstrated the presence of common cortical input to the motor neurons at the tremor frequency. Nonetheless, the strength of this input was uncorrelated to the net common synaptic input at the tremor frequency, suggesting a contribution of spinal afferents or secondary supraspinal pathways in projecting common input at the tremor frequency. These results provide the first systematic analysis of the neural drive to the muscle in ET and elucidate some of its characteristics that determine pathological tremulous muscle activity.

Influence of common synaptic input to motor neurons on the neural drive to muscle in essential tremor.

Shared synaptic input to motoneuron pools from different limbs in essential tremor

[PDF]  [Full Text]  [Abstract] , May , 2011; 110 (5): 1390-1399. J Appl Physiol Makii Muthalib, Hoseong Lee, Guillaume Y. Millet, Marco Ferrari and Kazunori Nosaka activity The repeated-bout effect: influence on biceps brachii oxygenation and myoelectrical [PDF]  [Full Text]  [Abstract] , February , 2012; 107 (3): 958-965. J Neurophysiol Dario Farina, Francesco Negro, Leonardo Gizzi and Deborah Falla experimental muscle pain Low-frequency oscillations of the neural drive to the muscle are increased with [PDF]  [Full Text]  [Abstract] , June 15, 2012; 107 (12): 3357-3369. J Neurophysiol Jakob L. Dideriksen, Francesco Negro, Roger M. Enoka and Dario Farina synaptic noise on force steadiness Motor unit recruitment strategies and muscle properties determine the influence of [PDF]  [Full Text]  [Abstract] , September 15, 2012; 113 (6): 929-936. J Appl Physiol Bradley M. Pitman and John G. Semmler elbow flexor muscles Reduced short-interval intracortical inhibition after eccentric muscle damage in human [PDF]  [Full Text]  [Abstract] , December 15, 2012; 108 (12): 3264-3275. J Neurophysiol Douglas A. Keen, Li-Wei Chou, Michael A. Nordstrom and Andrew J. Fuglevand direct cortical input Short-term synchrony in diverse motor nuclei presumed to receive different extents of

Flexor Muscles Brachii After Exercise-Induced Damage to Elbow Motor Unit Synchronization Is Increased in Biceps

The pathophysiology of essential tremor (ET), the most common movement disorder, is not fully understood. We investigated which factors determine the variability in the phase difference between neural drives to antagonist muscles, a long-standing observation yet unexplained. We used a computational model to simulate the effects of different levels of voluntary and tremulous synaptic input to antagonistic motoneuron pools on the tremor. We compared these simulations to data from 11 human ET patients. In both analyses, the neural drive to muscle was represented as the pooled spike trains of several motor units, which provides an accurate representation of the common synaptic input to motoneurons. The simulations showed that, for each voluntary input level, the phase difference between neural drives to antagonist muscles is determined by the relative strength of the supraspinal tremor input to the motoneuron pools. In addition, when the supraspinal tremor input to one muscle was weak or absent, Ia afferents provided significant common tremor input due to passive stretch. The simulations predicted that without a voluntary drive (rest tremor) the neural drives would be more likely in phase, while a concurrent voluntary input (postural tremor) would lead more frequently to an out-of-phase pattern. The experimental results matched these predictions, showing a significant change in phase difference between postural and rest tremor. They also indicated that the common tremor input is always shared by the antagonistic motoneuron pools, in agreement with the simulations. Our results highlight that the interplay between supraspinal input and spinal afferents is relevant for tremor generation.

The Phase Difference Between Neural Drives to Antagonist Muscles in Essential Tremor Is Associated with the Relative Strength of Supraspinal and Afferent Input

Objective. Pathological tremors are symptomatic to several neurological disorders that are difficult to differentiate and the way by which central oscillatory networks entrain tremorogenic contractions is unknown. We considered the alternative hypotheses that tremor arises from one oscillator (at the tremor frequency) or, as suggested by recent findings from the superimposition of two separate inputs (at the tremor frequency and twice that frequency). Approach. Assuming one central oscillatory network we estimated analytically the relative amplitude of the harmonics of the tremor frequency in the motor neuron output for different temporal behaviors of the oscillator. Next, we analyzed the bias in the relative harmonics amplitude introduced by superimposing oscillations at twice the tremor frequency. These findings were validated using experimental measurements of wrist angular velocity and surface electromyography (EMG) from 22 patients (11 essential tremor, 11 Parkinson’s disease). The ensemble motor unit action potential trains identified from the EMG represented the neural drive to the muscles. Main results. The analytical results showed that the relative power of the tremor harmonics in the analytical models of the neural drive was determined by the variability and duration of the tremor bursts and the presence of the second oscillator biased this power towards higher values. The experimental findings accurately matched the analytical model assuming one oscillator, indicating a negligible functional role of secondary oscillatory inputs. Furthermore, a significant difference in the relative power of harmonics in the neural drive was found across the patient groups, suggesting a diagnostic value of this measure (classification accuracy: 86%). This diagnostic power decreased substantially when estimated from limb acceleration or the EMG. Signficance. The results indicate that the neural drive in pathological tremor is compatible with one central network providing neural oscillations at the tremor frequency. Moreover, the regularity of this neural oscillation varies across tremor pathologies, making the relative amplitude of tremor harmonics a potential biomarker for diagnostic use.

One central oscillatory drive is compatible with experimental motor unit behaviour in essential and Parkinsonian tremor

We describe a novel technique for identification of cortical centres that have electrical activity coupled to the activity of skeletal muscles in pathological tremor. This technique utilises concurrent recordings of highdensity surface electromyograms (EMG) and electroencephalograms (EEG). First, the discharge patterns of individual motor units are identified from surface EMG signals by previously introduced Convolution Kernel Compensation technique. Next, spike-triggered averaging is applied to the EEG signals, using the identified motor unit discharges as triggering spikes. As a result, the cortical activities coupled to the discharges of a selected skeletal muscle are identified. The extracted EEG averages are then inserted into Statistical Parametric Mapping (SPM) tool and used to identify the cortical sources contributing to the observed EEG averages. When tested on 5 Parkinsonian and 5 essential tremor patients, this methodology consistently identified two cortical centres, one in the contralateral sensorimotor cortex, and the other in the contralateral prefrontal/premotor cortex.

A novel technique for assessment of neuromuscular coupling in pathological tremor

Closed-Loop Modulation of a Notch-Filter Stimulation Strategy for Tremor Management with a Neuroprosthesis

1. Neuroengineering and Cognitive Science Group, Centre for Automation and Robotics, 10 Consejo Superior de Investigaciones Científicas, 28500 Arganda del Rey, Spain. 11 2. Department of Neurorehabilitation Engineering, Bernstein Focus Neurotechnology 12 Göttingen, Bernstein Center for Computational Neuroscience, University Medical Center 13 Göttingen, Georg-August University, 37075 Göttingen, Germany. 14 3. Faculty of Electrical Engineering and Computer Science, University of Maribor, 2000 15 Maribor, Slovenia. 16 4. Neural Rehabilitation Group, Cajal Institute, Consejo Superior de Investigaciones 17 Científicas, 28002, Madrid, Spain. 18 5. Department of Neurology, College of Physicians and Surgeons, and Department of 19 Epidemiology, Mailman School of Public Health, Columbia University, 10032 New York, 20 New York, USA. 21 6. Post-graduate Program, Universidade Federal do Espírito Santo, 29075-910, Vitória, 22 Brazil. 23 24

INFLUENCE OF COMMON SYNAPTIC INPUT TO MOTOR 3 NEURONS ON THE NEURAL DRIVE TO MUSCLE IN 4 ESSENTIAL TREMOR 5 6

Detection of Common Synaptic Inputs Shared by Populations of Motor Neurons Innervating Different Muscles: Methodology and Considerations for Neuroprosthetic Treatment of Tremor

Surface EMG in Neurorehabilitation and Ergonomics: State of the Art and Future Perspectives

Larger Motor-Unit Forces in Old Adults Motor-Unit Synchronization Is Not Responsible for

Background Essential tremor (ET) is characterised by postural and action tremors with a frequency of 4–12 Hz. Previous studies suggest that the tremor activity originates in the cerebello-thalamocortical pathways. Alprazolam is a short-acting benzodiazepine that attenuates tremors in ET. The mechanisms that mediate the therapeutic action of alprazolam are unknown; however, in healthy subjects, benzodiazepines increase cortical beta activity. In this study, we investigated the effect of alprazolam both on beta and tremor-related cortical activity and on alterations in tremor presentation in ET patients. Therefore, we characterised the dynamics of tremor and cortical activity in ET patients after alprazolam intake. Methods We recorded hand tremors and contralateral cortical activity in four recordings before and after a single dose of alprazolam. We then computed the changes in tremors, cortico-muscular coherence, and cortical activity at the tremor frequency and in the beta band. Results Alprazolam significantly attenuated tremors (EMG: 76.2±22.68%), decreased cortical activity in the tremor frequency range and increased cortical beta activity in all patients (P<0.05). At the same time, the cortico-muscular coherence at the tremor frequency became non-significant (P<0.05). We also found a significant correlation (r = 0.757, P<0.001) between the reduction in tremor severity and the increased ratio of cortical activity in the beta band to the activity observed in the tremor frequency range. Conclusions This study provides the first quantitative analysis of tremor reduction following alprazolam intake. We observed that the tremor severity decreased in association with an increased ratio of beta to tremor-related cortical activity. We hypothesise that the increase in cortical beta activity may act as a blocking mechanism and may dampen the pathological oscillatory activity, which in turn attenuates the observed tremor.

Effects of Alprazolam on Cortical Activity and Tremors in Patients with Essential Tremor

Upper limb tremor is the most prevalent movement disorder and, unfortunately, it is not effectively managed in a large proportion of the patients. Neuroprostheses that stimulate the sensorimotor pathways are one of the most promising alternatives although they are still under development. To enrich the interpretation of data recorded during long-term tremor monitoring and to increase the intelligence of tremor suppression neuroprostheses we need to be aware of the context. Context awareness is a major challenge for neuroprostheses and would allow these devices to react more quickly and appropriately to the changing demands of the user and/or task. Traditionally kinematic features are used to extract context information, with most recently the use of joint angles as highly potential features. In this paper we present two algorithms that enable the robust extraction of joint angle and related features to enable long-term continuous monitoring of tremor with context awareness. First, we describe a novel relative sensor placement identification technique based on orientation data. We focus on relative rather than absolute sensor location, because in many medical applications magnetic and inertial measurement units (MIMU) are used in a chain stretching over adjacent segments, or are always placed on a fixed set of locations. Subsequently we demonstrate how tremor parameters can be extracted from orientation data using an adaptive estimation algorithm. Relative sensor location was detected with an accuracy of 94.12% for the 4 MIMU configuration, and 100% for the 3 MIMU configurations. Kinematic tracking error values with an average deviation of 8% demonstrate our ability to estimate tremor from orientation data. The methods presented in this study constitute an important step toward more user-friendly and context-aware neuroprostheses for tremor suppression and monitoring.

Automatic real-time monitoring and assessment of tremor parameters in the upper limb from orientation data

1. Neuroengineering and Cognitive Science Group, Centre for Automation and Robotics, 10 Consejo Superior de Investigaciones Cientificas, 28500 Arganda del Rey, Spain. 11 2. Department of Neurorehabilitation Engineering, Bernstein Focus Neurotechnology 12 Gottingen, Bernstein Center for Computational Neuroscience, University Medical Center 13 Gottingen, Georg-August University, 37075 Gottingen, Germany. 14 3. Faculty of Electrical Engineering and Computer Science, University of Maribor, 2000 15 Maribor, Slovenia. 16 4. Neural Rehabilitation Group, Cajal Institute, Consejo Superior de Investigaciones 17 Cientificas, 28002, Madrid, Spain. 18 5. Department of Neurology, College of Physicians and Surgeons, and Department of 19 Epidemiology, Mailman School of Public Health, Columbia University, 10032 New York, 20 New York, USA. 21 6. Post-graduate Program, Universidade Federal do Espirito Santo, 29075-910, Vitoria, 22 Brazil. 23 24

A neuroprosthesis for tremor management through the control of muscle co-contraction

Pathological tremor is the most prevalent movement disorder. In spite of the existence of various treatments for it, tremor poses a functional problem to a large proportion of patients. This paper presents the design and implementation of a novel neuroprosthesis for tremor management. The paper starts by reviewing a series of design criteria that were established after analyzing users needs and the expected functionality of the system. Then, it summarizes the design of the neuroprosthesis, which was built to meet the criteria defined previously. Experimental results with a representative group of 12 patients show that the neuroprosthesis provided significant (p <; 0.001) and systematic tremor attenuation (in average 52.33 ± 25.48 %), and encourage its functional evaluation as a potential new treatment for tremor in a large cohort of patients.

2013 35th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC)

Design and validation of a neuroprosthesis for the treatment of upper limb tremor

Online detector of movement intention based on EEG - Application in tremor patients

On Repeatability of Motor Unit Characterization in Pathological Tremor

Pathological tremors are accepted to originate from the projection of supraspinal pathological oscillations to motor neurons that innervate the affected muscles. These oscillations interact with other neural mechanisms such as reflexes, and, together with the mechanical properties of the limb, determine the characteristics of the tremor. However, much is yet unknown about the exact mechanisms that mediate the different types of tremor, and how they interact. Given that the neural drive to muscle encodes information about all pathways that regulate movement, we are investigating the properties of motor unit activities in tremor patients and the factors that determine them as a means to further our understanding of the disorder. This paper presents a simulation study that supports our departure hypothesis (that tremor is a common cortical projection to the motor neuron pool), and first experimental evidences on a patient with essential tremor. The latter illustrate that the predictions derived from the model provide significant support for the analysis of real data, and demonstrate the potential of the analysis techniques here employed.

Motor Unit Properties and Underlying Determinants in Pathological Tremor

Advances in the Assessment and Suppression of Pathological Tremor in the Framework of TREMOR Project

This work aims to create an advanced human-computer interface called ENLAZA for people with cerebral palsy (CP). Although there are computer-access solutions for disabled people in general, there are few evidences from motor disabled community (e.g., CP) using these alternative interfaces. The proposed interface is based on inertial sensors in order to characterize involuntary motion in terms of time, frequency and range of motion. This characterization is used to design a filtering technique that reduces the effect of involuntary motion on person-computer interaction. This paper presents a robust Kalman filter (RKF) design to facilitate fine motor control based on the previous characterization. The filter increases mouse pointer directivity and the target acquisition time is reduced by a factor of ten. The interface is validated with CP users who were unable to control the computer using other interfaces. The interface ENLAZA and the RKF enabled them to use the computer.

A Robust Kalman Algorithm to Facilitate Human-Computer Interaction for People with Cerebral Palsy, Using a New Interface Based on Inertial Sensors

Tremor is the most prevalent movement disorder, and its incidence is increasing with aging. In spite of the numerous therapeutic solutions available, 65% of those suffering from upper limb tremor report serious difficulties during their daily living. This gives rise to research on different treatment alternatives, amongst which wearable robots that apply selective mechanical loads constitute an appealing approach. In this context, the current work presents a multimodal human-robot interface to drive a neuroprosthesis for tremor management. Our approach relies on the precise characterization of the tremor to modulate a functional electrical stimulation system that compensates for it. The neuroprosthesis is triggered by the detection of the intention to move derived from the analysis of electroencephalographic activity, which provides a natural interface with the user. When a prediction is delivered, surface electromyography serves to detect the actual onset of the tremor in the presence of volitional activity. This information in turn triggers the stimulation, which relies on tremor parameters-amplitude and frequency-derived from a pair of inertial sensors that record the kinematics of the affected joint. Surface electromyography also yields a first characterization of the tremor, together with precise information on the preferred stimulation site. Apart from allowing for an optimized performance of the system, our multimodal approach permits the implementation of redundant methods to both enhance the reliability of the system and adapt to the specific needs of different users. Results with a representative group of patients illustrate the performance of the interface presented here and demonstrate its feasibility.

IEEE Transactions on Systems, Man, and Cybernetics, Part C (Applications and Reviews)

A Multimodal Human–Robot Interface to Drive a Neuroprosthesis for Tremor Management

Background Tremor is the most common movement disorder and strongly increases in incidence and prevalence with aging. Although not life threatening, upper-limb tremors hamper the independence of 65% of people suffering from them affected persons, greatly impacting their quality of life. Current treatments include pharmacotherapy and surgery (thalamotomy and deep brain stimulation). However, these options are not sufficient for approximately 25% of patients. Therefore, further research and new therapeutic options are required to effectively manage pathological tremor. Methods This paper presents findings of two research projects in which two different wearable robots for tremor management were developed based on force loading and validated. The first consisted of a robotic exoskeleton that applied forces to tremulous limbs and consistently attenuated mild and severe tremors. The second was a neuroprosthesis based on transcutaneous neurostimulation. A total of 22 patients suffering from parkinsonian or essential tremor (ET) of different severities were recruited for experimental validation, and both systems were evaluated using standard tasks employed for neurological examination. The inclusion criterion was a postural and/or kinetic pathological upper-limb tremor resistant to medication. Results The results demonstrate that both approaches effectively suppressed tremor in most patients, although further research is required. The work presented here is based on clinical evidence from a small number of patients (n = 10 for robotic exoskeleton and n = 12 for the neuroprosthesis), but most had a positive response to the approaches. In summary, biomechanical loading is non-invasive and painless. It may be effective in patients who are insufficiently responsive (or have adverse reactions) to drugs or in whom surgery is contraindicated. Discussion This paper identifies and evaluates biomechanical loading approaches to tremor management and discusses their potential.

Biomechanical Loading as an Alternative Treatment for Tremor: A Review of Two Approaches

Walking on irregular surfaces and in the presence of unexpected events is a challenging problem for bipedal machines. Up to date, their ability to cope with gait disturbances is far less successful than humans': Neither trajectory controlled robots, nor dynamic walking machines Limit Cycle Walkers are able to handle them satisfactorily. On the contrary, humans reject gait perturbations naturally and efficiently relying on their sensory organs that, if needed, elicit a recovery action. A similar approach may be envisioned for bipedal robots and exoskeletons: An algorithm continuously observes the state of the walker and, if an unexpected event happens, triggers an adequate reaction. This paper presents a monitoring algorithm that provides immediate detection of any type of perturbation based solely on a phase representation of the normal walking of the robot. The proposed method was evaluated in a Limit Cycle Walker prototype that suffered push and trip perturbations at different moments of the gait cycle, providing 100% successful detections for the current experimental apparatus and adequately tuned parameters, with no false positives when the robot is walking unperturbed.

Detection of gait perturbations based on proprioceptive information. Application to Limit Cycle Walkers

This paper presents the fully automatic identification of motor unit spike trains from high-density surface electromyograms (EMG) in pathological tremor. First, a mathematical derivation is provided to theoretically prove the possibility of decomposing noise-free high-density surface EMG signals into motor unit spike trains with high correlation, which are typical of tremor contractions. Further, the proposed decomposition method is tested on simulated signals with different levels of noise and on experimental signals from 14 tremor-affected patients. In the case of simulated tremor with central frequency ranging from 5 Hz to 11 Hz and signal-to-noise ratio of 20 dB, the method identified ∼8 motor units per contraction with sensitivity in spike timing identification ≥95% and false alarm and miss rates ≤5%. In experimental signals, the number of identified motor units varied substantially (range 0–21) across patients and contraction types, as expected. The behaviour of the identified motor units was consistent with previous data obtained by intramuscular EMG decomposition. These results demonstrate for the first time the possibility of a fully non-invasive investigation of motor unit behaviour in tremor-affected patients. The method provides a new means for physiological investigations of pathological tremor.

Non-invasive characterization of motor unit behaviour in pathological tremor

Tremor constitutes the most common motor disorder, and poses a functional problem to a large number of patients. Despite of the considerable experience in tremor management, current treatment based on drugs or surgery does not attain an effective attenuation in 25 % of patients, motivating the need for research in new therapeutic alternatives. In this context, this paper presents the concept design, development, and preliminary validation of a soft wearable robot for tremor assessment and suppression. The TREMOR neurorobot comprises a Brain Neural Computer Interface that monitors the whole neuromusculoskeletal system, aiming at characterizing both voluntary movement and tremor, and a Functional Electrical Stimulation system that compensates for tremulous movements without impeding the user perform functional tasks. First results demonstrate the performance of the TREMOR neurorobot as a novel means of assessing and attenuating pathological tremors.

2011 IEEE International Conference on Robotics and Automation, 9-13 May 2011, Shanghai, China

An EEG-Based Design for the Online Detection of Movement Intention

Characterization of Pathological Tremor from Motor Unit Spike Trains

This paper presents analysis of kinematic data of tremor patients while performing different tasks with Ensemble Empirical Mode Decomposition (EEMD), a novel noise-assisted data analysis method. EEMD automatically separates raw kinematic data into three components: 1) noise from various sources, 2) tremulous movement, and 3) voluntary movement. Comparison of this technique with other decomposition methods such as recursive forth and back filters or Empirical Mode Decomposition (EMD) shows a better performance; EEMD separation of tremor diminishes EMD error in a 45.2 % (mean error 0.041 ± 0.036 rad/s). Moreover, postprocessing of EEMD separated tremor allows the calculation of the Hilbert spectrum, a high resolution time-energy-frequency distribution that improves analysis of tremors.

Analysis of kinematic data in pathological tremor with the Hilbert-Huang transform

A robust surface EMG decomposition tool, referred to as tremor-optimized Convolution Kernel Compensation (CKC) technique, is described. This technique modifies and extends the previously published CKC method in order to circumvent the typical assumption on regularity and asynchrony of motor unit firings in normal condition and adapt to the discharge patterns in pathological tremor. The results on synthetic and experimental surface EMG signals demonstrate high performance of decomposition. In the case of simulated surface EMG with 20 dB SNR, excitation level of 20% maximum voluntary contraction (MVC) and simulated tremor frequency of 8 Hz, the newly proposed method identified 8 ± 2 motor units with sensitivity of motor unit discharge identification > 95 % and false alarm and miss rates < 5%. The performance worsened with increasing noise power, with 5 ± 2 motor units identified at 10 dB SNR and 3 ± 1 at 0 dB SNR. In 24 recordings of high-density surface EMG signals from four tremor-affected patients, the modified CKC technique identified 134 motor units (6 ± 4 motor units per contraction).

Noninvasive analysis of motor unit behavior in pathological tremor

An ambulatory BCI-driven tremor suppression system based on functional electrical stimulation

In spite of decades of intense research, pathological tremors still constitute unknown disorders. This study addresses, based on a multi-scale model, the behavior of an entire pool of motor neurons in tremor, under the hypothesis that tremor is an oscillation of central origin commonly projected to all motor neurons that innervate a muscle. Our results show that under such conditions both paired discharges and enhanced motor neuron synchronization, two of the characteristic landmarks of tremor, emerge. Moreover, coherence and correlation analyses suggest that the central tremor oscillator is transmitted linearly by the motor neuron pool given that a small set (7 or 8) of motor neurons are sampled.

A modelling study on transmission of the central oscillator in tremor by a motor neuron pool

Estimation of gait parameters by measuring upper limb–walker interaction forces

Extraction of user's navigation commands from upper body force interaction in walker assisted gait

This paper presents a two stage algorithm for real-time estimation of instantaneous tremor parameters from gyroscope recordings. Gyroscopes possess the advantage of providing directly joint rotational speed, overcoming the limitations of traditional tremor recording based on accelerometers. The proposed algorithm first extracts tremor patterns from raw angular data, and afterwards estimates its instantaneous amplitude and frequency. Real-time separation of voluntary and tremorous motion relies on their different frequency contents, whereas tremor modelling is based on an adaptive LMS algorithm and a Kalman filter. Tremor parameters will be employed to drive a neuroprosthesis for tremor suppression based on biomechanical loading.

Real-Time Estimation of Pathological Tremor Parameters from Gyroscope Data

Pathological tremor constitutes the most common movement disorder, and is increasing its prevalence with ageing. Treatment forms range from drugs to surgery in those patients refractory to drugs, however, tremor is not effectively managed in about 25% of patients. According to this, new management techniques such as wearable robots that take advantage of selective biomechanical loading seem an interesting alternative. Our objective is to design robotic exoskeletons which suppress tremor, letting the user perform a voluntary movement, by means of intelligent control approaches that include accurate tremor models. In this context, we propose a two-stage algorithm for real-time estimation of time varying tremor amplitude and frequency. It is based on the assumption that tremor alters voluntary motion in an additive manner, and happens in a higher frequency band. The two-stage algorithm first generates an estimation of voluntary movement based on its inherent slower dynamics, and then removes it from the total motion, directly providing an estimate of tremor. This tremor estimation is then fed into an adaptive filter, which provides instantaneous tremor characteristics. Accurate and robust tremor amplitude and frequency estimates are obtained.

Estimation of instantaneous tremor parameters for FES-based tremor suppression

Tremor constitutes the most common movement disorder; in fact 14.5% of population between 50 to 89 years old suffers from it. Moreover, 65% of patients with upper limb tremor report disability when performing their activities of daily living (ADL). Unfortunately, 25% of patients do not respond to drugs or neurosurgery. In this regard, TREMOR project proposes functional compensation of upper limb tremors with a soft wearable robot that applies biomechanical loads through functional electrical stimulation (FES) of muscles. This wearable robot is driven by a Brain Neural Computer Interface (BNCI). This paper presents a multimodal BCI to assess generation, transmission and execution of both volitional and tremorous movements based on electroencephalography (EEG), electromyography (EMG) and inertial sensors (IMUs). These signals are combined to obtain: 1) the intention to perform a voluntary movement from cortical activity (EEG), 2) tremor onset, and an estimation of tremor frequency from muscle activation (EMG), and 3) instantaneous tremor amplitude and frequency from kinematic measurements (IMUs). Integration of this information will provide control signals to drive the FES-based wearable robot.

2010 Annual International Conference of the IEEE Engineering in Medicine and Biology

Walking in the presence of perturbations poses a demanding challenge to bipedal robots. In this context, we propose an approach based on an algorithm that observes continuously the state of the robot, and if a perturbation is detected, triggers a recovery action. This paper focuses in the former, it presents a simple algorithm to detect online the occurrence of a perturbation with short delay. Simulations with a complex biped model yield no false positives when walking stably, and provide detection of trips with an average delay of 30.2 ms, comparable to short latency reflexes in humans.

2010 3rd IEEE RAS & EMBS International Conference on Biomedical Robotics and Biomechatronics

Brain neural computer interface for tremor identification, characterization and tracking

On the use of inertial measurement units for real-time quantification of pathological tremor amplitude and frequency

Wearable Robots in Rehabilitation Engineering Tremor Suppression

INTRODUCTION Measurement of the evolution of the physical activity in assistive devices (ADs) of daily use might increase the flexibility of the rehabilitation programmes [1]. Also, while walking ADs become more a more autonomous and intelligent [2], reliable and simple methods to assess and adapt performance are demanded. MEMs-based Inertial sensors are called to become standard devices for human motion capture.

Inertial sensing-based method for characterization of activities with walking assitive devices

Mass transfer enhancement in supercritical fluids extraction by means of power ultrasound.

The influence of high-intensity ultrasound on supercritical CO2 extraction of oil from particulate almonds was studied. An ultrasonic transducer was installed inside a high pressure 5 L extractor and a power of 50W was applied during the extraction. All experiments were performed at 280 bar and 55oC with and without ultrasound in order to examine the effects of the acoustic waves. The experimental results showed that the kinetic parameter, considering the process as a second order reaction, was improved about 30% due to ultrasonic radiation and the oil extraction yield was enhanced in about 20% at the end of the process (8.5 h). For design purposes, the experimental data were described applying two empirical models (Naik and Weibull) as well as the model proposed by Sovovà.

EFFECT OF HIGH-INTENSITY ULTRASOUND ON THE PARTICULATE ALMONDS OIL EXTRACTION KINETICS USING SUPERCRITICAL CO 2

Power ultrasound in food industry processing represents a novel tool, which is becoming increasingly appreciated. The use of ultrasonic energy is very promising because it can act without affecting the main characteristics and quality of the products. This work investigates the kinetics of ultrasonic dehydration processes of vegetables by direct contact vibrator-product. To that purpose, a parametric study of the relative influence of the main physical parameters involved in the process has been carried out. A specific experimental set-up has been designed, developed and tested. Trials were carried out with potatoes and apples. A 20kHz resonant transducer was designed with the aim to obtain high-amplitude displacements. Assessment of the properties of the samples (residuary moisture content and viscoelastic constants) is obtained from the analysis of high frequency (0.5-1MHz) wideband ultrasonic signals transmitted through the samples by using air-coupled transducers. The dehydration results show a notable influence of ultrasonic vibration on the kinetics of the process. Introduction Dehydration is a method to preserve food. Nowadays, some dehydrated products like fruits and vegetables have suffered a notable increase on their demand in the market. Therefore new drying technologies are under development with the aim to obtain good quality product at moderate cost. Ultrasonic energy has been used in drying processes because high-amplitude vibrations are capable of increasing heat and mass transfer processes in materials. In this way is possible to remove moisture without significantly heating the product. This is one of the main reasons to use ultrasonic energy in many applications in food technology [1,2,3,4,5,6,7,8]. The aim of this work is to investigate the kinetics of the ultrasonic dehydration process of fruits and vegetables, in which the ultrasonic vibrations are applied in direct contact with the product under certain static pressure. Dehydration curves were determined by a parametric study of the main physical parameters involved in the process. Drying kinetics was modeled by the diffusion equation (Fick’s second law) [9], for which a very good agreement with the experimental data was obtained. The effective diffusivity (De) was determined by a correlation based on the air velocity, the temperature and the nondimensional moisture content of the samples. In parallel, an ultrasonic characterization technique of moisture content in food materials was developed. It is based on the analysis of high frequency (0.5-1MHz) wideband signals transmitted through the samples by using air-coupled transducers. DIFFERENTIAL PRESSURE METER STATIC PRESSURE METER IMPEDANCE MATCHING BOX

Mass transfer processes in supercritical fluid extraction (SFE) can be enhanced by power ultrasound. This is probably the unique practical way to produce a deep agitation under the high-pressure conditions of SFE because the use of mechanical stirrers is unable on an industrial scale. For the generation of the ultrasound a 20kHz sandwich-type piezoelectric transducer for a power capacity of about 100W was designed, constructed and characterized. To drive and keep it at resonance during the trials, a specific electronic system was developed. This system permits to generate constant output power in the fluid under conditions ranging from the normal gas regime (1bar and 20oC) up to the supercritical regimen (280bar and 55oC). The feasibility of the ultrasonic technology to assist supercritical extraction processes was demonstrated in almond oil extraction where improvements of about 30% in the kinetic of the process were reached. Introduction Ultrasonic energy is a tool with a wider application potential in chemical, pharmaceutical and food industries. Supercritical fluid extraction (SFE) processes assisted by power ultrasound represent a clear example of this potential. The term supercritical fluid (SCF) can be applied to any fluid that is compressed to a pressure greater than its critical pressure, PC, and heated to a temperature above its critical temperature, TC [1]. At temperatures T>TC the substance cannot be liquefied by increase the pressure. Fluids under supercritical conditions exhibit enhanced dissolving power and have transport properties that favor high extraction capabilities. In particular, supercritical fluids have a relative lower viscosity and higher diffusivity than liquid solvents. Therefore, they can penetrate into porous solid materials more effectively than liquid solvents [2]. One emergent application of power ultrasound in chemical and food industries is the enhancement of mass transfer in different processes. In this way some authors [3,4,5] recently started with the study and development of the application of ultrasonic energy in supercritical fluid extraction processes. Due to the environmental regulations, supercritical CO2 has grown as an alternative “green” solvent to conventional solvent methods in many analytical and industrial processes. This is because it presents important advantages (cheap, recyclable, non-toxic, non-flammable, improves product quality and recovery). A difficulty when applying a supercritical fluid as solvent for extraction is the slow kinetics of the process. The traditional way to accelerate extraction processes is the application of a mechanical agitation system. The use of power ultrasound represents a potential efficient way to produce deep agitation, enhancing mass transfer processes. Additionally ultrasonic waves can be used for determination of the critical state of the fluid by using resonance methods and through transmission techniques [6,7,8,9,10,11]. The aim of this work was to study the generation and effects of ultrasound on particulate almond oil extraction kinetics by using supercritical CO2. Experimental set-up and method The basic scheme of supercritical extraction facility assisted by power ultrasound is shown in Figure 1. It consists of one high-pressure vessel with 5L of capacity, two separation units (a cyclone and a decanter), a diaphragm pump and different sensors for temperature, pressure and flow rate measurements. The fluid employed in the extractor was supercritical CO2 (PC=7.38MPa; TC=31,1oC; ρC=0,468g/mL) [12,13]. This fluid is the most commonly used for SFE applications due to their properties as well as its availability in high purity at low cost. The ultrasonic system includes : a) two different power piezoelectric sandwich transducers working at 18kHz and 20kHz, respectively, with a power capacity of 100W; b) an impedance matching box and a power generator unit composed by a power amplifier and a resonant frequency control system to keep constant the power applied to the transducer. This control system allows the parameters of the driving signal to be stored during the trials (resonant frequency, impedance, voltage, current phase and power). The pressure and the density of the supercritical CO2 inside the reactor were also measured and stored into a computer. Therefore, the behavior of the ultrasonic transducer was followed during all the process. That means, from the initial instant in which the gas CO2 was introduced into the extractor unit (at 1bar and 20oC), during the time needed to reach the operational conditions (at 280bar and 55oC), as well as during the extraction WCU 2003, Paris, september 7-10, 2003

GENERATION AND EFFECTS OF HIGH-INTENSITY ULTRASOUND IN SUPERCRITICAL FLUIDS

Finite element three-dimensional analysis of the vibrational behaviour of the Langevin-type transducer.

PRECISE MEASUREMENTS OF PARTICLE ENTRAINMENT IN A STANDING-WAVE ACOUSTIC FIELD BETWEEN 20 AND 3500 Hz

Acoustic agglomeration for electrostatic retention of fly-ashes at pilot scale: influence of intensity of sound field at different conditions

Acoustic preconditioning of coal combustion fumes for enhancement of electrostatic precipitator performance: I. The acoustic preconditioning system

Acoustic preconditioning of coal combustion fumes for enhancement of electrostatic precipitator performance: II. Performance evaluation

JOURNAL DE PHYSIQUE IV 
Colloque C1, supplement au Journal de Physique III, Volume 2, avril 1992 Deuxieme Congres Francais d'Acoustique / Second French Conference on Acoustics 
4 paginas, 2 figuras

THEORETICAL PROCEDURE TO OBTAIN THE MECHANICAL BEHAVIOUR OF POROUS MATERIALS BY THE BIOT'S THEORY AND THE CONTINUITY EQUATIONS

NEW ADVANCES IN THE GENERATION OF DIRECTIONAL SONIC AND ULTRASONIC RADIATION

EXPERIMENTAL MODEL OF PILOT PLANT FOR ULTRASONIC DEPURATION OF CARBON BLACK SMOKE.

El desarrollo global que actualmente enfrenta nuestra realidad es motivo de una urgente preocupacion para proyectar una configuracion urbano-arquitectonica distinta a la actual y sobre todo desde una mirada latinoamericana. Por lo tanto, se presenta un tema que consideramos debe ser prioritario dentro de las estrategias de planificacion urbana y que sin embargo siempre esta ausente o en ultimo lugar: el espacio publico recreativo, asi como su concepto y su estrategia de construccion a partir del diseno. Estamos convencidos de que este espacio es parte esencial de una sintesis geometrica y antropologica que amalgama a las comunidades locales con un sentido de lucha y resistencia hacia la preservacion de sus riquezas culturales.

El espacio público de la recreación: expresión de identidad y cultura local

La comunidad de Malinaltenango se ubica en el municipio de Ixtapan de la Sal, al suroeste del Estado de Mexico, Mexico. La poblacion tiene menos de 1000 habitantes registrados (882 segun Censo de Poblacion y Vivienda 20101 del Instituto Nacional de Estadistica, Geografia e Informatica [INEGI]), muchos de ellos han emigrado para encontrar una mejor economia familiar. Por la migracion y el poco desarrollo economico del lugar, se tienen muchas casas en abandono y deterioro, parcial o total. El asentamiento cuenta con 344 viviendas (segun datos del INEGI), con la mayor concentracion en el centro, incluidas las construidas con adobe. A raiz de la migracion, se han presentado factores que afectan la conservacion de las construcciones, por un lado, el abandono permite el crecimiento de maleza por el nulo mantenimiento, esto es visible en muchas de las casas, con casos en los que se han caido partes de ellas, y otros en los que solo queda el arranque de los muros. Por el otro lado, la creencia popular concerniente a la debilidad del adobe respecto al concreto, ha hecho que muchas se hayan derrumbado intencionalmente con el fin de construir una nueva a base de ladrillo o bloque de hormigon y concreto. Incluso hay casos en los que se construye con estos nuevos materiales mezclados con la construccion de adobe. Mediante entrevistas se recabo informacion referente a la los datos historicos y fisicos de los inmuebles con el fin de realizar mapas de distribucion espacial. Esta investigacion tiene por objetivo acercarse a la poblacion con el fin de conocer las razones por las que se esta perdiendo el patrimonio de adobe, pues algunas de las viviendas son centenarias y es importante proponer a los propietarios una manera eficiente y de bajo costo para conservarlas.

Abandono y deterioro en las casas de adobe en Malinaltenango, Estado de México, México

Las transformaciones isometricas juegan un papel importante en el aprendizaje de la geometria y en el desarrollo de habilidades como la percepcion espacial, la visualizacion y el dibujo. En el nivel basico en lo que respecta a la simetria axial se espera que los estudiantes la manejen como si fuese un espejo, tambien se hace uso del doblado de papel para sugerir la reflexion. Algunos resultados como la falta de conservacion de invariantes, asi como, el conflicto que representa el eje de reflexion oblicuo, han sido anteriormente observados por otros autores. En este trabajo nos dirigimos hacia la deteccion de los referentes espaciales que son utilizados por los estudiantes de cuarto grado de primaria para orientar el objeto geometrico, deseamos determinar si existen patrones de comportamiento en esta tarea. Esta informacion nos permitiria mirar el proceso desde el punto de vista de la organizacion espacial que hace el estudiante, ademas de permitirnos incidir en la toma de decisiones del estudiante respecto a los referentes usados.

El aprendizaje de la reflexión en geometría entre estudiantes de primaria

LA INFLUENCIA DE LAS NORMAS DE INFORMACION FINANCIERA EN AREA FISCAL Y EL PRINCIPIO DE PLENA COMPETENCIA (ARMS LENGTH PRINCIPLE)

Antiglomerular basement membrane disease presenting during pregnancy is very uncommon. We present a case of a pregnant female who presented with acute renal failure needing dialysis from Goodpasture's disease. She responded very well to just plasma exchange, high dose steroids, and hemodialysis. Cyclophosphamide was never started on this patient. She had a spontaneous abortion in her 8th week of pregnancy and henceforth did very well to regain her renal function. Patient became hemodialysis independent at 2 months and returned to her baseline kidney function at 6 months. We present this remarkable case of recovery from acute renal failure in a patient with anti-GBM disease. We think the flare-up of renal failure was pregnancy related which resolved after spontaneous abortion.

Anti-GBM of Pregnancy: Acute Renal Failure Resolved after Spontaneous Abortion, Plasma Exchange, Hemodialysis, and Steroids

Purple urine bag syndrome (PUBS) is a unique disease entity characterized by an alarming purple discoloration of the urine secondary to recurrent urinary tract infections with indigo- and indirubin-producing bacteria. It is usually associated with prolonged urinary catheterization and chronic debilitated states. We hereby present a concise review of this rare phenomenon with historic perspectives, epidemiology, emphasizing on current concepts of etiology, pathogenesis, relevant clinical associations, treatment modalities, prognosis, and future directions in PUBS. In addition, we highlight an interesting occurrence of this intriguing phenomenon in a 39-year-old gentleman at our institution.

Purple Urine Bag Syndrome: An Alarming Hue? A Brief Review of the Literature

Use of charcoal hemoperfusion with sequential hemodialysis to reduce serum methotrexate levels in a patient with acute renal insufficiency.

The predictive processing theory of cognition and neural encoding dictates that hierarchical regions in the neocortex learn and encode predictive hypotheses of current and future stimuli. To better handle uncertainty these regions must also learn, infer, and encode the precision of stimuli. In this treatment we investigate the potential of handling uncertainty within a single learned predictive model. We exploit the rich predictive models formed by the learning of temporal sequences within a Hierarchical Temporal Memory (HTM) framework, a cortically inspired connectionist system of self-organizing predictive cells. We weight a cell’s feedforward response by the degree of its own temporal expectations of a response. We test this model on data that has been saturated with temporal or spatial noise, and show significant improvements over traditional HTM systems. In addition we perform an experiment based on the Posner cuing task and show that the system displays phenomena consistent with attention and biased competition. We conclude that the observed effects are similar to those of precision encoding.

Precision without Precisions: Handling uncertainty with a single predictive model

To understand how the brain represents incoming sensory stimuli, one must study the interplay between signal and noise. The signal might be thought of as the variation in neuronal responses due to different sensory stimuli, whereas the noise might be thought of as the trial-to-trial variation in responses to repetitions of the same stimulus. The trial-to-trial variability of neural activity can limit the fidelity of information encoded about a sensory stimulus, but only if that variability lies along the same axes by which a downstream area reads out the sensory stimulus (i.e., stimulus-encoding dimensions). One might expect that most of the trial-to-trial shared variability (i.e., variability shared across neurons) resides in dimensions orthogonal to the stimulus-encoding dimensions, simply because two low-dimensional subspaces comprising randomly-chosen dimensions are likely to be close to orthogonal in a high-dimensional space. This would allow for a high-fidelity readout by a downstream area. However, this interplay between signal and noise has not been empirically tested. In this proposed work, we use dimensionality reduction techniques to identify stimulus-encoding dimensions within a high-dimensional population activity space, and to identify dimensions that capture the shared variability (i.e., shared-noise dimensions). For a population of recorded neurons in visual cortical area V4, we find that the stimulus-encoding and shared-noise dimensions are remarkably similar, which presents substantial problems for stimulus readout by downstream areas. We also find that the shared-noise dimensions largely comprise shared activity that slowly drifts across an experimental session, on the order of minutes. In order to understand how a downstream area deals with this “slow drift,” we simultaneously recorded populations of neurons from V4 and pre-frontal cortex (PFC), a downstream area known to receive input from V4. We find that V4 and PFC neurons have access to the same slow drift, effectively cancelling the slow drift’s interference with the stimulus-encoding dimensions to preserve sensory stimulus information. Overall, these results provide an avenue for understanding how the brain deals with noise in a rapidly fluctuating sensory environment.

The influence of trial-to-trial variability on downstream readout in the brain

It has become increasingly popular to view the brain as a prediction machine. This view has informed a number of theories of brain function, the most prominent being predictive processing, where generative hypotheses are iteratively updated by error signals. In this treatment we take a lower level approach by examining the hierarchical temporal memory framework, which views individual pyramidal cells as the primary predictive unit of a self-organizing networked sequence learning system. Within this computational framework, the cell behaviour is constrained by a number of parameters which are static and shared across all cells. To further increase the adaptability of the cells, we shift away from this paradigm by introducing the concept of dynamic thresholds. This allows for the activation threshold (the amount of activity on a distal dendrite needed to form a prediction) to be adjusted continuously and individually for each cell. As a metric we use the prior, or unconditional, probability of activity on t...

Biometrics has come a long way over the past decade in terms of technologies and devices that are used to verify user identities. Three of the more well studied modalities in this field are the face, iris and fingerprint, with the latter two reporting very high user identification/verification rates. In the biometric community there has been little work in studying biomedical signals for user recognition purposes. In this paper, we propose using electromyograph (EMG) signals as a person's biometric signature. The EMG records the motor unit action potentials (MUAP) during any physical motion. Our study is done within the context of a person using a keyboard to type a password or any other fixed phrase. Along with EMG signals, we log key press times for the user and study the feasibility of using this data too as a biometric feature. Keypress timings alone if used as a biometric, are very easy to spoof and hence we fuse this modality with EMG signals. In order to classify these features, we use subspace modeling as well as Bayesian classifiers. The experiments have been performed within the context of a user typing a fixed pass phrase at a workstation. The idea is to monitor both biometric modalities when this action is performed and study user verification across data capture sessions and within capture sessions. Our approach yields high values of verification rates, which shows the promise of using these modalities as user specific biometric signatures.

2015 IEEE Conference on Computer Vision and Pattern Recognition Workshops (CVPRW)

Electromyograph and keystroke dynamics for spoof-resistant biometric authentication

Cortically-Inspired Overcomplete Feature Learning for Colour Images

The rate of disease progression in autosomal-dominant (AD) polycystic kidney disease (PKD) exhibits high intra-familial variability suggesting that environmental factors may play a role. We hypothesized that a prevalent form of renal insult may accelerate cystic progression and investigated tubular crystal deposition. We report that calcium oxalate (CaOx) crystal deposition led to rapid tubule dilation, activation of PKD-associated signaling pathways, and hypertrophy in tubule segments along the affected nephrons. Blocking mTOR signaling blunted this response and inhibited efficient excretion of lodged crystals. This mechanism of "flushing out" crystals by purposefully dilating renal tubules has not previously been recognized. Challenging PKD rat models with CaOx crystal deposition, or inducing calcium phosphate deposition by increasing dietary phosphorous intake, led to increased cystogenesis and disease progression. In a cohort of ADPKD patients, lower levels of urinary excretion of citrate, an endogenous inhibitor of calcium crystal formation, correlated with increased disease severity. These results suggest that PKD progression may be accelerated by commonly occurring renal crystal deposition which could be therapeutically controlled by relatively simple measures.

Crystal deposition triggers tubule dilation that accelerates cystogenesis in polycystic kidney disease.

TO035CALCIUM OXALATE CRYSTALS PROMOTE CYTOGENESIS AND AGGRAVATE POLYCYSTIC KIDNEY DISEASE

Renal cysts, which arise from renal tubules, can be seen in a variety of hereditary and nonhereditary entities. Common mechanisms associated with renal cyst formation include increased cell proliferation, epithelial fluid secretion, and extracellular matrix remodeling. Hereditary polycystic kidney disease (PKD) is seen as a component of numerous diseases. Autosomal dominant (AD) PKD is the most common potentially fatal hereditary disease in humans, causes renal failure in approximately 50% of affected individuals, and accounts for approximately 5% of end stage renal disease cases in the United States. ADPKD is caused by mutation in one of two genes-85% of cases are caused by mutation in PKD1 on chromosome 16 and 15% of cases are caused by mutation in PKD2 on chromosome 4. Polycystin-1, encoded by PKD1, is a large protein, has multiple transmembrane spanning domains, has extracellular regions suggesting a role in cell-cell or cell-matrix interactions, has intracellular domains suggesting a role in signal transduction, and can physically interact with Polycystin-2. Polycystin-2 is smaller, has transmembrane domains, can act as a cation channel with calcium permeability, and may be regulated by Polycystin-1. These proteins, and many others associated with cystic kidney disease, localize to primary cilia, which may act as flow sensors in the kidney; cystic kidney diseases have also been termed ciliopathies. An increasing number of intracellular mechanisms, which are abnormally regulated in PKD, have been described and are potential targets for therapy, which is lacking in this common hereditary disease. © 2017 American Physiological Society. Compr Physiol 7:945-975, 2017.

Evaluation of [¹⁸F]PFH PET renography to predict future disease progression in a rat model of autosomal dominant polycystic kidney disease.

tubule cells and suppressed in cyst epithelia Kid-1 expression is high in differentiated renal proximal

Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine

Synthesis and in vivo evaluation of ortho-[(124)I]iodohippurate for PET renography in healthy rats.

Evaluation of para-18F-fluorohippurate PET renography to predict future disease progression in a rat model of ADPKD

The objective of this study was to evaluate four new (68) Ga-labeled 1,4,7,10-cyclododeca-1,4,7,10-tetraacetic acid (DOTA)/1,4,7-triazacyclononane-1,4,7-triacetic acid derived (NODAGA)-glycine/hippurate conjugates and select a lead candidate for potential application in positron emission tomography (PET) renography. The non-metallated conjugates were synthesized by a solid phase peptide synthesis method. The (68) Ga labeling was achieved by reacting an excess of the non-metallated conjugate with (68) GaCl4 (-) at pH -4.5 and 10-min incubation either at room temperature for NODAGA or 90 °C for DOTA. Radiochemical purity of all (68) Ga conjugates was found to be >98%. (68) Ga-NODAGA-glycine displayed the lowest serum protein binding (0.4%) in vitro among the four (68) Ga conjugates. Biodistribution of (68) Ga conjugates in healthy Sprague Dawley rats at 1-h post-injection revealed an efficient clearance from circulation primarily through the renal-urinary pathway with <0.2% of injected dose per gram remaining in the blood. The kidney/blood and kidney/muscle ratios of (68) Ga-NODAGA-glycine were significantly higher than other (68) Ga conjugates. On the basis of these results, (68) Ga-NODAGA-glycine was selected as the lead candidate. (68) Ga-NODAGA-glycine PET renograms obtained in healthy rats suggest (68) Ga-NODAGA-glycine as a PET alternate of (99m) Tc-Diethylenetriaminepentaacetic acid (DTPA).

Synthesis and in vivo evaluation of gallium-68-labeled glycine and hippurate conjugates for positron emission tomography renography.

Antiglomerular basement membrane (GBM) disease presenting during pregnancy is uncommon. We present a case of a pregnant female who presented with acute renal failure requiring dialysis due to anti-GBM disease. She responded well to plasma exchange, high-dose steroids, and hemodialysis. Cyclophosphamide was discussed but not given at the patient’s request due to concerns for the well-being of the fetus. Unfortunately, she suffered a spontaneous abortion in her eighth week of pregnancy. Subsequently, she had progressive improvement in her renal function and became hemodialysis independent at 2 weeks after diagnosis. Her renal function returned to baseline 3 months after diagnosis. We present this case in detail and review the literature regarding anti-GBM disease in pregnancy.

Aminopeptidase N (APN; CD13; EC 3.4.11.2) is a zinc-dependent membrane-bound exopeptidase that catalyzes the removal of N-terminal amino acids from peptides. APN is known to be highly expressed on renal cortical proximal tubules. APN expression levels are markedly decreased under the influence of nephrotoxins and in the tumor regions of renal cancers. Thus, molecular imaging of kidney APN expression could provide pathophysiological information about kidneys noninvasively. Probestin is a potent APN inhibitor and binds to APN. Abdominal SPECT imaging was conducted at 1 h postinjection of 99mTc-probestin in a group of 12 UPII-SV40T transgenic and wild-type mice. UPII-SV40T mice spontaneously develop urothelial carcinoma in situ and invasive transitional cell carcinoma (TCC) that invade kidneys. Histopathology and immunohistochemistry analysis were used to confirm the presence of tumor and to evaluate APN expression in kidney. Radioactivity in normal tissue regions of renal cortex was clearly visible in SPECT images, whereas tumor regions of renal cortex displayed significantly lower or no radioactivity uptake. Histopathological analysis of kidney sections showed normal morphology for both renal pelvic and cortical regions in wild-type mice and abnormal morphology in some transgenic mice. Proliferating cell nuclear antigen staining confirmed the presence of tumor in those abnormal regions. Immunohistochemical analysis of kidney sections using anti-CD13 antibody showed significantly lower APN expression in tumor regions compared to normal regions. Results obtained in this study demonstrate the potential use of 99mTc-probestin SPECT as a novel technique for noninvasive imaging of kidney APN expression.

Evaluation of 99mTc-Probestin SPECT As a Novel Technique for Noninvasive Imaging of Kidney Aminopeptidase N Expression

Recent Advances in Understanding the Pathogenesis of Polycystic Kidney Disease

Our patient, a 30-year-old man with end-stage renal disease attributed to congenital dysplastic kidneys who had been on hemodialysis for 3.5 years, was admitted to the hospital with severe hypertension, hyperkalemia, and an infected arm arterio-venous graft after missing his regular dialysis treatment. Previously, he had been hospitalized on multiple occasions for hypertension, peptic ulcer disease, seizures, peripheral neuropathy, venous thrombosis, and failure to maintain his dialysis schedule. His blood pressure was 211/139 and his arterio-venous graft was erythematous and indurated. Serum potassium was 7.4 meq/L, hemoglobin was 9.9 gm/dL, platelet count was 217,000/µL, and white blood cell count was 9,400/µL with a normal differential. He improved with dialysis and was initially treated with piperacillin/tazobactam, gentamicin, and vancomycin for the graft infection. Blood cultures were negative. He left the hospital against medical advice on the 3rd day but returned on the 6th day, when antibiotic treatment was resumed with piperacillin/tazobactam, vancomycin, and ciprofloxacin. On Day 11, his platelet count decreased to 70,000/µL from 201,000/µL the previous day (Fig. 1). His vital signs were normal and his clinical status was stable. Hemoglobin was 8.4 gm/dL and white blood cell count was 8,000/µL, similar to previous measurements. The peripheral blood smear confirmed the decreased platelet count; red cell and white cell morphology were normal; serum lactate dehydrogenase (LDH) was 112 U/L; coagulation studies were normal. 
 
Figure 1 
 
Platelet counts and piperacillin administration in the patient presented in this report. The bars at the top represent administration of piperacillin on Days 1–3, 6–10, and 19–21. 
 
Acute, unexpected thrombocytopenia in a patient hospitalized for multiple medical problems has multiple potential etiologies. In a patient being treated for infection and at risk for additional infectious complications, sepsis must be the initial consideration because of the risk for sudden, critical deterioration. In a patient on multiple medications, drug-induced thrombocytopenia (DITP) is the other principal consideration. The patient had isolated thrombocytopenia, without evidence for microangiopathic hemolysis, consistent with both of these etiologies. The absence of evidence for microangiopathic hemolysis (no schistocytes [fragmented red blood cells] were seen on examination of the peripheral blood smear, serum LDH was normal) excluded consideration of thrombotic thrombocytopenic purpura. 
 
His medications on Day 11 were piperacillin/tazobactam, phenytoin, gabapentin, pantoprazole, sertraline, aliskerin, amlodipine, isosorbide mononitrate, labetalol, clonidine, hydralazine, lisinopril, kayexalate, vitamin B12 complex, calcium acetate, erythropoietin, morphine, hydromorphone, quetiapine, diphenhydramine, ondansetron, promethazine, bacitracin ointment, and heparin (given as prophylaxis, 5,000 U every 8 h and also for dialysis). Heparin-dependent platelet-reactive antibody ELISA assay was negative. Also on Day 11, blood cultures were reported as positive for vancomycin-resistant Enterococcus faecium; piperacillin/tazobactam was stopped and quinupristin/dalfopristin was started; 3 days later, quinupristin/dalfopristin was changed to daptomycin. On Day 13, the platelet count began to recover after reaching a nadir of 33,000/µL, becoming normal on Day 16 (Fig. 1). All medications other than piperacillin/tazobactam had been continued. 
 
The list of medications was extensive, but this is similar to many patients hospitalized for multiple medical problems. Although heparin may be the most common cause of DITP, and although half of patients with heparin-induced thrombocytopenia may not have thrombotic complications recognized at the time of diagnosis, heparin does not typically cause sudden and severe thrombocytopenia [1]. The negative test for heparin-dependent antibodies was evidence against heparin as the cause of the thrombocytopenia. The recovery of his platelet count while continuing heparin confirmed that heparin was not the etiology of the thrombocytopenia. Among the other medications, there have been reports of thrombocytopenia, with varying levels of evidence, caused by piperacillin, phenytoin, pantoprazole, amlodipine, hydralazine, morphine, quetiapine, and ondansetron (www.ouhsc.edu/platelets). However, all medications except piperacillin/taxobactam were continued while the platelet count recovered to normal, excluding them from consideration of the etiology of the thrombocytopenia. At this time, Enterococcus faecium bacteremia was considered to be the etiology of the thrombocytopenia. 
 
On Day 20, blood cultures were reported as positive for Klebsiella oxytoca and piperacillin/tazobactam was restarted. The platelet count decreased from 377,000/µL on Day 20 to 91,000/µL on Day 21 and to 18,000/µL on Day 22 at which time the patient developed hematemesis, hematochezia, and hemoptysis for which he received two units of red cells and one unit of single donor platelets. On Day 22, piperacillin/tazobactam was stopped when it was recognized that both episodes of thrombocytopenia had occurred while piperacillin/tazobactam was being administered and that all other medications had been continued during the intervening platelet count recovery. The patient’s platelet count recovered to normal 3 days after piperacillin/tazobactam was stopped (Fig. 1). 
 
Although recurrent bacteremia remained a potential etiology of thrombocytopenia, the onset of thrombocytopenia within 1 day of resuming piperacillin/tazobactam and the recovery of the platelet count to normal within 3 days after piperacillin/tazobactam was stopped provided strong evidence that it was the cause of the thrombocytopenia. Using previously established clinical criteria [2], there appeared to be definite evidence for piperacillin/tazobactam as the etiology of the thrombocytopenia (Table I). However, some doubt persisted because of the recurrent bacteremia with multiple organisms; bacterial sepsis remained a possible though unlikely etiology of the thrombocytopenia. 
 
TABLE I 
 
Clinical Criteria and Levels of Evidence for Evaluation of Patients with Suspected Drug-Induced Thrombocytopenia 
 
Hospital records documented that our patient had received five courses of piperacillin/tazobactam of 3–10 days each between July 2006 and September 2008 with no occurrence of thrombocytopenia documented by daily platelet counts. 
 
DITP typically occurs within 1–2 weeks after beginning daily treatment with a new drug, or after intermittent use for a longer time. The absence of thrombocytopenia during five previous treatment courses with piperacillin/tazobactam added uncertainty to the etiology of the thrombocytopenia. Also, if piperacillin/tazobactam was the etiology, it was important to determine which antibiotic of this combination was responsible. Review of the database for published reports of drug-induced thrombocytopenia (www.ouhsc.edu/platelets) documented that there have been two previous reports of thrombocytopenia caused by piperacillin. One report described thrombocytopenia related to piperacillin/tazobactam; this report documented drug-dependent, platelet-reactive antibodies with piperacillin but not with tazobactam [3]. An additional report described piperacillin-induced thrombocytopenia, providing definite evidence defined by recurrent thrombocytopenia with repeated piperacillin administration [4]. 
 
Piperacillin as the etiology of the thrombocytopenia in our patient was confirmed by documentation of piperacillin-dependent platelet-reactive antibodies and by the absence of tazobactam-dependent platelet-reactive antibodies (Fig. 2) [5]. Our patient’s platelet count has been normal for the following 6 months. 
 
Figure 2 
 
Demonstration of a piperacillin-dependent, platelet-reactive antibody in the patient presented in this report (left) and absence of a detectable tazobactam-dependent, platelet-reactive antibody (right). Results shown are representative of three independent ...

Recurrent acute thrombocytopenia in the hospitalized patient: Sepsis, DIC, HIT, or antibiotic‐induced thrombocytopenia

Calcium, cyclic AMP, and MAP kinases: dysregulation in polycystic kidney disease.

Persistent progress has been made in the understanding of processes that are responsible for renal cyst formation and progression in hereditary polycystic kidney disease (PKD). Multiple lines of evidence support a role for epithelial cell proliferation, transepithelial fluid secretion, and extracellular matrix remodeling in PKD (1). More recent studies have begun to illuminate intracellular mechanisms that are responsible for abnormal cell proliferation and fluid secretion in PKD.

For many years, investigators have attempted to alter disease progression in animal models of PKD, originally with the intention of testing hypotheses regarding disease pathogenesis. Advances in the understanding of disease mechanisms in PKD have allowed refinement in attempts to alter disease progression, with the idea of testing in human clinical trials interventions that are effective in multiple different animal models. These early steps in developing effective, specific treatments for PKD represent a maturation of the scientific understanding of PKD. At the 2007 Annual Meeting of the American Society of Nephrology, a new feature, “Meeting within a Meeting,” focused on PKD and included a session entitled “New Insights, Treatments, and Management Strategies for ADPKD.” The articles in this Moving Points in Nephrology series summarize the information presented at that session.

Human autosomal dominant PKD (ADPKD) causes complications in multiple organs, including the kidneys. Because the most common, serious complication is ESRD, interest focuses on altering this aspect of ADPKD. With a complication that occurs in only 50% of patients, especially one that progresses slowly, it is difficult to demonstrate …

Introduction: new insights, treatments, and management strategies for ADPKD.

End-stage renal disease due to polyomavirus in a cardiac transplant patient

Hereditary polycystic kidney disease (PKD) is a common cause of renal failure. Increasing knowledge is available regarding mechanisms of cyst development and progression, and renal functional deterioration in PKD. On the basis of this information and theories regarding the pathophysiology of these processes, studies to alter progression and potentially treat PKD have been reported. Cyst development and progression requires epithelial cell proliferation, transepithelial fluid secretion and extracellular matrix remodelling. Several interventions designed to inhibit cell proliferation or alter fluid secretion modify the progression of PKD in selected animal models. Renal functional deterioration appears to involve interstitial inflammation and fibrosis, and tubular apoptosis. Glucocorticoids with anti-inflammatory and antifibrotic properties slow the progression of cystic disease and renal functional deterioration in animal models of PKD. Other interventions, such as dietary modification and angiotensin antagonism, shown to be of benefit in non-PKD models of slowly progressive renal disease, are also of benefit in animal models of PKD. Caution should be used in extrapolating interventional studies in one animal model to another model and certainly to human disease, since examples exist in which treatments in one model of PKD have different effects in another model. Nonetheless, early attempts to determine whether potential treatments are tolerated and of potential benefit in patients with PKD are beginning to appear. Ultimately, treatment of PKD may involve efforts to identify patients at greatest risk for disease progression, thus allowing targeted therapy, use of surrogate markers for disease progression to assist assessment of therapeutic efficacy, and combination therapy to retard disease progression and renal functional deterioration in this common hereditary cause of chronic renal failure.

Recent advances in understanding the pathogenesis of polycystic kidney disease: therapeutic implications.

The proliferation of mural epithelial cells is a major cause of progressive cyst enlargement in autosomal-dominant polycystic kidney disease (ADPKD). Adenosine 3', 5' cyclic monophosphate (cAMP) stimulates the proliferation of cells from ADPKD cysts, but not cells from normal human kidney cortex (HKC), through the activation of protein kinase A (PKA), mitogen-activated protein kinase kinase (MEK), and extracellular signal-regulated kinase (ERK/MAPK). In the current study, we examined the signaling pathway between PKA and MEK in ADPKD and HKC cells.

METHODS
Primary cultures of human ADPKD and HKC cells were prepared from nephrectomy specimens. We determined the effects of cAMP and epidermal growth factor (EGF) on the activation of ERK, B-Raf and Raf-1 in ADPKD and HKC cells by immune kinase assay and Western blot.

RESULTS
8-Br-cAMP increased phosphorylated ERK (2.7- +/- 0.6-fold, N = 7), and B-Raf kinase activity (3.6- +/- 1.1-fold, N = 5) in cells from ADPKD kidneys; levels of phosphorylated Raf-1 were not changed. Inhibition of PKA by H89 strikingly decreased cAMP-stimulated phosphorylation of ERK and B-Raf, and MAPK inhibition by PD98059 blocked the effect of the nucleotide to activate ERK. By contrast, in HKC cells 8-Br-cAMP did not activate B-Raf and ERK. EGF stimulated the phosphorylation of ERK and Raf-1 in both ADPKD and HKC cells, but had no effect on B-Raf. 8-Br-cAMP and EGF conjointly increased ERK activation above that of either agonist alone in ADPKD cells, and this combined effect was abolished by PD98059, indicating that ERK was activated by EGF- and cAMP-responsive cascades that converge at MAPK.

cAMP activates ERK and increases proliferation of ADPKD epithelial cells, but not cells from normal human kidney cortex, through the sequential phosphorylation of PKA, B-Raf and MAPK in a pathway separate from, but complementary to, the classical receptor tyrosine kinase cascade. Consequently, cAMP and EGF have great potential to accelerate the progressive enlargement of renal cysts.

Cyclic AMP activates B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys.

Abnormal proliferation of renal tubule epithelial cells is a central factor in the biogenesis and sustained expansion of cysts in autosomal-dominant polycystic kidney disease (ADPKD). Recent evidence from in vitro studies of human cyst wall epithelial cells has implicated a role for the mitogen-activated protein (MAP) kinase pathway in this aberrant proliferation. To determine the extent to which this signaling pathway is involved in cyst pathogenesis in vivo, we measured the expression of select components of the MAP kinase cascade in Han:SPRD rats with ADPKD at an early stage of the disease.

METHODS
Kidneys of 8-week-old normal Han:SPRD rats (+/+) or rats heterozygous (Cy/+) for ADPKD were examined by Western blot analysis and immunohistochemistry to determine the expression of extracellular-regulated kinase (ERK), phosphorylated ERK (P-ERK), Raf-1 (MAPKKK), phosphorylated Raf-1 (P-Raf-1), B-Raf, Rap-1 and phosphorylated protein kinase A (P-PKA).

RESULTS
P-ERK was expressed to a greater extent in Cy/+ kidneys (3.74 +/- 1.07 fold) than in normal kidneys, whereas ERK abundance was not different. P-Raf-1 levels were higher in Cy/+ than in +/+ kidneys (1.53 +/- 0.08 fold) consistent with upstream stimulation of receptor tyrosine kinase. B-Raf and Raf-1 abundances were greater in Cy/+ than in +/+ (1.74 +/- 0.25 and 1.27 +/- 0.08 fold, respectively). In Cy/+, immunohistochemistry showed increased P-ERK and B-Raf expression in the abnormal mural epithelial cells within cysts. These findings, together with the detection of P-PKA and the small G protein, Rap-1, in cyst epithelial cells, implicate a potential role for cyclic adenosine monophosphate (AMP) in the activation of ERK in ADPKD cells.

We conclude that the MAP kinase pathway is activated to the level of ERK in the abnormal mural epithelial cells lining cysts in animals with a dominantly inherited type of polycystic kidney disease. We suggest that cAMP, acting through PKA, Rap-1 and B-Raf, may contribute to the activation of ERK in a way that complements receptor tyrosine kinase-mediated agonists in the promotion of cyst enlargement.

Renal activation of extracellular signal-regulated kinase in rats with autosomal-dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) progresses to renal insufficiency in >50% of patients and is characterized by interstitial inflammation and fibrosis in the end stage. In a rat model of ADPKD, monocytes accumulate within the renal interstitium in association with increased levels of monocyte chemoattractant protein-1 (MCP-1) in cyst mural cells and increased excretion of this chemokine into the urine. For determining the extent to which this chemokine is abnormally expressed in patients with ADPKD, a cross-section study was performed of MCP-1 in urine, serum, and cyst fluid and MCP-1 production by mural epithelial cells cultured from the cysts of human patients with ADPKD. Upper boundaries for urinary MCP-1 excretion (>263 pg/mg creatinine) and serum creatinine concentration (>1.5 mg/dl) determined in 19 normal individuals were used to sort 55 ADPKD patients into three groups. In group 1 (n = 13), urine MCP-1 excretion (136 +/- 14 pg/mg creatinine) was not different from normal volunteers (152 +/- 16 pg/mg); serum creatinine levels and urine total protein excretion were normal as well. In group 2 (n = 27), urine MCP-1 excretion was increased (525 +/- 39 pg/mg creatinine), but serum creatinine levels and urine protein excretion were not different from normal. In group 3 (n = 15), urine MCP-1 excretion increased further (1221 +/- 171 pg/mg), serum creatinine levels increased to 4.3 +/- 0.8 mg/dl, and urine protein excretion rose to 0.64 +/- 0.28 mg/mg creatinine. Serum MCP-1 levels of ADPKD patients (84 +/- 9.9 pg/ml; n = 15) did not differ from normal. Levels of MCP-1 much higher than in serum or urine were found in cyst fluids obtained from nephrectomy specimens (range, 767 to 40,860 pg/ml; mean, 6434 +/- 841 pg/ml; n = 73). Polarized, confluent cultures of ADPKD cyst epithelial cells secreted MCP-1 into the apical fluid to levels eightfold greater than in the basolateral medium. Similar results were obtained with tubule epithelial cells cultured from normal human renal cortex. On the basis of these results, it is concluded that urinary excretion of MCP-1 is increased in the majority of adult patients with ADPKD and that the source of some of this chemokine may be the mural epithelium of cysts. Furthermore, it seemed that urinary MCP-1 excretion may have increased in these ADPKD patients before appreciable increases in serum creatinine concentration or urine protein excretion were detected. It is reasonable to include urine MCP-1 excretion among candidate surrogate markers in controlled, longitudinal studies of ADPKD.

Urinary excretion of monocyte chemoattractant protein-1 in autosomal dominant polycystic kidney disease.

Erratum: Increased renal expression of monocyte chemoattractant protein-1 and osteopontin in ADPKD in rats (Kidney International (2001) 60 (2087-2096))

Human autosomal-dominant polycystic kidney disease (ADPKD) is variable in the rate of deterioration of renal function, with end-stage renal disease (ESRD) occurring in only approximately 50% of affected individuals. Evidence suggests that interstitial inflammation may be important in the development of ESRD in ADPKD. Han:SPRD rats manifest ADPKD that resembles the human disease. Homozygous cystic (Cy/Cy) rats develop rapidly progressive PKD and die near age 3 weeks. Heterozygous (Cy/+) females develop slowly progressive PKD without evidence of renal dysfunction until the second year of life, whereas heterozygous (Cy/+) males develop more aggressive PKD with renal failure beginning by 8 to 12 weeks of age.

METHODS
To examine the relationship between proinflammatory chemoattractants and the development of interstitial inflammation and ultimately renal failure in ADPKD, we evaluated monocyte chemoattractant protein-1 (MCP-1) and osteopontin mRNAs and proteins in kidneys from Han:SRPD rats.

RESULTS
MCP-1 and osteopontin mRNAs, expressed at low levels in kidneys from normal (+/+) animals at all ages, were markedly elevated in kidneys from 3-week-old Cy/Cy animals. In kidneys from heterozygous (Cy/+) adults of either gender, MCP-1 and osteopontin mRNAs were more abundant than normal; MCP-1 mRNA was more abundant in Cy/+ males than in females. Thus, chemoattractant mRNA expression correlated with the development of renal failure in Cy/Cy and Cy/+ rats. Osteopontin mRNA, localized by in situ hybridization, was moderately expressed in the renal medulla of normal animals; however, this mRNA was expressed at very high levels in the cystic epithelia of Cy/+ and Cy/Cy animals. MCP-1 and osteopontin proteins, localized by immunohistochemistry, were weakly detected in +/+ kidneys but were densely expressed in Cy/Cy and in adult Cy/+ kidneys, primarily over cystic epithelium. Increased expression of chemoattractants was associated with the accumulation of ED-1 positive cells (macrophages) in the interstitium of cystic kidneys.

We suggest that proinflammatory chemoattractants have a role in the development of interstitial inflammation and renal failure in ADPKD.

Increased renal expression of monocyte chemoattractant protein-1 and osteopontin in ADPKD in rats.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive renal enlargement and renal failure. We evaluated sequential radiocontrast-enhanced computed tomography (CT) scans to determine the rate of kidney enlargement in patients with ADPKD.

METHODS
Ten adult patients with ADPKD (4 men and 6 women) with initial serum creatinine levels </=1.6 mg/dL had at least two sequential CT scans more than three years apart. The mean patient age at the initial CT study was 33.8 years, and the mean initial serum creatinine concentration was 1.1 mg/dL (range 0.6 to 1.6 mg/dL; range of calculated creatinine clearances 60 to 135 mL/min/1. 73 m2). Total volume (Vt) was determined by manual tracing of renal areas in contiguous 5 to 10 mm thick axial CT slices for each kidney. The area of noncystic parenchyma (Vp) in each slice was determined by differential densitometry segmentation analysis of contrast-enhanced tissue, and total cyst volume (Vc) was the difference between Vt and Vp. The mean diameters of individual cysts were measured sequentially in selected cases.

RESULTS
The mean initial Vt, Vp, and Vc values (+/- SEM) were 561 +/- 66, 243 +/- 19, and 317 +/- 57 mL per kidney, respectively. In 10 patients, after a mean of 5.7 years (range 3.3 to 11.9), Vt increased 323 +/- 79 mL (P < 0.01, range -25 to 1182 mL); the rate of volume increase was 53.9 +/- 10.4 mL/year/kidney (P < 0.001). In eight patients with repeat contrast-enhanced scans, Vt, Vp, and Vc increased 211 +/- 58 mL (P < 0.005), 26 +/- 11 mL (P > 0.05), and 185 +/- 52 mL (P < 0.01), respectively. In 19 individual spherical cysts selected in six patients, the mean initial volume was 15.0 +/- 7.2 mL (range 1.1 to 137 mL), and the average rate of volume increase was 0.52 +/- 0.21 mL/month (P < 0.025, range 0.02 to 4.15 mL/month). In five patients who eventually required dialysis, 11.2 years after the initial CT scan, the initial cyst/kidney volume ratio (combined for both kidneys) exceeded 0.43; four patients with lower cyst/kidney volume ratios had serum creatinine levels <1.5 mg/dL, 8.7 years after the initial CT scan.

On the basis of this preliminary survey of archival material, we conclude that conventional contrast-enhanced CT scans can be used to quantitate volume components of progression in ADPKD. The rates of individual kidney and cyst enlargement are highly variable within and between patients, but overall, the values increase over time. The volume fraction of kidneys comprised of cysts may be a useful indicator of ADPKD progression.

Volumetric determination of progression in autosomal dominant polycystic kidney disease by computed tomography.

We are combining techniques of quantitative ultrasonic imaging to study polycystic kidney disease (PKD) as the disease progresses to renal failure. Our goal is to use ultrasound noninvasively to detect morphological changes early in the disease process when interventions are most likely to be successful and prior to a significant loss in renal function. We are examining the kidneys of normal rats and those with PKD at various ages with several techniques to obtain comprehensive knowledge of the disease progression. The Han:SPRD rat inherits PKD as an autosomal dominant trait (ADPKD) that closely mimics ADPKD in humans. Changes in renal function are assessed using tracer kinetics (DTPA) and IOH clearance). Ultrasonic techniques, based on measurements of acoustic backscatter coefficients and parameters derived from these measurements, are sensitive to microscopic changes in the tissue morphology. Elasticity imaging is used to study the changes in the tissue macrostructure. All acoustic measurements are made using a state-of-the-art clinical imaging system (Siemens Elegra). Our results show that ultrasonic techniques are very sensitive to early changes in renal microstructure and macrostructure. Ultrasound can be used to detect changes in the renal cortex long before there is a measurable loss of renal function. These techniques are also useful for monitoring the progression of the disease. Most importantly, these techniques are noninvasive and directly applicable to humans.

Utility of quantitative ultrasound for tracking the progression of polycystic kidney disease

The cDNA coding for the transcriptional repressor protein Kid-1 was cloned in a screen for zinc finger proteins, which are regulated during renal development and after renal ischemia. Kid-1 mRNA levels increase in the course of postnatal renal development and decrease after acute renal injury caused by ischemia or administration of folic acid. We have raised a monoclonal anti-Kid-1 antibody and demonstrate that the Kid-1 protein is strongly expressed in the proximal tubule of the adult rat kidney. During nephron development, the Kid-1 protein appears after the S-shaped body stage concomitantly with the brush-border enzyme alkaline phosphatase. In two animal models of polycystic kidney disease, the expression of Kid-1 is downregulated. The loss of expression of Kid-1 in cyst wall cells correlates with the loss of alkaline phosphatase histochemical staining. Kid-1 mRNA levels are also reduced in rodent renal cell carcinomas, another condition characterized by epithelial cell dedifferentiation and increased proliferation. We propose that Kid-1 plays an important role during the differentiation of the proximal tubule.

Kid-1 expression is high in differentiated renal proximal tubule cells and suppressed in cyst epithelia.

Using a combination of techniques, we are studying the progression of polycystic kidney disease (PKD) in a rat model as the disease progresses to renal failure. The goal of our work is to use ultrasound to noninvasively detect morphological changes early in the disease process when interventions are most successful and before there is a significant loss in renal function.

1998 IEEE Ultrasonics Symposium. Proceedings (Cat. No. 98CH36102)

Tracking progressive renal disease with quantitative ultrasonic imaging

The effect of paclitaxel on the progression of polycystic kidney disease in rodents.

Gene transfer into kidney tubules and vasculature by adenoviral vectors.

Gender and the effect of gonadal hormones on the progression of inherited polycystic kidney disease in rats.

Renal expression of a transforming growth factor-alpha transgene accelerates the progression of inherited, slowly progressive polycystic kidney disease in the mouse.

Modification of disease progression in rats with inherited polycystic kidney disease.

Gene transfer into the mammalian kidney has proved difficult because of the structural complexity of the organ and its low mitotic index. This article describes the use of intra-arterially injected adenovirus to study gene transfer into the rat kidney in vivo. By pre-chilling the kidney, and incubating the virus with the kidney in the cold for extended periods of time, we were able to successfully transfer a beta-galactosidase (beta-gal) reporter gene into the vasculature without ischemic injury to the kidney. Transfer occurred largely in the cortex when cold was used alone, whereas with the use of cold and vasodilators, transfer was accomplished into the outer medulla in both the inner and outer stripes. In the Han:SPRD rat model of autosomal dominant polycystic kidney disease (ADPKD), gene transfer occurred into the vasculature, some epithelial cysts and interstitial cells. This is the first description of substantial in vivo gene transfer into both normal and cystic kidneys. The methodology could find application in the creation of new models of renal disease, for in vivo therapeutic intervention or for genetic modification of an allograft at the time of harvest.

In vivo adenovirus-mediated gene transfer into normal and cystic rat kidneys.

Methylprednisolone retards the progression of inherited polycystic kidney disease in rodents.

To examine at a molecular level the repair process during recovery from acute renal failure, we determined, after nephrotoxic acute renal injury, levels for several RNAs associated with differentiated functions in the kidney. To delineate changes in different regions, we determined RNA levels separately in cortex, outer medulla, and inner medulla of adult rat kidney. Several RNAs were regionally distributed in control kidneys, including epidermal growth factor (EGF, highest in cortex and outer medulla), aldose reductase (highest in inner medulla), and prostaglandin synthase (highest in inner medulla). Futhermore, RNA for the heat shock protein Hsp70 was present at high levels in the inner medulla of controls. A single intraperitoneal dose of folic acid caused reversible, nonoliguric acute renal failure with impairment of glomerular filtration, tubular sodium reabsorption, and urinary concentration. Fractional excretion of sodium returned to normal by day 3, while serum creatinine, serum urea nitrogen, and urinary osmolality remained abnormal until day 7. During acute renal failure there was a marked, reversible decrease in the regional mRNA levels for EGF, aldose reductase, prostaglandin synthase, and Hsp70. Aldose reductase, prostaglandin synthase, and Hsp70 RNA levels returned to control levels by 7 to 10 days, while EGF remained depressed for a more prolonged period. High levels of aldose reductase, prostaglandin synthase, and Hsp70 RNAs in the inner medulla and their loss/recovery during acute renal failure with a time course similar to alterations in urinary osmolality were consistent with regulation in response to changes in inner medullary osmolality, as has been demonstrated for aldose reductase in normal animals. (ABSTRACT TRUNCATED AT 250 WORDS)

Temporal alterations in regional gene expression after nephrotoxic renal injury.

Human alveolar macrophages (AM) produce a number of inflammatory mediators including tumor necrosis factor (TNF). TNF-alpha has been implicated in several forms of lung injury including that associated with oxygen toxicity. To investigate whether oxygen could induce or augment the release of TNF from AM, we acquired AM from nonsmoking volunteers and determined TNF release after in vitro hyperoxia. Although TNF release was not induced by oxygen exposure alone, if lipopolysaccharide (LPS) stimulation occurred simultaneously, there was significant augmentation by 60 and 95% oxygen over LPS-stimulated AM exposed to 21% oxygen. This increase was paralleled by a significant increase of interleukin (IL)-1 beta. Dimethylthiourea (DMTU), a hydroxyl radical scavenger, inhibited this release. The increase in TNF extracellular concentrations induced by hyperoxia was not associated with significant increases in intracellular concentration or detectable mRNA over LPS-stimulated AM exposed to 21% oxygen. We hypothesize that hyperoxia exposure may alter the LPS-stimulated AM cytoplasmic milieu, thus further enhancing TNF-alpha production by a post-transcriptional mechanism.

Hyperoxia amplifies TNF-alpha production in LPS-stimulated human alveolar macrophages.

suggested cells in polycystic disease (PKD) exist in a developmentally immature state ( 1 ,2) as manifested morpho-logic. functional, and molecular abnormalities. During normal development,

Abnormal expression of epidermal growth factor and sulfated glycoprotein SGP-2 messenger RNA in a rat model of autosomal dominant polycystic kidney disease.

C57BL/6J mice homozygous for the cpk gene exhibit an autosomal recessive (AR) form of polycystic kidney disease (PKD), similar to human ARPKD, with massive collecting duct cysts. These cysts are lined by epithelial with an immature phenotype. Since renal expression of epidermal growth factor (EGF) is also significantly decreased in affected mice, we hypothesized that renal EGF is necessary for normal developmental maturation of the collecting duct. To determine if the lack of EGF may be a decisive factor in the initiation and/or growth of collecting duct cysts, we administered exogenous EGF (1 microgram/g body wt subcutaneously) daily for Postnatal Days 3-9 (a critical period for collecting duct maturation) to C57BL/6J-cpk mice. EGF but not sham or albumin treatment retarded the development of PKD, reduced the degree of renal failure associated with the disease, and prolonged the survival of cystic mice. Sulfated glycoprotein-2 gene expression, a marker of immaturity in collecting duct cells, was reduced in cystic kidney by EGF treatment. This finding indicates that EGF treatment was associated with an increase in the maturation of the collecting duct epithelial cells. These findings support the view that decreased EGF may play a significant role in promoting the enlargement of collecting duct cysts in a hereditary model of ARPKD and that PKD involves defective and/or arrested collecting duct cell maturation.

Epidermal growth factor ameliorates autosomal recessive polycystic kidney disease in mice.

As a function of the urinary concentrating mechanism, the cells of the renal medulla are exposed to elevated and constantly varying osmolalities and adapt to this environment by selectively expressing certain mRNAs. We evaluated the expression and regulation of two RNAs that may be important in adaptation of rental medullary cells to hyperosmolality. We demonstrate selective, modulated expression in the renal medulla of heat shock protein HSP-70 mRNA and prostaglandin synthase-1 mRNA, with the abundance of these two mRNAs regulated in vivo in concert with changes in medullary sodium and urea. We also determined the abundance of these mRNAs in cultured kidney cells (MDCK) in response to an increase in extracellular osmolality due to selected osmotic agents. HSP-70 and prostaglandin synthase-2 mRNA levels increased when extracellular osmolality was increased to 400-600 mosmol/kg by the addition of NaCl. At 500 mosmol/kg this response was evident at 6 h, was maximal near 24 h, and persisted for a total of 90 days. Prostaglandin synthase-1 mRNA levels in MDCK cells were also increased after chronic exposure to extracellular osmolality. Increased extracellular osmolality caused by agents to which cells are impermeable caused increased levels of HSP-70 and prostaglandin synthase-2 mRNAs, whereas increased extracellular osmolality caused by agents to which cells are permeable did not; thus osmotic regulation involved osmotic water movement. We conclude that the abundance of HSP-70 and prostaglandin synthase-1 mRNAs in the renal medulla is regulated in response to renal medullary osmolality and suggest that this may also be true for other medullary mRNAs yet to be described.

In vivo and in vitro osmotic regulation of HSP-70 and prostaglandin synthase gene expression in kidney cells.

Effect of lovastatin on the development of polycystic kidney disease in the Han:SPRD rat.

Polycystic kidney disease in the C57BL/6J (cpk) mouse is an autosomal recessive disorder which leads to the rapid development of renal cysts and kidney failure during the first 3 to 4 postnatal weeks. Previously, we showed that the cystic kidneys of affected mice have abnormally elevated levels of c-myc mRNA. In the study presented here, it is shown that mRNAs for the proto-oncogenes c-fos and c-Kiras, as well as c-myc, are markedly elevated in cystic kidneys, suggesting that there is a more general abnormality in gene expression associated with the disease. It is also evident that there are two stages to this abnormal proto-oncogene expression. In the first stage, which occurs up through the second postnatal week, there are modest increases in proto-oncogene mRNA which parallel the increased cell proliferation that accompanies cyst growth at this time. In the second stage, which occurs after the second postnatal week, there are markedly elevated levels of proto-oncogene mRNA that are seen at a time when cell proliferation is declining. The development of this latter stage suggests either that there is a fundamental abnormality intrinsic to polycystic kidneys that leads to uncontrolled proto-oncogene expression later in disease progression or that there is a secondary response in the kidney to the progressive renal failure.

Elevated proto-oncogene expression in polycystic kidneys of the C57BL/6J (cpk) mouse.

The pregnant uterus contains TNF-alpha, a potent cytokine with pleotrophic effects. The uterus also contains numerous macrophages, which are well described sources of TNF-alpha. In order to determine if uterine TNF-alpha originated with these macrophages, patterns of macrophage tissue distribution and population densities were first established in rat uterine tissues from early, mid, and late stages of gestation by immunohistology. The potential of these and other uterine and placental cells to synthesize TNF-alpha was then tested by in situ hybridization with the use of biotinylated antisense and sense RNA probes. Although TNF-alpha mRNA was present during all stages of pregnancy, hybridization signals were highest in gestation day 15 tissues. The predominant TNF-alpha mRNA-containing cells were uterine epithelium, decidual cells, and placental trophoblast cells; these cells also contained immunoreactive TNF. Transcription of the TNF gene in the uterus and placenta was also documented by Northern blotting experiments, which showed that the transcript sizes for uterine, placental, and macrophage TNF mRNA were similar. Although stromal cells that were located in macrophage-rich uterine compartments (myometrium, metrial gland) contained TNF-alpha mRNA, the cells did not contain high levels of immunoreactive TNF-alpha. Thus, cells other than macrophages are likely to be the major contributors of TNF-alpha during uncomplicated pregnancy in the rat.

Tumor necrosis factor-alpha mRNA and protein in rat uterine and placental cells.

Sorbitol accumulates in renal medullary cells by synthesis from glucose in a reaction catalyzed by aldose reductase. Medullary sodium and urea are high and vary with urinary concentration. Sorbitol varies similarly, consistent with its role as a compatible intracellular organic osmolyte. We measured renal medullary sodium, urea, sorbitol, aldose reductase (protein and activity), and aldose reductase mRNA in rats treated to change medullary sodium and urea. In untreated Brattleboro rats all measurements were low and increased after 7 days of treatment with arginine vasopressin. In contrast, when normal rats were water deprived for 3 days, urea increased out of proportion to sodium, and sorbitol, aldose reductase, and aldose reductase mRNA were unchanged. After 2 h of diuresis, normal rats had lower medullary sodium and urea and reduced mRNA and sorbitol; however aldose reductase did not change. These data are consistent with previous results from cultured cells in which altered extracellular sodium, but not urea, leads to rapid changes in aldose reductase mRNA and slow changes (days) in aldose reductase. In addition, acute decreases in extracellular sodium increase leakage of sorbitol from cells. We also confirm previous results showing medullary glycerophosphorylcholine correlates best with urea, whereas the sum of all compatible osmolytes correlates best with sodium.

In vivo osmoregulation of aldose reductase mRNA, protein, and sorbitol in renal medulla.

Aldose reductase (AR) is an enzyme responsible for converting glucose into sorbitol and galactose into galactitol. In the renal inner medulla, where sorbitol production plays a role in cellular osmoregulation, AR gene expression has been shown to be osmotically regulated. The present study examined the effects of the accumulation of the AR end product, galactitol, induced by galactose feeding, on AR gene expression and on the balance of other cellular osmolytes, including inositol, in the renal medulla. To differentiate between the effects of excess substrate, product, and intervening osmotic factors, rats were fed either control, galactose, galactose and sorbinil (an AR inhibitor), or control plus sorbinil diets. Renal papillae were assayed for AR mRNA, sodium, urea, galactose, galactitol, sorbitol, inositol, and other organic osmolytes. Galactose feeding resulted in a great accumulation of galactitol and reduction in AR mRNA levels in renal papillae. Associated with these changes was a significant depletion of renal papillary sorbitol, inositol, and glycerolphosphocholine. These effects were largely attenuated by sorbinil. The present findings suggest that renal cellular accumulation of the enzyme's polyol product causes downregulation of AR gene expression. Furthermore, our findings suggest that the inositol depletion associated with sorbitol or galactitol accumulation in various cell types during hyperglycemia may be a function of cellular osmoregulation.

Feedback inhibition of aldose reductase gene expression in rat renal medulla. Galactitol accumulation reduces enzyme mRNA levels and depletes cellular inositol content.

Sequential protooncogene expression in regenerating kidney following acute renal injury.

Cells generally respond to long-term hyperosmotic stress by accumulating nonperturbing organic osmolytes. Unlike bacteria, in which molecular mechanisms involved in the increased accumulation of osmolytes have been identified, those in multicellular organisms are virtually unknown. In mammals, during antidiuresis, cells of the renal inner medulla are exposed to high and variable extracellular NaCl. Under these conditions, the cells contain a high level of sorbitol and other osmolytes which help balance the high extracellular osmolality. PAP-HT25 is a continuous line of cells derived from rabbit renal inner medulla. When medium osmolality is increased by raising the NaCl concentration, these cells accumulate sorbitol. The sorbitol is synthesized from glucose in a reaction catalyzed by aldose reductase. When the medium is made hyperosmotic, aldose reductase activity increases because of a larger increase in the amount of enzyme. This increase is produced by the accelerated rate of synthesis of aldose reductase protein. The purpose of the present studies was to examine the mechanism of this increase in aldose reductase protein by measuring the relative abundance of aldose reductase mRNA. A cDNA clone coding for rabbit kidney aldose reductase was isolated. Antisense RNA probes transcribed from this clone hybridized specifically with a 1.5-1.6 kilobase mRNA in Northern blots. Cells grown chronically in hyperosmotic medium had a relative abundance of this specific mRNA which was six times that of cells grown in isoosmotic medium. When cells grown in isoosmotic medium were switched to hyperosmotic medium, the level of aldose reductase mRNA peaked (18-fold) at 18-24 h. The induction of aldose reductase mRNA by osmotic stress was reversible. Our finding of increased abundance of a specific mRNA in direct response to hyperosmotic stress represents the first report of such an effect in animals.

Molecular cloning of cDNA coding for kidney aldose reductase. Regulation of specific mRNA accumulation by NaCl-mediated osmotic stress.

The C57BL/6J-cpk genetic murine model of autosomal recessive polycystic kidney disease was examined to gain insight into the pathogenesis of renal cystic disease. Fetal through 3-week-old offspring of heterozygote matings were used to study growth parameters and morphology of this genetic form of cystic disease. The kidneys were examined by light and electron microscopy and nephron segments were microdissected. Two phases of cystic disease development were morphologically identified. The first phase in fetal and newborn affected pups was characterized by proximal tubule enlargement and a general increase in the tubular mitotic index. The proximal tubules showed cytologic abnormalities along with an increased necrotic cell index. The later phase, in one through 3-week-old cystic pups, was characterized by progressive enlargement of the kidneys due mainly to cystic change of the collecting ducts and by development of azotemia. Secondary to the azotemia was a stunted body growth. Significant tubular epithelial hyperplasia was not found by mitotic index during the second phase, but an increase in collecting duct cellularity was present. Histone H4 gene expression, which is tightly coupled to DNA synthesis and thus an index of cell proliferation, showed only a minimal increase in cystic kidneys at 1, 2, and 3 weeks of age. Therefore, the degree of cell proliferation necessary to allow the observed tubular enlargement appears to be minimal.

Autosomal recessive polycystic kidney disease in a murine model. A gross and microscopic description.

The polycystic kidney diseases (PKDs) are a group of disorders characterized by the growth of epithelial cysts from the nephrons and collecting ducts of kidney tubules. The diseases can be inherited or can be provoked by environmental factors. To investigate the molecular basis of the abnormal cell growth associated with PKD, c-myc protooncogene expression was studied in a mouse model for autosomal recessive PKD. Homozygous recessive C57BL/6J (cpk/cpk) mice develop massively enlarged cystic kidneys and die from renal failure shortly after 3 weeks of age. Quantitative dot blot and RNA blot hybridization experiments in which whole kidney poly(A)+ RNA was hybridized with a c-myc RNA probe showed a 2- to 6-fold increase in c-myc mRNA at 2 weeks, and a 25- to 30-fold increase in c-myc mRNA at 3 weeks of age in polycystic mice, as compared to normal littermates. c-myc expression was also examined under two conditions in which kidney cell growth was experimentally induced in normal adult mice: compensatory renal hypertrophy and tubule regeneration following folic acid-induced renal cell injury. While compensatory hypertrophy resulted in only a small (less than 3-fold) increase in c-myc, folic acid treatment gave rise after 24 hr to a 12-fold increase in c-myc mRNA. The induction of c-myc by folic acid is consistent with increased cellular proliferation in regenerating tubules. In contrast, polycystic kidneys show only a minimal increase in cellular proliferation over that seen in normal kidneys, while c-myc levels were found to be markedly elevated. Thus, the level of c-myc expression in cystic kidneys appears to be out of proportion to the rate of cell division, suggesting that elevated and potentially abnormal c-myc expression may be involved in the pathogenesis of PKD.

Elevated c-myc protooncogene expression in autosomal recessive polycystic kidney disease.

Macromolecules in rabbit serum inhibit the cellular uptake and transepithelial secretion of [14C]urate and p-[3H]aminohippurate ([3H]PA) in rabbit S2 proximal tubule segments. To understand better the potential role these inhibitors may have in the regulation of renal organic anion excretion, we examined the specificity and relative inhibitory effects on tubule urate and PAH transport of albumin and gamma-globulin, the major inhibitory proteins in rabbit serum. Native rabbit serum markedly inhibited the cellular accumulation of urate and PAH by isolated nonperfused segments [50% inhibition (K0.5) = 0.4 and 0.65 g/dl, respectively]. Urate and PAH transport was also inhibited by bovine serum, human serum, Cohn-fractionated rabbit albumin, and rabbit gamma-globulin, but not by Cohn-fractionated bovine serum albumin. alpha-Lactalbumin and beta-lactoglobulin, derived from milk, also inhibited urate and PAH transport, but to a lesser extent than albumin and gamma-globulin. The transport inhibitory effects of proteins were independent of their binding to urate and PAH. Unidirectional influx and the steady-state intracellular accumulation of urate and PAH in suspensions of proximal tubules were decreased by rabbit serum proteins, suggesting that these inhibitors act on the external face of the cells to diminish the uptake of the organic anions. These studies indicate that the principal plasma proteins (albumin and gamma-globulin) significantly inhibit urate and PAH transporters in the basolateral membranes of S2 proximal tubules. We suggest that circulating plasma proteins that can penetrate the basement membrane of proximal tubules may directly modulate the renal excretion of urate and PAH.

Tubule urate and PAH transport: sensitivity and specificity of serum protein inhibition.

Attention-deficit/hyperactivity disorder (ADHD) is characterized by involuntary fluctuations of attention in continuous performance tasks (CPTs) wherein attention must be sustained over long periods of time. The neuronal basis underlying aberrant attentional fluctuations in time scales from seconds to minutes have remained poorly understood. Neuronal alpha- and gammaband oscillations are thought to implement attentional and top-down control of sensorimotor processing. We hypothesized that aberrant behavioral fluctuations in ADHD would be caused by aberrant endogenous brain dynamics in alpha and gamma-band oscillations and specifically by their aberrant long-range temporal correlations (LRTCs). We measured brain activity with magnetoencephalography (MEG) from adult participants diagnosed with ADHD (N = 19) and from healthy control subjects (N = 20) during resting state and two CPTs; a threshold stimulus detection task and a Go/NoGo task. We then estimated LRTCs of neuronal oscillations and behavioral fluctuations with detrended fluctuation analysis (DFA). ADHD was associated with aberrant LRTCs in both behavioral performance and of neuronal oscillations. LRTCs were correlated with symptom severity with a U-shaped correlations indicating that the LRTCs were largest with moderate symptom scores. These data demonstrate the presence of aberrant temporal dynamics of neuronal oscillations in adult ADHD patients, which may underlie involuntary attentional fluctuations in ADHD. Taken that LRTCs are a hallmark of brain critical dynamics, these data show that moderate ADHD symptoms scores maximize brain criticality which is thought to be beneficial for performance.

Is mild ADHD beneficial: Brain criticality is maximal with moderate ADHD symptom scores

Inter-brain synchronization occurs without physical co-presence during cooperative online gaming

Children’s inhibition skills are associated with their P3a latency—results from an exploratory study

Evaluation of Neurofeedback Learning in Patients with ADHD: A Systematic Review

Abstract In adults, music and speech share many neurocognitive functions, but how do they interact in a developing brain? We compared the effects of music and foreign language training on auditory neurocognition in Chinese children aged 8–11 years. We delivered group-based training programs in music and foreign language using a randomized controlled trial. A passive control group was also included. Before and after these year-long extracurricular programs, auditory event-related potentials were recorded (n = 123 and 85 before and after the program, respectively). Through these recordings, we probed early auditory predictive brain processes. To our surprise, the language program facilitated the children’s early auditory predictive brain processes significantly more than did the music program. This facilitation was most evident in pitch encoding when the experimental paradigm was musically relevant. When these processes were probed by a paradigm more focused on basic sound features, we found early predictive pitch encoding to be facilitated by music training. Thus, a foreign language program is able to foster auditory and music neurocognition, at least in tonal language speakers, in a manner comparable to that by a music program. Our results support the tight coupling of musical and linguistic brain functions also in the developing brain.

Improved Auditory Function Caused by Music Versus Foreign Language Training at School Age: Is There a Difference?

Neurofeedback for attention deficit/hyperactivity disorder (ADHD) has long been studied as an alternative to medication, promising non-invasive treatment with minimal side-effects and sustained outcome. However, debate continues over the efficacy of neurofeedback, partly because existing evidence for efficacy is mixed and often non-specific, with unclear relationships between prognostic variables, patient performance when learning to self-regulate, and treatment outcomes. We report an extensive analysis on the understudied area of neurofeedback learning. Our data comes from a randomised controlled clinical trial in adults with ADHD (registered trial ISRCTN13915109; N = 23; 13:10 female:male; age 25–57). Patients were treated with either theta-beta ratio or sensorimotor-rhythm regimes for 40 one-hour sessions. We classify 11 learners vs 12 non-learners by the significance of random slopes in a linear mixed growth-curve model. We then analyse the predictors, outcomes, and processes of learners vs non-learners, using these groups as mutual controls. Significant predictive relationships were found in anxiety disorder (GAD), dissociative experience (DES), and behavioural inhibition (BIS) scores obtained during screening. Low DES, but high GAD and BIS, predicted positive learning. Patterns of behavioural outcomes from Test Of Variables of Attention, and symptoms from adult ADHD Self-Report Scale, suggested that learning itself is not required for positive outcomes. Finally, the learning process was analysed using structural-equations modelling with continuous-time data, estimating the short-term and sustained impact of each session on learning. A key finding is that our results support the conceptualisation of neurofeedback learning as skill acquisition, and not merely operant conditioning as originally proposed in the literature.

Neurofeedback Learning Is Skill Acquisition but Does Not Guarantee Treatment Benefit: Continuous-Time Analysis of Learning-Curves From a Clinical Trial for ADHD

In a novel experimental setting, we augmented a variation of traditional compassion meditation with our custom-built VR environment for multiple concurrent users. The presence of another user’s avatar in shared virtual space supports social interactions and provides an active target for evoked compassion. The system incorporates respiration and brainwave-based biofeedback to enable closed-loop interaction of users based on their shared physiological state. Specifically, we enhanced interoception and the deep empathetic processes involved in compassion meditation with real-time visualizations of: breathing rate, level of approach motivation assessed from EEG frontal asymmetry, and dyadic synchrony of those signals between two users. We manipulated these interventions across eight separate conditions (dyadic or solo meditation; brainwave, breathing, both or no biofeedback) in an experiment with 39 dyads (N=8), observing the effect of conditions on self-reported experience and physiological synchrony. We found that each different shared biofeedback type increased users’ self-reported empathy and social presence, compared to no-biofeedback or solo conditions. Our study illustrates how dyadic synchrony biofeedback can expand the possibilities of biofeedback in affective computing and VR solutions for health and wellness.

The link between flow and performance is moderated by task experience

Abstract Attention-deficit/hyperactivity disorder (ADHD) in adults is understudied, especially regarding neural mechanisms such as oscillatory control of attention sampling. We report an electroencephalography (EEG) study of such cortical mechanisms, in ADHD-diagnosed adults during administration of Test of Variables of Attention (TOVA), a gold-standard continuous performance test for ADHD that measures the ability to sustain attention and inhibit impulsivity. We recorded 53 adults (28 female, 25 male, aged 18–60), and 18 matched healthy controls, using 128-channel EEG. We analyzed sensor-space features established as neural correlates of attention: timing-sensitivity and phase-synchrony of response activations, and event-related (de)synchronization (ERS/D) of α and θ frequency band activity; in frontal and parietal scalp regions. TOVA test performance significantly distinguished ADHD adults from neurotypical controls, in commission errors, response time variability (RTV) and d′ (response sensitivity). The ADHD group showed significantly weaker target-locked and response-locked amplitudes, that were strongly right-lateralized at the N2 wave, and weaker phase synchrony (longer reset poststimulus). They also manifested significantly less parietal prestimulus 8-Hz θ ERS, less frontal and parietal poststimulus 4-Hz θ ERS, and more frontal and parietal prestimulus α ERS during correct trials. These differences may reflect excessive modulation of endogenous activity by strong entrainment to stimulus (α), combined with deficient modulation by neural entrainment to task (θ), which in TOVA involves monitoring stimulus spatial location (not predicted occurrence onset which is regular and task-irrelevant). Building on the hypotheses of θ coding for relational structure and rhythmic attention sampling, our results suggest that ADHD adults have impaired attention sampling in relational categorization tasks.

Reduced Power in Fronto-Parietal Theta EEG Linked to Impaired Attention-Sampling in Adult ADHD

Psychometric analysis of the flow short scale translated to Finnish

Traumatic brain injury (TBI) is characterized by a complex pattern of abnormalities in resting-state functional connectivity (rsFC), and neuropathology focused on network dysfunction. Here we report a fMRI study of brain network changes induced during a randomised controlled trial of neurological music therapy in 23 moderate/severe TBI patients. Our ROI-to- ROI approach used four networks as sources: the frontoparietal (FPN), dorsal attention (DAN), default mode (DMN), and salience (SAL) networks. These networks include high-degree nodes or network hubs, and have all been associated with cognitive impairment after TBI. Furthermore, we investigated the correlation between brain network changes and executive function (EF). Lastly, we implemented a seed-to-voxel analysis to cross-link whole-brain rsFC with brain morphometry results obtained in our previous study of this data. The neurological music therapy increased the coupling between the FPN and DAN as well as between these networks and primary sensory networks that were engaged during musical training. By contrast, the DMN was less connected with sensory networks after the intervention. Similarly, there was a shift towards a less connected state within the FPN and SAL networks, which are typically hyperconnected following TBI. Improvements in EF were correlated with rsFC within the FPN and between the DMN and sensorimotor networks. Finally, the increase in grey matter volume in frontal regions was associated with greater rsFC in areas implicated in music processing. This study is the largest of its kind, and suggests that rsFC in response to music-based rehabilitation may provide sensitive biomarkers of cognitive recovery after TBI.

Resting-State Network Plasticity Induced by Music Therapy after Traumatic Brain Injury

1 Faculty of Educational Sciences, University of Helsinki, Helsinki, Finland, Department of Digital Humanities, Faculty of Arts, University of Helsinki, Helsinki, Finland, 3 Institut Supérieur de l’Aéronautique et de l’Espace (ISAE-SUPAERO), Toulouse, France, 4 Liverpool John Moores University, Liverpool, United Kingdom, Hautes études Commerciales Montréal, Université de Montréal, Montreal, QC, Canada

Editorial: High Performance Cognition: Information-Processing in Complex Skills, Expert Performance, and Flow

Attention-deficit hyperactivity disorder (ADHD) in adults is understudied, especially regarding neural mechanisms such as oscillatory control of attention sampling. We report an EEG study of such cortical oscillations, in ADHD-diagnosed adults taking a continuous performance test that measures the ability to sustain attention and inhibit impulsivity for a prolonged period of time. We recorded 53 adults (28f, 25m, aged 18-60), and 18 matched healthy controls, using 128-channel EEG. We analysed features with established links to neural correlates of attention: event-related (de)synchronisation (ERS), alpha and theta frequency band activation, and stimulus-locking indices; in frontal and parietal scalp regions. Test performance distinguished healthy controls from ADHD adults. The ADHD group manifested significantly less parietal 4 Hz theta ERS during correct inhibition trials, in addition to having greater sensitivity to targets in stimulus-locking measures. Our results suggest that ADHD adults have impaired attention sampling in relational categorisation tasks.

Strength of attention-sampling parietal EEG theta rhythm is linked to impaired inhibition in adult ADHD

Physiological arousal can be a signal of attention, reflecting predictability and significance of stimuli or events. We explored temporal patterns in task-related physiological arousal and their connection to performance in repeated trials of a visuomotor steering task. Participants (N = 9) played a total of forty trials of a high-speed steering task in eight sessions over a period of 2-3 weeks. Temporal changes in electrodermal activity during task performance were modelled as habituation, and connections between performance, perceived importance and individual differences in habituation rate were examined. Additionally, withinsubject changes in habituation were compared to deviations from predicted performance. We found that sustained task-related arousal (slow habituation) was connected to better performance both between groups and within participants. Slow habituation was also related to higher subjective reports of perceived importance. Taken together, these results suggest that temporal changes in task-related arousal during learning are related to the processing of task-relevant cues and may reflect motivational states that direct selective attention.

Temporal Pattern Models for Physiological Arousal During a Steering Task

Flow is a state of “optimal experience” that arises when skill and task demands match. Flow has been well studied in psychology using a range of self-report and experimental methods; with most research typically focusing on how Flow is elicited by a particular task. Here, we focus on how the experience of Flow changes during task skill development. We present a longitudinal experimental study of learning, wherein participants (N = 9) play a novel steering-game task designed to elicit Flow by matching skill and demand, and providing clear goals and feedback. Experimental design involves extensive in-depth measurement of behavior, physiology, and Flow self-reports over 2 weeks of 40 game trials in eight sessions. Here we report behavioral results, which are both strikingly similar and strong within each participant. We find that the game induces a near-constant state of elevated Flow. We further find that the variation in Flow across all trials is less affected by overall performance improvement than by deviation of performance from the expected value predicted by a power law model of learning.

Flow Experiences During Visuomotor Skill Acquisition Reflect Deviation From a Power-Law Learning Curve, but Not Overall Level of Skill

Biosignals reflect pair-dynamics in collaborative work: EDA and ECG study of pair-programming in a classroom environment

Studying the integrated functional cognitive basis of sustained attention with a Primed Subjective-Illusory-Contour Attention Task

Existing tools for the preprocessing of EEG data provide a large choice of methods to suitably prepare and analyse a given dataset. Yet it remains a challenge for the average user to integrate methods for batch processing of the increasingly large datasets of modern research, and compare methods to choose an optimal approach across the many possible parameter configurations. Additionally, many tools still require a high degree of manual decision making for, e.g., the classification of artifacts in channels, epochs or segments. This introduces extra subjectivity, is slow, and is not reproducible. Batching and well-designed automation can help to regularize EEG preprocessing, and thus reduce human effort, subjectivity, and consequent error. The Computational Testing for Automated Preprocessing (CTAP) toolbox facilitates: (i) batch processing that is easy for experts and novices alike; (ii) testing and comparison of preprocessing methods. Here we demonstrate the application of CTAP to high-resolution EEG data in three modes of use. First, a linear processing pipeline with mostly default parameters illustrates ease-of-use for naive users. Second, a branching pipeline illustrates CTAP's support for comparison of competing methods. Third, a pipeline with built-in parameter-sweeping illustrates CTAP's capability to support data-driven method parameterization. CTAP extends the existing functions and data structure from the well-known EEGLAB toolbox, based on Matlab, and produces extensive quality control outputs. CTAP is available under MIT open-source licence from https://github.com/bwrc/ctap.

Computational Testing for Automated Preprocessing 2: Practical Demonstration of a System for Scientific Data-Processing Workflow Management for High-Volume EEG

Flow is a state of `optimal experience' that arises when skill and task demands match. Flow has been well studied in psychology using a range of self-report and experimental methods; with most research typically focusing on how Flow is elicited by a particular task. Here, we focus on how the experience of Flow changes during task skill development. We present a longitudinal experiment of learning to play a bespoke steering-game task designed to elicit Flow by matching skill and demand, and providing clear goals and feedback. We measure Flow self-reports over 40 game trials in eight sessions, and find the game induces a near constant state of elevated Flow. We further find that the variation in Flow across all trials is less affected by overall performance improvement than by deviation of performance from the expected value predicted by a power law model of learning. Finally, concurrent measurement of physiology shows that spontaneous blink rate, a putative index of striatal dopamine, relates to the individual rate of learning, and that this relationship is moderated by Flow.

Global learning, local Flow: subjective Flow report responds to proximal performance reference-level in a longitudinally-measured game-like task

The PSICAT protocol - Primed Subjective-Illusory-Contour Attention Task for studying integrated functional cognitive basis of sustained attention

General game playing artificial intelligence has recently seen important advances due to the various techniques known as ’deep learning’. However the advances conceal equally important limitations in their reliance on: massive data sets; fortuitously constructed problems; and absence of any humanlevel complexity, including other human opponents. On the other hand, deep learning systems which do beat human champions, such as in Go, do not generalise well. The power of deep learning simultaneously exposes its weakness. Given that deep learning is mostly clever reconfigurations of well-established methods, moving beyond the state of art calls for forwardthinking visionary solutions, not just more of the same. I present the argument that general game playing artificial intelligence will require a generalised player model. This is because games are inherently human artefacts which therefore, as a class of problems, contain cases which require a human-style problem solving approach. I relate this argument to the performance of state of art general game playing agents. I then describe a concept for a formal category theoretic basis to a generalised player model. This formal model approach integrates my existing ’Behavlets’ method for psychologically-derived player modelling: Cowley, B., & Charles, D. (2016). Behavlets: a Method for Practical Player Modelling using Psychology-Based Player Traits and Domain Specific Features. User Modeling and User-Adapted Interaction, 26(2), 257–306.

How to move beyond general game playing artificial intelligence by player modelling

The application of psychophysiology in human-computer interaction is a growing field with significant potential for future smart personalised systems. Working in this emerging field requires comprehension of an array of physiological signals and analysis techniques. 
Respiration is unique among physiological signals in that it can be consciously controlled which has to be taken into account when designing applications. Respiration is tightly connected to other physiological signals, especially cardiovascular activity, and often analyzed in conjunction with other signals. When analyzed separately, an increase in the rate of respiration can be seen as an increase in metabolic demand which indicates activate states such as engagement and attention. We present a short review on the application of respiration in human-computer interaction. 
This paper aims to serve as a primer for the novice, enabling rapid familiarisation with the latest core concepts. We put special emphasis on everyday human-computer interface applications to distinguish from the more common clinical or sports uses of psychophysiology. 
This paper is an extract from a comprehensive review of the entire field of ambulatory psychophysiology, including 12 similar chapters, plus application guidelines and systematic review. Thus any citation should be made using the following reference: 
B. Cowley, M. Filetti, K. Lukander, J. Torniainen, A. Henelius, L. Ahonen, O. Barral, I. Kosunen, T. Valtonen, M. Huotilainen, N. Ravaja, G. Jacucci. The Psychophysiology Primer: a guide to methods and a broad review with a focus on human-computer interaction. Foundations and Trends in Human-Computer Interaction, vol. 9, no. 3-4, pp. 150--307, 2016.

A short review and primer on respiration in human computer interaction applications

Behavlets: a method for practical player modelling using psychology-based player traits and domain specific features

Background: We report a randomized controlled clinical trial of neurofeedback therapy intervention for ADHD/ADD in adults. We focus on internal mechanics of neurofeedback learning, to elucidate the primary role of cortical self-regulation in neurofeedback. We report initial results; more extensive analysis will follow. Methods: Trial has two phases: intervention and follow-up. The intervention consisted of neurofeedback treatment, including intake and outtake measurements, using a waiting-list control group. Treatment involved ~40 h-long sessions 2–5 times per week. Training involved either theta/beta or sensorimotor-rhythm regimes, adapted by adding a novel “inverse-training” condition to promote self-regulation. Follow-up (ongoing) will consist of self-report and executive function tests. Setting: Intake and outtake measurements were conducted at University of Helsinki. Treatment was administered at partner clinic Mental Capital Care, Helsinki. Randomization: We randomly allocated half the sample then adaptively allocated the remainder to minimize baseline differences in prognostic variables. Blinding: Waiting-list control design meant trial was not blinded. Participants: Fifty-four adult Finnish participants (mean age 36 years; 29 females) were recruited after screening by psychiatric review. Forty-four had ADHD diagnoses, 10 had ADD. Measurements: Symptoms were assessed by computerized attention test (T.O.V.A.) and self-report scales, at intake and outtake. Performance during neurofeedback trials was recorded. Results: Participants were recruited and completed intake measurements during summer 2012, before assignment to treatment and control, September 2012. Outtake measurements ran April-August 2013. After dropouts, 23 treatment and 21 waiting-list participants remained for analysis. Initial analysis showed that, compared to waiting-list control, neurofeedback promoted improvement of self-reported ADHD symptoms, but did not show transfer of learning to T.O.V.A. Comprehensive analysis will be reported elsewhere. Trial Registration: “Computer Enabled Neuroplasticity Treatment (CENT),” ISRCTN13915109.

Computer Enabled Neuroplasticity Treatment: A Clinical Trial of a Novel Design for Neurofeedback Therapy in Adult ADHD

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and a variant of autism spectrum disorder (ASD). The FXS population is quite heterogeneous with respect to comorbidities, which implies the need for a personalized medicine approach, relying on biomarkers or endophenotypes to guide treatment. There is evidence that quantitative electroencephalography (EEG) endophenotype-guided treatments can support increased clinical benefit by considering the patient's neurophysiological profile. We describe a case series of 11 children diagnosed with FXS, aged one to 14 years, mean 4.6 years. Case data are based on longitudinal clinically-observed reports by attending physicians for comorbid symptoms including awake and asleep EEG profiles. We tabulate the comorbid EEG symptoms in this case series, and relate them to the literature on EEG endophenotypes and associated treatment options. The two most common endophenotypes in the data were diffuse slow oscillations and epileptiform EEG, which have been associated with attention and epilepsy respectively. This observation agrees with reported prevalence of comorbid behavioral symptoms for FXS. In this sample of FXS children, attention problems were found in 37% (4 of 11), and epileptic seizures in 45% (5 of 11). Attention problems were found to associate with the epilepsy endophenotype. From the synthesis of this case series and literature review, we argue that the evidence-based personalized treatment approach, exemplified by neurofeedback, could benefit FXS children by focusing on observable, specific characteristics of comorbid disease symptoms.

Epileptic Electroencephalography Profile Associates with Attention Problems in Children with Fragile X Syndrome: Review and Case Series

Background: Recognition of objects and their context relies heavily on the integrated functioning of global and local visual processing. In a realistic setting such as work, this processing becomes a sustained activity, implying a consequent interaction with executive functions. Motivation: There have been many studies of either global-local attention or executive functions; however it is relatively novel to combine these processes to study a more ecological form of attention. We aim to explore the phenomenon of global-local processing during a task requiring sustained attention and working memory. Methods: We develop and test a novel protocol for global-local dissociation, with task structure including phases of divided (“rule search”) and selective (“rule found”) attention, based on the Wisconsin Card Sorting Task (WCST). We test it in a laboratory study with 25 participants, and report on behavior measures (physiological data was also gathered, but not reported here). We develop novel stimuli with more naturalistic levels of information and noise, based primarily on face photographs, with consequently more ecological validity. Results: We report behavioral results indicating that sustained difficulty when participants test their hypotheses impacts matching-task performance, and diminishes the global precedence effect. Results also show a dissociation between subjectively experienced difficulty and objective dimension of performance, and establish the internal validity of the protocol. Contribution: We contribute an advance in the state of the art for testing global-local attention processes in concert with complex cognition. With three results we establish a connection between global-local dissociation and aspects of complex cognition. Our protocol also improves ecological validity and opens options for testing additional interactions in future work.

Forest, Trees, Dynamics: Results from a Novel Wisconsin Card Sorting Test Variant Protocol for Studying Global-Local Attention and Complex Cognitive Processes

Digital monitoring of physiological signals can allow computer systems to adapt unobtrusively to users, so as to enhance personalised 'smart' interactions. In recent years, physiological computing has grown as a research field, and it is increasingly considered in diverse applications, ranging from specialised work contexts to consumer electronics. Working in this emerging field requires comprehension of several physiological signals, psychophysiological states or 'indices', and analysis techniques. The resulting literature encompasses a complex array of knowledge and techniques, presenting a clear challenge to the practitioner. We provide a foundational review of the field of psychophysiology to serve as a primer for the novice, enabling rapid familiarisation with the core concepts, or as a quick-reference resource for advanced readers. We place special emphasis on everyday human-computer interface applications, drawing a distinction from clinical or sports applications, which are more commonplace. The review provides a framework of commonly understood terms associated with experiential constructs and physiological signals. Then, 12 short and precisely focused review sections describe 10 individual signals or signal sources and present two technical discussions of online data fusion and processing. A systematic review of multimodal studies is provided in the form of a reference table. We conclude with a general discussion of the application of psychophysiology to human-computer interaction, including guidelines and challenges.

The Psychophysiology Primer: A Guide to Methods and a Broad Review with a Focus on Human-Computer Interaction

It is known that periods of intense social interaction result in shared patterns in collaborators’ physiological signals. However, applied quantitative research on collaboration is hindered due to scarcity of objective metrics of teamwork effectiveness. Indeed, especially in the domain of productive, ecologically-valid activity such as programming, there is a lack of evidence for the most effective, affordable and reliable measures of collaboration quality. In this study we investigate synchrony in physiological signals between collaborating computer science students performing pair-programming exercises in a class room environment. We recorded electrocardiography over the course of a 60 minute programming session, using lightweight physiological sensors. We employ correlation of heart-rate variability features to study social psychophysiological compliance of the collaborating students. We found evident physiological compliance in collaborating dyads’ heart-rate variability signals. Furthermore, dyads’ self-reported workload was associated with the physiological compliance. Our results show viability of a novel approach to field measurement using lightweight devices in an uncontrolled environment, and suggest that self-reported collaboration quality can be assessed via physiological signals.

Cognitive Collaboration Found in Cardiac Physiology: Study in Classroom Environment

As mentioned in Introduction, electrodermal activity (EDA) was also recorded during the pair programming sessions. EDA is a valuable addition to almost any psychophysiological experiment due to its ability to measure sympathetic arousal without being influenced by parasympathetic activation. Contrasted to the heart-rate variability (HRV) which is controlled by both branches of the autonomic nervous system (ANS), the combination of EDA and HRV produces the most complete picture of the ANS responses. EDA is temporally more responsive when compared to HRV as responses typically occur within 1-3 s after a stimulus onset [3] where as the time-scale for HRV is in minute-scale. Unfortunately a large portion of the collected EDA data had to be discarded due to excessive artifacts in the data. However, we report here visual analysis

S 1 : Analysis of Electrodermal Activity Recordings in Pair Programming from 2 Dyads

The psychophysiological method can be used to detect some simple cognitive states such as arousal, attentiveness, or mental workload. This approach can be especially interesting when cognition has some productive purpose, as in knowledge work, and tends to be related to human-computer interaction (HCI). However more interesting for applied purposes are acts of coordinated high-level cognition. High- level (or higher-order) cognition (HLC) is typically associated with decision making, problem solving, and executive control of cognition and action. Further, an intuitive approach for assessing whether someone is engaged in HLC is to measure their performance of a known task. Given this, it is reasonable to define high-performance cognition (HPC) as HLC under some performance restriction, such as real-time pressure or expert skill level. Such states are also interesting for HCI in work, and their detection represents an ambitious aim for using the psychophysiological method. We report a brief review of the literature on the topic.

Psychophysiology and high-performance cognition: a brief review of the literature

Quantifying Mental Workload With Minimally Disruptive Measurements Of Cardiac And Electrodermal Activity In Real-Life Situations: [poster]

Abstract Motivated by the link between play and learning, proposed in literature to have a neurobiological basis, we study the electroencephalogram and associated psychophysiology of “learning game” players. Forty-five players were tested for topic comprehension by a questionnaire administered before and after solo playing of the game Peacemaker (Impact Games 2007), during which electroencephalography and other physiological signals were measured. Play lasted for one hour, with a break at half time. We used the Bloom taxonomy to distinguish levels of difficulty in demonstrated learning—with the first five levels assigned to fixed questions—and “gain” scores to measure actual value of demonstrated learning. We present the analysis of the physiological signals recorded during game play and their relationship to learning scores. Main effects related to biomarkers of vigilance and motivation—including decreased delta power and relatively balanced fronto-hemispheric alpha power—predicted learning at the analysed Bloom levels. Results suggest multiple physiological dispositions that support on-task learning styles, and highlight the utility of the psychophysiological method for interpreting game-based learning evaluations.

Learning in balance: Using oscillatory EEG biomarkers of attention, motivation and vigilance to interpret game-based learning

The QUARTIC Process Model for Developing Serious Games: ‘Green My Place’ Case Study

We report research on player modeling using psychophysiology and machine learning, conducted through interdisciplinary collaboration between researchers of computer science, psychology, and game design at Aalto University, Helsinki. First, we propose the Play Patterns And eXperience (PPAX) framework to connect three levels of game experience that previously had remained largely unconnected: game design patterns, the interplay of game context with player personality or tendencies, and state-of-the-art measures of experience (both subjective and non-subjective). Second, we describe our methodology for using machine learning to categorize game events to reveal corresponding patterns, culminating in an example experiment. We discuss the relation between automatically detected event clusters and game design patterns, and provide indications on how to incorporate personality profiles of players in the analysis. This novel interdisciplinary collaboration combines basic psychophysiology research with game design patterns and machine learning, and generates new knowledge about the interplay between game experience and design.

This paper reports on the PsychoPhysiological Assessment Component which measures the emotional/psychological state of serious game players, to support their competence development within a novel Technology Enhanced Learning (TEL) platform. The authors describe the methods used to build and validate the emotional-state Naive Bayes classifier (NBC). Our approach is tested in two experiments. In the first experiment, participants had to perform emotional- elicitation tasks and we achieved an arousal classification accuracy of ~92%. In the second experiment, participants were asked to play the TEL serious game and we achieved an arousal classification accuracy of ~68%. The results show that our arousal classification system, based on a simple set of sensors, can provide a real- time index of what can be considered a baseline measure of the player's capacity to learn: in a state of increased arousal/activation, the potential to learn is higher.

Arousing Learning: Real-Time Emotion Recognition for Technology Enhanced Learning

Administration of ammonium chloride aggravates, while short-term administration of sodium or potassium bicarbonate lessens the development of polycystic kidney disease in Han:SPRD rats. We have conducted studies to determine whether the protection afforded by the administration of sodium bicarbonate is sustained and prevents development of uremia during chronic administration and whether the effects of the administration of ammonium chloride and sodium bicarbonate are also observed in a different model of polycystic kidney disease, the CD1-pcy/pcy mouse. We found that chronic administration of 200 mM sodium bicarbonate to Han:SPRD rats inhibited cystic enlargement and prevented the subsequent development of interstitial inflammation, chronic fibrosis, and uremia. We also found that, while the administration of ammonium chloride has similar effects in Han:SPRD rats and CD1-pcy/pcy mice, the administration of sodium bicarbonate is only protective in the Han:SPRD rats. This probably reflects differences in these models (predominately involvement of proximal tubules in Han:SPRD rats and of collecting ducts and distal tubules in pcy/pcy mice) and the different location and nature of the renal metabolic responses to the administration of acid or alkaline load.

Long-Term Ammonium Chloride or Sodium Bicarbonate Treatment in Two Models of Polycystic Kidney Disease

Fusion of forehead EEG with machine vision for real-time fatigue detection in an automatic processing pipeline

"ICIC Express Letters, Part B: Applications An International Journal of Research and Surveys"

A NOVEL FATIGUE DETECTION SYSTEM COMBINING EYE IMAGES AND BRAINWAVES

This article presents a novel method for activation detection in task-related functional magnetic resonance imaging (fMRI) based on the Empirical Mode Decomposition (EMD) algorithm. The basic concept stems mainly from the idea that the EMD performs well in isolating the imbedded stimulus from the activated Blood Oxygen Level Dependent (BOLD) signal. The power of the proposed method was compared with the General Linear Model (GLM), spatial Independent Component Analysis (ICA) and Region Growing (RG) methods on simulated and real datasets. Experimental results suggest an almost identical performance for the proposed method compared with the standard approach of fMRI signal detection (the GLM), which indicates that it is to become a viable alternative to fMRI analysis.

A novel approach to activation detection in fMRI based on empirical mode decomposition.

Cooperative Multiple Task Assignment Considering Precedence Constraints Using Multi-Chromosome Encoded Genetic Algorithm

This paper extends the reinforcement learning ideas into the multi-agents system, which is far more complicated than the previously studied single-agent system. We studied two different multi-agents systems. One is the fully-connected neural network consists of multiple single neurons. Another one is the simplified mechanical arm system which is controlled by multiple neurons. We suppose that each neuron is like an agent and it can do Gibbs sampling of the posterior probability of stimulus features. The policy is optimized in a way that the cumulative global rewards are maximized. The algorithm for the second system is based on the same idea but we incorporate the physics model into the constraints. The simulation results show that for the first system our algorithm converges well. For the second system it does not converge well in a reasonable simulation time length. In summary, we took the initial endeavor to study the reinforcement learning for multi-agents system. The computational complexity is always an issue and significant amount of works have to be done in order to better understand the problem.

A broadband and compact coplanar waveguide (CPW) coupled‐fed metasurface (MS)‐based antenna for C‐band synthetic aperture radar (SAR) imaging application is proposed in this article, which is consisted of 16 uniform periodic square patches performed as radiators. The CPW feeding structure gives two following functions: (1) It excites an aperture coupling slot structure underneath the center of MS patch array. (2) It acts as a ground plane for the metasurface patch units. Different slots were investigated and eventually an hourglass‐shaped slot is applied to enhance bandwidth for imaging applications. A prototype with a dimension of 60 × 60 × 1.524 mm3 (1.1λ0 × 1.1λ0 × 0.03λ0) operating at the center frequency 5.5 GHz (f0) has been fabricated and measured to verify the design principle. This antenna has a measured impedance bandwidth of 12.4% from 5.14 to 5.82 GHz, a peak gain of 9.2 dBi and averaged gain of 7.2 dBi at broadside radiation. Microwave imaging experiments using the proposed antenna have been carried out and a good performance is achieved.

Broadband compact CPW‐fed metasurface antenna for SAR‐based portable imaging system

In this paper, we propose a small-sized self-oscillating active antenna directly integrated microwave FET oscillator operating in C-band. A bended monopole lies over a truncated ground plane. One of ends directly connects to drain terminal of FET, other connects to gate terminal via weak-coupling gap. It forms a feedback loop circuit approximately. Characteristics of passive antenna and oscillator have been obtained using simulators. The proposed active antenna operates at 5.05 GHz. The passive antenna has end-fire radiating direction and 2.31 dBi realized gain. The output power spectrum shows that fundamental frequency has 10.1dBm power level.

2017 IEEE International Symposium on Antennas and Propagation & USNC/URSI National Radio Science Meeting

In this paper, a compact wideband coupler is designed and fabricated between S-Band and C-Band. And a single-antenna radar transceiver utilizing this coupler is proposed. The advantages of the coupler are wideband, compact size, ease of integration and good isolation. Measured and simulated results show that the bandwidth of the coupler is 95% (2.5 to 7.2 GHz) when the port connected to transmitter is excited, and 98% (2.5 to 7.3 GHz) when the port connected to antenna is excited. Also, isolation is more than 20dB over the operating frequencies.

2017 Sixth Asia-Pacific Conference on Antennas and Propagation (APCAP)

In this paper, a compact two-dimensional multi-beam antenna fed by two-layer SIW Butler matrix is designed at 30 GHz. This multibeam antenna can generate four beams in two planes. The simulation results demonstrate that the beam directions are (30°, 35°), (115°, 20°), (−75°, 25°), and (−135°, 40°), respectively. The gains for each beam are almost 9 dBi. This multibeam antenna takes the advantages of low loss, cost effective, compact size and ease of integration, which can be applied in 5G communication systems.

A compact two-dimensional multibeam antenna fed by two-layer SIW butler matrix

In this paper, we introduced an antenna concept based on an unmatched coupling element with a tunable matching network for LTE mobile application. The combination of impedance tuning with intrinsically unmatched antennas can reduce the antenna size to about 400 mm3 (about a quarter size of the traditional LTE antenna design) to support multiband, small volume and slim design.

2016 IEEE International Symposium on Antennas and Propagation (APSURSI)

A compact tunable capacitive coupling element antenna for LTE mobile application

In this paper, the study of the mm-Wave phased array in mobile terminal for the fifth generation (5G) mobile communication system is proposed. The design methodologies are presented based on the concept of coupled oscillator arrays, making the phased array without the need of conventional phase shifter and complex feeding network. The operating band of the proposed phased array is in 21 GHz-22 GHz, which is one of the candidate bands for 5G cellular. The design of tunable coupling networks can achieve the desired scanning beam by tuning the phase gradient states of adjacent oscillator elements. The overall array is low cost and low profile, which is suitable for 5G mobile system.

Design of mm-wave phased array in mobile terminal for 5G mobile system

In this paper, we introduced a mobile phone closed loop WAN antenna system with tunable RF circuits and automatic S11 calculation algorithm that can dynamically optimize antenna return loss to reduce the head and hand user effects on the antenna impedance matching. Measured antenna S11 indicates that antenna resonance can shift back to original frequency even it is detuned for over 150 MHz at 900 band.

A closed loop WAN antenna to reduce head and hand effects for mobile phone applications

A numerical approach for the evaluation of the double integrals that arise in the analysis of printed circuit antennas is developed. In this method, the integration variables in the integrals are transferred to the polar coordinate system (λ, θ). The approach focuses on the fact that the oscillating frequency of the integrand in the azimuth direction θ is nearly proportional to the radius A. An adaptive scheme to increase sampling points in the θ direction is therefore introduced. Numerical results show that the sampling points can be reduced by 50%. © 1994 John Wiley & Sons, Inc.

An efficient approach for the evaluation of the double integrals in the analysis of printed circuit antennas

A symmetrical coplanar waveguide with finite ground plane (SCPW) has been analyzed. The symmetrical configuration is obtained by simply placing a dielectric substrate above a conventional finite ground plane coplanar waveguide (FCPW). The conformal mapping method is used to calculate the quasistatic effective permittivity ϵeff and characteristic impedance Z0. The SCPW has a larger ϵeff and a smaller Z0, compared with the conventional FCPW. This configuration should be useful for the design of balanced mixer circuits and for applications to the design of balanced feed lines in printed antennas. © 1993 John Wiley & sons, Inc.

A coplanar waveguide antenna (CWA) is proposed and investigated experimentally. The CWA consists of an open coplanar waveguide circuit and is fed by a coplanar waveguide with a characteristic impedance of 50 Ω. The measured return loss shows that the radiation mainly comes from the slot surrounding the open coplanar waveguide circuit. The area of the CWA is about 1/8 that of the corresponding microstrip antenna. © 1993 John Wiley & sons, Inc.

A compact slot loop antenna is proposed and investigated experimentally. The antenna consists of a slot loop printed on a substrate, and is fed by a coaxial cable. The loop perimeter is about λ/2 and the area of the antenna is about 1/8 of that of a microstrip antenna with the same operating frequency. The operating bandwidth (defined by return loss less than or equal to -10 dB) of the antenna is quite large (22%). The gain is comparable with that of a λ/2 dipole. The antenna should find wide applications in TV reception, mobile communications, and satellite communications. © 1993 John Wiley & sons, Inc.

A new type of printed polygonal loop antenna (PPLA) has been devised by the authors. In the paper, analytical results of the new PPLA by the spectral domain method are shown, and two-dimensional current distribution on the printed circuit is obtained. The current distribution reveals that the new PPLA behaves like a slot antenna, unlike a conventional microstrip patch antenna. The radiation patterns and the input impedances are calculated from the current distribution. The results of numerical analysis agree very well with empirical results.

A new type of low-profile antenna arrangement is introduced for producing an omnidirectional conical pattern of circularly polarised radiation, and named the combined polygonal loop antenna (CPLA). The maximum gain of 4dBi is obtained at about 40 degrees off broadside, where cross-pol discrimination is more than 10 dB. Over a frequency range of 16% the radiation pattern remains almost unchanged and the input VSWR is lower than 20.

Combined polygonal loop antenna with circularly polarised conical pattern

In this study we investigated the role and mechanism of cardamonin on IL-1β induced injury in OA. CHON-001 cells were treated with cardamonin and IL-1β and transfected with silencing nuclear factor erythroid 2-related factor 2 (siNrf2). Cell viability was detected by Cell Counting Kit-8 assay and flow cytometer assay was utilized for cell apoptosis assessment. IL-6, IL-8, TNF-α and Nrf2 mRNA expression was tested by qRT-PCR. Western blot was employed to evaluate MMP-3, MMP-13, Collagen II, Nrf2, NQO-1, NLRP3, Caspase 1 and apoptosis-associated speck-like protein containing a caspase-1 recruitment domain (ASC) protein levels. In CHON-001 cells, IL-1β suppressed cell viability and Collagen II level while promoting cell apoptosis and expression of pro-inflammatory cytokines (IL-6, IL-8, TNF-α), MMPs (MMP-3, MMP-13), NQO-1, and NLRP3 inflammasome (NLRP3, Caspase 1 and ASC), with no significant influence on Nrf2. Cardamonin reversed the effect of IL-1β on cell viability, cell apoptosis, pro-inflammatory cytokines, MMPs, Collagen II, and NLRP3 inflammasome levels. In addition, cardamonin advanced Nrf2 and NQO-1 expression of CHON-001 cells. SiNrf2 reversed the function of cardamonin on IL-1β-induced cell apoptosis and expression of pro-inflammatory cytokines, Nrf2, NQO-1, and NLRP3 inflammasome in chondrocytes. Taken together Cardamonin inhibited IL-1β induced injury by inhibition of NLRP3 inflammasome via activating Nrf2/NQO1 signaling pathway in chondrocyte.

Cardamonin Inhibited IL-1β Induced Injury by Inhibition of NLRP3 Inflammasome via Activating Nrf2/NQO-1 Signaling Pathway in Chondrocyte

Neuroendocrine tumors of the ovary are uncommon malignant carcinomas with a poor prognosis. There are no standardized management guidelines because of lack of knowledge about these tumors. The objective of this study is to analyze the clinical manifestations, diagnosis and treatment of ovarian neuroendocrine tumors (ONETs).
Results

Median age at diagnosis was 38.4 years (range 20–58). The main clinical presentations were abdominal pain or a pelvic mass. Two patients underwent fertility-sparing surgery and the others underwent cytoreductive surgery. The finial diagnosis depended on postoperative histopathology. According to the staging standard of the International Federation of Gynecology and Obstetrics (FIGO), three patients had stage I disease, one stage II, and six patients had stage III disease. Eight patients received chemotherapy alone postoperatively, one was maintained with Olaparib after chemotherapy, and one received chemotherapy followed by radiotherapy. The follow-up time for patients raged from 10 to 48 months. One patient died, while the other 9 patients were in follow-up. Seven patients experienced tumor recurrence.

Ovarian neuroendocrine tumors are characterized by high malignancy, low incidence and poor prognosis. Histopathological analysis is considered the gold standard for diagnosis. Surgical resection may be the first choice of therapy, and adjuvant chemotherapy and possible radiotherapy may prolong the survival of some patients.

Systematic retrospective analysis of 10 cases of neuroendocrine tumors of the ovary: diagnosis, treatment and follow-up

 Background: Ovarian neuroendocrine tumors (O-NETs) are uncommon malignant carcinomas with a poor prognosis. There are no standardized practice guidelines as impacted by the lack of sufficient data regarding the clinicopathologic features and management of O-NETs. This study aimed to analyze the clinical manifestations, diagnosis and treatment of O-NETs.Methods: We retrospectively analyzed ten cases with ONETs admitted to the Department of Gynecology of the First Affiliated Hospital of Zhengzhou University from August, 2015 to May, 2020.Results: The median age of cases at diagnosis was 38.4 years (from 20 to 58). The most common presentation was abdominal pain (4/10), followed by pelvic mass (3/10), and vaginal bleeding (1/10). Two cases had no symptoms. All cases underwent the surgery. The diagnosis was confirmed by the postoperative histopathology. Tumors expressed at least one neuroendocrine marker (e.g., CD56, chromogranin-A, synaptophysin, or neuron specific enolase). By complying with the International Federation of Gynecology and Obstetrics (FIGO) staging system (2014), three cases were stage I tumors, one case was stage II tumor, and six cases were stage III tumors. Eight cases only received chemotherapy postoperatively, one was administrated with olaparib maintenance after chemotherapy, and one received the chemotherapy followed by the radiotherapy. The follow-up time for cases raged from 10 to 48 months. Two cases died of disease recurrence, while the other 8 cases were in the follow-up. Six cases experienced tumor recurrence.Conclusion: O-NETs were characterized by high malignancy, low incidence and poor prognosis. The histopathological analysis was considered the gold standard for diagnosis. Surgical resection might be the first choice of therapy, and adjuvant chemotherapy and possible radiotherapy might prolong the survival of some cases.

A non-classical calpain, calpain 6 (CAPN6), can inhibit skeletal muscle differentiation and regeneration. In the present study, the role of CAPN6 in the regulation of the autophagy of myoblasts in vitro was investigated. The underlying molecular events and the CAPN6 level in atrophic skeletal muscle in a rat model of chronic kidney disease (CKD) were also investigated. In vitro, CAPN6 was overexpressed, or knocked down, in rat L6 myoblasts to assess autophagy and related gene expression and co-localization. Subsequently, myoblasts were treated with a mixture of cytokines, and relative gene expression and autophagy were assessed. A rat model of CKD for muscle atrophy was established, and blood chemical level and the expression of CAPN6 in muscle were assessed. The data revealed that the knockdown of CAPN6 in rat myoblasts resulted in increased microtubule-associated protein 1 light chain 3 (LC3) levels, while its overexpression decreased LC3 levels and impaired autophagy. Additionally, it was observed that the co-localization of mammalian target of rapamycin (mTOR) and lysosomal-associated membrane protein 1 (LAMP1), a lysosomal marker, proteins was increased. In addition, mTOR, Raptor and α-tubulin (a marker of microtubules) increased in the CAPN6 overexpression group. However, inflammatory cytokines, such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (INF)-γ and lipopolysaccharides upregulated CAPN6 expression, inhibited L6 myoblast autophagy and stabilized mTOR activity. Furthermore, the animal model successfully mimicked human disease as regards an increase in body weight, and a reduction in muscle mass, cross-sectional area and blood biomarker concentrations; a slight increase in CAPN6 mRNA and protein levels in muscles was observed. Finally, the data of the present study suggested that CAPN6 reduced autophagy via the maintenance of mTOR signaling, which may play a role in CKD-related muscle atrophy. However, future studies are required to determine whether CAPN6 may be used as an intervention target for CKD-related skeletal muscle atrophy.

Calpain 6 inhibits autophagy in inflammatory environments: A preliminary study on myoblasts and a chronic kidney disease rat model

The current study was designed to seek the role of the glycogen synthase kinase-3β (GSK-β)-regulated NF-E2-related factor 2 (Nrf2) pathway in the antioxidant effect induced by Apigenin-7-O-β-D-(-6”-p-coumaroyl)-glucopyranoside (APG). Rat primary cultured cortical neurons were challenged by oxygen and glucose deprivation/reoxygenation (OGD/R) and then treated with APG. Cell viability, phosphorylation of GSK-β at Ser9 and nuclear expression of Nrf2 were measured. Male Sprague Dawley rats challenged by 2-h middle cerebral artery occlusion were treated with 50 mg/kg APG, and the neurological score, infarct volume, phosphorylation of GSK-3β and nuclear expression of Nrf2 were analyzed. The neuroprotective effect of APG and the expression levels of antioxidant enzymes and oxidative products were also examined in the presence and absence of Nrf2-siRNA and PI3K inhibitors. APG reduced the apoptotic proportion, attenuated LDH release and increased cell viability, and in vivo, APG improved neurological scores and reduced infarct volume. APG increased GSK-3β phosphorylation and Nrf2 nuclear translocation, while these effects were prevented by PI3K inhibitors or Nrf2-siRNA treatment in both OGD/R cell cultures and ischemic/reperfusion rats. These findings reveal that GSK-3β phosphorylation-mediated Nrf2 activation is involved in the neuroprotective effect of APG.

Apigenin-7-O-β-D-(-6”-p-coumaroyl)-glucopyranoside treatment elicits a neuroprotective effect through GSK-3β phosphorylation-mediated Nrf2 activation

CKD autophagy activation and skeletal muscle atrophy—a preliminary study of mitophagy and inflammation

This communication proposes a low-profile dual-band circularly polarized (CP) antenna for satellite communication at K and Ka-bands. The antenna consists of a folded transmitarray (TA) operating at 20 GHz and a multi-feed reflectarray (RA) operating at 30 GHz. The dual split rings are used as the TA and RA elements. The TA is placed above the RA. The TA acts as the phase-controlling surface at 20 GHz and does not affect the transmission of plane waves at 30 GHz generated by the RA. The RA simultaneously serves as the phase-controlling surface at 30 GHz and as the ground for the folded TA at 20 GHz. Owing to the combination of the folded TA and multi-feed RA with a small focal length-to-diameter ratio, the antenna profile is reduced, and the height-to-diameter ratio is only 0.4. Compared with the traditional horn feed system, the CP patch arrays integrated on the TA surface are used as the feeds in this design. The orthomode transducer (OMT) and circular polarizer are not needed, which significantly saves space and cost. The antenna was manufactured and measured to verify its performance. The measured results keep good consistent with the simulated results.

Low-Profile Dual-Band Circularly Polarized Antenna Combining Transmitarray and Reflectarray for Satellite Communications

In this article, a novel double‐layer wideband reflectarray antenna using polynomial optimization technology is proposed. The reflectarray element has two main variable parameters. When each of the variables is adjusted, the reflectarray element cannot achieve 360° phase shift. However, as the two variables work together, 360° phase shift is easy to be achieved. The polynomial technology is used to connect the two variables, and the differential evolution algorithm is adopted to optimize the element to obtain the appropriate polynomial coefficients. The phase shift curves of different frequencies are parallel to each other and the slopes of the phase shift curves are consistent, which makes the proposed element achieve wideband characteristics. In order to verify the correctness of the proposed design method and reflectarray element, a 441‐element reflectarray antenna was designed, processed, and measured. The proposed reflectarray antenna achieves 35% 1‐dB gain bandwidth. At 12 GHz, the gain and efficiency of the proposed reflectarray antenna are 29 dBi and 62% respectively. In the whole bandwidth, the sidelobe was less than –16 dB and the cross‐polarization was less than –38 dB. It is proved that polynomial automatic optimization technology can guide the design of the multi‐variable wideband reflectarray antenna.

Double‐layer wideband reflectarray using polynomial optimization technology

This article presents a dual‐band dual‐polarized transmitarray (TA) with independent control of polarization at each band. Five‐layer cross dipoles and rectangular patches are utilized to control the transmission characteristics at Ku (13.5 GHz) and K (22 GHz) bands, respectively. Cross loops are used to improve the independence between two bands and transmission response. The phases can be controlled independently at both bands because of the band independence of the element. The vertical polarization and horizontal polarization phases at each band can also be controlled independently because of the polarization independence of the element. A TA with the specific beam direction for each polarization at each band is designed to verify the characteristics of the element. The TA antenna is fabricated and measured. The simulated results are consistent with the experimental results.

Dual‐band dual‐polarized transmitarray with independent control of polarization at each band

This paper presents a double-layer, dual-band, orthogonally polarized, highly efficient transmitarray antenna (TA) operated in the Ku/K band (14 GHz/20 GHz) for millimeter wave (MMW) wireless communication systems (WCS). The proposed TA consists of two types of multi-resonant dipoles with metal vias, operating in the Ku and K bands. The Ku and K elements are interlaced with each other independently to ensure dual-band orthogonally polarized operation. The proposed double-layer elements obtained a 360° phase shift range with transmission amplitude greater than −2 dB. They also achieved independent phase responses in both bands by two orthogonally arranged elements. The proposed TA has been designed, manufactured and measured. The measurement results, which are consistent with simulation results, indicate that maximum gains of 25.2 and 27.4 dBi corresponding to aperture efficiencies of 55% and 49% are obtained at 13.75 and 20 GHz, respectively. Moreover, 1-dB gain bandwidths of 10% and 6% are also achieved in the Ku and K frequency bands, respectively. Therefore, the proposed double-layer Ku/K dual-band TA with high efficiency and simple design is a good candidate for MMW WCS.

Double-Layer Ku/K Dual-Band Orthogonally Polarized High-Efficiency Transmitarray Antenna

This letter presents a double-layer 45° linearly polarized (LP) wideband and highly efficient transmitarray antenna (TA). The proposed element is composed of two multi-resonant dipoles and four metal vias. The dipoles are placed on the diagonal of the unit cell and printed on both sides of the dielectric substrate. The metal vias which penetrate the substrate and connect the upper and lower dipoles are used to improve the transmission efficiency and obtain the large phase shift range of the proposed element. The proposed element realizes a full 360° phase shift range with a smooth slope in the band, and the magnitude loss is less than 1.5 dB at 20 GHz. The proposed TA is designed, manufactured, and measured. The measurement and simulation results are consistent. Measurement results indicate that the proposed TA has a maximum gain of 26.9 dBi at 20 GHz and an aperture efficiency of 53.5% with a 1 dB gain bandwidth of 12% (18.8–21.2 GHz). The proposed double-layer 45° LP TA shows enhanced bandwidth and simple design. Using a double-layer structure opens possibilities for TA design.

Double-Layer 45° Linearly Polarized Wideband and Highly Efficient Transmitarray Antenna

A reflect-transmit-array antenna (RTA) with dual-operating modes is proposed in this letter. The proposed RTA, which has a three-layer structure without air layers, can achieve a reflectarray-mode (RAM) at 11–14 GHz and a transmitarray-mode (TAM) at 15–19 GHz. When the incident electromagnetic (EM) wave is y-polarization, the RTA operates at RAM, and the reflected EM wave is y-polarization. In comparison, the RTA operates at TAM and the transmitted EM wave is circular polarization (CP) when the incident EM wave is x-polarization. The dual-mode wideband RTA has been fabricated and measured to validate the design. The measured results indicate that 1 dB bandwidth of 15.7% (11.7–13.7 GHz) can be achieved in RAM and that the maximum aperture efficiency is 63% at 12.4 GHz. Furthermore, 1 dB bandwidth of 17.6% (15.5–18.5 GHz) can be achieved in TAM, and the axial ratio (AR) is less than 2.3 dB within the operating band. Our findings prove a RTA, which can produce different polarizations linear polarization and CP radiation at different modes with a simple architecture without an air layer.

Dual-Band Wideband Reflect-Transmit-Array With Different Polarizations Using Three-Layer Elements

In this communication, a single‐layer ultra‐wideband element composed of quasi‐spiral dipole is proposed. For the symmetry of the element structure, the element has the same phase response for horizontal, vertical, and circular polarization so that the reflectarray can achieve corresponding polarization if a feed with linear or circular polarization illuminates the reflectarray. For the structure of the quasi‐spiral dipole element, 360° linear phase shift in a wide band (9‐19GHz) is achieved in a small space and it can expand the bandwidth through the sub‐wavelength structure. Compared to the traditional two‐degree‐of‐freedom element, the element can achieve a 360° phase shift in a wide bandwidth and the phase curve is nearly parallel to each other. A 270 mm × 270 mm (27 × 27 elements) reflectarray is designed and fabricated based on the proposed elements. The simulation results almost agree with the measure results. The measured 1‐dB gain bandwidth about 44% (11.5‐18GHz) is achieved and 68% of aperture efficiency at 12GHz, which demonstrates wideband operation for the proposed reflectarray.

A single‐layer high‐efficiency ultra‐wideband reflectarray by using quasi‐spiral dipole

A multifunctional tri-band antenna combining transmitarray (TA) and reflectarray (RA) is presented in this communication. Five-layer patches etched on three dielectric substrates with two air gaps are used as the unit cell. Cross dipoles inserted in cross slots control transmission characteristics at <italic>Ku</italic>-band (14 GHz). Double square rings on the top and bottom layers control reflection characteristics at <inline-formula> <tex-math notation="LaTeX">${K}$ </tex-math></inline-formula> (21 GHz)- and <italic>Ka</italic> (30 GHz)-bands, respectively. The antenna has dual-polarized characteristics in each band. The phase shift range that can be obtained is 360° for 3 dB transmission magnitude at <italic>Ku</italic>-band and 0.15 dB reflection magnitude at <inline-formula> <tex-math notation="LaTeX">${K}$ </tex-math></inline-formula>- and <italic>Ka</italic>-bands. The tri-band dual-polarized TA/RA antenna is designed, manufactured, and measured to verify the performance. The simulated results keep consistent with the measured ones. The measured results show that the TA has a peak gain of 23.8 dBi with an aperture efficiency of 40% at 14.25 GHz and 1 dB gain bandwidth of 6.5%. The RA has a peak gain of 28 dBi with an aperture efficiency of 44% at 21 GHz and 1 dB gain bandwidth of 7.3%, and has a peak gain of 31.5 dBi with an aperture efficiency of 47% at 30.5 GHz and 1 dB gain bandwidth of 7.1%.

Multifunctional Tri-Band Dual-Polarized Antenna Combining Transmitarray and Reflectarray

A high-efficiency double-layer transmitarray (TA) operating at 14.25 GHz is proposed using low-loss dual-linearly polarized elements. Each element comprises only two layers of patches printed on a dielectric substrate and four vias. Cross dipoles and spiral dipoles with four L-shaped patches are used as the first and second unit cells, respectively. L-shaped patches are employed to increase the transmission magnitude. The phase shift range is 360° for a transmission magnitude of −1 dB. A square TA composed of 400 elements is designed, manufactured, and tested to verify the design. The simulated results are consistent with the experimental results. The experimental results show that the TA has a gain of 29.18 dBi at 14.25 GHz, an aperture efficiency of 60.3%, and a 1 dB gain bandwidth of 6.8%.

A High-Efficiency Double-Layer Transmitarray Antenna Using Low-Loss Dual-Linearly Polarized Elements

A hat‐fed reflector antenna with large radius of ring‐shaped phase center (RSPC) is reported in this article. First, a new phase efficiency calculation model (PECM) based on new phase reference point is presented, which can accurately calculate the phase efficiency of a hat‐fed with arbitrary radius of RSPC. Second, based on the invented PECM, the hat‐fed can be optimized by using cosimulation method of HFSS and MATLAB, high aperture efficiencies are achieved in the whole band. To prove the validity of the new PECM, a hat‐fed reflector antenna with large radius of RSPC is designed, manufactured, and measured. The measured results are in good agreement with the simulations. The results show that the developed hat‐fed reflector antenna has achieved a VSWR of less than 1.18, the peak realized gain of 43.5 dBi and an aperture efficiency of higher than 67.4% in the entire band from 12.25 to 14.5 GHz.

A new phase efficiency calculation model for optimization of a hat‐fed reflector antenna with arbitrary radius of ring‐shaped phase center

A broadband double‐layer transmissive metasurface (TMS) for effective generate vortex electromagnetic wave is presented in this paper. The proposed TMS consists of two types of elements. The first element is composed of a multi‐resonant dipole and four metal vias. The metal vias increase the coupling strength between the upper and lower layers to improve transmission efficiency. On the basis of the first element, the second element adds stubs to ensure sufficient phase shift. The far‐field cross polarisation is eliminated by special element arrangement. Then, a centre‐fed linear polarisation TMS is designed to generate orbital angular momentum beams with mode l = −1. The proposed TMS is designed, manufactured and measured to verify the proposed design. The measured results indicate that a maximum gain of 20.8 dBi and narrow divergence angle of ±5° are achieved at 18 GHz. Furthermore, mode purity is higher than 86.1% within the 17 to 19 GHz band. The proposed double‐layer TMS saved costs, reduced weight and without assembly error is a good candidate for OAM generator.

An efficient method of generating vortex electromagnetic wave based on double‐layer transmissive metasurface

This paper presents a two-dimensional low-profile Luneburg lens that is designed by using a glide-symmetric metasurface. The entire lens consists of two mirrored metal plates with periodic metal pins, and the pins on one plate are glided exactly a half period of the unit cell compared with the pins on the other plate. The proposed design has not only a stable refractive index over a wide operating band but also no dielectric loss compared to other metamaterial-based lenses. In addition, it is easy to manufacture and can also largely reduce the production cost. The complete Luneburg lens is simulated in CST Microwave Studio, and the results demonstrate that the lens can work within 14 GHz–22 GHz, which is greater than 44% of the bandwidth. The measured results show that the lens also agrees well with the simulated lens. This lens antenna would be an excellent candidate for satellite communication applications.

Wideband Low-Profile Luneburg Lens Based on a Glide-Symmetric Metasurface

This paper presents a dual band/dual polarization compact feed chain for Satellite Communication Applications. The system operates in receiving and transmitting k/ka band with polarization diversity, achieving the right-and left-hand circular polarization in each band. The chain consists an OMJ, four low-pass filters, a turnstile power divider, two septum polarizers, and a corrugated horn. Over the whole Rx and Tx bands, the return loss is less than -30dB. Axial ratio on axis is below 0.35 dB. Between Rx and Tx ports, isolation is higher than 100 dB in both bands. The port-port isolation is higher than 18 dB.

A Dual Band/Dual Polarization Compact Feed Chain for Satellite Communication Applications

A ku dual-band hat-fed reflector antenna is presented in this paper. Firstly, a new phase efficiency calculation model is employed for calculating phase efficiency of hat-fed accurately. By that method, accurate results can be obtained compared with former works. Secondly, the model of the hat feed is established by ANSOFT HFSS. Based on GA algorithms, a satisfying efficiency of the hat feed for reflector is obtained. Then, the OMT is designed. Finally, a ku dual-band hat-fed reflector antenna is proposed. The simulated results show that the proposed hat fed reflector antenna has a VSWR of less than 1.23 and an aperture efficiency of higher than 70% in the lower band (12.25-12.75GHz) and a VSWR of less than 1.16 and an aperture efficiency of higher than 71.2% in the higher band(14-14.5GHz).

In this paper, a planar substrate integrated waveguide mono-pulse slot array antenna is presented. The $\pmb{8\times 8}$ slot array antenna and the sum-difference comparator are designed on separated layers which takes the advantage of low profile and high aperture efficiency. The round corners are adopted to design the feeding network. The maximum gain of sum pattern at 10 GHz is around 22.1dB with side lobe suppression of -14 dB in both E-plane and H-plane. This proposed antenna presents a good candidate for the directional-finding systems which are restricted by profile.

2018 International Conference on Microwave and Millimeter Wave Technology (ICMMT)

A Planar Substrate Integrated Waveguide Mono-Pulse H-Shaped Slot Array Antenna

A novel compact micro-strip mono-pulse antenna array is proposed. The antenna unit use L-shaped coupling feed. Then a $\mathbf{4 \times 4}$ planar circularly polarized planar mono-pulse antenna array is made up. A broadband feeding network which is composed of the sum-difference network and four power dividers is designed. The simulation results show that a gain peak value of 19dBic and51.9% of efficiency at 2.2G Hz have been obtained, the 3 dB axial-ratio bandwidth can reach 36% (2.05-2.75GHz), and the impedance bandwidth of the antenna is reach 45% (1.75GHz-2.75GHz), respectively. It fully shows that the two antenna arrays have high gain, wide bandwidth and circular polarization, which proves the validity of the design method.

A Novel Broadband Low-Profile Planar Circularly Polarized Micro-Strip Mono-Pulse Antenna Array

hMOF induces cisplatin resistance of ovarian cancer by regulating the stability and expression of MDM2

 BackgroundPrevious research revealed that ETS Proto-Oncogene 1, Transcription Factor (ETS1) might be useful in cancer immunotherapy. However, the processes underlying its therapeutic potential have yet to be thoroughly investigated. The goal of this work was to look into the association between ETS1 expression and immunity and depict its prognostic landscape in pan-cancer. MethodsThe TCGA provides raw data on 33 different types of cancer. GEO gave GSE67501, GSE78220, and IMvigor210. In addition, we looked at ETS1's genetic changes, expression patterns, and survival studies. The researchers investigated the links between ETS1 and the TME and its linkage to immunological processes/elements and the major histocompatibility complex better to understand the importance of ETS1 in cancer immunotherapy. Meanwhile, three distinct immunotherapeutic cohorts were employed to study the relationship between ETS1 and immunotherapeutic response. Finally, PPI analysis and functional gene enrichment were performed using GSEA. ResultsETS1 expression was shown to be higher in tumor tissue on average. Elevated ETS1 expression has been connected to a worse clinical outcome in patients with OS. ETS1 has been linked to immune cell infiltration, immunological modulators, and immunotherapeutic markers. Furthermore, increased ETS1 expression has been connected to immune-related pathways. However, there was no statistically significant link found between ETS1 and immunotherapeutic response. ConclusionsETS1 might be a biomarker for immune infiltration and poor cancer prognosis. It is possible that treatment targets should be researched further.

An Integrative Pan-Cancer Analysis Revealing ETS1 as an Oncogenic Immune Protein in Tumor Microenvironment

Statement of Retraction We, the Editors and Publisher of the journal Cell Cycle, have retracted the following article: Mingbo Cai, Zhenhua Hu, Liping Han, and Ruixia Guo. MicroRNA-572/hMOF/Sirt6 regulates the progression of ovarian cancer. Cell Cycle. 2020;19(19):2509-2518. doi: 10.1080/15384101.2020.1809258. Since publication, concerns have been raised about the integrity of the data in the article. When approached for an explanation, the authors have been unable to provide their original data and any further supporting information. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article. The authors agree with the retraction. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

RETRACTED ARTICLE: MicroRNA-572/hMOF/Sirt6 regulates the progression of ovarian cancer

ABSTRACT Autophagy, characterized by the elevator of autophagy-related gene 14 (ATG14) and the dysregulation of autophagy-related proteins, contributes to the cisplatin (DDP) resistance in ovarian cancer. Forkhead box protein P1 (FOXP1), which is a well-defined transcription factor, is reported to have the oncogenic effect on ovarian cancer. This study aims to identify the effect of miR-29c-3p/FOXP1/ATG14 pathway in regulating autophagy and DDP resistance in ovarian cancer. The expressions of miR-29c-3p, FOXP1, ATG14 and autophagy-related proteins were detected in DDP-sensitive ovarian cancer cell lines (SKOV3 and A2780) and DDP-resistant cell lines (SKOV3/DDP and A2780/DDP). Cell viability was detected using the MTT assay. The therapeutic effect of miR-29c-3p overexpression was observed in the xenograft model of nude mice.Compared with DDP-sensitive cells, miR-29c-3p was decreased in DDP-resistant cells, and an enhancement of FOXP1, ATG14, autophagy, and drug resistance was shown in DDP-resistant cells. The anti-resistant effect of miR-29c-3p was observed as overexpressing miR-29c-3p inhibited cell viability of DDP-resistant cells. Moreover, FOXP1 was a target of miR-29c-3p, which was confirmed by the luciferase reporter assay, and ATG14 was transactivated by FOXP1, which was confirmed by the ChIP assay. Overexpression of miR-29c-3p increased DDP sensitivity by downregulating FOXP1/ATG14 in vitro. The tumor volume was reduced after the injection of miR-29c-3p-overexpressing SKOV3/DDP cells in vivo. Overexpression of miR-29c-3p inhibited autophagy and DDP resistance partly via downregulating FOXP1/ATG14 pathway, suggesting miR-29c-3p as a novel target in overcoming DDP resistance in ovarian cancer.

miR-29c-3p inhibits autophagy and cisplatin resistance in ovarian cancer by regulating FOXP1/ATG14 pathway

LncRNA H19 over-expression inhibited Th17 cell differentiation to relieve endometriosis through miR-342-3p/IER3 pathway

LncRNA GAS5 confers the radio sensitivity of cervical cancer cells via regulating miR-106b/IER3 axis.

Platelet-activating factor receptor (PAFR) promotes tumorigenesis, angiogenesis and metastasis. Here, we defined the PAFR as a yielding new inhibiting target to selectively enhance the sensitivity of prostate cancer (PCa) cells to radiation. The selective responding to PAFR inhibiter may be caused by the differential expression pattern of PAFR in PCa cells. In this study, we also determined PAFR as a molecular basis by which the radiation induces autophagy suppression independent of activating mTOR pathway. PAFR can bind to the autophagy-indispensable protein Beclin 1, leading to the disability in its serine phosphorylation. The PAFR antagonist Ginkgolide B (GB) can sensitize radiotherapy by disrupting the formation of PAFR/Beclin 1 complex in PC3 and LNCaP cells, which have elevated PAFR expression after radiation exposure. Most importantly, GB efficiently radiosensitized PC3 and LNCaP tumor xenografts in vivo, and significantly reduced tumor burden. Overall, our results elucidated a significant role of GB in selectively improving the outcomes of PCa receiving radiation therapy.

PAFR selectively mediates radioresistance and irradiation-induced autophagy suppression in prostate cancer cells

As a tumor-associated carbohydrate antigen, elevated expression of Lewis y promotes the malignant behaviors of tumor cells. Although our preliminary study showed that the increased expression of Lewis y antigen decreased the expression of cell cycle inhibitor protein p27, the relevant mechanism remains unclear. Autophagy and the ubiquitin-proteasome system are two main ways of intracellular protein degradation, whose abnormal activities are closely associated with progression of malignant tumors. In our present study, we constructed two stable transfected cell lines with high expression of Lewis y antigen, named CAOV3-FUT1 and SKOV3-FUT1. We showed that the proportion of cells at S phase was significantly increased after FUT1 transfection, whereas p27 protein was obviously decreased. The autophagy activity, the levels of ubiquitination, and chymotrypsin-like protease activity were increased remarkably in the transfected cells. Interestingly, Lewis y antigen promoted the degradation of p27 by increasing ubiquitin-proteasome activity. In the vivo studies, Lewis y antigen improved the tumorigenic ability of ovarian cancer cells in nude mice and reduced the expression of p27. These findings suggested that Lewis y antigen activated both the autophagy and ubiquitin-proteasome activity and promoted the degradation of p27 through the ubiquitin-proteasome pathway.

Lewis y antigen promotes p27 degradation by regulating ubiquitin-proteasome activity

Objective To study the structural relationship between annexin A4 and the Lewis y antigen and compare their expression and significance in ovarian clear cell carcinoma, and to explore how annexin A4 fucose glycosylation effects the interaction between annexin A4 and NF-kB p50, and how it promotes tumour progression of ovarian clear cell carcinoma. Methods Structural relationships between annexin A4 and Lewis y antigen were detected using immunoprecipitation. Annexin A4 and Lewis y antigen expression in various subtypes of ovarian cancer tissues was detected by immunohistochemistry, and the relation between their expression was examined. Any interactions between annexin A4 and NF-kB p50 in ovarian clear cell carcinoma were detected by co-immunoprecipitation. Then looked for changes in expression of Lewis y antigen, annexin A4, NF-kB p50 and a number of downstream related molecules before and after transfection annexin A4 or FUT1, and also analyzed changes in biological processes. Results Lewis y antigen is a part of annexin A4 structure. The expression rate of both annexin A4 and Lewis y antigen was significantly higher in ovarian clear cell carcinoma than in other subtypes of epithelial ovarian cancer, and are associated with the clinical stages, chemotherapy resistance and poor prognostic. The interaction between annexin A4 and NF-kB p50 promoted cell proliferation, adhesion, invasion, metastasis ability and autophagy, and inhibits apoptosis, Lewis y enhanced this interaction. Conclusion Annexin A4 contains Lewis y structure, Lewis y antigen modification of annexin A4 enhances its interaction with NF-kB p50, which promotes ovarian clear cell carcinoma malignancy progression.

Annexin A4 fucosylation enhances its interaction with the NF-kB p50 and promotes tumor progression of ovarian clear cell carcinoma

Autophagy is modulated by multiple factors including CD147, but little is know about the effects and mechanism by which the modification of CD147 by Lewis y antigen regulates autophagy of ovarian cancer cell. Here, we reported that Lewis y antigen can promote basic autophagy activity and restrain autophagic cell death in ovarian cancer cells. Furthermore, human whole genome expression profile microarrays and massage pathway analysis revealed that during early stages of autophagy in ovarian cancer cells with highly expressing Lewis y antigen, PI3K/Akt-mTOR activity was reduced, in contrast, the PI3K/Akt-mTOR signaling pathway was activated as the length of amino acid deprivation increased, which inhibited eIF4G2 expression, further decreased the transcription of autophagy-related genes, suppressed autophagic cell death. we also elaborated that co-regulates protein degradation in cells via the ubiquitin-proteasome system and the autophagy-lysosome pathway. These findings suggested that the modification of CD147 by Lewis y antigen enhanced the survival ability by promoting basic autophagy activity and restraining autophagic cell death in ovarian cancer, thus playing an important role in ovarian cancer malignant progression.

The fucosylated CD147 enhances the autophagy in epithelial ovarian cancer cells

Expression and clinical significance of annexin A2 and human epididymis protein 4 in endometrial carcinoma

Expression of FOXP1 in epithelial ovarian cancer (EOC) and its correlation with chemotherapy resistance and prognosis

The expression and correlation between the transcription factor FOXP1 and estrogen receptors in epithelial ovarian cancer.

Human MOF (hMOF) is a major acetylase of human H4K16 involved in the regulation of physiological and pathological processes. We investigated the expression of hMOF in different ovarian tissues and its correlation with ovarian cancer prognosis. Reverse transcription PCR and western blot analysis were used to detect hMOF mRNA and protein expression, respectively, in different ovarian tissues. Immunohistochemistry was also performed to detect hMOF expression in different ovarian tissues, including ovarian epithelial cancer, borderline tumor, benign tumor and normal ovarian tissues. In addition, the relationships between hMOF expression and clinicopathological ovarian cancer data were analyzed. The Cox proportional-hazards regression model was used to analyze the factors associated with ovarian cancer prognosis. To analyze the effects of hMOF expression on ovarian cancer prognosis, a survival curve was plotted from the follow-up data of 77 patients with ovarian cancer. Compared with normal ovarian tissues, hMOF mRNA and protein expression was significantly decreased in ovarian epithelial cancer tissues. The proportions of high hMOF expression in normal and benign ovarian epithelial tumor tissues, were much higher than those in ovarian epithelial cancer tissues. Furthermore, hMOF protein expression was closely associated with the ovarian cancer stage. The expression of hMOF protein was determined as an independent risk factor influencing ovarian cancer prognosis. Patients with high hMOF levels showed improved survival than those with low hMOF levels. hMOF mRNA and protein expression decreased in ovarian epithelial cancer, thus the hMOF protein potentially serves as a new clinical marker of ovarian cancer prognosis.

Expression of hMOF in different ovarian tissues and its effects on ovarian cancer prognosis.

Expression of CD147 and Lewis y antigen in ovarian cancer and their relationship to drug resistance

Beclin 1 is an autophagy-associated protein involved in apoptosis and drug resistance, as well as various malignancies. We investigated the expression of Beclin 1 protein in ovarian epithelial tissues and correlated it with the prognosis of ovarian cancer. Beclin 1 protein expression was determined using immunohistochemistry in 148 patients with ovarian epithelial cancer, 26 with ovarian borderline tumor, 25 with benign ovarian tumor, and 30 with normal ovarian tissue. The relationships between Beclin 1 protein expression and ovarian cancer pathological characteristics were analyzed. The risk factors for ovarian cancer prognosis were analyzed using Cox’s regression model. A survival curve was plotted from the follow-up data of 93 patients with ovarian cancer to analyze the effects of Beclin 1 expression on the prognosis of ovarian cancer. The positive rates of Beclin 1 were significantly higher in ovarian epithelial cancer (148) and borderline tumor (26) than in benign ovarian tumor (25) or normal ovarian tissue (30) (all p < 0.001). The surgical stage and Beclin 1 expression were both independent risk factors for ovarian cancer prognosis (both p < 0.05). Patients with high Beclin 1 levels showed better survival than those with low Beclin 1 levels (p = 0.009). Beclin 1 protein is upregulated in ovarian epithelial cancer and is a prognostic factor of ovarian cancer.

Beclin 1 Expression in Ovarian Tissues and Its Effects on Ovarian Cancer Prognosis

We propose a new principle for transfer learning, based on a straightforward intuition: if two domains are similar to each other, the model trained on one domain should also perform well on the other domain, and vice versa. To formalize this intuition, we define the performance gap as a measure of the discrepancy between the source and target domains. We derive generalization bounds for the instance weighting approach to transfer learning, showing that the performance gap can be viewed as an algorithm-dependent regularizer, which controls the model complexity. Our theoretical analysis provides new insight into transfer learning and motivates a set of general, principled rules for designing new instance weighting schemes for transfer learning. These rules lead to gapBoost, a novel and principled boosting approach for transfer learning. Our experimental evaluation on benchmark data sets shows that gapBoost significantly outperforms previous boosting-based transfer learning algorithms.

Transfer Learning via Minimizing the Performance Gap Between Domains

In spite of achieving revolutionary successes in machine learning, deep convolutional neural networks have been recently found to be vulnerable to adversarial attacks and difficult to generalize to novel test images with reasonably large geometric transformations. Inspired by a recent neuroscience discovery revealing that primate brain employs disentangled shape and appearance representations for object recognition, we propose a general disentangled deep autoencoding regularization framework that can be easily applied to any deep embedding based classification model for improving the robustness of deep neural networks. Our framework effectively learns disentangled appearance code and geometric code for robust image classification, which is the first disentangling based method defending against adversarial attacks and complementary to standard defense methods. Extensive experiments on several benchmark datasets show that, our proposed regularization framework leveraging disentangled embedding significantly outperforms traditional unregularized convolutional neural networks for image classification on robustness against adversarial attacks and generalization to novel test data.

Disentangled Deep Autoencoding Regularization for Robust Image Classification

A computer-vision based approach to co-register frames from egocentric video recordings

Realistic and complex decision tasks often allow for many possible solutions. How do we find the correct one? Introspection suggests a process of trying out solutions one after the other until success. However, such methodical serial testing may be too slow, especially in environments with noisy feedback. Alternatively, the underlying learning process may involve implicit reinforcement learning that learns about many possibilities in parallel. Here we designed a multi-dimensional probabilistic active-learning task tailored to study how people learn to solve such complex problems. Participants configured three-dimensional stimuli by selecting features for each dimension and received probabilistic reward feedback. We manipulated task complexity by changing how many feature dimensions were relevant to maximizing reward, as well as whether this information was provided to the participants. To investigate how participants learn the task, we examined models of serial hypothesis testing, feature-based reinforcement learning, and combinations of the two strategies. Model comparison revealed evidence for hypothesis testing that relies on reinforcement-learning when selecting what hypothesis to test. The extent to which participants engaged in hypothesis testing depended on the instructed task complexity: people tended to serially test hypotheses when instructed that there were fewer relevant dimensions, and relied more on gradual and parallel learning of feature values when the task was more complex. This demonstrates a strategic use of task information to balance the costs and benefits of the two methods of learning.

Humans combine value learning and hypothesis testing strategically in multi-dimensional probabilistic reward learning

Learning what is relevant for rewards via value-based serial hypothesis testing

Functional magnetic resonance imaging (fMRI) offers a rich source of data for studying the neural basis of cognition. Here, we describe the Brain Imaging Analysis Kit (BrainIAK), an open-source, free Python package that provides computationally optimized solutions to key problems in advanced fMRI analysis. A variety of techniques are presently included in BrainIAK: intersubject correlation (ISC) and intersubject functional connectivity (ISFC), functional alignment via the shared response model (SRM), full correlation matrix analysis (FCMA), a Bayesian version of representational similarity analysis (BRSA), event segmentation using hidden Markov models, topographic factor analysis (TFA), inverted encoding models (IEMs), an fMRI data simulator that uses noise characteristics from real data (fmrisim), and some emerging methods. These techniques have been optimized to leverage the efficiencies of high-performance compute (HPC) clusters, and the same code can be se amlessly transferred from a laptop to a cluster. For each of the aforementioned techniques, we describe the data analysis problem that the technique is meant to solve and how it solves that problem; we also include an example Jupyter notebook for each technique and an annotated bibliography of papers that have used and/or described that technique. In addition to the sections describing various analysis techniques in BrainIAK, we have included sections describing the future applications of BrainIAK to real-time fMRI, tutorials that we have developed and shared online to facilitate learning the techniques in BrainIAK, computational innovations in BrainIAK, and how to contribute to BrainIAK. We hope that this manuscript helps readers to understand how BrainIAK might be useful in their research.

Living in a world where any object bears features in many dimensions, it is crucial but also challenging for humans to figure out what dimensions are relevant for rewards. How do humans learn from trial and error to obtain rewards when multiple (or an unknown number of) dimensions need to be taken into account, and feedback is probabilistic? In this work, we designed a paradigm tailored to study such complex but naturalistic scenarios. In the experiment, participants configured threedimensional stimuli by selecting features for each dimension and received probabilistic feedbacks. Participants demonstrated learning, selecting more rewarding features over the course of a game. To investigate their learning process, we compared three classes of learning models: a Bayesian model, reinforcement learning models and serial hypothesis testing models, and found evidence supporting the latter. This suggests that when facing complex learning scenarios with a great number of possible rules, people tend to actively test one hypothesis at a time, as opposed to evaluating all the possibilities or learning values of all features incrementally.

Learning what is relevant for rewards via serial hypothesis testing

Background With advances in methods for collecting and analyzing fMRI data, there is a concurrent need to understand how to reliably evaluate and optimally use these methods. Simulations of fMRI data can aid in both the evaluation of complex designs and the analysis of data. New Method We present fmrisim, a new Python package for standardized, realistic simulation of fMRI data. This package is part of BrainIAK: a recently released open-source Python toolbox for advanced neuroimaging analyses. We describe how to use fmrisim to extract noise properties from real fMRI data and then create a synthetic dataset with matched noise properties and a user-specified signal. Results We validate the noise generated by fmrisim to show that it can approximate the noise properties of real data. We further show how fmrisim can help researchers find the optimal design in terms of power. Comparison with other methods fmrisim ports the functionality of other packages to the Python platform while extending what is available in order to make it seamless to simulate realistic fMRI data. Conclusions The fmrisim package holds promise for improving the design of fMRI experiments, which may facilitate both the pre-registration of such experiments as well as the analysis of fMRI data. Highlights fmrisim can simulate fMRI data matched to the noise properties of real fMRI. This can help researchers investigate the power of their fMRI designs. This also facilitates open science by making it easy to pre-register analysis pipelines.

Facilitating open-science with realistic fMRI simulation: validation and application

Functional magnetic resonance imaging (fMRI) is widely used to study brain circuitry in healthy controls and in psychiatry. A major problem of fMRI studies is motion, which affects the quality of images, is a major source of noise, and can confound data if, for example, the experimental groups move differently. Despite continual reminders to experimental subjects about keeping still, however, movement in the scanner remains a problem. The authors hypothesized that showing head movement during a scanning session may help subjects learn how to keep their head still. The authors scanned subjects and displayed in real time a plot of head movement that had three regions. The authors found, in a limited sample, that the improvements were marginal and inconsistent. Thus, they concluded that this strategy, even if likely to work for some people, is probably not sufficiently successful to be implemented at this time.

Real time functional MRI training to decrease motion in imaging studies: Lack of significant improvement.

Human Orbitofrontal Cortex Represents a Cognitive Map of State Space

A repeated stimulus is judged as briefer than a novel one. It has been suggested that this duration illusion is an example of a more general phenomenon-namely that a more expected stimulus is judged as briefer than a less expected one. To test this hypothesis, we manipulated high-level expectation through the probability of a stimulus sequence, through the regularity of the preceding stimuli in a sequence, or through whether a stimulus violates an overlearned sequence. We found that perceived duration is not reduced by these types of expectation. Repetition of stimuli, on the other hand, consistently reduces perceived duration across our experiments. In addition, the effect of stimulus repetition is constrained to the location of the repeated stimulus. Our findings suggest that estimates of subsecond duration are largely the result of low-level sensory processing.

Perceived duration is reduced by repetition but not by high-level expectation.

Perceived duration can be influenced by various properties of sensory stimuli. For example, visual stimuli of higher temporal frequency are perceived to last longer than those of lower temporal frequency. How does the brain form a representation of duration when each of two simultaneously presented stimuli influences perceived duration in different way? To answer this question, we investigated the perceived duration of a pair of dynamic visual stimuli of different temporal frequencies in comparison to that of a single visual stimulus of either low or high temporal frequency. We found that the duration representation of simultaneously occurring visual stimuli is best described by weighting the estimates of duration based on each individual stimulus. However, the weighting performance deviates from the prediction of statistically optimal integration. In addition, we provided a Bayesian account to explain a difference in the apparent sensitivity of the psychometric curves introduced by the order in which the two stimuli are displayed in a two-alternative forced-choice task.

Duration estimates within a modality are integrated sub-optimally

How is duration information from multiple sensory sources combined

When observers experience a constant delay between their motor actions and sensory feedback, their perception of the temporal order between actions and sensations adapt (Stetson et al., 2006). We present here a novel neural model that can explain temporal order judgments (TOJs) and their recalibration. Our model employs three ubiquitous features of neural systems: (1) information pooling, (2) opponent processing, and (3) synaptic scaling. Specifically, the model proposes that different populations of neurons encode different delays between motor-sensory events, the outputs of these populations feed into rivaling neural populations (encoding “before” and “after”), and the activity difference between these populations determines the perceptual judgment. As a consequence of synaptic scaling of input weights, motor acts which are consistently followed by delayed sensory feedback will cause the network to recalibrate its point of subjective simultaneity. The structure of our model raises the possibility that recalibration of TOJs is a temporal analog to the motion aftereffect (MAE). In other words, identical neural mechanisms may be used to make perceptual determinations about both space and time. Our model captures behavioral recalibration results for different numbers of adapting trials and different adapting delays. In line with predictions of the model, we additionally demonstrate that temporal recalibration can last through time, in analogy to storage of the MAE.

A Neural Model for Temporal Order Judgments and Their Active Recalibration: A Common Mechanism for Space and Time?

This article examines the uptake of social justice and climate change as focal issues among the largest U.S. environmental nonprofits. We use 2016 Internal Revenue Service (IRS) filings to identify 5,413 large environmental nonprofits of which 8% attend to issues of climate and 10% to issues of social justice. Larger organizations are more likely to attend to issues of climate change and social justice, as are groups founded more recently. Latent Dirichlet allocation (LDA) topic modeling of organizational mission statements and descriptions of major activities is used to assign groups to six distinct issue categories. Results highlight the divide between wildlife groups that are decidedly unlikely to attend to issues of either climate or justice, and the rest of the national environmental movement. Energy and natural resource groups, while strongly vested in climate issues, rarely attend to social justice. These findings have clear implications for climate and justice advocates seeking change in the environmental advocacy sector.

Characteristics of Large Environmental Nonprofits That Identify Climate Change and Social Justice as Focal Concerns

ABSTRACT Over the past four decades, criminal, as opposed to civil or administrative, prosecutions have assumed an increasingly visible role in US environmental law enforcement. There is little understanding about the types of acts and defendants criminally prosecuted for pollution offenses in the United States or the sanctions received. In this paper, a unique dataset on virtually all federal criminal prosecutions of pollution-related offenses between 1985 and 2010 is used to assess aggregate trends in characteristics of pollution violations, offenders, and sanctions. Prosecutions increase dramatically in number and diversity over time, drawing in increasing numbers of low-level offenders. An early emphasis on hazardous waste violations is now complemented by prosecution of a large variety of activities associated with pollution of land, water and air, especially activities that pose direct threats to human health. Although most serious criminal violations occur within formal-organizations, individual actors are increasingly held criminally responsible, particularly low-level employees, with a trend away from prosecuting top-executives and large corporations.

The criminalization of environmental harm: a study of the most serious environmental offenses prosecuted by the U.S. federal government, 1985-2010

ABSTRACT What accounts for the remarkable growth of environmental sciences and studies (ESS) in US higher education over the past 50 years? This paper focuses on institutional characteristics to explain this ‘long green wave’ of expansion. Drawing on data from 1345 US higher-education institutions from 1980–2010, we employ three-level hierarchical models to assess institutional and state-level factors associated with the presence of environmental studies and sciences. Findings indicate that environmental studies majors are most likely to be present at liberal arts schools and in states more inclined to adopting environmentally friendly policies, and less likely to exist at schools with large minority enrollments. Environmental sciences majors are less likely to be present at schools with large female enrollments. Two case studies of early adopters highlight the role of faculty, rather than student activists, as change-agents pushing for the development of ESS on college campuses in the 1960s and 70s.

Riding a long green wave: interdisciplinary environmental sciences and studies in higher education

Abstract:Public support for environmental protection has evinced declines in recent years that are widely attributed to growing antipathy among self-identified Republicans. Fractures in what was long considered broad and enduring support for the environment in the United States have called attention to the broader socio-political context in which individual opinion on the environment is formed, and especially the role of political parties and their leaders in shaping opinion. Empirical analyses of environmental support, however, remain strongly focused on individual-level correlates of support. We apply recent methodological advances in age-period-cohort models to scrutinize changes in Americans' willingness to pay more for environmental protection between 1973 and 2014. Analyses distinguish the importance of individual traits, such as political identification, from cohort and especially period-based fluctuations that result from changing economic and political conditions. Individual-level covariate results are reflective of previous research on environmental opinion (e.g., age is negatively and education positively associated with environmental support). We further find that political context across time periods matters as much as, and interacts with, individual political affiliation to influence support for the environment. Americans of all political stripes demonstrate decreases in support for environmental spending during Democratic presidential administrations and during difficult economic times. Declines during Democratic presidencies are especially pronounced among Republicans. Analyses also highlight parallels between the high levels of political polarization in environmental support found at the end of the Obama Presidency and the end of the Carter era.

Political Polarization and Long-Term Change in Public Support for Environmental Spending

Since Gamson's (1975) landmark study of social movement organizations, scholars have debated whether it is more advantageous to concentrate on a narrow or diverse set of issues. This paper recasts this debate in terms of organizational survival. Drawing on ideas from theories of category spanning and social movements, we argue that an organization that occupies a distinct niche conveys its purpose more effectively, which increases its chances of survival when compared to more diverse SMOs. Using a longitudinal dataset on environmental social movement organizations (ESMOs), we find organizations that span multiple and distant issue categories are significantly more likely to disband, compared to those with a more specialized focus. Other characteristics of ESMOs affect their survival rate in ways that are strikingly similar to for-profits and other types of nonprofits. Larger and more complex ESMOs benefit from economies of scale, while younger, less established organizations are more likely to perish.

THE RISK OF OCCUPYING A BROAD NICHE FOR ENVIRONMENTAL SOCIAL MOVEMENT ORGANIZATIONS*

This paper examines how threatening economic conditions and preexisting community resources facilitated the spread of Occupy Wall Street protest groups to more than 600 counties in the continental United States in 2011. Using a generalized linear mixed model, we find that economic threats and accessible resources are complementary facilitators of movement mobilization. But contrary to the expectations based on earlier media and scholarly accounts, the “disruptive threats” caused by the Great Recession failed to predict the formation of Occupy groups. Instead, groups were more likely to mobilize in counties that had the “positional threats” of relatively higher income inequality and relatively lower median incomes in comparison to state norms. However, the effect of positional economic threats was nuanced as counties with lower than average unemployment more likely had groups mobilized. In addition, resources continue to demonstrate empirical importance in explanations of social movement mobilization, as Occupy groups were more likely to form in counties with greater access to social-organizational and human resources. Combined, these findings suggest that scholars can strengthen their analyses by considering threats and resources as complementary facilitators of local protest mobilization and by focusing greater attention on how differing types of threats may influence the mobilization of social movements.

The Mobilizing Effects of Economic Threats and Resources on the Formation of Local Occupy Wall Street Protest Groups in 2011

Cohort replacement is one widely implicated, but seldom studied, mechanism of long-term change in public opinion toward environmental protection. A key difficulty in extant research has been empirically distinguishing cohort effects from those of age. Applying recent methodological advances in age–period–cohort models, we examine the disaggregated effects of age, time period, and birth cohort on changes in Americans’ support of federal spending for environmental protection between 1973 and 2016. Results suggest that cohort replacement provides little explanatory power. Instead, we find large age effects, with the young more likely to be pro-environmental in their views, and substantial changes across time periods (but not steady rising support). These results suggest that there is no inexorable march toward greater environmentalism as younger cohorts with greater environmental awareness replace older ones, and highlight the relative lack of explicit theorizing about the relationship between age and the environment.

It Is Not a Cohort Thing: Interrogating the Relationship Between Age, Cohort, and Support for the Environment

Since Gamson’s (1975) landmark study of social movement organizations, scholars have debated whether it is more advantageous to concentrate on a narrow or diverse set of issues. This paper recasts this debate in terms of organizational survival. Drawing on ideas from theories of category spanning and social movements, we argue that an organization that occupies a distinct niche conveys its purpose more effectively, which increases its chances of survival when compared to more diverse SMOs. Using a longitudinal dataset on environmental social movement organizations (ESMOs), we find organizations that span multiple and distant issue categories are significantly more likely to disband, compared to those with a more specialized focus. Other characteristics of ESMOs affect their survival rate in ways that are strikingly similar to for-profits and other types of non-profits. Larger and more complex ESMOs benefit from economies of scale, while younger, less established organizations are more likely to perish.

The Risk of Occupying a Broad Niche for Environmental Social Movement Organizations

The extent to which environmental sociology remains a fringe specialty or a leading area of research and practice within the larger discipline is frequently commented on, but rarely examined systematically. This paper assesses environmental sociology’s integration with the core of the discipline with an analysis of environmental publications in the US sociology’s most prestigious mainstream journals between 1970 and 2014. We draw on the theory of scientific intellectual movements (SIMs) to develop a coherent narrative of this integration process and develop testable hypotheses about its extent and timing. Findings indicate that environmental sociology has a growing presence in the top-tier US journals, especially after 1990, and that a unique core of knowledge, focused on the relationship between society and the physical environment has increasingly come to characterize the literature in environmental sociology. A key finding is that growing acceptance of the field by the sociological mainstream was critically facilitated by increased attention to core sociological concerns of stratification and inequality within environmental sociology literature. We also find that cross-national research and global environmental concerns receive notably increased attention in top disciplinary journals over the observation period, especially after the 1992 Rio Earth Summit.

The US environmental movement of the 1960s and 1970s : Building frameworks of sustainability

The current environmental problems are continuously getting worse, and as structural and societal change demand a relatively large time period to prove successful, the need for the individual to engage in pro-environmental behavior is as crucial as it is important. In this study we sought to appeal to individuals’ environmental concerns by using two different framings of an environmental cause in an attempt to persuade them to engage in monetary donation, and as such, engage in pro-environmental behavior. We detected that a framing appealing to one value orientation of environmental concern generated more donations as compared to a framing that appealed to all value orientations (egoistic, altruistic, and biospheric). We discuss and interpret these results, as well as suggest further research improvements. (Less)

Me, You and Nature Vs Nature - how do two different framings affect donations to an environmental cause?

Abstract 
We know a great deal about the ways in which routines of news coverage may bias newspaper content, but little about how different article retrieval practices influence newspaper data assembled by scholars. Using the New York Times as a source of data on social movement activity, we compare depictions of protest by the African-American Civil Rights movement over time produced using the two most common article retrieval methods: index versus full-story coding. Full-story coding clearly offers more depth and greater breadth in terms of the events identified. Moreover, many of the same event characteristics associated with selection bias in newspaper reporting (e.g., size and confrontational nature of a protest event, presence of counter-demonstrators or police, and event sponsorship by a recognized social movement organization) are selected upon again when stories are indexed by New York Times staff.

The Effect of New York Times Event Coding Techniques on Social Movement Analyses of Protest Data

Dissertation: The Impact of DNA Ancestry Testing on Racial Identity Formation

The Effect of New York Times Event Coding Techniques on the Analysis of Protest Data

This article describes the scope and composition of national associational populations in four similar countries (Australia, Canada, the United Kingdom, and United States), by way of introducing an important new data release on national associational populations. Special attention is devoted to the subset of associations attending to social inequality issues of gender, race/ethnicity, and sexual orientation, and which are of particular interest to social movement and interest group scholars. No evidence is found for the Tocquevillian notion of heightened national-level associational activity in the United States. The nonmembership associational form is, however, particularly prominent in the United States. Associations attending to social inequality issues in the United Kingdom are structured very differently from these other nations, likely as a result of the unitary nature of government in that country rather than a strong federal system.

Toward International Comparative Research on Associational Activity

The extensive use of digital social media by social movement actors is an emerging trend that restructures the communication dynamics of social protest, and it is widely credited with contributing to the successful mobilizations of recent movements (e.g., Arab Spring, Occupy Wall Street). Yet, our understanding of both the roles played by social movement's use of social media and the extent of its impact is largely derived from anecdotal evidence, news reports, and a thin body of scholarly research on Web-based technologies. In this research we explore several computational methods for measuring the impact of social media on a social movement. Inspired by methodologies originally developed for analyzing computer networks and other dynamic systems, these methods measure various static and dynamic aspects of social networks, and their relations to an underlying social movement. We demonstrated the feasibility and benefits of these measurement methods in the context of Twitter and the Occupying Wall Street movement (OWS). By analyzing tweets related to OWS, we demonstrated the link between the vitality of the movement and the volume of the related tweets over time. We show that there is a positive correlation between the dynamic of tweets and the short-term trend of OWS. The correlation makes it possible to forecast the short-term trend of a social movement using social media data. By ranking users based on the number of their OWS-related tweets and the durations of their tweeting, we are able to identify “buzz makers”. Using a strategy similar to the page-rank algorithm, we define the influence of a user by the number of re-tweets that his/her original tweets incite. By tracing where OWS-related tweets are generated, we measure the geographic diffusion of OWS. By analyzing the percentage of OWS tweets generated from different sources, we show that smart phones and applications such as tweet deck had been used extensively for tweeting in the OWS movement. This indicates the involvement of a younger and more technology-inclined generation in OWS.

2013 IEEE/ACM International Conference on Advances in Social Networks Analysis and Mining (ASONAM 2013)

Analyzing the impact of social media on social movements: A computational study on Twitter and the Occupy Wall Street movement

Views of Environmental Spending: Birth Cohorts, Time Periods, and Changing Correlates

Understanding selection bias, time-lags and measurement bias in secondary data sources: Putting the Encyclopedia of Associations database in broader context.

McHugh’s inquiries, an accessible introduction to the more theoretical aspects of the field might be Jenny Diski’s What I Don’t Know About Animals, in which the arguments of Derrida, Donna Haraway, J. M. Coetzee, and Vicki Hearne all make appearances over the course of a theoretically informed “pet memoir.” In describing the pitfalls of theorizing about animals, Marianne Dekoven writes that the failure to specify whether the animal in question is a dog or crustacean “leaves many theoretical discussions of the animal and animality open to the accusation of overgeneralizing from a small group of intelligent, cultureand affectbearing, communicating animals.” Overall, Animal Stories avoids this critique, bringing specificity to the lives of particular literary animals. By using narrative forms to navigate between the paradigms of literary studies and ethology, McHugh offers new insights into the complexity of what it means to live with other species and to write with them in mind.

Book Review: Recycling Reconsidered: The Present Failure and Future Promise of Environmental Action in the United States

This study examines the role of “ecological threat” in shaping the U.S. environmental movement. Statistical analysis combines founding data on 772 national environmental movement organizations with ecological data on air pollution levels and amphibian and bird populations. We examine these data longitudinally, from 1962 through 1998. Net of other social, economic, and political factors suggested by social movement theory, we find evidence of segmented effects in the expected directions: Declines in wildlife populations are associated with the foundings of wildlife and wilderness protection organizations while increases in air pollution are associated with the foundings of organizations focused on ecosystem well-being and public health. These findings help refine long-held assumptions about the relationship between ecological degradation and environmental activism, and demonstrate the broader utility of the threat concept for strengthening theories of social movement mobilization.

Ecological Threat and the Founding of U.S. National Environmental Movement Organizations, 1962–1998

This study builds on political mediation and movement infrastructure models to highlight contingent and synergistic ways in which social movements may impinge upon the U.S. national policy-making process. Analyses employ a variety of datasets to examine the role of environmental movement organizational capacity, protest and institutional activity in garnering Congressional attention to, and action on, salient issues from 1961 through 1990. We find all types of movement activity, but especially the development of national organizational infrastructures, to be positively associated with the convening of Congressional hearings on the environment. Only when there are high levels of both protest and institutional activity is there any evidence that the environmental movement directly influences the passage of environmental laws.

Movement Organizations, Synergistic Tactics and Environmental Public Policy

Although a macro-organizational perspective has become increasingly commonplace in social movement analyses, few studies examine the full spectrum of organizations in any single social movement industry (SMI). Utilizing a unique source of data on Japanese environmental movement organizations, we compare characteristics of groups focused primarily on environmental issues with those for whom environmental issues are part of a larger multi-issue focus. We then profile across distinct, and theoretically important, organizational domains to assess how local, prefectural and national groups compare on a variety of organizational attributes, including: size, membership type, tactics and activities, and issues. We conclude by discussing the implications of our findings for understanding both Japanese environmentalism and the structure of SMIs generally.

Socio 20 DOI: Although a macro-organizational perspective has become increasingly commonplace in social movement analyses, few studies examine the full spectrum of organizations in any single social movement industry (SMI). Utilizing a unique source of data on Japanese environmental movement organizations, we compare characteristics of groups focused primarily on environmental issues with those for whom environmental issues are part of a larger multi-issue focus. We then profile across distinct, and theoretically important, organizational domains to assess how local, prefectural and national groups compare on a variety of organizational attributes, including: size, membership type, tactics and activities, and issues. We conclude by discussing the implications of our findings for understanding both Japanese environmentalism and the structure of SMIs generally.

The Texas legislature passed the Top 10% Law in 1996 guaranteeing automatic admission to any Texas public college or university for seniors who graduate in the top decile of their high school class.Using data on a representative sample of seniors (N = 12,029) enrolled in 96 Texas public high schools, we examine whether and how this law affects the educational aspirations and expectations of graduating seniors, as well as whether they apply to college.Hierarchical generalized linear models demonstrate that the knowledge of a percent plan has played an important role in raising the sights of students who might not otherwise consider college. This effect is particularly pronounced for minority students, although peer, family and high school context play pivotal roles.

Minority College Aspirations, Expectations and Applications under the Texas Top 10% Law

During the 1960s and 70s the United States environmental movement experienced dramatic growth in both absolute size and in the diversity of organizational structures and issues represented within the movement. We assess the importance of change in movement size and compositional diversity on two important stages within the legislative process. Findings indicate that U.S. environmental movement size is positively associated with the incidence of Congressional environmental agenda-setting activities, but not the passage of environmental laws. An increased diversity of issue representation within the movement is consistently and positively associated with the incidence of agenda setting and law-passage activity. The growth of EMOs attending simultaneously to both traditional conservation and "new" quality of life issues, in particular, is associated with elevated rates of policy activity.

Social Movement Size, Organizational Diversity and the Making of Federal Law

Histories of the environmental movement have emphasized the importance of a shift in focus from those issues traditionally associated with the movement, such as resource and wildlife protection, towards ''new'' quality of life issues, such as environmental pollution and its human health effects. Here, time-series data between 1970 and 2000 on the issue agendas of fifty leading environmental movement organizations (EMOs) are used to empirically assess the veracity of this hypothesized shift. Results indicate that while there is dramatic growth in the salience of new environmental issues, those issues traditionally associated with the environmental movement continue to dominate the collective agendas of major EMOs. Further, new environmental issues are most likely to be represented in organizational fields composed of smaller EMOs on average. The selection and problematization of issues are central to the mobili- zation, development and, ultimately, success or failure of a social move- ment, as well as individual social movement organizations (SMOs). In addition, the issues to which SMOs attend have potentially important public policy implications. Perhaps more so than for any other contem- porary movement, changing issue representation holds a central theo- retical position in analyses of U.S. environmentalism. Scholars suggest that the shift in focus away from issues of resource and wildlife protection towards the ''new'' quality of life issues, such as environmental pollution and its human health effects, represents the most significant transformation in the twentieth century environmental movement. The extent of this qualitative shift is so dramatic that many analysts conceive of the development of a distinct movement (e.g. Dalton 1994; Hays 1987). Changing issue representation is thought to have broadened the scope and constituency of the environmental movement and contributed to growth in both new and existing environmental organizations (McLaughlin and Khawaja 2000; Mitchell,

Changing issue representation among major United States environmental movement organizations

Research examining the political outcomes of social movement activities has been characterized by a nearly exclusive focus on the final stage of the political process, the passage of laws, as well as a limited conceptualization of how movements affect that process. Here, we empirically assess, for one social movement, the importance of organizational capacity, protest and institutional activities, public opinion, and political opportunities in garnering policy-maker attention to movement-salient issues at two distinct stages in the policy making process. Our findings strongly suggest that environmental movement organizational capacity as well as protest and institutional activities directly influence agenda setting stages in the political process. While we find only limited evidence that the environmental movement directly influenced the passage of federal environmental laws, there is some indication that successful agenda setting facilitated this outcome. Beginning in the late 1960s and continuing through the mid 1980s, the U.S. environmental movement experienced an upsurge in organization building and direct action protest activities. Environmental issues, meanwhile, became an increasingly institutionalized element of the federal policy making agenda during this period (Andrews 1999; Portnoy 1990). Although observers have tended to assume a link between citizen mobilization around environmental issues and federal attention to those same issues, empirically this link remains largely unexplored. What role, if any, did the environmental movement have in affecting change in federal policy making? Has the movement been more influential at certain stages of the legislative process than others? And, how did the movement achieve success: does the use of disruptive tactics, participation in institutionalized politics, or greater organizational capacity best account for political success? In addressing these questions this research contributes to understanding developments within the U.S. environmental movement, one of the largest and most politically active social movements in the United States today. Beyond this substantive contribution, we advance the study of social movement outcomes generally by explicitly addressing two shortcomings in the extant literature. First, existing empirical analyses have tended to emphasize single causal factors of policy change, such as the role of movement organizational capacity (McVeigh, Welch and Bjarnason 2003), movement activities (Soule et al 1999), public opinion (Page and Shapiro 1983; Stimson, MacKuen and Erikson 1995), or political opportunities (Jenkins and Perrow 1977) limiting our understanding of the relative importance of these factors and the way they combine and interact to effect the policy making process. We simultaneously account for each of the major causal factors hypothesized to influence policy change. Second, reviews of the empirical literature on social movement political outcomes make clear that this work has been limited by a nearly exclusive focus on the final, and most visible, outcome of political action: the passage of laws that align with the goals of a social movement (Andrews and Edwards 2004; Burstein 1998; Burstein and Linton 2002; Giugni 1998). Here, we conceive of federal policy making as a continuous process. Rather than examine only the endpoint of that process, we employ indicators at multiple points, paying particular attention to agenda setting activities in the United States Congress. While high agenda salience does not necessarily assure outcomes desired by “the movement,” it does represent an intermediary step that is expected to increase the likelihood of achieving desirable outcomes (Baumgartner and Jones 1993; Cobb and Elder 1975; Kingdon 1984). We suspect that social movement mobilization is more successful at garnering congressional attention to its key issues than it is at achieving desirable policy change outcomes. THE MODERN ENVIRONMENTAL MOVEMENT Though rooted in the late nineteenth and early twentieth century conservation movement, it is the extensive period of organization building beginning in the late 1960s, and continuing through the 1980s, which marks the beginning of the modern environmental movement in America (Brulle 2000; Gottlieb 1993). The rate of new environmental movement organization (EMO) foundings surged after 1965, peaked in 1970, and remained high throughout the 1980s, as the total size of the U.S. environmental social movement industry continually expanded (Johnson and McCarthy 2004). A great many of the EMOs founded during this period can be aptly characterized as proto-typical professional movement organizations (McCarthy and Zald 1977), with a heavy reliance on full-time paid staffs of scientists, lawyers, and lobbyists rather

Where Do Movements Matter? The United States Environmental Movement and Congressional Hearings and Laws, 1961-1990

ENVIRONMENTALISM IN THE UNITED STATES: AN ASSESSMENT OF THE MOVEMENT’S NATIONAL ORGANIZATIONAL INFRASTRUCTURE, 1955-1998

THE MOBILIZING EFFECT OF THREAT AND OPPORTUNITY: A MIXED MODEL ANALYSIS OF THE OCCUPY MOVEMENT By NATHAN CHARLES LINDSTEDT A thesis submitted in partial fulfillment of the requirements for the degree of MASTER OF ARTS IN SOCIOLOGY

We have earlier demonstrated T-cell-independent antitumor effects of a combination of anti-CD40 monoclonal antibody (mAb) and CpG oligodeoxynucleotides (CpG) which involved macrophages. As some immunotherapeutic treatments can be potentiated by chemotherapy, we tested if cyclophosphamide (CY) would enhance the antitumor effect of anti-CD40 mAb+CpG. Treatment of B16 melanoma-bearing mice with CY and anti-CD40 mAb+CpG resulted in a significant reduction in tumor growth in immunocompetent mice compared with either CY alone or anti-CD40 mAb with CpG. This enhanced antitumor effect was maintained in severe combined immunodeficiency mice, as measured by both tumor growth and overall survival. Natural killer cells were not required for this antitumor effect as it was also observed in severe combined immunodeficiency/beige mice. Moreover, although CY treatment of immunocompetent mice suppressed natural killer cell activity, it did not negatively affect the antitumor activity of their macrophages when assayed in vitro. Depletion of macrophages in vivo reduced the antitumor effect of CY and anti-CD40 mAb+CpG. These results suggest that therapeutic strategies to activate macrophages may have potential for clinical application in cancer patients receiving chemotherapy.

Enhanced T-cell-independent Antitumor Effect of Cyclophosphamide Combined With Anti-CD40 mAb and CpG in Mice

Purpose: Radiofrequency ablation (RFA) is a common treatment modality for surgically unresectable tumors. However, there is a high rate of both local and systemic recurrence. Experimental Design: In this preclinical study, we sought to enhance the antitumor effect of RFA by combining it with huKS-IL2 immunocytokine [tumor-specific monoclonal antibody fused to interleukin-2 (IL2)] in mice bearing CT26-KS colon adenocarcinoma. Mice were treated with RFA, huKS-IL2 via intratumoral injection, or combination therapy. Results: Treatment of mice bearing s.c. tumors with RFA and huKS-IL2 resulted in significantly greater tumor growth suppression and enhanced survival compared with mice treated with RFA or huKS-IL2 alone. When subtherapeutic regimens of RFA or huKS-IL2 were used, tumors progressed in all treated mice. In contrast, the combination of RFA and immunocytokine resulted in complete tumor resolution in 50% of mice. Treatment of a tumor with RFA and intratumoral huKS-IL2 also showed antitumor effects against a distant untreated tumor. Tumor-free mice after treatment with RFA and huKS-IL2 showed immunologic memory based on their ability to reject subsequent challenges of CT26-KS and the more aggressive parental CT26 tumors. Flow cytometry analysis of tumor-reactive T cells from mice with complete tumor resolution showed that treatment with RFA and huKS-IL2 resulted in a greater proportion of cytokine-producing CD4 T cells and CD8 T cells compared with mice treated with RFA or huKS-IL2 alone. Conclusions: These results show that the addition of huKS-IL2 to RFA significantly enhances the antitumor response in this murine model, resulting in complete tumor resolution and induction of immunologic memory.

Radiofrequency Ablation Combined with KS-IL2 Immunocytokine (EMD 273066) Results in an Enhanced Antitumor Effect against Murine Colon Adenocarcinoma

Intratumoral immunocytokine treatment results in enhanced antitumor effects

Abstract Although great advances have been made in the treatment of low- and intermediate-risk neuroblastoma in recent years, the prognosis for advanced disease remains poor. Therapies based on monoclonal antibodies that specifically target tumour cells have shown promise for treatment of high-risk neuroblastoma. This article reviews the use of monoclonal antibodies either as monotherapy or as part of a multifaceted treatment approach for advanced neuroblastoma, and explains how toxins, cytokines, radioactive isotopes or chemotherapeutic drugs can be conjugated to antibodies to enhance their effects. Tumour resistance, the development of blocking antibodies, and other problems hindering the effectiveness of monoclonal antibodies are also discussed. Future therapies under investigation in the area of immunotherapy for neuroblastoma are considered.

A 30-Year Analysis of Colorectal Adenocarcinoma in Transplant Recipients and Proposal for Altered Screening

To better understand the factors underlying the continued incidence of clinical episodes of falciparum malaria in E-2025 countries targeting elimination, we characterized the molecular epidemiology of Plasmodium falciparum disease transmission after a clonal outbreak in Ecuador. Here we study disease transmission by documenting the diversity and population structure of the major variant surface antigen of the blood stages of P. falciparum encoded by the var multigene family. We used a high-resolution genotyping method, “varcoding”, involving targeted amplicon sequencing to fingerprint the DBLα encoding region of var genes to describe both antigenic var diversity and var repertoire similarity or relatedness in parasite isolates from clinical cases. We identified nine genetic varcodes in 58 P. falciparum isolates causing clinical disease in 2013-2015. Network analyses revealed that four of the varcodes were highly related to the outbreak varcode, with identification of possible diversification of the outbreak parasites by recombination as seen in three of those varcodes. The majority of clinical cases in Ecuador were associated with parasites with highly related or recombinant varcodes to the outbreak clone and due to local transmission rather than recent importation of parasites from other endemic countries. Sharing of types in Ecuadorian varcodes to those sampled in South American varcodes reflects historical parasite importation of some varcodes, especially from Colombia and Peru. Our findings highlight the translational application of varcoding for outbreak surveillance in epidemic/unstable malaria transmission, such as in E-2025 countries, and point to the need for surveillance of local reservoirs of infection in Ecuador to achieve the malaria elimination goal by 2025.

Molecular epidemiology of continued Plasmodium falciparum disease transmission after an outbreak in Ecuador

Counting the number of species, items, or genes that are shared between two groups, sets, or communities is a simple calculation when sampling is complete. However, when only partial samples are available, quantifying the overlap between two communities becomes an estimation problem. Furthermore, to calculate normalized measures of β-diversity, such as the Jaccard and Sorenson-Dice indices, one must also estimate the total sizes of the communities being compared. Previous efforts to address these problems have assumed knowledge of total community sizes and then used Bayesian methods to produce unbiased estimates with quantified uncertainty. Here, we address communities of unknown size and show that this produces systematically better estimates—both in terms of central estimates and quantification of uncertainty in those estimates. We further show how to use species, item, or gene count data to refine estimates of community size in a Bayesian joint model of community size and overlap.

Bayesian estimation of community size and overlap from random subsamples

Counting the number of species, items, or genes that are shared between two sets is a simple calculation when sampling is complete. However, when only partial samples are available, quantifying the overlap between two sets becomes an estimation problem. Furthermore, to calculate normalized measures of β-diversity, such as the Jaccard and Sorenson-Dice indices, one must also estimate the total sizes of the sets being compared. Previous efforts to address these problems have assumed knowledge of total population sizes and then used Bayesian methods to produce unbiased estimates with quantified uncertainty. Here, we address populations of unknown size and show that this produces systematically better estimates—both in terms of central estimates and quantification of uncertainty in those estimates. We further show how to use species count data to refine estimates of population size in a Bayesian joint model of populations and overlap.

Bayesian estimation of population size and overlap from random subsamples

Fourier ring correlation was recently proposed in fluorescence microscopy as an objective measure of image resolution. In this study we show that FRC has serious limitations. For several common image processing techniques, we show that FRC can be made to be systematically biased to classify objectively lower resolution images as better resolved than objectively higher resolution images. Thus, rather than providing an objective, realistic measure of spatial resolution, care must be taken in interpreting FRC-based results. In revealing some of FRC’s limitations, this study also highlights the need for a more objective, principled approach to estimating resolution.

Limitations of Fourier ring correlation as an image resolution metric

Background: Within recent years, parks built on top of former landfills have come under scrutiny for their effectiveness at mitigating the effects of the landfill underneath. The purpose of this study is to identify the biogas emissions of converted landfills nearly a century after landfill closure.
Methods: Soil and air emissions for methane and carbon dioxide were collected at 112 sites within the North and South portions of Parc Baldwin in Montreal, Quebec, as well as the presumed boundaries of the former landfill.
Results: Overall, it was found that South Baldwin and the immediate area (previously a landfill) had a higher mean average methane concentration, as well as a greater number of sites with methane present than North Baldwin. Particular raised areas in South Baldwin showed anomalously high carbon dioxide concentrations. There was a large degree of heterogeneity between emissions at different sites.
Limitations: The Eagle 2 machine is limited to measuring only up to 5,000 ppm or 0.5% volume. Another difficulty with the variation in collection of the data is the differences in collection dates.
Conclusions: Ultimately, while South Baldwin did have higher CO2 and methane emissions compared to its counterpart, it is inconclusive whether or not this phenomenon is related to the landfill or other factors. Gas concentrations were significantly below the lower explosive limit in both parks.

Examining the Effects of Covered Landfills on Gas Emissions in Parc Baldwin, Montreal

Changing water dynamics: The consequences of shifting snow, ice, and running water for ecosystems, people, and national forests in Alaska

Identifying nitrogen sources to thermal tide pools in Kapoho, Hawai'i, U.S.A, using a multi-stable isotope approach.

Surface Water Metabolism Potential in Groundwater-Fed Coastal Waters of Hawaii Island, USA

Surface water metabolism potential of groundwater-fed near shore waters on the leeward coast of the Island of Hawaii

In any instance when unanimity embraces an idea, a thoughtful person might ask whether there's true agreement or perhaps just a cone of vagueness that accommodates a variety of opinions and lets eyes of the beholders see what they want to see. With value-based care, it may be the latter.

As plans and providers collaborate to manage post-discharge care, they will also need to take heed of the nonclinical variables. Limitations in performing activities of daily living (ADLs) and social determinants of health (SDOH) have as great an impact on health care spending among the elderly as the presence of chronic conditions.

More Medicare Advantage Plans Offering Post-acute Discharge Care.

Managing the total cost of professional liability should be a top priority for health systems as professional liability costs will increase in coming years. The frequency of hospital professional liability claims has entered a period of modest growth. The severity of claims continues to grow, with claim severity projected to increase 4 percent in 2011. The combined effect of frequency and severity indicates HPL loss rates are expected to increase 5 percent in 2011.

Healthcare financial management : journal of the Healthcare Financial Management Association

OBJECTIVE
To compare pharmacokinetics of levetiracetam in serum and CSF of cats after oral administration of extended-release (ER) levetiracetam.

ANIMALS
9 healthy cats.

Cats received 1 dose of a commercially available ER levetiracetam product (500 mg, PO). Thirteen blood and 10 CSF samples were collected over a 24-hour period for pharmacokinetic analysis. After 1 week, cats received 1 dose of a compounded ER levetiracetam formulation (500 mg, PO), and samples were obtained at the same times for analysis.

RESULTS
CSF concentrations of levetiracetam closely paralleled serum concentrations. There were significant differences between the commercially available product and the compounded formulation for mean ± SD serum maximum concentration (Cmax; 126 ± 33 μg/mL and 169 ± 51 μg/mL, respectively), Cmax corrected for dose (0.83 ± 0.10 μg/mL/mg and 1.10 ± 0.28 μg/mL/mg, respectively), and time to Cmax (5.1 ± 1.6 hours and 3.1 ± 1.5 hours, respectively). Half-life for the commercially available product and compounded formulation of ER levetiracetam was 4.3 ± 2.0 hours and 5.0 ± 1.6 hours, respectively.

The commercially available product and compounded formulation of ER levetiracetam both maintained concentrations in healthy cats 12 hours after oral administration that have been found to be therapeutic in humans (ie, 5 μg/mL). Results of this study supported dosing intervals of 12 hours, and potentially 24 hours, for oral administration of ER levetiracetam to cats. Monitoring of serum concentrations of levetiracetam can be used as an accurate representation of levetiracetam concentrations in CSF of cats.

Pharmacokinetics of a commercially available product and a compounded formulation of extended-release levetiracetam after oral administration of a single dose in cats.

Practice Variation and Resource Use in the Evaluation of Pediatric Vasovagal Syncope: Are Pediatric Cardiologists Over-Testing?

Practice Variation and Resource Utilization In the Evaluation of Pediatric Vasovagal Syncope: Are Pediatric Cardiologists Over-Testing?

The majority of sudden, nontraumatic deaths in young, otherwise healthy individuals result from an unknown underlying cardiac abnormality. The low sensitivity of the traditional history and physical exam in detecting these anomalies has led to a debate regarding the use of routine screening electrocardiograms (ECGs) in young adults. The present study screened 1,099 ROTC cadets applying for aviator status during the summers of 2005 and 2006. Seven candidates (0.6%) were disqualified because of ECG abnormalities, including two with Wolf Parkinson White syndrome. None of the individuals were identified by history and physical exam. ECG was an effective screening tool for detecting silent abnormalities with potential for arrhythmia in our population of healthy young adults. Other ECG findings indicative of anatomic abnormalities were not found. ECG screening can be a valuable tool and should be used in evaluating certain subsets of the population.

The role of screening electrocardiograms in the evaluation of ROTC cadets applying for flight status.

Evolutionary biologists have grown increasingly interested in laterality, a phenomenon where bilaterally symmetrical organisms show a side bias in some trait. Lateralized behavior is particularly interesting because it is not necessarily tied to morphological asymmetry. What causes lateralized behavior remains largely unknown, although previous research in fishes suggest that fish might favor one eye over another to view potential food sources, mates, and to assess predation risk. Here we test the hypothesis that a history of predation risk predicts lateralized behavior in the livebearing fish Brachyrhaphis rhabdophora. To do this, we used a detour assay to test for eye bias when a focal fish approached various stimuli (predator, potential mate, novel object, and empty tank control). Contrary to our predictions, we found no differences in lateralized behavior between fish from populations that co-occurred with fish predators relative to those that do not co-occur with predators. In fact, we found no evidence for behavioral lateralization at all in response to any of the stimuli. We explore several possible explanations for why lateralized behavior is absent in this species, especially considering a large body of work in other livebearing fishes that shows that lateralized behavior does occur.

Predation history has no effect on lateralized behavior in Brachyrhaphis rhabdophora

Xenophallus umbratilis is a freshwater livebearing fish that exhibits unique antisymmetry in the male gonopodium, which terminates in either a dextral or sinistral twist. This asymmetry in the gonopodium suggests that males might exhibit side-biased behavior when interacting with females to mate. We conducted two assays to assess the laterality of male and female mating interactions based on gonopodial morphology. We observed lateralized mating behavior in one test where males with sinistral gonopodial morphology interacted with a single female. However, we did not find lateralized mating behavior in males with dextral gonopodial morphology. We also examined male and female positioning in trials that placed a single female with five males, all with the same morphology. These trials also showed no evidence of lateralized body positioning.

Does male gonopodial morphology affect male-female mating positioning in the livebearing fish Xenophallus umbratilis?

Does Negative Frequency-Dependent Selection Maintain Gonopodial Asymmetry in Xenophallus umbratilis?

Why bilaterally symmetrical organisms express handedness remains an important question in evolutionary biology. In some species, anatomical asymmetries have evolved that accompany behavioral handedness, yet we know remarkably little about causal links between asymmetric morphological traits and behavior. Here, we explore if a dextral or sinistral orientation of the male intromittent organ predicts side preferences in male behaviors. Our study addresses this question in the Costa Rican livebearing fish, Xenophallus umbratilis. This fish has a bilaterally symmetrical body plan, with one exception—the male anal fin (gonopodium), used to inseminate females, terminates with a distinct left- or right-handed corkscrew morphology. We used a detour assay to test males for side biases in approach behavior when exposed to four different stimuli (predator, potential mate, novel object, empty tank control). We found that left morph males preferred using their right eye to view potential mates, predators, and the control, and that right morph males preferred to use their left eye to view potential mates and predators, and their right eye to view the control. Males of both morphs displayed no eye bias when approaching the novel object. Our results suggest that there is a strong link between behavior and gonopodium orientation, with right and left morph males responding with opposite directional behaviors when presented with the same stimuli. This presents the intriguing possibility that mating preferences—in this case constrained by gonopodial morphology—could be driving lateralized decision making in a variety of non-mating behaviors.

Does Asymmetrical Gonopodium Morphology Predict Lateralized Behavior in the Fish Xenophallus umbratilis?

Abstract Species delimitation is ever more critical for assessing biodiversity in threatened regions of the world, with cryptic species offering one of the greatest challenges. Our study focuses on a conservation hotspot in northeastern Madagascar where at least five species of mouse lemur (Microcebus spp.) occur, some of them in sympatry. One of these, M. jonahi, is described here as new to science and is accompanied by a complete genome. While morphometric analyses confirmed the cryptic nature of taxa, phylogenetic and population genetic analyses clarified species boundaries despite some interspecific gene flow, including introgression of mtDNA. The sister species pair that includes M. jonahi passed all tests of species delimitation, whereas the other pair showed more marginal results. This is at least partially due to differences in effective population sizes, which affect coalescence rates and thus influence the recently introduced genealogical divergence index (gdi). Whole-genome and RADseq analyses suggest a precipitous decline in effective population sizes associated with successive divergence events of lineages leading to the micro-endemics M. jonahi and its sister species, giving rise to grave conservation concern for both. Finally, our study demonstrates the power of genomic species delimitation approaches for revealing hidden evolutionary processes in cryptic species complexes.

Complex processes of cryptic speciation in mouse lemurs from a micro-endemism hotspot in Madagascar

Tetrahymena thermophila is a ciliated protist and a well-studied organism that is used as an experimental analogue for ciliary function in other eukaryotes. We studied it as a model for human endotracheal ciliary response to toluene, a compound found in both cigarettes and e-cigarettes. We performed three experiments with four replicates each: a motility assay to study the effects of toluene on movement, a food vacuole assay measuring the ability of T. thermophila to phagocytose Congo-red stained yeast using their oral cilia and a cell viability assay in order to determine whether cells without food vacuoles were still alive. We found significant differences in the percentage of moving cells in the first assay as we increased the concentration of toluene, as well as significant and similar differences regarding food vacuole formation in our second assay. Our last assay found no significant difference in the amount of viable cells without food vacuoles at each of three concentrations tested. Taken together, these data suggest that short-term exposure to toluene does not kill T. thermophila, but may inhibit ciliary function. The mechanism by which toluene acts on cilia is unknown, however previous studies have suggested that the toxicity of toluene is associated with its methyl side chain, as it can form hydrogen bonds with other molecules.

The effects of toluene on the ciliary function of Tetrahymena thermophila

Parents who report motor difficulties as their primary concern receive autism intervention services earlier than those first concerned with communication. This study revealed that parent perceptions of their child’s social responsiveness correlated with standardized scores of motor proficiency. Promoting awareness of this relationship could lead parents to seek services sooner.

Parent Perceptions of Social Behaviors Associated With Autism Spectrum Disorder Are Related to Motor Skills

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by persisting impairments in social communication and interaction as well as restricted and repetitive behavior, interest, and activity patterns presenting in early development [1]. There is currently no motor-related diagnostic criteria other than repetitive, stereotypic movement patterns, such as rocking or hand flapping [1]. Motor abilities implicated in children with ASD vary significantly. The presence of motor involvement in children with ASD is widespread, with up to 79% of children with ASD presenting with Purpose: Children with autism spectrum disorder (ASD) show motor deficits in addition to the social communication and repetitive behaviors characteristic of the disorder. However, these deficits have traditionally been targeted independently during intervention. The primary purpose of this systematic review was to determine whether interventions with motor targets improved language or social communication outcomes in individuals with ASD.

Motor-based interventions improve language outcomes in children with autism: a systematic review

Visual and verbal semantic productions in children with ASD, DLD, and typical language.

Inverse Compton scattering sources are finding increasing use as intense sources of high-energy photons. When operated at high field strength, ponderomotive detuning of the scattered emission can lead to decreased source performance. Up to now, the calculations of spectra for such nonlinear Thomson scattering have been done assuming a perfectly aligned electron interacts with the incident laser beam and several authors have investigated whether pondermotive detuning may be mitigated or cured by suitable incident laser chirping prescriptions. In order to determine if these chirping prescriptions are suitable in real beams with nonzero emittance, it is necessary to include misaligned boundary conditions in the electron motion and calculate the resulting spectra from the exact motion. In this paper we provide the exact solution for the electron equations of motion in the case of a misaligned electron passing through a laser pulse of high field strength. This solution is then used to calculate the scattered radiation distribution and we determine the emittance limits for the simplest chirping prescription.

The application of using accelerator-science to improve current remote atmospheric survey techniques has been explored. A literature review has been conducted to asses the needs of NASA ’s Active Sensing of CO2 Over Nights, Days and Seasons (ASCENDS) versus the current capabilities of contemporary atmospheric survey technology, and the parameters of a free electron laser (FEL) source were calculated for a lidar system that will meet these needs. By using the “Next Linear Collider” accelerating structure from the Stanford Linear Accelerator Center (SLAC) [1], a mobile FEL-based lidar may be constructed for airborne surveillance. The calculated energy of the lidar pulse is 0.1 joule -a three orders of magnitude gain over current lidar systems [2]. Therefore in principle, the mobile FEL will exceed the needs of ASCENDS.

Previous work on calculating energy spectra from Compton scattering events has either neglected considering the pulsed structure of the incident laser beam, or has calculated these effects in an approximate way subject to criticism. In this paper, this problem has been reconsidered within a linear plane wave model for the incident laser beam. By performing the proper Lorentz transformation of the Klein-Nishina scattering cross section, a spectrum calculation can be created which allows the electron beam energy spread and emittance effects on the spectrum to be accurately calculated, essentially by summing over the emission of each individual electron. Such an approach has the obvious advantage that it is easily integrated with a particle distribution generated by particle tracking, allowing precise calculations of spectra for realistic particle distributions in collision. The method is used to predict the energy spectrum of radiation passing through an aperture for the proposed Old Dominion University inverse Compton source. Many of the results allow easy scaling estimates to be made of the expected spectrum.

Orbital debris has become an increasing concern for countries wishing to deploy space assets. Orbital debris can impact spacecraft with a relative velocity of up to 15 km per second and micrometeoroids can travel with relative velocities up to 70 km per second. Consequently, micrometer sized particles can seriously damage spacecraft and spacecraft subsystems. Ground based radars can only detect particles with a characteristic size greater than 0.5-1 cm and ranges less than 1000-2000 kilometers. The Debris Resistive/ Acoustic Grid Orbital Navy Sensor (DRAGONS) is a spacecraft instrument that will detect and measure the characteristics of these smaller particles. The mission objective of DRAGONS is to deploy an instrument to detect hypervelocity impacts of particles 50 microns or larger using inexpensive and low resource technology to collect a sufficient population of data to update current debris models. It will provide data on the particle environment to improve debris and micrometeoroid models and alert spacecraft controllers in real time. An acoustic subsystem will accomplish the objective by measuring the characteristics of the waveform generated by an impacting particle on a spacecraft surface. Obtained simultaneously will be measurements of resistance changes caused by broken links of a resistive grid subsystem deposited on the surface. These sets of observations will provide important complementary information about the characteristics of impact particles, which will lead to a better debris model and improved assessment of the risks from space debris. Real time monitoring of the debris field will permit spacecraft controllers to change orbit parameters to avoid reentering intensive debris fields.

The measured elliptic flow (v2) of identified particles as a function of pT and centrality at RHIC suggests the created medium in Au+Au collisions achieves early local thermal equilibrium that is followed by hydrodynamic expansion. It is not known if the eta dependence on v2 is a general feature of elliptic flow or reflects other changes in the particle spectra in going from mid-rapidity to foward rapidities. The BRAHMS experiment provides a unique capability compared to the other RHIC experiments to measure v2 for identified particles over a wide rapidity range. From Run 4 Au+Au collision at sqrt{s_{NN}} = 200GeV, identified elliptic flow is studied using the BRAHMS spectrometers, which cover 0<eta<3.4. The BRAHMS multiplicity array is used to determine the v2 event plane for the identified particle elliptic flow and to measure the pT-integrated flow for charged hadrons.

Study of the neutron flux in a model for a252Cf cold neutron source

A harmonic oscillator consisting of a neodymium magnet attached inside a spring is driven through resonance. Eddy currents, induced in pipes surrounding the magnet, result in a damping of the motion of the magnet. Our experiment makes precise measurements of the motion and damping of the magnet as we vary pipe composition, length, thickness, radius, and position. A theoretical analysis combining the standard differential equation for a damped, driven harmonic oscillator and Faraday’s law of electromagnetic induction gives excellent agreement with the experimental results. This analysis allows for the calculation of electromagnetic damping for any pipe configuration which is coaxial with the magnet’s motion and provides strong evidence for the eddy current damping analysis of the common demonstration of dropping a magnet down a conducting tube.

Optimal sensor placement enhances the efficiency of a variety of applications for monitoring dynamical systems. It has been established that deterministic solutions to the sensor placement problem are insufficient due to the many uncertainties in system input and parameters that affect system response sensor measurements. Accounting for the uncertainties in this typically expensive optimization is challenging due to computational intractability. This study proposes a stochastic environment in the form of a Markov Decision Process and a sensor placement agent that aims to maximize the information gain from placing a particular number of sensors of different types within the system. The agent is trained to maximize its reward based on an information-theoretic reward function. To verify the efficacy, the approach is applied to place a set of heterogeneous sensors in a shear building model. This methodology can be used to accommodate uncertainties in the sensor placement problem in real-world systems.

Measurement Optimization under Uncertainty using Deep Reinforcement Learning

Modeling and model updating of a full-scale experimental base-isolated building

AbstractMeasured force-displacement sensing data are analyzed to create nonlinear hysteretic models for elastic sliding bearings and steel dampers. These data were collected during full-scale exper...

Modeling the Dynamic Behavior of Isolation Devices in a Hybrid Base-Isolation Layer of a Full-Scale Building

A hybrid probabilistic framework for model validation with application to structural dynamics modeling

AbstractModels, typically given by systems of mathematical equations, are built to help represent, understand, and further characterize physical phenomena. The choice of a model for a particular ph...

Computationally Efficient Bayesian Model Selection for Locally Nonlinear Structural Dynamic Systems

Full‐scale dynamic testing and earthquake engineering experiments are often costly, yet they are vital for advancing the understanding of the complex interactions between seismic protective systems and structural responses. E‐Defense (a part of the Japan's National Research Institute for Earth Science and Disaster Resilience) constructed and tested a four‐story reinforced‐concrete base‐isolated building to study, among other things, how different anti‐seismic devices in the isolation layer of a building improve its response. This structure was subjected in August 2013 to a series of tests, including random ground motions and simulated earthquakes. Analyzing the acceleration responses from these random excitations forms the first step in identifying the dynamic characteristics of this test structure. The advanced numerical algorithm for subspace state‐space system identification (N4SID), from the family of subspace identification methods, is used to estimate the nominal modal parameters of this structure for both input–output and output‐only models. These models are then evaluated for their generalizability by using them to predict the response of the structure to both random excitations and seismic inputs. Additional identification is performed using responses recorded during simulated earthquakes, and the recovered modal parameters are compared against the nominal parameters to analyze how the building's isolation system impacts its response. The results indicate that the interaction between seismic excitation and the base‐isolation layer has both local and global structural effects. Locally, the modes most directly associated with isolation layer displacements experience, as expected, significant decreases in frequency and increases in damping; globally, the modes with more substantial displacements across the superstructure also experience decreases in frequency and increases in damping but at a greatly reduced scale. Further, even in the presence of seismic forces large enough to induce nonlinear restoring forces in the isolation layer, the relative changes in identified modal parameters for the superstructure associated modes remained modest.

Constructing and evaluating generalized models for a base‐isolated structure

AbstractModels are used to represent and characterize physical phenomena. When there are many plausible models for a particular phenomenon, the modeler can exploit the computational tool called mod...

Investigation of Model Falsification Using Error and Likelihood Bounds with Application to a Structural System

AbstractDamage detection for civil structures is limited by several factors including poor signal-to-noise ratios, a large number of unknown parameters, and a limited set of measured responses. Global vibration techniques that track modal parameters often remain insensitive to common forms of structural damage. Moreover, large sets of identified parameters make inverse problems ill-conditioned. To overcome some of these limitations, researchers have advanced substructure identification as a methodology to directly detect local stiffness changes using measured responses to improve damage detection and scalability in civil structures. This paper develops a substructure identification estimator that identifies the story stiffness of a shear building. Concurrent with the estimator derivation, identified parameter confidence intervals are developed and identification performance is predicted. Using the developed estimator, experimental testing is performed on a 3.66-m (12-ft) four-story steel structure subject...

Experimental Verification of Substructure Identification for Damage Detection in Shear Buildings

This thesis explores the feasibility of embedding communication within the power transfer channel of a near field wireless power transfer system in order to increase the versatility and efficiency of the system. The system was built around the LTC4125 auto-resonant wireless power transmitter IC. Both the transmitter and receiver were tuned to approximately 100kHz with a communication data bit rate of 1kHz. The thesis covers both resonant wireless power transfer theory, the details of the embedded communication and the results obtained. Thesis Supervisor: Eko Lisuwandi Title: Senior Design Engineer, Linear Technology Thesis Supervisor: David Perreault Title: Professor of Electrical Engineering

Resonant wireless power transfer with embedded communication for more versatile and efficient applications

An efficient exponential predictor-corrector time integration method for structures with local nonlinearity

Hybrid Time/Frequency Domain Identification of Real Base-Isolated Structure

AbstractEvaluating controllable damping designs typically requires simulation of the resulting inherently nonlinear closed-loop system because linear design strategies cannot always be reliably used. These analyses typically require many simulations, each a function evaluation in a parameter study or optimization. For complex structural models, these simulations can require significant computational resources. Further, complex structural models requiring repeated solutions of high-order Riccati equations for each function evaluation further exacerbate the computational burden. This paper demonstrates that a reduced-order model for designing the control strategy, resulting in a low-order control law, coupled with the full model of the original system, falls in the class of systems that are mostly linear but with very localized nonlinearities. For such systems, the authors have previously developed an approach that reduces the equations of motion to a low-order nonlinear Volterra integral equation that can ...

Rapid Controllable Damper Design for Complex Structures with a Hybrid Reduced-Order Modeling/Simulation Approach

A variety of strategies have been developed over the past few decades to determine controllable damping device forces to mitigate the response of structures and mechanical systems to natural hazards and other excitations. These “smart” damping devices produce forces through passive means but have properties that can be controlled in real time, based on sensor measurements of response across the structure, to dramatically reduce structural motion by exploiting more than the local “information” that is available to purely passive devices. A common strategy is to design optimal damping forces using active control approaches and then try to reproduce those forces with the smart damper. However, these design forces, for some structures and performance objectives, may achieve high performance by selectively adding energy, which cannot be replicated by a controllable damping device, causing the smart damper performance to fall far short of what an active system would provide. The authors have recently demonstrated that a model predictive control strategy using hybrid system models, which utilize both continuous and binary states (the latter to capture the switching behavior between dissipative and non-dissipative forces), can provide reductions in structural response on the order of 50% relative to the conventional clipped-optimal design strategy. This paper explores the robustness of this newly proposed control strategy through evaluating controllable damper performance when the structure model differs from the nominal one used to design the damping strategy. Results from the application to a two-degree-of-freedom structure model confirms the robustness of the proposed strategy.

Performance and robustness of hybrid model predictive control for controllable dampers in building models

This paper proposes a computationally efficient framework for design optimization under uncertainty for structures with local nonlinearities. To reduce the high computational cost of Monte Carlo simulation of such problems, an exact model reduction to a low-order Volterra integral equation is used to accelerate each simulation, and variance-reduced sampling is used to reduce the number of simulations required for the uncertainty quantification. This optimization framework is applied to a benchmark cable-stayed bridge problem, designing one pair of passive tuned mass dampers given a pair of uncertain passive power law dampers, providing significant gains in computational efficiency, two orders of magnitude, compared to traditional approaches.

Efficient optimal design-under-uncertainty of passive structural control devices

This paper is mainly aimed at stressing some fundamental features of the GSHP design and is based on a broad research we are performing at the University of Pisa. In particular, we focus the discussion on an environmentally sustainable approach, based on performance optimization during the entire operational life. The proposed methodology aims at investigating design and management strategies to find the optimal level of exploitation of the ground source and refer to other technical means to cover the remaining energy requirements and modulate the power peaks. The method is holistic, considering the system as a whole, rather than focusing only on some components, usually considered as the most important ones. Each subsystem is modeled and coupled to the others in a full set of equations, which is used within an optimization routine to reproduce the operative performances of the overall GSHP system. As a matter of fact, the recommended methodology is a 4-in-1 activity, including sizing of components, lifecycle performance evaluation, optimization process, and feasibility analysis. The paper reviews also some previous works concerning possible applications of the proposed methodology. In conclusion, we describe undergoing research activities and objectives of future works.

On sustainable and efficient design of ground-source heat pump systems

Full-scale dynamic earthquake engineering experiments are costly, yet they are vital for the advancement of seismic protection for large structures. The main goal of such large-scale studies is to accurately replicate the response of complex structures. E-Defense, a part of Japan’s National Research Institute for Earth Science and Disaster Prevention (NIED), constructed and tested a four-story reinforced-concrete base-isolated building to study, among other objectives, how different energy dissipation devices in the building isolation layer improve the response subjected to strong impulsive and long period excitations. This structure was subjected in August 2013 to a series of tests. Analyzing the resulting acceleration responses from the random ground motion tests forms the first step in identifying the dynamic characteristics of this test structure. Specifically, enhanced canonical correlation analysis (ECCA) and the advanced numerical algorithm for subspace state-space system identification (N4SID), from the stochastic subspace identification (SSI) family of methods, were used to estimate the modal parameters. Additional identification was then performed using responses recorded during simulated earthquakes. The recovered modal parameters were compared against the nominal parameters to analyze the behavior of the building’s isolation system, as well as the effectiveness of the identification methods. doi: 10.12783/SHM2015/166

Modal Analysis of a Full-scale Four-story Reinforced-concrete Base-isolated Building Subjected to Random and Simulated Earthquake Shake Table Excitations

Efficient optimal design of passive structural control applied to isolator design

Performance Evaluation of High-Rise Buildings with Mid-Story Isolation Through Shake Table Real-Time Hybrid Simulation

In Bayesian model selection, suitable mathematical models are selected among a set of possible models using Bayes’ theorem. To simplify the analysis, linear structural models are often used, though they are not always adequate to accurately compute the structural response. Nonlinear models, which may be more accurate, significantly increase the required computation time for Bayesian model selection. A method is proposed in this paper to reduce the computational cost by incorporating into the model selection process the authors’ previously developed efficient dynamic response algorithm for response of locally nonlinear systems. The efficacy of the approach is demonstrated, using the numerical example of a base-isolated building on hysteretic lead rubber bearing (LRB) isolators, with different linear and nonlinear model classes as candidates to represent the LRBs. doi: 10.12783/SHM2015/288

Efficient Bayesian Model Selection for Identifying Locally Nonlinear Systems Incorporating Dynamic Measurements

NEES: Database for Structural Control and Monitoring Benchmark Problems

Efficient optimal design of passive hysteretic base isolators by Volterra integral equations

Offline implementation of hybrid MPC for semiactive control of structures

AbstractRecent developments of a distributed mass damper (DMD) system integrate structural and environmental control systems for buildings. This system simultaneously improves building safety and sustainability by using external shading fins as mass dampers, controlling the amount of sunlight coming into the building for energy efficiency, and reducing structural movements during strong motions. Unlike traditional mass dampers, which are usually placed at the tops of structures, the shading fin mass dampers (SFMDs) are distributed throughout structures because fins are placed along the entire heights of buildings. A recent paper by the authors shows that the passive DMD system is as effective in response mitigation as a conventional tuned mass damper (TMD). In this paper, active control strategies for mass damper control are analyzed and simulated to show further response reductions. Nonpassive controls are of interest for the SFMD system because actuators are already needed to control the positions of th...

AbstractThe time evolution of the parameter sensitivity of a nonlinear dynamical system is essential to its successful design, control, and identification. For an important class of systems, the governing equations of motion can be expressed as a linear system of ordinary differential equations augmented with a low-rank parameter-dependent (generally nonlinear) vector function. This paper builds on previous efforts by the authors to devise an approach for computing not only the responses of such systems but also the sensitivities of their responses to changes in design parameters in a computationally efficient manner. The proposed solution procedure first segregates the degrees of freedom appearing in the augmented functions from those that involve only linear deterministic operations. Second, the responses and sensitivities of the augmented terms are determined by solving the Volterra integral equations of reduced dimension. Finally, the responses and sensitivities of all remaining desired outputs are co...

Efficient Sensitivity Analysis of Structures with Local Modifications. I: Time Domain Responses

Designing control strategies for smart structures, such as those with semiactive devices, is complicated by the nonlinear nature of the feedback control, secondary clipping control and other additional requirements such as device saturation. The usual design approach resorts to large-scale simulation parameter studies that are computationally expensive. The authors have previously developed an approach for state-feedback semiactive clipped-optimal control design, based on a nonlinear Volterra integral equation that provides for the computationally efficient simulation of such systems. This paper expands the applicability of the approach by demonstrating that it can also be adapted to accommodate more realistic cases when, instead of full state feedback, only a limited set of noisy response measurements is available to the controller. This extension requires incorporating a Kalman filter (KF) estimator, which is linear, into the nominal model of the uncontrolled system. The efficacy of the approach is demonstrated by a numerical study of a 100-degree-of-freedom frame model, excited by a filtered Gaussian random excitation, with noisy acceleration sensor measurements to determine the semiactive control commands. The results show that the proposed method can improve computational efficiency by more than two orders of magnitude relative to a conventional solver, while retaining a comparable level of accuracy. Further, the proposed approach is shown to be similarly efficient for an extensive Monte Carlo simulation to evaluate the effects of sensor noise levels and KF tuning on the accuracy of the response.

Computationally efficient design of optimal output feedback strategies for controllable passive damping devices

Linear control laws are the most common control strategies, primarily due to their simplicity in both design and implementation. While there are a multitude of accepted techniques for designing linear control strategies for mitigating the response of structures due to external loads and excitations, there are no elegant and widely-applied nonlinear methods. While the optimal linear control law that minimizes a quadratic cost function can be carried out simply with standard tools (e.g., MATLAB's lqr command), a nonquadratic cost function leads to a Hamilton-Jacobi-Bellman (HJB) partial differential equation that results in an optimal nonlinear controller. However, finding the exact analytical solution of the HJB equation is very difficult; it may only have a solution when the cost function is cast in a particular form. This paper suggests a particular form of a nonlinear control law for civil structures designed to minimize one objective (a serviceability and performance measure) for small excitation and small response, and a different objective (life safety) for larger motion. An analytical approach is presented to cast the nonquadratic cost function in a form for which the HJB equation can be solved. The resulting optimal nonlinear control law can be written as the sum of a linear term, which is related to an LQR problem and is effective in small excitations, and some nonlinear terms that dominate when the excitation level is large. The performance of the proposed nonlinear control strategy is demonstrated by a numerical simulation for a simple building model subjected to different historical earthquakes and a synthetic ground motion, showing that it can successfully achieve both life safety (drift reduction) and serviceability (acceleration reduction) objectives at different excitation levels.

HJB-based optimal nonlinear control for multiple objectives in different levels of excitations

Fast optimal design and reliability analysis of a large-scale smart structure

AbstractThe deterministic frequency response analysis and the stationary random vibration of large, linear structural models are often computationally intensive tasks. The computational expense is only exacerbated when stiffness and damping variabilities are present in the system’s description. This paper proposes an approach for the highly computationally efficient and accurate computation of the sensitivities, to changes in design parameters that are spatially localized within some small portion of the computational model, of the transfer functions (TFs), power spectral densities, and mean-square responses of a structural system. The proposed method is derived, first for system TFs and then their sensitivities; the corresponding spectral densities are then derived using the TF approach. Finally, the proposed method is applied to two examples, one simple model where exact solutions can be computed, and a second, more realistic, building example with a high-order model that causes significant difficulties...

Efficient Sensitivity Analysis of Structures with Local Modifications. II: Transfer Functions and Spectral Densities

Structural control systems are installed in structures to mitigate large structural vibration during strong earthquakes or high-speed winds. During the majority of time when no such hazards are present, the role of these control systems can be temporarily shifted to facilitate more accurate characterization of structural health. This novel use of control devices provides another benefit of installing control systems in buildings at minimum extra cost. The authors proposed, in previous studies, a substructure identification method applicable to shear structures. The error analysis proved that the identification accuracy of this method can be improved if the responses of the substructure being identified are changed in a specific way by using feedback vibration control. Exploiting these results, an alternative control algorithm is designed to improve the identification accuracy. A numerical simulation demonstrates that the new controlled identification method, using semiactive braces, can greatly improve the accuracy of structural parameter estimation. To verify experimentally that dynamic response changes can improve identification accuracy, shake table tests are performed on a two-story shear structure model with passive modifications; the results show that the structural parameters are more accurately identified with these changes than without.

Response Modification to Improve the Parameter Identification of Shear Structures: An Experimental Verification

Rapid reanalysis of the generalized eigenvalue problem of locally modified linear dynamical systems

Optimal structural control design for controllable passive dampers is difficult and computationally expensive. Even with a linear structure, the controlled system is nonlinear since the control appears parametrically and the damper that can only exert dissipative forces. The authors previously introduced a novel method, based on a low-order nonlinear Volterra integral equation (NVIE), that provides a computationally efficient means to simulate responses for such systems. Thus far, the authors have considered deterministic models with semiactive control devices; however, uncertainties in key structural elements cannot be neglected in real-world systems and may intensify the computational burden, generally demanding a Monte Carlo simulation to characterize the effects of uncertainty. Herein, a 100 degree-of-freedom isolated building model with a controllable damper in the isolation is studied with uncertainty in the isolation rubber bearing stiffness and damping. Numerical results confirm the accuracy, stability, and computational efficiency of the proposed simulation methodology.

Computationally Efficient Control Design for a Smart Structure with Uncertainty

Controllable damping studies for seismic protection of elevated highway bridges found that a clipped LQR strategy achieves performance similar to that with a fully linear actuator when attempting to reduce the bridge deck response, but only comparable to that with a purely passive damper when seeking to reduce pier response (Erkus et al., 2002). This paper examines this more challenging pier response problem using a dynamic programming approach to obtain the optimal dissipative control force - assuming the excitation is deterministic and known a priori - through a numerical solution of the Euler-Lagrange equations. The resulting (non-causal) optimal performance, an upper bound on the performance of any controllable damping strategy, is still rather lower than active control performance (which is causal, requiring no future excitation information). This result suggests that even highly adaptive control laws to command controllable dampers may never approach fully active system performance for some control objectives.

Optimal Semiactive Control of Elevated Highway Bridges: An Upper Bound on Performance via a Dynamic Programming Approach

Improved Substructure Identification Through Use of an Active Control Device

Computationally Efficient Design of Semiactive Structural Control in the Presence of Measurement Noise

AbstractIn previous studies by the authors, a substructure identification method for shear structures was proposed to identify all structural story stiffness and damping parameters from top to bottom inductively. In the method derivation, the structural responses were required to be wide sense stationary to convert structural dynamic equations to differential equations in the correlation functions of structural responses, which are used to formulate substructure identifications. In this paper, this method is extended to accommodate nonstationary structural responses. A different derivation procedure is adopted to formulate substructure identifications directly from the Fourier transform of the structural dynamic equations, resulting in a formulation nearly the same as its stationary response predecessor. An identification error analysis for the substructure identification method reveals how structural responses affect the identification accuracy. On the basis of this result, a smart reference selection ru...

Substructure Identification for Shear Structures with Nonstationary Structural Responses

Substructure identification is a structural health monitoring technique that identifies a reduced-order model of structural behavior using local vibration measurements. The authors’ prior research on this inherently decentralized technique demonstrated that substructure identification can detect and localize stiffness changes in a shear building. However, identification performance varies from story to story, with parameters of a few stories not satisfactorily identified. To overcome this limitation, the authors and colleagues showed that a structural control device can be used to temporarily change the dynamics of the structure to improve identification performance; however, prior studies assumed full-state feedback, which is not achievable in full-scale implementations. This paper investigates structural control using limited sensor measurements to improve substructure identification. The substructure method is first summarized, followed by an error analysis that can predict a priori the level of error in story parameter estimates. Then, a novel controlled substructure identification procedure is introduced with constraints to ensure that the controlled responses improve substructure identification while reducing overall structural response. State feedback is utilized, with a Kalman filter to estimate states using various sets of acceleration sensor measurements to understand the performance trade-offs. The implementation methodology using an object-oriented programing paradigm is explained; a 3.66-m (12-ft) four-story single-bay steel structure model, subject to low levels of ground motion, is the test bed used for numerical simulations to demonstrate the proposed methodology. The control strategies that include a sensor measuring ground acceleration are shown to be nearly as effective in estimating stiffnesses as the full-state feedback control and all controlled strategies perform better than the uncontrolled case.

Improving Substructure Identification Using Structural Control with Limited Sensor Measurements

Optimal Nonlinear Control Using a Non-quadratic Cost Function for Scalar Systems

In this paper, a substructure identification method for shear structures is proposed. A shear structure is divided into many small substructures; utilizing the dynamic equilibrium of a one-floor substructure, an inductive identification problem is formulated, using the cross-power spectral densities between structural floor accelerations and a reference response, to estimate the parameters of that one story. Repeating this procedure, all story parameters of the shear structure are identified from top to bottom recursively. An identification error analysis is performed for the proposed substructure method, revealing how uncertain factors (e.g. measurement noise) in the identification process affect the identification accuracy. According to the error analysis, a smart reference selection rule is designed to choose the optimal reference response that further enhances the identification accuracy. Moreover, based on the identification error analysis, explicit formulae are developed to calculate the variances of the parameter identification errors. A ten-story shear structure is used to illustrate the effectiveness of the proposed substructure method. The simulation results show that the method, combined with the reference selection rule, can very accurately identify structural parameters despite large measurement noise. Furthermore, the proposed formulae provide good predictions for the variances of the parameter identification errors, which are vital for providing accurate warnings of structural damage.

Substructure identification for shear structures: cross-power spectral density method

Control of semiactive devices, such as magnetorheological fluid dampers for mitigating earthquake- and wind-induced motion of structures, is often accomplished using a clipped-optimal approach. This control strategy uses a primary optimal controller designed assuming the devices were active, linear and ideal, and a secondary bang-bang controller to make the semiactive device produce forces that mimic, as closely as possible, the desired active control. With multiple control devices, one or more may be inactive at any one time when the corresponding desired force is non-dissipative and cannot be exerted by a semiactive device. This approach effectively uses a gain scheduling type of approach, but it has not previously been studied in that context. This paper investigates a variety of schedule combinations of control gains to determine which approaches strongly affect the performance of the closed-loop response and find optimal gain schedule designs. The example demonstrates that improvements of at least 15%, relative to a standard clipped-optimal control, are achievable with a simple gain schedule design.

This paper proposes a real-time hybrid simulation method that will allow complex systems to be tested within the hybrid test framework by employing the convolution integral (CI) method. The proposed CI method is potentially transformative for real-time hybrid simulation. The CI method can allow real-time hybrid simulation to be conducted regardless of the size and complexity of the numerical model and for numerical stability to be ensured in the presence of high frequency responses in the simulation. This paper presents the general theory behind the proposed CI method and provides experimental verification of the proposed method by comparing the CI method to the current integration time-stepping (ITS) method. Real-time hybrid simulation is conducted in the Advanced Hazard Mitigation Laboratory at the University of Connecticut. A seismically excited two-story shear frame building with a magneto-rheological (MR) fluid damper is selected as the test structure to experimentally validate the proposed method. The building structure is numerically modeled and simulated, while the MR damper is physically tested. Real-time hybrid simulation using the proposed CI method is shown to provide accurate results.

Real-time hybrid simulation using the convolution integral method

High fidelity system identification is a prerequisite for successful damage detection. In real world applications, signal noise is a major source of uncertainty and leads to poor results because many methods are unable to accommodate low signal to noise ratios. Controlled substructure identification has emerged as a technique to combat these limitations and provide accurate system identification with high levels of noise (up to 40% rms). This method works by first isolating a substructure for identification. Next, the commands to a structural control device are temporarily reconfigured with a specially designed control law that has been shown to improve identification accuracy. This process is repeated on other substructures until the entire structure is identified. Accurate identification has been demonstrated in simulation for a variety of structural control devices and building systems (Zhang & Johnson, 2011). Moreover, small scale experimental verification has taken place and simulation results were confirmed (Zhang, DeVore, & Johnson, 2010). This paper builds on the body of knowledge by documenting medium scale experimental testing undertaken at the University of Connecticut. Currently, a 12' steel structure is being fabricated and configured as a four story shear building structure. This experimental model represents a more realistic model of a civil building structure than previous work. Prior to experimental testing, numerical simulation is performed to develop performance estimates and guide testing procedure. This paper documents the numerical simulations and shows that controlled substructure identification can improve identification accuracy in substructures with poor identification accuracy.

Experimental Verification of Controlled Substructure Identification Using Control Devices: A Preliminary Simulation Study

The writers recently proposed a new type of mass damper system to integrate structural and environmental control systems for buildings. External shading fins are used as mass dampers such that they can (1) control building energy consumption by adjusting the fins and, thus, the amount of sunlight entering the building; and (2) control structural movements by dissipating energy with the dampers during strong motions. Because shading fins are placed along the height of the building, the mass dampers are distributed along the building height instead of concentrated in one or a few locations like traditional tuned mass dampers (TMDs). The distributed mass damper (DMD) system is formulated and simulated for earthquake motions. Optimization is performed on damper parameters (i.e., masses, stiffness, and damping coefficients) of the passive DMD system to minimize structural responses. A near-optimal DMD system outperforms a single TMD system. The movable shading fins are also briefly discussed; they show a subst...

Distributed Mass Damper System for Integrating Structural and Environmental Controls in Buildings

This paper investigates the dissipativity and performance characteristics of the semiactive control of the base isolated benchmark structure with MR fluid dampers. Previously, the authors introduced the concepts of dissipativity and dissipativity indices in semiactive control of structures with smart dampers and investigated dissipativity characteristics of simple structures with idealized dampers. To investigate the effects of dissipativity characteristics of semiactive controller on the overall performance of the base isolated benchmark building, a clipped optimal control strategy with a LQG controller and a 20 ton MR fluid damper model is used. A cumulative index is proposed to quantify the overall dissipativity of a control system with multiple control devices. Two control designs with different dissipativity and performance characteristics are considered as the primary controller in a clipped optimal control. Numerical simulations reveal that the dissipativity indices can be classified into two groups that exhibit two distinct patterns. It is shown that the dissipativity indices identify primary controllers that are more suitable for application with MR dampers and provide useful information in the semiactive design process that compliments other performance indices. Computational efficiency of the proposed dissipativity indices is verified by comparing computation times.

Dissipativity Analysis of the Base Isolated Benchmark Structure with MR Fluid Dampers

This paper investigates the dissipativity and performance characteristics of the semiactive control of the base isolated benchmark structure with magnetorheological (MR) fluid dampers. Previously, the authors introduced the concepts of dissipativity and dissipativity indices in the semiactive control of structures with smart dampers and studied the dissipativity characteristics of simple structures with idealized dampers. To investigate the effects of semiactive controller dissipativity characteristics on the overall performance of the base isolated benchmark building, a clipped optimal control strategy with a linear quadratic Gaussian (LQG) controller and a 20 ton MR fluid damper model is used. A cumulative index is proposed for quantifying the overall dissipativity of a control system with multiple control devices. Two control designs with different dissipativity and performance characteristics are considered as the primary controller in clipped optimal control. Numerical simulations reveal that the dissipativity indices can be classified into two groups that exhibit distinct patterns. It is shown that the dissipativity indices identify primary controllers that are more suitable for application with MR dampers and provide useful information in the semiactive design process that complements other performance indices. The computational efficiency of the proposed dissipativity indices is verified by comparing computation times.

Dissipativity analysis of the base isolated benchmark structure with magnetorheological fluid dampers

Efficient uncertainty quantification of dynamical systems with local nonlinearities and uncertainties

Recent developments of a distributed mass damper (DMD) system integrate structural and environmental control systems for buildings. External shading fins are used as mass dampers such that they can (i) control building energy consumption by adjusting the fins and, thus, the amount of sunlight coming into the building and (ii) control structural movements by dissipating energy with the dampers during strong motions due to wind or earthquakes. Shading fins are placed along the height of the building, distributing the mass along the building instead of being concentrated in a few locations like traditional tuned mass dampers (TMDs). This eliminates any large damper mass on the top of the building that can be a structural and architectural challenge to design. The DMD system is formulated, simulated and analyzed with passive, active and semiactive control strategies. The passive DMD is shown to be as effective in response mitigation as a conventional TMD; active and semiactive strategies give further improvements. The building energy consumption using the movable shading fins is also briefly presented in this paper.

In this paper, a new function of Variable Stiffness & Damping Device (VSDD) brace control systems is explored: facilitating structural parameter estimation and damage detection. In previous studies by the authors, a substructure identification method has been proposed to identify the structural parameters (story stiffness and damping coefficients) of a shear building. An error analysis shows that the accuracy of the estimated parameters can be greatly improved by amplifying the interstory acceleration near the substructure natural frequency. To achieve this structural response change, two kinds of control strategies are studied herein to design a VSDD system: an on-off passive strategy and a semiactive strategy. Since the accuracy of substructure identification is only dependent on the controlled substructure responses, it is shown that the proposed control-facilitated identification is robust to one common control system error: feedback measurement noise. Finally, a numerical example of a 5-story shear building structure is used to illustrate the efficacy of the proposed control method for improving the accuracy of the substructure identification.

Design of a VSDD brace control system for parameter estimation of shear structures

Structural Health Monitoring (SHM) is an important and growing field in civil engineering. The goal of SHM techniques is to identify, quantify and locate damage in structures. In light of the aging infrastructure and recent failures of important bridges, long-term monitoring techniques are being increasing investigated and adopted. In addition to SHM, structural control (SC) is increasingly adopted in modern structures around the world. In the past two decades a number of SC techniques, including, passive, semi-active, and active control methods have been developed and adopted in civil engineering–particularly, in infrastructure such as important tall buildings, critical facilities, and long span bridges. Both SHM and SC technology face significant challenges due to the size and scale of civil engineering structures. In response of these challenges researchers in the U.S.A and around the world have developed new and innovative techniques.This paper summarizes some of the ongoing research in the U.S.A. in the area of monitoring, damage detection and control in civil engineering structures.

Current Directions of Structural Health Monitoring and Control in USA

Many branches of engineering, mathematics, and sciences, have relied on benchmark problems as a standard means to compare different solution techniques. Since 1996, the ASCE Structural Control and Monitoring Committee and Task Group on Benchmark Problems, the U.S. Panel on structural control, and IASCM have developed a series of benchmark control problems that offer a set of carefully modeled real‐world structures in which different control strategies can be implemented, evaluated, and compared using a common set of performance indices. First‐, second‐ and third‐generation benchmark problems focusing on the response control of seismic and wind‐excited buildings, and seismically excited long‐span cable‐stayed bridges have been developed and evaluated.

Structural control benchmark problem: Phase II—Nonlinear smart base‐isolated building subjected to near‐fault earthquakes

A BSTRACT : Stay cables, such as are used in cable-stayed bridges, are prone to vibration due to their low inherent damping characteristics. Transversely-attached passive viscous dampers have been implemented in many bridges to dampen such vibration. Several studies have investigated optimal passive linear viscous dampers; however, even the optimal passive device can only add a small amount of damping to the cable when attached a reasonable distance from the cable/deck anchorage. This paper investigates the potential for improved damping using semiactive devices. The equations of motion of the cable/damper system are derived using an assumed modes approach and a control-oriented model is developed. The control-oriented model is shown to be more accurate than other models and facilitates low-order control designs. The effectiveness of passive linear viscous dampers is reviewed. The response of a cable with passive, active and semiactive dampers is studied. The response with a semiactive damper is found to be dramatically reduced compared to the optimal passive linear viscous damper for typical damper configurations, thus demonstrating the potential benefits using a semiactive damper for absorbing cable vibratory energy.

The connected control method (CCM) has been shown previously to be a viable means to protect adjacent flexible structures. The CCM works by using an auxiliary structure to provide a reaction force for control. The CCM can be applied to a variety of structural systems including civil, mechanical, or aerospace structures, and can incorporate various types of control strategies including passive, active, or semiactive control. This paper focuses on the application of the CCM to seismically excited adjacent buildings employing semiactive control and extends the previous research in semiactive coupled building control to examine the effects of relative building height and coupling link location on the semiactive performance. The optimal semiactive coupled building configuration is shown to follow two guidelines: (1) The dominant frequencies of the two coupled buildings do not coincide and (2) the coupling link is not placed at the node of a dominant vibratory mode. Additionally, it is shown that semiactive con...

Semiactive Connected Control Method for Adjacent Multidegree-of-Freedom Buildings

INVESTIGATION OF DISSIPATIVITY FOR SEMIACTIVE CONTROL OF THE BASE ISOLATED BENCHMARK BUILDING WITH MR DAMPERS

Stay cables, such as are used in cable-stayed bridges, are prone to vibration due to their low inherent damping characteristics. Transversely attached passive viscous dampers have been implemented in many bridges to dampen such vibration. However, only minimal damping can be added if the attachment point is close to the bridge deck. For longer bridge cables, the relative attachment point becomes increasingly smaller, and passive damping may become insufficient. A recent analytical study by the authors demonstrated that “smart” semiactive damping can provide increased supplemental damping. This paper experimentally verifies a smart damping control strategy employing H2 ∕linear quadratic Gaussian (LQG) clipped optimal control using only force and displacement measurements at the damper for an inclined flat-sag cable. A shear mode magnetorheological fluid damper is attached to a 12.65 m inclined flat-sag steel cable to reduce cable vibration. Cable response is seen to be substantially reduced by the smart da...

The first phase of the seismically excited base‐isolated benchmark building was received well by the structural control community, culminating in the March 2006 journal special issue. The special issue contained contributions from over dozen participants world‐wide. While the focus of the Phase I effort was on linear isolation systems, Phase II attempts to galvanize research efforts on control of base‐isolated buildings with nonlinear isolation systems. Primarily, friction and hysteretic lead–rubber‐bearing (LRB) isolation systems are included in this effort. The superstructure and the control framework remains the same as the Phase I benchmark. The main difference will be in the nonlinear isolation systems used, and consequently the controllers necessary to control such systems. The primary objective of this paper is to present the Phase II benchmark problem definition along with a sample controller for friction isolation system. A sample controller for the LRB isolation system was presented earlier as a part of the Phase I special issue. Included in this paper is a broad set of carefully chosen performance measures, which remain the same as Phase I, so that the participants may evaluate their respective control designs. The control algorithms may be passive, active or semiactive. The benchmark structure considered in the Phase II study is an eight‐story base‐isolated building that is identical to the one considered for the Phase I study. The base isolation system consists of a combination of linear, nonlinear bearings and control devices. The superstructure is considered to be a linear elastic system with lateral–torsional behavior. The nonlinearities due to the isolators and control devices are limited to the isolation level only. A nonlinear dynamic analysis program and sample controllers are made available to the participants to facilitate direct comparison of results of different control algorithms. Copyright © 2008 John Wiley & Sons, Ltd.

Smart base‐isolated benchmark building part IV: Phase II sample controllers for nonlinear isolation systems

Coupled building control has been shown to be an effective means of protection for flexible building structures. Numerous researchers have proposed various active, passive, and semiactive coupled building control strategies for both high-rise and low-rise buildings. Actual applications of coupled building control for low-rise buildings and high-rise buildings have been successfully implemented in Japan using passive and active control technology. Much of the research in the literature has focused on specific building pairs. To date, there have been no detailed studies of the effects of the building configuration and connector location on the overall system performance. This paper examines these effects and compares the efficacy of passive and active coupled building control for flexible adjacent buildings.

Coupled Building Control Considering the Effects of Building/Connector Configuration

Structural health monitoring (SHM) is an active area of research devoted to systems that can autonomously and proactively assess the structural integrity of bridges, buildings, and aerospace vehicles. Recent technological advances promise the eventual ability to cover a large civil structure with low-cost wireless sensors that can continuously monitor a building's structural health, but researchers face several obstacles to reaching this goal, including high data-rate, data-fidelity, and time-synchronization requirements. This article describes two systems the authors recently deployed in real-world structures.

Structural health monitoring (SHM)isan important application areaforwireless sensornetworks. SHM techniques attempttoautonomously detect andlocalize damageinlarge civil structures. Structural engineers oftenimplement and testSHM algorithms ina higher level language suchas C/Matlab. Inthispaper,we describe thedesign andevaluation ofNETSHM,a sensor networksystemthatallows structural engineers toprogram SHM applications inMatlabor C ata highlevel ofabstraction. Inparticular, structural engineers donothavetounderstand theintricacies of wireless networking, orthedetails ofsensordataacquisition. We haveimplemented a damagedetection technique anda damagelocalization technique on a complete NETSHM prototype. Ourexperiments on smallandmedium-scale structuresshowthatNETSHM isabletodetectandlocalized damageperfectly withvery fewfalse-positives andno false negatives, andthatitisrobust even inrealistic wireless environments.

The smart base isolated benchmark problem is the ﬁrst benchmark building problem that is fully three-dimensional and subjected to both horizontal components of ground excitation (vertical excitation is not considered). The benchmark structure is an eight-storey base isolated building, similar to existing buildings in Los Angeles, CA. The superstructure is modeled as a linear elastic system with lateral-torsional behaviour. The base isolation system, which accounts for lateral-torsional coupling, includes both linear and nonlinear bearings and control devices; nonlinear biaxial interaction in the bearings is included. A new nonlinear, computationally eﬃcient, MATLAB-based dynamic analysis program has been developed to facilitate direct comparison of results of diﬀerent control algorithms. The control algorithms may be passive, active or semi-active. The problem state-ments and associated MATLAB data/models can be downloaded via the web at the following URL: The smart base isolated benchmark problem is aimed at evaluating diﬀerent control strategies; it includes four parts (1) part I, deﬁnition of the benchmark problem, (2) part II, phase I sample controllers for linear isolation system, (3) part III, phase II sample controller for the bilinear elastomeric isolation system, and (4) part IV, phase II sample controller for sliding isolation system. The earlier published special issue on the Phase I of the smart base isolated benchmark problem, focused primarily on linear base isolated structures (Part I and II). Participants of the Phase I study proposed diﬀerent devices, active and semiactive control strategies, evaluated, and reported their results when compared to the results of the sample controllers for linear isolation systems. The nonlinear isolation

Special Issue on “Structural Control Benchmark Problem: Phase II‐Nonlinear Smart Base Isolated Building Subjected To Near Fault Earthquakes”

This paper presents the benchmark problem definition for seismically excited base‐isolated buildings. The objective of this benchmark study is to provide a well‐defined base‐isolated building with a broad set of carefully chosen parameter sets, performance measures and guidelines to the participants, so that they can evaluate their control algorithms. The control algorithms may be passive, active or semi‐active. The benchmark structure considered is an eight‐storey base‐isolated building similar to existing buildings in Los Angeles, California. The base isolation system includes both linear and nonlinear bearings and control devices. The superstructure is considered to be a linear elastic system with lateral–torsional behavior. A new nonlinear dynamic analysis program has been developed and made available to facilitate direct comparison of results of different control algorithms. Copyright © 2005 John Wiley & Sons, Ltd.

Smart base‐isolated benchmark building. Part I: problem definition

K. Chintalapudi,T. Fu, E. Johnson, R. Govindan," Distributed Structural Damage Detection and Localization Using Wireless Sensor Networks

This paper investigates the effects of dissipativity on the performance of semiactive systems with smart dampers via linear matrix inequality (LMI) methods. First, a linear quadratic regulator (LQR) problem is defined in terms of a linear objective function and several LMI constraints. Second, two dissipativity indices are proposed to quantify the dissipative nature of a force. One of the dissipativity indices is appended as an LMI constraint in its weak form to the LMI-LQR problem to exploit the dissipative nature of a smart damper. The dissipativity indices and the proposed controller are employed for a two-degree-of-freedom structure with a clipped optimal control problem. It is observed that the proposed method is able to improve the dissipative nature of the controller, improving the semiactive performance.

Investigation of dissipativity for control of smart dampers via LMI synthesis

With the advent of miniaturized sensing technology, it has become possible to envision smart structures containing millions of sensors embedded in concrete for autonomously detecting and locating incipient damage. Where are we today in our march towards this vision of autonomous structural health monitoring (SHM) using networked embedded sensing? In this paper, we summarize some of the systems we have developed towards this vision. Wisden is a wireless sensor network that allows continuous monitoring of structures and NetSHM is a programmable system that allows civil engineers to implement and deploy SHM techniques without having to understand the intricacies of wireless sensor networking. We highlight our experiences in developing these systems, and discuss the implications of our experiences on the achievability of the overall vision.

11th IEEE International Conference on Embedded and Real-Time Computing Systems and Applications (RTCSA'05)

This paper describes an ongoing project investigating embedded networked sensing for structural health monitoring applications. The vision is of many low-power sensor “motes” embedded throughout the structure with a smaller number of nodes that can provide local excitation. The challenge is to develop both the networking algorithms to reliably communicate within the network, and distributed algorithms to monitor the state of the structure. A wireless data acquisition network is described, including the methods of storing and transmitting the data. A damage detection scheme is described that uses extremely low transmission bandwidth, and is shown to be effective in detecting damage in a simulated structure. Finally, a large-scale structural testbed that is being used for this project is described. The outcome of this work-in-progress is expected to be strong recommendations and algorithms for distributed wireless sensor/actuator structural health monitoring networks.

Structural health monitoring (SHM) is a promising field with widespread application in civil engineering. Structural health 
monitoring has the potential to make structures safer by observing both long-term structural changes and immediate postdisaster damage. 
However, the many SHM studies in the literature apply different monitoring methods to different structures, making side-by-side comparison 
of the methods difficult. This paper details the first phase in a benchmark SHM problem organized under the auspices of the 
IASC–ASCE Structural Health Monitoring Task Group. The scale-model structure adopted for use in this benchmark problem is described. 
Then, two analytical models based on the structure—one a 12 degree of freedom (DOF) shear-building model, the other a 
120-DOF model, both finite element based—are given. The damage patterns to be identified are listed as well as the types and number of 
sensors, magnitude of sensor noise, and so forth. MATLAB computer codes to generate the response data for the various cases are 
explained. The codes, as well as details of the ongoing Task Group activities, are available on the Task Group web site at 
 .

Phase I IASC-ASCE Structural Health Monitoring Benchmark Problem Using Simulated Data

This paper presents the benchmark problem definition for seismically excited base-isolated buildings. The objective of this benchmark study is to provide a well defined base isolated building with a broad set of carefully chosen parameter sets, performance measures and guidelines to the participants, so that they can evaluate their control algorithms. The control algorithms may be passive, active or semi-active. The benchmark structure considered is an eight story base isolated building similar to existing buildings in Los Angeles, California. The base isolation system includes both linear and nonlinear bearings and control devices. The superstructure is considered to be a linear elastic system with lateral-torsional behavior. A new nonlinear dynamic analysis program has been developed and made available to facilitate direct comparison of results of different control algorithms.

This paper presents a tutorial control design for the base isolated benchmark building with bilinear hysteretic bearings ( e.g. , lead-rubber bearings) by addressing the coupled problem of finding a good linear model for the controlled nonlinear system and designing a linear optimal controller. First, the dynamics of the benchmark structure are reviewed and developed in a control-oriented manner. Second, an initial linear model, based on small-motion behavior, is developed. This model is then used to determine a reasonable cost function, trading off drifts and absolute accelerations in the structure. Then, an iterative study is described for developing the linearized model and corresponding linear control design. A Kalman filter is used as an estimator, and a Kanai-Tajimi filter is used in the control design to model typical ground motion frequency content. Finally, the responses of the controlled equivalent linear system and the controlled nonlinear system are compared for a specific ground motion data.

A Control Design Methodology for the Benchmark Base Isolated Building with Bilinear Isolation

Accurate diagnosis of structural health is a vital step in protecting structures. An autonomous monitoring system that has the capability of predicting the location of damage would have a positive economic impact, not to mention the potential for saving lives, by giving quick assessments of structural health and whether immediate evacuation of, or rerouting, around a structure is necessary. The process of monitoring structural health and identifying damage severity and location is generally termed structural health monitoring. The core of this project is to investigate how variable stiffness and damping devices (VSDD) can be most effectively used to identify local damage in bridges and building structures. Using one or more VSDDs to modify the response, simulated damage is detected, localized and quantified. One fundamental goal is to determine the best VSDD actions, whether adding damping or stiffness, to precisely and robustly locate and identify bridge damage. This study is based on simulation of bridge motion and other structures due to ambient excitation sources. Several VSDD behaviors, such as variable stiffness mode and variable damping mode, are studied in the context of a frequency domain analysis. These analyses are performed on simple models of bridge and building dynamics (e.g., 2 degree-of-freedom shear model systems and a 6 degree-of-freedom model). Structural behavior is assumed locally linear before damage and after damage. Generally, VSDDs were successful in improving the damage identification in structures using the variable stiffness mode but rather unsuccessful in the variable damping only mode. In addition to demonstrating the potential of using variable stiffness and damping devices to improve structural health monitoring, this study also provides some insights into future research directions.

PARAMETRIC FREQUENCY DOMAIN IDENTIFICATION USING VARIABLE STIFFNESS AND DAMPING DEVICES

A benchmark study in structural health monitoring based on simulated structural response data was developed by the joint IASC–ASCE Task Group on Structural Health Monitoring. This benchmark study was created to facilitate a comparison of various methods employed for the health monitoring of structures. The focus of the problem is simulated acceleration response data from an analytical model of an existing physical structure. Noise in the sensors is simulated in the benchmark problem by adding a stationary, broadband signal to the responses. A structural health monitoring method for determining the location and severity of damage is developed and implemented herein. The method uses the natural excitation technique in conjunction with the eigensystem realization algorithm for identification of modal parameters, and a least squares optimization to estimate the stiffness parameters. Applying this method to both undamaged and damaged response data, a comparison of results gives indication of the location and extent of damage. This method is then applied using the structural response data generated with two different models, different excitations, and various damage patterns. The proposed method is shown to be effective for damage identification. Additionally the method is found to be relatively insensitive to the simulated sensor noise.

NATURAL EXCITATION TECHNIQUE AND EIGENSYSTEM REALIZATION ALGORITHM FOR PHASE I OF THE IASC-ASCE BENCHMARK PROBLEM: SIMULATED DATA

Optical Energy Gap in Amorphous/Microcrystalline Silicon Prepared by DC Saddle-Field Glow Discharge Method

Accurate diagnosis of structural health is a vital step in protecting structures. Whether caused by acute events, such as earthquakes or other natural disasters, or long-term degradation from environment and human use (and abuse), structural damage can threaten both human life and economic loss. An autonomous monitoring system that has the capability of predicting the location of damage would have a positive economic impact, not to mention the potential for saving lives by giving quick assessments of structural health and whether immediate evacuation of, or re-routing, around a structure is necessary. The process of monitoring structural health and identifying damage severity and location is generally termed structural health monitoring (SHM). The core of this project is to investigate how variable stiffness and damping devices (VSDD) can be most effectively used to identify local damage in bridge and building structures. Using one or more VSDDs to modify the response, simulated damage is detected, localized, and quantified. One fundamental goal is to determine the best VSDD actions — whether adding damping or stiffness — to precisely and robustly locate and identify bridge damage. This study is based on simulation of bridge motion and other structures due to ambient excitation sources. Several VSDD behaviors, such as variable stiffness mode and variable damping mode, are studied in the context of a frequency domain analysis. These analyses are performed on simple models of bridge and building dynamics, e.g., two degree-of-freedom (2DOF) shear model systems and a six degree-of-freedom (6DOF) model. Structural behavior is assumed locally linear before damage and after damage. Generally, VSDDs were successful in improving the damage identification in structures using the variable stiffness mode but rather unsuccessful in the variable damping only mode. In addition to demonstrating the potential of using variable stiffness and damping devices to improve structural health monitoring, this study also provides some insights into further avenues of future research to build on the improvements studied herein.

PROJECT Project 0110 PARAMETRIC FREQUENCY DOMAIN IDENTIFICATION USING VARIABLE STIFFNESS AND DAMPING DEVICES FINAL REPORT

This paper is a summary of the discussions regarding structural health monitoring (SHM) during the Working Group 2 session of the 4th International Workshop on Structural Control on the afternoon of Thursday 10 June 2004 at Columbia University. The state-of-the-art in SHM hardware, the development of SHM benchmark studies and other research recommendations are discussed.

Structural Vibration Mitigation Using Dissipative Smart Damping Devices

Parametric Frequency Domain Identification Using Variable Stiffness and Damping Device [Final Report]

Cables, such as are used in cable-stayed bridges, suspension bridges, guy wires, transmission lines, and flexible space structures, are prone to vibration due to their low inherent damping characteristics. The mitigation of cable vibration is necessary to minimize negative impact. Transversely-attached passive viscous dampers have been implemented on some cables to dampen vibration. However, it can be shown that only minimal damping can be added if the damper attachment point is close to the end of the cable. For long cables, passive dampers may provide insufficient supplemental damping to eliminate vibration problems. A recent study by the authors demonstrated that “smart” semiactive damping can provide significantly superior supplemental damping for a cable modeled as a taut string. This paper extends the previous work by adding sag, inclination, and axial flexibility to the cable model. The equations of motion are given. A new control-oriented model is developed for cables with sag. Passive, active, and smart (semiactive) dampers are incorporated into the model. Cable response is seen to be dramatically reduced by semiactive dampers for a wide range of cable sag and damper location.

Approximately uniform distributions of sample points are useful in certain problems in engineering and mathematics, notably optimization and uncertainty. For example, weight-controlled Monte Carlo simulation (MCS), a technique to improve estimates of low-probability events, would ideally have samples approximately uniformly distributed throughout the sample space with weights estimating probability. Response surface methodologies likewise benefit from an even distribution of sample points, not only over the input space but also over the output space, particularly in regions where steep gradients occur. The notion of uniformity can be quantified by the concept of discrepancy, which is a measure of the difference between a sample distribution and an ideal distribution -- in this case, a uniform distribution. This paper advances the discrepancy sensitivity, a linear approximation for the change in discrepancy when adding or removing a particular sample point, as a numerical measure of a sample point’s contribution to uniformity. Essentially, this quantifies the level of “new” information provided by a sample point. Several examples are given of its use in choosing sample points for response surface characterization. The example problems, while of trivial computational complexity, exhibit some of the “difficult” behaviors — such as multimodality, sharp corners, and so forth — that are typical of many real world applications. It is demonstrated that using the discrepancy sensitivity, sample points can be effectively spread throughout the “interesting” regions of these functions. Some indications of the current work-inprogress and future directions are given. †

USE OF DISCREPANCY SENSITIVITY IN UNCERTAINTY QUANTIFICATION AND OPTIMIZATION

Numerical Solution of the Four-Dimensional Nonstationary Fokker-Planck Equation

Stay cables, such as are used in cable-stayed bridges, are prone to vibration due to their low inherent damping characteristics. Transversely-attached passive viscous dampers have been implemented in many bridges to dampen such vibration. However, only minimal damping can be added if the attachment point is close to the deck. For longer bridge cables, passive damping is insufficient. A recent study by the authors demonstrated that "smart" semiactive damping can provide significantly superior supplemental damping. This paper experimentally verifies a smart damping control strategy for an inclined flat-sag cable. Cable response is seen to be substantially reduced by the smart damper.

Proceedings of the 2001 American Control Conference. (Cat. No.01CH37148)

Significant advances have been made in structural health monitoring in recent 
years, and further breakthroughs have the potential to make structures safer by 
observing both long-term structural changes and immediate post-disaster damage. 
However, it is difficult to compare various health monitoring methods since the 
studies reported in the literature examine different structures and use different 
evaluation criteria. To provide a basis for common comparisons, this paper 
describes the first phase in a SHM benchmark problem organized by the IASCASCE 
Structural Health Monitoring Task Group. This first phase defines a series of 
simulated measured acceleration records for a scale-model structure, using several 
different building models and with various damage patterns. The ongoing activities 
of the Task Group are further detailed at http://wusceel.cive.wustl.edu/asce.shm/ .

A Simulated Data Benchmark Problem in Structural Health Monitoring

A BSTRACT Studying large complex problems that often arise in computational stochastic dynamics (CSD) demands significant computer power and data storage. Parallel processing can help meet these requirements by exploiting the computational and storage capabilities of multiprocessing computational environments. The challenge is to develop parallel algorithms and computational strategies that can take full advantage of parallel machines. This paper reviews some of the characteristics of parallel computing and the techniques used to parallelize computational algorithms in CSD. The characteristics of parallel processor environments are discussed, including parallelization through the use of message passing and parallelizing compilers. Several applications of parallel processing in computational stochastic dynamics are then developed: solutions of the Fokker-Planck equation, Monte Carlo simulation of dynamical systems, and random eigenvector problems. In these examples, parallel processing is seen to be a promising approach through which to resolve some of the computational issues pertinent to computational stochastic dynamics. 1. I NTRODUCTION Studying large complex problems that often arise in computational stochastic dynamics (CSD) demands significant computer power and data storage. This is particularly true when highprecision solutions are required. Parallel processing can help alleviate these requirements by taking advantage of the computational and storage abilities of multiprocessing computational environments. Very high performance can be achieved by using powerful microprocessors in parallel, and the distributed memory in some parallel paradigms can provide significantly more memory than is often available in serial computers. The challenge is to develop parallel algorithms and computational strategies that can fully utilize the capabilities of parallel machines for solving problems in CSD. To do so requires recasting many algorithms originally written for sequential processing. To achieve high performance in parallel processing, the numerical algorithms must meet stringent requirements in terms of concurrency and minimizing the overhead costs associated with task management [2,3].

A "smart" base isolation system (SBIS) is proposed and shown to effectively protect structures against extreme earthquakes without sacrificing performance during the more frequent, moderate seismic events. The proposed SBIS is composed of conventional low-damping elastomeric bearings and "smart" controllable (semiactive) dampers, such as magnetorheological fluid dampers. To demonstrate the advantages of this approach, the SBIS is compared to lead-rubber bearing isolation systems. The effectiveness of the isolation approaches are judged based on computed responses to several historical earthquakes scaled to various magnitudes. The limited performance of passive systems is revealed and the potential advantages of smart dampers are shown. Two- and 6-degree-of-freedom models of a base-isolated structure are used as a test bed in this study. Smart isolation is shown to achieve notable decreases in base drifts over comparable passive systems with no accompanying increase in base shears or in accelerations imparted to the superstructure. In contrast to passive lead-rubber bearing systems, the adaptable nature of the SBIS provides good protection to both the structure and its contents over a wide range of ground motions and magnitudes.

Consideration of near-source, high velocity, long-period seismic pulses, as were recorded during the Northridge and Kobe earthquakes, has taught engineers and researchers that ground motions due to such earthquakes can be difficult to accommodate. This paper discusses a base isolation system using "smart" dampers, such as magnetorheological fluid dampers, that can adapt to, and protect against, seismic excitatiorn of different characteristics. A linear, two degree-of-freedom, lumped-mass model of a base-isolated budding is used as the testbed for this study. Linear viscous dampers are shown to have an optimal damping level for several design earthquakes to achieve minimum peak accelerations. A study of a family of controllers for the smart damper is used to find an "optimal" isolation system over the suite of ground motions considered. This "optimal" system further decreases the base drift compared to the "optimal" linear viscous damper without increasing the accelerations imparted into the superstructure. The "smart" damper is shown to be a most effective alternative for a broad class of earthquakes including near-source events.

Jsme International Journal Series C-mechanical Systems Machine Elements and Manufacturing

Coupling adjacent buildings with supplemental damping devices is a developing method of mitigating structural responses due to wind and seismic excitations. The concept is to allow structures, vibrating at different frequencies, to exert control forces upon one another to reduce the overall responses of the system. Previous studies have identified optimal coupled building configurations and have introduced passive, active and 'smart' damping control strategies. This paper will focus on the application of 'smart' dampers as coupling link devices to produce control forces between three tall buildings. Smart dampers are semi-active dampers capable of changing their dynamic characteristics in real-time to allow for a variety of control forces to be produced without requiring significant energy. A clipped optimal control strategy is employed for the smart dampers that can provide increased performance, over a comparable passive control strategy, during moderately severe seismic events.

Stay cables, such as are used in cable-stayed bridges, are prone to vibration due to their low inherent damping characteristics. Transversely-attached passive viscous dampers have been implemented in many bridges to dampen such vibration. Several studies have investigated optimal passive linear viscous dampers, however even the optimal passive device can only add minimal damping to the cable when attached a reasonable distance from the cable deck anchor. This paper investigates the potential for improved damping using semiactive devices. The equations of motion of the cable/damper system are derived using an assumed modes approach and a control-oriented model is developed. The control-oriented model is shown to be more accurate that other models and facilitates low-order control designs. The effectiveness of passive linear viscous dampers are reviewed. The response of a cable with passive, active and semiactive dampers is studied. The response with a semiactive damper is found to be dramatically reduced compared to the optimal passive linear viscous damper for typical damper configurations, thus demonstrating the efficacy of a semiactive damper for absorbing cable vibratory energy.

Structural health monitoring (SHM) is a promising field with widespread application in civil engineering. 
However, many SHM studies apply different methods to different structures, often making side-by-side 
comparison of the methods difficult. This paper details the first phase in a benchmark SHM problem organized 
under the auspices of the IASC-ASCE Structural Health Monitoring Task Group. The scale-model 
structure adopted for use in this benchmark problem is described. Then, two analytical models based on 
the structure — one a 12DOF shear-building model, the other a 120DOF model, both finite-element based 
— are given. The damage patterns to be identified are listed as well as the types and number of sensors, 
magnitude of sensor information, and so forth. More details are available on the Task Group web site at 
wusceel.cive.wustl.edu/asce.shm/ .

A BENCHMARK PROBLEM FOR STRUCTURAL HEALTH MONITORING AND DAMAGE DETECTION

Stay cables, such as used in cable-stayed bridges, are prone to vibration due to their low inherent damping characteristics. Several studies have investigated the use of an optimal viscous damper attached transversely to dampen such vibration. This paper investigates the potential for improved damping using a semiactive device. The equations of motion of the cable/damper system are derived and the effectiveness of various levels of attached viscous damping are reviewed. The response of a cable with linear viscous, active, and semi-active dampers are studied. The response with a semiactive damper is found to be 55% better than the optimal linear viscous damper, thus demonstrating the efficacy of a semi-active damper for absorbing cable vibratory energy.

Response of stochastic dynamical systems driven by additive Gaussian and Poisson white noise : Solution of a forward generalized Kolmogorov equation by a spectral finite difference method

Stay cables, such as are used in cable-stayed bridges, are prone to vibration due to their low inherent damping characteristics. Transversely attached passive viscous dampers have been implemented in many bridges to dampen such vibration. Several studies have investigated optimal passive linear viscous dampers; however, even the optimal passive device can only add a small amount of damping to the cable when attached a reasonable distance from the cable/deck anchorage. This paper investigates the potential for improved damping using semiactive devices. The equations of motion of the cable/damper system are derived using an assumed modes approach and a control-oriented model is developed. The control-oriented model is shown to be more accurate than other models and facilitates low-order control designs. The effectiveness of passive linear viscous dampers is reviewed. The response of a cable with passive, active, and semiactive dampers is studied. The response with a semiactive damper is found to be dramatically reduced compared to the optimal passive linear viscous damper for typical damper configurations, thus demonstrating the potential benefits using a semiactive damper for absorbing cable vibratory energy.

This paper completes a recent benchmark study in active structural control of a civil engineering structure. The previous work gave an analytical definition of a structure combined with actuators and sensors, along with 15 papers applying various control strategies to this common problem using the same evaluation and performance criteria. As actual implementation is the ultimate test of controller evaluation, this paper reports the experimental performance of these control strategies as applied to a 3-story model building with an Active Mass Driver (AMD).

C ONTROL S TRATEGIES FOR A S TRUCTURAL C ONTROL B ENCHMARK S TUDY : V ERIFICATION BY E XPERIMENT

Passive base isolation systems are one of the most successful and widely implemented technologies for seismic hazard mitigation. However, recent changes to the building codes have made the design requirements such that some of the potential gains of such systems may not be realized. This paper investigates the effects of using controllable semiactive dampers, such as magnetorheological fluid dampers, in a base isolation system. A two degree-of-freedom model of a base isolated building is used, with linear viscous, active, and semiactive supplemental damping devices in the isolation layer. Using an H 2 /LQG design, semiactive and active devices are able to achieve a notable decrease in base drifts, compared to the optimal linear passive designs, with no accompanying increase in accelerations imparted into the superstructure.

An intelligent base-isolation system, comprised of low damping isolation bearings and controllable fluid dampers, is studied in this paper. The damper employs a magnetorheological (MR) fluid that change its properties in the presence of a magnetic field, resulting in a damper whose characteristics may be modified in real time to adapt to changing excitations in a stable and cost-effective manner. A model of a five-story building is used to study and compare the efficacy of a passive base-isolation alone, with the addition of an active control device, and with a semi-active MR damper. A preliminary study of active H 2 /LQG designs shows that mostly dissipative designs exist, which may be implemented using far less power in an approximate manner with an MR damper. Simulations of the semi-active system demonstrate that the ‘smart’ damper can achieve most of the decrease in base displacement and peak acceleration typical of an active device.

On-Line Monitoring, Control, and Reliability of Structural Dynamical Systems

On-Line Modal State Monitoring of Slowly Time-Varying Structures

In the process of attempting to verify statistical moments of response for nonlinear stochastic systems obtained through the numerical solution of the Fokker-Planck equation, the authors observed significant discrepancies between their results and those obtained through direct solution of moment equations employing various closure schemes. Further investigation has led to the examination of the convergence properties of those methods, and some results of that effort are reported herein.

Abstract. The nite elementmethod has been previously applied to the solution of the Fokker-Planck equation for second order systems under additive white noise excitation. Animation of these solutions has provided insights into previously unstudied nonstationary behavior of the transition probability density functions of these systems. This work has now been extended to encompass systems subjected to both additive and multiplicative white noise excitations. In this paper we will examine a sequence of Du ng systems having a negative linear restoring force, and we will demonstrate through inspection of the probability density functions that adding parametric excitation to the linear part of the sti ness term results in stabilization at the origin. We will also compute second moments for each system and show the limited accuracy of several closure methods for this class of systems.

ROBUST NUMERICAL SOLUTION OF THE FOKKER-PLANCK EQUATION FOR SECOND ORDER DYNAMICAL SYSTEMS UNDER PARAMETRIC AND EXTERNAL WHITE NOISE EXCITATIONS

Despite the progress in deep learning networks, efficient learning at the edge (enabling adaptable, low-complexity machine learning solutions) remains a critical need for defense and commercial applications. We envision a pipeline to utilize large neuroimaging datasets, including maps of the brain which capture neuron and synapse connectivity, to improve machine learning approaches. We have pursued different approaches within this pipeline structure. First, as a demonstration of data-driven discovery, the team has developed a technique for discovery of repeated subcircuits, or motifs. These were incorporated into a neural architecture search approach to evolve network architectures. Second, we have conducted analysis of the heading direction circuit in the fruit fly, which performs fusion of visual and angular velocity features, to explore augmenting existing computational models with new insight. Our team discovered a novel pattern of connectivity, implemented a new model, and demonstrated sensor fusion on a robotic platform. Third, the team analyzed circuitry for memory formation in the fruit fly connectome, enabling the design of a novel generative replay approach. Finally, the team has begun analysis of connectivity in mammalian cortex to explore potential improvements to transformer networks. These constraints increased network robustness on the most challenging examples in the CIFAR-10-C computer vision robustness benchmark task, while reducing learnable attention parameters by over an order of magnitude. Taken together, these results demonstrate multiple potential approaches to utilize insight from neural systems for developing robust and efficient machine learning techniques.

Exploiting Large Neuroimaging Datasets to Create Connectome-Constrained Approaches for more Robust, Efficient, and Adaptable Artificial Intelligence

There are multiple scales of abstraction from which we can describe the same image, depending on whether we are focusing on fine-grained details or a more global attribute of the image. In brain mapping, learning to automatically parse images to build representations of both small-scale features (e.g., the presence of cells or blood vessels) and global properties of an image (e.g., which brain region the image comes from) is a crucial and open challenge. However, most existing datasets and benchmarks for neuroanatomy consider only a single downstream task at a time. To bridge this gap, we introduce a new dataset, annotations, and multiple downstream tasks that provide diverse ways to readout information about brain structure and architecture from the same image. Our multi-task neuroimaging benchmark (MTNeuro) is built on volumetric, micrometer-resolution X-ray microtomography images spanning a large thalamocortical section of mouse brain, encompassing multiple cortical and subcortical regions. We generated a number of different prediction challenges and evaluated several supervised and self-supervised models for brain-region prediction and pixel-level semantic segmentation of microstructures. Our experiments not only highlight the rich heterogeneity of this dataset, but also provide insights into how self-supervised approaches can be used to learn representations that capture multiple attributes of a single image and perform well on a variety of downstream tasks. Datasets, code, and pre-trained baseline models are provided at: https://mtneuro.github.io/ .

MTNeuro: A Benchmark for Evaluating Representations of Brain Structure Across Multiple Levels of Abstraction

The brain is arguably the most powerful computation system known. It is extremely efficient in processing large amounts of information and can discern signals from noise, adapt, and filter faulty information all while running on only 20 watts of power. The human brain's processing efficiency, progressive learning, and plasticity are unmatched by any computer system. Recent advances in stem cell technology have elevated the field of cell culture to higher levels of complexity, such as the development of three-dimensional (3D) brain organoids that recapitulate human brain functionality better than traditional monolayer cell systems. Organoid Intelligence (OI) aims to harness the innate biological capabilities of brain organoids for biocomputing and synthetic intelligence by interfacing them with computer technology. With the latest strides in stem cell technology, bioengineering, and machine learning, we can explore the ability of brain organoids to compute, and store given information (input), execute a task (output), and study how this affects the structural and functional connections in the organoids themselves. Furthermore, understanding how learning generates and changes patterns of connectivity in organoids can shed light on the early stages of cognition in the human brain. Investigating and understanding these concepts is an enormous, multidisciplinary endeavor that necessitates the engagement of both the scientific community and the public. Thus, on Feb 22–24 of 2022, the Johns Hopkins University held the first Organoid Intelligence Workshop to form an OI Community and to lay out the groundwork for the establishment of OI as a new scientific discipline. The potential of OI to revolutionize computing, neurological research, and drug development was discussed, along with a vision and roadmap for its development over the coming decade.

First Organoid Intelligence (OI) workshop to form an OI community

The nervous systems of animals exhibit complex recurrent topologies. These networks often show key properties like small-worldness and clustering, forming a complex hierarchical topology that is very different from many standard random graphs. Current machine learning techniques are dominated by feed-forward networks without recurrent connectivity, or specialized architectures for gated recurrent connectivity (such as Long-Short Term Memory Networks). Reservoir computing networks, such as echo state networks, represent an exciting alternative form of recurrent networks, which require limited training data compared to other recurrent networks. Echo state networks, however, typically use randomized network topologies. We introduce a novel reservoir computing network, with a hierarchical network structure inspired by organization of biological networks, utilizing hierarchical stochastic block models. We demonstrate the use of this network for predicting dynamic system evolution, and we compare this network to existing echo state network topologies. We find that the best performing networks utilize our new topology, and, for Mackey-Glass system prediction as well as MNIST classification, the overall distribution of solutions is improved. For the Mackey-Glass system, the median population NRMSE improved from 0.856 to 0.08, and for MNIST the median population accuracy increased from 92.5% to 96.8%. This may be preliminary indication of improving network function through changing network topology. The spectral radii of the produced HSBM topologies do not always obey the echo state property, and we show that both the spectral radius as well as common graph metrics do not predict the best performing networks. This argues for further investigation into the structural properties of high performing networks utilizing reservoir computing.

Investigating Echo State Network Performance with Biologically-Inspired Hierarchical Network Structure

Neuroscientists now have the opportunity to analyze synaptic resolution connectomes that are larger than the memory on single consumer workstations. As dataset size and tissue diversity have grown, there is increasing interest in conducting comparative connectomics research, including rapidly querying and searching for recurring patterns of connectivity across brain regions and species. There is also a demand for algorithm reuse — applying methods developed for one dataset to another volume. A key technological hurdle is enabling researchers to efficiently and effectively query these diverse datasets, especially as the raw image volumes grow beyond terabyte sizes. Existing community tools can perform such queries and analysis on smaller scale datasets, which can fit locally in memory, but the path to scaling remains unclear. Existing solutions such as neuPrint or FlyBrainLab enable these queries for specific datasets, but there remains a need to generalize algorithms and standards across datasets. To overcome this challenge, we present a software framework for comparative connectomics and graph discovery to make connectomes easy to analyze, even when larger-than-RAM, and even when stored in disparate datastores. This software suite includes visualization tools, a web portal, a connectivity and annotation query engine, and the ability to interface with a variety of data sources and community tools from the neuroscience community. These tools include MossDB (an immutable datastore for metadata and rich annotations); Grand (for prototyping larger-than-RAM graphs); GrandIso-Cloud (for querying existing graphs that exceed the capabilities of a single work-station); and Motif Studio (for enabling the public to query across connectomes). These tools interface with existing frameworks such as neuPrint, graph databases such as Neo4j, and standard data analysis tools such as Pandas or NetworkX. Together, these tools enable tool and algorithm reuse, standardization, and neuroscience discovery.

Despite groundbreaking progress in reinforcement learning for robotics, gameplay, and other complex domains, major challenges remain in applying reinforcement learning to the evolving, open-world problems often found in critical application spaces. Reinforcement learning solutions tend to generalize poorly when exposed to new tasks outside of the data distribution they are trained on, prompting an interest in continual learning algorithms. In tandem with research on continual learning algorithms, there is a need for challenge environments, carefully designed experiments, and metrics to assess research progress. We address the latter need by introducing a framework for continual reinforcement-learning development and assessment using Lifelong Learning Explorer (L2Explorer), a new, Unity-based, first-person 3D exploration environment that can be continuously reconfigured to generate a range of tasks and task variants structured into complex and evolving evaluation curricula. In contrast to procedurally generated worlds with randomized components, we have developed a systematic approach to defining curricula in response to controlled changes with accompanying metrics to assess transfer, performance recovery, and data efficiency. Taken together, the L2Explorer environment and evaluation approach provides a framework for developing future evaluation methodologies in open-world settings and rigorously evaluating approaches to lifelong learning. In recent years, Deep Reinforcement Learning (DRL) approaches have begun to deliver powerful results for a variety of compelling domains, including games such as Chess, Go, and Shogi (Silver et al. 2018); Atari video games (Mnih et al. 2013); more complex strategy video games (Berner et al. 2019; Vinyals et al. 2019); and dexterous robotic manipulation (Rajeswaran et al. 2017). Despite the groundbreaking success in training autonomous agents, resulting policies tend to be very brittle and generalize poorly (Chan et al. 2019). When presented with a new task or a task variant, DRL approaches are susceptible to a performance drop (Zhang et al. 2018; Kirk et al. 2021) due to the catasCopyright © 2022, Association for the Advancement of Artificial Intelligence (www.aaai.org). All rights reserved. DISTRIBUTION STATEMENT A. Approved for public release. Distribution Unlimited. trophic forgetting problem (French 1999; McCloskey and Cohen 1989), which may not be overcome by domain randomization strategies alone. As the field moves from environments which are fixed to evolving, open-world scenarios, current DRL approaches will be insufficient. This performance gap has led to an interest in Continual Learning, which seeks to design algorithms to learn over sequences of tasks. In the related, but broader, concept of Lifelong Learning (Chen and Liu 2018), an agent learns over a lifetime of experiences (see Fig. 1) in an evolving environment (for purposes of this paper, however, we treat continual learning as synonymous with lifelong learning as our approach is applicable to both concepts). Much recent work has been on supervised classification under distribution shifts (Song et al. 2020) and learning a sequence of tasks (Parisi et al. 2019; Hsu et al. 2018). Continual RL (Khetarpal et al. 2020) seeks to create agents which can maintain performance in the face of nonstationary distributions. A key issue in developing Continual RL algorithms is how to assess performance in a rigorous and informative way. There are existing attempts to address this with procedurally generated open worlds (Risi and Togelius 2020), which generate tasks using randomly parameterized environments. A recent software framework has begun integrating metrics, baselines, and environments for Continual RL (Powers et al. 2021). We argue that successful Continual RL assessment requires both sufficiently complex environments and highly reconfigurable tasks, as well as carefully structured experiments and metrics. We must also consider a multidimensional approach to assessment (in terms of raw performance, generalization, task transfer, and data efficiency). To help address this need, we have developed Lifelong Learning Explorer (L2Explorer), a first-person-view (FPV), highly configurable UnityTM environment1. The environment allows for procedural generation through Python code for open-ended task and task variant definitions. Moreover, the environment is set up for testing lifelong learning curricula with a set of lifelong learning metrics. While the Unity environment itself is designed for Continual RL assessment, this work also outlines an approach for taking complex, reconfigurable open-world environments and creating rigorous evaluation for lifelong learning algorithms.

L2Explorer: A Lifelong Reinforcement Learning Assessment Environment

The healthy human brain has long been considered a sterile environment, with the blood brain barrier preventing the formation of a bacterial brain microbiome. Recent electron microscopy (EM) imaging of brain tissue has, however, provided the first preliminary evidence of bacteria in otherwise healthy brain slices. Whether due to contamination, disease, or a previously unknown relationship of bacteria to healthy brain tissue, novel tools are needed to detect and search for bacteria in nanoscale, volumetric EM images. While computer vision tools are widely used in cell segmentation and object detection problems in EM imaging, no bacteria detection tool or dataset exists. Overcoming the rarity of training data, this work presents the first pipeline for training a bacteria detection network for EM images, leveraging existing deep networks for object detection. A deployment and proofreading pipeline is presented, along with characterization of deployment to public EM image datasets. While bacteria in healthy brain tissue were not discovered in this work, this tool presents an opportunity for large scale bacteria search in EM imaging for both scientific discovery and experimental quality control, and serves more generally as a framework for sparse object detection in large imagery datasets.

In search of a brain microbiome: A machine learning search pipeline for electron microscopy images of brain tissue

Capturing general deforming scenes from monocular RGB video is crucial for many computer graphics and vision applications. However, current approaches suffer from drawbacks such as struggling with large scene deformations, inaccurate shape completion or requiring 2D point tracks. In contrast, our method, Ub4D, handles large deformations, performs shape completion in occluded regions, and can operate on monocular RGB videos directly by using differentiable volume rendering. This technique includes three new in the context of non-rigid 3D reconstruction components, i.e., 1) A coordinate-based and implicit neural representation for non-rigid scenes, which in conjunction with differentiable volume rendering enables an unbiased reconstruction of dynamic scenes, 2) a proof that extends the unbiased formulation of volume rendering to dynamic scenes, and 3) a novel dynamic scene flow loss, which enables the reconstruction of larger deformations by leveraging the coarse estimates of other methods. Results on our new dataset, which will be made publicly available, demonstrate a clear improvement over the state of the art in terms of surface reconstruction accuracy and robustness to large deformations.

Unbiased 4D: Monocular 4D Reconstruction with a Neural Deformation Model

Technological advances in imaging and data acquisition are leading to the development of petabyte-scale neuroscience image datasets. These large-scale volumetric datasets pose unique challenges since analyses often span the entire volume, requiring a unified platform to access it. In this paper, we describe the Brain Observatory Storage Service and Database (BossDB), a cloud-based solution for storing and accessing petascale image datasets. BossDB provides support for data ingest, storage, visualization, and sharing through a RESTful Application Programming Interface (API). A key feature is the scalable indexing of spatial data and automatic and manual annotations to facilitate data discovery. Our project is open source and can be easily and cost effectively used for a variety of modalities and applications, and has effectively worked with datasets over a petabyte in size.

The Brain Observatory Storage Service and Database (BossDB): A Cloud-Native Approach for Petascale Neuroscience Discovery

Author Correction: A framework for rigorous evaluation of human performance in human and machine learning comparison studies

Author Correction: Online learning for orientation estimation during translation in an insect ring attractor network

A framework for rigorous evaluation of human performance in human and machine learning comparison studies

Neuroscientists can leverage technological advances to image neural tissue across a range of different scales, potentially forming the basis for the next generation of brain atlases and circuit reconstructions at submicron resolution, using Electron Microscopy and X-ray Microtomography modalities. However, there is variability in data collection, annotation, and storage approaches, which limits effective comparative and secondary analysis. There has been great progress in standardizing interfaces for large-scale spatial image data, but more work is needed to standardize annotations, especially metadata associated with neuroanatomical entities. Standardization will enable validation, sharing, and replication, greatly amplifying investment throughout the connectomics community. We share key design considerations and a usecase developed for metadata for a recent large-scale dataset.

Connectomics Annotation Metadata Standardization for Increased Accessibility and Queryability

State-of-the-art methods for self-supervised learning (SSL) build representations by maximizing the similarity between different transformed"views"of a sample. Without sufficient diversity in the transformations used to create views, however, it can be difficult to overcome nuisance variables in the data and build rich representations. This motivates the use of the dataset itself to find similar, yet distinct, samples to serve as views for one another. In this paper, we introduce Mine Your Own vieW (MYOW), a new approach for self-supervised learning that looks within the dataset to define diverse targets for prediction. The idea behind our approach is to actively mine views, finding samples that are neighbors in the representation space of the network, and then predict, from one sample's latent representation, the representation of a nearby sample. After showing the promise of MYOW on benchmarks used in computer vision, we highlight the power of this idea in a novel application in neuroscience where SSL has yet to be applied. When tested on multi-unit neural recordings, we find that MYOW outperforms other self-supervised approaches in all examples (in some cases by more than 10%), and often surpasses the supervised baseline. With MYOW, we show that it is possible to harness the diversity of the data to build rich views and leverage self-supervision in new domains where augmentations are limited or unknown.

Mine Your Own vieW: Self-Supervised Learning Through Across-Sample Prediction

Methods for resolving the brain’s microstructure are rapidly improving, allowing us to image large brain volumes at high resolutions. As a result, the interrogation of samples spanning multiple diversified brain regions is becoming increasingly common. Understanding these samples often requires multi-scale processing: segmentation of the detailed microstructure and large-scale modelling of the macrostructure. Current brain mapping algorithms often analyze data only at a single scale, and optimization for each scale occurs independently, potentially limiting the consistency, performance, and interpretability. In this work we introduce a deep learning framework for segmentation of brain structure at multiple scales. We leverage a modified U-Net architecture with a multi-task learning objective and unsupervised pre-training to simultaneously model both the micro and macro architecture of the brain. We successfully apply our methods to a heterogeneous, three-dimensional, X-ray micro-CT dataset spanning multiple regions in the mouse brain, and show that our approach consistently outperforms another multi-task architecture, and is competitive with strong single-task baselines at both scales.

Online learning for orientation estimation during translation in an insect ring attractor network

As connectomics datasets continue to grow in size and complexity, methods to search for and identify interesting graph patterns offer a promising approach to quickly reduce data dimensionality and enable discovery. Recent advances in neuroscience have enabled brain structure exploration at the level of individual synaptic connections. These graphs are often too large to be analyzed manually, presenting significant barriers to searching for structure and testing hypotheses. We combine graph database and analysis libraries with an easy-to-use neuroscience grammar suitable for rapidly constructing queries and searching for subgraphs and patterns of interest. This abstracts many of the computer science and graph theory challenges associated with nanoscale brain network analysis and allows scientists to quickly achieve reproducible findings at scale. We demonstrate these tools to search for motifs on simulated data and real public connectomics datasets, and share simple and complex structures relevant to the neuroscience community. We contextualize these results and provide case studies to motivate future neuroscience questions. All of our tools are released open source to empower other scientists to use and extend these methods.

Connectome subgraph isomorphisms and graph queries with DotMotif

Connecting Neural Reconstruction Integrity (NRI) to Graph Metrics and Biological Priors

Recent advances in neuroscience have enabled the exploration of brain structure at the level of individual synaptic connections. These connectomics datasets continue to grow in size and complexity; methods to search for and identify interesting graph patterns offer a promising approach to quickly reduce data dimensionality and enable discovery. These graphs are often too large to be analyzed manually, presenting significant barriers to searching for structure and testing hypotheses. We combine graph database and analysis libraries with an easy-to-use neuroscience grammar suitable for rapidly constructing queries and searching for subgraphs and patterns of interest. Our approach abstracts many of the computer science and graph theory challenges associated with nanoscale brain network analysis and allows scientists to quickly conduct research at scale. We demonstrate the utility of these tools by searching for motifs on simulated data and real public connectomics datasets, and we share simple and complex structures relevant to the neuroscience community. We contextualize our findings and provide case studies and software to motivate future neuroscience exploration.

DotMotif: an open-source tool for connectome subgraph isomorphism search and graph queries

Neuroscientists are collecting Electron Microscopy (EM) datasets at increasingly faster rates. This modality offers an unprecedented map of brain structure at the resolution of individual neurons and their synaptic connections. Despite sophisticated image processing algorithms such as Flood Filling Networks, these huge datasets often require large amounts of hand-labeled data for algorithm training, followed by significant human proofreading. Many of these challenges are common across neuroscience modalities (and in other domains), but we use EM as a use case because the scale of this data emphasizes the opportunity and impact of rapidly transferring methods to new datasets. We investigate transfer learning for these work-flows, exploring transfer to different regions within a dataset, between datasets from different species, and for datasets collected with different image acquisition techniques. For EM data, we investigate the impact of algorithm performance at different workflow stages. Finally, we assess the impact of candidate transfer learning strategies in environments with no training labels. This work provides a library of algorithms, pipelines, and baselines on established datasets. We enable rapid assessment and improvements to processing pipelines, and an opportunity to quickly and effectively analyze new datasets for the neuroscience community.

Transfer Learning Analysis of Image Processing Workflows for Electron Microscopy Datasets

Container-Based Clinical Solutions for Portable and Reproducible Image Analysis

Recent years have seen a renaissance in artificial intelligence (AI) technology and its applications, including robotics. Many of these solutions focus on solving a particular problem in a particular domain or environment. Creating robust and generalizable AI solutions is an area of great interest with applications to many different problem spaces. Biological organisms and biological nervous systems serve as an existence proof that such a generalized intelligence solution is possible. We develop and explore a framework for the simulation of biological networks and extend these simulations to a real-world robotic platform. We focus our initial exploration on a simple, well-defined and highly stereotyped biological neural network (i.e., connectome) derived from the Caenorhabditis elegans nematode. We implement a reference anatomical connectome on a robotic platform, then perturb the network to study the influence of the network parameters on output behavior. Target perturbations can be derived from neuroscience, robotics, or machine learning domains. This platform is useful for exploring the relationship between learning and behavior for biological organisms and robots. To foster further discovery, we share an open source, easy to use framework with visualization and simulation capabilities and provide an interface to a TurtleBot using ROS.

Worminator: A platform to enable bio-inspired (C. elegans) robotics

Electricity transmission redistributes environmental impacts across space. We exploit episodes of high electricity transmission system congestion to explore changes in ambient concentrations of air pollutants in the eastern United States. Reducing electricity system congestion decreases ozone and PM2.5 concentrations in New England and New York and increases them in the western portions of the Pennsylvania-New Jersey-Maryland electricity market and much of the Midwestern states. We quantify the health impacts of changes in environmental pollution induced by a reduction in congestion and find overall health losses in central states such as Illinois, Indiana, and Ohio and health gains in Atlantic.

Congestion in the Electricity Transmission System Redistributes Pollution Across Long Distances

The share of electric power generated from renewable energy sources such as wind and solar PV must increase dramatically in the coming decades if greenhouse gas emissions are to be reduced to sustainable levels. An under-researched implication of such a transition in deregulated electricity markets is that greater wind and solar generation capacity directly affects wholesale price variability. In theory, two counter-vailing forces should be at work. First, greater wind and solar generation capacity should reduce shortrun variance in the wholesale electricity price due to a stochastic merit-order effect. However, increasing the generation capacity of these technologies may increase price variance due to an intermittency effect. Using an instrumental variables identification strategy to control for endogeneity, we find evidence that greater combined wind and solar generation capacity is associated with an increase in the quarterly variance of wholesale electricity prices. That is, the intermittency effect dominates the stochastic merit-order effect.

Renewable Generation Capacity and Wholesale Electricity Price Variance

Peak shifting and cross-class subsidization: The impacts of solar PV on changes in electricity costs

In most countries, environmental regulation focuses on local pollution, which causes damages near the emission source, while regulation on global pollutants such as greenhouse gases (GHGs) has been slow. Theoretically, local and global pollutants can either be substitutes or complements in production. A firm's response to local pollution regulation can lead greenhouse gas emissions to decrease if the firm switches energy source from oil to natural gas, or to increase if it reduces the temperature of a natural gas-fired boiler, which causes NOx emissions to fall but CO2 emissions to rise. Consequently, local pollution regulation may either intensify or reduce global warming concerns. We exploit new data on US GHG emissions and variation in local pollution regulation across US counties to estimate this relationship. We find no evidence that more stringent local pollution regulation changes GHG emissions from the non-energy sectors. The lack of a statistically detectable effect cannot be explained by a decrease in production or by firms switching production to less regulated countries, and it is true on aggregate as well as for individual polluting industries, though in some instances the coefficients are not precisely estimated. Therefore, local pollution regulation is unlikely to suffice to address global warming.

Two Birds, One Stone? Local Pollution Regulation and Greenhouse Gas Emissions

Teaching an old dog new tricks: Firm learning from environmental regulation

In most countries, environmental regulation has focused on local pollution, which causes damages near the emission source, while national regulation on greenhouse gases (GHG) has been slow. In this paper, we ask whether US local air pollution regulations have had an effect on GHG emissions. On the one hand, a firm required to lower emissions of local pollutants might respond by adopting technologies that concurrently reduce GHG, thereby contributing to limiting global warming. On the other hand, if global and local pollutants are substitutes in production, mandating a decrease in local pollution could encourage a deterioration of the environment through other pollutants. The analysis exploits variation in local pollution regulation across US counties as well as exogenous changes to air quality standards to estimate the effect on GHG emissions using both a propensity score matching estimator and a fixed effects regression. Results suggest that counties which have implemented more stringent local pollution regulation do not exhibit GHG emission levels that are systematically different from counties with less stringent regulation. The lack of evidence of a significant complementarity between local and global pollution suggests that current efforts to control local air pollution would not necessarily translate into reductions in global pollution, impressing further the need for global cooperation on GHG reductions.

The effects of local pollution regulation on greenhouse gas emissions

In deregulated electricity markets, economic support schemes for renewable energy (RES-E) technologies are typically implemented under the pretense of shielding investors from revenue risk arising from stochastic wholesale electricity prices. Two dominant RES-E support policies worldwide are feed-in tariffs (FIT) and renewable portfolio standards (RPS). Thus far, the economic and policy literature has failed to acknowledge a key benefit to retail electricity providers (and, ultimately, to consumers)—that stimulating investment in RES-E generation itself reduces wholesale price risk. Using a simple theoretical model of an electricity market, we demonstrate that greater RES-E generation should reduce the short-run variance in the wholesale electricity price, and thus in total electricity expenditures per unit (which include payments to RES-E related to the prevailing support policy). We find empirical support for this hypothesis using a panel of policy, price, and generation data for 19 countries over the period 20002011. Both FIT and RPS are found to reduce the short-run variance in total electricity expenditures per unit, due largely to a reduction in the variance in wholesale prices. Moreover, we find evidence that FIT reduces the variance in electricity expenditures per unit over the long-run, whereas RPS does not. † This research was presented at the 17 Annual CU Environmental and Resource Economics Workshop (Sept. 4-5, 2015, Vail, CO), the Association for Public Policy Analysis & Management (APPAM) 2015 Fall Research Conference (Nov. 12-14, 2015, Miami, FL), and the 85 Annual Meetings of the Southern Economic Association (Nov. 21-23, 2015, New Orleans, LA). We thank participants of those events for a number of helpful comments and observations. Additionally, we thank Wesley Burnett, Christoph Graf, Ian Lange, and Mark Lively for many useful comments and suggestions. We are indebted to Nick Johnstone for providing the international RPS and FIT data. Chris Blackburn provided essential graduate assistant work related to data cleaning, and Mishal Ahmed performed minor graduate assistant work related to data collection. Finally, we thank the Georgia Tech School of Economics for financial support. * Johnson: erik.johnson@econ.gatech.edu Oliver: matthew.oliver@econ.gatech.edu

Electricity Expenditure Risk with Renewable Energy Support Schemes †

Feed-in Tariffs Versus Renewable Portfolio Standards: An Estimation of Policy Risk in the Electricity Sector

The cost of carbon dioxide abatement from state renewable portfolio standards

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Three Essays in Environmental Economics and Applied Econometrics

Many states have adopted policies aimed at promoting the growth of renewable electricity within their state. The most salient of these policies is a renewable portfolio standard (RPS) which mandates that retail electricity providers purchase a predetermined fraction of their electricity from renewable sources. Renewable portfolio standards are a policy tool likely to persist for many decades due to the long term goals of many state RPSs and the likely creation of a federal RPS alongside any comprehensive climate change bill. However, there is little empirical evidence about the costs of these RPS policies. I take an instrumental variables approach to estimate the long-run price elasticity of supply of renewable generation. To instrument for the price paid to renewable generators I use the phased-in implementation of RPSs over time. Using this IV strategy, my preferred estimate of the supply elasticity is 2.7. This parameter allows me to measure the costs of carbon abatement in the electricity sector and to compare those costs with the costs of a broader based policy. Using my parameter estimates, I find that a policy to reduce the CO2 emissions in the northeastern US electricity sector by 2.5% using only an RPS would cost at least six times more than the regional cap-and-trade system (Regional Greenhouse Gas Initiative). The marginal cost of CO2 abatement is $12 using the most optimistic assumptions for an RPS compared to a marginal cost of abatement of $2 in the Regional Greenhouse Gas Initiative. Erik Johnson School of Economics 221 Bobby Dodd Way, #217 Georgia Institute of Technology Atlanta, GA 30332 erik.johnson@econ.gatech.edu

The Price Elasticity of Supply of Renewable Electricity Generation: Evidence from State Renewable Portfolio Standards

There have been substantial advances in dynamic structural models and in the econometric literature about techniques to estimate those models over the past two decades. One area in which these new developments has lagged is in studying robustness to distributional assumptions and finite sample properties in small samples. This paper extends our understanding of the behavior of these estimation techniques by replicating John Rust’s (1987) influential paper using the nested fixed-point algorithm (NFXP) and then using Monte Carlo techniques to examine the finite sample properties of the estimator. I then examine the consequences of the distributional assumptions needed to estimate the model on the parameter estimates. I find that even in sample sizes of up to 8,000 observations, the NFXP can display finite sample bias and variances substantially larger than the theoretical asymptotic variance. This is also true with departures from distributional assumptions, with the mean square error increasing by a factor of 10 for some distributions of unobserved variables. Erik P. Johnson Georgia Institute of Technology 221 Bobby Dodd Way, Atlanta, GA 30332 erik.johnson@econ.gatech.edu Monte Carlo Simulations of the Nested Fixed-Point Algorithm Erik Johnson October 2010 Preliminary and incomplete. Please do not cite or quote.

The US Environmental Protection Agency (EPA) estimates that exposure to residential radon causes 7,000 to 30,000 lung cancer deaths per year. The EPA has provided extensive technical analysis of and support for their recommended policy response of remediating all homes above a threshold level of radon, but these and other benefit-cost analyses typically do not consider many important dimensions of household heterogeneity, specifically residential mobility. We add to the literature on benefit-cost analysis by using agent based models that allow for heterogeneous benefits. Using this model, we re-examine the EPA’s recommendations for radon remediation. Since there is both a capital and an annual cost of radon remediation, many well informed households are better off not complying with the EPA’s recommendation. We find that most households are better of by not paying the annual cost of remediation and that only the least mobile households with smokers would undertake the capital cost of radon remediation in houses with very high radon concentrations. Since only a small fraction of the population values radon remediation, our model suggests that approximately 10% of the capital cost is likely to be capitalized into the resale value of the house. Erik Johnson Georgia Institute of Technology 221 Bobby Dodd Way, Atlanta, GA 30332 erik.johnson@econ.gatech.edu Paul N. Courant University of Michigan 818 Hatcher Graduate Library South, Ann Arbor, MI 48109 pnc@umich.edu David Mendez University of Michigan 1415 Washington Heights; M3232 SPH II, Ann Arbor, Michigan 48109 dmendez@umich.edu Kenneth E. Warner University of Michigna 1420 Washington Heights; M3174, SPH II, Ann Arbor, Michigan 48109 kwarner@umich.edu Cost Effectiveness of Residential Radon Remediation with Household Mobility Erik P. Johnson, Paul N. Courant, David Mendez, Kenneth E. Warner

Cost Effectiveness of Residential Radon Remediation with Household Mobility

ABSTRACT Persons with Autism Spectrum Disorder (ASD) may have strengths in musical skills and music perception. Some children with ASD may also have better social engagement in music activities, making music a potential strength for interacting with others. Although children with ASD may be mainstreamed into music education classes, there is little known research on the impact of peer support. The purpose of this project was to examine the impact of peer-assisted learning (PAL) on musical creatiFvity and pro-social skills, between neurotypical (NT) and students with ASD. The following questions were investigated: (a) does music making with a peer impact music creativity differently in NT children and children with ASD, (b) does music making with a peer promote pro-social skills differently in NT children and in children with ASD. The sample included eighteen children with ASD and twenty-eight children with no known disability, between the ages of 9–14. Results of this study provide initial evidence that PAL experiences may be mutually beneficial for children with ASD and NT peers. In particular, an increase in pro-social skills were observed for some children grouped with NT peers, while the amount of time in creative music-making was similar between NT and NT/ASD peer groups.

Musical Creativity in Autism: Exploring Growth through Collaborative Peer Interaction

The impact of physical space in the College Union and students' sense of community on campus

The purpose of this study was to examine the effect of two different reciprocal peer-assisted learning (PAL) arrangements on music achievement and learner engagement in the secondary instrumental music classroom. Using a quasi-experimental design, students from six separate seventh-grade bands from one large urban/suburban school district (N = 261) were randomly assigned to one of two treatment conditions: symmetrical PAL, where students of like ability were paired together, and asymmetrical PAL, where students of divergent ability were paired together. Students worked in pairs over the course of four weeks and took turns being the “learner” and the “teacher” to improve sight-reading ability and music theory knowledge. Student pairs were allowed to determine their own rules for interaction, turn taking, and the amount of material to be covered in each session. Three pre-/posttest outcome variables were assessed: sight-reading performance, music theory knowledge, and learner engagement. Additionally, individual socioeconomic status (SES) and motivation orientation were compared as potential moderating variables. Hierarchical linear regression analyses indicated that regardless of PAL pairings, there were significant gains for each of the outcome variables. Moreover, interaction effects were found between learner engagement, method of instruction, and SES.

The Effect of Symmetrical and Asymmetrical Peer-Assisted Learning Structures on Music Achievement and Learner Engagement in Seventh-Grade Band

Mini-concerts are regularly occurring, low-stakes curricular events in the classroom where students perform music of their choice for their peers. An idea generated by music educators in domestic and international K–12 schools who strive to meet the needs of diverse student populations, mini-concerts have helped generate student excitement and cultural awareness in general music, bands, orchestras, and choirs in large and small programs alike. By creating a curricular space for students to share school-appropriate music that interests them in an informal and fun environment, mini-concerts can also help build student confidence through the active support of peers. This article includes resources and weekly schedules and describes ways that mini-concerts offer a platform for developing performance skill, music literacy, audience etiquette, and innovative thinking.

Peer-teaching is an instructional technique that has been used by teachers world-wide to successfully engage, exercise and deepen student learning. Yet, in some instances, teachers find the application of peer-teaching in large music ensembles at the secondary level to be daunting. This article is meant to be a practical resource for secondary school music teachers to incorporate peer-teaching into their classroom. Additionally, several philosophical angles associated with peer-teaching are presented for teachers to consider including the theoretical underpinnings of collaborative learning, the cultural conceptualization of “struggle to learn,” and the suggested degree structure in peer-assisted learning exercises.

Research on pre-service music teacher occupational identity often highlights two competing identities: performer and teacher (L’Roy, 1983; Roberts, 1991; Pellegrino, 2009). Of the many factors that contribute to the occupational identity of the pre-service music teacher (Woodford, 2002), conducting has the potential to integrate performer and teacher identities. Previous research indicates that high school and college ensemble conductors have an influence on the occupational identity of the pre-service music teacher (L’Roy, 1983; Bauer & Berg, 2001; Isbell, 2008), yet little is known about how socialization to the norms of a conducting community influences the development of pre-service music teacher occupational identity. The present investigation used qualitative case study methodology (Stake, 1995) to describe the status of pre-service music teacher occupational identity at one institution during a first-semester beginning conducting course. Using a community of practice framework (Wenger, 1998), I examined the following questions: (1) how does conducting instruction influence the development of pre-service music teacher occupational identity; (2) how does a student’s perceived trajectory relate to their approach to conducting instruction; (3) how does a student’s previous and current socialization impact the awareness and participation in a conducting community of practice? Data analysis suggested four primary themes: (a) conducting as teaching; (b) conducting as performing; (c) participants learn by watching others conduct; (d) participants seek to assume the role of the expert. Findings suggest that a pre-service music teacher’s occupational identity is affected by their perceived trajectory (Wenger, 1998) as they interact in or move through a community of practice.

"Conducting is Everywhere!" A Case Study of the Development of Preservice Music Teacher Occupational Identity in a Beginning Conducting Course

The effect of symmetrical and asymmetrical peer-assisted structures on music achievement and learner engagement in the secondary large ensemble

Among the elements required to develop a comprehensive understanding of music is students’ ability to perceive, recognize, and label the harmonies they hear. Harmonic dictation is among the strategies that teachers have traditionally chosen to help students develop harmonic awareness. However, the highly idiosyncratic ways that students approach harmonic dictation have often left music teachers at a loss for well-developed strategies to make this task transparent for students. To help students develop harmonic awareness, this article presents (a) a system of singing arpeggiated chords to guide and increase student accuracy through harmonic dictation exercises, (b) a set of part-writing procedures to help students organize common part-writing strategies, (c) a review of research supporting these strategies, and (d) potential applications of this model in large-ensemble instruction. The ultimate goal of this article is to help teachers demystify the process of teaching harmonic dictation while increasing their ability to use singing and dictation as tools to improve students’ musicianship.

The aims of this study were to determine which theoretical frameworks have been employed in music education research and which academic fields of knowledge have had an influence on music education research. Studies published in the JRME between 1979 and 2009 (N = 726) were coded to determine: (a) whether each article cited a theoretical framework related to the respective problem under investigation or not; (b) the emphasis area of the study (e.g., sample characteristic); and (c) the academic field of knowledge in which the theory was generated. Cady's (1992) definition of theory was used to develop the codes: "a logical deductive relationship among declarative sentences whose propositional quality yields the attitude found in statements of belief that offer an explanation of a phenomenon" (p. 62). Intercoder agreement across categories was excellent (96%). Thirty-two percent of all articles cited a theoretical framework, with a range of 9% to 48% across specific years. A large number (144) of distinct theoretical frameworks was found. Leblanc's Interactive Theory of Music Preference was the most commonly cited theory (n = 30), followed by Piaget's Genetic Epistemology (n = 12) and Attribution Theory (n = 10). Studies dealing with elementary/secondary-general music and higher-education/teacher education were most likely to incorporate theoretical frameworks. Psychology (n = 108), music education (n = 78), and general education (n = 35) were the most commonly represented fields of knowledge.

Theoretical Frameworks Applied in Music Education Research: A Content Analysis of the "Journal of Research in Music Education", 1979 to 2009

The Effect of Peer-Based Instruction on Rhythm Reading Achievement.

Teachers who conduct ensembles of any ability level know that many skills are required for students to successfully participate. Often neglected or overlooked are the skills that students must have to interact musically with their peers. This article focuses on listening as a way to help make successful ensemble collaboration a reality. The method comprises three levels of listening that provide structure for student interaction in an ensemble rehearsal. Interaction is divided into three levels driven by what students hear, giving students the ability to organize an overwhelming number of possibilities into manageable segments. Based on peer teaching research as well as real-life application, this article addresses the ability of teachers to shape a participant structure where all students are given the chance to have a voice and develop individual ownership. By giving individual students and peers the opportunity to solve musical problems, the traditional teacher-centered power structure of the typical ensemble rehearsal is redefined. The benefit of raised awareness based on listening and musical interaction in a rehearsal can also fuel creative development in other areas of the music curriculum, such as composition and evaluating music and performance.

A 20-year-old woman with a history of migraine presented with 4 days of progressive ptosis, discoordination, paresthesias in her hands and feet progressing to her forearms and shins, and diplopia after an upper respiratory tract illness the prior week. Laboratory evaluation at this time was notable for a positive immunoglobulin (Ig)G Lyme antibody (negative IgM), antinuclear antibody (ANA) 1:80 in a speckled pattern, and a positive GD1b antibody. Lumbar puncture (LP) showed white blood cells 30/mL (87% lymphs), red blood cells 3/mL, protein 68 mg/dL, glucose 49 mg/dL, and a negative Gram stain and bacterial culture. Brain magnetic resonance imaging (MRI) was normal. She was diagnosed with Miller-Fisher variant Guillian-Barre Syndrome and treated with a 5-day course of intravenous Ig, after which her symptoms markedly improved. She was evaluated in the clinic 3 times over the course of the next 4 months, and was found to have a normal neurologic examination except for absent reflexes at each clinic visit, and was otherwise asymptomatic. She was then lost to follow-up. Two-and-a-half years later, she again sought medical attention after a transient sensory disturbance which she described as numbness that began in the roof of her mouth with progression over the course of 10 minutes to involve her entire face and left arm. The numbness lasted 1 hour and then fully resolved. She had experienced a minor headache 2 hours prior that was alleviated by caffeine. Neurologic examination at this time was normal, but a brain MRI showed abnormal leptomeningeal enhancement (Figure 1), and a subsequent LP showed a lymphocytic pleocytosis with a markedly elevated protein and low glucose (Table 1). She underwent an extensive evaluation but no cause for the leptomeningeal enhancement on MRI or the abnormal cerebrospinal fluid (CSF) profile was identified. Two months later, she began to develop progressively worsening vertigo, headache, nausea, and diplopia. The MRI showed new enhancing lesions in the brain and enhancement of the leptomeninges along the entire length of the spinal cord (Figure 1). Evaluation of the spinal fluid at this time again showed CSF pleocytosis and hypoglycorrhacia with an opening pressure of 14 cm water (Table 1), but a cause for these abnormal radiologic and CSF findings could not be identified. Neurosurgical evaluation deemed a biopsy of the affected area would subject the patient to an unacceptably high risk of serious permanent neurologic deficit, and therefore biopsy was deferred. She was placed on empiric treatment for tuberculous meningitis with rifampin, isoniazid, pyridoxine, ethambutol, and a steroid taper. Her symptoms improved rapidly and she was asymptomatic over the course of the next 2 months, with an interval LP demonstrating improvement in the CSF profile (Table 1), and brain MRI showing near resolution of her leptomeningeal enhancement. Unfortunately, after completing her steroid taper she developed nausea, vomiting, and a headache that was worse when lying in the recumbent position. The MRI showed worsening hydrocephalus with return of contrast enhancement of the basilar leptomeninges, as well as the presence of fluid in the maxillary sinus with mucosal thickening. A right inferior nasal turbinate biopsy was unrevealing. Lumbar puncture again showed a CSF lymphocytic pleocytosis with elevated protein and low glucose (Table 1). She was restarted on dexamethasone. One month later, she had a generalized tonic-clonic seizure that was witnessed by her boyfriend. The MRI showed worsening hydrocephalus, and a LP revealed an elevated opening pressure of 40 cm water. A ventriculoperitoneal (VP) shunt was placed at this time to

A 41-year-old man with a history of diet-controlled diabetes mellitus developed acute-onset confusion and mild holocephalic headache relieved by acetaminophen. His confusion worsened over the course of 5 days, and he was subsequently brought to his primary care physician by his family, where he was noted to have an altered mental status. He was admitted to a local hospital for evaluation. Magnetic resonance imaging (MRI) of the brain showed an area of restricted diffusion on diffusion-weighted imaging in the left temporal cortex, consistent with a subacute infarction. Diagnostic testing with lumbar puncture, computed tomography (CT) angiogram of the head and neck, transthoracic echocardiogram (TTE) without saline contrast bubble, fasting lipid analysis, hypercoagulability analysis, and routine laboratory analysis showed only a hemoglobin of 11.9 g/dL (ref 14.0-17.5 g/dL), an elevated creatine phosphokinase (CPK) at 510 U/L (ref 55-380 U/L), elevated postprandial glucose at 252 mg/dL, a low-density lipoprotein (LDL) cholesterol of 122 mg/dL (ref 1-100 mg/dL), and a high-density lipoprotein (HDL) cholesterol of 32 mg/dL (ref 40-85 mg/dL). The patient was diagnosed with a subacute ischemic stroke in the left temporal lobe, producing a Wernicke aphasia, and was discharged home on aspirin and pravastatin with primary care follow-up to better control his elevated blood glucose. 
 
Over the course of the next 9 months the patient was readmitted to the hospital 4 times for progressively worsening mental status, aggressive behaviors, right-hand side weakness, and seizures. Brain imaging on each admission showed progressive infarcts in multiple vascular territories (Figure 1 ). During this time, a transesophageal echocardiogram (TEE) with saline contrast bubble was performed, which showed flow across the interatrial septum with Valsalva maneuver, consistent with a small patent foramen ovale (PFO). However, lower extremity doppler ultrasound and MR venogram of the pelvis failed to show evidence of deep vein thrombosis. The patient was placed on aspirin and warfarin for presumed paradoxical embolus and transferred to this facility for further evaluation. 
 
Figure 1. 
 
Imaging of progressive multifocal infarcts. A, Noncontrast CT scan of the brain 10 days after initial presentation showing a focal area of encephalomalacia in the left temporal lobe, representing an old infarct as well as an area of low attenuation and ... 
 
Other than impaired glucose tolerance, his medical history was significant only for hearing loss, requiring the use of hearing aids. The patient worked in a cannery until he became ill, with no known exposures to chemicals or infectious agents while at work or at home. He did not smoke tobacco, drink alcohol, or use illicit drugs. The patient's mother, father, and one of his brothers had diabetes. Of his 5 sisters, 4 had early miscarriages. His paternal aunt and first cousin both had a seizure disorder. 
 
On admission to this hospital, temperature was 36.8°C, blood pressure 107/61 mm Hg, pulse 103 beats/min, respiratory rate 18/min, and oxygen saturation 97% on room air. General physical examination showed a cachectic patient in no apparent distress, with anicteric sclerae, a clear oropharynx, a regular cardiac rhythm with normal s1 and s2 heart sounds, lungs clear to ascultation, a nontender and nondistended abdomen, urinary incontinence requiring a diaper, and ecchymosis on the right anterior shin. Neurologic examination showed an alert patient able to regard the examiner but oriented only to person, without dysarthria but speaking in 1- to 3-word sentences with perseveration and echolalia, unable to follow commands, normal cranial nerves, antigravity strength in all 4 extremites but favoring the left over the right, 3+ deep tendon reflexes throughout, with slightly brisker reflexes on the right-hand side compared to the left, withdrawal to pain in all 4 extremities, and a narrow but unsteady gait. 
 
A repeat MRI of the brain with and without contrast was unchanged from the most recent study performed at the referring hospital (Figure 1E). The patient was placed on telemetry monitoring. A repeat TEE with saline contrast bubble showed no evidence of right-to-left shunt, atrial or ventricular thrombus, or pathology within the aortic arch. A diagnostic cerebral angiogram was performed, which showed no evidence of atherosclerosis or vasculitis within the cerebral arteries. An extensive serum laboratory analysis was performed, the results of which are shown in Table 1 . 
 
Table 1. 
 
Serum Laboratory Testsa 
 
The patient underwent a repeat lumbar puncture. The cerebrospinal fluid (CSF) was clear and colorless, with 2 white blood cells and 650 red blood cells, glucose of 69 mg/dL (serum glucose 153 mg/dL), elevated protein at 89 mg/dL (ref 15-50 mg/dL), lactate dehydrogenase level of 15 U/L, elevated lactate at 6.5 mmol/L (ref 1.1-2.8 mmol/L), normal pyruvate, no oligoclonal bands present, and an elevated immunoglobulin G (IgG) index at 0.8 (ref 0.3-0.6). Polymerase chain reaction on the CSF for varicella zoster virus and herpes simplex 1 and 2 viruses was negative. Cerebrospinal fluid cryptococcal antigen, Borrelia burgdorferi antibodies, and venereal disease research laboratory (VDRL) test for syphilis were also negative. A diagnostic test was performed.

Bell's like mononeuropathies of two lower cranial nerves and review of the literature

The increase in violent crime has lead to an increase in gunshot-induced fractures in the United States. Injuries to the upper extremity are common. The treatment of gunshot injuries depends on the extent of soft tissue disruption and the type and location of fracture. Most of these injuries are a result of low-energy gunshot wounds that may be treated conservatively under the appropriate conditions. Low-energy fractures that require operative stabilization may be done with predictable results for achieving union with intramedullary fixation or compression plating. Complex open fractures from gunshot wounds associated with neurovascular injuries present a therapeutic challenge to the orthopaedic surgeon. The fractures associated with these injuries often are comminuted and unstable. Bone loss is common. Soft tissue disruption plays a more important role in high-energy gunshot-induced fractures. In these cases, external fixation is the treatment of choice for stabilization. Recent advances in the use of external fixation have led to quick fracture stabilization, stability for vascular repair, and access to the wound for debridement and subsequent soft tissue surgery.

Recent advances in the treatment of Gunshot fractures of the humeral shaft : Current concepts and principles of Gunshot musculoskeletal injuries

Recent advances in the treatment of gunshot fractures of the humeral shaft.

Current evidence suggests that oligomers of the amyloid‐β (Aβ) peptide are involved in the cellular toxicity of Alzheimer's disease, yet their biophysical characterization remains difficult because of lack of experimental control over the aggregation process under relevant physiologic conditions. Here, we show that modification of the Aβ peptide backbone at Gly29 allows for the formation of oligomers but inhibits fibril formation at physiologic temperature and pH. Our results suggest that the putative bend region in Aβ is important for higher‐order aggregate formation. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

Peptide backbone modification in the bend region of amyloid‐β inhibits fibrillogenesis but not oligomer formation

Synthesis of a ditopic verdazyl ligand and investigation of its coordination to transition metals

Venomous animals immobilize prey using protein toxins that act on ion channels and other targets of biological importance. Broad use of toxins for biomedical research, diagnosis, and therapy has been limited by inadequate target discrimination, for example, among ion channel subtypes. Here, a synthetic toxin is produced by a new strategy to be specific for human Kv1.3 channels, critical regulators of immune T cells. A phage display library of 11,200 de novo proteins is designed using the α-KTx scaffold of 31 scorpion toxin sequences known or predicted to bind to potassium channels. Mokatoxin-1 (moka1) is isolated by affinity selection on purified target. Moka1 blocks Kv1.3 at nanomolar levels that do not inhibit Kv1.1, Kv1.2, or KCa1.1. As a result, moka1 suppresses CD3/28-induced cytokine secretion by T cells without cross-reactive gastrointestinal hyperactivity. The 3D structure of moka1 rationalizes its specificity and validates the engineering approach, revealing a unique interaction surface supported on an α-KTx scaffold. This scaffold-based/target-biased strategy overcomes many obstacles to production of selective toxins.

A designer ligand specific for Kv1.3 channels from a scorpion neurotoxin-based library

We have decided to use the delta-opioid receptor (372 residues) as a model system to develop methods for the total chemical synthesis of G protein-coupled receptors. The most important feature of this receptor from a chemical synthesis perspective is the wealth of cysteines spread throughout its sequence, which are required for native chemical ligation. A total of 13 cysteines are located in the the delta-opioid receptor polypetide chain in both loop and putative transmembrane (TM) regions. We envisioned a synthesis of the polypeptide that would make use of peptide-alpha-thioesters ranging from 37 to 63 residues in length. Here, we report data from an exploratory synthesis of such a set of peptide-alpha-thioesters. For all seven peptides, the crude material approximately 30 residues into the synthesis was sufficiently homogeneous to make isolation and purification straightforward. Extension of the peptides to between 40 and 50 residues in length generally produced a significant decrease in the quality of the crude products, although in most cases, we judged that high purity peptides could probably be isolated. By 60 residues, however, the crude peptide product mixtures are probably too heterogeneous to purify to homogeneity by reversed-phase HPLC. In general, delta-opioid receptor peptides with a single predicted TM domain were sufficiently soluble to handle postcleavage and to analyze by reversed-phase HPLC, whereas 1.5 TM domains rendered the peptides too hydrophobic to handle or analyze by standard protocols. Given the challenges of chain assembly, handling, and purification of these peptides, a synthetic strategy that uses approximately 12 or 13 shorter peptide segments of 20-40 residues each is probably a more feasible approach.

Exploratory synthesis of peptide-alpha-thioester segments spanning the polypeptide sequence of the delta-opioid receptor, a G protein-coupled receptor.

Insights from atomic-resolution X-ray structures of chemically synthesized HIV-1 protease in complex with inhibitors.

Exploratory synthesis of peptide–α‐thioester segments spanning the polypeptide sequence of the δ‐opioid receptor, a G protein‐coupled receptor

Towards the total chemical synthesis of integral membrane proteins: a general method for the synthesis of hydrophobic peptide-thioester building blocks.

As part of our ongoing studies of the human immunodeficiency virus type 1 (HIV-1) protease enzyme, we set out to develop a modular chemical synthesis of the protein from multiple peptide segments. Our initial attempts were frustrated by the insolubility of intermediate peptide products. To overcome this problem, we designed a synthetic strategy combining the solubility-enhancing properties of C-terminal (Arg)n tags and the biological phenomenon of autoprocessing of the Gag-Pol polyprotein that occurs during maturation of the HIV-1 virus in vivo. Synthesis of a 119-residue peptide chain containing 10 residues of the reverse transcriptase (RT) open reading frame plus an (Arg)(10) tag at the C-terminus was straightforward by native chemical ligation followed by conversion of the Cys residues to Ala by Raney nickel desulfurization. The product polypeptide itself completed the final synthetic step by removing the C-terminal modification under folding conditions, to give the mature 99-residue polypeptide. High-purity homodimeric HIV-1 protease protein was obtained in excellent yield and had full enzymatic activity; the structure of the synthetic enzyme was confirmed by X-ray crystallography to a resolution of 1.07 A. This efficient modular synthesis by a biomimetic autoprocessing strategy will enable the facile synthesis of unique chemical analogues of the HIV-1 protease to further elucidate the molecular basis of enzyme catalysis.

Modular total chemical synthesis of a human immunodeficiency virus type 1 protease.

Native chemical ligation of unprotected peptide segments involves reaction between a peptide-alpha-thioester and a cysteine-peptide, to yield a product with a native amide bond at the ligation site. Peptide-alpha-thioalkyl esters are commonly used because of their ease of preparation. These thioalkyl esters are rather unreactive so the ligation reaction is catalyzed by in situ transthioesterification with thiol additives. The most common thiol catalysts used to date have been either a mixture of thiophenol/benzyl mercaptan, or the alkanethiol MESNA. Despite the use of these thiol catalysts, ligation reactions typically take 24-48 h. To gain insight into the mechanism of native chemical ligaton and in order to find a better catalyst, we investigated the use of a number of thiol compounds. Substituted thiophenols with pK(a) > 6 were found to best combine the ability to exchange rapidly and completely with thioalkyl esters, and to then act as effective leaving groups in reaction of the peptide-thioester with the thiol side chain of a cysteine-peptide. A highly effective and practical catalyst was (4-carboxylmethyl)thiophenol ('MPAA'), a nonmalodorous, water-soluble thiol. Use of MPAA gave an order of magnitude faster reaction in model studies of native chemical ligation and in the synthesis of a small protein, turkey ovomucoid third domain (OMTKY3). MPAA should find broad use in native chemical ligation and in the total synthesis of proteins.

Insights into the mechanism and catalysis of the native chemical ligation reaction.

We demonstrate the potential of 4-methoxy-2-nitrobenzyl as a Boc chemistry-compatible fully reversible backbone modification for synthetic peptides.

Synthesis, stability and optimized photolytic cleavage of 4-methoxy-2-nitrobenzyl backbone-protected peptides.

Total chemical synthesis, folding, and assay of a small protein on a water-compatible solid support.

We have undertaken fundamental studies on the solubility properties of a peptide derived from the fourth transmembrane (TM) domain of signal peptide peptidase, a 7-TM intramembrane-cleaving protease. We have found that by disfavoring secondary structure formation we are able to greatly improve the solubility, handling, and purification properties of this peptide. Our findings suggest that preventing secondary structure formation by reversible modification of the polypeptide backbone of hydrophobic transmembrane peptides may be a useful strategy for the total chemical protein synthesis of integral membrane proteins.

Studies on the insolubility of a transmembrane peptide from signal peptide peptidase.

The fault current limiter represents a developing technology which will greatly improve the reliability and stability of the power grid. By reducing the magnitude of fault currents in distribution systems, fault current limiters can alleviate much of the damage imposed by these events. Solid-state fault current limiters in particular offer many improved capabilities in comparison to the power system protection equipment which is currently being used for fault current mitigation. The use of silicon carbide power semiconductor devices in solid-state fault current limiters produces a system that would help to advance the infrastructure of the electric grid. A solid-state fault current limiter utilizing silicon carbide super gate-turn off thyristors (SGTOs) and silicon carbide PiN diodes was designed, built, and tested as a technology demonstrator. The impact of using silicon carbide (SiC) devices in this application was assessed, as well as the associated design challenges. The feasibility of implementing SiC based solidstate fault current limiters for 15 kV class distribution systems was investigated in order to determine the practicality of wide-scale deployment. This dissertation is approved for recommendation to the Graduate Council. Dissertation Director: ____________________________ Dr. H. Alan Mantooth Dissertation Committee: ____________________________ Dr. Simon Ang ____________________________ Dr. Juan Balda ____________________________ Dr. Alex Lostetter _____________________________ Dr. Roy McCann DISSERTATION DUPLICATION RELEASE I hereby authorize the University of Arkansas Libraries to duplicate this dissertation when needed for research and/or scholarship. Agreed_____________________________ Erik Darnell Johnson Refused_____________________________ Erik Darnell Johnson

A silicon carbide based solid-state fault current limiter for modern power distribution systems

We discuss the status of, and our plans for developing the NSLS-II injector. The injector consists of a 200 MeV linac, a 3-GeV booster, transport lines and an injection straight section. The system design now is almost complete, and the development of the injector in the procurement phase. We plan to commission the injector in 2012-2013.

Brookhaven National Laboratory (BNL) is developing a state-of-the-art 3 GeV synchrotron light source, the NSLS-II [1]. The 9.3 meter-long injection straight section of its storage ring now fits a conventional injection set-up consisting of four kickers producing a closed bump, together with a DC septum and a pulsed septum. In this paper, we analyze an alternative option based on injection via a pulsed sextupole magnet. We discuss the dynamics of the injected and stored beams and, subsequently, the magnet's specifications and tolerances. We conclude by summarized the advantages and drawbacks of each injection scheme.

Analysis of Glyoxal Concentrations Among a Deciduous Forest Canopy

The undeniable threat of nuclear terrorism presents an opportunity for innovation in developing active interrogation technology. The proposed system aims to detect the smuggling of special nuclear material (SNM) in maritime containers. Identifying the importation of SNM will be instrumental in protecting the American public from a nuclear terrorist attack made possible by the construction of a weapon with fissile material from abroad. The proposed system uses a directionally-biased beam of low-energy neutrons (60 100 keV) generated from a 7Li(p,n)7Be reaction run near threshold. These neutrons are directed towards a cargo container of unknown composition. If SNM is present in the container and the neutrons can reach it, high-energy fission neutrons will be detectable outside the cargo container. MCNP models indicate that even low-energy neutrons will be able to penetrate through reasonable amounts of material likely to be encountered in cargo environments. The only major exception is hydrogenous material, which could alter the radiation signature. The presence of shielding material may further alter these results. Small amounts of shielding that is hydrogenous will thermalize incident neutrons and raise the likelihood of generating fissions. An abundance of shielding material could mask the presence of fissile material but will also result in changes in the induced gamma energy spectrum and greatly increase the flux of thermal neutrons even outside the cargo container. Still, this material would not be resistant to other radiological techniques and the presence of an abundance of hydrogen will be evident and potentially raise suspicion in and of itself. Further MCNP simulations of the neutron source impinging on cargo containers suggest that this technique can respond, as expected, qualitatively differently to containers containing SNM from containers that do not. Containers that contain small amounts of fissile isotopes as in the case of a few grams of uranium-235 in a kilogram of depleted uranium will also respond to this method but much more weakly. The system as proposed is viable and further simulation and experimental work will elucidate the behavior of this system under a wide range of cargo environments. Thesis Supervisor: Richard C. Lanza Title: Senior Research Scientist in Nuclear Science and Engineering

Monte Carlo model of a low-energy neutron interrogation system for detecting fissile material

A high-flux insertion device and beamline for macromolecular crystallography has been built at the National Synchrotron Light Source (NSLS) that employs a mini-gap undulator source developed by the NSLS. The mini-gap undulator at beamline X29 is a hybrid-magnet device of period 12.5 mm operating at proven gaps of 3.3-10 mm. The beamline provides hard X-rays for macromolecular crystallography experiments from the second and third harmonics over an energy range of 5-15 keV. The X-ray optics is designed to deliver intense and highly collimated X-rays. Horizontal focusing is achieved by a cryogenically cooled sagittally focusing double-crystal monochromator with approximately 4.1:1 demagnification. A vertical focusing mirror downstream of the monochromator is used for harmonic rejection and vertical focusing. The experimental station hosts an Area Detector Systems Quantum 315 CCD detector with 2.2 s readout time between exposures and Crystal Logic goniostat for crystal rotation and detector positioning. An auto-mounter crystal changer has been installed to facilitate the high-throughput data collection required by the major users, which includes structural genomics projects and the Macromolecular Crystallography Research Resource mail-in program. X29 is 10(3) times brighter than any existing bending-magnet beamline at NSLS with an actual flux of 2.5 x 10(11) photons s(-1) through a 0.12 mm square aperture at 11.271 keV.

Beamline X29: a novel undulator source for X-ray crystallography.

Center for Synchrotron Biosciences, Case Proteomics Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA, Protein Crystallography Research Resource, Biology Department, Brookhaven National Laboratory, Upton, NY 11973, USA, National Synchrotron Light Source, Brookhaven National Laboratory, Upton, NY 11973, USA, Department of Biochemistry, University of Georgia, Southeast Regional CAT at the APS, Argonne National Laboratory, Argonne, IL 60439, USA, and LR DESIGN, Scottsdale, AZ, USA. E-mail: mark.chance@case.edu

Beamline X 29 : a novel undulator source for X-ray crystallography

Beam line X29 of the National Synchrotron Light Source (NSLS) has been operating for a year for macromolecular crystallography (PX) research, employing a mini-gap, in-vacuum undulator as its X-ray source. Development of this facility involved a close collaboration among the groups of Mark Chance (Case Proteomics Center, Case Western Reserve Univ. [CWR]), Erik Johnson [NSLS], and Robert Sweet (Macromolecular Crystallography Research Resource [PXRR] of BNL's Biology Dept.). There were several joint objectives and complexities to this project. Firstly, we hoped to provide an undulator-based beam line with the attractive features of high collimation and high flux for macromolecular crystallography at the NSLS.

Technical Reports: An Undulator Beamline for Protein Crystallography at the NSLS: Commissioning and Operation of X29

Tunability is one of the key aspects of any laser system. In High-Gain Harmonic Generation Free Electron Laser (HGHG FEL) the seed laser determines the output wavelength. Conventional scheme of tunable HGHG FEL requires tunable seed laser. The alternative scheme [1] is based on compression of the electron bunch with energytime correlation (chirped bunch) in the FEL dispersive section. The chirped energy modulation, induced by the seed laser with constant wavelength, is compressed as the whole bunch undergoes compression. In this paper we discuss experimental verification of the proposed approach at the DUV FEL [3,4] and compare experimental results with analytical estimates.

EXPERIMENTAL DEMONSTRATION OF WAVELENGTH TUNING IN HIGH-GAIN HARMONIC GENERATION FREE ELECTRON LASER

Ultraviolet high-gain harmonic-generation free-electron laser at BNL

Saturation of a high-gain harmonic-generation free-electron laser (HGHG-FEL) at 266 nm has been accomplished at the Brookhaven National Laboratory/Deep Ultra Violet Free Electron Laser Facility (BNL/DUV-FEL) by seeding with an 800 nm Ti:sapphire laser. We describe the diagnostics used to characterize the electron beam and the FEL output. Analytic and simulation calculations of the HGHG output are presented and compared with the experimental data. We also discuss the chirped pulse amplification of a frequency chirped seed by an energy chirped electron beam. The third harmonic at 88 nm accompanying the 266 nm fundamental has been used in an ion pair imaging experiment in chemistry, the first application of the BNL/DUV-FEL.

EXPERIMENTAL STUDY OF A HIGH-GAIN HARMONIC-GENERATION FREE-ELECTRON LASER IN THE ULTRAVIOLET

By making a relativistic electron beam wiggle its way through an array of magnets, one can generate intense coherent light with wavelengths tunable from centimeters to angstroms.

The visible-infrared self-amplified spontaneous emission amplifier (VISA) free electron laser (FEL) is an experimental device designed to show self-amplified spontaneous emission (SASE) to saturation in the near infrared to visible light energy range. It generates a resonant wavelength output from 800\char21{}600 nm, so that silicon detectors may be used to characterize the optical properties of the FEL radiation. VISA is designed to show how SASE FEL theory corresponds with experiment in this wavelength range, using an electron beam with emittance close to that planned for the future Linear Coherent Light Source at SLAC. VISA comprises a 4 m pure permanent magnet undulator with four 99 cm segments, each of 55 periods, 18 mm long. The undulator has distributed focusing built into it, to reduce the average beta function of the 70\char21{}85 MeV electron beam to about 30 cm. There are four FODO cells per segment. The permanent magnet focusing lattice consists of blocks mounted on either side of the electron beam, in the undulator gap. The most important undulator error parameter for a free electron laser is the trajectory walk-off, or lack of overlap of the photon and electron beams. Using pulsed wire magnet measurements and magnet shimming, we were able to control trajectory walk-off to less than $\ifmmode\pm\else\textpm\fi{}50\ensuremath{\mu}\mathrm{m}$ per field gain length.

Visible-infrared self-amplified spontaneous emission amplifier free electron laser undulator

X14B, the newest beamline at the NSLS, saw its first light early this summer. Designed solely for deep x-ray lithography (DXRL), it is intended for processing large quantities of deep (up to a few mm), but essentially 2D in design, parts. It has an effective scan area of 637 cm2, and a hydraulic scan stage to move that area through the beam. In addition, work is being done at X27B for the development of in-the-round and true 3D lithography. The hydraulic scan stages, filter motors, and sample positioning motors on both beamlines are computer controlled. Scan time and speed are calculated based on beam current, and a beam monitor stops the scan if necessary (due to unexpected beam dump, etc) and re-starts it when appropriate. The user can start a scan to run overnight, and return the next morning to pick up a completed sample. In addition, scan progress can be checked remotely via a web page.

Brookhaven National Laboratory has established an initiative in FEL science and technology development which includes the Deep Ultra-Violet Free Electron Laser (DUV-FEL) experiment. It is configured as a sub-harmonically seeded High Gain Harmonic Generator (HGHG) to improve coherence and pulse control as contrasted with other schemes that start up from noise. In its initial configuration the DUV-FEL will allow operation at wavelengths down to 200 nm at pulse lengths below a picosecond. The DW-FEL will be used as a test-bed for experiments to utilize the UV radiation it produces, and serve as model for extending its principles to much shorter wavelengths (x-rays).

The Deep Ultra-violet Free Electron Laser (DUV-FEL) at Brookhaven National Laboratory

Brookhaven National Laboratory has established an initiative in FEL science and technology development which includes the Deep Ultra-Violet Free Electron Laser (DUV-FEL) experiment. It is configured as a sub-harmonically seeded High Gain Harmonic Generator to improve coherence and pulse control as contrasted with other schemes that start up from noise. In its initial configuration the DUV-FEL will allow operation at wavelengths down to 200 nm at pulse lengths below a picosecond. The DUV-FEL will be used as a test-bed for experiments to utilize the UV radiation it produces, and serve as model for extending its principles to much shorter wavelengths (x-rays).

Deep-ultraviolet free-electron laser (DUV-FEL) at Brookhaven National Laboratory

The Visible-Infrared SASE Amplifier (VISA) FEL is an experimental device designed to show Self Amplified Spontaneous Emission (SASE) to saturation in the visible light energy range. It will generate a resonant wavelength output from 800--600 nm, so that silicon detectors may be used to characterize the optical properties of the FEL radiation. VISA is the first SASE FEL designed to reach saturation, and its diagnostics will provide important checks of theory. This paper includes a description of the VISA undulator, the magnet measuring and shimming system, and the alignment strategy. VISA will have a 4 m pure permanent magnet undulator comprising four 99 cm segments, each with 55 periods of 18 mm length. The undulator has distributed focusing built into it, to reduce the average beta function of the 70--85 MeV electron beam to about 30 cm. There are four FODO cells per segment. The permanent magnet focusing lattice consists of blocks mounted on either side of the electron beam, in the undulator gap. The most important undulator error parameter for a free electron laser is the trajectory walkoff or lack of overlap of the photon and electron beams. Using pulsed wire magnet measurements and magnet shimming, the authors expect to be able to control trajectory walkoff to less than {+-}50 pm per field gain length.

We have constructed an experimental station (beamline) at the National Synchrotron Light Source to measure circular dichroism (CD) using soft x-rays (250 less than or equal to hv less than or equal to 900 eV) from a time modulated elliptically polarizing wiggler. The polarization of the soft x-ray beam switches periodically between two opposite polarizations, hence permitting the use of phase-sensitive (lock-in) detection. While the wiggler can be modulated at frequencies up to 100 Hz, switching transients limit the actual practical frequency to approximately equals 25 Hz. With analog detection, switching transients are blocked by a chopper synchronized to the frequency and phase of the wiggler. The CD is obtained from the ratio of the signal recovered at the frequency of polarization modulation, f, to the average beam intensity, which is recovered by synchronous detection at frequency 2f.

Soft x-ray circular dichroism and scattering using a modulated elliptically polarizing wiggler and double synchronous detection

For several years we have explored the use of hard x-rays for a broad range of lithographic applications. The high energy available from the NSLS x-ray ring (E>15 keV) allows the exposure of resist up to several cm thick, while maintaining micron level precision. The high flux and close proximity to the source at this machine make it possible to achieve workable exposures on realistic time scales, enabling production work. In addition to the conventional two-dimensional exposure schemes, we have demonstrated methods for achieving fully figured three dimensional objects with internal re-entrant geometry. Users from outside BNL have been sufficiently successful with their work at our prototype beamline (X-27B) that we have initiated the construction of a dedicated exposure station (X-14B) for High Aspect Ratio Precision Manufacture. An overview of our previous work as well as the current status of the new beamline will be described.

This workshop examine the uniqued requirements of beamlines at short‐wavelength FELs, including detector requirements. Additional topics were the heat loads from a short‐wavelength FEL, optics for a short‐wavelength FEL beamline, and new technologies using short‐wavelength FELs.

Beamline instrumentation for short‐wavelength FELs (invited, abstract)

Scientific opportunities for FEL amplifier based VUV and X-ray research

The use of primary electron counting techniques as an alternative to the more usual parallel plate avalanche chamber that has been employed in soft x‐ray scattering experiments is being investigated at the National Synchrotron Light Source. The theoretical aspects of primary electron counting and motivation behind building a primary electron counting detector are described, as well as characteristics and future improvements of the device constructed at the NSLS. The detector consists of a low electric field drift region and a low pressure multistep avalanche region which can be operated with two or three stages of electron multiplication. The device has worked well in extensive tests as a simple parallel plate avalanche chamber, providing energy resolutions of 58% and 43% at 277 and 500 eV, respectively. Operated as a primary electron counter, preliminary results show an energy resolution of 38% at 500 eV.

Use of primary electron counting for detection of ultrasoft x‐rays with a low‐pressure multistep gaseous detector

The second generation scanning photoelectron microscope at beamline X1A of the National Synchrotron Light Source (X1A SPEM-II) is designed for spatially resolved elemental and chemical analysis by x ray photoelectron spectroscopy (XPS) on material surfaces. This microscope can focus photon energies between 300 to 800 eV with submicron spatial resolution. Multiple photoelectron images can be acquired simultaneously with the use of a hemispherical sector analyzer (HSA) with multi-channel detection (MCD), which enables a technique called 'parallel imaging for chemical state mapping' (PICSM). The PICSM technique was demonstrated using a Si/SiO2 pattern.

Chemical state mapping on material surfaces with the X1A second-generation scanning photoemission microscope (X1A SPEM-II)

The National Synchrotron Light Source (NSLS) has initiated an ambitious project to develop fourth generation radiation sources. To achieve this goal, the Source Development Laboratory (SDL) builds on the experiences gained at the NSLS, and at the highly successful BNL Accelerator Test Facility. The SDL accelerator system will consist of a high brightness short pulse linac, a station for coherent synchrotron and transition radiation experiments, a short bunch storage ring, and an ultra-violet free electron laser utilizing the NISUS wiggler. The electrons will be provided by a laser photocathode gun feeding a 210 MeV S-band electron linac, with magnetic bunch compression at 80 MeV. Electron bunches as short as 100 micrometers with 1 nC charge will be used for pump-probe experiments utilizing coherent transition radiation. Beam will also be injected into a compact storage ring which will be a source of millimeter wave coherent synchrotron radiation. The linac will also serve as the driver for an FEL designed to allow the study of various aspects of single pass amplifiers. The first FEL configuration will be as a self-amplified spontaneous emission FEL at 900 nm. Seeded beam and sub-harmonic seeded beam operations will push the output wavelength below 200 nm. Chirped pulse amplification operation will also be possible, and a planned energy upgrade (by powering a fifth linac section) to 310 MeV will extend the wavelength range of the FEL to below 100 nm.

The NSLS has a long-standing interest in providing the best possible synchrotron radiation sources for its user community, and hence, has recently established the Source Development Laboratory (SDL) to pursue research into fourth generation synchrotron radiation sources. A major element of the program includes development of a high peak power FEL meant to operate in the vacuum ultraviolet. The objective of the program is to develop the source, and experimental technology together to provide the greatest impact on UV science. The accelerator under construction for the SDL consists of a high brightness rf photocathode electron gun followed by a 230 MeV short pulse linac incorporating a magnetic chicane for pulse compression. The gun drive laser is a wide bandwidth Ti:sapphire regenerative amplifier capable of pulse shaping which will be used to study non-linear emittance compensation. Using the compressor, 1 nC bunches with a length as small as 50 micrometer sigma (2 kA peak current) are available for experiments. In this paper we briefly describe the facility and detail our plans for utilizing the 10 m long NISUS wiggler to carry out single pass FEL experiments. These include a 1 micrometer SASE demonstration, a seeded beam demonstration at 300 nm, and a high gain harmonic generation experiment at 200 nm. The application of chirped pulse amplification to this type of FEL also is discussed.

Recently, there has been a great deal of interest in x‐ray magnetic circular dichroism (MCD) and its applications to the study of magnetic thin films and multilayers due to the dramatically enhanced dichroic effect and its element specific nature. In this work, the soft x‐ray magneto‐optical Kerr effect, an effect closely related to MCD, is investigated. Detailed comparison between MCD and the Kerr effect is discussed. As an example, recent results from a thin bcc Co film will be presented. In the Kerr effect measurement, specular reflectivity as a function of incident angle and photon energy was measured using both linearly polarized and circularly polarized x rays. To give the largest effect, in the case of linearly polarized light, specular reflectivity was measured in the transverse configuration, while in the case of circularly polarized light, the measurement was carried out in the longitudinal configuration. In both cases very large changes in reflectivity, up to 40% in the linearly polarized case ...

During the past few years, we have built and commissioned a scanning photoemission microscope (X1-SPEM). It was the first photoemission microscope to achieve submicron resolution. To improve the performance, we are designing a second generation instrument. The major changes in the instrument are the replacement of the home-made single pass cylindrical mirror analyzer (CMA) with a hemispherical sector analyzer (HSA) and the construction of a new chamber with a scheme to manipulate the zone plate and the order sorting aperture (OSA) with more flexibility. The design concepts and expected performance of the instrument are discussed.

Design of the second-generation scanning photoemission microscope at the National Synchrotron Light Source

Second-generation scanning photoemission microscope at the National Synchrotron Light Source

The technique of Auger photoelectron coincidence spectroscopy (APECS) using synchrotron radiation is discussed. Technical considerations and experimental details are emphasized. Results from Cu(100), Ta(100), and Al(111) are presented to show the kinds of new information that APECS can provide.

Auger photoelectron coincidence spectroscopy using synchrotron radiation

Design criteria are described, and test results are presented, for prototype undulator beam position monitors at the Advanced Light Source (ALS). The design is based on monitors presently in use at the National Synchrotron Light Source, Brookhaven National Laboratory, with modifications to account for the widely varying and large K values of the undulators to be installed at the ALS. In particular, we have modified the design to simplify the thermal engineering and we have explored techniques to suppress the response of the monitors to soft photons, below 100 eV, so that the beam position can be determined by measuring the higher energy photons which are better collimated.

Prototype photon position monitors for undulator beams at the Advanced Light Source

There are many applications in synchrotron radiation research where window valves can be usefully employed. Examples include gas cells for monochromator calibration, filters for high‐order light rejection, and as vacuum isolation elements between machine and experimental vacua. Often these devices are fairly expensive, and have only fixed (i.e., nonremovable) windows. The development of a new type of seal technology by VAT for their series 01 valves provides a gate surface which is free from obstructions due to internal mechanical elements. This feature allows a threaded recess to be machined into the gate to receive a removable window frame which can carry standard size Luxel thin‐film windows. The combination of these features results in a DN 40 (2.75‐in. conflat flange) valve which provides a clear aperture of 21‐mm diameter for the window material.

The NSLS x‐ray ring exhibits a direct correlation between photon beam motion, and distortion of the ring vacuum chamber induced by fluctuations in the cooling system. We have made long term measurements of photon beam vertical position, accelerator vacuum chamber motion, process water temperatures, and angular motions of the magnets around one superperiod of the NSLS x‐ray ring. Short term transients in water temperature cause deflection of the ring vacuum chamber which have in turn been shown to induce very small angular rotations of the magnets, on the order of 10 μrad. A larger and more difficult to correct effect is the drift in beam position over the course of a fill. This problem has been shown to be related to the thermal gradients that develop across the vacuum chamber which, as a consequence of the configuration of the chamber cooling, depend upon stored current. Orbit simulations based upon the measured rotations are in agreement with the observed beam motions, and reveal that certain patterns o...

Correlation of photon beam motion with vacuum chamber cooling on the NSLS x-ray ring

We present recent developments with the scanning photoelectron microscope at beam line X1A (X1-SPEM) at the National Synchroton Light Source. It was the first to demonstrate elemental and chemical imaging with primary photoelectrons and achieve submicron resolution [Appl. Phys. Lett. 56, 1841-1843 (1990)]. Subsequent improvements allow us now to acquire XPS images with lateral resolution approaching 0.1 μm. We have utilized the instrument to examine artificial structures such as microelectronic devices and describe here our preliminary work in the study of photon-beam-mediated chemistry on aluminium surfaces.

Improved images with the scanning photoelectron microscope at the national synchrotron light source

The optics of synchrotron radiation beamlines is reviewed. Phase space considerations are emphasized and crystal monochromators are discussed in detail. (AIP)

Beamlines at synchrotron radiation facilities: The link between the user and the machine

Methods for kinematically mounting equipment are well established, but applications at synchrotron radiation facilities are subject to constraints not always encountered in more traditional laboratory settings. Independent position adjustment of beamline components can have significant benefits in terms of minimizing time spent aligning, and maximizing time spent acquiring data. In this article, we use examples taken from beamlines at the National Synchrotron Light Source to demonstrate approaches for optimization of the reproducibility, stability, excursion, and set‐up time for various situations. From our experience, we extract general principles which we hope will be useful for workers at other synchrotron radiation facilities.

Kinematic mounting systems for National Synchrotron Light Source beamlines and experiments

Some tests have been made of phosphors for photon beam diagnosis. Plasma‐sprayed coatings were checked for damage and decay during a period of several ampere hours of irradiation from the x‐ray ring at the National Synchrotron Light Source. Surface temperatures were measured and extrapolated to give an indication of the temperatures expected in more powerful photon beams. Based on our findings we have chosen plasma‐sprayed coatings of europium‐doped yttrium oxide as the best candidate for use on masks and flags in ‘‘white’’ photon beams of the new facilities.

Brookhaven National Laboratory is designing an ultraviolet free-electron laser (UV-FEL) user facility that will provide picosecond and subpicosecond pulses of coherent ultraviolet radiation for wavelengths from 300 to 75 nm. Pulse width will be variable from about 7 ps to approximately equals 200 fs, with repetition rates as high as 104 Hz, single pulse energies > 1 mJ and, hence, peak pulse power > 200 MW and average beam power > 10 W. The facility will be capable of `pump-probe' experiments utilizing the FEL radiation with: (1) synchronized auxiliary lasers, (2) a second, independently tunable FEL beam or, (3) broad- spectrum, high-repetition rate recirculating superconducting linear accelerator which feeds pulses of electrons to two magnetic wigglers. Within these two devices, photons from tunable `conventional' lasers would be frequency multiplied and amplified. By synchronously tuning the seed laser and modulating the energy of the electron beam, tuning of as much as 60% in wavelength is possible between alternating pulses supplied to different experimental stations, with Fourier transform limited resolution. Thus, up to four independent experiments may operate at one time, each with independent control of the wavelength and pulse duration. The UV-FEL will make possible new avenues of inquiry in time-resolved studies of diverse fields including chemical, surface, and solid state physics, biology, and materials science. The experimental area is scheduled to include a station dedicated to biological research. The complement of experimental and support facilities required by the biology station will be determined by the interests of the user community.

Proposed ultraviolet free-electron laser at Brookhaven National Laboratory: a source for time-resolved biochemical spectroscopy

For the study of condensed‐matter systems x‐ray scattering experiments are often the best choice as they have several desirable features including complete conservation of momentum in the incident and detected particles, well characterized initial and final electronic states, and insensitivity of photon transport to external electric and magnetic fields (as compared to photoelectrons, for example). To extend these techniques to soft x‐ray region (ℏν<1 keV) the lack of suitable detectors, and the difficulties associated with performing scattering experiments in vacuum must be overcome. In this article we provide details of our instrumental development program, and show some representative examples of experiments we have performed to date.

Recent advances in soft x‐ray scattering instrumentation at the National Synchrotron Light Source

Methods for kinematically mounting equipment are well established, but applications at synchrotron radiation facilities are subject to constraints not always encountered in more traditional laboratory settings. Independent position adjustment of beamline components can have significant benefits in terms of minimizing time spent aligning, and maximizing time spent acquiring data. In this paper, we use examples taken from beamlines at the NSLS to demonstrate approaches for optimization of the reproducibility, stability, excursion, and set-up time for various situations. From our experience, we extract general principles which we hope will be useful for workers at other synchrotron radiation facilities. 7 refs., 4 figs.

A brief review of using soft x-ray resonant magnetic scattering in the study of magnetic thin films and multilayers is given. Results from recent studies of thin Fe films and Fe/Gd multilayers are used as examples to demonstrate the information that can be obtained and the unique features of this technique. Comparison is made with related techniques: magneto- optical Kerr effect, Faraday effect, and magnetic circular dichroism.

Soft x-ray resonant magnetic scattering study of thin films and multilayers

We have recently completed the first generation scanning photoemission microscope at beamline X1A at the National Synchrotron Light Source (NSLS), the X1‐SPEM. The instrument is designed to use the soft x‐ray undulator at the NSLS as a high brightness source to illuminate a Fresnel zone plate, thus forming a finely focused probe, ≤0.4 μm in size, on the specimen surface. A grating monochromator selects the photon energy in the 400–800 eV range with an energy resolution of 0.8–2 eV. The flux in the zone plate focus is in the 108–109 photons/s range. A single pass cylindrical mirror analyzer (CMA) is used to record photoemission spectra, or to form an image within a fixed electron energy bandwidth as the specimen is mechanically scanned. The best one‐dimensional resolution achieved so far is 0.1 μm, as judged by the 25%–75% intensity rise across an edge. This is close to the diffraction limit of the zone plate used. Due to astigmatism introduced by the beamline optics, the two‐dimensional resolution in the ...

Images of a microelectronic device with the X1‐SPEM, a first generation scanning photoemission microscope at the National Synchrotron Light Source

A brief discussion of the resonant magnetic scattering process is given. Results from recent studies of thin Fe films and Fe/Gd multilayers are used as examples to demonstrate the information can be obtained and the unique features of this techniques: large resonant enhancement, sensitivity to magnitization, elemental specificity, and tunability of the penetration depth. Comparison is made with related techniques: magneto-optical Kerr effect, Faraday effect, and magnetic circular dichroism. 9 refs., 4 figs.

Soft X-RAY Magnetic Scattering Study of thin Films and Multilayers

We are in the process of developing and commissioning a scanning photoelectron microscopy (SPEM) at the X1A beamline of the National Synchrotron Light Source (NSLS). It is desigend to make use of the Soft X-ray Undulator (SXU) at the NSLS. This high brightness source illuminates a Fresnel zone plate, which forms a focused probe, ≤0.2 µm in size, on the specimen surface. A grating monochromator selects the photon energy in the 400-800 eV range with an energy resolution of better than 1 eV. The expected flux in the focus is in the 5 × 107-109 photons/s range. A single pass Cylindrical Mirror Analyzer (CMA) is used to record photoemission spectra, or to form an image within a fixed electron energy bandwidth as the specimen is mechanically scanned. As a first test, a 1000 mesh Au grid was successfully imaged with a resolution of about 1 µm and the CMA tuned to the Au 4f photoelectron peak. Once it is commissioned, a program is planned which will utilize the microscope to study beam sensitive systems, such as thin oxide/sub-oxide films of alumina and silica, and ultimately various adsorbates on these films.

The scanning photoelectron microscope at the National Synchrotron Light Source (NSLS) has recently recorded micrographs with a resolution below half a micron. To demonstrate elemental and chemical sensitivity at the submicron level, an artificial structure consisting of Al and SiO2 lines on a boron‐doped silicon substrate was examined. Al 2p and Si 2p primary photoelectrons as well as O KVV Auger electrons were used for image formation. Contrast reversal between the the Si and SiO2 areas was observed in images formed from Si 2p and oxide‐shifted Si 2p photoelectrons. The soft x‐ray undulator at the NSLS provides coherent illumination of a zone plate to produce the microprobe. The sample is mechanically scanned through the beam allowing the formation of images from photoelectrons detected by a single‐pass cylindrical mirror analyzer, or a more complete spectroscopic examination of a selected area of the sample.

Scanning photoelectron microscope with a zone plate generated microprobe

We have developed a new compact water‐cooled beam position monitor for use at the NSLS X‐13 Insertion Device Development beamline, currently fitted with a high‐power, high‐brightness soft‐x‐ray undulator. We describe the novel geometry of the monitor and present the results of tests which explore its sensitivity, stability, and linearity. These results were obtained on the NSLS Beamline Research and Development white light beamline, U14B, on the VUV ring and suggest that beam position monitors of this type might be adapted to other facilities with similar spectral characteristics.

The scope and breadth of the conference are reviewed form the personal perspective of the author. The need for additional desorption data and more rapid development and testing of prototype vacuum system components for the next generation facilities are highlighted.

Closing Remarks: A perspective from the advanced synchrotron light source conference on the vacuum design of advanced and compact synchrotron light sources

Possibilities for a Scanning Photoemission Microscope at the NSLS

We report the first implementation of an in situ glow discharge cleaning procedure for the removal of carbon contamination from x‐ray optical surfaces. In situ cleaning obviates the need for the time‐consuming and costly process of element removal, cleaning or repolishing, remounting, and realignment usually necessary to restore x‐ray optics to their original condition. The apparatus required is quite simple and can easily be fitted to most existing UHV (ultrahigh vacuum) mirror boxes or monochromators. Results with several monochromators at the Brookhaven National Labs National Synchrotron Light Source (NSLS) show that better than original performance can be obtained at the carbon K edge, since the elements are not exposed to atmosphere after in situ cleaning and do not accumulate the adventitious carbon layer associated with more traditional methods. Possible improvements and extensions of the technique are also described.

In situ reactive glow discharge cleaning of x‐ray optical surfaces

We have studied oxide films on Al(110) by photon stimulated desorption (PSD) on the Bell Labs U4 PGM at the National Synchrotron Light Source. Utilizing a time of flight technique we have obtained ion energy distribution (IED) and relative ion yield (RIY) data at the Al 2p and O 1s edges for oxides prepared at various temperatures. These initial studies suggest that different sites for the surface hydroxyls exist, that they can be selectively prepared, and examined by PSD. 15 refs., 9 figs.

Photon stimulated desorption from oxidized Al(110). [Surface hydroxyls]

Summary Abstract: Characterization of planar aluminas by x‐ray photoelectron and electron energy loss spectroscopy

Abstract Planar transition aluminas are gaining attention as models for alumina-based catalysts [I] because of their attractiveness for study by modern surface analytical techniques [2], electron optical methods [3], and reflection spectroscopy [4–7]. In this context “planar” means a thin (<10–4 cm) flat oxide layer of uniform thickness. Conventional high surface area aluminas which are used commercially for adsorbents, catalysts, and catalyst supports usually require grinding and /or pressing into disks for characterization by these approaches. This can expose unwanted inner structures or expose the samples to potential contamination by the grinding and pressing tools or uncontrolled atmospheres. In addition, difficulties arise in attempting to study the various stages of alumina development involved with commercial methods since these entail sols, gels, powdered hydroxides, and other inconvenient structures.

Abstract The complexes CpCoL2 (Cp = C5H5; L = CO or CH2=CH2) mediate the cycloisomerizations of α,δ,ω-enynenes containing allylic ether linkages to 3-(oxacyclopentyl or cycloalkyl)furans via the intermediacy of isolable CpCo-η 4-dienes. A suggested mechanism comprises initial complexation of the triple bond and one of the double bonds, then oxidative coupling to a cobalt-2-cyclopentene, terminal double bond insertion to assemble a cobalta-4-cycloheptene, β-hydride elimination, and reductive elimination to furnish a CpCo-η 4-diene. When possible, the cascade continues through cobalt-mediated hydride shifts and dissociation of the aromatic furan ring. The outcome of a deuterium labeling experiment supports this hypothesis. The reaction exhibits variable stereoselectivity with a preference for the trans-product (or, when arrested, its syn-Me CpCo-η 4-diene precursor), but is completely regioselective in cases in which the two alkyne substituents are differentiated electronically by the presence or absence of an embedded oxygen. Regioselectivity is also attained by steric discrimination or blocking one of the two possible β-hydride elimination pathways. When furan formation is obviated by such regiocontrol, the sequence terminates in a stable CpCo-η 4-diene complex. The conversion of the cyclohexane-fused substrate methylidene-2-[5-(2-propenyloxy)-3-pentynyl]cyclohexane into mainly 1-[(1R*,3aS*,7aS*)-7a-methyloctahydroinden-1-yl]-1-ethanone demonstrates the potential utility of the method in complex synthesis.

Stoichiometric and Catalytic (η 5-Cyclopentadienyl)cobalt-Mediated Cycloisomerizations of Ene-Yne-Ene Type Allyl Propargyl Ethers

Cenicriviroc is a once-daily oral CCR5/CCR2 antagonist in development for treatment of HIV infection. CVC Study 202 (652-2-202; NCT01338883) excluded treatment-naive subjects demonstrated to harbor non-R5 (CXCR4-tropic or dual-mixed) tropic HIV-1 by either genotypic or phenotypic tropism testing. Here we compare the results of genotypic and phenotypic tropism testing in Study 202. A total of 304 subjects screened had paired genotypic and phenotypic results. Genotypic tropism testing (GTT) incorporated triplicate population sequencing using the geno2pheno algorithm and the PSSM algorithm, followed by ultradeep sequencing (UDS) for samples with R5 results. All samples were further evaluated with a phenotypic test, the enhanced-sensitivity Trofile assay (ESTA). Concordance between GTT and ESTA was 80% and increased to 84% when only geno2pheno was used for triplicate population sequencing. GTT (geno2pheno) classified 18% of the samples as non-R5 compared to 16% by ESTA. Only one-third of samples with non-R5 results by either test were classified as non-R5 by both tests. Median CD4((+)) cell counts were lower in patients with concordant non-R5 results by UDS and ESTA than in subjects with an R5 result by either assay (p=0.0004). UDS detected non-R5 virus in an additional 27/304 subjects (median 15% non-R5, interquartile range: 3.7-62%) with R5 results by ESTA. In conclusion, the geno2pheno algorithm improves concordance of GTT with a clinically validated phenotypic tropism assay as does the use of UDS. These findings provide support for recent guidelines indicating that genotypic tropism testing may be considered as an alternative to phenotypic testing.

Comparison of genotypic and phenotypic HIV type 1 tropism assay: results from the screening samples of Cenicriviroc Study 202, a randomized phase II trial in treatment-naive subjects.

A tropism test is required prior to initiation of CCR5 antagonist therapy in HIV-1 infected individuals, as these agents are not effective in patients harboring CXCR4 (X4) coreceptor-using viral variants. We developed a clinical laboratory-based genotypic tropism test for detection of CCR5-using (R5) or X4 variants that utilizes triplicate population sequencing (TPS) followed by ultradeep sequencing (UDS) for samples classified as R5. Tropism was inferred using the bioinformatic algorithms geno2pheno[coreceptor] and PSSMx4r5. Virologic response as a function of tropism readout was retrospectively assessed using blinded samples from treatment-experienced subjects who received maraviroc (N = 327) in the MOTIVATE and A4001029 clinical trials. MOTIVATE patients were classified as R5 and A4001029 patients were classified as non-R5 by the original Trofile test. Virologic response was compared between the R5 and non-R5 groups determined by TPS, UDS alone, the reflex strategy and the Trofile Enhanced Sensitivity (TF-ES) test. UDS had greater sensitivity than TPS to detect minority non-R5 variants. The median log10 viral load change at week 8 was −2.4 for R5 subjects, regardless of the method used for classification; for subjects with non-R5 virus, median changes were −1.2 for TF-ES or the Reflex Test and −1.0 for UDS. The differences between R5 and non-R5 groups were highly significant in all 3 cases (p<0.0001). At week 8, the positive predictive value was 66% for TF-ES and 65% for both the Reflex test and UDS. Negative predictive values were 59% for TF-ES, 58% for the Reflex Test and 61% for UDS. In conclusion, genotypic tropism testing using UDS alone or a reflex strategy separated maraviroc responders and non-responders as well as a sensitive phenotypic test, and both assays showed improved performance compared to TPS alone. Genotypic tropism tests may provide an alternative to phenotypic testing with similar discriminating ability.

A Genotypic Test for HIV-1 Tropism Combining Sanger Sequencing with Ultradeep Sequencing Predicts Virologic Response in Treatment-Experienced Patients

Preparation of α-Hydroxy-β-FmocAmino Acids from N-Boc Amino Acids

[4083-64-1] C8H7NO3S (MW 197.23) 
 
InChI = 1S/C8H7NO3S/c1-7-2-4-8(5-3-7)13(11,12)9-6-10/h2-5H,1H3 
 
InChIKey = VLJQDHDVZJXNQL-UHFFFAOYSA-N 
 
(converts oxiranes to 2-oxazolinones;2 undergoes many [2 + x] cycloadditions; useful for (thio)carbonyl to imine functional group interchange; introduces the Tac protecting group to amino acids3) 
 
Alternate Name: tosyl isocyanate. 
 
Physical Data: bp 144 °C/10 mmHg; d 1.295 g cm−3. 
 
Solubility: sol chlorinated, aromatic, and ethereal solvents; reacts violently with H2O and basic and protic solvents. 
 
Form Supplied in: colorless liquid; widely available. 
 
Handling, Storage, and Precautions: lachrymator; corrosive; use only in a fume hood. Wear protective gloves and, preferably, a NIOSH-approved respirator. All transfers and reactions should be carried out under anhydrous conditions. Store in a cool dry place, taking care to avoid contamination with protic, basic, or organometallic materials, as these may induce polymerization. See Karol4a and Henderson4b for toxicity data of isocyanates.

System for speculatively prefetching in a multi-core messaging platform (300), comprising: at least one processor (310, 310a, 310b), each of said minimum number of a processor (310, 310a, 310b) at least a core (311a, 311b, 311c, 311d), wherein the system comprises a plurality of cores (311a, 311b , 311c, 311d) comprises a receiving core (105) among the plurality of cores including a local cache (113), at least one message queue (107) for storing received messages, and a messaging prefetcher (109) communicatively coupled to a shared cache and / or a shared memory (111) is coupled, and also to the local cache (113) is coupled, having, an interconnection messaging among the plurality of cores, and a transmitting core (103) among the plurality of cores for sending a message to the receiving core, wherein a message having a memory reference, both the at least one message queue (107) and at the messaging prefetcher (109) of the receiving core (105 ) is sent ...

Method and system for speculatively prefetching in a multi-processor / multi-core messaging machine

ABSTRACT Multicopy plasmids in Escherichia coli are not randomly distributed throughout the cell but exist as defined clusters that are localized at the mid-cell, or at the 1/4 and 3/4 cell length positions. To explore the factors that contribute to plasmid clustering and localization, E. coli cells carrying a plasmid RK2 derivative that can be tagged with a green fluorescent protein-LacI fusion protein were subjected to various conditions that interfere with plasmid superhelicity and/or DNA replication. The various treatments included thymine starvation and the addition of the gyrase inhibitors nalidixic acid and novobiocin. In each case, localization of plasmid clusters at the preferred positions was disrupted but the plasmids remained in clusters, suggesting that normal plasmid superhelicity and DNA synthesis in elongating cells are not required for the clustering of individual plasmid molecules. It was also observed that the inhibition of DNA replication by these treatments produced filaments in which the plasmid clusters were confined to one or two nucleoid bodies, which were located near the midline of the filament and were not evenly spaced throughout the filament, as is found in cells treated with cephalexin. Finally, the enhanced yellow fluorescent protein-RarA fusion protein was used to localize the replication complex in individual E. coli cells. Novobiocin and nalidixic acid treatment both resulted in rapid loss of RarA foci. Under these conditions the RK2 plasmid clusters were not disassembled, suggesting that a completely intact replication complex is not required for plasmid clustering.

Gyrase Inhibitors and Thymine Starvation Disrupt the Normal Pattern of Plasmid RK2 Localization in Escherichia coli

ABSTRACT Early steps of retroviral replication involve reverse transcription of the viral RNA to yield a linear double-stranded cDNA copy and then integration of the viral cDNA into a chromosome of the host cell. A portion of the viral cDNA can also follow nonproductive pathways in which it becomes circularized. In one pathway, the ends of the linear cDNA become joined together by the cellular nonhomologous DNA end-joining system to form two-long terminal repeat (2-LTR) circles. It has been argued that 2-LTR circles are quickly degraded in human immunodeficiency virus (HIV)-infected cells, allowing the presence of 2-LTR circles to be used as a marker for ongoing de novo infection in patients. Following this idea, detection of 2-LTR circles in patients undergoing successful highly active antiretroviral therapy has led to the proposal that viral replication persists despite treatment. We have used fluorescence-monitored PCR (Taqman) to quantitate the metabolism of HIV cDNA early after infection. Contrary to previous work, we find that 2-LTR circles are actually quite stable in experiments where confounding variables are controlled. Thus, studies relying on the lability of 2-LTR circles are open to reinterpretation. We also used the quantitative PCR methods to analyze the effects of MG132, a proteasome inhibitor, which revealed that viral complexes containing mostly completed cDNAs are the primary substrates for proteasome-mediated degradation.

Human Immunodeficiency Virus cDNA Metabolism: Notable Stability of Two-Long Terminal Repeat Circles

[18926-24-4] C4H4BrNO2 (MW 177.99) 
 
InChI = 1S/C4H4BrNO2/c5-2-1-4(8)6-3-7/h1-2H2 
 
InChIKey = JZKAOWBNIUWMLP-UHFFFAOYSA-N 
 
(derivatizing agent for alcohols,1 phenols,2 and arylamines;3 brominating agent potentially present in N-bromosuccinimide brominations;4 bifunctional cyclization reagent5) 
 
Alternate Name: 3-bromopropanoyl isocyanate. 
 
Physical Data: volatile liquid. 
 
Solubility: sol chlorinated, aromatic, and ethereal solvents; reacts violently with H2O, and with basic and protic solvents. 
 
Form Supplied in: prepared from N-Bromosuccinimide as needed.6 
 
Handling, Storage, and Precautions: lachrymator; corrosive; use only in a fume hood; wear protective gloves and preferably a NIOSH-approved respirator. All transfers and reactions should be carried out under anhydrous conditions. Store in a cool dry place, taking care to avoid contamination with protic, basic, or organometallic materials, as these may induce polymerization. Toxicity data for isocyanates are available.7

ABSTRACT The parCBA operon of the 3.2-kb stabilization region of plasmid RK2 encodes three cotranslated proteins. ParA mediates site-specific recombination to resolve plasmid multimers, ParB has been shown to be a nuclease, and the function of ParC is unknown. In this study ParB was overexpressed by cotranslation with ParC inEscherichia coli by using a plasmid construct that contained the parC and parB genes under the control of the T7 promoter. Purification was achieved by treatment of extracts with Polymin P, followed by ammonium sulfate precipitation and heparin and ion-exchange chromatography. Sizing-column analysis indicated that ParB exists as a monomer in solution. Analysis of the enzymatic properties of purified ParB indicated that the protein preferentially cleaves single-stranded DNA. ParB also nicks supercoiled plasmid DNA preferably at sites with potential single-stranded character, like AT-rich regions and sequences that can form cruciform structures. ParB also exhibits 5′→3′ exonuclease activity. This ParB activity on a 5′-end-labeled, double-stranded DNA substrate produces a 3′,5′-phosphorylated dinucleotide which is further cleaved to a 3′,5′-phosphorylated mononucleotide. The role of the ParB endonuclease and exonuclease activities in plasmid RK2 stabilization remains to be determined.

The development and piloting of a potential manufacturing process for ACE/NEP dual inhibitor CGS30440 is described. The synthesis proceeds sequentially from 1-aminocyclopentanecarboxylic acid via N-protection, peptide coupling with l-tyrosine ethyl ester, O-methylation of N-protected [(1-amino-1-cyclopentyl)carbonyl]-l-tyrosine ethyl ester, N-deprotection, peptide coupling of [(1-amino-1-cyclopentyl)carbonyl]-O-methyl-l-tyrosine ethyl ester with d-2-bromo-3-methylbutyric acid, and final displacement of bromide with thioacetate. This approach is superior to shorter Discovery routes based upon final peptide coupling of l-2-(acetylthio)-3-methylbutanoic acid to [(1-amino-1-cyclopentyl)carbonyl]-O-methyl-l-tyrosine ethyl ester.

Efficient Large Scale Preparation of Neutral Endopeptidase/Angiotensin-Converting Enzyme Dual Inhibitor CGS30440

and interaction with the ParD antitoxin protein . Plasmid RK 2 toxin protein ParE : purification

MACROLACTAMIZATION VIA PALLADIUM PI -ALLYL ALKYLATION. PREPARATION OF CGS25155 : A 10-MEMBERED LACTAM NEUTRAL ENDOPEPTIDASE 24.11 INHIBITOR

Retrograde activation of CB1R by muscarinic receptors protects against central organophosphorus toxicity

Assessment of mouse strain differences in baseline esterase activities and toxic response to sarin.

Abstract Mice and other rodents are typically utilized for chemical warfare nerve agent research. Rodents have large amounts of carboxylesterase in their blood, while humans do not. Carboxylesterase nonspecifically binds to and detoxifies nerve agent. The presence of this natural bioscavenger makes mice and other rodents poor models for studies identifying therapeutics to treat humans exposed to nerve agents. To obviate this problem, a serum carboxylesterase knockout (Es1 KO) mouse was created. In this study, Es1 KO and wild type (WT) mice were assessed for differences in gene expression, nerve agent (soman; GD) median lethal dose (MLD) values, and behavior prior to and following nerve agent exposure. No expression differences were detected between Es1 KO and WT mice in more than 34 000 mouse genes tested. There was a significant difference between Es1 KO and WT mice in MLD values, as the MLD for GD-exposed WT mice was significantly higher than the MLD for GD-exposed Es1 KO mice. Behavioral assessments of Es1 KO and WT mice included an open field test, a zero maze, a Barnes maze, and a sucrose preference test (SPT). While sex differences were observed in various measures of these tests, overall, Es1 KO mice behaved similarly to WT mice. The two genotypes also showed virtually identical neuropathological changes following GD exposure. Es1 KO mice appear to have an enhanced susceptibility to GD toxicity while retaining all other behavioral and physiological responses to this nerve agent, making the Es1 KO mouse a more human-like model for nerve agent research.

Evaluating mice lacking serum carboxylesterase as a behavioral model for nerve agent intoxication

Neuropathological and behavioral sequelae in IL‐1R1 and IL‐1Ra gene knockout mice after soman (GD) exposure

Interleukin-18 expression increases in response to neurovascular damage following soman-induced status epilepticus in rats

Increased expression of the chemokines CXCL1 and MIP-1α by resident brain cells precedes neutrophil infiltration in the brain following prolonged soman-induced status epilepticus in rats

The acute phase response and soman-induced status epilepticus: temporal, regional and cellular changes in rat brain cytokine concentrations

Glutamate receptor pathology is present in the hippocampus following repeated sub-lethal soman exposure in the absence of spatial memory deficits.

Animals exposed to chemical nerve agent (i.e. soman, sarin, cyclosarin, tabun or VX) develop convulsive seizures that rapidly progress to status epilepticus and brain injury. Nerve agent-induced brain injury is caused primarily by the magnitude and duration of seizures, but inflammation may also play a role in the pathogenesis. Since a major goal of our neuroprotection program is to reduce nerve agent-induced brain damage, a more comprehensive survey of inflammatory factors in the brain is needed to accurately direct antiinflammatory pharmacological intervention. The present study investigated the temporal expression of inflammatory mediators in the piriform cortex, correlated these findings with brain pathology and determined the anti-inflammatory therapeutic window for attenuation of neurodegeneration following acute nerve agent exposure. Male Sprague-Dawley rats were pretreated with oxime HI-6 30 min prior to soman challenge and treated with atropine methylnitrate one minute afterwards. At various time points (30 min, 1, 3, 6, 12, 24, 48 or 72 hr) after the onset of seizures, brains were processed for pathological and immunohistochemical studies or high throughput LuminexTM multiplex immunoassay. An extensive loss of microtubule-associated protein 2 (MAP-2) was observed in the piriform cortex beginning at 12 hr after the onset of seizures. At 24 hr after onset of seizures, MAP-2 immunoreactivity was completely lost in layer three of the piriform cortex. By LuminexTM immunoassay, the expression of several inflammatory mediators was also found to be timedependent and parallel with severe brain injury. The expression of MIP-1α, TNFα and GRO KC was increased as early as one hour, and the expression of IL-1α, IL-1β and MCP-1 was elevated at 6 hr. Of these inflammatory markers, MIP-1α, TNFα, IL-1α, IL-1β and GRO KC expression levels peaked at 12 hr in the piriform cortex, coincident with a severe loss of MAP-2. These observations suggest a correlation between increasing neuroinflammation and brain damage following acute soman exposure. In addition, these results suggest that a therapeutic window for prophylactic anti-inflammatory treatment exists for at least 6 hr following soman exposure as evidenced by the less advanced state of MAP-2 pathology at this time point. Moreover, brain cytokines released into the blood or urine could be used clinically in the diagnosis, prognosis and therapeutic evaluation of brain injury induced by nerve agent. Kan, R.K.; Johnson, E.A.; Fath, D.M.; Tompkins, C.P.; Hamilton, T.A.; Hoard-Fruchey, H. (2007) Temporal Expression of Neuroinflammatory Markers and Brain Injury Following Acute Soman Poisoning. In Defence against the Effects of Chemical Hazards: Toxicology, Diagnosis and Medical Countermeasures (pp. 1-1 – 1-14). Meeting Proceedings RTO-MP-HFM-149, Paper 1. Neuilly-sur-Seine, France: RTO. Available from: http://www.rto.nato.int. Temporal Expression of Neuroinflammatory Markers and Brain Injury Following Acute Soman Poisoning 1 2 RTO-MP-HFM-149 1.0 INTRODUCTION Soman (pinacolylmethylphosphonofluoridate; O-1,2,2-trimethylpropylmethyl-phosphonofluoridate) is an organophosphonate nerve agent that causes convulsive seizures and death. The initiation of seizures is related to soman’s ability to irreversibly inhibit acetylcholinesterase (AChE), leading to an excessive accumulation of the neurotransmitter acetylcholine (ACh) in neural and myoneural junctions (Shih, 1982; Lallement et al., 1992; McDonough and Shih, 1997). However, the secondary recruitment of the excitatory amino acid glutamate following the early phase of cholinergically induced hyperexcitation is believed to be the cause of severe brain injury after soman exposure (Wade et al., 1987; Lallement et al., 1992; McDonough and Shih, 1993; Solberg and Belkin, 1997). McDonough and Shih (1993) reported that anticholinergic drugs scopolamine and atropine failed to block soman-induced seizures when given 40 min after onset of somaninduced seizures, but MK-801 (dizocilpine), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, was effective in terminating seizures induced by soman. In addition, MK-801 has been shown to arrest soman-induced seizures and reduced neuronal necrosis, further supporting a role of glutamate in soman poisoning (Braitman and Sparenborg, 1989; Sparenborg et al., 1992). Nerve agent-induced neuropathology was first described by Petras (1981), who demonstrated profound axonal degeneration in the brains of rats poisoned with soman that survived for 15-28 days. Subsequently, a number of laboratories have confirmed that brain damage is a pathological characteristic of animals surviving an acute soman exposure (Lemercier et al., 1983; McLeod et al., 1984; McDonough et al., 1987; Ballough et al., 1995). Although the regional brain pathology has been defined by these investigators, a time-course of brain injury induced by soman poisoning has not been extensively studied. The presence of reactive astrocytes, activation of microglial cells and release of inflammatory mediators, independently of the primary insult, may contribute to the progression of neuronal injury (Willard et al., 1999; Rizzi et al., 2003; Ravizza et al., 2005). It has been shown that activation of astrocytes and microglia is a pathological feature of soman-induced seizures (Zimmer et al., 1997). Although evidence of neuroinflammation has been found following chemical nerve agent exposure (Williams et al., 2003; Chapman et al., 2006), information on the extent and progression of the inflammatory process in the damaged areas of the brain is still limited. The present study was designed to evaluate the time course of brain injury progression and neuroinflammatory mediator expression following soman-induced seizures. The piriform cortex was used to study the progression of injury as it is a brain region that consistently showed damage in the rat exposed to soman. 2.0 MATERIALS AND METHODS Male Sprague-Dawley rats (CRL: CD[SD]-BR), weighing 200-225 g, were used in the study. All animals were housed in individual cages on a standard 12/12 h light/dark cycle with free access to food and water. All experiments were conducted in compliance with the regulations and standards of the Animal Welfare Act and adhered to the principles of the Guide for the Care and Use of Laboratory Animals, National Research Council, 1996. The facility where this research was conducted is fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International. Representative animals were surgically implanted with cortical screw electrodes for monitoring the time of seizure initiation. The animals were allowed to recover from the surgery for 7 days before experimentation. On the day of the experiment, animals were randomly divided into control and experimental animals. Experimental animals were further divided into groups to be euthanized at different time points after the onset Temporal Expression of Neuroinflammatory Markers and Brain Injury Following Acute Soman Poisoning RTO-MP-HFM-149 1 3 of seizures (30 min, 1 hr, 3 hr, 6 hr, 12 hr, 24 hr, 48 hr or 72 hr). Animals that were implanted with an electrode were connected to EEG recording apparatus, and baseline EEG activity and behavior were monitored for 15 min; animals that did not have electrode implants remained in their cages. All animals were then pretreated with the oxime HI-6 (125 mg/kg, ip) 30 min prior to soman challenge (1.6 LD50 or180 μg/kg, sc). One minute after soman injection, animals were treated with atropine methyl nitrate (AMN) (2.0 mg/kg, im). HI-6 and AMN were used to decrease the mortality of soman-exposed animals (Shih et al., 1991). The concentration of soman was selected because it has been shown to produce seizures in 100% of the animals (Shih et al., 1991). Vehicle control animals received an equivalent volume of vehicle, HI-6 and AMN. 2.1 Brain Tissue Procurement Animals were anesthetized with sodium pentobarbital (65 mg/kg, ip) at designated time points after seizure onset. For immunohistochemical studies, animals were transcardially perfused with 0.9% saline, followed by 10% phosphate buffered formalin (10% PBF). Following perfusion, brains were removed immediately from the skull and further fixed in 10% PBF at 4°C for 18 hr. Brains were then coronally cut into 3mm slices using a rat brain metrix (ASI Instrument, Warren, MI), paraffin processed and serially cut at 5 μm. Sections between bregma -2.30 mm and -3.80 mm, as described by Paxinos and Watson (Paxinos and Watson, 1998) were subjected to MAP-2 immunohistochemistry. For multiplex array immunoassay, brain tissue was processed as previously described (Johnson et al., 2005). Briefly, the piriform cortex was excised, rinsed with cold PBS, snap frozen in liquid nitrogen and homogenized in ice-cold triple detergent lysis buffer containing a CompleteTM protease inhibitor cocktail (Roche Biochemicals; Indianapolis, IN). 2.2 Microwave-Assisted MAP-2 Immunohistochemistry Sections were dewaxed in xylene and then hydrated in decreasing concentrations of ethyl alcohol to distilled water. To suppress endogenous peroxidase activity, sections were incubated in 5% hydrogen peroxide at room temperature for 20 min. Following thorough washing in running tap water (5 min), sections were rinsed in dH2O and treated in the microwave (Kan et al., 2005). Briefly, sections were boiled 2 times (5 min each time) in 10 mM citric acid (Sigma-Aldrich, St Louis, MO; Lot 30H-0627) in a microwave (Pelco 3440 Max, 800 watts; Ted Pella, Inc, Redding, CA), and cooled at room temperature for 20 min prior to immunohistochemical staining. Indirect immunohistochemistry was performed using the avidin-biotin-peroxidase complex (ABC) method of Hsu and co-workers (Hsu et al., 1981). Following microwave antigen retrieval, brain sections were incubated in 5% horse serum for 30 min at 4°C to block tissue immunoglobulins that could react wit

Temporal Expression of Neuroinflammatory Markers and Brain Injury Following Acute Soman Poisoning

Abstract : Previously, we examined regional neuronal damage following soman-induced seizures using Fluoro-Jade (FJ), which exhibits a marked affinity for degenerating neurons. However, with FJ alone, the degree of neuronal loss cannot be ascertained. The present study was conducted to develop a protocol to double-label a single paraffin-embedded rat brain section with both Fluoro-Jade C (FJ-C) and Neuronspecific nuclear protein (NeuN) to evaluate neuronal injury. Rats pretreated with HI-6 (125 mg/kg, i.p.) were challenged with soman (1.6 LD50; 180 g/kg, s.c.) and administered atropine methyl nitrate (2.0 mg/kg, i.m.) to minimize peripheral toxic effects. All soman-exposed animals displayed prolonged convulsive behavior consistent with seizures. Brains harvested at 24 hr were paraffin-processed, sectioned, and stained with NeuN monoclonal antibody and FJ-C. The extent of neuronal injury was determined by measuring NeuN and FJ-C labeling using imaging analysis. In the piriform cortex of soman-exposed rats, FJ-C positive cells were detected in areas where NeuN immunofluorescence was lost, and pronounced necrotic lesions with depletion of NeuN staining and remnants of neuronal FJ-C fluorescence were observed. Co-localization of NeuN and FJ-C suggests that neurons are damaged, but surviving. To determine whether or not these neurons are capable of recovering, a timecourse evaluation of NeuN and FJ-C beyond 24 hr after exposure is necessary. Results indicate that double-labeling sections with NeuN and FJ-C is an effective method for assessing neuronal injury and loss.

Development of a Protocol to Evaluate Neuronal Injury and Loss Following Soman-Induced Seizures Using NeuN and Fluoro-Jade C

Generation of aberrant forms of DFF40 concurrent with caspase-3 activation during acute and chronic liver injury in rats.

Abstract : Behavioral studies investigating chemical weapon nerve agent (CWNA) exposure often utilize guinea pigs because their levels of carboxylesterase enzymes are similar to humans (Maxwell et al. 1987; Shih and McDonough 1999; Shih and McDonough 2000; de Groot et al. 2001). However, the guinea pig model does present a significant problem when trying to correlate behavioral and protein changes due to the absence of guinea pig-specific antibodies. We have developed a procedure to determine the specificity of commercially available, non-guinea pig-specific antibodies in guinea pig lysates. Common Western blotting techniques were used to compare immunostaining patterns of tissue lysates between a known species, rat, and the guinea pig using antibodies to several common CNS proteins. Of the sixteen antibodies tested, nine revealed the exact same banding patterns as their rat lysate controls, five had similar banding patterns but required further characterization and two revealed no immunoreactivity. This report outlines the procedure for characterizing the immunoreactivity of these antibodies for use in guinea pig tissue lysates and identifies nine CNS proteins that can be labeled in this manner. This procedure should be of benefit to all investigators using the guinea pig behavioral model who wish also to investigate any underlying protein changes.

Analyzing Protein Changes in Guinea Pig Tissue Lysates Using Non-guinea Pig Specific Antibodies: Procedures for Western Blotting and Examples Using 16 Individual Antibodies for Common CNS Proteins

Cell-specific DNA fragmentation may be attenuated by a survivin-dependent mechanism after traumatic brain injury in rats

This document is dedicated to my wife, Karie, for her loving and unwavering support during this process. iv ACKNOWLEDGMENTS I would first and foremost like to thank my wife, Karie, for her undying support and patience during these long years. No matter what the situation, she is always waiting there with a smile and she has helped me more than she will ever know. I would also like to thank my parents, Arlen and Patricia Johnson, for their love, dedication and fantastic parenting skills. Without these, I would not be the person I am today and I would never have been able to pursue this level of education. I would like to thank Dr. Ronald Hayes for the opportunity to pursue this novel research and for the opportunity to contribute to the scientific community. I would also like to thank past and present committee members, Dr. their help and guidance in completing these studies. Lastly, I would like to thank all the members of Dr. Hayes' laboratory for their assistance and friendship throughout the years. I would like to especially thank Jeremy

SURVIVIN EXPRESSION AFTER TRAUMATIC BRAIN INJURY : POTENTIAL ROLES IN NEUROPROTECTION

In this study, we examined the expression and cellular localization of survivin and proliferating cell nuclear antigen (PCNA) after controlled cortical impact traumatic brain injury (TBI) in rats. There was a remarkable and sustained induction of survivin mRNA and protein in the ipsilateral cortex and hippocampus of rats after TBI, peaking at five days post injury. In contrast, both survivin mRNA and protein were virtually undetectable in craniotomy control animals. Concomitantly, expression of PCNA was also significantly enhanced in the ipsilateral cortex and hippocampus of these rats with similar temporal and spatial patterns. Immunohistochemistry revealed that survivin and PCNA were co-expressed in the same cells and had a focal distribution within the injured brain. Further analysis revealed a frequent co-localization of survivin and GFAP, an astrocytic marker, in both the ipsilateral cortex and hippocampus, while a much smaller subset of cells showed co-localization of survivin and NeuN, a mature neuronal marker. Neuronal localization of survivin was observed predominantly in the ipsilateral cortex and contralateral hippocampus after TBI. PCNA protein expression was detected in both astrocytes and neurons of the ipsilateral cortex and hippocampus after TBI. Collectively these data demonstrate that the anti-apoptotic protein survivin, previously characterized in cancer cells, is abundantly expressed in brain tissues of adult rats subjected to TBI. We found survivin expression in both astrocytes and a sub-set of neurons. In addition, the expression of survivin was co-incident with PCNA, a cell cycle protein. This suggests that survivin may be involved in regulation of neural cell proliferative responses after traumatic brain injury.

Cell-specific upregulation of survivin after experimental traumatic brain injury in rats.

17β-Estradiol extends ischemic thresholds and exerts neuroprotective effects in cerebral subcortex against transient focal cerebral ischemia in rats

Neuroprotective effects of estrogens are demonstrated consistently in the cerebral cortex, but not in subcortical areas. In the present study, transient middle cerebral artery occlusions (MCAO) were induced for various duration, and protective effects of estrogen treatment on the cerebral cortex and subcortex were evaluated. MCAO was induced for 30, 40 or 60 min in ovariectomized rats. Animals were treated with 17beta-estradiol (E2) or vehicle (OVX) 2 h before MCAO and sacrificed 24 h after the indicated duration of MCAO. Ischemic lesion was evaluated by 2,3,5-triphenyltetrazolium chloride staining, hematoxylin and eosin staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. E2 treatment reduced the magnitude and delayed the appearance of the total ischemic lesion area and largely prevented TUNEL staining in the cortex. In the subcortex, E2 treatment prevented the ischemic lesion in the 30-min group, reduced lesion area in the 40-min group, but had no effect on ischemic lesion area in the 60-min group. E2 treatment significantly decreased apoptotic cell number in the subcortical area at 30 and 40 min, but not at 60 min of MCAO. This study demonstrated that estrogen treatment can protect the cerebral subcortex in a severity-dependent manner, suggesting that the lack of protective effects of estrogen treatment in the subcortex is not due to the lack of estrogen receptors. Further, this study indicates that estrogens could be used as a neuroprotectant to prolong the therapeutic window of thrombolysis and prolong the time of cerebral circulation intervention for neurosurgical procedure.

17beta-Estradiol extends ischemic thresholds and exerts neuroprotective effects in cerebral subcortex against transient focal cerebral ischemia in rats.

Although a number of increased CSF proteins have been correlated with brain damage and outcome after traumatic brain injury (TBI), a major limitation of currently tested biomarkers is a lack of specificity for defining neuropathological cascades. Identification of surrogate biomarkers that are elevated in CSF in response to brain injury and that offer insight into one or more pathological neurochemical events will provide critical information for appropriate administration of therapeutic compounds for treatment of TBI patients. Non‐erythroid αII‐spectrin is a cytoskeletal protein that is a substrate of both calpain and caspase‐3 cysteine proteases. As we have previously demonstrated, cleavage of αII‐spectrin by calpain and caspase‐3 results in accumulation of protease‐specific spectrin breakdown products (SBDPs) that can be used to monitor the magnitude and temporal duration of protease activation. However, accumulation of αII‐spectrin and αII‐SBDPs in CSF after TBI has never been examined. Following a moderate level (2.0 mm) of controlled cortical impact TBI in rodents, native αII‐spectrin protein was decreased in brain tissue and increased in CSF from 24 h to 72 h after injury. In addition, calpain‐specific SBDPs were observed to increase in both brain and CSF after injury. Increases in the calpain‐specific 145 kDa SBDP in CSF were 244%, 530% and 665% of sham‐injured control animals at 24 h, 48 h and 72 h after TBI, respectively. The caspase‐3‐specific SBDP was observed to increase in CSF in some animals but to a lesser degree. Importantly, levels of these proteins were undetectable in CSF of uninjured control rats. These results indicate that detection of αII‐spectrin and αII‐SBDPs is a powerful discriminator of outcome and protease activation after TBI. In accord with our previous studies, results also indicate that calpain may be a more important effector of cell death after moderate TBI than caspase‐3.

Accumulation of non‐erythroid αII‐spectrin and calpain‐cleaved αII‐spectrin breakdown products in cerebrospinal fluid after traumatic brain injury in rats

CLLBC High Temperature Scintillation Characterization and Detector Integration

Upgrades to the Spallation Neutron Source at Oak Ridge National Laboratory will provide a second target station and an increased neutron flux, which will offer a more powerful tool for neutron reflectometry. To fully utilize the higher neutron flux, a high-speed, neutron-imaging device (an imaging plane) specifically for reflectometry is required. The neutron imaging plane requires a detection efficiency of 60% for 2 Å neutrons for event rates exceeding 2 Mcps/cm<sup>2</sup> with less than 10% dead time. A novel organic glass scintillator material loaded with a boron compound demonstrated good neutron sensitivity. Simulations show that the detection efficiency for thermal neutrons can reach 60% with a 500-<inline-formula> <tex-math notation="LaTeX">$\mu \text{m}$ </tex-math></inline-formula> thickness, if the glass is loaded with 99% enriched <inline-formula> <tex-math notation="LaTeX">$^{10}\text{B}$ </tex-math></inline-formula> compound at 10% wt. A lower concentration of 95% enrichment at 5% wt loading can provide 60% efficiency with a thickness slightly above 1 mm. The decay time of the scintillator is less than 100 ns, providing a fast response for high rate counting. The instrument design is based on detecting the neutron with a fast scintillation material and integrating silicon photomultipliers (SiPMs) with high-speed digital electronics. Traditional pulse sampling using a high-speed analog to digital converter (ADC) to conduct pulse shape discrimination is not viable for imaging, and a new technique has been formulated for this material using a time over threshold (TOT) method to isolate neutrons from gamma-ray interactions. The gamma-neutron peak separation is greater than two sigma, and with a thin scintillator, the gamma-ray rejection per detected neutron should meet the design specification of <inline-formula> <tex-math notation="LaTeX">$10^{-6}$ </tex-math></inline-formula>. Using the TOT method, the digital information to be processed by an interfacing ADC is reduced allowing for readout per SiPM, providing a position resolution close to 1 mm.

Design of a High-Speed Neutron Imager Using a Boron-Loaded Organic Glass Scintillator

Nuclear power plants regularly generate spent fuel that must be stored on the decade timescale. Often this is done in dry nuclear waste storage casks. Long-term monitoring would provide data that improves the safe maintenance of stored spent fuel. This requires measuring the conditions within waste casks using a self-contained sensor system. Radiation Monitoring Devices, Inc. is developing a system that detects damaged fuel rod cladding by sensing and quantifying the amount of 85Kr present using a diamond sensor. A potential means for power and data transfer through the cask wall uses an ultrasonic transmission method. The work described here advances the prototype toward inclusion in a specific model fuel cask, the NUHOMS® 32 PTH1 manufactured by Orano (formally, Areva Transnuclear, Inc.). The results include extensive radiological modeling studies, an estimation of the leaked activity due to 85Kr after a cladding breach (~ 1013Bq) derived from a literature review, a design for a prototype, and the characterization of a diamond detector at room temperature and in the presence of 85Kr.

2020 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC)

The Miniature Neutron Spectrometer: A CLYC-based Detector for the LunaH-Map Mission

Active dosimeters for astronauts and space weather monitors are critical tools for mitigating radiation induced health issues or system failure on capital equipment. Commercial spaceflight, deep space flight, and satellites require smarter, smaller, and lower power dosimeters. There are a number of instruments with flight heritage, yet as identified in NASA’s roadmaps, these technologies do not lend themselves to a viable solution for active dosimetry for an astronaut, particularly for deep space missions. For future missions, nano- and micro-satellites will require compact instruments that will accurately assess the radiation hazard without consuming major resources on the spacecraft. RMD has developed the methods for growing an advanced scintillation material called phenylcarbazole, which provides pulse shape discrimination between protons and electrons. When used in combination with an anti-coincidence detector system, an assessment of the dose from charged ions and neutral particles can be determined. This is valuable as damage on a system (such as silicon or tissue) is dependent on the particle species. Using this crystal with readout electronics developed in partnership with COSMIAC at the University of New Mexico, the design of the Small Mixed field Autonomous Radiation Tracker (SMART) Dosimeter consists of a low-power analog to digital conversion scheme with low-power digital signal processing algorithms, which are to be implemented within a compact system on a chip, such as the Xilinx Zynq series. A review of the conceptual design is presented.

There is strong evidence that water-ice is relatively abundant within permanently shadowed lunar surface materials, particularly at the poles. Evidence for water-ice has been observed within the impact plume of the LCROSS mission and is supported by data gathered from the Lunar Exploration Neutron Detector (LEND) and the Lunar Prospector Neutron Spectrometer (LPNS). Albedo neutrons from the Moon are used for detection of hydrogen, where the epi-thermal neutron flux decreases as hydrogen content increases. The origin on the concentration of water within permanently shadowed regions is not completely understood, and the Lunar Polar Hydrogen Mapper (LunaH-Map) mission is designed to provide a high-resolution spatial distribution of the hydrogen content over the southern pole using a highly elliptical, low perilune orbit. The LunaH-Map spacecraft is a 6U cubesat consisting of the Miniature Neutron Spectrometer (Mini-NS). Mini-NS is not collimated, requiring a low altitude to achieve a higher spatial resolution compared to previous missions. To develop a compact neutron detector for epi-thermal neutrons, the Mini-NS comprises of 2-cm thick slabs of CLYC (Cs2LiYCl6), which provide a sensitivity similar to a 10-atm, 5.7-cm diameter He-3 tubes, as used in LPNS. The Mini-NS digital processing electronics can discriminate by shape and height to determine signal (albedo neutrons) from background (cosmic rays). The Mini-NS achieves a total active sensing area of 200 cm2 and is covered with a cadmium sheet to shield against thermal neutrons. The research and development on the detector modules show a robust design ready for space flight.

The recent reduction of dark current in Silicon Solid-state photomultipliers (SiSSPMs) makes them an attractive alternative to conventional photomultiplier tubes (PMTs) for scintillation detection applications. Nuclear Physics experiments often require large detector volumes made using scintillation materials, which require sensitive photodetectors, such as a PMTs. PMTs add to the size, fragility, and high-voltage requirements as well as distance requirements for experiments using magnetic fields. This work compares RMD’s latest detector modules, denoted as the “year 2 prototype”, of plastic scintillators that discriminate gamma and high-energy particle events from neutron events using pulse shape discrimination (PSD) coupled to a SiSSPM to the following two detector modules: a similar “year 1 prototype” and a scintillator coupled to a PMT module. It characterizes the noise floor, relative signal-to-noise ratio (SNR), the timing performance, the PSD figure-of-merit (FOM) and the neutron detection efficiency of RMD’s detectors. This work also evaluates the scaling of SiSSPM detector modules to accommodate the volumes needed for many Nuclear Physics experiments. The Si SSPM detector module provides a clear advantage in Nuclear Physics experiments that require the following attributes: discrimination of neutron and gamma-ray events, operation in or near strong magnetic fields, and segmentation of the detector.

Neutron detection with plastic scintillators coupled to solid state photomultiplier detectors

Abstract : Lithium-ion batteries are the common technology for powering portable electronics. The nuclear reactions within the batteries are sensitive to neutrons. By characterizing this dependence, neutron dose and fluence information can be determined. The dose information can be used on an individual basis to provide forensic information including evidence for exposure to special nuclear material or on a broad geographic scale, mapping out exposure conditions after a catastrophic nuclear event. The goals of the program primarily focus on the correlations of the incident neutron spectrum to isotopic changes within the battery. These changes can be determined by an activation analysis of long-lived radioactive elements created from neutron interactions.

Solid-state photomultiplier (SSPM) devices are a viable alternative to photomultiplier tubes for nuclear and space radiation detection and science instruments. Noise terms such as dark noise, cross talk, after-pulsing, and their radiation sensitivity directly affect the photodetector performance for harsh environment applications. This paper presents the results from proton radiation-hardness tests conducted for two sets of SSPMs designed and fabricated in two different commercial complementary metal oxide silicon (CMOS) processes: 0.18-μm and 0.8 μm. Following proton exposures to the SSPMs at 100 krad, 500 krad and 1 Mrad, the measured proton induced dark noise at unity gain is higher in 0.18-μm SSPMs, but the dark current in Geiger mode is higher in 0.8 μm devices. The results and analysis suggest a higher proton-induced surface/sidewall dark current than bulk dark current in 0.18-μm samples. The proton induced bulk defect densities are similar between 0.18-μm and 0.8 μm SSPMs. Reasonable excess noise measurement results were obtained in 0.18-μm SSPM samples, and inter-pixel cross talk and after-pulsing remain statistically unchanged after proton exposure. The radiation insensitivity of after-pulsing noise suggests that shallow trap density responsible for after-pulsing is not significantly affected by proton irradiations in these CMOS high gain photodetectors.

Effects of Proton Radiation on Noise Performance in Solid-State Photomultipliers

Emerging UV to blue light emitting scintillation materials promise improved radiation detection capabilities such as dual neutron-gamma detection and higher energy resolution. The use of traditional photomultiplier tubes (PMTs), with their associated high-voltage electronics often represents form factor and power-limiting component. The unique capabilities of a solid-state photomultiplier (SSPM) provides an alternative to PMTs. Though silicon based SSPMs (SiPMs) have been gaining wide attention in recent years, a major limiting factor is the dark current, especially for detectors that require sufficiently large detection area on a single chip. To scale up the detector area without drastic increase in dark current, we are developing new photodetector elements in Al0.8Ga0.2As. The wide-band-gap characteristic, combines with the maturity of GaAs material processing, makes Al0.8Ga0.2As an excellent material for developing large area SSPMs with lower dark current and high detection efficiency within the blue to UV region, which is important for state-of-the-art scintillation materials, such as LaBr3, CeBr3, and CLYC. This work presents the design, fabrication, and characterization results of Al0.8Ga0.2As Geiger mode photodiodes, as well as preliminary results of radiation hardness evaluation of these devices for harsh environment applications.

2015 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC)

Activation analysis study on Li-ion batteries for nuclear forensic applications

Avalanche photodiodes (APD) manufactured at RMD are fabricated using deep diffusion processes, resulting in a thick reach-through APD with excellent performance characteristics. These include a high quantum efficiency (<50% for visible photons) and low excess noise (F ~ 2). Due to the structure of the APD, the devices have very low junction capacitance (~0.7pF/mm2). These devices have been made as squares or hexagons on the order of 2-4” dimensionally and require <1000 V for operation. Due to the high operating bias, studies on the Geiger behavior were dismissed. The low capacitance is conducive to developing large-area devices, and the large drift region allows for charge steering toward the high breakdown field region. These results provide initial data on the performance characteristics of RMD’s APDs when operated in Geiger mode. Due to the thickness of these devices, they provide a high gain-bandwidth product for near IR single photon counting. A small area (~4 mm2) APD was biased beyond the reverse bias breakdown voltage (~1700 V at -50 C), where the device showed typical Geigermode behavior with a low dark count rate (<54 kHz at 1700 V at an excess bias of 3 V). The data indicates a uniform response over the diode region, yet due to the large dark currents, the device was only operated to 5 V in excess bias beyond the breakdown voltage. The Geiger probability at 5V excess bias was measured as 3%, which is consistent with simulations that suggest an excess bias of ~300 V is required for 100% Geiger probability.

Characterization on Geiger-mode operation of deep diffused silicon APDs

The reduced availability of 3He is a motivation for developing alternative neutron detectors. 6Li-enriched CLYC (Cs2LiYCl6), a scintillator, is a promising candidate to replace 3He. The neutron and gamma ray signals from CLYC have different shapes due to the slower decay of neutron pulses. The long decay time associated with the scintillation emission of CLYC often results in pulse pileup for event rates exceeding 100 kHz. Discriminating neutrons in a mixed field of gamma rays and neutrons is a challenging task especially when the event rate is high. There have been other methods that successfully distinguish neutrons at less than 100 kHz event rates, but separating them at higher event rates has not been satisfactory. In this work, we propose an algorithm that discriminates the neutron events directly based on their decay time and energy spectral density (ESD). The approach is assessed with data collected for different event rates (13 kHz to 1660 kHz) for an average data record length of about 750 ms in each case, providing more than 100,000 events to analyze. The results show accurate clusters of neutron events in the pulse shape discrimination (PSD) plot even during high event rates, and the approach gives a uniform figure of merit (FOM) ranging between 1.28-1.35 for all event rates.

Using decay time to discriminate neutron and gamma ray pulses from a CLYC detector

Gamma–neutron imaging system utilizing pulse shape discrimination with CLYC

We report Al0.8Ga0.2As recessed-window single-photon avalanche photodiodes with high internal single-photon detection efficiency and low dark count probability. External quantum efficiency was increased by a factor of 2 at λ = 405 nm. Annealing in arsine with hydrogen carrier gas reduced the dark count probability by a factor of 100, to ~10-6/gate with a ~5 ns gate, at room temperature. The activation energies of primary carrier traps, which give rise to afterpulsing, are extracted in a temperature range from 150 to 200 K.

CLYC is a scintillation material that is a viable alternative to 3He for neutron detection because the shape of the scintillation emission depends on the linear energy transfer producing the event, e.g., electrons from gamma-rays versus charged ions from neutrons. Analyzing the pulse shape on an event-by-event basis discriminates the neutron events from the gamma-ray event, which is called pulse shape discrimination. The long decay time associated with the scintillation emission of CLYC can result in pulse pile-up for event rates exceeding 100 kHz. One method to address this issue is to develop digital signal processing algorithms to remove pile up, while providing gamma-neutron discrimination and gamma spectra. Research on the algorithm development using saved CLYC pulses processed offline on a personal computer with C++ code indicate that CLYC can provide pulse shape discrimination exceeding 600,000 events per second, primarily from gamma events. The algorithm digitally suppressed the decay tail, allowing for unique temporal identification of a pulse (pile-up removal). Additional filtering of the pulse is done to reduce noise, and peak-to-tail information is obtained on filtered data within a time frame less than 1 μs to provide the pulse shape discrimination.

2015 IEEE International Symposium on Technologies for Homeland Security (HST)

We report Al0.8Ga0.2As avalanche photodiodes with low dark current and low excess noise. In linear mode when biased to a photocurrent gain of 200, a 150-μm diameter device exhibits dark current of 32 pA (180 nA/cm2). The external quantum efficiency is 31% at 490 nm and the excess noise factor corresponds to k ~ 0.15. In Geiger mode operation, low dark count probability of 10-5 at room temperature is reported.

Linear- and Geiger-Mode Characteristics of Al0.8Ga0.2As Avalanche Photodiodes

Modern space electronics used in satellites are vulnerable to performance degradations and even system failure due to exposure to highly energized charged particles, such as electrons and protons originating from solar particle events, galactic cosmic rays, and trapped particles in the Van Allen Belts. The compact, radiation hard, detector system reported here distinguishes between electron events and proton events and provides the dose for both types of radiation on an event-by-event basis. This information enables an accurate estimate of component lifetimes and the damage effects in electronics resulting from total ionizing dose (TID), displacement damage dose (DDD), and single event upsets (SEU). The detector components consist of a space-compatible scintillation material, crystalline Diphenylanthracene (DPA), coupled to a Solid-State Photomultiplier (SSPM) to detect and discriminate electrons and protons based on pulse shape discrimination (PSD) techniques. The results presented here demonstrate further characterization of the detector's critical components including PSD capabilities for DPA coupled to RMD's 2nd generation SSPMs. The sensor characterization results show that proton events with energies below ~400 MeV can be distinguished from electron events with energies below ~200 MeV. The low energy threshold for the sensor is 240 keV at room temperature. The sensor is tested with a 241AmBe source, where the electron dose, from gamma rays, is 0.19 mGy, the proton dose (from neutron recoils) is 0.70 mGy, compared to the measured dose of 0.16 mSv from a Victoreen 451 survey meter. Additionally, this paper describes the dose calculation method, assumptions, and the FPGA-based readout system that has been designed to process the DPA-SSPM detector output for identification of electron-proton events.

Considerations and designs for a space-compatible, DPA-SSPM based space radiation monitor

The reduced availability of 3He is a motivation for developing alternative neutron detectors. 6Li-enriched CLYC (Cs2LiYCl6), a scintillator, is a promising candidate to replace 3He. The neutron and gamma ray signals from CLYC have different shapes due to the slower decay of neutron pulses. Some of the well-known pulse shape discrimination techniques fail to produce the desired results in a mixed radiation environment, particularly at high event rates. In the work presented here, we have applied a normalized cross correlation (NCC) approach to real neutron and gamma ray pulses produced by exposing CLYC scintillators to a mixed radiation environment generated by 137Cs and 252Cf/AmBe at different event rates. The cross correlation analysis produces distinctive results for measured neutron pulses and gamma ray pulses when they are cross correlated with reference neutron and/or gamma templates even at high event rates where the pileup is significant. With the NCC analysis shown to be a valid approach, efforts are continuing to develop a suitable algorithm to automatically process the NCC results to not only count the pulses but also to provide rudimentary neutron and gamma energy spectra. Ultimately, the technique will be implemented in an FPGA.

2014 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC)

Neutron and gamma ray discrimination for CLYC using normalized cross correlation analysis

Lithium-ion batteries, which are widely used in consumer electronics, have the potential to serve as neutron detectors after a nuclear detonation. Their small size permits collection of many samples for subsequent investigations. Besides a large cross section in the 6Li(n,α)3H reaction, there are multiple possible neutron threshold detector materials in the battery. Inductively coupled plasma mass spectrometry provided detailed material information on a coin-cell LiMnO2 battery. With this trace element analysis measuring Fe, Mn, Cr, Ni, Al, Na, Cu and Co, the possible reactions, their threshold energies and products were tabulated. This study performed MCNP modeling of battery exposure to neutrons from a detonation and comparison to experimental results from reactor irradiated batteries. As nearly all of the resulting radionuclides are photon emitters, the gamma spectrum can be obtained without disassembling the batteries. Two sets of gamma spectra were measured 1 to 3 days after the exposure to mimic the latency anticipated between device detonation and the collection and measurement of samples in the event of an actual incident.

2013 IEEE Nuclear Science Symposium and Medical Imaging Conference (2013 NSS/MIC)

Intercepting and identifying potentially dangerous radioactive materials and nuclear weapons is a high priority issue both for homeland security and for protecting our warfighters. In addition to locating radioactive sources, imaging can improve signal-to-noise ratio and provide higher sensitivity than discrete detectors. This can also reduce the frequency of false alarms since some legitimate sources and NORM can be readily identified as not being threats from the image. Thus, better nuclear imaging systems with both gamma-ray and neutron imaging capabilities would be of significant value for improved detection of such materials. To address this critical problem, RMD is investigating the design and construction of a portable gamma-ray/neutron imaging system based on RMD’s successful RadCam instrument. The instrument, which is based on the new generation of scintillator materials that have the capability to discriminate gamma rays from neutrons, will simultaneously image gamma rays and neutrons. Detecting and imaging neutrons provides the ability to detect sources that are heavily shielded for gamma rays. Since few materials emit neutrons, the presence of neutrons in the image is a strong indicator of the presence of fissile material. The system would also be useful for active interrogation. This paper will discuss camera design and examine the trade-offs needed to optimize both the gamma ray and neutrons imaging systems and present measured gamma and neutron images.

Combined Gamma-Ray / Neutron Imaging System for Detecting Nuclear Material

To address the limitations of existing silicon solid-state photomultipliers (SSPMs), we are developing new photodetector elements in Al Ga As. With 80% aluminum concentration in the GaAs compound, the material effectively becomes a wide band-gap semiconductor with a band-gap energy of 2.1 eV. The wide band-gap characteristic and the relative maturity of GaAs material processing makes Al Ga As an excellent material for developing improved SSPMs with lower dark current. Materials with larger band gaps have a lower limit in the associated thermally generated dark current. With a proper device structure, the AlGaAs SSPM is expected to provide a smaller dark current with high detection efficiency within the blue to UV spectral region, which is ideal for state-of-the-art scintillation materials, such as LaBr , CeBr , and CLYC that emit in the UV region. Utilizing commercially grown AlGaAs epitaxial wafers as the starting material, prototype photodiode elements have been designed and fabricated. The photodiodes, which have a mesa structure, exhibit a 20–30-V reverse bias breakdown. This work presents the fabrication and characterization of prototype avalanche photodiodes. Geiger pulses induced by both thermal electrons and photons are also presented, and the photon detection efficiency at low excess bias is estimated.

Development of Photodiodes for Use in Wide Band-Gap Solid-State Photomultipliers

Early CMOS SSPM pixel designs utilize a highly doped layer near the surface as a component for the Geiger junction, which limits the collection of charge from the surface and the UV response of the high gain solid state photodetector. To address these limitations, we are developing a new generation of CMOS SSPMs using pixel elements with a buried layer as a component of the Geiger junction in a process with smaller feature sizes. The new SSPM, an array of newly designed Geiger photodiode elements, is designed and fabricated to provide improvements in blue light response and dark noise performance. This work compares the performance of the early and new CMOS SSPM designs. Results showed ~2-4× improvement of detection efficiency in the blue/shallow UV region (350nm to 450nm), and a 10× reduction in detector dark count rate. Due to higher operating bias, the after pulse multiplier is no larger than a factor of 1.5 larger than the previous design. Inter-pixel cross-talk is similar to previous SSPM designs at comparable Geiger probabilities.

Next generation CMOS SSPMs for scintillation detection applications

MCNP estimation of trace elements in lithium-ion batteries subjected to neutron irradiation

Detection of special nuclear material (SNM) at extended ranges (>100 m) through the utilization of high energy (>20 MeV) bremsstrahlung photons requires optimizing the structure and interrelation of irradiation (beam-on) and detection (counting) periods. Conventional inspection schemes at lower energies and smaller distances primarily operate by pulsing an accelerator at frequencies of 0.1-1 kHz while collecting emitted radiation from the target under inspection for the few milliseconds in between pulses. Simulation and experimental results for long stand-off scenarios with source photons >20 MeV, however, indicate that two primary phenomena--(1) induced photoneutrons in proximity to the accelerator and (2) beam induced activation of air and soil--preclude the use of conventional inspection schemes. By considering the time structure and magnitude of the beam-induced photon and neutron backgrounds, signals of interest from the target, and natural backgrounds, inspection schemes have been developed to maximize signal to noise ratios (SNR). Analysis of the data indicates that the highest SNR values are found with short (2-5 s) irradiations followed by a 1-2 s period of collecting emitted neutron and photon signatures.

Optimizing Inspection Parameters for Long Stand‐Off Detection of SNM

Space neutron spectrometer design with SSPM-based instrumentation

Performance Characteristics of the Next Generation Solid-State Photomultipliers

For detecting neutrons, 3-He tubes provide sensitivity and a unique capability for detecting and discriminating neutron signals from background gamma-ray signals. A solid-state scintillation-based detector provides an alternative to 3-He for neutron detection. A real-time, portable, and low cost thermal neutron detector has been constructed from a 6Li-enriched Cs2LiYCl6:Ce (CLYC) scintillator crystal coupled with a CMOS solid-state photomultiplier (SSPM). These components are fully integrated with a miniaturized multi-channel analyzer (MCA) unit for calculation and readout of the counts and count rates. CLYC crystals and several other elpasolites including Cs2LiLaCl6:Ce (CLLC) and Cs2LiLaBr6:Ce (CLLB) have been considered for their unique properties in detecting neutrons and discriminating gamma ray events along with providing excellent energy resolution comparable to NaI(Tl) scintillators. CLYC's slower rise and decay time for neutrons (70ns and 900ns respectively) relative to a faster rise and decay time for gamma ray events (6ns and 55ns respectively) allows for pulse shape discrimination in mixed radiation fields. Light emissions from CLYC crystals are detected using an array of avalanche photodiodes referred to as solid-state photomultipliers. SSPMs are binary photon counting devices where the number of pixels activated is directly proportional to the light output of the CLYC scintillator which is proportional to the energy deposited from the radiation field. SSPMs can be fabricated using standard CMOS processes and inherently contain the low noise performance associated with ordinary photomultiplier tubes (PMT) while providing a light and compact solution for portable neutron detectors.

6-Li enriched Cs2LiYCl6:Ce based thermal neutron detector coupled with CMOS solid-state photomultipliers for a portable detector unit

Performance measurements from LYSO scintillators coupled to a CMOS position sensitive SSPM detector

Using an advanced CMOS process, an improved Geiger photodiode (GPD) element is realized as the detection efficiency is increased with a decrease in noise terms. Using an inverted geometry, the surface doping concentration and diode volume are small. The GPD shows a reduction of at least a factor of ten in the dark count rate compared to a previous CMOS GPD design, due to the limited volume within the GPD active region and low doping profile. The inverted design allows for the electrical field to approach the surface of the diode enabling better UV detection, the detection efficiency is increased by more than a factor of roughly two at 380 nm compared to the previous design. The diode shows an over all increase of a factor 1.3 compared to the previous design. Due to the large operating bias, the after pulse multiplier is no larger than a factor of 1.5 larger than the previous design. Even with higher after pulsing, the diode will exhibit a significant improvement over previous solid-state photomultiplier designs using previous GPDs, since a larger Geiger probability, with a overall improvement in the detection efficiency, is accessible with a significantly lower dark current.

High performance geiger photodiodes in a 0.18-µm feature size CMOS technology

Detection of single photons is crucial for a number of applications. Geiger photodiodes (GPD) provide large gains with an insignificant amount of multiplication noise exclusively from the diode. When the GPD is operated above the reverse bias breakdown voltage, the diode can avalanche due to charged pairs generated from random noise (typically thermal) or incident photons. The GPD is a binary device, as only one photon is needed to trigger an avalanche, regardless of the number of incident photons. A solid-state photomultiplier (SSPM) is an array of GPDs, and the output of the SSPM is proportional to the incident light intensity, providing a replacement for photomultiplier tubes. We have developed CMOS SSPMs using a commercial fabrication process for a myriad of applications. We present results on the operation of these devices for low intensity light pulses. The data analysis provides a measured of the junction capacitance (~150 fF), which affects the rise time (~2 ns), the fall time (~32 ns), and gain (>106). Multipliers for the cross talk and after pulsing are given, and a consistent picture within the theory of operation of the expected dark current and photodetection efficiency is demonstrate. Enhancement of the detection efficiency with respect to the quantum efficiency at unity gain for shallow UV photons is measured, indicating an effect due to fringe fields within the diode structure. The signal and noise terms have been deconvolved from each other, providing the fundamental model for characterizing the behavior at low-light intensities.

Large-area CMOS solid-state photomultipliers and recent developments

High-energy, gamma-ray calorimetry typically employs large scintillation crystals coupled to photomultiplier tubes. These calorimeters are segmented to the limits associated with the costs of the crystals, photomultiplier tubes, and support electronics. A cost-effective means for construction of a calorimeter system is to use solid-state photomultipliers (SSPM) with front-end electronics, which is at least half the cost, but the SSPM must provide the necessary energy resolution defined by the physics goals. One experiment with plans to exploit this advantage is an upgrade to the PRIMEX experiment at Jefferson Laboratories. We have developed a large-area SSPM (1 cm × 1 cm) for readout of large scintillation crystals. As PbWO4 has excellent properties (small Molière radius and radiation hard) for high-energy gamma-rays (>1 GeV) but low light yields (~150 photons/MeV at 0 °C), evaluation of the SSPM and support readout electronics with LaBr3 provides a measure of the device performance. Using the known detection efficiency and dark current of the SSPM, an excess noise factor associated with after pulsing and cross talk is determined. The contribution to the energy resolution from the detector module is calculated as <1% for gamma rays greater than ~2.5 GeV (0.7% at 4.5 GeV).

CMOS solid-state photomultipliers for high energy resolution calorimeters

Emerging Detectors for Measuring Neutron Dose in a Space Environment

The potential threat of harsh radiation environment requires reliable, fault-tolerant sensors capable of providing real-time dosimetry during a space mission, which cannot be achieved by using existing thermoluminescent dosimeter (TLD) technology, especially during an extravehicular activity (EVA). Dose monitoring in real time is especially important for manned low-Earth orbiting spacecraft and interplanetary space vehicles to alert the crew when Solar Particle Events (SPE) increases the radiation level of the spacecraft environment. The development of a tissue-equivalent, CMOS chip-based, personal space dosimeter will meet the demanding requirements for manned space missions.

Solid-state photomultipliers (SSPM) are photodetectors composed of avalanche photodiode pixel arrays operating in Geiger mode (biased above diode breakdown voltage). They are built using CMOS technology and can be used in a variety of applications in high energy and nuclear physics, medical imaging and homeland security related areas. The high gain and low cost associated with the SSPM makes it an attractive alternative to existing photodetectors such as the photomultiplier tube (PMT). The capability of integrating CMOS on-chip readout circuitry on the same substrate as the SSPM also provides a compact and low-power-consumption solution to photodetector applications with stringent area and power requirements. The optical performance of the SSPM, specifically the detection and quantum efficiencies, can depend on the geometry and the doping profile associated with each photodiode pixel. The noise associated with the SSPM not only includes dark noise from each pixel, but also consists of excess noise terms due to after pulsing and inter-pixel cross talk. The magnitude of the excess noise terms can depend on biasing conditions, temperature, as well as pixel and inter-pixel dimensions. We present the optical and noise performance of SSPMs fabricated in a conventional CMOS process, and demonstrate the dependence of the SSPM performance on pixel/inter-pixel geometry, doping profile, temperature, as well as bias conditions. The continuing development of CMOS SSPM technology demonstrated here shows that low cost and high performance solid state photodetectors are viable solutions for many existing and future optical detection applications.

Optical and noise performance of CMOS solid-state photomultipliers

Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment

Advances in CMOS Solid-state Photomultipliers for Scintillation Detector Applications.

The complexity of space-flight design requires reliable, fault-tolerant equipment capable of providing real-time dosimetry during a mission, which is not feasible with the existing thermoluminescent dosimeter (TLD) technology, especially during extravehicular activity (EVA). Real-time monitoring is important for low-Earth orbiting spacecraft and interplanetary space flight to alert the crew when Solar Particle Events (SPE) increase the particle flux of the spacecraft environment. A tissue-equivalent, chip-based, personal dosimeter represents an attractive approach to meet the demanding requirements for manned space missions. A dosimeter-on-a-chip for personal dosimetry is comprised of a tissue-equivalent scintillator coupled to a solid-state photomultiplier (SSPM) built using CMOS technology. The radiation sensitive component of the dosimeter is coupled to analog signal processing components and a microprocessor, which can successfully process up to 5×105 events per second. The dynamic range of the dosimeter has been verified with 1-GeV protons (0.22 keV/µm in H20) to 300 MeV/n Fe (238 keV/µm in H20). The dosimeter reconstructed does over 6 to 36 µSv from 1-GeV protons to within 3%. We present dose equivalent performance of the device, along with power consumption parameters, expected space flight performance, and design upgrades.1 2

Performance characteristics of the CMOS SSPM tissue-equivalent space dosimeter

Solid-State Photomultiplier with Integrated Front End Electronics

The detection of illicit nuclear sources and SNM requires a ubiquitous network of sensors. While He proportional counters are excellent neutron detectors, there is an insufficient global supply of He to create the required number of detectors. Alternatives to He must be efficient, insensitive to gamma radiation, easily manufactured, rugged, and inexpensive to enable the procurement of a large numbers of sensors. The use of a high sensitivity solid-state optical detector coupled to scintillation materials, loaded with a neutron absorber such as Li can fulfill these design constraints. We are developing a neutron detector with low-cost CMOS solid-state photomultiplier and with emerging, interesting scintillation material like Cs2LiYCl6:Ce (CLYC). This will provide better performance than He tube in terms of efficiency and gamma rejection rate. In this work, we show some simulations and measurements made to quantify the performance of the detector system.

A dosimeter-on-a-chip (DoseChip) comprised of a tissue-equivalent scintillator coupled to a solid-state photomultiplier (SSPM) built using CMOS technology represents an ideal technology for a space-worthy, real-time solar-particle monitor for astronauts. It provides a tissue-equivalent response to the relevant energies and types of radiation for low-Earth orbit and interplanetary space flight to the moon or Mars. The DoseChip will complement the existing Crew Passive Dosimeters by providing real-time dosimetry and as an alarming monitor for solar particle events (SPEs). A prototype of the DoseChip was exposed to protons at three incident energies at the NASA space radiation laboratory at Brookhaven National Laboratory. The prototype provides an unambiguous, proportional response for 200, 500, and 1000 MeV protons. The measured response produced a detector response function that was used to model the behavior of an improved instrument. The data presented here indicate that a 3 × 3 × 3 mm3 piece of BC-430 plastic scintillator coupled to a 2000-pixel SSPM can accommodate the needed dynamic range for protons with an incident energy of 20 MeV and greater.

Adequate monitoring and tracking of radiation at department of energy legacy sites requires deployment of highly sensitive detectors. Utilizing the high sensitivity of inorganic scintillation materials usually requires a photomultiplier tube, which increases the cost, size, and power consumption of the detector. A gamma-ray detector consisting of a CMOS-based solid-state photomultiplier (SSPM), which offers low power consumption and a very small form factor, coupled to a variety of scintillation materials has been developed. We have compared the sensitivity of the CMOS SSPM radiation meter with regard to source identification and overall sensitivity as a function of incident gamma-ray energy. Two prototype configurations are compared with respect to homeland security applications: an SSPM spectrometer, with a high resolution scintillation material and many channels of readout, and a low resolution rate-meter with only four channels of energy information. Each device utilizes a 3 mm × 3 mm SSPM with 2024 pixels coupled to a scintillator matched to the size of the SSPM.

Comparison of two solid-state photomultiplier-based scintillation gamma-ray detector configurations

To replace PMTs for readout of optical photons from scintillation materials in harsh environments, prototype solid-state photodetectors has been developed to operate in harsh environments, which implies temperatures down to 4 °K and magnetic fields up to 7 T. A photodiode structure developed out of RMD's CMOS SSPM technology shows avalanche multiplication at temperatures down to 4 °K when operated in a proportional mode (below breakdown). The diode and photodetector characteristics are discussed, providing information on the implementation of these devices for the HIFROST target, which will be used to study the proton spin polarizabilities. The photodetector shows a quantum efficiency of ~45% at 532 nm for 4 °K operation with a dark current of ~0.1 μA/mm2 and a gain of ~100 for an operating bias of 31.8 V. Light pulses of 500 photons were easily read out using amplifiers operated at room temperature.

Characteristics of CMOS avalanche photodiodes at cryogenic temperatures

Effect of SSPM Surface Coating on Light Collection Efficiency and Optical Crosstalk for Scintillation Detection

Characteristics of CMOS Light Detectors at Cryogenic Temperatures

A high fill factor SSPM built using a standard CMOS fabrication process can provide an energy resolution of 12.4% at 511 keV using CsI(Tl) crystals. The SSPM was operated at an excess bias of 2 V and 0 °C. The magnitude of the noise terms of the SSPM under these conditions are provided. This is compared to the energy resolution of 11.7% using a PMT at room temperature and the identical crystal. CMOS SSPMs can provide PMT-like energy resolution. Additional developments in back-illuminated and position-sensitive SSPMs devices are provided. A back-illuminated device has the promise of a low-noise, high fill-factor design, and the initial results of the quantum efficiency of back-illuminated, thinned devices, fabricated with an existing SSPM design, are provided. For position-sensitive SSPMs, an image of a 3 × 3 CsI array has been made with an SSPM based on a resistive-network configuration to provide position information has been made with minimal distortions.

Counting individual scintillation pulses produced by radiation provides excellent sensitivity for dosimeter applications, however, the light pulse produced by the scintillation material has previously needed the high gain of a PMT to read out the signal. The recent development of solid-state photomultipliers provides the high gain, high-bandwidth performance needed to implement event counting with the scintillation detector. The CMOS SSPM detector is a compact, rugged, low-power photodetector that is well suited for scintillation-based applications. The digital representation of scintillator photon multiplicity provides a convenient basis for digital radiation measurements. Traditional tissue equivalent scintillation materials provide a direct measure of the energy deposited and the dose equivalent and are a good match for charged-particle dosimetry, as they typically produce relatively small light pulses for gamma ray events. In addition, new scintillation materials are being developed that detect neutrons and can implement pulse shape discrimination to reject interfering gamma ray signals on an event-by-event basis. This work presents preliminary evaluations of three types of radiation detectors constructed from an SSPM. An LYSO scintillator gamma-ray dosimeter, a charged-particle detector using tissue-equivalent plastic scintillator for space dosimetry, and a neutron detector made from boron-loaded plastic are demonstrated..

Radiation measurements using solid-state Photomultipliers: Gammas, charged particles, and neutrons

Geiger-mode photodiodes (GPD) act as binary photon detectors that convert analog light intensity into digital pulses. Fabrication of arrays of GPD in a CMOS environment simplifies the integration of signal-processing electronics to enhance the performance and provide a low-cost detector-on-a-chip platform. Such an instrument facilitates imaging applications with extremely low light and confined volumes. High sensitivity reading of small samples enables twodimensional imaging of DNA arrays and for tracking single molecules, and observing their dynamic behavior. In this work, we describe the performance of a prototype imaging detector of GPD pixels, with integrated active quenching for use in imaging of 2D objects using fluorescent labels. We demonstrate the integration of on-chip memory and a parallel readout interface for an array of CMOS GPD pixels as progress toward an all-digital detector on a chip. We also describe advances in pixel-level signal processing and solid-state photomultiplier developments.

CMOS Geiger photodiode array with integrated signal processing for imaging of 2D objects using quantum dots

Solid State Photomultipliers for Nuclear and High Energy Experiment Applications.

Solid-State Photomultipliers Operated In Extreme Experimental Conditions.

Review for "Role of Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) in Neurodegenerative Dementias"

An immunomodulatory extract (AndoSan™) based on the medicinal mushroom Agaricus blazei Murill (AbM) has shown to reduce blood cytokine levels in healthy volunteers after 12 days’ ingestion, pointing to an anti‐inflammatory effect. The aim was to study whether AndoSan™ had similar effects on cytokines in patients with ulcerative colitis (UC) and Crohn’s disease (CD). Calprotectin, a marker for inflammatory bowel disease (IBD), was also measured. Patients with CD (n = 11) and with UC (n = 10) consumed 60 ml/day of AndoSan™. Patient blood plasma was harvested before and after 6 h LPS (1 ng/ml) stimulation ex vivo. Plasma and faecal calprotectin levels were analysed using ELISA and 17 cytokines [IL‐2, IFN‐γ, IL‐12 (Th1), IL‐4, IL‐5, IL‐13 (Th2), IL‐7, IL‐17, IL‐1β, IL‐6, TNF‐α, IL‐8, MIP‐1β, MCP‐1, G‐CSF, GM‐CSF and IL‐10] by multiplex assay. After 12 days’ ingestion of AndoSan™, baseline plasma cytokine levels in UC was reduced for MCP‐1 (40%) and in LPS‐stimulated blood for MIP‐1β (78%), IL‐6 (44%), IL‐1β (41%), IL‐8 (30%), G‐CSF (29%), MCP‐1 (18%) and GM‐CSF (17%). There were corresponding reductions in CD: IL‐2 (100%), IL‐17 (55%) and IL‐8 (29%) and for IL‐1β (35%), MIP‐1β (30%), MCP‐1 (22%), IL‐8 (18%), IL‐17 (17%) and G‐CSF (14%), respectively. Baseline concentrations for the 17 cytokines in the UC and CD patient groups were largely similar. Faecal calprotectin was reduced in the UC group. Ingestion of an AbM‐based medicinal mushroom by patients with IBD resulted in interesting anti‐inflammatory effects as demonstrated by declined levels of pathogenic cytokines in blood and calprotectin in faeces.

Effect of an Extract Based on the Medicinal Mushroom Agaricus blazei Murill on Expression of Cytokines and Calprotectin in Patients with Ulcerative Colitis and Crohn’s disease

An extract based on the medicinal mushroom Agaricus blazei Murill stimulates monocyte-derived dendritic cells to cytokine and chemokine production in vitro.

An immunostimulatory extract based on the medicinal mushroom Agaricus blazei Murill (AbM) has been shown to stimulate mononuclear phagocytes in vitro to produce pro‐inflammatory cytokines, and to protect against lethal peritonitis in mice. The present aim was to study the effect of AbM on release of several cytokines in human whole blood both after stimulation ex vivo and in vivo after oral intake over several days in healthy volunteers. The 17 signal substances examined were; T helper 1 (Th1) cytokines [interleukin (IL)‐2, interferon (IFN)‐γ and IL‐12], T helper 2 cytokines (IL‐4, IL‐5 and IL‐13), pleiotropic (IL‐7, IL‐17), pro‐inflammatory [IL‐1β, IL‐6, tumour necrosis factor (TNF)‐α (mainly produced by Th1 cells)] – and anti‐inflammatory (IL‐10) cytokines, chemokines [IL‐8, macrophage inhibitory protein (MIP)‐1β and monocyte chemoattractant protein (MCP)‐1] and leukocyte growth factors [granulocyte colony‐stimulating factor (G‐CSF), granulocyte/macrophage colony stimulating factor]. After stimulation of whole blood ex vivo with 0.5–5.0% of a mushroom extract, AndoSan™ mainly containing AbM, there was a dose‐dependent increase in all the cytokines studied, ranging from two to 399‐fold (TNF‐α). However, in vivo in the eight volunteers who completed the daily intake (60 ml) of this AbM extract for 12 days, a significant reduction was observed in levels of IL‐1β (97%), TNF‐α (84%), IL‐17 (50%) and IL‐2 (46%). Although not significant, there was a trend towards reduced levels for IL‐8, IFN‐γ and G‐CSF, whilst those of the remaining nine cytokines tested, were unaltered. The discrepant results on cytokine release ex vivo and in vivo may partly be explained by the antioxidant activity of AbM in vivo and limited absorption of its large, complex and bioactive β‐glucans across the intestinal mucosa to the reticuloendothelial system and blood.

Effect of an Extract Based on the Medicinal Mushroom Agaricus blazei Murill on Release of Cytokines, Chemokines and Leukocyte Growth Factors in Human Blood Ex Vivo and In Vivo

Agaricus blazei Murill (AbM) is an edible, medicinal mushroom of Brazilian origin. It is used traditionally against a range of diseases, including cancer and chronic hepatitis, and has been cultivated commercially for the health food market. AbM has recently been shown to have strong immunomodulating properties, which has led to increasing scientific interest. In this article, we review current knowledge as to the immunological properties of AbM, and its possible clinical use in connection with infections and cancer. We also present some novel findings, which point to highly different biological potency between AbM extracts of different source and manufacturing.

Effects of the Medicinal Mushroom Agaricus blazei Murill on Immunity, Infection and Cancer

Effects on gene expression and viral load of a medicinal extract from Agaricus blazei in patients with chronic hepatitis C infection.

Effect of a medicinal extract from Agaricus blazei Murill on gene expression in a human monocyte cell line as examined by microarrays and immuno assays.

An increasing number of cell types, including peripheral blood mononuclear cells (PBMCs), have been demonstrated to release heat shock proteins (Hsps). In this paper we investigate further the hypothesis that Hsps are danger signals. PBMCs and Jurkat cells released Hsp70 (0·22 and 0·7 ng/106 cells, respectively) into medium over 24 h at 37°C. Release of Hsp70 was stimulated 10‐fold by GroEL (P < 0·001) and more than threefold by lipopolysaccharide (LPS) (P < 0·001). Although Hsp60 could be detected in the medium of cells cultured at 37°C for 24 h, the low rates of release were due probably to cell damage. Significant release of Hsp60 was observed when Jurkat cells were exposed to GroEL (2·88 ng/106 cells) or LPS (1·40 ng/106 cells). The data are consistent with the hypothesis that Hsp70 and Hsp60 are part of a danger signalling cascade in response to bacterial infection.

Heat shock proteins form part of a danger signal cascade in response to lipopolysaccharide and GroEL

The aim was to investigate the antibacterial effect of the biologically active and edible mushroom Agaricus blazei Murill (AbM). A water extract of AbM or PBS control was administered orally before or with challenge to NIH/OlaHsd mice, experimentally infected intraperitoneally with the moderately virulent Streptococcus pneumoniae serotype 6B. End points were bacteraemia and survival rate. The AbM extract, protected against systemic S. pneumoniae 6B infection in the mice. It was most effective when given 24 h before inoculation but did also have protective effects when given together with challenge compared with control. The lack of antibiotic effect on pneumococci in vitro and increased levels of cytokines MIP‐2 and TNF‐α in the serum of mice receiving AbM extract, indicated that the protective effect of AbM was due to the involvement of the native immune system. This is the first report of anti‐infection effects of AbM in vivo. Our results suggest that AbM extract may be useful as additional prophylactic and possibly therapeutic treatment against bacterial and possibly other infections in humans.

An Extract of the Mushroom Agaricus blazei Murill Administered Orally Protects Against Systemic Streptococcus pneumoniae Infection in Mice

Effects of C5a and FMLP on Interleukin-8 Production and Proliferation of Human Umbilical Vein Endothelial Cells

Patients with Crohn's disease (CD) (n = 10) and ulcerative colitis (UC) (n = 10) were tested for immune responses against various antigens from Mycobacterium avium subsp. paratuberculosis; alkyl hydroperoxide reductase C (AhpC) and alkyl hydroperoxide reductase D (AhpD), which are constitutively expressed in this species as opposed to other mycobacteria, a 14‐kDa secreted antigen and PPD‐J. The CD patients had significantly elevated antibody levels against the 14 kDa protein (P < 0.05) that were negatively correlated with the duration of the disease (rs = − 0.85). They also seemed to have increased antibody levels against AhpC and AhpD, but the differences between the two groups were not significant. However, taken together, the antibody responses to three individual mycobacterial antigens in CD patients strengthen the possibility that the observed responses are caused by mycobacterial infection. No significant differences in the interferon (IFN)‐γ production, the interleukin (IL)‐10 production and the ability to proliferate upon stimulation with these antigens were observed. These results show that measuring antibody responses against purified specific antigens is a suitable and simple approach when assessing the connection between CD and mycobacteria in patients with clinical CD. Another important aspect in such studies is to have well defined patient groups tested at the onset of clinical symptoms.

Elevated Antibody Responses in Patients with Crohn's Disease against a 14‐kDa Secreted Protein Purified from Mycobacterium avium subsp. paratuberculosis

The effects of MHC and nonMHC (background) genetics on the kinetics of primary and secondary antibody responses to T-cell-dependent (SRBC) and T-cell-independent [Brucella abortus (BA)] antigens were investigated. Eight genetic groups were represented, with four homozygous MHC haplotypes [B1-IrGATlow (IrGAT = immune response to GAT locus); B1-IrGAThigh; B19-Ir-GATlow; B19-IrGAThigh] on two genetic backgrounds, the S1 and G lines. Birds were injected simultaneously with BA and SRBC at 4 and 7 wk of age, and blood samples were taken weekly from 4 to 10 wk of age for measurement of total agglutinating serum antibody levels. A quadratic equation and its first derivative were computed for each bird to approximate individual curve parameters: y max, the maximum titer; t max, the time required to achieve y max; and c coefficient, the rate of decline in the titer. Curve parameters of birds from different lines were analyzed separately by using the General Linear Model procedure. A second analysis that included line effect evaluated the nonMHC gene effects and their interactions with erythrocyte antigen B locus (Ea-B) or IrGAT. In the S1 line, there was an interaction (P < 0.05) between MHC haplotypes and sex for primary response to BA. In contrast, there were no significant main effects nor interactions in the G line background for primary and secondary responses to BA and SRBC. There was an effect (P < 0.05) of line background on y max for primary BA and for secondary SRBC responses. A positive correlation (P < 0.05) was found between the c coefficients of BA and SRBC secondary responses, suggesting that the rate of decline in the secondary response is similar between these T-dependent and T-independent responses. The overall results of this study indicate complex interactions between specific MHC alleles and the nonMHC background of the lines in which they are studied.

Genetic line and major histocompatibility complex effects on primary and secondary antibody responses to T-dependent and T-independent antigens.

The proinflammatory cytokines interleukin 1 alpha (IL-1 alpha), tumor necrosis factor alpha (TNF alpha) and interleukin 6 (IL-6) modulate the synthesis of complement factors B and C3 by endothelial cells (EC), and are considered to play an important role in the development of sepsis. By using agarose beads activating the alternative pathway of complement, we wanted to study the net effect of these cytokines on EC synthesis of the alternative and terminal pathways, measured by binding of anti-C3c and anti-TCC (terminal complement complex) antibodies to beads kept with the EC. Addition of IL-1 alpha and TNF alpha at concentrations of 50 and 100 U/ml resulted in a significant increase in binding of these antibodies to co-incubated beads, most pronounced for anti-C3c. IL-6 from 50-200 U/ml resulted in a stronger (two to fourfold) binding for both antibodies compared to experiments with IL-1 alpha and TNF. However, increased concentrations of IL-1 alpha (200 U/ml) and IL-6 (400 U/ml) resulted in a strong reduction in binding of anti-C3c and anti-TCC antibodies to the co-cultured beads. This study indicates that proinflammatory cytokines upregulate the synthesis by EC of the functional alternative and terminal pathways of complement.

APMIS : acta pathologica, microbiologica, et immunologica Scandinavica

Interleukin-1 alpha, interleukin 6 and tumor necrosis factor alpha increase the synthesis and expression of the functional alternative and terminal complement pathways by human umbilical vein endothelial cells in vitro.

Monocytes cultured under serum‐free conditions secreted protein which bound covalently and non‐covalently to agarose beads, an activator of the alternative pathway of complement. There was a significant binding of monoclonal anti‐C3c antibodies, polyclonal anti‐C5, anti‐C6, anti‐C7, anti‐C8, and anti‐C9 antibodies, and of a monoclonal antibody against a neoantigen of polymerized C9 to agarose beads incubated with the monocytes for 24, 48, 72 or 96 h. From these results, we conclude that monocytes produce C5, C6, C7, C8 and C9 that assemble as the terminal complement complex on the surface of the agarose beads. Activation by agarose of the alternative pathway with generation of particle bound C3 and C5 convertases is a prerequisite for the subsequent formation of the terminal complement complex. Whether SC5b‐9 or the membrane attack of complement (C5b‐9) is formed on the beads will be examined.

Synthesis of Complement Components C5, C6, C7, C8 and C9 in Vitro by Human Monocytes and Assembly of the Terminal Complement Complex

A. Anastassov, J. E. Duboscq, K. K. Gan, C. Gwon, T. Hart, K. Honscheid, D. Hufnagel, H. Kagan, R. Kass, J. Lorenc, T. K. Pedlar, H. Schwarthoff, E. von Toerne, M. M. Zoeller, S. J. Richichi, H. Severini, P. Skubic, A. Undrus, S. Chen, J. Fast, J. W. Hinson, J. Lee, N. Menon, D. H. Miller, E. I. Shibata, I. P. J. Shipsey, V. Pavlunin, D. Cronin-Hennessy, Y. Kwon, A.L. Lyon, E. H. Thorndike, C. P. Jessop, H. Marsiske, M. L. Perl, V. Savinov, D. Ugolini, X. Zhou, T. E. Coan, V. Fadeyev, I. Korolkov, Y. Maravin, I. Narsky, R. Stroynowski, J. Ye, T. Wlodek, M. Artuso, R. Ayad, C. Boulahouache, K. Bukin, E. Dambasuren, S. Karamov, S. Kopp, G. Majumder, G. C. Moneti, R. Mountain, S. Schuh, T. Skwarnicki, S. Stone, G. Viehhauser, J.C. Wang, A. Wolf, J. Wu, S. E. Csorna, I. Danko, K. W. McLean, Sz. Márka, Z. Xu, R. Godang, K. Kinoshita, I. C. Lai, S. Schrenk, G. Bonvicini, D. Cinabro, L. P. Perera, G. J. Zhou, G. Eigen, E. Lipeles, M. Schmidtler, A. Shapiro, W. M. Sun, A. J. Weinstein, F. Würthwein, D. E. Jaffe, G. Masek, H. P. Paar, E. M. Potter, S. Prell, V. Sharma, D. M. Asner, A. Eppich, J. Gronberg, T. S. Hill, D. J. Lange, R. J. Morrison, H. N. Nelson, R. A. Briere, B. H. Behrens, W. T. Ford, A. Gritsan, J. Roy, J. G. Smith, J. P. Alexander, R. Baker, C. Bebek, B. E. Berger, K. Berkelman, F. Blanc, V. Boisvert, D. G. Cassel, M. Dickson, P. S. Drell, K. M. Ecklund, R. Ehrlich, A. D. Foland, P. Gaidarev, L. Gibbons, B. Gittelman, S. W. Gray, D. L. Hartill, B. K. Heltsley, P. I. Hopman, C. D. Jones, D. L. Kreinick, M. Lohner, A. Magerkurth, T. O. Meyer, N. B. Mistry, C. R. Ng, E. Nordberg, J. R. Patterson, D. Peterson, D. Riley, J. G. Thayer, P. G. Thies, B. Valant-Spaight, A. Warburton, P. Avery, C. Prescott, A. I. Rubiera, J. Yelton, J. Zheng, G. Brandenburg, A. Ershov, Y. S. Gao, D. Y.-J. Kim, R. Wilson, T. E. Browder, Y. Li, J. L. Rodriguez, H. Yamamoto, T. Bergfeld, B. I. Eisenstein, J. Ernst, G. E. Gladding, G. D. Gollin, R. M. Hans, E. Johnson, I. Karliner, M. A. Marsh, M. Palmer, C. Plager, C. Sedlack, M. Selen, J. J. Thaler, J. Williams, K. W. Edwards, R. Janicek, P. M. Patel, A. J. Sadoff, R. Ammar, P. Baringer, A. Bean, D. Besson, R. Davis, I. Kravchenko, N. Kwak, X. Zhao, S. Anderson, V. V. Frolov, Y. Kubota, S. J. Lee, R. Mahapatra, J. J. O’Neill, R. Poling, T. Riehle, A. Smith, J. Urheim, S. Ahmed, M. S. Alam, S. B. Athar, L. Jian, L. Ling, A. H. Mahmood, M. Saleem, S. Timm, and F. Wappler

Using data recorded with the CLEO II and CLEO II.V detector configurations at the Cornell Electron Storage Rings, we report the first observation and mass measurement of the Sigma(*+)(c) charmed baryon, and an updated measurement of the mass of the Sigma(+)(c) baryon. We find M(Sigma(*+)(c))-M(Lambda(+)(c)) = (231.0+/-1.1+/-2.0) MeV, and M(Sigma(+)(c))-M(Lambda(+)(c)) = (166.4+/-0.2+/-0.3) MeV, where the errors are statistical and systematic, respectively.

First observation of the sigma(*+)(c) baryon and a new measurement of the sigma(*+)(c) mass.

We have searched a sample of 9.6 million B ¯ B events for the ﬂavor-changing neutral current decays B → Kℓ + ℓ − and B → K ∗ (892) ℓ + ℓ − . We subject the latter decay to the requirement that the dilepton mass m ℓℓ exceed 0.5 GeV. There is no indication of a signal. We obtain the 90% conﬁdence level upper limits B ( B → Kℓ + ℓ − ) < 1 . 7 × 10 − 6 and B ( B → K ∗ (892) ℓ + ℓ − ) m ℓℓ > 0 . 5GeV < 3 . 3 × 10 − 6 . We also obtain an upper limit on the weighted average 0 . 65 B ( B → Kℓ + ℓ − ) + 0 . 35 B ( B → K ∗ (892) ℓ + ℓ − ) m ℓℓ > 0 . 5GeV < 1 . 5 × 10 − 6 . The weighted-average limit is only 50% above the Standard Model prediction.

We report results of a search for the rare radiative decay B 0 ! D 0. Using 9:66 10 6 B B meson pairs collected with the CLEO detector at the Cornell Electron Storage Ring, we set an upper limit on the branching ratio for this decay of 5:010 ?5 at 90% CL. This provides evidence that anomalous enhancement is absent in W-exchange processes and that weak radiative B decays are dominated by the short-distance b ! ss mechanism in the Standard Model.

The tau decays to six-pion final states have been studied with the CLEO detector at the Cornell Electron Storage Ring. The measured branching fractions are B(tau(-)-->2pi(-)pi(+)3pi(0)nu(tau)) = (2.2+/-0.3+/-0.4)x10(-4) and B(tau(-)-->3pi(-)2pi(+)pi(0)nu(tau)) = (1.7+/-0.2+/-0.2)x10(-4). A search for substructure in these decays shows that they are saturated by intermediate states with eta or omega mesons. We present the first observation of the decay tau(-)-->2pi(-)pi(+)omega(nu)tau and the branching fraction is measured to be (1.2+/-0.2+/-0.1)x10(-4). The measured branching fractions are in good agreement with the isospin expectations but somewhat below the conserved-vector-current predictions.

Using a data sample of $\Upsilon(2S)$ events collected with the CLEO II detector at the Cornell Electron Storage Ring, we have investigated the hadronic transitions between the $\Upsilon(2S)$ and the $\Upsilon(1S)$. The charged dipion transition $\Upsilon(2S)\to \Upsilon(1S)\pi^+\pi^-$ was studied using two different analysis techniques. Selecting events in which $\Upsilon(1S)$ decays into a $\mu\mu$ or $ee$ lepton pair(``exclusive'' analysis), we measured the branching fraction of B=0.189+-0.004+-0.009, while using a method allowing $\Upsilon(1S)$ to decay into anything (``inclusive'' analysis) we found B=0.0196+-0.002+-0.010. The appropriate average of the two measurements gives B=0.0192+-0.002+-0.010. Combining the exclusive and inclusive results we derive the $\Upsilon(1S)$ leptonic branching ratios B_{ee}=0.0229+-0.0008+-0.0011 and B_{\mu\mu}=0.0249+-0.0008+-0.0013 We also studied $\Upsilon(2S)\to \Upsilon(1S)\pi^0\pi^0$ and obtained the branching fraction of B=0.092+-0.006+-0.007. Parameters of the $\pi\pi$ system (dipion invariant mass spectra, angular distributions) were analyzed and found to be consistent with current theoretical models. Lastly, we searched for the $\eta$ and single $\pi^0$ transitions and obtained the upper limits of 0.0028 and 0.0011 respectively.

Using data collected with the CLEO II detector at the Cornell Electron Storage Ring, we determine the ratio Rchrg for the mean charged multiplicity observed in Υ(1S) → ggγ events, < n±gluon >, to the mean charged multiplicity observed in ee → qq̄γ events, < n±quark >. We find Rchrg ≡ <n gluon >

Study of gluon versus quark fragmentation in Υ→ggγ and e^{+}e^{-}→qq[over ¯]γ events at sqrt[s]=10 GeV

Using data recorded by the CLEO-II detector at CESR, we report new measurements of the branching fractions for the decays of the charmed baryon Λ_c^+ into pK^-π^+π^0, pK^0, pK^0π^+π^-, and pK^0π^0, all measured relative to pK^-π^+. The relative branching fractions are 0.67±0.04±0.11,0.46±0.02±0.04,0.52±0.04±0.05, and 0.66±0.05±0.07, respectively.

Using data recorded by the CLEO-II detector at CESR, we report evidence of a pair of excited charmed baryons, one decaying into + c + and the other into + c ?. The doubly charged state has a measured mass diierence M((+ c +)? M((+ c) of 234:5 1:1 0:8 MeV and a width of 17:9 +3:8 ?3:2 4:0 MeV, and the neutral state has a measured mass diierence M((+ c ?) ? M((+ c) of 232:6 1:0 0:8 MeV and a width of 13:0 +3:7 ?3:0 4:0 MeV. We identify these states as ++ c and 0 c , the spin 3 2 + excitations of the c baryons. 3 Recently, we reported 1,2] the observation of two narrow states decaying into c , which we identiied as the J P = 3 2 + spin excitations of the charmed-strange 0 c and + c baryons. Until now, however, evidence for J P = 3 2 + spin excitations of their non-strange analogues, the c baryons, has been restricted to a cluster of 6 + c + events 3] with an estimated mass diierence, M M ((c) ? M ((+ c) of 245 5 5 MeV. Here we report evidence for two particles decaying into + c + and + c ? , respectively. The two states have similar cross sections, masses and widths. We identify these states as the ++ c and 0 c baryons 4]. The data presented here were taken by the CLEO II detector 5] operating at the Cor-nell Electron Storage Ring. The sample used in this analysis corresponds to an integrated luminosity of 4.8 f b ?1 from data taken on the (4S) resonance and in the continuum at energies just above and below the (4S). We detected charged tracks with a cylindrical drift chamber system inside a solenoidal magnet. Photons were detected using an electromagnetic calorimeter consisting of 7800 cesium iodide crystals. We reconstructed + c baryons using 13 diierent decay modes 6]. Measurements of the branching fractions into all these modes and the general procedures for nding them have previously been presented by the CLEO collaboration 7,8]. For this search and data set, the exact cuts have been optimized for high eeciency and low background. Brieey, particle identiication of p; K ? , and candidates was performed using speciic ionization measurements in the drift chamber, and when present, time-of-ight measurements. Hyperons were …

Observation of Two Excited Charmed Baryons Decaying into {sup +}{sub {ital c}}{sup ±}

We have searched for lepton flavor violating decays of the {tau} lepton using final states with an electron or a muon and one or two {pi}{sup 0} or {eta} mesons but no neutrinos. The data used in the search were collected with the CLEO II detector at the Cornell Electron Storage Ring (CESR) and correspond to an integrated luminosity of 4.68 fb{sup {minus}1} . No evidence for signals was found, resulting in much improved limits on the branching fractions for the one-meson modes and the first upper limits for the two-meson modes. {copyright} {ital 1997} {ital The American Physical Society}

As similarly observed in nutrient-poor media at 37°C, Escherichia coli forms small rods in nutrient-rich media at temperatures near 8°C, the minimum temperature of growth. A study was initiated to identify proteins required to facilitate the small rod morphology at low temperature. E. coli contains three nonessential SPOR domain proteins (DamX, RlpA, and DedD) that have been demonstrated to bind to the septal ring. In contrast to the normal growth and small rod morphology of damX and rlpA null mutants at 10°C, the dedD null mutant exhibited reduced growth and formed filamentous cells. The presence of plasmid-encoded DedD restored growth and small rods. Plasmid-encoded FtsN, an essential SPOR domain protein that functions to stabilize the septal ring and to initiate septation, in the dedD null mutant resulted in increased growth and the formation of shorter chained cells. However, plasmid-encoded DedD failed to restore growth and cell division of cells lacking FtsN at 10°C. In contrast to cell division protein DedD, RodZ is a cell elongation protein particularly required for growth at 30°C. However, the rodZ null mutant grew similarly as the wild type strain and produced cocci in LB broth at 10°C. Moreover at 10°C, the concerted deletion of dedD and rodZ resulted in severe inhibition of growth accompanied with the formation of swollen prolate ellipsoids due to a block in septal ring assembly and cell elongation. The data indicate the cellular requirement of both FtsN and DedD for septation as well as RodZ for cell elongation to maintain the small rod morphology at temperatures near 8°C. In comparison to the growth and small rods of the wild type in M9-glucose minimal media at 37°C, the dedD null mutant grew at the same rate and produced elongated cells while the rodZ null mutant grew at a slightly slower rate and produced cocci. The data indicate that DedD and RodZ are also required to maintain the small rod morphology in nutrient-poor media, but there is a higher cellular requirement of DedD for growth and cell division in nutrient-rich media at low temperature.

A requirement for cell elongation protein RodZ and cell division proteins FtsN and DedD to maintain the small rod morphology of Escherichia coli at growth temperatures near 8°C.

Caenorhabditis elegans CEP-1 and its mammalian homolog p53 are critical for responding to diverse stress signals. In this study, we found that cep-1 inactivation suppressed the prolonged lifespan of electron transport chain (ETC) mutants, such as isp-1 and nuo-6, but rescued the shortened lifespan of other ETC mutants, such as mev-1 and gas-1. We compared the CEP-1-regulated transcriptional profiles of the long-lived isp-1 and the short-lived mev-1 mutants and, to our surprise, found that CEP-1 regulated largely similar sets of target genes in the two mutants despite exerting opposing effects on their longevity. Further analyses identified a small subset of CEP-1-regulated genes that displayed distinct expression changes between the isp-1 and mev-1 mutants. Interestingly, this small group of differentially regulated genes are enriched for the “aging” Gene Ontology term, consistent with the hypothesis that they might be particularly important for mediating the distinct longevity effects of CEP-1 in isp-1 and mev-1 mutants. We further focused on one of these differentially regulated genes, ftn-1, which encodes ferritin in C. elegans, and demonstrated that it specifically contributed to the extended lifespan of isp-1 mutant worms but did not affect the mev-1 mutant lifespan. We propose that CEP-1 responds to different mitochondrial ETC stress by mounting distinct compensatory responses accordingly to modulate animal physiology and longevity. Our findings provide insights into how mammalian p53 might respond to distinct mitochondrial stressors to influence cellular and organismal responses.

CEP-1, the Caenorhabditis elegans p53 Homolog, Mediates Opposing Longevity Outcomes in Mitochondrial Electron Transport Chain Mutants

In a previous study we demonstrated that vesicular stomatitis virus (VSV) can be used as a vector to express a soluble protein in mammalian cells. Here we have generated VSV recombinants that express four different membrane proteins: the cellular CD4 protein, a CD4-G hybrid protein containing the ectodomain of CD4 and the transmembrane and cytoplasmic tail of the VSV glycoprotein (G), the measles virus hemagglutinin, or the measles virus fusion protein. The proteins were expressed at levels ranging from 23-62% that of VSV G protein and all were transported to the cell surface. In addition we found that all four proteins were incorporated into the membrane envelope of VSV along with the VSV G protein. The levels of incorporation of these proteins varied from 6-31% of that observed for VSV G. These results suggest that many different membrane proteins may be co-incorporated quite efficiently with VSV G protein into budding VSV virus particles and that specific signals are not required for this co-incorporation process. In fact, the CD4-G protein was incorporated with the same efficiency as wild type CD4. Electron microscopy of virions containing CD4 revealed that the CD4 molecules were dispersed throughout the virion envelope among the trimeric viral spike glycoproteins. The recombinant VSV-CD4 virus particles were about 18% longer than wild type virions, reflecting the additional length of the helical nucleocapsid containing the extra gene. Recombinant VSVs carrying foreign antigens on the surface of the virus particle may be useful for viral targeting, membrane protein purification, and for generation of immune responses.

Foreign glycoproteins expressed from recombinant vesicular stomatitis viruses are incorporated efficiently into virus particles.

A novel insertion sequence-like (IS) element, designated IS982, was found on the lactose plasmid, pSK11L, from Lactococcus lactis subsp. cremoris SK11 and was located between the origin of replication and the oligopeptide transport gene cluster. The 1003-base pair (bp) IS982 was flanked by 18-bp perfect inverted repeats. IS982 contained an open reading frame encoding a putative transposase of 296 amino acids. An almost identical IS-like element (99% DNA sequence identity) was cloned and partially sequenced from the chromosome of Lactococcus lactis subsp. cremoris Wg2 with 17-bp perfect inverted repeats. Southern analysis indicated that in 12 lactococcal strains examined, IS982 was present with copy numbers ranging from 1 to at least 20. IS982 displayed sequence homology to the putative IS element RSBst-alpha from Bacillus stearothermophilus CU21, IS982 and RSBst-alpha were not related to other known insertion sequences and may represent a new family of IS elements.

We havedeveloped a long-extension-PCR strategy whichamplifies approximately halfofthemitochondrial genome(6.3 kb)ofCaenorhabditis elegans using anindividual wormastarget. Weanalyzed three strains overtheir life spantoassess thenumberofdetectable deletions inthemitochondrial genome.Twoofthese strains arewild-type forlife spanwhile thethird is mutantintheage-1gene,approximately doubling its maximumlife span.Atthemeanlife spaninwild-type strains, there wasasignificant difference between the frequency ofdeletions detected inthemitochondrial genomecompared withthemeannumberofdeletions inyounganimals. Inaddition, deletions inthemitochondrial genomeoccuratasignificantly lower ratein age-1 mutants ascompared withwild type. Wecloned andidentified thebreakpoints oftwodeletions and foundthat oneofthedeletions hadadirect repeat of8 bpatthebreakpoint. Thisisthelargest single study (over 900individual animals) characterizing thefrequencyofdeletions inthemitochondrial genomeasa function ofageyetcarried out.

Increased frequency ofdeletions inthemitochondrial genome with ageofCaenorhabditis elegans

Several aspects of the photophysiology of wild-type Arabidopsis thaliana seedlings were compared with those of a phytochrome A null mutant, phyA-1, and a mutant, fhy1, that is putatively involved in the transduction of light signals from phytochrome A. Although phyA seedlings display a near wild-type phenotype when grown in white light (W), they nevertheless display several photomorphogenic abnormalities. Thus, whereas the germination of wild-type and fhy1 seeds is almost fully promoted by a pulse of red light (R) or by continuous far-red light (FR), phyA seed germination is responsive only to R. Following growth under day/night cycles, but not under continuous W, the hypocotyls of light-grown phyA and fhy1 seedlings are more elongated than those of wild-type seedlings. For seedlings grown under low red/far-red (R/FR) ratio light conditions, phyA and fhy1 seedlings display a more marked promotion of hypocotyl elongation than wild-type seedlings. Similarly, seedlings that are doubly null for phytochrome A and phytochrome B(phyA phyB) also have more elongated hypocotyls under low R/FR ratio conditions than phyB seedlings. This indicates that phytochrome A action in light-grown seedlings is antagonistic to the action of phytochrome B. Although wild-type, fhy1, and phyA seedlings flower at essentially the same time under both short-day and long-day conditions, an obvious consequence of phytochrome A deficiency is a pronounced late flowering under conditions where a short day of 8 h of fluorescent W is extended by 8 h of low-fluence-rate incandescent light. The evidence thus indicates that phytochrome A plays a role in seed germination, in the control of elongation growth of light-grown seedlings, and in the perception of daylength.

Photoresponses of Light-Grown phyA Mutants of Arabidopsis (Phytochrome A Is Required for the Perception of Daylength Extensions)

Phytochrome is a family of photoreceptors that regulates plant photomorphogenesis; the best-characterized member of this family is phytochrome A. Here, we report the identification of novel mutations at three Arabidopsis loci (fhy1, fhy2, and fhy3) that confer an elongated hypocotyl in far-red but not in white light. fhy2 mutants are phytochrome A deficient, have reduced or undetectable levels of PHYA transcripts, and contain structural alterations within the PHYA gene. When grown in white light, fhy2 mutants are morphologically indistinguishable from wild-type plants. Thus, phytochrome A appears to be dispensable in white light-grown Arabidopsis plants. fhy2 alleles confer partially dominant phenotypes in far-red light, suggesting that the relative abundance of phytochrome A can affect the extent of the far-red-mediated hypocotyl growth inhibition response. Plants homozygous for the recessive fhy1 and fhy3 mutations have normal levels of functional phytochrome A. The FHY1 and FHY3 gene products may be responsible for the transduction of the far-red light signal from phytochrome A to downstream processes involved in hypocotyl growth regulation.

Phytochrome A null mutants of Arabidopsis display a wild-type phenotype in white light.

Crystal orientation dependence of the spin-orbit coupling in InAs nanowires

Thermal motion of two liquid lead inclusions attached to the same ﬁ xed dislocation in an Al-0.65 at% Pb alloy is studied in situ at 447 ° C using transmission electron microscopy. Observations of their motion is recorded on video and analyzed frame by frame. Random oscillatory motion of the inclusions on the dislocation line occurs as a result of their mutual repulsion and their repulsion from the ﬁ xed ends of the dislocation caused by the dislocation line tension. The oscillations of the inclusions can be considered as correlated thermal motion in coupled potential wells. The effective potentials, in which the inclusions move, and the effective potential of their interactions are evaluated. It is found that the spatial correlations of the positions of the inclusions on the dislocation depend strongly on the interaction potential. The observed correlations of the positions of the inclusions suggest that they move along their averaged trajectories in a synchronous-like manner.

Apr 30, 2019 Correlated thermal motion of two liquid Pb inclusions attached to a fixed dislocation in

Thermal motion of two liquid lead inclusions attached to the same fixed dislocation in an Al-0.65 at% Pb alloy is studied in situ at 447 °C using transmission electron microscopy. Observations of their motion is recorded on video and analyzed frame by frame. Random oscillatory motion of the inclusions on the dislocation line occurs as a result of their mutual repulsion and their repulsion from the fixed ends of the dislocation caused by the dislocation line tension. The oscillations of the inclusions can be considered as correlated thermal motion in coupled potential wells. The effective potentials, in which the inclusions move, and the effective potential of their interactions are evaluated. It is found that the spatial correlations of the positions of the inclusions on the dislocation depend strongly on the interaction potential. The observed correlations of the positions of the inclusions suggest that they move along their averaged trajectories in a synchronous-like manner.

Correlated thermal motion of two liquid Pb inclusions attached to a fixed dislocation in an Al matrix

Epitaxially connected nanowires allow for the design of electron transport experiments and applications beyond the standard two terminal device geometries. In this Letter, we present growth methods of three distinct types of wurtzite structured InAs nanocrosses via the vapor-liquid-solid mechanism. Two methods use conventional wurtzite nanowire arrays as a 6-fold hexagonal basis for growing single crystal wurtzite nanocrosses. A third method uses the 2-fold cubic symmetry of (100) substrates to form well-defined coherent inclusions of zinc blende in the center of the nanocrosses. We show that all three types of nanocrosses can be transferred undamaged to arbitrary substrates, which allows for structural, compositional, and electrical characterization. We further demonstrate the potential for synthesis of as-grown nanowire networks and for using nanowires as shadow masks for in situ fabricated junctions in radial nanowire heterostructures.

Growth of InAs Wurtzite Nanocrosses from Hexagonal and Cubic Basis.

Step-controlled Brownian motion of nanosized liquid Pb inclusions in a solid Al matrix

Any device exposed to ambient conditions will be prone to oxidation. This may be of particular importance for semiconductor nanowires because of the high surface-to-volume ratio and only little is known about the consequences of oxidation for these systems. Here, we study the properties of indium arsenide nanowires which were locally oxidized using a focused laser beam. Polarization dependent micro-Raman measurements confirmed the presence of crystalline arsenic, and transmission electron microscopy diffraction showed the presence of indium oxide. The surface dependence of the oxidation was investigated in branched nanowires grown along the [ 0001 ] and [ 01 1 ¯ 0 ] wurtzite crystal directions exhibiting different surface facets. The oxidation did not occur at the [ 01 1 ¯ 0 ] direction. The origin of this selectivity is discussed in terms transition state kinetics of the free surfaces of the different crystal families of the facets and numerical simulations of the laser induced heating.

Morphology and composition of oxidized InAs nanowires studied by combined Raman spectroscopy and transmission electron microscopy

Intimate interconnection of crystal growth, (oriented) aggregation and phase transformation seem common in the formation of nano- and microcrystalline materials from solutions. Yet, the mechanistic linkages between the different processes have not been fully understood. In this work, we studied the hydrothermal growth of akaganeite (β-FeOOH) nanorods and their transformation to micron-sized hematite (α-Fe2O3) spindles using high-resolution cryogenic transmission electron microscopy (cryo-TEM). Only akaganeite particles and hematite spindles were detected in the samples. Further, cryo-electron 3D tomograms show that akaganeite nanorods were aggregated into loose three-dimensional networks with some embedded hematite spindles. Based on our cryo-TEM and additional X-ray diffraction, electron microscopy, and chemical data, we propose the following mechanism: first, formation of the early-stage hematite spindles is driven by phase stability change due to increase in size caused by oriented aggregation of akaganeite. Then, akaganeite particles continue to transform to hematite upon contact with and recrystallization onto hematite surfaces, making hematite grow with a constant aspect ratio and forming micron-sized nano-porous single-crystal spindles. Our growth model interprets experimental observations well and it resolves previous long-time debate over whether the hematite spindles are formed via classical Ostwald ripening or by oriented aggregation of hematite nanoparticles. Possibly, this aggregation-based concurrent growth and transformation model may also be applicable to crystal growth and phase transformation in other systems.

Aggregation-induced growth and transformation of β-FeOOH nanorods to micron-sized α-Fe2O3 spindles

The III-V nanowire structure (zinc blende or wurtzite) grown by the vapor-liquid-solid process is shown to be highly dependent on the parameters which shape the droplet at the top of the nanowire. Under conditions that the droplet volume does not exceed a certain value, it is demonstrated that when the nucleation of the solid starts at the solid-liquid-vapor triple line, a relatively large droplet volume and low wetting angle favor the formation of the wurtzite structure. We show that the effective V/III flux ratio is the primary parameter controlling the structure.

Impact of the liquid phase shape on the structure of III-V nanowires.

Growth of SiC nanowhiskers from wooden precursors, separation, and characterization

Correction: Low‐Temperature Superionic Conductivity in Strained Yttria‐Stabilized Zirconia

Very high lateral ionic conductivities in epitaxial cubic yttria‐stabilized zirconia (YSZ) synthesized on single‐crystal SrTiO3 and MgO substrates by reactive direct current magnetron sputtering are reported. Superionic conductivities (i.e., ionic conductivities of the order ∼1 Ω−1cm−1) are observed at 500 °C for 58‐nm‐thick films on MgO. The results indicate a superposition of two parallel contributions – one due to bulk conductivity and one attributable to conduction along the film–substrate interface. Interfacial effects dominate the conductivity at low temperatures (<350 °C), showing more than three orders of magnitude enhancement compared to bulk YSZ. At higher temperatures, a more bulk‐like conductivity is observed. The films have a negligible grain‐boundary network, thus ruling out grain boundaries as a pathway for ionic conduction. The observed enhancement in lateral ionic conductivity is caused by a combination of misfit dislocation density and elastic strain in the interface. These very high ionic conductivities in the temperature range 150–500 °C are of great fundamental importance but may also be technologically relevant for low‐temperature applications.

Low‐Temperature Superionic Conductivity in Strained Yttria‐Stabilized Zirconia

Alloys displaying positive enthalpy of mixing demix below a critical temperature. In Co-Cu and related ternaries the miscibility gap is metastable, i.e. it occurs at temperatures lower than the liquidus. In order to study the liquid phase separation high melt undercooling is necessary. This was obtained via rapid solidification techniques using melt spinning and casting in moulding devices, as well as high temperature DSC experiments with samples embedded in a flux. Results are given for Co-Cu, Co-Cu-Fe and Co-Cu-Ni systems. Phase diagrams were optimised using the DSC data. The mechanism of phase separation was investigated by comparing samples produced under different cooling conditions. The hierarchy of microstructures obtained was interpreted accounting for the processing technique and the phase diagram. They constitute a database useful for the interpretation of the thermal history of samples processed in microgravity.

The Solidification in the Presence of a Metastable Miscibility Gap: The Case of Co-Cu and Co-Cu-X Alloys

By combining a 2D PILATUS 100 K detector and a surface diffractometer, high‐resolution 3D reciprocal space maps with a resolution up to 2 × 10−3 A−1 have been obtained, at an acquisition speed of 20 min per Bragg point. To illustrate the possibilities, the shape and facets of molecular beam epitaxy grown GaAs nanowires are identified by studying the diffuse scattering around Bragg points from the different crystal structures in the wires. The wires are bound by {111} facets from alternating domains with zincblende structure and its twin, creating a microfaceted wire with a hexagonal cross‐section.

High‐resolution three‐dimensional reciprocal space mapping of semiconductor nanostructures

Dissolution kinetics of nanoscale liquid Pb/Bi inclusions at a grain boundary in aluminum

Materials Science and Engineering A-structural Materials Properties Microstructure and Processing

Thermodynamics and mechanism of demixing in undercooled CU-Co-Ni alloys

Thermal motion of nanoscale liquid Pb inclusions attached to fixed dislocations in thin Al foils is investigated using in-situ TEM. In contrast with 3D random motion of free inclusions, the attached inclusions demonstrate oscillations in the close proximity of the dislocations. This is due to the elasticity of the dislocations. It is found that inclusions captured by one dislocation repulse at small separations, and attract at large ones and this is also caused by the dislocation elasticity. Such behaviour of trapped inclusions can be considered as a motion in a potential well or in coupled potential wells in the case of motion of several trapped inclusions on one dislocation. The potential of interaction of an inclusion with a dislocation and the potential of mutual interaction between inclusions are determined.

Influence of Elasticity of Dislocations on Thermal Motion of Trapped Liquid Pb Inclusions in Al

The melting behavior of faceted particles embedded in the solid state: A family of Wulff shapes

Abstract In-situ transmission electron microscopy (TEM) observations reveal a permanent chaotic motion of nanosized liquid Pb inclusions embedded in thin aluminum foils. Individual trajectories of the inclusions were analysed to determine the character of their motion. The inclusions moving freely inside a crystal display motion with three-dimensional random walk characteristics while inclusions attached to dislocations display spatially confined random motion localized to the close vicinity of the dislocation lines. The diffusion coefficients of inclusions moving freely in the matrix were determined using Einstein’s classical equation for diffusion of Brownian particles. The diffusion coefficients of inclusions trapped on dislocations were found using an equation based on Smoluchowski’s analysis of Brownian motion of a particle under the action of a linear elastic restoring force. The dependence of the diffusivity on the size of the inclusions suggests that their mobility is controlled by kinetic processes on the inclusion/matrix interfaces. The Arrhenius analysis exhibits two regions with different temperature dependencies. We suppose that this is related to the existence of {111} facets on the inclusion/matrix interfaces.

Diffusional behavior of nanoscale lead inclusions in crystalline aluminum

Diffusion of nano-sized liquid Pb inclusions in thin aluminum foils is investigated using in-situ transmission electron microscopy (TEM). Free diffusion of the inclusions in the bulk and diffusion constrained by dislocations trapping is studied. The motion of trapped Pb inclusions is spatially confined in close proximity to the dislocations. The diffusion coefficients of free motion of the inclusions are determined using Einstein's equation. The diffusion coefficients of trapped inclusions were obtained using an equation based on Smoluchowski's analysis of the Brownian motion of particle in a harmonic potential. The agreement of the diffusion coefficients of free and trapped inclusions indicates the same underlying microscopic mechanism, and no strong influence from dislocations. The microscopic mechanism controlling the mobility is discussed.

In Situ TEM Investigation of Diffusion of Nano-Scale Liquid Pb Inclusions on Dislocations and in Bulk Aluminum

Abstract The increasing role of interfaces with decreasing scale is particularly important for small inclusions, grains or precipitates. In this work, we present a brief review of some of our recent TEM investigations of faceted singular interfaces and interface junctions in crystals. Direct observations by high-resolution electron microscopy allow us to relate the size, shape, and local interface structure to the behavior of nanoscale inclusions. The effect of facet junctions on equilibrium shapes of inclusions, on the structure of grain boundary grooves at surfaces and on grain-boundaries in anisotropic bicrystals are illustrated with examples from recent work by this group.

TEM observations on the behavior of facet junctions in interfaces and inclusions

Observations of vacancy-controlled decay of elastic strain caused by phase transformation of small Pb inclusions in Al

Extended abstract of a paper presented at Microscopy and Microanalysis 2004 in Savannah, Georgia, USA, August 1–5, 2004.

Strain Accommodation During Solidification of Nanosize PbCd Inclusions Embedded in Al

The effect of partial crystallization on elevated temperature flow stress and room temperature hardness of a bulk amorphous Mg60Cu30Y10 alloy

Transmission electron microscopy has been used for structural and physical characterization of nanoscale inclusions of lead and noble gases in aluminum. When the inclusion sizes approach nanoscale dimensions, many of their properties are seen to deviate from similar properties in bulk and in most cases the deviations will increase as the inclusion sizes decrease. Binary alloys of lead and noble gases with aluminum are characterized by extremely low mutual solubilities and inclusions will, therefore, exist as practically pure components embedded in the aluminum matrix. Furthermore, the thermal vacancy mobility in aluminum at and above room temperature is sufficiently high to accommodate volume strains associated with the inclusions thus leading to virtually strain free crystals. The inclusions grow in parallel cube alignment with the aluminum matrix and have a cuboctahedral shape, which reflects directly the anisotropy of the interfacial energies. Inclusions in grain boundaries can have single crystalline or bicrystalline morphology that can be explained from a generalized Wulff analysis such as the ξ‐vector construction. The inclusions have been found to display a variety of nanoscale features such as high Laplace pressure, size‐dependent superheating during melting, deviations from the Wulff shape displaying magic size effects, a shape dependence of edge energy, and so on. All these effects have been observed and monitored by TEM using conventional imaging conditions and high‐resolution conditions in combination with in‐situ analysis at elevated temperatures. Microsc. Res. Tech. 64:356–372, 2004. © 2004 Wiley‐Liss, Inc.

Nanoscale lead and noble gas inclusions in aluminum: Structures and properties

Nanoscale lead-tin inclusions in aluminium (Eighth Conference on Frontiers of Electron Microscopy in Materials Science)

Experimental studies of the liquid-solid interface are complicated because the interface is embedded and involves only a small number of atoms relative to the bulk liquid and solid. In his Perspective, [Johnson][1] highlights recent advances toward characterizing the interface. He highlights the report by [ Donnelly et al .][2], who have used transmission electron microscopy (TEM) to study xenon inclusions in aluminum. The report provides evidence for progressive layering in the liquid near the interface, demonstrating the power of well-designed TEM studies to elucidate such interfaces.

 [1]: http://www.sciencemag.org/cgi/content/full/296/5567/477
 [2]: http://www.sciencemag.org/cgi/content/short/296/5567/507

Nuclear Instruments & Methods in Physics Research Section B-beam Interactions With Materials and Atoms

Equilibrium shape and interface roughening of small liquid Pb inclusions in solid Al

High-Fluence Implantation of Erbium into Silicon-Germanium Alloys: Structural and Thermal Properties

Kinetic Limitations to Shape Equilibration of Liquid Pb Inclusions In Al

Al-Sn surface alloys with 2-3 at.% Sn have been made by ion implantation of Sn in Al. The microstructure of the alloys consists of dense distributions of nanoscale Sn inclusions embedded in the Al matrix. For implantations carried out at 425 K the inclusions have sizes in the range from about 2 to 15 nm. The structure of the inclusions is tetragonal - the white Sn structure – with lattice parameters of a = 0.583 nm and c = 0.318 nm respectively, i.e. identical to the lattice parameters of bulk Sn. The inclusions grow in preferred alignment with the matrix and the most commonly observed orientation relationships is given by ( 100 ) Sn ||( 111 ) Al and [ 010 ] Sn || [ 2 11 ] Al . The shape of the inclusions is partly faceted and partly rounded with larger flat facets on the {100} Sn /{111} Al interfaces. Melting and solidification of the inclusions, which have been studied by in-situ transmission electron microscopy (TEM) and Rutherford backscattering spectrometry (RBS) in combination with channeling, shows a distinct hysteresis. Melting of the inclusions which is associated with a distinct premelting, takes place in the range from about 430 K to 485 K, i.e. significantly below the bulk melting point of 505 K. The premelting is size dependent and the smallest inclusions melt at the lowest temperatures. Solidification requires a substantial undercooling and takes place from around 400 K with a much weaker size dependence.

Nanoscale Sn Inclusions in Al – Structure and Melting-Solidification Properties

We present transmission electron microscopy (TEM) results from an experimental study of the morphological changes of liquid Pb and (Pb,Bi) inclusions embedded in an Al matrix. Such inclusions are insoluble up to the bulk melting point of aluminium. We use rapidly solidified samples which gives inclusion sizes in the range from 20 to 250 nm. The experiments consist of heating cycles of the liquid inclusions from the melting point of around 600 K up to around 800 K and back to their solidification. The solid Pb and (Pb,Bi) inclusions are topotactically aligned with the Al matrix, with an incoherent boundary. The shape is a cuboctahedron with hexagonal {111} facets and square {100} facets. We have found a hysteresis in the morphology of the liquid inclusions. Immediately after melting the (100) planes bulge outwards and become rounded whereas the (111) planes remain flat until the temperature reaches 750-800 K where the inclusions rapidly become spherical. During subsequent cooling the inclusions were retained their spherical shape until solidification. Since atomic and vacancy mobility is high at all temperatures above the melting point we suggest that diffusion cannot be rate controlling. The experiments were made with inclusion and host material of various purities to test the possibility that the presence of impurities in the interfaces was rate controlling.

Shape Changes of Nanosized Liquid Pb Inclusions in Al at Elevated Temperatures

TEM Characterization of Shape, Size and Melting Behavior of PbInclusions in Al Grain Boundaries

Aluminum-lead alloys containing dense distributions of nanosized lead precipitates have been made by rapid solidification and ion implantation. Embedded precipitates grow in parallel-cube alignment with the aluminum matrix; they have a cuboctahedral shape resulting from a minimization of the total interface energy, and atomically smooth {111} and {100} facets. The smallest precipitates, less than about 20 nm in size, adopt a series of magic sizes determined by periodic minima in the residual strain energy. In this size range the energy of the cuboctahedral edges becomes significant. This leads to changes in the aspect ratio of the precipitates so that the smaller precipitates are less truncated. Fitting the experimental data to an analytical expression gives a value of 1.15 for the ratio between the {100} and {111} interface energies and a value of 2.06.a Pb for the ratio of energies between the edges and {111} interfaces.

Nanosized Lead Inclusions in Aluminum-Magic Sizes and Aspect Ratios

Abstract Al(110) single-crystal samples were implanted at T = 200°C with In+ ions of 250 keV energy with fluences ranging from 4×1020 to 3×1021 m−2. The implantation resulted in the formation of In precipitates growing with fluence in topotactical alignment with the host matrix. High-fluence implantation was used in an attempt to produce single-crystal buried layers of In embedded into Al. Rutherford back-scattering (RBS)-channelling analysis of the implanted samples and transmission electron microscopy studies of the incorporated In layer morphology were carried out. With increasing fluence the peak In concentration was observed to increase gradually until a maximum value of about 38 at.% was reached at an implantation dose of 1·5×1021 m−2. The buried layer thus formed was found to have fragmentary morphology consisting of large In precipitates. During further implantation the peak concentration decreased drastically to reach a steady state. In order to study a possible effect of sputtering on the In pro...

High-fluence ion implantation of In into Al crystals: Formation and evolution of buried layers

Microstructural investigation of a rapidly solidified 12Cr-Mo-V steel

TEM and RBS/channelling of nanosized bicrystalline (Pb,Cd) inclusions in Al made by sequential ion implantation

We show that the equilibrium shapes of small solid Pb inclusions embedded in an Al matrix are size dependent. Using high resolution electron microscopy we have observed that small inclusions a few nanometers in size adopt equilibrium shapes with smooth {l_brace}111{r_brace} facets. Inclusion dimensions follow preferred sizes shown to result from the nature of the residual strain which oscillates and decreases with size. As a result, the inclusion shape is controlled by the residual strain energy at small sizes and by the interface energy at larger sizes. {copyright} {ital 1997} {ital The American Physical Society}

Abstract Ion implantation of pure aluminium with thallium gives rise to the formation of nano-sized thallium inclusions due to the immiscibility of thallium in aluminium. Previous investigations have shown that the thallium inclusions can have either a fcc or a bcc structure. In this paper we report the size distribution and phases of thallium inclusions embedded in an aluminium matrix and the dependence of the size distribution and the phase on the implantation temperature. It is shown that implantations at different temperatures give rise to different sizes and phases of the thallium inclusions. Small inclusions (diameter less than about 10 nm) are almost always fcc while larger inclusions (diameter larger than about 10 nm), formed at higher implantation temperatures, usually are bcc, but hcp inclusions are also seen. Also presented in this paper are some results on the melting and solidification temperatures in relation to the structure and size of the inclusions. Among the fcc inclusions, the smaller ...

Sizes, structures and phase transformations of nano-sized thallium inclusions in aluminium

Si single crystals were implanted in a random direction at a temperature of 835 K with 150 keV Pb + ions to a fluence of 1.10 20 m -2 corresponding to a mean implantation depth of about 60 nm and an average concentration of 2-3 at%. The implanted samples have been studied by Rutherford Backscattering (RBS)/channelling and transmission electron microscopy (TEM) techniques. The RBS analysis showed that in as-implanted samples the main fraction of implanted Pb was located on substitutional sites in the Si matrix thus providing a highly supersaturated solution of Pb in Si. Spontaneous precipitation of Pb, giving rise to formation of nanosized Pb inclusions, was found to take place only in the peak region of the implantation profile where the Pb concentration was highest (∼ 4 at.%). TEM analysis of the as-implanted Si crystals showed that the Pb precipitates had sizes from about 2 to 20 nm and that they grew in parallel cube orientation relationship with the host matrix. The shape of the inclusions was found to be approximately cuboctahedral with poorly developed {111} and {100} facets. In-situ RBS/channelling heating/cooling experiments on both as-implanted samples and samples previously furnace-annealed at 1175 K showed a distinct melting/solidification hysteresis of the Pb inclusions around the bulk melting point for Pb at 600 K. These results were verified by in-situ TEM heating/cooling experiments on as-implanted samples.

Channeling study of melting and solidification of lead nanocrystals in aluminium

Supercooling of crystalline bismuth inclusions in aluminium crystals has been observed and studied with different techniques: X-ray diffraction, in situ Rutherford backscattering/channelling spectrometry and transmission electron microscopy. The results of the measurements with different experimental methods (and on different samples) agree remarkably well. The inclusions melt at temperatures at or below the bismuth bulk melting point, and the solid/liquid phase transition exhibits a hysteresis of 100-150 K. Average inclusion sizes ranged from a few nm to some tens of nm. The X-ray diffraction melting data are discussed in relation to different existing models for the melting temperature of an inclusion as a function of its size. From this an approximate size distribution for the inclusions is derived.

Melting and Solidification of nanosized Lead Crystallites in Aluminium Studied by Means of Channeling

Structure, morphology and melting hysteresis of ion-implanted nanocrystals

Channeling and TEM investigation of nanosized thallium inclusions in aluminium

Na inclusions with diameters in the range from 2 nm to 15 nm have been made by ion implantation of Na into 70 nm thick single-crystalline Pt foils followed by annealing. The structure of solid inclusions and the diffusion of molten inclusions have been studied by transmission electron microscopy. At room temperature the inclusions are faceted and crystalline with a BCC structure and they are aligned topotactically with the Pt (FCC) matrix. The diffusion of inclusions in the liquid state was investigated by annealing at temperatures of 1227 K, 1432 K and 1534 K. The diffusion coefficient was found to have a dependence on the inclusion radius and an activation energy of 2.8+or-0.2 eV, this being consistent with a mechanism by which volume self-diffusion of Pt controls the diffusion rate of the inclusions. Diffusion of Pt at the interfaces between the Pt matrix and the liquid Na inclusions was found to be strongly inhibited compared with the free surface self-diffusion of Pt. The results are used to propose a method to produce sources for positron annihilation spectroscopy at high temperatures.

Fundamental aspects of inert gases in solids: S.E. Donnelly and J.H. Evans (eds.) (Plenum, London, 1991) pp. 473 + xi. Hardcover, $125.00 ($150.00 outside the US and Canada). ISBN 0-306-44051-2

Crystallization of aluminium-based metallic glasses: processes and kinetics

Phase Transformation and Modification by Beam-Solid Interactions

Backscattering and channeling study of lead inclusions in Pb-implanted aluminium

Aluminum single crystals cut in the {l angle}111{r angle} direction were implanted with 2{times}10{sup 20} m{sup {minus}2} Pb{sup +} ions at 75 or 150 keV. The implanted insoluble lead precipitated as epitaxially oriented crystallites in the aluminum matrix. The precipitates were studied by x-ray diffraction at Riso 9( ), DESY, and Brookhaven National Laboratory, and showed large superheating as well as supercooling during repeated heating cycles. The as-implanted precipitates had a characteristic size of {similar to}140 A, which grew to 210--260 A during repeated heating cycles. A detailed annealing study shows that the growth rate of the precipitates changes discontinuously at the onset of melting. This shows that significant precipitate growth takes place by coalescence. The diffracted x-ray intensities showed characteristic truncation rods (streaks), indicating that the solid precipitates were octahedra limited by {l brace}111{r brace} planes and truncated at the corners by {l brace}100{r brace} facets.

Sputtering and RBS investigations of ordered and disordered Ni4Mo

RBS analysis of diffusion and evaporation of implanted lead in aluminium

Thermodynamic properties of the melts of several Al–Y and Al–Fe–Y alloys are studied by means of calibrated differential thermal analysis. The results can be used to optimize process parameters of rapid solidification which are important for glass formation in the Al-based alloys. Close examinations of the melt-spun alloys show that the process parameters, particularly the temperature of the melts, will influence not only the amorphicity and the chemical short-range order but also the crystallization process of the glasses. A key point of glass formation in the Al-based alloys is found to be related to the content in the melts of a certain amount of the intermetallic compounds which are gradually dissolved in the premelted α Al matrix.

Size distribution and melting/solidification behavior of nm-size metal inclusions

Abstract Crystallization reactions, crystal morphologies and phase evolutions have been studied in melt-spun binary Al-Y and ternary AI-Fe-Y metallic glasses using X-ray diffraction, differential scanning calorimetry, electron microscopy and Mossbauer spectroscopy. The binary samples crystallize by a one-stage or two-stage primary reaction to form the α-Al phase, followed by polymorphous reactions to form different metastable compounds. The ternary glasses devitrify by either polymorphous or eutectic reactions. The ternary crystalline compounds are characteristically a metastable Al9(Fe, Y)2 phase with strongly textured columnar morphology, and a tetragonal Al70Fe16Y14 phase. The structure of the early-stage crystallization products depends on the nature of the short-range chemical order structures existing at different temperatures in the melts, which are partly retained in the glass phases.

Crystallization of Al-based metallic glasses. Structural aspects

Small lead and indium inclusions growing topotactically in aluminium

Angular distributions of sputtered particles from Lithium-implanted Aluminium and Copper crystals

Metastable phase characterization in ion implanted and rapidly solidified aluminium-based alloys

Energy-beam processing of materials. Advanced manufacturing using various energy sources: (Oxford series on advanced manufacturing 5) Edited by Norio Taneguchi, Masayuki Ikeda, Toshiuki Miyazaki and Iwao Miyamoto (Oxford University Press, Oxford, 1989) pp. 315, Hardbound, £50.00, ISBN 0198590059

Depth distribution of martensite in xenon-implanted stainless steels

Analytical techniques for thin films Treatise on materials science and technology, vol. 27) edited by K.N. Tu and R. Rosenberg (Academic Press, San Diego and London, 1988) pp. xii + 493, hard cover, US $89.95. ISBN 0-12-341827-X

Martensitic transformations in 304 stainless steel after implantation with helium, hydrogen and deuterium

Temperature and fluence effects in lead-implanted cobalt single crystals

X-ray studies of krypton, xenon and lead inclusions in aluminium single crystals☆

Depth distribution analysis of martensitic transformations in Xe implanted austenitic stainless steel

Segregation and structural effects of boron in rapidly solidified copper-boron alloys

Revue de la transformation cubique a faces centrees→hexagonal compact dans le nickel et de la transformation cubique a faces centrees→cubique centre dans les aciers inoxydables. Analyse de la distribution des phases et des microstructures. Comparaison pour les aciers inoxydables avec la transformation martensitique conventionnelle. Relation de la transformation avec les modifications structurales induites par faisceau ionique, particulierement avec l'amorphisation

The effect of boron implantation on the corrosion behaviour, microhardness and contact resistance of copper and silver surfaces

Structure and phase stability in rapidly solidified and ion-implanted martensitic stainless steels

Mössbauer and TEM study of martensitic transformations in ion implanted 17/7 stainless steel

Microscopic methods in metals: ed. U. Gonser, topics in current physics, vol. 40 (Springer, Berlin-Heidelberg-New York-Tokyo, 1986) pp. xvi + 458 with 258 figures, DM 115,-, cloth bound. ISBN 3-540-16251-8

Alloys of Cu-Sn and Cu-B have been processed by both melt spinning and ion implantation. In some instances (eg Cu-Sn alloys) rapidly solidified ribbons have been subjected to further implantation. This paper describes the similarities and differences in structure of materials subjected to a dynamic and contained process. For example in Cu-B alloys (up to 2wt% Boron) extended solubility is found in implanted alloys which is not present to the same degree in rapidly solidified alloys of the same composition. Likewise the range and nature of the reversible martensitic transformation is different in both cases as examined by electron microscopy and differential scanning calorimetry.

Copper-Base Alloys Processed by Rapid Solidification and Ion Implantation

Ion implantation and martensitic transformations in a 17/7 stainless steel

Sputtering yields of cobalt crystals bombarded with Ar + ions: Dependence of yield on energy

COMPARISON OF STRUCTURES PRODUCED BY ION IMPLANTATION AND RAPID SOLIDIFICATION

Abstract Anion voidage and anion void lattice formation in electron irradiated (100 keV–1 MeV) fluorite (CaF2) has been investigated by in situ transmission electron microscopy. At low fluences (≲1 dpa) the damage consists of randomly distributed anion voids and large bubble-like defects associated with fluorine gas. At higher fluences (≳ 1 dpa) the anion voids form a three-dimensional ordered superlattice with a simple cubic structure, whose axes are commensurate with those of the matrix. The superlattice has a unit cell parameter A0 in the range 15–30 nm and a ratio A0/R(superlattice parameter/anion void radius) in the range 3–6. The fully ordered superlattice “crystallizes” from randomly distributed anion voids by an ordering process in which locally ordered areas grow together after a fashion similar to that of epitaxy, leaving distorted superlattice regions between individual, fully ordered blocks. The basic radiation damage events are radiolytic and confined to the anion sublattice. Damage processes...

Anion voidage and the void superlattice in electron irradiated Caf2

“In situ” electron irradiation of sodalite in the transmission electron microscope (TEM) results in formation of radiolytic damage in the form of chlorine ion voids and chlorine gas bubbles. The chlorine ion-voids are identical with metallic sodium particles. The damaging process is discussed in terms of point defects and radiation induced voidage. The latter is confined to the chlorine ion sublattice. 
 
„In situ”-Bestrahlung von Sodalith im Transmissions-Elektronenmikroskop erzeugt radiolytisch Chlorionen-Locher und Chlorgasblasen. Die Chlorionen-Locher sind identisch mit Partikeln von metallischem Natrium. Der Schadigungsprozes wird diskutiert auf der Grundlage von Gitterleerstellen und strahlungsinduzierter Locherbildung, die auf das Chlorionen-Untergitter beschrankt ist.

Modeling current and future habitat suitability of an iconic bird to inform restoration planning in southeastern Louisiana, U.S.A.

 Woodcreepers (Dendrocolaptinae) represent a remarkably uniform group of brownish birds that move by hitching up tree trunks as they forage for arthropod prey. Despite these superficial similarities, we were able to uniquely differentiate the niches of all 13 species north of Manaus by integrating morphological traits (e.g., mass and bill size) with behavioral traits (e.g., sociality, stratum use, and foraging maneuvers). The 5 ant-following (myrmecophilous) species, with their larger bodies and heavier bills, were morphologically distinct from the 7 species that join mixed-species flocks. A combination of vertical stratum, mass, and bill length further distinguished among mixed-flocking species. Two canopy species—the solitary Dendrexetastes rufigula and the mixed-flocking Lepidocolaptes albolineatus—consistently foraged at higher strata than other species. For the remaining mixed-flocking species, the largest 3 species differed significantly by mass, whereas the smallest 3 species, which overlapped broadly in mass, were uniquely distinguished by bill length. The 5 ant-following species differed in their degree of specialization on ant swarms, from facultative (Hylexetastes perrotii) to obligate (Dendrocincla merula). The ant-followers also showed nearly discrete mass distributions that essentially differed by Hutchinsonian 1:1.3 ratios, which likely allows them to maintain interspecific dominance hierarchies at the front of raiding army ant swarms. The behaviors we quantified (sociality, vertical strata, and myrmecophily), together with morphology (mass and bill size), separated all 13 species. We speculate that niche partitioning and competitive exclusion allow each woodcreeper to uniquely access invertebrate prey, permitting coexistence and contributing to high alpha diversity at our study site.

Sociality and morphology differentiate niches of 13 sympatric Amazonian woodcreepers (Dendrocolaptinae)

Body size mediates life history, physiology and inter- and intra-specific interactions. Within species, sexes frequently differ in size, reflecting divergent selective pressures and/or constraints. Both sexual selection and differences in environmentally mediated reproductive constraints can drive sexual size dimorphism, but empirically testing causes of dimorphism is challenging. Manakins (Pipridae), a family of Neotropical birds comprising approximately 50 species, exhibit a broad range of size dimorphism from male- to female-biased and are distributed across gradients of precipitation and elevation. Males perform courtship displays ranging from simple hops to complex aerobatic manoeuvres. We tested associations between sexual size dimorphism and (a) agility and (b) environment, analysing morphological, behavioural and environmental data for 22 manakin species in a phylogenetic framework. Sexual dimorphism in mass was most strongly related to agility, with males being lighter than females in species performing more aerial display behaviours. However, wing and tarsus length dimorphism were more strongly associated with environmental variables, suggesting that different sources of selection act on different aspects of body size. These results highlight the strength of sexual selection in shaping morphology—even atypical patterns of dimorphism—while demonstrating the importance of constraints and ecological consequences of body size evolution.

Migratory behavior and connectivity revealed in a secretive Neotropical migratory songbird, the Swainson’s Warbler

Host specificity is a key element to our understanding of symbiont diversification and is driven by multiple macro- and microevolutionary processes. Broad scale (e.g., species-level) studies can uncover relevant processes such as cospeciation and host-switching that shape host-symbiont evolutionary histories.

Population genomics of avian feather mites with contrasting host specificities

Abstract. The Eastern Black Rail (Laterallus jamaicensis jamaicensis) is a conservation priority species, yet distributional and habitat data continue to be lacking. In Louisiana, USA, the species is known from 13 documented records and scattered anecdotal reports. From May 2017 to April 2019, we conducted Louisiana's first systematic survey using point count and drag-line techniques. During breeding and non-breeding point counts, we detected one or more Black Rails during 3.1% (n = 1,239) of surveys across 13.8% (n = 152) of point locations at 33.3% (n = 33) of sites. Detection probability was highest from March to May (0.245 ± 0.055 SE) and occupancy was best explained by increasing Gulf cordgrass (Spartina spartinae) cover. During non-breeding season drag-line surveys, we tallied 36 detections at 43.8% (n = 16) of sites. We deployed VHF radios on 13 Black Rails between December 2018 and March 2019 and estimated a home range of 0.71 (± 0.13 SE) ha. These surveys provided the first evidence of a year-round Black Rail population in Louisiana. Additional study is urgently needed to understand habitat management needs, including prescribed fire, mechanical shrub removal, and cattle (Bos taurus) grazing intensities. Meanwhile, aggressive conservation actions are needed to preserve remaining habitat.

Status and Habitat Relationships of the Black Rail (Laterallus jamaicensis) in Coastal Louisiana, USA

ABSTRACT Determination of a bird's age or cohort is critical for studies on avian demography, occurrence patterns, behavior, and conservation management. Age designations have largely been developed in north-temperate regions and utilize calendar-based or seasonally based codes; however, in tropical regions and in the southern hemisphere, these coding systems have limited utility at best. To address these issues, we had previously devised the “WRP system,” based on the nomenclature of Humphrey and Parkes (H–P) and Howell et al., which defines molts in an evolutionary context applicable to birds globally. Here we refine and build upon core concepts and definitions of the WRP coding system, resolving key limitations that were identified during its first decade of use. The WRP system employs a three-letter alpha code in which each letter describes a different aspect of H–P terminology: the molt cycle (which informs a bird's age) and molt and plumage status within the cycle (each of which can also inform age). Here we recommend the continued use of most of the original (“core”) WRP coding while augmenting the system with an optional adjunct-code entry for comprehensiveness, clarity, and flexibility, and we clarify a few additional codes to cover less common molting and plumage strategies. For most users, from 7 to 13 core and 1 adjunct WRP code will be sufficient to describe all plumages and provide molt status and ages for demographic studies or other purposes. The revised WRP system is flexible enough to be adapted to the specific goals of programs while also providing core codes that can facilitate the comparison of avian age, molt, and plumage status on a global basis. We anticipate that our revised and standardized version of the WRP system will be easily adopted and could eventually replace calendar-based and seasonally based coding. LAY SUMMARY Age determination of birds is critical for studies on avian demography and conservation. Several age-designation systems currently in use are applicable to the temperate northern hemisphere but cannot be used in tropical regions or the southern hemisphere. The “WRP” coding system was thus designed for global use in demographic and other studies examining the ages and cohorts of birds. WRP coding is based on a rigidly defined molt terminology that designates molt cycle along with molt and plumage status, each of which informs age. Here we make recommendations to enhance and stabilize the core WRP system, providing clarified coding that can be adapted to individual programs while also being comparable on a global basis.

Application of a global age-coding system (“WRP”), based on molts and plumages, for use in demographic and other studies of birds

Abstract - Hurricanes can have strong effects on wildlife populations and their habitats, with complex positive and negative outcomes. I demonstrate the utility of Audubon Christmas Bird Count (CBC) data by comparing results of the first Creole CBC after Hurricanes Laura (Category 4 on 27 August) and Delta (Category 2 on 9 October) in 2020 against 7 years of pre-hurricane Creole CBC baseline data in coastal Cameron Parish, LA. Bird community structure following the hurricanes was significantly different compared to the previous 7 years. Species richness significantly decreased in core (i.e., absent from 2 or fewer baseline CBCs) and irregularly (absent from 3 or more baseline CBCs) occurring bird species. Particularly hard hit were landbirds, whereas waterfowl, waterbirds, and shorebirds were more likely to show positive responses. Marshbird and raptor counts had the most neutral post-hurricane responses. Migratory species across all 6 guilds were also less likely than resident species to show negative responses and more likely to show positive responses to the hurricanes. These results demonstrate differing vulnerabilities of birds to hurricanes, an understanding of which is critical for developing conservation strategies to minimize negative population effects in the face of future increased hurricane intensity.

Short-Term Effects of Two Hurricanes on Bird Populations in Southwestern Louisiana

Since 1980, 30 to 69% of species have shown reductions in mass, increases in wing length, and decreases in mass:wing ratio.

Morphological consequences of climate change for resident birds in intact Amazonian rainforest

ABSTRACT The slow-paced life history of many Neotropical birds (e.g., high survival and low fecundity) is hypothesized to increase lifetime fitness through investments in self-maintenance over reproduction relative to their temperate counterparts. Molt is a key investment in self-maintenance and is readily shaped by environmental conditions. As such, variation in molt strategies may be a key mechanism underlying life-history trade-offs and adaptation to new environments. Here, we review molt strategies from a diversity of lowland Neotropical landbirds and examine how variation in molt strategies, characterized by differences in molt insertions, timing, extent, and duration contribute to life-history variation and adaptation to diverse ecological conditions. In addition to our synthesis, we present a case study to examine the relationship between home range size and duration of the definitive prebasic molt of a well-studied subset of Amazonian landbirds. Our results suggest a connection between prolonged molt duration and larger home range size of small-to-medium-sized Amazonian landbirds. Our aims were to identify key gaps in our knowledge of Neotropical bird molt, to stimulate further comparative studies into the evolution of molt strategies, and to highlight how variation in molt strategies may be a key mechanism underlying life-history variation across latitudes. LAY SUMMARY Songbirds inhabiting Neotropical forests replace feathers, or molt, in a diversity of ways. Our review found that closely related species exhibit similar molt strategies. Because molt is an investment in self-maintenance and is readily shaped by a bird's environment, variation in molt likely reflects adaptation to different ecological niches. To test whether molt reflects adaptation to a bird's ecological niche, we examined differences among molt duration, home range size, and wing length across multiple Amazonian bird species. These results suggest that ant-following birds with small wings and large home ranges adaptively slowed molt duration to inhabit a new ecological niche. Our findings demonstrate how variation in molt strategies may be a key mechanism underlying life-history variation and ecological differentiation across latitudes.

Ecological and evolutionary significance of molt in lowland Neotropical landbirds

How are rainforest birds faring in the Anthropocene? We use bird captures spanning > 35 years from 55 sites within a vast area of intact Amazonian rainforest to reveal reduced abundance of terrestrial and near-ground insectivores in the absence of deforestation, edge effects or other direct anthropogenic landscape change. Because undisturbed forest includes far fewer terrestrial and near-ground insectivores than it did historically, today's fragments and second growth are more impoverished than shown by comparisons with modern 'control' sites. Any goals for bird community recovery in Amazonian second growth should recognise that a modern bird community will inevitably differ from a baseline from > 35 years ago. Abundance patterns driven by landscape change may be the most conspicuous manifestation of human activity, but biodiversity declines in undisturbed forest represent hidden losses, possibly driven by climate change, that may be pervasive in intact Amazonian forests and other systems considered to be undisturbed.

Long-term change in the avifauna of undisturbed Amazonian rainforest: ground-foraging birds disappear and the baseline shifts.

Abstract Bergmann’s rule is a well‐established, ecogeographical principle that states that body size varies positively with latitude, reflecting the thermoregulatory benefits of larger bodies as temperatures decline. However, this principle does not seem to easily apply to migratory species that are able to avoid the extreme temperatures during winter at higher latitudes. Further, little is known about the ontogeny of this relationship across life stages or how it is influenced by ongoing global climate change. To address these knowledge gaps, we assessed the contemporary relationship between latitude and body size in a long‐distance migratory species, the prothonotary warbler (Protonotaria citrea) across life stages (egg to adult) on their breeding grounds. We also measured historic eggs (1865‐1961) to assess if the relationship between latitude and size during this life stage has changed over time. In accordance with Bergmann’s rule, we found a positive relationship between latitude and body mass during all post‐embryonic life stages, from early nestling stage through adulthood. We observed this same predicted pattern with historic eggs, but contemporary eggs exhibited the reverse (negative) relationship. We suggest that these results indicate a genetic component to this pattern and speculate that selection for larger body size in altricial nestlings as latitude increases may possibly drive the pattern in migratory species as even rare extreme cold weather events may cause mortality during early life stages. Furthermore, the opposite relationships observed in eggs, dependent on time period, may be related to the rapidly warming environments of higher latitudes that is associated with climate change. Although it is unclear what mechanism(s) would allow for this recent reversal in eggs (but still allow for its maintenance in later life stages). This evidence of a reversal suggests that anthropogenic climate change may be in the process of altering one of the longest‐standing principles in ecology.

Bergmann's rule is followed at multiple stages of postembryonic development in a long‐distance migratory songbird

ABSTRACT Coastal Louisiana—and its Mississippi River Delta, in particular—provides large and diverse habitats for many types of birds in North America and beyond. The Mississippi River and its dist...

The regional, national, and international importance of Louisiana's coastal avifauna

 Estimates of migratory connectivity are needed for full annual cycle population models of migratory bird species experiencing rapid declines in abundance. One technique to determine migratory connectivity is through stable isotope analysis. This low-resolution method may be influenced by how data are calibrated between isotopes measured in precipitation and those measured in feathers, and can be informed by incorporating relative abundance into the assignment model. eBird abundance maps are a new tool combining citizen science data into a predictive species distribution model. In the Prothonotary Warbler (Protonotaria citrea), a wetland-associated songbird with a patchy breeding distribution, we sought to use stable-hydrogen isotope analysis informed by a species-specific calibration equation and eBird abundance data to determine the strength of migratory connectivity. We developed a species-specific calibration equation using known-origin samples from the breeding grounds and found that stable-hydrogen isotope values measured in precipitation explained 50% of the variation in stable-hydrogen isotope values among feathers. We found that the assignment model incorporating eBird abundance data correctly identified the true origins of 66% of individuals, and that the average assignment area (as a measure of precision) was 64% of the breeding distribution. These results represented a 7% increase in precision and a 3% decrease in accuracy when compared to a model that was not informed by abundance. Based on these models, wintering populations from 6 countries represented a mix of likely breeding origins, suggesting low migratory connectivity for Prothonotary Warblers. We found evidence that wintering latitude was related to likely breeding origin, with individuals at western wintering locations more likely to have southern breeding origins, but this relationship was weak. These results corroborate studies using archival light-level geolocators and high-resolution genetic markers, which also demonstrated weak migratory connectivity in this species. For patchily distributed species, eBird abundance data may not provide a useful increase in precision and accuracy for isotope assignments.

Using stable isotopes to estimate migratory connectivity for a patchily distributed, wetland-associated Neotropical migrant

ABSTRACT One of the greatest challenges to informed conservation of migratory animals is elucidating spatiotemporal variation in distributions. Without such information, it is impossible to understand full-annual-cycle ecology and effectively implement conservation actions that address where and when populations are most limited. We deployed and recovered light-level geolocators (n = 34) at 6 breeding sites in North America across the breeding range of a declining long-distance migratory bird, the Prothonotary Warbler (Protonotaria citrea). We sought to determine migratory routes, stopover location and duration, and the location of overwintering grounds. We found that the species exhibits a large-scale, east—west split in migratory routes and weak migratory connectivity across its range. Specifically, almost all individuals, regardless of breeding origin, overlapped in their estimated wintering location in northern Colombia, in an area 20% the size of the breeding range. Additionally, most of the individuals across all breeding locations concentrated in well-defined stopover locations in Central America while en route to Colombia. Although error inherent in light-level geolocation cannot be fully ruled out, surprisingly much of the estimated wintering area included inland areas even though the Prothonotary Warbler is considered a specialist on coastal mangroves in winter. Based on these results, conservation efforts directed at very specific nonbreeding geographical areas will potentially have benefits across most of the breeding population. Our findings highlight the importance of using modern technologies to validate assumptions about little-studied portions of a species' annual cycle, and the need to distribute sampling across its range.

Concentration of a widespread breeding population in a few critically important nonbreeding areas: Migratory connectivity in the Prothonotary Warbler

Migratory connectivity is a measure of the strength of spatial connections between populations at different periods of the annual cycle, such as the breeding and overwintering periods of migratory birds. There is a general lack of studies focused on migratory connectivity for small songbirds of conservation concern, making conservation planning problematic. The challenge in determining migratory connectivity is in the identification of non-breeding and breeding areas for specific populations. Through the miniaturization of geolocators, it is now possible to track small songbirds of conservation concern year-round providing the data needed to determine migratory connectivity. The Canada Warbler (Cardellina canadensis) is a threatened Neotropical migrant. This species has declined by 2.3% per year from 1966 to 2012. The rate of decline is not consistent across its range; eastern population are declining more than western populations and southern populations are faring better than northern populations. The cause of overall population decline is unknown, as is the variation among the rates of decline across their range, but it is hypothesized to be linked to wintering ground factors. Most of the existing research on Canada Warblers is focused on breeding ground ecology. For the conservation of Canada Warblers to be successful, more information is required on wintering sites, as well as the potential drivers of the population decline. Our objective was to determine the migratory connectivity of the Canada Warbler to guide conservation priorities. We tracked individuals using geolocators from seven sites spatially stratified across the breeding range. Using these geolocator data, we quantified migratory connectivity of seven breeding populations by using Mantel tests, and determined whether these geographically distinct breeding populations overwinter in overlapping areas. Understanding migratory connectivity is critical, as it is invaluable tool in drafting conservation plans for at-risk species.

C-PIF-02. CONTRIBUTED PAPERS BIOLOGY OF NEARCTIC-NEOTROPICAL MIGRATORY BIRDS

Twenty years later: an update to the birds of the Biological Dynamics of Forest Fragments Project, Amazonas, Brazil

Forest recovery in post-pasture Amazonia: Testing a conceptual model of space use by insectivorous understory birds

Prothonotary Warblers (Protonotariacitrea) are Nearctic-Neotropic migrants that have experienced declining populations over the past 50 yr. Determining their migration routes and wintering areas are critical steps in identifying habitats used by species and populations of conservation concern. We captured a male Prothonotary Warbler on its breeding territory in Louisiana in June 2013 and attached a geolocator. We recaptured this male in March 2014 and analysis of the geolocator data revealed that the male traveled an estimated 7950 km through seven countries. Fall migration was characterized by movements south into Central America on 13 August 2014, then east to the Greater Antilles for about 1 mo, followed by a second movement south to Panama or Colombia on 15 November 2014 where the male remained for the rest of the winter. Spring migration occurred rapidly, with the bird leaving its southern wintering area on 4 March 2014 and returning to its breeding territory on 23 March 2014. The movements of this male Prothonotary Warbler add to accumulating evidence that many migrant birds exhibit either prolonged stopover behavior or secondary migratory movements. Factors contributing to prolonged stopover behavior or additional migratory movements of the Prothonotary Warbler in our study warrant further investigation.

Geolocator reveals migratory and winter movements of a Prothonotary Warbler

Primary tropical rain forests are being rapidly perforated with new edges via roads, logging, and pastures, and vast areas of secondary forest accumulate following abandonment of agricultural lands. To determine how insectivorous Amazonian understory birds respond to edges between primary rain forest and three age classes of secondary forest, we radio‐tracked two woodcreepers (Glyphorynchus spirurus, N = 17; Xiphorhynchus pardalotus, N = 18) and a terrestrial antthrush (Formicarius colma, N = 19). We modeled species‐specific response to distance to forest edge (a continuous variable) based on observations at varying distances from the primary‐secondary forest interface. All species avoided 8–14‐yr‐old secondary forest. Glyphorynchus spirurus and F. colma mostly remained within primary forest <100 m from the young edge. Young F. colma rarely penetrated >100 m into secondary forest 27–31 yr old. Young Formicarius colma and most G. spirurus showed a unimodal response to 8–14‐yr‐old secondary forest, with relative activity concentrated just inside primary forest. After land abandonment, G. spirurus was the first to recover to the point where there was no detectable edge response (after 11–14 yr), whereas X. pardalotus was intermediate (15–20 yr), and F. colma last (28–30 yr +). Given the relatively quick recovery by our woodcreeper species, new legislation on protection of secondary forests > 20‐yr old in Brazil's Pará state may represent a new opportunity for conservation and management; however, secondary forest must mature to at least 30 yr before the full compliment of rain forest‐dependent species can use secondary forest without adverse edge effects.

Changes in Habitat Use at Rain Forest Edges Through Succession: a Case Study of Understory Birds in the Brazilian Amazon

Heterogeneous movement of insectivorous Amazonian birds through primary and secondary forest: A case study using multistate models with radiotelemetry data

ABSTRACT Avian molt, or the regularly scheduled replacement of feathers, is an important life history event, particularly in central Amazonian rainforest birds for which a relatively high proportion of the annual cycle can be dedicated to this process. Here, we detail molt strategies of 18 antbird species (Thamnophilidae) based on 2,362 individuals captured from lowland tropical rainforest at the Biological Dynamics of Forest Fragmentation Project near Manaus, Brazil. All species exhibited a molt strategy consistent with the Complex Basic Strategy, in which birds undergo an inserted preformative molt within the first cycle, but apparently lack prealternate molts. The preformative molt and resulting formative plumage aspect of the 18 antbird species can be grouped by three distinct patterns: 1) a complete molt resulting in an adult-like formative plumage without molt limits; 2) a partial molt involving body feathers, lesser coverts, at least some or all median and greater coverts, and sometimes tertials or rectrices, resulting in an adult-like formative plumage with molt limits; and 3) a partial molt as in ‘2’ but resulting in an adult female-like formative plumage in both sexes with plumage maturation delayed in males until the second prebasic molt. In addition, we show that one species, Percnostola rufifrons, exhibited an extra inserted molt (a partial auxiliary preformative molt) in the first cycle before initiating a complete preformative molt making this, to our knowledge, the first description of an auxiliary preformative molt for a suboscine. The extent of the preformative molt or delayed plumage maturation was not predicted by ecological guild, raising questions about how phylogenetic relatedness and ecological adaptation drive variation in molt patterns across antbirds.

Thamnophilidae (antbird) molt strategies in a central Amazonian rainforest

ABSTRACT Howell et al. (2003) published an innovative augmentation to terminology proposed by Humphrey and Parkes (1959) that classified bird molt on the basis of perceived evolutionary relationships. Despite apparent universal applicability, Howell et al.'s (2003) proposed terminological changes were met with criticism that cited a failure to verify the evolutionary relationships of molt and an inability to recognize homologous molts even within closely related taxa. Eleven years after Howell et al. (2003), we revisit arguments against a terminological system of molt based on evolutionary relationships, suggest an analytical framework to satisfactorily respond to critics, clarify terminology, and consider how to study molt variation within an evolutionary framework.

Searching for consensus in molt terminology 11 years after Howell et al.'s “first basic problem”

ABSTRACT. 
 Amazonia now contains vast areas of secondary forest because of widespread regeneration following timber harvests, yet the value of secondary forest to wildlife remains poorly understood. Secondary forest becomes structurally similar to primary forest after abandonment, and therefore we predicted that avian movement across the interface of primary and secondary forest (hereafter “the interface”) would gradually increase with time since abandonment until recovery to pre-isolation levels. From 1992 to 2011, we captured 2,773 understory birds of 10 foraging guilds along the interface of primary forest fragments and zero- to 30-year-old secondary forest at the Biological Dynamics of Forest Fragments Project near Manaus, Brazil. Our objectives were to understand the differences in land-use history that affect cross-interface movement and to determine how long it takes each guild to recover to pre-isolation capture rates. Across guilds, age of secondary forest within 100 m of the interface was the most important explanatory variable affecting capture rates; rates increased with age of secondary forest for all guilds except non-forest species. Mean recovery to pre-isolation was 26 years (asymmetric SE = 13 years below and 16 years above estimate) after secondary forest abandonment and 9 of 10 guilds recovered within 13 to 34 years. In the slowest guild to recover, terrestrial insectivores, 6 of 12 species were never caught along the interface, and we projected that this guild would recover in ∼60 years. Our recovery estimates quantify the dynamic permeability of the interface and contribute to a better understanding of the value of secondary forests as corridors among primary forest fragments.

Recovery of Understory Bird Movement Across the Interface of Primary and Secondary Amazon Rainforest

Amazonian forest bird communities are among the richest in the world. Even so, relatively little is known about the organization of the entire avian community at local scales or about differences across Amazonia. These are fundamental data not only for understanding the processes generating and maintaining tropical diversity, but also as a baseline for evaluating anthropogenic changes to Amazonian forests. Here we provide a description of the entire bird community for a 100 ha plot of terra firme forest at the Biological Dynamics of Forest Fragments Project, near Manaus, Brazil, based on spot‐map and mist net surveys augmented by additional field and analytical techniques. Although our results are from a single plot surveyed in a single year, our methods and interpretation reflect nearly 30 years of ornithological research at the site. We found 228 species on the plot, of which 207 were considered part of the core regional avifauna. Median density was five individuals/100 ha. Only 13 species (6% of the core species) had densities ≥ 20 individuals on the plot, although 55 species (27%) had ≤ 2 individuals. No species had territories smaller than 3 ha; median territory size was 11 ha for the 103 species for which we could make reasonable estimates. Measured by numbers of species or individuals, the plot was dominated by insectivores (54% of species, 62% of individuals). Biomass, however, was dominated by frugivores and granivores (59%). Compared to available data from other Amazonian forests, our site appears to have comparable richness of a similar set of species, but lower density and greater patchiness. Our results suggest that the area required to support populations of many species will be even greater in central Amazonia than in western Amazonia. KEy-WoRDS: Amazonia, bird communities, biomass, species richness, rainforest. Our understanding of Amazonian birds has increased extraordinarily in recent decades. Distributions, includ‐ ing dramatic rediscoveries and range extensions, are con‐ stantly being refined (e.g., Cohn‐Haft 1993, Aleixo et al. 2000, Lane et al. 2006, Naka et al. 2007). Research focus on habitat specialization has revealed distinct avifaunas associated with savannas, flooded forest, and sandy soil forests (Borges and Carvalhaes 2000, Alonso and Whit‐ ney 2003, Aleixo and Poleto 2007, Cintra et al. 2007). Phylogeographic studies show the evolutionary relation‐ ships of Amazonian birds to their relatives in Atlantic Forest and across the Andes, as well as the role of rivers ARtIGo Revista Brasileira de Ornitologia, 19(1):1-16 Marco de 2011

Revista Brasileira de Ornitologia - Brazilian Journal of Ornithology

Diversity, biomass, and trophic structure of a central amazonian rainforest bird community

Abstract Urban habitat fragments may provide birds the resources necessary to sustain viable populations in close proximity to human settlement. Conversely, urban habitat fragments may also act as ecological traps, where birds are lured into habitats that negatively affect reproduction or survival. In this study, we compared annual survival estimates of six common resident bird species captured at Bluebonnet Swamp, a 41.7-ha forest fragment bordered by the urban matrix of Baton Rouge, LA, with values derived from the Institute for Bird Populations' MAPS program to determine if populations sampled in the habitat fragment demographically deviated from regional baseline estimates. We found that three species captured at Bluebonnet Swamp exhibited survival estimates consistent with regional averages, whereas Cardinalis cardinalis (Northern Cardinal), Toxostoma rufum (Brown Thrasher), and Poecile carolinensis (Carolina Chickadee) survival estimates were lower than baseline. Edge effects associated with a relatively small preserve coupled with disease and semiannual movements in and out of the study area may be influencing Cardinal and Thrasher survival. We recommend that other studies focus on measuring avian demographics within habitat fragments to identify and mitigate factors that limit population sustainability in human-modified landscapes, as relative density alone may not be an appropriate metric for understanding the value of habitat fragments to birds.

Annual Survival of Birds Captured in a Habitat Island Bordered by the Urban Matrix of Baton Rouge, LA

ABSTRACT. 
 Although it has long been recognized that many tropical birds do not share the same narrow breeding periods as temperate birds, conventional thinking considers tropical breeding seasons to be discrete periods generally governed by rainfall seasonality. We used a database of >31,000 captures of 104 species collected over 17 years in rainforest near Manaus, Brazil (2.5'S), to examine timing of breeding. The proportion of individuals with active incubation patches peaked at 7% in the dry season, from October through December. The peak was about twice as high as the lowest rate, in the late wet season (April—June). From 9 to 15 families and >20 species bred in every month. Many taxa did not conform to the general pattern, instead peaking in the wet season (e.g., Galbulidae, Sclerurinae, Grallariidae, and Formicariidae). Most well-sampled species, even those with strong seasonal peaks, bred at almost any time of year, a pattern also shown by some individual birds that were captured multiple times in breeding condition. Among the 10 species with >50 incubation patches, all bred in at least 9 months, and 7 bred in 11–12 months. Earlier results from the same data set showed extremely protracted molts that regularly overlapped breeding. Collectively, molt and breeding data suggest that the annual cycle of some equatorial birds, particularly suboscines, differs fundamentally from that of temperate species, with much less fixed timing of breeding.

The energetically challenging periods of molting and breeding are usually temporally separated in temperate birds, but can occur simultaneously in tropical birds, a condition known as molt–breeding overlap. Here, we document great variation in the timing and duration of molting and breeding, and in the extent of molt–breeding overlap, among 87 species of understory passerines in central Amazonia. We analyzed molt and breeding from 26 871 birds captured over a 30-yr period near Manaus, Brazil. Although most species typically bred during the late dry season (about October through January), many thamnophilids apparently bred year-round, whereas a few other species from a variety of families bred mainly during the wet season (about January through May). Of all breeding birds with an active brood patch, 12.7% were simultaneously molting. Molt–breeding overlap was more frequently observed among suboscines (13.3%), especially thamnophilids (23.0%), than oscines (6.4%). Some families had <5% molt–breeding overlap frequency, including Tyrannidae (4.4%), Tityridae (0.0%), Pipridae (1.5%), Turdidae (0.0%), and Thraupidae (0.0%), indicating that not all tropical species exhibit molt–breeding overlap. Among 31 well-sampled species (n ≥15 brood patches), variation in molt–breeding overlap frequency was positively correlated with each species’ average duration of flight feather replacement (range 98–301 d). We also measured feather growth rates of individual birds in nine species; in five of these, slower-growing feathers increased with an individual's probability of having molt–breeding overlap. Among furnariids, molt–breeding overlap occurred either at the beginning or end of the molt cycle, suggesting that physiological mechanisms typically separate molting from breeding. Thamnophilids showed a much different pattern; molt–breeding overlap occurred at any stage of feather replacement, apparently not regulated to be independent of breeding. These results reveal substantial life-history variation among Amazonian birds. Future work to resolve the physiological regulation of molting and breeding in tropical birds will greatly contribute to understanding these patterns and their relevance to avian diversity.

The phenology of molting, breeding and their overlap in central Amazonian birds

s of TCBES Symposium 39 Pac. Agric. Nat. Resour. Vol. 2: 37-42, 2010 variation in allele frequencies would be observed among populations of pubescent trees along the elevation gradient than among populations of glabrous trees. Preliminary analyses reveal little genetic structuring and high gene flow among populations. Further analysis is underway including tests of isolation by distance, allele frequency differences of glabrous and pubescent populations, and an analysis of rare alleles found within populations. Results will yield insight into the early stages of reproductive isolation between populations and the roles of environmental pressures and geographic isolation on diversification within woody species. Brett Rodomsky Quantification of Lava Texture as Evidence for Substrate Control Over Plant Colonization Patterns The dynamic island of Hawai’i is an exceptional system for study of ecological succession. Here, volcanoes frequently extrude basaltic lava flows of ‘a’a, pahoehoe and intergraded lava textures, differing in surface area and morphology. Nearly a century of observations, hypotheses, and data indicate pioneering plants differentially colonize contemporaneous lavas depending on texture morphology. Variation in lava texture represents diversity of habitat available to pioneering plants. Conclusions about plant colonization patterns on different textures remain confounded by existing interactions with climate variables including moisture and temperature across hypsometric surface area. For this study on the 1855-56 Mauna Loa flow, I hypothesize that lava texture measured at local (100 m2) and micro(1 m2) spatial scales interacts with climate variables analogoustotopographyandclimateinteractingatlandscap espatialscales. A topographic roughness metric will be applied to vegetation plot data collected at local and micro-spatial scales across lava roughness gradients. Hypsometric point-intercept data will be converted into Digital Elevation Models with GIS software. This methodology produces a quantified unit-less measure of ‘a’a and pahoehoe lava texture based on hypsometric surface area. Lava roughness will then be used as a predictor variable for plant colonization patterns. Variables such as slope, aspect, and flow accumulation will be derived from DEMs and included in the lava texture model. Ultimately, this study is an attempt to create a quantified model of lava texture correlated to associated vegetation data, in an attempt at increasing understanding of substrate texture control over pioneering plant colonization patterns on Hawai’i. Christopher Todd Prey Abundance and Seasonal Movements of the Hawaiian Hoary Bat (Lasiurua cinereus semotus) The Hawaiian Hoary bat (Lasiurus cinereus semotus) is the only terrestrial mammal native to the Hawaiian Islands and currently is listed as an endangered species due to apparent population declines, lack of knowledge concerning it distribution, and habitat loss. Echolocation surveys indicated that Hawaiian hoary bats display striking seasonal movements along the steep gradient of elevation across eastern Hawai`i Island. Changes in temperature and rainfall are a likely cause for these migrations. However, the extent to which peaks in food correspond with the bat’s migration has received little study. Here we present preliminary data on insect phenology and abundance across an annual cycle at five sites along a gradient of elevation. We link these insect data to echolocation surveys to gain insights on how availability of prey corresponds with seasonal migratory movements. We hypothesize that insect abundance will show a positive correlation with bat vocalization activity. Data collected from early April to August 2009 at two low elevation sites shows that as overall insect abundance increase there is an increase in bat activity. Data collected at a mid elevation site shows that in early April there is a spike in insect activity, primarily Lepidoptera, while bat occurrence is still relatively low. The following survey in June shows an increase in bat occurrence and supports a hypothesis previously predicted by T. Menard that bats migrate from high interior elevations to coastal lowlands to reproduce in summer months. Erik Johnson & Ambyr Mokiao-Lee (Poster) Tracing Sewage-Derived Nutrients into a Coastal Zone in Kapoho, Hawai’i Worldwide, sewage effluent is a major source of nutrients to coastal waters causing eutrophication. According to the U.S. Environmental Protection Agency, cesspools are more widely used as a means of domestic sewage disposal in Hawaii than any other state in the country, with 77% of Hawaii County’s population being serviced by cesspools. One region on the southeast coast of Hawaii County where there has been concern about sewage pollution since the 1970’sisKapoho. The community of Kapoho is designated a critical wastewater disposal area and also contains a Marine Life Conservation District within its boundaries. Previous work by Hawaii Department of Health documented that flow of cesspool wastewaters into Kapoho Bay was rapid, ~20minutes. It is suspected that sewage-enriched groundwater is entering the coastal zone and possibly contributing to human health hazards and ecological damage. The goal of the following study is to determine the source of nutrients into the area and the potential effect on the organisms and habitat. This was accomplished by determining the sources of groundwater inputs and to date the transport of groundwater to Kapoho tidepools have been mapped and seepage areas have been identified. Additionally, preliminary water quality samples have been collected from the region. Future work will entail determining the source of nitrogen into these coastal waters and its utilization by primary 40 Abstracts of TCBES Symposium Pac. Agric. Nat. Resour. Vol. 2: 37-42, 2010 producers examining stable nitrogen, oxygen, and boron stable isotopes signature in sewage, groundwater, oceanwater, and macroalgae. Information generated from this study will aid managers in creating a water quality database and thresholds for nutrients entering marine environments. Narrissa Spies (Poster) Quantification of Calcium Binding Proteins from Skeletal Growth Anomalies in Montipora capitata Skeletal growth anomalies (SGA) are protrusions on the coral skeleton that have been documented in oceans worldwide. There is an unusually high incidence of SGA at the Wai’opae MLCD on Hawaii island. Very little is known about the calcification process in healthy coral skeletons, and even less is known about how SGA coral calcifies. Galaxin is a calcium-binding protein found in corals that is involved in skeletogenesis and calcification. Calcyclin is a calciumbinding protein that is involved in several cellular processes and has been shown to be upregulated during tumor growth and formation. We will collect samples from healthy and SGA Montipora capitata and use real-time PCR to look for expression of calcyclin and galaxin. This will tell us if expression of these proteins is up-regulated in SGA coral. Melissa Netze (Poster) Maternal Investment of Hawaiian Monk Seal [Monachus schauinslandi] Inhabiting the Main Hawaiian Islands Hawaiian monk seals (Monachus schauinslandi) are currently classified as critically endangered, with fewer than 1100 individuals remaining. Though managed as a single stock, there are six recognized subpopulations of Hawaiian monk seals located in the Northwest Hawaiian Islands (NWHI), and one spread throughout the main Hawaiian Island chain (MHI). The population of Hawaiian monk seals located in the NWHI is declining at an annual rate of approximately4.5%. In contrast, the MHI subpopulation is increasing, with a conservative estimated growth rate of about 5.6%. In recent years, the growing population size, positive body condition, and increased juvenile survival rate of Hawaiian monk seals inhabiting the MHI has prompted scientists to take a closer look at this subpopulation. The objective of this study is to investigate the maternal investment of Hawaiian monk seals inhabiting the MHI using four seasons of nursing behavioral data. Previous studies how the recovery of a threatened or endangered species is strongly linked to offspring survival, which is often positively correlated with maternal investment. Here, nursing bout frequency and duration are compared by week to investigate trends and patterns in nursing behaviors of MHI seals. This study also examines what habitat is most utilized for nursing, and the frequency of which the nursing bout is terminated by the mother. This study is the first of its kind, and provides managers a clear look at the nursing behaviors of Hawaiian monk seals in the MHI, vital information for future conservation efforts of the species. David Benitez A Biogeographical Comparison of Invasive Forest Weeds in Hawai’i Plant invasions are economically and ecologically costly. Research suggests a species may differ physiologically and ecologically between invasive and native ranges and these differences may enhance invasiveness. I examined biogeographical growth and defense differences of three aggressive invaders in Hawaiian forests: the tree strawberry guava (Psidium cattleianum), the shrub Koster’s curse (Clidemia hirta) and the herb cane tibouchina (Tibouchina herbacea). In quarantine in Volcano, Hawai‘i, I tested the Evolution of Increased Competitive Abilities (EICA) hypothesis postulating individuals from invasive (Hawaiian) populations, and are faster growing than individuals from native (South American) populations also less defended chemically and structurally. Seeds of focal taxa were collected in native ranges (Brazil and Venezuela) and introduced ranges (Hawai‘i) and grown in a common garden for 120-180 days. Plant height, mass and relative growth rates were quantified for 30 paired populations. Key structural traits leaf hair density and specific leaf area were quantified and feeding trials with s

Inferences about species loss following habitat conversion are typically drawn from short-term surveys, which cannot reconstruct long-term temporal dynamics of extinction and colonization. A long-term view can be critical, however, to determine the stability of communities within fragments. Likewise, landscape dynamics must be considered, as second growth structure and overall forest cover contribute to processes in fragments. Here we examine bird communities in 11 Amazonian rainforest fragments of 1–100 ha, beginning before the fragments were isolated in the 1980s, and continuing through 2007. Using a method that accounts for imperfect detection, we estimated extinction and colonization based on standardized mist-net surveys within discreet time intervals (1–2 preisolation samples and 4–5 post-isolation samples). Between preisolation and 2007, all fragments lost species in an area-dependent fashion, with loss of as few as <10% of preisolation species from 100-ha fragments, but up to 70% in 1-ha fragments. Analysis of individual time intervals revealed that the 2007 result was not due to gradual species loss beginning at isolation; both extinction and colonization occurred in every time interval. In the last two samples, 2000 and 2007, extinction and colonization were approximately balanced. Further, 97 of 101 species netted before isolation were detected in at least one fragment in 2007. Although a small subset of species is extremely vulnerable to fragmentation, and predictably goes extinct in fragments, developing second growth in the matrix around fragments encourages recolonization in our landscapes. Species richness in these fragments now reflects local turnover, not long-term attrition of species. We expect that similar processes could be operating in other fragmented systems that show unexpectedly low extinction.

Understory Bird Communities in Amazonian Rainforest Fragments: Species Turnover through 25 Years Post-Isolation in Recovering Landscapes

Wolfe et al. (2010. Journal of Field Ornithology 81: 186–194) proposed a coding system for ageing birds based on the sequence of molts and plumages, which is more practical than a calendar-based system, especially in tropical and southern latitudes where species often breed across 1 January. The Wolfe–Ryder–Pyle (hereafter, W–R–P) three-letter system is based on recognition of molt cycle (first, second, third, definitive, and so on) and plumage phase (juvenile, supplemental, formative, alternate, and basic). For example, a bird in First Cycle Formative plumage is coded as FCF. We propose the use of two additional code options that further refine age brackets. First, we suggest the use of an “after” or “A” code in place of the “C,” or cycle code, where an earlier molt cycle or plumage can be ruled out. For example, a bird that exhibits Staffelmauser might be aged as after-third cycle basic, or TAB. Second, we suggest using “pre” or “P” in place of the “C,” or cycle code, when birds are actively molting, such as for birds undergoing the second prebasic molt or SPB. For both codes, we discuss their applicability using examples based on actual banding data. Our proposed codes will improve the utility of the W–R–P system by better refining age brackets and by expanding its applicability to a diverse array of taxa. 
 
RESUMEN 
 
Wolfe et al. (2010. Journal of Field Ornithology 81: 186–194) propuso un sistema de codificacion para clasificar la edad de las aves, basada en la secuencia de mudas y plumajes, que es mas practico que un sistema basado en el calendario, especialmente en latitudes tropicales y sur templadas donde las especies a menudo se reproducen alrededor del 1 de enero. El sistema de tres letras Wolfe–Ryder–Pyle (en adelante, W–R–P) se basa en el reconocimiento del ciclo de muda (primero, segundo, tercero, definitivo, y asi sucesivamente) y la fase de plumaje (juvenil, suplemental, formativa, alternativa y basica). Por ejemplo, un pajaro en el Primer Ciclo Formativo de plumaje se codifica como PCF. Aqui proponemos el uso de dos tipos de codigos adicionales que afinan mas la clasificacion de la edad. En primer lugar, sugerimos el uso de un “despues” o codigo “D” en lugar de la “C,” o codigo de ciclo, cuando un ciclo de muda o plumaje anterior puede ser descartado. Por ejemplo, un pajaro que exhibe Staffelmauser podria ser codificado como despues del tercero ciclo basico, o TDB. Segundamente, recomendamos el uso de “pre” o “P” en lugar de la “C,” o codigo del ciclo, cuando las aves estan activamente mudando, como para las aves en la segunda muda pre-basica o SPB. Para ambos codigos, se discute su aplicacion con ejemplos basados en datos de anillamiento reales. Nuestros codigos propuestos mejoraran la utilidad del sistema W–R–P mediante una refinacion de la clasificacion de la edad y ampliando su aplicabilidad a una variedad de taxones.

Modifications to a molt‐based ageing system proposed by Wolfe et al. (2010)

Seed dispersal is a crucial component of plant population dynamics. Human landscape modifications, such as habitat destruction and fragmentation, can alter the abundance of fruiting plants and animal dispersers, foraging rates, vector movement, and the composition of the disperser community, all of which can singly or in concert affect seed dispersal. Here, we quantify and tease apart the effects of landscape configuration, namely, fragmentation of primary forest and the composition of the surrounding forest matrix, on individual components of seed dispersal of Heliconia acuminata, an Amazonian understory herb. First we identified the effects of landscape configuration on the abundance of fruiting plants and six bird disperser species. Although highly variable in space and time, densities of fruiting plants were similar in continuous forest and fragments. However, the two largest-bodied avian dispersers were less common or absent in small fragments. Second, we determined whether fragmentation affected foraging rates. Fruit removal rates were similar and very high across the landscape, suggesting that Heliconia fruits are a key resource for small frugivores in this landscape. Third, we used radiotelemetry and statistical models to quantify how landscape configuration influences vector movement patterns. Bird dispersers flew farther and faster, and perched longer in primary relative to secondary forests. One species also altered its movement direction in response to habitat boundaries between primary and secondary forests. Finally, we parameterized a simulation model linking data on fruit density and disperser abundance and behavior with empirical estimates of seed retention times to generate seed dispersal patterns in two hypothetical landscapes. Despite clear changes in bird movement in response to landscape configuration, our simulations demonstrate that these differences had negligible effects on dispersal distances. However, small fragments had reduced densities of Turdus albicollis, the largest-bodied disperser and the only one to both regurgitate and defecate seeds. This change in Turdus abundance acted together with lower numbers of fruiting plants in small fragments to decrease the probability of long-distance dispersal events from small patches. These findings emphasize the importance of foraging style for seed dispersal and highlight the primacy of habitat size relative to spatial configuration in preserving biotic interactions.

Disentangling the drivers of reduced long-distance seed dispersal by birds in an experimentally fragmented landscape.

ABSTRACT. 
 Interpreting habitat quality requires an understanding of the consequences of habitat use because bird density alone may not reflect habitat quality. Although habitat use can be readily quantified, subsequent effects remain elusive for most species, especially for migrants on the wintering grounds. Wintering Henslow's Sparrow (Ammodramus henslowii) densities in Longleaf Pine (Pinus palustris) savannas are fire-dependent, with highest bird densities in the first winter after a fire, but reduced density in subsequent winters without fire. We determined habitat characteristics associated with variation in bird density in the first and second winters following fire and then followed birds' diet, condition, and survival in 10 plots over two winters. Habitat structure and seed energy availability, but not plant species composition, were equally important for explaining bird density, except for two outlier plots with extremely high seed production and fewer birds than expected. Henslow's Sparrows consumed a variety of seeds and arthropods, which indicates that they are generalists capable of responding to fire-mediated changes in seed composition. Body condition decreased in midwinter, associated with a decrease of arthropods in the birds' diet. Although Henslow's Sparrow densities responded strongly to ephemeral savanna conditions, consequences of habitat use were negligible because survival and three measures of body condition did not vary with years since fire or among age and sex classes. These aspects of the winter ecology of sexually monochromatic Henslow's Sparrows are consistent with tenets of the ideal free distribution, whereby differences in bird density between habitats result in equal fitness.

Habitat use does not Reflect Habitat Quality for Henslow's Sparrows (Ammodramus henslowii) Wintering in Fire-Managed Longleaf Pine Savannas

No evidence for widespread bird declines in protected South American forests

Fragmentation sensitivity and its consequences on demography and host-ectoparasite dynamics in amazonian birds

—Boat-billed Tody-Tyrant Hemitriccus josephinae occurs in north-east South America, but there are large gaps in its distribution and we know little of its natural history. We discovered a small population of H. josephinae at the Biological Dynamics of Forest Fragmentation Project (BDFFP), 80 km north of Manaus, Brazil, a range extension of 60 km. In 2007–09, we located five territories at the BDFFP. The species foraged in disturbed areas within mature forest by hopping sideways along small horizontal branches in the subcanopy and by upward-strikes or aerially hawking for insects. We described four vocalisations, two of which have not been previously described. Home range size is between 4.6 ha (minimum convex polygon method) and 5.7 ha (95% kernel density estimate). We provide one of the first ecological descriptions of an Amazonian Hemitriccus and comparisons against closely related species should be conducted to understand the complicated phylogenetic relationships of this group.

A Range Extension and Ecology of Boat billed Tody tyrant Hemitriccus Josephinae in Central Amazonian Brazil

Abstract. Fall arrival is an important period in the life history of migratory birds because processes during this period determine where birds spend the winter, which is linked to subsequent survival and condition at the time of spring migration. Henslow's Sparrows (Ammodramus henslowii) winter in savannas of longleaf pine (Pinus palustris), but their secretive behavior limits our knowledge of their winter ecology, including behavioral processes that lead to their documented preference of an ephemeral habitat—recently burned savannas. We expected that upon arrival Henslow's Sparrows actively seek out recently burned savannas and that their over-winter location is dependent on intraspecific interactions during the arrival period. We conducted a 2-year mark—recapture study in southeastern Louisiana longleaf pine savannas to examine these predictions. Bird densities were highest in savannas burned during the previous growing season. There was a large turnover of transient individuals in October and early November, but the proportion of dispersing birds was not related to the number of years since fire or to the bird's age or sex. Early-season movements did not result in skewed age or sex distributions associated with years since fire, suggesting the lack of a class-mediated competitive hierarchy. Birds were then site faithful from late November through spring departure, which began in March and lasted through mid April, with males departing first.

Timing of Migration and Patterns of Winter Settlement by Henslow's Sparrows

Abstract Abstract. The Henslow's Sparrow (Ammodramus henslowii), a species of conservation concern, winters primarily in longleaf pine (Pinus palustris) forest ecosystems in the southeastern U.S. These pine savannas have been reduced to 5% of their former range, with remaining patches requiring active management with fire to maintain characteristic structure and plant diversity. Wintering Henslow's Sparrow abundance tracks growing-season fires; bird abundance peaks in the winter following burning, then declines in subsequent winters. Fire also determines dominant plant species, suggesting that Henslow's Sparrows may respond to abundance of preferred seeds. To determine diet preferences of Henslow's Sparrows, we tested seeds from eight species of native plants from southeastern Louisiana pine savannas, including species common in the first winter after burning (‘fire grasses’) and species that increase in abundance in the second and subsequent winters after burning. Seed consumption by individual birds differed considerably, suggesting that Henslow's Sparrows forage on a variety of resources in the highly diverse savannas. Henslow's Sparrows preferred fire grasses, especially Muhlenbergia expansa (cutover muhly). They also preferred Dichanthelium angustifolium (needleleaf rosette grass), a species more common in the second year after burning, but consumed relatively little of the sedges Rhynchospora plumosa (plumed beaksedge) and R. gracilenta (slender beaksedge), species common in the second winter after fire. Birds consumed almost none of the ubiquitous grass Schizachyrium scoparium (little bluestem). These results suggest that preferred seeds may include those that are most common in the first winter after burning, but that some suitable seeds are available for at least another winter.

Seed Preferences of Wintering Henslow's SparrowsPreferencias De Consumo De Semillas Por Parte De Ammodramus Henslowii Durante El InviernoHenslow's Sparrow Seed Choice

Effects of fire on habitat associations, abundance, and survival of wintering Henslow's Sparrows (Ammodramus henslowii) in southeastern Louisiana longleaf pine savannas

Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer’s disease mutations but not by inhibition of BACE1

A small molecule named ISRIB has recently been described to enhance memory in rodents. In this study we aimed to test whether ISRIB would reverse learning and memory deficits in the J20 mouse model of human amyloid precursor protein (hAPP) overexpression, a model that simulates many aspects of Alzheimer’s disease in which memory deficits are a hallmark feature. We did not observe a significant rescue effect with ISRIB treatment on spatial learning and memory as assessed in the Morris water maze in J20 mice. We also did not observe a significant enhancement of spatial learning or memory in nontransgenic mice with ISRIB treatment, although a trend emerged for memory enhancement in one cohort of mice. Future preclinical studies with ISRIB would benefit from additional robust markers of target engagement in the brain.

A small molecule targeting protein translation does not rescue spatial learning and memory deficits in the hAPP-J20 mouse model of Alzheimer’s disease

Diverse lines of evidence suggest that amyloid-β (Aβ) peptides causally contribute to the pathogenesis of Alzheimer disease (AD), the most frequent neurodegenerative disorder. However, the mechanisms by which Aβ impairs neuronal functions remain to be fully elucidated. Previous studies showed that soluble Aβ oligomers interfere with synaptic functions by depleting NMDA-type glutamate receptors (NMDARs) from the neuronal surface and that overexpression of the receptor tyrosine kinase EphB2 can counteract this process. Through pharmacological treatments and biochemical analyses of primary neuronal cultures expressing wild-type or mutant forms of EphB2, we demonstrate that this protective effect of EphB2 depends on its PDZ-binding motif and the presence of neuronal activity but not on its kinase activity. We further present evidence that the protective effect of EphB2 may be mediated by the AMPA-type glutamate receptor subunit GluA2, which can become associated with the PDZ-binding motif of EphB2 through PDZ domain-containing proteins and can promote the retention of NMDARs in the membrane. In addition, we show that the Aβ-induced depletion of surface NMDARs does not depend on several factors that have been implicated in the pathogenesis of Aβ-induced neuronal dysfunction, including aberrant neuronal activity, tau, prion protein (PrPC), and EphB2 itself. Thus, although EphB2 does not appear to be directly involved in the Aβ-induced depletion of NMDARs, increasing its expression may counteract this pathogenic process through a neuronal activity- and PDZ-dependent regulation of AMPA-type glutamate receptors.

Increasing the Receptor Tyrosine Kinase EphB2 Prevents Amyloid-β-induced Depletion of Cell Surface Glutamate Receptors by a Mechanism That Requires the PDZ-binding Motif of EphB2 and Neuronal Activity*

Aging is the principal demographic risk factor for Alzheimer disease (AD), the most common neurodegenerative disorder. Klotho is a key modulator of the aging process and, when overexpressed, extends mammalian lifespan, increases synaptic plasticity, and enhances cognition. Whether klotho can counteract deficits related to neurodegenerative diseases, such as AD, is unknown. Here we show that elevating klotho expression decreases premature mortality and network dysfunction in human amyloid precursor protein (hAPP) transgenic mice, which simulate key aspects of AD. Increasing klotho levels prevented depletion of NMDA receptor (NMDAR) subunits in the hippocampus and enhanced spatial learning and memory in hAPP mice. Klotho elevation in hAPP mice increased the abundance of the GluN2B subunit of NMDAR in postsynaptic densities and NMDAR-dependent long-term potentiation, which is critical for learning and memory. Thus, increasing wild-type klotho levels or activities improves synaptic and cognitive functions, and may be of therapeutic benefit in AD and other cognitive disorders.

Life Extension Factor Klotho Prevents Mortality and Enhances Cognition in hAPP Transgenic Mice

Pharmacological characterization of recombinant human neuronal nicotinic acetylcholine receptors ha2

Isolation and Characterization of a CHO Cell Line Expressing rhFSH in Low Protein and Protein-Free Media

Email of the presenting author: rosner@uni-muenster.de Al-Pb composites consisting of nanometer-sized Pb inclusions embedded in a polycrystalline Al matrix serve as model systems for size-dependent melting studies [1]. To analyze the impact of the surrounding matrix on the melting and solidification temperatures of the Pb nanoparticles, Ga was added to the matrix within the solute solution regime. The alloying of Ga expands the lattice of the Al matrix and thus reduces the mismatch between matrix and particle. Although Ga is immiscible with Pb, the melting and solidification of the Pb nanoparticles was affected by the Ga addition. A large undercooling of the solidification onset of up to 100K with respect to melting was found with increasing Ga content [2]. Chemical analyses (EDX) were performed using a double-corrected, monochromated Titan 60-300 with ChemiSTEMTM technology. The results of this investigation are shown in the Figures. The Pb nanoparticles were oriented along the <110>-direction of the fcc matrix and imaged by HAADF-STEM (Fig. 1). The chemical analysis shows that Ga segregates at the particle-matrix hetero-interface (Fig. 2). The Ga concentration has been traced in the form of a profile across the Pb nano-particle (see boxed area in Fig. 2). It shows peaks in the Ga signal at the interfaces to about 7.4 at.% (Fig. 3). The level across the Pb nanoparticle is about 1.2 at.% higher on average than the surrounding matrix concentration of 4.7 at.% due to the other Ga enriched interfaces which are projected in plan view. The width of the Ga enriched zone around the Pb nanoparticle is about 2.2 nm. This Ga enriched zone acts as a buffer between the nanoparticle and the nominal Al94Ga6-matrix inhibiting the nucleation of the liquid Pb. It has been shown that vacancies play a key role in accommodating the misfit strain upon solidification of nanoparticles embedded in Al [1,3]. Presumably the increased number of vacancies available around the Pb nanoparticles relative to the matrix lead to an accelerated Ga diffusion in this region and thus to the observed Ga segregation. The Ga segregation, in turn, leads to solid solution hardening of the buffer phase, which then becomes more rigid with the Ga increase. This hinders an elastic accommodation of the mismatch strain from the matrix side. The scenario of a suppressed nucleation upon cooling is hence explicable since the liquid Pb nanoparticles contract upon solidification and thus bring a negative pressure on the Pb particles. Thus the undercooling of the Pb nanoparticles can be explained by thermodynamics according to Clausius-Clapeyron. [1] E. Johnson, H.H. Andersen, U. Dahmen, Microsc. Res. Techniq. 64 (2004), p. 356. [2] A. Moros et al. to be published. [3] L.H. Zhang, E. Johnson, U. Dahmen, Acta Mater. 53 (2005) p.3635.

MS-9-O-1620 Chemical analyses of Ga segregation at Pb nanoparticles using ChemiSTEM Technology

Diffusion of nanosized liquid Pb inclusions attached to dislocations in thin aluminum foils was investigated in a wide temperature range using in-situ transmission electron microscopy. Trajectories of motion of the inclusions along the dislocations were used to determine their diffusion coefficients. The temperature and size dependences of diffusion coefficients of the inclusions were obtained. They indicate that (i) studied inclusions hold {111} facets on their surface in the studied temperature range; (ii) the mobility of the inclusions is controlled by step nucleation at the {111} facets.

Effect of Morphology on the Mobility of Nanosized Liquid Pb Inclusions in Solid Al

In situ electron microscopy study of the thermal motion of liquid lead nanoparticles in thin aluminum foils

Lead inclusions in aluminium. A model system for nanoscale properties

Brownian motion of liquid lead inclusions along dislocations in aluminum

Electron microscopy observations on special boundaries and their junctions

Investigation of Strain Accommodation upon Phase Transformation of Small Inclusions in Aluminum

Development of glue type potentials for the Al-Pb system: computer simulation of Pb/Al interfaces and phase diagram calculation

High-quality crystalline Si0.75Ge0.25 alloy crystals were implanted with 70 keV Er+ ions at 550 °C to a fluence of 1019 m−2. In situ Rutherford backscattering/channeling spectrometry with a 500 keV He2+ beam revealed Er atoms located on regular lattice sites of the host matrix. Angular scans taken around the 〈100〉, 〈110〉, and 〈111〉 crystallographic axes showed that a considerable fraction of Er atoms occupy tetrahedral interstitial sites.

Lattice location of erbium in high-fluence implanted silicon-germanium: Backscattering/channeling study

The equilibrium shape of liquid inclusions in a crystalline matrix is a direct measure of the orientation dependence, or anisotropy, of the liquid/solid interfacial energy. In this work we have used diffraction contrast imaging in TEM to observe the shape of nanoscale liquid Pb inclusions in a solid Al matrix as a function of temperature. While a previous investigation reported a highly anisotropy equilibrium shape [1], more recent work showed that the inclusion shape depends on size, temperature and thermal history [2-4]. Here we report on a new method to make accurate automated measurements of these particle shapes during in-situ heating above the melting point of the inclusions. Fig.l shows a typical bright field image of an array of liquid Pb inclusions in a solid Al matrix recorded at temperature during in-situ heating to 423°C. Under these two-beam diffraction conditions, particles are visible by absorption contrast and appear dark on a light background.

7-Parameter Automated Measurement of the Shapes of Nanoscale Inclusion by TEM

Transmission electron microscopy plays a key role in the investigation of precipitates and inclusions because it provides direct information at high spatial resolution, on their shape, orientation relationship, interface structure and composition. This work has utilized high resolution and in-situ electron microscopy to study the equilibrium shapes and thermal behavior of Pb precipitates in Al. It was found that PB precipitates within Al grains form in parallel-cube orientation relationship, are cuboctahedral in shape, adopt a sequence of magic sizes, and display an increase in aspect ratio with decreasing size. These observations have been explained in terms of interfacial energy and residual strain energy. When the same Pb precipitates form on grain boundaries, their shapes are significantly different. This is apparent from figure 1 which shows a 90° <110> tilt grain boundary in Al with a small cuboctahedral Pb precipitate in the upper grain and a large complex-shaped Pb particle on the grain boundary.

Tem Investigation Of Precipitate Shapes And New Interface Phenomena In Al-Pb Alloys

Much work has been devoted to TEM studies of nanoscale precipitates consisting of non-soluble elements in Al, as the Al matrix acts as a unique crucible enabling the study of melting/ solidification and crystal phase transformations at a nanometer scale. Recently, this work has been extended to include the ternary system of Al-Pb-Cd. This system is of particular interest, as both Pb and Cd display a large liquid miscibility gap with Al, but together they form a eutectic system. Bimetallic inclusions consist of an fcc Pb and an hcp Cd segment, joined along an internal interface parallel to the {111}Al planes. In this work, the microstructure and composition of off-eutectic Pb-Cd inclusions are studied. Polycrystalline Al samples were implanted with 1 x 1020 ions/m2 (∼3 at.%) with a Cd:Pb ratio of either 8:2 or 2:8, at temperatures to form inclusions in the 10 nm size range.

TEM analyses of Si implanted with immiscible elements have shown that the implanted species characteristically segregate to form nanoscale inclusions in the amorphous Si matrix. Subsequen annealing induced recrystallization was found to lead to simultaneous removal of nearly all of the implanted species, explained in terms of stress-induced trapping of the implanted atoms at the amc phous/crystalline interface as it progresses towards the surface. The solubility of Pb in Si is negligible, and it has previously been shown-that elemental nanoscale inclusions can be formed in Si either by ion implantation at elevated temperature or by rapid solidi cation. In the present work single crystals of <110> Si have been implanted with 80 keV Pb+ k at 300K, 625K and 925K respectively. The implanted fluence was 8-1019 m−2 corresponding to an average concentration of about 3 at.%. Combined TEM and RBS/channeling analysis showed that implantations at 300 K and 625 K induced amorphization of the implanted layer with dense distributions of nanoscale lead inclusions embedded in the amorphous silicon matrix (fig. 1).

Xe inclusions can be formed in an Al matrix by ion implantation. The inclusion size and state (solid, liquid or vapor) can be controlled by changing the total ion dose and implantation temperature. Inclusions below about 10nm in size have been reported to be solid with a face centered cubic structure and a lattice parameter of about 0.6nm. Small solid inclusions have cuboctahedral shapes bounded by {111} and to a lesser extent by {100} facet planes. Larger liquid inclusions maintain their facets on the {111} planes of Al but the {100} facets become rounded . It is found that high resolution images of these liquid Xe inclusions exhibit an unusual contrast effect similar to that previously observed for liquid Pb inclusions in Al. This contrast is limited to the {111} facets and could indicate the presence of a thin solid layer of Xe. In this work we investigate the origin of this contrast effect by HRTEM observation and image simulation. Nanosized Xe precipitates were formed in an Al matrix by ion implantation with 35 keV Xe at 474K to a dose 5×1015 ions/cm2. Through focus series of high resolution electron micrographs in the <110> zone axis orientation were taken on the Berkeley ARM-1000 at an accelerating voltage of 800kV.

Image Simulation of Solid Xe Layers at an Interface of a Liquid Xe Inclusion and an Al matrix

Nanosized lead inclusions in silicon produced by ion implantation

This work describes experimental aspects of the measurement of relative interfacial energies from the equilibrium dihedral angles of small liquid inclusions or precipitates at interfaces in solids using in situ transmission electron microscopy. We demonstrate how limitations such as faceting, free surfaces, and projection errors can be handled to minimize experimental errors. Microsc. Res. Tech. 42:241–247, 1998. © 1998 Wiley‐Liss, Inc.

In situ measurement of dihedral angles at liquid grain boundary inclusions

Small Pb inclusions in Al have been studied by a number of investigators because the alloy system offers the possibility of observing the processes of melting and solidification directly. Both solids are fee, and the mutual solubility of solid Pb and Al is negligible. Despite a large difference in lattice parameter, it has been found that inclusions follow a parallel-cube orientation relationship and their equilibrium shape is a cuboctahedron, bounded by ﹛111﹜ and ﹛100﹜ facets [1]. Following Herring, the relative extent of the two types of facet directly indicates a ratio of interfacial energies γl00/γ111- However, recent investigations have shown that for inclusions in the range of a few to a few tens of nanometers the equilibrium shape becomes a function of size [2]. In the present work, this size dependence of the equilibrium shape has been investigated further. Al alloys with about lat.% Pb were prepared by rapid solidification or by ion implantation, and equilibrated by annealing at about 300°C.

In Situ Transmission Electron Microscopy Observations of Alloying of Nanoscale Pb Inclusions by Implantation with Cd Ions

In the present study we have used a well-defined bicrystal geometry to study the morphology and structure of lead grain boundary inclusions in mazed bicrystal aluminum films containing mainly 90{degrees} tilt boundaries with fixed misorientation but variable inclination. It was found that the shape, size and orientation of the inclusions in the grain boundaries depend on the inclination, i.e. the orientation of the grain boundary plane. Inclusions were all single crystalline and invariably faceted toward one aluminum grain and more rounded toward the other grain. Independent of grain boundary inclination, the faceted side was a section of the cuboctahedral equilibrium shape of inclusions in parallel topotaxy with the bulk aluminum matrix. The rounded side, where the inclusions were rotated by 90{degrees} with respect to the aluminum lattice, approximated a spherical cap consisting partly of somewhat flatter segments with complex faceting, illustrating the lack of distinctly flat low-energy facets.

Equilibrium shapes of Pb inclusions at 90{degrees} tilt grain boundaries in Al

Equilibrium Shapes of Pb Inclusions at 90° Tilt Grain Boundaries in Al

Electrostatic precipitators have a relatively low efficiency for the collection of submicron particles. One way to increase their efficiency is to enforce the agglomeration and thereby form larger particles. In this work, a study has been initiated for enhancing the agglomeration between oppositely charged particles by using an alternating electric field to increase the relative motion between such particles. A simple first order computer model was developed for establishing the magnitude of agglomeration and for characterizing the interdependence of different parameters of importance. A laboratory experimental unit was established for studying various practical configurations for agglomeration in alternating electric field, using finely dispersed limestone powder. For the measurements of particle size distributions, a Berner Low Pressure Impactor was used. The preliminary results have shown a 50% reduction in the mass concentration of submicron particles, for oppositely charged particles in an alternatin...

An Experimental Investigation for Agglomeration of Aerosols in Alternating Electric Fields

XTEM microscopy of martensitic transformations in noble gas implanted stainless steel

Exploring the Linguistic and Institutional Contexts of Writing Instruction in TESOL

The last time one of us in this group engaged in a (public) collective critical reading such as the one we attempt to do in this article, it was from the position of a student. The backdrop was the late 1990s, and several people anticipated the discussions in Professor Margie Berns’s seminar at Purdue University; in that particular sequence of classes, the students were ardently debating the contents of Robert Phillipson’s Linguistic Imperialism. They became so involved with the text that they turned class reflections into an article (Berns et al, 1998), first published in InJAL and later featured in Barbara Seidlhofer’s Controversies in Applied Linguistics as an authorized appearance alongside Phillipson’s own comments.

[IMRJ_10-126forum] Reading Pennycook critically: a groups reflections on critical applied linguistics

As we, an instructor and her students, read through Alastair Pennycook's Critical Applied Linguistics (2001) in a PhD seminar by the same name, we found ourselves contrasting and comparing the insights provided in that book with those in other critical texts and wondering what the ten years since the work's publication had meant. This article is a collection of such reflections, one that is guided by our belief that activities relating to language use, change, and teaching are inherently political and dynamic, and that therefore we must be prepared for the challenges that operating within this paradigm always brings. After a brief introduction to the work itself, we present our thoughts on what critical approaches do—in particular what Critical Applied Linguistics as proposed by Pennycook intends to do—the relationship between the critical and linguistics, the possibility of change through the critical, and the role of questioning and skepticism in forging a different reality.

Reading Pennycook Critically 10 Years Later: A Group's Reflections On and Questions About Critical Applied Linguistics

World Wide Presentation and Critique of Design Proposals with Web-PHIDIAS

Continual learning without catastrophic forgetting is a challenge for artificial systems but it is done naturally across a range of biological systems, including in insects. A recurrent circuit has been identified in the fruit fly mushroom body to consolidate long term memories (LTM), but there is not currently an algorithmic understanding of this LTM formation. We hypothesize that generative replay is occurring to consolidate memories in this recurrent circuit, and find anatomical evidence in synapse-level connectivity that supports this hypothesis. Next, we introduce a computational model which combines an initial experience phase and LTM phase to perform generative replay based continual learning. When evaluated on a CIFAR-100 class-incremental continual learning task, the modeled LTM phase increases classification performance by 20% and approaches within 2% of the performance for a non-incremental upper bound baseline. Unique elements of the proposed generative replay model include: 1) coupling high dimensional sparse activation patterns with generative replay and 2) sampling and reconstructing higher level representations for training generative replay (as opposed to reconstructing sensory-level or processed sensory-level representations). Additionally, we make the experimentally testable prediction that a specific set of synapses would need to undergo experience-dependent plasticity during LTM formation to support our generative replay based model.

Informing generative replay for continual learning with long-term memory formation in the fruit fly

The Spinal Cord Injury (SCI) patient population suffers not only from severe restrictions of sensory and motor function, but also impacts on a range of autonomic nervous system functions. This can include orthostatic hypotension and reduced bladder function. The significant health issues in this population require technological developments in order to im-prove patient outcomes and restore key healthy functions. Spinal cord epidural stimulation (scES), a new approach, has the potential to regulate systolic blood pressure, improve bladder function, and restore sensory and motor activity in people with SCI through targeted modulation of neural populations in the spinal cord. Here, we present two innovative tools for improving efficacy of scES. The first is a technique for automatic segmen-tation and visualization to aid in individualized placement of epidural stimulation electrodes. The second is a system for closed loop control of stimulation parameters for epidural stimulation, capable of implementing real-time control algorithms based on sensory measurements to modify therapy parameters. This is implemented as an application on a tablet for future clinical and at home testing. Preliminary prototypes of each system are described and demonstrated, to motivate future closed-loop studies in a clinical setting. Taken together, these novel visualization and control tools can overcome critical barriers to improve outcomes for SCI patients using scES.

2023 11th International IEEE/EMBS Conference on Neural Engineering (NER)

Automated Tools to Improve Spinal Cord Injury Outcomes with Epidural Stimulation

Bladder dysfunction is a highly prevalent quality of life issue in individuals with chronic spinal cord injury (SCI). The current study examined control of storage and emptying with neuromodulation in an SCI individual newly implanted with a spinal cord epidural stimulation (scES) electrode array. The goals of this pilot trial were 1) to enable dynamic human in-the-loop, sensor feedback, learning algorithm-controlled neuromodulation of micturition pathways in the home environment, and 2) to improve the transition from bladder storage to voiding in the home-setting by flexibly adjusting preset parameters in accordance with real-time physiological responses to bladder distention (e.g., sensations of fullness). Application of scES with a neurostimulator attached to a 16-electrode array was first examined in a controlled lab setting during filling cystometry by interactively identifying optimal stimulation parameters (cathode/anode configuration, stimulation frequency and amplitude) for storage and voiding. Efficacy was then tested in the lab for six-hour periods during natural bladder filling, followed by at-home use. The current report is on the first of four participants, a 40-year-old male T3 level of injury (AIS A) approximately 12 years post-injury, who entered the study having high filling pressures and low voiding efficiency. At-home daily training with scES (cohorts determined with prior in-lab mapping experiments) revealed effective storage at low fill pressure and efficient voiding, which improved over time. A major advantage of this system is afforded by the versatility of the multi-electrode array and technology advancements (STIMX) allowing for smooth transition from the storage to emptying phase, enabled by the ability to activate multiple spinal cord regions and associated functions with a single electrode placement and device using numerous cohorts simultaneously. Our next step is to develop a closed-loop, adaptive, real-time processing system that is used to automatically modulate epidural stimulation parameters based on acquired multi-modal sensor data. Funding provided by NIH Roadmap Initiative - Office of Strategic Coordination, Other Transactions, SPARC Program Award # OT2OD024898, University of Louisville Hospital, and Medtronic Inc. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

At-home void training with spinal epidural stimulation in an individual with chronic spinal cord injury using advanced customized software

Learning new tasks and skills in succession without overwriting or interfering with prior learning (i.e., “catastrophic forgetting”) is a computational challenge for both artificial and biological neural networks, yet artificial systems struggle to achieve even rudimentary parity with the performance and functionality apparent in biology. One of the processes found in biology that can be adapted for use in artificial systems is sleep, in which the brain deploys numerous neural operations relevant to continual learning and ripe for artificial adaptation. Here, we investigate how modeling three distinct components of mammalian sleep together affects continual learning in artificial neural networks: (1) a veridical memory replay process observed during non-rapid eye movement (NREM) sleep; (2) a generative memory replay process linked to REM sleep; and (3) a synaptic downscaling process which has been proposed to tune signal-to-noise ratios and support neural upkeep. To create this tripartite artificial sleep, we modeled NREM veridical replay by training the network using intermediate representations of samples from the current task. We modeled REM by utilizing a generator network to create intermediate representations of samples from previous tasks for training. Synaptic downscaling, a novel con-tribution, is modeled utilizing a size-dependent downscaling of network weights. We find benefits from the inclusion of all three sleep components when evaluating performance on a continual learning CIFAR-100 image classification benchmark. Maximum accuracy improved during training and catastrophic forgetting was reduced during later tasks. While some catastrophic forget-ting persisted over the course of network training, higher levels of synaptic downscaling lead to better retention of early tasks and further facilitated the recovery of early task accuracy during subsequent training. One key takeaway is that there is a trade-off at hand when considering the level of synaptic downscaling to use - more aggressive downscaling better protects early tasks, but less downscaling enhances the ability to learn new tasks. Intermediate levels can strike a balance with the highest overall accuracies during training. Overall, our results both provide insight into how to adapt sleep components to enhance artificial continual learning systems and highlight areas for future neuroscientific sleep research to further such systems.

Continual learning benefits from multiple sleep stages: NREM, REM, and Synaptic Downscaling

Continuous state estimation is a fundamental problem addressed by neural systems which underlies complex capabilities such as navigation. While studies in heading direction estimation of the fruit fly D. melanogaster have uncovered how this computation can be performed in a ring attractor architecture, it is unclear how additional synapse-level architectural details contribute to the functional performance of heading direction estimation. In this work, we find a consistent, repeated, motif in synapse-level connectivity data which captures the connectivity distributions of connections between all investigated neurons in the ring attractor. This identified motif contains novel, additional synapses to adjacent motifs that differ from previous theoretical models and anatomical studies. To investigate the properties of this identified highly-recurrent architecture in computational studies of angular path integration, we develop a parameterized backpropagation-through-time approach to train the attractor based on both observed experimental activation patterns and heading direction estimation accuracy. We find that a synapse-constrained network model with the identified additional directional offsets can perform angular path integration, but does not have improvements in accuracy in relation to models with null comparison architectures, which suggests potential additional functional roles of this connectivity structure. Our work presents a proof of principle for how detailed synapse-level motifs can be investigated via network optimization based on both experimental observations and functional performance as well as furthers a detailed understanding of continuous state estimation in biological systems.

Continuous State Estimation With Synapse-constrained Connectivity

The ability to form and store several types of associations between representations of natural images is an area of ongoing research in artificial deep neural networks, which may be informed by biologically-inspired computational models. It is hypothesized that replay of sensory stimuli through cortical-hippocampal connections is responsible for training associations between events, as a powerful form of associative learning. While models of associative memories and sensory processing have been studied extensively, there is a potential for spiking models encompassing sensory processing, reasoning over associations, and learning representations which has not been previously demonstrated. Such networks would be suitable for reasoning and learning from visual data on neuromorphic hardware. In this work, we demonstrate a novel visual reasoning network capable of representing semantic relationships and learning new associations through replay-based association with spiking models using natural images. This is demonstrated through associations of natural images from Tiny Imagenet with a knowledge graph derived from WordNet, and we show that relations in the knowledge graph can be accurately traversed for multiple sequential queries. We also demonstrate learning of a novel association after replayed presentations of natural images. This represents a novel capability for machine learning and reasoning with spiking neural networks which may be amenable to neuromorphic hardware.

A spiking network model for semantic representation and replay-based association acquisition

The sense of touch provides an intimate connection to our surroundings and is a critical component for navigating the environment and manipulating objects. To better capture and convey touch information to prosthetic arm users or autonomous robots, it is useful to leverage biological representations of tactile signals for rapid and efficient processing. We developed a software pipeline that simulates and analyzes biomimetic tactile signals for developing better techniques and approaches for robotic systems that rely on the sense of touch. Touch sensor signals were simulated with a virtual hand model (MuJoCo HAPTIX) and were converted to a biological representation of tactile afferent spiking activity using existing neuron models (TouchSim). We simulated virtual hand object interaction, at three different movement speeds, and found that biomimetic tactile signals yield better results (91%) compared to using traditional force signals (61%) at classifying the different hand speeds. This software toolkit enables researchers to quickly generate, capture, and analyze biologically realistic tactile behavior for creating smarter and more effective robotic systems.

2021 10th International IEEE/EMBS Conference on Neural Engineering (NER)

Simulation and analysis of neuromorphic tactile data for object interaction speed detection

The use of programmatically generated input data in place of human-generated input data poses problems for many computer applications in use today. Mouse clicks and keyboard strokes can automatically be generated to cheat in online games, or to perpetrate click fraud. The ability to discern whether input data was computationally generated instead of created by a human input device is therefore of paramount importance to these types of applications. This paper describes a method for detecting input data that was computationally modified or fabricated. This includes detecting data that was not directly generated by a physical human input device such as a keyboard or mouse. A prototype of this system was built on existing hardware and was shown to be effective at detecting attacks on a real application. This detection method is capable of addressing the majority of input-based attacks currently in use. When used in conjunction with a trusted peripheral, it offers a robust mechanism for ensuring a computer is not at the controls.

The complexity of packet-processing applications continues to grow, with encryption, compression, and XML processing becoming common on packet-processing devices at the edge of enterprise and service provider networks. While performance remains a key differentiator for these devices, the complexity and rate of change in the supported applications has made general-purpose platforms an attractive alternative to ASICs and network processors. General-purpose platforms offer excellent programmability and a wealth of existing software, in the form of operating systems, libraries, and applications that can be used to build a packet-processing system; however, the performance of general-purpose operating systems is unacceptable for many environments. This has driven developers to either make derivative versions of existing operating systems or to use special-purpose operating systems with a less comprehensive and familiar library of existing software. As part of the Symerton project, we propose using virtualization to address these issues. We have designed a system that has a virtual machine dedicated to high-performance networking, and a virtual machine dedicated to hosting non-performance critical tasks in a general-purpose operating system. Using a proof-of-concept implementation, we show that the resulting system outperforms a general-purpose operating system by an average of 22% for a real networking application. We also discuss tradeoffs that will need to be considered in further development of systems using this design.

2006 Symposium on Architecture For Networking And Communications Systems

A programming environment for packet-processing systems: Design considerations

Network edge packet-processing systems, as are commonly implemented on network processor platforms, are increasingly required to support a rich set of services. These multi-service systems are also subjected to widely varying and unpredictable traffic. Current network processor systems do not simultaneously deal well with a variety of services and fluctuating workloads. For example, current methods of worst-case, static provisioning can meet performance requirements for any workload, but provisioning each service for its worst case reduces the total number of services that can be supported. Alternately, profile-driven automatic-partitioning compilers create efficient binaries for multi-service applications for specific workloads but they are sensitive to workload fluctuations. Run-time adaptation is a potential solution to this problem. With run-time adaptation, the mapping of services to system resources can be dynamically adjusted based on the workload. We have implemented an adaptive system that automatically changes the mapping of services to processors, and handles migration of services between different processor core types to match the current workload. In this paper we explain our adaptive system built on the Intelreg IXP2400 network processor. We demonstrate that it outperforms multiple different profile-driven compiled solutions for most workloads and performs within 20% of the optimal compiled solution for the remaining workloads.

2005 Symposium on Architectures for Networking and Communications Systems (ANCS)

Framework for supporting multi-service edge packet processing on network processors

Implementors of packet-processing applications on multi-core processors must balance two requirements: (1) adapt processor allocations dynamically to reduce the overall resource provisioning requirement for the system, achieve robustness to traffic fluctuations, and reduce energ y consumption; and (2) utilize, for each application stage, r esources (e.g., memory levels, inter-processor communication mechanisms, etc.) closer or local to the processors on which the stages are mapped to achieve the highest possible throughput. In this paper, we describe the design and implementation of a run-time adaptation system that can meet these two requirements simultaneously. Our design allows each application stage to utilize local resources whenever possible in the steady state. Upon adapting the allocation of processors to stages, the run-time system (1) binds each resource usage within a stage to a new resource instance; and (2) checkpoints and migrates the state from the previous resource instance to the newly-bound resource instance . We describe the design and implementation of our adaptation system in the context of a packet processing system designed using the Intel R © IXP2400 network processor. We show that our design has little impact (14%) on the steadystate throughput of the system. We further show that our design is able to perform resource adaptation for a real application in less than 100ms, allowing processor allocatio ns to be adapted at a very fine time-scale.

Software and firmware engineers developing products based on the Intel IXP2400 or IXP2800 network processors will find this guide to be an invaluable resource, whether they are new to programming Intel network processors or already familiar with the IXP1200 processor. Users will progress through a set of tasks typically faced by network software engineers, from basic receive and transmit operations to more complex packet processing. Each task is deconstructed, through working example code, into what the appropriate parts of the software and hardware can do and why it is important to the design and implementation. The various tradeoffs that are possible within the software and hardware are also fully analyzed. This coding guide progresses in steps from simple, single-threaded programs to a complete multithreaded reference application using the microblock programming paradigm. Application and programming notes are used throughout to accelerate the pace for readers already familiar with IXP1200 programming. Complete and working code examples from the book and the Intel IXA Software Developer's Kit are included on the CD-ROM. 
Author Biography: Eric J. Johnson and Aaron R. Kunze are senior network software engineers with Intel's research and development group. They designed and implemented the microACE architecture in the IXP12xx Software Development Kit, which helps software engineers create reusable packet-processing modules and combine them into network processor applications. They also designed reusable Quality of Service (QoS) components for use with Intel's network processor family. They are the coauthors of IXP1200 Programming. They live in Portland, Oregon.

Succinctly explaining the ways to accomplish a complete range of typical tasks, this reference shows how the IXP1200 hardware influences the programming environment. As users progress from neophyte to veteran IXP1200 programmers, insights in the book help with tuning IXP1200 code for high performance. An IXP hardware and software overview and advice on writing a first microcode program are provided. To help developers progress to experienced user levels, important topics crucial to the IXP 1200 programming environment such as receiving and packet processing, and intra-microengine packet processing are discussed in detail.

Primarily used for metabolic engineering and synthetic biology, genome-scale metabolic modeling shows tremendous potential as a tool for fundamental research and curation of metabolism. Through a novel integration of flux balance analysis and genetic algorithms, a strategy to curate metabolic networks and facilitate identification of metabolic pathways that may not be directly inferable solely from genome annotation was developed. Specifically, metabolites involved in unknown reactions can be determined, and potentially erroneous pathways can be identified. The procedure developed allows for new fundamental insight into metabolism, as well as acting as a semi-automated curation methodology for genome-scale metabolic modeling. To validate the methodology, a genome-scale metabolic model for the bacterium Mycoplasma gallisepticum was created. Several reactions not predicted by the genome annotation were postulated and validated via the literature. The model predicted an average growth rate of 0.358±0.12, closely matching the experimentally determined growth rate of M. gallisepticum of 0.244±0.03. This work presents a powerful algorithm for facilitating the identification and curation of previously known and new metabolic pathways, as well as presenting the first genome-scale reconstruction of M. gallisepticum.

Semi-automated Curation of Metabolic Models via Flux Balance Analysis: A Case Study with Mycoplasma gallisepticum

Designing effective antisense sequences is a formidable problem. A method for predicting efficacious antisense holds the potential to provide fundamental insight into this biophysical process. More practically, such an understanding increases the chance of successful antisense design as well as saving considerable time, money and labor. The secondary structure of an mRNA molecule is believed to be in a constant state of flux, sampling several different suboptimal states. We hypothesized that particularly volatile regions might provide better accessibility for antisense targeting. A computational framework, GenAVERT was developed to evaluate this hypothesis. GenAVERT used UNAFold and RNAforester to generate and compare the predicted suboptimal structures of mRNA sequences. Subsequent analysis revealed regions that were particularly volatile in terms of intramolecular hydrogen bonding, and thus potentially superior antisense targets due to their high accessibility. Several mRNA sequences with known natural antisense target sites as well as artificial antisense target sites were evaluated. Upon comparison, antisense sequences predicted based upon the volatility hypothesis closely matched those of the naturally occurring antisense, as well as those artificial target sites that provided efficient down-regulation. These results suggest that this strategy may provide a powerful new approach to antisense design.

Volatility in mRNA secondary structure as a design principle for antisense

Distributed, Collaborative Data Analysis from Heterogeneous Sites Using a Scalable Evolutionary Technique

Distributed Clustering Using Collective Principal Component Analysis

Wireless integrated sensor networks involve information processing over large wired and wireless networks with limited bandwidth. Moreover, the computing capabilities of sensing devices are usually limited because of design restrictions, limited power supply, and other mission specific requirements. Analyzing data sets collected over such sensor networks usually requires downloading voluminous data sets to a central site. This fundamentally impairs the scalability and the overall response time of the application. In a mission critical applications, data analysis in such networks must deliver results within a certain time frame and often slower response completely defeats the purpose of analyzing sensor data. This paper presents a framework for collective data analysis from distributed heterogeneous data that calls for a fundamentally different perspective. This approach analyzes data in a distributed fashion without downloading everything to a central site. We examine several of the unsupervised Collective Data Mining algorithms for performing tasks associated with this extraction of useful information from sensor arrays. We further present a manner in which these algorithms may be incorporated into the knowledge extraction process from the sensor networks, and also propose an architecture geared towards the use of these algorithms.

Collective unsupervised data mining for heterogeneous wireless integrated network sensor arrays

Scheduling in Optical WDM Networks Using Hidden Markov Chain Based Traffic Prediction

Collective, Hierarchical Clustering from Distributed, Heterogeneous Data

This paper develops collective data mining, a unique approach for nding patterns from a network of databases, each with a distinct feature space. This paper addresses both distributed cooperative learning at the global level and also learning at the local data sites. In addition to developing the foundation of the collective data mining , it also presents BODHI, a distributed data mining (DDM) system that implements the collective data mining approach. Although the architecture is ideal for accommodating diierent in-ductive learning algorithms for data analysis at diierent sites, this paper suggests one scalable approach using a gene expression based evolutionary algorithm. This approach is used for distributed fault detection in an electrical power distribution network. Experimental results demonstrating the success of the developed system are also presented.

Collective Data Mining From Distributed , Vertically PartitionedFeature

CITATION Hartung T, Smirnova L, Morales Pantoja IE, Akwaboah A, Alam El Din D-M, Berlinicke CA, Boyd JL, Caffo BS, Cappiello B, Cohen-Karni T, Curley JL, Etienne-Cummings R, Dastgheyb R, Gracias DH, Gilbert F, Habela CW, Han F, Harris TD, Herrmann K, Hill EJ, Huang Q, Jabbour RE, Johnson EC, Kagan BJ, Krall C, Levchenko A, Locke P, Maertens A, Metea M, Muotri AR, Parri R, Paulhamus BL, Plotkin JD, Roach P, Romero JC, Schwamborn JC, Sillé F, Szalay AS, Tsaioun K, Tornero D, Vogelstein JT, Wahlin KJ and Zack DJ. The Baltimore declaration toward the exploration of organoid intelligence. Front Sci (2023) 1:1068159. doi: 10.3389/fsci.2023.1068159

The Baltimore declaration toward the exploration of organoid intelligence

Public Work Programs and Gender-Based Violence : Evidence from Lao PDR

Educating the workforce of tomorrow is an increasingly critical challenge for areas such as data science, machine learning, and artificial intelligence. These core skills may revolutionize progress in areas such as health care and precision medicine, autonomous systems and robotics, and neuroscience. Skills in data science and artificial intelligence are in high demand in industrial research and development, but we do not believe that traditional recruiting and training models in industry (e.g., internships, continuing education) are serving the needs of the diverse populations of students who will be required to revolutionize these fields. Our program, the Cohort-based Integrated Research Community for Undergraduate Innovation and Trailblazing (CIRCUIT), targets trailblazing, high-achieving students who face barriers in achieving their goals and becoming leaders in data science, machine learning, and artificial intelligence research. Traditional recruitment practices often miss these ambitious and talented students from nontraditional backgrounds, and these students are at a higher risk of not persisting in research careers. In the CIRCUIT program we recruit holistically, selecting students on the basis of their commitment, potential, and need. We designed a training and support model for our internship. This model consists of a compressed data science and machine learning curriculum, a series of professional development training workshops, and a team-based robotics challenge. These activities develop the skills these trailblazing students will need to contribute to the dynamic, team-based engineering teams of the future.

STEM Leadership and Training for Trailblazing Students in an Immersive Research Environment

Stakeholder Engagement Plan (SEP) - Integration of Social Accountability into National and Sub-national Systems - P172632

Environmental and Social Commitment Plan (ESCP) - Integration of Social Accountability into National and Sub-national Systems - P172632

Stakeholder Engagement Plan (SEP) - Engaging Citizens to Improve Service Delivery Through Social Accountability - P172630

The development objective of the Voice and Action: Social Accountability for Improved Service Delivery Project is to support the improvement of service delivery in schools, health centers and communes, for rural households in selected districts. This will be achieved by local government and service providers engaging with communities in the ISAF process (access to information, open budgets, citizen monitoring) to improve performance and responsiveness.A joint letter was received by the Bank from the Executive Directors of Save the Children (SC) and World Vision (WV) on March 22, 2018 requesting several changes to the project.There are four main reasons for this restructuring: a. Change in the Definition of Operating Costs for Save the Children only; b. Reallocation Between Disbursement Categories; c. Extension of the Closing Date; and Revision of the Results Framework.

Disclosable Restructuring Paper - Voice and Action: Social Accountability for Improved Service Delivery - P146160

Urbanization in Cambodia offers the potential for inclusive growth and poverty reduction. The proportion of people living in cities is on the rise, and many of the drivers of growth for the country are urban based industries such as manufacturing, tourism, and trade. This creates an important opportunity for the country, as the decisions made today will affect the urbanization process in significant ways for decades to come. This report aims to help inform urbanization policy in Cambodia, understand the economic potential of cities, key constraints to realizing that potential, and develop a strategic approach for improving urban growth and resilience in those cities. The report includes three sections, i) an introduction to patterns of urbanization and the economic potential of cities in Urbanization; ii) analysis of key challenges; and iii) policy and program options for achieving the full potential of urbanization.

The Tina River Hydropower Development Project (TRHDP) is a 15 megawatts hydropower scheme on the island of Guadalcanal, Solomon Islands, 30 km south of the capital Honiara. The TRHDP is managed by a dedicated Project Office under the supervision of the Ministry of Mines, Energy and Rural Electrification (MMERE), and will supply power to the Honiara grid – providing more reliable and plentiful power than the current overburdened supply from diesel and reducing the retail price of electricity for consumers. Some of the negative impacts and mitigation measures include: reducing the burden of work on women and improving their livelihood opportunities through access to resources and services; Ensuring gender equality in opportunities for education, skill building, training and employment; promoting the voice, participation and empowerment of women, and reducing opportunities for elite capture of funds; and women noted that infrastructure improvements brought about by the project (for example improved access roads, rural electrification and clean water access) had the potential to reduce the burden of labor they faced on a daily basis. Of these three improvements, clean water access seemed to elicit the most interest from women. The project has taken this priority on board, and clean water access is the focus of one of the three working groups currently being established to plan responsible spending of the community benefit share. To date, the majority of interest in working group participation has been from women.

Urbanization presents an enormous opportunity for Cambodia. As has been demonstrated in countries around the world, urbanization is a driving force for growth and poverty reduction. Given Cambodia’s relatively early stage of urbanization, there is still an important opportunity to shape the future direction of urbanization. To positively shape the future of Cambodian cities, strong institutions for urban planning and management, collaboration across agencies, and a sustained commitment to the importance of principles of sustainability and inclusion will be needed. This report provides a summary of key issues related to urbanization in Cambodia, with a particular focus on Phnom Penh given its role as the country’s largest and most prosperous city. Section one provides context on urbanization, institutional and financial arrangements, urban planning, urban service delivery, and sustainability and inequality. Section two focuses in on three underlying constraints to efficient urbanization and section three includes priorities for Phnom Penh as a competitive, sustainable, and inclusive city.

The development objective of Tina River Hydroelectric Development Project (TRHDP) for Solomon Islands is to supply much needed electricity to Honiara, the capital city. Some of the negative impacts and mitigation measures include: (a) locate the project infrastructure and construction activities where they will do the least damage to people’s livelihoods and property; (b) provide sufficient lead time for threatened assets and their owners to be clearly identified, and to enable them to establish replacement assets and maximize returns from existing gardens etc.; (c) replace lost assets within the acquired land with similar assets at the same or better standard to ensure continuity of current livelihoods. This will be achieved through provision of materials, seedlings, labor, and expertise; (d) employ able youth in the local communities to undertake reestablishment of garden, tree plantings etc. to provide them with employment experience and training; (e) provide incentives for owners of natural assets such as food gardens, fruit and nut trees, timber trees, and structures to re-establish these assets; (f) for temporary or permanent loss of common property or shared livelihoods assets, the assets will be replaced where possible by the project or compensation will be paid into a collective fund to be used for community social and economic development and customary events; and (g) provide funds and training programs to enable especially disadvantaged and vulnerable owners and users of assets to improve their wellbeing and build more sustainable livelihoods.

The development objective of the Tina River Hydropower Facility (TRHPF) for Solomon Islands is a 15 megawatts hydropower scheme on the island of Guadalcanal, Solomon Islands, 30 km south of the capital Honiara. The TRHDP is managed by a dedicated Project Office under the supervision of the Ministry of Mines, Energy and Rural Electrification (MMERE), and will supply power to the Honiara grid – providing more reliable and plentiful power than the current overburdened supply from diesel and reducing the retail price of electricity for consumers. Some of the negative impacts and mitigation measures include: vegetation clearance at the dam site and for the access road, downstream water quality degradation by sediment from erosion during access road construction and from installation of the cofferdams, conversion of 2.5 km of flowing water to a lacustrine environment, and movement of heavy equipment and large volumes of materials along the local road and the main road from Honiara; loss of habitat and biodiversity, pressure for land development, land disputes, challenges to local traditions and cultural practices, increases in employment opportunities, and substance abuse and criminal practices; Dust will be generated from earth movement activities and traffic; ambient air quality will be temporary, local, and not significant; heavy equipment and blasting will be sources of noise and vibration– the latter potentially of high intensity but limited duration; Prevention of dam-related accidents and preparedness for and response to them is addressed; erosion during land clearing and road construction, and releases of concrete leachate and wash water from the concrete batching plant are more amenable to mitigation.

Policy Making Beyond the Politics of Conflict: Civil Society Think Tanks in the Middle East and North Africa

Cambodia - Voice and Action: Social Accountability for Improved Service Delivery : P146160 - Implementation Status Results Report : Sequence 01

In a course for engineering freshmen, peer leaders facilitated optional study sessions, which implemented peer-led team learning workshops. Some leaders were paid teaching assistants, but most were undergraduate volunteers. To understand the experiences of the peer leaders, we asked them to keep weekly reflective journals. By performing a basic qualitative analysis of fourteen journals from two semesters, we developed a description of the experience of leading peer-led team learning workshops over the course of the semester. At the beginning of the semester, the leaders were apprehensive about teaching and concerned with correctly answering students’ questions. As the semester progressed, the leaders were often frustrated with the difficulty of teaching, and the leaders tried new ways of encouraging student participation. At the end of the semester, the leaders reported that they increased self-confidence, developed an appreciation for intellectual diversity, and gained an increased interest in teaching.

Integrated Safeguards Data Sheet (Appraisal Stage) - Solomon Islands Rural Development Program II - P149282

Solomon Islands - Rural Development Program : P089297 - Implementation Status Results Report : Sequence 07

ECE 110 is a required course for freshmen majoring in electrical engineering or computer engineering at the University of Illinois at Urbana- Champaign. ECE 110 students may choose to attend optional supervised study sessions, which implement peer-led team learning workshops. In the sessions, students work on difficult problems from previous semesters' exams under the supervision of a team leader. The team leaders are graduate teaching assistants, undergraduate teaching assistants, and undergraduate volunteers. In the Spring and Fall 2008 semesters, team leaders were asked to keep weekly reflective journals. We qualitatively analyzed 14 journals and found that leaders faced common challenges such as irregular student attendance and inadequate student preparation. Leaders reported that they increased their self-confidence, developed an appreciation for intellectual diversity, and gained an increased interest in teaching.

Work in progress - how do students benefit as peer leaders of learning teams?

1. Introduction 2. Think Tanks and Governance 3. Think Tanks, Politics and Public Policy in the Americas 4. Comparative Politics and Policy Advice in Europe 5. Comparative Politics and Policy Advice in the Asia Pacific Region 6. Comparative Politics and Policy Advice in Africa 7. Comparative Politics and Policy Advice in the Middle East 8. Concluding Remarks 9. Data Appendix.

In 2002 the World Bank Institute and Europe and Central Asia Region (ECA) launched the Community Empowerment Network (CEN): four national networks linked through regional activities that would build the capacity of communities and development partners to implement community-driven development (CDD) projects. CEN has to date had clear successes as well as difficulties-particularly in linkage to World Bank operations and improving local coordination with multiple donors. CEN's experience points to specific lessons that could be applied in creating other communities of practice, for example, emphasizing peer review among countries and establishing clear indicators of progress as well as a number of specific administrative lessons.

Communities of practice for local capacity in Central Asia: the community empowerment network

A joint initiative was launched in early 2002 to explore the potential of communities of practice (CoPs) as a tool for capacity building for development in the Middle East and North Africa (MENA) region. Under the aegis of the Mediterranean Development Forum (MDF), the initiative took the form of a partnership between the World Bank Institute (WBI), the United Nations Development Programme (UNDP) and prominent regional think tanks dedicated to the empowerment of civil society to engage in public policymaking. CoPs are informal networks of professionals or practitioners who are dedicated to sharing experience and knowledge. In the development field, CoPs often contribute to a more informed dialogue with decision-makers. They also facilitate problem solving among individual members, stimulate learning, promote professional development, address individual questions and generate the type of knowledge that members need in their daily work. The impetus for this initiative came from a concern among the key stakeholders of the MDF that the MDF was not achieving a lasting impact from its main programme activity, a large-scale regional development conference held once every two years. As year-round, interactive knowledge sharing groups, it was felt that CoPs could complement the large conferences by both generating ideas for the conferences, and by continuing the networking and dialogue that takes place during the events. The WBI/UNDP collaboration focused on two main activities. The first was a desk study on ‘Regional communities of practice’ completed in June 2002 (Traboulsi 2002). The second activity was technical and financial support to three regional development related CoPs that were identified through an international competition. Together with the desk study, the experience of the three CoPs has provided WBI and UNDP with lessons on the challenges and opportunities of supporting regional networking activities. This paper highlights those lessons through a review of the progress of the three CoPs, as well as the key findings of the desk study, including an update in 2004 of the 2002 survey.

Communities of practice for development in the Middle East and North Africa

Since November 1997, the World Bank Institute (WBI) and the Center for International Private Enterprise (CIPE) have co-sponsored four regional capacity building workshops for policy institutes, or think tanks. Events have been held in Cairo, Egypt (November 1997); Moscow, Russia (September 1998); Beirut, Lebanon (February 1999); and Harare, Zimbabwe (March 1999). A worldwide conference of think tanks is currently being planned for December 1999. Regional events are also being considered in Latin America and South Asia. WBI and CIPE have also jointly evaluated the workshops; in order to derive lessons learned that could help improve future programs. The preliminary findings of the Beirut evaluation, for example, were communicated to the program manager responsible for the Harare event, held one month later. The evaluation design for the Harare conference was tailored to fit the specific context. The evaluation was based on the results of one pre and one post-conference questionnaire. Given the interest of WBI and CIPE in forging long-term partnerships with think tanks, the pre-conference questionnaire targeted the single issue of the expectations of the participants.

A joint evaluation of a conference on think tanks sponsored by WBI and CIPE

Since November 1997, the Center for International Private Enterprise (CIPE) and the World Bank Institute (WBI) have co-sponsored four regional capacity building workshops for think tanks. One thing that sets these workshops apart from standard conferences is the linked relationship between the succeeding events. Each conference plays a part in the identification of the objectives or in the improvement of the methodology for the next conference. A global conference of think tanks is currently being planned for December 1999. The evaluation design of the conference held in Beirut, Lebanon (February 6-8, 1999). The evaluation was based on the results of one pre- and one post- conference questionnaire. The pre-conference questionnaire targeted the single issue of the expectations of the participants. Participants were asked about the degree to which they were interested by the objectives and the lectures of the conference, and what they expected to take from the conference and apply in their organization. The post-conference questionnaire measured the degree to which the expectations of the participants were fulfilled and the extent to which the conference met its objectives as stated at the outset. The post-conference questionnaire was also designed to capture the effectiveness of the conference in three areas: discussion on policy issues, institutional strengthening, and information sharing among think tanks. The questionnaires offered a mix of closed quantitative and open qualitative questions.

A joint evaluation of a conference on think tanks sponsored by the World Bank Institute and the center for international private enterprise

This paper couples a traditional hedonic model with architectural style classifications from human experts and machine learning (ML) enabled classifiers to estimate sales price premia over architectural styles, both at the building and the neighborhood-level. We find statistically and economically significant price differences for houses from distinct architectural styles across an array of specifications and modeling assumptions. Comparisons between classifications from ML models and human experts illustrate the conditions under which ML classifiers may perform at least as reliable as human experts in mass appraisal models. Hedonic estimates illustrate that the impact of architectural style on price is attenuated by properties with less well-defined styles and we find no evidence for differential price effects of Revival or Contemporary architecture for new construction.

This paper makes three contributions: First, it introduces an algorithm that collects pictures of individual buildings from Google Street View. Second, it trains a deep convolutional neural network (CNN) to classify residential buildings into architectural styles, taking into account spatial dependencies of building vintages. Third, it investigates whether architectural styles influence house prices. For re-sales, the architectural style is a significant determinant of transaction prices while no such effect is found for new buildings. This indicates that any premia are for vintage-related quality characteristics and not for a home’s beauty.

Using detailed trip-level taxi and for-hire-vehicle data and new incident-level complaints data, we study how the entry of Uber and Lyft has affected the quality of taxi services in New York City. In a panel setting with 263 NYC taxi-zones over the time period from 2014 to 2017, we find that increased competition measured by the number of daily Uber/Lyft trips in a given taxi-zone has led to more complaints regarding a variety of service quality dimensions such as unsafe driving, rude behavior and fare refusal. Our results are robust to accounting for potential simultaneity in the determination of complaints and Uber and Lyft penetration.

The Impact of Uber and Lyft on Taxi Service Quality: Evidence from New York City

Intergenerational conflict and the political economy of higher education funding

With the tremendous growth of research in industrial agglomeration has come increased complexity in the construction of a `better' measure of agglomeration. The research presented here tests the properties of commonly used agglomeration indices through a series of simulations. Results suggest that applied researchers benefit from continuous measures of agglomeration like the Duranton-Overman index or a continuous version of the Gini coefficient, especially for industries with fewer establishments. Conclusions suggest that commonly used estimators of industrial agglomeration vary in how they quantify spatial distributions and researchers need to use the agglomeration index best suited for their specific research question.

Econometrics: Econometric & Statistical Methods - Special Topics eJournal

While there is a rich literature on both the spatial impact of taxation and the optimal composition of differential classified taxes, there is a paucity of research on the role of spatial land competition in the choice of these taxes. This paper analyzes the distortion minimizing choice of a classified land tax under differing types of spatial competition through the use of open or closed monocentric city models with absentee landowners or pubic landownership. A key result of this analysis is that optimal classified land taxes may be distortionary with public landownership; taxes result in changes in population, resident utility, and land usage. Comparing an open and closed city with absentee landowners, differential tax rates are set in a closed city, but it is never optimal to have differential tax rates in an open city.

The effect of property taxes on vacation home growth rates: Evidence from Michigan

Urban economists hypothesize that industrial diversity matters for urban growth and development, but metrics for empirically testing this relationship are limited to simple concentration metrics (e.g. location quotient) or summary diversity indices (e.g. Gini, Herfindahl). As shown by recent advances in how we measure localization and specialization, these measures of industrial diversity may be subject to bias under small samples or the Modifiable Areal Unit Problem. Furthermore, empirically examining industrial diversity requires statistically testing for patterns of industry mix that deviate from random firm location. Extending recent work by [S. Billings & E. Johnson. 2012. A Nonparametric Test for Industrial Specialization. Journal of Urban Economics. 71(3):312-331.], we develop a nonparametric microdata based test for industrial co-specialization. Our test employs establishment densities for specific pairs of industries, a population counterfactual, and a new correction for multiple hypothesis testing to determine the statistical significance of co-specialization across both places and industries. The results of these pairwise tests are then mapped out as networks of proximate industries unique to each place within our study area. We use pairs and triads of industries to highlight specific four digit industries that may drive co-specialization and a larger network of industrial diversification. Results give us new understanding of the relationship between industrial co-specialization and urbanization, with manufacturing industries tending to be more co-specialized in less dense areas than business services, while business services show more connected and transitive spatial networks. Finally, we discuss the role that intransitivities in industry triads may play in the econometric identification of co-specialization and underlying place specific agglomerative forces.

The location quotient as an estimator of industrial concentration

Corrigendum to “A non-parametric test for industrial specialization” [Journal of Urban Economics 71 (2012) 312–331]

The Tiebout model assumes that individuals 'vote with their feet' and choose to locate in the jurisdiction which best matches their fiscal preferences. In this paper, we test Tiebout's voting mechanism by examining whether housing purchase decisions are sensitive to changes in local property tax rates. Results from previous empirical tests of the link between property taxes and mobility are mixed and typically suffer from a myriad of identification problems including the confounding influence of tax rates on public good levels, tax endogeneity arising as a result of jurisdictional composition, and aggregation bias. In this paper, we are able to overcome many of the traditional obstacles to identification by: 1) focusing on purchasers of vacation homes who arguably receive no benefits from public goods funded by the tax change; 2) examining an exogenous and differential change in tax rates that arose from Michigan's Proposal A in 1994; and 3) using a high-resolution tax dataset at the Census Tract level. Our results provide some of the clearest evidence to date that household location choices are sensitive to tax changes. Further, consistent with theoretical predictions, the impact of tax changes on housing counts is found to be sensitive to the elasticity of housing supply.

The Effect of Property Taxes on Location Decisions:Evidence from the Market for Vacation Homes

We introduce a nonparametric microdata based test for industrial specialization and apply it to a single urban area. Our test employs establishment densities for specific industries, a population counterfactual, and a new correction for multiple hypothesis testing to determine the statistical significance of specialization across both places and industries. Results highlight patterns of specialization that are extremely varied, with downtown places specializing in a number of service sector industries, while suburban places specialize in both manufacturing and service industries. Business service industries are subject to more specialization than non-business service industries while the manufacturing sector contains the lowest representation of industries with specialized places. Finally, we compare results for specialization with localization and show that both measures contribute to our understanding of industry and place specific agglomerative forces. JEL Classification: R12

www.econstor.eu A Nonparametric Test for Industrial Specialization

Comparison of amyloid burden in individuals with Down syndrome versus autosomal dominant Alzheimer's disease: a cross-sectional study

Alzheimer’s disease (AD) progresses through a lengthy asymptomatic period during which pathological changes accumulate prior to development of clinical symptoms. As disease-modifying treatments are developed, tools to stratify risk of clinical disease will be required to guide their use. In this study, we examine the relationship of AD biomarkers in healthy middle-aged individuals to health history, family history, and neuropsychological measures and identify cerebrospinal fluid (CSF) biomarkers to stratify risk of progression from asymptomatic to symptomatic AD. CSF from cognitively normal (CN) individuals (N=1149) in the Emory Healthy Brain Study were assayed for Aβ42, total Tau (tTau), and phospho181-Tau (pTau), and a subset of 134 cognitively normal, but biomarker-positive, individuals were identified with asymptomatic AD (AsymAD) based on a locally-determined cutoff value for ratio of tTau to Aβ42. These AsymAD cases were matched for demographic features with 134 biomarker-negative controls (CN/BM-) and compared for differences in medical comorbidities and family history. Dyslipidemia emerged as a distinguishing feature between AsymAD and CN/BM-groups with significant association with personal and family history of dyslipidemia. A weaker relationship was seen with diabetes, but there was no association with hypertension. Examination of the full cohort by median regression revealed a significant relationship of CSF Aβ42 (but not tTau or pTau) with dyslipidemia and diabetes. On neuropsychological tests, CSF Aβ42 was not correlated with performance on any measures, but tTau and pTau were strongly correlated with visuospatial perception and visual episodic memory. In addition to traditional CSF AD biomarkers, a panel of AD biomarker peptides derived from integrating brain and CSF proteomes were evaluated using machine learning strategies to identify a set of 8 peptides that accurately classified CN/BM- and symptomatic AD CSF samples with AUC of 0.982. Using these 8 peptides in a low dimensional t-distributed Stochastic Neighbor Embedding analysis and k-Nearest Neighbor (k=5) algorithm, AsymAD cases were stratified into “Control-like” and “AD-like” subgroups based on their proximity to CN/BM- or AD CSF profiles. Independent analysis of these cases using a Joint Mutual Information algorithm selected a set of 5 peptides with 81% accuracy in stratifying cases into AD-like and Control-like subgroups. Performance of both sets of peptides was evaluated and validated in an independent data set from the Alzheimer’s Disease Neuroimaging Initiative. Based on our findings, we conclude that there is an important role of lipid metabolism in asymptomatic stages of AD. Visuospatial perception and visual episodic memory may be more sensitive than language-based abilities to earliest stages of cognitive decline in AD. Finally, candidate CSF peptides show promise as next generation biomarkers for predicting progression from asymptomatic to symptomatic stages of AD.

Predictors of Cognitive Decline in Healthy Middle-Aged Individuals with Asymptomatic Alzheimer’s Disease

Quantitative Mass Spectrometry Analysis of Cerebrospinal Fluid Protein Biomarkers in Alzheimer’s Disease

Large scale −omics datasets can provide new insights into normal and disease-related biology when analyzed through a systems biology framework. However, technical artefacts present in most −omics datasets due to variations in sample preparation, batching, platform settings, personnel, and other experimental procedures prevent useful analyses of such data without prior adjustment for these technical factors. Here, we demonstrate a tunable median polish of ratio (TAMPOR) approach for batch effect correction and agglomeration of multiple, multi-batch, site-specific cohorts into a single analyte abundance data matrix that is suitable for systems biology analyses. We illustrate the utility and versatility of TAMPOR through four distinct use cases where the method has been applied to different proteomic datasets, some of which contain a specific defect that must be addressed prior to analysis. We compare quality control metrics and sources of variance before and after application of TAMPOR to show that TAMPOR is effective at removing batch effects and other unwanted sources of variance in −omics data. We also show how TAMPOR can be used to harmonize −omics datasets even when the data are acquired using different analytical approaches. TAMPOR is a powerful and flexible approach for cleaning and harmonization of −omics data prior to downstream systems biology analysis.

Batch correction and harmonization of –Omics datasets with a tunable median polish of ratio

CSF proteome profiling across the Alzheimer’s disease spectrum reflects the multifactorial nature of the disease and identifies specific biomarker panels

Multi-platform proteomic analysis of Alzheimer’s disease cerebrospinal fluid and plasma reveals network biomarkers associated with proteostasis and the matrisome

Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid

Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer's disease: a longitudinal observational study

The hallmark amyloid-β and tau deposition of Alzheimer’s disease (AD) represents only a fraction of its diverse pathophysiology. Molecular subtyping using large-scale -omic strategies can help resolve this biological heterogeneity. Using quantitative mass spectrometry, we measured ~8,000 proteins across >600 dorsolateral prefrontal cortex tissues from Religious Orders Study and Rush Memory and Aging Project participants with clinical diagnoses of no cognitive impairment, mild cognitive impairment (MCI), and AD dementia. Unbiased classification of MCI and AD cases based on individual proteomic profiles resolved three classes with expression differences across numerous cell types and biological ontologies. Two classes displayed molecular signatures atypical of those previously observed in AD neurodegeneration, such as elevated synaptic and decreased inflammatory markers. In one class, these atypical proteomic features were associated with clinical and pathological hallmarks of cognitive resilience. These results promise to better define disease heterogeneity within AD and meaningfully impact its diagnostic and therapeutic precision.

Unbiased Classification of the Human Brain Proteome Resolves Distinct Clinical and Pathophysiological Subtypes of Cognitive Impairment

Alzheimer's disease (AD) is the most common form of dementia, with cerebrospinal fluid (CSF) {beta}-amyloid (A{beta}), total Tau, and phosphorylated Tau providing the most sensitive and specific biomarkers for diagnosis. However, these diagnostic biomarkers do not reflect the complex changes in AD brain beyond plaque and tangle pathologies. Here we report a sensitive, quantitative, and scalable targeted proteomics assay of AD biomarkers representing mainly neuronal, glial, vasculature and metabolic pathways. As quality controls (QCs), we pooled CSF from individuals having normal A{beta} and Tau levels (AT-), and individuals having low A{beta} and high Tau levels (AT+) to determine the coefficient of variation (CV) and fold-change of protein measurements. Additionally, we analyzed 390 CSF samples using selective reaction monitoring-based mass spectrometry (SRM-MS). Following trypsin digestion, 133 controls (cognitively normal and AT-), 127 asymptomatic (cognitively normal and AT+) and 130 symptomatic AD (cognitively impaired and AT+), and 30 pooled CSF samples were analyzed by SRM-MS using a 15-minute targeted liquid chromatography-mass spectrometry method. Isotopically labeled peptide standards were added for relative quantification by reporting the area ratios for each targeted peptide. We reproducibly detected 62 peptides from 51 proteins in all clinical samples with an average CV of approximately 13% across pools. Proteins that could best distinguish AsymAD and AD cases from controls included SMOC1, GDA, 14-3-3 proteins, and proteins involved in glucose metabolism. In contrast, proteins that could best distinguish AD from AsymAD were mainly neuronal/synaptic proteins including VGF, NPTX2, NPTXR, and SCG2. Collectively, this highlights the utility of high-throughput SRM-MS to quantify peptide biomarkers in CSF that can potentially monitor disease progression.

Quantitative Mass Spectrometry Analysis of Cerebrospinal Fluid Biomarker Proteins Reveals Stage-Specific Changes in Alzheimer's Disease

Despite being twice as likely to get Alzheimer’s disease (AD), African Americans have been grossly underrepresented in AD research. While emerging evidence indicates that African Americans with AD have lower cerebrospinal fluid (CSF) levels of Tau compared to Caucasians, other differences in AD CSF biomarkers have not been fully elucidated. Here, we performed unbiased proteomic profiling of CSF from African Americans and Caucasians with and without AD to identify both common and divergent AD CSF biomarkers. Multiplex tandem mass tag-based mass spectrometry (TMT-MS) quantified 1,840 proteins from 105 control and 98 AD patients of which 100 identified as Caucasian while 103 identified as African American. Consistent with previous findings, the increase of Tau levels in AD was greater in Caucasians than in African Americans by both immunoassay and TMT-MS measurements. Network analysis organized the CSF proteome into 14 modules associated with brain cell-types and biological pathways. CSF modules which included 14-3-3 proteins (YWHAZ and YWHAG), demonstrated equivalent disease-related elevations in both African Americans and Caucasians with AD, whereas other modules demonstrated more profound disease changes within race. Modules enriched with proteins involved with glycolysis and neuronal/cytoskeletal proteins, including Tau, were more increased in Caucasians than in African Americans with AD. In contrast, a module enriched with synaptic proteins including VGF, SCG2, and NPTX2 was significantly lower in African Americans than Caucasians with AD. Using a targeted proteomic approach (selected reaction monitoring) followed by a receiver operating characteristic curve (ROC) analysis we measured levels of VGF, SCG2, and NPTX2, which were significantly better at classifying African Americans than Caucasians with AD. Collectively, our findings provide insight into additional protein biomarkers and pathways reflecting underlying brain pathology that are shared or differ by race.

Quantitative proteomics of cerebrospinal fluid from African Americans and Caucasians reveals shared and divergent changes in Alzheimer’s disease

Insights into the changes in the proteome of Alzheimer disease elucidated by a meta-analysis

The development of disease‐modifying therapies against Alzheimer’s disease (AD) requires biomarker panels that reflect the diverse pathological pathways specifically involved in AD. Here we aimed to identify and validate panels of cerebrospinal fluid (CSF) proteins covering different molecular pathways for early and specific diagnosis of AD.

CSF protein panels reflecting multiple pathophysiological mechanisms for early and specific diagnosis of Alzheimer’s disease

The biological processes that are disrupted in the Alzheimer’s disease (AD) brain remain incompletely understood. We recently performed a proteomic analysis of >2000 brains to better understand these changes, which highlighted alterations in astrocytes and microglia as likely key drivers of disease.

Large‐scale deep multi‐layer analysis of Alzheimer’s disease brain reveals strong proteomic disease‐related changes not observed at the RNA level

Large-scale deep multi-layer analysis of Alzheimer’s disease brain reveals strong proteomic disease-related changes not observed at the RNA level

Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation

Targeted mass spectrometry to quantify brain-derived cerebrospinal fluid biomarkers in Alzheimer’s disease

The repeated failures of amyloid‐targeting therapies have underscored the need for additional biomarkers of Alzheimer’s disease (AD) that reflect its complex multi‐network dysfunction. Using a network‐based proteomic approach, we previously defined a wide range of protein system alterations in the AD brain. In this study, we integrated these brain networks with proteomic analysis of cerebrospinal fluid (CSF), resulting in the identification of CSF biomarker panels reflective of diverse pathophysiology within the AD brain.

Proteomics identifies CSF biomarker panels reflective of pathological networks in the Alzheimer's disease brain

Review for "Lack of association between LGMN and Alzheimer’s disease in the Southern Han Chinese population"

Integrative proteomic analysis identifies CSF biomarker panels linked to brain-based pathophysiologies in Alzheimer’s disease. Alzheimer’s disease (AD) lacks protein biomarkers reflective of its diverse underlying pathophysiology, hindering diagnostic and therapeutic advancements. Here, we used integrative proteomics to identify cerebrospinal fluid (CSF) biomarkers representing a wide spectrum of AD pathophysiology. Multiplex mass spectrometry identified ~3500 and ~12,000 proteins in AD CSF and brain, respectively. Network analysis of the brain proteome resolved 44 biologically diverse modules, 15 of which overlapped with the CSF proteome. CSF AD markers in these overlapping modules were collapsed into five protein panels representing distinct pathophysiological processes. Synaptic and metabolic panels were decreased in AD brain but increased in CSF, while glial-enriched myelination and immunity panels were increased in brain and CSF. The consistency and disease specificity of panel changes were confirmed in >500 additional CSF samples. These panels also identified biological subpopulations within asymptomatic AD. Overall, these results are a promising step toward a network-based biomarker tool for AD clinical applications.

Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease

Background: There is a need for novel biomarkers of Alzheimer’s disease (AD) that broadly serve as accurate indicators of the underlying pathophysiological processes occurring throughout disease. Thus, biomarker discovery should focus on identifying not only tar-gets that are easily accessible and reliably measured, but also those with clear associations to the most critical mechanisms driving neu-rodegeneration. To achieve this goal, we used an unbiased proteomic approach to quantify protein levels in AD cerebrospinal ﬂuid (CSF) and linked these changes to network-based pathophysiology in diseased brains. Methods: Using quantitative liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) we compara-tively analyzed the CSF proteomes from 40 samples, including 20 cognitively normal individuals (avg. MoCA ¼ 26.7) and 20 subjects with clinical diagnoses of AD (avg. MoCA ¼ 13.8). AD individuals demonstrated low amyloid (223.4 pg/mL) and high tau (143.5 pg/ mL) levels compared to controls (540.4 pg/mL and 70.2 pg/mL, respectively) as measured by ELISA. The top 14 most abundant proteins in each CSF samplewere depleted prior to proteolytic digestion and labeling with isobaric tandem-mass tags (TMT). Differential expression analysis resolved CSF proteins increased or decreased in AD. CSF protein biomarkers of AD were then mapped to TMT proteomic networks generated from control, AD, asymptomatic AD (AsymAD), and Parkinson’s disease (PD) postmortem brain tis-sue ( n ¼ 67 tissues). Results: CSF proteomic analysis revealed a total of 2,875 proteins across all 40 samples, of which w 70% were also measured in our brain proteome. Network analysis of the brain pro-teome identiﬁed a total of 8,817 proteins organized into 44 modules. Fifteen brain modules had a signiﬁcant overlap with proteins identiﬁed in CSF. Synaptic and mitochondrial proteins mapping to three modules enriched with neuronal markers showed overall decreased levels in the AD brain, but increased levels in AD CSF. Conversely, Tau and microglial proteins mapping to modules associated with neuroinﬂammation ( n ¼ 3) showed increased abundance in both the brain and CSF. Expression levels of these microglial modules in Asy-mAD brains indicated that these changes may start early in disease. Conclusions: These results provide a framework for identifying CSF markers highly reﬂective of underlying disease pathophysiology that could potentially serve as therapeutic targets. extracts vs CSF, and in normal vs AD CSF to evidence potential changes occurring during tau active secretion from neurons. Methods: We developed highly sensitive and speciﬁc mass spectrometry method using parallel reaction monitoring (PRM) to identify p-tau sites. This method enabled site-speciﬁc p-tau/tau rates measurements independent from abso-lute tau concentrations. Measurements were performed on sarko-syl-soluble tau from human brain lysates and CSF pools from participants with (n ¼ 5) and without AD (n ¼ 7) according to amyloid status. Results: We detected more than 30 distinct phosphorylated tau sites in sarkosyl-soluble human brain lysate and 12 sites on truncated tau in CSF. Phosphorylation comparison evidenced pT205 and pS208, that are recognized by AT8 antibody and deﬁne Braak stages of brain tau aggregation, were not detected in brain soluble tau but were found in both normal and AD CSF. Phosphorylation rates comparison evidenced that active release of tau from soluble brain fraction to CSF modiﬁed the phosphorylation abundance in a site-speciﬁc manner. CSF tau from non-AD participants were signiﬁcantly hyperphosphorylated at T111, T205, S208, T217 and T231. In AD CSF, hyperphosphorylation on these sites was exacerbated and phosphorylation on T153 and T175 were specif-ically detected. Inversely, we found S199 and S202 were hypophos-phorylated in normal CSF compared to brain, and not hyperphosphorylated in AD CSF. Conclusions: Tau phosphorylation sites are differentially affected in different compartment in central nervous system. Our results suggest CSF tau site-speciﬁc hyperphosphorylation is a physiological process, which may impli-cate a clearance mechanism protecting cells against intracellular accumulation of AT8 positive isoforms. This process is ampliﬁed by AD pathology, and sites with exacerbated hyperphosphorylation

AND PROTEOMICS INTEGRATIVE PROTEOMICS LINKS CEREBROSPINAL FLUID BIOMARKERS TO PATHOLOGICAL NETWORKS IN THE ALZHEIMER’S DISEASE BRAIN HIPPOCAMPAL ATROPHY

INTEGRATIVE PROTEOMICS LINKS CEREBROSPINAL FLUID BIOMARKERS TO PATHOLOGICAL NETWORKS IN THE ALZHEIMER’S DISEASE BRAIN

Here, we report a method for the generation of complementary tryptic (CompTryp) isotope-labeled peptide standards for the relative and absolute quantification of proteins by mass spectrometry (MS). These standards can be digested in parallel with either trypsin (Tryp-C) or trypsin-N (Tryp-N), to generate peptides that significantly overlap in primary sequence having C- and N-terminal arginine and lysine residues, respectively. As a proof of concept, an isotope-labeled CompTryp standard was synthesized for Tau, a well-established biomarker in Alzheimer's disease (AD), which included both N- and C-terminal heavy isotope-labeled (15N and 13C) arginine residues and flanking amino acid sequences to monitor proteolytic digestion. Despite having the exact same mass, the N- and C-terminal heavy Tau peptides are distinguishable by retention time and MS/MS fragmentation profiles. The isotope-labeled Tau CompTryp standard was added to human cerebrospinal fluid (CSF) followed by parallel digestion with Tryp-N and Tryp-C. The native and isotope-labeled peptide pairs were quantified by parallel reaction monitoring (PRM) in a single assay. Notably, both tryptic peptides were effective at quantifying Tau in human CSF, and both showed a significant difference in CSF Tau levels between AD and controls. Treating these CompTryp Tau peptide measurements as independent replicates also improved the coefficient of variation and correlation with Tau immunoassays. More broadly, we propose that CompTryp standards can be generated for any protein of interest, providing an efficient method to improve the robustness and reproducibility for MS analysis of clinical and research samples.

Mass Spectrometry-Based Quantification of Tau in Human Cerebrospinal Fluid Using a Complementary Tryptic Peptide Standard.

Identification of Conserved Proteomic Networks in Neurodegenerative Dementia

Deep proteomic network analysis of Alzheimer’s disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease

Polymorphic alleles in the apolipoprotein E (APOE) gene are the main genetic determinants of late-onset Alzheimer's disease (AD) risk. Individuals carrying the APOE E4 allele are at increased risk to develop AD compared to those carrying the more common E3 allele, whereas those carrying the E2 allele are at decreased risk for developing AD. How ApoE isoforms influence risk for AD remains unclear. To help fill this gap in knowledge, we performed a comparative unbiased mass spectrometry-based proteomic analysis of post-mortem brain cortical tissues from pathologically-defined AD or control cases of different APOE genotypes. Control cases (n = 10) were homozygous for the common E3 allele, whereas AD cases (n = 24) were equally distributed among E2/3, E3/3, and E4/4 genotypes. We used differential protein expression and co-expression analytical approaches to assess how changes in the brain proteome are related to APOE genotype. We observed similar levels of amyloid-β, but reduced levels of neurofibrillary tau, in E2/3 brains compared to E3/3 and E4/4 AD brains. Weighted co-expression network analysis revealed 33 modules of co-expressed proteins, 12 of which were significantly different by APOE genotype in AD. The modules that were significantly different by APOE genotype were associated with synaptic transmission and inflammation, among other biological processes. Deconvolution and analysis of brain cell type changes revealed that the E2 allele suppressed homeostatic and disease-associated cell type changes in astrocytes, microglia, oligodendroglia, and endothelia. The E2 allele-specific effect on brain cell type changes was validated in a separate cohort of 130 brains. Our systems-level proteomic analyses of AD brain reveal alterations in the brain proteome and brain cell types associated with allelic variants in APOE, and suggest further areas for investigation into the upstream mechanisms that drive ApoE-associated risk for AD.

Effects of APOE Genotype on Brain Proteomic Network and Cell Type Changes in Alzheimer's Disease

The Lunar Polar Hydrogen Mapper (LunaH-Map) mission will map the distribution of hydrogen around the lunar South Pole using a miniature neutron spectrometer. The mission builds upon a decade of lunar science, which has revealed both regional and more localized enrichments of water ice near the lunar poles. Localized enrichments are primarily within permanently shadowed regions (PSRs) and craters throughout the South Pole. The spatial extent of these regions is often below the resolution of previous neutron instruments that have flown on lunar missions. The neutron leakage spectrum from planetary surfaces is primarily sensitive to hydrogen abundance in the top meter of regolith, however, for neutron spectrometers with omnidirectional sensitivity, the spatial resolution is limited by the spacecraft orbital altitude above the surface. A low altitude measurement from a distance on the same scale of the PSRs could spatially isolate and constrain the hydrogen enrichments both within and around within those regions. A small spacecraft mission is ideally suited to acquire the low-altitude measurements required to localize hydrogen enrichments using neutron spectroscopy at the lunar South Pole. LunaH-Map will use a solid iodine ion propulsion system, X-Band radio communications through the NASA Deep Space Network, star tracker, Command & Data Handling System, and EPS systems from Blue Canyon Technologies, solar arrays from MMA Designs, LLC, mission design and navigation by KinetX. Spacecraft systems design, integration, qualification, test, and mission operations are performed by Arizona State University, AZ Space Technologies and Qwaltec.

Chalk is predominantly calcite, CaCO3, in the form of skeletal remains called coccoliths, produced by some species of algae. Chalk is permeable and can hold large volumes of oil but pore spaces are small and the particle surface properties control oil adhesion, hence reservoir productivity. Our goal was to investigate the surface composition of chalk particles as a clue for elucidating the controls on oil retention. Using a new method, we fished individual coccoliths from weakly consolidated chalk, using a silicon tip and an atomic force microscope (AFM). We isolated individual grains and placed them on transmission electron microscopy (TEM) grids. TEM showed intact coccoliths with a discontinuous layer (~25 to 50 nm thick) covering the individual elements. Energy dispersive X-ray spectrometry (EDXS) indicated Fe, K and Si:Al = 3:1, clear evidence for clay. It has grown over the calcite elements, implying that surfaces in contact with reservoir fluids, at least in some cases, are not calcite but clay. This would change wetting behaviour and may inhibit the recrystallisation necessary for diagenesis.

Dehydration of the subducting lithosphere induces oxidation and partial melting in the mantle wedge above subduction zones, and storage of water in the form of hydroxyl in high-pressure mineral phases may be an important mechanism for transfer of water to the mantle. It is therefore important to quantify water content of fluids and oxygen fugacity in subduction zones, but these variables can be difficult to measure or infer in many rocks. This study experimentally investigates the possibility of determining oxygen fugacity or water activity based on OH concentration measurements in rutile (TiO2), a common accessory mineral.

A Record of Magmatic Water Content Preserved in Hydroxyl Concentrations of Plagioclase Phenocrysts From the 1980-1981 Eruption Sequence of Mount St. Helens

It is important to know how to determine the speciation and concentration of H in feldspars because this information could be used to determine primary magmatic water activity or to estimate the degree of hydrothermal alteration in igneous rocks. FTIR spectroscopy is sensitive to changes in speciation of hydrogen, and can be calibrated for quantitative determination of H concentration using H MAS (magic-angle spinning) NMR spectroscopy. Three pegmatitic albites, one metamorphic albite, three volcanic plagioclases (albite, andesine, and anorthite) and one pegmatite oligoclase were used in this study to provide a range of plagioclase compositions. Two pegmatitic microclines and one sanidine were also studied. Polarized infrared spectra were obtained in the three principal optical directions for each specimen. Samples were prepared for H MAS NMR experiments at 12 kHz spinning speed in a dry box, without the use of a liquid grinding aid. A spectrum from anhydrous synthetic corundum was used as a baseline for feldspar NMR spectra. The pegmatitic and metamorphic albites are transparent, but contain submicroscopic fluid inclusions as evidenced by a broad band at 3400 cm and an asymmetric band at 5200 cm in the IR spectra that shift to bands characteristic of ice upon cooling to 77 K. These albites have a very sharp band at 4.7 ppm (relative to TMS) in their NMR spectra consistent with fluid inclusion water. In addition to the broad fluid inclusion band, the pegmatitic albites have sharp bands in the mid-IR similar the OH bands found in quartz. All other plagioclases have broad, anisotropic bands around 3200 cm in the mid-IR and MOH combination stretch-bend bands near 4500 cm in the near-IR, indicative of structural OH. The NMR spectra of these plagioclases have a broad band at 4.7 to 4.9 ppm TMS. The OH vector in plagioclases is preferentially aligned parallel to the a crystallographic axis. The concentration of structural OH in the plagioclases ranges from 50-200 ppm H2O by weight. The microclines contain structural H2O molecules (1000-1400 ppm H2O) and sanidine contains structural OH (170 ppm H2O). Plots of the total integrated mid-IR absorbance and total mid-IR peak height vs. concentration of structural H in plagioclase and alkali feldspars produce linear trends. Therefore, it is sufficient to use one absorption coefficient for both types of structural H (OH and H2O) in all feldspar compositions. The integral absorption coefficient for total mid-IR peak area is 16 ppm·cm or 114000 L·(mol H2O) ·cm. The absorption coefficient for total mid-IR peak height is 0.06 ppm·cm or 418 L·(mol H2O) ·cm. Since most of the mid-IR band intensity occurs with E\\a in plagioclase, it may be possible to determine H concentration in plagioclase using a single polarized spectrum with E\\a}, facilitating the measurement of H concentration in fine-grained or twinned natural feldspars.

An FTIR Calibration for Structural Hydrogen in Feldspars Using 1H MAS NMR

Introduction: Previous studies have established that hydrous species in nominally anhydrous minerals (NAMs) are an important potential reservoir of water in the mantle, but less is known about the role and significance of hydrogen in anhydrous crustal minerals. Trace amounts of hydrogen in feldspars are possibly preserved from original magmatic conditions or result from hydrothermal activity, and may be indicative of thermodynamic variables (ƒH2O or ƒO2) or the amount of water that has passed through a system (water/rock ratio). FTIR spectroscopy is a useful tool for studying hydrogen species in NAMs, but it must be calibrated using a separate method such as H magic-angle spinning (MAS) NMR to be quantitative. Previous workers [1], [2] have pointed out the difficulties of removing proton signals due to adsorption of water on grain boundaries and onto the NMR probe or rotor. Using careful sample preparation techniques and blanks the concentration and species (OH or H2O) of hydrogen in microcline and three plagioclase feldspars were determined with H MAS NMR, and FTIR absorption coefficients for these feldspars were calculated. Experimental Procedures: Feldspar samples used in this study were: microcline from the White Queen Mine pegmatite, CA; albite from Amelia, VA; anorthite from Miyake Island, Japan; and andesine from a tuff near Halloran Springs, CA. Samples free of inclusions were ground and packed into NMR rotors inside a dry box. No liquid was used as a grinding aid. H MAS NMR spectra were recorded using a Bruker DSX 500 MHz spectrometer and spinning speeds of 6-14 kHz. A 4 μs 90° – 8 μs 180° pulse depth sequence [3] was used to minimize probe background. Dry nitrogen was used for cooling and spinning samples during variable temperature experiments (173 – 373 K). TTMS was used as a chemical shift reference. Analcime from Table Mountain, CO, and ussingite from Ilímaussaq, Greenland, were run as hydrogen concentration standards. Synthetic corundum containing no hydrogen was prepared in the same way as the feldspar samples and was used as a blank. Polarized FTIR spectra were taken on a Nicolet Magna-860 spectrometer at 2 cm resolution. Results: The concentration of hydrogen in the microcline determined by NMR was 1300 ppm H2O by weight, compared to a concentration of 1400 ppm previously measured [4]. The plagioclase feldspars had lower hydrogen concentrations: 350 ppm in the albite, 45 ppm in the anorthite, and 110 ppm in the andesine. Spinning sideband intensities suggested the microcline contains structural hydrogen in the form of isolated H2O molecules, and the plagioclase feldspars contain structural OH. The albite and anorthite OH showed dynamic behavior on the time scale of NMR experiments. The chemical shift (in ppm vs. TTMS) of hydrogen peaks in each sample revealed greater hydrogen bonding and deshielding for ussingite OH groups (13.8, 15.5, and 11.0 ppm) compared to feldspar OH (albite, 4.8 and 5.0 ppm; anorthite, 5.0 ppm; and andesine, 4.8 and 2.1 ppm) and H2O (microcline, 4.7 ppm). FTIR integrated absorption coefficients (I’, in 1/(ppm•cm)) for the feldspars were calculated with Beer’s law using the hydrogen concentration determined by NMR and the integrated peak area of OH and H2O bands in the 3000-3700 cm -1 region of the IR spectra (Fig. 1). The absorption coefficient for all the feldspars in this study, regardless of hydrous species, is 16.13±3.83, determined by fitting a line through the data and the origin in Fig. 1. The albite IR spectra has sharp peaks overlying broad OH bands and might be expected to have different peak absorptivity from the other feldspar samples that only have broad OH bands. If the albite is excluded, an I’ = 15.51±0.74 is calculated. Future analysis of other samples will clarify if it is appropriate to use one or more I’ to calculate hydrogen concentration in feldspars using FTIR spectra. References: [1] Kohn S. C. (1996) Am. Min., 81, 1523–1526. [2] Keppler H. and Rauch M. (2000) Phys. Chem. Min., 27, 371-376. [3] Cory D. G. and Ritchey W. M. (1988) J. Magn. Reson., 80, 128–132. [4] Yesinowski J. P. et al. (1988) J. Am. Chem. Soc., 110, 1367-1375.

The Concentration and Speciation of Hydrogen in Feldspars from 1H MAS NMR and FTIR Spectroscopy

Carbon in Sediments at the KT Boundary Site of the Brazos River, Texas

utah county has the second largest county population in the state of utah and ranks 16th out of 29 in total land area over 90 of the countys quarter of a million residents live in the area known as utah valley a relatively narrow strip of land situated between the wasatch mountains and utah lake in addition to a large population most of which was realized during the 1970s utah valley also contains the bulk of the countys important agricultural land not surprisingly the expanding population in utah valley has created competition between agricultural and urban uses for limited land area what is surprising however is the extensive amount of relatively undisturbed agricultural land in utah county that in spite of rapid urban growth remains in close proximity to adjacent municipalities most of the urban and suburban growth in utah county has located within the boundaries of existing cities with little corresponding growth taking place in adjacent unincorporated areas research reveals that of the four most urban counties in the state utah county has more fully retained the nuclear pattern of settlement established by the mormon pioneers who settled the region compared with all of the counties in the state ter utah county has the second lowest percent of population living in unincorporated areas in fact the unincorporated population in utah county has actually declined since 1950 in spite of only a normal amount of land falling under city annexations and incorporations corporatio these peculiar characteristics have developed in utah county as a result of deliberately chosen countylevel nty planning l policies designed to protect greenbelt land and discourage residential expansion into unincorporated zones

County-Level Land Use Planning Policies and Regulations Impacting the Pattern of Settlement in Utah County, Utah

We develop a method for searching for Hajós constructions. Our results include the discovery of new constructions for some well-known graphs, including the Grötzsch graph, Chvátal graph, and Brinkmann graph; also, we prove that the first two of these are shortest possible constructions. These are the first published constructions for these graphs.

Reflections on America's first union depot : Indianapolis Union Station

Maskless Patterned Plasma Fabrication of Interdigitated Back Contact Silicon Heterojunction Solar Cells: Characterization and Optimization

When solar cells are used as the photoanode for direct water splitting, the output voltage required typically exceeds that of a single‐junction photovoltaic device. Toward this application, in this work, triple radial junction silicon nanowire (3RJ SiNW) solar cells are fabricated via a plasma‐assisted vapor‐liquid‐solid method using hydrogenated amorphous silicon (a‐Si:H) for all the absorber layers, as well as for the doped ones. A high open‐circuit voltage (VOC) of 2.05 V, short‐circuit current density (JSC) of 3.8 mA cm−2, and power conversion efficiency of 4.4% are obtained for solar cells with areas of 0.03 cm2 by optimizing the density of SiNWs grown on ZnO:Al/Ag/Corning glass substrates. For lower‐efficiency devices, however, VOC values as high as 2.2 V are consistently achieved. At these higher voltages, large variations in JSC are observed, attributed to small local variations in SiNW density. Herein, for the first time, the excellent potential of 3D radial junction solar cells for applications requiring high voltages and high surface areas, such as water splitting is demonstrated.

Triple Radial Junction Hydrogenated Amorphous Silicon Solar Cells with >2 V Open‐Circuit Voltage

Ultrathin Ge epilayers on Si produced by low-temperature PECVD acting as virtual substrates for III-V / c-Si tandem solar cells

We present results from the application of a novel, contactless patterning technique to form the doped fingers required for interdigitated back contact silicon heterojunction (IBC-SHJ) solar cells. The technique involves patterning the RF powered electrode in a custom-designed RF-PECVD chamber. The patterned powered electrode – which has 1 mm wide opening-slits in it - is brought in close proximity to the substrate surface, to localize the plasma and the process it performs. In this work, the localized plasma process being employed is an NF3/Ar etching, and is used to form doped fingers that are sub-mm wide and 60 mm long. The interdigitated structure (alternating electron and hole collection zones) is created by first uniformly depositing an intrinsic/n-type a-Si:H passivation stack, followed by an n-type/p-type µc-Si:H recombination junction on the rear side. A passivation layer is also deposited on the front side. The regions for the hole collection zones are then etched down to the intrinsic a-Si:H layer, and finally, a uniform p-type a-Si:H layer is deposited everywhere. The etched finger areas are first investigated by profilometry and spectroscopic ellipsometry, showing that the process can be controlled to leave as little as a few nanometers of passivating intrinsic a-Si:H. This fine control is achieved by pulsing the plasma, to slow the etching rate to a few Å/s. To evaluate the detailed opto-electronic properties of the structure, the samples are mapped out using two contactless techniques: Photoluminescence and Surface Photovoltage measurements (done with a macroscopic scanning Kelvin probe performed under dark and illuminated conditions). These measurements enable one to see both zones of degraded passivation, and the effectiveness of the doped regions in generating an open circuit voltage under illumination.

A Contactless Patterned Plasma Processing for Interdigitated Back Contact Silicon Heterojunction Solar Cells Fabrication

Plasma-enhanced chemical vapor deposition of silicon from a SiF4/H2/Ar gas mixture is observed on a SiOxNy surface, while under the same plasma conditions, silicon films do not grow on AlOx or on Al surfaces. Transmission electron microscopy confirms that the silicon deposited on SiOxNy has a microcrystalline structure. After the plasma process, fluorine is detected in abundance on the AlOx surface by x-ray photoelectron spectroscopy and energy dispersive x-ray chemical analyses. This suggests that Al–F bonds are formed on this surface, blocking any deposition of silicon on it. In situ ellipsometry studies show that deposition can be initiated on AlOx surfaces by increasing the temperature of the electrodes or increasing the RF plasma power, leading to a loss of selectivity.

Origin of area selective plasma enhanced chemical vapor deposition of microcrystalline silicon

Area selective deposition of silicon by plasma enhanced chemical vapor deposition using a fluorinated precursor

We present a novel technique to perform contactless and mask-free patterned plasma enhanced chemical vapour deposition and etching. When a powered electrode with narrow slits is placed very close to the substrate, plasma is selectively ignited within the slits due to the hollow cathode effect, and so deposition or etching occurs only within an area smaller than the size of the slit. This technique is demonstrated through the deposition of hydrogenated amorphous silicon using a gas mixture of hydrogen, argon and silane. Slits as small as 1 mm generate a plasma, and for this width, the lines deposited are about 750 μm wide, homogenous over their length (60 mm), and are deposited at a rate of 50 nm min−1. The phenomenon is studied using 2D Particle In Cell (PIC) modelling with a simplified argon chemistry. The electron localization observed in the PIC modelling provides an explanation of why the deposition is narrower than the slit.

Maskless and contactless patterned silicon deposition using a localized PECVD process

Observation of photovoltaic effect within locally doped silicon nanojunctions using conductive probe AFM

Driving radiofrequency capacitively coupled plasmas by multiharmonic tailored voltage waveforms (TVWs) has been shown to allow considerable control over various plasma properties for surface processing applications. However, industrial adoption of this technology would benefit from more efficient solutions to the challenge of impedance matching the radiofrequency power source to the load simultaneously at multiple harmonic frequencies. The authors report on the design and demonstration of a simple, practical multifrequency matchbox (MFMB) based on a network of LC resonant circuits. The performance of the matchbox was quantified in terms of a range of matchable impedances (when matching a single frequency at a time), as well as for the independence of each match to changes at adjacent harmonics. The effectiveness of the MFMB was demonstrated experimentally on an Ar plasma excited by a three-frequency TVW with a fundamental frequency of 13.56 MHz. Under the plasma conditions studied, the power coupling efficiency (at the generator output) was increased from less than 40% (without impedance matching) to between 80% and 99% for the different exciting frequencies.Driving radiofrequency capacitively coupled plasmas by multiharmonic tailored voltage waveforms (TVWs) has been shown to allow considerable control over various plasma properties for surface processing applications. However, industrial adoption of this technology would benefit from more efficient solutions to the challenge of impedance matching the radiofrequency power source to the load simultaneously at multiple harmonic frequencies. The authors report on the design and demonstration of a simple, practical multifrequency matchbox (MFMB) based on a network of LC resonant circuits. The performance of the matchbox was quantified in terms of a range of matchable impedances (when matching a single frequency at a time), as well as for the independence of each match to changes at adjacent harmonics. The effectiveness of the MFMB was demonstrated experimentally on an Ar plasma excited by a three-frequency TVW with a fundamental frequency of 13.56 MHz. Under the plasma conditions studied, the power coupling effi...

Experimental demonstration of multifrequency impedance matching for tailored voltage waveform plasmas

Erratum: Multi frequency matching for voltage waveform tailoring (2018 Plasma Sources Sci. Technol. 27 095012)

Microcrystalline silicon thin film deposition from silicon tetrafluoride: Isolating role of ion energy using tailored voltage waveform plasmas

We show how the use of TVW's allow one to access regimes of operation (in terms of ion current and energy) unavailable through standard, single frequency excitation (figure 2), in particular for the case of an electronegative plasma used to texture-etch a silicon wafer. Doing so, we show how using such a plasma excitation technique allows one to isolate and separate the roles of ion energy and flux.

Tailored Voltage Waveform Plasmas for Control of Surface Processing

Structural study of NiOx thin films fabricated by radio frequency sputtering at low temperature

In this paper, we use a fluid model to simulate the excitation of a hydrogen radio-frequency discharge, and employ tailored voltage waveforms to assess the effect of charged species transport properties. Results of the fluid simulation are compared with experimental data and previous results obtained with a hybrid model. Several expressions for electron and ion transport coefficients are compared, and their impact on the self-bias potential is studied. The self-bias is shown to be insensitive to the choice of electron transport coefficients, while remarkably sensitive to variations in ion mobility. Besides, our results show that fluid models can be competitive with hybrid models, provided self-consistent ion transport models and rate constants are used.

Impact of charged species transport coefficients on self-bias voltage in an electrically asymmetric RF discharge

We study light trapping and parasitic losses in hydrogenated amorphous silicon thin film solar cells fabricated by plasma-enhanced chemical vapor deposition on nanostructured back reflectors. The back reflectors are patterned using polystyrene assisted lithography. By using O2 plasma etching of the polystyrene spheres, we managed to fabricate hexagonal nanostructured back reflectors. With the help of rigorous modeling, we study the parasitic losses in different back reflectors, non-active layers, and last but not least the light enhancement effect in the silicon absorber layer. Moreover, simulation results have been checked against experimental data. We have demonstrated hexagonal nanostructured amorphous silicon thin film solar cells with a power conversion efficiency of 7.7% and around 34.7% enhancement of the short-circuit current density, compared with planar amorphous silicon thin film solar cells.

Optical Study and Experimental Realization of Nanostructured Back Reflectors with Reduced Parasitic Losses for Silicon Thin Film Solar Cells

Customized voltage waveforms composed of a number of frequencies and used as the excitation of radio-frequency plasmas can control various plasma parameters such as energy distribution functions, homogeneity of the ion flux, or ionization dynamics. So far this technology, while being extensively studied in academia, has yet to be established in applications. One reason for this is the lack of a suitable multi frequency matching network that allows for maximum power absorption for each excitation frequency that is generated and transmitted via a single broadband amplifier. In this work, a method is introduced for designing such a network based on network theory and synthesis. Using this method, a circuit simulation is established that connects an exemplary matching network to an equivalent circuit plasma model of a capacitive radio-frequency discharge. It is found that for a range of gas pressures and number of excitation frequencies the matching conditions can be satisfied, which proves the functionality and feasibility of the proposed concept. Based on the proposed multi frequency impedance matching, tailored voltage waveforms can be used at an industrial level.

Texturing optimization for bifacial n-PERT: are pyramids and/or black silicon the way to go for thinner devices?

Evolution of Microstructure and Incorporation of Excess Hydrogen During the Growth of Hydrogenated Polymorphous Silicon at High Rate

We examine the electrical benefits of creating contacts with sizes in the 1 μm range on partially contacted surfaces for c-Si PERC/L solar cells. In such a design, a dielectric layer that provides surface passivation is periodically opened to create contacts. Analytical models demonstrate that small contacts in the 1 μm range and separated by a few microns result in lower ohmic losses when compared to a typical contact configuration. In order to obtain a good surface passivation quality, surface recombination velocities below 103cm/s are needed for the contacted area. From PC-1D simulations of a reference structure, a clear advantage for small contacts is deduced for surface recombination at the contacts in the 102–105 cm/s range. Additionally, a fabrication process to achieve the desired contact configuration is described using Al 2 O 3 and thermally grown SiO 2 films. This process is based on colloidal lithography using polystyrene nanoparticles. For Al 2 O 3 films, an incomplete contact opening is observed, while much more repeatable results are obtained for SiO 2 films.

Partially contacted surfaces with contact size in the 1 μm range for c-Si PERC solar cells

Using a plasma to generate a surface texture with feature sizes on the order of tens to hundreds of nanometers ("nanotexturing") is a promising technique being considered to improve efficiency in thin, high-efficiency crystalline silicon solar cells. This study investigates the evolution of the optical properties of silicon samples with various initial surface finishes (from mirror polish to various states of micron-scale roughness) during a plasma nanotexturing process. It is shown that during said process, the appearance and growth of nanocone-like structures are essentially independent of the initial surface finish, as quantified by the auto-correlation function of the surface morphology. During the first stage of the process (2 min to 15 min etching), the reflectance and light-trapping abilities of the nanotextured surfaces are strongly influenced by the initial surface roughness; however, the differences tend to diminish as the nanostructures become larger. For the longest etching times (15 min or more), the effective reflectance is less than 5% and a strong anisotropic scattering behavior is also observed for all samples, leading to very elevated levels of light-trapping.

Plasma nanotexturing of silicon surfaces for photovoltaics applications: influence of initial surface finish on the evolution of topographical and optical properties.

Progress on Voltage Waveform Tailoring for plasmas: From science to process, from lab to fab

Improvement of near-infrared diffuse reflectance of silver back reflectors through Ag2O formation by a UV-ozone exposure process

Current-induced and light-induced macroscopic changes in thin film solar cells: Device degradation mechanism

Unravelling a simple method for the low temperature synthesis of silicon nanocrystals and monolithic nanocrystalline thin films

Deleterious electrostatic interaction in silicon passivation stack between thin ALD Al2O3 and its a-SiNX:H capping layer: numerical and experimental evidences

Low-pressure capacitively coupled radio frequency discharges operated in O2 and driven by tailored voltage waveforms are investigated experimentally and by means of kinetic simulations. Pulse-type (peaks/valleys) and sawtooth-type voltage waveforms that consist of up to four consecutive harmonics of the fundamental frequency are used to study the amplitude asymmetry effect as well as the slope asymmetry effect at different fundamental frequencies (5, 10, and 15 MHz) and at different pressures (50–700 mTorr). Values of the DC self-bias determined experimentally and spatio-temporal excitation rates derived from phase resolved optical emission spectroscopy measurements are compared with particle-in-cell/Monte Carlo collisions simulations. The spatio-temporal distributions of the excitation rate obtained from experiments are well reproduced by the simulations. Transitions of the discharge electron heating mode from the drift-ambipolar mode to the α-mode are induced by changing the number of consecutive harmonics included in the driving voltage waveform or by changing the gas pressure. Changing the number of harmonics in the waveform has a strong effect on the electronegativity of the discharge, on the generation of the DC self-bias and on the control of ion properties at the electrodes, both for pulse-type, as well as sawtooth-type driving voltage waveforms The effect of the surface quenching rate of oxygen singlet delta metastable molecules on the spatio-temporal excitation patterns is also investigated.

Power coupling mode transitions induced by tailored voltage waveforms in capacitive oxygen discharges

Hydrogenated polymorphous silicon (pm-Si:H) is a material consisting of a small volume fraction of nanocrystals embedded in an amorphous matrix. pm-Si:H solar cells demonstrate interesting initial degradation behaviors such as rapid initial change in photovoltaic parameters and large macroscopic structural change during light-soaking. The precise dynamics of the light-induced degradation was studied in a series of light-soaking experiments. Complementary studies reveal that the initial degradation of pm-Si:H solar cells originate from the modification of silicon-hydrogen bonding on the surface of silicon nanocrystals in pm-Si:H.

Real-time observation of light-induced macroscopic changes in thin film solar cells: Device degradation mechanism

Based on recent advancements of radial junction silicon nanowire (RJ SiNWs) solar cells, a demonstration of $5\mathrm{x}5 \pmb{\mathrm{cm}^{2}}$ RJ $\mathbf{SiNW}$ solar mini-module is presented in this work. The $\mathbf{SiNW}$ devices were grown by plasma-assisted vapor-liquid-solid technique at low temperature in a plasma-enhanced chemical vapor deposition reactor. The $\pmb{5\mathrm{x}5\ \mathrm{cm}^{2}}$ mini-modules have been obtained using a commercial laser scribing apparatus. The laser scribing insures a monolithic integration of electrically separated cells. We have obtained a power generation of 10 $\mathbf{mW}$ from 5 individual cells of total active area of 8.6 $\pmb{\mathrm{cm}^{2}}$. The mini-module has an open-circuit voltage of 3.85 V. The performance was evaluated using solar simulator and short comings (high series resistance) were analyzed using a home-made electroluminescence setup.

First Demonstration of Radial Junction Silicon Nanowire Solar Mini-Modules Prepared by PECVD and Laser Scribing

Tailored Voltage Waveforms in an SF6/O2 discharge: slope asymmetry and its effect on surface nanotexturing of silicon

In this paper, we investigate the excitation of a capacitively coupled plasma using a non-sinusoidal voltage waveform whose amplitude- and slope-asymmetry varies continuously with a period which is a multiple of the fundamental RF period. We call this period the ‘beating’ period. Through particle-in-cell (PIC) simulations, we show that such waveforms cause oscillation of the self-bias at this beating frequency, corresponding to the charging and discharging of the external capacitor. The amplitude of this self-bias oscillation depends on the beating period, the value of the external capacitor, and the ion flux to the electrodes. This self-bias oscillation causes temporal modulation of the ion flux distribution function (IFDF), albeit at a constant ion flux and constant mean ion energy, and allows the energy width of the IFDF (averaged over the beating period) to be varied in a controlled fashion.

Controlling the shape of the ion energy distribution at constant ion flux and constant mean ion energy with tailored voltage waveforms

The matrix-distributed electron cyclotron resonance plasma-enhanced chemical vapor deposition (MDECR-PECVD) technique has been shown to achieve high deposition rates for hydrogenated microcrystalline silicon (μc-Si:H) thin film. Due to the fact that plasma is sustained by a microwave discharge, by biasing the substrate holder with additional power supply, one can achieve independent control over the plasma density and the maximum ion bombardment energy (IBE). In this work, we present studies of the impact of IBE on the microstructural properties of the μc-Si:H film deposited by MDECR-PECVD. Insufficient ion bombardment is found to be responsible for the substantial presence of nano-porous regions within the material, resulting in significant post-deposition oxidation. Good agreement between transmission electron microscopy (TEM) Fresnel contrast analysis and the results of infrared absorption and hydrogen effusion measurements for the deposited films suggest that moderate IBE is of vital importance to achieve high quality μc-Si:H. In doing so, denser films with significantly decreased nano-porous regions and better stability are obtained, which is of great interest to optimize the process parameters for solar cell applications. (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Using MDECR-PECVD to study the impact of ion bombardment energy on microstructural properties of μc-Si:H thin film grown from an SiF4/H2 chemistry

Study of Electronic Properties of Hydrogenated Amorphous Silicon Thin Film from SiH4/H2 using Tailored Voltage Waveforms

For the growth of hydrogenated microcrystalline silicon (μc-Si:H) thin films by low temperature plasma-enhanced chemical vapor deposition (PECVD), silicon tetrafluoride (SiF4) has recently attracted interest as a precursor due to the resilient optoelectronic performance of the resulting material and devices. In this work, μc-Si:H films are deposited at high rates (7 Å s−1) from a SiF4 and hydrogen (H2) gas mixture by matrix-distributed electron cyclotron resonance PECVD (MDECR-PECVD). Increased substrate temperature and moderate ion bombardment energy (IBE) are demonstrated to be of vital importance to achieve high quality μc-Si:H films under such low process pressure and high plasma density conditions, presumably due to thermally-induced and ion-induced enhancement of surface species migration. Two well-defined IBE thresholds at 12 eV and 43 eV, corresponding respectively to SiF+ ion-induced surface and bulk atomic displacement, are found to be determinant to the final film properties, namely the surface roughness, feature size and crystalline content. Moreover, a study of the growth dynamics shows that the primary challenge to producing highly crystallized μc-Si:H films by MDECR-PECVD appears to be the nucleation step. By employing a two-step method to first prepare a highly crystallized seed layer, μc-Si:H films lacking any amorphous incubation layer have been obtained. A crystalline volume fraction of 68% is achieved with a substrate temperature as low as 120 °C, which is of great interest to broaden the process window for solar cell applications.

Microcrystalline silicon thin films deposited by matrix-distributed electron cyclotron resonance plasma enhanced chemical vapor deposition using an SiF4 /H2 chemistry

Unusual quasi-fivefold symmetric electron diffraction patterns are observed for silicon thin films grown by plasma-enhanced chemical vapour deposition and containing oxygen and carbon impurities in the range of 0.3–5.5%. These films were grown on crystalline (100) silicon wafers using a liquid precursor, hexa­methyl­disiloxane (HMDSO), mixed with silane, hydrogen and diborane diluted in argon. The occurrence of this quasi-fivefold symmetry is explained by multiple twinning and imperfect epitaxy. A quantitative method performed on the diffraction patterns is developed to evaluate the number of twin operations. This method is also used to discriminate twin positions from random microcrystalline ones in the diffraction patterns and thus to estimate their respective ratios for different growth conditions. Quite remarkably, the random microcrystalline part remains in the range of a few per cent and the diffracted intensities are the sum of two main contributions: multiple (micro-) twinned and amorphous. Increasing the amount of HMDSO decreases the microtwinned part directly to the benefit of the amorphous part with no significant microcrystalline phase. The causes of twinning are presented and discussed by comparing the observations with the literature; dynamical considerations where the system tends to align {111} planes with the growth direction would explain multiple twinning and, in turn, the fivefold symmetry.

Quasi‐fivefold symmetric electron diffraction patterns due to multiple twinning in silicon thin films grown from hexamethyldisiloxane

The invention relates to an impedance matching circuit, an assembly comprising such a circuit and a particular use of this set. The impedance matching circuit (100) is adapted to provide a simultaneous impedance matching between a generator (G) and a load (CH) to a power signal having at least two different frequencies to the the other, said circuit (100) comprising a floor (S1) impedance matching adapted to perform impedance matching between the generator and the load to the first frequency, this stage (S1) comprising a circuit (C1 ) comprising at least one tuning impedance (ZTUNE) intended to be mounted in series between the generator (G) and the load (CH) and a load impedance (ZLOAD) intended to be mounted between the generator (G) and mass, said circuit (100) for impedance matching further comprising at least one pair of additional stages (S2, S'2) adapted to perform impedance matching, simultaneously, between the generator and the load for the second frequency, said pair of additional stages (S2, S'2) compr oming: - a first additional stage (S2) having a charging circuit (C2) connected in parallel with respect to the load impedance (ZLOAD) of the stage (S1) impedance matching, said load circuit (C2) comprising at least one inductor (Lload2) and a capacitor (Cload2) connected in series, and - a second additional stage (S'2) having a tuning circuit (C'2) connected in series with respect to agreement impedance (ZTUNE) of the stage (S1) impedance matching, said tuning circuit (C'2) comprising at least one inductor (L'tune2) and a capacitor (C'tune2) connected in parallel, the impedance matching stage (S1) being also connected between the first additional stage (S2) and the second additional stage (S'2).

Circuit matching impedance between a generator and a load at multiple frequencies, together comprising such a circuit and utlisation linked.

Selective deposition for ''chamber clean-free'' processes using tailored voltage waveform plasmas

Summary form only given. The spatio-temporal electron impact excitation dynamics in a capacitively coupled RF discharge driven by tailored voltage waveforms in Ar and CF4 are investigated experimentally and by PIC simulations. In the experiment, the discharge is driven by up to three consecutive harmonics of 13.56 MHz with individually adjustable harmonics' amplitudes and phases based on a novel RF supply system at pressures between 3 Pa and 200 Pa. The excitation dynamics are investigated by Phase-Resolved Optical Emission Spectroscopy for different shapes of the driving voltage waveform (peaks/valleys/ sawtooth) at fixed total voltage amplitudes. The DC self bias and the ion energy distribution function (IEDF) at the electrodes are also measured. The formation of the IEDFs is understood based on a model that determines sheath voltage waveforms. It is demonstrated that the mean ion energy and the excitation dynamic can be controlled by adjusting the harmonics' phases. In CF4, strongly different excitation dynamics are observed compared to Ar at high pressures and are understood based on the simulation results. The plasma is divided spatially into two different halves of strongly different electronegativity for specific driving voltage waveforms. This asymmetry can be reversed by inverting the driving waveform. For Sawtooth waveforms, the discharge asymmetry and the sign of the DC self bias are found to reverse as the pressure is increased, due to a transition of the electron heating mode from the α-to the Drift-Ambipolar heating mode.

Electron power absorption dynamics and ion energy distributions in capacitive discharges driven by customized voltage waveforms in argon and CF4

Hydrogenated polymorphous silicon (pm-Si:H) is a material consisting of a small volume fraction of nanocrystals embedded in an amorphous matrix. pm-Si:H solar cells demonstrate interesting initial degradation behaviors such as rapid initial change in photovoltaic parameters and self-healing after degradation during light-soaking. The precise dynamics of the light-induced degradation was studied in a series of light-soaking experiments under various illumination conditions such as AM1.5G and filtered 570 nm yellow light. Hydrogen effusion experiment before and after light-soaking further revealed that the initial degradation of pm-Si:H solar cells originate from the modification of silicon–hydrogen bonding on the surface of silicon nanocrystals in pm-Si:H.

Light-induced changes in silicon nanocrystal based solar cells: Modification of silicon–hydrogen bonding on silicon nanocrystal surface under illumination

The use of hexamethyldisiloxane (HMDSO) as an oxygen source for the growth of p-type silicon-based layers deposited by Plasma Enhanced Chemical Vapor Deposition is evaluated. The use of this source led to the incorporation of almost equivalent amounts of oxygen and carbon, resulting in microcrystalline silicon oxycarbide thin films. The layers were examined with characterisation techniques including Spectroscopic Ellipsometry, Dark Conductivity, Fourier Transform Infrared Spectroscopy, Secondary Ion Mass Spectrometry and Transmission Electron Microscopy to check material composition and structure. Materials studies show that the refractive indices of the layers can be tuned over the range from 2.5 to 3.85 (measured at 600 nm) and in-plane dark conductivities over the range from 10-8 S/cm to 1 S/cm, suggesting that these doped layers are suitable for solar cell applications. The p-type layers were tested in single junction amorphous silicon p-i-n type solar cells.

Use of hexamethyldisiloxane for p-type microcrystalline silicon oxycarbide layers

We evaluate the use of p‐type silicon oxide (p‐SiOx) dielectric layers as a boron diffusion source for n‐type crystalline silicon (c‐Si) substrates. The p‐SiOx layers grown on n‐type c‐Si substrates by plasma enhanced chemical vapor deposition using a gas mixture of He/hexamethyldisiloxane/CO2/B2H6 are thermally stable and do not peel off during annealing up to 1050 °C, making them effective diffusion sources. The layers were examined before and after annealing with characterization techniques including spectroscopic ellipsometry and secondary ion mass spectrometry. We observe that there is a reduction in the thickness of the p‐SiOx layer after annealing by about 50%, and that boron diffuses into the n‐type c‐Si substrate, forming a p+ layer, limited by the formation of a carbon‐rich layer above the c‐Si surface. The concentration of holes in the diffused region was measured by the electrochemical capacitance–voltage technique, and it was found that essentially all the boron that diffused into the n‐type c‐Si was active, unaffected by the presence of carbon and oxygen atoms. The concentration of carriers can be controlled by the initial thickness of the p‐SiOx layers and the depth of the p+/n junction can be controlled by the time of annealing. A surface carrier concentration of 3 × 1019 at cm−3 and a sheet resistance of the order of 120 Ω sq−1 was obtained upon annealing at 1050 °C for 30 min.

Analysis of p‐type SiOx layers as a boron diffusion source for n‐type c‐Si substrates

In this work we focus on two techniques developed to extract the individual open circuit voltages (Voc) of tandem devices, as well as their sub‐cell current–voltage (I–V) characteristics. These were developed to work on the micromorph cell, the subcells of which have only a limited region of overlapping photoresponse due to the very different band gaps of its constituent cells, which allows for selective illumination. However, it is not known if such techniques will work in tandem structures consisting of high Voc structures (compared to the micromorph device), such as combinations of hydrogenated amorphous silicon oxide (a‐SiO:H), polymorphous silicon (pm‐Si:H), and amorphous silicon (a‐Si:H) in a‐SiO:H/pmSi:H a‐Si:H/pm‐Si:H device stacks. These novel structures have proven to suffer from less light induced degradation (LID), which is one of the main drawbacks of devices using a‐Si:H. The presence of similar band gaps (difference of less than 150 mV in both cases) and overlapping external quantum efficiencies (EQEs) above 500 nm implies that some of the hypotheses used may not be valid for high Voc devices. In this work we show the difficulties that arise when using these characterization techniques in such devices.

Challenges in advanced characterization techniques for high Voc thin‐film tandem solar cells

We report investigations of capacitively coupled carbon tetrafluoride (CF4) plasmas excited with tailored voltage waveforms containing up to five harmonics of a base frequency of 5.5 MHz. The impact of both the slope asymmetry, and the amplitude asymmetry, of these waveforms on the discharge is examined by combining experiments with particle-in-cell simulations. For all conditions studied herein, the discharge is shown to operate in the drift-ambipolar mode, where a comparatively large electric field in the plasma bulk (outside the sheaths) is the main mechanism for electron power absorption leading to ionization. We show that both types of waveform asymmetries strongly influence the ion energy at the electrodes, with the particularity of having the highest ion flux on the electrode where the lowest ion energy is observed. Even at the comparatively high pressure (600 mTorr) and low fundamental frequency of 5.5 MHz used here, tailoring the voltage waveforms is shown to efficiently create an asymmetry of both the ion energy and the ion flux in geometrically symmetric reactors.

Slope and amplitude asymmetry effects on low frequency capacitively coupled carbon tetrafluoride plasmas

Exciting processing plasmas using non-sinusoidal, “Tailored” voltage waveforms (TVWs), have recently been shown to be effective to separately control the maximum ion bombardment energy (IBE) and the ion flux on each electrode in the capacitively coupled plasma (RF-CCP) processes. In this work, we use it to deposit hydrogenated amorphous silicon (a-Si:H) thin films from hydrogen-diluted silane by low temperature plasma-enhanced chemical vapor deposition. The impact of using TVWs on the material's structural and electronic properties is examined. Excessively low IBE can lead to a high Si-H2bonded hydrogen content within the deposited films, which results in a deterioration of the material stability upon light-soaking, detectable at a microstructure level. A low content of hydrogen bonded in a Si-H2configuration and a low sub-gap density of states was observed in the film deposited using a “sawtooth-down” type of waveform. Such excitation also produced the a-Si:H films with the best transport properties (majority and minority carrier μτ-products and the ambipolar diffusion length) and stability under light-soaking. (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Deposition of a-Si:H thin films using tailored voltage waveform plasmas: impact on microstructure and stability

Plasma-Assisted Growth of Silicon Nanowires by Sn Catalyst: Step-by-Step Observation

New materials with electrical properties similar to those of hydrogenated amorphous silicon (a-Si:H) or hydrogenated amorphous silicon germanium alloys, but that are stable under light soaking, could be a breakthrough for multi-junction thin-film silicon solar cell technology. With this aim, hydrogenated microcrystalline silicon-carbon alloy (μ ?>c-Si1−xCx ?>:H) thin films seem like promising candidates as the variation of the carbon in the alloy composition can be used to tune the effective bandgap, keeping a high crystalline fraction. In this study, a highly hydrogen-diluted silane and methane gas mixture was used to deposit μ ?>c-Si1−xCx ?>:H thin films by radio frequency plasma enhanced chemical vapor deposition (RF-PECVD). The effect of the independent variation of three deposition parameters (variation of methane flow rate, addition of a small amount of silicon tetrafluoride and variation of the RF-power density) on the electronic transport and defect properties was investigated. Selected samples were studied in their ‘as deposited’ state, after light soaking until saturation, and after a high temperature annealing. Particular care was paid to comparing the behaviour of this new material system to that of a reference a-Si:H sample, deposited by standard RF-PECVD.

Electrical properties of hydrogenated microcrystalline silicon carbon alloys: effect of deposition parameters and light soaking

Density of states measurements of RF-power, SiF4 and CH4 –tuned-hydrogenated microcrystalline silicon carbon alloy thin films using Fourier transform photocurrent spectroscopy (FTPS)

Control of electron heating dynamics and DC self bias in electronegative capacitive CF$_{4}$ plasmas by voltage waveform tailoring

Gaining greater control and understanding of processing plasmas through Tailored Voltage Waveforms

Capacitively coupled CF 4 discharges excited by tailored waveforms: experiments and kinetic simulations

The ionization dynamics in geometrically symmetric parallel plate capacitively coupled plasmas driven by radio frequency tailored voltage waveforms is investigated using phase resolved optical emission spectroscopy (PROES) and particle-in-cell (PIC) simulations. Temporally asymmetric waveforms induce spatial asymmetries and offer control of the spatiotemporal dynamics of electron heating and associated ionization structures. Sawtooth waveforms with different rise and fall rates are employed using truncated Fourier series approximations of an ideal sawtooth. Experimental PROES results obtained in argon plasmas are compared with PIC simulations, showing excellent agreement. With waveforms comprising a fast voltage drop followed by a slower rise, the faster sheath expansion in front of the powered electrode causes strongly enhanced ionization in this region. The complementary waveform causes an analogous effect in front of the grounded electrode.

Strong ionization asymmetry in a geometrically symmetric radio frequency capacitively coupled plasma induced by sawtooth voltage waveforms.

Structural properties of hydrogenated microcrystalline silicon–carbon alloys deposited by Radio Frequency Plasma Enhanced Chemical Vapor Deposition: Effect of microcrystalline silicon seed layer and methane flow rate

Doping of Thin Film Silicon Layers Using Alternative Doping Precursors

Microcrystalline silicon deposited from SiF4/H2/Ar gas mixtures is used as active absorbing layer in thin film solar cells. Best solar cells are made from active layers deposited at the amorphous-to-microcrystalline transition where only a few percent of amorphous phase is present. Based on mass spectrometry measurements, we propose a simple model which accounts for the relevant features of the complex plasma chemistry: namely the depletion of H2, the formation of HF molecules and the amorphous to microcrystalline silicon transition. The specificity of SiF4/H2/Ar plasma is the ability to tightly tune the transition irrespective of the control of the deposition rate. A high crystalline fraction allows thicknesses above 3 μm with a high short-circuit current and no deterioration of the open-circuit voltage.

High efficiency thin film solar cells deposited at the amorphous-tomicrocrystalline transition using SiF4/H2/Ar gas mixtures

Evolution in morphological, optical, and electronic properties of ZnO:Al thin films undergoing a laser annealing and etching process

In the search for a material with electrical properties similar to those of amorphous silicon or amorphous silicon germanium, but stable under light soaking, hydrogenated microcrystalline silicon–carbon alloy (µc-Si1 − xCx:H) thin films are a promising candidate. The interest in these materials lies in the possibility of varying the effective band gap by changing the amount of carbon in the alloy composition, while keeping a high crystalline fraction to maintain stability under light-soaking. In this study, µc-Si1 − xCx:H thin films were deposited by radio frequency (RF) plasma enhanced chemical vapour deposition using a silane and methane gas mixture highly diluted in hydrogen. Three deposition parameters were investigated as a means to control the film crystallinity: the RF power density, the methane flow rate and the presence of a small amount of silicon tetrafluoride in the gas mixture. Although all three parameters can result in materials with a Raman crystalline volume fraction above 50%, it is shown that they result in very different microstructures, as evidenced by x-ray diffraction and scanning transmission electron microscopy analyses. A growth model is proposed to explain the influence of each of these parameters on the final film structure.

Use of radio frequency power, silicon tetrafluoride and methane as parameters to tune structural properties of hydrogenated microcrystalline silicon carbon alloys

The use of tailored voltage waveforms to excite a plasma has been shown to be an effective technique to decouple maximum ion energy from the ion flux on the electrode. We use it here as a way to scan through the maximum ion energy in order to study this quantity's role in the growth of μc-Si:H. We find that at critical energies (30 and 70 eV), a stepwise increase in the a-Si:H/μc-Si:H transition thickness is observed, together with change in the surface morphology. These thresholds correspond to SiHx+- and H3+ -induced displacement energies, respectively. A model is proposed to account for the impact of these ions on the morphology of μc-Si:H growth and is confirmed by comparison with epitaxial growth on a crystalline wafer.

Effect of Ion Energy on Microcrystalline Silicon Material and Devices: A Study Using Tailored Voltage Waveforms

The influence of textured transparent conducting oxide (TCO) substrate and p -layer on the performance of single-junction hydrogenated polymorphous silicon ( pm -Si:H) solar cells has been addressed. Comparative studies were performed using p - i - n devices with identical i / n -layers and back reflectors fabricated on textured Asahi U-type fluorine-doped SnO 2 , low-pressure chemical vapor deposited (LPCVD) boron-doped ZnO and sputtered/etched aluminum-doped ZnO substrates. The p -layers were hydrogenated amorphous silicon carbon and microcrystalline silicon oxide. As expected, the type of TCO and p -layer both have a great influence on the initial conversion efficiency of the solar cells. However they have no effect on the defect density of the pm -Si:H absorber layer.

Substrate and p-layer effects on polymorphous silicon solar cells

We report on the growth of microcrystalline silicon films from the dissociation of SiF4/H2/Ar gas mixtures. For this growth chemistry, the formation of HF molecules provides a clear signature of the amorphous to microcrystalline growth transition. Depositing films from silicon tetrafluoride requires the removal of F produced by SiF4 dissociation, and this removal is promoted by the addition of H2 which strongly reacts with F to form HF molecules. At low H2 flow rates, the films grow amorphous as all the available hydrogen is consumed to form HF. Above a critical flow rate, corresponding to the full removal of F, microcrystalline films are produced as there is an excess of atomic hydrogen in the plasma. A simple yet accurate phenomenological model is proposed to explain the SiF4/H2 plasma chemistry in accordance with experimental data. This model provides some rules of thumb to achieve high deposition rates for microcrystalline silicon, namely, that increased RF power must be balanced by an increased H2 flow rate.

Understanding the amorphous-to-microcrystalline silicon transition in SiF4/H2/Ar gas mixtures.

Influence of sputtering conditions on the optical and electrical properties of laser-annealed and wet-etched room temperature sputtered ZnO:Al thin films

Structural and electrical properties of hydrogenated microcrystalline silicon-carbon alloys deposited at low substrate temperature by RF-PECVD

The use of Tailored Voltage Waveforms is a technique wherein one uses non-sinusoidal waveforms with a period equivalent to RF frequencies to excite a plasma. It has been shown to be an effective technique to decouple maximum Ion Bombardment Energy (IBE) from the ion flux at the surface of the electrodes. In this paper, we use it for the first time as a way to scan through the IBE in order to study the growth mechanism of hydrogenated microcrystalline silicon using a SiH4/H2 chemistry. We find that at critical energies, a stepwise increase in the amorphous to microcrystalline transition thickness is observed, as detected by Real Time Spectroscopic Ellipsometry. The same energy thresholds (30 eV and 70 eV) are found to be very influential on the final surface morphology of the samples, as observed by Atomic Force Microscopy. These thresholds correspond to SiHx+ bulk displacement (30 eV) and Hx+ (70 eV) surface displacement energies. A model is therefore proposed to account for the impact of these ions on th...

Growth mechanisms study of microcrystalline silicon deposited by SiH4/H2 plasma using tailored voltage waveforms

Understanding Light Harvesting in Radial Junction Amorphous Silicon Thin Film Solar Cells

Plasma-enhanced chemical vapor deposition (PECVD) enables epitaxial silicon deposition for up to several micrometers and at low temperatures (as low as 150 °C). We present herein a detailed study of the effect of ion energy at high (above 2 torr) and low (below 1 torr) pressure, where the plasma and surface reactions are expected to be different, i.e., driven, respectively, by high-order and low-order silane precursors. We find a sharp energy threshold at low pressure, above which no epitaxy can be obtained, but this threshold is relaxed at high pressure. The occurrence of epitaxy breakdown is studied and compared in detail for these two different pressure regimes.

Ion Energy Threshold in Low-Temperature Silicon Epitaxy for Thin-Film Crystalline Photovoltaics

Two sets of hydrogenated microcrystalline silicon carbon alloys were deposited by standard radio frequency (RF) plasma enhanced chemical vapor deposition at a substrate temperature of 175 °C. The effect of the methane flow rate and of the RF-power were investigated. Samples were deposited from a silane and methane gas mixture, highly diluted in hydrogen. The increase in methane flow rates leads to a decrease of the crystalline volume fraction and an increase in carbon incorporation. On the other hand, decreasing the RF-power shifts the microcrystalline-to-amorphous transition at higher methane flow rates. Moreover, for similar amount of carbon incorporated, the decrease in RF-power leads to materials showing higher crystalline volume fraction and average grains sizes. Both ion bombardment energy and carbon incorporation contributes to the microstructural properties of the deposited alloys. (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Low temperature hydrogenated microcrystalline silicon-carbon alloys deposited by RF-PECVD

Impact on Thin Film Silicon Properties and Solar Cell Parameters of Texture Generated by LaserAnnealing and Chemical Etching of ZnO:Al

Using a range of different diagnostics we have performed a detailed experimental characterization of a capacitively coupled rf plasma discharge excited by tailored voltage waveforms in argon (3–13 Pa). The applied pulse-type tailored waveforms consist of between 1 and 5 harmonics (with a fundamental of 15 MHz), and are used to generate an electrically asymmetric plasma response, manifested by the formation of a strong dc bias in the geometrically symmetric reactor used. Experimental measurements of the dc bias, electron density, ion current density, ion-flux energy distributions at the electrodes and discharge current waveforms, are compared with a one-dimensional particle-in-cell simulation for the same operating conditions. The experimental and simulation results are found to be in good agreement over the range of parameters investigated, and demonstrate a number of unique features present with pulse-type tailored waveforms, including: increased plasma density and ion flux with the number of harmonics, and a broader control range of the ion bombarding energy.

Radio-frequency capacitively coupled plasmas excited by tailored voltage waveforms: comparison of experiment and particle-in-cell simulations

Structural and electrical characterization of microcrystalline silicon-carbon alloys deposited by RF-PECVD

Thin Film Deposition with Tailored Voltage Waveforms: Material Questions and Practical Answers

Polarized Raman spectroscopy analysis of SiHX bonds in nanocrystalline silicon thin films

We report on the use of an innovative optical characterization technique—real-time Mueller polarimetric imaging in transmission—for the characterization of thin-film silicon solar cells. In this work, we used this technique to monitor the evolution of optical retardance induced by the mechanical stresses in hydrogenated amorphous and polymorphous silicon (a-Si : H and pm-Si : H) p–i–n (PIN) solar cells. Under current injection of 200 mA cm−2, the retardance of the pm-Si : H PIN solar cells decreased, while that of the a-Si : H PIN solar cells showed no significant change. After the current injection, the pm-Si : H PIN solar cells showed dramatic macroscopic changes on a scale of tens of micrometres, such as local peel-off and delamination from the substrate. Our results demonstrate that current injection introduces local stress relaxation, which can be efficiently monitored prior to irreversible damage from a decrease in the retardance of the pm-Si : H PIN solar cells.

Real-time transmission Mueller polarimetry on hydrogenated polymorphous silicon under current injection

Substrate versus superstrate configuration for stable thin film silicon solar cells

Tailored Voltage deposition of µc-Si1-xCx:H from H2 diluted SiH4 and CH4 gas mixtures

We report on light-induced electrical and macroscopic changes in hydrogenated polymorphous silicon (pm-Si:H) PIN solar cells. To explain the particular light-soaking behavior of such cells - namely an increase of the open circuit voltage (Voc ) and a rapid drop of the short circuit current density (Jsc )- we correlate these effects to changes in hydrogen incorporation and structural properties in the layers of the cells. Numerous techniques such as current-voltage characteristics, infrared spectroscopy, hydrogen exodiffusion, Raman spectroscopy, atomic force microscopy, scanning electron microscopy and spectroscopic ellipsometry are used to study the light-induced changes from microscopic to macroscopic scales (up to tens of microns). Such comprehensive use of complementary techniques lead us to suggest that light-soaking produces the diffusion of molecular hydrogen, hydrogen accumulation at p-layer/substrate interface and localized delamination of the interface. Based on these results we propose that light-induced degradation of PIN solar cells has to be addressed from not only as a material issue, but also a device point of view. In particular we bring experimental evidence that localized delamination at the interface between the p-layer and SnO2 substrate by light-induced hydrogen motion causes the rapid drop of Jsc.

Light induced electrical and macroscopic changes in hydrogenated polymorphous silicon solar cells

Irreversible light-induced degradation and stabilization of hydrogenated polymorphous silicon solar cells

The use of tailored voltage waveforms (TVW's) to excite a plasma for the deposition of thin films of hydrogenated microcrystalline silicon (µc-Si:H) has been shown to be an effective technique to decouple mean ion bombardment energy (IBE) from injected power. In this work, we examine the changes in material properties controlled by this technique through Raman scattering and spectroscopic ellipsometry for films deposited from H2-diluted SiH4, and we examine the electrical properties of such films using temperature dependent conductivity. As the laboratory-scale deposition system used had neither a load lock nor an oxygen filter in the H2 line, accidental O-doping was observed for the µc-Si:H films. We investigated suppression of this doping by adding varying amounts of SiF4, and using an SiF4/Ar pre-etch step to clean the reactor. This technique is shown to be effective in decreasing the accidental doping of the films, and intrinsic µc-Si:H films are produced with an activation energy of up to 0.55 eV. As well, an important difference in the amorphous-to-microcrystalline transition is observed once SiF4 is included in the gas mixture.

Tailored Voltage Waveform Deposition of Microcrystalline Silicon Thin Films from Hydrogen-Diluted Silane and Silicon Tetrafluoride: Optoelectronic Properties of Films

Hydrogenated microcrystalline silicon thin films deposited by RF-PECVD under low ion bombardment energy using voltage waveform tailoring

Thin film solar cells in a p-i-n structure with an absorbing layer of intrinsic hydrogenated microcrystalline silicon (μc-Si:H) deposited through plasma enhanced chemical vapour deposition excited by tailored voltage waveforms have been prepared. The use of an asymmetric voltage waveform decouples the ion-bombardment energy at the growth surface from the injected power and allows the growth of good quality μc-Si:H at reasonable deposition rates (3 A/s) using low pressure, powder-free conditions. Unoptimized photovoltaic devices with an efficiency of 6.1% are demonstrated using an i-layer deposited at 1.3 A/s and a process pressure of 500 mTorr.

Microcrystalline silicon solar cells deposited using a plasma process excited by tailored voltage waveforms

We experimentally characterize an argon plasma in a geometrically symmetric, capacitively coupled rf discharge, excited by pulse-type tailored waveforms (generated using multiple voltage harmonics). The results confirm a number of predictions made by recent particle-in-cell simulations of a similar system and demonstrate a unique form of control over the ion flux and ion energy in capacitively coupled plasmas; by increasing the number of applied harmonics (equivalent to decreasing the pulse width), it is possible to increase the plasma density and ion flux (together with the power deposition) while keeping the average ion energy on one of the electrodes low and constant.

Separate control of the ion flux and ion energy in capacitively coupled radio-frequency discharges using voltage waveform tailoring

Light Induced Changes in PIN Solar Cells: Beyond the Staebler-Wronski Effect

We summarize our research studies on the synthesis of silicon and germanium nanocrystals and their application to the growth of a variety of thin films, spanning the range from fully disordered amorphous up to fully ordered crystalline. All these films are deposited in a standard radio-frequency glow discharge system at low temperature (~200 °C). We show how the plasma synthesis of silicon nanocrystals, initially a side effect of powder formation, has become over the years an exciting field of research which has opened the way to new opportunities in the field of materials deposition and their application to optoelectronic devices. Our results suggest that epitaxy requires the melting/amorphization of the nanocrystals upon impact on the substrate, the subsequent epitaxial growth being favored on (100) c-Si substrates. As a consequence, the control of the impact energy is a critical aspect of the growth which will require new strategies such as the use of tailored voltage waveforms.

Low Temperature Plasma Synthesis of Nanocrystals and their Application to the Growth of Crystalline Silicon and Germanium Thin Films

Excimer laser annealing and chemical texturing of ZnO:Al sputtered at room temperature for photovoltaic applications

In studying photovoltaic devices made with silicon thin films and considering them according to their grain size, it is curious that as the crystalline fraction increases, the open-circuit voltage (V oc ) – rather than approaching that of the single-crystal case – shows a decline. To gain an insight into this behavior, observed in hydrogenated microcrystalline silicon (μ c-Si:H) solar cells prepared under a variety of deposition conditions, we have used a detailed electrical-optical computer modeling program, ASDMP. Two typical μ c-Si:H cells with low (~79%) and higher (~93%) crystalline volume fractions (F c ), deposited in our laboratory and showing this general trend, were modeled. From the parameters extracted by simulation of their experimental current density – voltage and quantum efficiency characteristics, it was inferred that the higher F c cell has both a higher band gap defect density as well as a lower band gap energy. Our calculations reveal that the proximity of the quasi-Fermi levels to the energy bands in cells based on highly crystallized μ c-Si:H (assumed to have a lower band gap), results in both higher free and trapped carrier densities. The trapped hole population, that is particularly high near the P/I interface, results in a strong interface field, a collapse of the field in the volume, and hence a lower open-circuit voltage. Interestingly enough, we were able to fabricate fluorinated μ c-Si:H:F cells having 100% crystalline fraction as well as very large grains, that violate the general trend and show a higher V oc . Modeling indicates that this is possible for the latter case, as also for a crystalline silicon PN cell, in spite of a sharply reduced band gap, because the lower effective density of states at the band edges and a sharply reduced gap defect density overcome the effect of the lower band gap.

Factors limiting the open-circuit voltage in microcrystalline silicon solar cells

Control of Nanocrystalline Silicon Growth Phase and Deposition Rate through Voltage Waveform Tailoring during PECVD

This article investigates the optimal efficiency of a photovoltaic system based on a silicon thin film tandem cell using polymorphous and microcrystalline silicon for the top and bottom elementary cells, respectively. Two ways of connecting the cells are studied and compared: (1) a classical structure in which the two cells are electrically and optically coupled; and (2) a new structure for which the “current-matching” constraint is released by the electrical decoupling of the two cells. For that purpose, we used a computer simulation to perform geometrical optimization of the studied structures as well as their electrical performance evaluation. The simulation results show that the second structure is more interesting in terms of efficiency.

Geometrical optimization and electrical performance comparison of thin-film tandem structures based on pm-Si:H and μc-Si:H using computer simulation

Room Temperature Fabricated ZnO:Al with Elevated and Unique Light-Trapping Performance

Tailored Voltage Waveforms for the Deposition of Microcrystalline Silicon

Assignment of High Wave-number Absorption and Raman Scattering Peaks in Microcrystalline Silicon

The dynamics of the open‐circuit voltage (VOC) of polymorphous silicon (pm‐Si:H) solar cells deposited at high and low rates (8 and 1.5 Å/s, HR and LR) and containing lightly or heavily doped p‐layers (LD or HD) are compared through in situ, variable intensity measurements during light‐soaking (LS). The VOC's of the LR cells show an increase with LS, regardless of doping level, whereas the HR cells show decreasing VOC's. This result is in contrast to the changes predicted by the dark diode characteristics, which predict increasing VOC for all the devices. The device measurements are compared to the analogous measurements on co‐deposited coplanar p–i layer stacks to determine whether the VOC dynamics can be linked to changes in the p‐layer doping efficiency during LS. The changes to the macroscopic electrical behaviour of the cell under varying light conditions are modelled using a simple, three parameter function, and are compared to results from a detailed, numerical modelling tool, AFORS‐HET.

Open‐circuit voltage increase dynamics in high and low deposition rate polymorphous silicon solar cells

Performance of microcrystalline silicon single and double junction solar cells of different degrees of crystallinity

Control of Microcrystalline Silicon Deposition by RF Waveform Tailoring

Plasma synthesis of silicon nanocrystals as a new route for large area electronic applications

We have studied the solar cell behaviour under variable light intensity (VLI) of a standard a-Si:H pin solar cell with a wide band gap a-SiC:H emitter layer, and microcrystalline (μc)-Si:H solar cells of different degrees of crystallinity, using experiments in conjunction with detailed electrical-optical modelling. Both experiments and modelling reveal that whereas the fill factor (FF) of the a-Si:H pin cell decreases with increasing light intensity, starting from a low applied light bias, that of the μc-Si:H cells increases with light intensity over a major part of this range. This fact enables one to attain the maximum of the open-circuit voltage - fill factor product (Voc x FF) at 1 to 2 suns intensity for the latter case; however this is not achieved for the a-Si:H cell. Using modelling we try to understand this difference in behaviour of the FF under VLI for the two types of cells. We also predict under what conditions it would be possible to shift the (Voc x FF)max for the a-Si:H cell towards one sun intensity. (© 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Performance of amorphous and microcrystalline silicon pin solar cells under variable light intensity

In this article, the authors investigate the contamination of hydrogenated amorphous silicon thin films with aluminum recycled from the walls and electrodes of the deposition reactor. Thin films of hydrogenated amorphous silicon were prepared under various conditions by a standard radio frequency plasma enhanced chemical vapor deposition process in two reactors, the chambers of which were constructed of either aluminum or stainless steel. The authors have studied the electronic properties of these thin films and have found that when using an aluminum reactor chamber, the layers are contaminated with aluminum recycled from the chamber walls and electrode. This phenomenon is observed almost independently of the deposition conditions. The authors show that this contamination results in slightly p-doped films and could be detrimental to the deposition of device grade films. The authors also propose a simple way to control and eventually suppress this contamination.

Aluminum recycling from reactor walls: A source of contamination in a-Si:H thin films

We demonstrate the application of RF waveform tailoring to generate an electrical asymmetry in a capacitively coupled plasma-enhanced chemical vapour deposition system, and its use to control the growth mode of hydrogenated amorphous and nanocrystalline silicon thin films deposited at low temperature (150 °C). A dramatic shift in the dc bias potential at the powered electrode is observed when simply inverting the voltage waveform from ‘peaks’ to ‘troughs’, indicating an asymmetric distribution of the sheath voltage. By enhancing or suppressing the ion bombardment energy at the substrate (situated on the grounded electrode), the growth of thin silicon films can be switched between amorphous and nanocrystalline modes, as observed using in situ spectroscopic ellipsometry. The effect is observed at pressures sufficiently low that the collisional reduction in average ion bombardment energy is not sufficient to allow nanocrystalline growth (<100 mTorr).

Nanocrystalline silicon film growth morphology control through RF waveform tailoring

In-Situ Observation of High Deposition Rate Hydrogenated Polymorphous Silicon Cell Degradation through Variable Intensity Method Measurements

Raman scattering analysis of SiH bond stretching modes in hydrogenated microcrystalline silicon for use in thin-film photovoltaics

The electrical potential at the substrate surface during the growth of hydrogenated microcrystalline silicon in a direct current saddle field (SF) plasma enhanced chemical vapor deposition (PECVD) system has been previously shown to be a limiting factor for the formation of the microcrystalline phase in the resulting thin films. The authors examine the extension of this concept to large areas under conditions necessary to obtain microcrystalline silicon in a SF-PECVD system—namely the use of hydrogen-diluted silane as a source gas, pressures between 100 and 300 mTorr, and substrate electrical bias between 100 and 250 V. The response of the SF-PECVD system to electrical substrate bias under these conditions is examined in detail, and four regimes of operation are identified, only one of which is useful for the growth of this particular material system. The delineation of these regimes provides new constraints and guidelines for the application of SF-PECVD technology to large-area deposition of thin films sensitive to ion bombardment during growth, such as microcrystalline silicon.The electrical potential at the substrate surface during the growth of hydrogenated microcrystalline silicon in a direct current saddle field (SF) plasma enhanced chemical vapor deposition (PECVD) system has been previously shown to be a limiting factor for the formation of the microcrystalline phase in the resulting thin films. The authors examine the extension of this concept to large areas under conditions necessary to obtain microcrystalline silicon in a SF-PECVD system—namely the use of hydrogen-diluted silane as a source gas, pressures between 100 and 300 mTorr, and substrate electrical bias between 100 and 250 V. The response of the SF-PECVD system to electrical substrate bias under these conditions is examined in detail, and four regimes of operation are identified, only one of which is useful for the growth of this particular material system. The delineation of these regimes provides new constraints and guidelines for the application of SF-PECVD technology to large-area deposition of thin films s...

Operational regimes of the saddle field plasma enhanced chemical vapor deposition system

Polymorphous and Nanocrystalline Silicon Thin-Film Solar Cells Deposited at 150°C on Plastic Substrates

It is generally accepted that increasing the deposition rate of amorphous (a-Si : H) and microcrystalline (μc-Si : H) thin films grown by plasma enhanced chemical vapour deposition leads to a deterioration in the films' properties. This ‘common sense’ rule places an upper limit on the deposition rate for a given film quality and thus on photovoltaic device efficiency. While this applies to a-Si : H and μc-Si : H films produced by the dissociation of silane and grown via the ‘radical path’, we have found that it is possible to increase the deposition rate and still improve or maintain film properties when the deposition process involves not only radicals but also silicon nanocrystals produced in the plasma. This will be illustrated in the case of polymorphous (pm-Si : H) and microcrystalline (μc-Si : H) materials and solar cells. The transfer of these processes from small area reactors to industrial ones is an exciting challenge for the low pressure plasma community, and one whose solution will open a route to lower cost photovoltaics in particular and large area electronics in general.

Low temperature plasma synthesis of silicon nanocrystals: a strategy for high deposition rate and efficient polymorphous and microcrystalline solar cells

We demonstrate the directional growth of Ge on a GaAs {100} wafer at 175°C using radio-frequency plasma-enhanced chemical vapor deposition at 13.56MHz under conditions where nanocrystals are the primary contributors to film growth. High resolution transmission electron microscopy (HRTEM) verifies the transport of plasma-formed nanocrystals to the substrate surface where they are initially mobile. Furthermore, cross-sectional HRTEM images show directional growth on the GaAs wafer, wherein the incident Ge nanocrystals have adopted the orientation of the underlying lattice.

Directional growth of Ge on GaAs at 175°C using plasma-generated nanocrystals

Polymorphous silicon thin films deposited at high rate : Transport properties and density of states

Device grade hydrogenated polymorphous silicon deposited at high rates

The open-circuit voltage in microcrystalline silicon solar cells of different degrees of crystallinity

Microcrystalline silicon thin film pin solar cells with a highly crystallized intrinsic μc‐Si:F:H absorber were prepared by RF‐plasma enhanced chemical vapour deposition using SiF4 as the gas precursor. The cells were produced with a vacuum break between the doped layer and intrinsic layer depositions, and the effect of different subsequent interface treatment processes was studied. The use of an intrinsic μc‐Si:H p/i buffer layer before the first air break increased the short circuit current density from 22.3 mA/cm2 to 24.7 mA/cm2. However, the use of a hydrogen‐plasma treatment after both air breaks without an interface buffer layer improved both the open circuit voltage and the fill factor. Although the material used for the absorber layer showed a very high crystalline fraction and thus an increased spectral response at long wavelengths, an open‐circuit voltage (VOC) of 0.523 V was nevertheless observed. Such a value of VOC is higher than is typically obtained in devices that employ a highly crystallized absorber as reported in the literature (see abstract figure). Using a hydrogen‐plasma treatment, a single junction μc‐Si:F:H pin solar cell with an efficiency of 8.3% was achieved.

Decoupling crystalline volume fraction and VOC in microcrystalline silicon pin solar cells by using a µc‐Si:F:H intrinsic layer

Why does the open-circuit voltage in a micro-crystalline silicon PIN solar cell decrease with increasing crystalline volume fraction?

Application of High Deposition Rate (9 A/s) pm-Si:H to Photovoltaic Modules

We present a material study on RF PECVD-grown a-Ge:H showing that thin films of such material can be produced without using the conventional techniques of high power density or powered-electrode substrate placement. We demonstrate the production of material with PDS signatures superior to material produced at ten times higher power density. This is achieved through the use of Ar and H 2 dilution and by growing the films at high pressures under conditions where nanocrystals formed in the gas phase contribute significantly to the growth as confirmed by HRTEM. The conditions described result in material which demonstrates activated conduction down to room temperature. Additionally, the quality of the material has been demonstrated through its application in n-i-p diodes. A spectral response at 0.9um of 0.38 and an AM1.5 efficiency of 2.1% have been demonstrated utilizing an absorber layer thickness of only 60nm.

High Quality a-Ge:H Films and Devices Through Enhanced Plasma Chemistry

Spectral response and field enhanced reverse current in a-Ge:H nip photodiodes

Physical, electrical, and optical properties of SF-PECVD-grown hydrogenated microcrystalline silicon with growth surface electrical bias

Raman scattering characterization of SF-PECVD-grown hydrogenated microcrystalline silicon thin films using growth surface electrical bias

Dependence of Microcrystalline Silicon Growth on Ion Flux at the Substrate Surface in a Saddle Field PECVD

We have been developing an instrument that combines the techniques of x‐ray photoelectron spectroscopy and zone plate microfocusing to perform spectromicroscopy. The X1A undulator provides a bright photon source in the soft x‐ray range with a high degree of spatial coherence (a requirement for zone plate focusing). A spherical grating monochromator selects the desired photon energy in the 280–800 eV range. A Fresnel zone plate focuses the beam to a small spot. Photoelectron spectra can be acquired from the small irradiated area with an electron energy analyzer. With the beam focused on the surface and the sample mechanically scanned, element‐specific or chemical‐state‐specific images of the surface can be obtained.

Development of a second generation scanning photoemission microscope with a zone plate generated microprobe at the National Synchrotron Light Source

The Second Generation Scanning Photoemission Microscope at the beamline X1a of the National Synchrotron Light Source (NSLS), X1A SPEM II, is designed for spatially resolved elemental and chemical analysis by X-ray Photoelectron Spectroscopy (XPS) on material surfaces. Based on Fresnel Zone Plate (ZP) microfocusing techniques with the use of a bright and coherent photon source, this microscope is capable of acquiring XPS spectra from a small area irradiated by the focused beam and taking element-specific (using photopeaks) or chemical-state-specific (by detecting the chemical core level shifts) images with a spatial resolution defined by the focused spot size.

Applications of the Xia Scanning Photoemission Spectromicroscope for Element Identification on Material Surfaces

Recent advances in human stem cell-derived brain organoids promise to replicate critical molecular and cellular aspects of learning and memory and possibly aspects of cognition in vitro. Coining the term “organoid intelligence” (OI) to encompass these developments, we present a collaborative program to implement the vision of a multidisciplinary field of OI. This aims to establish OI as a form of genuine biological computing that harnesses brain organoids using scientific and bioengineering advances in an ethically responsible manner. Standardized, 3D, myelinated brain organoids can now be produced with high cell density and enriched levels of glial cells and gene expression critical for learning. Integrated microfluidic perfusion systems can support scalable and durable culturing, and spatiotemporal chemical signaling. Novel 3D microelectrode arrays permit high-resolution spatiotemporal electrophysiological signaling and recording to explore the capacity of brain organoids to recapitulate the molecular mechanisms of learning and memory formation and, ultimately, their computational potential. Technologies that could enable novel biocomputing models via stimulus-response training and organoid-computer interfaces are in development. We envisage complex, networked interfaces whereby brain organoids are connected with real-world sensors and output devices, and ultimately with each other and with sensory organ organoids (e.g. retinal organoids), and are trained using biofeedback, big-data warehousing, and machine learning methods. In parallel, we emphasize an embedded ethics approach to analyze the ethical aspects raised by OI research in an iterative, collaborative manner involving all relevant stakeholders. The many possible applications of this research urge the strategic development of OI as a scientific discipline. We anticipate OI-based biocomputing systems to allow faster decision-making, continuous learning during tasks, and greater energy and data efficiency. Furthermore, the development of “intelligence-in-a-dish” could help elucidate the pathophysiology of devastating developmental and degenerative diseases (such as dementia), potentially aiding the identification of novel therapeutic approaches to address major global unmet needs.

Organoid intelligence (OI): the new frontier in biocomputing and intelligence-in-a-dish

Carbon dioxide (CO2) is a critical biological signal that is noxious to many animals at high concentrations. The earthworm Dendrobaena veneta lives in subterranean burrows containing high levels of CO2 and respires through its skin. Despite the ecological and agricultural importance of earthworms, relatively little is known about how they make decisions in their environment, including their response to elevated levels of CO2. To examine CO2 detection in this species, we designed the exudate assay, in which we placed an earthworm in a sealed container, exposed it to varying concentrations of CO2 for one minute, and recorded the amount of exudate secreted. Because earthworms excrete exudate in response to noxious stimuli, we hypothesized that the amount of exudate produced was proportional to the amount of irritation. We repeated these experiments after treatment with several blockers for molecules with potential involvement in CO2 detection, including carbonic anhydrases, guanylate cyclase, TRPA1 channels, ASICs, and OTOP channels. We also confirmed the presence of homologous transcripts for each of these gene families in an epithelial transcriptome for D. veneta. Additionally, since organisms often detect CO2 levels indirectly by monitoring the conversion to carbonic acid (a weak acid), we used the exudate assay to evaluate aversion to additional weak acids (formic acid, acetic acid, and propionic acid). Earthworms excreted significantly more exudate in response to CO2 in a dosage-dependent manner, and this response was muted by the general carbonic anhydrase inhibitor acetazolamide, the carbonic anhydrase IX/XII inhibitor indisulam, the calcium channel blocker ruthenium red, the sodium channel blocker amiloride, and the acid-sensing ion channel blocker diminazene aceturate. These data provide evidence of the role of carbonic anhydrase and ENaCs in earthworm CO2 detection and contribute to our understanding of the mechanisms used by earthworms to detect and react to weak acids in their environment. Contribution to the field statement: Carbon dioxide (CO2) is a major byproduct of cellular respiration and an important biological signal. The metabolism of animals living underground in burrows can cause the concentration of CO2 to increase above atmospheric CO2. Most animals have multiple molecular mechanisms that detect CO2 and find high concentrations aversive or noxious; some subterranean animals have adaptations that make them more tolerant of concentrated CO2. Earthworms live in burrows, are a keystone species for subterranean ecosystems, and in their lightless environment must rely primarily on tactile and chemical signals. Despite the profound importance of earthworms to the ecosystems, few if any of the molecular mechanisms they use to detect these signals have been characterized. Here we use RNA sequencing to develop a list of candidate mechanisms that the European nightcrawler may use to respond to CO2. We also have developed an assay for comparing how noxious different concentrations of volatile compounds are to earthworms. In the present study, we utilize that assay with inhibitors to further narrow the possible multiple molecular mechanisms responsible for the detection of CO2. We suspect that our study is among the first attempts to combine RNA-sequencing technology and pharmacology to describe earthworm sensory biology.

Mechanisms of carbon dioxide detection in the earthworm Dendrobaena veneta

In insects, adipokinetic hormone is the primary hormone responsible for the mobilization of stored energy. While a growing body of evidence has solidified the role of adipokinetic hormone (AKH) in modulating the physiological and behavioral responses to metabolic stress, little is known about the upstream endocrine circuit that directly regulates AKH release. We evaluated the AKH-producing cell (APC) transcriptome to identify potential regulatory elements controlling APC activity and found that a number of receptors showed consistent expression levels, including all known dopamine receptors and the pigment dispersing factor receptor (PDFR). We tested the consequences of targeted genetic knockdown and found that APC limited expression of RNAi elements corresponding to each dopamine receptor and caused a significant reduction in survival under starvation. In contrast, PDFR knockdown significantly extended lifespan under starvation, whereas expression of a tethered PDF in APCs resulted in significantly shorter lifespans. These manipulations caused various changes in locomotor activity under starvation. We used live-cell imaging to evaluate the acute effects of the ligands for these receptors on APC activation. Dopamine application led to a transient increase in intracellular calcium in a trehalose-dependent manner. Furthermore, coapplication of dopamine and ecdysone led to a complete loss of this response, suggesting that these two hormones act antagonistically. We also found that PDF application led to an increase in cAMP in APCs and that this response was dependent on expression of the PDFR in APCs. Together, these results suggest a complex circuit in which multiple hormones act on APCs to modulate metabolic state.

Modulation of Metabolic Hormone Signaling via a Circadian Hormone and Biogenic Amine in Drosophila melanogaster

All organisms confront the challenges of maintaining metabolic homeostasis in light of both variabilities in nutrient supplies and energetic costs of different physiologies and behaviors. While all cells are nutrient sensitive, only relative few cells within Metazoans are nutrient sensing cells. Nutrient sensing cells organize systemic behavioral and physiological responses to changing metabolic states. One group of cells present in the arthropods, is the adipokinetic hormone producing cells (APCs). APCs possess intrinsic nutrient sensors and receive contextual information regarding metabolic state through other endocrine connections. APCs express receptors for different hormones which modulate APC physiology and the secretion of the adipokinetic hormone (AKH). APCs are functionally similar to alpha cells in the mammalian pancreas and display a similar physiological organization. AKH release results in both hypertrehalosemia and hyperlipidemia through high affinity binding to the AKH receptor (AKHR). Another hallmark of AKH signaling is heightened locomotor activity, which accompanies starvation and is thought to enhance foraging. In this review, we discuss mechanisms of nutrient sensing and modulation of AKH release. Additionally, we compare the organization of AKH/AKHR signaling in different taxa. Lastly, we consider the signals that APCs integrate as well as recent experimental results that have expanded the functional repertoire of AKH signaling, further establishing this as both a metabolic and stress hormone.

The Intrinsic Nutrient Sensing Adipokinetic Hormone Producing Cells Function in Modulation of Metabolism, Activity, and Stress

Adipokinetic Hormone (AKH) is the primary insect hormone that mobilizes stored energy and is functional equivalent to mammalian glucagon. While most studies have focused on exploring the functional roles of AKH, relatively little is known about how AKH secretion is regulated. We assessed the AKH cell transcriptome and mined the data set for specific insight into the identities of different ion channels expressed in this cell lineage. We found reliable expression of multiple ion channel genes with multiple members for each ionic species. Specifically, we found significant signals for 39 of the either known or suspected ion channel genes within the Drosophila genome. We next performed a targeted RNAi screen aimed to identify the functional contribution of these different ion channels that may participate in excitation-secretion coupling in AKH producing cells (APCs). We assessed starvation survival, because changes in AKH signaling have previously been shown to impact starvation sensitivity. Genetic knockdown of three genes (Ca-Beta, Sur, and sei), in AKH producing cells caused highly significant changes (P < 0.001) in both male and female lifespan, and knockdown of six other genes (Shaw, cac, Ih, NaCP60E, stj, and TASK6) caused significant changes (P < 0.05) in only female lifespan. Specifically, the genetic knockdown of Ca-Beta and Sur led to increases in starvation lifespan, whereas the knockdown of sei decreased starvation survivorship. Focusing on these three strongest candidates from the behavioral screen, we assessed other AKH-dependent phenotypes. The AKH hormone is required for starvation-induced hyperactivity, and we found that these three ion channel gene knockdowns changed activity profiles and further suggest a modulatory role of these channels in AKH release. We eliminated the possibility that these genetic elements caused AKH cell lethality, and using independent methods, we verified expression of these genes in AKH cells. Collectively, these results suggest a model of AKH-cell excitability and establish an experimental framework for evaluating intrinsic mechanisms of AKH release.

Regulation of Metabolism by an Ensemble of Different Ion Channel Types: Excitation-Secretion Coupling Mechanisms of Adipokinetic Hormone Producing Cells in Drosophila

In insects, Adipokinetic hormone is the primary hormone responsible for the mobilization of stored energy. While a growing body of evidence has solidified AKH’s role in modulating the physiological and behavioral responses to metabolic stress, little is known about the upstream endocrine circuit that directly regulates AKH release. We evaluated the AKH-expressing cell transcriptome to identify potential regulatory elements controlling AKH cell activity, and found that a number of receptors show consistent expression levels, including all known dopamine receptors, dopamine ecdysone receptor (DopEcR), Dopamine 2-like receptor (D2R), Dopamine 1-like receptor 2 (DopR2), DopR, and the Pigment Dispersing Factor (PDFR). We tested the consequences of targeted genetic knockdown and found that RNAi elements targeting each dopamine receptor caused a significant reduction in survival under starvation. In contrast, PDFR knockdown significantly extended lifespan under starvation whereas expression of a tethered PDF in AKH cells resulted in a significantly shorter lifespan during starvation. These manipulations also caused various changes in locomotor activity under starvation. Specifically, there were higher amounts of locomotor activity in dopamine receptor knockdowns, in both replete and starved states. PDFR knockdown resulted in increased locomotion during replete conditions and locomotion levels that were comparable to wild-type during starvation. Expression of a membrane-tethered PDF led to decreased locomotion under baseline and starvation. Next, we used live-cell imaging to evaluate the acute effects of the ligands for these receptors (dopamine, ecdysone, and Pigment Dispersing Factor) on AKH cell activation. Dopamine application led to a transient increase in intracellular calcium in a sugar-dependent manner. Furthermore, we found that co-application of dopamine and ecdysone led to a complete loss of this response, suggesting that these two hormones are acting antagonistically. We also found that PDF application directly led to an increase in cAMP in AKH cells, and that this response was dependent on expression of the PDFR in AKH cells. Together these results suggest a complex circuit in which multiple hormones act on AKH cells to modulate metabolic state.

Modulation of metabolic hormone signaling via a circadian hormone and a biogenic amine in Drosophila melanogaster

Homodimerization of Drosophila Class A neuropeptide GPCRs: Evidence for conservation of GPCR dimerization throughout metazoan evolution.

Unexpected role of a conserved domain in the first extracellular loop in G protein-coupled receptor trafficking.

There has been disagreement over the functional roles of the painless gene product in the detection and subsequent behavioral aversion to the active ingredient in wasabi, allyl isothiocyanate (AITC). Originally, painless was reported to eliminate the behavioral aversion to AITC, although subsequent reports suggested that another trpA homolog, dTRPA1, was responsible for AITC aversion. We re-evaluated the role of the painless gene in the detection of AITC, employing several different behavioral assays. Using the proboscis extension reflex (PER) assay, we observed that AITC did not reduce PER frequencies in painless or dTRPA1 mutants but did in wild-type genotypes. Quantification of food intake showed a significant decline in food consumption in the presence of AITC in wild-type, but not painless mutants. We adapted an oviposition choice assay and found wild-type oviposit on substrates lacking AITC, in contrast to painless and dTRPA1 mutants. Lastly, tracking individual flies relative to a point source of AITC, showed a consistent clustering of wild-type animals away from the point source, which was absent in painless mutants. We evaluated expression patterns of both dTRPA1 and painless, which showed expression in distinct central and peripheral populations. We identified the transmitter phenotypes of subsets of painless and dTRPA1 neurons and found similar neuropeptides as those expressed by mammalian trpA expressing neurons. Using a calcium reporter, we observed AITC-evoked responses in both painless and dTRPA1 expressing neurons. Collectively, these results reaffirm the necessity of painless in nociceptive behaviors and suggest experiments to further resolve the molecular basis of aversion.

Behavioral Aversion to AITC Requires Both Painless and dTRPA1 in Drosophila

Sex Steroid Hormones Regulate Leptin Transcript Accumulation and Protein Secretion in 3T3-L1 Cells

2.21 – Stressed Out Insects II. Physiology, Behavior, and Neuroendocrine Circuits Mediating Stress Responses

Insect growth is punctuated by molts, during which the animal produces a new exoskeleton. The molt culminates in ecdysis, an ordered sequence of behaviors that causes the old cuticle to be shed. This sequence is activated by Ecdysis triggering hormone (ETH), which acts on the CNS to activate neurons that produce neuropeptides implicated in ecdysis, including Eclosion hormone (EH), Crustacean cardioactive peptide (CCAP) and Bursicon. Despite more than 40 years of research on ecdysis, our understanding of the precise roles of these neurohormones remains rudimentary. Of particular interest is EH; although it is known to upregulate ETH release, other roles for EH have remained elusive. We isolated an Eh null mutant in Drosophila and used it to investigate the role of EH in larval ecdysis. We found that null mutant animals invariably died at around the time of ecdysis, revealing an essential role in its control. Further analyses showed that these animals failed to express the preparatory behavior of pre-ecdysis while directly expressing the motor program of ecdysis. Although ETH release could not be detected, the lack of pre-ecdysis could not be rescued by injections of ETH, suggesting that EH is required within the CNS for ETH to trigger the normal ecdysial sequence. Using a genetically encoded calcium probe, we showed that EH configured the response of the CNS to ETH. These findings show that EH plays an essential role in the Drosophila CNS in the control of ecdysis, in addition to its known role in the periphery of triggering ETH release. Summary: The Drosophila Eclosion hormone null mutant phenotype reveals an essential role for Eclosion hormone in the CNS, where it is required for Ecdysis triggering hormone to activate ecdysis.

Genetic analysis of Eclosion hormone action during Drosophila larval ecdysis

Identification of a Circadian Output Circuit for Rest:Activity Rhythms in Drosophila

Connecting nutrient sensing and the endocrine control of metabolic allocation in insects.

Adipokinetic hormone (AKH) is the equivalent of mammalian glucagon, as it is the primary insect hormone that causes energy mobilization. In Drosophila, current knowledge of the mechanisms regulating AKH signaling is limited. Here, we report that AMP-activated protein kinase (AMPK) is critical for normal AKH secretion during periods of metabolic challenges. Reduction of AMPK in AKH cells causes a suite of behavioral and physiological phenotypes resembling AKH cell ablations. Specifically, reduced AMPK function increases life span during starvation and delays starvation-induced hyperactivity. Neither AKH cell survival nor gene expression is significantly impacted by reduced AMPK function. AKH immunolabeling was significantly higher in animals with reduced AMPK function; this result is paralleled by genetic inhibition of synaptic release, suggesting that AMPK promotes AKH secretion. We observed reduced secretion in AKH cells bearing AMPK mutations employing a specific secretion reporter, confirming that AMPK functions in AKH secretion. Live-cell imaging of wild-type AKH neuroendocrine cells shows heightened excitability under reduced sugar levels, and this response was delayed and reduced in AMPK-deficient backgrounds. Furthermore, AMPK activation in AKH cells increases intracellular calcium levels in constant high sugar levels, suggesting that the underlying mechanism of AMPK action is modification of ionic currents. These results demonstrate that AMPK signaling is a critical feature that regulates AKH secretion, and, ultimately, metabolic homeostasis. The significance of these findings is that AMPK is important in the regulation of glucagon signaling, suggesting that the organization of metabolic networks is highly conserved and that AMPK plays a prominent role in these networks.

Energy-Dependent Modulation of Glucagon-Like Signaling in Drosophila via the AMP-Activated Protein Kinase

Organisms must utilize multiple mechanisms to maintain energetic homeostasis in the face of limited nutrient availability. One mechanism involves activation of the heterotrimeric AMP-activated protein kinase (AMPK), a cell-autonomous sensor to energetic changes regulated by ATP to AMP ratios. We examined the phenotypic consequences of reduced AMPK function, both through RNAi knockdown of the gamma subunit (AMPKγ) and through expression of a dominant negative alpha (AMPKα) variant in Drosophila melanogaster. Reduced AMPK signaling leads to hypersensitivity to starvation conditions as measured by lifespan and locomotor activity. Locomotor levels in flies with reduced AMPK function were lower during unstressed conditions, but starvation-induced hyperactivity, an adaptive response to encourage foraging, was significantly higher than in wild type. Unexpectedly, total dietary intake was greater in animals with reduced AMPK function yet total triglyceride levels were lower. AMPK mutant animals displayed starvation-like lipid accumulation patterns in metabolically key liver-like cells, oenocytes, even under fed conditions, consistent with a persistent starved state. Measurements of O2 consumption reveal that metabolic rates are greater in animals with reduced AMPK function. Lastly, rapamycin treatment tempers the starvation sensitivity and lethality associated with reduced AMPK function. Collectively, these results are consistent with models that AMPK shifts energy usage away from expenditures into a conservation mode during nutrient-limited conditions at a cellular level. The highly conserved AMPK subunits throughout the Metazoa, suggest such findings may provide significant insight for pharmaceutical strategies to manipulate AMPK function in humans.

Altered Metabolism and Persistent Starvation Behaviors Caused by Reduced AMPK Function in Drosophila

Four Irritating Odorants Target the Trigeminal Chemoreceptor TRPA1

All organisms are confronted with dynamic environmental changes that challenge homeostasis, which is the operational definition of stress. Stress produces adaptive behavioral and physiological responses, which, in the Metazoa, are mediated through the actions of various hormones. Based on its associated phenotypes and its expression profiles, a candidate stress hormone in Drosophila is the corazonin neuropeptide. We evaluated the potential roles of corazonin in mediating stress-related changes in target behaviors and physiologies through genetic alteration of corazonin neuronal excitability. Ablation of corazonin neurons confers resistance to metabolic, osmotic, and oxidative stress, as measured by survival. Silencing and activation of corazonin neurons lead to differential lifespan under stress, and these effects showed a strong dependence on sex. Additionally, altered corazonin neuron physiology leads to fundamental differences in locomotor activity, and these effects were also sex-dependent. The dynamics of altered locomotor behavior accompanying stress was likewise altered in flies with altered corazonin neuronal function. We report that corazonin transcript expression is altered under starvation and osmotic stress, and that triglyceride and dopamine levels are equally impacted in corazonin neuronal alterations and these phenotypes similarly show significant sexual dimorphisms. Notably, these sexual dimorphisms map to corazonin neurons. These results underscore the importance of central peptidergic processing within the context of stress and place corazonin signaling as a critical feature of neuroendocrine events that shape stress responses and may underlie the inherent sexual dimorphic differences in stress responses.

Corazonin Neurons Function in Sexually Dimorphic Circuitry That Shape Behavioral Responses to Stress in Drosophila

SUMMARY In Drosophila, two related G-protein-coupled receptors are members of the corticotropin releasing factor (CRF) receptor subfamily. We have previously reported that one of these receptors, encoded by CG8422 is a functional receptor for a diuretic hormone, DH44. Here, we report that the other CRF receptor subfamily member, encoded by CG12370, is also a receptor for the DH44 neuropeptide. The lines of evidence to support this identification include increases in cAMP levels due to CG12370 receptor activation and the recruitment of β-arrestin–GFP to the plasma membrane in response to DH44 application. We compared these features of the receptors DH44-R2 (encoded by CG12370) and DH44-R1 (encoded by CG8422) and found fundamental differences in signaling, association with the arrestins, and peptide sensitivity. We found that the sensitivity of DH44-R2 to the DH44 peptide is lower than that of DH44-R1, specifically an estimated EC50 of 7.98E-07 moll–1 for DH44 by DH44-R2 to an EC50 of 5.12E-09 moll–1 by DH44-R1 and found that previous reports on the sensitivity of the tubule to DH44 is in agreement with our measurements of DH44-R2 sensitivity. We employed a specific RNAi construct to selectively knock-down DH44-R2 expression and this led to heightened sensitivity to osmotic challenges. The functional characterization of this diuretic hormone receptor in Drosophila demonstrates a high degree of conservation of CRF-like signaling.

Functional differences between two CRF-related diuretic hormone receptors in Drosophila

31 – Stressed-Out Insects: Hormonal Actions and Behavioral Modifications

Functional characterization of kurtz, a Drosophila non-visual arrestin, reveals conservation of GPCR desensitization mechanisms.

SUMMARY Recent studies have firmly established pigment dispersing factor (PDF), a C-terminally amidated octodecapeptide, as a key neurotransmitter regulating rhythmic circadian locomotory behaviours in adult Drosophila melanogaster. The mechanisms by which PDF functions as a circadian peptide transmitter are not fully understood, however; in particular, nothing is known about the role of extracellular peptidases in terminating PDF signalling at synapses. In this study we show that PDF is susceptible to hydrolysis by neprilysin, an endopeptidase that is enriched in synaptic membranes of mammals and insects. Neprilysin cleaves PDF at the internal Ser7–Leu8 peptide bond to generate PDF1-7 and PDF8-18. Neither of these fragments were able to increase intracellular cAMP levels in HEK293 cells cotransfected with the Drosophila PDF receptor cDNA and a firefly luciferase reporter gene, confirming that such cleavage results in PDF inactivation. The Ser7–Leu8 peptide bond was also the principal cleavage site when PDF was incubated with membranes prepared from heads of adult Drosophila. This endopeptidase activity was inhibited by the neprilysin inhibitors phosphoramidon (IC50, 0.15 μmol l–1) and thiorphan (IC50, 1.2 μmol l–1). We propose that cleavage by a member of the Drosophila neprilysin family of endopeptidases is the most likely mechanism for inactivating synaptic PDF and that neprilysin might have an important role in regulating PDF signals within circadian neural circuits.

Metabolic inactivation of the circadian transmitter, pigment dispersing factor (PDF), by neprilysin-like peptidases in Drosophila

Neuropeptides related to vertebrate tachykinins have been identified in Drosophila. Two Drosophila G-protein-coupled receptors (GPCRs), designated NKD (CG6515) and DTKR (CG7887), cloned earlier, display sequence similarities to mammalian tachykinin receptors. However, they were not characterized with the endogenous Drosophila tachykinins (DTKs). The present study characterizes one of these receptors, DTKR. We determined that HEK-293 cells transfected with DTKR displayed dose-dependent increases in both intracellular calcium and cyclic AMP levels in response to the different DTK peptides. DTK peptides also induced internalization of DTKR-green fluorescent protein (GFP) fusion constructs in HEK-293 cells. We generated specific antireceptor antisera and showed that DTKR is widely distributed in the adult brain and more scarcely in the larval CNS. The distribution of the receptor in brain neuropils corresponds well with the distribution of its ligands, the DTKs. Our findings suggest that DTKR is a DTK receptor in Drosophila and that this ligand-receptor system plays multiple functional roles.

Widely distributed Drosophila G-protein-coupled receptor (CG7887) is activated by endogenous tachykinin-related peptides.

SUMMARY The Drosophila orphan G protein-coupled receptor encoded by CG17415 is related to members of the calcitonin receptor-like receptor (CLR) family. In mammals, signaling from CLR receptors depend on accessory proteins, namely the receptor activity modifying proteins (RAMPs) and receptor component protein (RCP). We tested the possibility that this Drosophila CLR might also require accessory proteins for proper function and we report that co-expression of the mammalian or Drosophila RCP or mammalian RAMPs permitted neuropeptide diuretic hormone 31 (DH31) signaling from the CG17415 receptor. RAMP subtype expression did not alter the pharmacological profile of CG17415 activation. CG17415 antibodies revealed expression within the principal cells of Malpighian tubules, further implicating DH31 as a ligand for this receptor. Immunostaining in the brain revealed an unexpected convergence of two distinct DH signaling pathways. In both the larval and adult brain, most DH31 receptor-expressing neurons produce the neuropeptide corazonin, and also express the CRFR-related receptor CG8422, which is a receptor for the neuropeptide diuretic hormone 44 (DH44). There is extensive convergence of CRF and CGRP signaling within vertebrates and we report a striking parallel in Drosophila involving DH44 (CRF) and DH31 (CGRP). Therefore, it appears that both the molecular details as well as the functional organization of CGRP signaling have been conserved.

A novel diuretic hormone receptor in Drosophila: evidence for conservation of CGRP signaling

PDF Receptor Signaling in Drosophila Contributes to Both Circadian and Geotactic Behaviors

SUMMARY Diuretic hormone 44 (DH) is a bioactive neuropeptide that mediates osmotic balance in a wide variety of insects through increases in cAMP. It is structurally similar to mammalian corticotrophin releasing factor (CRF) peptides. In the moth Manduca and the cricket Acheta, functional studies have shown that its cognate receptor (DH-R) is related to the mammalian CRF receptor. The Drosophila genome contains two genes (CG8422 and CG12370) orthologous to Manduca and Acheta DH-Rs. Here, we present multiple lines of evidence to support the hypothesis that the orphan CG8422 G-protein-coupled receptor is a functional DH-R. When expressed in mammalian cells, CG8422 conferred selective sensitivity to DH, as indicated by translocation of aβ -arrestin-2-GFP reporter from the cytoplasm to the cell membrane. Consistent with its in vivo activities in other insects, DH activation of CG8422 elicited increases in a cAMP reporter system (CRE-luciferase), with an EC50 of 1.7 nmol l-1. CG8422 activation by DH also led to increases in intracellular calcium but at substantially higher doses (EC50 ∼300 nmol l-1). By microarray analysis, the CG8422 transcript was detectable in Drosophila head mRNA of different genotypes and under different environmental conditions. The identification of a Drosophila receptor for the DH neuropeptide provides a basis for genetic analysis of this critical factor's roles in maintaining physiological homeostasis.

Drosophila CG8422 encodes a functional diuretic hormone receptor

Proctolin is a bioactive neuropeptide that modulates interneuronal and neuromuscular synaptic transmission in a wide variety of arthropods. We present several lines of evidence to propose that the orphan G protein-coupled receptor CG6986 of Drosophila is a proctolin receptor. When expressed in mammalian cells, CG6986 confers second messenger activation after proctolin application, with an EC50 of 0.3 nM. In competition-based studies, the CG6986 receptor binds proctolin with high affinity (IC50 = 4 nM). By microarray analysis, CG6986 transcript is consistently detected in head mRNA of different genotypes, and under different environmental conditions. By blot analysis, anti-CG6986 antibodies detect a band in tissue homogenates similar to the predicted size of the protein. Proctolin receptor immunosignals are found in the hindgut, heart, and in distinct neuronal populations of the CNS; such patterns correlate with previous demonstrations of proctolin biological activity, and in several instances, with areas of proctolin peptide immunosignals. The identification of a bona fide proctolin receptor provides the basis for a mechanistic analysis of this critical synaptic modulator.

Identification and characterization of a G protein-coupled receptor for the neuropeptide proctolin in Drosophila melanogaster

Activation of G protein-coupled receptors (GPCR) leads to the recruitment of β-arrestins. By tagging the β-arrestin molecule with a green fluorescent protein, we can visualize the activation of GPCRs in living cells. We have used this approach to de-orphan and study 11 GPCRs for neuropeptide receptors in Drosophila melanogaster. Here we verify the identities of ligands for several recently de-orphaned receptors, including the receptors for the Drosophila neuropeptides proctolin (CG6986), neuropeptide F (CG1147), corazonin (CG10698), dFMRF-amide (CG2114), and allatostatin C (CG7285 and CG13702). We also de-orphan CG6515 and CG7887 by showing these two suspected tachykinin receptor family members respond specifically to a Drosophila tachykinin neuropeptide. Additionally, the translocation assay was used to de-orphan three Drosophila receptors. We show that CG14484, encoding a receptor related to vertebrate bombesin receptors, responds specifically to allatostatin B. Furthermore, the pair of paralogous receptors CG8985 and CG13803 responds specifically to the FMRF-amide-related peptide dromyosuppressin. To corroborate the findings on orphan receptors obtained by the translocation assay, we show that dromyosuppressin also stimulated GTPγS binding and inhibited cAMP by CG8985 and CG13803. Together these observations demonstrate the β-arrestin-green fluorescent protein translocation assay is an important tool in the repertoire of strategies for ligand identification of novel G protein-coupled receptors.

Identification of Drosophila Neuropeptide Receptors by G Protein-coupled Receptors-β-Arrestin2 Interactions*

Proctolin is a bioactive neuropeptide that modulates interneuronal and neuromuscular synaptic transmission in a wide variety of arthropods. We present several lines of evidence to propose that the orphan G protein-coupled receptor CG6986 of Drosophila is a proctolin receptor. When expressed in mammalian cells, CG6986 confers second messenger activation after proctolin application, with an EC(50) of 0.3 nM. In competition-based studies, the CG6986 receptor binds proctolin with high affinity (IC(50) = 4 nM). By microarray analysis, CG6986 transcript is consistently detected in head mRNA of different genotypes, and under different environmental conditions. By blot analysis, anti-CG6986 antibodies detect a band in tissue homogenates similar to the predicted size of the protein. Proctolin receptor immunosignals are found in the hindgut, heart, and in distinct neuronal populations of the CNS; such patterns correlate with previous demonstrations of proctolin biological activity, and in several instances, with areas of proctolin peptide immunosignals. The identification of a bona fide proctolin receptor provides the basis for a mechanistic analysis of this critical synaptic modulator.

Identification and characterization of a G protein-coupled receptor for the neuropeptide proctolin in Drosophilamelanogaster.

Carrier transport and luminescence in composite organic inorganic light-emitting devices

We show for the first time that signal processing schemes based on noncoherent signal addition will require signal transfer characteristics exhibiting high degrees of curvature. We quantify this by proposing a set of single-input, dual-output, power-conserving transfer functions and generating designs based on these characteristics. We then analyze the sensitivity of such a design scheme to nonidealities in the signal level and device behavior, and show that a sampling operation is only possible for transfer characteristics with residual "low" output of less than about 10% and low intensity reflectivity higher than 98%. For single device signal loss of up to 0.1 dB, we show that the best possible crosstalk-to-noise ratio in a packet forwarder (27 dB), is limited by the availability of the sampling operation.

Function and sensitivity of signal processing systems based on addition followed by limiting

All-optical signal processing and packet forwarding using nonmonotonic intensity transfer characteristics

It has previously been shown that a wide number of optical logic functions can be performed using single or sets of optical limiters with optical transfer functions. The derived optical logic functions make use of a ternary logic system, in which normalised power levels of 0, 1 and 2 are each discretely valued in the system and enable the implementation of a complete logic set. A useful and practical application to be implemented using these all-optical logic gates is a true all-optical packet router. Our router design reads the header on an optical time-domain packet, determines its destination address, and transmits the signal along any given output path.

LEOS 2000. 2000 IEEE Annual Meeting Conference Proceedings. 13th Annual Meeting. IEEE Lasers and Electro-Optics Society 2000 Annual Meeting (Cat. No.00CH37080)

The Figure-of-8 Walk test (F8W), a measure of walking skill, incorporates both straight and curved paths. While gait variability during straight-path walking is associated with adverse outcomes, variability during curved-path walking is critical for efficient turning. We examined variability of step length (SLV), step time (STV), and stride width (SWV) during F8W and expected greater variability in those with better motor skill. 
 
Thirty-two older adults (mean age 72.1 ± 9.3 yrs) completed the F8W (walking a figure-of-8 around two cones 5 feet apart) on an instrumented walkway. Gait measures were: 1) variability, standard deviations of SLV, STV, and SWV, 2)F8W number of steps and time to complete, s. We examined differences in variability by skill group using ANOVAs (F8W time ≤ 8 seconds (F8H, high skill), F8W time > 8 seconds (F8L, low skill)). Correlations (r) adjusted for speed were used to examine associations between F8W and variability. 
 
Motor skill groups differed for SLV (SLV: F8H = 22.2, F8L= 18.2, p=.024) and SWV (F8H = 23, F8L = 17.2, p<.001); no group differences for STV. Variability measures related to curved-path walking ability, F8W time (SLV, r= -.40, SWV r=-.70, STV r=-.51), and number of steps (SLV, r= -.42, SWV r=-.80, STV r=-.60). 
 
Better motor skill in walking is associated with greater spatial variability. Individuals with better curved path walking ability (F8W time) are able to actively adjust spatial parameters for the walking task. Rehabilitation should include practice of curved paths and experience in active adjustments of step length and width.

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Statistics in asteroseismology: Evaluating confidence in stellar model fits

Chlortetracycline modulates acute phase response of ex vivo perfused pig livers, and inhibits TNF-alpha secretion by isolated Kupffer cells.

Real-time neural network based semiactive model predictive control of structural vibrations

Recently, a distributed mass damper (DMD) has been proposed for architectural design considerations. By placing a mass damper in every story of a building, building designers can (1) integrate shading fins (that are typically installed in every story) and mass dampers to synergistically improve safety and energy efficiency, and (2) solve many architectural design and implementation issues (e.g., complications of a large damper mass near the top or the prime space of a building) with small damper masses. The passive DMD system was shown effective in response mitigation as a conventional tuned mass damper. In this paper, two semiactive DMD strategies are evaluated: a conventional semiactive clipped‐optimal LQR strategy, and a proposed gain‐scheduled semiactive DMD strategy. A conventional clipped‐optimal approach turns individual dampers off when their control forces are nondissipative, whereas the proposed strategy uses a redesigned control force, using an alternate control gain, to maximize the number of dampers exerting dissipative forces. A five‐story shear structure with one semiactive tuned mass damper per floor is used as a testbed to evaluate these control strategies. Both semiactive DMD strategies best the passive DMD system in reducing structural response; further, the semiactive gain‐scheduling strategy notably outperforms the established clipped‐optimal semiactive control strategy. Copyright © 2016 John Wiley & Sons, Ltd.

Structures today may be equipped with passive structural control devices to achieve some performance criteria. The optimal design of these passive control devices, whether via a formal optimization algorithm or a response surface parameter study, requires multiple solutions of the dynamic response of that structure, incurring a significant computational cost for complex structures. These passive control elements are typically point‐located, introducing a local change (possibly nonlinear, possibly uncertain) that affects the global behavior of the rest of the structure. When the structure, other than these localized devices, is linear and deterministic, conventional solvers (e.g., Runge–Kutta, MATLAB's ode45, etc.) ignore the localized nature of the passive control elements. The methodology applied in this paper exploits the locality of the uncertain and/or nonlinear passive control element(s) by exactly converting the form of the dynamics of the high‐order structural model to a low‐dimensional Volterra integral equation. Design optimization for parameters and placement of linear and nonlinear passive dampers, tuned mass dampers, and their combination, as well as their design‐under‐uncertainty for a benchmark cable‐stayed bridge, is performed using this approach. For the examples considered herein, the proposed method achieves a two‐orders‐of‐magnitude gain in computational efficiency compared with a conventional method of comparable accuracy. Copyright © 2016 John Wiley & Sons, Ltd.

Efficient optimal design and design‐under‐uncertainty of passive control devices with application to a cable‐stayed bridge

The development of control strategies for controllable passive dampers — ‘semiactive’ damping devices — is complicated by the nonlinear and dissipative nature of the devices and the nonlinear nature of the closed‐loop system with any form of parametric feedback control. Control design for nonlinear systems is often achieved by designing a control for a linearized model since strategies for linear systems are straightforward. One such approach is clipped‐optimal control in which the desired damper forces are determined from an optimal controller (e.g., linear quadratic regulator, linear quadratic Gaussian, H2 and H∞), which is designed assuming that the damping devices are fully linear actuators that can exert any forces (dissipative or nondissipative), and a secondary bang–bang controller commands the controllable damper to exert forces as close as possible to the desired forces. However, designs using any linearized model generally result in suboptimal (and sometimes very poor) performance because the linear actuator assumption differs from the actual implementation with a dissipative damping device. Thus, one must generally resort to a large‐scale parameter study in which the nonlinear system is simulated many times to determine control strategies that are actually optimal for the nonlinear controlled closed‐loop system. This paper demonstrates how an approach developed by the authors, which can reduce the model of a system with local modifications to a lower order set of Volterra integral equations in the modification forces, can significantly decrease the computational burden of a complex control design study for controllable dampers. The approach is first adapted to use a state feedback control with a bang–bang on–off secondary controller. Then, the structural and damping device models are detailed. The optimal semiactive control design is demonstrated via both a parameter study and an optimization algorithm. Numerical examples demonstrate that the approach is effective and, compared with a conventional simulation approach, can reduce computation time by two orders of magnitude. Copyright © 2014 John Wiley & Sons, Ltd.

Computationally efficient design of optimal strategies for controllable damping devices

In this paper, a substructure identification method is proposed to estimate the parameters of any story in a shear structure by using only limited floor accelerations. A two‐story standard substructure is used to divide a shear structure into substructures; two identification problems are derived for the standard substructure, each of which identifies the parameters of one story given that the parameters of the other are known. By connecting these two identification problems in a loop manner, the loop substructure identification (LSI) method formulates a sequence of estimation problems to directly identify both story parameters of the standard substructure. If the structural masses are unknown, this loop identification method can still be applied to estimate mass‐normalized structural parameters as well as the relative mass distribution of the structure. An error analysis is carried out for the two identification problems, the results of which are used to derive the condition for convergence of the LSI. The result shows that the loop identification sequence is conditionally converged and some structural responses play a vital role in determining the convergence. To ensure the convergence and the subsequent accurate estimates, the controlled LSI method is proposed, which utilizes specially designed structural control systems to temporarily change the structural dynamic closed‐loop responses and achieve converged accurate identification results. A five‐story shear building is used to verify the convergence condition and to demonstrate that the specially designed control systems can provide the converged estimation results. Copyright © 2013 John Wiley & Sons, Ltd.

Controlled loop substructure identification for shear structures

Recent developments of a distributed mass damper (DMD) system integrate structural and environmental control systems to improve building safety and energy efficiency. Such a system can also enhance Structural health monitoring (SHM) by using its multiple active mass dampers to excite the structure and analyze the resulting responses. SHM reliability depends on accurate estimations of structural characteristics from structural response measurements. However, some structural characteristics, such as structural modes, may not be well represented or identifiable depending on how structures are excited, thereby compromising the effectiveness of SHM. Utilizing combinations of the DMD's multiple active dampers to target structural modes of interest, the authors showed that damage detection in structures was significantly improved.

Structural health monitoring with a distributed mass damper system

The companion paper proposed a substructure identification method for shear structures and derives the method's error analysis, demonstrating that the identification errors are closely related to two important structural responses: (i) the frequency response of the interstory acceleration of the identified story and (ii) the frequency response ratio between interstory accelerations of two adjacent stories. The identification accuracy of this substructure method can be improved by amplifying the first response and reducing the second response near the substructure natural frequency. Herein, a controlled substructure identification method is proposed, which utilizes two kinds of structural control systems, an active mass driver system, and a passive interstory brace system, to temporarily shift the system dynamics to improve the accuracy of parameter identification. The optimal parameters of two control systems are obtained by solving specially designed optimization problems. Because the accuracy of the controlled substructure identification does not directly depend on complex modal properties of the closed‐loop controlled structure but only on the controlled structural responses, the controlled substructure identification method is quite robust to control system errors. Numerical simulations demonstrate that both control methods did greatly improve the accuracy of the identification and were robust to fairly large feedback measurement noise. Copyright © 2012 John Wiley & Sons, Ltd.

Substructure identification for shear structures II: Controlled substructure identification

Structural health monitoring using wireless sensor networks has drawn considerable attention in recent years. The ease of deployment of tiny wireless devices that are coupled with sensors and actuators enhances the data collection process and makes prognostic and preventive maintenance of an infrastructure much easier. In this paper, the deployment problem is considered for finding node locations to reliably diagnose the health of a structure while consuming minimum energy during data collection. A simple shear structure is considered and modal analysis is performed. The example verifies the expectation that placing nodes further apart from each other reduces the mode shape errors but increases the energy consumption during data collection. A min–max, energy‐balanced routing tree and an optimal grid separation formulation are proposed that minimize the energy consumption as well as provide fine grain measurements. Copyright © 2012 John Wiley & Sons, Ltd.

Energy‐efficient deployment strategies in structural health monitoring using wireless sensor networks

A substructure identification method for shear structures is proposed herein. A shear structure is partitioned into many simple substructures; an inductive identification procedure is derived to estimate the structural parameters from top to bottom. In each identification step, the dynamic equilibrium of a one‐floor substructure is utilized to construct a substructure identification problem, estimating the story stiffness and damping coefficient. An identification error analysis for least‐square error identification problems, based on the linearization of the least‐square error problem, is proposed and applied to the substructure identification method. The results show that the identification errors are closely related to two important structural responses: the frequency response of the interstory acceleration of the identified story and the frequency response ratio between adjacent interstory accelerations. Further, these responses are critical to the substructure identification only near a certain frequency, the substructure natural frequency of the identified story substructure. The larger the first response is and/or the smaller the second response is, the more accurate the estimation results will be. A numerical example of a five‐story shear structure is given to demonstrate the effectiveness of the proposed substructure identification method and to verify the identification error analysis results. From the results of the identification error analysis, a companion paper proposes a controlled substructure identification method, utilizing specially designed algorithms for structural control devices to change the two key structural responses that affect the identification accuracy, to improve the accuracy of the substructure identification. Copyright © 2012 John Wiley & Sons, Ltd.

Substructure identification for shear structures I: Substructure identification method

This paper investigates the dissipativity and performance of semiactive systems with smart dampers via linear matrix inequality (LMI) synthesis. For this purpose, a dissipativity index is proposed to modify a standard linear quadratic regulator (LQR) using the techniques available in LMI‐based multiobjective convex programming for better semiactive performance. First, a review of available dissipativity indices is given, and two new dissipativity indices are defined based on the concept of energy dissipation rate. Second, an LQR problem is defined in terms of a linear objective function and several LMI constraints. Then, for each dissipativity index, a dissipativity inequality constraint is defined. It is observed that only one of the dissipativity constraints can be represented in terms of LMIs and implemented in the LQR problem. A modified LMI‐based LQR controller is obtained by attaching the dissipativity constraint in its weak form. The dissipativity indices and the proposed controller are employed for two numerical examples to investigate the dissipativity and performance of semiactive systems. The first example is a 2DOF building with an ideal damper attached in the first storey, and an LQR controller is selected such that it has high dissipativity levels. The second example is a 2DOF model of a highway bridge where a realistic magnetorheological (MR) fluid damper is attached at the bearing location resulting in an LQR controller with low dissipativity levels. Comprehensive parametric studies are carried out for both examples using the modified LQR with various dissipativity constraint values and the standard LQR. For the first example, it is found that the indices are very useful to identify the dissipative nature and semiactive performance relations. Also, the proposed method is able to improve the dissipative nature of the controller improving the semiactive performance. On the other hand, for the second example, although the proposed method is able to improve the dissipativity, the overall semiactive performance does not show a major improvement due to drastically lowered dissipativity levels caused by the realistic damper model. Copyright © 2006 John Wiley & Sons, Ltd.

Dissipativity and performance analysis of smart dampers via LMI synthesis

This paper presents a sample control design for the base‐isolated benchmark building with bilinear hysteretic bearings (e.g. lead–rubber bearings). Since there is no well‐defined control strategy for nonlinear structures, and available linear strategies are well‐known among the civil engineering community, a linear quadratic Gaussian (LQG) controller is selected for this purpose. To utilize an LQG controller, a linearized model of the nonlinear structure is required. A good linearized model, however, should be able to represent the nonlinear structure responses when both are controlled. It is shown that design problems of an equivalent linear model and an LQG controller are not, in fact, independent and require one for the other. In this study, the LQG controller is designed based on some parametric studies, and an iterative method is proposed for the development of an equivalent linear model. In the iterative method, the equivalent linear model is formed by replacing the nonlinear isolation elements that have bilinear stiffness and zero damping in the benchmark structure with a linear stiffness and a linear damping. Here, the linear stiffness is determined in the iterative method such that the RMS force of the bilinear isolation elements in the controlled (nonlinear) benchmark structure is equivalent to that of the corresponding isolation elements in the equivalent linear model. The overall approach is applied to the benchmark structure for seven historical earthquake ground acceleration data, and both an LQG controller and an equivalent linear model are obtained. The numerical simulations show that the equivalent linear model successfully replicates the nonlinear response, and the controller is able to improve the overall performance. As the final designs are not intended to be competitive, the method proposed can be improved in several ways to obtain better results. While the equivalent linear model developed herein may be used as a starting point in studying this benchmark problem, because of the strong interaction between controller and equivalent linear model, the participants of the base isolation benchmark problem are strongly encouraged to develop their own controller‐specific equivalent linear models. Copyright © 2005 John Wiley & Sons, Ltd.

Smart base‐isolated benchmark building Part III: a sample controller for bilinear isolation

Structural health monitoring (SHM) is a well-established multi-disciplinary research field, in which the goal is to develop technologies and techniques to automatically detect, localize, and classify damage in large structures. This paper is focused, starting with a simple SHM problem and a simple structure, on how wireless sensor networking technologies can help advance SHM. Specifically, a distributed damage detection algorithm is developed based on shifted spectra of response at the sensor nodes. While damage detection using frequency shifts is fairly well-understood in the SHM community, the development here adheres to sensor network architectural principles: the technique is amenable to in-network processing and duty-cycling, and can be implemented on a long-running sensor network. The efficacy is demonstrated using simulations on structural models, and actual measurements on real, albeit simple, structures

Proceedings of the 2005 IEEE International Symposium on, Mediterrean Conference on Control and Automation Intelligent Control, 2005.

Structural Damage Detection Using Wireless Sensor-Actuator Networks

Structural health monitoring (SHM) is the process of monitoring structural health and identifying damage existence, severity and location. Clear needs for SHM exist for various types of civil structures; for example, approximately 25% of U.S. bridges are rated as deficient and require significant expenditures to rebuild or replace them (FHWA, 2002). However, the dominant method for monitoring the health of civil structures is manual visual inspection - a time- and labor-intensive procedure. Global vibration-based SHM techniques have been studied, but no approach has been well established and accepted due to limitations of ambient excitation sources for most civil structures. One approach that may help alleviate some of the SHM difficulties for civil structures would be to use variable stiffness and damping devices (VSDDs) - controllable passive devices that have received significant study for vibration mitigation - to improve damage estimates. In addition to providing near optimal structural control strategies for vibration mitigation, these low-power and fail-safe devices can also provide parametric changes to increase global vibration measurement sensitivity for SHM. This paper proposes using VSDDs in structures to improve SHM, and demonstrates the benefits in contrast with conventional passive structures. It is shown that using VSDDs in identification gives parameter estimates that have better means and smaller variations than the conventional structure approach. The improvements in the identification process are even more effective when adding higher effective levels of stiffness or damping to a structural system, even though the resulting VSDD forces due to ambient excitation are small.

Health monitoring of structures under ambient vibrations using semiactive devices

Cables, such as those used in cable–stayed bridges, suspension bridges, guy wires, transmission lines, and flexible space structures, are prone to vibration due to their low inherent damping characteristics. The mitigation of cable vibration is necessary to minimize negative impact. Transversely attached passive viscous dampers have been implemented on some cables to dampen vibration. However, it can be shown that only minimal damping can be added if the damper attachment point is close to the end of the cable. For long cables, passive dampers may provide insufficient supplemental damping to eliminate vibration problems. A recent study by the authors demonstrated that “smart” semiactive damping can provide significantly superior supplemental damping for a cable modeled as a taut string. This article extends the previous work by adding sag, inclination, and axial flexibility to the cable model. The equations of motion are given. A new control–oriented model is developed for cables with sag. Passive, active, and smart (semiactive) dampers are incorporated into the model. Cable response is seen to be reduced by semiactive dampers for a wide range of cable sag and damper location.

Structural vibration mitigation using semiactive control strategies has received special attention recently due to the attractive properties of semiactive devices. The main restriction of a semiactive device is that it can only produce dissipative forces, which may be expressed in mathematical terms as a nonlinear inequality constraint. Standard active control algorithms do not generally account for this kind of constraint. In this paper, the nonlinear dissipativity constraint is integrated into the well-known linear quadratic regulator (LQR) algorithm using linear matrix inequality (LMI) techniques to be utilized in the semiactive control of the structures. First, the linear quadratic regulator problem is recast as an eigenvalue problem (EVP) in terms of LMIs. Then, the dissipativity constraint is appended in weak expected value form to the other constraints in the EVP. The proposed method is demonstrated in semiactive control of a 2-DOF structural system. It is found that although the dissipativity constraint is represented in its weak form, the proposed method yielded control forces more dissipative than standard H/sub 2//LQR methodologies.

Proceedings of the 2002 American Control Conference (IEEE Cat. No.CH37301)

Passive base isolation systems are one of the most successful and widely implemented technologies for seismic hazard mitigation. However, recent changes to the building codes have made the design requirements such that some of the potential gains of such systems may not be realized. This paper investigates the effects of using controllable semi-active dampers, such as magnetorheological fluid dampers, in a base isolation system. A two degree-of-freedom model of a base isolated building is used, with linear viscous, active, and semi-active supplemental damping devices in the isolation layer. Using an H/sub 2//LQG control design, semi-active and active devices are able to achieve a notable decrease in base drifts, compared to the optimal linear passive designs, with no accompanying increase in accelerations imparted into the superstructure.

Proceedings of the 1999 American Control Conference (Cat. No. 99CH36251)

Opposing directions of stage-specific body shape change in a close relative of C. elegans

[This corrects the article DOI: 10.17912/micropub.biology.000131.].

Corrigendum: Caenorhabditis Intervention Testing Program: the tyrosine kinase inhibitor imatinib mesylate does not extend lifespan in nematodes. microPublication Biology July 3, 2019. 10.17912/micropub.biology.000131

Automated lifespan determination across Caenorhabditis strains and species reveals assay-specific effects of chemical interventions

Standardized Protocols from the Caenorhabditis Intervention Testing Program 2013-2016: Conditions and Assays used for Quantifying the Development, Fertility and Lifespan of Hermaphroditic Caenorhabditis Strains

Department of Ophthalmology, Saint Louis University, Saint Louis, Missouri, USA; Ophthalmic Plastic and Cosmetic Surgery, Inc., Des Peres, Missouri, USA; Department of Ophthalmology, Washington University in St. Louis, St. Louis, Missouri, USA; Ophthalmic Plastic and Cosmetic Surgery, Inc., Atlanta, Georgia, USA; Byers Eye Institute at Stanford, Stanford, California, USA; Department of Otolaryngology-Head and Neck Surgery, Saint Louis University, Saint Louis, Missouri, USA

Response to “Comparison of non-absorbable silk and absorbable polyglactin sutures for external ptosis repair”

ABSTRACT Purpose: The authors compare the outcomes and revision rates for external levator aponeurotic advancement for the treatment of involutional ptosis using non-absorbable silk and absorbable polyglactin sutures. Methods: An IRB-approved retrospective chart review identified 121 patients who underwent external levator advancement for involutional ptosis between 2015 and 2016 by the senior author (JBH). All patients underwent ptosis repair using either 5–0 polyglactin 910 on a S–14 spatulated needle or 6–0 silk on a G–1 reverse cutting needle for the aponeurotic advancement. Ptosis etiologies other than involutional ptosis were excluded. Patients with >0.5 mm of upper lid height asymmetry post-operatively underwent surgical adjustment. Demographics, clinical findings and revision rates were collected and analyzed from follow-up visits. Results: 116 patients (190 eyelids) met inclusion criteria. Fewer ptosis repairs performed using silk sutures necessitated adjustment when compared to those using polyglactin (1/73 [1.4%] vs. 14/117 [12.0%], p = 0.010). Silk direct connection sutures had no better stability than polyglactin direct connection sutures (p = 0.16), but silk hang-back sutures were significantly superior to polyglactin hang-back sutures (p = 0.035). Thirteen out of fifteen (86.7%) revisions were advancements to raise the eyelid, while two (13.3%) were recessions. Conclusion: Non-absorbable silk suture may be superior to absorbable polyglactin, necessitating fewer surgical revisions. Silk demonstrated superiority to polyglactin when a hang-back suture was employed. Since the need to place direct or hang-back sutures cannot be made pre-operatively, the authors modified their technique to utilize silk sutures for external aponeurotic ptosis repair.

Comparison of non-absorbable silk and absorbable polyglactin sutures for external ptosis repair

ABSTRACT A passive visual end of service life indicator (ESLI) for certain organic vapors has been attached to the inside wall of an organic vapor respirator cartridge. The opposite side of the ESLI touches activated carbon inside the cartridge. During use, organic vapors moving through the cartridge adsorb into both the carbon and the ESLI. The cartridge body is clear so that when vapor concentrations meet a certain threshold, the user may observe the progressive development of an indicator bar down the side of the ESLI. The cartridge is deemed ready to change when any part of the indicator bar touches a marked end line. The performance of the ESLI was observed when the cartridge was tested against a variety of organic vapors, exposure concentrations above the minimum indication level, humidities, temperatures, flow rates, and mixtures. In all cases, the ESLI indicated end of service life with more than 10% cartridge service life remaining (which is a NIOSH test criteria). The results were also compared to mathematical predictions of cartridge service life.

Evaluation of a passive optical based end of service life indicator (ESLI) for organic vapor respirator cartridges

Common Questions Safety Managers Ask About Using ESLIs for Organic Vapors.

Respirators are used to help reduce exposure to a variety of contaminants in workplaces. Test aerosols used for certification of particulate respirators (PRs) include sodium chloride (NaCl), dioctyl phthalate, and paraffin oil. These aerosols are generally assumed to be worst case surrogates for aerosols found in the workplace. No data have been published to date on the performance of PRs with welding fumes, a hazardous aerosol that exists in real workplace settings. The aim of this study was to compare the performance of respirators and filters against a NaCl aerosol and a welding fume aerosol and determine whether or not a correlation between the two could be made. Fifteen commercial PRs and filters (seven filtering facepiece, two replaceable single-type filters, and six replaceable dual-type filters) were chosen for investigation. Four of the filtering facepiece respirators, one of the single-type filters, and all of the dual-type filters contained carbon to help reduce exposure to ozone and other vapors generated during the welding process. For the NaCl test, a modified National Institute for Occupational Safety and Health protocol was adopted for use with the TSI Model 8130 automated filter tester. For the welding fume test, welding fumes from mild steel flux-cored arcs were generated and measured with a SIBATA filter tester (AP-634A, Japan) and a manometer in the upstream and downstream sections of the test chamber. Size distributions of the two aerosols were measured using a scanning mobility particle sizer. Penetration and pressure drop were measured over a period of aerosol loading onto the respirator or filter. Photos and scanning electron microscope images of clean and exposed respirators were taken. The count median diameter (CMD) and mass median diameter (MMD) for the NaCl aerosol were smaller than the welding fumes (CMD: 74 versus 216 nm; MMD: 198 versus 528 nm, respectively). Initial penetration and peak penetration were higher with the NaCl aerosol. However, pressure drop increased much more rapidly in the welding fume test than the NaCl aerosol test. The data and images clearly show differences in performance trends between respirator models. Therefore, general correlations between NaCl and weld fume data could not be made. These findings suggest that respirators certified with a surrogate test aerosol such as NaCl are appropriate for filtering welding fume (based on penetration). However, some respirators may have a more rapid increase in pressure drop from the welding fume accumulating on the filter. Therefore, welders will need to choose which models are easier to breathe through for the duration of their use and replace respirators or filters according to the user instructions and local regulations.

Comparison of pressure drop and filtration efficiency of particulate respirators using welding fumes and sodium chloride.

This study investigated particle-size-selective protection factors (PFs) of four models of N95 filtering facepiece respirators (FFRs) that passed and failed fit testing. Particle size ranges were representative of individual viruses and bacteria (aerodynamic diameter d(a) = 0.04-1.3 μm).

METHODS
Standard respirator fit testing was followed by particle-size-selective measurement of PFs while subjects wore N95 FFRs in a test chamber. PF values obtained for all subjects were then compared to those obtained for the subjects who passed the fit testing.

RESULTS
Overall fit test passing rate for all four models of FFRs was 67%. Of these, 29% had PFs <10 (the Occupational Safety and Health Administration Assigned Protection Factor designated for this type of respirator). When only subjects that passed fit testing were included, PFs improved with 9% having values <10. On average, the PFs were 1.4 times (29.5/21.5) higher when only data for those who passed fit testing were included. The minimum PFs were consistently observed in the particle size range of 0.08-0.2 μm.

Overall PFs increased when subjects passed fit testing. The results support the value of fit testing but also show for the first time that PFs are dependent on particle size regardless of fit testing status.

Effect of fit testing on the protection offered by n95 filtering facepiece respirators against fine particles in a laboratory setting.

Predicting the effect of high RH on organic vapor cartridge performance.

—Learning new tasks and skills in succession without overwriting or interfering with prior learning (i.e., “catastrophic forgetting”) is a computational challenge for both artiﬁcial and biological neural networks, yet artiﬁcial systems struggle to achieve even rudimentary parity with the performance and functionality apparent in biology. One of the processes found in biology that can be adapted for use in artiﬁcial systems is sleep, in which the brain deploys numerous neural operations relevant to continual learning and ripe for artiﬁcial adaptation. Here, we investigate how modeling three distinct components of mammalian sleep together affects continual learning in artiﬁcial neural networks: (1) a veridical memory replay process observed during non-rapid eye movement (NREM) sleep; (2) a generative memory replay process linked to REM sleep; and (3) a synaptic downscaling process which has been proposed to tune signal-to- noise ratios and support neural upkeep. To create this tripartite artiﬁcial sleep, we modeled NREM veridical replay by training the network using intermediate representations of samples from the current task. We modeled REM by utilizing a generator network to create intermediate representations of samples from previous tasks for training. Synaptic downscaling, a novel con- tribution, is modeled utilizing a size-dependent downscaling of network weights. We ﬁnd beneﬁts from the inclusion of all three sleep components when evaluating performance on a continual learning CIFAR-100 image classiﬁcation benchmark. Maximum accuracy improved during training and catastrophic forgetting was reduced during later tasks. While some catastrophic forget- ting persisted over the course of network training, higher levels of synaptic downscaling lead to better retention of early tasks and further facilitated the recovery of early task accuracy during subsequent training. One key takeaway is that there is a trade-off at hand when considering the level of synaptic downscaling to use - more aggressive downscaling better protects early tasks, but less downscaling enhances the ability to learn new tasks. Intermediate levels can strike a balance with the highest overall accuracies during training. Overall, our results both provide insight into how to adapt sleep components to enhance artiﬁcial continual learning systems and highlight areas for future neuroscientiﬁc sleep research to further such systems.

Continual learning benefits from multiple sleep mechanisms: NREM, REM, and Synaptic Downscaling

A dynamic spike threshold with correlated noise predicts observed patterns of negative interval correlations in neuronal spike trains

Negative correlations in the sequential evolution of interspike intervals (ISIs) are a signature of memory in neuronal spike-trains. They provide coding benefits including firing-rate stabilization, improved detectability of weak sensory signals, and enhanced transmission of information by improving signal-to-noise ratio. Here we predict observed ISI serial correlations from primary electrosensory afferents of weakly electric fish using an adaptive threshold model with a noisy spike threshold. We derive a general relationship between serial correlation coefficients (SCCs) and the autocorrelation function of added noise. Observed afferent spike-trains fall into two categories based on the pattern of SCCs: non-bursting units have negative SCCs which remain negative but decay to zero with increasing lags (Type I SCCs), and bursting units have oscillatory (alternating sign) SCCs which damp to zero with increasing lags (Type II SCCs). Type I SCCs are generated by low-pass filtering white noise before adding it to the spike threshold, whereas Type II SCCs are generated by high-pass filtering white noise. Thus, a single parameter (the sign of the pole of the filter) generates both types of SCCs. The filter pole (equivalently time-constant) is estimated from the observed SCCs. The predicted SCCs are in geometric progression. The theory predicts that the limiting sum of SCCs is −0.5, and this is confirmed from the expressions for the two types of filters. Observed SCCs from afferents have a limiting sum that is slightly larger at −0.475 ±0.04 (mean ±s.d.). The theoretical limit of the sum of SCCs leads to a perfect DC block in the power spectrum of the spike-train, thereby maximizing signal-to-noise ratio during signal encoding. The experimentally observed sum of SCCs is just short of this limit. We conclude by discussing the results from the perspective of optimal coding.Many neurons spontaneously emit spikes (impulses) with a random time interval between successive spikes (interspike interval or ISI). The spike generation mechanism can have memory so that successive ISIs are dependent on one another and exhibit correlations. An ISI which is longer than the mean ISI tends to be followed by an ISI which is shorter than the mean, and vice versa. Thus, adjacent ISIs are negatively correlated, and further these correlations can extend over multiple ISIs. A simple model describing negative correlations in ISIs is an adaptive threshold with noise added to the spike threshold. A neuron becomes more resistant (refractory) to spiking immediately after a spike is output, with refractoriness increasing as more spikes are spaced closer together. Refractoriness reduces as spikes are spaced further apart. We show that a neuron can generate experimentally observed patterns of correlations by relating it to the noise in the spike threshold. Two different types of filtered noise (low-pass and high-pass) generate the observed patterns of correlations. We show that the theoretical sum of the sequence of correlations has a limiting value which maximizes the information a neuron can transmit. The observed sum of correlations is close to this limit.

Adaptation with correlated noise predicts negative interval correlations in neuronal spike trains

The rat vibrissal (whisker) system is one of the oldest and most important models for the study of active tactile sensing and sensorimotor integration. It is well established that primary sensory neurons in the trigeminal ganglion respond to deflections of one and only one whisker, and that these neurons are strongly tuned for both the speed and direction of individual whisker deflections. During active whisking behavior, however, multiple whiskers will be deflected simultaneously. Very little is known about how neurons at central levels of the trigeminal pathway integrate direction and speed information across multiple whiskers. In the present work, we investigated speed and direction coding in the trigeminal brainstem nuclei, the first stage of neural processing that exhibits multi-whisker receptive fields. Specifically, we recorded both single-unit spikes and local field potentials from fifteen sites in spinal trigeminal nucleus interpolaris and oralis while systematically varying the speed and direction of coherent whisker deflections delivered across the whisker array. For 12/15 neurons, spike rate was higher when the whisker array was stimulated from caudal to rostral rather than rostral to caudal. In addition, 10/15 neurons exhibited higher firing rates for slower stimulus speeds. Interestingly, using a simple decoding strategy for the local field potentials and spike trains, classification of speed and direction was higher for field potentials than for single unit spike trains, suggesting that the field potential is a robust reflection of population activity. Taken together, these results point to the idea that population responses in these brainstem regions in the awake animal will be strongest during behaviors that stimulate a population of whiskers with a directionally coherent motion.

Representation of Stimulus Speed and Direction in Vibrissal-Sensitive Regions of the Trigeminal Nuclei: A Comparison of Single Unit and Population Responses

A minimum-error, energy-constrained neural code is an instantaneous-rate code

Multiple nutrient sensors in central neurons that regulate reproduction inDrosophila

Minimum-error, energy-constrained source coding by sensory neurons

A minimum-error, energy-constrained neural encoder predicts an instantaneous spike-rate code

In the nervous system, sensory neurons encode signals as a sequence of action potentials (spikes). However, spike generation is metabolically expensive. Achieving high coding fidelity may require a high spike rate. Here we propose that neurons achieve a trade-off by optimally timing spikes so that maximum fidelity is achieved for a given spike rate. The proposed neural encoder generates spikes which are reconstructed by a linear filter, with energy modeled as a constraint proportional to the average spike-rate. We develop expressions for the encoding error and derive the optimal parameters in the limit of high spike-firing rates. The energy-constrained neural encoder is compared with experimental spike-times from two sensory neurons, one cortical and one peripheral. The proposed energy-constrained neural encoder closely approximates the experimentally recorded spike-times, and the decoded experimental inputs are within 2dB of the predicted distortion-energy curve for both neurons.

Minimum squared-error, energy-constrained encoding by adaptive threshold models of neurons

A neural code based on sequences of spikes can consume a significant portion of the brain's energy budget. Thus, energy considerations would dictate that spiking activity be kept as low as possible. However, a high spike-rate improves the coding and representation of signals in spike trains, particularly in sensory systems. These are competing demands, and selective pressure has presumably worked to optimize coding by apportioning a minimum number of spikes so as to maximize coding fidelity. The mechanisms by which a neuron generates spikes while maintaining a fidelity criterion are not known. Here, we show that a signal-dependent neural threshold, similar to a dynamic or adapting threshold, optimizes the trade-off between spike generation (encoding) and fidelity (decoding). The threshold mimics a post-synaptic membrane (a low-pass filter) and serves as an internal decoder. Further, it sets the average firing rate (the energy constraint). The decoding process provides an internal copy of the coding error to the spike-generator which emits a spike when the error equals or exceeds a spike threshold. When optimized, the trade-off leads to a deterministic spike firing-rule that generates optimally timed spikes so as to maximize fidelity. The optimal coder is derived in closed-form in the limit of high spike-rates, when the signal can be approximated as a piece-wise constant signal. The predicted spike-times are close to those obtained experimentally in the primary electrosensory afferent neurons of weakly electric fish (Apteronotus leptorhynchus) and pyramidal neurons from the somatosensory cortex of the rat. We suggest that KCNQ/Kv7 channels (underlying the M-current) are good candidates for the decoder. They are widely coupled to metabolic processes and do not inactivate. We conclude that the neural threshold is optimized to generate an energy-efficient and high-fidelity neural code.

Brain-computer interfaces (BCI) utilizing steady-state visually evoked potentials (SSVEP) recorded by electroencephalography (EEG) have exciting potential to enable new systems for disabled individuals and novel controls for robotic and computer systems. To interact with SSVEP-based BCIs, users attend to visual stimuli modulated at predetermined frequencies. A key problem for SSVEP-based BCIs is to classify which modulation frequency the user is attending, for which there is an inherent trade-off between speed and accuracy. As SSVEP signals vary with time and stimulation frequency, a fixed-length data window does not necessarily optimize this trade-off. We propose a strategy, developed from sequential analysis, to vary the window-length used for classification. Our proposed technique adapts to the data, continuing to collect data until it is confident enough to make a classification decision. Our strategy was compared to a fixed window-length method using a simple experiment involving five frequencies presented individually to three participants. Using a canonical correlation analysis classifier to compare the proposed variable-length scheme to a standard fixed-length scheme, the variable-length approach improved the classifier information transfer rate by an average of 43%.

Sequential selection of window length for improved SSVEP-based BCI classification

Many applications involve sparse signals with unknown, continuous parameters; a common example is a signal consisting of several sinusoids of unknown frequency. Applying compressed sensing techniques to these signals requires a highly oversampled dictionary for good approximation, but these dictionaries violate the RIP conditions and produce inconsistent results. We consider recovering both a sparse vector and parameter perturbations from an initial set of parameters. Joint recovery allows for accurate reconstructions without highly oversampled dictionaries. Our algorithm for sparse recovery solves a series of linearized subproblems. Recovery error for noiseless simulated measurements is near zero for coarse dictionaries, but increases with the oversampling. This technique is also used to reconstruct Radio Frequency data. The algorithm estimates sharp peaks and transmitter frequencies, demonstrating the potential practical use of the algorithm on real data.

Joint recovery of sparse signals and parameter perturbations with parameterized measurement models

Cooperative round Robin Tournaments: An Effective Way to Teach Sports Skills

The Effectiveness of Programmed Instruction in Teaching Basic Gymnastics

The proposed Brookhaven National Laboratory ultraviolet free-electron laser (UV-FEL) user facility will provide pico-second and sub-picosecond pulses of coherent ultraviolet radiation for wavelengths from 300 to 75 nra. Pulse width will be variable from about 7 ps to _, 200 fs, with repetition rates as high as 104 Hz, single pulse energies > 1 ml' and hence peak pulse power > 200 MW and average beam power > 10 W. The facility will be capable of "pumpprobe" experiments utilizing the FEL radiation with: 1) synchronized auxiliary lasers, 2) a second, independently tunable FEt. beam, or 3) broad-spectrum, high.-intensity x-rays from an insertion device lr,. the x-ray ring of the adjacent National Synchrotron Light Source.

The proposed Brookhaven National Laboratory ultraviolet free-electron laser (UV-FEL) user facility will provide pico-second and sub-picosecond pulses of coherent ultraviolet radiation

Current and future funding streams for paediatric postmortem imaging: European Society of Paediatric Radiology survey results

Background and Purposes  The wrist is the fourth most common joint to be involved in juvenile inflammatory arthritis (JIA), which is a common rheumatological condition affecting children. Wrist arthroscopy is well established in rheumatoid arthritis, but remains unexplored in JIA. The aim of this study is to investigate the role of wrist arthroscopy in JIA, with focus on those who are refractory to medical management. Methods  This is a prospective observational study, including consecutive patients with JIA undergoing arthroscopy between January 2016 and December 2020. Those over the age of 18 years and those with other rheumatological diagnoses were excluded. Data including pre-, intra-, and postoperative variables, demographics, and patient-reported outcomes were collated and are reported using standard measures. Results  A total of 15 patients underwent arthroscopy ( n  = 20 wrists). Synovitis was noted in all wrists on arthroscopy and synovectomy was performed in all cases. Other procedures were performed as indicated during the procedure. The median follow-up duration was 11.3 (interquartile range [IQR] 8.1-24.2) months. Median reduction of 4 (IQR 2.25-6) points on the Visual Analogue Score for pain on loading was noted postoperatively. Grip strength was improved in n  = 11/20 wrists and functional improvement was noted in n  = 18/20 wrists. Restriction of range of motion was achieved with a shrinkage procedure in patients with hypermobile joints. There were no postoperative complications, and no patients were lost to follow-up. Conclusion  In experienced hands, wrist arthroscopy is feasible, safe, and efficacious in the management of JIA, among patients who are refractory to medical management. Level of Evidence  This is a Level II study.

Juvenile Dermatomyositis Magnetic Resonance Imaging Score (JIS) does not correlate with criteria for clinically inactive disease: a single-centre retrospective evaluation

Joint European Society of Paediatric Radiology (ESPR) and International Society for Forensic Radiology and Imaging (ISFRI) guidelines: paediatric postmortem computed tomography imaging protocol

Abstract Objectives We aimed to develop and assess the reliability of a novel MRI-based scoring system for reporting the severity of MRI findings in children with suspected JDM. Methods Nine consultant paediatric radiologists independently assessed and scored 40 axial and 30 coronal thigh MR images of children with suspected JDM on two occasions using the juvenile dermatomyositis magnetic resonance Imaging Score (JIS). JIS was calculated for both reads for each plane and each limb, with possible scores ranging from 0 (normal) to 100 (severe). Inter- and intraobserver agreement was calculated using the intraclass correlation coefficient (ICC) and two- and one-way random effects models, respectively. Bland-Altman plots of the difference in JIS against the average JIS were also produced for each rater. Results Overall, the interobserver reliability and agreement was good—for axial images, JIS ranged from 46.8 to 61.0 [ICC = 0.88 (95% CI: 0.82, 0.92)] for the left limb and 47.9–61.4 [ICC = 0.87 (95% CI: 0.81, 0.92)] for the right limb. For coronal images, JIS ranged from 56.7 to 65.1 [ICC = 0.90 (95% CI: 0.85, 0.95)] for the left limb and 55.7 to 66.8 [ICC = 0.90 (95% CI: 0.84, 0.94)] for the right limb. The intraobserver reliability and agreement was good, with ICC ranging from 0.90 to 0.94. Conclusion JIS is a semi-objective scoring system with potential to serve as a reliable biomarker of disease severity and response to therapeutic interventions in children with JDM.

Introduction of a novel magnetic resonance imaging-based scoring system for assessing disease activity in children with juvenile dermatomyositis

A 1-month-old baby was referred to a tertiary paediatric centre from a local hospital with a 2-day history of reduced movement and swelling of the left elbow. There was no history of preceding trauma or relevant obstetric history.

On examination, tenderness and swelling of the left elbow with restriction of movement was noted. There was no evidence of systemic illness or infection.

Left elbow radiographs were performed (figure 1):

Figure 1 
AP and lateral radiographs of the left elbow.

What is the diagnosis? 

1. Elbow dislocation

2. Distal humeral supracondylar fracture

3. Septic arthritis

4. Distal humeral transphyseal fracture

Transphyseal …

The answer is not always in black and white: a frequently missed diagnosis in a child presenting with elbow pain

Poster: "ESSR 2015 / P-0126 / Radiological Differences Between Juvenile Idiopathic Arthritis And Adult Rheumatoid Disease " by: " D. Mak , C. Chisholm, K. Johnson; Birmingham/UK"

Radiological Differences Between Juvenile Idiopathic Arthritis And Adult Rheumatoid Disease

Inflicted non-accidental skeletal injuries form a small but important part of the spectrum of child abuse, with the majority of skeletal injuries occurring in children under 2 years of age. Radiology plays a vital role in the detection and evaluation of these skeletal injuries. A thorough detailed radiological evaluation should be undertaken in order to investigate appropriately a child for suspected inflicted non-accidental injury. This is to detect accurately, and possibly date, any injuries, exclude normal variants of growth which may mimic fractures and possibly to diagnose any underlying metabolic or genetic disorder of the bone which may predispose a child to fracturing. Any fracture may be the result of an inflicted injury or accidental event. It is therefore appropriate that any fracture that is identified is correlated with relevant appropriate clinical history. Certain injuries, such as rib or metaphyseal fractures, require a more specific method of causation and therefore have a higher degree of suspicion of being the result of an inflicted injury than other fracture types, such as skull and clavicular fractures, which are relatively non-specific in their mechanism of causation. In all cases, correlation with the clinical history is mandatory. While radiology does play an important role in the dating of injuries, the dating of fractures from the radiological findings is difficult and imprecise.

Inflicted non-accidental skeletal injuries form a small but important part of the spectrum of child abuse, with the majority of skeletal injuries occurring in children under 2 years of age. Radiology plays a vital role in the detection and evaluation of these skeletal injuries. A thorough detailed radiological evaluation should be undertaken to investigate a child appropriately for a suspected inflicted non-accidental injury to accurately detect and possibly date any injuries and also to exclude normal variants of growth that may mimic fractures. In some cases, the survey may diagnose an underlying metabolic or genetic disorder of the bone that may predispose the child to fracturing. While radiology plays an important role in the dating of injuries, the dating of fractures from radiological appearances is difficult and imprecise. Any fracture may be the result of an inflicted injury or accidental event. Therefore, it is important that all fractures identified are correlated with any relevant clinical history. Certain injuries, such as rib and metaphyseal fractures, require a more specific method of causation and therefore carry a higher degree of suspicion of being the result of an inflicted injury compared with other fracture types, which are relatively non-specific in their mechanisms of causation, such as skull and clavicular fractures. In all cases, correlation with clinical history is mandatory.

An evaluation of the diagnostic accuracy of ultrasound in the diagnosis of paediatric intussusceptions

Audit of outcomes following pneumatic reduction for paediatric intussusceptions

Multiple radiographic images may be necessary during the standard procedure of in-situ pinning of slipped capital femoral epiphysis (SCFE) hips. This procedure can be performed with the patient positioned on a fracture table or a radiolucent table. Our study aims to look at any differences in the amount and duration of radiation exposure for in-situ pinning of SCFE performed using a traction table or a radiolucent table. Sixteen hips in thirteen patients who were pinned on radiolucent table were compared for the cumulative radiation exposure to 35 hips pinned on a fracture table in 33 patients during the same time period. Cumulative radiation dose was measured as dose area product in Gray centimeter2 and the duration of exposure was measured in minutes. Appropriate statistical tests were used to test the significance of any differences. Mean cumulative radiation dose for SCFE pinned on radiolucent table was statistically less than for those pinned on fracture table (P<0.05). The mean duration of radiation exposure on either table was not significantly different. Lateral projections may increase the radiation doses compared with anteroposterior projections because of the higher exposure parameters needed for side imaging. Our results showing decreased exposure doses on the radiolucent table are probably because of the ease of a frog leg lateral positioning obtained and thereby the ease of lateral imaging. In-situ pinning of SCFE hips on a radiolucent table has an additional advantage that the radiation dose during the procedure is significantly less than that of the procedure that is performed on a fracture table.

Radiation exposure during in-situ pinning of slipped capital femoral epiphysis hips: does the patient positioning matter?

Aim: Assess healing pattern of Achilles tendons across gap created by percutaneous tenotomy and maintained by cast in club feet. Methods and Results: 21 tenotomies in 16 patients (Age range 12 weeks–36 months) were monitored with dynamic and static ultrasonographic studies. Ultrasounds performed before, immediately after and at approximately 3, 6, 12 weeks post tenotomy. Cast removal was done at 3 weeks. Two patients above age of two were casted for 6 weeks. The healing pattern went through different phases although they were not distinctively exclusive from each other and did show considerable overlap. First phase showed formation of bulbous mass with some continuity of scar tissue across tendon gap. The transition zone between new fibre and the original tend quite distinct. However dynamic ultrasound showed the Achilles tendon moved as a single unit. Second phase showed fibres resembling normal tendon crossing the gap and reduction of bulbous mass. The transition zone was still discernible. Final stage demonstrated more homogenous fibres of Achilles tendon with an indistinct transition zone. Two older children showed a distinctly longer process of healing. At 3 weeks there was no evidence of healing. At 6 weeks an irregular mass of fluid and soft tissue structures was seen. At 12 weeks there was evidence of continuation of tendon fibres, but transition zone partly visible. Conclusion: Young Child ( Older Child-Safe to consider percutaneous tenotomy in children up to 3 years of ages provided the period of immobilisation is extended.

PHASES IN GAP HEALING FOLLOWING PONSETI TYPE ACHILLES TENOTOMIES–AN ULTRASONOGRAPHIC STUDY

The Ponseti technique is well established in the management of clubfoot deformity, and an Achilles tenotomy is frequently performed to facilitate dorsiflexion of the foot. This report describes the ultrasonographic phases of healing of the tendon gap created by the Achilles tenotomy and how the healing varies, if at all, with patient age.

METHODS
A prospective ultrasonographic study of gap healing following a Ponseti-type tenotomy in twenty-seven tendons in twenty patients with idiopathic congenital clubfoot was performed. Serial ultrasound examinations (both static and dynamic) were performed at three, six, and twelve weeks after the tenotomy. The casts were removed routinely three weeks after the tenotomy. The end point of healing was defined as the observation of tendon homogeneity across the gap zone on ultrasound, with the divided tendon ends being indistinct.

RESULTS
Three phases of healing were apparent on ultrasound assessment at three, six, and twelve weeks after the tenotomy. These sequential phases are similar to those previously described in the healing of tendons with no gap. The transition to normal structure was frequently demonstrated by ultrasonography only at twelve weeks (in thirteen of twenty-one tendons).

Although there is evidence of continuity of the Achilles tendon by three weeks after tenotomy, healing is not complete until at least twelve weeks. The time needed for the tendon to completely heal should be taken into consideration before a revision Achilles tenotomy is planned.

Ultrasonographic phases in gap healing following Ponseti-type Achilles tenotomy.

Chapter 2a Chest and cardiac: Clinical presentations and role of imaging

Chapter 5a Hepatobiliary: Clinical presentations and role of imaging

The use of MRI in the assessment of the musculoskeletal system in children has important differences from its use in adults. Growth in children has significant impact on the epiphysis and growth plate, which are important structures in the growing child, and there are radiological features that differ from those in adults: disease may alter structures during a period of growth; the pathologies themselves are a distinct group of diseases at variance with adult arthritis and myositis, with a different spectrum of differential diagnoses; and many technical issues are different when imaging a child. These are important considerations in choosing the appropriate imaging. MRI is a powerful and valuable imaging technique in pediatric musculoskeletal pathologies, with considerable potential for future developments to enhance its role in diagnosis, management, and therapeutic intervention for these children.

MRI in Juvenile Idiopathic Arthritis and Juvenile Dermatomyositis

Chapter 6a Musculoskeletal: Clinical presentations and role of imaging

Tienda online donde Comprar Paediatric Radiology al precio 58,19 € de Karl Johnson, tienda de Libros de Medicina, Libros de Radiologia - Radiologia Pediatrica

Comprar Paediatric Radiology | Karl Johnson | 9780199204793 | Oxford University Press

Chapter 4a Genitourinary (GU): Clinical presentations and role of imaging

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Comprar Imaging in Pediatric Skeletal Trauma · Techniques and Applications | Johnson, Karl J. | 9783540661962 | Springer

Imaging Techniques and Procedures.- Paediatric Trauma Radiography.- Radiographic Positioning.- CT.- Ultrasound in Paediatric Trauma.- Magnetic Resonance Imaging.- Nuclear Medicine.- Clinical Problems.- Normal Anatomical Variants and Other Mimics of Skeletal Trauma.- Basic Science of Paediatric Fractures.- Long Bone Fractures.- Growth Plate (Physeal) Injuries.- Non-accidental Injury.- Pelvic Fractures.- The Hip Joint.- The Paediatric Knee.- Ankle.- Foot Fractures.- Shoulder.- Elbow Injuries.- The Hand and Wrist.- The Spine.- Pathological Fractures in the Immature Skeleton.

Imaging in pediatric skeletal trauma : techniques and applications

Standards for radiological investigations of suspected non-accidental injury

The hip is a relatively common site for disease and infection throughout childhood. Some conditions may be benign and self-limiting whilst others, if left untreated, can lead to significant joint damage and long-term disability. MR imaging is being increasingly used to assess joint disease in childhood both in acute and chronic conditions. When evaluating the hips, it is important to be aware of the different pathological conditions which can be present, so that imaging can be done appropriately. One of the most important considerations is the age of the child, as conditions significantly vary in their incidence during childhood.

The Pediatric Lower Extremity : The Unique Lesions of Childhood " The Pediatric Hip

A CT scan of the abdomen was done which confirmed the ultrasound findings of a well-loculated cyst in the right lobe of the liver ( fig. 2 ). The shunt tube was seen to enter the abdomen anteriorly, extending around the right A 7-year-old boy with a history of a myelomeningocele repaired at birth and a ventriculoperitoneal shunt inserted at the age of 4 months had a routine abdominal ultrasound scan for investigation of his kidneys. This scan showed a 4 ! 3 ! 5.7-cm subcapsular hepatic pseudocyst within the right lobe of the liver posteriorly ( fig. 1 ). An echogenic tubular structure was also seen within the cyst. The rest of the liver appeared normal. Both kidneys, urinary bladder, and spleen were structurally normal. There was no free peritoneal fluid.

An ultrasound scan of the abdomen was done the day after surgery, which showed that the subcapsular hepatic cyst in the right lobe of the liver had decreased in size ( fig. 4 ). The cyst now measured 3.5 ! 2.5 ! 1.8 cm. Hepatic CSF pseudocyst is an extremely rare complication of ventriculo-peritoneal shunts. We identified only 2 such cases [1, 2] . In the first case, a child was reported to have epigastric pain, signs of raised intracranial pressure and deranged liver function tests. They treated the pseudocyst with simple repositioning, which A 7-year-old boy with a history of myelomeningocele repaired at birth and a ventriculo-peritoneal shunt inserted at the age of 4 months had a routine abdominal ultrasound scan for investigation of his kidneys. This scan showed a 4 ! 3 ! 5.7 cm subcapsular hepatic pseudocyst within the right lobe of the liver posteriorly ( fig. 1 ). An echogenic tubular structure was also seen within the cyst. The rest of the liver appeared normal. Both kidneys, urinary bladder and spleen were structurally normal. There was no free peritoneal fluid. A CT scan of the abdomen was done, which confirmed the ultrasound findings of a well-loculated cyst in the right liver lobe ( fig. 2 ). The shunt tube was seen to enter the abdomen anteriorly, extending around the right side of the abdominal wall, around the liver edge to lie beneath the liver capsule in the loculated fluid collection ( fig. 3 ). The loculated fluid collection was homogenous and was displacing the liver. These appearances were suggestive of a cerebrospinal fluid (CSF) pseudocyst associated with the peritoneal catheter of the VP shunt. The patient did not have any symptoms or signs due to the pseudocyst. There were no signs of infection. He did not have any history of previous intra-abdominal surgery. Liver function tests were normal. He was admitted electively for revision of the distal end of the shunt. Upon exploration of the abdominal wound, the shunt distal tube was identified and withdrawn easily. CSF was flowing freely from the shunt. The catheter was placed in a new peritoneal position, anteriorly to the liver and the abdominal incision was closed.

Liver Cyst Caused by the Peritoneal Catheter of a Cerebrospinal Fluid Shunt

The course of 32 untreated patients with spinal stenosis was studied. The mean patient age was 60 years, and the mean period of observation was 49 months. About 75% of the patients had spinal claudication. In the follow-up survey, the same number of patients had claudication, but the symptoms were milder. In estimation by visual analog scale, symptoms in 70% of the cases were unchanged, 15% showed improvement, and 15% worsened. No proof of severe deterioration was found after four years, and expectant observation may be an alternative to surgical treatment.

MRI based assessment of sacroiliac joints in juvenile idiopathic arthritis (JIA)

OBJECTIVE
A proportion of children with oligoarthritis have an aggressive disease course. Identifying these children at presentation would help guide prognosis and management. We examined if magnetic resonance imaging (MRI) of clinically unaffected joints is more sensitive than clinical assessment in identifying those at risk of developing arthritis in more than one joint.

METHODS
Ten children were recruited; they had a mean age of 9.4 (range 5.2-14.2) years at presentation of a monoarthritis. MRI of a clinically unaffected knee was performed within 4 months of presentation, and was reported by 2 pediatric radiologists blinded to the clinical findings. All MR examinations included post-gadolinium sequences. Joints with clinically apparent arthritis were recorded regularly over a median of 37.0 (range 6.6-47.0) months by a median of 6.0 (range 2-8) pediatric rheumatologists blinded to the MR result.

RESULTS
Four children developed arthritis in other joints over a median of 3.9 (range 3-6) months after the MRI scan; all had abnormal MRI scans at presentation. Three of these developed clinical features in the previously normal knee 4-11 months after MRI identified small joint effusions, synovial hypertrophy, and lymph node enhancement. One child developed a polyarthritis, but never developed clinical features in the imaged knee over 3.8 years of followup. Four other children had a persistent monoarthropathy with a median followup of 29.5 (range 6.6-42.0) months. All 4 had normal MRI. Two children had reactive arthritis.

MRI distinguished between patients with a persistent monoarthritis and those who developed further clinical arthritis up to 1 year later. The results suggest a widespread inflammatory process may exist in children whose arthritis extends, and this has implications for our understanding of disease and the design and timing of therapeutic interventions.

Magnetic resonance imaging identifies features in clinically unaffected knees predicting extension of arthritis in children with monoarthritis.

Clinical image. Systemic hyalinosis with extensive lytic bone lesions.

Commentary on "Inter- and intrareader variability in the interpretation of two radiographic classification systems for juvenile rheumatoid arthritis"

Childhood arthritis has now been reclassified into a single internationally recognized entity of juvenile idiopathic arthritis (JIA). Radiology provides an important role in the management of JIA, in helping in the differential diagnosis, monitoring disease progression and detecting complications. Traditionally, plain radiographs have been the imaging investigation of choice but magnetic resonance imaging (MRI) and ultrasound are now providing a more effective and safer alternative. The appropriate use of sequences in MR imaging is important in the early detection of joint abnormalities in JIA.

AIMS
Early diagnosis of juvenile idiopathic arthritis (JIA) facilitates earlier more aggressive therapy, and improved outcome. Recognition of the features of early, untreated JIA on magnetic resonance imaging (MRI) will improve disease detection and expedite treatment. This study aims to highlight the relevant MRI features.

METHODS
MRI examinations of the knee joint were performed on 11 children with clinically confirmed, early, untreated JIA. The MRI images were obtained at a mean of 2 months after symptom onset and independently evaluated by two consultant paediatric radiologists.

RESULTS
Abnormalities were found on all MRI examinations. Synovial hypertrophy, joint effusions, popliteal lymph nodes and soft tissue swelling were present in all patients. Gadolinium DTPA enhancement improved the detection of synovial hyperplasia. Metaphyseal splaying and condylar overgrowth were seen in five cases (41%), oedema of the lateral collateral ligament in two cases (18%) and superficial cartilage thinning in one case. Bony erosions and deep cartilage destruction were not demonstrated.

MRI of the knee joint identifies early joint changes which are distinct from those in later disease. The presence of these features should alert the radiologist to the possible diagnosis of JIA and post gadolinium DTPA sequences should be performed. Gadolinium DPTA enhancement increases the sensitivity for the detection of inflammatory changes in JIA.

The early magnetic resonance imaging features of the knee in juvenile idiopathic arthritis.

Evaluation of mebrofenin hepatoscintigraphy in neonatal-onset jaundice

Background. The prog- nosis of infants with prolonged neo- natal jaundice is dependent on early diagnosis because of the need for prompt surgical management of bil- iary atresia. Objective. To evaluate the useful- ness of 99 m Tc m -trimethylbromo-im- inodiacetic acid (TBIDA, mebrofenin) in the investigation of infantile jaundice. Materials and methods. A retrospec- tive study was undertaken of 58 pa- tients with unexplained prolonged neonatal jaundice. Sixty-eight scans were reviewed. Results. Mebrofenin scintigraphy confirmed the presence of a chole- dochal cyst in three of the four cases with that diagnosis. There were no false negative results in the nine pa- tients with extrahepatic biliary atre- sia (EHBA). Three further infants had an incorrect histological diag- nosis of EHBA. A gall bladder was identified by US in each case and in one of these, scintigraphy showed

The authors describe a geometric layout of quantum-dot cellular automata (QCA) cells and an associated set of clock signals that can be used to implement a programmable array of logic (PAL). PALs are an important category of programmable logic that can be programmed (typically once) to perform a particular sum-of-products Boolean operation. The particular device described has six inputs, four product terms, and one output. The connections between the inputs and the product terms are fully reprogrammable, while the connections between the product terms and the output are hardwired. This device takes 22 clock cycles to load the connection data and then completes the calculation in 57 cycles. The connection data are preserved in memory, so additional calculations with the same set of connections can be performed in just 57 cycles each.

Programmable Logic Implemented Using Quantum-Dot Cellular Automata

A magnetically compensated buoyancy balance is described. This instrument provides precise and continuous indications of gas and vapor densities falling in the range of 0 to 4 g/l. Measurements can be made at temperatures that are freely variable up to 220°C; mildly corrosive vapors can be handled; and the data are automatically corrected for adsorption effects. The long term reproducibility of the readings is 0.001 g/l.Magnetic compensation is attained by adjusting the current in an external electromagnet until this magnet's interaction with a small permanent magnet sealed in the balance beam restores the beam to a standard null position. The virtually linear relationship between this ``restoring'' current and the ambient vapor density is established by calibration with a standard substance. High constancy of calibration has been achieved through the use of a special beam suspension which, though extremely friction free, is unaffected by repeated and relatively severe mechanical and thermal shocks.

Background: In 2011, the Veterans Health Administration (VHA) implemented homeless-tailored primary care medical home models, called the Homeless Patient Aligned Care Teams (HPACT) to improve care for homeless Veterans. The aim of this study was to describe the existing peer-reviewed literature on HPACTs by systematically reviewing studies published since 2011 to date. Methods: We conducted a systematic review of peer-reviewed studies published from 2011 to June 2019 to evaluate the literature since the inception of the VHA Homeless PACT program implementation. We included original research articles evaluating the Homeless PACT and excluded those that did not contain original data. Results: Of 379 studies screened, 20 studies met our inclusion criteria and were included for analysis. Given wide variability in research designs and outcome measures, a narrative review was conducted. The 20 included studies were categorized into 3 groups: Early HPACT pilot implementations; Association of HPACT clinics with quality and utilization; and Specialized programs within HPACTs. Observational findings suggest reductions in emergency department utilization, improvements in primary care treatment utilization, engagement, and patient experience; but limited rigorous studies exist beyond single site pilots and a few large observational cohort studies. Discussion: The HPACT model has been successfully implemented in VHA medical centers throughout the country with multiple studies showing increased primary care engagement and improved patient experience; however, further studies are needed about quality, utilization and whether the model can be implemented outside the VHA system. Registration Number/Funding source: none

Primary Care for Homeless Veterans: A Systematic Review of the Homeless Patient Aligned Care Team (HPACT)

Abstract:Adequate, safe, and affordable housing is an important determinant of health, yet studies on subsidized housing and health are limited in number and scope. This exploratory survey assessed the health conditions, needs, accessibility of services, and health issues perceived as most important by federally-subsidized affordable housing participants in Virginia. Results for residents of public housing complexes, tenants with housing vouchers, and a nationally representative sample are compared. Findings highlight issues related to cost of care, transportation, medication adherence, depression, and asthma. While housing subsidies are intended to reduce economic burden by enabling residents to use financial resources for other purposes (e.g., preventive health care, access to food), findings suggest that participants continue to experience cost-related barriers and poor health.

Subsidized Housing and Health: An Exploratory Study Examining Resident Perspectives on Community Health and Access to Care

Instant Gratification as a Method to Promote Critical Care Providers Practice Guideline Adherence: A Systematic Review

This research paper is mainly focused on nursing staffing and the patient outcomes that are achieved from staffing. Staffing trends and styles differ in various healthcare organizations. Staffing plays a very important role in patient outcomes. It seeks to bring out the importance of strategic staffing and put to light all the challenges that might be met in a nursing profession. Understanding this challenges or shortcomings is key in coming up with recommendations to improve the current status. Patient outcome is also analyzed and viewed in terms of patient safety and quality assurance. Adequately staffed care units can improve patient outcomes and patient satisfaction. Patient satisfaction has also been discussed in deep measures to ensure that the patients are well cared for. Three kinds of different models used in nursing have also been discussed. Patient satisfaction is the main thing to focus on if one is running a hospital. There is no point in having a hospital where the morality rates are high. The patient outcome can be used to measure the performance of a hospital. A hospital that can be described as providing quality care is one that has an excellent patient satisfaction or at least trying to achieve excellence. The consideration of various quality measures from structural, process, and outcomes have been researched and showing that there is a direct correlation of staffing and patient outcomes. Strategic leadership plays a vital role in the expectations of the organization and care expectations standards. Nursing Staffing and Patient Outcomes 3

Fostering future global nurse leaders to work toward meeting Millennium Development Goals (MDGs) and Sustainable Development Goals (SDGs): a global health intern program at Johns Hopkins University School of Nursing

From buzzword to lasting change: The journey from headcount diversity to truly inclusive nursing communities

Fostering an understanding of global nursing through international exchange

As part of an overall research program to create a set of web-based interactive distance learning modules, an educational needs assessment was conducted. The educational needs assessment is undertaken to collect information via observation and interview as to which knowledge areas are most desirable for incorporation into the interactive distance learning modules. This research is best undertaken with a neutral stance and without any preconceptions or hypotheses as to which knowledge areas are likely to be most useful. The interactive modules were designed to enhance the utilization of telemedicine by health care providers. This paper is a report on the methodology used and the findings of the needs assessment. The educational needs assessment acts as a compass to guide the creation of curricula. In the design of interactive learning, the needs assessment may be an important tool that informs not only the selection of the content, but also the selection of technology and courseware processes. The methodology described herein may be useful as a template for other authors of interactive learning courseware. The results of this study identified four clusters of content to be offered and confirmed the selection of interactive, web-based distance learning as the most appropriate delivery approach.

Preparing Healthcare Professionals for Telemedicine: Results from Educational Needs Research

Sequencing HIV-neutralizing antibody exons and introns reveals detailed aspects of lineage maturation

Jiwon Lee, Depart. of Chemical Engineering, University of Texas at Austin, Austin g1lee@utexas.edu Daniel R. Boutz, Center of Systems and Synthetic Biology, University of Texas at Austin, Austin Andrew P. Horton, Center of Systems and Synthetic Biology, University of Texas at Austin, Austin Jonathan R. McDaniel, Depart. of Chemical Engineering, University of Texas at Austin, Austin Erik L. Johnson, Depart. of Chemical Engineering, University of Texas at Austin, Austin Alexander Frühwirth, Institute for Research in Biomedicine, Switzerland. Leontios Pappas, Institute for Research in Biomedicine, Switzerland. Davide Corti, Institute for Research in Biomedicine, Switzerland. Edward M. Marcotte, Center of Systems and Synthetic Biology, University of Texas at Austin, Austin Gregory C. Ippolito, Depart. of Molecular Biosciences, University of Texas at Austin, Austin Antonio Lanzavecchia, Institute for Research in Biomedicine, Switzerland. George Georgiou, Depart. of Chemical Engineering, University of Texas at Austin, Austin

Longitudinal landscapes of serum antibody repertoires after influenza infection and vaccination

Corrigendum: Facile Discovery of a Diverse Panel of Anti-Ebola Virus Antibodies by Immune Repertoire Mining

ABSTRACT Ricin is a toxin that could potentially be used as a bioweapon. We identified anti-ricin A chain antibodies by sequencing the antibody repertoire from immunized mice and by selecting high affinity antibodies using yeast surface display. These methods led to the isolation of multiple antibodies with high (sub-nanomolar) affinity. Interestingly, the antibodies identified by the 2 independent approaches are from the same clonal lineages, indicating for the first time that yeast surface display can identify native antibodies. The new antibodies represent well-characterized reagents for biodefense diagnostics and therapeutics development.

Discovery of high affinity anti-ricin antibodies by B cell receptor sequencing and by yeast display of combinatorial VH:VL libraries from immunized animals

Significance We applied a very recently developed experimental strategy for high-throughput sequencing of paired antibody heavy and light chains along with large-scale computational structural modeling to delineate features of the human antibody repertoire at unprecedented scale. Comparison of antibody repertoires encoded by peripheral naive and memory B cells revealed (i) preferential enrichment or depletion of specific germline gene combinations for heavy- and light-chain variable regions and (ii) enhanced positive charges, higher solvent-accessible surface area, and greater hydrophobicity at antigen-binding regions of mature antibodies. The data presented in this report provide fundamental new insights regarding the biological features of antibody selection and maturation and establish a benchmark for future studies of antibody responses to disease or to vaccination. Elucidating how antigen exposure and selection shape the human antibody repertoire is fundamental to our understanding of B-cell immunity. We sequenced the paired heavy- and light-chain variable regions (VH and VL, respectively) from large populations of single B cells combined with computational modeling of antibody structures to evaluate sequence and structural features of human antibody repertoires at unprecedented depth. Analysis of a dataset comprising 55,000 antibody clusters from CD19+CD20+CD27− IgM-naive B cells, >120,000 antibody clusters from CD19+CD20+CD27+ antigen–experienced B cells, and >2,000 RosettaAntibody-predicted structural models across three healthy donors led to a number of key findings: (i) VH and VL gene sequences pair in a combinatorial fashion without detectable pairing restrictions at the population level; (ii) certain VH:VL gene pairs were significantly enriched or depleted in the antigen-experienced repertoire relative to the naive repertoire; (iii) antigen selection increased antibody paratope net charge and solvent-accessible surface area; and (iv) public heavy-chain third complementarity-determining region (CDR-H3) antibodies in the antigen-experienced repertoire showed signs of convergent paired light-chain genetic signatures, including shared light-chain third complementarity-determining region (CDR-L3) amino acid sequences and/or Vκ,λ–Jκ,λ genes. The data reported here address several longstanding questions regarding antibody repertoire selection and development and provide a benchmark for future repertoire-scale analyses of antibody responses to vaccination and disease.

Large-scale sequence and structural comparisons of human naive and antigen-experienced antibody repertoires

Facile Discovery of a Diverse Panel of Anti-Ebola Virus Antibodies by Immune Repertoire Mining

Production and Characterization of Chemically Inactivated Genetically Engineered Clostridium difficile Toxoids.

Selon des modes de realisation, la presente invention concerne des composants abradables de de turbine et de compresseur pour turbomachines, avec des aretes et des rainures composites a surfaces abradables, a trois angles, en motif de forme en plan de "bâton de hockey". Le motif de forme en plan a trois angles incorpore differents segments composites avant, intermediaires, et arriere. Les formes en plan et les profils des aretes/rainures a trois angles reduisent, reorientent, et/ou bloquent la fuite de flux d'air en aval en bout de pale dans les rainures plutot que depuis les cotes haute pression vers les cotes basse pression des surfaces portantes de pales de turbine. Selon certains modes de realisation, les rainures sont separees ou divisees en une pluralite de sections pour interrompre le flux circulant a l'interieur de la rainure et entrainer une mise sous pression locale qui reduit l'ecoulement de fuite de bout de pale. Certains modes de realisation d'aretes ou nervures presentent egalement une premiere zone inferieure et une seconde zone superieure d'usure. La zone inferieure optimise les caracteristiques de flux d'air moteur, tandis que la zone superieure est optimisee pour reduire au minimum l'espace et l'usure de bout de pale en etant plus facilement abradable que la zone inferieure.

Carénage de turbine à couche abradable ayant des arêtes et rainures composites non fléchies à trois angles

L'invention concerne un composant abradable (160) de turbine comprenant : une surface de support destinee a etre couplee a un carter de turbine; un substrat abradable couple a la surface de support, presentant une surface de substrat faisant face aux aubes, dotee d'un motif forme de motifs lineaires composites respectifs, en plan, en "bâtons de hockey" (162A, 168A; 162B, 168B), avant cote amont et arriere cote aval, interfaces, a rainures a orientations multiples et a nervures faisant saillie verticalement, qui sont concus pour etre orientes de maniere a se trouver a proximite d'une trajectoire circonferentielle decrite par l'extremite d'une aube de turbine en rotation possedant un bord d'attaque, un point de coupure a mi-corde sur sa surface convexe cote intrados, au niveau duquel une tangente a la surface est sensiblement parallele a un axe de rotation de turbine correspondant, et un bord de fuite; le motif de la zone avant (A) etant delimite approximativement entre le bord d'attaque et le point de coupure a mi-corde de l'aube de turbine correspondante et oriente sensiblement parallelement a la direction d'ecoulement de gaz de combustion de la turbine correspondante; et le motif de la zone arriere (B) etant defini approximativement entre le point de coupure a mi-corde et le bord de fuite de l'aube de turbine correspondante, et presentent une orientation angulaire opposee a la direction de rotation de l'aube de turbine correspondante.

Rainures composites en « bâtons de hockey » sur une surface d'un segment de virole de turbine

Silicium couche mince 
 
La technologie PV de silicium en couches minces: des coups durs pendant la crise, et comment regagner son mojo

La technologie PV de silicium en couches minces: des coups durs pendant la crise, et comment regagner son mojo Erik Johnson

Cette invention se rapporte a un appareil qui sert a analyser plusieurs parties d'image d'au moins une zone d'un echantillon et qui comprend a cet effet plusieurs processeurs destines a recevoir et a analyser au moins l'une des parties d'image, ces processeurs etant concus pour fonctionner en parallele. Cet appareil comprend egalement un systeme de distribution de donnees destine a recevoir les donnees d'image, a selectionner au moins un premier processeur destine a recevoir une premiere image en provenance des donnees d'image, a selectionner au moins un second processeur destine a recevoir une seconde image en provenance des donnees d'image, et a produire en sortie les premiere et seconde parties d'image pour les appliquer aux processeurs selectionnes.

Procede et appareil d'inspection de reticules executant un traitement en parallele

We report in situ synthesis of crystalline indium islands on InAs nanowires grown by molecular beam epitaxy. Structural analysis by transmission electron microscopy showed that In crystals grew in a tetragonal body-centered crystal structure within two families of orientations relative to wurtzite InAs. The crystalline islands had lengths < 500 nm and low-energy surfaces, suggesting that growth was driven mainly by surface energy minimization. Electrical transport through In/InAs devices exhibited Cooper pair charging, evidencing charge parity preservation and a pristine In/InAs interface, with an induced superconducting gap ∼ 0.45 meV. Cooper pair charging persisted to temperatures > 1.2 K and magnetic fields ∼ 0.7 T, demonstrating that In/InAs hybrids belong to an expanding class of semiconductor/superconductor hybrids operating over a wider parameter space than state-of-the-art Al-based hybrids. Engineering crystal morphology while isolating single islands using shadow epitaxy provides an interesting alternative to previous semiconductor/superconductor hybrid morphologies and device geometries.

Superconductivity and Parity Preservation in As-Grown In Islands on InAs Nanowires.

Semiconductor-superconductor hybrids are widely used for realising complex quantum phenomena such as topological superconductivity and spins coupled to Cooper pairs. Accessing exotic regimes at high magnetic fields and increasing operating temperatures beyond the state-of-the-art requires new, epitaxially matched semiconductor-superconductor materials. The challenge is to generate favourable conditions for heterostructure formation between materials with the desired inherent properties. Here, we harness increased knowledge of metal-on-semiconductor growth to develop InAs nanowires with epitaxially matched, single crystal, atomically flat Pb films along the entire nanowire. These highly ordered heterostructures have a critical temperature of 7 K and a superconducting gap of 1.25 meV, which remains hard at 8.5 T, thereby more than doubling the available parameter space. Additionally, InAs/Pb island devics exhibit magnetic field-driven transitions from Cooper pair to single electron charging; a pre-requisite for use in topological quantum computation. Introducing semiconductor-Pb hybrids potentially enables access to entirely new regimes for an array of quantum systems.

Shadow Epitaxy: Shadow Epitaxy for In Situ Growth of Generic Semiconductor/Superconductor Hybrids (Adv. Mater. 23/2020)

The quality of interfaces and surfaces is crucial for the performance of nanoscale devices. A pertinent example is the close tie between current progress in gate-tunable and topological superconductivity using semiconductor/superconductor electronic devices and the hard proximity-induced superconducting gap obtained from epitaxial indium arsenide/aluminium heterostructures. Fabrication of devices requires selective etch processes; these only exist for InAs/Al hybrids, which precludes the use of other, potentially better material combinations in functional devices. We present a crystal growth platform based on three-dimensional structuring of growth substrates for synthesising semiconductor nanowires with in-situ patterned superconductor shells, which enables independent choice of material by eliminating etching. We realise and characterise all the most frequently used architectures in superconducting hybrid devices, finding increased yield and electrostatic stability compared to etched devices, along with evidence of ballistic superconductivity. In addition to aluminium, we present hybrid devices based on tantalum, niobium and vanadium.

Shadow lithography for in-situ growth of generic semiconductor/superconductor devices

We report MBE synthesis of InAs/vanadium hybrid nanowires. The vanadium was deposited without breaking ultra-high vacuum after InAs nanowire growth, minimizing any effect of oxidation and contamination at the interface between the two materials. We investigated four different substrate temperatures during vanadium deposition, ranging from −150 °C to 250 °C. The structural relation between vanadium and InAs depended on the deposition temperature. The three lower temperature depositions gave vanadium shells with a polycrystalline, granular morphology and the highest temperature resulted in vanadium reacting with the InAs nanowire. We fabricated electronic devices from the hybrid nanowires and obtained a high out-of-plane critical magnetic field, exceeding the bulk value for vanadium. However, size effects arising from the nanoscale grains resulted in the absence of a well-defined critical temperature, as well as device-to-device variation in the resistivity versus temperature dependence during the transition to the superconducting state.

Uniform, defect‐free crystal interfaces and surfaces are crucial ingredients for realizing high‐performance nanoscale devices. A pertinent example is that advances in gate‐tunable and topological superconductivity using semiconductor/superconductor electronic devices are currently built on the hard proximity‐induced superconducting gap obtained from epitaxial indium arsenide/aluminum heterostructures. Fabrication of devices requires selective etch processes; these exist only for InAs/Al hybrids, precluding the use of other, potentially superior material combinations. This work introduces a crystal growth platform—based on 3D structuring of growth substrates—which enables synthesis of semiconductor nanowire hybrids with in situ patterned superconductor shells. The platform eliminates the need for etching, thereby enabling full freedom in the choice of hybrid constituents. All of the most frequently used superconducting hybrid device architectures are realized and characterized. These devices exhibit increased yield and electrostatic stability compared to etched devices, and evidence of ballistic superconductivity is observed. In addition to aluminum, hybrid structures based on tantalum, niobium, and vanadium are presented.

Shadow Epitaxy for In Situ Growth of Generic Semiconductor/Superconductor Hybrids

Topological protection in hybrid semiconductor-superconductor materials largely relies on the hybrid electronic properties. This paper presents growth and characterization of epitaxial InAs${}_{1\ensuremath{-}x}$Sb${}_{x}$/Al nanowires where both composition and crystal structure of the semiconductor is varied. Among the findings are a strong spin-orbit coupling at intermediate compositions, large effective $g$ factors, induced hard-gap superconductivity in nanowires with both zincblende and wurtzite structure, and signatures of topological superconductivity

Engineering hybrid epitaxial InAsSb/Al nanowires for stronger topological protection

The combination of strong spin-orbit coupling, large $g$-factor, and coupling to a superconductor can be used to create a topological state in a semiconductor nanowire. Here we study the compositional degree of freedom between the two semiconductors InAs and InSb, and investigate the spin-orbit interaction and $g$-factor as well as the structural and compositional properties of hybrid InAs$_{1-x}$Sb$_{x}$/Al core-shell nanowires. We show bare semiconductor InAs$_{1-x}$Sb$_{x}$ zincblende nanowires exhibiting a non-monotonic spin-orbit interaction as a function of the Sb fraction ($x$), with the shortest spin-orbit length measured at $x$ $\sim$ 0.5. For the hybrid InAsSb/Al system, the bi-crystal interfaces show characteristic epitaxial relations, associated with interfacial dislocations and interfacial broadening dependent on composition. Despite these interfacial characteristics the induced superconducting gap remains hard and comparable to atomically sharp InAs/Al interfaces. With tunneling and Coulomb charging experiments, we show measurements consistent with topological phase transitions at low magnetic fields where it is possible to find zero bias peaks protected by a hard superconducting gap. Finally, we present a method to grow wurtzite InAsSb/Al nanowires, and find enhanced electrostatic gate response as well as a hard induced superconducting gap.

Hybrid Epitaxial InAsSb/Al Nanowires Towards Topological Applications

Semiconducting nanowires grown by quasi-van-der-Waals epitaxy on graphite flakes are a new class of hybrid materials that hold promise for scalable nanostructured devices within opto-electronics. Here we report on high aspect ratio and stacking fault free Ag-seeded InAs nanowires grown on exfoliated graphite flakes by molecular beam epitaxy. Ag catalyzes the InAs nanowire growth selectively on the graphite flakes and not on the underlying InAs substrates. This allows for easy transfer of the flexible graphite flakes with as-grown nanowire ensembles to arbitrary substrates by a micro-needle manipulator. Besides the possibilities for fabricating novel nanostructure device designs, we show how this method is used to study the parasitic growth and bicrystal match between the graphite flake and the nanowires by transmission electron microscopy.

Ag-catalyzed InAs nanowires grown on transferable graphite flakes

Hard proximity induced superconducting gap in semiconductor-superconductor epitaxial hybrids

Experimental determination of adatom diffusion lengths for growth of InAs nanowires

Straight, axial InAs nanowire with multiple segments of GaxIn1−xAs was grown. High resolution X-ray energy-dispersive spectroscopy (EDS) mapping reveals the distribution of group III atoms at the axial interfaces and at the sidewalls. Significant Ga enrichment, accompanied by a structural change is observed at the GaxIn1−xAs/InAs interfaces and a higher Ga concentration for the early grown GaxIn1−xAs segments. The elemental map and EDS line profile infer Ga enrichment at the facet junctions between the sidewalls. The relative chemical potentials of ternary alloys and the thermodynamic driving force for liquid to solid transition explains the growth mechanisms behind the enrichment.

Direct observation of interface and nanoscale compositional modulation in ternary III-As heterostructure nanowires

Theoretical Formalism and Modeling of III-V Nanowire Growth Dynamics

Nanowire (NW) crystal growth via the vapour–liquid–solid mechanism is a complex dynamic process involving interactions between many atoms of various thermodynamic states. With increasing speed over the last few decades many works have reported on various aspects of the growth mechanisms, both experimentally and theoretically. We will here propose a general continuum formalism for growth kinetics based on thermodynamic parameters and transition state kinetics. We use the formalism together with key elements of recent research to present a more overall treatment of III–V NW growth, which can serve as a basis to model and understand the dynamical mechanisms in terms of the basic control parameters, temperature and pressures/beam fluxes. Self-catalysed GaAs NW growth on Si substrates by molecular beam epitaxy is used as a model system.

Au free GaAs nanowires with zinc blende structure, free of twin planes and with remarkable aspect ratios, have been grown on (111) Si substrates by molecular beam epitaxy. Nanowires with diameters down to 20 nm are obtained using a thin native oxide layer on the Si substrates. We discuss how the structural phase distribution along the wire length is controlled by the effective V/III ratio and temperature at the growth interface and explain how to obtain a pure twin plane free zinc blende structure.

Structural phase control in self-catalyzed growth of GaAs nanowires on silicon (111).

We present an investigation of the morphology and composition of novel types of axial nanowire heterostructures where Ga(x)In(1-x)As is used as barrier material in InAs nanowires. Using aberration-corrected scanning transmission electron microscopy and energy dispersive X-ray analysis we demonstrate that it is possible to grow junctions by changing the group III elements, and we find that a substantial fraction of Ga can be incorporated in axial InAs/Ga(x)In(1-x)As/InAs, retaining straight nanowire configurations. We explain how the adatoms are transferred to the incorporation site at the growth interface via two different routes, (1) interface diffusion and (2) volume diffusion through the catalyst particle.

Junctions in axial III-V heterostructure nanowires obtained via an interchange of group III elements.

Molecular beam epitaxy growth of free-standing plane-parallel InAs nanoplates.

ABSTRACT When Ghana gained its independence from colonial rule in March 1957, there was a midnight ceremony, and the new Prime Minister, Kwame Nkrumah, delivered a speech. Nkrumah’s Midnight Speech is an act of rhetorical invention adapted to postcolonial political foundation and, with Ghana as the first sub-Saharan African country to gain independence, an available model of transfigurative politics for decolonizing Africa and its diaspora. I use the four constituents of Ghana’s independence ceremony—the crowd, Nkrumah, the Old Polo Grounds on which they gathered, and the midnight timing—to outline salient elements of emergent Ghana’s rhetorical culture. First, I argue that the crowd was the manifestation of the mass public of Ghana and a catalyst of colonial freedom. Next, I examine how Nkrumah personified the mass state that was caught between forms of anticolonial organizing and the media of the postcolonial state. Then, I analyze the Old Polo Grounds to focus on how Nkrumah’s rededication of national becoming to pan-African union sought to avoid the perpetuation of neocolonial dynamics. Finally, I argue that the liminal potential of midnight projected a new social imaginary that transfigured both present routines and prior traditions.

In the midnight hour: anticolonial rhetoric and postcolonial statecraft in Ghana

Abstract:In southern Louisiana's Mississippi basin, the parishes upriver from New Orleans are home to multiple restored sugar plantations and museums focused on the history of plantation slavery and the culture of the region. This interview-essay is based on interviews conducted individually with slave plantation site and museum operators, artists, academics, and those between and beyond these categories. The interviews are presented as a staged dialogue on the dynamics of violence, commerce, identity, and agency that construct plantation slavery tourism in Louisiana in conflicting ways.

Slavery, Tourism, and Memory in New Orleans's "Plantation Country"

Located at the eastern-most point of the New Guinea islands, Bougainville comprises two large and many smaller islands. It has a population of approximately 200,000 and over a dozen different languages. A province of Papua New Guinea since 1975, Bougainville is now an autonomous region within the country, the result of a nine-year revolt that left tens of thousands killed, a divided and traumatized population, degraded infrastructure, and a shattered economy brought on by the collapse of its main industry, mining. Prior to the conflict, women played vital roles in community-level decision-making and were key agents of development. Overall, women held important positions in the family and community. The dynamics of the conflict and post-conflict period weakened this role, resulting in women being marginalized from community decision-making processes. Further, during the conflict, women suffered violence as victims of torture, rape, and forced labor. The weakened capacity of women as agents of development within their communities and the low capacity of government departments working at the local level are widely viewed as significant challenges to development efforts.

Papua New Guinea - Inclusive development in post-conflict Bougainville : supporting and strengthening the participation of women in Bougainville's development processes

This article analyzes Kwame Nkrumah’s Ghana: The Autobiography of Kwame Nkrumah, which was published to coincide with Ghana’s independence on March 6, 1957. Whereas the political and social imagination of the Anglo-American world during the postwar years was riddled with anxieties concerning the masses, the crowd scenes of Nkrumah’s Ghana elaborate the characteristics of a political community centered on mass society. The article concludes by noting the possibility of a mass civic art culled from the rhetorical tradition of Ghana.

The Motivations and Challenges of Acquiring U.S. Citizenship For South Sudanese Refugees in the Greater Phoenix Area When Language is a Potential Barrier

Bougainville is located at the eastern-most point of the New Guinea islands and comprises two large and many smaller islands. It has a population of approximately 200,000 with over a dozen different language groups. A province of Papua New Guinea since 1975, Bougainville is now an autonomous region within the country, a result of a nine-year revolt that left tens of thousands killed, a divided and traumatized population, degraded infrastructure, and a shattered economy brought on by the collapse of its main industry, mining. Prior to the conflict, women played vital roles in community-level decision-making and were key agents of development. Overall, women held important positions in the family and community. The dynamics of the conflict and post-conflict period weakened this role resulting in women being marginalized from community decision-making processes. Further, during the conflict, women suffered violence as victims of torture, rape, and forced labor. The weakened capacity of women as agents of development within their communities and the low capacity of government departments working at the local level are widely viewed as significant challenges to development efforts.

Papua New Guinea - Inclusive development in post-conflict Bougainville

Never Never Land: Lieutenant General Albert C. Wedemeyer in China, October 1944 to August 1945

I created and analyzed an interactive computer
system capable of exploring geometry concepts through inductive
investigation. My system begins with a limited set of knowledge
about basic geometry and enables a user interacting with the system
to teach the system additional geometry concepts and theorems by
suggesting investigations the system should explore to see if it
"notices anything interesting." The system uses random sampling and
physical simulations to emulate the more humanlike processes of
manipulating diagrams "in the mind's eye." It then uses symbolic
pattern matching and a propagator-based truth maintenance system to
appropriately generalize findings and propose newly discovered
theorems. These theorems could be rigorously proved using external
proof assistants, but are also used by the system to assist in its
explorations of new, higher-level concepts. Through a series of
simple investigations similar to an introductory course in
geometry, the system has been able to propose and learn a few dozen
standard geometry theorems.

Automated elementary geometry theorem discovery via inductive diagram manipulation

A landscape-scale investigation into the risk of lodgepole pine mortality caused by mountain pine beetle dendroctonus ponderosae (Coleoptera: Curculioidae: Scolytinae)

An initial assessment of rapid dieback and mortality of aspen in southwest Colorado suggests that it represents a decline disease incited by acute, warm drought. Predisposing factors include low elevation, south and southwest aspects, droughty soils, open stands, and physiological maturity. Contributing factors include Cytospora canker, two bark beetles, poplar borer, and bronze poplar borer. Because this is a true decline disease distinct from “aspen decline” as often discussed in the literature, we refer to it as sudden aspen decline. There has been little regeneration response to overstory loss.

Sudden aspen decline in southwest Colorado: Site and stand factors and a hypothesis on etiology

Rapid mortality of Populus tremuloides in southwestern Colorado, USA

Summary Aerial survey, also referred to as aerial sketchmapping, is the technique of observing symptoms of forest damage from an aircraft and transferring the information manually onto a base map. Recent high levels of bark beetle mortality across the western United States have generated greater demands for, and more disparate uses of, aerial survey data. While aerial survey data are typically considered to be qualitative in nature, the recent application of the data has driven an interest in assessing its spatial and categorical accuracies quantitatively. This paper describes methods for assessing the accuracy of aerial survey data and discusses several implications and applications related to the error results. The error matrix and kappa (k) statistic, commonly used to assess accuracies of image classifications in remote sensing, were used to describe errors present in the aerial survey data. Field crews collected ground data that were used to validate the aerial classifications on 233 plots across 17.3 million ha. An additional 24 plots were incorporated into the validation from a complementary project, bringing the total number of plots to 257. Errors within the aerial survey data were found to be acceptable for coarse-scale analyses but excessive for use at fine spatial scales. In addition, this paper discusses the benefits of error analysis which include the quantification of errors for reporting purposes, the inclusion of error rates in the metadata, and the ability to focus training programs and technology development by highlighting classes with the highest error. Finally, the cost associated with accuracy assessment implementation is described and weighed against the benefits.

Abstract The Douglas-fir beetle, Dendroctonus pseudotsugae Hopkins, attacks Douglas-fir, Pseudotsuga menziesii (Mirb.) Franco (Pinaceae), throughout western North America. Periodic outbreaks cause increased mortality of its host. Land managers and forest health specialists often need to determine population trends of this insect. Bark samples were obtained from 326 trees distributed over 21 stands during a 2-year period in late winter to early spring of 1997 and 1998 in the Colorado Front Range. The variance to mean relationship of brood adults was examined using the Taylor power law, and a fixed-precision sampling plan was developed using Green’s method. Stop lines and minimum number of samples required to estimate brood adult density per 0.046 m2 with precision levels of 0.1, 0.2, and 0.3 were calculated. A resampling simulation conducted with an independent data set indicated that desired precision levels were not met. Theoretical precision levels were adjusted until desired precision levels were achieved. Average number of samples needed to estimate brood adult densities up to 25.1 adults per 0.046 m2 with precision levels of 0.09, 0.2, and 0.3 were 91, 20, and 8, respectively. For densities greater than 25.1 brood adults per 0.046 m2, conservative estimates are obtained with 72, 15, and 6 samples for precision levels of 0.09, 0.2, and 0.3, respectively. An emergence ratio can be obtained by dividing the estimated density of brood adults by twice the number of gallery starts. This system provides the user with an immediate assessment of the population trend of Douglas-fir beetle. The data collected compare favorably with data from other Douglas-fir beetle outbreaks reported in the literature. The use of this plan outside the Colorado Front Range, or by sampling at a different height, should be cautioned until additional data from other locations and sampling heights are examined. Résumé Le Dendroctone du Douglas, Dendroctonus pseudotsugae Hopkins, s’attaque aux sapins de Douglas, Pseudotsuga menziesti (Mirb.) Franco (Pinaceae), dans tout l’ouest nord-américain. Les épidémies périodiques entraînent une hausse de la mortalité chez les hôtes. Les responsables de l’aménagement des terres et les spécialistes en foresterie ont souvent besoin d’évaluer les tendances démographiques de cet insecte. Des échantillons d’écorce ont été recueillis sur 326 arbres répartis dans 21 boisés au cours d’une période de 2 ans, à la fin de l’hiver et au début du printemps en 1997 en 1998 dans la chaîne de montagnes Colorado Front Range. Le rapport entre la variance et la moyenne a été étudié chez la progéniture émergente à l’aide de la loi de puissance de Taylor et un plan d’échantillonnage à précision pré-établie a été conçu selon la méthode de Green. Les lignes d’arrêt et le nombre minimum d’échantillons nécessaires pour estimer la densité des adultes émergés par 0,046 m2 à des niveaux de précision de 0,1, 0,2 et 0,3 ont été calculés. La simulation d’un nouvel échantillonnage avec une nouvelle matrice indépendante de données a permis de constater que les niveaux de précision n’ont pas été atteints. Les niveaux de précision théoriques ont été ajustés jusqu’à ce que les niveaux de précision désirés soient obtenus. Le nombre d’échantillons requis pour estimer la densité des adultes à l’émergence jusqu’à 25,1 adultes par 0,046 m2 était de 91 à un niveau de précision de 0,09, de 20 à un niveau de 0,2 et de 8 à un niveau de 0,03. Aux densités supérieures à 25,1 adultes par 0,046 m2, des estimations conservatrices de 72 (0,09), 15 (0,02) et 6 (0,03) échantillons ont été obtenues. Un rapport à l’émergence peut être calculé en divisant la densité estimée d’adultes par deux fois le nombre de galeries commencées. Ce système fournit à l’utilisateur une estimation immédiate de la tendance démographique du dendroctone. Ces données se comparent favorablement à celles obtenues au cours d’épidémies de dendroctones mentionnées dans la littérature. L’utilisation de ce plan en dehors de cette chaîne de montagnes, ou l’échantillonnage à d’autres hauteurs est à déconseiller si l’on n’obtient pas d’abord des données additionnelles sur d’autres localités et hauteurs d’échantillonnage. [Traduit par la Rédaction]

DEVELOPMENT AND VALIDATION OF A FIXED-PRECISION SEQUENTIAL SAMPLING PLAN FOR ESTIMATING BROOD ADULT DENSITY OF DENDROCTONVS PSEUDOTSUGAE (COLEOPTERA: SCOLYTIDAE)

Innovation and Marketing in the Video Game Industry: Avoiding the Performance Trap by David Wesley and Gloria Barczak. Surrey, UK: Gower, 2010. 266 + xiv pages. US$124.95.

The Innovator's DNA: Mastering the Five Skills of Disruptive Innovators Jeff Dyer, Hal Gregersen, and Clayton Christensen. Boston, MA: Harvard Business Review Press, 2011. 296 + vi pages. US$29.95.

Business Model Generation: A Handbook for Visionaries, Game Changers, and Challengers by Alexander Osterwalder and Yves Pigneur. Hoboken, NJ: John Wiley & Sons, 2010. 281 + iv pages. US$34.95.

The Lords of Strategy: The Secret Intellectual History of the New Corporate World Walter Kiechel. Boston, MA: Harvard Business School Press, 2010. 347 + xiv pages. US$26.95.

Cracking the Ad Code by Jacob Goldenberg, Amnon Levav, David Mazursky, and Sorin Solomon

This volume comsprises the proceedings of the Fourth International Conference on Stochastic Structural Dynamics, which took place in Notre Dame, Indiana, USA, in August 1998.

Stochastic structural dynamics : proceedings of the fourth International Conference on Stochastic Structural Dynamics - SSD'98 , Notre Dame/Indiana/USA/6-8 August 1998

The effects of the flipped learning model on student attitude and performance in high school biology

MOVES Research & Education Systems Seminar: Presentation; Session 7: Computer Gaming and Web-Delivered Simulation; Moderator: Perry McDowell; MOVES’ Visualization Capabilities; speaker: Erik Johnson

MOVES Research & Education Systems Seminar: Presentation; Session 3c: Human Systems and Training (Operational Systems); Moderator: Mike McCauley; ROGUEVIDEO: CyberAttack; speaker: Erik Johnson

An analysis of and response to Vietnam War education in the American high school curriculum

Abstract First price and Dutch auctions are theoretically isomorphic, but previous experiments report that the institutions are not behaviorally isomorphic. This article uses facial analysis of video recordings of laboratory experiments to investigate whether these auctions invoke different emotional responses from bidders. The results indicate that bidders are angrier during the Dutch auction and that winners exhibit more contempt after the first price auction. Overall, subjects in both auctions appear to be mostly bored and depressed, but there is evidence that bidders exhibit more positive emotions as prices fall in the Dutch auction.

Fire & explosion hazards due to thermal runaway propagation in lithium-ion battery systems

Ultrasonic inspection of lithium-ion batteries to detect cell safety and prevent thermal runaway

Characterization of Thermally Induced Runaway in Pouch Cells for Propagation

Accurately estimating state of charge (SOC), state of health (SOH), and other metrics of battery safety remains a challenge for lithium ion batteries outside the laboratory, where one may use techniques such as X-ray diffraction, electrochemical impedance spectroscopy, or neutron imaging. Existing in situ methods to estimate SOC and SOH employ voltage monitoring or Coulomb-counting. Unfortunately, these methods remain inaccurate because they assume a battery capacity or voltage per discharge, while capacity and voltage are known to vary with C-rate and cycle age. The present work explores the viability of interpreting SOC, SOH, and safety metrics by monitoring and interpreting ultrasonic signals propagating through a battery as it is cycled between charged and discharged states in various environmental conditions. Of specific interest are cases where a battery enters dangerous operating conditions which lead to the formation of gases within the battery as well as increases in internal temperature, pressure, and battery volume. To investigate this regime, the received ultrasonic signals are monitored over the course of charging and discharging cycles and analyzed in the time and frequency domains in an effort to provide an in situ means to estimate SOC, SOH and battery safety metrics.

Ultrasonic inspection of lithium-ion batteries to determine state of charge, state of health, and battery safety

PARAMETER ESTIMATION FOR BATTERY KINETIC AND THERMOPHYSICAL PARAMETERS

ABSTRACT In previous work, a prototypic recombinant vesicular stomatitis virus Indiana serotype (rVSIV) vector expressing simian immunodeficiency virus (SIV) gag and human immunodeficiency virus type 1 (HIV-1) env antigens protected nonhuman primates (NHPs) from disease following challenge with an HIV-1/SIV recombinant (SHIV). However, when tested in a stringent NHP neurovirulence (NV) model, this vector was not adequately attenuated for clinical evaluation. For the work described here, the prototypic rVSIV vector was attenuated by combining specific G protein truncations with either N gene translocations or mutations (M33A and M51A) that ablate expression of subgenic M polypeptides, by incorporation of temperature-sensitive mutations in the N and L genes, and by deletion of the VSIV G gene to generate a replicon that is dependent on trans expression of G protein for in vitro propagation. When evaluated in a series of NHP NV studies, these attenuated rVSIV variants caused no clinical disease and demonstrated a very significant reduction in neuropathology compared to wild-type VSIV and the prototypic rVSIV vaccine vector. In spite of greatly increased in vivo attenuation, some of the rVSIV vectors elicited cell-mediated immune responses that were similar in magnitude to those induced by the much more virulent prototypic vector. These data demonstrate novel approaches to the rational attenuation of VSIV NV while retaining vector immunogenicity and have led to identification of an rVSIV N4CT1gag1 vaccine vector that has now successfully completed phase I clinical evaluation. IMPORTANCE The work described in this article demonstrates a rational approach to the attenuation of vesicular stomatitis virus neurovirulence. The major attenuation strategy described here will be most likely applicable to other members of the Rhabdoviridae and possibly other families of nonsegmented negative-strand RNA viruses. These studies have also enabled the identification of an attenuated, replication-competent rVSIV vector that has successfully undergone its first clinical evaluation in humans. Therefore, these studies represent a major milestone in the development of attenuated rVSIV, and likely other vesiculoviruses, as a new vaccine platform(s) for use in humans.

Neurovirulence and Immunogenicity of Attenuated Recombinant Vesicular Stomatitis Viruses in Nonhuman Primates

We evaluated the immunological responses of African green monkeys immunized with multiple F and G protein-based vaccines and assessed protection against the Memphis 37 strain of respiratory syncytial virus (RSV).

METHODS
Monkeys were immunized with F and G proteins adjuvanted with immunostimulatory (CpG) oligodeoxyribonucleotides admixed with either Alhydrogel or ISCOMATRIX adjuvant. Delivery of F and G proteins via replication incompetent recombinant vesicular stomatitis viruses (VSVs) and human adenoviruses was also evaluated. Mucosally or parenterally administered recombinant adenoviruses were used in prime-boost regimens with adjuvanted proteins or recombinant DNA.

RESULTS
Animals primed by intranasal delivery of recombinant adenoviruses, and boosted by intramuscular injection of adjuvanted F and G proteins, developed neutralizing antibodies and F/G protein-specific T cells and were protected from RSV infection. Intramuscular injections of Alhydrogel (plus CpG) adjuvanted F and G proteins reduced peak viral loads in the lungs of challenged monkeys. Granulocyte numbers were not significantly elevated, relative to controls, in postchallenge bronchoalveolar lavage samples from vaccinated animals.

This study has validated the use of RSV (Memphis 37) in an African green monkey model of intranasal infection and identified nonreplicating vaccines capable of eliciting protection in this higher species challenge model.

Nonreplicating vaccines can protect african green monkeys from the memphis 37 strain of respiratory syncytial virus.

Non-propagating, recombinant vesicular stomatitis virus vectors encoding respiratory syncytial virus proteins generate potent humoral and cellular immunity against RSV and are protective in mice.

Dynamics and stability in virus maturation: mechanisms of a molecular machine

Refined methods for propagating vesicular stomatitis virus vectors that are defective for G protein expression.

Structure-based engineering of an icosahedral virus for nanomedicine and nanotechnology.

There is a pressing need for the archival and curation of raw X-ray diffraction data. However, the relatively large size of these datasets has presented challenges for storage in a single worldwide repository. This problem can be avoided by using a federated approach, where each institution or university utilizes its institutional repository. Institutional repositories are relatively stable and adequately funded, ensuring persistence. Here we describe a simple repository solution utilizing Fedora open source database software, and data annotation and deposition tools that can be deployed at any site cheaply and easily. Datasets and associated metadata from federated repositories are given a unique and persistent handle, providing a simple mechanism for search and retrieval via web interfaces. We call this initiative ‘The Australian Repositories for Diffraction Images (TARDIS)’ and have created a website (http://www.tardis.edu.au) where the deposition tools can be downloaded freely. The site will also function as a central portal allowing searching and browsing across all registered Australian repositories. In addition to ensuring that valuable data is not lost, the provision of raw data has several uses for the crystallographic community. Most importantly, structure determination can only be truly repeated or verified when the raw data is available. In addition, the availability of raw data is extremely useful for the development of improved methods of image analysis and data processing.

Virus Particle Explorer: an X-ray and electron microscopy database for icosahedral virus structures

ABSTRACT Recombinant vesicular stomatitis virus (rVSV) has shown great potential as a new viral vector for vaccination. However, the prototypic rVSV vector described previously was found to be insufficiently attenuated for clinical evaluation when assessed for neurovirulence in nonhuman primates. Here, we describe the attenuation, neurovirulence, and immunogenicity of rVSV vectors expressing human immunodeficiency virus type 1 Gag. These rVSV vectors were attenuated by combinations of the following manipulations: N gene translocations (N4), G gene truncations (CT1 or CT9), noncytopathic M gene mutations (Mncp), and positioning of the gag gene into the first position of the viral genome (gag1). The resulting N4CT1-gag1, N4CT9-gag1, and MncpCT1-gag1 vectors demonstrated dramatically reduced neurovirulence in mice following direct intracranial inoculation. Surprisingly, in spite of a very high level of attenuation, the N4CT1-gag1 and N4CT9-gag1 vectors generated robust Gag-specific immune responses following intramuscular immunization that were equivalent to or greater than immune responses generated by the more virulent prototypic vectors. MncpCT1-gag1 also induced Gag-specific immune responses following intramuscular immunization that were equivalent to immune responses generated by the prototypic rVSV vector. Placement of the gag gene in the first position of the VSV genome was associated with increased in vitro expression of Gag protein, in vivo expression of Gag mRNA, and enhanced immunogenicity of the vector. These findings demonstrate that through directed manipulation of the rVSV genome, vectors that have reduced neurovirulence and enhanced immunogenicity can be made.

Attenuation of Recombinant Vesicular Stomatitis Virus-Human Immunodeficiency Virus Type 1 Vaccine Vectors by Gene Translocations and G Gene Truncation Reduces Neurovirulence and Enhances Immunogenicity in Mice

 Highly attenuated recombinant vesicular stomatitis virus (rVSV) vectors expressing HIV-1 Gag have been shown to be immunogenic in preclinical animal models. Here we explored the potential to enhance immunogenicity through co-delivery of either replication-competent (rVSV-N3CT9) or non-propagating (rVSV-Gstem) vectors expressing GM-CSF. A construct expressing both antigen and cytokine, Gstem-Gag1-GMCSF6, was also generated. BALB/c mice were injected i.m. with Indiana rVSV vectors and boosted 8 weeks later with New Jersey glycoprotein-exchange vectors. Co-delivery of 105pfu of N3CT9-GMCSF5 and 105 pfu of N4CT9-Gag1 resulted in Gag specific IFN-g responses that were approximately two-fold higher than responses elicited by 105pfu of N4CT9-Gag1 alone. These results were confirmed by CBA analysis of supernatants from peptide-restimulated cells. Interestingly, MHC-pentamer staining revealed no significant difference in the frequency of Gag specific CD8+ cells between the two immunization groups. Similar observations were made in tests of the Gstem vector, where 106pfu of Gstem-Gag1-GMCSF6 elicited a more robust IFN-g response after boost than 106pfu of Gstem-Gag1, while the percentage of Gag specific CD8+ cells remained equivalent. In conclusion, GM-CSF exerted immunomodulatory effects in vivo, distinguished here by the enhanced functional differentiation of vaccine elicited effector cells.
 This work was supported by NIH contract NO1-AI-25458

Immunogenicity of co-administered recombinant VSV vectors expressing GM-CSF and HIV-1 Gag in mice (47.25)

Quantitative multiplex assay for simultaneous detection of the Indiana serotype of vesicular stomatitis virus and HIV gag.

Certain virus structures can be assembled in the form of a periodic lattice with nanometer-range ordering. Cowpea mosaic virus is crystallized in body-centered-cubic geometry and used as a template for fabrication of metallized thin films with three-dimensional morphology. Calculations predict that these crystals exhibit a normal-incidence reflectivity of 7% for wavelengths around 35 nm, which can be utilized for soft X-ray optical systems

Small-angle X-ray scattering (SAXS) has emerged as an important method for studying large-scale dynamic processes, ranging from protein folding to virus particle polymorphism. The renaissance of this method has resulted from a variety of advances in molecular biology and X-ray instrumentation, and these have dramatically increased the information content of the derived results. Modern synchrotron X-ray sources and advanced detector systems have lead to higher-resolution data in both the spatial and time domains. The purpose of this chapter is to address practical aspects of SAXS as they relate to and complement macromolecular crystallography. 
 
Keywords: 
 
data collection; 
data processing; 
protein folding; 
small-angle X-ray scattering; 
solution X-ray scattering; 
synchrotron radiation; 
time-resolved studies

Neurovirulence properties of recombinant vesicular stomatitis virus vectors in non-human primates

ABSTRACT A variety of rational approaches to attenuate growth and virulence of vesicular stomatitis virus (VSV) have been described previously. These include gene shuffling, truncation of the cytoplasmic tail of the G protein, and generation of noncytopathic M gene mutants. When separately introduced into recombinant VSV (rVSV), these mutations gave rise to viruses distinguished from their “wild-type” progenitor by diminished reproductive capacity in cell culture and/or reduced cytopathology and decreased pathogenicity in vivo. However, histopathology data from an exploratory nonhuman primate neurovirulence study indicated that some of these attenuated viruses could still cause significant levels of neurological injury. In this study, additional attenuated rVSV variants were generated by combination of the above-named three distinct classes of mutation. The resulting combination mutants were characterized by plaque size and growth kinetics in cell culture, and virulence was assessed by determination of the intracranial (IC) 50% lethal dose (LD50) in mice. Compared to virus having only one type of attenuating mutation, all of the mutation combinations examined gave rise to virus with smaller plaque phenotypes, delayed growth kinetics, and 10- to 500-fold-lower peak titers in cell culture. A similar pattern of attenuation was also observed following IC inoculation of mice, where differences in LD50 of many orders of magnitude between viruses containing one and two types of attenuating mutation were sometimes seen. The results show synergistic rather than cumulative increases in attenuation and demonstrate a new approach to the attenuation of VSV and possibly other viruses.

Synergistic Attenuation of Vesicular Stomatitis Virus by Combination of Specific G Gene Truncations and N Gene Translocations

An efficient helper-virus-free method for rescue of recombinant paramyxoviruses and rhadoviruses from a cell line suitable for vaccine development.

Mechanistic biology is frequently confronted with an experimental paradox. High-resolution structures are required to develop a chemical description of macromolecular interactions, but the processes themselves are dynamic and not amenable to highresolution methods. Chemists and molecular biologists have been successful in generating homogeneous components and entire complex systems that are amenable to crystallization and highresolution analysis. If the dynamics of the systems are small, as in the case of some enzymes and electron-transfer reactions, timeresolved studies can be performed in the context of the crystal lattice using Laue diffraction (Moffat, 1997; Genick et al., 1997; Srajer et al., 1996). If the dynamic features of the biological reactions are large, the motility must be studied in solution. During the last decade, small-angle X-ray scattering (SAXS) has emerged as an important method for studying large-scale dynamic processes, ranging from protein folding to virus particle polymorphism. The renaissance of this method has resulted from a variety of advances in molecular biology and X-ray instrumentation, and these have dramatically increased the information content of the derived results. Modern synchrotron X-ray sources and advanced detector systems have lead to higher-resolution data in both the spatial and time domains. Computational analyses of the data have improved dramatically, resulting, in some favourable cases, in de novo threedimensional density functions from SAXS data that are comparable to a 20 A-resolution electron-microscopy reconstruction. Modelbased approaches to interpreting SAXS data have expanded their usefulness to the validation of mechanistic hypotheses involving movement or association of components independently determined at high resolution. Finally, SAXS studies have benefited from the same molecular-biology advances that provide large quantities of homogeneous material for crystallographic and NMR studies. The purpose of this chapter is to address practical aspects of SAXS as they relate to and complement macromolecular crystallography.

Preliminary x-ray characterization of authentic providence virus and attempts to express its coat protein gene in recombinant baculovirus

Revised RNA2 sequence of the tetravirus, Nudaurelia capensis omega virus (NomegaV). Annotated Sequence Record.

Revised RNA2 sequence of the tetravirus, Nudaurelia capensis ω virus (NωV)

Introduction Helicoverpa armigera stunt virus (HaSV) is a nonenveloped, single-stranded T=4 RNA virus whose capsid undergoes a large-scale, pH-induced conformational change. Previously, a similar virus, Nudaurelia capensis ω virus (NωV), was the main focus of the investigation on this pH-induced phenomenon [1]. There were at least two types of NωV capsids, a precursor form of about 480 Å and a mature form of about 410 Å [1]. The structure of the NωV mature form was analyzed by x-ray crystallography [2]. The precursor form and the structural transition were studied by electron cryomicroscopy and image reconstruction [1]. To better understand the pH-induced structural rearrangement of virus capsids, HaSV was expressed, and the mature form was crystallized for x-ray crystallographic studies.

Structure Determination of a T = 4 Virus , Helicoverpa armigera stunt virus

Introduction His-tag–Ni resin is a well-established system for purification of heterologously expressed proteins. However, His-tags can also be engineered onto an icosahedral virus, Cowpea mosaic virus (CPMV), to alter the surface properties of the capsid and be exploited beyond the binding of nickel ions for new activities. Several virus mutants are made with the His-tag presented in the icosahedral constellation. As a first step in characterizing these mutants, the “mode” of His-tag–Ni binding is being investigated. The CPMV/His-tag virus particles are crystallized and subjected to structural studies.

Structural Studies of an Icosahedral Virus Engineered with His-Tags

An experimental AIDS vaccine based on attenuated, recombinant vesicular stomatitis virus (rVSV), when administered by a combination of parenteral and mucosal routes, has proven effective at preventing AIDS in a rhesus macaque model (Rose NF, et al.: Cell 2001;106:539-549). In an effort to determine the optimal route of vaccine administration we evaluated the ability of rVSV-based vaccine vectors expressing HIV-1 Env and SIV Gag proteins, when given either intramuscularly (i.m.) or intranasally (i.n.), to elicit antigen-specific cellular and humoral immune responses, and to protect from a subsequent vaginal challenge with simian-human immunodeficiency virus (SHIV89.6P). Our results demonstrate that macaques vaccinated by the i.n. route developed significantly higher antigen-specific cellular immune responses as determined by MHC class I tetramer staining, IFN-gamma ELISPOT, and cytotoxic T cell assays. However, systemic and mucosal humoral immune responses did not vary significantly with the route of vaccine administration. Given the importance of cell-mediated immune responses in slowing AIDS progression, intranasal delivery of a VSV-based AIDS vaccine may be an optimal as well as practical route for vaccination and should be considered in design of clinical trials.

Immunogenicity of attenuated vesicular stomatitis virus vectors expressing HIV type 1 Env and SIV Gag proteins: comparison of intranasal and intramuscular vaccination routes.

In this work, we evaluate the stability, dynamics and protein-nucleic acid interaction in Flock House virus (FHV). FHV is an RNA insect virus, non-enveloped, member of the family Nodaviridae. It is composed of a bipartite single-stranded RNA genome packaged in an icosahedral capsid of 180 copies of an identical protein (alpha protein). A fundamental property of many animal viruses is the post-assembly maturation required for infectivity. FHV is constructed as a provirion, which matures to an infectious virion by cleavage of alpha protein into beta and gamma subunits. We used high pressure, temperature and chemical denaturing agents to promote perturbation of the viral capsid. These effects were monitored by spectroscopy measurements (fluorescence, light scattering and CD) and size-exclusion chromatography. The data showed that FHV was stable to pressures up to 310 MPa at room temperature. The fluorescence emission and light scattering values showed small changes that were reversible after decompression. When we combined pressure and sub-denaturing urea concentrations (1 M), the changes were more drastic, suggesting dissociation of the capsid. However, these changes were reversible after pressure release. The complete dissociation of FHV could be observed only under high urea concentrations (10 M). There were no significant changes in emission spectra up to 5 M urea. FHV also was stable when we used temperature treatments (high and low). We also compared the effects of urea and pressure on FHV wild type and cleavage-defective mutant VLPs (virus-like particles). The VLPs and authentic particles are distinguishable by protein-RNA interactions, since VLPs pack cellular RNA and native particles contain viral RNA. Our results demonstrated that native particles are more stable than VLPs to physical and chemical treatments. Our data point to the specificity of the interaction between the capsid protein and the viral RNA. This specificity is crucial to the stability of the particle, which makes this interaction an excellent target for drug development.

Virus stability and protein-nucleic acid interaction as studied by high-pressure effects on nodaviruses.

Introduction The bacteriophage HK97 offers an accessible system for mechanistic studies of viral maturation and large-scale conformational changes of macromolecular machineries. Its capsid, upon formation, undergoes a maturation process with large-scale structural rearrangements from a precursor Prohead to the final mature capsid Head II. HK97 differs from all other known viruses in that almost all 420 subunits form autocatalytic, intermolecular crosslinks in maturation to Head II, resulting in molecular chainmail. There is a crucial intermediate in the late stage of the maturation, called Head I. Head I is morphologically similar to Head II but without the chainmail [1]. To better understand the mechanism of HK97 capsid maturation, a stable Head II mutant was produced and crystallized for x-ray crystallographic studies.

K. Brister, R. Fourme, H.-K. Mao, J.E. Johnson, T. Lin Consortium for Advanced Radiation Sources (CARS), The University of Chicago, Chicago, IL, U.S.A. Synchrotron Soleil, Universite Paris-Sud, Orsay, France Geophysical Laboratory, Carnegie Institution of Washington, Washington, DC, U.S.A. Department of Molecular Biology and Center for Integrative Molecular Biosciences, The Scripps Research Institute, La Jolla, CA, U.S.A.

High-pressure X-ray Crystallographic Studies of Complex Viral Assemblies

Effects of the cowpea chlorotic mottle bromovirus beta-hexamer structure on virion assembly.

Evolutionary and taxonomic implications of conserved structural motifs between picornaviruses and insect picorna-like viruses

Large-scale conformational changes transform viral precursors into infectious virions. The structure of bacteriophage HK97 capsid, Head-II, was recently solved by crystallography, revealing a catenated cross-linked topology. We have visualized its precursor, Prohead-II, by cryoelectron microscopy and modeled the conformational change by appropriately adapting Head-II. Rigid-body rotations (∼40 degrees) cause switching to an entirely different set of interactions; in addition, two motifs undergo refolding. These changes stabilize the capsid by increasing the surface area buried at interfaces and bringing the cross-link–forming residues, initially ∼40 angstroms apart, close together. The inner surface of Prohead-II is negatively charged, suggesting that the transition is triggered electrostatically by DNA packaging.

Virus Maturation Involving Large Subunit Rotations and Local Refolding

The kinetics and mechanism of acid-catalyzed Z/E isomerization of O-methylbenzohydroximoyl chloride (1Za and 1Ea), methyl O-methylbenzohydroximate (1Zb and 1Eb), ethyl O-methylbenzohydroximate (1Zc and 1Ec and five para and meta substituted derivatives), O-methylcinnamohydroximoyl chloride (2Za and 2Ea), and methyl O-methylcinnamohydroximate (2Zb and 2Zb) have been investigated. The kinetics of Z/E isomerization of these imines have been studied in glacial acetic acid (1Ea and 1Zc) and in dioxane solutions containing HCl, trifluoromethanesulfonic acid, or tetrafluoroboric acid (1Ea, 1Zb, 2Ea, and 2Zb). The isomerization takes place by either (a) rotation about the carbon-nitrogen double bond of the protonated imine (iminium ion rotation) or (b) nucleophilic attack on the protonated imine to form a tetrahedral intermediate that undergoes stereomutation and loss of the nucleophile (nucleophilic catalysis). The hydroximoyl chlorides 1Eaand 2Ea only isomerize by the nucleophilic catalysis mechanism. The hydroximate 1Zb appears to be capable of isomerizing by either mechanism. The hydroximate 2Zb may be isomerizing only by iminium ion rotation. Theoretical calculations support the notion that increased conjugation in the protonated imine increases the rate of iminium ion rotation.

Betanodaviruses are causative agents of neurological disorders in several species of fish. We cloned and sequenced the RNA2 segment of two grouper viruses isolated from Epinephelus malabaricus (malabaricus grouper nervous necrosis virus, MGNNV) and Epinephelus lanceolatus (dragon grouper nervous necrosis virus, DGNNV). The sequences of the two RNAs were 99% identical and comparison with previously sequenced RNA2 segments of fish nodaviruses striped jack nervous necrosis virus, Atlantic halibut virus, sea bass encephalitis virus, and greasy grouper nervous necrosis virus (GGNNV) revealed that MGNNV and DGNNV were most closely related to GGNNV. No correlation of sequence with geographical habitat was detected. The MGNNV coat protein, the gene product of RNA2, was expressed in Sf21 cells with a recombinant baculovirus system and virus-like particles (VLPs) spontaneously formed. Two types of VLPs were observed: a slower sedimenting particle was RNase-sensitive and stain-permeable, while the faster sedimenting particle survived RNase treatment and was not stain-permeable. An image reconstruction of the latter, obtained with electron cryomicroscopy data, revealed a morphology consistent with T = 3 quasi-symmetry but with features significantly different from insect nodavirus structures at the same resolution. This assembly system allows the first biophysical comparisons of fish and insect nodavirus structure, assembly, and stability.

Characterization of virus-like particles assembled in a recombinant baculovirus system expressing the capsid protein of a fish nodavirus.

Time-resolved small-angle X-ray scattering (TR-SAXS) was used to study the kinetics of a large conformational change that occurs during the maturation of an icosahedral virus. Virus-like particles (VLPs) of the T=4 non-enveloped RNA virus Nudaurelia capensis omega virus (NomegaV) were shown to undergo a large pH-dependent conformational change. Electron cryo-microscopy (cryoEM) and X-ray solution scattering were used to show that the precursor VLP (procapsid) was 16 % larger in diameter than the resulting capsid, which was shown by the cryoEM study to closely resemble the infectious mature virion. The procapsid form of the VLPs was observed at pH 7.5 and was converted to the capsid form at pH 5.0. Static SAXS measurements of the VLPs in solutions ranging between these pH values determined that the half-titration point of the transition was pH 6.0. Time-resolved SAXS experiments were performed on VLP solutions by initiating a pH change from 7.5 to 5.0 using a stopped-flow device, and the time-scale of the conformational change occurred in the subsecond range. Using a less drastic pH change (lowering the pH to 5.8 or 5.5), the conformational change occurred more slowly, on the subminute or minute time-scale, with the detection of a fast-forming intermediate in the transition. Further characterization using static SAXS measurements showed that the conformational change was initially reversible but became irreversible after autoproteolytic maturation was about 15 % complete. In addition to characterizing the large quaternary conformational change, we have been able for the first time to demonstrate that it takes place on the subsecond time-scale, a regime comparable to that observed in other multisubunit assemblies.

Analysis of rapid, large-scale protein quaternary structural changes: time-resolved X-ray solution scattering of Nudaurelia capensis omega virus (NomegaV) maturation.

TheL-A virus (LAV) particle is a specialized compartment for the transcription and replication of double-stranded RNA. It is 390 A in diameter and infects yeast. The particle is formed by a capsid containing 120 copies of a 680-residue gene product arranged with T = 1 icosahedral symmetry, approximately two copies of an RNA-directed RNA polymerase, and a 4.6-kb linear, duplex RNA. LAV crystals diffracting to at least 4.5-A resolution were grown in a combination of polyethylene glycol 8000, ethylene glycol, and lithium chloride. Following crystallization the reservoir solution was replaced by a 2x concentrated reservoir solution in order for ethylene glycol to function as a cryoprotectant even though initial crystals would not grow at sufficiently high concentrations of ethylene glycol for cryoprotection. A complete data set was collected to 6-A resolution from a frozen crystal obtained with this procedure. The crystals belong to space group P2(1). The unit cell dimensions are a = 406.7 A, b = 403.3 A, c = 572.5 A, beta = 90.3 degrees with two virus particles in the unit cell. The particle orientation was determined with the rotation function and the particle center was estimated on the basis of packing considerations.

Purification, crystallization, and preliminary X-ray analysis of L-A: a dsRNA yeast virus.

The crystal structure of the double-stranded DNA bacteriophage HK97 mature empty capsid was determined at 3.6 angstrom resolution. The 660 angstrom diameter icosahedral particle contains 420 subunits with a new fold. The final capsid maturation step is an autocatalytic reaction that creates 420 isopeptide bonds between proteins. Each subunit is joined to two of its neighbors by ligation of the side-chain lysine 169 to asparagine 356. This generates 12 pentameric and 60 hexameric rings of covalently joined subunits that loop through each other, creating protein chainmail: topologically linked protein catenanes arranged with icosahedral symmetry. Catenanes have not been previously observed in proteins and provide a stabilization mechanism for the very thin HK97 capsid.

Topologically linked protein rings in the bacteriophage HK97 capsid.

An assembly intermediate of a small, non-enveloped RNA virus has been discovered that exhibits striking differences from the mature virion. Virus-like particles (VLPs) of Nudaurelia capensis omega virus (NomegaV), a T=4 icosahedral virus infecting Lepidoptera insects, were produced in insect cells using a baculovirus vector expressing the coat protein. A procapsid form was discovered when NomegaV VLPs were purified at neutral pH conditions. These VLPs were fragile and did not undergo the autoproteolytic maturation that occurs in the infectious virus. Electron cryo-microscopy (cryoEM) and image analysis showed that, compared with the native virion, the VLPs were 16% larger in diameter, more rounded, porous, and contained an additional internal domain. Upon lowering the pH to 5.0, the VLP capsids became structurally indistinguishable from the authentic virion and the subunits autoproteolyzed. The NomegaV protein subunit coordinates, which were previously determined crystallographically, were modelled into the 28 A resolution cryoEM map of the procapsid. The resulting pseudo-atomic model of the NomegaV procapsid demonstrated the large rearrangements in quaternary and tertiary structure needed for the maturation of the VLPs and presumably of the virus. Based on this model, we propose that electrostatically driven rearrangements of interior helical regions are responsible for the large conformational change. These results are surprising because large structural rearrangements have not been found in the maturation of any other small RNA viruses. However, similarities of this conformational change to the maturational processes of more complex DNA viruses (e.g. bacteriophages and herpesvirus) and to the swelling of simple plant viruses suggest that structural changes in icosahedral viruses, which are integral to their function, have similar strategies and perhaps mechanisms.

Large conformational changes in the maturation of a simple RNA virus, nudaurelia capensis omega virus (NomegaV).

Protein kinase C is specifically activated by binding two membrane lipids: the second messenger, diacylglycerol, and the amino phospholipid, phosphatidylserine. This binding provides the energy to release an autoinhibitory pseudosubstrate from the active site. Interaction with these lipids recruits the enzyme to the membrane by engaging two membrane-targeting modules: the C1 domain (present as a tandem repeat in most protein kinase Cs) and the C2 domain. Here we dissect the contribution of each domain in recruiting protein kinase C betaII to membranes. Binding analyses of recombinant domains reveal that the C2 domain binds anionic lipids in a Ca(2+)-dependent, but diacylglycerol-independent, manner, with little selectivity for phospholipid headgroup beyond the requirement for negative charge. The C1B domain binds membranes in a diacylglycerol/phorbol ester-dependent, but Ca(2+)-independent manner. Like the C2 domain, the C1B domain preferentially binds anionic lipids. However, in striking contrast to the C2 domain, the C1B domain binds phosphatidylserine with an order of magnitude higher affinity than other anionic lipids. This preference for phosphatidylserine is, like that of the full-length protein, stereoselective for sn-1, 2-phosphatidyl-L-serine. Quantitative analysis of binding constants of individual domains and that of full-length protein reveals that the full-length protein binds membranes with lower affinity than expected based on the binding affinity of isolated domains. In addition to entropic and steric considerations, the difference in binding energy may reflect the energy required to expel the pseudosubstrate from the substrate binding cavity. This study establishes that each module is an independent membrane-targeting module with each, independently of the other, containing determinants for membrane recognition. The presence of each of these modules, separately, in a number of other signaling proteins epitomizes the use of these modules as discreet membrane targets.

The C1 and C2 domains of protein kinase C are independent membrane targeting modules, with specificity for phosphatidylserine conferred by the C1 domain.

Evidence suggests that both host and viral factors influence disease severity after infection with respiratory syncytial virus (RSV). To characterize the effects of pertussis toxin (PT) sensitization on subsequent RSV infection, BALB/c mice were treated with PT parenterally before RSV challenge. Priming with purified and detoxified PT before RSV challenge increased postchallenge weight loss and mortality. PT priming changed the kinetics, location, and composition of the cellular infiltrate in the lung but altered neither antibody responses nor virus titers. Passive transfer of PT-sensitized splenocytes produced similar responses. Priming with purified, but not genetically detoxified, PT propagated a modest type 2 cytokine response to RSV antigens. However, anti-interleukin-4 treatment before RSV challenge failed to abrogate the effects of PT priming. These data confirm that the preexisting immune environment can change virus-specific immunity and provide both a model for study of RSV disease and evidence that noninfectious immunomodulators may impact pathogen-specific immunity.

Pertussis toxin sensitization alters the pathogenesis of subsequent respiratory syncytial virus infection.

A third-generation synchrotron source was used to collect data from crystals with a very large unit cell. There was an increase in the effective resolution of the data from 5 to 3.5 A. Data were collected on crystals of HK97 mature empty capsids, space group P2(1), with unit-cell parameters a = 580, b = 625, c = 790 A, beta = 90.0 degrees. Like other crystals with very large unit-cell dimensions, the intensity falls off rapidly as a function of resolution, with a precipitous drop beginning at 9 A resolution. Synchrotron data from these crystals were previously observed at the CHESS F1 beamline to about 3.5 A resolution, but the intensities could not be accurately measured beyond 5 A. In experiments conducted at the Advanced Photon Source (APS) beamline 14-BM-C, data from identical crystals could be processed to a resolution of 3.5 A. The lifetime of the crystals in the beam was increased from one exposure per crystal volume to between four and eight exposures per crystal volume. More than 500 images were collected in two trips, allowing the extension of the resolution of the data set and the structure determination to 3.5 A resolution. Factors in the increased resolution may include X-ray flux, beamline geometry and low background scatter. These results suggest that other crystals with large unit cells and pronounced intensity falloff with resolution may benefit from the use of this or similar beamlines.

Increased resolution data from a large unit cell crystal collected at a third-generation synchrotron X-ray source.

3D domain swapping modulates the stability of members of an icosahedral virus group.

A complete DNA copy of the genome of a Jeryl Lynn strain of mumps virus (15,384 nucleotides) was assembled from cDNA fragments such that an exact antigenome RNA could be generated following transcription by T7 RNA polymerase and cleavage by hepatitis delta virus ribozyme. The plasmid containing the genome sequence, together with support plasmids which express mumps virus NP, P, and L proteins under control of the T7 RNA polymerase promoter, were transfected into A549 cells previously infected with recombinant vaccinia virus (MVA-T7) that expressed T7 RNA polymerase. Rescue of infectious virus from the genome cDNA was demonstrated by amplification of mumps virus from transfected-cell cultures and by subsequent consensus sequencing of reverse transcription-PCR products generated from infected-cell RNA to verify the presence of specific nucleotide tags introduced into the genome cDNA clone. The only coding change (position 8502, A to G) in the cDNA clone relative to the consensus sequence of the Jeryl Lynn plaque isolate from which it was derived, resulting in a lysine-to-arginine substitution at amino acid 22 of the L protein, did not prevent rescue of mumps virus, even though an amino acid alignment for the L proteins of paramyxoviruses indicates that lysine is highly conserved at that position. This system may provide the basis of a safe and effective virus vector for the in vivo expression of immunologically and biologically active proteins, peptides, and RNAs.

Repeated, specific interactions between capsid protein (CP) subunits direct virus capsid assembly and exemplify regulated protein-protein interactions. The results presented here reveal a striking in vivo switch in CP assembly. Using cryoelectron microscopy, three-dimensional image reconstruction, and molecular modeling, we show that brome mosaic virus (BMV) CP can assemble in vivo two remarkably distinct capsids that selectively package BMV-derived RNAs in the absence of BMV RNA replication: a 180-subunit capsid indistinguishable from virions produced in natural infections and a previously unobserved BMV capsid type with 120 subunits arranged as 60 CP dimers. Each such dimer contains two CPs in distinct, nonequivalent environments, in contrast to the quasi-equivalent CP environments throughout the 180-subunit capsid. This 120-subunit capsid utilizes most of the CP interactions of the 180-subunit capsid plus nonequivalent CP-CP interactions. Thus, the CP of BMV, and perhaps other viruses, can encode CP-CP interactions that are not apparent from mature virions and may function in assembly or disassembly. Shared structural features suggest that the 120- and 180-subunit capsids share assembly steps and that a common pentamer of CP dimers may be an important assembly intermediate. The ability of a single CP to switch between distinct capsids by means of alternate interactions also implies reduced evolutionary barriers between different capsid structures. The in vivo switch between alternate BMV capsids is controlled by the RNA packaged: a natural BMV genomic RNA was packaged in 180-subunit capsids, whereas an engineered mRNA containing only the BMV CP gene was packaged in 120-subunit capsids. RNA features can thus direct the assembly of a ribonucleoprotein complex between alternate structural pathways.

RNA-controlled polymorphism in the in vivo assembly of 180-subunit and 120-subunit virions from a single capsid protein.

Comoviruses are a group of plant viruses in the picornavirus superfamily. The type member of comoviruses, cowpea mosaic virus (CPMV), was crystallized in the cubic space group I23, a = 317 A and the hexagonal space group P6(1)22, a = 451 A, c = 1038 A. Structures of three closely similar nucleoprotein particles were determined in the cubic form. The roughly 300-A capsid was similar to the picornavirus capsid displaying a pseudo T = 3 (P = 3) surface lattice. The three beta-sandwich domains adopt two orientations, one with the long axis radial and the other two with the long axes tangential in reference to the capsid sphere. T = 3 viruses display one or the other of these two orientations. The CPMV capsid was permeable to cesium ions, leading to a disturbance of the beta-annulus inside a channel-like structure, suggesting an ion channel. The hexagonal crystal form diffracted X rays to 3 A resolution, despite the large unit cell. The large ( approximately 200 A) solvent channels in the lattice allow exchange of CPMV cognate Fab fragments. As an initial step in the structure determination of the CPMV/Fab complex, the P6(1)22 crystal structure was solved by molecular replacement with the CPMV model determined in the cubic cell.

The refined crystal structure of cowpea mosaic virus at 2.8 A resolution.

HK97 is a member of the Siphovirus family of dsDNA bacteriophages. It is similar in architecture to bacteriophage lambda, the type member of this family, with an icosahedral capsid of triangulation number T = 7. No high-resolution structural information is available for the dsDNA phages, and HK97 is the only dsDNA bacteriophage capsid to produce crystals which diffract X-rays. At 650 A in diameter, the large size of the particle and resultant large unit cell create crystallographic challenges. The empty Head II (mature) particles were expressed in Escherichia coli and assembled in vitro, but they have the same morphology as the mature HK97 capsid. Previously reported Head II crystals diffracting to 3.5 A resolution are examined here in detail. Although the cell dimensions suggest an orthorhombic lattice, further analysis demonstrated that the space group was monoclinic. This has been confirmed by the present study. Images were recorded on the F1 beamline at CHESS and they were processed and scaled, resulting in a data set with a cumulative completeness of 65% and a scaling R factor of 7.7% to 7 A. The cell dimensions after post-refinement were a = 580, b = 626, c = 788 A, beta = 90.0 degrees. From the particle dimensions determined by cryo-electron microscopy (cryo-EM), there were determined to be two particles per unit cell. Systematic absences of even reflections along the 0k0 lattice line indicate that the space group is P21. The rotation function was used to determine the orientation of the particles in the unit cell and to confirm the space group. An icosahedral twofold axis is approximately, but not exactly, aligned with the crystallographic screw (b) axis. An icosahedral twofold axis orthogonal to the one approximately parallel to the b axis, is rotated 18 degrees away from the a axis. The centers of the two particles must be positioned close to the minimum-energy packing arrangement for spheres, which places one particle at ((1/4), 0, (1/4)) and the other particle at ((3/4), (1/2), (3/4)). The particle position and orientation were confirmed by calculating a Patterson function. The particles interact closely along icosahedral threefold axes, which occurs both along the crystallographic a axis and along the b axis. The particle dimensions derived from this packing arrangement agree well with those determined by cryo-EM and image reconstruction. The cryo-EM reconstruction will be used as a model to initiate phase determination; structure determination at 7 A is under way.

Crystallographic analysis of the dsDNA bacteriophage HK97 mature empty capsid.

The N-terminal domain of the capsid protein cleavage product of the flock house virus (FHV) consists of 21 residues and forms an amphipathic alpha-helix, which is thought to play a crucial role in permeabilizing biological membranes for RNA translocation in the host cell. We have found that the Met --> Nle variant of this domain (denoted here as gamma1) efficiently induces the formation of the interdigitated gel phase (LbetaI) of 1, 2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) bilayers. In situ scanning force microscopy of solid supported bilayers and fluorescence spectroscopy of peptide-treated DPPC vesicles provide evidence for the formation of acyl chain interdigitated lipid domains. It could be shown by fluorescence spectroscopy that the peptide inserts in the DPPC matrix above the main transition temperature of the lipid, while the formation of domains with decreased thickness occurs after the sample is cooled to 25 degrees C. The orientation and secondary structure of the peptide in lipid bilayers were investigated using attenuated total reflectance infrared (ATR-IR) and circular dichroism (CD) spectroscopy. These results enabled us to formulate a mechanistic model for the peptide-mediated induction of interdigitation in DPPC bilayers. Moreover, the membrane activity of gamma1 with gel phase lipids established in this study may have further implications for the infection strategy adopted by simple RNA viruses.

An animal virus-derived peptide switches membrane morphology: possible relevance to nodaviral transfection processes.

A synthetic peptide (peptide 10) representing a surface-exposed, linear B cell epitope from outer-membrane (OM) protein F of Pseudomonas aeruginosa was shown previously to afford protection in mice from P. aeruginosa infection. This peptide was expressed in tandem with the protein F peptide 18 on each of the two coat proteins of cowpea mosaic virus (CPMV). The chimaeric virus particles (CVPs) expressing the peptides on the S (small) coat protein (CPMV-PAE4) and L (large) coat protein (CPMV-PAE5) were used to immunize mice. Following subcutaneous immunization in Freund's and QuilA adjuvants, CPMV-PAE4 induced antibodies predominantly against peptide 18, whereas CPMV-PAE5 produced antibodies exclusively against peptide 10, indicating that the site of peptide expression on CPMV influences its immune recognition. The anti-peptide antibodies elicited by CPMV-PAE5 were predominantly of the IgG2a isotype, indicating a highly polarized TH1-type response. The peptide-specific IgG2a strongly recognized the whole F protein, but more importantly, recognized protein F in all seven Fisher-Devlin immunotypes of P. aeruginosa. Furthermore, the peptide-specific IgG2a in CVP/QS-21 adjuvant-immunized mice was shown to bind complement and to augment phagocytosis of P. aeruginosa by human neutrophils in vitro. The ability of CPMV-PAE5 to induce P. aeruginosa-specific opsonic IgG2a gives it potential for further development as a protective vaccine against P. aeruginosa.

Pseudomonas aeruginosa outer-membrane protein F epitopes are highly immunogenic in mice when expressed on a plant virus.

What do Src kinase, Ras-guanine nucleotide exchange factor, cytidylyltransferase, protein kinase C, phospholipase C, vinculin, and DnaA protein have in common? These proteins are amphitropic, that is, they bind weakly (reversibly) to membrane lipids, and this process regulates their function. Proteins functioning in transduction of signals generated in cell membranes are commonly regulated by amphitropism. In this review, the strategies utilized by amphitropic proteins to bind to membranes and to regulate their membrane affinity are described. The recently solved structures of binding pockets for specific lipids are described, as well as the amphipathic alpha-helix motif. Regulatory switches that control membrane affinity include modulation of the membrane lipid composition, and modification of the protein itself by ligand binding, phosphorylation, or acylation. How does membrane binding modulate the protein's function? Two mechanisms are discussed: (1) localization with the substrate, activator, or downstream target, and (2) activation of the protein by a conformational switch. This paper also addresses the issue of specificity in the cell membrane targetted for binding.

Amphitropic proteins: regulation by reversible membrane interactions (review).

Respiratory syncytial virus (RSV) is the most significant viral cause of lower respiratory tract disease in infants and children. This study tested the hypothesis that a humanized murine monoclonal antibody (MAb) would protect against RSV infection in mice and have minimal suppressive effect upon the immune response because it is directed against a single epitope. A humanized murine MAb (RSHZ19) was tested for both prophylaxis and treatment of RSV infection in BALB/c mice and compared with a polyclonal product. Mice were rechallenged when passively administered antibody was undetectable (day 104). RSHZ19 reduced virus titer and protected against illness when used in prophylaxis and effected rapid virus clearance when used as treatment. Polyclonal antibody was also an effective prophylaxis but required 200 times the dose in total protein. Peak neutralizing antibody responses were delayed and somewhat suppressed in the prophylactically treated groups, but mice were protected against infection on rechallenge. Secondary antibody response to rechallenge in passively immunized mice was equal to that in untreated mice.

Prophylaxis with respiratory syncytial virus F-specific humanized monoclonal antibody delays and moderately suppresses the native antibody response but does not impair immunity to late rechallenge.

ABSTRACT We describe a replication-competent, recombinant vesicular stomatitis virus (VSV) in which the gene encoding the single transmembrane glycoprotein (G) was deleted and replaced by anenv-G hybrid gene encoding the extracellular and transmembrane domains of a human immunodeficiency virus type 1 (HIV-1) envelope protein fused to the cytoplasmic domain of VSV G. An additional gene encoding a green fluorescent protein was added to permit rapid detection of infection. This novel surrogate virus infected and propagated on cells expressing the HIV receptor CD4 and coreceptor CXCR4. Infection was blocked by SDF-1, the ligand for CXCR4, by antibody to CD4 and by HIV-neutralizing antibody. This virus, unlike VSV, entered cells by a pH-independent pathway and thus supports a pH-independent pathway of HIV entry. Additional recombinants carrying hybrid env-G genes derived from R5 or X4R5 HIV strains also showed the coreceptor specificities of the HIV strains from which they were derived. These surrogate viruses provide a simple and rapid assay for HIV-neutralizing antibodies as well as a rapid screen for molecules that would interfere with any stage of HIV binding or entry. The viruses might also be useful as HIV vaccines. Our results suggest wide applications of other surrogate viruses based on VSV.

Replication-Competent Rhabdoviruses with Human Immunodeficiency Virus Type 1 Coats and Green Fluorescent Protein: Entry by a pH-Independent Pathway

Abstract The plant virus cowpea mosaic virus (CPMV) has been developed as an epitope-presentation system. Numerous epitopes have been expressed in the βB-βC loop of the CPMV small coat protein, all of which undergo a cleavage reaction between their two carboxyterminal residues. Although many peptides presented in this manner give an authentic immune response, this was not the case for the NIm-1A epitope from human rhinovirus-14. Crystallography revealed significant differences between the structure of NIm-1A on CPMV compared with its native configuration. The 3D structure of CPMV expressing NIm-1A was used to design alterations to the context of the NIm-1A graft.

Position-Dependent Processing of Peptides Presented on the Surface of Cowpea Mosaic Virus

A highly membrane-active peptide in Flock House virus: implications for the mechanism of nodavirus infection.

The structure and function of nodavirus particles: a paradigm for understanding chemical biology.

Cryoelectron microscopy and three-dimensional image reconstruction analysis has been used to determine the structure of native and in vitro assembled cowpea chlorotic mottle virus (CCMV) virions and capsids to 25-A resolution. Purified CCMV coat protein was used in conjunction with in vitro transcribed viral RNAs to assemble RNA 1 only, RNA 2 only, RNA 3/4 only, and empty (RNA lacking) virions. The image reconstructions demonstrate that the in vitro assembled CCMV virions are morphologically indistinguishable from native virions purified from infected plants. The viral RNA (vRNA) is packaged similarly within the different types of virions. The centers of all assembled particles are generally devoid of density and the vRNA packs against the interior surface of the virion shell. The vRNA appears to adopt an ordered conformation at each of the quasi-threefold axes.

Comparison of the native CCMV virion with in vitro assembled CCMV virions by cryoelectron microscopy and image reconstruction.

HK97 is a temperate dsDNA bacteriophage of Escherichia coli that is structurally similar to phage lambda, with an icosahedral head of triangulation (7) number 7. Although the capsids of several large dsDNA phages have been studied extensively using a variety of biophysical approaches, no high-resolution structure is available. We have grown crystals of mature but empty bacteriophage HK97 capsids that diffract to at least 3.5 A using synchrotron radiation. The HK97 Head II crystals are the first capsid crystals from a dsDNA bacteriophage that diffract X-rays to high resolution. A capsid precursor (prohead) was made in vivo by expressing capsid proteins in E. coli. This prohead was purified, converted to Head II in vitro, and used to grow crystals. The empty Head II has the same form as the mature HK97 capsid, but without DNA. The crystals were grown in a mixture of ammonium sulfate and PEG 8000, directly in an X-ray capillary to minimize crystal handling. The unit cell is monoclinic, with dimensions a = 580 A, b = 625 A, c = 790 A, beta = 90.0 degrees and two particles per unit cell.

Crystallization and preliminary X-ray analysis of the dsDNA bacteriophage HK97 mature empty capsid.

An automated procedure was developed to determine the geometrical and chemical interactions of crystalline virus particles using the crystal parameters, particle position, orientation, and atomic coordinates for an icosahedral asymmetric unit. Two applications of the program are reported: (1) An analysis of a novel pseudo-rhombohedral (R32) symmetry present in the monoclinic crystal lattices of both Nodamura Virus (NOV) and Coxsackie virus B3 (CVB3). The study shows that in both cases the interactions between particles is substantially increased by minor deviations from exact R32 symmetry and that only particles with the proper ratio of dimensions along twofold and fivefold symmetry axes (such as southern bean mosaic virus) can achieve comparable buried surface area in the true R32 space group. (2) An attempt was made to correlate biological function with remarkably conserved interparticle contact regions found in different crystal forms of three members of the nodavirus family, NOV, Flock House Virus (FHV), and Black Beetle Virus (BBV). Mutational evidence implicates the quasi-threefold region on the viral surface in receptor binding in nodaviruses and this region is dominant in particle contacts in all three virus crystals. Examination of particle contacts in numerous crystal structures of viruses in the picornavirus super-family showed that portions of the capsid surface known to interact with a receptor or serve as an epitope for monoclonal antibodies frequently stabilize crystal contacts.

Molecular packing in virus crystals: geometry, chemistry, and biology.

We are probing the mechanism of the lipid selective membrane interactions of CTP:phosphocholine cytidylyltransferase (CT). We have proposed that the membrane binding domain of CT (domain M) consists of a continuous amphipathic alpha-helix between residues approximately 240-295 [Dunne, S. J., et al. (1996) Biochemistry 35, 11975-11984]. This study examined the secondary structure and membrane binding properties of synthetic peptides derived from domain M: a 62mer peptide encompassing the entire domain (Pep62), a 33mer corresponding to the N-terminal portion (PepNH1), and two 33mers corresponding to the three C-terminal 11mer repeats, one with the wild-type sequence (Pep33Ser), and one with the three serines in the nonpolar face substituted with alanine (Pep33Ala). Peptide secondary structure was analyzed by circular dichroism, and lipid interactions were analyzed by a direct vesicle binding assay, by effects of lipid vesicles on peptide tryptophan fluorescence, and by monolayer surface pressure changes. All peptides bound to vesicles as alpha-helices with selectivity for anionic lipids. Binding involved intercalation of the peptide tryptophan into the hydrophobic membrane core. PepNH1, the peptide with the highest positive charge density, showed strong selectivity for anionic lipids. PepNH1 and Pep33Ser did not bind to PC vesicles; however, the more hydrophobic peptides, Pep33Ala and Pep62, did bind to PC vesicles, with apparent partition coefficients for PC that were only approximately 1 order of magnitude lower than those for PC/PG (1/1). Our results suggest that the polar serines interrupting the nonpolar face of the amphipathic helix serve to lower the lipid affinity and thereby enhance selectivity for anionic lipids. Although diacylglycerol is an activator of the enzyme, none of the peptides responded differentially to PC/diacylglycerol vesicles versus pure PC vesicles, suggesting that domain M alone is not sufficient for the enzyme's response to diacylglycerol. Increases in surface pressure at an air-water interface indicated that the domain M peptides had strong surface-seeking tendencies. This supports a binding orientation for domain M parallel to the membrane surface. Binding of CT peptides to spread lipid monolayers caused surface pressure reductions, suggesting condensation of lipids in the formation of lipid-peptide complexes. At low monolayer surface pressures, Pep62 interacted equally with anionic and zwitterionic phospholipids. This suggests that one determinant of the selectivity for anionic lipids is the lipid packing density (area per molecule).

Conformation and lipid binding properties of four peptides derived from the membrane-binding domain of CTP:phosphocholine cytidylyltransferase.

Protein kinase C: a paradigm for regulation of protein function by two membrane-targeting modules.

The structure of tobacco ringspot virus: a link in the evolution of icosahedral capsids in the picornavirus superfamily.

Energetics of quasiequivalence: computational analysis of protein-protein interactions in icosahedral viruses.

The structure of Nudaurelia capensis omega virus (NomegaV), a single-stranded RNA virus, was determined to 2.8 A resolution. Triclinic crystals (a = 413.6, b = 410.2, c = 419.7 A, alpha = 59.13, beta = 58.9, gamma = 64.0 degrees ) diffracted X-rays beyond 2.7 A resolution. The unit cell contained one icosahedral virus particle, providing 60-fold non-crystallographic symmetry (n.c.s.) and structural redundancy. The particle orientation in the unit cell was determined by self-rotation function analyses. Initial phases to 18 A resolution were derived from a hollow spherical model of 192 A outer radius and 139 A inner radius, filled with uniform electron density. Radii of the model were determined by maximizing the correlation of the model-based calculated data with the low-resolution X-ray diffraction and solution-scattering data. Phases were refined by 60-fold non-crystallographic electron-density averaging and extended in small steps to a resolution of 5 A. The phases obtained represented a mixture of four different phase sets, each consistent with the icosahedral symmetry constraints. The resulting electron density was not interpretable. A difference Fourier map computed with the native and an isomorphous heavy-atom derivative data sets and phases refined by real-space averaging was interpretable only if data within the 10 A resolution shell were used. Maps calculated with data significantly higher than 10 A resolution failed to display a constellation of heavy-atom sites consistent with the T = 4 icosahedral symmetry. Attempts to extend the phases beyond 10 A resolution, starting with either phases based on a model or single isomorphous replacement, were unsuccessful. Successful phase extension was achieved by computing the phases for the higher resolution reflections from a partial atomic model (poly gly) built into the averaged 10 A electron-density map. Phases from this model served as the starting point for n.c.s. phase refinement and extension to slightly higher resolution. The atomic model was improved at each extension interval and these phases were used for the subsequent phase calculation and extension. The entire polypeptide backbone corresponding to the NomegaV structure was built into the map at 4 A. The same procedure for phase refinement was used to extend the phases to 2.8 A in small increments of resolution. The overall molecular averaging R factor and correlation coefficient at 2.8 A resolution were 18.4% and 0.87, respectively.

Single crystal diffraction data were collected from virus crystals in the resolution range of 270 to 14 A using a synchrotron X-ray source and a small-angle scattering instrument adapted for single crystal measurements. Reflections were measured from single crystals of the capsid of the double-stranded DNA bacteriophage HK97 and synthetic Flock House virus-like particles (sFHV). The quality of the low-resolution measurements was confirmed by excellent scaling statistics for both data sets. The sFHV amplitudes between 270 and 90 A resolution were closely similar to independently measured solution scattering data, and to data calculated from the Fourier transform of a uniform density sphere of 315 A diameter. A rotation function computed with the sFHV data between 70 and 20 A resolution was readily interpretable. A uniform density sphere model was used to compute phases for measured amplitudes between 270 and 68 A resolution. The calculated phases were refined and extended to 14 A resolution with real space averaging employing an external mask shape defined by the high-resolution structure. The resulting electron density map displayed regions interpretable as loosely ordered RNA that connected ordered RNA segments seen in a published 3.0 A resolution map. The published high-resolution electron density map lacked data inside 15 A resolution and the interior of the particle in that map appeared hollow. Difference electron density maps corresponding to bulk RNA were computed by subtracting the contribution of the protein shell, based on the available high-resolution atomic model, from either the cryo-electron microscopy density or the low-resolution X-ray density. Features of the RNA were closely similar in the cryo-electron microscopy and X-ray maps, demonstrating the consistency of the two imaging methods. Electron density maps computed at 14 and 6 A resolution with the X-ray amplitudes showed that RNA contributed little to the scattering beyond 14 A resolution.

Imaging RNA and dynamic protein segments with low-resolution virus crystallography: experimental design, data processing and implications of electron density maps.

Previous studies showed that the HIV-1 envelope (Env) protein was not incorporated into vesicular stomatitis virus (VSV) virions unless its cytoplasmic tail was replaced with that of the VSV glycoprotein (G). To determine whether the G tail provided a positive incorporation signal for Env, or if sequences in the Env tail prevented incorporation, we generated mutants of Env with its 150-amino-acid tail shortened to 29, 10, or 3 amino acids (Envtr mutants). Cells infected with VSV recombinants expressing these proteins or an Env-G tail hybrid showed similar amounts of Env protein at the surface. The Env-G tail hybrid or the Envtr3 mutant were incorporated at the highest levels into budding VSV virions. In contrast, the Envtr29 or Envtr10 mutants were incorporated poorly. These results defined a signal preventing incorporation within the 10 membrane-proximal amino acids of the Env tail. Confocal microscopy revealed that this signal functioned by causing localization of human immunodeficiency virus type 1 Env to plasma membrane domains distinct from the VSV budding sites, where VSV proteins were concentrated.

A plasma membrane localization signal in the HIV-1 envelope cytoplasmic domain prevents localization at sites of vesicular stomatitis virus budding and incorporation into VSV virions.

This study addresses the molecular basis for protein kinase C's specific activation by phosphatidylserine. Specifically, we ask whether protein kinase C's phospholipid specificity arises from specific protein/lipid interactions or whether it arises from unique membrane-structuring properties of phosphatidylserine. We measured the interaction of protein kinase C betaII to membranes that differed only in being enantiomers to one another: physical properties such as acyl chain composition, membrane fluidity, surface curvature, microdomains, headgroup packing, and H-bonding with water were identical. Binding and activity measurements reveal that protein kinase C specifically recognizes 1, 2-sn-phosphatidyl-L-serine, independently of membrane structure. High-affinity binding and activation are abolished in the presence of enantiomeric membranes containing 2,3-sn-phosphatidyl-L-serine, 2, 3-sn-diacylglycerol, and 2,3-sn-phosphatidylcholine. Our data also show that the stereoselectivity for 1,2-sn-diacylglycerol is not absolute; 2,3-sn-diacylglycerol modestly increases the membrane affinity of protein kinase C provided that 1, 2-sn-phosphatidyl-L-serine is present. We also find that the stereochemistry of the bulk phospholipid, in this case phosphatidylcholine, has no significant influence on protein kinase C's membrane interaction. These data reveal that specific molecular determinants on protein kinase C stereospecifically recognize structural determinants of phosphatidylserine.

Lipid structure and not membrane structure is the major determinant in the regulation of protein kinase C by phosphatidylserine.

The different partially folded states of the capsid protein that appear in the disassembly pathway of cowpea severe mosaic virus (CPSMV) were investigated by examining the effects of hydrostatic pressure, sub-zero temperatures and urea. The conformational states of the coat protein were analyzed by their intrinsic fluorescence, binding of bis(8-anilinonaphthalene-1-sulfonate) (bis-ANS) and susceptibility to trypsin digestion. CPSMV could be disassembled by pressure at 2.5 kbar. Intrinsic fluorescence and hydrodynamic measurements showed that pressure-induced dissociation was completely reversible. Virus pressurization in the presence of ribonuclease revealed that viral RNA was not exposed, since it was not digested by the enzyme, suggesting the maintenance of protein-nucleic acid interactions under pressure. When the temperature was decreased to -10 degrees C under pressure, CPSMV disassembly became an irreversible process and in this condition, viral RNA was completely digested by ribonuclease. These results suggest a relationship between protein-RNA interactions and CPSMV assembly. Bis-ANS binding and trypsin digestion of coat proteins revealed that they assume a different conformation when they are denatured by low temperatures under pressure or than when they are denatured by urea at atmospheric pressure. The results indicate that the coat proteins can exist in at least four states: (1) The native conformation in the virus capsid; (2) bound to RNA when the virus is dissociated by pressure at room temperature, assuming a conformation that retains the information for reassembly; (3) free subunits in a molten-globule conformation when the virus is dissociated by low temperature under pressure; and (4) free subunits completely unfolded by high concentrations of urea.

Partially folded states of the capsid protein of cowpea severe mosaic virus in the disassembly pathway.

The structure and assembly of icosahedral virus capsids composed of one or more gene products and displaying quasi-equivalent subunit associations are discussed at three levels. The principles of quasi-equivalence and the related geodesic dome formation are first discussed conceptually and the geometric basis for their construction from two-dimensional assembly units is reviewed. The consequences for such an assembly when three-dimensional protein subunits are the associating components are then discussed with the coordinates of cowpea chlorotic mottle virus (CCMV) used to generate hypothetical structures in approximate agreement with the conceptual models presented in the first section. Biophysical, molecular genetic, and atomic structural data for CCMV are then reviewed, related to each other, and incorporated into an assembly model for CCMV that is discussed with respect to the modular, chemical nature of the viral subunit structure. The concepts of quasi-equivalence are then examined in some larger virus structures containing multiple subunit types and auxiliary proteins and the need for additional control points in their assembly are considered. The conclusion suggests that some viral assembly principles are limited paradigms for protein associations occurring in the broader range of cell biology including signal transduction, interaction of transcription factors and protein trafficking.

Monoclinic crystals of nodamura virus (NOV) have two virus molecules per asymmetric unit. Packing analysis reveals a pseudo-rhombohedral (pseudo-C2 monoclinic) arrangement of particles in the actual P2(1) space group (a = 562.1, b = 354.1, c = 612.8 A, beta = 110.9 degrees ). The R32 symmetry is broken rotationally and translationally. The pseudo-symmetry of the unit cell results in three possible monoclinic origins and also restrains the four particles in the unit cell to similar orientations. NOV particles deviate by less than 3 degrees from the ideal orientations, causing overlap of peaks in the rotation function and the generation of peaks that were not interpretable as particle symmetry elements. The space-group ambiguity was resolved by analysing the relationship between the particle orientations determined by high-resolution rotation functions and the attenuation of peak heights in native Patterson maps. Particles were centered less than 1 A from the R32 special positions. Three different approaches were required to identify the correct particle center. Following the solutions of the rotation and translation problems, phases were computed using the coordinates of flock house virus (FHV), another member of this virus family. The phases were improved by real-space molecular averaging with a 120-fold non-crystallographic symmetry and by solvent flattening with a spherical mask. The final model for the NOV structure was built using the 3.3 A averaged map. While the overall subunit structure was very similar to that of other nodaviruses, FHV and black beetle virus, NOV showed distinct structural features near particle threefold and quasi-threefold axes and at the protein-RNA interfaces that are consistent with phenotype differences among the related viruses.

Resolution of space-group ambiguity and structure determination of nodamura virus to 3.3 A resolution from pseudo-R32 (monoclinic) crystals.

K. Fukuyama, S. S. Abdel-Meguid, J. E. Johnson, and M. G. Rossmann (J. Mol. Biol. 167:873-984, 1983) reported the structure of alfalfa mosaic virus assembled from the capsid protein as a T=1 icosahedral empty particle at 4.5-A resolution. The information contained in the structure included the particle size, protein shell thickness, presence of wide holes at the icosahedral fivefold axes, and a proposal that the capsid protein adopts a beta-barrel structure. In the present work, the X-ray diffraction data of Fukuyama et al. as well as the data subsequently collected by I. Fita, Y. Hata, and M. G. Rossmann (unpublished) were reprocessed to 4.0-A resolution, and the structure was solved by molecular replacement. The current structure allowed the tracing of the polypeptide chain of the capsid protein confirming the beta-sandwich fold and provides information on intersubunit interactions in the particle. However, it was not possible to definitively assign the amino acid sequence to the side chain density at 4-A resolution. The particle structure was also determined by cryoelectron microscopy and image reconstruction methods and found to be in excellent agreement with the X-ray model.

The structure of alfalfa mosaic virus capsid protein assembled as a T=1 icosahedral particle at 4.0-A resolution

The three-dimensional structure of cucumber mosaic virus (CMV) was analyzed at 23 A resolution by cryoelectron microscopy and image reconstruction, demonstrating structural similarity to cowpea chlorotic mottle virus (CCMV), another member of the Bromoviridae family. The CMV structure was determined at 8 A resolution by X-ray crystallography with phases determined by single isomorphous replacement and refined by fivefold noncrystallographic symmetry averaging. The X-ray structure agreed with the electron microscopy reconstruction; the electron density is consistent with beta-barrel subunits arranged with T = 3 quasi-symmetry in an orientation similar to that observed in CCMV. Strong density surrounding the icosahedral threefold axes (quasi sixfold axes in the T = 3 particle) between 80 and 100 A from the particle center formed a cylinder of radius 11 A, similar to the density observed in the same region of CCMV. This density corresponds to the beta-annulus of CCMV, which differentiates hexamers from pentamers and determines the formation of the T = 3 particles. The CMV and CCMV amino acid sequences were aligned, providing information (based on the CCMV atomic model) about the probable distribution of residues in the three-dimensional structure of CMV.

The structure of cucumber mosaic virus: cryoelectron microscopy, X-ray crystallography, and sequence analysis.

We describe spontaneous second-site reversions within the coat protein open reading frame that rescue the systemic-spread phenotype and increase virion stability of a mutant of brome mosaic virus. Based on the crystal structure of the related cowpea chlorotic mottle virus, we show that the modified residues are spatially clustered to affect the formation of hexamers and pentamers and therefore virion stability.

Structure-based rationale for the rescue of systemic movement of brome mosaic virus by spontaneous second-site mutations in the coat protein gene

Abstracts of presentations on plant protection issues at the xth international congress of virology

Adjuvants influence the quantitative and qualitative immune response in BALB/c mice immunized with respiratory syncytial virus FG subunit vaccine.

Although interleukin-4 (IL-4) expression has been implicated in vaccine-enhanced respiratory syncytial virus (RSV) disease, its role in mediating the immune response to primary RSV infection remains unclear. To assess the effect of IL-4 production on typical RSV infection, transgenic mice which either overexpress or fail to express IL-4 were challenged intranasally with RSV and their responses were compared to those of the parent strains. IL-4-deficient mice eliminated virus from the lung as quickly as did C57BL/6 controls. In contrast, mice which constitutively overexpress IL-4 showed delayed virus clearance compared with mice of the FVB/N control strain, although peak viral titers did not differ. IL-4 overexpression increased the magnitude of the subsequent antibody response. Lung lymphocytes harvested from IL-4-overexpressing mice post-RSV challenge showed diminished RSV-specific cytolytic activity compared with controls. Both IL-4-deficient and IL-4-overexpressing strains resisted rechallenge. These data imply that constitutive IL-4 expression delays or suppresses the development of a virus-specific cytotoxic lymphocyte population important in clearing primary RSV infection.

Overexpression of interleukin-4 delays virus clearance in mice infected with respiratory syncytial virus

We generated replication-competent, recombinant vesicular stomatitis viruses (VSVs) expressing the human immunodeficiency virus (HIV) envelope protein or an HIV-VSV chimeric envelope protein in which the cytoplasmic domain of the HIV envelope protein was replaced with that from the VSV glycoprotein (G). These recombinants were generated with HIV type 1 (HIV-1) envelopes from both laboratory and primary isolates of HIV-1. The replication-competent recombinant viruses were stable and expressed the foreign proteins at high levels from extra transcription units in VSV. The foreign proteins were processed appropriately and transported to the cell surface. The incorporation of HIV gp120 into VSV particles was demonstrated biochemically only for the construct expressing the chimeric envelopes containing the VSV G cytoplasmic domain. The incorporation of the chimeric HIV envelope protein into the membrane of the recombinant VSV was also demonstrated by electron microscopy with gold-conjugated antibodies. To determine whether specific infection of CD4-positive cells could be demonstrated for these recombinants, we neutralized VSV infectivity due to VSV glycoprotein with anti-VSV serum. The neutralized recombinants expressing the chimeric envelope were able to infect only HeLa cells expressing CD4, and this CD4-specific infectivity was neutralized with anti-HIV serum. This assay also detected a 100-fold-lower titer of CD4-specific infectivity for the VSV recombinant expressing the wild-type HIV envelope. Our results illustrate that it is possible to express functional HIV envelopes from the VSV genome and target the recombinant virus to an alternative receptor. The recombinants may also prove useful as HIV vaccines.

Specific targeting to CD4+ cells of recombinant vesicular stomatitis viruses encoding human immunodeficiency virus envelope proteins

An amphipathic alpha-helix is the principle membrane-embedded region of CTP:phosphocholine cytidylyltransferase. Identification of the 3-(trifluoromethyl)-3-(m-[125I]iodophenyl) diazirine photolabeled domain.

Tobacco ringspot virus, a plant virus that is believed to fill an apparent niche in the evolution of picornavirus-like capsids, has been crystallized by vapor diffusion with potassium phosphate and polyethylene glycol buffered at pH 6.5 in a new crystal form. The monoclinic crystals belong to the space group C2 with unit-cell dimensions of a = 407.1, b = 399.7, c = 285.9 A and beta = 129.1 degrees and diffract synchrotron radiation to 3.3 A. One half of a virus particle constitutes the crystallographic asymmetric unit. The orientation of the virus particle in the unit cell was determined by the rotation function analysis of a partial data set that has been collected at CHESS using image plates. Development of a suitable phasing model for the high-resolution structure determination of TRSV with the real-space molecular replacement technique is now under way.

Crystallization and preliminary X-ray analysis of tobacco ringspot virus.

Capsid proteins of a number of plant viruses are permissive to genetic modifications in which foreign polypeptides are inserted in exposed loops or at their C termini. Plant viruses with these genetic alterations often grow at wild-type levels, providing gram quantities of modified viruses. Presented polypeptides studied most extensively correspond to antigenic epitopes of animal viruses and in some cases appropriately altered plant viruses generate neutralizing antibodies to the cognate animal virus when the plant virus is used as a vaccine. Structure-based analyses of these animal-plant virus chimeras have led to rational alterations to the presentation in efforts to increase the efficacy of the presented peptide.

Presentation of heterologous peptides on plant viruses: genetics, structure, and function.

Structure-based design of peptide presentation on a viral surface: the crystal structure of a plant/animal virus chimera at 2.8 A resolution.

Expression of a soluble CD4 molecule (sCD4-KDEL) containing a specific retention signal for the endoplasmic reticulum was shown previously to block propagation of the HIV-1MN prototype strain in a transformed T cell line. However, the virus present in HIV-1-infected individuals is more closely represented by primary HIV-1 isolates which, unlike the HIV-1MN strain, have not been adapted to growth in cell lines. To determine if sCD4-KDEL could block replication of primary isolates we used the PM1 cell line that has been shown to propagate primary isolates without adaptation. Here we show that the replication of four primary HIV-1 isolates was strongly inhibited in PM1 cells that expressed sCD4-KDEL under control of the HIV-1 LTR. Infection with primary HIV-1 isolates induced sCD4-KDEL expression driven by the LTR, HIV-1 spread was dramatically reduced, and reverse transcriptase activity in the cell culture supernatants was greatly diminished sCD4-KDEL, therefore, represents a potent inhibitor of HIV-1 replication for gene therapy-based approaches for the treatment of AIDS.

Replication of primary HIV-1 isolates is inhibited in PM1 cells expressing sCD4-KDEL.

Simple RNA animal viruses generally enter cells through receptor-mediated endocytosis followed by acid pH dependent release and translocation of RNA across the endosomal membrane. The T = 3 nodaviruses contain prefabricated pentameric helical bundles that are cleaved from the remainder of the subunits by an assembly-dependent auto-proteolysis and they are positioned for release through 5-fold axes of the particle. We previously proposed that these bundles may serve as conduits for RNA membrane translocation. Additional support for this hypothesis is now provided by the first atomic resolution structure of a T = 4 RNA virus, where we find cleavage sites and helical bundles nearly identical with those observed in T = 3 nodaviruses. The helices are of sufficient length to span a membrane bilayer and the internal diameter of the coiled bundle could accommodate ssRNA. The T = 4 particle has a mean outer diameter of 410 A and is formed by 240 copies of a single subunit type. The subunit is composed of a helical inner domain (where the cleavage occurs) containing residues preceding and following a canonical, viral, eight-stranded beta-sandwich that forms the contiguous shell. Inserted between two strands of the shell domain are 133 residues with an immunoglobulin c-type fold. The initial gene product consists of 644 amino acid residues and is cleaved between residues Asn570 and Phe571 in the mature particle determined in this analysis.

The 2.8 A structure of a T = 4 animal virus and its implications for membrane translocation of RNA.

Biological processes often require that a single gene product participate in multiple types of molecular interactions. Viruses with quasiequivalent capsids provide an excellent paradigm for studying such phenomena because identical protein subunits are found in different structural environments. Differences in subunit joints may be controlled by protein segments, duplex or single-stranded RNA, metal ions, or some combination of these. Each of the virus groups examined display a distinctive mechanism for switching interface interactions, illustrating the magnitude of options that are likely to be found in other biological systems. In addition to determining capsid morphology, assembly controls the timing of autocatalytic maturation cleavage of the viral subunits that is required for infectivity in picorna-, noda-, and tetraviruses. The mechanism of assembly-dependent cleavage is conserved in noda- and tetraviruses, although the quaternary structures of the capsids are different as are the molecular switches that control subunit interfaces. The function of the cleavage in picorna-, noda-, and tetraviruses is probably to release polypeptides that participate in membrane translocation of RNA.

Functional implications of protein-protein interactions in icosahedral viruses.

Low resolution meets high: towards a resolution continuum from cells to atoms.

The coast protein of alfalfa mosaic virus (AMV) was cloned and expressed in Escherichia coli as a fusion protein containing a 37 amino acid extension with a (His)6 region for affinity purification. About half of the expressed recombinant coat protein (rCP) was soluble upon extraction and half was insoluble in inclusion bodies. Western blot analysis confirmed the identity of the rCP and protoplast infectivity assays indicated that the rCP was biologically active in an early event of AMV infection, called genome activation. The rCP assembled into T = 1 empty icosahedral particles, as described previously for native coat protein. Empty particles formed hexagonal crystals that diffracted X-rays to 5.5 A resolution. The crystals of trypsin-treated particles of rCP appear to be isomorphous with crystals of trypsin-treated particles of native coat protein, Spherical particles containing RNA assembled when the rCP was combined with in vitro transcripts of AMV RNA4, the smallest naturally encapsidated AMV RNA. Bacilliform particles that resembled native virions assembled when the rCP was combined with transcripts of RNA1, the largest genomic RNA.

Purification, characterization, assembly and crystallization of assembled alfalfa mosaic virus coat protein expressed in Escherichia coli.

Epitopes from human rhinovirus 14 (HRV-14) and human immunodeficiency virus type (HIV-1) have been expressed on the surface of particles of the plant virus, cowpea mosaic virus (CPMV). The chimaeras retain their ability to grow in plants and large quantities of virions can be easily purified. Immunological studies have shown that purified particles have the antigenic properties of the insert, and, in the case of the HIV-1 chimaera, can elicit the production of neutralising antibodies in mice. The chimaera containing the epitope from HRV-14 has been crystallised and the crystals shown to diffract to atomic resolution.

The development of cowpea mosaic virus as a potential source of novel vaccines.

It has been proposed that the domain of the regulatory enzyme, CTP:phosphocholine cytidylyltransferase, which mediates reversible binding of the enzyme to membranes, is an amphipathic alpha-helix of approximately 60 amino acid residues and that this domain is adjacent to the putative active site domain of this enzyme. Circular dichroism indicated that the secondary structures of two overlapping peptides spanning this region were predominantly alpha-helical in the presence of PG vesicles or sodium dodecyl sulfate micelles. Interproton distances were obtained from two-dimensional NMR spectroscopic measurements to solve the structures of these two peptides. The C-terminal 22 amino acid peptide segment (corresponding to Val267-Ser288) was a well-defined alpha-helix over its length. The N-terminal 33-mer (corresponding to Asn236-Glu268) was composed of an alpha-helix from Glu243 to Lys266, a well-structured bend of about 50 degrees at Tyr240-His241-Leu242, and an N-terminal four-residue helix. It is proposed that the three residues involved in generating the bend act as the hinge between the catalytic and regulatory domains. The nonpolar faces of the 33-mer and 22-mer were interrupted by Ser260, Ser271, and Ser282. These residues may serve to limit the hydrophobicity and facilitate reversible and lipid-selective membrane binding. The hydrophobic faces of the helices were flanked by a set of basic amino acid residues on one side and basic amino acid residues interspersed with glutamates on the other. The disposition of these side chains gives clues to the basis for the specificities of these peptides for anionic surfaces.

Structure of the membrane binding domain of CTP:phosphocholine cytidylyltransferase.

Determination of 3D viral structure from solution X-ray scattering

We have expressed the gene encoding the coat protein (CP) of Nudaurelia capensis omega virus in insect cells with a baculovirus vector. Expression of CP resulted in formation of virus-like particles (VLPs) having a size consistent with the T = 4 quasi-symmetry observed for native virions. This is the first demonstration of assembly for a T = 4 particle, with chemically identical subunits present in four distinct environments, by heterologous expression. Initial yields of VLPs were low, and an efficient one step nondenaturing procedure involving separation on discontinuous glycerol gradients was developed. Using this method, VLPs were obtained in quantities sufficient for further characterization. Electron microscopic observation revealed 40-nm particles that were morphologically similar to native virus. SDS-PAGE revealed that these particles were composed of a 62-kDa major protein and a minor 70-kDa protein. Pulse-chase experiments revealed that the larger species was processed into the smaller one very slowly over the course of an infection. It was also determined that this cleavage was apparently dependent on release of these particles from the cell. Furthermore, these particles were found to encapsidate the polyhedrin promoter-directed CP mRNA with an apparently striking degree of specificity and selectivity. This investigation establishes that a specific encapsidation signal exists within the CP coding sequences and that the components required for reconstructing most, if not all, steps in the morphogenesis of this virus can be accomplished in baculovirus-infected cells. The results presented here are consistent with the belief that similar biological strategies are utilized by T = 3 nodaviruses and T = 4 tetraviruses in particle assembly.

Assembly of the T = 4 Nudaurelia capensis omega virus capsid protein, post-translational cleavage, and specific encapsidation of its mRNA in a baculovirus expression system.

Determination of three-dimensional low-resolution viral structure from solution x-ray scattering data.

The crystal structure of coxsackievirus B3 (CVB3) has been determined to 3.5 A resolution. The icosahedral CVB3 particles crystallize in the monoclinic space group, P2(1), (a = 574.6, b = 302.1, c = 521.6 A, beta = 107.7 degrees ) with two virions in the asymmetric unit giving 120-fold non-crystallographic redundancy. The crystals diffracted to 2.7 A resolution and the X-ray data set was 55% complete to 3.0,4, resolution. Systematically weak reflections and the self-rotation function established pseudo R32 symmetry with each particle sitting on a 32 special position. This constrained the orientation and position of each particle in the monoclinic cell to near face-centered positions and allowed for a total of six possible monoclinic space-group settings. Correct interpretation of the high-resolution (3.0-3.2 A) self-rotation function was instrumental in determining the deviations from R32 orientations of the virus particles in the unit cell. Accurate particle orientations permitted the correct assignment of the crystal space-group setting amongst the six ambiguous possibilities and for the correct determination of particle positions. Real-space electron-density averaging and phase refinement, using human rhinovius 14 (HRV14) as an initial phasing model, have been carried out to 3.5 A resolution. The initial structural model has been built and refined to 3.5 A resolution using X-PLOR.

Structure determination of coxsackievirus B3 to 3.5 A resolution.

Structures of the native and swollen forms of cowpea chlorotic mottle virus determined by X-ray crystallography and cryo-electron microscopy.

Comparative studies of T = 3 and T = 4 icosahedral RNA insect viruses.

A peptide corresponding to a portion of the amphipathic alpha-helical region of CTP:phosphocholine cytidylyltransferase was synthesized. This region of the enzyme was proposed to be the membrane-binding domain [Kalmar, G.B., Kay, R.J., Lachance, A., Aebersold, R., & Cornell, R.B. (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 6029]. We have shown that the peptide is physically associated with PG vesicles. CD of the peptide in buffer suggested a primarily random structure, while, in the presence of trifluoroethanol, the peptide was alpha-helical. Anionic lipid vesicles promoted an alpha-helical conformation, whereas neutral or cationic lipid vesicles did not alter the random structure of the peptide, suggesting a selective stabilization of the alpha-helix by anionic membranes. The fluorescence of the single tryptophan residue, which lies on the hydrophobic face of the amphipathic alpha-helix, was studied. Anionic lipid vesicles specifically induced a shift in the fluorescence to a lower wavelength. Fluorescence quenching by the aqueous-phase quencher, I-, and the lipid-phase quencher 9,10-dibromo-PC was used to determine the accessibility of the tryptophan to each of these environments. The presence of anionic lipid vesicles, but not nonanionic lipid vesicles, decreased the quenching by I- suggesting that, in the presence of anionic lipids, the tryptophan residue is poorly accessible to the aqueous I-. Dibromo-PC significantly quenched the fluorescence only when present in anionic vesicles, confirming the membrane location of the tryptophan residue and the lipid specificity of this interaction.(ABSTRACT TRUNCATED AT 250 WORDS)

Membrane-binding amphipathic alpha-helical peptide derived from CTP:phosphocholine cytidylyltransferase.

It is of considerable interest to separate the processes of viral infectivity and virion assembly. Until recently this has only been possible with viruses that could be disassembled and reassembled in vitro. Even in these cases it was difficult to establish the authenticity of reassembled capsid protein because of possible irreversible damage that may have occurred to the protein during disassembly. An ideal method for the study of virus assembly is a protein expression system in which conditions are appropriate for spontaneous particle formation from freshly synthesized polypeptides. The baculovirus expression system has proven to be an excellent means to this end. Recently, this approach has been used to study the T = 3 Flock House insect virus and it has been demonstrated that subunits with the wild-type protein sequence, and with site-specific mutations that prevent particle maturation, will assemble and crystallize. This same approach has now been used at Purdue to study the T = 4 Nudaurelia omega capensis insect virus. There is no cell culture system currently available for the study of NomegaV, thus the expression system provides the first opportunity to study assembly under controlled conditions.

Production and crystallization of virus-like particles assembled in a heterologous protein expression system.

Functional implications of quasi-equivalence in a T = 3 icosahedral animal virus established by cryo-electron microscopy and X-ray crystallography.

It has recently been shown that cowpea plants can be infected with a cowpea mosaic virus (CPMV) chimera containing an antigenic site from foot-and-mouth disease virus (Usha et al., Virology 197, 366-374, 1993). Analysis of progeny RNA produced during such an infection has revealed that the inserted sequence is rapidly lost during serial passaging, probably by a process of homologous recombination. Using the information gained from this analysis, we have redesigned the chimeras in such a way that they are now genetically stable. The modified constructs have been used to obtain large quantities of purified virus particles expressing epitopes derived from human rhinovirus 14 (HRV-14) and human immunodeficiency virus type 1 (HIV-1). The chimeric virus particles possess the antigenic properties of the inserted sequence and, in the case of the HRV-14-derived construct, it has been shown that the inserted epitope is immunogenic in rabbits. These results demonstrate that CPMV can be used as a high-yielding system for the presentation of foreign peptide sequences.

Development of cowpea mosaic virus as a high-yielding system for the presentation of foreign peptides.

A comparison of pressure stability of empty capsids and ribonucleoprotein particles of cowpea mosaic virus (CPMV) is presented. A combination of high pressure and subdenaturing concentrations of urea was utilized to promote dissociation and denaturation. We found that RNA plays an important role in stabilizing the particles as well as in conferring reversibility to the pressure-induced denaturation. Dissociation and denaturation of the top component (empty capsid) was observed at 2.5 kbar and in the presence of 2.5 M urea. The pressure-dissociated state of the capsid protein had the characteristics of a denatured conformation as suggested by fluorescence spectra, lifetime of tryptophans, and binding of bis-ANS. The properties of the dissociated capsid protein were more similar to those of a molten-globule conformation, different from the more drastically unfolded state obtained using high concentrations of urea. Whereas the fluorescence of bis-ANS increased for the pressure-dissociated protein (1.5 M urea and 2.5 kbar), it decreased for the virus denatured by 6.0 M urea. Middle and bottom components underwent less than 50% change in center of spectral mass at 2.5 kbar and 2.5 M urea. The particles containing RNA could be fully affected by pressures of 2.5 kbar--as measured by the spectral shift--only in the presence of 5.0 M urea. RNA-containing capsids denatured by pressure did not bind bis-ANS, suggesting that the capsid protein continues to be bound to the RNA after the protein-protein contacts are broken by pressure. Reassembly of the nucleoprotein particles was obtained after decompression, reinforcing the idea that proteins had not dissociated from RNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Differences in pressure stability of the three components of cowpea mosaic virus: implications for virus assembly and disassembly.

The binding properties of seven mouse monoclonal antibodies (McAbs) raised against cowpea mosaic virus (CPMV) were characterized by conventional and inhibition enzyme-linked immunosorbent assay (ELISA) technique. McAb binding to CPMV on electron microscope (EM) grids was also assayed with gold-labeled anti-mouse antibodies. Two of the seven McAbs (5B2 and 10B7) were found to bind tighter to CPMV than the others in the inhibition ELISA and the EM assay. F(ab) fragments from both of these McAbs were prepared and complexed with CPMV in solution. Electron micrographs of flash frozen (vitrified) samples of native CPMV and CPMV complexed with F(ab) fragments from McAbs 5B2 and 10B7 as well as IgGs from 5B2 were recorded and reconstructions were computed at 23 A resolution for the CPMV/F(ab) complexes and 30 A resolution for the CPMV/IgG complex. Structures of all three complexes clearly displayed the F(ab) fragments distributed with icosahedral symmetry on the surface of CPMV. The IgG bound in a monodentate fashion with only one F(ab) attached to the virus surface. F(ab) fragments from 5B2 and 10B7 bound to nearly identical positions. The refined 2.8 A X-ray structure of CPMV was used to identify the roughly 30 amino acids covered by the F(ab) fragments. The "footprint" spans a subunit interface and appears spatially similar to antigenic site 3B on poliovirus. In a previous, preliminary report of the CPMV/F(ab) 5B2 complex (Wang et al., 1992, Nature 355, 275-278) the wrong enantiomorph of the reconstruction was chosen. This was corrected and, since the F(ab) binds close to a mirror plane, the change in the footprint was minor.

Direct imaging of interactions between an icosahedral virus and conjugate F(ab) fragments by cryoelectron microscopy and X-ray crystallography.

Identification of the membrane-binding domain of rat liver CTP:phosphocholine cytidylyltransferase using chymotrypsin proteolysis.

The capsid protein (CP) of alfalfa mosaic virus (AIMV) is required for viral replication when susceptible plants are inoculated with purified viral genomic RNA. The discovery of AIMV CP in the zinc activated RNA-dependent RNA polymerase complex prompted our further investigation of AIMV virions and the potential involvement of AIMV CP in metal binding. AIMV CP, isolated from nucleoprotein components, fractionated into four distinct ionic species when purified by cation exchange fast protein liquid chromatography. The CP existed as zinc complexed homodimers, metal-free homodimers, and two forms of proteolyzed heterodimers, as analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, gel filtration chromatography, amino-terminal sequencing, and atomic absorption spectroscopy. Although the relative amounts of proteolyzed heterodimers varied, the ratio of zinc complexed homodimers to metal-free homodimers (1:10) was constant between virus and protein isolations for the strains 425 and WISC14. Purified metal-free and zinc-complexed homodimers could be interconverted in vitro by incubation with zinc chloride or with the metal chelator, sodium diethyldithiocarbamate (NaDDC). The potential role of zinc in AIMV nucleoprotein structure and infectivity was investigated by treatment of the virions with NaDDC. Electron microscopy and sucrose density gradient studies failed to detect any gross structural changes for zinc depleted virus; however, a decrease in infectivity was observed with local lesion leaf assays, suggesting a functional role for zinc in viral replication.

A chromatographic analysis of capsid protein isolated from alfalfa mosaic virus: zinc binding and proteolysis cause distinct charge heterogeneity.

The structure of the black beetle nodavirus has been refined at 2.8 A resolution by alternate use of restrained least-squares atomic coordinate refinement and phase refinement by real space averaging with the 5-fold non-crystallographic symmetry in the crystal. The coordinates were also refined by simulated annealing. The final R-factor for all data with I/sigma(I) > 4 was 22.1%. A total of 7692 atoms were refined in one icosahedral asymmetric unit which included 273 oxygen atoms of ordered water molecules. Three identical gene products of 407 amino acids form one icosahedral asymmetric unit. Each is located in a structurally unique position, identified as A, B or C, consistent with a T = 3 quasi equivalent lattice. Icosahedral pentamers are formed by A subunits while B and C subunits alternate about icosahedral 3-fold axes to form quasi hexamers. Five calcium ions are located within the icosahedral asymmetric unit and stabilize the quasi 3-fold related intersubunit contacts between A, B and C. The final model consists of coordinates for residues 56 to 379 of all three subunits and residues 20 to 31 from the C subunit only. Atom positions for the sugar-phosphate backbone were modeled for ten nucleotides close to the icosahedral 2-fold axes. Symmetry equivalent polyribonucleotides form a helical duplex at each icosahedral 2-fold axis. The three subunits display an eight-stranded beta-barrel fold, very similar to the subunit structures observed in most other icosahedral RNA viruses analyzed. Quasi equivalence is regulated by the ordered RNA and residues 20 to 31 in the C subunit to form a "flat inter subunit contact" at icosahedral 2-fold joints. The RNA and polypeptide are disordered at the quasi 2-fold joints and this results in a "bent inter subunit contact". Although similar quaternary structures were seen in T = 3 plant viruses studied, RNA did not play a role as a molecular switch in those structures. The autocatalytic, post assembly, cleavage of the initial gene product at residue Asn363/Ala364 to form a stable and infectious particle is probably the result of an acid catalyzed main-chain hydrolysis in which Asp75 is the proton donor. The reaction is initiated by assembly which places Asp75 in a hydrophobic environment created by quaternary interactions which raises its pK to 5.6. The region in which the reaction occurs is formed by an internal helical bundle that has not been seen in other virus structures.

The refined three-dimensional structure of an insect virus at 2.8 A resolution.

Capsid assembly in a family of animal viruses primes an autoproteolytic maturation that depends on a single aspartic acid residue.

To investigate if cowpea mosaic virus (CPMV) particles can be used to express foreign protein sequences, oligonucleotides encoding an epitope derived from VP1 of foot-and-mouth disease virus (FMDV) were cloned into the region of the CPMV genome encoding the small (S) coat protein. The chimeras were designed so that the foreign sequence was expressed either as an insertion or as a replacement for part of the wild-type sequence. While RNA from both chimeras was able to replicate in cowpea protoplasts only the construct containing the FMDV sequence as an insertion was able to direct capsid formation and infect whole cowpea plants. The modified S protein produced in plants infected with the insertion derivative reacted with FMDV-specific antiserum. These results show that CPMV can be used as an antigen presentation system and raises the possibility of producing vaccines in plants using a RNA virus-based vector.

Expression of an animal virus antigenic site on the surface of a plant virus particle.

Crystals of cowpea chlorotic mottle virus (CCMV) that diffract X-rays to 3.1 A resolution were grown in a succinate-PEG solution buffered at pH 3.3. The crystals are in space group P2(1)2(1)2(1) with unit cell dimensions of a = 381.26 A, b = 381.26 A, and c = 408.59 A. Four particles occupy the unit cell, placing a single virion in the crystallographic asymmetric unit. Diffraction intensities measured from 196 films collected at the Cornell High Energy Synchrotron Source accounted for 55% of the theoretically possible data to 3.2 A. Unit cell dimensions and rotation function analyses of the X-ray data revealed that the particles were organized in a pseudo-tetragonal relationship with the pseudo-fourfold axis along the crystal c axis. Analysis of electron micrographs of two-dimensional crystals of CCMV revealed a remarkable similarity between these and planes of particles perpendicular to the crystallographic c axis in the three-dimensional crystal.

Preliminary X-ray data analysis of crystalline cowpea chlorotic mottle virus.

Raman dynamic probe of hydrogen exchange in bean pod mottle virus: base-specific retardation of exchange in packaged ssRNA.

We have crystallized Nodamura virus, a T = 3 icosahedral virus that can infect both mammalian and insect hosts. Crystals are monoclinic, with two crystallographically independent virus molecules per asymmetric unit. Packing analysis reveals a pseudo-rhombohedral (pseudo-C2 in the monoclinic setting) arrangement of virus particles in the crystal lattice. Crystals differ from the R32 symmetry by rotational and translational deviations. The rhombohedral packing arrangement and its failure to describe the exact virus packing is analyzed in detail. The icosahedral threefold axis is rotated from the body diagonal of the pseudo-rhombohedral cell, breaking the rhombohedral symmetry. The C2 pseudo-symmetry breaks down rotationally and/or translationally.

A monoclinic crystal with R32 pseudo-symmetry: a preliminary report of Nodamura virus structure determination.

Flock house virus coat protein expressed in a baculovirus system spontaneously assembles into viruslike particles, which undergo an autocatalytic postassembly cleavage equivalent to that of the native virus. Mutations of the asparagine at the Asn/Ala cleavage site result in assembly of provirion-like particles that are cleavage defective. Crystals of the mutant provirions have been grown, and they diffract X rays beyond 3.3-A (0.33-nm) resolution. The crystals are monoclinic space group P2(1) (a = 464.8 A [46.48 nm]; b = 333.9 A [33.39 nm]; c = 325.2 A [32.52 nm]; beta = 91.9 degrees) with two provirion-like particles per unit cell. Thus, it should be possible to determine the high-resolution structure of the provirion, which will be compared with the crystal structure of the mature authentic virion. This collation should provide mechanistic detail for understanding the cleavage event. Moreover, this demonstrates that the baculovirus expression system displays sufficient fidelity to permit crystallographic analysis of the assembly process of biological macromolecules.

Crystallization of viruslike particles assembled from flock house virus coat protein expressed in a baculovirus system

Isolated tobacco streak virus strain mild (TSV-M) top nucleoprotein component (TV) was crystallized by vapor diffusion with polyethylene glycol (PEG) and methyl pentanediol. The morphology of the crystal suggested a hexagonal space group, however, the crystals were disordered as analyzed by X-ray diffraction. Capsid protein from TSV (strains M and white clover) was treated with trypsin to remove 87 amino terminal residues. The modified capsid protein was purified by ion exchange chromatography and crystallized in both hexagonal and triclinic forms. Hexagonal crystals grown by vapor diffusion in PEG diffract X rays to 4.5 A. The crystals, in the space group P6(2) or its enantiomorph, possess unit cell dimensions of a = 98.3 A, c = 108.7 A and probably contain 12 dimers/unit cell. Triclinic crystals grown by vapor diffusion in ammonium sulfate diffracted X rays to 2.4 A resolution when exposed to X-ray synchrotron radiation. The crystals have unit cell dimensions of a = 60.1 A, b = 77.5 A, c = 73.9 A with alpha = 67.8 degrees, beta = 130 degrees, and gamma = 106 degrees and probably contain 4 dimers/unit cell.

Crystallization and preliminary X-ray characterization of tobacco streak virus and a proteolytically modified form of the capsid protein.

Flock house virus (FHV) is a small icosahedral insect virus of the family Nodaviridae. Its genome consists of two messenger-sense RNA molecules, both of which are encapsidated in the same particle. RNA1 (3.1 kb) encodes proteins required for viral RNA replication; RNA2 (1.4 kb) encodes protein alpha (43 kDa), the precursor of the coat protein. When Spodoptera frugiperda cells were infected with a recombinant baculovirus containing a cDNA copy of RNA2, coat protein alpha assembled into viruslike precursor particles (provirions) that matured normally by autocatalytic cleavage of protein alpha into polypeptide chains beta (38 kDa) and gamma (5 kDa). The particles were morphologically indistinguishable from authentic FHV and contained RNA derived from the coat protein message. These results showed that RNA1 was required neither for virion assembly nor for maturation of provirions. Expression of mutants in which Asn-363 at the beta-gamma cleavage site of protein alpha was replaced by either aspartate, threonine, or alanine resulted in assembly of particles that were cleavage defective. For two of the mutants, unusual structural features were observed after preparation for electron microscopy. Particles containing Asp at position 363 were labile and showed a strong tendency to break into half-shells. Particles in which Asn-363 was replaced by Ala displayed a distinct hole in an otherwise complete shell. The third mutant, containing Thr at position 363, was indistinguishable in morphology from authentic FHV.

Use of recombinant baculoviruses in synthesis of morphologically distinct viruslike particles of flock house virus, a nodavirus

Sequence and analysis of the capsid protein of Nudaurelia capensis omega virus, an insect virus with T = 4 icosahedral symmetry.

The CTP: phosphocholine cytidylyltransferase (CT) gene from yeast and cDNA from rat liver were over-expressed 20-30-fold in COS cells. Most of the CT activities were found in the cytosolic fraction. The regulation of the yeast CT activity (Y-CT) by lipids was characterized for the first time in comparison with the regulation of the well-studied rat CT (R-CT). Sonicated vesicles composed of egg phosphatidylcholine (PC) or 1-stearoyl-2-oleoyl PC had no effect on Y-CT and only slightly stimulated R-CT activity. Both CTs were activated 10-50-fold by the anionic lipids cardiolipin, phosphatidyl-glycerol, phosphatidylinositol and oleic acid. The effects of varying the vesicle concentration and the mol% of anionic lipid in PC vesicles were tested. The concentration optima for the activation of Y-CT by oleic acid or anionic phospholipids were 5-10-fold lower than those for R-CT. For example, the stimulation of Y-CT activity by phosphatidylglycerol vesicles was optimal between 5 and 15 microM and declined at higher concentrations, but R-CT activation by these vesicles saturated at approximately 25 microM. The positively charged aminolipid sphingosine antagonized the stimulation by oleic acid of both Y-CT and R-CT. Y-CT activity was insensitive to PC vesicles containing the neutral lipids diacylglycerol, monoacylglycerol or oleyl alcohol. However, R-CT was stimulated 10-20-fold by vesicles containing these neutral lipids. Translocation of the CTs to microsomal membranes enriched with anionic or neutral lipids was compared. Oleic acid enrichment promoted translocation of Y-CT and R-CT, whereas diacylglycerol promoted only R-CT translocation. These data show that the activity of Y-CT is lipid-sensitive. Y-CT is affected only by charged lipids, whereas R-CT responds to charged and neutral lipid activators. The data are consistent with different modes of interaction of the two CTs with lipids.

Comparison of the lipid regulation of yeast and rat CTP: phosphocholine cytidylyltransferase expressed in COS cells.

We report and interpret laser Raman spectra of the three virion components of bean pod mottle virus (BPMV). The top component of BPMV is an empty capsid; middle and bottom components package the RNA2 and RNA1 genome segments, respectively. All components were investigated as both single crystals and aqueous solutions, the latter over wide ranges of temperature and ionic strength. The isolated RNA2 molecule of BPMV middle component was also investigated in both H2O and D2O solutions. The results permit assessment of RNA and protein structures, their mutual interactions in the virions, and their conformational thermostabilities and comparison of these structural characteristics for solution and crystal states of the particles. The principal findings of this study are (i) The extent of ordered A-form backbone (74%) and of base pairing (38% AU + 22% GC) in unpackaged (aqueous) RNA2 are significantly altered by packaging. The A-form secondary structure of RNA2 is increased by 12 +/- 4%, and guanine base interactions are also substantially increased with packaging. (ii) The thermostability of Raman-monitored secondary structure of unpackaged RNA2 (Tm approximately 43 degrees C) is greatly increased in the packaged state (Tm approximately 53 degrees C). This increase corresponds to a stabilization of the A-form backbone geometry in 15 +/- 5% of genome nucleotides. (iii) Packaging of RNA2 in the middle component stabilizes subunit-subunit interactions of the capsid, as evidenced by a thermal denaturation temperature Td approximately 65 degrees C for the virion, compared with Td approximately 55 degrees C for the empty capsid. (iv) Raman marker-band shifts implicate the purine 7N sites of RNA2 and aromatic side chains of subunits as the principal targets for RNA-subunit interaction. (v) At the conditions of the present experiments (8 degrees C, pH approximately 7, moderate ionic strength), the subunit secondary structures observed for solutions of the top, middle, and bottom components are indistinguishable by Raman spectroscopy from secondary structures observed for corresponding crystalline samples. (vi) On the other hand, side chains of subunits in the top component (empty capsid) yield significantly different Raman intensities in crystalline and solution states. These differences are interpreted as the result of changes in a small number of side-chain environments between crystal and solution. (vii) Similarly, small differences exist between RNA Raman markers of crystalline and aqueous virions, which are attributed to altered environments of nucleotide residues and to a small increase in the amount of A-form backbone geometry upon going from the crystal to the solution.(ABSTRACT TRUNCATED AT 400 WORDS)

Conformations, interactions, and thermostabilities of RNA and proteins in bean pod mottle virus: investigation of solution and crystal structures by laser Raman spectroscopy.

Flock House virus, purified from infected cultured Drosophila cells, crystallizes into three different forms under identical growth conditions. Two crystal forms grow in the trigonal space group R3, both with equivalent cell constants a = 323.6 A, alpha = 61.7 degrees. The difference between the two trigonal crystal forms is 1.1 degrees in the orientation of the virus particle as determined from the rotation function. Early crystal setups grew in one form, while recent crystals grew in the other form. The third space group, which accounts for 5% of the observed crystals and grows with both trigonal forms, is orthorhombic I222 with cell parameters a = 416.7, b = 332.1, c = 351.2 A. The trigonal crystal forms contain one virion per unit cell and the orthorhombic form contains two particles per cell. All three crystal forms diffract X-rays to 2.8 A resolution.

Crystallization and preliminary data analysis of Flock House virus.

The microtubule-associated protein tau forms a triple-stranded left-hand helical polymer.

The three-dimensional structure of frozen-hydrated Nudaurelia capensis beta virus, a T = 4 insect virus.

Structures of protein and RNA components of bean pod mottle virus (BPMV) have been investigated by use of laser Raman spectroscopy. Raman spectra were collected from both aqueous solutions and single crystals of BPMV capsids (top component) and virions (middle and bottom components, which package, respectively, small and large RNA molecules). Analysis of the data permits the assignment of conformation-sensitive Raman bands to viral protein and RNA constituents and observation of structural similarities and differences between solution and crystalline states of BPMV components. The Raman results show that the protein subunits of the empty capsid contain between 45% and 55% beta-strand and beta-turn secondary structure, in agreement with the recently determined X-ray crystal structure, and that this total beta-strand content undergoes a small increase (approximately 5%) with packaging of RNA. The subunits are relatively deficient in alpha-helix secondary structure, estimated at less than 25%, and therefore must contain extensive amounts (greater than 20%) of loops and irregular chain conformations. The Raman spectra also show the following: (1) The molecular environments of as many as four tryptophan residues per subunit are altered upon packaging RNA, resulting in stronger 1N-H hydrogen bonding for two Trp residues and more hydrophobic environments for two indole rings. (2) Hydrogen-bonding states of the seven Tyr residues per subunit do not change detectably when RNA is packaged. At least five tyrosine OH groups are involved exclusively as strong hydrogen bond donors to protein acceptor groups, which suggests restricted access of solvent H2O molecules to these parahydroxyls.(ABSTRACT TRUNCATED AT 250 WORDS)

Structural studies of bean pod mottle virus, capsid, and RNA in crystal and solution states by laser Raman spectroscopy.

Structural homology among four nodaviruses as deduced by sequencing and X-ray crystallography.

A "zinc-finger"-type binding domain in tobacco streak virus coat protein.

Nearly 20 percent of the packaged RNA in bean-pod mottle virus (BPMV) binds to the capsid interior in a symmetric fashion and is clearly visible in the electron density map. The RNA displaying icosahedral symmetry is single-stranded with well-defined polarity and stereochemical properties. Interactions with protein are dominated by nonbonding forces with few specific contacts. The tertiary and quaternary structures of the BPMV capsid proteins are similar to those observed in animal picornaviruses, supporting the close relation between plant comoviruses and animal picornaviruses established by previous biological studies.

Protein-RNA interactions in an icosahedral virus at 3.0 A resolution.

Liposome structure and solute entrapment in multilayered vesicles (MLVs) prepared by reverse-phase evaporation (REV) were studied. MLV-REV vesicles prepared from ether/water emulsions have high entrapment. Entrapment depends on drug, drug concentration, lipid, lipid concentration, and the container used to prepare the vesicles. By use of 300 microL of aqueous phase and 100 mg of phosphatidylcholine (PC), vesicles prepared in a test tube 25 mm X 175 mm have higher entrapment than vesicles prepared in a 100-mL round-bottom or pear-shaped flask. By use of a test tube, 100 mg of PC, and 300 microL of aqueous phase containing sucrose (1-50 mg/mL), greater than 90% sucrose entrapment was obtained. Increasing lipid content to 150 mg of PC decreased entrapment to approximately 80%. Neutral PC MLV-REV vesicles have optimum entrapment. Mixing negatively charged lipids or cholesterol (CH) with PC to make MLV-REV vesicles results in decreased entrapment compared to using only PC. Preparing vesicles with the solid lipid dipalmitoylphosphatidylcholine (DPPC) or DPPC/CH mixtures (0 less than or equal to mol % CH less than or equal to 50) results in approximately 30-40% entrapment when diethyl ether is used to make the MLV-REV emulsion. Substituting diisopropyl ether for diethyl ether and heating the MLV-REV emulsion during vesicle formation generate DPPC/CH vesicles that entrap 60% of added solutes. The high entrapment found for MLV vesicles prepared from water/organic solvent emulsions depends on maintaining a core during the process of liposome formation. A method to calculate the fraction of water residing in the liposomes' core is presented and used to compare multilayered vesicles prepared by different processes. X-ray diffraction data demonstrate that a heterogeneous distribution of lipid may exist in multilayered vesicles prepared by the REV process.

Multilayered vesicles prepared by reverse-phase evaporation: liposome structure and optimum solute entrapment.

1H, 13C, and 31P nuclear magnetic resonance studies of cowpea mosaic virus: detection and exchange of polyamines and dynamics of the RNA.

The spherically averaged structures of cowpea mosaic virus components by X-ray solution scattering.

Structure of a T = 1 aggregate of alfalfa mosaic virus coat protein seen at 4.5 A resolution.

Crystallographic studies of cowpea mosaic virus by electron microscopy and x-ray diffraction.

Structure of lobster apo-D-glyceraldehyde-3-phosphate dehydrogenase at 3.0 A resolution.

The structure of southern bean mosaic virus at 22.5 a resolution.

The packing of southern bean mosaic virus in various crystal cells.

Single crystal x-ray diffraction studies of Southern bean mosaic virus.

The crystal structure of bis-(2,2′-bipyridylamine)copper(II) perchlorate, [Cu(C10H9N3)2](ClO4)2, was determined from single crystal X-ray diffraction data which was measured on a diffractometer. The crystals are monoclinic, space group C2/c, with a= 9·35, b= 12·88, c= 19·69 A, β= 102·8°, and Z= 4. The structure was solved by conventional Patterson and Fourier methods. The two-fold axis of the space group is utilized by the complex with the pyridine nitrogen atoms co-ordinating to the copper in a pseudotetrahedral arrangement. The dihedral angle between the N–Cu–N planes of the two ligands is 55·6°. This geometry seems to result from steric interaction between the ligands.

Journal of The Chemical Society A: Inorganic, Physical, Theoretical

Crystal and molecular structure of bis-(2,2-bipyridylamine)copper(II) perchlorate

ICR, F6), they were injected into blastocysts derived from the agouti cross B6D2F1 3 ICR. 25. The line EGFP Tg contains a transgene expressing enhanced green fluorescent protein (EGFP) under the control of a CMV-IE enhancer/chicken b-actin promoter combination active in most, if not all, tissues. 26. J. A. Thomson et al., Science 282, 1145 (1998). 27. M. J. Shamblott et al., Proc. Natl. Acad. Sci. U.S.A. 95, 13726 (1998). 28. J. B. Gurdon, A. Colman, Nature 402, 743 (1999). 29. D. L. Clarke et al., Science 288, 1660 (2000). 30. L. Studer, V. Tabar, R. D. McKay, Nature Neurosci. 1, 290 (1998). 31. We thank P. Song and M. Studer for technical assistance and advice. Supported in part by a generous contribution from The Rockefeller University and by a grant to T.W. from the Rockefeller Brothers Fund.

CEVL training for coronal/distal shaft hypospadias repair: a guide for attendings, residents, and OR staff.

The effect of spinal cord level on sexual function in the spina bifida population.

Angelman syndrome (AS) is an inherited neurodevelopmental disorder that is clinically characterized by severe speech impairment, unusually happy demeanor, ataxia, microcephaly, and EEG abrnomalities. Functional deficits of the UBE3A gene in the 15q11-13 region of the maternal chromosome lead to the Angelman syndrome phenotype. Genetic analysis has revealed four mechanisms that are known to cause Angelman syndrome. They have been grouped in classes I though IV. Class I defects account for 70% of AS patients and result from a deletion in chromosome 15q11-13. Class II defects are less common and are the result of uniparental disomy. Class III patients have imprinting defects of 15q11-13. Class IV patients account for 20% of AS and have mutations in the UBE3A gene. The type of deletion has been linked to phenotypic severity and class I patients generally have the most severe phenotypes. We have been following a 10-year-old boy with a novel UBE3A mutation and a normal methylation pattern. His mutation is a G—> A substitution at position 1434 in exon 9 of UBE3A. He has some classical Angelman features, including a wide mouth, flat face, happy demeanor, severe speech impairment, and sleep disturbance. However, he is not microcephalic, has no EEG abnormalities, and is not ataxic. This patient's presentation presented a diagnostic challenge because he lacks multiple “classical” Angelman characteristics. We hypothesize that this novel UBE3A mutation produced a unique variant phenotype and provides further knowledge to genotype-phenotype relationships within the Angelman syndrome spectrum.

387 ANGELMAN SYNDROME: A NOVEL UBE3A MUTATION AND A UNIQUE VARIANT PHENOTYPE.

Due to increased demand and deployment of new technologies, such as electric vehicles, utilities face increasing fault currents in their systems. As a consequence protection devices must have higher ratings. Replacing existing infrastructure can prove expensive and complicated. Fault current limiters promise an upgrade solution that will mitigate the need for replacing existing breakers to keep fault currents within the ratings of existing protection equipment. SiC offers several key advantages to grid-connected power electronics, such as smaller footprint, faster switching speeds, and simpler cooling systems. This paper describes a 4 kV Silicon Carbide (SiC) fault current limiter that demonstrated the technologies' potential.

Solid-state fault current limiters (SSFCLs) offer a number of benefits when incorporated within transmission and distribution systems. SSFCLs can limit the magnitude of a fault current seen by a system using different methods, such as inserting a large impedance in the current path or controlling the voltage applied to the fault. However, these two methods can introduce a few problems when SSFCLs are used in a system along with other protection equipment such as protective relays and sensors. An experiment was designed and implemented to evaluate the behavior of the protective relays in a mimic distribution system with a SSFCL. This paper introduces the details of the experiment and the result shows that the distorted current and voltage waveforms resulting from the action of the SSFCL disturb the protective equipment.

Impact of solid-state fault current limiters on protection equipment in transmission and distribution systems

The need for high-voltage power semiconductor devices in utility applications ranging from isolating faults within a quarter cycle and efficient use of renewal energy resources is rapidly growing. To this end, silicon carbide thyristor power modules were fabricated and characterized electrically. In particular, three SiC thyristors were attached on a common direct bond copper substrate with a copper heat spreader to form a power module. Series resistances were inserted to achieve a good matching of their on-state currents. Experimental results revealed that this power module offered good thermal matching for parallel operation.

2009 IEEE 6th International Power Electronics and Motion Control Conference

Packaging and characterization of silicon carbide thyristor power modules

SiC semiconductor devices are becoming more common in high power applications. This is largely due to higher blocking voltages and faster switching speeds. The development of SiC devices, specifically thyristors and GTOs, is still an evolving process [1]. There is not yet a single device capable of handling the magnitude of current typically seen in transmission and distribution systems and as a result these devices must be paralleled into a single switching position. SiC thyristors were used to carry out a study on paralleled SiC bipolar devices. Si bipolar devices are much better matched than SiC devices, but they exhibit much slower turn-on times [2]. Thus, the most suitable method of inducing current sharing in these devices is through gate control. However, SiC devices exhibit fast turn-on times while being poorly matched. Using various methods of gate control for SiC bipolar devices in parallel does not significantly affect the current sharing. The best way to improve current sharing is obtained using series resistors. These resistors should be chosen so that the voltage drop and power losses are minimized. The effects of thermal runaway are observed as well. As a device rises in temperature relative to the other devices, it conducts more current due to its negative temperature coefficient of on-state resistance. In order to maintain proper heat sharing, a design for a package is presented that includes three thyristors in parallel on a common substrate.

As utilities face increasing fault currents in their systems as a result of increasing demand and/or deployment of new technologies, fault current limiters promise a solution that will mitigate the need for replacing existing breakers as well as being a general protective device for elements connected to the grid. This paper describes some recent advances in semiconductor-based fault current limiting technology including both the more mature silicon developments along with early developments using silicon carbide. The capabilities and limitations of these technologies are compared and contrasted. Some example scenarios of FCLs have been analyzed and are briefly described along with advanced features that semiconductor FCLs may bring to the solution space.

2008 IEEE Power and Energy Society General Meeting - Conversion and Delivery of Electrical Energy in the 21st Century

Solid-state fault current limiters: Silicon versus silicon carbide

Memo for McGeorge Bundy describing interest in nuclear power plants within Yugoslavia and Romania.

The antimony-121 Mössbauer spectra of Eu10Mn6Sb13 have been measured between 2 and 295 K. Although the Zintl formalism indicates that the nine crystallographically distinct antimony sites in Eu10Mn6Sb13 should have formal valence states of -2, -1, 0, and +1, the Mössbauer spectral isomer shifts reveal that the valence states of the different sites are all quite similar and correspond to an average electronic configuration for antimony of 5s(1.7)5p(4.0). This configuration corresponds to an excess of negative charge on the antimony of 0.7 or an average valence of -0.7, a valence which is rather consistent with the average antimony valence of -0.61 obtained from the Zintl formalism for the nine antimony sites in Eu10Mn6Sb13. The spectra obtained between 90 and 295 K are more consistent with the absence rather than the presence of any transferred magnetic hyperfine field at the antimony. In contrast, the spectra obtained at 2 and 5 K reveal the presence of an average transferred magnetic hyperfine field of ca. 8 T, a field that arises from the ferromagnetic ordering of the near-neighbor manganese(II) ions.

Magneto-Transport Study of Disordered Electron Systems in a Gallium Arsenide Heterojunction.

Nouveaux regards sur les forêts de laminaires de l’île d’Anticosti

Aux latitudes moyennes, les grandes algues sont une composante essentielle des ecosystemes cotiers comme source de nourriture et d’habitat pour les communautes benthiques. Les assemblages de macroalgues dans l’ecosysteme marin du Saint-Laurent (EMSL) sont largement domines par les fucales (Fucus, Ascophyllum) dans l’etage mediolittoral et par les laminaires (Alaria, Saccharina, Agarum) et les algues calcaires dans l’etage infralittoral. Peu d’efforts ont ete consacres a l’etude de leur ecologie alors meme que les activites de recolte sont en croissance. En depit des similitudes entre l’EMSL et les ecosystemes comparables de l’est du Canada et d’Europe, il y a des differences fonctionnelles frappantes associees a 2 sources de perturbations : le broutage intense des algues par les oursins dans l’etage infralittoral et l’abrasion des communautes de l’etage mediolittoral par les glaces. Dans plusieurs regions de l’EMSL, ces perturbations reduisent l’extension des assemblages d’algues, ce qui genere des incertitudes sur le potentiel d’exploitation de cette ressource. Il en ressort qu’il faut approfondir les connaissances sur la repartition et l’abondance des especes mais aussi developper l’algoculture, cela autant pour conserver les ressources naturelles et leurs services ecologiques que pour assurer un approvisionnement stable des marches emergents avec des ressources de qualite. A terme, ces informations seront indispensables pour anticiper les changements causes par le rechauffement climatique et par l’augmentation des invasions biologiques.

Les macroalgues du Saint-Laurent : une composante essentielle d’un écosystème marin unique et une ressource naturelle précieuse dans un contexte de changement global

L'invention concerne des methodes de detection directe d'agent(s) microbien(s) dans un echantillon polymicrobien, par exemple un echantillon biologique preleve chez un etre humain, sans mise en culture du ou des agents microbiens. La detection directe peut identifier des melanges de bacteries et/ou de champignons dans l'echantillon. L'invention concerne egalement des sequences d'amorces et des techniques d'amplification permettant de mettre en œuvre lesdites methodes de detection directe.

La presente invention concerne des procedes de diagnostic de la vaginose bacterienne sur la base d'une analyse d'un echantillon d'un patient. Par exemple, des echantillons de test du patient sont analyses concernant la presence ou l'absence d'un ou plusieurs lactobacilli et de deux ou plusieurs organismes pathogenes. La presence ou l'absence d'un ou plusieurs lactobacilli et de deux ou plusieurs organismes pathogenes peut etre detectee a l'aide d'une analyse par PCR de segments d'acide nucleique correspondant a chaque organisme cible. La quantite des organismes cibles peut ensuite etre utilisee pour determiner une note qui revele un diagnostic de vaginose bacterienne.

Most institutions of higher learning prioritize three areas in which its faculty must excel: research, teaching, and service. These three areas are often the sites where administrations make us accountable at the time of tenure and promotion. Rarely, however, do any of us excel in all three without making some kind of personal sacrifice or succumbing to burnout. Before tenure, teaching might suffer so that we can work on a book manuscript or produce a string of “paradigm shifting” articles. After tenure, the research may wane when we are overextended with committees. The road to full professor may take yet another toll on our teaching as we work on the second or third book manuscript. Whatever the case, ours is a constant negotiation of priorities and balancing acts in which we aspire to be good citizens of the academy. I know of no other person who assailed all three as adeptly and gracefully as Dwight Conquergood. His life and his legacy stand as academic benchmarks. I met Dwight in the spring of 1990 during my first year of graduate school at the University of North Carolina at Chapel Hill. My thesis advisor, D. Soyini Madison, one of Dwight’s advisees, invited him to campus to screen his documentary, The Heart Broken in Half (1990), an ethnographic film about the life of the Latin King street gang in Chicago. Soyini designated me as Dwight’s host until she was done teaching that day and asked me to pick him up at the airport. I remember being so excited to meet the Dwight Conquergood, the scholar who had done all of this courageous work with street gangs and who had become an advocate on their behalf. As I peered through the crowd at baggage claim, I did not expect to find the short, salt-and-pepper–haired, timid-looking man that was Dwight. “How on earth,” I thought, “did this man befriend street gangs?” After a long and engaging lunch with him, I came to understand how. Behind that mildmannered smile, easygoing demeanor, and gentle spirit, was a fierce intellectual and an even fiercer ethnographer and activist. Much of his commitment to social justice was due to his working-class background. He was born in Thunder Bay, Ontario, but grew up on a farm in Indiana,

Social workers are currently caught in a “structural bind” in which the field’s original normative mission, rooted in social justice and social change, is increasingly at odds with the reality of working in a hierarchical neoliberal managed care setting. While most practitioners are at risk of burnout under these strained conditions, not all will respond in the same way. This article considers the possibility that some practitioners will exhibit authoritarian character traits (e.g., submission to and unquestioned compliance with institutional rules) in conformity with the institutional setting of neoliberal managed care. Using the Maslach Burnout Inventory for Health Services Occupations (MBI-HSS) and Dunwoody and Funke’s Aggression-Submission-Conventionalism (ASC) authoritarianism scale, the authors explore the previously unexamined relationship between authoritarianism and burnout among a sample of 532 social workers in the US. As hypothesized, correlations between each of the MBI-HSS subscales and ASC subscales yielded an inverse relationship between authoritarianism and burnout.

Neoliberal managed care and the changing nature of social work practice

Choose your driver: How Super Mario Kart helps explain Bourdieusian sociology

Student– Public– Sociologist: On Dialogue with our First Public, and in Widening Access to Higher Education

As a dialogue, this section engaged a wider range of participants than previous attempts. The email invitation to respond to the provocation and cases generated responses from contributors to four of the six cases, interestingly reflecting the contexts of England and Scotland; early career and recently retired academics, on more or less precarious contracts; and in ancient and modern universities. To what extent is public sociology as educational practice sustainable, even possible, within the neoliberal university? The challenges of engaging with integrity in educational practice within the neoliberal university, however that is mediated and experienced, has prompted an engaging and impassioned debate which will undoubtedly continue. Moreover, the personal cost of public sociology as educational practice has also been articulated. The context of the neoliberal university makes public sociology, and indeed educational practice with any integrity, a constant battle: exhausting, upsetting and demoralising. The medium of email exchange has mediated the emotional content, but the experience of rage, and tears, and indignation, is clearly shared by the dialogical participants....

Dialogue III: Public Sociology Practices, Privatising Universities

Shetland's world-famous Viking-themed Up Helly Aa fire festival is a distinctive celebration of community and heritage. Recently media attention and local debate has begun to focus on an ongoing controversy surrounding the exclusion of women and girls from participating in certain roles in the town of Lerwick's Up Helly Aa event. This paper provides some insight into the developing situation and critically examines the claims of heritage and tradition in the face of accusations of locally sanctioned discrimination. With input from members of the grassroots organisation Up Helly Aa for Aa, who campaign for gender equality in the festival (and which the lead author is a member of), the opportunity is taken to provide the perspective of those challenging the status quo.

Fuel for the fire: tradition and the gender controversy in Lerwick's Up Helly Aa

The Council on Social Work Education's (CSWE) instruction on diversity and social justice is central to the mission of social work education. The population of the United States has become more diverse and social work education has a pressing need to ensure students understand how diversity and social justice issues shape human experiences. Little research has systematically examined Bachelor of Social Work (BSW) programs in that regard. This paper examines correlations among demographic characteristics and program directors' impressions on teaching diversity and social justice in the United States' (BSW) programs. Using Qualtrics, a web-based survey tool, 36 program directors responded to a 47-item instrument composed of both closed and open-ended questions. Content analysis of the data was conducted with the assistance of Nvivo 12 to identify themes and nodes. However, due to inadequate information from the program directors, the open-ended questions were analyzed using thematic analysis. Emergent themes primarily pertained to implicit and explicit curricula. A central finding from the data was that there was variation in the way schools approached instruction regarding diversity and social justice assessment. The study raises questions for continued research and may have implications for the role of accrediting organizations in offering guidelines for diversity and social justice instruction and assessment.

THE IMPORTANCE OF DIVERSITY AND SOCIAL JUSTICE IN BSW PROGRAMS: IMPLICATIONS FOR SOCIAL WORK EDUCATION IN THE U.S.

ABSTRACT This article considers support programmes for direct entrant (DE) student transitions as a widening participation strategy. We reflect upon one induction and support project with 27 students transitioning from further education into the second year of undergraduate social science degree programmes in a Scottish university. We use focus group data to discuss what works (barriers to successful transitions, project successes and limitations) and primarily who works; how responsibility for supporting DE student transitions is distributed and which students benefit. Original findings confirm existing evidence that becoming an ‘independent learner’ is a challenge for DE students. However, analysis problematizes and significantly expands existing understandings of relationships with staff and peer support, and contributes new insight into how the materiality and everyday logistics of the university relate to DE student transitions. We argue for more institutionally embedded approaches to supporting student transitions, including resourcing academic staff to develop and provide this support.

What (and who) works in widening participation? Supporting direct entrant student transitions to higher education

The Scottish Enhancement Theme of Transitions has largely been explored by institutions in terms of pre/post undergraduate degree, with a tangential focus on employability. Less considered are transitions between and through undergraduate levels, despite the impact they have on successful student engagement and retention (Whittle, 2015). To ensure positive transition through their degree, students must be engaged in dialogue with staff and have the opportunity to influence curriculum adaptation and development (Bovill, Cook-Sather, & Felten, 2011). Having experienced the Honours year from both a student and tutor perspective, the authors developed Don’t Panic: The Psych/Soc Student’s Guide to Fourth Year . A practical response to student concerns, the guide was designed to reflect the final year ‘life cycle’ with the simple aim of offering honest advice and encouragement to psychology and sociology students at Queen Margaret University (QMU), as an informal companion to the dissertation handbook. Development is ongoing, and following dissemination activities the guide has attracted interest from students and faculty across the United Kingdom and beyond. It is apparent that several institutions lack such a form of support for final year students – and while Don’t Panic is not presented as the solution to all transitional problems, it can serve as an example of innovation to empower the student voice. Don’t Panic has led to the author’s increasing involvement in, and understanding of, issues relating to learning and teaching, access and retention. They reflect on these matters in academic and professional literature, through the prism of their own student-to-staff transitional experience.

Don’t Panic: Common Sense and the Student Voice in a Transitional Guide

From Sabbath To Weekend: Recreation, Sabbatarianism, And The Emergence Of The Weekend

In this paper, the authors retrace the philosophy and method of Natural Resources 407, "Religion, Ethics, and the Environment," which has been continuously taught at Cornell University by the lead author since 1974. The works of Iris Murdoch, Stanley Hauerwas, Reinhold Niebuhr, Joseph Sax, and Thomas Merton are discussed, culminating in an aesthetic vision of environmental ethics as "praise for all things." The course aims more to foster a general moral maturity rather than to instill any any particular set of environmental behaviors in students, and the authors believe that such an aim makes a lasting contribution to environmental ethics.

From Delight to Wisdom: Thirty Years of Teaching Environmental Ethics at Cornell

Angioneurotic edema, agranulocytosis, and fatal septicemia following captopril therapy.

Cause and Prevention of Overstimulation of the Modern American Child

Efficient Large Scale Preparation of Neutral Endopeptidase/Angiotensin-Converting Enzyme Dual Inhibitor CGS30440.

Macrolactamization via Palladium π-Allyl Alkylation. Preparation of CGS25155 (VIII): Endopeptidase 24.11 Inhibitor.

A number of basidiomycete sesquiterpenoids exhibit considerable toxic, antibiotic, and antitumor activity, including members of the protoilludane, illudane, marasmane, and sterpurane families. The first type is considered to play an important biogenetic role with respect to the remainder. Among the synthetically most challenging protoilludanes ranks illudol (1), because it combines the task of constructing the unusual angular and strained hydrocyclobutaindane nucleus with that of controlling five contiguous stereocenters. The authors report the synthesis of illudol.

Stereoselective, one-step assembly of the strained protoilludane framework by cobalt-mediated cyclization of an acyclic enediyne precursor. A total synthesis of illudol

Stereoselective, One-Step Assembly of the Strained Protoilludane Framework by Cobalt-Mediated Cyclization of an Acyclic Enediyne Precursor. A Total Synthesis of Illudol.

ABSTRACT Handheld and wearable smart devices have enabled augmented reality (AR) technologies (ART), including AR hypermedia (ARH) print ads, in which mobile smart devices act as viewfinders to superimpose virtual, hyperlinked, 2-D images over traditional print ads. This study utilizes eight constructs—attitude toward the ad (Aad), informativeness, entertainment, irritation, advertising value, time–effort, novelty, and ad effectiveness—to compare consumer response to three different ad formats, a traditional print ad, a quick response (QR) code hypermedia (QRH) print ad, and an ARH print ad. Results showed the ARH print ad was preferred, yielding higher perceptions of informativeness, novelty, and effectiveness; whereas the QRH print ad resulted in higher irritation; and the traditional print ad resulted in higher time–effort. Theoretical and managerial recommendations are offered based on these findings.

Augmented Reality Marketing: Consumer Preferences and Attitudes Toward Hypermedia Print Ads

Augmented Reality (AR) is an emerging form of experience in which the Real World (RW) is enhanced by computer-generated content tied to specific locations and/or activities. Over the last several years, AR applications have become portable and widely available on mobile de- vices. AR is becoming visible in our audio-visual media (e.g., news, entertainment, sports) and is beginning to enter other aspects of our lives (e.g., e-commerce, travel, marketing) in tangible and exciting ways. Facilitating ubiquitous learning, AR will give learners instant access to location- specific information compiled and provided by numerous sources (2009). Both the 2010 and 2011 Horizon Reports predict that AR will soon see widespread use on US college campuses. In prepa- ration, this paper offers an overview of AR, examines recent AR developments, explores the impact of AR on society, and evaluates the implications of AR for learning and education.

Augmented Reality: An Overview and Five Directions for AR in Education

More than a dozen visiting motion picture artists and scholars, including Tom

The computing resources of the TeraGrid are a powerful tool for research by graduate students throughout the world. In this paper we analyze the usage of the TeraGrid by a sample of 876 graduate students from the institutions that form the Committee on Institutional Cooperation. We investigate demographic information and usage of TeraGrid resources and present visualizations. We also analyze the sample using data mining algorithms, specifically rule association learning and hierarchical clustering, and create interactive visualizations. This work reveals interesting patterns about the research done by graduate students on the TeraGrid and the resources they use.

Data Visualization and Analysis of CIC Graduate Student TeraGrid Resource Usage

With the development of petascale computing systems, a long-term effort is needed to educate and train the next generation of researchers. As part of its graduate education component, the Virtual School of Computational Science and Engineering held a summer school in August 2008 entitled "Accelerators for Science and Engineering Applications," providing participants with knowledge and hands-on experience with graphics processing units (GPUs). In this paper, we present visualizations exploring the broad spectrum of summer school applicants and participants. We examine demographic information of the overall applicant pool, accepted and attending applicants, and remote participants, as well as apply hierarchical clustering and rule association techniques to all applicant data. These statistical and data mining analyses demonstrate the wide range of fields of study where research applications can be readily accelerated through the use of massively parallel computing resources.

Visualization and Analysis of GPU Summer School Applicants and Participants

Since 1987, the Man-Systems Integration Standards (MSIS) has been accepted as the definitive document for specifying the human interface requirements to be met when designing any type of hardware for use in manned space-flight. To date, all copies of the document, including two rather thorough revisions, have been created with a desk-top publisher, and distributed to customers in paper form. From the MSIS’s inception, there has been a continuous search for an efficient method to distribute the document to customers electronically. An SBIR project completed in FY97, and some further funded effort completed in FY98, have resulted in the development of an on-line system which presents the MSIS in a very customer friendly configuration. This new, hyper-text, multi-media software utilized by the MSIS Web-site is known as PHIDIAS. This on-line version includes all text and graphics from the MSIS, plus clips from the associated Living and Working in Space video. Numerous attributes of the Web-compatible version of PHIDIAS make it an ideal choice for placing the MSIS on line. PHIDIAS is easily adaptable to allow inputting of the source information, be it text, graphics, tables, charts, photos, or audio or video clips, in whatever format they may exist originally. On query from the Web-site visitor, PHIDIAS creates Web-pages “on the fly”, allowing outputs of exactly the information requested, and eliminating the wait for multiple screens of unneeded data to be downloaded.

The New on-Line Version of the Man-Systems Integration Standards (NASA-STD-3000)

Using argumentative agents to catalyze and support collaboration in design

Proceedings of the 14th Annual Conference of the Association for Computer Aided Design in Architecture (ACADIA)

Refractory schizo-obsessive disorder responsive to electroconvulsive therapy.

Studies with goldfish (Carassius auratus) have suggested that N-methyl-D-aspartate (NMDA) receptors are concentrated most densely in the telencephalon, a simple structure homologous to the limbic structure of higher vertebrates. The present study investigated the amnestic effects of microinjections of the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) to the goldfish telencephalon on avoidance conditioning. Results showed that microinjections of D-AP5 before training impaired avoidance learning at doses that did not impair performance processes. High-performance liquid chromatography measurements showed that D-AP5 was detected only in the telencephalon following microinjections. Thus, D-AP5 impaired avoidance learning through its interaction with telencephalic NMDA receptors in goldfish. Furthermore, microinjections of D-AP5 to the goldfish telencephalon immediately following training did not impair memory consolidation of avoidance conditioning.

The role of telencephalic NMDA receptors in avoidance learning in goldfish (Carassius auratus).

Review for "Factors associated with dropout in the longitudinal Vogel Study of cognitive decline"

We are in the process of developing and commissioning a scanning photoelectron microscopy (SPEM) at the X1A beamline of the National Synchrotron Light Source (NSLS). It is desigend to make use of the Soft X-ray Undulator (SXU) at the NSLS. This high brightness source illuminates a Fresnel zone plate, which forms a focused probe, ⩽0.2 µm in size, on the specimen surface. A grating monochromator selects the photon energy in the 400-800 eV range with an energy resolution of better than 1 eV. The expected flux in the focus is in the 5 × 107-109 photons/s range. A single pass Cylindrical Mirror Analyzer (CMA) is used to record photoemission spectra, or to form an image within a fixed electron energy bandwidth as the specimen is mechanically scanned. As a first test, a 1000 mesh Au grid was successfully imaged with a resolution of about 1 µm and the CMA tuned to the Au 4f photoelectron peak. Once it is commissioned, a program is planned which will utilize the microscope to study beam sensitive systems, such as thin oxide/sub-oxide films of alumina and silica, and ultimately various adsorbates on these films.

Maskless Interdigitated A-Si:H Pecvd Process on Full M0 C-Si Wafer: Homogeneity and Passivation Assessment

Development of recombination layer in Perovskite/Microcrystalline Si tandem solar cells

The NSLS-II injection straight section (SR) consists of pulsed and DC bumps, septa system, beam trajectory correction and diagnostics systems. In this paper we discuss overall injection straight layout, preliminary element designs, specifications for the pulsed and DC magnets and their power supplies, vacuum devices and chambers and diagnostics devices. Prior to selecting the current 'conventional' design of the injection straight section we analyzed an option of injection via pulsed multipole pioneered at PF-AR. We found that this promising approach was not suited to the NSLS-II storage ring optics, since it would require a impractically compact arrangement of the injection straight section components and a complex modification of the transport line optics due to the strong focusing of the injected beam passing off the pulsed multipole axis. In addition, the requirement for a small injection transient of the stored beam orbit severely constrains the vertical alignment tolerance of the pulsed multipole. The design of the NSLS-II injection straight section is now completed with exception of transition chamber details, which will be adjusted to accommodate the actual layouts of the pulsed magnets.

We present the conceptual design of the NSLS-II injection system [1, 2]. The injection system consists of a low-energy linac, booster and transport lines. We review two different injection system configurations; a booster located in the storage ring tunnel and a booster housed in a separate building. We briefly discuss main parameters and layout of the injection system components.

Currently the facility upgrade project is in progress at the NSLS (at Brookhaven National Laboratory). The goal of the NSLS-II is a 3 GeV ultra-low-emittance storage ring that will increase radiation brightness by three orders of magnitude over that of the present NSLS X-ray ring. The low emittance of the high brightness ring’s lattice results in a short lifetime, so that a top-off injection mode becomes an operational necessity. Therefore, the NSLS-II injection system must provide, and efficiently inject, an electron beam at a high repetition rate. In this paper, we present our concept of the NSLS-II injection system and discuss the conditions for, and constraints on, its design.

We present preliminary design of full-energy booster for NSLS-II. In the paper we analyse single-and multi-bunch modes of the booster operations. The booster lattice consists of 24 theoretical minimum emittance (TME) cells with two dispersion suppressors. Lattice design, initial design of the magnets and eddy current contribution to the booster chromaticity is briefly discussed.

High-gain harmonic generation has been demonstrated at the shortest wavelength to date (266 nm). Megawatt levels of 89 nm radiation are also produced. Experimental applications of the deep ultraviolet light and FEL issues are discussed.

Postconference Digest Quantum Electronics and Laser Science, 2003. QELS.

A deep ultraviolet ultrafast source driven by high gain harmonic generation in a free electron laser

The Deep Ultra Violet Free Electron Laser (DUV-FEL) experiment has reached a milestone by saturating the Free Electron Laser using High Gain Harmonic Generation (HGHG) method in the Source Development Laboratory (SDL) at NSLS. It utilizes the 10 m long, 3.9 cm period NISUS wiggler. The goal of the project is to produce radiation at a wavelength less than 100 nm, utilizing the HGHG method. HGHG at 266 nm has been accomplished by seeding with the 800 nm Ti:Sapphire laser and observed saturation. The third harmonic at 88 nm accompanying the 266 nm is being used in an ion pair imaging experiment in chemistry. We discuss the measurement of energy, gain, spectrum, and pulse length of the FEL output. We also describe the diagnostics used for operating the FEL.

The Source Development Lab at NSLS consists of a Sband photoinjector with Ti:Sapphire drive laser, 200 MeV linac, chicane bunch compressor, and 10 m long NISUS undulator. Experiments are underway to measure and understand the emission of intense, coherent infrared radiation and accompanying microbunching structure observed on the electron beam during pulse compression. Results are reported for measured radiation power, electron beam energy and time profiles, and comparisons are made with recently developed coherent synchrotron radiation (CSR) instability theory.

The far-infrared coherent emission from short electron bunches has been detected and partially characterized for two source locations at the NSLS Source Development Lab (SDL) accelerator system. One location is designed to extract dipole edge radiation while the other extracts transition radiation produced a short distance downstream of the SDL linac. The coherently radiated energy per pulse is 10's of nJ, and depends quadratically on bunch charge. The spectral content agrees with the longitudinal bunch density as determined from other measurements.

PACS2001. Proceedings of the 2001 Particle Accelerator Conference (Cat. No.01CH37268)

Coherent radiation measurements at the NSLS Source Development Lab

The DUVFEL electron linac is designed to produce sub-picosecond, high brightness electron bunches for driving a short wavelength FEL. Four experiments have been commissioned to address the challenge of accurately measuring bunch lengths on this timescale. In the frequency domain, a short 12 period undulator is used to produce both off-axis coherent emission and on-axis incoherent single-shot spectra. The total coherent infrared power scales inversely with the bunch length and the spectral cutoff is an indication of bunch length. The density of the power spikes in the single-shot visible spectrum may also be used to estimate the bunch length. In the time domain, the linac accelerating sections and a bending magnet are used to implement the RF-zero phasing method, and a subpicosecond streak camera is also installed. The beam measurements with comparisons of these methods are reported.

The DUVFEL photoinjector consists of a 1.6 cell BNL gun IV with copper cathode, variable pulse length Ti:Sapp laser, and solenoid magnet. The beam dynamics and the electromagnetic fields in the photoinjector have been characterized by producing a short electron beam with very low charge that is used as a field probe. The transverse beam size and divergence are measured as a function of the initial RF phase and the initial spot size and compared with simulations using the code HOMDYN. The electromagnetic fields used in the simulations are produced by SUPERFISH, and have been verified with RF measurements. The simulations and measurements of beam dynamics are presented.

The DUVFEL electron linac is designed to produce sub-picosecond, high brightness electron bunches to drive an ultraviolet FEL. The accelerator consists of a 1.6 cell S-band photoinjector, variable pulse length Ti:Sapp laser, 4 SLAC-type S-band accelerating sections, and 4-dipole chicane bunch compressor. In preparation for FEL operation, the compressed electron beam has been fully characterized. Measurement of the beam parameters and simulation of the beam are presented.

Measured properties of the DUVFEL high brightness, ultrashort electron beam

Measurements of the thermal emittance of an electron beam produced by photoemission from the copper cathode of a high power RF cavity are presented. The RMS normalized emittance has been measured as a function of laser spot size, applied surface field, and polarization of the laser beam at normal incidence. Local field enhancement due to surface effects is found to increase the emittance substantially beyond that expected for a perfect planar surface.

The Plasma Window is a stabilized plasma are used as an interface between accelerator vacuum and pressurized targets. There is no solid material introduced into the beam and thus it is also capable of transmitting particle beams and electromagnetic radiation with low loss and of sustaining high beam currents without damage. Measurements on a prototype system with a 3 mm diameter opening have shown that pressure differences of more than 2.5 atmospheres can be sustained with an input pressure of /spl sim/10-6 Torr. The system is capable of scaling to higher-pressure differences and larger apertures. Various plasma window applications for synchrotron light sources, high power lasers, internal targets, high current accelerators such as the HAWK, ATW, APT, DARHT, spallation sources, as well as for a number of commercial applications, are discussed.

Proceedings of the 1999 Particle Accelerator Conference (Cat. No.99CH36366)

The plasma window: a windowless high pressure-vacuum interface for various accelerator applications

The accelerator at the Source Development Lab at BNL consists of a 1.6 cell RF photocathode electron gun followed by a 230 MeV SLAC-type linac that includes a magnetic chicane bunch compressor. The nominal specifications call for a 10 ps FWHM bunch of 2nC charge to be compressed in time by a factor of 25 at an energy of 85 MeV. The design of the compressor magnets and the beam dynamics from the gun through the magnetic chicane are described.

Proceedings of the 1997 Particle Accelerator Conference (Cat. No.97CH36167)

A new beam diagnostic to measure transverse profiles of electron beams is described. This profile monitor uses a Yttrium:Aluminum:Garnet (YAG) crystal doped with a visible-light scintillator to produce an image of the transverse beam distribution. The advantage of this material over traditional fluorescent screens is that it is formed from a single crystal, and therefore has improved spatial resolution. The current system is limited to a resolution of about 10 microns. Improvements in the optical transport will enable measurements of RMS beam sizes of less than 1 micron. The total cost of the system is modest.

Despite the recent progress in treatment of multiple myeloma (MM), it is still an incurable malignant disease, and we are therefore in need of new risk stratification tools that can help us to understand the disease and optimize therapy. Here we propose a new subtyping of myeloma plasma cells (PCs) from diagnostic samples, assigned by normal B-cell subset associated gene signatures (BAGS). For this purpose, we combined fluorescence-activated cell sorting and gene expression profiles from normal bone marrow (BM) Pre-BI, Pre-BII, immature, naïve, memory, and PC subsets to generate BAGS for assignment of normal BM subtypes in diagnostic samples. The impact of the subtypes was analyzed in 8 available data sets from 1772 patients' myeloma PC samples. The resulting tumor assignments in available clinical data sets exhibited similar BAGS subtype frequencies in 4 cohorts from de novo MM patients across 1296 individual cases. The BAGS subtypes were significantly associated with progression-free and overall survival in a meta-analysis of 916 patients from 3 prospective clinical trials. The major impact was observed within the Pre-BII and memory subtypes, which had a significantly inferior prognosis compared with other subtypes. A multiple Cox proportional hazard analysis documented that BAGS subtypes added significant, independent prognostic information to the translocations and cyclin D classification. BAGS subtype analysis of patient cases identified transcriptional differences, including a number of differentially spliced genes. We identified subtype differences in myeloma at diagnosis, with prognostic impact and predictive potential, supporting an acquired B-cell trait and phenotypic plasticity as a pathogenetic hallmark of MM.

A multiple myeloma classification system that associates normal B-cell subset phenotypes with prognosis.

Environmental indicators help companies monitor, evaluate, and mitigate their environmental impacts, but not all companies in Costa Rica make effective use of these tools. We worked with la Cámara de Industrias (CICR) in San Jose, Costa Rica to better understand the benefits, barriers, and best practices associated with the use of environmental indicators in Costa Rica. Our group interviewed and surveyed environmental experts and company representatives to determine specific applications of environmental indicators for Costa Rican companies. We developed a workbook to allow companies to easily track their environmental data using indicators, and we proposed recommendations to assist CICR in promoting the use of environmental indicators among their member companies.

Recommending Environmental Indicators and Identifying Common Barriers to Their Use for Companies in Costa Rica

Impact of febrile neutropenia on R-CHOP chemotherapy delivery and hospitalizations among patients with diffuse large B-cell lymphoma

What does it mean to be a “responsible engineer”? The question has been asked throughout history, including during times that were fraught with challenge, but the problems awaiting engineering students in Canada in 2021 are arguably unprecedented in their complexity. Technologically difficult problems resulted in recent advances such as the World Wide Web and 5G mobile communications, but today’s challenge derives not only from the global scale of man-made environmental problems and their impacts, but from lack of agreement around appropriate mitigation strategies and on the need to act at all. The engineering students of today must develop solutions to problems that have newly acknowledged and highly contentious human factors. In the Canadian context, new policy is emerging from Canada’s recognition that it must reconcile the harms of past policies towards Indigenous peoples. This recognition has created a discourse around equity that will shape the landscape in which graduates will practice. In preparing young engineers to navigate technological and social complexity, and to equip them to find personal fulfillment in an uncertain landscape, a reinvigorated emphasis on critical and relational thinking is required. In 2019 and 2020, students in a fourth-year class in Sustainability, (which includes a study of law, policy, and sustainability reporting metrics) participated in multiple group exercises that asked them to explore multiple facets of problematic or politically current issues. These learning activities sought to support a transformative learning experience in which students would come to recognize their ability to contribute as citizens to the development of responsible public policy. In these exercises they examined opposing positions and assessed the strengths, weaknesses, opportunities and risks, associated with each. That there was no RIGHT conclusion was emphasized. The only criteria for assessment was depth of exploration and logical chaining of evidence. Students learned about cultural perspectives from an Indigenous educator, and as they explored the diversity of viewpoints around the question of pipeline expansion in Canada. A final exercise asked students to reflect on the meanings of responsible policy and practice and how they would operationalize sustainability thinking.

Proceedings of the Canadian Engineering Education Association (CEEA)

Applications of machine learning techniques to eDiscovery, information governance, and other related forms of classification and categorization continue to improve in performance and efficiency, but traditional search-based methods of exploration and classification—searches for keywords, key phrases, proximity searches, regular expression searches, and their Boolean combinations—have not disappeared. Part of their persistence lies in their suitability for specialized tasks such as identification of privileged or hot documents. Even in the presence of machine learning techniques to relevance filtering and information governance classification, search-based methods often play a role—as in the initial identification of seed sets used for initial training. In fact, it’s hardly surprising to see search-based methods used to support machine learning techniques and technologically assisted review. In this paper, we look at a way in which statistical techniques can be used to increase search quality, focusing on increasing precision using automated and semi-automated tools to analyze the contexts immediately surrounding search-term matches. Standardly, search quality is assessed at the document level, depending on two properties: whether a document is relevant to the goal of the search and whether the document is returned by the search. Precision—the ratio of relevant documents returned to all documents returned—is a measure of correctness. If we know (or can estimate) the number of relevant documents in the search universe, we can define the corresponding measure of completeness known as recall as the ratio of relevant documents returned to the known or estimated total of relevant documents in the search universe. Büttcher et al. describe a Boolean query designed to address TREC topic 426—a topic created for TREC 1999 involving ‘the use of dogs worldwide for law enforcement purposes’ [1, p. 25]. The proposed query [1, p. 67] takes the form:

From this perspective, the core attribute of PC is the de-linking of volume and cost, while maintaining or improving quality. But there are other valuable perspectives on PC. At first glance, the range of available PC systems and solutions is bewildering. A closer look reveals that the landscape is governed by a small number of structural choices—choices posed by the problems that predictive coding confronts. The goal of this paper is to isolate these structural choices and to show how particular responses to them provide a characterization of both the predictive coding systems themselves and also their range of applications. One justification for this goal is simple: characterizing the structural choices of PC solutions yields a clearer delineation of the range of systems available in principle and a clearer understanding of the different advantages and disadvantages of the particular systems available in the current e-Discovery marketplace. A core reason to focus on the range and compatibility of structural choices rather than particular technologies is that some of the relevant technology components play different structural roles in different structural configuations. A note on terminology: the terms ‘predictive coding’, ‘technology assisted review’ (TAR), and sometimes ‘computer assisted review’ (CAR) are at times conflated. In what follows, we use the term ‘predictive coding’ in a specific sense to denote review systems and protocols in which one or more documents are coded or labeled with review-sensitive information (‘responsive’ (R), ‘non-responsive’ (NR), etc.) without direct document-particular human supervision. (Of course, valuable systems of predictive coding will apply non-individual document coding to many more documents than just one. But we can draw a principled line at a single document.) In contrast, in human linear review—non-predictive coding—every label on every document is supplied through direct human judgment. In this terminology, then, ‘predictive coding’ stands in direct contrast to human linear review. If we take ‘technology assisted review’ and ‘computer assisted review’ in their natural interpretations, these phrases apply to any form of review assisted or aided by technology or computation—including many systems that do not apply any form of predictive coding. (Anyone using MD5 hashes for review deduplication is using TAR/CAR. But they’re not necessarily using PC.)

How is a cricket like a rat? Insights from the application of cybernetics to evasive food protective behaviour

Privacy issues are a growing concern in today’s increasingly connected society. Advances in the capabilities to gather and store information are ever expanding. These advances give rise to questions like what information is being collected, who is collecting and viewing it and how is it being used? Another chapter in this complicated saga of information collection comes from video mining. This new form of data mining gives businesses exciting and innovative opportunities for efficiency. But what does the public think of all these new capabilities? This study attempts to answer these questions by conducting a survey of 807 college-age students and their opinions concerning video mining. An overview of video mining as well as the results from the survey is covered in this paper. A discussion detailing the survey and its goals follows the results. The potential future of video mining is also mentioned along with ways in which researchers and consumers alike can further discuss the issue. INTRODUCTION It seems like every day another story breaks in the news about the government requesting information about individuals from commercial entities for the sake of national security. There is little doubt in the minds of Americans which is more important, national security or someone looking at personal phone records. But what if personal information could be used to enhance the shopping experience and make retail businesses more profitable and efficient? Would consumers be willing to risk their personal privacy for such benefits? Questions such as this one have arisen with a recent advancement in the field of data mining. The advancement comes to society through a video camera lens; just like the lenses used for security purposes in stores all across the world. Video mining is the process of using statistical data software to sift through digital video taken of customers and their behavior. The process of video mining starts when customers and their behaviors are recorded into an anonymous database, usually offsite, through cameras placed in the stores by the owners or video mining companies. Following the recording stage one of two things happens; the recorded material is used by the video mining company that will perform the mining or the owner mines the information them self using purchased software. Next, the 2 Journal of Undergraduate Research at Minnesota State University, Mankato, Vol. 6 [2006], Art. 6 https://cornerstone.lib.mnsu.edu/jur/vol6/iss1/6 recordings are run through data mining software which can present reports based on patterns observed in the recordings. Finally, the information gained can be sold to economists, bankers, and retailers among others. While data mining, which uses only numbers, has been around since the mid 1990’s, video mining, is slightly newer, first being offered around the turn of the century. One reason these two types of “knowledge-discovery” practices are such recent developments is because they require massive amounts of computer storage and processing ability made possible only in the last few years by advances in computing technology. Even though these technologies are so young, many businesses have already begun to tap their potential. Wal-Mart, the world’s largest retailer, was a pioneer when it came to using data mining technologies. As of 2004, a leading video mining company, ShopperTrak RCT, reportedly had over 40,000 cameras in 380 malls and 130 retail clients to boot. While the numbers are staggering, ShopperTrak is not alone; other companies such as Advanced Interfaces Inc.’s aptly named VideoMining unit also sell software and perform video mining services. Some of ShopperTrak’s clientele include well known retailers such as Gap, Banana Republic, Victoria’s Secret, American Eagle Outfitters and PaylessShoe Source. Noting the number of cameras already in use, the CEO of Advanced Interfaces Inc., Rajeev Sharma, says the market for video mining is growing and this is only the beginning. As mentioned before, video mining is a fast growing industry and is of great importance to businesses of all kinds. However, if video mining is so important, why is there an uproar about personal privacy? To answer that question, an understanding of the abilities of video mining must be explored as well as the pros and cons associated with those abilities. Video mining software is able to automatically characterize a customer’s gender, ethnicity and age by using proprietary face detection and pattern recognition software. The software, depending on its individual specifications, can then discern information concerning a vast number of topics of interest to retailers. These topics include how many people enter and exit the store, where they go, what they pick up, what they purchase, how long they are in each part of the store, how long they look at each item and what their intent is based on comparing the previous statistics. Technologies in development allow stores to place cameras that can then provide information from a customer’s facial movement and gestures. There is almost no limit to the type and amount of information video mining can gather regarding a retailer’s customers. 3 Goodmanson et al.: Assessment of the Mankato Area's young Adult Population's Knowled Published by Cornerstone: A Collection of Scholarly and Creative Works for Minnesota State University, Mankato, 2006 The positive aspects of video mining are many. Video mining enables businesses to be more efficient in their practices and to better serve their patrons. More specifically, video mining helps businesses by letting them know when and where to schedule employees, where to place advertisements, where to locate products and how much product to stock, along with many other invaluable efficiency aspects. Customers also benefit by businesses becoming more efficient in this way because the items they want are placed in more convenient locations and the advertisements that concern them are targeted to them, resulting in a more effective shopping experience. Even while the positive aspects of video mining are so obvious, the negative ones cast an ominous shadow. Unlike data mining, video mining gives retailers and other interested parties the unique ability to link faces with information. Currently, those involved with video mining are quick to point out that no humans ever see the recorded video and that only software analyzes the data. They also point out that all recordings are promptly deleted after the mining has taken place. While this may comfort some, critical thinking skills will lead us to suspect that like everything else in today’s digital world, nothing recorded on a computer is truly permanently erased. Furthermore, the statement regarding confidentiality is one made on the honor system. No laws currently govern the use of the data gathered from muted video surveillance by commercial entities. It is here where the personal privacy issues take hold. As with all good things, it is only a matter of time before they are used in a corrupt manner. Rajeev Sharma also points out that in the future it is theoretically possible for retailers to create a sort of personal profile about their patrons by linking personal information from credit cards and other payment sources with the information gathered through video mining. Even more disturbing is the fact that because this information is digital and sent over the Internet, it is susceptible to hacking associated with identity theft. The last issue concerning video mining is rooted in ethics. In the past it has been thought unethical for an employer to monitor its employees without their knowledge. Is it not then unethical for businesses to monitor their customers to this degree without their knowledge or consent? Academia and other research institutions are subject to strict ethical standards when conducting research on human subjects. Why should the business world be able to escape such ethical parameters entirely? There is no legislation concerning this issue either. 4 Journal of Undergraduate Research at Minnesota State University, Mankato, Vol. 6 [2006], Art. 6 https://cornerstone.lib.mnsu.edu/jur/vol6/iss1/6 Currently, there is a plethora of information about data mining and video mining, but there is almost no information concerning the public’s opinions toward the growing use of these technologies and their potentials. In view of the ominous consequences and despite the vast benefits video mining provides, these researchers hypothesize that, “If the public were polled, regarding their thoughts and opinions about video mining, then the majority would be concerned with its use.” This research study addresses this notion to assess the public’s feelings about the subject. RESEARCH In order to test the hypothesis, research was conducted through a survey. The survey contained five short questions concerning public opinion associated with video mining. In order to eliminate redundancy and in order to avoid any other problems with consent, disclaimers were clearly printed at the top asking students who had taken the survey not to take it again and that the survey was optional. Questions were stated on a half sheet of white paper as follows along with a section where students could note any additional comments they may have had: 1. Did you know this occurs? 2. Does this invade the privacy of the consumer? 3. Would you change your shopping habits if the store used video mining? 4. Would you shop at a store that used video mining? 5. Does this marketing technique concern you in any way? Additional Comments: The survey was given to 807 students on the Minnesota State University, Mankato campus. Surveys were given to students in classes with different curriculums such as music, biology and sociology among others. The classes were for the most part introductory level classes. The process of conducting the survey occurred in the following fashion: A researcher gained permis

Journal of Undergraduate Research at Minnesota State University, Mankato

Assessment of the Mankato Area's young Adult Population's Knowledge of Mall Video Mining for Marketing Research

Formaldehyde was analyzed by vibrational self-consistent field (VSCF) calculations at two different levels of theory, Hartree-Fock (HF) and Möller-Plesset 2ndOrder Perturbation Theory (MP2). The calculations were repeated using three different basis sets, aug-cc-pVnZ, n = 2 − 4. Convergence was observed for the VSCF-PT2 (MP2) frequencies for each of the six normal modes of vibration as the basis set was expanded. There was also good agreement between VSCF-PT2 calculated frequencies and experimental values for frequencies of the modes. The chemical shielding constants were calculated using NMR calculations based on the coordinates at 16 different displacements along the vibrational motions for each of the modes. The average chemical shielding values for each mode were determined using the chemical shielding values at the 16 different displacements from equilibrium and the values of the wavefunctions of the modes of vibration at each different displacement. Another NMR calculation was

QUANTUM CHEMICAL CALCULATIONS APPLIED TO SOMO-HOMO CONVERSION AND VIBRATIONALLY AVERAGED NMR SHIELDING PARAMETERS

Transmission electron microscopy (TEM) is used to study growth of MoS2 nanocrystals in situ. The nanocrystals are formed from a submonolayer molybdenum oxide dispersed on an oxide support by sulfidation in an H2S/H2 atmosphere. From series of time-resolved TEM images, it is revealed that single-layer MoS2 nanocrystals form preferentially and that multi-layer nanocrystals form late in the sulfidation process. The TEM images pinpoint that step sites in the support can act as nucleation centers for single-layer nanocrystals and that single-layer nanocrystals grow along the support surface. Moreover, the TEM images reveal that multi-layer MoS2 nanocrystals form in a layer-by-layer mode by the homogeneous nucleation of additional MoS2 layers onto already formed single-layer MoS2 nanocrystals. Hereby, the atomic-scale observations suggest that the formation of multi-layer MoS2 nanocrystals is an energetically more activated process than growth of single-layers. These findings explain why process parameters, suc...

A library of gemini surfactants is employed to study surfactant directed anisotropic growth of gold nanoparticles. The surfactants are modified with respect to the length and type of the tails, as well as of the spacer group. By analyzing the structure of the anisotropic nanoparticles, it is possible to extract information on how the structure of the surfactants influences the anisotropic gold nanocrystal growth. We find that the tail length of the surfactants has a greater influence on the resulting nanoparticle aspect ratio compared to the chemical nature of the spacer group. While clear trends between the aspect ratio and the tail as well as spacer length remain elusive, we observe that surfactants with a critical micelle concentration of similar to 1 mM produce particles with the highest aspect ratio. A crystallographic analysis of nanorods obtained using gemini surfactants reveals that they grow along 100 and are bound by {310} facets. This observation, which is specific for gemini surfactants, is explained by taking into account the preferential alignment of gemini surfactants with surface steps as suggested by electronic structure calculations.

Additional Article Notification: Anisotropic growth of gold nanoparticles using cationic gemini surfactants: effects of structure variations in head and tail groups

1. Haldor Topsøe A/S, Nymøllevej 55, DK-2800 Kgs. Lyngby, Denmark. 2. Nano-Science Center, Niels Bohr Institute, Universitetsparken 5, DK-2100, Copenhagen, Denmark. 3. SuperSTEM Laboratory, STFC Daresbury, Keckwick Lane, Daresbury WA4 4AD, United Kingdom 4. Lawrence Berkeley National Laboratory, National Center for Electron Microscopy and Joint Center for Artificial Photosynthesis, Berkeley CA 94708, United States of America.

Electron Microscopy Studies of Structure and Dynamics in MoS2-based Hydrodesulfurization Catalysts

A library of gemini surfactants is employed to study surfactant directed anisotropic growth of gold nanoparticles. The surfactants are modified with respect to the length and type of the tails, as well as of the spacer group. By analyzing the structure of the anisotropic nanoparticles, it is possible to extract information on how the structure of the surfactants influences the anisotropic gold nanocrystal growth. We find that the tail length of the surfactants has a greater influence on the resulting nanoparticle aspect ratio compared to the chemical nature of the spacer group. While clear trends between the aspect ratio and the tail as well as spacer length remain elusive, we observe that surfactants with a critical micelle concentration of ∼1 mM produce particles with the highest aspect ratio. A crystallographic analysis of nanorods obtained using gemini surfactants reveals that they grow along 〈100〉 and are bound by {310} facets. This observation, which is specific for gemini surfactants, is explained by taking into account the preferential alignment of gemini surfactants with surface steps as suggested by electronic structure calculations.

Anisotropic growth of gold nanoparticles using cationic gemini surfactants: effects of structure variations in head and tail groups

Department of Physics, Chemistry and Pha (SDU), Campusvej 55 DK-5230 Odense M Fax: +45-6615 8760; Tel: +45-6550 3529 Department of Chemical Engineering, Biote University of Southern Denmark (SDU), N Denmark Nano Science Center, Niels Bohr I Universitetsparken 5, Copenhagen 2100, De † Electronic supplementary informati experimental procedures, the growth m detailed XPS analysis are given along images. See DOI: 10.1039/c3ta10238f Cite this: J. Mater. Chem. A, 2013, 1, 6030

A robust catalyst support is pivotal to Proton Exchange Membrane Fuel Cells (PEMFCs) to overcome challenges such as catalyst support corrosion, low catalyst utilization and overall capital cost. SiC is a promising candidate material which could be applied as a catalyst support in PEMFCs. SiC nanocrystals are here synthesized using nano-porous carbon black (Vulcan® XC-72) as a template using two different reactions, which result in particle sizes in the ranges of 50–150 nm (SiC-SPR) and 25–35 nm (SiC-NS). Pt nano-catalysts of size 5–8 nm and 4–5 nm have successfully been uniformly deposited on the nanocrystals of SiC-SPR and SiC-NS by the polyol method. The SiC substrates are subjected to an acid treatment to introduce the surface groups, which help to anchor the Pt nano-catalysts. These SiC based catalysts have been found to have a higher electrochemical activity than commercially available Vulcan based catalysts (BASF & HISPEC). These promising results signal a new era of SiC based catalysts for fuel cell applications.

SiC nanocrystals as Pt catalyst supports for fuel cell applications

Supporting Information SiC nanocrystals as Pt catalyst supports for fuel cell applications

Structure–activity relationships of Pt/Al2O3 catalysts for CO and NO oxidation at diesel exhaust conditions

Innentitelbild: Atomic‐Scale Edge Structures on Industrial‐Style MoS2 Nanocatalysts (Angew. Chem. 43/2011)

The anisotropic, layered structure of graphite is encountered in a variety of complex compound materials such as the transition metal disulfides MS2 (M=Mo, W). These compounds consist of S-M-S layers with covalent intralayer bonds and with a weak van der Waals interlayer interaction. Like graphene, such S-M-S layers have within the last two decades been found to form numerous of nanoscale polymorfs (including fullerene-like structures, nanotubes/wires and platelets), each with unique physico-chemical properties significantly different from the corresponding bulk materials [1]. Here, we focus on planar, single-layer MoS2 nanoparticles, which is of broad, current interest as catalyst for the industrial oil refining, hydrogen evolution and photo-oxidation.

Contribution (Oral/Poster/Keynote) Single-atom sensitive imaging of two-dimensional MoS2 nanoparticles

Atomic-scale edge structures on industrial-style MoS2 nanocatalysts.

Inside Cover: Atomic‐Scale Edge Structures on Industrial‐Style MoS2 Nanocatalysts (Angew. Chem. Int. Ed. 43/2011)

Introduction The awareness of soot abatement in the exhaust from diesel engines is currently increasing due to new environmental legislations for exhaust specifications. An attractive approach for effective soot removal includes the introduction of filters on the diesel-driven vehicles and the functionalization of the filters for catalytic soot oxidation (1,2). Ceria-based materials are widely adopted for this purpose. It is generally accepted that the redox properties of ceria are crucial to the catalytic effect, but the detailed reaction mechanism and the location of the catalytic active sites are still being debated. For instance, it has been proposed that the reaction occurs at the soot-ceria interface (3) and that the reaction occurs through spill-over of oxygen from ceria to reaction centers located at the soot surfaces (2-4). Averaging techniques, such as temperature-programmed oxidation and thermo-gravimetric analysis, have mainly been used to study the soot oxidation reaction, e.g. (2-5). Although these studies provide significant insight, previous work on metal-catalyzed gasification of graphite suggests that environmental transmission electron microscopy (ETEM) may be a beneficial complement, because the technique allows direct observations at the carbon-catalyst interface to be obtained in situ during reaction (6). In this contribution we present an ETEM study of the reaction mechanisms and kinetics involved in ceria-catalyzed soot oxidation related to diesel engine emission control (7).

In situ TEM studies of catalysts for diesel engine exhaust abatement

Gold nanorods (AuNRs) are of interest for a wide range of applications, ranging from imaging to molecular electronics, and they have been studied extensively for the past decade. An important issue in AuNR applications is the ability to self-assemble the rods in predictable structures on the nanoscale. We here present a new way to end-to-end link AuNRs with a single or few linker molecules. Whereas methods reported in the literature so far rely on modification of the AuNRs after the synthesis, we here dimerize gold nanoparticle seeds with a water-soluble dithiol-functionalized polyethylene glycol linker and expose the linked seeds to growth conditions identical to the synthesis of unlinked AuNRs. Doing so, we obtain a large fraction of end-to-end linked rods, and transmission electron microscopy provides evidence of a 1-2 nm wide gap between the AuNRs. Flow linear dichroism demonstrates that a large fraction of the rods are flexible around the hinging molecule in solution, as expected for a molecularly linked nanogap. By using excess of gold nanoparticles relative to the linking dithiol molecule, this method can provide a high probability that a single molecule is connecting the two rods. In essence, our methods hence demonstrate the fabrication of a nanostructure with a molecule connected to two nanoelectrodes by bottom-up chemical assembly.

Self-assembled nanogaps via seed-mediated growth of end-to-end linked gold nanorods.

Catalytic soot oxidation studied by Environmental Transmission Electron Microscopy

Direct Observations of Ceo2-Catalyzed Soot Oxidation at the Nano-Scale Using Environmental Transmission Electron Microscopy

The invention relates to a photovoltaic module (1) comprising at least two photovoltaic cells (7, 7 ') in series, each cell (7, 7') respectively comprising a rectangular first back electrode film (5, 5 '), photovoitaique a stack of at least two active materials (3) between the rear electrode (5) and a transparent conductive electrode (CT) in a thin layer (4), said TC electrode (4, 4 ') being adapted to collect and transmitting an electric current (10, 10 ') generated by the photovoltaic stack (3, 3'), the two photocells (7, 7 ') being electrically connected in series by an electrical contact strip (6) included TC between the electrode (4) of the first cell (7) and the back electrode (5 ') of the second cell (7'). According to the invention, the local thickness (e) of the electrode TC (4) of the cell (7) varies with the distance to the electrical contact strip (6). The invention also relates to deposition methods and etching the transparent conductive layer (TC) for producing simultaneously a plurality of cells (7, 7 ', 7 "...) of a same module (1).

Photovoltaic module comprising a transparent conductive electrode of variable thickness and processes for manufacturing such a module

Mobile devices are subject to an increased attack surface vector as compared to desktop computing, due to the nature of sensors, radios, and increased peripherals. We investigate in this work mobile botnets with a specific focus on Android, which is the most widely adopted mobile platform, and a prime target for malicious software, 79% of reported malware threats to mobile operating systems are targeted at Android. Our analysis focuses on a short messaging service (SMS) botnet structure and investigates a new detection model using the concept of intents. We show that transparent control can be achieved by a remote endpoint, yet also detected by our proposed intent detection model. Intents are late run-time bindings mechanisms provided to applications in the Android operating system. Intents provide a clear and accurate picture of device behaviour with external sources, due to their design as a late run time binding mechanism in the Android Operating System. We propose an intent logging system to capture sample data, and use this as the basis to design and evaluate our proposed detection scheme.

2015 IEEE 34th Symposium on Reliable Distributed Systems Workshop (SRDSW)

SMS Botnet Detection for Android Devices through Intent Capture and Modeling

Aging is characterized by declining health that results in decreased neuromuscular function and cellular resilience. The relationship between lifespan and health, and the influence of genetic background on that relationship, has important implications in the development of anti-aging interventions. Here we combined survival under thermal and oxidative stress with swimming performance, to evaluate health effects across a nematode genetic diversity panel for three compounds previously studied in the Caenorhabditis Intervention Testing Program – NP1, propyl gallate, and resveratrol. We show that oxidative stress resistance and thermotolerance vary with compound intervention, genetic background, and age. The effects of tested compounds on swimming locomotion, in contrast, are largely species-specific. Additionally, thermotolerance, but not oxidative stress or swimming ability, correlates with lifespan. Our results demonstrate the importance of assessing health and lifespan across genetic backgrounds in the effort to identify reproducible aging interventions.

The coupling between healthspan and lifespan in Caenorhabditis depends on complex interactions between compound intervention and genetic background

The Caenorhabditis Intervention Testing Program (CITP) is an NIH-funded research consortium of investigators who conduct analyses at three independent sites to identify chemical interventions that reproducibly promote health and lifespan in a robust manner. The founding principle of the CITP is that compounds with positive effects across a genetically diverse panel of Caenorhabditis species and strains are likely engaging conserved biochemical pathways to exert their effects. As such, interventions that are broadly efficacious might be considered prominent compounds for translation for pre-clinical research and human clinical applications. Here, we report results generated using a recently streamlined pipeline approach for the evaluation of the effects of chemical compounds on lifespan and health. We studied five compounds previously shown to extend C. elegans lifespan or thought to promote mammalian health: 17α-estradiol, acarbose, green tea extract, nordihydroguaiaretic acid, and rapamycin. We found that green tea extract and nordihydroguaiaretic acid extend Caenorhabditis lifespan in a species-specific manner. Additionally, these two antioxidants conferred assay-specific effects in some studies—for example, decreasing survival for certain genetic backgrounds in manual survival assays in contrast with extended lifespan as assayed using automated C. elegans Lifespan Machines. We also observed that GTE and NDGA impact on older adult mobility capacity is dependent on genetic background, and that GTE reduces oxidative stress resistance in some Caenorhabditis strains. Overall, our analysis of the five compounds supports the general idea that genetic background and assay type can influence lifespan and health effects of compounds, and underscores that lifespan and health can be uncoupled by chemical interventions.

Antioxidants green tea extract and nordihydroguaiaretic acid confer species and strain specific lifespan and health effects in Caenorhabditis nematodes

The genetic manipulability and short lifespan of C. elegans make it an important model for aging research. Widely applied methods for measurements of worm aging based on manual observation are labor intensive and low-throughput. Here, we describe the Worm Collective Activity Monitoring Platform (WormCamp), a system for assaying aging in C. elegans by monitoring activity of populations of worms in standard 24-well plates. We show that metrics based on the rate of decline in collective activity can be used to estimate the average lifespan and locomotor healthspan in the population. Using the WormCamp, we assay a panel of highly divergent natural isolates of C. elegans and show that both lifespan and locomotor healthspan display substantial heritability. To facilitate analysis of large numbers of worms, we developed a robotic imaging system capable of simultaneous automated monitoring of activity, lifespan, and locomotor healthspan in up to 2,304 populations containing a total of ~90,000 animals. We applied the automated system to conduct a large-scale RNA interference screen for genes that affect lifespan and locomotor healthspan. The WormCamp system is complementary to other current automated methods for assessing C. elegans aging and is well suited for efficiently screening large numbers of conditions.

High-throughput imaging of Caenorhabditis elegans aging using collective activity monitoring

Metformin, the most commonly prescribed anti-diabetes medication, has multiple reported health benefits, including lowering the risks of cardiovascular disease and cancer, improving cognitive function with age, extending survival in diabetic patients, and, in several animal models, promoting youthful physiology and lifespan. Due to its longevity and health effects, metformin is now the focus of the first proposed clinical trial of an anti-aging drug-the Targeting Aging with Metformin (TAME) program. Genetic variation will likely influence outcomes when studying metformin health effects in human populations. To test for metformin impact in diverse genetic backgrounds, we measured lifespan and healthspan effects of metformin treatment in three Caenorhabditis species representing genetic variability greater than that between mice and humans. We show that metformin increases median survival in three C. elegans strains, but not in C. briggsae and C. tropicalis strains. In C. briggsae, metformin either has no impact on survival or decreases lifespan. In C. tropicalis, metformin decreases median survival in a dose-dependent manner. We show that metformin prolongs the period of youthful vigor in all C. elegans strains and in two C. briggsae strains, but that metformin has a negative impact on the locomotion of C. tropicalis strains. Our data demonstrate that metformin can be a robust promoter of healthy aging across different genetic backgrounds, but that genetic variation can determine whether metformin has positive, neutral, or negative lifespan/healthspan impact. These results underscore the importance of tailoring treatment to individuals when testing for metformin health benefits in diverse human populations.

Metformin treatment of diverse Caenorhabditis species reveals the importance of genetic background in longevity and healthspan extension outcomes.

Caenorhabditis elegans (C. elegans) lifespan assays constitute a broadly used approach for investigating the fundamental biology of longevity. Traditional C. elegans lifespan assays require labor-intensive microscopic monitoring of individual animals to evaluate life/death over a period of weeks, making large-scale high throughput studies impractical. The lifespan machine developed by Stroustrup et al. (2013) adapted flatbed scanner technologies to contribute a major technical advance in the efficiency of C. elegans survival assays. Introducing a platform in which large portions of a lifespan assay are automated enabled longevity studies of a scope not possible with previous exclusively manual assays and facilitated novel discovery. Still, as initially described, constructing and operating scanner-based lifespan machines requires considerable effort and expertise. Here we report on design modifications that simplify construction, decrease cost, eliminate certain mechanical failures, and decrease assay workload requirements. The modifications we document should make the lifespan machine more accessible to interested laboratories.

creatine analog β-guanidinopropionic acid does not extend lifespan in nematodes Anna L Coleman-Hulbert, Erik Johnson, Christine A Sedore, Stephen A Banse, Max Guo, Monica Driscoll, Gordon J Lithgow and Patrick C Phillips 1Institute of Ecology and Evolution, University of Oregon, Eugene, Oregon 97403, USA 2Division of Aging Biology, National Institute on Aging, Bethesda, Maryland 20892, USA 3Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854, USA 4The Buck Institute for Research on Aging, Novato, California 94945, USA §Correspondence to: Patrick C Phillips (pphil@uoregon.edu (mailto:pphil@uoregon.edu))

Caenorhabditis Intervention Testing Program: the creatine analog β-guanidinopropionic acid does not extend lifespan in nematodes

Caenorhabditis Intervention Testing Program: the tyrosine kinase inhibitor imatinib mesylate does not extend lifespan in nematodes Anna L. Coleman-Hulbert, Erik Johnson, Christine A. Sedore, Stephen A. Banse, Max Guo, Monica Driscoll, Gordon J. Lithgow, and Patrick C. Phillips 1. Institute of Ecology and Evolution, University of Oregon, Eugene, Oregon 97403, USA 2. Division of Aging Biology, National Institute on Aging, Bethesda, Maryland 20892, USA 3. Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854, USA 4. The Buck Institute for Research on Aging, Novato, California 94945, USA *Contributed equally to this work §Correspondence to: Patrick C. Phillips (pphil@uoregon.edu)

Caenorhabditis Intervention Testing Program: the tyrosine kinase inhibitor imatinib mesylate does not extend lifespan in nematodes

A large close relative of C. elegans is slow-developing but not long-lived

Impact of genetic background and experimental reproducibility on identifying chemical compounds with robust longevity effects

Cost-effective selective deuteration of aromatic amino acid residues produces long-lived solution 1H NMR magnetization in proteins.

Elucidating the role of the gut microbiota in the physiological effects of dietary fiber

Advances in the separation of gangliosides by counter-current chromatography (CCC).

Dietary phosphatidylcholine supplementation reduces atherosclerosis in Ldlr-/- male mice2.

Objectives: In parenteral nutrition-dependent infants and children, intestinal failure (IF)-associated liver disease (IFALD) remains an important problem. A comparative study was undertaken of parenteral mixed lipid (ML), &ohgr;-3 predominant fish oil (FO), and &ohgr;-6 predominant soybean oil (SO) emulsions in regards to hepatic phytosterol, neutral lipid, fatty acid (FA) content, and the relationship to cholestasis in piglets. Methods: Neonatal piglets received parenteral nutrition, varying in lipid dose (5 or 10 g· kg−1 · day−1) and formulation: SO5 (n = 5), SO10 (n = 5), FO5 (n = 5), and ML10 (n = 5). On day 14, liver chemistry, bile flow, histology and neutral lipid staining were assessed. Hepatic triglyceride FA content was determined using thin layer and gas chromatography, and phytosterol content was assessed using gas chromatography-mass spectrometry. Results: SO groups had higher prevalence of biochemical cholestasis (P < 0.04) and lower bile flow (P < 0.0001). Hepatic campesterol, stigmasterol, and &bgr;-sitosterol were highest in SO10 (P < 0.0001). Hepatic FA (P < 0.03) and &ohgr;-6/&ohgr;-3 FA ratio (P < 0.0001) were higher in the SO groups. Neutral lipid accumulation (P = 0.3) and liver histology (P = 0.16) were not different between groups. Univariate predictors of bile flow were: campesterol (r = −0.77, P = 0.001), &bgr;-sitosterol (r = −0.74, P = 0.002), stigmasterol (r = −0.74, P = 0.002), &ohgr;-6 FA (r = −0.72, P = 0.002), and &ohgr;-3 FA (r = 0.59, P = 0.02). Only campesterol independently predicted bile flow. Conclusions: ML and FO lipid emulsions reduce cholestasis in association with lowered hepatic phytosterol and lipid content. Lower hepatic phytosterol and &ohgr;-6 FA content, and higher &ohgr;-3 FA content are hepatoprotective. Multivariate analysis suggests reduced phytosterol accumulation may best explain the hepatoprotective effect of fish oil-containing lipids.

Mixed Lipid, Fish Oil, and Soybean Oil Parenteral Lipids Impact Cholestasis, Hepatic Phytosterol, and Lipid Composition

Choline, an essential nutrient, is required for cell membranes, lipoprotein secretion, and methyl-group metabolism. Recently, it has been proposed that excess dietary choline consumption is metabolized to trimethylamine (TMA) by the gut microbiota; TMA is then oxidized to trimethylamine N-oxide (TMAO) in the liver. Epidemiological studies have clearly shown a positive correlation between plasma TMAO concentrations and cardiovascular events. Furthermore, some studies have shown an association between excess dietary choline, plasma TMAO concentrations, and atherosclerotic lesion size in apoE knockout (Apoe-/-) mice.

OBJECTIVE
The aim of this study was to further investigate the relation between dietary choline and atherosclerosis in 2 atherogenic mouse models, the LDL receptor knockout (Ldlr-/-) and Apoe-/- mice.

METHODS
Six feeding trials were performed in Ldlr-/- (40% high-fat diet) and Apoe-/- (unpurified diet) male mice, aged 8-10 wk. Mice randomly received control diet (0.1% choline), or choline- (1% choline), betaine- (0.1% choline and 0.9% betaine), or TMAO- (0.1% choline and 0.12% or 0.2% TMAO) supplemented diet for ≤28 wk. After the dietary intervention, the animals were killed and tissues and blood collected. Aortic atherosclerotic plaque area, plasma lipids, and choline metabolites were quantified.

RESULTS
In Ldlr-/- mice, dietary supplementation for 8 wk with choline or TMAO increased plasma TMAO concentrations by 1.6- and 4-fold, respectively. After 16 wk, there was a 2-fold increase in plasma TMAO after dietary TMAO supplementation. In Apoe-/- mice, dietary supplementation with choline, betaine, or TMAO for 12 wk did not increase plasma TMAO concentrations. However, choline and TMAO supplementation for 28 wk significantly increased plasma TMAO concentrations by 1.8- and 1.5-fold, respectively. Contrary to predictions, atherosclerotic lesion size was not altered by any of the dietary interventions, irrespective of mouse model.

In our study, high intakes of dietary choline or TMAO supplementation did not influence atherosclerosis development in Ldlr-/- or Apoe-/- male mice.

Dietary Choline or Trimethylamine N-oxide Supplementation Does Not Influence Atherosclerosis Development in Ldlr-/- and Apoe-/- Male Mice.

Autotaxin catalyzes the formation of lysophosphatidic acid, which stimulates tumor growth and metastasis and decreases the effectiveness of cancer therapies. In breast cancer, autotaxin is secreted mainly by breast adipocytes, especially when stimulated by inflammatory cytokines produced by tumors. In this work, we studied the effects of an ATX inhibitor, GLPG1690, which is in phase III clinical trials for idiopathic pulmonary fibrosis, on responses to radiotherapy and chemotherapy in a syngeneic orthotopic mouse model of breast cancer. Tumors were treated with fractionated external beam irradiation, which was optimized to decrease tumor weight by approximately 80%. Mice were also dosed twice daily with GLPG1690 or vehicle beginning at 1 day before the radiation until 4 days after radiation was completed. GLPG1690 combined with irradiation did not decrease tumor growth further compared with radiation alone. However, GLPG1690 decreased the uptake of 3′-deoxy-3′-[18F]-fluorothymidine by tumors and the percentage of Ki67-positive cells. This was also associated with increased cleaved caspase-3 and decreased Bcl-2 levels in these tumors. GLPG1690 decreased irradiation-induced C-C motif chemokine ligand-11 in tumors and levels of IL9, IL12p40, macrophage colony-stimulating factor, and IFNγ in adipose tissue adjacent to the tumor. In other experiments, mice were treated with doxorubicin every 2 days after the tumors developed. GLPG1690 acted synergistically with doxorubicin to decrease tumor growth and the percentage of Ki67-positive cells. GLPG1690 also increased 4-hydroxynonenal-protein adducts in these tumors. These results indicate that inhibiting ATX provides a promising adjuvant to improve the outcomes of radiotherapy and chemotherapy for breast cancer.

Inhibition of Autotaxin with GLPG1690 Increases the Efficacy of Radiotherapy and Chemotherapy in a Mouse Model of Breast Cancer

Phosphatidylethanolamine N‐methyltransferase (PEMT) is an important enzyme in hepatic phosphatidylcholine (PC) biosynthesis. Pemt−/− mice fed a high‐fat diet are protected from obesity and whole‐body insulin resistance. However, Pemt−/− mice develop severe nonalcoholic steatohepatitis (NASH). Because NASH is often associated with hepatic insulin resistance, we investigated whether the increased insulin sensitivity in Pemt−/− mice was restricted to nonhepatic tissues or whether the liver was also insulin sensitive. Strikingly, the livers of Pemt−/− mice compared with those of Pemt+/+ mice were not insulin resistant, despite elevated levels of hepatic triacylglycerols and diacylglycerols, as well as increased hepatic inflammation and fibrosis. Endogenous glucose production was lower in Pemt−/− mice under both basal and hyperinsulinemic conditions. Experiments in primary hepatocytes and hepatoma cells revealed improved insulin signaling in the absence of PEMT, which was not due to changes in diacylglycerols, ceramides, or gangliosides. On the other hand, the phospholipid composition in hepatocytes seems critically important for insulin signaling such that lowering the PC:phosphatidylethanolamine (PE) ratio improves insulin signaling. Thus, treatments to reduce the PC:PE ratio in liver may protect against the development of hepatic insulin resistance.—Van der Veen, J. N., Lingrell, S., McCloskey, N., LeBlond, N. D., Galleguillos, D., Zhao, Y. Y., Curtis, J. M., Sipione, S., Fullerton, M. D., Vance, D. E., Jacobs, R. L. A role for phosphatidylcholine and phosphatidylethanolamine in hepatic insulin signaling. FASEB J. 33, 5045–5057 (2019). www.fasebj.org

A role for phosphatidylcholine and phosphatidylethanolamine in hepatic insulin signaling

Breast cancer patients are usually treated with multiple fractions of radiotherapy (RT) to the whole breast after lumpectomy. We hypothesized that repeated fractions of RT would progressively activate the autotaxin–lysophosphatidate-inflammatory cycle. To test this, a normal breast fat pad and a fat pad containing a mouse 4T1 tumor were irradiated with X-rays using a small-animal “image-guided” RT platform. A single RT dose of 7.5 Gy and three daily doses of 7.5 Gy increased ATX activity and decreased plasma adiponectin concentrations. The concentrations of IL-6 and TNFα in plasma and of VEGF, G-CSF, CCL11 and CXCL10 in the irradiated fat pad were increased, but only after three fractions of RT. In 4T1 breast tumor-bearing mice, three fractions of 7.5 Gy augmented tumor-induced increases in plasma ATX activity and decreased adiponectin levels in the tumor-associated mammary fat pad. There were also increased expressions of multiple inflammatory mediators in the tumor-associated mammary fat pad and in tumors, which was accompanied by increased infiltration of CD45+ leukocytes into tumor-associated adipose tissue. This work provides novel evidence that increased ATX production is an early response to RT and that repeated fractions of RT activate the autotaxin–lysophosphatidate-inflammatory cycle. This wound healing response to RT-induced damage could decrease the efficacy of further fractions of RT.

Repeated Fractions of X-Radiation to the Breast Fat Pads of Mice Augment Activation of the Autotaxin-Lysophosphatidate-Inflammatory Cycle

A309 EFFECT OF MIXED LIPID, ω-3 FISH OIL AND ω-6 SOYBEAN OIL PARENTERAL LIPID EMULSIONS ON LIVER DISEASE, HEPATIC LIPID AND PHYTOSTEROL COMPOSITION IN NEONATAL PIGLETS.

Lysophosphatidate (LPA) signaling through 6 receptors is regulated by the balance of LPA production by autotaxin (ATX) vs. LPA degradation by lipid phosphate phosphatases (LPPs). LPA promotes an inflammatory cycle by increasing the synthesis of cyclooxygenase‐2 and multiple inflammatory cytokines that stimulate further ATX production. We aimed to determine whether the anti‐inflammatory glucocorticoid (GC) dexamethasone (Dex) functions partly by decreasing the ATX–LPA inflammatory cycle in adipose tissue, a major site of ATX secretion. Treatment of human adipose tissue with 10–1000 nM Dex decreased ATX secretion, increased LPP1 expression, and decreased mRNA expressions of IL‐6, TNF‐α, peroxisome proliferator‐activated receptor (PPAR)‐γ, and adiponectin. Cotreatment with rosiglitazone (an insulin sensitizer), insulin, or both abolished Dex‐induced decreases in ATX and adiponectin secretion, but did not reverse Dex‐induced decreases in secretions of 20 inflammatory cytokines and chemokines. Dex‐treated mice exhibited lower ATX activity in plasma, brain, and adipose tissue; decreased mRNA levels for LPA and sphingosine 1‐phosphate (S1P) receptors in brain; and decreased plasma concentrations of LPA and S1P. Our results establish a novel mechanism for the anti‐inflammatory effects of Dex through decreased signaling by the ATX‐LPA‐inflammatory axis. The GC action in adipose tissue has implications for the pathogenesis of insulin resistance and obesity in metabolic syndrome and breast cancer treatment.—Meng, G., Tang, X., Yang, Z., Zhao, Y., Curtis, J. M., McMullen, T. P. W., Brindley, D. N. Dexamethasone decreases the autotaxin‐lysophosphatidate‐inflammatory axis in adipose tissue: implications for the metabolic syndrome and breast cancer. FASEB J. 33, 1899‐1910 (2019). www.fasebj.org

Dexamethasone decreases the autotaxin‐lysophosphatidate‐inflammatory axis in adipose tissue: implications for the metabolic syndrome and breast cancer

Doxorubicin is a widely used chemotherapeutic with deleterious cardiotoxic side effects. HDL has been shown to protect cardiomyocytes in vitro against doxorubicin-induced apoptosis. Scavenger receptor class B type 1 (SR-B1), a high-affinity HDL receptor, mediates cytoprotective signaling by HDL through Akt. Here, we assessed whether increased HDL levels protect against doxorubicin-induced cardiotoxicity in vivo and in cardiomyocytes in culture and explored the intracellular signaling mechanisms involved, particularly the role of SR-B1. Transgenic mice with increased HDL levels through overexpression of human apolipoprotein A1 (apoA1Tg/Tg) and wild-type mice (apoA1+/+) with normal HDL levels were treated repeatedly with doxorubicin. After treatment, apoA1+/+ mice displayed cardiac dysfunction, as evidenced by reduced left ventricular end-systolic pressure and +dP/d t, and histological analysis revealed cardiomyocyte atrophy and increased cardiomyocyte apoptosis after doxorubicin treatment. In contrast, apoA1Tg/Tg mice were protected against doxorubicin-induced cardiac dysfunction and cardiomyocyte atrophy and apoptosis. When SR-B1 was knocked out, however, overexpression of apoA1 did not protect against doxorubicin-induced cardiotoxicity. Using primary neonatal mouse cardiomyocytes and human immortalized ventricular cardiomyocytes in combination with genetic knockout, inhibitors, or siRNA-mediated knockdown, we demonstrated that SR-B1 is required for HDL-mediated protection of cardiomyocytes against doxorubicin-induced apoptosis in vitro via a pathway involving phosphatidylinositol 3-kinase and Akt1/2. Our findings provide proof of concept that raising apoA1 to supraphysiological levels can dramatically protect against doxorubicin-induced cardiotoxicity via a pathway that is mediated by SR-B1 and involves Akt1/2 activation in cardiomyocytes. NEW & NOTEWORTHY We have identified an important role for the scavenger receptor class B type 1 in facilitating high-density lipoprotein-mediated protection of cardiomyocytes against stress-induced apoptosis and shown that increasing plasma high-density lipoprotein protects against the deleterious side effects of the chemotherapeutic and cardiotoxic drug doxorubicin.

HDL protects against doxorubicin-induced cardiotoxicity in a scavenger receptor class B type 1-, PI3K-, and Akt-dependent manner.

Doxycycline attenuates breast cancer related inflammation by decreasing plasma lysophosphatidate concentrations and inhibiting NF-κB activation

The development of a choline rich cereal based functional food: Effect of processing and storage

A method was developed that applies hydrophilic interaction liquid chromatography with tandem mass spectrometry in the multiple reaction monitoring mode to separate and accurately quantify trimethylamine and trimethylamine N-oxide in a single chromatographic run. This was achieved by converting trimethylamine to ethyl betaine, which is less volatile and hence results in greatly improved quantitation. Ethyl betaine also gives a similar response to trimethylamine N-oxide using positive-ion electrospray ionization mass spectrometry. It is readily separated from trimethylamine N-oxide by hydrophilic liquid chromatography in a 5 min run and with improved peak shape compared to underivatized trimethylamine. Validation of the method yielded a limit of detection (S/N ≥ 3) of 0.5 ng/mL for trimethylamine and 0.25 ng/mL for trimethylamine N-oxide. Method accuracies of 91.4-105.3% with precisions of 0.4-5.5% were obtained for standard mixtures over the range of 2.5-500 ng/mL. Recoveries measured for the extraction of trimethylamine and trimethylamine N-oxide spikes into mouse plasma were both >90%. The method, which simultaneously measures trimethylamine and trimethylamine N-oxide, was successfully applied to mouse plasma samples and could be adapted for use with other biological fluids.

Simultaneous determination of trimethylamine and trimethylamine N-oxide in mouse plasma samples by hydrophilic interaction liquid chromatography coupled to tandem mass spectrometry.

Additional file 1: of Doxycycline attenuates breast cancer related inflammation by decreasing plasma lysophosphatidate concentrations and inhibiting NF-ÎşB activation

Tetracyclines increase the expression of lipid phosphate phosphatases on plasma membranes and the turnover of plasma lysophosphatidate

Measurement of the total choline content in 48 commercial dairy products or dairy alternatives

Phosphatidylethanolamine N‐methyltransferase (PEMT) is a hepatic enzyme that converts phosphatidylethanolamine into phosphatidylcholine (PC) via three methylation reactions. The PEMT pathway makes 30% of the PC required in the liver and is the only de novo source of choline. PEMT deficient mice are protected against atherosclerosis when bred with either the Ldlr−/− and Apoe−/− mice. PEMT deficiency causes decreased VLDL secretion, plasma LDL levels and homocysteine, which are risk factors for atherosclerosis. Recently, choline supplementation was shown to enhance atherosclerosis in ApoE−/− mice and was dependent on the conversion of choline to trimethylamine (TMA) by the microbial flora in the gut, which was oxidized to trimethylamine N‐oxide (TMAO) by hepatic enzymes. In addition, plasma choline and TMAO have been associated with increased risk of CVD in multiple cohort studies. The purpose of this study was to examine the effects of dietary choline supplementation on plasma TMAO levels, and investigate whether choline supplementation eliminates the atheroprotective effect of PEMT deficiency in LDLR−/− mice

Ldlr−/− Mice Lacking PEMT Have Elevated Plasma Trimethylamine‐oxide Levels But Are Protected From High Fat Diet‐Induced Atherosclerosis.

An LC/MS/MS method for the simultaneous determination of individual sphingolipid species in B cells.

Extracellular lysophosphatidate and sphingosine 1-phosphate (S1P) are important bioactive lipids, which signal through G-protein-coupled receptors to stimulate cell growth and survival. The lysophosphatidate and S1P signals are terminated partly by degradation through three broad-specificity lipid phosphate phosphatases (LPPs) on the cell surface. Significantly, the expression of LPP1 and LPP3 is decreased in many cancers, and this increases the impact of lysophosphatidate and S1P signaling. However, relatively little is known about the physiological or pharmacological regulation of the expression of the different LPPs. We now show that treating several malignant and nonmalignant cell lines with 1 μg/ml tetracycline, doxycycline, or minocycline significantly increased the extracellular degradation of lysophosphatidate. S1P degradation was also increased in cells that expressed high LPP3 activity. These results depended on an increase in the stabilities of the three LPPs and increased expression on the plasma membrane. We tested the physiological significance of these results and showed that treating rats with doxycycline accelerated the clearance of lysophosphatidate, but not S1P, from the circulation. However, administering 100 mg/kg/day doxycycline to mice decreased plasma concentrations of lysophosphatidate and S1P. This study demonstrates a completely new property of tetracyclines in increasing the plasma membrane expression of the LPPs.

Tetracyclines increase lipid phosphate phosphatase expression on plasma membranes and turnover of plasma lysophosphatidate[S]

Autotaxin (ATX) is a secreted enzyme, which produces extracellular lysophosphatidate (LPA) from lysophosphatidylcholine (LPC). LPA activates six G protein-coupled receptors and this is essential for vasculogenesis during embryonic development. ATX is also involved in wound healing and inflammation, and in tumor growth, metastasis, and chemo-resistance. It is, therefore, important to understand how ATX is regulated. It was proposed that ATX activity is inhibited by its product LPA, or a related lipid called sphingosine 1-phosphate (S1P). We now show that this apparent inhibition is ineffective at the high concentrations of LPC that occur in vivo. Instead, feedback regulation by LPA and S1P is mediated by inhibition of ATX expression resulting from phosphatidylinositol-3-kinase activation. Inhibiting ATX activity in mice with ONO-8430506 severely decreased plasma LPA concentrations and increased ATX mRNA in adipose tissue, which is a major site of ATX production. Consequently, the amount of inhibitor-bound ATX protein in the plasma increased. We, therefore, demonstrate the concept that accumulation of LPA in the circulation decreases ATX production. However, this feedback regulation can be overcome by the inflammatory cytokines, TNF-α or interleukin 1β. This enables high LPA and ATX levels to coexist in inflammatory conditions. The results are discussed in terms of ATX regulation in wound healing and cancer.

Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine 1-phosphate[S]

Abstract Epidemiological studies identify meat as a major source of choline; however, the most comprehensive reference for food choline content, the United States Department of Agriculture (USDA) database for dietary choline, does not include values for meats of importance in some regions. In this work, the total choline and choline-containing moieties of 20 samples of meat were analyzed by LC–MS/MS; 16 samples analyzed are absent from the USDA database and 4 samples included for comparison. Average total choline for one serving (75 g) was 50 ± 12 mg, which was 82.6% ± 5.5% phosphatidylcholine. There was general agreement between total choline levels in the meats analyzed in this work and USDA values. A strong negative correlation (r = −0.777, p < 0.001) between total choline and fat content was found. This research added choline composition data to a food group that is a major source of choline and ultimately this data will assist in obtaining more accurate estimates of dietary choline.

Measurement of the abundance of choline and the distribution of choline-containing moieties in meat

Autotaxin is a secreted enzyme that converts extracellular lysophosphatidylcholine to lysophosphatidate (LPA). In cancers, LPA increases tumour growth, metastasis and chemoresistance by activating six G-protein coupled receptors. We examined >200 human thyroid biopsies. Autotaxin expression in metastatic deposits and primary carcinomas was four- to tenfold higher than in benign neoplasms or normal thyroid tissue. Autotaxin immunohistochemical staining was also increased in benign neoplasms with leukocytic infiltrations. Malignant tumours were distinguished from benign tumours by high tumour autotaxin, LPA levels and inflammatory mediators including IL1β, IL6, IL8, GMCSF, TNFα, CCL2, CXCL10 and platelet-derived growth factor (PDGF)-AA. We determined the mechanistic explanation for these results and revealed a vicious regulatory cycle in which LPA increased the secretion of 16 inflammatory modulators in papillary thyroid cancer cultures. Conversely, treating cancer cells with ten inflammatory cytokines and chemokines or PDGF-AA and PDGF-BB increased autotaxin secretion. We confirmed that this autotaxin/inflammatory cycle occurs in two SCID mouse models of papillary thyroid cancer by blocking LPA signalling using the autotaxin inhibitor ONO-8430506. This decreased the levels of 16 inflammatory mediators in the tumours and was accompanied by a 50-60% decrease in tumour volume. This resulted from a decreased mitotic index for the cancer cells and decreased levels of vascular endothelial growth factor and angiogenesis in the tumours. Our results demonstrate that the autotaxin/inflammatory cycle is a focal point for driving malignant thyroid tumour progression and possibly treatment resistance. Inhibiting autotaxin activity provides an effective and novel strategy for decreasing the inflammatory phenotype in thyroid carcinomas, which should complement other treatment modalities.

Autotaxin is an inflammatory mediator and therapeutic target in thyroid cancer.

In this study, the characterization of phospholipids (PL) was achieved by using a combination of LC/MS/MS and two-dimensional LC/MS. A HILIC LC column was used for PL class separation, while the further molecular species separation of each PL class was achieved by using online HILIC × C18 LC. The double bond positions along the fatty acyl chains of these PL molecular species were also obtained by using the combination of 2D-LC and in-line ozonolysis-MS analysis. The ozonolysis device is composed of a gas-permeable, liquid-impermeable Teflon tube passing through a glass chamber filled with ozone gas, which is then placed in-line between the 2D-LC and the mass spectrometer. The eluting PL molecules in the LC mobile phase passed through the device where they rapidly reacted with the ozone that penetrated through the tubing wall. The ozonolysis products were then detected by MS in real-time, which allowed the localization of the double bonds along the fatty acyl chains in these PL molecular species. This comprehensive method was successfully applied to an egg yolk PL extract, which revealed the detailed structures of the PL molecules.

Characterization of phospholipids by two-dimensional liquid chromatography coupled to in-line ozonolysis-mass spectrometry.

Total Choline and Choline-Containing Moieties of Commercially Available Pulses

Lipid phosphate phosphatase-1 (LPP1) degrades lysophosphatidate (LPA) and attenuates receptor-mediated signaling. LPP1 expression is low in many cancer cells and tumors compared with normal tissues. It was hypothesized from studies with cultured cells that increasing LPP1 activity would decrease tumor growth and metastasis. This hypothesis has never been tested in vivo. To do this, we inducibly expressed LPP1 or a catalytically inactive mutant in cancer cells. Expressing active LPP1 increased extracellular LPA degradation by 5-fold. It also decreased the stimulation of Ca2+ transients by LPA, a nondephosphorylatable LPA1/2 receptor agonist and a protease-activated receptor-1 peptide. The latter results demonstrate that LPP1 has effects downstream of receptor activation. Decreased Ca2+ mobilization and Rho activation contributed to the effects of LPP1 in attenuating the LPA-induced migration of MDA-MB-231 breast cancer cells and their growth in 3D culture. Increasing LPP1 expression in breast and thyroid cancer cells decreased tumor growth and the metastasis by up to 80% compared with expression of inactive LPP1 or green fluorescent protein in syngeneic and xenograft mouse models. The present work demonstrates for the first time that increasing the LPP1 activity in three lines of aggressive cancer cells decreases their abilities to produce tumors and metastases in mice.

Lipid phosphate phosphatase-1 expression in cancer cells attenuates tumor growth and metastasis in mice[S]

Performance of two immobilized lipases for interesterification between canola oil and fully-hydrogenated canola oil under supercritical carbon dioxide

Autotaxin is a secreted enzyme that produces most extracellular lysophosphatidate, which stimulates 6 G‐protein‐coupled receptors. Lysophosphatidate promotes cancer cell survival, growth, migration, invasion, metastasis, and resistance to chemotherapy and radiotherapy. The present work investigated whether inhibiting autotaxin could decrease breast tumor growth and metastasis. We used a new autotaxin inhibitor (ONO‐8430506; IC90=100 nM), which decreased plasma autotaxin activity by >60% and concentrations of unsaturated lysophosphatidates by >75% for 24 h compared with vehicle‐treated mice. The effects of ONO‐8430506 on tumor growth were determined in a syngeneic orthotopic mouse model of breast cancer following injection of 20,000 BALB/c mouse 4T1 or 4T1‐12B cancer cells. We show for the first time that inhibiting autotaxin decreases initial tumor growth and subsequent lung metastatic nodules both by 60% compared with vehicle‐treated mice. Significantly, 4T1 cells express negligible autotaxin compared with the mammary fat pad. Autotaxin activity in the fat pad of nontreated mice was increased 2‐fold by tumor growth. Our results emphasize the importance of tumor interaction with its environment and the role of autotaxin in promoting breast cancer growth and metastasis. We also established that autotaxin inhibition could provide a novel therapeutic approach to blocking the adverse effects of lysophosphatidate in cancer.—Benesch, M. G. K., Tang, X., Maeda, T., Ohhata, A., Zhao, Y. Y., Kok, B. P. C., Dewald, J., Hitt, M., Curtis, J. M., McMullen, T. P. W., Brindley, D. N. Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice. FASEB J. 28, 2655–2666 (2014). www.fasebj.org

Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice

Elucidation of phosphatidylcholine isomers using two dimensional liquid chromatography coupled in-line with ozonolysis mass spectrometry.

Characterisation of non-polar dimers formed during thermo-oxidative degradation of β-sitosterol.

A novel method for the identification of conjugated linoleic acid (CLA) isomers has been developed in which silver ion liquid chromatography is coupled to in-line ozonolysis/mass spectrometry (Ag(+)-LC/O3-MS). The mobile phase containing CLA isomers eluting from the Ag(+)-LC column flows through a length of gas-permeable tubing within an ozone rich environment. Ozone penetrating the tubing wall reacts with the conjugated double bonds forming ozonolysis product aldehydes. These, and their corresponding methanol loss fragment ions formed within the atmospheric pressure photoionization (APPI) source, were detected by in-line MS and used for the direct assignment of double bond positions. Assignment of positional isomers is based entirely on the two pairs of diagnostic ions seen in the in-line O3-MS mass spectra. In this way, de novo identification of CLA positional isomers, i.e. without requiring comparison to CLA standards, was achieved. The Ag(+)-LC/O3-MS method was applied to the analysis of CLA isomers in a commercial CLA supplement, milk fat, and the lipid extract from a Lactobacillus plantarum TMW1460 culture. The results demonstrate how Ag(+)-LC/O3-MS can be used for the direct and fast determination of CLA isomers at low concentrations and in complex lipid mixtures.

Identification of conjugated linoleic acid (CLA) isomers by silver ion-liquid chromatography/in-line ozonolysis/mass spectrometry (Ag+-LC/O3-MS).

Lactobacillus hammesii converts linoleic acid into an antifungal hydroxy fatty acid. High speed counter-current chromatography (HSCCC) using a hexane/ethyl acetate/methanol/water solvent system [3.5:1.5:3:2 (v/v/v/v)] allowed isolation of the antifungal hydroxy fatty acid. A method was developed for characterization of antifungal hydroxy fatty acids using normal phase liquid chromatography combined with atmospheric pressure photoionization-tandem mass spectrometry (LC/APPI-MS/MS). The position of unsaturations and hydroxyl groups was determined directly from crude lipid extracts and their hydroxylated derivatives. The antifungal compounds were identified as a racemic mixture of 10-hydroxy-cis-12-octadecenoic and 10-hydroxy-trans-12-octadecenoic acid. Additionally, HSCCC and LC/APPI-MS/MS methods were used to elucidate the pathway of conversion of linoleic acid by Lactobacillus sanfranciscensis , Lactobacillus plantarum , and L. hammesii to hydroxy fatty acids and conjugated linoleic acid. This study links previously reported 10-hydroxy-12-octadecenoic acid producing Lactobacillus strains to antifungal activities.

Antifungal lipids produced by lactobacilli and their structural identification by normal phase LC/atmospheric pressure photoionization−MS/MS.

The development of a capillary microreactor for transesterification reactions using lipase immobilized onto a silica monolith

The direct determination of double bond positions in lipid mixtures by liquid chromatography/in-line ozonolysis/mass spectrometry.

β-Galactosidases (β-Gal) of lactic acid bacteria produce oligosaccharides from lactose when suitable acceptor carbohydrates are present. This study aimed to elucidate the structure of oligosaccharides formed by galactosylation of N-acetylglucosamine (GlcNAc) and fucose. Crude cellular extract of Lactobacillus bulgaricus and LacLM of Lactobacillus plantarum were used as sources of β-Gal activity. Disaccharides obtained by galactosylation of GlcNAc were identified as Gal-β-(1→4)-GlcNAc or Gal-β-(1→6)-GlcNAc by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and comparison with external standards. Trisaccharides were identified as Gal-β-(1→6)-Gal-β-(1→[4 or 6])-GlcNAc by LC-MS, analysis of the MS/MS spectra of selected in-source fragment ions, and their relative retention times. LC-MS analysis revealed the presence of five galactosylated fucosides, but their linkage type could not be identified, partly due to the lack of reference compounds. β-Gal of lactic acid bacteria may serve as suitable tools for the chemoenzymatic synthesis of therapeutic oligosaccharides.

Structural identification of novel oligosaccharides produced by Lactobacillus bulgaricus and Lactobacillus plantarum.

Validation of an LC-MS/MS method for the quantification of choline-related compounds and phospholipids in foods and tissues.

Monitoring the Epoxidation of Canola Oil by Non-aqueous Reversed Phase Liquid Chromatography/Mass Spectrometry for Process Optimization and Control

RATIONALE
The ozonolysis of vegetable oils has been proposed as step to functionalise unsaturated lipids for the production of bio-based chemicals and materials. The observation of ozonolysis products by mass spectrometry will facilitate mechanistic studies that are essential for the further development of industrial processes based on lipid ozonolysis.

METHODS
Ozonolysis of the model lipids methyl oleate and triolein was performed and samples were taken over a range of reaction times. Ozonlysis products were separated by normal and non-aqueous reversed-phase (NARP) liquid chromatography (LC) coupled to electrospray ionization (ESI) mass spectrometry (MS) and tandem mass spectrometry (MS/MS) using a hybrid quadrupole-time of flight instrument. Post-column addition of ammonium acetate solutions aided ionization. Volatile reaction products were observed using gas chromatography/electron impact mass spectrometry (GC/MS).

RESULTS
Secondary ozonides, reaction intermediates and previously unreported high molecular weight product dimers were observed as intact molecular ammonium ion adducts under positive ESI. The main fragment ions obtained by MS/MS were from cleavage of the trioxolane group, loss of fatty acyl chain and fragmentation between n-8 and n-9 on the fatty acyl chain. The MS/MS spectra and exact mass measurements explain most of the ozonolysis reaction products.

LC/MS, LC/MS/MS and GC/MS results demonstrate that the products from the ozonolysis of the model lipids methyl oleate and triolein are consistent with known ozonolysis reaction pathways. LC/MS techniques using non-aqueous chromatography have permitted the direct observation of mono-, di- and tri-1,2,4-triloxanes which are the secondary ozonides formed by the ozonolysis of triolein. It was also shown that intermediates formed during the ozonolysis of triolein can combine to form high molecular weight ozonide dimers.

A study of the ozonolysis of model lipids by electrospray ionization mass spectrometry.

Measurement of phospholipids by hydrophilic interaction liquid chromatography coupled to tandem mass spectrometry: the determination of choline containing compounds in foods.

Sitosterol Thermo-oxidative Degradation Leads to the Formation of Dimers, Trimers and Oligomers: A Study Using Combined Size Exclusion Chromatography/Mass Spectrometry

We report a nanoelectrospray ionization (nESI) with high-field asymmetric waveform ion mobility spectrometry (FAIMS) and tandem mass spectrometry (MS-MS) method for determination of small molecules of m/z 50 to 200 and its potential application in environmental analysis. Integration of nESI with FAIMS and MS-MS combines the advantages of these three techniques into one method. The nESI provides efficient sample introduction and ionization and allows for collection of multiple data from only microliters of samples. The FAIMS provides rapid separation, reduces or eliminates background interference, and improves the signal-to-noise ratio as much as 10-fold over nESI-MS-MS. The tandem quadrupole time-of-flight MS detection provides accurate mass and mass spectral measurements for structural identification. Characteristics of FAIMS compensation voltage (CV) spectra of seven nitrosamines, N-nitrosodimethylamine (NDMA), N-nitrosomethylethylamine (NMEA), N-nitrosodiethylamine (NDEA), N-nitrosodi-n-propylamine (NDPA), N-nitrosodi-n-butylamine (NDBA), N-nitrosopiperidine (NPip), and N-nitrosopyrrolidine (NPyr), were analyzed. The optimal CV of the nitrosamines (at DV -4000 V) were: -1.6 V, NDBA; 2.6 V, NDPA; 6.6 V, NPip; 8.8 V, NDEA; 13.2 V, NPyr; 14.4 V, NMEA; and 19.4 V, NDMA. Fragmentation patterns of the seven nitrosamines in the nESI-FAIMS-MS-MS were also obtained. The specific CV and MS-MS spectra resulted in positive identification of NPyr and NPip in a treated water sample, demonstrating the potential application of this technique in environmental analysis.

Identification of N-nitrosamines in treated drinking water using nanoelectrospray ionization high-field asymmetric waveform ion mobility spectrometry with quadrupole time-of-flight mass spectrometry.

Formation of nine N-nitrosamines has been investigated when seven different source waters representing various qualities were each treated with eleven bench-scale disinfection processes, without addition of nitrosamine precursors. These disinfection treatments included chlorine (OCl-), chloramine (NH2Cl), chlorine dioxide (ClO2), ozone (O3), ultraviolet (UV), advanced oxidation processes (AOP), and combinations. The total organic carbon (TOC) of the seven source waters ranged from 2 to 24 mg x L(-1). The disinfected water samples and the untreated source waters were analyzed for nine nitrosamines using a solid phase extraction and liquid chromatography-tandem mass spectrometry method. Prior to any treatment, N-nitrosodimethylamine (NDMA) was detected ranging from 0 to 53 ng x L(-1) in six of the seven source waters, and its concentrations increased in the disinfected water samples (0-118 ng x L(-1)). N-nitrosodiethylamine (NDEA), N-nitrosomorpholine (NMor), and N-nitrosodiphenylamine (NDPhA) were also identified in some of the disinfected water samples. NDPhA (0.2-0.6 ng x L(-1)) was formed after disinfection with OCl-, NH2Cl, O3, and MPUV/OCl-. NMEA was produced with OCl- and MPUV/OCl-, and NMor formation was associated with O3. In addition, UVtreatment alone degraded NDMA; however, UV/ OCl- and AOP/OCl- treatments produced higher amounts of NDMA compared to UV and AOP alone, respectively. These results suggest that UV degradation or AOP oxidation treatment may provide a source of NDMA precursors. This study demonstrates that environmental concentrations and mixtures of unknown nitrosamine precursors in source waters can form NDMA and other nitrosamines.

Formation of N-nitrosamines from eleven disinfection treatments of seven different surface waters.

N-nitrosodimethylamine (NDMA) was the first nitrosamine identified as a disinfection by-product (DBP); other nitrosamines such as N-nitrosomorpholine (NMor) and N-nitrosopyrrolidine (NPyr) have recently been detected in drinking water and identified as DBPs. However there is little information on the formation and occurrence of non-volatile and thermally unstable nitrosamines because they are not detected by commonly used gas chromatography methods. Here we describe the development of a new solid phase extraction-high performance liquid chromatography-tandem mass spectrometry (SPE-HPLC-MS/MS) method for analysis of both volatile and non-volatile nitrosamines at low ng.L -1 concentrations. This method has successfully detected a non-volatile nitrosamine DBP (N-nitrosodiphenylamine) in a drinking water distribution system and was used to study nitrosamine formation when source waters of various qualities were disinfected by eleven different processes.

Analysis of N-nitrosamines Formed in Various Source Waters Treated with Eleven Disinfection Processes

We report a hydrophilic interaction liquid chromatography (HILIC) separation with tandem mass spectrometry (MS) detection method for analysis of seven urinary estrogen conjugates. HILIC separation employing a mobile phase with high organic solvent content resulted in enhanced electrospray ionization efficiency and MS sensitivity compared with reversed-phase (RP) LC-MS methods. Solid-phase extraction (SPE) was used to further improve the limit of detection and to eliminate interferences for the analysis of urine samples. No hydrolysis or derivatization was required in the sample pretreatment. This SPE/HILIC-MS/MS method provided limits of quantification (LOQs at S/N = 10) for the seven conjugates ranging from 2 to 1000 pg/mL with only 1 mL of urine sample, representing an improvement of 1 order of magnitude over the RPLC tandem MS methods previously reported. This method provided a linear dynamic range of 3 orders of magnitude, recovery of 92-109%, intraday accuracy of 84-109%, intraday precision of 1-14%, interday accuracy of 80-111%, and interday precision of 1-22%. We have successfully applied this technique to determine the seven estrogen conjugates in urine samples of a pregnant woman and found unique concentration changes of six estrogen conjugates at different stages of pregnancy while the concentration of estriol-3-glucuronide (E3-3G) remained constant. We further studied the profiles of individual estrogen conjugates in breast cancer patients before and after treatment and found patient-dependent effects of aromatase inhibitor treatment on estrogen phase-II metabolism, which have not been reported previously. This study demonstrates the potential clinical application of the HILIC-MS/MS technique for sensitive monitoring of the changes of urinary estrogen conjugates in a clinical setting.

Hydrophilic interaction liquid chromatography-tandem mass spectrometry determination of estrogen conjugates in human urine.

Immobilization enzyme fluorescence capillary analysis for determination of lactic acid.

Determination of pyruvic acid by using enzymic fluorescence capillary analysis.

Column-switching reversed phase-hydrophilic interaction liquid chromatography/tandem mass spectrometry method for determination of free estrogens and their conjugates in river water.

Emerging disinfection by‐products (DBPs) in drinking water are an important public health concern. Certain DBPs, such as nitrosamines, are probable carcinogens, and exposure to halogenated DBPs may lead to birth defects. It is difficult to obtain complete separation of nitrosamines by chromatographic techniques. Thus we explored high‐field asymmetric waveform ion mobility spectrometry (FAIMS) as an alternative separation technique for the characterization of individual DBPs in a complex matrix. We first used ESI‐FAIMS‐MS to separate four nitrosamines: N‐nitrosodi‐n‐butylamine (NDBA), N‐nitrosodi‐n‐propylamine (NDPA), N‐nitrosopiperidine (NPip), and N‐nitrosodiethylamine (NDEA) in the compensation voltage (CV) spectra. The optimal CVs with a fixed dispersion voltage of –4000 V were found to be –1.2 V (NDBA), 2.7 V (NDPA), 7.5 V (NPip) and 10.1 V (NDEA). In addition, FAIMS‐MS effectively reduced the chemical noise and dramatically improved the LODs by as much as tenfold compared to the conventional ESI‐MS technique. To further improve sensitivity, an on‐line CE system was used in combination with FAIMS‐MS to take advantage of the higher ionization efficiency. The calibration curves for the four nitrosamines were linear over a range of 5 ng/mL to 1000 ng/mL with an r2 value of 0.9929 to 0.9992. To increase sample throughput, a multiple‐injection strategy was developed, in which the CV values were preprogrammed so that the FAIMS device allowed different nitrosamines to pass through at selected time windows. The potential application of the proposed method was demonstrated for the analysis of drinking water samples spiked with nitrosamines.

Analysis of nitrosamines by capillary electrospray‐high‐field asymmetric waveform ion mobility spectrometry‐MS with programmed compensation voltage

N-Nitrosodimethylamine (NDMA), a member of a group of probable human carcinogens, has been detected as a disinfection byproduct (DBP) in drinking water supplies in Canada and the United States. To comprehensively investigate the occurrence of possible nitrosamines in drinking water supplies, a liquid chromatography-tandem mass spectrometry technique was developed to detect both thermally stable and unstable nitrosamines. This technique consisted of solid-phase extraction (SPE), liquid chromatography (LC) separation, and tandem quadrupole linear ion trap mass spectrometry (MS/MS) detection. It enabled the determination of sub-ng/L levels of nine nitrosamines. Isotope-labeled N-nitrosodimethylamine-d6 (NDMA-d6) was used as the surrogate standard for determining recovery, and N-nitrosodi-n-propylamine-dl4 (NDPA-dl4) was used as the internal standard for quantification. The method detection limits were estimated to be 0.1-10.6 ng/L, and the average recoveries were 41-111% for the nine nitrosamines; of these, NDMA, N-nitrosopyrrolidine (NPyr), N-nitrosopiperidine (NPip), and N-nitrosodiphenylamine (NDPhA) were identified and quantified in drinking water samples collected from four locations within the same distribution system. In general, the concentrations of these four nitrosamines in this distribution system increased with increasing distance from the water treatment plant, indicating that the amount of formation was greater than the amount of decomposition within this time frame. The identification of NPip and NDPhA in drinking water systems and the distribution profiles of these nitrosamines have not been reported previously. These nitrosamines are toxic, and their presence as DBPs in drinking water may have toxicological relevance.

Characterization of new nitrosamines in drinking water using liquid chromatography tandem mass spectrometry.

The development of a technique combining solid-phase microextraction (SPME) with microbore high-performance liquid chromatography (micro-HPLC)-tandem quadrupole time-of-flight (QTOF) mass spectrometry (MS) for determination of dissolved microcystins in water is reported. Several important parameters affecting the efficiency of SPME extraction of microcystins are investigated. A microbore C18 column HPLC coupled with tandem QTOF-MS with information-dependent acquisition (IDA) is developed to effectively analyze microcystins in microliter volumes of SPME extracts. The micro-HPLC-QTOF-MS with IDA technique provides comprehensive information, including a survey chromatogram (total ion chromatogram), full scan mass spectrum, and product ion scan mass spectra at different collision energies for individual analytes, which allows for both identification and quantitation in the same run. Linear calibration curves of microcystin standard [microcystin (MC)-arginine (R)R] 1-100 microg/L and of microcystin standard [MC-leucine (L)R] 1-250 microg/L are obtained with a correlation coefficient of 0.996. The combination of SPME with HPLC-QTOF-MS and IDA offers limits of detection of 0.6 pg for MC-RR and 1.6 pg for MC-LR. Analysis of spiked lake-water samples shows a recovery of > 86% for MC-RR and > 70% for MC-LR. This technique requires small sample volumes, minimizes the use of organic solvents, and provides sensitive and information-rich analysis of unknown samples.

Determination of microcystins in water using integrated solid-phase microextraction with microbore high-performance liquid chromatography-electrospray quadruple time-of-flight mass spectrometry.

We report the interaction of intact human holo-transferrin (holo-Tf) with oxaliplatin (an anticancer drug), and the characterization of a complex composed of (1:1) intact holo-Tf and the parent oxaliplatin molecule using nanoelectrospray ionization quadrupole time-of-flight mass spectrometry (nanoESI-QTOF-MS). The molecular weight of this complex was determined to be 80,077 Da, which was an increase of 397 mass units compared to the protein alone (79,680 Da), suggesting that a parent drug molecule was bound to the intact protein. We further examined the interaction between the intact protein and oxaliplatin using size-exclusion high-performance liquid chromatography/inductively coupled plasma mass spectrometry (HPLC/ICPMS). The protein complex and free oxaliplatin were separated by HPLC and quantitatively determined by simultaneous monitoring of both 195Pt and 56Fe using ICPMS. The HPLC/ICPMS detected both Pt and Fe signals at retention time of 2.6 min, identifying the protein-drug complex. The Fe signal at 2.6 min did not change with the increase in incubation time of the reaction mixture containing holo-Tf and oxaliplatin, while the Pt signal at the same retention time increased over time, further demonstrating that the formation of this complex does not affect the protein-bound Fe. The binding constant of the (1:1) intact human holo-Tf-oxaliplatin complex was determined to be 7.7x10(5) M-1. Both nanoESI-MS and HPLC/ICPMS results support that the holo-Tf and parent oxaliplatin molecules form complexes through non-covalent binding, suggesting that holo-Tf may be a useful carrier for oxaliplatin delivery.

A new catalytic kinetic spectrophotometry method for the determination of trace chromium has been developed. It is based on the catalytic effect of Cr? on the oxidation of potassium bromate with chlorophosponazoⅢ in diluted sulphuric acid medium. The linear range of Cr? is 0.02～1.0?μg/mL,and the detection limit is 0.005?μg/mL. The method is accurate, sensitive, simple with a stable system. It has been widely applied to the determination of chromiumin water with satisfactory results.

Determination of aliphatic amines using N-succinimidyl benzoate as a new derivatization reagent in gas chromatography combined with solid-phase microextraction.

Use of a Novel Sol–Gel Dibenzo-18-Crown-6 Solid-Phase Microextraction Fiber and a New Derivatizing Reagent for Determination of Aliphatic Amines in Lake Water and Human Urine

N-Hydroxysuccinimidyl phenylacetate as a novel derivatizing reagent for aliphatic amines in gas chromatography

The determination of impurities in caprolactam by capillary gas chromatography-mass spectrometry

A new derivatizing reagent, N-hydroxysuccinimidyl-α-naphthylacetate (SINA), has been used as a precolumn derivatizing reagent for the separation and determination of amino acids (AAs) and oligopeptides with HPLC. The spectral properties of SINA derivatives with AAs and oligopeptides have been studied. The derivatization and separation conditions of SINA derivatives with most amino acids and some oligopeptides have been investigated. With spectrophotometric detection at 280 nm, the detection limits were in the range of 0.49–2.76 pmol; with fluorescence detection at λex/λem = 299/338 nm, the detection limits were in the range of 19–376 fmol when the ratio of signal to noise (S/N = 3) was 3.

N-HYDROXYSUCCINIMIDYL-α-NAPHTHYLACETATE AS A DERIVATIZING REAGENT FOR AMINO ACIDS AND OLIGOPEPTIDES IN RP-HPLC

Iodine is one necessary substance in human body.Uric iodine is the most important mark that can reflect the quantity of iodine in human body.This article generally introduces such methods to determine uric iodine and explores how to measure uric iodine with iodine ion selective electrode.

Study on the Method of Determining Uric Iodine Using Iodine-ion-selective Electrode

Abstract N-Hydroxysuccinimidyl-3-indolylacetate (SIIA) was firstly synthesized in a very simple route and used as a pre-column derivatizing reagent, which can react with amino compounds selectively under mild conditions. Its derivatives of peptides and their hydrolysates were separated and determined by reversed-phase high performance liquid chromatography (HPLC). In a mobile phase of methanol-water (17:83, v:v) containing 10 mmol/L citric acid-sodium phosphate buffer (pH 3.8), the derivatives of glutathione (GSSG), glycyl glycine (Gly-Gly), glutamic acid (Glu), cystine ((Cys)

N-Hydroxysuccinimidyl-3-indolylacetate As Pre-column Derivatizing Reagent to Separate and Determine Peptides and Their Hydrolysates by Reversed-Phase High Performance Liquid Chromatography

The temperature responsive mechanism of fiber surface plasmon resonance sensor

The effect of the TiO2 film on the performance of the optical fiber SPR sensor

Tungsten disulfide (WS2) nanosheets is a promising two-dimension (2D) material for offering lots opportunities in the development of new biological and chemical sensors and sensing strategies. Fiber SPR sensor is a powerful tool in the field of biology and chemistry. In this work, we simulated the effect of different tickness WS2 nanosheets on the fiber SPR sensor. The result show that, the SPR sensor perform best when WS2 nanosheets is 9.6 nm. Its refractive index sensitivity is 2018.4nm/RIU, the full width at half maximum is 151.4 nm, and the quality factor is 1.333.

Simulation study of tungsten disulfide nanosheets -Au fiber surface plasmon resonance sensor

Gas/liquid detection system based on intra-cavity absorption spectroscopy and tilted fiber Bragg grating

This paper designed a photoelectric detection system based on C8051F350 , which can be used in the grating spectrometer system. Aiming at traditional detecing methods, this paper puts forward a multi sensor data fusion technology which can fuse detecting data from multi photomultipliers. It has very strong practicability that detection data can be transmit to the computer through the serial port to draw curve of spectrum.

The Design of Spectrometer Detection and Control System Based on C8051F350

Temperature sensing technique of optical fiber grating is used to realize online leak detection to heating power pipeline.When the pipeline is leaking,the temperature field around pipeline is increasing.By using temperature characteristic of optical fiber grating temperature sensor with the changing law of temperature field at leakage location,theoretical analysis on leakage of heating power pipeline is carried out and leak detection system of optical fiber grating is applied to the engineering.The system of optical fiber grating is realized the continual monitor of the temperature at key point,which can find leakage of pipeline truly and offer a new method to leak detection to pipeline.

Leak Detection to Heating Power Pipeline with Optical Fiber Grating

Influence of blocking the short wave visible light on the stability of tear film in healthy people

Introduction: Increasing evidence indicates that lncRNA TUG1 represents an oncogenic factor in cancer. But, the mechanisms by which lncRNA TUG1 contributes to lung adenocarcinoma (LAC) remain undocumented. Methods: The relationship between lncRNA TUG1/miR-138-5p expression and clinical outcomes in patients with LAC was indicated by qPCR, FISH, and TCGA cohort. Gain- or loss-of-function experiments and in vivo tumorigenesis were used to assess the role of lncRNA TUG1 in LAC. The interplay between TUG1 and miR-138-5p was validated by luciferase gene report and RIP assays. qPCR and Western blot analyses were used to investigate the effects of TUG1 on miR-138-5p/HIF1A axis in LAC cells. Results: We found that upregulation of TUG1 or downregulation of miR-138-5p was associated with lymph node or distant metastasis and indicated a poor survival in LAC. Reduced expression of TUG1 restrained the growth of LAC cells, while restored expression of TUG1 had the opposite effects. TUG1 was identified to negatively regulate miR-138-5p expression, and miR-138-5p reversed TUG1-induced cell proliferation by targeting HIF1A. Elevated expression of HIF1A predicted a poor survival in LAC. Conclusion: Our findings demonstrate that lncRNA TUG1 promotes the growth of LAC by regulating miR-138-5p-HIF1A axis.

LncRNA TUG1 contributes to the tumorigenesis of lung adenocarcinoma by regulating miR-138-5p-HIF1A axis

Genomic bases underlying the adaptive radiation of core landbirds

Abstract The mechanism on of how salinity affects seed fatty acids accumulation remains unclear in halophytes. The present results revealed that the content of total unsaturated fatty acids in black seeds was higher than in brown seeds in the euhalophyte Suaeda salsa under controlled saline conditions. Salinity (200 mM NaCl) significantly increased the total oil content, unsaturated acid/saturated acid ratio, and content of α-linolenic acid (C18:3) (ALA), especially in brown seeds. The most abundant fatty acid in dimorphic seeds is linoleic acid (C18:2) (>70%). It appears that more ALA accumulated in brown seeds compared to black seeds. The enzyme activity of omega-3 fatty acid desaturase (ω-3 FAD) in brown seeds was much higher than that in black seeds, but salinity had no significant effect on the activity of ω-3 FAD in both brown and black seeds. The relative expression of SsFAD7 was increased by salinity, and the value in brown seeds was much higher than that in black seeds. This means salinity can, salinity can improve the quantity of fatty acids in dimorphic seeds of S. salsa, and the enzyme of ω-3 FAD and SsFAD7 may involve in the accumulation of ALA in dimorphic seeds under salinity.

Plant Biosystems - An International Journal Dealing with all Aspects of Plant Biology

Traits of fatty acid accumulation in dimorphic seeds of the euhalophyte Suaeda salsa in saline conditions

Analysis of storage compounds and inorganic ions in dimorphic seeds of euhalophyte Suaeda salsa.

Utilisation of stored lipids plays an important role in germination of oil seeds. In the present study, key enzyme activity (lipase, isocitrate lyase and malate synthase) in lipid utilisation was determined during germination in dimorphic seeds of euhalophyte Suaeda salsa (L.) Pall. The results revealed that the percentage of germination were highest in intertidal brown seeds, followed by inland brown seeds and then inland black seeds moistened with 0 and 300mM NaCl during early seed germination. The same trend was found in the activity of three enzymes and soluble sugar content when seeds were moistened with 0 and 300mM NaCl for 3h. Salinity reduced the activity of three enzymes in inland brown and black seeds in the initial 3h, except that salinity had no adverse effect on isocitrate lyase activity of brown seeds. Salinity had no adverse effect on three enzymes in inland brown and black seeds in the initial 30h, except that it decreased malate synthase activity of black seeds. Salinity had no effect on three enzymes in intertidal brown seeds in the initial 3h and 30h. In conclusion, high activity of these enzymes in brown seeds may play an important role in utilisation of stored lipids during their rapid seed germination.

Utilisation of stored lipids during germination in dimorphic seeds of euhalophyte Suaeda salsa.

Transcriptomic profiling of genes in matured dimorphic seeds of euhalophyte Suaeda salsa

To investigate the phenotypic variation of cucumber photosynthesis, net photosynthetic efficiency of cucumbers were measured by LI-6400XT Portable Photosynthesis System. Non-rectangular hyperbolic model was adopted to fit the light response curve. We used 16 cucumber accessions selected from the core collection that consists of over 400 accessions. As a result, cucumbers show a moderate variance in the phenotype of light compensation point (LCP), light saturation point (LSP) and apparent quantum efficiency (AQY), dark respiration rate (Rd), and maximum net photosynthetic rate (Amax). In a detail, the coefficient of variation (CV) of LCP and Rd is 48.97% and 48.09%, respectively, which is relatively high. In contrast, the CV values of Amax, LSP and AQY are all smaller than 25%. These results help us get better understanding about the phenotypic variation of photosynthesis in cucumber germplasm.

Phenotypic Diversity of Photosynthetic Characteristics in 16 Cucumber Accessions Selected from the Core Collection

In quest of optimal salt-acclimation concentration of NaCl solution and high-salt-resistance ability as well as of expression difference of salt-resistance-associated proteins,the wheat seedlings of Triticum aestivum L.cv xinmai 9,were undergone high-salt stress after salt-acclimation by 5 different concentrations of NaCl solution;their protein expression difference was analyzed by SDS-PAGE and POD expression difference by renaturation electrophoresis using samples collected at seventh day after high-salt stress.The results showed:(1)The high salt-resistance ability of wheat seedlings could be enhanced by salt-acclimation,which was greatly enhanced in 2.50 g NaCl/kg sand;(2) The two new proteins of 225 and 233 kD were detected in wheat seedlings undergone salt-acclimation of 2.5 g NaCl/kg sand when salt-stressed by 3.75 g NaCl/kg sand;(3)The three extra POD bands of 57,59 and 84 kD were all detected in the wheat seedlings undergone salt-acclimation in contrast to the control,but the three bands of 52,55 and 60 kD were not found in the control.The wheat seedlings after salt-acclimation of 2.5 gNaCl/kg sand had the strongest ability of high-salt-resistance;new protein and POD band were found in wheat seedlings undergone hige-salt stress.

Effects of Salt-acclimation on Salt-resistance and Expression Difference of Proteins and POD Isozymes of Wheat Seedlings

The rapid propagation techniques of in vitro sweetpotato plantlets using sigle node cutting as culture materials were studied in the paper. The results showed that single node cuttings growth was normal on medium of MS and 1/2 MS, and MS medium was more suitful to the growth. The single node cutting grew better on MS medium containing 0.5 mg/L NAA than on MS medium. When it was cultured on MS medium containing 0.1 mg/L GA 3, internodes length of in vitro sweetpotato plantlets increased, and the nodes were 1 or 2 more than the CK. In additional, sucrose concentration at 50 g/L, room temperature at 28℃, light intensity at 3000 lx were most suitable for single node cuttings propagation.

Study on Rapid Propagation Techniques of in vitro Sweetpotato Plantlets from Meristem Tip Culture

Since the publication of Cohesive in English co-authored by Halliday and Hasan in 1976, more linguistics at home and abroad have been analyzing and studying this theory in detail. Thus, cohesion theory has been steadily growing. Existing studies, however, tended to focus on the analysis of cohesive devices in a variety of discourses other than the texts from English textbooks for Chinese high school learners. To address this gap, this study used 5 articles from New Senior English for China Student’s Book 5 and 6 to explore the non-structure cohesive devices. By means of the coding scheme suggested by Halliday and Hasan in 1976, the cohesive patterns in a text were represented. The results showed that coherence in the 5 texts largely depends on lexical cohesion. Then, a further analysis of the five lexical cohesive devices showed that among them, same item having reference that is identical proved to be the most in the texts. The main reasons is perhaps that since the texts are from school textbooks for Chinese teenagers, the student readers almost certainly do not have the ability to make much sense of a fairly complex text whose coherence may largely depends on substitution or ellipsis.

A Study of Non-structure Cohesion in the Texts in New Senior English for China Student’s Book 5 and 6

W. H. Auden’s syllabic poetics within the framework of world literature

This study aimed to empirically investigate the influence of China postgraduates’ both gender and participation in research projects. A sample of 260 postgraduates (106 males and 143 females) from a China university performed the Kaufman domains of creativity scale and the questionnaire on scientific project participation. The results showed that the female’s performance in everyday creativity was significantly better than the male, whereas the male’s performance in scientific creativity was significantly better than the female. The amount of research project participation could also affect postgraduates’ creative performance, with a markedly better performance for the students participating in two or more projects than others. These results suggest gender and participation in research projects both greatly contribute to the postgraduates’ creative performance.

The Influence of Gender and Scientific Program Experience on Postgraduates' Creativity

Paper cutting, as an ancient and unique Chinese characteristics of the folk traditional culture elements, comes from people's daily life, which reflects people's the most simple pursuit and yearning for a better life , is an embodiment of a traditional concept of creation in life. As the time goes on, the full integration of folk paper-cut with local culture and a variety of unique styles embodies the concept of creation and the origin of cultural spirit is a great help to the modern design. With the exploration of paper-cut culture, this paper researches the modern product design, inspirates from its creation technique and art, in order to inherit the ancient folk culture, at the same time, gives some help to the product design in the new era.

The Revelation Research of Folk Paper-Cut Creation Concept on Modern Product Design

Digital Resources and Their Use in Chinese Language Classrooms and Beyond

Composition of the intestinal microbiota of infant rhesus macaques at different ages before and after weaning

Within the framework of density functional theory calculations, the structural, vibrational, and electronic properties of Zrn Cn − 1 (n = 2, 3, and 4) and their functionalized MXenes have been investigated. We find that the most stable configurations for Zr-C MXene are the ones that the terminal groups F, O, and OH locate on the common hollow site of the superficial Zr layer and its adjacent C layer. F and OH-terminated Zr3 C2 and Zr4 C3 have small imaginary acoustic phonon branches around Γ point while the others have no negative phonon modes. The pristine MXenes (Zr2 C, Zr3 C2 and Zr4 C3 ) are all metallic with large DOS contributed by the Zr atom at the Fermi energy. When functionalized by F, O and OH, new hybridization states appear and the DOS at the Fermi level are reduced. Moreover, we find that their metallic characteristic increases with an increase in n. For (Zrn Cn − 1 )O2, Zr2 CO2 is a semiconductor, Zr3C2O2 is a semimetal, and Zr4 C3O2 becomes a metal.

A First-Principles Study on the Vibrational and Electronic Properties of Zr-C MXenes*

By means of first principles calculations, Zr-Al-C nanolaminates have been studied in the aspects of chemical bonding, elastic properties, mechanical properties, electronic structures, and vacancy stabilities. Although the investigated Zr-Al-C nanolaminates show crystallographic similarities, their predicated properties are very different. For (ZrC)nAl3C2 (n = 2, 3, 4), the Zr-C bond adjacent to the Al-C slab with the C atom intercalated in the Zr layers is the strongest, but the one with the C atom intercalated between the Zr layer and Al layer is the weakest. In contrast, the situation for (ZrC)nAl4C3 (n = 2, 3) is just the opposite. For Zr-Al-C nanolaminates, the calculated bulk, shear and Young's modulus increase in the sequence of Zr2AlC < Zr3AlC2 < Zr2Al4C5 < Zr3Al4C6 < Zr2Al3C4 < Zr3Al3C5 < Zr4Al3C6. The (ZrC)nAl3C2 (n = 2, 3, 4) series exhibit the most outstanding elastic properties. In the presence of the external pressure, the bulk and shear moduli exhibit a linear response to the pressure, except for Zr2AlC and Zr3AlC2, both of which belong to the so-called MAX phases. The two materials also exhibit very distinct properties in the strain-stress relationship, electronic structures and vacancy stabilities. As the intercalated Al layers increase, the formation energy of VZr and VAl increases, while the formation energy of VC decreases. 
 
This article is protected by copyright. All rights reserved.

Elastic, mechanical, electronic, and defective properties of Zr–Al–C nanolaminates from first principles

The Yb3+-doped PCF is prepared by powder melting technology based on high temperature plasma furnace. The optical properties are good and the background attenuation is less than 0.5dB/m. The peak shifts to longer wavelength as the length increases.

Optical properties of Yb3+-doped photonic crystal fiber with powder melting technology

Kupffer cells suppress perfluorononanoic acid-induced hepatic peroxisome proliferator-activated receptor α expression by releasing cytokines

An Aircraft Conceptual Design and Optimization Platform and Its Application for Nature Laminar Flow Aircraft Study

Construction project management in China modeled after the foreigner countries. In China, construction project management staff usually in low level, low salary, high responsibility and distrusted by employers. Analyze the reason through the government department, employer, and the project management enterprise. Then suggest that the government should improve the laws and regulations; the employer should give rights to project management engineers; the project management enterprise should promote their staff ability. Finally make project management better service to construction.

A new concept has been put forward in the code of bills of quantities and valuation for construction works 2013, that is rate of variability for tender sum (RVFTS). This paper concentrates on the conception of the rate through the code and explores the application in combine with a practical project. Then a discussion about the influences of the bills of quantities (BQ) for tendering, the tender sum limit and the bid price is present. Finally, a conclusion can be extracted that the rate actually protects the employers benefit and makes the contractor in a disadvantageous position.

An Analysis of the Influence of Rate of Variability for Tender Sum

An Integrated Platform for Aircraft Conceptual Design and Optimization

Project investment is the most important factor in construction. Project-establishment, design, project bidding and construction phases are the basic stages in construction. According to different phases, scientific investment estimation method, cost engineers participating in design, realistic tender sum limit and strictly overall controlling are the validation methods. Eventually, realize the goal of controlling construction cost.

As promoted by the vision of "everything as a service", all products provided by cloud computing can recognized as a service. The concept "IT as a service" is an effective solution to the IT difficulties of the port industry. This paper has done a study on cloud computing application in port industry. Combining the architecture of cloud computing with the actual needs of the port business, this paper proposes the cloud computing platform architecture of port industry. This paper holds that SOA infrastructure and cloud computing architecture can meet the IT demand of port industry. Moreover, this paper also provides steps for port enterprises to adopt cloud computing.

2009 International Conference on Computational Intelligence and Software Engineering

Background LncRNA PTCSC3 (PTCSC3) inhibits thyroid cancer cervical carcinoma and glioma, while its roles in gastric cancer are unknown. Studies have reported that HULC could serve as a potential biomarker for the diagnosis and prognosis of gastric cancer (GC). Our study aimed to investigate the potential interaction between PTCSC3 and HULC in gastric cancer. Methods This study enrolled 77 gastric cancer patients at the First Affiliated Hospital of Anhui Medical University from January 2016 to January 2018. RT-qPCR was performed to analyze gene expression levels. Cell transfections were carried out to evaluate gene interactions. Transwell assays and wound healing assays were used to analyze the effects of transfection on cell invasion and migration. Western blotting was also used to illustrate the possibility that lncRNA PTCSC3 and lncRNA HULC negatively affected each other through WNT signal path. Results We showed that PTCSC3 was downregulated in tumor tissues of gastric cancer patients in comparison to that in adjacent healthy tissues, and an inverse correlation between the expression levels of PTCSC3 and AJCC stage was observed. LncRNA HULC (HULC) was upregulated in tumor and inversely correlated with PTCSC3 in tumor tissues. Overexpression of PTCSC3 mediated the inhibition of HULC, while overexpression of HULC also mediated the inhibition of PTCSC3. PTCSC3 inhibited, while HULC promoted invasion and migration of gastric cancer cells. In addition, overexpression of HULC attenuated the effects of overexpression of PTCSC3. However, overexpression of PTCSC3 showed no significant effects on cell proliferation. We also found that PTCSC3/HULC affected each other to regulate cell invasion and migration through the Wnt/β-catenin signaling. Conclusion Therefore, overexpression of PTCSC3 inhibited the invasion and migration of gastric cancer cells, and the function of PTCSC3 is associated with HULC.

LncRNA PTCSC3 and lncRNA HULC Negatively Affect Each Other to Regulate Cancer Cell Invasion and Migration in Gastric Cancer

Abstract Background We developed a computer-assisted diagnosis model to evaluate the feasibility of automated classification of intrapapillary capillary loops (IPCLs) to improve the detection of esophageal squamous cell carcinoma (ESCC). Methods We recruited patients who underwent magnifying endoscopy with narrow-band imaging for evaluation of a suspicious esophageal condition. Case images were evaluated to establish a gold standard IPCL classification according to the endoscopic diagnosis and histological findings. A double-labeling fully convolutional network (FCN) was developed for image segmentation. Diagnostic performance of the model was compared with that of endoscopists grouped according to years of experience (senior > 15 years; mid level 10 – 15 years; junior 5 – 10 years). Results Of the 1383 lesions in the study, the mean accuracies of IPCL classification were 92.0 %, 82.0 %, and 73.3 %, for the senior, mid level, and junior groups, respectively. The mean diagnostic accuracy of the model was 89.2 % and 93.0 % at the lesion and pixel levels, respectively. The interobserver agreement between the model and the gold standard was substantial (kappa value, 0.719). The accuracy of the model for inflammatory lesions (92.5 %) was superior to that of the mid level (88.1 %) and junior (86.3 %) groups (P < 0.001). For malignant lesions, the accuracy of the model (B1, 87.6 %; B2, 93.9 %) was significantly higher than that of the mid level (B1, 79.1 %; B2, 90.0 %) and junior (B1, 69.2 %; B2, 79.3 %) groups (P < 0.001). Conclusions Double-labeling FCN automated IPCL recognition was feasible and could facilitate early detection of ESCC.

Computer-assisted diagnosis of early esophageal squamous cell carcinoma using narrow-band imaging magnifying endoscopy

Cancer recognition is the prerequisite to determine appropriate treatment. This paper focuses on the semantic segmentation task of microvascular morphological types on narrowband images to aid clinical examination of esophageal cancer. The most challenge for semantic segmentation is incomplete-labeling. Our key insight is to build fully convolutional networks (FCNs) with double-label to make pixel-wise predictions. The roi-label indicating ROIs (region of interest) is introduced as extra constraint to guild feature learning. Trained end-to-end, the FCN model with two target jointly optimizes both segmentation of sem-label (semantic label) and segmentation of roi-label within the framework of self-transfer learning based on multi-task learning theory. The learning representation ability of shared convolutional networks for sem-label is improved with support of roi-label via achieving a better understanding of information outside the ROIs. Our best FCN model gives satisfactory segmentation result with mean IU up to 77.8% (pixel accuracy > 90%). The results show that the proposed approach is able to assist clinical diagnosis to a certain extent.

Fully convolutional networks with double-label for esophageal cancer image segmentation by self-transfer learning

Abstract Background. Lymph node metastasis (LNM) from early gastric cancer (EGC) is rare, especially for differentiated-type EGC. However, LNM has been reported in a few cases after endoscopic curative resection of differentiated-type EGC. This study aimed to evaluate LNM risk factors to identify those that should be considered during the preoperative evaluation of differentiated-type EGC. Patients and methods. A total of 976 EGC patients who underwent radical gastrectomy were reviewed in this study. Univariate and multivariate analyses were used to analyze the predictive factors for LNM based on the histology of the differentiated-type EGC cases. Results. Differentiated-type EGC was observed in 59% of the cases. The rate of LNM was 6.6% (38/576 patients) in the differentiated-type EGC cases. Macroscopic shape, ulcers, tumor size, deeper invasion and lymphovascular invasion were shown to be related to LNM in differentiated-type EGC. Multivariate analysis revealed that size, depth, ulceration and lymphovascular invasion were independent predictors of LNM in differentiated-type EGC. When lymphovascular invasion was absent, the presence of one or more of the risk factors of ulcer lesions, tumor size >30 mm and submucosal invasion increased the rate of LNM. Thirteen patients who underwent radical gastrectomy were shown to have differentiated-type EGC with LNM that met the standard and expanded criteria of endoscopic submucosal dissection. Conclusions. As endoscopic resection is widely used, it is important to clarify the clinical significance of LNM in differentiated-type EGC and to screen for LNM with this incidence in mind and to follow the clinical courses of such cases, especially in China.

Lymph node metastasis in differentiated-type early gastric cancer: a single-center retrospective analysis of surgically resected cases

Objective 
To investigate the efficacy of the four commonly used diagnostic methods in infection of Helicobacter pylori(H. pylori). 
 
Methods 
The study included 133 patients with upper gastrointestinal symptoms. Three fresh gastric biopsy were extracted from the lesser curvature of antrum when patients accepting gastroscopy, for the rapid urease test(RUT) test strip, RUT gel method, and histological examination, respectively.14C-urease breath test(14C-UBT) was carried out 1 hour after the procedure. The result of histological examination was served as the golden reference.Any two tests positive were served as the relative golden reference.The diagnostic accuracy of the four methods and the consistence with golden reference and relative golden reference was evaluated. 
 
Results 
The positive results were obtained in 111 cases by RUT test strip, 76 by RUT gel method, 70 by 14C-UBT, and 62 by Warthin—Starry stain. With Warthin—Starry positive as the golden reference, the finding of RUT test strip was poorly consistent with the result of Warthin—Starry(Kappa=0.295). However, the findings of RUT gel method and 14C-UBT were highly consistent with the result of Warthin—Starry(Kappa=0.672, 0.670). Because of the poor specificity of RUT test strip, any two positive tests from Warthin—Starry, RUT gel method and 14C-UBT were used as the relative golden reference to evaluate the diagnostic accuracy. The findings of Warthin—Starry and 14C-UBT were perfectly consistent with the golden reference(Kappa=0.821, 0.850), and the finding of RUT gel method was highly consistent with the golden reference(Kappa=0.763). However, the finding of RUT test strip was poorly consistent with golden reference(Kappa=0.280). When the delta cutoff value for the UBT was calculated as a standard value(DMP≥100), the area under the ROC curve was 0.932 (0.884-0.979), and the sensitivity, specificity and accuracy of 14C-UBT were 100.0%, 86.3% and 92.5%, respectively.When the delta cutoff value for the UBT was recalculated as a new value(DMP≥166), the area under the ROC curve increased to 0.949(0.906-0.992). With the golden reference as the evaluation, the sensitivity, specificity and accuracy of UBT test were 96.7%, 93.2% and 94.7%, respectively. 
 
RUT test strip shows low accuracy; RUT gel method, UBT and histological examination have high accuracy and similar efficacy. When the delta cutoff value for the test is recalculated as DMP≥166, the accuracy of the test can be improved. 
 
Key words: 
Helicobacter pylori; Rapid urease test; Histology; Urease breath test

A comparative study on routine diagnostic methods in infection of Helicobacter pylori

Hydrogel electronics have attracted growing interest for emerging applications in personal healthcare management, human-machine interaction, etc. Herein, a "doping then gelling" strategy to synthesize supramolecular PANI/PAA hydrogel with a specific strand entangled network is proposed, by doping the PANI with acrylic acid (AA) monomers to avoid PANI aggregation. The high-density electrostatic interaction between PAA and PANI chains serves as a dynamic bond to initiate the strand entanglement, enabling PAA/PANI hydrogel with ultra-stretchability (2830%), high breaking strength (120 kPa), and rapid self-healing properties. Moreover, the PAA/PANI hydrogel-based sensor with a high strain sensitivity (gauge factor = 12.63), a rapid responding time (222 ms), and a robust conductivity-based sensing behavior under cyclic stretching is developed. A set of strain sensing applications to precisely monitor human movements is also demonstrated, indicating a promising application prospect as wearable devices.

A Strand Entangled Supramolecular PANI/PAA Hydrogel Enabled Ultra-Stretchable Strain Sensor.

Abnormal optical response of PAMAM dendrimer-based silver nanocomposite metamaterials

Carbon‐based single‐atom iron electrocatalysts with nitrogen coordination (CSAIN) have recently shown enormous promise to replace the costly Pt for boosting the cathodic oxygen reduction reaction (ORR) in fuel cells. However, there remains a great challenge to achieve highly efficient CSAIN catalysts for the ORR in acidic electrolytes. Herein, a novel CSAIN catalyst is synthesized by pyrolyzing a precursor mixture consisting of metal–organic framework and conductive polymer hybrid. After pyrolysis at a high temperature, the CSAIN with a structure of carbon nanosheet supported polyhedral carbon is achieved, where the unique structure endows CSAIN with expediting electron transfer and mass transport, as well as largely exposed surface to host atomically dispersed iron active sites. As a result, the optimal CSAIN catalyst shows a high ORR activity with its half‐wave potential of 0.77 V (vs RHE) and a Tafel slope of 74.1 mV dec–1, which are comparable to that of commercial Pt/C catalyst (0.80 V and 81.9 mV dec–1).

Polyhedral Carbon Anchored on Carbon Nanosheet with Abundant Atomic Fe‐Nx Moieties for Oxygen Reduction

To improve the anti-tribocorrosion property, and decrease the metal dissolution and wear of stainless-steel components caused by the synergistic action of corrosion and friction in marine environments, Ti-DLC coatings were obtained on steel substrate using a filtered cathodic vacuum arc (FCVA) system by adjusting bias voltage. The structure, mechanical properties, corrosion, and tribocorrosion behavior were investigated. Increasing the bias voltage from −50 V to −300 V, Ti content decreased from 23.9 to 22.5 at.%, and grain size decreased first, and then increased. Obvious TiC grains embedded in the amorphous carbon matrix were observed in the coating from the TEM result. Hardness increased from 30.23 GPa to 34.24 GPa with an increase in bias voltage from −50 to −200 V. The results of tribocorrosion testing showed that the Ti-DLC coatings at −200 V presented the best anti-tribocorrosion performance with the smallest friction coefficient of 0.052, wear rate of 2.48 × 10−7 mm3/N∙m, and high open-circuit potential, which is mainly due to the dense structure, high value of H/E* and H3/E*2, and great corrosion resistance. Obtained results suggest that the Ti-DLC coating with nanocomposite structure is a potential protective material for marine equipment.

Enhanced Anti-Tribocorrosion Performance of Ti-DLC Coatings Deposited by Filtered Cathodic Vacuum Arc with the Optimization of Bias Voltage

Tribocorrosion and tribological behavior of Ti-DLC coatings deposited by filtered cathodic vacuum arc

Simultaneous precise localization and activity evaluation of a biomolecule in a single living cell is through an enzyme‐specific signal‐amplification process, which involves the localized, site‐specific self‐assembly, and activation of a presignaling molecule. The inactive presignaling tetraphenylethylene (TPE)‐peptide derivative, TPE‐YpYY, is nondetectable and highly biocompatible and these small molecules rapidly diffuse into living cells. Upon safely arriving at an active site, and accessing the catalytic pocket of an enzyme, TPE‐YpYY immediately and quantitatively accumulates in situ in response to enzymatic activity, forms an enzyme anchor TPE‐YYY nanoassembly, displays aggregation‐induced emission behavior, and finally lights up the active enzyme, indicating its activity, and allowing its status in living cells to be tracked. This simple and direct self‐portrait method can be used to monitor dynamic self‐assembly processes in individual living cells and may provide new insights that reveal undiscovered biological processes and that aid in developing biomedical hybrid devices. In the future, this strategy of molecular design can be further expanded to the noninvasive investigation of other bioactive molecules, thus facilitating quantitative imaging.

Spatiotemporally Controllable Peptide‐Based Nanoassembly in Single Living Cells for a Biological Self‐Portrait

Cell Imaging: Spatiotemporally Controllable Peptide‐Based Nanoassembly in Single Living Cells for a Biological Self‐Portrait (Adv. Mater. 32/2017)

Ultrasmall nanoparticles provide us with essential alternatives for designing more efficient nanocarriers for drug delivery. However, the fast clearance of ultrasmall nanoparticles limits their application to some extent. One of the most frequently used compound to slow the clearance of nanocarriers and nanodrugs is PEG, which is also approved by FDA. Nonetheless, few reports explored the effect of the PEGylation of ultrasmall nanoparticles on their behavior in vivo. Herein, we investigated the impact of different PEG grafting level of 2 nm core sized gold nanoparticles on their biological behavior in tumor-bearing mice. The results indicate that partial (∼50%) surface PEGylation could prolong the blood circulation and increase the tumor accumulation of ultrasmall nanoparticles to a maximum extent, which guide us to build more profitable small-sized nanocarriers for drug delivery.

Ultrasmall Gold Nanoparticles Behavior in Vivo Modulated by Surface Polyethylene Glycol (PEG) Grafting.

We are interested in developing systems for simultaneous delivery of two or more chemotherapeutic agents. Simple physical mixing of drugs may reduce the therapeutic effect and cause unexpected or even dangerous side-effects. For example, when 10-hydroxycamptothecin (HCPT) and doxorubicin (DOX) injection solutions are mixed, the curative effect is actually reduced in clinical practice. In this study we demonstrated that when HCPT and DOX are combined into a single nanoparticle, their toxicity to tumor cells in vitro is synergistically enhanced. We used a simple and "green" reprecipitation method to successfully create a carrier-free dual-drug delivery system by self-nanocrystallization of the drug molecules. When HCPT and DOX were coassembled, they formed small, spherical nanodrug particles with a positive surface charge. Cellular uptake of HCPT was improved and nuclear accumulation increased as much as 1.57-fold in comparison to HCPT alone. The carrier-free HCPT/DOX nanoparticles demonstrated enhanced synergistic cytotoxicity against breast cancer cells in vitro, while an antagonistic effect was observed when HCPT and DOX were directly mixed at high concentration.

Synergistically Enhanced Therapeutic Effect of a Carrier-Free HCPT/DOX Nanodrug on Breast Cancer Cells through Improved Cellular Drug Accumulation.

Microenvironment in biology is diverse and complex which has been a great challenge for in vivo imaging materials, and so materials with environmental tolerance and photostability need to be explored. For aggregation-induced emission (AIE) molecules, the fluorescence is closely related to the restricted structure which is directly affected by the microenvironment. Inorganic silica nanoparticles can provide a rigid microenvironment which can stabilize AIE molecules to obtain fluorescent materials with environmental tolerance. Here, stable fluorescent SiO2 nanoparticles (CWQ-11@SiO2 NPs) have been prepared by doping with typical AIE molecules named CWQ-11. CWQ-11@SiO2 NPs have narrow size distribution and spherical morphology with a size of around 50 nm. The fluorescence intensity of CWQ-11@SiO2 NPs is nearly 45.4 times higher than that of free CWQ-11. CWQ-11@SiO2 NPs maintain excellent fluorescence stabilities under various conditions, such as in solutions with different pH values, different viscosities, or continuous irradiation, and even in simulated gastric fluid (SGF). Cellular imaging research represents efficient imaging ability of CWQ-11@SiO2 NPs in two different tumor cells including MCF-7S and HepG-2. All these results demonstrate that the CWQ-11@SiO2 NPs have been successfully prepared and remain stable under different harsh conditions, and have promising potential in imaging, tracing for drugs or diagnosis in complicated biological systems.

Multi-stable fluorescent silica nanoparticles obtained from in situ doping with aggregation-induced emission molecules.

Carrier-free pure nanodrugs (PNDs) that are composed entirely of pharmaceutically active molecules are regarded as promising candidates to be the next generation of drug formulations and are mainly formulated from supramolecular self-assembly of drug molecules. It benefits from the efficient use of drug compounds with poor aqueous solubility and takes advantage of nanoscale drug delivery systems. Here, a type of all-in-one nanoparticle consisting of multiple drugs with enhanced synergistic antiproliferation efficiency against drug-resistant cancer cells has been created. To nanoparticulate the anticancer drugs, 10-hydroxycamptothecin (HCPT) and doxorubicin (DOX) were chosen as a typical model. The resulting HD nanoparticles (HD NPs) were formulated by a "green" and convenient self-assembling method, and the water-solubility of 10-hydroxycamptothecin (HCPT) was improved 50-fold after nanosizing by coassembly with DOX. The formation process was studied by observing the morphological changes at various reaction times and molar ratios of DOX to HCPT. Molecular dynamics (MD) simulations showed that DOX molecules tend to assemble around HCPT molecules through intermolecular forces. With the advantage of nanosizing, HD NPs could improve the intracellular drug retention of DOX to as much as 2-fold in drug-resistant cancer cells (MCF-7R). As a dual-drug-loaded nanoformulation, HD NPs effectively enhanced drug cytotoxicity to drug-resistant cancer cells. The combination of HCPT and DOX exhibited a synergistic effect as the nanosized HD NPs improved drug retention in drug-resistant cancer cells against P-gp efflux in MCF-7R cells. Furthermore, colony forming assays were applied to evaluate long-term inhibition of cancer cell proliferation, and these assays confirmed the greatly improved cytotoxicity of HD NPs in drug-resistant cells compared to free drugs.

Nanodrug Formed by Coassembly of Dual Anticancer Drugs to Inhibit Cancer Cell Drug Resistance.

Phenylboronic acid-functionalized magnetic nanoparticles for one-step saccharides enrichment and mass spectrometry analysis

A seedless method has been developed for the synthesis of high aspect ratio gold nanorods. Gold nanorods with a longitudinal surface plasmon resonance of larger than 1400 nm were synthesized in one step. The yield was high, and no purification step was needed. We also synthesized normal aspect ratio gold nanorods by a seedless method. The conditions for the synthesis of uniform gold nanorods with different width and aspect ratio by a seedless method were explored. A better understanding of the seedless method enables the facile synthesis of nanomaterials with a broader size tunability and better reproducibility.

Seedless synthesis of high aspect ratio gold nanorods with high yield

Fluorescent metal nanoclusters (NCs) have given rise to a new class of fluorescent nanomaterials for the detection of heavy metals. Here, we design a simple, rapid and highly sensitive sensing nanosystem for the detection of Hg2+ and Cu2+ based on fluorescence quenching of ultrasmall DNA-Ag NCs. The fluorescence intensity of DNA-Ag NCs was selectively quenched by Hg2+ and Cu2+, and the limit of detection (LOD) was found to be 5 nM and 10 nM, respectively. The technique was renewable employment by EDTA addition and successfully applied to detection of Hg2+ and Cu2+ in domestic water samples. The quantum yield (QY) of DNA-Ag NCs was significantly higher to ~30% compared to traditional water-soluble fluorescent metal NCs. The DNA-Ag NC detection system make it potentially suitable for detecting Hg2+ and Cu2+ and monitoring water quality in a wide range of samples regulated under the Environmental Protection Agency.

Highly Sensitive Simultaneous Detection of Mercury and Copper Ions by Ultrasmall Fluorescent DNA-Ag Nanoclusters.

Platinum-based anticancer drugs such as cisplatin, oxaliplatin, and carboplatin are some of the most potent chemotherapeutic agents but have limited applications due to severe dose-limiting side effects and a tendency for cancer cells to rapidly develop resistance. The therapeutic index can be improved through use of nanocarrier systems to target cancer cells efficiently. We developed a unique strategy to deliver a platinum(IV) drug to prostate cancer cells by constructing glutathione-stabilized (Au@GSH) gold nanoparticles. Glutathione (GSH) has well-known antioxidant properties, which lead to cancer regression. Here, we exploit the advantages of both the antioxidant properties and high surface-area-to-volume ratio of Au@GSH NPs to demonstrate their potential for delivery of a platinum(IV) drug by targeting the neuropilin-1 receptor (Nrp-1). A lethal dose of a platinum(IV) drug functionalized with the Nrp-1-targeting peptide (CRGDK) was delivered specifically to prostate cancer cells in vitro. Targeted peptide ensures specific binding to the Nrp-1 receptor, leading to enhanced cellular uptake level and cell toxicity. The nanocarriers were themselves nontoxic, but exhibited high cytotoxicity and increased efficacy when functionalized with the targeting peptide and drug. The uptake of drug-loaded nanocarriers is dependent on the interaction with Nrp-1 in cell lines expressing high (PC-3) and low (DU-145) levels of Nrp-1, as confirmed through inductively coupled plasma mass spectrometry and confocal microscopy. The nanocarriers have effective anticancer activity, through upregulation of nuclear factor kappa-B (NF-κB) protein (p50 and p65) expression and activation of NF-κB-DNA-binding activity. Our preliminary investigations with platinum(IV)-functionalized gold nanoparticles along with a targeting peptide hold significant promise for future cancer treatment.

Neuropilin-1-targeted gold nanoparticles enhance therapeutic efficacy of platinum(IV) drug for prostate cancer treatment.

Tetraphenylethene and doxorubicin are assembled into a self-indicating drug delivery system (TD NPs). TD NPs are decomposed into DOX and TPE NPs in lysosome. Since TD NPs, TPE NPs and DOX are all fluorescent, the detachment of DOX from TPE NPs is accompanied by fluorescence changing. By observing the fluorescence changes, the spatiotemporal drug release is visualized.

Spatiotemporal Drug Release Visualized through a Drug Delivery System with Tunable Aggregation‐Induced Emission

In this study, an orally administered macrophage-targeting peptide delivery system was constructed through in situ self-assembly of Q11 peptide inside hollow glucan particles (GPs), which are approved by the FDA. The glucan shell efficiently protected the encapsulated peptide from enzymatic degradation in the gastrointestinal tract. β-1,3-(d)-Glucan is recognized by the membrane receptor dectin-1, which is highly expressed by intestinal antigen-presenting cells, including macrophages. GPs are thus efficiently phagocytized by intestinal macrophages. This study is applicable to the pharmaceutical industry for the development of orally delivered macrophage-targeting systems for effective and personalized remedies like immunotherapeutic vaccines.

In situ self-assembly of peptides in glucan particles for macrophage-targeted oral delivery.

The advent of nanotechnology has reignited interest in the field of pharmaceutical science for the development of nanomedicine. Nanomedicinal formulations are nanometer-sized carrier materials designed for increasing the drug tissue bioavailability, thereby improving the treatment of systemically applied chemotherapeutic drugs. Nanomedicine is a new approach to deliver the pharmaceuticals through different routes of administration with safer and more effective therapies compared to conventional methods. To date, various kinds of nanomaterials have been developed over the years to make delivery systems more effective for the treatment of various diseases. Even though nanomaterials have significant advantages due to their unique nanoscale properties, there are still significant challenges in the improvement and development of nanoformulations with composites and other materials. Here in this review, we highlight the nanomedicinal formulations aiming to improve the balance between the efficacy and the toxicity of therapeutic interventions through different routes of administration and how to design nanomedicine for safer and more effective ways to improve the treatment quality. We also emphasize the environmental and health prospects of nanomaterials for human health care.

Innovative pharmaceutical development based on unique properties of nanoscale delivery formulation.

Human α defensins human neutrophil peptide 1-3 (HNP 1-3) are potential prognostic cancer biomarkers. Metalloprotein anthrax lethal factor (ALF) binds to HNP 1-3 in a Zn2+-dependent manner. We conjugated ALF to the surface of magnetic nanoparticles (MNP) to magnetically isolate the HNPs, and used Zn2+ to control the capture and release HNPs.

High throughput detection of human neutrophil peptides from serum, saliva, and tear by anthrax lethal factor-modified nanoparticles.

Nanomaterials offer opportunities to construct novel compounds for many different fields. Applications include devices for energy, including solar cells, batteries, and fuel cells, and for health, including contrast agents and mediators for photodynamic therapy and hyperthermia. Despite these promising applications, any new class of materials also bears a potential risk for human health and the environment. The advantages and innovations of these materials must be thoroughly compared against risks to evaluate each new nanomaterial. Although nanomaterials are often used intentionally, they can also be released unintentionally either inside the human body, through wearing of a prosthesis or the inhalation of fumes, or into the environment, through mechanical wear or chemical powder waste. This possibility adds to the importance of understanding potential risks from these materials. Because of fundamental differences in nanomaterials, sound risk assessment currently requires that researchers perform toxicology studies on each new nanomaterial. However, if toxicity could be correlated to the basic physicochemical properties of nanomaterials, those relationships could allow researchers to predict potential risks and design nanomaterials with minimum toxicity. In this Account we describe the physicochemical properties of nanoparticles (NPs) and how they can be determined and discuss their general importance for cytotoxicity. For simplicity, we focus primarily on in vitro toxicology that examines the interaction of living cells with engineered colloidal NPs with an inorganic core. Serious risk assessment of NPs will require additional in vivo studies. Basic physicochemical properties of nanoparticulate materials include colloidal stability, purity, inertness, size, shape, charge, and their ability to adsorb environmental compounds such as proteins. Unfortunately, the correlation of these properties with toxicity is not straightforward. First, for NPs released either unintentionally or intentionally, it can be difficult to pinpoint these properties in the materials. Therefore, researchers typically use NP models with better defined properties, which don't include the full complexity of most industrially relevant materials. In addition, many of these properties are strongly mutually connected. Therefore, it can be difficult to vary individual properties in NP models while keeping the others constant.

The challenge to relate the physicochemical properties of colloidal nanoparticles to their cytotoxicity.

Phase jump in resonance harmonic emission driven by strong laser fields

Degradation reactions of perfluorosulfonic acid ionomers via H or OH radicals were investigated employing B3LYP/6-311++G (2d,2p) and ωB97XD/6-311++G (2d,2p). All important degradation reaction mech...

DFT Studies of Perfluorosulfonic Acid Ionomer Degradation in Fuel Cells

The structural and dynamic properties of a brush-type hydrocarbon copolymer are investigated using first-principles molecular dynamics simulations. Two model compounds, one with mainly hydrophilic domains and one with mainly hydrophobic domains, were selected and used in the simulations. A series of radial distribution functions of different groups, such as water–water, sulfonic group–hydrogen, and ether–hydrogen, is obtained to investigate the structure of the whole systems. The radial distribution functions of sulfonic groups, gS–S(r), and the structure of water clusters indicate the formation of a well-developed water channel in the studied copolymer. Analysis of proton dissociation reveals that the protons in both systems are not completely dissociated when the number of water molecules per sulfonic group is equal to 4. The low dissociation nature of this copolymer compared with that of Nafion is explained by its intrinsic acid strength and the presence of ineffective hydrogen bonds in the system, whe...

First-Principles Molecular Dynamics Study of a Hydrocarbon Copolymer for Use in Polymer Electrolyte Membrane Fuel Cells

Understanding in vivo protein folding mechanisms requires understanding the milieu of cellular processes governing protein biogenesis, one of which is co-translational folding. Co-translational folding occurs when a protein folds as it is being synthesized. We study co-translational folding using lattice protein models, focusing on two previously characterized lattice proteins that differ in their contact topologies. Equilibrium simulations of the full length proteins at various temperatures reproduces a known temperature dependence on folding kinetics. The energy spectra of the two proteins as a function of protein chain length are characterized and found not to favor folding to the native state without nearly the entire chain present. Non-equilibrium co-translational folding simulations are run on the two proteins at two different temperatures. Remarkably, it is observed that more simulations at the lower temperature lead to the folded state than simulations at the higher temperature, despite the higher temperature being the optimal temperature for fast-folding of the full length proteins. It is likely that near-native conformations at intermediate chain lengths are not stable at the higher temperature.

Six model compounds of hydrocarbon polymer electrolyte membrane (PEM) with different neighboring pendants have been investigated using density functional theory (DFT). The effect of the neighboring pendant on the proton dissociation properties of the PEMs and on the chemical stability of the key adjacent bond containing a sulfonic group was evaluated. Results of the proton dissociation properties of the six model compounds indicate that the introduction of a strong electron-withdrawing group, such as CF, CF2, or CN, on the neighboring pendant of the acid group can improve the proton dissociation properties of PEMs. The calculated pKa values confirm the relative acid strength of the six model compounds, whose properties are, to some extent, related to the proton conductivity. Our results demonstrate that a model compound containing a strong electron-withdrawing group in the neighboring pendant has stronger acid strength. DFT calculations on the C–S bond degradation reactions caused by OH or H radicals show...

Theoretical Studies of Pendant Effects on the Properties of Sulfonated Hydrocarbon Polymer Electrolyte Membranes

Theoretical studies on the degradation of hydrocarbon copolymer ionomers used in fuel cells

M4, has been studied based on density functional theory. These four model compounds have the same proton donor group, sulfonic acid, while differ by types of neighboring pendants, non-fluorinated and fluorinated. We find that the protons in the fluorinated model compounds can be dissociated when hydrated by 3 water molecules, comparable to Nafion, while for those non-fluorinated compounds, the protons can be dissociated only hydrated by 4 water molecules. The results indicate that the neighboring pendants have a significant effect on the proton dissociation property of the model compounds. The electron-withdrawing group involved in the neighboring pendants can improve the proton dissociation property of the compounds, which would be meaningful for finding a novel polymer electrolyte membrane with good conductivity.

A DFT Study on the Dissociation Property of Sulfonic Acids with Different Neighboring Pendants in Polymer Electrolyte Membranes

SPEEK is known to possess high proton conductivity at high water content, being comparable with other popular membranes used in fuel cells, such as Nafion and sulfonated polyethersulfone (SPES). However, much less is known about its fundamental properties, including the status of proton dissociation and spectral features. In this work, the properties of two model molecules of SPEEK, M1 (20 atoms), M2 (50 atoms) and their hydrated systems, M1 + nH2O and M2 + nH2O (n = 1-9), have been investigated using static electronic structure calculations and the ab initio molecular dynamics (MD) method. Optimized structures for all of the systems and the trajectories of M1 + nH2O (n = 3-6) at finite temperatures have been computed using density functional theory at the B3LYP level of theory. Proton dissociation has been discussed in detail, especially for n = 3 and n = 4. In addition, the infrared spectra of SPEEK and its hydrated systems have been studied using a combination of theory and experiment. The characteristic bands of SPEEK and the surrounding water clusters have been assigned with emphasis on their relationship with the degree of proton dissociation. We have found that the hydronium ion stretching modes, which appear in the 2000-3000 cm(-1) region in static electronic structure calculations, are not observed experimentally. This discrepancy is explained by the stationary structure and the temperature effect.

Ab initio studies on the proton dissociation and infrared spectra of sulfonated poly(ether ether ketone) (SPEEK) membranes.

As an ingredient in fuel cells, polymer elect rolyte membrane (PEM), its performance plays an important role in the performance of a fuel cell. Especially the stability of the membrane, to a large content, dete rmines the durability of a fuel cell. According to the gen eral standard from industry, the lifetime of fuel cell m ade by industry is including that a lifetime durability of > 40000 and 8000h of uninterrupted service at > 80%power, f or stationary applications. For bus and cars, > 20000 and > 6000 operating hours are required, respectively. 1-2

DFT Studies on the Degradation of New Hydrocarbon Copolymer Used in Fuel Cells

Vibrational Dynamics of Sulfate Anion Adsorption on Pt(111) Surface: Ab Initio Molecular Dynamics Simulations

The noble material platinum nitride (PtN) was studied by means of first-principle calculations. The electronic and optical properties were calculated in order to learn the peculiar characterize of this compound. The platinum nitride has the rock-salt structure which can only been synthesized in the laboratories. There must be some special hybridization between platinum and nitride that combine the two atoms together. The electronic structure and X-ray absorption spectra were performed to study this hybridization.

2013 International Conference on Computer Sciences and Applications

The effect of graphite oxide on the thermoelectric properties of polyaniline

The nonlinear Schrodinger equations (NLSE) with several potentials are simulated and analyzed in details. A family of self-similar quantum solutions, which can be described as solitons, are found in the nonlinear medium. It is indicated that the density of state described the nonlinear Schrodinger equations always has stable state with different state parameters. The results show that the optical signals can transmit in the soliton form with proper parameters in the nonlinear medium.

2011 7th International Conference on Wireless Communications, Networking and Mobile Computing

The extractive technique of allicin was investigated in this paper. The optimum extractive condition of allicin was determined through orthogonal design and response surface analysis as follows: the enzymatic hydrolysis time was 32.4min; temperature was 30; pH was 6.0; ratio of material to ethanol was 1:6.4; extracting time was 60min; extracting temperature 27.4; 95% ethanol. Under such condition, the extraction yield of allicin was 2.81‰ which was in good agreement with the response surface model.

Proceedings 2011 International Conference on Human Health and Biomedical Engineering

First-principle calculations were performed for the study of the superconductor MgB2 and AlB2. The doping effect of compound Mg1-xAlxB2 was analyzed by supercell method. Band structure, electronic bands structure, total and partial densities of states were calculated and analyzed in detail. Covalent bond effects (CBC) appeared in the electronic bands structure when doping Al to MgB2. It is found that this CBC effects on Mg1-xAlxB2 samples have prominent relations to superconductivity. The study of the density of state indicates that the superconductivity decreases with the increase of compound Al. In particular, there exists the transition of superconductor to non-superconductor with the change of x. The theoretical predictions agreed well with experimental measurements.

Covalent Bond Cluster Effects and Phase Transitions in Superconductor Mg1-xAlxB2 Compounds

Body-centered tetragonal C4 (bct C4) is a new form of crystalline sp3 carbon, which is found to be transparent, dynamically stable at zero pressure and more stable than graphite beyond 18.6 GPa. Symmetry analysis of the vibrational modes of bct C4 at Brillouin zone center is performed, Raman and infrared active modes are identified. The analysis results show that, different from cubic diamond and hexagonal diamond, there is an infrared active mode in bct C4. Based on first-principle method within the local density approximation, vibrational frequencies, Born effective charge tensors, and infrared absorption intensity of bct C4 are obtained. The vibrational modes of bct C4 are presented and compared with those of cubic diamond and hexagonal diamond in detail.

An analytic expression for π and π* electronic structure of graphene is derived within the tight-binding approximation. Including up to fifth-nearest neighbors, the tight-binding description of electronic dispersion quite accurately reproduces the first-principle calculation result over the entire Brillouin zone. The maximal deviation of the fifth-nearest tight-binding result from the first-principle result is only 6 meV for π band, and 25 meV for π* band. This 25 meV deviation is only one-tenth of the maximal deviation of the third-nearest tight-binding result. It is more important that the fitted parameters exponentially approach to zero as the distance between interacting atoms increases.

CONDENSED MATTER: ELECTRONIC STRUCTURE, ELECTRICAL, MAGNETIC, AND OPTICAL PROPERTIES: Fifth-Nearest-Neighbor Tight-Binding Description of Electronic Structure of Graphene

Implementing Thermal Feedback Control of a Helium-Neon Laser for Frequency Stabilization

The effect of NH 4Cl on the nitridation of intermetallic compound TiAl was investigated. It is showed that NH 4Cl has a remarkable catalytical effect on the nitridation of TiAl based alloy. The addition of NH 4Cl can increase the thickness of the nitrided layer, the rate of the nitriding process and the surface hardness of the nitrided alloys.

The Effect of NH_4Cl on the Nitridation of Intermetallic Compound TiAl

Suppressors of cytokine signaling (SOCS) act as negative feedback regulators of the Janus kinase/signal transducer (JAK-STAT) signaling pathway by inhibiting the activity of JAK kinase. The kinase inhibitory region (KIR) of SOCS1 targets the substrate binding groove of JAK with high specificity, as demonstrated by significantly higher IC50 following the mutation of any of residue. To gain a greater understanding of the mechanisms of the inhibition of SOCS1 for JAK1, the binding mode, binding free energy decomposition, and desorption mechanism of JAK-SOCS1 complexes as well as a number of mutant systems were identified by extensive molecular dynamics (MD) simulations and the constant pulling velocity (PCV) method. Electrostatic interactions were identified for their contribution to protein-protein binding, which drove interactions between JAK1 and SOCS1. The polar residues Arg56, Arg59, and Asp105 of SOCS1 and Asp1042 and Asp1040 of JAK1 were key components in the binding, and electrostatic interactions of the side chains were prominent. The binding free energies of the six mutant proteins were lower when compared with those of the control proteins, and the side chain interactions were weakened. The residue Asp1040 played a crucial role in KIR close to the binding groove of JAK1. Moreover, salt bridges contributed significantly to JAK1 and SOCS1 binding and cleavage processes. The study presented herein provides a comprehensive understanding of the thermodynamic and dynamic processes of SOCS1 and JAK1 binding that will contribute meaningfully to the design of future studies related to peptide inhibitors based on SOCS1.

Atomistic insight into the inhibition mechanisms of suppressors of cytokine signaling on Janus kinase.

Free rotor model or rigid rotor model for CH3F-Ne complex and comparison with other CH3F-rare gas systems

Theoretical study on the hydrogen abstraction reactions of CF3CHFCF3 and CF3CF2CHF2 with X atoms (X = F, Cl, and Br)

Mechanisms and kinetics of hydrogen abstraction of methylhydrazine and deuterated methylhydrazine with H/D atoms

For theoreticians, ionic liquids represent a major challenge. This is due to the fact that intermolecular interactions are particularly strong because of ionic liquids' ionicity. This, in turn, causes a subtle interplay between different scales which is encoded in the measured macro- and mesoscopic properties and also in the molecular electrostatic characteristics. Therefore, force fields have to describe the microscopic processes correctly in order to reproduce macroscopic properties accurately over a large range of state variables. Herein, imidazolium-based ionic liquids were studied at different scales, going from the detailed quantum electronic scale to the classical atomistic scale. It is indicated how the information gained at each level could be used for the other scales. In particular, the issue of deriving suitable partial charges for use in classical force fields is addressed. The Blöchl method was employed to generate partial charges reproducing the multipole distribution accurately for bulk systems. This led naturally to absolute ionic charges of less than /l e/, i.e., charge scaling. So, the monopole structure of the herein introduced force field mimics the quantum chemical behaviour observed in the liquid phase. This led to a substantial improvement in the description of dynamical properties of immediate experimental interest, such as electric conductivity. For further insight, the electric dipole moment of the ions was taken as physical indicator of their electronic structure. The electric dipole moment was found to fluctuate strongly and to depend on polarisation. Hence, our scale-combined study offers a gateway to rational design of models, based on the relevant underlying physics rather than on mere numerical parameterisation, and thereby to (possibly) more direct physical interpretation of experimental results.

Ionic liquids studied across different scales: a computational perspective.

In this article, we determine the ground‐state equilibrium geometries of the linear anionic carbon clusters C  n− (n = 4–17) by means of the density functional theory B3LYP, CAM‐B3LYP, and coupled cluster CCSD(T) calculations, as well as their electronic spectra obtained by the multireference second‐order perturbation theory CASPT2 method. These studies indicate that these linear anions possess doublet 2∏g or 2∏u ground state, and the even‐numbered clusters are generally acetylenic, whereas the odd‐numbered ones are essentially cumulenic. The energy differences, electron affinities, and incremental binding energies of C  n− chains all exhibit a notable tread of parity alternation, with n‐even chains being more stable than n‐odd ones. In addition, the predicted vertical excitation energies from the ground state to four low‐lying excited states are in reasonably good agreement with the available experimental observations, and the calculations for the higher excited electronic transitions can provide accurate information for the experimentalists and spectroscopists. Interestingly, the absorption wavelengths of the 12∏u/g ← X2∏g/u transitions of the n‐even clusters show a nonlinear trend of exponential growth, whereas those of the n‐odd counterparts are found to obey a linear relationship as a function of the chain size, as shown experimentally. Moreover, the absorption wavelengths of the transitions to the higher excited states of C  n− series have the similar linear size dependence as well. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011

Ab initio characterization of size dependence of electronic spectra for linear anionic carbon clusters Cn− (n = 4–17)

The hydrogen abstraction reaction of Cl atoms with CF3CH2Cl (HCFC-133a) is investigated by using density function theory and ab initio approach, and the rate constants are calculated by using the dual-level direct dynamics method. Optimized geometries and frequencies of reactants, transition state, and products are computed at the B3LYP/6-311+G(2d,2p) level. To refine the energetic information along the minimum energy path, single-point energy calculations are carried out at the G3(MP2) level of theory. The interpolated single-point energy method is employed to correct the energy profiles for the title reaction. The rate constants are evaluated by using the canonical variational transition state theory with a small-curvature tunneling correction over a wide range of temperature, 2002000 K. The variational effect for the reaction is moderate at low temperatures and very small at high temperatures. However, the tunneling correction has an important contribution in the lower temperature range. The agreement between calculated rate constants and available experimental values is good at lower temperatures but diverges significantly at higher temperatures. (C) 2012 Wiley Periodicals, Inc. Int J Chem Kinet 44: 661667, 2012

Direct dynamics study of the hydrogen abstraction reaction of CF3CH2Cl+Cl -> CF3CHCl+HCl

Dual-level direct dynamics studies on the hydrogen abstraction reactions of fluorine atoms with CF3CH2X(X=F, Cl)

A theoretical study of electronic spectra in the linear cationic chains NC2n+1N+ (n = 1–6)

Hydrogen abstraction reactions of OH radicals with CF2ClCClXH (X = F, Cl) and CFCl2CClXH (X = F, Cl): a mechanistic and kinetic study

Electronic spectra of the linear cationic chains NC2nN+ (n = 1–7): an ab initio study

Direct dynamics studies for the reactions of CF3CHFCF3 and CF3CF2CHF2 with H atoms

We present a detailed calculation of partial charges for the 1,3-dimethylimidazolium chloride ionic liquid. We first analyze MP2 electronic structure calculations and DFT results on isolated ion pairs with various methods of assigning partial charges to the atomic centers. In a second run we analyze the trajectory of a 25 ps long Car-Parrinello MD run of 30 ion pairs under bulk conditions using a charge fitting procedure due to Blöchl. Both, the single ion pair and the bulk system, provide us with a similar total ionic charge considerably less than unity. Especially the liquid state DFT results give convincing evidence for a reduced ionic charge on the ions. The similarity of both results suggest that the delocalization of the Cl charge is due only to local interactions. The relevance of our results is 2-fold; on the one hand they shed light on the basic property of the liquid and its reduced ionic character, and on the other hand, the ab initio derived partial charges provide a fundamental theoretical basis for the recent attempts to use the total ionic charge as an adjustable parameter. Furthermore, all our partial charges are subject to large fluctuations, hinting to the importance of polarization effects.

Ionic charge reduction and atomic partial charges from first-principles calculations of 1,3-dimethylimidazolium chloride.

Theoretical study and rate constants calculation of hydrogen abstraction reactions CF3CHCl2 + F and CF3CHClF + F

Synthesis of artificial antigens of diethylstilbestrol and preparation of its antibody

Towards multiscale modeling of ionic liquids: From electronic structure to bulk properties

The influences of two different commonly employed force fields on statical and dynamical properties of ionic liquids are investigated for [EMIM][BF(4)]. The force fields compared in this work are the one of Canongia Lopes and Padua [J. Phys. Chem. B 110, 19586 (2006)] and that of Liu et al. [J. Phys. Chem. B 108, 12978 (2004)]. Differences in the strengths of hydrogen bonds are found, which are also reflected in the static ion distributions around the cation. Moreover, due to the stronger hydrogen bonding in the force field of Liu et al., the diffusive motions of cations and anions and the rotational behavior of the cations are slower compared with those obtained with the force field of Canongia Lopes and Padua. Both force fields underestimate the zero-field electrical conductivity, while the experimental dielectric constant can be reproduced within the expected statistical error boundaries.

A comparative study of two classical force fields on statics and dynamics of [EMIM][BF4] investigated via molecular dynamics simulations.

The 1,3-dimethyl imidazolium chloride [MMIM]Cl is an example of ionic liquid and frequently studied in literature. In this article [MMIM]Cl is studied using an ab initio method [second order Moller-Plesset perturbation theory (MP2), density functional theory (DFT)] and classical force field approach with the aim of looking at some properties on different scales. Selected properties are studied with the different methods and compared to each other. The comparison between the results obtained with MP2 and the DFT approach allows us to comment on the validity of this latter and thus on its employment in larger systems. On the other hand, the comparison between the DFT results and those of the classical approach allows us to test the reproducibility of electrostatic properties by this latter approach. As the results show the used DFT setup is rather satisfactory, while the classical force fields are describing the electrostatic properties in an insufficient way. A revision (improvement) of the classical force fields is at this stage necessary in order to capture the electrostatic properties in a proper way.

Study of 1,3-dimethylimidazolium chloride with electronic structure methods and force field approaches.

Polycoordinate planar B compounds BX(n) (X=B, Al, C, N and Si; n=3-8) are optimized at B3LYP/6-311++G (3df,p) theoretical level. For X=B, center B atom can coordinate three to eight atoms, while for X=Al, C, Si, and N, it can only coordinate three to five atoms. The natural bond orbital analysis shows that the center B atom does not violate the octet rule, though the numbers of coordinated atom even reach 8. According to molecular orbital analysis and nucleus independent chemical shift value calculation, it seems that these polycoordinate planar B compounds BX(n) (X=B, Al, C, N, and Si; n=3-8) hold twofold (alpha and pi) aromatic, which play an important role in their stability and keeping all atoms in one plane.

Structure and properties of polycoordinate planar boron compounds.

Various isomers of macropolyhedral borane ions [B20H18]n (n = 0, −2, −4) are investigated by using the density functional theory methods at RB3LYP/6‐31+G* and RB3LYP/6‐31G* levels to obtain the optimized geometries, harmonic vibrational frequencies, electron structures, and the stability order. The calculated results show that optimized bond lengths are consistent with the available experimental values and the natural populations, taking [a2‐B20H18]4− (4) as an example, are also in agreement with NMR spectra. The calculated vibrational frequencies are all real, so all of these isomers could be stable, among which [a2‐B20H18]2− (3) and [a2‐B20H18]0 (7) are considered for the first time in this paper. On the basis of the contour maps of molecular orbitals, the delocalized characteristic of molecular orbitals and the possible redox mechanism of these ions are also discussed. Moreover, the analysis on counting of skeletal bonding electrons shows that the isomers (1)–(6) obey the electronic requirement predicted by the mno rule, whereas the newly predicted isomer (7) does not match the mno rule. © 2006 Wiley Periodicals, Inc. J Comput Chem, 2006

Ab initio studies on isomers of macropolyhedral borane ions [B20H18]n (n = 0, –2, –4)

Theoretical study on the stability of the novel B32 isomers and their metal-poly-boron MB32 cluster

Theoretical study for (BN)10 isomers and (BN)nC20 − 2n ring structures

Density functional theory study of the B10, B-10 and B+10 clusters and their sandwich-type metal compounds

Structural and electronic properties of BPA-fructose complex used in boron neutron capture therapy

A theoretical study on the structural and functional features of BSH Agent used in boron neutron capture therapy

The Dammann grating (DG), which redistributes a collimated laser beam into a spot array with a uniform intensity, is a widely adopted approach for profile measurement. Conventional DGs for dense spot projection are binary phase gratings with precisely designed groove structures, which suffer from low efficiency, poor uniformity, and a hard-to-fabricate fine feature size when utilized for a large field of view (FOV). Here, we propose a new, to the best of our knowledge, hybrid DG architecture consisting of two different grating periods which effectively generates an engineering M2 × N2 spot array with a non-complex structural design. As a proof-of-concept, a dual-period hybrid DG with a two-scale grating period ratio of 11.88 μm/95.04 μm (∼1/8) is designed and fabricated as a means to generate a dense 72 × 72 diffraction spot array with a FOV of 17° × 17°. In addition, the DG exhibits superior performance, with a high efficiency (>60%) and a low non-uniformity (<18%) at a wavelength of 532 nm. This kind of hybrid DG constructed from photoresist patterns with a minimum feature size of ∼1.2 μm can be perfectly fabricated by maskless projection lithography for large-scale and low-cost production. The proposed dual-period hybrid DG can pave the way for depth-perception-related applications such as face unlocking and motion sensing.

Generating an M2 × N2 spot array with a dual-period hybrid Dammann grating fabricated using maskless projection lithography.

In many integrated optics systems, grating couplers are a key component of interfacing the external light source with in-plane photonic devices. Grating couplers with dual-band capability are often desired for expanding the operation spectrum of photonic systems. Here, we propose and theoretically investigate, for the first time, a 4.95 µm-8.5 µm dual-band grating coupler on a Ge-on-SOI platform. In addition to conventional structures, Bragg gratings are introduced to two wavelength division directions for crosstalk suppression. With this design, the simulated coupling efficiencies have respectively reached 59.93% and 46.38% for the 4.95 µm and 8.5 µm bands. This mid-infrared dual-band grating coupler may be useful for defense and environmental monitoring applications.

Efficient 4.95 µm-8.5 µm dual-band grating coupler with crosstalk suppression capability.

Maskless lithography technologies have been developed and played an important role in the fabrication of functional micronano devices for microelectronics, biochips and photonics. Optical projection lithography based on digital micromirror device (DMD) is an efficient maskless lithography technology that can rapidly fabricate complex structures. The precise modulation of gap width by DMD maskless optical projection lithography (MOPL) using femtosecond laser becomes important for achieving micronano structures. Herein, we have investigated the relationship between the structure morphology and the light intensity distribution at the image plane by multi-slit diffraction model and Abbe imaging principle, and optimized the gap width more accurately by modulating exposure energy. The aperture diameter of the objective lens has a substantial effect on the pattern consistency. The continuously adjustable structural gap widths of 2144 nm, 2158 nm and 1703 nm corresponding to 6, 12, 24 pixels are obtained by varying the exposure energy in the home-built MOPL system. However, the ideal gap structure cannot be obtained only by adjusting the exposure energy when the gap width is small, such as 1 or 2 pixels. Furthermore, we have proposed an alternative way to achieve fine gap structures through the structural decomposition design and precise control of exposure energy in different regions without changing the MOPL optical system. This study would provide a promising protocol for fabricating gap microstructures with controllable configuration using MOPL technique.

Consistent pattern printing of the gap structure in femtosecond laser DMD projection lithography.

Neural network-based inverse lithography technology (NNILT) has been used to improve the computational efficiency of large-scale mask optimization for advanced photolithography. NNILT is now mostly based on labels, and its performance is affected by the quality of labels. It is difficult for NNILT to achieve high performance and extrapolation ability for mask optimization without using labels. Here, we propose a label-free NNILT (LF-NNILT), which is implemented completely without labels and greatly improves the printability of the target layouts and the manufacturability of the synthesized masks compared to the traditional ILT. More importantly, the optimization speed of LF-NNILT is two orders of magnitude faster than the traditional ILT. Furthermore, LF-NNILT is simpler to implement and can achieve better solvers to support the development of advanced lithography.

Label-free neural networks-based inverse lithography technology.

Additive and subtractive manufacturing of gold micro/nanostructures by using laser trapping and ablation

In digital micromirror device (DMD)-based projection photolithography, the throughput largely depends on the effectiveness of the laser energy utilization, which is directly correlated to the diffraction efficiency of DMD. Here, to optimize the DMD diffraction efficiency and thus the laser energy utilization, we calculate the diffraction efficiencies Ediffraction of DMD with various pitch sizes at wavelengths ranging from 200 nm to 800 nm, using the two-dimensional blazed grating diffraction theory. Specifically, the light incident angle is optimized for 343 nm laser and 7.56 μm pitch-size DMD, and the maximum single-order diffraction efficiency Ediffraction is increased from 40% to 96%. Experimentally, we use the effective energy utilization ηeff = Ediffraction,(m,n)/Σ[Ediffraction,(m,n)] at the entrance pupil plane of the objective to verify the effectiveness of the optimized illumination angle in a lithography illumination system with parallel beams of two wavelengths (343 nm and 515 nm). The ηeff of a "blaze" order at a 34° angle of incidence can be optimized up to 88%. The experimental results are consistent with the tendency of the calculated results, indicating that this optimization model can be used to improve the energy utilization of projection lithography with the arbitrarily designable wavelengths and the DMD's pitch size.

Maximizing energy utilization in DMD-based projection lithography.

Plasmon-enhanced nanosoldering of silver nanoparticles for high-conductive nanowires electrodes

The emerging demand for device miniaturization and integration prompts the patterning technique of micronano-cross-scale structures as an urgent desire. Lithography, as a sufficient patterning technique, has been playing an important role in achieving functional micronanoscale structures for decades. As a promising alternative, we have proposed and demonstrated the maskless optical projection nanolithography (MLOP-NL) technique for efficient cross-scale patterning. A minimum feature size of 32 nm, which is λ/12 super resolution breaking the optical diffraction limit, has been achieved by a single exposure. Furthermore, multiscale two-dimensional micronano-hybrid structures with the size over hundreds of micrometers and the precision at tens of nanometers have been fabricated by simply controlling the exposure conditions. The proposed MLOP-NL technique provides a powerful tool for achieving cross-scale patterning with both large-scale and precise configuration with high efficiency, which can be potentially used in the fabrication of multiscale integrated microsystems.

λ/12 Super Resolution Achieved in Maskless Optical Projection Nanolithography for Efficient Cross-Scale Patterning.

Light-driven micron-scale 3D hydrogel actuator produced by two-photon polymerization microfabrication

In this work, we demonstrate a developed 3D printing based on two-photon polymerization for achieving millimeter-scale, micron-accuracy 3D structures (MM-3DS), which combines the femtosecond laser of 800 nm and low magnification objective lens of 10×. The commercial photoresist SU-8 is used in 3D printing system for improving mechanical strength and chemical stability of MM-3DS. The 3D microstructures are preprogrammed and optimized by considering the scanning mode and experiment parameters. During 3D printing process, micron features are written within the interior of SU-8 film via localized polymerization driven by nonlinear two-photon absorption process. By the 3D movement in ~1 mm scale of the focused beam, a customized MM-3DS can be produced. We have fabricated a customized MM-3DS with a size of 1.6 mm and an accuracy of 10 μm. The influence of volume for the printing structures Vs on the printing time T exhibits a linear behavior, indicating that the printing speed is 0.248 mm3/h under the current conditions. This technology offers a flexible and low-cost method of generating highly customizable, precisely controlled MM-3DS, which is promising for the manufacture of complex functional structures and devices for the microfluidics, microelectronics, photonics and so on.

Additive manufacturing of millimeter-scale micron-accuracy 3D structures

We have introduced a novel water-soluble two-photon photoinitiator based on the host-guest interaction between 3,6-bis[2-(1-methyl-pyridinium)vinyl]-9-pentyl-carbazole diiodide (BMVPC) and cucurbit[7]uril (CB7) because most of the commercial photoinitiators have poor two-photon initiating efficiency in aqueous solutions. The binding ratio of BMVPC and CB7 was determined as 1:1 by isothermal titration calorimetry and quantum chemical calculation. The formation of the host-guest complex increases the two-photon absorption cross-section about five times, and improves the water solubility required as the photoinitiator for hydrogel fabrication. The BMVPC-CB7 inclusion complex was used as the one-component photoinitiator, and the polyethylene glycol diacrylate with promising biocompatibility was used as the hydrogel monomer to form the aqueous-phase photoresist system applied to two-photon polymerization microfabrication. A relatively low laser threshold of 4.5 mW, a high fabricating resolution of 180 nm, and the true three-dimensional (3D) fabricating capability in the aqueous solution have been obtained by using the as-prepared photoresist system. Finally, 3D engineering hydrogel scaffold microstructures with low toxicity and good biocompatibility have been fabricated and cocultured with living HeLa cells, which demonstrates the potential for further application in tissue engineering.

Cucurbit[7]uril-Carbazole Two-Photon Photoinitiators for the Fabrication of Biocompatible Three-Dimensional Hydrogel Scaffolds by Laser Direct Writing in Aqueous Solutions.

Poly(ethylene) glycol diacrylate(PEGDA)-based hydrogel materials with the excellent biocompatibility are widely used not only for cell culturing and tissue engineering but also for damaged bone repairing. In order to guarantee the stability of PEGDA as cell scaffolds and the compatibility with the host tissue, a further knowledge of interaction between PEGDA micronanostructure and cells is indispensable. In this study, two kinds of three-dimensional PEGDA micronanostructures have been designed and fabricated by two-photon polymerization for fibroblasts culturing. The PEGDA (average molecular weight 700) used in our study can preferably reconcile with a quantitative crosslinker to enhance the mechanical strength of structures. The polymerized line width as a function of the experimental conditions such as laser power and scanning speed during the two-photon polymerization has been investigated. Through investigating the adhesion, proliferation, and spread of fibroblasts on PEGDA micronanostructures in vitro, a response between micro-structures and fibroblast has been investigated. This study would provide the potential application of PEGDA hydrogel in biophotonics and tissue engineering.

Biocompatible three-dimensional hydrogel microstructures fabricated by two-photon polymerization

The biocompatibility of the three-dimensional (3D) hydrogel cell scaffolds that sodium hyaluronate (SH) and carboxymethyl chitosan (Chitosan) has been investigated. The minimum processing threshold of 2.94 mW and the feature line width of 80 nm have been obtained by the two-photon polymerization (TPP) technology using the as-prepared biocompatible photoresist. Through tuning the contents of the cross-linker in the hydrogel, the mechanical property of 3D hydrogel scaffold can be optimized to ensure the stability and affinity of scaffold. Furthermore, we have fabricated the SH and Chitosan assisted 3D hydrogel cell scaffolds and investigated the biocompatibility. This study provides a facile method to develop 3D biocompatible hydrogel cell scaffold, which would open up new avenues for the potential application in tissue engineering.

Biocompatible Three-Dimensional Hydrogel Cell Scaffold Fabricated by Sodium Hyaluronate and Chitosan Assisted Two-Photon Polymerization

Stepwise Optimized 3D Printing of Arbitrary 3D Structures at Millimeter Scale with High Precision Surface

Here, we report a preparation method to fabricate 3D micro-cones with controllable morphology based on two-photon photolithography. Two-photon photolithography offers the unique ability to create arbitrarily complex 3D polymeric structures. The voxel shape of polymerization point is crucial for the topography of the micro-cone structure. Therefore, the relationship between focused voxel features of femtosecond laser and the shape of micro-cone were analyzed systematically, and a micro-cone structure with a cone height of 2 μm, cone tip of 50 nm, and a cone angle of 20° was successfully obtained in this study. In addition, 3D micro-cone structures with 10°, 20°, and 30° sharp corners have been fabricated by means of controlling the relative movement between laser focus and moving direction. Besides, the structures with a varied slope angle from 0° to 90° on the substrate surface can be obtained by controlling the post treatment process. Furthermore, a large array of 3D micro-cones has been achieved based on the proposed preparation method.

Three-dimensional micro-cones fabricated via two-photon photolithography

We report a flexible and efficient method to pattern two-dimensional (2D) multi-scale structures by digital-mask projective lithography (DMPL) with an alterable projective scaling system. In the developed DMPL system, femtosecond laser was modulated by digital micromirror device (DMD) to generate a designable intensity distribution with digital image information. The projective law of this DMPL system based on the geometric optics theory verified for different projective scaling lens systematically has been studied. With the combination of the customizable DMD elements and alterable projective scaling system, 2D designable patterned microstructures with multi-scale size range from millimeter to hundred nanometer have been achieved by a single exposure. In addition, an engineered Fresnel zone plate (FZP) with numerical aperture (NA) of 0.36 and focal length of 114 μm has been achieved by a single exposure of 1.2 s. The acquisition of the array of FZP lens shows the stability and efficiency of the pattern process. The proposed method could be expected to play an important role in the flexible and efficient fabrication of engineered 2D multi-scale structures.We report a flexible and efficient method to pattern two-dimensional (2D) multi-scale structures by digital-mask projective lithography (DMPL) with an alterable projective scaling system. In the developed DMPL system, femtosecond laser was modulated by digital micromirror device (DMD) to generate a designable intensity distribution with digital image information. The projective law of this DMPL system based on the geometric optics theory verified for different projective scaling lens systematically has been studied. With the combination of the customizable DMD elements and alterable projective scaling system, 2D designable patterned microstructures with multi-scale size range from millimeter to hundred nanometer have been achieved by a single exposure. In addition, an engineered Fresnel zone plate (FZP) with numerical aperture (NA) of 0.36 and focal length of 114 μm has been achieved by a single exposure of 1.2 s. The acquisition of the array of FZP lens shows the stability and efficiency of the pattern p...

Multi-scale structure patterning by digital-mask projective lithography with an alterable projective scaling system

Magnetic-field-driven ultra-small 3D hydrogel microstructures: Preparation of gel photoresist and two-photon polymerization microfabrication

In this study, two kinds of novel carbazole-based ethynylpyridine salts: 3,6-bis[2-(1-methylpyridinium)ethynyl]-9-pentyl-carbazole diiodide (BMEPC) and 3,6-bis[2-(1-methylpyridinium)ethynyl]-9-methyl-carbazole diiodide (BMEMC) have been employed as photosensitizers owing to their excellent antibacterial activity. These molecules possess symmetric A−π–D−π–A-type structures, which would bring in the unique optical properties. The inhibition zone measurement of a gradient concentration from 0 to 100 μM showed BMEPC and BMEMC photoinduced antibacterial activity against Escherichia coli. Diameters of zone of inhibition were up to 15 and 14 mm under laser irradiations. Under the exposure of the laser of 442 nm with a power density of 20 mW/cm2, the minimum inhibitory concentrations (MICs) of BMEPC on E. coli were between 3.5 and 6.9 μM and that of BMEMC were between 9.4 and 18.8 μM, respectively. In the dark experiments as a control, the MIC value is between 6.9 and 13.8 μM for BMEPC, whereas it is between 187.5 and 225.0 μM for BMEMC. By the comparison of the MIC values of BMEPC and BMEMC with laser irradiation and in dark, the laser-induced toxicity on bacteria is more evident, though both of the derivatives have dark toxicity. With the laser irradiation duration of 30 s and 10 min for BMEPC and BMEMC, respectively, the survival rate of E. coli approximates zero. An antibacterial mechanism has been proposed based on the electron paramagnetic resonance characterization, which indicates that a nitride radical is generated under laser irradiation. The carbazole-based ethynylpyridine photosensitizers would provide high potential for further applications in photodynamic therapy.

Laser-Induced Antibacterial Activity of Novel Symmetric Carbazole-Based Ethynylpyridine Photosensitizers

The three-dimensional (3D) focus exhibiting pagoda-like light intensity distribution has been realized with the assistance of interference of the incident beam and the reflected beam. Benefiting from this designable laser focus tailored by the polymerization threshold, we have fabricated 3D multilayer structures with the submicron-scale by two-photon polymerization with a single scan. The light intensity distribution in the focus is simulated by the Fresnel formula, which indicates the mechanism for modulating the 3D multilayer submicrostructures with designable cross-section morphology. Furthermore, the influences of laser power and focus height on the linewidth have been investigated experimentally and theoretically. The multilayer submicrostructure fabricated by a single scan and the morphology modulation mechanism proposed in this study would be of profound importance for further applications in the fields of photonic devices, microfabrication, and biomimetic surfaces.

Tunable multilayer submicrostructures fabricated by interference assisted two-photon polymerization

Mechanical property of PEG hydrogel and the 3D red blood cell microstructures fabricated by two-photon polymerization

The microtechnology of controlling stimuli-responsive biomaterials at micrometer scale is crucial for biomedical applications. Here, we report bovine serum albumin (BSA)-based three-dimensional (3D) microstructures with tunable surface morphology and pH-responsive properties via two-photon polymerization microfabrication technology. The laser processing parameters, including laser power, scanning speed, and layer distance, are optimized for the fabrication of well-defined 3D BSA microstructures. The tunable morphology of BSA microstructures and a wide range of pH response corresponding to the swelling ratio of 1.08-2.71 have been achieved. The swelling behavior of the microstructures can be strongly influenced by the concentration of BSA precursor, which has been illustrated by a reasonable mechanism. A panda face-shaped BSA microrelief with reversible pH-responsive properties is fabricated and exhibits unique "facial expression" variations in pH cycle. We further design a mesh sieve-shaped microstructure as a functional device for promising microparticle separation. The pore sizes of microstructures can be tuned by changing the pH values. Therefore, such protein-based microstructures with controllable morphology and pH-responsive properties have potential applications especially in biomedicine and biosensors.

Protein-Based 3D Microstructures with Controllable Morphology and pH-Responsive Properties.

We have demonstrated an approach of silver nanostructure microfabrication by femtosecond laser direct writing of silver ion aqueous solution containing biocompatible amino acids with different molecular architectures. The amino acids-assisted multiphoton photoreduction (MPR) lowers the incident femtosecond laser threshold to 0.32 mW for glycine, 0.72 mW for valine, 0.6 mW for proline, and 0.35 mW for leucine. The line widths of the silver nanowires are varied with the composition of the biocompatible amino acids. The highest resolution of 186 nm has been achieved. Furthermore, the corresponding electrical conductivities of silver nanowires are determined to be 1.48 × 10–6, 4.1 × 10–7, 7.04 × 10–7, and 1.35 × 10–6 Ω m, which have been significantly improved compared to that of the previously reported silver wires fabricated by MPR microfabrication. The proposed protocol for fabricating silver nanostructure would pave the way for fabricating metallic nanostructures and play an extremely important role in th...

Laser Direct Writing of Silver Nanowire with Amino Acids-Assisted Multiphoton Photoreduction

We present the design and realization of silver grid transparent electrodes (SGTEs) easily fabricated by femtosecond laser direct writing of silver aqueous solution. The fabricated SGTEs with a sheet resistance down to 47 Ω/□ and optical transmittance up to 93% are demonstrated. These sheet resistance and transmittance values are comparable to commercially available indium tin oxide. High uniform morphology of the directly written SGTEs results in the ultra-stable tailored performance parameter at electronic and optical fields. The sheet resistance and transmittance can be tailored precisely by manipulating the filling fraction of the uniform SGTEs. This study provides an approach for creating SGTEs in a controllable fashion, and the SGTEs exhibit high transmittance and low sheet resistance, which could open up new avenues towards widespread application in electronics, photovoltaics, and optoelectronics.

Tailored silver grid as transparent electrodes directly written by femtosecond laser

We propose a flexible design for implementation of the Luneburg lens with gradient photonic crystals. The full-wave simulation results demonstrate the excellent performance of omnidirectional focusing of the designed Luneburg lens over a broad frequency band, and firstly exhibit anisotropic focusing in the designed Luneburg lens with a specific frequency band. In this study, our effort is focused on figuring out the operating wavelength range where the effective medium approximation theory is applicable, and the mechanism for generating anisotropic and omnidirectional focusing in Luneburg lens structure.

Anisotropic and omnidirectional focusing in Luneburg lens structure with gradient photonic crystals

Three-dimensional Luneburg lens at optical frequencies (Laser Photonics Rev. 10(4)/2016)

We focus on investigating the optical transmittance of silver grid transparent electrodes (SGTEs) in variable angle view theoretically and experimentally, rather than the optical transmittance under the normal incidence. The variable angle transmittance (VAT) values of SGTEs are measured on a home-made experimental setup. The experimental results about difference of the transmittance difference under different angles are small and negligible, although the measured angle is changed. Theoretically, the physical mechanism on nearly constant transmittance for different angle view can be well explained according to the theory of geometrical optics. This study provides an approach for investigating the VAT values of SGTEs in a controllable fashion and the influence of viewing angle of the touch screen.

Variable angle transmittance of silver grid transparent electrodes

A Luneburg lens is a fascinating gradient refractive index (GRIN) lens that can focus parallel light on a perfect point without aberration in geometrical optics. Constructing a three‐dimensional (3D) Luneburg lens at optical frequencies is a challenging task due to the difficulty of fabricating the desired GRIN materials. Here, we present the practical implementation of a 3D Luneburg lens at optical frequencies. Such a 3D Luneburg lens is designed with GRIN 3D simple cubic metamaterial structures, and fabricated with dielectric metamaterials by femtosecond laser direct writing in the commercial negative‐photoresist IP‐L. Simulated and experimental results exhibit an interesting 3D ideal focus for the infrared light. The protocol for developing the 3D Luneburg lens with ideal focus would prompt the potential applications in integrated light‐coupled devices and lab‐on‐chip integrated biological sensors based on infrared light.

Hydrogels with precise 3D configuration (3D hydrogels) are crucial for biomedical applications such as tissue engineering and drug delivery, which require the improvement of the spatial resolution on both the microscopic and the nanometric scale. In this study, a water soluble two-photon polymerization (TPP) initiator (WI) with high initiating efficiency was prepared by using a poloxamer (PF127) to encapsulate 2,7-bis(2-(4-pentaneoxy-phenyl)-vinyl)anthraquinone via a hydrophilic-hydrophobic assembly. The threshold energy for WI was 6.29 mW at a linear scanning speed of 10 μm s-1, which was much lower than those reported previously. A lateral spatial resolution of 92 nm was achieved as the resolution breakthrough of 3D hydrogels. Finally, the microstructure with high accuracy simulating the morphology of adenovirus was fabricated at the laser power close to the threshold energy of TPP, further demonstrating the ultrahigh resolution of 3D hydrogels.

3D hydrogels with high resolution fabricated by two-photon polymerization with sensitive water soluble initiators.

The photonic band gap effect which originates from the translational invariance of the periodic lattice of dielectrics has been widely applied in the technical applications of microwave, telecommunication and visible wavelengths. Among the various examples, polymers based three dimensional (3D) photonic crystals (PhCs) have attracted considerable interest because they can be easily fabricated by femo-second (fs) ultrafast laser direct writing (DLW) method. However, it is difficult to realize complete band gap in polymers PhCs due to the low index contrast between polymers and air. Here, we report the design and experimental realization of light's nonreciprocal propagation in woodpile PhCs fabricated with DLW method. Firstly, we fabricated several polymers woodpile PhCs on glass substrate with different crystal planes. The Fourier transform infrared spectroscopy (FTIR) measurements are in agreement with the theoretical predictions, which proves the validity and the accuracy of our DLW method. Further measurements of the transmission spectra with respect to the incident angle reveal that the surface crystal planes and incident wave vectors play important roles in the optical response. Furthermore, we designed and fabricated a 30° PhC wedge. And we find nonreciprocal transmission effect between the forward and backward waves, resulting from the nonsymmetrical refraction of the light in different planes. Our results may find potential applications in future 3D photonic integrated circuits and pave the way for the fabrication of other photonic and optical devices with DLW method.

Fabrication and optical transmission characteristics of polymers woodpile photonic crystal structures with different crystal planes

Transition metal (Mn, Fe, Co and Ni)-doped tungsten oxides nanoparticles with magnetic properties may be applied in various catalysts such as water treatment as they are easy to be recycled. Structural, electronic and magnetic properties of TMn@W[Formula: see text]O[Formula: see text] (TM=Mn, Fe, Co and Ni, [Formula: see text]=1–4) clusters have been calculated at PBE level. The results reveal that the centers of the TM[Formula: see text] clusters are in accordance with that of the W[Formula: see text]O[Formula: see text] clusters while the TM4 clusters deviate obviously from the center of the W[Formula: see text]O[Formula: see text] cages. All TMn@W[Formula: see text]O[Formula: see text] clusters exhibit slightly less structural stability and obviously more chemical reactivity than the W[Formula: see text]O[Formula: see text] clusters. Mülliken spin densities of a TM atom embedded are almost kept except for the Ni@W[Formula: see text]O[Formula: see text] clusters. The spin densities of TMn clusters in the TM3@W[Formula: see text]O[Formula: see text] and TM4@W[Formula: see text]O[Formula: see text] clusters are offset. The magnetic TM modification strategy is helpful to design recyclable tungsten oxide catalysts.

First principles calculations on the structures, electronic and magnetic properties of the TMn@W12O36 (TM=Mn, Fe, Co and Ni, n =1–4) clusters

Optimized structural and mechanical properties of borophosphate glass

Low-temperature sintering and ferrimagnetic properties of LiZnTiMn ferrites with Bi2O3-CuO eutectic mixture

The effects of Bi modification on the microstructural development and gyromagnetic properties of low-temperature sintered ferrites with composition of Li0.42Zn0.27Ti0.11Mn0.1Fe2.1−xBixO4 (x = 0.0-0.1) have been studied in order to adapt the development of low-temperature cofired ceramics technology (LTCC) and produce gyromagnetic devices with a multilayer process. In the present work, a pure spinel phase can be formed with a sintering temperature ranging from 880°C to 900°C, which allows them to be co-fired with silver. We found that Bi3+ ions could enter into the ferrite lattice, which enhanced the grain growth and densification during sintering due to the activation of the lattice. Results show that the modifying of x = 0.003 cannot only double saturation induction but also drastically reduce ferromagnetic resonance line width at 9.3 GHz, indicating that Bi modification is a good approach for lowing the sintering temperature of LiZnTiMn ferrites.

Composition, microstructures and ferrimagnetic properties of Bi-modified LiZnTiMn ferrites for LTCC application

A reversible metabolic stress-sensitive regulation of CRMP2A orchestrates EMT/stemness and increases metastatic potential in cancer.

Spindle cell carcinoma (SCC) is a rare pulmonary malignancy, accounting for only 0.2%–0.3% of all lung cancers. Therefore, the prognosis and treatment of pulmonary SCC is unclear. There are only 13 reported cases in literature, only three of which had a survival of more than 11 months. Here we reported a long-term survival of a patient with pulmonary SCC who underwent treatment with traditional Chinese medicine. At the most recent follow-up in July 2018, her survival after diagnosis is 48 months and she continues to do well. To our knowledge, this is the longest survival of late stage SCC with the largest tumour burden.

Long-term survival in a patient with pulmonary spindle cell carcinoma treated with traditional Chinese medicine

Objective: To evaluate the efficacies and adverse reactions of the chemotherapy with capecitabine combined with hyperthermic intraperitoneal chemotherapy with cisplatin contrast to  intraperitoneal injection of lentinan in the treatment of elderly patients with advanced gastric cancer and malignant ascites. Methods: Sixty-three elderly patients with advanced gastric carcinoma and malignant ascites were randomly divided into two groups: the study group receiving oral capecitabine combined with hyperthermic intraperitoneal chemotherapy with cisplatin, and the control group receiving oral capecitabine combined with intraperitoneal injection of lentinan. The treatment was repeated every 21-28 days. All patients received 2 cycles of chemotherapy. Efficacy and toxicities were evaluated after 2 cycles of treatment. Results: The control rates [complete response (CR)+partial response (PR) for malignant ascites in the study group and the control group were 75.8% and 50.0%, respectively; the disease control rates for measurable lesions [(CR+PR+stable disease (SD)] were 66.7% and 53.3%, respectively; the improved rates for KPS were 69.7% and 66.7%, respectively. The main toxicities were nausea, vomitting, diarrhea, myelo- suppression and hand–foot syndrome, the adverse reactions for most patients were grades Ⅰ-Ⅱ. No patients died from the adverse reactions. Conclusion: The method of oral capecitabine combined with hyperthermic intraperitoneal chemotherapy with cisplatin in the treatment of elderly patients with advanced gastric cancer was effective and safty, and can improve the life quality of the patients. It should be widely spreaded in clinics. DOI:10.3781/j.issn.1000-7431.2014.44.153

Clinical observation of capecitabine combined with hyperthermic intraperitoneal chemotherapy with cisplatin in the treatment of elderly patients with advanced gastric cancer and malignant ascites

Chemotherapeutic drugs endow gastric cancer mesenchymal stem cell with stronger tumor-promoting ability

Gastric cancer derived mesenchymal stem cells promoted DNA repair and cisplatin resistance through up-regulating PD-L1/Rad51 in gastric cancer.

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association

Gastric cancer mesenchymal stem cells via the CXCR2/HK2/PD-L1 pathway mediate immunosuppression.

Lactate induced mesenchymal stem cells activation promotes gastric cancer cells migration and proliferation.

Gastric cancer-derived mesenchymal stem cells promote gastric cancer cell lines migration by modulating CD276 expression.

Human pluripotent stem cell (hPSC)–derived hepatocyte‐like cells (HLCs) are valuable tools to study liver biology. HLCs, however, lack certain key in vivo characteristics relevant to their physiological function. One such characteristic is cellular polarity, which is critical to hepatocyte counter‐current flow systems involving canalicular bile secretion and sinusoidal secretion of large quantities of serum proteins into blood. Model systems using non‐polarized hepatocytes, therefore, cannot recapitulate this physiological function of hepatocytes. Here, we describe a stepwise protocol to generate hPSC‐derived polarized HLCs (pol‐HLCs), which feature clearly defined basolateral and apical membranes separated by tight junctions. Pol‐HLCs not only display many hepatic functions but are also capable of directional cargo secretion, mimicking the counter‐current flow systems. We describe protocols for stem cell culture maintenance and for differentiating hPSCs into pol‐HLCs. In addition, we describe protocols to assay the pol‐HLCs for basic hepatic functions and polarized hepatic characteristics. Once successfully differentiated, these pol‐HLCs can be used as an in vitro model system to study hepatocyte biology, disease mechanisms, genetic variation, and drug metabolism. The establishment of hepatic polarity from non‐polarized hPSCs also provides a useful tool to study the development and maintenance of hepatic polarity. © 2022 Wiley Periodicals LLC.

Generation of Human Pluripotent Stem Cell‐Derived Polarized Hepatocytes

Background Gastric cancer (GC) is the third leading cause of cancer-associated deaths worldwide. Stromal cells, especially mesenchymal stem cells (MSCs), play significant roles in the development of therapy resistance depending on their paracrine function. The PD-1/PD-L1 crosstalk between cancer and immune cells has been well studied. Emerging evidence suggests that PD-L1 also contributes to tumor resistance to therapy. Methods Cell survival and apoptosis were assessed using CCK-8, colony formation, and flow cytometry assays. Protein alterations were analyzed via Western blot. Gene knockdown and overexpression were achieved with siRNA/shRNA and lentiviral infection, respectively. Drug effects on tumors in vivo were assessed with xenografts in nude mice. In addition, GC patient samples after chemotherapy treatment were collected to observe the relationship between chemotherapy effect and CTCF or PD-L1. Results In response to 5-fluorouracil or paclitaxel treatment, GCMSC-CM enhanced the cell viability and decreased the apoptosis rate. Furthermore, blocking PD-L1 or CTCF in GC cells prevented GCMSC-induced drug resistance accompanied by a decline in cell stemness. Consistent with these in vitro observations, mice treated with GCMSC-CM showed a lower sensitivity to 5-fluorouracil. In addition, high expression of CTCF and PD-L1 was associated with poor chemotherapy progression in the clinic. Conclusion Study results demonstrate a mechanism where GCMSC-CM promotes GC chemoresistance by upregulating CTCF-PD-L1 and provide strong evidence in support of targeting CTCF-PD-L1 signaling as a strategy to prevent resistance in the clinic.

Inhibition of CCCTC Binding Factor-Programmed Cell Death Ligand 1 Axis Suppresses Emergence of Chemoresistance Induced by Gastric Cancer-Derived Mesenchymal Stem Cells

Gastric cancer-derived exosomes induce PD-L1 expression on human bone marrow mesenchymal stem cells through the AKT-c-Myc signal axis

Methods and Results We isolated primary CFs from Sprague-Dawley rats (1–3 days old) and treated them with lipopolysaccharide (LPS) and LPS+sEVs. RNA sequencing analysis revealed that angiopoietin-like 4 (Angptl4) was increased in the LPS+sEVs group more than in the LPS group. After inhibition of Angptl4 expression in sEVs and CFs, cell proliferation, Transwell migration, and tube formation assays were used to detect the angiogenic activity of human umbilical vein endothelial cells. β-Catenin expression in CFs was detected by western blotting. The β-catenin inhibitor ICG001 was used to examine whether β-catenin was involved in the proangiogenic potential of CFs promoted by sEVs. sEVs enhanced the proangiogenic potential of CFs under inflammatory conditions, which was associated with β-catenin signaling. The proangiogenic potential of CFs was decreased when Angptl4 was knocked down in CFs and in hucMSCs. Conclusions The sEVs regulated CFs to promote angiogenesis via Angptl4 in an inflammatory environment. This may provide a research basis for treating myocardial injury with sEVs.

Small Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells Enhanced Proangiogenic Potential of Cardiac Fibroblasts via Angiopoietin-Like 4

Objective To investigate whether conditional medium of gastric cancer mesenchymal stem cells (GCMSCs-CM) could up-regulate the expression of programmed death 1 ligand 1 (PD-L1) and promote gastric cancer progression by vestigial-like protein 4 (VGLL4). Methods Western blot was used to detect the expression of VGLL4 in SGC-7901, HGC-27 and MGC-803 gastric cancer cells. The expression of VGLL4 in HGC-27 and SGC-7901 cells was inhibited by being transfected with VGLL4 specific siRNA and plasmid was used to overexpress VGLL4 in SGC-7901 cells. The gastric cancer cells were divided into control group, GCMSCs-CM treatment group, VGLL4 interference or overexpression group, and VGLL4 interference followed by GCMSCs-CM treatment group. The expression of PD-L1 in each group was detected by Western blot and real time quantitative PCR (qRT-PCR). The proliferation of SGC-7901 cells was detected by colony formation assay. The migration of SGC-7901 cells was detected by TranswellTM migration assay. Human peripheral blood mononuclear cells adoptive NCG immunodeficiency mouse (PBMCs-NCG) subcutaneous tumor model was constructed to observe the tumor growth in mice. The mice were divided into control group, GCMSCs-CM treatment group, VGLL4 knockdown group, and VGLL4 knockdown followed by GCMSCs-CM treatment group. VGLL4 and PD-L1 mRNA levels of tumor tissue were detected by qRT-PCR. Immunohistochemical staining was used to detect the expression of VGLL4, PD-L1, ki67, CD8 and granzyme B (GZMB). Results VGLL4 is expressed in SGC-7901, HGC-27 and MGC-803 cells. The expression of PD-L1 mRNA and protein decreased significantly in SGC-7901 and HGC-27 cells transfected with siVGLL4. The expression of PD-L1 mRNA and protein was up-regulated after overexpression of VGLL4 in SGC-7901 cells. The expression of VGLL4 increased after GCMSCs-CM treatment of HGC-27 and MGC-803 cells. Inhibition of VGLL4 in HGC-27 could reverse the up-regulation of PD-L1 by GCMSCs-CM. Inhibition of VGLL4 in SGC-7901 weakened the ability of GCMSCs-CM to promote cell proliferation and migration. Knockdown of VGLL4 inhibited the effect of GCMSCs-CM in promoting tumor growth in mice and enhanced the anti-tumor immunity of PBMCs-NCG mice. Conclusion GCMSCs-CM promotes the expression of PD-L1 and tumor growth by upregulating VGLL4 in gastric cancer cells.

Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology

[Conditional medium of gastric cancer mesenchymal stem cells promotes PD-L1 expression in gastric cancer cells and tumor growth via upregulating VGLL4].

Background and Objectives Galectin-3 promotes fibroblast-to-myofibroblast differentiation and facilitates injury repair. Previous studies have shown that exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-ex) promote the differentiation of myocardial fibroblasts into myofibroblasts under inflammatory environment. Whether hucMSC-ex derived Galectin-3 (hucMSC-ex-Galectin-3) plays an important role in fibroblast-to-myofibroblast differentiation is the focus of this study. Methods and Results Galectin-3 was knocked-down by siRNA in hucMSCs, and then exosomes were extracted. Fibroblasts were treated with LPS, LPS＋hucMSC-ex, LPS＋negative control-siRNA-ex (NC-ex), or LPS＋Galectin-3-siRNA-ex (si-ex) in vitro. The coronary artery of the left anterior descending (LAD) branch was permanently ligated, followed by intramyocardial injection with phosphate buffered saline(PBS), hucMSC-ex, hucMSC-NC-ex, or hucMSC-si-ex in vivo. Western blot, RT-PCR, and immunohistochemistry were used to detect the expression of markers related to fibroblast-to-myofibroblast differentiation and inflammatory factors. Migration and contraction functions of fibroblasts were evaluated using Transwell migration and collagen contraction assays, respectively. β-catenin expression was detected by western blot and immunofluorescence. The results showed that hucMSC-ex increased the protein expression of myofibroblast markers, anti-inflammatory factors, and β-catenin. HucMSC-ex also reduced the migration and promoted the contractility of fibroblasts. However, hucMSC-si-ex did not show these activities. Conclusions HucMSC-ex-Galectin-3 promoted the differentiation of cardiac fibroblasts into myofibroblasts in an inflammatory environment, which was associated with increased β-catenin levels.

Galectin-3 Derived from HucMSC Exosomes Promoted Myocardial Fibroblast-to-Myofibroblast Differentiation Associated with β-catenin Upregulation

Acute myocardial infarction (AMI) remains the main cause of mortality worldwide. Despite surgery and medical treatment, the non‐regeneration of dead cardio‐ myocytes and the limited contractile ability of scar tissue can lead to heart failure. Therefore, restoring blood flow in the infarcted area is important for the repair of myocardial injury. The objective of the present review was to summarize the factors influencing angiogenesis after AMI, and to describe the application of angiogenesis for cardiac repair. Collectively, this review may be helpful for relevant studies and to provide insight into future therapeutic applications in clinical practice.

Targeting angiogenesis in myocardial infarction: Novel therapeutics (Review)

The dysfunction of natural killer (NK) cells has been increasingly reported in malignancies, especially in solid tumours. Mesenchymal stem cells (MSCs) exhibit pleiotropic functions that include mediating immune cell exhaustion which is implicated in cancer progression. However, the association of MSCs derived from gastric cancer (gastric cancer mesenchymal stem cells: GCMSCs) with the dysfunction of NK cells remains poorly understood. In this study, we demonstrated that GCMSCs effectively contributed to the exhaustion of NK cells through the release of soluble factors. Furthermore, passivation of the antitumour effect in NK cells was closely associated with their dysfunctional state. The GCMSC-conditioned medium prevented the frequency and effector function of infiltrating NK cells in tumour-bearing mouse models, thus promoting tumour growth. Mechanistically, mammalian target of rapamycin (mTOR) signalling, a critical regulator of cellular metabolism that mediates the function of immune cells, was inhibited in NK cells treated with GCMSCs. However, the checkpoint receptor PD-1 was still present at minimal levels with or without GCMSCs. The study results revealed that GCMSCs contributed to dysfunctional NK cells involved at least partially in the inhibition of mTOR signalling, suggesting potential directions for NK cell-based cancer immunotherapy.

Gastric Cancer Mesenchymal Stem Cells Inhibit NK Cell Function through mTOR Signalling to Promote Tumour Growth

Background: Tumor-associated stromal cells have been widely recognized for their tumor-promoting capability involving paracrine signaling. However, the underlying mechanism and the effects of the molecules in the glycolysis pathway in gastric cancer-associated mesenchymal stem cells (GCMSCs) and gastric cancer cells on tumor progression remain unclear. Methods: The expression of hepatocyte growth factor (HGF) in GCMSCs and bone marrow mesenchymal stem cells (BMMSCs) was detected by enzyme-linked immunosorbent assay (ELISA). The effect of HGF derived from GCMSCs on the proliferation, metastasis, and HK2 expression of gastric cancer cells was evaluated in vitro and in vivo. The effects of G6PD on the production of HGF in mesenchymal stem cells (MSCs) were analyzed by immunoblotting. Results: HGF derived from GCMSCs promoted glycolysis, proliferation, and metastasis of gastric cancer by upregulating c-Myc-HK2 signal. The progression of the disease induced by GCMSCs decelerated in the absence of HK2. The expression of G6PD activated NF-κB signaling and stimulated the production of HGF in GCMSCs. Blocking HGF derived from GCMSCs decreased proliferation, metastasis, and angiogenesis of gastric cancer cells in vivo. Conclusions: GCMSCs highly expressed G6PD and facilitated the progression of gastric cancer through the G6PD-NF-κB-HGF axis coordinates. Blocking HGF derived from GCMSCs is a potential new therapeutic target for the treatment of gastric cancer.

G6PD-NF-κB-HGF Signal in Gastric Cancer-Associated Mesenchymal Stem Cells Promotes the Proliferation and Metastasis of Gastric Cancer Cells by Upregulating the Expression of HK2

Introduction The dysfunction of natural killer (NK) cells has been widely reported in malignancies, including in solid tumours. Gastric cancer mesenchymal stem cells (GCMSCs) are one of the vital elements of stromal cells in the tumour environment (TME) which possess immunosuppressive activity. This study aimed to determine whether GCMSCs are involved in the inhibition of NK cell immune function and explore its underlying mechanism. Material and methods CD107a and perforin expression of GCMSCs conditioned medium (GCMSCs-CM)-primed NK cells were detected by flow cytometry. To determine NK cell cytotoxicity, the CytoTox96 Non-Radioactive Cytotoxicity Assay kit was used. Glucose uptake and lactate production assay were performed to evaluate the metabolism state of NK cells treated with GCMSCs-CM. The expression of FBP1 in NK cells was analysed by immunoblotting. Results GCMSCs inhibited the degranulation capacity, perforin production and cytotoxicity of NK cells. GCMSCs-CM restrained NK cell glucose uptake and lactate production, thus weakening their glycolytic metabolism. FBP1 expression of NK cells was upregulated in the presence of GCMSCs-CM. Using FBP1 inhibitor could reverse the dysfunctional state of NK cells. Conclusions This study indicated that GCMSCs could exert immunosuppressive effects on NK cells by up-regulating FBP1 expression, opening up new avenues for NK cell-based GC immunotherapy.

Gastric cancer mesenchymal stem cells inhibit natural killer cell function by up-regulating FBP1

Colorectal cancer (CRC) is the third most common cancer in the world known for its poor recurrence-free prognosis. Previous studies have shown that it is closely linked with cancer stem cells (CSCs), which have self-renewal potential and the capacity to differentiate into diverse populations. Nanog is an important transcription factor that functions to maintain the self-renewal and proliferation of embryonic stem cells; however, many recent studies have shown that Nanog is also highly expressed in many cancer stem cells. To investigate whether Nanog plays a crucial role in maintaining the stemness of colorectal CSCs, RNA interference was used to downregulate Nanog expression in the CRC stem cell line, EpCAM+CD44+HCT-116 cells (CCSCs). We examined the anti-tumor function of Nanog in vitro and in vivo, using small interfering RNA. Our results revealed that the Nanog mRNA expression level in CCSCs was higher than that in HCT-116 cells. We found that the depletion of Nanog inhibited proliferation and promoted apoptosis in CCSCs. In addition, the invasive ability of CCSCs was markedly restricted when Nanog was silenced by small interfering RNA. Furthermore, we found that the silencing of Nanog decreased tumor size and weight and improved the survival rate of tumor-bearing mice. In conclusion, these findings collectively demonstrate that Nanog, which is highly expressed in CRC stem cells, is a key factor in the development of tumor growth, and it may serve as a potential marker of prognosis and a novel and effective therapeutic target for the treatment of CRC.

RNAi mediated silencing of Nanog expression suppresses the growth of human colorectal cancer stem cells.

Rationale: Mesenchymal stem cells (MSCs) have been the focus of many studies because of their abilities to modulate immune responses, angiogenesis, and promote tumor growth and metastasis. Our previous work showed that gastric cancer MSCs (GCMSCs) promoted immune escape by secreting of IL-8, which induced programmed cell death ligand 1 (PD-L1) expression in GC cells. Mounting evidence has revealed that PD-L1 expression is related to intrinsic tumor cell properties. Here, we investigated whether GCMSCs maintained a pool of cancer stem cells (CSCs) through PD-L1 signaling and the specific underlying molecular mechanism. Methods: Stem cell surface markers, aldehyde dehydrogenase (ALDH) activity, migration and sphere formation abilities were tested to evaluate the stemness of GC cells. PD-L1-expressing lentivirus and PD-L1 specific siRNA were used to analyze the effects of PD-L1 on GC cells stemness. Annexin V/PI double staining was used to assess apoptosis of GC cells induced by chemotherapy. Co-Immunoprecipitation (Co-IP) and Mass spectrometry were employed to determine the PD-L1 binding partner in GC cells. PD-L1Negative and PD-L1Positive cells were sorted by flow cytometry and used for limiting dilution assays to verify the effect of PD-L1 on tumorigenic ability in GC cells. Results: The results showed that GCMSCs enhanced the CSC-like properties of GC cells through PD-L1, which led to the resistance of GC cells to chemotherapy. PD-L1 associated with CTCF to contribute to the stemness and self-renewal of GC cells. In vivo, PD-L1Positive GC cells had greater stemness potential and tumorigenicity than PD-L1Negative GC cells. The results also indicated that GC cells were heterogeneous, and that PD-L1 in GC cells had different reactivity to GCMSCs. Conclusions: Overall, our data indicated that GCMSCs enriched CSC-like cells in GC cells, which gives a new insight into the mechanism of GCMSCs prompting GC progression and provides a potential combined therapeutic target.

Gastric cancer mesenchymal stem cells regulate PD-L1-CTCF enhancing cancer stem cell-like properties and tumorigenesis

Abstract The discovery of induced pluripotent stem cells (iPSCs) revolutionized the approach to cell therapy in regenerative medicine. Reprogramming of somatic cells into an embryonic‐like pluripotent state provides an invaluable resource of patient‐specific cells of any lineage. Implementation of procedures and protocols adapted to current good manufacturing practice (cGMP) requirements is critical to ensure robust and consistent high‐quality iPSC manufacturing. The technology developed at Allele Biotechnology for iPSC generation under cGMP conditions is a powerful platform for derivation of pluripotent stem cells through a footprint‐free, feeder‐free, and xeno‐free reprogramming method. The cGMP process established by Allele Biotechnology entails fully cGMP compliant iPSC lines where the entire manufacturing process, from tissue collection, cell reprogramming, cell expansion, cell banking and quality control testing are adopted. Previously, we described in this series of publications how to create iPSCs using mRNA only, and how to do so under cGMP conditions. In this article, we describe in detail how to culture, examine and storage cGMP‐iPSCs using reagents, materials and equipment compliant with cGMP standards. © 2020 The Authors. Basic Protocol 1: iPSC Dissociation Support Protocol 1: Stem cell media Support Protocol 2: ROCK inhibitor preparation Support Protocol 3: Vitronectin coating Basic Protocol 2: iPSC Cryopreservation Basic Protocol 3: iPSC Thawing

Human‐Induced Pluripotent Stem Cell Culture Methods Under cGMP Conditions

Introduction Glioma is the primary malignant brain tumor with poor prognosis. Berberine (BBR) was the potential drug for anti-tumor in glioma cells. Based on its limitation of poor aqueous solubility and instability, little information of BBR nanoparticles is reported in glioma. Methods Different solutions including 5% glucose, 1*PBS, ddH2O, 0.9% NaCl, cell culture medium were selected, and only 5% glucose and ddH2O exhibited BBR-related nanoparticles. After heating for a longer time or adding a higher concentration of glucose solution, BBR nanoparticles were detected by TEM analysis. The uptake of BBR-Glu or BBR-Water nanoparticles were detected by immunofluorescence analysis for BBR autofluorescence. Cell viability was measured by MTT assay and Western blotting analysis. Apoptosis was performed with flow cytometric analysis and was detected by cleaved caspase-3 immuno-fluorescent staining. Cell cycle was used by flow cytometric analysis. Cytoskeleton was observed by confocal analysis using the neuron specific Class III ß-tubulin and ß-tubulin antibodies. Mitochondrial-related proteins were detected by Western blotting analyses and mito-tracker staining in live cells. Mitochondrion structures were observed by TEM analysis. ROS generation and ATP production were detected by related commercial kits. The tracking of BBR-Glu or BBR-Water nanoparticles into blood–brain barrier was observed in primary tumor-bearing models. The fluorescence of BBR was detected by confocal analyses in brains and gliomas. Results BBR-Glu nanoparticles became more homogenized and smaller with dose- and time-dependent manners. BBR-Glu nanoparticles were easily absorbed in glioma cells. The IC50 of BBR-Glu in U87 and U251 was far lower than that of BBR-Water. BBR-Glu performed better cytotoxicity, with higher G2/M phase arrest, decreased cell viability by targeting mitochondrion. In primary U87 glioma-bearing mice, BBR-Glu exhibited better imaging in brains and gliomas, indicating that more BBR moved across the blood–brain tumor barrier. Discussion BBR-Glu nanoparticles have better solubility and stability, providing a promising strategy in glioma precision treatment.

Glucose-coated Berberine Nanodrug for Glioma Therapy through Mitochondrial Pathway

Cardioprotective effects of exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-exosomes) postmyocardial infarction (post-MI) have been reported in our previous study. It is known that fibroblasts are pro-inflammatory phenotypes, while myofibroblasts are anti-inflammatory phenotypes. This study aimed to investigate whether hucMSC-exosomes promoted cardiac fibroblast-to-myofibroblast differentiation in inflammatory environments and protected cardiomyocytes. Rats were performed by permanent ligation of the left anterior descending coronary artery and underwent intramyocardial injection of hucMSC-exosomes or phosphate-buffered saline (PBS) in surgery. Fibroblasts were stimulated by lipopolysaccharide (LPS) to create inflammatory environments in vitro. Western blot and immunohistochemical and immunofluorescence staining for α-smooth muscle actin were used to demonstrate fibroblast-to-myofibroblast differentiation. Transwell migration assay and CCK-8 assay were used to evaluate migration and proliferation of fibroblasts. Reverse transcription-polymerase chain reaction, western blot, and immunohistochemical staining were used to detect expressions of inflammatory factors. To investigate cardioprotective effects, cardiomyocytes were treated with supernatant derived from fibroblasts pretreated with LPS or LPS plus hucMSC-exosomes in hypoxic environments. Cardiomyocyte apoptosis was determined using TUNEL assay and western blot. Results indicated that hucMSC-exosomes increased the density of myofibroblasts in infarct areas during inflammatory phases post-MI, promoted fibroblast-to-myofibroblast differentiation in inflammatory environments, and attenuated inflammatory responses in vitro and in vivo. Culture medium derived from fibroblasts pretreated with LPS plus hucMSC-exosomes reduced cardiomyocyte apoptosis. In vivo, apoptotic cells in acute myocardial infarction (AMI)+exosomes groups were also less than AMI+PBS groups. In conclusion, hucMSC-exosomes can promote fibroblast-to-myofibroblast differentiation in inflammatory environments, then protecting cardiomyocytes.

Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Promote Fibroblast-to-Myofibroblast Differentiation in Inflammatory Environments and Benefit Cardioprotective Effects.

Increasing evidence supports the concept that cancer stem cells (CSCs) are responsible for cancer progression and metastasis, therapy resistance and relapse. In addition to conventional therapies for colon cancer, the development of immunotherapies targeting cancer stem cells appears to be a promising strategy to suppress tumor recurrence and metastasis. In the present study, dendritic cells (DCs) were pulsed with whole-tumor cell lysates or total RNA of CD44+ colon cancer stem cells (CCSCs) isolated from mouse colon adenocarcinoma CT-26 cell cultures and investigated for their antitumor immunity against CCSCs in vivo and in vitro. In a model of colon adenocarcinoma using BALB/c mice, a sequential reduction in tumor volume and weight was associated with an extended survival in tumor-bearing mice vaccinated with DCs pulsed with RNA or CCSC lysate. In addition, a lactate dehydrogenase assay indicated that cytotoxic T-cells derived from the treated mice exhibited strong cytotoxic activity. Additionally, an enzyme-linked immunosorbent assay revealed that the cytotoxic T-cells of the treated mice released higher levels of interferon-γ against CCSCs compared with those of the control group. In all experiments, the antitumor efficacy of the lysate-pulsed DC-treated and RNA-pulsed DC-treated groups were significantly higher compared with that of the DC-treated and control groups. The results of the present study indicated the potential use of DCs pulsed with cancer stem cell lysates as a potent therapeutic antigen to target CSCs in colon cancer. Additionally, the results provided a rationale for using lysate-pulsed DCs in vivo to eliminate residual tumor deposits in post-operative patients.

Dendritic cells loaded with CD44+ CT-26 colon cell lysate evoke potent antitumor immune responses

Gastric cancer mesenchymal stem cells derived IL-8 induces PD-L1 expression in gastric cancer cells via STAT3/mTOR-c-Myc signal axis

Oncostatin M (OSM) induces the differentiation of liver cancer stem cells (LCSCs) and increases sensitivity to the chemotherapeutic agent 5-fluorouracil, whereas salinomycin (Sal) induces apoptosis in cancer stem cells and inhibits the proliferation of liver cancer cells. However, there have been no studies investigating the anticancer effects of combination treatment with OSM and Sal. In the present study, we investigated the synergistic effects of OSM and Sal on LCSCs, the CD133+ subpopulations from HepG2 human liver cancer cells. CD133+ LCSCs were isolated using an immunomagnetic bead technique and identified through colony formation. After incubating with OSM and Sal, the ability of LCSC proliferation and invasion, as well as apoptosis rates were evaluated, and the expression of stemness-related genes was examined by quantitative real-time polymerase chain reaction. Additionally, the secretion of α-fetoprotein (AFP) and albumin (ALB) were analyzed by enzyme-linked immunosorbent assay. Our results indicated that OSM combined with Sal significantly suppressed LCSC proliferation and invasion and induced apoptosis, as determined by flow cytometry and increases in cleaved caspase-3 levels detected by western blotting. The results of the JC-1 staining assay indicated that this effect involved the mitochondrial pathway. Moreover, combination treatment reduced the expression of CD133 in LCSCs and suppressed stemness-related gene expression. Furthermore, the LCSCs produced lower levels of AFP and higher levels of ALB following combination treatment. In all experiments, combination treatment elicited more efficient anticancer effects on LCSCs as compared with single-drug treatment; therefore, our results demonstrated that combined treatment with OSM and Sal inhibited proliferation and induced differentiation and apoptosis in LCSCs, suggesting combined use of OSM and Sal as a therapeutic strategy for liver cancer.

Enhanced anticancer effect of oncostatin M combined with salinomycin in CD133+ HepG2 liver cancer cells

It has been previously reported that exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC)‑exosomes exhibit cardioprotective effects on the rat acute myocardial infarction (AMI) models and cardiomyocyte hypoxia injury models in vitro, however the exact mechanisms involved require further investigation. The present study aimed to investigate the repair effects of hucMSC‑exosomes on myocardial injury via the regulation of mothers against decapentaplegic homolog 7 (Smad7) expression. Compared with sham or normoxia groups (in vivo and in vitro, respectively), western blotting demonstrated that Smad7 expression was significantly decreased in the borderline area of infraction myocardium and in H9C2(2‑1) cells following hypoxia‑induced injury. Additionally, microRNA (miR)‑125b‑5p expression was markedly increased using reverse transcription‑quantitative polymerase chain reaction, but was reversed by hucMSC‑exosomes. Trypan blue staining and lactate dehydrogenase release detection demonstrated that cell injury was significantly increased in the AMI + PBS and hypoxia group compared with in the sham and normoxia groups and was inhibited by hucMSC‑exosomes. A dual luciferase reporter gene assay confirmed that Smad7 is a target gene of miR‑125b‑5p. In addition, miR‑125b‑5p mimics promoted H9C2(2‑1) cell injury following 48 h exposure to hypoxia. Downregulation of Smad7 expression under hypoxia was increased by miR‑125b‑5p mimics compared with the mimic negative control, and hucMSC‑exosomes partially alleviated this phenomenon. In conclusion, hucMSC‑exosomes may promote Smad7 expression by inhibiting miR‑125b‑5p to increase myocardial repair. The present study may provide a potential therapeutic approach to improve myocardial repair following AMI.

Exosomes derived from human umbilical cord mesenchymal stem cells improve myocardial repair via upregulation of Smad7.

The clinical application of human bone marrow mesenchymal stem cells (hBM-MSCs) has generated a great deal of interest because of their potential use in regenerative medicine and tissue engineering. However, safety concerns over hBM-MSCs limit their clinical application. In this study, we observed that hBM-MSC-conditioned medium (hBM-MSC-CM) promotes gastric cancer development via upregulation of c-Myc. Our results showed that c-Myc was upregulated in MGC-803 and BGC-823 cells after hBM-MSC-CM treatment. Moreover, we found that the c-Myc inhibitor JQ1 and c-Myc siRNA decreased the expression of c-Myc in hBM-MSC-CM-treated tumor cells in vitro. Additionally, hBM-MSC-CM enhanced the migration and glucose uptake of gastric cancer cells. In vivo studies showed that JQ1 inhibited hBM-MSC-CM-induced gastric cancer growth. These results indicated that hBM-MSC-CM induced gastric cancer growth via upregulation of c-Myc, which may be a potential risk factor and/or a therapeutic target for clinical applications.

Human Bone Marrow Mesenchymal Stem Cells Promote Gastric Cancer Growth via Regulating c-Myc

Gastric cancer mesenchymal stem cells (GC‐MSCs) can promote the development of tumour growth. The tumour‐promoting role of tumour‐associated MSCs and T cells has been demonstrated. T cells as the major immune cells may influence and induce a pro‐tumour phenotype in MSCs. This study focused on whether CD4+ T cells can affect GC‐MSCs to promote gastric cancer growth.

Enhanced gastric cancer growth potential of mesenchymal stem cells derived from gastric cancer tissues educated by CD4+ T cells

Several studies show that mesenchymal stem cells (MSCs) homing to tumors not only provide the microenvironment for tumor cells but also promote tumor growth and metastasis. However, the exact mechanism remains unclear. Our study aims to investigate the role of gastric cancer MSCs (GCMSCs)-derived IL15 during GC progression. The effects of IL15 secreted by GCMSCs on GC development were evaluated by detecting the stemness, epithelial-mesenchymal transition (EMT), and migration abilities of GC cell lines. The expression of IL15 in serum and tissues of GC patients was also assessed. We found that IL15 derived from GCMSCs enhanced stemness, induced EMT and promoted migration of GC cell lines. The level of IL15 was higher in GC patients both in serum and tissues compared with that in healthy donors, which was associated with lymph node metastasis. In addition, the results have shown that IL15 in GC microenvironment was mainly produced by GCMSCs. Moreover, IL15 upregulated Tregs ratio through activation of STAT5 in CD4+T cells was accompanied by elevated expression of programmed cell death protein-1 (PD-1). Our data proved that the high concentration of IL15 in tumor microenvironment, which was mainly secreted by GCMSCs, may contribute to tumor cell metastasis and offer a new opportunity to develop effective therapeutics for intercepting tumor progression.

Human Gastric Cancer Mesenchymal Stem Cell-Derived IL15 Contributes to Tumor Cell Epithelial-Mesenchymal Transition via Upregulation Tregs Ratio and PD-1 Expression in CD4+T Cell.

Background Bone marrow-derived mesenchymal stem cells (BM-MSCs) have been identified to be closely associated with cancer progression. Our previous experimental results showed that BM-MSCs promote tumor growth and metastasis of gastric cancer through paracrine-soluble cytokines or exosomes. However, the elements that affect the role of BM-MSCs in promoting tumor metastasis are not clear. It is known that thrombocytosis in cancer patients is very common. Recently, platelets are recognized to play a critical role in tumor progression. Purpose This study aims to observe the effect of BM-MSCs which were co-cultured with platelets on tumor cell metastasis. Methods Platelet aggregation rate and the expression of P-selectin of platelets co-incubated with conditioned medium of SGC-7901 cells and BM-MSCs were detected by flow cytometry and platelet aggregometer. We also analyzed the change of BM-MSCs after co-incubation with platelets or platelets which were treated with SGC-7901 cells using transwell assay and Western blot analysis. The proliferation and migration ability and expression of VEGF, c-Myc, and sall-4 in SGC-7901 cells treated with medium of BM-MSCs which were co-cultured with platelets were detected. SGC-7901 cells were injected into Balb/c nude mice and the extent of lung metastasis was observed. Both in vitro and in vivo assays were used to analyze the effect of platelets on enhancing the ability of BM-MSCs to promote cancer metastasis. Results Results suggested that BM-MSCs and tumor cells can promote platelet aggregation rate and the expression of P-selectin. The protein levels of α-smooth muscle actin, vimentin, and fibroblast activation protein in BM-MSCs were higher after co-incubation with platelets, and SB431542 was used to confirm the effect of TGF-β on transdifferentiation of BM-MSCs into cancer-associated fibroblasts. Medium of BM-MSCs treated with platelets enhanced the proliferation and migration ability of SGC-7901 cells. More lung metastases were found in mice which were injected with SGC-7901 cells treated with conditioned medium from BM-MSCs co-incubated with platelets. Conclusion Tumor cells and BM-MSCs activate platelets which can change the characteristics of BM-MSCs through secretion of TGF-β. Moreover, we found that platelets enhanced the effect of BM-MSCs on tumor metastasis, which suggested a potential target and approach for gastric cancer therapy.

Platelets enhance the ability of bone-marrow mesenchymal stem cells to promote cancer metastasis

Laboratory exercise is helpful for medical students to understand the basic principles of molecular biology and to learn about the practical applications of molecular biology. We have designed a lab course on molecular biology about the determination of single nucleotide polymorphism (SNP) in human REV3 gene, the product of which is a subunit of DNA polymerase ζ and SNPs in this gene are associated with altered susceptibility to cancer. This newly designed experiment is composed of three parts, including genomic DNA extraction, gene amplification by PCR, and genotyping by RFLP. By combining these activities, the students are not only able to learn a series of biotechniques in molecular biology, but also acquire the ability to link the learned knowledge with practical applications. This comprehensive experiment will help the medical students improve the conceptual understanding of SNP and the technical understanding of SNP detection. © 2017 by The International Union of Biochemistry and Molecular Biology, 45(4):299–304, 2017.

A comprehensive experiment for molecular biology: Determination of single nucleotide polymorphism in human REV3 gene using PCR–RFLP

Gastric cancer tissue‐derived mesenchymal stem cells impact peripheral blood mononuclear cells via disruption of Treg/Th17 balance to promote gastric cancer progression

Abstract Aims: Metallothionein 2A (MT2A) and nuclear factor-kappaB (NF-κB) are both involved in carcinogenesis and cancer chemosensitivity. We previously showed decreased expression of MT2A and IκB-α in human gastric cancer (GC) associated with poor prognosis of GC patients. The present study investigated the effect of diallyl trisulfide (DATS), a garlic-derived compound, and docetaxel (DOC) on regulation of MT2A in relation to NF-κB in GC cells. Results: DATS attenuated NF-κB signaling in GC cells, resulting in G2/M cell cycle arrest and apoptosis, culminating in the inhibition of cell proliferation and tumorigenesis in nude mice. The anti-GC effect of DATS was attributable to its capacity to epigenetically upregulate MT2A, which in turn enhanced transcription of IκB-α to suppress NF-κB activation in GC cells. The combination of DATS with DOC exhibited a synergistic anti-GC activity accompanied by MT2A upregulation and NF-κB inactivation. Histopathologic analysis of GC specimens from patients showed a significant increase in MT2A expression following DOC treatment. GC patients with high MT2A expression in tumor specimens showed significantly improved response to chemotherapy and prolonged survival compared with those with low MT2A expression in tumors. Innovation and Conclusion: We conclude that DATS exerts its anti-GC activity and enhances chemosensitivity of GC to DOC by epigenetic upregulation of MT2A to attenuate NF-κB signaling. Our findings delineate a mechanistic basis of MT2A/NF-κB signaling for DATS- and DOC-mediated anti-GC effects, suggesting that MT2A may be a chemosensitivity indicator in GC patients receiving DOC-based treatment and a promising target for more effective treatment of GC by combination of DATS and DOC. Antioxid. Redox Signal. 24, 839–854.

Epigenetic Upregulation of Metallothionein 2A by Diallyl Trisulfide Enhances Chemosensitivity of Human Gastric Cancer Cells to Docetaxel Through Attenuating NF-κB Activation

: We have previously demonstrated the cardioprotective effects of exosomes derived from mesenchymal stem cells (MSCs). It is well-known that the activation of Akt is involved in stem cell-induced cardioprotection. In the present study, we investigated whether exosomes released from Akt-overexpressing MSCs showed a beneficial effect on cardioprotection and angiogenesis. MSCs were collected from human umbilical cord (hucMSCs), and Akt was transfected into hucMSCs (Akt-hucMSCs) by using an adenovirus transfection system. Exosomes were isolated from control hucMSCs (Exo) and Akt-hucMSCs (Akt-Exo). An acute myocardial infarction model was created by ligation of the left anterior decedent coronary artery (LAD) in rats. Various source exosomes (400 µg of protein) were infused via the tail vein immediately after LAD ligation. The cardiac function was evaluated by using echocardiography after different treatments for 1 and 5 weeks, respectively. Endothelial cell proliferation, migration, and tube-like structure formation, as well as chick allantoic membrane assay, were used to evaluate the angiogenetic effects of Akt-Exo. The results indicated that cardiac function was significantly improved in the animals treated with Akt-Exo. In addition, Akt-Exo significantly accelerated endothelial cell proliferation and migration, tube-like structure formation in vitro, and blood vessel formation in vivo. The expression of platelet-derived growth factor D (PDGF-D) was significantly upregulated in Akt-Exo. However, the angiogenesis was abrogated in endothelial cells treated with the exosomes obtained from MSCs transfected with PDGF-D-siRNA. Our studies suggest that exosomes obtained from Akt-modified hucMSCs are more effective in myocardial infarction therapy through promoting angiogenesis. PDGF-D plays an important role in Akt-Exo-mediated angiogenesis.

SIGNIFICANCE
Cardioprotective effects of exosomes derived from mesenchymal stem cells (MSCs) have been demonstrated in previous studies. It is unknown whether exosomes released from Akt gene-modified MSCs have a better effect on regenerating ischemic myocardium. This study suggests that exosomes released from Akt gene-modified human umbilical cord MSCs are more effective in improving cardiac function through promoting angiogenesis, which may provide a basis for developing a new therapeutic strategy for acute myocardial infarction.

Exosomes Derived From Akt-Modified Human Umbilical Cord Mesenchymal Stem Cells Improve Cardiac Regeneration and Promote Angiogenesis via Activating Platelet-Derived Growth Factor D.

Reprogramming somatic cells to generate induced pluripotent stem cells (iPSCs) has presented the biomedical community with a powerful platform to develop new models for human disease. To fully realize the promise of this technology in cell therapy and regenerative medicine, creating iPSCs under current Good Manufacture Practice (cGMP) conditions is paramount. Some reports have described efforts in this regard, resulting in iPSC lines that are cGMP compliant. The technology developed at Allele Biotechnology for footprint-free, feeder-free, and xeno-free reprogramming using only mRNA is very suitable for creating iPSC lines through an established cGMP process. This technology has resulted in a licensing agreement between Allele Biotechnology and Ocata (formerly ACT, now a wholly owned division of Astellas) for clinical applications. All reagents and vessels are certified as cGMP-produced, all equipment and software are certifiable, and all procedures are carried out in Industry ISO 7 or Class 10,000-grade cleanrooms. In this revised version of the unit, we describe the core improvements to implement steps toward cGMP-compliant generation of iPSCs. Recreating a process close to cGMP production in academic research will make these findings more applicable to translational research. © 2016 by John Wiley & Sons, Inc.

cGMP Generation of Human Induced Pluripotent Stem Cells with Messenger RNA.

We have previously demonstrated the cardioprotective effects of exosomes derived from mesenchymal stem cells (MSCs). It is well known that the activation of Akt is involved in stem cell‐induced cardioprotection. In the present study, we investigated whether exosomes released from Akt‐overexpressing MSCs showed a beneficial effect on cardioprotection and angiogenesis. MSCs were collected from human umbilical cord (hucMSCs), and Akt was transfected into hucMSCs (Akt‐hucMSCs) by using an adenovirus transfection system. Exosomes were isolated from control hucMSCs (Exo) and Akt‐hucMSCs (Akt‐Exo). An acute myocardial infarction model was created by ligation of the left anterior decedent coronary artery (LAD) in rats. Various source exosomes (400 µg of protein) were infused via the tail vein immediately after LAD ligation. The cardiac function was evaluated by using echocardiography after different treatments for 1 and 5 weeks, respectively. Endothelial cell proliferation, migration, and tube‐like structure formation, as well as chick allantoic membrane assay, were used to evaluate the angiogenetic effects of Akt‐Exo. The results indicated that cardiac function was significantly improved in the animals treated with Akt‐Exo. In addition, Akt‐Exo significantly accelerated endothelial cell proliferation and migration, tube‐like structure formation in vitro, and blood vessel formation in vivo. The expression of platelet‐derived growth factor D (PDGF‐D) was significantly upregulated in Akt‐Exo. However, the angiogenesis was abrogated in endothelial cells treated with the exosomes obtained from MSCs transfected with PDGF‐D‐siRNA. Our studies suggest that exosomes obtained from Akt‐modified hucMSCs are more effective in myocardial infarction therapy through promoting angiogenesis. PDGF‐D plays an important role in Akt‐Exo‐mediated angiogenesis. Stem Cells Translational Medicine 2017;6:51–59

Exosomes Derived from Akt‐Modified Human Umbilical Cord Mesenchymal Stem Cells Improve Cardiac Regeneration and Promote Angiogenesis via Activating Platelet‐Derived Growth Factor D

Safety evaluation of exosomes derived from human umbilical cord mesenchymal stromal cell.

This study is aimed at investigating whether human umbilical cord mesenchymal stem cell- (hucMSC-) derived exosomes (hucMSC-exosomes) have a protective effect on acute myocardial infarction (AMI). Exosomes were characterized under transmission electron microscopy and the particles of exosomes were further examined through nanoparticle tracking analysis. Exosomes (400 μg protein) were intravenously administrated immediately following ligation of the left anterior descending (LAD) coronary artery in rats. Cardiac function was evaluated by echocardiography and apoptotic cells were counted using TUNEL staining. The cardiac fibrosis was assessed using Masson's trichrome staining. The Ki67 positive cells in ischemic myocardium were determined using immunohistochemistry. The effect of hucMSC-exosomes on blood vessel formation was evaluated through tube formation and migration of human umbilical vein endothelial cells (EA.hy926 cells). The results indicated that ligation of the LAD coronary artery reduced cardiac function and induced cardiomyocyte apoptosis. Administration of hucMSC-exosomes significantly improved cardiac systolic function and reduced cardiac fibrosis. Moreover, hucMSC-exosomes protected myocardial cells from apoptosis and promoted the tube formation and migration of EA.hy926 cells. It is concluded that hucMSC-exosomes improved cardiac systolic function by protecting myocardial cells from apoptosis and promoting angiogenesis. These effects of hucMSC-exosomes might be associated with regulating the expression of Bcl-2 family.

Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Relieve Acute Myocardial Ischemic Injury

Interleukin-23A is associated with tumor growth in Helicobacter-pylori-related human gastric cancer

Selective expression of tumor necrosis factor-related apoptosis-inducing ligand mediated by microRNA suppresses renal carcinoma growth

Mesenchymal stem cell-like cells from children foreskin inhibit the growth of SGC-7901 gastric cancer cells.

Oncogenic potential of BEST4 in colorectal cancer via activation of PI3K/Akt signaling

Circadian Clock Disruption Suppresses PDL1+ Intraepithelial B Cells in Experimental Colitis and Colitis-Associated Colorectal Cancer

Targeting Erbin in B cells for therapy of lung metastasis of colorectal cancer

The oncogene c‐Myc is aberrantly expressed and plays a key role in malignant transformation and progression of hepatocellular carcinoma (HCC). Here, we report that c‐Myc is significantly up‐regulated by tumor necrosis factor receptor–associated factor 6 (TRAF6), an E3 ubiquitin ligase, in hepatocarcinogenesis. High TRAF6 expression in clinical HCC samples correlates with poor prognosis, and the loss of one copy of the Traf6 gene in Traf6+/– mice significantly impairs liver tumorigenesis. Mechanistically, TRAF6 first interacts with and ubiquitinates histone deacetylase 3 (HDAC3) with K63‐linked ubiquitin chains, which leads to the dissociation of HDAC3 from the c‐Myc promoter and subsequent acetylation of histone H3 at K9, thereby epigenetically enhancing the mRNA expression of c‐Myc. Second, the K63‐linked ubiquitination of HDAC3 impairs the HDAC3 interaction with c‐Myc and promotes c‐Myc protein acetylation, which thereby enhances c‐Myc protein stability by inhibiting carboxyl terminus of heat shock cognate 70‐kDa–interacting protein–mediated c‐Myc ubiquitination and degradation. Importantly, TRAF6/HDAC3/c‐Myc signaling is also primed in hepatitis B virus–transgenic mice, unveiling a critical role for a mechanism in inflammation–cancer transition. In clinical specimens, TRAF6 positively correlates with c‐Myc at both the mRNA and protein levels, and high TRAF6 and c‐Myc expression is associated with an unfavorable prognosis, suggesting that TRAF6 collaborates with c‐Myc to promote human hepatocarcinogenesis. Consistently, curbing c‐Myc expression by inhibition of TRAF6 activity with a TRAF6 inhibitor peptide or the silencing of c‐Myc by small interfering RNA significantly suppressed tumor growth in mice. Conclusion: These findings demonstrate the oncogenic potential of TRAF6 during hepatocarcinogenesis by modulating TRAF6/HDAC3/c‐Myc signaling, with potential implications for HCC therapy.

Tumor Necrosis Factor Receptor–Associated Factor 6 Promotes Hepatocarcinogenesis by Interacting With Histone Deacetylase 3 to Enhance c‐Myc Gene Expression and Protein Stability

Liver metastasis is the main cause of death in patients with colorectal cancer (CRC). Here, we searched for CRC metastasis‐associated circular RNA in a mouse model of liver metastasis of CRC by using RNA (transcriptome)‐sequencing. We identified a novel and conserved circular RNA, circ‐NSD2, functioning as a promoter of CRC metastasis. Circ‐NSD2 expression was elevated in CRC tissues and was markedly increased in advanced stages or metastatic tumours of CRC patients. Gain‐of‐function and loss‐of‐function experiments demonstrated that circ‐NSD2 promoted migration and metastasis of CRC in vitro and in vivo. Mechanistically, circ‐NSD2 acted as a sponge for the tumour suppressor miR‐199b‐5p and activated DDR1 (discoidin domain receptor tyrosine kinase 1) and JAG1 (Jagged 1) genes, which synergistically helped with cell–matrix interaction, migration and metastasis of CRC cells. Taken together, our findings highlight a novel oncogenic function of circ‐NSD2 and uncover a key mechanism for the circ‐NSD2/miR‐199b‐5p/DDR1/JAG1 axis in CRC metastasis, which may serve as a prognostic factor and therapeutic target for antimetastatic therapy in CRC patients. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

NSD2 circular RNA promotes metastasis of colorectal cancer by targeting miR‐199b‐5p‐mediated DDR1 and JAG1 signalling

The oncogene c-Myc is aberrantly expressed and plays a key role in malignant transformation and progression of hepatocellular carcinoma (HCC). Here, we report that c-Myc is significantly upregulated by TRAF6, an E3 ubiquitin ligase, in hepatocarcinogenesis. High TRAF6 expression in clinical HCC samples correlates with poor prognosis, and the loss of one copy of the Traf6 gene in Traf6+/- mice significantly impairs liver tumorigenesis. Mechanistically, TRAF6 first interacts with and ubiquitinates histone deacetylase 3 (HDAC3) with K63-linked ubiquitin chains, which leads to the dissociation of HDAC3 from the c-Myc promoter and subsequent acetylation of histone H3 at K9, thereby epigenetically enhancing the mRNA expression of c-Myc. Second, the K63-linked ubiquitination of HDAC3 impairs the HDAC3 interaction with c-Myc and promotes c-Myc protein acetylation, which thereby enhances c-Myc protein stability by inhibiting CHIP-mediated c-Myc ubiquitination and degradation. Importantly, TRAF6/HDAC3/c-Myc signaling is also primed in HBV-Tg mice, unveiling a critical role for a novel mechanism in inflammation-cancer transition. In clinical specimens, TRAF6 positively correlates with c-Myc at both the mRNA and protein levels, and high TRAF6 and c-Myc expression is associated with an unfavorable prognosis, suggesting that TRAF6 collaborates with c-Myc to promote human hepatocarcinogenesis. Consistently, curbing c-Myc expression by inhibition of TRAF6 activity with a TRAF6 inhibitor peptide, or the silencing of c-Myc by siRNA, significantly suppressed tumor growth in mice. Conclusion: These findings demonstrate the oncogenic potential of TRAF6 during hepatocarcinogenesis by modulating TRAF6/HDAC3/c-Myc signaling, with potential implications for novel approaches to HCC therapy. This article is protected by copyright. All rights reserved.

TRAF6 promotes hepatocarcinogenesis by interacting with HDAC3 to enhance c-Myc gene expression and protein stability.

ABSTRACT MicroRNAs (miRNAs) play important roles in the development of skeletal muscle. In our previous study, expression of miR-195 and miR-497 were shown to be upregulated during muscle development in pigs. In this study, we investigated the roles of these two miRNAs in myogenesis and analyzed their transcriptional regulation. Our results showed that miR-195 and miR-497 were upregulated during muscle development and myoblast differentiation. Moreover, miR-195 and miR-497 inhibited proliferation but not differentiation in C2C12 cells. Further investigation revealed that Igf1r, Insr, Ccnd2 and Ccne1 were directly targeted by miR-195 and miR-497 in myoblasts. In addition, we confirmed that miR-195 and miR-497, which shared the similar expression profiling, were negatively regulated by nuclear factor κB (NF-κB) in both myoblasts and skeletal muscle tissue. Our data illustrate that the signaling pathway NF-κB–miR-195/497–Igf1r/Insr-Ccnd2/Ccne1 plays important roles in myogenesis. Our study provides novel evidence for the roles of miR-195 and miR-497 in muscle development. Summary: miR-195 and miR-497 are negatively regulated by the myogenic factor NF-κB, and they could inhibit myoblast proliferation through targeting the Igf1r, Insr and cyclin genes.

The NF-κB-modulated microRNAs miR-195 and miR-497 inhibit myoblast proliferation by targeting Igf1r, Insr and cyclin genes

Ubiquitin specific protease 4 (USP4) is a deubiquitinating enzyme with key roles in the regulation of p53 and TGFβ signaling, suggesting its importance in tumorigenesis. However, the mechanisms and regulatory roles of USP4 in cancer, including colorectal cancer, remain largely elusive. Here, we present the first evidence that USP4 regulates the growth, invasion, and metastasis of colorectal cancer. USP4 expression was significantly elevated in colorectal cancer tissues and was significantly associated with tumor size, differentiation, distant metastasis, and poor survival. Knockdown of USP4 diminished colorectal cancer cell growth, colony formation, migration, and invasion in vitro and metastasis in vivo. Importantly, we found that phosphatase of regenerating liver-3 (PRL-3) is indispensable for USP4-mediated oncogenic activity in colorectal cancer. Mechanistically, we observed that USP4 interacted with and stabilized PRL-3 via deubiquitination. This resulted in activation of Akt and reduction of E-cadherin, critical regulators of cancer cell growth and metastasis. Examination of clinical samples confirmed that USP4 expression positively correlates with PRL-3 protein expression, but not mRNA transcript levels. Taken together, our results demonstrate that aberrant expression of USP4 contributes to the development and progression of colorectal cancer and reveal a critical mechanism underlying USP4-mediated oncogenic activity. These observations suggest that the potential of harnessing proteolytic degradation processes for therapeutic manipulation may offer a much-needed new approach for improving colorectal cancer treatment strategies.

Ubiquitin-Specific Protease 4-Mediated Deubiquitination and Stabilization of PRL-3 Is Required for Potentiating Colorectal Oncogenesis.

Nur77, an immediate‐early response gene, participates in a wide range of biological functions. Its human homologue, NUR77, is known by several names and has the HGNC‐approved gene symbol NR4A1. However, the role of Nur77 in inflammatory bowel disease (IBD) and its underlying mechanisms remain elusive. Here, using public data from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) on the most recent genome‐wide association studies (GWAS) for ulcerative colitis (UC) and Crohn's disease (CD), we found that genetic variants of the NUR77 gene are associated with increased risk for both UC and CD. Accordingly, Nur77 expression was significantly reduced in colon tissues from patients with UC or CD and mice treated with DSS. Nur77 deficiency increased the susceptibility of mice to DSS‐induced experimental colitis and prevented intestinal recovery, whereas treatment with cytosporone B (Csn‐B), an agonist for Nur77, significantly attenuated excessive inflammatory response in the DSS‐induced colitis mouse model. Mechanistically, NUR77 acts as a negative regulator of TLR–IL‐1R signalling by interacting with TRAF6. This interaction prevented auto‐ubiquitination and oligomerization of TRAF6 and subsequently inhibited NF‐κB activation and pro‐inflammatory cytokine production. Taken together, our GWAS‐based analysis and in vitro and in vivo studies have demonstrated that Nur77 is an important regulator of TRAF6/TLR–IL‐1R‐initiated inflammatory signalling, and loss of Nur77 may contribute to the development of IBD, suggesting Nur77 as a potential target for the prevention and treatment of IBD. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

NUR77 exerts a protective effect against inflammatory bowel disease by negatively regulating the TRAF6/TLR–IL‐1R signalling axis

Objective 
To observe the effects of lutein on cell proliferation and apoptosis of in vitro culture human cervical cancer HeLa cells. 
 
Methods 
Select human HeLa cells of the logarithmic growth phase for the study. Using a random number table method, those HeLa cells were randomly divided into six groups: 20, 40, 80, 160, 320 μmol/L lutein group and control group, then added 200 μL RPMI1640 medium contained final concentration of 20, 40, 80, 160, 320 μmol/L lutein and HeLa cells in 20, 40, 80, 160, 320 μmol/L lutein group, respectively, and added 200 μL RPMI1640 medium only and HeLa cells in control group.The HeLa cells proliferation inhibitory rates were determined by methyl thiazolyl tetrazolium(MTT) assay and the apoptosis rates of HeLa cells were determined by flow cytometry.Analyzed rates of proliferation inhibitory and apoptosis of HeLa cells that cultured the same time but in different concentrations of lutein and cultured in the same concentration of lutein but at different time points by statistical method. 
 
Results 
When HeLa cells cultured the same time(24 h or 48 h or 72 h), with lutein concentration increased by turns(20, 40, 80, 160, 320 μmol/L, respectively), compared with the previous low concentration group, the proliferation inhibitory rates and apoptosis rates increased significantly, and the differences were statistically significant(P<0.01); When HeLa cells cultured in the same concentration(20 μmol/L or 40 μmol/L or 80 μmol/L or 160 μmol/L or 320 μmol/L) of lutein, with the culture time extended (24, 48, 72 h, respectively), compared with the previous time point, the proliferation inhibitory rates and apoptosis rates were significantly increased, and the differences were statistically significant(P<0.01). 
 
Conclusions 
Lutein can inhibit the cell proliferation and induce the apoptosis of in vitro culture human HeLa cells.The rates of proliferation inhibitory and apoptosis of in vitro culture human HeLa cells could increase with lutein concentration increasing and culture time prolonging. 
 
Key words: 
Uterine cervical neoplasms; HeLa cells; Lutein; Cell proliferation; Apoptosis

Effects of lutein on cell proliferation and apoptosis of human cervical cancer HeLa cells

Previous studies indicated that miR-29c is important for muscle development in mice and human, but its role in pigs is unknown. In this study, we detected the expression of miR-29c in Meishan longissimus lumborum (LL) muscle. The results showed that miR-29c was gradually upregulated during development of skeletal muscle in pig. Moreover, the expression of YY1 and Akt3 genes, which were confirmed to be targeted by miR-29c in mice, was decreased along with muscle development. Furthermore, the expression level of miR-29c was significantly higher in adult Meishan pigs than Large White pigs, while the expression of YY1 and Akt3 genes was significantly lower in Meishan pigs. These results indicated that the expression pattern of miR-29c was opposite to that of YY1 and Akt3 genes in pigs. Also, the luciferase assay indicated that miR-29s can target the YY1 gene in pigs. In addition, we identified a T to C mutation in the primary transcript of miR-29c, which was associated with the postmortem muscle pH in pigs. Based on these results, we concluded that miR-29c is also important in skeletal muscle development of pigs.

The microRNA, miR-29c, participates in muscle development through targeting the YY1 gene and is associated with postmortem muscle pH in pigs

Nur77, an orphan member of the nuclear receptor superfamily, has been implicated in tumorigenesis. However, its contributions to colorectal cancer (CRC) invasion and metastasis are largely under characterized. Here, we present the first evidence that the invasion and metastasis of CRC is regulated by Nur77. High expression of Nur77 was observed in clinical CRC tissues, and this elevated expression was significantly associated with advanced tumor, lymph nodes, distant metastasis stage (P = 0.003), lymph node metastasis (P = 0.001) and poor survival (P = 0.03). Overexpression of Nur77 in CRC cells enhanced cell invasion in vitro, whereas knockdown of Nur77 diminished cell invasion and metastasis both in vitro and in vivo. In studying the possible mechanism by which overexpression of Nur77 contributes to CRC invasion and metastasis, we observed that the nuclear protein Nur77 promoted the expression of matrix metalloproteinase (MMP)-9, a novel downstream target of Nur77, and subsequently decreased the expression of E-cadherin. Examination of clinical samples further showed that Nur77 expression is positively correlated with MMP-9, whereas negatively correlated with E-cadherin. Interestingly, Nur77-mediated CRC invasion via MMP-9 and E-cadherin could be mimicked by some metastasis-inducible factors including hypoxia and prostaglandin E2. Collectively, our study demonstrated that Nur77 could promote the invasion and metastasis of CRC cells through regulation of MMP-9/E-cadherin signaling. These observations provide a possible new strategy for potentially treating or preventing the metastasis of CRC through targeting of Nur77.

Orphan nuclear receptor Nur77 promotes colorectal cancer invasion and metastasis by regulating MMP-9 and E-cadherin.

OBJECTIVE
To investigate effects of two kinds of anti-cancer bioactive peptide (ACBP) on proliferation and cell cycle in human nasopharyngeal carcinoma strain CNE.

METHODS
Cell culture was used in vitro, CNE cells were exposed to different concentration ACBP, in all groups, contrast groups were set up. And 24, 48, 72 hours later, growth characteristics of CNE cells were studied by morphological observation and MTT assay . Cell cycle and apoptosis were analyzed by flow cytometry (FCM).

RESULTS
In normal contrast group, CNE cells grew intensively and contacted with each other. However, cells which were treated with ACBP were inhibitory greatly in higher dose ACBP group, necrosis could be found. MTT assay showed that ACBP inhibited growth of CNE cell. FCM showed that ACBP (20.0 microg/ml) could raise cell ratio of S phase and induce apoptosis of CNE cells. CNE cells were treated by two kind of ACBP (5.0 microg/ml) for 24 h, FCM showed that early apoptosis rate were (11.8 +/- 0.3)% and (8.1 +/- 0.2)% respectively, which showed statistical significance in comparison with control group (t = 42.535, 47.300 respectively, P = 0.000). Under light microscope, some sings of cell apoptosis including coagulation of chromatin, fragmentation of nuclei and apoptotic body could be found.

Two kinds of ACBP inhibited human nasopharyngeal carcinoma strain CNE proliferation and arrested the cells to S phase, also induced the cells to apoptosis. Nasopharyngeal neoplasms;

Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery

[Effects of anti-cancer bioactive peptide on cell cycle in human nasopharyngeal carcinoma strain CNE].

 Magnetite nanoparticles show promising applications in drug delivery, catalysis and spintronics. The surface of magnetite plays an important role in these applications. Therefore, it is critical to understand the surface structure of Fe3O4 at atomic scale. Here, using a combination of first-principles calculations, particle swarm optimization (PSO) method and machine learning, we investigate the possible reconstruction and stability of Fe3O4(001) surface. The results show that besides the subsurface cation vacancy (SCV) reconstruction, an A layer with Fe vacancy (A-layer-VFe) reconstruction of the (001) surface also shows very low surface energy especially at oxygen poor condition. Molecular dynamics simulation based on the iron-oxygen interaction potential function fitted by machine learning further confirms the thermodynamic stability of the A-layer-VFe reconstruction. Our results are also instructive for the study of surface reconstruction of other metal oxides.

Reconstruction and stability of Fe3O4(001) surface: an investigation based on PSO and machine learning

Two-dimensional (2D) magnetic materials show promising applications in spintronic devices. Heterostructures and superlattices play an important role in property tuning and device design. Vertical heterostructures of 2D magnets have been widely studied while the study of in-plane heterostructures is quite limited. Here, based on density functional theory, we propose that a perfect CrI2/CrI3 in-plane heterostructure or superlattice can be obtained via deposition of Cr atoms on the CrI3 monolayer. Our results show that CrI2/CrI3 superlattices are magnetic semiconductors with the magnetic order depending on the width of the CrI2 ribbon. Interestingly, space charge separation exists in CrI2/CrI3 superlattices independent of the width of CrI2 and CrI3 ribbons. Under appropriate excitation, holes accumulate in the CrI2 part of the superlattice and 100% spin polarized electrons accumulate in the CrI3 part. A 3% tensile strain on the superlattice will induce a phase transition of the CrI2 part. Nevertheless, the space charge separation in the CrI2/CrI3 superlattice occurs under tensile strain smaller than 6%. The tunable magnetic order and robust space charge separation indicate promising applications of CrI2/CrI3 superlattices in spintronic devices.

In-plane CrI2/CrI3 2D superlattices: novel electronic properties and strain induced phase transition.

Electronic phase separation (EPS) originates from an incomplete transformation between electronic phases, causing the inhomogeneous spatial distribution of electronic properties. In the system of two-dimensional electron gas (2DEG), the EPS is usually identified based on a percolative metal-to-superconductor transition. Here, we report a metal-insulator transition (MIT) in KTaO 3 -based 2DEG with the width of conductive channel decreasing into micrometer scale. Hysteretic resistance-temperature relations are observed due to the competition between metallic and insulating phases, which is tunable by magnetic field. Such a size-dependent MIT effect is attributed to the coexistence and separation of metallic and insulating phases. Combining density functional theory calculation, we propose a theoretical model to simulate the dynamic process of the EPS using the percolation theory, demonstrating the mechanism of size-dependent MIT. Our work suggests a clear and simple 2DEG platform to achieve the spatial coexistence of metallic and insulating phases.

Metal-insulator phase separation in KTaO3-based two-dimensional electron gas

Perfect optical vortex beams (POV) have attracted considerable attention in many novel applications because they have the advantage of a radial profile that is independent of the topological charge (TC). Nowadays, there are few effective methods to measure both the integer and the fractional TCs of the POV. In this paper, we achieve the precise measurement of arbitrary TCs through the approach of dynamic angular double slits (ADS), which performs the transformation from the POV to the interference intensity patterns at the angular bisector direction of the ADS. The information of the TC can be obtained from the periodically changing interference pattern. The deviation is less than 2% by comparing the theoretical values with the fitting results, therefore the detection method is effective and reasonable.

Measure the arbitrary topological charge of perfect optical vortex beams by using the dynamic angular double slits.

Two-dimensional (2D) magnets show promising applications in spintronic devices and appeal increasing attention. CrI2, a counterpart of CrI3, is a magnetic van der Waals crystal. However, the structure of CrI2 at the monolayer limit is not well studied. Here, based on the density functional theory, we revealed the relationship between different phases of CrI2 monolayer and proposed a novel and stable chain structure. The one-dimensional (1D) CrI2 chain is a ferromagnetic semiconductor with robust electronic properties against twisting and tensile strain. Interestingly, the CrI2 chain exhibits superelasticity with a failure strain as large as 39%. In addition, both the magnetic moments on Cr atoms and the exchange energy increase with an increase in the tensile strain. Our results push magnetic ordering from 2D to 1D, which shows possible application prospects in magnetoelectric and spintronic devices.

Transition of CrI2 from a two-dimensional network to one-dimensional chain at the monolayer limit.

The interplay between unconventional Cooper pairing and quantum states associated with atomic scale defects is a frontier of research with many open questions. So far, only a few of the high-temperature superconductors allow this intricate physics to be studied in a widely tunable way. We use scanning tunneling microscopy to image the electronic impact of Co atoms on the ground state of the LiFe_{1-x}Co_{x}As system. We observe that impurities progressively suppress the global superconducting gap and introduce low energy states near the gap edge, with the superconductivity remaining in the strong-coupling limit. Unexpectedly, the fully opened gap evolves into a nodal state before the Cooper pair coherence is fully destroyed. Our systematic theoretical analysis shows that these new observations can be quantitatively understood by the nonmagnetic Born-limit scattering effect in an s±-wave superconductor, unveiling the driving force of the superconductor to metal quantum phase transition.

Quantum Phase Transition of Correlated Iron-Based Superconductivity in LiFe_{1-x}Co_{x}As.

Quantum Phase Transition of Correlated Iron-Based Superconductivity in LiFe1- xCoxAs

Modulation of multiphoton resonant high-order harmonic spectra driven by two frequency-comb fields

In the framework of the Bogoliubov–de Gennes equation, we investigate the thermal transport properties in topological-insulator-based superconducting hybrid structures with mixed spin-singlet and spin-triplet pairing states, and emphasize the different manifestations of the spin-singlet and spin-triplet pairing states in the thermal transport signatures. It is revealed that the temperature-dependent differential thermal conductance strongly depends on the components of the pairing state, and the negative differential thermal conductance only occurs in the spin-singlet pairing state dominated regime. It is also found that the thermal conductance is profoundly sensitive to the components of the pairing state. In the spin-singlet pairing state controlled regime, the thermal conductance obviously oscillates with the phase difference and junction length. With increasing the proportion of the spin-triplet pairing state, the oscillating characteristic of the thermal conductance fades out distinctly. These results suggest an alternative route for distinguishing the components of pairing states in topological-insulator-based superconducting hybrid structures.

Thermal transport in topological-insulator-based superconducting hybrid structures with mixed singlet and triplet pairing states

Recent experiments on Zn-substituted 122-type iron-based superconductors (FeSCs) at electron- and hole- doped region provide us with a testing ground for understanding the effect of Zn impurities in these systems. Our first-principle calculations of the electronic structure reveal that the Zn 3d orbitals are far below the Fermi level and chemically inactive, while the Zn 4s-orbital is partially occupied and its wave function overlapping with those 3d-orbitals of neighboring Fe-ions. This suggests that the impurity effect is originating in the Zn 4s-orbital, not its 3d-orbitals. Employing a phenomenological two-orbital lattice model for 122-FeSCs and the self-consistent Bogoliubov-de Gennes equations, we study how the Zn-impurities suppress the superconductivity in electron- and hole- doped compounds. Our obtained results qualitatively agree with the experimental measurements.

Effects of single- and multi-substituted Zn ions in doped-122 type iron-based superconductors

Tilted anisotropic Dirac cones in partially hydrogenated graphene

Yuan-Yuan Zhao1,3, Yong-Liang Zhang1, Mei-Ling Zheng1,Xian-Zi Dong1, Zhen-Sheng Zhao1* and Xuan-Ming Duan1,2* 1 Laboratory of Organic NanoPhotonics, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, No. 29, Zhongguancun East Road, Beijing, 100190, P. R. China 2 Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, No.266 Fangzheng Ave, Shuitu technology development zone, Beibei District, Chongqing 400714, P. R. China 3 University of Chinese Academy of Sciences, Beijing, 100190, P. R. China Email: xmduan@mail.ipc.ac.cn, zhaozhsh@mail.ipc.ac.cn

Fantastic Focusing Direction of Luneburg Lens with Gradient Photonic Crystals Structure in Metamaterial Regime

Recent experiments demonstrated that the isovalent doping system gives a similar phase diagram as the heterovalent doped cases. For example, with the phosphorous (P) doping, the magnetic order in BaFe2(As1–xPx)2 compound is first suppressed, then the superconductivity dome emerges to an extended doping region but eventually it disappears at large x. With the help of a minimal two-orbital model for both BaFe2As2 and BaFe2P2, together with the self-consistent lattice Bogoliubov-de Gennes (BdG) equation, we calculate the phase diagram against the P content x in which the doped isovalent P atoms are treated as impurities. Furthermore, we show that our numerical results can qualitatively compare with the experimental measurements.

Phase diagram of the isovalent phosphorous-substituted 122-type iron pnictides

Recent studies on the isovalent phosphorous-substituted 122-type iron pnictides

Phase diagram with doping dependence in phosphorous-doped iron-based superconductor and magnetic order study

Inter-surface coupling in thin-film topological insulators can reduce the surface state mobility by an order of magnitude in low-temperature transport measurements. The reduction is caused by a reduction in the group velocity and an increased sz component of the surface-state spin which weakens the selection rule against large-angle scattering. An intersurface potential splits the degenerate bands into a Rashba-like bandstructure. This reduces the intersurface coupling, it largely restores the selection rule against large angle scattering, and the ring-shaped valence band further reduces backscattering by requiring, on average, larger momentum transfer for backscattering events. The effects of temperature, Fermi level, and intersurface potential on the Coulomb impurity scattering limited mobility are analyzed and discussed.

The competition on population inversion between two lasing modes in one-dimensional (1D) active random media is investigated by simultaneously solving Maxwell's equations and rate equations of electronic population. Results indicated that the increasing of concentration of the dye increase the spectral intensity of the dimer and the increase of the pump energy produces a major radiative and non-radiative energy transfers from monomers to dimers. The simulations of the new monomerdimer laser model agree very well with the experimental datas and promote the development of random lasing in the mixed dye media.

The competition between two lasing modes in one-dimensional active random media

The Witten effect tells that a unit magnetic monopole can bind a half elementary charge in an axion media. We present an exact solution of a magnetic monopole in a topological insulator that was proposed to be an axion media recently. It is found that a magnetic monopole can induce one zero energy state bound to it and one surface state of zero energy. The two states are quite robust, but the degeneracy can be removed by external fields. For a finite size system, the interference of two states may lift the degeneracy, and the resulting states have one half near the origin and another half around the surface, which realizes the Witten effect. However, the energy difference decays exponentially with the size of the system. The exact solution does not fully support the realization of the Witten effect in a topological insulator.

A magnetic monopole in topological insulator: exact solution and Witten effect

Analytical studies of the effect of edge decoration on the energy spectrum of semi-infinite one-dimensional (1D) model and zigzag edged graphene (ZEG) are presented by means of transfer matrix method, in the frame of which the conditions for the existence of edge states are determined. For 1D model, the zero-energy surface state occurs regardless of whether the decorations exist or not, while the non-zero-energy surface states can be induced and manipulated through adjusting the edge decoration. On the other hand, the case for the semi-infinite ZEG model with nearest-neighbour interaction is discussed in the analogous way. The non-zero-energy surface states can be induced by the edge decoration and moreover, the ratio between the edge hopping and the bulk hopping amplitudes should be within a certain threshold.

Analytical study of surface states caused by the edge decoration

Analytical studies of the effect of edge decoration on the energy spectrum of semi-infinite onedimensional (1D) lattice chain with Peierls phase transition and zigzag edged graphene (ZEG) are presented by means of transfer matrix method, in the frame of which the sufficient and necessary conditions for the existence of the edge states are determined. For 1D lattice chain, the zero-energy edge state exists when Peierls phase transition happens regardless whether the decoration exists or not, while the non-zero-energy edge states can be induced and manipulated through adjusting the edge decoration. On the other hand, the semi-infinite ZEG model with nearest-neighbor interaction can be mapped into the 1D lattice chain case. The non-zero-energy edge states can be induced by the decoration as well, and we can obtain the condition of the decoration on the edge for the existence of the novel edge states.

Effect of edge decoration on the energy spectrum of semi-infinite lattices

A rigorous proof for non-existence of edge state in the semi-infinite armchair edged graphene

Relationship between photolysis mechanism and photo-enhanced toxicity to Vibrio Fischeri for neonicotinoids with cyano-amidine and nitroguanidine structures.

Identification of active or inactive agonists of tumor suppressor protein based on Tox21 library.

Metabolomic responses in livers of female and male zebrafish (Danio rerio) following prolonged exposure to environmental levels of zinc oxide nanoparticles.

Comparison of Modes of Action Between Fish, Cell and Mitochondrial Toxicity Based on Toxicity Correlation, Excess Toxicity and QSAR for Class-based Compounds.

Knockdown of long non-coding RNA TPT1-AS1 inhibits invasion and migration of hepatocarcinoma cells

High-throughput assessment of oxidative respiration in fish embryos: Advancing adverse outcome pathways for mitochondrial dysfunction.

Tissue-specific metabolite profiling and quantitative analysis of ginsenosides in Panax quinquefolium using laser microdissection and liquid chromatography–quadrupole/time of flight-mass spectrometry

Polypeptide milk is a kind of functional milk produced by modern enzymolysis technology. Compared with the single enzyme, papain and neutral protease composited with the proportion of 1:1 was found to be the optimum enzyme system for polypeptide milk production. The suitable enzymolysis condition was that the composited enzyme addition of 750U/g milk protein, 55°C and 25min, under this condition the hydrolysis degree of the milk was 44.08%.

Study on Production of Polypeptide Milk by Enzymolysis Technology

Changes in the composition of triacylglycerols (TAGs) of three varieties of flaxseeds (H52, O116 and P129) during development were investigated using non-aqueous reversed phase liquid chromatography coupled to atmospheric pressure photoionization-mass spectrometry (LC-APPI-MS). 17 species of triacylglycerols were found and their fatty acyl composition was confirmed by fragment ions in the mass spectra. The major forms observed were LnLnLn, LnLLn, LnOLn, LLLn, LnLnP, OOLn and OLLn. The highest change in these compounds occurred in the early development period for most TAGs. The most active period of triacylglycerol synthesis was between 7 and 35 days after flowering (DAF). LnLnLn exhibited the most significant increase during flaxseed development. At maturity, similar TAG profiles were found for the three samples.

Changes in the triacylglycerol content of flaxseeds during development using liquid chromatography-atmospheric pressure photoionization-mass spectrometry (LC-APPI-MS)

Comparative study on the seismic performance of subway stations using reinforced concrete cast-in-place columns and truncated columns

Numerical simulation of particle erosion in the vertical-upward-horizontal elbow under multiphase bubble flow

Behavior of deformation joints of RC utility tunnels considering considering multi-hazard conditions

Performance of an underground structure seismic mitigation system improved by frictional deformation absorbing braces

AbstractSteel corrugated shear walls (SCSWs) are an alternative to ordinary steel plate shear walls (SPSWs) with flat infill plates. This paper deals with the shear resistance design of corrugated ...

Shear Resistance and Design of Infill Panels in Corrugated-Plate Shear Walls

In this article, finite element method is used to analyze the properties of the reactor core under seismic load, and redesign the center assemblies to resist deformation and impact force. The result shows that the maximum force on the lug boss is decreased while the springs are applied.

In this article, the entity model of the bearing-rotor system is established and meshed in ANSYS. The natural frequency and vibration mode of the rotor system is analyzed in order to avoid the occurrence of resonance. At the same time, the results showed that not only the location of the unbalance incentive of the system should be taken into account, but also consider the size of the unbalanced force.

9019 Background: Based on IMPOWER 150, atezolizumab in combination with bevacizumab and platinum-based chemotherapy has been the first-line treatment for advanced non-squamous NSCLC with negative driver genes. AK112 is a global first-in-class anti-PD-1/VEGF bi-specific antibody developed by Akesobio. Preclinical and clinical studies have indicated that AK112 possess potential anti-tumor efficacy in solid tumors. Therefore, we aimed to assess the efficacy and safety of AK112 in combination with chemotherapy for patients with advanced NSCLC. Methods: This was an open-label, multi-center phase II study evaluating the efficacy and safety of AK112 in combination with chemotherapy in pts with advanced NSCLC. Enrolled pts were divided into three cohorts: Previously untreated advanced NSCLC pts with wide-type EGFR/ALK (Cohort 1), pts with EGFR mutations who had failed prior EGFR-TKI therapies without T790M mutation or failed osimertinib treatment (Cohort 2), and pts who progressed after anti-PD-1/L1 and platinum-based chemotherapy (Cohort 3). Pts were treated with 10mg/kg or 20mg/kg AK112 once every 3 weeks in combination with carboplatin and pemetrexed or carboplatin and paclitaxel for Cohort 1/2, and docetaxel for Cohort 3. Primary endpoint was ORR as assessed by investigator per RECIST v1.1. Results: 133 pts were enrolled from Feb 03, 2021 to Dec 31, 2021 and received AK112 plus chemotherapy (44 received AK112 10 mg/kg and 89 received AK112 20 mg/kg). As of Dec 31, 2021, in cohort-1, among 26 evaluable pts with squamous cell carcinoma, 20 partial response and 6 stable disease were observed for a 76.9% ORR and a 100.0% DCR, median DOR and median PFS was not reached while 6-month PFS rate was 86.2%. In Cohort-2, among 19 evaluable pts, 13 partial response and 5 stable disease were observed for a 68.4% ORR and a 94.7% DCR while median DOR was 5.5 months, and median PFS was 8.3 months. In Cohort-3, among 20 evaluable pts, 8 partial response and 8 stable disease were observed for a 40.0% ORR and a 80.0% DCR, median DOR and median PFS was not reached while 6-month PFS rate was 71.1%. Treatment emergent adverse events (TEAE) occurred in 86.5% (115/133) of the pts, and grade ≥3 AEs occurred in 28.6% (38/133) of pts including two deaths. Most common AE (incidence ≥ 5%) included alanine/aspartate aminotransferase increased, epistaxis, anemia, vomiting, nausea, rash, leukopenia, thrombocytopenia, and neutropenia. Treatment discontinuation due to AE occurred in 3.0% (4/133) of the pts. Conclusions: AK112 plus chemotherapy has shown a promising anti-tumor efficacy in each cohort and warrants potentially superior safety in comparison to anti-PD-(L)1 and anti-VEGF combination therapies in advanced NSCLC. PFS and ORR were also significantly improved with AK112 plus chemotherapy. Therefore, phase III registration studies of AK112 plus chemotherapy in advanced NSCLC will be initiated in 2022. Clinical trial information: NCT04736823.

A phase II study of AK112 (PD-1/VEGF bispecific) in combination with chemotherapy in patients with advanced non-small cell lung cancer.

P1.11-09 Risk of Second Primary Malignancy After Non-Small-Cell Lung Cancer: A Competing Risk Nomogram Based on the SEER Database

Aim Our previous research showed that AKT inactivation via small molecule inhibitors did not induce significant apoptosis, but rather markedly increased autophagy in nasopharyngeal carcinoma (NPC). The purpose of the current study was to determine whether autophagy inhibition can enhance the anticancer efficacy of an AKT inhibitor (MK-2206). Materials and methods NPC cell lines CNE-2 (Epstein–Barr virus negative) and C666-1 (Epstein–Barr virus positive) were used to conduct the research. Autophagy induction effects were evaluated via Western blotting. Eukaryotic elongation factor-2 (eEF-2) kinase was specifically and stably knocked down using shRNA. The growth and proliferation of the cells were assessed by Cell Counting Kit-8. In CNE-2 xenograft tumors, the antitumor effects of an AKT inhibitor (MK-2206) combined with an eEF-2 kinase inhibitor (NH125) were tested. Results MK-2206 induced eEF-2 kinase-dependent autophagy in NPC cell lines. Knockdown of eEF-2 kinase using shRNA blunted the autophagy activated by MK-2206. Compared with treatment with MK-2206 alone, shRNA or NH125 suppressed eEF-2 kinase and increased the growth-inhibitory effect of MK-2206 on the human NPC cell lines. The synergistic effects of eEF-2 kinase inhibition and MK-2206 were similar to those of the combination of hydroxychloroquine and MK-2206. Moreover, NH125 showed good synergistic effects with MK-2206 in vivo. Conclusion eEF-2 kinase-mediated autophagy induced by AKT inhibition played a protective role in NPC cells. Inhibition of eEF-2 kinase may be an effective method for increasing the efficacy of an AKT inhibitor such as MK-2206 in NPC.

Inhibiting eEF-2 kinase-mediated autophagy enhanced the cytocidal effect of AKT inhibitor on human nasopharyngeal carcinoma

There are increasing concerns about the negative impacts of chemotherapy near the end of life (EOL). There is discrepancy among different countries about its use, and little is known about the real-world situation in China.

This retrospective study was conducted at six representative hospitals across China. Adult decedents with a record of advanced solid cancer and palliative chemotherapy were consecutively screened from 2010 through 2014. The prevalence of EOL chemotherapy within the last 1 month of life was set as the primary outcome. The correlations among EOL chemotherapy, clinicopathological features, and overall survival (OS) were investigated.

RESULTS
A total of 3,350 decedents who had had cancer were consecutively included; 2,098 (62.6%) were male and the median age was 56 years (range, 20-88). There were 177 (5.3%), 387 (11.6%), and 837 (25.0%) patients who received EOL chemotherapy within the last 2 weeks, 1 month, and 2 months of life, respectively. We identified inferior OS (median OS, 7.1 vs. 14.2 months; hazard ratio, 1.37; 95% confidence interval [CI], 1.23-1.53; p < .001), more intensive treatments (e.g., admitted to intensive care unit [ICU] in the last month of life, received cardiopulmonary resuscitation and invasive ventilation support), and hospital death (odds ratio, 1.53; 95% CI, 1.14-2.06; p = .005) among patients who received continued chemotherapy within the last month compared with those who did not. However, subgroup analyses indicated that receiving oral agents correlated with fewer ICU admissions and lower rates of in-hospital death.

This study showed that EOL chemotherapy is commonly used in China. Intravenous chemotherapy at the EOL significantly correlated with poor outcomes and the role of oral anticancer agents warrants further investigation. The Oncologist 2017;22:53-60Implications for Practice: The role of chemotherapy toward the end of life (EOL) in patients with solid cancers is debatable. This article is believed to be the first to report the current prevalence of EOL chemotherapy in China. This study found that, compared with oral anticancer agents, intravenous chemotherapy at the EOL was significantly associated with poor outcomes. Therefore, the role of oral anticancer agents at the EOL stage deserves further investigation.

Chemotherapy Near the End of Life for Chinese Patients with Solid Malignancies.

TPS10142Background: The peripheral neurotoxicity induced by cisplatin is a common adverse event in non-small cell lung cancer (NSCLC) patients. This phase III trial will evaluate the efficacy and s...

A multicenter, randomized, double-blind, placebo-controlled phase III study of monosialoganglioside (GM1) preventing neurotoxicity induced by cisplatin-based chemotherapy in non-small cell lung cancer patients.

Purpose The aim of this study was to analyze and summarize the clinicopathological and molecular characteristics of classic biphasic pulmonary blastoma (PB) to improve its diagnosis and treatment. Patients and methods A retrospective analysis was performed in patients who were diagnosed with PB at Sun Yat-Sen University Cancer Center from March 1995 to March 2015. Genomic DNA was profiled using a capture-based targeted sequencing panel. Results Sixteen patients with an average age of 40 years were included in this study. Accurate preoperative diagnosis was very challenging as surgically resected tissues with immunohistochemical staining were required for the diagnosis. Surgery was the optimal treatment for localized disease and there was no standard management for metastatic disease. Mutations were detected among 9 out of the 56 genes profiled, including BRCA2, ERBB4, ALK, MET, BRAF, RAF1, PTEN, EGFR, and PIK3CA. Conclusion Due to the low incidence rate and the reclassification of PB, no standard treatment is available. Although the numbers of cases are few with varying individual experiences, it is important to improve our understanding regarding this rare lung cancer. Targeted DNA sequencing may be of clinical use for molecular testing and the effects of targeted therapy need to be confirmed.

A retrospective analysis of the clinicopathological and molecular characteristics of pulmonary blastoma

Multiple oncogenic mutations related to targeted therapy in nasopharyngeal carcinoma

QoL analyses from INFORM study, a phase III study of gefitinib versus placebo as maintenance therapy in advanced NSCLC

AbstractAlthough epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) have been proved synergistic effect when combined with cytotoxic agents for advanced nonsmall cell lung cancer (NSCLC), the results of relevant clinical trials remain controversial. The purpose of this meta-analysis was to assess the advantage and toxicity profile of chemotherapy plus EGFR-mAbs versus chemotherapy alone for patients with NSCLC.We rigorously searched electronic databases for eligible studies reporting EGFR-mAbs combined with chemotherapy versus chemotherapy alone for patients with advanced NSCLC. The primary outcome was overall survival (OS). Pooled results were calculated using proper statistical methods.Nine phase II/III randomized controlled trials involved a total of 4949 participants were included. In general, compared with chemotherapy alone, the addition of EGFR-mAbs significantly improved OS (hazard ratio [HR] = 0.91, 95% confidence interval [CI]: 0.86–0.97, P = 0.006), progression-free survival (HR = 0.83, 95% CI: 0.87–0.98, P = 0.01), response rate (odd ratio [OR] = 1.28, 95% CI: 1.12–1.47, P = 0.0003), and disease control rate (OR = 1.17, 95% CI: 1.01–1.36, P = 0.04). Subgroup analysis showed that apparent OS benefit present in patients with squamous NSCLC (HR = 0.83, 95% CI: 0.74–0.93, P = 0.001), and those treatment-naive population (HR = 0.88, 95% CI: 0.82–0.95, P = 0.0006). Several manageable adverse events were markedly increased by EGFR-mAbs, such as acne-like rash, infusion reactions, and diarrhea. The risk for some ≥Grade 3 toxicities, such as leukopenia, febrile neutropenia, and thromboembolic events were slightly increased by the addition of EGFR-mAbs. In general, the toxicities of the combination strategy were tolerable and manageable.The addition of EGFR-mAbs to chemotherapy provided superior clinical benefit along with acceptable toxicities to patients with advanced NSCLC, especially those harboring squamous cancer and treatment-naive. Further validation in front-line investigation, proper selection of the potential benefit population by tumor histology, and development of prognostic biomarkers are warranted for future research and clinical application of EGFR-mAbs.

The Efficacy of Combining EGFR Monoclonal Antibody With Chemotherapy for Patients With Advanced Nonsmall Cell Lung Cancer

Abstract Preclinical researches indicated a potential synergistic effect of taxanes-containing chemotherapy (TCC) and antiangiogenic agents (AAs) on the treatment of advanced nonsmall-cell lung cancer (NSCLC). The advantage of adding AA to TCC in the real world remains confusing. We summarized the current evidences from relevant phase II/III randomized controlled trials (RCTs) by performing this meta-analyses. Electronic databases were searched for eligible literatures. The primary endpoint was overall survival (OS). Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes were calculated using RevMan 5.2. A total of 14 phase II/III RCTs involving 9703 participants were included. Compared to standard TCC, the addition of AA was associated with the significant better OS (HR 0.92, 95% CI 0.87–0.97, P = 0.002), prolonged progression-free survival (HR 0.79, 95% CI 0.71–0.87, P < 0.00001), superior response rate (risk ratio [RR] 1.69, 95% CI 1.47–1.95, P < 0.0001), and disease control rate (RR 1.19, 95% CI 1.08–1.32, P < 0.00001). Subgroup analyses indicated that patient treated with monoclonal antibodies (HR 0.89, 95% CI 0.82–0.96, P = 0.02) as well as application in second-line (HR 0.91, 95% CI 0.85–0.96, P = 0.02) acquired significant OS improvement. Other clinical factors directing significant OS improvement by the combination strategy included nonsquamous cancer (P = 0.002), nonsmokers (P = 0.0005), and female (P = 0.02). Toxicities were greater but generally mild or moderate in the combination group, and were mostly manageable. In summary, the addition of AAs to TCC could improve prognosis of advanced NSCLC. Furthermore, proper selection of patient population and AAs is crucial for clinical trials design and clinical practice in the future.

Efficacy of Addition of Antiangiogenic Agents to Taxanes-Containing Chemotherapy in Advanced Nonsmall-Cell Lung Cancer

AIM
To confirm whether the aflibercept dose, plus docetaxel, in western study TCD6120 is appropriate for Chinese patients with nasopharyngeal carcinoma (NPC) and other solid tumors.

MATERIALS & METHODS
To assess dose-limiting toxicity of every 3-week 4 mg/kg or 6 mg/kg aflibercept plus 75 mg/m(2) docetaxel.

RESULTS
Previously treated patients (16 with NPC and 4 with lung cancer) were enrolled. At 6 mg/kg aflibercept: one dose-limiting toxicity was seen (neutropenic infection); the most frequently reported all-grade adverse events were oropharyngeal pain, stomatitis and alopecia; the most frequently reported grade 3/4 adverse events were oropharyngeal pain, stomatitis and neutropenic infection. Eleven patients had partial response and 3 had stable disease.

Preliminary efficacy data for docetaxel/aflibercept are encouraging in Chinese patients with NPC.

This study was registered with the University Hospital Medical Information Network Clinical Trials Registry ( ClinicalTrials.gov , NCT01148615).

Phase I dose-escalation study of aflibercept plus docetaxel in nasopharyngeal carcinoma and other solid tumors.

Both platinum-based doublet chemotherapy (PBC) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) prolong the survival of patients with advanced non-small cell lung cancer (NSCLC). In early studies, most patients underwent PBC as first-line treatment, but not all patients could afford EGFR-TKIs as second-line treatment. To understand the impact of PBC and EGFR-TKIs on NSCLC prognosis, we evaluated the association between the receipt of both regimens and overall survival (OS). Using MEDLINE and EMBASE, we identified prospective, randomized, controlled phase III clinical trials in advanced NSCLC that met the inclusion criteria: in general population with advanced NSCLC, the percentage of patients treated with both PBC and EGFR-TKIs was available in the trial and OS was reported. After collecting data from the selected trials, we correlated the percentage of patients treated with both PBC and EGFR-TKIs with the reported OS, using a weighted analysis. Fifteen phase III clinical trials—involving 11,456 adult patients in 32 arms—were included in the analysis, including 6 trials in Asian populations and 9 in non-Asian (predominantly Caucasian) populations. The OS was positively correlated with the percentage of patients treated with both PBC and EGFR-TKIs (r = 0.797, P < 0.001). The correlation was obvious in the trials in Asian populations (r = 0.936, P < 0.001) but was not statistically significant in the trials in predominantly Caucasian populations (r = 0.116, P = 0.588). These results suggest that treatment with PBC and EGFR-TKIs may provide a survival benefit to patients with advanced NSCLC, highlighting the importance of having both modalities available for therapy.

The impact of both platinum-based chemotherapy and EGFR-TKIs on overall survival of patients with advanced non-small cell lung cancer

Introduction: The use of bevacizumab combined with chemotherapy represents a recent advance in clinical oncology for significantly improving the survival of patients who have non-small cell lung cancer (NSCLC). There is an unmet need for biomarkers that can predict response to such treatment and identify patients sensitive to it. Our study was designed to investigate the predictive value of intratumoral microvascular density (MVD) in patients with NSCLC treated with bevacizumab. Methods: Sixteen patients with NSCLC who underwent chemotherapy combined with bevacizumab were included into this study. Paraffin-embedded tumor samples were sectioned and stained immunohistochemically for the blood vessel markers CD34 and CD31 to characterize the intratumoral vasculature. A computerized image analysis program was used to quantitatively calculate the intratumoral MVD. Treatment response was evaluated by computed tomography scanning. Results: Two types of blood vessels, undifferentiated (CD31+/CD34−) and differentiated (CD34+), were identified. A positive correlation was found between the largest percentage of tumor shrinkage and the MVD of undifferentiated (CD31+/CD34−) vessels, with Spearman correlation coefficient being 0.576 (p = 0.019). No correlation between tumor shrinkage and differentiated vessel MVD (CD34+) was found. Moreover, seven of the eight patients with more undifferentiated vessels showed a partial response, versus only one of the seven patients with fewer undifferentiated vessels (p = 0.009). Conclusions: There are two major types of microvessel in lung cancer vasculature. The MVD of undifferentiated vessels is a favorable predictor for patients with NSCLC treated with a chemotherapy regimen plus bevacizumab, with a higher MVD value correlating with better treatment response. Further studies are needed to verify the predictive role of MVD in treatment of NSCLC with bevacizumab.

Predictive Value of Intratumoral Microvascular Density in Patients with Advanced Non-small Cell Lung Cancer Receiving Chemotherapy Plus Bevacizumab

Gemcitabine has high activity against nasopharyngeal carcinoma (NPC). The level of ribonucleotide reductase subunit M1 (RRM1) expression is closely related to the efficacy of gemcitabine on non-small cell lung cancer and pancreatic cancer. However, the expression of RRM1 and its association with sensitivity to gemcitabine-based chemotherapy in advanced NPC is not known. In this study, we retrospectively collected 48 formalin-fixed, paraffin-embedded NPC tissues to evaluate the expression of RRM1 using immunohistochemistry. All patients were diagnosed and treated with gemcitabine-based chemotherapy at Sun Yat-sen University Cancer Center. RRM1 expression was positive in 17 (35%) patients. RRM1 expression was not associated with sex, age, performance status, WHO histological type, number of distant metastases, previous treatment, or cycles of gemcitabine-based chemotherapy (P > 0.05). The progression-free survival of the RRM1-positive group was shorter than that of the RRM1-negative group (5 months vs. 7 months, P = 0.036), and the response rate of the RRM1-positive group was somewhat lower than that of the RRM1-negative group (51.6% vs. 35.3%, P = 0.278). There was no significant difference in median survival between the RRM1-positive and RRM1-negative groups (22 months vs. 19 months, P = 0.540). Our results show that RRM1-negative expression is related with longer progression-free survival in advanced NPC patients treated with gemcitabine-based regimens.

Expression of RRM1 and its association with resistancy to gemcitabine-based chemotherapy in advanced nasopharyngeal carcinoma

Changes of bone resorption marker (NTX) in chemotherapy plus zoledronic acid versus chemotherapy alone for nasopharyngeal cancer patients with bone metastases.

The relationship between drug exposure and clinical outcomes of non-small cell lung cancer patients treated with gefitinib

Clinical factors and molecular markers can be used to predict the prognosis of gefitinib-treated locally advanced or metastatic non-small cell lung cancer (NSCLC). This study was to identify predictive factors for the response and survival of gefitinib-treated locally advanced or metastatic NSCLC patients in China.

METHODS
Clinical data of 256 gefitinib-treated Chinese NSCLC patients from two existing clinical trials were analyzed. Univariate and multivariate analyses were performed to determine predictive factors of response and survival.

RESULTS
The objective response rate was 24.6%; the disease control rate was 54.7%. Median survival time was 11.43 months (95% CI, 8.64-14.22 months). The 1-year survival rate was 48.0% (95% CI, 41.0%-55.0%). Adenocarcinoma and skin rash were associated with better response. The patients with lower performance status (PS) score (0-1) and those with disease control (complete remission, partial remission, and stable disease) had longer survival when compared with their counterparts.

Adenocarcinoma and skin rash are predictors of better response to gefitinib. Low PS score and disease control are predictors of longer survival after treatment of gefitinib.

[Predictive factors for response and survival of gefitinib-treated locally advanced or metastatic non-small cell lung cancer patients: a retrospective analysis of two phase II clinical trials].

6063 Background: ZOL is the only bisphosphonate that has demonstrated efficacy for the prevention of skeletal-related events (SREs) in patients with BM in a wide range of tumor types. Recent retrospective analyses also showed that normalization of N-telopeptide of type I collagen (NTX) over 3 months by the treatment of ZOL provided a continuum of SRE risk reduction and survival benefit in patients with BM (Lipton et al. ASCO 2007). Therefore, we conducted the prospective open-label randomized phase II trial to evaluate the changes of NTX after administration of ZOL in NPC patients with BM. Methods: Newly diagnosed NPC patients with BM were randomized to receive chemotherapy of cisplatin (20mg/m2 IV, D1–5) plus FU (500mg/m2 IV, D1–5) (CF regimen, q3wks) and intravenous ZOL (4mg, q4wks, for 3months, CF+ZOL Group) or the same chemotherapy alone (CF Group). Urinary NTX was measured by ELISA method (Coleman et al. JCO 2005) at baseline and 1, 2, 3 months after administration of ZOL in all patients. Results: Si...

A prospective, open-label, randomized phase II trial to evaluate the changes of bone resorption marker after administration of zoledronic acid (ZOL) in nasopharyngeal cancer (NPC) patients with bone metastases (BM)

Hemicellulose was pre-extracted from poplar by the KOH extraction method. A series of activated carbons with high VOCs adsorption capacity were prepared using hemicellulose pre-extraction residue (HPR) as carbon precursor and KOH as the activator. The results showed that the pre-extraction using organic solvent (benzene-ethanol mixture) had no significant effect on the hemicellulose removal efficiency and the microporous structure of activated carbons. After the selective pre-extraction of 38.2 to 65.7 wt% hemicellulose from poplar, the final yield of activated carbons only decreased by 1.1 to 2.0%, but the pore structure of activated carbons was greatly improved. A total of 40.7 wt% hemicellulose in poplar was removed under 4 wt% alkali concentration and 3 h KOH treatment. The activated carbons prepared from HPR of poplar gave the highest BET surface area (3066 m2·g-1) and pore volume (1.32 cm3·g-1). The pore structures of activated carbons can be controlled to some extent by changing the removal degree of hemicellulose. The activated carbon obtained under the optimized conditions showed excellent adsorption capacity for toluene (733 mg·g-1) and dichloromethane (184 mg·g-1). The correlation between adsorption properties and pore structure shows that the adsorption capacities of toluene and dichloromethane were closely related to micropores (＜ 2 nm) and ultramicropores (＜ 0.6 nm) of activated carbon, respectively. The pre-extraction of hemicellulose greatly improved the volatile organic compound (VOC) adsorption capacity of activated carbons by increasing the percentage of micropores.

Preparation of high-performance activated carbons from hemicellulose pre-extracted residues of poplar and their application in VOCs removal

Anti‐oxidant and anti‐fatigue properties of apple pomace polysaccharides by acid or alkali extraction

Extraction methods, chemical characterizations and biological activities of mushroom polysaccharides: A mini-review.

Pleurotus eryngii polysaccharide (PEP) was obtained using hot water extraction and ethanol precipitation. Three purified polysaccharide fractions (namely PEP1‐A, PEP2‐A and PEP3‐A) were obtained from PEP using DEAE‐cellulose‐52 chromatography and a gel permeation Sephadex G‐100 column. Firstly, this paper examined the characterisation of PEP1‐A, PEP2‐A and PEP3‐A. The corresponding molecular weights were 5.378 × 10⁵, 9.506 × 10⁶ and 4.975 × 10⁵ Da, respectively. PEP1‐A, PEP2‐A and PEP3‐A had similar monosaccharide compositions. PEP1‐A was β‐configuration, and PEP2‐A and PEP3‐A were α‐configuration. PEP1‐A, PEP2‐A and PEP3‐A had pyran‐type rings, (1 → 3) glucose and (1 → 6) galactose linkages. Secondly, PEP, PEP1‐A, PEP2‐A and PEP3‐A possessed antioxidant activities, and PEP was best. Therefore, only PEP was used to study its anti‐fatigue activity in vivo. The result proved that PEP had anti‐fatigue activity. PEP could be used as a valuable natural food supplement for preventing anti‐fatigue or functional food.

Extraction, isolation, characterisation, antioxidant and anti‐fatigue activities of
 Pleurotus eryngii
 polysaccharides

The hot water extraction of polysaccharides from the fruiting body of Pleurotus eryngii was studied. In this paper, according to single-factor experiments, a response surface methodology and the Box–Behnken design were applied to optimize the extraction parameters of Pleurotus eryngii polysaccharides (PEP). The optimal extraction conditions were as follows: a temperature of 79 °C, a time of 3.11 h, a ratio of water to fruiting bodies of 52.6 mL g−1. Under these parameters, the yield of PEP was 7.53%. When mice with hyperlipidemia were administered low, medium or high doses of PEP, their body weight was reduced compared with the model group, and the degree of weight loss was proportional to the dose. At the 16th week of PEP treatment, blood lipid biochemical parameters such as total cholesterol, triglycerides, low-density lipoprotein-cholesterol, aspartate aminotransferase, and alanine aminotransferase levels were all decreased. However, high-density lipoprotein-cholesterol levels increased after PEP treatment. Histopathological examination of the liver showed that low, medium and high doses of PEP had a certain liver protective effect. High-dose PEP treatment had the best effect in regard to lipid-lowering and liver protection. In addition, the metabolome of the mice was analyzed by LC-MS, and the results indicated that C16 sphinganine can be used as a potential biomarker, which displayed significant differences among the six groups. In conclusion, the possible metabolic mechanism of the PEP on lipid-lowering was closely related to sphingolipid metabolism.

Optimization of extraction parameters of Pleurotus eryngii polysaccharides and evaluation of the hypolipidemic effect

Deinking is an important process in waste paper recycling process, and this study mainly focuses on the properties of the deinking agent and process optimization. DIA-30 prepared in our laboratory, and FS and LD, were the three representative deinking agents studied herein. Brightness, effective residual ink concentration (ERIC), dirt, macro-stickies, fiber loss during repulping, flotation, and washing processes were measured to evaluate the performance of the deinking agents and optimize process conditions. Each of the deinking agents exhibited different advantages: DIA-30 was optimal for deinking efficiency, brightness enhancement, as well as dirt and macrostickies removal, whereas LD was optimal for ink removal during flotation process but performed poorly in terms of brightness enhancement. FS showed a relatively balanced performance compared to those of DIA-30 and LD in the deinking process, but DIA-30 is the best option for deinking due to its outstanding comprehensive properties. The optimal repulping conditions for the deinking of 100% old magzines (OMG) using DIA-30 are as follows: repulping temperature, 60°C; pulp consistency, 13 wt%; repulping time, 20 min; H2O2 dosage, 0.5 wt% (oven-dried pulp); NaOH dosage, 1.2 wt% (oven-dried pulp); Na2SiO3 dosage, 0.3 wt% (oven-dried pulp); and optimum DIA-30 dosage, 0.1 wt%.

PBM · Modified Lignin Sulfonates Deinking Agent Evaluation and Optimization of Old Magzines Deinking Process of a Modified Lignin Sulfonates Deinking Agent

Abstract Uptake and in-plant transport of formaldehyde by six plants with or without soil microorganisms were investigated. The capabilities of fresh and boiled leaf extracts to dissipate added formaldehyde were also measured to evaluate formaldehyde metabolism in plant tissues. Results show that when the initial formaldehyde level in air was 0.56 ± 0.04 mg·m−3, the removal rate in the plant-only systems varied from 1.91 to 31.8 μg·h−1·g−1 FW (fresh weight). The removal rate of plants in the plant-only systems were ordered as Helianthus annuus Linn > Lycopersicon esculentum Miller > Oryza sativa > Sansevieria trifasciata Prain > Bryophyllum pinnatum > Mesembryanthemum cordifolium L. f. Most reduction of formaldehyde in the air was due to degradation by active components in the plant tissues, of which 4–64% of these were through to be enzymatic reactions. In the microbe-plant systems, formaldehyde removal rates increased by 0.24–9.53 fold compared to the plant-only systems, with approximately 19.6–90.5% of the formaldehyde reduction resulting from microbial degradation. Microorganisms added to the rhizosphere solution enhanced phytoremediation by increasing the downward transport of formaldehyde and its release by roots. Results suggest a new means to screen for efficient plant species that can be used for phytoremediation of indoor air.

Formaldehyde removal in the air by six plant systems with or without rhizosphere microorganisms

Extraction and characterization of collagen hydrolysates from the skin of Rana chensinensis

Extraction and antioxidant activity of polysaccharides from Rana chensinensis skin.

In the present work, enzymatic/mild acidolysis lignin (EMAL) was isolated from the raw material Cunninghamia lanceolata, and hydrothermal depolymerization was carried out in subcritical water (from 250 to 350 °C) using a cylindrical autoclave. The results revealed that the lowest yield of solid residue and highest liquid product yield were achieved at 325 °C. The liquid products were primarily composed of phenolic monomers and oligomers. As the reaction temperature increased, repolymerization of the liquid products and dehydrogenation and deoxidation of the solid residues occurred. The high heating value (HHV) of the residues was larger than that of the EMAL, and it reached a maximal level at 275 °C. Hydrothermal depolymerization and condensation reactions took place simultaneously even under mild conditions (250 °C). Carbonization of the EMAL was remarkable when the reaction temperature reached 325 °C.

Temperature Impact on the Hydrothermal Depolymerization of Cunninghamia lanceolata Enzymatic/Mild Acidolysis Lignin in Subcritical Water

Characterization and antioxidant activity in vitro and in vivo of polysaccharide purified from Rana chensinensis skin.

Predicting optimal hydropower generation with help optimal management of water resources by Developed Wildebeest Herd Optimization (DWHO)

Nowadays, energy conservation and emission reduction have become the top priority of metro systems. This paper concentrates on the application of regenerative braking technology in the energy-saving operation of metro systems. The research focus of this paper is maximizing the utilization of regenerative energy. We propose an energy-saving optimization method for train operation plans. Firstly, the train operation plan optimization model is constructed based on the adjustment of train operation interval and opposite departure interval. Secondly, we design a simulation algorithm that can effectively solve such a problem. Finally, the real-world line structure and speed profiles are used to verify the effectiveness of the optimization model and the algorithm. The results show that the optimization effects of this method are 0.8% and 2.2%, respectively, during peak and off-peak hours when the power grid is separated, and the optimization effects are 3% and 3.6%, respectively, during peak and off-peak hours when the power grid is connected. The method improves the utilization of regenerative energy and reduces the waste of resources significantly. Compared with taking the overlapping time to represent available regenerative energy, the energy calculation method proposed in this paper is more accurate.

2020 IEEE 23rd International Conference on Intelligent Transportation Systems (ITSC)

A train operation plan optimization method to maximize the utilization of regenerative energy for metro systems

The green behavioral effect of clean coal technology on China's power generation industry.

Going green in the maritime industry : a perspective from LNG as marine fuel Part II

With the development of the economy, the logistics activities on the ecological devastation of the environment such as air pollution, noise pollution, waste of resources, traffic congestion, increased waste, has also become more and more serious, and all the consequences to a certain extent, contrary to the principles of social sustainable development. The sustainable development theory as the guide, making great efforts to develop green logistic, and analysis the relationship between green logistics and social sustainable development. On the basis of studying our logistics status, exploring effective approaches to develop green logistics.

In the low-carbon economic era, competitions among enterprises are no longer confined to the traditional cost, service and quality, and environmental protection measures will inevitably become one of the important assessment criteria for customers to choose transportation service providers. In this paper, starting from the nature of low-carbon economy, it analyzes the dilemma faced in the development of green transportation industry in China, and then proposes effective countermeasures pertinently for achieving a green transport.

On Dilemma and Countermeasures of the Green Transportation Industry Development in China in the Low-Carbon Economic Era

Study on Sustainable Utilization of Water Resources in Tieling City Based on System Dynamics Approach

On the basis of previous studies, the water quality and hydraulic reliability of water distribution system was analyzed. Then the calculation models of the hydraulic and water quality reliability are established. Finally, a simulated municipal water distribution system is taken as the example to validate the rationality and feasibility of the models. The results show that the models established in this paper is reasonably and feasibly to be used into practice.

Notice of Retraction Hydraulic and water quality reliability analysis of water distribution system

2010 The 2nd Conference on Environmental Science and Information Application Technology

Notice of RetractionHydraulic and water quality reliability analysis of water distribution system

The factors that impacted hydraulic vulnerability of water distribution system are discussed, and a quantitative hydraulic vulnerability and risk assessment model is presented in this paper. In this model, EPANET is employed as the hydraulic solver of water networks and Monte-Carlo stochastic simulation is incorporated for randomly generating failure scenarios of both pipes and water plants. Finally, the proposed methodology is used to carry out vulnerability and risk assessment in a real-life water distribution system of a high-tech zone in North China. The results show the high efficiency of the model. The research could provide a theoretical basis to the water supply enterprises and help them to identify the vulnerable area, evaluate risk of the consumers and develop specific plan for risk reduction.

Study on hydraulic vulnerability and risk assessment of water distribution system

Partial least squares regression model to predict water quality in urban water distribution systems

Simple and accurate visual detection of single nucleotide polymorphism based on colloidal gold nucleic acid strip biosensor and primer-specific PCR.

Abstract No. 686 A novel thermosensitive x-ray contrast iodized oil for transcatheter arterial embolization of VX2 tumor model

Photodynamic therapy (PDT) is a clinically approved and minimally invasive form of cancer treatment. However, due to hypoxia at the tumor site and phototoxicity to normal tissues, monotherapies using photosensitizers remain suboptimal. This study aimed to develop a highly selective controlled catalase-enhanced synergistic photodynamic and photothermal cancer therapy based on gold nanostars. Methods: Gold nanostars (GNS) with high thermal conversion efficiency were used as the core for photothermal therapy (PTT) and the shell consisted of the photosensitizer Ce6-loaded mesoporous silicon. The shell was modified with catalase (E), which catalyzes the conversion of hydrogen peroxide to oxygen at the tumor site, alleviating hypoxia and increasing the effect of the photodynamic treatment. Finally, a phospholipid derivative with c(RGDyK) was used as the targeting moiety and the nanoparticle-encapsulating material. Results: The nanoprobe exhibited good dispersion, high stability, and high photothermal conversion efficiency (~28%) for PTT as well as a photodynamic "on-off" effect on Ce6 encapsulated in mesoporous channels. The "release" of Ce6 was only triggered under photothermal stimulation in vivo. Due to its targeting ability, 72 h after injection of the probe, the tumor site in mice showed an observable CT response. The combined treatment using photothermal therapy (PTT) and catalase-enhanced photo-controlled PDT exerted a superior effect to PTT or PDT monotherapies. Conclusion: Our findings demonstrate that the use of this intelligent nanoprobe for CT-targeted image-guided treatment of tumors with integrated photothermal therapy (PTT) and catalase-enhanced controlled photodynamic therapy (PDT) may provide a novel approach for cancer theranostics.

Intelligent gold nanostars for in vivo CT imaging and catalase-enhanced synergistic photodynamic & photothermal tumor therapy

In this paper, gold nanorods and InP/ZnS quantum dots were encapsulated together in a silica medium, and the targeting molecular peptide c(RGDfC) was further connected after surface modification with PEG and PEG derivatives to prepare a multifunctional Au@QD@SiO2/PEG-c(RGDfC) probe. Dynamic Light Scattering showed that the probe size was about 215.01 ± 2.72 nm, and its dispersibility was good. In in vitro experiments when the concentration was as high as 200 μg mL-1, the activity of the cells was still 85% due to low toxicity. In vivo experiments showed that the probe had excellent tumor targeting, X-ray computed tomography (CT) imaging and fluorescence imaging capabilities. The experiments revealed that the probe had a long blood circulation time (T1/2 = 7.78 h) in mice. Biochemical analysis, liver enzyme analysis and histomorphological analysis after probe injection showed that the probe had no obvious side effects on the normal functions of the main organs, indicating good biosafety. In vivo imaging experiments showed that 6 d after intravenous injection, the tumor sites of a HeLa tumor-bearing nude mice positive group presented obvious fluorescence and CT signals, indicating that the prepared nanoprobe had good tumor targeting dual-mode imaging capabilities and therefore showed great potential in biomedical imaging applications, especially the diagnosis of cancer.

In vivo tumor active cancer targeting and CT-fluorescence dual-modal imaging with nanoprobe based on gold nanorods and InP/ZnS quantum dots.

Graphene oxide-assisted Au nanoparticle strip biosensor based on GR-5 DNAzyme for rapid lead ion detection.

Recent advancements of high efficient donor–acceptor type blue small molecule applied for OLEDs

Nickel cobalt sulphides with different stoichiometric nickel and cobalt contents have been synthesized and used as pseudocapacitive materials for supercapacitors. The as-employed polyol method is robust enough to use a one-pot synthesis of nickel cobalt sulphides with similar porous morphology and crystal structure at different nickel and cobalt ratios. The electrochemical performance of the nickel cobalt sulphides can be easily tuned by the varying the Ni and Co content. Owing to the combined contributions from both Ni and Co ions, the bimetallic Ni–Co sulphides show a superior pseudocapacitance compared to monometallic Co and Ni sulphides in terms of high specific capacitance, excellent rate capability and long cycle stability. In particular, the Ni1.5Co1.5S4 sample shows the highest specific capacitance of 1093 F g−1 at 1 A g−1, superior rate capability of 69% capacitance retention after a 50-fold increase in current densities, and longer cycle stability with increased specific capacitance of 108% of capacitance retention after 2000 cycles. In addition, the Ni1.5Co1.5S4 was also used to assemble an asymmetric supercapacitor with reduced graphene oxide and attains excellent capacitive performance with high specific capacitance (113 F g−1 at 1 A g−1), high energy density (37.6 W h kg−1 at 775 W kg−1) and high power density (23.25 kW kg−1 at 17.7 W h kg−1).

One-pot synthesis of porous nickel cobalt sulphides: tuning the composition for superior pseudocapacitance

A novel and facile one-step method for growing α-phase nickel–cobalt hydroxides is developed. The use of 1-methyl-2-pyrrolidone (NMP) in the mixed solvent plays the decisive role in the precipitation of metal ions and the formation of α-phase hydroxides. The synthetic method is robust enough to synthesize Ni–Co hydroxides with different stoichiometric ratios of Ni and Co, and can be extended to the fabrication of Ni0.67Zn0.33 hydroxide in the α phase. More encouragingly, the method employed can be further used to grow layered nickel-cobalt hydroxides on Ni foam. As the electroactive materials for pseudocapacitors, the Ni–Co hydroxides deliver an ultrahigh specific capacitance (1337.4 F g−1 at 1 A g−1 for Ni0.67Co0.33 hydroxide) with improved rate capability and cycling stability. Moreover, a greatly increased specific capacitance (2248.9 and 2286.7 F g−1 at 1 A g−1 for Ni0.5Co0.5 and Ni0.67Co0.33 hydroxides, respectively) with superior cycling stability is obtained after growth on Ni foam.

One-Pot Fabrication of Layered α-Phase Nickel–Cobalt Hydroxides as Advanced Electrode Materials for Pseudocapacitors

In this study, silica coated Au nanospheres (Au@SiO2) were prepared by a reverse microemulsion method; subsequently, a layer of fluorescent quantum dots (QDs) were adsorbed onto it and then it was coated with silica again. After modifying with PVP, the composite silica coated gold nanosphere and quantum dots nanoparticle (Au@SiO2-QDs/SiO2-PVP) was obtained. This composite structure contained Au and QDs, and it could be used for contrast-enhanced X-ray CT imaging and fluorescence imaging. Characterization showed that the composite nanoparticle had good dispersity, a high fluorescence intensity and a good effect of X-ray absorption, and it was suitable for using as a bimodal imaging probe.

Composite silica coated gold nanosphere and quantum dots nanoparticles for X-ray CT and fluorescence bimodal imaging.

Composite nanoparticle of Au and quantum dots for X-ray computed tomography and fluorescence dual-mode imaging in vivo

Magnetic fluorescent nanoparticles (NPs) have great potential applications for diagnostics, imaging and therapy. We developed a facile polyol method to synthesize multifunctional Fe3O4@CeF3:Tb@CeF3 NPs with small size (<20 nm), high water solubility and good biocompatibility. The NPs were modified by ligand exchange reactions with citric acid (CA) to obtain carboxyl-functionalized NPs (Fe3O4@CeF3:Tb@CeF3-COOH). Folic acid (FA) as an affinity ligand was then covalently conjugated onto NPs to yield Fe3O4@CeF3:Tb@CeF3-FA NPs. They were then applied as multimodal imaging agents for simultaneous in vitro targeted fluorescence imaging and magnetic resonance imaging (MRI) of HeLa cells with overexpressed folate receptors (FR). The results indicated that these NPs had strong luminescence and enhanced T2-weighted MR contrast and would be promising candidates as multimodal probes for both fluorescence and MRI imaging.

Folic acid-targeted magnetic Tb-doped CeF3 fluorescent nanoparticles as bimodal probes for cellular fluorescence and magnetic resonance imaging.

In this article, a fluorescence-CT dual-mode nanoprobe is successfully synthesized by making use of distearoylphosphatidylethanolamine-poly(ethylene glycol)-folate (DSPE-PEG2000-FA) and other amphiphilic molecules to coat silver sulfide (Ag2S) quantum dots (QDs) and iodinated oil simultaneously. In vitro experiments show that the fluorescence wavelength of the nanoprobe is 1170 nm in the near infrared-II region. Its size is 139.6 nm, it has good dispersibility, and it has low cellular toxicity at concentrations up to 25 μg mL(-1) Ag. In vivo experiments revealed that the probe has a rather long circulation time (blood half-life of 5.7 hours), and the tissue histopathological tests show that it is not obviously harmful to major organs' normal function. Biochemical analysis (glutamic pyruvic transaminase and glutamic oxaloacetic transaminase levels) and blood analysis (white blood cell, red blood cell, hemoglobin and blood platelet counts) reveal that it has little influence on blood within 15 days of administration. When injected into HeLa xenograft nude mice by the tail vein, the probe elicited intensely enhanced fluorescence and X-ray computed tomography (CT) signals in the tumors after 24 hours, and the structure, size and position of tumor tissue were shown clearly. In a word, the probe has good tumor targeting capabilities, and it has significant value in fluorescence-CT dual-mode imaging in vivo.

In vivo cancer targeting and fluorescence-CT dual-mode imaging with nanoprobes based on silver sulfide quantum dots and iodinated oil.

Hybrid nanoprobes of bismuth sulfide nanoparticles and CdSe/ZnS quantum dots for mouse computed tomography/fluorescence dual mode imaging

PEG-phospholipid-encapsulated bismuth sulfide and CdSe/ZnS quantum dot core–shell nanoparticle and its computed tomography/fluorescence performance

Gold nanoparticles coated with mesoporous silica (Au@mSiO2) have been prepared by a facile one-pot two-step method. The resultant Au@mSiO2 exhibit an ideal core-shell structure with uniform mSiO2 coverage and without any interfacial adhesive layer on the Au surface. Some new explanations on the role that CTAB plays in the synthesis of Au@mSiO2 are discussed.

One-pot two-step synthesis of core-shell mesoporous silica-coated gold nanoparticles.

Facilely synthesized α phase nickel–cobalt bimetallic hydroxides: Tuning the composition for high pseudocapacitance

We developed a simple and efficient method to synthesize a novel probe for both computed tomography (CT) and fluorescence imaging. Gold nanospheres were coated with positively charged mesoporous silica (Au@mSiO2-TTA) using a one-pot method to cohydrolyze quaternary ammonium silane and tetraethyl orthosilicate. Subsequently, IR-783, a negatively charged and water-soluble near-infrared fluorescent dye, was electrostatically adsorbed into the silica shell. Transmission electron microscopy imaging, X-ray powder diffraction, and energy dispersive X-ray spectroscopy indicated that Au@mSiO2-TTA had a clear core-shell structure, was monodisperse, had a large surface area (530 m2/g), and had a uniform pore size (2.2 nm). The mesoporous structure could effectively load fluorescent dye. After loading, the zeta potential of the nanoparticle dropped from 48 mV to 30 mV, and after additional modification with polyvinylpyrrolidone, it further reduced to 6 mV. Probe fluorescence was stable over time, and the probe was an effective CT contrast agent and as a near-infrared fluorescent probe. The half-life of the probe in the blood was 1.5 h, and the probe was mainly distributed in the spleen and liver 4 h after injection. Tissue sections showed that major organs were normal and without visible morphological changes, 6 days post injection, indicating the biocompatibility of the probe.

Facile Synthesis of Gold Nanospheres Modified by Positively Charged Mesoporous Silica, Loaded with Near-Infrared Fluorescent Dye, for in Vivo X-ray Computed Tomography and Fluorescence Dual Mode Imaging.

Probe bismuth sulfide modified with Pluronic F127 (Bi2S3-PF127), which has high biocompatibility and dispersibility, is synthesized using triblock copolymer Pluronic F127 to modify hydrophobic Bi2S3 nanoparticles that are prepared by a hot injection method. TEM results show that most of the probe has a length of about 14.85 ± 1.70 nm and a breadth of about 4.79 ± 0.63 nm. After injected into the tail vein of a mouse, the probe has obvious CT contrast enhancement capability from x-ray CT imaging results. Meanwhile, the probe’s in vivo toxicity is also studied. It is found that hematoxylin and eosin stains of major organs have no change. A biochemical analysis (alanine aminotransferase and aspartate aminotransferase) prove the probe has no adverse effects. The results of a blood analysis (white blood cell count, red blood cell count, hemoglobin, and platelet count) are also normal. The biological distribution of Bi by ICP-AES shows that most of nanoparticles are cleaned out after injection 48 h, and the circulation half-life of the probe is 5.0 h, suggesting that Bi2S3-PF127 has a long circulation and indicating that the Bi2S3-PF127 probe has good biocompatibility and safety.

In vitro and in vivo CT imaging using bismuth sulfide modified with a highly biocompatible Pluronic F127

Carcino-embryonic antigen detection based on fluorescence resonance energy transfer between quantum dots and graphene oxide.

In situ growth of NiCo2S4 nanotube arrays on Ni foam for supercapacitors: Maximizing utilization efficiency at high mass loading to achieve ultrahigh areal pseudocapacitance

Multifunctional nanoparticles (NPs) have great potential for multimodal cancer imaging and effective therapy. We have developed multifunctional NPs (GNR@SiO2@QDs) by incorporating gold nanorods (GNRs) and CdSe/ZnS quantum dots (QDs) into silica. Folic acid (FA) as a targeting ligand was covalently conjugated on the surfaces of GNR@SiO2@QDs with a silane coupling agent. Cell viability assay showed that these NPs had low cytotoxicity. And confocal fluorescence images illustrated that they could selectively target HeLa cells overexpressing folate receptors (FRs) rather than FR-deficient A549 cells. In vitro cell imaging experiments revealed that these NPs exhibited strong X-ray attenuation for X-ray computed tomography (CT) imaging and strong fluorescence for fluorescence imaging. They also showed an enhanced photothermal therapy (PTT) effect for cancer cells due to GNRs' high absorption coefficient in the near infrared (NIR) region and a better heat generation rate. All results show that they have great potential in theranostic applications such as for targeted tumor imaging and therapy.

Folic acid-conjugated silica-coated gold nanorods and quantum dots for dual-modality CT and fluorescence imaging and photothermal therapy.

Monodispersed Bi2S3-QD@SiO2-PEG nanoparticles are prepared by a one-pot method in a reverse microemulsion system, which exhibited remarkable performances in CT and fluorescence imaging in vitro and in vivo.

Reverse microemulsion-mediated synthesis of Bi2S3-QD@SiO2-PEG for dual modal CT-fluorescence imaging in vitro and in vivo.

Here we report the use of sulfuric acid as a catalyst for the facile and homogeneous synthesis of core-shell SiO(2)@TiO(2) nanocomposites using simple apparatus, under ambient pressure and temperature. The resultant SiO(2)@TiO(2) exhibits an ideal core-shell structure with uniform nanoscale TiO(2) coverage. The shell thickness of SiO(2)@TiO(2) can be conveniently tuned through adjustment of the esterification reaction parameters. Moreover, SiO(2)@TiO(2) shows improved catalytic activity in the photodegradation of methyl orange.

Homogeneous synthesis of SiO2@TiO2 nanocomposites with controllable shell thickness and their enhanced photocatalytic activity.

A facile method was used for the synthesis of CNTs@TiO2 nanocomposites using a simple apparatus at ambient pressure and temperature. CNTs@TiO2 exhibit core-shell structure without any interfacial adhesive layer on the CNT surface. The photodegradation of methyl orange suggests enhanced photoactivity of CNTs@TiO2 under UV light. The morphology, structure and composition of CNTs@TiO2 were also investigated.

Facile synthesis of carbon nanotube-inorganic hybrid materials with improved photoactivity.

Quantum Dots: Tracking the Down‐Regulation of Folate Receptor‐α in Cancer Cells through Target Specific Delivery of Quantum Dots Coupled with Antisense Oligonucleotide and Targeted Peptide (Small 24/2013)

TiO2-based composites with tunable properties and improved performance were synthesized by a general and controllable method in environmentally benign conditions. The particle size, phase transformation, and thermal stability of composites can be conveniently tuned through the adjustment of reaction parameters. This work demonstrates that this approach not only helps us to easily and unrestrictedly design composites with the desired properties but it also provides the possibility for a large scale screening of potential functional materials for the future synthesis of smart devices.

Facile fabrication of TiO2-based composites with tunable properties and improved performance through a general and controllable method

Based on the multivalent binding capability of streptavidin (SA) to biotin, a multifunctional quantum dot probe (QD-(AS-ODN+p160)) coupled with antisense oligonucleotide (AS-ODN) and peptide p160 is designed for real-time tracking of targeted delivery of AS-ODN and regulation of folate receptor-α (hFR-α) in MCF-7 breast cancer cells. Fluorescence spectra, capillary electrophoresis (CE) and dynamic light scattering (DLS) are used to characterize the conjugation of AS-ODN and p160 with quantum dots (QDs), DLS results confirm the well stability of the probe in aqueous media. Confocal imaging and quantitative flow cytometry show that QD-(AS-ODN+p160) is able to specifically target human breast cancer MCF-7 cells. Low temperature and ATP depletion treatments reveal the cellular uptake of QD-(AS-ODN+p160) is energy-dependent, and the effects of inhibition agents and co-localization imaging further confirm the endocytic pathway is mainly receptor-mediated. Transmission electron microscopy (TEM) shows the intracellular delivery and endosomal escape of QD probe along with incubation time extended. Two transfection concentrations of QD probe (10 nM and 50 nM) below half inhibitory concentration (IC50 ) value are chosen according to MTT assay. Real-time PCR shows at these two concentration cases the relative mRNA expression levels of hFR-α reduce to 72.5 ± 3.9% and 17.6 ± 1.0%, respectively. However, western blot and quantitative ELISA analysis show the expression level of hFR-α protein has a significant decrease only at 50 nM, indicating that gene silence is concentration-dependent. These results demonstrate that the QD-(AS-ODN+p160) probe not only achieves gene silence in a cell-specific manner but also achieves real-time tracking during AS-ODN intracellular delivery.

Tracking the down-regulation of folate receptor-α in cancer cells through target specific delivery of quantum dots coupled with antisense oligonucleotide and targeted peptide.

Synthesis and characterization of Bi2S3 composite nanoparticles with high X-ray absorption

We designed an aptasensor for the detection of adenosine triphosphate (ATP) based on chemiluminescence resonance energy transfer (CRET). An adenosine aptamer was cut into two pieces of ssDNA, which were attached to quantum dots (QDs) and horse radish peroxidase (HRP), respectively. They could reassemble into specific structures in the presence of ATP and then decrease the distance of HRP and QDs. ATP detection can be easily realized according to the fluorescent intensity of QDs, which is excited by CRET between luminol and QDs. Results show that the concentration of ATP is linear relation with the fluorescent intensity of the peak of QDs emission and the linear range for the linear equation is from 50 μM to 231 μM and the detection limit was 185 nM. When the concentration of ATP was 2 mM, the efficiency of CRET is 13.6%. Good specificity for ATP had been demonstrated compared to thymidine triphosphate (TTP), cytidine triphosphate (CTP) and guanosine triphosphate (GTP), when 1 mM of each was added, respectively. This method needs no external light source and can avoid autofluorescence and photobleaching, and ATP can be detected selectively, specifically, and sensitively in a low micromolar range, which means that the strategy reported here can be applicable to the detection of several other target molecules.

A new strategy for the detection of adenosine triphosphate by aptamer/quantum dot biosensor based on chemiluminescence resonance energy transfer.

Due to the significance of reactive oxygen species (ROS) in numerous physiological processes including pathogen response, apoptosis, and induction of defense genes, various methods have been developed for their quantitative analysis. However, the conventional methods using exogenous tracers lack the capability to conduct real-time in vivo measurements. The electrochemical biosensors have shown their potentials for in vivo applications with the rapid and reagentless detection processes. In this article, electrochemical biosensors that are capable of making in vivo ROS detections are reviewed. The different configurations of these biosensors with corresponding strategies to enhance sensitivity and selectivity are discussed in detail. With further studies to promote the biosensor performance, these devices promise to provide more facile ways for ROS research in life sciences.

In Vivo Electrochemical Biosensors for Reactive Oxygen Species Detection: A Mini-Review

Mesoscopic nitrogen-doped TiO2 spheres for quantum dot-sensitized solar cells

A convenient method of preparing gene vector for real time monitoring transfection process based on the quantum dots

Due to the significance of hydrogen peroxide (H(2)O(2)) in biological systems and its practical applications, the development of efficient electrochemical H(2)O(2) sensors holds a special attraction for researchers. Various materials such as Prussian blue (PB), heme proteins, carbon nanotubes (CNTs) and transition metals have been applied to the construction of H(2)O(2) sensors. In this article, the electrocatalytic H(2)O(2) determinations are mainly focused on because they can provide a superior sensing performance over non-electrocatalytic ones. The synergetic effect between nanotechnology and electrochemical H(2)O(2) determination is also highlighted in various aspects. In addition, some recent progress for in vivo H(2)O(2) measurements is also presented. Finally, the future prospects for more efficient H(2)O(2) sensing are discussed.

Recent advances in electrochemical sensing for hydrogen peroxide: a review.

Phytosterol liposomes were prepared using the thin film method and used to encapsulate nattokinase (NK). In order to obtain a high encapsulation efficiency within the liposome, an orthogonal experiment (L9 (3)4) was applied to optimise the preparation conditions. The molar ratio of lecithin to phytosterols, NK activity and mass ratio of mannite to lecithin were the main factors that influenced the encapsulation efficiency of the liposomes. Based on the results of a single-factor test, these three factors were chosen for this study. We determined the optimum extraction conditions to be as follows: a molar ratio of lecithin to phytosterol of 2 : 1, NK activity of 2500 U mL−1 and a mass ratio of mannite to lecithin of 3 : 1. Under these optimised conditions, an encapsulation efficiency of 65.25% was achieved, which agreed closely with the predicted result. Moreover, the zeta potential, size distribution and microstructure of the liposomes prepared were measured, and we found that the zeta potential was −51 ± 3 mV and the mean diameter was 194.1 nm. From the results of the scanning electron microscopy, we observed that the phytosterol liposomes were round and regular in shape and showed no aggregation.

Optimisation of preparation conditions and properties of phytosterol liposome-encapsulating nattokinase

Quantum dots (QDs) fluorescent probes based on oligonucleotide aptamers and peptides with specific molecular recognition have attracted much attention. In this paper, CdSe/ZnS QDs probes for targeted delivery to mouse and human cells using aptamer GS24 and peptide T7 specific to mouse/human transferrin receptors were developed. Capillary electrophoresis analyses indicated that the optimal molar ratios of QDs to aptamer or peptide were 1:5. Fluorescence and confocal microscope imaging revealed QD-GS24 and QD-T7 probes were able to specifically recognize B16 cells and HeLa cells respectively. Quantitative flow cytometry analysis indicated the transportation of QD-GS24 or QD-T7 into cells could be promoted by corresponding free transferrin. Transmission electron microscopy confirmed the uptake of probes in cells and the effective intracellular delivery. MTT assay suggested the cytotoxicity of probes was related to the surface ligand, and aptamer GS24 (or peptide T7) could reduce the cytotoxicity of probes to a certain degree. The study has great significance for preparing QDs fluorescent probes using non-antibody target molecules.

Targeted quantum dots fluorescence probes functionalized with aptamer and peptide for transferrin receptor on tumor cells

Characterization of CdTe/CdSe quantum dots-transferrin fluorescent probes for cellular labeling.

Tunable energy band CdSexS(1−x) quantum dots (QD) are developed for QD-sensitized solar cells(QDSSCs) by the successive ionic layer adsorption and reaction (SILAR) technique. The results indicated that the energy band and the light absorption of CdSexS(1−x) QDs could be controlled by the ratio of the sulphur (S) and the selenium (Se). Compared with the conventional CdS/CdSe system, its absorption spectrum and monochromatic incident photon-to-electron conversion efficiency (IPCE) spectrum show higher light harvest ability and a broader response wavelength region. As a result, a high energy conversion efficiency of 2.27% was obtained with the CdSexS(1−x) QDSSCs under AM 1.5 illumination of 100 mW cm−2. After being further treated with CdSe QDs, the CdSexS(1−x)/CdSe QDSSC yielded an energy conversion efficiency of 3.17% due to the enhanced absorption and the reduced recombination. It can be expected that tunable energy band QDs controlled by the ratio of atoms can contribute to higher efficiency QDSSCs.

Efficient quantum dot-sensitized solar cell with tunable energy band CdSexS(1−x) quantum dots

CdPbS quantum dots-sensitized TiO2 photoelectrode was prepared using chemical bath codeposition technique by dipping TiO2 film into a 0.5 M Cd(NO3)2-Pb(NO3)2 solution (molar ratio 9:1) and a 0.5 M Na2S methanol solution. The CdPbS quantum dots have the size about 4 to 6 nm and distribute homogeneously in the TiO2 film. The as-prepared electrode showed improved absorption spectra. The assembled quantum dots-sensitized solar cell (QDSSC) yielded a power conversion efficiency (nu) of 1.88% and a short-circuit current of 15.28 mA/cm2 under AM 1.5 illumination of 100 mW/cm2, far outperformed the single PbS, CdS QDSSC and the nu increased 49.2% than coupled PbS/CdS QDSSC. The solar cell presented IPCE peak value of 45.7% and the effective photovoltaic range covers the visible region and near infrared region.

Efficient CdPbS quantum dots-sensitized TiO2 photoelectrodes for solar cell applications.

Photometry was employed to study the optimum extraction conditions of anthraquinone derivatives from rhizomes of Rheum officinale Baill in this study. The influences of extraction solvents (chloroform, benzene, ethanol, methanol, and glycerol), acid, and extraction time on the extraction yield were discussed. The results indicate that, to the Rhubarb rhizomes powder with the average particle size 0.18 mm, the conditions of the extraction solvent composed by chloroform, glycerol, and sulfuric acid (20%) in the ratio of 4:1:1 (v:v), the weight of dried Rhubarb to the solvent volume in the ratio of 1:12 (w:v), extraction time of 110 min, the anthraquinone derivatives extraction could achieve the best yield. And the antibacterial tests showed the raw extraction products had the MIC (minimal inhibitory concentration) of 20 μg/mL and 30 μg/mL to Staphylococcus aureus and Escherichia coli, respectively.

EXTRACTION OF ANTHRAQUINONE DERIVATIVES FROM RHUBARB RHIZOMES AND THEIR ANTIBACTERIAL TESTS

The presence of complex protein constituents and difficulties in extracting protein from rapeseed meal limit the application of rapeseed protein in food processing. However, double-low rapeseed (low erucic acid, low glucosinolate) protein is a type of complete protein that is of potential use in the food industry. In this study the characteristics and functional properties of rapeseed protein prepared by ultrasonic-assisted extraction, ultrafiltration and isoelectric precipitation were analysed and compared with those of soybean protein.

RESULTS
The extraction efficiency with the ultrasonic-assisted method was significantly higher than that obtained with the traditional method. Ultrafiltration and isoelectric precipitation yielded three different proteins: ultrafiltered protein RPs and precipitated proteins RP5.8 and RP3.6. Chromatographic separation of RPs resulted in four fractions: RPsI, RPsII, RPsIII and RPsIV. The distribution of the isoelectric point of rapeseed protein was investigated by two-dimensional electrophoresis. The amino acid composition of RPs renders it suitable for human consumption. The hydrophobic/hydrophilic amino acid ratio of rapeseed protein was higher than that of soybean protein. The functional properties (oil adsorption ability, emulsifying capacity, foaming capacity and foam stability) of RPs, RP5.8 and RP3.6 were found to be better than those of soybean protein.

Ultrasonication and ultrafiltration were significantly better than the traditional method of rapeseed protein extraction. The ultrafiltered rapeseed protein RPs had superior functional properties. The results of this study provide useful indicators for rapeseed protein as a potential replacement for other proteins.

Some characteristics and functional properties of rapeseed protein prepared by ultrasonication, ultrafiltration and isoelectric precipitation.

Here the distance dependence of metal-enhanced quantum dots (QDs) fluorescence in solution is studied systematically by capillary electrophoresis (CE). Complementary DNA oligonucleotides-modified CdSe/ZnS QDs and gold nanoparticles (Au NPs) were connected together in solution by the hybridization of complementary oligonucleotides, and a model system (QD-Au) for the study of metal-enhanced QDs fluorescence was constructed, in which the distance between the QDs and Au NPs was controlled by adjusting the base number of the oligonucleotide. In our CE experiments, the metal-enhanced fluorescence of the QDs solution was only observed when the distance between the QDs and Au NPs ranged from 6.8 to 18.7 nm, and the maximum enhancement by a factor of 2.3 was achieved at 11.9 nm. Furthermore, a minimum of 19.6 pg of target DNA was identified in CE based on its specific competition with the QD-DNA in the QD-Au system. This work provides an important reference for future study of metal-enhanced QDs fluorescence in solution and exhibits potential capability in nucleic acid hybridization analysis and high-sensitivity DNA detection.

Distance-dependent metal-enhanced quantum dots fluorescence analysis in solution by capillary electrophoresis and its application to DNA detection.

Simultaneous detection of dual single-base mutations by capillary electrophoresis using quantum dot-molecular beacon probe.

Influence of Dy-doping on ferroelectric and dielectric properties in Bi1.05−xDyxFeO3 ceramics

A feasible method of improving the quantum yield of CdTe/CdS quantum dots by the first heating–cooling cycle and their application in cancer cell recognition

Since the mechanism of Cd(2+) stress for plants is not clear, an in vivo method to monitor Cd(2+) stress for plants is necessary. However, oxidative burst (OB) is a signal messenger in the process of Cd(2+) stress for plants.

OBJECTIVE
To establish an electrochemical method with poly-o-phenylenediamine and Pt microparticle modified Pt electrode (POPD-Pt-MP-Pt) as a microbiosensor for the in vivo detection of oxidative burst induced by Cd(2+) stress in oilseed rape (Brassica napus L.).

METHODOLOGY
The optimal fabrication of POPD-Pt-MP-Pt biosensor was achieved. Electrochemical signal was collected by amperometry.

RESULTS
After oilseed rape was exposed to 84.9 mM CdCl(2) stress, three oxidative bursts were observed in oilseed rape by amperometry at 3.3 h, 8.4 h and 13.2 h, respectively. However, there was no obvious signal observed in the controlled assay.

This contribution presents the in vivo monitoring of the OB process induced by Cd(2+) stress in oilseed rape by POPD-Pt-MP-Pt microbiosensor in real-time. The novel electrochemical microbiosensor not only facilitates the real-time study in plant self-defence response to the adverse environment such as Cd(2+) stress, but also provides an effective tool for probing the self-defence mechanism in plants.

In vivo monitor oxidative burst induced by Cd2+ stress for the oilseed rape (Brassica napus L.) based on electrochemical microbiosensor.

Colloids and Surfaces A: Physicochemical and Engineering Aspects

Bioconjugation of concanavalin and CdTe quantum dots and the detection of glucose

Immobilized protease on the magnetic nanoparticles used for the hydrolysis of rapeseed meals

The optical properties of antiphotobleaching and the advantage of long-term fluorescence observation of quantum dots are fully adopted to study the effects of iron on the endocytosis of transferrin. Quantum dots are labeled for transferrin and endocytosis of transferrin in HeLa cells is observed under the normal state, iron overloading, and an iron-deficient state. In these three states, the fluorescence undergoes a gradual process of first dark, then light, and finally dark, indicating the endocytosis of transferrin. The fluorescence intensity analysis shows that a platform emerges when fluorescence changes to a certain degree in the three states. Experienced a same period of time after platform, the fluorescence strength of cells in the normal state is 1.2 times the first value, and the iron-deficiency state is 1.4 times, but the iron overloading state was 0.85 times. We also find that the average fluorescence intensity in cells detected by the spectrophotometer in the iron-deficiency state is almost 7 times than that in a high iron state. All this proves that iron overloading would slow the process, but iron deficiency would accelerate endocytosis. We advance a direct observational method that may contribute to further study of the relationship of iron and transferrin.

Real-time observation of the effect of iron on receptor-mediated endocytosis of transferrin conjugated with quantum dots.

Microwave-assisted approach for the rapid enzymatic digestion of rapeseed meal

Electrocatalytic activity of salicylic acid on the platinum nanoparticles modified electrode by electrochemical deposition.

High-sensitivity quantum dot-based fluorescence resonance energy transfer bioanalysis by capillary electrophoresis.

Quantum dots (QDs) are widely used in the life sciences because of their novel physicochemical properties. However, the cytotoxity of these nonoparticles have attracted great attention recently because this has not been well resolved. Four probes were synthesized by chemical coupling and protein denaturation with CdSeZnS, CdTe QDs, and transferrin. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and capillary electrophoresis were used to verify the conjugation of these luminescent probes. The cytotoxicity of these four luminescent probes and the original QDs were evaluated in HeLa cells. The results showed that over 92% of HeLa cells were still alive after being exposed to 3.2-microM CdSeZnS QDs capped with denatured transferrin for 72 h. Furthermore, while the probe preparation was very simple, the photoluminescence quantum yield of this probe was 7% higher than the original CdSeZnS QDs. This provides a new way for exploiting QD probes with low cytotoxicity, which will expand applications of nanocomposite assembly in biolabeling and imaging.

Special method to prepare quantum dot probes with reduced cytotoxicity and increased optical property.

Electrocatalytic oxidation of phytohormone salicylic acid at copper nanoparticles-modified gold electrode and its detection in oilseed rape infected with fungal pathogen Sclerotinia sclerotiorum.

In this paper, amino capped CdSe/ZnS quantum dots (QDs) were immobilized on the 11-mercaptoundecanoic acid (MUA) self-assembled Au surface (SAM/Au) by 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide hydrochloride (EDC). Atomic force microscopy (AFM), fluorescence imaging and electrochemistry were employed to characterize the surface. The results showed that CdSe/ZnS QDs were immobilized on the surface of SAM/Au successfully. Based on this method, the fluorescence of the QDs on the SAM/Au was monitored on-line.

SELF-ASSEMBLED QUANTUM DOTS ON AU AND THE INTERFACE FLUORESCENCE

In vivo monitoring of oxidative burst induced by ultraviolet A and C stress for oilseed rape by microbiosensor

A novel quantum dots (QDs) fluorescent encoding method was demonstrated in this paper by using Au coated polystyrene (Au @ PS) beads. In the experiments, Au nanoparticles were deposited onto the polystyrene bead to form a stable Au coating through Layer-by-Layer assembly, and the surface morphology of the Au @ PS beads was studied by Scanning Electronic Microscope (SEM). Furthermore, the QDs encoding abilities, including the loading of QDs, the anti-photo bleaching ability and the multi-color encoding feasibility were studied using Au @ PS beads. The QDs leakage from doped QDs encoded Au @ PS was also studied. This study shows that Au particles improve the QDs encoding performance and the QD-encoded Au @ PS beads are the ideal material for the optical encoding.

Enhanced optical property of Au coated polystyrene beads for multi-color quantum dots encoding.

Evaporative deposition of lipophilic quantum dots for an enzyme modified electrode

Preparation of Au nanoparticles-coated polystyrene beads and its application in protein immobilization

Water-soluble CdTe nanoparticles and hemoglobin (Hb) were immobilized on a glassy carbon (GC) electrode with Nafion. The direct electrochemistry of Hb on this surface was studied. The results indicated that CdTe nanoparticles could effectively promote the direct electron transfer of Hb at the interface of a electrode. The average surface coverage of Hb on the surface could be calculated as 2.63×10^–9 mol/cm^2, the heterogeneous electron transfer rate constant, k , was calculated as 0.068 s^–1 and the transfer coefficient, α , was 0.59, further study indicated that immobilized Hb still kept its catalytic activity to H_2O_2 reduction. The apparent Michaelis–Menten constant was calculated to be 17.7 μM. It was also found that the modified electrode could be used as a sensor for H_2O_2; the linear range of detection was 5.0×10^–6 – 4.5×10^–5 M, with a detection limit of 8.4×10^–7 M. The sensor exhibited high sensitivity, reproducibility and stability.

Direct Electrochemistry and Elctrocatalytic Activity of Hemoglobin at CdTe Nanoparticle/Nafion Film-modified Electrode

Ascorbic acid biosensor based on laccase immobilized on an electrode modified with a self-assembled monolayer and coated with functionalized quantum dots

A highly efficient capillary electrophoresis-based method for size determination of water-soluble CdSe/ZnS core-shell quantum dots.

Hydrogen peroxide biosensor based on direct electron transfer of horseradish peroxidase with vapor deposited quantum dots

Microsensor in vivo monitoring of oxidative burst in oilseed rape (Brassica napus L.) leaves infected by Sclerotinia sclerotiorum.

Abstract A biosensor for hydrogen peroxide was fabricated by co-immobilizing cadmium telluride (CdTe) nanoparticles, chitosan, and hemoglobin (Hb) matrix. There was a pair of nearly reversible redox peaks around −0.360 V, and the electrochemical behavior of Hb was a surface-controlled process, with an electron-transfer rate constant of 1.36 s−1 and surface coverage of 2.62 × 10−10 mol cm−2. Fourier transform infrared (FT-IR) spectra and ultraviolet–visible (UV-vis) spectra indicated that Hb sustained its natural conformation. It was demonstrated that Hb in the matrix kept its bioactivity and exhibited catalytic ability toward H2O2, with a response ranging from 7.44 × 10−6 to 6.95 × 10−4 M and a detection limit of 2.23 × 10−6 M.

Biosensor for Hydrogen Peroxide Based on Chitosan and Nanoparticle Complex Film–Modified Glassy-Carbon Electrodes

Quantum dot (QD) solubilization, conjugation with biomolecules, column purification, and labeling of human HepG2 cells with transferrin-QD (Tf-QD) conjugates are reported in detail in this article. Water-soluble QDs (WQDs) were obtained using sodium thiolycolate to replace the surface ligand tri-n-octylphosphine oxide (TOPO) on the surface of oil-soluble QDs, and Tf-QD conjugates were produced by coupling Tf to WQD. The resulting Tf-QDs were characterized by UV and luminescence spectrophotometry and purified by Sephadex column. The results indicate that Tf has been conjugated to QD successfully. Based on transferrin/transferrin-receptor-mediated delivery system, the Tf-QD conjugates were used to label human HepG2 cells. After a short incubation, the QDs were mainly localized to the membrane of cells. After 12-h incubation, QDs appear mainly in the cytoplasm portion. However, QDs were not found in the nucleus of the cells. Furthermore, the fluorescence intensity of QDs in the cells reduces gradually over time, and fluorescence cannot be observed after 10 days. However, the growth of the labeled cells was not markedly affected by the toxicity of QDs, and they are alive for 10 days. These results can be used for further application of QDs in bioscience.

Solubilization and bioconjugation of QDs and their application in cell imaging.

Study on molecular interactions between proteins on live cell membranes using quantum dot-based fluorescence resonance energy transfer

Modification of CdTe quantum dots as temperature-insensitive bioprobes.

Influence of quantum dot's quantum yield to chemiluminescent resonance energy transfer.

A novel method concerning the coding technology of polystyrene beads with Si encapsulated quantum dot (QD) particles (Si@QDs particles) is studied in this paper. In the reverse microemulsion system containing tetraethoxysilane (TEOS), water-soluble QDs (emission peak at 600 nm) were enveloped within the silica shell, forming Si@QDs particles. The Si@QDs particles were characterized by TEM, showing good uniform size, with an average diameter of about 167.0 nm. In comparison with the pure water-soluble QDs, the encapsulation of water-soluble QDs in the silica shell led to an enhancement in anti-photobleaching by providing inert barriers for the QDs. Images presented by SEM and confocal laser scanning microscopy demonstrated that the Si@QDs particles were equably coated on the surface of carboxyl functionalized polystyrene (PS) beads. Then, with the assistance of ethyl-3-(dimethyl aminopropyl) carbodiimide/N-hydroxysuccinimide (EDC/NHS), human IgG could be successfully crosslinked to Si@QDs particle coated PS-COOH beads. Furthermore, the Si@QDs coated PS-COOH beads with human IgG were examined in immunoassay experiments, and the results indicated that these beads could be applied in the specific recognition of goat-anti-human IgG in solution. This investigation is expected to provide a new route to bead coding in the field of suspension microarrays, based on the use of QDs.

Optical encoding of microbeads based on silica particle encapsulated quantum dots and its applications

Purification of denatured bovine serum albumin coated CdTe quantum dots for sensitive detection of silver(I) ions

Transferrin and mouse anti-human CD71 monoclonal antibody were respectively conjugated covalently to the core/shell CdSe/ZnS quantum dots with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydrocylsulfo-succinimide (Sulfo-NHS). The conjugation worked well and the bioactivities of these macromolecules still remained, which was verified by column filtration, sodium dodecyl sulfate polyacrylamide gel electrophoresis, absorption spectra, fluorescence spectra, and circular dichroism spectrometry. Thus, these two kinds of quantum dot conjugates were used to recognize the tumor cells involved. In case of pseudo positivity, FITC-labeling secondary antibody IgG was used, and the results showed that as-prepared fluorescent quantum dot bioprobes were highly specific to tumor cells.

Bioconjugate recognition molecules to quantum dots as tumor probes.

Photoluminescence enhancement by coupling of ovalbumin and CdTe quantum dots and its application as protein probe

Multi-color encoding of polystyrene microbeads with CdSe/ZnS quantum dots and its application in immunoassay.

Acetylene-Substituted Two-Photon Absorbing Molecules With Rigid Elongated Pi-Conjugation: Synthesis, Spectroscopic Properties and Two-Photon Fluorescence Cell Imaging Applications

Fluorescence resonance energy transfer between FITC and water-soluble CdSe/ZnS quantum dots

A Feasible and Quantitative Encoding Method for Microbeads with Multicolor Quantum Dots

Oxalic acid (OA), a non-host-specific toxin secreted by Sclerotinia sclerotiorum during pathogenesis, has been demonstrated to be a major phytotoxic and pathogenic factor. Oxalate oxidase (OXO) is an enzyme associated with the detoxification of OA, and hence the introduction of an OXO gene into oilseed rape (Brassica napus L.) to break down OA may be an alternative way of increasing the resistance of the plant to Sclerotinia sclerotiorum. In order to investigate the activation of OXO in transgenic oilseed rape, a convenient and accessible method was used to monitor changes in pH in response to stress induced by OA. The pH sensor, a platinum microcylinder electrode modified using polyaniline film, exhibited a linear response within the pH range from 3 to 7, with a Nernst response slope of 70 mV/pH at room temperature. The linear correlation coefficient was 0.9979. Changes induced by OA in the pH values of leaf tissue of different oilseed rape species from Brassica napus L. were monitored in real time in vivo using this electrode. The results clearly showed that the transgenic oilseed rape was more resistant to OA than non-transgenic oilseed rape.

In vivo measurements of changes in pH triggered by oxalic acid in leaf tissue of transgenic oilseed rape.

The luminescent silica nanoparticle has attracted the researchers' concentration in bioanalysis recently. Its extensive application is based on the immobilization of various biomolecules such as deoxyribonucleic acid, antibody, and so forth onto the surface. By comparing different introduction methods of amine groups, it was confirmed that the "two-step" route is more preferable by adding tetraethyl orthosilicate and 3-aminopropyl-(triethoxyl)silane in sequence, to attain ideal amine-modified silica nanoparticles. On this basis, carboxyl groups were derived from amine groups on the nanoparticle surface and then were activated by 1-ethyl-3-3-(3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxy-succinimide. Finally, mouse monoclonal antihuman CD71 antibody (McAb CD71) and transferrin were effectively linked with the carboxyl groups and successfully labeled the receptors in the membrane of fibroblast cells, respectively.

Optimization of the methods for introduction of amine groups onto the silica nanoparticle surface.

A multi-wall carbon nanotubes (MWNTs)-quantum dots (QDs) composite-modified glassy carbon electrode (GCE) was prepared. The complex was characterized by transmission electron microscopy (TEM). The electrochemical behavior of levodopa at MWNTs and QDs-modified GCEs (MWNTs-QDs/GCE) was studied by cyclic voltammetry (CV) and chronocoulometry (CC). It was found that its electrochemical behavior was a two-charge-two-proton process. The modified electrode had high electrocatalytic activity for levodopa with a standard heterogeneous rate constant of 0.595 cm s^–1, which was greatly increased compared with the values for bare GCE and individual MWNTs modified GCE. The better electrocatalytic activity for levodopa at MWNTs-QDs/GCE may due to a synergistic effect between MWNTs and QDs. This result provides a novel way to promote research on biomicromolecules at nano-dimensions.

Electrochemical Behavior of Levodopa at Multi-Wall Carbon Nanotubes-Quantum Dots Modified Glassy Carbon Electrodes

The interface behavior and biocatalytic activity of superoxide dismutase at carbon nanotube.

Continuous wave-based multiphoton excitation fluorescence for capillary electrophoresis.

Microbeads with embedded encode characteristics are of considerable interest due to their potential use in multiplexed bioassays, high-throughput screening and combinatorial chemistry. Lots of encoding strategies for tagging or labeling microbeads have arisen in the past couple of years. Compared with the organic dye counterparts, the ideal optical properties of quantum dots (QDs) (e.g. characteristic narrow and symmetric spectra, size-tunable emission and simultaneous excitation) make it possible to tag microbeads in a quantitative way. In this paper, quantitative doping of commercial polystyrene microbeads with single color quantum dots was reported. A detailed analysis of the optical characteristics of the QD-tagged microbeads was presented based on the combination of fluorescent spectroscopy and microscope imaging.

Quantitative doping of commercial polystyrene microbeads with quantum dots

Preparation of silica encapsulated quantum dot encoded beads for multiplex assay and its properties.

A novel green synthesis of semiconductor nanoparticles was introduced and it was used as optical probes for bio-imaging. Quantum dots are known as <10nm scaled semiconductor nanoparticles, which could dramatically improve fluorescent imaging. Since these nanocrystals act as robust broadly tunable nano-emitters that can be excited by a single light source, they could pride significant advantages over current labels (e.g. traditional organic dyes, isotope and fluorescent proteins) in vitro and in vivo. As for a novel green synthesis, the usage of dangerous organic composites under rigorously air-free conditions was avoided, and ZnS-capped CdSe semiconductor nanoparticles was prepared economically. And the surface of as- synthesized nanoparticle would be modified by hydrophilic molecules for optical bio-probes. Moreover, such optical probes under aqueous biological conditions could maintain many characters: economy, photostability, colloidal stability, efficient fluorescence, low non-specific adsorption, biological compatibility and validity for multiplex assays.

Synthesis and properties of quantum dots optical probes for bio-imaging

Temperature-dependent photoluminescence of water-soluble quantum dots for a bioprobe

Characterization of the coupling of quantum dots and immunoglobulin antibodies

A novel multiplex analysis technology based on quantum dot (QD) optical encoded beads was studied. Carboxyl functionalized polystyrene beads, about 100 microm in size, were precisely encoded by the various ratios of two types of QDs whose emission wavelengths are 576 and 628 nm, respectively. Then the different encoded beads were covalently immobilized with different probes in the existing of sulfo-NHS and 1-[3-(Dimethylamino) propyl]-3-ethylcarbodiimide methiodide, and the probe density could reach to 3.1 mmol/g. These probe-linked encoded beads were used to detect the target DNA sequences in complex DNA solution by hybridization. Hybridization was visualized using fluorescein isothiocynate-labeled DNA sequences. The results show that the QDs and target signals can be obviously identified from a single-bead-level spectrum. This technology can detect DNA targets effectively with a detection limit of 0.2 microg/mL in complex solution.

Quantum dot optical encoded polystyrene beads for DNA detection.

Preparation of Au coated polystyrene beads and their application in an immunoassay.

A flow cytometric assay technology based on quantum dots-encoded beads.

Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy

Vibrational spectroscopic encoding of polystyrene-based resin beads: converting the encoding peaks into barcodes.

Comparison of porcine ALG and rabbit ATG on outcomes of HLA-haploidentical hematopoietic stem cell transplantation for patients with acquired aplastic anemia

Objectives To systematically review the effects of dezocine (DZC) on the occurrence rate and severity of opioid-induced cough (OIC). Design Systematic review and meta-analysis Data sources PubMed, Embase, Cochrane Library, Ovid, Web of Science as well as Chinese BioMedical Literature & Retrieval System, China National Knowledge Infrastructure, Wanfang and VIP Data were searched from 1978 to 31 December 2020. Inclusion criteria All randomised controlled trials (RCTs) comparing DZC with placebo on the occurrence rate and severity of OIC. Data analysis All data were analysed by using RevMan V.5.3. Each outcome was tested for heterogeneity, and randomised-effects or fixed-effects model was used in the presence or absence of significant heterogeneity. Results Our search yielded 33 RCTs including 4442 patients, and 2521 patients were allocated into the DZC group and 1921 into the control group. Fentanyl was administrated in 1880 patients and sufentanil in 2562 patients during the induction of general anaesthesia. The meta-analysis demonstrated that DZC significantly reduced the occurrence rate of OIC induced by either fentanyl (8.8% vs 49.7%, OR=0.07, 95% CI 0.04 to 0.12, p<0.00001) or sufentanil (5.0% vs 41.5%, OR=0.07, 95% CI 0.04 to 0.12, p<0.00001). The meta-analysis also indicated that the occurrence rate of mild, moderate and severe OIC in the DZC group was remarkably lower than that of the control group (mild: 3.6% vs 13.6%, OR=0.19, 95% CI 0.14 to 0.25, p<0.00001; moderate: 2.0% vs 13.6%, OR=0.12, 95% CI 0.09 to 0.18, p<0.00001; severe: 1.0% vs 13.9%, OR=0.08, 95% CI 0.05 to 0.12, p<0.00001). Additionally, the current meta-analysis indicated that DZC pretreatment was not associated with increased occurrence rate of adverse effects (7.0% vs 4.2%, OR=2.34, 95% CI 0.60 to 9.14, p=0.22) except for dizziness (11.8% vs 0%, OR=8.06, 95% CI 1.40 to 46.35, p=0.02). Conclusion This meta-analysis demonstrated that DZC significantly inhibited OIC and may be used to manage OIC. More high-quality RCTs are needed to complement the safety of DZC. PROSPERO registration number CRD42019141255.

Efficacy of dezocine on preventing opioid-induced cough during general anaesthesia induction: a PRISMA-compliant systematic review and meta-analysis

A comprehensive assessment of single nucleotide polymorphisms associated with lung cancer risk: a protocol for systematic review and network meta-analysis

Introduction Cough is often observed when administrating a bolus of opioids. Opioid-induced cough (OIC) is mostly transient, benign and self-limiting, but could be associated with adverse effects. Numerous pharmacological and non-pharmacological interventions have been used to manage OIC with controversial efficacy and safety. Recent studies suggested that, pretreatment of intravenous dezocine (DZC) could completely suppress OIC during anaesthesia induction. To address this knowledge lack, we will perform a systemic review and meta-analysis to evaluate the efficacy of DZC on OIC and possible complications. We provide here a protocol that will outline the methods and analyses planned for the systematic review. Methods PubMed, Embase, Cochrane Library, Web of Science as well as Chinese BioMedical Literature & Retrieval System (SinoMed), China National Knowledge Infrastructure, Wanfang Data and VIP Data will be searched from 1978 to 31 December 2019 to identify all randomised controlled trials comparing DZC with placebo on the incidence and severity of OIC. Primary outcomes of interest include the incidence and severity of OIC. Secondary outcomes of interest include possible complications or adverse effects of DZC. Two authors will independently extract relevant variables and outcome data. For continuous variables, treatment effects will be calculated as weighted mean difference and 95% CI. For dichotomous data, treatment effects will be calculated as OR and 95% CI. Each outcome will be tested for heterogeneity, and randomised-effects or fixed-effects model will be used in the presence or absence of significant heterogeneity. Sensitivity analyses will be done by examining the influence of statistical model and individual trial(s) on estimated treatment effects. Publication bias will be explored through visual inspection of funnel plots of the outcomes. Statistical significance will be defined as p<0.05. Ethics and dissemination This study is a protocol of meta-analysis of previously published literatures, ethical approval was not necessary according to the Ethical Committee of Fuwai Hospital. The study will be submitted to a peer-reviewed journal and disseminated via research presentations. PROSPERO registration number CRD42019141255.

Is dezocine effective and safe in preventing opioids-induced cough during general anaesthesia induction? A protocol for systematic review and meta-analysis

Background: Levosimendan (LEVO), is an inotropic agent which has been shown to be associated with better myocardial performance, and higher survival rate in cardiac surgical patients. However, preliminary clinical evidence suggested that LEVO increased the risk of post-operative bleeding in patients undergoing valve surgery. Currently, there has been no randomized controlled trials (RCTs) designed specifically on this issue. Therefore, we performed present systemic review and meta-analysis. Methods: Electronic databases were searched to identify all RCTs comparing LEVO with Control (placebo, blank, dobutamine, milrinone, etc). Primary outcomes include post-operative blood loss and re-operation for bleeding. Secondary outcomes included post-operative transfusion of red blood cells (RBC), fresh frozen plasma (FFP) and platelet concentrates (PC). For continuous variables, treatment effects were calculated as weighted mean difference (WMD) and 95% confidential interval (CI). For dichotomous data, treatment effects were calculated as odds ratio (OR) and 95% CI. Results: Search yielded 15 studies including 1,528 patients. Meta-analysis suggested that, LEVO administration was not associated with increased risk of reoperation for bleeding post-operatively (OR = 1.01; 95%CI: 0.57 to 1.79; p = 0.97) and more blood loss volume (WMD = 28.25; 95%CI: –19.21 to 75.72; p = 0.24). Meta-analysis also demonstrated that, LEVO administration did not increase post-operative transfusion requirement for RBC (rate: OR = 0.97; 95%CI: 0.72 to 1.30; p = 0.83 and volume: WMD = 0.34; 95%CI: –0.55 to 1.22; p = 0.46), FFP (volume: WMD = 0.00; 95%CI: –0.10 to 0.10; p = 1.00) and PC (rate: OR = 1.01; 95%CI: 0.41 to 2.50; p = 0.98 and volume: WMD = 0.00; 95%CI: –0.05 to 0.04; p = 0.95). Conclusion: This meta-analysis suggested that, peri-operative administration of LEVO was not associated with increased risks of post-operative bleeding and blood transfusion requirement in cardiac surgical patients.

The effect of levosimendan on postoperative bleeding and blood transfusion in cardiac surgical patients: a PRISMA-compliant systematic review and meta-analysis

Supplemental Digital Content is available in the text. Rationale: Right ventricular (RV) fibrosis in pulmonary arterial hypertension contributes to RV failure. While RV fibrosis reflects changes in the function of resident RV fibroblasts (RVfib), these cells are understudied. Objective: Examine the role of mitochondrial metabolism of RVfib in RV fibrosis in human and experimental pulmonary arterial hypertension. Methods and Results: Male Sprague-Dawley rats received monocrotaline (MCT; 60 mg/kg) or saline. Drinking water containing no supplement or the PDK (pyruvate dehydrogenase kinase) inhibitor dichloroacetate was started 7 days post-MCT. At week 4, treadmill testing, echocardiography, and right heart catheterization were performed. The effects of PDK activation on mitochondrial dynamics and metabolism, RVfib proliferation, and collagen production were studied in RVfib in cell culture. Epigenetic mechanisms for persistence of the profibrotic RVfib phenotype in culture were evaluated. PDK expression was also studied in the RVfib of patients with decompensated RV failure (n=11) versus control (n=7). MCT rats developed pulmonary arterial hypertension, RV fibrosis, and RV failure. MCT-RVfib (but not left ventricular fibroblasts) displayed excess mitochondrial fission and had increased expression of PDK isoforms 1 and 3 that persisted for >5 passages in culture. PDK-mediated decreases in pyruvate dehydrogenase activity and oxygen consumption rate were reversed by dichloroacetate (in RVfib and in vivo) or siRNA targeting PDK 1 and 3 (in RVfib). These interventions restored mitochondrial superoxide and hydrogen peroxide production and inactivated HIF (hypoxia-inducible factor)-1α, which was pathologically activated in normoxic MCT-RVfib. Redox-mediated HIF-1α inactivation also decreased the expression of TGF-β1 (transforming growth factor-beta-1) and CTGF (connective tissue growth factor), reduced fibroblast proliferation, and decreased collagen production. HIF-1α activation in MCT-RVfib reflected increased DNMT (DNA methyltransferase) 1 expression, which was associated with a decrease in its regulatory microRNA, miR-148b-3p. In MCT rats, dichloroacetate, at therapeutic levels in the RV, reduced phospho-pyruvate dehydrogenase expression, RV fibrosis, and hypertrophy and improved RV function. In patients with pulmonary arterial hypertension and RV failure, RVfib had increased PDK1 expression. Conclusions: MCT-RVfib manifest a DNMT1-HIF-1α-PDK–mediated, chamber-specific, metabolic memory that promotes collagen production and RV fibrosis. This epigenetic mitochondrial-metabolic pathway is a potential antifibrotic therapeutic target.

Epigenetic Metabolic Reprogramming of Right Ventricular Fibroblasts in Pulmonary Arterial Hypertension

The incidence of invasive fungal disease (IFD) is high in patients with hematological malignancies, including those with acute myeloid leukemia(AML)/myelodysplastic syndrome(MDS), and those receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). IFD is an important prognostic factor in patients with hematological malignancies. IFD is difficult to diagnose, and the efficacy of treatment is poor. Therefore, antifungal treatment begins with prevention. At present, there are still controversies about the clinical indications, drugs, administration time and efficacy of IFD chemoprevention. This article intends to review the research progress on the epidemiology and risk factors of IFD, as well as the clinical outcomes of antifungal agents for antifungal prophylaxis in patients with hematological malignancies. 
 
Key words: 
Antifungal agents; Hematologic neoplasms; Epidemiologic studies; Chemoprevention; Invasive fungal disease

Research progress on prevention and treatment of invasive fungal diseases in patients with hematological malignancies

Background and Objective There is no consensus concerning small bowel preparation before capsule endoscopy (CE). This study evaluated the effects of 4 regimens on small bowel cleansing and diagnostic yield. Methods Patients were randomly divided into 4 groups. Group A consumed a clear liquid diet after lunch on the day before CE, followed by overnight fasting. Group B took 250 mL 20% mannitol and 1 L 0.9% saline orally at 05:00 hours on the day of the procedure. In group C, the same regimen was taken at 20:00 hours on the day before and at 05:00 hours on the day of CE. In group D, in addition to the group C regimen, 20 mL oral simethicone was taken 30 minutes before CE. Results Two hundred patients were prospectively enrolled, and 7 were excluded from the final analysis because of incomplete small bowel transit. No significant difference was noted among the 4 groups for small bowel transit time. Bowel preparation in group D was significantly better than for the other regimens for overall cleansing of the proximal small bowel, and showed improved overall cleansing of the distal small bowel when compared with 10-hours overnight fasting. Pathological lesions of the proximal and distal small bowel were, respectively, achieved in 82 and 74 patients, mostly distributed in group D. Conclusions Small bowel preparation that involves split-dose oral mannitol plus single-dose simethicone for CE can improve mucosal visualization and subsequent diagnostic yield when compared with 10-hours overnight fasting.

Small Bowel Preparations for Capsule Endoscopy With Mannitol and Simethicone: A Prospective, Randomized, Clinical Trial

OBJECTIVE
To study the clinical characteristics and diagnosis of primary ciliary dyskinesia (PCD).

METHODS
Four cases diagnosed as PCD by cilia electron microscopy examination from Jan. 2007 to Aug. 2009 in this hospital were retrospectively analyzed, and the related literature was reviewed.

RESULTS
In the 4 patients, there were 1 male and 3 females. The age at disease onset was 0 - 10 years, and the age at diagnosis was 15 - 53 years. The most common symptoms were productive cough (4/4), sinusitis (3/4), and shortness of breath (3/4). Other manifestations included situs inversus (2/4), infertility (1/4), and tympanitis (1/4). Hypoxemia was found in 3 cases. Obstructive ventilatory impairment accompanied with diffusion dysfunction was observed in 2 cases, while the pulmonary function tests were normal in the other 2 cases. All 4 cases received chest CT scan, and bronchiectasis was present in all of them. Bilateral diffuse micronodules and patchy infiltrates were found in 3 and 2 cases respectively. Electron microscopic examination of the endobronchial biopsy specimen showed lack of dynein arms in 4, lack of muco-cilia in 2, and abnormal arrangement of microtubules in 2 cases.

The Kartagener syndrome is relatively easy to be diagnosed, because it is characterized by the triad of sinusitis, bronchiectasis and situs inversus. However, PCD without situs inversus often goes unrecognized. PCD should be considered in patients with childhood onset disease, bronchiectasis, centrilobular micronodules or tree-in-bud signs in CT scan. Examination of the ciliary ultrastructure is essential to the confirmation of the diagnosis.

Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases

[Clinical analysis of four cases of primary ciliary dyskinesia and literature review].

Evolution and major changes of the diagnosis and treatment protocol for COVID‐19 patients in China 2020–2023

414.9: Shared Transcriptional Trajectory of Tissue Tregs Between Tolerant-Grafts and Lymphoid Organs in Transplant Tolerance

414.12: Potent Suppressive Function of Xeno-Antigen Reactive Human HLADR+CD27+Tregs via Enhanced CD95 and ICOS Expressions

Tolerance Induction in Islet Transplantation by Regulatory Macrophages and Memory-like, Regulatory T Cells

 Background: Regulatory T cells (Tregs) are critical immunomodulators during pregnancy by preventing maternal T-cell activation against fetal cells. However, how characteristics of maternal Tregs vary during pregnancy is still unclear. We analyzed the proportion and phenotypic characteristics of peripheral blood Tregs in normal pregnant women, women with recurrent pregnancy loss (RPL) or gestational diabetes mellitus (GDM), and non-pregnant women.Methods: We investigated the proportion of CD4+ Tregs, CD8+ Tregs and the expression of PD-1, GITR, HLA-G and CTLA-4 on them in the peripheral blood of normal pregnancies during 1st (n = 28), 2nd (n = 43), and 3rd trimester (n = 33); In addition, we evaluated pregnancies in the 1st trimester complicated by RPL (n = 21), in the 2nd (n = 17) and 3rd trimester (n = 28) complicated by GDM. Non-pregnant women (n = 57) were also investigated using flow cytometry.Results: During normal pregnancy, the proportion of CD4+ Tregs in all trimester and CD8+ Tregs in 2nd and 3rd trimester were higher(P ＜ 0.05，respectively) compared with non-pregnancy women. Moreover, the proportion of CD4+ Tregs was higher in 2nd trimester compared to 1st and 3rd trimester (P ＜ 0.01) while the proportion of CD8+ Tregs was higher in 3rd trimester compared to 1st and 2nd trimester (P ＜ 0.05). Compared to non-pregnant studies, the proportion of GITR+/CD8+ Tregs and HLA-G+/CD8+ Tregs in all trimester were higher(P ＜ 0.05, respectively). Moreover, the proportion of PD-1+/CD4+ Tregs, GITR+/CD4+ Tregs, PD-1+/CD8+ Tregs and CTLA-4+/CD8+ Tregs in 3rd trimester were significantly higher compared to 1st, 2nd trimester and non-pregnant group(P ＜ 0.05, respectively).In RPL and GDM groups, the proportions of CD4+ Tregs in all trimesters were decreased while the proportions of CD8+ Tregs in all trimesters were increased compared to normal pregnant group (P ＜ 0.05，respectively).In RPL group, the proportion of PD-1+/CD4+ Tregs, GITR+/CD4+ Tregs and HLA-G+/CD4+ Tregs were decreased compared to 1st trimester normal pregnant group (P ＜ 0.05，respectively). In 2nd trimester GDM group, the proportion of HLA-G+/CD4+ Tregs were decreased compared to 2nd trimester normal pregnant group (P ＜ 0.05，respectively). In 3rd trimester GDM group, the proportion of PD-1+/CD4+ Tregs, GITR+/CD4+ Tregs, PD-1+/CD8+ Tregs, GITR+/CD8+ Tregs and HLA-G+/CD8+Tregs were decreased compared to 3rd trimester normal pregnant group (P ＜ 0.05, respectively).Conclusions: The proportion of CD4+ Tregs and CD8+ Tregs increased during pregnancy, the proportions and subsets of CD4+ Tregs decreased and those of CD8+ Tregs increased in pregnancies complicated by RPL and GDM, indicating that regulatory T cells play a role in pregnancy maintenance, and the abnormal expression of Tregs might be related to the complicated pregnancy.

The Fluctuation of Regulatory T Cells during Pregnancy and Obstetrical Complications

Background Regulatory T cells (Tregs) play a crucial role in maternal-fetal tolerance, but little is known about the characteristic of Tregs in peripheral blood (PB), maternal-fetal interface and cord blood (CB) in normal and complicated pregnancies with preeclampsia (PE), gestational diabetes mellitus (GDM) and premature rupture of membranes (PROM). Methods PB, retro-placental blood (RPB), and CB were collected immediately after delivery in women with normal full-term pregnancy (NP), PE, GDM, and PROM. The proportion of CD4 + CD25 + CD127 low/- T cells (Tregs) and the expression of PD-1, GITR, HLA-G and CTLA-4 on T cell subsets were investigated by flow cytometric analysis. The data were analyzed based on sample origins (PB, RPB, and CB) and the obstetrical study groups (NP, PE, GDM, and PROM). PB, RPB, and CB. Deregulated PD-1 and GITR expressions on Tregs may be associated with obstetrical complications, such as PE, GDM and PROM. HLA-G + Tregs in RPB may serve for the maternal-fetal tolerance during pregnancy. Further studies are needed to investigate the maternal factors and microenvironment, which affect the development and function of Tregs during pregnancy.

Maternal and Fetal CD4+CD25+CD 127low/- Regulatory T Cells in Pregnancies with Gestational Diabetes, Preeclampsia, and Premature Rupture of Membranes

IDENTIFICATION OF A NOVEL SUBSET OF XENO-ANTIGEN SPECIFIC MEMORY CD4+FOXP3+TREGS IN ISLET-XENOTRANSPLANT TOLERANCE

FOXP3+TREGS THAT EXPRESSED CD127 EXISTING MEMORY TREGS FEATURE IN A TOLERANT MOUSE MODEL AND IN HUMAN SKIN

 Background Regulatory T cells (Tregs) play a crucial role in maternal-fetal tolerance, but little is known about the characteristic of Tregs in peripheral blood (PB), maternal-fetal interface and cord blood (CB) in normal and complicated pregnancies with preeclampsia (PE), gestational diabetes mellitus (GDM) and premature rupture of membranes (PROM). Methods PB, retro-placental blood (RPB), and CB were collected immediately after delivery in women with normal full-term pregnancy (NP), PE, GDM, and PROM. The proportion of CD4 + CD25 + CD127 low/- T cells (Tregs) and the expression of PD-1, GITR, HLA-G and CTLA-4 on T cell subsets were investigated by flow cytometric analysis. The data were analyzed based on sample origins (PB, RPB, and CB) and the obstetrical study groups (NP, PE, GDM, and PROM). Results The proportions of Tregs in PB, RPB, and CB from NP were significantly higher than the other obstetrical groups (P < 0.01, respectively). However no significant differences were present among the PE, GDM and PROM groups (P = NS). The proportion of PD-1 + and GITR + Tregs in RPB and PB as well as PD-1 + Tregs in CB from NP were significantly higher than those of the same origin in each obstetrical study group (P < 0.01, respectively). There were no differences in HLA-G + and CTLA-4 + Tregs between different origins in each obstetrical study group. In NP, the proportion of PD-1 + Tregs was significantly decreased in CB as compared to those of PB and RPB (P < 0.05, respectively). Among the four groups, the proportion of GITR + Tregs were significantly higher in PB as compared to those of CB and RPB (P < 0.01, respectively). The proportion of HLA-G + Tregs in PB was significantly lower than that of CB and RPB (P < 0.01, respectively). The proportion of CTLA-4 + Tregs had no significant differences (P = NS). Conclusions In conclusion, the proportion and characteristics of Tregs vary in the maternal, fetal and maternal-fetal junction at the time of delivery. The different feature and density of Tregs in maternal and fetal tissue may suggest the multiple and complicated roles of Tregs during pregnancy.

Maternal and Fetal CD4+CD25+CD127low/- Regulatory T Cells in Pregnancies with Gestational Diabetes, Preeclampsia, and Premature Rupture of Membranes

Introduction Previously we demonstrated CTLA-4Fc/MR-1 antibodies induced tolerance towards porcine islet cell cluster (NICC) xenografts in mice, and Foxp3Tregs from these mice showed dominant and specific tolerance to NICC. In this study, we are verifying the Tregs from long-term tolerance mice contain the memory-Tregs, distinguished memory-Tregs from activated-Tregs phenotypically in the NICC transplant model, and assessing the suppressive function of memory-Tregs from spleens into islet transplanted Reg KO mice. Methods C57BL/6-DEREG mice who have diphtheria toxin receptor-GFP attached to their Foxp3 gene were transplanted with 4000 IEQ NICC under the renal capsule, and treated IP with CTLA-4Fc (500ug) and MR-1 (500ug) at day 0, 2, 4 and 6. The phenotype of Foxp3 Tregs in the lymph nodes, draining lymph node and spleen were analyzed by flow-cytometry. CD4+GFP+ Tregs and highly selected (CD4+GFP-CD44+CD127+CD62L-) Tregs (>2×105) were isolated from spleens of naïve (n=5), rejected (n=3) and tolerant (n=8) DEREG mice, all the tolerant mice over 100-days post-transplant. On day 25, those Tregs were injected into the immune-deficient transplanted Rag KO mice into the tail vein separately. On day 45, injected transplanted Rag KO mice were challenged by CD4+GFP- T cells at a ratio of 1:3 from the Naïve C57BL/6-CD45.1GFP mice by tail vein. Transplanted Rag KO mice with no cells injected (n=2) and with only CD4+GFP- T cells injected (n=2) as positive and negative control groups. All mice would be sacrificed at day 100 after adoptive transfer. Results NICC xenograft tolerance was confirmed in recipient Foxp3-GFP mice, and rejected in control group. In phenotype, upregulations of CD44, MHC-II, CD39, especially CD127 (85.8% VS 4.3%) (p=0.002) in splenic CD3+CD4+Foxp3+Tregs occurred on the day 70 or more than 100 days after transplantation, and downregulations of CD27 (p < 0.0001) and CD62L (p = 0.0025) were found in the mouse with tolerant NICC grafts (5.6%, 3.7%), compared to Tregs of rejected group (73.8%, 36.6%) and naïve-Tregs of non-transplanted mice (78.8%, 46.1%). Additionally, in pooled draining lymph nodes from the transplanted mice more than 100 days, tolerant-Tregs also showed the increased CD127 (71.3% vs 12.5%) and decreased of CD27 (15.2% vs 74.7%) and CD62L (14.6% vs 49.3%), compared to rejected-Tregs. However, the up and down in long-term pooled lymph nodes were only found in CD127 and L-selection of the comparison between rejected-Tregs and tolerant-Tregs, which from 19.4% to 43.9%, and 51.2% to 38.4% respectively. For suppressive function, the sorted adoptive-transferred Tregs and T cells can be detected separately on 88-day by flow after adoptive transfer in Rag KO mice. Conclusion Tolerant-Treg induced by costimulation-blockade by CTLA-4Fc and anti-CD154 antibodies in mice with NICC grafts may contain the memory-Tregs at the long-term time point, but function needs to be examined by histology further when they up to 100-day. NHMRC 1037321.

In-vivo Costimulation-Blockade induced Foxp3 Tregs from DEREG Mice with Neonatal Islet Cell Cluster Tolerant Xenografts Exist Memory Tregs Phenotype

Centre for Transplant & Renal Research. Introduction Human regulatory macrophages (Mregs) have been shown to suppress mitogen-driven T cell proliferation in vitro and are under evaluation as a cellular therapy in renal transplantation in THE ONE STUDY clinical trial. In this study, we investigated whether human Mregs were capable of suppressing the allogeneic response in vitro and protecting islet xeno-grafts in humanizing mice in vivo. Methods Human CD14+ cells were isolated from healthy donor peripheral blood monocytes (PBMCs) using CD14 magnetic beads. Mregs induction was performed by culturing CD14+ cells with M-CSF for 6 days and be stimulated with IFN-&ggr; for a further 24 hr. The phenotype of Mregs was characterized by flow cytometry, and their suppressive activity was tested by mixed-lymphocyte reaction (MLR) using human PBMCs as responder cells, autologous Mregs as suppressor cells and irradiated allogeneic PBMCs as stimulator cells. In a separate transwell MLR setting, responder and allogeneic stimulator cells were cultured in the upper chamber and autologous Mregs were seeded in the lower chamber. Supernatants collected from MLR cultures were used for cytokine detection. Isolated the neonatal porcine islet cell clusters (NICCs) and cultured for 6 days. In vivo, every 5,000 IEQ NICCs were transplanted into NOD-SCID IL2R gamma -/- mice under the two sides of renal capsules. Adoptive transfer of human PBMCs and Mregs were suspended in PBS and injected into mice at doses of 10×106 and 2×106 by tail vein within 7 days after transplant. Graft rejection was defined as little or no intact graft with a heavy lymphocytic infiltrate on histological examination, survival was analyzed by H&E staining and endocrine secreting cells was analyzed by insulin staining. Results The resulting induced human Mregs demonstrated a typical Mregs phenotype, CD14lowCD80lowCD86+HLA-DR+CD83-/lowCD16-, and as a result, potent suppression of proliferating alloreactive PBMC even at Mregs: responder cells ratios >1:16. Separation of Mregs from responder and allogeneic stimulators in a transwell MLR system had the mild impact on their suppressive potency in the allogeneic response at all ratios of Mregs: responder cells tested. Upregulated levels of Mregs function related molecules TGF-b and IDO were detected in the supernatants collected from both non-transwell and transwell MLR cultures containing Mregs. In treated mice, the human PBMC were identified in the porcine-NICC-xenografts, as well as systemically in the spleens, blood, and kidneys. However, injected Mregs cannot be detected by flow cytometry, and there were no intact xenografts were found with mid-term. Conclusions In vitro induced human Mregs showed the capacity to suppress the allogeneic response in vitro and that was not cell-cell contact dependent. The porcine-NICC-xenografts cannot be protected by Human-Mregs in vivo as Mregs cannot proliferation. The suppressive function of the Mregs have more potency in vitro, but not in vivo.

The Suppressive Function of the Human Regulatory Macrophages In-Vitro have more Potency but not In-Vivo

For xenotransplantation to truly succeed, we must develop immunomodulatory strategies to suppress the xenoimmune response but by minimizing immunosuppression over the long term. Regulatory macrophages (Mreg) have been shown to suppress polyclonal T‐cell proliferation in vitro and prolong allograft survival in vivo. However, the question of whether they are capable of suppressing xenoimmune responses remains unknown. This study assessed the potential of human Mreg to be used as an effective immunomodulatory method in xenotransplantation.

Human regulatory macrophages are potent in suppression of the xenoimmune response via indoleamine‐2,3‐dioxygenase‐involved mechanism(s)

Overcoming drug-resistance is one of the major challenges to control tuberculosis (TB). The up-regulation of efflux pumps is one common mechanism that leads to drug-resistance. Therefore, immunotherapy targeting these efflux pump antigens could be promising strategy to be combined with current chemotherapy. Considering that CD8+ cytotoxic T lymphocytes (CTLs) induced by antigenic peptides (epitopes) could elicit HLA-restricted anti-TB immune response, efflux pumps from classical ABC family (Mycobacterium tuberculosis, Mtb) were chosen as target antigens to identify CTL epitopes. HLA-A2 restricted candidate peptides from Rv2937, Rv2686c and Rv2687c of Mycobacterium tuberculosis were predicted, synthesized and tested. Five peptides could induce IFN-γ release and cytotoxic activity in PBMCs from HLA-A2+ PPD+ donors. Results from HLA-A2/Kb transgenic mice immunization assay suggested that four peptides Rv2937-p168, Rv2937-p266, Rv2686c-p151, and Rv2686c-p181 could induce significant CTL response in vivo. These results suggested that these novel epitopes could be used as immunotherapy candidates to TB drug-resistance.

Novel epitopes identified from efflux pumps of Mycobacterium tuberculosis could induce cytotoxic T lymphocyte response

Physical-Layer Network Coding (PNC) employed on a two-way relay channel (TWRC) is an active research area due to potential doubling of the throughput compared with traditional routing. In this paper, we investigate the effects of impulsive noise added at the relay and sink nodes of a TWRC employing link-by-link coded PNC. The Gaussian mixture model is chosen to model the impulsive noise and the performance of BICM-ID and turbo codes on the TWRC is evaluated through simulation results and extrinsic information transfer (ExIT) charts for different mixtures of impulsive noise. It is shown that with increasing impulsiveness, a PNC system with BICM-ID codes with actually outperforms a comparable PNC system with turbo codes, where both coding schemes have the same block size, code rate and constraint length.

2017 International Conference on Cyber-Enabled Distributed Computing and Knowledge Discovery (CyberC)

Performance Analysis of Turbo Code and Trellis BICM-ID on PNC over Impulsive Channel

Physical-Layer Network Coding (PNC) employed on a conventional two-way relay communications is an active research area due to the potential doubling of the throughput compared with traditional routing. In this paper, we investigate the effects of impulsive noise added at the relay and sink nodes of a TWRC employing link-by-link coded PNC. The Gaussian mixture model is chosen to model the impulsive noise and the performance of bit-interleaved coded modulation with iterative decoding (BICM-ID) and turbo codes on the conventional two-way relay communications is evaluated through simulation results for different mixtures, , of impulsive noise. For high and low values of the turbo codes outperform trellis BICM, but it is shown that for values between = 0.1 and = 0.5, a PNC system with trellis BICM outperforms a comparable PNC system with turbo codes, where both coding schemes have the same block size, code rate and constraint length.

Iterative Channel Coded Physical Layer Network Coding on Impulsive Noise Channels

Non-binary turbo codes promise excellent performance for a wide range of applications and environments, but research in this area is sparse. The performance of a non-binary turbo code defined in GF(4) on a two-way wireless relay channel (TWRC) employing physical-layer network coding, which is affected by impulsive noise is investigated. Simulation results for binary and non-binary turbo codes are presented and validated with an error floor analysis at the relay of the TWRC and it is observed that non-binary turbo codes significantly outperform binary turbo codes at low signal-to-noise ratios.

Non-binary turbo-coded physical-layer network coding on impulsive noise channels

This paper aims to present a performance evaluation of multilevel convolutional codes defined in Galois field (GF(q)) on Physical-layer network coding (PNC) over an impulsive conventional two-way relay channel(TWRC). A comparison between binary to non-binary convolutional codes with different mixtures of impulsiveness is being made, along with the lower bound analysis of non-binary convolutional codes. We want to show that the non-binary convolutional code is always a good choice for PNC over impulsive channel.

2016 International Conference for Students on Applied Engineering (ICSAE)

Convolutional codes defined in GF(q) combine with PNC over impulsive noise channels

Iterative decoding combined with physical-layer network coding on impulsive noise channels

Physical-Layer Network Coding (PNC) employed on a conventional two-way relay channel (TWRC) is an active research area due to the potential doubling of the throughput compared with traditional routing. In this paper, we investigate the effects of impulsive noise added at the relay of a TWRC employing link-by-link coded PNC, where the coding scheme of interest is the turbo code. The Gaussian mixture model is chosen to model the impulsive noise and its effect on the performance of rate 1/2 and rate 1/3 turbo codes on the TWRC is evaluated through simulation results and extrinsic information transfer (ExIT) charts. An error floor analysis is also presented for different mixtures, α, of impulsive noise and theoretical bounds are derived that explain the source of the error floors exhibited in the simulation results.

Link-By-Link Coded Physical Layer Network Coding on Impulsive Noise Channels

A novel joint adaptive modulation scheme for the broadcast phase of a two-way relay channel is presented. Over Rayleigh flat fading channels, by jointly encoding and modulating the messages from both users according to each user's instantaneous channel quality, the relay can greatly improve its bits-per-symbol throughput during the broadcast phase. Also, each user can receive at the data rate decided by its instantaneous channel quality under the target average bit error ratio constraint by interference cancellation using its own information. Computer simulation shows the proposed scheme provides about 3 dB gain over the network coding based adaptive modulation scheme.

The current work synthesized Ni-SiC composite coating with different SiC microparticle contents. The role of the SiC microparticle in designing the Ni-SiC composite microstructure was revealed. The SiC microparticle physically interrupted the continuous growth of the underlying columnar Ni grains. The columnar Ni grain between the embedded SiC microparticle grew without disturbance. Only upon SiC microparticles was a new layer starting with refined Ni grains observable. The vertical columnar Ni grains reappeared as the position departed the SiC microparticle upper surface. The increase in the contents of the SiC microparticle led to an increased level of grain refinement and the elimination of the (200) fiber texture. Besides that, the number of V-shaped valleys increased as well. Corrosion testing results show that the corrosion resistance of Ni-SiC composite coating increased with the increased SiC contents, which was mainly due to the optimized microstructure.

Investigation on Microstructure and Properties of the Electrodeposited Ni-SiC Composite Coating

Lightweight concrete is one of the effective means to solve the problems of structural component weight, energy efficiency, and fire safety in modern civil engineering. Heavy calcium carbonate-reinforced epoxy composite spheres (HC-R-EMS) were prepared by the ball milling method, and HC-R-EMS, cement, and hollow glass microspheres (HGMS) were mixed into the mold by the molding method to prepare composite lightweight concrete. The relationship between the HC-R-EMS volumetric fraction, the initial inner diameter of the HC-R-EMS, the number of layers of HC-R-EMS, the HGMS volume ratio, the basalt fiber length and content, and the multi-phase composite lightweight concrete density and compressive strength was studied. The experimental results show that the density of the lightweight concrete ranges between 0.953–1.679 g/cm3 and the compressive strength ranges between 1.59–17.26 MPa, where the volume fraction of HC-R-EMS is 90%, the initial internal diameter is 8–9 mm, and the number of layers of HC-R-EMS is three. The lightweight concrete can meet the requirements of high strength (12.67 MPa) and low density (0.953 g/cm3). In addition, the addition of basalt fiber (BF) can effectively improve the compressive strength of the material without changing the density of the material. From a micro-level perspective, HC-R-EMS is closely combined with the cement matrix, which is conducive to increasing the compressive strength of concrete. Basalt fibers connect the matrix into a network, improving the maximum limit force of the concrete.

Study of the Compressive Properties of Heavy Calcium Carbonate-Reinforced Epoxy Composite Spheres (HC-R-EMS) Composite Lightweight Concrete

Improvement in comprehensive properties of nanocomposite coatings electro-codeposited with nitride and ceria

Achievement of high strength-ductility combination in austenitic and ferritic duplex stainless steel by heterogeneous deformation

Correction: Wu et al. 3D Thermal Network Supported by CF Felt for Improving the Thermal Performance of CF/C/Epoxy Composites. Polymers 2021, 13, 980

The formation of highly thermally conductive composites with a three-dimensional (3D) oriented structure has become an important means to solve the heat dissipation problem of electronic components. In this paper, a carbon fiber (CF) felt with a 3D network structure was constructed through the airflow netting forming technology and needle punching. The carbon fiber/phenolic composites were then fabricated by CF felt and phenolic resin through vacuum impregnation and compression molding. The effects of CF felt content and porosity on the thermal conductivity of carbon fiber/phenolic composites were investigated. The enhancement of carbon skeleton content promotes the conduction of heat inside the composites, and the decrease of porosity also significantly improves the thermal conductivity of the composites. The results indicate that the composites exhibit a maximum in-plane thermal conductivity of 1.3 W/mK, which is about 650% that of pure phenolic resin, showing that the construction of 3D thermal network structure is conducive to the reinforcement of thermal conductivity of composites. The method can provide a certain theoretical basis for constructing a thermally conductive composite with a three-dimensional structure.

Carbon Fiber/Phenolic Composites with High Thermal Conductivity Reinforced by a Three-Dimensional Carbon Fiber Felt Network Structure

Abstract In recent years, there have been more and more researches on the dielectric properties of carbon-based composites, and its dielectric tunability is a hot research topic. In this paper, epoxy resin/carbon fiber/phenolic residual carbon (EP/CF/C) was prepared by high-temperature sintering, vacuum liquid phase impregnation and hot-press curing methods. The AC conduction behavior, dielectric properties and impedance properties of composites with different CF/C compression ratios (1, 1.5, 2) are studied. With the increase of CF/C compression ratio, the negative dielectric properties of composites are getting stronger and stronger. The results show that when the CF/C compression ratio is 1, the composites occur percolation phenomenon and dielectric constant is negative. When the CF/C compression ratio is 2, the absolute value of the negative dielectric coefficient of the EP/CF/C composite reaches 9.8 × 104, and the conductivity reaches 0.54 S/cm. In addition, impedance analysis has further confirmed that the inductance properties lead to the negative dielectric properties of the material. The adjustable negative dielectric properties of EP/CF/C composites can provide some suggestions for the field of electromagnetic shielding and capacitors.

A study of preparation and properties of epoxy resin/carbon fiber/phenolic residual carbon composites with adjustable negative permittivity behavior

Pure nickel (Ni), TiB2 reinforced nickel (Ni-TiB2), nickel-phosphorus (Ni-P), and TiB2 reinforced nickel-phosphorus (Ni-P-TiB2) composite coatings were deposited on AISI-1045 steel substrates from Watts bath and phosphorous-containing solution, respectively. The composition and microstructure of these coatings were analyzed by energy dispersive x-ray spectroscopy (EDS), scanning electron microscope (SEM) and x-ray diffraction (XRD) analysis. The properties of these coatings, including hardness, were assessed and compared. The electrochemical performance of these coatings was investigated in a 3.5 wt% sodium chloride solution using electrochemical spectroscopy (EIS) and the potentiodynamic polarization technique at room temperature. The effect of TiB2 on the microstructure, phase, and properties of the coatings was investigated. The results indicate that the incorporation of TiB2 particles in the nickel matrix greatly increased the hardness and anti-corrosion properties of the nickel coatings by refining of the microstructure and reducing the defects. The enhancement effect of TiB2 on Ni-P coating is not as significant as that of TiB2 on nickel coating. However, with the incorporation of TiB2 ceramic particles, the corrosion resistance and hardness of the Ni-P-TiB2 coating increased by about 50% and 10%, respectively, compared with the original Ni-P coating. The present study provides insight into the potential applications of novel TiB2 ceramic particle-reinforced nickel composite coatings in the areas of wear and corrosion resistance.

Enhanced mechanical properties and corrosion resistance of nickel and nickel-phosphorous coatings fabricated by electrodeposition embedding with TiB2 ceramic particles

Quenching-partitioning-tempering (Q-P-T) heat treatment is a relatively novel approach to attain excellent ductility in high-strength steels. In the present work, the microstructural evolution and the mechanical properties of a low carbon microalloyed advanced steel were systematically investigated after the Q-P-T process. The microstructural evolution was explored by employing X-ray diffraction, transmission electron microscopy and scanning electron microscopy. The results indicate that the multiphase microstructures strongly depend on both the initial microstructure and the processing parameters of the quenching and partitioning process, especially the quenching temperature. Compositional inhomogeneity during the Q-P-T process results in multiphase microstructures, in which the mechanical properties of the quenching and partitioning steels may be strongly impacted by the distribution of heterogeneous austenite phase in the steel matrix.

Effects of Compositional Inhomogeneity on the Microstructures and Mechanical Properties of a Low Carbon Steel Processed by Quenching-Partitioning-Tempering Treatment

Epoxy/ copper-nickel metal foam composites with high thermal conductivity using an electroplating method

Compressive Behavior of Lightweight Concrete Using Aerogel-reinforced Expanded Polystyrene Foams

The development of ultrahigh molecular weight polyethylene (UPE) has been restricted due to its linear structure and low thermal conductivity. In this paper, graphene oxide (GO) was prepared by the modified Hummers method, and then UPE/reduced graphene oxide (rGO) powder was prepared by reduction with hydrazine hydrate. UPE/natural graphite (NG), UPE/carbon nanofiber (CNF), and UPE/rGO are prepared by hot compression molding. With the increase of thermally conductive fillers, the high density of the composite makes the thermal conductivity of the crystal structure more regular and the thermal conductivity path increases accordingly. Both TGA and SEM confirmed the uniform dispersion of carbon filler in epoxy resin. Among the three composites, UPE/NG has the best thermal conductivity. When the NG filling content is 60 phr, the thermal conductivity of the UPE/NG composite is 3.257 W/(mK), outperforming UPE/CNFs (0.778 W/(mK) and pure UPE (0.496 W/(mK) by 318.64 and 556.65%, respectively. UPE/CNFs have the best dielectric properties. Comparison of various carbon fillers can provide some references for UPE’s thermal management applications.

Study on Preparation and Properties of Ultrahigh Molecular Weight Polyethylene Composites Filled with Different Carbon Materials

Study on compressive strength of lightweight concrete filled with cement-reinforced epoxy Macrospheres and basalt fibers

Effect of Ti microparticles on the microstructure and properties of Ni-Ti composite coating prepared by electrodeposition

Thermal barrier coatings (TBCs) play a vitally important role in protecting the hot parts of a gas turbine from high temperature and corrosion effectively. More and more attention has been paid to the performance modification of ZrO2-based ceramics and seeking for new ceramic materials to meet requirements of gas turbine TBCs. The working principle, merits, and demerits of main technologies for coating preparation are elaborated in this paper, and the properties of new ceramic materials are reviewed. It is found that the thermal conductivity, thermal stability, mechanical properties, and other performances of traditional ZrO2-based ceramics could be improved effectively by doping modification. The emphases for new ceramic materials research were put on pyrochlores, magnetoplumbites, rare-earth tantalates, etc. Rare-earth tantalates with great potentials as new top ceramic materials were described in detail. In the end, the development directions of advanced top ceramic coatings, combining doping modification with preparation technology to regulate and control structure property of high-performance ceramic material, were put forward.

Research Progresses on Ceramic Materials of Thermal Barrier Coatings on Gas Turbine

Roles definition of TiN particles in enhancing the creep properties of IN718C high temperature alloys

Tailoring effect of Cr and graphene particles on the microstructure and properties of Ni matrix nanocomposite coatings

Abstract As one of the most effective energy storage compounds, phase change materials (PCMS) play an important role in energy conservation and storage. However, the inherent poor thermal conductivity and liquid leakage of PCMS seriously limit their practical application. Polyethylene glycol·calcium chloride (PEG·CaCl2) phase change materials filled with three-dimensional carbon fiber network were prepared by liquid phase impregnation and hot pressing molding method. The experimental results show that carbon fiber network (CF felt) and PEG·CaCl2 complex structure increase the thermal conductivity and stability. The in-plane thermal conductivity of PEG·CaCl2/CF composite (47.73% carbon content) is 0.97 W/mK, about 103% higher than that of PEG. PEG·CaCl2/CF composite does not present leakage even heating at 80 °C for 45 min (35 °C higher than the melting point of pure PEG), showing low leakage ability. High thermal conductivity, low leakage and low density of this composite suggest a promising route for thermal storage applications.

High thermal conductivity and low leakage phase change materials filled with three-dimensional carbon fiber network

Na2SO4 + NaCl molten salts corrosion mechanism of thermal barrier coatings used in ships

Because the aerogel has ultra-low density and good impact resistance, the aerogel material, epoxy-hardener system, and expandable polystyrene beads (EPS) were used to prepare the lightweight aerogel reinforced hollow epoxy macro-spheres (AR-HEMS). The multi-phase epoxy syntactic foam (ESF) was manufactured with the epoxy-hardener system, HGMS (EP-hardener-HGMS), and AR-HEMS by “the compression modeling method.” In this experiment, in order to enhance the strength of the ESF, some different kinds of the carbon fiber (CF) were added into the EP-hardener-HGMS system (CFR-EP). The influence of the volume stacking fraction, inner diameter, and layer of the AR-HEMS and the content and type of the CF in the EP-HGMS (CFR-EP) system on the compressive strength of the ESF were studied. Weighing the two factors of the density and compressive strength, the ESF reinforced by 1.5 wt% CF with 90% AR-HEMS has the better performance. This kind of the ESF has 0.428 g/cm3 nd 20.76 Mpa, which could be applied in 2076 m deep sea.

Carbon Fiber Reinforced Multi-Phase Epoxy Syntactic Foam (CFR-Epoxy-Hardener/HGMS/Aerogel-R-Hollow Epoxy Macrosphere(AR-HEMS))

Heat dissipation problem is the primary factor restricting the service life of an electronic component. The thermal conductivity of materials has become a bottleneck that hinders the development of the electronic information industry (such as light-emitting diodes, 5G mobile phones). Therefore, the research on improving the thermal conductivity of materials has a very important theoretical value and a practical application value. Whether the thermally conductive filler in polymer composites can form a highly thermal conductive pathway is a key issue at this stage. The carbon fiber/carbon felt (CF/C felt) prepared in the study has a three-dimensional continuous network structure. The nickel-coated carbon fiber/carbon felt (CF/C/Ni felt) was fabricated by an electroplating deposition method. Three-dimensional CF/C/Ni/epoxy composites were manufactured by vacuum-assisted liquid-phase impregnation. By forming connection points between the adjacent carbon fibers, the thermal conduction path inside the felt can be improved so as to improve the thermal conductivity of the CF/C/Ni/epoxy composite. The thermal conductivity of the CF/C/Ni/epoxy composite (in-plane K∥) is up to 2.13 W/(m K) with 14.0 wt % CF/C and 3.70 wt % Ni particles (60 min electroplating deposition). This paper provides a theoretical basis for the development of high thermal conductivity and high-performance composite materials urgently needed in industrial production and high-tech fields.

Epoxy Composites with High Thermal Conductivity by Constructing Three-Dimensional Carbon Fiber/Carbon/Nickel Networks Using an Electroplating Method

The heat generated by a high-power device will seriously affect the operating efficiency and service life of electronic devices, which greatly limits the development of the microelectronic industry. Carbon fiber (CF) materials with excellent thermal conductivity have been favored by scientific researchers. In this paper, CF/carbon felt (CF/C felt) was fabricated by CF and phenolic resin using the “airflow network method”, “needle-punching method” and “graphitization process method”. Then, the CF/C/Epoxy composites (CF/C/EP) were prepared by the CF/C felt and epoxy resin using the “liquid phase impregnation method” and “compression molding method”. The results show that the CF/C felt has a 3D network structure, which is very conducive to improving the thermal conductivity of the CF/C/EP composite. The thermal conductivity of the CF/C/EP composite reaches 3.39 W/mK with 31.2 wt% CF/C, which is about 17 times of that of pure epoxy.

3D Thermal Network Supported by CF Felt for Improving the Thermal Performance of CF/C/Epoxy Composites

The low thermal conductivity and poor shape stability of phase change materials (PCMs) have seriously restricted their applications in energy storage and energy saving. In this paper, poly(ethylene glycol)–calcium chloride/carbon/carbon fiber felt (PEG-CaCl2/CCF) PCMs were fabricated by a liquid-phase impregnation–vacuum drying–hot compression molding method with carbon/carbon fiber felt as the three-dimensional (3D) thermal skeleton and PEG-CaCl2 as the polymer PCM matrix. PCMs were heated and compressed by the compression confinement method to improve the contact area between 3D skeleton carbon fibers. The carbon fibers in PCMs presented a 3D (X–Y–Z) network structure and the fiber arrangement was anisotropic, which were beneficial to improve the thermal conductivity of PCMs in the fiber direction. The compression confinement can improve the contact area between the fibers in the 3D skeleton. As a result, the thermal conductivity of PEG-CaCl2/CCF PCMs can reach 3.35 W/(m K) (in-plane) and 1.94 W/(m K) (through-plane), about 985 and 571% of that of PEG-CaCl2, respectively. Due to the complexation of PEG and CaCl2 and the 3D skeleton support of carbon fiber felt, PCMs have excellent shape stability. The paper may provide some suggestions for the preparation of high thermal conductivity and excellent shape stability PCMs.

Polyethylene Glycol–Calcium Chloride Phase Change Materials with High Thermal Conductivity and Excellent Shape Stability by Introducing Three-Dimensional Carbon/Carbon Fiber Felt

As electronic devices tend to be integrated and high-powered, thermal conductivity is regarded as the crucial parameter of electronic components, which has become the main factor that limits the operating speed and service lifetime of electronic devices. However, constructing continuous thermal conductive paths for low content particle fillers and reducing interface thermal resistance between fillers and matrix are still two challenging issues for the preparation of thermally conductive composites. In this study, 3D-oriented carbon fiber (CF) thermal network structures filled with boron nitride flakes (BN) as thermal conductive bridges were successfully constructed. The epoxy composite was fabricated by thermal conductive material with a 3D oriented structure by the vacuum liquid impregnation method. This special 3D-oriented structure modified by BN (BN/CF) could efficiently broaden the heat conduction pathway and connected adjacent fibers, which leads to the reduction of thermal resistance. The thermal conductivity of the boron nitride/carbon fiber/epoxy resin composite (BN/CF/EP) with 5 vol% 10 mm CF and 40 vol% BN reaches up to 3.1 W m−1 K−1, and its conductivity is only 2.5 × 10−4 S cm−1. This facile and high-efficient method could provide some useful advice for the thermal management material in the microelectronic field and aerospace industry.

Epoxy composite with high thermal conductivity by constructing 3D-oriented carbon fiber and BN network structure

The synergistic role of Ti microparticles and CeO2 nanoparticles in tailoring microstructures and properties of high-quality Ni matrix nanocomposite coating

The thermal shock resistance and the thermal barrier effects are the key indices for thermal barrier coating (TBC) performances. The performance optimization of 7∼8 wt. % Y2O3 stabilized ZrO2 (7∼8YSZ) TBCs is a research focus at present. In this work, an orthogonal test was employed to study the relationship between parameters and performances and match process parameters for TBCs preparation. The scanning electron microscope was employed to analyze the microstructures of 8YSZ TBCs. The thermal shock resistance test and thermal barrier effect test were conducted to judge the performances of 8YSZ TBCs. It was found that the process factor had the greatest influences on porosity and elastic modulus was spraying distance and the factor had the greatest influence on bond strength was spraying power. The selected parameters were a spraying distance of 90 mm, an argon flow of 32 L/min, a hydrogen flow of 8 L/min, an electric current of 550 A, a spraying power of 35 kW, a feeding rate of 45 g/min, and a substrate preheating temperature of 373 K. The thermal shock life was ∼100 times under 1173∼298 K, and the thermal barrier temperature of optimized 8YSZ TBCs with thicknesses of 250 and 300 µm was ∼90 and ∼130 K under 1473 K, respectively. Through a comparative study, both thermal shock resistance and thermal barrier effects of 8YSZ TBCs were improved after process parameters’ optimization conducted by this method.

Optimization of process parameters for thermal shock resistance and thermal barrier effects of 8YSZ thermal barrier coatings through orthogonal test

Effect of spraying power on the microstructure and wear behavior of the plasma-sprayed FeCoCrNiMo0.2 coating

Short carbon fiber (CF), epoxy-hardener (EP-hardener), and expanded polystyrene (EPS) beads were used to prepare CF-reinforced hollow epoxy macrospheres (CFR-HEMS) by the “rolling ball method”. The multiphase epoxy syntactic foam (ESF) was prepared with CFR-HEMS, the EP-hardener system, and hollow glass microspheres (HGMS) by the “compression modeling method”. In this experiment, the influences of the stacking volume fraction, wall thickness, and inner diameter of the CFR-HEMS and HGMS types and contents in the EP-hardener system on the properties of the ESF were studied. In addition, CFs with different meshes were used to reinforce hollow epoxy macrospheres (HEMS) to study the effect of different kinds of CFs on the compressive strength of the ESF. During the mixing of the EP-hardener and HGMS (EP-hardener–HGMS), 300 AW CFs with different contents were added to the system to enhance the compressive strength of the ESF. The CFR-HEMS spherical wall was combined tightly with the EP-hardener–HGMS system by a scanning electron microscope (SEM). The ESF, which has better properties relatively in the experiment, can be used in 2673 m deep water and provide 490 kg/m3 buoyancy, which can be of help in the preparation of buoyancy materials in detection systems and oil extraction systems in the deep sea.

Preparation and Mechanical Properties of Carbon Fiber Reinforced Multiphase Epoxy Syntactic Foam (CF-R-Epoxy/HGMS/CFR-HEMS Foam)

Boride-based cermet can serve as a good protective coating for low-corrosion and wear-resistant materials, such as carbon steels, due to their mechanical and chemical properties. In this study, M3B2 (M: Mo, Ni, Fe, and Cr) boride-based cermet coatings were fabricated on Q235 steel with mixed powders of Mo, B, Ni60, and Cr by laser cladding synthesis, and the effects of laser power on the properties of the cermet layer were investigated. Three laser powers (2200, 2500, and 2800 W) were used at the same scanning speed. The X-ray diffraction (XRD), scanning electron microscopy (SEM), and energy-dispersive X-ray spectroscopy (EDS) analysis confirmed that all the coatings were composed of M3B2-type borides and {Fe, Ni} alloys. The micro-hardness, corrosion, and frictional experiments showed that the cermet coatings enhanced the corresponding performances of the Q235 steels at the three laser powers. However, the micro-hardness of the coatings decreased as the power increased, and the maximum micro-hardness value was 1166.3 HV (Vickers Hardness). The results of the corrosion and frictional experiments showed that the best performance was obtained at a laser power of 2500 W, followed by 2800 and 2200 W.

The Effect of Laser Power on the Properties of M3B2-Type Boride-Based Cermet Coatings Prepared by Laser Cladding Synthesis

Polyimide is type of heterocyclic polymer compound characterized by an imide ring structure. The aromatic ring structure in polyimide facilitates good electrical properties, mechanical properties, thermal properties and radiation resistance, etc. It is widely used in the aerospace field, in electronic components and in the semiconductor industry. Traditional methods for the preparation of polyimide films have different limitations. Here, a new one-step method was established to prepare polyimide coatings using liquid flame spray. The effect of different mass fraction on the surface and cross section structure characteristics of polyimide coatings was studied. The formation process of the polyimide-alumina composite coatings was analyzed using single particles and coatings with different amount of alumina. The composite coating shows a flat and dense structure and excellent dielectric properties. The results shed light on construction of polymer-inorganic composite layers for widespread applications.

Facile Fabrication of Polyimide-alumina Composite Coatings by Liquid Flame Spray

Hollow glass microsphere-reinforced epoxy hollow spheres (HGMS–EHSs) were prepared by a “rolling ball method” using expanded polystyrene beads, HGMSs, and epoxy resin (EP). The three-phase epoxy syntactic foam (epoxy/HGMS–EHS–HGMS composite) was fabricated by combining HGMS–EHS as a lightweight filler with EP and HGMS by a “molding method”. The HGMS–EHS and epoxy curing agent systems were well mixed by scanning electron microscopy. Experiments show that higher HGMS–EHS stack volume fraction, lower HGMS–EHS layer number, higher HGMS–EHS diameter, lower HGMS–EHS density, higher HGMS volume fraction, and lower HGMS density result in a decrease in the density of the three-phase epoxy syntactic foam. However, the above factors have the opposite effect on the compressive strength of the three-phase epoxy syntactic foam. Therefore, in order to obtain the “high-strength and low-density” three-phase epoxy syntactic foam, the influence of various factors should be considered comprehensively to achieve the best balance of compressive strength and density of the three-phase epoxy syntactic foam. This can provide some advice for the preparation of buoyancy materials for deep sea operations.

Development and Mechanical Characterization of HGMS–EHS-Reinforced Hollow Glass Bead Composites

Porosity in plasma-sprayed coatings is vital for most engineering applications. Porosity has its merits and demerits depending on the functionality of the coating and the immediate working environment. Consequently, the formation mechanisms and development of porosity have been extensively explored to find out modes of controlling porosity in plasma-sprayed coatings. In this work, a comprehensive review of porosity on plasma-sprayed coatings is established. The formation and development of porosity on plasma-sprayed coatings are governed by set spraying parameters. Optimized set spraying parameters have been used to achieve the most favorable coatings with minimum defects. Even with the optimized set spraying parameters, defects like porosity still occur. Here, we discuss other ways that can be used to control porosity in plasma-sprayed coating with emphasis to atmospheric plasma-sprayed chromium oxide coatings. Techniques like multilayer coatings, nanostructured coatings, doping with rare earth elements, laser surface re-melting and a combination of the above methods have been suggested in adjusting porosity. The influences of porosity on microstructure, properties of plasma-sprayed coatings and the measurement methods of porosity have also been reviewed.

The hard and corrosion resistant coatings of Mo2NiB2 cermet were prepared by the laser cladding technique. The influences of the Mo:B ratio and the laser scanning speed on the microstructure and property of the Mo2NiB2 cermet coatings were investigated. The results showed that the laser scanning speed of 1.5 mm/s and the Mo:B ratio of 1 were more beneficial to the formation of Mo2NiB2 cermet than 2.0 mm/s and 0.8, 1.2, respectively. The amount of the Mo2NiB2 ceramic phases were decreased from the top layer to the bottom layer of the coating. The changes of microstructure and composition led to the changes of hardness and corrosion resistance of the Mo2NiB2 cermet coatings. The coating prepared at the Mo:B ratio of 1 and the scanning speed of 1.5 mm/s possessed the highest hardness, and the hardness gradually decreased from the top layer to the bottom layer of the coating. The formation of Mo2NiB2 and {FeM} phases led to the enhanced corrosion resistance of the Mo2NiB2 cermet coatings, and the coating prepared at the Mo:B ratio of 0.8 possessed the best corrosion resistance and the minimum corrosion current.

Investigation on Microstructure, Hardness, and Corrosion Resistance of Mo–Ni–B Coatings Prepared by Laser Cladding Technique

Porosity in plasma sprayed coatings is vital for most engineering applications. It is either advantageous or disadvantageous depending on the functionality of the coating and the immediate working environment. Consequently, the formation mechanisms and development of porosity has been extensively explored to find out modes of controlling porosity in plasma sprayed coatings. In this work, a comprehensive review of porosity on plasma sprayed coatings is established. The formation and development of porosity on plasma sprayed coatings are governed by set spraying parameters. Optimized set spraying parameters have been used to achieve the most favorable coatings with minimum defects. Even with the optimized set spraying parameters, defects like porosity still occur. Here, we discuss other ways that can be used to control porosity in plasma sprayed coating with emphasis to atmospheric plasma sprayed chromium oxide coatings. Techniques like multi-layer coatings, nano-structured coatings, doping with rare earth elements, laser surface re-melting and a combination of the above methods have been suggested in adjusting porosity. The influences of porosity on properties of plasma sprayed coatings and the measurement methods of porosity have also been reviewed.

Porosity and Its Significance in Plasma Sprayed Coating: A Review

Influences of Al and Ti particles on microstructure, internal stress and property of Ni composite coatings

Although Q235 steel materials are widely used in offshore engineering, the service life is severely shortened by its inferior resistance to wear and corrosion in harsh marine working environments. Boride-based cermet composites could be a good surface-protective coating to enhance surface hardness, wear resistance, and corrosion resistance. M3B2 (M: Mo, Ni, Fe, Cr) boride-based cermet coatings composed of hard ceramics of M3B2-type complex borides and an {Fe, Ni} metal matrix was fabricated on Q235 steels with mixed Mo, Cr, B, and Ni60 powders using a laser cladding synthesis technique. The influences of laser cladding parameters on the microstructure, phase composition, microhardness, and corrosion resistance of the coatings were comprehensively investigated. Results showed that the microstructures of the coatings mainly consisted of three layers, which were, from the top to bottom layer, a metal layer with fewer ceramic phases, a ceramic layer with fewer metal phases, and another metal layer with fewer ceramic phases. The ceramic phases were mainly M3B2-type borides, and the metal phases were mainly {Fe, Ni} alloys. The appearance of Fe-enriching metal phases was due to the supply of Fe elements from Q235 substrates. With squash pretreatment and without a remelting aftertreatment, ceramics uniformly dispersed in the cermet coatings, and their sizes decreased. The results of microhardness showed that the microhardness of the coating first increased and then decreased from the top layer to the bottom layer, and maximum microhardness was obtained in the layer of ceramics with less metal phases. An electrochemical corrosion test showed that the cermet coatings (jcorr = 6.35 μA/cm2) could improve the corrosion resistance of Q235 steels (j = 43.76 μA/cm2) by one order of magnitude.

Microstructure and Properties of M3B2-Type Boride-Based Cermet Coatings Prepared by Laser Cladding Synthesis

Roles of growth mechanisms of Ni deposits on corrosion behaviors of NixAlyTi composite coatings

Porosity in plasma sprayed coatings is vital for most engineering applications. It is either 13 advantageous or disadvantageous depending on the functionality of the coating and the immediate 14 working environment. Consequently, the formation mechanisms and development of porosity has 15 been extensively explored to find out modes of controlling porosity in plasma sprayed coatings. In 16 this work, a comprehensive review of porosity on plasma sprayed coatings is established. The 17 formation and development of porosity on plasma sprayed coatings are governed by set spraying 18 parameters. Optimized set spraying parameters have been used to achieve the most favorable 19 coatings with minimum defects. Even with the optimized set spraying parameters, defects like 20 porosity still occur. Here, we discuss other ways that can be used to control porosity in plasma 21 sprayed coating with emphasis to atmospheric plasma sprayed chromium oxide coatings. 22 Techniques like multilayer coatings, nanostructured coatings, doping with rare earth elements, laser 23 surface re-melting and a combination of the above methods have been suggested in adjusting 24 porosity. The influences of porosity on properties of plasma sprayed coatings and the measurement 25 methods of porosity have also been reviewed. 26

1 Porosity and Its Significance in Plasma Sprayed 2 Coating : A Review 3

Investigation on microstructure and properties of electrodeposited Ni-Ti-CeO 2 composite coating

Surface mechanical property and residual stress of peened nickel-aluminum bronze determined by in-situ X-ray diffraction

The influences of co-deposited Ti particles on corrosion behavior of electrodeposited Ni-Ti coatings were investigated. The co-deposited Ti particles caused the refined crystallite size and random-oriented texture of Ni-Ti coating. In 3.5 wt% sodium chloride (NaCl) solution, the buried Ti particles in Ni matrix blocked the corrosion path and rapid intercrystalline corrosion. The inert TiO2 could form on the exposed Ti particles and hinder localized corrosion. In 10 wt% sodium hydroxide (NaOH) solution, Ni matrix crystallites, refined by co-deposited Ti particles, contributed to formation of the passive Ni(OH)2 film. The corrosion current of Ni-Ti coating decreased by about one order of magnitude in both solutions with respect to pure Ni coating, demonstrating the co-deposited Ti particles greatly improved the corrosion resistance of Ni-Ti composite coatings. Finally, a corrosion mechanism was built to explain the co-deposited Ti particles improved corrosion resistance of the Ni-Ti composite coatings.

The Roles of Ti Particles in Improving the Corrosion Resistance of Electrochemically Assembled Ni-Ti Composite Coatings

Hard and Corrosion-Resistant Ni-xAl-yTi Nanocomposite Coatings for CNT/Al Composites

The microstructure, mechanical properties, and oxidation behavior of beta-gamma TiAl alloy with excellent hot workability

Effect of Cu and Sn Addition on Microstructure and Properties of Brazing Filler 4343 Al Alloy

Microstructural characterization and corrosion behaviors of Ni-Cu-Co coatings electrodeposited in sulphate-citrate bath with additives

Microstructural evolution of hot-forged high Nb containing TiAl alloy during high temperature tension

Pretreatment Behaviors and Improved Corrosion Resistance for Cu/Co-Ni-Cu Coating Electrodeposition on Magnesium Alloy

Effects of annealing process on sagging resistance of cold-rolled three-layer Al alloy clad sheets

Residual stress and microstructure of the CNT/6061 composite after shot peening

Effect of shot peening on the residual stresses and microstructure of tungsten cemented carbide

Investigation on the evolution of microstructure and texture of electroplated Ni–Ti composite coating by Rietveld method

Effects of Co contents on the microstructures and properties of the electrodeposited NiCo–Zr composite coatings

Microstructure and corrosion behavior of Ti nanoparticles reinforced Ni–Ti composite coatings by electrodeposition

Fabrication and characterization of Ni–Zr composite coatings using electrodepositing technique

Effect of Si addition on the microstructure and mechanical properties of ECAPed Mg–15Al alloy

Microstructure and mechanical properties of an Mg–10Al alloy fabricated by Sb-alloying and ECAP processing

3, 4-dicaffeoylquinic acid (3, 4-DiCQA) is a dicaffeoylquinic acid, which possesses antioxidant, anti-inflammatory, antibacterial, antiviral, anticancer, hypoglycemic, hypotensive and hepatoprotective activities. In this study, a rapid and reliable method using ultra-high performance liquid chromatography equipped with linear ion trap-orbitrap mass spectrometry (UHPLC-LTQ-Orbitrap MS) was developed to identify the metabolites of 3, 4-DiCQA in rat plasma, urine, feces and tissues. The metabolic profile of 3, 4-DiCQA was determined after oral administration to rats at a dose of 200 mg/kg. A strategy of full scan-parent ions list acquisition (FS-PIL) coupled to diagostic product ions (DIPs) analysis for screening and identification of target metabolites was used. A total of 67 metabolites were observed and characterized for the first time, combined with accurate mass measurement, diagnostic ions, neutral losses and reference standards. The results indicated that hydrolysis, methylation, hydrogenation, hydration, dehydroxylation, dehydrogenation, sulphate conjunction and glucuronide conjunction were the major metabolic reactions of 3, 4-DiCQA in vivo.

The metabolite profiling of 3, 4-DiCQA in SD rats using ultra-high performance liquid chromatography equipped with linear ion trap-orbitrap mass spectrometry.

In Vitro Intestinal Absorption and Metabolism of Magnoflorine and its Potential Interaction in Coptidis Rhizoma Decoction in Rat

To predit the mechanism of metabolic drug-drug interactions of hydroxygenkwanin with other drugs, we investigated the inhibition inhibitory effect of hydroxygenkwanin on UGTs and UGT1A1 activities of different liver microsomes. In the present study, 4-nitrophenol (4-NP) and β-estradiol were elected as substrates to determine activities of UGTs and UGT1A1 by UV and HPLC, respectively. The results showed that, hydroxygenkwanin significantly inhibited UGTs activity in rat, mouse and human liver microsomes. UGT1A1 activity was inhibited by hydroxygenkwanin to varying degrees, with IC₅₀ about 190, 10.93, 20.07, 76.31 μmol•L⁻¹ in mouse liver microsome(MLM), rat liver microsome (RLM) and recombinant UGT1A1, and human liver microsome (HLM), respectively. The inhibition types were competitive inhibition (RLM, HLM) and linear mixed-typed linear inhibition (recombinant UGT1A1). The order for the inhibitory intensity was RLM>rUGT1A1>HLM>MLM. In conclusion, hydroxygenkwanin has an inhibitory effect on UGTs and UGT1A1 activities of different liver microsomes, with differences in species, indicating its potential drug interactions based on UGT1A1 enzyme. This study aims to provide a reliable experimental basis for its further research and development of hydroxygenkwanin, and provide theoretical reference for the clinic drug combination research.

Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica

[Inhibitory effect of different species of hydroxygenkwanin on UGTs and UGT1A1 activities].

In the present study, the effects of six Coptidis alkaloids (berberine, epiberberine, coptisine, jatrorrhizine, palmatine and magnoflorine) on liver microsomes UGTs and UGT1A1 activities in rats and mice were investigated in vitro and in vivo to study the mechanism of metabolic drug-drug interactions of Coptidis Rhizoma with other drugs. In vitro rat and mice liver microsomal incubation systems combined with UDPGA were applied, as well as mice liver microsomes after administration of six Coptidis alkaloids. 4-Nitrophenol and β-estradiol were selected as substrates to determine activities of UGTs and UGT1A1 by UV and HPLC, respectively. According to the in vitro rat study, berberine, epiberberine, coptisine and jatrorrhizine significantly inhibited rat liver microsome UGTs activity, particularly epiberberine showed the strongest inhibition. UGT1A1 activity was lowly inhibited by jatrorrhizine, with IC₅₀ at about 227 μmol•L⁻¹, whereas coptisine and magnoflorine significantly activated UGT1A1. According to the in vitro mice study, berberine, coptisine, jatrorrhizine and palmatine significantly inhibited mice liver microsome UGTs activity, and the six alkaloids all significantly activated UGT1A1. According to the in vivo mice study, UGTs activity was significantly activated only in berberine group, while UGT1A1 activity was significantly activated only in jatrorrhizine group. In conclusion, the effects of Coptidis alkaloids on UGT activity showed significant differences in species and between in vitro and in vivo. Meanwhile, the changes in structures of Coptidis alkaloids also have a big impact on UGT activity, which may be one of the causes for the drug-drug interactions between Coptidis Rhizoma and other drugs.

[In vitro and In vivo effects of six Coptidis alkaloids on liver microsomes UGTs and UGT1A1 activities in rats and mice].

Prediction of the pharmacokinetics and tissue distribution of levofloxacin in humans based on an extrapolated PBPK model

Abstract Context Previous studies have shown that Scutellariae Radix, the dried root of Scutellaria baicalensis Georgi (Labiatae), has a certain inhibitory effect on P-glycoprotein (P-gp), but the effects of its main active constituents on P-gp are still ambiguous. Objectives In vitro studies were performed to investigate the effects of its main active constituents (baicalin and its aglycone, baicalein) on the activity and expression of P-gp in intestine using Caco-2 cells and rat gut sacs. Materials and methods In Caco-2 cell experiments, the effects of baicalin and baicalein on P-gp activity were investigated using a P-gp substrate, rhodamine 123 and non-substrate fluorescein Na, by determining their intracellular fluorescence accumulation, and their effects on P-gp expression were determined using flow cytometry. In addition, rat gut sac model was selected to investigate the effects of baicalin and baicalein on the transport of verapamil, a classical P-gp substrate. The gut sacs of male Sprague–Dawley rats were filled with 0.4 mL the test solution contained verapamil (0.2575 mg/mL) and the drugs [baicalin and baicalein, at concentrations of 1/8 IC50 (59.875, 41.5 μg/mL), 1/4 IC50 (119.75, 83 μg/mL) and 1/2 IC50 (239.5, 166 μg/mL)], and then incubated in Tyrode’s solution for a period of time. After termination of the incubation, the incubated solution was processed for the subsequent detection. Results According to the results of MTT assay, the IC50 values of verapamil, baicalin and baicalein were 104, 479, 332 μg/mL, respectively. The obtained results from the two models were confirmed mutually. As a result, baicalin exhibited no obvious effect on intracellular accumulation of Rh-123, and almost had no effect on P-gp expression and verapamil transportation, while baicalein significantly increased intracellular accumulation of Rh-123 (p < 0.01), down-regulated P-gp expression (p < 0.01) and increased the transport of verapamil (p < 0.05). Discussion and conclusion The results indicated that baicalein may be a P-gp inhibitor, which presented obvious inhibitory effects on P-gp activity and expression level. A comparison of the structures of baicalin and baicalein indicates that the existence of glucosyl plays a decisive role in influencing the activity and expression of P-gp.

In vitro potential modulation of baicalin and baicalein on P-glycoprotein activity and expression in Caco-2 cells and rat gut sacs

Coptisine (COP), a protoberberine alkaloid (PBA) from Chinese medicinal plants (such as family Berberidaceae), may be useful for improving central nervous system disorders. However, its pharmacokinetics, disposition and metabolism are not well defined. In the present study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established for the analysis of COP in biological samples. To better understand its in vivo pharmacological activities, COP concentrations in rat plasma were determined after oral (50 mg/kg) and intravenous administration (10 mg/kg). For the brain distribution study, the concentration of COP in five different regions was examined after intravenous administration at 10 mg/kg. Pharmacokinetic parameters from the COP concentration-time profiles in plasma and brain, and the brain-to-plasma coefficient (Kp, brain) were calculated by non-compartmental analysis. The metabolites of COP in rats in vivo and in vitro (urine, bile, liver microsomes and intestinal bacteria incubation) were also identified. Seventeen metabolites, including 11 unconjugated metabolites formed by hydroxylation, hydrogenation, demethylation, dehydrogenation, demethylation, and 6 glucuronide and sulfate conjugates were identified for the first time. The results suggested that COP had low oral bioavailability of 8.9% and a short (plasma) half-life (T1/2=0.71 h) in rats. After intravenous administration, it quickly crossed the blood-brain barrier, accumulating at higher concentrations and then was slowly eliminated from different brain regions. Moreover, COP was transformed into metabolites through multiple metabolic pathways in vivo and in vitro. These results should help to promote further research on COP and contribute to clarifying the metabolic pathways of PBAs.

Pharmacokinetics and Brain Distribution and Metabolite Identification of Coptisine, a Protoberberine Alkaloid with Therapeutic Potential for CNS Disorders, in Rats.

Proteomics approach to analyze protein profiling related with ADME/Tox in rat treated with Scutellariae radix and Coptidis rhizoma as well as their compatibility.

The aim of this study is to develop a physiologically based pharmacokinetic (PBPK) model in intra-abdominal infected rats, and extrapolate it to human to predict moxifloxacin pharmacokinetics profiles in various tissues in intra-abdominal infected human. 12 male rats with intra-abdominal infections, induced by Escherichia coli, received a single dose of 40 mg/kg body weight of moxifloxacin. Blood plasma was collected at 5, 10, 20, 30, 60, 120, 240, 480, 1440 min after drug injection. A PBPK model was developed in rats and extrapolated to human using GastroPlus software. The predictions were assessed by comparing predictions and observations. In the plasma concentration versus time profile of moxifloxcinin rats, Cmax was 11.151 µg/mL at 5 min after the intravenous injection and t1/2 was 2.936 h. Plasma concentration and kinetics in human were predicted and compared with observed datas. Moxifloxacin penetrated and accumulated with high concentrations in redmarrow, lung, skin, heart, liver, kidney, spleen, muscle tissues in human with intra-abdominal infection. The predicted tissue to plasma concentration ratios in abdominal viscera were between 1.1 and 2.2. When rat plasma concentrations were known, extrapolation of a PBPK model was a method to predict drug pharmacokinetics and penetration in human. Moxifloxacin has a good penetration into liver, kidney, spleen, as well as other tissues in intra-abdominal infected human. Close monitoring are necessary when using moxifloxacin due to its high concentration distribution. This pathological model extrapolation may provide reference to the PK/PD study of antibacterial agents.

The Korean Journal of Physiology & Pharmacology : Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology

Prediction of Pharmacokinetics and Penetration of Moxifloxacin in Human with Intra-Abdominal Infection Based on Extrapolated PBPK Model

Magnoflorine, an important aporphine alkaloid in Coptidis Rhizoma, is increasingly attracting research attention because of its pharmacological activities. The in vivo and in vitro metabolism of magnoflorine was investigated by LC LTQ-Orbitrap MS. In vivo samples including rat urine, feces, plasma and bile were collected separately after both oral (50 mg kg(-1) ) and intravenous administration (10 mg kg(-1) ) of magnoflorine, along with in vitro samples prepared by incubating magnoflorine with rat intestinal flora and liver microsome. As a result, 12 metabolites were found in biological samples. Phase I metabolites were identified in all biological samples, while phase II metabolites were mainly detected in urine, plasma and bile. In a pharmacokinetic study, rats were not only dosed with magnoflorine via oral (15, 30 and 60 mg kg(-1) ) and intravenous administration (10 mg kg(-1) ) but also dosed with Coptidis Rhizoma decoction (equivalent to 30 mg kg(-1) of magnoflorine) by intragastric administration to investigate the interaction of magnoflorine with the rest of compounds in Coptidis Rhizoma. Studies showed that magnoflorine possessed lower bioavailability and faster absorption and elimination. However, pharmacokinetic parameters altered significantly (p < 0.05) when magnoflorine was administered in Coptidis Rhizoma decoction. Oral gavage of Coptidis Rhizoma decoction decreased the absorption and elimination rates of magnoflorine, which revealed that there existed pharmacokinetic interactions between magnoflorine and the rest of ingredients in Coptidis Rhizoma.

In vitro and in vivo identification of metabolites of magnoflorine by LC LTQ-Orbitrap MS and its potential pharmacokinetic interaction in Coptidis Rhizoma decoction in rat.

Epiberberine, one of the most important isoquinoline alkaloid in Coptidis Rhizoma, possesses extensive pharmacological activities. In this paper, the liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to study phase I and phase II metabolites. A Thermo HPLC system (including Surveyor AS, Surveyor LC Pump, Surveyor PDA. USA) was used. The cocktail probe drugs method was imposed to determine the content change of metoprolol, dapsone, phenacetin, chlorzoxazone and tolbutamide simultaneously for evaluating the activity of CYP2D6, CYP3A4, CYP1A2, CYP2E1 and CYP2C9 under different concentrations of epiberberine in rat liver microsomes. The result showed that epiberberine may have phase I and phase II metabolism in the rat liver and two metabolites in phase I and three metabolites in phase II are identified in the temperature incubation system of in vitro liver microsomes. Epiberberine showed significant inhibition on CYP2D6 with IC50 value of 35.22 μmol L(-1), but had no obvious inhibiting effect on the activities of CYP3A4, CYP1A2, CYP2E1 and CYP2C9. The results indicated that epiberberine may be caused drug interactions based on CYP2D6 enzyme. This study aims to provide a reliable experimental basis for its further research and development of epiberberine.

[Identification of metabolites of epiberberine in rat liver microsomes and its inhibiting effects on CYP2D6].

To figure out the stability and intestinal bacteria metabolites of rats in vitro of astragaloside IV ( AST), this research was done to explore the stability of AST in the artificial gastric juice. artificial intestinal juice and rat liver homogenate and the metabolism in rat intestinal in vitro. HPLC was used to calculate the remaining rate of AST in biological samples by measuring the content of AST, while metabolites were determined by combining the methods of TLC, HPLC and LC-MS/MS. It turned out that AST was difficult to metabolize in the artificial gastric juice, artificial intestinal juice and rat liver. Also, the metabolic pathway of AST was stepped by deglycosylation. Firstly, AST was converted to its secondary etabolites (6-O-β-D-glucopyranosyl- cycloastragenol, CMG) by removal of xylose moiety at C-3, then transformed into cycloastragenol (CAG) after hydrolytic removal of the glucose moiety at C-6. All the results suggested that the metabolism of AST in vivo occurs mainly in the intestinal by hydrolysis of glycosyl. In conclusion, hydrolysis of intestinal flora is the main reason that AST metabolizes.

[Stability study in biological samples and metabolites analysis of astragaloside IV in rat intestinal bacteria in vitro].

Honokiol, isolated from the Chinese traditional herb magnolia, is a poorly water-soluble component and has been found to have anti-tumor properties. In the current study, honokiol submicron lipid emulsions (HK-SLEs) were prepared by high pressure homogenization technology. After HK-SLEs were physically characterized, their pharmacokinetics, tissue distribution and antitumor activity after intravenous (i.v.) administration to tumor-burdened mice were examined, using honokiol solution (HK-SOL) as the control. The results showed that the mean particle size, zeta potential, pH value, osmolality, drug loading (DL)% and entrapment efficiency (EE)% of HK-SLEs were 186.6 +/- 1.7 nm, -35.65 +/- 0.67 mV, 7.22 +/- 0.26, 298 +/- 2.3 mOsm/L, 7.1 +/- 0.2% and 95.5 +/- 0.2%, respectively. HK-SLEs were stable for at least 12 months when stored at 4 +/- 2 degrees C. The pharmacokinetic results showed that the drug concentration-time curves of HK-SLEs and HK-SOL could both be described by an open two-compartment model. The half-life of HK-SLEs (t1/2(alpha) = 8.014 min, t1/2(beta) = 35.784 min) was remarkably prolonged compared to that of HK-SOL (t1/2(alpha) = 4.318 min, t1/2(beta) = 15.522 min). HK-SLEs exhibited a greater AUC and reduced plasma clearance. The tissue distribution results indicated that HK-SLEs have better targeting properties to lung and tumor tissues compared with those of HK-SOL. Both HK-SLEs and HK-SOL tended to accumulate in brain tissue. In vivo study showed that HK-SLEs treatment caused significant inhibition of mouse sarcoma S180 tumor growth compared to HK-SOL. These results suggest that HK-SLEs might be an effective parenteral carrier for honokiol delivery in cancer treatment.

Characterization, pharmacokinetics, tissue distribution and antitumor activity of honokiol submicron lipid emulsions in tumor-burdened mice.

Abstract: Since the 1970s, resource crisis, environmental pollution and ecological degradation have become prominent globally, and the limits to growth have always been an important theoretical and policy issue. The technological system of early warning and regulation based on carrying capacity evaluation has great potential in natural resource utilization, environmental management and ecosystem conservation. In this paper, the evolution of carrying capacity research and the concept of ecological carrying capacity are summarized, and the existing evaluation methods of ecological carrying capacity are classified into ecological footprint method, comprehensive index system method, ecosystem service analysis method and human appropriation of net primary productivity method. The current problems in ecological carrying capacity study were analyzed and the trend was outlooked. Combined with the special issue, the recent proceeding of ecological carrying capacity study in the Belt and Road Initiative (BRI) region was narrated, from the aspects of ecological carrying capacity evaluation method and application, the supply and consumption of ecosystem services, and the resources use and environment change. Some suggestions have been proposed to improve the accuracy and reliability of ecological carrying capacity evaluation: 1) the spatial heterogeneity and temporal dynamic change of ecological carrying capacity should be explored furtherly; 2) the interaction between ecological process and human activities should be simulated; 3) factors such as climate change, human activities and ecological products and ecological service flows should be integrated into the evaluation system of ecological carrying capacity.

Ecological Carrying Capacity and Green Development in the “Belt and Road” Initiative Region

Research of Canal Heritage Tourism Development Based on the Network Text and ASEB Grid Analysis -A Case Study of Qingming Bridge Scenic Area in Wuxi

中国の女性社会科学研究人材の学科と空間分化研究は2000年から2015年までの国家の社会基金プロジェクトに基づいている。【JST・京大機械翻訳】

Analysis of temporal and spatial evolution pattern of gas flow superiority in China

Differentiations of subject distribution and regional distribution of Chinese female social science talents: based on National Social Science Fund Projects 2000-2015

Abstract 
 This paper analyzed the development of different types of natural gas flow zones in China, and then divided all provinces into four flow types: non-flow zones, output centers, input centers and exchanging centers. Next, we analyzed the concentration and diffusion characteristics, current spatial pattern and evolution of source and terminal regions of natural gas resource flows. The numbers of non-flow zones, output centers, input centers and exchanging centers all stabilized during the Eleventh Five-Year Plan period. The number of output centers is small but the quantity of flow is large. The number of input centers is large and they are widely distributed. Generally speaking, it presents a significant characteristic of centralized output and dispersed input in geographic space. The current situation for China's natural gas output source has random distribution characteristics, but the terminal regions of natural gas flow have strong positive spatial correlation, presenting a significant spatial agglomeration pattern. Shandong, Jiangsu, Zhejiang and Shanghai have a high-high agglomeration mode, but Yunnan, Sichuan, Tibet, Qinghai and Gansu have a low-low agglomeration mode. Spatial pattern changes in China's natural gas output zones had three different stages: relatively stable from 2001–2003; moved northwestward, expanded in space, and widely dispersed during 2004–2006; and transferred to the east, spatially contracted and significantly concentrated during 2007–2011. Spatial pattern changes in China's natural gas input zones have two stages: expanded in east-west direction while contracted in north-south direction during 2001–2005; and relatively stable in spatial structure with intensification from 2006–2011.

Types, Concentration, Diffusion and Spatial Structure Evolution of Natural Gas Resource Flow in China

Abstract: 
 Eastern China's crude oil pipeline network is of the largest scale and freight volume in China. Here, we analyze 37 oil pipelines and one railway (38 oil flow channels), 20 oil fields with output of over a million tons of crude oil, and 32 refineries each of which refine over a million tons of crude oil. We construct a supply and demand balance sheet of oil sources and sinks by considering the transportation cost variance of variant pipeline diameters to determine the spatial optimization of Eastern China’s pipeline network. In 2009, the optimal cost of this network was 34.5% lower than the total actual cost, suggesting that oil flow is overall inefficient and there is huge potential to improve flow efficiency. Within Eastern China, the oil flow of the Northeast network was relatively better than others, but the flow in Northern China is inefficient because all pipelines are underload or noload, and there were similar conditions in the Huanghuai region. We assumed no difference in pipeline transport speed, compared to rail or road transportation, thus transportation distance, rather than time, is the main influential factor under the definite transporting cost of variant pipeline diameters.

The Spatial Optimization of Eastern China's Crude Oil Pipeline Network upon Cost Minimum

Along with the continuous development of China's economy,MICE tourism is waking into our life,which,as a new economic growth point,makes a great contribution to promoting the development of the local tourism as well as its economy.Nowadays,MICE tourism,with its high profit margins,attracts more and more cities.Without a doubt,as one of cities which have a slow development in the central area,Taiyuan is also attempting to seize the opportunity and make the most of local distinguishing feature to promote its economic development.This paper,based on the SWOT analysis method to analyze the advantages and disadvantages,chances and threats of the current development of MICE tourism in Taiyuan,puts forward a solution to the sustainable development of MICE tourism in Taiyuan in the future,by comparing with other typical cities in the central area which have a higher level of MICE tourism and caring out a deep research of the present situation of MICE tourism development in Taiyuan.

The SWOT Aanalysis of Situation and Solution of MICE Tourism in Taiyuan

This article from the electronic journal development and characteristics of carding,through the analysis of electronic magazine's advantage and predicament in the development of,and actively explore a way to promote its sustainable development,and puts forward some suggestions.

Discussion on the Sustainable Development of Electronic Magazine Industry

Resource flow has become a popular research perspective in the field of resource science. A variety of methods and empirical techniques are used in resource efficiency analysis, value accounting analysis of resources and the environment, energy saving and emission reduction, performance appraisal, and other areas of policy formulation and decision-making. Resource flow research is important, but there has been a lack of theoretical and systematic study of the concept. This paper summarizes research into resource flow and extracts authoritative literature from the Journal of Natural Resources and Resources Science. We then systematically summarize and comment on Chinese and international resource flow studies from overall development trends, theories, subject characteristics and research perspectives. We conclude that resource flow studies outside China are found in the material flow study field, which has a long history and is more complete. Chinese research commenced relatively late and awareness is growing. The main difference between resource flow research done within and outside China is that Chinese studies explicitly use the concept of resource flow, and carry out theoretical and empirical tests. Study on tourism resource flow and natural resource flow is the current hot topic. The Institute of Geographic Sciences and Natural Resources Research, Chinese Academy of Sciences is leading research into natural resource flow. The domestic focus has been on flow directions, theories and methods. There are insufficiencies in resource flow research that need to be addressed and these are discussed.

Abstract Chlorophyll-a concentration (Chla) is a key indicator of water quality, and accurate estimates of Chla using remote sensing data remain challenging in turbid waters. Previous research has demonstrated the feasibility of retrieving Chla in vegetation using spectral index, which may be the potential reference for Chla inversion in turbid waters. In this study, 106 hyperspectral indices, including vegetation, fluorescence, and trilateral indices, as well as combinations thereof, are calculated based on the in situ spectra data of 2004 to 2011 in Taihu Lake, China, to explore their potential use in turbid waters. The results show that the normal chlorophyll index (NCI) ( R 690 / R 550 − R 675 / R 700 ) / ( R 690 / R 550 + R 675 / R 700 ) is optimal for Chla estimation, with a determination coefficient ( R 2 ) of 0.92 and a root mean square error (RMSE) of 14.36     mg / m 3 for the data from July to August 2004, when Chla ranged from 7 to 192     mg / m 3 . Validation using the datasets of 2005, 2010, and 2011 shows that after reparameterization, the NCI model yields low RMSEs and is more robust than the three- and four-band algorithms. The results indicate that the NCI model can satisfactorily estimate Chla in multiple datasets without the need of additional band tuning.

Remote estimation of chlorophyll-a concentration in turbid water using a spectral index: a case study in Taihu Lake, China

Remote sensing estimation of Chlorophyll a and suspended sediment concentration in turbid water based on spectral separation

By the end of 2008,about 90% of China's crude oil transportation has been taken by pipeline,and it has been the primary way of China's crude oil flow.So that it is important to deeply analyze the spatial structure of China's national and regional crude oil pipeline networks.On the basis of a huge mass of reference materials,this paper examines three fractal dimensions,that is,weighted length-radius,dendrite-radius and spatial correlation,and then elaborates the influencing factors of this structure,including the distribution of networks' nodes and lines,the development of regional networks and others. In sum,the amended results reveal that:1) As to national networks,the weighted length-radius dimension is characterized as linear distribution in the east while scattered distribution in the west,which reflects that the networks tend to cluster and the networks' density has become lower from the east to the west.Similarly,the dendrite-radius dimension changes from scatters to linear distribution from the east to the west,reflecting the networks' structure gets complicated and the connectivity is improved accordingly.Differed from two dimensions above,the dimension of spatial correlation expresses the whole scattered distribution,which reflects the general low accessibility.The reasons are as follows.First,the trunk of pipeline networks in East China have relatively developed,contrasting with the networks in South China and West China.Second,there are evenly some isolated pipelines in East China's networks,which limit eastern networks' connectivity.Third,some nodes of national networks are not located at the trunk pipelines,resulting in general low accessibility. 2) As to regional networks,the overall distribution of density characteristics is similar to that of national networks,while the overall connectivity characteristic is different.Specifically,as to Xinjiang Region,its fractal dimension value of dendrite-radius is over 2,that is,its connectivity in the central part of the networks is lower than in the surrounding area,which is abnormal;the dimension value of dendrite-radius in Shanxi-Gansu-Ningxia networks is 1.216,reflecting its connectivity is relatively good,compared with less than one in East China and null value in South China.Furthermore,as to the accessibility,all regions' dimension values of spatial correlation are less than one,but the spatial correlation in East China tends to be in linear distribution.The reasons are as follows.First,the indirect oil transportation pattern of oilfield A-oilfield B-…-refineries in Xinjiang networks,increases the branches of networks,making it too complicated and limiting the connectivity of the networks.Second,the construction of pipeline networks in East China is lagging better than in other regions.Third,the construction of networks in South China is lagging behind other regions,thus its networks hasn't been shaping. 3) With the theory and methods of fractal,it could be effective to reflect the spatial structure and its distribution of China's crude oil pipeline networks.In the future,it is necessary to further analyze the harmony or correction between fractal feature of regional pipeline networks and regional oil production and consumption,then to reveal the interactive mechanism between them.

Research on Structure of China's Crude Oil Pipeline Networks Based upon Fractal Theory

With the appearance and the development of low-carbon conception,low-carbon tourism has become the common direction of tourism in the whole world.There is a large amount of direct energy consumption in the form of fossil fuels or indirect energy consumption in the form of electricity during the journey.In this paper,the methods of measuring carbon dioxide emissions from tourism are studied by consulting domestic and abroad relevant references.Through the literature studies,the researches of measuring tourist carbon emissions are divided into two broad categories: measuring carbon dioxide emissions of tourist industry and measuring carbon dioxide emissions of tourist destination,and then,the methods of the two categories have been summarized and analyzed with foreign research cases respectively.Measuring carbon dioxide emissions of tourist industry mostly construct frameworks based on the angle of industrial structure,which has two primary methods: empirical research and the measuring method based on TSA(tourism satellite account).And the studies of measuring carbon dioxide emissions from tourist destinations mostly based on the relationship among tourist origin areas、transportation and tourist destination,because we need to view a tourist destination as a whole unit which not only has traffic flow exchange with tourist origin areas but also with residential places for employees.Understanding these methods and their characteristics exactly will help us choose the suitable method for measuring carbon dioxide emissions from tourism.This article points out that the measurement of carbon dioxide emissions from Chinese tourism can be divided into three levels in geography: national carbon dioxide emissions,regional carbon dioxide emissions and carbon dioxide emissions from tourist destination.Moreover,it is very important to use different methods to measure the same object,so that the results of them can be confirmed and complemented by each other.The measuring results will provide information for policy-making and strategy of low-carbon tourism,and also will certainly to be able to promoting the development of low-carbon tourism.

THE METHOD OF MEASURING CARBON DIOXIDE EMISSIONS IN TOURISM ON THE BASIS OF LOW-CARBON TOURISM

Climate change is projected to have great impact on tourism in various ways;however,tourism also contributes to climate change through the carbon dioxide emissions from transport,accommodation and other tourist activities.Now low-carbon tourism is becoming a popular choice to protect the environment for tourists.A lot of people have already accepted the low-carbon conception,and more and more people like it.But there are still numerous hurdles on the road to really achieve the low-carbon goal in our travels,because there is a large amount of direct energy consumption in the form of fossil fuels or indirect energy consumption in the form of electricity during the whole journey.And this consumption directly leads to more emissions of carbon dioxide.According to international experience,measuring carbon dioxide emissions from tourism is a key step to developing low-carbon tourism.However,the study of low-carbon tourism in China is still in its initial stage. Under the background of global energy conservation and emissions reduction,this paper builds up a rational method for measuring carbon dioxide emissions from tourism according to the situation of Chinese tourism.This measurement is based on a better understanding of the conception of low carbon,and it can strip tourist energy consumptions away from energy consumptions by related industries by using "tourist consuming minus coefficient".Taking the Yangtze River Delta as an example,we attempt to measure carbon dioxide emissions from tourism of Jiangsu and Zhejiang provinces as well as Shanghai,and then compare and analyze the results of measurement. The results are shown as follows.In the present stage,carbon dioxide emissions from tourism present an increasing trend.Moreover,there is a positive correlation between carbon dioxide emissions from tourism and the gross income of tourism in the Yangtze River Delta.It should be noticed that the main part in the total amount of carbon dioxide emissions from tourism is closely associated with transportation,storage industry,post,and telecommunication services.Besides,the carbon-dioxide emissions from tourism closely associated with dining,accommodation and shopping cannot be ignored.In general,there is considerable conflict between the increase of tourism income and the development of low-carbon tourism,hence the transformation of the development way of current tourism is urgently needed.

Measuring carbon dioxide emissions from energy consumption by tourism in Yangtze River Delta

In the 21st century,Africa has been a strategic place for major oil importers seeking to diversify imports in order to achieve greater oil security,and also Africa has been the second biggest source for China,so that analyses of Africa's position shift in world oil supply pattern could help us to get a better understanding of Africa's advantages and disadvantages in the oil supply,in order to optimize China's strategy for oil cooperation with Africa.In this paper,boxplots and spatial cluster analysis are integrated,together with modified share and rank analysis,to examine and compare Africa's positions and their shift in the patterns of world oil proved reserves,oil production,reserves-to-production ratio,and exports.The results show that,Africa is the most concentrated area of oil supplying countries besides Middle East,and with the supersession of the old by the new,its overall supply position is relatively steady or even promoted;Africa's relative advantages in world oil supply pattern are its high reserves-to-production ratio and high export ratio,so that it is one of the key areas to provide sustained growth of oil production and export in the future;Africa has gradually penetrated the world's heartland of oil supply,and its oil geopolitical importance is enhanced greatly;in the long-term perspective,Africa will still be one of the major oil sources for China,and China should promote diverse strategies to Africa and enter Africa's core oil market,in order to enlarge supply,and achieve risk diversification.

The food production and development in Africa is faced with numerous difficulties and challenges,and African food problems have always been one of the hot concerns of the international community.This article is from the perspective of time and space for the evolution process of African food problems.The article has also held a preliminary discussion on the causes of African food problems.From the temporal perspective,researching from 1994 to 2007 year,this article focus on the evolutions of African food production, food consumption and the productive food gap;from the spatial perspective, between the global and regional levels,this article discusses different types of food self-sufficiency among African nations,and their spatial differences and evolutions.Finally this article has proposed some countermeasures and suggestions to solve African food issues.

Study on the Temporal and Spatial Evolution of African Food Problems

Historically,Nanking is the capital of six dynasties.Meanwhile,a lot of republic of China culture remains in it,and this republic of china buildings are at the core of the culture.Through the modern,we first of all may analyze the total travelling income of Nanking,and then according to the analysis,we think out some ways of increasing the travelling income. Secondly,combined with the current situation in which how the republic of china buildings is taken advantage of,we will explore the creative ways to increase the travelling income.Eventually,on one hand we augment travelling income;on the other hand,we give publicity to Nanking's local historical culture.

Analysis of the Use of Tourism Resources in the Republic of China Based on Nanjing Tourism Income Model

Based on the relative research of past researchers,the paper probes into the token sign system of cultural tourism attractions.According to the three levels theory of culture structure,it establishes the token symbol system of cultural tourism attractions,represents four different kinds of cultural token symbols as follows:historical culture,modern culture,folk culture and ethical culture.The paper raises up the way to avoid superficial recognization about destination culture.The way points out that both system cultural and spiritual cultural symbol systems are recognized as the "curtain" of a "stage",and the "stage" can show tourists "front" to "background".Different meaning and value of symbols fits for different social states,which is social choice mechanism.It is constructed according to the mainstream values of the society in order to meet the social and psychololgical orientation and tourists' interest.

Based on the Markov chain and the spatial autocorrelation analysis,it was investigated the spatio-temporal evolution characters of regional disparities of the Yangtze River Delta by analyzing per capita GDP data of 16 cities in the Yangtze River Delta during 1978-2007.By constructing the type of per capita GDP of the Markov transition probability matrix at the city level,it was concluded that the Yangtze River Delta areas existed obvious "club convergence" phenomenon in economic development,which trended toward low and middle income group and high-income group;By spatial autocorrelation analysis to investigate the spatial relationships between cities and their surrounding neighbors,it was found that regions and its neighbors had a positive relevance,and based on these recommendations,it was put forward for co-ordination of regional development strategies and strengthen the regional interactive mechanism so as to promote regional economy of the Yangtze River Delta to trend toward high-income convergence club.

Spatio-temporal evolution of regional economic disparities in the Yangtze River Delta since reform and opening-up

How to use the limited land resources is an important content of regional sustainable development. Taking Jinkouhe as an example, based on the analyzing of land use status and existed problems, the paper applies linear programming method to establish configuration optimizing model of land use according to the restriction qualifications of land area, population, macro planning and ecological protection. And the optimization result has good comprehensive benefits. The study show that using linear programming to allocate land resources can improve the rationality of analyzing, reduce the unnecessary disturbance and provide scientific reference to new general planning of land use.

Guided with the rent theory and spaces demand curve and using GIS,this article analyzes the relationship between the spatial distribution of large supermarket and land price,transportation and population density in Nanjing,and discusses the features and reasons of supermarket spatial distribution.The conclusions are as follows:first,most supermarkets are located the second level of commercial center.Second,most supermarkets are perched on both sides of main roads and traffic nodes which have convenient transportation.Then,supermarkets run to the large residential area rather than core area which is densely populated.Finally,by the buffer of service radius of supermarkets at GIS,the service radius of supermarkets in Nanjing is about 700m,and supermarkets are so densely that the competition is too intense.

To deal with the challenges that face the energy sustainable development in Jiangsu Province,this paper aimed at ensuring balanced supply and demand of energy and coordinating energy-economy-environment system,focused on energy structure optimization,energy supply system optimization and promotion of energy conversion efficiency and its cleanability,and took full utilization of advantages for energy development in various locations in Jiangsu as the main thread,so as to extract basic patterns of energy sustainable development in Jiangsu,which consisted of optimal exploitation pattern of own resources and the exploitation pattern of imported resources.The optimal exploitation pattern of own resources can be subdivided into three sub-patterns,that is,Xuzhou Coal Industrial Complex,North Jiangsu Oil Industry Base and Coastal Mudflat Renewable Energy Base;the exploitation pattern of imported resources can be also subdivided into three sub-patterns,that is,Yangtze Electricity Industry Base,South Jiangsu Load Center and Coastal Port Energy Base.Such energy sustainable development patterns coordinate with each other,which helps enhance Jiangsu's ability to achieve energy sustainable development.

RESEARCH ON ENERGY SUSTAINABLE DEVELOPMENT PATTERNS IN JIANGSU PROVINCE

The scientific outlook on development is intrinsically related to Deng Xiaoping's overall development thought in many ways,Article from "the overall development of economy and society、the "human centered" and the "overall consideration" three aspects argues for that the scientific outlook on development is the inheritance and development of Deng Xiaoping's overall development thought.

On Deng Xiaoping's Overall Development Thought and the Scientific Outlook on Development

This study takes crude oil flow in China as the research subjects,and takes provincial-level administrative units as the nodes of crude oil flow.Meanwhile,selecting five typical years in 1985-2007 as the time points for research and with Zipf law,this paper discusses the rank-size distribution variation of input and output flow of crude oil in China.Some results are obtained as follows.(1) The rank-size distributions of input and output flow is consistent with Zipf law in the five typical years.(2) The non-scaling range of the output flow varies very little,while the one of input flow is narrowed at first and then enlarged gradually.(3) As to the spatial fractal structure,the output flow has no segmentation in its non-scaling range,and appears as a single fractal all along.However,the input flow experiences a process from double fractals to single fractal.(4) There are differences between the spatial distribution pattern of input flow and output flow.The one of input flow changed from lognormal distribution in 1985 to Pareto distribution in 1995,then lognormal distribution again in 1999,and it finally became Pareto distribution in 2003 and 2007.Meanwhile,the spatial distribution pattern of output flow maintains Pareto distribution.(5) Generally,the variations of output flow and input flow are not synchronous,which is closely related to the spatial distribution of huge oil fields,the distribution of petrochemical industries,the oil distribution system and so on in China.

Study on the rank-size distribution and variation of crude oil flow in China

This paper aims to analyze the status and the progress of low-carbon tourism through literature stud-ies.The result shows that,firstly,domestic low-carbon tourism researches are still in the primary stage at pre-sent,so there is little relevant references which is mostly news reports.Moreover,domestic studies usually are adopted qualitative approach to conduct researches on low-carbon tourism in macro view and focus on the way of realization.Secondly,compared with domestic researches of low-carbon tourism,foreign researches are relatively abundant.Many developed countries are keeping close watch on low-carbon tourism develop-ment,and official statistics are full and accurate.Using questionnaire survey,interviews,constructing models and other research methods,researchers can collect a series of information that not exist in official database.The differences between domestic researches and foreign researches are that foreign studies focus on measur-ing carbon emissions of tourism sectors,tourist destinations and tourist activities.In addition,some studies analyzing the influence of tourist carbon emissions on climate by empirical research,top-down analysis and bottom-up analysis.Finally,based on the examining of research progress,contents and methods of low-car-bon tourism,the authors conclude that low-carbon tourism development not only needs to rely on itself,but also needs rely on many related industries and sectors.Therefore,this paper argues that the future develop-ment in low-carbon tourism in China should be depending on close cooperation of the government,organiza-tions,enterprises and departments.So,the related supports of policy,economy,and technology are needed,and the joint efforts of the government,the tourism industry and the tourists are also needed.It is important to strengthen the function of the government in guiding a healthy development of low-carbon tourism.Tourist department also should establish a scientific and rational effective system of low-carbon estimation,and in this way,'low-carbon' scenic spots will be established.Also,the authors point out that low-carbon tourism developing experience in China is very limited.So,the international communication and cooperation to explore a suitable mode for China's national conditions should be paid more attention to.

A STUDY ON PROGRESS OF DOMESTIC AND OVERSEAS LOW-CARBON TOURISM AND ITS ENLIGHTMENT

Taking proved oil reserves as indicator,this paper analyzes the spatial distribution pattern of global oil resources and its evolution in 1980-2009.According to the staged increase trend of global proved oil reserves during 1980-2009,the evolution process can be divided into five stages,and their characteristic time points could be selected correspondingly;then,the spatial rank distribution pattern and spatial organization of global oil resources at each time point can be discussed based on the function of spatial classification and visualization of ArcView GIS.The results are as follows.1) The overall spatial distribution pattern of global oil resources can be characterized as irregular multi-centric layer structures,thereinto,Persian Gulf oil region and Mexico Gulf-Caribbean Sea oil regions are the two global oil poles in the Eastern and Western Hemispheres respectively,and their central roles were increasingly strengthened,while the other local oil regions,such as North American continent oil region,Caspian Sea oil region,Eurasia oil region,North Africa oil region,West Africa oil region,North Sea oil region and Java Sea oil region,experience different growth patterns.2) The evolution of global distribution of oil resources is characterized as rise in the East and fall in the West,and the overall distribution pattern experienced an evolution process of diversification during 1980-1985,centralization during 1986-1990,re-diversification during 1991-1997,re-centralization during 1998-2001,and diversification again during 2002-2009,which eventually results in centralization in the North and diversification in the South.3) The distribution space of oil resources in Western Hemisphere splited gradually into two layer structures with Venezuela and Canada as their reserve centers respectively,while four oil regions of North Africa,Persian Gulf,Caspian Sea and Eurasia lying through the mid-Eastern Hemisphere have been spatially joining together to form a huge crescent-like oil reserve belt,which could extend southward from Far East in the future.

Spatial Distribution Pattern of Global Oil Resources and Its Evolution

Appraisaling the land-use change degree of urban land objectively, analyzing the reasons, and proposing the countermeasures have important meanings to promote land sustainable development. The article analyzed the dynamic change of land-use ecological footprint in Harbin City from 1996 to 2006. Through the measurement of ecological footprint to assess the social impact and the extent of sustainable land-use. The results showed that the per capita ecological footprint in Harbin had increased year by year, while the per capita ecological carrying capacity had decreased, the per capita ecological deficit was increasing, and land-use in Harbin City was in an overload status. Finally, reasonable land-use proposals were proposed.

Land-use Change and Ecological Footprint Analysis of Harbin City

At present,there have been relatively serious environmental problems caused by energy consumption in Jiangsu province,which obstructs the socio-economic sustainable development in Jiangsu,so that it is important to evaluate quantitatively the environment situation and environmental capacity for energy consumption.Therefore,at the beginning of this paper,energy ecological footprint is defined according to the definition of Ecological Footprint,which is used to evaluate the regional or global capacity for energy consumption quantitatively.After that,the paper evaluated Jiangsu′s energy ecological footprint from 1985 to 2006,and then analyzed the principal influencing factors of energy ecological footprint for each year with coefficient of elasticity.(1) Upon calculating the energy ecological footprint of Jiangsu with input-output analysis and carbon sequestration method,the paper shows that there was average annual 10% growth of energy ecological footprint in Jiangsu from 1985 to 2006.Meanwhile,the main part of energy ecological footprint was the energy consuming ecological footprint,which contributed 97.5% of the average annual growth of energy ecological footprint.(2)After comparing the analyzing results of some statistical methods,such as multiple correlation analysis and multiple linear regression analysis,etc,we find that the coefficient elasticity method was more suitable for analyzing the influencing factors of Jiangsu′s energy ecological footprint.However,the forecasting analysis of the influencing factors remains to be further studied.Furthermore,we may try to continue in-deep study of influencing factors analysis of energy ecological footprint with other methods.(3) There is a strong direct relationship between the evolution of energy ecological footprint and socio-economic development pattern of Jiangsu.During 1985—2003,there were three periods with different principal influencing factors,that is,variable-factors-driven period(1985—1995),land-factor-driven period(1996—2000) and population-factor-driven period(2001—2003).After 2003,as a result of rebound of secondary industry development,the proportion of secondary industry has been the primary influencing factor that enlarges energy ecological footprint in Jiangsu.Meanwhile,energy ecological footprint has expanded because of the acceleration of urbanization(50% in 2005) as the secondary factors,and the declining of energy efficiency(energy saving rate per unit GDP has increased from 0.78 to 0.89 tce / ten thousand Yuan) has also resulted in the growth of energy ecological footprint.(4)Jiangsu has just started to coordinate the ecological sustainable development and the rapidly socio-economic development.Though there was a decline in the growth of coal,crude oil and other energy consumption,energy ecological footprint was rapidly increasing during 1985—2006.This was because people neglected other factors(except energy itself) that raise energy ecological footprint,and this was mainly caused by social and economic development,e.g.the increase of proportion of secondary industry,the rapidly reducing of total area under cultivation and so on.(5) Due to the difficulty of data acquisition,the paper only calculated the energy ecological footprint,but failed to measure the energy ecological carrying capacity.Thus we did not figure out the ecological deficit in Jiangsu from 1985 to 2006,which is also to be further studied besides the better way to analyze influencing factors of Jiangsu′s energy ecological footprint.

Influencing factors' analysis of Jiangsu's energy ecological footprint upon coefficient elasticity

Actually, tourism development can not only bring forth lots of negative impacts on economy, socio-culture and environment, but also damage the legal rights and interests of host community residents to different extents. It is common for the legal rights and interests of rural residents in and near tourist destinations of China to be damaged due to tourism development. But so far, this kind of negative impact has rarely been addressed in the light of law. Since 1990s, Chinese scholars have focused on two kinds of issues of right and interest damage. One is caused by land exploitation near urban areas, and the other is from off-farm workers. The issue, caused by tourism development, of rights and interests damage of rural residents in and near tourist destinations is almost a blind area in the light of either tourism or law research society. Strengthening its studies can promote the theoretical study on tourism impacts, and also will be of great realistic significance in solving the issues in host destinations concerning the so-called three-nong problems, namely agriculture, countryside and farmers. With Zhangjiang National Park as a case, the paper aims to examine the legal right and interest that rural residents have in tourism development. Meanwhile, it attempts to unveil some common rights and interests damages by tourism development. The paper argues that host community residents should have diverse political, personal, economic, socio-cultural rights, and the legal rights and interests of local residents are damaged owing to various factors, including land exploitation, resident displacement, touism pollution, and unfair distribution of tourism interests as well.

ANALYSIS ON TOURISM DEVELOPMENT AT NATIONAL PARK AND ITS DAMAGE TO THE RIGHTS AND INTERESTS OF RURAL COMMUNITY RESIDENTS——A Case Study of Zhangjiang National Park,Guizhou

Based on the panel data of five departments in Jiangsu during the period from 1990 to 2007,this paper calculates the theoretical amount of energy consuming,technology efficiency(TE) and total-fact energy efficiency(TFEE) with the model of DEA(Data Envelopment Analysis) in terms of CRS(Constant Returns to Scale).Meanwhile,this paper analyses Changes and Influencing Factors of TFEE in Jiangsu with measurement of Pearson's correlation coefficient and combination of explanation of Hoffman's Index and other factors.The main conclusions of the paper are as follows: Since 1990,TE has been the primary factor of promoting TFEE and scale efficiency has been having more negative impact on TFEE.As to the department,the manufacturing is the main hamper of TFEE in Jiangsu from 1990 to 2007.

An Analysis on Changes and Influencing Factors of Total-factor Energy Efficiency in Jiangsu

The characters of land use in Jinkouhe Area were analyzed and rationality of land use were diagnosed through quantitative geography and landscape ecology,The results showed that there were obvious difference in land distribution,quantitative structural,landscape pattern and utilization level in the interior of region according to the nature and economic condition.Based on the problems of land use,some countermeasures and suggestions were put forward.

The land along railway route is an important source area of passengers.The land use structure and intensity along railway route will influence both the volume and stability of passengers.This paper analyses the rationality of city railway planning,taking the impact of land use to passenger volume and its stability as criterion.The study area is divided into 14 parts of zones which the railway passes through.GIS data is used to analyses the rationality of railway planning of the city. Two categories of indicators are used in the process of analysis.One is related to land use structure including landscape diversity index,dominance index and the contagion index;the other is used to describe the land use intensity including population density,structure density and floor area ratio.According to the urban land use classification system,the land use along Dongguan city railway route can be classified into 13 categories and 26 sub-categories,that is,residential land,commercial land,industrial land,land for storage,transportation,road and square,public green space,specially used land,agricultural land,water area,open space and hill land.The Fragstats 3.3 is used to analyze landscape indices. Based on the analysis,it is concluded that land use along the railway route is intent to a high diversity,and the structure and intensity of local land use suitable for the operation of transit.The land of the study area can steadily provide large amount of passengers for the city railway transport in the future and the planning of the Dongguan city railway route has a higher rationality.Some part of the railway transit,i.e.Guancheng,Nancheng,Houjie,Chang'an and Dongcheng are planned more rationally.As for Mayong and Daojiao,because of their low landscape diversity,population density,structure density and occupied by a large proportion of agricultural land and water area,the rationality of the planning is relatively lower.Some indices especially the land use intensity indices are favorable to the operation of the transit,but they are with uncertainty for building of the transit due to great amount of compensation to the residents and the land owners living in the buffer.So we should dialectically understand the value of the indices.

Rationality of City Railway Planning Based on Land Use:A Case Study in Dongguan City,PRC

The scientific development conception is a kind of advanced regional development conception,which is the amalgamation of coordination thought of man-land,systematic science thought and the sustainable development thought,and it leads the regional development theory to evolve to "comprehensive integration methodology".This paper,with the guidance of scientific development conception and comprehensive integration methodology,in the background that the regional development emphases of the Yangtse Delta sets in the riverside areas,analyses the resources character,the structure of industry and the development stage,and then constructs the sustainable development system of Nanjing riverside area,which is the demonstration of the sustainable development of Yangtse Delta area.This system integrates elements of economy,society,ecosystem,human and its wisdom into a whole,and its main frame contains four subsystems that is Objective Subsystem,CPU Subsystem,Supporting Subsystem and Restriction Subsystem..(1) Objective Subsystem is the layout of regional development,and is the aim and command of the regional development.(2) CPU Subsystem is the main performance system,and in it,the concerted exploitation of resources is the main thread of the regional development,the concerted upgrade of industry structure is the nuclear part,and the concerted optimization of spatial structure is the base and coordinator of the former two.(3) Supporting Subsystem is the construction system of regional development environment,and it has the support and mutual promotion to CPU Subsystem.(4) Restriction Subsystem is the monitor and harmonizing system,and it provide limit,assurance and promotion to the former three.These four subsystems function with the feedback mechanism.Furthermore,this paper expatiates on the detail construction items and the function flow of the sustainable development system of Nanjing riverside area.

CONSTRUCTION OF REGIONAL SUSTAINABLE DEVELOPMENT SYSTEM OF YANGTSE DELTA ——A Case Study of Nanjing Riverside Area

Scientific research is one of the bases on which a university fulfill its social service functions. The industrial function of a university is mainly symbolized by the transformation of its fruits of scientific research into the productivity of enterprises. A university science park, different from a high_tech development zone, is expected to focus on its incubator function. That is, besides promoting the transformation of science and technology into productivity and fulfilling the industrial function of a university, the park is supposed to stimulate the development of scientific research and the interaction among industry, education, and research of the university.

A Discussion on the Development Pattern of University science park ——Incubator or Industry?

Based on the survey of land desertification and its damage in Jinta County,Gansu Province,this article gives a detailed analysis on the development causes of desertification in the region.The systematic control and reconstruction strategies are formulated for the sake of the environmental treatment in the Heihe River Catchment.

Problems and Countermeasures for Land Desertification In Jinta County

Starting with the traditional energy system, this thesis expounds the essentiality to acquire the large energy system outlook in the case of the sharper contradiction with resources environment and development. The authors point out that in the sustainable energy system, economic factor,ecological factor and so on are no longer external environment of energy system, but are the component parts of the system. Then the objective,the principle and the overall strategy of the sustainable energy development are discussed.

ACQUIRING THE LARGE ENERGY SYSTEM OUTLOOK AND PROMOTING SUSTAINABLE DEVELOPMENT OF ENERGY

Since the latter half of 1996,the contradiction between energy supply and demand in China has been moderating. The contents of energy development strategy have been changing from showing concern for balance between supply and demand of energy system to showing concern for the coordinative development among energy social-economy and environment. Taking Jiangsu Province for example,this thesis builds the multiobjective decision model in coordinative development among energy social-economy and environment.This model provides a useful decision method for the policymaker. The calculation shows as follows: (1)From the economic benefit point of view,nuclear power generation and wind power generation aren't able to compete with fossil fuel power generation in short term,because of the comparatively large investment in the early period of construction.In 2005,coal will stillmake up 72% of energy consumption in Jiangsu.Since then,the in crease of coal consumption will be tending to tardy along with the in crease of the expenses of preventing pollution and pollution emission limit.It is essential to lay equal stress on coal,oil and natural gas?and nuclear energy in the energy structure of Jiangsu Proince in 2020. (2)Coal still occupies an important place in energy consumption in Jiangsu.It not only tallies with the characteristics of energy resources in China, but also is economical. The key is to lay stress on developing domestic large-typed fossil fuel power plant and clean coal technologies. (3)After the year of 2005, oil and gas will increase in rapid speed. In view of limited oil and gas resources in Jiangsu and limited average resources per capita in our country, it is necessary to expand imports of oil and gas, and to develop the outward oriented energy economy based on making full use of domestic or international resources and markets. (4)Nuclear power will play an important role in promoting the coordinative developemtn among energy social-economy and environment in Jiangsu. Jiangsu possesses developed economy and technology,and has an advantage in developing nuclear power stations. But the developing speed is not at all quick. One of the nost important reasons is to worry about safety, because Jiangsu has a large population,average 700 people per square kilometre. In fact the safety of nuclear power station is indubitable. Jiangsu should unswervingly develop nuclear power generation.While constructing Tianwan nuclear power station in Lianyuangang,the second and the third phases of the project should be started as quickly as possible. (5)Jiangsu has comparatively rich wind energy resources. But their utilization is still in the olwer degree.In China wind power generation has been main attack direction of developing new energy.Jiangsu should grab at this opportunity to quicken the tempo of construction of the large and middle-sized wind power stations.

Multi-Objective Decision in Coordinative Development among Energy Social-Economy and Environment——A case study of Jiangsu Province

The paper analyses the current situation and existing problem of energy supply and demand in Jiangsu Province.Based on the principle of sustainable development,the energy policy of energy development and conservation,substitution,energy structure adjustment and optimization,reducing energy consumption and increasing energy utilization efficiency should be carried out in Jiangsu Province to realize the sustainable development of energy,social economy and environment.

On the basis of the analysis of energy development strategies in different kinds of countries, this paper obtains the useful inspirations to Jingsu:1)Resource diversity is the starting point of energy strategy. 2)Making energy structure high-quality by fully utilizing the domestic resources and the resources abroad is the core of energy strategy. 3)Establishing the resources-thrift type of national economic system and mode of consume is an important component part of energy strategy. 4)Realizing the coordinate development among resource、economy and environment is the target of energy strategy.

THE ENERGY DEVELOPMENT STRATEGY IN THE WORLD AND ITS INSPIRATIONS TO JIANGSU

Starting with the significance to enforce famous brand strategy, this paper analyses superior conditions of the North Lake Scenic Area in Zhenjiang. Then taking it for example, the paper expounds emphatically the building principle of tourist famous brand strategy.

On Famous Brand Strategy in Exploit and Construction of Tourist Area —A Case Study of the North Lake Scenic Area in Zhenjiang

The emergence of global environmental problems has close links with energy exploitation. The effects of energy exploitation to global environmental problems are systematically analyzed in this thesis, such as global climate change, acid rain and atmospheric pollution, and marine pollution. Then the author points out: in order to realize the sustainable energy development, it is imperative to coordinate energy exploitation with environment. Protecting environment should be an important component part of energy strategy.

Stereoelectroencephalography-guided radiofrequency thermocoagulation of epileptic foci in the eloquent motor cortex: feasibility, safety and efficacy.

Clinica chimica acta; international journal of clinical chemistry

Prognostic significance of serum annexin A7 in severe traumatic brain injury: a prospective longitudinal cohort study.

Correlation of tenascin-C concentrations in serum with outcome of traumatic brain injury in humans.

Granulomatous hypophysitis: experience with eight surgical cases of a single center

Objective 
To determine the dynamic change of serum procalcitonin (PCT) level after traumatic brain injury and the related clinical significance. 
 
Methods 
Serum levels of PCT and adrenocorticotropic hormone (ATCH) in 137 patients with traumatic brain injury and 20 normal volunteers were measured by electrochemiluminescence assay. Correlation between serum PCT level and severity of traumatic brain injury was evaluated. 
 
Results 
Percentage of serum PCT level at low inflammatory-risk threshold detected from day 1 to day 14 after admission was descended from 80.3% to 63.5%. Meanwhile, the percentage of serum PCT level at high inflammatory-risk threshold was a rising-fall-rising trend, but the percentages of serum PCT level at median and definite inflammatory-risk thresholds showed sustained increase from 13.9% to 27.0% and 0.7% to 3.7% separately. Based on the Glasgow Coma Scale (GCS), the dynamic change of serum PCT level demonstrated a distinct bimodal pattern in severe injury group, a gradual falling after rising mode in middle injury group which was significantly and positively correlated with GCS (r=0.463, P<0.05), and a rising-falling-slight rising tendency in minor injury group. In addition, the GCS in each group only closely related to the positive detections of serum PCT level detected at days 3 and 7 (χ2=10.32, 16.31 respectively P<0.01). Serum ATCH level at day 1 was far higher than that at day 14 in severe injury group and was significantly higher in severe injury group compared with minor and middle injury groups (P<0.01 or 0.05). 
 
Positive serum PCT may be predictive of the traumatic brain injury and injury degree within 3-7 days after the injury. The dynamic change of serum PCT is associated with the specialized mechanism of traumatic brain injury and neuronendocrine response, and it may be a useful parameter to assess posttraumatic stress response and prognosis. 
 
Key words: 
Brain injuries; Prognosis; Procalcitonin

Changes of serum procalcitonin level and its significance in patients with traumatic brain injury

Meningiomas are typically benign tumors, and the papillary variant of meningioma with cyst formation is extremely rare. Here, we describe a female patient with cystic papillary meningioma in the left parietal area with cystic recurrence, brain invasion, and extracranial metastasis after gross total surgical resection and postoperative radiotherapy (RT). The solid metastatic lesion was located in the extradural mater and infiltrated into the skull. Considering the severe malignancy of this disease, gross total resection including removal of the cystic wall and adjuvant postoperative RT were deemed necessary. This is a first report of a cystic papillary meningioma with a local cystic recurrence and contemporary extracranial metastasis after gross total surgical resection and postoperative RT. Cyst formation mechanism, correlation with recurrence rates, and treatment modalities are discussed.

Cystic Papillary Meningioma Recurrence With Extracranial Metastasis After Surgery and Postoperative Radiotherapy: A Case Report

Objective To investigate the diagnosis and management of granulomatous hypophysitis.Methods Seven patients with granulomatoushypophysitis were retrospectively analyzed with their signs and symptoms,radiological characteristics,diagnosis,and treatments.Results In the seven cases,six cases were misdiagnosed before operations.The clinical signs were headaches,diabetes inspidus,hyperprolactinemia,and hypopituitarism.Pituitary stalk thickening is a prominent image feature and is associated with the tongue-like extension of the sellar lesion into the suprasellar region.Surgery via the transsphenoidal route was performed on six cases and the transfrontal approach was chosen for one patient due to the additional diagnosis of onabscess preoperatively.Most of the patients had remission of clinical symptoms and signs after surgery with steroids and hormones replacement and lesions were reduced or even disappeared on MRI images.Conclusions Surgical intervention should be performed because it is difficult to make correct pathological diagnosis of granulomatous hypophysitis preoperatively and may improve symptoms and signs.Steroids and hormones replacement should be administrated after surgery and patients should be followed-up because of the natural course of the disorder. 
 
Key words: 
Granulomatous hypophysitis ;  Diabetes inspidus ;  Hyperprolactinemia; Hypopituitarism;  Treatment

Rapid local recurrence of an extraventricular neurocytoma that had disappeared after gamma knife radiosurgery.

The research and development of powered exoskeletons is expected to support the walking of paraplegic patients. At the current stage, exoskeletons do not allow patients to voluntarily control their gait, nor do they provide sensory feedback to compensate for the loss of lower-body sensation. This paper proposes a wearable walking control interface to achieve voluntary gait control, and an electrical stimulation method to inform the patients about their foot position for voluntary gait control. In this study, a walking robot that simulated a paraplegic patient wearing an exoskeleton was used to investigate the performance of the proposed interface and stimulation method. We confirmed that, by using the interface, the subjects were able to control the robot gait for a distance of 3 m. Moreover, the accuracy of the electrical stimulation feedback was confirmed to approximate the visual feedback achieved through the human eyes. The experimental results revealed that the proposed interface and electrical stimulation feedback could be applied to a walking support system for patients with complete paraplegia.

Precise Foot Positioning of Walking Robot for Paraplegic Patient Wearing Exoskeleton by Using Electrical Stimulation Feedback

Electric stimulation and cooperative control for paraplegic patient wearing an exoskeleton

When a paraplegic patient walks with the aid of an exoskeleton, the patient can only follow the preset walking trajectory and cannot receive any lower limb sensory feedback. This paper firstly proposes an index finger interface that allows a paraplegic patient to control the walking trajectory through an index finger voluntarily. The proposed interface consists of two rotatable links and one ring, and the interface is installed in the front of a crutch handle. The user controls the foot position of the foot position via a ring while keeping the balance with the crutch. On this basis, this paper also proposes an electrical stimulation feedback pattern that conveys the foot position to the user to assist the walking control. The electrical stimulation device contains 20 stimulation points that correspond to the spatial position. The electrical stimulus presents the foot position by switching the stimulation frequency and the stimulation position. For safety reasons, we conducted a preliminary study of the interface and feedback model with a healthy subject and a walking robot. We validated the effectiveness of the index finger interface and the electrical stimulation pattern through three experiments:1)pseudo-trajectory recognition under electrical stimulation feedback condition, 2) robot walking control under visual feedback condition, and 3) robot walking control under electrical stimulation feedback condition.

2017 IEEE-RAS 17th International Conference on Humanoid Robotics (Humanoids)

Electrical stimulation feedback for gait control of walking simulator

Through analysis of the kinematics model of soccer robot,with time change,nonlinear and other characteristics of this system in consideration,a control method combining fuzzy control with traditional PID control is presented.To solve the problems of robot soccer motion system,the methods of dynamically regulate the three PID parameters(kp,ki,kd) based on fuzzy control is proposed.The improvement of control effect is verified by experimental result.

Motion Control of Omni-directional Robot Based on Fuzzy PID Control

How to eliminate the surplus torque of a loading system is one of the key problems to design a load simulator. Based on the learning characteristic of neural network and the function approximation ability of the wavelet, a hybrid control based on wavelet networks was proposed. The application results in the unmanned aerial vehicle load simulator show that the proposed controller can effectively eliminate the surplus torque and fairly improve the dynamic loading performances of the loading simulator. In addition, the results show that the proposed controller belongs to the fine robustness for unknown external loading disturbances.

Proceedings of the 2003 International Conference on Machine Learning and Cybernetics (IEEE Cat. No.03EX693)

Hybrid control of load simulator for unmanned aerial vehicle based on wavelet networks

Composition of phenolic compounds in wastewater from the fixed-bed gasification of Baishihu coal

Magnetic Solid-Phase Extraction Followed by HPLC–DAD for Highly Sensitive Determination of Phthalate Esters in Edible Vegetable Oils

Effects of nickel additives with different anions on the structure and pyrolysis behavior of Hefeng coal

Study on extraction phenol from coal tar with high flux centrifugal extractor

A subbitumious coal from Erdos, Inner Mongolia, China, was extracted with isometric carbon disulfide/tetrahydrofuran (CS2/THF) mixed solvent. The components and structure features of CS2/THF soluble factions were analyzed by FTIR and GC/MS. The results show that the total extract yield was 6.6% after five extractions with fresh mixed solvent. And the mass fraction of the first extract was biggest which the 68% amount of the total extracts was. The FTIR spectra of the extracts had abundance functional group information, which can fully indicate that the extracts contain aliphatic compounds, aromatic compounds and heteroatom-containing compounds. Only the first extract can be detected by GC/MS among the five extracts and seven compounds were detected by GC/MS clearly and they are aromatic compounds, in which the three larger relative abundance compounds are retene, 7-butyl-1-hexylnaphthalene and 7-isopropyl-1,1-dimethyl-1,2,3,4-tetrahydro- phenanthrene.

Analysis of Soluble Fraction with Carbon Disulfide/tetrahydrofuran of Erdos Coal by FTIR and GC/MS

OBJECTIVE
To optimize the extraction process of compund kaliziran gel.

METHOD
Orthogonal design was used to optimize the extracting process of eight herb medicines with the extract yield, the content of psoralen, isopsoralen and osthole as indexes, and to optimize the extracting process of Polygonum multflorumi and Seman sinapis albae with the extract yield and the content of 2,3,5,4'-tetrehydroxy-stilbene glucoside as indexes.

RESULT
The optimum extraction progress was as follows:eight herb medicines were extract 2 times for 1 hour with 8 times of 60% alcohol; P. multflorumi and S. sinapis albae were extract 2 times for 1 hour with 8 times of 40% alcohol.

The optimum extraction processes are stable and feasible.

[Optimization of extraction process for compund kaliziran gel with orthogonal design].

The aromatic substances in the fruit of Luofu,Hoangxia,Changjun and Yipinxiang cultivars,belonging to Chaenomeles speciosa were determined by using headspace solid phase microextraction and GC-MS.Differences among 4 cultivars were studied.The results showed that 121 kinds of substances were detected,57 kinds in Luofu,55 kinds in Hongxia,43 kinds in Changjun and 50 kinds in Yipinxiang.The main substances in Luofu and Changjun were aldehydes and alcohols such as E-2-Hexenal,trans-2,4-hexadienal,2,4-Hexadien-1-ol,Z-3-hexen-1-ol.,the relative content of which was 40.63%,44.54% and 36.76%,43.03%.The main substances in Hongxia and Yipinxiang were the esters and aldehydes such as ethyl acetate,hexanoic acid,ethyl ester,butanoic acid,ethyl ester and E-2-hexenal,the relative content were 69.98%,52.62%,14.23% and 21.97%.

GC-MS analysis of aromatic components in different Chaenomeles cultivars in Yizhou

ABSTRACT A disintegrin and a metalloprotease (ADAM)9 upregulated within human hepatocellular carcinoma (HCC) cells, but its effect on HCC radiosensitivity remains unknown. The present work aimed to examine the effect of ADAM9 on HCC radiosensitivity and to reveal its possible mechanism, which may be helpful in identifying a potential therapeutic strategy. Changes in ADAM9 expression after X-ray irradiation were identified using western blot, qRT-PCR, and immunofluorescence. ADAM9 stable knockdown and overexpression cell lines were constructed using lentivirus packaging. The radiosensitivity of HCC cells with altered ADAM9 expression was examined by CCK-8 assays, subcutaneous tumorigenesis experiments, and clone formation assays. This study also determined how autophagy affected HCC cell radiosensitivity. Furthermore, ADAM9, p62 and Bax expressions in HCC tissues that were removed after radiotherapy were detected by immunohistochemistry, and the relationship among the levels of these molecules was statistically analyzed. The level of ADAM9expression in HCC cells increased after X-ray irradiation. Through CCK-8 assays, subcutaneous tumorigenesis experiments, and clone formation assays, this work discovered the increased MHCC97H cell radiosensitivity after ADAM9 knockdown, and the radiosensitivity of Huh7 cells decreased after the overexpression of ADAM9. Furthermore, ADAM9 induced HCC cell autophagy via downregulating Nrf2 expression, while autophagy inhibition or induction reversed the effects of altered ADAM9 expression on radiosensitivity. Moreover, ADAM9 level showed a negative correlation with Bax and p62 expression within HCC tissues after radiotherapy. Taken together, ADAM9 decreased the radiosensitivity of HCC cells, and autophagy mediated this process.

Overexpression of ADAM9 decreases radiosensitivity of hepatocellular carcinoma cell by activating autophagy

 Background: To improve the conversion efficiency between single-lung and double-lung ventilation after Double-lumen tube(DLT) intubation, we invented a Y-shaped rotatable adjustment between three-lumen tube and double-lumen tube connector (YRC). The performance of YRC was studied with the traditional Y-shaped reconnector (YC) as the control. Methods: A total of 60 adult patients who underwent thoracic surgery with double-lumen endotracheal tube insertion were included in the study. The subjects after endotracheal tube insertion were randomly divided into two groups: YRC connecting group (YRC group, n=30) and a traditional connector connecting group (YC group, n=30), respectively. Primary endpoints were intubation time and conversion time of single-lung ventilation to double-lung ventilation. The secondary endpoints of this study were the internal gas volume of the two joints, airway pressure, and the time required for sputum aspiration during the operation. Results: Intubation time in YRC group was shorter than that in YC group (89.75±14.28s vs 107.80±14.96s, p=0.00). Compared with the YC group, the time required for ventilation conversion between single-lung and double-lung ventilation during the operation in the YRC group were significantly shortened (3.60±1.20svs9.05±2.53s, p=0.00). The internal gas volume in YRC (17.20ml) is smaller than YC (24.12ml). There was no statistical difference in airway pressure and the time required for sputum aspiration between YRC group and YC group (P > 0.05). Conclusion: Compared with the traditional connectors, the YRC can improve the conversion efficiency between single-lung ventilation and double-lung ventilation with double-lumen endotracheal tube, save positioning time, and can be safely used for the anesthesia management of double-lumen endotracheal tube. Trial registration: This clinical research was registered at the Chinese Clinical Trial Registry(www.chictr.org.cn,ChiCTR2000040188).

A Comparative Study of the Efficacy of an Improved Double-Lumen Tube Ventilation Control Device Versus A Conventional Device in Thoracic Surgery: A Randomized Controlled Trial

Association between adjuvant chemotherapy and survival in patients with rectal cancer and pathological complete response after neoadjuvant chemoradiotherapy and resection

PURPOSE Differentiating the irinotecan dose on the basis of the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotype improves the pathologic complete response (pCR) rate. In this study, we further investigated preoperative irinotecan combined with capecitabine-based chemoradiotherapy for locally advanced rectal cancer. PATIENTS AND METHODS We conducted this randomized, open-label, multicenter, phase III trial in China. Eligible patients with clinical T3-4 and/or N+ rectal adenocarcinoma, UGT1A1 genotype *1*1 or *1*28 were randomly allocated to the control group: pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine, followed by oxaliplatin and capecitabine; or the experimental group: radiation with capecitabine combined with weekly irinotecan 80 mg/m2 for patients with UGT1A1*1*1 or 65 mg/m2 for patients with UGT1A1*1*28, followed by irinotecan and capecitabine. The primary end point was pCR. This trial was registered with ClinicalTrials.gov (ClinicalTrials.gov identifier: NCT02605265). RESULTS Of the 360 patients initially enrolled, 356 were evaluated as the modified intention-to-treat population (n = 178 in both groups). Surgery was performed in 87% and 88% of patients in the control and experimental groups, respectively. The pCR rates were 15% (n = 27 of 178) and 30% (n = 53 of 178) in the control and experimental groups (risk ratio, 1.96; 95% CI, 1.30 to 2.97; P = .001). Four and 6 patients achieved complete clinical response in the control and experimental groups, respectively. Grade 3-4 toxicities were recorded in 11 (6%) and 68 (38%) patients in the control and experimental groups, respectively (P < .001). The commonest grade 3-4 toxicities were leukopenia, neutropenia, and diarrhea. The overall surgical complication rate was not significantly different between the two groups (11% v 15%; P < .001). CONCLUSION Adding irinotecan guided by UGT1A1 genotype to capecitabine-based neoadjuvant chemoradiotherapy significantly increased complete tumor response in Chinese patients.

Multicenter, Randomized, Phase III Trial of Neoadjuvant Chemoradiation With Capecitabine and Irinotecan Guided by UGT1A1 Status in Patients With Locally Advanced Rectal Cancer

Promoter Methylation of DNA Repair Genes Predicts Disease-free Survival of Gastric Adenocarcinoma after Adjuvant Radiotherapy

The tripartite motif (TRIM) family proteins play a great role in carcinogenesis. However, the expression pattern, prognostic value and biological functions of tripartite motif containing 23 (TRIM23) in colorectal cancer (CRC) are poorly understood. Here, we found that TRIM23 is up‐regulated and associated with tumour size, lymph node metastasis, American Joint Committee on Cancer (AJCC) stage and poor prognosis in CRC. Multivariate Cox regression analyses revealed that TRIM23 overexpression could be identified as an independent prognostic factor for CRC. TRIM23 could promote the proliferation of CRC cell in vitro and in vivo; additionally, TRIM23 depletion induced G1phase arrest. Gene set enrichment analysis (GSEA) revealed that P53 and cell cycle signalling pathway‐related genes were enriched in patients with high TRIM23 expression levels. We show in this study that TRIM23 physically binds to P53 and enhances the ubiquitination of P53, thereby promoting tumour proliferation. Thus, our data indicated that TRIM23 acts as an oncogene in colorectal carcinogenesis and may provide a novel therapeutic target for CRC management.

TRIM23 overexpression is a poor prognostic factor and contributes to carcinogenesis in colorectal cancer

Background: Our previous study identified irinotecan dose differentiated by UGT1A1 genotype in the neoadjuvant chemoradiotherapy and showed improved pCR. The objective of this phase III study was to further investigate irinotecan combined with capecitabine-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer. 
 
Methods: We underwent a randomized, open-label, multicenter, phase 3 trial in China. Eligible patients with clinical T3-4 and/or N+ rectal adenocarcinoma were randomly allocated to the control arm (CapRT arm): pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine 825 mg/m2 twice daily 5 days per week, followed by a cycle of XELOX two weeks after the end of CRT; or the experimental arm (CapIriRT arm): radiation with capecitabine 625 mg/m2 twice daily 5 days per week and combined with weekly irinotecan of 80mg/m2 for UGT1A1*1*1 or 65mg/m2 for UGT1A1*1*28, followed by a cycle of XELIRI. The primary endpoint is pathological complete response (pCR). This trial was registered with ClinicalTrials.gov, number NCT02605265. 
 
Findings: Of the 360 patients initial enrolled, 356 were evaluated in mITT dataset (both 178 in two arms). Surgery was performed in 87% and 88% of patients in two arms, with 39% and 31% of patients got abdominoperineal resection respectively. The pCR rates were 18% (27/154) in CapRT arm and 34% (53/157) in CapIriRT arm (risk ratio 1.93; 95% CI 1.28–2.89, p=0.001), additional 4 and 6 patients were marked as complete clinical response (cCR). therefore, the overall CR rates were 17% and 33%, respectively. The most common grade 3-4 toxicities during CRT were leukopenia (3% vs. 25%), neutropenia (2% vs. 20%), and diarrhoea (2% vs. 13%). The overall rate of surgical complications were not significantly different between arms (11% vs. 15%). 
 
Interpretation: Adding irinotecan guided by UGT1A1 to capecitabine-based neoadjuvant chemoradiotherapy significantly increases complete tumor response. The treatment toxicities were increased but tolerable. 
 
Trial Registration: ClinicalTrials.gov, number NCT02605265 
 
Funding Information: This study was funded by grants from Fudan University Shanghai Cancer Center (YJLC201601) and National Natural Science Foundation of China (81773357). We thank the patients, investigators, and institutions involved in this study. 
 
Competing Interest Declaration: I/We declare no competing interests. 
 
Ethical Approval Statement: The study was approved by the central ethics committee of Fudan University Shanghai Cancer Center (Shanghai, China)

Multicentre Randomised Phase III Trial of Capecitabine With or Without Irinotecan Guided by UGT1A1 Status in Patients Undergoing Neoadjuvant Chemoradiation for Locally Advanced Rectal Cancer

Chemoradiotherapy in inoperable non-small cell lung cancer (NSCLC) is standard, but accompanied by undesirable adverse effects such as radiation pneumonitis. Polyene phosphatidylcholine (PPC) is a hepatoprotective agent and can be used as nutritional adjuvant to chemotherapy. We aimed to investigate influence of PPC on tumor radiosensitivity as well as radiation therapy related injury in healthy tissues. Thus, a retrospective analysis was carried out in 133 NSCLC patients to assess impact of daily PPC administration on radiation pneumonitis. PPC effects on radiation related tissue injury were additionally investigated in mice receiving total body irradiation. Influence of PPC on tumor radiosensitivity was further evaluated using tumor xenografted mice, lewis lung carcinoma (LLC) and A549 cell lines. Uni- and multivariate analyses suggested that daily PPC intake is significantly associated with reduced risk in developing symptomatic radiation pneumonitis in NSCLC patients. In comparison to patients without PPC supplementation, patients who received PPC benefited from a slower decline in lung function post radiotherapy. Total body irradiation in mice further confirmed that PPC administration protected against radiation induced fatal tissue damage and this protective effect was directly linked to increased cellular antioxidant defense. Radiation resulted in significant growth inhibition of cultured LLC and A549 cells as well as of LLC xenografted tumors, however, this was not affected by PPC treatment. In conclusion, PPC protects against radiation induced injury of healthy tissues and thus may serve as meaningful adjuvant for radiotherapy in NSCLC as well for other cancer entities to dampen adverse effects.

Polyene phosphatidylcholine protects against radiation induced tissue injury without affecting radiotherapeutic efficacy in lung cancer.

BACKGROUND AND OBJECTIVES
MicroRNA (miR-221/222) is frequently overexpressed in many cancers and is associated with poor prognosis. However, the role of miR-221/222 in retinoblastoma (RB) remains unclear. This study aimed to detect the clinical significance of miR-221/222 in RB patients and explore its role in RB cells in vitro.

METHODS
Expression of miR-221/222 was assessed in fresh RB tissue collected from 64 eyes and normal retinal tissues from 18 unrelated donor cadaver eyes by quantitative real time RT-PCR analysis (qRT-PCR), and correlated with the histopathological findings. Human RB Y79 cells were transfected with miR-221/222 precursors or inhibitors to overexpress or downregulate miR-221/222 expression, respectively, using Lipofectamine 2000 reagent. The biological effects of miR-221/222 were then assessed by cell viability assays, colony formation assays, apoptosis detection assays, Matrigel® invasion assays, and wound-healing assays.

RESULTS
Higher miR-221/222 expression was detected in RB tissues compared to that of the normal retinal tissues (p< 0.001). Higher miR-221/222 expression was correlated with invasion in patients with RB. Targeting of miR-221/222 induced apoptosis and inhibited Y79 cell proliferation, migration, and invasion in vitro. However, overexpression of miR-221/222 promoted Y79 cell proliferation, migration, and invasion in vitro.

Overexpression of miR-221/222 was associated with tumor invasiveness in patients with RB. The miR-221/222 cluster might be used as a potential therapeutic strategy in clinical practice.

Upregulated miR-221/222 promotes cell proliferation and invasion and is associated with invasive features in retinoblastoma.

Polyene phosphatidylcholine overcomes oxaliplatin resistance in human gastric cancer BGC823 cells.

3510 Background: Our phase I/II study identified irinotecan dose differentiated by UGT1A1 genotype in the neoadjuvant CRT and showed improved pCR. The objective of this phase III study was to further investigate irinotecan combined with capecitabine-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer. Methods: We underwent a prospective, randomized, open-label, multicenter, phase 3 trial in China from Nov.2015 to Dec.2017. Eligible patients with clinical stage T3-4 and/or N+ rectal adenocarcinoma were randomly allocated to two arms. The approach in control arm (Arm A, n = 180) was pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine 825 mg/m2 twice daily 5 days per week, followed by a cycle of XELOX two weeks after the end of CRT. The experimental arm (Arm B, n = 180) was pelvic radiation with capecitabine 625 mg/m2 twice daily 5 days per week and combined with weekly irinotecan. The irinotecan dose was used based on UGT1A1 genotype of 80mg/m2 for UGT1A1*1*1 or 65mg/m2 for UGT1A1*1*28 weekly, followed by a cycle of XELIRI. The primary endpoint is pathological complete response (pCR). This trial was registered with ClinicalTrials.gov, number NCT02605265. Results: Surgery was performed in 86.5% and 88.2% of patients in two groups, with 38.9% and 30.5% of patients got abdominoperineal resection respectively. The pCR rate was 17.5% in Arm A and 33.8% in Arm B (P = 0.001). Four and 6 patients maintained a complete clinical response status at least 12 months and were marked as cCR. The CR rate, including pCR and cCR, was 17.4% in Arm A and 33.1% in Arm B (P = 0.001). The most common grade 3-4 adverse events during preoperative treatment were leucopenia (3.4% vs. 25.3%), neutropenia (1.7% vs. 19.7%) and diarrhea (1.7% vs. 13.5%) in two arms. The overall rate of surgical complications were not significantly different between arms (11.0% vs. 14.6%). Conclusions: Adding irinotecan guided by UGT1A1 to capecitabine-based neoadjuvant chemoradiotherapy significantly increases complete tumor response. The treatment toxicities were increased but tolerable. This treatment can be as an option for ‘watch and wait’ approach. Clinical trial information: NCT02605265.

A multicenter randomized phase III trial of capecitabine with or without irinotecan driven by UGT1A1 in neoadjuvant chemoradiation of locally advanced rectal cancer (CinClare).

Oxaliplatin (L-OHP) is a platinum compound that is widely used to treat certain solid tumors, including gastric tumors. L-OHP is an effective anti-cancer treatment; however, its usage increases the probability of patients developing hepatic injury with inflammation, referred to as chemotherapy-associated steatohepatitis. The present study aimed to evaluate the outcome of L-OHP treatment combined with polyenephosphatidylcholine (PPC), a major component of essential phospholipids used to treat steatohepatitis, on SGC-7901 gastric cancer cell proliferation. This would help to determine whether combination therapy with L-OHP and PPC is clinically beneficial for patients with gastric cancer. The viability of SGC-7901 cells was verified by an MTT assay; flow cytometry was used to analyze the cell cycle and rates of cell apoptosis; oxidation-related indicators were measured by spectrophotometry, and the expression of cell cycle- and apoptosis-related proteins was determined by western blotting. The results demonstrated that L-OHP significantly inhibited SGC-7901 cell growth in a dose- and time-dependent manner (F=194.193, P<0.01 and F=12.428, P=0.01, respectively). Furthermore, PPC stimulated the growth of SGC-7901 cells and greatly promoted their apoptosis induced by L-OHP, which was supported by the upregulation of cytochrome c and the downstream activation of caspases 3 and 9. Finally, following treatment with a combination of PPC and L-OHP, the expression of cyclins D1 and E was downregulated; however, PPC did not alter the production of reactive oxygen species caused by L-OHP (P=0.88). The present study determined that the combination of L-OHP and PPC exerts a synergistic anti-tumor effect, suggesting that L-OHP and PPC combination therapy may be used as a treatment for patients with gastric cancer that reduces the side effects of L-OHP without inhibiting its efficacy.

Effect of oxaliplatin combined with polyenephosphatidylcholine on the proliferation of human gastric cancer SGC-7901 cells

Multidrug resistance (MDR) to doxorubicin (DOX) limits its effectiveness against tumor cells. Arsenic trioxide (As2O3) has been reported to reduce MDR in various types of cancer, but the mechanisms involving Ras and p-glycoprotein (P-gp) remain to be fully elucidated. The objectives of the present study were to evaluate As2O3 in reversing MDR to DOX, and to identify the association in antitumor activities between the effectiveness of DOX and Ras/phosphorylated (p-) extracellular signal-regulated kinase (ERK)1/2 signaling in SGC7901/ADM and SGC7901/S human gastric cancer cell lines. Cytotoxicity and sensitivity towards As2O3 were assessed using non-toxic and mildly-toxic concentrations (0.1 and 0.5 µM, respectively). The reversing effect of As2O3 on MDR was investigated prior to and following treatment with a cytokine activation of the recombinant human granulocyte colony stimulating factor ERK pathway. The SGC7901/ADM and SGC7901/S cells had the same sensitivity to As2O3. The SGC7901/ADM cells were resistant to DOX and As2O3 treatment reduced the level of resistance to DOX (P<0.01). The expression of P-glycoprotein (P-gp) in the SGC7901/ADM cells was higher than in the SGC7901/S cells (P<0.001). As2O3 treatment decreased the levels of P-gp in a time- and dose-dependent manner (P<0.01). The expression of Ras was higher in the SGC7901/ADM cells than in the SGC7901/S cells, while the expression of p-ERK1/2 remained the same. As2O3 decreased the levels of Ras and p-ERK1/2 (P<0.01). Following pretreatment with rhG-CSF, the levels of Ras and p-ERK1/2 were further decreased (P<0.01). Drug-resistant gastric cancer cells had higher expression levels of P-gp and Ras, but not of p-ERK1/2. Non- and mildly-toxic doses of As2O3 reduced MDR to DOX through Ras/p-ERK1/2 signaling.

Downregulation of P-gp, Ras and p-ERK1/2 contributes to the arsenic trioxide-induced reduction in drug resistance towards doxorubicin in gastric cancer cell lines

Background:The standard treatment for most localised breast cancer patients is the breast-conservating sugery followed by postoperative radiation worldwide. Preliminary studies of intraoperative radiotherapy with electrons(ELIOT) in selected patients, mainly in Europe since 1999, have shown good local control, less toxicity and satisfatory cosmetic apperance. However few studies have been conducted among non-western populations. To investigate the feasibility of ELIOT in China, we introduced ELIOT in selected early breast cancer patients. Risk of local relapse is the main outcome objective, toxicity and cosmetic results are also studied. Patients and Methods:From June 2007 to May 2010, 51 patients diagnosed with unifocal breast carcinoma up to a diameter of 3cm received a wide excision of the primary tumor followed by a radiotherapy of 21Gy delivered to the breast tissue at the surface of the tumor bed, biologically equivalent to 58 to 60 Gy in standard fractionation. The median age of the treated patients was 47 years, with 38/51(74.5%) patients younger than 50. 8 patients(15.7%) were found to have positive axillary I-nodes(six patients had one node involved, one patient had two and one had three positive nodes). Pathologic free margins ≥10 mm were obtained in all patients. Patients were evaluated semiannunally after surgery, and thereafter every 6 months for cosmetic results, complications and other events. Results: After a follow-up from 4 to 36 months(median time12 months), 3 patients developed fat deliquescence, 16 patients showed wound edema and excess fluid and no one had incision infection or hematoma. Two patients developed local relapses. One was comfirmed unrecognised multi-focal cancer in other quadrants of the breast remain dormant. The other patient was confirmed ipsilateral positive axillary III-nodes and no relapse was found in the same quadrant. Neither contralateral breast cancer nor distant metastases were observed. No replase was found in patients aged Conclusion:The incidence of breast cancer remains to increase in China with the aging of society and changes of lifestyle, and the highest incidence is found in the age group 45-50 years.Our study suggested the toxicity and cosmetic evalution were good. Data on local control were encouraging, especially for those under 50. ELIOT of 21Gy was a well-tolerated treatment in early stage Chinese breast cancer patients. And further follow up is still needed. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-10.

Abstract P4-11-10: A Study of Intraoperative Radiotherapy with Electrons in Breast-Conserving Surgery in China: 3 Year Results

Comparative studies on mitochondrial electron transport chain complexes of Sitophilus zeamais treated with allyl isothiocyanate and calcium phosphide.

A power-efficient low-voltage buffer is presented. The proposed buffer contains a low-frequency zero generation circuit to perform frequency compensation and a slew-rate enhancement (SRE) circuit to provide large dynamic current for driving the pass device of the low-dropout (LDO) voltage regulator. Whatpsilas more, the proposed buffer, consuming small quiescent current over full load range, can work at low supply voltage, when comparing to conventional voltage buffer. A 1.2-V, 200-mA LDO with the proposed buffer has been designed in a 0.18-mum standard CMOS process. The low-voltage operation ability, high current efficiency and excellent transient response performance can be achieved. With a 1-muF ceramic output capacitor, the overshoot and undershoot of the output voltages are less than 20-mV when the load step changes between 1 and 200-mA in 100 ns, while the current efficiency is up to 99.99% at full-load current.

A fast-response low-dropout regulator based on power-efficient low-voltage buffer

1.0-V, 50-mA capacitor-less low-dropout (LDO) voltage regulator with 100pF internal output capacitor for SoC applications is presented. The proposed LDO makes use of a bi-directional asymmetric buffer (BDAB), which provides a signal inversion feedback path and a signal non-inversion feedforward path with different magnitudes at the same time. The feedback path can perform frequency compensation and transient enhancement, while the feedforward path can improve the stability and increase the unit-gain frequency (UGF) by removing right-half-plane (RHP) zero. Simulation results show that the LDO has robust stability, high UGF (up to 1.7-MHz even at no-load), and excellent transient response performance. The overshoot and undershoot of the output voltages are less than 100-mV when the load step changes between 0 and 50-mA in 1-mus, the settling time is 2-mus, while the dropout voltage is 100-mV at full-load current.

A capacitor-less low-dropout regulator for SoC with bi-directional asymmetric buffer

This paper presents a low-voltage, low-quiescent current, low-dropout voltage regulator (LDO) with a novel capacitor-multiplier frequency compensation technique. The proposed compensation strategy can make the LDO stable under the entire load-current range without relying on an ESR zero. By eliminating cascode structure or buffer stage, the proposed LDO facilitates low voltage operation. Moreover, the capacitor-multiplier circuit reduces the on-chip compensation capacitor greatly and can be effectively realized without extra current budget. Implemented in a 0.18-mum CMOS technology, the LDO is able to provide 200 mA load current with 160 mV dropout voltage while consuming only 20 muA ground current. With a 1 muF output capacitor, the load-transient output variation is 17 mV through maximum current step changes. The on-chip compensation capacitor is reduced to 1 pF.

A low-voltage CMOS low-dropout regulator with novel capacitor-multiplier frequency compensation

Utilizing a novel unit-gain compensation cell (UGCC) to perform frequency compensation and power supply rejection (PSR) enhancement, a low-voltage high-PSR low-dropout regulator (LDO) is presented in this paper. The proposed UGCC, consisting of a 1 pF on-chip capacitor and six transistors, effectively overcomes the drawbacks that exist in the conventional compensation schemes by generating an internal low-frequency zero. A LDO that adopts this new structure is implemented and simulated using a standard 0.18-mum CMOS process. Simulation results show that the circuit can work properly when the supply voltage is as low as 1.2 V. The PSR over the frequency range of dc to 1 GHz is better than -40dB in all cases at 1.2 V supply voltage. The dropout voltage is 200 mV when the load current is 100mA. Therefore, it is well suited for low-voltage ripple-sensitive applications

2006 8th International Conference on Solid-State and Integrated Circuit Technology Proceedings

Design of Low-Voltage Low-Dropout Regulator with Wide-Band High-PSR Characteristic

Geological conditions of urban subway foundation pits are controllable factors in determining the deformation of pits. In this paper, the monitoring data and statistical data of a subway deep foundation pit in North China are presented and compared with those of Tianjin subway. The deformation characteristics of the proposed pit, open excavated with triple-layer steel supports, are introduced in detail. Based on the aforementioned information, the energy conservation equation of the mobilized strength design (MSD) method in which the compression deformation energy of internal support is considered is applied to predict the maximum lateral movement. The maximum lateral movement turns out to be 22.2 mm according to the improved MSD method, which is very close to the measured value.

A Case Study on the Deformation of Metro Foundation Pit in Silt Stratum in North China

This article deals with the frequency analysis of viscoelastic sandwich disk with graphene nano-platelets (GPLs) reinforced viscoelastic concrete (GPLRVC) face sheets and honeycomb core. The honeycomb core is made of aluminum due to its low weight and high stiffness. The rule of the mixture and modified Halpin–Tsai model are engaged to provide the effective material constant of the concrete. By employing Hamilton's principle, the governing equations of the structure are derived and solved with the aid of the Generalize Differential Quadrature Method (GDQM). In this paper, viscoelastic properties are modeled according to Kelvin-Voigt viscoelasticity. The deflection as the function of time can be solved by the fourth-order Runge-Kutta numerical method. Afterward, a parametric study is carried out to investigate the effects of the outer to inner radius ratio, hexagonal core angle, thickness to length ratio of the concrete, the weight fraction of GPLs into concrete, and the thickness of honeycomb core to inner radius ratio on the frequency of the viscoelastic sandwich disk with honeycomb core and FGGPLRVC face sheet.

Computer simulation for stability analysis of the viscoelastic annular plate with reinforced concrete face sheets

Analytical modeling of the linear and nonlinear dynamic characteristics of the non-uniform axially functionally graded cylindrical beam based on the strain gradient theory

Stress loss of prestressed steel strands of existing bridges influences their bearing capacity, so it is of great significance to realize the stress detection. A steel strand that has an inductive property is designed into the resonant circuit, which can realize the stress measurement of the steel strands by testing the resonant frequency. This method is a promising approach for the stress detection of the steel strands. Previous research found that structural stress made the permeability of steel strands change due to the influence of magnetoelastic effect. In the process, the length of steel strands is also changed. Therefore, further research needs to be done to verify the main influence parameter affecting the resonant frequency of the circuit. Furthermore, it is very important to know how the stress affects the resonant frequency to realize the detection of the prestressed force of the steel strands. Therefore, in this paper, the relationship between stress and relative permeability and length is analyzed theoretically, and the theory of stress frequency of steel strands is modified and verified by experiments. The stress-frequency experiments of steel strands and aluminum strands with great difference in relative permeability are carried out. Experiments on stress frequencies of 7-Ф15.20 mm steel strands with different lengths are carried out. The influence of length and permeability parameters on resonance frequency is analyzed. The experimental results show that under the same conditions, the resonant frequencies of steel strands and aluminum strands are almost the same on LC electric circuits, and the resonant frequency decreases linearly with the increase of the natural length of the component and increases linearly with the increase of stress. Consequently, compared with the influence of length change on LC electromagnetic resonance frequency, the relative permeability of the stress change component can be ignored. The stress changes the resonant frequency mainly by changing the length of the strands.

Study on the Main Factors of Frequency Variation of LC Resonant Prestress Detection Method

Study on the Seismic Behavior of Monolithic Precast Shape Steel Oblique Multi-Ribbed Composite Wall

In this paper, follow-up grinding of crankshaft is studied and the mathematical model of follow-up grinding motion is established. Taking the double grinding wheel crankshaft follow-up grinder as the research object, the motion errors of the machine tool are obtained by analyzing the motion relations among the moving bodies. Based on the kinematics theory of multi-body system, the kinematics model of the whole machine tool is established. The position matrix of any cutting point is described according to the kinematic chain of “bed-workpiece” and “bed-tool”, and the precise machining model of double grinding wheel follow-up grinding machine tool is established by using the coincidence principle of tool actual trajectory and tool path. The coordinate system of each moving body is established, the transformation matrix between moving bodies is obtained, and the precision machining model of double grinding wheel follow-up crankshaft CNC grinding machine is solved, which lays a foundation for error compensation of the machine.

Modeling of Precision Machining for Crankshaft Follow-up Grinder

In view of the lack of relevant research on CNC grinders in the field of reliability research of CNC machine tools at present, This research collected reliability data based on 19 MSK series grinder machine tools of a machine tool factory., found out the crucial subsystem which is the most important component to the whole, and analyzed the reliability of the subsystem adopting FTA (Fault Tree Analysis) . Statistical researched on 438 reliability data collected, combining with the actual production situation, the results shows that cooling system is the key to the reliability of the whole grinder machine tool. The 29 minimum cut sets obtained by FTA can be adjusted to improve the reliability of the cooling system, what is more, the reliability of grinder machine tool would be improved as well.

Reliability analysis of cooling system of CNC grinding machine based on FTA analysis

The wind power industry in our country has a rapid development. The continuous innovation of wind power technology has made wind turbine generators and electrical equipment integrated into one and has become a complicated mechatronic device. Wind power equipment has been greatly improved. Wind turbines have different categories in different ways,which according to the structure of wind turbines can be divided into two categories, including horizontal axis wind turbines and vertical axis wind turbines. Currently employed to grid-connected power generation are mostly horizontal axis wind turbines. The wind turbine is a complicated and systematic device that integrates electromechanical and electrical equipment. Aerodynamics is the sole energy source for the systematic equipment to output electrical energy. The aerodynamic characteristics of the wind turbine directly affect the ability of the crew to capture wind energy. The overall performance of the fan plays a crucial role, becoming an important issue in the development of wind power technology at home and abroad.

Study of the Establishment of Typical Wind Speed Model Based on Numerical Simulation

For assemble-type composited wall, 4 pieces of wall which are 1/2 scale models were made. By pseudo-static tests under low cyclic loading, the aseismic behavior indexes were compared and analyzed, including failure characteristics, bearing capacity, stiffness, deformation, ductility, energy dissipation, and so on. The results showed that the frame which composed by rib beams, rib column, and invisible frame can restraint bricks bearing and crack developing; the structure failed beginning at brick, then rib grim, and ending at invisible frame; this course can be described that the structure had multi-defense lines to resistant earthquake, and every components were used efficiently. The framework curve changed gently from yield to failure; there was no mutation and no collapse, which means that the wall had a good collapse-resistant capacity. A numerical modeling was built by ABAQUS to do push-over analysis, and the results were consistent with test results in load–displacement curve and frame stress nephogram. Furthermore, the influence of the changing key parameters were analyzed by numerical simulation to understand the axial compression ratio, the aspect ratio, and other key parameters how to affect the structure’s stiffness, bearing capacity, and displacement ductility.

Experimental investigations and finite element simulation of cutting heat in vibrational and conventional drilling of cortical bone.

Bone drilling is widely used in orthopedic surgery. Microcracks will be generated in bone drilling, which may cause fatigue damages and stress fractures. Fresh bovine cortical bones were drilled via vibrational and conventional ways. Drilling operations were performed by a dynamic material testing machine, which can provide the vibration while maintaining uniform feed motion. The drill site and bone debris were observed through scanning electron microscope (SEM). The experimental results showed that fewer and shorter micro-cracks were formed in vibrational drilling than those formed in conventional way. And the surface morphology of bone debris fromtwo different drilling ways was also quite different. It is expected that vibrational drilling in orthopedic surgery operation could decrease the microdamage to the bone, which could lower the incidence of stress fracture and contribute to the postoperative recovery.

Experimental investigations on microcracks in vibrational and conventional drilling of cortical bone

As a new structural system with a bright prospect, multi-ribbed composite slab structure has the advantages of ecological materials and seismic performance. In this paper, the formula of vibration period of multi-ribbed composite slab structure is discussed. Based on the analysis of FEM model and the regression analysis of experimental data, an empirical formula was put forward. It has been shown that the calculated results fit well with the test results.

Research on the Formula of Vibration Period of Multi-Ribbed Composite Slab Structure

Multi-ribbed frame grid (hereinafter referred to as MRFG) is an important part of Multi-ribbed composite wall and consisted of outer frame and ribbed grid. The reinforcement of outer frame is the main influence factor on the performance of MRFG. In this study, an MRFG specimen under laterally cyclic and axial loading in literature is numerically simulated with 5 kinds of different reinforcement ratio of outer frame, by a general finite element software and user-defined material model. The influence of different reinforcement ratio of outer frame on the mechanical behavior of MRFG has been discussed.

Influence Analysis of Reinforcement in outer Frame on the Mechanical Behavior of Multi-ribbed Frame Grid

A wideband mode multiplexer based on multi-core fiber structure can realize six-spatial-mode operation

A Wideband Mode Multiplexer Which Can Realize Six-Spatial-Mode Operation

In this paper, we propose a broadband mode converter based on photonic crystal fiber (PCF) starting from the method of propagation constant height fitting. Using the finite element method and the beam propagation method, three typical mode converters in the S + C + L range, LP01 to LP11, LP01 to LP21, and LP01 to LP31, are calculated. Numerical results show that the mode coupling efficiency of this mode converter is over 90% and the mode extinction ratio is over 10 dB. This converter can realize pattern multiplexing in a cascade manner. On this basis, we propose a multi-core mode multiplexer structure. On the premise of sacrificing some performance, three modes can be reused at the same time. Mode converters of PCF structure can be fabricated by PCF post-processing technology. It is expected to become an important part of the future mode division multiplexing (MDM) optical communication system.

A photonic crystal fiber broadband mode converter with highly fitting propagation constant

A broadband mode-division multiplexer based on asymmetric three-core photonic crystal fiber is proposed in this paper. The device is mainly composed of a central core, which can provide the transmission of fundamental mode and higher-order mode, and two side cores providing fundamental mode transmission. According to the theory of optical coupling, the LP01 mode light is input to the three fiber cores at the initial port separately, and in the transmission process the LP01 mode on the left side core will be coupled and converted into the LP21 mode light in the central core gradually. Similarly, the LP01 mode of the right side core is transformed into the LP31 mode of the center core. By optimizing the structural design and selecting the length of optical fiber, the best conversion from side core into central core can be completed at the output end simultaneously, thereby realizing the multiplexing of LP01, LP21 and LP31 modes in the central core. In the opposite direction, if the output end of the device is used as the initial port, the demultiplexing of three modes of light from the central core to the three cores can be realized. In thiswork, the finite element method and beam propagation method are used to optimize the simulation, and the optical coupling theory and supermode theory are combined to conduct analysis and calculation. The results show that at wavelength band from 1.49 μm to 1.63 μm, the maximum insertion loss of the device is 0.72 dB, and the lowest insertion loss is 0.543 dB at 1.55 μm, which is far lower than the general evaluation standard of 1 dB insertion loss. The low insertion loss also makes it possible to design cascaded multi-core photonic-crystal-fiber mode-division multiplexer. Compared with the existing mode-division multiplexing scheme, the device is more integrated and less affected by the external environment. When it is used with multi-core space division multiplexing fiber, it can better improve the mode-conversion efficiency and mode purity, reduce the coupling complexity and expand the communication capacity.

Design and research of a broadband mode-division multiplexer based on three-core photonic crystal fiber

The cross-section image of microstructure optical fiber (MOF) is usually characterized by the irregular shape, disordered distribution of the air pores, and multiple sources of noise. The traditional modeling of fiber structure does not work for these MOFs, and it is difficult to obtain the actual cross-section structure. A new method based on the digital image processing technique and finite element method (FEM) is introduced. With this method, the actual cross-section structure of MOFs can be rapidly modeled by gray scale processing, filtering, threshold, and edge detection, which is vital to the simulation of the basic properties of the fiber with FEM precisely. The method is proved to be feasible and reliable in that the dispersion coefficients of an actual fiber simulated are greatly consistent with the experimental results. In addition, the influence of perfect matched layer thinkness, as well as the curve fitting interval selection of the dispersion coefficients on the research results, is explored in the paper, which forms a basis for the correct setting of these parameters. The method has the advantages of strong adaptability, good modeling effect, rapid simulation, and accurate results. Finally, the method applies to all kinds of cross-section modeling of fiber, especially for disordered structure modeling.

A Novel Method Based on Digital Image Processing Technique and Finite Element Method for Rapidly Modeling Optical Properties of Actual Microstructured Optical Fibers

Photonic crystal fiber can generate particular dispersion properties and highly nonlinear, because of the special guiding mechanism and the adjustable structure parameters，which provides new conditions for the study of nonlinear fiber optics. There are rich nonlinear spectral properties produced by a variety of nonlinear physical effect, under different pump light pulse parameters in photonic crystal fibers with different structure and transmission properties. At present many papers have reported the experimental results of nonlinear optical properties in photonic crystal fiber, but there is little theoretical analysis about the produced mechanism and the change rule of the nonlinear spectrum. In the paper, solving nonlinear Schrodinger equation with split-step Fourier method, transmission process of femtosecond laser pulse in photonic crystal fiber is simulated. The relationship between the output spectrum and incident light pulse parameters (the peak power of pump light P, the wavelength of pump light λ, the shape of light pulse, the width of light pulse TFWHM), the structure parameters of optical fiber (the pitch Λ, the hole-to-pitch ratio d/Λ, the length of fiber), the transmission characteristics (the dispersion properties, the nonlinear coefficient) is obtained. The spectral characteristics produced by nonlinear effects of the Raman soliton, dispersive wave, self-phase modulation are analyzed. The nonlinear optical spectrum of cladding note in photonic crystal fiber is studied in experiments, the broadband spectrum of soliton wave and dispersive wave is obtained. There are blue-shift dispersive wave near the wavelength of 0.5 μm, residual pump light near the wavelength of 0.82 μm, soliton wave near the wavelength of 1.1 μm, red-shift broadband dispersion wave near the wavelength of 2 μm in the spectrum obtained both in theory and experiment. The numerical simulation is confirmed through experimental observation. The physics principle of the nonlinear spectrum in photonic crystal fiber is revealed. These are useful and practical to realize the controllable output of broadband spectrum. These provide guidance for the structure design, fabrication, applied research of high nonlinear photonic crystal fiber.

[Study on Nonlinear Spectral Properties of Photonic Crystal Fiber in Theory and Experiment].

With the homemade solid-core silica-based photonic crystal fiber (PCF), we observe the generation of soliton and four-wave mixing (FWM) when the femtosecond pulse is pumped at 0.822 μm, belonging to the normal-dispersion regime. It is generally acknowledged that FWM is unrelated to third-order dispersion, whereas we use the fourth-order Runge-Kutta method to simulate the PCF properties by taking into account the third-order dispersion or not; the result we got is different from the conventional one. The numerical simulations are greatly consistent with the experiment results, and the FWM is dominated by negative fourth-order and negative sixth-order dispersion in the experiment. The main dynamic process is explained as the soliton, and the FWM generation can be induced by third-order dispersion. We indicate that low Raman threshold has played a very active role in this process, and we propose a conception of stimulated FWM effect in this paper.

Soliton and Four-Wave Mixing Effects Induced by the Third-Order Dispersion in a Photonic Crystal Fiber With Femtosecond Pulses Pumping at Normal-Dispersion Regime

Correlation between the birefringence and the structural parameter in photonic crystal fiber

In this paper the mode property of a photonic crystal flber with triangle-lattice array in a silica matrix has been simulated by fast multipole method. The PCFs studied in this paper have a silica core, obtained by introducing a defect, that is by removing three holes in the center of the flber transverse section. The model flelds, efiective index and conflnement loss about the fundamental mode in the flbre are analysed and compared. It is demonstrated that lower conflnement loss and higher birefringence can be realized in the condition of fewer rings of air holes. At the wavelength of 1.55"m the conflnement loss is 7:3£10 i6 dB/m and the birefringence is 1:65£10 i3 in this flber. The simulation results show that birefringence of this triangle-lattice PCF is dominated by inner-ring air holes in the flbre efiectively. The simulation results in this paper have important meaning for instructing the fabrication of birefringent photonic crystal flber. 1. INTRODUCTION In recent year, great interest has been focused on the study of photonic crystal flber (PCF). By using the structure adjustability of the PCF, zero dispersive wavelength moving towards short- wave spectroscopy, chromatic dispersion compensating, dispersion truncating, high nonlinearity and birefringence can be realized (1{15). The mode birefringence of PCF mainly comes from the geometer structure of flber and the usual method to cause birefringence is employing double-core or multi-core structure, changing the flber core or the shape of the air holes and altering the distri- bution of the air holes. High birefringence PCF can be used in optical flber sensor, interferometer and polarizer, etc. In addition, by designing the high birefringence and intensive nonlineality PCF required, we can make a flber not only high birefringence, but also intensive nonlineality. We can also make the large mode property polarization maintaining PCF (15). This can make the prop- erty of PCF integrate, so it can be used in the Raman magniflcation, ex-continous spectum of the polarization, four-wave frequency mixing and the crossing phase modulation. The development of the birefringence PCF will promote the study and appliance of the new photoelectric device. In the progress of making the PCF flber, we flnd that maintaining the ideal structure of the flber and the number of air holes layers of the PCF cladding is a contradiction (2,4,17). Generally speaking, the more layers the PCF cladding have, the smaller the conflnement loss will be, but at the same time increasing the layers will make the distortion of the air holes a big problem when the flbers are produced. On the fundament of the traditional triangular arrayed air holes, this article proposes a birefringence structure PCF which has C2v symmetry. And by using the fast multipole method, its modal property is numerically simulated. It is found that in this PCF, there will be several conductive modes, and its fundamental mode has very low conflnement loss and high birefringence. 2. BASIC THEORY The ordinary solution about multipole theory at the complex boundary electrostatic fleld has been deduced and developed by Zheng Qinhong. Nie Zaiping (22) analyzed the three dimensional vector scattering of complicated object by using the fast multipole method. These examples show that the multipole method is an efiective way to analyze electromagnetic fleld theory. Using the multipole method to simulate the dispersion and the loss property of microstructured flber is originally proposed by T. P. White and B. T. Kuhlmey (23{25) in Sydney University. Zhao Mingzhu (26) also simulated the PCF by using multipole method. This method is adopted when the air holes of microstructured flber is cylindrical. By using this method, we can get real part and imaginary part of the efiective refractive index of the flber and the mode propagation constant. And then by using the real part, we can analyze the dispersion, or using the imaginary part to analyze the conflnement loss of limited cladding air holes. We can also use this method to get its propagation constant corresponding to the input wavelength (or frequency). Accordingly, we can consider the material dispersion in the progress of simulation by using the Sellmeier formula. In this paper, the theory of T. P. White (23,24) is used for reference

Numerical Simulation and Analysis on Mode Property of Photonic Crystal Fiber with High Birefringence by Fast Multipole Method

Identification and molecular mechanism of novel tyrosinase inhibitory peptides from the hydrolysate of 'Fengdan' peony (Paeonia ostii) seed meal proteins: Peptidomics and in silico analysis

pH and non-enzymatic glucose response at ultra-low concentration using submicrochannel heterogeneous membrane

Directional and on-demand ion transport regulated by pH and voltage in submicrochannel heteromembrane based on conducting polymer

Behavioural determinants of an individual's intention to adapt to climate change: Both internal and external perspectives

Critical transmission sectors for CO2 emission mitigation in supply chains

Does reducing air pollution improve the progress of sustainable development in China?

Trade-off between environmental benefits and time costs for public bicycles: An empirical analysis using streaming data in China.

Energy demand, emission reduction and health co-benefits evaluated in transitional China in a 2 °C warming world

Objective 
To investigate the value of integrative weaning index (IWI) on weaning from mechanical ventilation. 
 
Methods 
The PubMed, Web of Science, EMbase, CNKI, WangFang Databases were searched for IWI diagnostic accuracy on weaning from mechanical ventilation up to October 2018. Two reviewers independently screened the literatures based on the inclusion and exclusion criteria. The methodological quality of included studies was assessed by QUADAS-2. Data were analyzed by Meta-DiSc software. 
 
Results 
Five studies involving 783 patients were included. The summary estimates for IWI diagnostic accuracy on weaning from mechanical ventilation included: sensitivity 0.95 (95%CI: 0.90-0.99), specificity 0.81 (95%CI: 0.68-0.94), positive likelihood ratio 4.46 (95%CI: 1.98~10.07), negative likelihood ratio 0.08 (95%CI: 0.03-0.19), diagnosis odds ratio 60.34 (95%CI: 16.54-220.05), and the area under the curve of SROC was 0.9466. 
 
IWI can improve the diagnostic accuracy on weaning from mechanical ventilation. 
 
Key words: 
Integrative weaning indexl; Mechanical ventilation; Weaning; Meta-analysis

Diagnosis accuracy of integrative weaning index for weaning from mechanical ventilation: A Meta-analysis

A bibliometric analysis of climate change adaptation based on massive research literature data

Based on Artificial Immune System, a novel Immune System Multiobjective Optimization Algorithm (ISMOA) for Analysis of Communication Network Planning is proposed. The problem can be transformed into multiobjective 0/1 knapsack problem by modeling. By fixing the avidity properly, presenting vaccine operation and clonal selection operation, ISMOA guides the selection process towards the Pareto-optimal front and preserves the diversity of the solutions. The comparisons of ISMOA with other algorithms suggest that ISMOA clearly outperforms in solutions performances of coverage and distribution.

2014 10th International Conference on Natural Computation (ICNC)

Immune system multiobjective optimization algorithm for analysis of communication network planning

The practices of product placement have grown rapidly during the past decade. However, our understanding about what consumers think about the practices of product placement has not fully developed, how product placement affect people, as well as factors involved in this process are still unclear. The purpose of this study is to examine the influences of different factors on consumers’ attitude and attitude change towards product placement brands. In addition, the study investigates consumers’ attitude towards product placement practices in television programs. The results indicate that consumers’ attitude towards product placement practices in television programs are generally supportive, although most people hold quite strong views on putting ethically-charged products (i.e. alcohol, cigarettes, and guns) in television programs, especially those can be watched by children and teenagers. In addition, brand consciousness and attitude towards product placement practices in general both have limited influence on consumers’ attitude towards brands that actually placed in programs. However, this study found that watching length affect consumers’ brand attitude changed significantly. And the influence of program characters on consumers’ attitude towards the placed brands cannot be ignored.

Consumers’ Attitude Towards Product Placement In Television Programs (Available on Internet)

Living labs provide real-world environments that combine experimentation with concurrent innovation and change of user behaviour. It serves as a platform for collaboration among many stakeholders, being it firms, public agencies, universities, institutes or customers, to create, validate and test new services, products and theories in real-life contexts. Among this complex network, links between research community and companies represent a specific type. This paper presents an online instrument to enact the collaborative relationships between research community and companies. This instrument is more than an online survey instrument, but a combination of online survey instrument and online consultant instrument. As an illustration, studies in the area of knowledge worker productivity assessment carried out through this instrument will be given in this paper to better understand its distinguishing features. In the end, we argue that fast feedback loop and instant communications between researchers and stakeholders maintain contributions both to theory building in terms of researchers, and on the other hand to practice guidance in terms of companies.

An online collaboration platform between researchers and companies in living labs

Abstract In China, suicide accounts for twenty-six percent of all suicides worldwide; however, researches on the suicidal ideation among older people living alone in the rural region are few. We performed a cross-sectional study to explore the prevalence and influence factors of suicidal ideation, and provide a theoretical basis for suicide prevention among older people living alone in rural region. 695 older people living alone in rural region were selected by using stratified cluster sampling. Chi-square for categorical variables, T-test for continuous variables, and path analysis were conducted to statistical analysis. The prevalence of suicidal ideation among the elderly living alone in rural China was 23.6%. Path analyses showed that depression had the most substantial influence on suicidal ideation among the elderly living alone, it was also as a mediator between physical, economic status, social support, anxiety, and suicidal ideation; anxiety and social support had both direct and indirect influence on suicidal ideation; physical status and economic status had indirection impact. The incidence of suicidal ideation among the elderly living alone was high in Dangtu county. Psychological disorders (anxiety and depression) had the strongest impact on suicidal ideation. Strategies and measures targeting these relevant factors (economic status, physical status, and social support) should be taken to reduce the burdens of suicidal ideation among the elderly living alone in China.

Risk factors for suicidal ideation among the older people living alone in rural region of China

Abstract Depressive symptoms and empty nest phenomenon of rural elderly people are both important public health issues, which should not be ignored. We aimed to estimate the prevalence of depressive symptoms and related factors of the empty nest elderly in rural China. We recruited 3182 eligible subjects and gathered data by face-to-face interview. Multivariate logistic regression models were used to explore the related factors of depressive symptoms. The present study showed that the prevalence of depressive symptoms significantly differed between empty nest old adults and non-empty nesters (24.1% vs. 19.0%). The elderly living alone had highest OR of depressive symptoms. Depressive symptoms of empty nest elderly was associated with sleep quality, economic status, pain, social support and ADL. While it was associated with gender, economic status, pain and PSMS in non-empty nest group. Number of chronic disease showed significant associations with depressive symptoms in the elderly living alone. Subjective support, support utilization and pain were positively associated with depressive symptoms in the elderly living with spouse. Sleep quality, economic status and ADL were common factors. Depressive symptoms obviously prevail among empty nest elderly than non-empty nesters. It reminded us that complementary social support from family and society is essential.

The factors associated with geriatric depression in rural China: stratified by household structure

ABSTRACT Background: The number of elderly individuals living in China is increasing rapidly. The aim of this study was to examine the potential risk factors of geriatric depression in rural areas. Methods: A repeated cross-sectional study was conducted between January 2015 and October 2016 in rural China. Nine hundred forty-five elderly individuals were included in both investigations. A generalized estimating equation (GEE) was used to examine the relationships between geriatric depression and socio-demographics, the number of chronic diseases, ADL (Activity of Daily Living) disability, cognitive impairment, and anxiety. Results: Among the participants, the majority was female (61.4%) and illiterate (81.5%) and had a general economic status (63.0%) and more than two kinds of chronic diseases (62.9%). The bivariate analysis indicated that geriatric depression was associated with social support, education level, economic status, ADL disability, anxiety disorders, and cognitive impairment at both survey time points. The GEE results showed that poor economic status (OR = 8.294, p < 0.001), the presence of more than two chronic diseases (OR = 1.681, p = 0.048), ADL disability (OR = 2.184, p < 0.001), cognitive impairment (OR = 1.921, p < 0.001), and anxiety (OR = 5.434, p < 0.001) were risk factors for geriatric depression in rural China; better social support (OR = 0.924, 95% CI = 0.899–0.949, p < 0.001) was found to be a protective factor. Conclusions: Geriatric depression in rural China was associated with several socio-demographic, physical, and mental factors. Targeted interventions are essential to improve the psychological health of aged individuals in rural China.

Risk factors of geriatric depression in rural China based on a generalized estimating equation

Objective 
To investigate the current situation of hazardous and harmful drinking and nicotine dependence of rural elderly in Anhui Province, and to explore the associated factors of hazardous and harmful drinking and nicotine dependence. 
 
Methods 
A cross-sectional survey was conducted in 10 villages between December 2014 and January 2015. Using the cluster sampling methods, the elderly aged 60 years or more and lived 1 or more years in the villages were recruited to voluntarily participate in the survey. Questionnaires about physical, mental health and related social resources of the elderly were used to assess the socio-demographic, alcohol use disorder and nicotine dependence, anxiety, depression, social support, activities of daily living. Ordinal Logistic regression analysis was used to explore the associated factors for hazardous and harmful drinking. 
 
Results 
A total of 3 182 elderly people completed the assessment, including 507(15.93%) drinkers, 538(16.91%) smokers and 259 (8.14%) that were both drinkers and smokers. The prevalence of the hazardous and harmful drinking behaviors among elderly was 7.13%. The rate of nicotine dependence was 8.64%. Ordinal Logistic regression analysis showed that male gender(OR=12.293, 95%CI=8.758-17.253, P<0.01), age(OR=0.980, 95%CI=0.960-0.997, P=0.024), unmarried (OR=1.815, 95%CI=1.027-3.203, P=0.027), smoking(OR=2.795, 95%CI=2.210-3.532, P<0.01), poor instrumental activities of daily living(OR=0.933, 95%CI=0.884-0.985, P=0.012), small labor intensity (OR=0.547, 95%CI=0.394-0.760, P<0.01), poor physical condition(OR=0.378, 95%CI=0.261-0.547, P<0.01) and general physical condition(OR=0.546, 95%CI=0.425-0.751, P<0.01) were the influence factors of hazardous and harmful drinking. Male gender(OR=46.572, 95%CI=28.703-75.566, P<0.01), age(OR=0.974, 95%CI=0.956-0.993, P=0.008) and drinking(OR=2.689, 95%CI=2.132-3.394, P<0.01) was the influence factors of nicotine dependence. 
 
The current situation of hazardous and harmful drinking and nicotine dependence of rural elderly is serious. Age, gender, unmarried, instrumental activities of daily living, labor intensity, smoking, and physic condition are the associated factors of hazardous and harmful drinking; gender, age, and drinking are associated factor of nicotine dependence. 
 
Key words: 
Hazardous and harmful drinking; Nicotine dependence; Rural elderly; Social support; Activities of daily living

The hazardous and harmful drinking and nicotine dependence of rural elderly in Anhui Province

ABSTRACT Background: Elder self-neglect (ESN) has become a public health issue globally. Limited studies have focused on ESN, as well as the relationship between ESN and quality of life (QoL) in developing countries. The study's objective is to explore the association between ESN and QoL among rural elderly in China. Methods: A cross-sectional study was conducted among 3,182 elder adults aged 60 years or older, using a cluster-sampling technique in one township in Dangtu, a county in Anhui province. All participants completed face-to-face interview in their household. QoL was assessed using a brief form of the World Health Organization's quality of life questionnaire (WHOQOL-BREF), and ESN was assessed using the Scale of the Elderly Self-neglect (SESN). Hierarchical linear regression models were used to analyze the associations between the ESN scores and QoL scores after adjusting for sociodemographic, social support, and physical and psychological variables. Results: The scores of overall ESN and five domains were significantly correlated with the scores of four QoL domains (p < 0.001). After adjusting for sociodemographic characteristics, social support, and physical and psychological health characteristics, elders who reported higher overall self-neglect scores had significantly lower scores in the four QoL domains (p < 0.001). Education, economic level, physical health, ADL, depression, and cognitive function are consistent predictors across all QoL domains. Conclusions: ESN is an independent risk factor for poor QoL in elderly people in rural China. Understanding the role of ESN and its influence on QoL is important for the management of and intervention in ESN.

Associations of self-neglect with quality of life in older people in rural China: a cross-sectional study

Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi

Association between apolipoprotein E gene polymorphism and depression

老年虐待是一个世界性的社会问题,在美国公认为家庭暴力之一.有关老年虐待的研究最早出现在1975年英国并受到老年问题研究者的关注[1],同年,Butler也探讨了"受虐老年人症候群",至20世纪70年代天期,有关老年虐待研究的文献开始在英国与美国出现,美国俄亥俄州克里夫兰慢性疾病研究中心开始以老年虐待为主题进行研究. 关键词：虐待;老年人;研究

Arginine methylations can regulate important biological processes and affect many cellular activities, and the enzymes that catalyze the methylations are protein arginine methyltransferases (PRMTs). The biological consequences of arginine methylations depend on the methylation states of arginine that are determined by the PRMT's product specificity. Nevertheless, it is still unclear how different PRMTs may generate different methylation states for the target proteins. PRMT7 is the only known member of type III PRMT that produces monomethyl arginine (MMA) product. Interestingly, its E181D and E181D/Q329A mutants can catalyze, respectively, the formation of asymmetrically dimethylated arginine (ADMA) and symmetrically dimethylated arginine (SDMA). The reasons as to why the mutants have the abilities to add the second methyl group and E181D (E181D/Q329A) has the unique product specificity in generating ADMA (SDMA) have not been understood. Here, quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) and potential of mean force (PMF) free-energy simulations are performed for the E181D and E181D/Q329A mutants to understand the origin for their ability to generate, respectively, ADMA and SDMA. The simulations show that the free-energy barrier for adding the second methyl group to MMA in E181D (E181D/Q329A) to produce ADMA (SDMA) is considerably lower than the corresponding barriers in wild type and E181D/Q329A (wild type and E181D), consistent with experimental observations. Some important factors that contribute to the change of the activity and product specificity due to the E181D and E181D/Q329A mutations are identified based on the data from the simulations and analysis. It is shown that the transferable methyl group (from SAM) and Nη2 (the nitrogen atom that is methylated in the substrate MMA) can only form good near-attack conformations in the E181D reaction state for the methyl transfer (not in wild type and E181D/Q329A), while the transferable methyl group and Nη1 (the nitrogen atom that is not methylated in the substrate MMA) can only form good near-attack conformations in E181D/Q329A (not in wild type and E181D). The results suggest that the steric repulsions in the reaction state between the methyl group on MMA and active-site residues (e.g., Q329) and the release of such repulsions (e.g., from the Q329A mutation) may play an important role in generating specific near-attack conformations for the methyl transfer and controlling the product specificity for the mutants. The general principle identified in this work for PRMT7 is expected to be useful for understanding the activity and product specificity of other PRMTs as well.

Unraveling the Origins of Changing Product Specificity Properties of Arginine Methyltransferase PRMT7 by the E181D and E181D/Q329A Mutations through QM/MM MD and Free-Energy Simulations.

The methylation of the lysine residue can affect some fundamental biological processes, and specific biological effects of the methylations are often related to product specificity of methyltransferases. The question remains concerning how active-site structural features and dynamics control the activity as well as the number (1, 2, or 3) of methyl groups on methyl lysine products. SET domain containing protein 3 (SETD3) has been identified recently as the β-actin histidine73-N3 methyltransferase, and also, it has a weak methylation activity on the H73K β-actin peptide for which the target H73 residue is mutated into K73. Interestingly, the K73 methylation activity of SETD3 increases significantly as a result of the N255 → A or N255 → F/W273 → A mutation, and the N255A product specificity also differs from that of wild-type. Here, we performed QM/MM molecular dynamics and potential of mean force (PMF) simulations for SETD3 and its mutants (N255A and N255F/W273A) to study how SETD3 and its mutants could have different product specificities and activities for the K73 methylation. The PMF simulations show that the barrier for the first methylation of K73 is higher compared to the barrier of the H73 methylation in SETD3. Moreover, the second methylation of K73 has been found to have a barrier from the free energy simulation that is higher by 2.2 kcal/mol compared to the barrier of the first methyl transfer to K73, agreeing with the suggestion that SETD3 is a monomethylase. For the first, second, and third methylations of K73 in the N255A mutant, the barriers obtained from the PMF simulations for transferring the second and third methyl groups are found to be lower relative to the barrier for the first methyl transfer. Thus, N255A can be considered as a trimethyl lysine methyltransferase. In addition, for the first K73 methylation, the activities from the PMF simulations follow the order of N255F/W273A > N255A > WT, in agreement with experiments. The examination of the structural and dynamic results at the active sites provides better understanding of different product specificities and activities for the K73 methylations in SETD3 and its mutants. It is demonstrated that the existence of well-balanced interactions at the active site leading to the near attack conformation is of crucial importance for the efficient methyl transfers. Moreover, the presence of potential interactions (e.g., the C-H···O and cation-π interactions) that are strengthening at the transition state can also be important. Furthermore, the activity as well as product specificity of the K73 methylation also seems to be controlled by certain active-site water molecules which may be released to provide extra space for the addition of more methyl groups on K73.

Structural and Energetic Origin of Different Product Specificities and Activities for SETD3 and Its Mutants on the Methylation of the β-Actin H73K Peptide: Insights from a QM/MM Study.

Computational Study of Methionine Methylation Process Catalyzed by SETD3

Arginine methylations can regulate important biological processes and affect many cellular activities, and the enzymes that catalyze the methylations are protein arginine methyltransferases (PRMTs). The biological consequences of arginine methylations depend on the methylation states of arginine that are determined by the PRMT’s product specificity. Although the product specificity is a very important property, it is still unknown concerning why different PRMTs may generate different methylation states for the target arginine residues on protein substrates. PRMT7 is the only known member of Type III PRMT that produces mono-methylarginine (MMA) product. Interestingly, its E181D and E181D/Q329A mutants can catalyze, respectively, the formation of asymmetrically di-methylated arginine (ω-NG, NG-dimethylarginine or ADMA) and symmetrically di-methylated arginine (ω-NG, N'G-dimethylarginine or SDMA). The exact reasons for such product specificity modification as a result of the mutations have been unclear. Here QM/MM molecular dynamics (MD) and potential of mean force (PMF) free-energy simulations are performed for the E181D and E181D/Q329A mutants to understand the catalytic mechanism and the origin of their different product specificities from that of the wild-type PRMT7 as well as between E181D and E181D/Q329A. The simulations show that while the free energy barriers of E181D and E181D/Q329A for the first methylation are higher than that of the wild type, E181D and E181D/Q329A have the ability to add the second methyl group to the target mono-methyl arginine and generate ADMA and SDMA, respectively. The free energy barriers for E181D and E181D/Q329A to produce ADMA and SDMA, respectively, are considerably lower than the corresponding barriers involving the wild-type enzyme. Moreover, the computational study identifies some important structural, electronic and dynamic features that lead to the different product specificities and activities of the wild-type PRMT7, E181D and E181D/Q329A. These factors may play important roles in controlling the activity and product specificity of other PRMTs as well.

Understanding the Origins of Changing the Product Specificity Properties of Arginine Methyltransferase PRMT7 by E181→D and E181→D/Q329→A Mutations: A QM/MM Study

Updated Genetic Testing of Primary Hyperoxaluria Type 1 in a Chinese Population: Results from a Single Center Study and a Systematic Review

Volitinib is a novel selective cMet inhibitor. This study is to evaluate its preclinical ADME/PK profile. Volitinib has high membrane permeability (Papp (A>B) 28×10 − 6 cm/s) without efflux transport across Caco-2 cell monolayer and exhibits negligible P-gp inhibition (IC 50 > 17 μM). Metabolic stability of volitinib in liver microsomes and S9 fractions of rat, dog, monkey and human was evaluated. Five phase I metabolites were observed in liver microsomes and S9 fractions of different species, and three major metabolites resulted from demethylation (M1), hydroxylation (M2) and mono-oxygenation (M3) were found to be mediated by multiple enzymes, including CYP450s and aldehyde oxidase. Rat was the most similar species to human in terms of the in vitro metabolism and metabolite profile. Metabolism is the main route of elimination for volitinib in rat due to the fact that the fecal, urinary and biliary excretion of the parent volitinib accounted for max max =1.9 h) and moderately low distribution (Vss=0.7 L/kg), the poor oral bioavailability (1.9%) of volitinib in monkey is considered to be the result of excessive first-pass extraction. Overall, volitinib exhibited favorable preclinical PK/ADME properties. Citation Format: Yi Gu, Yang Sai, Jian Wang, Sumei Xia, Guanglin Wang, Yuansheng Zhao, Li Zhang, Wenqing Yang, Guangxiu Dai, Weihan Zhang, Qisun Gong, Zhenping Tian, Weiguo Su. Preclinical disposition and pharmacokinetics of volitinib, a novel selective cMet inhibitor . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3371. doi:10.1158/1538-7445.AM2013-3371

Abstract 3371: Preclinical disposition and pharmacokinetics of volitinib, a novel selective cMet inhibitor .

Molecular targeted drugs is now widely used in non-small cell lung cancer (NSCLC) clinical treatment. Icotinib hydrochloride is a new type of oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs). In this study, we examined the role of EGFR, K-RAS, B-RAF somatic mutations and EGFR mRNA expression in tumor specimens from advanced NSCLC patients as predicators of the efficacy of icotinib hydrochloride.

METHODS
We analyzed tumor paraffin-embedded specimens, which were obtained from 14 of 40 patients with advanced NSCLC who enrolled in the stage I clinical trial of icotinib hydrochloride. Somatic mutations were evaluated by mutant-enriched liquidchip (MEL) technology, and EGFR mRNA expression was measured by branched DNA liquidchip (MBL) technology.

RESULTS
In the 14 specimens, seven patients showed EGFR mutations, exon 19 deletion (3/7) and exon 21 point mutation (4/7); and two patients showed K-RAS mutation. No mutations in EGFR exon 20 or B-RAF were detected. In patients with EGFR mutation, one patient developed progress disease (PD), three patients had stable disease (SD), two patients had partial responses (PR) and one patient had a complete response (CR). In patients with wild-type EGFR, four patients had PD, three patients acquired SD, and none had PR/CR (P = 0.0407). EGFR mutations were associated with better progress-free survival (PFS) (141 days vs. 61 days) but without a statistically significant difference (P = 0.8597), and median overall survival (OS) (≥ 449 days vs. 140 days). EGFR mRNA expression levels were evaluated (three high, eight moderate, one low, and two that can not be measured due to insufficient tumor tissue) and no statistically significant relationships was observed with response, PFS or OS.

The EGFR mutation rate was consistent with that reported in the Asian population, so the MEL technology is reliable for measuring EGFR mutation with high throughput and rapidity. EGFR exon 19 deletions and exon 21 point mutation are predictive biomarkers for response to icotinib hydrochloride as second line treatment or above.

Tumor gene mutations and messenger RNA expression: correlation with clinical response to icotinib hydrochloride in non-small cell lung cancer.

In-situ characterization of porcine fibroblasts in response to silver ions by Raman spectroscopy and liquid scanning transmission electron microscopy.

It is challenging to design complex synthetic life-like systems that can show both autoevolution and fuel-driven transient behaviors. Here, we report a new class of chemical reaction networks (CRNs) to construct life-like polymer hydrogels. The CRNs are constituted of autocatalytic cascade reactions and fuel-driven reaction networks. The reactions start with only two compounds, that is, thiol of 4-arm-PEG-SH and thiuram disulfides, and undergo thiol oxidation (k1), disulfide metathesis (k2), and thionate hydrolysis-coupling reactions (k3) subsequently, leading to a four-state autonomous transition of sol(I) → soft gel → sol(II) → stiff gel. Moreover, thiuram disulfides can be applied as a fuel to drive the repeated occurrence of metathesis and hydrolysis-coupling reactions, generating dissipative stiff gel → sol(II) → stiff gel cycles. Systematic kinetics studies reveal that the event and lifetime of every transient state could be delicately tailored-up by varying the thiuram disulfide concentration, pH of the system, and thiuram structures. Since the consecutive transient behaviors are precisely predictable, we envision the strategy's potential in guiding the molecular designs of autonomous and adaptive materials for many fields.

Programming Hydrogels with Complex Transient Behaviors via Autocatalytic Cascade Reactions.

The medical applications of electrical biostimulation and silver ions have been evaluated in laboratory experiments and clinical studies for more than two decades. Their effects on preventing infection and promoting wound healing have been described. However, little is known about the role of electrical biostimulation and/or silver ion on changes in cellular transcriptome dynamics. To our knowledge, few studies have been conducted to investigate the potential of electrical biostimulation and silver ions in cell reprogramming. Besides, it is essential to assess any possible adverse effects or potential benefits of the silver ions on mammalian cells to address its safety concerns and to improve silver medical products. In this study, we investigated transcriptomic changes in porcine fibroblast cells in response to electrical biostimulation in the presence of silver ions. Exposed cells presented distinct morphological changes after treatment, which was mainly due to the exposure of silver ions rather than the electrical current itself. Gene expression analyses suggested that electrical biostimulation and silver ions did not increase the expression of pluripotency genes. Interestingly, a set of genes related to cellular metabolic processes were differentially expressed after cells were exposed to electrically generated silver ions for 21 hours. We found that 2.00 mg/L of electrically generated silver ion caused an increase of ATP generation and an increase of the total pool of NAD+ and NADH, while ROS production did not change. Aside from toxic effects, the results reported herein demonstrate the alternative effects of silver ions on mammalian cells, especially an oxidative phosphorylation burst. To our knowledge, this response of mammalian cells to silver ions has not been described previously. Although the function of this burst is not understood, it may lead to alterations in cellular activities such as metabolic remodeling and cell reprogramming, and/or serve an as-yet unknown function in neutralization or detoxification of the silver ions within the cells.

Effects of electrical biostimulation and silver ions on porcine fibroblast cells.

Somatostatin receptors (SSTRs) are G-protein-coupled plasma membrane receptors that have been determined to be expressed in normal and cancer tissues. Activation of SSTRs frequently results in inhibition of cell proliferation and therefore somatostatin analogues (SSAs) have been used in cancer treatment. However, the variable outcomes of SSA treatment were considered to be the consequences of loss-of-expression of SSTRs and/or subtype-specific effects. In the present study, the patterns of SSTR expression in 160 breast cancer tissues were investigated, and the mechanisms of SSTR activation and the influence on cell proliferation were further characterized. The expression levels of SSTR1-5 were determined using immunohistology. Hemagglutinin-SSTR1 and MYC-SSTR4 were transiently overexpressed in MDA-MB-435S cells, and the potential receptor dimerization was determined using immunofluorescence and co-immunoprecipitation. The influence of SSTR1 and SSTR4 expression/activation on cell proliferation was monitored using flow cytometry. The results demonstrated that all five SSTR subtypes were expressed at variable levels in tumor tissues, with the highest positive expression instance being determined for SSTR1 and SSTR4, with positive expression levels in 90.0 and 71.3% of tumor tissues, respectively. Immunofluorescence and co-immunoprecipitation revealed SSTR1/SSTR4 heterodimerization, which was increased in response to receptor activation using the subtype-specific SSA L-803087. The translocation of SSTR1/SSTR4 dimers into the cytoplasm upon receptor activation was also observed. Additionally, it was identified using flow cytometry that co-expression and activation of SSTR1 and SSTR4 in MDA-MB-435S cells resulted in a decreased proportion of S-phase cells. The results of the present study revealed that SSTR1 and SSTR4 are the most frequently expressed SSTR subtypes in breast cancer, and that the cell cycle arrest was mediated by SSTR1/SSTR4 dimerization/activation.

Expression and selective activation of somatostatin receptor subtypes induces cell cycle arrest in cancer cells

The soil pollution is getting worse with the rapid development of industry in recent years, Heavy metals can ultimately affect human health through the food chain. So immobilization of heavy metals in soil is of great significance. Here, six single stabilizer and six composite stabilizers, including CaO, bone char (BC), Na2S, calcium superphosphate (SSP), sodium diethyldithiocarbamate (DDTC-Na) and FeSO4, were investigated to immobilize heavy metals and As in mine soil. Toxicity Characteristic Leaching Procedure (TCLP) was adopted to evaluate the stabilization effectiveness of the stabilizers on Pb, Zn, Cu, Cd and As, and the best stabilizers for simultaneously immobilizing Pb, Zn, Cu, Cd and As in soil were selected based on the TCLP results. The results in this study provide useful information for remediation of heavy metals contaminated soil.

Effectiveness of Single and Composited Stabilizers on Enhancing Stability of Multiple Metals in Mine Soil

Isolation and characterization of trophoblast-derived stem-like cells from peri-implantation porcine embryos.

Short-chain chlorinated paraffins(SCCPs) is a new candidate of persistent organic pollutants by the "Stockholm Convention". In this study, the occurrence, congener specific profiles, source and biota-sediment accumulation factor(BSAF) of SCCPs in sediments and biota samples collected from the Liao river estuary were investigated. The concentrations of SCCPs range from 64.9 to 1683.4 ng/g dw(mean 419.7) in the sediments and 1.55 to 11.9 μg/g dw(mean 6.14). C10 and C11 homologue groups of SCCPs are predominant in the sediments and organism with the summed relative contribution of 69.5% and 84.0%, respectively. Cl5, Cl6 and Cl7 congeners are the main congener groups in the sediments and organisms with the total relative contribution of 84.5% and 90.8%, respectively. The results also imply that the major pollution sources of SCCPs in this area are the productive activities and usage of CP-42 and CP-52, and one major source route is the riverine input. The average BSAF of ∑SCCPs(2.34) is higher than 1 shows an obvious bioaccumulation in mollusks. Significant negative correlation between BSAF and chlorine atoms(P0.05) is observed, indicating that the behavioral enrichment of zoobenthos and fish are quite different due to the influence of physicochemical properties and feeding way.

Congener specific distribution and bioaccumulation of short-chain chlorinated paraffins in Liao estuary

Concentration-dependent photodegradation kinetics and hydroxyl-radical oxidation of phenicol antibiotics.

Photochemical degradation is a central factor in determining the fate of antibiotic micropollutants in surface waters. In this study, the photodegradation kinetics, influencing factors and transformation products of linezolid, a representative oxazolidinone antibiotic, were investigated. Under simulated sunlight irradiation (λ290 nm), the photodegradation followed the pseudo-first-order kinetics with an apparent quantum yield of 0.834±0.054 in pure water. The rates of linezolid photodegradation were slower in freshwater or seawater than in pure water, which was attributed to the effects of the ubiquitous aqueous dissolved matter on the photodegradation. pH, Cl – and seawater salinity did not affect the photodegradation kinetics (P0.05), while humic acid, NO 3 and Fe(III) acted mainly as radiation filters and inhibited the photodegradation (P≤0.05). Under simulated sunlight as well as UV-vis (λ200 nm) irradiation, scavenging experiments revealed that linezolid underwent direct photolysis and self-sensitized photodegradation via 1 O 2 , which resulted in a negative correlation between the photolysis rate constants and the initial concentrations. The main photodegradation products and pathways varied under irradiation of different light sources. Linezolid mainly underwent defluorination and photoinduced hydrolysis under UV-vis irradiation, whereas morpholine-dehydrogen was primary under simulated sunlight.

Aqueous photochemical behavior of oxazolidinone antibiotic linezolid

Extraction of soil nitrate nitrogen (NO3 −-N) and ammonium nitrogen (NH4 +-N) by chemical reagents and their determinations by continuous flow analysis were used to ascertain factors affecting analysis of soil mineral N. In this study, six factors affecting extraction of soil NO3 −-N and NH4 +-N were investigated in 10 soils sampled from five arable fields in autumn and spring in northwestern China, with three replications for each soil sample. The six factors were air drying, sieve size (1, 3, and 5 mm), extracting solution [0.01 mol L−1 calcium chloride (CaCl2), 1 mol L−1 potassium chloride (KCl), and 0.5 mol L−1 potassium sulfate (K2SO4)] and concentration (0.5, 1, and 2 mol L−1 KCl), solution-to-soil ratio (5:1, 10:1, and 20:1), shaking time (30, 60, and 120 min), storage time (2, 4, and 6 weeks), and storage temperature (−18 oC, 4 oC, and 25 oC) of extracted solution. The recovery of soil NO3 −-N and NH4 +-N was also measured to compare the differences of three extracting reagents (CaCl2, KCl, and K2SO4) for NO3 −-N and NH4 +-N extraction. Air drying decreased NO3 −-N but increased NH4 +-N concentration in soil. Soil passed through a 3-mm sieve and shaken for 60 min yielded greater NO3 −-N and NH4 +-N concentrations compared to other treatments. The concentrations of extracted NO3 −-N and NH4 +-N in soil were significantly (P < 0.05) affected by extracting reagents. KCl was found to be most suitable for NO3 −-N and NH4 +-N extraction, as it had better recovery for soil mineral N extraction, which averaged 113.3% for NO3 −-N and 94.9% for NH4 +-N. K2SO4 was not found suitable for NO3 −-N extraction in soil, with an average recovery as high as 137.0%, and the average recovery of CaCl2 was only 57.3% for NH4 +-N. For KCl, the concentration of extracting solution played an important role, and 0.5 mol L−1 KCl could fully extract NO3 −-N. A ratio of 10:1 of solution to soil was adequate for NO3 −-N extraction, whereas the NH4 +-N concentration was almost doubled when the solution-to-soil ratio was increased from 5:1 to 20:1. Storage of extracted solution at −18 °C, 4 °C, and 25 °C had no significant effect (P < 0.05) on NO3 −-N concentration, whereas the NH4 +-N concentration varied greatly with storage temperature. Storing the extracted solution at −18 oC obtained significantly (P < 0.05) similar results with that determined immediately for both NO3 −-N and NH4 +-N concentrations. Compared with the immediate extraction, the averaged NO3 −-N concentration significantly (P < 0.05) increased after storing 2, 4, and 6 weeks, respectively, whereas NH4 +-N varied in the two seasons. In conclusion, using fresh soil passed through a 3-mm sieve and extracted by 0.5 mol L−1 KCl at a solution-to-soil ratio of 10:1 was suitable for extracting NO3 −-N, whereas the concentration of extracted NH4 +-N varied with KCl concentration and increased with increasing solution-to-soil ratio. The findings also suggest that shaking for 60 min and immediate determination or storage of soil extract at −18 oC could improve the reliability of NO3 −-N and NH4 +-N results.

Comparison of Factors Affecting Soil Nitrate Nitrogen and Ammonium Nitrogen Extraction

With exposure experiment, this paper studied the accumulation and elimination of cadmium (Cd) in the viscera, muscle and gill of Paralichthys olivaceus, and the effects of TOC concentration in seawater on the Cd accumulation. The results showed that when the exposure concentration of Cd was 0.5 mg x L(-1), its accumulation in test tissues increased with time, and reached equilibrium on the 10th day. The accumulation was in order of viscera (147.73 mg x kg(-1) DW) > gill (15.55 mg x kg(-1) DW) > muscle (4.578 mg x kg(-1) DW), which meant that viscera was the main place for Cd accumulation. Determinations after moving the fish into clear seawater on the 13th day of exposure showed that due to depuration, the Cd accumulation in test tissues decreased with time. On the 15th day after moving, the Cd elimination was in order of viscera (80.66%) > gill (73.66%) > muscle (56.84%), suggesting that the Cd accumulation in Paralichthys olivaceus could be reduced to meet safe food standard. The TOC concentration in seawater had a significant effect on Cd accumulation, i.e., the accumulation of Cd decreased significantly with increasing TOC concentration, demonstrating that the TOC in seawater could decrease the bioavailability of cadmium.

[Bioavailability of cadmium in seawater to Paralichthys olivaceus].

Freeze-dried (FD) fruit and vegetable materials with a large amount of sugar are unstable. With the aim to understand the structure formation of FD products, the effects of fructose content on the texture and microstructure of FD matrix were investigated by using pectin-cellulose cryogel model. Cryogels containing fructose of 0-40% were produced using freeze-drying at three different primary drying temperatures of -40, -20, and 20°C. The resultant cryogels were characterized by texture profile analyzer, scanning electron microscope, and μCT. Results indicated that at drying temperature of -40°C, increasing fructose concentration promoted the hardness of the cryogels, and cryogels of 16% fructose obtained maximum hardness. Excessive fructose (≥20%) weakened the described hardness, while exhibiting stronger springiness and resilience. The microstructure showed that dense pores and increased wall thickness due to fructose aggregation were critical factors responsible for increased hardness. The porous structure as well as relatively large pore size were necessary for crispness, in addition, rigid pore wall with certain strength were also required. At the drying temperature of 20°C, large hetero-cavities dominated the microstructure of cryogels with 30% and 40% fructose, caused by melting inside during FD process. In this situation, lower Tm (-15.48 and -20.37°C) were responsible for cryogels' melting In conclusion, if possible, regulating fructose content and state may enable the precision texture design of FD fruit and vegetable foods.

The role of fructose at a range of concentration on the texture and microstructure of freeze-dried pectin-cellulose matrix cryogel.

Shrimp fried in vegetable oil is a very popular food, so it is important to study the changes in the quality of the oil during frying. In order to more precisely study the nature of frying oil during the cooking process, this study investigated the quality changes of high-oleic sunflower oil during the frying of South American white shrimp (Litopenaeus vannamei). The oxidation and hydrolysis products of frying oils were investigated by integrating the proton nuclear magnetic resonance technique with traditional oil evaluation indexes in an integrated manner. The results showed that the color difference as measured using the ΔE* value increased gradually during the process. Moreover, the acid value, carbonyl value, and total oxidation significantly increased with prolonged frying time. The major oxidation products formed during frying were (E,E)-2-alkenals, (E,E)-2,4-alkadienals, and E,E-conjugated hydroperoxides. This indicated that longer treatment times corresponded with an increased accumulation of aldehydes and ketones, and an increased degree of oxidative deterioration of the oil. However, the proportion of oleic acid in the frying oil increased with the frying of shrimp, reaching 80.05% after 24 h. These results contribute to our understanding of the oxidative deterioration of high-oleic oils during frying, and provide an important reference for the application properties of high-oleic oils.

Changes in the Quality of High-Oleic Sunflower Oil during the Frying of Shrimp (Litopenaeus vannamei)

Understanding of osmotic dehydration on mass transfer and physical properties of freeze‐dried apple slices: a comparative study of five saccharides osmotic agents

Effect of the odour compound from Periploca sepium Bunge on the physiological and biochemical indices, photosynthesis and ultrastructure of the leaves of Humulus scandens (Lour.) Merr.

Dose-dependent effects of apple pectin on alleviating high fat-induced obesity modulated by gut microbiota and SCFAs

As the most widely consumed fruit in the world, apple (Malus domestica Borkh.) fruits provide a high level of phenolics and have many beneficial effects on human health. The composition and content of phenolic compounds in natural apples differs according to the tissue types and cultivar varieties. The bioavailability of apple-derived phenolics, depending on the absorption and metabolism of phenolics during digestion, is the key determinant of their positive biological effects. Meanwhile, various processing technologies affect the composition and content of phenolic compounds in apple products, further affecting the bioavailability of apple phenolics. This review summarizes current understanding on the compositions, distribution, absorption, and metabolism of phenolic compounds in apple and their stability when subjected to common technologies during processing. We intend to provide an updated overview on apple phenolics and also suggest some perspectives for future research of apple phenolics.

Systematic Review of Phenolic Compounds in Apple Fruits: Compositions, Distribution, Absorption, Metabolism, and Processing Stability.

Characterization of tissue‐specific differences in cell wall pectic polysaccharides of carrot root

Effect of ultrasound on mass transfer kinetics and phenolic compounds of apple cubes during osmotic dehydration

Pectin and homogalacturonan with small molecular mass modulate microbial community and generate high SCFAs via in vitro gut fermentation.

Stability of phenolic compounds and drying characteristics of apple peel as affected by three drying treatments

BACKGROUD. Carrot carotenoids are typically located in chromoplasts, forming a specific sub-structure of crystalline. As a consequence, cell walls and chromoplasts constitute two major physical barriers for carotenoid releasing from the food matrix during digestion. The release of carotenoids from these physical barriers is supposed to be substantially affected by the mechanical factors during food processing and oral mastication. Given the above implications, the effect of four different processing procedures and various mastication levels on carotenoid bioaccessibility of carrot chips were evaluated. RESULTS: Restructuring and drying methods substantially affected the carotenoid bioaccessibility of carrot chips. The highest carotenoid bioaccessibility was obtained for the air dried combined instant pressure drop dried (AD-DIC) restructured chips. Though the fresh carrots possessed the highest content of carotenoids, their bioaccessibility was the lowest compared to those of the carrot chips. The evolution of particle size of the samples was responsible for the changes of carotenoid bioaccessibility due to oral masitication. The particle size of the fresh carrots was decreased with enhancing extent of oral masitication, which was favor of carotenoid bioaccessibilty. However, the freeze dried combined instant pressure drop dried restructural chips (R-FD-DIC) demonstrated opposite trend, probably caused by the severe aggregation of the sample during digestion, which compromised the effect of masitcation for carotenoid releasing. CONCLUSION: Detailed data of the effects of drying process and oral mastication digestion behavior of the samples suggested that AD-DIC dried restructured carrot chips are effective in enhance carotenoid bioaccessibility, which help to understand the key factors for carotenoid releasing in case of carrot chips prepared by particular process. This article is protected by copyright. All rights reserved.

Evaluation of processing methods and oral mastication on the carotenoid bioaccessibility of restructured carrot chips.

The effect of freeze drying (FD), far‐infrared radiation drying (FIRD), heat pump drying (HPD), hot air drying (HAD), and hot air combined instant controlled pressure drop drying (DIC) were compared on the drying efficiency and quality attributes of dried shiitake mushrooms. The results showed that in comparison with the HPD, HAD, and DIC, the FIRD shiitake mushroom exhibited better appearance with less shrinkage and lower ΔE (6.10), lower hardness (34.82 N), and higher rehydration ratio (7.55), which were more resemble to those of the FD sample. Besides, a significantly higher (p < 0.05) retention of protein was found in the FD and FIRD sample (2.47 mg/g and 2.30 mg/g), as well as higher retention of polysaccharide (1.79 mg/g and 1.39 mg/g). In addition, FIRD shiitake mushroom were superior to FD product in terms of saving drying time as 66.25% and exhibiting maximum numbers of flavor components, among which specific sulfides showed the highest percentage (24.59%). Therefore, the FIRD dried shiitake mushroom obtained a better overall quality among the products dried by the five drying methods. PRACTICAL APPLICATIONS: Shiitake mushrooms are wildly planted edible fungi, which are consumed mostly in dried form around the word. Recently, the demand of efficient application have promoted an increasingly use of novel drying technologies in mushroom processing. This study presents comprehensive evaluations on some vital quality attributes of shiitake mushrooms using five drying methods that already commercialized in China. FIRD was more suitable to produce dried shiitake mushrooms with desirable appearance and texture, as well as relatively rich flavor and nutrients.

Evaluation of sensory, textural, and nutritional attributes of shiitake mushrooms (
 Lentinula edodes
 ) as prepared by five types of drying methods

Characteristics of cell wall pectic polysaccharides affect textural properties of instant controlled pressure drop dried carrot chips derived from different tissue zone.

ABSTRACT Shiitake mushrooms are mostly used in the forms of dried products, and the pretreatments could help to improve the product quality. The effects of ultrasound pretreatment on water diffusion during short- and medium-wave infrared drying and overall product quality of shiitake mushroom were investigated. Shiitake mushroom slices were pretreated with ultrasonic wave at 28 kHz and 600 W for 15 min and then conducted infrared dried at 1350 W and 60°C. The results demonstrated that the drying time of the samples previously subjected to ultrasound pretreatment was remarkably reduced by 21.43%, as compared to the samples without pretreatment. Moreover, homogenous porous microstructure was obtained by dried mushrooms pretreated by ultrasound. In addition, the honeycomb-like microstructure pointed to superior texture, which also lead to reduce hardness and increase crispness of dried products. Furthermore, the dried products exhibited higher lightness (78.46) and better shape than those of the other pretreatment samples. In conclusion, ultrasound pretreatment coupled with infrared drying might be a potential method to produce high-quality dried shiitake mushrooms slices.

Improving of texture and rehydration properties by ultrasound pretreatment for infrared-dried shiitake mushroom slices

An abundance of shiitake mushrooms is consumed in dried form around the world. In the present study, changes in water state, water distribution and microstructure of shiitake mushrooms during hot-air drying (HAD) and far-infrared radiation drying (FIRD) processes were investigated using low-field nuclear magnetic resonance and scanning electron microscopy. Quality attributes of the dried products were compared in terms of drying property, appearance, rehydration behavior, texture and storage stability.

RESULTS
Compared with HAD, the rate of water diffusion and evaporation of the shiitake mushrooms dried by FIRD was higher, thus resulting in a shorter drying time (630 min), a lower water content (0.07 g g-1 wet basis) and a higher glass transition temperature (7.88 °C) for dried products. Moreover, a homogenous and porous microstructure with less shrinkage and case hardening was demonstrated by the FIRD samples, indicating a superior texture, including a larger pileus diameter (3.4 cm), a higher rehydration ratio (7.31), a lower hardness (37.93 N) and a higher crispness (1.41 mm) for FIRD shiitake mushrooms.

High-quality shiitake mushrooms with a desirable texture could be produced by FIRD by enhancing the diffusion of internal water and alleviating the case hardening during a relatively short drying process. © 2018 Society of Chemical Industry.

Comparison of dynamic water distribution and microstructure formation of shiitake mushrooms during hot air and far infrared radiation drying by low-field nuclear magnetic resonance and scanning electron microscopy.

Abstract The effects of instant controlled pressure drop (DIC) drying, and blanching-assisted DIC (B + DIC) on texture, volume ratio (VR), colour, microstructures of different tissues, and cell-morphology of fruit and vegetable chips was examined. Results revealed that B + DIC had a significant effect on fruits and vegetable chips as compared with DIC treated. The DIC dried mango chips were observed to have low hardness (26.12 N) and maximum crispness (10.43) that were also observed in mango chips under B + DIC treated (14.66), exhibiting a puffy structure and crispy texture. Well expanded structure which reflected by VR was found in the mango (0.46 mL) and king oyster mushroom (KOM) (0.36 mL) chips under both treatments. The maximum total colour changes (∆E) were also obtained in the mango (30.40) and carrot (42.87) chips under B + DIC. The microstructures of the apple, carrot, KOM and potato chips products, which corresponded to its well expanded appearances, showed a honeycomb-like pores structure, observed for DIC treated apple, fresh potato, B + DIC dried KOM as well as in sweet potato. In addition, the B + DIC-treated carrot chips, pores size, increased the cell wall and expanded. Moreover, the mushroom chips mostly were shrunken after hot water blanching.

Effects of Instant Controlled Pressure Drop (DIC) Drying on the Texture and Tissue Morphology of Fruits and Vegetables

Abstract Instant controlled pressure drop (ICPD) is an emerging drying technique that can produce fruit chips with crispy texture. To improve the qualities of ICPD-dried apple chips, six types of saccharides with different polymerization were used for osmotic pretreatment on apple slices. Firstly, the effects of different saccharides on the osmotic behavior and texture of ICPD-dried apple chips were evaluated. Then, the effects of osmotic conditions of a selected saccharide, i.e. stachyose, on the qualities of ICPD-dried apple chips were studied. The results showed that sucrose, raffinose, and stachyose could significantly enhance the crispness of the ICPD-dried apple chips. In addition, the ICPD-dried apple chips pretreated with stachyose possessed the highest Tg (29.74 °C) and superior porous structure compared with pretreatments using the other saccharides. Moreover, limited color change (ΔE) was found in the samples pretreated with stachyose at 40 °C for 30 min, as well as higher retention of polyphenols. In conclusion, it is confirmed that the types of saccharides significantly influence the qualities of the ICPD-dried apple chips, and osmotic pretreatment at 40 °C for 30 min using stachyose was suggested for improving the overall quality of ICPD-dried apple chips.

Osmotic pretreatment for instant controlled pressure drop dried apple chips: Impact of the type of saccharides and treatment conditions

In this study, four different biochar application rates and a control were set up using indoor potted tobacco, to study the effects of biochar on the microbial diversity and metabolism of tobacco-growing soil. The five treatments were as follows: control—0% biochar (w/w) + 26 g fertilizer/pot; biochar treatments—1% biochar (w/w) + 26 g fertilizer/pot, 2% biochar (w/w) + 26 g fertilizer/pot, 3% biochar (w/w) + 26 g fertilizer/pot, and 4% biochar (w/w) + 26 g fertilizer/pot. We found that biochar increases the microbial diversity of soils and simultaneously changes the microbial community structure. Under the influence of biochar, soil urease activity increased by 18%, invertase activity increased by 23.40%, polyphenol oxidase activity increased by 59.50%, and catalase activity increased by 30.92%. Biochar also significantly increased the microbial biomass carbon and nitrogen content of the soil. Soil microbial biomass nitrogen had a positive correlation on bacterial diversity, with the highest coefficient, while soil microbial biomass carbon had a positive correlation on fungal diversity, with the highest coefficient. The microbial diversity and metabolic capacity of soil are improved under the influence of biochar, and soil enzyme activity and microbial biomass carbon and nitrogen have positive impacts on soil microbial diversity.

Effect of Biochar on Rhizosphere Soil Microbial Diversity and Metabolism in Tobacco-Growing Soil

Floral analysis in fruit crops: A potential tool for nutrient constraints diagnosis

Variation in spectral characteristics of dissolved organic matter derived from rape straw of plants grown in Se-amended soil

Selenium induces changes of rhizosphere bacterial characteristics and enzyme activities affecting chromium/selenium uptake by pak choi (Brassica campestris L. ssp. Chinensis Makino) in chromium contaminated soil.

Selenium alleviated chromium stress in Chinese cabbage (Brassica campestris L. ssp. Pekinensis) by regulating root morphology and metal element uptake.

Selenium reduces the pathogenicity of Sclerotinia sclerotiorum by inhibiting sclerotial formation and germination.

Dissolved organic matter derived from rape straw pretreated with selenium in soil improves the inhibition of Sclerotinia sclerotiorum growth.

Selenium reduces cadmium accumulation in seed by increasing cadmium retention in root of oilseed rape (Brassica napus L.)

Cadmium (Cd) is highly toxic, even at very low concentrations, to both animals and plants. Pollen is extremely sensitive to heavy metal pollutants; however, less attention has been paid to the protection of this vital part under heavy metal stress. A pot experiment was designed to investigate the effect of foliar application of Se (1 mg/L) and Mo (0.3 mg/L) either alone or in combination on their absorption, translocation, and their impact on Cd uptake and its further distribution in Brassica napus, as well as the impact of these fertilizers on the pollen grains morphology, viability, and germination rate in B. napus under Cd stress. Foliar application of either Se or Mo could counteract Cd toxicity and increase the plant biomass, while combined application of Se and Mo solutions on B. napus has no significant promotional effect on plant root and stem, but reduces the seeds’ weight by 10–11%. Se and Mo have decreased the accumulated Cd in seeds by 6.8% and 9.7%, respectively. Microscopic studies, SEM, and pollen viability tests demonstrated that pollen grains could be negatively affected by Cd, thus disturbing the plant fertility. Se and Mo foliar application could reduce the toxic symptoms in pollen grains when the one or the other was sprayed alone on plants. In an in vitro pollen germination test, 500 μM Cd stress could strongly inhibit the pollen germination rate to less than 2.5%, however, when Se (10 μM) or Mo (1.0 μM) was added to the germination medium, the rate increased, reaching 66.2% and 39.4%, respectively. At the molecular level, Se and Mo could greatly affect the expression levels of some genes related to Cd uptake by roots (IRT1), Cd transport (HMA2 and HMA4), Cd sequestration in plant vacuoles (HMA3), and the final Cd distribution in plant tissue at the physiological level (PCS1).

Can Selenium and Molybdenum Restrain Cadmium Toxicity to Pollen Grains in Brassica napus?

Action of selenium against Sclerotinia sclerotiorum: Damaging membrane system and interfering with metabolism.

The joint effects of earthworms and crop straw on toxic metal speciation are not clear, and very limited information is available regarding the effects of their interaction on Cd mobility in Cd contaminated soil or in remediation processes involving plants. This study evaluated their impacts on Cd mobile form changes in soil and their effects on Cd uptake by plants. Treatments included both planted and unplanted-Cd-contaminated soil with or without rice straw and/or earthworms. The results revealed that earthworms, rice straw, and plant interactions change the Cd mobile forms in soil. The order of Cd concentration of different chemical forms was as follows: exchangeable > residual > bound to Fe-Mn oxide > bound to organic matter for earthworms, and exchangeable > bound to organic matter > residual > bound to Fe-Mn oxide for rice straw treatment, with a recovery rate of 96 ± 3%. The accumulation of Cd in plants increased in the presence of earthworms and decreased in the presence of rice straw. FT-IR spectra indicated that the degradation of rice straw increases C–O, C–O–H, C–H, and O–H functional groups which could complex with Cd ions. These findings highlighted that earthworms’ activities and crop straw can modify soil properties and structure and promote the remediation of heavy metal. This study suggests that the ecological context of remediation instead of being limiting on soil-earthworms-plant interaction, should integrate the natural resources forsaken which can provide a positive influence on both plant health and the remediation of heavy metal in contaminated soil.

Earthworms, Rice Straw, and Plant Interactions Change the Organic Connections in Soil and Promote the Decontamination of Cadmium in Soil

Identifying the contributions of constituents to the fracture performance and failure mechanism of fiber metal laminate

Phosphorus doping significantly enhanced the catalytic performance of cobalt-single-atom catalyst for peroxymonosulfate activation and contaminants degradation.

Energy dissipation mechanism of fiber metal laminate under low-velocity impact

Quasi‐static fracture characterization of fiber metal laminate with crack resistance curve based on
 δ
 5

Inverse determine the interfacial strength and surface geometry effects concerning carbon fiber reinforced epoxy composites by experiment aided
 FFT
 ‐based spectral analysis

Flame retardation of vinyl ester resins and their glass fiber reinforced composites via liquid DOPO-containing 1-vinylimidazole salts

Low-temperature thermal insulation materials with high impact resistance made from feather-fibres

Used lubricating oil contains more than 90% of good base oil and available additives, providing the potential of energy conservation, environmental protection, and economy, though it loses its useful performance because of contamination by impurities, oxidation, and degradation of additives. Many countries around the world have focused on reclamation and re-refining methods to treat and reuse waste lubricating oils for many years. But the regeneration rate of waste oils is very low in China, less than 20% of the lubricant consumption. Few studies on the performance, especially lubrication properties of recycled lubricating oils, have been considered. In this article, based on differences between used and fresh oils, used oils were reclaimed and replenished with additives (henceforth refortified oils). The physical and chemical properties, including viscosity, total acid number, moisture content, copper corrosion, and water separability from petroleum oil and synthetic fluid as well as the lubrication characteristics of three kinds of refortified hydraulic oils were investigated. The lubrication performance was evaluated using a four-ball tribotester and a Universal Micro-Tribotester (UMT) reciprocating tester. Moreover, the worn surfaces were analyzed using confocal scanning optical microscopy (CSOM), scanning electron microscopy (SEM) with energy dispersive X-ray spectroscopy (EDS), and Raman spectroscopy. The results showed that refortified oils provided good physical and chemical properties, close to those of fresh oils, and produced better tribological characteristics than used and even fresh oils. There were compositional differences between the films of fresh, used, and refortified oils.

Evaluation of Lubrication Properties of Refortified Hydraulic Oils

Tribological and economic evaluation of recycled mineral lubricating oils

Polymer-modified cement compounds for waterproofing membrane is widely used in tunnel, reservoir, rooftop, bathroom, cellar and other construction work for the better mechanic properties and waterproof effect. And all these properties are decided by the interaction between the compositions and the final microstructure they formed. However, different polymer cement ratio lead to excellent different properties, people have done a lot of research on polymer-modified cement compounds for water-proofing membrane, but the micro explain has been researched rarely. In this paper, scanning electron microscope was used to observe the microstructure between different waterproofing membranes, the properties of tensile strength, braking elongation and water absorption rate were tested, and the relationship between them were also researched.

Research on the Relationship between Microstructure and Properties of Polymer-Modified Cement Compounds for Waterproofing Membranes

The experiment about ramie fabrics processed by oxygen plasma was introduced. The mass spectrum of residual gas was measured by QMS, and quantities of hydrogen, carbon, oxygen and its compounds was observed from vacuum residual gas. The microcosmic characteristic of ramie treated by oxygen plasma show that the surface of the ramie fibre was effectively eroded by energetic particle and active molecules. It can be obviously seen from X-Ray diffraction analysis that the crystalline-indices of ramie fibre were slightly reduced after processing in oxygen plasma. Experiment results reveal that, with the increase of the processing time and power, the physical chemical properties such as wettability and dyeability were obviously improved.

The spiro[indoline-3,3′-pyrrolidin]-2-ones were synthesized via a silica gel and alumina-mediated sequential transformation based on tryptamine-derived ynesulfonamide substrates under neat conditions. The inherent tendency of C−C bond migration through Wagner-Meerwein rearrangement in the synthesis of spirooxindole was prevented by water trapping to the spiroindoleninium intermediate. The functional group tolerances of the methodology were investigated using a variety of substrates. The detailed mechanism of the sequential transformation was probed by the isotope-labeled experiments. This strategy was further applied in the formal syntheses of indole alkaloids coerulescine and horsfiline.

Ynesulfonamide‐Based Silica Gel and Alumina‐Mediated Diastereoselective Cascade Cyclizations to Spiro[indoline‐3,3′‐pyrrolidin]‐2‐ones under Neat Conditions

Ynamides, as versatile synthetic precursors, have attracted much attention from synthetic chemists and sparked the development of a number of methodologies for the construction of various structures. 1H-Pyrrolo[2,3-d]carbazole is a core scaffold of a series of monoterpene indole alkaloids found in Kopsia, Strychnos, and Aspidosperma, for example. In this study, 1H-pyrrolo[2,3-d]carbazole derivatives were synthesized by a Brønsted acid-catalyzed tandem cyclization starting from tryptamine-based ynamides. This strategy prevented Wagner-Meerwein rearrangement by instantaneous intramolecular nucleophilic trapping of the indoleninium to afford a tetracyclic indoline via an in situ-formed enol species induced by the formation of a more stable conjugate diene moiety. The functional group tolerances were investigated by using a series of readily available substrates. A plausible mechanism has been proposed based on the evidence of the capture of the hemiaminal intermediate. Lastly, a Büchi ketone, which is the pivotal intermediate in the synthesis of the indole alkaloid vindorosine, was synthesized by utilizing our newly developed methodology.

Brønsted Acid-Catalyzed Tandem Cyclizations of Tryptamine-Ynamides Yielding 1H-Pyrrolo[2,3-d]carbazole Derivatives.

Front Cover: Brønsted Acid‐Catalyzed Tandem Cyclizations of Tryptamine‐Ynamides Yielding 1H‐Pyrrolo[2,3‐d]carbazole Derivatives (Chem. Eur. J. 16/2018)

A highly regioselective DBU-catalyzed [3 + 2] annulation of Morita-Baylis-Hillman carbonates with isothiocyanates was developed. This method allows rapid and efficient synthesis of spirocyclic oxindole dihydrothiophene products in moderate to high yields with excellent regioselectivities under simple conditions. A plausible reaction mechanism is also proposed.

Synthesis of Spirocyclic Oxindole Dihydrothiophenes by DBU-Catalyzed [3 + 2] Annulation of Morita-Baylis-Hillman Carbonates with Isothiocyanates.

An interesting effect of the N-substituent of the NHC-catalyst on the selectivity of the cycloaddition of 2-aroylvinylcinnamaldehydes with α,β-unsaturated imines is reported.

N‐Heterocyclic Carbene‐Catalyzed Diastereoselective and Enantioselective Reaction of 2‐Aroylvinylcinnamaldehydes with α,β‐Unsaturated Imines: Complete Control and Switch of Diastereoselectivity by N‐Substituents of Catalysts.

Depending on the amount of base used, this method yields either benzofurans (III) and (V) with high diastereoselectivity or benzopyrans (VI) and (VII).

N-Heterocyclic Carbene/Broensted Base Cascade Catalysis: Base-Controlled Selective Synthesis of Multifunctional Benzofuran-3-ones or Flavone Derivatives from the Reaction of 3-(2-Formylphenoxy)propenoates with Imines.

Highly diastereoselective and enantioselective reactions between 2-aroylvinylcinnamaldehydes and α,β-unsaturated imines were achieved under asymmetric catalysis of chiral triazole carbene catalysts. In the presence of N-anisylindeno[2,1-b]triazolo[4,3-d][1,4]oxazinium salt, the reaction of 2-aroylvinylcinnamaldehydes with α,β-unsaturated imines afforded indeno[2,1-c]pyran-1-one derivatives 4 with 90%-99% ee, while enantiopure indenocyclopentan-1-ones 5 (>99% ee) were obtained under the catalysis of N-mesitylindeno[2,1-b]triazolo[4,3-d][1,4]oxazinium salt. A slight variation of an N-substituent on triazole carbenes was found to switch completely the diastereoselectivity of the reaction for the formation of indeno[2,1-c]pyran-1-ones.

N-heterocyclic carbene-catalyzed diastereoselective and enantioselective reaction of 2-aroylvinylcinnamaldehydes with α,β-unsaturated imines: complete control and switch of diastereoselectivity by N-substituents of catalysts.

Organocatalyzed Asymmetric Vinylogous Allylic—Allylic Alkylation of Morita—Baylis—Hillman Carbonates with Olefinic Azlactones: Facile Access to Chiral Multifunctional α-Amino Acid Derivatives.

Vinylogous reactivity of olefinic azlactones was realized through the development of a chiral amine-catalyzed highly stereoselective allylic-allylic alkylation with Morita-Baylis-Hillman carbonates. The Lewis base activation of electrophile and Brønsted base activation of nucleophile were efficiently combined, giving access to multifunctional acyclic α-amino acid derivatives in a highly stereocontrolled manner. The synthetic utility of these versatile synthons was further demonstrated by the facile synthesis of protected cyclic quaternary α-amino acids.

Organocatalyzed Asymmetric Vinylogous Allylic-Allylic Alkylation of Morita-Baylis-Hillman Carbonates with Olefinic Azlactones: Facile Access to Chiral Multifunctional α-Amino Acid Derivatives.

The unprecedented NHC/Brønsted base-cocatalyzed dimerization reaction of 2-(aroylvinyl)arylaldehydes was reported. In the presence of a triazole carbene catalyst alone, no reaction of 2-(aroylvinyl)arylaldehydes was observed. However, the combination of triazole carbene and 4-methoxyphenolate efficiently catalyzed the dimerization of 2-(aroylvinyl)arylaldehydes to proceed through a benzoin-Michael-Michael reaction cascade, producing 6-aroyl-5-(aroylmethyl)-11a-hydroxybenzo[a]fluoren-11-ones as the sole diastereomers in good yields.

Changing the reaction pathway by NHC/Brønsted base cooperative catalysis: highly stereoselective synthesis of multifunctional benzo[a]fluoren-11-ones from the dimerization of 2-(aroylvinyl)arylaldehydes.

The unprecedented title synthesis requires both the triazole catalyst and 4-methoxyphenolate as a co-catalyst and proceeds via a benzoin-Michael-Michael cascade reaction sequence.

Changing the Reaction Pathway by NHC/Broensted Base Cooperative Catalysis: Highly Stereoselective Synthesis of Multifunctional Benzo[a]fluoren‐11‐ones from the Dimerization of 2‐(Aroylvinyl)arylaldehydes.

An asymmetric formal [5 + 1] cyclization of oxindoles and ester-tagged bisenones is developed using a bifunctional thiourea catalyst.

Hydrogen‐Bond‐Directed Formal [5 + 1] Annulations of Oxindoles with Ester‐Linked Bisenones: Facile Access to Chiral Spirooxindole δ‐Lactones.

N‐Heterocyclic Carbene/Brønsted Base Cascade Catalysis: Base‐Controlled Selective Synthesis of Multifunctional Benzofuran‐3‐ones or Flavone Derivatives from the Reaction of 3‐(2‐Formylphenoxy)propenoates with Imines

The title reaction yields indenopyranones (III) and (VI) in good yields and with high diastereoselectivity.

N-Heterocyclic Carbene Catalyzed Reaction of 2-(2-Aroylvinyl)cinnamaldehydes with α,β-Unsaturated Imines: An Efficient Method for the Stereoselective Synthesis of Highly Functionalized Indane Derivatives.

A novel bifunctional thiourea catalyzed formal [5 + 1] cycloaddition of oxindoles and ester-linked bisenones was successfully developed. This strategy involves two sequential Michael additions, leading to spirooxindole δ-lactones with three contiguous stereocenters including an all-carbon quaternary center with high diastereo- and enantioselectivites. In addition, a remarkable N-substituent effect was observed on the reactivity and selectivity.

Hydrogen-bond-directed formal [5 + 1] annulations of oxindoles with ester-linked bisenones: facile access to chiral spirooxindole δ-lactones.

The reaction of β-lactam carbenes with tetrazine (II) is controlled by the reaction temperature.

The Reaction of β-Lactam Carbenes with 3,6-Di(2-pyrimidinyl)tetrazine: Regulating Products by Reaction Conditions.

The reaction of β-lactam carbenes with 3,6-di(2-pyrimidinyl)tetrazine: regulating products by reaction conditions

The NHC-catalyzed reaction of 2-(2-aroylvinyl)cinnamaldehydes with α,β-unsaturated imines was studied, which produced­ good yields of novel 3-aryl-9-[1,3-diaryl-3-(4-tolylsulfonamido)allyl]-9,9a-dihydroindeno[2,1- c ]pyran-1(4a H )-ones with high diastereoselectivity. The products can be easily converted into different highly functionalized indane derivatives via simple operations. Thus, this work provides a simple and efficient method for the stereoselective synthesis of 1,2,3-trisubstituted indane derivatives.

N-Heterocyclic Carbene Catalyzed Reaction of 2-(2-Aroylvinyl)cinnamalde­hydes with α,β-Unsaturated Imines: An Efficient Method for the Stereoselective Synthesis of Highly Functionalized Indane Derivatives

Why estimation alone causes Markowitz portfolio selection to fail and what we might do about it

Die Grunde fur den Anstieg an der Nachfrage der Kapitalgarantien begrunden sich im Risiko kurz- und mittelfristig investiertes Geld zu verlieren, den niedrigen Zinsen seit 2000 und den Altern der Bevolkerung. Der Abschnitt Zwei wird vier Arten der Kapitalgarantie, Kapitalgarantie an der Falligkeit, multi-periodische Kapitalgarantie, die Renditekapitalgarantie und Benefizkapitalgarantie abdecken. Der Abschnitt Drei beschreibt Garantiefonds und Garantiezertifikate um eine Kapitalgarantie anzubieten. Die Wertabsicherungsstrategien beziehen sich auf die Portfolioversicherungen in dem Abschnitt Vier, wobei der erwarteter Ausfall und die Garantiekosten mit der Monte Carlo Simulation auch berucksichtigt werden. Die Auswirkungen der Auszahlungen und des erwarteten Ausfallen von den Wertabsicherungsstrategien, der Kapitalkosten, der Verwaltungsgebuhren und der Verschiebung des Risikos sind die Themen des Abschnitt Funf.

In this paper, CuO nanoparticles were synthetized via a sol–gel method and their corresponding gas sensor was achieved simultaneously. CuO nanoparticle samples were characterized by X-ray diffraction, Raman spectroscopy, X-ray photoelectron spectroscopy and field emission scanning electron microscopy, respectively. The results show that the sample we have synthesized was CuO and the morphology of the sample was nanoparticles with an average diameter of ∼100 nm. We determined the operating temperature of the gas sensors to be 220 °C, considering their appropriate sensitivity, rapid response and the uniformity of testing. Under this working temperature, the sensitivity and response/recovery time of the gas sensor were tested with acetone, methanol and ethanol gas. It was found that the CuO nanoparticles gas sensor performed a high response to the low concentrations of these three gases. At a gas concentration of 0.1 ppm and 10 ppm, the response to the three gases was about 2.5, 1.9, 2.7 and 5.3, 5.9, 5.3, respectively. It is believed that the CuO nanoparticles may be a promising candidate for low concentration reducing volatile organic gases sensing applications.

A highly sensitive gas sensor based on CuO nanoparticles synthetized via a sol–gel method

The TiO_2 with small primary particle size(30 nm),PS particles and carbon fibers were employed as the skeleton material of porous ceramic and pore-forming agents respectively.A new kind of porous ceramic with uniformly distributed,uniform-size pores and another unidirectional-oriented channels was obtained by extrusion process,due to the monodispersity of PS particles(3 μm) and dimension of cylindrical carbon fibers.The investigations suggest that the porosity and bending strength of sintered ceramic were highly related with the sintering temperatures,types of pore-forming agents and their contents.

Eu2+ activated long persistent strontium aluminate nano scaled phosphor prepared by precipitation method

Eu2+ Activated Long Persistent Strontium Aluminate Nano Scaled Phosphor Prepared by Precipitation Method.

Rietveld Analysis for Eu2+ Doped 4SrO×7Al2O3 and Its Luminescent Properties.

Rietveld analysis for Eu2+ doped 4SrO·7Al2O3 and its luminescent properties

Effect of composition on the luminescent properties of Sr4Al14O25: Eu2+, Dy3+ phosphors

Gas nitriding behavior of TiAl based alloys in an ammonia atmosphere

Research in western countries has shown that adolescents who self-identify as lesbian, gay, or bisexual (LGB) are at increased risk for depression, but little is known about this relationship among adolescents in China. A school-based cross-sectional survey was conducted among 1816 high school students in Jiangxi province. Logistic regression was used to explore the relationship between sexual orientation and depressive symptoms. Approximately 4% of participants self-identified as LGB, and 14% reported being unsure of their sexual identity. After controlling for potential confounding factors, students who self-identified as LGB had significantly higher odds of depressive symptoms compared with heterosexual students: adjusted odds ratio = 6.16 (2.13-17.83) and adjusted odds ratio = 2.29 (1.13-4.63) for males and females, respectively. Culturally appropriate programs and policies that support LGB students and address discrimination and victimization are needed to improve the mental health of Chinese LGB youth.

Sexual Orientation and Depressive Symptoms Among High School Students in Jiangxi Province

A cross-sectional study was conducted with 261 people living with HIV (PLWH) in Southeast China. A social capital questionnaire was used to measure social capital dimensions (trust, social connection, and social participation). A Chinese version of the Medical Outcomes Study HIV Health Survey (MOS-HIV) was used to assess Quality of Life (QoL); Physical Health Summary Scores (PHS) and Mental Health Summary Scores (MHS) were calculated. Multiple regression assessed whether social capital and its dimensions were associated with PHS and MHS. After controlling for sociodemographics and HIV-related factors, lower PHS scores were found among participants with low overall social capital (P < .01) and low trust (P < .001). Lower MHS scores were found among participants with low overall social capital (P < .001), low trust (P < .001) and low social connection (P < .01). Our findings identify potential intervention targets to improve QoL among PLWH in Southeast China, including the promotion of social capital.

Social Capital and Quality of Life Among People Living With HIV/AIDS in Southeast China

OBJECTIVE
To understand and assess changes of health workforce in county anti-schistosomiasis institutions of Jiangxi Province, so as to provide the evidence for improving the health workforce construction.

METHODS
The status of health workforce of county anti-schistosomiasis institutions was surveyed with self-designed questionnaire, and the results were compared with the baseline survey results in 2007.

RESULTS
The total number of employees was 1 384 in 2010 with the decrease of 71 persons compared with that in 2007. The average number of people per institution was 40.71, with the decrease of 0.86 per institution, compared with that of 2007. Compared with 2007, the employees with bachelor degree increased by 6.17%, those with college degree increased by 6.8%, and the attending rate of training and further study also increased.

The health workforce has improved in county anti-schistosomiasis institutions of Jiangxi Province. The professional workers should be trained continually to improve their diathesis.

Zhongguo xue xi chong bing fang zhi za zhi = Chinese journal of schistosomiasis control

[Investigation on health workforce in county anti-schistosomiasis institutions of Jiangxi Province, 2010].

Objective:To understand the current situation of accessibility of maternal health care service in rural areas of Anhui province,aiming to institute interventions and provide scientific evidence for improving maternal health care service in China.Methods:Service providers and regional key people who knew the ropes to do qualitative research with focus group discussions and individual interviews were selected.Results:Antenatal checkup,hospital delivery,postnatal visit and health education was developed in township hospitals,but the amount and quality didn't reached the request.Family planning department assisted to develop part of maternal health care service.Recent recognition,devotion of funds,training of staff,propaganda was enhanced,and executive management was changed.The accessibility of maternal health care service was improved.But there were many problems to restrict maternal health care,such as,devotion of funds was insufficient,allocation of funds was imbalance,thought much of clinic but thought less of health care,health education was not enough,the maternal health care network was not perfect,there was restrict factor of manpower,private clinics increased.Conclusion:There are some achievements in maternal health care service in rural areas,but some problems restricts the accessibility of the service.Measures to local conditions should be taken.New style of devotion of government,township-country mode of maternal health care should be probed.Uniform criterion of maternal health care should be established.

Qualitative study on accessibility of maternal health care service in rural area

Objective To observe the germicidal efficacy of two iodine-containing buccal tablets (Xi-Di-Dian Tablet and Wei-Shan-Dian Tablet) and their germicidal regularity in saliva.Methods Suspension quantitative germicidal test and available iodine measurement method were used to carry out experimental examination.Results The killing rates of Staphylococcus aureus, Candida albicans and Escherichia coli in suspension exposed to the two buccal tablets containing available iodine 750 mg/L for 2 min were 100%. The killing rates of above 3 microorganisms in saliva exposed to the 2 buccal tablets containing 750 mg/L available iodine for 2～8 min were 96.5%～99%. After the 2 iodine-containing buccal tablets were put separately in 1 ml of saliva for 2 min, the available iodine content of Xi-Di-Dian Tablet was 0 mg and that of Wei-Shan-Dian Tablet was 0.88 mg. Both buccal tablets were packed in plastics and aluminum pack. After storing at room temperature for 8 years, the available iodine in Xi-Di-Dian Tablet decreased by 66.7% and that in Wei-Shan-Dian Tablet decreased by 62.0%.Conclusions The iodine-containing buccal tablet has good efficacy in killing vegetative forms of bacteria in water suspension and its efficacy in killing bacteria in saliva significantly decreased as compared with that in killing bacteria in water suspension. The available iodine of both tablets decreased rapidly in saliva and that of Xi-Di-Dian Tablet decreased more rapidly.

STUDY ON GERMICIDAL REGULARITY OF TWO IODINE-CONTAINING BUCCAL TABLETS

OBJECTIVE
To investigate risk factors for the development of advanced schistosomiasis.

METHODS
The case-control study was designed with a match of 1:1 and 1:2. Healthy persons and chronic schistosomiasis patients were used as control. Each group was composed of 213 cases. Items investigated included: history of schistosomiasis and treatment, exposure to the contaminated water, social-economical condition and nutritional status, other concomitant diseases. Cellular and humoral immunity, HBVMs and ABO blood groups were also detected. Statistical analysis was performed by 1:1 and 1:2 matched single and stepwise conditional logistic regression analysis with SAS software.

RESULTS
By stepwise conditional logistic regression analysis, it was revealed that number of schistosomiasis examination (OR = 1.168-1.311), interval from first infection to last treatment(OR = 1.142), interval from first infection to this investigation (OR = 1.089), HBsAg+ (OR = 4.683-10.759), HBcAb+ (OR = 2.873), HBsAg+ + HBeAb+ + HBcAb+ (OR = 7.64) were risk factors of developing advanced schistosomiasis. The average living space and cellular immunity were lower in advanced schistosomiasis patients than others. No association was found between advanced schistosomiasis and ABO blood groups.

The development of advanced schistosomiasis is associated with repeated infections, and delayed or incomplete treatment. Combined infection with hepatitis B, poor socio-economic conditions and impaired cellular immunity may increase the pathogenetic risk of schistosomiasis.

Zhongguo ji sheng chong xue yu ji sheng chong bing za zhi = Chinese journal of parasitology & parasitic diseases

[A case-control study on risk factors for advanced schistosomiasis japonica].

Improved corrosion resistance and biofilm inhibition ability of copper-bearing 304 stainless steel against oral microaerobic Streptococcus mutans

Microstructure and arc erosion behaviors of Ag-CuO contact material prepared by selective laser melting

An SEM-based approach to characterize the microstructural evolution in a gradient CoCrFeNiMo0.15 high-entropy alloy

Enhancement of strength and ductility by Cu-rich precipitation in Cu-bearing 304L austenitic stainless steel

Strengthening the FeCoCrNiMo0.15 high entropy alloy by a gradient structure

A FeCoNiAlTiCrSi high entropy alloy coating was cladding on the surface of Q235 steel by laser using FeCoNiAlTiCrSi as basic alloy powder in which B, C, and Y2O3 were added as a in situ synthesized elements. The results show that the 2mm thickness coating with no crack and pores was prepared under the optimized laser process parameters that the power is 1380W, spot size is 6mm × 4mm, scanning speed is 6mm/s, overlapping rate is 36% and shielding gas velocity is 1.5L/min. The structure is mainly composed of FCC and TiC particle phase, the size of the TiC particle synthesized in-situ is about 0.5µm-3µm. The average microhardness of coating is 450HV0.2, The dispersed TiC particles play the role of strengthening and toughening. The 2 mm thickness FeCoNiAlTiCrSi high entropy alloy coating prepared by this laser cladding method has good hardness and toughness.

FeCoNiAlTiCrSi high entropy alloy coating prepared by laser cladding

This paper is concerned with the stabilization problem for fuzzy Markovian jumping systems with distributed time delay. First, fuzzy Markovian jumping systems with distributed time delay are peoposed. Second, a novel criterion of delay-dependent robust stabilization for fuzzy Markovian jumping systems is established in terms of linear matrix inequalities (LMIs) by using Lyapunov stability theory and free-weighting matrix method. When these LMIS are feasible, an explicit expression of a desired adjustable state feedback controller is given. Based on the obtained criterion, the introduced controller ensures the overall closed-loop system asymptotically stable in mean square sense for all admissible uncertainties and time delay.

Stabilization of Fuzzy Markovian Jumping Systems with Distributed Delay

Discriminating measurement of strain and temperature is demonstrated by using a long period fiber grating according to its spectrum characteristics. The resonant wavelength of the first and third-order loss peak is selected, and temperature and strain sensitivity of each resonant wavelength are experimented. The self-wavelength shift resulting from parameter variation can be obtained by observing its corresponding spectrum. The temperature and strain sensitivity are calibrated. Both wavelengths have good linear response of temperature and strain in a certain variation range. Then, slandered matrix equation is set up and solved according to the corresponding parameter. Experimental results show root mean square deviation of ±16με and ±0.62°C for strain and temperature, respectively. This method can realize discriminating measurement of strain and temperature avoiding cross sensitivity. System accuracy is also improved efficiently.

Discriminating Measurement of Temperature and Strain by Using Long Period Grating’s Spectra

KCNMA1 promotes obesity-related hypertension: Integrated analysis based on genome-wide association studies.

Background: Corin is a transmembrane serine protease that activates pro-forms of atrial and brain natriuretic peptides. Numerous studies have indicated that corin played an important role in cardiovascular diseases (CVDs). However, there have been few studies about the correlation between single-nucleotide polymorphisms (SNPs) in the 3' untranslated region (3'UTR) of CORIN and CVDs. The aims of this study were to investigate the associations of three SNPs (rs3749585, rs4695253, and rs12641823) in the 3'UTR of CORIN with CVDs and to find the seed regions of microRNAs (miRNAs) that bind to SNPs of CORIN. Methods and Results: A case–control study (n = 3,537) was performed in a Han population of northeastern China. CVDs included essential hypertension (EH), atrial fibrillation (AF), heart failure (HF), and coronary artery disease (CAD). Genotyping was performed using high-resolution melt analysis. In the EH-control study, rs3749585T was significantly associated with the risk of EH after adjusting for sex and age in allelic (padj = 0.049; OR: 1.113) and dominant (padj = 0.015, OR: 1.233) models. Rs4695253T was significantly associated with the risk of EH in the recessive model after adjusting for sex and age (padj = 0.005, OR: 2.084). Rs3749585T was significantly and negatively associated with AF in the dominant and additive models after adjusting for sex, age, EH, HF, T2DM, and CAD (dominant: padj = 0.009, OR: 0.762; additive: padj = 0.048, OR: 0.873). In the HF-control study and CAD-control study, none of the three SNPs was associated with HF and CAD after adjusting for covariates in any models (padj > 0.05). The levels of high-density lipoprotein (HDL) in rs4695253CC+CT were lower than the levels of HDL in rs4695253TT (42.47 ± 10.30 vs. 48.0 ± 10.24 mg/dl, padj = 0.008). The levels of total cholesterol (TC) in rs4695253CC+CT were lower than the levels of TC in rs4695253TT (164.01 ± 49.15 vs. 180.81 ± 43.92 mg/dl, padj = 0.036). Luciferase assay revealed that the relative luciferase activity of rs3749585CC-transfected cells was significantly decreased by miR-494-3p, in comparison to cells transfected with rs3749585TT (p < 0.001). A significant decrease in the relative luciferase activity of rs3749585TT reporter was observed as compared with rs3749585CC reporter in the presence of miR-1323 or miR-548o-3p (p = 0.017 and 0.012, respectively). Conclusions: We found significant associations between rs3749585T and rs4695253T and EH, between rs4695253T and the levels of TC and HDL, and between rs3749585T and AF. Hsa-miR-494-3p may serve as a potential therapeutic target for EH and AF patients in the future.

Single-Nucleotide Polymorphisms in the 3' Untranslated Region of CORIN Associated With Cardiovascular Diseases in a Chinese Han Population: A Case–Control Study

Identification of rare variants in cardiac sodium channel β4-subunit gene SCN4B associated with ventricular tachycardia

A 19-year-old male with early refractory hypertension, hypokalemia, serum potassium level of 3.4 mmol/l and hypoaldosteronemia was indicated in the present study. According to the results of laboratory tests and examinations, the patient was suspected of having Liddle's syndrome (LS). Genetic analysis of SCNN1B revealed a deletion mutation (c.1721delC). This mutation caused a length extension of SCNN1B coding sequence, which resulted in p.Pro574HisfsX675. A total of 34 family members were enrolled in the study and 29 of these family members underwent genetic testing. A total of 10 family members were clinically diagnosed with hypertension. Notably, 5 family members shared the same gene mutation as the proband and all cases with the mutation had hypertension. Blood pressure of the gene mutation carriers was well controlled by tailored treatment. In conclusion, a patient with early onset and refractory hypertension, hypokalemia and hypoaldosteronemia was diagnosed clinically and genetically with LS. Notably, a novel mutation (c.1721delC) was identified by DNA analysis. The present findings indicate that genetic analysis is useful, not only in the diagnosis of LS, but also in designing a tailored treatment.

A family with Liddle's syndrome caused by a new c.1721 deletion mutation in the epithelial sodium channel β-subunit.

Atrial fibrillation (AF) affects 33.5 million individuals worldwide. It accounts for 15% of strokes and increases risk of heart failure and sudden death. The voltage‐gated cardiac sodium channel complex is responsible for the generation and conduction of the cardiac action potential, and composed of the main pore‐forming α‐subunit Nav1.5 (encoded by the SCN5A gene) and one or more auxiliary β‐subunits, including Navβ1 to Navβ4 encoded by SCN1B to SCN4B, respectively. We and others identified loss‐of‐function mutations in SCN1B and SCN2B and dominant‐negative mutations in SCN3B in patients with AF. Three missense variants in SCN4B were identified in sporadic AF patients and small nuclear families; however, the association between SCN4B variants and AF remains to be further defined. In this study, we performed mutational analysis in SCN4B using a panel of 477 AF patients, and identified one nonsynonymous genomic variant p.Gly8Ser in four patients. To assess the association between the p.Gly8Ser variant and AF, we carried out case‐control association studies with two independent populations (944 AF patients vs. 9,81 non‐AF controls in the first discovery population and 732 cases and 1,291 controls in the second replication population). Significant association was identified in the two independent populations and in the combined population (p = 4.16 × 10−4, odds ratio [OR] = 3.14) between p.Gly8Ser and common AF as well as lone AF (p = 0.018, OR = 2.85). These data suggest that rare variant p.Gly8Ser of SCN4B confers a significant risk of AF, and SCN4B is a candidate susceptibility gene for AF.

Significant association of rare variant p.Gly8Ser in cardiac sodium channel β4‐subunit SCN4B with atrial fibrillation

Significant Association between OPG/TNFRSF11B Variant and Common Complex Ischemic Stroke.

Significant genetic association of a functional TFPI variant with circulating fibrinogen levels and coronary artery disease

Background Idiopathic ventricular tachycardia (VT) is a type of cardiac arrhythmia occurring in structurally normal hearts. The heritability of idiopathic VT remains to be clarified, and numerous genetic factors responsible for development of idiopathic VT are as yet unclear. Variations in FGF12 (fibroblast growth factor 12), which is expressed in the human ventricle and modulates the cardiac Na+ channel NaV1.5, may play an important role in the genetic pathogenesis of VT. Methods and Results We tested the hypothesis that genetic variations in FGF12 are associated with VT in 2 independent Chinese cohorts and resequenced all the exons and exon–intron boundaries and the 5′ and 3′ untranslated regions of FGF12 in 320 unrelated participants with idiopathic VT. For population‐based case–control association studies, we chose 3 single‐nucleotide polymorphisms—rs1460922, rs4687326, and rs2686464—which included all the exons of FGF12. The results showed that the single‐nucleotide polymorphism rs1460922 in FGF12 was significantly associated with VT after adjusting for covariates of sex and age in 2 independent Chinese populations: adjusted P=0.015 (odds ratio: 1.54 [95% CI, 1.09–2.19]) in the discovery sample, adjusted P=0.018 (odds ratio: 1.64 [95% CI, 1.09–2.48]) in the replication sample, and adjusted P=2.52E‐04 (odds ratio: 1.59 [95% CI, 1.24–2.03]) in the combined sample. After resequencing all amino acid coding regions and untranslated regions of FGF12, 5 rare variations were identified. The result of western blotting revealed that a de novo functional variation, p.P211Q (1.84% of 163 patients with right ventricular outflow tract VT), could downregulate FGF12 expression significantly. Conclusions In this study, we observed that rs1460922 of FGF12 was significantly associated with VT and identified that a de novo variation of FGF12 may be an important genetic risk factor for the pathogenesis of VT.

De Novo FGF12 (Fibroblast Growth Factor 12) Functional Variation Is Potentially Associated With Idiopathic Ventricular Tachycardia

Genomic Variant in IL-37 Confers A Significant Risk of Coronary Artery Disease

Alpha-actin-2 mutations in Chinese patients with a non-syndromatic thoracic aortic aneurysm

Identification of rare variants in TNNI3 with atrial fibrillation in a Chinese GeneID population

Genomic variant in CAV1 increases susceptibility to coronary artery disease and myocardial infarction.

Brugada syndrome (BrS) is an inherited primary arrhythmia disorder, leading to sudden cardiac death due to ventricular tachyarrhythmia, but does not exhibit clinical cardiac abnormalities. The sodium voltage-gated channel α subunit 5 (SCN5A) gene, which encodes the α subunit of the cardiac sodium channel, Nav1.5, is the most common pathogenic gene, although ≥22 BrS‑susceptibility genes have previously been identified. In the present study, a novel genetic variant (p.D1690N) localized in the S5‑S6 linker of domain IV of the Nav1.5 channels was identified in a Chinese Han family. Wild‑type (WT) and p.D1690N Nav1.5 channels were transiently over‑expressed in HEK293 cells and analyzed via the whole-cell patch clamp technique. The p.D1690N mutation significantly reduced the peak sodium current density to 23% of WT (at ‑20 mV; P<0.01), shifted steady‑state activation by 7 mV to increasingly positive potentials (P<0.01). Furthermore, prolonging of the recovery from inactivation was observed in the p.D1690N mutant. No significant change was identified in steady‑state inactivation. Thus, the mutant‑induced changes contributed to the loss of function of Nav1.5 channels, which indicates that the p.D1690N variant may have a pathogenic role in BrS.

p.D1690N sodium voltage-gated channel α subunit 5 mutation reduced sodium current density and is associated with Brugada syndrome.

Regulation of SCN3B/scn3b by Interleukin 2 (IL-2): IL-2 modulates SCN3B/scn3b transcript expression and increases sodium current in myocardial cells

Nav1.5, the pore-forming α subunit of the cardiac voltage-gated Na+ channel complex, is required for the initiation and propagation of the cardiac action potential. Mutations in Nav1.5 cause cardiac arrhythmias and sudden death. The cardiac Na+ channel functions as a protein complex; however, its complete components remain to be fully elucidated. A yeast two-hybrid screen identified a new candidate Nav1.5-interacting protein, αB-crystallin. GST pull-down, co-immunoprecipitation, and immunostaining analyses validated the interaction between Nav1.5 and αB-crystallin. Whole-cell patch clamping showed that overexpression of αB-crystallin significantly increased peak sodium current (INa) density, and the underlying molecular mechanism is the increased cell surface expression level of Nav1.5 via reduced internalization of cell surface Nav1.5 and ubiquitination of Nav1.5. Knock-out of αB-crystallin expression significantly decreased the cell surface expression level of Nav1.5. Co-immunoprecipitation analysis showed that αB-crystallin interacted with Nedd4-2; however, a catalytically inactive Nedd4-2-C801S mutant impaired the interaction and abolished the up-regulation of INa by αB-crystallin. Nav1.5 mutation V1980A at the interaction site for Nedd4-2 eliminated the effect of αB-crystallin on reduction of Nav1.5 ubiquitination and increases of INa density. Two disease-causing mutations in αB-crystallin, R109H and R151X (nonsense mutation), eliminated the effect of αB-crystallin on INa. This study identifies αB-crystallin as a new binding partner for Nav1.5. αB-Crystallin interacts with Nav1.5 and increases INa by modulating the expression level and internalization of cell surface Nav1.5 and ubiquitination of Nav1.5, which requires the protein-protein interactions between αB-crystallin and Nav1.5 and between αB-crystallin and functionally active Nedd4-2.

αB-Crystallin Interacts with Nav1.5 and Regulates Ubiquitination and Internalization of Cell Surface Nav1.5*

Two polymorphisms, rs7597774 and rs1739843 in ADD2 and HSPB7 respectively, were found to be associated with dilated cardiomyopathy (DCM) in European cohorts but the results were not validated in the Chinese Han population. We aimed to test the association of the two variants with DCM in a cohort of Chinese Han population. DCM (399) and control (1384) individuals were identified from the GeneID database in China, and DNA was isolated from peripheral blood lymphocytes for genotyping. Alleles were amplified by PCR, and amplicons harboring polymorphisms rs1739843 and rs7597774 were directly genotyped using high-resolution melting analysis. Statistical analysis was subsequently performed to evaluate the association of the variants with DCM. Allelic analysis demonstrated that rs7597774 was significantly related to DCM (P-adj = 0.0157), and an increased risk of DCM was specifically associated with the minor allele A (OR = 1.582). High-grade cardiac dysfunction (NYHA III/IV) was a clinical parameter significantly associated with the rs7597774 genotypes AA + AC relative to genotype CC (P = 0.021). Furthermore, DCM patients with the rs7597774 genotype AA tended to undergo more invasive medical interventions than those with the genotype CC (P = 0.008). No association was detected between rs1739843 and DCM under any allelic (P-adj = 0.407, OR = 0.920) or genotypic model. In the Chinese Han population, rs7597774 but not rs1739843 was found to be associated with DCM. This study is the first to demonstrate that underlying genotypes of rs7597774 may assist in assessing the heart functional status of DCM patients and also in the prediction of the benefit of particular therapies for these patients.

Common variant rs 7597774 in ADD 2 is associated with dilated cardiomyopathy in Chinese Han population

Atrial fibrillation (AF) is the most common cardiac arrhythmia at the clinic. Recent GWAS identified several variants associated with AF, but they account for <10% of heritability. Gene-gene interaction is assumed to account for a significant portion of missing heritability. Among GWAS loci for AF, only three were replicated in the Chinese Han population, including SNP rs2106261 (G/A substitution) in ZFHX3, rs2200733 (C/T substitution) near PITX2c, and rs3807989 (A/G substitution) in CAV1. Thus, we analyzed the interaction among these three AF loci. We demonstrated significant interaction between rs2106261 and rs2200733 in three independent populations and combined population with 2,020 cases/5,315 controls. Compared to non-risk genotype GGCC, two-locus risk genotype AATT showed the highest odds ratio in three independent populations and the combined population (OR=5.36 (95% CI 3.87-7.43), P=8.00×10-24). The OR of 5.36 for AATT was significantly higher than the combined OR of 3.31 for both GGTT and AACC, suggesting a synergistic interaction between rs2106261 and rs2200733. Relative excess risk due to interaction (RERI) analysis also revealed significant interaction between rs2106261 and rs2200733 when exposed two copies of risk alleles (RERI=2.87, P<1.00×10-4) or exposed to one additional copy of risk allele (RERI=1.29, P<1.00×10-4). The INTERSNP program identified significant genotypic interaction between rs2106261 and rs2200733 under an additive by additive model (OR=0.85, 95% CI: 0.74-0.97, P=0.02). Mechanistically, PITX2c negatively regulates expression of miR-1, which negatively regulates expression of ZFHX3, resulting in a positive regulation of ZFHX3 by PITX2c; ZFHX3 positively regulates expression of PITX2C, resulting in a cyclic loop of cross-regulation between ZFHX3 and PITX2c. Both ZFHX3 and PITX2c regulate expression of NPPA, TBX5 and NKX2.5. These results suggest that cyclic cross-regulation of gene expression is a molecular basis for gene-gene interactions involved in genetics of complex disease traits.

Molecular Basis of Gene-Gene Interaction: Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation

Post-transcriptional regulation of cardiac sodium channel gene SCN5A expression and function by miR-192-5p.

Two polymorphisms, rs7597774 and rs1739843 in ADD2 and HSPB7 respectively, were found to be associated with dilated cardiomyopathy (DCM) in European cohorts but the results were not validated in the Chinese Han population. We aimed to test the association of the two variants with DCM in a cohort of Chinese Han population. DCM (399) and control (1384) individuals were identified from the GeneID database in China, and DNA was isolated from peripheral blood lymphocytes for genotyping. Alleles were amplified by PCR, and amplicons harboring polymorphisms rs1739843 and rs7597774 were directly genotyped using high-resolution melting analysis. Statistical analysis was subsequently performed to evaluate the association of the variants with DCM. Allelic analysis demonstrated that rs7597774 was significantly related to DCM (P -adj = 0.0157), and an increased risk of DCM was specifically associated with the minor allele A (OR = 1.582). High-grade cardiac dysfunction (NYHA III/IV) was a clinical parameter significantly associated with the rs7597774 genotypes AA + AC relative to genotype CC (P = 0.021). Furthermore, DCM patients with the rs7597774 genotype AA tended to undergo more invasive medical interventions than those with the genotype CC (P = 0.008). No association was detected between rs1739843 and DCM under any allelic (P -adj = 0.407, OR = 0.920) or genotypic model. In the Chinese Han population, rs7597774 but not rs1739843 was found to be associated with DCM. This study is the first to demonstrate that underlying genotypes of rs7597774 may assist in assessing the heart functional status of DCM patients and also in the prediction of the benefit of particular therapies for these patients.

Common variant rs7597774 in ADD2 is associated with dilated cardiomyopathy in Chinese Han population.

Heart failure affects 1–2% of the adult population worldwide and coronary artery disease (CAD) is the underlying etiology of heart failure in 70% of the patients. The pathway of apelin and its apelin receptor (APJ) was implicated in the pathogenesis of heart failure in animal models, but a similar role in humans is unknown. We studied a functional variant, rs9943582 (-154G/A), at the 5’-untranslated region, that was associated with decreased expression of the APJ receptor gene (APLNR) in a population consisting of 1,751 CAD cases and 1,022 controls. Variant rs9943582 was not associated with CAD, but among CAD patients, it showed significant association with left ventricular systolic dysfunction (431 CAD patients with left ventricular systolic dysfunction (LV ejection fraction or LVEF< 40%) versus 1,046 CAD patients without LV systolic dysfunction (LVEF>50%) (P-adj = 6.71×10-5, OR = 1.43, 95% CI, 1.20–1.70). Moreover, rs9943582 also showed significant association with quantitative echocardiographic parameters, including left ventricular end-diastolic diameter (effect size: increased 1.67±0.43 mm per risk allele A, P = 1.15×10-4), left atrial size (effect size: increased 2.12±0.61 mm per risk allele A, P = 9.56×10-4) and LVEF (effect size: decreased 2.59±0.32 percent per risk allele A, P = 7.50×10-15). Our findings demonstrate that allele A of rs9943582 was significantly associated with left ventricular systolic dysfunction, left ventricular end-diastolic diameter, the left atrial diameter and LVEF in the CAD population, which suggests an important role of the apelin/APJ system in the pathology of heart failure associated with ischemic heart disease.

Association of SNP Rs9943582 in APLNR with Left Ventricle Systolic Dysfunction in Patients with Coronary Artery Disease in a Chinese Han GeneID Population

Elevated serum chloride is an independent risk factor for coronary heart disease: A retrospective study of more than 13,000 Han Chinese.

BRG1 variant rs1122608 on chromosome 19p13.2 confers protection against stroke and regulates expression of pre-mRNA-splicing factor SFRS3

Erratum: The IL-33-ST2L pathway is associated with coronary artery disease in a Chinese han population (American Journal of Human Genetics (2013) 93 (652-660))

Background and Purpose— ANRIL has long been considered as the strongest candidate gene at the 9p21 locus, robustly associated with stroke and coronary artery disease. However, the underlying molecular mechanism remains unknown. The present study works to elucidate such a mechanism. Methods— Using expression quantitative loci analysis, we identified potential genes whose expression may be influenced by genetic variation in ANRIL. To verify the identified gene(s), knockdown and overexpression of ANRIL were evaluated in human umbilical vein endothelial cells and HepG2 cells. Ischemic stroke and coronary artery disease risk were then evaluated in the gene(s) demonstrated to be mediated by ANRIL in 3 populations of Chinese Han ancestry: 2 ischemic stroke populations consisting of the Central China cohort (903 cases and 873 controls) and the Northern China cohort (816 cases and 879 controls) and 1 coronary artery disease cohort consisting of 772 patients and 873 controls. Results— Expression quantitative loci analysis identified CARD8 among others, with knockdown of ANRIL expression decreasing CARD8 expression and overexpression of ANRIL increasing CARD8 expression. The minor T allele of a previously identified CARD8 variant (rs2043211) was found to be significantly associated with a protective effect of ischemic stroke under the recessive model in 2 independent stroke cohorts. No significant association was found between rs2043211 and coronary artery disease. Conclusions— CARD8 is a downstream target gene regulated by ANRIL. Single nucleotide polymorphism rs2043211 in CARD8 is significantly associated with ischemic stroke. ANRIL may increase the risk of ischemic stroke through regulation of the CARD8 pathway.

Regulation of CARD8 Expression by ANRIL and Association of CARD8 Single Nucleotide Polymorphism rs2043211 (p.C10X) With Ischemic Stroke

Background—Genomic variants identified by genome-wide association studies (GWAS) explain <20% of heritability of coronary artery disease (CAD), thus many risk variants remain missing for CAD. Identification of new variants may unravel new biological pathways and genetic mechanisms for CAD. To identify new variants associated with CAD, we developed a candidate pathway-based GWAS by integrating expression quantitative loci analysis and mining of GWAS data with variants in a candidate pathway. Methods and Results—Mining of GWAS data was performed to analyze variants in 32 complement system genes for positive association with CAD. Functional variants in genes showing positive association were then identified by searching existing expression quantitative loci databases and validated by real-time reverse transcription polymerase chain reaction. A follow-up case–control design was then used to determine whether the functional variants are associated with CAD in 2 independent GeneID Chinese populations. Candidate pathway-based GWAS identified positive association between variants in C3AR1 and C6 and CAD. Two functional variants, rs7842 in C3AR1 and rs4400166 in C6, were found to be associated with expression levels of C3AR1 and C6, respectively. Significant association was identified between rs7842 and CAD (P=3.99×10−6; odds ratio, 1.47) and between rs4400166 and CAD (P=9.30×10−3; odds ratio, 1.24) in the validation cohort. The significant findings were confirmed in the replication cohort (P=1.53×10−5; odds ratio, 1.37 for rs7842; P=8.41×10−3; odds ratio, 1.21 for rs4400166). Conclusions—Integration of GWAS with biological pathways and expression quantitative loci is effective in identifying new risk variants for CAD. Functional variants increasing C3AR1 and C6 expression were shown to confer significant risk of CAD for the first time.

Candidate Pathway-Based Genome-Wide Association Studies Identify Novel Associations of Genomic Variants in the Complement System Associated With Coronary Artery Disease

Role of microRNA-27a in down-regulation of angiogenic factor AGGF1 under hypoxia associated with high-grade bladder urothelial carcinoma.

206: Significant association of a genetic variant in IL-37 with coronary artery disease in the Chinese Han Population

Meta-analysis identifies robust association between SNP rs17465637 in MIA3 on chromosome 1q41 and coronary artery disease.

The IL-33-ST2L pathway is associated with coronary artery disease in a Chinese Han population.

Significant association of SNP rs2106261 in the ZFHX3 gene with atrial fibrillation in a Chinese Han GeneID population

Genome-wide association identifies a susceptibility locus for coronary artery disease in the Chinese Han population

Functional dominant-negative mutation of sodium channel subunit gene SCN3B associated with atrial fibrillation in a Chinese GeneID population.

Ultra-robust, repairable and smart physical hydrogels enabled by nano-domain reconfiguration of network topology

In order to reduce the environmental pollution caused by waste rubber and to realize the recycling of resources, we proposed a facile method for the hydrophilic modification of waste rubber powder (HRP) and used it to reinforce a composite hydrogel. In the presence of toluene, dibenzoyl peroxide (BPO) diffused into the waste rubber powder. After the solvent was removed, BPO was adsorbed in the rubber powder, which was used to initiate the grafting polymerization of the acrylamide monomer on the rubber–water interface. As a result, the polyacrylamide (PAM) molecular chains were grafted onto the surface of the rubber powder to realize hydrophilic modification. The success of the grafting modification was confirmed by FTIR, contact angle testing, and thermogravimetric analysis. The hydrophilic modified waste rubber powder was used to reinforce the PAM hydrogel. Mechanical tests showed that the tensile strength and elongation at the break of the composite hydrogel reached 0.46 MPa and 1809%, respectively, which was much higher than those of pure PAM hydrogel. Such a phenomenon indicates that the waste rubber particles had a strengthening effect.

Preparation of High-Performance Composite Hydrogel Reinforced by Hydrophilic Modified Waste Rubber Powder

Many high-strength hydrogels have been developed in recent years; however, few of them are both tough and resilient, and their intrinsic paradoxical nature makes designing a gel with both high toughness and high resilience a great challenge. To address this problem, we introduced both N,N,N,N-pentamethyldiethylenetriamine (PA) and N,N-methylenebisacrylamide (MBA) into polyacrylamide hydrogel networks to construct an entangled network that contains chemically cross-linked chains and branched chains simultaneously. The entanglements of branched chains can act as a physical cross-linking point to uniformly disperse stress on molecular chains, and chemical cross-linking ensures the stability of the hydrogel network. The increase in the number and length of branched chains is able to achieve an enhancement in strength while the slip of the entangled polymer chains can effectively achieve energy dissipation and can improve the toughness of the gel. Moreover, the resultant hydrogels exhibit an excellent resilience (>98%). Therefore, high toughness and resilience are achieved simultaneously. In addition, we also investigated the initiation mechanism of PA. This strategy creates a new way for the preparation of next-generation high toughness and high resilience hydrogel-based materials, which have promising applications in wearable, flexible strain/pressure sensors.

Tough and Resilient Hydrogels Enabled by a Multifunctional Initiating and Cross-Linking Agent

Technoeconomic evaluation of recent process improvements in production of sugar and high-value lignin co-products via two-stage Cu-catalyzed alkaline-oxidative pretreatment

Enhancing bagasse enzymatic hydrolysis through combination of ball-milling and LiCl/DMSO dissolution and regeneration

The high recalcitrance of plant cell walls is an obstacle for effective chemical or biological conversion into renewable chemicals and transportation fuels. Here, we investigated the utilization of...

Effective Biomass Fractionation through Oxygen-Enhanced Alkaline–Oxidative Pretreatment

To improve the salt tolerance/sensitivity of cellulose nanofibrils (CNFs), the zwitterionic cellulose nanofibrils (ZCNFs) were prepared from softwood bleached kraft pulp fibers via a sequential process of anionic modification with 2,2,6,6-tetramethylepiperidin-1-oxyl (TEMPO)-mediated oxidation, cationic modification with (2,3-Epoxypropyl) trimethylammonium chloride (EPTMAC), and high pressure homogenization. To produce ZCNFs with different contents of cation groups, EPTMAC loadings of 0.15 to 1.15 g/g fiber were explored. The obtained ZCNFs were characterized by Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectra (XPS), thermogravimetric analysis (TGA), transmission electron microscopy (TEM), and rheological measurements. The salt tolerance of the ZCNFs was investigated by adding mixed salts into the ZCNF dispersions. The results demonstrated that the ZCNFs with both anionic and cationic charges were produced. Compared to the TEMPO-mediated oxidized cellulose nanofibrils (TOCNFs), the ZCNFs exhibited an excellent "salt-thickening" behavior under the studied salt concentrations (2-24% w/w). Moreover, increasing the content of the cation group increased the salt tolerance/sensitivity of ZCNFs. This work demonstrated that introducing cationic charges to the anionic charged TOCNFs imparts the produced ZCNFs with excellent salt sensitivity and tolerance, which could expand the application of nanocellulose in oil recovery or waste water treatment.

Zwitterionic Cellulose Nanofibrils with High Salt Sensitivity and Tolerance.

A comparison of different pre-extraction methods followed by steam pretreatment of bamboo to improve the enzymatic digestibility and ethanol production

Cellulose nanofibril-polymer hybrids for protecting drilling fluid at high salinity and high temperature.

High Titer Ethanol Production from Combined Alkaline/Alkaline Hydrogen Peroxide Pretreated Bamboo at High Solid Loading

The oxidation of cellulose to modify the fiber surface is widely recognized as a promising strategy to improve the production of cellulose nanofibrils (CNFs) from pulp fibers. In this study, an eco...

Evaluation of Ultraviolet Light and Hydrogen Peroxide Enhanced Ozone Oxidation Treatment for the Production of Cellulose Nanofibrils

Two-stage alkaline/copper 2,2′-bipyridine-catalyzed alkaline hydrogen peroxide (Cu-AHP) pretreatment is an effective strategy for improving the enzymatic digestibility of hybrid poplar. To reduce the chemical inputs and processing costs associated with this process, we investigated the effect of increasing the temperature for both the alkaline pre-extraction and the Cu-AHP pretreatment stages. The results indicate that increasing the alkaline pre-extraction and the Cu-AHP pretreatment temperatures from 30 to 120 and 80 °C, respectively, allowed us to reduce both the pretreatment time of the Cu-AHP stage and the chemical loadings. Incubating alkaline pre-extracted hybrid poplar for 12 h with 10% NaOH (w/w biomass), 8% hydrogen peroxide (w/w biomass), and a Cu2+ and 2,2′-bipyridine (bpy) concentration of 1 mM yielded monomeric sugar yields of approximately 77% glucose and 66% xylose (based on the initial sugar composition) following enzymatic hydrolysis. Technoeconomic analysis (TEA) indicates that these ch...

Integrated Two-Stage Alkaline–Oxidative Pretreatment of Hybrid Poplar. Part 2: Impact of Cu-Catalyzed Alkaline Hydrogen Peroxide Pretreatment Conditions on Process Performance and Economics

Hydrogels prepared from cellulose nanofibrils via ferric ion-mediated crosslinking reaction for protecting drilling fluid.

Comparison of alkaline and acid-catalyzed steam pretreatments for ethanol production from tobacco stalk

Improving corn stover enzymatic saccharification via ferric chloride catalyzed dimethyl sulfoxide pretreatment and various additives

Improving the production of nanofibrillated cellulose from bamboo pulp by the combined cellulase and refining treatment

Enhancing the redispersibility of TEMPO-mediated oxidized cellulose nanofibrils in N,N-dimethylformamide by modification with cetyltrimethylammonium bromide

We previously demonstrated that a two-stage pretreatment comprising of an alkaline pre-extraction followed by a Cu-catalyzed alkaline–oxidative treatment is effective at pretreating hardwoods under relatively mild reaction conditions. In this work, we focus on characterizing how biomass source and reaction conditions used during the alkaline pre-extraction impact the subsequent processing stages as well as lignin yields and properties. Specifically, three hybrid poplars were subjected to the first stage alkaline pre-extraction under various conditions including differences in time (15–300 min), temperature (95–155 °C), and alkali loadings (50–200 mg NaOH/g biomass), and the impact on total mass solubilization, lignin recovery, and lignin purity was determined. Empirical correlations were developed between reaction conditions and mass solubilization and lignin recovery during the pre-extraction stage. For select conditions, lignin properties were assessed and include β-O-4 content determined by 13C NMR, mo...

Integrated Two-Stage Alkaline-Oxidative Pretreatment of Hybrid Poplar. Part 1: Impact of Alkaline Pre-Extraction Conditions on Process Performance and Lignin Properties

The poor salt tolerance, thermal stability, and environmental performance of petrochemicals can severely limit their applications in drilling engineering. In this study, cellulose nanofibril (CNF) hydrogels with improved salt tolerance and thermal stability were prepared, and their filtration performance was evaluated. The hydrogels were prepared through the simultaneous grafting of 2-acrylamido-2-methylpropane sulfonic acid (AMPS) and butyl acrylate (BA) onto the CNF surface through ceric ammoniumnitrate-induced radical polymerization. The modified and original CNF samples were characterized using Fourier Transform infrared spectroscopy (FT-IR) and rheological measurements. The FT-IR analysis results showed that both AMPS and BA were grafted onto the CNF backbone, affirming the successful preparation of the grafted CNFs. The rheological analysis results showed that the modified CNF hydrogels exhibited significantly improved salt tolerance, thermal stability, and “salt-thickening” effect. Moreover, the results of the fluid loss test showed that the modified CNF hydrogels exhibited a much better fluid loss control than the original CNF hydrogels. In addition, after adding 2% modified CNF hydrogels as a filtrate reducer in the drilling fluids prepared with a 6% combined salt solution, the filtrate loss was significantly reduced even after aging for 72 h at 160°C.

Preparation and Performance of Salt Tolerance and Thermal Stability Cellulose Nanofibril Hydrogels and Their Application in Drilling Engineering

In this study, a poplar high-yield pulp [preconditioning refiner alkaline peroxide mechanical pulp (P-RC APMP)] was used to produce lignin-containing cellulose nanofibril (LCCNF) dispersions throug...

Preparation and Characterization of Lignin-Containing Cellulose Nanofibril from Poplar High-Yield Pulp via TEMPO-Mediated Oxidation and Homogenization

Ultraviolet light enhanced sodium persulfate oxidation of cellulose to facilitate the preparation of cellulose nanofibers

Ethanol production from bamboo using mild alkaline pre-extraction followed by alkaline hydrogen peroxide pretreatment.

Enhancement of hydrophobicity of nanofibrillated cellulose through grafting of alkyl ketene dimer

Evaluation of an organosolv-based biorefinery process to fractionate wheat straw into ethanol and co-products

Enhancement of sugar recovery and ethanol production from wheat straw through alkaline pre-extraction followed by steam pretreatment.

Production of bioethanol and value added compounds from wheat straw through combined alkaline/alkaline-peroxide pretreatment.

A biorefinery scheme to fractionate bamboo into high-grade dissolving pulp and ethanol

An eco-friendly scheme to eliminate silica problems during bamboo biomass fractionation

Increasing efficiency of enzymatic hemicellulose removal from bamboo for production of high-grade dissolving pulp.

Evaluation of an integrated process to fully utilize bamboo biomass during the production of bioethanol.

In this work, the hydrothermal pretreatment under both acidic and alkaline conditions were conducted to study hemicellulose and silica removal from bamboo. In the first part of this work, evolution of proton concentration was examined during both autoand dilute-acid hydrolysis of hemicellulose from green bamboo. An approximate mathematical model (toy model) to describe the proton concentration based upon conservation of mass and charge during deacetylation and ash neutralization coupled with a number of competing equilibria, was derived. This model was qualitatively compared to experiments where pH was measured as a function of time, temperature, and initial acid level. The toy model predicts the existence of a steady state proton concentration dictated by equilibrium constants, initial acetyl groups, and initial added acid. At room temperature, it was found that pH remains essentially constant both at low initial pH and autohydrolysis conditions. At elevated temperatures, one case of non-monotonic behaviour in which the pH initially increased, and then decreased at longer times, was found. As silica in bamboo creates processing problems, in the second part of this work, alkaline pretreatment of pure amorphous silica particles, bamboo powder and bamboo chips was carried out to study the underlying mechanism for silica and hemicellulose extraction. Response surface methodology was also used to optimize the treatment

Insight into the evolution of the proton concentration during autohydrolysis and dilute-acid hydrolysis of hemicellulose

Effect of alkaline pre-extraction of hemicelluloses and silica on kraft pulping of bamboo (Neosinocalamus affinis Keng)

A novel polymerizable borate ester surfactant was prepared by boric acid,ethanolamine and methacryloyl chloride,and characterized and identified by IR.Experimental study of raw material ratio and the selection of polymerization inhibitor selection that effects the yield of boric acid ester coupling agent is implemented,and the product physical,hydrolysis and polymerization performance are inspected.The results show that boric acid ester coupling agent is of good self-storage properties and practical performance.

DEVELOPMENT OF BORIC ACID ESTER COUPLING AGENT FOR MODIFIED BORATE WHISKER

A novel polymerizable borate ester coupling agent(BE-1)was prepared by boric acid,ethanolamine,and methacryloyl chloride.BE-1 was used in the magnesium borate whisker surface that formed the organic coatings by the polymerization,and PP/magnesium borate whisker composites were prepared by the modified magnesium borate whisker.The results revealed that IR test results can be inferred that synthetic product was boric acid ester polymer coupling agent BE-1.The hydrolytic stabilization time of BE-1 was longer than 960 h and the solubility and storage capacity of BE-1 was well.The best reaction temperature and time of organic coating was 78 ℃ and 6 h.Tensile strength,flexural strength,heat distortion temperature of the BE-1 modified whisker composites increased respectively by 30%,40% and 104% compared with polypropylene which was increased respectively by 11.05%,23.52% and 15.29% compared with unmodified magnesium borate whisker/PP.

To obtain additives that could simultaneously increase the dry strength and wet strength of paper sheets, we synthesized a series of crosslinked cationic glyoxalated polyacrylamide (GPAM) resins by using acrylamide (AM), 2-methacryloxyethyl trimethyl ammonium chloride (DMC), N-methylolacrylamide (NMA), 2-mercaptoethanol, and glyoxal as the main materials. GPAM demonstrated excellent properties and had a good strengthening ability under the following polymerization conditions: dosage of AM = 55 wt %, dosage of the cationic monomer DMC = 5.5 wt %, dosage of the crosslinking monomer NMA = 8.0 wt %, dosage of chain-transfer agent 2-mercaptoethanol = 1.0 wt %, dosage of glyoxal = 30 wt %, and charge of the initiator (ammonium persulfate/sodium bisulfite = 1 : 2) = 0.5 wt %. The products were characterized by Fourier transform infrared spectroscopy, 1H-NMR, size exclusion chromatography, and Ubbelohde viscometry. The copolymers with a viscosity-average molecular weight of approximately 26,000 and a polydispersity index of 1.460 had a much better strengthening ability. When these GPAM resins were used as paper-strengthening agents, the mechanical strength of the paper was remarkably enhanced, and the dry and wet tensile indices of the handsheets increased by 24.6 and 381%, respectively, compared with those of handsheets without GPAM. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2012

Preparation and characterization of crosslinked glyoxalated polyacrylamide paper‐strengthening agent

The glyoxalted polyacrylamide(GPAM) resins were obtained by cross-linking reaction between glyoxal and cationic polyacrylamide(CPAM) through aqueous solution copolymerization. The based CPAM was synthesized with acrylamide(AM) and diallyl dimethyl ammonium chloride(DADMAC) as raw materials by living free radical solution polymerization. Various synthesis conditions were discussed and the optimum conditions for copolymer’s synthesis were as follows: the amount of DADMAC 20%(wt), the charge of the initiator 0.5%(wt), the dosage of chain transfer agent(2-mercaptoethanol) 1.0%(wt), and the charge of crosslinking monomer 9.0%, the dosage of glyoxal 25%(wt), the pH value of the tertiary reaction 7.5-8.0 and the tertiary temperature about 65°C. The structure of the resulting product was characterized by FT-IR, 1H-NMR. Then the GPAM resins were used in the process of paper-making as wet-end additive, the results showed that the paper sheets can get a significant increase in strength properties from the added novel product.

Synthesis and Application of Glyoxalted Polyacrylamide Paper Strengthening Agent

Fund flows and performance: New evidence from retail and institutional SRI mutual funds

Executive characteristics have a significant impact on corporate decision-making, corporate sustainable behavior, and stock market performance, which may influence the corporations’ sustainable development in the long run. The role of returnee talents in the corporate sustainable development has received extensive academic attention. Using data of Chinese A-share listed companies over the period of 2008–2018, we find that there is a negative relationship between executives’ foreign experience and stock price synchronicity. We also prove that corporate social responsibility (CSR) has a significant mediating effect on the relationship between returnee executives and stock price synchronicity. The returnee executives tend to pursue long-term sustainable activities and improve CSR engagement quality, thereby reducing stock price synchronicity. Our extended analysis reveals that the benefit of returnee executives is more pronounced for non-SOEs and for firms located in regions with a low degree of marketization. This study has some implications for the Chinese firms in relation to their CSR information disclosure behavior, and it gives suggestions to strengthen capital market efficiency for the sustainable development of corporations.

Returnee Executives, Corporate Social Responsibility, and Stock Price Synchronicity

Performance and Market Maturity in Mutual Funds: Is Real Estate Different?

This paper examines the performance and the diversification benefits of U.S.-registered, active, global real estate mutual funds (GREMFs). It considers both the industry as a whole and 76 individual funds, relative to a global and to a domestic benchmark, and before and net of expenses. We estimate alpha, the conditional outperformance, and use the cross-sectional wild bootstrap method to separate funds with genuine skills from merely lucky ones. We find that the actively-managed GREMF industry, as a whole, displays no skills to beat either the global or the domestic benchmarks, even before deduction of expenses. The latter result suggests that there is no benefit from international real estate investment. We also undertake recursive estimates of alpha and conclude that, after an initial period when there were fewer than five funds, there has been no evidence of skills. At the individual fund level, against the global benchmark, we find only one skilled fund but only before expenses are deducted; and, against the domestic benchmark, we find one after the deduction of expenses. Against both benchmarks, we find a number of funds which display a significant lack of skills rather than bad luck, particularly once expenses are taken into account. We undertake a series of robustness checks, including using different benchmarks, and conclude that our results are robust. We also explore possible explanations of performance and conclude that it is linked to over-weighting portfolios in countries/regions with higher economic growth and better investor protection.

Global Real Estate Mutual Funds: Managerial Skills and Diversification Benefits?

Problem The evalue ontology has a transactional perspective on the exchange of values. If one object is exchanged, some other object is exchanged in return. However, this only a limited view on how pricing can be done in a business model. For instance, sometimes you have to subscribe yourself (and pay a fee for doing so), before you can actually obtain a good or service. Also, you might get a discount if you buy a product in large quantities.

An Investigation of Hurdle Rates in the Real Estate Investment Process

This paper makes an empirical test on the correlation between financial restatement and audit report lag (ARL) using data of non-financial listed companies in China during the period 2009–2012. The empirical results show that there is a significant positive correlation between financial restatement and ARL. The longer the ARL is, the more likely it is for the company to perform a financial restatement in the future. The research results of this paper can provide suggestions for the corporate governance of listing Corporation financial restatement from external audit perspective, at the same time, the research on ARL also provides the basis for policy makers to reduce the time of audit report disclosure.

2017 International Conference on Service Systems and Service Management

Empirical study on the phenomenon of audit report lag and financial restatement in Chinese listing corporation

We firstly examine the performance of active sector funds as a whole as equal- and value-weighted portfolios, against a stock market benchmark (Carhart four-factor model), an associated sector market benchmark, and the combined five-factor model benchmarks. We consider the gross and net returns to show the impact of expenses on performance. We also employ the residual bootstrap approach for portfolios to separate genuine skills from luck. We also look into individual sector fund managers, to examine the proportion of truly skilled sector fund managers after false discoveries have been controlled using false discovery rate (FDR) approach. Among all 13 sectors, most sector fund managers on average cannot add enough to cover expenses irrespective of benchmarks. We find mediocre performance on real estate mutual funds (REMFs), comparing with funds of other sectors. Weak evidence of outperformance relative to sector index is found in sectors of gold, and consumer services, even after deduction of expenses. Healthcare and technology sectors, as a whole, can marginally beat the stock market. When the combined sector and stock market benchmark is employed, funds of health care and technology oriented sectors overall can still outperform after costs. Finally, at each sector fund level, we implement joint test to control false discoveries from false positive-alpha funds, and find limited proportion of skilled sector fund managers, after costs.

Cross-sector fund performance comparison: the role of real estate mutual funds

We examine the performance of global active real estate mutual fund (REMF) industry as a whole and at individual fund level, relative to the global real estate and stock markets, and both before and net of expenses. We have used the cross-sectional bootstrap to separate genuine skills from luck. We also evaluate whether global active REMF, at aggregate industry and individual fund level, can gain significant benefit from investing internationally, by comparing them with U.S. domestic real estate and stock market. A series of robustness tests are implemented, especially conditional model, timing model, subperiod test, recursive estimates, and Kalman filter, to examine whether performance and global diversification benefit are sensitive to the impact of macroeconomic background. We find that actively-managed global REMF industry, as a whole, fails to beat the global real estate market and stock market, even before the consideration of expenses. It also cannot beat the U.S. domestic real estate and stock market either, implying no significant benefit from globalization. Same inferences hold when the combined benchmark models are employed. At the individual global REMF level, we find limited evidence for the existence of skills and diversification benefits for any global REMFs. These results hold after a series of robustness checks are implemented. Implementing cross-sectional bootstrap provides new insight to the conventional tests based on asymptotic assumptions. Based on simulated empirical cross-sectional distribution, we find fewer fund managers are truly skilled, and most of the outperformed funds are merely lucky.

Global Real Estate Mutual Funds Performance: Managerial Skills and Diversification Benefits?

This paper examines the performance of active US domestic real estate mutual funds (REMFs) relative to a passive benchmark, both before and after fund managers' compensation. We consider both the REMF sector as a whole, and also individual funds, separately against stock market and real estate market benchmarks. For individual funds, a cross-section bootstrap is used to separate fund managers' genuine skills from luck. We find that the REMF sector as a whole can beat a real estate benchmark but this is cancelled out by fees; and we find that the REMF sector cannot beat the stock market even when fees are not taken into account. For individual REMFs, we find no outperformance against the stock market; and we find genuine stock-picking skills, net of fees, only for a small number of funds in the extreme right tail, relative to the real estate benchmark.

The in situ detection of low-content cancer biomarkers by an endogenous activator instead of an exogenous initiator in vitro remains a great challenge, leaving a gap in the development of a tumor-specific nanosensor with an endogenous protease-activatable manner. Herein, we proposed an endogenous protease-activatable nanosensor (PA-NS) guided by peptide nucleic acid-peptide-DNA copolymers to realize AND-gated and dual-model sensing of miRNA-21 (miR-21) by combining electrochemical detection with optical imaging in living tumor cells, without an additional introduction of an exogenous activator or nanomaterials. Moreover, the PA-NS can only be activated by "dual keys" (overexpressed miR-21 and cathepsin B protease in tumor cells) simultaneously, which enables effective improvement of the tumor-to-healthy cells ratio. The fluorescence intensity measured in single tumor cells was ∼3.5-fold higher than that in single healthy cells, and the electrochemical response decreased ∼30% in the presence of target miRNA. Furthermore, studies on regulation of the protease activity and miR-21 fluctuation under external stimulation have contributed to our understanding of the biological processes and drug screenings underlying disease development. This specific endogenous protease-mediated manner for dual-model detection of miRNA guarantees excellent tumor-selective capability, which offers new opportunities to study cell heterogeneity and provides more reliable fundamentals for the diagnosis and treatment of cancer down to the single-cell level.

Endogenous Protease-Activatable Nanosensor Based on PNA-Peptide-DNA Engineering for AND-Gated and Dual-Model Detection of MicroRNA in Single Living Tumor Cells.

Image deep steganography (IDS) is a technique that utilizes deep learning to embed a secret image invisibly into a cover image to generate a container image. However, the container images generated by convolutional neural networks (CNNs) are vulnerable to attacks that distort their high-frequency components. To address this problem, we propose a novel method called Low-frequency Image Deep Steganography (LIDS) that allows frequency distribution manipulation in the embedding process. LIDS extracts a feature map from the secret image and adds it to the cover image to yield the container image. The container image is not directly output by the CNNs, and thus, it does not contain high-frequency artifacts. The extracted feature map is regulated by a frequency loss to ensure that its frequency distribution mainly concentrates on the low-frequency domain. To further enhance robustness, an attack layer is inserted to damage the container image. The retrieval network then retrieves a recovered secret image from a damaged container image. Our experiments demonstrate that LIDS outperforms state-of-the-art methods in terms of robustness, while maintaining high fidelity and specificity. By avoiding high-frequency artifacts and manipulating the frequency distribution of the embedded feature map, LIDS achieves improved robustness against attacks that distort the high-frequency components of container images.

Low-frequency Image Deep Steganography: Manipulate the Frequency Distribution to Hide Secrets with Tenacious Robustness

A self-assembled bilayer polypeptide-engineered hydrogel for spatiotemporal modulation of bactericidal and anti-inflammation process in osteomyelitis treatment

Investigation of the bioactivity and fluorescence imaging of multicellular tumor spheroid targeted labelling with CdSe/ZnS quantum dots

Application of multifunctional nanoprobes in tumor immunotherapy guided by medical imaging

Highly efficient MnO2/reduced graphene oxide hydrogel motors for organic pollutants removal

Ion current rectification (ICR) phenomena in conical nanopores have been extensively investigated since their early discovery. Several theoretical explanations were proposed to quantitatively describe ICR behavior and to interpret the influences of various configurations. However, if the inner surface of the nanopore is modified with charged molecules or even polymers, the charge species should not be considered simply as mass points. Consequently, the spatial charge distribution in the confined nanopore domains has no reason to be neglected. Here, we proposed a theoretical model to interrogate this kind of ICR behavior by using the Poisson–Nernst–Planck equation. The influence of a series of parameters including ion concentration, bias potential, nanopore dimension, and charge density and its spatial distribution on the mass transfer properties of various nanopores, especially the ICR behavior, are investigated. This study is expected to extend the understanding of nanopore ICR characteristics and open u...

Ion Current Rectification Behavior of Conical Nanopores Filled with Spatially Distributed Fixed Charges

Hollow gold nanoshells-incorporated injectable genetically engineered hydrogel for sustained chemo-photothermal therapy of tumor

An injectable multifunctional hydrogel based on an engineered coiled-coil polypeptide, Ag2S quantum dots (QDs), and paclitaxel (PTX) has been developed for sustained chemo-photothermal therapy. Oil-soluble Ag2S QDs and PTX were first loaded into nanogels formed with engineered polypeptide PC10A by ultrasonic treatment to prepare PC10A/Ag2S QD/PTX nanogels. The multifunctional PC10A/Ag2S QD/PTX hydrogels were prepared by dissolving the PC10A/Ag2S QD/PTX nanogels into the PC10A hydrogel. The PC10A/Ag2S QD/PTX hydrogel can be injected directly into the site of tumors. In vitro and in vivo toxicity results showed that the PC10A/Ag2S QD/PTX hydrogel presented excellent biocompatibility. Compared with single near-infrared photothermal therapy and chemotherapy, the combined therapy could effectively suppress the growth of SKOV3 ovarian carcinoma tumor. In addition, real-time monitoring of the in vivo degradation of the PC10A/Ag2S QD/PTX hydrogel was achieved by near-infrared fluorescence imaging and photoacoustic imaging. These results demonstrated that this injectable multifunctional PC10A/Ag2S QD/PTX hydrogel has the potential as a theranostic platform for sustained cancer treatments.

An injectable hybrid hydrogel based on a genetically engineered polypeptide for second near-infrared fluorescence/photoacoustic imaging-monitored sustained chemo-photothermal therapy.

The value of pH plays an important role in biological systems, and fluorescence pH probes enable noninvasive monitoring of the change and distribution of pH. Here, we introduce a new class of pH probe based on the genetically engineered polypeptide stabilized second near-infrared fluorescence-enhanced core/shell Ag2S quantum dots. The core/shell Ag2S quantum dots synthesized by seed-mediated growth methods showed a good linear relationship between fluorescence intensity and pH value in the range 2.1–7.2. In addition, the core/shell Ag2S quantum dots exhibited excellent reversibility and good biocompatibility, which can serve as multifunctional probes for the imaging and detecting of Gram-negative bacteria without the influence of autofluorescence in the extremely acidic environment.

Seed-Mediated Synthesis of Polypeptide-Engineered Stabilized Fluorescence-Enhanced Core/Shell Ag2S Quantum Dots and Their Application in pH Sensing and Bacterial Imaging in Extreme Acidity

The Preparation of Multifunctional Fluorescent Drug-loaded Hollow Gold Nanosphere

Hollow gold nanospheres (HGNs) have great potential applications in biological sensing, biomedical imaging, photothermal therapy, and drug delivery due to their unique localized surface plasmon resonance (LSPR) feature, easy modification, good biocompatibility, and excellent photothermal conversion properties. In this review, the latest developments of HGNs in biosensing, bioimaging, photothermal therapy, and drug delivery are summarized, the synthesis methods, surface modification and bioconjugation of HGNs are also covered in this summary.

Preparation, Modification, and Application of Hollow Gold Nanospheres

The upconversion nanophosphors are a kind of fluorescence materials with near infrared excitation and short wavelength emission. The upconversion nanophosphors can compensate for the deficiencies of the traditional fluorescent labeling materials because of the stability, non-photobleaching, weak photodamage of biological samples, and high fluorescence signal to noise ratio of biological samples. This review focuses on the upconversion nanophosphors in bioimaging applications.

Research progress in upconversion nanophosphors for biological imaging

Applications of gold nanorods in biomedical imaging and related fields

The Mascarene High (MH), is a key component of the Asian‐Africa‐Australia monsoon system in austral winter (JJA), spanning over the South Indian Ocean (15°–35°S, 15°–110°E). Its three‐dimensional structures and maintenance mechanisms are examined in this study. It is a low‐level subtropical high dominating the southern Africa and South Indian Ocean, characterized by a north‐westward tilt with height, which is attributed to its spatially inhomogeneous thermal structure. Large‐scale subsidence characterizes the main body of the MH, with the stronger subsidence to the east than to the west. Diagnosis using the complete form of the vertical vorticity tendency equation shows that the anticyclonic structure of the MH, which can be described by the distribution of meridional wind, is maintained mainly by the vertical gradient of diabatic heating, change in static stability, and friction dissipation. In particular, a combination of sensible heating and longwave radiative cooling results in a vertical decreasing gradient of diabatic heating in the lower troposphere. It generates the stronger southerlies over the subtropical South Indian Ocean than over the southern Africa. Meanwhile, over the South Indian Ocean, the increasing static stability as a result of the downward transport of a more stable atmosphere partly offsets the effect of the vertical gradient of diabatic heating, and southerlies still prevail there. Over the southern Africa, topographic friction dissipation induces northerlies, balancing the effect of the vertical gradient of diabatic heating with a stronger magnitude, and northerlies prevail.

Structure and maintenance mechanisms of the Mascarene High in austral winter

 <p>Using a recently developed methodology, namely, the multiscale window transform (MWT), and the MWT-based theory of canonical transfer and localized multiscale energetics analysis, we investigate in an eddy-following way the nonlinear eddy-background flow interaction in the North Pacific storm track, based on the ERA40 reanalysis data from ECWMF. It is found that more than 50% of the storms occur on the northern flank of the jet stream, about 40% are around the jet center, and very few (less than 5%) happen on the southern flank. For storms near or to the north of the jet center, their interaction with the background flow is asymmetric in latitude. In higher latitudes, strong downscale canonical available potential energy transfer happens, especially in the middle troposphere, which reduces the background baroclinicity and decelerates the jet; in lower latitudes, upscale canonical kinetic energy transfer intensifies at the jet center, accelerating the jet and enhancing the middle-level baroclinicity. The resultant effect is that the jet strengthens but narrows, leading to an anomalous dipolar pattern in the fields of background wind and baroclinicity. For the storms on the southern side of the jet, the baroclinic canonical transfer is rather weak. On average, the local interaction begins from about 3 days before a storm arrives at the site of observation, achieves its maximum as the storm arrives, and then weakens.</p>

The asymmetric eddy-background flow interaction in the North Pacific storm track

Using a recently developed methodology, namely the multiscale window transform (MWT) and the MWT‐based theory of canonical transfer and localized multiscale energetics analysis, we investigate in an eddy‐following way the nonlinear eddy–background flow interaction in the North Pacific storm track, based on the ERA‐40 reanalysis data from the European Centre for Medium‐Range Weather Forecasts. It is found that more than 50% of the storms occur on the northern flank of the jet stream, about 40% are around the jet centre, and very few (less than 5%) happen on the southern flank. For storms near or to the north of the jet centre, their interaction with the background flow is asymmetric in latitude. In higher latitudes, strong downscale canonical available potential energy transfer happens, especially in the mid‐troposphere, which reduces the background baroclinicity and decelerates the jet; in lower latitudes, upscale canonical kinetic energy transfer intensifies at the jet centre, accelerating the jet and enhancing the middle‐level baroclinicity. The resultant effect is that the jet strengthens but narrows, leading to an anomalous dipolar pattern in the fields of background wind and baroclinicity. For the storms on the southern side of the jet, the baroclinic canonical transfer is rather weak. On average, the local interaction begins about 3 days before a storm arrives at the site of observation, achieves its maximum as the storm arrives, and then weakens.

The asymmetric eddy–background flow interaction in the North Pacific storm track

Charney’s Model—the Renowned Prototype of Baroclinic Instability—Is Barotropically Unstable As Well

Causes and underlying dynamic processes of the mid-winter suppression in the North Pacific storm track

Previous studies show that in boreal winters when the Pacific jet is extremely strong, the Pacific storm track is, however, unexpectedly weak. Using a recently developed technique, namely, the multiscale window transform (MWT), and the MWT-based localized multiscale energetics analysis, we investigate in this study the underlying mechanism of this counterintuitive phenomenon, based on ERA-40 data. It is found that most of the synoptic storms are generated at latitudes far north of the jet core, which lowers the relevance of the jet strength to the storm-track intensity, and the inverse relationship between the Pacific jet strength and storm-track intensity is mainly attributed to the internal dynamics. In the strong jet state, on one hand, the jet is narrow, and thus the jet winds at high latitudes are weak, resulting in weak baroclinic instabilities and hence reduced eddy growth rate; on the other hand, although baroclinic instabilities are strong at the jet core, inverse kinetic energy (KE) cascades are even stronger (by 43%). The resultant effect is that more eddy energy is transferred back to the background flow, leaving an overall weak storm track in a strong Pacific jet. In addition, diabatic processes are found to account for the inverse relationship: it is greatly weakened (by 25%) in the strong-core jet state. Apart from these, we also find that the role that barotropic canonical transfer plays in the inverse relationship is opposite to that in the formation of the midwinter minimum (MWM), another counterintuitive phenomenon in the Pacific storm track.

On the Inverse Relationship between the Boreal Wintertime Pacific Jet Strength and Storm-Track Intensity

Eddy-shedding is a highly nonlinear process that presents a major challenge in geophysical fluid dynamics. Using the newly developed localized multiscale energy and vorticity analysis (MS-EVA), this study investigates an observed typical warm eddy-shedding event as the Kuroshio passes the Luzon Strait, in order to gain insight into the underlying internal dynamics. Through multiscale window transform (MWT), it is found that the loop-form Kuroshio intrusion into the South China Sea (SCS) is not a transient feature, but a quasi-equilibrium state of the system. A mesoscale reconstruction reveals that the eddy does not have its origin at the intrusion path, but comes from the Northwest Pacific. It propagates westward, preceded by a cyclonic (cold) eddy, through the Kuroshio into the SCS. As the eddy pair runs across the main current, the cold one weakens and the warm one intensifies through a mixed instability. In its development, another cold eddy is generated to its southeast, which also experiences a mixed instability. It develops rapidly and cuts the warm eddy off the stream. Both the warm and cold eddies then propagate westward in the form of a Rossby wave (first baroclinic mode). As the eddies approach the Dongsha Islands, they experience another baroclinic instability, accompanied by a sudden accumulation of eddy available potential energy. This part of potential energy is converted to eddy kinetic energy through buoyancy conversion, and is afterwards transferred back to the large-scale field through inverse cascading, greatly reducing the intensity of the eddy and eventually leading to its demise. This article is protected by copyright. All rights reserved.

Nonlinear multiscale interactions and internal dynamics underlying a typical eddy‐shedding event at Luzon Strait

By means of the Ford–Kac–Mazur formalism, the heat current and local kinetic energy of a dielectric chain with Fermi–Pasta–Ulam–β nonlinear interactions are derived out in the stationary equilibrium and analyzed numerically. We find that the anharmonicity reduces the heat current for repulsive interactions and enhances the heat current for attractions. The magnitudes of heat current are relevant strong at low frequencies, while the local kinetic energy is bigger in the high-frequency regime. The local kinetic energy displays a periodic oscillation due to the interference of the thermal waves. In particular, the transmission matrix exhibits oscillations due to scattering of phonons for the imperfect contacts. In general, the thermal transport is qualitatively altered by the differences of temperature between reservoirs, nonlinear interactions and the size of chain as well as the contacts.

THERMAL TRANSPORT THROUGH A DIELECTRIC CHAIN WITH FERMI–PASTA–ULAM INTERACTIONS

Effects of G-jitter on Experiments Conducted in Low-Earth Orbit: A Review

Robust Strategy Optimization of Networked Evolutionary Games with Disturbance Inputs

Site Selection for Land Consolidation Project Using Ant Colony Optimization

Second-extraconnectivity of 3-ary n -cube networks: Second-extraconnectivity of 3-ary n -cube networks

Earliest Deadline First (EDF) is a favorable algorithm in the field of dynamic scheduling which plans the task scheduling during system running. The CPU utilization of EDF algorithm may achieve to one hundred percent. Although EDF has many excellent performances and is used broadly in actual embedded real-time systems, it has many shortages. In order to reduce the release time of EDF scheduling algorithm and to decrease scheduling spending, the Deoxyribonucleic acid Genetic Algorithm (DNA-GA) is used to optimize the preemptive EDF scheduling algorithm in off-line model. Simulation experiments are carried out to compare the performances. Compared with the scheduling spending before optimized, the scheduling spending after optimized was reduced dramatically and the real-time performance was improved.

Horse traversing problem was a hard problem to solve with traditional computer; and there were no efficient algorithms to solve this problem with traditional computer when the measurement of problem was very great. In order solve this problem, the extended horse traversing problem was transformed into directed Hamilton path problem, and was solved by using Adleman DNA computing model. A DNA algorithm was introduced to solve this kind of problems through an instance on a chess-board, the experiment steps were also given; at the same time, the solution of the instance was got by simulation experiment. At last, the complexity of the algorithm was illustrated.

2009 International Workshop on Intelligent Systems and Applications

A DNA Algorithm of Horse Traversing Problem Based on Adleman Model

Physical education majors shall have solid professional knowledge and have proficiency in teaching techniques so as to competent for the physical education teaching.Teaching techniques are the acquired capacities which demand practice.By the method of teaching experiment,the paper adopts microteaching method to conduct teaching technique training of the physical education majors.The experiment shows that through microteaching,the teaching technique training for the physical education majors can promote their teaching capacities.It is an effective way for the physical education majors to adopt teaching techniques.

Experimental Study on the Effect of Microteaching to the Techniques of the Physical Education Majors

As our college to a foreign university summer school learning products,short-term system has got more and more colleges and universities favor.However,sports colleges and sports professionals set up short-team system rarely and research on it so far is a blank.This paper makes study on setting up short-term system and find out existing problem.Through analysis,try to find out solution and provide development measurements for college physical education major.

Research on Development Condition of Short-term System of College Physical Education Major

As a new form of the tourism market,sports tourism is not only a simple form of the tourist activity but also a new field which combines tourism and sports industry.Therefore,this essay will expound the problems mentioned above,do some research and find the solution to the problems such as the present condition of this specialty and course offering.

A Research on the Present Condition of the Specialty of Sports Tourism in Universities

With the rapid development of volleyball technology,athletes are required to master more accurate techniques.On basis of the analysis of "Hawkeye" technology,combining with various "Hawkeye" techniques used in sports,"Hawkeye" technology has been introduced into volleyball competition.Combining the characteristics of volleyball competition and the problems that may occur after the introduction of "Hawkeye",this paper explores whether "Hawkeye" should be applied to volleyball competition,and how to use the "Hawkeye" technology reasonably.

Feasibility Analysis of "Hawkeye" Technique Employed in Volleyball Competition

GnRH Inhibits FSH-Induced Steroidogenenisis by Suppressing FSH Receptor Expression via USF2 Transcriptional Factor.

With the methods of literature review and mathematical statistics,the test scores of some students physical health standard in Changchun Normal University were analyzed.The relevant data was drawn with the statistical software spss13.5.The results showed that most students are located in the standard range between 18.5～23.0,and the value of BMI for boys is higher than girls.College students should establish health life style,regularly do physical exercises,and cultivate the lifelong sports consciousness.

Distribution Characteristics and Analysis of Students Body Mass Index(BMI) in Changchun Normal University

Objective To study the effect and eradication of Kuiyang Decoction(decoction for ulcer) plus triad-therapy of western medicine on helicobacter pylori(Hp) positive duodenal ulcer.Methods The 140 cases were randomly divided into two groups.The control group,70 cases,was treated by standard triad-therapy:omeprazole,amoxicillin and metronidazole per os for one week in succession,then only omeprazole,20mg each time,twice a day,3 weeks in succession.The treatment group,70 cases,was treated by Kuiyang Decoction per os,one dose each day,for 4 weeks in succession in addition to taking the above-mentioned western medicines in the same way as the control group.Before and after treatment both groups were given the Hp test for comparing the therapeutic effect.Results The treatment group was better than the control group in the effect under gastroscope,Hp eradication rate,symptom improvement,and one-year recurrent rate(P0.05).Conclusion The combination of Kuiyang Decoction plus triad-therapy of western medicine for the treatment of Hp positive duodenal ulcer is remarkable in improving eradicative rate of Hp.

Clinical Observation on the Effect of Kuiyang Decoction plus Triad-therapy of Western Medicine on 70 Cases of Helicobacter Pylori Related Duodenal Ulcer

The leisure has already became the civilized symbol of social development,and the idea of leisure sports has been deeply rooted in the hearts of the people as a brand-new sports idea.Therefore,the re-cognition of the leisure and the leisure sports fron the viewpoint of sociology is not only helpful to the development of leisure sports,but has very important practical significance in constructing the socialist harmonious society.

The Influence of Leisure Sports on Modern Society from the Viewpoint of Sociology

Granulosa cells (GCs) are the most important cells in the ovary that undergo serious changes morphologically and physiologically during the processes of follicular proliferation, differentiation, ovulation, lutenization and atresia. Oocyte (OC) directs GC proliferation and differentiation, while GCs influence OC maturation. Many ovarian factors are involved in the regulation of these processes via different molecular mechanisms and signal pathways. P38 MAPK can selectively regulate steroidogenesis in GCs controlled by FSH; Transcript factors LRH-1 and DAX-1 play an important role in this process; FSH induces GC proliferation and differentiation by stimulating PCNA and StAR expression and steroidogenesis. Activated ERK1/2 signal pathway may be involved in the FSH-regulated GC proliferation and differentiation. Therefore, GC is an ideal model for studying cell proliferation, differentiation and interaction, as well as signal transduction. This review briefly summarizes the latest data in the literature, including the results achieved in our laboratory.

Granulosa cell proliferation differentiation and its role in follicular development

AIM: To examine expression of transforming growth factor-beta 1 (TGF-β1) and TGFβ receptor II (TβR-II) and steroidogenic acute regulatory protein (StAR) in the corpus luteum (CL) of pregnant monkeys at various stages and to study possible effect of IFN-γ on their production. METHODS: In situ hybridization and immunohistochemistry were applied to detect mRNA and protein. RESULTS: The expression of StAR, TGF-β1, and TβR-II in the pregnant monkey CL was progressively decreased from d 15 to d 35 of gestation. IFN-γ down-regulated the expression of TGF-β1, TβR-II, as well as StAR. CONCLUSION: TGF-β1 may play an important role in the CL formation and functional maintaining; IFN-γ down-regulates the expression of TGF-β1, TβR-II , and StAR.

Regulatory effect of IFN-y on expression of TGF-ss1, TssR-II, and StAR in corpus luteum of pregnant rhesus monkey

Expression of P16(INK4a) in testis of rhesus monkey during heat stress and testosterone undecanoate induced azoospermia or oligozoospermia.

Apoptosis occurs in implantation site of the rhesus monkey during early stage of pregnancy.

The localization and distribution of mRNAs and antigens of tissue type (t) and urokinase type (u) plasminogen activator (PA) plus their corresponding inhibitors type-1 (PAI-1) and type-2 (PAI-2) were studied in human and rhesus monkey placentae by in situ hybridization and immunofluorencence. We have demonstrated that (1) plasminogen activators (tPA and uPA), and their inhibitors (PAI-1 and PAI-2) for both mRNAs and proteins in most cases, co-localized in the same areas, but with different extent, in human and rhesus monkey placentae; (2) All the molecules, tPA, uPA, PAI-1, and PAI-2 and their mRNAs were identified in the wall of blood vessels of villi stem and decidua, extravillous cytotrophoblast cells of basal plate between Rohr's and Nitabuch's striae, trophoblast shell and decidual gland cells as well as cytotrophoblast cells of villi. However, tPA and PAI-1 were found to be more evident in the regions adjacent to abscission planes from the maternal tissue, while uPA and PAI-2 concentrated mainly in villous trophoblast and extravillous trophoblast cells; (3) Distribution of the mRNAs of the 4 genes is generally consistent with the immunofluorescent pattern of the corresponding antigens, however, no expression of the mRNAs, but their proteins was observed in syncytiotrophoblast cells of villi; (4) The patterm of distribution and synthesis of the activators and inhibitors coincides with the distribution of fibrin-like molecules; (5) The distribution pattern of the mRNAs and their proteins was similar in monkey and human placentae, no spcies-difference was demonstrated. The data suggest that the activators and the inhibitors described here interact at a variety of crucial physiological stages of pregnancy. They may interact in tightly restricted locations to the matrix fibrinoids in rather short ranges and at specific times, particularly during early and late pregnancy, to promote healthy gestation. It is possible that failure of the local control over the system may be important in failure of implantation and premature rupture of membranes. We now propose that the location of these molecules gives the system potential in the control over establishment of uterofetal blood circulation and placentation in the first two trimesters of gestation and abscission during the third stage of labour and predict a role in the pathology of abrupio placenta and retained placental products.

In situ Hybridization and Immunofluoflurescent Localization of tPA,uPa,PAI-1 and PAI-2 in Human and Rhesus Monkey Placentae

Sertoli cells play a central role in the control and maintenance of spermatogenesis. Isolated Sertoli cells of mouse and rat testes have been shown to secrete plasminogen activator (PA) and a plasminogen activator inhibitor type-1 (PAI-1) in culture. In this study, we have investigated the hormonal regulation of PA and PAI-1 activities in cultured monkey Sertoli cells. Sertoli cells (5×10 5 cells/well) isolated from infant rhesus monkey testes were preincubated at 35 o C for 16 h in 24-well plates precoated with poly(D-lysine) (5 μg/cm 2 ) in 0.5 ml McCoy's 5a medium containing 5% of fetal calf serum and further incubated for 48 h in 0.5 ml serum-free medium with or without various hormones or other compounds. PA as well as PAI-1 activities in the conditioned media were assayed by fibrin overlay and reverse fibrin autography techniques respectively. The Sertoli cells in vitro secreted only tissue-type PA (tPA), no detectable amount of urokinase-type PA (uPA) could be observed. Monkey Sertoli cells were also capable of secreting PAI-1. Immunocytochemical studies indicated that both tPA and PAI-1 positive staining localized in the Sertoli cells, spermatids and residual bodies of the seminiferous epithelium; Northern blot analysis further confirmed the presence of both tPA and PAI-1 mRNA in monkey Sertoli cells. Addition of follicle-stimulating hormone (FSH) or cyclic adenosine monophosphate (cAMP) derivatives or cAMP-generating agents and gonadotrophin-releasing hormone (GnRH) agonist or phorbol ester (PMA) to the cell culture significantly increased tPA activity. PAI-1 activity in the culture was also enhanced by these reagents except 8-bromo-dibutyryl-cAMP, forskolin and 3-isobutyl-1-methylxanthin (MIX) which greatly stimulated tPA activity, whereas decreased PAI-1 activity, implying that neutralization of PAI-1 activity by the high level of tPA in the conditioned media may occur. These data suggest that increased intracellular signals which activate protein kinase A (PKA), or protein kinase C (PKC) can modulate Sertoli cell tPA and PAI-1 activities. The concomitant induction of PA and PAI-1 by the same reagents in the Sertoli cells may reflect a finely tuned regulatory mechanism in which PAI-1 could limit the excession of the proteolysis

Endocrinology and Paracrinology: Hormonal regulation of tissue-type plasminogen activator and plasminogen activator inhibitor type-1 in cultured monkey Sertoli cells

Hormonal regulation of tissue-type plasminogen activator and plasminogen activator inhibitor type-1 in cultured monkey Sertoli cells

Changes of plasminogen activators (PA) during different stages of development of the corpus luteum, and their possible physiological role in luteolysis were studied in rhesus monkeys. It was demonstrated for the first time that monkey corpus luteal cells not only produce PA, but that the function of the corpus luteum is also closely related to the activity of this enzyme system. Generally, the life span for a corpus luteum in monkey is approximately 14-16 days, its demise beginning thereafter. In the present study, we found that urokinase in the corpus luteum is higher on day 5 and day 10 after human chorionic gonadotrophin injection, while the tissue type (t) PA is mainly produced on day 13 when luteolysis may take place. Progesterone production remained high on day 5 and day 10 and decreased dramatically from day 13, indicating the important role of tPA but not urokinase (u) PA in suppressing luteal function. When purified tPA (but not uPA) monoclonal antibody was added to luteal cell culture to neutralize endogenously produced tPA activity, progesterone production in the cells was increased significantly. Interestingly, prolactin alone was capable of increasing PA production by luteal cells; prolactin together with luteinizing hormone, however, had a synergistic luteotrophic effect.

The possible involvement of tissue type plasminogen activator in luteolysis of rhesus monkey

We have demonstrated for the first time that (i) mouse Sertoli cells predominantly secrete tPA under the action of FSH and cAMP-generating agents, whereas Leydig cells mainly produce uPA; (ii) Sertoli cells are also capable of secreting PAI-1, as well as FSH, growth factors and GnRH increase PAI-1 gene expression; (iii) the increases in tPA and PAI-1 activities by different hormones in the conditioned media of Sertoli cells correspond to the increases in the levels of tPA and PAI-1 mRNA in the cultured cells, suggesting that the synthesis of the activator-inhibitor in mouse Sertoli cells is regulated at a transcriptional level and the tPA secreted by Sertoli cells may be involved in the spermatogenesis.

Hormonal Regulation of Tissue-type Plasminogen Activator and Plasminogen Activator Inhibitor Type-1 Gene Expression in Cultured Mouse Sertoli Cells

The present studies have demonstrated that infant monkey granulosa cells, like the adult ones, have the potential of responding markedly in vitro to human FSH, cyclic-AMP and forskolin, resulting in the increase of progesterone and estrogen production. Exogenous hCG was also capable of increasing FSH-stimulated progesterone biosynthesis in both infant and adult granulosa cells, but did not stimulate the infant granulosa cells to secrete estrogen. Addition of a synthetic estrogen, diethylstilbestrol, to the culture of monkey granulosa cells enhanced the FSH-stimulated progesterone and estrogen production. The steroidogenesis of monkey granulosa cells was also dramatically stimulated by a gonadotropin-releasing hormone agonist. Monkey granulosa cells, unlike the other animal cells, secrete measurable amount of estrogen in the absence of androgen substrate. The findings reported here are significant in regard to understanding of the mechanism of hormonal regulation of primate ovarian function.

REGULATION OF STEROIDOGENESIS OF INFANT AND ADULT RHESUS MONKEY GRANULOSA CELLS in vitro

In this paper, a Bayesian variable selection method for spatial autoregressive (SAR) quantile models is proposed on the basis of spike and slab prior for regression parameters. The SAR quantile models, which are more generalized than SAR models and quantile regression models, are specified by adopting the asymmetric Laplace distribution for the error term in the classical SAR models. The proposed approach could perform simultaneously robust parametric estimation and variable selection in the context of SAR quantile models. Bayesian statistical inferences are implemented by a detailed Markov chain Monte Carlo (MCMC) procedure that combines Gibbs samplers with a probability integral transformation (PIT) algorithm. In the end, empirical numerical examples including several simulation studies and a Boston housing price data analysis are employed to demonstrate the newly developed methodologies.

A Bayesian Variable Selection Method for Spatial Autoregressive Quantile Models

The main purpose of this article is to develop a Bayesian adaptive lasso procedure for analyzing linear regression models with nonignorable missing responses, in which the missingness mechanism is specified by a logistic regression model. A sampling procedure combining the Gibbs sampler and Metropolis-Hastings algorithm is employed to obtain the Bayesian estimates of the regression coefficients, shrinkage coefficients, missingness mechanism models parameters, and their standard errors. We extend the partial posterior predictive 
 
 p
 
 value for goodness-of-fit statistic to investigate the plausibility of the posited model. Finally, several simulation studies and the air pollution data example are undertaken to demonstrate the newly developed methodologies.

Bayesian Adaptive Lasso for Regression Models with Nonignorable Missing Responses

Theory for socio-demographic enrichment performance using the inverse discrete choice modelling approach

In the development of simplex mixed-effects models, random effects in these mixed-effects models are generally distributed in normal distribution. The normality assumption may be violated in an analysis of skewed and multimodal longitudinal data. In this paper, we adopt the centered Dirichlet process mixture model (CDPMM) to specify the random effects in the simplex mixed-effects models. Combining the block Gibbs sampler and the Metropolis–Hastings algorithm, we extend a Bayesian Lasso (BLasso) to simultaneously estimate unknown parameters of interest and select important covariates with nonzero effects in semiparametric simplex mixed-effects models. Several simulation studies and a real example are employed to illustrate the proposed methodologies.

Bayesian Variable Selection and Estimation in Semiparametric Simplex Mixed-Effects Models with Longitudinal Proportional Data

Logistic mixed-effects models are widely used to study the relationship between the binary response and covariates for longitudinal data analysis, where the random effects are typically assumed to have a fully parametric distribution. As this assumption is likely limited or unreasonable in a multitude of practical researches, a semiparametric Bayesian approach for relaxing it is developed in this paper. In the context of binomial distribution logistic mixed-effects models, a general Bayesian framework is presented in which a semiparametric hierarchical modelling with an approximate truncated Dirichlet process prior distribution is specified for the random effects. The stick-breaking prior and the blocked Gibbs sampler using Pólya-Gamma mixture are employed to efficiently sample in the posterior analysis. Besides, a procedure calculating DIC for Bayesian model comparison is addressed. The methodology is demonstrated through simulation studies and a real example.

A semiparametric Bayesian approach to binomial distribution logistic mixed-effects models for longitudinal data

ABSTRACT Simplex regression model is often employed to analyze continuous proportion data in many studies. In this paper, we extend the assumption of a constant dispersion parameter (homogeneity) to varying dispersion parameter (heterogeneity) in Simplex regression model, and present the B-spline to approximate the smoothing unknown function within the Bayesian framework. A hybrid algorithm combining the block Gibbs sampler and the Metropolis-Hastings algorithm is presented for sampling observations from the posterior distribution. The procedures for computing model comparison criteria such as conditional predictive ordinate statistic, deviance information criterion, and averaged mean squared error are presented. Also, we develop a computationally feasible Bayesian case-deletion influence measure based on the Kullback-Leibler divergence. Several simulation studies and a real example are employed to illustrate the proposed methodologies.

A semiparametric Bayesian approach to simplex regression model with heterogeneous dispersion

In this paper, we relax the fully parametric distributional assumption of measurement errors (MEs) to establish mixture Bernoulli model by a centered Dirichlet process. A hybrid algorithm is presented to generate observations required for a Bayesian inference from the posterior distributions of parameters and covariates subject to MEs in Bernoulli model by combining the stick-breaking prior and the Gibbs sampler together with the Metropolis-Hastings algorithm. Two Monte Carlo studies illustrate the superiority of the measurement error estimators in certain situations.

Semiparametric Bayesian Estimation of Bernoulli Model with Measurement Error

Inspired by the idea of Kuo and Mallick, Bayesian subset selection for inverse Gauss regression models is studied by Gibbs sampler and Metropolis-Hastings algorithm in this paper. Simulation study and the aerobic fitness data example are employed to demonstrate the proposed methodology. Keywords—Bayesian subset selection; Gibbs sampler; Metropolis-Hastings algorithm; Inverse Gauss regression models

ABSTRACT The growing availability of geotagged big data has stimulated substantial discussion regarding their usability in detailed travel behaviour analysis. Whilst providing a large amount of spatio-temporal information about travel behaviour, these data typically lack semantic content characterising travellers and choice alternatives. The inverse discrete choice modelling (IDCM) approach presented in this paper proposes that discrete choice models (DCMs) can be statistically inverted and used to attach additional variables from observations of travel choices. Suitability of the approach for inferring socioeconomic attributes of travellers is explored using mode choice decisions observed in London Travel Demand Survey. Performance of the IDCM is investigated with respect to the type of variable, the explanatory power of the imputed variable, and the type of estimator used. This method is a significant contribution towards establishing the extent to which DCMs can be credibly applied for semantic enrichment of passively collected big data sets while preserving privacy.

Inverse discrete choice modelling: theoretical and practical considerations for imputing respondent attributes from the patterns of observed choices

Normality assumption of the random errors and the random effects is a routinely used technique in data analysis. However, this assumption might be unreasonable in many practical cases. In this paper the limitation is relaxed by assuming that the random error follows a reproductive dispersion model and the random effect is distributed as a skew-normal distribution, which is termed as a multivariate skew-normal reproductive dispersion random effects model. We propose a Bayesian procedure to simultaneously estimate the random effects and the unknown parameters on the basis of the Gibbs sampler and Metropolis-Hastings algorithm. In the end, the Framingham cholesterol data example is employed to demonstrate the preceding proposed Bayesian methodologies.

Proceedings of 2018 International Conference on Mathematics and Artificial Intelligence

Bayesian analysis for multivariate skew-normal reproductive dispersion random effects models

The growing availability of transport big data from information and communications technologies has stimulated substantial discussion regarding their applicability for detailed travel behaviour analysis (Pawlak et al., 2015). In parallel to the enthusiasm created by such opportunities, researchers have become increasingly aware of the major limitations of such data; particularly their lack of semantic content – typical big data sources containing little information on data point. For example, unless supplemented with an add-on survey, data from a GPS logger typically provide numerous data points with accurate geographical coordinates and timestamps but no readily accessible and meaningful information on the respondents or their activities. Since such contextual information is critical for travel behaviour analysis and policymaking practices, the weak semantics of transport big data can significantly limit analytical depth of the possible insights and can even lead to inferences erroneous and misguiding policy-making.

Semantic Enrichment through Inverse Discrete Choice Modelling : A Mutual Information Approach

Various mixed models were developed to capture the features of between- and within-individual variation for longitudinal data under the normality assumption of the random effect and the within-individual random error. However, the normality assumption may be violated in some applications. To this end, this article assumes that the random effect follows a skew-normal distribution and the within-individual error is distributed as a reproductive dispersion model. An expectation conditional maximization (ECME) algorithm together with the Metropolis-Hastings (MH) algorithm within the Gibbs sampler is presented to simultaneously obtain estimates of parameters and random effects. Several diagnostic measures are developed to identify the potentially influential cases and assess the effect of minor perturbation to model assumptions via the case-deletion method and local influence analysis. To reduce the computational burden, we derive the first-order approximations to case-deletion diagnostics. Several simulation studies and a real data example are presented to illustrate the newly developed methodologies.

Maximum-likelihood estimation and influence analysis in multivariate skew-normal reproductive dispersion mixed models for longitudinal data

Abstract We propose a full Bayesian subset selection method for reproductive dispersion linear models, which bases on expanding the usual link function to a function that incorporates all possible subsets of predictors by adding indictors as parameters. The vector of indicator variables dictates which predictors to delete. An efficient MCMC procedure that combining Gibbs sampler and Metropolis-Hastings algorithm is presented to approximate the posterior distribution of the indicator variables. The promising subsets of predictors can be identified as those with higher posterior probability. Several numerical examples are used to illustrate the newly developed methodology.

Bayesian Subset Selection for Reproductive Dispersion Linear Models

The main thrust of this paper is to study Bayesian analysis of simplex distribution nonlinear mixed models for longitudinal data. A hybrid algorithm that combines the Gibbs sampler and Metropolis-Hastings algorithm is implemented to produce the joint Bayesian estimates of parameters and random effects. Simulation studies and a real example are presented to illustrate the methodologies.

Bayesian estimation of simplex distribution nonlinear mixed models for longitudinal data

In recent years, double regression models, in which we jointly model the mean and the dispersion (or variance) directly as a function of the explanatory variables, are widely used in many practical problems. Further, the inverse Gaussian distribution is one of the basic models for describing positively skewed data which arise in a variety of applications. Therefore, in this paper we consider Bayesian estimation for the parameters of double generalized linear regression models of the inverse Gaussian distribution. A computational efficient MCMC method which combines the Gibbs sampler and Metropolis-Hastings algorithm is implemented to simultaneously obtain the Bayesian estimates of unknown parameters, as well as their standard deviation estimates. Finally, several simulation studies are presented to illustrate the proposed methodology.

Bayesian Inference for Double Generalized Linear Regression Models of the Inverse Gaussian Distribution

Semiparametric Bayesian analysis of nonlinear reproductive dispersion mixed models for longitudinal data

Application of survival analysis methods to pulsed exposures: Exposure duration, latent mortality, recovery time, and the underlying theory of survival distribution models

Affected by the changes of drainage basin and marine environment and human activities, estuarine wetland is fragile, sensitive, and complex in evolution. Jiuduansha Wetland is the largest estuarine shoal wetland in the Yangtze Estuary, and is undergoing rapid changes due to the reduction of sediment inputs and the invasion of alien species Spartina alterniflora. In this study, the changes of Jiuduansha Wetland from 1989 to 2020 were analyzed through remote sensing interpretation, field investigation, and topographic data analysis. The impacts of watershed sediment reduction and S. alterniflora invasion on Jiuduansha Wetland were analyzed based on the hydrological data of Datong station and the invasion history of S. alterniflora. The results showed that the total area of Jiuduansha Wetland (above -5 m) first increased and then decreased since 1991, reaching its maximum in 2005 (421.16 km2). The area of tidal flat wetland (above 0 m) and wetland vegetation increased continuously from 1989 to 2020, with 1.5 times and 47.1 times increases, respectively. The decreases of sediment supply led to a decrease in the total area of Jiuduansha Wetland (above -5 m) and a decrease growth rate of tidal flat wetland area above 0 m and vege-tation area. The invasive species S. alterniflora had expanded rapidly, occupied the space of native species, and became the dominant species in Jiuduansha Wetland since it was introduced in 1997. Sediment reduction and S. alterniflora invasion had led to the rapid changes of Jiuduansha Wetland structure. In order to avoid the degradation of ecological service, wetland protection and restoration should be taken to maintain the stability and health of Jiu-duansha Wetland.

[Pattern evolution and impact factor of Jiuduansha Wetland at the Yangtze Estuary during 1989-2020].

Pinpointing stage‐specific causes of recruitment bottlenecks to optimize seed‐based wetland restoration

Unraveling the wheel of recruitment for salt-marsh seedlings: Resistance to and recovery after dislodgement.

A solution for restoration of critical wetlands and waterbird habitats in coastal deltaic systems.

Effective seed dispersal is critical for enabling rapid state shift from a bare tidal flat to a vegetated marsh. While tidal currents are the main dispersal vector in coastal environments, biological characteristics that keep seeds afloat have been shown to influence primary seed dispersal, i.e., seed departure from the parent plant. In contrast, secondary seed dispersal processes that move (germinated) seeds trapped within microsites have been largely neglected. Here, we explore the extent to which the coupling between biotic traits and abiotic factors affects secondary seed dispersal, and whether secondary seed dispersal may explain sudden saltmarsh establishment (i.e., rapid colonization of bare tidal flat by large numbers of seedlings in spring). We used two widely spread pioneer species: Scripus mariqueter and Spartina alterniflora. Combined flume and field results demonstrated that: (1) germination stage, current velocity, and sedimentary regime have a marked effect on the probability of secondary seed dispersal by influencing the threshold lift‐off velocity of (germinated) seeds within microsites; (2) density and bud length are critical biotic traits that best predict the potential of secondary‐dispersal onset after seed germination; (3) S. alterniflora possess a stronger secondary dispersal ability compared to S. mariqueter; and (4) secondary dispersal of germinated seeds in spring may explain observed sudden marsh establishment on bare tidal flats. Our findings provide novel insight relevant to understanding the drivers of seed dispersal and thereby sudden saltmarsh establishment events, with important implications for understanding the effects of climate change on critical state transitions and enabling human‐aided restoration.

The onset of secondary seed dispersal is controlled by germination‐features: A neglected process in sudden saltmarsh establishment

Re-invasion of Spartina alterniflora in restored saltmarshes: Seed arrival, retention, germination, and establishment.

Restoration has been promoted as an important strategy to reverse the decline of salt marsh ecosystems. Physical and biological processes limiting the colonization of bare tidal flats by pioneer salt marsh species are commonly recognized. Recently, the window of opportunity (WoO) concept has been proposed as a framework to provide an explanation for the initial establishment of biogeomorphic ecosystems on tidal flats under high physical stress. Understanding the thresholds for early seedling establishment and colonization is critical for the successful restoration and management of this threatened ecosystem. In this study, we investigated the WoOs for the establishment and colonization of a Scirpus mariqueter salt marsh at a large-scale restoration site in the Yangtze Estuary. A set of field monitoring and measurements were conducted to identify the potential physical and biological thresholds that could provide a mechanistic insight on the establishment and colonization of this pioneer marsh. The results showed that the successful colonization and expansion of the S. mariqueter marsh on the tidal flat required passing both physical and biological thresholds to open WoOs for establishment and colonization. The concurrence of WoOs, that is, propagule availability in the early growing season at a suitable tidal flat elevation with a benign sedimentary regime together with the removal of competition from invasive species, is presumed to be essential for the success of S. mariqueter marsh establishment and colonization. In applying such ecological insights, the seed-sowing field experiment proved that by surpassing these thresholds, an S. mariqueter salt marsh can be successfully restored in a cost-effective manner. We suggest that these WoOrelated establishment and colonization thresholds as well the cost-effectiveness of using these WoOs should be considered in future large-scale restorations of salt marshes.

Windows of opportunity for salt marsh establishment: the importance for salt marsh restoration in the Yangtze Estuary

Alternative stable states phenomenon widely exists in a variety of ecosystems and is closely related to ecosystem health and sustainable development. Although alternative stable states research has become the focus and hotspot of the ecology researches, only a few empirical evidences supported its behavior and mechanisms in coastal wetland ecosystems up to now. In our study, ta-king the intertidal wetland ecosystem in Chongming Dongtan Nature Reserve as study area, we aimed to: 1) test the existence of alternative stable states based on judgment conditions (bimodal characteristic and threshold effect) and determine the relative stable state types; 2) explore the formation mechanisms of alternative stable states by monitoring hydrological conditions, sediment accretion dynamics as well as vegetation growth parameters and analyzing the positive feedbacks between saltmarsh vegetation and sedimentary geomorphology. Our results showed that: 1) Normalized difference vegetation index (NDVI) frequentness distribution revealed obvious bimodality at saltmarsh pioneer zone. Propagule biomass threshold limited the establishment of plant patches representing the "saltmarsh" state. The presence of bimodality and biomass threshold demonstrated there are "mudflat" stable state and "saltmarsh" stable state with distinct structure and function in intertidal wetland ecosystem. 2) Current velocities, turbidities and direction perpendicular to the vegetation zone were the most important factors responsible for the sediments rapid accretion at saltmarsh pioneer zone in spring and summer. Sediments accretion significantly promoted the growth of saltmarsh plant. The positive feedbacks between plant growth and sediments accretion resulted in the formation of alternative stable states. 3) The expansion pattern of saltmarshes in the Chongming Dongtan intertidal wetland ecosystem also suggested that increases of sediments accretion could trigger the formation of "mudflat" stable state and "saltmarsh" stable state on landscape scale. The results from this study could enrich regime shift mechanisms researches and provide the scientific supports for coastal zone protection, restoration and comprehensive management, which could have important theoretical and practical meaning.

[Alternative stable states in coastal intertidal wetland ecosystems of Yangtze estuary, China].

Background: To develop an artificial intelligence system that can accurately identify acute non-traumatic intracranial hemorrhage (ICH) etiology based on non-contrast CT (NCCT) scans and investigate whether clinicians can benefit from it in a diagnostic setting. Materials and Methods: The deep learning model was developed with 1868 eligible NCCT scans with non-traumatic ICH collected between January 2011 and April 2018. We tested the model on two independent datasets (TT200 and SD 98) collected after April 2018. The model's diagnostic performance was compared with clinicians's performance. We further designed a simulated study to compare the clinicians's performance with and without the deep learning system augmentation. Results: The proposed deep learning system achieved area under the receiver operating curve of 0.986 (95% CI 0.967-1.000) on aneurysms, 0.952 (0.917-0.987) on hypertensive hemorrhage, 0.950 (0.860-1.000) on arteriovenous malformation (AVM), 0.749 (0.586-0.912) on Moyamoya disease (MMD), 0.837 (0.704-0.969) on cavernous malformation (CM), and 0.839 (0.722-0.959) on other causes in TT200 dataset. Given a 90% specificity level, the sensitivities of our model were 97.1% and 90.9% for aneurysm and AVM diagnosis, respectively. The model also shows an impressive generalizability in an independent dataset SD98. The clinicians achieve significant improvements in the sensitivity, specificity, and accuracy of diagnoses of certain hemorrhage etiologies with proposed system augmentation. Conclusions: The proposed deep learning algorithms can be an effective tool for early identification of hemorrhage etiologies based on NCCT scans. It may also provide more information for clinicians for triage and further imaging examination selection.

Deep-Learning Tool for Early Identifying Non-Traumatic Intracranial Hemorrhage Etiology based on CT Scan

Multimodality treatment for brain arteriovenous malformation in Mainland China: design, rationale, and baseline patient characteristics of a nationwide multicenter prospective registry

mTOR-FABP4 signal is activated in brain arteriovenous malformations in humans

Objective Elevated ICP is a well-recognized phenomenon in aneurysmal subarachnoid hemorrhage (aSAH) that has been demonstrated to lead to poor outcomes. Delayed cerebral ischemia (DCI) is the most important reason for a poor clinical outcome after a subarachnoid hemorrhage. DCI is understood as a multifactorial process that evolves over time, largely caused by the sequelae of increased intracranial pressure (ICP). The study aimed to assess how to better define the association between ICP and DCI, and whether rational ICP management can improve the outcome of aSAH patients. Methods We prospectively reviewed patients diagnosed with aSAH and received microsurgery clipping at our department from December 2019 to January 2021. Subdural ICP monitoring devices were kept to monitor the ICP. The ICP values were recorded every 1-h epochs. ICP -guided dehydration treatments were routinely performed to control the ICP level of patients after surgery. To evaluate whether the subdural ICP-directed management improved the prognosis of the aSAH patients, we compared the outcome data of the patients in our cohort with those treated at another ward of our hospital at the same period. Results In total, 144 consecutive aSAH patients received microsurgery clipping at our department, 68 of whom underwent ICP monitoring. A total of 11,424 1-h ICP measurements were recorded for the included patients (1.30 years of recordings). Of 68 patients with ICP monitoring, 27 (27/68, 39.7%) patients developed DCI. Univariate analysis showed that higher Hunt-Hess grade (OR 2.138, 95% CI 1.025–4.459, p = 0.043), higher preoperative modified Rankin Scale score (OR 1.534, 95% CI 1.033–2.276, p = 0.034), and the max ICP value of each day value >28.5 mmHg (OR 4.442, 95% CI 1.509–13.082, p = 0.007) were associated with DCI. Also, patients with ICP-directed treatment showed a significantly lower DCI incidence than patients without ICP monitoring. Conclusion Our study suggests that I less than 15 mmHg possibly constitute normal values and that 28.5 mmHg is the ICP threshold most strongly associated with the occurrence of DCI in aSAH patients. Patients who received the ICP-directed treatment presented a lower incidence of DCI. Our findings provide a basis for the recommendation of ICP-directed treatment after aSAH. Trial Registration Number NCT04785976.

Application of Intracranial Pressure-Directed Therapy on Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage

Rapid formation of innovative, inexpensive, personalized, and quickly reproducible artery bioresorbable stents (BRSs) is significantly important for treating dangerous and sometimes deadly cerebrovascular disorders. It is greatly challenging to give BRSs excellent mechanical properties, biocompatibility, and bioabsorbability. The current BRSs, which are mostly fabricated from poly-l-lactide (PLLA), are usually applied to coronary revascularization but may not be suitable for cerebrovascular revascularization. Here, novel 3D-printed BRSs for cerebrovascular disease enabling anti-stenosis and gradually disappearing after vessel endothelialization are designed and fabricated by combining biocompatible poly (p-dioxanone) (PPDO) and 3D printing technology for the first time. We can control the strut thickness and vessel coverage of BRSs by adjusting the printing parameters to make the size of BRSs suitable for small-diameter vascular use. We added bis-(2,6-diisopropylphenyl) carbodiimide (commercial name: stabaxol®-1) to PPDO to improve its hydrolytic stability without affecting its mechanical properties and biocompatibility. In vitro cell experiments confirmed that endothelial cells can be conveniently seeded and attached to the BRSs and subsequently demonstrated good proliferation ability. Owing to the excellent mechanical properties of the monofilaments fabricated by the PPDO, the 3D-printed BRSs with PPDO monofilaments support desirable flexibility, therefore offering a novel BRS application in the vascular disorders field.

3D-Printed Poly (P-Dioxanone) Stent for Endovascular Application: In Vitro Evaluations

Objective: The aim of this retrospective study is to evaluate the risk factors of malignant middle cerebral artery infarction (MMCAI) patients and explore an applicable prognostic predictor for MMCAI patients undergoing decompressive craniectomy (DC). Methods: Clinical data from the period 2012–2017 were retrospectively evaluated. Forty-three consecutive MMCAI patients undergoing DC were enrolled in this study. The 30-day mortality was assessed, and age, location, hypertension, pupil dilation, onset to operation duration, midline shift, and Glasgow Coma Scale (GCS) score were identified by univariate analysis and binary logistic regression. Results: In this retrospective study for DC patients, the 30-day mortality was 44.2%. In the univariate analysis, advanced age (≥60 years), right hemispheric location, hypertension, pupil dilation, shorter onset to operation duration (<48 h), improved midline shift (t = 4.214, p < 0.01), and lower pre-operation GCS score were significant predictors of death within 30 days. In binary logistic regression analysis, age [odds ratio (OR) = 1.141, 95% CI 1.011–1.287], the improvement of the midline shift (OR = 0.764, 95% CI 0.59–0.988), and pupillary dilation (OR = 15.10, 95% CI 1.374–165.954) were independent influencing factors. For the receiver operating characteristic (ROC) analysis of the relationship between post-operation outcomes and midline shift improvement, the area under the curve (AUC) was 0.844, and the cutoff point of midline shift improvement was 0.83 cm. Conclusion: Improved midline shift was a significant predictor of 30-day mortality. The improved midline shift of >0.83 cm indicated survival at 30 days.

Improvement in Midline Shift Is a Positive Prognostic Predictor for Malignant Middle Cerebral Artery Infarction Patients Undergoing Decompressive Craniectomy

Ischemic stroke is a complication of chronic macrovascular disease in type 2 diabetes. However, the pathogenesis of diabetic ischemic stroke has not yet been fully clarified. The aim of the present study was to investigate the underlying effects of endothelial progenitor cells (EPCs) and the matrix metalloproteinase inhibitor BB-94 on diabetic stroke. In vitro experiments were performed using oxygen-glucose deprivation/reoxygenation (OGD/R) model cells, established using HT22 mouse hippocampal cells. MTT assays and flow cytometry revealed that BB-94 prominently induced the proliferation of the OGD/R model cells and prevented their apoptosis. When EPCs and BB-94 were applied to the OGD/R model cells in combination, proliferation was further accelerated and oxidative damage was attenuated. In vivo experiments were also performed using a middle cerebral artery occlusion (MCAO) mouse model. The results of modified neurological severity scoring and oxidative stress marker analysis demonstrated that EPCs and BB-94 prominently alleviated cerebral ischemia/reperfusion injury in the MCAO model mice. Furthermore, reverse transcription-quantitative PCR and western blot assays revealed that EPCs in combination with BB-94 significantly downregulated the expression of matrix metalloproteinases (MMPs) and upregulated the expression of tissue inhibitor of metalloproteinases 1 in OGD/R cells and MCAO model mice. The results suggest that EPCs were successfully isolated and identified, and the OGD/R cell and MCAO mouse models were successfully established. They also indicate that EPCs alone or in combination with BB-94 may exert protective effects against ischemic stroke via the reduction of MMP expression.

Combination of endothelial progenitor cells and BB-94 significantly alleviates brain damage in a mouse model of diabetic ischemic stroke

 Background and objectiveOptic nerve sheath diameter (ONSD) and ONSD/ eyeball transverse diameter (ETD) ratio have been proved to be related to intracranial pressure. This study aimed to evaluate ONSD and ONSD/ETD ratio in comatose patients with supratentorial lesions and determine the relationship of these two indexes with the prognosis of these patients.MethodsA total of 54 comatose patients with supratentorial lesion and 50 cases of normal controls were retrospectively included in this study. ONSD and ETD was messured on un-enhanced computed tomography(CT). The difference of ONSD, ONSD/ETD ratio between the two groups was compared. The prognosis of comatose patients were scored unsing Glasgow outcome scale (COS) at 3-month follow-up and classified into good (score ≥ 3) and poor (score < 3) prognosis. The differences of ONSD and ONSD/ETD ratio between good and poor prognosis of comatose patients were compared statistically.ResultONSD and ONSD / EDT in the comatose group were 6.30 ± 0.60 mm and 0.27 ± 0.03, respectively, both were significantly greater than that in normal controls (5.10 ± 0.47 mm, t = 11.426, P < 0.0001 ; 0.22 ± 0.02, t = 11.468, P < 0.0001 ; respectively). ONSD in poor prognosis was siginificantly greater than that in good prognosis (6.40 ± 0.56 mm vs. 6.03 ± 0.61 mm, t = 2.197, P = 0.032). ONSD / EDT raito in poor grognosis was significantly higher than that in good gronosis (0.28 ± 0.02 vs 0.26 ± 0.03, t = 2.622, P = 0.011). The area under the responder operating charateristic curve to predict prognosis of comatose patients were 0.650 ( 95% CI: 0.486–0.815, P = 0.078) for ONSD and 0.711( 95% CI: 0.548–0.874, P = 0.014) for ONSD/ETD ratio, respectively.ConclusionsONSD and ONSD / EDT raito increased in comatose patients. ONSD / EDT raito may be more valuable than ONSD in evaluation for prognosis of comatose patients with Supratentorial lesions.

Clinical Value of Optic Nerve Sheath Diameter Assessment in Prognosis of Comatose Patients with Supratentorial Lesions

Delayed anastomotic occlusion occurred in a considerable proportion of hemorrhagic moyamoya disease (MMD) patients undergoing direct revascularization. This study aimed to investigate the predictors and outcomes of delayed anastomotic occlusion in adult hemorrhagic MMD. The authors retrospectively reviewed 87 adult hemorrhagic MMD patients. Univariate and multivariate logistic regression analyses were performed. After an average of 9.1 ± 6.9 months of angiographic follow-up, the long-term graft patency rates were 79.8%. The occluded group had significantly worse angiogenesis than the non-occluded group (p < 0.001). However, the improvement of dilated anterior choroidal artery–posterior communicating artery was similar (p = 0.090). After an average of 4.0 ± 2.5 years of clinical follow-up, the neurological statues and postoperative annualized rupture risk were similar between the occluded and non-occluded groups (p = 0.750; p = 0.679; respectively). In the multivariate logistic regression analysis, collateral circulation Grade III (OR, 4.772; 95% CI, 1.184–19.230; p = 0.028) and preoperative computed tomography perfusion (CTP) Grade I–II (OR, 4.129; 95% CI, 1.294–13.175; p = 0.017) were independent predictors of delayed anastomotic occlusion. Delayed anastomotic occlusion in adult hemorrhagic MMD might be a benign phenomenon. Good collateral circulation (Grade III) and compensable preoperative intracranial perfusion (CTP Grade I–II) are independent predictors for this phenomenon. Moreover, the delayed anastomotic occlusion has no significant correlations with the long-term angiographic and neurological outcomes, except neoangiogenesis.

Delayed Anastomotic Occlusion after Direct Revascularization in Adult Hemorrhagic Moyamoya Disease

Objective: Whether partial embolization could facilitate the post-stereotactic radiosurgery (SRS) obliteration for brain arteriovenous malformations (bAVMs) remains controversial. We performed this study to compare the outcomes of SRS with and without prior embolization for bAVMs. Methods: We retrospectively reviewed the Beijing Tiantan AVMs prospective registration research database from September 2011 to October 2014. Patients were categorized into two groups, combined upfront embolization and SRS (Em+SRS group) and SRS alone (SRS group), and we performed a propensity score matching analysis based on pre-embolization baseline characteristics; the matched groups each comprised 76 patients. Results: The obliteration rate was similar between SRS and Em+SRS (44.7 vs. 31.6%; OR, 1.754; 95% CI, 0.905–3.401; p = 0.096). However, the SRS group was superior to the Em+SRS group in terms of cumulative obliteration rate at a follow-up of 5 years (HR,1.778; 95% CI, 1.017–3.110; p = 0.033). The secondary outcomes, including functional state, post-SRS hemorrhage, all-cause mortality, and edema or cyst formation were similar between the matched cohorts. In the ruptured subgroup, the SRS group could achieve higher obliteration rate than Em+SRS group (56.5 vs. 31.9%; OR, 2.773; 95% CI, 1.190–6.464; p = 0.018). The cumulative obliteration rate at 5 years was also higher in the SRS group (64.5 vs. 41.3%; HR, 2.012; 95% CI, 1.037–3.903; p = 0.038), and the secondary outcomes were also similar between the matched cohorts. Conclusion: Although there was no significant difference in the overall obliteration rate between the two strategies, this study suggested that pre-SRS embolization may have a negative effect on post-SRS obliteration. Furthermore, the obliteration rates of the SRS only strategy was significantly higher than that of the Em+SRS strategy in the ruptured cohort, while no such phenomenon was found in the unruptured cohort.

Stereotactic Radiosurgery With vs. Without Prior Embolization for Brain Arteriovenous Malformations: A Propensity Score Matching Analysis

Clinical features of temporal lobe epilepsy caused by different pathological subtypes of focal cortical dysplasia with hippocampal sclerosis

Background: More and more elderly patients are being diagnosed with arteriovenous malformation (AVM) in this global aging society, while the treatment strategy remains controversial among these aging population. This study aimed to clarify the long-term outcomes of elderly AVMs after different management modalities. Methods: The authors retrospectively reviewed 71 elderly AVMs (>60 years) in two tertiary neurosurgery centers between 2011 and 2019. Patients were divided into four groups: conservation, microsurgery, embolization, and stereotactic radiosurgery (SRS). The perioperative complications, short-term and long-term neurological outcomes, obliteration rates, annualized rupture risk, and mortality rates were compared among different management modalities in the ruptured and unruptured subgroups. Kaplan-Meier survival analysis was employed to compare the death-free survival rates among different management modalities. Logistic regression analyses were conducted to calculate the odds ratios (ORs) and 95% confidence intervals (CI) for predictors of long-term unfavorable outcomes (mRS > 2). Results: A total of 71 elderly AVMs were followed up for an average of 4.2 ± 2.3 years. Fifty-four (76.1%) presented with hemorrhage, and the preoperative annualized rupture risk was 9.4%. Among these patients, 21 cases (29.6%) received conservative treatment, 30 (42.3%) underwent microsurgical resection, 13 (18.3%) received embolization, and 7 (9.9%) underwent SRS. In the prognostic comparison, the short-term and long-term neurological outcomes were similar between conservation and intervention both in the ruptured and unruptured subgroups (ruptured: p = 0.096, p = 0.904, respectively; unruptured: p = 0.568, p = 0.306, respectively). In the ruptured subgroup, the intervention cannot reduce long-term mortality (p = 0.654) despite the significant reduction of subsequent hemorrhage than conservation (p = 0.014), and the main cause of death in the intervention group was treatment-related complications (five of seven, 71.4%). In the logistic regression analysis, higher admission mRS score (OR 3.070, 95% CI 1.559–6.043, p = 0.001) was the independent predictor of long-term unfavorable outcomes (mRS>2) in the intervention group, while complete obliteration (OR 0.146, 95% CI 0.026–0.828, p = 0.030) was the protective factor. Conclusions: The long-term outcomes of elderly AVMs after different management modalities were similar. Intervention for unruptured elderly AVMs was not recommended. For those ruptured, we should carefully weigh the risk of subsequent hemorrhage and treatment-related complications. Besides, complete obliteration should be pursued once the intervention was initiated. Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT04136860

Long-Term Outcomes of Elderly Brain Arteriovenous Malformations After Different Management Modalities: A Multicenter Retrospective Study

Circular RNA 0025984 Ameliorates Ischemic Stroke Injury and Protects Astrocytes Through miR-143-3p/TET1/ORP150 Pathway

Background: Sedative agents such as dexmedetomidine have been found to transiently exacerbate or unmask limb motor dysfunction in patients with eloquent area brain gliomas. The present study aims to investigate whether dexmedetomidine can inhibit motor plasticity in patients with glioma via fMRI. Methods: 21 patients with brain glioma were prospectively recruited between September 2017 and December 2018. Patients were classified into pre-M1 (primary motor cortex) group (n=9), post-M1 group (n=6), and non-eloquent group (control group) (n=6) according to the tumor position related to M1. The hand movement task-fMRI and resting state fMRI (rs-fMRI) were performed before and after sedation using dexmedetomidine. The lateralization index (LI) of activation voxels and magnitude and the functional connectivity (FC) of motor network were compared before and after sedation and among different groups. Results: Permanent postoperative motor deficit of the upper limb was found in 5 of 6 patients in the pre-M1 group, and none in other groups (P < .01). Task-fMRI showed the LI of activation volume and activation magnitude at M1 significantly increased only in the pre-M1 group after sedation (P < .05). Rs-fMRI showed 60.0% (27 of 45) FCs of motor network decreased in pre-M1 group after sedation (p[FDR] < .05); whereas there was no FC reduction in post-M1 and control groups (p[FDR] > .05). Conclusions: In patients with eloquent area gliomas, dexmedetomidine can inhibit the unstable compensative motor plasticity on both task- and rs-fMRI. fMRI may be a promising method for elucidating the effect of sedative agents on motor plasticity.

Dexmedetomidine inhibits unstable motor network in patients with primary motor area gliomas

Background: Accurate and reliable models of intracranial hemorrhage (ICH) risk in the untreated course of brain arteriovenous malformation (BAVM) patients are needed to help weigh the risk-benefit ...

Abstract MP7: Multicenter Study of Intracranial Hemorrhage and Death Risk and Predictors in the Untreated Course of Brain Arteriovenous Malformation Patients

Objective Open microsurgery, often with bypass techniques, is indispensable for complex aneurysms. To date, it remains unknown whether arterial anatomy or quantitative blood flow measurements can predict insufficient flow-related stroke (IRS). The present study aimed to evaluate the risk factors for IRS in patients treated with open microsurgery with bypass procedures for complex internal carotid artery aneurysms. Methods Patients with complex aneurysms undergoing bypass surgery were retrospectively reviewed. The recipient/donor flow index (RDFI) was preoperatively evaluated using colour-coding angiography. RDFI was defined as the ratio of the cerebral blood volume of the recipient and donor arteries. The sizes of the recipient and donor arteries were measured. The recipient/donor diameter index (RDDI) was then calculated. IRS was defined as the presence of new postoperative neurological deficits and infarction on postoperative CT scans. We assessed the association between RDFI and other variables and the IRS. Results Twenty patients (38±12 years) were analysed. IRS was observed in 12 patients (60%). Patients with postoperative IRS had a higher RDFI than those without postoperative IRS (p<0.001). RDDI was not significantly different between patients with and without IRS (p=0.905). Patients with RDFI >2.3 were more likely to develop IRS (p<0.001). Conclusion Quantitative digital subtraction angiography enables preoperative evaluation of cerebral blood volume. RDFI >2.3, rather than RDDI, was significantly associated with postoperative IRS. This preoperative evaluation allows appropriate decisions regarding the treatment strategy for preventing postoperative IRS.

Quantitative angiographic haemodynamic evaluation of bypasses for complex aneurysms: a preliminary study

Object: Patients with aneurysmal subarachnoid hemorrhage (aSAH) have an increased incidence of cardiac events and short-term unfavorable neurological outcomes during the acute phase of bleeding. We studied whether troponin I elevation after ictus can predict future major adverse cardiac events (MACEs) and long-term neurological outcomes after 2 years. Methods: Consecutive aSAH patients within 3 days of bleeding were eligible for review from a prospective observational cohort (ClinicalTrials.gov Identifier: NCT04785976). Potential predictors of future MACEs and unfavorable long-term neurological outcomes were calculated by Cox and logistic regression analyses. Additional Kaplan–Meier curves were performed. Results: A total of 213 patients were enrolled with an average follow-up duration of 34.3 months. Individuals were divided into two groups: elevated cTnI group and unelevated cTnI group. By the last available follow-up, 20 patients had died, with an overall all-cause mortality rate of 9.4% and an annual all-cause mortality rate of 3.8%. Patients with elevated cTnI had a significantly higher risk of future MACEs (10.6 vs. 2.1%, p = 0.024, and 95% CI: 1.256–23.875) and unfavorable neurological outcomes at discharge, 3-month, 1-, 2-years, and last follow-up (p = 0.001, p < 0.001, p = 0.001, p < 0.001, and p < 0.001, respectively). In the Cox analysis for future MACE, elevated cTnI was the only independent predictor (HR = 5.980; 95% CI: 1.428–25.407, and p = 0.014). In the multivariable logistic analysis for unfavorable neurological outcomes, peak cTnI was significant (OR = 2.951; 95% CI: 1.376–6.323; p = 0.005). Kaplan–Meier analysis indicated that the elevated cTnI was correlated with future MACE (log-rank test, p = 0.007) and subsequent death (log-rank test, p = 0.004). Conclusion: cTnI elevation after aSAH could predict future MACEs and unfavorable neurological outcomes.

Prognostic Value of Elevated Cardiac Troponin I After Aneurysmal Subarachnoid Hemorrhage

The clinical and prognostic values of optic nerve sheath diameter and optic nerve sheath diameter/eyeball transverse diameter ratio in comatose patients with supratentorial lesions

Object Superficial temporal artery to middle cerebral artery (STA-MCA) bypass is the most effective treatment for Moyamoya disease (MMD). In this study, we aimed to assess whether aspirin improves STA-MCA bypass patency and is safe in patients with MMD. Methods We performed a retrospective medical record review of patients with ischaemic-onset MMD who had undergone STA-MCA bypass at two hospitals between January 2011 and August 2018, to clarify the effects and safety of aspirin following STA-MCA bypass. The neurological status at the last follow-up (FU) was compared between patients with FU bypass patency and occlusion. Results Among 217 identified patients (238 hemispheres), the mean age was 41.4±10.2 years, and 51.8% were male; the indications for STA-MCA bypass were stroke (48.2%), followed by a transient ischaemic attack (44.0%). Immediate bypass patency was confirmed in all cases. During the FU period (1.5±1.5 y), 15 cases were occluded at FU imaging, resulting in an overall cumulative patency rate of 94%. The patency rates were 93% and 94% in the short-term FU group (n=131, mean FU time 0.5±0.2 years) and long-term FU group (n=107, mean FU time 4.1±3.5 years), respectively. The STA-MCA bypass patency rate in the aspirin group was higher than that in the non-aspirin group (98.7% vs 89.7%; HR 1.57; 95% CI 1.106 to 2.235; p=0.012). No significant difference in the FU haemorrhagic events was observed between the aspirin and non-aspirin groups. Conclusions Among adult patients with ischaemic-onset MMD undergoing STA-MCA bypass procedures, aspirin might increase the bypass patency rate, without increasing the bleeding risk. FU bypass patency may be associated with a better outcome. Additional studies, especially carefully designed prospective studies, are needed to address the role of aspirin after bypass procedures.

Effects and safety of aspirin use in patients after cerebrovascular bypass procedures

Glioma stem cells (GSCs) are considered the source for development, recurrence, and poor prognosis of glioma, so treatment targeted GSCs is of great interest. The frequently rearranged in advanced T cell lymphomas-1 (FRAT1) gene is an important member of the Wnt/β-catenin signaling transduction pathway, and aberrantly activation of Wnt signaling has been identified to contribute to the tumorigenesis, proliferation, invasion of a variety kinds of cancer stem cells. However, correlations between FRAT1 and GSCs and the specific mechanisms remain unclear. In this study, we aimed to investigate the effect of FRAT1 on GSCs proliferation, colony formation, sphere formation and tumorigenesity in vitro and in vivo and its underlying mechanism. Lentiviral transfection was used to construct GSCs with low FRAT1 expression. The expression of FRAT1 on GSCs proliferation in vitro was assessed by cell counting kit-8(CCK-8). Colony formation and sphere formation assays were conducted to assess the colony and sphere formation ability of GSCs. Then, an intracranial glioma nude mouse model was built to measure the effect of low FRAT1 expression on GSCs proliferation and tumorigenesity in vivo. Real-time PCR, Western blot, and Immunohistochemistry were processed to detect the mRNA and protein expressions of FRAT1, β-catenin in the glioma tissue of xenograft mice to study their correlations. The functional assays verifed that low FRAT1 expression inhibited CD133+Nestin+ GSCs proliferation, colony formation, sphere formation ability in vitro. In vivo GSCs xenograft mice model showed that low FRAT1 expression suppressed the proliferation and tumorigenesity of CD133+Nestin+ GSCs and reduced β-catenin mRNA and protein expression. Furthermore, the expression of FRAT1 and β-catenin were positively correlated. Altogether, results indicate that FRAT1 enhances the proliferation, colony formation, sphere formation and tumorigenesity of CD133+Nestin+ glioma stem cells in vitro and in vivo as well as the expression of β-catenin. Therefore, inhibiting proliferation of GSCs and FRAT1 may be a molecular target to GSCs in treating human glioma in the future.

FRAT1 Enhances the Proliferation and Tumorigenesis of CD133+Nestin+ Glioma Stem Cells In Vitro and In Vivo

Urinary biomarker discovery in gliomas using mass spectrometry-based clinical proteomics

OBJECTIVEPostoperative neurological deficits impair the overall outcome of revascularization surgery for patients with moyamoya disease (MMD). dl-3-n-butylphthalide (NBP) is approved for the treatment of ischemic stroke in China. This pilot study evaluated the effect of NBP on perioperative stroke and neurological deficits in patients with MMD.METHODSThe authors studied cases in which patients underwent combined revascularization surgery for MMD at their institution, with or without NBP administration. The overall study group included 164 patients (213 surgically treated hemispheres), including 49 patients who received NBP (25 mg twice daily) for 7 postoperative days. The incidence of perioperative stroke and transient neurological deficit (TND) and the severity of neurological deficits were compared between 49 propensity score-matched case pairs with or without NBP treatment. Subgroup analyses by type of onset and preoperative neurological status were also performed to determine specific characteristics of patients who might benefit from NBP administration.RESULTSIn the overall cohort, baseline characteristics differed with respect to preoperative stroke and modified Rankin Scale (mRS) score between patients who received NBP and those who did not receive it. In the 49 propensity score-matched pairs, postoperative stroke was observed in 11 patients and TND occurred in 21 patients, with no significant difference in incidence between the 2 groups. However, the TND was less severe in the NBP-treated group (p = 0.01). At 1 month after surgery, the neurological outcome was more favorable (p = 0.001) and the disability-free recovery rate was higher in patients with NBP treatment (p < 0.001). The number of patients who experienced an improved neurological function, compared to preoperative function, as measured by mRS, was greater in the NBP group than in the no-NBP group (p < 0.001). Multivariable analysis revealed that NBP administration was associated with decreased severity of TND (OR 0.28, p = 0.02), improved neurological function (OR 65.29, p = 0.04), and lower postoperative mRS score (OR 0.06, p < 0.001). These beneficial effects of NBP remained significant in ischemic type MMD and patients with preoperative mRS scores of 2 or greater.CONCLUSIONSPostoperative administration of NBP may alleviate perioperative neurological deficits after revascularization surgery for MMD, especially in patients with ischemic MMD and unfavorable preoperative status. The results of this study suggest that randomized controlled trials to assess the potential benefit of NBP in patients with MMD may be warranted.

dl-3-n-butylphthalide for alleviation of neurological deficit after combined extracranial-intracranial revascularization for moyamoya disease: a propensity score-matched analysis.

 Background: Treatments on middle cerebral arterial occlusions (MCAO) remain controversial. This study aims at investigating efficacies of surgical revascularizations in young and middle-aged patients (aged 18-65 y) with symptomatic MCAO, and making comparisons between surgical procedures.Methods: From a seven-year prospective consecutive registry, 115 cases were enrolled in this study. Patient individually received medical therapy alone (medical group, n=64) and medical therapy plus direct or indirect revascularization (surgical group, n=51). The secondary ischemic events (SIE) was defined as the primary outcome. SIE incidences and SIE-free survival rates were compared between groups. Risk factors were analyzed using the Cox regression analysis.Results: During a follow-up of 42.7 months on average, SIE occurred in 11cases of medical group and 10 cases of surgical group. SIE incidences were indifferent between groups (surgical:medical = 19.6%:17%, P=0.810, 95%CI 0.455-3.034). SIE incidences were 29.4% and 0% in direct revascularization subgroup and indirect revascularization subgroup, respectively. Indirect revascularization induced a higher SIE-free survival rate than direct revascularization (Log-rank P=0.015) and medical therapy (Log-rank P=0.044). An age>43y, with concomitant intracerebral arterial stenosis, and hyperlipidaemia history were correlated to the occurrence of SIE, while presences of compensatory arteries and taking antihypertensive drugs reduced risks of SIE.Conclusions: Indirect revascularization plus medical therapy was suggested to be more effective on SIE prevention than both medical treatments alone and direct revascularization plus medical therapy in young and middle aged patients with symptomatic MCAO. Direct revascularization was not recommended, for its similar efficacy to medical therapy alone.

Efficacy of Surgical Revascularizations in Young and Middle-aged Patients with Symptomatic Middle Cerebral Arterial Occlusion

Abstract Background: Microscopic transsphenoidal surgery (MTS) has been considered as the gold standard for transsphenoidal pituitary surgery, but nowadays endoscopic transsphenoidal surgery (ETS) has become popular due to its wide view and improved lighting. Material and methods: The electronic databases were systematically searched, and the meta-analyses of the eligible studies that evaluated endoscopic versus microscopic methods in patients with pituitary surgery were conducted with Review Manager 5.0. The primary outcomes included visual improvement, gross tumor removal (GTR), cerebrospinal fluid (CFS) leak, diabetes insipidus (DI), other complications, and length of hospital stay. The Egger’s test was conducted to estimate possible publication bias. Results: In total, 13 articles eventually met the inclusion criteria. The meta-analyses suggested that the differences with regard to visual improvement, overall complication rate, GTR, CSF leak, diabetes insipidus (DI), meningitis, visual impairment, syndrome of inappropriate antidiuretic hormone secretion (SIADH), new onset hypopituitarism, and hypothyroidism between the endoscopic and microscopic groups were not statistically significant. The length of hospital stay was much longer with the microscopic approach when compared with the endoscopic method. Conclusion: The endoscopic and microscopic approaches show similar effects and complication rates. The endoscopic technique could be adopted as a reasonable alternative in pituitary surgery.

A systematic review of effects and complications after transsphenoidal pituitary surgery: endoscopic versus microscopic approach

Objective The aims of this study are to clarify the long-term outcomes of brainstem arteriovenous malformations (AVMs) after different management modalities. Methods The authors retrospectively reviewed 61 brainstem AVMs in their institution between 2011 and 2017. The rupture risk was represented by annualised haemorrhagic rate. Patients were divided into five groups: conservation, microsurgery, embolisation, stereotactic radiosurgery (SRS) and embolisation+SRS. Neurofunctional outcomes were evaluated by the modified Rankin Scale (mRS). Subgroup analysis was conducted between different management modalities to compare the long-term outcomes in rupture or unruptured cohorts. Results All of 61 brainstem AVMs (12 unruptured and 49 ruptured) were followed up for an average of 4.5 years. The natural annualised rupture risk was 7.3%, and the natural annualised reruptured risk in the ruptured cohort was 8.9%. 13 cases were conservative managed and 48 cases underwent intervention (including 6 microsurgery, 12 embolisation, 21 SRS and 9 embolisation+SRS). In the selection of interventional indication, diffuse nidus were often suggested conservative management (p=0.004) and nidus involving the midbrain were more likely to be recommended for intervention (p=0.034). The risk of subsequent haemorrhage was significantly increased in partial occlusion compared with complete occlusion and conservative management (p<0.001, p=0.036, respectively). In the subgroup analysis, the follow-up mRS scores of different management modalities were similar whether in the rupture cohort (p=0.064) or the unruptured cohort (p=0.391), as well as the haemorrhage-free survival (p=0.145). In the adjusted Bonferroni correction analysis of the ruptured cohort, microsurgery and SRS could significantly improve the obliteration rate compared with conservation (p<0.001, p=0.001, respectively) and SRS may have positive effect on avoiding new-onset neurofunctional deficit compared with microsurgery and embolisation (p=0.003, p=0.003, respectively). Conclusions Intervention has similar neurofunctional outcomes as conservation in these brainstem AVM cohorts. If intervention is adopted, partial obliteration should be avoided because of the high subsequent rupture risk. Trial registration number NCT04136860.

Long-term outcomes of brainstem arteriovenous malformations after different management modalities: a single-centre experience

Hemodynamic changes in superficial arteriovenous malformation surgery measured by intraoperative ICG fluorescence videoangiography with FLOW 800 software

Quantitative Angiographic Hemodynamic Evaluation After Revascularization Surgery for Moyamoya Disease

Perilesional and Extralesional Iron Deposition on Quantitative Susceptibility Mapping

Contemporary management of brain arteriovenous malformations in mainland China: a web-based nationwide questionnaire survey

Management protocol for emergency aneurysm craniotomy clipping in non-major COVID-19 epidemic areas in Beijing, China

Supplemental Digital Content is available in the text. Background and Purpose: Symptomatic hemorrhage contributes to an increased risk of repeated bleeding and morbidity in cerebral cavernous malformation (CCM). A better understanding of morbidity after CCM hemorrhage would be helpful to identify patients of higher risk for unfavorable outcome and tailor individualized management. Methods: We identified 282 consecutive patients who referred to our institute from 2014 to 2018 for CCM with symptomatic hemorrhage and had an untreated follow-up period over 6 months after the first hemorrhage. The morbidity after hemorrhage was described in CCM of different features. Nomogram to predict morbidity was formulated based on the multivariable model of risk factors. The predictive accuracy and discriminative ability of nomogram were determined with concordance index (C-index) and calibration curve, and further validated in an independent CCM cohort of a prospective multicenter study from 2019 to 2020. Results: The overall morbidity of CCM was 26.2% after a mean follow-up of 1.9 years (range 0.5–3.5 years) since the first hemorrhage. The morbidity during untreated follow-up was associated with hemorrhage ictus (adjusted odds ratio per ictus increase, 4.17 [95% CI, 1.86–9.33]), modified Rankin Scale score at initial hemorrhage (adjusted odds ratio per point increase, 2.57 [95% CI, 1.82–3.63]), brainstem location (adjusted odds ratio, 2.93 [95% CI, 1.28–6.68]), and associated developmental venous anomaly (adjusted odds ratio, 2.21 [95% CI, 1.01–4.83]). Subgroup analysis revealed similar findings in brainstem and non-brainstem CCM. Nomogram was contracted based on these features. The calibration curve showed good agreement between nomogram prediction and actual observation. The C-index of nomogram predicting morbidity was 0.83 (95% CI, 0.77–0.88). In validation cohort, the nomogram maintained the discriminative ability (C-index, 0.87 [95% CI, 0.78–0.96]). Conclusions: Multiple symptomatic hemorrhages, initial neurological function after hemorrhage, brainstem location, and associated developmental venous anomaly were associated with morbidity of CCM hemorrhage. The nomogram represented a practical approach to provide individualized risk assessment for CCM patients. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT04076449.

Morbidity After Symptomatic Hemorrhage of Cerebral Cavernous Malformation

Objective: Hemorrhagic transformation (HT) in ischemic moyamoya disease (MMD), reasonably defined as hemorrhage events in patients with ischemic onset manifestation, leads to a poor outcome. This study aims to reveal factors associated with HT in patients with ischemic onset manifestation and to assess the outcome of these patients. Methods: A total of 683 surgically managed patients with onset ischemic manifestation were included. The clinical variables of the HT and non-HT groups were compared, and risk factors were analyzed using logistic regression analysis. Recurrent stroke events (including hemorrhagic and ischemic) during the follow-up were documented. The cumulative incidence rate of stroke events was generated via Kaplan–Meier survival analysis. Outcomes were compared between HT and non-HT groups using propensity score analysis to account for between-group differences in baseline characteristics. Results: Of 683 patients surgically treated in the overall cohort, 29 (4.3%) were classified as cases of HT. The majority manifestation of these patients was transient ischemic attack. Multivariate analysis showed that the normal cerebral perfusion according to the CT perfusion was identified as factors associated with HT [odds ratio (OR) 13.464, 95% CI 3.529–51.363, P < 0.001]. Patients who occurred HT had a worse outcome than patients without HT. Conclusions: HT in adult ischemic MMD is a rare phenomenon, but it is strongly associated with increased disability rates and mortality. The normal cerebral perfusion is a possible risk factor associated with HT in adult ischemic MMD. Recognition of HT in adult ischemic MMD may contribute to an improved outcome.

Hemorrhagic Transformation in Ischemic Moyamoya Disease: Clinical Characteristics, Radiological Features, and Outcomes

A three-dimensional color-printed system allowing complete modeling of arteriovenous malformations for surgical simulations

Long-term outcomes and prognostic predictors of 111 pediatric hemorrhagic cerebral arteriovenous malformations after microsurgical resection: a single-center experience

Moyamoya disease (MMD) is a kind of disease characterized with progressive cerebrovascular occlusion. Electroencephalography (EEG) is a well-established tool for brain assessment and has a close connection with cerebral blood flow (CBF). This article reviews the characteristics of MMD, the correlation between EEG and CBF, EEG features, and its clinical application in intraoperative monitoring, prognosis assessment, and diagnosis and differential diagnosis of episodic events in MMD. MMD patients show a relatively special EEG pattern and EEG is useful for diagnosis, intraoperative brain monitoring, and prognosis assessment in MMD, especially for children. 
 
Key words: 
Moyamoya disease; Electroencephalography; Re-build up; Epilepsy; Intraoperative monitoring

Role of electroencephalography in diagnosis and treatment of moyamoya disease

The association between ELP4 rs986527 polymorphism and the occurrence and development of intracranial arachnoid cyst was studied in this paper.

Association between ELP4 rs986527 polymorphism and the occurrence and development of intracranial arachnoid cyst

Comparison of Dolenc and pterional approach in the microsurgery for blood blister-like aneurysms (BBAs) of internal carotid artery

Background An in situ recanalization procedure of endovascular therapy (ET) or carotid endarterectomy (CEA) has been attempted in patients with symptomatic chronic internal carotid artery occlusions (ICAOs), though the recanalization rates of both are low. Objective To investigate the outcomes of Multimodality In situ Recanalization for ICAOs in a Hybrid Operating Room (MIRHOR) at the same session. Methods Symptomatic chronic ICAOs were classified into type A or B (short occlusion with or without a tapered residual root [TRR]), and C or D (long occlusion with or without TRR), and managed in a hybrid operating room with ET, CEA, or both, as needed. Primary efficacy outcome was technical success of recanalization with Thrombolysis in Myocardial Infarction 3. Secondary efficacy outcome was any stroke or death within 30 days (primary safety outcome) plus an ipsilateral ischemic stroke after 30 days. Results Technical success was finally achieved in 35 (83.3%) of 42 consecutively enrolled patients with ICAO, which was significantly higher than 35.7% (15/42, p<0.001) from the initial ET or CEA alone. Furthermore, the success rate was in descending order: 100% (18/18) for type A and B occlusions, 75% (6/8) for type C occlusions, and 69% (11/16) for type D occlusions (p=0.017). Two secondary efficacy outcome events (5.1%) without mortality, including one (2.4%) primary safety outcome, were observed during a mean follow-up of 10.5 months. Conclusion The MIRHOR for symptomatic chronic ICAOs at the same session significantly improves technical success, with low periprocedural complications and favorable clinical outcomes. The ICAO classification appears valuable in predicting technical success.

Outcomes of Multimodality In situ Recanalization in Hybrid Operating Room (MIRHOR) for symptomatic chronic internal carotid artery occlusions

Microsurgical ligation for incompletely coiled or recurrent intracranial aneurysms: a 17-year single-center experience

Introduction: Accurately balancing risks of interventional treatment and intracranial hemorrhage (ICH) in the untreated course of unruptured brain arteriovenous malformation (uBAVM) patients is cri...

Abstract TP585: Long-Term Outcomes in Unruptured Brain Arteriovenous Malformation Patients: The Multicenter Arteriovenous Malformation Research Study (MARS)

Abnormal embryonic development of cerebral arteries as a potential cause of moyamoya disease.

Revascularization Surgery in Patients with Ischemic-Type Moyamoya Disease: Predictors for Postoperative Stroke and Long-Term Outcomes.

International expert consensus statement about methods and indications for keyhole microneurosurgery from International Society on Minimally Invasive Neurosurgery

OBJECTIVEThe effect of indirect revascularization to improve cerebral perfusion for moyamoya disease (MMD) is based on ingrowth of new vessels into the cortical brain. Preoperative indicators for neoangiogenesis would be helpful to the selection of appropriate procedures for MMD patients but have not yet been investigated. Our study aimed to identify potential predictors for neovascularization after indirect bypass surgery.METHODSThe authors reviewed consecutive cases with complete clinical and radiological documentation of patients who had undergone surgery between December 2010 and January 2018. Patients who were treated with indirect bypass surgery were included. Cerebrovascular characteristics were evaluated by catheter angiography. Neoangiogenesis after indirect bypass was determined as "good" or "poor" based on the Matsushima standard. Univariate and multivariate analyses were performed to identify predictors for neoangiogenesis after indirect bypass. Subgroup analyses by onset type and surgical type were carried out to identify specific predictors for different populations.RESULTSIn total, 231 hemispheres of 209 patients (mean ± SD age 23.06 ± 15.09 years, range 3-61 years) were retrospectively included. In 146 (63.2%) hemispheres, good neoangiogenesis was observed after indirect revascularization. Multivariate analysis showed that the status of ICA moyamoya vessels (p < 0.001, OR [95% CI] 3.242 [2.007-5.236]) is a predictor of favorable neoangiogenesis after indirect bypass surgery, whereas hemorrhagic onset (p < 0.001, OR [95% CI] 0.138 [0.054-0.353]) is a risk factor for poor neoangiogenesis. In addition, younger age was significantly associated with good neovascularization in patients with hemorrhagic onset (p = 0.027, OR [95% CI] 0.893 [0.808-0.987]), whereas age was not a significant predictor for neovascularization in non-hemorrhagic-onset patients (p = 0.955). Hemispheres with good revascularization had lower incidence of rebleeding, lower modified Rankin Scale scores, and more improvement of symptoms during long-term follow-up (p = 0.026, 0.006, and 0.013, respectively).CONCLUSIONSHemorrhagic onset predicts poor neovascularization after indirect bypass surgery for MMD patients. Abundant ICA moyamoya vessels indicate good neoangiogenesis after indirect bypass and vice versa, whereas absent ICA moyamoya vessels predict poor revascularization. Good neovascularization was associated with better long-term outcome. Future studies are needed to further address this issue and clarify the underlying pathophysiological mechanisms.

Predictors of neoangiogenesis after indirect revascularization in moyamoya disease: a multicenter retrospective study.

Heterozygous loss of activin receptor-like kinase 1 (Alk1) can lead to hereditary hemorrhagic telangiectasia (HHT), which is a kind of vascular disease characterized by direct connections between arteries and veins with the lacking of capillaries, and develops into arteriovenous malformations (AVMs) in later stage. However, the changes of Alk1 in human sporadic cerebral AVMs (cAVMs) remain unknown. In the present study, we used endothelial cells (ECs) derived from human cAVMs (cAVM-ECs) specimens, to explore the characteristics of cAVM-ECs and the relationship between Alk1 and human sporadic cAVMs. Our data showed that there were obvious morphological changes in cAVM-ECs, and they could trans-differentiate into mesenchyme-like cells easily in a short period. In addition, the abilities of migration of cAVM-ECs were poorer than that in human aortic endothelial cells (HA-ECs). The abilities of proliferation of cAVM-ECs in patients with different ages were lower than HA-ECs. Immunofluorescent staining and Western blot showed that the levels of Alk1 mRNA and protein in the HA-ECs were both higher than that in cAVM-ECs. In addition, the levels of Alk1 mRNA had no significant differences between different ages in cAVM-ECs groups. The levels of VEGF-A mRNA in the cAVM were higher than HA-ECs. Besides, levels of VEGF-A mRNA expression were lower in older cAVM patients. Therefore, we conclude that Alk1 might induce the formation of sporadic human cAVMs through affecting migration and proliferation of endothelial cells combined with VEGF-A.

Activin Receptor-Like Kinase 1 Combined With VEGF-A Affects Migration and Proliferation of Endothelial Cells From Sporadic Human Cerebral AVMs

OBJECTIVE
Postoperative hemorrhage during the acute phase is rarely observed after revascularization surgery for moyamoya disease (MMD) but can have severe complications. Its risk factors and outcomes are still unclear. The aim of this study was to investigate the predictors of postoperative hemorrhage during the acute phase in MMD and examine the outcomes of the hemorrhage.

METHODS
The authors reviewed the preoperative clinical characteristics and radiographic features of 465 consecutive MMD cases (518 procedures) that had undergone direct or combined bypass surgery at their institution between 2009 and 2015. Patients with postoperative intracerebral hemorrhage (ICH) or ICH plus intraventricular hemorrhage (IVH) during the acute phase were screened, and then the incidence, location, and risk factors of hemorrhage in these patients were analyzed. Short-term and long-term outcomes (modified Rankin Scale scores) for these patients were also collected. Outcomes were compared between patients with and those without postoperative ICH using propensity score analysis to reduce the between-group differences in baseline characteristics.

RESULTS
Postoperative hemorrhage occurred in 11 (2.1%; ICH = 9, IVH = 2) of 518 procedures (mean patient age 39.82 ± 8.8 years). Hemorrhage occurred in the first 24 hours after the operation in 8 cases (72.7%). In the ICH group, most of the hemorrhage sites (77.8%) were located beneath the anastomosed area, and the mean hematoma volume was 16.98 ± 22.45 ml (range 3-57 ml). One case from the ICH group required hematoma evacuation. Among the adult patients (463 procedures [89.4%]), preoperative hypertension (p = 0.008), CT perfusion (CTP) stage > III (p = 0.013), and posterior circulation involvement (p = 0.022) were significantly associated with postoperative ICH. No significant differences between the postoperative ICH group and the no-hemorrhage group were detected in terms of postoperative neurofunctional status at discharge (p = 0.569) or at the last follow-up (p = 1.000). Neither was there a significant difference in future stroke risk (p = 0.538) between these two groups.

Preoperative hypertension, CTP stage > III, and posterior circulation involvement are independent risk factors for postoperative ICH after direct or combined revascularization for MMD. After appropriate perioperative management, postoperative ICH has no significant correlations with the postoperative short-term and long-term neurofunctional status.

Postoperative hemorrhage during the acute phase after direct or combined revascularization for moyamoya disease: risk factors, prognosis, and literature review.

In this study, we successfully established a stable method for the isolation of endothelial cells (ECs) from human cerebral arteriovenous malformation (cAVM) tissues. Despite human cAVM tissues having a minor population of ECs, they play an important role in the manifestation and development of cAVM as well as in hemorrhagic stroke and thrombogenesis. To characterize and understand the biology of ECs in human cAVM (cAVM-ECs), methods for the isolation and purification of these cells are necessary. We have developed this method to reliably obtain pure populations of ECs from cAVMs. To obtain pure cell populations, cAVM tissues were mechanically and enzymatically digested and the resulting single cAVM-ECs suspensions were then labeled with antibodies of specific cell antigens and selected by flow cytometry. Purified ECs were detected using specific makers of ECs by immunostaining and used to study different cellular mechanisms. Compared to the different methods of isolating ECs from tissues, we could isolate ECs from cAVMs confidently, and the numbers of cAVM-ECs harvested were almost similar to the amounts present in vessel components. In addition to optimizing the protocol for isolation of ECs from human cAVM tissues, the protocol could also be applied to isolate ECs from other human neurovascular-diseased tissues. Depending on the tissues, the whole procedure could be completed in about 20 days.

Procedure for the Isolation of Endothelial Cells from Human Cerebral Arteriovenous Malformation (cAVM) Tissues

The working road map in a neurosurgical Hybrid Angio-Surgical suite------ development and practice of a neurosurgical Hybrid Angio-Surgical suite

Biomarkers are measurable changes associated with the disease. Without the control of homeostatic mechanisms, urine accumulates systemic body changes and thus serves as an excellent early biomarker source. However, urine is affected by many factors other than disease. Although many candidate biomarkers have been identified in animal models, a large number of clinical samples might still be required for the disease related changes. A self-controlled study should be able to avoid the interferences of individual differences among patients. Gliomas are the most common primary malignant brain tumors and have a very poor prognosis. Early diagnosis of gliomas and the monitoring of tumor recurrence are crucial to improve glioma patient outcomes. Here we set to try if biomarker candidates can be identified by comparing urine samples from five glioma patients collected at the time of tumor diagnosis and after surgical removal of the tumor. Using label-free liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) quantification, twenty-seven urinary proteins were significantly changed after tumor resection (fold change ≥ 1.5, P-value < 0.05, and similar changes in all 5 patients), many of which have been previously associated with gliomas, such as CEACAM1, ANXA7, CALR, CRYAB, CD276, pIgR and cathepsin D. Functions of these proteins were significantly enriched in the regulation of tissue remodeling, autophagy, the inhibition of gene expression, the positive regulation of natural killer cell-mediated cytotoxicity and angiogenesis, which are associated with glioma development. Our results suggested that using the self-control of before and after tumor resection is an effective method to identify differential proteins associated with the disease, even with a small number of patients.

Candidate urine biomarker discovery from only five pairs of samples before and after tumor resection in glioma patients

Comparison of radiological and clinical characteristics between blood blister-like aneurysms (BBAs) and non-blister aneurysms at the supraclinoid segment of internal carotid artery

Three-dimensional intracranial middle cerebral artery aneurysm models for aneurysm surgery and training

Importance Chronic subdural hematoma (CSDH) is a trauma-associated condition commonly found in elderly patients. Surgery is currently the treatment of choice, but it carries a significant risk of recurrence and death. Nonsurgical treatments remain limited and ineffective. Our recent studies suggest that atorvastatin reduces hematomas and improves the clinical outcomes of patients with CSDH. Objective To investigate the safety and therapeutic efficacy of atorvastatin to nonsurgically treat patients with CSDH. Design, Setting, and Participants The Effect of Atorvastatin on Chronic Subdural Hematoma (ATOCH) randomized, placebo-controlled, double-blind phase II clinical trial was conducted in multiple centers in China from February 2014 to November 2015. For this trial, we approached 254 patients with CSDH who received a diagnosis via a computed tomography scan; of these, 200 (78.7%) were enrolled because 23 patients (9.1%) refused to participate and 31 (12.2%) were disqualified. Interventions Patients were randomly assigned to receive either 20 mg of atorvastatin or placebo daily for 8 weeks and were followed up for an additional 16 weeks. Main Outcomes and Measures The primary outcome was change in hematoma volume (HV) by computed tomography after 8 weeks of treatment. The secondary outcomes included HV measured at the 4th, 12th, and 24th weeks and neurological function that was evaluated using the Markwalder grading scale/Glasgow Coma Scale and the Barthel Index at the 8th week. Results One hundred ninety-six patients received treatment (169 men [86.2%]; median [SD] age, 63.6 [14.2] years). The baseline HV and clinical presentations were similar between patients who were taking atorvastatin (98 [50%]) and the placebo (98 [50%]). After 8 weeks, the HV reduction in patients who were taking atorvastatin was 12.55 mL more than those taking the placebo (95% CI, 0.9-23.9 mL; P = .003). Forty-five patients (45.9%) who were taking atorvastatin significantly improved their neurological function, but only 28 (28.6%) who were taking the placebo did, resulting in an adjusted odds ratio of 1.957 for clinical improvements (95% CI, 1.07-3.58; P = .03). Eleven patients (11.2%) who were taking atorvastatin and 23 (23.5%) who were taking the placebo underwent surgery during the trial for an enlarging hematoma and/or a deteriorating clinical condition (hazard ratio, 0.47; 95% CI, 0.24-0.92; P = .03). No significant adverse events were reported. Conclusions and Relevance Atorvastatin may be a safe and efficacious nonsurgical alternative for treating patients with CSDH. Trial Registration ClinicalTrials.gov Identifier: NCT02024373

Safety and Efficacy of Atorvastatin for Chronic Subdural Hematoma in Chinese Patients: A Randomized ClinicalTrial

Abstract Tumoral calcinosis is a rare disorder characterized by tumor-like calcified masses commonly occurring in the periarticular regions of the extremities. Conversely, intradural tumoral calcinosis of the spine is extremely rare, with only two previously reported cases. To our knowledge, this is the first intradural case located in the foramen magnum region.

Intradural tumoral calcinosis of the foramen magnum region: A case report

Association of Ring Finger Protein 213 Gene P.R4810k Polymorphism with Intracranial Major Artery Stenosis/Occlusion.

Multiple nodular dural cavernous angiomas occluding superior sagittal sinus and destructing calvarium: Case report and literature review

Abstract Glioma is the most common tumor among central nervous system tumors; surgical intervention presents difficulties. This is especially the case for gliomas in so-called “eloquent areas,” as surgical resection threatens vital structures adjacent to the tumor. Intraoperative magnetic resonance imaging (iMRI) combined with multimodal neuronavigation may prove beneficial during surgery. This study explored the applicability of 3.0 T high field iMRI combined with multimodal neuronavigation in the resection of gliomas in eloquent brain areas. We reviewed 40 patients with a glioma located in the eloquent brains areas who underwent treatment in the Neurosurgery Department of Peking University International Hospital between December 2015 and August 2017. The experimental group included 20 patients treated using iMRI assistance technology (iMRI group). The remaining 20 patients underwent treatment by conventional neuronavigation (non-iMRI group). Tumor resection degree, preoperative and postoperative ability of daily living scale (Barthel index), infection rate, and operative time were compared between the 2 groups. No difference in infection rate was observed between the 2 groups. However, compared with the non-iMRI group, the iMRI group had a higher resection rate (96.55 ± 4.03% vs 87.70 ± 10.98%, P = .002), postoperative Barthel index (90.75 ± 12.90 vs 9.25 ± 16.41, P = .018), as well as a longer operation time (355.85 ± 61.40 vs 302.45 ± 64.09, P = .011). The use of iMRI technology can achieve a relatively higher resection rate among cases of gliomas in eloquent brain areas, with less incidence of postoperative neurological deficits. Although the operative time using iMRI was longer than that taken to perform conventional navigation surgery, the surgical infection rate in these 2 procedures showed no significant difference.

Clinical application of 3.0 T intraoperative magnetic resonance combined with multimodal neuronavigation in resection of cerebral eloquent area glioma

Evaluation of Angioarchitectural Features of Unruptured Brain Arteriovenous Malformation by Susceptibility Weighted Imaging.

Acteoside (ACT) has been shown to exert antioxidant and neuroprotective effects in neurodegenerative diseases. However, the effect of ACT on cerebral ischemia-reperfusion (I/R) injury is not yet clear. In this study, we found that ACT administration reduced infarct volume and brain edema, and improved neurological deficits, as indicated by the decreased modified neurological severity score. Administration of ACT strikingly reduced oxidative stress, accompanied by decreased levels of reactive oxygen species and malondialdehyde and increased levels of superoxide dismutase and catalase in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). Furthermore, ACT administration reduced the number of terminal deoxynucleotidyl transferase uridine 5'-triphosphate (UTP) nick-end labeling-positive cells in the cerebral cortex of ischemic side of MCAO/R rats, accompanied by downregulation of B cell lymphoma 2 (Bcl-2) associated X protein and cleaved caspase-3 proteins and upregulation of Bcl-2 protein. Additionally, ACT treatment inhibited the protein kinase R/eukaryotic initiation factor-2α stress pathway in the brains of MCAO/R rats. Our results demonstrated that ACT attenuates oxidative stress and neuronal apoptosis in MCAO/R rats, suggesting that ACT may serve as a novel therapeutic candidate for the treatment of I/R brain injury.

Acteoside Attenuates Oxidative Stress and Neuronal Apoptosis in Rats with Focal Cerebral Ischemia-Reperfusion Injury.

P5249Fetal cardiac tumor: echocardiography characteristics, clinical manifestations and outcomes

s 26th European Stroke Conference Berlin, Germany, May 24–26, 2017 (available online as E-Book)

OBJECTIVE Bypass surgery is the most common treatment for moyamoya disease (MMD), but there is controversy over which surgical modality is best. The objective of this study was to evaluate the clinical outcome of patients with MMD after undergoing different surgical modalities. METHODS A series of 696 consecutive MMD patients treated between June 2009 and May 2015 were screened in this prospective cohort study. Patients who did not undergo revascularization surgeries and those who underwent different surgical modalities in bilateral hemispheres were excluded. Finally, 529 patients who were observed for at least 12 months were included: 438 patients underwent unilateral surgery, and 91 patients underwent bilateral surgery. Of these, 241 patients underwent direct bypass (DB); 81, a combined bypass (CB); and 207, an indirect bypass (IB). Three clinical outcomes were evaluated and compared between surgical groups: recurrent stroke events, modified Rankin Scale (mRS) scores, and change in the main symptoms. RESULTS The mean follow-up period was 40 months. During the follow-up period, recurrent stroke was observed in 43 patients, including 15 patients with hemorrhage, 26 patients with ischemia (transient ischemic attack in 19 patients and infarction in 7 patients), and 2 patients with both hemorrhage and cerebral infarction. Kaplan-Meier analysis showed that patients who underwent a CB or DB had a longer ischemia-free time than those who underwent IB (p = 0.013); however, there was no significant difference in the hemorrhage-free time between the different surgical modalities (p = 0.534). A good neurological status (mRS score ≤ 2) was achieved in 495 patients (93.6%) and was significantly achieved by more children (98.2%) than adults (92.3%; p = 0.022). Surgical modalities were not significantly associated with outcome neurological status (p = 0.860). Moreover, improvement in symptoms was observed in 449 patients (84.9%) and was also significantly more common in children (93.0%) than in adults (82.7%; p = 0.006). No significant difference was observed between the different surgical modalities (p = 0.548). CONCLUSIONS CB and DB are more effective at preventing recurrent ischemic strokes than IB. However, there is no evidence that these 3 surgical modalities demonstrate significant differences in preventing recurrent hemorrhage.

Effects of different surgical modalities on the clinical outcome of patients with moyamoya disease: a prospective cohort study.

Microsurgical Outcome of Unruptured Brain Arteriovenous Malformations: A Single-Center Experience.

Portable near-infrared rapid detection of intracranial hemorrhage in Chinese population

Introduction Although microsurgical resection is currently the first-line treatment modality for arteriovenous malformations (AVMs), microsurgery of these lesions is complicated due to the fact that they are very heterogeneous vascular anomalies. The Spetzler-Martin grading system and the supplementary grading system have demonstrated excellent performances in predicting the risk of AVM surgery. However, there are currently no predictive models based on multimodal MRI techniques. The purpose of this study is to propose a predictive model based on multimodal MRI techniques to assess the microsurgical risk of intracranial AVMs. Methods and analysis The study consists of 2 parts: the first part is to conduct a single-centre retrospective analysis of 201 eligible patients to create a predictive model of AVM surgery based on multimodal functional MRIs (fMRIs); the second part is to validate the efficacy of the predictive model in a prospective multicentre cohort study of 400 eligible patients. Patient characteristics, AVM features and multimodal fMRI data will be collected. The functional status at pretreatment and 6 months after surgery will be analysed using the modified Rankin Scale (mRS) score. The patients in each part of this study will be dichotomised into 2 groups: those with improved or unchanged functional status (a decreased or unchanged mRS 6 months after surgery) and those with worsened functional status (an increased mRS). The first part will determine the risk factors of worsened functional status after surgery and create a predictive model. The second part will validate the predictive model and then a new AVM grading system will be proposed. Ethics and dissemination The study protocol and informed consent form have been reviewed and approved by the Institutional Review Board of Beijing Tiantan Hospital Affiliated to Capital Medical University (KY2016-031-01). The results of this study will be disseminated through printed media. Trial registration number NCT02868008.

New predictive model for microsurgical outcome of intracranial arteriovenous malformations: study protocol

In the past decades, altered Follistatin-like 1 (FSTL1) expression has been documented in a variety of cancers, while its functional roles are poorly understood. Particularly in breast cancer, the expression of FSTL1 and its signaling pathway remain to be determined. In the present study, an elevated FSTL1 expression and a supressed cell proliferation were detected in a specific brain metastatic cell line MDA-MB-231-BR (231-BR), compared with its parental cell line MDA-MB-231. However, this protein was hardly detected in the other three breast cancer cell lines. Next, lentiviral vectors encoding FSTL1 or FSTL1 specific shRNAs were used to overexpress or knock down FSTL1 in MDA-MB-231 or 231-BR, respectively (MDA-MB-231FSTL1 or 231-BRsh FSTL1). Results showed that overexpression of FSTL1 inhibited MDA-MB-231 cell proliferation, while knockdown of FSTL1 in 231-BR cells promotes cell proliferation, compared with their corresponding control groups. These results were further confirmed in nude mouse xenografts. The tumor volume in 231-BR cell-bearing mice was significantly smaller than that of MDA-MB-231 group, and reduction of tumor volume was detected in MDA-MB-231FSTL1 cell-bearing mice compared with the control group. Previous studies revealed that TGF-β-Smad2/3 signaling pathway was activated in 231-BR and MDA-MB-231FSTL1 cells, which may contribute to the inhibited cell proliferation. In addition, Smad3 knockdown could restore the inhibition of cell proliferation induced by FSTL1 overexpression in MDA-MB-231FSTL1 cells, indicating that the anti-proliferative effect of FSTL1 overexpression may be associated with Smad3 involved TGF-β signaling pathway regulation. This study identified FSTL1 as an inhibitor of cell proliferation in MDA-MB-231 and 231-BR cell lines, which may provide new insights into the development and management of breast cancer.

Effects of FSTL1 on cell proliferation in breast cancer cell line MDA-MB-231 and its brain metastatic variant MDA-MB-231-BR

Translucent Appearance of Middle Cerebral Artery Bifurcation Aneurysms Is Risk Factor for Intraoperative Aneurysm Rupture During Clipping.

Predictive Factors of Postoperative Seizure for Pediatric Patients with Unruptured Arteriovenous Malformations.

Corrigendum to "Microsurgical Resection for Persistent Arteriovenous Malformations Following Gamma Knife Radiosurgery: A Case-Control Study" [World Neurosurg. 88 (2016) 277-288].

Giant Intracranial Aneurysms: Surgical Treatment and Analysis of Risk Factors.

1Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China. 2China National Clinical Research Center for Neurological Diseases, Beijing 100050, China. 3Department of Neurosurgery, Peking University International Hospital, Peking University Health Science Center, Beijing 102206, China. 4Center of Stroke, Beijing Institute for Brain Disorders, Beijing 100050, China. 5Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing 100050, China. *Authors contributed equally.

Cerebral ischemia at early postoperative period of direct revascularization for moyamoya disease: a case report and literature review

Comparison of Two Three-Dimensional Printed Models of Complex Intracranial Aneurysms for Surgical Simulation.

IntroductIon Microneurosurgery made its debut in the early 1960s. It became popular in the medical field and became a primary operation method in neurosurgery since it improved the efficacy of neurosurgery with a less surgery‐related injury. Over the past five decades, the accumulation of experience of microsurgery, improvement of microsurgery techniques, refined micro‐instruments, and advanced preoperative diagnostic imaging allowed the evolution of microneurosurgery techniques and further reduced surgery‐related trauma. The advanced development has made it possible for a neurosurgeon to treat more sophisticated lesions with smaller craniotomy. Keyhole neurosurgery, the combination of modern microsurgical techniques, preoperative imaging, neuroendoscopy, and modern minimally invasive surgery concept, is one of the techniques representing the medical advancement from microneurosurgery to minimally invasive neurosurgery.

Background and Purpose— Silent microhemorrhage (hemosiderin) has been observed in resected brain arteriovenous malformations (bAVM) tissue and may represent a subgroup at increased risk for clinical hemorrhage. Previous studies suggest that ruptured bAVMs have faster flow and shorter mean transit time of contrast in blood vessels than unruptured bAVMs. We hypothesized that flow would be faster in unruptured AVMs with hemosiderin compared with those without hemosiderin. Methods— We selected unruptured, supratentorial bAVMs >3.5 cc with pathology specimens. Hemodynamic features were evaluated using color-coding angiography, including contrast mean transit time of AVM nidus, time to peak (TTP) of feeding artery (FA) and draining vein (DV), and the ratio (TTP DV/FA). Characteristics of 9 cases with hemosiderin and 16 without hemosiderin were compared using 2-sample t tests and Fisher exact tests. Results— No difference in FA TTP and DV TTP was observed between groups. However, cases with hemosiderin had significantly shorter mean transit time compared with those without hemosiderin (1.11±0.28 versus 1.64±0.55 seconds; P=0.013) and a lower ratio of DV TTP/FA TTP (1.48±0.32 versus 1.94±0.61; P=0.045). Presence of venous varix was significantly associated with hemosiderin (P=0.003). No other clinical or angioarchitectural factors were associated with hemosiderin. Conclusions— Shorter mean transit time through the AVM nidus, lower DV TTP/FA TTP, and the high prevalence of venous varices suggests that high flow is an important feature of unruptured bAVMs with hemosiderin.

Higher Flow Is Present in Unruptured Arteriovenous Malformations With Silent Intralesional Microhemorrhages

Detailed and exact mechanisms underlying brain arteriovenous malformations (bAVM) are still clinically confusing. Understanding the quantitative changes in proteins and signaling pathways would provide useful information for clinicians to understand the formation and development of bAVM, guiding individualized treatment strategies. This study was performed to establish a large human bAVM proteome database using tandem mass tag labeling and to detect changes of protein expression and pathways in human bAVM.

Dysregulation of cell–cell interactions in brain arteriovenous malformations: A quantitative proteomic study

OBJECTIVE The optimal surgical modality for moyamoya disease (MMD) remains unclear. The aim of this study was to compare the surgical effects of direct bypass (DB) and indirect bypass (IB) in the treatment of adult ischemic-type MMD. METHODS Adult patients with ischemic-type MMD who underwent either DB or IB from 2009 to 2015 were identified retrospectively from a prospective database. Patients lost to follow-up or with a follow-up period less than 12 months were excluded. Recurrent stroke events and modified Rankin Scale (mRS) scores at the last follow-up were compared between the 2 surgical groups after 1:1 propensity score matching. RESULTS A total of 220 patients were considered, including 143 patients who underwent DB and 77 patients who underwent IB. After propensity score matching, 70 pairs were obtained. The median follow-up period was 40.5 months (range 14-75 months) in the DB group and 31.5 months (range 14-71 months) in the IB group (p = 0.004). Kaplan-Meier analysis showed that patients who received DB had a longer stroke-free time (mean 72.1 months) compared with patients who received IB (mean 61.0 months) (p = 0.045). Good neurological status (mRS score ≤ 2) was achieved in 64 patients in the DB group (91.4%) and 66 patients in the IB group (94.3%), but there was no significant difference (p = 0.512). CONCLUSIONS Although neurological function outcome was not determined by the surgical modality, DB is more effective in preventing recurrent ischemic strokes than IB for adult ischemic-type MMD.

Direct versus indirect bypasses for adult ischemic-type moyamoya disease: a propensity score-matched analysis.

AIM
For cerebral arteriovenous malformations (AVMs) involving language areas, right-sided language lateralization on functional magnetic resonance imaging (fMRI) has been reported, which is regarded as language cortex reorganization. The authors attempted to study if this right-sided language lateralization affects postoperative language outcome.

MATERIAL AND METHODS
Clinical and imaging data of 43 right-handed AVM patients who underwent preoperative fMRI were retrospectively reviewed. All lesions involved the language cortex, with the Broca area involved in 13 patients and the Wernicke area involved in 30 patients. Lateralization indices (LI) of BOLD signal activations were calculated to determine language lateralization. All patients underwent craniotomy and total resection. Western aphasia battery (WAB) was used to evaluate language functions preoperatively, 1-2 weeks after surgery and 6-30 months after surgery.

RESULTS
On preoperative fMRI, right-sided lateralization was observed in 18 patients (41.9%, R Group), including 3 with rightsided lateralization in the Broca area alone, 14 in the Wernicke area alone, and 1 in both areas. The other 25 patients were non-rightsided lateralized (NR Group). One week after surgery, 7 patients in the R Group (38.9%) and 11 patients in the NR Group (44.0%) had language function deterioration, and no significant difference was found (p=0.983). At long-term follow-up, 3 patients in the R Group (16.7%) and 4 patients in the NR Group (16.0%) still had aphasia, and no significant difference was observed (p=1.000).

Although right-sided lateralization on fMRI might suggest language cortex reorganization, it is not a factor predicting better postoperative language outcome for AVM patients.

Does Right-Sided Language Lateralization on BOLD-fMRI Affect Postoperative Language Outcome for AVM Patients?

Subsequent haemorrhage in children with untreated brain arteriovenous malformation: Higher risk with unbalanced inflow and outflow angioarchitecture

Background: Children with untreated brain arteriovenous malformations (bAVM) are at risk of encountering life-threatening hemorrhage very early in their lives. The primary aim of invasive treatment is to reduce unfavorable outcome associated with a bAVM rupture. A better understanding of the morbidity of bAVM hemorrhage might be helpful for weighing the risks of untreated bAVM and invasive treatment. Our aim was to assess the clinical outcome after bAVM rupture and identify features to predict severe hemorrhage in children. Methods: We identified all consecutive children admitted to our institution for bAVMs between July 2009 and December 2014. Clinical outcome after hemorrhagic presentation and subsequent hemorrhage was evaluated using the modified Rankin Scale (mRS) for children. The association of demographic characteristics and bAVM morphology with severe hemorrhage (mRS >3 or requiring emergency hematoma evacuation) was studied using univariate and multivariable regression analyses. A nomogram based on multivariable analysis was formulated to predict severe hemorrhage risk for individual patients. Results: A total of 134 patients were identified with a mean treatment-free follow-up period of 2.1 years. bAVM ruptured in 83 (62%) children: 82 had a hemorrhage at presentation and 6 of them experienced a recurrent hemorrhage during follow-up; 1 patient had other diagnostic symptoms but bled during follow-up. Among them, 49% (41/83) had a severe hemorrhage; emergency hematoma evacuation was required in 28% of them (23/83), and 24% (20/83) remained as disabled (mRS ≥3) at last follow-up. Forty-six percent (38/82) of children with hemorrhagic presentation were severely disabled (mRS >3). Forty-three percent (3/7) were severely disabled after subsequent hemorrhage. The annual rate of severe subsequent hemorrhage was 1% in the overall cohort and 3.3% in children with ruptured presentation. All the subsequent severe hemorrhage events occurred in children with severe hemorrhage history (7%, 3/41). Periventricular location, non-temporal lobe location, and long draining vein were predictors for severe hemorrhage in pediatric untreated bAVMs. A nomogram based on bAVM morphology was contracted to predict severe hemorrhage risk for individual patients, which was well calibrated and had a good discriminative ability (adjusted C-statistic, 0.72). Conclusions: Evaluating bAVM morbidity and morphology might be helpful for weighing the risks of untreated bAVM in pediatric patients.

Morbidity after Hemorrhage in Children with Untreated Brain Arteriovenous Malformation

Objective 
To investigate the association between silent intralesional micro-hemorrhage (SIM) and symptomatic intracranial hemorrhage (ICH) of brain arteriovenous malformations (bAVMs) by using evidence of old hemorrhage (EOOH) and hemosiderin dyeing results. 
 
Methods 
Sixty-three patients with bAVMs, admitted to our hospital from September 2014 to September 2016, were chosen in our study; their clinical and pathological data were retrospectively analyzed. Logistic regression analysis was performed to assess the correlations of ICH of bAVMs with EOOH and Prussian blue staining results after adjusting the factors as gender, age, lesion size, location, single or multiple supplying arteries and deep venous drainage. 
 
Results 
Gender, age, lesion size were not associated with ICH of bAVMs, while single or multiple supplying arteries, deep venous drainage and SIM were significantly associated with ICH of bAVMs. EOOH and Prussian blue staining results were the independent predictors of ICH of bAVMs (OR=5.507, 95%CI: 1.208-25.111, P=0.028; OR=6.055, 95%CI: 1.479-24.793, P=0.012). 
 
ICH of bAVMs could be proved by EOOH and hemosiderin, and EOOH could serve as a potential predictor of ICH of bAVMs. 
 
Key words: 
Brain arteriovenous malformation; Silent intralesional hemorrhage; Evidence of old hemorrhage

Association of silent intralesional micro-hemorrhage with intracranial hemorrhage of brain arteriovenous malformations

DNA Methylation Regulates Gene Expression in Intracranial Aneurysms.

The Association of the RNF213 p.R4810K Polymorphism with Quasi-Moyamoya Disease and a Review of the Pertinent Literature.

Risk Factors for Subsequent Hemorrhage in Patients with Cerebellar Arteriovenous Malformations.

The Effect of Age, Sex, and Lesion Location on Initial Presentation in Patients with Brain Arteriovenous Malformations.

Plasticity of motor function and surgical outcomes in patients with cerebral arteriovenous malformation involving primary motor area: insight from fMRI and DTI

Clinical Features and Long-Term Outcomes of Unilateral Moyamoya Disease.

The aim of the current study was to observe the effects of simvastatin and taurine on delayed cerebral vasospasm (DCVS) following experimental subarachnoid hemorrhage (SAH) in rabbits. A total of 48 New Zealand white rabbits were allocated at random into four groups (control, SAH, SAH + simvastatin and SAH + taurine groups; n=12 each). The rabbit model of DCVS was established using a double hemorrhage method, which involved injecting autologous arterial blood into the cisterna magna in the SAH groups. The SAH + simvastatin group was administered oral simvastatin (5 mg/kg) daily between days 0-6. The SAH + taurine group was administered oral taurine (50 mg/kg) daily between days 0-6. Starch (50 mg/kg) was administered orally to the animals in the other two groups (control and SAH groups). The control group were not subjected to any other injections or treatment. The internal diameter and internal diameter/wall thickness of the basilar artery (BA) were measured. The expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 were determined using immunohistochemical and quantitative polymerase chain reaction methods following the sacrifice of all animals on day 7. The activity of nuclear factor (NF)-κB in the BA was also measured using an electrophoretic mobility shift assay. The BA walls in the SAH + simvastatin and SAH + taurine groups exhibited reduced narrowing and corrugation of the tunica elastica interna compared with the SAH group. At the protein and cDNA levels, it was found that cerebral vasospasm of the BA in the SAH + simvastatin and SAH + taurine groups was alleviated, as indicated by the reduced expression of TNF-α, IL-1β, IL-6 and NF-κB compared with the SAH group (P<0.05). In conclusion, simvastatin and taurine reduced DCVS following SAH in rabbits, which suggests that these compounds may exert anti-inflammatory effects.

Effects of simvastatin and taurine on delayed cerebral vasospasm following subarachnoid hemorrhage in rabbits.

Difference of language cortex reorganization between cerebral arteriovenous malformations, cavernous malformations, and gliomas: a functional MRI study

Microsurgical Outcome of Cerebellar Arteriovenous Malformations: Single-Center Experience.

A Multicenter Analysis of Computed Tomography Angiography Alone Versus Digital Subtraction Angiography for the Surgical Treatment of Poor-Grade Aneurysmal Subarachnoid Hemorrhage.

There is no consensus regarding the optimal timing for surgery for poor-grade aneurysmal subarachnoid hemorrhage.

OBJECTIVE
To retrospectively evaluate variation in patient characteristics and outcomes between early and delayed surgery groups.

METHODS
Poor-grade aneurysmal subarachnoid hemorrhage was defined as a World Federation of Neurosurgical Societies grade of IV or V after resuscitation. Early surgery was defined as surgery performed within 72 hours of ictus, and delayed surgery was defined as surgery after 72 hours. Outcomes were assessed by modified Rankin score. The mean time of follow-up was 12.5 ± 3.4 months.

RESULTS
Of the 118 patients included in the study, 80 (68%) underwent early surgery and 38 (32%) underwent delayed surgery. Patients with brain herniation (P < .001) and a lower Fisher grade (P = .02) more often underwent early surgery. Patients in the early group more often underwent decompressive craniectomy (P < .001). Postoperative complications and length of hospital stay did not differ, and outcomes were similar between the 2 groups. Forty (34%) patients had an excellent outcome (modified Rankin score 0-1). Multivariate analysis showed a slight trend toward an excellent outcome in the early surgery group. Younger age, World Federation of Neurosurgical Societies grade IV after resuscitation, and middle cerebral artery aneurysms were independent predictors of an excellent outcome.

Although patients with brain herniation and a lower Fisher grade were more likely to undergo early surgery, there was a slight trend toward an excellent outcome in the early surgery group. Patients with a younger age, World Federation of Neurosurgical Societies grade IV after resuscitation, and middle cerebral artery aneurysms were more likely to experience an excellent outcome.

Variation in Patient Characteristics and Outcomes Between Early and Delayed Surgery in Poor-Grade Aneurysmal Subarachnoid Hemorrhage.

Objective 
s To develop a risk score before microsurgery for poor-grade aneurysmal subarachnoid hemorrhage(aSAH)and to evaluate the score for the accuracy of predicting prognosis. 
 
Methods 
A total of 119 patients with aSAH(World Federation of Neurosurgical Societies[WFNS]grade 4-5)treated with microsurgery in several medical centers in China from October 2010 to April 2014 were enrolled retrospectively. Preoperative risk scores(0-5 score)were conducted according to their age, WFNS score, having cerebral hernia or not, and having ventricle hematocele or not. They were followed up for 6-28(12.5±3.4)months. The modified Rankin scale(mRS)was used to evaluate the prognosis. The patients were divided into good prognosis(mRS 0-3)and poor prognosis(mRS 4-6). Receiver operating characteristic(ROC)curve was used to evaluate the risk score for the accuracy of predicting prognosis. 
 
Results 
Fifty-nine patients(49.6%)had good prognosis, 60(50.4%)had poor prognosis and 37 of them died(31.0%). There were significant prognosis differences in patients with different preoperative risk scores(χ2=42.077, P<0.01). In patients with preoperative score ≤ 1, the incidence of poor prognosis was 21.2%(11/52); preoperative score ≥ 4, the proportion of poor prognosis was 8/9. The higher the preoperative score, the higher the incidence of poor prognosis. The area under the curve of this score predicting poor prognosis was 0.79(95% CI 0.71-0.87, P<0.01). If the preoperative score was 2, it suggested that the sensitivity of poor prognosis was 82%, the specificity was 70%, and the goodness of fit was good(χ2=2.388, P=0.496). 
 
Preoperative risk score is helpful in predicting the prognosis of patients with aSAH who were treated with microsurgery. 
 
Key words: 
Intracranial aneurysm; Subarachnoid hemorrhage; Poor-grade; Microsurgery; Prognosis

Prediction of preoperative risk score for curative effect of microsurgery in patients with poor-grade aneurysmal subarachnoid hemorrhage

Microsurgical Resection for Persistent Arteriovenous Malformations Following Gamma Knife Radiosurgery: A Case-Control Study.

The relation between angioarchitectural factors of developmental venous anomaly and concomitant sporadic cavernous malformation

Cerebellar Arteriovenous Malformations: Clinical Feature, Risk of Hemorrhage and Predictors of Posthemorrhage Outcome.

Objective 
To preliminarily discuss the operation strategy in patients with intracranial cavernous hemangioma complicated with venous malformation. 
 
Methods 
The clinical data and postoperative follow-up results of 13 patients with intracranial cavernous hemangioma complicated with venous malformation operated at the Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University from January 2007 to December 2014 were analyzed retrospectively. 
 
Results 
In the 13 patients, intracranial cavernous malformation complicated with venous malformation achieved total resection in 7 patients. They all developed severe cerebral edema after procedure. Four of them were in the supratentorial region, their prognoses were good after strengthening dehydration treatment, and 1 in the supratentorial region died, and 2 left sequelae. The postoperative condition was stable and the prognosis was good in 4 patients whose abnormal expansion of medullary veins were resected, the main drainage veins were retained and in 2 patients whose venous vascular malformations were retained. 
 
In the operation of resection of intracranial cavernous malformation complicated with venous malformation, the resection of abnormally dilated medullary veins and retaining main draining veins at the same time of the total resection of cavernous malformation are more conducive to the rehabilitation of patients. 
 
Key words: 
Hemangioma, cavernous, central nervous system; Venous malformation; Microsurgery

Clinical analysis of the resection of intracranial cavernous malformation complicated with venous malformation

Background: Numerous dura substitutes are commercially available, but no absorbable synthetic dura repair product has been used for both onlay and suture applications. Objective: The safety and effectiveness of a new absorbable synthetic substitute composed of Poly-L-lactide microfibers as onlay dural graft were evaluated. Methods: Physical properties and performance of the microfibrous synthetic dural substitute implanted as an onlay or suturable grafts were compared with these commercial products, including CODMAN ETHISORB™ Dura Patch and DuraGen™ Dural Graft Matrix, in a canine duraplasty model. The cerebrospinal fluid (CSF) leakage, macroscopic and microscopic observation at 30 and 90 days after implantation were investigated. Results: The absorbable synthetic dural substitute exhibited good wettability and conformability. When implanted as an onlay graft, it can prevent CSF leakage and integrate with the surrounding tissue to repair dural defects, indicating its good efficacy and biocompatibility as an onlay graft. Conclusion: Based on the excellent physical properties and performances mentioned above, the new absorbable synthetic substitute can be applied as a dural graft for both onlay and suturable applications.

Evaluation of efficacy and biocompatibility of a new absorbable synthetic substitute as a dural onlay graft in a large animal model

Primary decompressive craniectomy for poor-grade middle cerebral artery aneurysms with associated intracerebral hemorrhage

Objective To determine factors and outcomes associated with ultra-early surgery for poor-grade aneurysmal subarachnoid haemorrhage (aSAH). Design A multicentre retrospective analysis, observational study. Setting High-volume teaching hospitals (more than 150 aSAH cases per year). Participants 118 patients with World Federation of Neurosurgical Societies (WFNS) grades IV and V underwent surgical treatment. Ultra-early surgery was defined as surgery performed within 24 h of aSAH, and delayed surgery as surgery performed after 24 h. Outcome was assessed by modified Rankin Scale (mRS). The mean time of follow-up was 12.5±3.4 months (range 6–28 months). Results 47 (40%) patients underwent ultra-early surgery, and 71 (60%) patients underwent delayed surgery. Patients with WFNS grade V (p=0.011) and brain herniation (p=0.004) more often underwent ultra-early surgery. Postoperative complications were similar in ultra-early and delayed surgery groups. Adjusted multivariate analysis showed the outcomes were similar between the two groups. Multivariate analysis of predictors of poor outcome, ultraearly surgery was not an independent predictor of poor outcome, while advanced age, postresuscitation WFNS V grade, intraventricular haemorrhage, brain herniation and non-middle cerebral artery (MCA) aneurysms were associated with poor outcome. Conclusions Although patients with WFNS grade V and brain herniation more often undergo ultra-early surgery, postoperative complications and outcomes in selected patients were similar in the two groups. Patients of younger age, WFNS grade IV, absence of intraventricular haemorrhage, absence of brain herniation and MCA aneurysms are more likely to have a good outcome. Ultra-early surgery could improve outcomes in carefully selected patients with poor-grade aSAH.

Factors and outcomes associated with ultra-early surgery for poor-grade aneurysmal subarachnoid haemorrhage: a multicentre retrospective analysis

Glioma is the most common malignancy of the central nervous system. Approximately 40 percent of intracranial tumors are diagnosed as gliomas. Difficulties in treatment are associated closely with the malignant phenotype, which is characterized by excessive proliferation, relentless invasion, and angiogenesis. Although the comprehensive treatment level of brain glioma is continuously progressing, the outcome of this malignancy has not been improved drastically. Therefore, the identification of new biomarkers for diagnosis and therapy of this malignancy is of significant scientific and clinical value. FRAT1 is a positive regulator of the Wnt/β-catenin signaling pathway and is overexpressed in many human tumors. In the present study, we investigated the expression status of FRAT1 in 68 patients with human gliomas and its correlation with the pathologic grade, proliferation, invasion, angiogenesis, and prognostic significance. These findings suggest that FRAT1 may be an important factor in the tumorigenesis and progression of glioma and could be explored as a potential biomarker for pathological diagnosis, an indicator for prognosis, and a target for biological therapy of malignancy.

Overexpression of FRAT1 Is Associated with Malignant Phenotype and Poor Prognosis in Human Gliomas

OC03.03: Assessment of ventricular global longitudinal function in hypoplastic left heart syndrome using velocity vector imaging

Large thrombosed anterior communicating artery aneurysm in the sella turcica: A review of literature.

The cavernous malformations (CMs) associated with venous anomalies (VAs) are now being described with increasing frequency. Assessment of the associated VAs is overlooked in surgical management of the CM. The clinical profiles of CMs with VAs were reviewed to investigate the value of T2*gradient echo (GRE)/susceptibility weighted imaging (SWI) in surgical risk evaluation. Twenty-six patients with symptomatic CMs associated with VAs between 2008 and 2013 were identified. Demographic, clinical, and radiological data were reviewed and functional outcomes were assessed using the modified Rankin Scale (mRS). The T2*GRE/SWI could allow more accurate evaluation of the boundary and drainage vicinity of VAs than contrast-enhanced images (6 vs. 2 patients with VAs on the eloquent region). Patients with VAs adjacent to eloquent brain showed poorer outcomes than those who had VAs in non-eloquent areas (P = 0.005), while the CMs adjacent to eloquent brain did not correlated with poor outcomes (P = 0.15). Type I and III variants of VAs were also significantly associated with poor outcomes, compared with type II variant (P = 0.002). Careful evaluation of VAs variant type and the association between VAs and eloquent brain is helpful for the management of CMs associated with VAs. We recommend T2*GRE/SWI in patients with CMs to assess the associated VAs. The evaluation of VA drainage vicinity on T2*GRE/SWI would be more useful for designing treatment strategies and risk stratification.

The Associated Venous Anomalies Variant and Adjacent Brain Function on Iron Sensitive Image Indicate Surgical Risk of Cavernous Malformation

OBJECTIVE
A retrospective study was conducted to analyze the clinical data of patients treated by retractorless surgery and explore the clinical feasibility and practical application of this strategy.

METHODS
A total of 194 patients undergone retractorless surgery in Beijing Tiantan Hospital from Nov 2013 to Oct 2014 were retrospectively reviewed. Complications related to microsurgical approaches, disease types, neurological function score and intraoperative compression or stretching were analyzed.

RESULTS
Of the 194 cases, there were 127 (65%) patients with cerebrovascular diseases and 67 (35%) patients with intracranial tumors. Sixty patients had anterior circulation aneurysms, of them, 21 aneurysms were accessed through frontal-lateral approaches and 39 reached via pterional approaches. Two patients with posterior inferior cerebellar artery (PICA) aneurysms were treated by far-lateral approaches. Fifteen patients with cerebellopontine angle (CPA) tumors were treated by retrosigmoid approaches. Elven patients with supratentorial tumors were treated by anterior and posterior interhemispheric approaches. Twenty patients with posterior fossa tumors were treated by suboccipital posterior median and paramedian approaches. Two patients with petroclival region lesions were treated by subtemporal approaches. Damage of tissues surrounding the approach occurred in 4 cases (2%). One patient received secondary procedures (0.52%) and 2 patients died after operation (1%). No change of postoperative neurological function was seen in 62.3% of cases, improvement of postoperative neurological function was seen in 29.4% and neurological function deterioration 8.24%.

Compared with the retractor surgery, retractorless surgery does not increase the rate of damage of tissues surrounding the approach. With the proficiency in micro-neurosurgery methods, retractorless surgery can reduce the postoperative complications.

[The clinical application of retractorless surgical technique in neurosurgical operation].

Brain arteriovenous malformation (BAVM) is an important risk factor for intracranial hemorrhage, especially in children and young adults. Inflammation has been implicated in BAVM lesion progression. Among various inflammatory components, macrophage is one of the major inflammatory cells present in human ruptured and unruptured BAVM and in the BAVM lesions of animal models. The role of macrophage in BAVM pathogenesis is not fully understood. In this review, we summarize recent studies on macrophages and introduce a non-invasive imaging protocol as a potential tool for detecting macrophage in BAVM and predicting the risk of BAVM rupture.

The Role of Macrophage in the Pathogenesis of Brain Arteriovenous Malformation.

By far, we have witnessed the rapid development of critical care medicine in the past 30 years. With the honorable milestones standing by, NCC is progressively regarded as an important part of neurosurgery. Functioning as a multidisciplinary subspecialty, NCC aims to provide joint effort from multiple disciplines, including Neurosurgery, Critical Care Medicine, Neurology, Emergency Medicine, Laboratory Medicine, Neurosurgical Nursing, etc. The Chinese Neurosurgery Society invited 356 experts in this subspecialty to formulate The Experts Consensus for Critical Care Management of Neurosurgical Patients in China (consensus).

The Experts Consensus for Patient Management of Neurosurgical Critical Care Unit in China (2015)

Effect of ATorvastatin On Chronic subdural Hematoma (ATOCH): a study protocol for a randomized controlled trial

Brain arteriovenous malformations in elderly patients: clinical features and treatment outcome

Abstract Objectives: Rebleeding is an unsatisfactory outcome for patients with haemorrhagic MMD. This study mainly investigated clinical features and outcomes in haemorrhagic MMD. Methods: A retrospective review was performed on a total of 154 patients with haemorrhagic MMD comprising 126 surgically treated and 28 conservatively treated patients. Results: There were 102 female and 52 male patients with a mean age at the initial bleeding of 33.95 years. Preoperative rebleeding occurred in 37 patients, and multivariate Cox regression analysis demonstrated that age at the time of initial bleeding (P < 0.001, HR = 1.093) was a risk factor for preoperative rebleeding. Of 124 patients with surgical revascularization, perioperative ischaemic stroke occurred in five (4.03%) and intracranial bleeding in four (3.23%). The mean follow-up period was 36.12 months. Recurrent bleeding occurred in six (10.17%) of 59 patients treated with direct revascularization, seven (20.69%) of 34 patients treated with indirect revascularization, two (6.45%) of 31 patients treated with combined revascularization and six (21.43%) of 28 patients treated conservatively. Kaplan–Meier analysis revealed no statistical differences in preventing rebleeding between direct, indirect and combined revascularization and conservative treatment (P = 0.311). Conclusions: Age at the initial bleeding is a risk factor for rebleeding in haemorrhagic MMD. Although surgical revascularization show the tendency to decrease the rebleeding rate, there is no statistical difference between direct revascularization, indirect revascularization, combined revascularization and conservative treatment in preventing rebleeding. Further study is needed to determine whether surgical revascularization is effective in select population or with certain techniques.

Clinical features and outcomes in 154 patients with haemorrhagic moyamoya disease: comparison of conservative treatment and surgical revascularization

OBJECT
The aim of this study was to describe the baseline clinical features and long-term outcomes of patients with moyamoya disease (MMD) based on a 25-year period at a single center in China.

METHODS
 Data obtained in 528 consecutive patients with MMD treated at the authors' hospital from 1984 to 2010 were reviewed retrospectively. Events of transient ischemic attack, new infarction, and hemorrhage were included. The Kaplan-Meier risk of stroke was calculated.

RESULTS
 The mean (±SD) patient age was 26±13 years (range 2-67 years), and the female/male ratio was 0.9:1. There were 332 cases of ischemia and 196 hemorrhages. Adults had a higher rate of bleeding than children (50.7% vs 14.0%, respectively; p<0.001). One hundred twenty-two patients were treated conservatively, and 406 patients underwent revascularization procedures. Of 528 patients, 331 (62.7%) had at least 1 year of follow-up (median 39.5 months) and data from these patients were analyzed. Rebleeding and mortality rates in patients with hemorrhagic MMD (n=104) were higher than in those with ischemic MMD (n=227) (26.9% vs 2.2% [p<0.001] and 4.8% vs 0.4% [p<0.05], respectively). Twenty-five of 60 (41.7%) conservatively treated patients and 8 of 271 (2.9%) surgically treated patients experienced rebleeding events, a difference that was significant in the Kaplan-Meier curve of rebleeding (p<0.01). An improvement in perfusion was found in 164 of 224 (73.2%) surgically treated patients 1 month after discharge. However, there was no significant difference in the rate of ischemic events in the surgical and conservative groups (18.8% and 28.3%, respectively; p=0.09). Among the 104 hemorrhagic cases, rebleeding attacks were observed in 25 patients in the nonsurgical group (n=60) and 3 patients in the surgical group (n=44) (41.7% and 6.8%, respectively; OR 9.7 [95% CI 2.7-35.0]; p<0.01).

 There was no difference in the sex distribution of Chinese patients with MMD. Patients with hemorrhagic MMD had a much higher rate of rebleeding and poorer prognosis than those with the ischemic type. Surgical revascularization procedures can improve cerebral perfusion and have a positive impact in preventing rebleeding in patients with hemorrhagic MMD.

Clinical features and long-term outcomes of moyamoya disease: a single-center experience with 528 cases in China.

Visual Field Preservation in Surgery of Occipital Arteriovenous Malformations: A Prospective Study.

Complications and outcomes after early surgical treatment for poor-grade ruptured intracranial aneurysms: A multicenter retrospective cohort.

Involvement of the visual pathway is not a risk factor of visual field deficits in patients with occipital arteriovenous malformations: an fMRI study

Surgical Treatment of Cerebellar Cavernous Malformations: A Single-Center Experience with 58 Cases.

P09.04: An analysis of echocardiographic characteristics of ventricular diverticula: from fetuses to adults

Aim: To test the hypothesis that lymphocyte infiltration in brain arteriovenous malformation (bAVM) is not associated with iron deposition (indicator of micro-hemorrhage). Methods: Sections of unruptured, previously untreated bAVM specimens (n = 19) were stained immunohistochemically for T-lymphocytes (CD3 + ), B-lymphocytes (CD20 + ), plasma cells (CD138 + ) and macrophages (CD68 + ). Iron deposition was assessed by hematoxylin and eosin and Prussian blue stains. Superficial temporal arteries (STA) were used as control. Results: Both T-lymphocytes and macrophages were present in unruptured, previously untreated bAVM specimens, whereas few B cells and plasma cells were detected. Iron deposition was detected in 8 specimens (42%; 95% confidence intervals = 20-67%). The samples with iron deposition tended to have more macrophages than those without (666 ± 313 vs. 478 ± 174 cells/mm 2 ; P = 0.11). T-cells were clustered on the luminal side of the endothelial surface, on the vessel-wall, and in the perivascular regions. There was no correlation between T-lymphocyte load and iron deposition (P = 0.88). No macrophages and lymphocytes were detected in STA controls. Conclusion: T-lymphocytes were present in bAVM specimens. Unlike macrophages, the load and location of T-lymphocytes were not associated with iron deposition, suggesting the possibility of an independent cell-mediated immunological mechanism in bAVM pathogenesis.

Distinctive distribution of lymphocytes in unruptured and previously untreated brain arteriovenous malformation

OBJECTIVE
To explore new treatment modalities for complex intracranial aneurysms.

METHODS
Under general anesthesia, intracranial aneurysm parent artery remodeling surgery was performed along with repeated immediate intraoperative cerebral angiogram to verify the effect of revascularization and therefore adjust the operation plan accordingly.

RESULTS
Aneurysm was successfully clipped without injuries of vascular branches. Prognosis was excellent.

Complex hybrid surgery is an ideal option for parent artery remodeling of complicated intracranial aneurysms.

[First domestic case of intracranial aneurysm parent artery remodeling hybrid surgery].

Objectives Ephrin type B receptor 4 (EphB4, Eph receptor) selectively binds ephrin B2 (Eph ligand). EphB4/ephrin B2 is involved in embryonic vessel development, vascular remodelling and pathological vessel formation in adults (including tumour angiogenesis). Binding of vascular endothelial growth factor (VEGF)-A to the endothelial-specific receptor VEGF receptor-2 is the main extracellular signal triggering angiogenic response. Little is known about the role of EphB4/ephrin B2 during angiogenesis and arteriovenous plasticity in cerebral arteriovenous malformation (cAVM). This study investigated EphB4 and ephrin B2 expression in cAVM. Methods Haemorrhagic (H-AVM) and nonhaemorrhagic (NH-AVM) specimens of AVM nidus, obtained after microsurgical cAVM resection, and normal superficial temporal artery (STA) specimens, were analysed retrospectively. VEGF-A, EphB4 and ephrin B2 expression were studied by immunohistochemistry and immunoblotting. Results In cAVM (10 H-AVM; 10 NH-AVM), VEGF-A was immunocytochemically localized to endothelial cells; strong endothelial cell staining was found for EphB4 in veins and ephrin B2 in arteries. Normal STA (n = 10) did not express EphB4 or ephrin B2. EphB4 and ephrin B2 expression was greater in H-AVM than in NH-AVM. Conclusions Endothelial cells are more active in H-AVM than NH-AVM. EphB4 and ephrin B2 play important roles in neovascularization and arteriovenous differentiation/plasticity. These data provide new insights into the aetiology of cAVM and lay a foundation for further study. The notch pathway induced by VEGF-A may be a key signalling pathway in this process.

Ephrin B2 and EphB4 selectively mark arterial and venous vessels in cerebral arteriovenous malformation

Background and objective Mirror-like intracranial aneurysms (MirAn) occur symmetrically at the corresponding intracranial arteries and are a subgroup of multiple intracranial aneurysms. The aim of this study was to analyze the risk factors, treatment, and prognosis of MirAn. Methods We retrospectively analyzed 43 cases of MirAn diagnosed between January 2000 and December 2009. The control groups comprised patients with non-mirror-like multiple aneurysms (nMirAn) and single aneurysms (SingAn). Sex, age, localization of MirAn, hypertension, diabetes, smoking, and rupture were identified as potential risk factors for MirAn. Results The male to female ratio of the MirAn patients was 1.0:5.1, which was significantly different from that of the nMirAn patients (1.0:1.9, P=0.037) and SingAn patients (1.0:1.3, P<0.001). There was no difference in age (P=0.8741), smoking (P=0.301), diabetes (P=0.267), or hypertension (P=0.874) between the MirAn and nMirAn patients. The aneurysms in 28 MirAn patients (65.1%) involved the internal carotid-posterior communicating arteries; in these patients, the rupture risk was significantly higher for larger aneurysms compared with smaller aneurysms (P<0.05). Conclusion More women suffered from MirAn than nMirAn or SingAn. The most common MirAn sites were the internal carotid-posterior communicating arteries. Our results suggest that MirAn was not associated with age, smoking, hypertension, or diabetes.

A comparative study of 43 patients with mirror-like intracranial aneurysms: risk factors, treatment, and prognosis

Objective To screen differential genes expression in brain arteriovenous malformations (AVMs) with the help of genome microarray techniques in order to identify the pathogenesis of AVMs.Methods 9 samples taking from AVMs patients received surgical therapy and 9 control brain vessel samples from temporal lobectomy for the treatment of medically intractable seizures were collected.The total RNA was isolated and transcribed into cDNA reversely.And the synthesized cRNA was hybridized with human genome oligo microarray after labeling with Cy3.The SAM (Significant Analysis of Microarray) software was used to screen the differentially expressed gene and those genes were analyzed by molecule annotation system (MAS) 3.0.RT-PCR technique was used to test the differentially expressed genes.Results 47 genes met the statistical significance criteria,and were identified as differentially expressed.Among them 37 genes were up-regulated and 10 genes were down-regulated.Those genes were majorly involved in the process such as cell adhcsion molecules,tight junction,regulation of actin cytoskeleton and MAKP signaling pathway.Conclusions Brain AVMs have significant differentially expressed genes in contrast to vessels from the control samples.Multiple genes and signaling pathways may be involved in the process of AVMs' genesis and development.The up-regulated genes VCAN,SPARC,ARHGAP18 and down-regulated gene DUSP2 may have an important significance in the process of AVM's genesis and development. 
 
Key words: 
Brain arteriovenous malformation ;  Genome microarray ;  RT-PCR

Screen of differential genes expression in brain arteriovenous malformation with application of genome microarray techniques

To compare the diagnostic value of transcranial color‐coded real‐time sonography and contrast‐enhanced color‐coded sonography in detection and characterization of intracranial arteriovenous malformations.

Comparison of Transcranial Color‐Coded Real‐time Sonography and Contrast‐Enhanced Color‐Coded Sonography for Detection and Characterization of Intracranial Arteriovenous Malformations

Intracranial hemorrhage from moyamoya disease during pregnancy and puerperium

OBJECTIVE
To explore the expression and role of Caveolin-1 in the angiogenesis of cerebral arteriovenous malformation (AVM).

METHODS
A total of 55 fresh AVM samples at Affiliated Hospital, Inner Mongolia Medical University and Beijing Tiantan Hospital from August 2013 to May 2014 were collected to test the expressions of Caveolin-1, vascular endothelial growth factor (VEGF), vascular endothelial growth factor-receptor 2 (VEGF-R2) and endothelial nitric oxide synthase (eNOS) by immunohistochemistry and Western blot. And the relationship between the expressions of Caveolin-1 and VEGF, VEGF-R2 and eNOS was analysed.

RESULTS
The expression rates of Caveolin-1, VEGF, VEGF-R2 and eNOS in human AVM were 100%, 87.27%, 76.36% and 85.45%. And the values were significantly higher than those in normal superficial temporal artery. Western blot showed that the expressions of Caveolin-1, VEGF, VEGF-R2 and eNOS in hemorrahge AVM were higher than those in non-hemorrahge counterpart (P < 0.05). The expressions of Caveolin-1, VEGF, VEGF-R2 and eNOS were consistent.

Caveolin-1 plays a positive regulatory role in the angiogenesis of AVM through the PI3K/Akt signaling pathway. In cerebral AVM, Caveolin-1 plays an important role in occurrence, progression, hemorrahge and degradation of brain AVM.

[Expression and role of Caveolin-1 in the angiogenesis of cerebral arteriovenous malformation].

In this study, we extracted total RNA from 15 intracranial aneurysms and 17 superficial temporal artery samples, then performed genome-wide expression profiling using the Affymetrix U133 Plus 2.0 GeneChip. Genes that were differentially expressed between intracranial aneurysms and arterial samples were identified using significance analysis for microarrays, and the expression patterns of three randomly-selected genes were verified by real-time polymerase chain reaction analysis. We identifi ed 3 736 differentially-expressed genes out of the 47 000 assayed transcripts. A total of 179 genes showed a >10-fold change in expression between the aneurysms and the arterial samples. Genes involved in the proliferation, migration, and apoptosis of vascular muscle cells, atherosclerosis, extracellular matrix disruption, and inflammatory reactions were associated with the formation of intracranial aneurysms. There were no significant differences in gene expression profile between unruptured and ruptured aneurysms.

Abstract Objective: Protein kinase B (PKB/Akt), which is phosphorylated and activated by upstream activators, exerts critical neuroprotective effects by phosphorylating downstream targets after traumatic brain injury (TBI). Studies on the regulation of Akt will be crucial for our understanding of neuronal survival. The goal of this study is to investigate the effects of carboxyl-terminal modulator protein (CTMP) on phosphorylation of Akt and neurological function in a mouse model of TBI. Methods: Traumatic brain injury in mice was performed by a controlled cortical impact device. The expression of Akt, phospho-Akt, and CTMP was examined in the injured cortices by immunohistochemistry and Western blot analysis. To determine the effects of CTMP, small interfering RNAs (siRNAs) directed against CTMP were injected in mice with TBI, and the expression of phosphorylated Akt and neurological function were evaluated. Results: Phospho-Akt significantly increased at 4 hours post-TBI in the nucleus (P < 0·01) and remained at high levels until 72 hours after TBI, as shown by Western blot analysis. In the cytosol, the expression of phospho-Akt reached its peak at 4 hours post-TBI, but decreased markedly at 24 hours and maintained below pre-TBI levels until 72 hours post-TBI. Interestingly, the expression of CTMP significantly increased 4 hours after TBI (P < 0·01) and sustained those levels until 72 hours without dramatic changes. Treatment with CTMP siRNA effectively augmented the phosphorylation of Akt and significantly improved the neurological functional recovery up to 28 days post-TBI. Conclusion: We conclude that Akt is phosphorylated and translocated to nucleus after TBI to exert neuroprotective effects. However, CTMP is simultaneously triggered to inhibit the phosphorylation of Akt. Inhibition of CTMP by siRNA improves the recovery of neurological functions after TBI.

Small interfering RNA directed against CTMP reduces acute traumatic brain injury in a mouse model by activating Akt

Introduction Intracranial arteriovenous malformations (AVMs) are associated with high morbidity and mortality. Modern microsurgery has improved the results of surgical treatment of AVMs; however, the treatment of AVMs, particularly eloquently located AVMs, still carries a high risk. Functional MRI (fMRI) has been reported to be used for the preoperative evaluation of AVMs in small case series. The purpose is to identify the utility and efficacy of fMRI-guided microsurgery of AVMs in a large randomised controlled trial. Methods and analysis The study is a prospective, randomised controlled clinical trial. This study will enrol a total of 600 eligible patients. These eligible patients will be randomised to the standard microsurgery group and the fMRI-guided microsurgery group in a 1:1 ratio. Patient baseline characteristics and AVM architecture and characteristics will be described. In the fMRI-guided group, fMRI mapping of an eloquent cortex in all AVMs will be identified. Surgical complications and outcomes at pretreatment, post-treatment, at discharge and at 1-month, 3-month and 6-month follow-up intervals will be analysed using the modified Rankin Scale (mRS). This trial will determine whether fMRI-guided microsurgery could improve outcomes in patients with AVMs and also identify the safety and efficacy of fMRI-guided microsurgery. Ethics and dissemination The study protocol and written informed consent were reviewed and approved by the Institutional Review Board of Beijing Tiantan Hospital Affiliated to Capital Medical University (ky2012-016-02). Study findings will be disseminated in the printed media. Trial registration number ClinicalTrials.gov NCT01758211.

Functional MRI-guided microsurgery of intracranial arteriovenous malformations: study protocol for a randomised controlled trial

Objective: To determine whether the risk of arteriovenous malformation (AVM) rupture is increased during pregnancy and puerperium. Methods: Participants included 979 female patients with intracranial AVM admitted to Beijing Tiantan Hospital between 1960 and 2010. Two neurosurgery residents reviewed medical records for each case. Of them, 393 patients with ruptured AVM between 18 and 40 years of age were used for case-crossover analysis. Number of children born and clinical information during pregnancy and puerperium were retrieved to identify whether AVM rupture occurred during this period. Results: Of the 979 women, 797 hemorrhages occurred during 25,578 patient-years of follow-up, yielding an annual hemorrhage rate of 3.11%. The annual AVM hemorrhage rate in patients aged 18 to 40 years (n = 579) was 2.78%, lower than the rate in other age groups (odds ratio = 0.75, 95% confidence interval 0.65–0.86, p < 0.05). Of the 393 patients with rupture of AVM aged 18 to 40 years, 12 hemorrhages occurred in 12 patients over 452 pregnancies, yielding a hemorrhage rate of 2.65% per pregnancy or 3.32% per year. Among the remaining 381 patients, 441 hemorrhages occurred during 10,627 patient-years of follow-up, yielding an annual hemorrhage rate of 4.14%. The odds ratio for rupture of AVM during pregnancy and puerperium, compared with the control period, was 0.71 (95% confidence interval 0.61–0.82). Conclusions: No increased risk of hemorrhage was found in patients with cerebral AVM during pregnancy and the puerperium. We therefore would not advise against pregnancy in women with intracranial AVM.

Risk of cerebral arteriovenous malformation rupture during pregnancy and puerperium

Background Microscope‐integrated near‐infrared indocyanine green video angiography (ICG‐VA) has been used in neurosurgery for a decade. This study aimed to assess the value of intraoperative indocyanine green (ICG) video angiography with Flow 800 software in cerebrovascular surgery and to discover its hemodynamic features and changes of cerebrovascular diseases during surgery. Methods A total of 87 patients who received ICG‐VA during various surgical procedures were enrolled in this study. Among them, 45 cases were cerebral aneurysms, 25 were cerebral arteriovenous malformations (AVMs), and 17 were moyamoya disease (MMD). A surgical microscope integrating an infrared fluorescence module was used to confirm the residual aneurysms and blocking of perforating arteries in aneurysms. Feeder arteries, draining veins, and normal cortical vessels were identified by the time delay color mode of Flow 800 software. Hemodynamic parameters were recorded. All data were analyzed by SPSS version 18.0 (SPSS Inc., USA). T‐test was used to analyze the hemodynamic features of AVMs and MMDs, the influence on peripheral cortex after resection in AVMs, and superficial temporal artery to middle cerebral artery (STA‐MCA) bypass in MMDs. Results The visual delay map obtained by Flow 800 software had more advantages than the traditional playback mode in identifying the feeder arteries, draining veins, and their relations to normal cortex vessels. The maximum fluorescence intensity (MFI) and the slope of ICG fluorescence curve of feeder arteries and draining veins were higher than normal peripheral vessels (MFI: 584.24±85.86 vs. 382.94±91.50, slope: 144.95±38.08 vs. 69.20±13.08, P <0.05). The arteriovenous transit time in AVM was significantly shorter than in normal cortical vessels ((0.60±0.27) vs. (2.08±1.42) seconds, P <0.05). After resection of AVM, the slope of artery in the cortex increased, which reflected the increased cerebral flow. In patients with MMD, after STA‐MCA bypass, cortex perfusion of corresponding branches region increased and local cycle time became shorter. Conclusion Intraoperative ICG video angiography combined with hemodynamic parameter analysis obtained by Flow 800 software appears to be useful for intraoperative monitoring of regional cerebral blood flow in cerebrovascular disease.

Clinical values of intraoperative indocyanine green fluorescence video angiography with Flow 800 software in cerebrovascular surgery

OP12.05: The analysis of fetal echocardiographic reference value and study on relationship of these measurements with gestational age (I)

P04.15: The analysis of fetal echocardiographic reference value in normal fetus and study on relationship of these measurements with gestational age (II)

The role of the sonic hedgehog signaling pathway in early brain injury after experimental subarachnoid hemorrhage in rats

OBJECTIVE
To explore the relationship between angio-architectures of cerebral arteriovenous malformations (AVM) and hemorrhage.

METHODS
A total of 55 consecutive surgical cases of AVM were collected in August 2010 to May 2011 at Beijing Tiantan Hospital. There were 34 males and 21 females with an average age of 32.5 years (range: 3 - 59). The initial symptoms included bleeding (n = 20), epilepsy (n = 21), headache (n = 7), neurological dysfunctions (n = 6) and others (n = 1). The relationship between size, location, type of feeding artery, type of draining vein, complicated venous aneurysm and hemorrhage was analyzed by single factor test.

RESULTS
The cases of AVM fed by perforators, located in basal ganglia and post-cranial fossa, with small size, exclusively deep drainage and complicated venous aneurysm were more likely to present with hemorrhage.

The hemorrhage of AVM is significantly correlated with many factors, such as the type of feeding artery, size and location of AVM, the type of draining vein and complicated venous aneurysm. But the number of draining vein is irrelevant.

[Correlations of angio-architectural factors with cerebral arteriovenous malformation hemorrhage].

Abstract Objective: Apoptotic cell death is an important factor influencing the prognosis after traumatic brain injury (TBI). Akt/GSK-3beta/beta-catenin signaling plays a critical role in the apoptosis of neurons in several models of neurodegeneration. The goal of this study was to determine if the mechanism of cell survival mediated by the Akt/GSK-3beta/beta-catenin pathway is involved in a rat model of TBI. Methods: TBI was performed by a controlled cortical impact device. Expression of Akt, phospho-Akt, GSK-3beta, phospho-GSK-3beta, beta-catenin, phospho-beta-catenin were examined by immunohistochemistry and Western blot analysis. Double immunofluorenscent staining was used to observe the neuronal expression of the aforementioned subtrates. Terminal deoxynucleotidyl transferase-mediated uridine 5’-triphosphate-biotin nick end-labeling (TUNEL) staining was performed to identify apoptosis. Results: Western blot analysis showed that phospho-Akt significantly increased at 4 hours post-TBI, but decreased after 72 hours post-TBI. Phospho-GSK-3beta – phosphorylated by phospho-Akt – slightly increased at 4 hours post-TBI and peaked at 72 hours post-TBI. These changes in Phospho-GSK-3beta expression were accompanied by a marked increase in expression of phospho-beta-catenin at 4 hours post-TBI which was sustained until 7 days post-TBI. Double staining of phospho-Akt and NeuN revealed the colocalization of phospho-Akt positive cells and neuronal cells. In addition, double staining of phospho-Akt and TUNEL showed no colocalization of phospho-Akt cells and TUNEL-positive cells. Conclusion: Phosphorylation of Akt (Ser473) and GSK3beta (Ser9) was accelerated in the injured cortex, and involved in the neuronal survival after TBI. Moreover, neuroprotection of beta-catenin against ischemia was partly mediated by enhanced and persistent activation of the Akt/GSK3beta signaling pathway.

Activation of Akt/GSK-3beta/beta-catenin signaling pathway is involved in survival of neurons after traumatic brain injury in rats

In this study, we determined the expression levels of matrix metalloproteinase-2 and -9 and matrix metalloproteinase tissue inhibitor-1 and -2 in brain tissues and blood plasma of patients undergoing surgery for cerebellar arteriovenous malformations or primary epilepsy (control group). Immunohistochemistry and enzyme-linked immunosorbent assay revealed that the expression of matrix metalloproteinase-9 and matrix metalloproteinase tissue inhibitor-1 was significantly higher in patients with cerebellar arteriovenous malformations than in patients with primary epilepsy. The ratio of matrix metalloproteinase-9 to matrix metalloproteinase tissue inhibitor-1 was significantly higher in patients with hemorrhagic cerebellar arteriovenous malformations compared with those with non-hemorrhagic malformations. Matrix metalloproteinase-2 and matrix metalloproteinase tissue inhibitor-2 levels were not significantly changed. These findings indicate that an imbalance of matrix metalloproteinase-9 and matrix metalloproteinase tissue inhibitor-1, resulting in a relative overabundance of matrix metalloproteinase-9, might be the underlying mechanism of hemorrhage of cerebellar arteriovenous malformations.

Imbalance of matrix metalloproteinase-9 and matrix metalloproteinase tissue inhibitor-1 may contribute to hemorrhage in cerebellar arteriovenous malformations☆

To compare the diagnostic value of transcranial color Doppler sonography (TCCS) with contrast‐enhanced transcranial color Doppler sonography (CE‐TCCS) for the detection and characterization of intracranial aneurysms.

Comparison of transcranial color Doppler sonography without and with contrast enhancement for detection and characterization of intracranial aneurysms

OBJECTIVE
To explore the medium and long-term outcomes of patients with Moyamoya disease (MD) undergoing surgery and conservative treatment at a single institution and analyze the related prognostic factors.

METHODS
A retrospective review was conducted for 97 MD patients at Beijing Tiantan Hospital from January 2000 to December 2007. They were divided into 3 groups according to treatments: superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis (n = 31), indirect vascular revascularization group (n = 38) and conservative treatment group (n = 28). The primary follow-up events included death, recurrent cerebral hemorrhage, new cerebral infarction and transient ischemic attack (TIA).

RESULTS
All were available for analysis with the complete follow-up data. The average follow-up period of was 85 ± 38 months. In total, there were 6 deaths with all-cause mortality (6.1%). Among them, 5 (5.1%) patients died from recurrent cerebral hemorrhage. And 17 episodes of rebleeding occurred in 11 patients. Two episodes of intracranial hemorrhage were found in 4 patients. The risk of rebleeding was 17.5%. In the STA-MCA group, 23(74%) cases had excellent recovery, 5 cases fared worse and there was no death case. Among the patients undergoing indirect vascular revascularization, 28 cases recovered favorably, 4 cases progressed and 3 cases died. In the conservative treatment group, 17 patients recovered favorably, 7 progressed, 9 experienced 15 episodes of rebleeding and 3 died. Multivariate Cox regression analysis showed that the method of treatment was an independent prognostic factor for MD and surgical revascularization was superior to conservative treatment. No correlation was found between the patient age, gender, familial history, unilateral or bilateral and prognosis (P > 0.05). Kaplan-Meier stroke risk analysis showed the risk of recurrent hemorrhage in the revascularization surgery group was lower than that in the conservative group. And no difference existed between STA-MCA and indirect arterial anastomoses.

Rebleeding is a major cause of poor prognosis, mobility and mortality in MD patients. Surgical revascularization offers better long-term outcomes than conservative treatment. And direct arterial anastomoses may decrease recurrent hemorrhage effectively.

[Experience of 97 patients with moyamoya disease: long-term follow-up at a single center].

Objective To investigate the long term outcomes after conservative and surgical treatment for haemorrhagic moyamoya disease. Methods 97 consecutive patients with haemorrhagic moyamoya disease from 1997 to 2009 were enrolled in this study (mean age 31±10 years; range 5–56 years). We reviewed the clinical charts and radiographs of patients at the first bleeding episode. Follow-up was obtained prospectively by questionnaires and radiographic examinations. Outcomes were compared based on initial treatment (conservative vs surgical). Results After a median follow-up of 7.1 years, 21 of the 97 (21.7%) patients developed a second episode of bleeding, and six patients (6.2%) died of intracranial rebleeding. The median interval from initial episode to subsequent rebleeding was 9.1 years (0.1–23.2 years). 17 of 43 (37.1%) conservatively treated patients and four of 54 (7.4%) surgically treated patients experienced a rebleeding event (OR 8.1; 95% CI 2.4 to 26.8; p<0.001). There was a difference in the Kaplan–Meier curve of rebleeding between the two groups (Breslow test p=0.047; log rank test p=0.05). The rebleeding ratio in patients who underwent direct bypass was lower than that in patients treated with indirect bypass alone (0% vs 28.5%, 95% CI 1.0 to 1.9; p=0.002). No significant correlation was found between rebleeding and the patient's age, sex, location of haemorrhage, hypertension status or presence of cerebral aneurysm (p>0.05). Conclusions There is a high risk of rebleeding after the first haemorrhagic episode in Chinese patients with haemorrhagic moyamoya disease. Revascularisation surgery can improve regional blood flow and have greater efficacy at preventing rebleeding than conservative treatment.

Long term outcome after conservative and surgical treatment of haemorrhagic moyamoya disease

Regional cerebral perfusion and ischemic status after standard superficial temporal artery–middle cerebral artery (STA-MCA) bypass surgery in ischemic cerebrovascular disease

OBJECTIVE
To explore the changes of regional cerebral blood flow at the site of anastomosis of superficial temporal artery-middle cerebral artery (STA-MCA) to guide the preventive treatment of symptomatic hyperperfusion.

METHODS
A total of 35 patients with Moyamoya disease were recruited from Beijing Tiantan Hospital. There were 22 males and 13 females with an average age of 29 years (range: 5 - 55). And there were 10 children. Regional cortical blood flow (rCBF) was measured by Laser Doppler flowmeter (LDF) before, after and at Day 1, 2, 3, 4, 5 and 6 postoperation of STA-MCA anastomosis. The probe of LDF was implanted adjacent to the area of anastomosis for 144 hours to record the values of rCBF.

RESULTS
The baseline LDF values of cortical rCBF near the area of anastomosis were (69 ± 24) PU before anastomosis, (66 ± 74) PU immediately after anastomosis, (123 ± 23) PU at the conscious time after anesthesia postoperation, (297 ± 17) PU at Day 1 postoperation. And the LDF values of the following 5 days were (302 ± 31), (317 ± 26), (272 ± 46), (363 ± 54) and (367 ± 24) PU respectively.

As a safe and effective treatment for Moyamoya disease, STA-MCA anastomosis has great risks for symptomatic hyperperfusion. The highest risk time for hyperperfusion is identified after STA-MCA.

[Studying change of regional cerebral blood flow after superficial temporal artery-middle cerebral artery anastomosis during acute stage in patients with Moyamoya disease].

Traditional acupuncture triggers a local increase in adenosine in human subjects.

M330 THE CONSEQUENCE OF ABNORMAL CYTOLOGY RESULT IN GESTATION PERIOD

W183 MIRROR SYNDROME: DIVERSE ETIOLOGY AND MATERNAL FETAL FEATURES

Objectives: Transient postoperative hyperperfusion may be the cause of the temporary neurologic deterioration (TND) frequently observed following superficial temporal artery-middle cerebral artery (STA-MCA) bypass surgery. The purpose of this study is to investigate the possible factors influencing postoperative temporary neurologic deterioration. 
 
Methods: The STA-MCA bypass surgery was performed in 13 patients with moyamoya disease and 9 patients with cerebrovascular occlusive disease. The diameter of the STA and MCA for anastomosis was measured and analyzed. Computed tomographic perfusion (CTP) was performed prior to the operation and on the third post-operative day to assess improvements in regional cerebral perfusion. 
 
Results: After surgery, five patients (22.7 %) with improvement of perfusion suffered TND such as dysphasia, motor deficit and sensory disturbance after surgery and 11 (50 %) patients with improvement of perfusion did not show temporary neurologic deterioration after surgery. There were six patients (27.3 %) without improvement of perfusion after surgery. The D-STA was 1.48 ± 0.92 mm in patients with TND, which was larger than the D-STA of 1.10 ± 0.14 mm in patients with improvement of perfusion and 1.08 ± 0.26 mm in patients without improvement of perfusion (P 0.05). 
 
Conclusions: The D-STA and D-MCA may influence the development of TND after STA-MCA bypass, but the TOT of the recipient arteries was not related to temporary neurologic deterioration.

Possible factors influencing postoperative temporary neurologic deterioration following standard superficial temporal artery-middle cerebral artery (STA-MCA) bypass surgery: diameter of STA and MCA (M4)

To analyze the reliability and clinical value of intraoperative ultrasound combined with neuronavigation for resection of intracranial cavernous malformations.

METHODS
From January 2007 to December 2009, 40 cases of intracranial cavernous malformations were operated under the application of intraoperative ultrasound combined with neuronavigation. There were 18 male and 22 female, aged 18 to 58 years, with a mean age of 34.5 years. Neuronavigation was used for all patients before operation to display the three-dimensional model of nervous system and lesions, so to design the operative approach and determine the scope of the incision. Lesions were allocated by real-time neuronavigation in order to continuously verify the accuracy of operative approach during the operation, supplemented by real-time monitoring of intraoperative ultrasound to guide the process of surgery and determine the extent of resection of lesions.

RESULTS
The registration error of neuronavigation was 1.3 - 3.2 mm, with an average of 2.0 mm. All the patients' three-dimensional model of nervous system and lesions were satisfactorily displayed, and the area of lesions were all accurately located. Structural brain-shifts occurred in 4 cases in the remove process of the lesion, with shift degree 5.0 - 10.0 mm, and were corrected by intraoperative ultrasound. All lesions were well displayed by intraoperative ultrasound. Gross total resection was achieved in all patients, with no patient infected or dead. Neurological deterioration was seen in 2 patients, the morbidity was 5.0%.

The combination of neuronavigation and intraoperative ultrasound for resection of intracranial cavernous malformations can provide valuable intraoperative informations of the location and resection level of the lesion, thereby maximize the accuracy of lesion localization and the extent of resection, with less complications and enhanced efficacy of the surgery.

[Application of intraoperative ultrasound combined with neuronavigation for resection of intracranial cavernous malformations in minimally invasive neurosurgery].

Evaluation of surgical microscope-integrated intraoperative near-infrared indocyanine green videoangiography during aneurysm surgery

Neurosurgery center of Beijing Tiantan Hospital, flagship of neurosurgery in China.

OBJECTIVE
To evaluate the microsurgical treatment for sylvian fissure arteriovenous malformations (AVMs).

METHODS
The clinical data of 94 sylvian fissure AVMs treated microsurgically was retrospectively collected. They were classified as medial, lateral, deep, anterior and simple AVMs according to the anatomic location of nidus in sylvian fissure.

RESULTS
Total lesion removal was achieved in all patients and it was confirmed by postoperative digital subtraction angiography. Transient neurological deficits, including slight hemiparesis (n = 5, 5.3%) and aphasia (n = 4, 4.3%), were documented. Another 2 patients (2.1%) presented with a postoperative epidural and an intracranial hematoma respectively. However, an excellent outcome was observed in all patients as indicated by the Karnofsky performance scale > 90.

The microsurgical treatment for sylvian fissure AVMs has been greatly restrained by the involvement of multiple brain functional regions and its anatomic complexity. A more aggressive approach is recommended.

[Microsurgical treatment for sylvian fissure arteriovenous malformations].

OBJECTIVE
To preliminarily explore the clinical characteristics and surgical outcomes of intracranial aneurysm.

METHODS
The data of 3322 cases of intracranial aneurysm from January 1955 to July 2009 were collected at our hospital for analysis. The clinical characteristics and surgical outcomes of patients with intracranial aneurysm were assessed. The surgical patients were divided into 2 groups by the date of admission: group A and group B. Such clinical characteristics as age, gender and Hunt-Hess grade at admission and first presentations were analyzed. The surgical outcomes were assessed by comparing the surgical complications between two groups.

RESULTS
Intracranial aneurysms were commonly diagnosed between 38 and 54 years old. Hemorrhage (84.89%), mass effect (8.13%) and non-hemorrhagic headache (5.18%) were the three initial common presentations and the male-to-female ratio was 0.875:1. There was no significant statistical difference in age distribution and gender ratio between two groups. According to the Hunt-Hess grade, the percentage of grades II, III and IV was lower in group B while the percentage of grades 0 and I higher than group A. No significant difference was found in the overall incidence of major post-operative complications between two groups (P > 0.05).

The major presentations of intracranial aneurysm are hemorrhage, mass effect and non-hemorrhagic headache. And the Hunt-Hess grades I and II patients account for a majority of aneurysms. Three most common locations of aneurysm are ICA-PCoA (internal carotid artery-posterior communicating artery), ACoA (anterior communicating artery) and MCA (middle cerebral artery). Giant aneurysm should be treated in the light of concrete conditions by choosing such a surgical approach as bypass.

[Clinical characteristics and surgical outcomes of intracranial aneurysm: a retrospective study of 3322 cases].

颅内动脉瘤是颅内动脉壁的异常突起,尸检发现率为0.2%～7.9%.颅内动脉瘤破裂所致蛛网膜下腔出血(SAH)约占70%,年发生率为6～35.3/10万[1].未破裂颅内动脉瘤指患者可能没有任何症状,只是在偶尔检查中被发现,也可能是因为瘤体占位效应引起的颅神经麻痹或脑干压迫症状而被发现[2].未破裂动脉瘤的三种治疗手段是观察、开颅手术夹闭和血管内介入.本文复习近年关于未破裂动脉瘤的国内外相关文献,就未破裂动脉瘤的自然史和治疗做一综述。

Color doppler hemodynamic study of the superficial temporal arteries in superficial temporal artery-middle cerebral artery (STA-MCA) bypass surgery for Moyamoya disease.

A single‐center study of hemorrhagic stroke caused by cerebrovascular disease during pregnancy and puerperium in China

OBJECTIVE
To evaluate the clinical practicability of integration of functional magnetic resonance imaging (fMRI) data into neuronavigation as a tool to localize the language area and their relationship with the lesion for the preoperative planning, intraoperative guidance and postoperative follow-up study of brain functions during minimally invasive surgeries in or adjacent to functional areas.

METHODS
Eighty eight patients with intracranial lesions located in or adjacent to the functional language area underwent fMRI (including examinations of lingual and visual function, and motor functions of the limbs and tongue). fMRI data was entered into a neuronavigation system for image fusion and preoperative registration and correction; minimally invasive neurosurgery was performed with fMRI navigation.

RESULTS
The shortest distance between the lesion and the functional cortex was less than 5 mm in 6 patients and was more than 5 mm but less than 10 mm in another 10 patients, respectively. 10 patients were recovered and improved in another 6 between 3 - 6 months after surgery, The follow-up time was between 3 months and 1 year. The morbidity rate was 6.8% (6/88). There was no postoperative mortality. Various brain areas were widely activated when the patients were reading and understanding the Chinese words. The unilateral speech functional maps were located in left Brodmann's 9, 46, 17, 18 and 19 areas.

fMRI-integrated neuronavigation can locate functional language areas and played an important role in intraoperative protection of functional lingual areas, execution of individualized therapeutic regimens, minimization of surgical complications and determination of prognosis. Total surgical resection was safe for lesions > 10 mm from functional lingual areas.

[The application of functional magnetic resonance imaging integrated neuronavigation in localization and lingual function protection].

Objective To evaluate the surgical effect of intraoperative combined use of B-ultrasound and indocyanine green angiography (ICGA) in the surgery of superficial cerebral arteriovenous malformations (AVMs). Methods Sixteen patients with superficial cerebral AVMs,admitted to our hospital from January 2009 to December 2009, were performed surgery with the help of intraoperative B-ultrasound and ICGA; the clinical data of these patients were retrospectively collected.The ability of intraoperative B-ultrasound and ICGA in distinguishing AVMs' vessels (draining veins,feeding and nidal arteries) from each other and from normal vessel was both evaluated.Results The combination of B-ultrasound and ICGA allowed accurate and real-time localization of the AVMs' nidus,helped to define the boundary and identify the draining veins and feeding arteries. Total lesion removal was achieved by 16 successful surgeries in 16 patients, which was confirmed by postoperative DSA.Conclusion The combination of B-ultrasound and ICGA in the surgery of superficial cerebral arteriovenous malformations allows accurate and real-time localization of the AVMs' indus and helps to assess the completeness of lesion removal, indicating its value in the surgery of superficial cerebral AVMs. 
 
Key words: 
Cerebral arteriovenous malformation; B-ultrasound; Fluorescein angiography

Intraoperative integration of B-ultrasound and indocyanine green angiography in the surgery of superficial cerebral arteriovenous malformations

OBJECTIVE
To describe the clinical manifestations of intracranial aneurysm in children and to evaluate the efficacy and safety of different therapeutic approaches for children with intracranial aneurysms.

METHODS
Clinical data of 23 pediatric patients with intracranial aneurysms diagnosed and treated at our hospital over the past 18 years were retrospectively reviewed. Follow-up data were also collected and analyzed.

RESULTS
Two patients received no further treatment. Surgery was performed in 16 patients. Among them, 15 achieved an excellent recovery and 1 died. 5 patients were treated with Guglielmi detachable coil (GDC). Aneurysm was successfully sealed off in one case and an excellent recovery achieved; remnant aneurysm was detected in two cases. One received trapping while another underwent aneurysmectomy. The patient died postoperatively. Another received neck clipping and resection. And the patient recovered well; two cases experienced aneurysm recanalization after interventional therapy. Among them, one received a second embolotherapy but it became recanalized again. And it was finally cured by aneurysmectomy.

Aneurysm surgery is proved to be a safe and effective treatment for children with intracranial aneurysm. Endovascular treatment of intracranial aneurysms with GDC is also shown to be effective and safe for pediatric patient with acute SAH. But a long-term follow-up study is required to determine the clinical outcome. Once a aneurysm remnant or recanalization occurs, a microsurgical management is recommended.

[Diagnosis and management of intracranial aneurysm in children].

OBJECTIVE
To review surgical outcomes in treating intracranial Giant arteriovenous malformations (AVMs). To find out the prognosis factors of surgical treatment.

METHODS
We collected 46 consecutive cases of giant AVMs treated at Beijing Tiantan Hospital, reviewed the radiological and Spetzler-Martin grading. 25 of the patients selected were male (54%), and 21 were female (46%), with a mean age of 30.6. The major presenting symptoms were seizures, headaches, hemorrhage and neurological deficits. According to the Spetzler-Martin Grading, 8 patients were Grade III, 22 were Grade IV, and 16 were Grade V. All patients received surgical treatment and postoperative DSA were performed. Clinical results and long term follow-up (KPS) were gathered for analysis.

RESULTS
One of the 35 patients who received postoperative DSA revealed residual AVMs. Among all patients, severe complications were observed in 9 patients, and 1 patient died in the hospital. Complications included hemiparalysis (15 cases), aphasia (6 cases), hemianopia (9 cases), cranial nerve dysfunction (5 cases), and seizure (5 cases). Normal perfusion pressure breakthrough (NPPB) was observed in 6 patients. After 6 - 108 months of follow-up, 33 of 37 survived follow-up patients presented normal function or minimal symptoms and ability to work or study, 4 patients died (2 were surgical-related).

Pre-surgical evaluation of every candidates and treatment choice are the determining factors in giant AVMs therapy. Microsurgery remains one of the most effective ways for eliminating giant cerebral AVMs, and the complication rate was acceptable. For giant cerebral AVMs located superficially or do not involve critical components, a good outcome can be expected through surgical resection.

[Surgical treatment of giant intracranial arteriovenous malformations].

BACKGROUND:The treatment of giant arteriovenous malformations (AVMs) remains a challenge in the neurosurgical field. Microsurgery is one of the most effective ways for eliminating giant cerebral AVMs. OBJECTIVE:To review surgical outcomes in treating the disease, and form conclusions regarding the indications for and outcomes of surgical treatment in giant intracranial AVMs. METHODS:We studied 40 consecutive cases of giant AVMs treated in Beijing Tiantan Hospital between 2000 and 2008. The radiologic and clinical features were analyzed. The Spetzler-Martin grading system was used to classify the patients. All patients were surgically treated, and the final outcomes of the patients were gathered for analysis. RESULTS:The major presenting symptoms were seizures, headaches, hemorrhage, and neurological deficits. The mean AVM diameter was 6.3 cm. According to the Spetzler-Martin grading system, 5 patients had grade III lesions, 21 had grade IV lesions, and 14 had grade V lesions. Out of the total 40 patients, 31 (77.5%) demonstrated excellent or good outcome. Complications included hemiparalysis, aphasia, hemianopia, cranial nerve dysfunction, and seizures. After follow-up, 27 of 30 (90%) surviving patients presented normal function or minimal symptoms. CONCLUSION:Presurgical evaluation of every candidate and treatment choice is the determining factor in therapy for giant AVMs. For giant cerebral AVMs located superficially or not involving critical components, a good outcome can be expected through surgical resection. The obliteration and recurrence rates were satisfying, and the complication rate was acceptable.

Surgical Treatment of Giant Intracranial Arteriovenous Malformations

OBJECTIVE
To evaluate the surgical effects of such adjuvant techniques as type B ultrasound, neuronavigation and intraoperative indocyanine green video-angiography (ICGA) on intracranial arteriovenous malformation (AVM) surgery.

METHODS
From January to October 2009, 43 AVM patients treated at our center were retrospectively studied, including 26 males and 17 females with an age range of 8 to 53 years old (mean: 26.51). Type B ultrasound, neuronavigation or ICGA were employed during surgical procedures in all cases. Intraoperative findings were compared with those of postoperative digital subtraction angiography (DSA) or computed tomography angiography (CTA). And the clinical outcomes were evaluated.

RESULTS
As confirmed by postoperative DSA or CTA, the lesions of all 43 patients were totally removed. Only 3 patients (7.0%) suffered from new neurological deficits, including homonymous hemianopia in 2 patients and diplopia in 1. And the Karnofsky performance scale was higher than 80 for each patient.

The feeding arteries and draining veins can be differentiated by intraoperative type B ultrasound, neuronavigation and ICGA. All three adjuvant techniques can define the lesion boundary. However, each of them has its own benefits and drawbacks. It indicates that the combination of two or more techniques may help to improve the quality and outcome of surgical procedures.

[Strategy for assisted cerebral arteriovenous malformation surgery].

OBJECTIVE
To identify the causes and risk factors of postoperative complications in elderly patients receiving meningioma removal.

METHODS
A total of 320 elderly patients received meningioma removal at our hospital between 1998 to 2007. Among them, 90 patients, aged 65 to 82 years old, developed postoperative complications.

RESULTS
The diagnoses were confirmed by pathological findings. The average diameter of tumors was 5 cm. The average operative duration was 4.8 hours. Local or systemic complications occurring in this group of patients included new-onset neurological deficit (n = 37), prolonged coma (n = 16), central nervous system infection (n = 14), postoperative hematoma (n = 10), cerebral infarction (n = 7), CSF leakage (n = 12), pulmonary infection (n = 18), deep vein thrombosis or pulmonary embolism (n = 15), gastrointestinal bleeding (n = 3) and myocardial infarction (n = 2). Twelve patients died within 30 days after operation. Postoperative complications prolonged hospitalization and increased medical costs.

Large size of tumors, difficulties in resection and preexisting conditions are primary causes of a high rate of operative morbidity in elderly patients receiving meningioma removal.

[Ninety cases of postoperative complications in elderly patients after surgical removal of meningiomas].

Aluminum nanoparticles enhance anticancer immune response induced by tumor cell vaccine

Standard superficial temporal artery-middle cerebral artery (STA-MCA) bypass surgery is an effective treatment for moyamoya disease, but recent evidence suggests that postoperative cerebral hyperperfusion can occur. In this study, the trendline of changes in regional cerebral blood flow (rCBF) after surgery were continually monitored near the site of anastomosis in order to investigate both the efficacy of the procedure for improving rCBF and the possible risk of hyperperfusion.

METHODS
Standard STA-MCA bypass surgery was performed on 13 patients. rCBF was measured continually using laser Doppler flowmetry (LDF) until the 5th day after the operation with the LDF probe implanted adjacent to the area of the anastomosis. The trendline of rCBF changes postoperatively was recorded for the analysis performed using SPSS 13.0.

RESULTS
The baseline LDF value of cortical rCBF was (84.68 + or - 14.39) perfusion unit (PU), which was linear relative to absolute perfusion volume before anastomosis and (88.90 + or - 11.26) PU immediately after anastomosis (P > 0.05). The value changed significantly from before to after anastomosis (P < 0.05); it was (417.72 + or - 21.35) PU on the 1st day after surgery, and (358.99 + or - 18.01) PU, (323.46 + or - 17.38) PU, (261.60 + or - 16.38) PU and (375.72 + or - 18.45) PU on the following 4 days, respectively. The rCBF decreased gradually from the 2nd day until the 4th postoperative day, but still was at a high level (P < 0.05). However, on the 5th postoperative day the rCBF increased again to the second highest level, which was significantly different compared with the baseline value (P < 0.05), but not significantly different compared with the values on the other 4 days (P > 0.05).

STA-MCA anastomosis improves the cerebral blood supply significantly in the early stage after surgery, however, the risk of symptomatic hyperperfusion may exist, which may possibly occur on the 1st day and 5th day after surgery. A LDF is useful for postoperative monitoring for both the efficacy of bypass and possible risk of neurologic deterioration or bleeding from hyperperfusion.

Laser Doppler flowmeter study on regional cerebral blood flow in early stage after standard superficial temporal artery-middle cerebral artery bypass surgery for moyamoya disease.

Surgical resection of a rare giant intracranial arteriovenous fistula.

Objective To observe the histopathological and ultrastructural changes,alterations in the expressions of type Ⅳ collagenases(MMP-2 and MMP-9),the tissue inhibitors(TIMP-1 and TIMP-2)and intercellular adhesion molecule-1(ICAM-1)in the internal carotid arteries(ICAs)of patients with moyamoya disease(MD),and explore the pathogenesis of MD.Methods The bilateral ICAs were obtained during autopsy from two MD patients.HE staining and Weigert staining was used for histological observation,and transmission electron microscopy Was employed to observe the ultrastructure of the ICAS.The expression of ICAM-1 in the ICAs was detected using immunohistochemical staining,and the mRNA expressions of MMLP-2,MMP-9,TMP-1 and TIMP-2 were assayed using in situ hybridization.The ICA specimens from two patients died from non-vascular diseases were used as the control.Restilts HE staining revealed thinning of the ICAs of the MD patients with luminal stenosis,obstruction and calcification.Weigert staining identified fibrous thickening of the intima,thinning and fragmentation of the elastica interna(EI)and elastica externa(EE),degenerafion of the smooth muscle cells in the media,and thinning and local exfoliation of the adventitia.Immunohistochemistry showed ICAM-1 expression in the ICAs of both MD and control patients,but the MD patients exhibited a stronger ICAM-1 positivity in the ICAs localized primarily in the tunica intima.The ICA wall was positive for MMP-9 mRNA expression,which Was especially intense in the elastica intema,as shown by in situ hybfidization.Conslusions The high expression of MMP-9 and ICAM-1,destruction of the elastic layer and adventitia,and collapse of the vascular wall result in luminal stenosis or everi obstruction of the ICAs,which can be associated with the occuITence of MD. 
 
Key words: 
Moyamoya disease; Internal carotid artery; ICAM-1; MMP-9

Histological changes and ICAM-1 and TMMP-9 expressions in the internal carotid arteries of patients with moyamoya disease

OBJECTIVE
To summarize the experience in surgical treatment for middle cerebral aneurysm (MCAA), and results and prognosis thereof.

METHODS
The clinical data, including location, size, main presentations, and Hunt & Hess grade, of 55 consecutive MCAA patients were prospectively analyzed. The surgical outcome was evaluated by Glasgow Outcome Scale (GOS). Follow-up was conducted for 23 (11-19) months.

RESULTS
According to the Hunt & Hess classification, there were 9 cases in grade 0, 12 cases in grade I, 23 cases in grade II, 8 cases in grade III, 2 cases in grade IV, and 1 case in grade V at admission. Headache (42 cases), vomiting (22 cases), and hemiplegia (11 cases) were the top 3 common presentations. Pterional craniotomy was adopted in all cases. Proximal to distal lateral fissure approach was used in 23 cases, distal to proximal approach in 27 cases, and trans-hematoma approach in 5 cases. There were 45 cases treated by direct neck-clipping (clipping and resecting in 6 cases), 7 cases by parent artery reconstruction, and 3 cases by wrapping by muscle. The location of MCAA was at the bifurcation in 37 cases (37.2%), at proximal middle cerebral artery (MCA) in 13 cases (23.6%), and at distal MCA in 5 cases (9.1%). The largest diameter was 15.5 (3-70) mm. The main postoperative complications included hemiplegia (12 cases), aphasia (3 cases), and seizure (2 cases). Follow-up showed good recovery in 45 cases, moderate disability in 5, and severe disability in 5 according to GOS. There was no vegetative state, death, and recurrence.

With modern imaging techniques, perfect surgical plan, appropriate surgical approach, and careful microsurgical techniques, treatment of MCAA can be perfected and achieve satisfying outcome.

OBJECTIVE
To evaluate the effects of surgical microscope-based indocyanine green videoangiography (ICGA) in aneurysm surgery and compare the values of ICGA and postoperative digital subtraction angiography (DSA).

METHODS
101 patients with intracranial aneurysm underwent clipping of 113 aneurysms. A microscope-integrated light source containing infrared excitation light illuminated the operating field. The dye ICG was injected intravenously, and the intravascular fluorescence was recorded by a video camera attached to the microscope with optical filtering to block ambient and laser light for collection of only ICG-induced fluorescence. All patients underwent DSA 6-13 days post-operatively. The results of patency of parent, branching, and perforating arteries and documentation of aneurysm obliteration shown by ICGA and DSA were compared.

RESULT
219 times of ICGA was performed in these 101 patients with excellent image quality and resolution, allowing intra-operative real-time assessment of the cerebral circulation. The ICG angiographic results could be divided into arterial, capillary, and venous phases, comparable to those observed with DSA. In all cases, the postoperative angiographic results corresponded to the intraoperative ICG video angiographic findings. In 3 cases, the information provided by intraoperative ICGA significantly changed the surgical procedure.

Simple and repeatable, microscope-based ICGA provides real-time information about vessels and aneurysm sac. This technique may be useful during routine aneurysm surgery as an adjunct to intraoperative microvascular Doppler ultrasonography and DSA.

[Effects of surgical microscope-based indocyanine green videoangiography during aneurysm surgery].

Abstract Objective: To analyse the imaging and clinical prognostic indicators for early hematoma enlargement after spontaneous intracerebral hemorrhage (ICH). Methods: In 126 patients, spontaneous ICH was diagnosed by computed tomography (CT) within 4 hours of disease onset. Repeat CT was performed after 24 hours to detect the development of hematoma enlargement. A regression equation was obtained by first examining the significance of correlations between possible risk factors and early hematoma progression, followed by verification using multivariate stepwise regression. Results: The incidence of early hematoma enlargement after spontaneous ICH was 25.4%, and the significant prognostic indicators were CT hematoma inhomogeneity, degree of consciousness impairment on admission and time between disease onset and initial CT. In addition, the characteristic 'hematoma enlargement border' on CT has important prognostic value in early hematoma enlargement. Conclusion: Clear prognostic indicators exist for early hematoma enlargement after spontaneous ICH, suggesting that hematoma inhomogeneity has important implications for predicting ICH progression, and we discovered as well as defined the 'hematoma enlargement border', an imaging characteristic of early hematoma enlargement.

Imaging and clinical prognostic indicators for early hematoma enlargement after spontaneous intracerebral hemorrhage

OBJECTIVE
To compare the effects of surgical and non-surgical treatments for high-grade intracranial arteriovenous malformation (AVM), identify the determinants of neurological function deterioration after surgery, and calculate the annual hemorrhage rate.

METHODS
98 high-grade intracranial AVM patients underwent surgery, and 44 high-grade intracranial AVM patients underwent conservative treatment. Follow-up was conducted on 141 of these 142 patients for (54+/-36) (6-118) months. MRI and DSA were conducted before and/or after treatment on most of the patients. Glasgow outcome score (GOS) was used to evaluate the neurological functions early and more then 6 months after discharge. The clinical data of these 142 patients were retrospectively analyzed. The annual hemorrhage rate associated with these lesions was calculated.

RESULTS
The annual hemorrhage rate of these 142 patients was 2.1%. The integrated rate of late disability and mortality of the operative group was 10.1%, remarkably higher than that of the non-operative group (25.0%). AVM size, adjacent brain functional region, Spetzler-Martin grade, deep perforating arterial supply, and intra-operative bleeding volume were significantly correlated with early and permanent neurological function deficits.

The long-term outcome of operatively managed intracranial high-grade AVMs is superior to that of the non-operatively treated ones. Spetzler-Martin grade and deep arterial perforating supply are the most important determinants of neurological deficit after microsurgical resection of AVM.

[Long-term outcome of operatively and non-operatively managed high-grade intracranial arteriovenous malformations and factors influencing postoperative neurological deficits].

Objective To explore the significance of ultrasound in localization tumors and directing operation.Methods Intraoperative ultrasound findings in 204 patients with cerebral vascular disease were analyzed retrospectively.Feeding arteries and draining veins need to be distinguished from normal vessels in patients with arteriovenous malformation(AVM).The findings of cavernous of intraoperative neuronavigator and intraoperative ultrasound before,during and after the resection were respectively compared.Results ①98% cerebral vascular disease can be displayed by intraoperative ultrasound.All of the AVM and cavernous hemangiomas were localized accurately,while 81% of aneurysms and 91% hemangioblastomas were displayed.②Feeding arteries and draining veins and be detected in 71% of AVMs.③The localization accuracy of intraoperative ultrasound tended to be higher than superior intraoperative neuronavigator before resection,but the difference were not significant(100% vs 95%,P=0.244).The localization accuracy of during and after the resection were significantly different between them(100% vs 74%,x2=19.513,P＜0.0001;100% vs 68%,x2=24.973,P＜0.0001).Conclusions Intraoperative ultrasound can display and localize cerebral vascular disease,reduce injury,shorten operation time,and improve the accuracy of operation. 
 
Key words: 
Ultrasonography; Cerebrovascular disorders

Evaluation of intraoperative ultrasound in cerebral vascular disease

Management of intracranial aneurysm in children: clipped and coiled

OBJECTIVE
To investigate the probable relationship between the genetic polymorphisms of III collagen alphal ( COL3A1) gene and sporadic intracranial aneurysm patients in China of Han nationality.

METHODS
Peripheral blood samples were collected from 56 randomly selected sporadic intracranial aneurysm patients and 57 control cases without intracranial aneurysm, related risk factors, subarachnoid hemorrhage, and stroke history. Genomic DNA was extracted. PCR and sequencing were performed to evaluate the frequency discrepancy of the single nucleotide polymorphisms (SNPs). After statistical analysis the polymorphism site correlated with intracranial aneurysm was further investigated with bioinformatics methods to explore the influence of the mutations of polymorphic sites on the stability of type III collagen.

RESULTS
Both the genotype and allele frequencies of rs1800255 between the intracranial aneurysm and control group were statistically significant. There were no significant differences in the genotype and allele frequencies of thee SNPs rs2271683, rs151446, and nt2346. Data showed that the amino acid change induced by the polymorphism site could sabotage the stability of type III collagen.

There is significant correlation between rs1800255 of COL3A1 gene and Chinese sporadic intracranial aneurysm patients of Han nationality, which confirms the COL3A1 gene is one of the susceptible genes of Chinese sporadic intracranial aneurysm patients of Han nationality.

[Correlation of COL3A1 gene with type III collagen stability in intracranial aneurysm].

OBJECTIVE
To investigate the reliability and clinical value of functional magnetic resonance imaging (fMRI)-integrated neuronavigation in minimally invasive neurosurgery and protection of brain function. We demonstrate the correlation between the lesion-to-fMRI activation distance and occurrence of new postoperative deficit.

METHODS
fMRI-integrated neuronavigation was used for minimally invasive neurosurgery in 20 patients with intracranial lesions located in or near eloquent brain areas. During standardized paradigms for hand, foot, and tongue movement, language and visual activation, echo-planar imaging T2 blood oxygen level dependent sequences were acquired by Siemens Medical Systems Trio 3.0 T and processed with SPM2. Neuronavigation was performed with Stealth station.

RESULTS
fMRI data was integrated into neuronavigation successfully in all cases, functional neuronavigation with integration of fMRI allowed easy and precise identification of the eloquent brain areas and lesions except for 1 case for brain shift because of tumor stroke just before the operation. The localization of the tumor was corrected by intraoperative ultrasonography. Gross total resection was achieved in 18 patients, 2 patients had a subtotal resection. Neurological deterioration was seen in 4 patients, tumors all located in eloquent brain areas, 2 patients were recovered in 3 months the morbidity was 10.0%. The distance of a lesion to fMRI activation was more than 10 mm in 14 cases. The functional maps were located in left Brodmann's 9, 46, 17, 18 and 19 areas in 11 cases when the patients reading and understanding the Chinese words.

Functional neuronavigation with integration of fMRI allows precise identification of the eloquent brain areas protects the brain function and decreases the morbidity especially for Chinese patients because of our special functional area of language. Our data suggest that the distance of a lesion to fMRI activation was more than 10 mm, complete resection can be achieved safely.

[Functional magnetic resonance imaging-integrated neuronavigation and protection of brain function].

Compared with smaller aneurysms, giant intracranial aneurysms (GICAs) have a poorer prognosis and require more meticulous surgical planning and techniques to exclude them from the circulation. GICAs continue to challenge the limits of neurosurgical techniques. A series of 170 patients with GICAs were reviewed for understanding the clinical characteristics, surgical treatment and outcomes of patients with GICAs.

METHODS
Collected data of 170 consecutive patients with GICAs from January 1995 to July 2007 were analyzed. The clinical characteristics in this study included age, sex, intracranial aneurysms size, the first presentations, locations and Hunt & Hess grade. Surgical methods included direct clipping of the aneurysm neck, parent artery reconstruction, proximal artery ligation, trapping and wrapping. Surgical results were evaluated postoperatively by the Glasgow Outcome Scale (GOS).

RESULTS
GICAs were more commonly diagnosed at age 30 to 50 years with a mean age of 39.3 years and without obvious gender preponderance in our study (88 male and 82 female patients). The size of the GICAs ranged from 2.5 cm to 8.0 cm (mean, 2.9 cm). Hemorrhage (41%), mass effect (34%) and headache (12%) were the first 3 most common presentations. Regarding the Hunt & Hess classification, at admission there were 100 cases in grade 0, 24 in grade 1, 21 in grade 2, 16 in grade 3, 8 in grade 4 and 1 in grade 5. There were 84 cases of GICAs treated by direct neck-clipping, 47 by parent artery reconstruction, 19 by proximal artery occlusion (with 4 combined with revascularization), 18 by trapping and 2 by wrapping. The follow-up study (ranging from 6 to 115 months, mean 32 months) showed good results in 108 cases, moderate disability in 26 and severe disability in 15 according to GOS. Six cases died.

Surgical treatment is an effective treatment for GICAs. Surgical strategies should be made carefully and individually. Doppler ultrasonography, neuroendoscope and intraoperative angiography are useful to perfect surgical results.

Clinical characteristics and surgical treatment of patients with giant intracranial aneurysms.

Stereotactic radiosurgery is an alternative to resection of intracranial cerebral arteriovenous malformations (AVMs), while it will fail in some cases. This study aimed to evaluate the changes after stereotactic radiosurgery for AVMs.

METHODS
Nineteen cases with cerebral AVMs had failure after stereotactic radiosurgery therapy. The symptoms and angiography were assessed. All patients underwent microsurgery. Pathologic examination was performed for all cases and electron microscopic examination was carried out in 6 patients.

RESULTS
Seven cases had hemorrhage from 12 to 98 months after stereotactic radiosurgery, 5 had headache, 4 had refractory encephalon edema, 2 had epilepsy as a new symptom and 1 had a pressure cyst 5 years after radiosurgery. Angiography in 18 cases, 8 - 98 months after radiation therapy, demonstrated no significant changes in 5 cases, slight reduction in 9, near complete obliteration in 1 and complete obliteration in 3. An abnormal vessel was found on pathologic examination in 17 cases, even one case had obliterated in angiography. Electron microscopy examination showed vessel wall weakness, but the vessels remained open and blood circulated. One case died because of a moribund state before surgery. The other 18 cases had no new neurological deficiencies, seizure control and no hemorrhage occurred after microsurgery at an average follow-up of 3 years.

Stereotactic radiotherapy for AVMs should have a long period follow-up. If serious complications occur, microsurgery can be performed as salvage treatment.

Clinical and pathological changes in cerebral arteriovenous malformations after stereotactic radiosurgery failure.

Oculomotor palsy is a common complication in patients with posterior communicating aneurysm. This study was conducted to investigate the postoperative recovery of patients with posterior communicating aneurysm complicated with oculomotor palsy and to analyze the factors influencing length of recovery.

METHODS
From 2000 to 2006, 148 patients with posterior communicating aneurysm were treated at our hospital, with 74 of them having concurrent unilateral oculomotor palsy. All of the patients underwent craniotomy after the diagnosis by means of whole-brain digital subtraction angiography (DSA). The patients were divided into two groups for observation of postoperative recovery during the follow-up period. Patients in group A were treated with simple pedicle clipping of the aneurysm while patients in group B were treated with pedicle clipping of the aneurysm and decompression of the oculomotor nerve.

RESULTS
Of the 40 patients in group A, 20 underwent surgery within 14 days and completely recovered from oculomotor palsy in 10 - 40 days. Fourteen patients underwent surgery within 14 - 30 days, of whom 12 completely recovered within 30 - 90 days and 2 cases recovered incompletely. The remaining six patients underwent surgery after more than 30 days; of these, four patients recovered completely and two recovered incompletely. Of the 34 cases in group B, 15 underwent surgery within 14 days and completely recovered from oculomotor palsy in 10 - 40 days. Sixteen patients underwent surgery in 14 - 30 days, of whom 14 completely recovered in 30 - 90 days and 2 recovered incompletely. The remaining three patients underwent surgery after more than 30 days, of whom two patients recovered completely and one recovered incompletely.

Early diagnosis and surgical treatment of patients with unilateral oculomotor palsy induced by posterior communicating aneurysm are important to full postoperative recovery of the oculomotor nerve. No correlation was found, however, between decompression of the oculomotor nerve, such as excision or puncture of the aneurysm, and postoperative recovery time.

Postoperative recovery from posterior communicating aneurysm complicated by oculomotor palsy.

The benefit of neuronavigation for the treatment of patients with intracerebral cavernous malformations

To evaluate the reliability of intraoperative microvascular Doppler ultrasonography (MDU) in cerebral aneurysm surgery.

METHODS
MDU was conducted among 46 patients with 51 cerebral aneurysms undergoing 47 operations to examine the blood flow velocity in the aneurysmal sac and in the adjacent vessels before and after aneurysm clipping.

RESULTS
MDU verified 6 cases of stenosis or occlusion of an adjacent vessel induced by clip positioning that had escaped detection by visual inspection (12.76%, 6/47). In addition, MDU demonstrated that one out of the 51 aneurysms failed to be occluded (1.96%). The incidence of stenosis, occlusion of adjacent vessel, and aneurysm failing to be occluded was closely correlated with the size of aneurysm, and such conditions were prone to occur in anterior communicating artery (ACoA) and internal carotid artery (ICA) aneurysms.

MDU should be used routinely in cerebral aneurysm surgery, especially in cases of giant aneurysms and aneurysms without obvious neck. In cases of ACoA and ICA aneurysms, MDU is more useful.

[Intraoperative microvascular Doppler ultrasonography monitoring in intracranial aneurysm surgery].

OBJECTIVE
To study the clinical and neuroimaging predictors of hematoma enlargement in spontaneous intracerebral hemorrhage (ICH).

METHODS
Ninety-eight patients with ICH within 4 hours of onset, 60 males and 38 females, aged 56+/-16, underwent the first CT examination at admission and the second CT examination 24 hours later to evaluate the occurrence of hematoma enlargement. Multivariate analysis was performed to assess the possible predictors.

RESULTS
Twenty-six of the 98 ICH patients (26.5%) developed hematoma enlargement. Multivariate analysis revealed that the following 4 factors were independently associated with hematoma enlargement: interval between first CT and onset, aniso-density hematoma, consciousness level at admission, and the history of cerebral infarction. A characteristic feature indicating the hematoma enlargement- "hematoma enlargement border" was found and named.

Hematoma enlargement after ICH has some clinical and neuroimaging predictors. The concepts and diagnostic criteria of aniso-density hematoma and hematoma enlargement border have been defined for the first time.

[Neuroimaging and clinical predictors of hematoma enlargement in spontaneous intracerebral hemorrhage].

The modification on the titanium implant surface is an effective method to improve the biocompatibility of titanium. This article describes efforts to improve implant biocompatibility by applying titania and hydroxyapatite to form a three-layer coating on the titanium surface. This three-layer coating is made up of HA as the top layer (formed by hydrothermal treatment), porous TiO2 as the middle layer (formed by micro-arc oxidation) and a dense TiO2 film as the inner layer (formed by preanodic oxidation). The physicochemical characteristics, cell behavior and in vivo studies were assessed. The physicochemical characteristics were investigated using scanning electron micoscopy observation, fibronectin and laminin adsorption, corrosion test and X-ray diffraction analysis. Cell behavior included morphology observation with scanning electron microscopy (SEM), number count with methylthiazol tetrazolium (MTT) assay and Alkaline phosphatase (ALP, a representative enzyme of osteoblastic differentiation) activity of osteoblast-like MC3T3-E1 cells. In study in vivo the specimens were embedded in skull wound for repair. By the analysis of experiments, the titanium coated with this three-layer coating has been proved to have excellent corrosion resistance and good biocompatibility, which can promote cell proliferation and bone formation. So this modified titanium is an improved alternative to untreated titanium for bone repair applications.

Biomimetic coating of compound titania and hydroxyapatite on titanium.

Comparison of CT-guided aspiration to key hole craniotomy in the surgical treatment of spontaneous putaminal hemorrhage: a prospective randomized study

OBJECTIVE
To investigate the effects and prospect of application of diffusion tensor imaging (DTI) fractography in minimally invasive surgery of brain tumors.

METHODS
DTI fractography was performed in 52 patients with malignant brain tumors. Based on the DTI fractography results, 34 of the 52 patients underwent operation under neuro-navigation, and 18 of the 52 patients underwent operation routine minimally invasive craniotomy and tumor resection without neuro-navigation.

RESULTS
The rate of total tumor resection was 86.5% (45/52). The mortality was 1.9% (1/52). The disability rate was 11.5% (6/52). No case needed the second operation.

DTI fractography has raised the minimally invasive neurosurgery to the level of protecting the nuclei and nerve tracts and guiding intra-operative management of infiltration of deep-seated tumors, especially when combined with neuro-navigation and interventional MRI.

[Application of diffusion tensor imaging fractography in minimally invasive surgery of brain tumors].

Clinical application of a neuronavigation system in transsphenoidal surgery of pituitary macroadenoma

This paper describes efforts to improve implant biocompatibility and durability by applying a hybrid technique using composite oxidation. Pure titanium was used as the substrate material. A porous oxide film as the outer layer was produced by micro-arc oxidation and a dense oxide film as the inner layer was produced by pre-anodic oxidation. In this study, physicochemical characteristics, corrosion test, cell attachment behavior, and in vivo studies were used to compare this gradient layer with untreated titanium. The results revealed that the gradient layer was composed of two layers of oxide films which were made up of rutile and anatase and the surface was porous with calcium and phosphor. The corrosion resistance of the gradient layer was improved remarkably, which was about three times the values for titanium and two times the value for the dense layer. The cell-material interaction study indicated that L929 cells seeded and cultured on the gradient layer appeared to attach well and the rate of proliferation was the greatest. The study in vivo showed that the gradient layer had good biocompatibility. This gradient layer provides a material with high corrosion resistance, bioactivity, and biological properties suitable for tissue engineering applications.

Corrosion test, cell behavior test, and in vivo study of gradient TiO2 layers produced by compound electrochemical oxidation.

Clinical characteristics and surgical results of patients with cerebral arteriovenous malformations.

Clinical experience of 153 patients with posterior circulation aneurysms

OBJECTIVE
To evaluate and compare the effectiveness of different types of surgical therapy for patients with hypertensive cerebral hemorrhage, and analyze the major risk factors of prognosis.

METHODS
2464 patients with hypertensive cerebral hemorrhage in 92 hospitals in different areas of China underwent different types of surgical treatment: Group I (n = 639), undergoing traditional craniotomy as control; Group II (n = 409), receiving minimally invasive hematoma evacuation; and Group III (n = 1416), receiving CT guided stereotaxic hematoma aspiration. The clinical data were collected and underwent multianalysis.

RESULTS
The factors influencing the short-term prognosis were Glasgow coma scale (GCS) score before surgery and the incidence of postoperative complications in Group II; GCS score before surgery and the incidence of postoperative complications and volume of hemorrhage, duration between ictus and surgery, use of urokinase in Group III; and GCS score before surgery, muscle power before surgery, diastolic pressure at admission and postoperative complications in Group III.

Analysis of prognosis related factors of cerebral hemorrhage plays a very important role in the selection of therapeutic strategy. It may be beneficial for standardizing surgical indications, further designing large scale clinical trial, helping the doctors select appropriate strategy of treatment, and serving the social population better.

[Multianalysis of short-term prognostic factors in surgical practices for hypertensive intracerebral hemorrhage].

OBJECTIVE
To investigate the value of intraoperative real-time ultrasound during surgery of cerebral arteriovenous malformations (AVMs).

METHODS
Thirteen patients with cerebral AVMs, 12 supratentorial and 1 infratentorial, underwent microsurgical treatment. Intraoperative ultrasound (IOUS) with multimodality was performed before the starting of resection in order to: (1) localize and delineate the AVM, (2) differentiate the embolized and perfused parts of AVM, and (3) identify the feeding arteries and draining veins. After removal of the lesion, sonographic examination was repeated to detect the residual AVM tissue and the findings were compared with the intra- and/or post-operative angiographic finding.

RESULTS
Total resection was achieved in all 13 patients with AVM under real-time ultrasonographic navigation. The niduses of AVM were localized and defined precisely by IOUS due to their dichromatic flow pattern. The embolized parts of AVM exhibited hyperechogenicity without blood signals. The feeding and draining vessels were distinguished from normal ones morphologically and hemodynamically. Complete removal of the AVM determined sonographically was then confirmed by angiography.

Intraoperative real-time ultrasound allows accurate localization and navigation of the cerebral AVMs, provides valuable information during surgery, and helps determine the degree of removal of the cerebral AVM.

[Application of intraoperative real-time ultrasound in the surgical treatment of cerebral arteriovenous malformation].

OBJECTIVE
To investigate the indications, technical considerations, and effects of neuronavigation and electrocorticography (ECOG) monitoring in resection of brain cavernous malformations (CM).

METHODS
From 1997 to 2003, 70 patients with CM, 53 males and 17 females, aged 33 (8 - 62), underwent resection of CM using neuronavigation and neurophysiological monitoring. The first episodes included hemorrhage (31 cases, 44.3%), seizure (29 cases, 41.4%), headache (5 cases, 7.1%), and focal neurological deficit (4 cases, 5.7%). One case was asymptomatic (1.4%), only discovered during physical examination. The size of CM focus was 21 mm (5-50 mm). The depth of tumor measured from the surface was 3-70 mm. Six patients had multiple lesions. The foci were located deep in the white matter of hemispheres in 39 cases, within the brainstem in 9 cases, within the basal ganglia or thalamus in 11 cases, within the cerebellum in 5 cases, and within the optic nerve in 1 case. Preoperatively a MRI procedure using 5 skin markers was performed with the data transferred to a neuronavigation workstation, thus reconstructing a three-dimensional image of the tumor. Supratentorial subcortical lobar cavernomas underwent microsurgery through sulcus and fissure approach. ECOG monitoring was performed on 29 patients with seizure during the operation and bipolar electrocoagulation on functional cortex was conducted. Follow-up was conducted for 19.4 months (6-24 months).

RESULTS
No intraoperative death was found. Postoperative disability rate was 8.6%. Complete removal of the lesion demonstrated by postoperative MRI was obtained in all patients. New transitory neurological deficits occurred in 4 patients after operation and recovered within 1 month. Hemiparesis developed in 1 patient with thalamus CM (1.4%) and facial paralysis developed in 1 patient with pons CM, and both recovered in 6 mouths. Nineteen out of the 24 patients with preoperative seizure history (79.2%) were postoperatively free of seizure, five (20.8%) of them showed improvement.

Patients with asymptomatic CM can be kept under observation. CM deep in brain after the first bleeding is the indication of surgical treatment. Combination of neuronavigation and neurophysiological monitoring contributes to safety of operation and decrease of postoperative disability rate.

[Neuronavigation and electrocorticography monitoring in resection of brain cavernous malformations].

OBJECTIVE
To study the correlation between a pentanucleotide repeats (PNR) polymorphism of APOA and the genesis of intracranial aneurysm.

METHODS
Fifty-eight patients with intracranial aneurysms diagnosed by angiography and 58 healthy controls were enrolled in our study. The gene polymorphism of APOA PNR were detected by polymerase chain reaction (PCR) and non-denatured polyacrylamide gels electropherosis (PAGE).

RESULTS
Eight kinds of gene types and 6 kinds of alleles were found in these two groups. There were two sites of sequence variance in the 5' control region of APOA gene, which were significantly different between the patients and controls.

Correlation may exist between intracranial aneurysm and APOA gene.

Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae

[Correlation between APOA gene polymorphism and intracranial aneurysm].

OBJECTIVE
To compare the efficacy and indications of the 3 approaches: conventional open craniotomy (COC), computed-tomography guided aspiration (CTGA), and key-hole approach (KHA) in neurosurgical management for hypertensive intracerebral hemorrhage (HICH).

METHODS
The clinical data of HICH 2464 patients, aged 14 - 75, operated on within 24 hours after stroke, with a Glasgow coma score >or= 5, hospitalized in 135 hospitals all over the mainland of China, were collected and underwent single-blind study.

RESULTS
Among the 2464 patients 639 underwent COC, 1416 underwent CTGA, and 409 were operated on via KHA. The overall mortality rates within one and three months after operation were 19.3% and 21.1% respectively. The mortality rate within 3 months after operation (M3m) of the patient with a GCS <or= 8 was 3.5 times as much as the M3m of the patients with a GCS >or= 8. The M3m of the patients with complications was 4.4 times as much as that of the patients without complications. The M3m of the patients with hemorrhage in thalamus was 2.4 times as much as that of the patients with cortical hemorrhage. The M3m of the COC group was 24.6%, higher than those of the KHA group (17.6%) and CTGA group (20,6%). The postoperative complication rate of the COC group was 29.9%, significantly higher than that of the CTGA group (24.8%, P = 0.015). There were no significant differences in postoperative complication rate between the COC and KHA groups and between the CTGA and KHA groups (both P > 0.05).

KHA and CTGA are both better than COC in treatment of HICH with more favorable outcome and less postoperative mortality and morbidity.

[The efficacy of three different approaches in treatment of hypertensive intracerebral hemorrhage: a multi-center single-blind study of 2464 patients].

OBJECTIVE
To analyze the treatments of multiple intracranial aneurysms.

METHODS
Natural conditions of 123 patients and treatments of multiple intracranial aneurysms were analyzed retrospectively.

RESULTS
Of 123 patients with multiple intracranial aneurysms. 101 harbored two aneurysms; 16, three; 4, four; 2, more than four. The female-to-male ratio was nearly 1.7:1(78 females to 45 males). The age range was from 11 to 74 with a mean of 50.37 years. Thirty(24.4%) patients received conservative treatment. 91(74.0%) neurosurgical treatment, 82 (90.1%) patients obtained excellent or good outcomes.Six(4.9%) endovascular embolization, one hemiparesis and one paralysis was observed.

Based on our results, we recommend that, if possible, all multiple aneurysms should be treated in one stage or multiple sessions. With Navigation and Keyhole Techniques, the injury and risk of surgery have been decreased, and outcomes have improved. Perfection of the endovascular occlusion technique also improves the prognosis of this disease.

Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences

OBJECTIVE
To discuss the efficacy, accuracy, and safety of computer-assistant neuronavigation in operation of vertebrae and spinal cord.

METHODS
The data of computer-assistant neuronavigation used in the operation for 41 cases, including 9 cases of neurinoma, 10 cases of ependymoma, 5 cases of angioreticuloma, 7 cases of spinal meningioma, 4 cases of astrocytoma, and 1 case of cysticercosis, and 1 case of osteoblastoma. from March 2001 to December 2003 were reviewed.

RESULTS
Twenty-six screws were fixed in 4 patients. Total removal was succeeded in 33 of the 37 cases of 37 spinal tumors and all patients survived after operation.

Image-guided navigation for spinal surgery is able to save time and reduce operational lesion. More importantly, it improves neurosurgeon's comprehension of spinal anatomy.

[Application of computer-assistant neuronavigation in spinal operation].

OBJECTIVE
To study the role of neuro-endoscope in the intracranial aneurismal surgery, analyzing its benefits, and disadvantages.

METHODS
Endoscopy was used as an adjunct in the microsurgical treatment of clipping aneurysms on 88 patients with 89 aneurysms, of which 82 aneurysms in 81 patients were located in the anterior circulation and 7 were located in the posterior circulation. Keyhole approach was performed on all patients, and micro-Doppler ultrasound technique was used before and after clipping. In 84 aneurysms, endoscope-assisted microneurosurgery (EAM) was used in addition to microsurgical dissection and clipping so as to observe the neck anatomic features and perforators and to verify the optimal clipping position. Endoscope-controlled microneurosurgery was used for 5 aneurysms to observe the anatomy around aneurysm, such as the posterior communicating artery and the opposite anterior communicating artery behind the internal carotid artery.

RESULTS
Postoperative angiography performed on 86 patients showed satisfactory aneurysm clipping. Operative mortality was 0. There were 7 cases of postoperative complications, with an incidence rate of 7.95%, and none case was directly related to endoscopy.

Improving observation of regional anatomy because of its ability in magnification, illumination, and looking around dead angle, neuro-endoscopy is very useful for complex aneurysms.

[Application of the neuro-endoscope to the intracranial aneurismal surgery].

Suboccipital bony decompression combined with removal of the dural band as treatment for Chiari I malformation.

Clinical characteristics and surgical results of 2086 patients with cerebral arteriovenous malformation

Surgical management of brain-stem cavernous malformations: report of 137 cases.

Apolipoprotein e ϵ4 and the risk of unfavorable outcome after aneurysmal subarachnoid hemorrhage

The APOE-E4 allele has been identified as a risk factor for Alzheimer's disease and unfavorable outcomes after brain injuries. The purpose of this study was to confirm that APOE allele polymorphism also represents a risk factor for unfavorable outcomes following aneurysmal subarachnoid hemorrhage (SAH).

METHODS
A total of 104 patients with aneurysmal SAH were studied. Computed tomography (CT) scan findings of SAH were assessed by Fisher's grade and clinical neurologic assessment was performed using the Hunt and Hess (H&H)grading system. Serum lipids were also analyzed. Outcomes at 3 months after SAH were determined using the Glasgow Outcome Scale.

RESULTS
The distributions of APOE genotypes and alleles of patients were matched with those of control subjects. That 5 of 18 patients with APOE-E4 allele (28%) had an unfavorable outcome was significantly different from those without APOE-E4 (8%, chi2, p = 0.032; OR = 4.34, 95% CI 1.20-15.75). However, the presence or absence of E2 or E3 alleles had no significant difference. The relative hazard of APOE-E4 for unfavorable outcome exited after adjustment for clinical assessment (OR = 6.95, 95% CI 1.21-39.75). Total serum cholesterol, low-density lipoprotein and apolipoprotein B were elevated in patients with unfavorable rather than favorable outcomes.

Our findings confirmed that the patients with APOE-E4 allele were predisposed to unfavorable outcomes after aneurysmal SAH even though an association between APOE and incidence of the SAH may not exist. The effect of APOE on neurobiology and lipoprotein metabolism seems to partially explain the difference in outcomes and deserves further study.

Apolipoprotein E epsilon4 and the risk of unfavorable outcome after aneurysmal subarachnoid hemorrhage.

The objective of this study was to assess the value of the application of frameless stereotaxy in craniotomy procedures. During the period from November 1997 to June 2002, using the SurgiScope and Stealth Station frameless stereotaxy image-guided neuronavigation system, 465 craniotomy procedures were performed, including surgery for 206 gliomas, 46 arteriovenous malformations (AVMs), 35 aneurysms, 37 meningiomas, 69 cavernous angiomas, 11 pituitary adenomas, 9 schwannomas, 8 cases of epilepsy, 6 angioblastomas, 5 metastases, 3 frameless biopsies, and 30 other lesions such as craniopharyngiomas, germinomas, and brain abscesses. In each of these cases, the patient's magnetic resonance imaging (MRI) data were loaded into the neuronavigation system, which allowed for three-dimensional rebuilding of the data set and simulation of surgical planning and procedures. In the course of the operation, the system allowed for patient registration, reference arc registration, instrument registration, and real-time positioning and guidance. All intracranial lesions and critical anatomical structures were accurately located and positioned. The computer showed an estimated error of within 2 mm. Postoperative neurologic complications occurred in 22 patients (4.7%). There was no incident of operative death. The use of a frameless stereotaxy image-guided neuronavigation system is most valuable in craniotomy procedures, especially in those cases with lesions located in the deep center of the brain. In addition, its accuracy of location is of great importance in protecting the normal brain tissues and in resecting the lesions completely. Such an application is changing the way in which surgeons perform craniotomies and is the foundation of minimally invasive neurosurgical procedures.

Application of Frameless Stereotaxy in Craniotomy Procedures: Clinical Evaluation

Assessment of toxic mechanisms and mode of action to three different levels of species for 14 antibiotics based on interspecies correlation, excess toxicity, and QSAR.

Classification of toxicity of phenols to Tetrahymena pyriformis and subsequent derivation of QSARs from hydrophobic, ionization and electronic parameters.

The ability to cross the blood brain barrier (BBB), sometimes expressed as BBB+ and BBB-, is a very important property in drug design. Several computational methods have been employed for the prediction of BBB-penetrating (BBB+) and nonpenetrating (BBB-) compounds with overall accuracies from 75 to 97%. However, most of these models use a large number of descriptors (67-199), and it is not easy to implement the models in order to predict values of BBB+/-. In this work, 19 simple molecular descriptors calculated from Algorithm Builder and fragmentation schemes were used for the analysis of 1593 BBB+/- data. The results show that hydrogen-bonding properties of compounds play a very important role in modeling BBB penetration. Several BBB models based on hydrogen-bonding properties, such as Abraham descriptors, polar surface area (PSA), and number of hydrogen bonding donors and acceptors, have been built using binomial-PLS analysis. The results show that the overall classification accuracy for a training set is over 90%, and overall prediction accuracy for a test set is over 95%.

Predicting Penetration Across the Blood-Brain Barrier from Simple Descriptors and Fragmentation Schemes

Literature values of the in vivo distribution (BB) of drugs from blood, plasma, or serum to rat brain have been assembled for 207 compounds (233 data points). We find that data on in vivo distribution from blood, plasma, and serum to rat brain can all be combined. Application of our general linear free energy relationship (LFER) to the 207 compounds yields an equation in log BB, with R2=0.75 and a standard deviation, SD, of 0.33 log units. An equation for a training set predicts the test set of data with a standard deviation of 0.31 log units. We further find that the in vivo data cannot simply be combined with in vitro data on volatile organic and inorganic compounds, because there is a systematic difference between the two sets of data. Use of an indicator variable allows the two sets to be combined, leading to a LFER equation for 302 compounds (328 data points) with R2=0.75 and SD=0.30 log units. A training equation was then used to predict a test set with SD=0.25 log units.

A data base for partition of volatile organic compounds and drugs from blood/plasma/serum to brain, and an LFER analysis of the data.

The Abraham linear free energy relationship, or solvation equation, has been applied to literature data on the partition of nonelectrolytes in the water to o-nitrophenyl octyl ether (NPOE) system. The resulting equation is compared to equations for other water to solvent systems using the D-parameter of Abraham and Martins and the theta-parameter of Ishihama and Asakawa. It is shown that as a solvent in partitioning systems, NPOE quite resembles nitrobenzene and 1,2-dichloroethane, and that the latter does not resemble an alkane-like solvent. Using descriptors for simple ions that we have previously obtained, we show that ions and nonelectrolytes can be included in the same linear free energy relationship.

Characterisation of the water/o-nitrophenyl octyl ether system in terms of the partition of nonelectrolytes and of ions.

[structure: see text] Partition coefficients of single ions in the octanol/water system (log P(oct)) have been assigned on the (Ph4As+, Ph4P+) = Ph4B- assumption. The log P(oct) values of Cl-, Br-, and I- ions are then used to obtain the partition coefficients of cations from partition coefficients of the neutral combination of anion and cation. Partition coefficients of 544 cations derived from 585 organic salts from the MedChem database have been studied. The contributions of the aliphatic charge N+ and aromatic charge n+ in these cations have been investigated. The results show that the contributions of N+ and n+ in different homologous series are affected by the attached functional groups and are not constant, although the effect of the central cation is constant along any given homologous series. The latter can be accounted for qualitatively and semiquantitatively by the electrostatic theory of ionic solvation of Abraham and Liszi. A number of regression equations have been established between partition coefficients of ions and partition coefficients of the corresponding neutral species. These equations can be used to estimate octanol/water partition coefficients for additional cations to about 0.5 log unit.

Octanol/water partition of ionic species, including 544 cations.

Literature values of Gibbs energies of transfer of ions from water to other solvents have been used in conjunction with our solvation equation to obtain descriptors for univalent ions. It is suggested that descriptors used for nonelectrolytes are not adequate to describe transfers of single ions, and that two specific ionic descriptors (J(+) and J(-)) for cations and anions, respectively, are required. The ions studied include the alkali metal and tetraalkylammonium cations, halide and other anions, and the tetraphenylarsonium, tetraphenylphosphonium, and tetraphenylborate ions. It is shown that simple cations such as Na(+) act as very strong hydrogen bond acids and that the R(4)N(+) ions are only weak hydrogen bond acids. The halide anions are very strong hydrogen bond bases, as is also the acetate anion. Other anions, such as azide, cyanide, and nitrate, are again very strong hydrogen bond bases. The tetraphenylarsonium, tetraphenylphosphonium, and tetraphenylborate ions have no hydrogen bond acidity but are quite strong hydrogen bond bases. It is suggested that this is due to the basic properties of the phenyl groups.

Determination of solvation descriptors for ionic species: hydrogen bond acidity and basicity.

The van der Waals volume is a widely used descriptor in modeling physicochemical properties. However, the calculation of the van der Waals volume (V(vdW)) is rather time-consuming, from Bondi group contributions, for a large data set. A new method for calculating van der Waals volume has been developed, based on Bondi radii. The method, termed Atomic and Bond Contributions of van der Waals volume (VABC), is very simple and fast. The only information needed for calculating VABC is atomic contributions and the number of atoms, bonds, and rings. Then, the van der Waals volume (A(3)/molecule) can be calculated from the following formula: V(vdW) = summation operator all atom contributions - 5.92N(B) - 14.7R(A) - 3.8R(NR) (N(B) is the number of bonds, R(A) is the number of aromatic rings, and R(NA) is the number of nonaromatic rings). The number of bonds present (N(B)) can be simply calculated by N(B) = N - 1 + R(A) + R(NA) (where N is the total number of atoms). A simple Excel spread sheet has been made to calculate van der Waals volumes for a wide range of 677 organic compounds, including 237 drug compounds. The results show that the van der Waals volumes calculated from VABC are equivalent to the computer-calculated van der Waals volumes for organic compounds.

Fast calculation of van der Waals volume as a sum of atomic and bond contributions and its application to drug compounds.

The McGowan volume has been widely used for the analysis of physicochemical and biochemical properties in chemistry and drug industry. Because McGowan volumes are not available for ions, its application is limited to only neutral compounds. Pauling radii of metallic ions have been collected and studied to obtain McGowan volumes for ions. Regression analysis was carried out between Pauling radii (R(p)) and McGowan radii (R(x)) for a wide range of compounds. It was found that Pauling radii and McGowan radii derived from McGowan volumes by using a volume-radius formula are linearly related (R(x) = 1.115R(p) + 0.0623, r(2) = 0.995). This equation is then used to calculate McGowan volumes for various ions and charged groups. McGowan volumes have been calculated for inorganic, organic, and organometallic compounds and correlated with van der Waals volumes. Results show that McGowan volumes (V(x)) are entirely equivalent to computer-calculated van der Waals volumes.

Determination of McGowan Volumes for Ions and Correlation with van der Waals Volumes

Evaluation of rat intestinal absorption data and correlation with human intestinal absorption.

Quantitative relationship between rat intestinal absorption and Abraham descriptors.

Imidazole derivatives as a novel class of hybrid compounds with inhibitory histamine N-methyltransferase potencies and histamine hH3 receptor affinities.

Erratum: Evaluation of human intestinal absorption data and subsequent derivation of a quantitative structure–activity relationship (QSAR) with the Abraham descriptors*

Evaluation of human intestinal absorption data and subsequent derivation of a quantitative structure-activity relationship (QSAR) with Abraham descriptors (vol 90, pg 749, 2001)

Application of hydrogen bonding calculations in property based drug design.

Characterization of a broad-spectrum endolysin rLysJNwz and its utility against Salmonella in foods

Isolation and Characterization of Two Novel Salmonella Phages and Their Application as a Cocktail for Biocontrol in Foods

Effectiveness of bacteriophage JN01 incorporated in gelatin film with protocatechuic acid on biocontrol of
 Escherichia coli
 O157:H7 in beef

Isolation and characterization of a novel Salmonella bacteriophage JNwz02 capable of lysing Escherichia coli O157:H7 and its antibacterial application in foods

Author response for "A Bacteriophage JN02 Infecting Multidrug‐resistant Shiga toxin‐producing Escherichia coli : Isolation, Characterization, and Application as a Biocontrol Agent in Foods"

A bacteriophage JN02 infecting multidrug‐resistant Shiga toxin‐producing
 Escherichia
 coli
 : isolation, characterisation and application as a biocontrol agent in foods

Quantification and Discrimination of Viable and Dead Escherichia coli O157:H7 Cells from Chicken Without Enrichment by Ethidium Bromide Monoazide Real-time Loop-Mediated Isothermal Amplification

Detection and Evaluation of Viable but Non-culturable Escherichia coli O157:H7 Induced by Low Temperature with a BCAC-EMA-Rti-LAMP Assay in Chicken Without Enrichment

The photochemical behaviors of chiral pollutants in aqueous solutions are rarely studied using chiral monomers, which may hamper their precise risk assessment and lead to suspicious conclusions. In this study, we systematically investigated the phototransformation behavior and toxicity evolution of two widely used chiral pesticides (triadimefon (TF) and triadimenol (TN)) at enantiomer and diastereomer levels, and proposed a calculation method of total photolysis rate constants of chiral mixture. Results show that TF and TN could be photodegraded faster in pure water than in natural waters, and the observed photolysis rate constants (kobs) of TN with two chiral centers exhibit enantioselectivity, i.e., kobs(TN-RS) = kobs(TN-SR) > kobs(TN-RR) = kobs(TN-SS). The photolysis of TF and TN mainly occurs through their excited singlet and triplet states, respectively. Their photodegradation pathways mainly include dechlorination and elimination of triazole ring. TF could also undergo ether bond cleavage. It is also found that, both TF and TN exhibit photo-induced toxicity to V. fischeri, due to the generation of more toxic products than parent compounds. Furthermore, TN exhibits enantioselective photo-induced toxicity after 240-min irradiation, which could be ascribed to the formation of chiral products. These results could benefit the understanding of enantioselective environmental behavior of chiral pollutants.

Photochemical behavior and photo-induced toxicity of chiral pesticides and their chiral monomers in aqueous environment.

Photolysis mechanism of eleven insecticides under simulated sunlight irradiation: Kinetics, pathway and QSAR.

Application of machine learning to predict the inhibitory activity of organic chemicals on thyroid stimulating hormone receptor.

Developmental toxicity of fenbuconazole in zebrafish: effects on mitochondrial respiration and locomotor behavior.

Endocrine disruption by azole fungicides in fish: A review of the evidence.

Comparison of modes of toxic action between Rana chensinensis tadpoles and Limnodrilus hoffmeisteri worms based on interspecies correlation, excess toxicity and QSAR for class-based compounds.

Predicting reaction rate constants of ozone with ionic/non-ionic compounds in water.

Liquid crystal monomers (LCMs), widely used in liquid crystal displays, have been recognized as a class of potential emerging pollutants in the environment. However, their atmospheric fate and toxi...

Atmospheric Fate and Risk Investigation of Typical Liquid Crystal Monomers

Atmospheric persistence and toxicity evolution for fluorinated biphenylethyne liquid crystal monomers unveiled by in silico methods.

Exposure to acetochlor impairs swim bladder formation, induces heat shock protein expression, and promotes locomotor activity in zebrafish (Danio rerio) larvae.

Relative comparison of strobilurin fungicides at environmental levels: Focus on mitochondrial function and larval activity in early staged zebrafish (Danio rerio).

Prediction of organic compounds adsorbed by polyethylene and chlorinated polyethylene microplastics in freshwater using QSAR.

Identification of active and inactive agonists/antagonists of estrogen receptor based on Tox21 10K compound library: Binomial analysis and structure alert.

Comparative analysis on the photolysis kinetics of four neonicotinoid pesticides and their photo-induced toxicity to Vibrio Fischeri: Pathway and toxic mechanism.

Behavioral and developmental toxicity assessment of the strobilurin fungicide fenamidone in zebrafish embryos/larvae (Danio rerio).

Assessing sub-lethal effects of the dinitroaniline herbicide pendimethalin in zebrafish embryos/larvae (Danio rerio).

A comprehensive review of 1,2,4-triazole fungicide toxicity in zebrafish (Danio rerio): A mitochondrial and metabolic perspective.

Bio-uptake, tissue distribution and metabolism of a neonicotinoid insecticide clothianidin in zebrafish.

Freshwater quality criteria of four strobilurin fungicides: Interspecies correlation and toxic mechanism.

Discrimination of active and inactive substances in cytotoxicity based on Tox21 10K compound library: Structure alert and mode of action.

Photolysis and photo-induced toxicity of pyraclostrobin to Vibrio fischeri: Pathway and toxic mechanism.

Quantitative structure-activity relationship models for predicting singlet oxygen reaction rate constants of dissociating organic compounds.

Predicting oxidative stress induced by organic chemicals by using quantitative Structure-Activity relationship methods.

MOA-based linear and nonlinear QSAR models for predicting the toxicity of organic chemicals to Vibrio fischeri

QSAR modeling for the ozonation of diverse organic compounds in water.

Evaluation of modes of action of pesticides to Daphnia magna based on QSAR, excess toxicity and critical body residues.

Relationship among the acute toxicity, critical body residue, and bioconcentration of ortho-dinitrobenzene in zebrafish (Danio rerio) based on toxicokinetics

Quantitative structure-activity relationship models for predicting reaction rate constants of organic contaminants with hydrated electrons and their mechanistic pathways.

The single toxicity (IC50) of zinc (Zn) and 11 nitro-substituted benzenes to Photobacterium phosphoreum were determined, respectively. On basis of single toxicity, the joint toxicity of binary mixtures of Zn and 11 nitro-substituted benzenes at different Zn concentrations of 0.2 IC50, 0.5 IC50, and 0.8 IC50 were measured. The joint toxicity was evaluated by toxic unit (TU) and additive index (AI) methods. The results indicated that the joint toxicity was not only depending on the Zn concentrations but also on the substituted groups of nitro-substituted benzenes. The quantitative structure-activity relation (QSAR) equations were developed and the results showed that the toxicity of nitro-substituted benzenes has different joint effect at the different Zn concentrations. At the Zn concentration of 0.2 IC50, the binary joint effects were mainly antagonism and the joint toxicity was negatively related to descriptors called VE2_B(p) and TIC3. At the Zn concentration of 0.5 IC50 and 0.8 IC50, the binary joint effects were mainly antagonism and simple addition, and the joint toxicity was related to the same descriptor Eig06_ AEA(dm). It indicated that the joint toxic actions were similar when combined at the medium and high concentrations of Zn.

Combined Toxicity of Nitro-Substituted Benzenes and Zinc to Photobacterium Phosphoreum: Evaluation and QSAR Analysis

Theoretical consideration on the prediction of in vivo toxicity from in vitro toxicity: Effect of bio-uptake equilibrium, kinetics and mode of action.

Toxicity assessment of the herbicide acetochlor in the human liver carcinoma (HepG2) cell line.

Comparison of modes of action among different trophic levels of aquatic organisms for pesticides and medications based on interspecies correlations and excess toxicity: Theoretical consideration.

Toxicity of some prevalent organic chemicals to tadpoles and comparison with toxicity to fish based on mode of toxic action.

Comparison of modes of action between fish and zebrafish embryo toxicity for baseline, less inert, reactive and specifically-acting compounds.

Kinetics and mechanism of OH-initiated atmospheric oxidation of organophosphorus plasticizers: A computational study on tri-p-cresyl phosphate.

Investigation on the relationship between critical body residue and bioconcentration in zebrafish based on bio-uptake kinetics for five nitro-aromatics.

The internal concentration represented by the critical body residue (CBR) is an ideal indicator to reflect the intrinsic toxicity of a chemical. Whilst some studies have been performed on CBR, the effect of exposure route on internal toxicity has not been investigated for fish. In this paper, acute toxicity data to fish comprising LC50 and LD50 values were used to investigate CBR. The results showed that exposure route can significantly affect the internal concentratio n. LD50 and CBR calculated from LC50 and BCF both vary i ndependently of hydrophobicity as expressed by log Kow; conversely, LC50 is related to log Kow. A poor relationship was observed between LC50 and LD50, but the relationship can be improved significantly by introduction of log Kow because log CBR is positively related to log LD50. The parallel relationsh ip of log CBR-log Kow and log LD50-log Kow indicates that LD50 does not reflect the actual internal concentration. The average LD50 is close to the average CBR for less inert and Electronic supplementary materi al The online versi on of this article (doi:10.1007/s11270-0 15-2427-1) contai ns supplementary material, which is available to authorized users. Y. Wen : L. Su : W. Qin : Y. Zhao (*) State Environmental Protection Key Laboratory of Wetland Ecology and Vegetation Restorati on, School of Environment, Northeast Normal University, Changchun, Jilin 130117, People’s Republic of China e-mail: zhaoyh@nenu.edu.cn J. C. Madden : F. P. Steinmetz : M. T. D. Cronin (*) School of Pharmacy and Biomolecular Sciences, Liver pool John Moores University, Liverp ool L3 3AF England, UK e-mail: m.t.cronin@ljmu.ac.uk reactive compounds, but greater than the average CBR for baseline compounds. This difference is due to the lipid fraction being the major storage site for most of the baseline compounds. Investigation on the calculated and observed CBRs shows that calculated CBRs are close to observed CBRs for most of compounds. However, systemic deviations of calculated CBRs have been observed for some compounds. The reas ons for these systemic deviations may be attributed to BCF, equilibrium time and experimental error of LC50. These factors are important and should be considered in the calculati on of CBRs.

LJMU Research Online Investigati on of Critical Body Residues and Mo des of Toxic Action Based on Injection and Aquatic Exposure in Fish

Mitochondrial bioenergetics and locomotor activity are altered in zebrafish (Danio rerio) after exposure to the bipyridylium herbicide diquat.

Paraquat affects mitochondrial bioenergetics, dopamine system expression, and locomotor activity in zebrafish (Danio rerio).

Development of thresholds of excess toxicity for environmental species and their application to identification of modes of acute toxic action.

Abstract Relationships of toxicities from intravenous (i.v.), intraperitoneal (i.p.), subcutaneous (s.c.) and intragastric (i.g.) exposure routes to mice were investigated. Regression analysis showed that the toxicities from i.v. route is strongly correlated with i.p. and s.c. routes, but poorly with i.g. route. Close toxicities from different routes for some compounds indicate that distribution rate is the determining step and dictates chemical concentration at the target site(s). On the other hand, the absorption rate is the determining step for many compounds, which lead to different toxicities between exposure routes. The classified compounds characterized as having either absorption or distribution rate determining step were based upon the comparison of toxicities from the different routes. We found that some aliphatic acids and benzoic acids have lower toxicity values from i.g. route compared to an i.v. route because of poor absorption. Many compounds show low toxic effects from i.g. route than those from other routes because of the first-pass metabolism in the gastrointestinal tract, resulting in the poor relationship for toxicities between i.g. and i.v. or other routes. Stepwise regression analysis showed that physicochemical properties of a compound, such as molecular volume, polarizability and hydrophobicity, significantly affect adsorption rate, which leads to different toxicities based upon exposure routes. Comparison of the toxicities between mice and rats indicate that toxic effect and the toxicokinetic processes in mice are very similar to that in rats. A universal correlation equation has been developed for the toxicities between rats and mice from different exposure routes, which can be applied to predict toxicities across species.

The impact of exposure route for class-based compounds: a comparative approach of lethal toxicity data in rodent models

Aqueous ·OH reaction rate constants ( kOH) for organophosphate esters (OPEs) are essential for assessing their environmental fate and removal potential in advanced oxidation processes (AOPs). Herein experimental and in silico approaches were adopted to obtain kOH values for a variety of OPEs. The determined kOH for 18 OPEs varies from 4.0 × 108 M-1 s-1 to 1.6 × 1010 M-1 s-1. Based on the experimental kOH values, a quantitative structure-activity relationship model that involves molecular structural information on the number of heavy atoms, content index, and the most negative charge of C atoms was developed for predicting kOH of other OPEs. Furthermore, appropriate density functional theory (DFT) and solvation models were selected, which together with transition state theory were employed to predict kOH of three representative OPEs. The deviation between the DFT calculated and the experimental kOH values ( kcal/ kexp) is within 2. Half-lives of the OPEs were estimated to be 0.5-22791.3 days in natural waters and 0.044-19.7 s in AOPs, indicating the OPEs are potentially persistent in natural waters and can be quickly eliminated by AOPs. The determined kOH values and the in silico methods offer a scientific base for assessing OPEs fate in aquatic environments.

Aqueous OH Radical Reaction Rate Constants for Organophosphorus Flame Retardants and Plasticizers: Experimental and Modeling Studies.

Fluazinam impairs oxidative phosphorylation and induces hyper/hypo-activity in a dose specific manner in zebrafish larvae.

Toxicity of 13 different antibiotics towards freshwater green algae Pseudokirchneriella subcapitata and their modes of action.

Discriminating modes of toxic action in mice using toxicity in BALB/c mouse fibroblast (3T3) cells.

Tris(2-chloroisopropyl) phosphate (TCPP), a widely used organophosphate flame retardant, has been recognized as an important atmospheric pollutant. It is notable that TCPP has potential for long-range atmospheric transport. However, its atmospheric fate is unknown, restricting its environmental risk assessment. Herein we performed quantum chemical calculations to investigate the atmospheric transformation mechanisms and kinetics of TCPP initiated by ·OH in the presence of O2/NO/NO2, and the effects of ubiquitous water on these reactions. Results show the H-abstraction pathways are the most favorable for the titled reaction. The calculated gaseous rate constant and lifetime at 298 K are 1.7 × 10-10 cm3molecule-1 s-1 and 1.7 h, respectively. However, when considering atmospheric water, the corresponding lifetime is about 0.5-20.2 days. This study reveals for the first time that water has a negative role in the ·OH-initiated degradation of TCPP by modifying the stabilities of prereactive complexes and transition states via forming hydrogen bonds, which unveils one underlying mechanism for the observed persistence of TCPP in the atmosphere. Water also influences secondary reaction pathways of selected TCPP radicals formed from the primary H-abstraction. These results demonstrate the importance of water in the evaluation of the atmospheric fate of newly synthesized chemicals and emerging pollutants.

Effects of Atmospheric Water on ·OH-initiated Oxidation of Organophosphate Flame Retardants: A DFT Investigation on TCPP.

Relationship between acute and chronic toxicity for prevalent organic pollutants in Vibrio fischeri based upon chemical mode of action.

Investigations on the relationship of toxicities between species play an important role in the understanding of toxic mechanisms to environmental organisms. In this paper, the toxicity data of 949 chemicals to fish and 1470 chemicals to V. fischeri were used to investigate the modes of action (MOAs) between species. The results show that although there is a positive interspecies correlation, the relationship is poor. Analysis on the excess toxicity calculated from toxic ratios (TR) shows that many chemicals have close toxicities and share the same MOAs between the two species. Linear relationships between the toxicities and octanol/water partition coefficient (log KOW) for baseline and less inert compounds indicate that the internal critical concentrations (CBRs) approach a constant both to fish and V. fischeri for neutral hydrophobic compounds. These compounds share the same toxic mechanisms and bio-uptake processes between species. On the other hand, some hydrophilic compounds exhibit different toxic effects with greatly different log TR values between V. fischeri and fish species. These hydrophilic compounds were identified as reactive MOAs to V. fischeri, but not to fish. The interspecies correlation is improved by adding a hydrophobic descriptor into the correlation equation. This indicates that the differences in the toxic ratios between fish and V. fischeri for these hydrophilic compounds can be partly attributed to the differences of bioconcentration between the two species, rather than the differences of reactivity with the target macromolecules. These hydrophilic compounds may more easily pass through the cell membrane of V. fischeri than the gill and skin of fish, react with the target macromolecules and exhibit excess toxicity. The compounds with log KOW > 7 exhibiting very low toxicity (log TR < –1) to both species indicate that the bioconcentration potential of a chemical plays a very important role in the identification of excess toxicity and MOAs.

Comparison of Toxicities to Vibrio fischeri and Fish Based on Discrimination of Excess Toxicity from Baseline Level

Discrimination of excess toxicity from baseline level for ionizable compounds: Effect of pH.

Although algal toxicity is species dependent, it is not clear if compounds share the same modes of action (MOAs) among algal species. Investigations on the algal toxicity to six species show that Pseudokirchneriella subcapitata is the most sensitive species and its toxicity is significantly related to Dunaliella tertiolecta toxicity, but relates poorly to other algal species. The excess toxicity calculated from a baseline model shows that most of the compounds share the same MOAs among different species, but some share different MOAs. Anilides show excess toxicity to P. subcapitata, but not to other species; they are predicted as reactive compounds to P. subcapitata, but narcotics to other algal species. On the other hand, although hydroxyquinones and phenylureas show greater toxicity to P. subcapitata than to any other algal species, they are predicted as reactive compounds to all algal species because of excess toxicity to all species. Development of any quantitative structure–activity relationship model should be based on a single algal species because algal toxicity is species dependent. Several outliers have been observed, such as acids and highly hydrophobic chemicals with long chains. Their toxicities are over-estimated from linear baseline models because of over-estimated logKOW for ionized acids and obstruction of algal cell membranes for long chain compounds.

Comparison of Chemical Toxicity to Different Algal Species Based on Interspecies Correlation, Species Sensitivity, and Excess Toxicity

The internal concentration represented by critical body residue(CBR) is an ideal indicator of the intrinsic toxicity of a chemical that can be used to assess toxicity to aquatic organisms. In this study, we systematically summarized the method for calculation of CBR in fish, CBR values with different modes of toxic action, the relationship between CBR and BCF, and the factors influencing the CBR based on the progress in this field as a result of studies conducted worldwide and our own investigations. The CBRs could be calculated by the LC50 and BCF based on the toxicokinetic model. The modes of toxic action of fish are usually recognized based on classification of organic compounds as acting by non-polar narcosis(baseline compounds), polar narcosis(less inert compounds), or reactive and specific acting mechanisms. Baseline toxicity is associated with chemicals acting narcosis mechanism, which is the reversible suppression of physiological function brought about by hydrophobic binding of chemicals to cell membranes and proteins. The CBRs to fish for narcotic chemicals vary in a narrow range and are close to constant. The CBRs for non-polar narcotic chemicals are higher than those for polar narcotic chemicals. Moreover, non-polar and polar narcotic compounds have different underlying mechanisms. Polar compounds intercalate less deeply into membranes, leading to lower CBR values than non-polar narcotic compounds. Reactive compounds interact and/or react with biological molecules, leading to enhanced toxicity relative to that associated with narcosis, and their CBRs are lower than those of narcotic compounds. Because the CBRs of narcotic compounds are close to constant, their toxicities are mainly affected by bioconcentration and linearly related to hydrophobicity. Conversely, the CBRs of reactive compounds are closely related to the reactivity of chemicals with biomolecules at the target site, with different values being observed for different reactive compounds. Their toxicities are not only related to the bioconcentration factor, but also to the descriptors used to describe the reactivity of chemicals with biomolecules(CBRs). Many factors can affect the CBRs of chemicals. For example, linear models of the relationship between log BCF and log Kow can underestimate the log BCF for compounds with log Kow 0.5 and overestimate the log BCF for compounds with log Kow 7, resulting in larger errors for CBRs calculated from the BCF and LC50 of highly hydrophilic and hydrophobic compounds. Organism size, lipid content, exposure time, metabolism and transformation, and uncertainty of toxic data can also affect the calculation or determination of CBRs.

Evaluation of toxicity data to green algae and relationship with hydrophobicity.

Discrimination of excess toxicity from narcotic effect: influence of species sensitivity and bioconcentration on the classification of modes of action.

Investigation on modes of toxic action to rats based on aliphatic and aromatic compounds and comparison with fish toxicity based on exposure routes.

Comparison of toxicity of class-based organic chemicals to algae and fish based on discrimination of excess toxicity from baseline level.

Investigation of Critical Body Residues and Modes of Toxic Action Based on Injection and Aquatic Exposure in Fish

Effects of TiO2 nanoparticles on ROS production and growth inhibition using freshwater green algae pre-exposed to UV irradiation.

Relationship between lethal toxicity in oral administration and injection to mice: effect of exposure routes.

Effect of exposure routes on the relationships of lethal toxicity to rats from oral, intravenous, intraperitoneal and intramuscular routes.

A linear free energy analysis of PAMPA models for biological systems.

The discrimination of excess toxicity from baseline effect: effect of bioconcentration.

Investigation on baseline toxicity to rats based on aliphatic compounds and comparison with toxicity to fish: effect of exposure routes on toxicity.

Investigation on the relationship between bioconcentration factor and distribution coefficient based on class-based compounds: The factors that affect bioconcentration.

Discrimination of excess toxicity from narcotic effect: comparison of toxicity of class-based organic chemicals to Daphnia magna and Tetrahymena pyriformis.

Linear and nonlinear relationships between biodegradation potential and molecular descriptors/fragments for organic pollutants and a theoretical interpretation.

Evaluation of joint toxicity of nitroaromatic compounds and copper to Photobacterium phosphoreum and QSAR analysis.

Linear and non-linear relationships between bioconcentration and hydrophobicity: theoretical consideration.

Linear and non-linear relationships between soil sorption and hydrophobicity: model, validation and influencing factors.

Soil contamination is an enormous problem in China and severely threatens environmental quality and food safety. Desorption of contaminants from soil is a critical process controlling the availability of soil contaminants and thus the risk associated with contaminated soil. All the currently adopted desorption models greatly simplify desorption by assuming that desorption is a simple reverse of adsorption. However, numerous studies have shown that desorption is indeed biphasic. A new dual-equilibrium desorption (DED) model to account for the biphasic desorption has been developed and tested using a wide range of laboratory data. In this paper, field data of major rivers in China were modeled with the DED isotherm and the linear isotherm. Results in the present study indicate that the DED model can more accurately quantify desorption of contaminants from soil and sediments, which proposed the application of the dual-equilibrium desorption model.

Applicability of a Dual-Equilibrium Desorption Model to the Desorption of Organic Compounds from the Sediments in China Rivers

Toxicity of organic chemicals to Tetrahymena pyriformis: effect of polarity and ionization on toxicity.

Interspecies correlations of toxicity to eight aquatic organisms: theoretical considerations.

Toxicity of substituted benzenes and algae (Scenedesmus obliquus) with solvation equation

Evaluation and QSAR Study of Joint Toxicity of Substituted Phenols and Cadmium to Photobacterium phosphoreum

Heavy metal pollution in intertidal sediments from Quanzhou Bay, China.

The biodegradability of 30 substituted phenols and benzoic acids was determined by BOD technique. The molecular weight (Mw), heat of formation (Hf) and the energy of the highest occupied molecular orbital (E(Homo)) of the studied compounds were calculated by the quantum chemical method MOPAC6.0-AMI. The quantitative structure-biodegradability relationships (QSBRs) were developed by the linear regression method and neural network approach, respectively. It has been shown that the neural network method is able to provide a superior fit to the training set data and test set data and produce a lower prediction error than the linear regression method.

Quantitative structure-activity relationships (QSARs) were developed for 43 aromatic compounds toxicity to Photobacterium phosphoreum and Daphnia magna based on four methods: octanol/water partition coefficient, linear solvation energy relationship, molecular connectivity index and group contribution. Through the evaluation of four QSAR methods, LSER was proved to be the best. And it applied to the widest range of chemicals with the greatest accuracy.

Comparative study of four QSAR models of aromatic compounds to aquatic organisms.

The toxicities of 33 non-polar narcotics and 15 polar narcotics have been correlated with the logarithm of the octanol-water partition coefficient (log P). Correlations have also been obtained of toxicities with polarisabilities (α) and free energy hydrogen bond acceptor factors (Ca) calculated using HYBOT-PLUS. There are clear differences in the way non-polar and polar narcotics correlate with log P and with α and Ca, indicating that the two classes of compound exert their toxicity by somewhat different mechanisms.

QSAR Studies of Compounds Acting by Polar and Non-polar Narcosis: an Examination of the Role of Polarisability and Hydrogen Bonding

Acute toxicity of 25 narcotic compounds to D. magna was determined in this paper. Acute/ Chronic Ratios (ACRs), which are often used to estimate chronic toxicity from acute toxicity data, are discussed based on Quantitative Structure‐Activity Relationships (QSARs) of the compounds between both acute and chronic toxicity data and n‐octanol/water partition coefficients, and an improved equation is derived to estimate chronic toxicity data from acute toxicity data. Application of the improved equation and ACRs is illustrated for D. magna and fathead minnow to estimate chronic toxicity from acute toxicity.

Acute/chronic ratios to estimate chronic toxicity from acute data

Theoretical quantitative structure-activity relationships have been established based on narcotic mechanisms of action and toxicity data to the fathead minnow, Daphnia magna and Vibrio fischeri. The results confirmed that hydrophobicity is important in modelling narcosis. However, the results of the present investigation also confirmed that molecular bulk may play an important role in toxicity to aqueous organisms, especially in the toxicity to organisms with lower lipid content, for example, V. fischeri. The results are discussed in the light of other inter-species differences that may occur as a consequence of accumulation and clearance kinetics and the relative metabolism of xenobiotics by each organism. Because of the complex tissue structure of organisms, classification of narcotic compounds using hydrophobicity parameters alone can sometimes lead to errors.

Quantitative Structure-Activity Relationships of Chemicals Acting by Non-polar Narcosis—Theoretical Considerations

Quantitative structure-activity relationships of nitroaromatic compounds to four aquatic organisms

Abstract In this paper, a new approach to measure Lewis acidity and basicity of benzene and its derivates, by molecular forces as predomaint mechanism is presented. The difference between partition coefficients in various solvent systems is mainly due to solvent‐solute interactions which are Lewis acid‐base action in a broad sense on the basis of valency‐bond theory. The logarithm difference of partition coefficients of compounds in di‐n‐butyl ether/water and in cyclohexane/water systems were used as the measurement of Lewis acidity, while the logarithm difference of partition coefficients in cholorform/water and in carbon tetrachloride/water systems were used as the measurement of Lewis basicity. Then, both qualitative analysis and quantitative comparison with solvatochromic parameters (hydrogen donor acidity α, hydrogen acceptor β, and dipolarity/polarizability π∗) were presented for these two parameters, which showed that they were reasonable although obtained by an approximate method. Finally, they we...

QUANTIFICATION AND APPLICATION OF LEWIS ACIDITY AND BASICITY OF BENZENE AND ITS DERIVATES

Effects of substituted anilines and phenols on root elongation of cabbage seed

Evaluation of the partitioning of hydrophobic pollutants between aquatic and solid phases in natural systems

USING THEORETICAL SOLVATOCHROMIC PARAMETERS IN PREDICTION OF ACUTE TOXICITY OF SUBSTITUTED AROMATIC COMPOUNDS TO AQUATIC ORGANISMS

Relationships between toxicities of substituted aromatic hydrocarbons to Daphnia magna and to Fathead minnows or Photobacterium phosphoreum were studied based on structure‐activity equations we established. Good relationships between toxicities of chemicals to Daphnia magna and to Fathead minnows, Photobacterium phosphoreum were found for a wide range of chemicals. The toxicity data of fish can be predicted by the toxicity data of Daphnia magna or Photobacterium phosphoreum. It is probable that the toxicities of chemicals to the three organisms are similar.

Predicting toxicities of substituted aromatic hydrocarbons to fish by toxicities to Daphnia Magna or Photobacterium Phosphoreum 1

Quantitative structure‐activity relationships of hydrophobic organic chemicals were studied based on equations we established. Results showed that observed toxicity of hydrophobic organic chemicals were correlated to two physical‐chemical parameters: reaction equilibrium constant of target molecule‐organic chemical; octanol/water partition coefficient. Regression results showed that the molecular connectivity index of first‐order was an ideal parameter instead of the equilibrium constant. Good relationships between toxicity data and the two parameters were found for three aquatic organisms with a wide range of chemicals.

Quantitative structure‐activity relationships of hydrophobic organic chemicals 1

Determination and estimation of physicochemical properties for phenylsulfonyl acetates

Quantitative structure-activity relationships—Relationship between toxicity of organic chemicals to fish and to photobacterium phosphoreum

Sysmex UN2000 detection of protein/creatinine ratio and of renal tubular epithelial cells can be used for screening lupus nephritis

 Objective To explore the association between increased blood eosinophils and frequent pathogens due to the infections in children. Methods A total of 2353 children with acute infections admitted to Guangzhou Women and Children's Medical Center from February 1, 2019 to January 31, 2020 were enrolled in the study. 277 children without infections were comprised the control group. Children’s age, peripheral blood parameters including white blood cells, eosinophils, C-reactive protein (CRP) were recorded. In addition, infection stage and departments the patients admitted to were investigated. Results Blood eosinophil numbers negatively correlated with the age of children, whereas had no relation to disease stage. The means of eosinophil for neonates (<0.1 year)，infancy (<1year) and children >1year with acute infections were 0.67±0.40, 0.40±0.68, 0.15±0.25 *109/L compared with control group matched for age(0.44±0.20, 0.45±0.27, 0.24±0.19*109/L, P <0.001, <0.001, 0.497, respectively). Among them, the mean of eosinophil in the neonates afflicted with acute infections was significantly higher than the others compared to age-matched controls (0.63±0.60 vs 0.44±0.20, P= 0.012). Areas under the curves (AUC) were 0.81 (95% CI 0.75–0.86) for eosinophil combined with CRP and 0.68 (95% CI 0.61–0.75) for CRP alone for acute infections in neonates (P=0.02). Patients admitted in ICU had higher eosinophils than outpatients (0.46±0.60 vs 0.16±0.24, P <0.001) but had no significant difference compared with control group (0.45±0.20, P >0.99). Conclusion Increased peripheral blood eosinophils may indicate acute infections among neonates. Eosinophil combined with CRP can contribute to evaluating this population.

Increased Peripheral Blood Eosinophils may Indicate Acute Infection in Neonates

B cells emerge from the bone marrow as transitional (TS) B cells that differentiate through T1, T2 and T3 stages to become naïve B cells. We have identified a bifurcation of human B cell maturation from the T1 stage forming IgMhi and IgMlo developmental trajectories. IgMhi T2 cells have higher expression of α4β7 integrin and lower expression of IL4 receptor (IL4R) compared to the IgMlo branch and are selectively recruited into gut-associated lymphoid tissue. IgMhi T2 cells also share transcriptomic features with marginal zone B cells (MZB). Lineage progression from T1 cells to MZB via an IgMhi trajectory is identified by pseudotime analysis of scRNA-sequencing data. Reduced frequency of IgMhi gut homing T2 cells is observed in severe SLE and is associated with reduction of MZB and their putative IgMhi precursors. The collapse of the gut-associated MZB maturational axis in severe SLE affirms its existence and importance for maintaining health.

Human marginal zone B cell development from early T2 progenitors

Preliminary study between IgG antibody in breast milk and neonatal jaundice

OBJECTIVE
To analyze serological and molecular characteristics of a case with Bw11 subtype.

METHODS
The ABO antigen and antibody in serum were respectively detected with the classical tube method, microcolumn gel method, and absorption and diffusion method. The ABO genotype was determined with PCR using sequence-specific primers (PCR-SSP). Exons 1-7 of the ABO gene were analyzed by Sanger sequencing. Haplotype analysis was carried out for exons harboring variants.

RESULTS
Forward and reverse typing with the microcolumn gel method has suggested type O, while forward and reverse typing with the classical tube method yielded inconsistent results. Absorption and diffusion test confirmed presence of B antigen. Antibody screening excluded presence of alloantibodies. The result of PCR-SSP suggested a B/O1 genotype.A 695T>C variant was identified in exon 7 as compared with the B101/O01 allele, which resulted in conversion of Leucine to Proline at position 232, and was confirmed as Bw11/O1 heterozygote.

The nt695T>C variant probably underlay the weakening of B antigenin the individual. There may be strong anti-B antibodies in Bw11 subtypes. Human-derived and certain monoclonal reagents may not detect Bw11 subtypes which is easy to be misjudged as type O. Application of molecular methods can identify ABO subtypes with accuracy.

Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics

Irritable bowel disease with CMV and EB virus mixed infection (with video)

Spatiotemporal segregation of human marginal zone and memory B cell populations in lymphoid tissue

Lymphocyte subset expression and serum concentrations of PD-1/PD-L1 in sepsis - pilot study

Objective 
To investigate the prevalence of Adenovirus(ADV) in respiratory infections in cilldren of chaoshan area and study the clinical symptoms associated with it. 
 
Methods 
2 668 nasopharyngeal aspirates specimens (NPA) were collected from children with respiratory tract infection from July 2012 to June 2016 in the Second Affiliated Hospital of Shantou University Medical College.Multiplex polymerase chain reaction (PCR) was applied to detect 10 kinds of viruses including adenovirus (ADV), respiratory syncytial virus (RSV), Human Rhinoviruses(HRV), WU Polyomavirus(WUPyV), human Boca virus (HBoV), influenza virus A, B type (InfA、InfB), parainfluenza virus type 1, 3, (PIV-1、PIV-3), human metapneumovirus (HMPV). The clinical characteristic of these ADV-positive cases were analyzed. 
 
Results 
There were 1 388 samples (52.02%) of the 2 668 NPA specimens were positive for viruses, which included 95(3.53%) cases positive for ADV.ADV infection could occur in a whole year and occurred in children at age of 0-6 years, especially at age of 0-3 years.The clinical symptoms of ADV infection included fever, cough, wheeze and polypnea.The co-infection group, with the increase of the number of the virus, the more obvious symptoms of cough and wheezing.Only 4 cases (4/95, 4.21%) diagnosed as severe pneumonia. 
 
ADV infection is not in the pandemic stage in chaoshan area from July 2012 to June 2016.ADV co-infected with other virus are common.The clinical manifestation, laboratory examination and imaging examination in children with ADV infection show no specific features.The co-infection groups, with the increase of the number of the virus, the more obvious symptoms of cough and wheezing.The clinical symptoms are generally mild for nearly 4 years of ADV respiratory infection in chaoshan area which has a low incidence of severe pneumonia. 
 
Key words: 
Adenovirus; Respiratory infections; Clinical symptoms; Severe

Epidemiological and clinical analysis of children with respiratory tract infection of Adenovirus in Chaoshan area

The principles of allelic exclusion state that each B cell expresses a single light and heavy chain pair. Here, we show that B cells with both kappa and lambda light chains (Igκ and Igλ) are enriched in some patients with the systemic autoimmune disease systemic lupus erythematosus (SLE), but not in the systemic autoimmune disease control granulomatosis with polyangiitis. Detection of dual Igκ and Igλ expression by flow cytometry could not be abolished by acid washing or by DNAse treatment to remove any bound polyclonal antibody or complexes, and was retained after two days in culture. Both surface and intracytoplasmic dual light chain expression was evident by flow cytometry and confocal microscopy. We observed reduced frequency of rearrangements of the kappa‐deleting element (KDE) in SLE and an inverse correlation between the frequency of KDE rearrangement and the frequency of dual light chain expressing B cells. We propose that dual expression of Igκ and Igλ by a single B cell may occur in some patients with SLE when this may be a consequence of reduced activity of the KDE.

Immunoglobulin light chain allelic inclusion in systemic lupus erythematosus

Correction. Immunoglobulin light chain allelic inclusion in systemic lupus erythematosus.

Clonal Distribution of B Cells Between Distant Foci of Gut-Associated Lymphoid Tissue in Humans.

OBJECTIVE
Granulomatosis with polyangiitis (GPA) is a rare and sometimes fatal systemic autoimmune disease. ANCAs specific for PR3 are associated with GPA. Remission in GPA can be achieved through B cell depletion (BCD) therapy. Our aim was to understand whether the frequencies of T cell subsets are influenced by BCD.

METHODS
The frequencies of circulating T follicular helper cells (cTFHs) and regulatory T cells (Tregs) from 36 GPA patients including 11 rituximab-treated patients and 10 healthy controls were studied by flow cytometry. The functional capacity of Tregs was assessed by in vitro co-culture assays.

RESULTS
We observed an increased frequency of cTFHs and a reduced frequency of antigen-experienced Tregs in peripheral blood from GPA patients on conventional therapies but not in those treated with rituximab compared with healthy controls. Furthermore, the ratio of cTFHs to Tregs was significantly higher in GPA patients on conventional therapies than in GPA patients treated with rituximab who were clinically improved or controls. Whereas Tregs were numerically reduced in GPA patients on conventional therapy, the suppressive capacity of Tregs on a per cell basis was not significantly altered in these individuals.

Our study illustrated increased cTFHs with decreased antigen-experienced Tregs in GPA patients on conventional therapies, but in B cell-depleted patients the levels of cTFHs and Tregs were similar to healthy controls. The negative correlation between cTFHs and Tregs implies the balance between T cell subsets and its B cell dependence impact on disease activity in GPA.

Circulating T follicular helper cell and regulatory T cell frequencies are influenced by B cell depletion in patients with granulomatosis with polyangiitis.

Objective To study the curative effect and mechanism of Kangxianling prescription of the professor GUO Zhen-qiu on schistosomiasis liver fibrosis treatment based on syndrome differentiation.Methods Based on syndrome differentiation,schistosomiasis patients with liver fibrosis were divided into 3 groups including Kangxianling prescriptionⅠ group(blood stasis with qi deficiency type),Kangxianling prescriptionⅡ group(blood stasis with qi stagnation type) and western medicine convention treatment group(two type mixing).After treatment for 40 days,clinical manifestation of disease and their curative effects,images of liver and spleen by B ultrasonic and their curative effects,the changes of collagen metabolism and plasma fibrinolytic enzyme indexes were observed.Results(1) After 40 days treatment,10 common disease manifestations of schistosomiasis liver fibrosis reduced obviously,the integral value of clinical disease manifestation were reduced by 7.76 points and 6.59 points respectively,disease manifestation total effective rates were 93.9% and 93.3% in the two Kangxianling prescription groups,respectively,which were significantly higher than those in western medicine convention treatment group(P0.01);(2) 7 indicators of the liver and spleen B ultra were improved obviously,B ultrasonic indexes differences between before treatment and after treatment in the two Kangxianling prescription groups were significantly higher than those in western medicine convention treatment group(P0.01);(3) The levels of serum HA and s HYP were significantly reduced and the levels of plasma PL and its activities were significantly increased in the two Kangxianling prescription groups,and all these changes were higher than those in western medicine convention treatment group.Conclusion The Kangxianling prescriptionⅠand Ⅱbased on syndrome differentiation of professor GUO Zhen-qiu have good effects of resistance to schistosomiasis liver fibrosis,which may be related with the regulation of the liver collagen metabolism,the inhibition of liver fiber interstitial cell proliferation,the improvement of the plasma PL activity,and then the repair of damaged tissues in the liver.

Clinical research of schistosomiasis liver fibrosis treatment with Kangxianling prescription

OBJECTIVE
Granulomatosis with polyangiitis (GPA) is a rare chronic autoimmune disease that may be triggered by upper airway infection. ANCAs specific for PR3 that is expressed by activated neutrophils and macrophages are associated with GPA. Our aim was to investigate regional immune mechanisms that might induce or support the autoimmune response in GPA.

METHODS
Biopsy samples from 77 patients including 8 with GPA were studied by immunohistochemistry. B-cell homing subsets in blood samples from 16 patients with GPA and 11 healthy controls were studied by FACS. The distribution of B-cell clones was searched in paired biopsies and blood samples from one patient by analysing immunoglobulin heavy chain gene (IGH) junctional sequences.

RESULTS
Activated B cells were located alongside PR3-expressing cells and B-cell survival factors BAFF and APRIL in mucosa from patients with GPA. We detected APRIL production by the granulomas and giant cells. B cells were proliferating in all cases and persistent for 5 years in biopsies obtained from one patient. However, there was no evidence of B-cell clones from the mucosal biopsies circulating in peripheral blood in GPA or any numerical or proportional change in B-cell subsets expressing markers of regional homing in blood in GPA.

Our study illustrates chronically activated B cells alongside autoantigens and B-cell survival factors in the mucosa in GPA.

Granulomatosis with polyangiitis involves sustained mucosal inflammation that is rich in B-cell survival factors and autoantigen.

Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics

[Underlying diseases in neonates requiring mechanical ventilation].

OBJECTIVE
To study the relationship between microbial gene 16SrRNA and intrauterine infection.

METHODS
Thirty cases of single preterm birth were enrolled, including 16 cases due to premature rupture of membranes (PROM) (rupture time>18 hrs), 6 cases due to spontaneous preterm birth and 8 cases due to iatrogenic preterm birth. Ten cases of single term birth were used as the control group. Fetal membrane and placenta samples were obtained. Amniotic fluid, blood from cord or newborn babies as well as gastric fluid and tracheal secretions from infants with mechanical ventilation were also obtained. The histological features of placenta and fetal membranes were observed. Polymerase chain reaction (PCR) was used to detect the presence of microbial 16SrRNA and ureaplasma urealyticum (UU) in placenta, fetal membranes and other samples.

RESULTS
Twenty-one (70%) cases were diagnosed as chorioamnionitis, characterized by neutrophil infiltration in fetal membrane and placenta tissues, especially in fetal membranes. Chorioamnionitis was most frequent in babies whose gestational age less than 32 weeks or birth weight lower than 1 500 g. Positive 16SrRNA gene was found in 12 cases, and positive UU gene in 10 cases in the preterm birth group. Neither 16SrRNA nor UU gene was detected in the control group. The PROM preterm babies developed more frequent infection than the babies premature born due to other causes, but there were no statistically significant differences in the incidence of infection.

Chorioamnionitis may be the major cause of PROM and premature birth. The detection of microbial genes is valuable in identification of intrauterine infection.

[Value of microbial gene 16SrRNA in the identification of antenatal infection].

Acinetobacter baumannii is one of the most common pathogens in nosocomial infection.In recent years,multi-drug resistant and pan-drug resistant Acinetobacter baumannii have been increasing,which seriously threatens clinical therapy. This article reviews the clinical antibiotic-resistant mechanisms of Acinetobacter baumannii. 
 
Key words: 
Acinetobacter baumannii; Drug-resistant mechanism

Mechanism of clinical antibiotic-resistant Acinetobacter baumannii

Mechanical ventilation plays an important role in the treatment of preterm infants,especially respiratory problems.With improvement in both antenatal and neonatal care and therapeutic strategies,premature babies are surviving more than ever.However,the incidence of bronchpulmonary dysplasia remains high which affects the clihical outcomes of premature infants.Non-invasive respiratory support techniques have been used in attempts to decrease lung injury and the complications of preterm infants.This review will focus on various ventilation modalities for managing preterm infants with respiratory failure and lung protective ventilation strategies to minimize lung injury in preterm infants. 
 
Key words: 
Mechanical ventilation; Infant,newborn,preterm; Respiratory distress syndrome; Bronchopulmonary dysplasia

Antisense transcripts of V(D)J rearrangements; artifacts caused by false priming?

Objective To explose the relationship between advanced schistosomiasis japonica and hepatitis. Methods 1∶1 and 1∶2 matched case control study was used in this study. Controls were chronic schistosomiasis patients and normal persons. Each group has 213 cases or persons. History of schistosomiasis, hepatitis and family's hepatitis were investigated and HBsAg, HBsAb, HBcAb, HBeAg, HBeAb were detected. SAS 6.12 software was used for statistical analysis. χ 2 test and conditional logistic regression were used. Results The prevalence rates of hepatitis and family's hepatitis and positive rates of HBsAg, HBcAb, HBeAg, HBeAb, HBsAg ++HBcAb ++HBeAg + and HBsAg ++HBcAb ++HBeAb + in advanced schistosomiasis patients (23.94%, 15.96%, 29.11%, 37.09 %, 15.02%, 38.50%, 4.23%, 19.72%) was significantly higher than that in chronic schistosomiasis patients (9.39%, 5.63 %, 14.08 %, 16.90%, 7.51%, 20.19%, 0, 7.89%) and normal persons(7.51%, 5.16%, 15.02%, 20.19%, 1.88%, 19.25 %, 0, 9.86%)( P 0.05). The results of conditional logistic analysis showed that the Odds ratio(OR) of HBsAg ++HBcAb ++HBeAg + and HBeAg + reached 20.934 and 8.00 high respectively (advanced schistosomiasis patients and normal persons 1∶1 matched). Conclusion Advanced schistosomiasis and hepatitis had a closed relationship. It may think that these two diseases have a promotion relationship each other.

A MATCHED STUDY OF RELATIONSHIP BETWEEN ADVANCED SCHISTOSOMIASIS JAPONICA AND HEPATITIS B

In the light of mathematical maximum likelyhood method,the conditioned probabitity of clinical manifestations in TCM syndrome of hyperlipidemia′s phlegm stasis was calculated to establish a “List of Quantitative Diagnosis Index of TCM Manifestations Differentiation for Phlegm Stasis in Hyperlidemia”.Based on the scoring of the above list,the rate of coincidence of retro spective test(susceptibility,particularity,accuracy,feasibility)of the three signs was more than 83%,and parameters of prospective test were more than 63% respectively.It suggested that list of quantitative diagnosis index be practical.

Investigation on Quantitative Diagnosis of Clinical Manifestations of Hyperlidemia Diagnosed on the Basis of Differentiation of Phlegm Stasis

By using WAB binder to adhere the surgical incision, satisfactory results could be achieved with fewer inflammatory reactions, less blood oozing, quick healing and good shape. It was proved better than the traditional suture.

Clinical Application of WAB Organism Binder in Adhering Surgical Operation Incision

Establishment of a novel loach-deodorization technology based on gas chromatography-ion mobility spectroscopy analysis

We investigated the protective effects and possible mechanisms of Aplysin against alcohol-induced liver injury. Rats were given daily either alcohol only (alcohol model group; 8 to 12 mL/kg body weight), one of three doses of Aplysin (50, 100, or 150 mg/kg Aplysin) plus alcohol, or volume-matched saline. After 6 weeks, the effects of Aplysin were assessed in terms of changes in histology, biochemical indices, and DNA oxidative damage. Potential mechanisms were analyzed through measurements of lipid peroxidation, antioxidant defense systems, expression of cytochrome P450 2E1, and expression of apoptosis-related genes. We found that Aplysin significantly protected the liver against alcohol-induced oxidative injury, evidenced by improved hepatic histological structure, inhibited alcohol-induced elevation of serum biochemical indices, attenuated extents of hepatocellular DNA damage. At a mechanistic level, Aplysin alleviated alcohol-induced oxidative stress as illustrated by the revivification of erythrocyte membrane fluidity, the attenuation of glutathione depletion, the restoration of antioxidase activities, and reduced malondialdehyde overproduction. Furthermore, the mRNA levels of Bax, cytochrome c, and cytochrome P450 2E1 were significantly down-regulated, whereas those of Bcl-2 and caspase-9 and caspase-3 were markedly up-regulated. These findings suggest that Aplysin provides significant protection against alcohol-induced liver injury, possibly through alleviating oxidative damage and modulating endogenous apoptosis-related genes expression.

PRACTICAL APPLICATION
Many natural components derived from alga have been used in the food, cosmetics, and biomedicine industries. Aplysin, a marine bromosesquiterpene, was extracted from the red alga Laurencia tristicha, which could effectively protect against alcohol-induced liver injury, might be a potential natural sources for preventing alcoholic liver damage.

Aplysin Protects Against Alcohol-Induced Liver Injury Via Alleviating Oxidative Damage and Modulating Endogenous Apoptosis-Related Genes Expression in Rats.

Eucalyptus alkaline peroxide mechanical pulp (APMP) fibers were modified by a low-temperature plasma (LTP) treatment within an air and oxygen mixture. An atomic force microscope (AFM) and electronic spectroscopy chemical analysis (ESCA) were used to analyze the morphological and chemical information of eucalyptus APMP fibers. According to the AFM results, LTP treatment etched the fibers’ surface, allowing for the removal of hydrophobic substances from the surface. According to the ESCA, the oxygen to carbon ratio of the APMP fiber surface increased from 50.08% to 55.47%, and the C1 peak area decreased from 8.89% to 8.45% after a LTP treatment. All of these results indicate that a LTP treatment can modify the APMP fibers and reduce the contents of lignin and extractives, thus exposing more carbohydrate.

Surface Characterization of Plasma-treated Eucalyptus Alkaline Peroxide Mechanical Pulp using Electronic Spectroscopy Chemical Analysis and Atomic Force Microscopy

Lignin-based anion exchangers (L-AE) were prepared by reacting lignin with epichlorohydrin and triethylamine in the presence of N,N-dimethylformamide and a catalyst. A multi-factor and multi-level orthogonal design of experiment was carried out in order to obtain the optimal conditions for the preparation of lignin-based anion exchangers. The optimized parameters including the dosages of catalysts, the amounts of triethylamine, graft reaction time, and the graft reaction temperature were defined. Data of nitrate removal and yield were used as performance indicators of the products prepared. The results indicated that the reaction temperature was the primary factor. The optimal synthesis reaction parameters were lignin:pyridine:triethylamine = 2 g:3 mL:12 mL. The optimal experimental temperature was 70 °C, and the reaction time was 7 h. The yield was 188.6% and the nitrate removal was 91.2%. Under some reaction conditions, the yields were found greater than 100%; this was due to the grafted mass from epoxidation with epichlorohydrin and quaternization (through the reaction of epoxide with triethylamine).

Preparation of Lignin-Based Anion Exchangers and their Utilization for Nitrate Removal

Transcutaneous electrical cranial‐auricular acupoint stimulation (TECAS) is a novel non‐invasive therapy that stimulates acupoints innervated by the trigeminal and auricular vagus nerves. An assessor‐blinded, randomized, non‐inferiority trial was designed to compare the efficacy of TECAS and escitalopram in mild‐to‐moderate major depressive disorder.

Transcutaneous electrical cranial‐auricular acupoint stimulation versus escitalopram for mild‐to‐moderate depression: An assessor‐blinded, randomized, non‐inferiority trial

Objective: To explore more refined classification methods of congenital middle ear cholesteatoma (CMEC) based on two existing staging systems. Subjects and Methods: This study involved a retrospective data review of 57 patients (61 ears involved) with CMEC requiring the surgical treatment. Patients were classified into different stages according to Nelson, Potsic, and Modified Nelson staging system. Preoperative data and intraoperative findings were recorded. Results: The mean age at operation was 15 ± 15.04 years with a median of 10 years. The main clinical manifestation was hearing loss (72.13%). CMEC mass was mainly located in the posterior portion of the tympanic cavity (65.57%). No patient was classified into Potsic stage II. The erosion of incus happened in all cases. Patients with Nelson type 2 and type 3 had erosions to the structures out of middle ear, such as dura mater, lateral semicircle canal, and facial canal. Postoperative follow-up time was more than 24 months. Recurrence occurred in four patients (6.56%), all of them in Nelson type 2, who had received canal wall down mastoidectomy (three cases) and canal wall up mastoidectomy (one case). Conclusions: Nelson staging system was more suitable for advanced CMEC patients than Potsic staging system. The rare case of Potsic stage II restricted the application of Potsic staging system. Moreover, since both of two staging systems do not distinguish the type of involved ossicles, the authors recommended to subdivide Nelson type 2 into type 2a and type 2b based on the erosion of the ossicular chain, as well as subdivide Nelson type 3 into type 3a and 3b based on the erosion of structures out of middle ear, which was named as Modified Nelson staging system.

Suggestion of a Modified Classification for Congenital Middle Ear Cholesteatoma: Based on the Clinical Characteristics and Staging of Fifty-Seven Patients.

Objective: The goal of this study was to determine whether laparoscopic splenectomy and esophagogastric devascularization (LSD) are superior to open splenectomy and esophagogastric devascularization (OSD) for portal hypertension. Methods: Articles comparing LSD and OSD for portal hypertension were searched in databases. Evaluated endpoints were operation outcomes, postoperation recovery, and postoperation complications. Results: Ten studies that recruited a total of 629 patients were identified for inclusion. Longer operation time [mean difference (MD), 43.15; 95% confidence interval (CI), 29.65 to 56.66; P < 0.00001], less intra-operation blood loss (MD, -149.31; 95% CI, -210.26 to -88.36; P < 0.00001), earlier time of passing flatus (MD, -1.13; 95% CI, -1.55 to -0.71; P < 0.00001), earlier time of oral intake (MD, -1.68; 95% CI, -2.03 to -1.33; P < 0.00001), less overall morbidity [odds ratio (OR), 0.58; 95% CI, 0.35-0.97; P = 0.04] and shorter hospital stay (MD, -4.30; 95% CI, -6.44 to -2.16; P < 0.0001) in the LSD group. There was no significant difference between the two groups in transfusion rate, hospital mortality, hospitalization cost, and bleeding recurrence rates. Conclusions: Laparoscopic splenectomy and esophagogastric devascularization is a feasible, effective, and safe surgical procedure, and is advantageous over open surgery for the treatment of portal hypertension.

Laparoscopic versus open splenectomy and esophagogastric devascularization for portal hypertension : a meta-analysis

This paper is concerned with semantic parsing for English as a second language (ESL). Motivated by the theoretical emphasis on the learning challenges that occur at the syntax-semantics interface during second language acquisition, we formulate the task based on the divergence between literal and intended meanings. We combine the complementary strengths of English Resource Grammar, a linguistically-precise hand-crafted deep grammar, and TLE, an existing manually annotated ESL UD-TreeBank with a novel reranking model. Experiments demonstrate that in comparison to human annotations, our method can obtain a very promising SemBanking quality. By means of the newly created corpus, we evaluate state-of-the-art semantic parsing as well as grammatical error correction models. The evaluation profiles the performance of neural NLP techniques for handling ESL data and suggests some research directions.

Grapheme-to-phoneme (G2P) conversion plays an important role in building a Mandarin Chinese text-to-speech (TTS) system, where the polyphone disambiguation is an indispensable task. However, most of the previous polyphone disambiguation models are trained on manually annotated datasets, which are suffering from data scarcity, narrow coverage, and unbalanced data distribution. In this paper, we propose a framework that can predict the pronunciations of Chinese characters, and the core model is trained in a distantly supervised way. Specifically, we utilize the alignment procedure used for acoustic models to produce abundant character-phoneme sequence pairs,which are employed to train a Seq2Seq model with attention mechanism. We also make use of a language model that is trained on phoneme sequences to alleviate the impact of noises in the auto-generated dataset. Experimental results demonstrate that even without additional syntactic features and pre-trained embeddings, our approach achieves competitive prediction results, and especially improves the predictive accuracy for unbalanced polyphonic characters. In addition, compared with the manually annotated training datasets, the auto-generated one is more diversified and makes the results more consistent with the pronunciation habits of most people.

Distant Supervision for Polyphone Disambiguation in Mandarin Chinese

It is reasonable to hypothesize that the divergence patterns formulated by historical linguists and typologists reflect constraints on human languages, and are thus consistent with Second Language Acquisition (SLA) in a certain way. In this paper, we validate this hypothesis on ten Indo-European languages. We formalize the delexicalized transfer as interpretable tree-to-string and tree-to-tree patterns which can be automatically induced from web data by applying neural syntactic parsing and grammar induction technologies. This allows us to quantitatively probe cross-linguistic transfer and extend inquiries of SLA. We extend existing works which utilize mixed features and support the agreement between delexicalized cross-linguistic transfer and the phylogenetic structure resulting from the historical-comparative paradigm.

Constructing a Family Tree of Ten Indo-European Languages with Delexicalized Cross-linguistic Transfer Patterns

Attention-based sequence-to-sequence architectures have made great progress in the speech recognition task. The SpeechTransformer, a no-recurrence encoder-decoder architecture, has shown promising results on small-scale speech recognition data sets in previous works. In this paper, we focus on a large-scale Mandarin Chinese speech recognition task and propose three optimization strategies to further improve the performance and efficiency of the SpeechTransformer. Our first improvement is to use a much lower frame rate, which is shown very beneficial to not only the computation efficiency but also the model performance. The other two strategies are scheduled sampling and focal loss, which are both very effective to reduce the character error rate (CER). On a 8,000 hours task, the proposed improvements yield 10.8%-26.1% relative gain in CER on four different test sets. Compared to a strong hybrid TDNN-LSTM system, which is trained with LF-MMI criterion and decoded with a large 4-gram LM, the final optimized Speech-Transformer gives 12.2%-19.1% relative CER reduction without any explicit language models.

The Speechtransformer for Large-scale Mandarin Chinese Speech Recognition

This paper studies semantic parsing for interlanguage (L2), taking semantic role labeling (SRL) as a case task and learner Chinese as a case language. We first manually annotate the semantic roles for a set of learner texts to derive a gold standard for automatic SRL. Based on the new data, we then evaluate three off-the-shelf SRL systems, i.e., the PCFGLA-parser-based, neural-parser-based and neural-syntax-agnostic systems, to gauge how successful SRL for learner Chinese can be. We find two non-obvious facts: 1) the L1-sentence-trained systems performs rather badly on the L2 data; 2) the performance drop from the L1 data to the L2 data of the two parser-based systems is much smaller, indicating the importance of syntactic parsing in SRL for interlanguages. Finally, the paper introduces a new agreement-based model to explore the semantic coherency information in the large-scale L2-L1 parallel data. We then show such information is very effective to enhance SRL for learner texts. Our model achieves an F-score of 72.06, which is a 2.02 point improvement over the best baseline.

Semantic Role Labeling for Learner Chinese: the Importance of Syntactic Parsing and L2-L1 Parallel Data

With the improvement of speech recognition, voice products are gradually applied to every scene of life. The existing approaches to handle various scenarios are often to build many different acoustic models using scenario-dependent data only, with each for a special scene. The obvious weakness of these approaches is that it seriously hampers the large-scale application and maintenance of voice products. To address this issue, acoustic modeling based on context-independent syllables optimized with CTC loss is presented for multiple scenarios of Mandarin speech recognition. On the one hand, context-independent modeling overcomes the shortcomings of context-dependent modeling overfitting a particular scene. Also, it sidesteps decision trees used in context-dependent modeling so that there is no need to consider the building of decision tree and whether to start training again in a real application. On the other hand, choosing longer-length syllable acoustic units can effectively preserve the co-articulation effect that context-dependent phone can model. Also, syllables in the Chinese language have its inherent advantages, as its number is fixed and it is trainable, effective generalization and better robustness. This paper also explores the differences between wideband and narrowband data caused by the front-end signal acquisition block, and proposes a unified training method based on the use of VGG in the bottom layer, and introduces layer normalization. The experimental results demonstrate that the proposed syllable-based CTC acoustic model for multiple scenarios can achieve more than 15% and 7% relatively improvement for mobile phone data and telephone data separately compare with scenarios-dependent modeling.

Syllable-Based Acoustic Modeling with CTC for Multi-Scenarios Mandarin speech recognition

Overview of the NLPCC 2018 Shared Task: Grammatical Error Correction

The use of future contextual information is typically shown to be helpful for acoustic modeling. However, for the recurrent neural network (RNN), it's not so easy to model the future temporal context effectively, meanwhile keep lower model latency. In this paper, we attempt to design a RNN acoustic model that being capable of utilizing the future context effectively and directly, with the model latency and computation cost as low as possible. The proposed model is based on the minimal gated recurrent unit (mGRU) with an input projection layer inserted in it. Two context modules, temporal encoding and temporal convolution, are specifically designed for this architecture to model the future context. Experimental results on the Switchboard task and an internal Mandarin ASR task show that, the proposed model performs much better than long short-term memory (LSTM) and mGRU models, whereas enables online decoding with a maximum latency of 170 ms. This model even outperforms a very strong baseline, TDNN-LSTM, with smaller model latency and almost half less parameters.

Gated Recurrent Unit Based Acoustic Modeling with Future Context

Motivated by the positive impact of empty category on syntactic parsing, we study neural models for pre- and in-parsing detection of empty category, which has not previously been investigated. We find several non-obvious facts: (a) BiLSTM can capture non-local contextual information which is essential for detecting empty categories, (b) even with a BiLSTM, syntactic information is still able to enhance the detection, and (c) automatic detection of empty categories improves parsing quality for overt words. Our neural ECD models outperform the prior state-of-the-art by significant margins.

Word-Level Permutation and Improved Lower Frame Rate for RNN-Based Acoustic Modeling

The shared-hidden-layer multilingual deep neural network (SHL-MDNN), in which the hidden layers of feed-forward deep neural network (DNN) are shared across multiple languages while the softmax layers are language dependent, has been shown to be effective on acoustic modeling of multilingual low-resource speech recognition. In this paper, we propose that the shared-hidden-layer with Long Short-Term Memory (LSTM) recurrent neural networks can achieve further performance improvement considering LSTM has outperformed DNN as the acoustic model of automatic speech recognition (ASR). Moreover, we reveal that shared-hidden-layer multilingual LSTM (SHL-MLSTM) with residual learning can yield additional moderate but consistent gain from multilingual tasks given the fact that residual learning can allievate the degradation problem of deep LSTMs. Experimental results demonstrate that SHL-MLSTM can relatively reduce word error rate (WER) by 2.1-6.8\% over SHL-MDNN trained using six languages and 2.6-7.3\% over monolingual LSTM trained using the language specific data on CALLHOME datasets. Additional WER reduction, about relatively 2\% over SHL-MLSTM, can be obtained through residual learning on CALLHOME datasets, which demonstrates residual learning is useful for SHL-MLSTM on multilingual low-resource ASR.

Multilingual Recurrent Neural Networks with Residual Learning for Low-Resource Speech Recognition

Theoretical and empirical evidences indicate that the depth of neural networks is crucial to acoustic modeling in speech recognition tasks. Unfortunately, the situation in practice always is that with the depth increasing, the accuracy gets saturated and then degrades rapidly. In this paper, a novel multidimensional residual learning architecture is proposed to address this degradation of deep recurrent neural networks (RNNs) on acoustic modeling by further exploring the spatial and temporal dimensions. In the spatial dimension, shortcut connections are introduced to RNNs, along which the information can flow across several layers without attenuation. In the temporal dimension, we cope with the degradation problem by regulating temporal granularity, namely, splitting the input sequence into several parallel sub-sequences, which can ensure information flowing across the time axis unimpededly. Finally, we place a row convolution layer on the top of all recurrent layers to comprehend appropriate information from several parallel sub-sequences to feed to the classifier. Experiments are illustrated on two quite different speech recognition tasks and 10% relative performance improvements are observed.

Multidimensional Residual Learning Based on Recurrent Neural Networks for Acoustic Modeling

This paper proposes a novel memory neural network structure, namely gating recurrent enhanced memory network (GREMN), to model long-range dependency in temporal series on language identification (LID) task at the acoustic frame level. The proposed GREMN is a stacking gating recurrent neural network (RNN) equipped with a learnable enhanced memory block near the classifier. It aims at capturing the long-span history and certain future contextual information of the sequential input. In addition, two optimization strategies of coherent SortaGrad-like training mechanism and a hard sample score acquisition approach are proposed. The proposed optimization policies drastically boost this memory network based LID system, especially on the large disparity training materials. It is confirmed by the experimental results that the proposed GREMN possesses strong ability of sequential modeling and generalization, where about 5% relative equal error rate (EER) reduction is obtained comparing with the approximate-sized gating RNNs and 38.5% performance improvements is observed compared to conventional i-Vector based LID system.

Gating Recurrent Enhanced Memory Neural Networks on Language Identification

Recurrent neural networks (RNNs) with a gating mechanism have been shown to give state-of-the-art performance in acoustic modeling, such as gated recurrent unit (GRU), long short-term memory (LSTM), long short-term memory projected (L-STMP), etc. But little is known about why these gated RNNs work and what the differences are among these networks. Based on a series of experimental comparison and analysis, we find that: a) GRU usually performs better than LSTM, for possibly GRU is able to modulate the previous memory content through the learned reset gates, helping to model the long-span dependence more efficiently for speech sequence; b) LSTMP shows comparable performance with GRU, since LSTMP has the similar ability of information selection and combination by an automatic learned linear transformation in a weight-sharing way. In experiments, a visual analysis method is adopted to understand the historical information selection mechanism in RNNs in contrast to DNN. Experimental results on three different speech recognition tasks demonstrate the above conclusions and 5%–13% relative PER or CER reduction is observed.

2016 10th International Symposium on Chinese Spoken Language Processing (ISCSLP)

Investigating gated recurrent neural networks for acoustic modeling

This paper proposes a novel attention-based recurrent neural network (RNN) to build an end-to-end automatic language identification (LID) system. Inspired by the success of attention mechanism on a range of sequence-to-sequence tasks, this work introduces the attention mechanism with long short term memory (LSTM) encoder to the sequence-to-tag LID task. This unified architecture extends the end-to-end training method to LID system and dramatically boosts the system performance. Firstly, a language category embedding module is used to provide attentional vector which guides the derivation of the utterance level representation. Secondly, two attention approaches are explored: a soft attention which attends all source frames and a hard one that focuses on a subset of the sequential input. Thirdly, a hybrid test method which traverses all gold labels is adopted in the inference phase. Experimental results show that 8.2% relative equal error rate (EER) reduction is obtained compared with the LSTM-based frame level system by the soft approach and 34.33% performance improvement is observed compared to the conventional i-Vector system.

End-to-End Language Identification Using Attention-Based Recurrent Neural Networks

With the increasing development and application of information and communication technologies, multi-database mining is becoming more and more important. Association rules mining is the major topic in multi-database. According to Piatetsky-Shapiropsilas argument, an association rule is interesting only if the rule meets the minimum interestingness condition. In this paper, we extended this condition to mine association rules in multi-database and improved it to check the correlation of association rules. An algorithm PNAR_MDB _on P-S measure is proposed and the experimental results demonstrated the algorithm is effective.

2008 International Conference on Intelligent Computation Technology and Automation (ICICTA)

Mining Positive and Negative Association Rules in Multi-database Based on Minimum Interestingness

(Dated: A proper genuine multipartite entanglement (GME) measure has been found for three-qubit pure states [see Xie and Eberly, Phys. Rev. Lett. 127 , 040403 (2021)], but capturing useful entanglement measures for mixed states remains an open challenge. So far, it requires not only a full tomography in experiments, but also huge calculational labor. A leading proposal was made by G¨uhne, Reimpell, and Werner [Phys. Rev. Lett. 98 , 110502 (2007)], who used expectation values of entanglement witnesses to describe a lower bound estimation of entanglement. We provide here an extension that also gives genuine upper bounds of entanglement. This advance requires only the expectation value of any Hermitian operator. Moreover, we identify a class of operators A 1 which not only give good estimations, but also require a remarkably small number of experimental measurements. In this note we deﬁne our approach and illustrate it by calculating entanglement measures for a number of pure and mixed states prepared in recent experiments.

Experimental study of quantum uncertainty from lack of information

Recently, a proper genuine multipartite entanglement measure has been found for three-qubit pure states [see Xie and Eberly, Phys. Rev. Lett. 127, 040403 (2021)PRLTAO0031-900710.1103/PhysRevLett.127.040403], but capturing useful entanglement measures for mixed states has remained an open challenge. So far, it requires not only a full tomography in experiments, but also huge calculational labor. A leading proposal was made by Gühne, Reimpell, and Werner [Phys. Rev. Lett. 98, 110502 (2007)PRLTAO0031-900710.1103/PhysRevLett.98.110502], who used expectation values of entanglement witnesses to describe a lower bound estimation of entanglement. We provide here an extension that also gives genuine upper bounds of entanglement. This advance requires only the expectation value of any Hermitian operator. Moreover, we identify a class of operators A_{1} that not only give good estimates, but also require a remarkably small number of experimental measurements. In this Letter, we define our approach and illustrate it by estimating entanglement measures for a number of pure and mixed states prepared in our recent experiments.

Yuan-Yuan Zhao,1, 2, 3, ∗ Filip Rozpędek,4, 5, 6, ∗ Zhibo Hou,1, 3 Kang-Da Wu,1, 3 Guo-Yong Xiang,1, 3, † Chuan-Feng Li,1, 3 and Guang-Can Guo1, 3 Key Laboratory of Quantum Information, University of Science and Technology of China, CAS, Hefei, 230026, China Center for Quantum Computing, Peng Cheng Laboratory, Shenzhen 518055, China CAS Center for Excellence in Quantum Information and Quantum Physics, University of Science and Technology of China, Hefei, 230026, China QuTech, Delft University of Technology, Lorentzweg 1, 2628 CJ Delft, The Netherlands Kavli Institute of Nanoscience, Delft University of Technology, Lorentzweg 1, 2628 CJ Delft, The Netherlands Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA (Dated: May 20, 2021)

Quantum uncertainty from lack of information: experimental verification

 If the presence of entanglement could be certified in a device-independent (DI) way, it is likely to provide various quantum information processing tasks with unconditional security. Recently, it was shown that a DI protocol, combining measurement-device-independent techniques with self-testing, is able to verify all entangled states, however, it imposes demanding requirements on its experimental implementation. In this work, we propose a much less-demanding protocol based on Einstein-Podolsky-Rosen (EPR) steering to certify entanglement. We establish a complete framework for DI verification of EPR steering in which all steerable states could be verified. We then analyze its robustness towards noise and imperfections of self-testing by considering the measurement scenario with three settings at each side. Finally, a four-photon experiment is implemented to demonstrate that even Bell local states can be device-independently verified. Our work may pave the way for realistic applications of secure quantum information tasks.

Device-independent verification of Einstein-Podolsky-Rosen steering

Einstein-Podolsky-Rosen steering is operationally defined as an entanglement verification task between two parties when one of their measurement devices is untrusted. Recent progress shows that the trustness of the other device can even be removed by preparing a set of tomographically complete quantum states along with it, in which the scheme is dubbed a measurement-device-independent (MDI) scenario. A benefit of the MDI scheme is that the original trusted measurement device does not need to perform quantum state tomography to characterize the set of steerable resources. In this work, we theoretically construct quantitative MDI steering witnesses without prior knowledge about the resource. By using these witnesses, we experimentally, for the first time, quantify the degree of steerability of the underlying steerable resource merely based on the observed statistics. Moreover, our result is not affected by the detection bias between the detectors of the Bell-state measurement. Finally, as two by-products, our experimental data directly estimates, also for the first time in a MDI manner, the degree of entanglement of the underlying state as well as the degree of measurement incompatibility of the involved measurements.

Experimental measurement-device-independent quantification of quantum steering.

Experimental demonstration of measurement-device-independent measure of quantum steering

Detecting a change point is a crucial task in statistics that has been recently extended to the quantum realm. A source state generator that emits a series of single photons in a default state suffers an alteration at some point and starts to emit photons in a mutated state. The problem consists in identifying the point where the change took place. In this work, we consider a learning agent that applies Bayesian inference on experimental data to solve this problem. This learning machine adjusts the measurement over each photon according to the past experimental results finds the change position in an online fashion. Our results show that the local-detection success probability can be largely improved by using such a machine learning technique. This protocol provides a tool for improvement in many applications where a sequence of identical quantum states is required.

Experimentally detecting a quantum change point via the Bayesian inference

It is well known that the violation of a local uncertainty relation can be used as an indicator for the presence of entanglement. Unfortunately, the practical use of these nonlinear witnesses has been limited to few special cases in the past. However, new methods for computing uncertainty bounds have become available. Here we report on an experimental implementation of uncertainty-based entanglement witnesses, benchmarked in a regime dominated by strong local noise. We combine the new computational method with a local noise tomography in order to design noise-adapted entanglement witnesses. This proof-of-principle experiment shows that quantum noise can be successfully handled by a fully quantum model in order to enhance the ability to detect entanglement.

Entanglement Detection by Violations of Noisy Uncertainty Relations: A Proof of Principle.

Wave-particle duality is a typical example of Bohr's complementarity principle that plays a significant role in quantum mechanics. Previous studies used the visibility of an interference pattern to quantify the wave property and used path information to quantify the particle property. However, coherence is the core and basis of the interference phenomenon. If we could use coherence to characterize the wave property, the understanding of wave-particle duality would be strengthened. A recent theoretical work [ Phys. Rev. Lett.116, 160406 (2016)] found two relations between quantum coherence and path information. Here, we demonstrate the new measure of wave-particle duality based on two kinds of coherence measures quantitatively for the first time. The wave property, quantified by the coherence in the l1-norm measure and the relative entropy measure, can be obtained via tomography of the target state, which is encoded in the path degree of freedom of the photons. The particle property, quantified by the path information, can be obtained via the discrimination of detector states, which is encoded in the polarization degree of freedom of the photons. Our work may deepen people's understanding of coherence and provide a new perspective regarding wave-particle duality.

Experimental demonstration of wave-particle duality relation based on coherence measure.

Quantum resource theories seek to quantify sources of nonclassicality that bestow quantum technologies their operational advantage. Chief among these are studies of quantum correlations and quantum coherence. The former isolates nonclassicality in the correlations between systems, and the latter captures nonclassicality of quantum superpositions within a single physical system. Here, we present a scheme that cyclically interconverts between these resources without loss. The first stage converts coherence present in an input system into correlations with an ancilla. The second stage harnesses these correlations to restore coherence on the input system by measurement of the ancilla. We experimentally demonstrate this interconversion process using linear optics. Our experiment highlights the connection between nonclassicality of correlations and nonclassicality within local quantum systems and provides potential flexibilities in exploiting one resource to perform tasks normally associated with the other.

Experimental Cyclic Interconversion between Coherence and Quantum Correlations.

Quantum state tomography is a key technology for fully determining a quantum state. Unfortunately, standard quantum state tomography is intractable for general many-body quantum states, because the number of measurements and the post-processing time increase exponentially with the size of the system. However, for the matrix product states (MPSs), there exists an efficient method using linearly scaled local measurements and polynomially scaled post-processing times. In this study, we demonstrate the validity of the method in practice by reconstructing a four-photon MPS from its local two- or three-photon reduced-density matrices with the presence of statistical errors and systematical errors in experiment.

Experimental demonstration of efficient quantum state tomography of matrix product states.

Experimental detection of entanglement polytopes via local filters

The Heisenberg's error-disturbance relation is a cornerstone of quantum physics. It was recently shown to be not universally valid and two different approaches to reformulate it were proposed.The first one focuses on how error and disturbance of two observables, A and B, depend on a particular quantum state. The second one asks how a joint measurement of A and B affects their eigenstates. Previous experiments focused on the first approach. Here, we focus on the second one. Firstly, we propose and implement an extendible method for quantum walk-based joint measurements of noisy Pauli operators to test the error-disturbance relation for qubits. Then, we formulate and experimentally test a new universally valid relation for the three mutually unbiased observables. We therefore establish a fundamentally new method of testing error-disturbance relations.

Heisenberg's error-disturbance relations: A joint measurement-based experimental test

We report an experimental implementation of a single-qubit generalised measurement scenario(POVM) based on a quantum walk model. The qubit is encoded in a single-photon polarisation. The photon performs a quantum walk on an array of optical elements, where the polarisation-dependent translation is performed via birefringent beam displacers and a change of the polarisation is implemented with the help of wave-plates. We implement: (i) Trine-POVM, i.e., the POVM elements uniformly distributed on an equatorial plane of the Bloch sphere; (ii) Symmetric-Informationally- Complete (SIC) POVM; and (iii) Unambiguous Discrimination of two non-orthogonal qubit states.

Experimental realisation of generalised qubit measurements based on quantum walks

Heisenberg's error-disturbance relations: a quantum walk-based experimental test

Dicke state is an widely used type of multi-particle entangled state in quantum information. However, very few works have been done on its nonlocality. Here we prepare a four-photon symmetric Dicke state, whose fidelity is as high as 0.904 ± 0.004, and devise a simple Bell-type inequality to demonstrate that it violates the local realism with 12 standard deviation.

Experimental violation of the local realism for four-qubit Dicke state.

Background: Gastric cancer is one of the most important malignancies with poor prognosis. Ferroptosis and cuproptosis are newly discovered metal-dependent types of programmed cell death, which may directly affect the outcome of gastric cancer. Long noncoding RNAs (lncRNAs) can affect the prognosis of cancer with stable structures, which could be potential prognostic prediction factors for gastric cancer. Methods: Differentially expressed metal-dependent programmed cell death (PCD)-related lncRNAs were identified with DESeq2 and Pearson’s correlation analysis. Through GO and KEGG analyses and GSEA , we identified the potential effects of metal-dependent PCD-related lncRNAs on prognosis. Using Cox regression analysis with the LASSO method, we constructed a 12-lncRNA prognostic signature model. Also, we evaluated the prognostic efficiency with Kaplan–Meier (K-M) survival curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) methods. The sensitivities for antitumor drugs were then predicted with the pRRophetic method. Also, we discuss Chinese patent medicines and plant extracts that could induce metal-dependent programmed cell death. Results: We constructed a metal-dependent PCD-related lncRNA-gene co-expression network. Also, a metal-dependent PCD-related gastric cancer prognostic signature model including 12 lncRNAs was constructed. The K-M survival curve revealed a poor prognosis in the high-risk group. ROC curve analysis shows that the AUC of our model is 0.766, which is better than that of other published models. Moreover, the half-maximum inhibitory concentration (IC50) for dasatinib, lapatinib, sunitinib, cytarabine, saracatinib, and vinorelbine was much lower among the high-risk group. Conclusion: Our 12 metal-dependent PCD-related lncRNA prognostic signature model may improve the OS prediction for gastric cancer. The antitumor drug sensitivity analysis results may also be helpful for individualized chemotherapy regimen design.

Metal-dependent programmed cell death-related lncRNA prognostic signatures and natural drug sensitivity prediction for gastric cancer

Objective Lung cancer has high morbidity and mortality. We aimed to determine the value of netrin-1 for the diagnosis and chemotherapeutic monitoring of lung cancer. Methods Thirty pairs of lung cancer tissues and serum were collected. Netrin-1 expression was detected by immunohistochemistry and enzyme-linked immunosorbent assay. Netrin-1 expression was downregulated in A549 cells using small interfering RNA, and the effect of netrin-1 on cisplatin-induced lung cancer cell apoptosis was determined by flow cytometry. Results Netrin-1-positivity was significantly higher in lung cancer tissues than in paracarcinoma tissues and high expression of netrin-1 was closely related to a poor prognosis. Serum netrin-1 levels were also significantly higher in lung cancer patients than in healthy donors, and were higher in patients with lung cancer before the beginning of chemotherapy compared with after the completion of four cycles of chemotherapy. Netrin-1 knockdown increased the rate of cisplatin-induced apoptosis in A549 cells. Conclusions Netrin-1 expression was increased in tissues and serum from lung cancer patients and decreased after chemotherapy, suggesting that it may be a potential diagnostic marker and indicator of chemosensitivity. Netrin-1 may participate in cisplatin resistance by reducing apoptosis, thus providing a new strategy for addressing chemoresistance in patients with lung cancer.

Detection of netrin-1 as a novel biomarker for diagnosis and chemotherapeutic monitoring of lung cancer

In order to solve the problem of early differential diagnosis of ovarian cancer, this paper proposes the role of bioinformatics analysis in early differential diagnosis of ovarian cancer. This method uses bioinformatics methods to mine the existing data in the tumor database and obtain tumor-related molecules. It is an efficient method to obtain effective biomarkers, screen signal pathway molecules, and reveal the internal mechanism of tumor occurrence and development. Using this method can greatly improve the efficiency and reliability of screening diagnosis, prognosis, and treatment targets. The results showed that 5821 new lncRNA transcripts and 4611 new lncRNA genes were identified by lncScore from the assembled transcripts. 10 new lncRNA transcripts and 174 new lncRNA genes were found to be differentially expressed in ovarian cancer.

Role of Bioinformatics Analysis in Early Differential Diagnosis of Ovarian Cancer

Abstract It has been extensively reported that long noncoding RNAs (lncRNAs) were closely associated with multiple malignancies. The aim of our study was to investigate the effects and mechanism of lncRNA POU6F2-AS1 in lung adenocarcinoma (LADC).The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets provided us the information of LADC clinical samples. High-regulation of POU6F2-AS1 was presented in LADC tissues compared with adjacent normal tissues, which was correlated with poor outcome of LADC patients. Functional experiments in Calu-3 and NCI-H460 cells showed that POU6F2-AS1 significantly promoted LADC cell proliferation, colony formation, invasion and migration. Moreover, through online prediction, luciferase reporter assay and Pearson’s correlation analysis, we found that POU6F2-AS1 may act as a competing endogenous RNA (ceRNA) of miR-34c-5p and facilitated the expression of potassium voltage-gated channel subfamily J member 4 (KCNJ4). The promoting effect of cell aggressiveness induced by POU6F2-AS1 was enhanced by KCNJ4, whilst was abrogated due to the overexpression of miR-34c-5p. Collectively, POU6F2-AS1 might function as a ceRNA through sponging miR-34c-5p to high-regulate KCNJ4 in LADC, which indicates that POU6F2-AS1 might be a promising therapeutic target with significant prognostic value for LADC treatment.

Long noncoding RNA POU6F2-AS1 regulates lung cancer aggressiveness through sponging miR-34c-5p to modulate KCNJ4 expression

Metastatic thyroid cancers are more difficult to treat and have a significantly worse prognosis than localized thyroid cancers. Previous studies have shown that follicular helper T cells (Tfh) may participate in antitumor immune responses. Here, we investigated the characteristics of Tfh cells in patients with differentiated thyroid cancer (DTC) at various severities, including patients with localized disease, cervical metastasis, and distant metastasis. In circulating CD4 T cells, the proportion of CD4+CXCR5+ Tfh‐like cells was significantly higher in patients with distant metastasis than in healthy controls, patients with local disease, and patients with cervical metastasis. Also, the expression of Tfh cell‐associated surface molecules, such as PD‐1, ICOS, and BTLA, tended to be higher in patients with cervical and distant metastasis than in healthy controls. However, the expression of secreted molecules, such as IL‐10, IL‐21, and CXCL13, was significantly lower in patients with distant metastasis than in healthy controls and patients with local disease. Additionally, circulating Tfh‐like cells from patients with distant metastasis were less capable of supporting B‐cell growth and IgM secretion. We also examined the CD4+CXCR5+ Tfh‐like cells in tumor samples. Tumor‐infiltrating Tfh‐like cells were highly enriched in the pulmonary metastasis compared to the local tumor and the cervical metastasis. However, tumor‐infiltrating Tfh‐like cells from pulmonary metastasis displayed higher PD‐1, TIM‐3, and lower IL‐21 expression than those from the local tumor. Together, this study identified that the metastasis of DTC patients was associated with an overabundance of defective Tfh cells.

Thyroid cancer metastasis is associated with an overabundance of defective follicular helper T cells

Objective 
To investigate the expression of INPP4B in gastric cancer and its relationship with clinicopathological features and prognosis. 
 
Methods 
The expressions of INPP4B mRNA in fresh cancer tissues of 36 patients with gastric cancer and the paracancerous normal gastric mucosa tissues in the Affiliated Cancer Hospital of Shanxi Medical University between July 2014 and December 2014 were detected by using real-time quantitative polymerase chain reaction (RT-qPCR). The expressions of INPP4B protein and its downstream molecule phosphorylation AKT (p-AKT) in paraffin-embedded tumor tissues and the corresponding margin tissues of 49 gastric cancer patients between January 2010 and December 2010 were detected by using immunohistochemistry. The relationship between the expression of INPP4B and clinicopathological features and prognosis was analyzed. 
 
Results 
RT-qPCR results showed that the expression level of INPP4B mRNA was 0.21±0.04 compared with adjacent cancer normal tissues (t = -2.208, P 0.05). The median overall survival time of patients with INPP4B negative expression was 47 months, and that of patients with INPP4B positive expression was 48 months, and there was no statistical difference (P > 0.05). 
 
The expression of INPP4B in gastric cancer tissue is low, which may play a role of tumor suppressor in the occurrence and development of gastric cancer by affecting the activity of AKT. 
 
Key words: 
Stomach neoplasms; INPP4B; Phosphorylation AKT; Prognosis

Expression of INPP4B in gastric cancer and its clinical significance

[Metastatic ovarian serous adenocarcinoma to clear cell renal cell carcinoma: report of a case].

Climate change and future trends in the Agro-Pastoral Transitional Zone in Northern China: The comprehensive analysis with the historical observation and the model simulation

The heavy rains and flooding characteristics,the flood level and flood forecasting are analyzed,effectively monitoring storm flood,flood control and command correctly,it plays an important role to improve the understanding of region flood rule and the formation mechanism.

2012 "8·04" Heavy Rains and Fooding Analysis in Liaoning Province

The objective of this study was to establish a method of extraction and determination of chlorogenic acid in chrysanthemum bud.Chlorogenic acid was ultrasonically extracted from chrysanthemum bud.The effect of extraction solvent,extraction time and solvent extraction ratio were investigated.The concentrations of chlorogenic acid were quantified using HPLC.The optimal extraction condition was methanol as solvent,80 min as the extraction time and 1:20 as the sample-solvent extraction ratio.This method was simple,rapid and accurate and hence was suitable for measuring the concentration of chlorogenic acid in chrysanthemum bud.

Ultrasonic Extraction of Chlorogenic Acid from Chrysanthemum Bud

Since 2009,Renminbi,China's money,has begun to go global,which will give rise to great challenges and opportunities both to China itself and the world.Internationalization of renminbi means a new era has come in the field of international monetary system.However,there are lots of difficulties and obstacles for the success of internationalization of renminbi.First,China is a big country for its economic size,but not an economic stronger nation.Second,China has developed modern financial system since the open and reforming policy in 1978,but its financial sector is still underdeveloped and therefore China is not a financial power in the world yet.Third,China has achieved great progress in the economic growth,but Chinese politics and military power don't match its economic power.All these factors above will hinder the step of internationalization of renminbi.Under the contemporary political and economic conditions in the world,China only has one hand—economic power to finish its internationalization of renminbi.If the economy of China can maintain long run growth,renminbi would become global currency in the seeable future.

The methodology of the Marxist theory of social development is the premise and foundation of Marx's theory of social development.Overall,materialist analysis,dialectical analysis and critical analysis are the mainly methods of Marx's theory of social development.Specifically,these methodologies include: social ontology and practice theory,human subject theory,contradictory analysis,systems analysis method,individual unity analysis.Researching methodology of Marx's theory of social development,on the one hand,it is helpful to better studying on Marx's theory of social development;on the other hand,it is helpful to our current social development.

The formation of social management and service force is a necessary requirement for the transformation of our society.Social organizations participating in social management and services are the inevitable result of economic and social development.There are four major difficulties on China's current social organizations participating in social management and services: inadequate government support,lack of social support,poor soils of law and problematic of social organization itself.How to solve these problems is the key point.These include: effectively change on the understanding,accelerate the transformation of government functions,strengthen the social self-construction,and build a sound legal system and the construction of social work personnel.

Study on Social Organizations Participating in Social Management and Services

Shanghai as a economic center of our country,attracts a large number of foreign-invested enterprises to invest here and RD internationalization has been improving continuously.This article chooses four indicators,including the perspective of internationalization of RD capital,organization,activity,output,then an longitudinal evaluation approach of differences driving has been used to evaluate the level of RD internationalization of enterprises in shanghai comprehensively.It shows the level of RD internationalization is on the rise overall.

Evaluation of the Level of R&D Internationalization of the Enterprises in Shanghai

Care Ethics emphasis on the expression of care,affection,responsibility,context and fairness,which is important values orientation in a variety of academic discourses.Ecofeminist environmental ethics of care on the basis of the ethics of care reflect the love and care from the construction of the ecological ethics culture,which is a new eco-cultural ethical development.In order to expand care ethics' application to this theory,it is necessary to introduce the view of ecological theory.From the discourse of ecofeminism and in the framework of care ethics,we re-interpreted care ethics' development in the environmental issues.

A Care Ethics Approach to Ecological Culture——Care Ethics of Ecofeminism

There are financing difficulties in coastal development of Nantong due to the large demand of capital and long period of project cycle.Therefore advanced financing mechanisms abroad can be introduced which mainly include sound project classification mechanism,standardized government investment mechanism,well-established social participation mechanism and investment compensation mechanism.While following the principles of being open with no discrimination,not insisting on the ownership of capital,deepening the reform while guarding against risks,protecting environment as industrial standard,Nantong coastal development should strive to establish sound financing mechanisms and construct multiplied financing modes.

Objective To detect Cryptosporidium contamination in tap water and rivers in fifteen cities of Xinjiang.Methods Water samples were collected from fifteen cities in Xinjiang.Samples were tested by a modified form of EPA method 1622 and nested PCR assay,respectively.The modified form of EPA method 1622 consists of several steps,such as filtration with a microporous membrane,elution,immunomagnetic separation,and immunofluorescence assay.Nested PCR was conducted as follows.First,genomic DNA of purified oocysts was extracted with a QIAamp DNA minikit.Two sets of special primers were synthesized based on the sequence of 18S rRNA as described in the literature.After DNA extraction,18SrRNA was amplified by nested PCR.Amplified products were then purified and digested with restriction enzymes SspⅠ and VspⅠ,respectively.Results Cryptosporidium parvum was not detected in tap water from any of the cities.The river water of Urumqi,Changji,Yining,and Tulufan was positive according to the modified form of EPA method 1622.Samples from Urumqi and Yining yielded fragments of about 830 bp according to nested PCR.However,samples from Tulufan and Changji were negative according to PCR.The species of Cryptosporidium isolated from Urumqi and Yining were C.muris,which was preliminarily identified by nested PCR-restriction fragment length polymorphism(nested PCR-RFLP).Conclusion Rivers in Urumqi and Yining were contaminated with Cryptosporidium that was preliminarily identified as C.muris.Sources of contamination must be traced.There was no Cryptosporidium in tap water,and this may be the result of advanced technology and effective management.

Comrade Mao Zedong not only used the scientific theory and cultural ideology to guide artistic creation,but also set an example to apply these theories and ideas to poetry writing.Because he combined literary theory with creative practice,his poetry not only has had profound implication of the traditional culture and possessed the national character and nationalization,but also shown a distinctive artistic characteristic with the democracy and popularity.Therefore,Mao Zedong's poetry not only inherited his predecessors' styles but also broke the old-fashioned stereotypes.He had achieved truly the principle of "the past serving the present" and "promoting innovation" in literary field.Mao Zedong's literary theory and cultural thought and his poetry writing practice play an important role and are major references for building socialism's culture with Chinese characteristics in the contemporary time.

The Traditional Culture Deposits and Distinct Times Characteristics of Mao Zedong's Poems

The article introduced the development status and shortages of emergency rescue system for major hazards in petrochemical works,analyzed the current situation of emergency rescue system for major hazards in a petrochemical plant and builded emergency rescue system for major hazards in the petrochemical plant.

Construction of emergency rescue system for major hazards in petrochemical plant

The paper analyzes the layout problems of tourist services facilities by integration,and tries to set different facilities at reasonable positions,in order to achieve an optimal combination and accommodate the human-made facilities to both the needs of tourists and the natural environment in the scenic areas.

Layout of Tourist Service Facilities in Scenic Areas Based on Space Syntax

The purpose of this paper is to evaluate the impacts of the earthquake on the natural ecosystems in Yushu,i.e.,the quake-stricken area,so as to bring forward recommendations for the post-disaster land use planning.Methods employed include satellite remote sensing measurement,geographical information system and social survey.The results indicate:(1)there are three basic features within the natural ecosystems of quake-stricken area,including high eco-functional values,closed structure and difficult to be restored(;2)the natural ecosystems with high regional values had been obviously influenced by the earthquake,among which the most damaged is the grassland ecosystem.It is concluded that(:1)the post-disaster land use planning in Yushu should insist on the rule of "Ecology First"(;2)land use structure and arrangement should be optimized basing on full consideration of ecological carrying capacity of quake-stricken area,meanwhile it is also based on the proper integration of ecological migration,development of local specific industries,coordination of urban and rural areas,and protection of historical and cultural heritage.

Evaluation on the Loss of Natural Ecosystems in Yushu after the Earthquake and the Land Use Planning

In recent years,with the logistics industry in China's rapid development of the fourth party logistics(4pl) has increasingly become the development of the theory of community and industry concern about the hot spots.This thesis from the concept of 4PL,superiorities and conditions of existing analysis proceed on the basis of the theory,a detailed analysis of the current status of china's logistics industry development of as well as the problems faced by,and to report thereon of corresponding countermeasures.

The Influence of Fourth Party Logistics to China's Logistics Industry

Five TDR instruments were used to measure soil water content under different soil salinity and compared with oven drying measurement.It is shown that soil salinity has significant affect on the measurement accuracy from different TDR instruments.The TDR100 measurement with different of probe length and spacing indicated that the water content measurement increases with increasing soil salinity and even a reasonable value could not come out for high soil salinity and water content.In the lower salinity,the measurement results of various instruments have a consistent trend with the oven drying measurements,and linear function could be used to calibrate the result with R2 above 0.94.

The Impact of Soil Salinity on Measurement of Water Content by Using TDR and the Calibration Method

With the development of higher education,the university students’ moral education was put on the schedule. The combination of Western Care Ethics and humanity view in ancient China points out the way for the development of university education. University moral education should carry out around care themes and pay attention to care practice. Care ethics should permeate in the moral education of students,and combine with actual education. Thus people can do a reasonable choice for the training mode of moral education in university combination with actual education of higher education.

Research on Morality Education in Colleges from the Caring Ethics Perspective

This paper provides a general overview of the latest studies of gender wage gaps in China.It analyzes each study based on its subject,method,data and its findings.Two trends are found in the studies of gender wage gaps in China.Firstly,there is a shift of focus from analysis of differences in mean level wages to that of differences in wages distributed across levels.Secondly,existing research on gender wage gaps has been increasingly integrated with that on gender occupational segregation and gender differences in labor participation.

Aiming to solve the weakness of defining the boundary of the construction land expansion within the current land use general planning,this paper tries to develop a method based on the spatial analysis technology of geographical information system(GIS).After quantitatively calculating the total amount of construction land within the boundary of construction land expansion through mathematical models,fully using the powerful spatial analysis ability of GIS,and comprehensively taking into account the sensitiveness of environment and the feasibility of construction land in different regions,this paper develops a"bottom-up"method to visually and quantitatively define the boundary of the construction land expansion.The result of research shows that the defined elastic boundary of construction land basically accords with the urban structure that planned in the Urban Planning of Beijing 2004-2020,i.e.,the so-called pattern of"two axis,two belts,and poly-centers",which thus reveals accuracy of the newly developed method in this paper.The conclusion of the study shows that the method is reliable and can be applied widely.Furthermore,if the developed method is ameliorated by combining the natural boundaries such as landform,rivers,and the artificial boundaries such as traffic and greenbelts,it will obviously improve the scientificity in defining the boundary of construction land expansion in the current land use general planning.

Planning Method for Defining the Boundary of the Urban and Rural Construction Land Expansion Based on Spatial Analysis Technology of GIS

As a kind of power,public power is special.It works for public profits.It's the reason why people give up part of their own rights.However there must be some organizations or people who master the power to put it in practice.And then the problems are coming,such as depravity.This text announces the origin and representation forms of the fragility of public power,and also analyses the ways to strengthen the public power and methods of decreasing the fragility from the subject and the system of public power.

Application of nitrogen fertilizer is one of the most important measures to increase production.The nitrogen use efficiency is closely related to nitrogen application rate,which decreased significantly with the increasing of nitrogen application rate,while the loss rate and soil residue rate showed upward trend.Most nitrogen was in the form of inorganic nitrogen in soil,including NO-3-N and NH+4-N,and the NO-3-N occupied the most part,while NH+4-N was very little and changed little.The three main types of their whereabouts were absorbed by seasonal crops,residued in the soil in the organic and inorganic form,and lost through various ways.Nitrogen is not only the main nutrient elements for yield formation,but also the necessary element for protein synthesis of wheat.

Research Progress on Dynamic Changes of Nitrogen Fertilizer in Farmland and Effect of Nitrogen Fertilization on Wheat Yield and Quality

After Nanjing Treaty was signed,Britain,Fance and The U.S.A demarcated respective residential district for businessmen one after the other,which became the concession.During several decades,the authorities of the concessions had taken advantage of all kinds of opportunities available for many times to intimidate the Qing government to enlarge the sizes of them.by force.At the time of demise of the Qing Dynasty,the concession in Shanghai extended to Bao Shan,which size of the area was several times bigger than before.

The Historical Review about Hired Kingdom in Shanghai during Late Qing

Traditional Cultures of China have a history of long standing,and have formed their unique characters in the past several thousand years.To criticize the view of Western traditional ethic on "subject-object dichotomy",it is necessary for ecofeminism to absorb these traditional cultures from China,such as "organic holism","harmony between man and nature" and "benevolence",and it is also an important step to develop ecofeminism itself.

Magnolia obovata,Prunus Sargenti and Aesculuschinensis Bunge were used as test materials in order to study the effects of low temperature on physiological and biochemical changes.Overwintering cold resistant mechanism of them was studied.Result showed that-30℃ was the critical temperature of Magnolia obovata during its living through the winter.Changes of proline content and exosmosis conductance rate were significant,which could be considered as the physiological index of identifying cold resistance of Magnolia obovata,Prunus Sargenti and Aesculuschinensis Bunge.

Controling the postacidification of yoghurt by Nisin was studied in this article. Results indicated that adding Nisin to the stirring yogurt can effectively control postacidification under condition of 20 ℃ and 4 ℃, moreover, the organization and the sense organ quality of yogurt are good. But must continue to lengthen guarantees the nature time, considered the product the cost and the quality of material and the feeling in the mouth, the most suitable recruitment is 0.2 g/kg and the sample sense organ quality is fine, and maintains the lactic acid fungus quantity were 107 cfu/mL.

Both ecofeminism and environmental justice are prevailing in the environmental ethnics fields.In this article, the homology and dissimilarity of the two thoughts were expatiated, so as to learning from each other and developing together.

Objective 
To explore the symptom burden of inflammatory bowel disease (IBD) patients and to compare the differences of symptom burden of IBD patients among different general information, disease types, disease state. 
 
Methods 
From April to May 2017, IBD patients in IBD information supporting platform patients of the First Affiliated Hospital of Soochow University were selected as subjects by convenience sampling. The questionnaire survey was carried out with the self-designed general information questionnaire and the adapted Memorial symptom assessment scale (MSAS) sent out by WeChat. The rank test was used to analyze the status of disease burden among patients with different characteristics. 
 
Results 
A total of 265 valid questionnaires were collected totally. There were 32.0 (26.0, 37.0) symptoms which showed one week self-reported by 264 patients. Anenergia was with one of the highest rates of symptom. Anxiety was with one of the highest rates of phychological symptom. The score of symptom burden was 60.0 (24.7, 102.4) . Anenergia and intestinal problems were common in patients with ulcerative colitis. Fatigue, malnutrition and psychological problems were common in patients with Crohn's disease. There were significant differences in scores of total symptom burden among IBD patients with a different situation in disease activities, duration courses, absenteeism or asking for leave due to disease, suspension of schooling or resignation because of disease, whether living with family or not (P<0.05) . 
 
IBD brings serious physical and mental symptom burden to patients. Nurses should strengthen comprehensive assessment and management of symptoms especially in anenergia and phychological symptoms. And then, nurses should take effective nursing intervention according to symptom with different characteristics so as to ease the symptom burden for patients and improve life quality. 
 
Key words: 
Questionnaires; Inflammatory bowel diseases; Symptom burden

Investigation and analysis on symptom burden in inflammatory bowel disease patients

Objective 
To explore the factors affecting non-compliance in bowel preparation for patients undergoing colonoscopy and to provide evidence for improving patients' compliance. 
 
Methods 
Guided by the phenomenological research method, semi-structured interviews were performed among 16 patients who had poor bowel preparation for colonoscopy at the digestive endoscopy center in 3 Class Ⅲ Grade A hospitals in Suzhou from January to April 2017. The data were analyzed by Colaizzi analysis method. 
 
Results 
Through the interviews, the factors influencing bowel preparation compliance were summed up into 3 themes: the neglect of the importance of strict compliance with bowel preparation, the inability to tolerate bowel preparation, and lack of specialized knowledge of bowel preparation. 
 
To improve the compliance of bowel preparation for patients undergoing colonoscopy, medical staff should correctly guide the patients to understand the importance of bowel preparation and ensure the full grasp of the specific requirements, on the other hand, should actively strive to improve the patient's tolerance of bowel preparation. 
 
Key words: 
Colonoscopy; Bowel preparation; Compliance; Qualitative research

Influencing factors of non-compliance in bowel preparation for patients undergoing colonoscopy: a qualitative research

Background/Aim: We conducted a prospective observational study to identify the incidence of and risk factors for inadequate bowel preparation in elderly Chinese patients. Patients and Methods: We enrolled 240 outpatients over 60 years of age scheduled for elective colonoscopy at our university hospital between November 2016 and April 2017. We recorded patient demographics, bowel preparation data, and clinical characteristics. Factors associated with inadequate bowel preparation were identified by multivariate logistical regression analysis. Results: The rate of inadequate bowel preparation was 34.6%. Factors associated with inadequate bowel preparation were a history of abdominal surgery (OR, 2.617; CI, 1.324–5.174; P = 0.006), chronic constipation (OR, 3.307; CI, 1.551–7.054; P = 0.002), non-compliance with dietary instructions (OR, 2.239; CI, 1.122–4.471; P = 0.022), non-compliance with polyethylene glycol (PEG) dosage (OR, 4.576; CI, 1.855–11.287; P = 0.001), walking <30 minutes during preparation (OR, 2.474; CI, 1.261–4.855; P = 0.008), interval between PEG ingestion and the onset of bowel activity (OR, 1.025; CI, 1.010–1.040; P = 0.001), and a last stool that was not clear and watery (OR, 4.191; CI, 1.529–11.485; P = 0.005). Conclusion: The incidence of adequate bowel preparation in elderly patients is not optimal. Walking <30 minutes during the PEG ingestion period may be a surrogate for bowel preparation failure. Future studies should identify elderly patients at risk for poor bowel preparation and develop interventions to improve outcomes in this population.

Saudi Journal of Gastroenterology : Official Journal of the Saudi Gastroenterology Association

The incidence of and risk factors for inadequate bowel preparation in elderly patients: A prospective observational study

Objective 
To explore the effects of cognitive behavior therapy on anxiety, depression and life quality in inflammatory bowel disease (IBD) . 
 
Methods 
The Cochrane Library, Pubmed, EMbase, CNKI, China biological medicine (CBM) , WanFang were searched and the randomised controlled trials (RCTs) related to cognitive-behavioral intervention for IBD data was collected. The RevMan 5.3 was used in statistical analysis. 
 
Results 
A total of 12 RCTs were enrolled in the study. Results showed that cognitive behavior therapy could improve patients' life quality [WMD=7.78, 95%CI (3.30, 12.27) , P=0.000 7], relieve anxiety [SMD=-0.47, 95%CI (-0.78, -0.16) , P=0.01]and depression [SMD=-2.48, 95%CI (-3.13, -1.83) , P 0.05) . 
 
In this systematic review, cognitive-behavioral intervention can improve life quality of patients with IBD and can relieve anxiety and depression of patients with IBD in the short term but with no effects in the long term. 
 
Key words: 
Anxiety; Depression; Quality of life; Cognitive-behavioral intervention; Inflammatory bowel disease; Systematic review

Effects of cognitive-behavioral intervention on anxiety, depression and life quality in inflammatory bowel disease patients: a Meta analysis

Objective 
To investigate the effect of bowel preparation before colonoscopy and its influencing factors. 
 
Methods 
A total of 283 patients with colonoscopy were recruited by convenience sampling method. They were investigated with basic information questionnaire of bowel preparation and their intestinal cleanliness were assessed by the Ottawa Assessment Scale. The status of bowel preparation and it′s influenced factors were analyzed. 
 
Results 
The total score of Ottawa Assessment Scale was (5.37 ± 2.22) points, and the efficiency of intestinal cleaning was only 59%(167/283). Logistic regression analysis showed that age (OR=1.033, P=0.013); history of chronic constipation (OR=10.341, P=0.000); history of appendectomy (OR=5.349, P=0.007); walking time during medication (OR=0.350, P=0.000); incomplete intake of the preparation (OR=0.078, P=0.000), the time interval between the initiation of ingestion and the onset of bowel activity (OR=1.034, P=0.000), defecation frequency (OR=0.794, P=0.004);characteristics of last stool (OR=0.159, P=0.000) were influencing factors of intestinal cleanliness. 
 
The intestinal cleanliness of patients with colonoscopy is still at a low level. In the future, medical personnel should identify patients with risk factors early, and give them specific bowel preparation, so as to improve the quality of bowel preparation effectively. 
 
Key words: 
Colonoscopy; Bowel preparation; Influencing factors

Investigation on the effect of bowel preparation before colonoscopy and its influencing factors

Geosynthetic-reinforced soil structures are mostly used to retain subgrade slope of highway and railway. For the design and performance analyses of geosynthetic-reinforced soil structures under repeated loading, such as those induced by compaction, traffic and earthquakes, the understanding of cyclic soil–geosynthetic interface behaviour is of great interest. Nevertheless, experimental data concerning this type of behaviour are very scarce. A laboratory study was carried out and is described in this paper. This paper presents the behaviour of an interface between a coarse-grained soil and a geogrid under cyclic loading conditions. A large-scale direct shear test device able to perform displacement-controlled cyclic tests was used. The results obtained are presented and discussed, especially the effects of the displacement amplitude and normal stress on the shear stiffness and damping ratio are investigated. The dynamic response parameters of the soil-geosynthetic interface are greatly affected by the number of cycles, and the variations in the two parameters with the number of cycles are related to the normal stress and the shear displacement amplitude. when at large displacements, the damping ratio decreases first and then stabilizes with the number of cycles. However, at small displacement, the shear stiffness and damping ratio are all decrease somewhat at the initial stage of cyclic shearing. As the experimental materials used in this study are relatively single, and further experimental research should be carried out in the future. The shear parameters of interface in this study can provide reference for the design of reinforced soil structure.

Experimental study on the shear stiffness and damping ratio of the coarse-grained soil against geogrid interface

In order to study the transient characteristics of a nuclear reactor coolant pump in coast-down process under power failure condition, a transient test device for the nuclear reactor coolant pump is set up. This study investigates the effects of the rotor of the nuclear reactor coolant pump and the circuit characteristics on the nuclear reactor coolant pump during the coast-down process by changing the rotary inertia of the flywheel and the resistance of the pipe system. The results show that the greater the moment of inertia is, the more slowly rotational speed, flow, and lift get down in the same coast-down period. The change in the pipe resistance has little effect on the rate of decline in the coast-down process, but it has a great influence on the descent speed of the flow rate and lift. When the pipe resistance is small, the corresponding flow rate decreases faster, but it is slower for the corresponding lift. The results are of great significance in controlling the stability and reliability of the nuclear reactor coolant pump in the coast-down process.

An Experimental Study on Transient Characteristics of a Nuclear Reactor Coolant Pump in Coast-Down Process Under Power Failure Condition

Background Prior national data showed a substantial in‐hospital mortality in septal myectomy (SM) with an inverse volume–outcomes relationship. This study sought to assess the contemporary outcomes of septal reduction therapy and volume–outcome relationship in obstructive hypertrophic cardiomyopathy. Methods and Results All septal reduction therapy admissions between 2010 to 2019 in the United States were analyzed using the National Readmission Databases. Hospitals were stratified into tertiles of low‐, medium‐, and high‐volume based on annualized procedural volume of alcohol septal ablation and SM. Of 19 007 patients with obstructive hypertrophic cardiomyopathy who underwent septal reduction therapy, 12 065 (63%) had SM. Two‐thirds of hospitals performed ≤5 SM or alcohol septal ablation annually. In all SM encounters, 482 patients (4.0%) died in‐hospital post‐SM. In‐hospital mortality was <1% in 1505 (88.4%) hospitals, 1% to 10% in 30 (1.8%) hospitals, and ≥10% in 167 (9.8%) hospitals. There were 63 (3.7%) hospitals (averaging 2.2 SM cases/year) with 100% in‐hospital mortality. Post‐SM (in low‐, medium‐, and high‐volume centers, respectively), in‐hospital mortality (5.7% versus 3.9% versus 2.4%, P=0.003; adjusted odds ratio [aOR], 2.86 [95% CI, 1.70–4.80], P=0.001), adverse in‐hospital events (21.30% versus 18.0% versus 12.6%, P=0.001; aOR, 1.88 [95% CI, 1.45–2.43], P=0.001), and 30‐day readmission (17.1% versus 12.9% versus 9.7%, P=0.001; adjusted hazard ratio, 1.53 [95% CI, 1.27–1.96], P=0.001) were significantly higher in low‐ versus high‐volume hospitals. For alcohol septal ablation, the incidence of in‐hospital death and all other outcomes did not differ by hospital volume. Conclusions In‐hospital SM mortality was 4% with an inverse volume‐mortality relationship. Mortality post‐alcohol septal ablation was similar across all volume tertiles. Morbidity associated with SM was substantial across all volume tertiles.

Hospital Procedural Volume and Clinical Outcomes Following Septal Reduction Therapy in Obstructive Hypertrophic Cardiomyopathy

Baseline and Longitudinal Imaging of Hypertrophic Cardiomyopathy in the Era of Emerging Therapeutics

Evolving epidemiology of transthyretin amyloid cardiomyopathy due to increased recognition in women.

Quantification of kappa opioid receptor ligand potency, efficacy and desensitization using a real-time membrane potential assay

We tested the hypothesis that exposure of glut3+/- mice to a ketogenic diet ameliorates autism-like features, which include aberrant behavior and electrographic seizures. We first investigated the life course sex-specific changes in basal plasma-cerebrospinal fluid (CSF)-brain metabolic profile, brain glucose transport/uptake, glucose and monocarboxylate transporter proteins, and adenosine triphosphate (ATP) in the presence or absence of systemic insulin administration. Glut3+/- male but not female mice (5 months of age) displayed reduced CSF glucose/lactate concentrations with no change in brain Glut1, Mct2, glucose uptake or ATP. Exogenous insulin-induced hypoglycemia increased brain glucose uptake in glut3+/- males alone. Higher plasma-CSF ketones (β-hydroxybutyrate) and lower brain Glut3 in females vs males proved protective in the former while enhancing vulnerability in the latter. As a consequence, increased synaptic proteins (neuroligin4 and SAPAP1) with spontaneous excitatory postsynaptic activity subsequently reduced hippocampal glucose content and increased brain amyloid β1-40 deposition in an age-dependent manner in glut3+/- males but not females (4 to 24 months of age). We then explored the protective effect of a ketogenic diet on ultrasonic vocalization, sociability, spatial learning and memory, and electroencephalogram seizures in male mice (7 days to 6 to 8 months of age) alone. A ketogenic diet partially restored sociability without affecting perturbed vocalization, spatial learning and memory, and reduced seizure events. We conclude that (1) sex-specific and age-dependent perturbations underlie the phenotype of glut3+/- mice, and (2) a ketogenic diet ameliorates seizures caused by increased cortical excitation and improves sociability, but fails to rescue vocalization and cognitive deficits in glut3+/- male mice.

Sex-Specific Life Course Changes in the Neuro-Metabolic Phenotype of Glut3 Null Heterozygous Mice: Ketogenic Diet Ameliorates Electroencephalographic Seizures and Improves Sociability

Endogenous Ovarian Hormones Affect Mitochondrial Efficiency in Cerebral Endothelium via Distinct Regulation of PGC-1 Isoforms

Early life nutrient restriction impairs blood–brain metabolic profile and neurobehavior predisposing to Alzheimer’s disease with aging

Insulin resistance plays an important role in the development of nonalcoholic fatty liver disease (NAFLD).At present,numerous studies support the two “hits” theory of NAFLD.The first “hit” on insulin resistance leads to hepatocyte simplicity steatosis,and the second “hit” indicates that hepatocyte steatosis may result in the fat cells transformation,inflammatory reaction,oxidative stress,and endoplasmic reticulum stress,damaging the function of liver cells,aggravating insulin resistance,and promoting the development of NAFLD. 
 
Key words: 
Nonalcoholic fatty liver disease; Insulin resistance; Insulin receptor substrate

Different pancreatic islet β cell function index for the evaluation of glucose metabolism in type 2 diabetes

Estrogen has well‐known vasoprotective effects. In cerebral arteries, we previously demonstrated that estrogen affects contractility by enhancing release of endothelial vasodilators nitric oxide (NO) and prostacyclin via both genomic and non‐genomic actions. We now report an additional mechanism by which estrogen acutely alters cerebrovascular tone in the absence of functional endothelium. Isolated segments of female mouse basilar artery relaxed upon exposure to either estrogen (EC50 = 1 x 10‐6 M) or the estrogen receptor (ER) alpha agonist, PPT (EC50 = 7 x 10‐7 M); these effects were inhibited by the ER antagonist, fulvestrant. DPN, an ER beta agonist, was relatively ineffective. Surprisingly the effects of estrogen and PPT were not blocked by inhibitors of NO synthase or cyclooxygenase. These findings indicate that ER alpha on the vascular smooth muscle mediates direct relaxation in cerebral arteries. This effect would complement the endothelial effects of estrogen to release vasodilators NO and PGI2. Moreover, such smooth muscle‐mediated relaxation may persist under conditions of endothelial dysfunction. [NIH Grant HL50775; Lundbeck Fdn; Candice Fdn]

Estrogen receptor alpha mediates endothelial‐independent relaxation of cerebral arteries

We examined the effects of 45‐min hypoxia (FiO2 0.08; Hx) vs. normoxia (FiO2 0.21; Nx) on the ipsilateral (Ipsi) and contralateral (Ctrl) sides of the brain in neuronal glucose transporter isoform 3 (Glut3) heterozygous null mice (glut3+/−) and their wild‐type littermates (WT), undergoing unilateral carotid artery ligation. Glut3+/− mice, under Nx, demonstrated a compensatory increase in blood–brain barrier/glial Glut1 protein concentration and a concomitant increase in neuronal nitric oxide synthase (nNOS) enzyme activity and Bax protein, with a decrease in procaspase 3 protein (P < 0.05 each). After Hx, reoxygenation in FiO2 of 0.21 led to no comparable adaptive up‐regulation of the ipsilateral brain Glut3 or Glut1 protein at 4 hr and Glut1 at 24 hr in glut3+/− vs. WT. These brain Glut changes in glut3+/− but not WT mice were associated with an increase in proapoptotic Bax protein and caspase‐3 enzyme activity (P < 0.01 each) and a decline in the antiapoptotic Bcl‐2 and procaspase‐3 proteins (P < 0.05 each). Glut3+/− mice after Hx demonstrated TUNEL‐positive neurons with nuclear pyknosis in most ipsilateral (hypoxic‐ischemia) brain regions. A subset (∼55%) of glut3+/− mice developed spontaneous seizures after hypoxic‐ischemia, confirmed by electroencephalography, but the WT mice remained seizure‐free. Pentylenetetrazole testing demonstrated an increased occurrence of longer lasting clinical seizures at a lower threshold in glut3+/− vs. WT mice, with no detectable differences in monamine neurotransmitters. We conclude that hypoxic‐ischemic brain injury in glut3+/− mice exacerbates cellular apoptosis and necrosis and precipitates spontaneous seizures. © 2010 Wiley‐Liss, Inc.

Hypoxic‐ischemic brain injury exacerbates neuronal apoptosis and precipitates spontaneous seizures in glucose transporter isoform 3 heterozygous null mice

Neuronal Glucose Transporter Isoform 3 Deficient Mice Demonstrate Features of Autism Spectrum Disorders

It has been shown that reactive oxygen species (ROS) contribute to the central effect of ANG II on blood pressure (BP). Recent studies have implicated an antihypertensive action of estrogen in ANG II-infused female mice. The present study used in vivo telemetry recording and in vitro living mouse brain slices to test the hypothesis that the central activation of estrogen receptors in male mice inhibits ANG II-induced hypertension via the modulation of the central ROS production. In male wild-type mice, the systemic infusion of ANG II induced a significant increase in BP (Delta30.1 +/- 2.5 mmHg). Either central infusion of Tempol or 17beta-estradiol (E2) attenuated the pressor effect of ANG II (Delta10.9 +/- 2.3 and Delta4.5 +/- 1.4 mmHg), and the protective effect of E2 was prevented by the coadministration of an estrogen receptor, antagonist ICI-182780 (Delta23.6 +/- 3.1 mmHg). Moreover, the ganglionic blockade on day 7 after the start of ANG II infusions resulted in a smaller reduction of BP in central Tempol- and in central E2-treated males, suggesting that estrogen inhibits the central ANG II-induced increases in sympathetic outflow. In subfornical organ slices, the application of ANG II resulted in a 21.5 +/- 2.5% increase in ROS production. The coadministration of irbesartan, an ANG II type 1 receptor antagonist, or the preincubation of brain slices with Tempol blocked ANG II-induced increases in ROS production (-1.8 +/- 1.6% and -1.0 +/- 1.8%). The ROS response to ANG II was also blocked by E2 (-3.2 +/- 2.4%). The results suggest that the central actions of E2 are involved in the protection from ANG II-induced hypertension and that estrogen modulation of the ANG II-induced effects may involve interactions with ROS production.

Central estrogen inhibition of angiotensin II-induced hypertension in male mice and the role of reactive oxygen species.

It has been shown that superoxide is involved in ANG II‐stimulated activation of the central nervous system (CNS), and that nitric oxide (NO) acts as a sympathoinhibitory substance within the CNS. The present study tested the effects of L‐NAME and Tempol on Ang II induced hypertension. Aortic blood pressure was measured in conscious, freely moving wild‐type male mice with the use of telemetry implants. Tempol (50 μg/kg/min, n=7), L‐NAME (500 μg/kg/d, n=3), or both (n=5) were chronically infused into lateral ventricle by brain infusion assembly with attached osmotic pump. ANG II (800 ng/kg/min) infused subcutaneously via an implanted osmotic pump increased MAP 31.1±2.4 mmHg (107.8±1.1 to137.8 ± 1.8 mmHg, n=6). Central infusions of Tempol, L‐NAME, or both did not change the basal blood pressure. However, Tempol attenuated the pressor effects of Ang II in male mice (137.8 ± 1.8, n=6 to 114.4 ± 2.6 mmHg, n=7), while L‐NAME had no effect (137.8 ± 1.8, n=6 to 133.3 ± 1.9 mmHg n=3). The change in blood pressure induced by Ang II during central infusion of both Tempol and L‐NAME was greater than that seen in infusion of Tempol alone (18.6 ±2.5, n=5 vs 10.9 ± 2.3 mmHg, n=3). Together, these data indicate that superoxide is a key mediator of excitatory actions of Ang II in CNS and that NO may modulate these effects.

The effects of L‐NAME and Tempol in Ang II induced hypertension in male mice

 Plant leaf litter decomposition provides a source of energy and nutrients in forest ecosystems. In addition to traditional environmental factors, the degradation process of litter is also affected by plant functional traits and litter quality. However, at the community level, it is still unclear whether the relative importance of plant traits and litter quality on the litter decomposition rate is consistent. A year-long mixed leaf litter decomposition experiment in a similar environment was implemented by using the litterbag method in seven typical forest types in Dongling Mountain, Beijing, North China, including six monodominant communities dominated by Juglans mandshurica, Populus cathayana, Betula dahurica, B. platyphylla, Pinus tabuliformis and Larix gmelinii var. principis-rupprechtii and one codominant community dominated by Fraxinus rhynchophylla, Quercus mongolica and Tilia mongolica. The results showed that there were considerable differences in the litter decomposition rate (k-rate) among the different forest types. The community weighted mean (CWM) traits of green leaves and litter quality explained 35.60% and 9.05% of the k-rate variations, respectively, and the interpretation rate of their interaction was 23.37%, indicating that the CWM traits and their interaction with litter quality were the main factors affecting the k-rate variations. In the RDA, leaf nitrogen content, leaf dry matter content, leaf tannin content and specific leaf area were the main factors affecting the k-rate variations. Therefore, we suggest that future studies should focus on the effects of the CWM traits of green leaves on litter decomposition at the community level.

Leaf litter decomposition characteristics and controlling factors across two contrasting forest types

The Endophytic Fungus Phomopsis liquidambaris Promotes Phosphorus Uptake by Arachis hypogaea L. by Regulating Host Auxin, Gibberellins, and Cytokinins Signaling Pathways

Soil Acidification Negatively Affects Arachis hypogeae L. Growth by Inhibiting Nodule Initiation and Nitrogen Fixation

ABSTRACT Fusarium wilt is a widespread disease causing serious production losses in watermelon (Citrullus lanatus L.). Accordingly, control agents to manage this disease should be developed to ensure the sustainability of watermelon cultivation. In this study, inactivated Fusarium oxysporum f. sp. niveum (FON) mycelia were used as a decoy inoculation agent, and the effects of this treatment on Fusarium wilt and its possible underlying mechanisms were investigated. Inoculation with inactivated FON mycelia significantly decreased rhizosphere FON number and Fusarium wilt disease severity, and this might be closely related to the observed improved abundances and community structures of native beneficial rhizosphere microorganisms. In addition, inactivated FON mycelia inoculation significantly enhanced soil enzyme activity levels and plant systemic resistance, which promoted resistance to Fusarium wilt and thus watermelon growth. These results demonstrated that inactivated FON mycelia could be used as a novel biocontrol agent to alleviate Fusarium wilt and increase yields in watermelon.

Inactivated pathogenic mycelia as a biocontrol agent against Fusarium wilt and its effects on continuously cropped watermelon

Destruction of the soil microbial ecological environment caused by the over-utilization of the rice-crayfish co-cropping pattern.

Endophytic Fungus Alleviates Soil Sickness in Peanut Crops by Improving the Carbon Metabolism and Rhizosphere Bacterial Diversity

Changes in soil characteristics and maize yield under straw returning system in dryland farming

O-N-Acetylglucosamine transferase (OGT) can catalyze the O-GlcNAc modification of thousands of proteins. The holoenzyme formation of OGT and adaptor protein is the precondition for further recognition and glycosylation of the target protein, while the corresponding mechanism is still open. Here, static and dynamic schemes based on statistics can successfully screen the feasible identifying, approaching, and binding mechanism of OGT and its typical adaptor protein p38α. The most favorable interface, energy contribution of hotspots, and conformational changes of fragments were discovered. The hydrogen bond interactions were verified as the main driving force for the whole process. The distinct characteristic of active and inactive p38α is explored and demonstrates that the phosphorylated tyrosine and threonine will form strong ion-pair interactions with Lys714, playing a key role in the dynamic identification stage. Multiple method combinations from different points of view may be helpful for exploring other systems of the protein-protein interactions.

Molecular dynamic simulations identifying the mechanism of holoenzyme formation by O-GlcNAc transferase and active p38α.

Studies on pharmacokinetic properties and absorption mechanism of phloretin: In vivo and in vitro.

Tea polyphenols (TP) are the main components in tea. Studies in vitro have shown they have significant biological activity; however, the results are inconsistent with experiments in vivo. For the low bioavailability, most TP are thought to remain in the gut and metabolized by intestinal bacteria. In the gut, the unabsorbed TP are metabolized to a variety of derivative products by intestinal flora, which may accumulate to exert beneficial effects. Numerous studies have shown that TP can inhibit obesity and its related metabolism disorders effectively. Meanwhile, it has demonstrated that TP and their derivatives may modulate intestinal micro-ecology. The understanding of the interaction between TP and intestinal microbiota will allow us to better evaluate the contribution of microbial metabolites of TP to the anti-obesity activity. This review showed implications for the use of TP as functional food with potential therapeutic utility against obesity by modulating intestinal microbiota, contributing to the improvement of human health. This article is protected by copyright. All rights reserved.

Interactions of tea polyphenols with intestinal microbiota and their implication for anti-obesity.

Naphthalimide derivatives are types of small-molecule anticancer drug candidates; however, their negative factors and potential side effects make their application limited. The pharmacophores select a direct access into the tumor cells as the first choice; this can reduce the side effect of the anti-cancer drugs on the normal cells. Herein, the delivery and binding of the naphthalimide-polyamine complex assisted by the bovine serum albumin (BSA) protein have been studied by combining several molecular dynamic simulations. The plausible transportation channels and the most favorable pathways for the delivery of the naphthalimide-polyamine complex to two drug sites (DSI and DSII), their thermodynamic and dynamic properties and the mechanisms have been discussed in detail. The residues His287 and Phe394 acted as guards in the DSI and DSII, respectively, which played a gating-switch role by flipping the ring from open to close during the compound delivery. The binding mode, binding energy and substituent effects have been also identified. The two drug sites have different preferences towards the compound with the electron-withdrawing and electron-donating substituents, and their strong interactions are more sensitive to the number of the substituent groups. The naphthalimide-polyamine complexes are more likely to choose DSI, both thermodynamically and dynamically, as compared to DSII. This selective specificity of these two drug sites manipulated by the electron-withdrawing and electron-donating substituents is quite promising for the design of new naphthalimide drugs.

Insight into the delivery channel and selectivity of multiple binding sites in bovine serum albumin towards naphthalimide-polyamine derivatives.

Product release mechanism and the complete enzyme catalysis cycle in yeast cytosine deaminase (yCD): A computational study.

Extensive combined quantum mechanical (B3LYP/6‐31G*) and molecular mechanical (QM/MM) molecular dynamics simulations have been performed to elucidate the hydrolytic deamination mechanism of cytosine to uracil catalyzed by the yeast cytosine deaminase (yCD). Though cytosine has no direct binding to the zinc center, it reacts with the water molecule coordinated to zinc, and the adjacent conserved Glu64 serves as a general acid/base to shuttle protons from water to cytosine. The overall reaction consists of several proton‐transfer processes and nucleophilic attacks. A tetrahedral intermediate adduct of cytosine and water binding to zinc is identified and similar to the crystal structure of yCD with the inhibitor 2‐pyrimidinone. The rate‐determining step with the barrier of 18.0 kcal/mol in the whole catalytic cycle occurs in the process of uracil departure where the proton transfer from water to Glu64 and nucleophilic attack of the resulting hydroxide anion to C2 of the uracil ring occurs synchronously. © 2016 Wiley Periodicals, Inc.

Combined QM(DFT)/MM molecular dynamics simulations of the deamination of cytosine by yeast cytosine deaminase (yCD)

: Enzymatic catalytic processes generally involve substrate delivery, selective catalytic reaction, and product release. Owing to the complex protein environment effect, any nonchemical or chemical step may determine the enzyme activity. Herein, to comprehensively understand enzymatic activity, extensive combined quantum mechanics/molecular mechanics (QM/MM) and molecular mechanics (MM) molecular dynamics (MD) simulations were carried out on several kinds of enzymes. Possible reaction mechanisms, roles of the conserved residues, and effects of the protein environment on the whole enzymatic process are discussed in detail, which will enrich the knowledge of reactivity in proteins. With the improvement and development of multiscale models and computational methods, it is expected that global simulations of extremely large and complicated enzymes will enable and lend support to enzyme engineering.

The highly homologous hydroxynitrile lyases from Manihot esculent (MeHNL) and Hevea brasiliensis (HbHNL) both belong to the α/β-hydrolase superfamily, and they convert cyanohydrins into the corresponding ketone (aldehyde) and hydrocyanic acid, which is important for biosynthesis for carbon–carbon formation. On the basis of extensive MM and ab initio QM/MM MD simulations, one-dimensional and two-dimensional free energy profiles on the whole enzymatic catalysis by MeHNL have been explored, and the effects of key residues around the channel on the delivery of substrate and product have been discussed. The residue Trp128 plays an important gate-switching role to manipulate the substrate access to the active site and product release. In particular, the release of acetone and HCN has been first detected to follow a stepwise mechanism. The release of HCN is quite facile, while the escape of acetone experiences a barrier of ∼10 kcal/mol. The chemical reaction is an endergonic process with a free energy barrier of...

A Comprehensive Understanding of Enzymatic Catalysis by Hydroxynitrile Lyases with S Stereoselectivity from the α/β-Hydrolase Superfamily: Revised Role of the Active-Site Lysine and Kinetic Behavior of Substrate Delivery and Sequential Product Release

The deamination reaction of 8-oxoguanine (8-oxoG) catalyzed by 8-oxoguanine deaminase (8-oxoGD) plays a critically important role in the DNA repair activity for oxidative damage. In order to elucidate the complete enzymatic catalysis mechanism at the stages of 8-oxoguanine binding, departure of 2-hydroxy-1H-purine-6,8(7H,9H)-dione from the active site, and formation of 8-oxoxanthine, extensive combined QM(PM3)/MM molecular dynamics simulations have been performed. Computations show that the rate-limiting step corresponds to the nucleophilic attack from zinc-coordinate hydroxide group to free 8-oxoguanine. Through conformational analyses, we demonstrate that Trp115, Trp123 and Leu119 connect to O8@8-oxoguanine with hydrogen bonds, and we suggest that mutations of tryptophan (115 and 123) to histidine or phenylalanine and mutation of leucine (119) to alanine could potentially lead to a mutant with enhanced activity. On this ground, a proton transfer mechanism for the formation of 8-oxoxanthine was further discussed. Both Glu218 and water molecule could be used as proton shuttles, and water molecule plays a major role in proton transfer in substrate. On the other hand, comparative simulations on the deamination of guanine and isocytosine reveal that, for the helping of hydrogen bonds between O8@8-oxoguanine and enzyme, O8@8-oxoguanine is the fastest to be deaminated among the three substrates which are also supported by the experimental kinetic constants.

Mechanisms for the deamination reaction of 8-oxoguanine catalyzed by 8-oxoguanine deaminase: A combined QM/MM molecular dynamics study

Excited-state properties of molecules play a pivotal role in understanding their photophysical and photochemical behaviors. With the fast development of computational methodologies, the low-lying states of biorelated systems have been extensively investigated theoretically. Here, we review our recent works on the excited states of selected nucleobases and their related systems in the gas and condensed phases. The simulated electronic spectra of coumarin reproduce the band shape of experimental spectra and provide a basis to reasonably assign the observed bands. The absorption spectra and the excited-state dynamics of nucleic acid bases and their analogs in the gas phase and in aqueous solution have been explored by the combined quantum mechanics and molecular mechanics (QM/MM) calculations and QM/MM-based dynamics simulations with surface hopping. Based on extensive calculations and dynamics simulations, the solvent effects on the excited states and their dynamical behaviors have been discussed. V C 2015 Wiley Periodicals, Inc.

Theoretical studies on excited states of biorelated systems from gas phase to aqueous solution

A full enzymatic catalysis cycle in the inosine-adenosine-guanosine specific nucleoside hydrolase (IAG-NH) was assumed to be comprised of four steps: substrate binding, chemical reaction, base release, and ribose release. Nevertheless, the mechanistic details for the rate-limiting step of the entire enzymatic reaction are still unknown, even though the ribose release was likely to be the most difficult stage. Based on state-of-the-art quantum mechanics and molecular mechanics (QM/MM) molecular dynamics (MD) simulations, the ribose release process can be divided into two steps: "ribose dissociation" and "ribose release". The "ribose dissociation" includes "cleavage" and "exchange" stages, in which a metastable 6-fold intermediate will recover to an 8-fold coordination shell of Ca(2+) as observed in apo- IAG-NH. Extensive random acceleration molecular dynamics and MD simulations have been employed to verify plausible release channels, and the estimated barrier for the rate-determining step of the entire reaction is 13.0 kcal/mol, which is comparable to the experimental value of 16.7 kcal/mol. Moreover, the gating mechanism arising from loop1 and loop2, as well as key residues around the active pocket, has been found to play an important role in manipulating the ribose release.

Mechanistic Insights into the Rate-Limiting Step in Purine-Specific Nucleoside Hydrolase.

Extensive ab initio surface-hopping dynamics simulations have been used to explore the excited-state nonadiabatic decay of two biologically relevant hypoxanthine keto-N7H and keto-N9H tautomers in aqueous solution. QM/MM calculations and QM/MM-based MD simulations predict different hydrogen bonding networks around these nucleobase analogues, which influence their photodynamical properties remarkably. Furthermore, different solvent effects on the conical intersection formation of keto-N7H and keto-N9H were found in excited-state MD simulations, which also change the lifetimes of the excited states. In comparison with the gas-phase situation, the S1 → S0 nonradiative decay of keto-N7H is slightly faster, while this decay process of keto-N9H becomes much slower in water. The presence of π-electron hydrogen bonds in the solvated keto-N7H is considered to facilitate the S1 → S0 nonradiative decay process.

A QM/MM MD insight into photodynamics of hypoxanthine: distinct nonadiabatic decay behaviors between keto-N7H and keto-N9H tautomers in aqueous solution.

The excited-state decay of the biologically relevant allopurinol keto-N9H tautomer populated at the optically bright S1((1)ππ*) state in the gas phase and in aqueous solution has been explored theoretically. In solution, the hybrid quantum-mechanical/molecular-mechanical simulations were performed, where the QM region (keto-N9H) was treated at the ab initio SA-CASSCF level, while the MM region (water) was described by the TIP3P model. Here we find that there exist four parallel relaxation pathways in the gas phase, but only two of them occur in aqueous solution. In addition, an ultrafast S1 → S0 internal conversion is found in vacuum, with an estimated excited-state lifetime of 104.7 fs, much faster than that in water (242.8 fs), showing reasonable agreement with the available experimental finding in aqueous solution (τ < 200 fs). Calculations indicate that the presence of water solvent plays an important role in the excited-state dynamics of DNA base, showing the pronounced environmental effects on its decay pathways and excited-state lifetimes.

Ab initio study on ultrafast excited-state decay of allopurinol keto-N9H tautomer from gas phase to aqueous solution.

The glucosamine 6-phosphate deaminase (NagB), which catalyzes the conversion of D-glucosamine 6-phosphate (GlcN6P) into d-fructose 6-phosphate (F6P) and ammonia, determines the final metabolic fate of N-acetylglucosamine (GlcNAc). Here using state-of-the-art ab initio QM/MM MD simulations, we have explored the plausible mechanisms for the enzymatic ring-opening of GlcN6P in the basic environment. Two different proton-shuttle mechanisms have been proposed. Calculations show that the protonated state of the amino group in the substrate dominates the concerted and stepwise catalytic pathways and a catalytic triad plays an important role in mediating the proton transfer and the resulting ring-opening process. The free energy barrier for the rate-determining step in the low-energy stepwise reaction is 17.9 kcal mol(-1). In acidic solution, the lid motif prefers a closed state while it always stays in the open state in basic solution upon substrate binding, which is basically dominated by the protonated state of the residue His145.

A QM/MM MD study of the pH-dependent ring-opening catalysis and lid motif flexibility in glucosamine 6-phosphate deaminase.

Hydroxynitrile lyases (HNLs) defend plants from herbivores and microbial attack by releasing cyanide from hydroxynitriles. The reverse process has been productively applied to bioorganic syntheses of pharmaceuticals and agrochemicals. To improve our understanding of the catalytic mechanism of HNLs, extensive ab initio QM/MM and classical MM molecular dynamics simulations have been performed to explore the catalytic conversion of cyanohydrins into aldehyde (or ketone) and HCN by hydroxynitrile lyases from Hevea brasiliensis (HbHNLs). It was found that the catalytic reaction approximately follows a two-stage mechanism. The first stage involves two fast processes including the proton abstraction of the substrate through a double-proton transfer and the C-CN bond cleavage, while the second stage concerns HCN formation and is rate-determining. The complete free energy profile exhibits a peak of ∼18 kcal mol(-1). Interestingly, the protonation state of Lys236 influences the efficiency of the enzyme only to some extent, but it changes the entire catalytic mechanism. The dynamical behaviors of substrate delivery and HCN release are basically modulated by the gate movement of Trp128. The remarkable exothermicity of substrate binding and the facile release of HCN may drive the enzyme-catalyzed reaction to proceed along the substrate decomposition efficiently. Computational mutagenesis reveals the key residues which play an important role in the catalytic process.

A full picture of enzymatic catalysis by hydroxynitrile lyases from Hevea brasiliensis: protonation dependent reaction steps and residue-gated movement of the substrate and the product.

Ministry of Science and Technology [2011CB808504, 2012CB214900]; National Science Foundation of China [21133007]

ABSORPTION SPECTRA OF NUCLEIC ACID BASES IN WATER ENVIRONMENT: INSIGHTS INTO FROM COMBINED QM/MM AND CLUSTER-CONTINUUM MODEL CALCULATIONS

Identification and quantification studies on structures, dynamics and mechanism for thermal and photo-degradation products of β-carotene

Dryland ecosystem services (ESs) have been severely harmed by global environmental changes and increased human activities. To improve ESs, it is necessary to understand how they interact in drylands. In this study, we selected Ordos dryland, which is situated in northern China, as the study area to assess its four key ESs—food supply (FS), carbon storage (CS), water yield (WY), and habitat quality (HQ)—and to identify the hotspots of multiple ES supply. Furthermore, we studied the constraint effects between ESs in Ordos in 2000, 2010, and 2020 and used a spatial trade-off model to map the trade-off and synergy areas of ESs from 2000 to 2010 and from 2010 to 2020. The results indicated that all four ESs in Ordos increased significantly over the study period. The hotspots for the supply of multiple ESs also increased in areal extent during this period, and the state of the regional ecological environment continued to improve. The constraint effect between ESs showed that as the CS increased, its constraint effect on WY and FS decreased and then increased, whereas its constraint effect on HQ only decreased; as the WY increased, its constraint effect on HQ decreased and then increased, and its constraint effect on FS continued to decrease; as the FS increased, its constraint effect on HQ continued to increase. From the change in the area of ESs trade-offs and synergies, there was an increase in the area of positive synergy for four pairs of ESs in Ordos, which were CS-WY, CS-HQ, WY-HQ, and FS-HQ. These findings help in establishing a scientific foundation for the management and optimization of ESs in drylands.

Relationships Between Key Dryland Ecosystem Services: A Case Study in Ordos, China

Ecosystem services (ES) provided by dryland ecosystems store nearly half and one‐third of the Earth's terrestrial biomass and biodiversity, respectively. Pakistan is a typical dryland region with significant land degradation and dramatic changes in ES in recent decades, which has not been sufficiently investigated. This study explored the spatiotemporal variations in ecosystem service values (ESV) over Pakistan (2001–2018) by combining land use/cover data, economic modeling, and hotspot analysis. From the achieved results, the total ESV indicated an improvement in ES before 2012 and then showed a declining trend. The largest contribution was attributed to the increase in forest/shrubland by 16.17% (2001–2006) and 10.36% (2006–2012). However, the ESV decreased to 7.76% from 2012 to 2018, which was mainly attributed to the decrease in cropland and grassland. Heterogeneous changes were observed in ESV. The hotspot of ESV change (approximately an area of 32,578 km2) was mainly located in the southern and southeastern parts of Khyber Pakhtunkhwa (KPK), the northeastern part of Balochistan and the central and western parts of Sindh Province. The cold spot (approximately an area of 24,491 km2) showed a distribution in the northern part of KPK and Gilgit Baltistan, northeastern Punjab, coastal regions, and southeastern Sindh Province. We also found that although the total ESV and gross domestic product (GDP) indicated growth, the proportion of ESV from the total ESV and GDP (%ESV) exhibited a negative trend. The Provinces of Punjab and Balochistan retained the highest value of %ESV, while Azad Kashmir and Gilgit Baltistan were much lower. These results reflected the spatial imbalance of ecosystem protection and economic development in Pakistan. We recommend that necessary actions for conserving ES are important to strengthen ecological conservation in Pakistan. Additionally, further interdisciplinary research is needed to fully explore synergies in conserving ES and economical conservation.

Assessment of spatiotemporal variations of ecosystem service values and hotspots in a dryland: A case‐study in Pakistan

Since the establishment of blown sand physics, surface roughness has been widely used in current research to indicate the ability of a surface to resist wind erosion and to evaluate the windproof effect of protective measures. However, since the calculation of surface roughness can result in different values and its applicability is poor, there are disadvantages to its use. Therefore, it is proposed that the boundary layer displacement thickness should be used rather than roughness as an indicator to solve such problems. To analyze the new indicator’s accuracy and applicability when evaluating the effect of protective measures, a wind tunnel simulation experiment on a typical mechanical protection measure commonly used for sand control in China was conducted. Indicators of roughness and boundary layer displacement thickness were compared in evaluating the windproof performance of a Salix psammophila sand barrier of differing heights, side lengths, and porosities. The wind speed acceleration rate and effective protection area, which can directly reflect the protective effect of a sand barrier, were analyzed as evaluation criteria. The results show that roughness can only reflect the influence of height on the windbreak effect of sand barriers, whereas the boundary layer displacement thickness accurately showed the influence of height, side length, and porosity on the windproof effect of the sand barriers. Compared with roughness, the boundary layer displacement thickness was more strongly correlated with the effective protection area. Therefore, the boundary layer displacement thickness, rather than roughness, should be used as a new indicator when evaluating the windproof effect of protective measures.

Application of Boundary Layer Displacement Thickness in Wind Erosion Protection Evaluation: Case Study of a Salix psammophila Sand Barrier

Hysteresis resulting in forestry heat storage underestimation: A case study of plantation forestry in northern China.

Monitoring of stomatal conductance to water vapor in psammophytes is important in studies of vegetation transpiration in sandy areas. Leaf temperature monitoring has the advantages of convenience, reduced damage to the plant without contact, and a larger measurement area. Stomatal conductance to water vapor estimation models, based on leaf temperature, have been proposed in agricultural studies in recent years. However, observations for verification of these models are still lacking, which has limited the application of these models. We performed a drought stress experiment on three typical psammophytes: Artemisia ordosica, Salix psammophila, and Caragana korshinskii. We monitored their leaf temperature and built two leaf temperature-based models to test whether the models could accurately estimate stomatal conductance. Results verified that neither of the two models accurately quantified psammophytes’ stomatal conductance in field operations. We further tested the differences among plants and identified that the differences in stomatal mechanism and physical morphology of the leaves drives leaf temperature differences, which affects the accuracy of stomatal conductance estimation using the models. We concluded that more precise measurements of leaf temperature-related parameters, such as wind speed and leaf physical morphology, are needed to improve the models’ estimation accuracy. Our study offers references for developing a practical application of stomatal conductance estimation models in field operations.

Leaf Temperature Fluctuations of Typical Psammophytic Plants and Their Application to Stomatal Conductance Estimation

Due to their simple layout and adaptability to various environments, straw checkerboards are widely used to control windblown sand in China. To fully understand the wind proofing and sand-fixing benefits of different board specifications, and to determine the restorative effects of straw checkerboard, we tested different sizes of checkerboard, determined their performance as a windbreak and in trapping shifting sand, and constructed models based on wind tunnel tests, enabling the wind speed flow field to be analysed. We also sampled the soil in areas where straw checkerboards had been established for several years and analysed the trends in soil physical and chemical properties over time. We found that all sizes of straw checkerboard effectively reduced the wind speed near the surface and formed a protected area, with the best protective effect achieved for a one-meter board. All sizes of straw checkerboard effectively intercepted windblown sand to form surface accumulation, with the one-meter board again showing the best performance. The use of a straw checkerboard also effectively improved the physical and chemical properties of soil and promoted ecological restoration. These results indicate that straw checkerboards are a low-cost engineering measure that could play an important role in desertification control and the ecological restoration of sandy land ecosystems.

Effect of Straw Checkerboards on Wind Proofing, Sand Fixation, and Ecological Restoration in Shifting Sandy Land

Linking wind erosion to ecosystem services in drylands: a landscape ecological approach

We constructed an aeolian soil database across arid, semi-arid, and dry sub-humid regions, China. Soil particle size distribution was measured with a laser diffraction technique, and fractal dimensions were calculated. The results showed that: (i) the predominant soil particle size distributed in fine and medium sand classifications, and fractal dimensions covered a wide range from 2.0810 to 2.6351; (ii) through logarithmic transformations, fractal dimensions were significantly positive correlated with clay and silt contents (R2 = 0.81 and 0.59, P < 0.01), and significantly negative correlated with sand content (R2 = 0.50, P < 0.01); (3) hierarchical cluster analysis divided the plots into three types which were similar to sand dune types indicating desertification degree. In a large spatial scale, fractal dimensions are still sensitive to wind-induced desertification. Therefore, we highly recommend that fractal dimension be used as a reliable and quantitative parameter to monitor soil environment changes in desertified regions. This improved information provides a firm basis for better understanding of desertification processes.

Characterization of Soil Particle Size Distribution with a Fractal Model in the Desertified Regions of Northern China

Plant temperature (Tp) is an important indicator of plant health. To determine the dynamics of plant temperature and self-cooling ability of the plant, we measured Tp in Artemisia ordosica in July, in the Mu Us Desert of Northwest China. Related factors were also monitored to investigate their effects on Tp, including environmental factors, such as air temperature (Ta), relative humidity, wind speed; and physiological factors, such as leaf water potential, sap flow, and water content. The results indicate that: 1) Tp generally changes in conjunction with Ta mainly, and varies with height and among the plant organs. Tp in the young branches is most constant, while it is the most sensitive in the leaves. 2) Correlations between Tp and environmental factors show that Tp is affected mainly by Ta. 3) The self-cooling ability of the plant was effective by midday, with Tp being lower than Ta. 4) Increasing sap flow and leaf water potential showed that transpiration formed part of the mechanism that supported self-cooling. Increased in water conductance and specific heat at midday may be additional factors that contribute to plant cooling ability. Therefore, our results confirmed plant self-cooling ability. The response to high temperatures is regulated by both transpiration speed and an increase in stem water conductance. This study provides quantitative data for plant management in terms of temperature control. Moreover, our findings will assist species selection with taking plant temperature as an index.

How the Plant Temperature Links to the Air Temperature in the Desert Plant Artemisia ordosica

Background Biological soil crusts are common components of desert ecosystem; they cover ground surface and interact with topsoil that contribute to desertification control and degraded land restoration in arid and semiarid regions. Methodology/Principal Findings To distinguish the changes in topsoil affected by biological soil crusts, we compared topsoil properties across three types of successional biological soil crusts (algae, lichens, and mosses crust), as well as the referenced sandland in the Mu Us Desert, Northern China. Relationships between fractal dimensions of soil particle size distribution and selected soil properties were discussed as well. The results indicated that biological soil crusts had significant positive effects on soil physical structure (P<0.05); and soil organic carbon and nutrients showed an upward trend across the successional stages of biological soil crusts. Fractal dimensions ranged from 2.1477 to 2.3032, and significantly linear correlated with selected soil properties (R2 = 0.494∼0.955, P<0.01). Conclusions/Significance Biological soil crusts cause an important increase in soil fertility, and are beneficial to sand fixation, although the process is rather slow. Fractal dimension proves to be a sensitive and useful index for quantifying changes in soil properties that additionally implies desertification. This study will be essential to provide a firm basis for future policy-making on optimal solutions regarding desertification control and assessment, as well as degraded ecosystem restoration in arid and semiarid regions.

Fractal Scaling of Particle Size Distribution and Relationships with Topsoil Properties Affected by Biological Soil Crusts

Aim of study: Forests have vital functions in global carbon cycle, and thus are of prime importance in efforts to curb climate change. This study intends to guide effective forestry solutions to combat climate change in China. Area of study: China, not only a major emitter of greenhouse gases, but also one of the five most-forest richest countries with the largest plantations in the world. Material and methods: We summarize and recommend carbon sequestration forestry by considering two Kyoto Protocol activities: afforestation/reforestation and forest management. Main results: Afforestation has a top priority of carbon sequestration forestry in China. However, the tree-based solution will reach its limits to growth in a predictable near future. Forest management contributes to break the deadlock. When scientifically and sustainably managed, forests still have a central role in climate change mitigation. Research highlights: China’s efforts on carbon sequestration forestry should shift the focus from afforestation to

Short Communication. Forestry solutions for mitigating climate change in China

China is the global leader in afforestation efforts to restore degraded forest ecosystems. However, it is diffi cult for these efforts to completely substitute for natural forests. In order to reveal the differences between plantations and natural forests, we compared stand spatial structure of plantations, mixed plantations, and natural forests by using the mingling degree (M i ), uniform angle index (W i ), and neighborhood comparison ( U i ) in the Mulan-Weichang Forestry Administrative region of the rocky mountain area, northern China. The results indicated that natural forests were characterized by varying species composition, individual tree distribution, and competitive relationships, which were more complex than monoculture plantations. Forest management is benefi cial to stand spatial structure improvement, resulting in mixed plantations that are closer to natural forests. On this basis, China’s forest policy should shift focus from afforestation for area expansion to forest management for ecological improvement.

COMPARISON OF STAND SPATIAL STRUCTURE IN DIFFERENT PLANTATIONS AND NATURAL FORESTS IN ROCKY MOUNTAIN AREA OF NORTHERN CHINA

The application and integration of mega data and cloud accounting technology not only changes the mode of enterprise accounting informatization construction, but also improves and promotes the traditional audit work. In the mega data environment, enterprise business processes are gradually increasing, and structured, unstructured and semi-structured data are becoming increasingly complex. It is difficult for a single financial data to effectively reflect the operational status of an enterprise, and it is urgent for auditing to comprehensively and thoroughly analyze the actual situation of an enterprise by comprehensively utilizing multiple data. Under the background of cloud computing as the foundation and mega data as the business engine, the content, mode and risk of traditional audit have changed, and an innovative model of "cloud audit" for mega data has emerged. This paper analyzes the impact of mega data and cloud accounting technology on audit from audit scope, audit data, audit risk, audit technology and auditors, establishes an audit implementation framework based on cloud accounting in mega data environment, and expounds the audit business development process under this framework.

Proceedings of the 3rd Asia-Pacific Conference on Image Processing, Electronics and Computers

Research and Implementation of Intelligent Financial Audit System Based on Data Mining and Cloud Computing

With the in-depth development and application of information technology, the world has entered the era of big data. Big data is coming to all walks of life with a fierce trend. Data has become a strategic resource as important as human resources and natural resources, which has a huge impact on society and economy, and has been widely concerned by the theoretical and practical circles. Accounting process is a series of activities to achieve accounting goals, which is the support of accounting work. The effectiveness of accounting process is very important for accounting to deal with big data. The emergence of cloud computing can better mobilize, expand and manage the resource storage capacity of computers, and can save a certain amount of cost. The rise of cloud computing has had a strong impact on the informatization and modernization of enterprises. This article provides an analysis for accounting to deal with big data from the aspect of accounting process through the reorganization of cloud computing accounting process.

2021 4th International Conference on Information Systems and Computer Aided Education

Research on Accounting Process Reengineering Based on cloud computing in the era of big data

Research on the design method of evidence-based design in activity-based workplace

Well-designed operation and management system of research laboratories is essential for scientific innovations and talent training.The reform of the traditional laboratory management to encourage science innovation and development is key to promoting the laboratories to develop in scale,level and efficiency.On the basis of profiling traditional lab management and its setbacks,the paper described the management mode and operation mechanism of Capital Medical University.Such mode and mechanism feature lab project Principal Investigation responsible system,and shared platform for large equipments and services.The paper also discussed lab operation and management system for universities at large. 
 
Key words: 
Laboratory management system;  Reform;  Principal investigator

Practice of research laboratories management in the medical university

Importance Length of hospital stay (LOHS) is the main cost-determining factor of hospitalization for stroke patients. However, previous analyses involving LOHS did not consider confounding or indirect factors, or the effects of other factors on LOHS and inpatient costs. Objective To investigate the direct and indirect effects of LOHS on the hospitalization costs of inpatients with ischemic and hemorrhagic stroke. Design, setting, and participants This was a population-based, retrospective, and observational study that analyzed data acquired from the Nationwide Inpatient Sample between 2015 and 2020 relating to ischemic and hemorrhagic stroke in Ningxia, China. Main outcomes and measures Hospitalizations were identified by the International Classification of Diseases 10th Revision (ICD-10). Inpatient costs were described by the median M (P25, P75). We used a quantile regression model to estimate the linear relationships between a group of independent variables X and the quantile of the explained variable hospitalization cost (Y). A structural equation model (SEM) was then used to investigate the direct and indirect effects of LOHS on inpatient costs. Results The study included 129,444 patients with ischemic stroke and 15,525 patients with hemorrhagic stroke. The median LOHS was 10 (8–13) days for ischemic stroke and 15 (10–22) days for hemorrhagic stroke. The median M (P25, P75) of inpatient costs was $1020 (742–1545) for ischemic stroke and 2813 (1576–6191) for hemorrhagic stroke. The total effect of LOHS on inpatient costs was 0.795 in patients with ischemic stroke. The effect of yearof discharge (X4) and CCI (X8) on inpatient costs was dominated by an indirect effect through the LOHS. The indirect effect was −0.071 (84.52% of the total effect value) and 0.034 (69.39% of the total effect value), respectively. The total effect of LOHS on inpatient costs in patients with hemorrhagic stroke was 0.754. The influence of CCI on inpatient costs was dominated by an indirect effect through LOHS; the indirect effect value was −0.028 (77.78% of the total effect value). The payment type, surgery, method of discharge, and hospital level also exerted an impact on inpatient costs by direct and indirect effects through the LOHS. Conclusions and relevance Length of hospital stay (LOHS) was identified as the main factor influencing hospitalization costs. However, other social factors were shown to indirectly influence hospitalization costs through the LOHS. Taking effective measures to further reduce hospitalization costs remains an effective way to control hospitalization costs for stroke patients.

The direct and indirect effects of length of hospital stay on the costs of inpatients with stroke in Ningxia, China, between 2015 and 2020: A retrospective study using quantile regression and structural equation models

China is facing an increasingly contradictory challenge between growing demand for health services for the oldest-old and the unbalanced and inadequate development in the context of rapid population aging. This study sought to evaluate the quality of life of the oldest-old in China under the active aging framework. Health, participation, and security data were sourced from China Statistics/Labor Statistics/Civil Affairs Yearbook 2000–2016 and National 1% Sample Survey Data 2005–2015. Then, we used the current life table, entropy method, coefficient variation, and panel data regression to evaluate the quality of life among the oldest-old and reveal its regional differences and mechanisms. The results show: (1) From 2005 to 2015, the overall quality of life in China steadily improved, and the quality of health, participation, and security of the oldest-old increased by 6.06%, 5.64%, and 47.48%, respectively. (2) Distinct regional disparities exist in the distribution of quality of life for the oldest-old in China; the “east–northeast–middle–west” stepped-declining pattern existed stably. (3) Population and family structure, economic development, and social security were the main reasons for the regional differences in quality of life for the oldest-old. Narrowing the socioeconomic gap between regions, promoting the function of family pension, and improving social old-age service supply will help improve the quality of life of the oldest-old.

Quality-of-Life Evaluation among the Oldest-Old in China under the “Active Aging Framework”

Introduction Although, especially in the past decade, poverty measurement approaches have been duly developed in two paths (from unidimensional to multidimensional poverty and from absolute to relative poverty), merely a few studies have focused on the combination of both perspectives. However, with global aging, poverty among older adults simultaneously presents multidimensionality and relativity characteristics. This paper explores a multidimensional relative poverty index (MRPI) relative to the aged group in four dimensions, namely, health, social, mental, and material, and then empirically evaluates the specific effects on the MRPI of one of the key targeted anti-poverty policies, that is, the health poverty alleviation policy (HPAP), which includes public health service, medical expense reimbursement, rewarding assistance, basic medical insurance, and so on. Methods Using pooled cross-sectional data of poverty alleviation from 2014 to 2020 with a total of 83,521 observations aged 60+ in County J, Shaanxi Province in China, we calculate the MRPI for the older adults via a fuzzy set approach. Statistical difference testing is used to analyze the characteristics and trends of the MRPI. In policy evaluation, to address endogenous problems, the treatment effect model based on Heckman's two-stage regression and finite distributed lag model are used with a controlled township cluster structure. Results From 2014 to 2020, the MRPI shows a significant upward trend for older adults in rural China, and the health component takes the dominant MRPI position. Empirically, we find that the HPAP can significantly alleviate the MRPI of older adults. Furthermore, among the health poverty alleviation measures, basic medical insurance is the most effective anti-poverty policy to support older adults. Specifically, empirical evidence shows that there is a more statistically significant reduction in the MRPI with the HPAP for the sub-group of older adults with chronic diseases or disabilities. Conclusion Both relativity and multidimensionality should be emphasized when analyzing poverty vis-à-vis the aging society, and for this, the MRPI is one of the effective tools. Comparing the relativity with the aged group engenders a more accurate understanding of their poverty situation. Moreover, the importance of the health component among all the four dimensions is more conducive to the detailed analysis of their poverty. The empirical analysis results show that regarding poverty reduction approaches in China, developing integrated health promotion systems is necessary and imminent, especially in the long run, such as long-term care insurance that covers typical disabled older adults with chronic diseases.

The multidimensional relative poverty of rural older adults in China and the effect of the health poverty alleviation policy

Based on the panel data of China Health and Retirement Longitudinal Study (CHARLS) in 2011, 2015, and 2018, this paper used the difference-in-difference (DID) method to evaluate the implementation effect how the Long-Term Care Insurance (LTCI) policy impacted on the medical expenses and the health status of the middle-aged and elder population. The empirical results show that LTCI has reduced the outpatient and inpatient quantity by 0.1689 and 0.1093 per year, and cut the outpatient and inpatient expenses by 23.9% and 19.8% per year. Moreover, the implementation of LTCI has improved the self-rated health, the activity of daily living (ADL), as well as the mental health. These conclusions verify the implementation value of LTCI system and provide policy implications for the medical reform and the further LTCI implementation in a larger scale.

The Impact of the Long-Term Care Insurance on the Medical Expenses and Health Status in China

The role of health behaviors in oral health conditions in individuals of extremely old age remains understudied. This study included 185 participants aged 100 years or older from the Nanjing Centenarians Study (NCS) to examine the associations between health behaviors and oral health and investigate the potential moderating role of education and living arrangements in such relationships. The oral health status as an outcome included the self-reported oral health status and edentulous status. Health behavior variables included smoking, eating fruits, eating vegetables, participating in leisure activities, and practicing oral hygiene behaviors. Sociodemographic characteristics and health status were considered as confounders. Descriptive statistics, ordinal regression, and logistic regression models were used to address the research questions. Results showed that better oral health was reported by centenarians who were non-smokers, participated in more leisure activities, and practiced higher frequency of oral hygiene behaviors. Those who ate fruits daily and practiced more frequently oral hygiene behaviors were more likely to be dentate. The positive association of oral hygiene behaviors was stronger for centenarians who were formally educated and co-resided with family members. The results suggest that effective interventions should consider health behaviors and living arrangements in this growing population to improve their oral health status.

Health Behaviors and Self-Reported Oral Health among Centenarians in Nanjing, China: A Cross-Sectional Study

Quality of Life and Its Influencing Factors Among Centenarians in Nanjing, China: A Cross-Sectional Study

Individual-level factors attributable to urban-rural disparity in mortality among older adults in China

Abstract The aim of this study was to examine the association between health behaviors and oral health among Chinese centenarians. Data from the Nanjing Centenarians Study (NCS) in China was used (N=185, Mean age = 102). Oral health status was measured by self-reported oral health and edentulous status. Results from ordinal regression and logistic regression models indicated that centenarians who were male, smoking, normal weight (18.5-24.9kg/m2), participated in more activities, and brushed teeth more frequently were more likely to report better oral health. Those who ate fruits daily and brushed teeth more frequently were more likely to be dentate. The association between frequent toothbrushing and oral health was stronger for those who had some formal education and were living with family members. Our study demonstrated the significance of health behaviors on oral health in very old age, and the importance of lifestyle on healthy aging.

Health Behaviors and Oral Health Among Centenarians in Nanjing, China: A Cross-Sectional Study

Adequate access to healthcare and added life expectancy among older adults in China

A structural equation model of factors associated with HIV risk behaviors and mental health among men who have sex with men in Malawi

Self-rated health in relation to fruit and vegetable consumption and physical activity among older cancer survivors

BMI, Physical Inactivity, and Pap Test Use in Asian Women in the U.S.

Objective 
To explore the clinical features of anxiety and insomnia during pregnancy and the therapeutic effects of cognitive behavior therapy for insomnia (CBT-I). 
 
Methods 
Forty-eight pregnant patients with insomnia and anxiety recruited from psychological clinic of Chongqing Women and Children Hospital from March to June 2018 were randomly divided into experimental group and control group. Experimental group received a 6-week-setting CBT-I therapy and control group was underwent health education at the same time. Assessment of Self-rating Anxiety Scale (SAS) and Pittsburg Sleep Quality Index (PSQI) were taken before intervention, 6 weeks after intervention, and 4 weeks after the end of intervention, and Cardiorespiratory Coupled Sleep Quality Assessment System (CPC) was used to measure sleep onset latency (SOL), time in bed (TIB), total sleep time (TST) and sleep efficiency (SE) at the same time points. 
 
Results 
Thirty-six (75.00%) pregnant women with insomnia and anxiety had a first pregnancy, 44 (91.67%) patients had bachelor′s degree or higher and 39 (81.25%) patients were still working. As for level of anxiety, 2 (4.17%) patients were mild anxiety, 36 (75.00%) patients were moderate anxiety and 10 (20.83%) patients were severe anxiety. SAS score after intervention in experimental group [(50.13±7.73)points] showed lower than that in control group [(60.25±8.69)points, t=-4.27, P 0.05)] 4 weeks after the end of intervention. PSQI score in experimental group after intervention [(10.50±2.34)points] showed lower than that in control group [(15.52±2.50)points, t=-6.68, P<0.05)]. PSQI score in experimental group 4 weeks after the end of intervention [(11.63±3.00)points] was also lower than that in control group [(14.83±2.99)points, t=-3.71, P<0.05)]. CPC showed that SOL in experimental group after intervention and 4 weeks after the end of intervention [(29.54±8.67)min, (28.88±9.18)min)] were both lower than those in control group [(54.58±16.20)min, (55.67±18.39)min, t=-6.68, -6.36, all P<0.05)] and TST[(347.50±38.12)min, (325.87±58.18)min] were both higher than those in control group[(230.25±68.75)min, (257.41±77.85)min, t=7.31, 3.45, all P<0.05)]. 
 
Pregnant women with insomnia and anxiety are mainly for the first time pregnant, bachelor degree or higher, and still working, mostly moderate anxiety. CBT-I can improve anxiety and sleep quality in pregnant patients with insomnia and anxiety, while its long-term therapeutic effect was not satisfying. 
 
Key words: 
Sleep initiation and maintenance disorders; Pregnant women; Anxiety; Cognitive behavioral therapy for insomnia

Clinical features of anxiety and insomnia during pregnancy and the therapeutic effect of cognitive behavior therapy for insomnia

Objective and subjective financial status and mortality among older adults in China.

Association between dietary patterns and depressive symptoms among middle-aged adults in China in 2016–2017

Greater financial resources are associated with lower self-perceived uselessness among older adults in China: The urban and rural difference.

Age and sex differences in the association between access to medical care and health outcomes among older Chinese

A comparison of perceived uselessness between centenarians and non-centenarians in China

Ovarian cancer (OC) is the sixth most common cancer among women, and its prognosis is not favorable. Diabetes mellitus (DM) is hypothesized to be associated with a higher mortality in ovarian cancer patients, but evidence is inconsistent. Thus, we aim to investigate if DM is associated with the long‐term all‐cause and long‐term cancer‐specific mortality in ovarian cancer patients by synthesizing available epidemiologic evidences. We used 4 electronic databases (PubMed, EMBASE, Web of Science, and Scopus) to search for eligible articles. Title/abstract screening, full‐text review, data extraction, and quality assessment were performed by reviewers independently. In meta‐analysis, studies reporting risk ratio (RR) or hazard ratio that investigated the association between DM and mortality of OC patients were synthesized by a random‐effect model. Subgroup and sensitivity analyses were performed by certain stratification or restrictive rules. Publication bias was assessed by funnel plots and Egger test. Statistical heterogeneity was evaluated by the I‐squared value and a chi‐squared test for the Cochrane Q statistic. Twelve cohort studies involving 14 outcome measures were included. In overall meta‐analysis, the synthesized RR for all‐cause mortality was 1.44 (95% CI 1.16‐1.79) without substantial statistical heterogeneity (PCochrane = .145, I2 = 34.1%); the synthesized RR for cancer‐specific mortality was 1.44 (95% CI 1.08‐1.93) with substantial heterogeneity (PCochrane < .001, I2 = 90.1%). No publication bias was observed. Our results suggest DM is associated with a higher all‐cause and cancer‐specific mortality in ovarian cancer patients. Future studies should be done to examine the association between type 1 DM and ovarian cancer mortality.

Diabetes mellitus and long‐term mortality of ovarian cancer patients. A systematic review and meta‐analysis of 12 cohort studies

Erratum to: Self-perceived uselessness and associated factors among older adults in China

Changes in perceived uselessness and risks for mortality: evidence from a National sample of older adults in China

Self-perceived uselessness and associated factors among older adults in China

Diabetes mellitus and risk of ovarian cancer. A systematic review and meta-analysis of 15 cohort studies.

Urban-rural differences in the association between access to healthcare and health outcomes among older adults in China

Association Between Life Event Stressors and Low Birth Weight in African American and White Populations: Findings from the 2007 and 2010 Los Angeles Mommy and Baby (LAMB) Surveys

Association between financial life event stressors and risk of low birth weight among African Americans and Whites: An analysis of Los Angeles Mommy and Baby (LAMB) surveys

Association Between Life Event Stressors And Risk Of Low Birth Weight Among African American And White Mothers ------A Multilevel Analysis Of The Los Angeles Mommy And Baby (lamb) Surveys

Objective To describe the cognitive levels about cervical cancer and it' s screening.Methods The investigated result of 100 women from a community in Beijing were analysed by a scale with convenience sampling method. Results The score of cervical cancer and the screening was lower than the average level. Only 38% can have medical checkups within last 2 years. There were also 38% have Palestinian cytology inspection and only 3% have the habit of having medical checkups at the regular intervals. Conclusions Women in community had lower cognitive levels about the cervical cancer and it's screening, and were short of relevance knowledge. They have prevention consciousness without pertinent activity. 
 
Key words: 
Women in community;  Cervical cancer;  Screening for cervical cancer;  Cognition

Investigation of cognitive levels about cervical cancer and it's screening among community women

Diabetes causes cognitive impairment, and the hippocampus is important for long-term and permanent memory function. However, the mechanism of their interaction is still unclear. In this study, rat models of diabetes mellitus were generated by a single injection of streptozotocin (STZ). This study aims to explore the changes in myelinated fibers in the hippocampus of type 1 diabetic rats. The unbiased stereological methods and transmission electron microscopy were used to obtain the total volume of the hippocampus, the total volume of the myelin sheath, the total length of the myelinated nerve fibers, the distribution of the length with different diameters of the myelinated fibers, and the distribution of the length with different thickness of the myelin sheath. Stereological analysis revealed that, compared to that of the control group, the total myelinated fibers volumes and the total myelinated fibers length were decreased slightly, while the total volume and the thickness of myelin sheaths were significantly decreased in the diabetic group. Finally, when compared with the control group, the total length of myelinated fibers in the diabetes group was significantly reduced, with diameters ranging from 0.7 to 1.1 μm and thicknesses of myelin sheaths from 0.15 to 0.17 μm. This study provides the first experimental evidence by stereological means to demonstrate that myelinated nerve fibers may be the key factor in cognitive dysfunction in diabetes.

Changes in myelinated fibers in the hippocampus of streptozotocin-induced diabetic rats: a stereological investigation.

The cognitive dysfunction associated with type 2 diabetes mellitus (T2DM) has been widely studied, and many structures in the hippocampus, such as neurons and synapses, have been shown to play a crucial role in the cognitive decline. However, the mechanism of these changes remains unknown. To further explore this issue, we investigated the changes in the blood supply of the hippocampus in transgenic T2DM mice. In the current study, histochemistry, immunohistochemistry, and unbiased stereological methods were utilized to research the effects of T2DM on hippocampal capillaries of transgenic db/db mice. Twenty (Leprdb) mut/mut mice and twenty (Leprdb) wt/wt mice were used in this study. The learning and memory ability was appraised by Morris water maze test.

Changes in hippocampal capillaries in transgenic type 2 diabetic mice: A stereological investigation

Objective 
To discuss the BRAF V600E mutation rate in papillary thyroid carcinoma (PTC) and its relationship with the clinicopathological features. 
 
Methods 
Two hundred and sixty-five PTC patients (including 226 cases of classical type, 29 cases of follicular type, 3 cases of high cell type, 2 cases of diffuse sclerosis type, 2 cases of eosinophilic type, 3 cases of cystic type) from August 2014 to October in Shanxi Provincial Cancer Hospital, were collected with completely clinical and pathological information. The BRAF V600E mutation was detected by real-time polymerase chain reaction (RT-PCR) method. Pearson χ 2 test and the exact probability method were used to analysis the relationship between gene mutations and clinicopathological data. 
 
Results 
BRAF V600E mutation rate in PTC patients was 73.21% (194/265). There was no significant difference in the mutation rate of BRAF V600E among patients with different age, gender, tumor location, tumor number and extravaginal invasion (all P > 0.05), but the mutation rates of BRAF V600E gene in patients with different tumor size, histopathological subtypes, lymph node metastasis and clinical stage were significantly different (all P < 0.05). 
 
The PTC patients with positive BRAF V600E mutation have poor clinicopathological features, and BRAF V600E mutation may be a predictor of advanced PTC. 
 
Key words: 
Thyroid neoplasms; Carcinoma, papillary; BRAF V600E mutation; Polymerase chain reaction

Correlation of BRAF V600E mutation with the clinicopathological features of papillary thyroid carcinoma

Previous studies have indicated that diabetes could cause hippocampus atrophy, neuron loss, and synaptic plasticity impairment. However, biological conclusions based on density were difficult to interpret because the changes in density could be due to an alteration of total quantity and/or an alteration in the reference volume. In the present study, we used unbiased stereological methods to investigate the effects of type 1 diabetes on the total volume of CA1 and dentate gyrus (DG), the total number of neurons and the total number of Spinophilin/NeurabinII‐positive boutons in CA1 and DG of streptozotocin‐treated rat model. Fifty Sprague–Dawley rats were randomly divided into sodium citrate buffer‐treated group (control group) and streptozotocin (STZ)‐treated group (diabetes group), in which type 1 diabetes was induced by streptozotocin injection. Learning and memory were measured using the Morris water maze test. Our results indicated that diabetes induced deficit in learning/memory, decrease in total CA1 volume (by 51.5%) and degeneration in synaptic structures in CA1sr (by 30.2%). While there were no significant changes in total DG volume, total neuron number in CA1 and DG, total Spinophilin/NeurabinII‐positive bouton number in DG. The present study provided the first evidence of changes in the total volume, the total neuron number and the total Spinophilin/NeurabinII‐positive bouton number in CA1 and DG of STZ‐induced diabetic rats. Anat Rec, 299:1174–1183, 2016. © 2016 Wiley Periodicals, Inc.

Changes in Neurons and Synapses in Hippocampus of Streptozotocin‐Induced Type 1 Diabetes Rats: A Stereological Investigation

Purpose To explore the effect of dextran sulfate (DS) on the angiogenesis, invasion, and migration of gastric cancer cells through interfering with the polarization of M2-type macrophages. Methods The infiltration of M2-type macrophages and microvascular density in gastric cancer and paracancerous tissues were analyzed using immunohistochemistry and immunofluorescence. The effects of DS on M2-type macrophages and the angiogenesis in metastatic tumors were investigated in the nude mice intraperitoneal metastasis model using immunohistochemistry and western blot. The differentiation and polarization of macrophage, immunocytochemistry, western blot, ELISA, and transwell migration assay were used to evaluate the effect of DS on the polarization of macrophage, Results The infiltration of M2-type macrophages and the microvascular density were highly expressed and positively correlated in the human gastric cancer tissue. DS can significantly inhibit the intraperitoneal metastases of gastric cancer in nude mice, and reduce the infiltration of M2-type macrophages and the angiogenesis in intraperitoneal metastatic tumors. Moreover, DS can prevent the polarization of M0-type macrophages to M2 type, reduce the expression of M2-type macrophage markers (CD206, CD163, IL-10, and Arg-1), down-regulate the IL-6-STAT3 pathway, and inhibit the recruitment capability of M2-type macrophages. Finally, the co-culture experiment showed that DS significantly reduced the promoting effects of M2-type macrophages on the angiogenesis, invasion, and migration of gastric cancer cells, as well as down-regulated the related expressions of proteins (VEGF, N-cadherin, MMP-2 and Vimentin) in gastric cancer cells. Conclusion DS can reduce the infiltration of M2-type macrophages and the microvascular density in intraperitoneal metastases of gastric cancer in nude mice, and inhibit the angiogenesis, invasion, and migration of gastric cancer cells by interfering with the polarization of M2-type macrophages through repression of the IL-6/STAT3 signaling pathway.

Dextran Sulfate Inhibits Angiogenesis and Invasion of Gastric Cancer by Interfering with M2-type Macrophages Polarization.

Wurfbainia villosa is a well-known medicinal and edible plant that is widely cultivated in the Lingnan region of China. Its dried fruits (called Fructus Amomi) are broadly used in traditional Chinese medicine for curing gastrointestinal diseases and are rich in volatile terpenoids. Here, we report a high-quality chromosome-level genome assembly of W. villosa with a total size of ~2.80 Gb, 42,588 protein-coding genes, and a very high percentage of repetitive sequences (87.23%). Genome analysis showed that W. villosa likely experienced a recent whole-genome duplication (WGD) event prior to the W. villosa-Zingiber officinale divergence (~11 MYA), and a recent burst of long terminal repeat (LTR) insertions afterward. The W. villosa genome enabled the identification of 17 genes involved in the terpenoid skeleton biosynthesis pathway and 66 terpene synthase (TPS) genes. We found that tandem duplication events have an important contribution to the expansion of WvTPSs, which likely drove the production of volatile terpenoids. In addition, functional characterization of 18 WvTPSs, focusing on the TPS-a and TPS-b subfamilies, showed that most of these WvTPSs are multi-product TPS and are predominantly expressed in seeds. This work provides insights into the genome evolution and the molecular basis of the volatile terpenoids diversity in W. villosa. The genome sequence also represents valuable resources for the functional gene research and molecular breeding of W. villosa.

Chromosome-level genome assembly and functional characterization of terpene synthases provide new insights into the volatile terpenoid biosynthesis of Wurfbainia villosa.

Figure 3 from: Li M, Sylvester SP, Wang Z-P, Pei Y-D, Gao X-F, Zhao Y, Jiang W-Q (2020) Re-instatement of Sorbus harrowiana (Rosaceae), based on morphometric analysis. PhytoKeys 166: 29-39. https://doi.org/10.3897/phytokeys.166.57672

Targeting DUSP7 signaling alleviates hepatic steatosis, inflammation and oxidative stress in high fat diet (HFD)-fed mice via suppression of TAK1.

Figure 2 from: Li M, Sylvester SP, Wang Z-P, Pei Y-D, Gao X-F, Zhao Y, Jiang W-Q (2020) Re-instatement of Sorbus harrowiana (Rosaceae), based on morphometric analysis. PhytoKeys 166: 29-39. https://doi.org/10.3897/phytokeys.166.57672

Figure 1 from: Li M, Sylvester SP, Wang Z-P, Pei Y-D, Gao X-F, Zhao Y, Jiang W-Q (2020) Re-instatement of Sorbus harrowiana (Rosaceae), based on morphometric analysis. PhytoKeys 166: 29-39. https://doi.org/10.3897/phytokeys.166.57672

Supplementary material 1 from: Li M, Sylvester SP, Wang Z-P, Pei Y-D, Gao X-F, Zhao Y, Jiang W-Q (2020) Re-instatement of Sorbus harrowiana (Rosaceae), based on morphometric analysis. PhytoKeys 166: 29-39. https://doi.org/10.3897/phytokeys.166.57672

Abstract Sorbus harrowiana (≡Pyrus harrowiana), previously considered a synonym of Sorbus insignis (≡Pyrus insignis) in the Flora of China, is re-instated here and shown to be distinct from S. insignis, based on morphometric analysis, coupled with herbarium and field investigation. We also present for the first-time full descriptions, distributional records and notes for S. harrowiana and S. insignis.

Re-instatement of Sorbus harrowiana (Rosaceae), based on morphometric analysis

Figure 4 from: Li M, Sylvester SP, Wang Z-P, Pei Y-D, Gao X-F, Zhao Y, Jiang W-Q (2020) Re-instatement of Sorbus harrowiana (Rosaceae), based on morphometric analysis. PhytoKeys 166: 29-39. https://doi.org/10.3897/phytokeys.166.57672

Reduce methane emission from rice paddies by man-made aerenchymatous tissues

Biogeochemical processes shift rapidly in both spatial (millimeter scale) and temporal (hour scale to day scale) dimensions at the oxic-anoxic interface in response to disturbances. Deciphering the rapid biogeochemical changes requires in situ, minimally invasive tools with high spatial and temporal sampling resolution. However, the available passive sampling devices are not very useful in many cases either due to their disposable nature or the complexity and extensive workload for sample preparation. To address this problem, a microdialysis profiler with 33 individual polyethersulfone nanomembrane tubes (semipermeable, <20 nm pore size) integrated into the one-dimensional skeleton (60 mm) was established to iteratively sample the dissolved compounds in porewater across the soil-water interface at a high resolution of 1.8 mm (outer diameter plus one spacing, i.e., 0.1 mm between probes). The sampling mechanism is based on the principle of concentration gradient diffusion. The automatic loading of degassed water allows minimal disturbance to the chemical species across the oxic-anoxic interface. This paper describes the procedures of device setup and continuous porewater sampling across the soil-water interface on a daily basis. Concentration-depth profiles were selectively measured before (on Day 6) and after (on Day 7) disturbances induced by irrigation. The results showed that concentration-depth profiles were undergoing rapid changes, especially for redox-sensitive elements (i.e., iron and arsenic). These protocols can help investigate the biogeochemical responses across the soil-water interface under various disturbances caused by physical, chemical, and biological factors. The paper thoroughly discusses the advantages and disadvantages of this method for potential use in the environmental sciences.

Dissolved Solute Sampling Across an Oxic-Anoxic Soil-Water Interface Using Microdialysis Profilers.

Anaerobic methane oxidation coupled to arsenate reduction in paddy soils: Insights from laboratory and field studies.

Iron Based Passivator Mitigates Arsenic Reduction Process Coupled to Methane Oxidation in Paddy Soils

pH dependence of arsenic speciation in paddy soils: The role of distinct methanotrophs.

Iron-based passivator mitigates the coupling process of anaerobic methane oxidation and arsenate reduction in paddy soils.

Simultaneous measurement of aqueous redox-sensitive elements and their species across the soil-water interface.

Distinct and dynamic distributions of multiple elements and their species in the rice rhizosphere

Arsenic (As) pollution in paddy fields is a major threat to rice safety. Existing As remediation techniques are costly, require external chemical addition and degrade soil properties. Here, we report the use of plastic tubes as a recyclable tool to precisely extract As from contaminated soils. Following insertion into flooded paddy soils, polyethylene tube walls were covered by thin but massive Fe coatings of 76.9-367 mg Fe m-2 in 2 weeks, which adsorbed significant amounts of As. The formation of tube-wall Fe oxides was driven by local Fe-oxidizing bacteria with oxygen produced by oxygenic phototrophs (e.g., Cyanobacteria) or diffused from air through the tube wall. The tubes with As-bound Fe oxides can be easily separated from soil and then washed and reused. We tested the As removal efficiency in a pot experiment to remove As from ~ 20 cm depth/40 kg soils in a 2-year experiment and achieved an overall removal efficiency of 152 mg As m-2 soil year-1, comparable to phytoremediation with the As hyperaccumulator Pteris vittata. The cost of Fe hooks was estimated at 8325 RMB ha-1 year-1, and the profit of growing rice (around 16080 RMB ha-1 year-1 can be still maintained. The As accumulated in rice tissues was markedly decreased in the treatment (>11.1 %). This work provides a low-cost and sustainable soil remediation method for the targeted removal of As from soils and a useful tool for the study and management of the biogeochemical Fe cycle in paddy soils.

Sustainable removal of soil arsenic by naturally-formed iron oxides on plastic tubes.

The Effect of Manure Application on Arsenic Mobilization and Methylation in Different Paddy Soils

The mechanisms to regulate arsenic behaviors in redox transition zones in paddy soils

Arsenic behavior across soil-water interfaces in paddy soils: Coupling, decoupling and speciation.

Mitigation effects of the microbial fuel cells on heavy metal accumulation in rice (Oryza sativa L.).

Mechanisms and challenges of microbial fuel cells for soil heavy metal(loid)s remediation.

One-step fabrication of binder-free air cathode for microbial fuel cells by using balsa wood biochar

Efficient cathode performance is crucial for the power generation of microbial fuel cells (MFCs). Therefore, the development of a cost effective and efficient cathode is urgently needed for the wider application of MFCs. In this study, a novel biochar air cathode with naturally porous structure and high oxygen reduction reaction (ORR) activity prepared from the pyrolysis of Balsa Wood chip at 800 C was proposed. The biochar chips can be installed directly in the MFC as an air cathode without the need to apply expensive catalysts, binders and a gas diffusion layers. In the single chamber MFC tests, the biochar air cathode achieved a maximum power density of 200 mW/m2 which was comparable to those of the other biochar based air cathodes. Moreover, when they were used in soil MFCs, our results showed that the chip thickness had effect on the performance of the soil MFCs. The 3.5 mm biochar produced the highest power density of 72 mW/m2, which was 45% higher than that of the soil MFC equipped with common carbon felt floating cathode. These findings demonstrate for the first time, that whole biochar chip could be considered as an effective and environmental-friendly material for the production of binderand catalysis-free air cathode. © 2020 Elsevier B.V. All rights reserved.

One-step fabrication of binder-free air cathode formicrobial fuel cells by using balsawood biochar

Relic DNA does not obscure the microbial community of paddy soil microbial fuel cells.

Arsenic alleviation in rice by using paddy soil microbial fuel cells

Soil organic matter amount determines the behavior of iron and arsenic in paddy soil with microbial fuel cells.

In flooded soils, soil–water interface (SWI) is the key zone controlling biogeochemical dynamics. Chemical species and concentrations vary greatly at micro- to cm-scales. Techniques able to track these changing element profiles both in space and over time with appropriate resolution are rare. Here, we report a patent-pending technique, the Integrated Porewater Injection (IPI) sampler, which is designed for soil porewater sampling with minimum disturbance to saturated soil environment. IPI sampler employs a single hollow fiber membrane tube to passively sample porewater surrounding the tube. When working, it can be integrated into the sample introduction system, thus the sample preparation procedure is dramatically simplified. In this study, IPI samplers were coupled to ICP-MS at data-only mode. The limits of detection of IPI-ICP-MS for Ni, As, Cd, Sb, and Pb were 0.12, 0.67, 0.027, 0.029, and 0.074 μg·L–1, respectively. Furthermore, 25 IPI samplers were assembled into an SWI profiler using 3D printing in a one-dimensional array. The SWI profiler is able to analyze element profiles at high spatial resolution (∼2 mm) every ≥24 h. When deployed in arsenic-contaminated paddy soils, it depicted the distributions and dynamics of multiple elements at anoxic–oxic transition. The results show that the SWI profiler is a powerful and robust technique in monitoring dynamics of element profile in soil porewater at high spatial resolution. The method will greatly facilitate studies of elements behaviors in sediments of wetland, rivers, lakes, and oceans.

Tracing the Dynamic Changes of Element Profiles by Novel Soil Porewater Samplers with Ultralow Disturbance to Soil–Water Interface

Simultaneous electricity production and arsenic mitigation in paddy soils by using microbial fuel cells

Simultaneous measurement of aqueous redox sensitive elements and their species across soil-water interface

The change in biotic and abiotic soil components influenced by paddy soil microbial fuel cells loaded with various resistances

Arsenic mitigation in paddy soils by using microbial fuel cells.

Antibiotic pollution has become one of the most important emerging soil contamination types, and has received great attentions in recent years. Understanding the microbial functional processes of soil ecosystems under antibiotic contamination is of critical importance for ecological risk assessment and pollution control. In this study, the responses of soil microbial respiratory activity and ammonification were studied under different concentrations of tetracycline, chlortetracycline, and norfloxacin. Generally, the antibiotic residuals showed a depressed effect on microbial respiration with residual concentrations of 1-20 ppm, and the effect was doseand type dependent. Depression was apparent at high doses. Stimulation effects were only occasionally observed at low concentrations. Similar results were also observed in ammonification with the maximal inhibition rate exceeding 8%. The depression effect on ammonification was gradually weakened in two weeks. Soil microbial cellulose decomposition activity was studied with the addition of tetracycline, chlortetracycline, norfloxacin, and enrofloxacin. The four types of antibiotics were tested separately under the same concentration (10 ppm). The cellulose decomposition rates with treatments of tetracycline, chlortetracycline, enrofloxacin and norfloxacin were 5.2%, 4.9%, 4.8%, and 4.5%, respectively, which were lower than the control (5.5%).

DEPRESSION OF SOIL MICROBIAL RESPIRATION, AMMONIFICATION AND CELLULOSE DEGRADATION UNDER THE STRESS OF ANTIBIOTIC RESIDUALS

Modifying ligands in four studied Ru(II) complexes have slight influence on their static first hyperpolarizabilities (βtot) values. However, the βtot values of complexes 1+/−–4+/− are all enhanced and the largest βtot value is observed for complex 4−.

Substituent and redox effects on the second-order NLO response of Ru(ii) complexes with polypyridine ligands: a theoretical study

Electrode/electrolyte additives for practical sodium-ion batteries: a mini review

It is important to search for efficient nonlinear optical (NLO) materials due to their potential applications in electro-optic devices. Theoretical investigations into the second-order NLO responses of ten novel Ru(II) polypyridyl complexes based on [Ru(phen)2(bipy)]2+ and [Ru(bphen)2(bipy)]2+ have been performed using density functional theory. The effects on the second-order NLO response of introducing a substituent to the bipy group and of varying the ligand from phen to bphen are studied. The introduction of an electron-withdrawing/donating group improves the static first hyperpolarizability (βtot) for [Ru(phen)2(bipy)]2+ derivatives, where the introduction of a strong electron-donating group, vinyl dimethylamine, increases the βtot value from 10 a.u. for an unsubstituted complex to 16 425 a.u. However, substituting the phen ligand for a bphen group has only a slight effect on the βtot values. Research into the electronic structures, UV-vis absorption spectra, and charge transfer properties was also carried out to further understand the second-order NLO properties of the ten complexes. The frontier orbital energy gap, electron density distribution, and charge-transfer direction and quantity are crucial elements impacting the second-order NLO responses of the complexes. Varying the electronic properties is considered to be an effective method for tuning the second-order NLO responses of materials. We hope our work will provide some helpful information for designing and synthesizing cost-effective and high-performance NLO materials.

A DFT study of the second-order nonlinear optical properties of Ru(II) polypyridine complexes.

Sn substitution and Sn doping reduce the band gap of MA2Pb(SCN)2I2 perovskites and make the absorption spectrum red-shifted.

A DFT study on the stability and optoelectronic properties of Pb/Sn/Ge-based MA2B(SCN)2I2 perovskites

Immobilization of simulated An4+ radioactively contaminated zeolite: Solidify mechanism and theory investigation

Structural, electrical, optical properties and stability of Cs2InBr5-yXy·H2O (X = Cl, I, y = 0, 1, 2, 3, 4, 5) perovskites: the first principles investigation

Electronic and Optical Properties of C4N2H14-Based Lead-Less Halide Perovskites Investigated by First Principles

Theoretical studies on the proton dissociation and degradation of sulfonated polyethylene electrolyte membrane

A series of neutral Ir(iii) complexes that possess cyclometalated ligands (C^N) and different ancillary ligands, N-heterocyclic carbene (NHC) and their ionic complexes 1+/−–5+/− have been investigated using density functional theory.

A computational study on second-order nonlinear optical properties based on bis-cyclometalated Ir(iii) complexes: redox and substituent effects

In an attempt to reveal a new structure–property interplay between the relative cavity size of the host–guest nanohoop complexes and nonlinear optical (NLO) responses, a series of “Russian doll” co...

New Structure-Nonlinear Optical Property Correlation in “Russian Doll” Complexes Formed by Nested Pd(II) Nanorings

Structure, electronic and optical properties of Cs2Ti(Br1-xYx)6 (Y = Cl, I; x = 0, 0.25, 0.5, 0.75, 1) perovskites: The first principles investigations

Novel cyclic and linearizing cyclic Pd(II) nanohoop-based cordination complexes achieving nonlinear optical activity transparency trade-off optimization

Recently, exploration of stabler and lead-free perovskite absorbers with better cost-effective processability and prominent light-harvesting capacity has attracted extensive attentions. Inorganic C...

Structural, Electronic, Stability, and Optical Properties of CsPb1–xSnxIBr2 Perovskites: A First-Principles Investigation

The high modularity of multicomponent photoactive BODIPY/carborane/diketopyrrolopyrrole hybrid chromophores was explored for linear/nonlinear optical applications.

A thorough understanding of the nonlinear optical properties of BODIPY/carborane/diketopyrrolopyrrole hybrid chromophores: module contribution, linear combination, one-/two-dimensional difference and carborane's arrangement

The intestinal epithelium barrier serves as a highly dynamic immunologic frontier in the defense against invading pathogenic bacteria and viruses. Hence, understanding of the complicated underlying relationship between enteric pathogens and the intestinal epithelium barrier is vital for developing strategies to improve the intestinal health of farm animals. To this end, Caco-2 cells were stimulated by 1 µg/ml lipopolysaccharide (LPS) for 24 h and 5 µg/ml polyinosinic-polycytidylic acid (ploy(I:C)) for 4 h to imitate bacterial and viral infection processes, respectively. The specific alterations in gene expression of Caco-2 cells after stimulation were characterized by transcriptome sequencing. Seventy differentially expressed genes (DEGs) were identified under LPS exposure, and 17 DEGs were observed under ploy(I:C) exposure. We found that most DEGs were specific, and only one common DEG SPAG7 was observed. Gene Ontology (GO) annotation analysis indicated that all DEGs identified in the different treatments were mainly derived from GO terms related to the maintenance of cellular homeostasis. Moreover, specific DEGs such as SLC39A10, MT2A, and MT1E regulated by LPS treatment, while IFIT2 and RUNX2 mediated by ploy(I:C) treatment, which are derived from immune function modulation related GO terms, were confirmed by both transcriptome sequencing and qRT-PCR. In addition, both transcriptome sequencing and qRT-PCR results verified that LPS specifically down-regulated the DEGs INHBE and ARF6, which are involved in inflammation responses related to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway including the TGF-beta signaling pathways and the Ras signaling pathway. Ploy(I:C) uniquely suppressed the DEGs GABARAP and LAMTOR3, which participated in viral replication-associated pathways including autophagy and mTOR signaling pathway.

Alterations in gene expressions of Caco-2 cell responses to LPS and ploy(I:C) stimulation

An important prerequisite for air pollution control is a more scientific and accurate prediction of the air quality index. In this paper, we first construct an air quality prediction model by BP neural network technique; then combine the variable screening method to optimize the independent variables in the input elements of the model, and finally select the variables that have the main influence on the air quality prediction model based on the test results. In this paper, taking Beijing as an example, we select the day-by-day data of air quality index and the day-by-day data of meteorological factors from 2017 to 2020, and apply the improved model for air quality prediction, and from the simulation results, it can be seen that the improved model using the variable screening method can improve the accuracy of predicting air quality index compared with BP neural network. The optimization of the model improves the validity of the prediction and can provide the scientific basis for subsequent air pollution prediction work and research.

2022 2nd International Conference on Computer Science, Electronic Information Engineering and Intelligent Control Technology (CEI)

Application of BP neural network in air quality prediction model

STAMBP promotes lung adenocarcinoma metastasis by regulating the EGFR/MAPK signaling pathway

Abstract Prior work shows that luxury brands predominantly prefer lifestyle advertisements to functional advertisements such that abstract or intangible elements are prevalent, but concrete or tangible elements are less common. This begs the following question: Is this because lifestyle advertisements are more effective than functional advertisements? This research shows that, depending on the situation, functional advertisements can be more effective for luxury products than lifestyle advertisements. Specifically, we apply a two-stage model of decision-making to the luxury purchase context. In stage 1, the motivation formation stage, consumers do not yet intend to buy a luxury product and are still forming purchase interest and motivation. In stage 2, the purchase decision-making stage, consumers desire to buy a luxury product, and their focus is on deciding which product to buy. Compared with stage 1, in stage 2, functional advertisements can be more effective for luxury products than lifestyle advertisements. This effect is consistent with the construal level theory. That is, the matching of construal levels between functional advertisements and the purchase decision-making stage increases the likelihood of making a purchase. This research contributes to literature on luxury branding, luxury advertising, lifestyle and functional branding and offers practical implications to luxury brand managers.

Dynamic Luxury Advertising: Using Lifestyle versus Functional Advertisements in Different Purchase Stages

Spatial and Temporal Analysis of Rainfall and Drought Condition in Southwest Xinjiang in Northwest China, Using Various Climate Indices

Investigation on the application of by-product steam in iron ore sintering: performance and function mechanism

Lung cancer is the second most common cancer in both men and women. The deubiquitinase PSMD7, as a core component of the 26S proteasome, is critical for the degradation of ubiquitinated proteins in the proteasome. Currently, PSMD7 expression and its roles in the progression of lung cancer remain largely unknown. In this study, we assessed PSMD7 expression and investigated the underlying molecular events by which PSMD7 regulates tumor progression in non-small cell lung cancer (NSCLC). The results showed that PSMD7 is more highly expressed in NSCLC tissues than in adjacent noncancerous tissues. PSMD7 expression was also closely associated with lymph node invasion and the laterality of the tumor in lung adenocarcinoma (LUAD). A high PSMD7 level predicted poor overall survival (OS) and disease-free survival (DFS) in LUAD patients, and PSMD7 knockdown significantly reduced cell proliferation and induced G0/G1-phase cell cycle arrest, cell senescence and apoptosis. PSMD7 knockdown inhibited expression of a set of proteins regulating cell cycle progression. Depletion of PSMD7 increased p53 levels and induced p21 and puma expression in a p53-dependent manner. Importantly, knockdown of PSMD7 markedly inhibited LUAD tumor growth in a xenograft mouse model. Taken together, these findings indicate that PSMD7 may serve as a valuable prognostic indicator and potential therapeutic target in LUAD.

PSMD7 downregulation suppresses lung cancer progression by regulating the p53 pathway

In this paper, we address the insufficiency of the popular atmospheric scattering model (ASM) used in the image dehazing problem. Unlike ASM assumes the global uniform atmospheric light and attenuation coefficients and thus often introduces unrealistic color after dehazing, we propose a novel dehazing model by relaxing the global uniform atmospheric assumption to local with additional color constraints to ensure more appealing and realistic dehazed results. More precisely, we make the modeling process as an optimization problem, whose cost function is composed of color constraint, local smooth of transmission map and atmospheric light. Consequently, we are able to generate more realistic dehazed images comparing to ASM, implying that deep neural networks trained with these samples could effectively learn how to dehaze images of complicated cases, especially when the global atmospheric assumption fails. Our extensive experimental studies also confirm that the proposed dehazing model outperforms the state-of-the-art methods by a noticeable margin on all three public benchmarks including HazeRD, RESIDE, and O-HAZE in terms of SSIM and PSNR.

2020 IEEE/CVF Conference on Computer Vision and Pattern Recognition Workshops (CVPRW)

Lung cancer is one of the most common malignant tumors in the world, with a high rate of malignancy and mortality. Seeking new biomarkers and potential drug targets is urgent for effective treatment of the disease. Deubiquitinase UCHL5/UCH37, as an important component of the 26S proteasome, plays critical roles in ubiquitinated substrate degradation. Although previous studies have shown that UCHL5 promotes tumorigenesis, its role in lung cancer remains largely unknown. In this study, we evaluated the expression and clinical significance of UCHL5 in non-small cell lung cancer (NSCLC). The results demonstrated that the UCHL5 expression level was significantly upregulated in NSCLC tissues compared with the adjacent noncancerous tissues. The level of UCHL5 was associated with tumor size, lymph node invasion, TNM stage and malignant tumor history in patients with lung adenocarcinoma (LUAD). Importantly, high UCHL5 expression predicted a poor overall survival (OS) and a poor disease-free survival (DFS) in patients with LUAD. Univariate regression analysis showed that tumor size, lymph node invasion, TNM stage and UCHL5 expression were associated with OS and DFS in patients with LUAD. The multivariate analysis indicated that the UCHL5 expression level was an independent prognostic factor for OS (HR=1.171, 95% CI=1.052-1.303) and DFS (HR=1.143, 95% CI=1.031-1.267) in these patients. UCHL5 knockdown in LUAD cells significantly inhibited cell proliferation and reduced the expression of key cell cycle proteins. These findings indicate that UCHL5 may serve as a potential prognostic marker and a new therapeutic target for patients with LUAD.

Deubiquitinase UCHL5 is elevated and associated with a poor clinical outcome in lung adenocarcinoma (LUAD)

PSMD14 is a 19S-proteasome-associated deubiquitinating enzyme that facilitates protein degradation by the 20S proteasome core particle. Although accumulating evidence indicates that PSMD14 has emerged as a critical oncogenic factor by promoting tumor growth, the expression and function of PSMD14 in non-small cell lung cancer (NSCLC) remain largely unknown. In this study, we assessed PSMD14 expression and correlated it with clinical-pathological features and patient survival in NSCLC. We also determined the roles of PSMD14 in the regulation of lung adenocarcinoma (LUAD) cell growth. The results showed that PSMD14 expression was significantly upregulated in human NSCLC tissues compared with adjacent non-cancerous tissues. The PSMD14 level was associated with tumor size, lymph node invasion, and TNM stage in LUAD patients. Importantly, high PSMD14 expression was associated with poor overall survival (OS) and disease-free survival (DFS) in LUAD patients. Further, knockdown of PSMD14 significantly inhibited cell growth and caused G1 arrest and cellular senescence by increasing p21 stability in LUAD cells. PSMD14 knockdown also promoted cell apoptosis by increasing cleaved caspase-3 levels in H1299 cells. PSMD14 may serve as a potential prognostic marker and therapeutic target for LUAD patients.

Upregulation of deubiquitinase PSMD14 in lung adenocarcinoma (LUAD) and its prognostic significance

Influences of soil properties and hydrological processes on soil carbon dynamics in the cropland of North China Plain

Breast cancer is the most common malignant tumor and the leading cause of cancer-related death in women. The ubiquitin-proteasome system regulates the stability of most proteins controlling various biological processes in human cells. PSMD7, as a core component of the 26S proteasome, is critical for the degradation of ubiquitinated proteins in the proteasome. Currently, PSMD7 expression and its roles in the progression of breast cancer remain largely unknown. In this study, we assessed the level of PSMD7 in breast cancer tissues and investigated the underlying molecular events by which PSMD7 could play a role in tumor progression. The results showed that the PSMD7 level was significantly upregulated in breast cancer tissues. PSMD7 expression was closely associated with tumor subtype, tumor size, lymph node invasion, and TNM stage. A high PSMD7 level predicted poor overall survival (OS) and disease-free survival (DFS) in breast cancer patients. Furthermore, univariate Cox regression analysis indicated that lymph node invasion, distant metastasis, and PSMD7 expression were associated with OS and DFS. Multivariate regression analysis indicated that PSMD7 was an independent predictor of OS (HR=1.310, 95% CI=1.038-1.652). Importantly, PSMD7 knockdown induced cell cycle arrest in the G0/G1 phase, leading to cell senescence and apoptosis. PSMD7 knockdown inhibited the expression of key cell cycle-related proteins and promoted the stability of p21 and p27 in breast cancer cells. PSMD7 may be a valuable prognostic indicator and potential therapeutic target for breast cancer.

Deubiquitinase PSMD7 regulates cell fate and is associated with disease progression in breast cancer.

An Internet of Things (IoT) platform with capabilities of sensing, data processing, and wireless communication has been deployed to support remote aquatic environmental monitoring. In this paper, the design and development of an IoT platform with multiple Mobile Sensor Nodes (MSN) for the spatiotemporal quality evaluation of surface water is presented. A survey planner is proposed to distribute the Sampling Locations of Interest (SLoIs) over the study area and generate paths for MSNs to visit the SLoIs, given the limited energy and time budgets. The SLoIs are chosen based on a cellular decomposition that is composed of uniform hexagonal cells. They are visited by the MSNs along a path ring generated by a planning approach that uses a spanning tree. For quality evaluation, an Online Water Quality Index (OLWQI) is developed to interpret the large quantities of online measurements. The index formulations are modified by a state-of-the-art index, the CCME WQI, which has been developed by the Canadian Council of Ministers of Environment (CCME) for off-line indexing. The proposed index has demonstrated effective and reliable performance in online indexing a large volume of measurements of water quality parameters. The IoT platform is deployed in the field, and its performance is demonstrated and discussed in this paper.

Automated Water Quality Survey and Evaluation Using an IoT Platform with Mobile Sensor Nodes

To establish and improve the ecological compensation system is an important part of the ecological civilization construction. At present, the construction of ecological compensation system has some weaknesses, such as the compensation fields, methods and standards are not clearly defined, which will be the difficulty of promoting the paid use system of resources and the ecological compensation system in the following work. Based on the major function zoning in Hebei province, this study suggests that the core task of improving the provincial ecological compensation mechanism lies in the perfection of pollution discharge management.

Research of Hebei Ecological Compensation System Based on the Main Functional Area

In order to perfect and popularize the method of using Tamarix cone sedimentary veins to reconstruct the climatic and environmental element sequences in arid zones, this paper has summarized the author's and relevant scholars' research progresses in this study area. In the area with modern strong wind-sandy action, the clear Tamarix cone sedimentary veins have become an effective dating method, and a paleo-climatic and environmental information carrier. There are clear sedimentary veins within Tamarix cones in Lop Nor region that can be used for dating directly. For the age sequence establishment of the Tamarix cones with discontinuous clear sedimentary veins, it is necessary to comprehensively use various kinds of dating methods including 210 Pbex, 137 Cs, and 14 C and so on. The parameters of sand material, the content of organic carbon and nitrogen, positive ion, the value of stable hydrogen and oxygen isotopes, as well as the sporo-pollen assemblage contained in Tamarix cone sedimentary veins, have sensitive responses to the climatic and environmental change. Although the single climatic and environmental proxy can reflect climatic and environmental change to a certain degree, comprehensively to use multiple proxies contained in Tamarix cone sedimentary veins to research the regional climatic and environmental change is more effective and accurate.

Study of the Response of Tamarix Cone Sedimentary Veins to Climatic and Environmental Elements in Arid Zones (DESERT TECHNOLOGY 11 INTERNATIONAL CONFERENCE)

In 1972, a Landsat MSS image clearly showed a "Big ear" shape in Lop Nor region, Xinjiang, China, which is one of the extreme drought regions in the world, and is a typical area to research environmental change of arid zones. For a long time, many researchers and common people expressed concern about the meaning and origin of the "Big ear" shape. In this paper we summarize research developments in these areas. The researched results show that the morphological pattern like the "Helix lines" of human being is the yearly and seasonal salt sedimentary structure lines in the process of forming salt crusts. The dark and light change of color tone depends on the burial depth of brine layers, the sand content in the salt crust, and the change in surface texture (roughness). There are different estimates of the age of formation of the "Big ear" from the 1930s to 1965. In the future, in order to clearly reveal the process of "Big ear" formation, it is necessary to conduct further accurate measures of the lake basin landform, and regional water balance analysis, and to systematically define the function of human activities in the process of Lop Nor drying. Lop Nor region is located in the eastern Tarim Basin, within Bayinguoleng Mongolian Autonomous Prefecture of Xinjiang, China, which is surrounded by Beishan Mountain in the east, by Tarim River in the west, by Jueluotagh Mountain of the front range of Tianshan Mountains in the north, and by the north slopes of the Altyn Mountains in the south. It is a famous area in the arid zone of China, the communication center of the ancient Silk Road, a passageway linking up the eastern cultures with the western cultures, and enjoys a high reputation in Chinese ancient history (Lop Nor Comprehensive Investigation Team of Xinjiang Branch of Chinese Academy of

Research Progresses in Morphological Features of the Area with "Big Ear" Image in Lop Nor Region and Its Environmental Significance (DESERT TECHNOLOGY 11 INTERNATIONAL CONFERENCE)

This study was designed to obtain the diurnal and seasonal changes of sap flow in Populus bolleana Lauche and Pinus sylvestris var. mongolica species so as to understand its water requirement and ecological significance. The thermal diffusion method and stem heat balance techniques were applied and meteorological factors were monitored at a flux tower during May-October 2011. The results showed that diurnal variation of sap flow fluctuation was transitionally changing in the growing season, adjusting to its way of water consumption. Sap flow of two species varied greatly under different weather, which reflected the dynamic of water absorption diverse. There was linear correlation between sap flow rate of Populus bolleana Lauche and reference evapotranspiration. Redundancy and Kendall’s tau analysis indicated air temperature, net radiation and vapour pressure deficit had great influence on sap flow of Populus bolleana Lauche, dominant environmental variables influencing sap flow were soil heat flux<wind speed<net radiation<air mean temperature<vapour pressure deficit. The variation in sap flow rate of Populus bolleana Lauche could be described by a multiple linear regression against the meteorological variables and the simulated value was significantly linearly correlated. The vertical distribution of soil moisture content was observed throughout the whole growing season. There was a highly linear relationship between sap flow rate to reference evapotranspiration and the amount of soil water in Pinus sylvestris var. mongolica woodland. In the 0.1-0.2 m soil layer contributed to most of the plant transpiration as the highest coefficient of determination at this layer. In the semi-arid district afforestation was limited to air mean temperature, net radiation, vapour pressure deficit and top soil moisture factors.

Sap flow response of afforestation species Populus bolleana Lauche and Pinus sylvestris var. mongolica to environmental factors in North-West China

We revisit the concept of public key encryption with delegated keyword search (PKEDS), a concept proposed by Ibraimi et al. A PKEDS scheme allows a receiver to authorize third-party server(s) to search in two ways: either according to a message chosen by the server itself or according to a trapdoor sent by the receiver. We show that the existing formulation has some defects and the proposed scheme is unnecessarily inefficient. Based on our analysis, we present a refined formulation of the primitive with a new security model. We then propose a new PKEDS scheme, which is proven secure and much more efficient than the original scheme by Ibraimi et al.

Refine the Concept of Public Key Encryption with Delegated Search

The public key encryption with keyword search (PEKS) provides a way for users to search data which are encrypted under the users’ public key on a storage system. However, the original schemes are based on the unrealistic assumption of a secure channel between the receiver and the server. Baek et al. [1] first proposed a secure channel-free public key encryption with keyword search (SCF-PEKS) to remove the assumption. However, Rhee et al. [2] point out that the SCF-PEKS scheme suffers from the keyword-guessing attack and proposed a scheme which satisfies the property of trapdoor indistinguishability without using an additional secure channel. In this paper, we construct a new efficient trapdoor-indistinguishable public key encryption with keyword search. Moreover, we prove that the proposed scheme can achieve the desired security properties.

A New Trapdoor-indistinguishable Public Key Encryption with Keyword Search

Tamarix cone is a kind of vegetation cones distributing in arid zone, in which there is a special internal structure consisting of the sand layer accumulated in spring and summer, and the layer of dead twigs and leaves accumulated in fall and winter form an annual deposit layer. This layer is called tamarix cone age layer. It can be utilized to estimate the age of sedimentary veins, and rebuild the sequence of environmental change.

Application of Tamarix Cone Age Layer in Studying on Environmental Change of Arid Zone

Under the impact of natural condition and historical factor, the area of lower reaches of Tarim River and Lop Nur region has been dried up for many years, and it has caused a lot of serious ecological consequences. In this paper the basic ways of ecological system's recovering and rebuilding have been put, and introduce Eco-benefits of emergent water transportation project to lower reaches of Tarim River.

Recovering and Rebuilding Ecological System of Lower Reaches of Tarim River and Lop Nur Region in Xinjiang(

Environmental significance exploration to Tamarix Cone Age Layer in Lop Nur Lake region

Stratification features of Tamarix cone and its possible age significance

Impact of oasis establishment on underground environment in salinized sandy lands

Sand circulation system in Taklimakan Desert: its past and present

Phthalocyanines are potentially promising photosensitizers (PSs) for photodynamic therapy (PDT), but the inherent defects such as aggregation-caused quenching effects and non-specific toxicity severely hinder their further application in PDT. Herein, we synthesized two zinc(II) phthalocyanines (PcSA and PcOA) monosubstituted with a sulphonate group in the alpha position with “O bridge” and “S bridge” as bonds and prepared a liposomal nanophotosensitizer (PcSA@Lip) by thin-film hydration method to regulate the aggregation of PcSA in the aqueous solution and enhance its tumor targeting ability. PcSA@Lip exhibited highly efficient production of superoxide radical (O2∙−) and singlet oxygen (1O2) in water under light irradiation, which were 2.6-fold and 15.4-fold higher than those of free PcSA, respectively. Furthermore, PcSA@Lip was able to accumulate selectively in tumors after intravenous injection with the fluorescence intensity ratio of tumors to livers was 4.1:1. The significant tumor inhibition effects resulted in a 98% tumor inhibition rate after PcSA@Lip was injected intravenously at an ultra-low PcSA@Lip dose (0.8 nmol g−1 PcSA) and light dose (30 J cm−2). Therefore, the liposomal PcSA@Lip is a prospective nanophotosensitizer possessing hybrid type I and type II photoreactions with efficient photodynamic anticancer effects.

A Sulfur-Bridging Sulfonate-Modified Zinc(II) Phthalocyanine Nanoliposome Possessing Hybrid Type I and Type II Photoreactions with Efficient Photodynamic Anticancer Effects

Most photodynamic therapy (PDT) paradigms work through the highly O2-dependent type II photoreaction to generate singlet oxygen (1O2). The hypoxic microenvironment of solid tumors severely hampers therapeutic outcomes. Here, we present a novel design that could transfer the photophysical and photochemical properties of traditional phthalocyanine-based photosensitizers from type II photoreaction to efficient type I photoreaction and vibrational relaxation-induced photothermal conversion. These features enable the obtained nanostructured phthalocyanine assemblies (e.g., NanoPcAF) to display excellent phototherapies under both normoxic and hypoxic conditions. Moreover, NanoPcAF has a high level of accumulation in tumor tissues after intravenous injection, and 94% of tumor growth is inhibited in a preclinical model at a NanoPcAF dose of 0.8 nmol g-1 and light dose of 300 J cm-2.

Nanostructured Phthalocyanine Assemblies with Efficient Synergistic Effect of Type I Photoreaction and Photothermal Action to Overcome Tumor Hypoxia in Photodynamic Therapy.

A phthalocyanine-based self-assembled nanophotosensitizer for efficient in vivo photodynamic anticancer therapy.

The substituted zinc(II) phthalocyanines using “sulfur bridge” as the linkages. Synthesis, red-shifted spectroscopic properties and structure-inherent targeted photodynamic activities

A phthalocyanine-based liposomal nanophotosensitizer with highly efficient tumor-targeting and photodynamic activity

We for the first time demonstrate that diversified molecular tuning approaches are available to effectively tailor phthalocyanine dyes for PTT.

New application of phthalocyanine molecules: from photodynamic therapy to photothermal therapy by means of structural regulation rather than formation of aggregates† †Electronic supplementary information (ESI) available: Experiment materials and methods, characterization data, additional data. See D

Phthalocyanines as medicinal photosensitizers: Developments in the last five years

Performance Study of RC Hollow Core Slab with Cracks Based on Extended Finite Element Method (XFEM)

Section Stress Redistribution of Concrete Composite Member Caused by Creep

The paper analyzed the cracks cause and damage type of old cement concrete pavement slab,introduced the cracks treatment and construction technology and evaluated the application and usage effect of physical works.

The Construction Technology of Cracks Treatment for Cement Concrete Slab

Aiming at gearbox operating characteristics,ANSYS software is applied to carry on modal analysis of gear box,and to analyze the influence of gear box modal mode to the box performance.By changing the box thickness,the box structure is optimized.The results show that the optimization makes the performance of the gear box more stable,and makes the stress distributed uniformly,reduces the maximum deformation,vibration,maximum equivalent stress. This method is useful to the stress uniform distribution and the purpose of vibration and noise reduction.

Floating frame oil pumping machine is the main equipment used in the oil exploitation.The damage of crankpin is the main malfunction of this equipment.However,the normal method can't solve the problem of crankpin.Based on analysis of jiggle abrasion for the reason of the crankpin,it finds that the crankpin is related to the jiggle abrasion.It analyzes the four damage basic forms including agglutination,attrite material,oxygenation and tiredness.In designing process,it is necessary to prevent the jiggle for the working life of the crankpin mechanisms.

Analysis of Crankpin Fracture in Floating Frame Oil Pumping Machine

The large-scale finite-elenent software ANSYS was scroll vacuum pump,thus analyzing simulatively the stress and deformation of the pump in its running process.The results showed that the analysis by virtue of the software can reveal basically the stress/deformation distribution and variation of the pump in its running process,so available to provide an effective way for determining the design parameters and relevant factors of the pump.

Simulative study on stress and deformation of scroll pump by ANSYS

Principle, damaging and precautions of fretting in aeroengine compressor blade mountings has been introduced in this paper. Embrittlement caused by soft metal, like sliver, when used as and - fretting coating in aeroengine compressor blade mountings has also been discussed for its start conditions and precautions here.

An Investigation on Fretting in Aeroengine Compressor Blade Mountings and "SilverEmbrittlement

In a state of self-compensate for wear, a BP neutral net model of copper and zinc element distribution law on 45 copper /brass rubbing secondary surface is set up. This net can predict precisely the distribution law of transfer element of copper and zinc on rubbing secondary surface. With L-M regular training it can promote the speed and precision of net convergence. This study provides an effective and convenient way for programmed calculation and analysis in tribology design.

Study on Element Distribution Law of Multiple Bed on Rubbing Surface

Band structure tunable synthesis of photocatalytic porous aromatic frameworks via Scholl reaction

A direct NO-releasing reaction of nitrite catalyzed by [N(afaCy)3Fe(OTf)]+ (afa (azafulvene-amine); OTf (trifluoromethanesulfonate); Cy (cyclohexyl)) was investigated using density functional theory (DFT) with D3 dispersion correction. The complex featured a secondary coordination sphere that facilitated the formation of the iron-oxo product [N(afaCy)3FeO]+ with three (Fe)OH-N hydrogen bonds. As a high-spin iron(ii), the O-binding initial intermediate Fe(O)-nitrito was thermodynamically favorable in the S = 2 state. The cleavage of the (Fe)O-NO bond was performed by a β-electron shift to produce Fe(iii)-O by electron rearrangement in the S = 5/2 state. The different electron configurations are responsible for the structural properties, the valence of iron in the complexes, and the pathways of the reactions. Moreover, the two different H-bonds, (Fe)OH-N and (Fe)O-HN (by O-protonation), in the product complexes played a role in determining the reaction channels by impacting the N-H bond rotation. Thus, an exothermic sequence of conversions Fe(ii) → Fe(iii)-O → Fe(iii)-OH → Fe(iii)-O was established for the targeted product formation. This process provided a clue to build two key intermediates, iron-oxo and iron-hydroxo, in a variety of biological and synthetic systems. The results of this study are in agreement with experimental observations and describe the roles of H-bonding in nitrite reduction catalyzed by the non-heme iron complex.

Computational analysis of non-heme iron-oxo formation by direct NO release in nitrite reduction.

Selective C-H hydroxylation by nonheme iron complexes offers a promising method in the field of organic synthesis. Aliphatic C-H bond oxidation reactions of pivalate (R) catalyzed by [Fe(S,S-PDP)(CH3CN)2]2+ (CAT1) were examined using the density functional theory. Our calculations of the CH3CN solvent agree with the experimental findings. However, it was observed that the gas-phase results did not replicate selective C-H hydroxylation observed experimentally when CAT1 catalyzed hydrocarbon oxidations by H2O2via an HO-FeV[double bond, length as m-dash]O oxidant (CAT1a). We inferred that the difference was mainly from hydrogen bonding formation, (CAT1a) O-HO[double bond, length as m-dash]C (R), in certain gaseous H-abstraction transition states (TSH). Then, the appearance of the stronger (CAT1a) O-HN[triple bond, length as m-dash]CCH3-solvent weakened the aforementioned interaction, leading to C-H activation influenced primarily by their electronic and steric properties. Such a deduction explained the same selective C-H found in both phases of reactions with CAT1b, a cyclic ferric peracetate oxidant, by the reason of TSH without the influence of H-bonding. Another interesting finding was that the commonly recognized radical intermediate was further isomerized by a favorable electron rearrangement. Thus, the subsequent OH-rebound behavior proceeded by an electrostatic interaction. This study provides mechanistic clues for modifying regioselective C-H hydroxylation for molecule synthesis applications.

Computational analysis of site differences in selective aliphatic C-H hydroxylation by nonheme iron-oxo complexes.

Metallofullerenes with two erbium atoms encapsulated in IPR C82 cage isomers Cs-6 (I), C2v-9 (II), and C3v-8 (III) were investigated using density functional theory. The calculations suggest that erbium atoms assume a trivalent state with Er (4f11) valence electronic configuration in Er2@C82 and Er2C2@C82, where two electrons (6s2) per Er atom are transferred to the cage carrying four negative charges (C824-), while the third electron is promoted from the 4f to the 5d shell, becoming involved in covalent bonding to near atoms. Experimentally, Er3+-like emission from 4I13/2 to 4I15/2 was observed, and our calculations indicate that the Er-Er covalent metal bond in Er2@C82, and the Er-C/C2 covalent bonds in Er2C2@C82, can account for the observed photoluminescence despite the cage with C824-. Such existence is the reason that the C2 unit was found to be neutral on the basis of MEM-Rietveld X-ray measurements, although formally it should be described as C22-. Our prediction for isomer photoluminescence intensity agrees with the experimentally determined order (III > I > II), where the most pronounced activity of isomer III in Er2C2@C82 stems from its higher charge of formal Er3+ and its largest HOMO-LUMO gap.

Er3+ Photoluminescence in Er2@C82 and Er2C2@C82 Metallofullerenes Elucidated by Density Functional Theory.

Physiological, transcriptome and co-expression network analysis of chlorophyll-deficient mutants in flue-cured tobacco

Identification of Bacteria Associated with Tobacco Mildew and Tobacco-Specific Nitrosamines During Tobacco Fermentation

Comparative transcriptome analysis of conventionally cultivated tobacco and tobacco grafted to eggplant

Abstract In this study, we aimed to determine molecular mechanisms underlying the effects of topping and grafting in tobacco ( Nicotiana tabacum L.) by comparing the alkaloid contents and enrichment pathways of differentially expressed genes (DEGs) among plants subjected to different combinations of topping and grafting treatments. Plants of the tobacco variety “Zhongyan 100” and eggplant ( Solanum melongena L.) were grafted in four combinations as scions and rootstocks, respectively. The four treatment groups were tobacco with topping, tobacco without topping, topped tobacco grafted onto an eggplant rootstock, and non‐topped tobacco grafted onto an eggplant rootstock. Tobacco leaves were collected on the day of topping, at 7 days after topping, and after flue curing, the alkaloid contents of the collected leaves were determined. Leaves of plants subjected to the different treatments were collected for RNA sequencing and screened for DEGs, which were subsequently subjected to functional enrichment analyses. Analyses revealed reductions in the leaf alkaloid contents of tobacco subjected to combined topping and eggplant grafting. Gene annotation indicated that topping influences biological processes such as starch metabolism and stress response, whereas grafting affected the biosynthesis and metabolic pathways of secondary metabolites. Downregulated DEGs between non‐topped tobacco and eggplant‐grafted topped tobacco and between topped and non‐topped tobacco are mainly involved in inositol phosphate metabolic and biosynthetic processes. Downregulated DEGs between different grafting methods (eggplant‐grafted non‐topped tobacco vs. non‐topped tobacco and eggplant‐grafted topped tobacco vs. topped tobacco) are mainly involved in sesquiterpene synthase activity and photosynthesis. The findings of this study provide important insights into the molecular mechanisms underlying the effects of topping and grafting on tobacco plants.

Topping and grafting affect the alkaloid content and gene expression patterns of tobacco ( Nicotiana tabacum L.)

The combination of transcriptome and metabolome reveals the molecular mechanism by which topping and salicylic acid treatment affect the synthesis of alkaloids in Nicotiana tabacum L.

Physiological and transcriptome analysis reveals the differences in nitrate content between lamina and midrib of flue-cured tobacco

 Background: Nitrosition of tobacco pyridine alkaloids by nitrate-derived NOx is the origin of tobacco-specifc nitrosamines (TSNAs) formed in tobacco, which are among the most notable toxicants present in tobacco products and smoke. Burley tobacco is particularly susceptible to TSNA formation because the cultivars exhibit a chloroplast-deficient and nitrogen-use-defciency phenotype which results in high accumulation of nitrate. Strategies to lower nitrate levels in tobacco could produce a corresponding decrease in TSNAs accumulation in leaves. Previous studies have showed that grafting with high nitrogen use efficiency rootstock was able to improve the nitrogen utilization of flue-cured tobacco. In this study, a reciprocativel grafting experiment has been conducted with two varieties of different tobacco types (burley tobacco ‘Eyan No.1’ and flue-cured tobacco ‘K326’) to investigate whether replacing burley tobacco root with flue-cured tobacco by grafting can enhance pigment biosynthesis and photosynthesis parameters and reduce nitrate content of burley tobacco leaves, and to explore the corresponding mechanism. Results: The results showed that compared with the self-rooted burley tobacco seedlings, grafting significantly increased the pigment content, net photosynthesis, biomass, total soluble sugar, reducing sugar, nitrate reductase activity, glutamine synthetase activities, NH4-N and soluble protein content of the leaves of Eyan No.1 while decreased the nitrate content and NO3-N/TN. Interestingly, transcription level analysis suggested that replacing burley tobacco root with flue-cured tobacco by grafting was able to up-regulate the genes involved in starch and sucrose metabolism, porphyrin and chlorophyll metabolism, carbon fixation in photosynthetic organism metabolism, carotenoid biosynthesis and nitrogen metabolism of burley tobacco leaves. In addition, the PPI network revealed gene_68511, gene_35043 and gene_77508 had higher degrees via replacing burley tobacco root with flue-cured tobacco, which might be hub proteins to reduce nitrate accumulation. Conclusions: In conclusion, grafting with high nitrogen use efficiency rootstock provided an exceptionally promising means of nitrate reduction in burley tobacco leaf , which is a principle precursor of TSNAs, due to the improvement of photosynthesis and nitrogen metabolism in the scion.

Reducing the nitrate content of burley tobacco by grafting with flue-cured tobacco

Influence of microbiota and metabolites on the quality of tobacco during fermentation

SCREENING OF ALGAL AND CYANOBACTERIAL STRAINS FOR OPTIMAL BIOMASS PRODUCTION AND NUTRIENT RECOVERY FROM DAIRY MANURE- BASED ANAEROBIC DIGESTION EFFLUENT by

Wheat bHLH-type transcription factor gene TabHLH1 is crucial in mediating osmotic stresses tolerance through modulating largely the ABA-associated pathway

Wheat WRKY Type Transcription Factor Gene TaWRKY1 is Essential in Mediating Drought Tolerance Associated with an ABA-Dependent Pathway

TabHLH1, a bHLH-type transcription factor gene in wheat, improves plant tolerance to Pi and N deprivation via regulation of nutrient transporter gene transcription and ROS homeostasis.

Wheat mitogen-activated protein kinase gene TaMPK4 improves plant tolerance to multiple stresses through modifying root growth, ROS metabolism, and nutrient acquisitions

Expression pattern analysis of microRNAs in root tissue of wheat (Triticum aestivum L.) under normal nitrogen and low nitrogen conditions

Growth traits and nitrogen assimilation-associated physiological parameters of wheat （Triticum aestivum L.） under low and high N conditions

Summary Excess red light induces a defence response by activating lipoxygenase at both the transcript and activity levels.

Phytochrome B-mediated activation of lipoxygenase modulates an excess red light-induced defence response in Arabidopsis

Neuronal ceroid lipofuscinosis type 2 (CLN2) is an autosomal recessive neurodegenerative disease caused by variants in the TPP1 gene that lead to the deficiency of the lysosomal enzyme tripeptidyl peptidase I (TPP1) activity. Herein, we report a rare case of CLN2 caused by two novel variants of TPP1. The patient presented with seizures at onset, followed by progressive cognitive impairment, motor decline, and vision loss. Novel compound heterozygous variants, c.544_545del and c.230-3C>G, in TPP1 were identified by whole-exome sequencing. The variant assessment showed that the c.544_545del is a frameshift variant mediating mRNA decay and that c.230-3C>G is a splice variant generating aberrantly spliced TPP1 mRNA, as confirmed by a Splicing Reporter Minigene assay. In conclusion, clinical history, variant assessment, and molecular analyses demonstrate that the novel compound heterozygous variants are responsible for CLN2 disease in this patient. This study expands the mutation spectrum of TPP1.

Case report: Analysis of novel compound heterozygous TPP1 variants in a Chinese patient with neuronal ceroid lipofuscinosis type 2

Rationale: As the central hallmark of liver fibrosis, transdifferentiation of hepatic stellate cells (HSCs), the predominant contributor to fibrogenic hepatic myofibroblast responsible for extracellular matrix (ECM) deposition, is characterized with transcriptional and epigenetic remodeling. We aimed to characterize the roles of H3K27 methyltransferase EZH2 and demethylase JMJD3 and identify their effective pathways and novel target genes in HSCs activation and liver fibrosis. Methods: In primary HSCs, we analyzed effects of pharmacological inhibitions and genetic manipulations of EZH2 and JMJD3 on HSCs activation. In HSCs cell lines, we evaluated effects of EZH2 inhibition by DZNep on proliferation, cell cycling, senescence and apoptosis. In CCl4 and BDL murine models of liver fibrosis, we assessed in vivo effects of DZNep administration and Ezh2 silencing. We profiled rat primary HSCs transcriptomes with RNA-seq, screened the pathways and genes associated with DZNep treatment, analyzed EZH2 and JMJD3 regulation towards target genes by ChIP-qPCR. Results: EZH2 inhibition by DZNep resulted in retarded growth, lowered cell viability, cell cycle arrest in S and G2 phases, strengthened senescence, and enhanced apoptosis of HSCs, decreased hepatic collagen deposition and rescued the elevated serum ALT and AST activities of diseased mice, and downregulated cellular and hepatic expressions of H3K27me3, EZH2, α-SMA and COL1A. Ezh2 silencing by RNA interference in vitro and in vivo showed similar effects. JMJD3 inhibition by GSK-J4 and overexpression of wild-type but not mutant Jmjd3 enhanced or repressed HSCs activation respectively. EZH2 inhibition by DZNep transcriptionally inactivated TGF-β1 pathway, cell cycle pathways and vast ECM components in primary HSCs. EZH2 inhibition decreased H3K27me3 recruitment at target genes encoding TGF-β1 pseudoreceptor BAMBI, anti-inflammatory cytokine IL10 and cell cycle regulators CDKN1A, GADD45A and GADD45B, and increased their expressions, while Jmjd3 overexpression manifested alike effects. Conclusions: EZH2 and JMJD3 antagonistically modulate HSCs activation. The therapeutic effects of DZNep as epigenetic drug in liver fibrosis are associated with the regulation of EZH2 towards direct target genes encoding TGF-β1 pseudoreceptor BAMBI, anti-inflammatory cytokine IL10 and cell cycle regulators CDKN1A, GADD45A and GADD45B, which are also regulated by JMJD3. Our present study provides new mechanistic insight into the epigenetic modulation of EZH2 and JMJD3 in HSCs biology and hepatic fibrogenesis.

Histone H3K27 methyltransferase EZH2 and demethylase JMJD3 regulate hepatic stellate cells activation and liver fibrosis

Interplay of pioneer transcription factor FOXA1 and estrogen receptor has been implicated in sexual dimorphism in hepatocellular carcinoma (HCC), but etiological relevance of its polymorphism was unknown. In the case control study (1152 patients vs 1242 controls), we observed significant increase in HCC susceptibility in hepatitis B virus carriers associated with a nonsynonymous Thr83Ala variant of FOXA1 (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.11-1.48, for Ala83-containing genotype, after validation in an independent population with 933 patients vs 1030 controls), a tightly linked (CGC)5/6or7 repeat polymorphism at its promoter (OR 1.32; 95% CI 1.10-1.60, for (CGC)6or7-repeat-containing genotype), and their combined haplotype (OR 1.50; 95% CI 1.24-1.81, for (CGC)6or7-Ala83 haplotype). The susceptible FOXA1-Ala83 impairs its interaction with ERα, attenuates transactivation toward some of their dual target genes, such as DIO1, UGT2B17 and NTCP, but correlates with strengthened cellular expression of AFP and elevated AFP serum concentration in HCC patients (n = 1096). The susceptible FOXA1 cis-variant with (CGC)6or7 repeat strengthens the binding to transcription factor EGR1 and enhances promoter activity and gene expression. Evolutionary population genetics analyses with public datasets reveal significant population differentiation and unique haplotype structure of the derived protective FOXA1-Thr83 and suggest that it may have undergone positive natural selection in Chinese population. These findings epidemiologically highlight the functional significance of FOXA1-ERα transcriptional program and regulatory network in liver cancer development.

Trans-acting nonsynonymous variant of FOXA1 predisposes to hepatocellular carcinoma through modulating FOXA1-ERα transcriptional program and may have undergone natural selection.

Hepatic stellate cells (HSCs) are the primary cell type responsible for liver fibrogenesis. Transforming growth factor beta 1 (TGF-β1) and platelet-derived growth factor (PDGF) are key profibrotic cytokines that regulate HSC activation and proliferation with functional convergence. Dual RNA interference against their receptors may achieve therapeutic effects. A novel RNAi strategy based on HSC-specific GFAP promoter-driven and lentiviral-expressed artificial microRNAs (amiRNAs) was devised that consists of an microRNA-30a backbone and effective shRNAs against mouse Pdgfrβ and Tgfbr2. Then, its antifibrotic efficacy was tested in primary and cultured HSCs and in mice affected with carbon tetrachloride-induced hepatic fibrosis. The study shows that amiRNA-mediated Pdgfrβ and Tgfbr2 co-silencing inhibits HSC activation and proliferation. After recombinant lentiviral particles were delivered into the liver via tail-vein injection, therapeutic amiRNAs were preferentially expressed in HSCs and efficiently co-knocked down in situ Tgfbr2 and Pdgfrβ expression, which correlates with downregulated expression of target or effector genes of their signaling, which include Pai-1, P70S6K, and D-cyclins. amiRNA-based HSC-specific co-silencing of Tgfbr2 and Pdgfrβ significantly suppressed hepatic expression of fibrotic markers α-Sma and Col1a1, extracellular matrix regulators Mmps and Timp1, and phenotypically ameliorated liver fibrosis, as indicated by reductions in serum alanine aminotransferase activity, collagen deposition, and α-Sma-positive staining. The findings provide proof of concept for the use of amiRNA-mediated co-silencing of two profibrogenic pathways in liver fibrosis treatment and highlight the therapeutic potential of concatenated amiRNAs for gene therapy.

Artificial MicroRNA-Mediated Tgfbr2 and Pdgfrb Co-Silencing Ameliorates Carbon Tetrachloride-Induced Hepatic Fibrosis in Mice.

As a central event in liver fibrogenesis, hepatic stellate cell (HSC) transdifferentiation involves loss of regulation by adipogenic transcription factors such as peroxisome proliferator‐activated receptor γ; (PPARγ), which is epigenetically silenced during HSC activation. We hypothesized that JMJD1A, an H3K9 demethylase involved in adipogenic metabolism, could regulate PPARγ. In human HSC cell line, rat primary HSCs, and carbontetrachloride‐induced mouse liver fibrogenesis model, we down‐regulated the expression of JMJD1A using small interfering or short hairpin RNAs, and overexpressed its wild‐type and mutant. We analyzed the effects of JMJD1A manipulation on the histone di‐methyl‐H3K9 (H3k9me2) status of PPARγ gene and the expression of PPARγ and fibrosis markers using chromatin immunoprecipitation, real‐time quantitative RT‐PCR and Western blot, and also investigated the in vitro and in vivo consequences on liver fibrosis and necrosis by Masson or hematoxylin‐eosin staining, respectively. JMJD1A knockdown in HSCs correlated with reinforced H3K9me2 in the PPARγ gene promoter, and its down‐regulation in both mRNA and protein led to increased expression of fibrosis markers, which could be consistently rescued by JMJD1A overexpression. Jmjd1a knockdown in situ resulted in significantly increased expression of α‐smooth muscle actin (P = 0.005) and Col1a (P = 0.036), strengthened production of collagens (P = 0.028), and remarkably enhanced necrosis (P = 0.007) 4 weeks after treatment. This study suggests JMJD1A as a novel epigenetic regulator that modulates HSC activation and liver fibrosis through targeting PPARγ gene expression.—Jiang, Y., Wang, S., Zhao, Y., Lin, C., Zhong, F., Jin, L., He, F., Wang, H. Histone H3K9 demethylase JMJD1A modulates hepatic stellate cells activation and liver fibrosis by epigenetically regulating peroxisome proliferator‐activated receptor γ. FASEB J. 29, 1830‐1841 (2015). www.fasebj.org

Histone H3K9 demethylase JMJD1A modulates hepatic stellate cells activation and liver fibrosis by epigenetically regulating peroxisome proliferator‐activated receptor γ

Revisiting the role of MCL1 in tumorigenesis of solid cancer: gene expression correlates with antiproliferative phenotype in breast cancer cells and its functional regulatory variants are associated with reduced cancer susceptibility

As an important part of local regular undergraduate institutions, private universities have played an important role in the service of local economic and social development and training of highly qualified technical personnel. Currently, the country accelerates the deployment of modern vocational education system, guide the transformation and development of a number of regular undergraduate colleges and universities. The private colleges and universities should explore strategic development path which in line with the actual situation of school and realize the real connotation development and leapfrog development. This paper detailed the theory exploration and practice innovation of school running mode, school-enterprise cooperation, talent training mode, personnel system in the school transformation development in order to provide reference for transformation development of other private undergraduate college.

Research on Transformation Development Path of the Private Undergraduate College

In recent years, with the rapid development of society and the deepening of education reform, the ideological and political education is more and more attention. Education courses in colleges and universities is the main channel of ideological and political education of college students, college students' autonomous learning is an important platform, in this paper, the difficulties facing education courses in colleges and universities and the trend of college students' autonomous learning ability weakened, talk about how to take the student as under the guidance of this concept, explore the application of autonomous learning in education courses, to enhance the efficiency of the education courses.

Research on autonomous learning methods in the ideological and political education of universities

The environmental microbiological curricula are required courses in the system of environmental specialty.This study did a survey to better understand the perspectives from students on the teaching content,methods and experimental part.Based on the survey results,and taking professional experiences from other universities at home and abroad,some ideas were put forward:differentiation and clearly defined the pre-courses and follow-up courses;increase in environmental engineering pollution control microbiology experiments;more practice on literature research and scientific paper writing;taking diverse forms of examination to improve teaching effectiveness,and to consolidate the students' understanding of basic knowledge,concepts,theory and applications of environmental microbiology.

Exploration and Discussion of the Biological Curricula Teaching for Environmental Specialty

Opening laboratory is an important reform to laboratory management.To deepen the reform in practice teaching link of undergraduate course in mechatronics specialty,cultivate human talents who have innovation inspirits and practice capability,and improve the ability to innovate designing and comprehensive practice,the instructive exploration of opening laboratory is carried out and the favorable results is also yielded.In this paper,the modus operandi,experience,impact and mending suggestion are summarized in detail.

Exploration on the Opening of Mechatronics Technicality Laboratory

Aiming at the current situation and problems of computer experimental teaching,and combined with its characteristic,presents some reformation advices from educational innovation,the enactment of educational concepts,experimental contents of courses,teaching method and construction of computer laboratory,as to raise experimental teaching effect and train experimental capabilities of students and to improve the quality of computer experimental teaching to a certain extent.

Students find hard to comprehend abstract knowledge with insufficient teaching devices and real working conditions.The introduction of MATLAB in teaching helps students carry out simulated analysis of telecommunication system,and greatly enhances students' interests and study performance as well as promotes their professional proficiency.

The case-based teaching method is one of the new teaching methodologies commonly accepted by comprehensive universities recently.But,in the process of application,there are some long-standing mistaken ideas about this teaching method,such as the traditional teaching method and the case-based teaching method are being made incompatible;the extent and scope of the application of case-based teaching are being over-generalized;and the role of teachers in the case-based teaching process is being one-sidedly orientated.Therefore,in order to perfect the case-based teaching approach,efforts should be made to establish the student-centered teaching concept,standardize the case-based teaching procedures,and construct a scientific evaluation system for the case-based teaching.

On Mistaken Conceptions of Case-based Teaching and Their Rectification

Allocation and characteristic of social science journals of colleges and universities is related to the quality and academic grade of social science journals,especially for some local colleges journals,should be based on reality of school's teaching research and local economic culture to allocate accurately,to have its own characteristics,to avoid comparing blindly and aiming too high.

Allocation and Characteristic of Social Science Journals of Colleges and Universities——From Publication Thought of Lvliang Higher College Journal

The major of Mechanical and Electrical in Higher Vocational College,the practice of the application and principles of Electric Control and PLC course plays an extremely important role in the whole teaching process.In order to train innovative talents who can adapt to the social demands,we must carry out the reform in experiment and practical teaching.This paper analyzes the practical teaching of the current situation of the course and puts forward some measures on the practical teaching aspect of the teaching requirements,teaching conditions,operating mode of reform measures.

The Reform and Practice of Higher Vocational Course——The Application and Principles of Electric Control and PLC

Problems in Researching E-learning: The Case of Computer-Assisted Language Learning

Learner corpus provides lots of information for foreign language teaching.Teachers can not only choose useful information from it to enrich the classroom teaching according to teaching purpose and content,but also make vivid PowerPoint with the help of learner corpus.Learner corpus is the source of improving the English textbooks and other relevant materials.

Network not only provides new position for college moral quality education but also brings unprecedented challenge.So those engaged in moral education should adapt themsewes to the network socialistion and try their best to improve their own qualities.They should try their best to widen channels of moral education.They should be good at quiding students to apply the network technologies and knowledges,expanding the advantages of college moral education,so as to serve it better through applying the network and its information.

The Exploration and Analysis of College Moral Education under the Background of Internet Socialization

In Comrade Hu Jintao's thesis on the socialist outlook on honor and shame,two basic issues of what kind of socialist citizens to train and how to train them during the new period are explicated in an all-round way.As a main base for training high-quality talents,HEIs should make the socialist outlook on honor and shame permeate through ideological and political work and the whole process of educating people,and make innovations in the connotation,form and system of ideological and political work.Only by doing so,is it possible to produce high-quality talents suitable to social needs.

The Socialist Outlook on Honor and Shame and the Innovation of Ideological and Political Work in HEIs

In college English teaching, teachers should help and direct students, create the language communication environment and the chances to express thoughts, make the colorful language activity run through the whole teaching. In this process, teachers play different roles.

The application of the educational psychology in college English teaching

P.E. specialties education in normal colleges,a specialized training characterized with its personality and innovation,is a multifactor system which is surely in need of a pluralistic and dynamic evaluation.The purpose of such evaluation is to promote teachers teaching and to improve students learning ability so as to better the quality of P.E. majors.Thus,there is a desperate need to build P.E. education programme an evaluation which is characterized with frequency,continuance,and instituationalization.

Some Thoughts on the Building of the Evaluation System for P.E. Programme in Normal Colleges

The teaching of architectural render should be reformed under new situation The teaching should give the first place to pen render, sketch, and improve the artistic accomplishments of students The author raises relevant teaching method

Initial Researches on the Teaching of Architectural Render Under New Situation

In order to strengthen students' quality education and ensure education effect further. We first should improve the teachers' qality. Then we should be well aware of the influence on education which denied from teachers' quality and analyze carefully teachers' quality levels enhance teachers' professional training, ethics and moral education and so on in different way. Only those who have high teaching level and good moral could shoulder the important task of education the high quality successors who are qualified in politics and profession for the socialist construction cause.

Some Observations and Reflections of strengthening College Teachers' Quality Education

It is the core content to cultivate the innovative abili ties in the graduate education ant it is also an important yardstick to improve the quality of the graduate students. Therefore, it is obvious that the key fact or in achieving this goal lies in the cultivation of their innovative abilities. The paper holds that in order to attain this goal the work can be done from two aspects: developing the spirit of innovation and the innovative thinking. And t he work must be carried out throughout the whole process of the graduate educati on. The paper also discusses and explores some specific ways to develop the grad uates' innovative abilities.

Under the background of modern education, secondary vocational education should not only cultivate high-quality technical talents, but also cultivate innovative talents with "craftsman spirit". Under the guidance of professional education theory, students should constantly update their ideological connotation and promote their diversified development. Therefore, in the actual education and teaching, secondary vocational schools and teachers should create a strong craftsman spirit atmosphere for students, design subject plans from various aspects such as professional skills and professional quality and provide direction and power for students' employment and development.

Research on the Theory and Practice Innovation of Cultivating "Craftsman Spirit" in Mechanical and Electrical Specialty of Secondary Vocational School

Early identification of disease progression in ALK-rearranged lung cancer using circulating tumor DNA analysis

Triple-negative breast cancer is a kind of breast cancer with negative estrogen receptor and progesterone receptor, and low expression of human epidermal growth factor receptor-2. Compared with other subtypes of breast cancer, triple-negative breast cancer has the characteristics of strong invasive potential, high recurrence rate and poor prognosis. It is one of the most intractable types of breast cancer. At present, there is a lack of effective treatment. As a new clinical treatment, immunotherapy has great clinical significance for the treatment of triplenegative breast cancer, and provides new treatment options for patients. The present article reviews the research progresses of immunotherapy for triple-negative breast cancer in recent years. The main contents cover the molecular classification, active immunotherapy, passive immunotherapy, oncolytic immunotherapy, and the prospect of immunotherapy for triple-negative breast cancer.

Non-small cell lung cancer (NSCLC) patients with ALK rearrangements are routinely treated with tyrosine kinase inhibitors (TKIs), leading to improved survival. However, clinical courses vary widely and the disease remains incurable. Therefore, early detection and molecular characterization of treatment failure is important for therapy guidance. To identify indicators of therapy response and resistance, we performed genotyping of circulating cell-free DNA (cfDNA), including panel-based deep sequencing (>4,200x coverage) and shallow whole-genome sequencing (sWGS; 0.5x coverage) from serial plasma samples (n=282) of 73 patients with ALK rearrangements. Variable mutation levels were marked in all patients and correlated with clinical features. At progression, individual dynamics of resistance mutations were seen: while some mutations became undetectable upon therapy switch, variant fractions of other alterations further increased. We also found mutated TP53 at the time of progression in patients with initially TP53 wild-type tumors. The progression-free survival of patients with acquired TP53 mutations was comparable to that of primarily TP53 mutated and shorter than that of persistently TP53 wild-type cases. Shallow WGS of cfDNA identified copy number variations (CNVs), some of which might contribute to disease progression. To quantitatively assess CNVs, trimmed median absolute deviation from copy number neutrality (t-MAD) scores were calculated from sWGS data. Longitudinal t-MAD assessment reflected the kinetics of mutant allele frequencies in cfDNA and allowed disease monitoring with increasing t-MAD and mutation levels at tumor progression. Moreover, EML4-ALK fusion variant 3 (V3) and TP53 mutations define molecular determinants of adverse outcome in ALK+ NSCLC. Shallow WGS of cfDNA identified increased t-MAD levels in patients with EML4-ALK V3 compared to those with fusion V1. Similarly, patients with TP53 mutations showed a higher t-MAD than TP53 wild-type cases. In summary, overall survival of patients with detectable mutations in plasma DNA at any time point during clinical follow-up was shorter than that of patients without detectable mutations in cfDNA. Similarly, overall survival time from the first detection of mutations cfDNA until death/end of follow-up was shorter than in cases without detectable mutations. Our data suggest that liquid biopsies could help to improve the care of ALK+ NSCLC patients through early detection of disease progression and tailored treatment of resistant tumors. Although individual courses were seen, rising mutation levels could indicate the need of radiologic reassessment earlier than scheduled. Detection of CNVs as surrogate for genomic instability and acquired TP53 mutations in liquid identified high-risk cases and suggests the potential clinical utility of cfDNA monitoring for this disease beyond profiling of ALK resistance mutations. Citation Format: Steffen Dietz, Petros Christopoulos, Lisa Gu, Volker Endris, Zhao Yuan, Simon J. Ogrodnik, Tomasz Zemojtel, Marc A. Schneider, Anna-Lena Volckmar, Michael Meister, Thomas Muley, Martin Reck, Matthias Schlesner, Michael Thomas, Albrecht Stenzinger, Holger Sultmann. Longitudinal analysis of cell-free DNA for therapy monitoring of ALK-positive non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A21.

Abstract A21: Longitudinal analysis of cell-free DNA for therapy monitoring of ALK-positive non-small cell lung cancer

Discovery of a novel small-molecule inhibitor of Fam20C that induces apoptosis and inhibits migration in triple negative breast cancer.

Longitudinal therapy monitoring of ALK-positive lung cancer by combined copy number and targeted mutation profiling of cell-free DNA

Genetic rearrangements involving the anaplastic lymphoma kinase (ALK) gene confer sensitivity to ALK tyrosine kinase inhibitors (TKIs) and superior outcome in non-small-cell lung cancer (NSCLC). However, clinical courses vary widely, and recent studies suggest that molecular profiling of ALK+ NSCLC can provide additional predictors of therapy response that could assist further individualization of patient management. As repeated tissue biopsies often pose technical difficulties and significant procedural risk, analysis of tumor constituents circulating in the blood, including ctDNA and various proteins, is increasingly recognized as an alternative method of tumor sampling (“liquid biopsy”). Here, we report the case of a KLC1–ALK-rearranged NSCLC patient responding to crizotinib treatment and demonstrate how analysis of plasma and serum biomarkers can be used to identify the ALK fusion partner and monitor therapy over time. Results of ctDNA sequencing and copy-number alteration profiling as well as serum protein concentrations at various time points during therapy reflected the current remission status and could predict the subsequent clinical course. At the time of disease progression, we identified four distinct secondary mutations in the ALK gene in ctDNA potentially causing treatment failure, accompanied by rising levels of CEA and CYFRA 21–1. Moreover, several copy-number variations were detected at the end of the treatment, including an amplification of a region on Chromosome 12 encompassing the TP53 regulator MDM2. In summary, our findings illustrate the utility of noninvasive longitudinal molecular profiling for assessing remission status, exploring mechanisms of treatment failure, predicting subsequent clinical course, and dissecting dynamics of drug-resistant clones in ALK+ lung cancer.

Serial liquid biopsies for detection of treatment failure and profiling of resistance mechanisms in KLC1–ALK-rearranged lung cancer

Oligodeoxynucleotide (ASODN) was synthesized and added to breast cancer MDA-MB-231 cells to see its influence on cell proliferation. After the transfection of HGF ASODN on the MDA-MB-231 cells, immunocytochemical method, western blot and RT-PCR methods were used to test the HGF, VEGF and PCNA level. Cell proliferation was analyzed by MTT method. The results showed that after transfection, 2-8 uM HGF ASODN. It can inhibit expression of HGF and cell proliferation. The inhibition effect begun at 24 hours and lasted to 96 hours. The inhibition effect was related to the concentration. HGF ASODN could also inhibit protein level of VEGF and PCNA. Besides, HGF ASODN in different concentration could also inhibit tumor growth. HGF promoting autocrine and paracrine of IGF-I is important to breast tumor growth.

Inhibition of HGF-ASODN in Breast Cancer and its influence on cell proliferation

OBJECTIVE:To study the effects of TGF-β1 shRNA in proliferation and adhesion of human salivary gland mucoepidermoid carcinoma cell Ms in vitro.METHODS:Ms cells,Ms cells transfected with empty vectors and Ms cells transfected with TGF-β1 shRNA were cultured in vitro.Cell count assay,clone formation assay were performed to measure the proliferation of Ms cells.Adhesive abilities were assessed by cell-to-cell adhesion and cell-to-FN adhesion.Coomassie brilliant blue staining assay was used to detect the changes in cytoskeleton and immunoflurescence was used to evaluate the expression of Ezrin protein on Ms cells.RESULTS:The population doubling times of TGF-β1 shRNA-transfected cells,empty vector-transfected cells and the control cells were 30.8,28.8 and 29.0,respectively.The rates of clone formation were 14.2%,24.5% and 25.1%,respectively.TGF-β1 shRNA transfection increased the cell-to-cell adhesion by 18.6% in a 30-min adhesion assay,but inhibited the cell-to-FN adhesion by 35.3% in a 1-h adhesion assay.Compared with control and Ms transfected with empty vectors,Ms cells stably transfected with TGF-β1 shRNA grew slowly.The ability of homogeneous adhesion was increased and that of heterogeneous adhesion was inhibited.TGF-β1 shRNA changed the cytoskeleton and down-regulated the expression of Ezrin protein.CONCLUSION:TGF-β1 shRNA could affect the proliferation and adhesion,which may be associated with the changes of cytoskeleton and Ezrin protein expression.

Effects of TGF-β1 shRNA in proliferation and adhesion of human salivary gland mucoepidermoid carcinoma cell Ms in vitro

Objective\ To evaluate the efficacy and toxicity of combination use of paclitaxel (TAX) with cis platin (CDDP) , leucovorin (LV) and fluorouracil (Fu) for advanced gastric cancer. \ Methods\ Fifty two patients with advanced gastric cancer were treated. The treatment schedule was composed of TAX 175 mg/m 2, iv drip, day 1 and day 8; CDDP 40 mg/m 2, iv drip, day 2-4; LV 200 mg/m 2, iv drip, day 2-4; Fu 250 mg/m 2, iv, day 2, and 1 500 mg/m 2 infusion for 72 h. A treatment cycle lasted 21 days. The efficacy was evaluated after two cycles of the chemotherapy.\ Results\ Complete response in three cases and partial response in 24 cases were recorded, with the overall response rate being 51.9%. The main reactions of toxicity were neutropenia and nausea as well as vomiting.\ Conclusion\ The combination chemotherapy is a high response regimen for advanced gastric cancer with mild toxicity.

EFFICACY OF COMBINATION THERAPY OF PACLITAXEL WITH CIS-PLATIN, LEUCOVORIN AND FLUOROURACIL FOR ADVANCED GASTRIC CANCER

Epitaxial‐like Hydrothermal Growth of Planar Hematite Films for Water Splitting by Waste Remediation

Preparation of High-Coverage Fluorinated Decyltrichlorosilane Self-Assembled Monolayers

1Department of Mechanical and Electronic Engineering, Shandong University of Science and Technology, 223 Daizong Street, Tai’an, Shandong Province 271019, P.R. China 2State Key Laboratory of Fluid Power and Mechatronic System, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang Province 310058, P.R. China 3State Key Laboratory of Mining Disaster Prevention and Control Co-founded by Shandong Province and the Ministry of Science and Technology, Shandong University of Science and Technology, 579 Qianwangang Road, Qingdao, Shandong Province 266590, P.R. China 4Beijing Aviation TaiLong Technoloy Co., Ltd., 54 Songzhuang Town Economic Development Zone, Beijing 101149, P.R. China

Sleeve-type Torque Sensor Based on Effect of Strain Induction Applied to Wide-blade Drill Rod

Purpose
This paper aims to propose a conceptual scale model of mobile drilling robot according to the actual drilling rig and working conditions to improve the safety and automation of drilling in tunnel construction and coal mining applications.

A couple of pinion and rack serves as the support mechanism driven by a motor with low rotation speed at high power, and these components are assembled in the center of the robot to tightly fasten the whole body together. The drilling rod and the sleeve are connected through a hole with screw thread so that the rod feeds and rotates simultaneously along with the sleeve. The robot model is automatically controlled by a single-chip microcomputer, and the anti-disturbance circuit is designed as well. A five-step rule obstacle avoidance method is proposed to ensure safe and reliable movement.

Findings
The results of simulation experiments on drilling operation do indicate that the mechanism and control method are feasible and effective.

Research limitations/implications
The robot is nearly complete but indeed remains only an experimental machine.

The design of the mechanism structure for the conceptual robot is novelty. The method of five-step rule obstacle avoidance can improve reliability of obstacle avoidance according to the experimental results, which can meet the requirements of complex working conditions underground coal mine.

This paper presents a self-centering bridge which is simplified as a deformation body ,while mechanical performance is still in the elastic range ,considering the influence of gravity pier ,the upper structure load ,prestressed tendons and dampers, the horizontal load vs. rotation curve of the self-centering bridge is obtained by theoretical derivation . The study for the self-centering bridge presented in this paper indicates that: under the cyclic loading hysteretic curve type is flag-shaped ,the prestressed tendons provide self-centering ability and dampers provide dissipating energy.

Study on the Mechanical Behavior of Self-Centering Bridge under Horizontal Loading

 Ulcerative colitis (UC) pathogenesis involves genetic susceptibility, immune-mediated tissue injury, and gut microbiota disturbances. Most approved therapies modify host immunity, rather than directly targeting the microbiota. Faecal microbiota transplantation provides encouraging evidence for the therapeutic potential of gut microbiome modulation. Gastrointestinal tract bacteria are ecologically differentiated by their ability to use specific glycans as growth substrates, making glycans a promising and safe alternative to target the microbiome. To explore this, we used an ex vivo faecal microbiota culture system to identify a synthetic glycan (KB295) with desirable microbiological activity and conducted a proof of principle study (NCT04508413) of safety and tolerability of KB295 in patients with UC.
 
 In ex vivo studies, faecal microbial communities from healthy subjects were incubated anaerobically (negative control) ± KB295. Taxa counts from shotgun metagenomic sequencing data were used to evaluate microbial response to KB295. Short-chain fatty acid (SCFA) levels were also assessed. KB295 was evaluated in an open-label single-arm study in adult patients with mild to moderate UC. KB295 was ingested over an 8-wk period. Objectives included KB295 safety (primary) and effect on gut microbiota composition and faecal biomarkers.
 
 In ex vivo studies, KB295 increased SCFA levels across 10 faecal samples to a median of 47.0 vs 15.2 mM with negative control, including increases in acetate, propionate, and butyrate levels. Metagenomic sequencing showed pathobiont depletion in the family Enterobacteriaceae with KB295 to a median relative abundance of 10.8% vs 38.2% with negative control. Pathobiont depletion was associated with enrichments of diverse genera in the phyla Bacteroidetes and Firmicutes. In patients with UC (n=12), KB295 was well tolerated with generally mild adverse events (AEs). The most frequently occurring AEs were bowel habit changes, flatulence, and headache. Median faecal calprotectin and lactoferrin levels decreased by 69.0% (n=11) and 86.0% (n=6), respectively, from screening to end of the KB295 intake. Consistent with our ex vivo results, of the patients for whom we have data to date, the relative abundance of the faecal pathobiont family Enterobacteriaceae decreased in 5 of 5 participants, and the commensal genus Parabacteroides was enriched in 4 of 5 participants.
 
 Our results establish a proof of principle for the glycan modulation of gut microbiome composition and function and provide insight into the potential utility of this strategy in patients with UC. The safety and tolerability of KB295, along with evidence of reduced inflammation, support a phase 2 study, which is planned.

P493 The synthetic glycan KB295 optimises microbiome composition and function in ulcerative colitis: Results from a proof of principle human study

Background Canine hemangiosarcoma (cHSA) is a highly metastatic mesenchymal cancer that disseminates by hematogenous and direct implantation routes. Therapies for cHSA are generally ineffective, in part due to advanced clinical disease stage at the time of diagnosis. The validation of conventional molecular methods for detecting novel biomarkers preferentially expressed by cHSA could lead to more timely diagnosis, earlier therapeutic interventions, and improved outcomes. In humans, prostate-specific membrane antigen (PSMA) is a transmembrane protein overexpressed by prostate carcinoma and tumor-associated endothelium of various solid cancer histologies. Importantly, the preferential overexpression of PSMA by certain cancers has been leveraged for the development of diagnostic molecular imaging reagents and targeted therapeutics. Recently, PSMA has been qualitatively demonstrated to be expressed in cHSA cell lines, however, quantitative PSMA expressions and the potential utility of PSMA transcript identification in biologic fluids to support the presence of microscopic cHSA burden has not been reported. Therefore, this study sought to characterize the differential quantitative expressions of PSMA between cHSA and non-malignant tissues, and to determine the potential diagnostic utility of PCR-generated PSMA amplicons as a surrogate of rare cHSA cells dwelling within peritoneal and pericardial cavities. Methods Quantitative gene and protein expressions for PSMA were compared between one normal endothelial and six cHSA cell lines by RT-PCR, western blot analysis, and fluorescent microscopy. Additionally, gene and protein expressions of PSMA in normal canine tissues were characterized. Graded expressions of PSMA were determined in spontaneously-arising cHSA tumor samples and the feasibility of qualitative PCR as a molecular diagnostic to detect PSMA transcripts in whole blood from healthy dogs and hemorrhagic effusions from cHSA-bearing dogs were evaluated. Results PSMA gene and protein expressions were elevated (up to 6-fold) in cHSA cells compared with non-malignant endothelium. By immunohistochemistry, protein expressions of PSMA were detectable in all cHSA tissue samples evaluated. As predicted by human protein atlas data, PSMA’s expression was comparably identified at substantial levels in select normal canine tissues including kidney, liver, and intestine. In young healthy pet dogs, PSMA amplicons could not be identified in circulating whole blood yet were detectable in hemorrhagic effusions collected from pet dogs with confirmed cHSA or PSMA-expressing cancer. Conclusions PSMA is quantitatively overexpressed in cHSA compared to normal endothelium, but its protein expression is not restricted to only cHSA tumor tissues, as specific visceral organs also substantively express PSMA. Optimized qualitative PCR methods failed to amplify PSMA amplicons sufficiently for visible detection in circulating whole blood derived from healthy young dogs, yet PSMA transcripts were readily identifiable in hemorrhagic effusions collected from pet dogs with histologically confirmed cHSA or PSMA-expressing cancer. While preliminary, findings derived from a limited cohort of normal and diseased pet dogs provocatively raise the potential value of PSMA amplicon detection as an ancillary molecular diagnostic test for supporting the presence of microscopic cHSA disease burden within hemorrhagic body cavity effusions.

Overexpression of prostate specific membrane antigen by canine hemangiosarcoma cells provides opportunity for the molecular detection of disease burdens within hemorrhagic body cavity effusions

Understanding the role of interleukin-8 (IL-8) in canine osteosarcoma metastasis

イミダゾピリジンジアシルグリセロールアシルトランスフェラーゼ2(DGAT2)阻害剤のわずかな構造変化は改良された安全性プロファイルを産生する【Powered by NICT】

Chitosan-based lifefoam improves survival in lethal noncompressible abdominal bleeding in swine.

Bleeding from injuries to the torso region is a leading cause of fatalities in the military and in young adults. Such bleeding cannot be stopped by applying direct pressure (compression) of a bandage. An alternative is to introduce a foam at the injury site, with the expansion of the foam counteracting the bleeding. Foams with an active hemostatic agent have been tested for this purpose, but the barrier created by these foams is generally not strong enough to resist blood flow. In this paper, we introduce a new class of foams with enhanced rheological properties that enable them to form a more effective barrier to blood loss. These aqueous foams are delivered out of a double-barrelled syringe by combining precursors that produce bubbles of gas (CO2) in situ. In addition, one barrel contains a cationic polymer (hydrophobically modified chitosan, hmC) and the other an anionic polymer (hydrophobically modified alginate, hmA). Both these polymers function as hemostatic agents due to their ability to connect blood cells into networks. The amphiphilic nature of these polymers also enables them to stabilize gas bubbles without the need for additional surfactants. hmC-hmA foams have a mousse-like texture and exhibit a high modulus and yield stress. Their properties are attributed to the binding of hmC and hmA chains (via electrostatic and hydrophobic interactions) to form a coacervate around the gas bubbles. Rheological studies are used to contrast the improved rheology of hmC-hmA foams (where a coacervate arises) with those formed by hmC alone (where there is no such coacervate). Studies with animal wound models also confirm that the hmC-hmA foams are more effective at curtailing bleeding than the hmC foams due to their greater mechanical integrity.

Amphiphilic biopolymers such as hydrophobically modified chitosan (hmC) have been shown to convert liquid blood into elastic gels. This interesting property could make hmC useful as a hemostatic agent in treating severe bleeding. The mechanism for blood gelling by hmC is believed to involve polymer-cell self-assembly, i.e., insertion of hydrophobic side chains from the polymer into the lipid bilayers of blood cells, thereby creating a network of cells bridged by hmC. Here, we probe the above mechanism by studying dilute mixtures of blood cells and hmC in situ using optical microscopy. Our results show that the presence of hydrophobic side chains on hmC induces significant clustering of blood cells. The extent of clustering is quantified from the images in terms of the area occupied by the 10 largest clusters. Clustering increases as the fraction of hydrophobic side chains increases; conversely, clustering is negligible in the case of the parent chitosan that lacks hydrophobes. Moreover, the longer the hydrophobic side chains, the greater the clustering (i.e., C12 > C10 > C8 > C6). Clustering is negligible at low hmC concentrations but becomes substantial above a certain threshold. Finally, clustering due to hmC can be reversed by adding the supramolecule α-cyclodextrin, which is known to capture hydrophobes in its binding pocket. Overall, the results from this work are broadly consistent with the earlier mechanism, albeit with a few modifications.

How Do Amphiphilic Biopolymers Gel Blood? An Investigation Using Optical Microscopy.

Expanding Hydrophobically Modified Chitosan Foam for Internal Surgical Hemostasis: Safety Evaluation in a Murine Model.

Hydrophobically modified chitosan gauze: a novel topical hemostat.

Determination of efficacy of a novel alginate dressing in a lethal arterial injury model in swine.

Hemorrhage (severe blood loss) from traumatic injury is a leading cause of death for soldiers in combat and for young civilians. In some cases, hemorrhage can be stopped by applying compression of a tourniquet or bandage at the injury site. However, the majority of hemorrhages that prove fatal are "non-compressible", such as those due to an internal injury in the truncal region. Currently, there is no effective way to treat such injuries. In this initial study, we demonstrate that a sprayable polymer-based foam can be effective at treating bleeding from soft tissue without the need for compression. When the foam is sprayed into an open cavity created by injury, it expands and forms a self-supporting barrier that counteracts the expulsion of blood from the cavity. The active material in this foam is the amphiphilic biopolymer, hydrophobically modified chitosan (hmC), which physically connects blood cells into clusters via hydrophobic interactions (the hemostatic mechanism of hmC is thus distinct from the natural clotting cascade, and it works even with heparinized or citrated blood). The amphiphilic nature of hmC also allows it to serve as a stabilizer for the bubbles in the foam. We tested the hmC-based hemostatic foam for its ability to arrest bleeding from an injury to the liver in pigs. Hemostasis was achieved within minutes after application of the hmC foams (without the need for external compression). The total blood loss was 90% lower with the hmC foam relative to controls.

Sprayable Foams Based on an Amphiphilic Biopolymer for Control of Hemorrhage Without Compression.

Hydrophobically-modified chitosan foam: description and hemostatic efficacy.

Polymer hydrogels have long been used to hold and culture biological cells within their three-dimensional (3-D) matrices. Typically, in such cases, the cells are passively entrapped in a mesh of polymer chains. Here, we demonstrate an alternate approach where cells serve as active structural elements (crosslinks) within a polymer gel network. The polymers used in this context are hydrophobically modified (hm) derivatives of common biopolymers such as chitosan and alginate. We show that hm-polymers rapidly transform a liquid suspension of cells into an elastic gel. In contrast, the native biopolymers (without hydrophobes) do not cause such gelation. Gelation occurs because the hydrophobes on the polymer get embedded within the hydrophobic interiors of cell bilayer membranes. The polymer chains thus connect the cells into a 3-D sample-spanning network, with the cells serving as the junctions in the network. We demonstrate that a variety of cell types, including blood cells, endothelial cells, and breast cancer cells can be gelled by this approach. Cells gelled by hm-alginate are shown to remain viable within the network. Also, since the crosslinking mechanism is based on hydrophobic interactions, we show that the addition of supramolecules with hydrophobic binding pockets can reverse the gelation and release the cells. Cell-gels can be employed as injectable biomaterials since the connections in the network are susceptible to shear, but recover rapidly once shear is stopped. The overall approach provides a simple route towards the directed assembly of cell clusters and potentially to living tissue.

Reversible gelation of cells using self-assembling hydrophobically-modified biopolymers: towards self-assembly of tissue.

We demonstrate that “nanofactory”‐loaded biopolymer capsules placed in the midst of a bacterial population can direct bacterial communication. Quorum sensing (QS) is a process by which bacteria communicate through small‐molecules, such as autoinducer‐2 (AI‐2), leading to collective behaviors such as virulence and biofilm formation. In our approach, a “nanofactory” construct is created, which comprises an antibody complexed with a fusion protein that produces AI‐2. These nanofactories are entrapped within capsules formed by electrostatic complexation of cationic (chitosan) and anionic (sodium alginate) biopolymers. The chitosan capsule shell is crosslinked by tripolyphosphate (TPP) to confer structural integrity. The capsule shell is impermeable to the encapsulated nanofactories, but freely permeable to small molecules. In turn, the capsules are able to take in substrates from the external medium via diffusion, and convert these via the nanofactories into AI‐2, which then diffuses out. The exported AI‐2 is shown to stimulate QS responses in vicinal Escherichia coli. Directing bacterial population behavior has potential applications in next‐generation antimicrobial therapy and pathogen detection. We also envision such capsules to be akin to artificial “cells” that can participate in native biological signaling and communicate in real‐time with the human microbiome. Through such interaction capabilities, these “cells” may sense the health of the microbiome, and direct its function in a desired, host‐friendly manner. Biotechnol. Bioeng. 2013; 110: 552–562. © 2012 Wiley Periodicals, Inc.

Encapsulated fusion protein confers “sense and respond” activity to chitosan–alginate capsules to manipulate bacterial quorum sensing

We describe a new class of hierarchical containers that are formed via single-step assembly and, at a later time, self-destruct because of their packaged contents. These containers are spherical capsules formed by electrostatic complexation of the anionic biopolymer, gellan gum, with the cationic biopolymer, chitosan. The capsules are termed "motherships" and are engineered to carry a cargo of much smaller containers (e.g., nanoscale liposomes ("babyships")), within their lumen. Additionally, we package an enzyme, chitosanase, in the capsule that is capable of degrading polymeric chitosan into short oligomers. Thereby, we create motherships that self-destruct, liberating their cargo of babyships into the external solution. The time scale for self-destruction can be engineered based on the internal concentration of enzyme. The motherships are stable when stored in a freeze-dried form and can be readily dispersed into water or buffer solutions at a later time, whereupon their "internal clock" for self-destruction is initiated. The above concept could be useful for the triggered release of a variety of payloads including drugs, biological therapeutics, cosmetics, and flavor ingredients.

Self-destructing "mothership" capsules for timed release of encapsulated contents.

BACKGROUND: Chitosan is a functional biopolymer that has been widely used as a hemostat. Recently, its efficacy has been questioned due to clinical failures as a result of poor adhesiveness. The purpose of this study was to compare, in a severe groin injury model in swine, the hemostatic properties of an unmodified standard chitosan sponge with standard gauze dressing and a novel hydrophobically modified (hm) chitosan sponge. Previous studies have demonstrated that hm-chitosan provides greatly enhanced cellular adhesion and hemostatic effect via noncovalent insertion of hydrophobic pendant groups into cell membranes. METHODS: Twenty-four Yorkshire swine were randomized to receive hm-chitosan (n = 8), unmodified chitosan (n = 8), or standard Accu-Sorb gauze dressing (n = 8) for hemostatic control. A complex groin injury involving arterial puncture (4.4-mm punch) of the femoral artery was made after splenectomy. After 30 seconds of uncontrolled hemorrhage, the randomized dressing was applied and compression was held for 3 minutes. Fluid resuscitation was initiated to achieve and maintain the baseline mean arterial pressure and the wound was inspected for bleeding. Failure of hemostasis was defined as pooling of blood outside the wound. Animals were then monitored for 180 minutes and surviving animals were killed. RESULTS: Blood loss before treatment was similar between groups (p < 0.1). Compared with the hm-chitosan sponge group, which had no failures, the unmodified chitosan sponge group and the standard gauze group each had eight failures over the 180-minute observation period. For the unmodified chitosan sponge failures, six of which provided initial hemostasis, secondary rebleeding was observed 44 minutes ± 28 minutes after application. Standard gauze provided no initial hemostasis after the 3-minute compression interval. CONCLUSIONS: Hm-chitosan is superior to unmodified chitosan sponges (p < 0.001) or standard gauze for controlling bleeding from a lethal arterial injury. The hm-chitosan technology may provide an advantage over native chitosan-based dressings for control of active hemorrhage.

Determination of efficacy of novel modified chitosan sponge dressing in a lethal arterial injury model in swine

A self-assembling hydrophobically modified chitosan capable of reversible hemostatic action.

The gelation of hydrophobically modified chitosan solutions can be accomplished through the incorporation of uniform carbon microspheres. The carbon particles act as nodes in the gel network where hydrophobic alkyl groups, attached to the polysaccharide backbone, interact with multiple carbon microspheres to form a three-dimensional matrix. Rheological characterizations show significant increases in elastic moduli upon incorporation of the carbon microspheres.

Carbon microspheres as network nodes in a novel biocompatible gel

We describe a simple way to create patterns of “soft” biomolecular nanostructures such as vesicles on “hard” surfaces such as gold. The key to our approach is the use of an amphiphilic biopolymer as an “interconnect” or tether. The polymer is hydrophobically modified chitosan (hm-chitosan), which is obtained by covalently attaching alkyl tails to the backbone of chitosan. We electrodeposit films of hm-chitosan onto microscale gold cathodes formed by lithography on a silicon wafer. Subsequently, the hm-chitosan films are used to spontaneously capture vesicles from solution; this is demonstrated both for surfactant as well as lipid vesicles (liposomes). Vesicles remain strongly bound to the hm-chitosan to a much greater extent than to native chitosan. This suggests that the mechanism for vesicle capture involves non-covalent binding of hydrophobes from hm-chitosan chains to the hydrophobic portions of vesicle bilayers. Importantly, the vesicles captured by hm-chitosan films are intact—this is shown both by direct visualization of captured vesicles (via optical and cryo-transmission electron microscopy) as well as through the capture and subsequent disruption of dye-filled vesicles. Various microscale patterns of immobilized vesicles are created and the vesicles are demonstrated to be capable of sensing a reporter molecule from the external solution.

Vesicle capture on patterned surfaces coated with amphiphilic biopolymers

We demonstrate that multiphoton-absorption-induced luminescence (MAIL) is an effective means of monitoring the uptake of targeted nanoparticles into cells. Gold nanoparticles (AuNPs) with diameters of 4.5 and 16 nm were surface-functionalized with monocyclic RGDfK, an RGD peptide analogue that specifically targets the α(v)β₃ integrin, a membrane protein that is highly overexpressed in activated endothelial cells during tumor angiogenesis. To determine whether cyclic RGD can enhance the uptake of the functionalized AuNPs into activated endothelium, human umbilical vein endothelial cells (HUVECs) were used as a model system. MAIL imaging of HUVECs incubated with AuNPs demonstrates differential uptake of AuNPs functionalized with RGD analogues: RGDfK-modified nanoparticles are taken up by the HUVECs preferentially compared to AuNPs modified with linear RGD (GRGDSP) conjugates or with no surface conjugates. The luminescence counts observed for the AuNP-RGDfK conjugates are an order of magnitude greater than for AuNP-GRGDSP conjugates. Transmission electron microscopy shows that, once internalized, the AuNP-RGDfK conjugates remain primarily within endosomal and lysosomal vesicles in the cytoplasm of the cells. Significant aggregation of these particles was observed within the cells. MAIL imaging studies in the presence of specific uptake inhibitors indicate that AuNP-RGDfK conjugate uptake involves a specific binding event, with α(v)β₃ integrin-mediated endocytosis being an important uptake mechanism.

Multiphoton-absorption-induced-luminescence (MAIL) imaging of tumor-targeted gold nanoparticles.

Blueprinting Self-Assembled Soft Matter: An `Easy' Approach to Advanced Material Synthesis in Drug Delivery and Wound Healing

We describe a new way to impart pH-responsive properties to gels of biopolymers such as gelatin. This approach involves the embedding of pH-sensitive nanosized vesicles within the gel. The vesicles employed here are those of sodium oleate (NaOA), a fatty-acid-based amphiphile with a single C18 tail. In aqueous solution, NaOA undergoes a transition from vesicles at a pH approximately 8 to micelles at a pH higher than approximately 10. Here, we combine NaOA and gelatin at pH 8.3 to create a vesicle-loaded gel and then bring the gel in contact with a pH 10 buffer solution. As the buffer diffuses into the gel, the vesicles within the gel get transformed into micelles. Accordingly, a vesicle-micelle front moves through the gel, and this can be visually identified by the difference in turbidity between the two regions. Vesicle disruption can also be done in a spatially selective manner to create micelle-rich domains within a vesicle-loaded gel. A possible application of the above approach is in the area of pH-dependent controlled release. A vesicle-to-micelle transition releases hydrophilic solutes encapsulated within the vesicles into the bulk gel, and in turn these solutes can rapidly diffuse out of the gel into the external bath. Experiments with calcein dye confirm this concept and show that we can indeed use the pH in the bath to tune the release rate of solutes from vesicle-loaded gels.

pH-responsive jello: gelatin gels containing fatty acid vesicles.

Muon decay provides one of the pillars of the Standard Model, the Fermi constant GF [1]. Its determination relies on precise measurements of the muon lifetime [2, 3] and mass [4], and on theoretical evaluation of radiative corrections. These corrections arise primarily from quantum electrodynamic (QED) interactions involving the muon and the daughter electron, and are expressed as a power series in the fine structure constant α ≃ 1/137. Very recently, a new term in this series has been calculated [5] using an expansion in the difference of the muon and electron masses. Here we confirm the most demanding parts of the expansion published in [5]. We also explain a pattern governing the first two terms of the expansion. Determination of the coefficients of increasing powers of α requires monumental efforts. A new result appears very rarely, approximately once every one or two generations of theorists. Each new result is witness to a new technology available in perturbative quantum field theory. First order corrections, calculated in 1955 [6], were in fact the first loop effects calculated for a decay process. They served as a model for subsequent studies of quantum chromodynamics (QCD) processes in heavy quark decays [7, 8]. It took more than 40 years before the second-order coefficient became known [9, 10]. That progress was made possible by the technique of recurrence relations based on integration-by-parts [11, 12] and on symbolic manipulations with computers [13]. Now, another two decades later, the coefficient of α has been determined [5]. Several theoretical developments underly this advancement. Laporta algorithm [14] allows to express multi-loop integrals in terms of a relatively small number of master integrals. This algorithm can be implemented in powerful symbolic algebra software capable of parallelization [15, 16]. Finally, despite the electron being about 207 times lighter that the muon, the calculation is done as an expansion around the situation where the electron and the muon masses, me and mμ, are equal [17–19]. Historically, radiative corrections to the muon decay were calculated before corrections to heavy quark decays, because QCD was developed only later. Computational technology is the same in both QED and perturbative QCD, and once the QED corrections are known, it is relatively easy to evaluate additional diagrams involving multi-gluon vertices. Ref. [5] presents corrections both for the muon and for the b-quark decays. Wherever our discussion below is relevant for both types of processes, we refer to the decaying particle’s mass as M , and denote the mass of the produced charged particle by m. We use δ = 1 −m/M to denote the expansion parameter: the relative difference of masses. In Section II we present our calculation of five terms of the expansion in δ for a subset of corrections, including the most demanding part with all quanta (photons or gluons) coupling to fermions. In Section III we demonstrate how the first two terms in the expansion in δ can be found from a form factor, first determined in 2004 in Ref. [17]. Section IV contains our conclusions.

We compute corrections to the gyromagnetic factor of an electron bound in a hydrogenlike ion at order α^{2}(Zα)^{5}. This result removes a major uncertainty in predictions for silicon and carbon ions, used to determine the atomic mass of the electron.

Two-Loop Binding Corrections to the Electron Gyromagnetic Factor.

QCD corrections to vector boson pair production in gluon fusion including interference effects with off-shell Higgs at the LHC

Production of two Z-bosons in gluon fusion in the heavy top quark approximation

The spectrum of electrons from muons decaying in an atomic bound state is significantly modified by their interaction with the nucleus. Somewhat unexpectedly, its first measurement, at the Canadian laboratory TRIUMF, differed from basic theory. We show, using a combination of techniques developed in atomic, nuclear, and high-energy physics, that radiative corrections eliminate the discrepancy. In addition to solving that outstanding problem, our more precise predictions are potentially useful for interpreting future high-statistics muon experiments that aim to search for exotic interactions at 10−16 sensitivity.

Differential distributions for top-quark hadro-production with a running mass

This report summarizes the proceedings of the 2014 Mainz Institute for Theoretical Physics (MITP) scientific program on High precision fundamental constants at the TeV scale. The two outstanding parameters in the Standard Model dealt with during the MITP scientific program are the strong coupling constant s and the top-quark mass mt. Lacking knowledge on the value of those fundamental constants is often the limiting factor in the accuracy of theoretical predictions. The current status on s andmt has been reviewed and directions for future research have been identified.

Between the Tevatron and LHC, top-quark physics is now becoming an area for precision physics. This has lead to an increase in theoretical activity to match the experimental accuracy of top anti-top production. We discuss the difficulty in properly defining the top-quark mass as measured by experiments and present results for differential distributions of top-quark pair production in a running mass scheme. The use of such a scheme shows better convergence in the perturbative expansion and improves the scale dependence as opposed to the typical on-shell scheme.

In models where lepton number is considered to be a spontaneously broken global symmetry a massless Goldstone boson, the Majoron ($J$), appears. We describe a procedure to explore the muon-electron-Majoron coupling using the results from $\ensuremath{\mu}\ensuremath{-}e$ conversion search experiments. To accomplish that, we determine how the energy spectrum of the muon decay into an electron and a Majoron is modified by binding effects in a muonic atom. We find that the future $\ensuremath{\mu}\ensuremath{\rightarrow}e$ conversion experiments may be able to produce bounds on the $\ensuremath{\mu}\ensuremath{\rightarrow}eJ$ rate which are comparable with the present ones from direct searches.

Bounds on Majoron emission from muon to electron conversion experiments

We present a new calculation of the order alpha^2 (Z alpha)^5 correction to the Lamb shift, which uses methods developed for multi-loop calculations.

Radiative-nonrecoil corrections of order α2(Zα)5 to the Lamb shift

We present results for the corrections of order alpha^2 (Z alpha)^5 to the Lamb shift. We compute all the contributing Feynman diagrams in dimensional regularization and a general covariant gauge using a mixture of analytical and numerical methods. We confirm results obtained by other groups and improve their precision. Values of the 32 master integrals for this and similar problems are provided.

Radiative-nonrecoil corrections of order alpha^2 (Z alpha)^5 to the Lamb shift

We have calculated the rate of the decay b -> clv to second order in alpha_s in the limit that the b and c quarks have equal masses. The results here confirm recent calculations done in the opposite limit where the c-quark is much lighter than the b-quark.

The rate of the semileptonic decay b{yields}cl{nu} is calculated with O({alpha}{sub s}{sup 2}) accuracy, as an expansion around the limit of equal masses of the b and c quarks. Recent results obtained around the limit of the c-quark much lighter than b are confirmed. Details of the new expansion method are described.

We compute the O({alpha}{sub s}{sup 2}) corrections to the differential rate of the semileptonic decay b{yields}cl{nu}{sub l} at the 'intermediate recoil' point, where the c-quark mass and the invariant mass of the leptons are equal. The calculation is based on an expansion around two opposite limits of the quark masses m{sub b,c}: m{sub c}{approx_equal}m{sub b} and m{sub c}<<m{sub b}. The former case was previously studied; we correct and extend that result. The latter case is new. The smooth matching of both expansions provides a check of both. We clarify the discrepancy between the recent determinations of the full NNLO QCD correction to the semileptonic b{yields}c rate, and its earlier estimate.

The decay width of b → ccclνl has been computed as an expansion in limit (1 − 3 m c mb ) ≪ 1 with zero lepton invariant mass. Considering O(α 2) corrections to b → clνl with zero invariant lepton mass, inclusion of our result is shown to rectify the disagreement between the expansions around (1 − m c mb ) ≪ 1 and mc mb ≪ 1 at smaller values.

Massive c-quark contributions to semileptonic b-quark decay near threshold

A logistics issue for guided air-drop systems is maintaining batteries inside the airborne guidance unit so that when the system is deployed the batteries are adequately charged to power onboard electronics and actuators. It is typical for a guided air-drop system to be packed and readied for use well before deployment, leading to nonnegligible battery self-discharge. This necessitates a process to both monitor battery life and recharge the systems after a certain time interval. This paper explores, using a small-scale wind turbine system, providing the requisite power for onboard electronics and actuation for a guided air-drop system. Sizing studies are reported to estimate the necessary size of the rotor and generator. Using this information, a full-scale airborne guidance unit was designed, fabricated, and tested in a wind tunnel. Results indicate that a 0.33 m diam turbine system can generate over 3.7 W of continuous power, which is sufficient to provide power to low-power consumption guided air-drop ...

Feasibility Study of Embedded Wind Energy Harvesting System for Parafoil-Payload Aircraft

This paper provides details on the repair of a High Pressure Turbine Casing of a General Electric Model D2 design, which was originally placed in operation in 1954. It discusses the unique requirements of the repair welding, the post-weld heat treatment and the effect of original manufacturing defects on the cracking of the casing.

Repair welding of a high pressure turbine casing subject to thermal fatigue cracking and original manufacturing defects

This paper describes the development of a severe diesel engine test and its use as a tool for the evaluation of high performance lubricants. The test has been designed to screen oils prior to submission for expensive multi-cylinder evaluation and uses a tight top land piston. The paper continues earlier work reported during 1985 and describes the influence of liner finish and other hardware effects on test repeatability. The resulting ABINGDON 1-J engine test has been used in the development of diesel oils superior in performance to CCMC D2. Traditionally, European Super High Performance diesel oils have been of 15W40 viscosity grade, but engine manufacturers are showing increasing interest in lower viscosities. The ABINGDON 1-J test has been used to evaluate both 5W30 and 10W40 oils of Super High Performance diesel quality. Performance of both mineral and synthetic basestocks are considered.

A Severe Single Cylinder Diesel Engine Test for European SHPD Oils

We recently disclosed SAR studies on systemically acting, amide-based inhibitors of diacylglycerol acyltransferase 2 (DGAT2) that addressed metabolic liabilities with the liver-targeted DGAT2 inhibitor PF-06427878. Despite strategic placement of a nitrogen atom in the dialkoxyaromatic ring in PF-06427878 to evade oxidative O-dearylation, metabolic intrinsic clearance remained high due to extensive piperidine ring oxidation as exemplified with compound 1. Piperidine ring modifications through alternate N-linked heterocyclic ring/spacer combination led to azetidine 2 that demonstrated lower intrinsic clearance. However, 2 underwent a facile cytochrome P450 (CYP)-mediated α-carbon oxidation followed by azetidine ring scission, resulting in the formation of ketone (M2) and aldehyde (M6) as stable metabolites in NADPH-supplemented human liver microsomes. Inclusion of GSH or semicarbazide in microsomal incubations led to the formation of Cys-Gly-thiazolidine (M3), Cys-thiazolidine (M5), and semicarbazone (M7) conjugates, which were derived from reaction of the nucleophilic trapping agents with aldehyde M6. Metabolites M2 and M5 were biosynthesized from NADPH- and l-cysteine-fortified human liver microsomal incubations with 2, and proposed metabolite structures were verified using one- and two-dimensional NMR spectroscopy. Replacement of the azetidine substituent with a pyridine ring furnished 8, which mitigated the formation of the electrophilic aldehyde metabolite, and was a more potent DGAT2 inhibitor than 2. Further structural refinements in 8, specifically introducing amide bond substituents with greater metabolic stability, led to the discovery of PF-06865571 (ervogastat) that is currently in phase 2 clinical trials for the treatment of nonalcoholic steatohepatitis.

Mitigating a Bioactivation Liability with an Azetidine-Based Inhibitor of Diacylglycerol Acyltransferase 2 (DGAT2) En Route to the Discovery of the Clinical Candidate Ervogastat.

G protein-coupled receptors (GPCRs) modulate diverse cellular signaling pathways and are important drug targets. Despite the availability of high-resolution structures, the discovery of allosteric modulators remains challenging due to the dynamic nature of GPCRs in native membranes. We developed a strategy to covalently tether drug fragments adjacent to allosteric sites in GPCRs to enhance their potency and enable fragment-based drug screening in cell-based systems. We employed genetic code expansion to site-specifically introduce noncanonical amino acids with reactive groups in C–C chemokine receptor 5 (CCR5) near an allosteric binding site for the drug maraviroc. We then used molecular dynamics simulations to design heterobifunctional maraviroc analogues consisting of a drug fragment connected by a flexible linker to a reactive moiety capable of undergoing a bioorthogonal coupling reaction. We synthesized a library of these analogues and employed the bioorthogonal inverse electron demand Diels–Alder reaction to couple the analogues to the engineered CCR5 in live cells, which were then assayed using cell-based signaling assays. Tetherable low-affinity maraviroc fragments displayed an increase in potency for CCR5 engineered with reactive unnatural amino acids that were adjacent to the maraviroc binding site. The strategy we describe to tether novel drug fragments to GPCRs should prove useful to probe allosteric or cryptic binding site functionality in fragment-based GPCR-targeted drug discovery.

Bioorthogonal Tethering Enhances Drug Fragment Affinity for G Protein-Coupled Receptors in Live Cells

The CTLH complex is a multi-subunit ubiquitin ligase complex that recognizes substrates with Pro/N-degrons via the substrate receptor GID4. Recently, focus has turned to this complex as a potential mediator of targeted protein degradation, but the role GID4-mediated substrate ubiquitylation and proteasomal degradation plays in humans has thus far remained unclear. Here, we report PFI-7, a potent, selective, and cell-active chemical probe that antagonizes Pro/N-degron binding to human GID4. Use of PFI-7 in proximity-dependent biotinylation enabled the identification of dozens of endogenous GID4-interacting proteins that bind via the GID4 substrate binding pocket, only a subset of which possess canonical Pro/N-degron sequences. GID4 interactors are enriched for nuclear and nucleolar proteins including RNA helicases. GID4 antagonism by PFI-7 altered protein levels of several proteins including RNA helicases as measured by label-free quantitative proteomics, defining proteins that are regulated by GID4 and the CTLH complex in humans. Interactions with GID4 via Pro/N-degron pathway did not result in proteasomal degradation, demonstrating that CTLH interactors are regulated through a combination of degradative and non-degradative functions. The lack of degradation of GID4 interactors highlights potential challenges in utilizing GID4-recruiting bifunctional molecules for targeted protein degradation. Going forward, PFI-7 will be a valuable research tool for defining CTLH complex biology and honing targeted protein degradation strategies.

A chemical probe to modulate human GID4 Pro/N-degron interactions

A series of small-molecule YEATS4 binders have been discovered as part of an ongoing research effort to generate high-quality probe molecules for emerging and/or challenging epigenetic targets. Analogues such as 4d and 4e demonstrate excellent potency and selectivity for YEATS4 binding versus YEATS1,2,3 and exhibit good physical properties and in vitro safety profiles. A new X-ray crystal structure confirms direct binding of this chemical series to YEATS4 at the lysine acetylation recognition site of the YEATS domain. Multiple analogues engage YEATS4 with nanomolar potency in a whole-cell nanoluciferase bioluminescent resonance energy transfer assay. Rodent pharmacokinetic studies demonstrate the competency of several analogues as in vivo-capable binders.

Discovery of High-Affinity Small-Molecule Binders of the Epigenetic Reader YEATS4.

Discovery efforts leading to the identification of ervogastat (PF-06865571), a systemically acting diacylglycerol acyltransferase (DGAT2) inhibitor that has advanced into clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) with liver fibrosis, are described herein. Ervogastat is a first-in-class DGAT2 inhibitor that addressed potential development risks of the prototype liver-targeted DGAT2 inhibitor PF-06427878. Key design elements that culminated in the discovery of ervogastat are (1) replacement of the metabolically labile motif with a 3,5-disubstituted pyridine system, which addressed potential safety risks arising from a cytochrome P450-mediated O-dearylation of PF-06427878 to a reactive quinone metabolite precursor, and (2) modifications of the amide group to a 3-THF group, guided by metabolite identification studies coupled with property-based drug design.

Discovery of Ervogastat (PF-06865571): A Potent and Selective Inhibitor of Diacylglycerol Acyltransferase 2 for the Treatment of Non-alcoholic Steatohepatitis.

One-Pot Synthesis of 2-Azaaryl Tetrahydroquinolines by a Base-Promoted Reaction

Generation and Regioselective 3,4-Difunctionalization of Pyridynes

G e o r g T h i e m e V e r l a g K G , R ü d i g e r s t r a ß e 1 4 , 7 0 4 6 9 S t u t t g a r t , G e r m a n y 975 D . I . B U G A E N K O * , M . A . Y U R O V S K A Y A , A . V . K A R C H A V A * ( M O S C O W S T A T E U N I V E R S I T Y , R U S S I A N F E D E R A T I O N ) From Pyridine-N-oxides to 2-Functionalized Pyridines through Pyridyl Phosphonium Salts: An Umpolung Strategy Org. Lett. 2021, 23, 6099–6104, DOI: 10.1021/acs.orglett.1c02165.

Umpolung Strategy to Functionalize Pyridines/Quinolines via Phosphonium Intermediates

Preparation of Imidazolidine-2-ones from N-Benzoyloxyureas by C–H Amination

Synthesis of 2,4,6-Trisubstituted Pyridines from Methyl Ketones and Alkynones

Preclinical and clinical data suggest that acetyl-CoA carboxylase (ACC) inhibitors have the potential to rebalance disordered lipid metabolism leading to improvements in non-alcoholic steatohepatitis (NASH). Consistent with these observations, first-in-human clinical trials with our ACC inhibitor PF-05175157 led to robust reduction of de novo lipogenesis (DNL), albeit with concomitant reductions in platelet count, which were attributed to the inhibition of fatty acid synthesis within bone marrow. Herein we describe the design, synthesis, and evaluation of carboxylic acid-based ACC inhibitors with organic anion transporting polypeptide (OATP) substrate properties, which facilitated selective distribution of the compounds at the therapeutic site of action (liver) relative to the periphery. These efforts led to the discovery of clinical candidate PF-05221304 (12), which selectively inhibits liver DNL in animals, while demonstrating considerable safety margins against platelet reduction in a non-human primate model.

Optimizing the Benefit/Risk of Acetyl-CoA Carboxylase (ACC) Inhibitors Through Liver Targeting.

Regioselective C–H Functionalization of Heteroarene N -Oxides Enabled by a Traceless Nucleophile

C–H Functionalization of Quinolines, Isoquinolines, and Pyridines by N-Alkenoxyhetareniums

Modular Rhodium-Catalyzed Synthesis of Quinolines from Anthranils and Acrylic Acids

Increased fructose consumption and its subsequent metabolism have been implicated in metabolic disorders such as non-alcoholic fatty liver disease and steatohepatitis (NAFLD/NASH) and insulin resistance. Ketohexokinase (KHK) converts fructose to fructose-1-phosphate (F1P) in the first step of the metabolic cascade. Herein we report the discovery of a first-in-class KHK inhibitor, PF-06835919 (8), currently in phase 2 clinical trials. The discovery of 8 was built upon our originally reported, fragment-derived lead 1 and the recognition of an alternative, rotated binding mode upon changing the ribose-pocket binding moiety from a pyrrolidinyl to an azetidinyl ring system. This new binding mode enabled efficient exploration of the vector directed at the Arg-108 residue, leading to the identification of highly potent 3-azabicyclo[3.1.0]hexane acetic acid-based KHK inhibitors by combined use of parallel medicinal chemistry and structure-based drug design.

Discovery of PF-06835919: A Potent Inhibitor of Ketohexokinase (KHK) for the Treatment of Metabolic Disorders Driven by the Overconsumption of Fructose.

Synthesis of Tricyclic Indoles from Iodoalkynes and an N-Tosyl Hydroxylamine

Exsanguination remains the leading cause of preventable death for trauma patients, many of whom die in the pre-hospital setting. Without expedient intervention, trauma-associated hemorrhage induces a host of systemic responses, including the acute coagulopathy of trauma. For this reason, healthcare providers and pre-hospital personnel face the challenge of rapid, effective hemorrhage control. The utilization of adjuncts to facilitate hemostasis was first recorded in 1886. Commercial products have since expanded to include topical hemostats, surgical sealants, and adhesives. The ideal product balances efficacy, safety, practicality, and cost-effectiveness. This review of hemostatic agents provides a guide for successful implementation and simultaneously highlights future opportunities.

A Comprehensive Review of Topical Hemostatic Agents: The Good, The Bad, and the Novel.

Synthesis of Di- and Trisubstituted Imidazoles from Methyl Ketones and Aldehydes

Synthesis of γ-Arylated Butenolides by Palladium or Copper Catalysis

Indole acids 1, 2, and 3 are potent 5′-adenosine monophosphate-activated protein kinase (AMPK) activators for the potential treatment of diabetic nephropathy. Compounds 1–3 were scaled to supply material for preclinical studies, and indole 3 was selected for advancement to first-in-human clinical trials and scaled to kilogram quantities. The progression of the synthesis strategy for these AMPK activators is described, as routes were selected for efficient structure–activity relationship generation and then improved for larger scales. The developed sequences employed practical isolations of intermediates and APIs, reproducible cross-coupling, hydrolysis, and other transformations, and enhanced safety and purity profiles and led to the production of 40–50 g of 1 and 2 and 2.4 kg of 3. Multiple polymorphs of 3 were observed, and conditions for the reproducible formation of crystalline material suitable for clinical development were identified.

Evolution of the Synthesis of AMPK Activators for the Treatment of Diabetic Nephropathy: From Three Preclinical Candidates to the Investigational New Drug PF-06409577

A straightforward method for preparing 3,6-disubstituted-1,2,4-triazines through a redox-efficient cyclodehydration of β-keto- N-acylsulfonamides with hydrazine salts is described. Two approaches for synthesizing the requisite β-keto- N-acylsulfonamides are presented, which allow for the late stage incorporation of either the C3 or C6 substituent in a flexible manner from acid chlorides or α-bromoketones, respectively. The scope of this methodology includes primary and secondary sp3-linked substituents at both the C3 and C6 positions, and the mild reaction conditions tolerate a variety of sensitive functionalities.

Modular Synthesis of 3,6-Disubstituted-1,2,4-triazines via the Cyclodehydration of β-Keto- N-acylsulfonamides with Hydrazine Salts.

The scalable syntheses of two imidazopyridine inhibitors of the enzyme diacylglycerol acyltransferase 2 (DGAT-2) are described. 6-Chloro-3-nitro-2-aminopyridine was the starting material for the convergent synthesis of the central imidazopyridine ring. Differentiation in reactivity of the C2- and C3-nitrogen substituents on the pyridine ring and the development of mild cyclodehydration conditions to form the imidazole ring were critical problems that were addressed to deliver a 3-kg batch of compound 1 (PF-06424439) and a 0.1-kg batch of compound 2 (PF-06450561).

Route Selection and Optimization in the Synthesis of Two Imidazopyridine Inhibitors of DGAT-2

Significance: A method for the palladium-catalyzed C4 arylation of pyrrolidines and piperidines with aryl or hetaryl iodides is described. The chemistry employs a C3 aminoquinoline amide directing group to promote C–H activation. Whereas many examples of C2-directed C3 arylation are known (D. P. Affron, O. A. Davis, J. A. Bull Org. Lett. 2014, 16, 4956), a general method for the C4 arylation of pyrrolidines through a C3-directing group was unknown before the present report. Indeed, the C2 position adjacent to nitrogen is electronically more activated than the C4 position; however, by employing a bulky aminoquinoline auxiliary in conjunction with a Boc-protected amino group, C–H activation is sterically directed to the C4 position. A stereoselective formal synthesis of the antidepressant (–)-paroxetine highlights the utility of this chemistry. Comment: Pyrrolidines and piperidines are the most widely used saturated N-heterocycles in medicinal chemistry (E. Vikatu, D. T. Smith, J. T. Njardarson J. Med. Chem. 2014, 57, 10257), and therefore new methods for their chemoand stereoselective functionalization are highly valued. The scope of the present method includes both electron-rich and electron-deficient aryl iodides, although the latter gave reduced yields. Importantly, the cis stereoisomer was produced with high selectivity, and the use of enantiopure starting material afforded enantiopure products without detectable racemization. Additionally, isomerization to the trans isomer was demonstrated under basic conditions without racemization. Therefore, access to any single stereoisomer is possible with high selectivity. Methods for converting the aminoquinoline auxiliary into an acid, ester, alcohol, or amide group are exemplified. N Boc O

Optimization of the pharmacokinetic (PK) properties of a series of activators of adenosine monophosphate-activated protein kinase (AMPK) is described. Derivatives of the previously described 5-aryl-indole-3-carboxylic acid clinical candidate (1) were examined with the goal of reducing glucuronidation rate and minimizing renal excretion. Compounds 10 (PF-06679142) and 14 (PF-06685249) exhibited robust activation of AMPK in rat kidneys as well as desirable oral absorption, low plasma clearance, and negligible renal clearance in preclinical species. A correlation of in vivo renal clearance in rats with in vitro uptake by human and rat renal organic anion transporters (human OAT/rat Oat) was identified. Variation of polar functional groups was critical to mitigate active renal clearance mediated by the Oat3 transporter. Modification of either the 6-chloroindole core to a 4,6-difluoroindole or the 5-phenyl substituent to a substituted 5-(3-pyridyl) group provided improved metabolic stability while minimizing propensity for active transport by OAT3.

Optimization of Metabolic and Renal Clearance in a Series of Indole Acid Direct Activators of 5'-Adenosine Monophosphate-Activated Protein Kinase (AMPK).

SNAr Reaction of Pyridinium Salts with N-, O-, or S-Nucleophiles

Inhibitors of the renal outer medullary potassium channel (ROMK) show promise as novel mechanism diuretics, with potentially lower risk of diuretic-induced hypokalemia relative to current thiazide and loop diuretics. Here, we report the identification of a novel series of 3-sulfamoylbenzamide ROMK inhibitors. Starting from HTS hit 4, this series was optimized to provide ROMK inhibitors with good in vitro potencies and well-balanced ADME profiles. In contrast to previously reported small-molecule ROMK inhibitors, members of this series were demonstrated to be highly selective for inhibition of human over rat ROMK and to be insensitive to the N171D pore mutation that abolishes inhibitory activity of previously reported ROMK inhibitors.

Discovery and in Vitro Optimization of 3-Sulfamoylbenzamides as ROMK Inhibitors.

Synthesis of 2-Azabicyclo[3.2.0]heptanes by [2+2] Photocycloaddition

Preparation of Quinazolines from Alkynes and 2-Aryldihydrophthalazinediones

Enantioselective Synthesis of Pyrrolidines with Vicinal Stereocenters

Small molecule DGAT2 inhibitors have shown promise for the treatment of metabolic diseases in preclinical models. Herein, we report the first toxicological evaluation of imidazopyridine-based DGAT2 inhibitors and show that the arteriopathy associated with imidazopyridine 1 can be mitigated with small structural modifications, and is thus not mechanism related.

Small structural changes of the imidazopyridine diacylglycerol acyltransferase 2 (DGAT2) inhibitors produce an improved safety profile.

Increased fructose consumption and its subsequent metabolism have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the principal enzyme responsible for fructose metabolism, identification of a selective KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small molecules have been limited due to the lack of viable in vivo pharmacological tools. Herein we report the discovery of 12, a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chemistry led to the identification of pyridine 12.

Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK).

Significance: A method for preparing 1H-indazoles through a Cu(OAc)2-catalyzed N–N bond formation is reported. This two-step protocol starts with 2-amino nitriles and involves (1) addition of a Grignard or organolithium species to generate an imine and (2) copper-catalyzed oxidative N–N bond formation to give the indazole. Classical methods for preparing indazoles involve condensation of toxic hydrazine derivatives with 2-halo ketones or aldehydes under harsh conditions, or alkylation of NH indazoles, which frequently affords a mixture of N1and N2-alkylated products. A conceptually similar indazole synthesis involving N–N bond formation through activation of an 2-amino oxime has been described (B. C. Wray, J. P. Stambuli Org. Lett. 2010, 12, 4576). Compared with this, however, the current method has an improved scope and requires fewer steps from a common intermediate. Comment: Although indazoles are rarely found in natural products, they are commonly explored in medicinal chemistry programs, and differentiated approaches towards these heterocycles are of interest. One of the main advantages of the current approach is the ability to start with amines as the N1 component, which should permit library exploration, given the large pool of available primary amines. A limited number of substrates were examined. Aryl and alkyl substituents are tolerated at N1 as well as at C3. Halo (Br, F, Cl) substituents are also tolerated, and a single example of a pyridine is presented. Sterically hindered N1 indazoles are readily prepared by using this method, which can be readily executed on gram scale. N

New Zealand-born opera star Teddy Tahu Rhodes has performed around the world and is the headline act for next month's Shepparton Festival highlight, Opera In The Orchard.

But here's something you might not know about Teddy - he's related to the Queen and used to be an accountant before succumbing to the lure of the stage.

Adenosine monophosphate-activated protein kinase (AMPK) is a protein kinase involved in maintaining energy homeostasis within cells. On the basis of human genetic association data, AMPK activators were pursued for the treatment of diabetic nephropathy. Identification of an indazole amide high throughput screening (HTS) hit followed by truncation to its minimal pharmacophore provided an indazole acid lead compound. Optimization of the core and aryl appendage improved oral absorption and culminated in the identification of indole acid, PF-06409577 (7). Compound 7 was advanced to first-in-human trials for the treatment of diabetic nephropathy.

Discovery and Preclinical Characterization of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577), a Direct Activator of Adenosine Monophosphate-activated Protein Kinase (AMPK), for the Potential Treatment of Diabetic Nephropathy.

More than 75 years after her grandfather Erwin Frenkel, and his Austrian passport, survived the sinking of the SS Arandora Star by a German U-boat, Michelle Frenkel is leading a push to recreate a memorial that once stood in Tatura to honour the victims of the 1940 tragedy.

Two orthogonal routes for preparing (S)-2-methylazetidine as a bench stable, crystalline (R)-(-)-CSA salt are presented. One route features the in situ generation and cyclization of a 1,3-bis-triflate to form the azetidine ring, while the second route involves chemoselective reduction of N-Boc azetidine-2-carboxylic acid. Both sequences afford the desired product in good overall yields (61% and 49%) and high enantiomeric excess (>99% ee), avoid column chromatography, and are suitable for the large-scale production of this material.

Functionalized Isoquinolines by Rh(III)-Catalyzed C–H Conjugate Addition

Recent studies in adipose tissue, pancreas, muscle, and macrophages suggest that MAP4K4, a serine/threonine protein kinase may be a viable target for antidiabetic drugs. As part of the evaluation of MAP4K4 as a novel antidiabetic target, a tool compound, 16 (PF-6260933) and a lead 17 possessing excellent kinome selectivity and suitable properties were delivered to establish proof of concept in vivo. The medicinal chemistry effort that led to the discovery of these lead compounds is described herein together with in vivo pharmacokinetic properties and activity in a model of insulin resistance.

Discovery of an in Vivo Tool to Establish Proof-of-Concept for MAP4K4-Based Antidiabetic Treatment.

The medicinal chemistry and preclinical biology of imidazopyridine-based inhibitors of diacylglycerol acyltransferase 2 (DGAT2) is described. A screening hit 1 with low lipophilic efficiency (LipE) was optimized through two key structural modifications: (1) identification of the pyrrolidine amide group for a significant LipE improvement, and (2) insertion of a sp(3)-hybridized carbon center in the core of the molecule for simultaneous improvement of N-glucuronidation metabolic liability and off-target pharmacology. The preclinical candidate 9 (PF-06424439) demonstrated excellent ADMET properties and decreased circulating and hepatic lipids when orally administered to dyslipidemic rodent models.

Discovery and Optimization of Imidazopyridine-Based Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2).

Significance: Reported is a one-pot method for constructing trisubstituted imidazoles by a 1,3-dipolar cycloaddition between an in situ generated phospha-münchnone and an N-nosyl imine or a tethered nitrile. Phospha-münchnones are conveniently prepared by simply mixing an imine, an acid chloride, and PPh(catechyl) in CDCl3 at room temperature. The present report thus provides a convenient alternative to the use of münchnones, which exhibit similar reactivity with tosyl imines (R. Consonni et al. J. Chem. Res. Synop. 1991, 188). The trisubstituted imidazole products are produced with full control of the resulting substitution pattern, including the regiochemistry of the Nsubstituent, based on the starting components. Comment: Imidazoles are present in commercial drugs and are frequently prepared by medicinal chemists in the evaluation of potential drug candidates (see Review below). In the intermolecular version, the reaction proceeds most efficiently with N-nosyl-substituted imines and is completely unreactive with nitriles. However, tethered nitriles readily engage in cycloaddition and provide access to interesting fused products. The scope of viable acid chlorides was reasonable and included aryl and alkyl substituents as well as chloroformates. The scope of viable imines was limited to those with C-aryl and C-heteroaryl substituents, although N-alkyl and N-aryl substituents were tolerated. The scope of viable N-nosyl imines is limited to those with C-aryl and C-heteroaryl substituents.

It was a long time coming but Benalla and Seymour yesterday broke premiership droughts in emphatic style to claim the Goulburn Valley League senior football and A Grade netball premierships respectively at Shepparton's Deakin Reserve.

Synthesis of Oxygen-Bridged Bicyclic Ethers by Prins Cyclization

The farming community of Yalca, near Nathalia, lost its historic Uniting Church in the recent storms but not even that tornado-like event could topple its living treasure, 101-year old Stan Brown.

18 A . R . R E D D Y, C . Y . Z H O U, Z . G U O , J . WE I , C . M . C H E * ( H K U S H E N Z H E N I N ST I T UT E O F R E SE AR C H A N D I N N O V A T I O N A N D T H E U N I V E R S I T Y O F H O N G K O N G , P. R . O F C HI N A ) Ruthenium–Porphyrin-Catalyzed Diastereoselective Intramolecular Alkyl Carbene Insertion into C–H Bonds of Alkyl Diazomethanes Generated In Situ from N-Tosylhydrazones Angew. Chem. Int. Ed. 2014, 53, 14175–14180.

Tetrahydrofurans and Pyrrolidines from N-Tosylhydrazones via C–H Insertion

Myeloperoxidase (MPO) is a heme peroxidase that catalyzes the production of hypochlorous acid. Clinical evidence suggests a causal role for MPO in various autoimmune and inflammatory disorders including vasculitis and cardiovascular and Parkinson's diseases, implying that MPO inhibitors may represent a therapeutic treatment option. Herein, we present the design, synthesis, and preclinical evaluation of N1-substituted-6-arylthiouracils as potent and selective inhibitors of MPO. Inhibition proceeded in a time-dependent manner by a covalent, irreversible mechanism, which was dependent upon MPO catalysis, consistent with mechanism-based inactivation. N1-Substituted-6-arylthiouracils exhibited low partition ratios and high selectivity for MPO over thyroid peroxidase and cytochrome P450 isoforms. N1-Substituted-6-arylthiouracils also demonstrated inhibition of MPO activity in lipopolysaccharide-stimulated human whole blood. Robust inhibition of plasma MPO activity was demonstrated with the lead compound 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999, 8) upon oral administration to lipopolysaccharide-treated cynomolgus monkeys. On the basis of its pharmacological and pharmacokinetic profile, PF-06282999 has been advanced to first-in-human pharmacokinetic and safety studies.

Discovery of 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999): A Highly Selective Mechanism-Based Myeloperoxidase Inhibitor for the Treatment of Cardiovascular Diseases.

Aminoindolines and -indoles by Rhodium-Catalyzed C–H Bond Activation

Anti-Markovnikov Hydroheteroarylation of Unactivated Alkenes with Indoles, Pyrroles, Benzofurans, and Furans Catalyzed by a Nickel–N-Heterocyclic Carbene System

Substituted α-Amino-β-Lactams via Sequential C–H Arylation/C–H Amidation

C2-Substituted Indoles via Ruthenium-Catalyzed C–H Bond Functionalization

The Furphy story of engineering and manufacturing in Shepparton is an iconic one spanning 150 years and now it has a new home, with the Furphy Museum set to open its doors to the public later this month.

Goulburn Murray locals have the chance to appear as extras in a movie starring Academy Award winner Kate Winslet, to be filmed later this year.

Stereoselective Synthesis of trans-Oxazolidinones via C–H Oxidation

C4-Alkenylation of 3-Formyl Indoles via Ruthenium(II)-Catalyzed C–H Activation

The ceramic works of John Perceval, collectively called the angel series, have been brought together for the first time in forty years for a ground-breaking exhibition at the Shepparton Art Museum.

A former intensive care nurse says he feared the worst as he went to the aid of Benalla Football Club legend John "Shorty" Martiniello who went into cardiac arrest while umpiring a reserves match at Rochester on the weekend.

Significance: Reported is the synthesis of isatoic anhydrides 2 via the carbonylation of substituted anilines 1 utilizing a C–H activation procedure. Optimization studies demonstrated the beneficial effects of potassium iodide and the importance of oxidant and solvent choice. A substrate-scope screen showed that electron-rich anilines were the most reactive (2a–c). However, electron-deficient anilines proved useful substrates with the addition of pivalic acid and increased pressure (2d–i). In the case of 2a, a catalytic procedure [with respect to Cu(OAc)2] using oxygen as the terminal oxidant was demonstrated, affording the desired isatoic anhydride in marginally reduced yield. Derivatization of 2a to the ortho-amino acid 3a, ester 3b, and primary amide 3c was reported. Comment: Isatoic anhydrides are useful reagents for the preparation of anthranilic acid derivatives and various heterocycles alike (see Review below). Traditionally these heterocycles have been prepared via various multi-step sequences, for example from the anthranilic acids themselves (E. C. Wagner, M. F. Fegley Org. Synth. 1947, 27, 45) or via oxidation of phthalimides. The current report is attractive for several reasons, including circumventing the need for regioselective prefunctionalization and employing readily available anilines 2 as starting material.

Enantioselective Aza-Diels–Alder Route to Quinolizidines via Aminothiourea Catalysis

God's Care for Creation: An Ode to "The Little Things that Run the World"

Heteroannulative C–H Activation Route to Pyrazoles and Indazoles

Synthesis of Isoxazolines and Pyrazolines via Radical C–H Oxidation

Significance: Described is an iron-catalyzed C–H amination synthesis of pyrrolidines. While several metal-catalyzed methods exist for accomplishing intramolecular C–H amination, most require the use of carbamate, sulfonamide or vinyl azide starting materials and thus give rise to a limited range of products. Conceptually similar approaches toward saturated nitrogen heterocycles include azide photolysis or Hoffmann–Löffler–Freytag cyclization. However, in contrast to the present approach, these methods typically require substrates that possess conformational preorganization, utilize harsh conditions, or have other limitations. The described iron-catalyzed cyclization process was most efficient in those cases in which C–H insertion occurred on an allylic, benzylic or tertiary C–H bond. C–H amination into secondary and primary C–H bonds was also viable, although yields for these substrates were very low in the catalytic manifold. Comment: Substituted pyrrolidines are present in numerous natural products and pharmaceutical agents. The present method constitutes a flexible and efficient approach for the synthesis of these systems under mild/neutral conditions, and establishes iron imido complexes as synthetically useful catalytic intermediates for intramolecular C–H amination. This process was first identified using stoichiometric quantities of the iron catalyst – initial attempts to render the process catalytic were plagued by product inhibition of the catalyst. Conducting this reaction in the presence of Boc anhydride enabled catalyst turnover through in situ protection of the amine product. Pyrrolidine ring formation was generally favored, though an allylic activating group is capable of directing cyclization to form a piperidine. A single example demonstrated the C–H amination process to be highly stereospecific. Unfortunately, many of the yields were determined through NMR analysis, and there was no clear demonstration of an application. N 2,6-Cl2C6H3

Au(I)-Catalyzed Synthesis of Indole- and Arene-Fused Hexahydroquinolizinones

Significance: Piperidines represent an important structural moiety in both pharmaceutical and natural product compounds. There is a continuing need for expeditious routes which allow simple access to highly substituted piperidines. Newer methodology for efficient access of this motif includes exploitation of the aza-Achmatowicz rearrangement (J. Org. Chem. 2006, 71, 8591), and ring-closing metathesis (J. Org. Chem. 2002, 67, 1982), although most strategies rely on multi-step routes. The Ni-catalyzed coupling of carbonyl compounds and alkynes and alkenes has been previously reported, and this work has been extended to access dienones and pyrans through the analogous oxidative coupling with unactivated ketones. The current study provides a wide range of substituted piperidines in a regioselective manner via reaction of alkynes with 3-azetidinones under mild conditions. Comment: This work shows significant overlap with a recent report by Aïssa (Chem. Eur. J. 2012, 18, 3486) on an identical transformation. However, in contrast, the reaction reported here by Louie proceeds with lower loadings of both catalyst and ligand, at lower temperatures, and in shorter reaction times. In addition, the scope of the chemistry has been extended to include challenging terminal alkynes. The observed regioselectivity for unsymmetrical alkynes is largely dictated by steric effects in the intermediate metallocycle. In examples which feature TMS substitution, the polarization of the alkyne coordinated to the nickel now predominates leading to the TMS occupying the α-position in the product. A chiral 2-substituted azetidinone was also tested, and the piperidine formed demonstrated the exclusive preference for the less substituted β-carbon of the azetidinone on the metal to migrate without any erosion of enantioselectivity. Cyclic alkynes were employed to form macrocyclic piperidones. Both Boc and tosyl groups are tolerated on the azetidinone, but the reaction fails with benzhydryl protection. N RS

Nickel-Mediated, Regioselective Syntheses of Substituted Piperidines

Palladium-Catalyzed Synthesis of Indoles via Oxidative C–H Activation

Ring-closing metathesis of the allylsilane (I) followed by methylation and desilylation allows a short route to teucladiol (V) and isoteucladiol (VI).

Ring‐Closing Metathesis of Allylsilanes as a Flexible Strategy Toward Cyclic Terpenes. Short Syntheses of Teucladiol, Isoteucladiol, Poitediol, and Dactylol and an Attempted Synthesis of Caryophyllene.

Synthesis of exo-methylidenecycloalkanes via Allylsilane ring-closing metathesis/SE' electrophilic desilylation. Short syntheses of teucladiol, poitediol, dactylol, and 4beta,6beta-dihydroxy-1alpha,5beta(H)-guai-9-ene (isoteucladiol)

The development of a strategy consisting of allylsilane ring-closing metathesis and subsequent S(E)' electrophilic desilylation (allylsilane RCM/S(E)') to construct exo-methylidenecycloalkanes is described. Its utility is documented in short syntheses of teucladiol and poitediol. A key transformation in the synthesis of teucladiol is an aldol addition that establishes three stereochemical relationships in one step with ≥10:1 diastereoselectivity and provides a fascinating example of double stereodifferentiation/kinetic resolution with racemic reaction partners in the context of natural product synthesis. The synthesis of (±)-teucladiol required five steps from cyclopentenone and proceeded in 28% overall yield; adaptation of this route to an enantioselective synthesis of (-)-teucladiol enabled the determination of the absolute configuration of this terpene natural product. The use of fluoride-mediated conditions in the final desilylation step preserves the location of the alkene, delivering the natural product (±)-isoteucladiol (five steps and 21% yield from cyclopentenone). The synthesis of poitediol showcases the power of RCM for constructing eight-membered rings and features a highly diastereoselective epoxidation/fluoride-mediated fragmentation sequence for installing the exo-methylidene group with an adjacent hydroxyl-bearing stereocenter. The synthesis of (±)-poitediol required seven steps and proceeded in 18% overall yield. Again, fluoride-mediated desilylation of a late-stage intermediate (with retention of double-bond location) delivered the natural product (±)-dactylol (seven steps and 24% yield). Efforts directed toward incorporating the RCM/S(E)' sequence into a synthesis of caryophyllene are also disclosed. While ultimately unsuccessful, these efforts resulted in the identification of a novel metal alkylidene-promoted deallylation reaction of terminal 1,4-dienes. A possible mechanism for this unexpected deallylation reaction of 1,4-dienes is provided.

Ring-closing metathesis of allylsilanes as a flexible strategy toward cyclic terpenes. short syntheses of teucladiol, isoteucladiol, poitediol, and dactylol and an attempted synthesis of caryophyllene.

A general strategy for the synthesis of exo-methylidenecycloalkanes, which are salient features of many terpenoid natural products, is presented. Ring-closing alkene metathesis of allylsilanes provides intermediates that can be protodesilylated with alkene transposition to afford the exocyclic alkene; alternatively, the reactivity of the cyclic allylsilane intermediate can be harnessed to introduce allylic functionality. These two modes of reactivity are showcased in short syntheses of the sesquiterpene natural products teucladiol and poitediol, respectively.

Ring-closing metathesis of allylsilanes/electrophilic desilylation to prepare exo-methylidenecycloalkanes. Short syntheses of teucladiol and poitediol.

An efficient synthesis of the side-chain precursor crucial to the preparation of 18-methoxycoronaridine (18-MC) has been developed. This procedure represents an improvement upon the original synthesis, in which regioisomers were separated by chromatography to provide the requisite precursor. Incorporation of the protected primary alcohol moiety in the early stages of the synthesis provides the requisite regioisomer unambiguously and obviates the need for chromatography at any point.

Efficient Preparation of the 18-Methoxycoronaridine Side-Chain Precursor

We present the class of Hida-Matérn kernels, a canonical family of covariance functions that densely represents the entire space of stationary Gauss-Markov processes. It extends upon the Matérn kernels with flexible oscillatory components. Any stationary kernel, including the widely used squared-exponential and spectral mixture kernels, are either directly within this class or are appropriate asymptotic limits, demonstrating the generality of this class. Taking advantage of its Markovian nature, we show how to analytically represent a Hida-Matérn process as a state-space model using only the kernel and its derivatives. In turn this allows us to perform Gaussian process inference more efficiently and side step the usual computational burdens. We further improve the numerical stability and reduce computational complexity by exploiting the structural properties of the state-space representation.

Background. Immune effector cell-associated neurotoxicity syndrome (ICANS) is a relatively common consequence of chimeric antigen receptor T-cell (CAR-T) therapy, with a wide range of possible cognitive presentations. The aim of this study was to characterise a real-word cognitive and psychological status of patients with advanced haematologic and solid organ malignancies planned for CAR-T. We also aimed to examine utility of two cognitive screening approaches. Methods. Patients underwent specialist cognitive assessment, including a self-report questionnaire of psychopathology and subjective cognitive function. A subset of individuals also completed the Montreal Cognitive Assessment (MoCA). Results. Of 60 patients included, 15-16 (25%-27%) presented with evidence of cognitive impairment, with six unique patterns of dysfunction. Impaired patients were more likely to have B-cell acute lymphoblastic leukaemia (BF10=9.30), be younger (BF10=7.76), have bone marrow involvement (BF10=5.18), report history of anxiety (BF10=4.85), or have evidence of psychopathology (BF10=31.30). Analyses did not support the utility of cognitive screening. Of those patients who completed a self-report measure of psychopathology, nine (15.8%) were elevated on at least one symptom domain. Conclusions. The findings demonstrate a broad spectrum of dysfunction and psychopathology in this cohort, emphasising the importance of baseline evaluation for detecting cognitive neurotoxicity symptoms that might arise after CAR-T infusion.

Complexity of baseline cognitive and psychological status in haematology patients planned for chimeric antigen receptor T-cell therapy

Abstract A 1.5-year-old castrated male domestic ferret (Mustela putorius furo) was referred for profound depression, dyspnea, and seizures with a 5 months history of chronic, yellowish-green diarrhea that was minimally responsive to typical therapies for helicobacteriosis. An exploratory laparotomy and liver biopsy had been performed 12 days prior to presentation showing only a tan-colored liver. Three other ferrets in the household also had chronic, intermittent soft stools. On presentation a CBC, radiographs and ultrasound showed a thrombocytopenia (10,000), a moderate diffuse bronchial pattern to all lung lobes, and a hepato-splenomegaly with normal echogenicity. Results of special staining of the liver biopsy showed evidence of Histoplasma spp. fungal organisms. The ferret was euthanized after it did not respond to treatment. Necropsy showed Histoplasma sp. organisms in the liver, lung, spleen, multiple lymph nodes, bone marrow, and brain. A serum AGID for antibodies to Histoplasma spp. was negative in this ferret and its 3 cage mates, but all four were positive on the urine antigen test to Histoplasma spp., the test of choice. The other 3 ferrets responded well to itraconazole, the drug of choice, based on resolution of clinical signs and subsequent negative urine antigen tests. Histoplasmosis is a differential for ferrets with chronic diarrhea.

Diagnosis and Treatment of Histoplasmosis in a Group of Four Domestic Ferrets (Mustela Putorius Furo) and a Review of Histoplasmosis

Patients with Hodgkin's disease who were previously untreated with chemotherapy received the chlorambucil, vinblastine, procarbazine, and prednisone (CHLVPP) regimen plus limited involved-field radiation therapy for treatment of Hodgkin's disease through the Nebraska Lymphoma Study Group. One hundred patients, 87 with newly diagnosed Hodgkin's disease and 13 who relapsed after receiving previous radiation therapy, were treated with this regimen between 1982 and 1989. Complete remissions (CRs) were obtained in 88 of 100 patients (88%), and there have been a total of eight relapses. The overall 3-year failure-free survival was 76%, with good-prognosis patients (ie, Karnofsky performance status greater than or equal to 80) having a 3-year failure-free survival of 87%. Toxicity with this regimen was minimal, with neutropenic fevers reported in 13% of the patient population, moderate alopecia in 5%, and mild to moderate nausea and vomiting in 11% of the patients. As primary induction therapy for Hodgkin's disease, CHLVPP is an effective regimen with a high patient acceptance profile.

CHLVPP chemotherapy with involved-field irradiation for Hodgkin's disease: favorable results with acceptable toxicity.

Salvage therapy for relapsed or refractory non-Hodgkin's lymphoma utilizing autologous bone marrow transplantation.

The substitution of chlorambucil for nitrogen mustard and vinblastine for vincristine has been suggested to be an equally effective and well-tolerated variation of the MOPP regimen (mechlorethamine, vincristine, procarbazine, and prednisone). We treated 76 patients with advanced (i.e., Stage III, IV, or II with bulky mediastinal mass) or recurrent Hodgkin's disease with chlorambucil 6 mg/m2, procarbazine 100 mg/m2, and prednisone 40 mg p.o. daily, all on days 1-14; plus vinblastine 6 mg/m2 i.v. on day 1 and 8 of each 28-day cycle (ChlVPP). There was no maximum dose of the myelosuppressive agents. Patients who had not previously been irradiated received from 2,300 to 4,100 cGY to sites of previously bulky diseases after completing 6 cycles of ChlVPP. ChlVPP was easy to administer (i.e., 87% of patients without previous chemotherapy received greater than or equal to 80% of the planned doses of myelosuppressive drugs) and was generally well tolerated, with only occasional vomiting from procarbazine and phlebitis from vinblastine. In patients without previous chemotherapy, 49 (76%) achieved a complete remission (CR) and 7 (11%) a stable partial remission (i.e., residual, stable radiographic abnormality). With a maximum follow-up of 4 years, only one CR has relapsed for an actuarial CR durability of 97%. ChlVPP with consolidative radiation therapy to sites of bulky disease is effective in advanced Hodgkin's disease and, compared with most other available regimens, is extremely well tolerated.

ChlVPP--an effective and well-tolerated alternative to MOPP therapy for Hodgkin's disease.

The substitution of chlorambucil for nitrogen mustard and vinblastine for vincristine has been suggested to be an equally effective and well-tolerated variation of the MOPP regimen (mechlorethamine, vincristine, procarbazine, and prednisone). We treated 76 patients with advanced (i.e., Stage III, IV, or II with bulky mediastinal mass) or recurrent Hodgkin's disease with chlorambucil 6 mg/m2, procarbazine 100 mg/m2, and prednisone 40 mg p.o. daily, all on days 1–14; plus vinblastine 6 mg/m2 i.v. on day 1 and 8 of each 28-day cycle (Ch1VPP). There was no maximum dose of the myelosuppressive agents. Patients who had not previously been irradiated received from 2,300 to 4,100 cGY to sites of previously bulky diseases after completing 6 cycles of Ch1VPP. Ch1VPP was easy to administer (i.e., 87% of patients without previous chemotherapy received ≥80% of the planned doses of myelosuppressive drugs) and was generally well tolerated, with only occasional vomiting from procarbazine and phlebitis from vinblastine. In patients without previous chemotherapy, 49 (76%) achieved a complete remission (CR) and 7 (11%) a stable partial remission (i.e., residual, stable radiographic abnormality). With a maximum follow-up of 4 years, only one CR has relapsed for an actuarial CR durability of 97%. Ch1VPP with consolidative radiation therapy to sites of bulky disease is effective in advanced Hodgkin's disease and, compared with most other available regimens, is extremely well tolerated.

Ch1VPP—An Effective and Well‐Tolerated Alternative to MOPP Therapy for Hodgkin's Disease

Non-Hodgkin's lymphoma (NHL) is a malignancy that occurs frequently in the elderly with a median age greater than 60 years. However, most chemotherapy trials have included predominantly patients less than 60 years of age. We treated 157 patients with diffuse aggressive NHL between September 1982 and May 1986 with cyclophosphamide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), procarbazine, bleomycin, vincristine, and prednisone (CAP/BOP). There were no treatment exclusions for age. Patients in this study ranged in age from 15 to 91 years (median, 63) with 112 patients greater than or equal to 60 years of age. The overall complete remission (CR) rate was 65% with no significant difference for age less than 60 (76%) v age greater than or equal to 60 (61%) (P = .18). With a median 36-month follow-up (range, 22 to 65 months), the overall 5-year survival was 42%. The patients less than 60 years old had a 62% 5-year survival in contrast to a 34% 5-year survival in those patients greater than or equal to age 60 (P = .01). The deaths attributed to tumor or treatment-related toxicity were similar above and below age 60. The difference in survival was due to other causes of death not obviously related to the lymphoma or its therapy-occurring in 22% of patients greater than or equal to 60 years of age but only 2% of patients less than 60 years (P = .005). Our data supports the position that aggressive NHL in elderly patients is not significantly less responsive than in younger patients; however, the inclusion of older patients in clinical trials will decrease the overall survival secondary to deaths due to apparently unrelated causes.

The importance of age in survival of patients treated with chemotherapy for aggressive non-Hodgkin's lymphoma.

Fifty-one patients with diffuse large-cell lymphoma (DLCL) were treated with a six-drug combination chemotherapy regimen including cyclophosphamide, doxorubicin, procarbazine, bleomycin, vincristine, and prednisone. The patients were restaged after three cycles of therapy, and restaging was repeated at 2-month intervals in patients who had persistent disease. Responding patients received two cycles of therapy after documentation of complete remission (CR). With all patients considered evaluable, 73% of the patients achieved a CR. Twenty-six of the 37 CRs (70%) achieved remission in the first three treatment cycles. The durability of remission in the rapidly responding patients was significantly better than for patients who required five cycles to achieve CR (80% v 40% at 2 years, P = .02) despite the latter patients having received two more cycles of therapy. Rapidly responding patients with DLCL do not require prolonged therapy and have a better prognosis than patients achieving a CR more slowly.

Chemotherapy for diffuse large-cell lymphoma--rapidly responding patients have more durable remissions.

INFECTIOUS mononucleosis has perplexed the clinician with a myriad of signs, symptoms, and complications. We describe an unusual patient in his presenting form and subsequent course. The first report of infectious mononucleosis in 1885 by Filatoff 1 * classified the disease as a juvenile cervical adenitis, an infectious disease of childhood. The prevalence was felt to be epidemic involving both infants and children. In Pfeiffer's classical description of "Drusenfieber" in 1889, 2 recognition was made of involvement of the liver and spleen. Forty years passed before the numerous complications and confusing forms of the disease began to reach the literature, including skin, hematologic, and serologic manifestations. 3-7 Recently, clinicians have become more aware of the complications of the central nervous system (CNS). Most of these have taken the form of meningoencephalitis, isolated peripheral neuropathy, or polyradiculitis. 8-10 Our patient was afflicted with a rare neurologic complication: a cerebellitis, which mimicked an

L'invention concerne des 3-azabicyclo[3.1.0]hexanes substitues servant d'inhibiteurs de cetohexokinase, des procedes de fabrication de ces composes ainsi que des procedes comprenant l'administration desdits composes a un mammifere en ayant besoin.

3-azabicyclo[3.1.0]hexanes substitués servant d'inhibiteurs de cétohexokinase

La presente invention concerne des composes indoliques et indazoliques de formule (I) qui activent la proteine kinase activee par la 5' adenosine monophosphate (AMPK). L'invention concerne egalement des compositions pharmaceutiques contenant lesdits composes ainsi que des methodes de traitement ou de prevention de maladies, ou de troubles attenues par l'activation de l'AMPK.

Cette invention concerne des composes d'indole et d'indazole de Formule (I) qui activent la proteine kinase activee par le 5' adenosine monophosphate (AMPK). Cette invention concerne egalement des compositions pharmaceutiques contenant lesdits composes et des methodes destinees a traiter ou a prevenir des maladies, des affections, ou des troubles ameliores par activation de l'AMPK.

La presente invention concerne des composes de formule (I) ou les variables sont telles que definies dans la presente invention, ainsi que leurs compositions pharmaceutiques et methodes d'application dans le traitement de la dyslipidemie et des maladies similaires.

 Health workers in developing countries need updated effective training and reference manuals. Health service representatives and teachers need to determine materials most urgently needed and curricula that needs revision. The writers must consider the educational background of the readers and approach the writing of the manual accordingly. The text should be locally relevant and contain only information specific to the particular group being addressed. Some manuals may be modified or adapted easily for use with a different category of health workers. The language used should correspond to user reading ability. Writers need to use case studies which correspond to local experiences, to use understandable illustrations, and to index the manuals well. The manual should be field-tested by the teachers and supervisors of the future users to determine readability, usefulness, and relevance. If the manual is approved, it can then be edited and printed. Distribution of the materials through health channels may be unreliable. Funds may need to be raised to distribute the manuals and publications. Careful evaluation of the manuals is necessary to effect constant revision and improvement.

The need exists to encourage developing countries to produce their own learning materials to meet the specific requirements of their own health personnel and to create a structure capable of functioning independently after any external funds and technical assistance have been phased out. In 1981 the World Health Organization (WHO) and the UN National Development Program established a joint Interregional Health Learning Materials (HLM) Program. It began with a small number of pilot projects in selected countries the intention being to extend it gradually to other countries in the light of experience. The program is aimed at helping developing countries to produce their own teaching and learning materials adapted to their special needs and encouraging them to work together and build up a network for sharing materials and expertise. An HLM project is part of a national program and makes use of local staff and infrastructure. Both teachers and students help in preparing the learning materials. A number of national projects are now in operation producing teaching aids manuals slides guides for teachers and textbooks for use in the field all of which are in line with national health priorities and goals and many of which are shared with other projects. Of the countries in which HLM projects are in operation all but 1 are in Africa. The only exception thus far is Nepal although a project has been requested by Fiji. Technical cooperation between the African projects is beginning to make headway despite initial problems because of differences in language. For national reliance to be achieved the training of key staff is essential. For this purpose WHO is collaborating with the African Medical and Research Foundation (AMREF) in Nairobi a nongovernmental organization with many years of experience in developing teaching materials for health workers in Africa. Special emphasis is now being given to the training of national project staff in the application of microcomputers. The aim is ultimately for external support to be no longer needed. The national plan for each HLM project foresees the withdrawal of external support after 5 years. By that time the project should have a core of trained staff the necessary equipment and an established HLM unit within the national system and should be self-reliant in planning testing producing and evaluating teaching and learning materials for its own health personnel. The production of health learning materials must clearly be part of an integrated plan for health manpower development.

AbstractPoor communications are a defect common to all levels of transaction within the health sector. Problems are posed in relation both to developing and industrialized countries, and some solutions offered. The need is stressed for research and development in many grey areas of the communication gap. In the long-term however, the human clement present the greatest problem. as resistance to change, whether among health workers or in the community, is a characteristic of human behaviour. But change there must be if 'Health Care for All by the Year 2000' is not just an idle dream – it is the stated goal of the 1977 World Health Assembly. But it will not be feasible until we learn to improve communication in all its aspects.

Good Health Communications: An Essential Part of Effective Health Care

Videotape recording apparatus was used to make records of case histories obtained from patients by students and doctors. These records were studied in order to identify the skills required to obtain a patient's history of illness. Each skill was defined. A questionnaire was developed in order to assess these skills and three independent observers watched the records of eighteen students and completed a questionnaire for each. The results of this were analysed for reliability and reproducibility between examiners. Moderate reliability and reproducibility were demonstrated. The questionnaire appeared to be a valid method of assessment and was capable of providing significant discrimination between students for each skill. A components analysis suggested that the marks for each skill depend on an overall impression obtained by each examiner and this overall impression is influenced by different skills for each examiner.

The definition and evaluation of the skills required to obtain a patient's history of illness: the use of videotape recordings

Summary Videotape recording apparatus wasusedtomake records ofcasehistories obtained frompatients by students anddoctors. Theserecords werestudied in order toidentify theskills required toobtain apatient's history ofillness. Eachskill wasdefined. A questionnaire wasdeveloped inorder toassess these skills and threeindependent observers watched therecords of eighteen students andcompleted aquestionnaire for each. Theresults ofthiswereanalysed forreliability andreproducibility between examiners. Moderate reliability andreproducibility weredemonstrated. Thequestionnaire appeared tobea valid method ofassessment andwascapable ofproviding significant discrimination between students foreach skill. Acomponents analysis suggested that themarks foreachskill depend onan overall impression obtained byeachexaminer andthis overall impression isinfluenced bydifferent skills foreachexaminer.

Thedefinition andevaluation oftheskills required toobtain apatient's history ofillness: theuse ofvideotape recordings

A fundamental problem in statistical neuroscience is to model how neurons encode information by analyzing electrophysiological recordings. A popular and widely-used approach is to fit the spike trains with an autoregressive point process model. These models are characterized by a set of convolutional temporal filters, whose subsequent analysis can help reveal how neurons encode stimuli, interact with each other, and process information. In practice a sufficiently rich but small ensemble of temporal basis functions needs to be chosen to parameterize the filters. However, obtaining a satisfactory fit often requires burdensome model selection and fine tuning the form of the basis functions and their temporal span. In this paper we propose a nonparametric approach for jointly inferring the filters and hyperparameters using the Gaussian process framework. Our method is computationally efficient taking advantage of the sparse variational approximation while being flexible and rich enough to characterize arbitrary filters in continuous time lag. Moreover, our method automatically learns the temporal span of the filter. For the particular application in neuroscience, we designed priors for stimulus and history filters useful for the spike trains. We compare and validate our method on simulated and real neural spike train data.

In Monte Carlo-based Bayesian inference, it is important to generate samples from a target distribution, which are then used, e.g., to compute expectations with respect to the target distribution. Quite often, the target distribution is the posterior of parameters of interest, and drawing samples from it can be exceedingly difficult. Monte Carlo-based methods, like adaptive importance sampling (AIS), is built on the importance sampling principle to approximate a target distribution using a set of samples and their corresponding weights. Variational inference (VI) attempts to approximate the posterior by minimizing the Kullback-Leibler divergence (KLD) between the posterior and a set of simpler parametric distributions. While AIS often performs well, it struggles to approximate multimodal distributions and suffers when applied to high dimensional problems. By contrast, VI is fast and scales well with the dimension, but typically underestimates the variance of the target distribution. In this paper, we combine both methods to overcome their individual drawbacks and create an efficient and robust novel technique for drawing better samples from a target distribution. Our contribution is two-fold. First, we show how to do a smart initialization of AIS using VI. Second, we propose a method for adapting the parameters of the proposal distributions of the AIS, where the adaptation depends on the performance of the VI step. Computer simulations reveal that the new method improves the performance of the individual methods and shows promise to be applied to challenging scenarios.

Improved Adaptive Importance Sampling Based on Variational Inference

In this paper, we address the problem of tracking objects with a network of passive tags that communicate with each other based on the principle of backscattering. The tags are RF powered and are able to passively reflect an external RF signal. While reflecting the signal, they also modulate it and thereby they transmit information. Based on the features of the signals they receive from their neighbors, the tags are capable of detecting if there is a new object in their proximity. They operate without access to absolute time, and they are not synchronized in any sense. We propose an approach for detecting an object, a protocol for communication among the tags while reporting the presence of the object to a center for data processing, and a method for estimating the trajectory of the object based on the received information from the tags.

2018 IEEE 19th International Workshop on Signal Processing Advances in Wireless Communications (SPAWC)

Tracking of Objects in a Passive Backscattering Tag-to-Tag Network

COMPOSITIONS ET MÉTHODES DE TRAITEMENT DU SYNDROME SEC ET D'AUTRES SURFACES ÉPITHÉLIALES NON KÉRATINISÉES AYANT SUBI UN TRAUMATISME

Cette invention concerne un biocapteur comprenant un substrat electroconducteur recouvert d'un biopolymere de chitosane modifie qui a ete electrodepose sur le substrat, ledit biopolymere de chitosane modifie comprenant au moins une molecule de liaison a des vesicules. Le biocapteur est fabrique par un procede consistant a electrodeposer sur un substrat un biopolymere de chitosane modifie. Le procede est egalement utilise pour fabriquer une pellicule de biopolymere de chitosane modifie par electrodeposition du chitosane sur le substrat, ladite pellicule etant ensuite retiree du substrat apres electrodeposition. La pellicule resultante peut etre utilisee dans des bandages pour traiter differents types de plaies. Le biocapteur peut egalement etre utilise pour detecter differents analytes dans des echantillons.

Procédé et système de capture et d'utilisation de vésicules intactes sur des pellicules de biopolymères hydrophobiquement modifiés électrodéposés

AbstractCoastal communities preparing for climate change and sea-level rise need to consider the impact large storms will have on belowground infrastructure. Although these communities often rely o...

Geospatial Modeling Suggests Threats from Stormy Seas to Rhode Island’s Coastal Septic Systems

Une etude biographique d'andre felibien (1619-1695) axee sur ses relations aux mondes litteraire, artistique et religieux du dixseptieme siecle, cette these a pour objectif de combler de nombreuses lacunes dans nos connaissances de sa vie : sa famille a chartres, ses debuts litteraires dans la societe de valentin conrart, son "amitie" avec poussin a rome, son association avec le brun, mlle de scudery et la fontaine dans l'entourage de foucquet, son "eviction" en tant que redacteur des conferences de l'academie royale de peinture et de sculpture, ce qui l'entraine a prendre des distances de la position officielle dans ses derniers entretiens. Elle comporte une analyse critique des sources de sa biographie (correspondance, journal, ouvrages inedits, temoignages de son epoque) afin de comprendre ce qui l'a conduit a devenir le premier historien de l'art en france. Elle etablit la chronologie des descriptions du chateau de vaux-le-vicomte. Elle confronte son oeuvre esthetique avec les conferences de l'academie de peinture, en particulier celles de le brun et de testelin, afin de determiner les ecarts de felibien d'avec la doctrine academique. Elle essaie de situer dans le cadre de sa theorie des "convenances" son traite inedit sur les costumes antiques. Elle analyse enfin l'influence de ses oeuvres de piete ainsi que ses affinites avec l'abbe de rance et avec la reforme de la trappe sur sa theorie esthetique afin de comprendre ce qui constitue pour lui la vraie fin de l'art.

The purpose of this study was to compare three stop, reverse, and start (SRS) techniques used in the game of ice hockey. Six S's from four levels of competition were instructed in the execution of three skills, then timed over a specified course performing each method. Additionally, selected S's within each group were filmed from frontal and lateral perspectives while performing the tests. A biomechanical analysis of all films was conducted. Both statistical and biomechanical analyses showed a superiority of the "feet parallel, thrust and glide" technique over both techniques employing the "cross over." Conclusion was that the former method should be included in the instructional and competitive programs in Ice Hockey.

Canadian journal of applied sport sciences. Journal canadien des sciences appliquees au sport

A comparison of selected stop, reverse and start (SRS) techniques in ice hockey.

The purpose of this study was to determine the effectiveness of three different methods of initiating forward movement (IFM). Six S's from four levels of Ice Hockey competition were instructed in the methods then were timed for 20 feet of forward skating from a standing start. Selected S's within each group were also analyzed biomechanically, via the cinema-computer process. Both statistical and biomechanical analysis showed a superiority of the rarely taught thrust and glide or "t" start over the two conventional techniques, the cross-over and normal standing start facing the direction of movement. Results indicate a need to include the thrust and glide in Ice Hockey instructional programs.

The brain is an intricate assembly of intercommunicating neurons whose input-output function is only partially understood. The role of active dendrites in shaping spiking responses, in particular, is unclear. Although existing models account for active dendrites and spiking responses, they are too complex to analyze analytically and demand long stochastic simulations. Here we combined cable and renewal theory to describe how input fluctuations shape the response of neuronal ensembles with active dendrites. We found that dendritic input readily and potently controls interspike interval dispersion. This phenomenon can be understood by considering that neurons display three fundamental operating regimes: one mean-driven regime and two fluctuation-driven regimes. We show that these results are expected to appear for a wide range of dendritic properties and verify the predictions of the model in experimental data. These findings have implications for the role of interspike interval dispersion in learning and for theories of attractor states.

Synapses show preferential responses to particular temporal patterns of activity. Across individual synapses, there is a large degree of response heterogeneity that is informally or tacitly separated into classes, and typically only two: facilitating and depressing short-term plasticity. Here we combined a kernel-based model and machine learning techniques to infer the number and the characteristics of functionally distinct subtypes of short-term synaptic dynamics in a large dataset of glutamatergic cortical connections. To this end, we took two independent approaches. First, we used unsupervised techniques to group similar synapses into clusters. Second, we used supervised prediction of cell subclasses to reveal features of synaptic dynamics that characterized cellular genetic profiles. In rodent data, we found five clusters with a remarkable degree of convergence with the transgenic-associated subtypes. Two of these clusters corresponded to different degrees of facilitation, two corresponded to depression with different degrees of variability and one corresponded to depression-then-facilitation. Strikingly, the application of the same clustering method in human data inferred highly similar clusters to those observed in rodents, supportive of a stable clustering procedure and suggesting a homology of functional subtypes across species. This nuanced dictionary of functional subtypes shapes the heterogeneity of cortical synaptic dynamics and provides a lens into the basic motifs of information transmission in the brain.

When a neuron breaks silence, it can emit action potentials in a number of patterns. Some responses are so sudden and intense that electrophysiologists felt the need to single them out, labeling action potentials emitted at a particularly high frequency with a metonym -- bursts. Is there more to bursts than a figure of speech? After all, sudden bouts of high-frequency firing are expected to occur whenever inputs surge. The burst coding hypothesis advances that the neural code has three syllables: silences, spikes and bursts. We review evidence supporting this ternary code in terms of devoted mechanisms for burst generation, synaptic transmission and synaptic plasticity. We also review the learning and attention theories for which such a triad is beneficial.

Neuroscience and artificial intelligence are closely intertwined, but so are the physics of dynamical system, philosophy and psychology. Each of these fields try in their own way to relate observations at the level of molecules, synapses, neurons or behavior, to a function. An influential conceptual approach to this end was popularized by David Marr, which focused on the interaction between three theoretical 'levels of analysis'. With the convergence of simulation-based approaches, algorithm-oriented Neuro-AI and high-throughput data, we currently see much research organized around four levels of analysis: observations, models, algorithms and functions. Bidirectional interaction between these levels influences how we undertake interdisciplinary science.

46 Serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) receive a diverse constellation of 47 long-range synaptic inputs, yet unifying principles of local circuitry and its dynamics are largely 48 unknown a crucial component of understanding how 5-HT output controls behavior. Here, we 49 developed a formalism bridging optogenetic, electrophysiological, computational and behavioral 50 strategies to reveal how the dynamics of local circuitry in DRN control the expression of reward 51 associations. Using long-range input from lateral habenula (LHb) to interrogate functional DRN 52 circuitry, we uncover 5-HT1A receptor-mediated local recurrent connections between 5-HT 53 neurons, refuting classical theories of autoinhibition by 5-HT1A receptors. These inhibitory 554 HT connections were slow, stochastic, strongly facilitating, and gated spike output of 5-HT 55 neurons. Targeted physiology and modeling approaches revealed that these functional 56 connectivity features collectively support the emergence of a paradoxical excitation-driven 57 inhibition in response to high frequency LHb activation, and of a winner-take-all computation 58 over protracted timescales. In vivo, we found that optogenetic activation of LHb inputs to DRN 59 transiently disrupted expression of a reward-conditioned response in an auditory conditioning 60 task. In accordance with quantitative model predictions, this disruption occurred exclusively at 61 the conjunction of high frequency LHb activation and high predicted reward value, and was not 62 due to a modulation of the underlying reward association. Thus, we propose that recurrent 63 dynamics in the DRN support a contextual value computation, where stable learned associations 64 are integrated with dynamic environmental inputs to support sharp behavioral state transitions in 65 changing environments. 66 67 68 69 70 71

The primary motor cortex (M1) is known to be a critical site for movement initiation and motor learning. Surprisingly, it has also been shown to possess reward-related activity, presumably to facilitate reward-based learning of new movements. However, whether reward-related signals are represented among different cell types in M1, and whether their response properties change after cue–reward conditioning remains unclear. Here, we performed longitudinal in vivo two-photon Ca2+ imaging to monitor the activity of different neuronal cell types in M1 while mice engaged in a classical conditioning task. Our results demonstrate that most of the major neuronal cell types in M1 showed robust but differential responses to both the conditioned cue stimulus (CS) and reward, and their response properties undergo cell-type-specific modifications after associative learning. PV-INs’ responses became more reliable to the CS, while VIP-INs’ responses became more reliable to reward. Pyramidal neurons only showed robust responses to novel reward, and they habituated to it after associative learning. Lastly, SOM-INs’ responses emerged and became more reliable to both the CS and reward after conditioning. These observations suggest that cue- and reward-related signals are preferentially represented among different neuronal cell types in M1, and the distinct modifications they undergo during associative learning could be essential in triggering different aspects of local circuit reorganization in M1 during reward-based motor skill learning.

Cell-type-specific responses to associative learning in the primary motor cortex

Author response: Cell-type-specific responses to associative learning in the primary motor cortex

Theories of attention and learning have hypothesized a central role for high-frequency bursting in cognitive functions, but experimental reports of burstmediated representations in vivo have been limited. Here we used a novel demultiplexing approach to separate independent streams of information from considering neurons as having three possible states: silent, singlet- and burst-firing. We studied this ternary neural code in vivo while animals learned to behaviorally report direct electrical stimulation of the somatosensory cortex and found two acquired yet independent representations. One code, the event rate, represented the stimulus in a small fraction of cells and showed a small modulation upon detection errors. The other code, the burst fraction, correlated more globally with stimulation and more promptly responded to detection errors. Bursting modulation was potent and its time course evolved, even in cells that were considered unresponsive based on the firing rate. During the later stages of training, this modulation in bursting happened earlier, gradually aligning temporally with the representation in event rate. The alignment of bursting and event rate modulation sharpened firing rate coded representations, and was strongly associated behavioral accuracy. Thus a fine grain separation of spike timing patterns reveals two signals that accompany stimulus representations: an error signal that can be essential to guide learning and a sharpening signal that could enact top-down attention.

Triggered activity bursts in place cells can increase and decrease the strength of some inputs.

Dendrites receive the vast majority of a single neuron's inputs, and coordinate the transformation of these signals into neuronal output. Ex vivo and theoretical evidence has shown that dendrites possess powerful processing capabilities, yet little is known about how these mechanisms are engaged in the intact brain or how they influence circuit dynamics. New experimental and computational technologies have led to a surge in interest to unravel and harness their computational potential. This review highlights recent and emerging work that combines established and cutting-edge technologies to identify the role of dendrites in brain function. We discuss active dendritic mediation of sensory perception and learning in neocortical and hippocampal pyramidal neurons. Complementing these physiological findings, we present theoretical work that provides new insights into the underlying computations of single neurons and networks by using biologically plausible implementations of dendritic processes. Finally, we present a novel brain–computer interface task, which assays somatodendritic coupling to study the mechanisms of biological credit assignment. Together, these findings present exciting progress in understanding how dendrites are critical for in vivo learning and behavior, and highlight how subcellular processes can contribute to our understanding of both biological and artificial neural computation.

Dendritic Mechanisms for In Vivo Neural Computations and Behavior

Neurons are very complicated computational devices, incorporating numerous non-linear processes, particularly in their dendrites. Biophysical models capture these processes directly by explicitly modelling physiological variables, such as ion channels, current flow, membrane capacitance, etc. However, another option for capturing the complexities of real neural computation is to use cascade models, which treat individual neurons as a cascade of linear and non-linear operations, akin to a multi-layer artificial neural network. Recent research has shown that cascade models can capture single-cell computation well, but there are still a number of sub-cellular, regenerative dendritic phenomena that they cannot capture, such as the interaction between sodium, calcium, and NMDA spikes in different compartments. Here, we propose that it is possible to capture these additional phenomena using parallel, recurrent cascade models, wherein an individual neuron is modelled as a cascade of parallel linear and non-linear operations that can be connected recurrently, akin to a multi-layer, recurrent, artificial neural network. Given their tractable mathematical structure, we show that neuron models expressed in terms of parallel recurrent cascades can themselves be integrated into multi-layered artificial neural networks and trained to perform complex tasks. We go on to discuss potential implications and uses of these models for artificial intelligence. Overall, we argue that parallel, recurrent cascade models provide an important, unifying tool for capturing single-cell computation and exploring the algorithmic implications of physiological phenomena.

Parallel and Recurrent Cascade Models as a Unifying Force for Understanding Subcellular Computation

Cortical pyramidal cells (PCs) have a specialized dendritic mechanism for the generation of bursts, suggesting that these events play a special role in cortical information processing. In vivo, bursts occur at a low, but consistent rate. Theory suggests that this network state increases the amount of information they convey. However, because burst activity relies on a threshold mechanism, it is rather sensitive to dendritic input levels. In spiking network models, network states in which bursts occur rarely are therefore typically not robust, but require fine-tuning. Here, we show that this issue can be solved by a homeostatic inhibitory plasticity rule in dendrite-targeting interneurons that is consistent with experimental data. The suggested learning rule can be combined with other forms of inhibitory plasticity to self-organize a network state in which both spikes and bursts occur asynchronously and irregularly at low rate. Finally, we show that this network state creates the network conditions for a recently suggested multiplexed code and thereby indeed increases the amount of information encoded in bursts. Author summary The language of the brain consists of sequences of action potentials. These sequences often contain bursts, short “words” consisting of a few action potentials in rapid succession. Bursts appear to play a special role in the brain. They indicate whether a stimulus was perceived or missed, and they are very effective drivers of synaptic plasticity, the neural substrate of learning. Bursts occur rarely, but consistently, a condition that is thought to maximize the amount of information they can communicate. In our article, we argue that this condition is far from self-evident, but requires very special circumstances. We show that these circumstances can be reached by homeostatic inhibitory plasticity in certain inhibitory neuron types. This may sound complicated, but basically works just like a thermostat. When bursts occur too often, inhibition goes up and suppresses them. When they are too rare, inhibition goes down and thereby increases their number. In computer simulations, we show that this simple mechanism can create circumstances akin to those in the brain, and indeed allows bursts to convey information effectively. Whether this mechanism is indeed used by the brain now remains to be tested by our experimental colleagues.

Self-organization of a doubly asynchronous irregular network state for spikes and bursts

The primary motor cortex (M1) is known to be a critical site for movement initiation and motor learning. Surprisingly, it has also been shown to possess reward-related activity, presumably to facilitate reward-based learning of new movements. However, whether reward-related signals are represented among different cell types in M1, and whether their response properties change after cue-reward conditioning remains unclear. Here, we performed longitudinal in vivo two-photon Ca2+ imaging to monitor the activity of different neuronal cell types in M1 while mice engaged in a classical conditioning task. Our results demonstrate that most of the major neuronal cell types in M1 showed robust but differential responses to both cue and reward stimuli, and their response properties undergo cell-type specific modifications after associative learning. PV-INs’ responses became more reliable to the cue stimulus, while VIP-INs’ responses became more reliable to the reward stimulus. PNs only showed robust response to the novel reward stimulus, and they habituated to it after associative learning. Lastly, SOM-IN responses emerged and became more reliable to both conditioned cue and reward stimuli after conditioning. These observations suggest that cue- and reward-related signals are represented among different neuronal cell types in M1, and the distinct modifications they undergo during associative learning could be essential in triggering different aspects of local circuit reorganization in M1 during reward-based motor skill learning.

Cell-Type Specific Responses to Associative Learning in the Primary Motor Cortex

The burst coding hypothesis posits that the occurrence of sudden high-frequency patterns of action potentials constitutes a salient syllable of the neural code. Many neurons, however, do not produce clearly demarcated bursts, an observation invoked to rule out the pervasiveness of this coding scheme across brain areas and cell types. Here we ask how identifiable spike-timing patterns have to be to preserve potent transmission of information. Should we expect that neurons avoid ambiguous patterns that are neither clearly bursts nor isolated spikes? We addressed these questions using information theory and computational simulations. By quantifying how information transmission depends on firing statistics, we found that the information transmitted is not strongly influenced by the presence of clearly demarcated modes in the interspike interval distribution, a feature often used to identify the presence of burst coding. Instead, we found that neurons having unimodal interval distributions were still able to ascribe different meanings to bursts and isolated spikes. In this regime, information transmission depends on properties of the synapses as well as the length and relative frequency of bursts. Furthermore, we found that common metrics used to quantify burstiness were also unable to predict the degree with which bursts could be used to carry information. Our results provide guiding principles for the implementation of coding strategies based on spike-timing patterns, and show that even unimodal firing statistics can be consistent with a bivariate neural code.

By means of an expansive innervation, the serotonin (5-HT) neurons of the dorsal raphe nucleus (DRN) are positioned to enact coordinated modulation of circuits distributed across the entire brain in order to adaptively regulate behavior. Yet the network computations that emerge from the excitability and connectivity features of the DRN are still poorly understood. To gain insight into these computations, we began by carrying out a detailed electrophysiological characterization of genetically-identified mouse 5-HT and somatostatin (SOM) neurons. We next developed a single-neuron modeling framework that combines the realism of Hodgkin-Huxley models with the simplicity and predictive power of generalized integrate-and-fire (GIF) models. We found that feedforward inhibition of 5-HT neurons by heterogeneous SOM neurons implemented divisive inhibition, while endocannabinoid-mediated modulation of excitatory drive to the DRN increased the gain of 5-HT output. Our most striking finding was that the output of the DRN encodes a mixture of the intensity and temporal derivative of its input, and that the temporal derivative component dominates this mixture precisely when the input is increasing rapidly. This network computation primarily emerged from prominent adaptation mechanisms found in 5-HT neurons, including a previously undescribed dynamic threshold. By applying a bottom-up neural network modeling approach, our results suggest that the DRN is particularly apt to encode input changes over short timescales, reflecting one of the salient emerging computations that dominate its output to regulate behavior.

Temporal derivative computation in the dorsal raphe network revealed by an experimentally driven augmented integrate-and-fire modeling framework

Author Correction: Burst-dependent synaptic plasticity can coordinate learning in hierarchical circuits

Decision letter: Bidirectional synaptic plasticity rapidly modifies hippocampal representations

A Synthetic Likelihood Solution to the Silent Synapse Estimation Problem.

Correction to: Linking demyelination to compound action potential dispersion with a spike-diffuse-spike approach

Synaptic dynamics differ markedly across connections and strongly regulate how action potentials are being communicated. To model the range of synaptic dynamics observed in experiments, we develop a flexible mathematical framework based on a linear-nonlinear operation. This model can capture various experimentally observed features of synaptic dynamics and different types of heteroskedasticity. Despite its conceptual simplicity, we show it is more adaptable than previous models. Combined with a standard maximum likelihood approach, synaptic dynamics can be accurately and efficiently characterized using naturalistic stimulation patterns. These results make explicit that synaptic processing bears algorithmic similarities with information processing in convolutional neural networks.

Short-term synaptic dynamics differ markedly across connections and strongly regulate how action potentials communicate information. To model the range of synaptic dynamics observed in experiments, we have developed a flexible mathematical framework based on a linear-nonlinear operation. This model can capture various experimentally observed features of synaptic dynamics and different types of heteroskedasticity. Despite its conceptual simplicity, we show that it is more adaptable than previous models. Combined with a standard maximum likelihood approach, synaptic dynamics can be accurately and efficiently characterized using naturalistic stimulation patterns. These results make explicit that synaptic processing bears algorithmic similarities with information processing in convolutional neural networks. Author summary Understanding how information is transmitted relies heavily on knowledge of the underlying regulatory synaptic dynamics. Existing computational models for capturing such dynamics are often either very complex or too restrictive. As a result, effectively capturing the different types of dynamics observed experimentally remains a challenging problem. Here, we propose a mathematically flexible linear-nonlinear model that is capable of efficiently characterizing synaptic dynamics. We demonstrate the ability of this model to capture different features of experimentally observed data.

Accurate Silent Synapse Estimation from Simulator-Corrected Electrophysiological Data Using the SilentMLE Python Package

Burst-dependent synaptic plasticity can coordinate learning in hierarchical circuits

Review for "Extending the integrate‐and‐fire model to account for metabolic dependencies"

Supervised capsule networks are theoretically advantageous over convolutional neural networks, because they aim to model a range of transformations of local physical or abstract objects and part-whole relationships among them. However, it remains unclear how to use the concept of capsules in deep generative models. In this study, to address this challenge, we present a statistical modelling of capsules in deep generative models where distributions are formulated in the exponential family. The major contribution of this unsupervised method is that parse trees as representations of part-whole relationships can be dynamically learned from the data.

Linking demyelination to compound action potential dispersion with a spike-diffuse-spike approach

Properties of synaptic release dictates the core of information transfer in neural circuits. Despite decades of technical and theoretical advances, distinguishing bona fide information content from the multiple sources of synaptic variability remains a challenging problem. Here, we employed a combination of computational approaches with cellular electrophysiology, two-photon uncaging of MNI-Glutamate and imaging at single synapses. We describe and calibrate the use of the fluorescent glutamate sensor iGluSnFR and found that its kinetic profile is close to that of AMPA receptors, therefore providing several distinct advantages over slower methods relying on NMDA receptor activation (i.e., chemical or genetically encoded Calcium indicators). Using an array of statistical methods, we further developed, and validated on surrogate data, an expectation-maximization algorithm that, by biophysically constraining release variability, extracts the quantal parameters n (maximum number of released vesicles) and p (unitary probability of release) from single-synapse iGluSnFR-mediated transients. Together, we present a generalizable mathematical formalism which, when applied to optical recordings, paves the way to an increasingly precise investigation of information transfer at central synapses.

Parsing Out the Variability of Transmission at Central Synapses Using Optical Quantal Analysis

The proportions of AMPA-lacking silent synapses are believed to play a fundamental role in determining the plasticity potential of neural networks. It is, however, unclear whether current methods to quantify silent synapses possess adequate estimation properties. Here, by developing a biophysically realistic sampling model, we assess the performance of a common method, the failure-rate analysis (FRA), in estimating the fraction of silent synapses. We find that the FRA estimator is unexpectedly characterized by strong systematic biases, poor reliability, and the need for prohibitively high sample sizes for adequate statistical power. Key predictions from these in silico simulations were validated by whole-cell recordings from mouse hippocampal neurons. To address the inherent limitations of the FRA formalism, we propose an alternative statistical approach, an approximate maximum-likelihood estimator (MLE) based on Monte Carlo simulations of the experimental methodology. This estimator exhibits no bias and low variance and is thus suitable for precise, accurate and high-throughput estimation of silent synapse fractions. These results reveal that previous FRA-based estimates of silent synapse fraction were erroneously large and highlights the use of computational models of experimental methodologies to improve their accuracy and precision. Significance statement The plasticity potential of networks of neurons is critically enhanced by the presence of silent (AMPA-lacking) synapses. The global fraction of these silent synapses in a network is developmentally regulated as well as altered by drugs of abuse in adulthood, yet current methods can only estimate this global fraction by recording from a small and potentially biased subset of electrically stimulated synapses. We show that a widely used failure-rate calculation returns highly variable results and false positives, and develop an alternate estimator employing synthetic (simulated) likelihood functions exhibiting dramatically decreased bias and variance. This allows investigators to reliably interrogate fine-grained changes in plasticity potential, and simultaneously demonstrates how computational models of methodologies can be adapted into statistical inference tools.

A synthetic likelihood solution to the silent synapse estimation problem

Memory consolidation in the neocortex Information transfer between brain structures located in the medial-temporal lobe and the neocortex is essential for learning. However, the neuronal underpinnings of this transfer are unknown. Doron et al. found that neurons located in the deep layers of the perirhinal cortex exhibit increased firing after microstimulation upon learning (see the Perspective by Donato). Learning was associated with the emergence of a small population of neurons in layer 5 of the somatosensory cortex that increased bursting upon stimulation. This increase in bursting was accompanied by an increase in dendritic activity, and silencing the perirhinal cortex to layer 1 projection effectively disrupted learning and its physiological correlates. During learning, perirhinal inputs thus act as a gate for the enhancement of cortico-cortical inputs, which are necessary for stimulus detection and are strengthened during learning. Science, this issue p. eaaz3136; see also p. 1410 Perirhinal input, predominantly to sensory cortical layer 1, controls hippocampal-dependent associative learning in mice. INTRODUCTION Arguably one of the biggest mysteries in neuroscience is how the brain stores long-term memories. Since the 1950s, it has been well established that long-term memories reside in the neocortex but that their formation is dependent on the hippocampus and medial-temporal lobe structures. It is therefore remarkable that we still do not know what cellular mechanisms underlie long-term memory storage in the neocortex or exactly where they are located. RATIONALE The primary challenge for investigating the neural circuit underlying memory formation in the neocortex is the distributed nature of the resulting memory trace throughout the cortex. We therefore used a behavioral paradigm dependent on both the hippocampus and neocortex that enabled us to generate memory traces in a specific cortical location by training rodents to associate the direct electrical microstimulation of the cortex with a reward. This also allowed us to specifically examine the contribution of circuit elements in the defined anatomical location. Rodents learned to behaviorally report the microstimulation within only a few trials and improved over a 3-day period, during which we examined the evolution of learned neuronal responses in the stimulated area. We hypothesized that the influence of the hippocampus on memory formation in the neocortex occurs at the interface between these two structures. RESULTS We first confirmed that learning to associate microstimulation of the primary somatosensory cortex (S1) with a reward depends on hippocampal activity using suppression of action potentials (APs) with lidocaine in this brain area. Using retrograde and anterograde tracing methods, we found that the perirhinal cortex (the last station in the medial-temporal loop projecting to S1) predominantly targets layer 1 (L1), suggesting that important events relating to memory formation occur in neocortical L1. We tested this with targeted chemogenetic suppression of perirhinal input to L1 above the stimulated S1 region. Notably, this very specific and localized manipulation was sufficient to disrupt learning. The effect was learning-specific and had no influence in expert animals, which demonstrated that the perirhinal input did not alter the ability to perceive and behaviorally report the stimulus, per se. We found that the perirhinal cortex signaled information related to successful behavior during learning, gated the evolution of distinct firing, and enhanced burst responses in 11% of layer 5 (L5) pyramidal neurons in S1 (40% of neurons had reduced firing responses and 49% showed no change in firing). Apical dendritic excitability was correspondingly enhanced in a similar proportion of L5 pyramidal neurons. This suggested that the mechanism for memory formation had a dendritic origin. Consistent with this hypothesis, we found that both activation of γ-aminobutyric acid type B (GABAB) receptors—which disrupt apical dendritic calcium (Ca2+) activity—and activation of dendritic-targeting, somatostatin-positive interneurons impaired memory formation similarly to suppressing perirhinal input to L1. Finally, we found that after learning the microstimulation detection task, evoking a single burst of APs (but not the same number of low-frequency spikes) in a single L5 pyramidal neuron could trigger behavior. CONCLUSION We found that medial-temporal input to neocortical L1 gates the evolution of specific firing responses in subpopulations of L5 pyramidal neurons including up- and down-regulated firing patterns and an elevation in burstiness by means of a mechanism that is most likely related to apical dendritic activity. After learning, these neocortical responses become independent of the medial-temporal influence but continue to evoke behavior with bursts conveying higher saliency. We conclude that L1 is the locus for hippocampal-dependent associative learning in the neocortex, where memory engrams are established in subsets of pyramidal neurons by enhancing the sensitivity of tuft dendrites to contextual inputs and driving burst firing. Probing the influence of the medial-temporal lobe on memory formation. (A) The perirhinal cortex (PRh), part of the medial-temporal lobe (MTL) structures (blue box), targets L1 in S1. (B) We performed microstimulation (μStim) of L5 in the sensory cortex while chemogenetically suppressing the axonal projection to cortical L1 (red) from PRh (blue arrow). (C) Rodents learned to associate μStim with water reward. (D to F) Learning was suppressed by blocking MTL input [(D) and (E)] that otherwise evoked dendritic activity in L5 pyramidal neurons [(F), orange tuft], which allowed them to associate contextual input to L1 with the μStim. (G) More than 3 days of learning led to subpopulations of firing responses in L5 cells in S1 such that evoking a burst but not low-frequency spikes in single L5 cells retrieved learned behavior. Hippocampal output influences memory formation in the neocortex, but this process is poorly understood because the precise anatomical location and the underlying cellular mechanisms remain elusive. Here, we show that perirhinal input, predominantly to sensory cortical layer 1 (L1), controls hippocampal-dependent associative learning in rodents. This process was marked by the emergence of distinct firing responses in defined subpopulations of layer 5 (L5) pyramidal neurons whose tuft dendrites receive perirhinal inputs in L1. Learning correlated with burst firing and the enhancement of dendritic excitability, and it was suppressed by disruption of dendritic activity. Furthermore, bursts, but not regular spike trains, were sufficient to retrieve learned behavior. We conclude that hippocampal information arriving at L5 tuft dendrites in neocortical L1 mediates memory formation in the neocortex.

To establish and exploit novel biomarkers of demyelinating diseases requires a mechanistic understanding of axonal propagation. Here, we present a novel computational framework called the stochastic spike-diffuse-spike (SSDS) model for assessing the effects of demyelination on axonal transmission. It models transmission through nodal and internodal compartments with two types of operations: a stochastic integrate-and-fire operation captures nodal excitability and a linear filtering operation describes internodal propagation. The effects of demyelinated segments on the probability of transmission, transmission delay and spike time jitter are explored. We argue that demyelination induced impedance mismatch prevents propagation in most part when the action potential leaves a demyelinated region, not when it enters a demyelinated region. In addition, we model sodium channel remodeling as a homeostatic control of nodal excitability. We find that the effects of mild demyelination on transmission probability and delay can be largely counterbalanced by an increase in excitability at the nodes surrounding the demyelination. The spike timing jitter, however, reflects the level of demyelination whether excitability is fixed or is allowed to change in compensation. This jitter can accumulate over long axons and leads to a broadening of the compound action potential, linking microscopic defects to a mesoscopic observable. Our findings articulate why action potential jitter and compound action potential dispersion can serve as potential markers of weak and sporadic demyelination.

Spike-Diffuse-Spike Modelling of Axonal Propagation Links Demyelination to Compound Action Potential Dispersion

Thick-tufted pyramidal neurons of the neocortex receive distinct types of inputs impinging on different parts of their dendritic arborization. A popular view holds that inputs arriving on the distal dendrites modulate the firing rate arising from inputs onto the proximal dendrites by a multiplicative factor. Here, we propose an alternative view whereby a single neural ensemble combines the two input streams while preserving information specific to both through modulation of the burst probability. Using computational simulations constrained by experimental data, we show that this novel type of neural multiplexing can in principle represent fast input fluctuations in both input streams. We find that the representation of the dendritic input is in practice restricted by the size of the ensemble and the slow onset dynamics of dendritic spikes. Secondly, we find that a microcircuitry combining short-term facilitation, short-term depression and inhibition can decode somatic and dendritic information streams independently and serve to optimize encoding quality. Our results suggest a novel functional role of the stereotypical interconnection pattern of inhibitory cell types in the neocortex. Burst ensemble multiplexing, we suggest, is a general code used by the neural system to rapidly and flexibly combine two distinct streams of information.

Burst Ensemble Multiplexing: A Neural Code Connecting Dendritic Spikes with Microcircuits

Burst ensemble multiplexing: connecting dendritic spikes with cortical inhibition

Significance Understanding the neural code is to attribute proper meaning to temporal sequences of action potentials. We report a simple neural code based on distinguishing single spikes from spikes in close succession, commonly called “bursts.” By separating these two types of responses, we show that ensembles of neurons can communicate rapidly changing and graded information from two sources simultaneously and with minimal cross-talk. Second, we show that this multiplexing can optimize the information transferred per action potential when bursts are relatively rare. Finally, we show that neurons can demultiplex these two streams of information. We propose that this multiplexing may be particularly important in hierarchical communication where bottom–up and top–down information must be distinguished. Many cortical neurons combine the information ascending and descending the cortical hierarchy. In the classical view, this information is combined nonlinearly to give rise to a single firing-rate output, which collapses all input streams into one. We analyze the extent to which neurons can simultaneously represent multiple input streams by using a code that distinguishes spike timing patterns at the level of a neural ensemble. Using computational simulations constrained by experimental data, we show that cortical neurons are well suited to generate such multiplexing. Interestingly, this neural code maximizes information for short and sparse bursts, a regime consistent with in vivo recordings. Neurons can also demultiplex this information, using specific connectivity patterns. The anatomy of the adult mammalian cortex suggests that these connectivity patterns are used by the nervous system to maintain sparse bursting and optimal multiplexing. Contrary to firing-rate coding, our findings indicate that the physiology and anatomy of the cortex may be interpreted as optimizing the transmission of multiple independent signals to different targets.

Sparse bursts optimize information transmission in a multiplexed neural code

We study how noise in active dendrites affects information transmission. A mismatch of both noise and refractoriness between a dendritic compartment and a somatic compartment is shown to lead to an input-dependent exchange of leadership, where the dendrite entrains the soma for weak stimuli and the soma entrains the dendrite for strong stimuli. Using this simple mechanism, the noise in the dendritic compartment can boost weak signals without affecting the output of the neuron for strong stimuli. We show that these mechanisms give rise to a noise-induced increase of information transmission by neural populations.

Noise Gated by Dendrosomatic Interactions Increases Information Transmission

17 Information can be encoded in the temporal patterning of spikes. How the brain reads these 18 patterns is of general importance and represents one of the greatest challenges in neuroscience. 19 We addressed this issue in relation to temporal pattern recognition in the anuran auditory system. 20 Many species of anurans perform mating decisions based on the temporal structure of 21 advertisement calls. One important temporal feature is the number of sound pulses that occur 22 with a species-specific interpulse interval. Neurons representing this pulse count have been 23 recorded in the anuran inferior colliculus, but the mechanisms underlying their temporal 24 selectivity are incompletely understood. Here, we construct a parsimonious model that can 25 explain the key dynamical features of these cells with biologically plausible elements. We 26 demonstrate that interval counting arises naturally when combining interval-selective inhibition 27 with pulse-per-pulse excitation having both fastand slow-conductance synapses. Interval28 dependent inhibition is modeled here by a simple architecture based on known physiology of 29 afferent nuclei. Finally, we consider simple implementations of previously proposed mechanistic 30 explanations for these counting neurons and show that they do not account for all experimental 31 observations. Our results demonstrate that tens of millisecond-range temporal selectivities can 32 arise from simple connectivity motifs of inhibitory neurons, without recourse to internal clocks, 33 spike-frequency adaptation or appreciable short-term plasticity. 34

Full title: Counting on dis-inhibition: a circuit motif for interval counting and selectivity

Input-Driven Spiking in Fast-Spiking Cells Inhibition-Controlled Switch Between Intrinsic and Somatosensory Cortical Inhibitory Interneurons: An Integration of Broadband Conductance Input in Rat

Single-neuron models are useful not only for studying the emergent properties of neural circuits in large-scale simulations, but also for extracting and summarizing in a principled way the information contained in electrophysiological recordings. Here we demonstrate that, using a convex optimization procedure we previously introduced, a Generalized Integrate-and-Fire model can be accurately fitted with a limited amount of data. The model is capable of predicting both the spiking activity and the subthreshold dynamics of different cell types, and can be used for online characterization of neuronal properties. A protocol is proposed that, combined with emergent technologies for automatic patch-clamp recordings, permits automated, in vitro high-throughput characterization of single neurons.

Automated High-Throughput Characterization of Single Neurons by Means of Simplified Spiking Models

Channel Inactivation + Spider Mechanoreceptor Neurons: The Role of Na Simulation of Different Firing Patterns in Paired

Information can be encoded in the temporal patterning of spikes. How the brain reads these patterns is of general importance and represents one of the greatest challenges in neuroscience. We addressed this issue in relation to temporal pattern recognition in the anuran auditory system. Many species of anurans perform mating decisions based on the temporal structure of advertisement calls. One important temporal feature is the number of sound pulses that occur with a species-specific interpulse interval. Neurons representing this pulse count have been recorded in the anuran inferior colliculus, but the mechanisms underlying their temporal selectivity are incompletely understood. Here, we construct a parsimonious model that can explain the key dynamical features of these cells with biologically plausible elements. We demonstrate that interval counting arises naturally when combining interval-selective inhibition with pulse-per-pulse excitation having both fast- and slow-conductance synapses. Interval-dependent inhibition is modeled here by a simple architecture based on known physiology of afferent nuclei. Finally, we consider simple implementations of previously proposed mechanistic explanations for these counting neurons and show that they do not account for all experimental observations. Our results demonstrate that tens of millisecond-range temporal selectivities can arise from simple connectivity motifs of inhibitory neurons, without recourse to internal clocks, spike-frequency adaptation, or appreciable short-term plasticity.

Counting on dis-inhibition: a circuit motif for interval counting and selectivity in the anuran auditory system.

Voltage Recordings and Genetic Algorithms Constraining Compartmental Models Using Multiple

Neural coding strategies for extracting motion estimates from electrosensory contrast

A complete single-neuron model must correctly reproduce the firing of spikes and bursts. We present a study of a simplified model of deep pyramidal cells of the cortex with active dendrites. We hypothesized that we can model the soma and its apical dendrite with only two compartments, without significant loss in the accuracy of spike-timing predictions. The model is based on experimentally measurable impulse-response functions, which transfer the effect of current injected in one compartment to current reaching the other. Each compartment was modeled with a pair of non-linear differential equations and a small number of parameters that approximate the Hodgkin-and-Huxley equations. The predictive power of this model was tested on electrophysiological experiments where noisy current was injected in both the soma and the apical dendrite simultaneously. We conclude that a simple two-compartment model can predict spike times of pyramidal cells stimulated in the soma and dendrites simultaneously. Our results support that regenerating activity in the apical dendritic is required to properly account for the dynamics of layer 5 pyramidal cells under in-vivo-like conditions.

Spike-timing prediction in cortical neurons with active dendrites

Finite-sized populations of spiking neurons are fundamental to brain function. Here we present a theory of the dynamics of finite-sized populations of neurons, based on a quasi-renewal description of neurons with adaptation. We derive an integral equation with colored noise that governs the stochastic dynamics of the population activity in response to time-dependent stimulation and calculate the spectral density in the stationary state. The theory is applicable to fully as well as randomly connected networks, and to leaky integrate-and-fire as well as to generalized spiking neurons with adaptation on multiple time scales.

Dynamics of interacting finite-sized networks of spiking neurons with adaptation

Is it possible to predict the spike times of a neuron with millisecond precision? In the classical picture of rate coding (Adrian, 1928), single spikes do not play a role, and the question would have to be answered negatively. For rate coding in a singleneuron, the relevant quantity to encode a stimulus such as pressure onto a touch sensor in the skin (Adrian, 1928) or presence of a light bar in the receptive field of a visual neuron (Hubel and Wiesel, 1959) is the number of spikes a neuron emits in a short time window of, e.g., 100ms. The timing of the spikes is considered as irrelevant. However, over the last 20 years many researchers have shown that it is not only the temporally averaged firing rate that carries information about the stimulus, but also the exact timing of spikes. For example, spike timing has shown to be relevant to encode force amplitude and direction in touch sensors of the skin (Johansson and Birznieks, 2004) as well as the whole-field visual movements (Bialek et al., 1991) or object movement (Gollisch and Meister, 2008) in visual neurons. If spike timing is important, a whole series of questions arises: What is the precision of spike timing if the same stimulus is repeated several times? Do spikes always appear at the same time? What would be a sensible measure of spike timing precision and reliability? Can a neuron model match the spike timing precision of a real neuron? Does it matter which neuron or what stimulus we take? If so, what would be a useful stimulus? To answer these related questions, let us think of the following experimental protocol. An experimentalist injects a time-dependent input of, say, 20 second duration into a single neuron. The neuron responds with spikes. The experimentalist now repeats the same stimulus sequence several times. At each repetition, the neuron responds with a spike train that may or may not look similar to the previous one: some spikes appear at exactly the same time during the stimulus sequence, some are missing, some are shifted by a few millisecond or appear at a completely different time. The information derived from this type of experiment which dates back to Bryant and Segundo (1976) and has been popularized by Mainen and Sejnowski (1995) should be sufficient to answer questions regarding precision and reliability of spike timing.

A complete single-neuron model must correctly reproduce the firing of spikes and bursts. We present a study of a simplified model of deep pyramidal cells of the cortex with active dendrites. We hypothesized that we can model the soma and its apical tuft with only two compartments, without significant loss in the accuracy of spike-timing predictions. The model is based on experimentally measurable impulse-response functions, which transfer the effect of current injected in one compartment to current reaching the other. Each compartment was modeled with a pair of non-linear differential equations and a small number of parameters that approximate the Hodgkin-and-Huxley equations. The predictive power of this model was tested on electrophysiological experiments where noisy current was injected in both the soma and the apical dendrite simultaneously. We conclude that a simple two-compartment model can predict spike times of pyramidal cells stimulated in the soma and dendrites simultaneously. Our results support that regenerating activity in the dendritic tuft is required to properly account for the dynamics of layer 5 pyramidal cells under in-vivo-like conditions.

Temporal whitening by power-law adaptation in neocortical neurons

How do neuronal populations encode time-dependent stimuli in their population firing rate? To address this question, I consider the quasi-renewal equation and the event-based expansion, two theoretical approximations proposed recently, and test these against peri-stimulus time histograms from L2-3 pyramidal cells in vitro. Parameters are optimized by gradient descent to best match the firing rate output given the current input. The fitting method can estimate single-neuron parameters that are normally obtained either with intracellular recordings or with individual spike trains. I find that quasi-renewal theory predicts the adapting firing rate with good precision but not the event-based expansion. Quasi-renewal predictions are equal in quality with state-of-the-art spike timing prediction methods, and does so without resorting to the indiviual spike times or the membrane potential responses.

An Integral Equation Approach to the Dynamics of L2-3 Cortical Neurons

Finite-sized populations of spiking elements are fundamental to brain function but also are used in many areas of physics. Here we present a theory of the dynamics of finite-sized populations of spiking units, based on a quasirenewal description of neurons with adaptation. We derive an integral equation with colored noise that governs the stochastic dynamics of the population activity in response to time-dependent stimulation and calculate the spectral density in the asynchronous state. We show that systems of coupled populations with adaptation can generate a frequency band in which sensory information is preferentially encoded. The theory is applicable to fully as well as randomly connected networks and to leaky integrate-and-fire as well as to generalized spiking neurons with adaptation on multiple time scales.

Fluctuations and information filtering in coupled populations of spiking neurons with adaptation.

Temporal decorrelation by power-law adaptation in pyramidal neurons

Neural representations of a moving object’s distance and approach speed are essential for determining appropriate orienting responses, such as those observed in the localization behaviors of the weakly electric fish, Apteronotus leptorhynchus. We demonstrate that a power law form of spike rate adaptation transforms an electroreceptor afferent’s response to “looming” object motion, effectively parsing information about distance and approach speed into distinct measures of the firing rate. Neurons with dynamics characterized by fixed time scales are shown to confound estimates of object distance and speed. Conversely, power law adaptation modifies an electroreceptor afferent’s response according to the time scales present in the stimulus, generating a rate code for looming object distance that is invariant to speed and acceleration. Consequently, estimates of both object distance and approach speed can be uniquely determined from an electroreceptor afferent’s firing rate, a multiplexed neural code operating over the extended time scales associated with behaviorally relevant stimuli.

Speed-invariant encoding of looming object distance requires power law spike rate adaptation

Cortical information processing originates from the exchange of action potentials between many cell types. To capture the essence of these interactions, it is of critical importance to build mathematical models that reflect the characteristic features of spike generation in individual neurons. We propose a framework to automatically extract such features from current-clamp experiments, in particular the passive properties of a neuron (i.e., membrane time constant, reversal potential, and capacitance), the spike-triggered adaptation currents, as well as the dynamics of the action potential threshold. The stochastic model that results from our maximum likelihood approach accurately predicts the spike times, the subthreshold voltage, the firing patterns, and the type of frequency-current curve. Extracting the model parameters for three cortical cell types revealed that cell types show highly significant differences in the time course of the spike-triggered currents and moving threshold, that is, in their adaptation and refractory properties but not in their passive properties. In particular, GABAergic fast-spiking neurons mediate weak adaptation through spike-triggered currents only, whereas regular spiking excitatory neurons mediate adaptation with both moving threshold and spike-triggered currents. GABAergic nonfast-spiking neurons combine the two distinct adaptation mechanisms with reduced strength. Differences between cell types are large enough to enable automatic classification of neurons into three different classes. Parameter extraction is performed for individual neurons so that we find not only the mean parameter values for each neuron type but also the spread of parameters within a group of neurons, which will be useful for future large-scale computer simulations.

Parameter extraction and classification of three cortical neuron types reveals two distinct adaptation mechanisms.

The response of a neuron to a time-dependent stimulus, as measured in a Peri-Stimulus-Time-Histogram (PSTH), exhibits an intricate temporal structure that reflects potential temporal coding principles. Here we analyze the encoding and decoding of PSTHs for spiking neurons with arbitrary refractoriness and adaptation. As a modeling framework, we use the spike response model, also known as the generalized linear neuron model. Because of refractoriness, the effect of the most recent spike on the spiking probability a few milliseconds later is very strong. The influence of the last spike needs therefore to be described with high precision, while the rest of the neuronal spiking history merely introduces an average self-inhibition or adaptation that depends on the expected number of past spikes but not on the exact spike timings. Based on these insights, we derive a ‘quasi-renewal equation’ which is shown to yield an excellent description of the firing rate of adapting neurons. We explore the domain of validity of the quasi-renewal equation and compare it with other rate equations for populations of spiking neurons. The problem of decoding the stimulus from the population response (or PSTH) is addressed analogously. We find that for small levels of activity and weak adaptation, a simple accumulator of the past activity is sufficient to decode the original input, but when refractory effects become large decoding becomes a non-linear function of the past activity. The results presented here can be applied to the mean-field analysis of coupled neuron networks, but also to arbitrary point processes with negative self-interaction.

Coding and Decoding with Adapting Neurons: A Population Approach to the Peri-Stimulus Time Histogram

The Performance (and Limits) of Simple Neuron Models: Generalizations of the Leaky Integrate-and-Fire Model

How do neurons dynamically encode and treat information? Each neuron communicates with its distinctive language made of long silences intermitted by occasional spikes. The spikes are prompted by the pooled effect of a population of pre-synaptic neurons. To understand the operation made by single neurons is to create a quantitative description of their dynamics. The results presented in this thesis describe the necessary elements for a quantitative description of single neurons. Almost all chapters can be unified under the theme of adaptation. Neuronal adaptation plays an important role in the transduction of a given stimulation into a spike train. The work described here shows how adaptation is brought by every spike in a stereotypical fashion. The spike-triggered adaptation is then measured in three main types of cortical neurons. I analyze in detail how the different adaptation profiles can reproduce the diversity of firing patterns observed in real neurons. I also summarize the most recent results concerning the spike-time prediction in real neurons, resulting in a well-founded single-neuron model. This model is then analyzed to understand how populations can encode time-dependent signals and how time-dependent signals can be decoded from the activity of populations. Finally, two lines of investigation in progress are described, the first expands the study of spike-triggered adaptation on longer time scales and the second extends the quantitative neuron models to models with active dendrites.

Multiple measures have been developed to quantify the similarity between two spike trains. These measures have been used for the quantification of the mismatch between neuron models and experiments as well as for the classification of neuronal responses in neuroprosthetic devices and electrophysiological experiments. Frequently only a few spike trains are available in each class. We derive analytical expressions for the small-sample bias present when comparing estimators of the time-dependent firing intensity. We then exploit analogies between the comparison of firing intensities and previously used spike train metrics and show that improved spike train measures can be successfully used for fitting neuron models to experimental data, for comparisons of spike trains, and classification of spike train data. In classification tasks, the improved similarity measures can increase the recovered information. We demonstrate that when similarity measures are used for fitting mathematical models, all previous methods systematically underestimate the noise. Finally, we show a striking implication of this deterministic bias by reevaluating the results of the single-neuron prediction challenge.

Variability in single neuron models is typically implemented either by a stochastic Leaky-Integrate-and-Fire model or by a model of the Generalized Linear Model (GLM) family. We use analytical and numerical methods to relate state-of-the-art models from both schools of thought. First we find the analytical expressions relating the subthreshold voltage from the Adaptive Exponential Integrate-and-Fire model (AdEx) to the Spike-Response Model with escape noise (SRM as an example of a GLM). Then we calculate numerically the link-function that provides the firing probability given a deterministic membrane potential. We find a mathematical expression for this link-function and test the ability of the GLM to predict the firing probability of a neuron receiving complex stimulation. Comparing the prediction performance of various link-functions, we find that a GLM with an exponential link-function provides an excellent approximation to the Adaptive Exponential Integrate-and-Fire with colored-noise input. These results help to understand the relationship between the different approaches to stochastic neuron models.

From Stochastic Nonlinear Integrate-and-Fire to Generalized Linear Models

Automatic characterization of three cortical neuron types reveals two distinct adaptation mechanisms

A recent competition encouraged modelers to predict neuronal activity. Which neuron model performed the best? Opinions strongly diverge on what constitutes a good model of a neuron (1–3). Two lines of thought on this have coexisted for a long time: detailed biophysical models (of the style proposed in 1952 by the physiologists Alan Hodgkin and Andrew Huxley) that describe ion channels on the tree-like spatial structure of the neuronal cell (4), and simple “integrate-and-fire” models based on the much older insight that pulsatile electrical activity (known as an action potential or spike) is a threshold process. Electrophysiologists generally prefer the biophysical models, familiar with the notion of ion channels that open and close (and hence, alter neuronal activity) depending on environmental conditions. Theoreticians, by contrast, typically prefer simple neuron models with few parameters that are amenable to mathematical analysis. Earlier this year, following previous attempts at model comparison on a smaller scale (5), the International Neuroinformatics Coordinating Facility (INCF) launched an international competition (6) that allowed a quantitative comparison of neuron models.

Firing patterns in the adaptive exponential integrate-and-fire model

How well are single-cell properties reproduced by the present-day neuronal models? Recently, several labs have approached this question by assessing the quality of the models with respect to spike timing prediction or characteristic features of the voltage trace. So far, every modeler used his own preferred performance measure on his own data set. The ‘Quantitative Single-Neuron Modeling Competition’ offers a coherent framework to compare neuronal models with four different experiments on layer V pyramidal neurons of the somatosensory cortex under somatic and dendritic stimulation. Specific performance measures are used on these four experiments to quantify specific performances of neuronal models under somatic and dendritic stimulation, e. g.: spike timing, inter-spike intervals, or subthreshold waveform. Expert and novice modelers have been invited to submit their prediction of neuronal behavior in any or all of these four different experimental setups. Here we present the results of this competition. Along with submissions from other labs, we show the performance of a stochastic Poisson neuron model and the adaptive Exponential Integrate-and-Fire model. The results are valuable for network modelers interested in finding the best trade-off between biological relevance and simplicity.

A benchmark test for a quantitative assessment of simple neuron models

As large-scale, detailed network modeling projects are flourishing in the field of computational neuroscience, it is more and more important to design single neuron models that not only capture qualitative features of real neurons but are quantitatively accurate in silico representations of those. Recent years have seen substantial effort being put in the development of algorithms for the systematic evaluation and optimization of neuron models with respect to electrophysiological data. It is however difficult to compare these methods because of the lack of appropriate benchmark tests. Here, we describe one such effort of providing the community with a standardized set of tests to quantify the performances of single neuron models. Our effort takes the form of a yearly challenge similar to the ones which have been present in the machine learning community for some time. This paper gives an account of the first two challenges which took place in 2007 and 2008 and discusses future directions. The results of the competition suggest that best performance on data obtained from single or double electrode current or conductance injection is achieved by models that combine features of standard leaky integrate-and-fire models with a second variable reflecting adaptation, refractoriness, or a dynamic threshold. Suggested Reviewers: Response to Reviewers: Attached as a separate file. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Biological Cybernetics manuscript No. (will be inserted by the editor) Renaud Jolivet · Felix Schürmann · Thomas K. Berger · Richard Naud · Wulfram Gerstner · Arnd Roth The Quantitative Single-Neuron Modeling Competition Received: date / Revised: date Abstract As large-scale, detailed network modeling projects are flourishing in the field of computational neuroscience, it is more and more important to design single neuron models that not only capture qualitative features of real neurons but are quantitatively accurate in silico representations of those. Recent years have seen substantial effort being put in the development of algorithms for the systematic evaluation and optimization of neuron models with respect to electrophysiological data. It is however difficult to compare these methods because of the lack of appropriate benchmark tests. Here, we describe one such effort of providing the community with a standardized set of tests to quantify the performances of single neuron models. Our effort takes the form of a yearly challenge similar to the ones which have been present in the machine learning community for some time. This paper gives an account of the first two chal-As large-scale, detailed network modeling projects are flourishing in the field of computational neuroscience, it is more and more important to design single neuron models that not only capture qualitative features of real neurons but are quantitatively accurate in silico representations of those. Recent years have seen substantial effort being put in the development of algorithms for the systematic evaluation and optimization of neuron models with respect to electrophysiological data. It is however difficult to compare these methods because of the lack of appropriate benchmark tests. Here, we describe one such effort of providing the community with a standardized set of tests to quantify the performances of single neuron models. Our effort takes the form of a yearly challenge similar to the ones which have been present in the machine learning community for some time. This paper gives an account of the first two chalR. Jolivet Inst. Pharmacology and Toxicology, University of Zurich Tel.: +41-44-255-3632 E-mail: rjolivet@pharma.uzh.ch F. Schürmann Brain Mind Institute, EPFL Tel.: +41-21-693-9647 E-mail: felix.schuermann@epfl.ch T. K. Berger Brain Mind Institute, EPFL Tel.: +41-21-693-1673 E-mail: thomas.berger@epfl.ch R. Naud Brain Mind Institute, EPFL Tel.: +41-21-693-6635 E-mail: richard.naud@epfl.ch W. Gerstner Brain Mind Institute, EPFL Tel.: +41-21-693-6713 E-mail: wulfram.gerstner@epfl.ch A. Roth Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK Tel.: +44-20-7679-6794 E-mail: arnd.roth@ucl.ac.uk lenges which took place in 2007 and 2008 and discusses future directions. The results of the competition suggest that best performance on data obtained from single or double electrode current or conductance injection is achieved by models that combine features of standard leaky integrate-and-fire models with a second variable reflecting adaptation, refractoriness, or a dynamic threshold.

Number : BICY-D-08-00052 R 1 Title : The Quantitative Single-Neuron Modeling Competition

Particle tracking is an optical microscopy based technique that can probe very small changes in the dynamics of microscopic objects. However, the information required to make use of this powerful tool is widely scattered in the scientific literature. The purpose of my thesis is to develop a comprehensive approach for single-particle tracking applied to the lateral diffusion of synaptic receptors. This thesis will describe the proper use of particle tracking including the description of how particle tracking algorithms are able to extract trajectories of particles from a set of consecutive digital time series images. Second, several methods to extract coefficients of motion from the trajectories will also be described, followed by a statistical analysis to determine the precision of the measured coefficients. Finally the application of particle tracking to measure the motion of synaptic receptors on the dendritic membrane of neurons will be presented. Overall, this document is a useful, up-to-date and concise thesis for biophysicists and molecular biologists who are interested in using particle tracking to measure the transport properties of membrane receptors using from time series microscopy images.

Particle tracking with application to the trafficking of synaptic receptors

The ability of simple mathematical models to predict the activity of single neurons is important for computational neuroscience. In neurons, stimulated by a time-dependent current or conductance, we want to predict precisely the timing of spikes and the sub-threshold voltage. During the last years several models have been tested on this type of data but never compared with the same protocol. One of the major outcome is that, from a certain degree of complexity, all are very efficient and gave statistically indistinguishable results. We studied a class of integrate-and-fire models (IF), with each member of the class implementing a selection of possible improvements: exponential voltage non-linearity1, spike-triggered adaptation current2, spike-triggered change in conductance, moving threshold3, sub-threshold voltage-dependent currents4. Each refinement adds a new term to the equations of the IF model. This IF family is extendable and adaptable to different neuron types and is able to deal with complex neural activities (i.e. adaptation, facilitation, bursting, relative refractoriness, ...). To systematically explore the effects of a given term of the model a new fitting procedure based on linear regression of voltage change5 is used. This method is fast, robust and allows the extraction of all the models parameters from a few seconds recordings of fluctuating injected current and membrane potential with hundreds spikes without any prior knowledge. To investigate the effect of our modifications, we used as training data three different Hodgkin-Huxley-like models, and two experimental recordings of fast spiking and regular spiking cells and then evaluate each IF model on a given test set. We observe that it is possible to fit a model that can reproduce the activity of neurons with high reliability (i.e. almost 100 % of the spike time and less than 1 mV of sub-threshold voltage difference). Using this framework one can classify IF models in terms of complexity and performance and evaluate the importance of each term for different stimulation paradigms.

Blind Recognition Algorithm for Scrambled Channel Encoder Based on the Features of Signal Matrix and Layered Neural Network

The Large Sky Area Multi-Object Fiber Spectroscopic Telescope (LAMOST) has produced massive medium-resolution spectra. Data mining for special and rare stars in massive LAMOST spectra is of great significance. Feature extraction plays an important role in the process of automatic spectra classification. The proper classification network can extract most of the common spectral features with minimum noise and individual features. Such a network has better generalization capabilities and can extract sufficient features for classification. A variety of classification networks of one dimension and two dimensions are both designed and implemented systematically in this paper to verify whether spectra is easier to deal with in a 2D situation. The experimental results show that the fully connected neural network cannot extract enough features. Although convolutional neural network (CNN) with a strong feature extraction capability can quickly achieve satisfactory results on the training set, there is a tendency for overfitting. Signal-to-noise ratios also have effects on the network. To investigate the problems above, various techniques are tested and the enhanced multi-scale coded convolutional neural network (EMCCNN) is proposed and implemented, which can perform spectral denoising and feature extraction at different scales in a more efficient manner. In a specified search, eight known and one possible cataclysmic variables (CVs) in LAMOST MRS are identified by EMCCNN including four CVs, one dwarf nova and three novae. The result supplements the spectra of CVs. Furthermore, these spectra are the first medium-resolution spectra of CVs. The EMCCNN model can be easily extended to search for other rare stellar spectra.

Automated Classification of Massive Spectra Based on Enhanced Multi-Scale Coded Convolutional Neural Network

Method for Direct Temperature Extraction of Brillouin Scattering Spectra Based on Radial Basis Function Neural Network

To solve problems appear in image processing with artificial neural network hardware, such as complex input of image data, difficulty in extracting image eigenvectors, knowledge management in chaos etc., a system for image recognition and knowledge management based on the KN1A artificial neural network module was designed and developed. In this system, images can be input and pretreated easily, and operation for extracting any area of images by calling KN1A hardware can be implemented conveniently. In the training process of neural networks, convergence properties can be observed in real time. Users can be freed from complex data processing and are allowed to focus on learning and parameter setting of neural networks to make the network performs better. It is proved that the system is reliability and accuracy with the license plate recognition applications.

Proceeding of the 11th World Congress on Intelligent Control and Automation

System design and implementation for image recognition and knowledge management based on neural network hardware

In order to improve the predictive accuracy of RBF neural network in function approximation, an improved RBF neural network was proposed. In this new model, human experience was added to the last layer as the activation function. The model of improved algorithm was built in Simulink, and was used to approximate a 2-dimensional function. The simulation result showed that the improved network performed well in function approximation. At last, a neural network system which was based on the improved algorithm was used in license plate recognition. In this system, the first two layers of the network were implemented in hardware, and the last layer was achieved in software. Experimental results show that the predictive accuracy of network is improved after joining human experience to the output layer.

2012 IEEE 2nd International Conference on Cloud Computing and Intelligence Systems

A license plate recognition system based on neural networks was designed and developed. The system used a neural-network chip to recognize license plates. The chip combined video image processing module with neural network module by using equalized image processing algorithm and network classification algorithm. A set of interface circuit was developed for implementing license-plate-number recognition. Experiment results show the system can guarantee a very low error rate at an acceptable recognition time.

2011 IEEE International Conference on Information and Automation

In these days, human face identification is the safe technique of computer which has been developing quickly within the scope of global. In this paper, we described the basic techniques of image processing, such as different edge detection techniques, harmony variation, and the method of image and face recognition. We focused on human interface system, which was the first step to structure the target system. In order to evaluate this new system, we did the experiment and identified the position of the human face, eyes, mouth and eyebrows. Finally, by testing, our experimental results show that the interface of the recognition system is easy to manipulate, the performance is stable and with good implementation function.

2010 International Conference on Intelligent Computation Technology and Automation

Development of a Novel Portable Robotic Human Face Recognition System

In the engineering realization of objective measurement of MRTD which is based on artificial neural network (viz.subjective judgment of eyes is replaced by intelligent objective judgment of computer in the detecting of infrared image),contrast of tripe and contrast of mean are educed as the eigenvector of training and identification.The rationality of eigenvector as the choice is discussed and the algorithm that can be realized easily by computer is offered.The experiment result illuminates that the defining of eigenvector is reasonable and feasible.

The Extraction of Character of Four Bacilliform Target Image in the Objective Measurement of MRTD

Unpaired image-to-image translation (UNIT) aims to map images between two visual domains without paired training data. However, given a UNIT model trained on certain domains, it is difficult for current methods to incorporate new domains because they often need to train the full model on both existing and new domains. To address this problem, we propose a new domain-scalable UNIT method, termed as latent space anchoring, which can be efficiently extended to new visual domains and does not need to fine-tune encoders and decoders of existing domains. Our method anchors images of different domains to the same latent space of frozen GANs by learning lightweight encoder and regressor models to reconstruct single-domain images. In the inference phase, the learned encoders and decoders of different domains can be arbitrarily combined to translate images between any two domains without fine-tuning. Experiments on various datasets show that the proposed method achieves superior performance on both standard and domain-scalable UNIT tasks in comparison with the state-of-the-art methods.

Domain-Scalable Unpaired Image Translation Via Latent Space Anchoring.

The size of image stacks in connectomics studies now reaches the terabyte and often petabyte scales with a great diversity of appearance across brain regions and samples. However, manual annotation of neural structures, e.g., synapses, is time-consuming, which leads to limited training data often smaller than 0.001\% of the test data in size. Domain adaptation and generalization approaches were proposed to address similar issues for natural images, which were less evaluated on connectomics data due to a lack of out-of-domain benchmarks.

An Out-of-Domain Synapse Detection Challenge for Microwasp Brain Connectomes

3D instance segmentation for unlabeled imaging modalities is a challenging but essential task as collecting expert annotation can be expensive and time-consuming. Existing works segment a new modality by either deploying pre-trained models optimized on diverse training data or sequentially conducting image translation and segmentation with two relatively independent networks. In this work, we propose a novel Cyclic Segmentation Generative Adversarial Network (CySGAN) that conducts image translation and instance segmentation simultaneously using a unified network with weight sharing. Since the image translation layer can be removed at inference time, our proposed model does not introduce additional computational cost upon a standard segmentation model. For optimizing CySGAN, besides the CycleGAN losses for image translation and supervised losses for the annotated source domain, we also utilize self-supervised and segmentation-based adversarial objectives to enhance the model performance by leveraging unlabeled target domain images. We benchmark our approach on the task of 3D neuronal nuclei segmentation with annotated electron microscopy (EM) images and unlabeled expansion microscopy (ExM) data. The proposed CySGAN outperforms pre-trained generalist models, feature-level domain adaptation models, and the baselines that conduct image translation and segmentation sequentially. Our implementation and the newly collected, densely annotated ExM zebrafish brain nuclei dataset, named NucExM, are publicly available at https://connectomics-bazaar.github.io/proj/CySGAN/index.html.

3D Domain Adaptive Instance Segmentation Via Cyclic Segmentation GANs.

Mapping neuronal networks that underlie behavior has become a central focus in neuroscience. While serial section electron microscopy (ssEM) can reveal the fine structure of neuronal networks (connectomics), it does not provide the molecular information that helps identify cell types or their functional properties. Volumetric correlated light and electron microscopy (vCLEM) combines ssEM and volumetric fluorescence microscopy to incorporate molecular labeling into ssEM datasets. We developed an approach that uses small fluorescent single-chain variable fragment (scFv) immuno-probes to perform multiplexed detergent-free immuno-labeling and serial electron microscopy on the same samples. We generated eight such fluorescent scFvs that targeted useful markers for brain studies (GFP, GFAP, calbindin, parvalbumin, Kv1.2, VGluT1, PSD-95, and neuropeptide Y). To test the vCLEM approach, six different fluorescent probes were imaged in a sample of the cortex of a cerebellar lobule (Crus 1), using confocal microscopy with linear unmixing, followed by ssEM imaging of the same sample. The results show excellent ultrastructure and superimposition of the different fluorescence channels. We document a poorly described cell type in the cerebellum, two types of mossy fiber terminals, and the subcellular localization of ion channels. Because scFvs can be derived from existing monoclonal antibodies, hundreds of such probes can be generated to enable a wide range of connectomic studies.

Multiplexed volumetric CLEM enabled by antibody derivatives provides new insights into the cytology of the mouse cerebellar cortex

The wiring and connectivity of neurons form a structural basis for the function of the nervous system. Advances in volume electron microscopy (EM) and image segmentation have enabled mapping of circuit diagrams (connectomics) within local regions of the mouse brain. However, applying volume EM over the whole brain is not currently feasible due to technological challenges. As a result, comprehensive maps of long-range connections between brain regions are lacking. Recently, we demonstrated that X-ray holographic nanotomography (XNH) can provide high-resolution images of brain tissue at a much larger scale than EM. In particular, XNH is wellsuited to resolve large, myelinated axon tracts (white matter) that make up the bulk of long-range connections (projections) and are critical for inter-region communication. Thus, XNH provides an imaging solution for brain-wide projectomics. However, because XNH data is typically collected at lower resolutions and larger fields-of-view than EM, accurate segmentation of XNH images remains an important challenge that we present here. In this task, we provide volumetric XNH images of cortical white matter axons from the mouse brain along with ground truth annotations for axon trajectories. Manual voxel-wise annotation of ground truth is a time-consuming bottleneck for training segmentation networks. On the other hand, skeleton-based ground truth is much faster to annotate, and sufficient to determine connectivity. Therefore, we encourage participants to develop methods to leverage skeleton-based training. To this end, we provide two types of ground-truth annotations: a small volume of voxel-wise annotations and a larger volume with skeleton-based annotations. Entries will be evaluated on how accurately the submitted segmentations agree with the ground-truth skeleton annotations.

The XPRESS Challenge: Xray Projectomic Reconstruction - Extracting Segmentation with Skeletons

Immersion Fixation and Staining of Multicubic Millimeter Volumes for Electron Microscopy–Based Connectomics of Human Brain Biopsies

This study investigates the transformative potential of Large Language Models (LLMs), such as OpenAI ChatGPT, in medical imaging. With the aid of public data, these models, which possess remarkable language understanding and generation capabilities, are augmenting the interpretive skills of radiologists, enhancing patient-physician communication, and streamlining clinical workflows. The paper introduces an analytic framework for presenting the complex interactions between LLMs and the broader ecosystem of medical imaging stakeholders, including businesses, insurance entities, governments, research institutions, and hospitals (nicknamed BIGR-H). Through detailed analyses, illustrative use cases, and discussions on the broader implications and future directions, this perspective seeks to raise discussion in strategic planning and decision-making in the era of AI-enabled healthcare.

The Impact of ChatGPT and LLMs on Medical Imaging Stakeholders: Perspectives and Use Cases

Instance segmentation for unlabeled imaging modalities is a challenging but essential task as collecting expert annotation can be expensive and time-consuming. Existing works segment a new modality by either deploying a pre-trained model optimized on diverse training data or conducting domain translation and image segmentation as two independent steps. In this work, we propose a novel Cyclic Segmentation Generative Adversarial Network (CySGAN) that conducts image translation and instance segmentation jointly using a unified framework. Besides the CycleGAN losses for image translation and supervised losses for the annotated source domain, we introduce additional self-supervised and segmentation-based adversarial objectives to improve the model performance by leveraging unlabeled target domain images. We benchmark our approach on the task of 3D neuronal nuclei segmentation with annotated electron microscopy (EM) images and unlabeled expansion microscopy (ExM) data. Our CySGAN outperforms both pretrained generalist models and the baselines that sequentially conduct image translation and segmentation. Our implementation and the newly collected, densely annotated ExM nuclei dataset, named NucExM, are available at https://connectomics-bazaar.github.io/proj/CySGAN/index.html.

Instance Segmentation of Unlabeled Modalities via Cyclic Segmentation GAN

Genopathomic profiling identifies signatures for immunotherapy response of lung adenocarcinoma via confounder-aware representation learning

Genopathomic Profiling Identifies Signatures for Immunotherapy Response of Lung Cancer Via Confounder-Aware Representation Learning

Recent advances in high-resolution connectomics provide researchers access to accurate reconstructions of vast neuronal circuits and brain networks for the first time. Neuroscientists anticipate analyzing these networks to gain a better understanding of information processing in the brain. In particular, scientists are interested in identifying specific network motifs, i.e., repeating subgraphs of the larger brain network that are believed to be neuronal building blocks. To analyze these motifs, it is crucial to review instances of a motif in the brain network and then map the graph structure to the detailed 3D reconstructions of the involved neurons and synapses. We present Vimo, an interactive visual approach to analyze neuronal motifs and motif chains in large brain networks. Experts can sketch network motifs intuitively in a visual interface and specify structural properties of the involved neurons and synapses to query large connectomics datasets. Motif instances (MIs) can be explored in high-resolution 3D renderings of the involved neurons and synapses. To reduce visual clutter and simplify the analysis of MIs, we designed a continuous focus&context metaphor inspired by continuous visual abstractions [MAAB∗18] that allows the user to transition from the highly-detailed rendering of the anatomical structure to views that emphasize the underlying motif structure and synaptic connectivity. Furthermore, Vimo supports the identification of motif chains where a motif is used repeatedly to form a longer synaptic chain. We evaluate Vimo in a user study with seven domain experts and an in-depth case study on motifs in the central complex (CX) of the fruit fly brain. CCS Concepts Human-Centered Computing → Visual motif analysis, Focus&Context, Scientific visualization, Neuroscience;

Development and Validation of a Pathomic Biomarker for Immunotherapy Response via Confounder-Aware Representation Learning

Existing deep learning real denoising methods require a large amount of noisy-clean image pairs for supervision. Nonetheless, capturing a real noisy-clean dataset is an unacceptable expensive and cumbersome procedure. To alleviate this problem, this work investigates how to generate realistic noisy images. Firstly, we formulate a simple yet reasonable noise model that treats each real noisy pixel as a random variable. This model splits the noisy image generation problem into two sub-problems: image domain alignment and noise domain alignment. Subsequently, we propose a novel framework, namely Pixel-level Noise-aware Generative Adversarial Network (PNGAN). PNGAN employs a pre-trained real denoiser to map the fake and real noisy images into a nearly noise-free solution space to perform image domain alignment. Simultaneously, PNGAN establishes a pixel-level adversarial training to conduct noise domain alignment. Additionally, for better noise fitting, we present an efficient architecture Simple Multi-scale Network (SMNet) as the generator. Qualitative validation shows that noise generated by PNGAN is highly similar to real noise in terms of intensity and distribution. Quantitative experiments demonstrate that a series of denoisers trained with the generated noisy images achieve state-of-the-art (SOTA) results on four real denoising benchmarks. Part of codes, pre-trained models, and results are available at https://github.com/caiyuanhao1998/PNGAN for comparisons.

Learning to Generate Realistic Noisy Images via Pixel-level Noise-aware Adversarial Training

14 We introduce MedMNIST v2 , a large-scale MNIST-like dataset collection of standardized biomedical images, including 12 datasets for 2D and 6 datasets for 3D. All images are pre-processed into a small size of 28 × 28 (2D) or 28 × 28 × 28 (3D) with the corresponding classiﬁcation labels so that no background knowledge is required for users. Covering primary data modalities in biomedical images, MedMNIST v2 is designed to perform classiﬁcation on lightweight 2D and 3D images with various dataset scales (from 100 to 100,000) and diverse tasks (binary/multi-class, ordinal regression, and multi-label). The resulting dataset, consisting of 708,069 2D images and 9,998 3D images in total, could support numerous research / educational purposes in biomedical image analysis, computer vision, and machine learning. We benchmark several baseline methods on MedMNIST v2, including 2D / 3D neural networks and open-source / commercial AutoML tools. The data and code are publicly available at https://medmnist.com/ .

MedMNIST v2 - A large-scale lightweight benchmark 1 for 2D and 3D biomedical image classiﬁcation 2

The mechanism of existing style transfer algorithms is by minimizing a hybrid loss function to push the generated image toward high similarities in both content and style. However, this type of approach cannot guarantee visual fidelity, i.e., the generated artworks should be indistinguishable from real ones. In this paper, we devise a new style transfer framework called QuantArt for high visual-fidelity stylization. QuantArt pushes the latent representation of the generated artwork toward the centroids of the real artwork distribution with vector quantization. By fusing the quantized and continuous latent representations, QuantArt allows flexible control over the generated artworks in terms of content preservation, style similarity, and visual fidelity. Experiments on various style transfer settings show that our QuantArt framework achieves significantly higher visual fidelity compared with the existing style transfer methods.

QuantArt: Quantizing Image Style Transfer Towards High Visual Fidelity

Automatic rib labeling and anatomical centerline extraction are common prerequisites for various clinical applications. Prior studies either use in-house datasets that are inaccessible to communities, or focus on rib segmentation that neglects the clinical significance of rib labeling. To address these issues, we extend our prior dataset (RibSeg) on the binary rib segmentation task to a comprehensive benchmark, named RibSeg v2, with 660 CT scans (15,466 individual ribs in total) and annotations manually inspected by experts for rib labeling and anatomical centerline extraction. Based on the RibSeg v2, we develop a pipeline including deep learning-based methods for rib labeling, and a skeletonization-based method for centerline extraction. To improve computational efficiency, we propose a sparse point cloud representation of CT scans and compare it with standard dense voxel grids. Moreover, we design and analyze evaluation metrics to address the key challenges of each task. Our dataset, code, and model are available online to facilitate open research at https://github.com/M3DV/RibSeg

RibSeg v2: A Large-scale Benchmark for Rib Labeling and Anatomical Centerline Extraction

Many video understanding tasks require analyzing multishot videos, but existing datasets for video object segmentation (VOS) only consider single-shot videos. To address this challenge, we collected a new dataset-YouMVaS-of 200 popular YouTube videos spanning ten genres, where each video is on average five minutes long and with 75 shots. We selected recurring actors and annotated 431K segmentation masks at a frame rate of six, exceeding previous datasets in average video duration, object variation, and narrative structure complexity. We incorporated good practices of model architecture design, memory management, and multi-shot tracking into an existing video segmentation method to build competitive baseline methods. Through error analysis, we found that these baselines still fail to cope with cross-shot appearance variation on our YouMVOS dataset. Thus, our dataset poses new challenges in multi-shot segmentation towards better video analysis. Data, code, and pre-trained models are available at https://donglaiw.github.io/proj/youMVOS

2022 IEEE/CVF Conference on Computer Vision and Pattern Recognition (CVPR)

YouMVOS: An Actor-centric Multi-shot Video Object Segmentation Dataset

Complex wiring between neurons underlies the information-processing network enabling all brain functions, including cognition and memory. For understanding how the network is structured, processes information, and changes over time, comprehensive visualization of the architecture of living brain tissue with its cellular and molecular components would open up major opportunities. However, electron microscopy (EM) provides nanometre-scale resolution required for full in-silico reconstruction1–6, yet is limited to fixed specimens and static representations. Light microscopy allows live observation, with super-resolution approaches7–15 facilitating nanoscale visualization, but comprehensive 3D-reconstruction of living brain tissue has been hindered by tissue photo-burden, photobleaching, insufficient 3D-resolution, and inadequate signal-to-noise ratio (SNR). Here we demonstrate saturated reconstruction of living brain tissue. We developed an integrated imaging and analysis technology, adapting stimulated emission depletion (STED) microscopy7,16 in extracellularly labelled tissue17 for high SNR and isotropic resolution. Centrally, a two-stage deep-learning approach leveraged previously obtained information on sample structure to drastically reduce photo-burden and enable automated volumetric reconstruction down to synapse level. Live reconstruction provides unbiased analysis of tissue architecture across time in relation to functional activity and targeted activation, and contextual understanding of molecular labelling. This adoptable technology will facilitate novel insights into the dynamic functional architecture of living brain tissue.

Evaluation practices for image super-resolution (SR) use a single-value metric, the PSNR or SSIM, to determine model performance. This provides little insight into the source of errors and model behavior. Therefore, it is beneficial to move beyond the conventional approach and reconceptualize evaluation with interpretability as our main priority. We focus on a thorough error analysis from a variety of perspectives. Our key contribution is to leverage a texture classifier, which enables us to assign patches with semantic labels, to identify the source of SR errors both globally and locally. We then use this to determine (a) the semantic alignment of SR datasets, (b) how SR models perform on each label, (c) to what extent high-resolution (HR) and SR patches semantically correspond, and more. Through these different angles, we are able to highlight potential pitfalls and blindspots. Our overall investigation highlights numerous unexpected insights. We hope this work serves as an initial step for debugging blackbox SR networks.

Image super-resolution (SR) is a fast-moving field with novel architectures attracting the spotlight. However, most SR models were optimized with dated training strategies. In this work, we revisit the popular RCAN model and examine the effect of different training options in SR. Surprisingly (or perhaps as expected), we show that RCAN can outperform or match nearly all the CNN-based SR architectures published after RCAN on standard benchmarks with a proper training strategy and minimal architecture change. Besides, although RCAN is a very large SR architecture with more than four hundred convolutional layers, we draw a notable conclusion that underfitting is still the main problem restricting the model capability instead of overfitting. We observe supportive evidence that increasing training iterations clearly improves the model performance while applying regularization techniques generally degrades the predictions. We denote our simply revised RCAN as RCAN-it and recommend practitioners to use it as baselines for future research. Code is publicly available at https://github.com/zudi-lin/rcan-it.

As connectomic datasets exceed hundreds of terabytes in size, accurate and efficient skeleton generation of the label volumes has evolved into a critical component of the computation pipeline used for analysis, evaluation, visualization, and error correction. We propose a novel topological thinning strategy that uses biological-constraints to produce accurate centerlines from segmented neuronal volumes while still maintaining biologically relevant properties. Current methods are either agnostic to the underlying biology, have non-linear running times as a function of the number of input voxels, or both. First, we eliminate from the input segmentation biologically-infeasible bubbles, pockets of voxels incorrectly labeled within a neuron, to improve segmentation accuracy, allow for more accurate centerlines, and increase processing speed. Next, a Convolutional Neural Network (CNN) detects cell bodies from the input segmentation, allowing us to anchor our skeletons to the somata. Lastly, a synapse-aware topological thinning approach produces expressive skeletons for each neuron with a nearly one-to-one correspondence between endpoints and synapses. We simultaneously estimate geometric properties of neurite width and geodesic distance between synapse and cell body, improving accuracy by 47.5% and 62.8% over baseline methods. We separate the skeletonization process into a series of computation steps, leveraging data-parallel strategies to increase throughput significantly. We demonstrate our results on over 1250 neurons and neuron fragments from three different species, processing over one million voxels per second per CPU with linear scalability.

Scalable Biologically-Aware Skeleton Generation for Connectomic Volumes

We present a recurrent network for 3D reconstruction of neurons that sequentially generates binary masks for every object in an image with spatio-temporal consistency. Our network models consistency in two parts: (i) local, which allows exploring non-occluding and temporally-adjacent object relationships with bi-directional recurrence. (ii) non-local, which allows exploring long-range object relationships in the temporal domain with skip connections. Our proposed network is end-to-end trainable from an input image to a sequence of object masks, and, compared to methods relying on object boundaries, its output does not require post-processing. We evaluate our method on three benchmarks for neuron segmentation and achieved state-of-the-art performance on the SNEMI3D [1] challenge.

2021 IEEE 18th International Symposium on Biomedical Imaging (ISBI)

Consistent Recurrent Neural Networks For 3d Neuron Segmentation.

AxonEM Dataset: 3D Axon Instance Segmentation of Brain Cortical Regions

UnMICST: Deep learning with real augmentation for robust segmentation of highly multiplexed images of human tissues

Developmental Stage Classification of Embryos Using Two-Stream Neural Network with Linear-Chain Conditional Random Field

MedMNIST v2 - A large-scale lightweight benchmark for 2D and 3D biomedical image classification

Deep convolutional neural networks (CNNs) have pushed forward the frontier of super-resolution (SR) research. However, current CNN models exhibit a major flaw: they are biased towards learning low-frequency signals. This bias becomes more problematic for the image SR task which targets reconstructing all fine details and image textures. To tackle this challenge, we propose to improve the learning of high-frequency features both locally and globally and introduce two novel architectural units to existing SR models. Specifically, we propose a dynamic high-pass filtering (HPF) module that locally applies adaptive filter weights for each spatial location and channel group to preserve high-frequency signals. We also propose a matrix multi-spectral channel attention (MMCA) module that predicts the attention map of features decomposed in the frequency domain. This module operates in a global context to adaptively recalibrate feature responses at different frequencies. Extensive qualitative and quantitative results demonstrate that our proposed modules achieve better accuracy and visual improvements against state-of-the-art methods on several benchmark datasets.

Dynamic High-Pass Filtering and Multi-Spectral Attention for Image Super-Resolution

We present PyTorch Connectomics (PyTC), an open-source deep-learning framework for the semantic and instance segmentation of volumetric microscopy images, built upon PyTorch. We demonstrate the effectiveness of PyTC in the field of connectomics, which aims to segment and reconstruct neurons, synapses, and other organelles like mitochondria at nanometer resolution for understanding neuronal communication, metabolism, and development in animal brains. PyTC is a scalable and flexible toolbox that tackles datasets at different scales and supports multi-task and semi-supervised learning to better exploit expensive expert annotations and the vast amount of unlabeled data during training. Those functionalities can be easily realized in PyTC by changing the configuration options without coding and adapted to other 2D and 3D segmentation tasks for different tissues and imaging modalities. Quantitatively, our framework achieves the best performance in the CREMI challenge for synaptic cleft segmentation (outperforms existing best result by relatively 6.1$\%$) and competitive performance on mitochondria and neuronal nuclei segmentation. Code and tutorials are publicly available at https://connectomics.readthedocs.io.

PyTorch Connectomics: A Scalable and Flexible Segmentation Framework for EM Connectomics

Deep convolutional neural networks (CNNs) are achieving great successes for image super-resolution (SR), where global context is crucial for accurate restoration. However, the basic convolutional layer in CNNs is designed to extract local patterns, lacking the ability to model global context. With global context information, lots of efforts have been devoted to augmenting SR networks, especially by global feature interaction methods. These works incorporate the global context into local feature representation. However, recent advances in neuroscience show that it is necessary for the neurons to dynamically modulate their functions according to context, which is neglected in most CNN based SR methods. Motivated by those observations and analyses, we propose context reasoning attention network (CRAN) to modulate the convolution kernel according to the global context adaptively. Specifically, we extract global context descriptors, which are further enhanced with semantic reasoning. Channel and spatial interactions are then introduced to generate context reasoning attention mask, which is applied to modify the convolution kernel adaptively. Such a modulated convolution layer is utilized as basic component to build the blocks and networks. Extensive experiments on benchmark datasets with multiple degradation models show that CRAN obtains superior results and favorable trade-off between performance and model complexity.

We acquired a rapidly preserved human surgical sample from the temporal lobe of the cerebral cortex. We stained a 1 mm3 volume with heavy metals, embedded it in resin, cut more than 5000 slices at ∼30 nm and imaged these sections using a high-speed multibeam scanning electron microscope. We used computational methods to render the three-dimensional structure containing 57,216 cells, hundreds of millions of neurites and 133.7 million synaptic connections. The 1.4 petabyte electron microscopy volume, the segmented cells, cell parts, blood vessels, myelin, inhibitory and excitatory synapses, and 104 manually proofread cells are available to peruse online. Many interesting and unusual features were evident in this dataset. Glia outnumbered neurons 2:1 and oligodendrocytes were the most common cell type in the volume. Excitatory spiny neurons comprised 69% of the neuronal population, and excitatory synapses also were in the majority (76%). The synaptic drive onto spiny neurons was biased more strongly toward excitation (70%) than was the case for inhibitory interneurons (48%). Despite incompleteness of the automated segmentation caused by split and merge errors, we could automatically generate (and then validate) connections between most of the excitatory and inhibitory neuron types both within and between layers. In studying these neurons we found that deep layer excitatory cell types can be classified into new subsets, based on structural and connectivity differences, and that chandelier interneurons not only innervate excitatory neuron initial segments as previously described, but also each other’s initial segments. Furthermore, among the thousands of weak connections established on each neuron, there exist rarer highly powerful axonal inputs that establish multi-synaptic contacts (up to ∼20 synapses) with target neurons. Our analysis indicates that these strong inputs are specific, and allow small numbers of axons to have an outsized role in the activity of some of their postsynaptic partners.

A connectomic study of a petascale fragment of human cerebral cortex

NucMM Dataset: 3D Neuronal Nuclei Instance Segmentation at Sub-Cubic Millimeter Scale

Image segmentation is a fundamental vision task and still remains a crucial step for many applications. In this paper, we propose a fast image segmentation method based on a novel super boundary-to-pixel direction (super-BPD) and a customized segmentation algorithm with super-BPD. Precisely, we define BPD on each pixel as a two-dimensional unit vector pointing from its nearest boundary to the pixel. In the BPD, nearby pixels from different regions have opposite directions departing from each other, and nearby pixels in the same region have directions pointing to the other or each other (i.e., around medial points). We make use of such property to partition image into super-BPDs, which are novel informative superpixels with robust direction similarity for fast grouping into segmentation regions. Extensive experimental results on BSDS500 and Pascal Context demonstrate the accuracy and efficiency of the proposed super-BPD in segmenting images. Specifically, we achieve comparable or superior performance with MCG while running at ~25fps vs 0.07fps. Super-BPD also exhibits a noteworthy transferability to unseen scenes.

Super-BPD: Super Boundary-to-Pixel Direction for Fast Image Segmentation

Nonlinear waves can be harnessed to make flexible structures crawl. The unique properties of nonlinear waves have been recently exploited to enable a wide range of applications, including impact mitigation, asymmetric transmission, switching, and focusing. Here, we demonstrate that the propagation of nonlinear waves can be as well harnessed to make flexible structures crawl. By combining experimental and theoretical methods, we show that such pulse-driven locomotion reaches a maximum efficiency when the initiated pulses are solitons and that our simple machine can move on a wide range of surfaces and even steer. Our study expands the range of possible applications of nonlinear waves and demonstrates that they offer a new platform to make flexible machines to move.

Computer vision - ECCV ... : ... European Conference on Computer Vision : proceedings. European Conference on Computer Vision

Two Stream Active Query Suggestion for Active Learning in Connectomics

Automated Measurements of Key Morphological Features of Human Embryos for IVF

Blastomere instance segmentation is important for analyzing embryos' abnormality. To measure the accurate shapes and sizes of blastomeres, their amodal segmentation is necessary. Amodal instance segmentation aims to recover the complete silhouette of an object even when the object is not fully visible. For each detected object, previous methods directly regress the target mask from input features. However, images of an object under different amounts of occlusion should have the same amodal mask output, which makes it harder to train the regression model. To alleviate the problem, we propose to classify input features into intermediate shape codes and recover complete object shapes from them. First, we pre-train the Vector Quantized Variational Autoencoder (VQ-VAE) model to learn these discrete shape codes from ground truth amodal masks. Then, we incorporate the VQ-VAE model into the amodal instance segmentation pipeline with an additional refinement module. We also detect an occlusion map to integrate occlusion information with a backbone feature. As such, our network faithfully detects bounding boxes of amodal objects. On an internal embryo cell image benchmark, the proposed method outperforms previous state-of-the-art methods. To show generalizability, we show segmentation results on the public KINS natural image benchmark. To examine the learned shape codes and model design choices, we perform ablation studies on a synthetic dataset of simple overlaid shapes. Our method would enable accurate measurement of blastomeres in in vitro fertilization (IVF) clinics, which potentially can increase IVF success rate.

Learning Vector Quantized Shape Code for Amodal Blastomere Instance Segmentation

MitoEM Dataset: Large-Scale 3D Mitochondria Instance Segmentation from EM Images

Ecological data is collected and shared at an increasingly rapid pace, but it is often shared in inconsistent and untraceable processed forms. Images of wood contain a wealth of information such as colours and textures but are most commonly reduced to ring-width measurements before they can be shared in various common file formats. Archiving digital images of wood samples in libraries, that have been developed for ecological analysis and are publicly available, remains the exception. We developed the Wood Image Analysis and Dataset (WIAD) an open-source application including a web-interface to integrate basic visual analysis of wood samples, such as increment cores, thin sections or x-ray films, basic data processing, and archiving of the images and derived data to facilitate transparency and reproducibility in studies using visual characteristics of wood. WIAD provides user-friendly tools to manipulate images of wood samples, mark and measure wood characteristics such as growth increments, density fluctuations, early- and latewood widths, and fire scars, and to visualise, process, and archive images, metadata, and the derived data. WIAD constitutes a step towards the reproducible automation of tree-ring analysis, while establishing an open-source foundation to create improved community developed repositories which would enable novel ecological studies harnessing the wealth of existing visual data.

The Wood Image Analysis and Dataset (WIAD): open-access visual analysis tools to advance the ecological data revolution

Interest is growing rapidly in using deep learning to classify biomedical images, and interpreting these deep-learned models is necessary for life-critical decisions and scientific discovery. Effective interpretation techniques accelerate biomarker discovery and provide new insights into the etiology, diagnosis, and treatment of disease. Most interpretation techniques aim to discover spatially-salient regions within images, but few techniques consider imagery with multiple channels of information. For instance, highly multiplexed tumor and tissue images have 30-100 channels and require interpretation methods that work across many channels to provide deep molecular insights. We propose a novel channel embedding method that extracts features from each channel. We then use these features to train a classifier for prediction. Using this channel embedding, we apply an interpretation method to rank the most discriminative channels. To validate our approach, we conduct an ablation study on a synthetic dataset. Moreover, we demonstrate that our method aligns with biological findings on highly multiplexed images of breast cancer cells while outperforming baseline pipelines.

Channel Embedding for Informative Protein Identification from Highly Multiplexed Images

One of the essential tasks in connectomics is the morphology analysis of neurons and organelles like mitochondria to shed light on their biological properties. However, these biological objects often have tangled parts or complex branching patterns, which make it hard to abstract, categorize, and manipulate their morphology. In this paper, we develop a novel topological nomenclature system to name these objects like the appellation for chemical compounds to promote neuroscience analysis based on their skeletal structures. We first convert the volumetric representation into the topology-preserving reduced graph to untangle the objects. Next, we develop nomenclature rules for pyramidal neurons and mitochondria from the reduced graph and finally learn the feature embedding for shape manipulation. In ablation studies, we quantitatively show that graphs generated by our proposed method align with the perception of experts. On 3D shape retrieval and decomposition tasks, we qualitatively demonstrate that the encoded topological nomenclature features achieve better results than state-of-the-art shape descriptors. To advance neuroscience, we will release a 3D segmentation dataset of mitochondria and pyramidal neurons reconstructed from a 100μm cube electron microscopy volume with their reduced graph and topological nomenclature annotations. Code is publicly available at https://github.com/donglaiw/ibexHelper.

A Topological Nomenclature for 3D Shape Analysis in Connectomics

Most current state-of-the-art connectome reconstruction pipelines have two major steps: initial pixel-based segmentation with affinity prediction and watershed transform, and refined segmentation by merging over-segmented regions. These methods rely only on local context and are typically agnostic to the underlying biology. Since a few merge errors can lead to several incorrectly merged neuronal processes, these algorithms are currently tuned towards over-segmentation producing an overburden of costly proofreading. We propose a third step for connectomics reconstruction pipelines to refine an over-segmentation using both local and global context with an emphasis on adhering to the underlying biology. We first extract a graph from an input segmentation where nodes correspond to segment labels and edges indicate potential split errors in the over-segmentation. In order to increase throughput and allow for large-scale reconstruction, we employ biologically inspired geometric constraints based on neuron morphology to reduce the number of nodes and edges. Next, two neural networks learn these neuronal shapes to further aid the graph construction process. Lastly, we reformulate the region merging problem as a graph partitioning one to leverage global context. We demonstrate the performance of our approach on four real-world connectomics datasets with an average variation of information improvement of 21.3%.

Biologically-Constrained Graphs for Global Connectomics Reconstruction

Traditional two-step agglomeration strategies tend to create very small segments at locations where the affinities are noisy, usually at very thin locations. In particular, the waterz agglomeration strategy tends to create many small segments (over 85% of segments are smaller than 0.01 μm). Many of these small segments are completely contained within a single z slice. These singletons often occur on dendritic spines and other thin locations for neuronal processes. Figure 1 shows an over-segmented dendrite with two enlarged spines each containing several singletons each. To reduce the number of singletons, we first identify all segments that lie entirely in one z slice. We then superimpose these singleton segments onto the neighboring slices and merge the singleton with any other segments that have an Intersection over Union score above 0.30. This threshold reduces a large number of the singletons while introducing very few merge errors.

Biologically-Constrained Graphs for Global Connectomics Reconstruction Supplementary Material

Detecting Synapse Location and Connectivity by Signed Proximity Estimation and Pruning with Deep Nets

For video and volumetric data understanding, 3D convolution layers are widely used in deep learning, however, at the cost of increasing computation and training time. Recent works seek to replace the 3D convolution layer with convolution blocks, e.g. structured combinations of 2D and 1D convolution layers. In this paper, we propose a novel convolution block, Parallel Separable 3D Convolution (PmSCn), which applies m parallel streams of n 2D and one 1D convolution layers along different dimensions. We first mathematically justify the need of parallel streams (Pm) to replace a single 3D convolution layer through tensor decomposition. Then we jointly replace consecutive 3D convolution layers, common in modern network architectures, with the multiple 2D convolution layers (Cn). Lastly, we empirically show that PmSCn is applicable to different backbone architectures, such as ResNet, DenseNet, and UNet, for different applications, such as video action recognition, MRI brain segmentation, and electron microscopy segmentation. In all three applications, we replace the 3D convolution layers in state-of-the art models with PmSCn and achieve around 14% improvement in test performance and 40% reduction in model size and on average.

Parallel Separable 3D Convolution for Video and Volumetric Data Understanding

We seek to understand the arrow of time in videos - what makes videos look like they are playing forwards or backwards? Can we visualize the cues? Can the arrow of time be a supervisory signal useful for activity analysis? To this end, we build three large-scale video datasets and apply a learning-based approach to these tasks. To learn the arrow of time efficiently and reliably, we design a ConvNet suitable for extended temporal footprints and for class activation visualization, and study the effect of artificial cues, such as cinematographic conventions, on learning. Our trained model achieves state-of-the-art performance on large-scale real-world video datasets. Through cluster analysis and localization of important regions for the prediction, we examine learned visual cues that are consistent among many samples and show when and where they occur. Lastly, we use the trained ConvNet for two applications: self-supervision for action recognition, and video forensics - determining whether Hollywood film clips have been deliberately reversed in time, often used as special effects.

2018 IEEE/CVF Conference on Computer Vision and Pattern Recognition

The web contains a treasure trove of design data, with many web pages being the product of careful thought about layout, font, and color scheme. Not only does the current web document current design trends, historical snapshots of the web are a lens into past fashions. The Internet Archive cite{internetarchive} has captured snapshots of the public Internet each year going back to 1996. In this paper, we present a curated dataset of 21 years of web design, scraped from the Internet Archive. We report initial analysis of design trends apparent in this data, and we demonstrate how the data can be modeled with deep neural networks to enable novel design applications, such as predicting the apparent year of a web design. The novelty of our work is two-fold: (1) mining the long-term temporal evolution of designs on the Internet, and (2) using deep neural networks as a tool for discovering design elements, which can complement the hand-curated features so far used in data-driven design mining.

Living in a constantly changing world, we cannot
help but notice the temporal regularities of visual changes around
us. These changes can be irreversible governed by physical laws,
such as glass bottles broken into pieces, or influenced by design
trends, such as web pages adopting templates with larger background
images. In this dissertation, we build computational models to
discover and apply the knowledge of the physics for arrow of time,
and the design trends for web pages from image sequences. In the
first part of the thesis, I train models to learn the visual cues
that are indicative of the arrow of time from large real world
video datasets. In the second part of the thesis, I investigate the
evolution of visual cues and layout in web page design through
screenshots over time. The knowledge of these visual temporal
structures are not only of scientific interest by themselves, but
also of practical uses demonstrated in this thesis.

Discovering physics and design trends from visual temporal structures

Significance Humans have difficulty seeing small motions with amplitudes below a threshold. Although there are optical techniques to visualize small static physical features (e.g., microscopes), visualization of small dynamic motions is extremely difficult. Here, we introduce a visualization tool, the motion microscope, that makes it possible to see and understand important biological and physical modes of motion. The motion microscope amplifies motions in a captured video sequence by rerendering small motions to make them large enough to see and quantifies those motions for analysis. Amplification of these tiny motions involves careful noise analysis to avoid the amplification of spurious signals. In the representative examples presented in this study, the visualizations reveal important motions that are invisible to the naked eye. Although the human visual system is remarkable at perceiving and interpreting motions, it has limited sensitivity, and we cannot see motions that are smaller than some threshold. Although difficult to visualize, tiny motions below this threshold are important and can reveal physical mechanisms, or be precursors to large motions in the case of mechanical failure. Here, we present a “motion microscope,” a computational tool that quantifies tiny motions in videos and then visualizes them by producing a new video in which the motions are made large enough to see. Three scientific visualizations are shown, spanning macroscopic to nanoscopic length scales. They are the resonant vibrations of a bridge demonstrating simultaneous spatial and temporal modal analysis, micrometer vibrations of a metamaterial demonstrating wave propagation through an elastic matrix with embedded resonating units, and nanometer motions of an extracellular tissue found in the inner ear demonstrating a mechanism of frequency separation in hearing. In these instances, the motion microscope uncovers hidden dynamics over a variety of length scales, leading to the discovery of previously unknown phenomena.

Structures and objects are often supposed to have idealized geometries such as straight lines or circles. Although not always visible to the naked eye, in reality, these objects deviate from their idealized models. Our goal is to reveal and visualize such subtle geometric deviations, which can contain useful, surprising information about our world. Our framework, termed Deviation Magnification, takes a still image as input, fits parametric models to objects of interest, computes the geometric deviations, and renders an output image in which the departures from ideal geometries are exaggerated. We demonstrate the correctness and usefulness of our method through quantitative evaluation on a synthetic dataset and by application to challenging natural images.

Convolutional Neural Network (CNN) has been successful in image recognition tasks, and recent works shed lights on how CNN separates different classes with the learned inter-class knowledge through visualization. In this work, we instead visualize the intra-class knowledge inside CNN to better understand how an object class is represented in the fully-connected layers. 
To invert the intra-class knowledge into more interpretable images, we propose a non-parametric patch prior upon previous CNN visualization models. With it, we show how different "styles" of templates for an object class are organized by CNN in terms of location and content, and represented in a hierarchical and ensemble way. Moreover, such intra-class knowledge can be used in many interesting applications, e.g. style-based image retrieval and style-based object completion.

Data-driven techniques can reliably build semantic correspondence among images. In this paper, we present a new regularization model for stereo or flow through transferring the shape information of the disparity or flow from semantically matched patches in the training database. Compared to previous regularization models based on image appearance alone, we can better resolve local ambiguity of the disparity or flow by considering the semantic information without explicit object modeling. We incorporate this data-driven regularization model into a standard Markov Random Field (MRF) model, inferred with a gradient descent algorithm and learned with a discriminative learning approach. Compared to prior state-of-the-art methods, our full model achieves comparable or better results on the KITTI stereo and flow datasets, and improves results on the Sintel Flow dataset under an online estimation setting.

We explore whether we can observe Time's Arrow in a temporal sequence - is it possible to tell whether a video is running forwards or backwards? We investigate this somewhat philosophical question using computer vision and machine learning techniques. We explore three methods by which we might detect Time's Arrow in video sequences, based on distinct ways in which motion in video sequences might be asymmetric in time. We demonstrate good video forwards/backwards classification results on a selection of YouTube video clips, and on natively-captured sequences (with no temporally-dependent video compression), and examine what motions the models have learned that help discriminate forwards from backwards time.

We propose a new random field (RF) model, smoothness-transfer random field (ST-RF) model, for image modeling. In the objective function of RF models, smoothness energy is defined with compatibility function to capture the relationship between neighboring local regions, while data energy for the evidence from local regions. Usually, the smoothness energy is constructed in terms of a fixed set of filters or basis which can be learned from training examples and steered to local structures in test examples. ST-RF, on the other hand, takes the data-driven approach to nonparametrically model the compatibility function for smoothness energy. The pipeline for our ST-RF model is as follows: first for each training example, we build a RF model with "ground truth smoothness energy", where the compatibility function is constructed from ground truth value. Then, for each test example, we use data-driven method to find its correspondence with training examples. Lastly, we construct the smoothness energy of ST-RF for each test example by transferring the compatibility function from matched region. After construction, we applies traditonal RF inference and learning algorithms to obtain the final estimation. We demonstrate that with transferred ground truth smoothness, random field can achieve state-of-the-art results in stereo matching and image denoising on standard benchmark dataset. Acknowledgments This thesis is not possible without the support, guidance and love from many people around me. I would like to especially thank my thesis advisor Prof. William T. Freeman. Bill has led me during my master thesis with his deep insights and unrelenting patience. I would also like to thank my former joint advisor Dr. John Fisher III for his limitless ideas and general enthusiasm in my research. I'm grateful to both Bill and John for their generous support in the past two years. I want to thank my mentor and collaborator Dr. Ce Liu, who helped me closely on this master thesis project from engineering skills to result presentation. More importantly , I am thankful to have such a loving person to guide me in life. I am grateful to Dr. Dahua Lin and Jason Chang for their guidance during the collaboration on my previous projects. I am also privileged to share office with Hyun We have shared so much conversation and laughter altogether. To the rest of my friends at MIT, thank you for your support and the happy memories we have shared. This thesis is impossible without my parents love and …

We develop a generative probabilistic model for temporally consistent super pixels in video sequences. In contrast to supermodel methods, object parts in different frames are tracked by the same temporal super pixel. We explicitly model flow between frames with a bilateral Gaussian process and use this information to propagate super pixels in an online fashion. We consider four novel metrics to quantify performance of a temporal super pixel representation and demonstrate superior performance when compared to supermodel methods.

In this project, we implement two Parallel Tiled Linear Algebra Algorithms in Julia, Cholesky and QR decomposition. We follow the algorithm description in [1] and use “dlsym” and “ccall” functions in Julia to load the OpenBLAS dynamic library [2] and call BLAS kernels. From this foundation, we are able to implement serial and parallel tiled linear algebra algorithms in Julia. For parallel implementation, spawned tasks could be dynamically scheduled based on their dependencies to the returned references of previous tasks.

Motivation: RNA secondary structure plays an important role in the function of many RNAs, and structural features are often key to their interaction with other cellular components. Thus, there has been considerable interest in the prediction of secondary structures for RNA families. In this article, we present a new global structural alignment algorithm, RNAG, to predict consensus secondary structures for unaligned sequences. It uses a blocked Gibbs sampling algorithm, which has a theoretical advantage in convergence time. This algorithm iteratively samples from the conditional probability distributions P(Structure | Alignment) and P(Alignment | Structure). Not surprisingly, there is considerable uncertainly in the high-dimensional space of this difficult problem, which has so far received limited attention in this field. We show how the samples drawn from this algorithm can be used to more fully characterize the posterior space and to assess the uncertainty of predictions. Results: Our analysis of three publically available datasets showed a substantial improvement in RNA structure prediction by RNAG over extant prediction methods. Additionally, our analysis of 17 RNA families showed that the RNAG sampled structures were generally compact around their ensemble centroids, and at least 11 families had at least two well-separated clusters of predicted structures. In general, the distance between a reference structure and our predicted structure was large relative to the variation among structures within an ensemble. Availability: The Perl implementation of the RNAG algorithm and the data necessary to reproduce the results described in Sections 3.1 and 3.2 are available at http://ccmbweb.ccv.brown.edu/rnag.html Contact: charles_lawrence@brown.edu Supplementary information: Supplementary data are available at Bioinformatics online.

RNAG: a new Gibbs sampler for predicting RNA secondary structure for unaligned sequences

International benchmarking competitions have become fundamental for the comparative performance assessment of image analysis methods. However, little attention has been given to investigating what can be learnt from these competitions. Do they really generate scientific progress? What are common and successful participation strategies? What makes a solution superior to a competing method? To address this gap in the literature, we performed a multi-center study with all 80 competitions that were conducted in the scope of IEEE ISBI 2021 and MICCAI 2021. Statistical analyses performed based on comprehensive descriptions of the submitted algorithms linked to their rank as well as the underlying participation strategies revealed common characteristics of winning solutions. These typically include the use of multi-task learning (63%) and/or multi-stage pipelines (61%), and a focus on augmentation (100%), image preprocessing (97%), data curation (79%), and postprocessing (66%). The"typical"lead of a winning team is a computer scientist with a doctoral degree, five years of experience in biomedical image analysis, and four years of experience in deep learning. Two core general development strategies stood out for highly-ranked teams: the reflection of the metrics in the method design and the focus on analyzing and handling failure cases. According to the organizers, 43% of the winning algorithms exceeded the state of the art but only 11% completely solved the respective domain problem. The insights of our study could help researchers (1) improve algorithm development strategies when approaching new problems, and (2) focus on open research questions revealed by this work.

A comprehensive approach involving both environmental and individual strategies offers opportunities to strengthen school-based interventions for childhood obesity.

To evaluate a theory-based comprehensive intervention implemented within primary schools for childhood obesity in China.

METHODS
A 1-year, cluster randomized controlled trial was conducted in twelve primary schools (7-11 years old) in Beijing, China. Environmental and individual factors were improved in the intervention group (6 schools, 930 children) to promote knowledge and behaviors related to energy balance. The control group (6 schools, 959 children) did not receive any intervention. The primary outcome was body mass index (BMI) and its Z-score at 12 months. Generalized linear mixed models were used controlling for the cluster effect of school.

RESULTS
No significant differences were found between groups on BMI (0.07 kg/m2 [95% confidence interval (CI) -0.16 to 0.31, p = 0.54]) and its Z-score (0.02 [95% CI: -0.08 to 0.11, p = 0.73]) at 12 months. Self-reported knowledge, daily consumption of sugar-sweetened beverage, and frequency of moderate to vigorous physical activity improved at 12 months.

The intervention did not mitigate excess weight gain, but did improve children's knowledge and several behaviors related to energy balance.

A School-Based Comprehensive Intervention for Childhood Obesity in China: A Cluster Randomized Controlled Trial.

Background Numerous school-based interventions for childhood obesity have been emerging in mainland China in recent decades, but little is known about the effectiveness of such interventions. This study aims to assess the effectiveness of school-based interventions for childhood obesity conducted in mainland China. Methods A systematic search was undertaken in eight databases to identify both randomized and non-randomized controlled trials from January 1990 to December 2015 examining the effectiveness of school-based obesity interventions. A random effects meta-analysis was conducted assessing the impact of included interventions on (body mass index) BMI. The quality of each included studies were assessed using Effective Public Health Practice Project Quality Assessment Tool. A P value <0.05 (two-sided) was considered statistically significant. Result Of the seventy-six included studies, we found physical activity and health education were the two most common components of interventions. More treatment studies were effective compared with prevention studies (85.0% vs. 58.3%). Comprehensive interventions involving physical activity and health education appeared more effective than the physical activity only interventions in both obesity treatment and prevention studies. The meta-analyses showed comprehensive interventions involving physical activity and health education had larger effect on the change of BMI than physical activity only interventions (treatment studies: -1.80 kg/m2 (95% CI: -2.15,-1.44) vs. -0.91 kg/m2 (95% CI: -1.15,-0.67); prevention studies: -0.19 kg/m2 (95% CI: -0.27, -0.11) vs. +0.05 kg/m2 (95% CI: -0.04, +0.15)). Conclusions Comprehensive school-based interventions may assist in tackling the rising prevalence of childhood obesity in mainland China.

Systematic review and meta-analysis of school-based obesity interventions in mainland China

Does local ambient temperature impact children’s blood pressure? A Chinese National Survey

OBJECTIVE
To explore the relations among screen-based sedentary behaviors (SSB), family factors and body mass index (BMI) of children, and to study how family factors have effect on BMI through influencing SSB.

METHODS
A total of 1,846 students aged 7-11 years from 12 primary schools in one district of Beijing were included. Their body weight and height were measured to calculate the BMI. The time of SSB and family factors were investigated by using questionnaires. The time of SSB was the total time of watching TV and videos, playing computer games and iPad each day during the past 7 days recalled by children. The family factors included the parents' education, occupation, the parents'time of SSB, whether the parents told their child the harm of SSB, the parents'time limit for the children's SSB. The parents'education and occupation were used for calculating the family socioeconomic score.

RESULTS
The median time of SSB for children was 1 hour/day, and the interquartile range was 1 hour/day. The BMI of the children with the parents' time limit for the children's SSB less than 120 min/day were smaller than the children with the parents'time limit not less than 120 min/day, in both the boys (1.63 kg/m2, P<0.001) and the girls (0.85 kg/m2, P=0.004). The family socioeconomic score, the parents'SSB time, whether the parents told their children the harm of SSB were not related to the children's BMI . The mediation effects of SSB time for children on the association between the parents'time limit for the children's SSB and BMI were -0.222 kg/m2 (95%CI:-0.432, -0.095) for boys and -0.187 kg/m2 (95%CI: -0.507, -0.049) for girls, which accounted for 13.67% of the total effects for boys and 22.11% for girls.

The parents' time limit for the children's SSB has effect on their BMI through influencing their SSB time. Parents' supervision on the behaviors of children produces larger benefit for BMI than health education conveyed by parents. Therefore, parents' participation in supervising the behaviors of children are indispensable for preventing and controlling childhood obesity.

[Study on the relations among the screen-based sedentary behaviors, family factors and body mass index of children].

Objective To explore the dietary status of primary school students in Beijing Sijiqing education district.Methods A total of 1436 students aged 7- 13 years from 8 primary schools in Sijiqing education district of Haidian district in Beijing were selected.A 3-day dietary recall questionnaire was conducted.Results The daily intake of energy of the boys and girls aged 11-13 were 87.6%,88.8% of the recommended volume and daily intake of protein of girls aged 11-13 was 87.2% of recommended volume,which were a little less than the recommended volume.Other students' daily intake of energy and protein nearly reached the recommended volume.For sources of energy,the proportion of carbohydrate was 40.8% which was less than the recommended volume,while that of fat was 45.6% and more than the recommended volume.The daily intake of Fe and Vitamin E were more than the recommended volume while Ca,Zn,vitamin A,and vitamin C were 38.8%-61.3%,67.6%-90.0%,51.1%-92.5%,10.2%-18.5%,which were all less than the recommended volume.In general,the proportions of energy from breakfast,lunch and dinner were 26.2%,34.8%,29.8%,which were consistent with the recommended volume.Conclusion The dietary pattern is unreasonable and intakes of nutrients are out off balance among students.Therefore,schools should strengthen health education of students and ensure the quality of school lunch in Sijiqing Education District.In addition,schools should contact with the parents to improve dietary nutrition of children at home in order to promote children' s health.

Study on the dietary status of primary school students in Beijing Sijiqing Education District

With the development of cross-fertilisation in various disciplines, flexible wearable sensing technologies have emerged, bringing together many disciplines, such as biomedicine, materials science, control science, and communication technology. Over the past few years, the development of multiple types of flexible wearable devices that are widely used for the detection of human physiological signals has proven that flexible wearable devices have strong biocompatibility and a great potential for further development. These include electronic skin patches, soft robots, bio-batteries, and personalised medical devices. In this review, we present an updated overview of emerging flexible wearable sensor devices for biomedical applications and a comprehensive summary of the research progress and potential of flexible sensors. First, we describe the selection and fabrication of flexible materials and their excellent electrochemical properties. We evaluate the mechanisms by which these sensor devices work, and then we categorise and compare the unique advantages of a variety of sensor devices from the perspective of in vitro and in vivo sensing, as well as some exciting applications in the human body. Finally, we summarise the opportunities and challenges in the field of flexible wearable devices.

Review of Flexible Wearable Sensor Devices for Biomedical Application

Author response for "The Wood Image Analysis and Dataset (WIAD): open‐access visual analysis tools to advance the ecological data revolution"

Text-Based Person Searching (TBPS) aims to identify the images of pedestrian targets from a large-scale gallery with given textual caption. For cross-modal TBPS task, it is critical to obtain well-distributed representation in the common embedding space to reduce the inter-modal gap. Furthermore, it is also essential to learn detailed image-text correspondence efficiently to discriminate similar targets and enable fine-grained target search. To address these challenges, we present a simple yet effective method that calibrates cross-modal features from these two perspectives. Our method consists of two novel losses to provide fine-grained cross-modal features. The Sew calibration loss takes the quality of textual captions as guidance and aligns features between image and text modalities. On the other hand, the Masking Caption Modeling (MCM) loss leverages a masked captions prediction task to establish detailed and generic relationships between textual and visual parts. The proposed method is cost-effective and can easily retrieve specific persons with textual captions. The architecture has only a dual-encoder without multi-level branches or extra interaction modules, making a high-speed inference. Our method achieves top results on three popular benchmarks with 73.81%, 74.25% and 57.35% Rank1 accuracy on the CUHK-PEDES, ICFG-PEDES, and RSTPReID, respectively. We hope our scalable method will serve as a solid baseline and help ease future research in TBPS. The code will be publicly available.

RGB color is a basic visual feature. Here we use machine learning and visual evoked potential (VEP) of electroencephalogram (EEG) data to investigate the decoding features of the time courses and space location that extract it, and whether they depend on a common brain cortex channel. We show that RGB color information can be decoded from EEG data and, with the task-irrelevant paradigm, features can be decoded across fast changes in VEP stimuli. These results are consistent with the theory of both event-related potential (ERP) and P300 mechanisms. The latency on time course is shorter and more temporally precise for RGB color stimuli than P300, a result that does not depend on a task-relevant paradigm, suggesting that RGB color is an updating signal that separates visual events. Meanwhile, distribution features are evident for the brain cortex of EEG signal, providing a space correlate of RGB color in classification accuracy and channel location. Finally, space decoding of RGB color depends on the channel classification accuracy and location obtained through training and testing EEG data. The result is consistent with channel power value distribution discharged by both VEP and electrophysiological stimuli mechanisms.

Decoding of the neural representation of the visual RGB color model

The automatic detection of abnormal events in surveillance videos with weak supervision has been formulated as a multiple instance learning task, which aims to localize the clips containing abnormal events temporally with the video-level labels. However, most existing methods rely on the features extracted by the pre-trained action recognition models, which are not discriminative enough for video anomaly detection. In this work, we propose a spatial-temporal attention mechanism to learn inter- and intra-correlations of video clips, and the boosted features are encouraged to be task-specific via the mutual cosine embedding loss. Experimental results on standard benchmarks demonstrate the effectiveness of the spatial-temporal attention, and our method achieves superior performance to the state-of-the-art methods.

Learning Task-Specific Representation for Video Anomaly Detection with Spatial-Temporal Attention

Reconstructing sources location of visual color cortex by the task-irrelevant visual stimuli through machine learning decoding

The complementarity of multimodal signal is essential for video anomaly detection. However, existing methods either lack exploration to multimodal data or ignore the implicit alignment of multimodal features. In our work, we address this problem using a novel fusion method and propose a Multimodal Supervise-Attention enhanced Fusion (MSAF) framework under weak supervision. Our framework can be divided into two parts: 1) the multimodal labels refinement part refines video-level ground truth into pseudo clip-level labels for subsequent training, 2) the multimodal supervise-attention fusion network enhances features via implicitly aligning different information, then fusing them effectively to predict anomaly scores with the help of refined labels. We validate our framework on four challenging datasets: ShanghaiTech, UCF-Crime, LAD, and XD-Violence. Extensive experiments on the benchmarks demonstrate the effectiveness of our framework, which achieves comparable results on several benchmarks and outperforms current state-of-the-art methods on the XD-Violence audiovisual multimodal dataset.

MSAF: Multimodal Supervise-Attention Enhanced Fusion for Video Anomaly Detection

 With the rapid development of brain-computer interfaces (BCIs), human visual decoding, one of the important research directions of BCIs, has attracted a substantial amount of attention. However, most visual decoding studies have focused on graphic and image decoding. In this paper, we first demonstrate the possibility of building a new kind of task-irrelevant, simple and fast-stimulus BCI-based experimental paradigm that relies on visual evoked potentials (VEPs) during colour observation. Additionally, the features of visual colour information were found through reliable real-time decoding. We selected 9 subjects who did not have colour blindness to participate in our tests. These subjects were asked to observe red, green, and blue screens in turn with an interstimulus interval of 1 second. The machine learning results showed that the visual colour classification accuracy had a maximum of 93.73%. The latency evoked by visual colour stimuli was within the P300 range, i.e., 176.8 milliseconds for the red screen, 206.5 milliseconds for the green screen, and 225.3 milliseconds for the blue screen. The experimental results hereby show that the VEPs can be used for reliable colour real-time decoding.

Decoding Human Visual Colour EEG Information Using Machine Learning and Visual Evoked Potentials

participants and only 50% of the participants performed ensembling based on multiple identical models (61%) or heterogeneous models (39%). 48% of the respondents applied postprocessing steps.

Biomedical image analysis competitions: The state of current participation practice

With the popularity of smartphones, abnormal driving detection via smartphone sensors has been proposed in recent years. However, existing methods are insufficient in exploring feature extraction, so the practical value is limited due to the low accuracy. To address this problem, we propose an attention-based auto-encoder framework for abnormal driving detection that combines the advantages of bi-directional long short-term memory and self-attention. Specifically, these two modules are embedded in the auto-encoder for modeling latent vector and exploring the internal correlations of spatial-temporal features, respectively, so as to improve the capability of reconstructing driving time series using small and representative features. We conduct experiments on the real-world datasets, and the results show that the proposed framework achieves significant performance with recall and F1-score of 96.2% and 95.0%, superior to the other baselines.

2022 IEEE International Symposium on Circuits and Systems (ISCAS)

Attention-Based Auto-Encoder Framework for Abnormal Driving Detection

Understanding driving behavior has never been more important to intelligent transportation. It has a significant impact on the advancement of safe and sociable autonomous vehicles. With the advent of smartphones and intelligent connected vehicles, portable data acquisition and efficient driving data processing are enabled, providing unprecedented potential for comprehensive driving behavior analysis (DBA). This research benefits many industries, such as vehicle energy management, autonomous driving systems, advanced driver assistance systems, intelligent traffic systems, and environmental protection. In this study, we conduct a comprehensive literature investigation of the dataset and DBA model. The dataset is reviewed based on available datasets, and we also outline the evaluation metrics of the DBA model. We provide an overview of the DBA model separately, briefly discuss five DBA tasks, and focus on reviewing the smartphone-based DBA model. In addition, we analyze the key research challenges and prospects for future work, hoping to provide guidelines for related researchers.

2021 3rd International Symposium on Smart and Healthy Cities (ISHC)

Video instance segmentation aims to detect, segment, and track objects in a video. Current approaches extend image-level segmentation algorithms to the temporal domain. However, this results in temporally inconsistent masks. In this work, we identify the mask quality due to temporal stability as a performance bottleneck. Motivated by this, we propose a video instance segmentation method that alleviates the problem due to missing detections. Since this cannot be solved simply using spatial information, we leverage temporal context using inter-frame attentions. This allows our network to refocus on missing objects using box predictions from the neighbouring frame, thereby overcoming missing detections. Our method significantly outperforms previous state-of-the-art algorithms using the Mask R-CNN backbone, by achieving 35.1% mAP on the YouTube-VIS benchmark. Additionally, our method is completely online and requires no future frames.

Object Propagation via Inter-Frame Attentions for Temporally Stable Video Instance Segmentation

Abnormal driving behavior detection (ADBD) is essential to improving driving safety. Traditional approaches usually extract features manually, resulting in insufficient exploration of deep features of driving behavior. To address the limitation of shallow feature-based approaches, we propose a one-dimensional convolutional neural network (1D CNN) model for ADBD and transforms it into the time series multi-classification. Firstly, we construct a dataset of driving behavior using smartphone sensors, and five fine-grained abnormal driving behaviors (Hard braking, Weaving, Swerving, Quick turn, Quick U-turn) are defined and labeled by analyzing the abnormal driving feature patterns. Then, we need to map the smartphone coordinate to the vehicle coordinate, and apply the low-pass filtering on the input data for high-frequency noise reduction. Finally, we train the dataset with the 1D CNN model for feature extraction and classification. The experimental results show that the proposed 1D CNN model efficiently achieves multi-classification of abnormal driving behaviors with an average accuracy of 97%, significantly better than the traditional algorithm of k-nearest neighbor and support vector machine.

2021 International Conference on Networking Systems of AI (INSAI)

One-Dimensional Convolutional Neural Network Model for Abnormal Driving Behaviors Detection Using Smartphone Sensors

With the rapid development of Brain-Computer Interfaces (BCI), human visual decoding, as one of the important research directions of BCI, has aroused great attention. But most visual decoding researches focused on graphics decoding. In this paper, we investigate the possibility to build a new kind of BCI visual decoding based on visual color observation for the first time. We selected 10 subjects without color blindness disease to participate in our tests. They were asked to observe red, green, blue screens in turn with an interval of 1 second. 5 subjects took the test without a task, while another 5 subjects took the test with a task of simply counting one of the appearances of the color. The result shows that the visual color classification for group A without task can reach 83.57% on average, whereas the visual color classification for group B with the task is 78.57% on average. It shows that these subjects may distract themselves while taking the task, however, the classification accuracy is relatively higher than 66.11% for selected channels for both cases with or without taking a task as interference to BCI.

RibSeg Dataset and Strong Point Cloud Baselines for Rib Segmentation from CT Scans

Many video processing algorithms rely on optical flow to register different frames within a sequence. However, a precise estimation of optical flow is often neither tractable nor optimal for a particular task. In this paper, we propose taskoriented flow (TOFlow), a flow representation tailored for specific video processing tasks. We design a neural network with a motion estimation component and a video processing component. These two parts can be jointly trained in a self-supervised manner to facilitate learning of the proposed TOFlow. We demonstrate that TOFlow outperforms the traditional optical flow on three different video processing tasks: frame interpolation, video denoising/deblocking, and video super-resolution. We also introduce Vimeo-90K, a large-scale, high-quality video dataset for video processing to better evaluate the proposed algorithm. †This work was done when Tianfan Xue was a student in MIT CSAIL.

With Ground Truth Flows Case II : With Task-Oriented Flows Input frames TOFlow Warped by TOFlow Denoised frame Video Denoising ?

Structures and objects are often supposed to have idealized geometries such as straight lines or circles. Although not always visible to the naked eye, in reality, these objects deviate from their idealized models. Our goal is to reveal and visualize such subtle geometric deviations, which can contain useful, surprising information about our world. Our framework, termed Deviation Magnification, takes a still image as input, fits parametric models to objects of interest, computes the geometric deviations, and renders an output image in which the departures from ideal geometries are exaggerated. We demonstrate the correctness and usefulness of our method through quantitative evaluation on a synthetic dataset and by application to challenging natural images. CR Categories: I.4.8 [Image Processing and Computer Vision]: Scene Analysis—Shape;

Deviation magnification : Revealing departures from ideal geometries Citation

Efficient removal of norfloxacin in water using magnetic molecularly imprinted polymer.

Bioreduction (AuIII to Au0) and stabilization of gold nanocatalyst using Kappa carrageenan for degradation of azo dyes.

Konjac glucomannan reduced-stabilized silver nanoparticles for mono-azo and di-azo contained wastewater treatment

ABSTRACT Novel magnetic molecularly imprinted polymers (MMIP) were prepared for selective removal of norfloxacin by effectively utilizing photocatalytic degradation and magnetic separation techniques. The imprinted material with titanium layer and multihole surface showed an excellent photocatalytic property. In this paper, the kinetics of photocatalytic degradation of norfloxacin by MMIP was explored, and the influences of environmental factors, including solution pH, humic acid, common ions and water media on photocatalytic performance of MMIP were elucidated. The results showed that MMIP had good adaptability and could degrade norfloxacin within 60 min, but the degradation rate constant decreased in surface water. Based on the identification of intermediate products, the possible degradation pathways of norfloxacin were analysed, speculating that it might be degraded into small molecules in the form of de-piperazine ring, de-carboxyl group and de-fluorine. Moreover, the mineralization ratio of norfloxacin could reach 84.2% after ultraviolet irradiation for 150 min, and the low cobalt release of MMIP enhanced the security of the material. The results of adsorption and degradation cycle tests showed that MMIP obtained by molecular imprinting technology had excellent performance in sustainable use for micro organic pollutants removal. GRAPHICAL ABSTRACT

Photocatalytic degradation of norfloxacin by magnetic molecularly imprinted polymers: influencing factors and mechanisms

Dicationic liquid containing alkenyl modified CuBTC improves the performance of the composites: Increasing the CO2 adsorption effect

Identification of water-soluble peptides in distilled spent grain and its angiotensin converting enzyme (ACE) inhibitory activity based on UPLC-Q-TOF-MS and proteomics analysis.

Green synthesis of Konjac glucomannan templated palladium nanoparticles for catalytic reduction of azo compounds and hexavalent chromium

O-doped graphdiyne as metal-free catalysts for nitrogen reduction reaction

Gold/Konjac glucomannan bionanocomposites for catalytic degradation of mono-azo and di-azo dyes

Distilled spent grain (DSG), the biggest by-product of the Chinese liquor industry, is rich in protein (167.8 g/kg DSG dry weight (DW)). Accounting for 60% of the total protein, prolamins are isolated from dried DSG (DDSG). In this study, angiotensin-converting enzyme (ACE) inhibitory peptides were screened from the prolamin hydrolysates of DDSG using two independent active-directed separations, ultrafiltration and reversed phase high performance liquid chromatography (RP-HPLC) coupled with ACE inhibitory activity evaluation. Six novel ACE inhibitory peptides, AVQ, YPQ, NQL, AYLQ, VLPVLS, and VLPSLN, were successfully identified and quantified from the active RP-HPLC fractions. AVQ and YPQ exhibited the highest activity, having the concentration inducing 50% inhibition (IC50) values for ACE of 181.0 and 220.0 μM, respectively. It was observed that VLPVLS was the most abundant peptide (16.96 mg/g DW) in prolamins. The results indicated that prolamin hydrolysates from DDSG could be served as a source of ACE inhibitory peptides.

In Vitro Production and Identification of Angiotensin Converting Enzyme (ACE) Inhibitory Peptides Derived from Distilled Spent Grain Prolamin Isolate

Single-atom catalysts (SACs) are highly desired for maximizing the efficiency of metal atoms and can entail high selectivity and activity. Bifunctional catalysts enable higher performance and lower cost than two single-function catalysts. Supported single-atom bifunctional catalysts are therefore of great economic interest and scientific importance. Density functional theory calculations are used to design SACs, isolated transition metal anchored on graphdiyne (TM@GDY), for oxygen reduction (ORR) and oxygen evolution (OER) reactions in alkaline media. A dual-volcano plot is constructed to thoroughly describe and predict the catalytic activity toward ORR and OER processes on TM@GDY materials. The results demonstrate that GDY could provide a unique platform for synthesizing uniform SACs with high catalytic activity toward ORR and OER. The theoretical evaluations show that Ni@GDY and Pt@GDY catalysts possess comparable electrocatalytic activity for ORR and OER in alkaline media. The study not only provides deep insights into the catalytic activity of TM@GDY, but also guides the design of GDY based SACs.

Molecule-level graphdiyne coordinated transition metals as a new class of bifunctional electrocatalysts for oxygen reduction and oxygen evolution reactions.

Effect of environmental factors on enhanced adsorption and photocatalytic regeneration of molecular imprinted TiO2 polymers for fluoroquinolones

: Development of sodium-based solid sorbents for decreasing CO 2 emission from coal-fired power plants is receiving more and more attention. Its carbonation behaviors have been studied recently, and it is understood that its primary downfall is the slow reaction with CO 2 during adsorption process. TiO 2 is examined as a potential dopant for sodium-based solid sorbent based CO 2 capture process in a bubbling fluidized-bed. SEM, XRD and Nitrogen Adsorption characterizations of Na 2 CO 3 /Al 2 O 3 doped with TiO 2 indicate that TiO 2 is stable within the temperature range necessary for such a process. More importantly, TiO 2 has a positive effect on the carbonation of Na 2 CO 3 and the reaction rate, as well as the CO 2 uptake, is observed to increase obviously. Carbonate reaction products are NaHCO 3 and Na 5 H 3 (CO 3 ) 4 . TiO 2 has little effect on the regeneration of sorbent.Despite this, the loading of TiO 2 should be limited, because too much TiO 2 doped may block the microstructure of sorbent which is unfavourable to carbonate reaction.

Effect of TiO 2 on the Carbonation/Regeneration Characteristics of Na 2 CO 3 /Al 2 O 3 in a Fluidized-bed Reactor

A feasible electrochemical method for tuning coatings wettability from superhydrophilicity to superhydrophobicity

Determination of plasticizer of phthalate esters in Chinese liquor by nonionic surfactant/vortex liquid-liquid microextraction combined with gas chromatography-mass spectrometry.

Based on the structure of lead compound N-(m-fluoro-benzyl)-6-amino-coumarin, a series of novel N-acyl-N-(m-fluoro-benzyl)-6-amino-coumarins were designed and synthesized through the principle of bioactive substructure combination. Their structures were characterized by 1 H NMR, ESI-MS and elemental analysis. N-trifluoroacetyl substituted compound d5 was further confirmed by X-ray single crystal diffraction. The herbicidal activities of synthesized compounds were evaluated as well. The results indicated that compounds substituted respectively by N-chloracetyl, N-bromoacetyl, N-trifluoroacetyl and N-(2,4-dichlorophenoxyacetyl) compounds d2, d3, d5 and d17 exhibited marked inhibition against the roots and stems of Amaranthus retroflexus with inhibitory rates above 75% at 100 mg/L, more active than acetochlor EC. In post-emergence treatment experiment, compounds d3 and d17 substituted respectively by N-bromoacetyl and N-(2,4-dichlorophenoxyacetyl) showed more than 76% inhibition against A. retroflexus and other dicotyledons at 1500 g/ha in greenhouse. Compound d17 is safe to monocotyledonous crops wheat, corn and rice at 1500 g a.i./hm 2 .

Synthesis and Herbicidal Activity of N-Acyl-N- (m-fluoro-benzyl)-6-amino-coumarin

Synthesis and membrane performance characterization of self-emulsified waterborne nitrocellulose dispersion modified with castor oil

Two copper(II) complexes of curcumin derivatives: synthesis, crystal structure and in vitro antitumor activity

Low-temperature bleaching of cotton fabric can be achieved by incorporating a so-called bleach activator into an aqueous solution of hydrogen peroxide. In this study, a series of N-[4-(dimethylalkylammoniomethyl)benzoyl]caprolactam chlorides were synthesised for use as cationic bleach activators with various alkyl chain lengths. All these synthesised cationic bleach activators were confirmed by 1H and 13C nuclear magnetic resonance spectroscopy and mass spectroscopy. Bleaching experiments revealed that these synthesised bleach activators were effective for bleaching of cotton fabric at 50 °C under near-neutral pH conditions, but the alkyl chain lengths had a great influence on their bleaching performance. Increasing the alkyl chain length from 2 to 6 carbon atoms could slightly enhance bleaching performance, while increasing the alkyl chain length from 8 to 16 carbon atoms markedly reduced bleaching performance.

Synthesis of N‐[4‐(dimethylalkylammoniomethyl) benzoyl]caprolactam chlorides as cationic bleach activators for low‐temperature bleaching of cotton fabric under near‐neutral pH conditions

Crystal structure, optical properties and biological imaging of two curcumin derivatives

Phenylurea groups were introduced into the frame of traditional cyanoacrylate and a series of N -(3-benzylamino-2-cyano-3-methylthioacrylyl)- N' -(substituted phenyl)ureas were synthesized. All compounds are new and their structures were confirmed by 1 H NMR, 13 C NMR and mass spectral analyses. KEY WORDS : Synthesis, Cyanoacrylate, Phenylurea derivatives Bull. Chem. Soc. Ethiop. 2013 , 27(2), 295-300. DOI: http://dx.doi.org/10.4314/bcse.v27i2.15

Synthesis and crystal structure of N-(3-benzylamino-2- cyano-3-methylthioacrylyl)-N'-(substituted phenyl)ureas

Spectrophotometric determination of trace lead in food contact materials by concentrated enrichment-flow injection analysis.

Adsorption thermodynamics and kinetics of disperse dye on poly(p-phenylene benzobisoxazole) fiber pretreated with polyphosphoric acid

Fluorescent carbon dots(CDs) were synthesized by a solvothermal method with glucose as the carbon source.The interaction between carbon dots and nucleic acids was studied with resonance light scattering technique.Based on the significant enhancement effect of the resonance light scattering between nucleic acids and carbon dots in the Tris buffer at pH 7.4,a convenient and feasible method for the determination of nucleic acids was proposed.The enhanced RLS intensity was found to be linearly to the concentration of nucleicacids in the ranges of 0.4 ～ 30 μg / mL,the detection limit of nucleic acids of 0.023 μg / mL(3σ).The method was applied to the detection of the nucleic acids in synthetical sample,with the recovery from 103% ～ 106% and the RSD lower than 3.7%.

Carbon dots used for the detection of nucleic acids with resonance light scattering signals

Water-soluble CdTe quantum dots(QDs) were synthesized by means of L-glutathione(GSH) as a modifying agent in an aqueous solution at 100 ℃.Based on the quenching of the fluorescence intensity of CdTe QDs by Ag(I),a simple,rapid and sensitive method for the determination of trace amounts of silver in anti-cancer drug oxaliplatin was developed.In the study,the effects of experimental conditions,including concentration of CdTe QDs,the type,concentration and pH of buffer,and reacting time on the determination of Ag(I) were investigated in detail.When the concentration of QDs was 0.004 g/L in the phosphate buffer at pH 7.4,the fluorescence quenching intensity of the CdTe QDs was linear with Ag(I) mass concentration in the range of 16.42～98.50 μg/L,with a linear correlation coefficient of 0.9975.The limit of detection(3() was0.12 μg/L.

Determination of trace amounts of silver in oxaliplatin by fluorescence quenching of CdTe quantum dots

L-glutathione(GSH) stabilized CdTe quantum dots(QDs) were directly prepared in aqueous solution.A convenient and feasible method based on the quenching of the fluorescence intensity of CdTe QDs was developed for the determination of fasudil hydrochloride.The effects of experimental conditions,including the type and pH of phosphate buffer,the concentration of CdTe QDs and the reaction time on the determination of fasudil hydrochloride were investigated.The results showed when the concentration of QDs was 4μg/ml in 0.01 mol/L phosphate buffer(pH 7.4),the degree of fluorescence quenching degree of CdTe QDs was linear with mass concentration of fasudil hydrochloride in the range of 0.525 - 78.7μg/ml.

Determination of Fasudil Hydrochloride by Fluorescence Quenching of Water-soluble CdTe Quantum Dots

In this study,a method for determining the content of oligosaccharides,including sucrose,raffinose,stachyose in tobacco casing materials by high performance liquid chromatography(HPLC) was developed.Separation and quantification were achieved by Waters Sugar Pak1(6.5 mm 300 mm,5 μm) with 1.0 mL/min pure water as the mobile phase,column temperature at 85℃ and Refractive Index Detector.The quantified analysis of external standard calibration curves was used.There were good linear correlations between the concentrations of three sugars and their chromatographic peak areas and the correlation coefficients were 0.9991-0.9997.The recoveries were 96.9%-103.5%,the RSD of the method was less than 4.7%.And the detection limits were 3.5-4.0 g/mL.This method is simple,rapid and accurate,and has been applied for eh quantitative analysis of sucrose,raffinose,stachyose in tobacco casing materials.

Determination of Oligosaccharides in Tobacco Casing Materials by HPLC

The stationary phase of silica gel bonded with poly N-isopropylacrylamide(SI-PNIPAM),was prepared from N-isopropylacrylamide,and applied to the separation of alkaline substances from esters.It was found that the separation of baseline from the components was achieved satisfactorily with symmetrical chromatographic peaks.The thermo-sensitive of SI-PNIPAM,by which phase transition from hydrophilic conformation to hydrophobic conformation was taken place in the temperature interval of 28-32 ℃ with a mixed solution of methanol-water(30+70) as mobile phase,was feasible to be applied to the analysis of polar compounds with obvious differences in polarity.

Application of the Stationary Phase of Silica Gel Bonded with Poly(N-isopropylacrylamide)

In this study, conventional fluorescence spectroscopy in the excitation, emission and synchronous scan modes and three-dimensional fluorescence spectroscopy in the form of excitation-emission matrix of fluorescence intensity as a function of excitation and emission wavelengths were applied to study the complexation between DOM extracted from landfill leachates and Hg(II) ions. The emission spectrum of DOM exhibited a broad peak with a center at 425 nm and a disorder change of the peak with increasing Hg(II) concentrations, which suggested that the structure of DOM was comparatively simple and the fluorescence character of DOM-Hg(II) complexes resulted from interaction of all fluorescence groups. The excitation spectrum of DOM showed that the intensities of two peaks at 392 and 458 nm both decreased with the addition of Hg(II), indicating that different sources, hydroxy and amido groups, were all involved in the DOM-Hg(II) complexation process. Synchronous-scan excitation spectra of DOM-Hg(II) complexation showed that Hg(II) not only produced fluorescence quenching effect, but also enhanced the rigid structure of DOM at a low concentration. The three-dimensional fluorescence spectra of DOM-Hg(II) showed that the peaks A and B reduced strongly and the two peaks tended to shift toward longer wavelength with the concentrations of Hg(II) increasing. These results indicated that protein-like matter reacted with Hg(II) and there was a charge-transfer transition either between energy level in its ligand and a mercury energy level or between two mercury energy levels at the same time. Besides, the decrease in fluorescence intensity of peaks C and D in three-dimensional fluorescence spectra suggested that carbonyl and carboxyl formed bonds with Hg(II) when DOM was complexed with Hg(II).

[Fluorescence spectroscopic chracterization of the complexation between mercury(II) and dissolved organic matter].

Trichloroacetic acid-acetone precipitation method (TCA method) and phenol isolation method (phenol method) were evaluated by measuring the yield ratio and purity of protein and analysis of the gel electrophoresis map on ovule of DPL971 and DPL972 in Gossypium arboreum during primary cell wall synthesis period. The results were as follows: firstly, the massive soluble proteins could be obtained by the two methods, but the yield ratio, quality and protein types by phenol method were better than those by TCA method; secondly, the types of extracted protein were different by two methods, the phenol method had better performance in acidic region and in high/low molecular weight region; finally, the phenol method could efficiently get rid of the interfering substance and achieve the excellent gels, therefore, the phenol method was suitable for protein extraction from the cotton ovule. As a result, the useful information can be provided for the proteomics research of cotton fiber during the development period and have certain significance for guiding the protein extraction of many other non-model plants containing various interfering elements.

Evaluations of Trichloroacetic Acid-acetone Method and Phenol Method for Protein Extraction from Cotton Ovule

The isothermal crystallization process and subsequent melting behavior of a cis-1,4-polybutadiene(PB) sample were investigated by differential scanning calorimetry(DSC).It was found that there existed a perfection process of crystals at the late stage of the isothermal crystallization process.In addition,the rate of crystallization decreased with an increase of the crystallization temperature.Melting of the PB crystals always starts at about 2 ℃ above the crystallization temperature.At a heating rate of 10 ℃/min,DSC thermogram shows a broad distribution of melting temperatures with a smaller shoulder on the low-temperature side,indicating that this sample possesses crystallites with different stabilities after isothermal crystallization.By extrapolating the melting points to zero crystallinity(Xc=0) or infinite long crystallization time(t-1c=0),we determined the equilibrium melting point T∞m of this PB specimen to be in between 9 and 17.6 ℃ according to the Hoffman-Weeks approach.

Crystallization and Melting Behavior of cis-1,4-Polybutadiene Analyzed by Differential Scanning Calorimetry

Since the public introduction of phthalic acid diamides and anthranilic diamides by Nihon Nohyaku,Bayer CropScience and DuPont,respectively,diamides have been the focus of synthesis in the field of agrochemical industry.Especially anthranilic diamides as insecticides,furthermore which also displayed good herbicidal and fungicidal activities,have recently attracted considerable attention.In the investigation of new agrochemicals,1,2,3-thiadiazole derivatives often display good biological activities,and some diamides containing 1,2,3-thiadiazole possess good insecticide and fungicidal activities.In order to search for novel diamides which have high activities,a series of novel anthranilic diamides containing 1,2,3-thiadiazole were designed and synthesized,their structures were identified by means of elemental analysis,1H NMR,and the structure of compound 7g was determined by X-ray single crystal diffraction method.The preliminary results of biological activity experiment show that some of the title compounds exhibited a favourable fungicidal activity.

Synthesis,Crystal Structure and Biological Activity of Novel Anthranilic Diamides Containing 1,2,3-Thiadiazole

In the investigation of new agrochemicals,we found 1,2,3-thiadiazole derivatives with good biological activities,had received only limited attention,but commercial pesticides containing 1,2,3-thiadiazole often possess a unique active mechanism,such as TDZ,BTH and tiadinil.We became interested in making 1,2,3-thiadiazoleacetamides,analogues of three commercial pesticides.In order to search for novel 1,2,3-thiadiazole derivatives with high activities,we designed and synthesized a series of novel 1,2,3-thiadiazole-4-acetamide(acetmorpholide)derivatives using diketene as the starting materials.Their structures were identified by means of elemental analysis,IR,1H NMR and MS spectra.The results of the preliminary biological activity tests show that some of the compounds exhibit a better anti-TMV activity,plant growth regulator activity and fungicidal activity.

Synthesis and Biological Activities of 1,2,3-Thiadiazol-4-acetamide (Acetmorpholide) Derivatives

Chlorogenic acid in Zhiyan tea was determined by HPLC in the paper.An Zorbax SB-Aq-ODS was used with a mobile phase consisted mixture of acetonitrile and 0.025 mol·L-1 phosphoric acid(13∶87) by flow rate of 1.0 mL·min-1 in this method.And UV detective wavelength is 327 nm.The calibration curve was linear within the range of 28.68~ 66.92 μg·mL-1 for chlorogenic acid(R= 0.9998).The average recoveries of chlorogenic acid was 98.5%,RSD = 1.35%(n=5).The method could be used for the quality control of Zhiyan tea.

Effects of environmental factors and denaturants on the variation rules of the specific absorption spectrum and fluorescence emission intensity of B-phycoerythrin were systematically investigated in the present paper. The results showed that B-phycoerythrin was relatively stable under certain conditions: the pH range from 4. 5 to 9. 5, temperature range from 25 to 60 degrees C, and illumination intensity at 2 800 lx in 24 h. The specific absorption spectrum and fluorescence emission intensity of B-phycoerythrin changed slightly. The conformation of B-phycoerythrin changed remarkably with 0. 5 %-3% SDS or 0. 25 %-1% beta-mercaptoethanol, the fluorescence emission intensity declined greatly, and the specific absorption peaks disappeared. The fluorescence emission intensity declined, while the specific absorption spectrum did not change, but the peak intensity reduced slightly with 10%-70% acetonitrile or 2-8 mol x L(-1) urea. The possible reasons for the conformation changes of B-phycoerythrin with various environmental factors and different denaturants were briefly discussed.

[Effects of environmental factors and denaturants on the specific absorption spectrum and fluorescence characters of B-phycoerythrin].

The method for determination of seven minim biogenic amines (tyramine, tyramine, histamine,putrescine, cadaverine, spermidine, spermine) by solid phase extraction- high performance liquid chro-matography is reported. Pre- column dansylation of the biogenic amines and subsequent solid- phase ex-traction of the derivatives through C18 cartridges. Then, dansyl derivatives are separated on InertsilODS- 3 column using a 20- min gradient elution with a binary system of acetonitrile- water, a flow- rateof 1 mL min-1.They are detected by fluorescent detector.The variation coefficients are 0.51 %～2.23 %,the detection limit is 1.29×10-6～2.57×10-4 μg/mL.

DETERMINATION OF SEVEN MINIM BIOGENIC AMINES BY SOLID PHASE EXTRACTION-HIGH PERFORMANCE LIQUID CHROMATOGRAPHY

Development of a surface plasmon resonance biosensor for the identification of Campylobacter jejuni.

The method for determination of seven biogenic amines (tyramine, tyramine, histamine, putrescine, cadaverine, spermidine, spermine) in butter by solid phase extraction- reversed- phase high performance liquid chromatography is reported. The sample is extracted with methanol and removed from protein and fat. Pre- col- umn dansylation of the biogenic amines and subsequent solid- phase extraction of the derivatives through C18 cartridges. Then, dansyl derivatives are separated on Inertsil ODS- 3 column using a 20min gradient elution with a binary system of acetonitrile- water, a flow- rate of 1mL/min. They are detected by fluorescent detector and quantified by external standard. Butter sample are fortified with seven biogenic amines at three levels. Five replicate analyses are performed in each level. The variation coefficients are 3.52%￣6.75%.The detection limit is 2.71×10-5￣1.36×10-3μg/mL. The recoveries of seven biogenic amines are 80.4%￣89.1%.

Determination of seven Pre- column dansylation of seven biogenic amines in butter by solid phase extraction- high performance liquid chromatography

In the course of cis copolymerization of butadiene(BD) with isoprene(IP) by using Nd(naph) 3 Al(C 2H 5) 3 ( t C 4H 9)Cl as catalyst in toluene, tert butylchloride or allyl chloride was added to give a soluble, gel free cyclized copolymer. Some parameters affecting the cyclization were investigated. The preliminary results of IR, 1H NMR analyses confirmed the cyclization of both BD and IP units and that the IP units were cyclized in a greater extent than BD units.

In situ Cyclization in the Course of Butadiene-Isoprene Copolymerization with Nd-based Catalyst

Mesoporous synthetic clays : synthesis, characterization, and use as HDS catalyst supports.

Synthesis, characterization, DFT studies, and adsorption properties of sulfonated starch synthesized in deep eutectic solvent.

Adsorption of copper (II) and cadmium (II) ions by in situ doped nano-calcium carbonate high-intensity chitin hydrogels.

The effect of steel strip-feeding ratio and superheat degree of molten steel on density and segregation of casting ingot is investigated by an original position analysis. It indicates that under the same degree of superheat condition, with the increase of feeding ratio, the average density of the casting ingot increases and the central segregation of the ingot decreases. Under the same feeding ratio conditions, the density and the central segregation increase with the increase of the degree of superheat.

Influence of Steel Strip-Feeding Process on Density and Segregation of Casting Ingot

Ag-28.1 wt. % Cu eutectic alloy solidifies in the form of eutectic dendrite at undercooling above 76 K. The remelting and ripening of the original lamellar eutectics result in the formation of the anomalous eutectics in the final microstructure. The addition of the third element Sb (0.5 and 1 wt. %) does not change the growth mode, but enlarges the volume fraction of anomalous eutectics because of the increasing recalescence rate. The additional constitutional supercooling owing to the Sb enrichment ahead of the eutectic interface promotes the branching of the interface and as a result fine lamellar eutectic arms form around the anomalous eutectics in the Sb-added Ag-28.1 wt. % Cu eutectic alloy.

Effect of Sb Addition on the Solidification of Deeply Undercooled Ag-28.1 wt. % Cu Eutectic Alloy

Steering mechanism is an important part of car driving system and the lock force is a key parameter to protect driver in the case of a frontal impact. But it is difficult to predict the range of lock force during impact since the material properties and friction of the system are variable in a certain range. Based on polynomial chaos expansion (PCE) and monomial cubature rules (MCRs), an efficient robust design method is presented to predict the lock force of a steering mechanism and select appropriate parameters for structure design. The advantage of the method is to reduce the intensive computational demand of uncertainty propagation by construction of PCE using points of MCRs, and the accuracy is enough for engineering problems.

Robust Design for Steering Mechanism by Using Points of Monomial Cubature Rules

The cooling rate is a key factor of controlling the slab surface microstructures during continuous casting of steel. The effect of cooling rate on phase transformation and microstructure of Nb­Ti microalloyed steel was investigated by a confocal laser scanning microscopy and a Gleeble-3800 thermal simulation machine. The process of phase transformation can be analyzed through in situ observation. A critical cooling rate of 5K·s11 was revealed, below which the proeutectoid ferrite along austenite grain boundaries and widmanstatten structures were observed, and carbonitrides precipitated were also observed in the proeutectoid ferrite. With the increase of cooling rate, the quantity of the precipitates decreases while the width of the proeutectoid ferrite becomes smaller. The carbonitrides precipitated along the austenite grain boundary result in the decrease of the carbon concentration near the grain boundary, which is more favorable to form the proeutectoid ferrite as well as to change its width. When the cooling rate was greater than or equal to 5K·s11, the precipitates were dispersed uniformly in the grain, and the bainite was observed mainly. [doi:10.2320/matertrans.M2013395]

Effect of Cooling Rate on Phase Transformation and Microstructure of Nb–Ti Microalloyed Steel

Effect of Cooling Rate on Phase Transformation and Microstructure of Nb Ti Microalloyed

An efficient method for estimating the range of forming force for an upsetting-extruding process was proposed, which may be useful to choose appropriate forming equipment. The accurate prediction of the forming force of an upsetting-extruding process is the key to form a work piece successfully. However, the forming force is variable in a certain range for the variation of material and process parameters. In general, the variation is dominated by some of the main effects and lower-order interactions due to the sparsity-of-effect principle. Therefore, the construction of polynomial chaos expansion with points of monomial cubature rules, which need fewer points than other kinds of integral, is particularly attractive in dealing with computational model for the forming simulation. An automobile threated plate is used to illustrate the validation of the method.

Tolerance Prediction for Forming Force of Upsetting-Extruding Process by Using Points of Monomial Cubature Rules

Effects of the technological parameters (superheat, cycle times and holding time) on undercooling and structure of Ag-28.1 wt.% Cu eutectic alloy were discussed by orthogonal experiment. It shows that the influence of the superheat on undercooling is biggest, followed by cycle times, and finally holding time. Then the optimum process parameters of getting different undercooling are given in this paper. In the Ag-28.1 wt.% Cu eutectic alloy melt, cellular growth of lamellar eutectics takes place because of the large difference in composition between the two eutectic phases and the very large thermal diffusion coefficient of the liquid, and when undercooling is equal to or higher than 76 K, lamellar eutectics grow in a dendritic form during rapid solidification.

Structures and Undercooling Technology of Ag-28.1 wt.% Cu Eutectic Alloy

Identification of nucleation parameter for cellular automaton model of dynamic recrystallization

New Solution for Polynomial Chaos Expansion and Application in Tolerance Prediction for Stamping Process

Abstract Robust optimization is a probabilistic approach to engineering design under uncertainty. The main idea is to select designs insensitive to changes in given parameters. Robust optimization using numerical simulations for black-box problems has received increasing interest. However, when the simulation programmes are computationally expensive, robust optimization is difficult to implement due to the intensive computational demand of uncertainty propagation. Based on polynomial chaos expansion (PCE), an efficient robust optimization method is presented. The PCE is constructed with points of monomial cubature rules (MCRs) to approximate the original model. As the number of points of MCRs is small and all of the points are sampled, the robust optimization procedure is computationally efficient and stable. Two engineering design problems are employed to demonstrate the availability of the proposed method.

Robust optimization based on a polynomial expansion of chaos constructed with integration point rules

Optimization and tolerance prediction of sheet metal forming process using response surface model

Uncertainty quantification using polynomial chaos expansion with points of monomial cubature rules

Tolérance de l’ixékizumab chez les patients adultes atteints de psoriasis modéré à sévère : données issues de 15 essais cliniques avec plus de 18 000 patients-années d’exposition

La presente invention concerne une composition de revetement conformable comprenant un copolymere cristallin, et son utilisation dans un revetement barriere.

Parmi les articles de securite personnalisables par laser, on trouve un document de securite multicouche et une bande de traitement optiquement transparente. Le document de securite multicouche comprend une couche de recouvrement optiquement transparente, une image composite et une couche imageable adjacente a la couche de recouvrement. La premiere surface de la couche de recouvrement est au moins partiellement une surface microstructuree, la surface microstructuree formant des microlentilles ou une surface lenticulaire. L'image composite est constituee d'une collection d'images completes ou partielles vues a travers la surface microstructuree de la couche de recouvrement. L'image composite est placee sur ou a l'interieur de la seconde surface de la couche de recouvrement. La couche imageable est une couche imageable par laser. La bande de traitement optiquement transparente mouille suffisamment la surface microstructuree pour rendre la surface microstructuree invisible pour un laser d'ecriture.

L'invention concerne une composition pre-adhesive reticulable, comprenant un copolymere de (meth)acrylate a fonctionnalite acide et un agent de reticulation d'aziridine, qui lorsqu'il est reticule produit un adhesif sensible a la pression et des articles adhesifs sensibles a la pression.

Cette invention se rapporte a des procedes destines a ameliorer le taux de transmission de vapeur d'eau d'une couche adhesive sensible a la pression dans un article medical avec une composition miscible, ainsi qu'a des articles medicaux qui comprennent la couche adhesive sensible a la pression amelioree.

Articles médicaux et procédés de fabrication utilisant une composition miscible

Le revetement selon l’invention comprend une premiere couche a base d’un alliage ceramique et une seconde couche disposee sur la premiere couche et comprenant du carbone. Le revetement a une epaisseur allant de 10 a 20 GPa et un coefficient de frottement inferieur ou egal a 0,12. Un procede de revetement d’un substrat comprend les etapes consistant a : nettoyer le substrat, former la premiere couche sur le substrat, et deposer la seconde couche sur la premiere couche pour revetir ainsi le substrat.

An automatic language identification system (LID) aims at identifying the identity of a spoken language using a short speech sample of an unknown speaker. The LID problem can be viewed as a stochastic process of language generation. An adaption to the LID problem, of the source-channel model commonly used for automatic language transcription is proposed. An important challenge, for the researchers in LID, consist in developing approaches and methods which make limited use of explicit knowledge concerning the languages to be processed. In order to guarantee an easy extension to additional languages, multilingual > symbol sets have been designed and multilingual or language-independent acoustic models have been estimated and experimented with using a restricted number of languages. The challenge is have them cover the acoustic space corresponding to the capacities of the human vocal apparatus. The definition and the use of multilingual phonemic inventories for acoustic modeling are major issues of our research. Within the framework of the phonotactic approaches to LID, the decision of the spoken language identity depends on an automatically decoded multilingual phoneme flow. To optimize the quality of this phoneme flow, two methods are explored: 1) increase the acoustic model accuracy by taking into account multilingual triphone contexts; 2) widen the scope of the units by considering a multilingual syllabic unit. Syllables are longer units and hence less subject to coarticulation effects than phonemes at the acoustic level. We validated our work by experiments of language identification, automatic transcription and by a detailed acoustic analysis of the vowels in eight languages (French, American English, German, Italian , Spanish, Portuguese, Arabic and Chinese Mandarin).

Modélisation acoustique multilingue pour l'identification automatique de la langue et la transcription de la parole

La maladie des « Gros Os », egalement appelee maladie de Kashin-Beck (KBD), touche plus de deux millions d’individus dans une zone geographique allant du sud-est de la Siberie au Tibet en passant par la Coree du Nord et le centre de la Chine [1, 2]. Dans certaines vallees de la region autonome du Tibet, la prevalence de cette maladie dans la population rurale s’eleve a plus de 80 % [3]. Connue chez les Cosaques au xvie siecle et peut-etre a l’âge de Bronze, cette affection a ete decrite par Kashin en 1861 et par Beck entre 1889 et 1902 [1]. Il s’agit d’une osteoarthropathie, caracterisee par la destruction des chondrocytes du cartilage qui est tres douloureuse au niveau des articulations et qui se manifeste graduellement chez les jeunes enfants, des l’âge de 2 ou 3 ans. Dans les regions hyperendemiques, elle peut entrainer dans les cas les plus graves un nanisme avec des deformations articulaires importantes a l’etat adulte.

La maladie de Kashin-Beck et le milieu rural au Tibet :un problème agri-environnemental

L'invention concerne un article a motifs comprenant des zones de surface alternees hydrophiles et hydrophobes. Les zones hydrophobes peuvent etre suffisamment etroites afin que l'humidite, accumulee dans la zone hydrophobe dans des conditions de rosee, se deplace vers les zones hydrophiles, ce qui empeche l'accumulation de gouttelettes d'eau. Dans des conditions de gel, les zones hydrophobes sont a peu pres exemptes de gel, ce qui leur permet de conserver une surface relativement transparente. Des particules d'oxydes inorganiques aux surfaces des zones hydrophobes peuvent leur conferer des proprietes de resistance a l'abrasion. L'invention concerne egalement un procede pour fabriquer des surfaces a motifs ; selon ce procede, un traitement permet d'enlever un liant organique pour exposer les particules d'oxydes inorganiques a la surface des regions hydrophiles.

Article a motifs comprenant des zones de surface alternees hydrophiles et hydrophobes

Cette invention concerne un procede de traitement de tapis qui permet d'eviter tout recours a un lavage industriel. D'apres ce procede, le tapis non lave est traite en surface, selon un procede de ramassage a faible mouillage, a l'aide d'une solution qui comprend des particules de silice, ou un additif organique similaire, ainsi qu'un agent fluorochimique ou un eventuel autre additif organique. Les tapis traites selon ce procede possedent d'excellentes proprietes de resistance aux salissures qui ne s'estompent que tres peu a l'usure ou apres des lavages. En outre, etant donne que ce procede fait appel a un ramassage avec un faible mouillage, la duree de sechage peut etre sensiblement reduite par rapport aux procedes traditionnels d'immersion dans des bains aqueux.

The centrality of population-level factors to network computation is demonstrated by a versatile approach for training spiking networks

Neuronal responses during behavior are diverse, ranging from highly reliable ‘classical’ responses to irregular or seemingly-random ‘non-classically responsive’ firing. While a continuum of response properties is frequently observed across neural systems, little is known about the synaptic origins and contributions of diverse response profiles to network function, perception, and behavior. Here we use a task-performing, spiking recurrent neural network model incorporating spike-timing-dependent plasticity that captures heterogeneous responses measured from auditory cortex of behaving rodents. Classically responsive and non-classically responsive model units contributed to task performance via output and recurrent connections, respectively. Excitatory and inhibitory plasticity independently shaped spiking responses and task performance. Local patterns of synaptic inputs predicted spiking response properties of network units as well as the responses of auditory cortical neurons from in vivo whole-cell recordings during behavior. Thus a diversity of neural response profiles emerges from synaptic plasticity rules with distinctly important functions for network performance.

Contributions and synaptic basis of diverse cortical neuron responses to task performance

Decision letter: Local online learning in recurrent networks with random feedback

Author response: Spike-timing-dependent ensemble encoding by non-classically responsive cortical neurons

Neurons recorded in behaving animals often do not discernibly respond to sensory input and are not overtly task-modulated. These non-classically responsive neurons are difficult to interpret and are typically neglected from analysis, confounding attempts to connect neural activity to perception and behavior. Here, we describe a trial-by-trial, spike-timing-based algorithm to reveal the coding capacities of these neurons in auditory and frontal cortex of behaving rats. Classically responsive and non-classically responsive cells contained significant information about sensory stimuli and behavioral decisions. Stimulus category was more accurately represented in frontal cortex than auditory cortex, via ensembles of non-classically responsive cells coordinating the behavioral meaning of spike timings on correct but not error trials. This unbiased approach allows the contribution of all recorded neurons – particularly those without obvious task-related, trial-averaged firing rate modulation – to be assessed for behavioral relevance on single trials.

Spike-timing-dependent ensemble encoding by non-classically responsive cortical neurons

Neurons recorded in behaving animals often do not discernibly respond to sensory input and are not overtly task-modulated. These nominally non-responsive neurons are difficult to interpret and are typically neglected from analysis, confounding attempts to connect neural activity to perception and behavior. Here we describe a trial-by-trial, spike-timing-based algorithm to reveal the hidden coding capacities of these neurons in auditory and frontal cortex of behaving rats. Responsive and nominally non-responsive cells contained significant information about sensory stimuli and behavioral decisions, and network modeling indicated that nominally non-responsive cells are important for task performance. Sensory input was more accurately represented in frontal cortex than auditory cortex, via ensembles of nominally non-responsive cells coordinating the behavioral meaning of spike timings on correct but not error trials. This unbiased approach allows the contribution of all recorded neurons - particularly those without obvious task-modulation - to be assessed for behavioral relevance on single trials.

Nominally non-responsive frontal and sensory cortical cells encode task-relevant variables via ensemble consensus-building

Trained recurrent networks are powerful tools for modeling dynamic neural computations. We present a target-based method for modifying the full connectivity matrix of a recurrent network to train it to perform tasks involving temporally complex input/output transformations. The method introduces a second network during training to provide suitable “target” dynamics useful for performing the task. Because it exploits the full recurrent connectivity, the method produces networks that perform tasks with fewer neurons and greater noise robustness than traditional least-squares (FORCE) approaches. In addition, we show how introducing additional input signals into the target-generating network, which act as task hints, greatly extends the range of tasks that can be learned and provides control over the complexity and nature of the dynamics of the trained, task-performing network.

full-FORCE: A target-based method for training recurrent networks

Recurrent neural networks are powerful tools for understanding and modeling computation and representation by populations of neurons. Continuous-variable or "rate" model networks have been analyzed and applied extensively for these purposes. However, neurons fire action potentials, and the discrete nature of spiking is an important feature of neural circuit dynamics. Despite significant advances, training recurrently connected spiking neural networks remains a challenge. We present a procedure for training recurrently connected spiking networks to generate dynamical patterns autonomously, to produce complex temporal outputs based on integrating network input, and to model physiological data. Our procedure makes use of a continuous-variable network to identify targets for training the inputs to the spiking model neurons. Surprisingly, we are able to construct spiking networks that duplicate tasks performed by continuous-variable networks with only a relatively minor expansion in the number of neurons. Our approach provides a novel view of the significance and appropriate use of "firing rate" models, and it is a useful approach for building model spiking networks that can be used to address important questions about representation and computation in neural systems.

Using Firing-Rate Dynamics to Train Recurrent Networks of Spiking Model Neurons

Methods for Building Network Models of Neural Circuits Brian DePasquale Artificial recurrent neural networks (RNNs) are powerful models for understanding and modeling dynamic computation in neural circuits. As such, RNNs that have been constructed to perform tasks analogous to typical behaviors studied in systems neuroscience are useful tools for understanding the biophysical mechanisms that mediate those behaviors. There has been significant progress in recent years developing gradient-based learning methods to construct RNNs. However, the majority of this progress has been restricted to network models that transmit information through continuous state variables since these methods require the input-output function of individual neuronal units to be differentiable. Overwhelmingly, biological neurons transmit information by discrete action potentials. Spiking model neurons are not differentiable and thus gradient-based methods for training neural networks cannot be applied to them. This work focuses on the development of supervised learning methods for RNNs that do not require the computation of derivatives. Because the methods we develop do not rely on the differentiability of the neural units, we can use them to construct realistic RNNs of spiking model neurons that perform a variety of benchmark tasks, and also to build networks trained directly from experimental data. Surprisingly, spiking networks trained with these non-gradient methods do not require significantly more neural units to perform tasks than their continuous-variable model counterparts. The crux of the method draws a direct correspondence between the dynamical variables of more abstract continuous-variable RNNs and spiking network models. The relationship between these two commonly used model classes has historically been unclear and, by resolving many of these issues, we offer a perspective on the appropriate use and interpretation of continuous-variable models as they relate to understanding network computation in biological neural circuits. Although the main advantage of these methods is their ability to construct realistic spiking network models, they can equally well be applied to continuous-variable network models. An example is the construction of continuous-variable RNNs that perform tasks for which they provide performance and computational cost competitive with those of traditional methods that compute derivatives and outperform previous non-gradient-based network training approaches. Collectively, this thesis presents efficient methods for constructing realistic neural network models that can be used to understand computation in biological neural networks and provides a unified perspective on how the dynamic quantities in these models relate to each other and to quantities that can be observed and extracted from experimental recordings of neurons.

Significance Studies of beta oscillations, highlighted clinically because of exaggerated beta-band activity in Parkinson’s disease, have focused on measures averaged over multiple trials, and readers outside the field could have the misperception that beta oscillations persist over seconds. We show that brief bursts of oscillation are responsible for virtually all beta-band activity in healthy monkeys. The state called “beta synchronization” consists of numerous brief (∼40–120 ms) bouts of oscillation within a nonoscillatory background, and these bouts can also occur during periods of “desynchronization.” Thus, postmovement “synchronization” of beta represents a transient increase in oscillation probability, with different time courses in the motor cortex and striatum. We suggest that the timing and duration of these bursts are critical parameters for network function. Studies of neural oscillations in the beta band (13–30 Hz) have demonstrated modulations in beta-band power associated with sensory and motor events on time scales of 1 s or more, and have shown that these are exaggerated in Parkinson’s disease. However, even early reports of beta activity noted extremely fleeting episodes of beta-band oscillation lasting <150 ms. Because the interpretation of possible functions for beta-band oscillations depends strongly on the time scale over which they occur, and because of these oscillations’ potential importance in Parkinson’s disease and related disorders, we analyzed in detail the distributions of duration and power for beta-band activity in a large dataset recorded in the striatum and motor-premotor cortex of macaque monkeys performing reaching tasks. Both regions exhibited typical beta-band suppression during movement and postmovement rebounds of up to 3 s as viewed in data averaged across trials, but single-trial analysis showed that most beta oscillations occurred in brief bursts, commonly 90–115 ms long. In the motor cortex, the burst probabilities peaked following the last movement, but in the striatum, the burst probabilities peaked at task end, after reward, and continued through the postperformance period. Thus, what appear to be extended periods of postperformance beta-band synchronization reflect primarily the modulated densities of short bursts of synchrony occurring in region-specific and task-time-specific patterns. We suggest that these short-time-scale events likely underlie the functions of most beta-band activity, so that prolongation of these beta episodes, as observed in Parkinson’s disease, could produce deleterious network-level signaling.

Bursts of beta oscillation differentiate postperformance activity in the striatum and motor cortex of monkeys performing movement tasks

Memory capacity of a random, recurrently connected network of neurons with multiple, biologically realistic facilitation and adaptation profiles

Spike-timing-dependent ensemble encoding by non-classically responsive 1 cortical neurons

Circadian rhythms are daily oscillations in behaviors that persist in constant light/dark conditions with periods close to 24 h. A striking feature of these rhythms is that their periods remain fairly constant over a wide range of physiological temperatures, a feature called temperature compensation. Although circadian rhythms have been associated with periodic oscillations in mRNA and protein levels, the question of how to construct a network of chemical reactions that is temperature compensated remains unanswered. We discuss a general framework for building such a network.

The dynamics of neural networks is influenced strongly by the spectrum of eigenvalues of the matrix describing their synaptic connectivity. In large networks, elements of the synaptic connectivity matrix can be chosen randomly from appropriate distributions, making results from random matrix theory highly relevant. Unfortunately, classic results on the eigenvalue spectra of random matrices do not apply to synaptic connectivity matrices because of the constraint that individual neurons are either excitatory or inhibitory. Therefore, we compute eigenvalue spectra of large random matrices with excitatory and inhibitory columns drawn from distributions with different means and equal or different variances.

Modeling & Simulating the Evacuation of a Building Based on Building Floor Plan and Evacuation Strategies

Cerebral cortex supports representations of the world in patterns of neural activity, used by the brain to make decisions and guide behavior. Past work has found diverse, or limited, changes in the primary sensory cortex in response to learning, suggesting the key computations might occur in downstream regions. Alternatively, sensory cortical changes may be central to learning. We studied cortical learning by using controlled inputs we insert: we trained mice to recognize entirely novel, non-sensory patterns of cortical activity in the primary visual cortex (V1) created by optogenetic stimulation. As animals learned to use these novel patterns, we found their detection abilities improved by an order of magnitude or more. The behavioral change was accompanied by large increases in V1 neural responses to fixed optogenetic input. Neural response amplification to novel optogenetic inputs had little effect on existing visual sensory responses. A recurrent cortical model shows that this amplification can be achieved by a small mean shift in recurrent network synaptic strength. Amplification would seem to be desirable to improve decision-making in a detection task, and therefore these results suggest that adult recurrent cortical plasticity plays a significant role in improving behavioral performance during learning.

Amplified cortical neural responses as animals learn to use novel activity patterns

Memories are encoded in neural ensembles during learning and stabilized by post-learning reactivation. Integrating recent experiences into existing memories ensures that memories contain the most recently available information, but how neural ensembles accomplish this critical process remains unknown. Here we show that in mice, a strong aversive experience drives the offline ensemble reactivation of not only the recent aversive memory but also a neutral memory formed two days prior, spreading the fear from the recent aversive memory to the previous neutral memory. We find that fear specifically spreads retrospectively, but not prospectively, to neutral memories across days. Consistent with prior studies, we find reactivation of the recent aversive memory ensemble during the offline period following learning. However, a strong aversive experience also increases co-reactivation of the aversive and neutral memory ensembles during the offline period. Finally, inhibiting hippocampal reactivation during this offline period abolishes the spread of fear from the aversive experience to the neutral memory. Taken together, these results demonstrate that strong aversive experience can drive retrospective memory integration through the offline co-reactivation of recent memory ensembles with memory ensembles formed days prior, providing a neural mechanism by which memories can be integrated across days.

Aversive experience drives offline ensemble reactivation to link memories across days

Cumulative stress is a major risk factor for developing major depressive disorder (MDD), yet not everyone experiencing chronic stress develops MDD. In those who do not, it is unclear at what point, or by what mechanism, a trajectory of stable resiliency emerges. Utilizing a 10-day repeated social defeat stress model (RSDS) for MDD, we observed that a critical period between 7 and 10 daily defeats marks the phenotypical divergence of resilient from susceptible mice. In response to ongoing stress, corticotropin-releasing factor (CRF) neurons of the oval nucleus of the bed nucleus of the stria terminalis (BNSTov) display a sustained increased firing rate in resilient, but not susceptible mice. This neurophysiological adaptation was self-sustaining, but only after 7 critical stress exposures, indicating that the process of developing resilience is dependent on stress history. Our study reveals a novel process by which individuals might persist in the face of adversity by way of stress-provoked activation, not inhibition of a key CRF limbic region that establishes a pathway to resilience.

CRF neurons establish resilience via stress-history dependent BNST modulation

Distinguishing between complex nonlinear neural time-series patterns is a challenging problem in neuroscience. Accurately classifying different patterns could be useful for a wide variety of applications, e.g. detecting seizures in epilepsy and optimizing control spaces for brain-machine interfaces. It remains challenging to correctly distinguish nonlinear time-series patterns because of the high intrinsic dimensionality of such data, making accurate inference of state changes (for intervention or control) difficult. On the one hand, simple distance metrics, which can be computed quickly, often do not yield accurate classifications; on the other hand, ensembles or deep supervised approaches offer high accuracy but are training data intensive. We introduce a reservoir-based tool, state tracker (TRAKR), which provides the high accuracy of ensembles or deep supervised methods while preserving the benefits of simple distance metrics in being applicable to single examples of training data (one-shot classification). We show that TRAKR instantaneously detects deviations in dynamics as they occur through time, and can distinguish between up to 40 patterns from different chaotic data recurrent neural networks (RNNs) with above-chance accuracy. We apply TRAKR to a benchmark time-series dataset – permuted sequential MNIST – and show that it achieves high accuracy, performing on par with deep supervised networks and outperforming other distance-metric based approaches. We also apply TRAKR to electrocorticography (ECoG) data from the macaque orbitofrontal cortex (OFC) and, similarly, find that TRAKR performs on par with deep supervised networks, and more accurately than commonly used approaches such as Dynamic Time Warping (DTW). Altogether, TRAKR allows for high accuracy classification of time-series patterns from a range of different biological and non-biological datasets based on single training examples. These results demonstrate that TRAKR could be a viable alternative in the analysis of time-series data, offering the potential to generate new insights into the information encoded in neural circuits from single-trial data.

Reservoir-based Tracking (TRAKR) For One-shot Classification Of Neural Time-series Patterns

Distinguishing Neural Time-series Patterns based on Reservoir-derived Error

BSTRACT We present a novel approach to use curricula to identify principles by which a system learns. Previous work in curriculum learning has focused on how curricula can be designed to improve learning of a model on particular tasks. We consider the inverse problem: what can a curriculum tell us about how a learning system acquired a task? Using recurrent neural networks (RNNs) and models of common experimental neuroscience tasks, we demonstrate that curricula can be used to differentiate learning principles using target-based and a representation-based loss functions as use cases. In particular, we compare the performance of RNNs using a target-based learning principle versus those using a representational learning principle on three different curricula in the context of two tasks. We show that the learned state-space trajectories of RNNs trained by these two learning principles under all curricula tested are indistinguishable. However, by comparing learning times during different curricula, we can disambiguate the learning principles and challenge traditional approaches of interrogating learning systems. Although all animals in neuroscience lab settings are trained by curriculum-based procedures called shaping, almost no behavioral or neural data are collected or published on the relative successes or training times under different curricula. Our results motivate the systematic collection and curation of data during shaping by demonstrating curriculum learning in RNNs as a tool to probe and differentiate learning principles used by biological systems, over statistical analyses of learned state spaces. trained state. Our results emphasize the importance of studying animals during shaping and the value of curriculum learning in RNNs as a hypothesis test-bed for probing learning principles in the biological brain.

Curriculum learning as a tool to uncover learning principles in the brain

The deep neural nets of modern artificial intelligence (AI) have not achieved defining features of biological intelligence, including abstraction, causal learning, and energy-efficiency. While scaling to larger models has delivered performance improvements for current applications, more brain-like capacities may demand new theories, models, and methods for designing artificial learning systems. Here, we argue that this opportunity to reassess insights from the brain should stimulate cooperation between AI research and theory-driven computational neuroscience (CN). To motivate a brain basis of neural computation, we present a dynamical view of intelligence from which we elaborate concepts of sparsity in network structure, temporal dynamics, and interactive learning. In particular, we suggest that temporal dynamics, as expressed through neural synchrony, nested oscillations, and flexible sequences, provide a rich computational layer for reading and updating hierarchical models distributed in long-term memory networks. Moreover, embracing agent-centered paradigms in AI and CN will accelerate our understanding of the complex dynamics and behaviors that build useful world models. A convergence of AI/CN theories and objectives will reveal dynamical principles of intelligence for brains and engineered learning systems. This article was inspired by our symposium on dynamical neuroscience and machine learning at the 6th Annual US/NIH BRAIN Initiative Investigators Meeting.

A brain basis of dynamical intelligence for AI and computational neuroscience

Neuroscience has seen a dramatic increase in the types of recording modalities and complexity of neural time-series data collected from them. The brain is a highly recurrent system producing rich, complex dynamics that result in different behaviors. Correctly distinguishing such nonlinear neural time series in real-time, especially those with non-obvious links to behavior, could be useful for a wide variety of applications. These include detecting anomalous clinical events such as seizures in epilepsy, and identifying optimal control spaces for brain machine interfaces. It remains challenging to correctly distinguish nonlinear time-series patterns because of the high intrinsic dimensionality of such data, making accurate inference of state changes (for intervention or control) difficult. Simple distance metrics, which can be computed quickly do not yield accurate classifications. On the other end of the spectrum of classification methods, ensembles of classifiers or deep supervised tools offer higher accuracy but are slow, data-intensive, and computationally expensive. We introduce a reservoir-based tool, state tracker (TRAKR), which offers the high accuracy of ensembles or deep supervised methods while preserving the computational benefits of simple distance metrics. After one-shot training, TRAKR can accurately, and in real time, detect deviations in test patterns. By forcing the weighted dynamics of the reservoir to fit a desired pattern directly, we avoid many rounds of expensive optimization. Then, keeping the output weights frozen, we use the error signal generated by the reservoir in response to a particular test pattern as a classification boundary. We show that, using this approach, TRAKR accurately detects changes in synthetic time series. We then compare our tool to several others, showing that it achieves highest classification performance on a benchmark dataset, sequential MNIST, even when corrupted by noise. Additionally, we apply TRAKR to electrocorticography (ECoG) data from the macaque orbitofrontal cortex (OFC), a higher-order brain region involved in encoding the value of expected outcomes. We show that TRAKR can classify different behaviorally relevant epochs in the neural time series more accurately and efficiently than conventional approaches. Therefore, TRAKR can be used as a fast and accurate tool to distinguish patterns in complex nonlinear time-series data, such as neural recordings.

TRAKR - A reservoir-based tool for fast and accurate classification of neural time-series patterns

In this era of globalisation and rapid development where proper utilisation of human resources is of utmost priority, the role of a standardized selection process with minimal human bias is indispensable. It is the objective of almost every recruiting agency to select the best candidates for the job. In most of the cases, the recruitment process comprises of two broad assessment categories viz. written examination and personality test. The scores of the written examination is on an absolute scale, but in the case of personality test the marks though awarded on an absolute scale, is nothing but a pseudo-ranking scale in most of the cases. The study aims to test the validity of un-structured personality tests for selection of best candidates, the validation is made through some statistical analysis comprising of nature of the data (Descriptive Statistics, Histogram with Normality Probability Plot, selected Percentile value and Box Plot) and measures of association (Pearsonian Correlation Co-efficient). The study considers all the subject-wise papers given by a candidate and his/her corresponding personality test scores. Moreover, the homogeneity and existence of measures of association among different personality testing boards for a single recruitment were considered to establish the relationship among the said interview boards. The outcome of the study revealed that there is a need for structured personality test in case of all recruitments whether the number of candidates is large or small.

Validity of Structured Personality Test : A Statistical Analysis Between Scores of Written Examination and Personality Test

Deep anomaly detection of seizures with paired stereoelectroencephalography and video recordings

Biological agents do not have inﬁnite resources to learn new things. For this reason, a central aspect of human learning is the ability to recycle previously acquired knowledge in a way that allows for faster, less resource-intensive acquisition of new skills. In spite of that, how neural networks in the brain leverage existing knowledge to learn new computations is not well understood. In this work, we study this question in artiﬁcial recurrent neural networks (RNNs) trained on a corpus of commonly used neuroscience tasks. Combining brain-inspired inductive biases we call functional and structural, we propose a system that learns new tasks by building on top of pre-trained latent dynamics organised into separate recurrent modules. These modules, acting as prior knowledge acquired previously through evolution or development, are pre-trained on the statistics of the full corpus of tasks so as to be independent and maximally informative. The resulting model, we call a Modular Latent Primitives (MoLaP) network, allows for learning multiple tasks while keeping parameter counts, and updates, low. We also show that the skills acquired with our approach are more robust to a broad range of perturbations compared to those acquired with other multi-task learning strategies, and that generalisation to new tasks is facilitated. This work offers a new perspective on achieving efﬁcient multi-task learning in the brain, illustrating the beneﬁts of leveraging pre-trained latent dynamical primitives. models of biologically plausible multi-task learning. Finally, we show that generalization to new tasks that share basic structure with the corpus is also facilitated. This draws a path towards cheaper multitask solutions, and offers new hypotheses for how continual learning might be implemented in the biological brain. which are used to pre-train separate network modules. B. During task training, recurrent weights remain frozen and only input and readout weights are adjusted. Task-speciﬁc responses can be obtained via separate readout weights. C. Parameter overview for the various multi-task training methods. Parameters trained (or updated) and total network size is compared across the three methods. MoLaP makes ∼ 2 orders of magnitude fewer parameter updates than DNI, at a relatively moderate increase of total parameter count.

Efficient and robust multi-task learning in the brain with modular latent primitives

In a real-world setting biological agents do not have infinite resources to learn new things. It is thus useful to recycle previously acquired knowledge in a way that allows for faster, less resource-intensive acquisition of multiple new skills. Neural networks in the brain are likely not entirely re-trained with new tasks, but how they leverage existing computations to learn new tasks is not well understood. In this work, we study this question in artificial neural networks trained on commonly used neuroscience paradigms. Building on recent work from the multi-task learning literature, we propose two ingredients: (1) network modularity, and (2) learning task primitives. Together, these ingredients form inductive biases we call structural and functional, respectively. Using a corpus of nine different tasks, we show that a modular network endowed with task primitives allows for learning multiple tasks well while keeping parameter counts, and updates, low. We also show that the skills acquired with our approach are more robust to a broad range of perturbations compared to those acquired with other multi-task learning strategies. This work offers a new perspective on achieving efficient multi-task learning in the brain, and makes predictions for novel neuroscience experiments in which targeted perturbations are employed to explore solution spaces.

Efficient and robust multi-task learning in the brain with modular task primitives

Miniature microscopes have gained considerable traction for in vivo calcium imaging in freely behaving animals. However, extracting calcium signals from raw videos is a computationally complex problem and remains a bottleneck for many researchers utilizing single-photon in vivo calcium imaging. Despite the existence of many powerful analysis packages designed to detect and extract calcium dynamics, most have either key parameters that are hard-coded or insufficient step-by-step guidance and validations to help the users choose the best parameters. This makes it difficult to know whether the output is reliable and meets the assumptions necessary for proper analysis. Moreover, large memory demand is often a constraint for setting up these pipelines since it limits the choice of hardware to specialized computers. Given these difficulties, there is a need for a low memory demand, user-friendly tool offering interactive visualizations of how altering parameters at each step of the analysis affects data output. Our open-source analysis pipeline, Minian (Miniscope Analysis), facilitates the transparency and accessibility of single-photon calcium imaging analysis, permitting users with little computational experience to extract the location of cells and their corresponding calcium traces and deconvolved neural activities. Minian contains interactive visualization tools for every step of the analysis, as well as detailed documentation and tips on parameter exploration. Furthermore, Minian has relatively small memory demands and can be run on a laptop, making it available to labs that do not have access to specialized computational hardware. Minian has been validated to reliably and robustly extract calcium events across different brain regions and from different cell types. In practice, Minian provides an open-source calcium imaging analysis pipeline with user-friendly interactive visualizations to explore parameters and validate results.

Self-Supervised Deep Anomaly Detection of Epileptic Seizures with Paired Stereoelectroencephalography and Video Recording

Functional neuroimaging studies indicate that interconnected parts of the subcallosal anterior cingulate cortex (ACC), striatum, and amygdala play a fundamental role in affect in health and disease. Yet, while the patterns of neural activity engaged in striatum and amygdala during affective processing are well established, especially during reward anticipation, little is known about subcallosal ACC. Here we recorded neural activity in non-human primate subcallosal ACC and compared this to interconnected parts of basolateral amygdala and rostromedial striatum while macaque monkeys performed reward-based tasks. Applying multiple analysis approaches, we found that neurons in subcallosal ACC and rostromedial striatum preferentially signal anticipated reward using short bursts of activity that form temporally specific patterns. By contrast, basolateral amygdala uses a mixture of both temporally specific and more sustained patterns of activity to signal anticipated reward. Thus, dynamic patterns of neural activity across populations of neurons are engaged in affect, especially in subcallosal ACC. HIGHLIGHTS Sustained changes in neural activity signal anticipated reward in basolateral amygdala Temporally specific patterns signal anticipated reward in all areas recorded Neurons exhibit more punctate encoding when tasks become more complex Temporally specific patterns of neural activity signal different anticipated rewards in BLA

Temporally specific patterns of neural activity in interconnected corticolimbic structures during reward anticipation

The neural control of behavior is distributed across many functionally and anatomically distinct brain regions even in small nervous systems. While classical neuroscience models treated these regions as a set of hierarchically isolated nodes, the brain comprises a recurrently interconnected network in which each region is intimately modulated by many others. Uncovering these interactions is now possible through experimental techniques that access large neural populations from many brain regions simultaneously. Harnessing these large-scale datasets, however, requires new theoretical approaches. Here, we review recent work to understand brain-wide interactions using multi-region 'network of networks' models and discuss how they can guide future experiments. We also emphasize the importance of multi-region recordings, and posit that studying individual components in isolation will be insufficient to understand the neural basis of behavior.

Rethinking brain-wide interactions through multi-region ‘network of networks’ models

Behavior arises from the coordinated activity of numerous anatomically and functionally distinct brain regions. Modern experimental tools allow unprecedented access to large neural populations spanning many interacting regions brain-wide. Yet, understanding such large-scale datasets necessitates both scalable computational models to extract meaningful features of inter-region communication and principled theories to interpret those features. Here, we introduce Current-Based Decomposition (CURBD), an approach for inferring brain-wide interactions using data-constrained recurrent neural network models that directly reproduce experimentally-obtained neural data. CURBD leverages the functional interactions inferred by such models to reveal directional currents between multiple brain regions. We first show that CURBD accurately isolates inter-region currents in simulated networks with known dynamics. We then apply CURBD to multi-region neural recordings obtained from mice during running, macaques during Pavlovian conditioning, and humans during memory retrieval to demonstrate the widespread applicability of CURBD to untangle brain-wide interactions underlying behavior from a variety of neural datasets.

Inferring brain-wide interactions using data-constrained recurrent neural network models

Unplanned hospital readmissions constitute a significant cost burden in healthcare. Identifying factors contributing to readmission risk presents opportunities for actionable change to reduce readmission rates.

OBJECTIVE
To combine machine learning classification and feature importance analysis to identify drivers of readmission in a large cohort of spine patients.

METHODS
Cases involving surgical procedures for degenerative spine conditions between 2008 and 2016 were retrospectively reviewed. Of 11 150 cases, 396 patients (3.6%) experienced an unplanned hospital readmission within 30 d of discharge. Over 75 pre-discharge variables were collected and categorized into demographic, perioperative, and resource utilization feature domains. Random forest classification was used to construct predictive models for readmission from feature domains. An ensemble tree-specific method was used to quantify and rank features by relative importance.

RESULTS
In the demographics domain, age and comorbidity burden were the most important features for readmission prediction. Surgical duration and intraoperative oral morphine equivalents were the most important perioperative features, whereas total direct cost and length of stay were most important in the resource utilization domain. In supervised learning experiments for predicting readmission, the demographic domain model performed the best alone, suggesting that demographic features may contribute more to readmission risk than perioperative variables following spine surgery. A predictive model, created using only enriched features showing substantial importance, demonstrated improved predictive capacity compared to previous models, and approached the performance of state-of-the-art, deep-learning models for readmission.

This strategy provides insight into global patterns of feature importance and better understanding of drivers of readmissions following spine surgery.

Machine Learning With Feature Domains Elucidates Candidate Drivers of Hospital Readmission Following Spine Surgery in a Large Single-Center Patient Cohort.

Neuronal Dynamics Regulating Brain and Behavioral State Transitions

The concept of feature selectivity in sensory signal processing can be formalized as dimensionality reduction: in a stimulus space of very high dimensions, neurons respond only to variations within some smaller, relevant subspace. But if neural responses exhibit invariances, then the relevant subspace typically cannot be reached by a Euclidean projection of the original stimulus. We argue that, in several cases, we can make progress by appealing to the simplest nonlinear construction, identifying the relevant variables as quadratic forms, or “stimulus energies.” Natural examples include non–phase–locked cells in the auditory system, complex cells in the visual cortex, and motion–sensitive neurons in the visual system. Generalizing the idea of maximally informative dimensions, we show that one can search for kernels of the relevant quadratic forms by maximizing the mutual information between the stimulus energy and the arrival times of action potentials. Simple implementations of this idea successfully recover the underlying properties of model neurons even when the number of parameters in the kernel is comparable to the number of action potentials and stimuli are completely natural. We explore several generalizations that allow us to incorporate plausible structure into the kernel and thereby restrict the number of parameters. We hope that this approach will add significantly to the set of tools available for the analysis of neural responses to complex, naturalistic stimuli.

Maximally Informative “Stimulus Energies” in the Analysis of Neural Responses to Natural Signals

Learning Quadratic Receptive Fields from Neural Responses to Natural Stimuli

Input-dependent Suppression of Chaos in Recurrent Neural Networks

To make optimal use of experimental data on the anatomy and physiology of brain circuits, and to account for the effects of plasticity and modulation on behavior, we must understand the relationship between the synaptic connectivity and neuronal properties, and the activity that these properties produce at the network level. Given detailed knowledge of the properties of a complex network, can we predict what it will do? If we know how plasticity mechanisms or modulators change those properties, can we predict how the activity will change? These are difficult questions to answer. In the broadest terms, my paper explores how knowledge of synaptic connectivity and neuronal gain can be used to predict the activity produced by a network model. Along the way I address some issues in sensory and motor physiology: the role of spontaneous activity in sensory processing, memory storage and motor pattern generation using insights from the physics of random matrices.

How are the spatial patterns of spontaneous and evoked population responses related? We study the impact of connectivity on the spatial pattern of fluctuations in the input-generated response, by comparing the distribution of evoked and intrinsically generated activity across the different units of a neural network. We develop a complementary approach to principal component analysis in which separate high-variance directions are derived for each input condition. We analyze subspace angles to compute the difference between the shapes of trajectories corresponding to different network states, and the orientation of the low-dimensional subspaces that driven trajectories occupy within the full space of neuronal activity. In addition to revealing how the spatiotemporal structure of spontaneous activity affects input-evoked responses, these methods can be used to infer input selectivity induced by network dynamics from experimentally accessible measures of spontaneous activity (e.g. from voltage- or calcium-sensitive optical imaging experiments). We conclude that the absence of a detailed spatial map of afferent inputs and cortical connectivity does not limit our ability to design spatially extended stimuli that evoke strong responses.

Inferring Stimulus Selectivity from the Spatial Structure of Neural Network Dynamics

Stimulus-dependent suppression of intrinsic variability in recurrent neural networks

Neuronal activity arises from an interaction between ongoing firing generated spontaneously by neural circuits and responses driven by external stimuli. Using mean-field analysis, we ask how a neural network that intrinsically generates chaotic patterns of activity can remain sensitive to extrinsic input. We find that inputs not only drive network responses, but they also actively suppress ongoing activity, ultimately leading to a phase transition in which chaos is completely eliminated. The critical input intensity at the phase transition is a nonmonotonic function of stimulus frequency, revealing a "resonant" frequency at which the input is most effective at suppressing chaos even though the power spectrum of the spontaneous activity peaks at zero and falls exponentially. A prediction of our analysis is that the variance of neural responses should be most strongly suppressed at frequencies matching the range over which many sensory systems operate.

Stimulus-dependent suppression of chaos in recurrent neural networks.

Trial-to-trial variability is an essential feature of neural responses, but its source is a subject of active debate. Response variability (Mast and Victor, 1991; Arieli et al., 1995 & 1996; Anderson et al., 2000 & 2001; Kenet et al., 2003; Petersen et al., 2003a & b; Fiser, Chiu and Weliky, 2004; MacLean et al., 2005; Yuste et al., 2005; Vincent et al., 2007) is often treated as random noise, generated either by other brain areas, or by stochastic processes within the circuitry being studied. We call such sources of variability external to stress the independence of this form of noise from activity driven by the stimulus. Variability can also be generated internally by the same network dynamics that generates responses to a stimulus. How can we distinguish between external and internal sources of response variability? Here we show that internal sources of variability interact nonlinearly with stimulus-induced activity, and this interaction yields a suppression of noise in the evoked state. This provides a theoretical basis and potential mechanism for the experimental observation that, in many brain areas, stimuli cause significant suppression of neuronal variability (Werner and Mountcastle, 1963; Fortier, Smith and Kalaska, 1993; Anderson et al., 2000; Friedrich and Laurent, 2004; Churchland et al., 2006; Finn, Priebe and Ferster, 2007; Mitchell, Sundberg and Reynolds, 2007; Churchland et al., 2009). The combined theoretical and experimental results suggest that internally generated activity is a significant contributor to response variability in neural circuits.

Interactions between Intrinsic and Stimulus-Evoked Activity in Recurrent Neural Networks

Neural network modeling is often concerned with stimulus-driven responses, but most of the activity in the brain is internally generated. Here, we review network models of internally generated activity, focusing on three types of network dynamics: (a) sustained responses to transient stimuli, which provide a model of working memory; (b) oscillatory network activity; and (c) chaotic activity, which models complex patterns of background spiking in cortical and other circuits. We also review propagation of stimulus-driven activity through spontaneously active networks. Exploring these aspects of neural network dynamics is critical for understanding how neural circuits produce cognitive function. 357 A nn u. R ev . N eu ro sc i. 20 05 .2 8: 35 737 6. D ow nl oa de d fr om a rj ou rn al s. an nu al re vi ew s. or g by C ol um bi a U ni ve rs ity o n 04 /1 1/ 07 . F or p er so na l u se o nl y. AR245-NE28-14 ARI 12 May 2005 9:53

The cricket is one of most popular games in the Asian subcontinent and its popularity is increasing every day. The issue of replacement of the cricket ball amidst the matches is always an uncomfortable situation for teams, umpires and even supporters. At present the basis of the replacement is solely on the judgement, experience and expertise of the umpires, which is subjective, controversial and debatable. In this paper, we have attempted a new approach to quantify the number of impacts or impact factor of a 4-piece leather ball used in the International one-day and test cricket matches. This gives a more objective and scientific basis/criteria for the replacement of the ball. Here, we have used a well known and widely used thermal infra-red (TIR) imaging to capture the dynamics of the thermal profile of the cricket ball, which has been heated for about 15 seconds. The idea behind this approach is the simple observation that an old ball (ball with a few impacts) has different thermal signature/profile compared to the that of a new ball. This could be due to the change in the surface profile and internal structure, minor de-shaping, opening of seam etc. The TIR video and its frames, which is inherently noisy, are restored using Hebbian learning based FIR filter, which performs optimal smoothing in relatively less number of iteration. We have focussed on the hottest region of the ball, i.e. the inner core, and tracked its thermal profile dynamics. Finally we have used multi-layer perceptron model (MLP) to quantify the impact factor with fairly good accuracy.

2006 International Conference on Advanced Computing and Communications

Kynurenate treatment of autaptic hippocampal microcultures affect localized voltage-dependent calcium diffusion in the dendrites.

Neural network modeling is often concerned with stimulus-driven responses, but most of the activity in the brain is internally generated. Here, we review network models of internally generated activity, focusing on three types of network dynamics: (a) sustained responses to transient stimuli, which provide a model of working memory; (b) oscillatory network activity; and (c) chaotic activity, which models complex patterns of background spiking in cortical and other circuits. We also review propagation of stimulus-driven activity through spontaneously active networks. Exploring these aspects of neural network dynamics is critical for understanding how neural circuits produce cognitive function.

The effect of a brief, unplanned treatment delay on neovascular age-related macular degeneration patients: a retrospective cohort study

Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society

Paraneoplastic Cone Dysfunction Secondary to Renal Cell Carcinoma: A Case Report.

A n 88-year-old Caucasian man presented with a 2-day history of acute, painless, binocular diplopia. His right eye had become progressively blurrier over the past several months. He additionally described a 2-week history of generalized weakness, shortness of breath, unsteadiness, and dysphagia. He denied recent upper respiratory infection. His past medical history was significant for cutaneous squamous cell carcinoma for which he was taking immunotherapy with cemiplimab as part of a clinical trial. He had taken a 44-mg weekly dose of intralesional cemiplimab for 4 weeks before his trial was halted because of his neurological symptoms. His past ocular history was remarkable for primary open-angle glaucoma status after selective laser trabeculectomy with stable intraocular pressure on medical therapy. Ophthalmologic examination showed a visual acuity of 20/50 in his right eye and 20/20 in his left eye. His pupils measured 3 mm in dark to 2 mm in light in both eyes, with a trace relative afferent pupillary defect in the right eye. Intraocular pressure measured 11 mm Hg in the right eye and 13 mm Hg in the left eye. He had bilateral, moderate ophthalmoplegia with a 24 deficit of elevation and depression and a 22 deficit of horizontal gaze (Fig. 1). On funduscopic examination, he had advanced asymmetric glaucomatous cupping (cup-to-disc ratio of 0.9 in the right eye and 0.7 in the left eye). The remainder of his structural eye examination was unremarkable. Neurologic examination showed ataxia, diffuse areflexia, and a bilateral ascending motor and sensory lower extremity polyneuropathy. MRI of the brain showed no brainstem lesion, but there was nonspecific age-related diffuse cerebral atrophic change with secondary ex-vacuo ventriculomegaly and diffuse chronic microvascular disease. Lumbar puncture showed normal cerebrospinal fluid cell (CSF) count and an elevated CSF protein of 69 mg/dL consistent with albuminocytologic dissociation. Serum anti-GQ1b antibody tested negative. Despite the negative anti-GQ1b antibody, a diagnosis of Guillain–Barre syndrome (GBS) was made, and given the ophthalmoplegia, ataxia, and areflexia, the Miller Fisher variant of GBS was suspected, which was felt to be triggered by cemiplimab. The cemiplimab was held indefinitely, and he underwent intravenous methylprednisolone and immunoglobulin therapy for 5 days, followed by a slow oral prednisone taper. The patient slowly began to see improvement of the generalized weakness and ophthalmoplegia over 7–10 days during the prednisone taper.

There is considerable trial-to-trial variability in single cortical neurons when performing the same action repeatedly. One possibility is that neural populations are more stable in representing actions; alternatively, they too may be distinctly engaged from trial-to-trial. To address the nature of variability in large neural populations, we captured the EEG signals time-locked to repeated voluntary thumb flexion movements (∼500 repetitions, 23 subjects). By using non-negative matrix factorization on the low-frequency sensorimotor cortical signals, we quantified the trial-to-trial motor-related potentials (MRPs) in terms of prototypical signals (meta-MRPs) and their corresponding prominence at each trial (meta-trials). Clustering the meta-MRPs across the sampled population revealed 5 distinct signal patterns. There were brain-wide correlates of these meta-MRP clusters. Cortical hemispheres were distinctly recruited from trial-to-trial as certain clusters were accompanied by bilateral motor negativity while others were characterized by ipsilateral motor negativity. The sensory feedback too was distinctly processed from trial-to-trial as the central post-movement positivity was present only for certain clusters. A poorly understood pre-motor positivity accompanied all clusters albeit varying in their timing from trial-to-trial. These patterns – including the time-varying positivity preceding the movement – were rendered invisible by the traditional averaging of the signals. We suggest that the variability in EEG signals is not just noise but a consequence of distinct activation patterns deployed by the cortex. We support the idea that the cortex flexibly switches between distinct forms of neural processing to achieve the same behavioral goals.

Multiple forms of neural processing when repeating voluntary thumb flexions

Can you hear me now? Momentary increase in smartphone usage enhances neural processing of task-irrelevant sound tones

ABSTRACT While map apps on smartphones are abundant, their everyday usage is still an open empirical research question. With tappigraphy – the quantification of smartphone touchscreen interactions – we aimed to capture continuous data stream of behavioural human-map app usage patterns. The current study introduces a first tappigraphy analysis of the distribution of touchscreen interactions on map apps in 211 remotely observed smartphone users, accumulating a total of 42 days of tap data. We detail the requirements, setup, and data collection to understand how much, when, for how long, and how people use mobile map apps in their daily lives. Supporting prior research, we find that on average map apps are only sparsely used, compared to other apps. The longitudinal fluctuations in map use are not random and are partly governed by general daily and weekly human behaviour cycles. Smartphone session duration including map app use can be clearly distinguished from sessions without any map apps used, indicating a distinct temporal behavioural footprint surrounding map use. With the transfer of the tappigraphy approach to a mobile map app use context, we see a promising avenue to provide research communities interested in the underlying behavioural mechanisms of map use a continuous, in-situ momentary assessment method.

Tappigraphy: continuous ambulatory assessment and analysis of in-situ map app use behaviour

A model of healthy aging based on smartphone interactions reveals advanced behavioral age in neurological disease

The discrete behavioral events captured on the smartphone touchscreen may help unravel real-world neural processing. We find that neural signals (EEG) surrounding a touchscreen event show peculiarly contralateral motor preparation, visual processing, and the consolidation of information. We leveraged these events in conjunction with kinematic recordings of the thumb and an artificial neural network to separate highly similar movements according to whether they resulted in a smartphone touch (goal-directed) or not (non-goal-directed). Despite their kinematic similarity underscored by the model, the signatures of neural control of movement and the post-movement processing were substantially dampened for the non-goal-directed movements, and these movements uniquely evoked error-related signals. We speculate that these unnecessary movements are common in the real world and although inconsequential the brain still provides limited motor preparation and tracks the action outcome. Real-world behavior is composed of neural processes that are difficult to capture in conventional laboratory-based tasks.

Neural processing of goal and non-goal-directed movements on the smartphone

Temporal clusters of age-related behavioral alterations captured in smartphone touchscreen interactions

The perceived distance between touches on the limbs is generally bigger for distances oriented across the width of the limb than for distances oriented along the length of the limb. The present study aimed to investigate the coherence of such distortions of tactile size perception across different skin surfaces. We investigated distortions of tactile size perception on the dorsal and palmar surfaces of both the left and right hands as well as the forehead. Participants judged which of two tactile distances felt larger. One distance was aligned with the proximodistal axis ( along the body), the other with the mediolateral axis ( across the body). Clear distortions were found on all five skin surfaces, with stimuli oriented across the width of the body being perceived as farther apart than those oriented along the length of the body. Consistent with previous results, distortions were smaller on the palmar than on the dorsal hand surface. Distortion on the forehead was intermediate between the dorsal and palmar surfaces. There were clear correlations between distortion on the left and right hands, for both the dorsal and palmar skin surfaces. In contrast, within each hand, there was no significant correlation between the two skin surfaces. Distortion on the forehead was not significantly correlated with that on any of the other skin surfaces. These results provide evidence for bilaterally symmetric representations underlying tactile size perception.

BIROn - Birkbeck Institutional Research Online symmetry distortions

Artificial neural network trained on smartphone behavior can trace epileptiform activity in epilepsy

Brain areas representing the body can change in response to behavioral alterations. This idea is firmly established for the adult cortex in response to extraordinary alterations such as traumatic amputation or casting of the limb. Here we address how adult cortical sensorimotor processing alters in response to a subtle perturbation in the form of smartphone deprivation lasting for ~7 days. We quantified the sensorimotor processes associated with the fingertips before and after the deprivation in right-handed smartphone users. The measurements were contrasted with those of a control group with unperturbed smartphone behavior. First, smartphone tapping speed in daily life became slower after the deprivation. Second, according to reaction time tests conducted in the laboratory the asymmetrically superior performance of the right vs. left thumb was eroded by the deprivation. Third, according to EEG measurements at physical rest, tactile stimulation at the right thumb tip resulted in smaller signal amplitudes after the deprivation. Moreover, the EEG measurements during smartphone use revealed larger signal amplitudes for tactile stimulation at the right little fingertip after the deprivation. We show that cortical plasticity can occur by merely disengaging from a common day-to-day behavior. We suggest that in daily life the adult brain continuously and selectively updates its sensorimotor processing according to recent experience.

Smartphone deprivation alters cortical sensorimotor processing of the hand

Trait-like nocturnal sleep behavior identified by combining wearable, phone-use, and self-report data

To compile and report the ocular manifestations of coronavirus disease 2019 (COVID-19) infection and summarize the ocular side effects of investigational treatments of this disease.

Conjunctivitis is by far the most common ocular manifestation of COVID-19 with viral particles being isolated from tears/secretions of infected individuals. Multiple therapeutic options are being explored across a variety of medication classes with diverse ocular side effects.

SUMMARY
Eye care professionals must exercise caution, as conjunctivitis may be the presenting or sole finding of an active COVID-19 infection. While no currently studied therapeutic agents have been found to reliably treat COVID-19, early vaccination trials are progressing and show promise. A video abstract is available for a more detailed summary. VIDEO ABSTRACT: http://links.lww.com/COOP/A36.

Ophthalmic manifestations of coronavirus disease 2019 and ocular side effects of investigational pharmacologic agents.

The distribution of intervals between human actions such as email posts or keyboard strokes demonstrates distinct properties at short versus long timescales. For instance, at long timescales, which are presumably controlled by complex process such as planning and decision making, it has been shown that those interevent intervals follow a scale-invariant (or power-law) distribution. In contrast, at shorter timescales-which are governed by different processes such as sensorimotor skill-they do not follow the same distribution and we know little about how they relate to the scale-invariant pattern. Here, we analyzed 9 million intervals between smartphone screen touches of 84 individuals which span several orders of magnitudes (from milliseconds to hours). To capture these intervals, we extend a priority-based generative model to smartphone touching events. At short timescale, the model is governed by refractory effects, while at longer timescales, the intertouch intervals are governed by the priority difference between smartphone tasks and other tasks. The flexibility of the model allows us to capture interindividual variations at short and long timescales, while its tractability enables efficient model fitting. According to our model, each individual has a specific power-law exponent which is tightly related to the effective refractory time constant suggesting that motor processes which influence the fast actions are related to the higher cognitive processes governing the longer interevent intervals.

Striatal dopamine synthesis capacity reflects smartphone social activity

Clinical observations suggest dynamic alterations in behavior after brain surgery. While some alterations reportedly occur within days others gradually develop over several months. These alterations can be attributed to the pre-surgical impact of the diseased tissue, neuronal damage caused by the surgery, and subsequent plasticity. A key step towards a systems-level understanding of the brain-behavior relationships is to capture the dynamics of the cognitive alterations. Here, we first established in 38 healthy individuals that the day-to-day smartphone interactions can be used to inform on cognitive processing speed. Next, we analyzed the smartphone interactions in 12 patients undergoing intracranial tumor surgery, with postsurgical follow-up of up to a year. In healthy individuals, the speed of the touchscreen interactions was highly correlated to choice reaction times (R2 = 0.71) but less so to simple reaction times (R2 = 0.15) on Deary-Liewald tests. Touchscreen interactions slowed immediately after surgery but the post-surgical changes varied between patients. Data-driven models revealed the time-constant of the short-term postsurgical changes and the time taken to stabilize after the surgery. Furthermore, by using conceptually distinct types of touchscreen interaction speeds - i.e. unlocking time and app locating speed - we established that the post-surgical changes are domain-specific. Interestingly, in this small sample, the pre-surgical smartphone speeds were highly related to the speeds post-stabilization (R2 = 0.75 to 0.95). The proxy measures of cognition seamlessly captured on the smartphone can reveal postsurgical dynamics inaccessible to conventional testing. We propose that the transient cognitive alterations indicate the time-constrained influence of distinct neuronal mechanisms triggered by the surgery.

Passive smartphone-based assessment of cognitive changes in neurosurgery

The details of past actions on a smartphone touchscreen are reflected by intrinsic sensorimotor dynamics

While pathologies of the central nervous system (CNS) are often associated with neuropsychological deficits, adequate quantification and monitoring of such deficits remains challenging. Due to their complex nature, comprehensive neuropsychological evaluations are needed, which are time-consuming, resource-intensive and do not adequately account for daily or hourly fluctuations of a patient’s condition. Innovative approaches are required to improve the diagnostics and continuous monitoring of brain function, ideally in the form of a simple, objective, time-saving and inexpensive tool that overcomes the aforementioned weaknesses of conventional assessments. As smartphones are widely used and integrated in virtually every aspect of our lives, their potential regarding the acquisition of data representing an individual’s behavior and health is enormous. Alterations in a patient’s physical or mental health state may be recognized as behavioral deviation from the physiological range of the normal population, but also in comparison to the patient’s individual baseline assessment. As smartphone-based assessment allows for continuous monitoring and therefore accounts for possible fluctuations or transiently occurring abnormalities in a patient’s neurologic state, it may serve as a surveillance tool in the acute setting for early recognition of complications, or in the long-term outpatient setting to quantify rehabilitation or disease progress. This may be particularly interesting for regions of the world where healthcare resources for comprehensive clinical/neuropsychological examinations are insufficient or distances to healthcare providers are long. Here, we highlight the potential of smartphone-based behavioral monitoring in healthcare. Clinical Trial Registration: www.clinicaltrials.gov, identifier NCT03516162.

Time to be “smart”—Opportunities Arising From Smartphone-Based Behavioral Analysis in Daily Patient Care

Capturing sleep–wake cycles by using day-to-day smartphone touchscreen interactions

Linking Elementary Properties of the Human Brain to the Behaviour Captured on Touchscreen Smartphones

Human activities from hunting to emailing are performed in a fractal-like scale invariant pattern. These patterns are considered efficient for hunting or foraging, but are they efficient for gathering information? Here we link the scale invariant pattern of inter-touch intervals on the smartphone to optimal strategies for information gathering. We recorded touchscreen touches in 65 individuals for a month and categorized the activity into checking for information vs. sharing content. For both categories, the inter-touch intervals were well described by power-law fits spanning 5 orders of magnitude, from 1 s to several hours. The power-law exponent typically found for checking was 1.5 and for generating it was 1.3. Next, by using computer simulations we addressed whether the checking pattern was efficient - in terms of minimizing futile attempts yielding no new information. We find that the best performing power law exponent depends on the duration of the assessment and the exponent of 1.5 was the most efficient in the short-term i.e. in the few minutes range. Finally, we addressed whether how people generated and shared content was in tune with the checking pattern. We assumed that the unchecked posts must be minimized for maximal efficiency and according to our analysis the most efficient temporal pattern to share content was the exponent of 1.3 - which was also the pattern displayed by the smartphone users. The behavioral organization for content generation is different from content consumption across time scales. We propose that this difference is a signature of optimal behavior and the short-term assessments used in modern human actions.

A hallmark of human behavior is the ability to choose from a set of available actions. According to one theory humans execute the task with the highest priority at each decision point Barabasi (2005); Vázquez et al. (2006). The easy access to smartphones forces us to decide between using the phone or performing some other activity that does not involve the phone. Here we show that the priority placed on the phone shapes the temporal dynamics of the behaviour across multiple time scales and we estimate the perceived importance of touchscreen actions in 84 individuals. Heavy-tailed powerlaw distribution of inter-event times emerged from repeating a simple decision process that decided between smartphone actions and all other actions. The shape of this distribution was determined by the allocated priority of smartphone actions such that the higher the priority on the smartphone over any other actions the fewer the longer gaps across multiple time scales. Quantification of real touchscreen activities showed a heavy-tailed power law distribution of inter-event times ranging from a second to several hours. Over the sampled population, the mean power-law exponent is 1.82 (±0.12) and we estimate that 4.8% of the population consider touchscreen tasks to be more important than any other activity. Results Intervals between smartphone touches are scale invariant The first aim of our study is to objectively quantify the priority that each individual places on their smartphone. The second aim is to find a non-arbitrary priority threshold such that in a given population, we can state what is the fraction of individuals who place a higher priority on their smartphone than any other activity. Here, we recorded the timing of the touchscreen touches from 84 individuals over a month long period. What is the priority theses individuals place on their smartphones? A naive possibility would be to simply count the number of touches per day N and claim that higher the N more the priority individuals place on their smartphone. However, the relationship between N and the priority placed on the smartphone is not obvious and any threshold N∗ would arbitrarily demarcate individuals who place a higher priority on the smartphone than any other activity. So this proposition would fall short of the 2 aims listed above. Here, we take the perspective that the intervals between touches carry the relevant information to characterise the level of priority placed on the smartphone. In particular, the presence of a lot of long inter-touch intervals (ITI) would be a sign that the smartphone is not that important to the individual. At which scale should those intervals be computed? Answering this is particularly complicated by the fact that at whatever scale we examine the data it appears with similar patterns (see Fig. 1a): short bursts are followed by long intervals. Quantitatively, the range of seconds to hours the distribution of inter-touch interval τ is scale free and can be described by a power-law distribution for intervals larger than τmin (see Fig. 1b) p(τ) ∝ τ−α τ > τmin (1) 1 ar X iv :1 61 2. 03 19 6v 1 [ cs .S I] 6 D ec 2 01 6

Quantifying the priority placed on scale-free smartphone actions

Smartphone users touch the screen of the phone thousands of times per day. The inter-touch intervals follow a power-law distribution. We propose a multi-scale statistical model for those smartphone touches. At short-time scale, the model is governed by refractory effects, while at longer time scales, the touching rate is governed by the priority difference between smartphone tasks and other tasks. We show that both the statistics of the short intervals as well as the longer intervals are well captured by the model. The model is described in continuous time and the inter-touch interval distribution can be computed analytically.

As a common neuroscientific observation, the more a body part is used, the less variable the corresponding computations become. We here report a more complicated scenario concerning the fingertips of smartphone users. We sorted 21-days histories of touchscreen use of 57 volunteers into social and non-social categories. Sensorimotor variability was measured in a laboratory setting by simple button depressions and scalp electrodes (electroencephalogram, EEG). The ms range trial-to-trial variability in button depression was directly proportional to the number of social touches and inversely proportional to non-social touches. Variability of the early tactile somatosensory potentials was also proportional to the number of social touches, but not to non-social touches. The number of Apps and the speed of touchscreen use also reflected this variability. We suggest that smartphone use affects elementary computations even in tasks not involving a phone and that social activities uniquely reconfigure the thumb to touchscreen use. Impact Statement Unconstrained behavior on a smartphone is a powerful predictor of neuronal functions measured in the laboratory and the details of the smartphone-neuronal association challenges the established ideas of brain plasticity.

Neuronal control of the fingertips is socially configured in touchscreen smartphone users

Modern humans are frequently faced with the problem of choosing between using the phone or doing something else. In the laboratory, how people choose between two simple activities is well studied but they cannot address how people solve the ubiquitous problem of using the phone in the real world. Here we extended an existing priority-based decision framework to theoretically link the timing of the touchscreen taps to the priority attributed to the corresponding behavior. The inter-event times of the output from this decision process could be fully described by a 3 parameter model. Next, we recorded the touchscreen interactions from 84 volunteers for a month-long period and the inter-event times were well described by using the 3 parameter model. Based on the fitted parameters we find that in 76% of the users the overall (mean) priority of smartphone use is higher than any other activity. The underlying priority distributions estimated from the recordings were typically (82% of the population) u-shaped with the priority values concentrated at the extreme values. We conclude that the priority attributed to the smartphone is not fixed and the perceived importance of the smartphone transitions from one extreme to another.

To tap or not to tap: a model-based quantification of the priority placed on smartphone actions

The distribution of intervals between human actions such as email posts or keyboard strokes demonstrates distinct properties at short vs long time scales. For instance, at long time scales, it has been shown that those inter-event intervals follow a scale-invariant (or power-law) distribution. In contrast, little do we know about the events that occur at the shorter time-scales and how they relate to the scale-invariant pattern. Here, we analysed the intervals between smartphone screen touches of 84 individuals which span several orders of magnitudes (from milliseconds to days). To capture these intervals, we propose a priority-based generative model for smartphone touching events. At short-time scale, the model is governed by refractory effects, while at longer time scales, the inter-touch intervals are governed by the priority difference between smartphone tasks and other tasks. The flexibility of the model allows to capture inter-individual variations at short and long time scales while its tractability enables very efficient model fitting. We show that each individuals has a specific power-low exponent which is tightly related to the effective refractory time constant suggesting that the fine motor control properties (which influence short intervals) are related to the higher cognitive processes (which affect longer intervals).

Voluntary motor commands reveal awareness and control of involuntary movement

A Diet Mimicking Fasting P romotes Regeneration and Reduces Autoimmunity and Multiple Sclerosis Symptoms Graphical

A Diet Mimicking Fasting Promotes Regeneration and Reduces Autoimmunity and Multiple Sclerosis Symptoms.

Use-Dependent Cortical Processing from Fingertips in Touchscreen Phone Users

Botulinum Toxin-A dose dependent perceptual loss on the hand after its cosmetic use on the face

[Smartphone use shapes cortical tactile sensory processing from the fingertips].

Involuntary movements share much of the motor control circuitry used for voluntary movement, yet the two can be easily distinguished. The Kohnstamm phenomenon (where a sustained, hard push produces subsequent involuntary arm raising) is a useful experimental model for exploring differences between voluntary and involuntary movement. Both central and peripheral accounts have been proposed, but little is known regarding how the putative Kohnstamm generator responds to afferent input. We addressed this by obstructing the involuntary upward movement of the arm. Obstruction prevented the rising EMG pattern that characterizes the Kohnstamm. Importantly, once the obstruction was removed, the EMG signal resumed its former increase, suggesting a generator that persists despite peripheral input. When only one arm was obstructed during bilateral involuntary movements, only the EMG signal from the obstructed arm showed the effect. Upon release of the obstacle, the obstructed arm reached the same position and EMG level as the unobstructed arm. Comparison to matched voluntary movements revealed a preserved stretch response when a Kohnstamm movement first contacts an obstacle, and also an overestimation of the perceived contact force. Our findings support a hybrid central and peripheral account of the Kohnstamm phenomenon. The strange subjective experience of this involuntary movement is consistent with the view that movement awareness depends strongly on efference copies, but that the Kohnstamm generator does not produces efference copies.

The perceived distance between touches on the limbs is generally bigger for distances oriented across the width of the limb than for distances oriented along the length of the limb. The present study aimed to investigate the coherence of such distortions of tactile size perception across different skin surfaces. We investigated distortions of tactile size perception on the dorsal and palmar surfaces of both the left and right hands as well as the forehead. Participants judged which of two tactile distances felt larger. One distance was aligned with the proximodistal axis (along the body), the other with the mediolateral axis (across the body). Clear distortions were found on all five skin surfaces, with stimuli oriented across the width of the body being perceived as farther apart than those oriented along the length of the body. Consistent with previous results, distortions were smaller on the palmar than on the dorsal hand surface. Distortion on the forehead was intermediate between the dorsal and palmar surfaces. There were clear correlations between distortion on the left and right hands, for both the dorsal and palmar skin surfaces. In contrast, within each hand, there was no significant correlation between the two skin surfaces. Distortion on the forehead was not significantly correlated with that on any of the other skin surfaces. These results provide evidence for bilaterally symmetric representations underlying tactile size perception.

Institute of Cognitive Neuroscience, University CollegeLondon, 17 Queen Square, London WC1N 3AR, UKSummaryCortical activity allotted to the tactile receptors on ﬁngertipsconforms to skilful use of the hand [1–3]. For instance, instring instrument players, the somatosensory cortical activ-ity in response to touch on the little ﬁngertip is larger thanthat in control subjects [1]. Such plasticity of the ﬁngertipsensory representation is not limited to extraordinary skillsand occurs in monkeys trained to repetitively grasp andrelease a handle as well [4]. Touchscreen phones alsorequire repetitive ﬁnger movements, but whether and howthe cortex conforms to this is unknown. By using electroen-cephalography(EEG),wemeasuredthecorticalpotentialsinresponsetomechanicaltouchonthethumb,index,andmid-dle ﬁngertips of touchscreen phone users and nonusers(owning only old-technology mobile phones). Although thethumb interacted predominantly with the screen, the poten-tials associated with the three ﬁngertips were enhanced intouchscreen users compared to nonusers. Within thetouchscreen users, the cortical potentials from the thumband index ﬁngertips were directly proportional to the inten-sity of use quantiﬁed with built-in battery logs. Remarkably,the thumb tip was sensitive to the day-to-day ﬂuctuations inphone use: the shorter the time elapsed from an episode ofintense phone use, the larger the cortical potential associ-ated with it. Our results suggest that repetitive movementson the smooth touchscreen reshaped sensory processingfrom the hand and that the thumb representation was up-dated daily depending on its use. We propose that corticalsensory processing in the contemporary brain is continu-ously shaped by the use of personal digital technology.ResultsCortical Fingertip Representations in Touchscreen PhoneUsers Differ from Those Found in NonusersWe analyzed 37 right-handed volunteers, 26 of whom usedtouchscreen phones and 11 of whom used old-technologymobile phones. Questionnaires provided few key insightsinto how the more modern phones were used. First,touchscreen users primarily used their right thumb on thescreen as opposed to other ﬁngers (Figure 1A), and none ofthemusedastylus.Thethumbpreferencewasexpectedgiventhat hand-held phones were designed as such [5]. Second, inagreement with a US national survey on smartphone use,80% of the touchscreen users in our study mainly used theirphone for receiving and sending text messages or e-mails,as opposed to passively listening to music, watching videos,or making calls [6]. Finally, according to the self-reports,touchscreen users spent noticeably more time with theirphones than did the nonusers (Figure 1B).Weinvestigatedwhetherthesomatosensorycorticalelectri-cal activity evoked from the ﬁngertips differed betweentouchscreen phone users and nonusers. Sixty-two surfaceelectrodes distributed over the entire scalp were used todetect cortical potentials evoked by touch on the thumb, in-dex, and middle ﬁngertips of the right hand. Each tactile stim-ulus consisted of a light mechanical contact that lasted for2 ms, and event-related potentials (ERPs) were based on1,250 stimulations on each ﬁngertip. For all three ﬁngertipstested both in touchscreen users and nonusers, the touch re-sulted in a dipole ﬁeld around the contralateral (to stimulation)somatosensory cortex with signal onset at 32 ms and peak at55 ms (on grand mean traces). The positive ERPs were de-tectedinthecontralateralparietalelectrodes,andthenegativesignalsweredetectedmoremediallyinthecontra-andipsilat-eral frontal electrodes (Figures 1C–1H). Based on the latencyand signal topology, we could assert that these signals origi-nated from the primary somatosensory cortex [7–9]. Weanalyzed the signal differences between the touchscreenusers and nonusers across all time points (50 ms prestimula-tionto120mspoststimulation)andforeachelectrodebyusingtwo-sample t tests corrected for multiple comparisons using2D spatiotemporal clustering [10]. Interestingly, for all of thetested ﬁngertips, the amplitude of the positive ERP was largerin touchscreen users compared to nonusers (Figures 1C–1H).Temporally,thepositivesignalsdifferedbetween39and68msforthethumbtip, between 38and60msfor theindex ﬁngertip,andbetween48and66msforthemiddleﬁngertip(Figures1C,1E, and 1G). Spatially, the statistical maps revealed that thedifferences were clustered on the contralateral parietal scalpfor all the three ﬁngertips (Figures 1D, 1F, and 1H). However,the spatial extent of these differences was the smallest forthe middle ﬁnger (Figure 1H).In short, touchscreen users relied mostly on their thumb tointeract with the screen, but the cortical potentials associatedwith the ﬁrst three ﬁngertips were enhanced in comparison tononusers. However, the spatiotemporal impact of phone usewas the least prominent for the middle ﬁngertip.The Amount of Touchscreen Phone Use InﬂuencesCortical ActivityTheincreasedcorticalactivityintouchscreen userscomparedtononuserscouldbeduetoamoreintenseusageofthehand,in the sense that the former group used the right thumb morethan the latter group did. Alternatively, it could be due tothe development of touchscreen-speciﬁc motor routines or‘‘skills’’ as the movements associated with push buttons (innonusers, who used only old-technology mobile phones)

Rapid functional reorganization of the forelimb cortical representation after thoracic spinal cord injury in adult rats

Withdrawal of voluntary inhibition unravels the off state of the spontaneous blink generator

Tactile underrepresentation of the forehead along the vertical axis

A hallmark of voluntary motor control is the ability to stop an ongoing movement. Is voluntary motor inhibition a general neural mechanism that can be focused on any movement, including involuntary movements, or is it mere termination of a positive voluntary motor command? The involuntary arm lift, or ‘floating arm trick’, is a distinctive long-lasting reflex of the deltoid muscle. We investigated how a voluntary motor network inhibits this form of involuntary motor control. Transcranial magnetic stimulation of the motor cortex during the floating arm trick produced a silent period in the reflexively contracting deltoid muscle, followed by a rebound of muscle activity. This pattern suggests a persistent generator of involuntary motor commands. Instructions to bring the arm down voluntarily reduced activity of deltoid muscle. When this voluntary effort was withdrawn, the involuntary arm lift resumed. Further, voluntary motor inhibition produced a strange illusion of physical resistance to bringing the arm down, as if ongoing involuntarily generated commands were located in a ‘sensory blind-spot’, inaccessible to conscious perception. Our results suggest that voluntary motor inhibition may be a specific neural function, distinct from absence of positive voluntary motor commands.

Using voluntary motor commands to inhibit involuntary arm movements

•  Voluntary motor commands and spinal reflexes both produce body movements that activate sensors located in the muscles, joints, tendon and skin. •  It is unknown whether perceptions generated by the sensory inputs from voluntary movements can be distinguished from perception of inputs due to spinal reflexes. Surprisingly, the perception of reflexes remains largely unaddressed. •  Knee‐jerk reflexes were perceived accurately on the basis of proprioceptive inputs alone, but perception was poorer when volunteers were instructed to voluntarily kick backwards or forwards as rapidly as possible in response to the tendon tap. •  This demonstrates that sensory inputs from a spinal reflex lead to movement perception. However, there is no clear perceptual landmark separating reflexes from voluntary movements, even when the two movements involve antagonistic muscles. •  These findings help us to understand how sensory feedback from body movement leads to movement perception and awareness of action.

The spinal reflex cannot be perceptually separated from voluntary movements

Astrocytes play a crucial role in maintaining neuronal function and monitoring their activity. According to neuronal activity maps, the body is represented topographically in the somatosensory cortex. In rats, neighboring cortical areas receive forelimb (FL) and hindlimb (HL) sensory inputs. Whether astrocytic activity is also restricted to the cortical area receiving the respective peripheral sensory inputs is not known. Using wide field optical imaging we measured changes in the concentration of astrocytic calcium within the FL and HL sensorimotor cortex in response to peripheral sensory inputs. Mapping the calcium signals upon electrical stimulation of the forepaw and hindpaw we found activity largely restricted to the FL and HL area, respectively. In comparison to neuronal activity the time course of the astrocytic calcium activity was considerably slower. The signal took 6 s to peak after the onset of a 2 Hz and 2 s long electrical stimulation of the hindpaw and 8 s for a 4 s stimulation. The astrocytic signals were delayed relative to cerebral blood flow measured using laser speckle imaging. The intensity of both the astrocytic and neuronal signals in the HL sensorimotor cortex declined with increase in stimulation frequency. Moreover, blocking neuronal input by tetrodotoxin abolished astrocytic calcium signals. We suggest that the topographical representation of the body is not only true for cortical neurons but also for astrocytes. The maps and the frequency‐dependent activations reflect strong reciprocal neuroglial communication and provide a new experimental approach to explore the role of astrocytes in health and disease. © 2013 Wiley Periodicals, Inc.

Astrocytes play a crucial role in maintaining neuronal function and monitoring their activity. According to neuronal activity maps, the body is represented topographically in the somatosensory cortex. In rats, neighboring cortical areas receive forelimb (FL) and hindlimb (HL) sensory inputs. Whether astrocytic activity is also restricted to the cortical area receiving the respective peripheral sensory inputs is not known. Using wide field optical imaging we measured changes in the concentration of astrocytic calcium within the FL and HL sensorimotor cortex in response to peripheral sensory inputs. Mapping the calcium signals upon electrical stimulation of the forepaw and hindpaw we found activity largely restricted to the FL and HL area, respectively. In comparison to neuronal activity the time course of the astrocytic calcium activity was considerably slower. The signal took 6 s to peak after the onset of a 2 Hz and 2 s long electrical stimulation of the hindpaw and 8 s for a 4 s stimulation. The astrocytic signals were delayed relative to cerebral blood flow measured using laser speckle imaging. The intensity of both the astrocytic and neuronal signals in the HL sensorimotor cortex declined with increase in stimulation frequency. Moreover, blocking neuronal input by tetrodotoxin abolished astrocytic calcium signals. We suggest that the topographical representation of the body is not only true for cortical neurons but also for astrocytes. The maps and the frequency-dependent activations reflect strong reciprocal neuroglial communication and provide a new experimental approach to explore the role of astrocytes in health and disease. V C 2013

Plastic interactions between face and hand cortical tactile circuits occur after severe injuries that affect the hand such as in amputation or spinal cord injury. However, whether loss of facial movements alters the cortical circuits involved in processing tactile inputs from the hand remains unknown. In this prospective observational study we used electroencephalography (EEG) to measure cortical activity evoked by tactile stimulation of the hands before and after botulinum toxin‐A‐induced facial paralysis. We found a reduction in the tactile event‐related potentials (ERPs) 6 weeks after the treatment. This suggests that the limited paralysis of facial muscles induced during cosmetic interventions designed to smooth lines and wrinkles on the face is sufficient to alter the cortical processing of tactile inputs from the hand.

Altered cortical activation from the hand after facial botulinum toxin treatment

A large thoracic spinal cord injury disconnects the hindlimb (HL) sensory-motor cortex from its target, the lumbar spinal cord. The fate of the synaptic structures of the axotomized cortical neurons is not well studied. We evaluated the density of spines on axotomized corticospinal neurons at 3, 7, and 21 days after the injury in adult mice expressing yellow fluorescence protein in a subset of layer 5 neurons. Spine density of the dendritic segment proximal to the soma (in layer 5) declined as early as 3 days after injury, far preceding the onset of somatic atrophy. In the distal segment (in layer 2/3), spine loss was slower and less severe than in the proximal segment. Axotomy of corticospinal axons in the brainstem (pyramidotomy) induced a comparable reduction of spine density, demonstrating that the loss is not restricted to the neurons axotomized in the thoracic spinal cord. Surprisingly, in both forms of injury, the spine density of putative non-axotomized layer 5 neurons was reduced as well. The spine loss may reflect fast rearrangements of cortical circuits after axotomy, for example, by a disconnection of HL cortical neurons from synaptic inputs that no longer provide useful information.

Heterogeneous spine loss in layer 5 cortical neurons after spinal cord injury.

Progressive loss of lung function and reversibility characterize chronic asthma. The conventional therapy is targeted to control the disease without targeting the loss of lung function or reversibility. In a prospective real-world observation of long-term use of add-on doxycycline as a matrix-metalloproteinase inhibitor, we documented significant improvement in lung function with possible reversal of remodeling. Background Chronic asthma shows progressive decline in lung function with reduction or even loss of reversibility secondary to remodeling. A set of endopeptidase enzymes known as matrix metalloproteinases are intimately related to the pathogenesis of asthma and remodeling. The inhibition of matrix metalloproteinases is recognized as a prospective way of treating asthma and its corresponding structural remodeling. Methods In a randomized, prospective, real-world study, we have observed the change in lung function (spirometry) with an add-on of long-term doxycycline to standard asthma therapy as per the Global Initiative for Asthma guidelines in a small asthmatic population. The change in terms of forced expiratory volume (FEV1), forced vital capacity (FVC), percent of FEV1 (FEV1%), and forced expiratory flow (FEF25–75) were noted following variable duration of doxycycline therapy. Results There has been a global improvement in all the parameters in all the six patients suggesting improvement in obstruction, and reduction in air trapping following a treatment of add-on doxycycline for a mean duration of 162.83 ± 83.07 days. Of the changes seen, the post bronchodilator FEV1, the FVC, and the FEF25–75 showed significant improvements with the P-value set at 0.004, 0.054, and 0.031, respectively. There was also evidence of the reversal of remodeling from the improvement in the FEV1/FVC ratio. Moreover there was a greater than expected improvement of pre-bronchodilator FEV1 after treatment that far surpassed the initial post-bronchodialator FEV1 value. Even after such a change, there were presences of some reversibility suggesting room for further improvement. Conclusion The results suggest significant improvements in the obstructive parameters used to evaluate asthma, with possible reversal of remodeling evident in chronic asthmatics when treated with doxycycline in addition to standard therapies. This observation needs further scientific validation.

Long-term use of doxycycline can improve chronic asthma and possibly remodeling: the result of a pilot observation

Rewiring of hindlimb corticospinal neurons after spinal cord injury

A lateral hemisection injury of the cervical spinal cord results in Brown-Séquard syndrome in humans and rats. The hands/forelimbs on the injured side are rendered permanently impaired, but the legs/hindlimbs recover locomotor functions. This is accompanied by increased use of the forelimb on the uninjured side. Nothing is known about the cortical circuits that correspond to these behavioral adaptations. In this study, on adult rats with cervical spinal cord lateral hemisection lesions (at segment C3/4), we explored the sensory representation and corticospinal projection of the intact (ipsilesional) cortex. Using blood oxygenation level-dependent functional magnetic resonance imaging and voltage-sensitive dye (VSD) imaging, we found that the cortex develops an enhanced representation of the unimpaired forepaw by 12 weeks after injury. VSD imaging also revealed the cortical spatio-temporal dynamics in response to electrical stimulation of the ipsilateral forepaw or hindpaw. Interestingly, stimulation of the ipsilesional hindpaw at 12 weeks showed a distinct activation of the hindlimb area in the intact, ipsilateral cortex, probably via the injury-spared spinothalamic pathway. Anterograde tracing of corticospinal axons from the intact cortex showed sprouting to recross the midline, innervating the spinal segments below the injury in both cervical and lumbar segments. Retrograde tracing of these midline-crossing axons from the cervical spinal cord (at segment C6/7) revealed the formation of a new ipsilateral forelimb representation in the cortex. Our results demonstrate profound reorganizations of the intact sensory-motor cortex after unilateral spinal cord injury. These changes may contribute to the behavioral adaptations, notably for the recovery of the ipsilesional hindlimb.

Functional and Anatomical Reorganization of the Sensory-Motor Cortex after Incomplete Spinal Cord Injury in Adult Rats

Functional reorganization in rat somatosensory cortex assessed by fMRI: Elastic image registration based on structural landmarks in fMRI images and application to spinal cord injured rats

Chronic spinal hemisection in rats induces a progressive decline in transmission in uninjured fibers to motoneurons

An excess of extracellular glutamate in the hippocampus has been linked to the generation of recurrent seizures and brain pathology in patients with medically intractable mesial temporal lobe epilepsy (MTLE). However, the mechanism which results in glutamate excess in MTLE remains unknown. We recently reported that the glutamate-metabolizing enzyme glutamine synthetase is deficient in the hippocampus in patients with MTLE, and we postulated that this deficiency is critically involved in the pathophysiology of the disease. To further explore the role of glutamine synthetase in MTLE we created a novel animal model of hippocampal glutamine synthetase deficiency by continuous (approximately 28 days) microinfusion of methionine sulfoximine (MSO: 0.625 to 2.5 microg/h) unilaterally into the hippocampus in rats. This treatment led to a deficiency in hippocampal glutamine synthetase activity by 82-97% versus saline. The majority (>95%) of the MSO-treated animals exhibited recurrent seizures that continued for several weeks. Some of the MSO-treated animals exhibited neuropathological features that were similar to mesial temporal sclerosis, such as hippocampal atrophy and patterned loss of hippocampal neurons. However, many MSO-treated animals displayed only minimal injury to the hippocampus, with no clear evidence of mesial temporal sclerosis. These findings support the hypothesis that a deficiency in hippocampal glutamine synthetase causes recurrent seizures, even in the absence of classical mesial temporal sclerosis, and that restoration of glutamine synthetase may represent a novel approach to therapeutic intervention in this disease.

Recurrent seizures and brain pathology after inhibition of glutamine synthetase in the hippocampus in rats.

Chronic thoracic hemisection spinal cord injury in adult rats induces a progressive decline in transmission from uninjured fibers to lumbar motoneurons

Hypertonicity induced apoptosis in HL-60 cells in the presence of intracellular potassium

Intrathecally infused antibodies against Nogo-A penetrate the CNS and downregulate the endogenous neurite growth inhibitor Nogo-A

Process Safety Assessment Considering Multivariate Non-linear Dependence Among Process Variables

The complexities of process plants are increasing because of process integration and plant-wide optimization. Failure models of a process system (henceforth referred to as process-accident models) should be able to capture the inherent dependence among process components and their associated variables and also the temporal dependencies among failures. This work demonstrates the suitability and applicability of process-accident models in capturing temporal dependence using process data. Performances of process-accident models are investigated to establish their competitive advantages as well as their limitations. Using experimental data from a pilot plant, the performances of three widely used accident models, namely, the fault tree (FT), the dynamic fault tree (DFT), and the dynamic Bayesian network (DBN), are evaluated in predicting abnormal events. Normal and abnormal process data is collected and used in studying the three different models to assess the process-accident probability. The study confirmed...

Modeling and Testing of Temporal Dependency in the Failure of a Process System

In this paper, seven critical parameters have been identified contributing to generation shortages, and affecting the peak load demand forecasting for power system generation planning. Due to the difficulty to predict the occurrence of each parameter effectively, the time series regression models of these parameters and the peak load demand are developed using the curve fitting tool box in MATLAB. The accuracy of the developed models is evaluated through the residual, goodness of fit, and percentage errors calculated between actual and calculated data.

2018 IEEE Canadian Conference on Electrical & Computer Engineering (CCECE)

Regression Models of Critical Parameters Affecting Peak Load Demand Forecasting

363 m/s n° 4, vol. 31, avril 2015 DOI : 10.1051/medsci/20153104006 La plasticité cérébrale au quotidien L’architecture de base de notre cerveau n’est pas complètement figée mais peut évoluer dans le temps, par exemple au cours du développement du système nerveux ou, chez l’adulte, pendant les phases d’apprentissage, en fonction du degré d’utilisation des différentes parties du corps. On appelle « plasticité cérébrale par l’usage » la capacité qu’a le cerveau à augmenter sélectivement le traitement de l’information associée à une partie du corps en réponse à une plus grande utilisation de celle-ci [1-3]. Jusqu’à présent, la plasticité cérébrale par l’usage a été mise en évidence dans des situations extrêmes, que ce soit chez des patients ayant perdu une partie du corps après un traumatisme (lésion de la moelle épinière, amputation, membre immobilisé) [4, 5], ou chez des sujets montrant des habiletés extraordinaires nécessitant une utilisation particulièrement intensive d’une partie du corps, comme les sportifs d’élite [6], les aveugles lisant le Braille [7] et les musiciens [8]. Chez les joueurs d’instruments à cordes [8] par exemple, la représentation corticale de la main gauche, occupée à raccourcir la longueur des cordes de l’instrument (ce qui requiert donc une grande dextérité manuelle et une forte stimulation sensorielle), était non seulement plus étendue que celle de la main droite, qui manie si besoin l’archet, mais également plus étendue que celle de la main gauche chez des sujets contrôles. Ces exemples de plasticité cérébrale chez des sujets hors du commun conduisent alors à se demander si ce phénomène intervient aussi dans notre vie quotidienne. Les technologies digitales personnelles telles que les téléphones portables avec écran tactile ou smartphones, constituent des « supports » de choix pour répondre à cette question. Non seulement ces petits appareils occupent une place prépondérante dans nos vies, mais ils permettent également d’utiliser leur propre technologie pour en suivre l’utilisation faite par leur propriétaire. L’électroencéphalographie (EEG) offre la possibilité d’étudier de manière non invasive, et avec une grande résolution temporelle, l’activité électrique générée par le cortex cérébral. L’étude relatée ici [9] a porté sur l’enregistrement de l’activité corticale par EEG de surface (62 électrodes sur le cuir chevelu) en réponse à des stimulations tactiles très focales (d’une durée de 2 ms, provoquant une légère déformation de la peau) appliquées sur la phalange distale du pouce, de l’index et du majeur droits chez 37 sujets droitiers : 26 possédaient un smartphone et 11 un téléphone portable d’ancienne génération, sans écran tactile. Des potentiels évoqués somatosensoriels (PES) ont été obtenus par le moyennage de 1 250 stimulations par doigt stimulé. Les technologies digitales personnelles façonnent le traitement de l’information tactile par le cerveau À notre plus grande surprise, alors que les utilisateurs de smartphones interagissaient avec l’écran tactile de leur appareil essentiellement par le pouce, l’amplitude de l’activité corticale en réponse aux stimulations tactiles des extrémités des trois doigts testés s’est avérée statistiquement plus grande chez les utilisateurs de smartphones que chez les utilisateurs de téléphones portables d’ancienne génération (Figure 1A). Cette différence s’observait spatialement au niveau des électrodes contralatérales pariétales pour les trois sites de stimulation, bien que plus faible suite à la stimulation du majeur (Figure 1B-C). Grâce à des stimulations tactiles simultanées des extrémités du pouce et de l’index, nous avons aussi démontré que l’augmentation de l’activité cérébrale chez les utilisateurs de smartphones ne s’était pas produite aux dépens des interactions inhibitrices [10] entre les doigts, phénomène qui permet d’augmenter la capacité de discrimination tactile. Restait alors à expliquer l’activité corticale des adeptes du smartphone. Pour ce faire, des analyses de régressions multiples ont été réalisées entre l’activité cérébrale moyenne de la populaL’utilisation de smartphones façonne le traitement cortical de l’information sensorielle tactile provenant de l’extrémité des doigts Anne-Dominique Gindrat1,*, Magali Chytiris1,2,*, Myriam Balerna1,2,*, Eric M. Rouiller1, Arko Ghosh2-4 NOUVELLE

L’utilisation de smartphones façonne le traitement cortical de l’information sensorielle tactile provenant de l’extrémité des doigts

Levodopa has remained the mainstay of medical therapy for Parkinson’s disease since its development in the 1980s. However, long-term medication use is associated with declining clinical efficacy and the emergence of motor complications. Unveiling the effects of levodopa on brain functional reorganisation at a relatively early treatment phase is therefore imperative to inform the optimisation of Parkinson’s therapeutics. In this study, we comprehensively investigated levodopa’s modulation on the resting-state functional connectivity in the cortico- basal ganglia-cerebellum system at regional and network levels, with dual cross-sectional and longitudinal designs. The data was extracted from the Parkinson’s Progression Marker Initiative (PPMI) dataset. The cross-sectional patient groups comprised 17 Parkinson’s patients on stable levodopa medication and 15 drug-naïve patients, while the longitudinal set included 14 Parkinson’s patients measured at both drug-naïve and levodopa-medicated conditions. With nodes defined across cortical, basal ganglia, and cerebellar networks, we conducted univariate comparisons of the internodal connectivity strength between the medication conditions using nonparametric permutation. At the network level, we computed multivariate combinations of individual connections within and between the networks, followed by an assessment of their discriminative capabilities on patients’ medication classes using supervised machine learning. The univariate seed-based approach showed no statistically significant effect of levodopa in either dataset. However, the network connectivity pattern between basal ganglia and the cerebellum displayed a robust classification power in the longitudinal dataset and a similar trend was observed in the cross-sectional. The role of the cerebellum is often overlooked in previous functional integration investigations of Parkinson’s disease and levodopa effects. Considering the recent evidence suggesting the bidirectional communications between the cerebellum and basal ganglia networks, our study provides further insight into the importance of inter-network functional connectivity in Parkinson’s, as well as in the functional and plastic processes following levodopa medication.

Modulatory Effect of Levodopa on the Basal Ganglia-Cerebellum Connectivity in Parkinson’s Disease

Sensorimotor adaptation enables us to adjust our goal-oriented movements in response to external perturbations. These phenomena have been studied experimentally and computationally at the level of human and animals reaching movements, and have clear links to the cerebellum as evidenced by cerebellar lesions and neurodegeneration. Yet, despite our macroscopic understanding of the high-level computational mechanisms it is unclear how these are mapped and are implemented in the neural substrates of the cerebellum at a cellular-computational level. We present here a novel spiking neural circuit model of the sensorimotor system including a cerebellum which control physiological muscle models to reproduce behaviour experiments. Our cerebellar model is composed of spiking neuron populations reflecting cells in the cerebellar cortex and deep cerebellar nuclei, which generate motor correction to change behaviour in response to perturbations. The model proposes two learning mechanisms for adaptation: predictive learning and memory formation, which are implemented with synaptic updating rules. Our model is tested in a force-field sensorimotor adaptation task and successfully reproduce several phenomena arising from human adaptation, including well-known learning curves, aftereffects, savings and other multi-rate learning effects. This reveals the capability of our model to learn from perturbations and generate motor corrections while providing a bottom-up view for the neural basis of adaptation. Thus, it also shows the potential to predict how patients with specific types of cerebellar damage will perform in behavioural experiments. We explore this by in silico experiments where we selectively incapacitate selected cerebellar circuits of the model which generate and reproduce defined motor learning deficits. Author summary A rich body of work in human motor neuroscience developed high-level computational theories of sensorimotor control, learning and adaptation. But there is a gap in understanding how this may be implemented and learn on the level of neurons, synapses and spikes. Conversely, studies of patients with cerebellar lesions or neurological disease highlight the essential role the cerebellum plays in our ability to perform motor learning. Yet, how these anatomical and molecular defects play out in terms of human movement have to date not been linked to a model that spans multiple level of biological organisation from neural circuits to reproducing human motor experiments. To address this gap, we present a spiking neuron of the sensorimotor system focused on the cerebellum, with which we can on the one side reproduce the high-level behaviour learning phenomena observed in healthy subjects, as well as quantitatively predicting the putative effects on human movement trajectories of cerebellar lesions implemented at the cellular level.

Reproducing Human Motor Adaptation in Spiking Neural Simulation and known Synaptic Learning Rules

Subtly altered topological asymmetry of brain structural covariance networks in autism spectrum disorder across 43 datasets from the ENIGMA consortium

We present an explainable AI framework to predict mortality after a positive COVID-19 diagnosis based solely on data routinely collected in electronic healthcare records (EHRs) obtained prior to diagnosis. We grounded our analysis on the 1/2 Million people UK Biobank and linked NHS COVID-19 records. We developed a method to capture the complexities and large variety of clinical codes present in EHRs, and we show that these have a larger impact on risk than all other patient data but age. We use a form of clustering for natural language processing of the clinical codes, specifically, topic modelling by Latent Dirichlet Allocation (LDA), to generate a succinct digital fingerprint of a patient's full secondary care clinical history, i.e. their co-morbidities and past interventions. These digital comorbidity fingerprints offer immediately interpretable clinical descriptions that are meaningful, e.g. grouping cardiovascular disorders with common risk factors but also novel groupings that are not obvious. The comorbidity fingerprints differ in both their breadth and depth from existing observational disease associations in the COVID-19 literature. Taking this data-driven approach allows us to avoid human-induction bias and confirmation bias during the selection of what are important potential predictors of COVID-19 mortality. Together with age, these digital fingerprints are the single most important factor in our predictor. This holds the potential for improving individual risk profiling for clinical decisions and the identification of groups for public health interventions such as vaccine programmes. Combining our digital precondition fingerprints with demographic characteristics allow us to match or exceed the performance of existing state-of-the-art COVID-19 mortality predictors (EHCF) which have been developed through expert consensus. Our precondition fingerprinting and entire mortality prediction analytics pipeline is designed so as to be rapidly redeployable, e.g. for COVID-19 variants or other pre-existing diseases.

Clustering of patient comorbidities within electronic medical records enables high-precision COVID-19 mortality prediction

Author Correction: Altered structural brain asymmetry in autism spectrum disorder in a study of 54 datasets

We wanted to study the ability of our brains and bodies to be augmented by supernumerary robot limbs, here extra fingers. We developed a mechanically highly functional supernumerary robotic 3rd thumb actuator, the SR3T, and interfaced it with human users enabling them to play the piano with 11 fingers. We devised a set of measurement protocols and behavioural “biomarkers”, the Human Augmentation Motor Coordination Assessment (HAMCA), which allowed us a priori to predict how well each individual human user could, after training, play the piano with a two-thumbs-hand. To evaluate augmented music playing ability we devised a simple musical score, as well as metrics for assessing the accuracy of playing the score. We evaluated the SR3T (supernumerary robotic 3rd thumb) on 12 human subjects including 6 naïve and 6 experienced piano players. We demonstrated that humans can learn to play the piano with a 6-fingered hand within one hour of training. For each subject we could predict individually, based solely on their HAMCA performance before training, how well they were able to perform with the extra robotic thumb, after training (training end-point performance). Our work demonstrates the feasibility of robotic human augmentation with supernumerary robotic limbs within short time scales. We show how linking the neuroscience of motor learning with dexterous robotics and human-robot interfacing can be used to inform a priori how far individual motor impaired patients or healthy manual workers could benefit from robotic augmentation solutions.

Learning to play the piano with the Supernumerary Robotic 3rd Thumb

Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood.

Objective
To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia.

Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244.

Interregional profiles of group difference in cortical thickness between cases and controls.

Results
A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders.

In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.

Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders.

OBJECTIVE
Attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. The authors sought to directly compare these disorders using structural brain imaging data from ENIGMA consortium data.

METHODS
Structural T1-weighted whole-brain MRI data from healthy control subjects (N=5,827) and from patients with ADHD (N=2,271), ASD (N=1,777), and OCD (N=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. The authors examined subcortical volume, cortical thickness, and cortical surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults, using linear mixed-effects models adjusting for age, sex, and site (and intracranial volume for subcortical and surface area measures).

RESULTS
No shared differences were found among all three disorders, and shared differences between any two disorders did not survive correction for multiple comparisons. Children with ADHD compared with those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller intracranial volume than control subjects and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared with adult control subjects and other clinical groups. No OCD-specific differences were observed across different age groups and surface area differences among all disorders in childhood and adulthood.

The study findings suggest robust but subtle differences across different age groups among ADHD, ASD, and OCD. ADHD-specific intracranial volume and hippocampal differences in children and adolescents, and ASD-specific cortical thickness differences in the frontal cortex in adults, support previous work emphasizing structural brain differences in these disorders.

Subcortical Brain Volume, Regional Cortical Thickness, and Cortical Surface Area Across Disorders: Findings From the ENIGMA ADHD, ASD, and OCD Working Groups.

Motor-learning literature focuses on simple laboratory-tasks due to their controlled manner and the ease to apply manipulations to induce learning and adaptation. Recently, we introduced a billiards paradigm and demonstrated the feasibility of real-world-neuroscience using wearables for naturalistic full-body motion-tracking and mobile-brain-imaging. Here we developed an embodied virtual-reality (VR) environment to our real-world billiards paradigm, which allows to control the visual feedback for this complex real-world task, while maintaining sense of embodiment. The setup was validated by comparing real-world ball trajectories with the trajectories of the virtual balls, calculated by the physics engine. We then ran our learning protocol in the embodied VR. Subjects played billiard shots when they held the physical cue and hit a physical ball on the table while seeing it all in VR. We found comparable learning trends in the embodied VR to those we previously reported in the physical real-world task. Embodied VR can be used for learning real-world tasks in a highly controlled environment which enables applying visual manipulations, common in laboratory-tasks and rehabilitation, to a real-world full-body task. Embodied VR enables to manipulate feedback and apply perturbations to isolate and assess interactions between specific motor-learning components, thus enabling addressing the current questions of motor-learning in real-world tasks. Such a setup can be used for rehabilitation, where VR is gaining popularity but the transfer to the real-world is currently limited, presumably, due to the lack of embodiment.

Embodied virtual reality for the study of real-world motor learning

Abstract Many recent studies found signatures of motor learning in neural beta oscillations (13–30Hz), and specifically in the post-movement beta rebound (PMBR). All these studies were in simplified laboratory-tasks in which learning was either error-based or reward-based. Interestingly, these studies reported opposing dynamics of the PMBR magnitude over learning for the error-based and reward-based tasks (increase verses decrease, respectively). Here we explored the PMBR dynamics during real-world motor-skill-learning in a billiards task using mobile-brain-imaging. Our EEG recordings highlight opposing dynamics of PMBR magnitudes between different subjects performing the same task. The groups of subjects, defined by their neural-dynamics, also showed behavioral differences expected for error-based verses reward-based learning. Our results suggest that when faced with the complexity of the real-world different subjects might use different learning mechanisms for the same complex task. We speculate that all subjects combine multi-modal mechanisms of learning, but different subjects have different predominant learning mechanisms.

Neural biomarkers of multiple motor-learning mechanisms in a real-world task

Playing the piano with a robotic third thumb: assessing constraints of human augmentation

Many recent studies found signatures of motor learning in neural Beta oscillations (13– 30Hz), and specifically in the post-movement Beta rebound (PMBR). All these studies were in controlled laboratory-tasks in which the task designed to induce the studied learning mechanism. Interestingly, these studies reported opposing dynamics of the PMBR magnitude over learning for the error-based and reward-based tasks (increase versus decrease, respectively). Here we explored the PMBR dynamics during real-world motor-skill-learning in a billiards task using mobile-brain-imaging. Our EEG recordings highlight the opposing dynamics of PMBR magnitudes (increase versus decrease) between different subjects performing the same task. The groups of subjects, defined by their neural dynamics, also showed behavioural differences expected for different learning mechanisms. Our results suggest that when faced with the complexity of the real-world different subjects might use different learning mechanisms for the same complex task. We speculate that all subjects combine multi-modal mechanisms of learning, but different subjects have different predominant learning mechanisms.

Brain Activity Reveals Multiple Motor-Learning Mechanisms in a Real-World Task

Background Left-right asymmetry is an important organizing feature of the healthy brain. Various studies have reported altered structural brain asymmetry in autism spectrum disorder (ASD). However, findings have been inconsistent, likely due to limited sample sizes and low statistical power. Methods We investigated 1,774 subjects with ASD and 1,809 controls, from 54 datasets, for differences in the asymmetry of thickness and surface area of 34 cerebral cortical regions. We also examined global hemispheric measures of cortical thickness and area asymmetry, and volumetric asymmetries of subcortical structures. Data were obtained via the ASD Working Group of the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. T1-weighted MRI data were processed with a single protocol using FreeSurfer and the Desikan-Killiany atlas. Results ASD was significantly associated with reduced leftward asymmetry of total hemispheric average cortical thickness, compared to controls. Eight regional thickness asymmetries, distributed over the cortex, also showed significant associations with diagnosis after correction for multiple comparisons, for which asymmetry was again generally lower in ASD versus controls. In addition, the medial orbitofrontal surface area was less rightward asymmetric in ASD than controls, and the putamen volume was more leftward asymmetric in ASD than controls. The largest effect size had Cohen’s d = 0.15. Most effects did not depend on age, sex, IQ, or disorder severity. Conclusion Altered lateralized neurodevelopment is suggested in ASD, affecting widespread cortical regions with diverse functions. Large-scale analysis was necessary to reliably detect, and accurately describe, subtle alterations of structural brain asymmetry in this disorder.

Altered structural brain asymmetry in autism spectrum disorder: large-scale analysis via the ENIGMA Consortium

Altered structural brain asymmetry in autism spectrum disorder in a study of 54 datasets

Abstract Visuomotor rotations are learned through a combination of explicit strategy and implicit recalibration. However, measuring the relative contribution of each remains a challenge and the possibility of multiple explicit and implicit components complicates the issue. Recent interest has focused on the possibility that eye movements reflects explicit strategy. Here we compared eye movements during adaptation to two accepted measures of explicit learning: verbal report and the exclusion test. We found that while reporting, all subjects showed a match among all three measures. However, when subjects did not report their intention, the eye movements of some subjects suggested less explicit adaptation than what was measured in an exclusion test. Interestingly, subjects whose eye movements did match their exclusion could be clustered into the following two subgroups: fully implicit learners showing no evidence of explicit adaptation and explicit learners with little implicit adaptation. Subjects showing a mix of both explicit and implicit adaptation were also those where eye movements showed less explicit adaptation than did exclusion. Thus, our results support the idea of multiple components of explicit learning as only part of the explicit learning is reflected in the eye movements. Individual subjects may use explicit components that are reflected in the eyes or those that are not or some mixture of the two. Analysis of reaction times suggests that the explicit components reflected in the eye movements involve longer reaction times. This component, according to recent literature, may be related to mental rotation.

Eye Movements during Visuomotor Adaptation Represent Only Part of the Explicit Learning

Recent technological developments in mobile brain and body imaging are enabling new frontiers of real-world neuroscience. Simultaneous recordings of body movement and brain activity from highly skillful individuals as they demonstrate their exceptional skills in real-world settings, can shed new light on neurobehavioural structure of human expertise. Driving is a real-world skill which many of us acquire on different levels of expertise. Here we ran a case-study on a subject with the highest level of driving expertise - a Formula E Champion. We studied the expert driver’s neural and motor patterns while he drove a sports car in the “Top Gear” race track under extreme conditions (high speed, low visibility, low temperature, wet track). His brain activity, eye movements and hand/foot movements were recorded. Brain activity in the delta, alpha, and beta frequency bands showed causal relation to hand movements. We demonstrate, here in summary, that even in extreme situations (race track driving) a method for conducting human ethomic (Ethology + Omics) data that encompasses information on the sensory inputs and motor outputs outputs of the brain as well as brain state to characterise complex human skills.

Abstract We discuss a new framework for understanding the structure of motor control. Our approach integrates existing models of motor control with the reality of hierarchical cortical processing and the parallel segregated loops that characterize cortical–subcortical connections. We also incorporate the recent claim that cortex functions via predictive representation and optimal information utilization. Our framework assumes that each cortical area engaged in motor control generates a predictive model of a different aspect of motor behavior. In maintaining these predictive models, each area interacts with a different part of the cerebellum and BG. These subcortical areas are thus engaged in domain-appropriate system identification and optimization. This refocuses the question of division of function among different cortical areas. What are the different aspects of motor behavior that are predictively modeled? We suggest that one fundamental division is between modeling of task and body whereas another is the model of state and action. Thus, we propose that the posterior parietal cortex, somatosensory cortex, premotor cortex, and motor cortex represent task state, body state, task action, and body action, respectively. In the second part of this review, we demonstrate how this division of labor can better account for many recent findings of movement encoding, especially in the premotor and posterior parietal cortices.

Summary The behavioral and neural processes of real-world motor learning remain largely unknown. We demonstrate the feasibility of real-world neuroscience, using wearables for naturalistic full-body motion tracking and mobile brain imaging, to study motor learning in billiards. We highlight the similarities between motor learning in-the-wild and classic toy-tasks in well-known features, such as multiple learning rates, and the relationship between task-related variability and motor learning. However, we found that real-world motor learning affects the whole body, changing motor control from head to toe. Moreover, with a data-driven approach, based on the relationship between variability and learning, we found the arm supination to be the task relevant joint angle. Our EEG recordings highlight groups of subjects with opposing dynamics of post-movement Beta rebound (PMBR), not resolved before in toy-tasks. The first group increased PMBR over learning while the second decreased. These opposite trends were previously reported in error-based learning and skill learning tasks respectively. Behaviorally, the PMBR decreasers better controlled task-relevant variability dynamically leading to lower variability and smaller errors in the learning plateau. We speculate that these PMBR dynamics emerge because subjects must combine multi-modal mechanisms of learning in new ways when faced with the complexity of the real-world.

Neurobehavioural signatures of learning that emerge in a real-world motor skill task

Objective Attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders. Methods Structural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures). Results We found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed. Conclusion Our findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders.

Subcortical brain volume, regional cortical thickness and cortical surface area across attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD)

Humans exhibit considerable motor variability even across trivial reaching movements. This variability can be separated into specific kinematic components such as extent and direction, which are thought to be governed by distinct neural processes. Here, we report that individual subjects exhibit different magnitudes of kinematic variability, which are consistent (within individual) across movements to different targets and regardless of which arm (right or left) was used to perform the movements. Simultaneous fMRI recordings revealed that the same subjects also exhibited different magnitudes of fMRI variability across movements in a variety of motor system areas. These fMRI variability magnitudes were also consistent across movements to different targets when performed with either arm. Cortical fMRI variability in the posterior-parietal cortex of individual subjects predicted their movement-extent variability. This relationship was apparent only in posterior-parietal cortex and not in other motor system areas, thereby suggesting that individuals with more variable movement preparation exhibit larger kinematic variability. We, therefore, propose that neural and kinematic variability are reliable and interrelated individual characteristics that may predispose individual subjects to exhibit distinct motor capabilities.

Individual movement variability magnitudes are predicted by cortical neural variability

Ipsilateral motor areas of cerebral cortex are active during arm movements and even reliably predict movement direction. Is coding similar during ipsilateral and contralateral movements? If so, is it in extrinsic (world-centered) or intrinsic (joint-configuration) coordinates? We addressed these questions by examining the similarity of multivoxel fMRI patterns in visuomotor cortical regions during unilateral reaching movements with both arms. The results of three complementary analyses revealed that fMRI response patterns were similar across right and left arm movements to identical targets (extrinsic coordinates) in visual cortices, and across movements with equivalent joint-angles (intrinsic coordinates) in motor cortices. We interpret this as evidence for the existence of distributed neural populations in multiple motor system areas that encode ipsilateral and contralateral movements in a similar manner: according to their intrinsic/joint coordinates. SIGNIFICANCE STATEMENT Cortical motor control exhibits clear lateralization: each hemisphere controls the motor output of the contralateral body. Nevertheless, neural populations in ipsilateral areas across the visuomotor hierarchy are active during unilateral movements. We show that fMRI response patterns in the motor cortices are similar for both arms if the movement direction is mirror-reversed across the midline. This suggests that in both ipsilateral and contralateral motor cortices, neural populations have effector-invariant coding of movements in intrinsic coordinates. This not only affects our understanding of motor control, it may serve in the development of brain machine interfaces that also use ipsilateral neural activity.

OBJECTIVE
Neuroimaging studies show structural differences in both cortical and subcortical brain regions in children and adults with autism spectrum disorder (ASD) compared with healthy subjects. Findings are inconsistent, however, and it is unclear how differences develop across the lifespan. The authors investigated brain morphometry differences between individuals with ASD and healthy subjects, cross-sectionally across the lifespan, in a large multinational sample from the Enhancing Neuroimaging Genetics Through Meta-Analysis (ENIGMA) ASD working group.

METHOD
The sample comprised 1,571 patients with ASD and 1,651 healthy control subjects (age range, 2-64 years) from 49 participating sites. MRI scans were preprocessed at individual sites with a harmonized protocol based on a validated automated-segmentation software program. Mega-analyses were used to test for case-control differences in subcortical volumes, cortical thickness, and surface area. Development of brain morphometry over the lifespan was modeled using a fractional polynomial approach.

RESULTS
The case-control mega-analysis demonstrated that ASD was associated with smaller subcortical volumes of the pallidum, putamen, amygdala, and nucleus accumbens (effect sizes [Cohen's d], 0.13 to -0.13), as well as increased cortical thickness in the frontal cortex and decreased thickness in the temporal cortex (effect sizes, -0.21 to 0.20). Analyses of age effects indicate that the development of cortical thickness is altered in ASD, with the largest differences occurring around adolescence. No age-by-ASD interactions were observed in the subcortical partitions.

The ENIGMA ASD working group provides the largest study of brain morphometry differences in ASD to date, using a well-established, validated, publicly available analysis pipeline. ASD patients showed altered morphometry in the cognitive and affective parts of the striatum, frontal cortex, and temporal cortex. Complex developmental trajectories were observed for the different regions, with a developmental peak around adolescence. These findings suggest an interplay in the abnormal development of the striatal, frontal, and temporal regions in ASD across the lifespan.

Cortical and Subcortical Brain Morphometry Differences Between Patients With Autism Spectrum Disorder and Healthy Individuals Across the Lifespan: Results From the ENIGMA ASD Working Group.

Interhemispheric functional connectivity abnormalities are often reported in autism and it is thus not surprising that structural defects of the corpus callosum (CC) are consistently found using both traditional MRI and DTI techniques. Past DTI studies however, have subdivided the CC into 2 or 3 segments without regard for where fibers may project to within the cortex, thus placing limitations on our ability to understand the nature, timing and neurobehavioral impact of early CC abnormalities in autism. Leveraging a unique cohort of 97 toddlers (68 autism; 29 typical) we utilized a novel technique that identified seven CC tracts according to their cortical projections. Results revealed that younger (<2.5 years old), but not older toddlers with autism exhibited abnormally low mean, radial, and axial diffusivity values in the CC tracts connecting the occipital lobes and the temporal lobes. Fractional anisotropy and the cross sectional area of the temporal CC tract were significantly larger in young toddlers with autism. These findings indicate that water diffusion is more restricted and unidirectional in the temporal CC tract of young toddlers who develop autism. Such results may be explained by a potential overabundance of small caliber axons generated by excessive prenatal neural proliferation as proposed by previous genetic, animal model, and postmortem studies of autism. Furthermore, early diffusion measures in the temporal CC tract of the young toddlers were correlated with outcome measures of autism severity at later ages. These findings regarding the potential nature, timing, and location of early CC abnormalities in autism add to accumulating evidence, which suggests that altered inter-hemispheric connectivity, particularly across the temporal lobes, is a hallmark of the disorder.

Toddlers later diagnosed with autism exhibit multiple structural abnormalities in temporal corpus callosum fibers

No evidence of early head circumference enlargements in children later diagnosed with autism in Israel

Humans exhibit considerable motor variability even across trivial reaching movements. This variability can be separated into specific kinematic components such as extent and direction that are thought to be governed by distinct neural processes. Here, we report that individual subjects (males and females) exhibit different magnitudes of kinematic variability, which are consistent (within individual) across movements to different targets and regardless of which arm (right or left) was used to perform the movements. Simultaneous fMRI recordings revealed that the same subjects also exhibited different magnitudes of fMRI variability across movements in a variety of motor system areas. These fMRI variability magnitudes were also consistent across movements to different targets when performed with either arm. Cortical fMRI variability in the posterior–parietal cortex of individual subjects explained their movement–extent variability. This relationship was apparent only in posterior-parietal cortex and not in other motor system areas, thereby suggesting that individuals with more variable movement preparation exhibit larger kinematic variability. We therefore propose that neural and kinematic variability are reliable and interrelated individual characteristics that may predispose individual subjects to exhibit distinct motor capabilities. SIGNIFICANCE STATEMENT Neural activity and movement kinematics are remarkably variable. Although intertrial variability is rarely studied, here, we demonstrate that individual human subjects exhibit distinct magnitudes of neural and kinematic variability that are reproducible across movements to different targets and when performing these movements with either arm. Furthermore, when examining the relationship between cortical variability and movement variability, we find that cortical fMRI variability in parietal cortex of individual subjects explained their movement extent variability. This enabled us to explain why some subjects performed more variable movements than others based on their cortical variability magnitudes.

Individual Movement Variability Magnitudes Are Explained by Cortical Neural Variability

Substantial controversy exists regarding the presence and significance of anatomical abnormalities in autism spectrum disorders (ASD). The release of the Autism Brain Imaging Data Exchange (∼1000 participants, age 6-65 years) offers an unprecedented opportunity to conduct large-scale comparisons of anatomical MRI scans across groups and to resolve many of the outstanding questions. Comprehensive univariate analyses using volumetric, thickness, and surface area measures of over 180 anatomically defined brain areas, revealed significantly larger ventricular volumes, smaller corpus callosum volume (central segment only), and several cortical areas with increased thickness in the ASD group. Previously reported anatomical abnormalities in ASD including larger intracranial volumes, smaller cerebellar volumes, and larger amygdala volumes were not substantiated by the current study. In addition, multivariate classification analyses yielded modest decoding accuracies of individuals' group identity (<60%), suggesting that the examined anatomical measures are of limited diagnostic utility for ASD. While anatomical abnormalities may be present in distinct subgroups of ASD individuals, the current findings show that many previously reported anatomical measures are likely to be of low clinical and scientific significance for understanding ASD neuropathology as a whole in individuals 6-35 years old.

The effort to determine morphological and anatomically defined neuronal characteristics from extracellularly recorded physiological signatures has been attempted with varying success in different brain areas. Recent studies have attempted such classification of cerebellar interneurons (CINs) based on statistical measures of spontaneous activity. Previously, such efforts in different brain areas have used supervised clustering methods based on standard parameterizations of spontaneous interspike interval (ISI) histograms. We worried that this might bias researchers toward positive identification results and decided to take a different approach. We recorded CINs from anesthetized cats. We used unsupervised clustering methods applied to a nonparametric representation of the ISI histograms to identify groups of CINs with similar spontaneous activity and then asked how these groups map onto different cell types. Our approach was a fuzzy C-means clustering algorithm applied to the Kullbach–Leibler distances between ISI histograms. We found that there is, in fact, a natural clustering of the spontaneous activity of CINs into six groups but that there was no relationship between this clustering and the standard morphologically defined cell types. These results proved robust when generalization was tested to completely new datasets, including datasets recorded under different anesthesia conditions and in different laboratories and different species (rats). Our results suggest the importance of an unsupervised approach in categorizing neurons according to their extracellular activity. Indeed, a reexamination of such categorization efforts throughout the brain may be necessary. One important open question is that of functional differences of our six spontaneously defined clusters during actual behavior.

Spontaneous Activity Does Not Predict Morphological Type in Cerebellar Interneurons

Visuomotor Task Learning and Performance During a Sequential Activity in the Supplementary Motor Area Related to

Directional selectivity during visually guided hand movements is a fundamental characteristic of neural populations in multiple motor areas of the primate brain. In the current study, we assessed how directional selectivity changes when reaching movements are dissociated from their visual feedback by rotating the visual field. We recorded simultaneous movement kinematics and fMRI activity while human subjects performed out-and-back movements to four peripheral targets before and after adaptation to a 45° visuomotor rotation. A classification algorithm was trained to identify movement direction according to voxel-by-voxel fMRI patterns in each of several brain areas. The direction of movements was successfully decoded with above-chance accuracy in multiple motor and visual areas when training and testing the classifier on trials within each condition, thereby demonstrating the existence of directionally selective fMRI patterns within each stage of the experiment. Most importantly, when training the classifier on baseline trials and decoding rotated trials, motor brain areas exhibited above-chance decoding according to the original movement direction and visual brain areas exhibited above-chance decoding according to the rotated visual target location, while posterior parietal cortex (PPC) exhibited chance-level decoding according to both. These results reveal that directionally selective fMRI patterns in motor system areas faithfully represent movement direction regardless of visual feedback, while fMRI patterns in visual system areas faithfully represent target location regardless of movement direction. Directionally selective fMRI patterns in PPC, however, were altered following adaptation learning, thereby suggesting that the novel visuomotor mapping, which was learned during visuomotor adaptation, is stored in PPC.

Dissociating Visual and Motor Directional Selectivity Using Visuomotor Adaptation

Do bistable states exist in cerebellar non-purkinje cells in vivo ?

Natural history, trajectory, and management of mechanically ventilated COVID-19 patients in the United Kingdom

Background. To date the description of mechanically ventilated patients with Coronavirus Disease 2019 (COVID-19) has focussed on admission characteristics with no consideration of the dynamic course of the disease. Here, we present a data-driven analysis of granular, daily data from a representative proportion of patients undergoing invasive mechanical ventilation (IMV) within the United Kingdom (UK) to evaluate the complete natural history of COVID-19. Methods. We included adult patients undergoing IMV within 48 hours of ICU admission with complete clinical data until death or ICU discharge. We examined factors and trajectories that determined disease progression and responsiveness to ARDS interventions. Our data visualisation tool is available as a web-based widget (https://www.CovidUK.ICU). Findings. Data for 623 adults with COVID-19 who were mechanically ventilated between 01 March 2020 and 31 August 2020 were analysed. Mortality, intensity of mechanical ventilation and severity of organ injury increased with severity of hypoxaemia. Median tidal volume per kg across all mandatory breaths was 5.6 [IQR 4.7-6.6] mL/kg based on reported body weight, but 7.0 [IQR 6.0-8.4] mL/kg based on calculated ideal body weight. Non-resolution of hypoxaemia over the first week of IMV was associated with higher ICU mortality (59.4% versus 16.3%; P<0.001). Of patients ventilated in prone position only 44% showed a positive oxygenation response. Non-responders to prone position show higher D-Dimers, troponin, cardiovascular SOFA, and higher ICU mortality (68.9% versus 29.7%; P<0.001). Multivariate analysis showed prone non-responsiveness being independently associated with higher lactate (hazard ratio 1.41, 95% CI 1.03-1.93), respiratory SOFA (hazard ratio 3.59, 95% CI 1.83-7.04); and cardiovascular SOFA score (hazard ratio 1.37, 95% CI 1.05-1.80). Interpretation. A sizeable proportion of patients with progressive worsening of hypoxaemia were also refractory to evidence-based ARDS strategies and showed a higher mortality. Strategies for early recognition and management of COVID19 patients refractory to conventional management strategies will be critical to improving future outcomes.

Natural history, trajectory, and management of mechanically ventilated COVID-19 patients in the United Kingdom.

DUCHENNE MUSCULAR DYSTROPHY - PHYSIOTHERAPY P.314Kinematic/behavioural fingerprints in Duchenne muscular dystrophy and their clinical applications

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Cathepsin C in the defence against Actinobacillus actinomycetemcomitans : studies on Papillon-Lefèvre syndrome

Visual stimuli compete with each other for cortical processing and attention biases this competition in favor of the attended stimulus. How does the relationship between the stimuli affect the strength of this attentional bias? Here, we used functional MRI to explore the effect of target-distractor similarity in neural representation on attentional modulation in the human visual cortex using univariate and multivariate pattern analyses. Using stimuli from four object categories (human bodies, cats, cars and houses), we investigated attentional effects in the primary visual area V1, the object-selective regions LO and pFs, the body-selective region EBA, and the scene-selective region PPA. We demonstrated that the strength of the attentional bias towards the target is not fixed but decreases with increasing distractor-target similarity. Simulations provided evidence that this result pattern is explained by tuning sharpening rather than an increase in gain. Our findings provide a mechanistic explanation for behavioral effects of target-distractor similarity on attentional biases and suggest tuning sharpening as the underlying mechanism in object-based attention.

Attention Modulates Human Visual Responses to Objects by Tuning Sharpening

Grasping the meaning of everyday visual events is a fundamental feat of human intelligence that hinges on diverse neural processes ranging from vision to higher-level cognition. Deciphering the neural basis of visual event understanding requires rich, extensive, and appropriately designed experimental data. However, this type of data is hitherto missing. To fill this gap, we introduce the BOLD Moments Dataset (BMD), a large dataset of whole-brain fMRI responses to over 1,000 short (3s) naturalistic video clips and accompanying metadata. We show visual events interface with an array of processes, extending even to memory, and we reveal a match in hierarchical processing between brains and video-computable deep neural networks. Furthermore, we showcase that BMD successfully captures temporal dynamics of visual events at second resolution. BMD thus establishes a critical groundwork for investigations of the neural basis of visual event understanding.

BOLD Moments: modeling short visual events through a video fMRI dataset and metadata

Eye movements are a ubiquitous and natural behavior, but in many tightly controlled experimental visual paradigms, eye movements are undesirable. Their occurrence can pose challenges to the interpretation of behavioral and neuroscientific data, in particular for magneto- and electroencephalography (M/EEG), which is sensitive to signals created by eye muscle movement. Here we compared the effect of two different fixation symbols – the standard fixation cross and the bullseye fixation cross – in the context of a visual paradigm with centrally presented naturalistic object images. We investigated eye movements and EEG data recorded simultaneously using behavioral and multivariate analysis techniques. Our findings comparing the bullseye to the standard fixation cross are threefold. First, the bullseye fixation cross reduces the number of saccades and amplitude size of microsaccades. Second, the bullseye fixation cross subtly reduces classification accuracy in both eye tracking and EEG data for the classification of single object images, but not for the superlevel category animacy. Third, using representational similarity analysis, we found a systematic relationship between eye tracking and EEG data at the level of single images for the standard, but not for the bullseye fixation cross. In conclusion, we recommend the bullseye fixation cross in experimental paradigms with fixation when particularly tight control of fixation is beneficial.

The influence of the bullseye versus standard fixation cross on eye movements and classifying natural images from EEG

Independent spatiotemporal effects of spatial attention and background clutter on human object location representations

Oscillatory brain signatures of dynamic visual integration in natural context

The spatiotemporal neural dynamics of object location representations in the human brain

Theta power and theta-gamma coupling during formation of novel representations in the infant brain

The human visual cortex enables visual perception through a cascade of hierarchical computations in cortical regions with distinct functionalities. Here, we introduce an AI-driven approach to discover the functional mapping of the visual cortex. We related human brain responses to scene images measured with functional MRI (fMRI) systematically to a diverse set of deep neural networks (DNNs) optimized to perform different scene perception tasks. We found a structured mapping between DNN tasks and brain regions along the ventral and dorsal visual streams. Low-level visual tasks mapped onto early brain regions, 3-dimensional scene perception tasks mapped onto the dorsal stream, and semantic tasks mapped onto the ventral stream. This mapping was of high fidelity, with more than 60% of the explainable variance in nine key regions being explained. Together, our results provide a novel functional mapping of the human visual cortex and demonstrate the power of the computational approach.

Unveiling functions of the visual cortex using task-specific deep neural networks

The sciences of biological and artificial intelligence are ever more intertwined. Neural computational principles inspire new intelligent machines, which are in turn used to advance theoretical understanding of the brain. To promote further exchange of ideas and collaboration between biological and artificial intelligence researchers, we introduce the 2023 installment of the Algonauts Project challenge: How the Human Brain Makes Sense of Natural Scenes (http://algonauts.csail.mit.edu). This installment prompts the fields of artificial and biological intelligence to come together towards building computational models of the visual brain using the largest and richest dataset of fMRI responses to visual scenes, the Natural Scenes Dataset (NSD). NSD provides high-quality fMRI responses to ~73,000 different naturalistic colored scenes, making it the ideal candidate for data-driven model building approaches promoted by the 2023 challenge. The challenge is open to all and makes results directly comparable and transparent through a public leaderboard automatically updated after each submission, thus allowing for rapid model development. We believe that the 2023 installment will spark symbiotic collaborations between biological and artificial intelligence scientists, leading to a deeper understanding of the brain through cutting-edge computational models and to novel ways of engineering artificial intelligent agents through inductive biases from biological systems.

The Algonauts Project 2023 Challenge: How the Human Brain Makes Sense of Natural Scenes

For coherent visual experience to emerge, the brain needs to spatially integrate the complex and dynamic information it receives from the environment. To meet this challenge, the visual system uses contextual information from one part of the visual field to create feedback signals that guide analysis in other parts of the visual field. Here, we set out to characterize the nature of this feedback across brain rhythms and cortical regions. In EEG and fMRI experiments, we experimentally recreated the spatially distributed nature of visual inputs by presenting natural videos at different visual field locations. Critically, we manipulated the spatiotemporal congruency of the videos, so that they did or did not demand integration into a coherent percept. Decoding stimulus information from frequency-specific EEG patterns revealed a shift from representations in feedforward-related gamma activity for spatiotemporally inconsistent videos to representations in feedback-related alpha activity for spatiotemporally consistent videos. Our fMRI data suggest high-level scene-selective areas as the putative source of this feedback. Combining the EEG data with spatially resolved fMRI recordings, we demonstrate that alpha-frequency feedback is directly associated with representations in early visual cortex. Together this demonstrates how the human brain orchestrates coherent visual experience across space: it uses feedback to integrate information from high-level to early visual cortex through a dedicated rhythmic code in the alpha frequency range.

Alpha-frequency feedback to early visual cortex orchestrates coherent natural vision

Empirically identifying and computationally modelling the brain-behaviour 3 relationship for human scene categorization 4 Abbreviated Title : Brain-behaviour link in scene categorization 5 6

We introduce Net2Brain, a graphical and command-line user interface toolbox for comparing the representational spaces of artiﬁcial deep neural networks (DNNs) and human brain recordings. While different toolboxes facilitate only single functionalities or only focus on a small subset of supervised image classiﬁcation models, Net2Brain allows the extraction of activations of more than 600 DNNs trained to perform a diverse range of vision-related tasks (e.g semantic segmentation, depth estimation, action recognition, etc.), over both image and video datasets. The toolbox computes the representational dissimilarity matrices (RDMs) over those activations and compares them to brain recordings using representational similarity analysis (RSA), weighted RSA, both in speciﬁc ROIs and with searchlight search. In addition, it is possible to add a new data set of stimuli and brain recordings to the toolbox for evaluation. We demonstrate the functionality and advantages of Net2Brain with an example showcas-ing how it can be used to test hypotheses of cognitive computational neuroscience.

Net2Brain: A Toolbox to compare artificial vision models with human brain responses

A large and rich EEG dataset for modeling human visual object recognition

Today most neurocognitive studies in humans employ the non-invasive neuroimaging techniques fMRI and EEG. However, how the data provided by fMRI and EEG relate exactly to the underlying neural activity remains incompletely understood. Here, we pursued this open question by relating EEG and fMRI data at the level of neural population codes using multivariate pattern analysis. For this, we recorded EEG and fMRI data while participants viewed everyday objects in different viewing conditions, and then related the data to ECoG data recorded for the same stimulus set. The comparison of EEG and ECoG data showed that object category signals emerge swiftly in the visual system and can be detected by both EEG and ECoG at similar temporal delays after stimulus onset. The correlation between EEG and ECoG reduces and onset latencies increase when object representations tolerant to changes in scale and orientation are considered. The comparison of fMRI and ECoG overall revealed a tighter relationship in occipital than in temporal regions, related to differences in fMRI signal-to-noise ratio. Together, our results reveal a complex relationship between fMRI, EEG and ECoG signals at the level of population codes that critically depends on the time point after stimulus onset, the region investigated, and the visual contents used.

A Multivariate Comparison of EEG and fMRI to ECoG Using Visual Object Representations in Humans

Similarities and differences in the spatio-temporal neural dynamics underlying the recognition of natural images and line drawings

Time-resolved multivariate pattern analysis of infant EEG data: A practical tutorial

Today, most neurocognitive studies in humans employ the non-invasive neuroimaging techniques functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG). However, how the data provided by fMRI and EEG relate exactly to the underlying neural activity remains incompletely understood. Here, we aimed to understand the relation between EEG and fMRI data at the level of neural population codes using multivariate pattern analysis. In particular, we assessed whether this relation is affected when we change stimuli or introduce identity-preserving variations to them. For this, we recorded EEG and fMRI data separately from 21 healthy participants while participants viewed everyday objects in different viewing conditions, and then related the data to electrocorticogram (ECoG) data recorded for the same stimulus set from epileptic patients. The comparison of EEG and ECoG data showed that object category signals emerge swiftly in the visual system and can be detected by both EEG and ECoG at similar temporal delays after stimulus onset. The correlation between EEG and ECoG was reduced when object representations tolerant to changes in scale and orientation were considered. The comparison of fMRI and ECoG overall revealed a tighter relationship in occipital than in temporal regions, related to differences in fMRI signal-to-noise ratio. Together, our results reveal a complex relationship between fMRI, EEG, and ECoG signals at the level of population codes that critically depends on the time point after stimulus onset, the region investigated, and the visual contents used.

A multivariate comparison of electroencephalogram and functional magnetic resonance imaging to electrocorticogram using visual object representations in humans

Drawings offer a simple and efficient way to communicate meaning. While line drawings capture only coarsely how objects look in reality, we still perceive them as resembling real-world objects. Previous work has shown that this perceived similarity is mirrored by shared neural representations for drawings and natural images, which suggests that similar mechanisms underlie the recognition of both. However, other work has proposed that representations of drawings and natural images become similar only after substantial processing has taken place, suggesting distinct mechanisms. To arbitrate between those alternatives, we measured brain responses resolved in space and time using fMRI and MEG, respectively, while participants viewed images of objects depicted as photographs, line drawings, or sketch-like drawings. Using multivariate decoding, we demonstrate that object category information emerged similarly fast and across overlapping regions in occipital and ventral-temporal cortex for all types of depiction, yet with smaller effects at higher levels of visual abstraction. In addition, cross-decoding between depiction types revealed strong generalization of object category information from early processing stages on. Finally, by combining fMRI and MEG data using representational similarity analysis, we found that visual information traversed similar processing stages for all types of depiction, yet with an overall stronger representation for photographs. Together our results demonstrate broad commonalities in the neural dynamics of object recognition across types of depiction, thus providing clear evidence for shared neural mechanisms underlying recognition of natural object images and abstract drawings.

spatiotemporal neural dynamics of object recognition for natural images and line drawings” recognition for natural images and drawings”

Drawings offer a simple and efficient way to communicate meaning. While line drawings capture only coarsely how objects look in reality, we still perceive them as resembling real-world objects. Previous work has shown that this perceived similarity is mirrored by shared neural representations for drawings and natural images, which suggests that similar mechanisms underlie the recognition of both. However, other work has proposed that representations of drawings and natural images become similar only after substantial processing has taken place, suggesting distinct mechanisms. To arbitrate between those alternatives, we measured brain responses resolved in space and time using fMRI and MEG, respectively, while human participants (female and male) viewed images of objects depicted as photographs, line drawings, or sketch-like drawings. Using multivariate decoding, we demonstrate that object category information emerged similarly fast and across overlapping regions in occipital, ventral-temporal, and posterior parietal cortex for all types of depiction, yet with smaller effects at higher levels of visual abstraction. In addition, cross-decoding between depiction types revealed strong generalization of object category information from early processing stages on. Finally, by combining fMRI and MEG data using representational similarity analysis, we found that visual information traversed similar processing stages for all types of depiction, yet with an overall stronger representation for photographs. Together, our results demonstrate broad commonalities in the neural dynamics of object recognition across types of depiction, thus providing clear evidence for shared neural mechanisms underlying recognition of natural object images and abstract drawings. SIGNIFICANCE STATEMENT When we see a line drawing, we effortlessly recognize it as an object in the world despite its simple and abstract style. Here we asked to what extent this correspondence in perception is reflected in the brain. To answer this question, we measured how neural processing of objects depicted as photographs and line drawings with varying levels of detail (from natural images to abstract line drawings) evolves over space and time. We find broad commonalities in the spatiotemporal dynamics and the neural representations underlying the perception of photographs and even abstract drawings. These results indicate a shared basic mechanism supporting recognition of drawings and natural images.

The Spatiotemporal Neural Dynamics of Object Recognition for Natural Images and Line Drawings

Laminar activation pattern of category-selective regions during imagery and perception

Recurrent processing during visual object recognition in the human brain

Recent advances in high-field fMRI have allowed differentiating feedforward and feedback information in the grey matter of the human brain. For continued progress in this endeavor, it is critical to understand how MRI data acquisition parameters impact the read-out of information from laminar response profiles. Here, we benchmarked three different MR-sequences at 7T - gradient-echo (GE), spin-echo (SE) and vascular space occupancy imaging (VASO) - in differentiating feedforward and feedback signals in human early visual cortex (V1). The experiment (N=4) consisted of two complementary tasks: a perception task that predominantly evokes feedforward signals and a working memory task that relies on feedback signals. In the perception task, participants saw flickering oriented gratings while detecting orthogonal color-changes. In the working memory task, participants memorized the precise orientation of a grating. We used multivariate pattern analysis to read out the perceived (feedforward) and memorized (feedback) grating orientation from neural signals across cortical depth. Analyses across all the MR-sequences revealed perception signals predominantly in the middle cortical compartment of area V1 and working memory signals in the deep compartment. Despite an overall consistency across sequences, SE-EPI was the only sequence where both feedforward and feedback information were differently pronounced across cortical depth in a statistically robust way. We therefore suggest that in the context of a typical cognitive neuroscience experiment as the one benchmarked here, SE-EPI may provide a favorable trade-off between spatial specificity and signal sensitivity. Highlights Here, we benchmarked three sequences at high-field fMRI -GE-BOLD, SE-BOLD and VASO - in differentiating feedforward and feedback signals across grey matter depth of area V1. We show that: All the MR-sequences revealed the feedforward and feedback signals at the middle and deep cortical bins, respectively. Such correspondence across the sequences indicates that widely used GE-BOLD is a suitable method for the exploration of signals in cortical depth. Only SE-BOLD yielded statistically reliable differences between the cortical bins carry- ing feedforward and feedback signals.

Benchmarking GE-BOLD, SE-BOLD, and SS-SI-VASO sequences for depth-dependent separation of feedforward and feedback signals in high-field MRI

Semantic scene-object consistency modulates N 300 / 400 EEG 1 components , but does

Abstract conceptual representations are critical for human cognition. Despite their importance, key properties of these representations remain poorly understood. Here, we used computational models of distributional semantics to predict multivariate fMRI activity patterns during the activation and contextualization of abstract concepts. We devised a task in which participants had to embed abstract nouns into a story that they developed around a given background context. We found that representations in inferior parietal cortex were predicted by concept similarities emerging in models of distributional semantics. By constructing different model families, we reveal the models’ learning trajectories and delineate how abstract and concrete training materials contribute to the formation of brain-like representations. These results inform theories about the format and emergence of abstract conceptual representations in the human brain.

The sciences of natural and artificial intelligence are fundamentally connected. Brain-inspired human-engineered AI are now the standard for predicting human brain responses during vision, and conversely, the brain continues to inspire invention in AI. To promote even deeper connections between these fields, we here release the 2021 edition of the Algonauts Project Challenge: How the Human Brain Makes Sense of a World in Motion (http://algonauts.csail.mit.edu/). We provide whole-brain fMRI responses recorded while 10 human participants viewed a rich set of over 1,000 short video clips depicting everyday events. The goal of the challenge is to accurately predict brain responses to these video clips. The format of our challenge ensures rapid development, makes results directly comparable and transparent, and is open to all. In this way it facilitates interdisciplinary collaboration towards a common goal of understanding visual intelligence. The 2021 Algonauts Project is conducted in collaboration with the Cognitive Computational Neuroscience (CCN) conference.

The Algonauts Project 2021 Challenge: How the Human Brain Makes Sense of a World in Motion

Humans can effortlessly categorize objects, both when they are conveyed through visual images and spoken words. To resolve the neural correlates of object categorization, studies have so far primarily focused on the visual modality. It is therefore still unclear how the brain extracts categorical information from auditory signals. In the current study we used EEG (N=47) and time-resolved multivariate pattern analysis to investigate (1) the time course with which object category information emerges in the auditory modality and (2) how the representational transition from individual object identification to category representation compares between the auditory modality and the visual modality. Our results show that (1) that auditory object category representations can be reliably extracted from EEG signals and (2) a similar representational transition occurs in the visual and auditory modalities, where an initial representation at the individual-object level is followed by a subsequent representation of the objects‘ category membership. Altogether, our results suggest an analogous hierarchy of information processing across sensory channels. However, we did not find evidence for a shared supra-modal code, suggesting that the contents of the different sensory hierarchies are ultimately modality-unique.

Resolving the time course of visual and auditory object categorization

Perceived and mentally rotated contents are differentially represented in cortical depth of V1

Time-resolved multivariate pattern analysis (MVPA), a popular technique for analyzing magneto- and electro-encephalography (M/EEG) neuroimaging data, quantifies the extent and time-course by which neural representations support the discrimination of relevant stimuli dimensions. As EEG is widely used for infant neuroimaging, time-resolved MVPA of infant EEG data is a particularly promising tool for infant cognitive neuroscience. MVPA methods have recently been applied to common infant imaging methods such as EEG and fNIRS. In this tutorial, we provide and describe code to implement time-resolved, within-subject MVPA with infant EEG data. A pipeline for time-resolved MVPA based on linear SVM classification is described and implemented with accompanying code in both Matlab and Python. Results from a test dataset indicated that in both infants and adults this method reliably produced above chance classification accuracy. Extensions of the core pipeline are presented including both geometric- and accuracy-based representational similarity analysis, implemented in Python. Common choices of implementation are presented and discussed. As the amount of artifact-free EEG data contributed by each participant is lower in studies of infants than in studies of children and adults, we also explore and discuss the impact of varying participant-level inclusion thresholds on resulting MVPA findings in these datasets.

Abstract Brain decoding can predict visual perception from non-invasive electrophysiological data by combining information across multiple channels. However, decoding methods typically conflate the composite and distributed neural processes underlying perception that are together present in the signal, making it unclear what specific aspects of the neural computations involved in perception are reflected in this type of macroscale data. Using MEG data recorded while participants viewed a large number of naturalistic images, we analytically decomposed the brain signal into its oscillatory and non-oscillatory components, and used this decomposition to show that there are at least three dissociable stimulus-specific aspects to the brain data: a slow, non-oscillatory component, reflecting the temporally stable aspect of the stimulus representation; a global phase shift of the oscillation, reflecting the overall speed of processing of specific stimuli; and differential patterns of phase across channels, likely reflecting stimulus-specific computations. Further, we show that common cognitive interpretations of decoding analysis, in particular about how representations generalize across time, can benefit from acknowledging the multicomponent nature of the signal in the study of perception.

Dissociable Components of Information Encoding in Human Perception

During natural vision, objects rarely appear in isolation, but often within a semantically related scene context. Previous studies reported that semantic consistency between objects and scenes facilitates object perception, and that scene-object consistency is reflected in changes in the N300 and N400 components in EEG recordings. Here, we investigate whether these N300/400 differences are indicative of changes in the cortical representation of objects. In two experiments, we recorded EEG signals while participants viewed semantically consistent or inconsistent objects within a scene; in Experiment 1, these objects were task-irrelevant, while in Experiment 2, they were directly relevant for behavior. In both experiments, we found reliable and comparable N300/400 differences between consistent and inconsistent scene-object combinations. To probe the quality of object representations, we performed multivariate classification analyses, in which we decoded the category of the objects contained in the scene. In Experiment 1, in which the objects were not task-relevant, object category could be decoded from around 100 ms after the object presentation, but no difference in decoding performance was found between consistent and inconsistent objects. By contrast, when the objects were task-relevant in Experiment 2, we found enhanced decoding of semantically consistent, compared to semantically inconsistent, objects. These results show that differences in N300/400 components related to scene-object consistency do not index changes in cortical object representations, but rather reflect a generic marker of semantic violations. Further, our findings suggest that facilitatory effects between objects and scenes are task-dependent rather than automatic.

Semantic scene-object consistency modulates N300/400 EEG components, but does not automatically facilitate object representations

Abstract During natural vision, our brains are constantly exposed to complex, but regularly structured, environments. Real-world scenes are defined by typical part–whole relationships, where the meaning of the whole scene emerges from configurations of localized information present in individual parts of the scene. Such typical part–whole relationships suggest that information from individual scene parts is not processed independently, but that there are mutual influences between the parts and the whole during scene analysis. Here, we review recent research that used a straightforward, but effective approach to study such mutual influences: By dissecting scenes into multiple arbitrary pieces, these studies provide new insights into how the processing of whole scenes is shaped by their constituent parts and, conversely, how the processing of individual parts is determined by their role within the whole scene. We highlight three facets of this research: First, we discuss studies demonstrating that the spatial configuration of multiple scene parts has a profound impact on the neural processing of the whole scene. Second, we review work showing that cortical responses to individual scene parts are shaped by the context in which these parts typically appear within the environment. Third, we discuss studies demonstrating that missing scene parts are interpolated from the surrounding scene context. Bridging these findings, we argue that efficient scene processing relies on an active use of the scene's part–whole structure, where the visual brain matches scene inputs with internal models of what the world should look like.

Abstract Visual scene perception is mediated by a set of cortical regions that respond preferentially to images of scenes, including the occipital place area (OPA) and parahippocampal place area (PPA). However, the differential contribution of OPA and PPA to scene perception remains an open research question. In this study, we take a deep neural network (DNN)-based computational approach to investigate the differences in OPA and PPA function. In a first step, we search for a computational model that predicts fMRI responses to scenes in OPA and PPA well. We find that DNNs trained to predict scene components (e.g., wall, ceiling, floor) explain higher variance uniquely in OPA and PPA than a DNN trained to predict scene category (e.g., bathroom, kitchen, office). This result is robust across several DNN architectures. On this basis, we then determine whether particular scene components predicted by DNNs differentially account for unique variance in OPA and PPA. We find that variance in OPA responses uniquely explained by the navigation-related floor component is higher compared to the variance explained by the wall and ceiling components. In contrast, PPA responses are better explained by the combination of wall and floor, that is, scene components that together contain the structure and texture of the scene. This differential sensitivity to scene components suggests differential functions of OPA and PPA in scene processing. Moreover, our results further highlight the potential of the proposed computational approach as a general tool in the investigation of the neural basis of human scene perception.

Unraveling Representations in Scene-selective Brain Regions Using Scene-Parsing Deep Neural Networks

Brain decoding can predict visual perception from non-invasive electrophysiological data by combining information across multiple channels. However, decoding methods typically confound together the multi-faceted and distributed neural processes underlying perception, so it is unclear what specific aspects of the neural computations involved in perception are reflected in this type of macroscale data. Using MEG data recorded while participants viewed a large number of naturalistic images, we analytically separated the brain signal into a slow 1/f drift (<5Hz) and a oscillatory response in the theta frequency band. Combined with a method for capturing between-trial variability in the way stimuli are processed, this analysis revealed that there are at least three dissociable components that contain distinct stimulus-specific information: a 1/f component, reflecting the temporally stable aspect of the stimulus representation; a global phase shift of the theta oscillation, related to differences in the speed of processing between the stimuli; and differential patterns of theta phase across channels, likely related to stimulus-specific computations. We demonstrate that common cognitive interpretations of decoding analysis can be flawed if the multicomponent nature of the signal is ignored, and suggest that, by acknowledging this fact, we can provide a more accurate interpretation of commonly observed phenomena in the study of perception.

Dissociable components of oscillatory activity underly information encoding in human perception

Visual Imagery and Perception Share Neural Representations in the Alpha Frequency Band

Rapid contextualization of fragmented scene information in the human visual system

Perceived and mentally rotated contents are differentially represented in cortical layers of V1

Temporal uncertainty enhances suppression of neural responses to predictable visual stimuli

A M/EEG-fMRI Fusion Primer: Resolving Human Brain Responses in Space and Time

Visual scene perception is mediated by a set of cortical regions that respond preferentially to images of scenes, including the occipital place area (OPA) and parahippocampal place area (PPA). However, the differential contribution of OPA and PPA to scene perception remains an open research question. In this study, we take a deep neural network (DNN)-based computational approach to investigate the differences in OPA and PPA function. In a first step we search for a computational model that predicts fMRI responses to scenes in OPA and PPA well. We find that DNNs trained to predict scene components (e.g., wall, ceiling, floor) explain higher variance uniquely in OPA and PPA than a DNN trained to predict scene category (e.g., bathroom, kitchen, office). This result is robust across several DNN architectures. On this basis, we then determine whether particular scene components predicted by DNNs differentially account for unique variance in OPA and PPA. We find that variance in OPA responses uniquely explained by the navigation-related floor component is higher compared to the variance explained by the wall and ceiling components. In contrast, PPA responses are better explained by the combination of wall and floor, that is scene components that together contain the structure and texture of the scene. This differential sensitivity to scene components suggests differential functions of OPA and PPA in scene processing. Moreover, our results further highlight the potential of the proposed computational approach as a general tool in the investigation of the neural basis of human scene perception.

Unravelling Representations in Scene-selective Brain Regions Using Scene Parsing Deep Neural Networks

Abstract Numerous theories propose a key role for brain oscillations in visual perception. Most of these theories postulate that sensory information is encoded in specific oscillatory components (e.g., power or phase) of specific frequency bands. These theories are often tested with whole-brain recording methods of low spatial resolution (EEG or MEG), or depth recordings that provide a local, incomplete view of the brain. Opportunities to bridge the gap between local neural populations and whole-brain signals are rare. Here, using representational similarity analysis (RSA) in human participants we explore which MEG oscillatory components (power and phase, across various frequency bands) correspond to low or high-level visual object representations, using brain representations from fMRI, or layer-wise representations in seven recent deep neural networks (DNNs), as a template for low/high-level object representations. The results showed that around stimulus onset and offset, most transient oscillatory signals correlated with low-level brain patterns (V1). During stimulus presentation, sustained β (∼20 Hz) and γ (>60 Hz) power best correlated with V1, while oscillatory phase components correlated with IT representations. Surprisingly, this pattern of results did not always correspond to low-level or high-level DNN layer activity. In particular, sustained β band oscillatory power reflected high-level DNN layers, suggestive of a feed-back component. These results begin to bridge the gap between whole-brain oscillatory signals and object representations supported by local neuronal activations.

Representational Content of Oscillatory Brain Activity during Object Recognition: Contrasting Cortical and Deep Neural Network Hierarchies

Duality Diagram Similarity: a generic framework for initialization selection in task transfer learning

Coherent natural scene structure facilitates the extraction of task-relevant object information in visual cortex

In everyday life, our visual surroundings are not arranged randomly, but structured in predictable ways. Although previous studies have shown that the visual system is sensitive to such structural regularities, it remains unclear whether the presence of an intact structure in a scene also facilitates the cortical analysis of the scene’s categorical content. To address this question, we conducted an EEG experiment during which participants viewed natural scene images that were either “intact” (with their quadrants arranged in typical positions) or “jumbled” (with their quadrants arranged into atypical positions). We then used multivariate pattern analysis to decode the scenes’ category from the EEG signals (e.g., whether the participant had seen a church or a supermarket). The category of intact scenes could be decoded rapidly within the first 100ms of visual processing. Critically, within 200ms of processing category decoding was more pronounced for the intact scenes compared to the jumbled scenes, suggesting that the presence of real-world structure facilitates the extraction of scene category information. No such effect was found when the scenes were presented upside-down, indicating that the facilitation of neural category information is indeed linked to a scene’s adherence to typical real-world structure, rather than to differences in visual features between intact and jumbled scenes. Our results demonstrate that early stages of categorical analysis in the visual system exhibit tuning to the structure of the world that may facilitate the rapid extraction of behaviorally relevant information from rich natural environments.

Real-world structure facilitates the rapid emergence of scene category information in visual brain signals

In real-life situations, the appearance of a person's face can vary substantially across different encounters, making face recognition a challenging task for the visual system. Recent fMRI decoding studies have suggested that face recognition is supported by identity representations located in regions of the occipitotemporal cortex. Here, we used EEG to elucidate the temporal emergence of these representations. Human participants viewed a set of highly variable face images of 4 highly familiar celebrities (2 males and 2 females), while performing an orthogonal task. Univariate analyses of event-related EEG responses revealed a pronounced differentiation between male and female faces, but not between identities of the same sex. Using multivariate representational similarity analysis, we observed a gradual emergence of face identity representations, with an increasing degree of invariance. Face identity information emerged rapidly, starting shortly after 100 ms from stimulus onset, but was modulated by sex differences and image similarities. From 400 ms after onset and predominantly in the right hemisphere, identity representations showed 2 invariance properties: 1) they equally discriminated identities of opposite sexes and of the same sex, and 2) they were tolerant to image-based variations. These invariant representations may be a crucial prerequisite for successful face recognition in everyday situations, where the appearance of a familiar person can vary drastically.

In a standard experimental paradigm typically used in cognitive neuroscience, time is discretized into distinct events and the presented stimulus material is sampled from a low number of categories. While this approach allows conducting highly controlled experiments, its ecological validity is limited, as in real life the human brain has to operate on a continuous time scale and also has to process complex stimuli that typically cannot be assigned to a low-dimensional stimulus space. The encoding model approach has been introduced to address these issues by using highdimensional sets of stimulus features as a means to analyze neuroimaging data from complex and timecontinuous tasks. Recently, activations from deep neural networks (DNNs) were proposed to serve as features in the encoding model approach. However, it has been argued that such DNN-based features might be uninformative for human neuroimaging data, as the behavior of a trained DNN does not necessarily have to resemble human behavior on a given task. Here, we present preliminary evidence (N = 1) that DNN activations from the top network layer can predict human behavior with high fidelity in three different Atari 2600 arcade games based on a linear model. These findings clear the way for extending this type of analysis to neuroimaging data, testing whether DNN activations extracted from hidden layers explain variance in the fMRI signal of task-related brain regions.

Low-frequency oscillations track the contents of visual perception and mental imagery

Spatial schemata determine cortical representations of the environment

Natural scenes are inherently structured, with meaningful objects appearing in predictable locations. Human vision is tuned to this structure: When scene structure is purposefully jumbled, perception is strongly impaired. Here, we tested how such perceptual effects are reflected in neural sensitivity to scene structure. During separate fMRI and EEG experiments, participants passively viewed scenes whose spatial structure (i.e., the position of scene parts) and categorical structure (i.e., the content of scene parts) could be intact or jumbled. Using multivariate decoding, we show that spatial (but not categorical) scene structure profoundly impacts on cortical processing: Scene-selective responses in occipital and parahippocampal cortices (fMRI) and after 255ms (EEG) accurately differentiated between spatially intact and jumbled scenes. Importantly, this differentiation was more pronounced for upright than for inverted scenes, indicating genuine sensitivity to spatial structure rather than sensitivity to low-level attributes. Our findings suggest that visual scene analysis is tightly linked to the spatial structure of our natural environments. This link between cortical processing and scene structure may be crucial for rapidly parsing naturalistic visual inputs.

In the last decade, artificial intelligence (AI) models inspired by the brain have made unprecedented progress in performing real-world perceptual tasks like object classification and speech recognition. Recently, researchers of natural intelligence have begun using those AI models to explore how the brain performs such tasks. These developments suggest that future progress will benefit from increased interaction between disciplines. Here we introduce the Algonauts Project as a structured and quantitative communication channel for interdisciplinary interaction between natural and artificial intelligence researchers. The project's core is an open challenge with a quantitative benchmark whose goal is to account for brain data through computational models. This project has the potential to provide better models of natural intelligence and to gather findings that advance AI. The 2019 Algonauts Project focuses on benchmarking computational models predicting human brain activity when people look at pictures of objects. The 2019 edition of the Algonauts Project is available online: this http URL.

The Algonauts Project: A Platform for Communication between the Sciences of Biological and Artificial Intelligence

Assessing Reproducibility of MEG and fMRI Data Fusion Method in Neural Dynamics of Object Vision

Scene Clutter and Attention Differentially Affect Object Category and Location Representations

With every glimpse of our eyes, we sample only a small and incomplete fragment of the visual world, which needs to be contextualized and integrated into a coherent scene representation. Here we show that the visual system achieves this contextualization by exploiting spatial schemata, that is our knowledge about the composition of natural scenes. We measured fMRI and EEG responses to incomplete scene fragments and used representational similarity analysis to reconstruct their cortical representations in space and time. We observed a sorting of representations according to the fragments' place within the scene schema, which occurred during perceptual analysis in the occipital place area and within the first 200 ms of vision. This schema-based coding operates flexibly across visual features (as measured by a deep neural network model) and different types of environments (indoor and outdoor scenes). This flexibility highlights the mechanism's ability to efficiently organize incoming information under dynamic real-world conditions.

A neural mechanism for contextualizing fragmented inputs during naturalistic vision

In real-life situations, the appearance of a person’s face can vary substantially across different encounters, making face recognition a challenging task for the visual system. Recent fMRI decoding studies have suggested that face recognition is supported by identity representations located in regions of the occipito-temporal cortex. Here, we used EEG to elucidate the temporal emergence of these representations. Human participants (both sexes) viewed a set of highly variable face images of four highly familiar celebrities (two male, two female), while performing an orthogonal task. Univariate analyses of event-related EEG responses revealed a pronounced differentiation between male and female faces, but not between identities of the same sex. Using multivariate representational similarity analysis, we observed a gradual emergence of face identity representations, with an increasing degree of invariance. Face identity information emerged rapidly, starting shortly after 100ms from stimulus onset. From 400ms after onset and predominantly in the right hemisphere, identity representations showed two invariance properties: (1) they equally discriminated identities of opposite sexes and of the same sex, and (2) they were tolerant to image-based variations. These invariant representations may be a crucial prerequisite for successful face recognition in everyday situations, where the appearance of a familiar person can vary drastically. Significance Statement Recognizing the face of a friend on the street is a task we effortlessly perform in our everyday lives. However, the necessary visual processing underlying familiar face recognition is highly complex. As the appearance of a given person varies drastically between encounters, for example across viewpoints or emotional expressions, the brain needs to extract identity information that is invariant to such changes. Using multivariate analyses of EEG data, we characterize how invariant representations of face identity emerge gradually over time. After 400ms of processing, cortical representations reliably differentiated two similar identities (e.g., two famous male actors), even across a set of highly variable images. These representations may support face recognition under challenging real-life conditions.

Animacy and real-world size are properties that describe any object and thus bring basic order into our perception of the visual world. Here, we investigated how the human brain processes real-world size and animacy. For this, we applied representational similarity to fMRI and MEG data to yield a view of brain activity with high spatial and temporal resolutions, respectively. Analysis of fMRI data revealed that a distributed and partly overlapping set of cortical regions extending from occipital to ventral and medial temporal cortex represented animacy and real-world size. Within this set, parahippocampal cortex stood out as the region representing animacy and size stronger than most other regions. Further analysis of the detailed representational format revealed differences among regions involved in processing animacy. Analysis of MEG data revealed overlapping temporal dynamics of animacy and real-world size processing starting at around 150 msec and provided the first neuromagnetic signature of real-world object size processing. Finally, to investigate the neural dynamics of size and animacy processing simultaneously in space and time, we combined MEG and fMRI with a novel extension of MEG–fMRI fusion by representational similarity. This analysis revealed partly overlapping and distributed spatiotemporal dynamics, with parahippocampal cortex singled out as a region that represented size and animacy persistently when other regions did not. Furthermore, the analysis highlighted the role of early visual cortex in representing real-world size. A control analysis revealed that the neural dynamics of processing animacy and size were distinct from the neural dynamics of processing low-level visual features. Together, our results provide a detailed spatiotemporal view of animacy and size processing in the human brain.

Tracking the Spatiotemporal Neural Dynamics of Real-world Object Size and Animacy in the Human Brain

Multivariate decoding methods applied to neuroimaging data have become the standard in cognitive neuroscience for unravelling statistical dependencies between brain activation patterns and experimental conditions. The current challenge is to demonstrate that information decoded as such by the experimenter is in fact used by the brain itself to guide behaviour. Here we demonstrate a promising approach to do so in the context of neural activation during object perception and categorisation behaviour. We first localised decodable information about visual objects in the human brain using a spatially-unbiased multivariate decoding analysis. We then related brain activation patterns to behaviour using a machine-learning based extension of signal detection theory. We show that while there is decodable information about visual category throughout the visual brain, only a subset of those representations predicted categorisation behaviour, located mainly in anterior ventral temporal cortex. Our results have important implications for the interpretation of neuroimaging studies, highlight the importance of relating decoding results to behaviour, and suggest a suitable methodology towards this aim.

Corrigendum to “Multivariate pattern analysis for MEG: A comparison of dissimilarity measures” [NeuroImage 173 (2018) 434–447]

Typical retinotopic locations impact the time course of object coding

Natural environments consist of multiple objects, many of which repeatedly occupy similar locations within a scene. For example, hats are seen on people's heads, while shoes are most often seen close to the ground. Such positional regularities bias the distribution of objects across the visual field: hats are more often encountered in the upper visual field, while shoes are more often encountered in the lower visual field. Here we tested the hypothesis that typical visual field locations of objects facilitate cortical processing. We recorded functional MRI while participants viewed images of objects that were associated with upper or lower visual field locations. Using multivariate classification, we show that object information can be more successfully decoded from response patterns in object-selective lateral occipital cortex (LO) when the objects are presented in their typical location (e.g., shoe in the lower visual field) than when they are presented in an atypical location (e.g., shoe in the upper visual field). In a functional connectivity analysis, we relate this benefit to increased coupling between LO and early visual cortex, suggesting that typical object positioning facilitates information propagation across the visual hierarchy. Together these results suggest that object representations in occipital visual cortex are tuned to the structure of natural environments. This tuning may support object perception in spatially structured environments. NEW & NOTEWORTHY In the real world, objects appear in predictable spatial locations. Hats, commonly appearing on people's heads, often fall into the upper visual field. Shoes, mostly appearing on people's feet, often fall into the lower visual field. Here we used functional MRI to demonstrate that such regularities facilitate cortical processing: Objects encountered in their typical locations are coded more efficiently, which may allow us to effortlessly recognize objects in natural environments.

Typical visual-field locations enhance processing in object-selective channels of human occipital cortex.

The Time Courses of Object Category and Location Representations in the Human Brain Depend on Clutter

In real-world vision, humans are constantly confronted with complex environments that contain a multitude of objects. These environments are spatially structured, so that objects have different likelihoods of appearing in specific parts of the visual space. Our massive experience with such positional regularities prompts the hypothesis that the processing of individual objects varies in efficiency across the visual field: when objects are encountered in their typical locations (e.g., we are used to seeing lamps in the upper visual field and carpets in the lower visual field), they should be more efficiently perceived than when they are encountered in atypical locations (e.g., a lamp in the lower visual field and a carpet in the upper visual field). Here, we provide evidence for this hypothesis by showing that typical positioning facilitates an object’s access to awareness. In two continuous flash suppression experiments, objects more efficiently overcame inter-ocular suppression when they were presented in visual-field locations that matched their typical locations in the environment, as compared to non-typical locations. This finding suggests that through extensive experience the visual system has adapted to the statistics of the environment. This adaptation may be particularly useful for rapid object individuation in natural scenes.

Typical visual-field locations facilitate access to awareness for everyday objects

To build a representation of what we see, the human brain recruits regions throughout the visual cortex in cascading sequence. Recently, an approach was proposed to evaluate the dynamics of visual perception in high spatiotemporal resolution at the scale of the whole brain. This method combined functional magnetic resonance imaging (fMRI) data with magnetoencephalography (MEG) data using representational similarity analysis and revealed a hierarchical progression from primary visual cortex through the dorsal and ventral streams. To assess the replicability of this method, here we present results of a visual recognition neuro-imaging fusion experiment, and compare them within and across experimental settings. We evaluated the reliability of this method by assessing the consistency of the results under similar test conditions, showing high agreement within participants. We then generalized these results to a separate group of individuals and visual input by comparing them to the fMRI-MEG fusion data of Cichy et al (2016), revealing a highly similar temporal progression recruiting both the dorsal and ventral streams. Together these results are a testament to the reproducibility of the fMRI-MEG fusion approach and allows for the interpretation of these spatiotemporal dynamic in a broader context.

Reliability and Generalizability of Similarity-Based Fusion of MEG and fMRI Data in Human Ventral and Dorsal Visual Streams

As incoming stimuli travel through our sensory pipelines, they are processed in multiple formats, spanning levels of abstraction as well as sensory domains. The spatiotemporal and representational dynamics of this processing cascade remain especially unclear in nonvisual modalities and nontypical populations; in particular, a stimulus representation may either facilitate or suppress its multisensory analogue. Here, we presented auditory alphabetic letter names to blind listeners with no visual letter experience, as well as sighted listeners with no braille (tactile) reading experience. Blind and sighted groups’ brain responses distinguished letter identity along similar time courses and accuracies. However, only blind listeners’ brain signals correlated with a low-level model of braille characters, while no such correlation was found between sighted listeners’ brain signals and a neural network model of low-level visual letter features. The results illustrate that visual experience modulates both the extent and nature of multisensory processing and object representation generally.

Auditory letter-name processing elicits crossmodal representations in blind listeners

Multivariate pattern analysis for MEG: A comparison of dissimilarity measures

Human visual recognition activates a dense network of overlapping feedforward and recurrent neuronal processes, making it hard to disentangle processing in the feedforward from the feedback direction. Here, we used ultra-rapid serial visual presentation to suppress sustained activity that blurs the boundaries of processing steps, enabling us to resolve two distinct stages of processing with MEG multivariate pattern classification. The first processing stage was the rapid activation cascade of the bottom-up sweep, which terminated early as visual stimuli were presented at progressively faster rates. The second stage was the emergence of categorical information with peak latency that shifted later in time with progressively faster stimulus presentations, indexing time-consuming recurrent processing. Using MEG-fMRI fusion with representational similarity, we localized recurrent signals in early visual cortex. Together, our findings segregated an initial bottom-up sweep from subsequent feedback processing, and revealed the neural signature of increased recurrent processing demands for challenging viewing conditions.

Ultra-Rapid serial visual presentation reveals dynamics of feedforward and feedback processes in the ventral visual pathway

Despite the importance of an observer’s goals in determining how a visual object is categorized, surprisingly little is known about how humans process the task context in which objects occur and how it may interact with the processing of objects. Using magnetoencephalography (MEG), functional magnetic resonance imaging (fMRI) and multivariate techniques, we studied the spatial and temporal dynamics of task and object processing. Our results reveal a sequence of separate but overlapping task-related processes spread across frontoparietal and occipitotemporal cortex. Task exhibited late effects on object processing by selectively enhancing task-relevant object features, with limited impact on the overall pattern of object representations. Combining MEG and fMRI data, we reveal a parallel rise in task-related signals throughout the cerebral cortex, with an increasing dominance of task over object representations from early to higher visual areas. Collectively, our results reveal the complex dynamics underlying task and object representations throughout human cortex.

The representational dynamics of task and object processing in humans

Scale-specific analysis of fMRI data on the irregular cortical surface

Everyday visual environments are spatially structured in that objects often appear at typical locations in space: for example, lamps hang from the ceiling, whereas carpets lie on the floor. As a consequence, objects repeatedly occupy similar visual field locations. The long-term experience with these spatial regularities prompts the hypothesis that the visual system is tuned to such retinotopic object locations. A key prediction is that typically positioned objects should be coded more efficiently. To test this prediction, we recorded electroencephalography (EEG) while participants viewed briefly presented objects appearing in their typical locations (e.g., an airplane in the upper visual field) or in atypical locations (e.g., an airplane in the lower visual field). Multivariate pattern analysis applied to the EEG data revealed that object classification depended on positional regularities: Objects were classified more accurately when positioned typically, rather than atypically, already at 140 ms, suggesting that relatively early stages of object processing are tuned to typical retinotopic locations. Our results confirm the prediction that long-term experience with objects occurring at specific locations leads to enhanced perceptual processing when these objects appear in their typical locations. This may indicate a neural mechanism for efficient natural scene processing, where a large number of typically positioned objects needs to be processed.

Typical real-world locations impact the time course of object coding

Object recognition is commonly described as a feedforward process, yet the tasks we carry out often affect what information in visual stimuli is diagnostic and may influence their processing. Surprisingly little is known about how task context is processed and when and how it interacts with the emerging representation of objects. Here we used magnetoencephalography (MEG) and multivariate decoding to investigate the temporal dynamics of task and object processing and their interaction. Participants viewed objects while we varied task context on a trial-by-trial basis, using both high-level conceptual and low-level perceptual tasks. Time-resolved multivariate decoding and temporal cross-classification revealed multiple distinct yet overlapping stages of task processing from the onset of a trial, likely reflecting a sequence of visual, semantic, mnemonic, and rule-related task representations. Object decoding was stronger in conceptual than perceptual tasks, with differences emerging around 530 ms after object onset. However, object decoding generalized well between task contexts, indicating differently strong but qualitatively similar brain responses. Using model-based MEG-fMRI fusion, we found that frontoparietal areas were strongly dominated by information about task context throughout the trial, while occipitotemporal regions reflected a mixture of both task and object category indicating their parallel encoding in the same brain area. Together, our results reveal the temporal evolution of task context representations and suggest that the impact of task context during object processing occurs late in time.

Representational dynamics of task context and its influence on visual object processing

Content-Dependent Fusion: Combining Human MEG and FMRI Data to Reveal Spatiotemporal Dynamics of Animacy and Real-world Object Size

Spatiotemporal dynamics of braille letter perception in blind readers

Decoding the orientation of contrast edges from MEG evoked and induced responses

Computational models of vision have become ubiquitous in many domains of science, with the most powerful models now competing with human performance in several tasks. Many popular models, such as deep neural networks and HMAX, are inspired by the human visual system, relying on a hierarchical cascade of feedforward transformations akin to the human ventral stream. Despite these advances, the human visual cortex remains unique in complexity, with feedforward and feedback pathways characterized by rapid spatiotemporal dynamics as visual information is transformed into semantic content. Thus, a systematic characterization of the spatiotemporal and representational space of the ventral visual pathway can offer novel insights in the duration and sequencing of cognitive processes, suggesting computational constraints and new architectures for computer vision models.

Similarity-based fusion of MEG and fMRI discerns early feedforward and feedback processing in the ventral stream

MEG decoding reveals the representational dynamics of task context in visual processing

Multivariate pattern analysis of MEG and EEG reveals the dynamics of human object processing

Despite the importance of an observer’s goals in determining how a visual object is categorized, surprisingly little is known about how humans process the task context in which objects occur and how it may interact with the processing of objects. Using magnetoencephalography (MEG), functional magnetic resonance imaging (fMRI) and multivariate techniques, we studied the spatial and temporal dynamics of task and object processing. Our results reveal a sequence of separate but overlapping task-related processes spread across frontoparietal and occipitotemporal cortex. Task exhibited late effects on object processing by selectively enhancing task-relevant object features, with limited impact on the overall pattern of object representations. Combining MEG and fMRI data, we reveal a parallel rise in task-related signals throughout the cerebral cortex, with an increasing dominance of task over category from early to higher visual areas. Collectively, our results reveal the complex dynamics underlying task and object representations throughout human cortex.

The Representational Dynamics of Task and Object Category Processing in Humans

Oscillatory signatures of object recognition across cortical space and time.

In natural environments, visual and auditory stimulation elicit responses across a large set of brain regions in a fraction of a second, yielding representations of the multimodal scene and its properties. The rapid and complex neural dynamics underlying visual and auditory information processing pose major challenges to human cognitive neuroscience. Brain signals measured non-invasively are inherently noisy, the format of neural representations is unknown, and transformations between representations are complex and often nonlinear. Further, no single non-invasive brain measurement technique provides a spatio-temporally integrated view. In this opinion piece, we argue that progress can be made by a concerted effort based on three pillars of recent methodological development: (i) sensitive analysis techniques such as decoding and cross-classification, (ii) complex computational modelling using models such as deep neural networks, and (iii) integration across imaging methods (magnetoencephalography/electroencephalography, functional magnetic resonance imaging) and models, e.g. using representational similarity analysis. We showcase two recent efforts that have been undertaken in this spirit and provide novel results about visual and auditory scene analysis. Finally, we discuss the limits of this perspective and sketch a concrete roadmap for future research. This article is part of the themed issue ‘Auditory and visual scene analysis’.

Resolving the neural dynamics of visual and auditory scene processing in the human brain: a methodological approach

Combining human MEG and fMRI data reveals the spatio-temporal dynamics of animacy and real-world object size

Multivariate pattern analysis (MVPA) methods such as decoding and representational similarity analysis (RSA) are growing rapidly in popularity for the analysis of magnetoencephalography (MEG) data. However, little is known about the relative performance and characteristics of the specific dissimilarity measures used to describe differences between evoked activation patterns. Here we used a multisession MEG dataset to qualitatively characterize a range of dissimilarity measures and to quantitatively compare them with respect to classification accuracy (for decoding) and between-session reliability of representational dissimilarity matrices (for RSA). We tested dissimilarity measures from a range of classifiers (Linear Discriminant Analysis – LDA, Support Vector Machine – SVM, Weighted Robust Distance – WeiRD, Gaussian Naïve Bayes – GNB) and distances (Euclidean distance, Pearson correlation). In addition, we evaluated three key processing choices: 1) preprocessing (noise normalisation, removal of the pattern mean), 2) weighting classification accuracies by decision values, and 3) computing distances in three different partitioning schemes (non-cross-validated, cross-validated, within-class-corrected). Four main conclusions emerged from our results. First, multivariate noise normalization dramatically improved classification accuracies and the reliability of dissimilarity measures. Second, LDA, SVM and WeiRD yielded high peak classification accuracies and nearly identical time courses. Third, while using classification accuracies for RSA was markedly less reliable than continuous distances, this disadvantage was ameliorated by decision-value-weighting of classification accuracies. Fourth, the cross-validated Euclidean distance provided unbiased distance estimates and highly replicable representational dissimilarity matrices. Overall, we strongly advice the use of multivariate noise normalisation as a general preprocessing step, recommend LDA, SVM and WeiRD as classifiers for decoding and highlight the cross-validated Euclidean distance as a reliable and unbiased default choice for RSA. Highlights We compared dissimilarity measures and preprocessing choices for MEG MVPA Multivariate noise normalisation is a key preprocessing step LDA, SVM and WeiRD are recommended classifiers for decoding Use of decision values improves reliability of classification accuracies The cross-validated Euclidean distance is a reliable and unbiased choice for RSA

Multivariate pattern analysis for MEG: a comprehensive comparison of dissimilarity measures

Deep Neural Networks explain spatio-temporal dynamics of visual scene and object processing

Comparison of deep neural networks to spatio-temporal cortical dynamics of human visual object recognition reveals hierarchical correspondence

Multivariate pattern analysis of magnetoencephalography (MEG) and electroencephalography (EEG) data can reveal the rapid neural dynamics underlying cognition. However, MEG and EEG have systematic differences in sampling neural activity. This poses the question to which degree such measurement differences consistently bias the results of multivariate analysis applied to MEG and EEG activation patterns. To investigate, we conducted a concurrent MEG/EEG study while participants viewed images of everyday objects. We applied multivariate classification analyses to MEG and EEG data, and compared the resulting time courses to each other, and to fMRI data for an independent evaluation in space. We found that both MEG and EEG revealed the millisecond spatio-temporal dynamics of visual processing with largely equivalent results. Beyond yielding convergent results, we found that MEG and EEG also captured partly unique aspects of visual representations. Those unique components emerged earlier in time for MEG than for EEG. Identifying the sources of those unique components with fMRI, we found the locus for both MEG and EEG in high-level visual cortex, and in addition for MEG in early visual cortex. Together, our results show that multivariate analyses of MEG and EEG data offer a convergent and complimentary view on neural processing, and motivate the wider adoption of these methods in both MEG and EEG research.

Multivariate pattern analysis of MEG and EEG: A comparison of representational structure in time and space

The complex multi-stage architecture of cortical visual pathways provides the neural basis for efficient visual object recognition in humans. However, the stage-wise computations therein remain poorly understood. Here, we compared temporal (magnetoencephalography) and spatial (functional MRI) visual brain representations with representations in an artificial deep neural network (DNN) tuned to the statistics of real-world visual recognition. We showed that the DNN captured the stages of human visual processing in both time and space from early visual areas towards the dorsal and ventral streams. Further investigation of crucial DNN parameters revealed that while model architecture was important, training on real-world categorization was necessary to enforce spatio-temporal hierarchical relationships with the brain. Together our results provide an algorithmically informed view on the spatio-temporal dynamics of visual object recognition in the human visual brain.

Deep Neural Networks predict Hierarchical Spatio-temporal Cortical Dynamics of Human Visual Object Recognition

Functional changes in visual cortex as a consequence of blindness are a major model for studying crossmodal neuroplasticity. Previous studies have shown that traditionally visual cortical regions activate in response to a wide range of nonvisual tasks (Merabet & Pascual-Leone, 2010; Kupers & Ptito, 2013). However, the underlying computations, while often inferred to be similar for the blind and the sighted, have almost never been examined in detail. Here we used magnetoencephalography (MEG) and advanced multivariate pattern analysis to compare visual letter recognition with Braille reading (Sadato et al., 1996; Reich et al., 2011). We presented blind and sighted volunteers with 10 single letters in random order while recording brain activity. Sighted subjects were presented with Roman visual letters, while blind subjects were presented with Braille tactile letters. We used linear support vector machines to decode letter identity from MEG data. We found that the classification time course of letter recognition in sighted subjects was generally faster, briefer, and more consistent than in blind subjects. We then used representational similarity analysis (Kriegeskorte et al., 2008) to compare how sighted and blind subjects represented letters both within and across groups. This analysis revealed high within-group correlations at ~200 ms for sighted and ~600 ms for blind subjects. Correlations between groups were an order of magnitude lower, though overall significantly positive. The results suggest that blind and sighted letter reading may be largely driven by distinct processes, but that brain regions recruited crossmodally may be performing some common underlying computations for analogous tasks. This work was supported by NIH R01-EY020484 to A.O. Meeting abstract presented at VSS 2015.

The neural dynamics of letter perception in blind and sighted readers.

Can visual information encoded in cortical columns be decoded from magnetoencephalography data in humans?

Every human cognitive function, such as visual object recognition, is realized in a complex spatio-temporal activity pattern in the brain. Current brain imaging techniques in isolation cannot resolve the brain’s spatio-temporal dynamics because they provide either high spatial or temporal resolution but not both. To overcome this limitation, we developed a new integration approach that uses representational similarities to combine measurements from different imaging modalities – magnetoencephalography (MEG) and functional MRI (fMRI) - to yield a spatially and temporally integrated characterization of neuronal activation. Applying this approach to two independent MEG-fMRI data sets, we observed that neural activity first emerged in the occipital pole at 50-80ms, before spreading rapidly and progressively in the anterior direction along the ventral and dorsal visual streams. These results provide a novel and comprehensive, spatio-temporally resolved view of the rapid neural dynamics during the first few hundred milliseconds of object vision. They further demonstrate the feasibility of spatially unbiased representational similarity based fusion of MEG and fMRI, promising new insights into how the brain computes complex cognitive functions.

Similarity-Based Fusion of MEG and fMRI Reveals Spatio-Temporal Dynamics in Human Cortex During Visual Object Recognition

Non-holistic coding of objects in lateral occipital complex with and without attention

The neural machinery underlying visual object recognition comprises a hierarchy of cortical regions in the ventral visual stream. The spatiotemporal dynamics of information flow in this hierarchy of regions is largely unknown. Here we tested the hypothesis that there is a correspondence between the spatiotemporal neural processes in the human brain and the layer hierarchy of a deep convolutional neural network (CNN). We presented 118 images of real-world objects to human participants (N=15) while we measured their brain activity with functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG). We trained an 8 layer (5 convolutional layers, 3 fully connected layers) CNN to predict 683 object categories with 900K training images from the ImageNet dataset. We obtained layer-specific CNN responses to the same 118 images. To compare brain-imaging data with the CNN in a common framework, we used representational similarity analysis. The key idea is that if two conditions evoke similar patterns in brain imaging data, they should also evoke similar patterns in the computer model. We thus determined 'where' (fMRI) and 'when' (MEG) the CNNs predicted brain activity. We found a correspondence in hierarchy between cortical regions, processing time, and CNN layers. Low CNN layers predicted MEG activity early and high layers relatively later; low CNN layers predicted fMRI activity in early visual regions, and high layers in late visual regions. Surprisingly, the correspondence between CNN layer hierarchy and cortical regions held for the ventral and dorsal visual stream. Results were dependent on amount of training and type of training material. Our results show that CNNs are a promising formal model of human visual object recognition. Combined with fMRI and MEG, they provide an integrated spatiotemporal and algorithmically explicit view of the first few hundred milliseconds of object recognition. Meeting abstract presented at VSS 2015.

Mapping human visual representations in space and time by neural networks.

Dynamics of scene representations in the human brain revealed by magnetoencephalography and deep neural networks

22. CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not. ABSTRACT 23 24 Human scene recognition is a rapid multistep process evolving over time from single 25 scene image to spatial layout processing. We used multivariate pattern analyses on 26 magnetoencephalography (MEG) data to unravel the time course of this cortical process. 27 Following an early signal for lower-level visual analysis of single scenes at ~100ms, we 28 found a marker of real-world scene size, i.e. spatial layout processing, at ~250ms 29 indexing neural representations robust to changes in unrelated scene properties and 30 viewing conditions. For a quantitative explanation that captures the complexity of scene 31 recognition, we compared MEG data to a deep neural network model trained on scene 32 classification. Representations of scene size emerged intrinsically in the model, and 33 resolved emerging neural scene size representation. Together our data provide a first 34 description of an electrophysiological signal for layout processing in humans, and a novel 35 quantitative model of how spatial layout representations may emerge in the human brain. 36 37 38 39 40 41 KEY WORDS 42 43 Scene perception, spatial layout, magnetoencephalography, deep neural network, 44 representational similarity analysis 45 46. CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not .

Title : Dynamics of scene representations in the human brain revealed by 1 magnetoencephalography and deep neural networks 2 3

Parietal and early visual cortices encode working memory content across mental transformations

Spatial attention enhances object coding in local and distributed representations of the lateral occipital complex

Human scene recognition is a rapid multistep process evolving over time from single scene image to spatial layout processing. We used multivariate pattern analyses on magnetoencephalography (MEG) data to unravel the time course of this cortical process. Following an early signal for lower-level visual analysis of single scenes at ∼ 100ms, we found a marker of real-world scene size, i.e., spatial layout processing, at ∼ 250ms indexing neural representations robust to changes in unrelated scene properties and viewing conditions. For a quantitative explanation that captures the complexity of scene recognition, we compared MEG data to a deep neural network model trained on scene classification. Representations of scene size emerged intrinsically in the model, and resolved emerging neural scene size representation. Together our data provide a first description of an electrophysiological signal for layout processing in humans, and a novel quantitative model of how spatial layout representations may emerge in the human brain. The supplemental materials are available at: http://brainmodels.csail.mit.edu/scene-size

Dynamics of Scene Representations in the Human Brain revealed by MEG and Deep Neural Networks

Achim Stephan, Sven Walter (Eds.), Handbuch Kognitionswissenschaft

• Fig. 1: Time courses with which clutter, contrast, and luminance representations emerged in the brain. • Fig. 2: Results of cross-classification analysis plotted with 95% confidence intervals as determined by bootstrapping participants (colored shaded areas). • Fig. 3: Scene clutter representations emerged with a distinct time course and were robust to changes in viewing conditions and other scene properties. • Fig. 4: Persistent components in scene representations. The details of this figure are given in Section 1.1 below. • Fig. 5: Layer-resolved prediction of emerging neural representations of single scene images by computational models. • Fig. 6: Comparison of the deep scene network against other computational models in predicting neural representations of single scene images. • Fig. 7: Complete layer-wise comparisons of scene representations in computational models of object and scene categorization. • Fig. 8: Comparison of size effect in the deep scene network without and with partialling out the effect of other experimental factors (clutter, contrast and luminance). • Fig. 9: Neural representations of scene clutter, contrast, and luminance explained by computational models. • Movie: MEG decoding accuracy matrix and multidimensional scaling solution in two dimensions. The movie shows the MEG decoding accuracy matrices over time in 1 millisecond steps, accompanied with a two-dimensional scaling solution (criterion: metric stress). Experimental conditions (images) are plotted in the two dimensional space, colorand shape-coded to indicate scene size and clutter level. Link: http://brainmodels.csail.mit.edu/scene-size 1.1. Explanation of Fig. 4

Supplemental Materials: Dynamics of Scene Representations in the Human Brain revealed by MEG and Deep Neural Networks

Humans recognize faces and objects with high speed and accuracy regardless of their orientation. Recent studies have proposed that orientation invariance in face recognition involves an intermediate representation where neural responses are similar for mirror-symmetric views. Here, we used fMRI, multivariate pattern analysis, and computational modeling to investigate the neural encoding of faces and vehicles at different rotational angles. Corroborating previous studies, we demonstrate a representation of face orientation in the fusiform face-selective area (FFA). We go beyond these studies by showing that this representation is category-selective and tolerant to retinal translation. Critically, by controlling for low-level confounds, we found the representation of orientation in FFA to be compatible with a linear angle code. Aspects of mirror-symmetric coding cannot be ruled out when FFA mean activity levels are considered as a dimension of coding. Finally, we used a parametric family of computational models, involving a biased sampling of view-tuned neuronal clusters, to compare different face angle encoding models. The best fitting model exhibited a predominance of neuronal clusters tuned to frontal views of faces. In sum, our findings suggest a category-selective and monotonic code of face orientation in the human FFA, in line with primate electrophysiology studies that observed mirror-symmetric tuning of neural responses at higher stages of the visual system, beyond the putative homolog of human FFA.

The Neural Code for Face Orientation in the Human Fusiform Face Area

Decoding orientation of visual stimuli from human magnetoencephalography data

Knowledge about the principles that govern large‐scale neural representations of objects is central to a systematic understanding of object recognition. We used functional magnetic resonance imaging (fMRI) and multivariate pattern classification to investigate two such candidate principles: category preference and location encoding. The former designates the preferential activation of distinct cortical regions by a specific category of objects. The latter refers to information about where in the visual field a particular object is located. Participants viewed exemplars of three object categories (faces, bodies, and scenes) that were presented left or right of fixation. The analysis of fMRI activation patterns revealed the following. Category‐selective regions retained their preference to the same categories in a manner tolerant to changes in object location. However, category preference was not absolute: category‐selective regions also contained location‐tolerant information about nonpreferred categories. Furthermore, location information was present throughout high‐level ventral visual cortex and was distributed systematically across the cortical surface. We found more location information in lateral‐occipital cortex than in ventral‐temporal cortex. Our results provide a systematic account of the extent to which the principles of category preference and location encoding determine the representation of objects in the high‐level ventral visual cortex. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.

Probing principles of large‐scale object representation: Category preference and location encoding

Mapping visual object recognition in the human brain with combined MEG and fMRI

A striking feature of human object perception is the ability to recognize objects in previously unseen views. Behavioral studies have shown that this view-invariance is largely dependent on attention (Thoma et al., 2004; Stankiewicz and Cooper, 1998). It has therefore been proposed that object recognition operates on two different representational formats depending on the availability of attentional resources (Hummel, 2001):

Neural correlates of structural and holistic object representations in dependence of attention

Translation tolerant and category-selective encoding of orientation in the fusiform face area

Visual imagery allows us to vividly imagine scenes in the absence of visual stimulation. The likeness of visual imagery to visual perception suggests that they might share neural mechanisms in the brain. Here, we directly investigated whether perception and visual imagery share cortical representations. Specifically, we used a combination of functional magnetic resonance imaging (fMRI) and multivariate pattern classification to assess whether imagery and perception encode the "category" of objects and their "location" in a similar fashion. Our results indicate that the fMRI response patterns for different categories of imagined objects can be used to predict the fMRI response patters for seen objects. Similarly, we found a shared representation of location in low-level and high-level ventral visual cortex. Thus, our results support the view that imagery and perception are based on similar neural representations.

Imagery and perception share cortical representations of content and location.

Zusammenfassung Seit dem Aufkommen der funktionellen Magnetresonanztomografie (fMRT) vor 20 Jahren steht eine neue Methode zur nicht invasiven Messung von Gehirnfunktionen zur Verfügung, welche in den kognitiven Neurowissenschaften inzwischen weit verbreitet ist. Traditionell wurden fMRT-Daten vor allem verwendet, um globale Änderungen der Aktivität in bestimmten Gehirnregionen zu messen, wie sie etwa während einer kognitiven Verarbeitung auftreten. Die Entwicklung neuer Methoden ermöglicht nun einen verfeinerten, inhaltsbasierten Ansatz. Das „multivariate Decoding“ erlaubt es, die kognitive Information zu untersuchen, die in feinkörnigen fMRT-Aktivitätsmustern enthalten ist. Damit lässt sich die Kodierung spezifischer kognitiver Inhalte und Repräsentationen im Gehirn näher bestimmen. Hier wird ein Überblick über verschiedene Entwicklungen des multivariaten Decoding gegeben von der Anwendung in den kognitiven Neurowissenschaften (Wahrnehmung, Aufmerksamkeit, Belohnung, Entscheidungsfindung, emotionale Kommunikation) über neuere methodische Entwicklungen (Informationsfluss, oberflächenbasiertes Searchlight-Decoding) bis hin zur medizinischen Diagnostik gegeben.

Multivariate Dekodierung von fMRT-Daten: Auf dem Weg zu einer inhaltsbasierten kognitiven Neurowissenschaft

Multivariate Decoding of fMRI Data: On the Way to a content-based cognitive Neuroscience

Orientation-encoding in the FFA is selective to faces: Evidence from multivoxel pattern analysis

Imagery and perception of objects share cortical representations

An initial transient-state and reliable measures of corticospinal excitability in TMS studies

74. Systematic fluctuations of TMS-induced motor-evoked potentials

Transcranial cortex stimulation and fMRI: Electrophysiological correlates of dual-pulse BOLD signal modulation

Fluctuations of the TMS induced MEP: a steady-state and reliable estimates

Durch die simultane Kombination von TES uber M1, fMRI und EMG sollen die neuronalen Verbindungen des menschlichen Motorsystems in vivo kartiert werden. Uberschwellige TES (120% RMT) uber M1 wurde bei 3 gesunden Probanden in latero-medialer (l-m) und postero-anteriorer (p-a) Orientierung durchgefuhrt. Die Onset-Latenzen der EMG-Potentiale im FDI dienten als elektrophysiologischer Marker fur die Differenzierung von direkten (TES l-m) und indirekten Stimulationseffekten (TES p-a) in Anlehnung an die D/I-wave-Hypothese (Patton und Amassian, 1954) und eigene Vorarbeiten (Brocke et al., 2005). In den erhobenen 3-T fMRI-Daten wurden die beteiligten kortikalen motorischen Areale anhand einer multivariaten ROI-Analyse (SPM2) in Ubereinstimmung von anatomischen Landmarken und probabilistischen Karten identifiziert. Die statistische Analyse der BOLD-Signal-Unterschiede zwischen den beiden Stimulationskonditionen erfolgte durch einseitige T-Tests (p<0,001, unkorrigiert). Die Latenzen der Muskelantworten waren in l-m-Orientierung signifikant kurzer als in p-a-Orientierung (19,97±1,60 und 22,55±2,14, p <0,0001, einseitige Anova). Folgende Areale des Motornetzwerkes (T-Test, p<0,001, unkorrigiert) waren in beiden Konditionen aktiviert: bilateraler S1, parietales Operkulum 1, Supplementar Sensorisches Areal (SSA), Insula sowie kontralateraler M1 (Abb. gepunktet). Die Aktivierung dieser Areale durch efferente und afferente Ruckkopplung kann hier nicht ausgeschlossen werden. Die direkte Stimulation induzierte erwartungsgemas keine Ferneffekte. Im Gegensatz dazu induzierte die indirekte Stimulation erwartungsgemas eine exklusive Aktivierung (T-Test, p<0,001, unkorrigiert) im ipsilateralen M1, bilateralen M2d, M2v, SMA, CMA, sowie im parietalen Operculum 3 & 4, im posteriorparietalen Kortex (PPC) und im Cerebellum (Abb. schraffiert). Diese motorischen und sensorischen Areale stellen das von afferenter und efferenter Ruckkopplung sowie willkurlicher Arealaktivierung freie Korrelat der Konnektivitat des motorischen Netzwerkes dar.

Kartierung der funktionellen Anatomie des menschlichen kortiko-kortikalen und kortikospinalen Systems durch simultane TES und fMRI

Neuroethik & Neurophilosophie: Transkranielle Hirnstimulation – Kausalitat zwischen Gehirn und Geist? -

Transkranielle Hirnstimulation – Kausalität zwischen Gehirn und Geist?

Functional connectivity of the motor system defined by transcranial electric stimulation (TES)

The phenomenon of intentionality, i.e. aboutness or of-ness is one of the major topics in contemporary philosophy of mind. In D.C. Dennett's highly influential, stimulating and in its richness unique philosophy the concept of intentionality takes centre stage as a presupposition for any other kind of philosophy of mind. This thesis critically evaluates the different forms that the Dennettian concept of intentionality has taken over time. It starts discussing Dennett's early instrumentalist philosophy and ends up with his concept of tools and memes. Conceptual relationships between subsequent phases in Dennett's development are stressed and given primary role. 3 In Appreciation of Mr T.W.

The role of gaze position in training visual brain encoders on free-viewing data

: Visual perception in humans is mediated by a large and complex network of brain regions. computations human brain: 1) rapid perception of natural scenes, studied with EEG and models of low-level image statistics; 2) the role of high-level semantics and action affordances in natural scene categorization, studied using multi-voxel pattern fMRI and deep neural network models; and 3) temporal dynamics of visual responses, studied with ECoG and temporal encoding models. Abstract: Illumination of the world around us enables vision and visual perception. Additionally, light exposure profoundly affects our physiology and behaviour by entraining the circadian system to the light-dark cycle and modifying melatonin production. These “non-visual” effects are mediated by a subset of retinal ganglion cells, the melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs). Demonstrating how the different photoreceptors in the eye – including the cones and rods – contribute to non-visual light-mediated functions requires specific methods for stimulating photoreceptors in isolation. Here, I will describe recent work on uncovering the mechanisms underlying the non-visual effects of light and recent forays into translating these findings into the real world. Abstract: Current artificial neural networks were originally inspired by classical vision models. Therefore, following their success in computer vision, it is not surprising that a growing body of literature considers deep learning as the ultimate framework also in visual neuroscience. The main difference between current deep networks and classical vision models is the procedure to obtain their free parameters: while vision models are intended to fit physiological or psychophysical measures, deep networks are optimized to fulfill a certain (visual) task over a training dataset. However, both strategies to get the parameters (fit the biology or fit the statistics) have fundamental problems to describe vision. On the one hand, traditional physiological/psychophysical Abstract: How does the brain learn to see properties of the world—like the glossiness of a surface—that cannot be measured by any other senses? Recent advances in unsupervised deep learning provide us with unprecedentedly powerful statistical learning systems, which may help shed light on how brains learn from their visual experience. I will discuss two projects in which we probe the visual representations learned by unsupervised deep neural networks trained on artificial environments. In one project, we train a convolutional PixelVAE network to model the pixel statistics in 10,000 static images of bumpy surfaces that have different shapes, materials and lighting. In another, we train a recurrent convolutional PredRNN network to predict the next frame in 10,000 video clips of moving objects with different shapes, materials, lighting and trajectories. In both cases, the models spontaneously come to encode those factors in their internal representations, providing a proof-of-principle for how knowledge about the outside world can be learned from visual experience alone. Most strikingly, the models make patterns of errors in their perception of material that follow, on an image-by-image basis, the patterns of errors made by human observers. The network trained on static images shows human-like failures of perceptual gloss constancy, and the network trained on moving videos learns a representation of material that combines both static and motion cues in human-like ways. Unsupervised Abstract: One major goal in vision neuroscience is characterizing the responses of higher order functional regions in the visual system. As visual computations are complex and grounded, it is likely that underlying their semantic selectivity (e.g. places, faces, objects, body parts) there exists a composite of image-computable features, and that these could be activated selectively. Exhaustively characterizing this composite experimentally would require showing massive amounts of stimuli; which - due to the variety of the visual world - is impossible in-vivo. An alternative approach would be deriving computational models from neuroimaging data and probing them as in-silico models with neural network sensitivity methods. This avenue now exists through convolutional neural network models of the visual system and is currently being explored. The direct route to brain-like in-silico models would be training them end-to-end on massive amounts of neuroimaging data. Using a large-scale functional MRI dataset where naturalistic videos were shown, we derived such a model of the visual system. To identify the preferred stimuli of voxels and regions, we used a neural network interpretability technique, based on a generative adversarial neural network (GAN) for synthesizing preferred images. The higher order areas in our model showed expected (e.g. faces and low spatial frequencies in FFA, places and high spatial frequencies in PPA) but also unexpected behavior. Preferred images for each investigated region were localized in highly distinct regions of Abstract: Signal detection, the ability to differentiate between two stimuli or a stimulus and background, is extensively studied in experimental psychology to precisely measure the limits of our sensations and perception. Here, I will discuss the same concept in modern deep neural networks. Thanks to their human-level performance, these models are ubiquitously explored as a tool to understand perception. I will focus on the visual domain covering several types of networks, such as Convolutional Neural Networks (CNN), Vision Transformers (ViT) and Variational Autoencoders (VAE). I will present the results of two projects where we compared the sensitivity of the human visual system to deep networks with the same paradigms. In one project, we measured the contrast sensitivity function (CSF) in deep networks. CSF is a fundamental signature of the visual system by defining the visibility threshold across all spatial frequencies. The results show that human-like CSF emerges in deep networks trained to perform high-level visual tasks. Our analysis indicates the inverted U-shape of CSF is directly utilised in the network’s performance. In the other project, we measured the chromatic discrimination threshold in deep networks and compared it to our colour vision. Similar to our visual system, deep networks trained on natural images become more sensitive to hue than saturation. Furthermore, the reported asymmetry in human colour discrimination also emerges in these networks. Altogether, these results suggest insights into low-level visual processing can be acquired by studying deep neural networks. Abstract: Main perceptual-cognitive limitations of CDOs (Colour Deficient Observers) are analysed, along with the uses and limitations of the tools that transform images so that CDOs can use them as CNOs (Colour Normal Observers): the so called daltonization tools. Our analysis is focused on daltonic people, including the most common CDO types (protanopia, deuteranopia, protanomaly and deuteranomaly). We begin pointing to the main cause of colour vision individual differences and of the CDOs problems to perform tasks based on colour: the existence of pseudoisochromatic stimuli and the corresponding colour space volume reduction. It is showed how this fact affects every one of the four colour uses included in the Chaparro and Chaparro tasks taxonomy. It is emphasised that three of these uses (denotative, connotative and aesthetic) are related to colour categories and not to specific colours. The last CIE (Commission Internationale de L’Eclairage) technical report on the “enhancement of images for colour-deficient observers” is used with two different goals. First, to divide daltonization methods into three different types (recoloring, edge enhancement and pattern superposition) considering how they transform original images to facilitate CDO use. Second, to show different ways to test daltonization accuracy. It is concluded that the choice of a daltonization tool requires considering, for every specific situation, both the kind of image, the color use required, and the individual characteristics of the CDOs. Simple images, such as “document images”, and simple uses, like denotative use, make daltonised images provided by simple daltonization tools adequate for very Abstract: The study of the underlying mechanisms in stereovision is mainly limited to static stereopsis (Howard & Rogers, 2012). Masking experiments and factor analytic techniques, using sinusoidal depth corrugations, have suggested the existence of more than two spatial-frequency disparity mechanisms (Serrano-Pedraza et al., 2013,JoV; Peterzell, et al., 2017,VR). Here, using individual differences, we want to investigate the possible existence of independent temporal-frequency disparity mechanisms in frontoparallel cyclopean motion. Cyclopean motion was constructed using sinusoidal disparity corrugations obtained with random gaussian-dots stereograms that changed every frame at 120Hz (no luminance motion was present monocularly, only the sinusoidal corrugation was moved). In total we tested 34 participants. We measured disparity thresholds for detecting the correct direction of motion of horizontal (left-right) and vertical (up-down) sinusoidal corrugations of 0.4 c/deg drifting at 0.25,0.5,1,2,4,6, and 8Hz. Results show a mild orientation anisotropy with higher thresholds for vertical corrugations. Disparity thresholds as a function of temporal frequency are almost constant from 0.25 up to 1c/deg and then they increase monotonically. Principal component analysis uncovered two factors that accounted for 72% of the variability. Varimax rotation showed that one component loaded from 0.25 to 2Hz and a second component from 4 to 8Hz. Direct Oblimin rotation indicates a moderate intercorrelation of both components. Our results suggest the 

Reconstructing complex and dynamic visual perception from brain activity remains a major challenge in machine learning applications to neuroscience. Here, we present a new method for reconstructing naturalistic images and videos from very large single-participant functional magnetic resonance imaging data that leverages the recent success of image-to-image transformation networks. This is achieved by exploiting spatial information obtained from retinotopic mappings across the visual system. More specifically, we first determine what position each voxel in a particular region of interest would represent in the visual field based on its corresponding receptive field location. Then, the 2D image representation of the brain activity on the visual field is passed to a fully convolutional image-to-image network trained to recover the original stimuli using VGG feature loss with an adversarial regularizer. In our experiments, we show that our method offers a significant improvement over existing video reconstruction techniques.

Brain2Pix: Fully convolutional naturalistic video frame reconstruction from brain activity

Learning Cortical Magnification with Brain-Optimized Convolutional Neural Networks

Line drawings convey meaning with just a few strokes. Despite strong simplifications, humans can recognize objects depicted in such abstracted images without effort. To what degree do deep convolutional neural networks (CNNs) mirror this human ability to generalize to abstracted object images? While CNNs trained on natural images have been shown to exhibit poor classification performance on drawings, other work has demonstrated highly similar latent representations in the networks for abstracted and natural images. Here, we address these seemingly conflicting findings by analyzing the activation patterns of a CNN trained on natural images across a set of photographs, drawings, and sketches of the same objects and comparing them to human behavior. We find a highly similar representational structure across levels of visual abstraction in early and intermediate layers of the network. This similarity, however, does not translate to later stages in the network, resulting in low classification performance for drawings and sketches. We identified that texture bias in CNNs contributes to the dissimilar representational structure in late layers and the poor performance on drawings. Finally, by fine-tuning late network layers with object drawings, we show that performance can be largely restored, demonstrating the general utility of features learned on natural images in early and intermediate layers for the recognition of drawings. In conclusion, generalization to abstracted images, such as drawings, seems to be an emergent property of CNNs trained on natural images, which is, however, suppressed by domain-related biases that arise during later processing stages in the network.

From photos to sketches - how humans and deep neural networks process objects across different levels of visual abstraction

Synthesizing preferred stimuli for individual voxels in the human visual system

Reconstructing complex and dynamic visual perception from brain activity remains a major challenge in machine learning applications to neuroscience. Here we present a new method for reconstructing naturalistic images and videos from very large single-participant functional magnetic resonance imaging data that leverages the recent success of image-to-image transformation networks. This is achieved by exploiting spatial information obtained from retinotopic mappings across the visual system. More specifically, we first determine what position each voxel in a particular region of interest would represent in the visual field based on its corresponding receptive field location. Then, the 2D image representation of the brain activity on the visual field is passed to a fully convolutional image-to-image network trained to recover the original stimuli using VGG feature loss with an adversarial regularizer. In our experiments, we show that our method offers a significant improvement over existing video reconstruction techniques.

Brain2Pix: Fully convolutional naturalistic video reconstruction from brain activity

Visual and auditory representations in the human brain have been studied with encoding, decoding and reconstruction models. Representations from convolutional neural networks have been used as explanatory models for these stimulus-induced hierarchical brain activations. However, none of the fMRI datasets currently available has adequate amounts of data for sufficiently sampling their representations. We recorded a densely sampled large fMRI dataset (TR=700 ms) in a single individual exposed to spatiotemporal visual and auditory naturalistic stimuli (30 episodes of BBC’s Doctor Who). The data consists of 120.830 whole-brain volumes (approx. 23 h) of single-presentation data (full episodes, training set) and 1.178 volumes (11 min) of repeated narrative short episodes (test set, 22 repetitions), recorded with fixation over a period of six months. This rich dataset can be used widely to study the way the brain represents audiovisual input across its sensory hierarchies.

A large single-participant fMRI dataset for probing brain responses to naturalistic stimuli in space and time

Cortical information flow (CIF) is a new framework for system identification in neuroscience. CIF models represent neural systems as coupled brain regions that each embody neural computations. These brain regions are coupled to observed data specific to that region. Neural computations are estimated via stochastic gradient descent. We show using a large-scale fMRI dataset that, in this manner, we can estimate models that learn meaningful neural computations. Our framework is general in the sense that it can be used in conjunction with any (combination of) neural recording techniques. It is also scalable, providing neuroscientists with a principled approach to make sense of the high-dimensional neural datasets.

Neural information flow (NIF) is a new framework for system identification in neuroscience. It integrates population receptive field estimation, neural encoding, connectivity analysis and hemodynamic response estimation in a single differentiable model that can be trained end-to-end via stochastic gradient descent. NIF models represent neural information processing systems as a network of coupled tensors, each encoding the representation of the sensory input contained in a brain region. The elements of these tensors can be interpreted as cortical columns whose activity encodes the presence of a specific feature in a spatiotemporal location. Each tensor is coupled to the measured data specific to a brain region via low-rank observation models that can be decomposed into the spatial, temporal and feature receptive fields of a localized neuronal population. Both these observation models and the convolutional weights defining the information processing within regions and effective connectivity between regions are learned end-to-end by predicting the neural signal during sensory stimulation. We trained a NIF model on the activity of early visual areas using a large-scale fMRI dataset. We show that we can recover plausible visual representations and population receptive fields that are consistent with empirical findings.

End-to-end neural system identification with neural information flow

Neural information flow (NIF) is a new framework for system identification in neuroscience. NIF models represent neural information processing systems as coupled brain regions that each embody neural computations. These brain regions are coupled to observed data specific to that region via linear observation models. NIF models are trained via backpropagation, directly leveraging the neural signal as the loss. Trained NIF models are accessible for in silico analyses. Using a large-scale fMRI video stimulation dataset and a feed-forward convolutional neural network-based NIF model as an example we show that, in this manner, we can estimate models that learn meaningful neural computations and representations. Our framework is general in the sense that it can be used in conjunction with any neural recording techniques. It is also scalable, providing neuroscientists with a principled approach to make sense of high-dimensional neural datasets.

Neural Information Flow: Learning neural information processing systems from brain activity

An important issue in neural network research is how to choose the number of nodes and layers such as to solve a classification problem. We provide new intuitions based on earlier results by An et al. (2015) by deriving an upper bound on the number of nodes in networks with two hidden layers such that linear separability can be achieved. Concretely, we show that if the data can be described in terms of N finite sets and the used activation function f is non-constant, increasing and has a left asymptote, we can derive how many nodes are needed to linearly separate these sets. This will be an upper bound that depends on the structure of the data. This structure can be analyzed using an algorithm. For the leaky rectified linear activation function, we prove separately that under some conditions on the slope, the same number of layers and nodes as for the aforementioned activation functions is sufficient. We empirically validate our claims.

Generalization of an Upper Bound on the Number of Nodes Needed to Achieve Linear Separability

Understanding the role of immune cells is at the core of cancer research. In this paper, we boost the potential of the You Only Look Once (YOLO) architecture applied to automatic detection of lymphocytes in gigapixel histopathology wholeslide images (WSI) stained with immunohistochemistry by (1) tailoring the YOLO architecture to lymphocyte detection in WSI; (2) guiding training data sampling by exploiting prior knowledge on hard negative samples; (3) pairing the proposed sampling strategy with the focal loss technique. The combination of the proposed improvements increases the F1-score of YOLO by 3% with a speed-up of 4.3X.

Generative adversarial networks for reconstructing natural images from brain activity

Convolutional neural network-based encoding and decoding of visual object recognition in space and time

Here, we present a novel approach to solve the problem of reconstructing perceived stimuli from brain responses by combining probabilistic inference with deep learning. Our approach first inverts the linear transformation from latent features to brain responses with maximum a posteriori estimation and then inverts the nonlinear transformation from perceived stimuli to latent features with adversarial training of convolutional neural networks. We test our approach with a functional magnetic resonance imaging experiment and show that it can generate state-of-the-art reconstructions of perceived faces from brain activations.

Deep convolutional neural networks (CNNs) have been put forward as neurobiologically plausible models of the visual hierarchy. Using functional magnetic resonance imaging, CNN representations of visual stimuli have previously been shown to correspond to processing stages in the ventral and dorsal streams of the visual system. Whether this correspondence between models and brain signals also holds for activity acquired at high temporal resolution has been explored less exhaustively. Here, we addressed this question by combining CNN-based encoding models with magnetoencephalography (MEG). Human participants passively viewed 1000 images of objects while MEG signals were acquired. We modelled their high temporal resolution source-reconstructed cortical activity with CNNs, and observed a feedforward sweep across the visual hierarchy between 75-200 ms after stimulus onset. This spatiotemporal cascade was captured by the network layer representations, where the increasingly abstract stimulus representation in the hierarchical network model was reflected in different parts of the visual cortex, following the visual ventral stream. We further validated the accuracy of our encoding model by decoding stimulus identity in a left-out validation set of viewed objects, achieving state-of-the-art decoding accuracy.

CNN-based Encoding and Decoding of Visual Object Recognition in Space and Time

Reconstructing perceived faces from brain activations with deep adversarial neural decoding

Artificial neural networks (ANNs) have seen renewed interest in the fields of computer science, artificial intelligence and neuroscience. Recent advances in improving the performance of ANNs open up an exciting new avenue for cognitive neuroscience research. Here, we propose that ANNs that learn to solve complex tasks based on reinforcement learning, can serve as a universal computational framework for analyzing the neural and behavioural correlates of cognitive processing. We demonstrate this idea on a challenging probabilistic categorization task, where neural network dynamics are linked to human behavioural and neural data as identical tasks are solved.

In the present research the flow over large roughness elements, representative of a rocket nozzle inner contour, is investigated. From the rocket nozzle inner surface roughness, three simplified roughness shapes were defined and tested: a forward facing step, a cavity, and a forward facing step plus cavity. The geometries vary in height from 6 to 46 percent of the boundary layer thickness. The flow over these roughness elements is studied at a free stream Mach number of 2. This was done numerically by means of RANS simulations and experimentally by means of Schlieren and PIV. For these geometries it was found that three flow classes can be distinguished. For large roughness heights, with a large length to depth ratio, the flow disruptions center around the steps, while the sections between the elements show flat-plate flow. Drag and heat transfer show large increases for these elements. At smaller roughness heights a smoother behavior of the flow can be seen which more resembles boundary layer behavior. For cases where the length to depth ratio of the elements becomes small, a third flow class can be defined. Here the flow is separated between the roughness elements, and the gap from element top to element top is bridged by a shear layer. It was observed that a boundary layer was formed on top of the elements. Based on these observations, a classification system is proposed which divides the roughness in different categories, for each of which it is recommended to use a separate modelling approach. Introduction To evaluate the thermal loading of a rocket nozzle, a good predictive capability of the heat transfer on the gas side is mandatory. For a smooth wall multiple design formulations are available to calculate the heat transfer, see White [5]. If the surface is rough the heating is likely to be different from the smooth case. The interest of the current research lies in the regime of large roughness heights (relative to the boundary layer thickness) since this is not well covered in literature. Jimenez [1] is one of the few sources that describes flows over larger roughnesses. In practice these rough wall geometries can have various forms and shapes. They can range from the distributed wall texture roughness, to discrete roughness elements. Material roughness has been extensively researched. It was shown by Nikuradse [3] that the turbulent boundary layer flow on a rough surface can be described by adapting the standard law of the wall. In this study, however, we consider discrete wall patterns that are designed to represent the surface irregularities on the inside of the baseline rocket nozzle due to the employed manufacturing technique. We will investigate the effects of such surface irregularities on the flow, focusing in particular on the size of these roughness profiles. The final goal is to find a model that can explain the observed effects. Different physical behavior has been observed in different configurations, and therefore a system will be proposed which classifies the roughness into categories with the same behavior. The investigation was carried out using a combined computational and experimental approach. First a CFD study has been performed on these geometries. These simulations where made for a turbulent flow over an adiabatic, heated and cooled wall. The non-adiabatic wall simulations, were run with a wall temperature of 0.5 and 1.5 times the adiabatic wall temperature, i.e. , 137.5 K and 412.5 K, respectively. In the experiments the flow was visualized using Schlieren. Particle Image Velocimetry (PIV) was subsequently used to measure the velocity in the flow field. Rough geometries To investigate the effect of element geometry on the wall shear and heat transfer, multiple geometries have been defined. These are variations on the baseline nozzle geometry. For optical access to the geometries in the experiments they have been implemented as spanwise two-dimensional shapes in a nominal flat-plate configuration. Fig. 1 A shows several elements of the baseline nozzle shape extrapolated to a flat plate with the free-stream from left to right.

Flow Categorization in Supersonic Flows with Large Roughness Heights

It may be concluded that, by use of the newly developed Swing-Turn-gear system, mobility of the disabled person using wheelchairs outdoors can be improved. The qualities of the drive gear in push and pull action, the free wheel, the full selection of frequency, and the range of moving the hand levers represent important progress in wheelchair engineering research. The handrim drive is an alternative, especially for indoor use. But, for the first time, an indoor wheelchair can be offered as a combination vehicle for both indoor and outdoor use. The acceptance of the new wheelchair integrated Swing-Turn-gear is much better than the conspicuous hand-lever drive in standard outdoor wheelchairs. At present, the German wheelchair manufacturer, MEYRA Vlotho, is preparing the new hand-lever drive system for production. Initially, the drive system will be adapted to a standard indoor wheelchair made by this company. Development of a lever drive system is also in progress in the United States, which employs force transmission characteristics in one direction.

Technological and physiological characteristics of a newly developed hand-lever drive system for wheelchairs.

We describe the feasibility of transjugular endovascular visualization and cannulation of the canine cervical thoracic duct using a flexible cholangioscope modified for lymphoscopy. The lymphoscope is composed of a prismatic side-view optic with a catheter guide channel attached by a metal cap to the terminal end. The technique has clinical applicability to the study of neoplastic diseases, examination and depletion of lymphocyte subpopulations in immunologic disorders, and perhaps the overcoming of increased resistance to lymph flow at the cervical lympho-venous junction in edematous conditions characterized by excessive lymph formation.

Thoracic duct cannulation via a transjugular vascular endoscope (lymphoscope) in the dog.

Multi-phase transformer for leistungsuebertragung in a supply network

A new technique  was developed  in  dogs  for  direct  visualization  of  the  thoracic  duct  -  innominate venous junction. A modified Dyonics needlescope introduced through the left extemal jugular vein permitted vascular endoscopy (lymphoscopy) with internal cannulation and retrograde  lymphangiography of the thoracic duct.

Endoscopy of the thoracic duct (lymphoscopy) via the external jugular vein in dogs.

Direct intravascular fibroscopic lymphoscopy and thoracic duct cannulation. A preliminary report

[Thoracic duct of the mini pig. Topography and method of canulation].

[Model for the study of lymphatic circulation and liver metabolism in the dwarf pig].

This review summarises the changing epidemiology of resistance to cephalosporins and fluoroquinolones among the Enterobacteriaceae since the 1980s and its potential impact on prescribing choices now and in the immediate future. Whilst multiresistant Enterobacteriaceae are not a novel problem for high-risk hospital units, such as intensive care, the emergence of Escherichia coli co-expressing extended-spectrum beta-lactamases, such as CTX-M types, along with fluoroquinolone resistance in the community is starting to impact in situations where cephalosporins and ciprofloxacin were seen as reliable first-line choices. The reduction in effective options to treat these infections, particularly of the urinary tract and bacteraemia, is likely to result in increased prescribing of carbapenems, thus generating further selective pressure for carbapenemases and other mechanisms of carbapenem resistance in the future.

Zentralblatt fur Bakteriologie, Parasitenkunde, Infektionskrankheiten und Hygiene. 1. Abt. Medizinisch-hygienische Bakteriologie, Virusforschung und Parasitologie. Originale

E. G. V. Evans and M. D. Richardson (eds): Medical Mycology: A Practical Approach.

Zusammenfassung 
 
Die Immunologie der menschlichen Kryptokokkose zeigt noch manche Unklarheiten. Recht haufig sind spezifische agglutinierende, prazipitierende oder komplementbindende Antikorper — selbst in fortgeschrittenen Fallen — nicht oder nur in geringfiigigen Titern nachweisbar. Analog fehlen Kapselreaktionen zwischen Patientenserum und korpusku-laren Kapselantigenen praktisch immer. 
 
Unter anderem wird die Immunologie der Kryptokokkose von folgenden Umstanden beeinflust: 
 
1 
der relativ geringen Immunogenitat der bekapselten Zellen von Cryptococcus neo-formans an Versuchstieren und beim infizierten Menschen; 
 
2 
der Unterdruckung der Phagozytose durch die Kapselsubstanz von C. neoformans und dadurch verminderte bzw. fehlende Stimulierung des Antikorper-bildenden Systems; 
 
3 
dem langsamen und unauffalligen Beginn der Krankheit mit geringen oder gar keinen Entzundungserscheinungen (ausgenommen Infektionen durch schwach bekapselte Zellen, die zur Entwicklung granulomatoser Veranderungen fuhren); 
 
4 
den bevorzugten Befall von Gehirn und Hirnhauten, d. h. Gewebe mit nur schwacher Antikorperbildungsaktivitat; 
 
5 
dem Erscheinen und Verweilen von Antikorper-bindendem Kapselmaterial in den Ge-weben und Korperflussigkeiten des Befallenen in Mengen, die oft die geringe Zahl von spezifischen Serumantikorpern abfangen und damit, vor allem in fortgeschrittenen Fallen, maskieren; 
 
6 
den moglichen Status einer, „immunologischen Paralyse”, verursacht durch eine uber-grose Dosis von Kapselmaterial; und 
 
7 
der moglichen Schwachung des Immunitatssystems beim Infizierten infolge einer pri-maren Grundkrankheit, z. B. Leukamie, Morbus Hodgkin, Krebs usw.

[Fungi: etiologic factor in inflammatory symptoms of the gastrointestinal tract?].

Problems of differential diagnosis of blastomyces and russell bodies

A man died in endocarditis due to listeriosis in the late autumn. He had been looking after two goats during the summer. Listeria monocytogenas was isolated from a rectal swab from one of the goats. The goat faeces isolate and the human blood isolate were of identical serovar. The two isolates, however, were shown to be different by multilocus electrophoretic enzyme analysis and ribotyping, as well as by biotyping. Thus, these results do not support the hypothesis that the man was infected by the goat.

Zentralblatt fur Veterinarmedizin. Reihe B. Journal of veterinary medicine. Series B

A fatal case of Listeria endocarditis in a man following his tending of goats suggests an epidemiological link which is not supported by the results.

International Committee on Systematic Bacteriology Subcommittee on the Taxonomy of Listeria, Brochothrix, and Erysipelothrix: Minutes of the Meetings, 4 and 7 July 1994, Prague, Czech Republic

Isolation of Listeria monocytogenes from Goat Cheese Associated with a Case of Listeriosis in Goat

Summary. A 45‐year‐old woman was found to have cerebral phaeohyphomycosis caused by an Exophiala species. The portal of entry of the fungus remained unknown. Despite surgery and antimy‐cotic therapy the patient died from circulation failure. The fungus is compared to several related Exophiala species.

International Committee on Systematic Bacteriology Subcommittee on Taxonomy of Listeria, Brochothrix, and Erysipelothrix: Minutes of the Meetings, 21, 23, and 25 August 1988, Pécs, Hungary

Mechanism of Pathogenesis — Why are Certain Mycoses Rare in AIDS Patients?

[Mycoses in AIDS patients. 3. Symposium on the subject of mycology; Paris, 20-23 November 1989].

This meeting with almost 200 participants was held under the special heading 'New mycotic pathologies: Alternariosis, Scedosporiosis'. Over 20 oral communications and 24listed posters gave an impressive overview on new developments in medical mycology, but also of the exemplary activities of French medical mycology. The large numbers of communications ( over70 type-written pages) allow to deal only with a few of them in this report. According to de Bievre, Pasteur Institute Paris, among the presently 80 species of Alternaria only eight have so far been observed from human lesions, primarily A. tenuissima, A. alternata and A. chartarum. The conditions of culture and the source of the strains contribute to a polymorphism hard to control. Badillet, Hopital St. Louis in Paris, lists so far45 cases of sufficiently studied cutaneous cases, 17 of which were reported from France. Most, but not all patients had predisposing conditions such as renal transplantation, leukemias, and long-term corticosteroid treatment. Gueho, Pasteur Institute Paris, and de Hoog, Baarn, dealt with the two anamorphs Scedosporium apiospermum and S. inflatum and drew attention to asexual forms with coraemia ('Graphium'like form). According to Dupont and co-workers (Pasteur Institute Paris) most infections are found among immunodepressed and agranulocytic patients and primarily due to S. apiospermum after cutaneous inoculation or by inhalation of water. The histology resembles very much the lesion caused by aspergilli. Bone-joint lesions seem to be primarily due to S. injlatum. Serological tests may help in the diagnosis. Surgical intervention is usually indicated, but azole derivatives may be helpful in treatment. This is also indicated by the beneficial results in two cases of scedosporiosis (ocular and bone involvement, respectively) reported by Piens, Gimenez and Mojon from Lyon. Their 33-year-old patient after bone marrow transplantation succumbed, however, with multiple organ involvement after unsuccessful application of amphotericin B. Similarly, two patients with neutropenia after antileukemic treatment did not respond to therapy when their eyes were infected by S. inflatum, as reported by Mavin, Martinez-Costa and others (Hospital 'Armau' de Villanova, Valencia). To these three observations may be added when S. apiospermum complicated mucoviscidosis (cf. Chabasse et al., CHRU, Angers). It is rather fortunate that according to Van Cutsem eta/. from the Janssen team, both Alternaria and Scedosporium strains are very sensitive to itraconazole in acceptable concentrations although a few strains need concentrations of 0.1 to I p.g rni-1 for complete inhibition in vitro. This abbreviated report on the main topic of a very successful meeting is admittedly incomplete without at least mentioning the address of Utz from Georgetown University, USA, who drew attention to the increasing frequency of histoplasmosis and coccidioido-mycosis in AIDS patients. Many of the other reports and posters will appear in due time in the newly created 'Journal de Mycologie Medicale' which as of January 1991 will replace the present Bulletin.

Meeting of the Société Française de Mycologie Médicale November 16–17, 1990, Paris, France

Zentralblatt fur Bakteriologie, Mikrobiologie, und Hygiene. Series A, Medical microbiology, infectious diseases, virology, parasitology

Pathogenicity testing of Listeria strains isolated from food in fertilized hen's eggs.

Serological analysis of the genus Listeria. Its values and limitations.

Listeriosis usually manifests at the extremes of age, during pregnancy or among immunocompromised individuals as an acute meningoencephalitis with or without associated septicemia. Localized infections are rare. We investigated the incidence of Listeria monocytogenes cholecystitis using the data of the Listeria reference laboratory of the University of Würzburg/FRG. Out of 467 culture proven L.m-infections in the years 1986 and 1987, two cases were localized infections of the gall bladder. Although studies of the microbiology of gallbladder infections have not demonstrated the recovery of Listeria monocytogenes as a pathogen in acute or chronic cases of cholecystitis, these two cases substantiate the existence of this rare form of listeriosis as an entity and support the theory of the importance of the gastrointestinal tract in the pathogenesis of Listeria infections.

A 40-year-old man with grade II sarcoidosis went on a two-week visit to Ecuador. Afterwards he was treated with low-dose corticosteroids because of slight deterioration on the X-ray film. Unilateral hilar enlargement followed by bouts of high fever and a greatly increased erythrocyte sedimentation rate, suggested an acute exacerbation of the sarcoidosis and was, therefore, treated with an increase in steroid dosage plus azathioprine. Bronchoalveolar lavage fluid and tissue samples from lung, bone-marrow and spleen were suggestive of an infection with Histoplasma capsulatum. There was now bilateral hilar enlargement with right upper lobe infiltration, marked hepatosplenomegaly and thrombocytopenia (17,000/microliters), but serological tests remained negative. The fulminant course with dissemination could not be arrested despite administration of fluconazole (400 mg/d) and amphotericin B (total dosage 1.14 g). Histoplasma capsulatum was cultured from lung and spleen tissue post-mortem.

[Disseminated histoplasmosis after a tropical visit in a patient with known sarcoidosis].

[Manifestation of a systemic mycosis (Paracoccidioides brasiliensis) in the oral cavity].

Zusammenfassung: Virchow (1856) beschrieb die Aspergillose des Menschen als Inhalationsmykose der Lunge auf dem Boden vorbestehender Lungenkavernen.

Aktuelle Gesichtspunkte zur Epidemiologie der Aspergillose*. Actual Aspects on the Epidemiology of Aspergillosis

[100 years ago: the discovery of Escherichia coli (Bacterium coli commune)].

Is haemolysis an in vitro marker of the pathogenic strains of the genus listeria

296 strains of Listeria monocytogenes have been submitted for confirmation and further studies to the Listeria Reference Laboratory at the Institute of Hygiene in Würzburg, Federal Republic of Germany. They have been isolated between 1969 and 1985 from human cases in the Federal Republic and West Berlin. The results of an analysis of the respective cases are presented here on the basis of questionnaires. A steady increase of Listeria isolations has been noted during the past few years. The largest number of strains originated from the district Nordrhein-Westfalen which has the largest population of all German federal districts. The highest incidence calculated from the number of strains and total population was found for the district of Saarland. There was no predominance detectable of listeriosis among the rural population. 60% of the strains came from patients living in urban areas. In 6 out of 21 cases of neonatal listeriosis at least one of the parents was engaged in professional medical services. The most frequently observed clinical entities were meningitis (41.14%) and septicaemia (36.00%). Among the newborns septicaemia was predominant with 40.90%. Listeriosis during pregnancy and among newborns was connected with 53.57% of all strains isolated. The questionnaire revealed for the underlying conditions in 35% and in 24% of cases malignancies and organ transplantations, respectively. There was no increased rate of predominance found among the elderly. However, 50% of all strains isolated originated from newborns. The sex distribution was almost equal; 52.56% from males of the total number of isolates and 51.22% from males among the newborns. 67% of these which had a meningitis after the first weeks of life were male. There was no seasonal incidence detectable. Serovar 4b was found in 66.22% of all isolates tested. 295 strains produced acid from rhamnose and alpha-methyl-d-mannose, but not from d-xylose and were thus typical for L. monocytogenes. One strain needs further studies.

International Journal of Systematic and Evolutionary Microbiology

International Committee on Systematic Bacteriology Subcommittee on the Taxonomy of Listeria, Brochothrix, and Erysipelothrix: Minutes of the Meetings, 7 and 8 September 1986, Manchester, England

Listeriolysin was isolated from target rabbit erythrocyte membranes after lysis of the cells with partially purified toxin derived from a culture supernatant of Listeria ivanovii. The membrane form of the toxin exhibited properties similar to those previously found for streptolysin O. Detergent-solubilized, delipidated listeriolysin was found to comprise a heterogeneous population of partially and fully circularized, amphiphilic oligomers whose embedment within the lipid bilayer generated large transmembrane pores. The molecular weight of the toxin monomer was estimated to be 55,000 to 60,000 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Immunological cross-reactions between the toxin and streptolysin O were demonstrable by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting. An immunoblot assay for detecting listeriolysin in agar-incorporated, lysed erythrocyte membranes was developed, and 28 defined, clinical isolates of Listeria monocytogenes were examined for toxin production. These isolates caused beta-hemolysis on the agar plates and had previously been regarded as listeriolysin producers. However, we found that only two isolates produced genuine listeriolysin, since the sensitive immunoblot assay entirely failed to detect the toxin in all other cases. We excluded that this finding derived from proteolytic degradation of membrane-bound toxin. Thus, the great majority of human pathogenic Listeria strains appear to produce one or several hemolysins that are immunologically and, by inference, molecularly distinct from the streptolysin O-related listeriolysin. We propose that the streptolysin O-related toxin be designated alpha-listeriolysin and that the other hemolysin(s) be termed beta-listeriolysin.

Production of listeriolysin by beta-hemolytic strains of Listeria monocytogenes

Public health action in emergencies caused by epidemics: a practical guide , Public health action in emergencies caused by epidemics: a practical guide , مرکز فناوری اطلاعات و اطلاع رسانی کشاورزی

DNA Relatedness Among Listeria monocytogenes and Listeria innocua Bacteriophages

The relative importance of other infections. Bacterial infections.

The wide-spread ubiquitous occurrence of molds and great masses of aerial spores (conidia, arthrospores etc.) as well as of yeast species with facultative pathogenicity, renders prophylaxis of respective human infections caused by such opportunists, rather difficult. Suppression of such fungi and continuous surveillance of endangered patients require considerable efforts and costs. Adequate control is particularly cumbersome in Candida infections, since the causative yeasts may be considered as "normal" commensals of the mucous membranes in many individuals. Overt secondary infections are frequently of endogenous origin, hence the name "endomycoses" as introduced by Gemeinhardt (1976). Under particular conditions such as care for patients with extended burns, or patients after bone-marrow transplantation or irradiation of the whole body, or patients after joint surgery, the complete elimination of yeasts is just as essential as the antibacterial decontamination over a limited period of time. In other groups of individuals similar drastic measures of control against Candida albicans are not deemed necessary. Reduction of local Candida cell counts to amounts below the individual level of tolerance may be deemed sufficient. Since the level of tolerance is, however, extremely low in infants and in many patients of the intensive care wards, especially in cases of malignant immunocytomas and leukemias of various nature, prophylaxis by proper hygienic measures and eventual preventive antimycotic treatment is an integral part of proper control.

Zentralblatt fur Bakteriologie, Mikrobiologie und Hygiene. 1. Abt. Originale B, Hygiene

The discovery of Achorion schoenleinii. Facts and stories (Johann Lucas Schoenlein and Robert Remak).

214 Listeria strains were isolated from purified municipal waste water. The differentiation was performed taking into account the newly described species within the genus Listeria, 92.5 per cent of isolated Listeria strains belonged to L. monocytogenes, 4.2 per cent to L. innocua, and 3.3 per cent to L. seeligeri.

The occurrence of different Listeria species in municipal waste water.

Listeria ivanovii sp. nov. HEINZ P. R. SEELIGER, JOCELYNE ROCOURT, ANGELIKA SCHRETTENBRUNNER, PATRICK A. D. GRIMONT, AND DOROTHY JONES Institut fur Hygiene und Mikrobiologie, 0-8700 Wurzburg, German Federal Republic; UnitP d’Ecologie Bacterienne, and UnitP des EntProbactPries, UnitP TNSERM 199, Institut Pasteur, F-75724 Paris Cedex 15, France; and Department of Microbiology, School of Medicine and School of Biological Sciences, University of Leicester, Leicester LEI 7RH, England

Within the classification of different Listeria species according to present knowledge, this study investigates the sources and distribution of both the known "classical" species of Listeria as well as the recently added species: L. monocytogenes, L. innocua, L. ivanovii, L. welshimeri, L. seeligeri, L. grayi and L. murrayi. For this purpose 573 isolates from the environment, food, healthy carriers and patients suffering from listeriosis were selected out of a total of approximately 6000 strains originating from all parts of the globe which are maintained at the Listeria Culture Collection of the Institute of Hygiene, Würzburg. The selection was made according to the criterium of widest possible geographic distribution. The results indicate the environment to be the natural reservoir of all of the 7 'new' Listeria species. Healthy animal carriers harbour in their intestinal tract all species of Listeria with the exception of L. murrayi, whilst in the excreta of healthy individuals only the species L. monocytogenes, L. ivanovii, and L. innocua were found. Identification of strains from pathological specimens of human and animal origin resulted invariably in the finding of L. monocytogenes or L. ivanovii. L. grayi (7 strains) was found sporadically in Europe and in the USA, whereas L. murrayi (9 strains) has been isolated only in the USA. 26 of 28 so far known strains of L. welshimeri originated from the USA, and only 2 strains of this species were found in Europe. L. seeligeri (80 strains) was identified among European isolates, L. innocua, however, in both USA and Europe. L. ivanovii occurs in Australia, Europe and the USA. L. monocytogenes is of global distribution. Table 1 presents a survey of species, serovariety and origin of the 573 isolates. As both pathogenic and non pathogenic listeria strains are found in the human environment, it is necessary to identify each isolate appropriately, particularly in view of the elucidation of the rather obscure epidemiology of human listeriosis.

Host defense mechanisms to perinatal and neonatal Listeria monocytogenes infection.

Hospital acquired infections due to fungi are primarily caused by yeast species of the genus Candida and mould species of the genus Aspergillus. Underlying disease with severely impaired defence mechanisms as well as certain forms of immunosuppressive and aggressive chemotherapy are the most important prerequisites for such secondary fungal infections. Aspergillus spec. usually infect man via exogenous routes, whereas Candida spec. mostly originate from the patient's own microbial flora. Under certain circumstances invasion of tissues follows (endomycoses). Exogenous Candida infections may likewise occur through contaminated hands of personnel and medical devices. The density of yeast cell distribution in hospital wards decreases with the distance from the primary source: the Candida infected human patient. Preventive measures protecting the patient at risk include: Permanent surveillance by routine cultural and serological examinations for the detection of an early infection of the skin, mouth, oesophagus, urinary tract, vagina and the bowel. Monitoring of patients is essential for early detection of dissemination and contributes to the control of fungal decontamination measures. Selective local decontamination is effected by the use of nonabsorbable compounds such as nystatin and amphotericin B in the gastrointestinal tract, and in oral and genital mucous membranes. Oral administration of ketoconazole has also been recommended. For the disinfection of skin appropriate chemicals are available. In the control of the environment of the endangered patient special attention must be paid to meticulous management of catheters.(ABSTRACT TRUNCATED AT 250 WORDS)

[Preventive measures for the control of fungal infections in the clinic].

The influence of culture medium composition on hemolytic effects produced by Listeria innocua on sheep blood agar has been investigated. Neither alpha- nor beta-hemolysis could be observed around L. innocua colonies grown on sheep erythrocyte agar lacking glucose. However, green zones of hemolytic phenomena were observed around colonies grown on such agar which contained 0,6% (w/v) glucose. By using L. innocua cell suspensions and culture filtrates this glucose-associated hemolysis only occurred in media which were weakly buffered (1 m M Na-PBS). This hemolytic phenomenon was attributed to the resulting acidification of the culture medium caused by the metabolic breakdown of glucose by Listeria. The results of this study demonstrate the necessity of including adequate buffer conditions when assaying the hemolytic property of a Listeria strain. It was found that the addition of 20 mM Na-PBS to the assay medium was sufficient to eliminate artificial "acidic-hemolysis". Moreover, the hemolysis observed with known hemolytic Listeria strains was unaffected by this buffering, as was in fact the case even when conditions of higher buffering capacity were employed. By testing in this manner, no evidence has been found which would suggest the existence of an hemolysin, either intra- or extracellular, produced by Listeria innocua. An accurate method for the determination of hemolysis caused by strains of the genus Listeria is proposed. This method of assaying hemolysis in a liquid grown medium has proven effective in determining the hemolytic properties of strains which appeared negative or questionable on blood agar as well as strains which in virulence tests were negative. The ability to accurately assess the hemolytic properties of Listeria strains, is essential in determining the association of Listeria hemolysin with pathogenicity of this genus. Together with current investigations on the genetics of hemolysin production by Listeria the determination of hemolytic activities will eventually allow to understand better the pathogenic principle of hemolytic strains of Listeria monocytogenes.

Hospital acquired infections due to fungi are primarily caused by yeast species of the genus Candida and mould species of the genus Aspergillus. Underlying disease with severely impaired defence mechanisms as well as certain forms of immunosuppressive and aggressive chemotherapy are the most important prerequisites for such secondary fungal infections. Aspergillus spec. usually infect man via exogenous routes, whereas Candida spec. mostly originate from the patient's own microbial flora. Under certain circumstances invasion of tissues follows (endomycosis). Exogenous Candida infections may likewise occur through contaminated hands of personnel and medical devices. The density of yeast cell distribution in hospital wards decreases with the distance from the primary source: the Candida infected human patient. Preventive measures protecting the patient at risk include: Permanent surveillance by routine cultural and serological examinations for the detection of an early infection of the skin, mouth, oesophagus, urinary tract, vagina and the bowel. Monitoring of patients is essential for early detection of dissemination and contributes to the control of fungal decontamination measures. Selective local decontamination is effected by the use of nonabsorbable compounds such as nystatin and amphotericin B in the gastrointestinal tract, and in oral and genital mucous membranes. Oral administration of ketoconazole has also been recommended. For the disinfection of skin appropriate chemicals are available. In the control of the environment of the endangered patient special attention must be paid to meticulous management of catheters. These measures are to be supported by careful disinfection policy concerning the hands of personnel and medical equipment.(ABSTRACT TRUNCATED AT 250 WORDS)

[Exophiala jeanselmei (Phialophora jeanselmei)--demonstration in the vitreous body of the eye].

Listeria monocytogenes is divided into serovars 1-7 (including subserovars) which belong to several genospecies as determined by gene homology studies. At least two of the five genomic species of L. monocytogenes are avirulent and cannot be separated by serological analysis from virulent strains. During the past two decades, several thousand Listeria strains have been analysed by the reference laboratory of the Institute of Hygiene in Würzburg, Germany. A study of the origin of the strains and their association with disease in animals and man in conjunction with biochemical and serological methods, allowed the separation of at least one group which is apathogenic and non-virulent to laboratory animals under ordinary test conditions. This apathogenic species, L. innocua should be separated from L. monocytogenes when Listeria-like strains are isolated from environmental sources.

Clinical and investigative medicine. Medecine clinique et experimentale

Modern taxonomy of the Listeria group relationship to its pathogenicity.

The biochemistry of murein and cell wall teichoic acids in the genus Listeria

Biochemical, genomic, and serological data indicate that strains currently referred to as Listeria monocytogenes serovar 5 are sufficiently distinct from other species of the genus Listeria to merit separate species status. It is proposed that these strains be designated Listeria ivanovii sp. nov. The type strain of L. ivanovii is strain SLCC 2379 (= ATCC 19119).

Zusammenfassung: Der Bericht bezieht sich auf serologische Untersuchungen an 4223 Patienten. Die Ergebnisse von Komplementbindungsreaktion (KBR), indirektem Hämagglutinationstest (HAT) und Immunelektrophorese (IE) mit metabolischem und somatischem Antigen werden beschrieben. Pathognomonische Titer nach einem negativen Ergebnis sind nach ein bis vier Wochen zu erwarten. Die positiven Befunde persistieren in der Regel nicht, sondern nähern sich relativ rasch dem Normalbereich. Nach ein bis acht Wochen ist wieder mit negativen Befunden zu rechnen. Ein erneuter Anstieg des Titers oder der Anzahl der Banden kann eine erneute Bedrohung durch Candida anzeigen. KBR und HAT erreichen im Durchschnitt wesentlich früher ihren Maximalwert als die Immunelektrophorese (p <0,001).

Serodiagnostik der Candida‐Infektionen/Serological Diagnosis of Candida Infections

Virulence of the five genomic groups of Listeria monocytogenes (sensu lato) was tested toward mice by determination of LD50 and growth or survival kinetics in vivo. Virulent strains included L. monocytogenes (sensu lato) (genomic group 1) and "L. bulgarica" (genomic group 2). The three other genomic groups, "L. innocua", "L. welshimeri" and "L. seeligeri", were apathogenic and avirulent under these experimental conditions.

[Comparative virulence of the 5 genomic groups of Listeria monocytogenes (sensu lato)].

CAMP-tests with Staphylococcus aureus and Rhodococcus equi and acid production from D-xylose allowed to separate the five DNA relatedness groups described for Listeria monocytogenes sensu lato; acid production from L-rhamnose and alpha-methyl-D-mannoside are secondary markers.

[Biochemical differentiation of the "Listeria monocytogenes" (sensu lato) genomic groups].

Fungal cultures, unstained smears and histological assessment of endoscopically obtained particles from ulcers in rectum, colon or terminal ileum were obtained in a prospective study of possible fungal infection in 78 patients with colitis of various aetiologies (Crohn's disease - 46; ulcerative colitis - 21; infectious colitis - 5; ischaemic colitis - 2; radiation colitis - 1; non-classifiable colitis - 3). Positive fungal culture was obtained in 13 patients (16.7%). The germ count was low (2--8 colonies per biopsy piece). The demonstrated fungi were almost exclusively Candida or Torulopsis. The potentially pathogenic mycelia phase of the fungi were never seen, either histologically or in unstained preparations. Stool specimens, obtained at the same time, were examined in 54 patients: positive cultures were obtained in 14 (25.9%). Only rarely were there concordance of positive fungal findings in both ulcer particles and faeces. It is concluded that (1) there is little danger of secondary fungal infection in colitis of various aetiologies; (2) positive faecal fungal culture is apparently of no pathogenic significance if the germ count is less than 10(6) per gram stool; (3) in the lower as well as the upper gastro-intestinal tract pathogenic fungal infection can be demonstrated only by endoscopy and biopsy.

We request that strain ATCC 15313 be replaced by strain NCTC 7973 as the type strain of Listeria monocytogenes.

Designation of a New Type Strain for Listeria monocytogenes Request for an Opinion

Zentralblatt fur Bakteriologie, Mikrobiologie und Hygiene. 1. Abt. Originale A, Medizinische Mikrobiologie, Infektionskrankheiten und Parasitologie = International journal of microbiology and hygiene. A, Medical microbiology, infectious...

Isolation of bacteriophages from Listeria monocytogenes Serovar 5 and Listeria innocua.

Reports of ocular histoplasma mycosis demonstrated serologically and in tissue are rare in Europe. This is principally due to the fact that histoplasmosis is not endemic in Europe (in contrast to the USA). A second reason is that it is hard to find laboratories which have experience in the differential diagnosis of histoplasmosis and forms of uveitis. In cases of uveitis it would be desirable to include histoplasmosis in the differential diagnosis and to use more staining methods (silver nitrate methenamine, fluorescein serology) and immunologic tests (intracutaneous test with histoplasmin, complement fixation test, countercurrent immuno-electrophoresis) for histoplasmosis. Report on a case of ocular histoplasmosis, positive in the skin test and in immunodiffusion, contracted 19 years previously in Mississippi, USA.

DNA relatedness among serovars ofListeria monocytogenes sensu lato

In the diagnosis of classical systemic mycoses, as caused by Blastomyces dermatidis, Coccidioides immitis, Histoplasma capsulatum and Paracoccidioides brasiliensis, serodiagnostic procedures in conjunction with skin tests are of significant diagnostic and prognostic value. The diagnosis of aspergillus mycosis is facilitated greatly by serological tests and the same is true for recognition of cryptococcus mycosis by means of serological detection of the cryptococcal antigen. Great progress has also been made in the evaluation of Candida antibodies in patients' sera.

Significance of immunological methods for diagnosis of fungal disease.

The special status of the strongly haemolytic strains of serovar (sv) 5 of Listeria monocytogenes is reviewed. Besides some biochemical reactions sv 5 strains are characterized by their excessive haemolysis on sheep blood agar and by a positive result of the CAMP test with R. equi. The haemolysis is caused by a soluble thermolabile protein which stimulates the formation of antibodies and which is inhibited by cholesterol. Sv 5-strains are less virulent than strains of sv 1/2a and sv 4b. The antibiotic sensitivity patterns characteristic for listeriae and for the principles of treating Listeria infections, are valid for sv 5-strains, too. The special position of sv 5 versus the other serovars of L. monocytogenes - with particular reference to its biochemical activity, its haemolytic properties, its lysosensitivity and its pathogenicity - calls for a reconsideration of its taxonomic position within the genus Listeria.

[Special position of strongly haemolytic strains of the genus Listeria].

In connexion with the separation of Listeria innocua (Seeliger and Schoofs, 1977) from Listeria monocytogenes (Murray et at., Pirie, 1940), resulting epidemiological and epizootological problems are discussed. L. innocua is apathogenic when conventional experimental models for testing Listeria monocytogenes are used. Under special conditions, i.e. use of suckling mice, strain Welshimer of L. innocua produced localized encephalitis (Patoĉka et al., 1979). The peculiarities of L. innocua justify further studies at the immunological, infectious-pathological and genetical level. A description of the new species is given in the appendix of this paper.

[Nonpathogenic listeriae: L. innocua sp. n. (Seeliger et Schoofs, 1977) (author's transl)].

Therapy of listeriosis with ampicillin was examined in two murine models with compromised defense mechanisms. In mice treated with dextran sulfate paralysing the function of the macrophage system, ampicillin was less able to reduce death rates as well as bacterial counts in the spleens than after infection of normal mice. In nude mice with chronic listeriosis, treatment with ampicillin was started 8 days after infection. The numbers of viable listeria cells decreased under therapy, but a bacteriologic cure was not achieved in a 6-day schedule. Relapse followed cessation of therapy.

Murine model for therapy of listeriosis in the compromised host. I. Effect of ampicillin.

The increase of both visceral mycoses and designations used for them requires, among other matters an accord on a better non-ambiguous terminology. The disease designation "blastomycosis" is quite obsolete and should be replaced by proper terms such as candida mycosis, cryptococcus mycosis, histoplasma mycosis etc. The frequently used term "systemic mycosis" should be restricted to exogenous mycotic infections of internal organs caused by obligatory pathogenic fungi such as Coccidioides immitis, Histoplasma capsulatum and others. The common term "endomycosis" is considered appropriate for fungal infections provoked by secondary disease provoking fungi of opportunistic pathogenicity especially by species of the form genus Candida. Other mycotic infections of visceral organs, mainly of the respiratory tract f.i. by species of Aspergillus and other molds, are likewise mostly of secondary nature and should not be considered as systemic mycosis in the restricted meaning of the word because of their lacking tendency to dissemination.

This report deals with three observations of Histoplasma mycosis (one acquired in Western Africa - large cell form; two in the USA - classical form) which were diagnosed from 10 to 35 years after primary infection. The laboratory diagnosis was based on immunological, histopathological and clinico-epidemiological data, since in none of the cases material was available for mycological culture. The histoplasmin skin test is considered to be the most sensitive procedure. A positive outcome may support other evidence or suspicion and may deliver an valid clue - particularly among individuals from non-endemic areas-to consider the possibility of Histoplasma infection. The demonstration of serum antibodies may assist in establishing a correct diagnosis in such cases.

Fungal contamination in hospital areas of risk and measures of control.

Lung resection showing giant cell (African) histoplasmosis was performed because of suspected lung tumour in a patient who had lived mainly in West Africa. A primary focus or signs of localisation in other organs were suspected radiographically in the maxilla and in the skeleton. However, they could not be confirmed as the patient declined further investigations for diagnosis and therapy.

Chapter II Serotyping of Listeria monocytogenes and Related Species

Zentralblatt fur Bakteriologie, Parasitenkunde, Infektionskrankheiten und Hygiene. Erste Abteilung Originale. Reihe A: Medizinische Mikrobiologie und Parasitologie

Neurotropic activity of a strain of Listeria innocua in suckling mice.

E. coli O142 K86 H34 has been isolated from stool specimens of five babies in a ward of premature infants. Diarrheal stools were observed in two of them; one infant temporarily failed to gain weight, and the other developed a temporary loss of weight. Smooth stools observed in the third baby as well as asymptomatic infections in two others did not affect their normal development. The outbreak lasted 15 days; the source of infection and the mode of transmission remained unknown. The pathogenesis and importance of human diarrheal disease caused by E. coli is reviewed. Enteritis of adults and children due to enteroinvasive (EIEC) and enterotoxigenic (ETEC) strains is described. The etiological role of so-called "enteropathogenic E. coli" (EPEC), rejected increasingly during the past decade, has been demonstrated again in recent studies. Routine search for EPEC is suggested in cases of infantile enteritis in hospitals and other institutions.

[Enteritis due to Escherichia coli O142 K86 H34 in a ward of premature infants. With a discussion on the problem of pathogenicity of "enteropathogenic serogroups of E. coli" (author's transl)].

[Tuberculosis as a cause of death in clinical autopsy (author's transl)].

Occurrence and frequency of facultatively pathogenic yeasts of the genus Candida in public swimming pools and connected premises.

[Atypical granulomatous tissue reactions in abnormal wound healing after dento-alveolar interventions].

Human cryptococcosis is an exogenous human infection of increasing frequency and growing importance. Early diagnosis is essential for the clinical outcome, no matter whether the infection is primary or secondary to underlying disease. Reliable and quick diagnostic methods are outlined and some pitfalls are discussed. Direct microscopy is essential, followed by cultivation procedures and serologic tests.

The role of macrophages on the course of an infection with Toxoplasma gondii has been examined. Stimulation of macrophage function by killed Bordetella pertussis cells did not show any beneficial effect as an increased susceptibility became apparent. The functional blockade of macrophages by dextran sulfate or carbon particles did not result in a higher susceptibility of mice to the lethal primary infection with T. gondii. Thus in vivo macrophages apparently do not play an essential role as effector cells as they do in infections with other obligate intracellular infective organisms such as Listeria monocytogenes. The spleen is apparently of crucial importance for resistance against T. gondii infection, since death occurred earlier in splenectomized mice than in control animals.

Macrophage function and host resistance against infection with Toxoplasma gondii.

Nude mice, congenitally lacking most thymus-derived lymphocytes, are neither more susceptible nor more resistant against primary infection with virulent T. gondii cells than normal control mice. Both mouse groups died at the same time after intraperitoneal infection. Treatment with sulfadiazine protected both mouse groups against acute fatal disease. After termination of treatment with sulfadiazine the Nude mice gradually died, whereas the normal hairy mice survived. The latter had developed high amounts of antibodies and protective immunity to an otherwise lethal challenge infection. In the serum of Nude mice no antibodies could be detected. Pathologic alterations existed in the livers of Nude mice at the time of death.

Infection of congenitally athymic (nude) mice with Toxoplasma gondii.

[Dermatomycoses caused by domestic animals with special reference to occupational infections].

Serovariants of Listeria monocytogenes and other Listeria species.

[Immunologic reaction induced by Candida albicans (1. continuation)].

During a research project on the occurrence of Listeria monocytogenes 194 strains were isolated in southern West Germany during the years 1972 to 1974:154 from soil and plant samples (20.3%), 16 from feces of deer and stag (15.7%), 9 from old moldy fodder and wildlife feeding grounds (27.2%), and 8 from birds (17.3%). The highest number of isolates was obtained from uncultivated fields. The beta-hemolytic serovars 1/2b and 4b were were predominant; other serovars (some of them identified for the first time), including nonhemolyzing strains, have been encountered frequently. It is suggested that Listeria monocytogenes is a saprophytic organism which lives in a plant-soil environment and therefore can be contracted by humans and animals via many possible routes from many sources.

During a research project on the occurrence of Listeria monocytogenes 194 strains were isolated in southern West Germany during the years 1972 to 1974: 154 from soil and plant samples (20.3%), 16 from feces of deer and stag (15.7%), 9 from old moldy fodder and wildlife feeding grounds (27.2%), and 8 from birds (17.3%). The highest number of isolates was obtained from uncultivated fields. The beta-hemolytic serovars 1/2b and 4b were predominant; other serovars (some of them identified for the first time), including nonhemolyzing strains, have been encountered frequently. It is suggested that Listeria monocytogenes is a saprophytic organism which lives in a plant-soil environment and therefore can be contracted by humans and animals via many possible routes from many sources.

[Considerations relative to compensable occupational diseases such as candida mycosis and other forms of mycotic infections (author's transl)].

[Further experimental data on clotrimazole: effectiveness against Cryptococcus neoformans, Sporothrix schenkii and Blastomyces dermatitidis Gilchrist].

Listeria monocytogenes was isolated from the intestinal lymph nodes of 8 out of 342 apparently healthy slaughter animals at the municipal abattoir in Lome (Togo) and from the faeces of 3 out of 236 bats. Except two strains of serovar 4b isolated from bats, all the nine others belonged to serovar 1/2a. The positive findings of slaughter animals were made from the carcasses of 2 pigs, 5 little ruminants and 1 cattle. The findings are discussed in the light of present knowledge on the occurrence of L. monocytogenes in some species of animals and its implications for the human being.

Isolation of Listeria monocytogenes in slaughter animals and bats of Togo (West Africa).

Eine Pilzkolonie, die in einer Sputumprobe gemeinsam mit anderen Pilzen isoliert wor‐den war, zeigte bei Differenzierung kulturelle und morphologische Eigenschaften, die auf das mögliche Vorliegen von Sporothrix schenckii hindeuteten. Die anschließend in 2 Labo‐ratorien durchgeführten Untersuchungen zur Differenzierung und Identifizierung des Pilz‐stammes werden beschrieben und unter den Gesichtspunkten der Routinediagnostik des mykologischen Labors erörtert. Der Stamm wurde als Angehöriger der Spezies Gliomastix Guégen identifiziert.

Comments on the Differentiation of a Gliomastix Isolated from Sputum versus Sporothrix schenckii *

[Candidamycosis -- with particular reference to genital infections (author's transl)].

[Use of acridin dyes in selective media for the isolation of Listeria monocytogenes. II. Modified stuart medium: a new Listeria-transport-enrichment-medium (author's transl)].

Use of acridine dyes in selective media for the isolation of Listeria monocytogenes. II. Modified Stuart medium: a new Listeria Transport Enrichment Medium.

[The increase of candida-mycosis with special reference to the genital tract (author's transl)].

[Cryptococcosis of the central nervous system with cellular immune reaction disorders].

[Differential diagnosis of histoplasmosis--darling's disease. Demonstration on a case history of histoplasma infection of oral cavity].

[Problems in the serological diagnosis of candida infections (author's transl)].

[Epidemiological observations concerning Candida fungemia in patients with indwelling venous catheters (author's transl)].

Proceedings: New outlook on the epidemiology and epizoology of listeriosis.

[Problems of simultaneous administration of antitetanic serum and tetanus toxoid].

[Bacteriological diagnosis of efferent urinary tract infections].

[Objectives and problems of bacteriological and serological examination programs at a hygiene institute in West Africa].

Executive Board of the International Committee on Nomenclature of Bacteria with the Chairmen and Secretaries of Taxonomic Subcommittees of ICNB: Minutes of the Meeting, 14 August 1970

[Use of acridin dyes in solid selective media for the isolation of Listeria monocytogenes].

[The occurrence of 2-mercaptoethanol resistant and sensitive listeria agglutinins in human and animal serums].

Draft of German text of the International Code of Nomenclature of Bacteria

Studies on the occurrence of toxoplasma antibodies sensitive or resistant to 2-mercaptoethanoI in man. II.

The epidemiology of listeriosis. Distribution of the listeria titre in different population groups in lower Franconia.

[Informative studies on the occurrence of human toxoplasma antibodies sensitive or resistant of 2-mercaptoethanol].

[Orientational studies for the demonstration of various antibodies against fungi in animal and human serums. II. The occurrence of IgM and IgG antibodies against C. albicans in human and rabbit serums].

[Studies on the importance of the antigen-fixation test for the serodiagnosis of Listeria monocytogenes infections].

[Epidemiology of listeria infections. Listeria titer distribution in various population groups].

[Adrenal cortex insufficiency in congenital adrenal gland hypoplasia].

[Orientational studies for the demonstration of various antibodies against fungi in animal and human serums. I. The appearance of 19S and 7S antibodies in animal immune serums against various inhaled molds].

[Critical studies on the question of acapsular formation in Listeria monocytogenes].

[On the diagnosis and sensitivity of skin fungi to modern antifungal agents].

[Effect of tetracycline administration on the child's dentition in the treatment of listeriosis in pregnant women].

Abstract : In view of the many unanswered questions regarding pathogen verification of subacute, chronic and asymptomatic listeric infections an attempt was made to utilize the immunity reaction of the host as an auxiliary means in detecting the distribution and frequency of listeriosis, as well as for diagnosis of cases not perceptible by bacteriologic means.

ABSTRACT
On the basis of morphological properties Bacterium
anitratum Schaub and Hauber 1948 is classified in the family Moraxellaceae Ryter and Piechaud 1963. Since the species differs in its physiological and biochemical properties from species of the genus Moraxella a new genus is proposed and named Lingelsheimia. It is proposed to transfer Bacterium
anitratum Schaub and Hauber 1948 to this genus. Lingelsheimia
anitrata
comb.
nov. is the type-species of the genus (basionym: Bacterium
anitratum Schaub and Hauber).

Transfer of Bacteriumanitratum Schaub and Hauber 1948 to the genus Lingelsheimiagen.nov.

International Committee on Nomenclature of Bacteria: IXth International Congress for Microbiology Academy of Medical Sciences Moscow, USSR, July 23-25

A. Introduction to the subject of the presentation In Germany and most German speaking countries medical mycology has primarily been dealt with by interested dermatologists during the first half of this century. This was quit natural for fungus infections of the skin seemed to be the predominant type of human disease caused by these organisms. In consequence a great deal of work has been devoted by dermatologically orientated mycologists (or mycologically orientated dermatologists) to the study of fungi. Most of the great textbooks, manuals and handbooks on medical mycology have been written or at least been edited by this group . To cite only one recent example of this : the supplements to Jadassohn's famous handbook on dermatology and venereal disease contain two volumes on medical mycology in which more than 90%of the papers have been covered by competent dermato-mycologists of which I only need to mention the name of my colleague Prof. Goetz who lectured at your convention last year. Since about 15 years-like in other countries, and particularly in Japan-other disciplines of biological sciences, medicine and veterinary medicine have developed an increasing interest in the study of fungi. The reasons for this are well known and need not to be discussed here, but it may be mentioned that this development was preceeded in the USA where since the middle of the thirty's an increasing number of non-dermatologists began to work on mycological problems. From the various mycological research groups in Western Germany the work of two mycological laboratories will be presented here. These are the mycology laboratories at the Institute of Hygiene , University of Bonn, where the speaker worked until 1965, and the fungus laboratory at the Institute of Hygiene and Microbiology at the University of Wurzburg, established by Dr . Staib. Due to fortunate circumstances both laboratories were combined into one unit when the speaker was appointed as chairman of the Wurzburg Institute of Hygiene, where as my associate Dr. Staib is head of the mycological service. Only the major lines of the scientific activities of the Wurzburg mycological center (with its two predecessors) will be briefly described and many casuistic and other observations made during the routine work will be excluded. For those interested, a full bibliography of the work performed by the authors of this paper and by their coworkers is available upon request.

A Survey of Scientific Studies Performed since 1950 at the Mycological Laboratories of the Universities of Bonn and Würzburg/Germany

Judicial Commission of the International Committee on the Nomenclature of Bacteria: Second Meeting, July 28, 1966 Academy of Medical Sciences Ulitza Solyanka 14, Moscow, USSR

[Is the Widal reaction for typhoid and paratyphoid influenced by the oral intake of larger amounts of killed Salmonella?].

[Studies on the problem of effects of ampicillin on Listeria monocytogenes].

The present position with regard to serodiagnosis in mycological infections.

[Orientational studies on the formation of sensitive and resistant antibodies to 2-mercaptoethanol in experimental Toxoplasma infections].

[Listeriosis as a confirmed cause in several patients with habitual abortions].

[A new selective medium for the isolation of C. neoformans from fecal material and from soil].

Preliminary investigations on the formation of antibodies sensitive and resistant to 2-mercaptoethanol in experimental toxoplasmosis.

A new selective medium for the isolation of Cryptococcus neoformans from faecal materials and soil.

[The isolation of Listeria monocytogenes from fecal, sewage sludge and soil samples (with reference to the epidemiology of listeriosis)].

[Annual report of 1960 and 1961 on Salmonella infections in the German Federal Republic including West Berlin].

Annual report for 1960 and 1961 on Salmonella Infection in West Germany including West Berlin.

The Isolation of Listeria monocytogenes from Stools, Sludge Fertilizer and Samples of Soil.

Investigations on the antigenic structure of actinomycetales IX. Serological classification of the Nocardiae with the polysaccharide fractions of their cell walls

[Listeriosis as a proved cause in some patients with habitual abortions].

Since the 1958 International Congress of Tropical Medicine in Lisbon considerable progress has been made in the immunological and immunochemical analysis of fungal antigens as well as in the study of the antigenic relationsships among pathogenic and non‐pathogenic fungi. This is due chiefly to the use of various chemical fractionating procedures to analyse the fungal cell constituents and by the application of recently developed, highly refined serological methods, such as agar‐gel diffusion, immuno‐electrophoresis and immuno‐fluorescence technics

[THE EPIDEMIOLOGY OF SALMONELLA INFECTIONS (EXCLUDING TYPHOID AND PARATHYROID FEVERS) IN EUROPE (1950-1960)].

Annales des Societes belges de medecine tropicale, de parasitologie, et de mycologie

USE OF SEROLOGICAL METHODS FOR THE DIAGNOSIS OF CRYPTOCOCCOSIS. A REVIEW.

Initially, should anti-epileptic drug therapy be used single or in combina tions ? Do patients with psychomotor seizures respond well to anti-grand mal drugs? In patients with recalcitrant epilepsy, what therapy other than drug therapy has been shown effective? Do children with petit mal epilepsy have low, average, or above average in telligence quotients? Should children with epilepsy be given more, less, or the same amount of affec tion and discipline as a child not subject to seizures? When patients, in rigid control, func tion on a level below their intellectual potential, what factors are usually re sponsible?

A serologlcal study on the antigenio relationships of the form genus Triohosporon.

[THE EFFECT OF A COMBINATION OF IODOCHLOROHYDROXYQUINOLINE AND 4,7-PHENANTHROLINE-5,6-QUINONE ON FECAL FLORA IN SUBJECTS WITH HEALTHY INTESTINE].

[Studies on the influence of colistin on the intestinal flora in infants].

Basic Science Review : Perinatal Infections Due to Listeria Monocytogenes

Detailed minutes concerning actions taken on Opinions During the Meetings of the Judicial. Commission of the International Committee on Bacteriological Nomenclature at the VIII International Microbiological Congress in Montreal, 1962

Minutes of the first meeting of the International Committee on Bacteriological Nomenclature, Pathology Building, McGill University, Montreal, August 18, 1962

Memorandum: Procedure for Requesting an Opinion from the Judicial. Commission of the International Committee on Bacteriological Nomenclature

By means of antisera prepared from all recognized species of the form genus Trichosporon (Behrend), it was shown in agglutination, precipitation, agar-gel diffusion and complement-fixation tests with whole cell antigens and crude polysaccharide extracts that the various Trichosporon species can be subdivided in three, possibly four, serological groups. Strains belonging to sero-group 1 (T. fermentans, T. capitatum, T. sericeum) give numerous unilateral or reciprocal cross reactions with Geotrichum candidum and Nadsonia elongata. Strains of sero-group 2 (T. cutaneum, T. infestans, T. margaritiferum) show common partial antigens with Cryptococcus species, Candida curvata and Candida humicola. T. pullulans holds an intermediate position between sero-group 1 and 2. T. behrendii is serologically distinct from the remaining Trichosporon species. A tentative antigenic scheme for the form genus Trichosporon was developed. The results are in good agreement with earlier work of the senior author and indicate close ...

A serological study on the antigenic relationships of the form genus Trichosporon

[Culture studies on the vaginal flora with special reference to bifidus bacteria].

[QUALITATIVE AND QUANTITATIVE RESEARCH ON THE HUMAN INTESTINAL FLORA].

Qualitative and Quantitative Investigations on the Bacterial Flora of the Human Intestine.

Minutes of the second meeting of the International Committee on Bacteriological Nomenclature, August 23, 1962, in Montreal

[On the diagnosis and clinical significance of an anaerobic strain of bacteria in pyosalpinx].

*Associcate Bacteriologist, Veterinary Research Laboratory, Montana State College, Bozeman. **Professor of Medical Microbiology, Hygiene Institute, Friedrich Wilhelm University, Bonn, Germany. ***Head, Bacteriological and Virus Research Laboratory, Asta-Werke A-K, Brackwede, Germany. This investigation was supported in part by Public Health Service Research Grant AI-02571-04 from the National Institute of Allergy and Infectious Dis-

PERINATAL INFECTIONS DUE TO LISTERIA MONOCYTOGENES. DO THESE AFFECT SUBSEQUENT PREGNANCIES?

[Studies on the question of the relation between serum antibodies and skin reactions in cases of suspected listeriosis].

[On antibiotic and sulfonamide sensitivity of Listeria monocytogenes. Results of in vitro studies and a literature survey].

Castellani's Absorption Test in the Diagnosis of Human Listeriosis.

The Toxic Effect of Methicillin on Guineapigs compared with its Lack of Toxic Effects on Rats.

Archivio italiano di scienze mediche tropicali e di parassitologia

[On Castellani's absorption test with special reference to its use in the serological diagnosis of human listeriosis].

[Bacteriological study methods for the differentiation of types of fungi. 2. On the determination of oxidases in cultures of budding fungi].

Minutes of the meetings of the Judicial Commission of the International Committee on Bacteriological Nomenclature held at Montreal, Canada, in connection with the VIII International Microbiological Congress August 19–25, 1962

Memorandum: General Procedure to be followed in the formation of taxonomic subcommittees within the International Committee on Bacteriological Nomenclature

[On flagellation of Listeria monocytogenes. Electronoptic and serological studies].

Differential Diagnosis of Enterobacteriaceae by the Lysin Decarboxylase Test.

[The toxic effect of penicillin and other antibiotics on guinea pigs].

Preparation of Salmonella O Phage for differentiating Enterobacteriaceae.

Zeitschrift fur Hygiene und Infektionskrankheiten; medizinische Mikrobiologie, Immunologie und Virologie

[On the differential diagnosis of Enterobacteriaceae with the lysine-decarboxylase test].

D. Bacteriological and Serological Measures in the Diagnosis of Listeriosis

[On the hygiene of medicinal waters, mineral waters and lemonades in the Federal Republic of Germany].

Production and therapy of subacute and chronic listeriosis in experimentally infected mice.

Any attempt to evaluate the prevalence of food-borne diseases in Europe is fraught with difficulty, partly because in some countries such diseases, if reported, are not clearly designated as food-borne, and partly because of the variety in terminology and methods of classification.Nevertheless, it is apparent that, although certain food-borne infections have decreased in prevalence, others have increased during the past decade. This increase has been shown to be related in some countries to the import of certain foodstuffs and fodder from tropical and subtropical regions and has resulted in a general spread of Salmonella infections by a wide variety of serotypes. Food-borne intoxications are predominantly caused by the ingestion of the toxins elaborated by the growth of Staphylococcus aureus in food and by spore-forming bacilli. Botulism is now rare in Europe.While the recent increase in the prevalence of these diseases calls for strict supervision of food products and improved measures of ensuring food hygiene, the efficacy of such steps as may be taken will depend on close co-operation between public health and veterinary public health authorities.

Zeitschrift für Immunitätsforschung und experimentelle Therapie

Investigations with Antimycotic Substances in Experiments on Animals. 2nd Communication: Comparative Studies on the Activity of orally or subcutane. ously administered Amphotericin B in Mice infected with Candida albicans, Cryptococcus neoformans, Mucor pusillus or Aspergillus fumigatus.

[The toxic effect of penicillin on the guinea pig and penicillinase demonstration in the guinea pig and rat brain].

Breakdown of aesculin by yeasts, with particular reference to the genus Cryptococcus.

Investigations with antimycotics in experimental animals. Part 2. Comparative investigations on the effectiveness of oral and subcutaneous applications of amphotericin B to Mice infected with C. albicans, C. neoformans, M. pusillus, or A. fumigatus.

Mycological findings in the faeces and urine during antibiotic therapy.

[Experimental animal studies with antimycotic substances. Part 2. Comparative studies on the effectiveness of peroral and subcutaneous application of amphotericin B on an experimental model of mice infected with Candida albicans, Cryptococcus neoformans, Mucor pusillus or Aspergillus fumigatus].

[On fungus findings in feces and urine during antibiotic therapy].

Nongenetic nature of the action of the cordinducingfactor. Cells of H37Ra which have grown in a corded fashion in presence of the factor revert to the noncorded form when subcultured on medium free of the factor. This shows that activity of the factor does not induce any genetic changes in H37Ra. Since H37Ra is incapable of multiplication in vivo, any virulence which might be associated with the altered morphology of H37Ra cells grown in the presence of the cord-inducing factor could be detected only by inoculation of massive amounts of corded H37Ra into a sensitive animal. We were not able to carry out this experiment. In his report of a cord-inducing factor from chick embryos, Bloch (J. Exptl. Med., 88, 355-360, 1948) described such an experiment. The altered cells showed a low level of virulence. Stocks of H37Ra and M. epidermidis were maintained as lyophilized cultures. In spite of this precaution, preparations of cord-inducing factor have varied in their activity. In recent months, this variability has become marked, and, in consideration of our inability to purify the cord-inducing factor, has influenced us to terminate this problem.

SEROLOGICAL TYPES OF LISTERIA MONOCYTOGENES OCCURRING IN THE UNITED STATES

Ergebnisse der Mikrobiologie, Immunitatsforschung und experimentellen Therapie

[Cultural, biochemical & serological behavior of the Cryptococcus group].

The cultural-biochemical and serological behaviour of the Cryptococcus group.

[Experimental studies on the induction and therapy of subacute Listeria infection in white mice. Part I. Studies on the therapy of listerosis].

The Isolation and Differentiation of Pathogenic E. coli from Stools with the aid of Antibiotic containing Filter Paper Strips.

[Animal experiments with antimycotic drugs. 1. Findings on the effects of mycostatin & amphotericin B on test models of mice infected with Candida albicans or Mucor pusillus].

[Isolation & differentiation of enteropathogenic coli bacteria from feces with antibiotic strips].

[A new type of Salmonella: Salmonella halle with reference to the turtle as a Salmonella reservoir].

[A new Salmonella type of the B group; S. nordenham (1,4,12,27:z:e,n)].

Rapid diagnosis of Cryptococcus meningitis by means of a precipitin test.

[The effect of erythromycin on the intestinal flora in healthy humans].

[Specificity of toxoplasma seroreactions; relationship between the antibodies of Toxoplasma and Listeria].

[The problem of dysbacteria, as seen from the viewpoint of the microbiologist].

The antigenic relationships between the different serotypes of Listeria monocytogenes and Staphylococcus aureus were investigated by means of agglutination, agglutinin-absorption, precipitation, and complement fixation tests. Reciprocal cross-reactions were demonstrated with serotypes 1, 2, and 3 of L. monocytogenes and many S. aureus strains, but not with serotypes 4a and 4b, using O suspensions of L. monocytogenes and autoclaved suspensions of S. aureus. Soluble heat-stable polysaccharide extracts, on the contrary, were quite specific in precipitin tests. Antisera against L. monocytogenes type 3 cross-precipitated unilaterally extracts of most S. aureus strains. In the absence of clear-cut serological species specificity in these two microorganisms, in their reactions with rabbit antisera, and with human sera from suspected cases of listeriosis, there is need for caution in the interpretation of positive serological tests as an aid to diagnosis.

Antigenic relationships between Listeria monocytogenes and Staphylococcus aureus.

The increase in mycological work by diagnostic laboratories has stimulated the development of simple and reliable procedures for routine screening and identification of fungus cultures. The writer has investigated the possibility of applying procedures for the diagnosis of yeasts other than the widely used sugar fermentation and assimilation tests. During earlier investigations it was found that capsulated and red pigment-producing yeasts hydrolyzed urea in Christensen's medium (Christensen, 1946) while candida strains and saccharomycetes did not. Therefore studies were initiated to determine whether urea hydrolysis could be used with advantage in routine mycological work. For this study yeast cultures were procured from several recognized laboratories. The results of the examinations were finally compared with a collection of strains at the Communicable Disease Center. Since the findings at both laboratories were in complete agreement and since the urease test offered improvement for the routine identification of yeasts and some yeast-like organisms, the results are given here. For the sake of completeness this report will also present the results with a number of yeasts from Dr. Wickerham's collection which were tested after the writer's return to Germany.

USE OF A UREASE TEST FOR THE SCREENING AND IDENTIFICATION OF CRYPTOCOCCI

Summary 1. In studying the mechanism of the “capsular reaction” one of the first questions to be answered is whether or not the capsule swells when antibody is added. Data presented here indicate that it does not, using C. neoformans as a test organism. Exposure of washed, encapsulated C. neoformans to antibody results in a prominent clarification of capsular outline, but no increase in capsular size as determined by packed cell volume after centrifugation and by direct microscopic measurement. When cells with large capsules are employed, there is an apparent decrease in capsular size during the reaction with antibody. 2. If capsulated cells are not washed free of soluble capsular polysaccharide present in the cultural supernate, the soluble antigen coprecipitates when antibody is added. This may lead to the erroneous conclusion that there is an increase in capsular volume.

Proceedings of the Society for Experimental Biology and Medicine

Failure to Demonstrate Capsular Swelling in Cryptococcus neoformans. ∗

[Antigenic relation between Shigella flexneri type 5 and a new Escherichia coli O group 129].

On the possibility of tising agar-gel precipitation in the analysis of O antigens in bacteria and fungi.

[Application possibility of precipitation in agargel in O-antigen analysis of bacteria and fungi].

[Serological cross-reaction between Listeria monocytogenes and enterococcus].

[Monosporiosis and maduromycosis; the so-called therapy-resistant actinomycoses].

INTRODUCTION PART 1. SOME COMPARISONS BETWEEN THE A number of years ago, Professor Robert S. GENERAL OUTLINE CLASSIFICATION PROPOSED Breed and the late Colonel A. Parker Hitchens BY KRASSILNIKOV, 1949, AND THE OUTLINE initiated the gathering of bacteriologists at the CLASSIFICATION THAT WILL BE USED IN 7TH annual meeting of the Society of American EDITION OF BERGEY'S MANUAL Bacteriologists to discuss problems and advanceROBERT S. BREED ments in the classification of microorganisms. The discussions have served as a place for airing Krassilnikov (10) recognized four classes in taxonomic opinions. They have aroused much Protophyta Sachs, 1874; Actinomycetes Krassilniinterest which at times resulted in noteworthy kov, 1945; Eubacteriae Stanier and van Niel, contributions to the classification of microorgan1941; Myxobacteriae Heller, 1921, and Spiroisms. The 1955 symposium was organized by chaetae Stanier and van Niel, 1941; in these four Professor Breed. Summaries of the papers classes he recognized 23 families and 88 genera. presented follow. In the comparable groups in the sixth edition of

[New medium for formation of pseudomycelium in Candida albicans].

Antigen Relation of Shigella flexneri Type 5 and a New Bacterium, coli 0-Group 129.

[Serologic study of the strains of Listeria monocytogenes isolated in France].

Precipitation in Agar-Gel for O-Antigen Analysis of Bacterial and Fungal Extracts.

The Value of Deoxycholate-Citrate Media in Shiga Dysentery. (Remarks on the Account of the Miinsterland Epidemic of 1952 by VOR DEM ESCHE.).

[Agglutination tests in convalescent serum of infants with infectious colienteritis].

[Usefulness of desoxycholic acid citrate as culture medium in Shiga-Kruse dysentery].

[In vitro sensitivity of Listeria monocytogenes to sulfonamides and antibiotics].

[Type-specific serums of Shigella dysenteriae 2 (Type Schmitz)].

[Studies on O antigens of Escherichia coli groups O 28, O 42 and of pathogenic Katwijk type].

The in vitro Sensitivity of Erysipelothrix monocytogenes (Pirie) to Sulphonamides and Antibiotics.

[Laboratory diagnosis of bacillary dysentery and its importance for epidemiology and pathology].

The Widal Reaction in Typhoid and Paratyphoid with particular reference to Chloramphenicol Treatment.

[Experimental and clinical studies on the effect of local sulfonamidegel therapy in tuberculous pulmonary disintegrating foci].

Listeria (Erysipelothrix) Infection and the Causative Agent (E. monocytogenes).

[Bacteriology of the anaerobic Corynebacteria and their incidence in pathological material].

[Methods and evaluation of determination of sulfonamide resistance by means of a modified plate tests in Listeria monocytogenes].

Zentralblatt fur Bakteriologie, Parasitenkunde, Infektionskrankheiten und Hygiene. Zweite naturwissenschaftliche Abt.: Allgemeine, landwirtschaftliche und technische Mikrobiologie

The Serological Diagnosis of 'Erysipelothrix Infections by Agglutination and Complement Fixation.

The Laboratory Diagnosis of Bacillary Dysentery and its Epidemiological and Clinical Significance.

[A little-known type of Escherichia as the probable cause of a dysenteriform disease].

[Paracoli strains of the Bethesda group in the diagnosis of pathogenic intestinal bacterial].

[Determination of indol in the three-sugar-iron-urea agar of Bader and Hotz].

The Aetiology of Granulomatosis Infantiseptica and Pseudotuber-eulosis.

Paracolon Strains of the Bethesda Group in the Diagnosis of Intestinal Infections.

A VARIANT OF ESCHERICHIA RESEMBLING A MANNITOL-FERMENTING SHIGELLA

[Preparation and use of diagnostic factor sera in type determination of Flexner Shigella].

[Differentiation of alcalescent bacteria, with special reference to motile cultures of Bacterium alcalescens Andrewes].

[Classification of a bacterium isolated from cases of acute enterocolitis and its pathogenic significance].

The Diagnosis of Alkalescens Strains with particular reference to Motile Cultures of Bad. alkalescens (Andrewes).

same rate as the parent strain, but they fermented pyruvate very slowly. Although the parent strain produced approximately 9 ,AM C02 from 10 jim pyruvate in 60 minutes, the variants produced less than 3 jAm in the same time. DSM in a concentration of 100 ,g per ml had no appreciable effect on the C02 production by the mutant strains. Experiments on the growth of the parent strain E. coli demonstrated that, although DSM did not inhibit the anaerobic CO2 production from glucose to any extent, the cells could not grow anaerobically in glucose synthetic medium in the presence of DSM. The dependent variant did not require DSM for the anaerobic dissimilation of glucose, but required the drug for growth in glucose synthetic medium. Viable counts of the resistant strain showed that it grows equally well with and without DSM in glucose synthetic medium. It appears that DSM inhibits some terminal step in both aerobic and anaerobic carbohydrate dissimilation, but no conclusions can be made at present as to the primary inhibitory effect of DSM.

THE POSITION OF BACILLUS KANDIENSIS VAR. KANDIENSOIDES (CASTELLANI)

A Mannitol Fermenting Strain Resembling a Shigella with a Seroiogical Relationship to Large-Sachs Type Q 771.

[A mannite-positive, Shigella-like strain, with serological relation to Large-Sachs type Q 771].

[Comparative study of forms of the dysentery bacillus called type F in the German nomenclature and certain American and British Shigella strains; with a note on dissociation in the Flexner group].

[Identity and classification of Roelck's Bacillus paradysenteriae palatinense (Roelcke)].

The Occurrence of a Shigella Type Previously Unrecognized in Germany (with a Review of the Problem of the Nomenclature of the Shigella paradysenteriae Group).

The Relationship between the' Dysentery Type N and Sh. paradysenteriae Lavington I (Etousa) and its Position in the Shigella Group. (With a Survey of the Recognized Shigella Types).

Results of Experiments Comparing the German Dysentery Types G, M and P with American and British Shigella Strains.

After traumatic events, simple cue-threat associative memories strengthen while episodic memories become fragmented. However, how the brain prioritizes cue associations over episodic coding of traumatic events remains unclear. Here, we developed a new episodic threat conditioning paradigm in which participants concurrently form two memory representations: cue associations and episodic cue sequence. We discovered that these two distinct memories compete for physiological fear expression, reorganizing overnight from an overgeneralized cue-based to a precise sequence-based expression. With multivariate fMRI, we track inter-area communication of the memory representations and demonstrate that a shift from hippocampal-dominant to prefrontal-dominant control of the fear regulatory circuit governs this memory maturation. Critically, this overnight reorganization is altered in individuals with heightened trait anxiety. Together, these findings suggest the brain prioritizes generalizable associative memories under recent traumatic stress, but resorts to selective episodic memories 24 hrs later. Time-dependent memory competition provides a unifying account for memory dysfunctions in posttraumatic stress disorders.

Time-dependent neural arbitration between cue associative and episodic fear memories

In human neuroscience, machine learning can help reveal lower-dimensional neural representations relevant to subjects’ behavior. However, state-of-the-art models typically require large datasets to train, so are prone to overfitting on human neuroimaging data that often possess few samples but many input dimensions. Here, we capitalized on the fact that the features we seek in human neuroscience are precisely those relevant to subjects’ behavior. We thus developed a Task-Relevant Autoencoder via Classifier Enhancement (TRACE), and tested its ability to extract behaviorally-relevant, separable representations compared to a standard autoencoder for two severely truncated machine learning datasets. We then evaluated both models on fMRI data where subjects observed animals and objects. TRACE outperformed both the autoencoder and raw inputs nearly unilaterally, showing up to 30% increased classification accuracy and up to threefold improvement in discovering “cleaner”, task-relevant representations. These results showcase TRACE’s potential for a wide variety of data related to human behavior.

"Task-relevant autoencoding" enhances machine learning for human neuroscience

Multiple time measurements of multidimensional psychiatric states from immediately before the COVID-19 pandemic to one year later: a longitudinal online survey of the Japanese population

The DecNef collection, fMRI data from closed-loop decoded neurofeedback experiments

Humans and animals are able to generalize or transfer information from previous experience so that they can behave appropriately in novel situations. What mechanisms-computations, representations, and neural systems-give rise to this remarkable ability? The members of this Generative Adversarial Collaboration (GAC) come from a range of academic backgrounds but are all interested in uncovering the mechanisms of generalization. We started out this GAC with the aim of arbitrating between two alternative conceptual accounts: (1) generalization stems from integration of multiple experiences into summary representations that reflect generalized knowledge, and (2) generalization is computed on-the-fly using separately stored individual memories. Across the course of this collaboration, we found that-despite using different terminology and techniques, and although some of our specific papers may provide evidence one way or the other-we in fact largely agree that both of these broad accounts (as well as several others) are likely valid. We believe that future research and theoretical synthesis across multiple lines of research is necessary to help determine the degree to which different candidate generalization mechanisms may operate simultaneously, operate on different scales, or be employed under distinct conditions. Here, as the first step, we introduce some of these candidate mechanisms and we discuss the issues currently hindering better synthesis of generalization research. Finally, we introduce some of our own research questions that have arisen over the course of this GAC, that we believe would benefit from future collaborative efforts.

Author response: Value signals guide abstraction during learning

This chapter provides a framework for developing interventions that specifi cally target intrusive events. It describes the challenges in defi ning intrusive thoughts and the diffi culty in distinguishing normal processes of cognition and emotion from indicators of dysfunction, defi ned from practical, neurobiological, or cultural points of view. Throughout, the term intrusive events is used to encompass both thoughts and images that become intrusive. Examples are explored as they occur in diff erent psychiatric disorders to demonstrate their variance in form, frequency, and controllability. Treatment modalities that have been used to alleviate intrusive events in diff erent psychiatric disorders are reviewed, including behavioral, pharmacological, and emerging electromagnetic brain interventions. Two clinical vignettes illustrate the nature and severity of intrusive events in patient populations as well as the complex, multidimensional nature of the clinical reality. Ways of measuring intrusive events are examined and deconstructed into components (e.g., sensory, motor, and cognitive features). By examining intrusive events across diagnostic categories, common basic biobehavioral processes may be revealed which, in turn, could facilitate the study of neural processes underlying the behaviors. A model of cognitive and emotional decision making is presented to provide a basis for understanding and studying intrusive events. Examples of how the model might account for the “failure modes” in intrusive events are used to formulate testable hypotheses, and future interventions that combine multiple treatment modalities are considered. The chapter concludes with a discussion of the broader cultural context of intrusive events. Group photos (top left to bottom right) Judson Brewer, Harriet de Wit, Aurelio Cortese, Martin Paulus, Emily Holmes, Judson Brewer, Damiaan Denys, Colleen Hanlon, Peter Tse, Jens Schwarzbach, Martin Paulus, Colleen Hanlon, Aurelio Cortese, Harriet de Wit, Judson Brewer, Peter Tse, Damiaan Denys, Martin Paulus, Harriet de Wit, Jens Schwarzbach, Emily Holmes From “Intrusive Thinking: From Molecules to Free Will,” edited by Peter W. Kalivas and Martin P. Paulus. Strüngmann Forum Reports, vol. 30, Julia R. Lupp, series editor. Cambridge, MA: MIT Press. ISBN 978-0-262-54237-1 348 J. Brewer et al.

The human brain excels at constructing and using abstractions, such as rules, or concepts. Here, in two fMRI experiments, we demonstrate a mechanism of abstraction built upon the valuation of sensory features. Human volunteers learned novel association rules based on simple visual features. Reinforcement-learning algorithms revealed that, with learning, high-value abstract representations increasingly guided participant behaviour, resulting in better choices and higher subjective confidence. We also found that the brain area computing value signals – the ventromedial prefrontal cortex – prioritised and selected latent task elements during abstraction, both locally and through its connection to the visual cortex. Such a coding scheme predicts a causal role for valuation. Hence, in a second experiment, we used multivoxel neural reinforcement to test for the causality of feature valuation in the sensory cortex, as a mechanism of abstraction. Tagging the neural representation of a task feature with rewards evoked abstraction-based decisions. Together, these findings provide a novel interpretation of value as a goal-dependent, key factor in forging abstract representations.

Decoded Neurofeedback–Process-Based Mechanistic Neural Targeting

The coronavirus disease 2019 (COVID-19) pandemic has profoundly affected the mental health of both infected and uninfected people. Although most psychiatric disorders have highly overlapping genetic and pathogenic backgrounds, most studies investigating the impact of the pandemic have examined only single psychiatric disorders. It is necessary to examine longitudinal trajectories of factors that modulate psychiatric states across multiple dimensions. 2274 Japanese citizens participated in online surveys presented in December 2019 (before the pandemic), August 2020, Dec 2020, and April 2021. These surveys included nine questionnaires on psychiatric symptoms, such as depression and anxiety. Multi-dimensional psychiatric time series data were then decomposed into four principal components. We used generalized linear models to identify modulating factors for effects of the pandemic on these components. The four principal components can be interpreted as general psychiatric burden, social withdrawal, alcohol-related problems, and depression/anxiety. Principal components associated with general psychiatric burden and depression/anxiety peaked during the initial phase of the pandemic. They were further exacerbated by the economic burden of the pandemic. In contrast, principal components associated with social withdrawal showed a delayed peak, with human relationships as an important risk modulating factor. In addition, being elderly and female were risk factors shared across all components. Our results show that COVID-19 has imposed a large and varied burden on the Japanese population since the commencement of the pandemic. Although components related to the general psychiatric burden remained elevated, peak intensities differed between components related to depression/anxiety and those related to social anxiety. These results underline the importance of using flexible monitoring and mitigation strategies for mental problems, according to the phase of the pandemic.

Multiple-time measurements of multidimensional psychiatric states from immediately before the COVID-19 pandemic to one year later: A longitudinal online survey of the Japanese population

Context. Large multi-site neuroimaging datasets have significantly advanced our quest to understand brain-behavior relationships and to develop biomarkers of psychiatric and neurodegenerative disorders. Yet, such data collections come at a cost, as the inevitable differences across samples may lead to biased or erroneous conclusions. Objective. We aim to validate the estimation of individual brain network dynamics fingerprints and appraise sources of variability in large resting-state functional magnetic resonance imaging (rs-fMRI) datasets by providing a novel point of view based on data-driven dynamical models. Approach. Previous work has investigated this critical issue in terms of effects on static measures, such as functional connectivity and brain parcellations. Here, we utilize dynamical models (hidden Markov models—HMM) to examine how diverse scanning factors in multi-site fMRI recordings affect our ability to infer the brain’s spatiotemporal wandering between large-scale networks of activity. Specifically, we leverage a stable HMM trained on the Human Connectome Project (homogeneous) dataset, which we then apply to an heterogeneous dataset of traveling subjects scanned under a multitude of conditions. Main Results. Building upon this premise, we first replicate previous work on the emergence of non-random sequences of brain states. We next highlight how these time-varying brain activity patterns are robust subject-specific fingerprints. Finally, we suggest these fingerprints may be used to assess which scanning factors induce high variability in the data. Significance. These results demonstrate that we can (i) use large scale dataset to train models that can be then used to interrogate subject-specific data, (ii) recover the unique trajectories of brain activity changes in each individual, but also (iii) urge caution as our ability to infer such patterns is affected by how, where and when we do so.

Brain network dynamics fingerprints are resilient to data heterogeneity

Abstractions are critical for flexible behaviours and efficient learning. However, how the brain forgoes the sensory dimension to forge abstract entities remains elusive. Here, in two fMRI experiments, we demonstrate a mechanism of abstraction built upon valuation of task-relevant sensory features. Human volunteers learned hidden association rules between visual features. Computational modelling of participants’ choice data with mixture-of-experts reinforcement learning algorithms revealed that, with learning, emerging high-value abstract representations increasingly guided behaviour. Moreover, the brain area encoding value signals - the ventromedial prefrontal cortex - also prioritized and selected latent task elements, both locally and through its connection to visual cortex. In a second experiment, we used multivoxel neural reinforcement to show how reward-tagging the neural sensory representation of a task’s feature evoked abstraction-based decisions. Our findings redefine the logic of valuation as a goal-dependent, key factor in constructing the abstract representations that govern intelligent behaviour.

In neuroscience, attention has been shown to bidirectionally interact with reinforcement learning (RL) processes. This interaction is thought to support dimensionality reduction of task representations, restricting computations to relevant features. However, it remains unclear whether these properties can translate into real algorithmic advantages for artificial agents, especially in dynamic environments. We design a model incorporating a self-attention mechanism that implements task-state representations in semantic feature-space, and test it on a battery of Atari games. To evaluate the agent's selective properties, we add a large volume of task-irrelevant features to observations. In line with neuroscience predictions, self-attention leads to increased robustness to noise compared to benchmark models. Strikingly, this self-attention mechanism is general enough, such that it can be naturally extended to implement a transient working-memory, able to solve a partially observable maze task. Lastly, we highlight the predictive quality of attended stimuli. Because we use semantic observations, we can uncover not only which features the agent elects to base decisions on, but also how it chooses to compile more complex, relational features from simpler ones. These results formally illustrate the benefits of attention in deep RL and provide evidence for the interpretability of self-attention mechanisms.

Attention or memory? Neurointerpretable agents in space and time

Generalization of information - integrative encoding or category-based inference?

Summary Background. Rising rates of suicide, the most dreadful consequence of mental health effects elicited by the coronavirus pandemic (COVID-19) are cause for grave concern. However, the exact association between mental health problems and suicide remains largely unknown in relation to COVID-19. Methods. To determine the impact of COVID-19 on suicide trajectory, we used an interrupted time-series design to analyze monthly suicides rates extracted from Japan's national database. We next used mixed-effects regression models to investigate the relationship between the nationwide suicide increase in August 2020 and psychiatric states of 4,348 individuals from an online survey performed immediately before (December 2019) and during (August 2020) the pandemic. Psychiatric states included depression, anxiety, and COVID-19-related PTSD, a form of severe event-related stress. FIndings. In Japan, suicides had gradually decreased before COVID-19 ({beta} = -0.7 x 10-3, t57 = -14.2, p = 8.6 x 10-46), but increased drastically after a state of emergency was declared in April 2020 ({beta} = 0.9 x10-2, t57 = 17.3, p = 2.3x10-67). We found that PTSD symptoms reliably predict COVID-19's impact on suicide rates ({beta} = 6.3 x 10-4, t3936 = 5.96, p = 2.7 x 10-9). In contrast, depression scores are a reliable indicator of stress vulnerability (i.e. future suicide increases, {beta} = 0.001, t3936 = 6.6, p = 4.5 x 10-11). Simulations revealed that a one-point reduction in PTSD score could decrease suicides by up to 3.1 per ten million people per month in Japan. Interpretation. PTSD symptoms may help to identify high-risk groups so as to increase efficacy of prevention policies. Funding. KDDI collaborative research contract, the Innovative Science and Technology Initiative for Security (JPJ004596), ATLA and AMED (JP20dm0307008).

PTSD symptoms related to COVID-19 as a high risk factor for suicide - Key to prevention

Unconscious reinforcement learning of hidden brain states supported by confidence

While it has been proposed that metacognition and conscious perception are related, the mechanistic relationship between the two is unclear. To address this question, we combined decoded neurofeedback (DecNef) in functional magnetic resonance imaging (fMRI) with concurrent psychophysics. Participants were rewarded for activating multivoxel patterns for color discrimination confidence while they detected color in mostly achromatic stimuli. We found that occurences of voxel patterns for high color discrimination confidence were associated with false alarms in the concurrent color detection task, suggesting a link between discrimination confidence and consciousness.

Multivoxel patterns for perceptual confidence are associated with false color detection

Chronic stress is a major risk factor for developing Alzheimer's disease (AD) and promotes the processing of amyloid precursor protein (APP) to β‐amyloid (Aβ). However, the precise relationship of stress and disease‐typical cognitive decline is presently not well understood. The aim of this study was to investigate how early life stress may affect cognition in adult mice with and without soluble Aβ pathology typical for the early stages of the disease. We focussed on sustained attention and response control, aspects of cognition mediated by the prefrontal cortex that are consistently impaired both in early AD and after chronic stress exposure. Young wild‐type mice as well as transgenic arcAβ mice overexpressing the hAPParc/swe transgene were exposed to a chronic unpredictable stress paradigm (age 3–8 weeks). At 15 weeks, these mice were tested on the 5‐choice serial reaction time task, a test of sustained attention and executive control. We found that, expectedly, chronic stress increased impulsive choices and impaired sustained attention in wild‐type mice. However, the same treatment reduced impulsivity and did not interfere with sustained attention in arcAβ mice. These findings suggest an unexpected interaction between chronic stress and Aβ whereby Aβ‐pathology caused by the hAPParc/swe mutation prevented and/or reversed stress‐induced cognitive changes through mechanisms that deserve further investigation. They also indicate that Aβ, in modest amounts, may have a beneficial role for cognitive stability, for example by protecting neural networks from the impact of further physiological or behavioural stress.

The Arctic/Swedish APP mutation alters the impact of chronic stress on cognition in mice

Abstract Closed-loop neurofeedback has sparked great interest since its inception in the late 1960s. However, the field has historically faced various methodological challenges. Decoded fMRI neurofeedback may provide solutions to some of these problems. Notably, thanks to the recent advancements of machine learning approaches, it is now possible to target unconscious occurrences of specific multivoxel representations. In this tools of the trade paper, we discuss how to implement these interventions in rigorous double-blind placebo-controlled experiments. We aim to provide a step-by-step guide to address some of the most common methodological and analytical considerations. We also discuss tools that can be used to facilitate the implementation of new experiments. We hope that this will encourage more researchers to try out this powerful new intervention method.

Can humans be trained to make strategic use of unconscious representations in their own brains? We investigated how one can derive reward-maximizing choices from latent high-dimensional information represented stochastically in neural activity. In a novel decision-making task, reinforcement learning contingencies were defined in real-time by fMRI multivoxel pattern analysis; optimal action policies thereby depended on multidimensional brain activity that took place below the threshold of consciousness. We found that subjects could solve the task, when their reinforcement learning processes were boosted by implicit metacognition to estimate the relevant brain states. With these results we identified a frontal-striatal mechanism by which the brain can untangle tasks of great dimensionality, and can do so much more flexibly than current artificial intelligence.

Metacognition facilitates the exploitation of unconscious brain states

The neural and cognitive architecture for learning from a small sample

Significance Conventional therapies for the treatment of anxiety disorders are aversive, and as a result, many patients terminate treatment prematurely. We have developed an unconscious method to bypass the unpleasantness in conscious exposure using functional magnetic resonance imaging neural reinforcement. Using this method, participants learn to generate brain patterns similar to the multivariate brain pattern of a feared animal. We demonstrate in a double-blind placebo-controlled experiment that neural reinforcement can lead to reliable reductions in physiological fear responses. Crucially, this intervention can be achieved completely unconsciously and without any aversive reaction. Extending our approach to other forms of psychopathologies, such as posttraumatic stress disorders, might eventually provide another means of intervention for patients currently receiving insufficient exposure treatments. Can “hardwired” physiological fear responses (e.g., for spiders and snakes) be reprogramed unconsciously in the human brain? Currently, exposure therapy is among the most effective treatments for anxiety disorders, but this intervention is subjectively aversive to patients, causing many to drop out of treatment prematurely. Here we introduce a method to bypass the subjective unpleasantness in conscious exposure, by directly pairing monetary reward with unconscious occurrences of decoded representations of naturally feared animals in the brain. To decode physiological fear representations without triggering excessively aversive reactions, we capitalize on recent advancements in functional magnetic resonance imaging decoding techniques, and use a method called hyperalignment to infer the relevant representations of feared animals for a designated participant based on data from other “surrogate” participants. In this way, the procedure completely bypasses the need for a conscious encounter with feared animals. We demonstrate that our method can lead to reliable reductions in physiological fear responses, as measured by skin conductance as well as amygdala hemodynamic activity. Not only do these results raise the intriguing possibility that naturally occurring fear responses can be “reprogrammed” outside of conscious awareness, importantly, they also create the rare opportunity to rigorously test a psychological intervention of this nature in a double-blind, placebo-controlled fashion. This may pave the way for a new approach combining the appealing rationale and proven efficacy of conventional psychotherapy with the rigor and leverage of clinical neuroscience.

Towards an unconscious neural reinforcement intervention for common fears

Toward a comprehensive understanding of the neural mechanisms of decoded neurofeedback

Identifying multivariate patterns for illusory color perception using decoded fMRI neurofeedback

Decoded fMRI neurofeedback can induce bidirectional confidence changes within single participants

Humans often assess their confidence in their own perception, e.g., feeling "confident" or "certain" of having seen a friend, or feeling "uncertain" about whether the phone rang. The neural mechanism underlying the metacognitive function that reflects subjective perception still remains under debate. We have previously used decoded neurofeedback (DecNef) to demonstrate that manipulating the multivoxel activation patterns in the frontoparietal network modulates perceptual confidence without affecting perceptual performance. The results provided clear evidence for a dissociation between perceptual confidence and performance and suggested a distinct role of the frontoparietal network in metacognition.

Can evolutionarily ‘hardwired’ fear responses, e.g. for spiders and snakes, be reprogramed unconsciously in the human brain? Currently, exposure therapy is amongst the most effective treatments for anxiety disorders1, but this intervention is subjectively aversive to patients, and rates of premature attrition from treatment have been reported to be as high as 70%2. Here we introduce a novel method to bypass the subjective unpleasantness in conscious exposure, by directly pairing monetary reward with unconscious occurrences of decoded representations of naturally feared objects in the brain. The typical way to identify multivoxel functional magnetic resonance imaging (fMRI) representations for feared objects involves repeated presentations of the relevant images explicitly to subjects. However, for our potential treatment method to be effective in actual clinical settings, we need to decode fear representations without triggering excessively aversive reactions which may cause patients to dropout from treatments prematurely. Here we overcome this challenge by capitalizing on recent advancements in fMRI decoding techniques: We employed a method called hyperalignment3,4 to infer the relevant representations of feared objects for a designated participant based on data from other ‘surrogate’ participants. This way the procedure completely bypasses the need for the conscious encountering of feared objects. We demonstrate that our method can lead to reliable reductions in physiological fear responses measured by skin conductance as well as amygdala hemodynamic activity. Not only do these results raise the intriguing possibility that naturally occurring fear can be ‘re-programmed’ outside of conscious awareness, importantly they also created the rare opportunity for a psychological intervention of this nature to be tested rigorously in a double-blind placebo-controlled fashion. This may pave the way for a novel treatment method, combining the appealing rationale and proven efficacy of conventional psychotherapy with the rigor and leverage of clinical neuroscience.

​ Can evolutionarily ‘hardwired’ fear responses, e.g. for spiders and snakes, be reprogramed unconsciously in the human brain? Currently, exposure therapy is amongst the most effective treatments for anxiety disorders​1​, but this intervention is subjectively aversive to patients, and rates of premature attrition from treatment have been reported to be as high as 70%​2​. Here we introduce a novel method to bypass the subjective unpleasantness in conscious exposure, by directly pairing monetary reward with unconscious occurrences of decoded representations of naturally feared objects in the brain. The typical way to identify multivoxel functional magnetic resonance imaging (fMRI) representations for feared objects involves repeated presentations of the relevant images explicitly to subjects. However, for our potential treatment method to be effective in actual clinical settings, we need to decode fear representations ​without​ triggering excessively aversive reactions which may cause patients to dropout from treatments prematurely. Here we overcome this challenge by capitalizing on recent advancements in fMRI decoding techniques:​ ​We employed a method called hyperalignment​3,4​ to infer the relevant representations of feared objects for a designated participant based on data from other ‘surrogate’ participants. This way the procedure completely bypasses the need for the conscious encountering of feared objects. We demonstrate that our method can lead to reliable reductions in physiological fear responses measured by skin conductance as well as amygdala hemodynamic activity. Not only do these results raise the intriguing possibility that naturally occurring fear can be ‘re-programmed’ outside of conscious awareness, importantly they also created the rare opportunity for a psychological intervention of this nature to be tested rigorously in a double-blind placebo-controlled fashion. This may pave the way for a novel treatment method, combining the appealing rationale and proven efficacy of conventional psychotherapy with the rigor and leverage of clinical neuroscience. 2 . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/170183 doi: bioRxiv preprint first posted online Jul. 30, 2017;

Fear reduction without fear through reinforcement of neural activity that bypasses conscious exposure

1. Dept. of Decoded Neurofeedback, ATR Cognitive Mechanisms Laboratories, Address: 22-2, Hikaridai, Seika-cho, Sorakugun, Kyoto, 619-0288, JAPAN 2. Dept. of Psychology, Columbia University, Address: 1190 Amsterdam Ave. 370 Schermerhorn Ext. MC:5501, New York, 10027, USA 3. Center for Information and Neural Networks (CiNet), NICT, Address: 1-4 Yamadaoka, Suita City, Osaka, 565-0871, JAPAN 4. Graduate School of Information Science, Nara Institute of Science and Technology, Address: 8916-5 Takayama, Ikoma Nara, 630-0192, JAPAN 5. Dept. of Psychology, UCLA, Address: BOX 951563, Los Angeles, CA 90095-1563, USA 6. Dept. of Psychology, Graduate School of Environmental Studies, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, JAPAN 464-8601, JAPAN 7. Brain Research Institute, UCLA, Address: Box 951761, Los Angeles, CA 90095-1761, USA 8. Dept. of Engineering, University of Cambridge, Address: Trumpington St, Cambridge CB2 1PZ, UK 9. These authors contributed equally to this work

Fear reduction without fear: Reinforcement of neural activity bypasses conscious exposure

Online fMRI Decoded Neurofeedback to Explore Metacognition and Awareness

Studies using real-time functional magnetic resonance imaging (rt-fMRI) have recently incorporated the decoding approach, allowing for fMRI to be used as a tool for manipulation of fine-grained neural activity. Because of the tremendous potential for clinical applications, certain questions regarding decoded neurofeedback (DecNef) must be addressed. Neurofeedback effects can last for months, but the short- to mid-term dynamics are not known. Specifically, can the same subjects learn to induce neural patterns in two opposite directions in different sessions? This leads to a further question, whether learning to reverse a neural pattern may be less effective after training to induce it in a previous session. Here we employed a within-subjects' design, with subjects undergoing DecNef training sequentially in opposite directions (up or down regulation of confidence judgements in a perceptual task), with the order counterbalanced across subjects. Behavioral results indicated that the manipulation was strongly influenced by the order and direction of neurofeedback. We therefore applied nonlinear mathematical modeling to parametrize four main consequences of DecNef: main effect of change in behavior, strength of down-regulation effect relative to up-regulation, maintenance of learning over sessions, and anterograde learning interference. Modeling results revealed that DecNef successfully induced bidirectional behavioral changes in different sessions. Furthermore, up-regulation was more sizable, and the effect was largely preserved even after an interval of one-week. Lastly, the second week effect was diminished as compared to the first week effect, indicating strong anterograde learning interference. These results suggest reinforcement learning characteristics of DecNef, and provide important constraints on its application to basic neuroscience, occupational and sports trainings, and therapies.

Decoded fMRI neurofeedback can induce bidirectional behavioral changes within single participants

Multivoxel neurofeedback selectively modulates confidence without changing perceptual performance

Keywords: Cultures et diversite ; Going East ; Section SV Reference EPFL-STUDENT-180848 Record created on 2012-08-17, modified on 2017-05-12

Background Rib fractures are associated with significant morbidity and mortality in polytraumatized patients. There is considerable variability in the management (operative vs. non-operative) and timing of operative intervention. Although Eastern Association for the Surgery of Trauma (EAST) guidelines recommend early operative intervention in patients with flail chest, there are no strong recommendations regarding operative fixation in patients with a non-flail chest rib fracture pattern. Methods We reviewed our Trauma Quality Improvement Program database for patients aged 18 to 99 who underwent operative intervention of ribs from January 2016 to July 2019. We examined hospital length of stay (LOS), intensive care unit (ICU) LOS, ventilator days, Injury Severity Score, age, discharge disposition and packed red blood cell transfusions. Similarly, we collected data from patients aged 18 to 99 who had one or more rib fractures in this time frame. We compared results in a 4:1 ratio of patients managed non-operatively to patients managed operatively. The patient groups were matched based on age, number of rib fractures and presence of bilateral rib fractures. Results Between January 2016 and July 2019, 33 of 4189 total patients diagnosed with rib fractures underwent operative fixation; the matched non-operative group consisted of 132 patients. The statistically significant differences included presence of bilateral rib fractures, displaced rib fractures and flail chest segments. The median ICU days were longer in the operative group (6.0 vs. 3.5 days). A subgroup analysis of patients without flail segments demonstrated a significant presence of displaced rib fractures. Our single-institution matched comparison of outcomes in operative intervention versus Non-operative Management (NOM) of rib fractures found an increased median number of ICU days. Patients who underwent operative intervention often stayed in the ICU preoperatively and postoperatively for aggressive pulmonary hygiene and pain control, suggesting observer bias. The increased incidence of displaced rib fractures and the presence of a flail segment in the operative group demonstrate congruence with EAST guidelines. A subgroup analysis of patients without flail segment did not demonstrate differences in outcomes nor shoulder girdle injury characteristics. Level of evidence This article presents level III evidence that can be used by other clinicians to analyze eligibility for patients to undergo surgical stabilization of rib fracture (SSRF) and to provide counterarguments for performing SSRF in a heterogenous group of patients.

Plate of ribs: single institution’s matched comparison of patients managed operatively and non-operatively for rib fractures

The surgeon : journal of the Royal Colleges of Surgeons of Edinburgh and Ireland

Quetiapine for delirium prophylaxis in high-risk critically ill patients.

Foreign body ingestion most commonly occurs in the pediatric population, with approximately 80–90% of objects passing spontaneously in individuals who are evaluated by medical professionals. Objects may be lodged in a variety of anatomic locations. Only about 10% of foreign bodies progress past the stomach. Of the 10–20% of objects that fail to pass, less than 1% requires surgical intervention. Small bowel obstructions are a rare presentation of foreign body ingestions. There are case reports, guidelines, and retrospective reviews in the literature regarding the management of ingested foreign bodies. In patients who do not have spontaneous passage of foreign bodies, endoscopic and surgical techniques have been utilized for successful retrieval. The timing and indication for endoscopic intervention is dependent upon several factors, including the type and location of the foreign body and is also contingent upon patient symptoms. Numerous case reports and studies describe the successful endoscopic removal of foreign bodies in the upper and lower gastrointestinal tract. Although the type and location of an ingested object is critical for determining the success of endoscopic intervention, the patient’s clinical exam and stability is also an aspect to consider when deciding on management of bowel obstructions caused by foreign bodies.

Background Enhanced recovery after surgery (ERAS) protocols are widely utilized for elective colorectal surgery to improve outcomes and decrease costs, but few studies have evaluated the impact of ERAS protocols on cost with respect to anatomic site of resection. This study evaluated the impact of ERAS protocol on elective colon resections by site and longitudinal impact over time. Methods A single-center retrospective cohort study of 598 consecutive patients undergoing elective colorectal resection before and after implementation of ERAS protocol from 2013 to 2017 was performed. The primary outcomes were length of stay (LOS) and cost. Comparative and multivariate inferential statistics were used to assess additional outcomes. Results A total of 598 patients (100 pre-ERAS vs 498 post-ERAS) were evaluated with an overall median LOS of 4 days for right and left colectomies and 3 days for transverse colectomies. When comparing type of resection before and after ERAS protocol introduction, an increased LOS for left hemicolectomies from 3.09 to 4.03 days (P = .047) was noted, with all other comparisons failing to reach statistical significance. Over time, an initial decrease in LOS for MIS approach after protocol introduction was observed; however, this effect diminished in the ensuing years and had no significant effect overall. Total cost of care was significantly increased post-ERAS for all cohorts except transverse colectomies. No further statistically significant differences were found. Conclusion After an initial improvement in outcomes, continued utilization of ERAS protocols demonstrated no improvement in LOS compared to pre-ERAS data and increased cost overall for patients regardless of site of resection.

Effect of Enhanced Recovery After Surgery Protocol Implementation on Cost and Outcomes by Type of Colectomy Performed

Dexmedetomidine versus propofol for prolonged sedation in critically ill trauma and surgical patients.

Foreign body ingestion most commonly occurs in the pediatric population, with approximately 80 to 90 per cent of objects passing spontaneously in individuals who are evaluated by medical professionals.1 Although objects may be lodged in a variety of anatomic locations, including the oropharynx and esophagus, the stomach is the most common location of foreign bodies at initial presentation. Only about 10 per cent of foreign bodies progress past the stomach. Of the 10 to 20 per cent of objects that fail to pass, less than 1 per cent require surgical intervention.1 Small bowel obstructions are a rare presentation of foreign body ingestions. There are published case reports, guidelines, and retrospective reviews in the literature regarding the management of ingested foreign bodies. Many of the publications focus on the use of endoscopic interventions in the pediatric population. In patients who do not have spontaneous passage of foreign bodies, endoscopic and surgical techniques have been used for successful retrieval. The timing and indication for endoscopic intervention are dependent on several factors, including the type and location of the foreign body,1 and are also contingent on patient symptoms. Those experiencing symptoms related to oropharyngeal obstruction require emergent intervention. Patients with a foreign body located in the distal esophagus may experience dysphagia or choking. In 1991, Berman et al.2 reported on the successful endoscopic retrieval of a button gastrostomy tube that was causing a small bowel obstruction at the ileocecal valve. Numerous case reports and studies in the literature describe the successful endoscopic removal of foreign bodies in the upper and lower gastrointestinal tract. Although the type and location of an ingested object are critical for determining the success of endoscopic intervention, the patient’s clinical examination and stability are also an important aspect to consider when deciding on appropriate management. A 35-year-old woman with cerebral palsy and pica presented to the ED with bright red blood in her colostomy bag. She was mildly distended and had a functioning gastrostomy tube in her left upper quadrant. Her vitals and laboratory results were normal. With a benign physical examination, she underwent a CT scan of the abdomen and pelvis to further evaluate her signs and symptoms. The CT scan (Fig. 1) demonstrated a second gastrostomy tube with the balloon inflated in the terminal ileum, causing a partial small bowel obstruction. General surgery was consulted for further recommendations regarding management. With general surgery immediately available to provide assistance, the patient underwent colonoscopy through her previously existing colostomy. During endoscopic examination, the ingested gastrostomy tube was easily visualized and able to be successfully retrieved (Fig. 2); however, the colonoscopy also revealed a cecal mass for which biopsies were obtained. Her small bowel obstruction resolved after removal of the foreign body. Biopsies of the cecal mass returned adenocarcinoma. The patient underwent further outpatient workup of her colon cancer. She returned and underwent an open right hemicolectomy. Her procedure went well, and she was discharged on postoperative day three. Final pathology diagnosis revealed T3 N0 M0 colon adenocarcinoma. Although the occurrence of foreign body ingestions is most common in the pediatric population, it also occurs in prisoners, intoxicated individuals, and adults with psychiatric disorders and developmental delay.1 More than 100,000 foreign body ingestions are reported each year, with estimated mortality rates around 3 per cent.3 In the literature, there is a wide range of ingested objects that may become lodged in different anatomic areas of the gastrointestinal tract. The distal small intestine at the ileocecal valve is a common place for objects to fail to pass and require intervention. The Address correspondence and reprint requests to Jessica E. Taylor, M.D., M.B.A., University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Box U-11, Knoxville, TN 37920. E-mail: jtaylor4@utmck.edu.

The Management of Small Bowel Obstruction Caused by Ingested Gastrostomy Tube

Depressive symptoms reduce when dorsolateral prefrontal cortex-precuneus connectivity normalizes after functional connectivity neurofeedback

The effect of effort on reward prediction error signals in midbrain dopamine neurons

Corrigendum: An Evolutionarily Threat-Relevant Odor Strengthens Human Fear Memory

A reciprocal inhibition model of alternations between under-/overemotional modulatory states in patients with PTSD

Olfaction is an evolutionary ancient sense, but it remains unclear to what extent it can influence routine human behavior. We examined whether a threat-relevant predator odor (2-methyl-2-thiazoline) would contextually enhance the formation of human fear memory associations. Participants who learned to associate visual stimuli with electric shock in this predator odor context later showed stronger fear responses to the visual stimuli than participants who learned in an aversiveness-matched control odor context. This effect generalized to testing in another odor context, even after extinction training. Results of a separate experiment indicate that a possible biological mechanism for this effect may be increased cortisol levels in a predator odor context. These results suggest that innate olfactory processes can play an important role in human fear learning. Modulatory influences of odor contexts may partly explain the sometimes maladaptive persistence of human fear memory, e.g., in post-traumatic stress disorders.

An Evolutionarily Threat-Relevant Odor Strengthens Human Fear Memory

Objective Traumatic life-events can leave individuals with contrasting posttraumatic stress disorder (PTSD) symptoms, including re-experiencing and avoidance. Notably, patients with PTSD are known to periodically switch between two opposing attentional biases; namely, toward threat and away from threat. We hypothesized that reciprocal inhibition between the amygdala and ventromedial prefrontal cortex (vmPFC) may induce alternations between these attentional biases, which in turn may contribute to the re-experiencing and avoidance symptoms, respectively. Methods To test this reciprocal inhibition model, we performed an experiment to measure the attentional biases of patients with PTSD. We examined the differential relationships between PTSD symptom clusters (re-experiencing/avoidance) and attentional biases (toward/away from threat). Additionally, we performed a meta-regression analysis to examine the role of amygdala reactivity in the imbalance between re-experiencing and avoidance symptoms. Results We found that attentional bias toward threat was selectively associated with re-experiencing symptoms whereas attentional bias away from threat was selectively associated with avoidance symptoms. Meta-regression analysis based on twelve participant populations (total N = 316) revealed that left amygdala activity was positively correlated with the severity of re-experiencing symptoms relative to avoidance symptoms. Conclusions Our findings support the hypothesis that reciprocal inhibition of common neural circuits may underlie the switch between attentional biases toward and away from threat as well as that between re-experiencing and avoidance symptoms. Re-experiencing and avoidance/emotional numbing are the core symptoms used to distinguish between the non-dissociative and dissociative PTSD subtypes. The reciprocal inhibition mechanism may help elucidate the mechanisms underlying those PTSD subtypes.

A reciprocal inhibition model of alternations between non-dissociative and dissociative states in patients with PTSD

Reward value enhances post-decision error-related activity in the cingulate cortex

In a complex and uncertain world, how do we select appropriate behavior? One possibility is that we choose actions that are highly reinforced by their probabilistic consequences (model-free processing). However, we may instead plan actions prior to their actual execution by predicting their consequences (model-based processing). It has been suggested that the brain contains multiple yet distinct systems involved in reward prediction. Several studies have tried to allocate model-free and model-based systems to the striatum and the lateral prefrontal cortex (LPFC), respectively. Although there is much support for this hypothesis, recent research has revealed discrepancies. To understand the nature of the reward prediction systems in the LPFC and the striatum, a series of single-unit recording experiments were conducted. LPFC neurons were found to infer the reward associated with the stimuli even when the monkeys had not yet learned the stimulus-reward (SR) associations directly. Striatal neurons seemed to predict the reward for each stimulus only after directly experiencing the SR contingency. However, the one exception was “Exclusive Or” situations in which striatal neurons could predict the reward without direct experience. Previous single-unit studies in monkeys have reported that neurons in the LPFC encode category information, and represent reward information specific to a group of stimuli. Here, as an extension of these, we review recent evidence that a group of LPFC neurons can predict reward specific to a category of visual stimuli defined by relevant behavioral responses. We suggest that the functional difference in reward prediction between the LPFC and the striatum is that while LPFC neurons can utilize abstract code, striatal neurons can code individual associations between stimuli and reward but cannot utilize abstract code.

Dissociable functions of reward inference in the lateral prefrontal cortex and the striatum

We used straightforward linear mixed effects models as described in Worsley et al. together with recent advances in smoothing to control the degrees of freedom, and random field theory based on discrete local maxima. This has been implemented in BRAINSTAT, a Python version of FMRISTAT. Our main novelty is voxel‐wise inference for both magnitude and delay (latency) of the hemodynamic response. Our analysis appears to be more sensitive than that of Dehaene‐Lambertz et al. Our main findings are greater magnitude (1.08% ± 0.17%) and delay (0.153 ± 0.035 s) for different sentences compared to same sentences, together with a smaller but still significantly greater magnitude for different speaker compared to same speaker (0.47% ± 0.08%). Hum Brain Mapp, 2006. © 2006 Wiley‐Liss, Inc.

Inference for magnitudes and delays of responses in the FIAC data using BRAINSTAT/FMRISTAT

EL MAQUETADO EN EL DESARROLLO DE APLICACIONES MÓVILES (ING. EN TIC’S EN EL TECNM CAMPUS APIZACO)

The automotive industry sector, made up of the assembly activities of all types of vehicles and the production of auto parts, has a wide variety of companies that contribute to the dynamics of the world economy, therefore, in this  project It is sought by simulating discrete events to create a digital twin where faults in the motorcycle assembly process can be identified, in this way it will be possible to detect any observed nonconformity and thus reduce pertinently all the faults presented, taking into account the exogenous factors that can increase operational costs and delay the assembly process, on this case, we want to implement an optimal model by simulating the process without assembly failures in times of pandemic, this in order to analyze and propose improvements in the process whose objective is strengthen decision-making in favor of customer satisfaction. At the end of this study, it was found that the assembly problems were more related to the reduction of personnel due to preventive isolation and delays in the preparation process, due to this it was recommended to reduce preparation times from 5 to 3.5 hours in order to start the assembly in less time and have the safety stock immediately in case of damage to the auto parts.

Un Modelo digital para la identificación de restricciones en el proceso de ensamblaje de motocicletas

Espirometria Forzada (EF), tecnica focalizada en explorar la funcion ventilatoria pulmonar medida a partir de la cantidad de aire que pueden retener durante el simulacro de espiracion obligada. Objetivo: determinar los valores de Volumen Espiratorio Forzado en el primer segundo (FEV1) y Capacidad Vital Forzada (FVC) normales/estandar en estudiantes de la Universidad de Guayaquil, entre 18 a 25 anos de edad, identificando los principales factores de riesgo causantes de la disminucion de la funcion pulmonar, comparables en la postpandemia COVID 19. Estudio epidemiologico de corte trasversal desarrollado durante Octubre 2018 - Marzo 2019. De un universo de 63.000 estudiantes, la muestra seleccionada al azar segun los criterios de inclusion de Mart Elkin fueron 715 estudiantes de Administracion, Ciencias Medicas y Jurisprudencia. La tecnica de recoleccion de datos fue la guia de observacion, siendo tabulados en Microsoft Excel2010, aplicando estadistica descriptiva con medidas de tendencia central. Resultados reflejaron que 83,644% oscila entre 18 y 23 anos, un 50,77% fueron del sexo femenino siendo este grupo etario el de menor estatura de los grupos estudiados. El 32,87% tiene sobrepeso u obesidad. Aunque el 75% no tiene el habito de fumar, Ciencias Medicas mostro 0,44% de los fumadores. La escala de severidad FVC es normal ubicandose >80 con coeficiente FVC1/ FVC para ambos sexos. Los valores espirometricos permiten decidir a partir de criterios clinicos cual, cuando y por que aplicar una terapia respiratoria lo que constituye un recurso valioso en tiempos de postpandemia Covid 19.

Espirometría forzada en estudiantes de 18 a 25 años de la Universidad de Guayaquil: Valores referenciales a considerar en la post pandemia COVID 19

espanolEl crecimiento que han experimentado en los ultimos anos los eventos deportivos exige a los organizadores a ser sensibles a las opiniones de los participantes, con el proposito de elaborar estrategias adecuadas para una gestion exitosa de los eventos deportivos. El objetivo del estudio era evaluar la calidad e impacto percibido por los deportistas del Campeonato de Espana de Descenso de Canones de 2019. Participaron 52 deportistas, 74% hombres y 26% mujeres, con una edad media de 36.26±8.86 anos. Se utilizo un cuestionario para la recogida de datos con tres secciones: datos socio-deportivos, calidad-satisfaccion, e impacto-repercusion. Los participantes reportaron una alta satisfaccion con el evento, y perciben el acontecimiento como generador de impactos positivos en el territorio en que se celebra. En relacion al impacto economico, la estimacion de gasto en el evento reportada directamente por los encuestados fue de 252,61€. La evaluacion de la calidad e impacto, es una estrategia util para los organizadores de eventos deportivos, tanto en la mejora y diseno de sus servicios, asi como muestra de evidencia de las inversiones realizadas por patrocinadores y administraciones. EnglishThe growth experienced by sports events during last years demands that managers need to be sensitive to the opinions of participants in order to develop appropriate strategies for the successful management of those sports events. This study aimed to evaluate the quality and perceived impact by the athletes of the Canyoning Championship of Spain in 2019. Fifty-two athletes participated, 74% men and 26% women, with a mean age of 36.26±8.86 years. A questionnaire including three sections was used for data collection: socio-sports data, quality-satisfaction, and impact-repercussion. Participants reported a high level of satisfaction with the event, and perceived the event as a generator of positive impacts on the territory where it was held. In relation to the economic impact, the estimated expenditure on the event reported directly by the respondents was €252.61. The evaluation of quality and impact is a useful strategy for the organisers of sports events, both in the improvement and design of their services and as well as evidence of the investments made by sponsors and administrations.

Revista Iberoamericana de Ciencias de la Actividad Física y el Deporte

Evaluación de eventos deportivos: el caso del campeonato de España de descenso de cañones 2019

The problem of reductionism is a perennial issue in the history and philosophy of science. In view of the polysemy of the term and the problems arising from naming an author or a theoretical current in science as a reductionist, this theoretical essay sought to assess what types of reductionist propositions Skinnerian thought is opposed to and which ones it approaches, under the justification of seeking to reduce mistakes in the use of this adjective to the thought of Skinner. To this purpose, a conceptual analysis of his extensive theoretical work was carried out, with regard to the possibility of being categorized as reductionist. Except period prior to the publication of Skinner's first book in 1938, three categories of reductionism were found discussed in Skinner's work. In the first meaning, Skinner stands against reductionism of derivational conduction, in the second, he stands against reductionism as oversimplification and, finally, a third function for the debate was introduced by identifying him as a defender of nomological status of behavior. It is concluded that to assign the label of reductionist to Skinner's thought is not a mistake, once this idea can change according to the reductionism type presented. Just one of three reductionism types, which one refers to a defense of the nomological status of behavior, share similarities with Skinner’s thoughts. The other two types, that are derivational and oversimplification, can be considered incompatible with the Skinnerian proposal of science. Keywords: behavior analysis; Skinner; reductionism; reduction; conceptual analysis.

A Serra da Jiboia abriga um dos ultimos fragmentos do norte da Mata Atlântica Brasileira, cobrindo uma regiao de 440 km 2 , com uma proposta em andamento para a criacao de uma Unidade de Conservacao. O contexto geologico e geomorfologico unico contribuiu para transformar a Serra da Jiboia em um refugio ecologico isolado no Estado da Bahia. A peculiaridade da Serra tambem explica a presenca de nascentes de rios importantes do Estado: Dona, Jiquirica, Paraguacu e Jaguaripe. A Serra e uma barreira orografica, limite entre clima seco e umido, e a regiao ao redor e explorado para atividades antropogenicas, principalmente a agricultura. Este estudo teve como objetivo caracterizar o relevo e a morfometria das bacias hidrograficas da Serra da Jiboia como uma das acoes fundamentais para apoiar a preservacao dos ultimos fragmentos florestais. Foram analisados: declividade, razao de relevo, terreno e curvatura da encosta, orientacao da encosta, curvas hipsometricas, coeficiente de compactacao (Kc), fator de forma (F), densidade de drenagem (Dd), densidade de drenagem (Dd), densidade hidrografica (Dh), numero de canais (N) e sinuosidade (S). Observamos a predominância de areas com rampa para declive acentuado e presenca de bacias mais jovens em areas de maior declive. A predominância de canais de primeira ordem mostra a fragilidade hidrologica do ecossistema da Serra e a baixa sinuosidade dos rios das principais bacias indica potenciais escoamento superficial, erosao e perda de solos. Concluimos que as caracteristicas geologicas e geomorfologicas sao aspectos fundamentais que comprovam a necessidade de manutencao da vegetacao natural para a conservacao do solo e da agua. Aspectos geomorfologicos e hidrograficos da Serra da Jiboia, Bahia A B S T R A C T The Jiboia Range is one of the last northern fragments of Brazilian Atlantic Tropical Forest, covering a 440 km 2 region, with an ongoing proposal for the creation of a Conservation Unit. The unique geological and geomorphological context contributed to transforming the Jiboia Range into an isolated ecological refuge in Bahia State. The peculiarity of the range also explains the presence of important river sources of the State: Dona, Jiquirica, Paraguacu, and Jaguaripe Rivers. The range is an orographic barrier, separating dry from and humid climate, then the surrounding environment is exploited for anthropogenic activities, mainly agriculture. This study aims to characterize the relief and morphometry of the watersheds in the Jiboia Range as one of the fundamental actions to support the preservation of last forest fragments. We analysed: slope aspect, relief ratio, terrain, and slope curvature, slope orientation, hypsometric curves, compactness coefficient (Kc), form factor (F), drainage density (Dd), hydrographic density (Dh), number of channels (N) and sinuosity (S). We observed the predominance of areas with rolling to steep slope and presence of younger basins in areas of higher slope. The predominance of first-order channels showed the hydrological fragility of the ecosystem of the range and the low sinuosity of the rivers of the main basins indicates potential surface runoff, erosion and soil loss. We concluded that the geological and geomorphological characteristics are fundamental aspects that prove the need to maintain natural vegetation for soil and water conservation. Keywords: tropical rainforest, soil fragility, conservation unit

Aspectos geomorfológicos e hidrográficos da Serra da Jiboia, Bahia

Estudio de coordinación de protecciones en la empresa TECNOGLASS S.A.

Identificación de Hongos y/o Bacterias Fitopatógenas Transportados por la Cochinilla (Capulinia sp), en el Cultivo de Guayaba (Psidium guajava), del Predio el Tahur y la Banqueta de la Universidad de los Llanos-Villanueva Casanare

Se informa el caso de una paciente portadora de fistula arteriovenosa del cuello, con el antecedente de traumatismo al nivel de la region mastoidea izquierda a la edad de 6 anos y formacion de un hematoma, lo que indica el origen traumatico de su afeccion. La paciente presenta otras anomalias congenitas como el arco aortico a la derecha y la estenosis del tronco venoso braquiocefalico izquierdo, lo que pudiera sustentar el criterio de que esta sea congenita, ya que las fistulas arteriovenosas congenitas van asociadas frecuentemente a otras anoma'ias. Se indica que de acuerdo con los resultados del cateterismo cardiaco no se hubiera llegado mas alla del diagnostico de persistencia del conducto arterioso, pero la presencia del soplo sistolico tan alto (en region mastoidea izquierda) y la circulacion venosa superficial aumentada, crearon cierta inquietud que llevo a la realizacion de un estudio angiografico que condujo al diagnostico correcto de fistula arteriovenosa de la rama occipital de la carotida externa izquierda. Se revisa la bibliografia acerca de esta entidad poco frecuente entidad nuestro pais.

Fístula arteriovenosa del cuello. Presentación de un caso y revisión de la literatura

La crisis climática y ecológica presenta un cuadro crítico en todo el mundo. No son suficientes los acuerdos climáticos establecidos a lo largo de estos años como forma de mitigación, adaptación y prevención a los impactos resultado de los efectos del cambio climático como iniciativas entre otras, del programa de Naciones Unidas para el ambiente. Científicos e investigadores lo consideran como una nueva Era Geológica, o Antropoceno. Justificando la responsabilidad humana, como un todo en relación a los cambios globales y se considera la interferencia humana como aspecto que prevalece en la crisis ambiental. Dentro de este espectro, la investigación vislumbra posicionar una reflexión crítica en relación a los actores realmente responsables, ubicando el Capitaloceno como una forma de perpetuar un sistema económico que reproduce desigualdades y privilegios. Diferentes organizaciones impulsan la llamada economía verde, como estrategia para ocultar el verdadero papel de las corporaciones en esta crisis y hacer compatible el capitalismo con la ecología.  Estos factores se relacionan además con los conceptos de justicia ambiental y racismo ambiental, reflejados en las condiciones que enfrenta esta crisis, siendo un factor determinante de opresion en los pueblos principalmente de personas negras y pobres. En las tierras del sur global, el capitalismo se potencia también con otros sistemas de opresión y patriarcado que perpetúan esta larga historia de violencia y despojo.

Justicia Ambiental, Capitaloceno y Cambio Climático en Brasil y Colombia. Reflexión crítica

Los estudiantes lograron realizar su practica empresarial en la empresa CONSTRUMAC INGENIEROS S.A.S, brindandoles confianza, inducciones y experiencia en el entorno laboral como supervisores tecnicos y administrativos en el contrato de consultoria 89 de 2019 cuyo objeto es “consultoria a todo costo para realizar la interventoria tecnica, administrativa y financiera del proyecto denominado “rehabilitacion de vias terciarias, vias para la paz, mediante la construccion de placas huella en algunas veredas de la zona rural del municipio de Santa Maria - Huila”. 
 
Los profesionales de la empresa CONSTRUMAC INGENIEROS S.A.S, integraron a la organizacion los practicantes al sitio de trabajo, realizandoles induccion donde se ofrecieron conocimientos basicos para la realizacion de sus actividades de supervision tecnica y administrativo de la obra, posterior a ello los practicantes estudiaron y analizaron los documentos pertinentes al contrato en referencia, colocando a prueba sus conocimientos teoricos que adquirieron en su formacion universitaria las cuales fueron presupuestos, analisis de precios unitarios, cantidades de obra, programacion de obra, interpretacion de planos, control de calidad, procesos constructivos para vias, legalizacion de un contrato y la etica profesional. Consecutivamente se procede a fortalecer las labores en obra por lo tanto los practicantes aplicaron sus conocimientos teorico-practicos en la realizacion de ensayos de materiales y construccion de obras civiles cumpliendo con las actividades segun el cargo de supervisores tecnicos y administrativos.

Supervisión tecnica y administrativa de apoyo a los contratos en ejecución por la empresa construmac ingenieros s.a.s

El estudio fue desarrollado en la provincia de Oxapampa region Pasco, tuvo como finalidad de determinar la fertilidad de suelo en plantaciones forestales y en agroecosistema degradado en la selva central de Oxapampa, Pasco. El tipo de investigacion fue descriptiva, diseno no experimental, la poblacion estuvo constituida por todos los suelos de la provincia, el tamano de muestra estuvo representada por diez puntos donde se muestreo el suelo de los sectores considerados. Se preparo 10 calicatas (5 en cada sector), se extrajo muestras de suelos a profundidades de 0 a 20 cm y de 21 a 60 cm, las muestras fueron analizadas en el Laboratorio de Suelos de la Universidad Nacional Agraria La Molina. Los resultados en cuanto a la variable fertilidad natural han encontrado que en los suelos bajo plantacion de eucaliptos es ligeramente mejor que en el resto de los suelos con un grado medio, lo que permite aseverar que, la biomasa producida por las especies introducidas en el proceso de reforestacion tiene un bajo porcentaje de mineralizacion que impide su incorporacion a los suelos. Se concluye que la fertilidad natural de los suelos han permito clasificarlos como suelos pobres en el caso del agroecosistema degradado, bosque secundario, bosque de cipreses y bosques de eucaliptos y solamente los suelos con bosque de eucaliptos son de mediana fertilidad natural

Fertilidad natural del suelo en plantaciones forestales y en agroecosistema degradado en selva central Oxapampa Pasco

Cardiopatias congénitas no período neonatal - estudo retrospectivo

La Direccion de Impuestos y Aduanas nacionales DIAN tiene como objetivo principal velar, administrar y controlar el cumplimiento de las obligaciones tributarias, aduaneras y cambiarias del estado colombiano. Dentro de los procesos tributarios, la DIAN cuenta con un G.I.T. de Asistencia al cliente, donde se lleva a cabo la practica social, empresarial y solidaria compartida por dos estudiantes de la Universidad Cooperativa de Colombia del programa de Administracion de empresas, apuntando hacia UN FOMENTO EFICIENTE DE LA CULTURA TRIBUTARIA EN EL DEPARTAMENTO DE ARAUCA, conociendo anticipadamente las normas y la actual situacion del conocimiento en las areas tributarias. 
El departamento de G.I.T Gestion de Asistencia al Cliente es el encargado de orientar y brindar asesoria personalizada al ciudadano cliente con respecto a los tramites necesarios para el cumplimiento de obligaciones tributarias. 
Para la ejecucion de esta practica social, empresarial y solidaria, se toma como referencia el problema que actualmente se evidencia en los contribuyentes y es el desconocimiento de la cultura tributaria, la cual presta sus servicios por tres medios a nivel nacional como lo son el medio presencial, telefonico y los servicios informaticos. Tambien es parte de la cultura tributaria el nuevo sistema de Agendamiento virtual de citas que se creo con el fin de realizar solicitud de tramites como la Inscripcion y/o Actualizacion de RUT para personas Naturales y Juridicas, la Emision o Renovacion de Firma electronica y Solicitudes Especiales (Cambio de regimen, cese de actividades en ventas o cancelacion del RUT). 
4 
El proposito de la practica social, empresarial y solidaria en la Direccion de Impuestos y Aduanas Nacionales DIAN –Seccional Arauca- es facilitar la comprension del Sistema Tributario al Ciudadano Cliente, con el apoyo de las estudiantes, desarrollando estrategias que se pueden ejecutar para el mejoramiento del servicio con el objetivo de garantizar el cumplimiento voluntario de sus responsabilidades por parte de los Ciudadanos Clientes.

La cultura tributaria en los ciudadanos clientes de la dirección seccional de impuestos y aduanas de Arauca – Dian-, a través del grupo interno de trabajo (G.I.T.) de gestión de asistencia al cliente

The development of the computer industry in recent years has brought with it novelty social conflicts typical of a postindustrial society, configuring a favourable environment for the emergence of new social actors. The objective of the present work is to elaborate an exploratory study about the communities of free software in Argentina today, considering how they are composed on different dimensions (such as cooperativism, research, recreation, commercial exchange, among others); constituting diverse goals and interests, and are developed in multiple geographic areas. The central question of the study is how the coordination, interaction and communication between these associations can manage them as a social movement that  introduces the discussion for an alternative model against the dominant model of private appropriation of informatics, basing it on a certain ethical and political conflict vision. For this approach, we will indagate over the actor’s experiences contexts and the intra-organizational arenas that are generated among these groups, also using the concept of multiple-positions to understand the different forms of activist’s commitment and the diverse perspectives that circulate inside of them. The information was collected by semi- structured interviews, bibliographic revision, and secondary data analysis.

Las comunidades alrededor del software libre y su articulación como movimiento social. El caso argentino

Atención de los pacientes con trauma grave durante los primeros días: evolución entre la urgencia, el pabellón y la unidad de cuidados intensivos

La hipertensión es una causa mayor de discapacidad y muerte a nivel mundial. El conocimiento de los pacientes es un factor importante para modificar conceptos erróneos y el riesgo que constituye la hipertensión como condicionante de daño cardiovascular. Objetivo: Describir los conocimientos, actitudes y prácticas de pacientes hiperten- sos de la comunidad de San José de Boque- rón, San Pedro Sula, julio del 2018. Pacien- tes y Métodos: Estudio descriptivo de corte transversal cuantitativo. La muestra fue de 30 pacientes con hipertensión arterial, seleccionados a través de muestreo no probabilístico por conveniencia. La recolección de datos se realizó mediante una encuesta aplicada a pacientes hipertensos que cumplían con criterios de inclusión y contaban con un consentimiento informado. Los datos se tabularon mediante Microsoft Excel 2016. Resultados: 76.7% de los pacientes eran mujeres y 64% tenía más de 60 años. El 50% de los pacientes conocía sobre hipertensión arterial, 56.7% refieren que los tratamientos caseros superan a los medicamentos. Un 10% considera que el consumo de sal era mayor del requerimiento diario. El 36.7% no sigue ninguna dieta y 60% no realiza al menos 30 minutos de ejercicio diario. Conclusión: El conocimiento en la población de la comunidad de San José de Boquerón fue adecuado, sin embargo, el conocimiento sobre la hipertensión arterial y los parámetros normales de presión arterial sigue siendo insatisfactorios. Hay una actitud positiva de los pacientes sobre asistir a consulta con un médico y mayor confianza en la medicina alternativa que en los farmacos. El mayor déficit fue encontrado en las prácticas de dieta y ejercicio. 
  
Revista Científica de la Escuela Universitaria de las Ciencias de la Salud

CONOCIMIENTOS, ACTITUDES Y PRÁCTICAS DE PACIENTES HIPERTENSOS EN SAN JOSÉ DE BOQUERÓN, JULIO 2018

Se analiza la asignacion de las bandas de frecuencias LTE en el espectro radioelectrico del Ecuador y se determina los espacios que se encuentran libres para realizar una reutilizacion de frecuencias con una adaptacion de senales que tengan caracteristicas 5G en propiedades de alta velocidad y baja latencia. Se establece 1750MHz como frecuencia libre, por el hecho de que asi se encuentra en la asignacion de canales de ARCOTEL para ejecutar la transmision y recepcion de la senal adaptada. Para esto, y como fase experimental se utilizara OFDM como tecnica de acceso al medio. Es decir, adaptar OFDM para ver si se puede encontrar baja latencia y alta velocidad.

Análisis de eficiencia espectral en las bandas LTE para inclusión de señales 5G usando OFDM.

El presente trabajo desarrolla una investigacion detallada acerca del Analisis y gestion de riesgos informaticos presentes al interior de la Gobernacion del Meta. Considerando que sobre el respecto no existe estandarizacion o normatividad vigente en el ambito nacional, los autores han dispuesto basarse en la metodologia MAGERIT 2.0, como un marco de referencia para la gestion de la seguridad informatica. 
La intension de los autores de este documento no solo es generar una herramienta documental valorativa que permita identificar las vulnerabilidades y amenazas mas relevantes que al materializarse puedan causar un impacto significativo sobre los activos informaticos de la entidad, sino tambien el de constituirse en un modelo de politica de seguridad de la Informacion ajustado al entorno de la Gobernacion del Meta. 
Se hace enfasis en que este es un documento formulativo, el cual tendra que ser objeto de revisiones y ajustes por parte de la Direccion de Sistemas de la Gobernacion del Meta para su posterior Implementacion. El primer proceso para proteger los activos informaticos de las organizaciones es el de conocer a que riesgos estan expuestos sus activos, determinando el nivel del riesgo y la frecuencia de ocurrencia, logrando con esto priorizar la implementacion de medidas o instrumentos de seguridad a los activos que se vean con mayor grado de exposicion. 
La finalidad de este trabajo entonces no es distinta a la de dotar a la Unidad de Sistemas de la Gobernacion del Meta, con un estudio de riesgos y con la formulacion de unos procedimientos y politicas de seguridad informatica que le permitan la mitigacion del riesgo a su minima expresion y que se garantice por consiguiente que el nivel de ocurrencia de incidentes se reduzca a su minima expresion.

Análisis y gestión de riesgos informáticos para la red LAN de la Gobernación del Meta.

Las estrategias de marketing digital y su incidencia en el posicionamiento de marca de las organizaciones de la economía popular y solidaria en Guayaquil.

Estilo de vida como factor desencadenante de la diabetes mellitus tipo 2

El presente trabajo se realizo con el objetivo de simular el modelo economico de Leontieff para identificar el grado de necesidad que tiene unas empresas de las otras y saber que todas las empresas no pueden depender por si solas en la ciudad de Villavicencio, identificando las problematicas en el ejercicio academico se perciben problemas relacionados con la falta de capacidad logica y raciocinio, frente a situaciones concretas de desarrollo de problemas matematicos. 
 
Teniendo en cuenta que los docentes carecen de herramientas que precisen la comprension, el analisis, el planteo y desarrollo de problemas. El instrumento utilizado para obtener la informacion necesaria, es una encuesta practicada a 94 empresas de distintos sectores las cules son 19 del sector agricola, 68 del sector servicios, 3 del sector plasticos, 4 del sector ganadero. 
De la aplicacion y analisis de la informacion recopilada se obtuvo el modelo economico de Leontief, se practico un analisis estadistico y una simulacion del modelo economico de Leontief, aplicando diferentes procesos matematicos y estadisticos, como el modelo insumo – producto, creando matrices de los diferentes sectores para obtener un valor agregado y un valor bruto en la produccion. Los datos reales fueron resultado de la aplicacion de una encuesta a 94 empresas de distintos sectores de la ciudad de Villavicencio. 
Se obtuvo una matriz 3 por 3 y una 2 por 2 lo cual nos permite conocer la necesidad de unas empresas de las otras.

Modelo económico de Leontief: simulación para la aplicación de problemas reales en el uso de matrices

El auge internacional de la certificacion en la norma tecnica ISO 13485 ha hecho que todas las organizaciones involucradas en una o mas etapas del ciclo de vida de los dispositivos medicos, entren en estos procesos de certificacion. Sin embargo, permanece latente la pregunta sobre si efectivamente la organizacion obtiene un beneficio por implementar este sistema de gestion de calidad basado en buenas practicas de manufactura segun dicha norma. 
Por lo tanto, este articulo presenta los resultados de una revision literaria efectuada en EBSCOHOST, Scopus, Pudmed y la revista Signos. La busqueda considero textos publicados entre 2011 y el 2019. La recuperacion de esta informacion se efectuo a traves de palabras claves en espanol e ingles. Se identificaron 4047 documentos, de los cuales se analizaron 25 en total. 
Dentro de la literatura cientifica, se pudo identificar que existe poca informacion del tema de investigacion en relacion a la implementacion de buenas practicas de manufactura de dispositivos medicos y los beneficios que se pueden obtener con la certificacion en la norma tecnica ISO 13485, ya que esta es una norma muy especifica de criterios relacionados con el funcionamiento de dispositivos medicos y servicios asociados. Los aportes de teorias de competitividad en Colombia fueron casi nulos; los antecedentes internacionales constituyeron un excelente marco de referencia y un punto de partida para esta revision.

El sistema de gestión de calidad ISO 13485:2016: elemento para la competitividad y la sostenibilidad de la producción de dispositivos médicos en Colombia

Construcción de un prototipo de software para el registro y control de acceso inteligente de motocicletas al parqueadero de la Universidad de Cundinamarca extensión Facatativá

"ADHERENCIA AL TRATAMIENTO CON HIERRO POLIMALTOSADO, CARACTERÍSTICAS DEMOGRÁFICAS DE MADRES Y REACCIONES ADVERSAS EN NIÑOS DE 6 A 12 MESES CON ANEMIA EN EL CENTRO DE SALUD DE ASCENSIÓN HUANCAVELICA 2019"

This document provides an overview of the existing methods for the application of strategic foresight as a strategic planning tool in organizations. An approach is made to 1 Ingeniero Industrial, MSc. en Administración de Empresas mención Producción y Servicios, Gestor A en Comunicación y Marketing, Constructora Hicacos, Matanzas, Cuba. E-mail: javier.duenas@gecot.co.cu) 2 Doctor en Ciencias, Profesor Titular de la Universidad de Matanzas, Cuba y Profesor Invitado de la Universidad Técnica de Babahoyo, Ecuador. Email: amedinaleon@gmail.com; alberto.medina@umcc.cu) 3 Docente de la Facultad de Administración Finanzas e Informática de la Universidad Técnica de Babahoyo, Ecuador. Asesor del Vicerrectorado Administrativo Financiero. Email:laramirezg@utb.edu.ec) 4 Docente Titular de la Facultad de Administración Finanzas e Informática de la Universidad Técnica de Babahoyo, Ecuador. Asesor Institucional UTB. Email: wcamacho@utb.edu.ec 5 Docente de la Facultad de Ciencias Jurídicas, Sociales y de la Educación. Universidad Técnica de Babahoyo. Ecuador. Asesor Institucional UTB. Email: jsobenis@utb.edu.ec Javier Dueñas, Alberto Medina León, Luis Ramírez Gómez, Washington Camacho Villota, Juan Sobenis Cortez 2 Revista Magazine de las Ciencias. Publicación cuatrimestral. Vol. 4, Año 2019, No. 3 (Julio-Septiembre) the identification of the key variables of the system; anticipate and understand the game of the actors; as well as perform a morphological analysis, identify possible futures and trace the actions that allow organizations to reach the desired scenario. The use of these tools also allows directing shared and desired directions of an organization through analysis of conditioned probabilities of occurrence of the scenarios. The fundamental result that shows the work is given in the critical analysis of each of the methods addressed and the realization of a proposal for its combined application based on the original idea of its main exponent, Godet (2003).

LA PROSPECTIVA ESTRATEGICA COMO HERRAMIENTA DE PLANEACIÓN A LARGO PLAZO

The present investigation had two objectives. First, to investigate how adults generalize social 
behaviors in two types of social categories. Second, to classify the intensity with which each social category is characterized in Naturalness, Uniformity and Cohesion. The investigation was constructed with an experimental methodology. The results were collected with an instrument that consisted of two parts, in the first part it was evaluated the way in which adults generalize the antisocial actions of a member of a group to all their social group. Secondly, the Classification situation was presented, where each participant had to evaluate 3 different dimensions (Naturalness, Uniformity and Cohesion) across 10 social groups. This research found that adults generalize social behaviors depending on the social category and the perception of the degree of naturalness, cohesion and uniformity that the participant has the social group presented. It can be concluded that the behavior of the generalization of adults works well in the function of nature and is more restricted than the generalization process of children. A question is left open: How does the process of generalization of social dispositions change in development?

Generalización de disposiciones sociales : un estudio exploratorio con jóvenes universitarios

Implementación del aprendizaje organizacional para mejorar la gestión educativa de la I.E.P. Cesar Vallejo, Huancayo - 2018

The objective of this research work is to characterize representative elements of employability of transgender people in the city of Bogotá. In the same way, the structure of the work is carried out around three central concepts that are: the advances of the legislative system related to inclusion and non-discrimination, influential factors in employability, external and internal, and the quality of employment. The approach is interpretive hermeneutics, employing information gathering techniques through document review and interviewing five people who have practical or theoretical experience on employability and knowledge of sexuality and gender identity, including people who are self-defined as transgender; making use of content analysis techniques to contrast the theories and previous studies with the reality evidenced by the participating subjects. Finding that this population presents difficulties in the access, permanence and culmination of educational training, barriers in entering the labor market, inequitable remunerations and labor guarantees; as well as discriminatory behaviors by peers and superiors.

Empleabilidad e inclusión laboral de personas transgénero en la ciudad de Bogotá

The present document developed under three aims, the most frequent osteomuscular identified the painful symptomatology in the personnel of clinical file of the Foundation I medicate Preventive; to evaluate the exhibition of disorders osteomusculares by means of the analysis of the working place and to design measures of intervention for the development of sure work. The type of investigation developed was descriptive, quantitative, which established the exhibition of the workers to factors of risk of disorders osteomusculares. The first aim developed across the Northern questionnaire Kuorinka. Analyzed the results one found that of 11 workers, 10 (90,9 %) presents some type of inconvenience and pain skeletal muscle. The most frequent observed prevalencia appeared in the neck followed by the right shoulder, right wrist and back. The second aim developed by means of the method RULA, where it was possible to observe six labor activities, with great postural load and repetitive movements, where an activity had punctuation of 6, level of action 3, with redesign of the task and five activities, with punctuation 7, level of action 4, which it needs of urgent changes in the developed activities. The analysis shows that the activities developed by the personnel of clinical file, it has a great component of physical effort, which has reverberated in muscle skeletal pain and inconveniences, affecting the health, well-being and quality of life of the worker.

Estrategias de prevención para lesiones osteomusculares del personal de archivo clínico fundación médico preventiva

Disputas numéricas en el periodismo brasileño: las dimensiones de la tragedia socioambiental en Mariana (Brasil) en diciembre de 2015

El objetivo del siguiente trabajo es el estudio y la elaboracion de concreto GRC (Glass Reinforced concrete) por medio de materiales no convencionales como la fibra de vidrio y particulas de PET (polietileno Tereftalato) donde se quiere dar a conocer la efectividad de la mezcla para su uso en las nuevas construcciones, darle un mejor manejo a los residuos plasticos ya que el Pet (polietileno de tereftalato) es altamente contaminante en la actualizad y a su vez poder reemplazar uno de los componentes habituales del concreto como lo es la grava, aglomerante con un proceso de trituracion pero que es fuente propia de los rios y lo cual por la accion del hombre por obtener este agregado produce danos en las cuencas hidrograficas alterando su morfologia. El proposito fundamental es garantizar las propiedades basicas del concreto y la de sus componentes para su aplicacion en el campo de la construccion y para el paso de nuevas investigaciones por medio de ensayos de laboratorio para asi poder determinar su viabilidad.

Elaboración de concreto GRC a partir de fibra de vidrio y micropartículas de PET

Creative Commons licenses are characterized for establishing a balance between the "All rights reserved" (Intellectual property laws) and the "Some rights reserved" (Creative Commons, 2017) statements. These licenses grant flexibility of the intellectual property rights of an author's works allowing the public to share and use their creative works under the terms and conditions of their choice. On the other hand, the main objective of the Open Access is to grant access, free and without restriction, to academic and scientific information in the digital domain. Based on the definition suggested by UNESCO, Open Access dismisses the majority of the existing copyright restrictions, enabling people to use, download, copy, and distribute the digital resources available on the public Internet (Swan, 2013). From the aforementioned, the relationship between Creative Commons licenses and the Open Access is evident, both aimed at digital content, free of charge, applicable to a wide variety of resources and militants against the restrictions of copyright. The merging of both initiatives makes possible the universal dissemination of information with the protection of improper uses. For such purposes, the following presentation will be aimed at discussing the important elements related to the development of Open Access on academic and scientific information, and the possibilities offered by the Creative Commons licenses to protect information without too many restrictions. The use and applicability of the Creative Commons licenses, types of licenses, steps to choose a license and examples of licenses applied to different types of digital resources among other subjects, will also be discussed.

Las Licencias Creative Commons dentro de la Iniciativa del Acceso Abierto

La reconstruccion de memoria historica es uno de los principales mecanismos para la comprender las razones del origen y transformacion del conficto armado interno colombiano, sus diferentes actores y las vivencias de las vctimas que han sufrido de supresion y silenciamento. Uno de los mecanismos para reconstruir y procesar elementos de la memoria historica del conficto armado y comprender su magnitud es el arte y como objeto de estudio de este trabajo, las instalaciones artsticas/interactivas que pudieran ser construidas con elementos de computo especcos en una combinacion de arte digital. La computacion pervasiva 1 , describe un paradigma en las ciencias de la computacion que investiga la creacion de ambientes saturados de computo invisible, en el que las interfaces humano-maquina se extienden a muchos tipos de sensores y pueden responder a necesidades humanas basandose en espacios inteligentes, movilidad, computo distribuido, invisibilidad, escalabilidad local y respuesta a eventos heterogeneos. Este trabajo propone el montaje de una instalacion interactiva como caso de estudio de aplicacion de la computacion pervasiva, teniendo como tema principal la reconstrucci on de memoria historica y la desaparicion forzada; analizando su impacto, areas de trabajo, proceso de construccion, proceso creativo, articulaci on con otras areas de la ingeniera y de las ciencias humanas, y otras facetas que permitan su aprovechamiento, distribucion y produccion.

Computación pervasiva aplicada creación artística para la reconstrucción de memoria histórica

Reconstrucción de la memoria pedagógica durante el periodo 2014-2017: una estrategia para consolidar la Cátedra de la paz en la ciudad de Montería departamento de Córdoba

This document seeks to establish an accurate reference of the scope and limits of the of a surgeon's civil liability when practicing a plastic surgery, this taking into consideration the type of intervention he is assuming and the rights and responsibilities that need to be fulfilled, specially, aesthetic interventions, where the surgeon agrees to deliver an specific result, assuming the risks of the procedure. Throughout this thesis, the fact that an aesthetic procedure can result as a sale relationship where the surgeon is the provider and the patient is the consumer will be analyzed.

Las guías quirúrgicas son dispositivos biomédicos indispensables para la inserción adecuada de los implantes dentales; actualmente se dispone de 2 tipos de guías: las “restrictivas” y las “no restrictivas”, siendo las primeras las que brindan un mayor grado de estabilidad y exactitud, pero a un costo muy elevado. En este trabajo se propone la elaboración de un nuevo tipo de guía que combina una determinación protésica y la incorporación de información tomográfica con técnicas de impresión 3D para obtener un dispositivo con buen ajuste y adecuada exactitud, pero a un menor precio. El producto obtenido fue elaborado en ácido poliláctico y mostró unas buenas propiedades de adaptación, rigidez y estabilidad lo que puede garantizar un buen desempeño clínico. Si bien las guías convencionales son muy económicas presentan problemas de estabilidad que comprometen la seguridad del procedimiento quirúrgico y por lo tanto la salud del paciente; con la técnica propuesta se puede obtener una guía quirúrgica precisa, estable y a un precio razonable conservando los principios de la predeterminación protésica y asegurando que los procedimientos quirúrgicos sean adecuados y seguros. La elaboración del dispositivo mediante impresión 3D a partir de una predominación protésica es técnicamente viable, sin mayores complejidades técnicas y podría ser una alternativa real a las guías restrictivas las cuales aún son demasiado complejas y costosas.

Elaboración de un nuevo tipo de guías quirúrgicas para implantes dentales mediante impresión 3D

Introduccion. El embarazo en adolescentes sucede en el 11% de los embarazos en el mundo; tiene implicaciones medicas importantes, pero tambien tiene implicaciones legales dado que en la mayor parte del pais es concebido como un delito pocas veces denunciado por el personal de salud a cargo de la atencion de las adolescentes embarazadas. Material y Metodos. Realizamos una revision del numero de embarazos adolescentes en la Jurisdiccion Sanitaria numero VII en el periodo 2010-2015, comparandolo con el numero de denuncias por delito de pederastia realizadas por servidores publicos. Resultados: De un universo de 661,530 habitantes con un elevado grado de marginacion social, analfabetismo y pobreza extrema, se reportaron 1418 embarazos adolescentes en el periodo comprendido, de los cuales el 49% fueron atendidos en las unidades de salud de la Jurisdiccion Sanitaria; se presento solo 1 denuncia por delito de pederastia realizada por una servidora publicada asignada al area de Trabajo Social. Discusion. Existe una tendencia a la no denuncia de los embarazos adolescentes por parte del personal de salud de la Jusrisdiccion Sanitaria numero VII, lo cual se opone a las obligaciones legales de denuncia tipificadas en el Codigo Penal correspondiente; este fenomeno puede ser multifactorial y los resultados deberan estudiarse en otras areas geograficas con caracteristicas sociodemograficas diferentes. Palabras Clave: Embarazo adolescente, pederastia, denuncia por servidores publicos.

Prevalencia de denuncias por pederastia en mujeres embarazadas menores a 15 años de edad en Veracruz, México: el papel de los servidores públicos

Disenar el tramo vial desde, K0+650 hasta K5+300, de la via “Agua de Dios-Nilo”, que comunica los municipios de Agua de Dios con Nilo, de acuerdo con el diseno AASTHO93.

Propuesta de diseño del tramo vial “Agua de Dios Nilo”, desde k0+650 hasta k5+300, que comunica los municipos de Agua de Dios con Nilo, en el departamento de Cundinamarca.

Consulta de acceso vascular: resultados antes y después de la instauración de un programa multidisciplinar con realización de ecografía doppler de rutina

Diseño de un Plan de Medios para la Quinta Agroturística "La Orilla", Cantón Milagro

The visions of the university - society linkage have gone transforming and enriching, biased for the university functions: teaching (professionalization), investigation (production of knowledge) and extension (social service). This reality generates debates, arguments and new proposals on the social function of the university (pertinence), as from the relation that is produced between these elements with the new scenes. In order to do the trick scientific: How interpreting the heterogeneity and the particularities of the linkage between the university and the society in contemporaneity; In order to have an effect on the change process of the society. The article has like objective to sell off a theoretic sketch of the university – society linkage, in order to demonstrate his historic need, besides, refers to the paradoxes of the linkage at the modern university; writing down the differences as to the understanding of the formation function, investigation and the extension and his social impact. They have utilized methods that allow accomplishing a theoretic analysis, source of reflections and debates guided to the explanation and materialization of the paper member in order to contribute to the theoretic reflection – economic and cultural of the contemporary university. Key word. University, society, linkage, substantival functions

En la actualidad los cambios economicos que van surgiendo en las empresas especificamente en el sector comercio dedicado a la venta de telas, crea la necesidad de vigilar la gestion en sus aspectos organizativos, administrativos, operativos y financieros de tal manera que se obtenga mayor eficiencia, eficacia y economia en el desarrollo de sus operaciones. La apertura de nuevos mercados tanto nacionales e internacionales y los niveles de competitividad que tienen que alcanzar, conlleva a las empresas a adoptar responsabilidades mas grandes para lograr sus metas y objetivos, ante tal situacion y con el fin de controlar y administrar de una forma mas eficiente sus recursos, obliga a mejorar y ampliar sus controles requiriendo los servicios de una persona que tenga los conocimientos adecuados para poner en practica el uso de una tecnica especializada como lo es la auditoria de gestion dentro de la organizacion, es aqui donde el rol del profesional en contaduria publica y auditoria tiene que tomar una nueva vision ante las expectativas que se van generando y formar parte del crecimiento y desarrollo de la entidad. Respecto a lo anterior, los profesionales de la carrera de contaduria publica, tienen la dificultad para realizar este tipo de trabajos, debido a que se carece de una herramienta tecnica de apoyo que sirva de guia y que ayude a evaluar las operaciones que se realizan en las empresas comercializadoras de telas, principalmente porque el conocimiento acerca de como llevar a cabo una auditoria de gestion es limitado debido a la poca experiencia obtenida por los profesionales, la falta de material bibliografico, capacitaciones y diplomados que proporcionen educacion continua en el area, y la falta de procedimientos definidos para desarrollar estos trabajos. En respuesta a la problematica antes expuesta, el presente trabajo consistio en proporcionar a los profesionales en contaduria publica, procedimientos de auditoria de gestion que sirvan como una herramienta tecnica para evaluar las operaciones de las empresas comercializadoras de telas del municipio de San Salvador. Para llevar a cabo la investigacion fue necesario aplicar el modelo hipotetico deductivo, el cual consiste en observar el problema en estudio, operar hipotesis y sus variables, para luego analizar a partir de toda informacion recopilada y obtenida por medio de cuestionarios y deducir las causas y medir sus efectos, lo que permitio obtener resultados estadisticos, que llevan a realizar un diagnostico sobre la investigacion, en el cual se expresa la existencia de la problematica antes mencionada. Para determinar el tamano de la muestra se utilizo el muestreo aleatorio simple, en donde cada uno de los elementos de la poblacion tiene la misma posibilidad de ser elegidos. La poblacion es finita y esta integrada por los profesionales clasificados como Personas Naturales, inscritos y autorizados por el Consejo de Vigilancia de la Profesion de la Contaduria Publica y Auditoria (CVPCPA) al 31 de diciembre de 2017. La recopilacion de la informacion que consta en el trabajo se realizo en forma bibliografica y de campo; las tecnicas utilizadas fueron la investigacion documental que consistio en la consulta de libros y textos sobre el tema y la investigacion de campo que se llevo a cabo a traves de cuestionarios dirigido a profesionales inscritos y autorizados por el Consejo de Vigilancia de la Profesion de Contaduria Publica y Auditoria (CVPCPA) , el cual permitio el alcance de los objetivos y asi determinar el grado de conocimiento que poseen los profesionales en la ejecucion de trabajos de auditoria de gestion y la practica en el desarrollo de ese tipo de trabajos. Despues de realizar el analisis de los resultados obtenidos en la investigacion, se concluyo que los profesionales en contaduria publica no cuentan con un modelo metodologico y bibliografico de auditoria de gestion, ni tampoco cuentan con un modelo de procedimientos de este tipo de auditoria para ejecutarlos en las empresas dedicadas al comercio textil y que este sea tomado como una herramienta tecnica de apoyo para el desarrollo de su trabajo. Como producto de la investigacion se concluye que en su mayoria los profesionales en contaduria publica carecen de la experiencia para realizar auditorias de gestion y desconocen la aplicacion, ventajas y beneficios que esta ofrece, limitandose en muchos casos, a realizar solamente auditorias financieras o fiscales, por lo que recomendamos tomar en cuenta los procedimientos presentados en este trabajo para el desarrollo de auditoria de gestion, ya que este documento, contiene parametros basicos para la realizacion de la misma y contribuye al desarrollo de un trabajo con mayor calidad profesional.

Procedimientos de auditoria para evaluar las operaciones en las empresas dedicadas al comercio textil del municipio de San Salvador.

El presente proyecto tiene como proposito disminuir el uso de las fuentes convencionales de electricidad y a cambio utilizar fuentes renovables, entre las cuales se escogio la energia solar para el uso a nivel domestico, de igual manera se realizaron varios estudios sobre la viabilidad de esta opcion de produccion, con el fin de conocer las caracteristicas para la implementacion del sistema solar fotovoltaico en el lugar de estudio, que esta ubicado en la localidad 19 de Bogota, ademas se realizo el respectivo analisis de las herramientas necesarias para la instalacion solar y sus principales caracteristicas para el funcionamiento, algunas de las herramientas son, modulos solares, reguladores de carga, baterias e inversores para sistemas solares; se analizaron varios aspectos de los dispositivos solares, como eficiencia, potencia, costos y ademas de las cantidades necesarias para la instalacion solar fotovoltaica; de igual manera se examinaron algunas aplicaciones que se le puede dar a la energia termica, entre ellos, el calentador solar. Finalmente, se realizo el diseno y elaboracion de un cargador fotovoltaico para celular, con el fin de demostrar algunos de los usos que se puede dar a la energia solar.

Viabilidad de la energía solar para una casa en la localidad 19 de la ciudad de Bogotá

In  this  paper the  methodological  sequence  for  the  application  of two  balance techniques  through  the  development  of  a  didactic  simulation  is  shown. The didactic  simulation  is  carried  out in  three  stages.  In  each  of  them,  the performance of the assembly process by monitoring key indicators such as time of delivery, efficiency, productivity, time of delay, in process inventory and cycle time is evaluated. After completing the simulations and comparing the results, the students understand the advantages, disadvantages and above all the adaptability of the balance methods according to the characteristics of the process and its restrictions. Keywords: line balance, indicators, didactic simulation.

Mejora de un proceso de ensamble mediante balanceo de línea. Simulación didáctica

Nosotros como estudiantes de la carrera de Desarrollo Rural Sostenible, nos hemos propuesto emprender el proyecto de “Acopio, procesamiento y comercializacion de cafe molido, de la variedad arabica, en el municipio de Las Sabanas Madriz”. 
El fin del proyecto es obtener capacidades para emprender y generar ingresos economicos de las familias, a traves de la compra de cafe pergamino a productores de la zona. 
La meta es ser una microempresa reconocida y aceptada por la calidad del producto de cafe molido, para satisfacer las necesidades de la poblacion y servicio prestado, siendo amigable con el medio ambiente, y cumpliendo con las demandas del producto, con un gran sentido y responsabilidad social. Con nuestro negocio pretendemos mejorar las necesidades de los pobladores y al mismo tiempo mejorar nuestros ingresos economicos de las familias. Este proyecto ha sido un esfuerzo de nosotros como estudiantes y de las familias, que con los conocimientos adquiridos nos propusimos emprender, para asi mejorar las necesidades economicas, y cubrir las demandas de la poblacion, tambien promover que el cafe se venda y se consuma en nuestro municipio, como un cafe 100% puro y disminuir el consumo de cafe instantaneo que es perjudicial para la salud. El proyecto se plantea beneficiar a 6 productores con la compra de cafe pergamino, y los vendedores de servicio de trillado, tostado, molido, y a 51 familias y 3 pulperias con la venta directa.

Acopio, procesamiento y comercialización de café molido de la variedad arábica, en el municipio de Las Sabanas Madriz.

En la actualidad las tecnologias de la informacion y las comunicaciones (TIC’s) son muy importantes para la competitividad empresarial, en cuanto se presente una mejora en la articulacion de las TIC’s en una compania, seguramente esto mejorara la gestion empresarial y en muchos casos optimiza el valor agregado de una organizacion. 
En Orange Business Services, se maneja un sistema de inventario que permite ubicar un equipo segun sea su orden de compra (conocida como PO) o serial. Asimismo el inventario cuenta con informacion extra de cada equipo como lo es el cliente, nombre del proyecto y marca. Todo este inventario se maneja por medio de un formato en Excel y un registro en una plataforma virtual llamada Camaleon. Dado que las limitaciones de manejar una base de datos por medio de un formato convencional en Excel en una red local cuyo alcance es sumamente protegido por los protocolos de seguridad de Orange, puede conllevar a limitaciones tan simples como no poder abrir el formato en un equipo con caracteristicas especificas como lo seria tener el software de Microsoft office o simplemente solo puede ser observado por una persona que tenga acceso a la red, se plantea crear el prototipo de una herramienta que pueda mejorar el manejo de la informacion que contiene el inventario, con un ambiente interactivo con el usuario, y facil de usar para que funcione por medio de un sistema conformado por una red LAN y WAN, que a su vez permita alojar una base de datos y que esta base de datos se pueda acceder por medio de un servicio desde una App movil de naturaleza de Android, tambien se pueda acceder la base de datos desde un computador del sistema operativo (SO) Windows.

Prototipo de sistema de gestión de inventario empleando dispositivos móviles

Trabajo de grado que se propone mitigar los efectos del sexismo, entendiendo este como problematica sociocultural que legitima y promueve la subordinacion entre seres humanos por condiciones de sexo y genero, traducidas en desigualdad, discriminacion y estereotipacion inscritas consciente e inconscientemente sobre el cuerpo. Todo a traves de la coeducacion corporal, la cual sera entendida como un discurso humanistico de la educacion fisica que resulta de la asociacion entre el concepto de coeducacion y la educacion corporal, y que tiene como objetivo principal garantizar el desarrollo integral de los seres humanos por medio de practicas y experiencias corporales que posibiliten reflexionar en torno a la igualdad y equidad, reconocimiento y valor de las diferencias, donde todas las concepciones de genero tengan cabida y sean reconocidas como modelos culturales de igual valia, derechos y oportunidades.

Coeducación corporal, una mirada no sexista del cuerpo en las prácticas educativas

En el presente seminario de graduacion estudia el tema principal Mercado de Servicio enfocado en la calidad de los servicios turisticos; ya que las empresas tienden a mejorar las estrategias en la prestacion de sus servicios para satisfacer las necesidades y expectativas de los turistas con el fin de obtener mayor demanda en los servicios turisticos. 
El objetivo general del presente trabajo es analizar la calidad de los servicios en la industria turistica, brindados por las empresas para proporcionar un grado de confiabilidad y satisfaccion del turista. 
Definir la calidad del servicio turistico y determinar como evaluarla y mejorarla ha sido motivo importante de diversos autores. En el presente trabajo se aborda la importancia de la calidad de los servicios turisticos y algunos de los modelos de evaluacion mas representativos que se caracterizan y analizan considerando sus perspectivas y dimensiones. Se observa que la percepcion del cliente es la perspectiva mas utilizada en estas evaluaciones destacandose el uso de modelos de la calidad del servicio. 
La metodologia utilizada en este informe fue investigacion documental de la cual se consulto seis libros sobre la linea de Mercado de servicio y calidad en las empresas turisticas de los cuales tres de ellos fueron de los autores: Ramirez cavassa cesar, 2002, Philip Kotler y Azerenza M.A, 2003. Asi mismo se utilizo el formato de normas APA sexta edicion para la estructuracion del documento.

Mercadeo de Servicio : Calidad de los Servicios en la Industria Turistica

espanolEl proceso investigativo tuvo un enfoque cuantitativo, de tipo observacional, descriptivo, transversal; con el proposito de caracterizar las lesiones intraepiteliales en 100 pacientes del canton Penipe, con edades comprendidas entre 20 a 65 anos, que asistieron a consulta ginecologica del Centro de Erradicacion del Bocio y Capacitacion a Minusvalidos (CEBYCAM), durante el mes de noviembre de 2014. Los datos fueron obtenidos empleando la tecnica de la medicion, a traves del empleo del Sistema Internacional de Reporte de Bethesda. El promedio de la edad fue 41.44 anos (± 13.60); la media aritmetica de la edad de inicio de las relaciones sexuales fue de 16,37 (± 4.49); predominaron las mujeres con dos hijos, aquellas cuyo test resulto negativo (88 %) y las que no utilizaban algun metodo anticonceptivo, asi como para la presencia de microorganismos con potencial patologico. La prueba de correlacion de Pearson arrojo la existencia de una relacion fuerte y positiva entre las variables paridad y edad. EnglishThe researching process had a quantitative, observational, descriptive, cross-sectional approach. It aimed to characterize the intraepithelial lesions in 100 patients from Penipe town, aged between 20 and 65 years, who are treated at the gynecological consultation of Centro de Erradicacion del Bocio y Capacitacion a Minusvalidos during the month of November 2014. The data were obtained through the use of the Bethesda International Reporting System measurement technique. The age was on average 41.44 (± 13.60); the arithmetic mean of the age of onset of sexual intercourse was 16.37 (± 4.49); women with two children predominated, those whose test was negative (88%) and those who did not use any contraceptive method, as well as the presence of microorganisms with pathological potential. The Pearson correlation test showed the existence of a strong and positive relationship between parity and age variables.

Caracterización de lesiones intraepiteliales en mujeres del cantón Penipe, Ecuador. Noviembre 2014

The gender unequal pay is a matter of concern in labour relations all across the world. The aim of this work is to introduce and aware of one of the biggest discriminations issues in the labour market, which is directed to put womens in a position of economic dependence. The International Labour Organization has been pioneer to embrace an International Agreement of gender equal pay, consequently the study of this matter can not be done without a reference to the origin and content of this international rule. The causes and efects of the salary gap between men and women around the world will also be subject of special attention in this labour. Furthermore the investigation deals with the efficacy of the collective bargaining fighting gender inequality in terms of wage. The work ends seeking the incidence of the norms of gender wage from ILO and EU standars in the spanish law, considering the legal and political position of Spain.

La igualdad de remuneración por razón de sexo y la acción de la OIT

RESUMEN El presente proyecto de investigacion tiene como proposito analizar los escenarios del clima causados por la perdida de bosque y ganaderia mediante una propuesta metodologica con vision ecosistemica salud- ambiente, a partir de informacion derivada de la base de datos del INHAMI, Earth Explorer y Worldclim durante un periodo de 60 anos aproximadamente. Se modelizo estadisticamente la variabilidad climatica para determinar los efectos de cambio del clima asociados a entornos ganaderos, obteniendo como resultado 52,55% de perdida en el area natural y un aumento de 30,48% en el area agropecuaria. Los valores obtenidos evidencian un alto grado de alteracion en el paisaje. La modelizacion SIG permitio disenar mapas para determinar el comportamiento de precipitacion y temperatura en el canton San Miguel de los ancos, concluyendo que la mayor parte de las areas naturales que se conservaran en el futuro seran areas fragmentadas. Este tipo de estudios seran de mucho valor para evitar y revertir la perdida de ecosistemas. Palabras clave: Modelado, clima, salud, ambiente, sistemas informacion geografica, fragmentacion.

ESCENARIOS DEL CLIMA CAUSADOS POR PÉRDIDA DE BOSQUE Y ACTIVIDAD GANADERA CON VISIÓN ECOSISTÉMICA SALUD-AMBIENTE EN CANTÓN SAN MIGUEL DE LOS BANCOS

Objetivo: analizar la correspondencia entre las acciones contenidas en el protocolo prevención de caídas del Ministerio de la Salud con la Clasificación de Intervenciones de Enfermería (NIC) por medio del mapeo cruzado. Método: estudio descriptivo realizado en cuatro etapas: levantamiento de acciones del protocolo, identificación de las interveciones NIC relacionadas al diagnóstico de enfermería riesgo de caídas, mapeo cruzado y validación del mapeo a partir de la técnica Delphi. Resultados: fueron identificadas 51 acciones en el protocolo y 42 intervenciones en la NIC. Fueron realizadas dos rodadas de evaluaciones del mapeo por los peritos. Hubo correspondencia de 47 acciones del protocolo con 25 intervenciones NIC. Las intervenciones NIC que presentaron mayor correspondencia con acciones del protocolo fueron: prevención contra caídas, control del ambiente-seguridad e identificación de riesgo. Sobre la clasificación de semejanza y abrangencia de las 47 aciones del protocolo levantadas, 44,7% fueron consideradas más detalladas y específicas de lo que la NIC, 29,8% menos específicas que la NIC y 25,5% fueron clasificadas como similares en significado a la NIC. Conclusión: la mayoría de las acciones contenidas en el protocolo es más específica y detallada, com todo, la NIC contempla mayor diversidad de intervenciones y puede fundamentar una revisión del protocolo para ampliación de las acciones relacionadas a la prevención de caídas.

Acciones del protocolo de prevención de caídas: levantamiento con la clasificación de intervenciones de enfermería

This research project was developed with the objective of identifying the curriculum quidelines that contribute to the deveiopment of the political dimension in primary schoo students while establishing eco-citizenship. immersed in a context where environmental education has become the development of meamngless and isolated activities this the researchers used a qualitative approached that allowed them to use descriptive-interpretative tools, focusing on the case study methodology. The results obtained showed some curriculum guidelines for the construction of eco-citizenship in primary school students, highlighting a cross-cutting curriculum with a systemic and complex approach, which permits the development of social values, the strengthening of a political identity and the generation of reflection, intervention and transformation processes of a determined environmental reality. This involves work and discussion of problem situations related to the subject?s context which iead to their involvement to achieve a common wellbeing. Based on these results, we can conclude that the transformations of an eco-citizenship requires applying processes of civic education related to the ethical, critical and political dimensions, which allow the qualification the relations of the subjects with others and the environment while reflecting, intervening and transforming the environmental reality of their context.

Hacia una Eco-Ciudadanía|bidentificación de lineamientos curriculares para la formación de la dimensión política de los estudiantes de primaria del Colegio Policarpa Salavarrieta IED. Estudio de caso

El presente trabajo de investigacion tiene como objetivo mostrar como influye el proceso de acorazamiento en la socavacion de pilares de puentes aplicado dicho proceso a un caso real: Puente Reque, pues esta estructura es de vital importancia para el acceso vial con la parte sur de la Region Lambayeque, pues como se recuerda en nuestro pais, durante el Meganino 1982 y 1983, caracterizado por fuertes crecidas fluviales especialmente en la costa norte, resultaron afectados y/o destruidos 55 puente y con la  llegada  del  Meganino de 1997 y 1998,  de similares caracteristicas, los datos en la infraestructura vial fueron tambien considerados y hubo 58 puentes destruidos y 28 puentes afectados. Practicamente la totalidad de las fallas ocurridas en ambos meganinos tuvo su origen en problemas de hidraulica fluvial, pues como indican las estadisticas mundiales los puentes fallan principalmente por problemas de hidraulica fluvial y uno de los principales factores que influyen en este problema es la “Socavacion”, entonces a partir de ahi diversos estudios han indicado que cuando se erosiona el fondo del cauce, remueve el material del lecho y del alrededor de los pilares aumentando considerablemente la socavacion dependiendo del material que se va depositando, dicho efecto se denomina acorazamiento, finalmente el transporte de sedimentos de los materiales gruesos que cubren a los finos va disminuyendo hasta llegar a una condicion estable en funcion del tiempo.

INFLUENCIA DEL PROCESO DE ACORAZAMIENTO EN LA SOCAVACIÓN DE LOS PILARES DEL PUENTE REQUE

El dolor lumbar es considerado un importante problema de salud publica y esta asociado con altos costos socioeconomicos, ausentismo laboral y discapacidad(1). La columna lumbar posee sistemas de estabilizacion vertebral durante tareas dinamicas (sistema activo y de control); sin embargo, las personas con dolor lumbar presentan cambios morfologicos y de control motor que afectan a su estabilidad. 
OBJETIVO: Describir la asociacion entre el grado de dolor en la zona lumbar y el nivel de contraccion isometrica de los musculos estabilizadores de la zona neutra a traves del Test de Estabilidad Central de Sahrmann; en pacientes que reciben tratamiento en el area de fisioterapia del hospital “Homero Castanier Crespo”. 
METODOLOGIA: Se realizo un estudio correlacional y transversal con 30 personas. Las escalas usadas fueron el test de Estabilidad Central de Sahrmann y la Escala Visual Analoga. Los resultados estan presentados usando frecuencias, porcentajes y el test de correlacion de Spearman. 
RESULTADOS: De la muestra estudiada, un 73,3% (n=22) de los pacientes presentaron niveles estabilidad de 0 y 1. El coeficiente de correlacion obtenido fue de 0,238 lo que indicaria una debil asociacion entre estas variables. Basados en un nivel de significancia de 0,05. Se obtuvo una probabilidad de error del 20,5% (ρ > 0,05). 
CONCLUSION: El grado de dolor y el nivel de contraccion isometrica parecen no estar relacionados, pero se observo que las personas con dolor lumbar presentan bajos niveles de estabilidad asociadas a cambios en el control motor

Asociación entre dolor y contracción isométrica de la zona neutra lumbar; Hospital Homero Castanier Crespo

Uno de los muchos objetivos de organizar un congreso nacional es presentar los trabajos libres, que la comunidad médica quiera presentar, por desgracia en nuestro país el 99% de los trabajos presentados corresponden a médicos en vías de adquirir la especialidad de Anestesiología y ciencias afines. Los temas presentados en un congreso deberán de ser incluidos en un libro de memorias o más frecuentemente en un sistema electrónico de almacenamiento de información. La Federación Mexicana de Colegios de Anestesiología, preocupada por difundir y premiar el esfuerzo de los médicos que presentan sus trabajos en el congreso nacional de Anestesiología, ofrece un espacio en la revista Anestesia en México (29-87)

Trabajos de investigación presentados en el L Congreso Mexicano de Anestesiología: Chihuahua 2017. México

Calcificación psamomatosa en un adenocarcinoma gástrico. Descripción de un caso y revisión bibliográfica.

Análisis de la didáctica en el ámbito de la educación superior : informe de semillero de dos estudios de caso

This research describes how the sixth-grade students make up natural multiplicative operators in the follow form a× and b (being one of the numbers, a or b, multiple of the other) in addition to relating these facts with the understanding of the notion of equivalence between fractional numbers that are reducible to the form 1/b

Una aproximación a la equivalencia de fraccionarios a partir de la composición de operadores multiplicativos naturales

Diagnosticar y ubicar geograficamente a las personas con discapacidad de las comunidades de San Miguel Alto, San Miguel Bajo, Mushuk Nan y Huayco Pungo de la parroquia San Rafael, del Canton Otavalo, provincia de Imbabura en el periodo Enero – Octubre del 2014.

Diagnóstico georeferenciado de la discapacidad en las comunidades de San Miguel Alto, San Miguel bajo, Mushuk Ñan y Huayco Pungo de la parroquia San Rafael del cantón Otavalo de enero-octubre del 2014.

En este estudio se analiza un fenomeno muy presente en la actualidad como es la violencia entre los menores adolescentes, tambien denominado Bullying profundizando en el perfil de los agresores como agentes claves en esta problematica desde el analisis de los factores sociofamiliares de los menores que ejercen dicho rol. Asimismo, para llevar a cabo este estudio de caracter piloto, se ha utilizado una muestra de cuatro personas adultas que admiten haber ejercido un rol de acosador con otros iguales durante su adolescencia y dos Trabajadores Sociales del ambito educativo que estan en contacto directo con dicha problematica, a traves de sus  labores profesionales en Educacion Secundaria y en ONG afines en la ciudad de Sevilla. Para completar la muestra, se ha contado con la participacion de cuarenta estudiantes del ultimo curso del Grado de Trabajo Social de la Universidad Pablo de Olavide. Para llevar a cabo la investigacion se ha utilizado una metodologia mixta, cuantitativa  por medio de cuestionarios y cualitativa por medio de entrevistas en profundidad. Destacar  entre los resultados y conclusiones el tratamiento cohercitivo-sancionador de la escuela hacia los agresores, desde el principio de atencion prioritaria a las victimas, dejando en manos de otros servicios e instituciones las posibilidades de su tratamiento y reinsercion.

Los agresores de Bullying ¿son también una víctima?: Estudio piloto sobre el perfil de los agresores de Bullying desde el Trabajo Social

En el siguiente articulo se tiene como objetivo el reemplazar el medio de comunicacion basado en radio frecuencia que utilizan los helicopteros de radio control recreativos y substituirlo por un protocolo de comunicacion a traves de internet inalambrico Wifi y utilizar un telefono con sistema operativo Android como terminal de control, esto con el fin de desarrollar un sistema controlable desde internet y que sea capaz de utilizarse en un futuro como sistema de vigilancia. El metodo para el desarrollo para este Articulo se dividio en cuatro partes fundamentales: la interpretacion del funcionamiento del helicoptero, el protocolo de comunicacion, la programacion de microcontroladores y la programacion de aplicaciones para Android.

Sistema de dirección de helicóptero recreativo a través de internet usando dispositivos con sistema operativo android

Our country is going through countless social economic problems, why the industrial and commercial companies have achieved greater openness; understanding that these are the most prosperous, but it is vitally important to make a thorough study of the great contributions that provide agricultural associations, the same as provide food to society with agricultural products: root crops, vegetables and cereals, the same as are the daily dietary supplement of humans. 
To know the economic situation of agricultural associations of our county, we will apply a number of techniques, the same as facilitate the development of clear, precise and concise in each of the associations accounting reports; capable of offering economic information – financial at any time and facilitating decision making. 
These agricultural associations need of agricultural mainly accounting to keep track of all transactions performed daily to maintain an accurate quantification of products gives them the MAGAP credits that are favored as associations, training, machinery, seeds; and so they can offer to all partners and institutions that support financially reliable reports. 
Our research is aimed at agricultural associations in the canton San Miguel de Bolivar, with the purpose of obtaining economic information an accounting system the same as to show existing shortcomings in the organization, with the application of agricultural accounting will be designed achieve greater support administrative and sophisticated financial. 
Finally able to improve the economic and financial situation of the associations, which would improve their way of life and that despite the lack of planning and limitations, we want to build a project that generates income for the agricultural sector.

La contabilidad agropecuaria aplicada a las asociaciones agrícolas, en el Ministerio de Agricultura, Ganadería, Acuacultura y Pesca; en el área de desarrollo durante el año 2016 en el cantón San Miguel provincia Bolívar, durante el año 2016.

FACTORES DE RIESGO DE ANEMIA FERROPENICA EN GESTANTES QUE ACUDEN AL CONTROL PRE NATAL EN EL P.S DE PALIAN EN EL 2015

Actualización del plan de gestión integral de residuos sólidos (PGIRS) del municipio de Tunja, Boyacá aplicando la resolución 754 de 2014

Proyecto tiene como objetivo analizar los factores y las tecnicas que se practican en la seleccion y capacitacion especificamente en el area operativa de ferro torre s.a (ft), empresa dedicada al sector industrial metalmecanico. Esta investigacion permitira a la empresa evaluar las herramientas utilizadas en los subsistemas mencionados anteriormente para identificar las falencias en el metodo empleado y proponer mejoras en su modelo de gestion de talento humano actual; con el proposito de ayudar a mejorar la seleccion del personal del area operativa y tecnica, la cual es una de las areas mas representativas en el giro del negocio de la compania. 
La herramienta fundamental para la evaluacion de este proyecto es el foda (fortalezas, oportunidades, debilidades y amenazas) dado que permite tener un diagnostico situacional actual y asi mismo permitira generar un diagnostico global en la propuesta de mejora.

Evaluación Del Modelo de Gestión Para Los Subsistemas de Selección y Capacitación en Una Empresa del Sector Metalmecánico y su Propuesta de Mejora.

Una encuesta aplicada a 200 empresas seleccionadas aleatoriamente en diferentes municipios de Zacatecas MA©xico, se encontrA³ lo siguiente: el crimen organizado cobraba cuotas a las empresas en promedio $5,000 existiendo empresas que pagaban hasta $8,000 por mes y estos pagos se siguieron realizando hasta llegar a un promedio en el aA±o de $9,000. El 95% indicA³ que el crimen organizado si afecta el desempeA±o de los negocios, por otro lado el 50% expreso que el crimen organizado ha facilitado la quiebra de las empresas ya que genero una baja en las ventas entre el 50% y el 80%, a su vez contesto un 65% que pagan entre los $9001 y $10,000 pesos por mes, igualmente un 63% seA±alo que los temas fiscales afectan la operaciA³n del negocio, un 65% indico que la probabilidad de que cierren sus empresas estAi entre el 51% y el 80% lo cual la posibilidad es superior. Es indudable que factores tanto emocionales, psicolA³gicos y econA³micos que interactAoan simultAineamente para entorpecer el sano funcionamiento de la oferta en el mercado zacatecano afectando indudablemente inversiones tanto en frecuencia como en cantidad, impactando tambiA©n en el Ainimo del empresario hacia hacer negocios en la regiA³n asA­ como un severo incremento de la incertidumbre en el ambiente de los negocios. Finalmente resaltar que es necesario que los empresarios desarrollen estrategias de adaptaciA³n al clima de violencia e inseguridad pAoblica para que puedan ser capaces de ejercer nuevas inversiones que permitan expandir sus operaciones. El desarrollo de alianzas estrategias sectoriales, vinculaciA³n robusta con el sector pAoblico y las autoridades en materia de seguridad pAoblica pueden ser algunas soluciones propuestas para que los empresarios puedan trabajar adecuadamente y mantener su permanencia en el mercado en el largo plazo.

Anã Lisis Descriptivo Del Impacto De La Actividad Del Crimen Organizado En Las Finanzas De Las Pymes En El Estado De Zacatecas

El video describe el contenido del curso de Recursos avanzados de e-learning, ademas de describir las unidades didacticas a estudiar.

Implementación de procedimientos administrativos y contables para la sostenibilidad de la “Fundación Tierra Buena”

El presente trabajo muestra la implementacion y configuracion de una nube privada 
para los servicios internos de la Direccion de Promocion a la Innovacion y Creatividad 
del Ministerio de la Juventud de Managua, MINJUVE. 
Para ello se uso la aplicacion de codigo abierto, Owncloud, esta posibilita la creacion de 
un servidor de archivos en la nube, en el que se puede tener un almacen de 
documentos, imagenes, musica y toda clase de datos; permitiendo el facil acceso y 
sincronizacion, desde cualquier dispositivo por medio del cliente Owncloud, siempre y 
cuando exista una conexion a internet. 
Se presentan una serie de conceptos y herramientas utilizadas, que serviran como 
base para la comprension del presente proyecto, y una fuente de conocimiento al tema 
en estudio. 
Se describen los metodos e instrumentos usados para la recoleccion y procesamiento 
de datos. 
Luego, como primer resultado se muestra los requerimientos operacionales de los 
usuarios de la Direccion de Promocion a la Innovacion y Creatividad, seguido de la 
caracterizacion de las plataformas de almacenamiento en la nube y por ultimo, se 
detalla la configuracion de la nube privada. 
Finalmente, se presentan las conclusiones y recomendaciones de la implementacion de 
la nube de owncloud para la direccion de promocion a la innovacion y creatividad. 
(MINJUVE)

Implementación de una nube privada para los servicios internos de la Dirección de Promoción a la Innovación y Creatividad del Ministerio de la Juventud de Managua, en el segundo semestre de 2016

El objetivo del presente articulo es determinar el grado de cumplimiento de las obligaciones tributarias en los contribuyentes del regimen de tercera categoria de la ciudad de Tarapoto en el ano 2016, por consiguiente el tipo de investigacion sera descriptivo, no experimental, llegando a encuestar 350 contribuyentes duenos de las bodegas, se concluye que un gran porcentaje de la poblacion en bodegas incumplen de manera permanente las obligaciones tributarias, debido a la falta de conciencia tributaria por parte de los duenos de los establecimientos, es importante mencionar que el cumplimiento de las obligaciones tributarias abarca dos factores importantes los cuales deben de ser tomados en cuenta antes de la determinacion, el primero son las obligaciones formales, en donde suelen estar la documentacion de inscripcion en los registros de la administracion, y segundo estan las obligaciones sustanciales, que basicamente son el pago de los impuestos generados por las compras y ventas.

El grado de cumplimiento de las obligaciones tributarias en los contribuyentes del régimen de tercera categoría, Tarapoto, 2016

O carrapato Boophilus microplus causa grandes prejuizos economicos a exploracao pecuaria brasileira em funcao da espoliacao dos bovinos e do alto custo operacional das tecnicas atuais de controle. Proteinas extraidas a partir de ovos de carrapatos podem ser usadas como ferramentas no controle dos mesmos. Com o objetivo de avaliar o potencial imunoprotetor de antigenos do carrapato foram realizados estudos de extracao de proteinas de ovos do carrapato B. microplus. Os ovos usados nos experimentos foram provenientes de uma colonia de carrapatos mantida no Laboratorio de Genetica da FAPAM. Os antigenos foram isolados por suas massas moleculares avaliadas por eletroforese em gel de SDS-poliacrilamida. Os ovos de B. microplus apresentaram um perfil bem variado de proteinas com varios pesos moleculares, as quais serao purificadas para analise imunoprotetoras no proximo trabalho.

Estudio del concreto de mediana a alta resistencia elaborado con residuos de concreto y cemento Portland Tipo I

The main purpose of this project is the implementation of a system for the monitoring of air pollution, using cellular network specifically the GSM standard for the recording and display data from carbon monoxide and carbon dioxide sensors in strategic areas of Riobamba. 
 
In the development of the system two equipment sets were implemented, they are: a transmitter and receiver, the transmitter is in charge of receiving data using sensors carbon monoxide and carbon dioxide sensors, which are connected to the control board, which is responsible for stabilizing data and sending them to the receiver by means of the Sim900 card using AT commands. The receiving computer fulfills the function of receiving data, establishing communication with the database in order to record the collected data and facilitate the visualization of the web application on the internet. 
 
The benefit of the monitoring system by using a cellphone network brings the benefit of optimizing the human, economic and time resources, since this system registers, sends data through text messages, stores them in a database automatically and in real time. With the help of communication from the cellular network using the GSM standard it allows to monitor the air pollution in several areas of Riobamba.

Diseño e implementación de un Sistema para el monitoreo de los Niveles de Contaminación del aire para el Proyecto de investigación de la Universidad Nacional de Chimborazo

Los contratiempos que se presentan en la escuela no son mas que un reflejo de una sociedad cada vez mas compleja y sometida a constantes cambios. Ante esta evidencia el presente trabajo plantea la necesidad y conveniencia de repensar los objetivos de la educacion, poniendo en relieve, que ademas de la adquisicion de los conocimientos establecidos en el curriculo oficial, es necesario que los mas jovenes adquieran recursos y estrategias para enfrentarse con las inevitables experiencias que la vida les depara. Para ello y siguiendo tanto a autores como Bisquerra (2003, 2010), Ruiz-Aranda, Fernandez-Berrocal, Cabello y Salguero (2008), y Ambrona, LopezPerez, y Marquez-Gonzalez, (2013), entre otros, como algunas experiencias practicas llevadas a cabo en Canarias (EMOCREA, 2014), justificaremos la incorporacion de la educacion emocional en los contextos escolares como herramienta eficaz para la prevencion y resolucion de conflictos y como una posible salida a los problemas urgentes del sistema educativo. Siguiendo esta linea de trabajo, ademas de reflexionar sobre estas cuestiones, reflexionaremos, con el respaldo 
de las contribuciones de autores como Petrus (2004), Parcerisa (2008), o Longas (2000), etc., sobre la incorporacion del educador/a social a los contextos escolares y las aportaciones que la educacion social puede ofrecer a la escuela en relacion a la educacion de las emociones con el fin de favorecer la construccion de un proyecto educativo integral.

Educación emocional para la resolución de conflictos en la escuela: una aproximación desde la educación social

Los cobros por servicios aeroportuarios en el Aeropuerto Internacional Toncontin, se derivan de la aplicacion de la Ley de Aeronautica Civil y del contrato de Concesion que el Estado tiene con la Empresa Interairport; el hacer efectivos estos cobros corresponde a la Concesionaria en coordinacion con la Agencia Hondurena de Aeronautica Civil. Este articulo analiza las razones por las cuales estos cobros no se dan con un cien por ciento de efectividad. La intencion de fondo del analisis es descubrir los obstaculos que estan disminuyendo el porcentaje de cobros y que pueden obstruir otros cobros y otras coordinaciones entre la Concesionaria y la Agencia Hondurena de Aeronautica Civil (AHAC), que se deben hacer en condiciones similares. Revista Ciencias Espaciales, Vol.6(1) 2013, 109-125

Cobro de servicios aeroportuarios a aeronaves privadas en el Aeropuerto Internacional Toncontín

La exposicion de ninos y ninas en edades entre los 12 a los 15 anos que hicieron parte de un grupo armado ilegal, genera impacto a nivel neuropsicologico y en sus sistemas relacionales / vinculares que es preciso abordar, ya que la violencia politica siempre es lesiva para quien la padece, como para todos aquellos que conviven en su contexto relacional deteriorado, con las secuelas que genera en la estructura del sistema nervioso central, aun en formacion en estos adolescentes. Se busca con el presente articulo reflexivo, aportar una aproximacion para la intervencion que integre la perspectiva de la neuropsicologia y la intervencion sistemica, lo cual parece ser redundante pues la misma neuropsicologia por su caracteristica rehabilitadora ya es sistemica, y asi aportar a los lineamientos actuales de atencion en pro de la trasformacion del impacto y de la hostilidad politica en sus cuerpos y en los procesos vitales , que tendran que afrontar para lograr su inclusion social, la restitucion de sus derechos y participar en la sociedad civil buscando superar o manejar las secuelas en su estructura fisiologica, que pueden afectar el desarrollo de su personalidad.

Abordaje sistémico y perfil neuropsicológico de la violencia en adolescentes que vivieron su impacto al interior de los grupos armados en Colombia

DEBIDO A LAS DIVERSAS EXIGENCIAS QUE OPTAN LAS PERSONAS AL CONSUMIR PRODUCTOS INDUSTRIALIZADOS, LAS PEQUENAS Y GRANDES EMPRESAS A NIVEL MUNDIAL SE VEN CON LA NECESIDAD DE OPTAR POR UNA NUEVA LINEA DE PRODUCTOS Y A LA VEZ ELABORAR ALIMENTOS INNOVADORES E INOCUOS PARA EL CONSUMO HUMANO, CON EL FIN DE SATISFACER LAS NECESIDADES DE LOS CONSUMIDORES...

TIPO DE EDULCORANTE EN LA ELABORACIÓN DE MANJAR DE SOYA Y CARACTERÍSTICAS SENSORIALES DEL PRODUCTO.

RESUMEN En este estudio se cuestionan las leyes N° 27240 y N° 28731 que otorgan a la madre trabajadora una hora diaria de permiso por lactancia hasta que su bebe recien nacido cumpla un ano de edad. Se sostiene que, al no reconocer tambien dicho beneficio a favor del padre trabajador, estas leyes vulneran los derechos fundamentales a la igualdad ante la ley y a la paternidad responsable. Las autoras parten de un concepto amplio de lactancia, que no se restringe al hecho biologico de amamantar al bebe, sino que comprende a un conjunto de actividades orientadas a su cuidado y alimentacion. Se analizan los alcances constitucionales de los derechos a la igualdad ante la ley y a la paternidad responsable; asimismo, se compara el tratamiento del permiso por lactancia en otros ordenamientos juridicos. La investigacion es aplicable al regimen laboral del Decreto Legislativo N° 728. Palabras clave: Lactancia, igualdad ante la ley, paternidad responsable, padre trabajador. ABSTRACT In this study the laws No. 27240 and No. 28731 which give working mothers a daily hour leave for breastfeeding until your newborn baby is one year old questioned. It is argued that by not also recognize this benefit for the working parent, these laws violate the fundamental rights to equality before the law and responsible parenthood. The authors start from a broad concept of breastfeeding, which is not restricted to biological fact -feeding a baby, but comprises a set of activities aimed at the care and feeding activities. The scope of the constitutional right to equality before the law and responsible parenthood are analyzed; also permit treatment compared by feeding in other jurisdictions. The research is applicable to the labor of Legislative Decree No. 728. Keywords: Breastfeeding, in equality law, responsible parenting, working parent.

LA VULNERACIÓN DE LOS DERECHOS A LA IGUALDAD Y A LA PATERNIDAD RESPONSABLE DEL PADRE TRABAJADOR EN LA REGULACIÓN DEL PERMISO POR LACTANCIA DENTRO DEL RÉGIMEN DEL DECRETO LEGISLATIVO N° 728

El Instituto de la Mujer y para la Igualdad de Oportunidades (IMIO) presenta una Guia para reforzar la prevencion y actuacion frente a la discriminacion escolar por orientacion sexual. 19 de octubre de 2015. Tres de cada cuatro jovenes de entre 15 y 29 anos han sido testigo de agresiones homofobas en sus centros educativos, y un 6,4% ha presenciado palizas a lesbianas, gays, bisexuales o transexuales, segun datos del Instituto de la Juventud (INJUVE). Ahora bien, el rechazo a la diversidad sexual es minoritario entre los jovenes, y entre la poblacion en general. Con todos estos elementos en la mano, el Instituto de la Mujer y para la Igualdad de Oportunidades, en colaboracion con el Ministerio de Educacion, Cultura y Deporte, ha presentado hoy el estudio “Abrazar la diversidad: propuestas para una educacion libre de homofobia y transfobia”. El documento incorpora una Guia de Accion para reforzar la prevencion, la deteccion y la actuacion frente a situaciones de discriminacion en los centros educativos por cuestion de orientacion sexual. Se trata de 30 recomendaciones generales y una serie de recomendaciones particulares dirigidas a toda la comunidad educativa, desde la direccion de los centros a los alumnos y sus familias, pasando, por supuesto, por el personal docente. 
Presentado por la directora del Instituto de la Mujer y para la Igualdad de Oportunidades, Rosa Urbon, el estudio plantea de forma expresa la introduccion de la educacion en diversidad sexual en los documentos oficiales del centro, asi como la puesta en marcha de material informativo sobre las realidades de los grupos LGBT. El coordinador de este trabajo ha sido Jose Ignacio Pichardo, de la Universidad Complutense de Madrid. 
Asimismo, se precisa una lista de indicadores para detectar casos de acoso escolar por homofobia o transfobia. 61 indicadores contrastables, organizados conforme a la diversidad de relaciones entre las partes: autoridades, personal docente, alumnado y familiares. Otros 16 indicadores permiten identificar si los centros educativos son espacios que favorecen el respeto a la diversidad sexual, familiar y de identidad de genero.

Abrazar la diversidad: propuestas para una educación libre de acoso homofóbico y transfóbico

El presente estudio aborda un aspecto de caracter social, donde se exponen, estudian, analizan y brindan soluciones a las amenazas que azotan la zona 1 del Mercado Oriental, con el proposito de resguardar la vida de las personas que transitan, visitan y compran. 
El objetivo de este trabajo es establecer estrategias dirigidas a mitigar las amenazas naturales y/o antropicas, mediante una estrategia comunicacional, adoptando un enfoque de gestion local de riesgo. 
Por lo tanto, se procedio a identificar las amenazas en la zona y posteriormente se realizo el analisis para determinar los factores de vulnerabilidad para determinar el nivel de riesgo que tiene en los diferentes sectores. 
La elaboracion del documento ha pasado por un proceso ordenado de consulta y de validacion por parte de los sujetos en estudio, pues son ellos el punto clave para lograr mitigar las amenazas existentes en la zona. 
Este proceso se llevo a cabo por la aplicacion de dos encuestas dirigidas a comerciantes y compradores, dos entrevistas dirigidas al Gerente General de COMMEMA, a Lisseth Rugama responsable de la zona 1, esto para lograr identificar las amenazas existentes, de igual forma determinar el grado de conocimiento que estos tienen sobre las diferentes amenazas naturales y/o antropicas. 
El proposito de esto es que los comerciantes, compradores e instituciones vinculadas al lugar tomen la iniciativa de hacer un cambio en la zona, para preservar la vida y erradicar las amenazas latentes en el lugar. Por tal razon, se tomo como parte fundamental de este estudio determinar el grado de participacion y compromiso de las instituciones locales y las instituciones que la Ley mandata para velar por el bienestar de la vida de las personas que a diario visitan este centro de compras. 
De tal forma, el Mercado Oriental esta a cargo de la municipalidad, se encuentra dividido en tres zonas comerciales creando asi un gran centro de produccion economico accesible para todo publico. 
Este centro de compras, no cuenta con una buena organizacion por parte de las instituciones, comerciantes y compradores. Por tal razon, no cuenta con desarrollo sostenible en cuanto a la prevencion, mitigacion y atencion de desastres. 
Es por esta razon, que se procedio a realizar una estrategia comunicacional para que ayude a prevenir, mitigar las amenazas presentes en la zona de estudio

Estrategia Comunicacional con enfoque en Gestión de Riesgo ante las diferentes amenazas presentes en la zona 1 del Mercado Oriental, en el segundo semestre del 2014

Eficacia del método en la estabilización de talud en la carretera Lampa - Caracara Puno 2014

In the investigation of the proper storage of auto parts distribution center, is given know the problems that it has at present, regarding proper handling of defective material (MDF). It conducted a study of the care, through three aspects, firstly, the characteristics of materials, second, costs are incurred and finally analysis of the shelves.

Determinación del almacenamiento adecuado de autopartes para vehículos de alta gama en el centro de distribución de una empresa importadora de repuestos en Bogotá D.C. – Colombia

ntroduction. The video games have acquired an important paper (role) in the entertainment of million children. Many people are the specialists of the heal...

Uso, abuso y consecuencias de los videojuegos en niños de 6 a 12 años en una escuela de educación básica

Objetivo: Elaborar una propuesta que sirva para determinar el valor historico y permita dar una correcta conservacion al Templo Parroquial San Pedro Apostol en el municipio de Alegria, departamento de Usulutan. Metodologia: se utilizo el metodo cientifico, partiendo del empirico-analitico por la manera correctiva y progresiva. Los instrumentos que se utilizaron son: analisis de documentacion, elaboracion de planos, diseno de maqueta virtual, revision de tesis con similitud al proyecto actual, entrevistas. El documento consta de cinco capitulos, a traves de los cuales se permite una completa descripcion y analisis del estado actual del inmueble, y poder dar la respectiva propuesta de restauracion del mismo. Conclusion: Mediante el proceso de elaboracion, se estudio acerca de la importancia de las epocas que existieron en el pais, principalmente en la colonial, que fue de grande influencia para la creacion de las principales obras arquitectonicas de la antiguedad, las cuales aun perduran, en el caso de El Templo Parroquial San Pedro Apostol, pueden observarse varios elementos que han sido creados, en base a sus criterios, podemos concluir que la mayoria de elemento son de ese origen, con pequenas influencias del gotico y barroco entre otras. En el capitulo III el "Diagnostico" se muestra una investigacion acerca del estado en el cual se conserva la Parroquia y cada elemento marcado en ella, asi como las alteraciones visibles y las que no lo son, se realizo un juego de planos acerca del estado en que actualmente se encuentra, observando algunas diferencias a su estado original. En el capitulo IV de "Analisis Arquitectonico" se estudio acerca de las zonas que comprenden El Templo Parroquial San Pedro Apostol, se realizo el analisis de cada elemento que la iglesia posee, se detallaron los materiales constructivos que posee y se llevo a cabo el analisis estilistico que da mayor conocimiento de cada movimiento de su construccion. En la seccion de "La propuesta" se dio el valor historico-cultural que posee El Templo Parroquial San Pedro Apostol, y esta orientado a dar el respectivo valor y emplear metodos de conservacion que sean de gran utilidad para mejorar su estado actual y volver a su estado actual.

Evaluación del estado de conservación, determinación del valor histórico-cultural y recomendaciones de conservación del Templo Parroquial San Pedro Apóstol, del municipio de Alegría, departamento de Usulután

Sindrome de Bloom e uma doenca autossomica recessiva caracterizada por eritema telangiectasico em face, fotossensibilidade e retardo de crescimento pre e pos-natal. A mutacao do gene BLM, traz uma instabilidade cromossomica importante, responsavel pelas manifestacoes da sindrome e pela maior susceptibilidade a neoplasias. Ha um registro mundial de pacientes com um total de 255 casos, sendo 16 do Brasil. Diante da raridade da sindrome, apresentamos o caso de duas irmas, filhas de pais consanguineos, ambas com baixa estatura, apresentando maculas eritematosas com telangiectasias em nariz e regiao perioral, micrognatismo, dolicocefalia, hipoplasia malar, face triangular, nariz proeminente, maculas hipocromicas e manchas cafe com leite em tronco e membros inferiores. O diagnostico e clinico e pode ser confirmado por citogenetica. Os portadores apresentam fenotipo tipico com telangiectasias em areas fotoexpostas. Ainda nao ha tratamento especifico, porem, deve-se oferecer suporte clinico e melhoria da qualidade de vida e diminuicao de estigmas.

The present research was conducted in the Bogota city during the period between 2013 and 2014 with the participation of different partners the company based on the analysis of their production processes. The objective of this research was to build a system for planning, scheduling and control of production processes CARMONA PROPERTY AND RUIZ AND CIA LTDA, which allows the optimization of resources, by improving levels manufacturing and fulfillment to their clients. All this in order to optimize processes and minimize the negative impacts that are there and therefore generate a production model based on the needs of the organization. And concluding that the result derived from the study is positive given that the company obtained organizational benefits that will meet with new targets set under the scheme of industrial engineering.

Planeación, programación y control de la producción para la empresa Muebles y Accesorios Ruíz Carmona y Compañía Ltda

Actores regionales de soporte en el fortalecimiento de la cadena de la guadua del eje cafetero

This research relating to infringements incurred or committed by the Metropolitan Police of Bogota, moments which are in administrative situations such as franchise, permit, vacations, suspended, disabled, toilet service, or hospitalization from the view of the thesis research, not always they can be interpreted as performances which warrant or lead to the initiation of an investigation of a disciplinary nature, by the Office of Internal Disciplinary Control of the Metropolitan Police of Bogota, in the understanding that some of them do not meet the legal and constitutional requirements for advance it and therefore fail to disciplinary action against the offender, although the Law 1015 of February 7, 2006, (Congress Regime Republic Discipline to the National Police), which configures standard cited as serious misconduct misdemeanor behavior. 
 
While it is true that the Colombian legislature through the Congress, to issue the disciplinary rule of special character, directed exclusively to active members of the National Police and to those in allocation of retirement or dismissed, incurred in transgression of said standard, as long as their behavior or action has been framed as a disciplinary offense who met moments in service and institutional function, so that it will be reproached and iniciarsele the disciplinary process, it must meet certain requirements given by the Constitutional Court (Judgement C - 819, MP Cordoba Trivino, Jaime October 4, 2006), on the understanding that referred High corporation and maximum body protector of constitutional rights, emphatically stated that ... as long as the necessary connectedness is established between behavior (...) undermining misdemeanor and civil ...; However, despite the established requirement, are not given the appropriate application to cases where a policeman incurred in contravention finding temporarily separated from the institution by either administrative situations pointing the norm, just enough that it Allegue the disciplinary body to report the complaint or proceed to investigate the official, without making the respective valuation established by the connectedness and impairment of the public service, by the way, in most cases do not meet the restrictive rule mentioned by the cut.

¿Cuál es el grado de cumplimiento de la exigencia argumentativa establecida por la corte constitucional, en el sentido de demostrar la conexidad entre contravención y función pública de parte de las autoridades disciplinarias de la Policía Nacional?

La sana convivencia se ha convertido en los ultimos tiempos en un tema importante de reflexion en relacion con el contexto globalizador contemporaneo del hombre, en los ambitos economico, social, cultural, informatico y principalmente educativo, que pueden favorecer o afectar el equilibrio de la sociedad. Con frecuencia centramos la atencion en aspectos tecnico pedagogicos y administrativos, como fundamento practico del exito escolar, sin darle el mismo sentido al estilo actitudinal que presenta la sociedad educativa, asi como los valores y relaciones interpersonales, base fundamental de la sana convivencia dentro y fuera de la escuela, tomando en cuenta los principios en los que se sustenta el enfoque de la ensenanza en Mexico, cuya influencia es decisiva para la correcta estructuracion de un aprendizaje cooperativo, fomentando ambientes propicios de aprendizaje entre los mismos estudiantes y estudiantes - profesor.

Promoción de valores: una metodología de estilo actitudinal a través del aprendizaje cooperativo en educación física

Proyecto de construcción. Línea de Alta Velocidad Santander-Bilbao : Tramo PK24+200-32+800

La importancia de la frontera militar en los siglos XVII y XVIII. El caso de la región de Noudar y Barrancos en Portugal

Introduction: Sudden deaths have increased. Survival depends on well-defined actions in the “chain of survival". Prehospital care often requires the application of cardiopulmonary resuscitation and early defibrillation. The term sudden death is used

Muerte súbita cardíaca: la importancia de la desfibrilación temprana y la resucitación cardiopulmonar

Realizar un diagnostico de suelos a partir de variables ambientales es de gran importancia para la planeacion e implementacion de estrategias de uso y manejo para el mejoramiento de este recurso. el presente trabajo tiene como fin plantear estrategias ambientales para los suelos de la cueca media del rio el palmar en el municipio de ubaque, cundinamarca; por lo cual se realizo una revision de la calidad y degradacion de los suelos agricolas en la cuenca media a traves de una fase de campo en la cual se tomaron 15 muestras de suelos, utilizando herramientas de muestreo como la ntc 3656/1994; para su posterior diagnostico, losanalisis fisicoquimicos se elaboraron conforme a los metodos analiticos de laboratorios de suelos establecidos por el instituto geografico agustin codazzi (igac); para la evaluacion y priorizacion de impactos se utilizo la metodologia epm, ademas de encuestas y entrevistas realizadas a la poblacion y al personal administrativo de la alcaldia municipal, lo cual permitio considerar los factores determinantes de degradacion del suelo en la zona de estudio. en cada uno de estos casos se mencionan las variables que indican la degradacion del suelo agricola como lo son la disminucion del porcentaje de humedad, salinizacion, perdida de materia organica, conflictos de uso del suelo y sus respectivos programas de uso y manejo; programa de control del contenido de humedad en los suelo, programa de disminucion de salinidad en los suelos, programa de regulacion del porcentaje de materia organica disponible en los suelos, programa de manejo de conflictos de uso del suelo coadyuvados de un programa de capacitacion y concientizacion, que permitan una mejor planificacion del territorio, en donde la interaccion entre la administracion municipal, la autoridad ambiental y la poblacion es un factor fundamental para establecer un equilibrio social, economico y ambiental.

Estrategias ambientales de uso y manejo de suelos en la cuenca del río el palmar en el municipio de Ubaque

Risoterapia y nivel del dolor, niños de 4 a 14 años, consultorio externo de quimioterapia, Hospital Regional Honorio Delgado, Arequipa 2013

Gelogogia y aplicacion geoquimica en la exploracio n del deposito skarn huacravilca

Resumen es: Este trabajo desarrolla un analisis acerca del concepto de participacion social en numerosas investigaciones bajo el enfoque de Ecosalud sobre enfermedad...

La participación social en proyectos de investigación con enfoque Ecosalud en dengue, malaria y Chagas en América Latina

En Latinoamerica el Boom literario sirvio de plataforma para que esta nueva forma de periodismo cobrara vida con mayor arraigo y sentido impermeable del periodismo de oficina. Mario Vargas Losa, Martin Caparros, Tomas Eloy y Martinez, Alma Guillermo Prieto, Octavio Paz, Gabriel Garcia Marquez, Juan Jose Hoyos y Alberto Salcedo Ramos, entre otros muchos que entendieron la dinamica de llegarle al lector con historias cotidianas, sencillas, fascinantes y sorprendentes materializadas en generos como cronica, reportaje, perfil y entrevista de personaje, entre otros. El Salvador no escapo a esta corriente periodistica, aunque de forma tardia y uno de los medios de comunicacion que se ha atrevido a emplearla es el periodico digital “El Faro”, en especial en su seccion “Sala Negra”, en donde los temas de violencia y corrupcion son abordados de esta manera diferente. Hecho que ha merecido ser estudiado. La presente investigacion es un analisis de contenido cualitativo sobre los recursos narrativos utilizados en las cronicas y reportajes de la seccion “Sala Negra”, del periodico digital El Faro, la cual fue desarrollada a partir del mes de marzo hasta agosto de 2014.

Análisis de contenido cualitativo: recursos narrativos utilizados en las crónicas y reportajes de la Sección “Sala Negra”, del Periódico Digital El Faro

En este trabajo presentamos en primer lugar, los resultados de investigacion que dan cuenta de las concepciones de un grupo de docentes de primaria en un ambiente de aprendizaje con Necesidades Educativas Especiales (en adelante N. E. E. ) asociadas a la discapacidad -alumnos sordos-, pudiendo asi identificar su perfil epistemologico y cognitivo. En segundo lugar, presentamos un ejemplo en el cual se hace un analisis de correlacion entre las concepciones evocadas por una docente y la practica realizada por ella en el aula. Puesto que hoy en dia es importante reconocer nuevos espacios de inclusion educativa y caracterizar la practica docente que se desarrolla en el aula de ciencias.

Concepciones epistemológicas y de aprendizaje de un grupo de docentes de primaria en un ambiente con necesidades educativas especiales en la clase de ciencias

Taking into account the importance of analyzing the components associated with a basin for thus establishing programs that achieve a sustainable use of the same, develops in this document a diagnostic of the biophysical, socio-economic and cultural conditions of the Sub-basin of the river Guaduero in the municipality of Guaduas - Cundinamarca, as this is an important source of production of waters that have a large amount of water from the municipality, being invaded increasingly by man in his eagerness to open the border agricultural and especially livestock.

Plan de manejo y ordenamiento de la cuenca del río Guaduero (Guaduas – Cundinamarca)

Hand-lettering y retórica: elementos de persuasión en cartelería publicitaria

The exploitation of the Salina of San Pedro del Pinatar has deeply changed throughout the history in the methods used in the processing and selling of salt, and in the company organization. The information given by interviews to workers, data and documents given by the company Salinera Espanola and the bibliography, allow us to describe the process of salt extraction, to classify the salt according to its uses and to characterize the stability reached in the production, the selling and the main markets. Also we can identify the weaknesses and the strengths that determine thapresent and future perspectives.

La explotación industrial de las salinas de San Pedro del Pinatar (Murcia)

En esta tesis se describe la conversion de sustratos baratos y de facil obtencion como derivados de carbohidratos y aminoacidos en productos de alto valor anadido, como C-nucleosidos, analogos de azanucleotidos y analogos de alcaloides mediante procesos secuenciales de escision radicalaria-oxidacion-adicion de nucleofilos. Estos procesos permiten eliminar una parte del sustrato en condiciones muy suaves (en la etapa de escision radicalaria-oxidacion), y reemplazarla por otras funciones (en la etapa de adicion de nucleofilos).
Primero se lleva a cabo la sintesis de C-nucleosidos aciclicos y ciclicos a partir de derivados de carbohidratos facilmente accesibles. El sustrato se somete a una escision radicalaria oxidativa, seguida de la adicion de derivados de aril cetonas, lo que permite generar C-nucleosidos aciclicos con distintos grupos arilo o heteroarilo. Posteriormente, estos derivados aciclicos son transformados en dos pasos en 1-aril 2-deoxipiranosas, mediante la reduccion de la aril cetona y ciclacion en medio acido. Ambos pasos transcurren con buenos rendimientos y excelente diastereoselectividad En la segunda parte se lleva a cabo la conversion directa de derivados de prolina en analogos de azanucleotidos, mediante un proceso secuencial de escision radicalaria-oxidacion-fosforilacion. El proceso se lleva a cabo en condiciones de reaccion suaves y dando altos rendimientos de los analogos de azanucleotidos. Es de destacar que la estereoselectividad de la reaccion depende del sustituyente sobre C-4, y asi los sustratos con funciones oxigenadas o los grupos azida dan preferentemente los productos 2,4-cis, mientras que los sustratos con otras funciones nitrogenadas generan preferentemente los productos 2,4-trans. De esta forma, la proporcion de diasteromeros cis/trans puede modificarse, pasando de 98:2 a 15:85.
En el ultimo capitulo se lleva a cabo la sintesis de analogos de alcaloides fenantroindolicidinicos citotoxicos a partir de derivados de hidroxiprolina, en solo dos pasos de reaccion. El paso clave es un proceso secuencial de escision radicalaria-oxidacion-alquilacion, para dar lugar a pirrolidinas sustituidas en la posicion 2 con una importante variedad de anillos aromaticos y heteroaromaticos. En un segundo paso de reaccion, se produce la saponificacion del grupo C4-OAc, que segun las condiciones de reaccion puede estar seguida o no de una ciclacion intramolecular, que generaria indolizidinonas. Los isomeros mayoritarios y minoritarios (ed 3:2 a 3:1) pueden separarse facilmente, permitiendo estudios estructura-actividad biologica (SAR). Estas moleculas se ensayaron frente a lineas de celulas tumorales de mama y neuroblastoma, dando en algunos casos una mortalidad ? 80% a dosis micromolares.

Síntesis estereoselectiva de análogos alcaloides y de nucleósidos por medio de un proceso secuencial de fragmentación-adición de nucleófilos

Diseño y Construcción de una Máquina Automática para el Conformado en Frío de Volutas en Varilla Cuadrada de hasta 1/2 Pulgada para Cerrajería Ornamental.

Presenta el analisis de la incorporacion de una practica cultural declarada Patrimonio Cultural Inmaterial (PCI) de la Humanidad en las estructuras formales del ordenamiento territorial. Analiza tambien la necesidad de reconocer una serie de valores que la comunidad le ha otorgado a la practica y que soportan la articulacion con el ordenamiento territorial, pasando por los beneficios economicos, politicos y sociales que traeria este proceso.

Análisis de la incorporación del Patrimonio Cultural Inmaterial en el Ordenamiento Territorial. Una propuesta de mecanismos de diálogo e inclusión para el caso de la Semana Santa de Popayán

Signos y síntomas de los tumores cerebrales primarios previos al diagnóstico, en pacientes entre los 6 meses y 17 años en el hospital Occidente de Kennedy evideciados entre enero de 2008 a noviembre de 2011

Propuesta de método para determinar la reserva rotante de energía en el SEIN

Plan de Autoprotección Oficinas Centrales Transportes Colectivos, SA (TCSA)

El transporte de moleculas entre el nucleo y el citoplasma es un proceso altamenteregulado y selectivo. Las proteinas que median tanto la importacion como laexportacion son las carioferinas, proteinas modulares, flexibles, capaces de reconocersecuencias especificas que portan las moleculas cargo para su transporte. Algunos deestos cargos son chaperones nucleares, que acompanan y protegen a las histonas ensu transito desde el citoplasma al nucleo, donde participan en procesos deremodelacion de la cromatina. En esta tesis hemos abordado el estudio,termodinamico y estructural, del complejo de importacion formado por el chaperonnucleoplasmina con su receptor de transporte, el heterodimero formado por lasimportinas ? y s. La NP, una proteina homopentamerica, es reconocida con altaafinidad por el heterodimero ?/s, pudiendo ocuparse todos sus centros de union, yformandose complejos flexibles, asimetricos y modulares, lo que podria facilitar sutransito a traves de los poros nucleares. Tambien hemos observado que la NP puedeasociarse simultaneamente a histonas e importinas, formando complejos definidosque podrian representar un posible mecanismo de cotransporte de NP e histonas alnucleo. La nucleofosmina (NPM) pertenece a la misma familia de chaperones dehistonas que la nucleoplasmina. Para desempenar sus funciones, que afectandirectamente al crecimiento celular, la NPM es transportada bidireccionalmente entrenucleo y citoplasma, es decir, es una ?shuttling protein?. La disfuncion de esta proteinaesta implicada en diversas patologias humanas; en particular, ciertas mutaciones quese correlacionan con la leucemia mieloide aguda, se caracterizan por una localizacioncelular aberrante de la proteina. En la tesis hemos abordado la interaccion de la NPMcon la exportina, con lo que globalmente, se ha perseguido profundizar en laimportacion y exportacion de estos chaperones de histonas oligomericos.

Ensamblaje de complejos de transporte nucleocitoplasmático con chaperones de histonas

La presencia d'amfores massaliotes a la costa castellonenca es escassa en comparacio amb altres formes de tipologia romana. La incorporacio de nous exemplars aporta dades arqueologiques significatives per al coneixement del comerc maritim en l'etapa prerromana.

Tesis (Magister en Educacion). Universidad Catolica de Manizales, Facultad de Educacion,2012

Reflexión ética, comunicativa y política de la Paideia desde las redes sociales virtuales

Una de las cuestiones que se plantean en el ambito de la presuncion de inocencia es si cabe entenderla destruida cuando se ha prescindido de una prueba de cargo directa mas segura cuya practica, sin embargo, era posible. Dicho con otras palabras, la cuestion es si la prueba indiciaria o incluso, la directa (por ejemplo, la declaracion de la supuesta victima de una agresion sexual) son suficientes para enervar la presuncion de inocencia cuando cabia la practica de otra prueba de cargo directa mas segura (por ejemplo, la de ADN). La cuestion se analizara a la luz de la doctrina tanto del TC como, en menor medida, del TS.

Destruye la presunción de inocencia una prueba de cargo menos segura cuando era posible una prueba de cargo directa más segura

Saneamiento interno de tierras de la comunidad Yaurichambi Provincia Los Andes del Departamento de La Paz

Biografia de Jons Jacob von Berzeliu y su importante contribucion para el desarrollo de la teoria atomica, asi como el analisis a sus diversas tablas de “pesos atomicos”.

The purpose of this study is to identify the functioning of the discourses of educational policy in Colombia between 2002 and 2010 to make visible the statements and practices discourses on human development. This is an archaeological and genealogical study based on the methodological principles of the French philosopher Michel Foucault. Taken the present discourses on human development in education policy from international to local will, from building an archive of documents was outlined the regime of truth about the statement of ―relevance‖ selected to demonstrate its repeatability and operation compared with other discursive formations. Finally, was analyzed the power relationships that emerge and operate within the Colombian education system from such discursive strategies. Was found that this statement and those that help it to define the expectation of educational policy, operate in such a way that, about human development, it is concluded that the expansion of opportunities from the development of human capabilities is a challenge that policy education arises as a discursive strategy, however the practices that are implemented by instances of governance realize reduction opportunities due to the need to train students for work, actions that serve to set a rigid and dependent on the potential labor market demands of a developing country.

El desarrollo humano en los discursos gubernamentales de la política educativa colombiana durante el periodo 2002 - 2010

Se realizo un estudio descriptivo, transversal, desde un enfoque o paradigma cuantitativo, a un grupo de adolescentes de la Escuela Secundaria Basica Urbana “Fernando Mederos” del municipio Guines, provincia La Habana, con el objetivo de determinar sus conocimientos sobre algunos factores relacionados con el consumo de drogas, durante el periodo de tiempo comprendido desde septiembre hasta diciembre del ano 2008. El analisis estadistico de los porcentajes se realizo usando la tabla de contingencia a traves de la docima X2. En los casos en que se alcanzo diferencias significativas se aplico la docima de comparacion Multiple de Duncan. Se demostro la presencia de consumo de drogas por los adolescentes estudiados, siendo el alcohol la sustancia toxica mas utilizada. En la mayoria de los adolescentes se establece un patron de consumo reiterado, asi como se comprobo escasos  conocimientos sobre factores de riesgos y protectores que los hacen mas vulnerables al consumo de sustancias toxicas. Se recomienda incorporar al plan de estudio de todas las ensenanzas una educacion integral sobre toxicomanias y su prevencion como elemento esencial en la formacion de nuestros jovenes y adolescentes.

Factores relacionados con el consumo de drogas en la adolescencia

Rincón lógico matemático para optimizar el desarrollo del pensamiento en los niños y niñas de la escuela "Miguel Andrade Manrique" del Recinto Carrizal perteneciente al Cantón Milagro

Alteración del patrón del sueño en los cuidadores familiares de personas con enfermedad crónica

En este proyecto, desarrollado para el Municipio de Palermo (Huila – Colombia), se logra la implementacion del Sistema de Video Vigilancia con el fin de mejorar la seguridad del Municipio. Este sistema consta de equipos de ultima tecnologia marca Pelco, permitiendo con esto una excelente calidad de imagen de las camaras, un alcance de vison de hasta 80 metros y angulos de giro de 360°, lo cual ayuda a realizar un trabajo mas eficiente a la Policia en su trabajo de brindar seguridad al Municipio. Con la implementacion de este sistema se esta ayudando a mejorar notablemente la seguridad del Municipio y sobre todo se esta recuperando la tranquilidad de sus pobladores la cual se habia perdido. Otro logro muy importante que se alcanza con la implementacion de este sistema, es la instalacion para el Municipio de un red de comunicacion por fibra optica, lo cual permite estar a la vanguardia de las comunicaciones y a la vez poder implementar a futuro servicios nuevos que se pueden prestar a traves de esta red como lo son: television digital, telefonia Ip e Internet.

Diseño de un Sistema de Video Vigilancia en la Plataforma de Telecomunicaciones del Programa Huila Digital para el Municipio de Palermo

La presente tesis sobre el efecto de la anestesia general en la cognicion del paciente de 50 a 70 anos atendido en el Hospital Nacional Regional San Juan de Dios de San Miguel se propone darnos a conocer si las personas que son intervenidas quirurgicamente presentan posterior a la cirugia algun deterioro cognitivo. 
La investigacion se realizo en el Hospital Nacional San Juan de Dios de San Miguel, con una poblacion de 50 pacientes programados para cirugia electiva que requerian anestesia general, Clasificados como ASA I, II o III, que no consumen alcohol, ni estupefacientes, sin trastornos neurologicos y dispuesto a colaborar en la investigacion. 
Este estudio se proponia determinar el efecto de la anestesia general en la cognicion, para alcanzarlo fue necesario evaluar el estado cognitivo del paciente antes aplicar la tecnica anestesica, asi como tambien 24 horas despues de su recuperacion, para posteriormente comparar los resultados obtenidos en las entrevistas realizadas anterior y posterior al procedimiento anestesico, para poder establecer diferencias en los parametros medidos. 
Los datos generales fueron ordenados en tablas de frecuencia y l a prueba de la hipotesis se hizo por medio de la “T STUDEN T”. Para comprobar si la anestesia general producia efecto en la cognicion de los pacientes. Despues de analizar e interpretar los datos obtenidos se pudo determinar que la anestesia general no produce alteracion en los procesos cognitivos (capacidad de concentracion, memoria, orientacion y lenguaje), la cual puede ser considerada una tecnica segura.

Efecto de la anestesia general en la cognición del paciente de 50 a 70 años de edad atendido en el Hospital Nacional Regional San Juan de Dios de San Miguel, en el período de abril a junio de 2009

Las micro, pequenas y medianas empresas, para enfrentar el desafio de alcanzar su crecimiento y desarrollo economico social en el mundo globalizado, demandan impulsar la diversificacion productiva y su colocacion en los mercados, a fin de generar mas oportunidades de negocios, empleos, ingresos y bienestar. Para integrarse en dicho proceso, es necesario: Contar con amplios y diversificados mercados. El conocimiento sobre las fortalezas y debilidades de la plataforma productiva y empresarial. El conocimiento sobre la de demanda potencial en los mercados locales y externos, y requisitos de posicionamiento de productos en los mismos. El recurso humano para desarrollar los procesos productivos. La infraestructura fisica y economica que faciliten el apoyo al desarrollo de las actividades productivas. Se debe partir del hecho que la economia mundial se encuentra sometida a una serie de ajustes y transformaciones, que desde todo angulo de analisis, se orienta hacia la mejora continua de los procesos productivos, comerciales y gerenciales, imponiendo nuevos retos y exigiendo formas creativas para mantener el crecimiento economico, el bienestar de la poblacion y que ello se transmita a los paises emergentes donde El Salvador es uno de ellos. La combinacion estrategica de nuestros recursos persigue la gradual y creciente reconversion del aparato productivo, partiendo de la identificacion, apoyo y desarrollo de actividades dinamicas capaces de incorporar nuevas tecnologias, generar altos niveles de valor agregado, a fin de cumplir con los requisitos de calidad-productividad-competitividad del posicionamiento de productos y servicios en los mercados. En el caso de El Salvador, afrontar y superar el desafio que se vincula con el cumplimiento de requisitos de desempeno de nuestras plataformas productivas, empresariales, legales e institucionales, y otros procesos del quehacer economico, constituyen el principal reto a superar. Partiendo de esta premisa, el presente documento es el resultado de la combinacion de esfuerzos entre la Coordinacion Academica de la Maestria en Consultoria Empresarial de la Universidad de El Salvador; y en colaboracion tecnica por parte del Proyecto Piloto Mentor “Programa de USAID”, para la Promocion de Exportaciones, como una iniciativa de la Agencia de los Estados Unidos para el Desarrollo Internacional y el Gobierno de El Salvador; con el objetivo de apoyar y promover las exportaciones de las pequenas y medianas empresas salvadorenas a Estados Unidos y otros mercados internacionales, ayudandolas a la vez aprovechar las oportunidades que se abren con la liberacion del comercio internacional. La implantacion del Proyecto Piloto Mentor, se efectuo mediante colaboraciones institucionales de las principales entidades de contrapartida que son: Ministerio de Economia y otras entidades del Gobierno de El Salvador; asi como Asociaciones Gremiales, Camaras, ONGs, Universidades y otras instituciones del sector privado, interesadas en promover las exportaciones del pais. Por lo anterior, la Universidad de El Salvador, comprometida con su mision, y compromiso social, ratificando su posicion de Universidad Publica que esta al servicio del bien comun y concibe el conocimiento como un bien social, en colaboracion con profesionales egresados de Maestria en Consultoria Empresarial, pone a disposicion sus conocimientos y destrezas adquiridas, para desarrollar una consultorias que conlleven a proponer soluciones a las empresas. En el caso particular, la consultoria se desarrollo con la finalidad del estudio y analisis en aquellos topicos en donde la empresa de lacteos Ortiza S.A de C.V., presenta debilidades, analizando diferentes elementos que intervienen de manera directa e indirecta en el proceso de produccion de lacteos; asi como tambien presentar propuestas para solucionar dichas debilidades, a fin de cumplir los objetivos que se ha planteado dicha empresa. Una de las areas con mayor debilidad, la constituye los costos en general, para lo cual se propuso un sistema automatizado para el manejo de los mismos. Para concluir, se presenta una sintesis de los capitulos que contiene esta investigacion, de tal forma el primer capitulo trata sobre los antecedentes basicos de la Empresa Ortiza S.A de C.V., filosofia corporativa, estructura organizativa actual, objetivos de la investigacion, metodologia, macro y micro variables. En el segundo capitulo, presenta la resena historica de la evolucion de la industria lactea a traves del tiempo; asi como su desarrollo en El Salvador; la contribucion que dicha industria tiene en la economia salvadorena; informe economico del sector industrial durante el ano 2007; analisis de la situacion economica que enfrentan las micro, pequenas y medianas empresas, y los desafios que enfrentan en una economia globalizada; se incluye de manera sintetizada, las instituciones que regulan, fiscalizan, ayudan y facilitan el buen desarrollo de empresas dedicadas a la produccion de lacteos. Ademas se incluye teoria sobre costos de produccion. En el tercer capitulo, se plantea el diagnostico correspondiente a la investigacion, en este se ha estructurado un analisis de la situacion actual de la empresa, con lo que se logro brindar conclusiones y recomendaciones a los hallazgos encontrados: y se utilizaron herramientas de diagnostico tales como: Analisis de las cinco fuerzas, diagnostico FODA, mapeo de grupos estrategicos, y razones financieras. Asi tambien, se presenta en el cuarto capitulo, la propuesta de Implantacion de un sistema de costos y precios para la empresa, el cual se dividio en seis etapas para efectuar los analisis de costos, e identificar de manera especifica los elementos que corresponden a cada seccion. En el quinto capitulo, se presentan como resultado de la consultoria realizada y con base a los datos recopilados y analizados, las conclusiones y recomendaciones concernientes a oportunidades de mejora encontradas en las areas analizadas, con la finalidad de aportar elementos y herramientas que contribuyan al fortalecimiento de los diferentes procesos.

Consultoría realizada a la empresa de productos lácteos ORTIZA S.A. de C.V.

El desarrollo de un cohete sonda involucra varios aspectos como son: - el sistema de propulsion, - la estructura - la aerodinamica y balistica del cohete. - la instrumentacion cientifica Entonces el objetivo general planteado en el presente trabajo es desarrollar un programa y un modelo matematico para el calculo de la aerodinamica y de la balistica que nos permita disenar la configuracion externa de un cohete sonda que tenga un buen comportamiento en vuelo y ademas nos permita predecir de forma exacta su trayectoria El primer objetivo es desarrollar un modelo matematico integral para el calculo de los coeficientes aerodinamicos que tome cuenta la gran variedad de factores de los cuales estos dependen y que se presentan durante el vuelo del cohete sonda. El conocimiento de estos coeficientes nos permitira: 1.-Garantizar un buen comportamiento del vehiculo en el aire. 2.-Tener una base completa de datos para su uso durante el calculo de la balistica externa. El segundo objetivo es la prediccion de la trayectoria de vuelo del vehiculo con un enfoque nuevo que es el uso de la base de datos en forma de matrices en 2D y 3D. Esto nos permitira obtener resultados con exactitud superior a los metodos actuales, ya que estos utilizan durante el computo de la trayectoria datos en forma de tablas o de ecuaciones que varian en funcion a una sola variable ya sea la velocidad, de la altura o del tiempo. Este grado de precision ira aumentando a medida que los valores de los intervalos tiempo, asi como intervalos de altitud en el programa desarrollado se vayan haciendo cada vez mas pequenos.

Balística externa de cohete sonda considerando los fenómenos de interferencia aerodinámica

Este proyecto simula el metodo de trabajo de una consultora 
informatica, que recibe la peticion de crear una tienda virtual de 
musica con diversas funcionalidades como registrar un usuario, 
insertar una cancion, comprarla y descargarla. 
Se realizara todo el proceso de un proyecto de este tipo, desde las 
reuniones con el cliente hasta su implementacion, pasando por el 
analisis de requerimientos, especificacion y diseno. 
Se utilizan tecnologias de codigo abierto. Con el paquete WAMP5 se 
instalara y configurara en un solo proceso un servidor Apache, el 
modulo de programacion PHP 5, la base de datos MySQL y la 
herramienta para administrar esta ultima, PHPMyAdmin. 
Se toma como base osCommerce, una solucion de comercio 
electronico desarrollado bajo GPL, programado en PHP, trabaja 
sobre Apache y usa MySQL. 
Una vez instalado osCommerce se tendra una tienda virtual 
operativa, pero que habra que adaptar a satisfacer las diferentes 
necesidades del cliente.

El crecimiento de la poblacion y la tala de arboles de las pocas areas naturales causan un deterioro ambiental y a la vez hacen que el espacio demografico del pais se reduzca generando grave problemas economicos y sociales, amenazando con danos irreversibles para el bienestar de las presentes y futuras generaciones asi como contaminacion tanto de rios como del ambiente, lo que motiva a organismos internacionales a invertir en programas que ayuden a erradicar de una manera u otra esta problematica a traves de instituciones no gubernamentales sin fines de lucro ONG´s las cuales llevan a cabo proyectos ambientalistas con la finalidad de contribuir a la recuperacion, proteccion, restauracion, y uso adecuado del medio ambiente. El campo de aplicacion de la auditoria cada dia se vuelve mas amplio y con la adopcion de Normativa Internacional y reformas a la legislacion salvadorena conllevan al profesional de la contaduria publica a estar actualizado. Una de las ramas de la auditoria de la que muchos auditores desconocen por la falta de practica es la auditoria a ONG´s, con el objetivo de contribuir al conocimiento de ello se presenta este documento con el que se pretende proporcionar al Auditor encargado de realizar una Auditoria Financiera a ONG´s una guia de procedimientos de Auditoria Financiera que le ayudara a mejorar la ejecucion de esta a efecto de que cuente con herramientas y tecnicas necesarias para realizar las pruebas o examenes pertinentes. La guia de procedimientos de Auditoria Financiera esta actualizada y de acuerdo a las necesidades de los organismos no gubernamentales para ofrecer garantia en sus registros, efectividad del control interno y la calidad de la gestion operativa. Esta documento esta desarrollado y disenado de acuerdo a la normativa tecnica vigente, al marco legal regulatorio relativos a ONG´s, asi tambien a los convenios suscritos con las diferentes entidades u organismos internacionales. La metodologia utilizada para sustentar este trabajo fue investigacion bibliografica y de campo, la primera fue enriquecida por medio de libros actualizados, de NIA’s, inclusive via internet; de igual manera se nos facilito una guia de Auditoria que utiliza un despacho, dicho documento contiene informacion actualizada en la materia. La investigacion de campo se realizo segun la muestra tomada en 17 ONG´s por medio de cuestionarios dirigidos al auditor encargado de realizar la Auditoria a ONG´s de los cuales siete fueron contestados por el Auditor Interno de la ONG mientras que los otros diez cuestionarios por el Auditor externo de la ONG. De los resultados obtenidos en la investigacion, se concluye principalmente que muchas ONG´s carecen del recurso y personal para desarrollar en su entidad una area de auditoria que le permita realizar las funciones que le competen a este, Mientras que algunos auditores externos creen tener el personal idoneo para desarrollar este trabajo pero carecen de herramientas, conocimiento y experiencia laboral necesaria que les permita realizar este tipo de Auditoria.

Auditoría financiera para ONG's ejecutoras de proyectos para la conservación del medio ambiente, ubicadas en el área metropolítana de San Salvador.

Objetivo principal: de esta investigacion fue sondear la preferencia en la restauracion de dientes que han recibido tratamiento de endodoncia entre docentes-tutores y estudiantes del Area de Restaurativa de la Facultad de Odontologia de la Universidad de El Salvador. Metodologia: La tecnica de recoleccion de datos utilizada para esta investigacion fue la entrevista y como instrumento fue utilizado el cuestionario el cual fue contestado por 12 docentes tutores y 19 estudiantes de IX y X ciclo respectivamente programados en el Area de Restaurativa de esta Facultad; para la obtencion de los datos el grupo investigador se dividio los instrumentos (cuestionario) en partes iguales de la siguiente manera: encuestador 1: 17 instrumentos, encuestador 2: 17 instrumentos y encuestador 3: 16 instrumentos; el proceso de recoleccion de datos se realizo dentro de las Clinicas de Restaurativa de esta Facultad, durante el turno de 7:00am a 9:00am (turno de restaurativa de IX ciclo) y de 1:00pm a 3:00pm (turno de restaurativa de X ciclo); solicitandole permiso al docente encargado del Area de Restaurativa. Una vez obtenida toda la informacion necesaria para realizar la investigacion se procedio a revisa r todos y cada uno de los instrumentos utilizados en la recoleccion de los datos. Para la tabulacion de los instrumentos fue necesaria la elaboracion de una hoja tabular general (Anexo 2). Posteriormente se realizo el vaciado de los mismos por medio de hojas electronicas de Excel para efectuar sumas y promedios a traves de filtros que nos proporciona este programa. El resumen de los resultados obtenidos se presento a traves de graficos de barra. Resultados: un 91.67% de docentes tutores y un 94.74 % estudiantes encuestados concuerdan al manifestar que la estructura dental remanente es el parametro que mas toman en cuenta para decidir si se coloca o no un poste para la reconstruccion de dientes tratados con endodoncia. Tanto docentes como estudiantes coinciden respecto a que la reconstruccion con resina es el tratamiento restaurador indicado en el caso de dientes que cuentan con cuatro paredes dentales remanentes posterior al tratamiento de endodoncia, ya que un 91.67% de docentes y un 73.68% de estudiantes eligio esta alternativa como primera opcion. En dientes que han perdido una o dos paredes dentarias remanentes un 50% de los docentes y un 52.63% respondieron que reconstruyen estos dientes con poste mas resina; un 41.67% de los docentes encuestados manifestaron indicar una corona en este caso; y solamente un 23.68% de estudiantes manifestaron reconstruir con resina este tipo de dientes. Cuando solo resta una pared de estructura dentaria remanente un 91.67% docentes y un 71.05% de estudiantes respondieron que colocan poste colado, y un 28.95% de alumnos colocaria una corona en este tipo de dientes. Reconstruccion con poste mas resina segun los resultados de este estudio es el tratamiento restaurador que se realiza con mayor frecuencia dentro de la Facultad ya que tanto docentes (83.33%), como estudiantes (73.68%) coincidieron en la apreciacion que tienen al respecto. El 33.33% de los docentes y el 36.84% de los alumnos respondieron que si se basan en una guia al momento de decidir el tratamiento restaurador en dientes tratados con endodoncia dentro de esta Facultad y el 66.67% de los docentes y un 63.16% de los alumnos estudiantes respondieron que no se basan en ninguna guia. Al sondear entre docentes y estudiantes si consideran que dentro de la Facultad de Odontologia de la Universidad de El Salvador se unifican criterios entre los docentes tutores del Area de Restaurativa al momento de seleccionar el tratamiento restaurador de dientes que han recibido previamente tratamiento de endodoncia, un 66.67% de docentes respondio que algunas veces y un 33.33% respondio que casi siempre. En cuanto a los estudiantes encuestados un 52.63% respondio que algunas veces y un 28.65% respondio que nunca. El 50% de docentes y el 50% de alumnos coincidieron al responder que si conocen una guia que les facilite la seleccion del tratamiento restaurador en dientes tratados con endodoncia de igual manera un 50% de los docentes y el 50% de los alumnos concordaron al responder que desconocen una guia. Conclusiones: Segun los docentes y alumnos encuestados el parametro que mas toman en cuenta para la seleccion de los diversos tratamientos en dientes tratados con endodoncia es la cantidad de estructura dentaria remanente. La apreciacion de los docentes y alumnos encuestados es que el tratamiento restaurador que se realiza con mayor frecuencia en dientes tratados con endodoncia dentro de la Facultad de Odontologia de la Universidad de El Salvador es poste mas resina.

Determinación del abordaje clínico restaurativo de dientes tratados con endodoncia (Clínicas Facultad de Odontología de la Universidad de El Salvador).

The carcasses of thirty suckling lambs (Suffolk Down x German Merino Precocius) were studied to estimate the effect of sex and slaughter weight on: hot carcass weight, carcass length, commercial and true dressing percentages, ribeye area, dorsal fat thickness, body components weight, and retail yield. The results were analysed considering two slaughter weights (10 and 15 kg), sex, and their interaction. Hot carcass weight, carcass length, ribeye area, and dorsal fat thickness were affected by slaughter weight. Leg, shoulder, and chops. Showed the highest commercial yields and were not affected by sex, slaughter weight. nor their interaction. Based on these results it can be said that this genotype has excellent qualities for meat production.

Efecto del peso de sacrificio y sexo sobre la canal de corderos lactantes del cruce Suffolk Down x merino precoz Alemán

Perfil socioeconômico, antropométrico, bioquímico e estilo de vida de pacientes atendidos no programa controle de peso

El mundo busca medios para enlentecer el proceso de envejecimiento, para poder hablar de la "Eterna Juventud", que se puede vincular con los ejercicios físicos, directamente con el estilo de buda. El Sistema de Salud Pública de Cuba, en coordinación con otros organismos y organizaciones del Estado, tiene como propósito contribuir a elevar el nivel de salud y la calidad de vida de las personas de la tercera edad. Por este motivo se realizó un estudio descriptivo retrospectivo en el período diciembre 2006 a marzo 2007, en el Círculo de Abuelos "Abel Santamaría" del consultorio # 18, del Policlínico "28 de Enero" del municipio Playa, en Ciudad de La Habana. El propósito de este trabajo fue valorar el grado de satisfacción de los adultos mayores con el programa de ejercicios físicos que realizaban. La población en este estudio la constituyeron los 34 abuelos pertenecientes al Círculo antes mencionado. La información se recogió a través de una encuesta que se les aplicó, una vez recogido su consentimiento. Los resultados permitieron concluir que a pesar de ser Adultos Mayores y las patologías que padecen, mejoraron su calidad de vida con la realización de los ejercicios físicos y fue palpable también el interés de los ancianos por la inclusión de otros ejercicios de la medicina tradicional oriental.

Diagnóstico del programa de ejercicios físicos realizados en el Círculo de abuelos "Abel Santamaría"

Plan Territorial Parcial del Valle de Aridane, Isla de La Palma (Canarias)

Mastitis is a disease of dairy cattle worldwide that causes decreased milk quality/yield, resulting in major economic losses. Mastitis is caused by a wide variety of organisms, including Staphylococcus aureus as a major pathogen. The purpose of this research was to characterize 20 Staphylococcus spp. isolates from the mammary gland of mastitic, lactating, backyard cattle, using both the Random Amplified Polymorphic DNA (RAPD) analysis, and sensitivity tests to 13 antibiotics and 1 detergent. Sensitivity tests to 13 antibiotics showed that all isolates were resistant to penicillin but sensitive to cephalothin, erythromycin, and trimethoprim. All isolates were susceptible to a 90% similarity in the RAPD band pattern, while isolates SA35 & SA36 were identical to each other. Nevertheless, all other isolates showed different amplification profiles. Isolates SA7 & SA8, SA30 & SA32, SA35 & SA36 had similar antibiotic resistance/RAPD patterns, suggesting re-isolation. Staphylococcus isolates collected in Tarimbaro, Michoacan showed several different amplification patterns.

Caracterización molecular de aislamientos de Staphylococcus spp. asociados a mastitis bovina en Tarímbaro, Michoacán

Actividad tripanomicida en el Tripanosoma cruzi del extracto etanólico de las semillas de la Xylopia aromatica

Ley de Desarrollo Social del Distrito Federal: Alcances, limitaciones y perspectivas

Análisis de los beneficios de implementar un sistema de seguridad industrial y salud ocupacional, basado en la norma técnica colombiana TNC OHSAS 18001 desde la experiencia de Ecopetrol planta Villeta: una propuesta para los contratistas

Este trabajo versa en la propuesta de una Guia Practica de Asesoramiento Financiero para las microempresas dedicadas a la fabricacion de prendas de vestir femeninas del Municipio de Mejicanos del Departamento de San Salvador, que contribuya a una adecuada planificacion y control de las utilidades, y ademas actualizara los conocimientos que permitan al microempresario tomar decisiones acertadas en el manejo de los recursos. El objetivo general de la Guia Practica de Asesoramiento Financiero es brindar asesoria tecnica a los microempresarios para enriquecer y actualizar los conocimientos basicos sobre el uso de herramientas que optimizan la eficiente administracion y control de los recursos financieros de la microempresa. Cabe mencionar que dicha guia permitira instalar las actividades presupuestales que se requieren durante la ejecucion del proceso productivo, asi mismo; servira de modelo para todas aquellas microempresas dedicadas a la fabricacion de productos que deseen aplicarla. La importancia de la elaboracion de una Guia Practica de Asesoramiento Financiero, es que contribuira al apoyo tecnico para una eficiente gestion de la funcion financiera del negocio, a fin de facilitar el crecimiento y desarrollo del mismo. El metodo que se empleo al efectuar la investigacion, fue el metodo cientifico a traves de la induccion; el tipo de investigacion fue la descriptiva utilizando como herramienta el cuestionario, mediante una serie de preguntas elaboradas y dirigidas a los microempresarios.El principal resultado de la investigacion fue que los microempresarios no cuentan con un sistema de administracion de los recursos financieros que le permitan establecer controles en el manejo eficiente de los mismos. Al finalizar el diagnostico se llego a la conclusion de que la elaboracion de una Guia Practica de Asesoramiento Financiero contribuira a que los microempresarios planifiquen, organicen y establezcan controles de los recursos financieros con los que cuenta para realizar sus actividades, logrando con ello hacer mas rentables sus negocios. En base a lo anterior se recomienda la implementacion de la Guia Practica de Asesoramiento Financiero en la administracion de las microempresas, y asi, lograr que los recursos con los que cuentan sean aprovechados al maximo.

Diseño de una guía práctica para el asesoramiento financiero de la microempresa dedicada a la fabricación de prendas de vestir femeninas en el municipio de San Salvador.

O diverticulo de Meckel (DM) e a mais prevalente anomalia do trato gastrointestinal, sendo mais encontrado no sexo masculino. Incide em 2por cento da populacao geral, com taxa de complicacoes ao longo da vida de 4por cento a qual vai diminuindo com a idade. Os autores descrevem o caso de um menino de um ano e sete meses com historia de melena e enterorragia com evolucao de seis meses. Durante a descricao do caso, os autores confirmam a maior sensibilidade da cintilografia para diagnostico de DM. Embora o DM seja uma patologia relativamente rara em criancas, dentre as anormalidades congenitas e a mais frequente. Isso justifica a descricao deste relato de caso

Desde hace algun tiempo se percibe una desilusion creciente respecto al proceso historico dominante en occidente durante los ultimos siglos: la Modernidad. Si sus logros resultan evidentes, sus carencias y desmanes tambien lo son. Por eso, la insatisfaccion parece sustituir al optimismo hasta hace poco reinante. Y a cambio, se abre paso un fenomeno todavia difuso llamado Postmodemidad. Unos la acogen fervorosamente, otros la rechazan. Quiza sea conveniente para todos realizar una valoracion critica de la misma y, en la medida de lo posible, abrir vias de reflexion.

Procedimiento para obtener un recubrimiento de un
material compuesto de una matriz metalica y particulas ceramicas de
refuerzo sobre un sustrato metalico. La invencion proporciona un procedimiento para
obtener un recubrimiento de un material compuesto de una matriz
metalica de un material base metalico y particulas ceramicas de
refuerzo sobre un sustrato metalico caracterizado porque comprende
las etapas de: (a) recubrimiento de las particulas ceramicas de
refuerzo con silice; (b) mezclado de las particulas ceramicas de
refuerzo recubiertas obtenidas en la etapa a) con el material base
metalico pulverizado; y (c) proyeccion por llama de la mezcla obtenida
en la etapa b) sobre el sustrato previamente tratado. Asimismo, la invencion proporciona el
recubrimiento de material compuesto asi obtenido que presenta buenas
propiedades de homogeneidad, porosidad, resistencia quimica y
resistencia frente a la humedad y al desgaste, y que es util en 
aplicaciones industriales tales como la obtencion de piezas
resistentes al desgaste o a la corrosion, o la reparacion de piezas
desgastadas.

Procedimiento para obtener un recubrimiento de un material compuesto de una matriz metalica y particulas ceramicas de refuerzo sobre un sustrato metalico.

Introduccion. Objetivo: comparar 2 guias terapeuticas que difieren en el manejo de liquidos y bicarbonato de sodio para corregir la deshidratacion y el desequilibrio acido base en pacientes con cetoacidosis diabetica (CAD). Material y metodos. Diseno: casos y controles. Se compararon 2 muestras a conveniencia de los registros de 16 pacientes con CAD tratados con una guia terapeutica que recomienda corregir la deshidratacion, considerando los liquidos basales mas las perdidas insensibles de liquidos por respiracion y las perdidas secundarias a diuresis osmotica, y que no recomienda el uso de bicarbonato de sodio para corregir la acidosis, con un grupo de control de 16 registros de pacientes con CAD expuestos a una guia terapeutica que no considera las perdidas insensibles por la taquipnea relacionada, y aquellas secundarias a diuresis osmotica para corregir la deshidratacion, y recomienda el uso de bicarbonato de sodio para corregir la acidosis. Se incluyeron en el estudio a pacientes que a su ingreso tenian deshidratacion grave con hiperglucemia igual o mayor a 300 mg/dL, pH igual o menor a 7.3 o bicarbonato menor a 15 mmol/L, cetonemia, glucosurias y cetonurias. Resultados. La correccion de la deshidratacion en 24 horas se logro en 81.2% del grupo de estudio y en 37.5% del grupo control (P =0.0005). Los liquidos suministrados en el grupo de estudio fueron de 5 287 ± 1 659 mL y el grupo control de 8 360 ± 7 391 mL (P =0.004). La glucemia al termino de 24 horas fue de 292 ± 45 mg en el grupo de estudio y 310 ± 76.4 mg en el grupo control, sin significancia estadistica (P =0.4). El pH de 7.32 ± 0.064 en el grupo de estudio y de 7.2 ± 0.146 en el grupo control, con significancia estadistica (P =0.005). El anion gap mostro al termino de 24 horas de 12.7 ± 1.57 en el grupo de estudio y de 29 ± 11.44 en el grupo control con alta significancia estadistica (P =0.0001). El sodio serico a las 24 horas fue de 133.9 ± 2.56 mEq/L en el grupo de estudio y de 147.8 ± 12.47 mEq/L en los controles (P =0.001). La osmolalidad para el grupo control fue de 276 ± 8.08, para el grupo de estudio de 296 ± 6.75 mOsmol/L, con alta significancia estadistica (P =0.0003). El potasio serico a las 24 horas en el grupo de estudio fue de 4.85 ± 1.15 mEq/L y de 4.2 ± 0.52 mEq/L en los controles (P =0.05). Conclusiones. Este protocolo ha demostrado ser muy practico y efectivo para el tratamiento hidroelectrolitico y el equilibrio acido base, mostrando mejor estabilizacion en 24 horas de tratamiento. El restablecimiento de la hidratacion y del equilibrio electrolitico y acido base son superiores en el grupo de estudio, no existen diferencias en cuanto a la correccion de la glucemia.

Tratamiento hidroelectrolítico y ácido base en pacientes con cetoacidosis diabética: comparación de dos guías terapéuticas

Frente a la problematica de la agricultura, y en general, frente a la falta de oportunidades, algunas personas habitantes de la comunidad se deciden por acciones desesperadas, en particular, emigrar de la comunidad hacia otros paises como: Estados Unidos y Canada. La investigacion se intereso por abordar la siguiente pregunta: ?De que sirven las remesas que reciben algunas familias? En general, son personas jovenes las que emigran, y si ellos son el presente y el futuro las probabilidades de que la comunidad sobresalga, podrian considerarse como lejanas, aunque no puede dejar de considerarse una solucion final. La investigacion encuentra una fortaleza que, de ser consolidada, podria constituirse en un eje de transformacion y desarrollo de la comunidad: la organizacion. No obstante, la misma organizacion pareciera que se debilita. 
El estudio retrata la vida y el rumbo de una comunidad, recordar el pasado y aprender de el. Descubrir la ensenanza que se deriva, no solo para la Comunidad Rutilio Grande, sino para toda la sociedad.

La Economía agrícola y las remesas familiares en la Comunidad Rutilio Grande

Historia de la sala cuna externa de San Salvador -- Historia de la lamina troquelada en El Salvador -- Situacion poblacional infantil de la sala cuna externa de San Salvador -- Estructura organizativa de la sala cuna externa de San Salvador

Propuesta de restauración para la sala cuna externa centro histórico de San Salvador

En el presente trabajo para optar al grado de Licenciatura en Ciencias Juridicas, con el tema “la utilizacion del Anticipo de Prueba como un medio de aseguramiento de elementos probatorios en el Juicio Oral”, se pretende analizar el Concepto, los Presupuestos, Naturaleza Juridica y Requisitos del mismo. Los objetivos generales requieren analizar el uso del Anticipo de Prueba que hacen Fiscales y Defensores Publicos, como un medio de aseguramiento de los elementos probatorios Irreproducibles en la Vista Publica, como tambien establecer la frecuencia con la que los Fiscales y Defensores Publicos utilizan el Anticipo de Prueba, para asegurar elementos Irreproducibles en la Vista Publica. Para cumplir con dichos objetivos se ha utilizado la investigacion cientifica, la pretende encontrar respuesta a los problemas relevantes que el hombre se plantea y lograr hallazgos significativos que aumenten su de conocimiento; sin embargo para que estos sean consistentes y confiables es necesario seguir un metodo y este es el cientifico que implica la concatenacion logica de una serie de etapas. Se ha concluido que; el Anticipo de Prueba como un Medio Procesal establecido en la Ley y util porque asegura elementos probatorios para la Vista Publica, constituye un aporte basico adoptado por el nuevo Modelo de Sistema Procesal Penal, Acusatorio Mixto Moderno, basado en la garantia del Juicio Previo y conformado por dos grandes fases: La Instruccion y la de Juicio Oral y Publico, en donde las pruebas deben ser producidas por regla general durante esa ultima, dado que en este sistema la Instruccion es solo la etapa preparatoria para el Juicio, en la cual se recolectan elementos probatorios para introducirlos en la Vista Publica; contrario a lo que se regulaba en el Codigo Procesal Penal de 1973, en el cual la Instruccion constituia la fase en la cual se comprobaba el cuerpo del delito y quien o quienes habian participado en el hecho, resultando que el mismo Juez seria quien conoceria del Juicio, por lo tanto dicho medio procesal no se establecia ya que existia un sistema de conversion automatica de los elementos recolectados en la Investigacion Preliminar, en elementos de cargo. Por el contrario con el Codigo Procesal Penal que entro en vigencia en 1998, ya se regula la posibilidad de Producir los elementos probatorios en forma anticipada, conocida con el nombre de: “Anticipo de Prueba”; pero, solo excepcionalmente, seran solicitados por las partes, o podra ser ordenado de oficio por el Juez, siempre que concurran los presupuestos de Previsibilidad e Irrepetibilidad de los Actos Definitivos e Irreproducibles.

Utilización del anticipo de prueba como medio de aseguramiento de elementos probatorios en el juicio oral, en el departamento de San Miguel, 2001-2003

The aim of this study was to analyze in vitro surface hardness (micro-indentation tester Wolpert) of different types of amalgam alloys varying the technique and polishing time. Tested were the amalgam: Velvalloy, Permite e Dispersalloy. For each material, 2 polishing techniques were accomplished: T1 (bladed finishing burs + abrasive rubber points + pumice-water slurry in Robinson polishing brush) and; T2 (abrasive rubber points + pumice-water slurry in Robinson polishing brush), at 2 periods of time: P1 (immediately - 15 min after condensation) and P2 (after 24 h). For each experimental condition, 5 samples were prepared. For each sample, 2 indentations were taken and the average was determined. Were made analysis using ANOVA and Tukey test. Were concluded that: a) using the Permite alloy with polishing after 24 h the surface hardness of restoration will be higher; b) the technique T2 enhances the hardness of dental amalgams and c) alloy Permite with polished immediately were statisticaly equal than Velvalloy polished after 24 h.

Evaluación de la dureza superficial en amalgamas en función de tipos de aleaciones, momentos y tipos de pulimentos

La metafisica tiene su propio objeto: las substancias separadas. Necesita tambien de un metodo propio. En esta tesis estudiamos el papel y la importancia de la separacion en este metodo. Este trabajo esta dividido en cuatro capitulos. El primero es una introduccion al tercer articulo de la cuestion quinta del comentario al libro de Boecio De Trinitae. Se explican la abstraccion y la separacion, como caracteristicas de las ciencias particulares y la metafisica respectivamente. Se estudia tambien la importancia de la separacion en la metafisica tomista y su originalidad respecto a la filosofia aristotelica, que es la nocion de esse (acto de ser o ser como acto). En el segundo capitulo, procuramos mostrar la separacion es necesaria para realizar el metodo de la resolucion en el ser (la via resolutionis o la reduccion el fundamento) que es el metodo propio de la metafisica. Estudiamos el fundamento de la separacion segun algunos autores, Geiger, Wippel, Le Roy, Sanguineti, Vicente y Vanteenskiste. Concluimos que el juicio negativo de separacion esta fundado en el caracter de absoluta primacia que caracteriza el esse y que la separacion permite descubrir la absluta trascendencia del ser sobre la materia y realizar la ascension de lo separable secundum esse para el Ipsum Esse Subsistens, del ser para Dios, de la criatura al Creador. En el tercero capitulo, procuramos una vision lo mas completa posible de la teoria tomista de la abstraccion y concluimos que Santo Tomas mantiene un pensamiento uniforme en este tema a lo largo de su vida. Aunque no mantenga la distincion estricta de terminos entre abstraccion y separacion, sin embargo mantiene lo esencial de su modo de pensar: la distincion entre la abstraccion segun la primera operacion y la segunda operacion de la mente, considerando siempre la separacion como caracteristica de la metafisica. Finalmente, en el cuarto capitulo, hacemos un con

Abstracción, separación y método en metafísica según Santo Tomás de Aquino

Análisis de un supuesto determinado de conflicto entre el derecho al honor y la libertad de expresión

Niveles bajos de alfafetoproteína en suero materno como indicador de riesgo perinatal

El dolmen de Alberite. Aportaciones al estudio de la ideología y del espacio megalítico

Estudio de los trastornos psíquicos y somáticos que inciden en el climaterio

LA EXHIBICION DE LA EXPO-FISICA 93, ORGANIZADA POR EL LABORATORIO DE FISICA DE LA FACULTAD DE QUIMICA (FQ), MOSTRO AL PUBLICO TRABAJOS DE CINEMATICA Y DINAMICA, ELECTROMAGNETISMO Y ONDAS.

LA EXPO-FISICA 93 BUSCA PROMOVER EL INTERES DE ALUMNOS POR ESTE CAMPO

Explotación de los recursos líticos en la prehistoria reciente de Cádiz

EN ESTE TRABAJO SE HA INTENTADO ALCANZAR EL SENTIDO DEL TEMOR, PARA LO CUAL HEMOS RECOPILADO CON LA AYUDA DE DISTINTAS CONCORDANCIAS, TODOS LOS TEXTOS DE LOS PROFETAS EN LOS QUE APARECIERA EL TEMOR BAJO CUALQUIERA DE SUS SIGNIFICADOS, CON LO QUE HEMOS AGOTADO, PRACTICAMENTE, TODO EL CAMPO SEMANTICO DEL TEMOR. EN EL CAPITULO I SE TRATAN LOS TERMINOS DISTINTOS DE YR; EN EL CAPITULO II SE ANALIZAN LOS DIVERSOS CONTENIDOS DE LA RAIZ YR; Y EN EL CAPITULO III SE ESTUDIA EL ALCANCE DE LA FORMULA 1-TYR. PRETENDEMOS DEMOSTRAR QUE EL VERBO YR TIENE UN CONTENIDO EMINENTEMENTE RELIGIOSO, MIENTRAS QUE LOS DEMAS VERBOS LO TIENEN EMINENTEMENTE PROFANO, CON LO QUE EL CONCEPTO DE "TEMOR DE DIOS" RESULTA DISTINTO DE LOS OTROS SENTIMIENTOS DE TEMOR QUE SE MANIFIESTAN EN EL HOMBRE. EL "TEMOR DE DIOS" VIENE A RESUMIR LA ACTITUD -PIEDAD, CULTO, COLABORACION, SOMETIMIENTO, AMOR, ESPERANZA, ETC.- DEL FIEL ISRAELITA HACIA DIOS.

El grupo de traducción del Instituto Hispano-Árabe de Cultura de Bagdad

El presente ensayo se realizo en la Granja Experimen¬tal del Centro de Desarrollo Ganadero (C.D.G.), en la seccion de Especies Menores, Ministerio de Agricultura y Ga¬naderia (MAG); ubicado en, el Canton El Matazano, jurisdiccion de Ilopango, Departamento de San Salvador; con una altura de 625 msnm; temperatura promedio de 23.6 °C, humedad relativa promedio de 76.8 7c y precipitacion promedio de 1697 mm. El objetivo fue evaluar cuatro diferentes edades de destete en conejos de engorde para poder determinar cual de ellos represento al final un mejor peso de la canal al momento del sacrificio y por consiguiente cual es mas rentable a nuestro medio.El ensayo tuvo una duracion de 17 semanas: cuatro y media de las cuales correspondieron a la gestacion de las conejas; 4-6 semanas en que se evaluaron las diferentes edades para el destete (T-1. = 25, = 35, T3= 45 y T4= 5 (dias): 5-7 semanas para completar la edad estipulada para el sacrificio (75 dias) Se formaron cuatro grupos de ocho hembras cada uno La alimentacion fue a base de concentrado peletizado comercial, cuyos nutrientes son: Proteina. 17.5%: fibra bruta, 14.5% y energia, 2000Kcal/Kg. Las ganancias de peso fueron medidas semanalmente. Se utilizo el diseno Completamente Randomizado y a los resultados obtenidos se les efectuo el respectivo analisis de varianza con la prueba de Duncan y no se encon¬tro diferencia estadistica entre tratamientos (edades de (destete)Al realizar el analisis bioeconomico se observo que el tratamiento T-1, produjo un mayor beneficio parcial de¬bido a que las cantidades de concentrado ofrecido fueron menores en comparacion a los demas tratamientos. Ademas, se ha considerado la variable reproductiva --(ritmo teorico de partos), la cual demuestra que la can¬tidad obtenida de gazapos en un periodo determinado (un ano), se incrementa debido al mayor numero de camadas paridas anualmente. En base a lo antes expuesto, se puede afirmar que el tratamiento T-1 (25 dias de destete), es beneficioso en una explotacion canicula.

Evaluación de cuatro diferentes edades de destete en el peso final de la canal en conejos de engorde.

La zona del proyecto esta localizada en el sur medio de la - sierra del Peru. Politicamente se situa en el departamento de Huancavelica, provincia de Castrovirreyna, distrito de Chupamarca. Geograficamente se encuentra ubicada en las coordenadas 75°37' de longitud oeste 13°02' de latitud sur y a una altitud promedio de 3,400 m.s.n.m.; pertenece a la cuenca hidrografica del rio San Juan cuyas aguas desembocan en el Oceano Pacifico. Las caracteristicas fisico ambientales en el area del proyecto son favorables para la produccion agricola. La estacion meteoroIogica representativa para caracterizar el clima es la de Armas que registra una precipitacion total anual promedio de 620 mm., una temperatura media anual de 10° C. y una humedad relativa media anual de 83 %.

Estudio integral de agua potable alcantarillado y drenaje pluvial de la ciudad de Tarma

Proyecto de bases para constituir la propiedad rústica en cotos redondos

Long-term quality of life changes after primary septorhinoplasty

We describe novel approaches to study exploration in humans beyond simple multi-armed bandit tasks.

To what extent do human reward learning and decision-making rely on the ability to represent and generate richly structured relationships between options? We provide evidence that structure learning and the principle of compositionality play crucial roles in human reinforcement learning. In a new multi-armed bandit paradigm, we found evidence that participants are able to learn representations of different reward structures and combine them to make correct generalizations about options in novel contexts. Moreover, we found substantial evidence that participants transferred knowledge of simpler reward structures to make compositional generalizations about rewards in complex contexts. This allowed participants to accumulate more rewards earlier, and to explore less whenever such knowledge transfer was possible. We also provide a computational model which is able to generalize and compose knowledge for complex reward structures. This model describes participant behaviour in the compositional generalization task better than various other models of decision-making and transfer learning.

Applicant reactions to social media assessment: A review and conceptual framework

Beyond uncertainty and information bonuses: Exploration as fun and empowerment

ABSTRACT Drawing on human-capital theory, we propose divergent associations of professional employees’ base pay and incentive pay with their levels of human capital in the small business context. Based on secondary data on 3,750 professional employees representing 65 small firms, we found that, whereas human capital has a positive relationship with base pay, the relationship between human capital and incentive pay is less apparent. Specifically, we found that the relationship between incentive pay and position-specific experience is negative. Our findings suggest that small firms may use higher incentive pay to initially attract talent. Yet, the incentive pay does not grow as professional employees gain firm-specific experience. Moreover, the incentive pay significantly falls as professionals gain more position-specific experience, and this negative relationship is stronger in small firms with higher sales productivity. Further, firm longevity shows a moderately significant positive relationship with base pay; however, the findings show that firm longevity is negatively related to incentive pay.

The levels of base pay and incentive pay used by small firms to compensate professional employees with general and specific human capital

Applicant reactions to selection procedures have attracted much scholarly attention in the work and organizational psychology literature over the past three decades. While this body of literature i...

Understanding Applicant Reactions to Social Media as a Selection Tool: An Integrative Model

A strong body of empirical research exists delineating an association between systems of high performance work practices (HPWPs) and organizational performance. However, insufficient attention has been paid to the vital role that supervisors play in implementing these practices. We conducted an experiment involving 320 subjects exposed to varying levels of supervisory support for HPWPs that subjects were promised they would receive and from which they would benefit. Individuals with supervisors who withheld support for some HPWPs responded with greater perceptions of procedural injustice committed against their interests by the supervisor, impressions of lessened managerial support and trust and a heightened proclivity to behave counterproductively toward the supervisor. Individuals with supervisors who withheld support for all HPWPs responded with greater perceptions of procedural injustice committed against their interests by both the organization and supervisor, and an enhanced tendency to behave count...

Broken Promises: Supervisory Support for High Performance Work Practices and Employee Perceptions

The Impact of Supervisory Support for High-Performance Human Resource Practices on Employee In-Role, Extra-Role and Counterproductive Behaviors

Drawing on human capital theory, we propose divergent associations of base pay and incentive pay with professional employee human capital in small high-tech firms. Based on secondary data on 3,750 professional employees representing 65 small hi-tech firms we found that while human capital has a positive relationship with base pay, the relationship between human capital and incentive pay is not so consistent. Our findings suggest the relationship between incentive pay and position-specific experience may be negative. We found that small high-tech firms use higher incentive pay to initially attract talent. Yet, the incentive pay does not grow as professional employees gain firm-specific experience. Moreover, the incentive pay significantly falls as professionals gain more position-specific experience.

Association of Professional's Base and Incentive Pay with Human Capital in Small High-tech Firms

Insufficient retirement savings behavior practiced by a significant number of employees underscores the importance of understanding the characteristics of those individuals most likely to choose the default contribution and asset allocation vehicles of an organization. We conducted an experiment of savings behavior involving 217 subjects asked to make choices about allocating 401(k) funds and investing those funds in investment vehicles. Individuals who specified their own allocation amounts invested significantly more money versus those who accepted a default. Psychological and demographic factors also predicted higher investment dollars and higher-risk investment choices. Changes in ambiguity tolerance significantly affected men’s decisions to choose high-risk investments for their 401(k) dollars, but these psychological variables did not affect women’s high-risk investment decisions. We offer implications for future research and practice.

Core employee based human capital and revenue productivity in small firms: An empirical investigation

Executive compensation research has primarily focused on CEO pay and paid very little attention to other executives. This study investigated compensation of upper level managers and their human capital excluding the CEO within firms. We also investigated if this relationship varies across firms with different levels of performance. Specifically, we examined firm-level performance moderated individual-level relationships between an upper-level manager’s human capital and his/her compensation. With multi-level analyses using 728 upper-level managers representing 87 firms we found that ROI growth rate exhibits positive cross-level positive moderating influence on the main effect of education and a negative moderating influence on the main effect of experience on compensation.

Upper-level managerial human capital and compensation relationship: A multi-level analysis

ABSTRACTWe asked 96 small business owners to rate the criticality of 10 Human Resource issues to their current businesses. The owners perceived the HR issues as having different criticality levels. The analysis showed that the innovation facet of Entrepreneurial Orientation (EO) explained significant differences in owners' perceptions of HR activities. The risk propensity facet of EO did not predict differences in the perceived criticality of HR issues. Relevant literature is presented, and then the survey method and measures are detailed. We discuss the findings, limitations and strengths of the research, and, finally, suggested next steps.INTRODUCTIONBased on the resource based view of the firm, entrepreneurship literature proposes that resource accumulation plays a significant role in the entrepreneurial process (Greene, Gene, & Edison, 1997; Haber & Reicheil, 2007). This stream of research in entrepreneurship posits that people are a significant source of competitive advantage. Human capital resources in terms of technical experts, design experts, productive service providers, expert factory workers, talented managers are all thought to be important resources that create competitive advantage and improve performance. Therefore, human resource practices to develop and utilize human resources become important for firm performance. Human resource practices have mainly been studied in large firms, and research in small firms is primarily descriptive (Heneman, Tansky, & Camp, 2000; Golhar & Deshpande, 1997). Deshpande and Golhar (1994) suggest that there are significant differences in human resource practices based on firm size.Accordingly, we are still not clear as to "what human resource management (HRM) advice can we offer to small- or medium-sized entrepreneurial enterprises" (Katz, Aldrich, Welboume, & Williams, 2000: p.7). The lack of research indicates a tremendous opportunity for expanding our knowledge of HRM practices in small and midsized enterprises (SMEs) (Heneman et al, 2000). Hence, scholars have suggested that more research of human resource practices in small firms would make a significant contribution to the SME literature (Rauch, Frese, & Letsch, 2005).Since a company's human capital is defined as the collective productive capacity of its employees (Buchholtz, Ribbens, & Houle, 2003), developing and maintaining employees who provide superior human capital is critical for improving productivity in SMEs. A lack of trained and qualified workers can therefore be a critical threat to the effectiveness of small firms (Ibielski, 1997). HRM practices that are designed to select and retain the best employees, such as hiring and compensation, are important factors in developing and maintaining human capital within SMEs. However, both the popular press and scholarly research in SMEs suggest that the task of attracting and retaining talented employees is more difficult for small firms compared to their larger counterparts (McKee, 1991; Hornsby & Kuratko, 1990; Gilbert & Jones, 2000; Kotey & Sheridan, 2001).The dearth of research makes the current knowledge of effective HRM practices in the context of SME sorely lacking. It is not clear if entrepreneurs vary in their perceptions of human resource practices as significant activities. Despite challenges to applying HRM in SMEs, the limited available research indicates that entrepreneurs' perceived importance of HRM differ depending on individual and firm characteristics (e.g., Cooper, Ramachandran, & Schoorman, 1997; Tocher & Rutherford, 2009). Furthermore, current studies are primarily descriptive and do not incorporate current theoretical knowledge about entrepreneurs. In this study, we propose that entrepreneurial orientation (EO) is a useful theory that may help researchers understand entrepreneurs' perceptions of HRM issues. Since entrepreneurs may possess different levels of EO based on their propensity for entrepreneurship, they may vary in terms of their perceived importance of specific human resource activities. …

Perceptions of entrepreneurs in the perceived criticality of human resource activities

The human capital of a firm as manifested by employee knowledge and experience represents a key resource of a firm's capabilities. Prior empirical studies have found that firms composed of high levels of human capital experience superior firm performance. Human capital theory proposes that an individual's general or firm-specific human capital is positively related to compensation. However, empirical studies examining firm-specific human capital's association with higher employee compensation have been inconclusive. The current study proposes that firm-specific human capital be categorized as task-specific and non-task-specific. Employees accumulate task-specific human capital through duties conducted in their current position. Non-task-specific human capital represents experiences gained in prior positions to an employee's current job within the firm. Utilizing human capital data from 38,390 employees representing 76 firms in the IT sector, this study examines the association between forms of human capital and employee compensation at different levels of firm productivity. Results show that task-specific human capital is associated with higher employee compensation. In addition, firm productivity moderates this association.

Firm productivity moderated link between human capital and compensation: The significance of task-specific human capital

The Smart Marketer’s Toolbox: The latest marketing inovations and how to use them to grow your business

We introduce the Berlin Numeracy Test, a new psychometrically sound instrument that quickly assesses statistical numeracy and risk literacy. We present 21 studies (n=5336) showing robust psychometric discriminability across 15 countries (e.g., Germany, Pakistan, Japan, USA) and diverse samples (e.g., medical professionals, general populations, Mechanical Turk web panels). Analyses demonstrate desirable patterns of convergent validity (e.g., numeracy, general cognitive abilities), discriminant validity (e.g., personality, motivation), and criterion validity (e.g., numerical and non-numerical questions about risk). The Berlin Numeracy Test was found to be the strongest predictor of comprehension of everyday risks (e.g., evaluating claims about products and treatments; interpreting forecasts), doubling the predictive power of other numeracy instruments and accounting for unique variance beyond other cognitive tests (e.g., cognitive reflection, working memory, intelligence). The Berlin Numeracy Test typically takes about three minutes to complete and is available in multiple languages and formats, including a computer adaptive test that automatically scores and reports data to researchers (http://www.riskliteracy.org). The online forum also provides interactive content for public outreach and education, and offers a recommendation system for test format selection. Discussion centers on construct validity of numeracy for risk literacy, underlying cognitive mechanisms, and applications in adaptive decision support.

The employment interview is the most frequently used selection device, but the majority of employment interviews are conducted by individuals with little or no training in the process (Chapman and Zweig, 2005; van der Zee el al., 2002). This lack of training seems puzzling given that there is strong evidence that managers often commit numerous errors during the interview process and in making hiring decisions (Schmidt and Zimmerman, 2004; Dougherty et al., 1986). Scholars have shown interviewers' questions often do not address the demands of the job (Hedge and Teachout, 1992; Taylor and Sniezek, 1984). Similarly, untrained managers frequently go on intuition or "gut" feelings about the candidate being interviewed, are overconfident about their judgments, and tend to overestimate how much they know (Harris and Eder, 1999). Additionally, managers often overlook many key points from the interview (Dougherty et al., 1994; Carlson et al., 1971) and also fail to take the most effective notes (Middendorf and Macan, 2002). As a result of their overconfidence, managers also fail to learn from their experiences and adjust their methods in later interviews (Kleinmuntz, 1990). Interviewer training has been shown to reduce the most common and egregious errors interviewers make (Chapman and Rowe, 2002; Howard and Dailey, 1979). Certainly, this impact may vary depending on the quality of the training program (Maurer and Fay, 1988), but research has demonstrated that providing interviewers training significantly enhances the quality of the employment decision (Conway et al., 1995; Huffcutt and Woehr, 1999; Highhouse, 2008). One reason that organizations might not provide interviewer training is because trainers often advocate for the use of a structured interview process. Although research clearly indicates that structured interviews have greater reliability and validity than unstructured interviews, (McDaniel et al., 1994; Huffcutt and Arthur, 1994; Weisner and Cronshaw, 1988), the majority of managers still apparently do not use a structured process (van der Zee et al., 2002). Lievens and DePaepe (2004) have shown that managers have pushed back against structured interviews due to their perceptions that they lose control of the interview process. Structured interviews also (initially) require preparation time from the interviewer (Harris and Eder, 1999). The Role of Human Resources Professionals in Interviewer Training Although there are a variety of ways that organizations can go about implementing interviewer training, one would expect that organizations that have Human Resource (HR) professionals on staff would involve these individuals in this process. Whether the decision is to internally develop interviewer training or purchase it externally from a vendor, HR professionals are the group that should have the most professional expertise to determine whether interviewer training is needed within an organization and if so, the best method to use. Due to their expertise and role within the organization, HR professionals might be the source that proposes to implement interviewer training and serves as advocates for this training within their organizations. Alternatively, some HR professionals might not see this type of training as an important priority and one that is likely to produce the most valued return, but still have to assume the advocacy role because it is assigned to them as part of their job duties. Of course, there are likely also circumstances where HR professionals have total discretion on this issue and decide not to take any action to encourage or advocate for interviewer training and might even advocate against it. Despite the importance of the role HR professionals can take to ensure interviewers are trained, there is a lack of research on how HR professionals view interviewer training. This study attempts to fill this void by examining HR professionals' perceptions of interviewer training and the factors that influence those attitudes. …

Human resource professionals' perceptions of interviewer training

Persistent bias in expert judgments about free will and moral responsibility: A test of the expertise defense

The recruitment of Information Technology professionals has reemerged as an important issue in the workplace. In "The State of the CIO 2006 Survey," 55 percent of IT executives indicated they plan to increase their IT staffs by an average of 11 percent during the year (Overby, 2006). Towers Perrin's study of 22 leading firms in 11 industries identified recruitment and retention of IT employees as a key to facilitating superior business performance (Towers Perrin, 2002). Reports that show firms devoting more revenues to staffing activities than any other human resource ac tivity underscore the importance of understanding effective recruiting practices (Society for Human Resource Management, 2001). Driving this effort are estimates indicating that the average actual and opportunity costs for a professional position remaining unfilled are prohibitively expensive. An organization's costs for a position remaining vacant are estimated to be $1,200 per day (Stanton, 2000) and, on average, to be the cost of two years of pay and benefits for a typical exempt position and six months of pay and benefits for a typical nonexempt one (Oneal, 1998). Importance of Recruiting Focus Scholars cite three factors for the constant importance for recruiting and retaining IT workers. The first is the job-hopping proclivities of workers with specialized skills. The average employee reportedly remains with an organization for a maximum of five years before departing (Wiener, 1998). The rapid voluntary exit of employees from firms places great demand on the recruiting practices of organizations (Humber, 2005). The second element necessitating continued IT recruitment is workforce projections forecasting a labor shortage in areas of technical expertise. The Bureau of Labor Statistics projects positions for computer systems analysts, database administrators, and computer scientists will grow sharply faster than other occupations as organizations' needs for complex technologies advance (Bureau of Labor Statistics, 2004). The final factor underscoring the importance of IT recruitment is that the increased importance of information technology in global competition has positioned human capital as the linchpin for organizational success (Gilpin, 2000). Research studies have found that information technology produces a lasting competitive advantage for those organizations that acquire human capital in the form of skilled employees who can match technology to the firm's needs (Mata et al., 1995; Ross et al., 1996). Human capital gives firms that optimally recruit IT professionals a strategic competitive advantage relative to their competitors (Agarwal and Ferratt, 1999). Recruitment Methods Organizations have available a wide variety of recruiting methods to identify and attract job applicants external to the organization. The present research investigates the effect of two commonly used recruitment practices on organizational performance measures. Prior surveys and recruitment research have found personal and professional relationships and monetary incentives represent, respectively, the second and third most commonly used recruitment practices to attract IT talent, trailing only local newspaper ads (Mencken and Winfield, 1998). This study focuses on the incremental impact of professional relationships and monetary incentives over other techniques (such as ads) due to the high costs in time, money and effort to implement these approaches. Personal and professional relationship recruiting techniques include employee referrals and networking (Ram, 1999). These practices have the advantage of producing affordable costs per hire, reducing uncertainty about the applicant in the hiring stage, and securing high-quality hires (Feldman and Klass, 2002). Monetary inducements for recruitment include offering salaries higher than competitors' offers (to keep candidates from considering them), as well as retention and project milestone bonuses, short- and long-term incentive opportunities, and signing bonuses (Milkovich and Newman, 2002). …

The market for betting on National Football League games is well established and can be observed on a weekly basis for four months every year. Despite the visibility of the market, past research has tested its efficiency from several angles and reported a variety of inefficient areas. This thesis uses more recent data and a system of probit models to test if some of these inefficiencies continue to exist and if they can be consistently exploited to earn above average returns. While a model that incorporates measures of overall team strength and recent performance can be used to reliably predict in-sample results, its ability to predict out-of-sample games is significantly weaker and it can only be used to generate excess profits if the gambler observes an extreme cut-point strategy. Furthermore, this model is also applied using a varying number of years to predict outcomes during the following season. The results suggest using a mid-range number of years, such as three, may actually generate the most successful model as inefficiencies evolve over time and a model that bases its predictions on more years may not capture recent trends as well.

In Search of “ Sure Things ” An Analysis of Market Efficiency in the NFL Betting Market

The use of merit pay is increasing in public institutions. The prevalence of merit pay has extended to public universities to evaluate faculty performance. A general perception is that faculty scholarship is disproportionably used relative to instructional and service activities in assessing whether merit pay is warranted. Yet, little actual empirical research has been conducted to predict what components of faculty performance lead to merit pay awards. A survey concerning perceptions of faculty performance and subsequent merit pay was distributed to the entire faculty of a large public eastern research university. Logistic regression analysis found faculty research activities were significantly more predictive of merit pay receipt compared to instructional and service performance. Female faculty members were less supportive of merit pay compared to their male colleagues and perceived less improvement in their overall performance post merit pay awards.

Merit Pay in a Public Higher Education Institution: Questions of Impact and Attitudes

There is a substantial body of research evidence regarding the importance of leadership development to organizational success, Charan, Drotter and Noel (2001), Fullmer and Goldsmith (2001), McCall and Hollenbeck (2002), McCauley, Moxley and Van Velsor (1998), Viceri and Fulmer (1997, Whetton and Cameron (2005). There is no more important task with regard to leadership development than identifying the competencies and metacompetencies that comprise leadership. However, to date, there has not been agreement regarding just what are the Global Leadership Competencies that should be taught and learned. In this paper leadership is defined as, “Influencing others to accomplish organizational goals,” (Tubbs, 2005). Based on the model presented in this paper, the rationale is advanced that some aspects of leadership are more or less fixed at a young age while others are able to be developed even well into adult life (i.e., the Global Leadership Competencies). This paper describes the model and identifies fifty Global Leadership Competencies in the form of a taxonomy of Global Leadership Competencies and Meta-competencies Most importantly, leadership development efforts must be targeted on the outermost circle in the model..

Exploring a taxonomy of global leadership competencies and meta-competencies

This study examines human resource (HR) professionals' perceptions of the outcomes, process dynamics and affect toward team interviews. Results indicate HR professionals with experience conducting team interviews have significantly more positive views than HR professionals without experience. Additionally, African Americans, compared to Caucasians, expressed a significantly more positive view of the process dynamics of team interviews. Results indicate HR professionals were more positive about participating in team interviews as an interviewer than as an interviewee.

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The special role of technical workers and technical training how technical training systems work how technical training is provided best practices in technical training - centralized systems best practices in technical training - decentralized systems best practices in technical training - integrated systems.

573. Towards Gene Correction in a Large Animal Model: Gene Correction of Canine Coagulation Factor IX Deficiency Via Homologous Recombination Mediated By Designer Nucleases

High-capacity adenoviral vectors (HCAdVs) are promising tools for gene therapy as well as for genetic engineering. However, one limitation of the HCAdV vector system is the complex, time-consuming, and labor-intensive production process and the following quality control procedure. Since HCAdVs are deleted for all viral coding sequences, a helper virus (HV) is needed in the production process to provide the sequences for all viral proteins in trans. For the purification procedure of HCAdV, cesium chloride density gradient centrifugation is usually performed followed by buffer exchange using dialysis or comparable methods. However, performing these steps is technically difficult, potentially error-prone, and not scalable. Here, we establish a new protocol for small-scale production of HCAdV based on commercially available adenovirus purification systems and a standard method for the quality control of final HCAdV preparations. For titration of final vector preparations, we established a droplet digital polymerase chain reaction (ddPCR) that uses a standard free-end-point PCR in small droplets of defined volume. By using different probes, this method is capable of detecting and quantifying HCAdV and HV in one reaction independent of reference material, rendering this method attractive for accurately comparing viral titers between different laboratories. In summary, we demonstrate that it is possible to produce HCAdV in a small scale of sufficient quality and quantity to perform experiments in cell culture, and we established a reliable protocol for vector titration based on ddPCR. Our method significantly reduces time and required equipment to perform HCAdV production. In the future the ddPCR technology could be advantageous for titration of other viral vectors commonly used in gene therapy.

Standard free droplet digital polymerase chain reaction as a new tool for the quality control of high-capacity adenoviral vectors in small-scale preparations.

Acute and chronic hepatitis B virus (HBV) infections remain to present a major global health problem. The infection can be associated with acute symptomatic or asymptomatic hepatitis which can cause chronic inflammation of the liver and over years this can lead to cirrhosis and the development of hepatocellular carcinomas. Currently available therapeutics for chronically infected individuals aim at reducing viral replication and to slow down or stop the progression of the disease. Therefore, novel treatment options are needed to efficiently combat and eradicate this disease. Here we provide a state of the art overview of gene therapeutic approaches to inhibit HBV replication. We discuss non-viral and viral approaches which were explored to deliver therapeutic nucleic acids aiming at reducing HBV replication. Types of delivered therapeutic nucleic acids which were studied since many years include antisense oligodeoxynucleotides and antisense RNA, ribozymes and DNAzymes, RNA interference, and external guide sequences. More recently designer nucleases gained increased attention and were exploited to destroy the HBV genome. In addition we mention other strategies to reduce HBV replication based on delivery of DNA encoding dominant negative mutants and DNA vaccination. In combination with available cell culture and animal models for HBV infection, in vitro and in vivo studies can be performed to test efficacy of gene therapeutic approaches. Recent progress but also challenges will be specified and future perspectives will be discussed. This is an exciting time to explore such approaches because recent successes of gene therapeutic strategies in the clinic to treat genetic diseases raise hope to find alternative treatment options for patients chronically infected with HBV.

Gene therapeutic approaches to inhibit hepatitis B virus replication.

669. Standard Free Droplet Digital PCR as a New Tool for More Precise and Reliable Quality Control of Gene Therapy Vectors

48. High-Throughput Cloning and Tagging of an Engineered Adenovirus-Library Empowers Vector Diversity for Broad Applications

103. Pas de Deux – A Single Inducible High-Capacity Adenoviral Vector for Delivery of a Functional TALEN Pair Directed Against Human Dystrophin for the Treatment of Duchenne Muscular Dystrophy (DMD)

Gene therapeutic approaches offer great opportunities to treat genetic diseases which require long-term effects after a single administration of a customized vector. For these specific approaches the optimal vector system should combine the following features: (1) it should efficiently transport the genetic cargo into target cells in vitro or in vivo, (2) it should lead to sufficient long-term expression of the therapeutic transgene, (3) it should not interfere with the expression profile or the composition of the host genome, and (4) it should not result in unwanted side effects such as immune responses or other toxic effects. Predominantly used vectors for maintenance of therapeutic DNA and long-term transgene expression in preclinical and clinical studies are based on integrase-, recombinase-, transposase- or designer nuclease-mediated somatic integration into the host genome. However, for these systems the risk of insertional mutagenesis represents a potential unwanted adverse event. Therefore, autonomously replicating genetic elements were developed and there is accumulating evidence that these episomal vectors which are maintained extrachromosomally are suitable for therapeutic applications in dividing cells. In this review we provide a state-of-the-art overview of used viral hybrid-vectors which efficiently deliver autonomous DNA (plasmid replicon pEPI and Epstein-Barr Virus-based replicons) and RNA replicons (Semliki Forest Virus replicons) into target cells. To date adenoviruses, herpesviruses and baculovirus were explored for efficient delivery of autonomous replicons into various cell types and tissues. Applications and advantages and limitations of these hybrid-vectors are discussed in this review. We believe that with further optimization autonomous replicons may play an increasingly important role in gene therapeutic applications.

It has long been envisaged that gene disruption or gene correction in affected target cells can be efficiently conducted in vitro and in vivo and over the recent years several tools for achieving this goal were developed. Designer nucleases such as zinc finger nucleases (ZFNs) were extensively explored and more recently transcription activator-like effector nucleases (TALENs) were introduced for sequence-specific genome engineering in the mammalian genome. ZFNs and TALENs are fusion proteins containing a customized DNA-binding motif for sequence-specific DNA binding linked to a nuclease for introduction of double-stranded DNA breaks. Both systems were explored in mammalian cells using non-viral and viral delivery methods. Herein, we will provide a state-ofthe-art overview of available virus-based delivery systems for sufficient expression of functional TALENs. We will cover the molecular design of recombinant viruses containing TALEN expression cassettes and we will mention advantages and disadvantages of the respective systems. Although the relevance of these viral vector systems for novel developments in molecular medicine and genome engineering need to be further evaluated, we believe that with further improvements these viral vectors for TALEN delivery will play an emerging role in bioengineering and for establishing novel therapeutic concepts.

It has long been envisaged that gene disruption or gene correction in affected target cells can be efficiently conducted in vitro and in vivo and over the recent years several tools for achieving this goal were developed. Designer nucleases such as zinc finger nucleases (ZFNs) were extensively explored and more recently transcription activator-like effector nucleases (TALENs) were introduced for sequence-specific genome engineering in the mammalian genome. ZFNs and TALENs are fusion proteins containing a customized DNA-binding motif for sequence-specific DNA binding linked to a nuclease for introduction of double-stranded DNA breaks. Both systems were explored in mammalian cells using non-viral and viral delivery methods. Herein, we will provide a state-ofthe- art overview of available virus-based delivery systems for sufficient expression of functional TALENs. We will cover the molecular design of recombinant viruses containing TALEN expression cassettes and we will mention advantages and disadvantages of the respective systems. Although the relevance of these viral vector systems for novel developments in molecular medicine and genome engineering need to be further evaluated, we believe that with further improvements these viral vectors for TALEN delivery will play an emerging role in bioengineering and for establishing novel therapeutic concepts.

A Novel Adenoviral Hybrid-vector System Carrying a Plasmid Replicon for Safe and Efficient Cell and Gene Therapeutic Applications

Background  Cervical Cancer is the second most common cancer among women. Nevertheless, similar tumours have only been rarely described in Great Apes. This report characterizes the pathological and molecular features of a metastatic endocervical adenocarcinoma in a Western lowland gorilla (Gorilla g. gorilla).

Metastatic endocervical adenocarcinoma in a western lowland gorilla (Gorilla g. gorilla) – no evidence of virus‐induced carcinogenesis

Despite a growing knowledge about the biological diversity of papillomaviruses (PV), only little is known about non-human PV in general and about PV mice models in particular. We cloned and sequenced the complete genomes of two novel PV types from the Norway rat (Rattus norvegicus; RnPV2) and the wood mouse (Apodemus sylvaticus; AsPV1) as well as a novel variant of the recently described MmuPV1 (originally designated as MusPV) from a house mouse (Mus musculus; MmuPV1 variant). In addition, we conducted phylogenetic analyses using a systematically representative set of 79 PV types, including the novel sequences. As inferred from concatenated amino acid sequences of six proteins, MmuPV1 variant and AsPV1 nested within the Beta+Xi-PV super taxon as members of the Pi-PV. RnPV2 is a member of the Iota-PV that has a distant phylogenetic position from Pi-PV. The phylogenetic results support a complex scenario of PV diversification driven by different evolutionary forces including co-divergence with hosts and adaptive radiations to new environments. PV types particularly isolated from mice and rats are the basis for new animal models, which are valuable to study PV induced tumors and new treatment options.

Isolation of Three Novel Rat and Mouse Papillomaviruses and Their Genomic Characterization

Viral warts from immunosuppressed organ transplant recipients (OTR) persist over years and may progress into non-melanoma skin cancer. The types of human papillomaviruses (HPV) in such lesions are different from that seen in the general population. A subset of these lesions is not infected with the classical wart-associated HPV types. In order to gain a better understanding of the HPV types in those lesions, we isolated ten novel HPVs from persisting keratotic lesions of immunosuppressed OTRs by rolling circle amplification and subsequent long-template PCR. Additionally, we sequenced and characterized the whole genome of the ten novel HPV types. Phylogenetic analyses revealed that nine HPV types belonged to the genus Gammapapillomavirus (γ-PV) and one to the genus Betapapillomavirus. In a phylogenetic analysis using L1 fragments of human and non-human PV types, primate papillomaviruses and our novel HPV types nested within the genus γ-PV in a highly polyphyletic pattern. This study significantly broadens the knowledge concerning the diversity and evolution of the poorly known γ-PV types.

Genomic characterization of ten novel cutaneous human papillomaviruses from keratotic lesions of immunosuppressed patients.

Knowledge about biological diversity is the prerequisite to reliably reconstruct the evolution of pathogens such as papillomaviruses (PV). However, complete genomes of non-human PV have only been cloned and sequenced from 8 out of 18 orders within the Placentalia, although the host-specific variety of PV is considered much larger. We isolated and sequenced the complete genome of the first insectivoran PV type from hair follicle cells of the European hedgehog (Erinaceus europaeus), designated EHPV. We conducted phylogenetic analyses (maximum-likelihood criterion and Bayesian inference) with the genomic information of a systematically representative set of 67 PV types including EHPV. As inferred from amino acid sequence data of the separate genes E1, E2 and L1 as well as of the gene combination E6-E7-E1-E2-L1, EHPV clustered within the beta-gamma-pi-Xi-PV supertaxon and constituted the closest relative of genus Betapapillomavirus infecting primates. Beside the typical organization of the PV genome, EHPV exhibited a 1172 bp, non-coding region between the E2 and the L2 open reading frames. This trait has been previously described for the only distantly related Lambdapapillomavirus, but a common evolutionary origin of both non-coding regions is unlikely. Our results underscore the modular organization of the PV genome and the complex natural history of PV.

Genomic characterization of the first insectivoran papillomavirus reveals an unusually long, second non-coding region and indicates a close relationship to Betapapillomavirus.

A series of papillomavirus (PV) types have been isolated from different rodent species, and most of them belong to the genus Pipapillomavirus. We isolated and sequenced the complete genome of a novel PV type (designated RnPV) from the oral cavity of the Norway rat (Rattus norvegicus), as well as an L1 gene fragment from hair-follicle cells of the European beaver (Castor fiber). As inferred from amino acid sequence data, RnPV clustered within the beta+gamma+pi+Xi-PV supertaxon as a member of the genus Pipapillomavirus. The closest relatives of RnPV were McPV-2 and MmPV, and time estimates indicated that the genus Pipapillomavirus originated in the late Cenozoic era. The close relationship of RnPV to other murid PV types supports the hypothesis of co-divergence between members of the genus Pipapillomavirus and their hosts. However, the derived Neogene origin of the genus Pipapillomavirus is much younger than has been considered for the Rodentia as the primary hosts, indicating that alternative interpretations of the phylogenetic trees should be conceived.

Isolation and genomic characterization of the first Norway rat (Rattus norvegicus) papillomavirus and its phylogenetic position within Pipapillomavirus, primarily infecting rodents.

Progress in understanding Southern Ocean heat exchange and wind forcing is discussed and new results presented. These include a metric of the zonal asymmetry between surface ocean heat gain in the Atlantic/Indian sector and heat loss in the Pacific sector. The asymmetry arises from an intersector variation in the humidity gradient between the sea surface and near-surface atmosphere. This gradient increases by 60% in the Pacific sector enabling a 20 Wm−2 stronger latent heat loss compared with the Atlantic/Indian sector. The new metric is used for intercomparison of atmospheric reanalyses and CMIP6 climate simulations. CMIP6 has weaker Atlantic/Indian sector heat gain compared with the reanalyses primarily due to Indian Ocean sector differences. The potential for surface flux buoys to provide an observation-based counterpart to the asymmetry metric is explored. Over the past decade, flux buoys have been deployed at two sites (south of Tasmania and upstream of Drake Passage). The data record provided by these moorings is assessed and an argument developed for a third buoy to sample the Atlantic/Indian sector of the asymmetry metric. To close, we assess evidence that the main westerly wind belt has strengthened and moved southward in recent decades using the ERA5 reanalysis. This article is part of a discussion meeting issue 'Heat and carbon uptake in the Southern Ocean: the state of the art and future priorities'.

A clearer view of Southern Ocean air–sea interaction using surface heat flux asymmetry

When a wave breaks, it produces bubbles whose sizes depend on the breaking severity. This paper attempts to estimate wave breaking dissipation through a passive acoustic method. Initially, regular waves were forced to break in a flume. The breaking energy loss (severity) and the underwater acoustic noise were recorded. Two kinds of thresholds, in terms of sound wave amplitude and the ratio of sound wave height to period, respectively, were used together to identify the sound waves generated by newly formed bubbles. The frequencies of these sound waves are connected with the bubble sizes. Thus, a relationship between the mean bubble radius and the breaking severity was established and found to be linear. This laboratory relationship was then applied to Lake George data to study the breaking dissipation rate across the spectrum. An average acoustic spectral density threshold was proposed to identify breaking events from acoustic records in the field. The sound waves associated with bubble formation were selected by means of the same two kinds of threshold as used in the laboratory. Thus, the mean bubble radius of each breaking event was obtained and translated into the breaking severity. The values of experimental dissipation were compared with previous relevant results obtained through different methods as well as the wave breaking dissipation source terms ST6 (WAVEWATCH-III model) and are in good agreement with both of them.

Passive acoustic determination of spectral wave breaking dissipation

Wintertime surface ocean heat loss is the key process driving the formation of Subantarctic Mode Water (SAMW), but there are few direct observations of heat fluxes, particularly during winter. The Ocean Observatories Initiative (OOI) Southern Ocean mooring in the southeast Pacific Ocean and the Southern Ocean Flux Station (SOFS) in the southeast Indian Ocean provide the first concurrent, multiyear time series of air–sea fluxes in the Southern Ocean from two key SAMW formation regions. In this work we compare drivers of wintertime heat loss and SAMW formation by comparing air–sea fluxes and mixed layers at these two mooring locations. A gridded Argo product and the ERA5 reanalysis product provide temporal and spatial context for the mooring observations. Turbulent ocean heat loss is on average 1.5 times larger in the southeast Indian (SOFS) than in the southeast Pacific (OOI), with stronger extreme heat flux events in the southeast Indian leading to larger cumulative winter ocean heat loss. Turbulent heat loss events in the southeast Indian (SOFS) occur in two atmospheric regimes (cold air from the south or dry air circulating via the north), while heat loss events in the southeast Pacific (OOI) occur in a single atmospheric regime (cold air from the south). On interannual time scales, wintertime anomalies in net heat flux and mixed layer depth (MLD) are often correlated at the two sites, particularly when wintertime MLDs are anomalously deep. This relationship is part of a larger basin-scale zonal dipole in heat flux and MLD anomalies present in both the Indian and Pacific basins, associated with anomalous meridional atmospheric circulation.

Mooring Observations of Air–Sea Heat Fluxes in Two Subantarctic Mode Water Formation Regions

The Australian marine research, industry, and stakeholder community has recently undertaken an extensive collaborative process to identify the highest national priorities for wind-waves research. This was undertaken under the auspices of the Forum for Operational Oceanography Surface Waves Working Group. The main steps in the process were first, soliciting possible research questions from the community via an online survey; second, reviewing the questions at a face-to-face workshop; and third, online ranking of the research questions by individuals. This process resulted in 15 identified priorities, covering research activities and the development of infrastructure. The top five priorities are 1) enhanced and updated nearshore and coastal bathymetry; 2) improved understanding of extreme sea states; 3) maintain and enhance the in situ buoy network; 4) improved data access and sharing; and 5) ensemble and probabilistic wave modeling and forecasting. In this paper, each of the 15 priorities is discussed in detail, providing insight into why each priority is important, and the current state of the art, both nationally and internationally, where relevant. While this process has been driven by Australian needs, it is likely that the results will be relevant to other marine-focused nations.

15 Priorities for Wind-Waves Research: An Australian Perspective

 <p>Wintertime surface ocean heat loss is the key driver of Subantarctic Mode Water (SAMW) formation. However, until now there have been very few direct observations of fluxes, particularly during winter. Here, we present results from the first concurrent (2015-17 with gaps), air-sea flux mooring deployments in two key SAMW formation regions: the Southern Ocean Flux Site (SOFS) in the Southeast Indian sector and the Ocean Observatories Initiative (OOI) mooring in the Southeast Pacific sector. Gridded Argo and ERA5 reanalysis provide temporal and spatial context for the mooring observations. Turbulent ocean heat loss is found to be on average 1.5 times larger at the Southeast Indian than Southeast Pacific sites with stronger extreme heat flux events in the Southeast Indian leading to larger cumulative winter heat loss. For the first time, we show that turbulent heat loss events in the Southeast Indian sector occur in two atmospheric regimes (a direct cold air pathway from the south and an indirect pathway circulating dry Antarctic air via the north). In contrast, heat loss events in the Southeast Pacific sector occur in a single atmospheric regime (cold air from the south). On interannual timescales, wintertime anomalies in net heat flux and mixed layer depth (MLD) are often correlated at the two sites, particularly when wintertime MLDs are anomalously deep. Using ERA5, we show that this is part of a larger zonal dipole in heat flux and MLD anomalies present in both the Indian and Pacific SAMW formation regions, associated with anomalous meridional atmospheric circulation. These recent results will be placed in the context of multidecadal variability in the SAMW formation region dominant heat flux patterns over the past 40 years over all 3 sectors of the Southern Ocean (Pacific, Indian and Atlantic).</p>

New insights into concurrent air-sea heat flux forcing of Subantarctic Mode Water formation from mooring observations in the Southeast Indian and Southeast Pacific sectors of the Southern Ocean

The generation and evolution of ocean waves by wind is one of the most complex phenomena in geophysics, and is of great practical significance. Predictive capabilities of respective wave models, however, are impaired by lack of field in situ observations, particularly in extreme Metocean conditions. The paper outlines and highlights important gaps in understanding the Metocean processes and suggests a major observational program in the Southern Ocean. This large, but poorly investigated part of the World Ocean is home to extreme weather around the year. The observational network would include distributed system of buoys (drifting and stationary) and autonomous surface vehicles (ASV), intended for measurements of waves and air-sea fluxes in the Southern Ocean. It would help to resolve the issues of limiting fetches, extreme Extra-Tropical cyclones, swell propagation and attenuation, wave-current interactions, and address the topics of wave-induced dispersal of floating objects, wave-ice interactions in the Marginal Ice Zone, Metocean climatology and its connection with the global climate.

Waves and Swells in High Wind and Extreme Fetches, Measurements in the Southern Ocean

Surface heat fluxes from four atmospheric reanalyses in the Southern Ocean are evaluated using air–sea measurements obtained from the Aurora Australis during off-winter seasons in 2010–12. The icebreaker tracked between Hobart, Tasmania (ca. 42°S), and the Antarctic continent, providing in situ benchmarks for the surface energy budget change in the Subantarctic Southern Ocean (58–42°S) and the eastern Antarctic marginal ice zone (MIZ, 68–58°S). We find that the reanalyses show a high-level agreement among themselves, but this agreement reflects a universal bias, not a “truth.” Downward shortwave radiation (SW↓) is overestimated (warm biased) and downward longwave radiation (LW↓) is underestimated (cold biased), an indication that the cloud amount in all models is too low. The ocean surface in both regimes shows a heat gain from the atmosphere when averaged over the seven months (October–April). However, the ocean heat gain in reanalyses is overestimated by 10–36 W m−2 (80–220%) in the MIZ but underestimated by 6–20 W m−2 (7–25%) in the Subantarctic. The biases in SW↓ and LW↓ cancel out each other in the MIZ, causing the surface heat budget to be dictated by the underestimation bias in sensible heat loss. These reanalyses biases affect the surface energy budget in the Southern Ocean by meaningfully affecting the timing of the seasonal transition from net heat gain to net heat loss at the surface and the relative strength of SW↓ at different regimes in summer, when the length-of-day effect can lead to increased SW↓ at high latitudes.

Surface heat budget in the Southern Ocean from 42°S to the Antarctic marginal ice zone: four atmospheric reanalyses versus icebreaker Aurora Australis measurements

Given the large uncertainties in surface heat fluxes over the Southern Ocean, an assessment of fluxes obtained by European Centre for Medium-Range Weather Forecasts interim reanalysis (ERA-Interim) product, the Australian Integrated Marine Observing System (IMOS) routine observations, and the Objectively Analyzed Air–Sea Heat Fluxes (OAFlux) project hybrid dataset is performed. The surface fluxes are calculated using the COARE 3.5 bulk algorithm with in situ data obtained from the NOAA Physical Sciences Division flux system during the Clouds, Aerosols, Precipitation, Radiation, and Atmospheric Composition over the Southern Ocean (CAPRICORN) experiment on board the R/V Investigator during a voyage (March–April 2016) in the Australian sector of the Southern Ocean (43°–53°S). ERA-Interim and OAFlux data are further compared with the Southern Ocean Flux Station (SOFS) air–sea flux moored surface float deployed for a year (March 2015–April 2016) at ~46.7°S, 142°E. The results indicate that ERA-Interim (3 hourly at 0.25°) and OAFlux (daily at 1°) estimate sensible heat flux H s accurately to within ±5 W m−2 and latent heat flux H l to within ±10 W m−2. ERA-Interim gives a positive bias in H s at low latitudes (<47°S) and in H l at high latitudes (>47°S), and OAFlux displays consistently positive bias in H l at all latitudes. No systematic bias with respect to wind or rain conditions was observed. Although some differences in the bulk flux algorithms are noted, these biases can be largely attributed to the uncertainties in the observations used to derive the flux products.

Assessing Surface Heat Flux Products with In Situ Observations over the Australian Sector of the Southern Ocean

The timing of pelagic spring blooms has received attention to understand controls on open ocean productivity and its potential responses to climate change. Many studies have relied on surface chlorophyll (Chl) to define bloom initiation because of its availability from satellite observations, but this has limited utility because it ignores the full water column budget and because biomass represents only the small residual term in the balance between production and loss. Additional important measures include net community production (NCP) which determines maximal energy available to fuel phytoplankton and higher trophic level biomass accumulations, and particulate organic carbon export (POC flux) which determines the distribution of this energy across pelagic, mesopelagic and benthic communities. Here we present high temporal resolution records for the winter to spring transition (July-December 2012) obtained from moored sensors at SOTS in the Subantarctic Zone (SAZ) south of Australia. Measurements included physical drivers (temperature, salinity, surface mixed layer depth, currents, wind speeds, insolation, and air-sea heat fluxes) and biological responses (Chl from fluorescence and light attenuation, NCP from O2/N2 ratios and nutrient concentrations from an autonomous water sampler, POC flux from sediment traps, and zooplankton abundances from four-frequency acoustic backscatter profiles). These observations provide a phenology across the four trophic levels (NPZD) commonly used in ocean biogeochemical models. Chl column inventories began to increase in early winter while mixed layers were still deepening, and were accompanied by increases in net community production. Acoustic metrics for grazing pressure were very low at this time. In contrast, surface Chl did not increase until later when stratification developed. The levels of spring net community production were relatively high and balanced by sinking particle fluxes close to global median values, despite the relatively low surface biomass levels. Overall this phenology suggests that the extent of exchange with SAMW waters via deep mixing is a key driver of the seasonality of production, support of higher trophic levels, and the mediation of pelagic-benthic coupling, and occurs sequentially via trophodynamic (de-coupling of production and grazing) and physical (stratification) mechanisms.

Autonomous Multi-Trophic Observations of Productivity and Export at the Australian Southern Ocean Time Series (SOTS) Reveal Sequential Mechanisms of Physical-Biological Coupling

Comparison of variability in air-sea heat fluxes and Subantarctic Mode Water formation from concurrent mooring observations in the Southeast Indian and Southeast Pacific

The Australian coastline and its infrastructure are vulnerable to the impacts of extreme coastal sea levels. The Bureau of Meteorology is developing a new system to provide forecasts of coastal sea level for the Australian coast. This system comprises two major components - a tropical ensemble system focusing on storm surge driven by Tropical Cyclones and a national deterministic system focusing on non-Tropical Cyclone driven coastal sea level variability. This paper outlines the configuration of each of these systems, presents some initial verification results and notes some areas for further improvement.

This study analyzed shipboard air-sea measurements acquired by the icebreaker Aurora Australis during its off-winter operation in December 2010 – May 2012. Mean conditions over 7 months (October-April) were compiled from a total of 22 ship tracks. The icebreaker traversed the water between Hobart, Tasmania and the Antarctic continent, providing valuable in situ insight into two dynamically important, yet poorly sampled, regimes: the sub-Antarctic Southern Ocean and the Antarctic marginal ice zone (MIZ) in the Indian Ocean sector. The transition from the open water to the ice-covered surface creates sharp changes in albedo, surface roughness, and air temperature, leading to consequential effects on air-sea variables and fluxes. Major effort was made to estimate the air-sea fluxes in the MIZ using the bulk flux algorithms that are tuned specifically for the sea-ice effects, while computing the fluxes over the sub-Antarctic section using the COARE3.0 algorithm. The study evidenced strong sea-ice modulations on winds, with the southerly airflow showing deceleration (convergence) in the MIZ and acceleration (divergence) when moving away from the MIZ. Marked seasonal variations in heat exchanges between the atmosphere and the ice margin were noted. The monotonic increase in turbulent latent and sensible heat fluxes after summer turned the MIZ quickly into a heat loss regime, while at the same time the sub-Antarctic surface water continued to receive heat from the atmosphere. The drastic increase in turbulent heat loss in the MIZ contrasted sharply to the non-significant and seasonally invariant turbulent heat loss over the sub-Antarctic open water.

Air‐sea interaction regimes in the sub‐Antarctic Southern Ocean and Antarctic marginal ice zone revealed by icebreaker measurements

This study uses shipborne cloud radar and surface radiation measurements collected over the Southern Ocean to characterize the cloud frequency, cloud fraction, and cloud radiative effects on the ocean surface. These cloud and radiative properties are also used to evaluate a regional forecast model. Low‐level clouds, either alone or cooccurring with cloud layers aloft, are present ~ 77% of the time in this data set. These clouds either had a very low or a very high cloud fraction at 12 km horizontal resolution, with about half of the clouds characterized by a cloud fraction higher than 80%. Overall, shortwave surface cooling effect dominates longwave heating, with an estimate net radiative cooling of −22 W m−2, resulting from a −71 W m−2 shortwave cooling and a +49 W m−2 longwave heating. A strong relationship between daily surface cloud radiative effect and daily low‐level cloud fraction is found, which, if confirmed with a larger data set, could be exploited in satellite retrievals or model parameterizations for the Southern Ocean. The regional model underestimates the frequency of low‐level clouds but largely overestimates the frequency of multilayer situations. The associated radiative errors are large and complex, including reduced surface radiative cooling due to low‐level clouds compensated by enhanced surface cooling in multilayer situations.

Shipborne observations of the radiative effect of Southern Ocean clouds

Observation of wind-waves from a moored buoy in the Southern Ocean

The Subantarctic Zone (SAZ), which covers the northern half of the Southern Ocean between the Subtropical and Subantarctic Fronts, is important for air‐sea CO2 exchange, ventilation of the lower thermocline, and nutrient supply for global ocean productivity. Here we present the first high‐resolution autonomous observations of mixed layer CO2 partial pressure (pCO2) and hydrographic properties covering a full annual cycle in the SAZ. The amplitude of the seasonal cycle in pCO2 (∼60 μatm), from near‐atmospheric equilibrium in late winter to ∼330 μatm in midsummer, results from opposing physical and biological drivers. Decomposing these contributions demonstrates that the biological control on pCO2 (up to 100 μatm), is 4 times larger than the thermal component and driven by annual net community production of 2.45 ± 1.47 mol C m−2 yr−1. After the summer biological pCO2 depletion, the return to near‐atmospheric equilibrium proceeds slowly, driven in part by autumn entrainment into a deepening mixed layer and achieving full equilibration in late winter and early spring as respiration and advection complete the annual cycle. The shutdown of winter convection and associated mixed layer shoaling proceeds intermittently, appearing to frustrate the initiation of production. Horizontal processes, identified from salinity anomalies, are associated with biological pCO2 signatures but with differing impacts in winter (when they reflect far‐field variations in dissolved inorganic carbon and/or biomass) and summer (when they suggest promotion of local production by the relief of silicic acid or iron limitation). These results provide clarity on SAZ seasonal carbon cycling and demonstrate that the magnitude of the seasonal pCO2 cycle is twice as large as that in the subarctic high‐nutrient, low‐chlorophyll waters, which can inform the selection of optimal global models in this region.

Seasonality of biological and physical controls on surface ocean CO2 from hourly observations at the Southern Ocean Time Series site south of Australia

The Southern Ocean is a key component of the global climate system: insulating the Antarctic polar region from the subtropics, transferring climate signals throughout the world's oceans and forming the southern component of the global overturning circulation. However, the air‐sea fluxes that drive these processes are severely under‐observed due to the harsh and remote location. This paucity of reference observations has resulted in large uncertainties in ship‐based, numerical weather prediction, satellite and derived flux products. Here, we report observations from the Southern Ocean Flux Station (SOFS); the first successful air‐sea flux mooring deployment in this ocean. The mooring was deployed at 47°S, 142°E for March 2010 to March 2011 and returned measurements of near surface meteorological variables and radiative components of the heat exchange. These observations enable the first accurate quantification of the annual cycle of net air‐sea heat exchange and wind stress from a Southern Ocean location. They reveal a high degree of variability in the net heat flux with extreme turbulent heat loss events, reaching −470 Wm−2in the daily mean, associated with cold air flowing from higher southern latitudes. The observed annual mean net air‐sea heat flux is a small net ocean heat loss of −10 Wm−2, with seasonal extrema of 139 Wm−2 in January and −79 Wm−2in July. The novel observations made with the SOFS mooring provide a key point of reference for addressing the high level of uncertainty that currently exists in Southern Ocean air‐sea flux datasets.

AbstractThe Southern Ocean Flux Station was deployed near 47°S, 140°E. The extreme wind and wave conditions at this location require appropriate mooring design, which includes dynamic fatigue analysis and static analysis. An accurate estimate of the wave conditions was essential. A motion reference unit was deployed in a nearby test mooring for 6 months. The motion data provided estimates of significant wave height that agreed well with the Australian Bureau of Meteorology wave model, increasing confidence in the model performance in the Southern Ocean. The results of the dynamic fatigue analysis using three input wave datasets and implications for the mooring design are described. The design analysis predicts the fatigue life for critical mooring components and guided the final selection of links and chain shackles. The three input wave climatologies do not differ greatly, and this is reflected in minimal changes to mooring components for each of the fatigue analyses.

Mooring Design Using Wave-State Estimate from the Southern Ocean

Dominant ocean wave direction measurements using the TIGER SuperDARN systems

Merchant, cruise, and research vessels make unique contributions to marine data collection using automated oceanic and atmospheric monitoring systems. The programs making these observations are reviewed along with the wide range of applications to atmospheric and oceanic research and operations. A vision for the next decade outlines where incremental improvements to instruments, platforms, and data stewardship can benefit the community. A series of recommendations are made to meet the challenges of future-ocean observing.

Automated Underway Oceanic and Atmospheric Measurements from Ships

The CSIRO, Bureau of Meteorology, University of Tasmania, and Antarctic Climate and Ecosystems CRC operate the Integrated Marine Observing System (IMOS) Southern Ocean Time Series (SOTS) facility with funding from the National Collaborative Research Infrastructure Strategy (NCRIS)- a set of moorings designed to quantify physical, chemical, and biological processes important to the transfer of heat, moisture, momentum, oxygen and carbon dioxide between the atmosphere and ocean. There are 3 mooring platforms at the SOTS site near 140°E, 47°S in ∼4500m water depth, in the Subantarctic Zone (SAZ) ∼36 hours by ship southwest of Tasmania: i) the Southern Ocean Flux Station (SOFS) - a large surface tower buoy that focuses on meteorological measurements, ii) the Pulse surface mixed layer mooring focusing on biological nutrient and carbon transformations using sensors and an automated water sampler, and iii) the deep SAZ sediment trap mooring (below 1000m depth) that quantifies sinking carbon fluxes to the ocean interior and returns particle samples for a broad range of biogeochemical studies. Additional applications include evaluation of wave models, calibration of isotopic proxies for past ocean conditions, and quantification of impacts of ocean acidification on foraminiferal zooplankton.

The Australian Integrated Marine Observing System Southern Ocean Time Series facility

A mobile unloading apparatus for unloading items from a variety of heights is disclosed wherein the apparatus has a frame supporting a ramp for movement between a first position spaced above a conveyor for permitting items to be placed directly on the conveyor and a second, downwardly sloping ramp position for moving items down the ramp to the conveyor. The apparatus includes a first walkway section supported by the frame on a first conveyor side above a supporting surface, a second walkway section supported by the frame on a second conveyor side above the supporting surface and a third walkway section. The third walkway section can be moved from a first, use position bridging the first and second walkway sections to a second, storage position.

The data management system for the Shipborne Automated Meteorological and Oceanographic System (SAMOS) initiative

A comparison of shelf observation platforms for assimilation in an eddy-resolving ocean model

Recent advances in a technique to identify and catalog waves that ride on larger-scale carrier waves are described in detail. The latest developments allow the riding wave removal technique to correctly identify and replace riding waves at the Nyquist frequency scale. Examples of the technique are provided for two diverse datasets: the Black Sea and Lake George. A sample of the riding wave characteristics extracted using this method is presented.

NOTES AND CORRESPONDENCE The Riding Wave Removal Technique: Recent Developments

Abstract Recent advances in a technique to identify and catalog waves that ride on larger-scale carrier waves are described in detail. The latest developments allow the riding wave removal technique to correctly identify and replace riding waves at the Nyquist frequency scale. Examples of the technique are provided for two diverse datasets: the Black Sea and Lake George. A sample of the riding wave characteristics extracted using this method is presented.

When tsunami waves propagate across the open ocean, they are steered by the Coriolis effect and refraction due to gentle gradients in the bathymetry on scales longer than the wavelength. When the wave encounters steep gradients at the edges of continental shelves and at the coast, the wave becomes nonlinear and conservation of momentum produces squirts of surface current at the head of submerged canyons and in coastal bays. High frequency (HF) coastal ocean radar is well conditioned to observe the surface current bursts at the edge of the continental shelf and give a warning of 40 minutes to 2 hours when the shelf is 50 to 200 km wide. The period of tsunami waves is invariant over changes in bathymetry and is in the range 2 to 30 minutes. Wavelengths for tsunamis (in 500 to 3000 m depth) are in the range 8.5 to over 200 km, and on a shelf where the depth is about 50 m (as in the Great Barrier Reef (GBR)) the wavelengths are in the range 2.5 to 30 km. In the use of HF radar technology, there is a trade‐off between the precision of surface current speed measurements and time resolution. It is shown that the phased array HF ocean surface radar being deployed in the GBR and operating in a routine way for mapping surface currents, can resolve surface current squirts from tsunamis in the wave period range 20 to 30 minutes and in the wavelength range greater than about 6 km. An advantage in signal‐to‐noise ratio can be obtained from the prior knowledge of the spatial pattern of the squirts at the edge of the continental shelf, and it is estimated that, with this analysis, the time resolution of the GBR radar may be reduced to about 2.5 minutes, which corresponds to a capability to detect tsunamis at the shelf edge in the period range 5 to 30 minutes. It is estimated that the lower limit of squirt velocity detection at the shelf edge would correspond to a tsunami with water elevation of about 2.5 cm in the open ocean. This means that the GBR HF radar is well conditioned for use as a monitor of small, as well as larger, tsunamis and has the potential to contribute to the understanding of tsunami genesis research.

The Bureau of Meteorology is scheduled in 2007 to expand its oceanographic services for the Australian community to include operational mesoscale ocean forecasts. The past decade has seen the rapid development of a near real-time global ocean observing system which includes both insitu and satellite instrumentation. The spatial coverage and frequency of observations has provided the capacity for developing ocean prediction systems. Operational oceanography is a significant investment both in terms of human and computational resources, which is being actively pursued in public centres throughout the world. BLUElink is a joint initiative of the Bureau of Meteorology, Commonwealth Scientific and Industrial Research Organisation and the Royal Australian Navy to develop this capability for Australia’s regional and territorial waters. Numerical ocean prediction is a computationally intensive task with the prototype system requiring resources comparable with numerical weather prediction and similarly takes full advantage of the very latest in high performance computing. In addition, the volume of observational, model and analysis data has demanded a comprehensive data management system. Effective information technology solutions are essential for managing, maintaining and servicing this new capacity to fulfil the needs of the Australian community.

BLUElink> Development of Operational Oceanography and Servicing in Australia

Abstract A method for routinely verifying numerical weather prediction surface marine winds with satellite scatterometer winds is introduced. The marine surface winds from the Australian Bureau of Meteorology’s operational global and regional numerical weather prediction systems are evaluated. The model marine surface layer is described. Marine surface winds from the global and limited-area models are compared with observations, both in situ (anemometer) and remote (scatterometer). A 2-yr verification shows that wind speeds from the regional model are typically underestimated by approximately 5%, with a greater bias in the meridional direction than the zonal direction. The global model also underestimates the surface winds by around 5%–10%. A case study of a significant marine storm shows that where larger errors occur, they are due to an underestimation of the storm intensity, rather than to biases in the boundary layer parameterizations.

An Assessment of Marine Surface Winds from the Australian Bureau of Meteorology Numerical Weather Prediction Systems

In just over 2 years since the First Workshop, Argo has matured enormously. There are now over 2400 fl oats, 80% of the Argo target. More than half of these fl oats are in the Southern Hemisphere, and global coverage has been achieved. The Global Ocean has never before been observed as it is at the present time. While 10 years are needed to fully demonstrate the value of Argo, now is the time to explore the Argo array’s real capabilities (as well as its limitations).

A method for removing ship motion from wind measurements using a simple and inexpensive strap-down system of accelerometers is described and analyzed. In slight seas, error analysis indicates that mean root-mean-square uncertainties associated with the motion correction are 0.03 and 0.006 m s 1 for the horizontal and vertical wind, respectively, for all runs analyzed. The mean uncertainty in the wind stress due to motion correction is 8 10 4 Nm 2 . In a shallow coastal sea setting, ship motion appears to almost always be successfully detected and removed from the vertical component of the observed wind. The horizontal wind components appear to be successfully corrected in 86% of the runs analyzed. Motion correction is shown to have a significant influence on the covariance-calculated wind stress. In approximately half of the runs analyzed the wind stress changes by more than 15%. Motion correction has a smaller effect on the heat fluxes.

Recent work has demonstrated that surface marine winds from the Bureau of Meteorology's operational Numerical Weather Prediction (NWP) systems are typically underestimated by 5 to 10%. This is likely to cause significant bias in modelled wave fields that are forced by these winds. A simple statistical adjustment of the wind components is shown to reduce the observed bias in Significant Wave Height considerably. The impact of increasing the vertical resolution of the NWP model and assimilating scatterometer data into the model is assessed by comparing the resulting forecast wind and waves to observations. It is found that, in general, the inclusion of scatterometer observations improves the accuracy of the surface wind forecasts. However, most of the improvement is shown to arise from the increased number of vertical levels in the atmospheric model, rather than directly from the use of the observations. When the wave model is forced with surface winds from the NWP model that includes scatterometer data, it...

The impact of the assimilation of scatterometer winds on surface wind and wave forecasts

Stationarity of Turbulence in Light Winds during the Maritime Continent Thunderstorm Experiment

The Bureau of Meteorology currently runs two NWP model systems operationally. These are LAPS (Limited Area Prediction System, Puri et al. 1998), and GASP (Global Assimilation and Prediction System, Seaman et al. 1995). The former is run at a variety of resolutions and over various domains. The verifications presented in this paper focus on LAPS-375 (0.375 horizontal resolution), henceforth called LAPS and the global system GASP (a spectral model currently run operationally at T239 resolution, approximately equivalent to a grid spacing at the equator of 0.75). Both systems have 29 vertical levels. The lowest level in LAPS is at approximately 10-m height while for GASP it is at approximately 70-m height.

R/V Franklin followed a drifter for 8 days in the equatorial Indian Ocean to test the accuracy of mixed-layer heat and freshwater budget closure. Four-hourly triangles were repeated, towing a SeaSoar with a photometer and conductivity-temperature-depth (CTD) profiler. Currents relative to the buoy at one depth were obtained from (a) a current meter at 25 m below the buoy; (b) a Global Positioning System estimate; (c) a drag estimate. Acoustic Doppler current profiler (ADCP) shears provided currents at other depths, (b) and (c) agreed closely but differed from (a), possibly due to severe conditions at the current meter. Vertical advection was estimated from ADCP divergence around each triangle. Measurements on the buoy and the ship, calibrated earlier in the Coupled Ocean-Atmosphere Response Experiment (COARE), provided bulk surface fluxes. Accuracy of net surface heat fluxes was estimated at ±10 W/m2. Rainfall differed considerably between the buoy and ship, but other quantities including shortwave radiation were very similar, even on cloudy days. A formalism for the budgets above a given isopycnal is developed, to clearly distinguish horizontal and vertical advection. When (b) and (c) above were used with the best estimate of surface fluxes, the 8-day heat budget misclose for water above the 21.5 isopycnal was (−4.6±5) W/m2; the diurnal heating cycle was well resolved. The freshwater budget misclose was (0.9±3.5) mm/d. A small amount of vertical diffusion, in the ratio determined by the slope of the T-S curve, will reduce both misclosures. Cruise design considerations for minimizing errors in the advection and storage components of heat and freshwater budgets are discussed.

Measurements of upper ocean heat and freshwater budgets near a drifting buoy in the equatorial Indian Ocean

2. Ashley H. Traut, graduate student, Dept. of Wildlife Ecology and Conservation; Mark E. Hostetler, associate professor and Extension wildlife specialist, Dept. of Wildlife Ecology and Conservation; Eric J. Schulz, Florida LAKEWATCH regional coordinator, Dept. of Fisheries and Aquatic Sciences; Mark V. Hoyer, scientific research manager, Dept. of Fisheries and Aquatic Sciences; Florida Cooperative Extension Service, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL 32611.

Florida LAKEWATCH and Aquatic Bird Surveys: A Winning Combination 1

AbstractThe abundance of Bull Trout Salvelinus confluentus in the Metolius River and Lake Billy Chinook, a hydroelectric reservoir, increased dramatically from 1998 to 2004, following implementation of restrictive fishery regulations. However, both adult Bull Trout and kokanee Oncorhynchus nerka (prey) populations have declined in more recent years. We investigated the relationships between Bull Trout spawner densities, emerging fry densities, and numbers of juveniles migrating into the reservoir to determine the potential role of juvenile production in this decline. We hypothesized that age-1 and older juvenile production is now limited by natal habitat capacity and that excess fry production is lost to density-dependent mortality. Bull trout redd densities in surveyed spawning reaches ranged from 14 to 39 redds/km during recent years. The estimated abundance of emerging Bull Trout fry in monitored spawning reaches has varied from about 1.0–2.5 million annually since 2005, while mean estimated densities ...

Recruitment of Young Bull Trout into the Metolius River and Lake Billy Chinook, Oregon

Abstract The degree of bacterial contamination of 99 Florida lakes was studied using total coliform and Escherichia coli (E. coli) counts as indicators. Over 75% of the 4055 samples analyzed for total colifoms and over 98% analyzed for E. coli were below Florida's state standards for total and fecal coliform bacteria, respectively. Thus, there is little evidence of widespread fecal contamination in the Florida lakes examined during this study. Future bacterial sampling in lake systems should consider the facts that open-water samples had significantly lower total coliform and E. coli counts than littoral samples, and that the variance in bacterial counts is greater among lakes over time than spatially within lakes. Additionally, lake trophic status and aquatic bird abundance were also positively related to both total coliform and E. coli counts, while lake surface area and percent area covered with aquatic macrophytes (PAC) showed no significant relations. The method of waste management around lakes is often a concern to many people citing septic tank systems for polluting aquatic systems. However, the data examined in this study showed no difference in bacterial counts between lakes managing waste with septic tanks and those with central waste water treatment systems. A routine, inexpensive bacterial monitoring program is recommended for lakes used for body-contact recreational activities to be safe and relieve concerns of the public about potential health problems.

Total Coliform and Escherichia Coli Counts in 99 Florida Lakes with Relations to Some Common Limnological Factors

Abstract An index of biotic integrity (IBI) that used eight fish assemblage metrics was examined for effectiveness in estimating anthropogenic impacts to 60 Florida lakes ranging in size from 2 ha to more than 12,400 ha. The lakes ranged in trophic status from oligotrophic to hypereutrophic and had aquatic macrophyte abundances (percent lake volume infested) ranging from less than 1% to 100%. Fish species were classified by trophic feeding guild and tolerance to increases in turbidity or warming and decreases in dissolved oxygen concentration. Fish assemblage metrics tested were as follows: Number of fish species, number of native fish species, number of Lepomis species, number of piscivorous species, number of generalist species, number of invertivore species, number of species intolerant of increased turbidity or warming and decreased dissolved oxygen concentration, and number of species tolerant of increased turbidity or warming and decreased dissolved oxygen concentration. The total IBI scores and the...

An Index of Biotic Integrity: A Test with Limnological and Fish Data from Sixty Florida Lakes

. We introduce an extension to the Discrete Multiplier Method (DMM) [1], called Minimal (cid:96) 2 Norm Discrete Multiplier Method (MN-DMM), where conservative ﬁnite diﬀerence schemes for dynamical systems with multiple conserved quantities are constructed procedurally, instead of analytically as in the original DMM. For large dynamical systems with multiple conserved quantities, MN-DMM alleviates diﬃculties that can arise with the original DMM at constructing conservative schemes which satisﬁes the discrete multiplier conditions. In particular, MN-DMM utilizes the right Moore-Penrose pseudoinverse of the discrete multiplier matrix to solve an underdetermined least-square problem associated with the discrete multiplier conditions. We prove consistency and conservative properties of the MN-DMM schemes. We also introduce two variants – Mixed MN-DMM and MN-DMM using Singular Value Decomposition – and discuss their usage in practice. Moreover, numerical examples on various problems arising from the mathematical sciences are shown to demonstrate the wide applicability of MN-DMM and its relative ease of implementation compared to the original DMM.

We develop novel first-kind boundary integral equations for Euclidean Dirac operators in 3D Lipschitz domains. They comprise square-integrable potentials and involve only weakly singular kernels. Generalized G̊arding inequalities are derived and we establish that the obtained boundary integral operators are Fredholm of index zero. Their finite dimensional nullspaces are characterized and we show that their dimensions are equal to the number of topological invariants of the domain’s boundary, in other words, to the sum of its Betti numbers. This is explained by the fundamental discovery that the associated bilinear forms agree with those induced by the 2D Dirac operators for surface de Rham Hilbert complexes whose underlying inner-products are the non-local inner products defined through the classical single-layer boundary integral operators for the Laplacian. Decay conditions for well-posedness in natural energy spaces of the Dirac system in unbounded exterior domains are also presented.

First-Kind Boundary Integral Equations for the Dirac Operator in 3-Dimensional Lipschitz Domains

Coupled Domain-Boundary Variational Formulations for Hodge–Helmholtz Operators

We consider the problem of recovering the divergence-free velocity field $\mathbf{U}\in\mathbf{L}^2(\Omega)$ of a given vorticity $\mathbf{F}=\mathrm{curl}\,\mathbf{U}$ on a bounded Lipschitz domain $\Omega\subset \mathbb{R}^3$. To that end, we solve the 'div-curl problem' for a given $\mathbf{F}\in\bigl[ \mathbf{H}_0(\mathrm{curl};\Omega)\bigr]'$. The solution is given in terms of a vector potential (or stream function) $\mathbf{A}\in\mathbf{H}^1(\Omega)$ such that $\mathbf{U}=\mathrm{curl}\,{\mathbf{A}}$. After discussing existence and uniqueness of solutions and associated vector potentials, we propose a well-posed construction for the stream function. A numerical example of the construction is presented at the end.

We consider the problem of recovering the divergence‐free velocity field U ∈ L2(Ω) of a given vorticity F=curlU on a bounded Lipschitz domain Ω⊂ℝ3 . To that end, we solve the ‘div–curl problem’ for a given F ∈ H−1(Ω). The solution is expressed in terms of a vector potential (or stream function) A ∈ H1(Ω) such that U=curlA . After discussing existence and uniqueness of solutions and associated vector potentials, we propose a well‐posed construction for the stream function. A numerical method based on this construction is presented, and experiments confirm that the resulting approximations display higher regularity than those of another common approach.

Div–curl problems and H1‐regular stream functions in 3D Lipschitz domains

Abstract We develop a framework shedding light on common features of coupled variational formulations arising in electromagnetic scattering and acoustics. We show that spurious resonances haunting coupled domain-boundary formulations based on direct boundary integral equations of the first kind originate from the formal structure of their Calderón identities. Using this observation, the kernel of the coupled problem is characterized explicitly, and we show that it completely vanishes under the exterior representation formula.

Spurious Resonances in Coupled Domain-Boundary Variational Formulations of Transmission Problems in Electromagnetism and Acoustics

Convergence of Discrete Exterior Calculus Approximations for Poisson Problems

1. Functions 1.1 Review of functions 1.2 Representing functions 1.3 Trigonometric functions and their inverses Review 2. Limits 2.1 The idea of limits 2.2 Definitions of limits 2.3 Techniques for computing limits 2.4 Infinite limits 2.5 Limits at infinity 2.6 Continuity 2.7 Precise definitions of limits Review 3. Derivatives 3.1 Introducing the derivative 3.2 Rules of differentiation 3.3 The product and quotient rules 3.4 Derivatives of trigonometric functions 3.5 Derivatives as rates of change 3.6 The Chain Rule 3.7 Implicit differentiation 3.8 Derivatives of inverse trigonometric functions 3.9 Related rates Review 4. Applications of the Derivative 4.1 Maxima and minima 4.2 What derivatives tell us 4.3 Graphing functions 4.4 Optimization problems 4.5 Linear approximation and differentials 4.6 Mean Value Theorem 4.7 L'Hopital's Rule 4.8 Newton's method 4.9 Antiderivatives Review 5. Integration 5.1 Approximating areas under curves 5.2 Definite integrals 5.3 Fundamental Theorem of Calculus 5.4 Working with integrals 5.5 Substitution rule Review 6. Applications of Integration 6.1 Velocity and net change 6.2 Regions between curves 6.3 Volume by slicing 6.4 Volume by shells 6.5 Length of curves 6.6 Surface area 6.7 Physical applications 6.8 Hyperbolic functions Review 7. Logarithmic and Exponential Functions 7.1 Inverse functions 7.2 The natural logarithm and exponential functions 7.3 Logarithmic and exponential functions with general bases 7.4 Exponential models 7.5 Inverse trigonometric functions 7.6 L'Hopital's rule and growth rates of functions Review 8. Integration Techniques 8.1 Basic approaches 8.2 Integration by parts 8.3 Trigonometric integrals 8.4 Trigonometric substitutions 8.5 Partial fractions 8.6 Other integration strategies 8.7 Numerical integration 8.8 Improper integrals Review 9. Differential Equations 9.1 Basic ideas 9.2 Direction fields and Euler's method 9.3 Separable differential equations 9.4 Special first-order differential equations 9.5 Modeling with differential equations Review 10. Sequences and Infinite Series 10.1 An overview 10.2 Sequences 10.3 Infinite series 10.4 The Divergence and Integral Tests 10.5 The Ratio, Root, and Comparison Tests 10.6 Alternating series Review 11. Power Series 11.1 Approximating functions with polynomials 11.2 Properties of power series 11.3 Taylor series 11.4 Working with Taylor series Review 12. Parametric and Polar Curves 12.1 Parametric equations 12.2 Polar coordinates 12.3 Calculus in polar coordinates 12.4 Conic sections Review 13. Vectors and Vector-Valued Functions 13.1 Vectors in the plane 13.2 Vectors in three dimensions 13.3 Dot products 13.4 Cross products 13.5 Lines and curves in space 13.6 Calculus of vector-valued functions 13.7 Motion in space 13.8 Length of curves 13.9 Curvature and normal vectors Review 14. Functions of Several Variables 14.1 Planes and surfaces 14.2 Graphs and level curves 14.3 Limits and continuity 14.4 Partial derivatives 14.5 The Chain Rule 14.6 Directional derivatives and the gradient 14.7 Tangent planes and linear approximation 14.8 Maximum/minimum problems 14.9 Lagrange multipliers Review 15. Multiple Integration 15.1 Double integrals over rectangular regions 15.2 Double integrals over general regions 15.3 Double integrals in polar coordinates 15.4 Triple integrals 15.5 Triple integrals in cylindrical and spherical coordinates 15.6 Integrals for mass calculations 15.7 Change of variables in multiple integrals Review 16. Vector Calculus 16.1 Vector fields 16.2 Line integrals 16.3 Conservative vector fields 16.4 Green's theorem 16.5. Divergence and curl 16.6 Surface integrals 16.6 Stokes' theorem 16.8 Divergence theorem Review

Table-Top Exercises on the Human Element and Autonomous Weapons Systems Summary Report

An optical ray trace luster prediction computer model is used to explain the reduced dye yield of microdenier yarns. Results from the model demonstrate that the reduced dye yield is a necessary consequence of the reduced path length of light inside the filaments. Data are shown for the predicted brightness of a set of standard denier per filament and microdenier PET ( Micromattique ) yarns.

Using Optical Ray Tracing to Explain the Reduced Dye Yield of Microdenier Yarns

Zusammenfassung Ziel der Studie Es gibt wenige Daten zum orthostatischen Blutdruck (BD) Verhalten und Veränderungen der Herzratenvariabilität (HRV) bei idiopathischer REM-Schlaf-Verhaltensstörung (iRBD). Unsere Hypothese war, dass orthostatische BD Veränderungen vorübergehend sind. Methodik Wir untersuchten 16 männliche iRBD Patienten und 15 altersgematchte männliche Kontrollprobanden (HC) im Hinblick auf eine Dysautonomie, HRV und kontinuierliche BD Messung während der Kipptischuntersuchung. Ergebnisse Die BD Abfälle in den ersten 5 Minuten Stehzeit waren bei iRBD Patienten signifikant größer. IRBD Patienten hatten häufiger eine reduzierte respiratorische Sinusarrhythmie (RSA). Schlussfolgerungen Mittels kontinuierlicher BD Messung ließen sich transiente orthostatische BD Abfälle bei iRBD detektieren. Longitudinale Daten werden zeigen, ob diese Änderungen Hinweise für eine periphere sympathoneurale Dysfunktion darstellen und frühe Marker einer späteren orthostatischen Hypotonie sein können.

Durch die kontinuierliche Blutdruckmessung lässt sich ein transienter orthostatischer Blutdruckabfall bei idiopathischer REM-Schlaf-Verhaltensstörung nachweisen

Zusammenfassung Eine Patientin wird mit schwerer Antriebsarmut und gedrückter Stimmung zunächst unter der Annahme einer schweren Depression behandelt. Im Verlauf manifestiert sich eine respiratorische Insuffizienz mit CO2-Retention. Auch fallen bei der Patientin eine schlaffe beinbetonte Tetraparese sowie distale Hypästhesien an den Extremitäten auf. Der elektrophysiologische Befund zeigt eine schwere axonale Polyneuropathie mit florider Denervierung in der Zwerchfellmuskulatur. Unter dem Verdacht eines subakuten axonal betonten Guillain-Barré-Strohl-Syndroms erfolgen immunsuppressive Maßnahmen mittels Immunglobulintherapie und Plasmapherese. Trotz Therapie kommt es zu einer Progredienz der Symptomatik. Die umfangreiche Diagnostik erbringt den Nachweis von SOX-1-Antikörpern. SOX-1-Antikörper sind Paraneoplasiemarker, die nach bisherigem Wissensstand mit dem kleinzelligen Bronchialkarzinom assoziiert sind. Die Tumorstaging erbringt allerdings keinen Tumornachweis. Eine Reevaluation ist geplant.

CO2-induzierte Beatmungspflichtigkeit aufgrund einer SOX1-Antikörper-positiven subakuten axonal-betonten sensomotorische Polyneuropathie

Anzahl der Komedikationen am Therapiebeginn bei ambulant behandelten Patienten mit Demenz vom Alzheimer Typ

Erwartungen von Demenzpatienten und Angehörigen an eine Demenztherapie mit transdermaler Applikationsform

Werkstoff-, Prozess- und Bauteiluntersuchungen zum Laserdurchstrahlschweißen von Kunststoffen

Short-pulse welding parameters for resistance spot welding (RSW) of aluminum alloy AA6016-T4 using mediumfrequency direct current (MFDC) systems were developed to reduce the heat input required for nugget formation. Optimization of current and time parameters is critical during RSW of aluminum alloys for reducing energy requirements and avoiding weld imperfections, such as solidification cracking and expulsion, while maintaining weld quality, particularly given the high electrical and thermal conductivities of the materials. The welding time and the applied current level of the current pulse were varied systematically for thin sheets (1 mm or 0.04 in.) of AA6016-T4. The quality of the welds was evaluated by pull-out testing, ultrasound testing, and metallography techniques. Simulations of the same welding processes were performed with the finite element-based SORPAS® software. The results showed short-pulse MFDC RSW can reduce the energy required for sound welds in this alloy without requiring an increase in welding current. The simulations and experiments also showed the welding process had distinct weld nugget nucleation and growth phases.

Short-Pulse Resistance Spot Welding of Aluminum Alloy 6016-T4 - Part 1

Electrode wear in short-pulse resistance spot welding of aluminum AA 6016-T4

The present paper reports detailed studies on the internal energy of matrixassisted laser desorbed ions using delayed extraction MALDI-TOF and atmosphericpressure MALDI. We used benzylpyridinium cations as internal energy probes. Our study reveals three distinct contributions to internal energy build-up in vacuumMALDI (classical MALDI-TOF), each one having different effects on ion fragmentation. Some fragments are formed before ion extraction (i.e. maximum 100 ns after the laser impact), and are therefore well resolved and sharp in the MALDITOF MS scan. This prompt fragmentation can have two origins: (i) in-plume thermal activation, presumably always present, and (ii) in-plume chemical reactions with hydrogen radicals. In addition to these promptly formed fragments, a broad peak slightly offset to higher masses could be detected, corresponding to fragments formed after the extraction has started. A third source of internal energy for MALDI ions is therefore (iii) the extraction-induced collisional activation of the ions with the neutral components of the plume. These three contributions are difficult to quantify in vacuum-MALDI, because of the combined influence of several parameters (nature of the matrix, spot-to-spot variability, total laser exposure, delay time, acceleration voltage) on extraction-induced fragmentation. Atmospheric pressure MALDI has two advantages for comparative studies of analyte fragmentation. First, extraction-induced fragmentation is absent, and only the contribution of early plume activation remains. Second, the reproducibility is far better than in vacuum-MALDI. AP-MALDI is therefore expected to shed a new light on the early steps of the MALDI process. † Present address : Mass Spectrometry Laboratory, Chemistry Department, University of Liège, Institut de Chimie, Bat. B6c, B-4000 Liège, Belgium.

Influence of the matrix on analyte fragmentation in atmospheric pressure MALDI

This paper reports detailed studies on the internal energy of ions formed in matrix-assisted laser desorption/ionization (MALDI) using delayed extraction MALDI-time-of-flight (TOF) and atmospheric pressure (AP) MALDI mass spectrometric (MS) methods. We use benzylpyridinium cations as internal energy probes. Our study reveals three distinct contributions to internal energy build-up in vacuum-MALDI (classical MALDI-TOF), each having different effects on ion fragmentation. Some fragments are formed before ion extraction (i.e. no more than 100 ns after the laser impact), and they are therefore well resolved and recorded as sharp signals in the MALDI-TOFMS scan. This prompt fragmentation can have two origins: (i) in-plume thermal activation, presumably always present, and (ii) in-plume chemical activation, in the course of reactions with hydrogen radicals. In addition to early internal energy build-up associated with these well-resolved promptly formed fragments, a broad peak slightly offset to higher masses could be detected corresponding to fragments formed after the extraction has started. This second signal corresponds to a third source of internal energy in MALDI ions, (iii) the extraction-induced collisional activation of the ions with the neutral components of the plume. These three contributions are difficult to quantify in vacuum-MALDI, because of the combined influence of several parameters (nature of the matrix, spot-to-spot variability, total laser exposure, delay time, acceleration voltage) on extraction-induced fragmentation. AP-MALDI, on the other hand, has two advantages for comparative studies of analyte fragmentation. First, extraction-induced fragmentation is absent, and only the contributions of early plume activation remain. Second, the reproducibility is far better than in vacuum-MALDI. AP-MALDI is therefore expected to shed new light on the early steps of the MALDI process.

Internal energy build-up in matrix-assisted laser desorption/ionization.

Analysis of air entrainment by secondary fibers. II: Laboratory investigation of air release from individual fiber stocks

Entrained air was measured in the furnish of a mill producing a multi-ply coated boxboard from secondary fibers. Very high levels of air were found throughout the stock-preparation areas for the filler ply, bottom liner and top liner as well as in the headbox furnishes for the bottom liner and filler ply. The top-liner headbox contained the lowest levels of entrained air. Entrained-air levels in successive process steps showed no correlation. Moreover, the amount of entrained air in the headbox showed no correlation with the amount of air introduced during stock preparation.

Analysis of air entrainment by secondary fibers. I: Entrained air in coated recycled boxboard mill

Combined Boron and Aluminum Implantation for High-Voltage Devices

A simple, precise method is presented for determining total soil fluoride. The soil sample is decomposed by a standard steam distillation in the presence of H2SO4. An aliquot of the resulting distillate is diluted 1:1 with a total ionic strength adjustment buffer (TISAB), and the fluoride determination is made by selective ion electrode (pF) procedure. This method, when compared with a double distillation-pF technique on 15 Ohio soils, yielded slightly but significantly higher results. The H2SO4 distillation-pF procedure is relatively quick, precise, and reproducible, and eliminates the hazard associated with the HClO4 distillation step used in most other techniques.

TOTAL SOIL FLUORIDE DETERMINATION BY A SINGLE DISTILLATION SELECTIVE ION ELECTRODE PROCEDURE

Zusammenfassung Publizierte Studien aus dem Jahr 2021, deren Datenerhebung Ende 2020 und vor der Zulassung des ersten COVID-19-Impfstoffes Comirnaty erfolgte, fanden medial einen großen Anklang, da sie unter anderem schlussfolgerten, dass im Besonderen Homöopathie-Anwender einer COVID-19-Impfung skeptisch gegenüberstünden. Die betrachteten Studien basieren auf einer Datenerhebung, die zu einem Zeitpunkt stattgefunden hat, der aus heutiger Sicht keine Grundlage dafür bietet, Aussagen über die COVID-19-Impfbereitschaft von Individuen in Deutschland abzuleiten. Der Wissensstand in der Bevölkerung bezüglich des neuartigen Impfstoffes, dessen Wirksamkeit und potenziellen Nebenwirkungen bzw. Impfschäden hat sich seitdem drastisch verändert. Jenseits des ungeeigneten Erhebungszeitraumes, weist die Studie signifikante methodische Mängel auf. So bedingen unscharf definierte Selektionskriterien für einige Fragebogen-Items potenzielle Verzerrungen der Ergebnisse. Bei der Fragestellung eines potentiellen Zusammenhanges zwischen Homöopathie-Anwendung und Impfskepsis ist eine wissenschaftlich zu fordernde Analyse auf mögliche Drittvariablen, die zu einer Scheinkorrelation führen, nicht erfolgt. Die Korrelation dann als Kausalzusammenhang zu präsentieren ist wissenschaftlich unzulässig. Aktuelle methodisch valide Untersuchungen belegen zudem, dass keine Korrelation zwischen der Einstellung zu Alternativmedizin und Impfskepsis besteht.

Gedächtnisambulanzen in Deutschland – strukturell-organisatorische Voraussetzungen und Aufgabenfelder

Einfluss von Torsionsspreizfedern auf die Effizienz und Dynamik von ölgekühlten Mehrscheibenkupplungen

In a clinical setting a standardized regime
was used on 33 patients with chronic or acute wounds to
detect and treat a wound infection. A GC-IMS was used
as a new method for Infection Diagnostics. Wound size,
germ colonization and clinical staging were documented on
three examination dates in a distance from one week. For
treatment of the wounds a novel wound powder Toxaprevent
skin® ("Klinoptilolith") was used.
Systematic trends were noticeable compared to the initial
findings, so that an antimicrobial effect of the treatment can
be assumed.
Due to the variability of germ infestation and the small
number of patients assigned, a statistically significant
statement is not to be made.
The results of microbiological studies using a classic wound
smear and the MCC-IMS technique show that the latter
has a distinct advantage over traditional microbiology.
This methodology allows for immediate germ assignment
and can be repeated as often as necessary. An advantage
of germ identification using IMS may be that the method
only responds to clinically relevant germ growth, while
traditional studies from the smear can also be positive
for randomly present ambient germs. The possibility of
immediate germ assignment makes promptly specific
therapy possible.
A prerequisite for a clinical application would be validation
on large groups in order to define the germ-specific
fingerprints even in the case of mixed infections.
Based on the study results so far, it can be concluded that the
Toxaprevent Skin powder® has a positive therapeutic effect
on wound healing, has good local tolerability and has a low
side effect profile.
In order to find out further therapeutic effects principles
of the Toxaprevent skin Powder®, further clinical
application studies under outpatient conditions would be
recommended, with the need to review local and systemic
examination parameters (e.g. local Wound assessment, germ
spectrum, systemic inflammatory parameters, immunology,
oxygen partial pressure, proteins, muscle enzymes).

Infektionskontrolle mittels GC-IMS und Einsatz von Wundpuder (Klinoptilolith) bei chronischen infizierten Wunden

Vergleichende Evaluation neuartiger Neurotensinrezeptor-1-Antagonisten im Nacktmausmodell

Wiederfindung von MDA zugeordneten Clustern bei realen Patientenmessungen aus IMS Spektren der Ausatemluft

Wirkungen einer physikalischen Stimulierung der spontanen arteriolären Vasomotion auf Mikrozirkulation und Immunsystem bei Diabetes und Wundheilungsstörungen

Zusammenfassung In einer placebokontrollierten Untersuchungsreihe wurde an einer Stichprobe aus 50-jährigen Rehabilitanden ermittelt, ob der komplementäre Einsatz einer physikalischen Behandlungsmethode zur Stimulierung der arteriolären Vasomotion den therapeutischen Erfolg etablierter Maßnahmen zur physischen Konditionierung steigern kann. Als Ergebnis zeigte sich, daß sowohl die mikro-zirkulatorische Durchblutungsregulation als auch die (zelluläre) Immunabwehr durch eine zusätzliche physikalische Vasomotions-stimulierung therapierelevant beeinflußt werden können.

Komplementär-therapeutische Stimulierung der defizitären autorhythmischen arteriolären Vasomotion mittels eines biorhythmisch definierten physikalischen Reizes auf die Mikrozirkulation und das Immunsystem bei 50-jährigen Rehabilitanden

Zusammenfassung In einer placebokontrollierten Untersuchungsreihe an einer Stich-probe aus Patienten mit diabetischer Polyneuropathie und trophischen Hautläsionen am Fußrand wurden Messungen von Funktionsmerkmalen der lokalen Mikrozirkulation und des Immun-systems zur Prüfung des komplementär-therapeutischen Erfolges einer biorhythmisch definierten Vasomotionsstimulation vorge-nommen. In einem 30-tägigen Behandlungszeitraum wurde ein komplementär-therapeutischer Erfolg der zusätzlich durchgeführten physikalischen Vasomotionsstimulation zur Steigerung des Thera-pieerfolges etablierter Behandlungskonzepte nachgewiesen.

Einfluss eines spezifisch biorhythmisch definierten physikalischen Reizes auf die defizitäre Vasomotion in kleinkalibrigen Arteriolen der Subkutis bei Patienten mit diabetischer Polyneuropathie

Zusammenfassung An zwei Stichproben aus Rehabilitanden unterschiedlicher Alters-gruppen (~38 Jahre und ~51 Jahre) wurde im Rahmen einer placebokontrollierten Untersuchungsreihe anhand repräsentativer Funktionsmerkmale der Mikrozirkulation der komplementär-thera-peutische Erfolg einer Zusatzbehandlung zur biorhythmisch definier-ten physikalischen Vasomotionsstimulation ermittelt. Als Ergebnis zeigte sich, dass bei älteren Rehabilitanden die Beträge der mikrozirkulatorischen Merkmaländerungen größer sind als bei jüngeren Rehabilitanden, sie klingen jedoch nach Beendigung der Zusatzbehandlung rascher als bei diesen ab.

Wirkungen einer physikalischen Stimulierung der spontanen arteriolären Vasomotion bei Rehabilitanden unterschiedlichen Alters

Eine Literaturubersicht stellt dar, das Schlafstorungen aus Elternsicht zu den haufigsten Problemen in den ersten Lebensjahren von Kindern gehoren. Vorgestellt werden epidemiologische Ergebnisse aus einer multizentrischen Geburtskohorte (M=1314), die in sechs Zentren in Deutschland mit 4 Wochen, 3 Monaten, 6 Monaten, 1 Jahr, 18 Monaten, 2 Jahren und 3 Jahren untersucht wurde. Neben der Haufigkeitsbeschreibung von Durchschlafproblemen (mit 2 Jahren schliefen z. B. Zweidrittel aller Kinder nachts durch) wird auf die Verhaltensstabilitat bzw. Persistenz von Durchschlafstorungen und auf statistisch abgesicherte Zusammenhange mit dem Stillen und dem Schlafort der Kinder eingegangen. Die Auswirkungen der Durchschlafproblematik auf die Familienstimmung werden beschrieben. Auch die Pravalenz von Einschlafproblemen in dieser Kohorte wird ausfuhrlich dargelegt, ln der Diskussion dieser Ergebnisse wird versucht, fur den Praktiker ein Schema zur Abklarung sogenanter Schlafstorungen vorzulegen. 
A review of the literature on sleeping "disorders" in infants and toddlers shows that sleep problems are very common. We report the results of a German multicenter epidemiological study on a birth cohort (N=1314). The children had medical examinations at 4 weeks, 3 months, 6 months, 1 year, 18 months, 2 years and 3 years. Most of the information on the sleeping behavior was gathered by structured interview and questionnaires. This paper gives information on the prevalence and the persistence of sleep problems in one to three year old children in Germany. Statistical analysis of correlations between breastfeeding and sleep and the place of sleep are reported. The consequences of sleep problems on the family overall well-being are also examined.

Biologie an der Humboldt-Universität nach 1945. Ihre Entwicklung im Spannungsfeld von Politik und Forschung

In times of discussing the use of fossil fuels with regard to profitability and ecological compatibility of existing and new power plants it gets even more important to increase the efficiency of combustion plants. A substantial way is the reduction of flue gas losses - especially in reference to the exhaust gas temperature. Thereby the acid dew point of the flue gas determines significantly the temperature range -in particular at the combustion of brown coal and other sulphurous fuels. In order to make sure that the sulphur acid does not condensate in the flue gas ductwork and the related corrosion is kept at a minimum, it is common to adjust the exhaust gas temperature at around 10 to 20 K above the assumed sulphur acid dew point. This, however, has only been definable by single measurements so far. By means of the acid dew point measuring device AMD 08 presented hereinafter the real acid dew point can be detected in a quasi-continuous way. It is based on the triboelectric measuring principle which has proven for dust concentration measurement in many cases. In knowing the chronology of the acid dew point the exhaust gas temperature can be reduced systematically resulting in a considerable potential of cost savings.

Kopfstutze mit einer Verstellvorrichtung zur Einstellung der Kopfstutze in Bezug auf eine Kopfposition eines Fahrgastes, mit mindestens zwei ubereinander angeordneten Elektroden, wobei in mindestens einem bestimmten Bereich der Kopfstutze ein Feldbeeinflussungselement angeordnet ist.

Die Erfindung betrifft ein Mittel zur Therapie und Prophylaxe von Hauterkrankungen, insbesondere von Psoriasis, Neurodermitis oder atopischer Dermatitis. Der Kerngedanke der Erfindung besteht darin, ein Mittel aus Zeolithen und Brennnesselextrakten bzw. Calcium- und/oder Magnesiumsalzen zur Verfugung zu stellen. Die Verabreichung des Mittels kann durch orale Einnahme und/oder durch topische Behandlung der Haut erfolgen.

Das Outsourcing von IT-Dienstleistungen wird seit einigen Jahren zumeist selektiv betrieben. Je umfassender IT-Leistungen an Sourcing-Partner vergeben werden, desto grosser sind die Anforderungen an das verbliebene IT-Management. Insbesondere wenn Entwicklung und Betrieb von (voneinander unabhangigen) Dritten durchgefuhrt werden, ist eine transparente und wirksame Steuerung durch das IT-Management zwingend notwendig, um die Leistungen der von einander unabhangigen Sourcing-Partner zu koordinieren. Die fundamentalen Koordinationsprozesse werden dabei erst durch eine systematische und ganzheitliche Ableitung einer Sourcing Governance aus der IT-Governance ermoglicht. Somit stellt eine idealtypische IT-Governance die grundlegenden Organisations- und Managementvoraussetzungen fur eine langfristige und wirtschaftliche Partnerschaft mit externen IT-Dienstleistern zur Verfugung.

Aims/hypothesis: To investigate the prevalence of impaired fasting glucose (IFT), impaired glucose tolerance (IGT), and adipositas in the progeny of mothers with gestational diabetes mellitus (GDM), based on parameters of the mother's glucose metabolism during pregnancy. Method: We analysed 227 children of mothers with GDM (1993 -1999). 132 children (58.1%, age 6 ± 2 years, BMI 16 ± 3 kg/m 2 ) were examined in our outpatient clinic: an oral glucose tolerance test (oGTT) was performed: BMI and blood pressure was measured and correlated with maternal parameters during pregnancy. In 50 children (22%) follow-up examinations were performed by local paediatricians. Two children had died before follow-up. 45 children (19,8%) could not be located for the follow-up. Results: At follow-up, all children had a normal blood glucose metabolism, including children of mothers who did not achieve normoglycaemia during pregnancy. Fasting glucose in children at the follow-up correlated directly with body fat (r=0.233; p 97th percentile in 6.3%) were found to be overweight. Children who were overweight at the follow-up had no increased perinatal morbidity but tended more often towards macrosomia at delivery (22 vs. 14%; n.s.). Mothers with overweight children at follow-up had a higher fasting blood glucose (5.6 ± 1.1 vs. 5.2 ± 0.8 mmol/l; p < 0.05) at diagnosis of GDM. Additionally, HbA1c was higher (5.0 ± 0.8 vs. 4.6 ± 0.5%; p < 0.05) in mothers of normal-weight children. After initiation of insulin therapy, mothers of overweight children achieved normoglycaemia by delivery comparable to mothers of children who had normal weight at follow-up. There was a direct correlation between BMI in children and mothers (r=0.324; p< 0.001) at follow-up and between postpartal weight gain in mothers and BMI of children (r=0.212; p<0.05) at the follow-up. Mothers with overweight children at follow-up had higher BMI (32 ± 8 kg/m 2 vs. 25±5kg/m 2 ; p<0.05). Maternal BMI after birth was the strongest predictor for overweight children at the follow-up in the multivariate analysis (F = 7.89; p < 0.01). Conclusions: Complications, i.e. being overweight, IFTand IGT, in the offspring of mothers with GDM can be avoided. Dietary habits of mothers are an important risk factor for obesity in children and correlate with maternal weight gain and BMI after delivery.

Prävalenz einer Glukosetoleranzstörung und Adipositas von Kindern im Alter von 6 Jahren nach Gestationsdiabetes der Mutter in der Indexgravidität

Die Wirkung des Wehenhemmers Th 1165a (Partusisten) auf kardiovaskuläre Parameter, Blutgase und pH-Werte von Mutter und Fet im Tier-experiment

Untersuchungen zur Genese der Herzfrequenzalterationen am ausgetragenen Schaf-Feten

Beschrieben
und dargestellt ist eine Schaltungsanordnung zur Erfassung der Kapazitat bzw. einer
Kapazitatsanderung
eines kapazitiven Schaltungs- oder Bauelementes, dargestellt als
Sensorkondensator (1), mit einer Spannungsquelle (2), mit mindestens
einem Umschaltkontakt (3), mit einem den Umschaltkontakt (3) steuernden,
vorzugsweise einen Taktgenerator enthaltenden Steuergerat (5), mit
mindestens einem Lade- bzw. Speicherkondensator (6) und mit einer
an den Lade- bzw. Speicherkondensator (6) angeschlossenen Auswerteschaltung
(7), wobei eine Elektrode (12) des Sensorkondensators (1) mit dem
Eingang (3a) des Umschaltkontakts (3) verbunden ist, der erste Ausgang
(3b) des Umschaltkondensators (3) mit einem Bezugspotential (11),
der zweite Ausgang (3c) des Umschaltkontakts (3) mit der ersten Elektrode
(12) des Lade- bzw. Speicherkondensators (6), die erste Elektrode
(12) des Lade- bzw. Speicherkondensators (6) einerseits mit der
Spannungsquelle (2) verbindbar und andererseits mit der Auswerteschaltung
(7) verbunden ist und die zweite Elektrode (13) des Lade- bzw. Speicherkondensators
(6) mit Bezugspotential (11) verbindbar ist, und wobei aus der bis
zum Erreichen einer bestimmten Spannung erfolgten Anzahl x von mit
einer Arbeitsfrequenz f 1 durchgefuhrten Umladezyklen
durch die Auswerteschaltung (7) ein Mesergebnis m 1 ermittelbar
ist, welches ein Mas fur die Kapazitat bzw. die
des Sensorkondensators (1) darstellt. Die erfindungsgemase ...

Verfahren zum Messen einer physikalischen Größe und Schaltungsanordnung zur Erfassung der Kapazität bzw. einer Kapazitätsänderung eines kapazitiven Schaltungs- oder Bauelements

Geschwindigkeitskontrolliertes Kugelstrahlen und Kugelstrahlumformen

AIM This paper analyses, in what way psychiatrists considered housing and work as criteria of social integration of mentally ill people and what models of care were suggested in Germany throughout the 20th century. METHOD Publications in 29 German professional and scientific psychiatric journals through the complete period from 1900 to 2000 and monographs were searched for papers on the above issues. RESULTS Until the second half of the century, integrative initiatives related to housing and work generated in asylums without the aim of a full social integration of the patients. In the activistic concept of NS-psychiatry, work became an obligation for patients and a criterion for selection that decided on life and death. Not until the late 1950s, there again was an orientation towards integration in psychiatric care in both German states. Whilst already in 1963 the "Rodewisch Theses" outlined recommendations for the rehabilitation of the mentally ill already in the GDR (East Germany), a similar mark of reform ideas was published in the "enquete" in the FRG (West Germany) in 1975. In the GDR initiatives were limited to a small number of locations. In the FRG and the re-unified Germany various forms of sheltered housing and work were established - also with significant regional variation. However, a clear discussion of underlying aims and implications for the structure of mental health care was not found in the psychiatric literature. CONCLUSIONS In the 20th century a tradition of psychiatric ideas related to housing and work did not develop in Germany. Particularly, there were only sporadic contributions from university psychiatry. Work was more frequently explicit subject of discussions than housing. Both areas were - slowly and in discontinuity - established as criteria of integration of people with mental illnesses, which was increasingly accepted as an aim of mental health care.

Wohnen und Arbeit als Kriterien einer „sozialen Integration” psychisch Kranker - Entwicklungen in Deutschland von 1900 bis 2000

Auswirkungen der Strahlmittelgeschwindigkeit und ihrer Verteilung auf die Almenintensität bei Kugelstrahlprozessen

Eine Architektur für Hochleistungs-Datenverarbeitung in Weitverkehrs-Workstation-Netzwerken

Die Erfindung betrifft ein Verfahren zur Diagnostik der Alzheimer-Krankheit und von Krankheiten analoger Ursachen sowie pharmazeutische Mittel zur Therapie. Anwendungsgebiete der Erfindung sind die Medizin und die pharmazeutische Industrie. Ausgangspunkt der Erfindung ist der uberraschende Befund, das ein auslosendes Prinzip der Alzheimer-Erkrankung die pathologische Produktion aktivierter, autospezifischer T-Lymphozyten im peripheren Blut ist. Die aktivierten T-Lymphozyten passieren die Blut-Hirn-Schranke, unterliegen bei Wechselwirkung mit Mikroglia-Zellen der Apoptose und leiten mit der Mikroglia-Aktivierung den charakteristischen neurotoxischen Entzundungsprozes ein. Das erfindungsgemase Verfahren benutzt eine Probe peripheren Probandenbluts, aus der die Alzheimer-Krankheit anhand des erhohten Anteils apoptotischer (absterbender) mononuklearer Zellen, anhand der Aktivierung von Monozyten/Makrophagen oder anhand beider Methoden in Kombination diagnostiziert wird. Das erfindungsgemase Mittel enthalt als Wirkstoff einen Faktor, der die Phagozytose-Aktivitat im Korper sowie in der Organspezifitat, insbesondere im Gehirn, steigert oder einen Stoff, der selektiv an Aktivierungsmarker oder Adhasionsrezeptoren auf aktivierten T-Lymphozyten oder an Adhasionsrezeptoren auf Endothelzellen bindet.

Verfahren zur diagnostik der alzheimer-krankheit sowie mittel zur therapie

Integration von Umweltinformationen in die Vorgangsbearbeitung am Beispiel von Ökoaudits

Laufende und umfassende Informationen uber den Zustand und die Entwicklung der Umwelt sind unabdingbare Voraussetzungen fur einen vorsorglichen Umgang mit unseren naturlichen Lebensgrundlagen. In Baden-Wurttemberg wurden und werden im Bereich der Umweltverwaltung taglich eine grose Menge von Mesdaten, Analysedaten, Verwaltungsdokumenten, statistischen Erhebungen und Berechnungen erzeugt. Diese Informationen zu sammeln, zu sichten, zu bewerten und bedarfsgerecht aufzuarbeiten, ist mit den herkommlichen Methoden der Verwaltungsarbeit nicht mehr moglich, sondern erfordert neue Methoden insbesondere auch der Informationstechnik. In Baden-Wurttemberg wird auf Beschlus der Landesregierung seit 1986 (jetzt unter Federfuhrung des Ministeriums fur Umwelt und Verkehr - UVM) ein Konzept fur ein ressortubergreifendes Umweltinformationssystem des Landes Baden-Wurttemberg entwickelt und umgesetzt.

Einsatz der aktiven Kipptisch-Orthostase-Untersuchung zur Beurteilung der Qualität der antihypertensiven Therapie im höheren Lebensalter

Über das Wohlergehen des ungeborenen Kindes kann man I n f o l g e der Geborgenheit im M u t t e r l e i b nur schwer Aussagen e rha l t en . In der k l i n i s c h e n Rout ine hat s ich a ls e inzige k o n t i n u i e r l i c h e Methode die Messung der fe ta len Herzfrequenz (FHF) und der m ü t t e r l i c h e n Wehe zur Beur te i lung des fe ta len Zustandes durchgesetzt. In rund 60 % der Fä l l e wurden unter der Geburt kurze feta le Bradykardien (Dezelerat ion) beobachtet, die mit den m ü t t e r l i c h e n Wehen ko r r e l i e r t s i n d . Für die Entstehung dieser Dezelerat ion werden folgende Gründe angenommen:

Störsignale im Elektround Phonokardiogramm werden bei automatisierten Messungen in der Perinatalen Medizin (2,3) meist dadurch eliminiert, indem man ihr zeitliches Auftreten elektronisch mit definierten Erwartungswerten vergleicht (s.1). Entgegen dieser "bewährten Praxis unterdrückt unser an anderer Stelle (5) ausführlich beschriebenes Meßverfahren solche Signal-Artefakte mit Hilfe selektiver BandpaßFilterung (vgl. 6).

Elektronische Messungen an fetalen Elektro- und Phonokardiogramm-Signalen.

Verbrauchscoagulopathie beim Neugeborenen durch Einschwemmung von Gewebethromboplastin

171. Spezielle Indikationen und spezielle Stimulationstechniken aus einem Krankengut von 1000 Schrittmacherpatienten

Zeitschrift fur Kinder- und Jugendpsychiatrie und Psychotherapie

Fortschritte der Ophthalmologie : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft

The morphology of surface grown polythylene fibres before and after zone-drawing is studied by electron microscopy using various preparation techniques, mainly chlorsulfonation staining and ultra-thin sectioning. Computer processing is applied in order improve the detectability of image details. Image analysis is carried out by digital or optical diffraction. It is found that, to a first approximation, the average lateral core size of the fibrils (≈ 4 nm) remains nearly constant during drawing. This is consistent with a successive “reeling in” process of chain segments from the molten shish kebab overgrowth and from the interfibriller matrix into the extended-chain backbone fibrils. The structural data derived by electron microscopy enable us to calculate the Young's moduli of the fibres within the scope of an unidirectional fibre composite model. Comparing these estimates with the results of mechanical testing yields quite a good agreement. On the other hand, the existance of gross morphological defects like kink bands, disordered boundary regions, voids, and distortions and terminations of fibril bundles, prove to cause a considerable deterioration of the fibre properties. 
 
Die Morphologie oberflachengewachsener Polyethylenfaden vor und nach einer Zonenreckung wird elektronenmikroskopisch unter Verwendung verschiedener Praparationstechniken, hauptsachlich der Kontrastierung durch Chlorsulfonierung und der Ultramikrotomie, untersucht. Computer-Bildverarbeitung wird angewandt, um die Erkennbakeit von Abbildungsdetails zu verbessern. Die Bildanalyse wird durch digitale oder optische Beugung vorgenommen. In erster Naherung wird gefunden, das die mittlere laterale Kerngrose der Fibrillen (≈ 4 nm) wahrend des Reckens etwa konstant bleibt. Diese Beobachtung entspricht einem allmahlichen „Auffadeln” von Kettensegmenten der geschmolzen “shish kebab” -Uberwachunsungen und der interfibrillaren Matrix auf die gestrecktkettigen Ruckgrat-Fibrillen. Die elektronenmikroskopisch gewonnenen Strukturdaten ermoglichen es, die Young-Moduli der Fasern im Rahmen eines Modells fur einen gerichteten Faserverbund zu berechnen. Die Ubereinstimmung dieser Abschazungen mit den Ergebnissen der mechanischen Messungen ist gut. Andererseits zeigt sich, das die Existenz grober morphologischer Detekte, wie Kinkbander, fehlgeordnete Grenzbereiche, Hohlraume und Verdrehungen und Abrisse von Fibrillenbundeln, eine betrachtliche Verschlechterung der Fasereigenschaften bewirkt.

Structure–property relationships of high-performance polyethylene fibres†

Schleifwerkzeug zur verwendung als eine abrichtvorrichtung für ein kissen zum chemisch-mechanischen polieren

: In a prospective study, serial serum determinations of gentamicin were made after its intratracheal application (40 mg/8 h) to 14 patients on ventilators (seven with normal renal function, seven with compensated, preterminal or dialysis-requiring renal failure). The patients with normal renal function had no therapeutic or toxicologically significant gentamicin concentration in their serum: less than 0.1 mg/l, in one case maximally 0.67 mg/l. But in patients with renal failure even the first gentamicin dose increased the serum level up to 1.5 mg/l. After repeated endotracheal application gentamicin accumulation in serum led to maximal values of 6.2 mg/l after the sixth and 7.5 mg/l after the seventh dose. The absorption of the drug from the tracheobronchial system differed between individuals. Thus serum concentrations were reached in patients with renal failure which are systemically effective and potentially toxic.

Gentamicin-Serumspiegel nach intratrachealer Applikation bei Beatmungspatienten mit normaler und eingeschränkter Nierenfunktion

In 50 patients who had a renal transplantation, treated with ciclosporin, regular monitoring of lymphocyte subpopulations was undertaken prospectively to assess its value with respect to cellular rejection, herpes virus infection, and ciclosporin overdosage. Herpes virus infection was characterized by inversion of the T4/T8 ratio below 1.0 (sensitivity 90%, specificity 88%), caused by proliferation of the T8 subpopulation, which--compared with the findings in patients with rejection crises--was significantly raised (P less than 0.001). But such rejection crises could not be predicted from the T4/T8 ratio. Ciclosporin had no effect on the ratio, total lymphocyte count in this group being higher (P less than 0.002) than in patients with rejection.

Diagnostischer Wert der Lymphozytendifferenzierung in der Frühphase nach Nierentransplantation

Incidence and course of herpes simplex infections was determined prospectively in 22 patients who had a kidney transplant and were treated with cyclosporin. In addition to clinical findings, serial studies were undertaken of throat washings for herpes simplex virus in cell culture, as well as of patient sera for herpes-specific IgG and IgM antibodies. There were 13 clinically manifest infections, 12 of them localized, while one had dissemination with necrotizing retinitis. Virus demonstration was successful in all cases in which virostatic drugs had not yet been used. Asymptomatic virus excretion was noted in three cases. Significant IgG titre rise occurred in six of the 13 cases, but a positive IgM titre in only two. Acyclovir proved to be an effective virostatic drug with few side effects. The outcome in the localized infections was favourable, but in the disseminated one residual defects remained.

Herpes-simplex-Infektionen nach Nierentransplantation unter Immunsuppression mit Ciclosporin: Diagnostische und therapeutische Erfahrungen

Die Bedeutung der Glutathionkonzentration der Erythrocyten für die Diagnose der Osteomyelofibrose

Vorrichtung und Verfahren in der kontaktierenden Rasterkraftmikroskopie mit periodischer Modulation der Auflagekraft zur Messung der lokalen elastischen und anelastischen Eigenschaften von Oberflächen unter Konstanthaltung der Deformation im Kontaktbereich von Meßsonde und Probenoberfläche

Die Selbsteinschaetzung von Alkoholbeeinflussung ist wesentlich vom Begleitwissen ueber die Wirkungen des Alkohols auf die Fahrtauglichkeit abhaengig. Hierzu ist ausreichend Aufklaerungsarbeit geleistet worden. Psychophysische Veraenderungen unter Alkoholeinfluss sind einer Selbstueberpruefung zugaenglich. Auf dieser Grundlage wird eroertert, unter welchen Voraussetzungen einem Trunkenheitsfahrer Vorsatz zur Last gelegt werden kann. Die Beeintraechtigung durch Betaeubungsmittel besitzt die Merkmale absichtlichen Handelns. Siehe auch IDS-Nummer 334806.

VORSATZ UND FAHRLAESSIGKEIT BEI TRUNKENHEITS- UND DROGENFAHRT - RECHTSMEDIZINISCHE KRITERIEN - ARBEITSKREIS II

Bewährte instrumentelle Entwicklungen in der Augenmuskelchirurgie

Funktionelle Ergebnisse nach kongenitaler bilateraler Katarakt — eine retrospektive Analyse

Direct trauma to the superior-oblique muscle of the eyeball may result in active and passive ocular motility disturbance, e.g. paresis. The author usually recommends indirect procedures, at the ipsilateral inferior oblique muscle, to correct excyclorotation, or at the contralateral inferior rectus muscle to correct paresis

Direktes Obliquus superior-Trauma und Dysfunktion: operative Möglichkeiten und Ergebnisse

4 patients with primary exotropia of divergent excess type and 6 patients suffering from secondary exotropia and raised AC/ A ratio have been operated with combined external rectus recession interal rectus ‘Fadenoperation’ and, if necessary, internal rectus resection. In all patients, the far-/near angle difference has been diminished, and in most of them microstrabism was achieved. Lateral gaze incomitance or a significant reduction of the motility of the globe did not occur. Thus, this kind of operation can be recommended for both groups of patients.

Operative Indikation und Ergebnisse bei Exotropien mit Divergenzexzess

Albrecht von Graefes Archiv für klinische und experimentelle Ophthalmologie

Ein vollautomatisch arbeitendes Torsionspendel für den Temperaturbereich von −180°C bis + 250°C

Erythropoetin (ESF) im Serum und Harn bei chronisch Nierenkranken und Gesunden unter hypoxischer Stimulation und hypoxischer Stimulation nach Androgengabe (Fluoxymesteron)

LIMNOFAUNA EUROPAEA. Eine Zusammenstellung aller die europäischen Binnengewässer bewohnenden mehrzelligen Tierarten mit Angaben über ihre Verbreitung und Ökologie.

Die Senkungsgeschwindigkeit der Leukocyten, Ihre Abhängigkeit von Deren Agglutinationsgrade und Ihre Unabhängigkeit von der Suspensionsstabilität der Erythrocyten

Das Geldgeschäft der ländlichen Spar- und Darlehnskassenvereine : unter dem Einfluß der Geldentwertung und nach Stabilisierung der Währung

The Marketing game = Bagaimana perusahaan-perusahaan terbaik dunia bermain untuk menang / Eric Schulz ; alih bahasa Hardjono Honggoamiseno dan Silvia Purba

Chunking as a rational solution to the speed–accuracy trade-off in a serial reaction time task

In everyday conversations, humans can take on different roles and adapt their vocabulary to their chosen roles. We explore whether LLMs can take on, that is impersonate, different roles when they generate text in-context. We ask LLMs to assume different personas before solving vision and language tasks. We do this by prefixing the prompt with a persona that is associated either with a social identity or domain expertise. In a multi-armed bandit task, we find that LLMs pretending to be children of different ages recover human-like developmental stages of exploration. In a language-based reasoning task, we find that LLMs impersonating domain experts perform better than LLMs impersonating non-domain experts. Finally, we test whether LLMs' impersonations are complementary to visual information when describing different categories. We find that impersonation can improve performance: an LLM prompted to be a bird expert describes birds better than one prompted to be a car expert. However, impersonation can also uncover LLMs' biases: an LLM prompted to be a man describes cars better than one prompted to be a woman. These findings demonstrate that LLMs are capable of taking on diverse roles and that this in-context impersonation can be used to uncover their hidden strengths and biases.

In-Context Impersonation Reveals Large Language Models' Strengths and Biases

Large language models are transforming research on machine learning while galvanizing public debates. Understanding not only when these models work well and succeed but also why they fail and misbehave is of great societal relevance. We propose to turn the lens of computational psychiatry, a framework used to computationally describe and modify aberrant behavior, to the outputs produced by these models. We focus on the Generative Pre-Trained Transformer 3.5 and subject it to tasks commonly studied in psychiatry. Our results show that GPT-3.5 responds robustly to a common anxiety questionnaire, producing higher anxiety scores than human subjects. Moreover, GPT-3.5's responses can be predictably changed by using emotion-inducing prompts. Emotion-induction not only influences GPT-3.5's behavior in a cognitive task measuring exploratory decision-making but also influences its behavior in a previously-established task measuring biases such as racism and ableism. Crucially, GPT-3.5 shows a strong increase in biases when prompted with anxiety-inducing text. Thus, it is likely that how prompts are communicated to large language models has a strong influence on their behavior in applied settings. These results progress our understanding of prompt engineering and demonstrate the usefulness of methods taken from computational psychiatry for studying the capable algorithms to which we increasingly delegate authority and autonomy.

Inducing anxiety in large language models increases exploration and bias

Large language models have shown tremendous performance in a variety of tasks. In-context learning -- the ability to improve at a task after being provided with a number of demonstrations -- is seen as one of the main contributors to their success. In the present paper, we demonstrate that the in-context learning abilities of large language models can be recursively improved via in-context learning itself. We coin this phenomenon meta-in-context learning. Looking at two idealized domains, a one-dimensional regression task and a two-armed bandit task, we show that meta-in-context learning adaptively reshapes a large language model's priors over expected tasks. Furthermore, we find that meta-in-context learning modifies the in-context learning strategies of such models. Finally, we extend our approach to a benchmark of real-world regression problems where we observe competitive performance to traditional learning algorithms. Taken together, our work improves our understanding of in-context learning and paves the way toward adapting large language models to the environment they are applied purely through meta-in-context learning rather than traditional finetuning.

Humans possess the ability to identify and generalize relevant features of natural objects, which aids them in various situations. To investigate this phenomenon and determine the most effective representations for predicting human behavior, we conducted two experiments involving category learning and reward learning. Our experiments used realistic images as stimuli, and participants were tasked with making accurate decisions based on novel stimuli for all trials, thereby necessitating generalization. In both tasks, the underlying rules were generated as simple linear functions using stimulus dimensions extracted from human similarity judgments. Notably, participants successfully identified the relevant stimulus features within a few trials, demonstrating effective generalization. We performed an extensive model comparison, evaluating the trial-by-trial predictive accuracy of diverse deep learning models' representations of human choices. Intriguingly, representations from models trained on both text and image data consistently outperformed models trained solely on images, even surpassing models using the features that generated the task itself. These findings suggest that language-aligned visual representations possess sufficient richness to describe human generalization in naturalistic settings and emphasize the role of language in shaping human cognition.

Language Aligned Visual Representations Predict Human Behavior in Naturalistic Learning Tasks

Large Language Models (LLMs) are transforming society and permeating into diverse applications. As a result, LLMs will frequently interact with us and other agents. It is, therefore, of great societal value to understand how LLMs behave in interactive social settings. Here, we propose to use behavioral game theory to study LLM's cooperation and coordination behavior. To do so, we let different LLMs (GPT-3, GPT-3.5, and GPT-4) play finitely repeated games with each other and with other, human-like strategies. Our results show that LLMs generally perform well in such tasks and also uncover persistent behavioral signatures. In a large set of two players-two strategies games, we find that LLMs are particularly good at games where valuing their own self-interest pays off, like the iterated Prisoner's Dilemma family. However, they behave sub-optimally in games that require coordination. We, therefore, further focus on two games from these distinct families. In the canonical iterated Prisoner's Dilemma, we find that GPT-4 acts particularly unforgivingly, always defecting after another agent has defected only once. In the Battle of the Sexes, we find that GPT-4 cannot match the behavior of the simple convention to alternate between options. We verify that these behavioral signatures are stable across robustness checks. Finally, we show how GPT-4's behavior can be modified by providing further information about the other player as well as by asking it to predict the other player's actions before making a choice. These results enrich our understanding of LLM's social behavior and pave the way for a behavioral game theory for machines.

Large language models are powerful systems that excel at many tasks, ranging from translation to mathematical reasoning. Yet, at the same time, these models often show unhuman-like characteristics. In the present paper, we address this gap and ask whether large language models can be turned into cognitive models. We find that -- after finetuning them on data from psychological experiments -- these models offer accurate representations of human behavior, even outperforming traditional cognitive models in two decision-making domains. In addition, we show that their representations contain the information necessary to model behavior on the level of individual subjects. Finally, we demonstrate that finetuning on multiple tasks enables large language models to predict human behavior in a previously unseen task. Taken together, these results suggest that large, pre-trained models can be adapted to become generalist cognitive models, thereby opening up new research directions that could transform cognitive psychology and the behavioral sciences as a whole.

Hippocampal spatio-predictive cognitive maps adaptively guide reward generalization

Meta-learning is a framework for learning learning algorithms through repeated interactions with an environment as opposed to designing them by hand. In recent years, this framework has established itself as a promising tool for building models of human cognition. Yet, a coherent research program around meta-learned models of cognition is still missing. The purpose of this article is to synthesize previous work in this field and establish such a research program. We rely on three key pillars to accomplish this goal. We first point out that meta-learning can be used to construct Bayes-optimal learning algorithms. This result not only implies that any behavioral phenomenon that can be explained by a Bayesian model can also be explained by a meta-learned model but also allows us to draw strong connections to the rational analysis of cognition. We then discuss several advantages of the meta-learning framework over traditional Bayesian methods. In particular, we argue that meta-learning can be applied to situations where Bayesian inference is impossible and that it enables us to make rational models of cognition more realistic, either by incorporating limited computational resources or neuroscientific knowledge. Finally, we reexamine prior studies from psychology and neuroscience that have applied meta-learning and put them into the context of these new insights. In summary, our work highlights that meta-learning considerably extends the scope of rational analysis and thereby of cognitive theories more generally.

Humans are skillful navigators: We aptly maneuver through new places, realize when we are back at a location we have seen before, and can even conceive of shortcuts that go through parts of our environments we have never visited. Current methods in model-based reinforcement learning on the other hand struggle with generalizing about environment dynamics out of the training distribution. We argue that two principles can help bridge this gap: latent learning and parsimonious dynamics. Humans tend to think about environment dynamics in simple terms – we reason about trajectories not in reference to what we expect to see along a path, but rather in an abstract latent space, containing information about the places’ spatial coordinates. Moreover, we assume that moving around in novel parts of our environment works the same way as in parts we are familiar with. These two principles work together in tandem: it is in the latent space that the dynamics show parsimonious characteristics. We develop a model that learns such parsimonious dynamics. Using a variational objective, our model is trained to reconstruct experienced transitions in a latent space using locally linear transformations, while encouraged to invoke as few distinct transformations as possible. Using our framework, we demonstrate the utility of learning parsimonious latent dynamics models in a range of policy learning and planning tasks.

Learning Parsimonious Dynamics for Generalization in Reinforcement Learning

Analogies to stochastic optimization are common in developmental psychology, describing a gradual reduction in randomness (“cooling oﬀ”) over the lifespan. Yet for lack of concrete empirical comparison, there is ambiguity in how to interpret this analogy. Using data from n = 281 participants ages 5 to 55, we show that “cooling oﬀ” does not only apply to the single dimension of randomness. Rather, development resembles an optimization process along multiple dimensions of learning (i.e

Developmental changes in learning resemble stochastic optimization

As children grow older, they develop an intuitive understanding of the physical processes around them. They move along developmental trajectories, which have been mapped out extensively in previous empirical research. We investigate how children’s developmental trajectories compare to the learning trajectories of artiﬁcial systems. Speciﬁcally, we examine the idea that cognitive development results from some form of stochastic optimization procedure. For this purpose, we train a modern generative neural network model using stochastic gradient descent. We then use methods from the developmental psychology literature to probe the physical understanding of this model at different degrees of optimization. We ﬁnd that the model’s learning trajectory captures the developmental trajectories of children, thereby providing support to the idea of development as stochastic optimization.

Stochastic Gradient Descent Captures How Children Learn About Physics

From learning to play the piano to speaking a new language, reusing and recombining previously acquired representations enables us to master complex skills and easily adapt to new environments. Inspired by the Gestalt principle of grouping by proximity and theories of chunking in cognitive science, we propose a hierarchical chunking model (HCM). HCM learns representations from noni.i.d sequential data from the ground up by first discovering the minimal atomic sequential units as chunks. As learning progresses, a hierarchy of chunk representation is acquired by chunking previously learned representations into more complex representations guided by sequential dependence. We provide learning guarantees on an idealized version of HCM, and demonstrate that HCM learns meaningful and interpretable representations in visual, temporal, visual-temporal domains and language data. Furthermore, the interpretability of the learned chunks enables flexible transfer between environments that share partial representational structure. Taken together, our results show how cognitive science in general and theories of chunking in particular could inform novel and more interpretable approaches to representation learning.

Learning Structure from the Ground up - Hierarchical Representation Learning by Chunking

Equipping artificial agents with useful exploration mechanisms remains a challenge to this day. Humans, on the other hand, seem to manage the trade-off between exploration and exploitation effortlessly. In the present article, we put forward the hypothesis that they accomplish this by making optimal use of limited computational resources. We study this hypothesis by meta-learning reinforcement learning algorithms that sacrifice performance for a shorter description length. The emerging class of models captures human exploration behavior better than previously considered approaches, such as Boltzmann exploration, upper confidence bound algorithms, and Thompson sampling. We additionally demonstrate that changes in description length produce the intended effects: reducing description length captures the behavior of brain-lesioned patients while increasing it echoes cognitive development during adolescence.

Context-dependent choice and evaluation in real-world consumer behavior

Human reinforcement learning (RL) is characterized by dif- ferent challenges. Exploration has been studied extensively in multi-armed bandits, while planning has been investigated in multi-step decision tasks. More recent work has added structured rewards to study generalization. However, past studies have often focused on a single one of these aspects, making it hard to compare results. We propose a generative model for constructing correlated trees to provide a unified and scalable method for studying exploration, planning, and general- ization in a single task. In an online experiment, we find that people use structure (when provided) to generalize and per- form uncertainty-directed exploration, with structure helping more in larger environments. In environments without struc- ture, exploration becomes more random and more planning is needed. All behavioral effects are captured in a single model with recoverable parameters. In conclusion, our results connect past research on human RL in one framework using cor- related trees.

Connecting Exploration, Generalization, and Planning in Correlated Trees

When exposed to perceptual and motor sequences, people are able to gradually identify patterns within and form a compact internal description of the sequence. One proposal of how sequences can be compressed is people’s ability to form chunks. We study people’s chunking behavior in a serial reaction time task. We relate chunk representation with sequence statistics and task demands, and propose a rational model of chunking that rearranges and concatenates its representation to jointly optimize for accuracy and speed. Our model predicts that participants should chunk more if chunks are indeed part of the generative model underlying a task and should, on average, learn longer chunks when optimizing for speed than optimizing for accuracy. We test these predictions in two experiments. In the first experiment, participants learn sequences with underlying chunks. In the second experiment, participants were instructed to act either as fast or as accurately as possible. The results of both experiments confirmed our model’s predictions. Taken together, these results shed new light on the benefits of chunking and pave the way for future studies on step-wise representation learning in structured domains.

E pluribus unum but how? Chunking as a rational solution to the speed-accuracy trade-off

While in most lab studies of exploration behaviour, the only potential downside to exploration is forgoing rewards, in real life, there can be actual risks to exploration, making Safe Exploration strategies important to avoid catastrophic outcomes. In the present study, we contrast exploration behaviour in safe with exploration behaviour in risky environments, i.e. in environments where reckless exploration can lead to the loss of all previously acquired rewards. Using computational modelling, we show that while people tend to use the same general strategy in both environments, they become more averse to uncertainty in risky environments compared to safe ones. We further investigate individual differences in exploration behaviour and show that while most types of anxiety and depression-related traits were associated with increased subjective uncertainty, there seemed to be two distinct strategies in dealing with this uncertainty: While subjects with high trait somatic anxiety decreased their exploration in risky environments, subjects high on depression and worry-related traits showed increased exploration and decreased aversion to uncertainty in risky environments. Our results reveal different aspects of exploration behaviour in a more ecologically valid task and show how this relates to transdiagnostic psychiatric traits, thereby illuminating potential disease mechanisms.

The two faces of anxiety in exploration: Taking risks or playing it safe

How do humans generalise to make better decisions? Previ- ous work has investigated this question using reward-guided decision-making tasks with low-dimensional and artificial stimuli. In this paper, we extend this work by presenting participants with a naturalistic decision-making task, in which op- tions were images of real-world objects and the underlying reward function was based on one of their latent dimensions. Even though participants received no explicit instruction about object features, they quickly learned to do the task and gen- eralised to unseen objects. To understand how they accomplished this, we tested a range of computational models and found that human behaviour is overall best explained by a linear model but that participants’ strategies changed during the experiment. Lastly, we showed that combining pixel-based representations extracted from convolutional neural networks with the original latent dimensions further improved our models. Taken together, our study offers new insights into human decision making under naturalistic settings.

Time pressure changes how people explore and respond to uncertainty

We study GPT-3, a recent large language model, using tools from cognitive psychology. More specifically, we assess GPT-3's decision-making, information search, deliberation, and causal reasoning abilities on a battery of canonical experiments from the literature. We find that much of GPT-3's behavior is impressive: It solves vignette-based tasks similarly or better than human subjects, is able to make decent decisions from descriptions, outperforms humans in a multiarmed bandit task, and shows signatures of model-based reinforcement learning. Yet, we also find that small perturbations to vignette-based tasks can lead GPT-3 vastly astray, that it shows no signatures of directed exploration, and that it fails miserably in a causal reasoning task. Taken together, these results enrich our understanding of current large language models and pave the way for future investigations using tools from cognitive psychology to study increasingly capable and opaque artificial agents.

Equipping artificial agents with useful exploration mechanisms remains a challenge to this day. Humans, on the other hand, seem to manage the trade-off between exploration and exploitation effortlessly. In the present article, we put forward the hypothesis that they accomplish this by making optimal use of limited computational resources. We study this hypothesis by meta-learning reinforcement learning algorithms that sacrifice performance for a shorter description length (defined as the number of bits required to implement the given algorithm). The emerging class of models captures human exploration behavior better than previously considered approaches, such as Boltzmann exploration, upper confidence bound algorithms, and Thompson sampling. We additionally demonstrate that changing the description length in our class of models produces the intended effects: reducing description length captures the behavior of brain-lesioned patients while increasing it mirrors cognitive development during adolescence.

Modeling Human Exploration Through Resource-Rational Reinforcement Learning

12 The brain forms cognitive maps of relational knowledge, an organizing principle thought to underlie our ability to generalize and make inferences. However, how can a relevant map be selected in situations where a stimulus is embedded in multiple relational structures? Here, we find that both spatial and temporal cognitive maps influence generalization in a choice task, where spatial location determines reward magnitude. Mirroring behavior, the hippocampus not only builds a map of spatial relationships but also encodes temporal distances. As the task progresses, participants’ choices become more influenced by spatial relationships, reflected in a strengthening of the spatial and a weakening of the temporal map. This change is driven by orbitofrontal cortex, which represents the evidence that an observed outcome is generated from the spatial rather than the temporal map and updates hippocampal representations accordingly. Taken together, this demonstrates how hippocampal cognitive maps are used and updated flexibly for inference. 13

Are young children just random explorers who learn serendipitously? Or are even young children guided by uncertainty-directed sampling, seeking to explore in a systematic fashion? We study how children between the ages of 4 and 9 search in an explore-exploit task with spatially-correlated rewards, where exhaustive exploration is infeasible and not all options can be experienced. By combining behavioral data with a computational model that decomposes search into similarity-based generalization, uncertainty-directed exploration, and random exploration, we map out developmental trajectories of generalization and exploration. The behavioral data show strong developmental differences in children's capability to exploit environmental structure, with performance and adaptiveness of sampling decisions increasing with age. Through model-based analyses, we disentangle different forms of exploration, finding signatures of both uncertainty-directed and random exploration. The amount of random exploration strongly decreases as children get older, supporting the notion of a developmental "cooling off" process that modulates the randomness in sampling. However, even at the youngest age range, children do not solely rely on random exploration. Even as random exploration begins to taper off, children are actively seeking out options with high uncertainty in a goal-directed fashion, and using inductive inferences to generalize their experience to novel options. Our findings provide critical insights into the behavioral and computational principles underlying the developmental trajectory of learning and exploration.

The brain forms cognitive maps of relational knowledge, an organizing principle thought to underlie our ability to generalize and make inferences. However, how can a relevant map be selected in situations where a stimulus is embedded in multiple relational structures? Here, we find that both spatial and temporal cognitive maps influence generalization in a choice task, where spatial location determines reward magnitude. Mirroring behavior, the hippocampus not only builds a map of spatial relationships but also encodes temporal distances. As the task progresses, participants’ choices become more influenced by spatial relationships, reflected in a strengthening of the spatial and a weakening of the temporal map. This change is driven by orbitofrontal cortex, which represents the evidence that an observed outcome is generated from the spatial rather than the temporal map and updates hippocampal representations accordingly. Taken together, this demonstrates how hippocampal cognitive maps are used and updated flexibly for inference.

Hippocampal spatio-temporal cognitive maps adaptively guide reward generalization

Information about risks and probabilities is ubiquitous in our environment, forming the basis for decisions in an uncertain world. Emotions are known to modulate subjective probability assessments when probabilistic information is emotionally valenced. Yet little is known about the role of emotions in subjective probability assessment of affectively neutral events. We investigated this in one correlational study (Study 1, N = 162) and one experimental study (Study 2, N = 119). As predicted, we found that emotional dominance modulated the degree of conservatism in respondents’ neutral probability estimates. Remarkably, this pattern also transferred to realistic risk assessments. Furthermore, respondents’ tendency to use the representativeness heuristic as a proxy for probability was increased in high dominance individuals. Our findings highlight the importance of considering emotions, particularly the little-understood emotion dimension dominance, in research on probabilistic cognition.

How does time pressure influence exploration and decision-making? We investigate this question using a within-subject design to manipulate decision time (limited vs. unlimited) and use a range of four-armed bandit tasks, designed to independently manipulate uncertainty and expected reward. With limited time, people have less opportunity to perform costly computations, thus shifting the cost-benefit balance of different exploration strategies. Through behavioral, reinforcement learning (RL), reaction time (RT), and evidence accumulation analyses, we show that time pressure changes how people explore and respond to uncertainty. Specifically, participants reduced their uncertainty-directed exploration under time pressure, were less value-directed, and repeated choices more often. Since our analyses relate uncertainty to slower responses and dampened evidence accumulation (i.e., drift rates), this demonstrates a resource-rational shift towards simpler, lower-cost strategies under time pressure. These results shed light on how people adapt their exploration and decision-making strategies to externally imposed cognitive constraints.

One of the greatest challenges for artificial intelligence is how to behave adaptively in scenarios with uncertain or no rewards. One---and perhaps the only---way to approach such complex learning problems is to build simple algorithms that grow into sophisticated adaptive agents, just like children do. But what drives children to explore and learn when external rewards are absent? Across three studies, we tested whether information gain itself acts as an internal reward and motivates children's actions. We measured 24- to 56-month-olds’ persistence in a game where they had to search for an object (animal or toy), which they never find, hidden behind a series of doors, manipulating the degree of uncertainty about \emph{which specific object} was hidden. We found that children were more persistent in their search when there was higher uncertainty, and therefore more information to be gained with each action, highlighting the importance of research on artificial intelligence to invest in curiosity-driven algorithms.

Toddlers search longer when there is more information to be gained

The Einstellung effect was first described by Abraham Luchins in his doctoral thesis published in 1942. The effect occurs when a repeated solution to old problems is applied to a new problem even though a more appropriate response is available. In Luchins' so-called water jar task, participants had to measure a specific amount of water using three jars of different capacities. Luchins found that subjects kept using methods they had applied in previous trials, even if a more efficient solution for the current trial was available: an Einstellung effect. Moreover, Luchins studied the different conditions that could possibly mediate this effect, including telling participants to pay more attention, changing the number of tasks, alternating between different types of tasks, as well as putting participants under time pressure. In the current work, we reconstruct and reanalyze the data of the various experimental conditions published in Luchins' thesis. We furthermore show that a model of resource-rational decision-making can explain all of the observed effects. This model assumes that people transform prior preferences into a posterior policy to maximize rewards under time constraints. Taken together, our reconstructive and modeling results put the Einstellung effect under the lens of modern-day psychology and show how resource-rational models can explain effects that have historically been seen as deficiencies of human problem-solving.

Learning and generalization in spatial domains is often thought to rely on a “cognitive map”, representing relationships between spatial locations. Recent research suggests that this same neural machinery is also recruited for reasoning about more abstract, conceptual forms of knowledge. Yet, to what extent do spatial and conceptual reasoning share common computational principles, and what are the implications for behavior? Using a within-subject design we studied how participants used spatial or conceptual distances to generalize and search for correlated rewards in successive multi-armed bandit tasks. Participant behavior indicated sensitivity to both spatial and conceptual distance, and was best captured using a Bayesian model of generalization that formalized distance-dependent generalization and uncertainty-guided exploration as a Gaussian Process regression with a radial basis function kernel. The same Gaussian Process model best captured human search decisions and judgments in both domains, and could simulate realistic learning curves, where we found equivalent levels of generalization in spatial and conceptual tasks. At the same time, we also find characteristic differences between domains. Relative to the spatial domain, participants showed reduced levels of uncertainty-directed exploration and increased levels of random exploration in the conceptual domain. Participants also displayed a one-directional transfer effect, where experience in the spatial task boosted performance in the conceptual task, but not vice versa. While confidence judgments indicated that participants were sensitive to the uncertainty of their knowledge in both tasks, they did not or could not leverage their estimates of uncertainty to guide exploration in the conceptual task. These results support the notion that value-guided learning and generalization recruit cognitive-map dependent computational mechanisms in spatial and conceptual domains. Yet both behavioral and model-based analyses suggest domain specific differences in how these representations map onto actions. Author summary There is a resurgence of interest in “cognitive maps” based on recent evidence that the hippocampal-entorhinal system encodes both spatial and non-spatial relational information, with far-reaching implications for human behavior. Yet little is known about the commonalities and differences in the computational principles underlying human learning and decision making in spatial and non-spatial domains. We use a within-subject design to examine how humans search for either spatially or conceptually correlated rewards. Using a Bayesian learning model, we find evidence for the same computational mechanisms of generalization across domains. While participants were sensitive to expected rewards and uncertainty in both tasks, how they leveraged this knowledge to guide exploration was different: participants displayed less uncertainty-directed and more random exploration in the conceptual domain. Moreover, experience with the spatial task improved conceptual performance, but not vice versa. These results provide important insights about the degree of overlap between spatial and conceptual cognition.

Similarities and differences in spatial and non-spatial cognitive maps

Correction: Similarities and differences in spatial and non-spatial cognitive maps

What are we curious about? Dubey and Griffiths propose a rational theory of curiosity that unifies previously contradictory novelty-based and complexity accounts. It also paves the way for future investigations, such as studying approximate models of curiosity as well as what causes abnormal levels of exploration.

How do people decide whether to try out novel options as opposed to tried-and-tested ones? We argue that they infer a novel option's reward from contextual information learned from functional relations and take uncertainty into account when making a decision. We propose a Bayesian optimization model to describe their learning and decision making. This model relies on similarity-based learning of functional relationships between features and rewards, and a choice rule that balances exploration and exploitation by combining predicted rewards and the uncertainty of these predictions. Our model makes 2 main predictions. First, decision makers who learn functional relationships will generalize based on the learned reward function, choosing novel options only if their predicted reward is high. Second, they will take uncertainty about the function into account, and prefer novel options that can reduce this uncertainty. We test these predictions in 3 preregistered experiments in which we examine participants' preferences for novel options using a feature-based multiarmed bandit task in which rewards are a noisy function of observable features. Our results reveal strong evidence for functional exploration and moderate evidence for uncertainty-guided exploration. However, whether or not participants chose a novel option also depended on their attention, as well as reflecting on the value of the options. These results advance our understanding of people's reactions in the face of novelty. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

It's new, but is it good? How generalization and uncertainty guide the exploration of novel options.

A variety of conceptualizations of psychological uncertaintyexist. From an information-theoretic perspective, probabilistic uncertainty can be formalized as mathematical entropy. Cognitive emotion theories posit that uncertainty appraisals and motivation to reduce uncertainty are modulated by emotional state. Yet little is known about how people evaluate probabilistic uncertainty, and about how emotional state modulates people’s evaluations of probabilistic uncertainty and behavior to reduce probabilistic uncertainty. We tested intuitive entropyevaluations and entropy reduction strategies across four emotion conditions in the Entropy Mastermind game. We used the unified Sharma-Mittal space of entropy measures to quantify participants’ entropy evaluations. Results suggest that many people use a heuristic strategy, focusing on the number of possible outcomes, irrespective of the probabilities in the probability distribution. This result is surprising, given that previous work suggested that people are very sensitive to the maximum probability when choosing queries on probabilistic classification tasks. Emotion induction generally increased participants’heuristic assessment. The uncertainty associated with emotional states also affected game play: participants needed fewer queries and spent less time on games in high-uncertainty than in low-uncertainty emotional states. Yet entropy perceptions were not related to subjectively reported uncertainty, numeracy or entropy knowledge, suggesting that entropy perceptions may form an independent psychological construct.

Author Correction: Generalization guides human exploration in vast decision spaces

Are young children just random explorers who learn serendipitously? Or are even young children guided by uncertainty-directed sampling, seeking to explore in a systematic fashion? We study how children between the ages of 4 and 9 search in an explore-exploit task with spatially-correlated rewards, where exhaustive exploration is infeasible and not all options can be experienced. By combining behavioral data with a computational model that decomposes search into similarity-based generalization, uncertainty-directed exploration, and random exploration, we map out developmental trajectories of generalization and exploration. The behavioral data show strong developmental differences in children’s capability to exploit environmental structure, with performance and adaptiveness of sampling decisions increasing with age. Through model-based analyses, we disentangle different forms of exploration, finding signatures of both uncertainty-directed and random exploration. The amount of random exploration strongly decreases as children get older, supporting the notion of a developmental “cooling off” process that modulates the randomness in sampling. However, even at the youngest age range, children do not solely rely on random exploration. Even as random exploration begins to taper off, children are actively seeking out options with high uncertainty in a goal-directed fashion, and using inductive inferences to generalize their experience to novel options. Our findings provide critical insights into the behavioral and computational principles underlying the developmental trajectory of learning and exploration.

How do people actively learn functional rules, i.e. a mapping of continuous inputs onto a continuous output? We investigate information search behavior in a multiple-featurefunction learning task in which participants either actively select or passively receive observations. We find that participants benefit from actively selecting information, inparticular in their function extrapolation performance. By introducing and comparing different models of active function learning, we find that participants are best described by a non-parametric function learning model that learns about both the underlying function and inputs that are likely to produce high outputs. These results enrich our understandingof active function learning in complex domains.

What drives people’s exploration in complex scenarios where they have to actively acquire information by making queries? How do people adapt their selection of queries to their environment? We explore these questions using Entropy Mastermind, a novel variant of the Mastermind code-breaking game, in which participants have to guess a secret code by making useful queries. Participants solved games more efficiently and more quickly if the entropy of the game environment was low; moreover, people adapted their initial queries to the scenario they were in. We also investigated whether it would be possible to predict participants’ queries within the generalized Sharma-Mittal information-theoretic framework. Although predicting individual queries is difficult, the modeling framework offered important insight on human behavior. Entropy Mastermind offers rich possibilities for modeling and behavioral research.

Despite the rapidly increasing computational power of today’s computers, a key challenge in robotics and artificial intelligence is successful and smooth interaction with the environment – something that comes naturally for most humans. Which strategies enable humans to learn about and adapt to an environment with such high computational complexity? What can machines learn from human strategies in order to exploit their computational powers efficiently and be a natural, understandable and manageable part of our everyday lives? We review how a proposed research program, centered around a novel version of the code-breaking game Mastermind, sets out to address these questions.

Entropy Mastermind: Learning from humans about intelligent systems

How does time pressure influence attitudes towards uncertainty? When time is limited, do people engage in different exploration strategies? We study human exploration in a range of four-armed bandit tasks with different reward distributions and manipulate the available time for each decision (limited vs. unlimited). Through multiple behavioral and model-based analyses, we show that reactions towards uncertainty are influenced by time pressure. Specifically, participants seek out uncertain options when time is unlimited, but avoid uncertainty under time pressure. Moreover, larger relative differences in uncertainty between options slowed down reaction times and dampened the drift rate of a linear ballistic accumulator model. These results shed new light on the differential effect of uncertainty and time pressure on human exploration.

Under pressure: The influence of time limits on human exploration

In this research project, a novel app-based version of the code breaking game Mastermind, Entropy Mastermind, was introduced and evaluated as a learning medium in undergraduate cognitive psychology and in primary mathematics education. In a quasi-experimental preand posttest design we investigated a) the role of individual differences in game play and learning, b) the effectiveness of Entropy Mastermind for giving students of different age groups experientially grounded access to the fundamental concepts of proportions and mathematical entropy, and c) effects of game play on students academic emotions, motivation and attitudes. Data analyses revealed significant associations between cognitive variables, emotional-motivational factors and game play parameters. We present computational modeling results of students search strategies and entropy intuitions within a unified framework of entropy measures, the Sharma-Mittal space. Potential applications in digitalized learning environments at the interface between mathematics and computer science will be discussed.

Masterminding in Education: Bringing cognition, emotion and motivation together in a unified mathematical framework

What drives children to explore and learn when external rewards are uncertain or absent? Across three studies, we tested whether information gain itself acts as an internal reward and suffices to motivate children's actions. We measured 24-56-month-olds' persistence in a game where they had to search for an object (animal or toy), which they never find, hidden behind a series of doors, manipulating the degree of uncertainty about which specific object was hidden. We found that children were more persistent in their search when there was higher uncertainty, and therefore, more information to be gained with each action, highlighting the importance of research on artificial intelligence to invest in curiosity-driven algorithms. RESEARCH HIGHLIGHTS: Across three studies, we tested whether information gain itself acts as an internal reward and suffices to motivate preschoolers' actions. We measured preschoolers' persistence when searching for an object behind a series of doors, manipulating the uncertainty about which specific object was hidden. We found that preschoolers were more persistent when there was higher uncertainty, and therefore, more information to be gained with each action. Our results highlight the importance of research on artificial intelligence to invest in curiosity-driven algorithms.

Preschoolers search longer when there is more information to be gained.

Heuristics, hacks, and habits: Boundedly optimal approaches to learning, reasoning and decision making

How do people plan ahead when searching for rewards? We investigate planning in a foraging task in which participants search for rewards on an infinite two-dimensional grid. Our results show that their search is best-described by a model which searches at least 3 steps ahead. Furthermore, participants do not seem to update their beliefs during planning, but rather treat their initial beliefs as given, a strategy similar to a heuristic called root-sampling. This planning algorithm corresponds well with participants’ behavior in test problems with restricted movement and varying degrees of information, outperforming more complex models. These results enrich our understanding of adaptive planning in complex environments.

Is covariance ignorance responsible for the success of heuristics?

The idea of a “cognitive map” was originally developed to explain planning and generalization in spatial domains through a representation of inferred relationships between experiences. Recently, new research has suggested similar principles may also govern the representation of more abstract, conceptual knowledge in the brain. We test whether the search for rewards in conceptual spaces follows similar computational principles as in spatial environments. Using a within-subject design, participants searched for both spatially and conceptually correlated rewards in multi-armed bandit tasks. We use a Gaussian Process model combining generalization with an optimistic sampling strategy to capture human search decisions and judgments in both domains, and to simulate human-level performance when specified with participant parameter estimates. In line with the notion of a domain-general generalization mechanism, parameter estimates correlate across spatial and conceptual search, yet some differences also emerged, with participants generalizing less and exploiting more in the conceptual domain.

Connecting conceptual and spatial search via a model of generalization

Humans master complex systems of interrelated concepts like mathematics and natural language. Previous work suggests learning these systems relies on iteratively and directly revising a language-like conceptual representation. We introduce and assess a novel concept learning paradigm called Martha’s Magical Machines that captures complex relationships between concepts. We model human concept learning in this paradigm as a search in the space of term rewriting systems, previously developed as an abstract model of computation. Our model accurately predicts that participants learn some transformations more easily than others and that they learn harder concepts more easily using a bootstrapping curriculum focused on their compositional parts. Our results suggest that term rewriting systems may be a useful model of human conceptual representations.

How do children and adults differ in their search for rewards? We considered three different hypotheses that attribute developmental differences to (a) children’s increased random sampling, (b) more directed exploration toward uncertain options, or (c) narrower generalization. Using a search task in which noisy rewards were spatially correlated on a grid, we compared the ability of 55 younger children (ages 7 and 8 years), 55 older children (ages 9–11 years), and 50 adults (ages 19–55 years) to successfully generalize about unobserved outcomes and balance the exploration–exploitation dilemma. Our results show that children explore more eagerly than adults but obtain lower rewards. We built a predictive model of search to disentangle the unique contributions of the three hypotheses of developmental differences and found robust and recoverable parameter estimates indicating that children generalize less and rely on directed exploration more than adults. We did not, however, find reliable differences in terms of random sampling.

Searching for Rewards Like a Child Means Less Generalization and More Directed Exploration

Forecasting is an increasingly important part of our daily lives. Many studies on how people produce forecasts frame their behavior as prone to systematic errors. Based on recent evidence on how people learn about functions, we propose that participants’ forecasts are not irrational but rather driven by structured priors, i.e. situationally induced expectations of structure derived from experience with the real world. To test this, we extract participants’ priors over various contexts using a free-form forecasting paradigm. Instead of exhibiting systematic biases, our results show that participants’ priors match well with structure found in real-world data. Moreover, given the same data set, structured priors induce predictably different posterior forecasts depending on the evoked situational context.

How do people decide whether to try out novel options as opposed to tried-and-tested ones? We argue that they infer a novel option's reward from contextual information learned from functional relations and take uncertainty into account when making a decision. We propose a Bayesian optimization model to describe their learning and decision making. This model relies on similarity-based learning of functional relationships between features and rewards, and a choice rule that balances exploration and exploitation by combining predicted rewards and the uncertainty of these predictions. Our model makes two main predictions. First, decision makers who learn functional relationships will generalize based on the learned reward function, choosing novel options only if their predicted reward is high. Second, they will take uncertainty about the function into account, and prefer novel options that can reduce this uncertainty. We test these predictions in three preregistered experiments in which we examine participants' preferences for novel options using a feature-based multi-armed bandit task in which rewards are a noisy function of observable features. Our results reveal strong evidence for functional exploration and moderate evidence for uncertainty-guided exploration. However, whether or not participants chose a novel option also depended on their attention, as well as reflecting on the value of the options. These results advance our understanding of people's reactions in the face of novelty.

It’s new, but is it good? How generalization and uncertainty guide the exploration of novel options

This workshop will cover new work that casts human learning as program induction — i.e. learning of programs from data. The notion that the mind approximates rational (Bayesian) inference has had a strong influence on thinking in psychology since the 1950s. In constrained scenarios, typical of psychology experiments, people often behave in ways that approximate the dictates of probability theory. However, natural learning contexts are typically much more open-ended — there are often no clear limits on what is possible, and initial proposals often prove inadequate. This means that coming up with the right hypotheses and theories in the first place is often much harder than ruling among them. How do people, and how can machines, expand their hypothesis spaces to generate wholly new ideas, plans and solutions? Recent work has begun to shed light on this problem via the idea that many aspects of learning can be better understood through the mathematics of program induction (Chater & Oaksford, 2013; Lake, Salakhutdinov, & Tenenbaum, 2015). People are demonstrably able to compose hypotheses from parts (Goodman, Tenenbaum, Feldman, & Griffiths, 2008; Piantadosi, Tenenbaum, & Goodman, 2016; Schulz, Tenenbaum, Duvenaud, Speekenbrink, & Gershman, 2017) and incrementally grow and adapt their models of the world (Bramley, Dayan, Griffiths, & Lagnado, 2017). A number of recent studies has formalized these abilities as program induction, using algorithms that mix stochastic recombination of primitives with memoization and compression to explain data (Dechter, Malmaud, Adams, & Tenenbaum, 2013; Ellis, Dechter, & Tenenbaum, 2015; Romano, Salles, Amalric, Dehaene, Sigman, & Figueria, 2017), ask informative questions (Rothe, Lake, & Gureckis, 2017), and support oneand few-shot-inferences (Lake et al., 2015). Program induction is also proving to be an important notion for understanding development and learning through play (Sim & Xu, 2017) and the formation of geometric understanding about the physical world (Amalric, Wang, Pica, Figueira, Sigman, & Dehaene, 2017).

How do people actively explore to learn about functional relationships, that is, how continuous inputs map onto continuous outputs? We introduce a novel paradigm to investigate information search in continuous, multi-feature function learning scenarios. Participants either actively selected or passively observed information to learn about an underlying linear function. We develop and compare different variants of rule-based (linear regression) and non-parametric (Gaussian process regression) active learning approaches to model participants’ active learning behavior. Our results show that participants’ performance is best described by a rule-based model that attempts to efficiently learn linear functions with a focus on high and uncertain outcomes. These results advance our understanding of how people actively search for information to learn about functional relations in the environment.

Foraging for food, developing new medicines, and learning complex games are search problems with vast numbers of possible actions. Under time or resource constraints, optimal solutions are generally unobtainable. How do humans generalize and learn which actions to take when not all outcomes can be explored? We present two behavioural experiments and competitively test 27 models for predicting individual search decisions. We find that a Bayesian function learning model, combined with an optimistic sampling strategy, robustly captures how humans use generalization to guide search behaviour. Taken together, these two form a model of exploration and generalization that leads to reproducible and psychologically meaningful parameter estimates, providing novel insights into the nature of human search in vast spaces. Importantly, our modelling results and parameter estimates are recoverable, and can be used to simulate human-like performance, bridging a critical gap between human and machine learning.

How do people explore in order to gain rewards in uncertain dynamical systems? Within a reinforcement learning paradigm, control normally involves trading off between exploration (i.e. trying out actions in order to gain more knowledge about the system) and exploitation (i.e. using current knowledge of the system to maximize reward). We study a novel control task in which participants must steer a boat on a grid, assessing whether participants explore strategically in order to produce higher rewards later on. We find that participants explore strategically yet conservatively, exploring more when mistakes are less costly and practicing actions that will be needed later on.

How do people pursue rewards in risky environments, where some outcomes should be avoided at all costs? We investigate participants’ search for spatially correlated rewards in scenarios where one must avoid sampling rewards below a given threshold. This requires participants to not only balance exploration and exploitation, but also to reason about how to avoid potentially risky areas of the search space. Within risky versions of the spatially correlated multi-armed bandit task, we show that participants’ behavior is aligned well with a Gaussian process function learning algorithm, which chooses points based on a safe optimization routine. Moreover, using leave-one-block-out cross-validation, we find that participants adapt their sampling behavior to the riskiness of the task, although the underlying function learning mechanism remains relatively unchanged. These results show that participants can adapt their search behavior to the adversity of the environment and enrich our understanding of adaptive behavior in the face of risk and uncertainty.

How do people decide whether to try out novel options? We argue that they utilize contextual information to efficiently generalize from learned functional relations in order to decide between known or novel options. In a contextual multi-armed bandit task, in which rewards are a noisy function of observable features, we assess participants’ preferences for newly introduced options. We show that participants preferably choose a novel option if its features indicate high rewards, but shun the option if its features indicate low rewards, a behavior that can only be explained by functional generalization. Moreover, we assess people’s preferences for novel options that have medium rewards to test whether they prefer options less similar to experienced options, consistent with choices guided by uncertainty. Given that novel options normally come with observable features, we argue that contextual learning is a parsimonious yet powerful explanation of behavior in the face of novelty.

It is new, but will it be good? Context-driven exploration of novel options

Project files for "It’s new, but is it good? How generalization and uncertainty guide the exploration of novel options"

Running head : SAFE SEARCH AND RISKY BANDITS 1 Generalization and search in risky environments

Running head : HEURISTICS AND ACTIVE LEARNING 1 Active learning reveals underlying decision strategies

This tutorial introduces the reader to Gaussian process regression as an expressive tool to model, actively explore and exploit unknown functions. Gaussian process regression is a powerful, non-parametric Bayesian approach towards regression problems that can be utilized in exploration and exploitation scenarios. This tutorial aims to provide an accessible introduction to these techniques. We will introduce Gaussian processes which generate distributions over functions used for Bayesian non-parametric regression, and demonstrate their use in applications and didactic examples including simple regression problems, a demonstration of kernel-encoded prior assumptions and compositions, a pure exploration scenario within an optimal design framework, and a bandit-like exploration-exploitation scenario where the goal is to recommend movies. Beyond that, we describe a situation modelling risk-averse exploration in which an additional constraint (not to sample below a certain threshold) needs to be accounted for. Lastly, we summarize recent psychological experiments utilizing Gaussian processes. Software and literature pointers are also provided.

A tutorial on Gaussian process regression: Modelling, exploring, and exploiting functions

We introduce the spatially correlated multi-armed bandit as a task coupling function learning with exploration-exploitation. Participants interact with bi-variate reward functions on a two-dimensional grid, with the goal of either gaining the largest average score or finding the largest payoff. By providing an opportunity to learn the underlying reward function through spatial correlations, we model to what extent people form beliefs about unexplored payoffs and how that guides search behavior. Participants adapted to assigned payoff conditions, performed better in smooth than in rough environments, and—surprisingly—sometimes seemed to perform equally well in short as in long search horizons. Our modeling results indicate a tendency towards local search options, which when accounted for, suggests participants were best-described as forming only very local inferences about unexplored regions, combined with a search strategy that directly trades off between exploiting high expected rewards and exploring to reduce uncertainty.

Mapping the unknown: The spatially correlated multi-armed bandit

How do humans generalize from observed to unobserved data? How does generalization support inference, prediction, and decision making? I propose that a big part of human generalization can be explained by a powerful mechanism of function learning. I put forward and assess Gaussian Process regression as a model of human function learning that can unify several psychological theories of generalization. Across 14 experiments and using extensive computational modeling, I show that this model generates testable predictions about human preferences over different levels of complexity, provides a window into compositional inductive biases, and --combined with an optimistic yet efficient sampling strategy-- guides human decision making through complex spaces. Chapters 1 and 2 propose that, from a psychological and mathematical perspective, function learning and generalization are close kin. Chapter 3 derives and tests theoretical predictions of participants' preferences over differently complex functions. Chapter 4 develops a compositional theory of generalization and extensively probes this theory using 8 experimental paradigms. During the second half of the thesis, I investigate how function learning guides decision making in complex decision making tasks. In particular, Chapter 5 will look at how people search for rewards in various grid worlds where a spatial correlation of rewards provides a context supporting generalization and decision making. Chapter 6 gauges human behavior in contextual multi-armed bandit problems where a function maps features onto expected rewards. In both Chapter 5 and Chapter 6, I find that the vast majority of subjects are best predicted by a Gaussian Process function learning model combined with an upper confidence bound sampling strategy. Chapter 7 will formally assess the adaptiveness of human generalization in complex decision making tasks using mismatched Bayesian optimization simulations and finds that the empirically observed phenomenon of undergeneralization might rather be a feature than a bug of human behavior. Finally, I summarize the empirical and theoretical lessons learned and lay out a road-map for future research on generalization in Chapter 8.

We introduce the contextual multi-armed bandit task as a framework to investigate learning and decision making in uncertain environments. In this novel paradigm, participants repeatedly choose between multiple options in order to maximise their rewards. The options are described by a number of contextual features which are predictive of the rewards through initially unknown functions. From their experience with choosing options and observing the consequences of their decisions, participants can learn about the functional relation between contexts and rewards and improve their decision strategy over time. In three experiments, we explore participants’ behaviour in such learning environments. We predict participants’ behaviour by context-blind (mean-tracking, Kalman filter) and contextual (Gaussian process and linear regression) learning approaches combined with different choice strategies. Participants are mostly able to learn about the context-reward functions and their behaviour is best described by a Gaussian process learning strategy which generalizes previous experience to similar instances. In a relatively simple task with binary features, they seem to combine this learning with a “probability of improvement” decision strategy which focuses on alternatives that are expected to lead to an improvement upon a current favourite option. In a task with continuous features that are linearly related to the rewards, participants seem to more explicitly balance exploration and exploitation. Finally, in a difficult learning environment where the relation between features and rewards is non-linear, some participants are again well-described by a Gaussian process learning strategy, whereas others revert to context-blind strategies.

Putting bandits into context: How function learning supports decision making

How can heuristic strategies emerge from smaller building blocks? We propose Approximate Bayesian Computation as a computational solution to this problem. As a first proof of concept, we demonstrate how a heuristic decision strategy such as Take The Best (TTB) can be learned from smaller, probabilistically updated building blocks. Based on a self-reinforcing sampling scheme, different building blocks are combined and, over time, tree-like non-compensatory heuristics emerge. This new algorithm, coined Approximately Bayesian Computed Take The Best (ABC-TTB), is able to recover a data set that was generated by TTB, leads to sensible inferences about cue importance and cue directions, can outperform traditional TTB, and allows to trade-off performance and computational effort explicitly.

Simple trees in complex forests: Growing Take The Best by Approximate Bayesian Computation

This tutorial introduces the reader to Gaussian process regression as a tool to model, actively explore and exploit unknown functions. Gaussian process regression is a powerful, non-parametric Bayesian approach towards regression problems that can be utilized in exploration and exploitation scenarios. This tutorial aims to provide an accessible introduction to these techniques. We will introduce Gaussian processes as a distribution over functions used for Bayesian non-parametric regression and demonstrate different applications of it. Didactic examples will include a simple regression problem, a demonstration of kernel-encoded prior assumptions, a pure exploration scenario within an optimal design framework, and a bandit-like exploration-exploitation scenario where the goal is to recommend movies. Beyond that, we describe a situation in which an additional constraint (not to sample below a certain threshold) needs to be accounted for and summarize recent psychological experiments utilizing Gaussian processes. Software and literature pointers will be provided.

A tutorial on Gaussian process regression with a focus on exploration-exploitation scenarios

Exploration-exploitation of functions, that is learning and optimizing a mapping between inputs and expected outputs, is ubiquitous to many real world situations. These situations sometimes require us to avoid certain outcomes at all cost, for example because they are poisonous, harmful, or otherwise dangerous. We test participants' behavior in scenarios in which they have to find the optimum of a function while at the same time avoid outputs below a certain threshold. In two experiments, we find that Safe-Optimization, a Gaussian Process-based exploration-exploitation algorithm, describes participants' behavior well and that participants seem to care firstly whether a point is safe and then try to pick the optimal point from all such safe points. This means that their trade-off between exploration and exploitation can be seen as an intelligent, approximate, and homeostasis-driven strategy.

Better safe than sorry: Risky function exploitation through safe optimization

We introduce the Contextual Multi-Armed Bandit task as a method to assess decision making in uncertain environments and test how participants behave in this task. Within an experimental paradigm named Mining in Space, participants see 4 different planets that are described by 3 different binary elements (the context) and then have to decide on which planet they want to mine (which arm to play). We find that participants adapt their decisions to the context well and can best be described by a Contextual Gaussian Process algorithm that probability matches according to expected outcomes. We conclude that humans are well-adapted to contextualized bandit problems even in potentially non-stationary environments through probability matching, a heuristic that used to be described as biased behavior. We argue that Contextual Bandit problems can provide further insight into how people make decisions in real world scenarios.

Exploration-Exploitation in a Contextual Multi-Armed Bandit Task

Contextual Multi-Armed Bandit (CMAB) tasks are a novel framework to assess decision making in uncertain environments. In a CMAB task, participants are presented with multiple options (arms) which are characterized by a number of features (context) related to the reward associated with the arms. By choosing arms repeatedly and observing the reward, participants can learn about the relation between context and reward and improve their decision strategy. We present two studies on how people behave in CMAB tasks. Within a stationary environment, we find that participants are best described by Thompson Sampling-based Gaussian Process models. In a dynamic CMAB task we again find that participants are best described by probability matching of Gaussian Process expectations. Our findings imply that behavior previously referred to as "irrational" can actually be seen as a well-adapted strategy based on powerful inference algorithms.

How should we choose a model that predicts human choices? Two important factors in this choice are a model's predictive power and a model's fexibility. In this paper, we compare these aspects of models in a large set of models applied to an experiment in which participants chose between brands of fictitious chocolate bars and a quasi-experiment predicting movies' gross revenue. We show that there is a trade-o ff between flexibility and predictive power, but that this trade-o ff appears to lie more towards the "flexible" side than what was previously thought.

L'invention concerne un conditionneur de polissage chimico-mecanique (CMP) qui comprend un substrat en ceramique ayant une surface principale et un revetement abrasif recouvrant la surface principale. La surface principale peut comprendre des micro-saillies disposees en un motif incurve. En variante, les micro-saillies peuvent etre disposees en un motif irregulier.

L'invention concerne un outil abrasif destine a conditionner des patins CMP comportant des grains abrasifs couples a un substrat par l'intermediaire d'une liaison metallique et un revetement, par exemple, un revetement nanocomposite dope au fluor. Les grains abrasifs peuvent etre disposes suivant une distribution aleatoire auto-evitante. Dans un mode de realisation, un outil abrasif comporte une plaque revetue et un article abrasif revetu presentant deux surfaces abrasives. D'autres modes de realisation concernent un processus de production d'un outil abrasif comportant un revetement sur une ou plusieurs de ses surfaces. L'invention concerne egalement des procedes de dressage d'un tampon CMP.

Outils de conditionnement cmp résistants à la corrosion et leurs procédés de fabrication et d'utilisation

La presente invention concerne un outil abrasif, comprenant un conditionneur de tampon pour processus CMP (polissage mecano-chimique) comportant un substrat comprenant une premiere surface principale, une seconde surface principale opposee a la premiere surface principale, et une surface laterale s'etendant entre la premiere surface principale et la seconde surface principale. Une premiere couche de grains abrasifs est fixee sur la premiere surface principale, et une seconde couche de grains abrasifs est fixee sur la seconde surface principale. Le conditionneur comprend en outre un premier element d'etancheite s'etendant selon une direction peripherique le long d'une partie de la surface laterale du substrat.

Outil abrasif à utiliser comme conditionneur de tampon pour polissage mécano-chimique

L'invention concerne des outils de conditionnement de tampons de planarisation chimico-mecanique (CMP) comprenant un substrat avec des particules abrasives couplees a au moins une surface. Les outils peuvent presenter diverses particules et configurations de liaison. Par exemple, des particules abrasives peuvent etre collees (par exemple, brasees ou autre technique de liaison de metal) a un cote, ou au recto et au verso. En variante, des particules abrasives sont collees au recto, et des particules de remplissage sont couplees au verso. Les particules abrasives peuvent former un motif (par exemple, hexagonal) et possedent des tailles particulaires qui sont suffisamment petites pour penetrer dans les pores d'un tampon CMP pendant le conditionnement, conduisant a moins de defauts sur les galettes polies avec le tampon CMP conditionne. Le collage de grain peut etre accompli a l'aide de films de brasage, meme si d'autres liaisons de metal peuvent egalement etre employees. De meme, le materiau de liaison equilibre (par exemple, brasage des deux cotes) permet une faible valeur de faux rond.

outils et techniques de conditionnement pour planarisation chimico-mécanique

On decrit un procede permettant d'appliquer au moins un metal, un oxyde, un nitrure et/ou un carbure de metal sur la surface d'un objet, dans lequel on liquefie le metal, l'oxyde, le nitrure et/ou le carbure de metal pour le pulveriser a l'etat liquide sur ladite surface au moyen d'un flux gazeux et l'y laisser se durcir. On se sert comme flux gazeux des gaz d'echappement d'un moteur a combustion interne et on pulverise le metal, l'oxyde, le nitrure et/ou le carbure de metal en fusion dans un milieu ambiant fait d'air. Le dispositif permettant de realiser ledit procede comprend un pulverisateur comportant un dispositif d'acheminement pour au moins deux fils d'un metal, d'un oxyde, d'un nitrure et/ou d'un carbure de metal, un dispositif generateur d'arc pour faire fondre le materiau du fil, ainsi qu'un dispositif de pulverisation pourvu d'une conduite de gaz pour le materiau en fusion. Ledit dispositif comprend par ailleurs un moteur a combustion interne, par exemple un moteur diesel, qui est relie du cote des gaz d'echappement a la conduite de gaz.

Procede et dispositif permettant d'appliquer au moins un metal, un oxyde, un nitrure et/ou un carbure de metal

Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology

Corrigendum to: European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases.

Plasma corticosterone, dexamethasone (DEX) suppression and DEX/CRH tests in a rat model of genetic vulnerability to depression

Cortisol hypersecretion in unipolar major depression with melancholic and psychotic features: Dopaminergic, noradrenergic and thyroid correlates

In most cell lines and animal tissues, glucocorticoid receptors undergo downregulation after exposure to corticosterone. However, corticosterone treatment has not shown a consistent effect on mineralocorticoid (MR) and glucocorticoid receptors (GR) in the hippocampus, and it has been rarely assessed in the anterior pituitary. In this study we investigated dose-dependent effects of corticosterone on MR and GR mRNAs in the hippocampus and anterior pituitary. Adrenalectomized rats substituted with corticosterone in drinking fluid were injected subcutaneously with vehicle or 1, 10, 50, 100, or 200 mg of corticosterone, and sacrificed 4 h later. In the hippocampus we found a progressive decrease in MR and GR mRNAs with increasing doses of corticosterone. This was significant with 50 and 100 mg corticosterone for MR mRNA and with 10–200 mg corticosterone for GR mRNA at plasma corticosterone levels above 30 µg/dl. The anterior pituitary did not show significant changes at any dose. A time-course with 2 mg of corticosterone (non-response dose range at 4 h) revealed a significant decrease in MR and GR mRNAs in the hippocampus 8 h after the subcutaneous injection. In the anterior pituitary both mRNAs showed an increase that was significant 24 h after injection for MR and from 8 to 24 h for GR. In the hippocampus, adrenalectomy (absence of corticosterone) induced a significant increase in MR and GR mRNAs on day 3, but not on days 1, 8 and 21 after adrenalectomy. In the anterior pituitary there were no significant changes at any time after adrenalectomy. In summary, we have found an in vivo corticosterone dose- and time-dependent downregulation of MR and GR mRNAs in the hippocampus, whereas anterior pituitary MRs and GRs seem relatively insensitive to the excess or the absence of corticosterone, suggesting the lack of an autoregulatory effect in this tissue. Significant mRNA changes appearing later in time could suggest a secondary response via a glucocorticoid-induced gene product. Corticosteroid receptor downregulation in the hippocampus could prevent overstimulation or tissue damage when plasma corticosterone is high, while increased corticosteroid receptors in the anterior pituitary could buffer the excessive brain drive on the pituitary during chronic stress or pathological conditions associated with increased plasma glucocorticoids, such as depression.

Mineralo- and Glucocorticoid Receptor mRNAs Are Differently Regulated by Corticosterone in the Rat Hippocampus and Anterior Pituitary

Chronic corticotropin-releasing hormone and vasopressin regulate corticosteroid receptors in rat hippocampus and anterior pituitary

Conventional psychiatric diagnosis is founded on symptom description; this then governs the choice of psychotropic medication. This purely descriptive approach resembles a description of diphtheria from the premicrobiology era. Based on current advances in basic and clinical neuroscience, we propose inserting an intermediate level of analysis between psychiatric symptoms and pharmacologic modes of action. Paradigm 1 is to analyze psychiatric symptoms in terms of which higher brain function(s) is (are) abnormal, ie, symptoms should be analyzed as higher brain dysfunction: a case study in obsessive-compulsive disorder reveals pointers in four common symptoms to the higher functions of working memory, emotional overlay, absence of voluntary control, and the ability to evaluate personal mental phenomena. Paradigm 2 is to view psychotropic drugs as modifying normal higher brain functions, rather than merely treating symptoms, which they do only secondarily: thus depression may respond to agents that act on related aspects of mental life derived from higher brain functions, eg, the ability to enhance bonding. We advocate a strategy in which psychiatric illness is progressively reclassified through knowledge in clinical neuroscience and treatment targets are revised accordingly.

Psychotropic medication, psychiatric disorders, and higher brain functions

Brain metabolites of progesterone such as tetrahydroprogesterone (THP) act on GABAA receptors and have anxiolytic properties. The formation of THP and its 5α‐reduced precursor, dihydroprogestrone (DHP) was measured in vitro in various microdissected brain areas obtained from males of two psychogenetically selected rat lines, i.e. the Roman High‐(RHA/Verh) and Low‐(RLA/Verh) Avoidance rats, which are known to differ in emotional reactivity and/or anxiety. The behavioural and neuroendocrine responses of these rats were also measured following exposure to a novel environment in two different test situations. The formation of DHP and THP was found to be significantly higher in the frontal cortex (FCX), and DHP in the bed nucleus of the stria terminalis (BST), of the hypoemotional RHA/Verh rats. In addition, enzymatic activity in the FCX was found to be inversely correlated with behavioural measures of anxiety. These results suggest that individual, possibly genetically‐determined differences in brain production of endogenous anxiolytics derived from progesterone may account at least in part for the behavioural differences characterizing these two lines, and provide further evidence that neurosteroids acting on the GABAergic system may play an important role in modulating physiological and/or behavioural responses to environmental stressors.

Brain Metabolism of Progesterone, Coping Behaviour and Emotional Reactivity in Male Rats from Two Psychogenetically Selected Lines

Neuroendocrine Correlates of Emotional Reactivity and Coping in Male Rats from the Roman High (RHA/Verh)-and Low (RLA/Verh)-Avoidance Lines

Expression of ionotropic glutamate receptor subunit mRNAs by paraventricular corticotropin-releasing factor (CRF) neurons

Abstract: Differences and similarities in the temporal organization of hormone secretion in plasma reflect the activity of CNS pacemakers. One aspect of this activity, the temporal synchronization of the secretion of different hormones is still poorly understood. We report the analysis of melatonin and testosterone plasma concentrations during two nights in 6 normal healthy young men. Blood was collected every 20 min between 2040 and 0640. Plasma testosterone concentrations increased by 1.5‐ to 2‐fold during the second part of the night, and melatonin by 2.5‐ to 4‐fold. In each subject, the individual temporal pattern of melatonin was quite stable over the two nights of sampling, while testosterone profiles showed fluctuations. There was a high degree of parallelism in these two hormones nocturnal secretion. These results, together with previous studies, suggest that melatonin might entrain the nocturnal secretion of testosterone.

Parallel nocturnal secretion of melatonin and testosterone in the plasma of normal men

Abstract: We have previously shown that exposure of rats to constant light (LL) induced a decrease in NO synthase (NOS) activity in the pineal gland. We present here the evidence that chronic (5 days) norepinephrine (NE) or isoproterenol treatment prevents the effect of LL and enhances pineal NOS activity in LL animals. This effect of NE appears to be mediated by β‐adrenoceptors, because it was not mimicked by the α‐agonist phenylephrine. Pineal NOS activity was reduced in 16‐h light/8‐h dark animals treated for 4 days with the β‐adrenergic antagonist propranolol but not with the α1‐antagonist prazosin, indicating again an involvement of β‐adrenergic receptor in the control of NOS. Treatment with adrenergic antagonists did not affect cortical NOS activity, suggesting that the control of NOS is different in these two tissues or that the pineal expresses a specific isoform of the enzyme. Taken together, these data suggest that NE controls NOS in the pineal gland through β‐adrenergic receptors. To our knowledge, this represent the first demonstration of a regulation of NOS by a neurotransmitter in the CNS, as assayed under Vmax conditions.

Roman high- (RHA) and low- (RLA) avoidance rats are selected and bred for rapid versus non-acquisition of two-way, active avoidance behavior in a shuttle box. They also show a number of other behavioral differences which appear to be essentially related to emotional factors, the RLA rats being emotionally more sensitive. The ACTH secretory response to stressors is also augmented in RLA rats. We thus raised the question whether the expression of corticotropin-releasing factor (CRF) and vasopressin (VP), two neurohormones exerting a synergistic action on ACTH release from corticotropic cells, is different in the two strains. Steady-state mRNA levels were examined in the parvicellular neurons of the paraventricular nucleus under basal conditions and 4 h after a single 8-min exposure to an open-field stressor. In situ hybridization histochemistry with 35S-labeled oligonucleotide probes was followed by quantitative cell by cell autoradiography. When basal CRF and VP mRNA levels were compared in the two lines, we found that the RLA rats had a significantly higher VP-labeling density than the RHA rats. No difference was found for CRF mRNA. During open-field exposure, we observed behavioral differences paralleled by elevated corticosterone compatible with an increased emotional response in RLA rats. Open-field exposure produced a significant increase in CRF but not VP mRNA in both RHA and RLA rats (by 43 and 57%, respectively). These results suggest that differences in basal VP expression in CRF neurons may participate in the mechanisms underlying the hyperactivity of the hypothalamo-pituitary-adrenal (HPA) axis in the emotionally more sensitive RLA rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Corticotropin-releasing factor and vasopressin mRNA levels in roman high- and low-avoidance rats: response to open-field exposure.

1. Nitric oxide released from endothelial cells is a potent vasodilator that might play an important role in cardiovascular regulation during pregnancy. Platelets, like endothelial cells, contain a constitutive form of nitric oxide synthase. 2. The present study aimed to measure the activity of this nitric oxide-forming enzyme in normotensive pregnant and non-pregnant women, as well as in women who had developed pre-eclampsia. Nitric oxide synthase activity was measured in the platelets of 21 normotensive pregnant women, 16 non-pregnant women and seven pregnant women who had developed pre-eclampsia. 3. The nitric oxide synthase activity was significantly higher in normotensive pregnant women [36.8 +/- 2.7 pmol h-1 mg-1 of protein (mean +/- SEM), P < 0.001] than in non-pregnant control subjects (16.8 +/- 1.4 pmol h-1 mg-1 of protein) and in women with pre-eclampsia (24.5 +/- 2.1 pmol h-1 mg-1 of protein, P < 0.01). 4. These data suggest that nitric oxide synthesis is increased during normal pregnancy, possibly contributing to the vasodilatation associated with this condition. Nitric oxide generation, however, may be inappropriately low in pregnant women developing pre-eclampsia, thus leading to an enhanced vasoconstriction.

Differential nitric oxide synthase activity in human platelets during normal pregnancy and pre-eclampsia.

Biological uniqueness and the definition of normality. Part 1--The concept of 'intrinsic' homeostasis.

Abstract: We report here a photoneural regulation of nitric oxide synthase (NOS) activity in the rat pineal gland. In the absence of the adrenergic stimulation following constant light exposure (LL) or denervation, pineal NOS activity is markedly reduced. A maximal drop is measured after 8 days in LL. When rats are housed back in normal light‐dark (LD) conditions (12:12), pineal NOS activity returns to normal after 4 days. A partial decrease in pineal NOS activity is also observed when rats are placed for 8 days in LD 18:6 or shorter dark phases, indicating that pineal NOS activity reflects the length of the dark phase. Because it is known that norepinephrine (NE) is released at night from the nerve endings in the pineal gland and this release is blocked by exposure to light, our data suggest that NOS is controlled by adrenergic mechanisms. Our observation may also explain the lack of cyclic GMP response to NE observed in animals housed in constant light.

Thyroid-stimulating hormone (TSH), cortisol, melatonin, prolactin, luteinizing hormone (LH), delta-sleep-inducing peptide (DSIP), its phosphorylated form (P-DSIP), heart rate, and body temperature were measured every half hour during two 24-h periods in five normal men. tau-Amino-butyric acid (GABA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured less frequently. The first period, the "activity" condition, included usual daily activities. The second period, or "rest" condition, consisted of fasting, constant bed rest during 34 h, and partial light deprivation. Compared with the "rest" condition, the "activity" condition increased heart rate, temperature, LH, and TSH in most subjects, and cortisol in two of five subjects. It retarded the onset of nocturnal cortisol and melatonin secretion. The temporal pattern and the absolute values of the concentrations of DSIP, P-DSIP, MHPG, GABA, and prolactin showed no or minimal changes during the two conditions. In spite of the influence of the "activity" versus "rest" condition on several hormones, the mean concentrations as well as the temporal organization of their secretion into plasma were quite stable within each subject, whereas they varied much more between individuals. TSH, cortisol, and melatonin values were also stable within an 8-month period in one subject who was studied on four occasions. The results illustrate that the patterns of hormones rhythms and their reactivity to changes in the environment are, to a large extent, specific to each subject.

Plasma concentration of nine hormones and neurotransmitters during usual activities or constant bed rest for 34 H.

Pineal nitric oxide synthase: characteristics, adrenergic regulation and function

Neuroendocrine and psychological effects of restricted environmental stimulation technique in a flotation tank

Biological uniqueness and the definition of normality. Part 2--The endocrine 'fingerprint' of healthy adults.

Abstract The concentration of free GABA was measured in the plasma of 18 normal young men, in three separate studies. Overall, it varied by a factor of about 4‐fold in normal subjects, from values of 0.10 nmol/ml to 0.40 nmol/ml. Day‐to‐day stability was found to be very high (r=0.94, n=8 subjects, p<0.002). Free GABA concentration was stable over more than 2 weeks (r=0.95, n=5 subjects, p<0.02). A study of circadian rhythms was carried out (n=5 subjects) comparing a condition with no food and partial light deprivation in a supine position during 34 hr. ("rest”; condition") with a condition of normal daily activities ("activity”; condition). No circadian rhythm was found in the “rest”; condition. In the “activity”; condition, there was a mid‐day rise in GABA concentrations in 3 out of 5 subjects. The significance of these changes was explored using different statistical tests.

The plasma concentration of GABA shows no evidence of a circadian rhythm and is stable over weeks in normal males

Neurokinin-1 (NK1) receptor expression in human striatum was analysed using the polymerase chain reaction. To determine whether cholinergic interneurones express this receptor, in situ hybridization histochemistry was then applied to caudate nucleus and putamen. Radioactive oligonucleotide probes specific for choline acetyltransferase (ChAT) and NK1 receptor mRNA were used on adjacent cryostat sections. All of the 160 identified neurones positive for ChAT were also labelled for NK1 receptor. Moreover, in the caudate nucleus, NK1 receptor mRNA was detected in a population of large neurones that were not cholinergic. These results are consistent with the hypothesis that NK1 receptor-mediated mechanisms are involved in the function of cholinergic interneurones. This might be relevant to pharmacological or pathophysiological situations where substance P inputs are modified.

NK1 receptor expression by cholinergic interneurones in human striatum.

Coexpression of dopamine D2, and substance P (neurokinin-1) receptor messenger RNAs by a subpopulation of cholinergic neurons in the rat striatum

COEXPRESSION OF DOPAMINE D2 AND SUBSTANCE P RECEPTORS BY A SUBPOPULATION OF CHOLINERGIC NEURONS IN THE RAT STRIATUM.

We compared the cortisol and melatonin circadian and ultradian rhythms in normal men using two approaches: 1) the men were exposed successively to two conditions, one normal and a second chosen to alter differently each of the hormones, i.e. complete bedrest for 34 h (supine, fasting, and under dim light), and 2) analyses of the rhythms using a combination of curve smoothing for the description of the 24-h rhythm, and peak detection and spectral analysis for the measurement of periodic phenomena. Blood was sampled every 30 min from 0700-0700 h. A diurnal rhythm was detected for both hormones, with different underlying frequencies. Plasma cortisol had an ultradian rhythm of 8 h. From 0000-0800 h (night) and 0830-1600 h (early day), the pulsatile activity and baseline values of cortisol were high, while from 1630-2400 h (late day), these variables were low. During complete bedrest, pulsatile activity and baseline values were even higher during the night period, and the nocturnal peak of cortisol, usually present between 0300-1000 h, was split in two, with an early peak at 0000-0400 h. There were two specific events during the day associated with synchronous, high amplitude pulses: awakening and eating at noon. No such pulses occurred at suppertime or when the men fasted. Melatonin secretion was organized around a 5.5-h period. In the rest condition, plasma melatonin values were higher during the night. The 24-h rhythms of cortisol and melatonin were temporally related. Plasma melatonin began to rise when plasma cortisol was at its lowest, it peaked when cortisol began to rise, and it began to decrease when cortisol reached its peak, with a 5-h phase delay between plasma cortisol and melatonin rise at night. In summary, melatonin and cortisol rhythms have different ultradian frequencies, suggesting an intrinsic difference in the mechanisms controlling their secretion. In addition, their responses to restricted physical activity in an environment with dim light were completely different; for plasma melatonin, the change was primarily quantitative, with an increase in total production especially at night, while for plasma cortisol, there was more of a qualitative change, with different patterns of pulsatile activity and possible splitting of the nocturnal peak. The differences in the ultradian organization of these two hormones imply that the correlation between their peaks must depend on a third factor, which is likely to be the 24-h organization of the day.

Differences between circadian and ultradian organization of cortisol and melatonin rhythms during activity and rest.

Solidification Microstructure of Aluminum AA 6016-T4 Resistance Spot Welds Using a Short-Pulse Technique

Discussion-based teaching has long been recognized as a way to promote civic engagement. However, increasing the amount and quality of student talk in social studies classrooms has proven very difficult in practice. This article's purpose is to show how teachers can design a discussion to increase student involvement. A well-designed discussion will satisfy the following three conditions: the topic will be arguable, located within the students' existing knowledge base, and educational in purpose. These conditions can be met by using the four discussion designs featured in this article, including responding to a problem, responding to an observation, responding to a narrative, and reflecting on classroom activities. Each of these designs is fully described and illustrated with examples. The article concludes with a teacher's description of how he designed and implemented a discussion in his classroom.

Utilizing geographic education research to increase learning in a seventh grade geography course

94th Annual Meeting German Society of Oto-Rhino-Laryngology, Head and Neck Surgery e.V., Bonn

Investigation on expression of adenovirus receptors CXADR and CD46 in laryngeal carcinoma for potential adenoviral therapy

Oncolytic viruses are a promising technology to attack cancer cells and to recruit immune cells to the tumor site. Since the Lipocalin-2 receptor (LCN2R) is expressed on most cancer cells, we used its ligand LCN2 to target oncolytic adenoviruses (Ads) to cancer cells. Therefore, we fused a DARPin adapter binding the knob of Ad type 5 (knob5) to LCN2 to retarget the virus towards LCN2R with the aim of analyzing the basic characteristics of this novel targeting approach. The adapter was tested in vitro with Chinese Hamster Ovary (CHO) cells stably expressing the LCN2R and on 20 cancer cell lines (CCLs) using an Ad5 vector encoding luciferase and green fluorescent protein (GFP). Luciferase assays with the LCN2 adapter (LA) showed 10-fold higher infection compared to blocking adapter (BA) in CHO cells expressing LCN2R and in cells not expressing the LCN2R. Most CCLs showed an increased viral uptake of LA-bound virus compared to BA-bound virus and for five CCLs viral uptake was comparable to unmodified Ad5. Flow cytometry and hexon immunostainings also revealed increased uptake of LA-bound Ads compared with BA-bound Ads in most tested CCLs. Virus spread was studied in 3D cell culture models and nine CCLs showed increased and earlier fluorescence signals for LA-bound virus compared to BA-bound virus. Mechanistically we show that the LCN2 adapter increases viral uptake only in the absence of its ligand Enterobactin (Ent) and independently of iron. Together, we characterized a novel DARPin-based system resulting in enhanced uptake demonstrating potential for future oncolytic virotherapy.

Targeting Oncolytic Adenoviruses to Cancer Cells Using a Designed Ankyrin Repeat Protein (DARPin) Lipocalin-2 (LCN2) Fusion Protein.

Depending on the therapy approach and disease background, the heterogeneity of muscular tissues complicates the development of targeted gene therapy, where either expression in all muscle types or restriction to only one muscle type is warranted. Muscle specificity can be achieved using promotors mediating tissue specific and sustained physiological expression in the desired muscle types but limited activity in non-targeted tissue. Several muscle specific promotors have been described, but direct comparisons between them are lacking.

OBJECTIVE
Here we present a direct comparison of muscle specific Desmin-, MHCK7, microRNA206- and Calpain3 promotor.

METHODS
To directly compare these muscle specific promotors we utilized transfection of reporter plasmids using an in vitro model based on electrical pulse stimulation (EPS) to provoke sarcomere formation in 2D cell culture for quantification of promotor activities in far differentiated mouse and human myotubes.

RESULTS
We found that Desmin- and MHCK7 promotors showed stronger reporter gene expression levels in proliferating and differentiated myogenic cell lines than miR206 and CAPN3 promotor. However, Desmin and MHCK7 promotor promoted gene expression also cardiac cells whereas miR206 and CAPN3 promotor expression was restricted to skeletal muscle.

Our results provides direct comparison of muscle specific promotors with regard to expression strengths and specificity as this is important feature to avoid undesired transgene expression in non-target muscle cells for a desired therapy approach.

Muscle Specific Promotors for Gene Therapy - A Comparative Study in Proliferating and Differentiated Cells.

High pre-existing antibodies against viral vectors reduce their functionality and may lead to adverse complications. To circumvent this problem in future gene therapy approaches, we tested the seroprevalence of a large range of human adenovirus types in patients with neuromuscular disorders (NMDs) to find appropriate viral vector candidates for gene replacement therapy for NMDs. Binding and neutralizing antibodies against 39 human adenovirus types were tested in the sera of 133 patients with NMDs and 76 healthy controls aged 17–92 years. The influence of age, sex, and NMDs on antibody levels was analyzed. The seroprevalence of different adenoviruses in the cohort varied widely. The highest levels of binding antibodies were detected against HAdV-D27, -C1, -D24, -D70, -B14, -C6, -D13, -B34, and -E4, whereas the lowest reactivity was detected against HAdV-F41, -A31, -B11, -D75, -D8, -D65, -D26, -D80, and -D17. The highest neutralizing reactivity was observed against HAdV-B3, -C2, -E4, -C1, -G52, -C5, and -F41, whereas the lowest neutralizing reactivity was observed against HAdV-D74, -B34, -D73, -B37, -D48, -D13, -D75, -D8, -B35, and -B16. We detected no influence of sex and only minor differences between different age groups. Importantly, there were no significant differences between healthy controls and patients with NMDs. Our data show that patients with NMDs have very similar levels of binding and neutralizing antibodies against HAdV compared to healthy individuals, and we identified HAdV-A31, -B16, -B34, -B35, -D8, -D37, -D48, -D73, -D74, -D75, and -D80 as promising candidates for future vector development due to their low binding and neutralizing antibody prevalence.

Seroprevalence of Binding and Neutralizing Antibodies against 39 Human Adenovirus Types in Patients with Neuromuscular Disorders

Abstract Oncolytic adenoviruses (OAd) represent an attractive treatment option for cancer. Clinical efficacy of commonly utilized human adenovirus type 5 (Ad5)-based oncolytic viruses is limited by variable expression levels of the coxsackie- and adenovirus receptor (CAR) in tumor cells and high prevalence of neutralizing antibodies against human Ad5. However, previous studies have highlighted alternative human Ad types as promising candidates for oncolytic therapy. In this study, we generated novel OAds based on Ad1, -2, -5, and -6 derived from species C Ads. These OAds contain a 24-bp deletion in the early gene E1A for tumor selective replication and express the RNAi inhibitor P19. We examined these OAds for in vitro anticancer activity on various cancer cell lines derived from lung, colon, gynecologic, bone, and pancreatic carcinoma. In most surveyed cell lines, OAds based on Ad1, -2, and -6 demonstrated higher cell lysis capability compared with Ad5, suggesting enhanced oncolytic potential. Moreover, enhanced oncolytic activity was associated with P19 expression in a cell type–dependent manner. We further explored a A549 tumor xenograft mouse model to compare the novel OAds directly with Ad5 and H101, an oncolytic adenovirus used in clinical trials. These P19-containing OAds based on Ad1, -2, and -6 showed significantly decelerated tumor progression compared with H101, indicating better antitumor potency in vivo. Our studies provide a novel path for OAd development based on alternative Ad types with improved effectiveness by RNA interference suppression.

Novel Group C Oncolytic Adenoviruses Carrying a miRNA Inhibitor Demonstrate Enhanced Oncolytic Activity In Vitro and In Vivo

To develop adenoviral cell- or tissue-specific gene delivery, understanding of the infection mechanisms of adenoviruses is crucial. Several adenoviral attachment proteins such as CD46, CAR and sialic acid have been identified and studied. However, most receptor studies were performed on non-human cells. Combining our reporter gene-tagged adenovirus library with an in vitro human gene knockout model, we performed a systematic analysis of receptor usage comparing different adenoviruses side-by-side. The CRISPR/Cas9 system was used to knockout CD46 and CAR in the human lung epithelial carcinoma cell line A549. Knockout cells were infected with 22 luciferase-expressing adenoviruses derived from adenovirus species B, C, D and E. HAdV-B16, -B21 and -B50 from species B1 as well as HAdV-B34 and -B35 were found to be CD46-dependent. HAdV-C5 and HAdV-E4 from species E were found to be CAR-dependent. Regarding cell entry of HAdV-B3 and -B14 and all species D viruses, both CAR and CD46 play a role, and here, other receptors or attachment structures may also be important since transductions were reduced but not completely inhibited. The established human knockout cell model enables the identification of the most applicable adenovirus types for gene therapy and to further understand adenovirus infection biology.

A Human In Vitro Model to Study Adenoviral Receptors and Virus Cell Interactions

Genomic and phylogenetic characterization of ChPV2, a novel goat PV closely related to the Xi-PV1 species infecting bovines

Human papillomaviruses (HPV) cause malignant epithelial cancers including cervical carcinoma, non-melanoma skin and head and neck cancer. They drive tumor development through the expression of their oncoproteins E6 and E7. Designer nucleases were shown to be efficient to specifically destroy HPV16 and HPV18 oncogenes to induce cell cycle arrest and apoptosis. Here, we used high-capacity adenoviral vectors (HCAdVs) expressing the complete CRISPR/Cas9 machinery specific for HPV18-E6 or HPV16-E6. Cervical cancer cell lines SiHa and CaSki containing HPV16 and HeLa cells containing HPV18 genomes integrated into the cellular genome, as well as HPV-negative cancer cells were transduced with HPV-type-specific CRISPR-HCAdV. Upon adenoviral delivery, the expression of HPV-type-specific CRISPR/Cas9 resulted in decreased cell viability of HPV-positive cervical cancer cell lines, whereas HPV-negative cells were unaffected. Transduced cervical cancer cells showed increased apoptosis induction and decreased proliferation compared to untreated or HPV negative control cells. This suggests that HCAdV can serve as HPV-specific cancer gene therapeutic agents when armed with HPV-type-specific CRISPR/Cas9. Based on the versatility of the CRISPR/Cas9 system, we anticipate that our approach can contribute to personalized treatment options specific for the respective HPV type present in each individual tumor.

Adenoviral Vectors Armed with PAPILLOMAVIRUs Oncogene Specific CRISPR/Cas9 Kill Human-Papillomavirus-Induced Cervical Cancer Cells

Oncolytic adenoviruses (Ads) are promising tools for cancer therapeutics. However, most Ad-based therapies utilize Ad type 5 (Ad5), which displays unsatisfying efficiency in clinical trials, partly due to the low expression levels of its primary coxsackievirus and adenovirus receptor (CAR) on tumor cells. Since the efficacy of virotherapy strongly relies on efficient transduction of targeted tumor cells, initial screening of a broad range of viral agents to identify the most effective vehicles is essential. Using a novel Ad library consisting of numerous human Ads representing known Ad species, we evaluated the transduction efficiencies in four breast cancer (BC) cell lines. For each cell line over 20 Ad types were screened in a high-throughput manner based on reporter assays. Ad types featuring high transduction efficiencies were further investigated with respect to the percentage of transgene-positive cells and efficiencies of cellular entry in individual cell lines. Additionally, oncolytic assay was performed to test tumor cell lysis efficacy of selected Ad types. We found that all analyzed BC cell lines show low expression levels of CAR, while alternative receptors such as CD46, DSG-2, and integrins were also detected. We identified Ad3, Ad35, Ad37, and Ad52 as potential candidates for BC virotherapy.

Spectrum-Wide Exploration of Human Adenoviruses for Breast Cancer Therapy

Adenovirus (AdV) infections in the respiratory tract may cause asthma exacerbation and allergic predisposition, and the house dust mite (HDM) may aggravate virus-induced asthma exacerbations. However, the underlying mechanisms of whether and how AdV affects asthmatic patients remains unclear. To address this question, we investigated nasal epithelial cells (NAEPCs) derived from a pediatric exacerbation study cohort for experimental analyses. We analyzed twenty-one different green-fluorescent protein- and luciferase-tagged AdV types in submerged 2D and organotypic 3D cell culture models. Transduction experiments revealed robust transduction of AdV type 5 (AdV5) in NAEPCs, which was associated with an increased uptake of AdV5 in the presence of HDM. In healthy and asthmatic NAEPCs exposed to HDM before infection, we observed a time- and dose-dependent increase of AdV5 uptake associated with upregulation of entry receptors for AdV5. Furthermore, electron microscopic and histologic analyses of 3D cell cultures revealed an impairment of the respiratory cilia after HDM exposition. This ex vivo pilot study shows the impact of AdV infection and HDM exposition in a primary cell culture model for asthma.

House Dust Mite Exposure Causes Increased Susceptibility of Nasal Epithelial Cells to Adenovirus Infection

Elisa Heuser, Arnt Ebinger, Silva Holtfreter, Andreas Zautner, René Ryll, Stephan Drewes, Beate Matzkeit, Bernd Hoffmann, Dirk Höper, Markus Keller, Allison Groseth, Gottfried Wilharm, Daniel Mrochen, Anna Obiegala, Frank Doss, Tobias Eisenberg, Sandra Niendorf, Sindy Böttcher, Michael H. Kohn, Charlotte Schröder, Joachim Reetz, Kati Franzke, Eric Ehrke-Schulz, Martin Pfeffer, Katja Schmidt, Martin Beer, Rainer G. Ulrich

The rat from an aircraft: Investigations for multiple pathogen detection

One-Vector System for Multiplexed CRISPR/Cas9 against Hepatitis B Virus cccDNA Utilizing High-Capacity Adenoviral Vectors

Viral Vector-Based Delivery of CRISPR/Cas9 and Donor DNA for Homology-Directed Repair in an In Vitro Model for Canine Hemophilia B

Gene correction at specific target loci provides a powerful strategy for overcoming genetic diseases. In the present study, we aimed to use an in vitro model for canine hemophilia B containing a single point mutation in the catalytic domain of the canine coagulation factor IX (cFIX) gene. To correct the defective gene via homology‐directed repair (HDR), we designed transcription‐activator like effector nucleases and clustered regularly interspaced short palindromic repeats including Cas9 (CRISPR/Cas9) for introduction of double‐strand breaks at the mutation site.

Designer nuclease‐mediated gene correction via homology‐directed repair in an in vitro model of canine hemophilia B

CRISPR/Cas9 delivery with one single adenoviral vector devoid of all viral genes

Adenovirus (Ad)-based vectors are efficient gene-transfer vehicles to deliver foreign DNA into living organisms, offering large cargo capacity and low immunogenicity and genotoxicity. As Ad shows low integration rates of their genomes into host chromosomes, vector-derived gene expression decreases due to continuous cell cycling in regenerating tissues and dividing cell populations. To overcome this hurdle, adenoviral delivery can be combined with mechanisms leading to maintenance of therapeutic DNA and long-term effects of the desired treatment. Several hybrid Ad vectors (AdV) exploiting various strategies for long-term treatment have been developed and characterized. This review summarizes recent developments of preclinical approaches using hybrid AdVs utilizing either the Sleeping Beauty transposase system for somatic integration into host chromosomes or designer nucleases, including transcription activator-like effector nucleases and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein-9 nuclease for permanent gene editing. Further options on how to optimize these vectors further are discussed, which may lead to future clinical applications of these versatile gene-therapy tools.

Recent Advances in Preclinical Developments Using Adenovirus Hybrid Vectors.

An Engineered Virus Library as a Resource for the Spectrum-wide Exploration of Virus and Vector Diversity.

Establishment of the CRISPR/Cas9 System for Targeted Gene Disruption and Gene Tagging.

High-capacity adenoviral vectors (HCAdV) devoid of all viral coding sequences represent one of the most advanced gene delivery vectors due to their high packaging capacity (up to 35 kb), low immunogenicity and low toxicity. However, for many laboratories the use of HCAdV is hampered by the complicated procedure for vector genome construction and virus production. Here, a detailed protocol for efficient cloning and production of HCAdV based on the plasmid pAdFTC containing the HCAdV genome is described. The construction of HCAdV genomes is based on a cloning vector system utilizing homing endonucleases (I-CeuI and PI-SceI). Any gene of interest of up to 14 kb can be subcloned into the shuttle vector pHM5, which contains a multiple cloning site flanked by I-CeuI and PI-SceI. After I-CeuI and PI-SceI-mediated release of the transgene from the shuttle vector the transgene can be inserted into the HCAdV cloning vector pAdFTC. Because of the large size of the pAdFTC plasmid and the long recognition sites of the used enzymes associated with strong DNA binding, careful handling of the cloning fragments is needed. For virus production, the HCAdV genome is released by NotI digest and transfected into a HEK293 based producer cell line stably expressing Cre recombinase. To provide all adenoviral genes for adenovirus amplification, co-infection with a helper virus containing a packing signal flanked by loxP sites is required. Pre-amplification of the vector is performed in producer cells grown on surfaces and large-scale amplification of the vector is conducted in spinner flasks with producer cells grown in suspension. For virus purification, two ultracentrifugation steps based on cesium chloride gradients are performed followed by dialysis. Here tips, tricks and shortcuts developed over the past years working with this HCAdV vector system are presented.

Cloning and Large-Scale Production of High-Capacity Adenoviral Vectors Based on the Human Adenovirus Type 5.

15. A Novel Fast Production Pipeline for High Capacity Adenoviral Vectors to Deliver All Components of CRISPR/Cas9 System for Somatic Gene Editing Using One Single Viral Vector with Multiple Guide RNAs

103. High-Capacity Adenoviral Vectors (HCAdV) Armed with a High Risk Human Papillomavirus (HPV) Oncogene Specific CRISPR/Cas9 Machinery Specifically Kill Cervical Cancer Cells

104. A Gene Deleted High Capacity Adenoviral Vector for Efficient Delivery of a Multiplex DMD Specific CRISPR/Cas9 Machinery

Quantification of designer nuclease induced mutation rates: a direct comparison of different methods

A High-Capacity Adenoviral Hybrid Vector System Utilizing the Hyperactive Sleeping Beauty Transposase SB100X for Enhanced Integration

18. Delivery of CRISPR/Cas9 or TALENs Against Hepatitis B Virus cccDNA by High-Capacity Adenoviral Vectors

14. Engineering and Characterization of a Cloned Adenoviral-Library to Explore Natural Virus Diversity

A High-Capacity Adenoviral Hybrid Vector System Utilizing the Hyperactive Sleeping Beauty Transposase SB100X for Enhanced Integration.

Objective 
To evaluate the cardiopulmonary effects of low-pressure (6 mmHg) peritoneal insufflation of varying duration in healthy cats during ovariectomy (OVE). 
 
Study Design 
Prospective, randomized study. 
 
Animals 
Female cats (n = 24). 
 
Methods 
After anesthesia induction, cats had short (Short LAP; n = 8) or long duration (Long LAP; n = 8) laparoscopic ovariectomy, or Open OVE (Open; n = 8) for comparison. Hemodynamic and pulmonary measurements were recorded after induction of anesthesia (T0), 5 minutes after abdominal insufflation had reached 6 mmHg of pressure (T1), after the 2nd ovary had been resected (T2), after abdominal decompression (T3), and at the end of anesthesia, after abdominal closure (T4). Hemodynamic and pulmonary variables were compared between groups. 
 
Results 
Low-pressure abdominal insufflation caused cardiopulmonary changes in cats. At T1 and T2, Long LAP and Short LAP caused a significant change in PvCO2 and RC when compared with Open. During T3, RC was lower only in Long LAP. At T2, there was decrease in SV, but not CO for Long LAP when compared with Open. 
 
Duration of insufflation was associated with worsening of negative cardiopulmonary effects; however, these effects were reversible and resolved by the end of the procedure.

Cardiopulmonary Effects of Laparoscopic Ovariectomy of Variable Duration in Cats

Objective 
To report complications of arthrodesis of the carpometacarpal (CMC) joint using a drilling technique in an adult horse. 
 
Case report. 
 
Animals 
Horse (n = 1). 
 
Method 
A 12-year-old Quarter Horse mare with CMC osteoarthritis (CMC-OA) had arthrodesis under general anesthesia in right lateral recumbency. Under fluoroscopic guidance, a 4.5 mm drill bit was inserted at 3 drilling sites 5–6 cm into the CMC joint and was fanned 30–45° in the plane of the joint and 5–10° in the long axis of the limb to destroy articular cartilage and expose the subchondral bone. 
 
Results 
The horse presented 2 weeks after surgery for severe lameness of the operated limb. A slab fracture of the 2nd carpal bone (C2) and subluxation of the middle carpal (MC) joint was diagnosed. The horse was humanely euthanatized due to poor prognosis. 
 
The fanning technique of arthrodesis of the CMC joint may lead to fracture of carpal bones, joint instability, and MC joint subluxation. A balance between articular surface destruction and maintenance of joint stability should be achieved when using this technique.

Second Carpal Bone Slab Fracture and Subluxation of the Middle Carpal Joint in a Horse Subsequent to Arthrodesis of the Carpometacarpal Joint

Objective: To assess the effect of autogenous cancellous bone graft (autograft) and novel plate use on radiographic healing and complications in tibial tuberosity advancement (TTA) for treatment of cranial cruciate ligament (CrCL)-deficient stifles in dogs. 
 
Study Design: Prospective clinical study. 
 
Animals: Consecutive dogs (n=125) with unilateral CrCL-deficient stifles. 
 
Methods: Four treatment groups: CPG, conventional plate with autograft; CPNG, conventional plate without autograft; NPG, novel plate with autograft; NPNG, novel plate without autograft were studied. Radiographs from 60 dogs were scored for healing at 6 and 10 weeks postoperatively; all 125 dogs were assessed for radiographic complications. Variables evaluated for relationship with healing scores and radiographic complications were age, weight, sex, cage and plate size, implant type, and graft use. 
 
Results: Dogs with autograft had overall higher healing scores at 6 and 10 weeks. Radiographic complications occurred in 13 dogs (12 minor, 1 major), and were not influenced by graft or novel plate use. 
 
Conclusion: Autograft increases healing scores, but was not found to have a significant impact on the rate of complications in TTA. The novel plate was not found to have healing scores or radiographic complication rates significantly different from the conventional plate design.

The Effect of Cancellous Autograft and Novel Plate Design on Radiographic Healing and Postoperative Complications in Tibial Tuberosity Advancement for Cranial Cruciate-Deficient Canine Stifles

Objective 
To evaluate inter- and intraobserver variability in the measurement of distal tibial axis/proximal tibial axis angle (DPA) from lateral radiographs of canine tibia in dogs with cranial cruciate ligament rupture (CCLR). 
 
Retrospective clinical study. 
 
Animals 
Dogs (n=100) with cranial cruciate ligament rupture. 
 
Methods 
Medical records of dogs diagnosed with CCLR were reviewed. In addition to signalment and TPA measurements, measured DPA (mDPA) was calculated for each lateral view of the tibia in each animal, twice, by 3 blinded observers. Subjective scoring of DPA (sDPA) was also recorded, twice, by 3 additional blinded observers from lateral views of the proximal half of the tibia in each dog. Inter- and intraobserver variability was measured by intraclass correlation coefficient (ICC) for each measurement. Correlation between mDPA and sDPA was also determined. 
 
Results 
Median tibial plateau angle (TPA) of the subject population was 27.9° (range 18.8–41.3°; IQR: 25.5–30.75°). Mean ± SD mDPA was 6.50 ± 2.81° (confidence intervals [CI]: 5.94–7.06°; range 0–13.33°). There was no correlation between age and weight of dogs and the mDPA (P=.58 and .12). There was a moderate correlation between mDPA and TPA (r2=0.49, P<.0001). There was a moderate correlation between sDPA and mDPA (r2=0.27, P<.0001). Good inter- and intraobserver agreement was found in the measurement of mDPA. 
 
mDPA is a reproducible measurement of caudal angulation of proximal tibia. Furthermore, mDPA of dogs with cranial cruciate ligament disease in this report are in concordance with previous reports.

Radiographic Quantitative Assessment of Caudal Proximal Tibial Angulation in 100 Dogs with Cranial Cruciate Ligament Rupture

Objective: To report the outcome after treatment of Monteggia fractures (MF) using a novel surgical technique. 
 
Study design: Clinical reports. 
 
Methods: One dog and 1 cat were treated for MF by use of a Tightrope suture, toggle, and button implant. In both patients the fracture/luxations were reduced using an open technique and the tightrope was placed using a cannulated drill system and guide wire from cranial to caudal. Cases were retrospectively reviewed at 1, 5, and 8 weeks (cat) and at 4 weeks and 4 months (dog) for complications and outcome. Outcomes were measured by subjective assessment of range of motion comparing affected to unaffected limbs, and lameness scoring and by client description of function. 
 
Results: Both animals returned to normal function with range of motion close to that of the unaffected limb. No complications were recognized. 
 
Conclusions: Tightrope repair of MF resulted in excellent clinical results with no complications.

Repair of Monteggia Fractures Using an Arthrex Tightrope System and Ulnar Plating

Objective: To evaluate the racing and sales performance of Thoroughbred horses with varus angular limb deformities of the carpus treated by unilateral or bilateral single transphyseal screw (STS) placement. 
 
Study Design: Case series. 
 
Animals: Thoroughbred horses (n=53). 
 
Methods: Medical records (January 1, 2005–December 31, 2006) of yearling Thoroughbreds treated for carpal angular limb deformity by transphyseal screw insertion in the distal aspect of the radius were reviewed. Retrieved data were sex, surgery, and screw removal dates, surgical site, appearance, limb(s) affected, type of angular limb deformity, and degree of angular deviation measured by a goniometer. Racing and sales data were collected for analysis from an online racing site for all treated horses and their maternal siblings. 
 
Results: No significant differences were identified between treated horses and their maternal siblings in yearling sale price, 2-year-olds in training sale price, percent starters, percent winners, and starts, earnings, and earnings/start made during the 2- and 3-year old years. 
 
Conclusions: No deleterious effects on sales or racing performance were identified after use of STS in the distal aspect of the radius of Thoroughbreds for the treatment of varus angular limb deformities of the carpus.

Racing and Sales Performance after Unilateral or Bilateral Single Transphyseal Screw Insertion for Varus Angular Limb Deformities of the Carpus in 53 Thoroughbreds

Objectives— To determine the relationship between plasma lactate concentration and colonic viability and survival in horses with ≥360° volvulus of the ascending colon. 
 
Study Design— Retrospective study. 
 
Animals— Horses (n=73) with ≥360° volvulus of the ascending colon. 
 
Methods— Medical records (January 2000–November 2005) of all horses examined for colic at Michigan State University Veterinary Teaching Hospital were reviewed. Horses were included only if plasma lactate concentration was measured preoperatively and a diagnosis of ≥360° volvulus of the ascending colon was confirmed by surgery or necropsy. Non-survivors were only included if the ascending colon was evaluated histopathologically. Logistic regression analysis was used to model the relationship between lactate, colonic viability, and survival. 
 
Results— Of 73 horses, 61 were discharged. Mean (±SD) plasma lactate concentration was significantly lower in survivors (2.98±2.53 mmol/L) compared with non-survivors (9.48±5.22 mmol/L; odds ratio [OR]=1.628, 95% confidence limit [CI]=1.259–2.105). Plasma lactate concentration was significantly lower in horses with a viable colon (3.30±2.85 mmol/L) compared with horses with a non-viable colon (9.1±6.09 mmol/L; OR=1.472, 95% CI=1.173–1.846). Plasma lactate concentration <6.0 mmol/L had a sensitivity of 84% and a specificity 83% for predicting horse survival. 
 
Conclusions— Our results demonstrate a strong association between plasma lactate concentration at the time of hospital admission and outcome in horses with ≥360° volvulus of the ascending colon. 
 
Clinical Relevance— Plasma lactate concentration may help predict colonic viability and horse survival after ascending colon volvulus in horses.

Plasma Lactate as a Predictor of Colonic Viability and Survival After 360° Volvulus of the Ascending Colon in Horses

Objective— To compare the effect of internal tibial rotation on the computed tomographic (CT) and standard radiographic assessment of tibial torsion (TT) in dogs. 
 
Study Design— In vitro study. 
 
Sample Population— Cadaveric canine hind limbs (6 pairs). 
 
Methods— The cranial cruciate ligament was transected, and caudo-cranial radiographic and transverse CT images were obtained with the femur and tibiae in a neutral position, and after 15° internal tibial rotation. Radiographic TT was determined by measuring the distance (d) between the calcaneus and the sulcus of the talus. CT determination of TT was performed using the proximal transcondylar and the distal cranial tibial axes. The distance (d) in the 2 groups and the difference in the CT determination of TT between groups were compared with a hypothetical mean value of 0 mm and 0°, respectively. 
 
Results— The mean distance (d) for the neutral radiographic group was not significantly different from 0 (P=.473); however, for the 15° group it was significantly different (P<.0001). The difference in the CT determination of TT did not differ from 0 (P=.317). 
 
Conclusion— The standard radiographic technique does not discriminate between internal TT and internal rotation of the tibia. Thus, dogs with normal tibial conformation can be depicted by radiography as torsed, whereas dogs with TT may be misinterpreted as normal because of arbitrary positioning. 
 
Clinical Relevance— Lateral displacement of the medial border of the calcaneus on a caudo-cranial radiograph should not be used as the sole arbiter of TT before surgical correction.

Comparison of Computed Tomographic and Standard Radiographic Determination of Tibial Torsion in the Dog

Methodological limits on sampling visual experience with mobile eye tracking

Prediction accuracy on held-out data has become a critical analysis for quantitative model evaluation and hypothesis testing in computational cognitive neuroscience. In this talk, I will discuss the limits of prediction accuracy as a standalone metric, and highlight other considerations for model evaluation and interpretation. First, comparing two models on prediction accuracy alone does not reveal the degree to which the models have common underlying factors. I will advocate addressing this issue with variance partitioning, a form of commonality analysis, to reveal shared and unique variance explained by different models. Concretely, I will show how variance partitioning reveals representation of body parts and object boundaries in responses to multiple data sets of movie stimuli. Second, prediction accuracy is a metric for the variance explained by a given model. But for any experiment, the stimulus constrains the variance in the measured brain responses. Any given stimulus set runs the risk of excluding important sources of variation. A popular way to address this issue is to use photographs or movie clips as stimuli. Such naturalistic stimuli are typically sampled broadly from the world and thus have increased ecological validity, but random selection of natural stimuli often results in correlated features both within and between models. This often leads to ambiguous results, e.g. shared variance between models intended to capture different types of features. Furthermore, I will show that the same models (again of body parts and object boundaries) can yield quantitatively and in some cases qualitatively different results when applied to different data sets. This raises a critical question: if results for the same model vary across stimulus sets, which result provides a more solid basis for future work? Just as two clocks telling different times need a reference clock to be set, I will argue that we need broadly sampled sets of natural stimuli to use as a baseline for what, in various feature domains, constitutes "natural" variation and covariation. I will describe our collaboration to create just such a dataset of human visual experience, in the form of hundreds of hours of first-person video.

Limits of prediction accuracy on randomly selected natural images for model evaluation.

Whole-network activation maximization: a flexible method for exploring visual selectivity in the brain

PCA Reveals Common Spatial Patterns of Motion Energy in Diverse Stimulus Sets and in Scene-Selective Area Voxel Tuning

Head-mounted devices allow recording of eye movements, head movements, and scene video outside of the traditional laboratory setting. A key challenge for recording comprehensive first-person stimuli and behavior outside the lab is the form factor of the head-mounted assembly. It should be mounted stably on the head to minimize slippage and maximize accuracy of the data; it should be as unobtrusive and comfortable as possible to allow for natural behaviors and enable longer duration recordings; and it should be able to fit a diverse user population. Here, we survey preliminary design iterations of the Visual Experience Database headset, an assembly consisting of the Pupil Core eye tracker, the Intel RealSense T265 ™ (T265) tracking camera, and the FLIR Chameleon™3 (FLIR) world camera. Strengths and weaknesses of each iteration are explored and documented with the goal of informing future ergonomic design efforts for similar head-mounted systems.

Ergonomic Design Development of the Visual Experience Database Headset

Pupil tracking in a bright outdoor environment is challenging due to low eye image quality and reduced pupil size in response to bright light. In this study we present research to develop robust outdoor pupil tracking without the need for shading the eyes. We first investigate the effect of camera post-processing settings in order to find values that enhance image quality for the purpose of pupil tracking under direct, oblique and overcast sunlight illuminations. We then tested the performance of the state-of-the-art pupil tracking techniques under these extreme real-world outdoor lighting conditions. Our results suggest that a key goal should be maintaining the contrast between iris and pupil to support accurate estimation of pupil position regardless of the overall eye image quality.

Deep neural networks (DNNs) provide powerful tools to identify and track features of interest, and have recently come into use for eye-tracking. Here, we test the ability of a DNN to predict keypoints localizing the eyelid and pupil under the types of challenging image variability that occur in mobile eye-tracking. We simulate varying degrees of perturbation for five common sources of image variation in mobile eye-tracking: rotations, blur, exposure, reflection, and compression artifacts. To compare the relative performance decrease across domains in a common space of image variation, we used features derived from a DNN (ResNet50) to compute the distance of each perturbed video from the videos used to train our DNN. We found that increasing cosine distance from the training distribution was associated with monotonic decreases in model performance in all domains. These results suggest ways to optimize the selection of diverse images for model training.

Characterizing the Performance of Deep Neural Networks for Eye-Tracking

Voxelwise modeling reveals selectivity for body part identity and location in BOLD fMRI responses to complex naturalistic stimuli

Human Scene-Selective Areas Represent 3D Configurations of Surfaces

LO represents motion and semantic categories in addition to object boundaries

Studies have shown that intermediate-level visual areas including Lateral Occipital cortex (LO) represent information about object boundaries. However, because most studies use tightly controlled stimuli (e.g. stimuli with contours and no motion or vice versa), it is unknown how important object boundary contours are relative to other features such as motion and visual categories. To address this issue, we measured fMRI responses while human subjects viewed two sets of movies that varied in many feature dimensions: rendered movies of artifcial scenes and cinematic movies. We modeled responses to both sets of movies independently using the same three models: models of motion energy, object boundary contours, and visual categories. In the rendered movies, we used the parameters of the virtual world to label boundary contours, and in the cinematic movie clips, we used a customized version of a recent convolutional neural network (DeepLab v2, ) to label contours. We used the encoding models for each type of feature to predict withheld fMRI data, and used variance partitioning to determine whether the various models explained unique or shared variance in each dataset.

Variance Partitioning Reveals Consistent Representation of Object Boundary Contours in LO Across Different Datasets

Convolutional neural networks represent shape dimensions—but not as accurately as humans

Both convolutional neural networks and voxel-wise encoding models of brain activity derived from ConvNets represent boundary-and surface-related features

The input to our visual system shifts every time we move our eyes. To maintain a stable percept of the world, visual representations must be updated with each saccade. Near the time of a saccade, neurons in several visual areas become sensitive to the regions of visual space that their receptive fields occupy after the saccade. This process, known as remapping, transfers information from one set of neurons to another, and may provide a mechanism for visual stability. However, it is not clear whether remapping transfers information about stimulus features in addition to information about stimulus location. To investigate this issue, we recorded blood-oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI) responses while human subjects viewed images of faces and houses (two visual categories with many feature differences). Immediately after some image presentations, subjects made a saccade that moved the previously stimulated location to the opposite side of the visual field. We then used a combination of univariate analyses and multivariate pattern analyses to test whether information about stimulus location and stimulus features were remapped to the ipsilateral hemisphere after the saccades. We found no reliable indication of stimulus feature remapping in any region. However, we also found no reliable indication of stimulus location remapping, despite the fact that our paradigm was highly similar to previous fMRI studies of remapping. The absence of location remapping in our study precludes strong conclusions regarding feature remapping. However, these results also suggest that measurement of location remapping with fMRI depends strongly on the details of the experimental paradigm used. We highlight differences in our approach from the original fMRI studies of remapping, discuss potential reasons for the failure to generalize prior location remapping results, and suggest directions for future research.

No Evidence for Automatic Remapping of Stimulus Features or Location Found with fMRI

A network of areas in the human brain-including the Parahippocampal Place Area (PPA), the Occipital Place Area (OPA), and the Retrosplenial Cortex (RSC)-represent visual scenes. However, it is still unclear whether these areas represent high-level features (such as local scene structure or scene category), or low-level features (such as high spatial frequencies and rectilinear corners). To better characterize the representation of visual features in PPA, OPA, and RSC, we define several feature spaces hypothesized to be represented in scene-selective areas, and use them to predict brain activity. The feature spaces we define reflect scene structure (3D orientation of large surfaces), scene expanse (distance from visible surfaces to the virtual camera), and local spatial frequency (Gabor wavelet transformations) of each rendered scene. We fit each feature space to BOLD fMRI data recorded while human subjects viewed movies of a virtual world rendered using 3D graphics software. The graphics software allows us to quantify scene structure and expanse with continuous parameters instead of categorical labels such as "open" or "closed". We fit models for all feature spaces using L2-regularized regression, and evaluate each model based on how much response variance it predicts in a withheld data set. The scene structure model explains more response variance in our data than the scene expanse and local spatial frequency models. A hybrid model that combines surface orientation and distance from the virtual camera explains still more variance. These results are consistent whether subjects attend to the size of each scene or to the number of objects in each scene. Together, these results suggest that PPA, OPA, and RSC represent conjunctions of the depth and orientation of walls, ceilings, and other large objects in scenes. Meeting abstract presented at VSS 2015.

A model of surface depth and orientation predicts BOLD responses in human scene-selective cortex.

Surface visualizations of fMRI provide a comprehensive view of cortical activity. However, surface visualizations are difficult to generate and most common visualization techniques rely on unnecessary interpolation which limits the fidelity of the resulting maps. Furthermore, it is difficult to understand the relationship between flattened cortical surfaces and the underlying 3D anatomy using tools available currently. To address these problems we have developed pycortex, a Python toolbox for interactive surface mapping and visualization. Pycortex exploits the power of modern graphics cards to sample volumetric data on a per-pixel basis, allowing dense and accurate mapping of the voxel grid across the surface. Anatomical and functional information can be projected onto the cortical surface. The surface can be inflated and flattened interactively, aiding interpretation of the correspondence between the anatomical surface and the flattened cortical sheet. The output of pycortex can be viewed using WebGL, a technology compatible with modern web browsers. This allows complex fMRI surface maps to be distributed broadly online without requiring installation of complex software.

Perception of natural visual scenes activates several functional areas in the human brain, including the Parahippocampal Place Area (PPA), Retrosplenial Complex (RSC), and the Occipital Place Area (OPA). It is currently unclear what specific scene-related features are represented in these areas. Previous studies have suggested that PPA, RSC, and/or OPA might represent at least three qualitatively different classes of features: (1) 2D features related to Fourier power; (2) 3D spatial features such as the distance to objects in a scene; or (3) abstract features such as the categories of objects in a scene. To determine which of these hypotheses best describes the visual representation in scene-selective areas, we applied voxel-wise modeling (VM) to BOLD fMRI responses elicited by a set of 1386 images of natural scenes. VM provides an efficient method for testing competing hypotheses by comparing predictions of brain activity based on encoding models that instantiate each hypothesis. Here we evaluated three different encoding models that instantiate each of the three hypotheses listed above. We used linear regression to fit each encoding model to the fMRI data recorded from each voxel, and we evaluated each fit model by estimating the amount of variance it predicted in a withheld portion of the data set. We found that voxel-wise models based on Fourier power or the subjective distance to objects in each scene predicted much of the variance predicted by a model based on object categories. Furthermore, the response variance explained by these three models is largely shared, and the individual models explain little unique variance in responses. Based on an evaluation of previous studies and the data we present here, we conclude that there is currently no good basis to favor any one of the three alternative hypotheses about visual representation in scene-selective areas. We offer suggestions for further studies that may help resolve this issue.

Fourier power, subjective distance, and object categories all provide plausible models of BOLD responses in scene-selective visual areas

Intermediate human visual areas represent the locations of silhouette edges in natural movies

Representation of object contour features in intermediate visual areas in the human brain

There are two dominant models for the functional organization of brain regions underlying object recognition. One model postulates category-specific modules while the other proposes a distributed representation of objects with generic visual features. Functional imaging techniques relying on metabolic signals, such as fMRI and optical intrinsic signal imaging (OISI), have been used to support both models, but due to the indirect nature of the measurements in these techniques, the existing data for one model cannot be used to support the other model. Here, we used large-scale multielectrode recordings over a large surface of anterior inferior temporal (IT) cortex, and densely mapped stimulus-evoked neuronal responses. We found that IT cortex is subdivided into distinct domains characterized by similar patterns of responses to the objects in our stimulus set. Each domain spanned several millimeters on the cortex. Some of these domains represented faces (“face” domains) or monkey bodies (“monkey-body” domains). We also identified domains with low responsiveness to faces (“anti-face” domains). Meanwhile, the recording sites within domains that displayed category selectivity showed heterogeneous tuning profiles to different exemplars within each category. This local heterogeneity was consistent with the stimulus-evoked feature columns revealed by OISI. Taken together, our study revealed that regions with common functional properties (domains) consist of a finer functional structure (columns) in anterior IT cortex. The “domains” and previously proposed “patches” are rather like “mosaics” where a whole mosaic is characterized by overall similarity in stimulus responses and pieces of the mosaic correspond to feature columns.

Object Representation in Inferior Temporal Cortex Is Organized Hierarchically in a Mosaic-Like Structure

The identity of an object is not only specified by its parts but also by the relations among the parts. Rearranging parts can produce a completely different object, in the same manner as rearranging the phonemes in "fur" can yield "rough." How does the visual system represent the relative positions of parts? Between-part relations can be characterized by specifying the relations between the medial axes (imaginary lines through the centers) of an object's parts. A functional magnetic resonance imaging multivoxel classification study tested whether the medial axis structure is represented in the human visual system independent of part identity and overall object orientation. Stimuli were line drawings of novel 3-part geometrical objects, which differed in the relations between their parts' medial axes (i.e., in their medial axis structures), the geons that composed each object, and the objects' orientations in plane and in depth. In regions of interest throughout visual cortex, a support vector machine classifier was trained to distinguish objects that shared either the same medial axis structures or the same orientations. By the level of V3, different medial axis structures were more accurately classified than different orientations, indicating a change in the representation of shape compared with earlier visual areas.

No recovery of function for a specific deficit in individuating faces 40 years after a lesion in the ventral occipito-temporal cortices at age five

Late ventral visual areas generally consist of cells having a significant degree of translation invariance. Such a "bag of features" representation is useful for the recognition of individual objects; however, it seems unable to explain our ability to parse a scene into multiple objects and to understand their spatial relationships. We review several schemes (e.g., global features and serial attention) for how to reconcile bag-of-features representation with our ability to understand relationships; we review structural description theories that, in contrast, suggest that a neural binding mechanism assigns the features of each object in a scene to a separate "slot" to which relational information for that object is explicitly bound. Four functional magnetic resonance imaging-adaptation experiments assessed how ventral stream regions respond to rearrangements of two objects in a minimal scene that depict scene translations and relational changes. Changes of relative position (e.g., elephant above bus changing to bus above elephant) produced larger releases of adaptation in the anterior lateral occipital complex (LOC) than physically equivalent translations, providing evidence that spatial relations are explicitly encoded in the anterior LOC in agreement with structural description theories.

The medial axis structures of novel objects are spontaneously perceived despite variability in the objects' orientations and component part shapes

Large change in representation: Introduction: Many theorists have hypothesized that when viewing a multi-object scene, the visual system assigns each object’s bundled features to separate ‘slots’. Such dynamic “binding” to multiple slots is at the heart of the Object Files theory (Kahneman, Treisman, & Gibbs 1992), Visual Short-Term Memory (VSTM) models, FINST theory (Pylyshyn 1989), Recognition-by-Components theory (Biederman 1987) and others. Such a slot-based representation is potentially very powerful because relation information can be explicitly associated with each slot, i.e., ‘this slot contains the top object’s features’, allowing for true understanding of visual structure. In contrast, certain scene manipulations will produce a disproportionately large change in neural representation: A B

Evidence for object file encoding in the posterior Fusiform Gyrus (pFs) and the Intraparietal Sulcus (IPS)

At what stage in the human ventral pathway is the greater sensitivity to nonaccidental over metric properties first manifested

Many of the phenomena underlying shape recognition can be derived from an assumption that the representation of simple parts can be understood in terms of independent dimensions of generalized cones, e.g., whether the axis of a cylinder is straight or curved or whether the sides are parallel or nonparallel. What enables this sensitivity? One explanation is that the representations derive from our immersion in a manufactured world of simple objects, e.g., a cylinder and a funnel, where these dimensions can be readily discerned independent of other stimulus variations. An alternative explanation is that genetic coding and/or early experience with extended contours—a characteristic of all naturally varying visual worlds—would be sufficient to develop the appropriate representations. The Himba, a seminomadic people in a remote region of Northwestern Namibia with little exposure to regular, simple artifacts, were virtually identical to western observers in representing generalized-cone dimensions of simple shapes independently. Thus immersion in a world of simple, manufactured shapes is not required for the development of a representation that specifies these dimensions independently.

A cross-cultural study of the representation of shape: Sensitivity to generalized cone dimensions

The release from adaptation in LOC from viewing a sequence of two different objects: An effect of shape or semantics?

Erratum to “Adaptation in the fusiform face area (FFA): Image or Person?” [Vision Research 49 (23) (2009) 2800–2807]

Voxels in LO-but not V1-distinguish the axis structures of highly similar objects

How translation invariant are object representations in the human posterior fusiform gyrus

Many theorists have hypothesized that when viewing a multi-object scene, the visual system assigns each object’s bundled features to separate ‘slots’. Such dynamic “binding” to multiple slots is at the heart of the Object Files theory (Kahneman, Treisman, & Gibbs 1992), Visual Short-Term Memory (VSTM) models, FINST theory (Pylyshyn 1989), Recognition-by-Components theory (Biederman 1987) and others.

The neural representation of spatial relationships by anatomical binding

• Even though the results in the “Regular” condition could be attributed to low-level features, the results in the “Noisy” condition could not • Since both “Noisy” and “Regular” runs showed the same pattern, we conclude that the same mechanism is at work in both • Humans are independently sensitive to dimensions of generalized cones, even after growing up in markedly different visual environments “Noisy” “Regular” • Subjects had to divide the display into two groups • Feedback was given after each trial in the form of a green line over the correct divide • “Noisy” displays were shown in dfifferent sessions to some subjects Experimental Task: texture segregation

A Cross-cultural test of the independence of the representation of generalized-cone dimensions

Adaptation to objects in the lateral occipital complex (LOC): Shape or semantics?

Hierarchical organization of functional structures in inferotemporal cortex

Correction to: Lipid class composition of annually bleached Caribbean corals

Correction to: Thirty years of coral heat-stress experiments: a review of methods

Thirty years of coral heat-stress experiments: a review of methods

Understanding the Impacts of Climate Change on Water Access and the Lives of Women in Tharparkar District, Sindh Province, Pakistan: A Literature Review, 1990-2018

Meeting the challenges of sugar crops and integrated industries in developing countries. 3rd International Conference IS-2008, Al-Arish, Egypt, 11-14 September 2008.

COVID-19, caused by SARS-CoV-2, is a systemic illness due to its multiorgan effects in patients. The disease has a detrimental impact on respiratory and cardiovascular systems. One early symptom of infection is anosmia or lack of smell; this implicates the involvement of the olfactory bulb in COVID-19 disease and provides a route into the central nervous system. However, little is known about how SARS-CoV-2 affects neurological or psychological symptoms. SARS-CoV-2 exploits host receptors that converge on pathways that impact psychological symptoms. This systemic review discusses the ways involved by coronavirus infection and their impact on mental health disorders. We begin by briefly introducing the history of coronaviruses, followed by an overview of the essential proteins to viral entry. Then, we discuss the downstream effects of viral entry on host proteins. Finally, we review the literature on host factors that are known to play critical roles in neuropsychiatric symptoms and mental diseases and discuss how COVID-19 could impact mental health globally. Our review details the host factors and pathways involved in the cellular mechanisms, such as systemic inflammation, that play a significant role in the development of neuropsychological symptoms stemming from COVID-19 infection.

Impact of SARS-CoV-2 on Host Factors Involved in Mental Disorders

The spread of COVID-19 misinformation highlights the need to correct misperceptions about health and science. Research on climate change suggests that informing people about a scientific consensus can reduce misinformation endorsement, but these studies often fail to isolate the effects of consensus messaging and may not translate to other issues. We therefore conduct a survey experiment comparing standard corrections with those citing a scientific consensus for three issues: COVID-19 threat, climate change threat, and vaccine efficacy. We find that consensus corrections are never more effective than standard corrections at countering misperceptions and generally fail to reduce them with only one exception. We also find that consensus corrections endorsed by co-partisans do not reduce misperceptions relative to standard corrections, while those endorsed by opposition partisans are viewed as less credible and can potentially even provoke a backfire effect. These results indicate that corrections citing a scientific consensus, including corrective messages from partisans, are less effective than previous research suggests when compared with appropriate baseline messages.

The limited effects of partisan and consensus messaging in correcting science misperceptions

Received: 21 January 2018 Final Accepted: 23 February 2018 Published: March 2018 Aggression directed toward medical staff by patients and escorts at emergency departments (EDs) is a critical and global phenomenon. The current study aims to improve our understanding of the causes of patients' and escorts' aggression, and to suggest an applicable tool of information provision, which may help to decrease this phenomenon. This study investigated the effect of information‟s content and its format of presentation on the relationship between patients‟ and escort‟s negative affectivity (NA) and aggressive tendencies toward medical staff in the ED. According to the scientific literature, aggression may be derived from NA, but it may also be a consequence of feelings of injustice. Moreover, providing information may improve the sense of justice, and further decrease aggression. In addition, it is possible that the type of information and its format of presentation may have different kinds of effects. Therefore, three hypotheses were suggested: (a) NA would be positively related to aggressive tendencies; (b) the type of information would moderate the relationship between NA and aggressive tendencies, that is, the relationship would be weakest for explanatory information, stronger for technical information, and strongest for neutral information; (c) format of presentation would moderate the moderation of the type of information. Participants in the study were patients and escorts who waited in the ED in two hospitals in Israel. They were exposed to either large signs, or pamphlets, which contained explanatory, technical, or neutral information regarding the ED. All participants filled out a questionnaire which measured their NA and aggressive tendencies. Results showed that NA and aggressive tendencies were positively related. However, the type of information did not moderate this relationship. A three-way interaction was found between NA, type of information and format of presentation, where in the private condition, neutral information had a stronger effect of decreasing the relationship between NA and aggressive tendencies. Explanatory and technical information did not have such effect. The effect was not found in the public condition. The study demonstrated the link between NA and aggression in the ED. Furthermore, the study showed that the combination of neutral information and private presentation may help lessen this relationship.

THE EFFECTS OF THE TYPE OF INFORMATION AND ITS FORMAT OF PRESENTATION ON THE RELATIONSHIP BETWEEN PATIENTS’ AND ESCORTS’ NEGATIVE AFFECTIVITY AND THEIR AGGRESSIVE TENDENCIES TOWARD MEDICAL STAFF IN THE EMERGENCY DEPARTMENT. Sarah Solomon and Dalit Lev-Arey Margalit

Received: 21 January 2018 Final Accepted: 23 February 2018 Published: March 2018 Aggression directed toward medical staff by patients and escorts in the ED, is a critical and global phenomenon. The current study aims to improve our understanding of the causes of patients' and escorts' aggression, and to suggest an applicable tool of information provision, which may help to decrease this phenomenon. This study investigated the effect of information‟s content and its format of presentation on the relationship between patients‟ and escort‟s negative affectivity (NA) and aggressive tendencies toward medical staff in the ED. According to the scientific literature, aggression may be derived from NA, but it may also be a consequence of feelings of injustice. Moreover, providing information may improve the sense of justice, and further decrease aggression. In addition, it is possible that the type of information and its format of presentation may have different kinds of effects. Therefore, three hypotheses were suggested: (a) NA would be positively related to aggressive tendencies; (b) the type of information would moderate the relationship between NA and aggressive tendencies, that is, the relationship would be weakest for explanatory information, stronger for technical information, and strongest for neutral information; (c) format of presentation would moderate the moderation of the type of information. Participants in the study were patients and escorts who waited in the ED in two hospitals in Israel. They were exposed to either large signs, or pamphlets, which contained explanatory, technical, or neutral information regarding the ED. All participants filled out a questionnaire which measured their NA and aggressive tendencies. Results showed that NA and aggressive tendencies were positively related. However, the type of information did not moderate this relationship. A three-way interaction was found between NA, type of information and format of presentation, where in the private condition, neutral information had a stronger effect of decreasing the relationship between NA and aggressive tendencies. Explanatory and technical information did not have such effect. The effect was not found in the public condition. The study demonstrated the link between NA and aggression in the ED. Furthermore, the study showed that the combination of neutral information and private presentation may help lessen this relationship.

THE EFFECTS OF THE TYPE OF INFORMATION AND ITS FORMAT OF PRESENTATION ON THE RELATIONSHIP BETWEEN PATIENTS’ AND ESCORTS’ NEGATIVE AFFECTIVITY AND THEIR AGGRESSIVE TENDENCIES TOWARD MEDICAL STAFF IN THE ED.

Debussy's Sonata for Flute, Viola, and Harp: An Analysis and Overview of the Flutist's Role in Chamber Music from the 18th to 20th Centuries

This paper examines the lack of awareness and feelings of personal responsibility for climate change. Previous literature suggests that while part of the United States population may be aware of climate change, they do not feel personally responsible for causing it despite feeling climate change’s effects just like everyone else. Furthermore, studies suggest that individuals also do not believe climate change will affect them now, but rather it is an issue for future generations. Using a survey, we examine which demographics and personal factors are most important in eliciting awareness for climate change, and furthermore, personal responsibility for its effects. Finally, we examine how an individual's’ beliefs regarding the effects and cause of climate change shape their sense of awareness and responsibility. Results show that for this sample, respondents take more responsibility for climate change if they believe climate change will impact them in the near future or was caused by human; respondents take less responsibility if they are “risker” or older. These results have broader implications since those who feel responsible for climate change often take more action that those who do not. Our study supports previous research, adds onto it, and leaves the groundwork to conduct choice experiments to determine willingness to pay to stop climate change.

Concepts contain rich structures that support flexible semantic cognition. These structures can be characterized by patterns of feature covariation: Certain features tend to cluster in the same items (e.g., feathers, wings, can fly). Existing computational models demonstrate how this kind of structure can be leveraged to slowly learn the distinctions between categories, on developmental timescales. However, it is not clear whether and how we leverage feature structure to quickly learn a novel category. We thus investigated how the internal structure of a new category is first extracted from experience, with the prediction that feature-based structure would have a rapid and broad influence on the learned category representation. Across three experiments, novel categories were designed with patterns of feature associations determined by carefully constructed graph structures, with Modular graphs-exhibiting strong clusters of feature covariation-compared against Random and Lattice graphs. In Experiment 1, a feature inference task using verbal stimuli revealed that Modular structure broadly facilitated category learning. Experiment 2 replicated this effect in visual categories. In Experiment 3, a statistical learning paradigm revealed that this Modular benefit relates to high-level structure rather than pairwise feature associations and persists even when category structure is incidental to the task. A neural network model was readily able to account for these effects, suggesting that correlational feature structure may be encoded within rapidly learned, distributed category representations. These findings constrain theories of category representation and link theories of category learning with structure learning more broadly. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The cognitive and neural structure of conceptual knowledge affects how concepts combine in language and thought. Examining the principles by which individual concepts (e.g., diamond, baseball) combine into more complex phrases (e.g., “baseball diamond”) can illuminate not only how the brain combines concepts but also the key ingredients of conceptual structure. Here we specifically tested the role of feature uncertainty in the modulation of conceptual brightness evoked by adjective-noun combinations (e.g., “dark diamond”) in male and female human subjects. We collected explicit ratings of conceptual brightness for 45 noun concepts and their “dark” and “light” combinations, resulting in a measure reflecting the degree of conceptual brightness modulation in each noun concept. Feature uncertainty was captured in an entropy measure, as well as in a predictive Bayesian model of feature modulation. We found that feature uncertainty (i.e., entropy) and the Bayesian model were both strong predictors of these behavioral effects. Using fMRI, we observed the neural responses evoked by the concepts and combinations in a priori ROIs. Feature uncertainty predicted univariate responses in left inferior frontal gyrus, and multivariate responses in left anterior temporal lobe were predicted by degree of conceptual brightness modulation. These findings suggest that feature uncertainty is a key ingredient of conceptual structure, and inform cognitive neuroscience theories of conceptual combination by highlighting the role of left inferior frontal gyrus and left anterior temporal lobe in the process of flexible feature modulation during comprehension of complex language. SIGNIFICANCE STATEMENT The meaning of a word depends on the words surrounding it. The challenge of understanding how flexible meaning emerges in language can be simplified by studying adjective-noun phrases. We tested whether the uncertainty of a feature (i.e., brightness) in a given noun concept (e.g., diamond) influences how the adjective and noun concepts combine. We analyzed feature uncertainty using two probabilistic measures, and found that feature uncertainty predicted people's explicit interpretations of adjective-noun phrases (e.g., “dark diamond”). Using fMRI, we found that combined concepts evoked responses in left inferior frontal gyrus and left anterior temporal lobe that related to our measures of feature modulation and uncertainty. These findings reveal the cognitive and neural processes supporting conceptual combination and complex language use.

Feature Uncertainty Predicts Behavioral and Neural Responses to Combined Concepts

Constructing complex social categories from distinct group membership information

Much has been learned about how individual concepts and semantic dimensions are represented in the human brain using methods from the field of cognitive neuroscience; however, the process of conceptual combination, in which a new concept is created from pre-existing concepts, has received far less attention. We discuss theories and findings from cognitive science and cognitive neuroscience that shed light on the processing stages and neural systems that allow humans to form new conceptual combinations. We review systematic and creative applications of cognitive neuroscience methods, including neuroimaging, neuropsychological patients, neurostimulation and behavioral studies that have yielded fascinating insights into the cognitive nature and neural underpinnings of conceptual combination. Studies have revealed important features of the cognitive processes that are central to successful conceptual combination. Furthermore, we are beginning to understand how regions of the semantic system, such as the anterior temporal lobe and angular gyrus, integrate features and concepts, and evaluate the plausibility of potential resulting combinations, bridging work in linguistics and semantic memory. Despite the relative newness of these questions for cognitive neuroscience, the investigations we review give a very strong foundation for ongoing and future work that seeks to fully understand how the human brain can flexibly integrate existing concepts to form new and never-before experienced combinations at will.

Our mental words are populated with concepts — rich representations of knowledge about things in the world (e.g., diamonds, pumpkins). In language, words are used to refer to these concepts (e.g., “diamond”, “pumpkin”) and to communicate with others. This is quite impressive given that a word does not activate the same information each time it is used: conceptual information is flexibly activated based on the context. For example, the phrases “raw diamond”, “baseball diamond”, and “diamond eyes” evoke different kinds of diamond information. This flexible concept use is not only exemplified in creative language, but in creative thought and natural language more generally. The goal of this thesis was to leverage methods in cognitive neuroscience, network science, and computational modeling to explore the kinds of conceptual structure that can support this flexible concept use. In the first study (Chapter 2) I capture the global structure of concepts in novel feature-based networks, and show that aspects of this network structure relate to text-based and empirical measures of flexible concept use. I subsequently narrow in on the local representations of conceptual features that relate to flexible concept use by observing what happens when concepts combine. In one fMRI study (Chapter 3) I show that feature uncertainty predicts the extent to which features (e.g., green, salty) are flexibly modulated in the brain during comprehension of adjective-noun combinations (e.g., “green pumpkin”, “salty cookie”). In follow-up studies (Chapter 4) I further reveal the relationship between feature uncertainty and flexible feature activations in combined concepts. In combinations that modify conceptual brightness (e.g., “dark diamond”, “light night”), an explicit behavioral measure of conceptual feature modulation is predicted by feature uncertainty as well as by a related predictive combinatorial Bayesian model. An associated fMRI study reveals that flexible feature modulation and feature uncertainty relate to responses in left inferior frontal gyrus (LIFG) and left anterior temporal lobe (LATL), suggesting roles for these regions in flexible concept activation. Taken together, this work reveals relationships between conceptual structure and flexible concept use in behavior and in the brain.

A single concept can manifest in many varied forms, depending on the context in which it is activated. That is, concepts appear to be flexible rather than static. Here we implement a compositional model of conceptual knowledge in which basic-level concepts are represented as graph theoretical networks, with the specific goal of quantifying conceptual flexibility. We collect within-concept statistics using online participants, construct network models, and validate these models in a classification analysis. We then extract network measures and find that network diversity and core-periphery structure correspond to conceptual flexibility and stability, respectively. These results suggest that a compositional network model can be used to extract formal measures that are interpretable and useful in the study of conceptual knowledge.

Quantifying Conceptual Flexibility in a Compositional Network Model

A meta-analysis of fMRI decoding: Quantifying influences on human visual population codes

Abstract Successful language comprehension requires one to correctly match symbols in an utterance to referents in the world, but the rampant ambiguity present in that mapping poses a challenge. Sometimes the ambiguity lies in which of two (or more) types of things in the world are under discussion (i.e., lexical ambiguity); however, even a word with a single sense can have an ambiguous referent. This ambiguity occurs when an object can exist in multiple states. Here, we consider two cases in which the presence of multiple object states may render a single-sense word ambiguous. In the first case, one must disambiguate between two states of a single object token in a short discourse. In the second case, the discourse establishes two different tokens of the object category. Both cases involve multiple object states: These states are mutually exclusive in the first case, whereas in the second case, these states can logically exist at the same time. We use fMRI to contrast same-token and different-token discourses, using responses in left posterior ventrolateral prefrontal cortex (pVLPFC) as an indicator of conflict. Because the left pVLPFC is sensitive to competition between multiple, incompatible representations, we predicted that state ambiguity should engender conflict only when those states are mutually exclusive. Indeed, we find evidence of conflict in same-token, but not different-token, discourses. Our data support a theory of left pVLPFC function in which general conflict resolution mechanisms are engaged to select between multiple incompatible representations that arise in many kinds of ambiguity present in language.

Competition between Mutually Exclusive Object States in Event Comprehension

Understanding events often requires recognizing unique stimuli as alternative, mutually exclusive states of the same persisting object. Using fMRI, we examined the neural mechanisms underlying the representation of object states and object-state changes. We found that subjective ratings of visual dissimilarity between a depicted object and an unseen alternative state of that object predicted the corresponding multivoxel pattern dissimilarity in early visual cortex during an imagery task, while late visual cortex patterns tracked dissimilarity among distinct objects. Early visual cortex pattern dissimilarity for object states in turn predicted the level of activation in an area of left posterior ventrolateral prefrontal cortex (pVLPFC) most responsive to conflict in a separate Stroop color-word interference task, and an area of left ventral posterior parietal cortex (vPPC) implicated in the relational binding of semantic features. We suggest that when visualizing object states, representational content instantiated across early and late visual cortex is modulated by processes in left pVLPFC and left vPPC that support selection and binding, and ultimately event comprehension.

The current study aimed to contribute to research in the areas of Sex-Role Identity (SRI) and Work-Family Conflict (WFC), as no research to date has examined how socially desirable and socially undesirable SRI‟s effect this inter-role conflict. The EPAQ-R was used to examine a differentiated model of SRI and Carlson et al.‟s WFC scale measured the bidirectional nature of WFC. This study made use of a cross-sectional, exploratory research design with 268 working mothers participating in this research. Under the COR framework and social constructionist theory, this study demonstrated that sex-role personality traits serve as resources that influence individual experiences of WFC. Results from a series of one and two-way ANOVA‟s indicated that socially desirable SRI‟s were associated with lower WFC than their undesirable counterparts. The results from this study provide support for the differentiated model of SRI. The practical and theoretical implications of this research are presented in this study.

Sex-role identity and work-family conflict in South African working mothers.

It is a sad reflection upon the field of heroin use disorder intervention that practices and procedures for the treatment of such disorders can be introduced and applied without (or even contrary to) evidence. In South Africa, the field of heroin use disorder intervention has been 'in transition' since the outbreak of the heroin epidemic. Yet, despite growing evidence of an association between heroin dependents' use of supplementary intervention services and intervention outcomes, heroin use disorder intervention programmes in South Africa generally fail to meet international research-based intervention standards. This study delved into the insights of 10 heroin use disorder specialists and synthesised the findings with the results of a previous study (Dos Santos and Van Staden, 2008; Dos Santos, 2009) relating to 40 long-term voluntarily abstinent heroin dependents. In terms of theory and practice, the findings of the study suggest that the field is less in transition now than it was in 1995. It is imperative that law-enforcement action be followed by an integrated programme of psychological, social, and pharmacological outreach. These programmes will have to be expanded to address new demands and will need to include specialised skills training. Many interventions and procedures have begun to be integrated routinely into clinical practice.

heroin use disorder intervention within the South African context

Immunotherapy has changed the therapeutic landscape in oncology. Advanced uterine leiomyosarcoma (ULMS) remains an incurable disease in most cases, and despite new drug approvals, improvements in overall survival have been modest at best. The goal of this study was to evaluate programmed‐death 1 (PD‐1) inhibition with nivolumab in this patient population.

Immunotherapy with single agent nivolumab for advanced leiomyosarcoma of the uterus: Results of a phase 2 study

11513Background: Most patients with mGIST initially benefit from IM therapy with durable disease control (DC), i.e. objective responses and stable disease, with median duration of approximately two...

Whole exome analysis of patients (pts) with metastatic GIST (mGIST) demonstrating exceptional survival with imatinib (IM) therapy compared to those with short term benefit.

11007Background: Immune checkpoint inhibition (ICI) with monoclonal antibodies such as nivolumab has induced dramatic results in several types of cancers, although sarcoma subtypes have not been ex...

Phase 2 study of nivolumab in metastatic leiomyosarcoma of the uterus.

This investigator-initiated trial provided the justification for the phase III GRID study resulting in worldwide regulatory approval of regorafenib as a third-line therapy for patients with metastatic gastrointestinal stromal tumors (GIST). We report the genotype analyses, long-term safety, and activity results from this initial trial of regorafenib in GIST.

The trial was conducted between February 2010 and January 2014, among adult patients with metastatic GIST, after failure of at least imatinib and sunitinib. Patients received regorafenib orally, 160 mg once daily, days 1-21 of a 28-day cycle. Clinical benefit rate (CBR), defined as complete or partial response (PR), or stable disease lasting ≥16 weeks per RECIST 1.1, progression-free survival (PFS), overall survival (OS), long-term safety data, and metabolic response by functional imaging were assessed.

RESULTS
Thirty-three patients received at least one dose of regorafenib. The median follow-up was 41 months. CBR was documented in 25 of 33 patients [76%; 95% confidence interval (CI) 58% to 89%], including six PRs. The median PFS was 13.2 months (95% CI 9.2-18.3 months) including four patients who remained progression-free at study closure, each achieving clinical benefit for more than 3 years (range 36.8-43.5 months). The median OS was 25 months (95% CI 13.2-39.1 months). Patients whose tumors harbored a KIT exon 11 mutation demonstrated the longest median PFS (13.4 months), whereas patients with KIT/PDGFRA wild-type, non-SDH-deficient tumors experienced a median 1.6 months PFS (P < 0.0001). Long-term safety profile is consistent with previous reports; hand-foot skin reaction and hypertension were the most common reasons for dose reduction. Notably, regorafenib induced objective responses and durable benefit in SDH-deficient GIST.

Long-term follow-up of patients with metastatic GIST treated with regorafenib suggests particular benefit among patients with primary KIT exon 11 mutations and those with SDH-deficient GIST. Dose modifications are frequently required to manage treatment-related toxicities.

CLINICAL TRIAL NUMBER
NCT01068769.

Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy.

10511 Background: Regorafenib (REGO) is a broad spectrum tyrosine kinase inhibitor with activity against KIT, PDGFR, VEGFR, and FGFR. Phase II and III trials demonstrated significant activity in patients (pts) with advanced GIST following failure of at least imatinib and sunitinib. Pts have continued on the Phase II trial, and we now report longer-term follow-up as related to primary and secondary tumor genotype (KIT, PDGFRA) and SDH expression. Methods: This multicenter Phase II study of RE in GIST enrolled 33 pts with metastatic GIST. REGO was started at a dose of 160mg per day, d1-21 of each 28d cycle. Anatomic restaging was performed every 2 cycles. Clinical benefit rate (CBR) was defined as CR, PR or prolonged SD (>16 wks) per RECIST 1.1. KIT genotype was determined for tumors with adequate tissue available. SDHB staining was performed on a subset of patients whose tumors lacked activating mutations in KIT or PDGFRA. Response, progression free survival (PFS), and overall survival (OS) were determined...

Prolonged survival and disease control in the academic phase II trial of regorafenib in GIST: Response based on genotype.

PURPOSE
Metastatic GI stromal tumor (GIST) is a life-threatening disease with no therapy of proven efficacy after failure of imatinib and sunitinib. Regorafenib is a structurally unique inhibitor of multiple cancer-associated kinases, including KIT and platelet-derived growth factor receptor (PDGFR), with broad-spectrum anticancer activity in preclinical and early-phase trials. Because KIT and PDGFR-α remain drivers of GIST after resistance to imatinib and sunitinib, we performed a multicenter single-stage phase II trial of regorafenib in patients with advanced GIST after failure of at least imatinib and sunitinib.

Patients received regorafenib orally, 160 mg daily, on days 1 to 21 of a 28-day cycle. Disease assessment was performed every two cycles per RECIST 1.1. Primary end point was clinical benefit rate (CBR), defined as objective responses (ie, complete or partial response [PR] as well as stable disease [SD] ≥ 16 weeks). Serial tumor biopsies were obtained from consenting patients whenever possible.

RESULTS
From February to December 2010, 34 patients were enrolled at four US centers. As of July 28, 2011, 33 patients had received at least two cycles of regorafenib (range, two to 17 cycles). CBR was 79% (95% CI, 61% to 91%). Four patients achieved PR, and 22 exhibited SD ≥ 16 weeks. Median progression-free survival was 10.0 months. The most common grade 3 toxicities were hypertension and hand-foot-skin reaction.

Regorafenib has significant activity in patients with advanced GIST after failure of both imatinib and sunitinib. A phase III trial of regorafenib versus placebo is ongoing to define more fully the safety and efficacy of regorafenib in this setting.

Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial.

10007 Background: Resistance remains a challenge in GIST after the failure of IM and SU. Regorafenib, a novel oral kinase inhibitor, blocks VEGFR2-3, c-KIT, TIE2, PDGFR beta, FGFR1, RET, RAF and p38 MAPK and has a broad spectrum of antitumor activity in preclinical and early phase trials. We conducted an investigator initiated, multi-center phase II trial of regorafenib in patients with advanced GIST after prior therapy with at least IM and SU.

METHODS
Eligible pts received regorafenib 160mg/day orally d1-21 of each 28d cycle. Pts were assessed for response by RECIST 1.1 every 2 cycles. Primary endpoint was clinical benefit rate (CBR) defined as CR, PR, and SD > 16 weeks. Tumor genotyping and optional pre and d15 tumor biopsies were performed.

RESULTS
34 pts were enrolled from Feb 2010 - Dec 2010. 33 pts received at least one dose of study drug. Median age was 54 yrs, median number of prior therapies = 3. As of Dec 1, 2010, 121 cycles of regorafenib have been administered (range 1 - 11). 19 pts required at least one dose reduction due to toxicity. Most common grade 3 treatment emergent toxicities were hypertension, hand-foot skin reaction, and hypophosphatemia, (29%, 25% and 14% of pts respectively). There were two grade 4 events, one hyperuricemia and one thrombosis. As of Dec 30, 2010, 22 eligible pts had been on protocol for at least 16 wks. 12 had restaging scans after 16 wks showing sustained clinical benefit (2 PR, 10 SD) CBR 54.5% (90% CI, 35.3% - 72.9%). 1 pt progressed at 7 wks. 2 pts withdrew prior to 16 wks. The remaining 7 pts demonstrated stable disease at a range of 14.9 - 15.6 wks. Therefore, 19 of 22 pts were without disease progression after 4 cycles of study drug dosing. Benefit was seen in pts whose tumors had primary KIT exon 11 mutations, KIT exon 9 mutations or wildtype kinase genotype. Immunoblotting of pre-study and day15 matched biopsies demonstrated ~50% inhibition of KIT and AKT phosphorylation, in 3 of 4 patients, all with SD for at least 4 cycles.

Regorafenib has significant activity in pts with advanced GIST previously treated with IM and SU. An international phase III trial is currently underway in pts with advanced GIST following treatment with IM and SU.

A multicenter phase II study of regorafenib in patients (pts) with advanced gastrointestinal stromal tumor (GIST), after therapy with imatinib (IM) and sunitinib (SU).

Brown trout (Salmo trutta) broodstock from a single population were separated prior to spawning and exposed to two different holding environments: a ‘raceway system’ and a ‘tank system’. Eggs were stripped from females and 13 measures of egg quality were collected, analysed individually, combined by principle components analysis into an integrated egg quality score which was validated against egg survival. The multivariate egg quality score (PC1) differed for fish held in the tank and raceway systems. Egg survival, chorion breaking strength and chorion Se concentrations were higher in eggs produced by broodstock held in the tank system compared to those in the raceway system. In contrast, chorion concentrations of P and K were higher in eggs from fish held in the raceway system. The results suggest that brown trout broodstock reared in tank systems produced higher quality eggs compared to trout reared in raceways. Finally, this study also indicates that multivariate statistical analysis can be used to determine egg quality from multiple egg parameters.

Effect of broodstock holding environment on egg quality in farmed brown trout (Salmo trutta)

If ‘the aim of biomineralisation is stability’, then with reference to the hen’s egg such stability is essential if the calcified package, constructed over a period of 20 hours, is to meet the demands of the developing embryo or withstand the rigours of selection, packaging and travel en route to the table. The pattern of mineralisation in which calcite, the most stable polymorph of calcium carbonate precipitates in an a-cellular milieu regulated by a variety of protein profiles, follows a specific design. The morphology of each of the six layers which comprise the ‘true’ shell is quite distinct but in terms of shell strength they are interdependent. Of these perhaps the mammillary (basal) layer plays the most crucial role insofar as its morphology is easily altered by a range of internal and external variables including disease and bird age.

The Influence of Organically Bound Minerals on the Process of Shell Construction

1. An experiment was designed to determine whether the inclusion of sodium selenite, Sel-Plex or Sel-plex + Bioplex in the diet exerted any influence on structural and functional properties of the eggshell at 22, 38, 58 and 72 weeks age. 2. Significant age effects were demonstrated for egg weight, dynamic stiffness and total shell thickness. 3. The eggshells from birds fed on the Sel-Plex + Bioplex treatment were statistically stronger than those produced by the birds on sodium selenite. 4. From mid-lay onwards the shells laid by birds fed on the Sel-Plex + Bioplex treatment displayed, at ultrastructural level, the crystal modification termed ‘confluence’ together with early fusion of the palisade columns which comprised the bulk of the shell. 5. At all periods of lay the shells of birds fed on sodium selenite, Sel-Plex and the control diet demonstrated the presence of a variety of crystalline aggregates localised between the forming palisade columns.

Structural and physical changes in the hen's eggshell in response to the inclusion of dietary organic minerals

In making a journey through the literature of the last 50 years one can easily highlight a sequence of seminal works–but the route has not been direct and to avoid the many profitable diversions and detours that have enriched and deepened our collective understanding of the subject of eggshell structure and function is to do the subject a serious disservice. This is a route march of science enabled by advances in technology.

Trace minerals in poultry nutrition - 5. Reaching optimal egg shell formation.

Scanning microfocus small angle X-ray scattering study of the avian eggshell

Reptilian lungs range in complexity from simple sac-like structures, as in the tegu lizard Tupinambis nigropunctatus (Klemm, Gatz, Westfall & Fedde, 1979), to multicameral lungs, as in varanid lizards (Perry & Duncker, 1978) and in the freshwater turtle Pseudemys scripta (Perry, 1978), so that it is not possible to define a simple model of the reptilian lung. The green turtle (Chelonia mydas) spends much of its life at sea, diving to considerable depths and often staying there for hours at a time. It can tolerate complete anoxia, if necessary for days at a time; provides, by means of vascular shunts, for the redistribution of blood away from the lungs during submersion; and even under normal conditions exhibits the periodic breathing pattern characteristic of many reptiles (Glass & Wood, 1983). It is to be expected, therefore, that the physiological stresses imposed upon the respiratory apparatus in the green turtle by its aquatic existence would be reflected in the structure of its lungs. This study attempts to assess lung structure in the green turtle in relation to other reptiles, and to identify and discuss those morphological adaptations related to its mode of existence.

An aquatic environment imposes a variety of strains on the internal economy of the body in terms of salt balance and so many reptiles and birds have evolved extrarenal mechanisms in the form of the lacrimal glands to dispose of excess concentrations of sodium and potassium (Bellairs, 1969). In all these species, however, the kidney still functions in the elimination of waste products and the maintenance of homeostasis by regulating the composition of the blood and body fluids. In recent years, only the proximal and distal tubules of the turtle nephron have received critical attention (Ericsson & Trump, 1969) and so this study set out in the first instance to identify the general features of the normal nephron using light, scanning and transmission microscopy. In addition to this general objective, particular attention has been paid to the lateral and basal modification ofthe tubular cell walls since Davis & Schmidt-Nielsen (1967), working with the crocodile kidney, have provided evidence to suggest that the formation of wide intracellular channels in the tubular cells facilitates the establishment of an osmotic gradient across the tubule wall.

1. This study set out to investigate if access to an enriched environment during the rearing phase influences subsequent production and eggshell quality in broiler breeders. 2. Broiler breeder pullets were reared under standard rearing conditions (control treatment) or under standard conditions with an environmental enrichment of bales of plastic-wrapped wood shavings (enriched treatment). At 19 weeks of age both groups were transported to a laying facility and housed in standard pens according to treatment type. 3. Egg weight, shape, shell thickness, non-destructive deformation, breaking strength, stiffness and ultrastructural quality were compared at beginning of lay (25 weeks old), peak production (31 weeks old), mid-lay (45 weeks old) and end of lay (57 weeks old). Production and hatchery data were also collected throughout lay. 4. Significant treatment–age interactions were detected for non-destructive deformation, breaking strength and stiffness, such that birds which had received prior enrichment went on to maintain a better shell quality with age. The measurements of total shell thickness, mammillary thickness and effective shell thickness all showed a trend for a treatment–age interaction. 5. Significant age effects were found for weight, shape index, shell thickness, breaking strength and stiffness. All production and hatchery data also demonstrated significant changes with age. 6. It is concluded that early enrichment with bales of wood shavings may provide a novel approach to the maintenance of eggshell quality at a time when calcium metabolism begins to reduce in efficiency.

Effect of environmental enrichment during the rearing phase on subsequent eggshell quality in broiler breeders

The aim of this study was to assess the extent to which three non-invasive measures of welfare in laying hens (egg-shell quality, corticosteroid levels as measured from the birds' faeces, and behavioural preferences) were correlated over a period of five days in two groups of birds. One group had access to an enriched test area (bark chips on the floor and a tray of sprouted wheat); the other group had access to a comparably sized barren area (bare wire mesh floor). The measure of preference used was the amount of time hens spent in the test area as measured each day. It was predicted that birds with access to the less preferred environment would show higher levels of faecal corticosteroids and egg-shell anomalies. However, although the birds showed a preference for the enriched environment from Day 1, the other two measures did not follow the same pattern. Faecal corticosteroid metabolites showed an initial increase in both groups, which declined significantly by Day 4, with the ‘enriched’ birds in fact showing a trend for higher levels than the ‘barren’ birds. Shell thickness also showed a change over the five days, but with a different time course: declining to a minimal level on Day 3 and then rising again by Day 5. No measure of shell quality was significantly different between the two environments, but there was a trend for changes in shell thickness to be more pronounced in eggs from enriched birds. The results indicate the caution that needs to be exercised in using shell quality or corticosteroid measurements in isolation from assessments of what the animals themselves prefer.

Time course of changes in egg-shell quality, faecal corticosteroids and behaviour as welfare measures in laying hens

The development of the respiratory tract of chicks between the age of I5-day-old embryos until 3-day-old chicks was carried out using scanning electron microscopy (SEM). The distribution of ciliated and microvillous cells was investigated, and given a score of 1 to 4 throughout the entire surface of the respiratory tract which include the middle nasal concha, larynx, cranial trachea, caudal trachea, intrapulmonary primary bronchus and secondary bronchus. The surface morphology of the intrapulmonary primary bronchus and secondary bronchus attained a mature densely ciliated epithelium as early as in the I5-day-old embryos. However, in the I9-to 20-day-old embryos, this was only found in the epithelium of the middle nasal concha, larynx, cranial and caudal trachea.

Surface morphology of the developing respiratory epithelium of chicks

The eggshell is a highly ordered structure resulting from the deposition of calcium carbonate and an organic matrix from the acellular uterine fluid. Characterization of the individual matrix components is necessary to determine their influence upon calcite crystal shape, size, and orientation during eggshell calcification. We have purified and sequenced a novel 32-kDa protein, ovocalyxin-32 (OCX-32), which is present at high levels in the uterine fluid during the terminal phase of eggshell formation, and is localized predominantly in the outer eggshell. Database searches identified expressed sequence tags (ESTs) whose alignment yielded the complete cDNA. OCX-32 protein possesses limited identity (32%) to two unrelated proteins: latexin, a carboxypeptidase inhibitor expressed in rat cerebral cortex and mast cells, and to a skin protein that is encoded by a retinoic acid receptor-responsive gene, TIG1. The timing of OCX-32 secretion into the uterine fluid suggests that it may play a role in the termination of mineral deposition.

Purification of Ovocalyxin-32, a Novel Chicken Eggshell Matrix Protein

The unilateral avian oviduct is divisible into five functional regions which, moving distally, include the infundibulum, magnum, isthmus, tubular shell gland and shell gland pouch. Each region subserves a variety of functions, which through their interaction give rise to the multilayered albumen, shell membranes and the organic/inorganic complex, which comprises the shell. The sequential activity of these structurally diverse regions is a necessary prerequisite for “normal” egg formation. The reproductive effort can be influenced by a number of disease processes either directly by virtue of the fact that they alter the ability of the lining cells to synthesise their integral components or indirect by generally compromising bird health. Notable amongst the former are Infectious Bronchitis, Newcastle Disease and Egg Drop Syndrome. All change the quality of the final product in terms of the shape and texture of the shell. In recent years it has become evident that environmental stress has an equally, if not more, important role to play in oviduct disfunction. In the absence of large areas of functional surface epithelium, the eggs laid were structurally defective at all levels from the mammillary layer outwards. As the epithelial layers regenerated, shell quality approximated normality, but never returned to the pre-stress condition. The process of candling signals amongst other internal defects a variety of inclusions variously classified as blood and meat spots. They are quite specific in their locations; thus blood spots originating from the rupture of ovarian blood vessels at ovulation, are invariably confined to the periphery of the yolk mass, while meat spots now classified according to their composition are confined to albumen. Within the latter they are recognised as tissue rich deposits, the result of oviduct breakdown and/or calcium rich fragments. The latter implies a breach in the barrier provided by the soft shell membranes.

Comparison of invasive and non-invasive measures of fear in commercial and traditional lines of chicken

A comparison of eggshell quality in traditional and commercial lines of chicken immediately after the onset of lay

Effect of growth rate and body weight on bone quality in the broiler chicken

The eggshell is a highly ordered structure resulting from the deposition of calcium carbonate concomitantly with an organic matrix upon the eggshell membranes. Mineralization takes place in an acellular uterine fluid, which contains the ionic and matrix precursors of the eggshell. We have identified a novel 32-kDa protein, ovocalyxin-32, which is expressed at high levels in the uterine and isthmus regions of the oviduct, and concentrated in the eggshell. Sequencing of peptides derived from the purified protein allowed expressed sequence tag sequences to be identified that were assembled to yield a full-length composite sequence whose conceptual translation product contained the complete amino acid sequence of ovocalyxin-32. Data base searches revealed that ovocalyxin-32 has limited identity (32%) to two unrelated proteins: latexin, a carboxypeptidase inhibitor expressed in the rat cerebral cortex and mast cells, and a skin protein, which is encoded by a retinoic acid receptor-responsive gene, TIG1. High level expression of ovocalyxin-32 was limited to the isthmus and uterus tissue, where immunocytochemistry at the light and electron microscope levels demonstrated that ovocalyxin-32 is secreted by surface epithelial cells. In the eggshell, ovocalyxin-32 localizes to the outer palisade layer, the vertical crystal layer, and the cuticle of the eggshell, in agreement with its demonstration by Western blotting at high levels in the uterine fluid during the termination phase of eggshell formation. Ovocalyxin-32 is therefore identified as a novel protein synthesized in the distal oviduct where hen eggshell formation occurs.

1. This study ascertained how bone of modern meat-type chickens develops under typical commercial conditions and compares development with that in genetic precursor stock. 2. A modern fast-growing selected strain and a slower-growing control strain were used. Birds were weighed weekly. A random sample was taken from each population at a range of ages up to 39 d. 3. A tibiotarsus from each bird was X-rayed and its dimensions and estimated resistance to bending were determined. Cortical bone samples were ashed to measure total mineral, calcium and phosphorus content. Cortical samples were also taken for porosity assessment. 4. As expected, the selected strain grew faster and heavier than the control strain. Despite this, both strains demonstrated similar periods of rapid bone formation (days 4 to 18) and mineralisation (days 4 to 11), and achieved similar estimates of resistance to bending. 5. However, cortical bone of the selected strain was less well mineralised and more porous than that of the control strain and showed a significant increase in the molar Ca:P ratios above the expected range of values during the first 2 to 3 weeks of life. 6. Despite production of bones with the correct dimensions for load support, the relatively poor density and mineral content of bone in the selected strain is likely to reduce effective breaking strength of the tibiotarsus. Possible reasons may be either inadequate dietary supply of Ca and P or impaired utilisation of the minerals due to a rapid growth rate or genetic factors.

The responses of skeletal health and blood calcium (Ca) and phosphorus (P) status to different dietary calcium and available P (avP) contents were examined in 2-week-old chickens. High avP content resulted in more inorganic P (P(i)) and less ionised Ca (Ca(2+)) in the blood. Birds on low Ca and high avP diets showed a higher incidence of tibial dyschondroplasia and hypocalcaemic rickets and were therefore assumed to be hypocalcaemic. However the molar Ca:P ratio in bone was closer to the expected 1.67:1 in diets high in avP. No significant dietary mineral content effect was found on bone mineral content, or breaking strength, within the range of diets used. Results suggest that variations in molar Ca:P ratios in bone have little effect on mechanical competence, and that diets for this strain should be higher in Ca, and could be lower in avP, than current recommendations.

Dietary effects on bone quality and turnover, and Ca and P metabolism in chickens.

1. The avian eggshell is a biomineralised composite ceramic consisting of calcium carbonate embedded in an organic matrix. Matrix components are supposed to be involved in the control of mineralisation, crystallographic texture and biomechanical properties of eggshell. 2. The structure and eggshell matrix composition of various domesticated bird species were compared to gain insight into the universality of the eggshell mineralisation process. 3. The SDS-PAGE profiles of soluble eggshell matrix were specific within groups of birds (a: laying hen, breeder hen, quail, pheasant and possibly turkey; b: guinea fowl; c: duck and goose) but some of the protein bands were common to all groups. 4. Analogies between species were confirmed by Western blotting using hen protein antibodies. Ovocleidin-17 (OC-17) and ovalbumin were revealed in all species (except quail for OC-17). Lysozyme was present only in hen eggshell. Another egg white protein: ovotransferrin showed a positive signal in hens, turkey and quail. Osteopontin was observed in laying and breeder hens and quail. 5. Different proteoglycans were localised to discrete regions within the eggshell. Dermatan sulphate was observed within the matrix of the calcified shell of all species except quail which contained chondroitin-6-sulfate. Keratan sulphate was observed in mammillary bodies of breeder and laying hen, quail, pheasant and turkey while chondroitin sulphate was also present in guinea fowl and duck. 6. The general structural organisation of the different avian eggshells was similar but specific differences were observed in the ultrastructure of the mammillary layer. Species of the same taxonomic family could be grouped according to their structural analogies: breeder hen, turkey and pheasant resembled that of the domestic fowl. Guinea fowl was unique. Goose and duck were quite similar with large and confluent mammillary bodies. 7. Some matrix components are therefore common to eggshells of various species but more information is needed to relate differences in matrix composition between taxonomic groups with differences in ultrastructure.

Organic matrix composition and ultrastructure of eggshell: a comparative study.

Material properties, ultrastructural integrity and protein chemistry of broiler breeder eggshells.

Application of current ultrastructural eggshell quality assessment in captive breeding programmes: observations on hatched and unhatched eggs of the Saker falcon (Falco cherrug).

Eggshell proteins and shell strength: molecular biology of eggshell matrix proteins and industry applications.

1. Eggshell pieces (1 cm2) were decalcified using a solution of EDTA (200 g/litre, pH 6.9 to 7.0) in paraformaldehyde (2 g/litre) and glutaraldehyde (0.5 g/litre) in phosphate buffer. 2. They were prepared for transmission electron microscopy (TEM). 3. TEM identified a vertically aligned matrix associated with the vertical crystal layer (VCL). It is hypothesised that the vertical orientation of calcite crystals in the VCL is closely linked to this vertical matrix. 4. TEM also revealed the presence of a 2-layered cuticle, the inner layer containing vesicles which were absent in the outer. 5. Cuticular vesicles contain hydroxyapatite and are thought to play a role in the termination of shell formation. The current paper presents data relating to microbial apatitic systems that strengthen this hypothesis.

Transmission electron microscopy of the vertical crystal layer and cuticle of the eggshell of the domestic fowl.

1. 1 cm2 pieces of eggshells from a commercial battery flock were plasma etched to remove the outer shell membranes. 2. They were decalcified using EDTA (200 g/l, pH 6.9 to 7.0) in paraformaldehyde (20 g/l) and 25% gluteraldehyde (20 ml in 0.98 l) in phosphate buffer, then prepared for light and transmission electron microscopy. 3. Light microscopy revealed a differential distribution of matrix material within all 3 regions of the palisade layer at the beginning of lay. 4. Transmission electron microscopy revealed a more even distribution of matrix at the beginning of lay, although morphological differences were observed. At the end of lay all 3 regions showed an increase in % matrix and vesicles/10 cm2 of micrograph compared to the middle and beginning of lay periods. 5. It is hypothesised that matrix vesicles are involved in the regulation of the physiochemical environment within the forming eggshell and that the decline in shell quality associated with the end of lay is related to a concomitant change in matrix quality.

Organic matrix morphology and distribution in the palisade layer of eggshells sampled at selected periods during lay.

Abstract A survey of the levels of marine turtle bycatch in the small-boat based fisheries in northern Cyprus and the Turkish Mediterranean (Alanya to Mersin) was undertaken by questioning a sample of fishermen (n = 54) in all harbours in the survey region. Fishermen in Turkey caught an estimated 2.5 turtles/boat/year versus an estimated 4.0 turtles/boat/year in Cyprus. This yielded a likely minimum bycatch estimate of over 2,000 marine turtles per year in the region. An estimated 10% of turtles were thought to be dead at the point of capture. Turtles were caught in both nets and on long-lines and were perceived as detrimental to the livelihood of fishermen either by damaging nets, spoiling catch or removing bait. Although few fishermen admitted to deliberately killing turtles, a larger proportion thought others did so. Given the likelihood that a proportion of sea turtles caught will be Green Turtles (Chelonia mydas), and due to the highly endangered status of this species in this region, interaction wit...

Interaction between marine turtles and artisanal fisheries in the eastern Mediterranean: a probable cause for concern?

Observations on pigmentation, hatchability and ultrastructure in guinea fowl eggshells.

Bisphosphonates: a potential role in the prevention of osteoporosis in laying hens.

The ovary and the oviduct the egg contents the pattern of mineralization structural variations in the mammillary layer surface defects physiochemical changes in oviductal architecture translucency eggshell colour a reinterpretation of eggshell strength, Maureen M.Bain.

1. Hatching chicks were exposed to 10.9 ppm of formaldehyde vapour during the last 3 d of incubation in a commercial situation. 2. Samples from pre-selected regions of the entire respiratory tract, taken at 0, 6, 30 and 54 h post-vaporisation of formaldehyde, were examined by scanning electron microscopy for surface morphological features and associated pathological changes. 3. Clumping of cilia, blebs on the cilial wall, deciliation and exfoliation of the epithelium were all observed under the scanning electron microscope. 4. Lesions were more severe in chicks exposed for 54 h as compared to those exposed for 6 and 30 h. There were no regional differences in the lesions throughout the respiratory tract of all the chicks. 5. Limited observations suggest that the passage of formaldehyde vapour across the egg shell wall may influence the morphology of the respiratory lining of the developing embryo.

Scanning electron microscopy of the respiratory epithelium of chicks fumigated with formaldehyde vapour.

1. Extra and intramineral eggshell matrix proteins were solubilised before and after demineralisation by sequential extractions using guanidine hydrochloride and EDTA. 2. The intramineral electrophoretic profile of SDS-PAGE showed the presence of 80, 66, 43, 36 and 15 kDa bands with a predominance of a 17 kDa band. In the extramineral part, the major protein was the 15 kDa band. 3. The introduction of intramineral extract to a metastable solution of calcium carbonate delayed the rate of crystal growth. The delay in the rate of precipitation was elicited by a single fraction (MW 50-80 kDa), isolated by gel filtration chromatography, of eggshell extracts. Extramineral extracts had no effect. 4. Addition in vitro of intramineral eggshell extracts modified the morphology of calcite; the crystals aggregated and showed irregular surfaces. 5. These observations suggest that constituents of the eggshell matrix are involved in the control of calcite growth and crytallographic structure of the hen's eggshell.

Soluble matrix of hen's eggshell extracts changes in vitro the rate of calcium carbonate precipitation and crystal morphology.

Bisphosphonates, used in the prevention and treatment of osteoporosis, in man, can prevent bone loss in experimental models of osteoporosis in mammals. In egg-laying hens there is a high incidence of bone fractures which are due to osteoporosis. Alendronate, a bisphosphonate, was given to three groups of hens in mid-lay. Different doses of alendronate were given to each group and group 4 was a control. The birds were killed after 2 weeks of treatment. The hens receiving the highest dosage of alendronate (1 mg/kg every 2nd day) ceased laying and had reduced serum calcium concentrations. Lower dosages of alendronate (0.1 and 0.01 mg/kg every 2nd day) resulted in normal egg production and serum calcium concentrations. Egg shells with ultra-structural features indicative of reduced shell quality were produced by hens on the two higher dosages, but the egg shells from the controls and from the hens on the lowest dosage were considered normal. When alendronate was administered to hens in mid-lay there was no effect on trabecular bone volumes, but there was a reduction in mean medullary bone volume in some groups. In a second experiment, pullets were treated with alendronate (0.01 mg/kg twice a week) before the onset of lay. The pullets were killed after laying their first egg. In the pullets treated with alendronate, this protocol resulted in a significantly greater volume of trabecular (structural) bone at the onset of lay.

The effect of a bisphosphonate on bone volume and eggshell structure in the hen.

1. Ultrastructural analyses of the eggshells of one strain of commercial layers indicated that the cuticular layer is rarely present as an even covering over the shell surface and the paired shell membranes are invariably pitted with holes larger than bacterial dimensions. 2. The above conditions pertain irrespective of the age of the laying bird. 3. Bacterial penetration of the eggshell is independent of pore numbers. 4. In the absence of a functional cuticle and with the shell membranes removed, bacteria are checked in their movement by structural modifications in the mammillary layer.

Relationship between shell structure and movement of Salmonella enteritidis across the eggshell wall.

The structure of the eggshell of the leatherback turtle, Dermocheleys coriacea. conforms generally to that described for contemporary chelonians (Hirsch 1983;' Solomon and Watt 1985;8 Solomon and Tippett 198?9). It is composed of an inner organic membrane and an outer inorganic or mineral layer of calcium carbonate deposited as aragonite. The latter occurs on the organic membrane in discrete units composed of spicules radiating from a central core. In addition to the aragonite crystals, the calcium carbonate can also be deposited as calcite which may assume a variety of shapes variously described as 'blocks, tabular crystals. or flattened lozengeshaped crystals occurring either singly or stacked' (Solomon and Watt 1985).8 The latter also reported the absence of an external cuticular layer which is known to be organic in nature and present in other chelonian eggshells (Hirsch 1983;4 Packard et al. 19845). Phosphorus, present in the eggshells of other sea turtles was not detected in leatherback eggshells (Solomon and Watt 1985).8 
 In view of the above differences. a further study was conducted" on leatherback eggshells from a different locale-Rantau Abang, Malaysia.

The structure and function of the eggshell of the leatherback turtle (dermoclzelys coriacea) from Malaysia, with notes on attached fungal forms

1. Adrenaline (1 mg in 1 ml water) was administered subcutaneously to three hens to determine whether any changes in the shell ultrastructure of subsequent eggs would occur. 2. The egg shells were examined in a scanning electron microscope after plasma etching. 3. The first three eggs laid by each bird after adrenaline injection were compared with previously-collected normal eggs from the same birds and also with control eggs collected over the same period from three hens which had received no adrenaline. 4. The first egg laid following adrenaline treatment was essentially normal but both the second and third eggs showed severe structural disorganisation at all levels, from the mamillary caps up to the cuticular layer. 5. Eggs laid 20 d or more after adrenaline treatment had reverted to normal. 6. The findings suggest that the abnormal eggs laid after hens have been exposed to disturbance or stress are likely to be affected in not only their external appearance but also to be of poor structural quality.

Effect of a single injection of adrenaline on shell ultrastructure in a series of eggs from domestic hens.

Consistent with their primary function as a protective covering, the carapace and plastron are heavily keratinised. In both species, the carapace is heavily pigmented and during the development and translocation of basal cells from the germinal layer of the epidermis, pigment granules migrate towards the surface layers. The epidermis is generally 2-4 cells thick; however at the growing points it can attain 6 cell layers. The epidermis is much thicker over the plastron of the loggerhead turtle. The ultrastructure of the epidermal cells supports the observation that the keratin scales are of the hard variety and the microfolds which characterise the scutes covering the carapace are discussed in relation to the lowering of frictional drag in water.

The structure of the carapace and plastron of juvenile turtles, Chelonia mydas (the green turtle) and Caretta caretta (the loggerhead turtle).

The kidneys of the green turtle are flattened, lobed and closely applied to the posterior wall of the pleuroperitoneal cavity. The ability to differentiate new functional nephrons is retained by five years old animals. The functional nephron comprises a glomerulus, proximal tubule, intermediate segment which can be subdivided into a proximal non-secretory segment and a distal mucus secreting segment, distal convoluted tubule and collecting tubule. Both the proximal and distal tubules exhibit complex foldings on their lateral cell walls in contradistinction to the characteristic basal infoldings observed in mammalian tubules.

The morphology of the kidney of the green turtle (Chelonia mydas L.).

The chelonian lung exhibits reptilian, mammalian and avian features. The respiratory epithelium is typically vertebrate, i.e. pseudostratified columnar with cilia; gaseous exchange areas appear at all levels from the respiratory bronchi down to the alveoli. The latter are invested with a capillary network and both type I and type II cells are present. The possible functional significance of the distribution of collagen, elastic tissue, cartilage and smooth muscle is discussed.

The respiratory epithelium of the lung in the green turtle (Chelonia mydas L.).

The axillary gland of the marine turtle lies in the angle formed by the carapace and plastron. The gland is compound tubular and the secretions released by the various acini are conveyed to the exterior via a large excretory duct lined by stratified squamous non-keratinised epithelium. The main secretory areas are lined by holocrine cells, i.e. they degenerate on discharging their contents. The epithelium lining the short ducts which carry the holocrine secretions to the large excretory duct is invaginated regularly giving rise to shallow intraepithelial acini. The cells lining these acini are of two types, granular and mitochondrial. These cells communicate via complex infoldings of their lateral cell walls. The granular cells produce an acidic mucosubstance. The holocrine regions are embedded in a large amount of striated muscle and are separated from the latter by a band of collagen containing variable numbers of melanocytes. The short secretory ducts and large excretory duct have less muscle associated with them but there is a corresponding increase in the volume of collagen. When handled, the adult turtle ejects a milky fluid via the plastral pore. This pungent secretion is weakly acidic.

The characterisation and distribution of cells lining the axillary gland of the adult green turtle (Chelonia mydas L.).

1. Beta-N-acetylglucosaminidase [EC 3.2.1.30] activity in the oviduct of the domestic fowl has been studied using biochemical and histochemical methods. 2. The principal source of the enzyme was the isthmus, where the enzyme was localised within the less dense region of the dual density granules which characterise this portion of the oviduct.

The localisation of beta-N-acetyl-glucosaminidase in the oviduct of the domestic fowl.

The development of a standard technique for fixing the developing follicle for ultrastructural studies is described. 2. The follicle wall is shown to be a multi-layered structure which exhibits a number of morphological changes concomitant with yolk protein transfer, the most significant of which are the intercellular channels which form between the granulosa cells during the fast phase of protein transfer.

The ultrastructure of the follicle wall of the domestic fowl during the phase of rapid growth.

Studies on the soft shell membranes of the egg shell of Chelonia mydas L.

Observations on the histology of the ovary of the Costa Rican green turtle, Chelonia mydas L

Observations on the ultrastructure of the oviduct of the Costa Rican green turtle (Chelonia mydas L.)

Studies on the egg shell (oviducal and oviposited) of Chelonia mydas L.

1. Electron microscopy, infra-red analysis and histochemical techniques have been used to determine the site of pigment deposition, the cellular localisation of pigment and the type of pigment precipitated in the egg shells of quail, White Leghorn, Brown Ranger and Black-Headed gull. 2. Transfer of pigment occurs via the surface epithelial cells of the shell gland. 3. Porphyrins are probably synthesised in the blood. 4. Possible pigment deposition mechanisms are discussed.

Localisation and characterisation of egg shell porphyrins in several avian species.

Fluctuating concentrations of calcium in the blood supplying the avian shell gland are not reflected at tissue level. Analyses of oviducal mucosa throughout the laying cycle show that the concentration of calcium remains relatively unaltered even at peak activity thereby implying a rapid transfer process. These experiments describe the use of potassium pyroantimonate as a localizing agent. The precipitate produced by injecting the latter via the aorta was identified as calcium pyroantimonate by electron diffraction and the efficiency of the precipitant estimated by neutron activation analysis of eggshells present in the shell gland at the time of operation. Results indicate that calcium is transferred across the surface epithelial cells of the shell gland (tubular and pouch regions). Its localization in the former is taken as an indication of the involvement of this region in the production of the mammillary mantle.

The ultrastructural localization of calcium in the avian shell gland

The isthmus extends from the aglandular zone, which delimits it from the magnum, to the tubular shell gland, which to the naked eye is marked by a distinct colour change from off-white to brown. 2. The surface epithelium comprises three cell types, ciliated, non-ciliated and mitochondrial, of which only the non-ciliated cells contribute towards the carbohydrate moiety of the shell membranes. 3. The gland cells are distinctive, containing granules of variable electron density, variations also occurring within individual granules. 4. Although two types of gland cell have been observed, they may merely represent different phases of development. 5. In the type 1 cell, the rough endoplasmic reticulum and Golgi complex are typical of the normal protein secreting cell; in the type 2 cell the RER is sparse, dilated and filled with intracisternal granules while the Golgi complex is likewise distended.

Studies on the reproductive tract of the domestic fowl (Gallus domesticus)

Synopsis The location of non‐specific acid phosphatase in the shell gland of the laying fowl was investigated at ultrastructural level. Free acid phosphatase occurred principally in the basal non‐ciliated surface epithelial cells during the first four hours of calcium deposition. Membrane‐bound acid phosphatase (i.e. lysosomal) was observed only in the tubular gland cells. A cyclical fluctuation in lysosome numbers was noted.

The ultrastructural localisation of acid phosphatase in the avian shell gland.

The characterisation and distribution of acidic mucopolysaccharides in the oviduct of the domestic fowl.

Synopsis Fluctuations in calcium and magnesium were measured in the shell gland fluid and blood from the inferior oviducal vein of the domestic fowl throughout the laying cycle. It was concluded that: The variations in calcium concentration reflected both the known uptake of this ion by the albumen and medullary bone formation and destruction. The variations in magnesium concentration did not parallel the changes in calcium concentration. Magnesium was released into the blood during medullary bone formation.

Fluctuations in total calcium and magnesium in the plasma and uterine fluid of the domestic fowl.

Abstract INTRODUCTION IT has been shown by Gutowska et al. (1943) and Paul and Snetsinger (1969), working on alkaline phosphatase, and by Taylor and Williams (1964), in studies of plasma alkaline and acid phosphatase that in the reproductively active domestic fowl the concentration of these enzymes varies consistently at different phases of the egg cycle. Since no comparable investigation of the concentrations of these enzymes in the shell gland fluid has been reported, it was decided to undertake this study and at the same time determine the location of the enzymes in the lining epithelium of the shell gland and the proprial secretory gland cells. According to Diculesco and Dinesco (1960) acid phosphatase activity is confined to the ciliated epithelial cells. MATERIALS AND METHODS The material used came from 50 laying White Leghorns which were held in individual wire cages. The birds were fed layers pellets ad libitum, with constant access…

Variations in phosphatases in plasma and uterine fluid and in the uterine epithelia of the domestic fowl.

No Development Without Girls: Gender, Development and Youth Associations in Mali

Nursing & health care : official publication of the National League for Nursing

We may not be able to make you love reading, but integrating public policy into the curriculum will lead you to love reading starting from now. Book is the window to open the new world. The world that you want is in the better stage and level. World will always guide you to even the prestige stage of the life. You know, this is some of how reading will give you the kindness. In this case, more books you read more knowledge you know, but it can mean also the bore is full.

Public policy curricula: past and present practices and future directions.

"You ain't seen nothing yet:" fight for federal funding of nursing education heats up.

Funding for FY 1985: authorization bill dies, but appropriations are up.

NIN passes Congress: the struggle to open the gates for nursing research.

We recently reported that HIV-1 resistant to 3 (cid:1) -azido-3 (cid:1) -deoxythymidine (AZT) is not cross-resistant to 3 (cid:1) -azido-2 (cid:1) ,3 (cid:1) -dideoxypurines. This ﬁnding suggested that the nucleoside base is a major determinant of HIV-1 resistance to nucleoside analogs. To further explore this hypothesis, we conducted in vitro selection experiments by serial passage of HIV-1 LAI in MT-2 cells in increasing concentrations of 3 (cid:1) -azido-2 (cid:1) ,3 (cid:1) -dideoxyguanosine (3 (cid:1) -azido-ddG), 3 (cid:1) -azido-2 (cid:1) ,3 (cid:1) -dideoxycytidine (3 (cid:1) -azido-ddC), or 3 (cid:1) -azido-2 (cid:1) ,3 (cid:1) -dideoxyadenosine (3 (cid:1) -azido-ddA). 3 (cid:1) -Azido-ddG selected for virus that was 5.3-fold resistant to 3 (cid:1) -azido-ddG compared to wild-type HIV-1 LAI passaged in the absence of drug. Population sequencing of the entire reverse transcriptase (RT) gene identiﬁed L74V, F77L, and L214F mutations in the polymerase domain and K476N and V518I mutations in the RNase H domain. However, when introduced into HIV-1 by site-directed mutagenesis, these 5 mutations only conferred (cid:2) 2.0-fold resistance. Single-genome sequencing analyses of the selected virus revealed a complex population of mutants that all contained L74V and L214F linked to other mutations, including ones not identiﬁed during population sequencing. Recombinant HIV-1 clones containing RT derived from single sequences exhibited 3.2- to 4.0-fold 3 (cid:1) -azido-ddG resistance. In contrast to 3 (cid:1) -azido-ddG, 3 (cid:1) -azido-ddC selected for the V75I mutation in HIV-1 RT that conferred 5.9-fold resistance, compared to the wild-type virus. Interestingly, we were unable to select HIV-1 that was resistant to 3 (cid:1) -azido-ddA, even at concentrations of 3 (cid:1) -azido-ddA that yielded high intracellular levels of 3 (cid:1) -azido-ddA-5 (cid:1) -triphosphate. Taken together, these ﬁndings show that the nucleoside base is a major determinant of HIV-1 resistance mechanisms that can be exploited in the design of novel nucleoside RT inhibitors.

The Base Component of 3 (cid:1) -Azido-2 (cid:1) ,3 (cid:1) -Dideoxynucleosides Inﬂuences Resistance Mutations Selected in HIV-1 Reverse Transcriptase (cid:1)

Synthesis, antiviral activity, cytotoxicity and cellular pharmacology of l-3'-azido-2',3'-dideoxypurine nucleosides.

ABSTRACT We recently reported that HIV-1 resistant to 3′-azido-3′-deoxythymidine (AZT) is not cross-resistant to 3′-azido-2′,3′-dideoxypurines. This finding suggested that the nucleoside base is a major determinant of HIV-1 resistance to nucleoside analogs. To further explore this hypothesis, we conducted in vitro selection experiments by serial passage of HIV-1LAI in MT-2 cells in increasing concentrations of 3′-azido-2′,3′-dideoxyguanosine (3′-azido-ddG), 3′-azido-2′,3′-dideoxycytidine (3′-azido-ddC), or 3′-azido-2′,3′-dideoxyadenosine (3′-azido-ddA). 3′-Azido-ddG selected for virus that was 5.3-fold resistant to 3′-azido-ddG compared to wild-type HIV-1LAI passaged in the absence of drug. Population sequencing of the entire reverse transcriptase (RT) gene identified L74V, F77L, and L214F mutations in the polymerase domain and K476N and V518I mutations in the RNase H domain. However, when introduced into HIV-1 by site-directed mutagenesis, these 5 mutations only conferred ∼2.0-fold resistance. Single-genome sequencing analyses of the selected virus revealed a complex population of mutants that all contained L74V and L214F linked to other mutations, including ones not identified during population sequencing. Recombinant HIV-1 clones containing RT derived from single sequences exhibited 3.2- to 4.0-fold 3′-azido-ddG resistance. In contrast to 3′-azido-ddG, 3′-azido-ddC selected for the V75I mutation in HIV-1 RT that conferred 5.9-fold resistance, compared to the wild-type virus. Interestingly, we were unable to select HIV-1 that was resistant to 3′-azido-ddA, even at concentrations of 3′-azido-ddA that yielded high intracellular levels of 3′-azido-ddA-5′-triphosphate. Taken together, these findings show that the nucleoside base is a major determinant of HIV-1 resistance mechanisms that can be exploited in the design of novel nucleoside RT inhibitors.

The Base Component of 3′-Azido-2′,3′-Dideoxynucleosides Influences Resistance Mutations Selected in HIV-1 Reverse Transcriptase

Synthesis and evaluation of 3'-azido-2',3'-dideoxypurine nucleosides as inhibitors of human immunodeficiency virus.

Cytotoxic function and cytokine profile of NK cells are compromised in patients with systemic lupus erythematosus (SLE). CD3ζ, an important molecule for NK cell activation, is downregulated in SLE T cells and contributes to their altered function. However, little is known about the role of CD3ζ in SLE NK cells. We studied CD3ζ levels and its contribution to cytotoxic, degranulation, and cytokine production capacity of NK cells from patients with SLE. Furthermore, we studied the human NK cell line, NKL, in which manipulation of CD3ζ levels was achieved using small interfering RNA and NK cells from Rag2 mice deficient in CD3ζ. We found reduced CD3ζ expression in NK cells from SLE patients independent of disease activity. Downregulation of CD3ζ expression in NK cells is mediated, at least in part, by Caspase 3, the activity of which is higher in NK cells from patients with SLE compared with NK cells from healthy donors. CD3ζ levels correlated inversely with natural cytotoxicity and the percentage of cells capable of producing the proinflammatory cytokines IFN-γ and TNF. In contrast, CD3ζ levels showed a direct correlation with levels of Ab-dependent cellular cytotoxicity. Experiments performed in CD3ζ-silenced NKL and CD3ζ-deficient NK cells from Rag2 mice confirmed the dependence of NK cell function on CD3ζ levels. Our results demonstrate a differential role for CD3ζ in natural cytotoxicity and Ab-dependent cellular cytotoxicity. We conclude that downregulated CD3ζ confers a proinflammatory phenotype to SLE NK cells and contributes to their altered function in patients with SLE.

Downregulation of CD3ζ in NK Cells from Systemic Lupus Erythematosus Patients Confers a Proinflammatory Phenotype

RNAi therapeutics can be designed to silence almost any gene of interest and have demonstrated high levels of efficacy and acceptable safety profiles in pre-clinical and clinical development for cardio-metabolic, hepatic infectious, central nervous system, and rare diseases. Minimizing microRNA-like off-target activity while maintaining on-target silencing is a means to maximize the safety profile. One strategy to mitigate off-target activity is to incorporate thermally destabilizing residues such as glycol nucleic acid in the seed region of the antisense strand of a double-stranded RNA. Here we demonstrate the benefit of this strategy using Alnylam's ESC+ conjugate platform by performing RNA-Seq in dose response to measure both on-target and off-target effects. Diverse measures and visualizations of transcriptomic noise will be presented, as well as estimates of relative on-target to off-target effects as a function of dose. These results show that ESC+ conjugates are capable of simultaneously achieving high levels of on-target silencing while maintaining low levels of transcriptomic noise.

Proceedings of the 2018 ACM International Conference on Bioinformatics, Computational Biology, and Health Informatics

RNA-Seq Dose Response Experiments for Quantification of Off-Target Effects with RNAi Therapeutics

In this paper, we report the progress on a harmonic kicker development as an injection device for the Rapid Cycling Synchrotron (RCS) of the Electron-Ion Collider (EIC) at Brookhaven National Laboratory (BNL). INTRODUCTION The RCS of the EIC is an electron energy booster in the injection complex to the Electron Storage Ring (ESR), which provides polarized (∼ 80%) electron beam with a high bunch charge (28 nC) in electron-ion collisions in the ESR [1]. In the RCS, the electron beam is accelerated up to 5-18 GeV, while forming a 28 nC-bunch out of four “smaller” 7 nC bunches via quasi-adiabatic merging. Injection of these bunches into the ring requires an ultra-fast deflecting kicker on the injected bunches, while not affecting preceding passing bunches spaced by 1/fb = 1.7 ns. A harmonic kicker resonator can generate such a sharp-peaked kick with rise/fall time comparable to 1/fb made of a linear combination of harmonic RF modes. Originally developed for the ultrafast beam exchange scheme in the CCR of the JLEIC [2], a harmonic kicker is applicable to a wide range of beam dynamics in the injection schemes. In this paper, we present a harmonic kicker design compatible with the RCS injection beam parameters of the pulsed beam—unlike the CW beam of the JLEIC—, which is injected at the period of 10 ms and revolves around the ring in Trev =12.8 μs. A normal conducting quarter wave resonator (QWR) can accommodate a few number of odd harmonic modes in a straightforward way with its co-axial structure and was prototyped as a kicker cavity for the CCR/JLEIC [3, 4]. We derive the expected RF performance of a QWR as a harmonic kicker for the RCS injection via a simple scaling of the figures of merit from a few JLEIC prototype designs. We also report the progress on the latest JLEIC prototype demonstration, whose fabrication is near completion. The prototype will be tested with the low-energy beam at the Upgraded Injector Test Facility (UITF) of the Jefferson Lab. INJECTION SCHEME OF THE RCS According to the injection scheme [1], one full-cycle of the beam injection from an injector (linac) to the RCS consists of four pairs of bunches separated by 10 ms—eight pairs with the upgrade. In each pair, two bunches are spaced by 2 μs and each bunch has a bunch charge of 7 nC and beam energy of 400 MeV—for a pulsed beam structure, see Fig. 1 and for the beam parameters, Table 1. In the RCS, each injected pair joins the ring via a harmonic kicker and circulates the ring with the revolution period Trev =12.8 μs. After many passes of the injected pair, the next pair is injected at the moment of one RF cycle (1/fb) after each bunch in the injected pair passes the kick point. At the end of a full injection cycle, there will be two bunch trains with each train consisting of four bunches ( eight bunches in upgrade), ready for acceleration and merging, which takes about 0.5∼ 1 s. RCS Injection line ~2μs ~10 ms the n-th bunch pair the (n+1)-th bunch pair kicker Linac 1 2 3 4 1 2 3 4 ~1.6ns ~2 μs Kick voltage envelope in the cavity Tdecay ~10μs Tfill ~10μs Tflat-top ~2μs Microwaveform Figure 1: The schematics of the RCS illustrating the injection scheme. The microwaveforms are near zero on passing (1,2,3) pairs while peaked on the injected pair (4). Table 1: The Beam Parameters of the RCS Injection. The Twiss Parameters are at the Injection Point Parameters Unit Value Revolution period Trev μs 12.8 Beam energy Eb MeV 400 Bunch charge Qb nC 7 Bunch length lb cm 12 Bunch rep. rate fb MHz 591.258 Kick angle θ mrad 1 Kick voltage Vk kV 400 Beam aperture g mm 40 WAVEFORM DESIGN Baseline Waveforms of a Harmonic Kicker A fast injection into the RCS without the preceding bunches (by 1/fb) affected can be achieved by a harmonic kicker that can provide a sharply peaked kick profile (around the injected bunch) with rise/fall time comparable to the bunch spacing: the kick voltage by a harmonic kicker is given as Vk(t) = ∑ N n=0 An cos nωkt, where N is the number of the modes, An amplitude of each mode, and ωk = 2πfk with fk base frequency. The baseline waveforms for the RCS 12th Int. Particle Acc. Conf. IPAC2021, Campinas, SP, Brazil JACoW Publishing ISBN: 978-3-95450-214-1 ISSN: 2673-5490 doi:10.18429/JACoW-IPAC2021-WEPAB019 WEPAB019 C on te nt fr om th is w or k m ay be us ed un de rt he te rm s of th e C C B Y 3. 0 lic en ce (© 20 21 ). A ny di st ri bu tio n of th is w or k m us tm ai nt ai n at tr ib ut io n to th e au th or (s ), tit le of th e w or k, pu bl is he r, an d D O I 2632 MC1: Circular and Linear Colliders T12 Beam Injection/Extraction and Transport injection are shown in Fig. 2 and the corresponding specification of harmonic kicker is listed in Table 2. As can be seen from Fig. 2, the baseline waveforms deliver zero kicks with zero kick slopes on passing bunches with the least degradation of the beam quality. According to Table 3, the 4-bunch scheme would require two kicker cavities (one at the base frequency of 147.8 MHz with n = 1, 3 and the other with n = 2), while the 8-bunch scheme needs one more cavity at 73.9 MHz with n = 1, 3, 5, 7. Both schemes would need the DC kicks by the magnets as well. 0 0.2 0.4 0.6 0.8 1 1.2 1.4 time (s) 10-8 -0.5 0 0.5 1 1.5 2 2.5 3 3.5 4

RF Harmonic Kicker R&D Demonstration and Its Application to the RCS Injection of the EIC

Further theoretical and experimental studies have been performed on the magnetrons with external reactive loads either with a low-Q RF cavity or with a power combiner like the TM010 mode or Magic-tee type. The frequency pushing by a trimming magnetic field and pulling by the reflection between the magnetron and reactive load have been shown to improve the injection phase locking stability and enhance the locking bandwidth compared to the scheme to a matched load only. This principle has been further studied based on S.C. Chen’s model [1, 2], equivalent circuit simulation, analytical calculation and finally compared with experimental data from the magnetron test stands at 2450 MHz.

Magnetron R&D for High Efficiency CW RF Sources for Industrial Accelerators

Medical students who underperform or find they are not a “good fit” for medicine have limited options. A terminal master's degree represents an exit alternative that recognizes students’ completed coursework and acknowledges their commitment to the medical sciences. Although medical educators have called for the creation of such programs, termed “compassionate off-ramps,” the prevalence of degree offerings in US programs is unknown. In the fall of 2020, a survey was sent to Student Affairs Deans at 141 LCME-accredited MD programs; 73 institutions responded (52%). Terminal master's degrees were offered by 19% of respondent institutions (n = 13). While 85% of those without a terminal master's (n = 48) endorsed degree benefits, only 36% (n = 21) had plans to create the degree. This study demonstrates that few US medical schools offer a terminal master's degree, leaving students who exit medicine with high levels of debt without an avenue for a degree to support employment or future academic pursuits. The authors identify implications for students, particularly those who are at a higher risk of failing Step 1, such as students who are underrepresented in medicine, socioeconomically disadvantaged, or who have a disability and are unaccommodated. Potential barriers to terminal master's program creation are identified and mitigating strategies are recommended.

Compassionate Off-Ramps: The Availability of Terminal Master's Degrees in US Medical Schools

Introduction: The use of substances such as whitish end of lizard dung, hydrogen sulphide gas (sewer gas), seed of Zakami, Premium Motor Spirit (PMS), rubber solutions, nail polish cleaners, pawpaw leave and seed, Moringa (Zogale) leave, tear gas, gun powder, Mandara (Kafra) and gutter from toilet for nonconventional purpose among Nigerian youths has become a source of concern at various levels of the society. 
Methods: A semi-structured questionnaire was administered to 220 participants recruited during two class sessions in the school. 
Results: More than half (117, 58.2 %) of the participants were males and over two-fifth (87, 43.5%) were between the ages of 21 and 25 years. A greater portion (174, 87%) of participants had heard about nonconventional use of these substances; whitish end of lizard dung, hydrogen sulphide gas (sewer gas), Premium Motor Spirit (PMS), rubber solutions, nail polish, pawpaw leave, pawpaw seed, Moringa (Zogale) leave, seed of Zakami, tear gas, gun powder, Mandara (Kafra) and gutter from toilet. Participants’ education, age group and geopolitical zones were associated with awareness level, influencing factors and complication as a result of nonconventional substance use. 
Conclusion: Most participants in this study affirmed that the use of nonconventional substances among youths in Nigeria is on the rampant, especially in the northern region.

Nonconventional Use of Substances among Youth in Nigeria: Viewpoints of Students in a Nigerian Tertiary Institution

Gait variability of healthy adults exhibits Long-Range Autocorrelations (LRA), meaning that the stride interval at any time statistically depends on previous gait cycles; and this dependency spans over several hundreds of strides. Previous works have shown that this property is altered in patients with Parkinson’s disease, such that their gait pattern corresponds to a more random process. Here, we adapted a model of gait control to interpret the reduction in LRA that characterized patients in a computational framework. Gait regulation was modeled as a Linear-Quadratic-Gaussian control problem where the objective was to maintain a fixed velocity through the coordinated regulation of stride duration and length. This objective offers a degree of redundancy in the way the controller can maintain a given velocity, resulting in the emergence of LRA. In this framework, the model suggested that patients exploited less the task redundancy, likely to compensate for an increased stride-to-stride variability. Furthermore, we used this model to predict the potential benefit of an active orthosis on the gait pattern of patients. The orthosis was embedded in the model as a low-pass filter on the series of stride parameters. We show in simulations that, with a suitable level of assistance, the orthosis could help patients recovering a gait pattern with LRA comparable to that of healthy controls. Assuming that the presence of LRA in a stride series is a marker of healthy gait control, our study provides a rationale for developing gait assistance technology to reduce the fall risk associated with Parkinson’s disease.

Model of Gait Control in Parkinson’s Disease and Prediction of Robotic Assistance

Humans consider the parameters linked to movement goal during reaching to adjust their control strategy online. Indeed, rapid changes in target structure or disturbances interfering with their initial plan elicit rapid changes in behavior. Here, we hypothesize that these changes could result from the continuous use of a decision variable combining motor and cognitive components. We combine an optimal feedback controller with a real-time monitoring of the expected cost-to-go, which considers target- and movement-related costs, in a common theoretical framework. This model reproduces human behaviors in presence of changes in the target structure occurring during movement and of online decisions to flexibly change target following external perturbations. It also predicts that the time taken to decide to select a novel goal after a perturbation depends on the amplitude of the disturbance and on the rewards of the different options, which is a direct result of the continuous monitoring of the cost-to-go. We show that this result was present in our previously collected dataset. Together our developments point towards a continuous monitoring of the cost-to-go during reaching to update control online and make efficient decisions about movement goal. Author summary The way humans perform reaching movements is compatible with models considering that they result from the minimization of a task-related cost function. However, these models typically assume a cost function that does not change within movement, which is incompatible with experimental findings highlighting humans’ ability to adjust reaching control online and change target flexibly. We hypothesized that this later ability relied on the cost-to-go, which integrates task- and body-related information, being evaluated continuously during movement. We show that this model can optimally select and adjust control during movement in a way that reproduces human behavior in a set of tasks involving change in cost function and change in goal target. Our model predicted that decision-time to change target must be postponed when limb displacements and alternative rewards are smaller, which was borne out in our previous experimental dataset. To conclude, our model explains dynamic updates in reach control and suggests the cost-to-go as decision variable linking decision-making and motor control.

Continuous monitoring of cost-to-go for flexible reaching control and online decisions

Abstract A hallmark of human reaching movements is that they are appropriately tuned to the task goal and to the environmental context. This was demonstrated by the way humans flexibly respond to mechanical and visual perturbations that happen during movement. Furthermore, it was previously showed that the properties of goal-directed control can change within a movement, following abrupt changes in the goal structure. Such online adjustment was characterized by a modulation of feedback gains following switches in target shape. However, it remains unknown whether the underlying mechanism merely switches between prespecified policies, or whether it results from continuous and potentially dynamic adjustments. Here, we address this question by investigating participants’ feedback control strategies in presence of various changes in target width during reaching. More specifically, we studied whether the feedback responses to mechanical perturbations were sensitive to the rate of change in target width, which would be inconsistent with the hypothesis of a single, discrete switch. Based on movement kinematics and surface EMG data, we observed a modulation of feedback response clearly dependent on dynamical changes in target width. Together, our results demonstrate a continuous and online transformation of task-related parameters into suitable control policies.

Continuous Tracking of Task Parameters Tunes Reaching Control Online

Abstract Humans exhibit lateralization such that most individuals typically show a preference for using one arm over the other for a range of movement tasks. The computational aspects of movement control leading to these differences in skill are not yet understood. It has been hypothesized that the dominant and nondominant arms differ in terms of the use of predictive or impedance control mechanisms. However, previous studies present confounding factors that prevented clear conclusions: either the performances were compared across two different groups, or in a design in which asymmetrical transfer between limbs could take place. To address these concerns, we studied a reach adaptation task during which healthy volunteers performed movements with their right and left arms in random order. We performed two experiments. Experiment 1 (18 participants) focused on adaptation to the presence of a perturbing force field (FF) and experiment 2 (12 participants) focused on rapid adaptations in feedback responses. The randomization of the left and right arm led to simultaneous adaptation, allowing us to study lateralization in single individuals with symmetrical and minimal transfer between limbs. This design revealed that participants could adapt control of both arms, with both arms showing similar performance levels. The nondominant arm initially presented a slightly worst performance but reached similar levels of performance in late trials. We also observed that the nondominant arm showed a different control strategy compatible with robust control when adapting to the force field perturbation. EMG data showed that these differences in control were not caused by differences in co-contraction across the arms. Thus, instead of assuming differences in predictive or reactive control schemes, our data show that in the context of optimal control, both arms can adapt, and that the nondominant arm uses a more robust, model-free strategy likely to compensate for less accurate internal representations of movement dynamics.

Different Control Strategies Drive Interlimb Differences in Performance and Adaptation during Reaching Movements in Novel Dynamics

Judging by the breadth of our motor repertoire during daily activities, it is clear that acquiring multiple motor skills is a hallmark of the human motor system. However, for reaching movements the different planning conditions under which this is possible in laboratory settings have remained a challenging question. Considering the sensitivity of limb afferent feedback relative to externally applied forces, we hypothesised that independent cues delivered by means of background loads could support simultaneous formation of different motor memories of various velocity-dependent force fields. We demonstrate in a series of experiments that indeed healthy adults can form internal priors about opposite force fields, independently of the direction of the background force cue. However, when the cue and force field were only related by their magnitude, a separation was still observed but the associated mechanism was subject to interference. Finally, we highlight that this paradigm allows dissociating trial-by-trial acquisition of internal representations from within-trial feedback adaptation, as these two adaptation mechanisms are associated with different time scales that can be measured reliably. Significance Statement The conditions under which humans can adapt to different contexts in parallel remain the subject of active debates. Mounting evidence highlights that contextual factors linked to movement planning are necessary to form different motor memories. Here we show that background forces indicative of the direction of a force field could play the role of contextual factors, and enable dual adaptation to different force fields. However, we uncovered that when the cue and the force field were in the same direction but of different magnitudes, the motor memories were still distinct but subject to interference. We further show that different timescales of adaptation observed can be explained by offline and online mechanisms in a model of reaching adaptation and control.

Separability of Human Motor Memories during reaching adaptation with force cues

Abstract Target reward influences motor planning strategies through modulation of movement vigor. Considering current theories of sensorimotor control suggesting that movement planning consists in selecting a goal-directed control strategy, we sought to investigate the influence of reward on feedback control. Here, we explored this question in three human reaching experiments. First, we altered the explicit reward associated with the goal target and found an overall increase in feedback gains for higher target rewards, highlighted by larger velocities, feedback responses to external loads, and background muscle activity. Then, we investigated whether the differences in target rewards across multiple goals impacted rapid motor decisions during movement. We observed idiosyncratic switching strategies dependent on both target rewards and, surprisingly, the feedback gains at perturbation onset: the more vigorous movements were less likely to switch to a new goal following perturbations. To gain further insight into a causal influence of the feedback gains on rapid motor decisions, we demonstrated that biasing the baseline activity and reflex gains by means of a background load evoked a larger proportion of target switches in the direction opposite to the background load associated with lower muscle activity. Together, our results demonstrate an impact of target reward on feedback control and highlight the competition between movement vigor and flexibility.

Reward-Dependent Selection of Feedback Gains Impacts Rapid Motor Decisions

Abstract Savings have been described as the ability of healthy humans to relearn a previously acquired motor skill faster than the first time, which in the context of motor adaptation suggests that the learning rate in the brain could be adjusted when a perturbation is recognized. Alternatively, it has been argued that apparent savings were the consequence of a distinct process that instead of reflecting a change in the learning rate, revealed an explicit re-aiming strategy. Based on recent evidence that feedback adaptation may be central to both planning and control, we hypothesized that this component could genuinely accelerate relearning in human adaptation to force fields (FFs) during reaching. Consistent with our hypothesis, we observed that on re-exposure to a previously learned FF, the very first movement performed by healthy volunteers in the relearning context was better adapted to the external disturbance, and this occurred without any anticipation or cognitive strategy because the relearning session was started unexpectedly. We conclude that feedback adaptation is a medium by which the nervous system can genuinely accelerate learning across movements.

Savings in Human Force Field Learning Supported by Feedback Adaptation

In humans, practically all movements are learnt and performed in a constant gravitational field. Yet, studies on arm movements and object manipulation in parabolic flight have highlighted very fast sensorimotor adaptations to altered gravity environments. Here, we wondered if the motor adjustments observed in those altered gravity environments could also be observed on Earth in a situation where the body is upside-down. To address this question, we asked participants to perform rhythmic arm movements in two different body postures (right-side-up and upside-down) while holding an object in precision grip. Analyses of grip-load force coordination and of movement kinematics revealed distinct adaptation patterns between grip and arm control. Grip force and load force were tightly synchronized from the first movements performed in upside-down posture, reflecting a malleable allocentric grip control. In contrast, velocity profiles showed a more progressive adaptation to the upside-down posture and reflected an egocentric planning of arm kinematics. In addition to suggesting distinct mechanisms between grip dynamics and arm kinematics for adaptation to novel contexts, these results also suggest the existence of general mechanisms underlying gravity-dependent motor adaptation that can be used for fast sensorimotor coordination across different postures on Earth and, incidentally, across different gravitational conditions in parabolic flights, in human centrifuges or in Space.

Distinct adaptation patterns between grip dynamics and arm kinematics when the body is upside-down.

Perception of limb position and motion combines sensory information from spindles in muscles that span one joint (monoarticulars) and two joints (biarticulars). This anatomical organization should create interactions in estimating limb position. We developed two models, one with only monoarticulars (MO Model) and one with monoarticulars and biarticulars (MB Model), to explore how biarticulars influence estimates of arm position in hand (x,y) and joint (shoulder,elbow) coordinates. In hand coordinates, both models predicted larger medial-lateral than proximal-distal errors, though the MB Model predicted that biarticulars would reduce this bias. In contrast, the two models made significantly different predictions in joint coordinates. The MO Model predicted that errors would be uniformly distributed because estimates of angles at each joint would be independent. In contrast, the MB Model predicted that errors would be coupled between the two joints, resulting in smaller errors for combinations of flexion or extension at both joints and larger errors for combinations of flexion at one joint and extension at the other joint. We also carried out two experiments to examine errors made by human subjects during an arm position matching task in which an robot passively moved one arm to different positions and the subjects moved their other arm to mirror-match each position. Errors in hand coordinates were similar to those predicted by both models. Critically, however, errors in joint coordinates were only similar to those predicted by the MB Model. These results highlight how biarticulars influence perceptual estimates of limb position by helping to minimize medial-lateral errors.

Inter-joint coupling of position sense reflects sensory contributions of biarticular muscles.

Sensorimotor adaptation is a central function of the nervous system, as it allows humans and other animals to flexibly anticipate their interaction with the environment. In the context of human reaching adaptation to force fields, studies have traditionally separated feedforward (FF) and feedback (FB) processes involved in the improvement of behavior. Here, we review computational models of FF adaptation to force fields and discuss them in light of recent evidence highlighting a clear involvement of feedback control. Instead of a model in which FF and FB mechanisms adapt in parallel, we discuss how online adaptation in the feedback control system can explain both trial-by-trial adaptation and improvements in online motor corrections. Importantly, this computational model combines sensorimotor control and short-term adaptation in a single framework, offering novel perspectives for our understanding of human reaching adaptation and control.

Adaptive Feedback Control in Human Reaching Adaptation to Force Fields

Humans are able to perform very sophisticated reaching movements in a myriad of contexts based on flexible control strategies influenced by the task goal and environmental constraints such as obstacles. However, it remains unknown whether these control strategies can be adjusted online. The objective of this study was to determine whether the factors which determine control strategies during planning also modify the execution of an ongoing movement following sudden changes in task demand. More precisely, we investigated whether, and at which latency, feedback responses to perturbation loads followed the change in the structure of the goal target or environment. We changed the target width (square or rectangle) to alter the task redundancy, or the presence of obstacles to induce different constraints on the reach path, and assessed based on surface EMG recordings when the change in visual display altered the feedback response to mechanical perturbations. Task-related EMG responses were detected within 150 ms of a change in target shape. Considering visuomotor delays of ~ 100 ms, these results suggest that it takes 50 ms to change control policy within a trial. An additional 30 ms delay was observed when the change in context involved sudden appearance or disappearance of obstacles. Overall, our results demonstrate that the control policy within a reaching movement is not static: contextual factors which influence movement planning also influence movement execution at surprisingly short latencies. Moreover, the additional 30 ms associated with obstacles suggest that these two types of changes may be mediated via distinct processes.

Online modification of goal-directed control in human reaching movements.

Humans can quickly adjust their grip force to a change in friction at the object-skin interface during dexterous manipulation in a precision grip. To perform this adjustment, they rely on the feedback of the mechanoreceptive afferents innervating the fingertip skin. Because these tactile afferents encode information related to skin deformation, the nature of the feedback signaling a change in friction must somehow originate from a difference in the way the skin deforms when manipulating objects of different frictions. To better characterize the origin of the underlying sensory events, we asked human participants to perform a grip-lifting task with a manipulandum equipped with an optical imaging system. This system enabled to monitor fingertip skin strains through transparent plates of glass that had different levels of friction. We observed that, following an unexpected change in friction, participants adapted their grip force within 370ms after contact with the surface. By comparing the deformation patterns when unexpectedly switching from a high to a low friction condition, we found a significant increase in skin deformation inside the contact area arising over 100ms before the motor response, during the loading phase, suggesting that local and partial deformation patterns prior to lift-off are used in the nervous system to adjust the grip force as a function of the frictional condition.

Fast Grip Force Adaptation To Friction Relies On Localized Fingerpad Strains

Visual and proprioceptive feedback both contribute to perceptual decisions, but it remains unknown how these feedback signals are integrated together or consider factors such as delays and variance during online control. We investigated this question by having participants reach to a target with randomly applied mechanical and/or visual disturbances. We observed that the presence of visual feedback during a mechanical disturbance did not increase the size of the muscle response significantly but did decrease variance, consistent with a dynamic Bayesian integration model. In a control experiment we verified that vision had a potent influence when mechanical and visual disturbances were both present but opposite in sign. These results highlight a complex process for multi-sensory integration, where visual feedback has a relatively modest influence when the limb is mechanically disturbed, but a substantial influence when visual feedback becomes misaligned with the limb.

Integration of proprioceptive and visual feedback during online control of reaching

Humans are able to perform very sophisticated reaching movements in a myriad of contexts based on flexible control strategies influenced by the task goal and environmental constraints such as obstacles. However, it remains unknown whether these control strategies can be adjusted online. The objective of this study was to determine whether the factors which determine control strategies during planning also modify the execution of an ongoing movement following sudden changes in task demand. More precisely, we investigated whether, and at which latency, feedback responses to perturbation loads followed the change in the structure of the goal target or environment. We changed the target width (square or rectangle) to alter the task redundancy, or the presence of obstacles to induce different constraints on the reach path, and assessed based on surface recordings when the change in visual display altered the feedback response to mechanical perturbations. Task-related EMG responses were detected within 150 ms of a change in target shape. Considering visuomotor delays of ∼ 100 ms, these results suggest that it takes 50 ms to change control policy within a trial. An additional 30 ms delay was observed when the change in context involved sudden appearance or disappearance of obstacles. Overall, our results demonstrate that the control policy within a reaching movement is not static: contextual factors which influence movement planning also influence movement execution at surprisingly short latencies. Moreover, the additional 30 ms associated with obstacles suggest that these two types of changes may be mediated via distinct processes. New & Noteworthy The present work demonstrates that the control strategies used to perform reaching movements are adjusted online when the structure of the target or the presence of obstacles are altered during movements. Thus, the properties of goal-directed reaching control are not simply selected during the planning stage of a movement prior to execution. Rather, they are dynamically and rapidly adjusted online, within ∼150ms, according to changes in environment.

Online modification of goal-directed control in human reaching movements

Abstract Motor learning and adaptation are important functions of the nervous system. Classical studies have characterized how humans adapt to changes in the environment during tasks such as reaching, and have documented improvements in behavior across movements. However, little is known about how quickly the nervous system adapts to such disturbances. In particular, recent work has suggested that adaptation could be sufficiently fast to alter the control strategies of an ongoing movement. To further address the possibility that learning occurred within a single movement, we designed a series of human reaching experiments to extract from muscles recordings the latency of feedback adaptation. Our results confirmed that participants adapted their feedback responses to unanticipated force fields applied randomly. In addition, our analyses revealed that the feedback response was specifically and finely tuned to the ongoing perturbation not only across trials with the same force field, but also across different kinds of force fields. Finally, changes in muscle activity consistent with feedback adaptation occurred in ∼250 ms following reach onset. The adaptation that we observed across trials presented in a random context was similar to the one observed when the force fields could be anticipated, suggesting that these two adaptive processes may be closely linked to each other. In such case, our measurement of 250 ms may correspond to the latency of motor adaptation in the nervous system.

Saccades are often directed toward a stimulus that provides useful information for observers to navigate the visual world. The quality of visual signals of a stimulus is influenced by global luminance, and the pupil constricts or dilates after a luminance increase or decrease, respectively, to optimize visual signals for further information processing. Although luminance level changes regularly in the real environment, saccades are mostly studied in the luminance‐unchanged setup. Whether pupillary responses triggered by global luminance changes modulate saccadic behavior are yet to be explored. Through varying background luminance level in an interleaved pro‐ and anti‐saccade paradigm, we investigated the modulation of pupillary luminance responses on the generation of reflexive and voluntary saccades. Subjects were instructed to either automatically look at the peripheral stimulus (pro‐saccade) or to suppress the automatic response and voluntarily look in the opposite direction from the stimulus (anti‐saccade). Level of background luminance was increased (light), decreased (dark), or unchanged (control) during the instructed fixation period. Saccade reaction time distributions of correct pro‐ and anti‐saccades in the light and dark conditions were differed significantly from those in the control condition. Moreover, the luminance condition modulated saccade kinematics, showing reduced performances in the light condition than in the control condition, particularly in pro‐saccades. Modeling results further suggested that both pupil diameter and pupil size derivative significantly modulated saccade behavior, though effect sizes were small and mainly mediated by intersubject differences. Together, our results demonstrated the influence of pupillary luminance responses on the generation of pro‐ and anti‐saccades.

Effects of pupillary light and darkness reflex on the generation of pro‐ And anti‐saccades

A challenge in neuroscience is to describe the contribution of the brain anatomical wiring to the emergence of coordinated neural activity underlying complex behavior. Indeed, patterns of remote coactivations that adjust with the ongoing task-demand do not systematically match direct, static anatomical links. Here, we propose that observed coactivation patterns, known as Functional Connectivity (FC), can be explained by a linear diffusion dynamics defined on the brain architecture and driven by control regions. Our model, termed structure-informed FC, is based on a novel interpretation of functional connectivity according to which different sets of brain regions controlling the information flow on a fixed anatomical wiring enable the emergence of state-specific FC. This observation leads us to introduce a framework for the identification of potential control centers in the brain. We find that well-defined, sparse and robust sets of control regions, which partially overlap across several task conditions and resting-state, produce FC patterns comparable to empirical ones. In conclusion, this work introduces a principled method for identifying brain regions underlying the task-specific control of brain activity. Significance statement Understanding how brain anatomy promotes particular patterns of coactivations among neural regions is a key challenge in neuroscience. This challenge can be addressed using network science and systems theory. Here, we propose that coactivations result from the diffusion of information through the network of anatomical links connecting brain regions, with certain regions controlling the dynamics. We translate this hypothesis into a model called structure-informed functional connectivity, and we introduce a framework for identifying control regions based on empirical data. We find that our model produces coactivation patterns comparable to empirical ones, and that distinct sets of control regions are associated with different functional states. These findings suggest that controllability is an important feature allowing the brain to reach different states.

Structure-informed functional connectivity driven by identifiable and state-specific control regions

Functional connectivity quantifies the statistical dependencies between the activity of brain regions, measured using neuroimaging data such as functional MRI BOLD time series. The network representation of functional connectivity, called a Functional Connectome (FC), has been shown to contain an individual fingerprint allowing participants identification across consecutive testing sessions. Recently, researchers have focused on the extraction of these fingerprints, with potential applications in personalized medicine.

METHODS
Here, we show that a mathematical operation denominated degree-normalization can improve the extraction of FC fingerprints. Degree-normalization has the effect of reducing the excessive influence of strongly connected brain areas in the whole-brain network. We adopt the differential identifiability framework and apply it to both original and degree-normalized FCs of 409 individuals from the Human Connectome Project, in resting-state and 7 fMRI tasks.

RESULTS
Our results indicate that degree-normalization systematically improves three fingerprinting metrics, namely differential identifiability, identification rate and matching rate. Moreover, the results related to the matching rate metric suggest that individual fingerprints are embedded in a low-dimensional space.

The results suggest that low-dimensional functional fingerprints lie in part in weakly connected subnetworks of the brain, and that degree-normalization helps uncovering them. This work introduces a simple mathematical operation that could lead to significant improvements in future FCs fingerprinting studies.

Improving Functional Connectome Fingerprinting with Degree-Normalization

Decision letter: Cerebellar patients have intact feedback control that can be leveraged to improve reaching

Abstract Humans adapt to mechanical perturbations such as forcefields (FFs) during reaching within tens of trials. However, recent findings suggested that this adaptation may start within one single trial, i.e., online corrective movements can become tuned to the unanticipated perturbations within a trial. This was highlighted in previous works with a reaching experiment in which participants had to stop at a via-point (VP) located between the start and the goal. An FF was applied during the first and second parts of the movement and then occasionally unexpectedly switched off at the VP during catch trials. The results showed an after-effect during the second part of the movement when participants exited the VP. This behavioral result was interpreted as a standard after-effect, but it remained unclear how it was related to conventional trial-by-trial learning. The current study aimed to investigate how long do such changes in movement representations last in memory. For this, we have studied the same reaching task with VP in two situations: one with very short residing time in the VP and the second with an imposed minimum 500 ms dwell time in the VP. In both situations, during the unexpected absence of the FF after VP, after-effects were observed. This suggests that online corrections to the internal representation of reach dynamics can be preserved in memory for around 850 ms of resting time on average. Therefore, rapid changes occurring within movements can thus be preserved in memory long enough to influence trial-by-trial motor adaptation.

Rapid Changes in Movement Representations during Human Reaching Could Be Preserved in Memory for at Least 850 ms

Humans excel at learning complex tasks and elite performers such as musicians or sportsmen develop motor skills that defy biomechanical constraints. All actions require the movement of massive bodies. Of particular interest in the process of sensorimotor learning and control is the impact of gravitational forces on the body. Indeed, efficient control and accurate internal representations of the body configuration in space depend on our ability to feel and anticipate the action of gravity. Here we review studies on perception and sensorimotor control in both normal and altered gravity. Behavioral and modeling studies together suggested that the nervous system develops efficient strategies to take advantage of gravitational forces across a wide variety of tasks. However, when exposed to altered gravity, the rate of strategy updating exhibited substantial variations from one experiment to another and sometimes led to partial adjustment only. Overall, these results support the hypothesis that the brain uses a multimodal and flexible representation of gravity effects on our body and movements. Future work is necessary to better characterize the nature of this internal representation and the extent to which it can adapt to novel contexts.

Compensating for sensorimotor noise and for temporal delays has been identified as a major function of the nervous system. Although these aspects have often been described separately in the frameworks of optimal cue combination or motor prediction during movement planning, control-theoretic models suggest that these two operations are performed simultaneously, and mounting evidence supports that motor commands are based on sensory predictions rather than sensory states. In this letter, we study the benefit of state estimation for predictive sensorimotor control. More precisely, we combine explicit compensation for sensorimotor delays and optimal estimation derived in the context of Kalman filtering. We show, based on simulations of human-inspired eye and arm movements, that filtering sensory predictions improves the stability margin of the system against prediction errors due to low-dimensional predictions or to errors in the delay estimate. These simulations also highlight that prediction errors qualitatively account for a broad variety of movement disorders typically associated with cerebellar dysfunctions. We suggest that adaptive filtering in cerebellum, instead of often-assumed feedforward predictions, may achieve simple compensation for sensorimotor delays and support stable closed-loop control of movements.

Filtering Compensation for Delays and Prediction Errors during Sensorimotor Control

Modern control theory highlights strategies that consider a range of factors, such as errors caused by environmental disturbances or inaccurate estimates of body or environmental dynamics. Here we reveal similar diversity in how humans naturally adapt and control their arm movements. We divided participants into groups based on how well they adapted to interaction loads during a single session of reaching movements. This classification revealed differences in how participants controlled their movements and responded to mechanical perturbations. Interestingly, variation in behaviour across good and partial adapters resembled simulations from stochastic and robust optimal feedback control, respectively, where the latter minimizes the effect of disturbances, including those introduced by inaccurate internal models of movement dynamics. In a second experiment, we varied the interaction loads over short time periods making it difficult to adapt. Under these conditions, participants who otherwise adapted well altered their behaviour and more closely resembled those using a robust control strategy. Taken together, the results suggest the diversity of how humans control and adapt their arm movements may reflect the accuracy of (or confidence in) their internal models. Our findings may open novel perspectives for interpreting motor behaviour in uncertain environments, or when neurologic dysfunction compromises motor adaptation.

Tradeoffs in optimal control capture patterns of human sensorimotor control and adaptation

Motor learning and adaptation are important functions of the nervous system. Classical studies have characterized how humans adapt to changes in the environment during tasks such as reaching, and have documented improvements in behavior across movements. Yet little is known about how quickly the nervous system adapts to such disturbances. In particular, recent work has suggested that adaptation could be sufficiently fast to alter the control strategies of an ongoing movement. To further address the possibility that learning occurred within a single movement, we designed a series of human reaching experiments to extract in muscles recordings the latency of feedback adaptation. Our results confirmed that participants adapted their feedback responses to unanticipated force fields applied randomly. In addition, our analyses revealed that the feedback response was specifically and finely tuned to the ongoing perturbation not only across trials with the same force field, but also across different kinds of force fields. Finally, changes in muscle activity consistent with feedback adaptation occurred in about 250ms following reach onset. We submit this estimate as the latency of motor adaptation in the nervous system.

Current models of motor learning suggest that multiple timescales support adaptation to changes in visual or mechanical properties of the environment. These models capture patterns of learning and memory across a broad range of tasks, yet do not consider the possibility that rapid changes in behavior may occur without adaptation. Such changes in behavior may be desirable when facing transient disturbances, or when unpredictable changes in visual or mechanical properties of the task make it difficult to form an accurate model of the perturbation. Whether humans can modulate control strategies without an accurate model of the perturbation remains unknown. Here we frame this question in the context of robust control (H∞-control), a control strategy that specifically considers unpredictable disturbances by increasing initial movement speed and feedback gains. Correspondingly, we demonstrate in two human reaching experiments including males and females that the occurrence of a single unpredictable disturbance led to an increase in movement speed and in the gain of rapid feedback responses to mechanical disturbances on subsequent movements. This strategy reduced perturbation-related motion regardless of the direction of the perturbation. Furthermore, we found that changes in the control strategy were associated with co-contraction, which amplified the gain of muscle responses to both lengthening and shortening perturbations. These results have important implications for studies on motor adaptation because they highlight that trial-by-trial changes in limb motion also reflected changes in control strategies dissociable from error-based adaptation. SIGNIFICANCE STATEMENT Humans and animals use internal representations of movement dynamics to anticipate the impact of predictable disturbances. However, we are often confronted with transient or unpredictable disturbances, and it remains unknown whether and how the nervous system handles these disturbances over fast time scales. Here we hypothesized that humans can modulate their control strategy to make reaching movements less sensitive to perturbations. We tested this hypothesis in the framework of robust control, and found changes in movement speed and feedback gains consistent with the model predictions. These changes impacted participants' behavior on a trial-by-trial basis. We conclude that compensation for disturbances over fast time scales involves a robust control strategy, which potentially plays a key role in motor planning and execution.

Robust Control in Human Reaching Movements: A Model-Free Strategy to Compensate for Unpredictable Disturbances

Impact of reinforcement on action selection, initiation and execution during motor skill learning

Humans and other animals adapt motor commands to predictable disturbances within tens of trials in laboratory conditions. A central question is how does the nervous system adapt to disturbances in natural conditions when exactly the same movements cannot be practiced several times. Because motor commands and sensory feedback together carry continuous information about limb dynamics, we hypothesized that the nervous system could adapt to unexpected disturbances online. Abstract Humans and other animals adapt motor commands to predictable disturbances within tens of trials in laboratory conditions. A central question is how does the nervous system adapt to disturbances in natural conditions when exactly the same movements cannot be practiced several times. Because motor commands and sensory feedback together carry continuous information about limb dynamics, we hypothesized that the nervous system could adapt to unexpected disturbances online. We tested this hypothesis in two reaching experiments during which velocity-dependent force fields (FFs) were randomly applied. We found that within-movement feedback corrections gradually improved, despite the fact that the perturbations were unexpected. Moreover, when participants were instructed to stop at a via-point, the application of a FF prior to the via-point induced mirror-image after-effects after the via-point, consistent with within-trial adaptation to the unexpected dynamics. These findings suggest a fast time-scale of motor learning, which complements feedback control and supports adaptation of an ongoing movement.

A Very Fast Time Scale of Human Motor Adaptation: Within Movement Adjustments of Internal Representations during Reaching

The human brain anatomical organization can be modeled as a complex network, called a connectome. This representation enables the use of powerful mathematical tools to detect individual differences in brain structure. In this paper, we propose three methods based on Support Vector Machines, to classify connectomes according to a given label. We demonstrate the efficiency of our methods compared to existing approaches through experiments on a dataset built from publicly available MRI data, and for the classification between male and female brains. We further interpret the classification outcome in regards to one particular wiring feature: the inter-hemispheric ratio.

2018 19th IEEE Mediterranean Electrotechnical Conference (MELECON)

Supervised classification of structural brain networks reveals gender differences

Successful performance in many everyday tasks requires compensating unexpected mechanical disturbance to our limbs and body. The long-latency reflex plays an important role in this process because it is the fastest response to integrate sensory information across several effectors, like when linking the elbow and shoulder or the arm and body. Despite the dozens of studies on inter-effector long-latency reflexes, there has not been a comprehensive treatment of how these reveal the basic control organization that sets constraints on any candidate model of neural feedback control such as optimal feedback control. We considered three contrasting ways that controllers can be organized: multiple independent controllers vs. a multiple-input multiple-output (MIMO) controller, a continuous feedback controller vs. an intermittent feedback controller, and a direct MIMO controller vs. a state feedback controller. Following a primer on control theory and review of the relevant evidence, we conclude that continuous state feedback control best describes the organization of inter-effector coordination by the long-latency reflex.

Long-latency reflexes for inter-effector coordination reflect a continuous state feedback controller.

Bimanual tasks involve the coordination of both arms, which often offers redundancy in the ways a task can be completed. The distribution of control across limbs is often considered from the perspective of handedness. In this context, although there are differences across dominant and nondominant arms during reaching control ( Sainburg 2002 ), previous studies have shown that the brain tends to favor the dominant arm when performing bimanual tasks ( Salimpour and Shadmehr 2014 ). However, biomechanical factors known to influence planning and control in unimanual tasks may also generate limb asymmetries in force generation, but their influence on bimanual control has remained unexplored. We investigated this issue in a series of experiments in which participants were instructed to generate a 20-N force with both arms, with or without perturbation of the target force during the trial. We modeled the task in the framework of optimal feedback control of a two-link model with six human-like muscles groups. The biomechanical model predicted a differential contribution of each arm dependent on the orientation of the target force and joint configuration that was quantitatively matched by the participants' behavior, regardless of handedness. Responses to visual perturbations were strongly influenced by the perturbation direction, such that online corrections also reflected an optimal use of limb biomechanics. These results show that the nervous system takes biomechanical constraints into account when optimizing the distribution of forces generated across limbs during both movement planning and feedback control of a bimanual task. NEW & NOTEWORTHY Here, we studied a bimanual force production task to examine the effects of biomechanical constraints on the distribution of control across limbs. Our findings show that the central nervous system optimizes the distribution of force across the two arms according to the joint configuration of the upper limbs. We further show that the underlying mechanisms influence both movement planning and online corrective responses to sudden changes in the target force.

Optimal use of limb mechanics distributes control during bimanual tasks.

Humans and animals adapt motor commands to predictable disturbances within tens of trials in laboratory conditions. However in natural conditions, adaptation likely occurs continuously and it remains unknown how the brain handles novel disturbances across time. Because motor commands and sensory feedback together carry continuous information about limb dynamics, we hypothesized that the nervous system could adapt to unexpected disturbances online. We tested this hypothesis in two reaching experiments during which opposing velocity-dependent force fields were randomly applied. We found that within-movement feedback corrections gradually improved, despite the fact that the perturbations were unexpected. Moreover, when participants were instructed to stop at a via-point, the application of a force field prior to the via-point induced mirror-image after-effects after the via-point, indicative of within-trial adaptation to the unexpected dynamics. These findings highlight a fast time-scale of motor learning, which supplements feedback control and supports adaptation of an ongoing movement. Significance Statement Adaption of human reaching control has revealed that the nervous system adapt internal representations of limb dynamics following changes in the environment. Here we show that that this process, usually characterized across movement repeats, also occurs online within a single movement. We show that perturbation to the limb evoked within movement adaptation in addition to feedback correction for the disturbance. Furthermore, the data suggest that adaptation occurred within the very first perturbed movement. These results are interpreted in the framework of adaptive control, which provides a computational framework for linking learning and control, and explains how these two neural processes occur in real time.

Many studies highlight that human movements are highly successful yet display a surprising amount of variability from trial to trial. There is a consistent pattern of variability throughout movement: initial motor errors are corrected by the end of movement, suggesting the presence of a powerful online control process. Here, we analyze the trial-by-trial variability of goal-directed reaching in nonhuman primates (five male Rhesus monkeys) and demonstrate that they display a similar pattern of variability during reaching, including a strong negative correlation between initial and late hand motion. We then demonstrate that trial-to-trial neural variability of primary motor cortex (M1) is positively correlated with variability of future hand motion (τ = ∼160 ms) during reaching. Furthermore, the variability of M1 activity is also correlated with variability of past hand motion (τ = ∼90 ms), but in the opposite polarity (i.e., negative correlation). Partial correlation analysis demonstrated that M1 activity independently reflects the variability of both past and future hand motions. These findings provide support for the hypothesis that M1 activity is involved in online feedback control of motor actions. SIGNIFICANCE STATEMENT Previous studies highlight that primary motor cortex (M1) rapidly responds to either visual or mechanical disturbances, suggesting its involvement in online feedback control. However, these studies required external disturbances to the motor system and it is not clear whether a similar feedback process addresses internal noise/errors generated by the motor system itself. Here, we introduce a novel analysis that evaluates how variations in the activity of M1 neurons covary with variations in hand motion on a trial-to-trial basis. The analyses demonstrate that M1 activity is correlated with hand motion in both the near future and the recent past, but with opposite polarity. These results suggest that M1 is involved in online feedback motor control to address errors/noise within the motor system.

Correlations Between Primary Motor Cortex Activity with Recent Past and Future Limb Motion During Unperturbed Reaching

The healthy human nervous system accurately and robustly controls movements despite nonlinear dynamics, noise, and delays. After a stroke, motor ability frequently becomes impaired. To provide insight into the relative impact of specific sensorimotor deficits on motor performance, we modeled neural control of reaching with the human upper limb as a near-optimally feedback-controlled two-degree-of-freedom system with biologically based parameters. We added three sensorimotor impairments commonly associated with post-stroke hemiparesis—abnormal joint coupling, increased noise on internally modeled dynamics, and muscular weakness— and examined the impact on reaching performance. We found that abnormal joint coupling unknown to the system’s internal model caused systematic perturbations to trajectories, longer reach durations, and target overshoot. Increasing internal model noise and muscular weakness had little impact on motor performance unless model noise was increased by several orders of magnitude. Many reaches performed by our perturbed models replicate features commonly observed in reaches by hemiparetic stroke survivors. The sensitivity to unmodeled abnormal joint coupling agrees with experimental findings that abnormal coupling (possibly related to internal model errors) is the main cause of post-stroke motor impairment.

Simulating the impact of sensorimotor deficits on reaching performance

Impact of series length on statistical precision and sensitivity of autocorrelation assessment in human locomotion.

Tactile and muscle afferents provide critical sensory information for grasp control, yet the contribution of each sensory system during online control has not been clearly identified. More precisely, it is unknown how these two sensory systems participate in online control of digit forces following perturbations to held objects. To address this issue, we investigated motor responses in the context of fingertip loading, which parallels the impact of perturbations to held objects on finger motion and fingerpad deformation, and characterized surface recordings of intrinsic (first dorsal interosseous, FDI) and extrinsic (flexor digitorum superficialis, FDS) hand muscles based on statistical modeling. We designed a series of experiments probing the effects of peripheral stimulation with or without anesthesia of the finger, and of task instructions. Loading of the fingertip generated a motor response in FDI at ~60 ms following the perturbation onset, which was only driven by muscle stretch, as the ring-block anesthesia reduced the gain of the response occurring later than 90 ms, leaving responses occurring before this time unaffected. In contrast, the motor response in FDS was independent of the lateral motion of the finger. This response started at ~90 ms on average and was immediately adjusted to task demands. Altogether these results highlight how a rapid integration of partially distinct sensorimotor circuits supports rapid motor responses to fingertip loading.NEW & NOTEWORTHY To grasp and manipulate objects, the brain uses touch signals related to skin deformation as well as sensory information about motion of the fingers encoded in muscle spindles. Here we investigated how these two sensory systems contribute to feedback responses to perturbation applied to the fingertip. We found distinct response components, suggesting that each sensory system engages separate sensorimotor circuits with distinct functions and latencies.

Multisensory components of rapid motor responses to fingertip loading.

OBJECTIVE
Gait instability and fall risk are major concerns in Parkinson's disease. This study shows that the temporal organization of gait variability can represent a marker of gait instability that complements standard assessment of motor deficits in Parkinson's disease.

METHODS
Temporal organization (long-range autocorrelation; LRA) of stride duration variability, collected from 20 persons with Parkinson's disease walking overground at a comfortable speed, was studied. The presence of LRA was based on the scaling properties of the series variability and the shape of the power spectral density. Simultaneously, measures of neurological impairment (MDS-UPDRS), balance (BESTest), and balance confidence (ABC-Scale) were collected. To precisely identify the relationship between LRA and functional measures, correlation coefficients were applied.

RESULTS
Degradation of LRA was strongly correlated with other clinical scores, in such a way that the temporal organization of gait variability was more random for patients presenting with greater motor impairments. Importantly, these measures were relatively independent of age, and gait speed, thus they can be applied to a wide clinical population.  Conclusion: The findings of this study emphasize that temporal organization of gait variability is related to degree of functional impairment in Parkinson's disease. LRA may thus be regarded as an objective and quantitative measure of gait stability for both clinical practice and research.

Temporal organization of stride duration variability as a marker of gait instability in Parkinson's disease.

Visual Overview Suppose that someone bumps into your arm at a party while you are holding a glass of wine. Motion of the disturbed arm will engage rapid and goal-directed feedback responses in the upper-limb. Suppose that someone bumps into your arm at a party while you are holding a glass of wine. Motion of the disturbed arm will engage rapid and goal-directed feedback responses in the upper-limb. Although such responses can rapidly counter the perturbation, it is also clearly desirable not to destabilize your grasp and/or spill the wine. Here we investigated how healthy humans maintain a stable grasp following perturbations by using a paradigm that requires spatial tuning of the motor response dependent on the location of a virtual target. Our results highlight a synchronized expression of target-directed feedback in shoulder and hand muscles occurring at ∼60 ms. Considering that conduction delays are longer for the more distal hand muscles, these results suggest that target-directed responses in hand muscles were initiated before those for the shoulder muscles. These results show that long-latency feedback can coordinate upper limb and hand muscles during object manipulation tasks.

Long-Latency Feedback Coordinates Upper-Limb and Hand Muscles during Object Manipulation Tasks123

Recent advances in movement neuroscience have consistently highlighted that the nervous system performs sophisticated feedback control over very short time scales (<100 ms for upper limb). These observations raise the important question of how the nervous system processes multiple sources of sensory feedback in such short time intervals, given that temporal delays across sensory systems such as vision and proprioception differ by tens of milliseconds. Here we show that during feedback control, healthy humans use dynamic estimates of hand motion that rely almost exclusively on limb afferent feedback even when visual information about limb motion is available. We demonstrate that such reliance on the fastest sensory signal during movement is compatible with dynamic Bayesian estimation. These results suggest that the nervous system considers not only sensory variances but also temporal delays to perform optimal multisensory integration and feedback control in real-time. SIGNIFICANCE STATEMENT Numerous studies have demonstrated that the nervous system combines redundant sensory signals according to their reliability. Although very powerful, this model does not consider how temporal delays may impact sensory reliability, which is an important issue for feedback control because different sensory systems are affected by different temporal delays. Here we show that the brain considers not only sensory variability but also temporal delays when integrating vision and proprioception following mechanical perturbations applied to the upper limb. Compatible with dynamic Bayesian estimation, our results unravel the importance of proprioception for feedback control as a consequence of the shorter temporal delays associated with this sensory modality.

Dynamic Multisensory Integration: Somatosensory Speed Trumps Visual Accuracy during Feedback Control

Nordic walking can improve dynamic stability of human gait in Parkinson disease

Perturbation Offset Displacement Can Be Rapidly Attenuated By Long-Latency and Voluntary Responses to an Arm

Introduction/Background: Stride duration continuously fluctuates in a complex manner over time, displaying long-range autocorrelations (LRA). The presence of such temporal dynamics is thought to be a critical marker of health and their breakdown as an index of pathological condition, especially associated to dynamic stability in locomotion. However, neurophysiological mechanisms generating such correlations remain a matter of debate. Material and Methods: To further investigate their origin and the influence of pathological locomotion, we studied LRA from 20 parkinsonian patients walking on treadmill and overground at a comfortable speed. The presence of LRA was based on scaling properties of the series variability (Hurst exponent) and the shape of the power spectral density (α exponent). Functional status of each patient was assessed using MDS-UPDRS and modified HY α: r=- 0,907), and BESTest score and LRA (Hurst: r=0,745; α: r=0,906), while no significant correlations were observed between MDS-UPDRS and ABC Scale with LRA obtained on overground walking. On treadmill, no correlations were observed between functional and balance measures with LRA. Conclusion: This study demonstrates the presence of LRA in parkinsonian gait on overground walking jointly evolving with balance status (BESTest) and supporting the relationship with dynamic stability. Furthermore, the modulation of LRA by treadmill and disease severity (H&Y scale) could suggest further participation of basal ganglia in control mechanisms of LRA.

Long-Range Autocorrelations in Parkinson’s Disease as a Reflect of Disease Severity and Dynamic Stability

Inertial torque during reaching directly impacts grip-force adaptation to weightless objects

Degradation of gait autocorrelation as precocious marker of fall risk in Parkinson's disease

A perspective on multisensory integration and rapid perturbation responses

Variability of Human Gait: Effect of Backward Walking and Dual-Tasking on the Presence of Long-Range Autocorrelations

4 5 6 7 8 9 10 11 12 13 14 15 16 Authors and addresses: 17 Isaac Kurtzer, Frédéric Crevecoeur, and Stephen H. Scott 18 Department of Biomedical Sciences 19 New York Institute of Technology College of Osteopathic Medicine, 20 Old Westbury, NY USA 21 Centre for Neuroscience Studies and Department of Medicine 22 Queen's University, Kingston, ON Canada 23 24 25 Corresponding author: 26 Isaac Kurtzer, Ph.D. 27 Department of Biomedical Sciences NYIT College of Osteopathic Medicine, 28 Old Westbury, NY USA 29 Tel: 516 686 3913; Fax: 516 686 3750 30 Email: ikurtzer@nyit.edu 31 32 Figures: 10 and 2 table 33 Pages: 45 34

Title : Fast feedback control involves two independent processes utilizing 1 knowledge of limb dynamics 2 Abbreviated Title : two feedback internal models

Variability of human gait: Long-range autocorrelations and fluctuation magnitude of stride duration

Recent theories of voluntary control predict that multiple motor strategies can be precomputed and expressed throughout movement. We examined online decisional processing in humans by asking them to make reaching movements with obstacles located just to the sides of a direct path between start and end targets. On random trials, the limb was perturbed with one of four mechanical loads that varied in direction and amplitude. Notably, we observed two different strategies when we applied a perturbation (left medium-sized) that deviated the participants' hand directly toward an obstacle. In some trials, subjects directed their hand between the obstacles and in other trials to the left of the obstacles. Importantly, changes in the muscle stretch response between these two strategies were observed in <60 ms after perturbation, during the R2 long-latency epoch (∼45–75 ms). As predicted, the selected strategy depended on the estimated position of the limb when it was perturbed. In our second experiment, we presented either one or three potential goal targets. Movements initially directed to the closest target could be quickly redirected to other potential targets after a perturbation. Differences in muscle stretch responses for redirected movements were observed ∼75 ms after perturbation during the R3 long-latency epoch (∼75–105 ms). The results show that decisional processes are rapidly implemented during movement execution. In addition, our data suggest a hierarchical process with corrective responses on “how” to attain a behavioral goal expressed during the R2 epoch and responses on “what” goal to attain during the R3 epoch.

Feedback delays are a major challenge for any controlled process, and yet we are able to easily control limb movements with speed and grace. A popular hypothesis suggests that the brain largely mitigates the impact of feedback delays (∼50 ms) by regulating the limb intrinsic visco-elastic properties (or impedance) with muscle co-contraction, which generates forces proportional to changes in joint angle and velocity with zero delay. Although attractive, this hypothesis is often based on estimates of limb impedance that include neural feedback, and therefore describe the entire motor system. In addition, this approach does not systematically take into account that muscles exhibit high intrinsic impedance only for small perturbations (short-range impedance). As a consequence, it remains unclear how the nervous system handles large perturbations, as well as disturbances encountered during movement when short-range impedance cannot contribute. We address this issue by comparing feedback responses to load pulses applied to the elbow of human subjects with theoretical simulations. After validating the model parameters, we show that the ability of humans to generate fast and accurate corrective movements is compatible with a control strategy based on state estimation. We also highlight the merits of delay-uncompensated robust control, which can mitigate the impact of internal model errors, but at the cost of slowing feedback corrections. We speculate that the puzzling observation of presynaptic inhibition of peripheral afferents in the spinal cord at movement onset helps to counter the destabilizing transition from high muscle impedance during posture to low muscle impedance during movement.

Beyond Muscles Stiffness: Importance of State-Estimation to Account for Very Fast Motor Corrections

Moving requires handling gravitational and inertial constraints pulling on our body and on the objects that we manipulate. Although previous work emphasized that the brain uses internal models of each type of mechanical load, little is known about their interaction during motor planning and execution. In this report, we examine visually guided reaching movements in the horizontal plane performed by naive participants exposed to changes in gravity during parabolic flight. This approach allowed us to isolate the effect of gravity because the environmental dynamics along the horizontal axis remained unchanged. We show that gravity has a direct effect on movement kinematics, with faster movements observed after transitions from normal gravity to hypergravity (1.8g), followed by significant movement slowing after the transition from hypergravity to zero gravity. We recorded finger forces applied on an object held in precision grip and found that the coupling between grip force and inertial loads displayed a similar effect, with an increase in grip force modulation gain under hypergravity followed by a reduction of modulation gain after entering the zero-gravity environment. We present a computational model to illustrate that these effects are compatible with the hypothesis that participants partially attribute changes in weight to changes in mass and scale incorrectly their motor commands with changes in gravity. These results highlight a rather direct internal mapping between the force generated during stationary holding against gravity and the estimation of inertial loads that limb and hand motor commands must overcome.

Gravity-dependent estimates of object mass underlie the generation of motor commands for horizontal limb movements.

Computational approaches for goal-directed movement planning and execution

Corrective muscle responses occurring 50-100 ms after a mechanical perturbation are tailored to the mechanical features of the limb and its environment. For example, the evoked response by the shoulder's extensor muscle counters an imposed shoulder torque, rather than local shoulder motion, by integrating motion information from the shoulder and elbow appropriate for their dynamic interaction. Previous studies suggest that arm muscle activity within this epoch, alternately termed the R2/3 response, or long-latency reflex, reflects the summed result of two distinct components: an activity-dependent component which scales with the background muscle activity, and a task-dependent component which scales with the required vigor of the behavioral task. Here we examine how the knowledge of limb dynamics expressed during the shoulder muscle's R2/3 epoch is related to these two functional components. Subjects countered torque steps applied to their shoulder and/or elbow under different conditions of background torque and target size to recruit the activity-dependent and task-dependent component in varying degrees. Experiment 1 involved four torque perturbations, two levels of background torques and two target sizes; this design revealed that both background torque and target size impacted the shoulder's R2/3 activity, indicative of knowledge of limb dynamics. Experiment 2 involved two perturbation torques, five levels of background torque and two target sizes; this design demonstrated that the two factors had an independent impact on the R2/3 activity indicative of knowledge of limb dynamics. We conclude that a sophisticated feature of upper limb feedback control reflects the summation of two processes having a common capability.

Fast feedback control involves two independent processes utilizing knowledge of limb dynamics.

Analysis of long-range autocorrelation series: effect of the number of cycles on statistical precision and sensitivity

Healthy subjects can easily produce voluntary actions at different speeds and with varying accuracy requirements. It remains unknown whether rapid corrective responses to mechanical perturbations also possess this flexibility and, thereby, contribute to the capability expressed in voluntary control. Paralleling previous studies on self-initiated movements, we examined how muscle activity was impacted by either implicit or explicit criteria affecting the urgency to respond to the perturbation. Participants maintained their arm position against torque perturbations with unpredictable timing and direction. In the first experiment, the urgency to respond was explicitly altered by varying the time limit (300 ms vs. 700 ms) to return to a small target. A second experiment addresses implicit urgency criteria by varying the radius of the goal target, such that task accuracy could be achieved with less vigorous corrections for large targets than small target. We show that muscle responses at ∼60 ms scaled with the task demand. Moreover, in both experiments, we found a strong intertrial correlation between long-latency responses (∼50-100 ms) and the movement reversal times, which emphasizes that these rapid motor responses are directly linked to behavioral performance. The slopes of these linear regressions were sensitive to the experimental condition during the long-latency and early voluntary epochs. These findings suggest that feedback gains for very rapid responses are flexibly scaled according to task-related urgency.

Feedback responses rapidly scale with the urgency to correct for external perturbations.

Dynamics of Revolution Time Variability in Cycling Pattern: Voluntary Intent Can Alter the Long-Range Autocorrelations

In every motor task, our brain must handle external forces acting on the body. For example, riding a bike on cobblestones or skating on irregular surface requires us to appropriately respond to external perturbations. In these situations, motor predictions cannot help anticipate the motion of the body induced by external factors, and direct use of delayed sensory feedback will tend to generate instability. Here, we show that to solve this problem the motor system uses a rapid sensory prediction to correct the estimated state of the limb. We used a postural task with mechanical perturbations to address whether sensory predictions were engaged in upper-limb corrective movements. Subjects altered their initial motor response in ∼60 ms, depending on the expected perturbation profile, suggesting the use of an internal model, or prior, in this corrective process. Further, we found trial-to-trial changes in corrective responses indicating a rapid update of these perturbation priors. We used a computational model based on Kalman filtering to show that the response modulation was compatible with a rapid correction of the estimated state engaged in the feedback response. Such a process may allow us to handle external disturbances encountered in virtually every physical activity, which is likely an important feature of skilled motor behaviour.

Priors Engaged in Long-Latency Responses to Mechanical Perturbations Suggest a Rapid Update in State Estimation

1 Feedback responses rapidly scale with the urgency to correct for external 2 perturbations 3 Running Title: Rapid Motor Responses Scale with Task Urgency 4 5 6 7 8 F. Crevecoeur, I. Kurtzer, T. Bourke, S. H. Scott 9 1 Centre for Neuroscience Studies, Queen's University 10 2 Department of Neuroscience and Histology, New York College of Osteopathic Medicine 11 3 Department Biomedical and Molecular Sciences, Queen’s University 12 13 14 15 Corresponding Author: 16 S. H. Scott, 17 Centre for Neuroscience Studies, Queen's University 18 Room 219, Botterell Hall, Kingston, ON K7L3N6, Canada 19 e-mail: steve.scott@queensu.ca 20 21 22 23 Acknowledgements 24 The authors thank K. Moore, H. Bretzke and J. Peterson for technical and logistic 25 support. This work was supported by the Natural Sciences and Engineering Research Council of 26 Canada (NSERC). FC is supported by a fellowship from the Canadian Institute of Health Research 27 (CIHR-IRSC). 28 Articles in PresS. J Neurophysiol (July 3, 2013). doi:10.1152/jn.00216.2013

Feedback responses rapidly scale with the urgency to correct for external 2 perturbations 3 Running Title : Rapid Motor Responses Scale with Task Urgency 4 5 6 7 8

Effects of age and walking speed on long-range autocorrelations and fluctuation magnitude of stride duration

A wealth of studies highlight the importance of rapid corrective responses during voluntary motor tasks. These studies used relatively large perturbations to evoke robust muscle activity. Thus it remains unknown whether these corrective responses (latency 20-100 ms) are evoked at perturbation levels approaching the inherent variability of voluntary control. To fill this gap, we examined responses for large to small perturbations applied while participants either performed postural or reaching tasks. To address multijoint corrective responses, we induced various amounts of single-joint elbow motion with scaled amounts of combined elbow and shoulder torques. Indeed, such perturbations are known to elicit a response at the unstretched shoulder muscle, which reflects an internal model of arm intersegmental dynamics. Significant muscle responses were observed during both postural control and reaching, even when perturbation-related joint angle, velocity, and acceleration overlapped in distribution with deviations encountered in unperturbed trials. The response onsets were consistent across the explored range of perturbation loads, with short-latency onset for the muscles spanning the elbow joints (20-40 ms), and long-latency for shoulder muscles (onset > 45 ms). In addition, the evoked activity was strongly modulated by perturbation magnitude. These results suggest that multijoint responses are not specifically engaged to counter motor errors that exceed a certain threshold. Instead, we suggest that these corrective processes operate continuously during voluntary motor control.

Fast corrective responses are evoked by perturbations approaching the natural variability of posture and movement tasks.

Effects of age and walking speed on long-range autocorrelations and on fluctuation magnitude of stride duration

Bollens, Benjamin ; Crevecoeur, Frédéric ; Guillery, Erwan ; Lejeune, Thierry. Effects of walking speed on long range autocorrelation and on fluctuation magnitude of stride duration.18th European Congress of Physical and Rehabilitation Medicine (Thessaloniki, du 28/05/2012 au 01/06/2012). In: European Journal of Physical and Rehabilitation Medicine : a journal of physical medicine and rehabilitation after pathological events, Vol. 48S1, no.87 (2012) http://hdl.handle.net/2078.1/145667

Effects of walking speed on long range autocorrelation and on fluctuation magnitude of stride duration

obstacles on rapid feedback responses Influence of the behavioral goal and environmental

The motor system must consider a variety of environmental factors when executing voluntary motor actions, such as the shape of the goal or the possible presence of intervening obstacles. It remains unknown whether rapid feedback responses to mechanical perturbations also consider these factors. Our first experiment quantified how feedback corrections were altered by target shape, which was either a circular dot or a bar. Unperturbed movements to each target were qualitatively similar on average but with greater dispersion of end point positions when reaching to the bar. On random trials, multijoint torque perturbations deviated the hand left or right. When reaching to a circular target, perturbations elicited corrective movements that were directed straight to the location of the target. In contrast, corrective movements when reaching to a bar were redirected to other locations along the bar axis. Our second experiment quantified whether the presence of obstacles could interfere with feedback corrections. We found that hand trajectories after the perturbations were altered to avoid obstacles in the environment. Importantly, changes in muscle activity reflecting the different target shapes (bar vs. dot) or the presence of obstacles were observed in as little as 70 ms. Such changes in motor responses were qualitatively consistent with simulations based on optimal feedback control. Taken together, these results highlight that long-latency motor responses consider spatial properties of the goal and environment.

Influence of the behavioral goal and environmental obstacles on rapid feedback responses.

In human beings, physiological signals are characterised by their complexity. Even under resting conditions, most of their features continuously fluctuate in a complex manner over the long-term, exhibiting long-range autocorrelations. Largely studied in stride duration variability and perturbed in walking of neurodegenerative disorders (Parkinson’s, Huntington’s diseases and amyotrophic lateral sclerosis) and under constrained conditions (metronome), long-range autocorrelations could result from a centrally mediated process (Hausdorff 2007). Walking and cycling represent two rhythmic tasks, involving similar neuronal and biomechanical processes and using the same peripheral structures. Nevertheless, contrary to stride duration variability, revolution time variability had received little attention. This study was designed in order to assess the magnitude and the dynamics of revolution time variability during cycling.

Manipulating a cup by the handle requires compensating for the torque induced by the moment of the mass of the cup relative to the location of the handle. In the present study, we investigated the control strategy of subjects asked to perform grip-lift movements with an object with center of mass located away from the grip axis. Participants were asked to lift the manipulandum with a two-fingers precision grip and stabilize it in front of a visual target. Subjects showed a gradual and slow adaptation of the grip-force scaling across trials: the grip force tended to decrease slowly, and the temporal coordination between grip-force and load-torque rates displayed gradually, better-coordinated patterns. Importantly, this adaptation was much slower than the stabilization of the same parameters measured either when no torque came into play or after previous adaptation to the presence of a torque. In contrast, the maximum rotation induced by the torque was controlled efficiently after only few trials, and an unexpected decrease in the tangential torque produced significant overcompensation. An unexpected increase in torque produced a consistent opposite effect. This shows that the compensation for the dynamic torque was based on an anticipatory, dynamic counter-torque produced by the arm and wrist motor commands. The comparatively slow stabilization of grip-force control suggests a specific adaptation process engaged by the presence of the torque. This paradigm, including tangential torques, clearly constitutes a powerful tool to extract the adaptive component of grip control during object manipulation.

Adaptive control of grip force to compensate for static and dynamic torques during object manipulation.

Improving the state estimation for optimal control of stochastic processes subject to multiplicative noise

Sensory noise and feedback delay are potential sources of instability and variability for the on-line control of movement. It is commonly assumed that predictions based on internal models allow the CNS to anticipate the consequences of motor actions and protect the movements from uncertainty and instability. However, during motor learning and exposure to unknown dynamics, these predictions can be inaccurate. Therefore a distinct strategy is necessary to preserve movement stability. This study tests the hypothesis that in such situations, subjects adapt the speed and accuracy constraints on the movement, yielding a control policy that is less prone to undesirable variability in the outcome. This hypothesis was tested by asking subjects to hold a manipulandum in precision grip and to perform single-joint, discrete arm rotations during short-term exposure to weightlessness (0 g), where the internal models of the limb dynamics must be updated. Measurements of grip force adjustments indicated that the internal predictions were altered during early exposure to the 0 g condition. Indeed, the grip force/load force coupling reflected that the grip force was less finely tuned to the load-force variations at the beginning of the exposure to the novel gravitational condition. During this learning period, movements were slower with asymmetric velocity profiles and target undershooting. This effect was compared with theoretical results obtained in the context of optimal feedback control, where changing the movement objective can be directly tested by adjusting the cost parameters. The effect on the simulated movements quantitatively supported the hypothesis of a change in cost function during early exposure to a novel environment. The modified optimization criterion reduces the trial-to-trial variability in spite of the fact that noise affects the internal prediction. These observations support the idea that the CNS adjusts the movement objective to stabilize the movement when internal models are uncertain.

Any motor action results from a complex combination of motor commands that control the muscular forces and produce the desired movement. For this purpose, the motor commands must continuously compensate for the action of external forces acting on the body, of which the omnipresent gravitational forces. As a consequence, an internal knowledge of the movement dynamics, including the effect of gravitational forces, is essential in order to achieve successful movements. Evidence for such internal representation can be found in existing studies, but the role that gravity plays in the internal models of dynamics remains a challenging problem. The present thesis uses an experimental and modeling approaches in order to better understand the role played by gravity in sensorimotor coordination. This thesis shows that motor behavior in hypergravity (1.8 times terrestrial gravity) is consistent with the hypothesis the motor commands are optimized, taking into account the action of gravitational forces on the limb in the optimization process. In addition, forces applied by the subjects on a manipulated object were in direct support to the fact that the object weight was used by the brain for calibrating the internal models of dynamics. These results gave significant insight on the problem of sensorimotor coordination in weightlessness (0 g), given that the sensory information resulting from the action of gravity on the limbs is lost. The results confirm that internal representation of dynamics adapts to the 0 g condition, but it suffers from more uncertainty and, therefore, potentially affects the movement stability. A stabilizing mechanism that accounts for the experimental results is proposed as model for motor behavior under uncertain internal representation of dynamics.

The gravitational forces as fundamental input for sensorimotor coordination

During object manipulation, predictive grip force modulation allows compensation for inertial forces induced by the object's acceleration. This coupling between grip force (GF) and load force (LF) during voluntary movements has demonstrated high levels of complexity, adaptability, and flexibility under many loading conditions in a broad range of experimental studies. The association between GF and LF indicates the presence of internal models underlying predictive GF control. The present experiment sought to identify the variables taken into account during GF modulation at the initiation of a movement. Twenty subjects performed discrete point-to-point movements under normal and hypergravity conditions induced by parabolic flights. Two control experiments performed under normal gravitational conditions compared the observed effect of the increase in gravity with the effects of a change in movement kinematics and a change in mass. In hypergravity, subjects responded accurately to the increase in weight during stationary holding but overestimated inertial loads. During dynamic phases, the relationship between GF and LF under hypergravity varied in a manner similar to the control test in which object mass was increased, whereas a change in movement kinematics could not reproduce this result. We suggest that the subjects' strategy for anticipatory GF modulation is based on sensorimotor mapping that combines the perception of the weight encoded during stationary holding with an internal representation of the movement kinematics. In particular, such a combination reflects a prior knowledge of the unequivocal relationship linking mass, weight, and loads under the invariant gravitational context experienced on Earth.

Towards a “gold-standard” approach to address the presence of long-range auto-correlation in physiological time series

6 Frédéric Crevecoeur, Jean-Louis Thonnard, Philippe Lefèvre 7 8 1 Center for Systems Engineering and Applied Mechanics (CESAME), Université catholique 9 de Louvain, Belgium 10 2 Institute of Neuroscience (IoNS), Université catholique de Louvain, Belgium 11 12 13 14 15 Corresponding author: 16 P. Lefèvre 17 4 Avenue Georges Lemaître 18 1348 Louvain-la-Neuve, Belgium 19 Tel: +3210472382 20 Fax: +3210472180 21 Email: philippe.lefevre@uclouvain.be 22 23 24

Does human gait exhibit comparable and reproducible long-range autocorrelations on level ground and on treadmill?

The planning and control of motor actions requires knowledge of the dynamics of the controlled limb to generate the appropriate muscular commands and achieve the desired goal. Such planning and control imply that the CNS must be able to deal with forces and constraints acting on the limb, such as the omnipresent force of gravity. The present study investigates the effect of hypergravity induced by parabolic flights on the trajectory of vertical pointing movements to test the hypothesis that motor commands are optimized with respect to the effect of gravity on the limb. Subjects performed vertical pointing movements in normal gravity and hypergravity. We use a model based on optimal control to identify the role played by gravity in the optimal arm trajectory with minimal motor costs. First, the simulations in normal gravity reproduce the asymmetry in the velocity profiles (the velocity reaches its maximum before half of the movement duration), which typically characterizes the vertical pointing movements performed on Earth, whereas the horizontal movements present symmetrical velocity profiles. Second, according to the simulations, the optimal trajectory in hypergravity should present an increase in the peak acceleration and peak velocity despite the increase in the arm weight. In agreement with these predictions, the subjects performed faster movements in hypergravity with significant increases in the peak acceleration and peak velocity, which were accompanied by a significant decrease in the movement duration. This suggests that movement kinematics change in response to an increase in gravity, which is consistent with the hypothesis that motor commands are optimized and the action of gravity on the limb is taken into account. The results provide evidence for an internal representation of gravity in the central planning process and further suggest that an adaptation to altered dynamics can be understood as a reoptimization process.

Optimal integration of gravity in trajectory planning of vertical pointing movements.

Feed forward compensation of hyper gravity in vertical pointing movements

ONLY crevecoeur , cluff and scott : goal-directed movement planning and execution 435 39 Computational Approaches for Goal-Directed Movement Planning and Execution

Author response for "Effects of pupillary light and darkness reflex on the generation of pro- And anti-saccades"

Brain activity is highly variable during simple and cognitively demanding tasks1,2 impacting performance3,4. Discovering, characterizing, and linking variability in brain activity to internal processes has primarily relied on experimentally inducing changes (e.g., via attention manipulation) to identify neuronal and behavioral consequences5 or studying spontaneous changes in ongoing brain dynamics6. However, changes in internal processing could arise from many factors, such as variation in strategy or arousal7, that are independent of experimental conditions8. Here we utilize a data-driven clustering method based on modularity-maximation to identify consistent spatial-temporal EEG activity patterns across individual trials and relate this activity to behavioral performance. Subjects (N = 25) performed a motion direction discrimination task with six interleaved levels of motion coherence. We identify two subsets of trials, Subtype 1 and Subtype 2, with distinct spatial-temporal brain activity. Surprisingly, even though Subtype 1 occurred more frequently with lower motion coherences, it was nonetheless associated with faster response times. Computational modeling suggested that Subtype 1 was characterized by a lower amount of information required to reach a decision. These results open a new way to identify brain states relevant to cognition and behavior not associated with experimental factors.

Brain signatures indexing variation in internal processing during perceptual decision-making

Knowing when confidence computations take place is critical for building mechanistic understanding of the neural and computational bases of metacognition. Yet, even though substantial amount of research has focused on revealing the neural correlates and computations underlying human confidence judgments, very little is known about the timing of confidence computations. Subjects judged the orientation of a briefly presented visual stimulus and provided a confidence rating regarding the accuracy of their decision. We delivered single pulses of transcranial magnetic stimulation (TMS) at different times after stimulus presentation. TMS was delivered to either dorsolateral prefrontal cortex (DLPFC) in the experimental group or to vertex in the control group. We found that TMS to DLPFC, but not to vertex, led to increased confidence in the absence of changes to accuracy or metacognitive ability. Critically, equivalent levels of confidence increase occurred for TMS delivered between 200 and 500 ms after stimulus presentation. These results suggest that confidence computations occur during a broad window that begins before the perceptual decision has been fully made and thus provide important constraints for theories of confidence generation.

The timing of confidence computations in human prefrontal cortex

Research in neuroscience often assumes universal neural mechanisms, but increasing evidence points towards sizeable individual differences in brain activations. What remains unclear is the extent of the idiosyncrasy and whether different types of analyses are associated with different levels of idiosyncrasy. Here we compute the within-subject reliability and subject-to-group similarity of activations for task, reaction time (RT), and confidence at both the single trial and block levels. We find that maps of RT and confidence effects at the block level feature substantially lower subject-to-group similarity values compared to RT and confidence effects at the trials level, and that this effect occurs despite high within-subject reliabilities for both analyses. Critically, we develop a computational model that can quantify the relative strength of group- and subject-level factors in observed brain activations. The model suggests that subject-level factors carry similar weight as group-level factors for analyses at the trial level, but are over six times more important for RT and confidence analyses at the block level. These results show that different analyses are associated with different levels of idiosyncrasy and specifically suggest that behavioral changes that occur at the block level are markedly more idiosyncratic compared to other mental processes. Highlights Brain activation among people differ. The extent of these differences at trial- and block-level analyses is unknown. Results indicate that block-level analyses are more idiosyncratic. These findings suggest the need to examine individual-subject results.

Using serial dependence to predict confidence across observers and cognitive domains

Meaningful variation in internal states that impacts cognition and behavior remains challenging to discover and characterize. Here we leveraged trial-to-trial fluctuations in the brain-wide signal recorded using functional MRI to test if distinct sets of brain regions are activated on different trials when accomplishing the same task. Subjects performed a perceptual decision-making task and provided confidence. We estimated the brain activations for each trial and clustered trials based on their similarity using modularity-maximization, a data-driven classification method. We identified three subtypes of trials that differed in both their activation profile and behavioral performance. Critically, Subtypes 1 and 2 were characterized by activations in different task-positive areas. Surprisingly, Subtype 3 exhibited strong activation in the default mode network, which is typically thought to decrease in activity during a task. Computational modeling revealed how the patterns of brain activity in each subtype emerged from interactions within and between large-scale brain networks. These findings demonstrate that the same task can be accomplished in the presence of widely varying brain activation patterns.

Appropriate perceptual decision making necessitates the accurate estimation and use of sensory uncertainty. Such estimation has been studied in the context of both low-level multisensory cue combination and metacognitive estimation of confidence, but it remains unclear whether the same computations underlie both sets of uncertainty estimation. We created visual stimuli with low vs. high overall motion energy, such that the high-energy stimuli led to higher confidence but lower accuracy in a visual-only task. Importantly, we tested the impact of the low- and high-energy visual stimuli on auditory motion perception in a separate task. Despite being irrelevant to the auditory task, both visual stimuli impacted auditory judgments presumably via automatic low-level mechanisms. Critically, we found that the high-energy visual stimuli influenced the auditory judgments more strongly than the low-energy visual stimuli. This effect was in line with the confidence but contrary to the accuracy differences between the high- and low-energy stimuli in the visual-only task. These effects were captured by a simple computational model that assumes common computational principles underlying both confidence reports and multisensory cue combination. Our results reveal a deep link between automatic sensory processing and metacognitive confidence reports, and suggest that vastly different stages of perceptual decision making rely on common computational principles.

Common computations in automatic cue combination and metacognitive confidence reports

Convolutional neural networks currently provide the best models of biological vision. However, their decision behavior, including the facts that they are deterministic and use equal number of computations for easy and difficult stimuli, differs markedly from human decision-making, thus limiting their applicability as models of human perceptual behavior. Here we develop a new neural network, RTNet, that generates stochastic decisions and human-like response time (RT) distributions, and also reproduces all foundational features of human accuracy, RT, and confidence. To test RTNet’s ability to predict human behavior on novel images, we collected accuracy, RT, and confidence data from 60 human subjects performing a digit discrimination task. We found that the accuracy, RT, and confidence produced by RTNet for individual novel images correlated with the same quantities produced by human subjects. Critically, human subjects who were more similar to the average human performance were also found to be closer to RTNet’s predictions. Overall, RTNet is the first neural network that exhibits all basic signatures of perceptual decision making, and therefore provides the most detailed model of all critical features of human behavior for novel images.

RTNet: A neural network that exhibits the signatures of human perceptual decision making

Human behavior is known to be idiosyncratic, yet research in neuroscience typically assumes a universal brain-behavior relationship. Here we test this assumption by estimating the level of idiosyncrasy in individual brain-behavior maps obtained using human neuroimaging. We first show that task-based activation maps are both stable within an individual and similar across people. Critically, although behavior-based activation maps are also stable within an individual, they strongly diverge across people. A computational model that jointly generates brain activity and behavior explains these results and reveals that within-person factors have much larger effect than group factors in determining behavior-based activations. These findings demonstrate that unlike task-based activity that is mostly similar among people, the relation between brain activity and behavioral outcomes is largely idiosyncratic. Thus, contrary to popular assumptions, group-level behavior-based maps reveal relatively little about each individual.

Idiosyncratic relation between human brain activity and behavior

One of the most important human faculties is the ability to acquire not just new memories but the capacity to perform entirely new tasks. However, little is known about the brain mechanisms underlying the learning of novel tasks. Specifically, it is unclear to what extent learning of different tasks depends on domain-general and/or domain-specific brain mechanisms. Here human subjects (N=45) learned to perform six new tasks while undergoing functional MRI. The different tasks required the engagement of perceptual, motor, and various cognitive processes (attention, expectation, speed-accuracy tradeoff, and metacognition). We found that a bilateral frontoparietal network was more active during the initial compared to the later stages of task learning, and that this effect was stronger for task variants requiring more new learning. Critically, the same frontoparietal network was engaged by all six tasks, demonstrating its domain generality. Finally, although task learning decreased the overall activity in the frontoparietal network, it increased the connectivity strength between the different nodes of that network. These results demonstrate the existence of a domain-general brain network whose activity and connectivity reflect learning for a wide variety of new tasks, and thus may underlie the human capacity for acquiring new abilities.

It is widely believed that feedback improves behavior, but the mechanisms behind this improvement remain unclear. Different theories postulate that feedback has either a direct effect on performance through automatic reinforcement mechanisms or only an indirect effect mediated by a deliberate change in strategy. To adjudicate between these competing accounts, we performed two large experiments on human adults (total N = 518); approximately half the participants received trial-by-trial feedback on a perceptual task, whereas the other half did not receive any feedback. We found that feedback had no effect on either perceptual or metacognitive sensitivity even after 7 days of training. On the other hand, feedback significantly affected participants’ response strategies by reducing response bias and improving confidence calibration. These results suggest that the beneficial effects of feedback stem from allowing people to adjust their strategies for performing the task and not from direct reinforcement mechanisms, at least in the domain of perception.

The Impact of Feedback on Perceptual Decision-Making and Metacognition: Reduction in Bias but No Change in Sensitivity

Shared brain responses but idiosyncratic relations between brain activity and behavior

The mystery of what probabilistic perception means and why we should focus on the complexity of the internal representations instead

Across-subject correlation between confidence and accuracy: A meta-analysis of the Confidence Database

Abstract Transcranial magnetic stimulation (TMS) is widely used for understanding brain function in neurologically intact subjects and for the treatment of various disorders. However, the precise neurophysiological effects of TMS at the site of stimulation remain poorly understood. The local effects of TMS can be studied using concurrent TMS-functional magnetic resonance imaging (fMRI), a technique where TMS is delivered during fMRI scanning. However, although concurrent TMS-fMRI was developed over 20 years ago and dozens of studies have used this technique, there is still no consensus on whether TMS increases blood oxygen level-dependent (BOLD) activity at the site of stimulation. To address this question, here we review all previous concurrent TMS-fMRI studies that reported analyses of BOLD activity at the target location. We find evidence that TMS increases local BOLD activity when stimulating the primary motor (M1) and visual (V1) cortices but that these effects are likely driven by the downstream consequences of TMS (finger twitches and phosphenes). However, TMS does not appear to increase BOLD activity at the site of stimulation for areas outside of the M1 and V1 when conducted at rest. We examine the possible reasons for such lack of BOLD signal increase based on recent work in nonhuman animals. We argue that the current evidence points to TMS inducing periods of increased and decreased neuronal firing that mostly cancel each other out and therefore lead to no change in the overall BOLD signal.

TMS Does Not Increase BOLD Activity at the Site of Stimulation: A Review of All Concurrent TMS-fMRI Studies

3D-printed stand, timing interface, and coil localization tools for concurrent TMS-fMRI experiments

Our perceptual system appears hardwired to exploit regularities of input features across space and time in seemingly stable environments. This can lead to serial dependence effects whereby recent perceptual representations bias current perception. Serial dependence has also been demonstrated for more abstract representations such as perceptual confidence. Here we ask whether temporal patterns in the generation of confidence judgments across trials generalize across observers and different cognitive domains. Data from the Confidence Database across perceptual, memory, and cognitive paradigms was re-analyzed. Machine learning classifiers were used to predict the confidence on the current trial based on the history of confidence judgments on the previous trials. Cross-observer and cross-domain decoding results showed that a model trained to predict confidence in the perceptual domain generalized across observers to predict confidence across the different cognitive domains. Intriguingly, these serial dependence effects also generalized across correct and incorrect trials, indicating that serial dependence in confidence generation is uncoupled to metacognition (i.e. how we evaluate the precision of our own behavior). We discuss the ramifications of these findings for the ongoing debate on domain-generality vs. specificity of metacognition.

Visual metacognition is the ability to evaluate one's performance on visual perceptual tasks. The field of visual metacognition unites the long tradition of visual psychophysics with the younger field of metacognition research. This article traces the historical roots of the field and reviews progress in the areas of (a) constructing appropriate measures of metacognitive ability, (b) developing computational models, and (c) revealing the neural correlates of visual metacognition. First, I review the most popular measures of metacognitive ability with an emphasis on their psychophysical properties. Second, I examine the empirical targets for modeling, the dominant modeling frameworks and the assumed computations underlying visual metacognition. Third, I explore the progress on understanding the neural correlates of visual metacognition by focusing on anatomical and functional studies, as well as causal manipulations. What emerges is a picture of substantial progress on constructing measures, developing models, and revealing the neural correlates of metacognition, but very little integration between these three areas of inquiry. I then explore the deep, intrinsic links between the three areas of research and argue that continued progress requires the recognition and exploitation of these links. Throughout, I discuss the implications of progress in visual metacognition for other areas of metacognition research, and pinpoint specific advancements that could be adopted by researchers working in other subfields of metacognition. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

A fundamental question for perception research is what sensory information is available for decision making, or, stated differently, what is the output of perception. One answer that has emerged in the last two decades is that perception is probabilistic, meaning that the brain represents probability distributions over world states. However, despite the apparent simplicity of this statement, there are substantial disagreements on exactly what probabilistic perception is and how it should be tested. In this adversarial collaboration, two proponents (Jehee and Denison) and two skeptics (Rahnev and Block) of probabilistic perception deliberate on the terms of the debate and present arguments for or against the notion that perception is probabilistic. We believe that this collaboration helps clarify the critical issues that need to be considered but that further work is required to reach consensus.

Qualitative speed-accuracy tradeoff effects that cannot be explained by the diffusion model under the selective influence assumption

We recently found a positive relationship between estimates of metacognitive efficiency and metacognitive bias. However, this relationship was only examined on a within-subject level and required binarizing the confidence scale, a technique that introduces methodological difficulties. Here we examined the robustness of the positive relationship between estimates of metacognitive efficiency and metacognitive bias by conducting two different types of analyses. First, we developed a new within-subject analysis technique where the original n-point confidence scale is transformed into two different (n-1)-point scales in a way that mimics a naturalistic change in confidence. Second, we examined the across-subject correlation between metacognitive efficiency and metacognitive bias. Importantly, for both types of analyses, we not only established the direction of the effect but also computed effect sizes. We applied both techniques to the data from three tasks from the Confidence Database (N > 400 in each). We found that both approaches revealed a small to medium positive relationship between metacognitive efficiency and metacognitive bias. These results demonstrate that the positive relationship between metacognitive efficiency and metacognitive bias is robust across several analysis techniques and datasets, and have important implications for future research.

Examining the robustness of the relationship between metacognitive efficiency and metacognitive bias

If one friend confidently tells us to buy product A while another friend thinks that product B is better but is not confident, we may go with the advice of our confident friend. Should we? The relationship between people’s confidence and accuracy has been of great interest in many fields, especially in the context of high-stakes situations like eye-witness testimony, but there is still little consensus about how much we should trust someone’s overall level of confidence. Here we examine the across-subject relationship between average accuracy and average confidence in 214 unique datasets from the Confidence Database. This approach allows us to empirically address this issue with unprecedented statistical power and check for the presence of various moderators. We find that the across-subject correlation between average accuracy and average confidence in this sample is R = .22. Importantly, this relationship is much stronger for memory than for perception tasks, as well as for confidence scales with fewer points. These results show that we should take one’s confidence seriously (and perhaps buy product A) and suggest several factors that moderate the relative consistency of how people make confidence judgments.

Moderators of relative confidence calibration: A meta-analysis of the across-subject relationship between confidence and accuracy

Despite the tangible progress in psychological and cognitive sciences over the last several years, these disciplines still trail other more mature sciences in identifying the most important questions that need to be solved. Reaching such consensus could lead to greater synergy across different laboratories, faster progress, and increased focus on solving important problems rather than pursuing isolated, niche efforts. Here, 26 researchers from the field of visual metacognition reached consensus on four long-term and two medium-term common goals. We describe the process that we followed, the goals themselves, and our plans for accomplishing these goals. If this effort proves successful within the next few years, such consensus building around common goals could be adopted more widely in psychological science.

Transcranial magnetic stimulation (TMS) is widely used for understanding brain function in neurologically intact subjects and for the treatment of various disorders. However, the precise neurophysiological effects of TMS at the site of stimulation remain poorly understood. The local effects of TMS can be studied using concurrent TMS-fMRI, a technique where TMS is delivered during fMRI scanning. However, although concurrent TMS-fMRI was developed over 20 years ago and dozens of studies have used this technique, there is still no consensus on whether TMS increases blood-oxygen-level-dependent (BOLD) activity at the site of stimulation. To address this question, here we review all previous concurrent TMS-fMRI studies that reported analyses of BOLD activity at the target location. We find evidence that TMS increases local BOLD activity when stimulating the primary motor and visual cortices but that these effects are likely driven by the downstream consequences of TMS (finger twitches and phosphenes). However, TMS does not appear to increase BOLD activity at the site of stimulation for areas outside of the primary motor and visual cortices when conducted at rest. We examine the possible reasons for such lack of BOLD signal increase based on recent work in non-human animals. We argue that the current evidence points to TMS inducing periods of increased and decreased neuronal firing that mostly cancel each other out and therefore lead to no change in the overall BOLD signal.

Using model comparisons to reveal the mechanisms of confidence generation

Brain connectivity profiles associated with perceptual task performance

The shape of metacognitive noise confounds metacognitive efficiency with confidence bias

Abstract Many studies have shown that confidence and accuracy can be dissociated in a variety of tasks. However, most of these dissociations involve small effect sizes, occur only in a subset of participants, and include a reaction time (RT) confound. Here, I develop a new method for inducing confidence–accuracy dissociations that overcomes these limitations. The method uses an external noise manipulation and relies on the phenomenon of criterion attraction where criteria for different tasks become attracted to each other. Subjects judged the identity of stimuli generated with either low or high external noise. The results showed that the two conditions were matched on accuracy and RT but produced a large difference in confidence (effect appeared for 25 of 26 participants, effect size: Cohen’s d = 1.9). Computational modeling confirmed that these results are consistent with a mechanism of criterion attraction. These findings establish a new method for creating conditions with large differences in confidence without differences in accuracy or RT. Unlike many previous studies, however, the current method does not lead to differences in subjective experience and instead produces robust confidence–accuracy dissociations by exploiting limitations in post-perceptual, cognitive processes.

A robust confidence–accuracy dissociation via criterion attraction

Sequential data with serial correlation and an unknown, unstructured, and dynamic background is ubiquitous in neuroscience, psychology, and econometrics. Inferring serial correlation for such data is a fundamental challenge in statistics. We propose a Total Variation (TV) constrained least square estimator coupled with hypothesis tests to infer the serial correlation in the presence of unknown and unstructured dynamic background. The TV constraint on the dynamic background encourages a piecewise constant structure, which can approximate a wide range of dynamic backgrounds. The tuning parameter is selected via the Ljung-Box test to control the bias-variance trade-off. We establish a non-asymptotic upper bound for the estimation error through variational inequalities. We also derive a lower error bound via Fano’s method and show the proposed method is near-optimal. Numerical simulation and a real study in psychology demonstrate the excellent performance of our proposed method compared with the state-of-the-art.

The nature of metacognitive noise confounds metacognitive sensitivity and metacognitive bias

Transcranial magnetic stimulation (TMS) has become one of the major tools for establishing the causal role of specific brain regions in perceptual, motor, and cognitive processes. Nevertheless, a persistent limitation of the technique is the lack of clarity regarding its precise effects on neural activity. Here, we examined the effects of TMS intensity and frequency on concurrently recorded blood‐oxygen‐level‐dependent (BOLD) signals at the site of stimulation. In two experiments, we delivered TMS to the dorsolateral prefrontal cortex in human subjects of both sexes. In Experiment 1, we delivered a series of pulses at high (100% of motor threshold) or low (50% of motor threshold) intensity, whereas, in Experiment 2, we always used high intensity but delivered stimulation at four different frequencies (5, 8.33, 12.5, and 25 Hz). We found that the TMS intensity and frequency could be reliably decoded using multivariate analysis techniques even though TMS had no effect on the overall BOLD activity at the site of stimulation in either experiment. These results provide important insight into the mechanisms through which TMS influences neural activity.

Transcranial magnetic stimulation alters multivoxel patterns in the absence of overall activity changes

Transcranial magnetic stimulation (TMS) is an effective research tool to elucidate mechanisms of function in the brain. Despite its widespread use, very few studies have looked at dynamic functional connectivity responses to TMS. This work performs an exploratory analysis of dynamic functional network connectivity (dynFNC) to evaluate evidence of brain response to TMS. Results show clear functional dynamic patterns categorized by frequency. Some patterns appear to be more directly linked to TMS, but there is one pattern that might be a TMS-independent response to the excitation. This first look presents an analysis methodology and important results to consider in future research.

2021 43rd Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC)

Evidence for Transcranial Magnetic Stimulation Induced Functional Connectivity Oscillations in the Brain

Humans exhibit substantial biases in their decision making even in simple two-choice tasks, but the origin of these biases remains unclear. I hypothesized that one source of bias could be individual differences in sensory encoding. Specifically, if one stimulus category gives rise to an internal-evidence distribution with higher variability, then responses should optimally be biased against that stimulus category. Therefore, response bias may reflect a previously unappreciated subject-to-subject difference in the variance of the internal-evidence distributions. I tested this possibility by analyzing data from three different two-choice tasks (ns = 443, 443, and 498). For all three tasks, response bias moved in the direction of the optimal criterion determined by each subject’s idiosyncratic internal-evidence variability. These results demonstrate that seemingly random variations in response bias can be driven by individual differences in sensory encoding and are thus partly explained by normative strategies.

Response Bias Reflects Individual Differences in Sensory Encoding

Scientific question Is perception probabilistic? This is a grand question about the fundamental nature of how our mind operates and how this operation is implemented in brain circuits. The question is also interpreted differently by different people, making progress difficult. In this adversarial collaboration, four scientists with different backgrounds and perspectives on this issue1–7 engaged in considerable discussion of how the issue of probabilistic perception can be operationalized as to be made empirically tractable. We have agreed that a critical dividing line between probabilistic and non-probabilistic views of perception is defined by the following question: Can humans perform flexible and deliberate (i.e., cognitive) computations that require access to more than summary statistics (mean and variance) of a perceptual likelihood function or posterior on a single-trial basis?

Humans have the metacognitive ability to judge the accuracy of their own decisions via confidence ratings. A substantial body of research has demonstrated that human metacognition is fallible but it remains unclear how metacognitive inefficiency should be incorporated into a mechanistic model of confidence generation. Here we show that, contrary to what is typically assumed, metacognitive inefficiency depends on the level of confidence. We found that, across five different datasets and four different measures of metacognition, metacognitive ability decreased with higher confidence ratings. To understand the nature of this effect, we collected a large dataset of 20 subjects completing 2,800 trials each and providing confidence ratings on a continuous scale. The results demonstrated a robustly nonlinear zROC curve with downward curvature, despite a decades-old assumption of linearity. This pattern of results was reproduced by a new mechanistic model of confidence generation, which assumes the existence of lognormally-distributed metacognitive noise. The model outperformed competing models either lacking metacognitive noise altogether or featuring Gaussian metacognitive noise. Further, the model could generate a measure of metacognitive ability which was independent of confidence levels. These findings establish an empirically-validated model of confidence generation, have significant implications about measures of metacognitive ability, and begin to reveal the underlying nature of metacognitive inefficiency.

The nature of metacognitive inefficiency in perceptual decision making

Humans have the metacognitive ability to judge the accuracy of their own decisions via confidence ratings. A substantial body of research has demonstrated that human metacognition is fallible but it remains unclear how metacognitive inefficiency should be incorporated into a mechanistic model of confidence generation. Here we show that, contrary to what is typically assumed, metacognitive inefficiency depends on the level of confidence. We found that, across 5 different data sets and 4 different measures of metacognition, metacognitive ability decreased with higher confidence ratings. To understand the nature of this effect, we collected a large dataset of 20 subjects completing 2,800 trials each and providing confidence ratings on a continuous scale. The results demonstrated a robustly nonlinear zROC curve with downward curvature, despite a decades-old assumption of linearity. This pattern of results was reproduced by a new mechanistic model of confidence generation, which assumes the existence of lognormally distributed metacognitive noise. The model outperformed competing models either lacking metacognitive noise altogether or featuring Gaussian metacognitive noise. Further, the model could generate a measure of metacognitive ability which was independent of confidence levels. These findings establish an empirically validated model of confidence generation, have significant implications about measures of metacognitive ability, and begin to reveal the underlying nature of metacognitive inefficiency. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

The nature of metacognitive inefficiency in perceptual decision making.

Transcranial magnetic stimulation (TMS) has become one of the major tools for establishing the causal role of specific brain regions in perceptual, motor, and cognitive processes. Nevertheless, a persistent limitation of the technique is the lack of clarity regarding its precise effects on neural dynamics. Here, we examined the effects of TMS intensity and frequency on concurrently recorded blood-oxygen level-dependent (BOLD) signals at the site of stimulation in dorsolateral prefrontal cortex. In Experiment 1, we delivered a series of pulses at high (100% of motor threshold) or low (50% of motor threshold) intensity, whereas in Experiment 2, we always used high intensity but delivered stimulation at four different frequencies (5, 8.33, 12.5, and 25 Hz). We found that the TMS intensity and frequency could be reliably decoded using multivariate analysis techniques even though TMS had no effect on overall BOLD activity at the site of stimulation in either experiment. These results provide important insight into the mechanisms through which TMS influences neural activity.

TMS alters multivoxel patterns in the absence of overall activity changes

It is widely believed that feedback improves behavior but the mechanisms behind this improvement remain unclear. Different theories postulate that feedback has either a direct effect on performance through automatic reinforcement mechanisms or only an indirect effect mediated by a deliberate change in strategy. To adjudicate between these two competing accounts, we performed a large-scale study including 443 subjects; approximately half of them received trial-by-trial feedback on a perceptual task, while the other half did not receive such feedback. We found that feedback had no effect on either perceptual or metacognitive sensitivity. On the other hand, feedback significantly affected subjects’ response strategies by reducing bias and improving calibration in both the perceptual and metacognitive judgments. These results strongly support the view that feedback does not improve behavior through direct reinforcement mechanisms but that its beneficial effects stem from allowing people to adjust their strategies for performing the task.

The impact of feedback on perceptual decision making and metacognition: Reduction in bias but no change in sensitivity

Abstract Lieder and Griffiths advocate for resource-rational analysis as a methodological device employed by the experimenter. However, at times this methodological device appears to morph into the substantive claim that humans are actually resource-rational. Such morphing is problematic; the methodological approach used by the experimenter and claims about the nature of human behavior ought to be kept completely separate.

The suboptimality of perceptual decision making with multiple alternatives

Post-training TMS abolishes performance improvement and releases future learning from interference

Abstract Electrophysiological recordings show that any visual stimulus produces a response in a large population of differently tuned sensory neurons. However, it remains unclear how this population response is used to make perceptual decisions. Major theories, such as probabilistic population codes and neural sampling, assume that the population response can be flexibly used for decision making. However, another possibility is that decision-making circuits do not have access to the sensory population code but only to a summary of this code. These possibilities can be disentangled for choices among n>2 discrete stimulus categories. In two experiments, we asked subjects to choose between n=4 colors or n=6 symbols. We then used the n-alternative condition to predict the performance on a different, 2-alternative condition where only two colors or symbols were given as available alternatives on each trial. A population model assuming that decision-making circuits have access to the whole distribution of the sensory activation levels across all colors or symbols significantly overestimated the performance in the 2-alternative condition. Instead, a summary model assuming that decision-making circuits only have access to the sensory activity associated with the dominant color predicted the 2-alternative condition very well and was preferred in Bayesian model comparison. Finally, a third experiment asked subjects to make two decisions in a row and also found the summary model to provide a better description of the data. These results show that the full population code in sensory cortex may not be available for deliberate decision making, at least within the context of decisions between discrete alternatives.

Trial-by-trial feedback does not improve performance or metacognition in a large-sample perceptual task

ABSTRACT Objectives: Older adults show clear deficits in working memory functioning. Here, we investigate the often-reported decline in focus switching, that is, the ability to shift items from the focus of attention into working memory, and back. Specifically, we examined whether equating subjects on early processing (perception and attention) might ameliorate the deficit. Method: We examined 1-Back and 2-Back performance in younger and older adults, with line segments of different orientation as the stimuli. Stimuli were calibrated depending on each individual’s 75% threshold for 1-Back performance. Subjects made match/mismatch judgments. Results: After the calibration on 1-Back performance, no age-related differences were found on either accuracy or sensitivity in the 2-Back task. Additionally, when investigating focus-switch trials versus non-focus-switch trials in a random-order 2-Back task, older adults were more efficient at switching the focus of attention than younger adults. Discussion: These results provide evidence for the view that age-related limitations in focus switching in working memory are caused (at least in part) by changes in early processing (perception and attention), suggesting that (at least some of the) age-related differences in working memory functioning may be due to shifts in trade-off between early processing and memory-related processing.

Resolving Age-Related Differences in Working Memory: Equating Perception and Attention Makes Older Adults Remember as Well as Younger Adults

Opportunities and challenges for a maturing science of consciousness

The nature of metacognitive imperfection in perceptual decision making

Previously learned information is known to be reactivated during periods of quiet wakefulness and such awake reactivation is considered to be a key mechanism for memory consolidation. We recently demonstrated that feature-specific awake reactivation occurs in early visual cortex immediately after extensive visual training on a novel task. To understand the exact role of awake reactivation, here we investigated whether such reactivation depends specifically on the task novelty. Subjects completed a brief visual task that was either novel or extensively trained on previous days. Replicating our previous results, we found that awake reactivation occurs for the novel task even after a brief learning period. Surprisingly, however, brief exposure to the extensively trained task led to “awake suppression” such that neural activity immediately after the exposure diverged from the pattern for the trained task. Further, subjects who had greater performance improvement showed stronger awake suppression. These results suggest that the brain operates different post-task processing depending on prior visual training.

Awake reactivation and suppression after brief task exposure depend on task novelty

Abstract It has been widely asserted that humans have a “Bayesian brain.” Surprisingly, however, this term has never been defined and appears to be used differently by different authors. I argue that Bayesian brain should be used to denote the realist view that brains are actual Bayesian machines and point out that there is currently no evidence for such a claim.

[This corrects the article DOI: 10.1093/nc/niz009.][This corrects the article DOI: 10.1093/nc/niz009.].

How experimental procedures influence estimates of metacognitive ability

Predictive cues reduce but do not eliminate intrinsic response bias

Overlapping and unique neural circuits support perceptual decision making and confidence

Abstract It is becoming widely appreciated that higher stimulus sensitivity trivially increases estimates of metacognitive sensitivity. Therefore, meaningful comparisons of metacognitive ability across conditions and observers necessitates equating stimulus sensitivity. To achieve this, one common approach is to use a continuous staircase that runs throughout the duration of the experiment under the assumption that this procedure has no influence on the estimated metacognitive ability. Here we critically examine this assumption. Using previously published data, we find that, compared to using a single level of stimulus contrast, staircase techniques lead to inflated estimates of metacognitive ability across a wide variety of measures including area under the type 2 ROC curve, the confidence-accuracy correlation phi, meta-d′, meta-d′/d′, and meta-d′–d′. Furthermore, this metacognitive inflation correlates with the degree of stimulus variability experienced by each subject. These results suggest that studies using a staircase approach are likely to report inflated estimates of metacognitive ability. Furthermore, we argue that similar inflation likely occurs in the presence of variability in task difficulty caused by other factors such as fluctuations in alertness or gradual improvement on the task. We offer practical solutions to these issues, both in the design and analysis of metacognition experiments.

Mixing different contrasts inflates estimated metacog-nitive ability in perceptual decision making

Overlapping and unique neural circuits are activated during perceptual decision making and confidence

Visual metacognition depends on regions within the prefrontal cortex (PFC). Two areas in particular have been implicated repeatedly: the dorsolateral PFC (DLPFC) and the anterior PFC (aPFC). However, it is still unclear what the function of each of these areas is and how they differ from each other. To establish the specific roles of DLPFC and aPFC in metacognition, we used online transcranial magnetic stimulation (TMS) to interfere causally with their functioning during confidence generation. Human subjects from both sexes performed a perceptual decision making and provided confidence ratings. We found a clear dissociation between the two areas: DLPFC TMS lowered confidence ratings, whereas aPFC TMS increased metacognitive ability, but only for the second half of the experimental blocks. These results support a functional architecture in which DLPFC reads out the strength of the sensory evidence and relays it to aPFC, which makes the confidence judgment by potentially incorporating additional, nonperceptual information. Indeed, simulations from a model that incorporates these putative DLPFC and aPFC functions reproduced our behavioral results. These findings establish DLPFC and aPFC as distinct nodes in a metacognitive network and suggest specific contributions from each of these regions to confidence generation. SIGNIFICANCE STATEMENT The prefrontal cortex (PFC) is known to be critical for metacognition. Two of its subregions, the dorsolateral PFC (DLPFC) and the anterior PFC (aPFC), have been specifically implicated in confidence generation. However, it is unclear whether these regions have distinct functions related to the underlying metacognitive computation. Using a causal intervention with transcranial magnetic stimulation, we demonstrate that DLPFC and aPFC have dissociable contributions: targeting DLPFC decreased average confidence ratings, whereas targeting aPFC affected metacognitive scores specifically. Based on these results, we postulated specific functions for DLPFC and aPFC in metacognitive computation and corroborated them using a computational model that reproduced our results. Our causal results reveal the existence of a specialized modular organization in PFC for confidence generation.

Distinguishing the Roles of Dorsolateral and Anterior PFC in Visual Metacognition

Training related skills in close succession results in interference but the reasons for this interference are not understood. Here we test the hypothesis that interference occurs due to competition of long-term potentiation (LTP): the LTP induced by one task impedes the LTP induced by the other. Human subjects performed two consecutive training sessions on different Gabor orientations. Immediately after the offset of the first training, we applied continuous theta burst stimulation (cTBS) to interfere with the LTP processes produced by the first training. We found that cTBS to a control site (vertex) resulted in substantial anterograde interference for the second training. Critically, cTBS to the visual cortex not only disrupted learning on the immediately preceding training, but also released the second training from the anterograde interference. These results provide strong support for the LTP-based theory of interference and suggest the possibility of directly manipulating the competition between different learning periods.

The influence of low-level stimulus characteristics on metacognitive efficiency

Abstract The disagreements among commentators may appear substantial, but much of the debate seems to stem from inconsistent use of the term optimality. Optimality can be used to indicate sensible behavior (adapted to the environment), globally optimal behavior (fully predicted from optimality considerations alone), locally optimal behavior (conforming to a specific model), and optimality as an empirical strategy (a tool for studying behavior). Distinguishing among these different concepts uncovers considerable common ground in the optimality debate.

Behavior is sensible but not globally optimal: Seeking common ground in the optimality debate

Research Articles: Systems/Circuits Feature-specific awake reactivation in human V1 after visual training Ji Won Bang, Yuka Sasaki, Takeo Watanabe and Dobromir Rahnev School of Psychology, Georgia Institute of Technology, Atlanta, GA, 30318, USA Department of Ophthalmology, School of Medicine, New York University, New York, NY, 10016, USA Department of Cognitive, Linguistic, and Psychological Sciences, Brown University, Providence, RI, 02912, USA

Feature-specific awake reactivation in human V 1 after visual training 1 Abbreviated title : Feature-specific awake reactivation in human V 1 2

Decision-stage representation: Full distribution over possible choices or information about the most likely choice only?

On the nature of the perceptual representation at the decision stage

The scientific study of consciousness emerged as an organized field of research only a few decades ago. As empirical results have begun to enhance our understanding of consciousness, it is important to find out whether other factors, such as funding for consciousness research and status of consciousness scientists, provide a suitable environment for the field to grow and develop sustainably. We conducted an online survey on people’s views regarding various aspects of the scientific study of consciousness as a field of research. 249 participants completed the survey, among which 80% were in academia, and around 40% were experts in consciousness research. Topics covered include the progress made by the field, funding for consciousness research, job opportunities for consciousness researchers, and the scientific rigor of the work done by researchers in the field. The majority of respondents (78%) indicated that scientific research on consciousness has been making progress. However, most participants perceived obtaining funding and getting a job in the field of consciousness research as more difficult than in other subfields of neuroscience. Overall, work done in consciousness research was perceived to be less rigorous than other neuroscience subfields, but this perceived lack of rigor was not related to the perceived difficulty in finding jobs and obtaining funding. Lastly, we found that, overall, the global workspace theory was perceived to be the most promising (around 28%), while most non-expert researchers (around 22% of non-experts) found the integrated information theory (IIT) most promising. We believe the survey results provide an interesting picture of current opinions from scientists and researchers about the progresses made and the challenges faced by consciousness research as an independent field. They will inspire collective reflection on the future directions regarding funding and job opportunities for the field.

An Informal Internet Survey on the Current State of Consciousness Science

Understanding the accuracy-RT relationship: Model-free approaches and limitations of the drift diffusion model

Brain activity patterns exhibited during task performance have been shown to spontaneously reemerge in the following restful awake state. Such “awake reactivation” has been observed across higher-order cortex for complex images or associations. However, it is still unclear whether the reactivation extends to primary sensory areas that encode simple stimulus features. To address this question, we trained human subjects from both sexes on a particular visual feature (Gabor orientation) and tested whether this feature will be reactivated immediately after training. We found robust reactivation in human V1 that lasted for at least 8 min after training offset. This effect was not present in higher retinotopic areas, such as V2, V3, V3A, or V4v. Further analyses suggested that the amount of awake reactivation was related to the amount of performance improvement on the visual task. These results demonstrate that awake reactivation extends beyond higher-order areas and also occurs in early sensory cortex. SIGNIFICANCE STATEMENT How do we acquire new memories and skills? New information is known to be consolidated during offline periods of rest. Recent studies suggest that a critical process during this period of consolidation is the spontaneous reactivation of previously experienced patterns of neural activity. However, research in humans has mostly examined such reactivation processes in higher-order cortex. Here we show that awake reactivation occurs even in the primary visual cortex V1 and that this reactivation is related to the amount of behavioral learning. These results pinpoint awake reactivation as a process that likely occurs across the entire human brain and could play an integral role in memory consolidation.

Feature-Specific Awake Reactivation in Human V1 after Visual Training

How are perceptual decisions made? The answer to this seemingly simple question necessitates that we specify the nature of perceptual representations on which decisions are based. Some traditional models postulate that the perceptual representation consists of a simple point estimate of the stimulus. Such models do not allow the estimation of sensory uncertainty. On the other hand, recent models have proposed that the perceptual representation involves a full probability distribution over the possible stimulus values. Such models allow a precise estimation of sensory uncertainty. These two possibilities -- point estimates vs. full distributions -- are often seen as the only alternatives but they are not. Here I present five possible perceptual representation schemes that allow the extraction of different levels of sensory uncertainty. I explain where popular models fall within the five schemes and explore the relevant empirical evidence and theoretical arguments. The overwhelming evidence is at odds with both point estimates vs. full distributions. This conclusion is in stark contrast with current popular models in computational neuroscience built on such distributions. Instead, the most likely scheme appears to be one in which the perceptual representation features a point estimate coupled with a strength-of-evidence value.

Stimulus expectation alters decision criterion but not sensory signal in perceptual decision making

Human perceptual decisions are often described as optimal. This view reflects recent successes of Bayesian approaches to both cognition and perception. However, claims regarding optimality have been strongly criticized for their excessive flexibility and lack of explanatory power. Rebuttals from Bayesian theorists in turn claim that critics unfairly pick on select few papers. To resolve the issue regarding the role of optimality in perceptual decision making, we review the vast literature on suboptimal performance in perceptual tasks. Specifically, we discuss eight different classes of suboptimal perceptual decisions, including improper placement, maintenance, and adjustment of perceptual criteria, inadequate tradeoff between speed and accuracy, inappropriate confidence ratings, misweightings in cue combination, and findings related to various perceptual illusions and biases. We then extract the proposed explanations for the suboptimal behavior seen in each type of task. Critically, we show that these explanations naturally fit within an overarching Bayesian framework. Specifically, each suboptimality can be explained by alternative likelihood functions, priors, cost functions, or decision rules (LPCDs). We argue that unless the observer’s likelihood functions, priors, and cost functions are known, statements about the optimality or suboptimality of decision rules are meaningless. Further, the very definition of optimal behavior is debatable and may ultimately require appeals to evolutionary history beyond the current scope of perceptual science. The field should therefore shift its focus away from optimality. We propose a “LPCD approach” to perceptual decision making that focuses exclusively on uncovering the LPCD components, without debating whether the uncovered LPCDs are “optimal” or not. SHORT ABSTRACT Human perceptual decisions are often described as optimal, but this view remains controversial. To resolve the issue, we review the vast literature on suboptimalities in perceptual tasks. We then extract the proposed explanations for the suboptimal behavior seen in each type of task and show that each suboptimality can be explained by alternative likelihood functions, priors, cost functions, or decision rules (LPCDs). We argue that general statements about the optimality or suboptimality of perceptual decisions are meaningless and propose a “LPCD approach” to perceptual decision making that focuses on the LPCD components rather than optimality.

How are perceptual decisions made? The answer to this seemingly simple question necessitates that we specify the nature of perceptual representations on which decisions are based. Recent work has taken for granted that the representation at the decision stage consists of a full probability distribution over all possible stimuli. However, to date, no empirical evidence has supported this assumption. Here I present five possible perceptual representation schemes that allow the extraction of different levels of sensory uncertainty. I review the empirical evidence from both continuous and discrete judgments and show that, at present, only the most primitive scheme based on a single point estimate can be rejected. In other words, at least four different representational schemes are consistent with the available data and therefore full probability distributions cannot be assumed. There is an urgent need for empirical research to adjudicate between these theoretical possibilities.

The case against full probability distributions in perceptual decision making

Although most work on perceptual decision making has focused on the processing within the visual, temporal, and parietal lobes, recent research points to an underappreciated but critical role of the prefrontal cortex (PFC). PFC provides high-level control of perception, but it is unclear whether this control can be subdivided into different processes and whether different PFC regions have different roles. Here I review evidence that prefrontal top-down control is organized in the processes of selection control, decision control, and evaluation. These three processes overlap and interact with each other while at the same time maintaining a temporal hierarchy. Further, these different stages are supported by dissociable regions within the PFC that control hierarchically organized cognition. The current proposal for PFC’s role in perceptual control can serve as the basis for a deeper understanding of both the functional organization of PFC and the processes underlying perceptual decision making.

Top-Down Control of Perceptual Decision Making by the Prefrontal Cortex

Visual metacognition is the ability to employ confidence ratings in order to predict the accuracy of ones decisions about visual stimuli. Despite years of research, it is still unclear how visual metacognitive efficiency can be manipulated. Here we show that a hierarchical model of confidence generation makes a counterintuitive prediction: Higher sensory noise should increase metacognitive efficiency. The reason is that sensory noise has a large negative influence on the decision (where it is the only corrupting influence) but a smaller negative influence on confidence (where it is one of two corrupting influences; the other one being metacognitive noise). To test this prediction, we used a perceptual learning paradigm to decrease the amount of sensory noise. In Experiment 1, seven days of training led to significant decrease in noise as well as a corresponding decrease in metacognitive efficiency. Experiment 2 showed the same effect in a brief 97-trial learning for each of two different tasks. Finally, in Experiment 3, we experimentally manipulated stimulus contrast to increase sensory noise and observed a corresponding increase in metacognitive efficiency. Our findings demonstrate the existence of a robust positive relationship between sensory noise and metacognitive efficiency. These results could not be captured by a standard model in which decision and confidence judgments are made based on the same underlying information. Thus, our study provides a novel way to directly manipulate metacognitive efficiency and suggests the existence of metacognitive noise that corrupts confidence but not the perceptual decision.

Post-cuing falsifies drift diffusion and signal detection theory

Presented on February 13, 2017 at 11:00 a.m. in the Engineered Biosystems Building (EBB), Room 1005

P288 Causal evidence for frontal cortex organization for perceptual decision-making

Human perception is increasingly described as optimal. This view reflects recent successes of Bayesian approaches to perception but ignores an extensive literature documenting suboptimal performance in perceptual tasks. Here we review several classes of suboptimal perceptual decisions, including improper placement, maintenance, and adjustment of perceptual criteria, inadequate tradeoff between speed and accuracy, and inappropriate confidence ratings. We examine suboptimalities in the cue combination literature, which has often been taken as evidence for optimality in perception. We further discuss how findings regarding visual illusions, adaptation, and appearance relate to the concept of optimality. We extract a number of principles that account for suboptimal behavior across all of these studies. Finally, we outline an "Objectives-Constraints-Mechanisms" approach for guiding future investigations and discussions of optimal and suboptimal perception. In this approach, findings of optimality or suboptimality are not ends in themselves but serve to characterize the perceptual system9s objectives (i.e., what it aims to achieve), constraints (i.e., what costs it incurs), and mechanisms (i.e., what processes it uses to trade off the objectives and constraints). We suggest that this conceptual framework, more than a focus on optimality per se, can advance our understanding of perception.

Significance The frontal cortex has long been understood as the seat of higher level cognition. Recent research, however, highlights its role in modulating perception. Here, we present a theoretical framework for frontal involvement in perceptual decision making and test it with the causal technique of transcranial magnetic stimulation. We find that progressively rostral regions of frontal cortex are involved in the control of progressively later stages of perceptual decision making. These causal findings are further corroborated by functional MRI and simulations of a dynamic model of decision making. Our results point to a critical role of the frontal cortex in the control of perceptual processes and reveal its intrinsic organization in support of modulating perception. Although recent research has shown that the frontal cortex has a critical role in perceptual decision making, an overarching theory of frontal functional organization for perception has yet to emerge. Perceptual decision making is temporally organized such that it requires the processes of selection, criterion setting, and evaluation. We hypothesized that exploring this temporal structure would reveal a large-scale frontal organization for perception. A causal intervention with transcranial magnetic stimulation revealed clear specialization along the rostrocaudal axis such that the control of successive stages of perceptual decision making was selectively affected by perturbation of successively rostral areas. Simulations with a dynamic model of decision making suggested distinct computational contributions of each region. Finally, the emergent frontal gradient was further corroborated by functional MRI. These causal results provide an organizational principle for the role of frontal cortex in the control of perceptual decision making and suggest specific mechanistic contributions for its different subregions.

Causal evidence for frontal cortex organization for perceptual decision making

Recent research has demonstrated that the prefrontal cortex (PFC) has a critical role in metacognitive judgments of confidence. Given that PFC receives inputs from across the visual cortex, one counter-intuitive prediction is that signals that are represented in different visual areas may interact with each other at the metacognitive level. We tested this prediction by asking subjects to judge the dominant color and shape in a set of 40 letters. In Experiment 1 we found that confidence "leaked" between the two tasks (i.e., high confidence on the color task was associated with higher confidence on the shape task on that same trial) even though no such effect was found for perceptual accuracy. To ensure that the results were not due to response priming, in Experiment 2 confidence was given on a continuous scale for one task, and through the "opt-out" paradigm (in which subjects can choose to withhold their response and earn a certain small reward) on the other. Despite that difference in responding procedures, confidence leak between the two tasks was just as strong manifesting in 42 of the 44 subjects across the two experiments. Experiments 3 and 4 showed that confidence leak was also present for simple Gabor stimuli and that manipulations of signal quality through contrast and attention did not change the strength of confidence interactions. Finally, in Experiment 5 we disrupted PFC function with theta-burst TMS and observed a decrease in confidence leak compared to TMS to control regions. The results across all experiments are well described by a single-parameter model based on Bayesian inference, in which observers are constantly predicting the overall strength of signals in the environment in order to respond to them optimality. The model thus provides a normative explanation for the ubiquitous and novel phenomenon of confidence leak between different tasks. Meeting abstract presented at VSS 2015.

Magnetic Stimulation on Perception The Neural Mechanisms of the Effects of Transcranial

Low attention impairs optimal incorporation of prior knowledge in perceptual decisions

People live in a continuous environment in which the visual scene changes on a slow timescale. It has been shown that to exploit such environmental stability, the brain creates a continuity field in which objects seen seconds ago influence the perception of current objects. What is unknown is whether a similar mechanism exists at the level of metacognitive representations. In three experiments, we demonstrated a robust intertask confidence leak—that is, confidence in one’s response on a given task or trial influencing confidence on the following task or trial. This confidence leak could not be explained by response priming or attentional fluctuations. Better ability to modulate confidence leak predicted higher capacity for metacognition as well as greater gray matter volume in the prefrontal cortex. A model based on normative principles from Bayesian inference explained the results by postulating that observers subjectively estimate the perceptual signal strength in a stable environment. These results point to the existence of a novel metacognitive mechanism mediated by regions in the prefrontal cortex.

Continuous theta burst stimulation (cTBS) is a technique that allows for altering of brain activity. Research to date has focused on the effect of cTBS on the target area, but less is known about its effects on the resting state functional connectivity between different brain regions. We investigated this issue by applying cTBS to the occipital cortex and probing its influence in retinotopically defined regions in early visual cortex using functional MRI. We found that occipital cTBS reliably decreased the resting state functional connectivity (i.e., the correlation of spontaneous activity) between regions of the early visual cortex. In the context of a perceptual task, such an effect could mean that cTBS affects the strength of the perceptual signal, its variability, or both. We investigated this issue in a second experiment in which subjects performed a perceptual discrimination task and indicated their level of certainty on each trial. The results showed that occipital cTBS decreased both subjects' accuracy and confidence. Signal detection modeling suggested that these impairments resulted primarily from a decreased strength of the perceptual signal, with a nonsignificant trend of a decrease in signal variability. We discuss the implications of these experiments for understanding the mechanisms by which cTBS influences brain activity and perceptual processes.

Continuous theta burst transcranial magnetic stimulation reduces resting state connectivity between visual areas.

Transcranial magnetic stimulation (TMS) is one of the most valuable tools at the disposal of cognitive neuroscientists due to its ability to perturb brain function with high temporal precision. To date, TMS has primarily been applied to disturb normal processing nonspecifically, similar to a “

Entrainment of Neural Activity Using Transcranial Magnetic Stimulation

When perceptual decisions are coupled to a specific effector, preparatory motor cortical activity may provide a window into the dynamics of the perceptual choice. Specifically, previous studies have observed a buildup of choice-selective activity in motor regions over time reflecting the integrated sensory evidence provided by visual cortex. Here we ask how this choice-selective motor activity is modified by prior expectation during a visual motion discrimination task. Computational models of decision making formalize decisions as the accumulation of evidence from a starting point to a decision bound. Within this framework, expectation could change the starting point, rate of accumulation, or the decision bound. Using magneto-encephalography in human observers, we specifically tested for changes in the starting point in choice-selective oscillatory activity over motor cortex. Inducing prior expectation about motion direction biased subjects' perceptual judgments as well as the choice-selective motor activity in the 8–30 Hz frequency range before stimulus onset; the individual strength of these behavioral and neural biases were correlated across subjects. In the absence of explicit expectation cues, spontaneous biases in choice-selective activity were evident over motor cortex. These also predicted eventual perceptual choice and were, at least in part, induced by the choice on the previous trial. We conclude that both endogenous and explicitly induced perceptual expectations bias the starting point of decision-related activity, before the accumulation of sensory evidence.

Prestimulus Oscillatory Activity over Motor Cortex Reflects Perceptual Expectations

Attention is thought to improve most aspects of perception. However, we recently showed that, somewhat surprisingly, endogenous attention can also lead to low subjective perceptual ratings (Rahnev et al., 2011). Here we investigated the neural basis of this effect and tested whether spontaneous fluctuations of the attentional state can lead to low confidence in one's perceptual decision. We measured prestimulus functional magnetic resonance imaging activity in the dorsal attention network and used that activity as an index of the level of attention involved in a motion direction discrimination task. Extending our previous findings, we showed that low prestimulus activity in the dorsal attention network, which presumably reflected low level of attention, was associated with higher confidence ratings. These results were explained by a signal detection theoretic model in which lack of attention increases the trial-by-trial variability of the internal perceptual response. In line with the model, we also found that low prestimulus activity in the dorsal attention network was associated with higher trial-by-trial variability of poststimulus peak activity in the motion-sensitive region MT+. These findings support the notion that lack of attention may lead to liberal subjective perceptual biases, a phenomenon we call "inattentional inflation of subjective perception."

Prestimulus hemodynamic activity in dorsal attention network is negatively associated with decision confidence in visual perception.

in visual perception network is negatively associated with decision confidence Pre-Stimulus hemodynamic activity in dorsal attention

Summary of results. We delivered low-intensity TMS to theoccipital cortex to disturb the normal visual processing of asmall tilted bar. The manipulation was successful in decreasingsubjects’ ability to identify the tilt of the bar. Interestingly,occipital TMS also led to higher conﬁdence ratings comparedwith stimulation to a control site (vertex). These counterintui-tive results were parsimoniously explained by a signal detec-tion model, in which TMS increased the variance of theunderlying signal representation. Site of stimulation within the visual cortex. It has sometimesbeen assumed that occipital TMS primarily targets the visualarea V1 (Boyer et al. 2005; Laycock et al. 2007; Silvanto et al.2005a, b). However, a recent study (Thielscher et al. 2010)found that the exact site of stimulation is likely to be V2d oreven V3. In this study, we are largely agnostic with respect tothe exact regions in the visual hierarchy that were stimulated,since the net effect of increased noise could be accomplished atseveral levels in the hierarchy.

accuracy but increases decision confidence Direct injection of noise to the visual cortex decreases

On the Conservative Influence of Attention on Subjective Perceptual Decision Making

Predictive coding models suggest that predicted sensory signals are attenuated (silencing of prediction error). These models, though influential, are challenged by the fact that prediction sometimes seems to enhance rather than reduce sensory signals, as in the case of attentional cueing experiments. One possible explanation is that in these experiments, prediction (i.e., stimulus probability) is confounded with attention (i.e., task relevance), which is known to boost rather than reduce sensory signal. However, recent theoretical work on predictive coding inspires an alternative hypothesis and suggests that attention and prediction operate synergistically to improve the precision of perceptual inference. This model posits that attention leads to heightened weighting of sensory evidence, thereby reversing the sensory silencing by prediction. Here, we factorially manipulated attention and prediction in a functional magnetic resonance imaging study and distinguished between these 2 hypotheses. Our results support a predictive coding model wherein attention reverses the sensory attenuation of predicted signals.

Attention reverses the effect of prediction in silencing sensory signals.

Violation of Bayesian Cue Integration Principle Under Attentional Cuing

Direct injection of neural noise leads to double dissociation between accuracy and confidence

The relationship between accuracy and confidence in psychophysical tasks traditionally has been assumed to be mainly positive, i.e., the two typically increase or decrease together. However, recent studies have reported examples of exceptions, where confidence and accuracy dissociate from each other. Explanations for such dissociations often involve dual-channel models, in which a cortical channel contributes to both accuracy and confidence, whereas a subcortical channel only contributes to accuracy. Here, we show that a single-channel model derived from signal detection theory (SDT) can also account for such dissociations. We applied transcranial magnetic stimulation (TMS) to the occipital cortex to disrupt the internal representation of a visual stimulus. The results showed that consistent with previous research, occipital TMS decreased accuracy. However, counterintuitively, it also led to an increase in confidence ratings. The data were predicted well by a single-channel SDT model, which posits that occipital TMS increased the variance of the internal stimulus distributions. A formal model comparison analysis that used information theoretic methods confirmed that this model was preferred over single-channel models, in which occipital TMS changed the signal strength or dual-channel models, which assume two different processing routes. Thus our results show that dissociations between accuracy and confidence can, at least in some cases, be accounted for by a single-channel model.

Direct injection of noise to the visual cortex decreases accuracy but increases decision confidence.

Attention induces conservative subjective biases in visual perception

How do expectations about the identity of a forthcoming visual stimulus influence the neural mechanisms of perceptual decision making in the human brain? Previous investigations into this issue have mostly involved changing the subjects' attentional focus or the behavioral relevance of certain targets but rarely manipulated subjects' prior expectation about the likely identity of the stimulus. Also, because perceptual decisions were often paired with specific motor responses, it has been difficult to dissociate neural activity that reflects perceptual decisions from motor preparatory activity. Here we designed a task in which we induced prior expectations about the direction of a moving-dot pattern and withheld the stimulus–response mapping until the subjects were prompted to respond. In line with current models of perceptual decision making, we found that subjects' performance was influenced by their expectation about upcoming motion direction. The integration of such information into the decision process was reflected by heightened activity in the dorsolateral prefrontal cortex. Activity in this area reflected the degree to which subjects adjusted their decisions based on the prior expectation cue. Furthermore, there was increased effective connectivity between sensory regions (motion-sensitive medial temporal area MT+) and dorsolateral prefrontal cortex when subjects had a prior expectation about the upcoming motion direction. Dynamic causal modeling suggested that stimulus expectation modulated both the feedforward and feedback connectivity between MT+ and prefrontal cortex. These results provide a mechanism of how prior expectations may affect perceptual decision making, namely by changing neural activity in, and sensory drive to, prefrontal areas.

Prior Expectation Modulates the Interaction between Sensory and Prefrontal Regions in the Human Brain

Supplementary Figures and Methods: 1. Supplementary Figure 1. Attentional cuing leads to conservative detection biases 2. Supplementary Figure 2. Results from a control experiment that involved eye tracking 3. Supplementary Figure 3. The influence of the unprobed stimulus on criterion in Experiment 1 4. Supplementary Figure 4. Hit and false alarm rates in Experiment 2 5. Supplementary Figure 5. A depiction of the signal detection theoretic model that accounted for our findings 6. Supplementary Figure 6. Model fits 7. Supplementary Figure 7. Models in which attention does not affect the variability of the distributions cannot account for the observed data 8. Supplementary Figure 8. Distributed attention leads to disproportionately high visibility ratings 9. Supplementary Methods

Subliminal stimuli in the near absence of attention influence top-down cognitive control

Predictive coding models of perception suggest that predicted sensory signals are attenuated (silencing of prediction error). These models, though influential, are challenged by the fact that prediction sometimes enhances, rather than reduces task-relevant sensory signals, as in the case of spatial cueing experiments. One possible explanation is that in these experiments, prediction (i.e. whether a stimulus is likely to be presented) is confounded with attention (i.e. whether a stimulus requires a behavioural response), which is known to boost rather than reduce sensory signal. However, recent theoretical work on predictive coding inspires an alternative hypothesis, and suggests that attention and prediction may operate synergistically to improve the precision of perceptual inference. This model posits that attention leads to heightened weighting of sensory evidence, thereby reversing the sensory silencing by prediction. We factorially manipulated attention and prediction in an fMRI study to test the validity of this model. Our results support a predictive coding model wherein attention reverses the sensory attenuation of predicted signals. This may explain the seemingly contradictory findings in the literature regarding the effects of prediction on neural responses.

Attention Reverses the Effect of Prediction in Silencing Sensory Signals

The paradoxical negative relationship between attention-related spontaneous neural activity and perceptual decisions

A very basic computational model is proposed to explain two puzzling findings in the time perception literature. First, spontaneous motor actions are preceded by up to 1–2 s of preparatory activity (Kornhuber and Deecke, 1965). Yet, subjects are only consciously aware of about a quarter of a second of motor preparation (Libet et al., 1983). Why are they not aware of the early part of preparation? Second, psychophysical findings (Spence et al., 2001) support the principle of attention prior entry (Titchener, 1908), which states that attended stimuli are perceived faster than unattended stimuli. However, electrophysiological studies reported no or little corresponding temporal difference between the neural signals for attended and unattended stimuli (McDonald et al., 2005; Vibell et al., 2007). We suggest that the key to understanding these puzzling findings is to think of onset detection in probabilistic terms. The two apparently paradoxical phenomena are naturally predicted by our signal detection theoretic model.

Probabilistic Model of Onset Detection Explains Paradoxes in Human Time Perception

Inattention boosts subjective visibility: Implications for inattentional and change blindness

Theta-burst transcranial magnetic stimulation to V1 impairs subjective confidence ratings and metacognition

In an effort to continue the development of methods to understand social cognition, we adopt a technique called conjoint analysis that mathematically deduces preferences from the implied tradeoffs people make when choosing between sets of attributes at varying levels. We asked 101 students to make a series of choices between prospective teammates in a trivia contest who varied on three dimensions relevant to the decisions (education, IQ, experience) and one dimension that was irrelevant (body weight). Although participants stated explicitly that weight had little impact on their decisions, weight actually accounted for more than 25% of the variance in their revealed preferences. Additional analyses demonstrated that participants gave up about 11 IQ points to have a thin rather than overweight teammate. We suggest that conjoint analysis can be a valuable tool for detecting and quantifying the social costs of covert attitudes that are not in sync with overt values.

Using ConJoint AnAlysis to deteCt disCriminAtion: reveAling Covert PreferenCes from overt ChoiCes

Introduction to Personality Psychology W2610 Fall 2007 Time: TR 10:35 - 11:50am Room: 614 Schermerhorn

When mice actively locomote, activity in their primary visual cortex (V1) is strongly modulated 1 . This observation has fundamentally altered conceptions of a brain region previously assumed to be a passive image processor, and extensive work has followed to dissect the sources, recipients, and functional consequences of running-correlated modulation 2–13 . However, it remains unclear whether visual processing in primates might similarly change during active locomotion. We therefore measured V1 activity in a nonhuman primate, the common marmoset ( Callithrix jacchus ), while they alternated between running and stationary. In contrast to the large increases in mouse V1 during running, responses in marmoset V1 were slightly but reliably decreased during running. Despite this superficially categorical difference, leveraging large-scale recordings to characterize the latent variables driving population activity revealed a common mechanism: trial-to-trial fluctuations of shared gain modulations were present across V1 in mice and marmosets. These gain modulations were larger in mice and were often positively correlated with running; they were smaller and more likely to be negatively correlated with running in marmosets. Thus, population-scale gain fluctuations reflect a common principle of mammalian visual cortical function, but important quantitative differences in their magnitudes and correlations

Running modulates primate and rodent visual cortex via common mechanism but quantitatively distinct implementation

Animals move their head and eyes as they explore and sample the visual scene. Previous studies have demonstrated neural correlates of head and eye movements in rodent primary visual cortex (V1), but the sources and computational roles of these signals are unclear. We addressed this by combining measurement of head and eye movements with high density neural recordings in freely moving mice. V1 neurons responded primarily to gaze shifts, where head movements are accompanied by saccadic eye movements, but not to head movements where compensatory eye movements stabilize gaze. A variety of activity patterns immediately followed gaze shifts, including units with positive, biphasic, or negative responses, and together these responses formed a temporal sequence following the gaze shift. These responses were greatly diminished in the dark for the vast majority of units, replaced by a uniform suppression of activity, and were similar to those evoked by sequentially flashed stimuli in head-fixed conditions, suggesting that gaze shift transients represent the temporal response to the rapid onset of new visual input. Notably, neurons responded in a sequence that matches their spatial frequency preference, from low to high spatial frequency tuning, consistent with coarse-to-fine processing of the visual scene following each gaze shift. Recordings in foveal V1 of freely gazing head-fixed marmosets revealed a similar sequence of temporal response following a saccade, as well as the progression of spatial frequency tuning. Together, our results demonstrate that active vision in both mice and marmosets consists of a dynamic temporal sequence of neural activity associated with visual sampling. Highlights During free movement, neurons in mouse V1 respond to head movements that are accompanied by a gaze-shifting saccadic eye movement, but not a compensatory eye movement. Neurons respond to gaze shifts with diverse temporal dynamics that form a sequence across the population, from early positive responses to biphasic and negative responses. In darkness, most neurons show a uniform suppression following a gaze shift. Temporal dynamics of responses correspond to a neuron’s temporal and spatial frequency preferences, consistent with a coarse-to-fine processing sequence. A similar temporal sequence following saccades is observed in foveal V1 of freely gazing head-fixed marmosets, demonstrating shared aspects of active visual processing across species.

A dynamic sequence of visual processing initiated by gaze shifts

Laminar Organization of Pre-Saccadic Attention in Marmoset Area MT

Each time we make an eye movement, attention moves before the eyes, resulting in a perceptual enhancement at the target. Recent psychophysical studies suggest that this pre-saccadic attention enhances the visual features at the saccade target, whereas covert attention causes only spatially-selective enhancements. While previous non-human primate studies have found that pre-saccadic attention does enhance neural responses spatially, no studies have tested if changes in neural tuning reflects an automatic feature enhancement. Here we examined pre-saccadic attention using a saccade foraging task developed for marmoset monkeys. We recorded from neurons in the middle temporal (MT) area with peripheral receptive fields that contained a motion stimulus which would either be the target of a saccade or a distracter as a saccade was made to another location. We established that marmosets, like macaques, show enhanced pre-saccadic neural responses for saccades towards the receptive field, including increases in firing rate and motion information. We then examined if the specific changes in neural tuning might support feature enhancements for the target. Neurons exhibited diverse changes in tuning, but predominantly showed additive and multiplicative increases that were uniformly applied across motion directions. These findings confirm that marmoset monkeys, like macaques, exhibit pre-saccadic neural enhancements during saccade foraging tasks with minimal training requirements. However, at the level of individual neurons, the lack of feature-tuned enhancements is similar to neural effects reported during covert spatial attention. Significance Statement Attention leads eye movements producing perceptual enhancements at saccade targets. Recent psychophysical studies indicate that increases in pre-saccadic sensitivity are concentrated around features of the target. We tested at the neural level how pre-saccadic attention modulates the tuning curves of visual neurons in area MT of marmoset monkeys. While neurons exhibited clear pre-saccadic enhancements that were consistent with previous studies in macaques, the changes in tuning were uniform across tuning. These results show pre-saccadic enhancements are a general feature of visual processing, shared by New World monkeys, but at the level of individual neuron’s enhancements are uniform across features much like what has been reported previously for covert attention.

The synaptic inputs to single cortical neurons exhibit substantial diversity in their sensory-driven activity. What this diversity reflects is unclear, and appears counter-productive in generating selective somatic responses to specific stimuli. One possibility is that this diversity reflects the propagation of information from one neural population to another. To test this possibility, we bridge population coding theory with measurements of synaptic inputs recorded in vivo with two-photon calcium imaging. We construct a probabilistic decoder to estimate the stimulus orientation from the responses of a realistic, hypothetical input population of neurons to compare with synaptic inputs onto individual neurons of ferret primary visual cortex (V1) recorded with two-photon calcium imaging in vivo. We find that optimal decoding requires diverse input weights and provides a straightforward mapping from the decoder weights to excitatory synapses. Analytically derived weights for biologically realistic input populations closely matched the functional heterogeneity of dendritic spines imaged in vivo with two-photon calcium imaging. Our results indicate that synaptic diversity is a necessary component of information transmission and reframes studies of connectivity through the lens of probabilistic population codes. These results suggest that the mapping from synaptic inputs to somatic selectivity may not be directly interpretable without considering input covariance and highlights the importance of population codes in pursuit of the cortical connectome.

Unraveling Functional Diversity of Cortical Synaptic Architecture Through the Lens of Population Coding

The synaptic inputs to single cortical neurons exhibit substantial diversity in their sensory-driven activity. What this diversity reflects is unclear, and appears counter-productive in generating selective somatic responses to specific stimuli. We propose that synaptic diversity arises because neurons decode information from upstream populations. Focusing on a single sensory variable, orientation, we construct a probabilistic decoder that estimates the stimulus orientation from the responses of a realistic, hypothetical input population of neurons. We provide a straightforward mapping from the decoder weights to real excitatory synapses, and find that optimal decoding requires diverse input weights. Analytically derived weights exhibit diversity whenever upstream input populations consist of noisy, correlated, and heterogeneous neurons, as is typically found in vivo. In fact, in silico weight diversity was necessary to accurately decode orientation and matched the functional heterogeneity of dendritic spines imaged in vivo. Our results indicate that synaptic diversity is a necessary component of information transmission and reframes studies of connectivity through the lens of probabilistic population codes. These results suggest that the mapping from synaptic inputs to somatic selectivity may not be directly interpretable without considering input covariance and highlights the importance of population codes in pursuit of the cortical connectome.

Synaptic diversity naturally arises from neural decoding of heterogeneous populations

Enhanced neural tuning in middle temporal area (MT) of the marmoset monkey during pre-saccadic attention

Synaptic inputs onto single cortical neurons in vivo exhibit substantial functional diversity with respect to sensory-driven activity. However, it is unclear what this diversity reflects, appearing counter-productive in generating tuned responses to specific stimuli. We propose that functional diversity naturally arises if neurons extract information encoded from noisy input populations. Focusing on a single sensory variable, orientation, we construct a probabilistic decoder that estimates orientation from the responses of a realistic hypothetical input population of neurons. Analytically derived weights exhibit diversity when input populations consist of noisy, correlated, and heterogeneous neurons. Weight diversity was necessary to accurately decode orientation. Further, in silico weight diversity matched the functional heterogeneity of dendritic spines imaged in vivo. This suggests that synaptic diversity is expected when information is extracted from realistic input populations, highlighting the importance of studying weighting structures in population coding theory and consideration in pursuits of the cortical connectome.

Cortical synaptic diversity naturally arises with heterogeneous neural populations

Visual motion processing is a well-established model system for studying neural population codes in primates. The common marmoset, a small new world primate, offers unparalleled opportunities to probe these population codes in key motion processing areas, such as cortical areas MT and MST, because these areas are accessible for imaging and recording at the cortical surface. However, little is currently known about the perceptual abilities of the marmoset. Here, we introduce a paradigm for studying motion perception in the marmoset and compare their psychophysical performance to human observers. We trained two marmosets to perform a motion estimation task in which they provided an analog report of their perceived direction of motion with an eye movement to a ring that surrounded the motion stimulus. Marmosets and humans exhibited similar trade-offs in speed vs. accuracy: errors were larger and reaction times were longer as the strength of the motion signal was reduced. Reverse correlation on the temporal fluctuations in motion direction revealed that both species exhibited short integration windows, however, marmosets had substantially less non-decision time than humans. Our results provide the first quantification of motion perception in the marmoset and demonstrate several advantages to using analog estimation tasks.

V1 neurons tuned for high spatial frequencies show pre-saccadic enhancement

Gaze and the Control of Foot Placement When Walking in Natural Terrain

The mechanisms underlying evidence accumulation in perceptual decision-making tasks have been the subject of much research. However, existing studies differ in their conclusions on whether the brain weighs evidence optimally over time, or whether it exhibits biases towards evidence presented early (primacy) or later (recency) in the trial. We resolve this discrepancy in the literature by proposing that previous tasks differ in how task-relevant information in the stimulus is partitioned into “sensory information” and “category information.” We demonstrate that similar stimulus-dependent biases arise naturally in two common models of approximate inference: neural sampling-based inference, and parametric inference (Variational Bayes). Finally, we test our model by designing a psychophysics task that systematically trades off these two sources of uncertainty in the stimulus against each other while keeping all other aspects of the task the same. We find that subjects’ evidence-weighting strategies change in the predicted direction and in a highly robust fashion, individually significant for every one of our 10 subjects.

A Perceptual Confirmation Bias from Approximate Online Inference

Human decisions are known to be systematically biased. A prominent example of such a bias occurs when integrating a sequence of sensory evidence over time. Previous empirical studies differ in the nature of the bias they observe, ranging from favoring early evidence (primacy), to favoring late evidence (recency). Here, we present a unifying framework that explains these biases and makes novel psychophysical and neurophysiological predictions. By explicitly modeling both the approximate and the hierarchical nature of inference in the brain, we show that temporal biases depend on the balance between “sensory information” and “category information” in the stimulus. Finally, we present new data from a human psychophysics task that confirms a critical prediction of our framework showing that effective temporal integration strategies can be robustly changed within each subject, and that allows us to exclude alternate explanations through quantitative model comparison.

A confirmation bias in perceptual decision-making due to hierarchical approximate inference

Gaze and the Control of Fo ot Placement When Walking in Natural Terrain Highlights

Abstract Perceptual decision-making is often modeled as the accumulation of sensory evidence over time. Recent studies using psychophysical reverse correlation have shown that even though the sensory evidence is stationary over time, subjects may exhibit a time-varying weighting strategy, weighting some stimulus epochs more heavily than others. While previous work has explained time-varying weighting as a consequence of static decision mechanisms (e.g., decision bound or leak), here we show that time-varying weighting can reflect strategic adaptation to stimulus statistics, and thus can readily take a number of forms. We characterized the temporal weighting strategies of humans and macaques performing a motion discrimination task in which the amount of information carried by the motion stimulus was manipulated over time. Both species could adapt their temporal weighting strategy to match the time-varying statistics of the sensory stimulus. When early stimulus epochs had higher mean motion strength than late, subjects adopted a pronounced early weighting strategy, where early information was weighted more heavily in guiding perceptual decisions. When the mean motion strength was greater in later stimulus epochs, in contrast, subjects shifted to a marked late weighting strategy. These results demonstrate that perceptual decisions involve a temporally flexible weighting process in both humans and monkeys, and introduce a paradigm with which to manipulate sensory weighting in decision-making tasks.

Strategic and Dynamic Temporal Weighting for Perceptual Decisions in Humans and Macaques

Over the past two decades, neurophysiological responses in the lateral intraparietal area (LIP) have received extensive study for insight into decision making. In a parallel manner, inferred cognitive processes have enriched interpretations of LIP activity. Because of this bidirectional interplay between physiology and cognition, LIP has served as fertile ground for developing quantitative models that link neural activity with decision making. These models stand as some of the most important frameworks for linking brain and mind, and they are now mature enough to be evaluated in finer detail and integrated with other lines of investigation of LIP function. Here, we focus on the relationship between LIP responses and known sensory and motor events in perceptual decision-making tasks, as assessed by correlative and causal methods. The resulting sensorimotor-focused approach offers an account of LIP activity as a multiplexed amalgam of sensory, cognitive, and motor-related activity, with a complex and often indirect relationship to decision processes. Our data-driven focus on multiplexing (and de-multiplexing) of various response components can complement decision-focused models and provides more detailed insight into how neural signals might relate to cognitive processes such as decision making.

The Role of the Lateral Intraparietal Area in (the Study of) Decision Making.

Measurement and manipulation of temporal weighting in perceptual decision-making

Signal transformation and noise correlation in the primate dorsal stream during sensory decision-making

Quantifying contributions of natural image variability to neural representations of speed in Area MT

On determining the intracranial sources of visual evoked potentials from scalp topography: A reply to Kelly et al. (this issue)

V1 is not uniquely identified by polarity reversals of responses to upper and lower visual field stimuli

Antibody-based protection against respiratory syncytial virus in mice and their offspring through vectored immunoprophylaxis

Epithelial ovarian cancer is the deadliest gynecological malignancy. The lack of effective treatments highlights the need for novel therapeutic interventions. The aim of this study was to investigate whether sustained adeno-associated virus (AAV) vector-mediated expression of vascular normalizing agents 3TSR and Fc3TSR and the antiangiogenic monoclonal antibody, Bevacizumab, with or without oncolytic virus treatment would improve survival in an orthotopic syngeneic mouse model of epithelial ovarian carcinoma. AAV vectors were administered 40 days post-tumor implantation and combined with oncolytic avian orthoavulavirus-1 (AOaV-1) 20 days later, at the peak of AAV-transgene expression, to ascertain whether survival could be extended. Flow cytometry conducted on blood samples, taken at an acute time point post-AOaV-1 administration (36 h), revealed a significant increase in activated NK cells in the blood of all mice that received AOaV-1. T cell analysis revealed a significant increase in CD8+ tumor specific T cells in the blood of AAV-Bevacizumab+AOaV-1 treated mice compared to control mice 10 days post AOaV-1 administration. Immunohistochemical staining of primary tumors harvested from a subset of mice euthanized 90 days post tumor implantation, when mice typically have large primary tumors, secondary peritoneal lesions, and extensive ascites fluid production, revealed that AAV-3TSR, AAV-Fc3TSR+AOaV-1, or AAV-Bevacizumab+AOaV-1 treated mice had significantly more tumor-infiltrating CD8+ T cells than PBS controls. Despite AAV-mediated transgene expression waning faster in tumor-bearing mice than in non-tumor bearing mice, all three of the AAV therapies significantly extended survival compared to control mice; with AAV-Bevacizumab performing the best in this model. However, combining AAV therapies with a single dose of AOaV-1 did not lead to significant extensions in survival compared to AAV therapies on their own, suggesting that additional doses of AOaV-1 may be required to improve efficacy in this model. These results suggest that vectorizing anti-angiogenic and vascular normalizing agents is a viable therapeutic option that warrants further investigation, including optimizing combination therapies.

AAV-Vectored Expression of the Vascular Normalizing Agents 3TSR and Fc3TSR, and the Anti-Angiogenic Bevacizumab Extends Survival in a Murine Model of End-Stage Epithelial Ovarian Carcinoma

Novel immunotherapies continue to be developed and tested for application against a plethora of diseases. The clinical translation of immunotherapies requires an understanding of their mechanisms. The contributions of antibodies in driving long-term responses following immunotherapies continue to be revealed given their diverse effector functions. Developing an in-depth understanding of the role of antibodies in treatment efficacy is required to optimize immunotherapies and improve the chance of successfully translating them into the clinic. However, analyses of antibody responses can be challenging in the context of antigen-agnostic immunotherapies, particularly in the context of cancers that lack pre-defined target antigens. As such, robust methods are needed to evaluate the capacity of a given immunotherapy to induce beneficial antibody responses, and to identify any therapy-limiting antibodies. We previously developed a comprehensive method for detecting antibody responses induced by antigen-agnostic immunotherapies for application in pre-clinical models of vaccinology and cancer therapy. Here, we extend this method to a high-throughput, flow cytometry-based assay able to identify and quantify isotype-specific virus- and tumor-associated antibody responses induced by immunotherapies using small sample volumes with rapid speed and high sensitivity. This method provides a valuable and flexible protocol for investigating antibody responses induced by immunotherapies, which researchers can use to expand their analyses and optimize their own treatment regimens.

Multiplex flow cytometry-based assay for quantifying tumor- and virus-associated antibodies induced by immunotherapies

Newcastle disease virus (NDV), also known as avian orthoavulavirus serotype-1, is a negative sense, single-stranded RNA virus that has been developed both as an oncolytic virus and a viral-vectored vaccine. NDV is an attractive therapeutic and prophylactic agent due to its well-established reverse genetics system, potent immunostimulatory properties, and excellent safety profile. When administered as an oncolytic virus or a viral-vectored vaccine, NDV elicits a robust antitumor or antigen-specific immune response, activating both the innate and adaptive arms of the immune system. Given these desirable characteristics, NDV has been evaluated in numerous clinical trials and is one of the most well-studied oncolytic viruses. Currently, there are two registered clinical trials involving NDV: one evaluating a recombinant NDV-vectored vaccine for SARS-CoV-2 (NCT04871737), and a second evaluating a recombinant NDV encoding Interleukin-12 in combination with Durvalumab, an antiPD-L1 antibody (NCT04613492). To facilitate further advancement of this highly promising viral vector, simplified methods for generating high-titer, in vivo-grade, recombinant NDV (rNDV) are needed. This paper describes a detailed procedure for amplifying rNDV in specified pathogen-free (SPF) embryonated chicken eggs and purifying rNDV from allantoic fluid, with improvements to reduce loss during purification. Also included are descriptions of the recommended quality control assays, which should be performed to confirm lack of contaminants and virus integrity. Overall, this detailed procedure enables the synthesis, purification, and storage of high-titer, in vivo-grade, recombinant, lentogenic, and mesogenic NDV for use in preclinical studies.

Production of High-titer Recombinant Newcastle Disease Virus from Allantoic Fluid.

Adeno-associated virus (AAV) vectors are among the most clinically advanced gene therapy vectors, with three AAV gene therapies approved for humans. Clinical advancement of novel applications for AAV involves transitioning from small animal models, such as mice, to larger animal models, including dogs, sheep, and nonhuman primates. One of the limitations of administering AAV to larger animals is the requirement for large quantities of high-titer virus. While suspension cell culture is a scalable method for AAV vector production, few research labs have the equipment (e.g., bioreactors) or know how to produce AAV in this manner. Moreover, AAV titers are often significantly lower when produced in suspension HEK 293 cells as compared to adherent HEK293 cells. Described here is a method for producing large quantities of high-titer AAV using cell stacks. A detailed protocol for titering AAV as well as methods for validating vector purity are also described. Finally, representative results of AAV-mediated transgene expression in a sheep model are presented. This optimized protocol for large-scale production of AAV vectors in adherent cells will enable molecular biology laboratories to advance the testing of their novel AAV therapies in larger animal models.

Production of Adeno-Associated Virus Vectors in Cell Stacks for Preclinical Studies in Large Animal Models.

Adeno-associated virus (AAV) vector mediated expression of therapeutic monoclonal antibodies is an alternative strategy to traditional vaccination to generate immunity in immunosuppressed or immunosenescent individuals. In this study, we vectorized a human monoclonal antibody (31C2) directed against the spike protein of SARS-CoV-2 and determined the safety profile of this AAV vector in mice and sheep as a large animal model. In both studies, plasma biochemical parameters and hematology were comparable to untreated controls. Except for mild myositis at the site of injection, none of the major organs revealed any signs of toxicity. AAV-mediated human IgG expression increased steadily throughout the 28-day study in sheep, resulting in peak concentrations of 21.4–46.7 µg/ mL, demonstrating practical scale up from rodent to large animal models. This alternative approach to immunity is worth further exploration after this demonstration of safety, tolerability, and scalability in a large animal model.

Safety and Tolerability of the Adeno-Associated Virus Vector, AAV6.2FF, Expressing a Monoclonal Antibody in Murine and Ovine Animal Models

Intranasal vaccination with a Newcastle disease virus-vectored vaccine protects hamsters from SARS-CoV-2 infection and disease

The significance of both solar elevation angle and azimuth are critical elements for examining Earth observation datasets. Illumination angle is a crucial parameter affecting the appearance of the topographically related and dependent features. Therefore, an improved methodology of data fusion for tectonic and geomorphic mapping is needed to augment the traditional false color composite analysis. A long-standing problem in such applications is the bias introduced by illumination geometry, specifically sun elevation and azimuth. A Landsat-5 image of Lesvos Island, Greece, was combined with digital elevation models to produce fused images with a wide range of illumination azimuths and elevation in a GIS environment. Sixteen combinations of sun elevation angle (using 15° and 30°) paired with azimuth (0° to 360° at 45° increments) were considered. This new technique compensates for local conditions such as generally cloudy winters which make it difficult to obtain images with low sun elevation or images of eroded landforms with subdued geomorphic expression. The resulting fused images combine the tonal information and high spatial resolution of Landsat with the strong topographic rendition of digital elevation models. Well-known faults, with more or less significant expression on the surface known from previous image interpretation and fieldwork, are more easily identifiable. Shaded relief maps produced by applying the lower illumination angle in combination with an azimuth perpendicular to the fault orientation produced the best results. Additionally, previously unknown linear and circular features, e.g., calderas, were represented in the low illumination angle image, independent of its azimuth. Fused images will be further combined with geologic and seismicity maps to study problems such as location of the Anatolian Plate’s boundaries and their nature (sharp or diffuse).

Fusing Landsat-5/TM Imagery and Shaded Relief Maps in Tectonic and Geomorphic Mapping: Lesvos Island, Greece

Understanding Intraplate Tectonic for the Global Earthquake Satellite System (GESS)

This paper presents two Robinson Projection versions of a map showing tectonic and volcanic activity of the geologic present, defined as the last one million years. One version is a shaded-relief base map computer-generated from a National Geophysical Data Center digital elevation model, the other a schematic version showing in addition the distribution of continental and oceanic crust. Volcanic features active within the last one million years were generalized from Smithsonian Institution Holocene volcanism compilations, supplemented by geologic maps and orbital photography. Global seismicity (1963–1998) was digitally compiled from National Geophysical Data Center and U.S. Geological Survey databases. Horizontal motions of Very Long Baseline Interferometry (VLBI) space geodesy stations were compiled from Goddard Space Flight Center data. Sources for all data are given, including the Internet URLs. The maps are all in the public domain and may be freely reproduced if the source is credited. Tectonic impli...

When forming a memory of an experience that is unfolding over time, we can use our schematic knowledge about the world (constructed based on many prior episodes) to predict what will transpire. We developed a novel paradigm to study how the development of a complex schema influences predictive processes during perception and impacts sequential memory. Participants learned to play a novel board game (‘four-in-a-row’) across six training sessions and repeatedly performed a memory test in which they watched and recalled sequences of moves from the game. We found that participants gradually became better at remembering sequences from the game as their schema developed, driven by improved accuracy for schema-consistent moves. Eye tracking revealed that increased predictive eye movements during encoding, which were most prevalent in expert players, were associated with better memory. Our results identify prediction as a mechanism by which schematic knowledge can improve episodic memory.

Schema-based predictive eye movements support sequential memory encoding

Abstract Perceptual decision-making is often conceptualized as the process of comparing an internal decision variable to a categorical boundary or criterion. How the mind sets such a criterion has been studied from at least two perspectives. One idea is that the criterion is a fixed quantity. In work on subjective phenomenology, the notion of a fixed criterion has been proposed to explain a phenomenon called “subjective inflation”—a form of metacognitive mismatch in which observers overestimate the quality of their sensory representation in the periphery or at unattended locations. A contrasting view emerging from studies of perceptual decision-making is that the criterion adjusts to the level sensory uncertainty and is thus sensitive to variations in attention. Here, we mathematically demonstrate that previous empirical findings supporting subjective inflation are consistent with either a fixed or a flexible decision criterion. We further lay out specific task properties that are necessary to make inferences about the flexibility of the criterion: (i) a clear mapping from decision variable space to stimulus feature space and (ii) an incentive for observers to adjust their decision criterion as uncertainty changes. Recent work satisfying these requirements has demonstrated that decision criteria flexibly adjust according to uncertainty. We conclude that the fixed-criterion model of subjective inflation is poorly tenable.

Challenging the fixed-criterion model of perceptual decision-making

The ability to sustain internal representations of the sensory environment beyond immediate perception is a fundamental requirement of cognitive processing. In recent years, debates regarding the capacity and fidelity of the working memory (WM) system have driven significant advances in our understanding of the nature of these representations. In particular, there is growing recognition that WM representations are not merely imperfect copies of a perceived object or event, as new experimental tools have revealed that observers possess richer information about the uncertainty in their memories, and take advantage of environmental regularities to use limited memory resources optimally. Meanwhile, computational models of visual WM formulated at different levels of implementation have converged on common principles relating capacity to variability and uncertainty. Here we review recent research in human visual WM from a computational perspective and the latest developments in identifying neural mechanisms that support it.

The study of the brain’s representations of uncertainty is a central topic in neuroscience. Unlike most other cases of representation, uncertainty is a property of an observer’s representation of the world, posing specific methodological challenges. We analyze how the literature on the neural representations of uncertainty addresses those challenges and distinguish between “code-driven” and “correlational” approaches. Code-driven approaches make assumptions about the neural code for representing world states and the associated uncertainty. By contrast, correlational approaches search for relationships between uncertainty and neural activity without constraints on the neural representation of the world state that this uncertainty accompanies. To compare these two approaches, we apply several criteria for neural representations: sensitivity, specificity, invariance, functionality. Our analysis rigorously characterizes the study of neural representations of uncertainty and reveals that the two approaches lead to different findings that are complementary, shaping new research questions and guiding future experiments.

Drift-like dynamics of working memory representations in human cortex

A local probabilistic model of features and segmentation learned by optimizing prediction

A visual system has to learn both which features to extract from images and how to group locations into (proto-)objects. Those two aspects are usually dealt with separately, although predictability is discussed as a cue for both. To incorporate features and boundaries into the same model, we model a layer of feature maps with a pairwise Markov random ﬁeld model in which each factor is paired with an additional binary variable, which switches the factor on or off. Using one of two contrastive learning objectives, we can learn both the features and the parameters of the Markov random ﬁeld factors from images without further supervision signals. The features learned by shallow neural networks based on this loss are local averages, opponent colors, and Gabor-like stripe patterns. Furthermore, we can infer connectivity between locations by inferring the switch variables. Contours inferred from this connectivity perform quite well on the Berkeley segmentation database (BSDS500) without any training on contours. Thus, computing predictions across space aids both segmentation and feature learning, and models trained to optimize these predictions show similarities to the human visual system. We speculate that retinotopic visual cortex might implement such predictions over space through lateral connections.

Unsupervised learning of features and object boundaries from local prediction

We apply efficient coding principles to derive the optimal population of neurons to encode rewards from a distribution. Similar to this optimal population, dopaminergic reward prediction error neurons have a broad distribution of optimistically placed thresholds, neurons with higher thresholds have higher gain and the curvature of their responses depends on the threshold. Thus, these neurons may broadcast an efficient reward signal, not necessarily a reward prediction error.

Reward prediction error neurons implement an efficient code for reward

The introduction of large-scale data sets in psychology allows for more robust accounts of various cognitive mechanisms, one of which is human learning. However, these data sets provide participants with complete autonomy over their own participation in the task, and therefore require precisely studying the factors influencing dropout alongside learning. In this work, we present such a data set where 1 , 234 , 844 participants play 10 , 874 , 547 games of a challenging variant of tic-tac-toe. We establish that there is a correlation between task performance and total experience, and independently analyze participants’ dropout behavior and learning trajectories. We find evidence for stopping patterns as a function of playing strength and investigate the processes underlying playing strength increases with experience using a set of metrics derived from a planning model. Finally, we develop a joint model to account for both dropout and learning functions which replicates our empirical findings.

A joint analysis of dropout and learning functions in human decision-making with massive online data

Many studies have investigated the contributions of vision, touch, and proprioception to body ownership, i.e., the multisensory perception of limbs and body parts as our own. However, the computational processes and principles that determine subjectively experienced body ownership remain unclear. To address this issue, we developed a detection-like psychophysics task based on the classic rubber hand illusion paradigm, where participants were asked to report whether the rubber hand felt like their own (the illusion) or not. We manipulated the asynchrony of visual and tactile stimuli delivered to the rubber hand and the hidden real hand under different levels of visual noise. We found that: (1) the probability of the emergence of the rubber hand illusion increased with visual noise and was well predicted by a causal inference model involving the observer computing the probability of the visual and tactile signals coming from a common source; (2) the causal inference model outperformed a non-Bayesian model involving the observer not taking into account sensory uncertainty; (3) by comparing body ownership and visuotactile synchrony detection, we found that the prior probability of inferring a common cause for the two types of multisensory percept was correlated but greater for ownership, which suggests that individual differences in rubber hand illusion can be explained at the computational level as differences in how priors are used in the multisensory integration process. These results imply that the same statistical principles determine the perception of the bodily self and the external world.

Uncertainty-based inference of a common cause for body ownership

An influential account of neuronal responses in primary visual cortex is the normalized energy model. This model is often implemented as a two-stage computation. The first stage is the extraction of contrast energy, whereby a complex cell computes the squared and summed outputs of a pair of linear filters in quadrature phase. The second stage is normalization, in which a local population of complex cells mutually inhibit one another. Because the population includes cells tuned to a range of orientations and spatial frequencies, the result is that the responses are effectively normalized by the local stimulus contrast. Here, using evidence from human functional MRI, we show that the classical model fails to account for the relative responses to two classes of stimuli: straight, parallel, band-passed contours (gratings), and curved, band-passed contours (snakes). The snakes elicit fMRI responses that are about twice as large as the gratings, yet a traditional divisive normalization model predicts responses that are about the same. Here, motivated by these observations and others from the literature, we implement a divisive normalization model, in which there is a preferential inhibition between cells matched in orientation tuning (“tuned normalization”). We first show that this model accounts for differential responses to these two classes of stimuli. We then show that the model successfully generalizes to other band-pass textures, both in V1 and in extrastriate cortex (V2 and V3). We conclude that even in primary visual cortex, complex features of images such as the degree of heterogeneity, can have large effects on neural responses.

The spatial distribution of visual items allows us to infer the presence of latent causes in the world. For instance, a spatial cluster of ants allows us to infer the presence of a common food source. However, optimal inference requires the integration of a computationally intractable number of world states in real world situations. For example, optimal inference about whether a common cause exists based on N spatially distributed visual items requires marginalizing over both the location of the latent cause and 2N possible affiliation patterns (where each item may be affiliated or non-affiliated with the latent cause). How might the brain approximate this inference? We show that subject behaviour deviates qualitatively from Bayes-optimal, in particular showing an unexpected positive effect of N (the number of visual items) on the false-alarm rate. We propose several “point-estimating” observer models that fit subject behaviour better than the Bayesian model. They each avoid a costly computational marginalization over at least one of the variables of the generative model by “committing” to a point estimate of at least one of the two generative model variables. These findings suggest that the brain may implement partially committal variants of Bayesian models when detecting latent causes based on complex real world data.

Bayesian optimal inference is often heralded as a principled, general framework for human perception. However, optimal inference requires integration over all possible world states, which quickly becomes intractable in complex real-world settings. Additionally, deviations from optimal inference have been observed in human decisions. A number of approximation methods have previously been suggested, such as sampling methods. In this study, we additionally propose point estimate observers, which evaluate only a single best estimate of the world state per response category. We compare the predicted behavior of these model observers to human decisions in five perceptual categorization tasks. Compared to the Bayesian observer, the point estimate observer loses decisively in one task, ties in two and wins in two tasks. Two sampling observers also improve upon the Bayesian observer, but in a different set of tasks. Thus, none of the existing general observer models appears to fit human perceptual decisions in all situations, but the point estimate observer is competitive with other observer models and may provide another stepping stone for future model development. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Point estimate observers: A new class of models for perceptual decision making.

Perceptual decision-making is often conceptualized as the process of comparing an internal decision variable to a categorical boundary, or criterion. How the mind sets such a criterion has been studied from at least two perspectives. First, researchers interested in consciousness have proposed that criterion-crossing determines whether a stimulus is consciously perceived. Second, researchers interested in decision-making have studied how the criterion depends on a range of stimulus and task variables. Both communities have considered the question of how the criterion behaves when sensory information is weak or uncertain. Interestingly, however, they have arrived at different conclusions. Consciousness researchers investigating a phenomenon called "subjective inflation" – a form of metacognitive mismatch in which observers overestimate the quality of their sensory representations in the periphery or at an unattended location – have proposed that the criterion governing subjective visibility is fixed. That is, it does not adjust to changes in sensory uncertainty. Decision-making researchers, on the other hand, have concluded that the criterion does adjust to account for sensory uncertainty, including under inattention. Here, we mathematically demonstrate that previous empirical findings supporting subjective inflation are consistent with either a fixed or a flexible decision criterion. We further show that specific experimental task requirements are necessary to make inferences about the flexibility of the criterion: 1) a clear mapping from decision variable space to stimulus feature space, and 2) a task incentive for observers to adjust their decision criterion as response variance increases. We conclude that the fixed-criterion model of subjective inflation requires re-thinking in light of new evidence from the probabilistic reasoning literature that decision criteria flexibly adjust according to response variance.

Re-thinking the fixed-criterion model of perceptual decision-making

The N-back task is a common working memory paradigm: subjects judge whether the current item in a sequence (the probe) matches the one presented N items ago (the target). Performance in the N-back task is susceptible to interference from intervening items (distractors), especially when the probe and the distractor are similar. However, the categorical stimuli usually used in the classic N-back task are not suitable for distinguishing possible causes of interference. Here, we instead used parametric stimuli (varying in orientation or color) to measure the amount of interference induced in a 2-back task by the 1-back distractor. As expected, we find that interference was larger when the feature distance between the probe and the distractor was smaller. To investigate the source of the interference, we fitted four mathematical models to the data. In the No interference model, the observer utilizes an optimal decision strategy. In the Early pooling model, the ob- server has access only to a mixed measurement of the target and distractor, but employs an optimal de-mixing strategy. In the Late pooling model, the observer mixes decision variables that are optimal for the target and distractor separately. In the Substitution model, the observer swaps the target with the distractor on some proportion of trials, and decides optimally otherwise. The No interference and the Early pooling models described the data substantially worse than the Late pooling and the Substitution models. However, we were not able to distinguish the Late pooling and Substitution models. Our modeling results suggest that interference in the 2-back task results either from the pooling of decision variables based the “target” and “distractor” separately, or from the substitution of the distractor for the target. Our study opens the door to parametrically examining the sources of interference in similar cognitive tasks.

Neural representations of visual working memory (VWM) are noisy, and thus, decisions based on VWM are inevitably subject to uncertainty. However, the mechanisms by which the brain simultaneously represents the content and uncertainty of memory remain largely unknown. Here, inspired by the theory of probabilistic population codes, we test the hypothesis that the human brain represents an item maintained in VWM as a probability distribution over stimulus feature space, thereby capturing both its content and uncertainty. We used a neural generative model to decode probability distributions over memorized locations from fMRI activation patterns. We found that the mean of the probability distribution decoded from retinotopic cortical areas predicted memory reports on a trial-by-trial basis. Moreover, in several of the same mid-dorsal stream areas the spread of the distribution predicted subjective trial-by-trial uncertainty judgments. These results provide evidence that VWM content and uncertainty are jointly represented by probabilistic neural codes.

Joint representation of working memory and uncertainty in human cortex

From navigation in unfamiliar environments to career planning, people typically first sample information before committing to a plan. However, most studies find that people adopt myopic strategies when sampling information. Here we challenge those findings by investigating whether contingency planning is a driver of information sampling. To this aim, we developed a novel navigation task that is a shortest path finding problem under uncertainty of bridge closures. Participants (n = 109) were allowed to sample information on bridge statuses prior to committing to a path. We developed a computational model in which the agent samples information based on the cost of switching to a contingency plan. We find that this model fits human behavior well and is qualitatively similar to the approximated optimal solution. Together, this suggests that humans use contingency planning as a driver of information sampling.

Neural correlates of uncertainty of visual spatial working memory in human cortex

The fate of scientific hypotheses often relies on the ability of a computational model to explain the data, quantified in modern statistical approaches by the likelihood function. The log-likelihood is the key element for parameter estimation and model evaluation. However, the log-likelihood of complex models in fields such as computational biology and neuroscience is often intractable to compute analytically or numerically. In those cases, researchers can often only estimate the log-likelihood by comparing observed data with synthetic observations generated by model simulations. Standard techniques to approximate the likelihood via simulation either use summary statistics of the data or are at risk of producing substantial biases in the estimate. Here, we explore another method, inverse binomial sampling (IBS), which can estimate the log-likelihood of an entire data set efficiently and without bias. For each observation, IBS draws samples from the simulator model until one matches the observation. The log-likelihood estimate is then a function of the number of samples drawn. The variance of this estimator is uniformly bounded, achieves the minimum variance for an unbiased estimator, and we can compute calibrated estimates of the variance. We provide theoretical arguments in favor of IBS and an empirical assessment of the method for maximum-likelihood estimation with simulation-based models. As case studies, we take three model-fitting problems of increasing complexity from computational and cognitive neuroscience. In all problems, IBS generally produces lower error in the estimated parameters and maximum log-likelihood values than alternative sampling methods with the same average number of samples. Our results demonstrate the potential of IBS as a practical, robust, and easy to implement method for log-likelihood evaluation when exact techniques are not available.

Unbiased and Efficient Log-Likelihood Estimation with Inverse Binomial Sampling

Confidence reports in decision-making with multiple alternatives violate the Bayesian confidence hypothesis

Perceptual organization is the process of grouping scene elements into whole entities. A classic example is contour integration, in which separate line segments are perceived as continuous contours. Uncertainty in such grouping arises from scene ambiguity and sensory noise. Some classic Gestalt principles of contour integration, and more broadly, of perceptual organization, have been re-framed in terms of Bayesian inference, whereby the observer computes the probability that the whole entity is present. Previous studies that proposed a Bayesian interpretation of perceptual organization, however, have ignored sensory uncertainty, despite the fact that accounting for the current level of perceptual uncertainty is one of the main signatures of Bayesian decision making. Crucially, trial-by-trial manipulation of sensory uncertainty is a key test to whether humans perform near-optimal Bayesian inference in contour integration, as opposed to using some manifestly non-Bayesian heuristic. We distinguish between these hypotheses in a simplified form of contour integration, namely judging whether two line segments separated by an occluder are collinear. We manipulate sensory uncertainty by varying retinal eccentricity. A Bayes-optimal observer would take the level of sensory uncertainty into account—in a very specific way—in deciding whether a measured offset between the line segments is due to non-collinearity or to sensory noise. We find that people deviate slightly but systematically from Bayesian optimality, while still performing “probabilistic computation” in the sense that they take into account sensory uncertainty via a heuristic rule. Our work contributes to an understanding of the role of sensory uncertainty in higher-order perception.

What are the contents of working memory? In both behavioral and neural computational models, the working memory representation of a stimulus is typically described by a single number, namely a point estimate of that stimulus. Here, we asked if people also maintain the uncertainty associated with a memory, and if people use this uncertainty in subsequent decisions. We collected data in a two-condition orientation change detection task; while both conditions measured whether people used memory uncertainty, only one required maintaining it. For each condition, we compared an optimal Bayesian observer model, in which the observer uses an accurate representation of uncertainty in their decision, to one in which the observer does not. We find that this “Use Uncertainty” model fits better for all participants in both conditions. In the first condition, this result suggests that people use uncertainty optimally in a working memory task when that uncertainty information is available at the time of decision, confirming earlier results. Critically, the results of the second condition suggest that this uncertainty information was maintained in working memory. We test model variants and find that our conclusions do not depend on our assumptions about the observer’s encoding process, inference process, or decision rule. Our results provide evidence that people have uncertainty that reflects their memory precision at an item-specific level, maintain this information over a working memory delay, and use it implicitly in a way consistent with an optimal observer. These results challenge existing computational models of working memory to update their frameworks to represent uncertainty.

When people view a consumable item for a longer amount of time, they choose it more frequently; this also seems to be the direction of causality. The leading model of this effect is a drift-diffusion model with a fixation-based attentional bias. Here, we propose an explicitly Bayesian account for the same data. This account is based on the notion that the brain builds a posterior belief over the value of an item in the same way it would over a sensory variable. As the agent gathers evidence about the item from sensory observations and from retrieved memories, the posterior distribution narrows. We further postulate that the utility of an item is a weighted sum of the posterior mean and the negative posterior standard deviation, with the latter accounting for risk aversion. Fixating for longer can increase or decrease the posterior mean, but will inevitably lower the posterior standard deviation. This model fits the data better than the original attentional drift-diffusion model but worse than a variant with a collapsing bound. We discuss the often overlooked technical challenges in fitting models simultaneously to choice and response time data in the absence of an analytical expression. Our results hopefully contribute to emerging accounts of valuation as an inference process.

Visual search, the task of detecting or locating target items amongst distractor items in a visual scene, is an important function for animals and humans. Different theoretical accounts make differing predictions for the effects of distractor statistics. Here we use a task in which we parametrically vary distractor items, allowing for a simultaneously fine-grained and comprehensive study of distractor statistics. We found effects of target-distractor similarity, distractor variability, and an interaction between the two, although the effect of the interaction on performance differed from the one expected. To explain these findings, we constructed computational process models that make trial-by-trial predictions for behaviour based on the full set of stimuli in a trial. These models, including a Bayesian observer model, provided excellent accounts of both the qualitative and quantitative effects of distractor statistics, as well as of the effect of changing the statistics of the environment (in the form of distractors being drawn from a different distribution). We conclude with a broader discussion of the role of computational process models in the understanding of visual search.

Explaining the effects of distractor statistics in visual search

Abstract Resource rationality holds great promise as a unifying principle across theories in neuroscience, cognitive science, and economics. The target article clearly lays out this potential for unification. However, resource-rational models are more diverse and less easily unified than might appear from the target article. Here, we explore some of that diversity.

Visual search is one of the most ecologically important perceptual task domains. One research tradition has studied visual search using simple, parametric stimuli and a signal detection theory or Bayesian modeling framework. However, this tradition has mostly focused on homogeneous distractors (identical to each other), which are not very realistic. In a different tradition, Duncan and Humphreys (1989) conducted a landmark study on visual search with heterogeneous distractors. However, they used complex stimuli, making modeling and dissociation of component processes difficult. Here, we attempt to unify these research traditions by systematically examining visual search with heterogeneous distractors using simple, parametric stimuli and Bayesian modeling. Our experiment varied multiple factors that could influence performance: set size, task (N-AFC localization vs detection), whether the target was revealed before or after the search array (perception versus memory), and stimulus spacing. We found that performance robustly decreased with increasing set size. When examining within-trial summary statistics, we found that the minimum target-to-distractor feature difference was a stronger predictor of behavior than the mean target-to-distractor difference and than distractor variance. To obtain process-level understanding, we formulated a Bayesian optimal-observer model. This model accounted for all summary statistics, including when fitted jointly to localization and detection. We replicated these results in a separate experiment with reduced stimulus spacing. Together, our results represent a critique of Duncan and Humphrey’s descriptive approach, bring visual search with heterogeneous distractors firmly within the reach of quantitative process models, and affirm the “unreasonable effectiveness” of Bayesian models in explaining visual search.

The psychophysics of visual search with heterogeneous distractors

Publisher Correction: Sources of suboptimality in a minimalistic explore–exploit task

Approximate Inference through Sequential Measurements of Likelihoods Accounts for Hick's Law

Publisher Correction: A diverse range of factors affect the nature of neural representations underlying short-term memory

We describe dead rectangles, a new stimulus class for research on perceptual organisation. These stimuli are generated by randomly placing rectangles inside an image window, which allows for occlusion, surface properties and ambiguous stimuli. To show their utility we asked 14 observers to judge whether two points in a dead rectangle stimulus belong to the same rectangle or not. We find observers to perform around 70% correct and judge the points to belong to the same rectangle considerably more often than they do. Also, some pairs of points were consistently judged to belong to the same rectangle although they were not. The possible decompositions of one stimulus into rectangles form a tree, which can be used for formal analysis. These stimuli may allow research on perceptual organisation to move on to more natural conditions, while maintaining experimental control and a rigorous mathematical framework.

Dead Rectangles as a Stimulus for Perceptual Organisation Research

Predicting human decisions in a sequential planning puzzle with a large state space

The psychophysics of visual search with heterogeneous distractors: effects ofset size, task, temporal order and stimulus spacing

Normalization by the variance across orientation channels in human V1–V3

A large body of evidence shows that perceptual decision making in humans and animals accounts for uncertainty in the relevant stimulus variable. This suggests that the decision is based on a distribution over stimuli given the neuronal activity rather than single point estimates. The likelihood over the stimuli captures this uncertainty for a fixed neuronal response. Because the neuronal population response can be high dimensional, estimating a per-trial likelihood can be challenging. Previous work has thus focused on parametric models, which can introduce a bias by ignoring noise correlations. Here, we present a simple yet general method to decode a per-trial likelihood based on neural networks. Our method applies to discrete and continuous, as well as static and time-series data. We demonstrate it on recordings from two experimental visual paradigms in macaque V1 and V2.

Drawing conclusions from spatial coincidences: a cumulative clustering account

A diverse range of factors affect the nature of neural representations underlying short-term memory

Unlike in perceptual tasks, it is unclear whether humans near-optimally use uncertainty information in their visual working memory (VWM) decisions. Some circumstantial evidence is available: people can explicitly report their uncertainty after a delay and can near-optimally integrate knowledge of uncertainty with working memories. However, it is unclear whether people can do the conjunction: accurately store uncertainty information in VWM and use it in a subsequent decision. To investigate this, we collected data in two orientation change detection tasks. One task did not require the maintenance of uncertainty information and the other did. We factorially evaluate Bayesian observer models with different assumptions about the memory noise generating process, the observer’s assumption of this process, and the observer’s decision rule. For both experiments, the model that best fits human data assumes that memory precision varies as a function of stimulus reliability and other internal fluctuations, observers know their memory uncertainty on an individual-item basis, and observers optimally integrate information across items when making their decision. These results provide evidence that participants are able to maintain uncertainty information across a delay, and use it optimally in subsequent decisions.

Optimal maintenance and use of uncertainty in visual working memory

In N-alternative Bayesian categorization, computing exact likelihoods and posteriors might be hard for the brain. We propose an approximate inference framework with active sampling inspired by Bayesian optimization. While it is common in Bayesian models to assume that the agent makes noisy measurements of a state of the world, here we use a more general (and more abstract) starting point. We assume that the true (ideal-observer) likelihoods and posteriors of the categories are unknown to the agent. The agent sequentially makes noisy measurements of those likelihoods, one category at a time, thus refining their beliefs over the true likelihoods and their belief over the true posterior probabilities. To decide whether to make another measurement, the agent simulates the consequences of doing so for the latter belief. This framework accounts for two types of empirical findings. First, we find that the average number of measurements grows approximately logarithmically with N, reminiscent of Hick’s law. Second, we account for a puzzling recent finding that decision confidence follows the difference between the two highest posteriors, rather than the highest posterior itself. Our framework provides a novel approach to explain human categorization by combining approximate inference with active sampling.

Approximate Inference through Active Sampling of Likelihoods Accounts for Hick's Law and Decision Confidence

Procrastination is prevalent in people’s daily lives. Empirical studies of procrastination have identified various contributing factors, including temporal discounting, perfectionism, and time pressure. Models of procrastination, however, have only considered temporal discounting and have ignored other factors. Also, they assume that people make a binary choice between working and delaying, which ignores the fact that people often also decide the amount of effort they put into their work. We bridge this gap by using reinforcement learning theory to re-examine procrastination. Our model predicts two scenarios in which a rational agent chooses to procrastinate: one is that people delay working until the last minute if their cost is sensitive to increases in effort when it is low, and another is that people do not work at all if they pursue perfection under time pressure. Our model raises questions about the common notion that procrastination is necessarily irrational, and suggests several experimental tests.

What algorithms do people use to make decisions with future consequences in complex environments? In order to investigate the cognitive processes underlying sequential planning, we collected large-scale behavioral data in a challenging variant of tic-tac-toe. This task is at an intermediate level of complexity, providing rich behavior for which modeling is still tractable. We argue that a data set of this nature is necessary for distinguishing theoretical frameworks for integration between prospective and retrospective decision-making, and show preliminary evidence for the existence of both systems in our task. We outline a computational model based on an intuitive value function and decision tree search to demonstrate that people engage in prospective planning. We then explain discrepancies between the model’s predictions and observed data in early game choices, finding behavioral patterns consistent with retrospective learning.

Prospective planning and retrospective learning in a large-scale combinatorial game

Spatial coincidences can lead to causal discoveries. We might expect to find a few ants on the sidewalk, but an unusually large cluster tips us off about the presence of a nearby food source. The leading cognitive explanation for this class of reasoning is Bayesian, but Bayesian models remain notoriously agnostic about the inner workings of the cognitive “black box.” In this cluster detection paradigm, we ask what algorithms the brain might actually implement to detect spatial coincidences in an “approximately Bayesian” way. We find evidence that the brain represents two variables of the generative model: 1) the location of a hypothesized causal source and 2) the location of the points to which it gave rise. However, we propose that the brain is limited to representing probability distributions over one but not both of these variables, resulting in strong deviations from Bayes-optimality. We find, counterintuitively, that subjects become more prone to false alarms as the amount of information increases, and our proposed cognitive algorithm accounts for this pattern. Our representation-level algorithm elucidates the cognitive processes underlying coincidence detection, and helps explain our tendency to perceive causal patterns where none exist.

A representation-level algorithm for detecting spatial coincidences

To understand decision-making behavior in simple, controlled environments, Bayesianmodels are often useful. First, optimal behavior is always Bayesian. Second, even when behavior deviates from optimality, the Bayesian approach offers candidate models to account for suboptimalities. Third, a realist interpretation of Bayesian models opens the door to studying the neural representation of uncertainty. In this tutorial, we review the principles of Bayesian models of decision making and then focus on five case studies with exercises. We conclude with reflections and future directions.

Previous work has shown that humans distribute their visual working memory (VWM) resources flexibly across items: the higher the importance of an item, the better it is remembered. A related, but much less studied question is whether people also have control over the total amount of VWM resource allocated to a task. Here, we approach this question by testing whether increasing monetary incentives results in better overall VWM performance. In three experiments, subjects performed a delayed-estimation task on the Amazon Turk platform. In the first two experiments, four groups of subjects received a bonus payment based on their performance, with the maximum bonus ranging from $0 to $10 between groups. We found no effect of the amount of bonus on intrinsic motivation or on VWM performance in either experiment. In the third experiment, reward was manipulated on a trial-by-trial basis using a within-subjects design. Again, no evidence was found that VWM performance depended on the magnitude of potential reward. These results suggest that encoding quality in visual working memory is insensitive to monetary reward, which has implications for resource-rational theories of VWM.

Prioritizing relevant information in visual working memory sculpts neural representations in retinotopic cortex to reduce their uncertainty

A common method, due to Zhang and Luck (2008), for analyzing delayed-estimation data with a circular stimulus variable is to fit a mixture of a Von Mises distribution and a uniform distribution. The uniform distribution represents random guesses, presumably made when an item is not kept in memory. When I generate synthetic data from a variable-precision model with zero guessing, the method estimates the guess rate to be nonzero and often high. This is due to model mismatch: the fitted model is not matched to the data-generating (true) model. In real data, this could be a problem if one considers the variable-precision model a plausible candidate model and draws conclusions based on the estimated guess rates. I describe five solutions to this problem: analyzing the residual, ruling out the variable-precision model, robust inference, fitting a hybrid model, and using model-free statistics. I hope that these solutions can contribute to good data analysis practices in the study of working memory.

Encoding precision in visual working memory decreases with the number of encoded items. Here, we propose a normative theory for such set size effects: the brain minimizes a weighted sum of an error-based behavioral cost and a neural encoding cost. We construct a model from this theory and find that it predicts set size effects. Notably, these effects are mediated by probing probability, which aligns with previous empirical findings. The model accounts well for effects of both set size and probing probability on encoding precision in nine delayed-estimation experiments. Moreover, we find support for the prediction that the total amount of invested resource can vary non-monotonically with set size. Finally, we show that it is sometimes optimal to encode only a subset or even none of the relevant items in a task. Our findings raise the possibility that cognitive "limitations" arise from rational cost minimization rather than from constraints.

A resource-rational theory of set size effects in human visual working memory

Author response: A resource-rational theory of set size effects in human visual working memory

Supplementary material from "The role of familiarity in signaller–receiver interactions"

In animal communication, individuals of species exhibiting individual recognition of conspecifics with whom they have repeated interactions, receive signals not only from unfamiliar conspecifics, but also from individuals with whom they have prior experience. Empirical evidence suggests that familiarity with a specific signaller aids receivers in interpreting that signaller's signals, but there has been little theoretical work on this effect. Here, we develop a Bayesian decision-making model and apply it to the well-studied systems of primate ovulation signals. We compare the siring probability of learner males versus non-learner males, based on variation in their assessment of the best time to mate and mate-guard females. We compare males of different dominance ranks, and vary the number of females, and their cycle synchrony. We find strong fitness advantages for learners, which manifest very quickly. Receivers do not have to see the full range of a signaller's signals in order to start gaining familiarity benefits. Reproductive asynchrony and increasing the number of females both enhance learning advantages. We provide theoretical evidence for a strong advantage to specific learning of a signaller's range of signals in signalling systems. Our results have broad implications, not only for understanding communication, but in elucidating additional fitness benefits to group-living, the evolution of individual recognition, and other characteristics of animal behavioural biology.

Abstract Given the many types of suboptimality in perception, I ask how one should test for multiple forms of suboptimality at the same time – or, more generally, how one should compare process models that can differ in any or all of the multiple components. In analogy to factorial experimental design, I advocate for factorial model comparison.

Humans can meaningfully report their confidence in a perceptual or cognitive decision. It is widely believed that these reports reflect the Bayesian probability that the decision is correct, but this hypothesis has not been rigorously tested against non-Bayesian alternatives. We use two perceptual categorization tasks in which Bayesian confidence reporting requires subjects to take sensory uncertainty into account in a specific way. We find that subjects do take sensory uncertainty into account when reporting confidence, suggesting that brain areas involved in reporting confidence can access low-level representations of sensory uncertainty, a prerequisite of Bayesian inference. However, behavior is not fully consistent with the Bayesian hypothesis and is better described by simple heuristic models that use uncertainty in a non-Bayesian way. Both conclusions are robust to changes in the uncertainty manipulation, task, response modality, model comparison metric, and additional flexibility in the Bayesian model. Our results suggest that adhering to a rational account of confidence behavior may require incorporating implementational constraints.

Comparing Bayesian and non-Bayesian accounts of human confidence reports

Given the same sensory stimuli in the same task, human observers do not always make the same response. Well-known sources of behavioral variability are sensory noise and guessing. Visual short-term memory (STM) studies have suggested that the precision of the sensory noise is itself variable. However, it is unknown whether precision is also variable in perceptual tasks without a memory component. We searched for evidence for variable precision in 11 visual perception tasks with a single relevant feature, orientation. We specifically examined the effect of distractor stimuli: distractors were absent, homogeneous and fixed across trials, homogeneous and variable, or heterogeneous and variable. We first considered 4 models: with and without guessing, and with and without variability in precision. We quantified the importance of both factors using 6 metrics: factor knock-in difference, factor knock-out difference, and log factor posterior ratio, each based on AIC or BIC. According to all 6 metrics, we found strong evidence for variable precision in 5 experiments. Next, we extended our model space to include potential confounding factors: the oblique effect and decision noise. This left strong evidence for variable precision in only 1 experiment, in which distractors were homogeneous but variable. Finally, when we considered suboptimal decision rules, the evidence also disappeared in this experiment. Our results provide little evidence for variable precision overall and only a hint when distractors are variable. Methodologically, the results underline the importance of including multiple factors in factorial model comparison: Testing for only 2 factors would have yielded an incorrect conclusion.

Significance We must routinely make decisions based on uncertain sensory information. Sometimes that uncertainty is related to our own cognitive state, such as when we are not paying attention. Do our decisions about what we perceive take into account our attentional state? Or are we blind to such internal sources of uncertainty, leading to poor decisions and overconfidence? We found that human observers take attention-dependent uncertainty into account when categorizing visual stimuli and reporting their confidence in a task in which uncertainty is relevant for performance. Moreover, they do so in an approximately Bayesian fashion. Human perceptual decision-making can therefore, at least in some cases, adjust in a statistically appropriate way to external and internal sources of uncertainty. Perceptual decisions are better when they take uncertainty into account. Uncertainty arises not only from the properties of sensory input but also from cognitive sources, such as different levels of attention. However, it is unknown whether humans appropriately adjust for such cognitive sources of uncertainty during perceptual decision-making. Here we show that, in a task in which uncertainty is relevant for performance, human categorization and confidence decisions take into account uncertainty related to attention. We manipulated uncertainty in an orientation categorization task from trial to trial using only an attentional cue. The categorization task was designed to disambiguate decision rules that did or did not depend on attention. Using formal model comparison to evaluate decision behavior, we found that category and confidence decision boundaries shifted as a function of attention in an approximately Bayesian fashion. This means that the observer’s attentional state on each trial contributed probabilistically to the decision computation. This responsiveness of an observer’s decisions to attention-dependent uncertainty should improve perceptual decisions in natural vision, in which attention is unevenly distributed across a scene.

Humans incorporate attention-dependent uncertainty into perceptual decisions and confidence

In natural perception, different items (objects) in a scene are rarely equally relevant to the observer. The brain improves performance by directing attention to the most relevant items, for example the ones most likely to be probed. For a general set of probing probabilities, it is not known how attentional resources should be allocated to maximize performance. Here, we investigate the optimal strategy for allocating a fixed resource budget E among N items when on each trial, only one item gets probed. We develop an efficient algorithm that, for any concave utility function, reduces the N-dimensional problem to a set of N one-dimensional problems that the brain could plausibly solve. We find that the intuitive strategy of allocating resource in proportion to the probing probabilities is in general not optimal. In particular, in some tasks, if resource is low, the optimal strategy involves allocating zero resource to items with a nonzero probability of being probed. Our work opens the door to normatively guided studies of attentional allocation.

Optimal allocation of attentional resource to multiple items with unequal relevance

Any mature field of research in psychology-such as short-term/working memory-is characterized by a wealth of empirical findings. It is currently unrealistic to expect a theory to explain them all; theorists must satisfice with explaining a subset of findings. The aim of the present article is to make the choice of that subset less arbitrary and idiosyncratic than is current practice. We propose criteria for identifying benchmark findings that every theory in a field should be able to explain: Benchmarks should be reproducible, generalize across materials and methodological variations, and be theoretically informative. We propose a set of benchmarks for theories and computational models of short-term and working memory. The benchmarks are described in as theory-neutral a way as possible, so that they can serve as empirical common ground for competing theoretical approaches. Benchmarks are rated on three levels according to their priority for explanation. Selection and ratings of the benchmarks is based on consensus among the authors, who jointly represent a broad range of theoretical perspectives on working memory, and they are supported by a survey among other experts on working memory. The article is accompanied by a web page providing an open forum for discussion and for submitting proposals for new benchmarks; and a repository for reference data sets for each benchmark. (PsycINFO Database Record

A resource-rational theory of set size effects in visual working memory

T186. Perceptual and Executive Behavioral Deficits in ADHD and Their Differential Correlation With Microsaccade Rate

Optimal sensory decision-making requires the combination of uncertain sensory signals with prior expectations. The effect of prior probability is often described as a shift in the decision criterion. Can observers track sudden changes in probability? To answer this question, we used a change-point detection paradigm that is frequently used to examine behavior in changing environments. In a pair of orientation-categorization tasks, we investigated the effects of changing probabilities on decision-making. In both tasks, category probability was updated using a sample-and-hold procedure. We developed an ideal Bayesian change-point detection model in which the observer marginalizes over both the current run length (i.e., time since last change) and the current category probability. We compared this model to various alternative models that correspond to different strategies – from approximately Bayesian to simple heuristics – that the observers may have adopted to update their beliefs about probabilities. We find that probability is estimated following an exponential averaging model with a bias towards equal priors, consistent with a conservative bias. The mechanism underlying change of decision criterion is a combination of on-line estimation of prior probability and a stable, long-term equal-probability prior, thus operating at two very different timescales. Author summary We demonstrate how people learn and adapt to changes to the probability of occurrence of one of two categories on decision-making under uncertainty. The study combined psychophysical behavioral tasks with computational modeling. We used two behavioral tasks: a typical forced-choice categorization task as well as one in which the observer specified the decision criterion to use on each trial before the stimulus was displayed. We formulated an ideal Bayesian change-point detection model and compared it to several alternative models. We found that the data are best fit by a model that estimates category probability based on recently observed exemplars with a bias towards equal probability. Our results suggest that the brain takes multiple relevant time scales into account when setting category expectations.

Perceptual organization is the process of grouping scene elements into whole entities, for example line segments into contours. Uncertainty in grouping arises from scene ambiguity and sensory noise. Some classic Gestalt principles of perceptual organization have been re-framed in terms of Bayesian models, whereby the observer computes the probability that the whole entity is present. Previous studies that proposed a Bayesian interpretation of perceptual organization, however, have ignored sensory uncertainty, despite the fact that accounting for the current level of uncertainty is the main signature of Bayesian decision making. Crucially, trial-by-trial manipulation of sensory uncertainty is necessary to test whether humans perform optimal Bayesian inference in perceptual organization, as opposed to using some non-Bayesian heuristic. We distinguish between these hypotheses in an elementary form of perceptual organization, namely judging whether two line segments separated by an occluder are collinear. We manipulate sensory uncertainty by varying retinal eccentricity. A Bayes-optimal observer would take the level of sensory uncertainty into account – in a very specific way - in deciding whether a measured offset between the line segments is due to non-collinearity or to sensory noise. We find that people deviate slightly but systematically from Bayesian optimality, while still performing “probabilistic computation” in the sense that they take into account sensory uncertainty via a heuristic rule. Our work contributes to an understanding of the role of sensory uncertainty in higher-order perception. Author summary Our percept of the world is governed not only by the sensory information we have access to, but also by the way we interpret this information. When presented with a visual scene, our visual system undergoes a process of grouping visual elements together to form coherent entities so that we can interpret the scene more readily and meaningfully. For example, when looking at a pile of autumn leaves, one can still perceive and identify a whole leaf even when it is partially covered by another leaf. While Gestalt psychologists have long described perceptual organization with a set of qualitative laws, recent studies offered a statistically-optimal – Bayesian, in statistical jargon – interpretation of this process, whereby the observer chooses the scene configuration with the highest probability given the available sensory inputs. However, these studies drew their conclusions without considering a key actor in this kind of statistically-optimal computations, that is the role of sensory uncertainty. One can easily imagine that our decision on whether two contours belong to the same leaf or different leaves is likely going to change when we move from viewing the pile of leaves at a great distance (high sensory uncertainty), to viewing very closely (low sensory uncertainty). Our study examines whether and how people incorporate uncertainty into perceptual organization, by varying sensory uncertainty from trial to trial in a simple perceptual organization task. We found that people indeed take into account sensory uncertainty, however in a way that subtly deviates from optimal behavior.

The Role of Sensory Uncertainty in Simple Perceptual Organization

We respond to the comments of Logie and Vandierendonck to our article proposing benchmark findings for evaluating theories and models of short-term and working memory. The response focuses on the two main points of criticism: (a) Logie and Vandierendonck argue that the scope of the set of benchmarks is too narrow. We explain why findings on how working memory is used in complex cognition, findings on executive functions, and findings from neuropsychological case studies are currently not included in the benchmarks, and why findings with visual and spatial materials are less prevalent among them. (b) The critics question the usefulness of the benchmarks and their ratings for advancing theory development. We explain why selecting and rating benchmarks is important and justifiable, and acknowledge that the present selection and rating decisions are in need of continuous updating. The usefulness of the benchmarks of all ratings is also enhanced by our concomitant online posting of data for many of these benchmarks. (PsycINFO Database Record

Benchmarks provide common ground for model development: Reply to Logie (2018) and Vandierendonck (2018).

Significance Information stored in working memory (WM) is incorporated into many daily decisions and actions, and many complex decisions involve WM; however, there has been little work on investigating what WM information is used in memory decisions. Here we try to draw connections between WM and decision making by manipulating prior beliefs in a standard WM task with rewards. We use this paradigm to show that WM contains a representation of the trial-by-trial uncertainty of visual stimuli. This uncertainty is incorporated into rewarded decisions along with other information, such as expectations about the environment. By studying WM in parallel with decision making, we can gain new insight into how these systems work together. Working memory (WM) plays an important role in action planning and decision making; however, both the informational content of memory and how that information is used in decisions remain poorly understood. To investigate this, we used a color WM task in which subjects viewed colored stimuli and reported both an estimate of a stimulus color and a measure of memory uncertainty, obtained through a rewarded decision. Reported memory uncertainty is correlated with memory error, showing that people incorporate their trial-to-trial memory quality into rewarded decisions. Moreover, memory uncertainty can be combined with other sources of information; after inducing expectations (prior beliefs) about stimuli probabilities, we found that estimates became shifted toward expected colors, with the shift increasing with reported uncertainty. The data are best fit by models in which people incorporate their trial-to-trial memory uncertainty with potential rewards and prior beliefs. Our results suggest that WM represents uncertainty information, and that this can be combined with prior beliefs. This highlights the potential complexity of WM representations and shows that rewarded decision can be a powerful tool for examining WM and informing and constraining theoretical, computational, and neurobiological models of memory.

Humans incorporate trial-to-trial working memory uncertainty into rewarded decisions

The original and corrected figures and equations are shown in the accompanying Publisher Correction.

Temporal dynamics of visual working memory representations across human cortex

Perceptual decisions are better when they take uncertainty into account. Here we show that human decision-making accounts for uncertainty arising not only from external factors, but from the observer’s cognitive state. We manipulated uncertainty in an orientation categorization task from trial to trial using only an attentional cue. Category and confidence decision boundaries shifted in an approximately Bayesian fashion. This responsiveness likely improves perceptual decisions in natural vision.

Humans flexibly incorporate attention-dependent uncertainty into perceptual decisions and confidence

The precision with which items are encoded in working memory and attention decreases with the number of encoded items. Current theories typically account for this “set size effect” by postulating a hard constraint on the allocated amount of encoding resource. While these theories have produced models that are descriptively successful, they offer no principled explanation for the very existence of set size effects: given their detrimental consequences for behavioral performance, why have these effects not been weeded out by evolutionary pressure, by allocating resources proportionally to the number of encoded items? Here, we propose a theory that is based on an ecological notion of rationality: set size effects are the result of a near-optimal trade-off between behavioral performance and the neural costs associated with stimulus encoding. We derive models for four visual working memory and attention tasks and show that they account well for data from eleven previously published experiments. Moreover, our results suggest that the total amount of resource that subjects allocate for stimulus encoding varies non-monotonically with set size, which is consistent with our rational theory of set size effects but not with previous descriptive theories. Altogether, our findings suggest that set size effects may have a rational basis and highlight the importance of considering ecological costs in theories of human cognition.

A rational theory of set size effects in working memory and attention

Based on my CV, you might think my path to becoming a tenured faculty member was pretty smooth: master's degree, Ph.D., two postdocs, faculty position. The true story, however, is much more twisted. During my graduate work in physics, I was so out of my depth that, as an escape, I spent more time on

When presented with the same sensory stimuli and performing the same task, people do not always make the same response. Such behavioral variability can have different causes, including sensory noise, decision noise, and guessing. In addition, recent work has proposed that the precision of sensory encoding is itself variable, both driven by the stimulus (heteroskedasticity) and independent of the stimulus. We analyzed data of 3 published and 8 new visual decision-making tasks with a single relevant feature, orientation. In modeling each experiment, we considered four factors: guessing (lapses), decision noise, orientation-dependent variable precision (oblique effect), and orientation-independent variable precision (inspired by visual working memory models). Modern computational power allows us to test all combinations of these factors; in a given model, each factor could be present or absent. To quantify the importance of each factor in explaining the data, we introduce three metrics: factor knock-in, factor knock-out and factor posterior probability. Across all experiments, we found strong evidence for guessing and for orientation-dependent variable precision. We found evidence for decision noise in only one experiment, and for orientation-independent variable precision only when distractors are variable across trials. On a methodological note, the factor importance metrics can be applied widely in factorial model comparison.

Quantifying the importance of guessing, decision noise, and variable precision in explaining behavioral variability in visual perception

SUBMISSION DETAILS Presentation Type Either Poster or Oral Presentation Presentation Abstract Summary Perceptual organization is the process of grouping scene elements into meaningful whole entities, for example line segments into contours. Some classic Gestalt principles of perceptual organization have been reframed in terms of Bayesian models, in which the observer computes the probability that the whole entity is present. These studies, however, leave open the possibility that people apply a fixed, learned stimulus-response mapping that mimics Bayesian inference. The alternative requires people to actually compute with probability distributions, i.e. flexibly take sensory uncertainty into account even when it varies from trial to trial. We distinguish between these hypotheses in a simple form of perceptual organization, namely judging whether two line segments separated by an occluder are collinear. We manipulate sensory uncertainty by varying retinal eccentricity. Probabilistic computation would imply that the observer takes the level of sensory uncertainty into account in deciding whether a measured offset between the line segments is due to non-collinearity or to sensory noise. We find that people indeed do so, providing the first evidence for probabilistic computation in perceptual organization. Paper Upload (PDF) CCN abstract Yanli,Luigi.pdf Co-author Information

Vertical line segments tend to be perceived as longer than horizontal ones of the same length, but this may in part be due to configuration effects. To minimize such effects, we used isolated line segments in a two-interval, forced choice paradigm, not limiting ourselves to horizontal and vertical. We fitted psychometric curves using a Bayesian method that assumes that, for a given subject, the lapse rate is the same across all conditions. The closer a line segment's orientation was to vertical, the longer it was perceived to be. Moreover, subjects tended to report the standard line (in the second interval) as longer. The data were well described by a model that contains both an orientation-dependent and an interval-dependent multiplicative bias. Using this model, we estimated that a vertical line was on average perceived as 9.2% ± 2.1% longer than a horizontal line, and a second-interval line was on average perceived as 2.4% ± 0.9% longer than a first-interval line. Moving from a descriptive to an explanatory model, we hypothesized that anisotropy in the polar angle of lines in three dimensions underlies the horizontal-vertical illusion, specifically, that line segments more often have a polar angle of 90° (corresponding to the ground plane) than any other polar angle. This model qualitatively accounts not only for the empirical relationship between projected length and projected orientation that predicts the horizontal-vertical illusion, but also for the empirical distribution of projected orientation in photographs of natural scenes and for paradoxical results reported earlier for slanted surfaces.

Orientation-dependent biases in length judgments of isolated stimuli.

Measuring and Modeling Attentional Limitations in Split-Second Visual Decisions

Asking subjects to rate their confidence is one of the oldest procedures in psychophysics. Remarkably, quantitative models of confidence ratings have been scarce. The Bayesian confidence hypothesis (BCH) states that an observer’s confidence rating is monotonically related to the posterior probability of their choice. I will report tests of this hypothesis in two visual categorization tasks: one requiring rapid categorization of a single oriented stimulus, the other a deliberative judgment typically made by scientists, namely interpreting scatterplots. We find evidence against the Bayesian confidence hypothesis in both tasks. Model. Let s be the world state of interest and x a set of noisy visual observations that follow a distribution p(x|s). A Bayes-optimal observer would compute the posterior over s, denoted by p(s|x). We model the observer’s decision as a maximum-a-posteriori (MAP) estimate,   ˆ argmax | s s p s x  , and the

Efficient probabilistic inference in generic neural networks trained with non-probabilistic feedback

In many studies of attention-deficit hyperactivity disorder (ADHD), stimulus encoding and processing (per-ceptual function) and response selection (executive function) have been intertwined. To dissociate deficits in these functions, we introduced a task that parametrically varied low-level stimulus features (orientation and color) for fine-grained analysis of perceptual function. It also required participants to switch their attention between feature dimensions on a trial-by-trial basis, thus taxing executive processes. Furthermore, we used a response paradigm that captured task-irrelevant motor output (TIMO), reflecting failures to use the correct stimulus-response rule. ADHD participants had substantially higher perceptual variability than Controls, especially for orientation, as well as higher TIMO. In both ADHD and Controls, TIMO was strongly affected by the switch manipulation. Across participants, the perceptual variability parameter was correlated with TIMO, suggesting that perceptual deficits are associated with executive function deficits. Based on perceptual variability alone, we were able to classify participants into ADHD and Controls with a mean accuracy of about 77%. Participants’ self-reported General Executive Composite score correlated not only with TIMO but also with the perceptual variability parameter. Our results highlight the role of perceptual deficits in ADHD and the usefulness of computational modeling of behavior in dissociating perceptual from executive processes.

A Low-Level Perceptual Correlate of Behavioral and Clinical Deficits in ADHD

Although visual working memory (VWM) has been studied extensively, it is unknown how people form confidence judgments about their memories. Peirce (1878) speculated that Fechner’s law—which states that sensation is proportional to the logarithm of stimulus intensity—might apply to confidence reports. Based on this idea, we hypothesize that humans map the precision of their VWM contents to a confidence rating through Fechner’s law. We incorporate this hypothesis into the best available model of VWM encoding and fit it to data from a delayed-estimation experiment. The model provides an excellent account of human confidence rating distributions as well as the relation between performance and confidence. Moreover, the best-fitting mapping in a model with a highly flexible mapping closely resembles the logarithmic mapping, suggesting that no alternative mapping exists that accounts better for the data than Fechner’s law. We propose a neural implementation of the model and find that this model also fits the behavioral data well. Furthermore, we find that jointly fitting memory errors and confidence ratings boosts the power to distinguish previously proposed VWM encoding models by a factor of 5.99 compared to fitting only memory errors. Finally, we show that Fechner’s law also accounts for metacognitive judgments in a word recognition memory task, which is a first indication that it may be a general law in metacognition. Our work presents the first model to jointly account for errors and confidence ratings in VWM and could lay the groundwork for understanding the computational mechanisms of metacognition.

Fechner’s Law in Metacognition: A Quantitative Model of Visual Working Memory Confidence

The precision of multisensory heading perception improves when visual and vestibular cues arising from the same cause, namely motion of the observer through a stationary environment, are integrated. Thus, in order to determine how the cues should be processed, the brain must infer the causal relationship underlying the multisensory cues. In heading perception, however, it is unclear whether observers follow the Bayesian strategy, a simpler non-Bayesian heuristic, or even perform causal inference at all. We developed an efficient and robust computational framework to perform Bayesian model comparison of causal inference strategies, which incorporates a number of alternative assumptions about the observers. With this framework, we investigated whether human observers’ performance in an explicit cause attribution and an implicit heading discrimination task can be modeled as a causal inference process. In the explicit inference task, all subjects accounted for cue disparity when reporting judgments of common cause, although not necessarily all in a Bayesian fashion. By contrast, but in agreement with previous findings, data from the heading discrimination task only could not rule out that several of the same observers were adopting a forced-fusion strategy, whereby cues are integrated regardless of disparity. Only when we combined evidence from both tasks we were able to rule out forced-fusion in the heading discrimination task. Crucially, findings were robust across a number of variants of models and analyses. Our results demonstrate that our proposed computational framework allows researchers to ask complex questions within a rigorous Bayesian framework that accounts for parameter and model uncertainty.

Bayesian comparison of explicit and implicit causal inference strategies in multisensory heading perception

How do people plan ahead in sequential decision-making tasks? In this article, we compare computational models of human behavior in a challenging variant of tic-tac-toe, to investigate the cognitive processes underlying sequential planning. We validate the most successful model by predicting choices during games, two-alternative forced choices and board evaluations. We then use this model to study individual skill differences, the effects of time pressure and the nature of expertise. Our findings suggest that people perform less tree search under time pressure, and that players search more as they improve during learning.

Humans can meaningfully report their confidence in a perceptual or cognitive decision. It is widely believed that these reports reflect the estimated probability that the decision is correct, but this belief is a hypothesis rather than an established fact. In a pair of perceptual categorization tasks, we tested whether explicit confidence reports reflect the Bayesian posterior probability of being correct, which would require subjects to take sensory uncertainty into account in a specific way. We find that subjects do take sensory uncertainty into account, but that they do so in a way that is inconsistent with the Bayesian hypothesis. Instead, heuristic models provide the best fit to confidence reports. This conclusion is robust to changes in the uncertainty manipulation, task, response modality, additional flexibility in the Bayesian model, and model comparison metric. Finally, we find that generic neural networks trained with error feedback produce confidence reports that are best fit by the same heuristic probabilistic models, suggesting that implementational constraints cause explicit confidence reports to deviate from being Bayesian.

Human confidence reports account for sensory uncertainty but in a non-Bayesian way

Decoding visual spatial working memory uncertainty from human cortex

We used a delayed-estimation paradigm to characterize the joint effects of set size (one, two, four, or six) and delay duration (1, 2, 3, or 6 s) on visual working memory for orientation. We conducted two experiments: one with delay durations blocked, another with delay durations interleaved. As dependent variables, we examined four model-free metrics of dispersion as well as precision estimates in four simple models. We tested for effects of delay time using analyses of variance, linear regressions, and nested model comparisons. We found significant effects of set size and delay duration on both model-free and model-based measures of dispersion. However, the effect of delay duration was much weaker than that of set size, dependent on the analysis method, and apparent in only a minority of subjects. The highest forgetting slope found in either experiment at any set size was a modest 1.14°/s. As secondary results, we found a low rate of nontarget reports, and significant estimation biases towards oblique orientations (but no dependence of their magnitude on either set size or delay duration). Relative stability of working memory even at higher set sizes is consistent with earlier results for motion direction and spatial frequency. We compare with a recent study that performed a very similar experiment.

The effects of delay duration on visual working memory for orientation

Since sensory measurements are noisy, an observer is rarely certain about the identity of a stimulus. In visual perception tasks, observers generally take their uncertainty about a stimulus into account when doing so helps task performance. Whether the same holds in visual working memory tasks is largely unknown. Ten human and two monkey subjects localized a single change in orientation between a sample display containing three ellipses and a test display containing two ellipses. To manipulate uncertainty, we varied the reliability of orientation information by making each ellipse more or less elongated (two levels); reliability was independent across the stimuli. In both species, a variable-precision encoding model equipped with an “uncertainty–indifferent” decision rule, which uses only the noisy memories, fitted the data poorly. In both species, a much better fit was provided by a model in which the observer also takes the levels of reliability-driven uncertainty associated with the memories into account. In particular, a measured change in a low-reliability stimulus was given lower weight than the same change in a high-reliability stimulus. We did not find strong evidence that observers took reliability-independent variations in uncertainty into account. Our results illustrate the importance of studying the decision stage in comparison tasks and provide further evidence for evolutionary continuity of working memory systems between monkeys and humans.

Monkeys and humans take local uncertainty into account when localizing a change

Microsaccades are high-velocity fixational eye movements, with special roles in perception and cognition. The default microsaccade detection method is to determine when the smoothed eye velocity exceeds a threshold. We have developed a new method, Bayesian microsaccade detection (BMD), which performs inference based on a simple statistical model of eye positions. In this model, a hidden state variable changes between drift and microsaccade states at random times. The eye position is a biased random walk with different velocity distributions for each state. BMD generates samples from the posterior probability distribution over the eye state time series given the eye position time series. Applied to simulated data, BMD recovers the “true” microsaccades with fewer errors than alternative algorithms, especially at high noise. Applied to EyeLink eye tracker data, BMD detects almost all the microsaccades detected by the default method, but also apparent microsaccades embedded in high noise—although these can also be interpreted as false positives. Next we apply the algorithms to data collected with a Dual Purkinje Image eye tracker, whose higher precision justifies defining the inferred microsaccades as ground truth. When we add artificial measurement noise, the inferences of all algorithms degrade; however, at noise levels comparable to EyeLink data, BMD recovers the “true” microsaccades with 54% fewer errors than the default algorithm. Though unsuitable for online detection, BMD has other advantages: It returns probabilities rather than binary judgments, and it can be straightforwardly adapted as the generative model is refined. We make our algorithm available as a software package.

A central question in the study of visual short-term memory (VSTM) has been whether its basic units are objects or features. Most studies addressing this question have used change detection tasks in which the feature value before the change is highly discriminable from the feature value after the change. This approach assumes that memory noise is negligible, which recent work has shown not to be the case. Here, we investigate VSTM for orientation and color within a noisy-memory framework, using change localization with a variable magnitude of change. A specific consequence of the noise is that it is necessary to model the inference (decision) stage. We find that (a) orientation and color have independent pools of memory resource (consistent with classic results); (b) an irrelevant feature dimension is either encoded but ignored during decision-making, or encoded with low precision and taken into account during decision-making; and (c) total resource available in a given feature dimension is lower in the presence of task-relevant stimuli that are neutral in that feature dimension. We propose a framework in which feature resource comes both in packaged and in targeted form.

There are many benefits to having a highly accurate representation of the environment. Why, then, has evolution equipped us with a visual working memory (VWM) system that can represent only a handful of items with high accuracy? Here, we offer a normative explanation for this limitation by conceptualizing VWM as a system that balances between two conflicting goals: keeping memory errors small and spiking activity low. We formalize this trade-off in a loss function and show that minimization of loss dictates a strategy in which memory precision declines with the number of remembered items. Using psychophysical data from 67 human subjects in 5 delayed-estimation experiments, we show that this normative model provides an excellent account of human VWM limitations. These results suggest that human VWM implements an optimal compromise between two conflicting ecological goals.

Two prominent ideas in the study of decision making have been that organisms behave near-optimally, and that they use simple heuristic rules. These principles might be operating in different types of tasks, but this possibility cannot be fully investigated without a direct, rigorous comparison within a single task. Such a comparison was lacking in most previous studies, because (a) the optimal decision rule was simple, (b) no simple suboptimal rules were considered, (c) it was unclear what was optimal, or (d) a simple rule could closely approximate the optimal rule. Here, we used a perceptual decision-making task in which the optimal decision rule is well-defined and complex, and makes qualitatively distinct predictions from many simple suboptimal rules. We find that all simple rules tested fail to describe human behavior, that the optimal rule accounts well for the data, and that several complex suboptimal rules are indistinguishable from the optimal one. Moreover, we found evidence that the optimal model is close to the true model: First, the better the trial-to-trial predictions of a suboptimal model agree with those of the optimal model, the better that suboptimal model fits; second, our estimate of the Kullback-Leibler divergence between the optimal model and the true model is not significantly different from zero. When observers receive no feedback, the optimal model still describes behavior best, suggesting that sensory uncertainty is implicitly represented and taken into account. Beyond the task and models studied here, our results have implications for best practices of model comparison. (PsycINFO Database Record

A detailed comparison of optimality and simplicity in perceptual decision making.

When we lift two differently-sized but equally-weighted objects, we expect the larger to be heavier, but the smaller feels heavier. However, traditional Bayesian approaches with “larger is heavier” priors predict the smaller object should feel lighter; this Size-Weight Illusion (SWI) has thus been labeled “anti-Bayesian” and has stymied psychologists for generations. We propose that previous Bayesian approaches neglect the brain’s inference process about density. In our Bayesian model, objects’ perceived heaviness relationship is based on both their size and inferred density relationship: observers evaluate competing, categorical hypotheses about objects’ relative densities, the inference about which is then used to produce the final estimate of weight. The model can qualitatively and quantitatively reproduce the SWI and explain other researchers’ findings, and also makes a novel prediction, which we confirmed. This same computational mechanism accounts for other multisensory phenomena and illusions; that the SWI follows the same process suggests that competitive-prior Bayesian inference can explain human perception across many domains.

The Size-Weight Illusion is not anti-Bayesian after all: a unifying Bayesian account

A detailed comparison of optimality and simplicity in visual search

We measured the precision with which an irrelevant feature of a relevant object is stored in visual short-term memory. In each experiment, 600 online subjects each completed 30 trials in which the same feature (orientation or color) was relevant, followed by a single surprise trial in which the other feature was relevant. Pooling data across all subjects, we find in a delayed-estimation task but not in a change localization task that the irrelevant feature is retrieved, but with much lower precision than when the same feature is relevant: The irrelevant/relevant precision ratio was 3.8% for orientation and 20.4% for color.

Crowdsourced single-trial probes of visual working memory for irrelevant features

Humans can meaningfully rate their confidence in a perceptual or cognitive decision. It is widely believed that these reports reflect the estimated probability that the decision is correct, but, upon closer look, this belief is a hypothesis rather than an established fact. In a pair of perceptual categorization tasks, we tested whether explicit confidence reports reflect the Bayesian posterior probability of being correct. This Bayesian hypothesis predicts that subjects take sensory uncertainty into account in a specific way in the computation of confidence ratings. We find that confidence reports are probabilistic: subjects take sensory uncertainty into account on a trial-to-trial basis. However, they do not do so in the way predicted by the Bayesian hypothesis. Instead, heuristic probabilistic models provide the best fit to human confidence ratings. This conclusion is robust to changes in the uncertainty manipulation, task, response modality, additional flexibility in the Bayesian model, and model comparison metric. To better understand the origins of the heuristic computation, we trained feedforward neural networks consisting of generic units with error feedback, mapped the output of the trained networks to confidence ratings, and fitted our behavioral models to the resulting synthetic datasets. We find that the synthetic confidence ratings are also best fit by heuristic probabilistic models. This suggests that implementational constraints cause explicit confidence reports to deviate from being Bayesian.

The computations underlying human confidence reports are probabilistic, but not Bayesian

Humans and other animals have been shown to perform near-optimal probabilistic inference in a wide range of psychophysical tasks. On the face of it, this is surprising because optimal probabilistic inference in each case is associated with highly non-trivial behavioral strategies. Yet, typically subjects receive little to no feedback during most of these tasks and the received feedback is not explicitly probabilistic in nature. How can subjects learn such non-trivial behavioral strategies from scarce non-probabilistic feedback? We show that generic feed-forward and recurrent neural networks trained with a relatively small number of non-probabilistic examples using simple error-based learning rules can perform near-optimal probabilistic inference in standard psychophysical tasks. The hidden layers of the trained networks develop a novel sparsity-based probabilistic population code. In all tasks, performance asymptotes at very small network sizes, usually on the order of tens of hidden units, due to the low computational complexity of the typical psychophysical tasks. For the same reason, the trained networks also display remarkable generalization to stimulus conditions not seen during training. We further show that in a probabilistic binary categorization task involving arbitrary categories where both human and monkey subjects have been shown to perform probabilistic inference, a monkey subject's performance (but not human subjects' performance) is consistent with an error-based learning rule. Our results suggest that near-optimal probabilistic inference in standard psychophysical tasks emerges naturally and robustly in generic neural networks trained with error-based learning rules, even when neither the training objective nor the training examples are explicitly probabilistic, and that these types of networks can be used as simple plausible neural models of probabilistic inference.

The Inevitability of Probability: Probabilistic Inference in Generic Neural Networks Trained with Non-Probabilistic Feedback

We consider model social networks in which information propagates directionally across layers of rational agents. Each agent makes a locally optimal estimate of the state of the world, and communicates this estimate to agents downstream. When agents receive information from the same source their estimates are correlated. We show that the resulting redundancy can lead to the loss of information about the state of the world across layers of the network, even when all agents have full knowledge of the network's structure. A simple algebraic condition identifies networks in which information loss occurs, and we show that all such networks must contain a particular network motif. We also study random networks asymptotically as the number of agents increases, and find a sharp transition in the probability of information loss at the point at which the number of agents in one layer exceeds the number in the previous layer.

In laboratory visual search experiments, distractors are often statistically independent of each other. However, stimuli in more naturalistic settings are often correlated and rarely independent. Here, we examine whether human observers take stimulus correlations into account in orientation target detection. We find that they do, although probably not optimally. In particular, it seems that low distractor correlations are overestimated. Our results might contribute to bridging the gap between artificial and natural visual search tasks.

Do People Take Stimulus Correlations into Account in Visual Search?

Humans and other animals base their decisions on noisy sensory input. Much work has been devoted to understanding the computations that underlie such decisions. The problem has been studied in a variety of tasks and with stimuli of differing complexity. However, how the statistical structure of stimuli, along with perceptual measurement noise, affects perceptual judgments is not well understood. Here we examine how correlations between the components of a stimulus—stimulus correlations—together with correlations in sensory noise, affect decision making. As an example, we consider the task of detecting the presence of a single or multiple targets among distractors. We assume that both the distractors and the observer’s measurements of the stimuli are correlated. The computations of an optimal observer in this task are nontrivial yet can be analyzed and understood intuitively. We find that when distractors are strongly correlated, measurement correlations can have a strong impact on performance. When distractor correlations are weak, measurement correlations have little impact unless the number of stimuli is large. Correlations in neural responses to structured stimuli can therefore have a strong impact on perceptual judgments.

Visual Decisions in the Presence of Measurement and Stimulus Correlations

Microsaccades (or small saccades) are fixational eye movements with high velocity. They have been proposed as an index for covert spatial attention, but this proposal has been contested. One reason why it has been difficult to reach consensus is that different studies use different, arbitrary detection criteria such as velocity thresholds. Here, we developed a principled method for identifying microsaccades, based on Bayesian changepoint detection. Our generative model contains a latent state variable that changes between "drift/tremor" and "microsaccade" states at random times. We model the eye position as a biased random walk with a different velocity distribution for each state; on average, microsaccades have higher speed. Using this generative model, we computed the posterior probability over the time series of the state variable given the entire eye position time series. To sample from this high-dimensional posterior while avoiding local maxima, we used parallel-tempered MCMC. To test the validity of our algorithm, we applied it to simulated eye position data from the generative model. At low noise levels, we recovered the true microsaccades near perfectly, while at higher noise levels, we found state vectors with higher posterior probabilities than the true time series. When we apply the algorithm to real data, the inferred microsaccades are comparable with those found by previous methods. Our approach has advantages over previous methods: (1) the detection criterion is derived, not assumed, (2) we obtain a probabilistic judgment (i.e. a confidence rating), instead of a binary one, (3) the method can be straightforwardly adapted as the generative model is refined. Meeting abstract presented at VSS 2015.

Technology consumption and cognitive control: Contrasting action video game experience with media multitasking

Bayesian learning with multiple priors and nonvanishing ambiguity

Sensory uncertainty decoded from visual cortex predicts behavior

Rhesus monkeys are widely used as an animal model for human memory, including visual working memory (VWM). It is, however, unknown whether the same principles govern VWM in humans and rhesus monkeys. Here, we tested both species in nearly identical change-localization paradigms and formally compared the same set of models of VWM limitations. These models include the classic item-limit model and recent noise-based (resource) models, as well as hybrid models that combine a noise-based representation with an item limit. By varying the magnitude of the change in addition to the typical set size manipulation, we were able to show large differences in goodness of fit among the five models tested. In spite of quantitative performance differences between the species, we find that the variable-precision model--a noise-based model--best describes the behavior of both species. Adding an item limit to this model does not help to account for the data. Our results suggest evolutionary continuity of VWM across primates and help establish the rhesus monkey as a model system for studying the neural substrates of multiple-item VWM.

The same type of visual working memory limitations in humans and monkeys.

The object-based view of working memory (Luck and Vogel, 1997) postulates that features of the same multi-feature object are remembered together. This would imply that irrelevant features are automatically encoded. Here, we tested this hypothesis directly. Stimuli were colored, oriented ellipses. Either color or orientation was designated to be the relevant feature throughout the experiment. Subjects viewed four stimuli and, after a delay, another four, where one item had changed in its relevant feature. Independently, one item (the same or a different one) had also changed in its irrelevant feature. In the first 30 trials, subjects were asked to locate the change in the relevant feature, but on the 31st trial, they were asked to locate the change in the irrelevant feature. Since the 31st trial suddenly makes the irrelevant feature relevant, there is no point in continuing the experiment thereafter. Thus, we get only one "irrelevant" trial per subject. To solve this problem, we crowd-sourced data from subjects on Amazon Mechanical Turk. Online subjects were able to recall the relevant feature, although not as well as lab subjects. Performance on "irrelevant" trials pooled across subjects was at chance, suggesting that the irrelevant memory was not retrieved. However, subjects might have discarded this memory right after seeing the second display. To address this, we used a delayed-estimation paradigm (Wilken and Ma, 2004), which does not have a second display. Online subjects viewed a single colored, oriented ellipse, and reported their estimate of its relevant feature on a continuum. Again, the 31st (last) trial was an "irrelevant" trial. Subjects' performance on "irrelevant" trials was well above chance, but not as high as on "relevant" trials. This supports a weak form of the object-based view of visual working memory, namely one in which memory quality is weighed by relevance. Meeting abstract presented at VSS 2015.

Visual working memory of irrelevant features in multi-feature objects.

Erratum to: Technology consumption and cognitive control: Contrasting action video game experience with media multitasking

Diminished neural responses predict enhanced intrinsic motivation and sensitivity to external incentive

Activity in early visual areas reflects the trial-by-trial precision of perception

“Plateau”-related summary statistics are uninformative for comparing working memory models

In natural scenes, objects generally appear together with other objects. Yet, theoretical studies of neural population coding typically focus on the encoding of single objects in isolation. Experimental studies suggest that neural responses to multiple objects are well described by linear or nonlinear combinations of the responses to constituent objects, a phenomenon we call stimulus mixing. Here, we present a theoretical analysis of the consequences of common forms of stimulus mixing observed in cortical responses. We show that some of these mixing rules can severely compromise the brain's ability to decode the individual objects. This cost is usually greater than the cost incurred by even large reductions in the gain or large increases in neural variability, explaining why the benefits of attention can be understood primarily in terms of a stimulus selection, or demixing, mechanism rather than purely as a gain increase or noise reduction mechanism. The cost of stimulus mixing becomes even higher when the number of encoded objects increases, suggesting a novel mechanism that might contribute to set size effects observed in myriad psychophysical tasks. We further show that a specific form of neural correlation and heterogeneity in stimulus mixing among the neurons can partially alleviate the harmful effects of stimulus mixing. Finally, we derive simple conditions that must be satisfied for unharmful mixing of stimuli.

Bayesian observer models are very effective in describing human performance in perceptual tasks, so much so that they are trusted to faithfully recover hidden mental representations of priors, likelihoods, or loss functions from the data. However, the intrinsic degeneracy of the Bayesian framework, as multiple combinations of elements can yield empirically indistinguishable results, prompts the question of model identifiability. We propose a novel framework for a systematic testing of the identifiability of a significant class of Bayesian observer models, with practical applications for improving experimental design. We examine the theoretical identifiability of the inferred internal representations in two case studies. First, we show which experimental designs work better to remove the underlying degeneracy in a time interval estimation task. Second, we find that the reconstructed representations in a speed perception task under a slow-speed prior are fairly robust.

A Framework for Testing Identifiability of Bayesian Models of Perception

Organisms must act in the face of sensory, motor, and reward uncertainty stemming from a pandemonium of stochasticity and missing information. In many tasks, organisms can make better decisions if they have at their disposal a representation of the uncertainty associated with task-relevant variables. We formalize this problem using Bayesian decision theory and review recent behavioral and neural evidence that the brain may use knowledge of uncertainty, confidence, and probability.

Three questions have been prominent in the study of visual working memory limitations: (a) What is the nature of mnemonic precision (e.g., quantized or continuous)? (b) How many items are remembered? (c) To what extent do spatial binding errors account for working memory failures? Modeling studies have typically focused on comparing possible answers to a single one of these questions, even though the result of such a comparison might depend on the assumed answers to both others. Here, we consider every possible combination of previously proposed answers to the individual questions. Each model is then a point in a 3-factor model space containing a total of 32 models, of which only 6 have been tested previously. We compare all models on data from 10 delayed-estimation experiments from 6 laboratories (for a total of 164 subjects and 131,452 trials). Consistently across experiments, we find that (a) mnemonic precision is not quantized but continuous and not equal but variable across items and trials; (b) the number of remembered items is likely to be variable across trials, with a mean of 6.4 in the best model (median across subjects); (c) spatial binding errors occur but explain only a small fraction of responses (16.5% at set size 8 in the best model). We find strong evidence against all 6 documented models. Our results demonstrate the value of factorial model comparison in working memory.

The uninformativeness of summary statistics for comparing working memory models

Looking for a target in a visual scene becomes more difficult as the number of stimuli increases. In a signal detection theory view, this is due to the cumulative effect of noise in the encoding of the distractors, and potentially on top of that, to an increase of the noise (i.e., a decrease of precision) per stimulus with set size, reflecting divided attention. It has long been argued that human visual search behavior can be accounted for by the first factor alone. While such an account seems to be adequate for search tasks in which all distractors have the same, known feature value (i.e., are maximally predictable), we recently found a clear effect of set size on encoding precision when distractors are drawn from a uniform distribution (i.e., when they are maximally unpredictable). Here we interpolate between these two extreme cases to examine which of both conclusions holds more generally as distractor statistics are varied. In one experiment, we vary the level of distractor heterogeneity; in another we dissociate distractor homogeneity from predictability. In all conditions in both experiments, we found a strong decrease of precision with increasing set size, suggesting that precision being independent of set size is the exception rather than the rule.

Independence is elusive: set size effects on encoding precision in visual search.

During speech perception, humans integrate auditory information from the voice with visual information from the face. This multisensory integration increases perceptual precision, but only if the two cues come from the same talker; this requirement has been largely ignored by current models of speech perception. We describe a generative model of multisensory speech perception that includes this critical step of determining the likelihood that the voice and face information have a common cause. A key feature of the model is that it is based on a principled analysis of how an observer should solve this causal inference problem using the asynchrony between two cues and the reliability of the cues. This allows the model to make predictions about the behavior of subjects performing a synchrony judgment task, predictive power that does not exist in other approaches, such as post-hoc fitting of Gaussian curves to behavioral data. We tested the model predictions against the performance of 37 subjects performing a synchrony judgment task viewing audiovisual speech under a variety of manipulations, including varying asynchronies, intelligibility, and visual cue reliability. The causal inference model outperformed the Gaussian model across two experiments, providing a better fit to the behavioral data with fewer parameters. Because the causal inference model is derived from a principled understanding of the task, model parameters are directly interpretable in terms of stimulus and subject properties.

There is strong behavioral and physiological evidence that the brain both represents probability distributions and performs probabilistic inference. Computational neuroscientists have started to shed light on how these probabilistic representations and computations might be implemented in neural circuits. One particularly appealing aspect of these theories is their generality: they can be used to model a wide range of tasks, from sensory processing to high-level cognition. To date, however, these theories have only been applied to very simple tasks. Here we discuss the challenges that will emerge as researchers start focusing their efforts on real-life computations, with a focus on probabilistic learning, structural learning and approximate inference.

Supplemental Information Supervised Calibration Relies on the Multisensory Percept

Causal inference in sensory cue combination is the process of determining whether multiple sensory cues have the same cause or different causes. Psychophysical evidence indicates that humans closely follow the predictions of a Bayesian causal inference model. Here, we explore how Bayesian causal inference could be implemented using probabilistic population coding and plausible neural operations, but conclude that the resulting architecture is unrealistic.

Towards a neural implementation of causal inference in cue combination.

Significance Categorization is an important part of perception and cognition. For example, an animal must successfully categorize a disturbing sound as being due to the wind or to a predator. Computationally, categorization amounts to applying decision boundaries to noisy stimulus measurements. Here, we examine how these decision boundaries change as the quality of the sensory evidence varies unpredictably from trial to trial. We show that both humans and monkeys adjust their decision boundaries from trial to trial, often near-optimally. We further show how a neural network can perform this computation near-optimally. Our results might lead to a better understanding of categorization. Categorization is a cornerstone of perception and cognition. Computationally, categorization amounts to applying decision boundaries in the space of stimulus features. We designed a visual categorization task in which optimal performance requires observers to incorporate trial-to-trial knowledge of the level of sensory uncertainty when setting their decision boundaries. We found that humans and monkeys did adjust their decision boundaries from trial to trial as the level of sensory noise varied, with some subjects performing near optimally. We constructed a neural network that implements uncertainty-based, near-optimal adjustment of decision boundaries. Divisive normalization emerges automatically as a key neural operation in this network. Our results offer an integrated computational and mechanistic framework for categorization under uncertainty.

Trial-to-trial, uncertainty-based adjustment of decision boundaries in visual categorization

Monkeys show the same basic mechanisms of visual short-term memory as humans: (630982013-019)

Monkeys Show the Same Basic Mechanisms of Visual Short-Term Memory as Humans: (633262013-604)

Change detection is a classic paradigm that has been used for decades to argue that working memory can hold no more than a fixed number of items (“item-limit models”). Recent findings force us to consider the alternative view that working memory is limited by the precision in stimulus encoding, with mean precision decreasing with increasing set size (“continuous-resource models”). Most previous studies that used the change detection paradigm have ignored effects of limited encoding precision by using highly discriminable stimuli and only large changes. We conducted two change detection experiments (orientation and color) in which change magnitudes were drawn from a wide range, including small changes. In a rigorous comparison of five models, we found no evidence of an item limit. Instead, human change detection performance was best explained by a continuous-resource model in which encoding precision is variable across items and trials even at a given set size. This model accounts for comparison errors in a principled, probabilistic manner. Our findings sharply challenge the theoretical basis for most neural studies of working memory capacity.

A key function of the brain is to interpret noisy sensory information. To do so optimally, observers must, in many tasks, take into account knowledge of the precision with which stimuli are encoded. In an orientation change detection task, we find that encoding precision does not only depend on an experimentally controlled reliability parameter (shape), but also exhibits additional variability. In spite of variability in precision, human subjects seem to take into account precision near-optimally on a trial-to-trial and item-to-item basis. Our results offer a new conceptualization of the encoding of sensory information and highlight the brain’s remarkable ability to incorporate knowledge of uncertainty during complex perceptual decision-making.

Probabilistic Computation in Human Perception under Variability in Encoding Precision

Not Noisy, Just Wrong: The Role of Suboptimal Inference in Behavioral Variability

Processes of proactive interference were explored using the pigeon as a model system of memory. This study shows that proactive interference extends back in time at least 16 trials (and as many minutes), revealing a continuum of interference and providing a framework for studying memory. Pigeons were tested in a delayed same/different task containing trial-unique pictures. On interference trials, sample pictures from previous trials reappeared as test pictures on different trials. Proactive-interference functions showed greatest interference from the most recent trial and with the longer of two delays (10 s vs. 1 s). These interference functions are accounted for by a time-estimation model based on signal detection theory. The model predicts that accuracy at test is determined solely by the ratio of the elapsed time since the offset of the current-trial sample to the elapsed time since the offset of the interfering sample. Implications for comparing memory of different species and different types of memory (e.g., familiarity vs. recollection) are discussed.

de Gardelle and Summerfield (1) claimed that, when judging the mean of a set of stimuli, it is optimal to downweight outliers, and that human subjects follow this robust averaging strategy. Here, we show that, in their task, the optimal observer would equally weight all observations. In ref. 1, subjects were presented with a set of eight colors that are denoted by a vector x = (x1, …, x8) and drawn independently from a Gaussian distribution on a red–blue color axis with variance σ2 and mean of either μ (blue) or −μ (red). On a given trial, μ was set randomly to one of two values, and σ2 was set randomly to one of three values. The subject indicated whether the mean was blue (C = 1) or red (C = −1). When the prior probabilities are equal, the optimal decision is based on the likelihoods of both options [i.e., p(x|C = 1) and p(x|C=−1)]. Because μ and σ2 are unknown to the observer, the optimal observer computes these likelihoods by averaging (marginalizing) over all six possibilities (Eq. 1):

Variability in encoding precision accounts for the limitations of visual short-term memory

The brain encodes visual information with limited precision. Contradictory evidence exists as to whether the precision with which an item is encoded depends on the number of stimuli in a display (set size). Some studies have found evidence that precision decreases with set size, but others have reported constant precision. These groups of studies differed in two ways. The studies that reported a decrease used displays with heterogeneous stimuli and tasks with a short-term memory component, while the ones that reported constancy used homogeneous stimuli and tasks that did not require short-term memory. To disentangle the effects of heterogeneity and short-memory involvement, we conducted two main experiments. In Experiment 1, stimuli were heterogeneous, and we compared a condition in which target identity was revealed before the stimulus display with one in which it was revealed afterward. In Experiment 2, target identity was fixed, and we compared heterogeneous and homogeneous distractor conditions. In both experiments, we compared an optimal-observer model in which precision is constant with set size with one in which it depends on set size. We found that precision decreases with set size when the distractors are heterogeneous, regardless of whether short-term memory is involved, but not when it is homogeneous. This suggests that heterogeneity, not short-term memory, is the critical factor. In addition, we found that precision exhibits variability across items and trials, which may partly be caused by attentional fluctuations.

Deciding whether a set of objects are the same or different is a cornerstone of perception and cognition. Surprisingly, no principled quantitative model of sameness judgment exists. We tested whether human sameness judgment under sensory noise can be modeled as a form of probabilistically optimal inference. An optimal observer would compare the reliability-weighted variance of the sensory measurements with a set size-dependent criterion. We conducted two experiments, in which we varied set size and individual stimulus reliabilities. We found that the optimal-observer model accurately describes human behavior, outperforms plausible alternatives in a rigorous model comparison, and accounts for three key findings in the animal cognition literature. Our results provide a normative footing for the study of sameness judgment and indicate that the notion of perception as near-optimal inference extends to abstract relations.

It is commonly believed that visual short-term memory (VSTM) consists of a fixed number of “slots” in which items can be stored. An alternative theory in which memory resource is a continuous quantity distributed over all items seems to be refuted by the appearance of guessing in human responses. Here, we introduce a model in which resource is not only continuous but also variable across items and trials, causing random fluctuations in encoding precision. We tested this model against previous models using two VSTM paradigms and two feature dimensions. Our model accurately accounts for all aspects of the data, including apparent guessing, and outperforms slot models in formal model comparison. At the neural level, variability in precision might correspond to variability in neural population gain and doubly stochastic stimulus representation. Our results suggest that VSTM resource is continuous and variable rather than discrete and fixed and might explain why subjective experience of VSTM is not all or none.

Variability in encoding precision accounts for visual short-term memory limitations

Report Visual Short-Term Memory Compared in Rhesus Monkeys and Humans

1 Theory .......................................................................................................................... 1 1.1 Global log likelihood ratio ................................................................................... 1 1.2 Local log likelihood ratio (neural form) ............................................................... 3 1.3 Local log likelihood ratio (behavioral form) ........................................................ 5 1.4 Relation of optimal model to max and sum models ............................................. 7 1.5 Non-optimal local decision variables ................................................................... 8 2 Behavioral experiments ............................................................................................... 8 2.1 Experiments 1a and 2a ......................................................................................... 8 2.2 Individual-subject ROCs ...................................................................................... 9 2.3 Bayesian model comparison ................................................................................. 9 3 Neural implementation .............................................................................................. 10 3.1 Intuition behind a nonlinearity ........................................................................... 10 3.2 Network performance ......................................................................................... 10 3.3 Effect of non-Poisson-like statistics ................................................................... 11 Supplementary Figures are at the end.

Human performance in searching for a tilted target among vertical distractors is well described by signal detection theory (SDT) models which combine the outputs of noisy detectors using a maximum or summation operation [1]. These theories assume that each detector is a neuron best tuned to the target, and that a detector’s response to the target or distractor follows a Gaussian distribution. However, recent work has questioned the validity of SDT measures in search tasks with more complex stimulus distributions, for instance ones in which distractors flank the target in orientation space [2]. Instead, a saliency-based signal-to-noise ratio was proposed to measure task difficulty. A drawback of this theory is that it cannot predict receiver operating characteristics (ROCs).

Optimal integration of information across space in homogeneous and heterogeneous search displays: data and neural implementation

Beyond magical numbers: towards a noise-based account of visual-short term memory limitations

Signal detection theory, uncertainty, and Poisson-like population codes

The importance of autonomy for rural Chinese children's motivation for learning

Human ability to simultaneously track multiple items declines with set size. This effect is commonly attributed to a fixed limit on the number of items that can be attended to, a notion that is formalized in limited-capacity and slot models. Instead, we propose that observers are constrained by stimulus uncertainty that increases with the number of items but use Bayesian inference to achieve optimal performance. We model five data sets from published deviation discrimination experiments that varied set size, number of deviations, and magnitude of deviation. A constrained Bayesian observer better explains each data set than do the traditional limited-capacity model, the recently proposed slots-plus-averaging model, a fixed-uncertainty Bayesian model, a Bayesian model with capacity limit, and a simple averaging model. This indicates that the notion of limited capacity in attentional tracking needs to be revised. Moreover, it supports the idea that Bayesian optimality of human perception extends to high-level perceptual computations.

No capacity limit in attentional tracking: evidence for probabilistic inference under a resource constraint.

Watching a speaker's facial movements can dramatically enhance our ability to comprehend words, especially in noisy environments. From a general doctrine of combining information from different sensory modalities (the principle of inverse effectiveness), one would expect that the visual signals would be most effective at the highest levels of auditory noise. In contrast, we find, in accord with a recent paper, that visual information improves performance more at intermediate levels of auditory noise than at the highest levels, and we show that a novel visual stimulus containing only temporal information does the same. We present a Bayesian model of optimal cue integration that can explain these conflicts. In this model, words are regarded as points in a multidimensional space and word recognition is a probabilistic inference process. When the dimensionality of the feature space is low, the Bayesian model predicts inverse effectiveness; when the dimensionality is high, the enhancement is maximal at intermediate auditory noise levels. When the auditory and visual stimuli differ slightly in high noise, the model makes a counterintuitive prediction: as sound quality increases, the proportion of reported words corresponding to the visual stimulus should first increase and then decrease. We confirm this prediction in a behavioral experiment. We conclude that auditory-visual speech perception obeys the same notion of optimality previously observed only for simple multisensory stimuli.

Lip-Reading Aids Word Recognition Most in Moderate Noise: A Bayesian Explanation Using High-Dimensional Feature Space

WITHDRAWN: Linking neurons to behavior in multisensory perception: A computational review.

Linking neurons to behavior in multisensory perception: A computational review

Watching a speaker’s facial movements can dramatically enhance our ability to comprehend words, especially if the speech sound is corrupted by noise. It was recently found in an open-set word recognition task that the improvement in percentage correct due to the use of visual information is maximal not at high but at intermediate auditory noise levels [1]. This seems to contradict the principle of inverse effectiveness often found for multisensory cue combination (the enhancement due to one sensory modality is largest when the other modality has the lowest signal-to-noise ratio). To better characterize this apparent disagreement we reproduce the result under better controlled conditions and show that a novel visual stimulus that provides only temporal information produces a behavior conflicting with, and even opposite to inverse effectiveness.

Auditory-Visual Speech Recognition is Consistent with Bayes- Optimal Cue Combination

Neural mechanisms underlying temporal aspects of conscious visual perception

Recently, it has been shown that visual perception can be radically altered by signals of other modalities. For example, when a single flash is accompanied by multiple auditory beeps, it is often perceived as multiple flashes. This effect is known as the sound-induced flash illusion. In order to investigate the principles underlying this illusion, we developed an ideal observer (derived using Bayes' rule), and compared human judgements with those of the ideal observer for this task. The human observer's performance was highly consistent with that of the ideal observer in all conditions ranging from no interaction, to partial integration, to complete integration, suggesting that the rule used by the nervous system to decide when and how to combine auditory and visual signals is statistically optimal. Our findings show that the sound-induced flash illusion is an epiphenomenon of this general, statistically optimal strategy.

A detection theory account of visual short-term memory for color

Optimality of segregation/integration of auditory and visual signals in the human brain

A signal detection account of visual short-term memory for orientation and spatial frequency

Previous studies have suggested that visual short-term memory (VSTM) has a storage limit of approximately four items. However, the type of high-threshold (HT) model used to derive this estimate is based on a number of assumptions that have been criticized in other experimental paradigms (e.g., visual search). Here we report findings from nine experiments in which VSTM for color, spatial frequency, and orientation was modeled using a signal detection theory (SDT) approach. In Experiments 1-6, two arrays composed of multiple stimulus elements were presented for 100 ms with a 1500 ms ISI. Observers were asked to report in a yes/no fashion whether there was any difference between the first and second arrays, and to rate their confidence in their response on a 1-4 scale. In Experiments 1-3, only one stimulus element difference could occur (T = 1) while set size was varied. In Experiments 4-6, set size was fixed while the number of stimuli that might change was varied (T = 1, 2, 3, and 4). Three general models were tested against the receiver operating characteristics generated by the six experiments. In addition to the HT model, two SDT models were tried: one assuming summation of signals prior to a decision, the other using a max rule. In Experiments 7-9, observers were asked to directly report the relevant feature attribute of a stimulus presented 1500 ms previously, from an array of varying set size. Overall, the results suggest that observers encode stimuli independently and in parallel, and that performance is limited by internal noise, which is a function of set size.

Randomized Placebo-Controlled Trial of Topical Mupirocin to Reduce Staphylococcus aureus Colonization in Infants in the Neonatal Intensive Care Unit.

Randomized Trial of 42-Day Compared with 9-Day Courses of Dexamethasone for the Treatment of Evolving Bronchopulmonary Dysplasia in Extremely Preterm Infants.

Low rate of necrotizing enterocolitis in extremely low birth weight infants using a hospital-based preterm milk bank

Predictive Validity of the Bayley Scales of Infant and Toddler Development, Third Edition: (521682015-012)

Objective: To determine the predictive validity of the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) at age 2 years for cognitive abilities in preschool children born at ⩽30 weeks' gestation. Methods: This prospective regional study included all 187 liveborn infants ⩽30 weeks' gestation born between July 2005 and June 2006. Of the 172 children who survived to 4 years, 156 (91%) were evaluated at 2 and 4 years. A socioeconomically matched term control group also was recruited to provide normative data. The predictive validity of the Bayley-III cognitive and language scales for the Weschler Preschool and Primary Scale of Intelligence-III (WPPSI-III) was examined through correlation coefficients and sensitivity and specificity of the Bayley-III to predict normal and abnormal cognitive outcomes. Results: Correlations of the WPPSI-III intelligence quotient (IQ) score with the Bayley-III cognitive and language scores were .81 and .78, respectively. The preterm children were classified as normal (Bayley Scales of Infant Development-Third Edition [BSID-III] cognitive score or WPPSI-III IQ score not lower than 1 SD below the control group mean), mild to moderately delayed (scores between 1 and 2 SD deviations below the control group mean), or severely delayed (scores greater than 2 SD below the control group mean). At 2 and 4 years, 126 (81%) preterm children retained the same developmental classification. Conclusions: In contrast with previous editions of the BSID, the Bayley-III has strong predictive validity for WPPSI-III IQ at age 4 years in preterm children. This has important implications for more timely evaluation of perinatal interventions, establishment of guidelines for neonatal care, and counseling parents.

Predictive Validity of the Bayley, Third Edition at 2 Years for Intelligence Quotient at 4 Years in Preterm Infants

Mumps exposure of a health care provider working in a neonatal intensive care unit leads to a hospital-wide effort that prevented an outbreak.

OBJECTIVE: To determine changes that have occurred over the past 20 years in perinatal characteristics, neonatal treatments, morbidities, and early neurodevelopmental outcomes of infants born at ≤30 weeks' gestation. METHODS: This was a prospective regional study including all live-born infants ≤30 weeks' gestation born between July 1985 and June 1986 (cohort 1) and July 2005 and June 2006 (cohort 2). Sociodemographically matched term controls were recruited for each cohort. Perinatal characteristics, mortality rates, and survival with and without impairments at 24 months' corrected age were compared. RESULTS: There was a 35% increase in the number of live-born preterm births (138 in cohort 1 and 187 in cohort 2) despite a >10% decline in total births in the region (P < .001). Assisted fertility (rarely available for mothers in cohort 1) was responsible for 20% of pregnancies in cohort 2. Survival to hospital discharge increased over 20 years from 82% to 93% (P = .002), primarily because of higher survival for infants born at <27 weeks' gestation (63% vs 88%; P = .004). Changes in management in cohort 2 included the use of surfactant (62% of infants) and increased use of postnatal steroids (39% vs 9%; P < .001), that were associated with a shorter median duration of mechanical ventilation (13 vs 21 days; P < .001); however, the incidence of bronchopulmonary dysplasia was higher in cohort 2 (56% vs 35%; P < .001). There was a significant decrease in incidence of severe ultrasound abnormalities from 17% in cohort 1 to 7% in cohort 2 (P = .008). At 24 months of age, 7% of cohort 1 and 5% of cohort 2 had an abnormal neurologic exam. Bayley cognitive scores were improved in cohort 2 (significantly closer to the mean of their controls). As a result, survival without severe neurodevelopmental impairment increased from 62% in cohort 1 to 81% in cohort 2 (P < .001). CONCLUSION: Over 20 years, there has been a significant increase in live births at ≤30 weeks' gestational age, with a greater percentage of these neonates surviving without severe neurodevelopmental impairment at 24 months.

Outcome of Extreme Prematurity: A Prospective Comparison of 2 Regional Cohorts Born 20 Years Apart

OBJECTIVE. Although low birth weight premature infants and parents are at high risk for adverse health outcomes, there is a paucity of studies that test early NICU interventions with parents to prevent the development of negative parent-infant interaction trajectories and to reduce hospital length of stay. Our objective was to evaluate the efficacy of an educational-behavioral intervention program (ie, Creating Opportunities for Parent Empowerment) that was designed to enhance parent-infant interactions and parent mental health outcomes for the ultimate purpose of improving child developmental and behavior outcomes. DESIGN, SETTING, AND PARTICIPANTS. A randomized, controlled trial was conducted with 260 families with preterm infants from 2001 to 2004 in 2 NICUs in the northeast United States. Parents completed self-administered instruments during hospitalization, within 7 days after infant discharge, and at 2 months' corrected age. Blinded observers rated parent-infant interactions in the NICU. INTERVENTION. All participants received 4 intervention sessions of audiotaped and written materials. Parents in the Creating Opportunities for Parent Empowerment program received information and behavioral activities about the appearance and behavioral characteristics of preterm infants and how best to parent them. The comparison intervention contained information regarding hospital services and policies. MAIN OUTCOME MEASURES. Parental stress, depression, anxiety, and beliefs; parent-infant interaction during the NICU stay; NICU length of stay; and total hospitalization were measured. RESULTS. Mothers in the Creating Opportunities for Parent Empowerment program reported significantly less stress in the NICU and less depression and anxiety at 2 months' corrected infant age than did comparison mothers. Blinded observers rated mothers and fathers in the Creating Opportunities for Parent Empowerment program as more positive in interactions with their infants. Mothers and fathers also reported stronger beliefs about their parental role and what behaviors and characteristics to expect of their infants during hospitalization. Infants in the Creating Opportunities for Parent Empowerment program had a 3.8-day shorter NICU length of stay (mean: 31.86 vs 35.63 days) and 3.9-day shorter total hospital length of stay (mean: 35.29 vs 39.19 days) than did comparison infants. CONCLUSIONS. A reproducible educational-behavioral intervention program for parents that commences early in the NICU can improve parent mental health outcomes, enhance parent-infant interaction, and reduce hospital length of stay.

Reducing Premature Infants' Length of Stay and Improving Parents' Mental Health Outcomes With the Creating Opportunities for Parent Empowerment (COPE) Neonatal Intensive Care Unit Program: A Randomized, Controlled Trial

Objective. Postnatal dexamethasone treatment of ventilator-dependent preterm infants results in rapid improvement in lung function and reduction in chronic lung disease. However, limited data are available on long-term outcomes after such therapy. We studied growth, neurodevelopmental, and pulmonary outcomes at adolescence in children who had participated in a double-blind, placebo-controlled trial of dexamethasone beginning at 2 weeks of age for the prevention of chronic lung disease. Methods. Thirty-six infants (birth weight ≤1250 g and gestational age ≤30 weeks) who were dependent on mechanical ventilation at 2 weeks of age received a 42-day course of dexamethasone, an 18-day course of dexamethasone, or saline placebo. Twenty-two children survived to 15 years (69% of the 42-day dexamethasone group, 67% of the 18-day dexamethasone group and 45% of the control group), and all were evaluated. Intact survival was defined as survival with normal neurologic examination, IQ >70, and receiving education in the regular classroom. Results. There were no differences among groups for growth or incidence of neurologic abnormalities. The mean IQ for the 42-day dexamethasone group was 85 ± 10 compared with 60 ± 20 for the 18-day dexamethasone group and 73 ± 23 for the control group. All children in the 42-day dexamethasone group were receiving education in the regular classroom compared with only 50% of the 18-day dexamethasone group and 40% of the control group. As a result, intact survival was significantly greater for the 42-day dexamethasone group (69%) than for either the 18-day dexamethasone group (25%) or the control group (18%). Pulmonary function was significantly better for the 42-day dexamethasone group compared with the 18-day dexamethasone group (eg, forced expiratory volume in 1 second: 90 ± 16 vs 71 ± 15% predicted, respectively). Conclusion. A 42-day course of dexamethasone therapy beginning at 2 weeks of age in preterm infants who are at high risk for severe chronic lung disease was associated with improved long-term neurodevelopmental outcome. Although additional research is needed to establish the optimal steroid preparation, dosage, and duration of therapy, these data support the view that moderately early (beginning at 1-2 weeks) corticosteroid treatment is advantageous for a select group of ventilator-dependent preterm infants.

Follow-up at 15 Years of Preterm Infants From a Controlled Trial of Moderately Early Dexamethasone for the Prevention of Chronic Lung Disease

Objective. Survival rates for preterm infants who weigh between 501 and 1500 g at birth have continued to improve over time. In response to this continuing decrease in birth weight of surviving preterm infants, Enfamil Human Milk Fortifier has recently been reformulated to meet the nutritional requirements of these smaller, more rapidly growing infants. It now provides an increased protein level of 1.1 g/58 kJ, a decreased carbohydrate level of 0.2 g/58 kJ, and a combined linoleic and α-linolenic fatty acid content of 157 mg/58 kJ. As these very small preterm infants have an increased requirement for dietary iron, the fortifier has been supplemented with 1.44 mg/58 kJ of iron, an amount of iron similar to that provided in a typical iron-fortified term infant formula. An iron-fortified product obviates the need for administration of an iron supplement, a hyperosmolar-inducing intervention. The purpose of this prospective, double-blind, randomized, controlled study was to evaluate growth, safety, and efficacy in a population of very low birth weight (VLBW) preterm infants who received human milk fortified with either the reformulated iron-fortified powdered human milk fortifier test product (HMF-T) or a powdered commercially available human milk fortifier control product (HMF-C). Methods. Infants who weighed ≤1500 g, had a gestational age ≤33 weeks postmenstrual age, and had an enteral intake of at least 100 mL/kg per day of unfortified human milk were stratified by gender and birth weight and randomized to receive HMF-T or HMF-C product from study day 1 to study day 28, hospital discharge, or the termination of human milk feedings, whichever came first. Unless medically indicated, investigators were not to administer iron supplements from study days 1 to 14. Infants were assessed serially for growth; enteral and parenteral intake; serum chemistry and hematologic values; clinical histories, including the administration of blood transfusions; feeding tolerance; respiratory outcomes; and morbidities, including adverse events. Results. Of the 181 participating infants in this study, 96 received HMF-T and 85 received HMF-C. At randomization, there were no significant differences in infant characteristics between the fortifier groups. The percentage of participants who remained in the study for 28 days was similar between fortifier groups (57% HMF-T, 46% HMF-C). For both fortifier groups, the most frequent reasons for discontinuing the study before study day 28 were unavailability of human milk and hospital discharge. Rate of weight gain was similar between the fortifier groups (17.5 ± 0.53 g/kg per day for HMF-T and 17.3 ± 0.59 g/kg per day for HMF-C). Mean achieved weight, length, and head circumference were comparable between groups across the 28-day study period. Total protein intake from enteral and parenteral nutrition was significantly greater for the HMF-T fortifier group; however, this difference did not result in any difference in growth between the 2 fortifier groups. An analysis of the growth and energy intake data of a subset of the intent-to-treat population who adhered more strictly to the study feeding protocol yielded results similar to those seen for the intent-to-treat population. There were no clinically significant differences in the results of laboratory studies between the groups at study days 0, 14, and 28. Anemia of prematurity was prevalent in both study groups; by study day 28, median hematocrit levels were 27.0% (interquartile range [IQR]: 24.0%–29.6%) for the HMF-T group and 26.0% (IQR: 24.0%–31.0%) for the HMF-C group. Median ferritin levels were 77.0 ng/mL (IQR: 37-155 ng/ml) for HMF-T and 92.0 ng/mL (IQR: 33-110 ng/mL) for HMF-C. There were no significant differences between the study fortifier groups in regard to the receipt of medically indicated iron supplements on or before study day 14 or in the administration of blood transfusions before study day 0 or from study days 0 through 14. However, from study day 15 to study day 28, fewer HMF-T infants (n = 12) required a blood transfusion than did HMF-C infants (n = 20). Although the higher levels of iron in the HMF-T fortifier (1.44 mg vs 0.35 mg for HMF-C per 4 packets of powdered fortifier) did not prevent anemia per se, it did reduce the frequency of one of the most serious outcomes of anemia: the need for a blood transfusion. There was no statistically significant difference between fortifier groups in regard to feeding tolerance. Rates of suspected sepsis (26% HMF-T vs 31% HMF-C) and confirmed sepsis (5% HMF-T, 7% HMF-C) were low as were the rates of suspected necrotizing enterocolitis (NEC; 6% HMF-T and 5% HMF-C) and confirmed Bell's stage 2 or more NEC (1% HMF-T and 1% HMF-C). There were no statistically significant differences between the study fortifier groups in regard to the incidence of confirmed and suspected sepsis and NEC. Conclusion. Both human milk fortifiers studied are safe, are well tolerated, and facilitate comparable good growth; however, using the iron-fortified product may reduce the need for blood transfusions in VLBW infants. The similar low rates of suspected and confirmed NEC and sepsis seen in both fortifier groups in this study refutes the premise that the inclusion of iron in fortifiers will increase the incidence of sepsis and NEC. Indeed, the incidence for NEC and sepsis for both groups in this study was lower than is reported for VLBW infants and similar to that seen for infants who are fed human milk.

Growth, Efficacy, and Safety of Feeding an Iron-Fortified Human Milk Fortifier

OBJECTIVE
To compare school performance at age 10 years in a cohort of extremely preterm children and term control subjects and to examine the impact of family composition and stability on performance.

Prospective, longitudinal follow-up from birth to 10 years of age of a regional cohort of children born at 24 to 31 weeks of gestational age and sociodemographically matched term control subjects. Family composition, extent of parental care giving, and family moves were tracked sequentially. At 10 years, academic achievement and school performance were ascertained for 118 of 125 (94%) preterm survivors and 119 of 125 (95%) term children.

RESULTS
Term children were more likely to demonstrate optimal school outcome (appropriate grade level without additional classroom assistance) than were preterm children (odds ratio 3.4, 95% CI 1.9-6.0). Medical complications related to prematurity had little impact on school outcome. Among preterm children, optimal school outcome was significantly associated with increased parental education, child rearing by 2 parents (regardless of marital status), and stability in family composition and geographic residence over 10 years. These environmental influences were less pronounced among term control subjects.

Although preterm children performed less well in school than term children, family factors were stronger predictors of school performance than were perinatal complications.

Impact of family structure and stability on academic outcome in preterm children at 10 years of age.

BackgroundThe tissue accretion of long-chain polyunsaturated fatty acids is compromised in infants born prematurely. Human milk contains long-chain polyunsaturated fatty acids, but most preterm infant formulas do not. The long-term effects of preterm formula supplemented with arachidonic acid and docosahexaenoic acid, in proportions typical of those in human milk, were therefore investigated. MethodsIn this double-blind, randomized study, 288 preterm infants received experimental formula (n = 77), unsupplemented (control) formula (n = 78), or human milk (n = 133) until 48 weeks postconceptional age (PCA). Term formula, without supplemental long-chain polyunsaturated fatty acids, was administered from 48 to 92 weeks PCA to formula-fed infants and to infants weaned from human milk. Anthropometric and fatty acid data were assessed by using analysis of variance. ResultsAt 92 weeks PCA, no statistically significant anthropometric measurement differences were found except for midarm circumference, which was smaller in human milk–fed infants than in those fed formula. Phospholipid concentrations were similar in the experimental and human milk–fed groups, and docosahexaenoic acid levels were significantly greater than in the control group. The types and incidences of adverse events were similar among the feeding groups. ConclusionsThe results of this study demonstrate the efficacy and long-term safety of preterm formula supplemented with long-chain polyunsaturated fatty acids.

A Multicenter Long-Term Safety and Efficacy Trial of Preterm Formula Supplemented with Long-Chain Polyunsaturated Fatty Acids

Background/Aims: Human milk fortification has been advocated to enhance premature infants’ growth. We, therefore, undertook this study of a new human milk fortifier containing more protein than a reference one. Methods: Open, randomized, controlled, multiclinic trial, with weekly growth parameters and safety evaluations in premature infants <1,500 g. Results: The 2 groups did not differ in demographic and baseline characteristics. The adjusted daily milk intake was significantly higher in the infants fed reference human milk fortifier (n = 29; 154.2 ± 2.1 vs. 144.4 ± 2.5 ml/kg/day, mean ± SE; p < 0.05). Both human milk fortifiers produced increases over baseline in weight, length, and head circumference, with greater gains observed in the new human milk fortifier-fed infants for the former two parameters (weight gain 26.8 ± 1.3 and 20.4 ± 1.2 g/day, p < 0.05; head circumference 1.0 ± 0.1 and 0.8 ± 0.1 cm/week; length 0.9 ± 0.1 and 0.8 ± 0.1 cm/week, respectively). Serum chemistries were normal and acceptable for age. Study events were typical for premature infants and similar in both groups. Conclusions: This new human milk fortifier had comparable safety to the reference human milk fortifier and promoted faster weight gain and head circumference growth.

Growth in Human Milk-Fed Very Low Birth Weight Infants Receiving a New Human Milk Fortifier

The last trimester of pregnancy is a period of rapid accretion of long-chain polyunsaturated fatty acids, both in the central nervous system and the body as a whole. Human milk contains these fatty acids, whereas some preterm infant formulas do not. Infants fed formulas without these fatty acids have lower plasma and erythrocyte concentrations than infants fed human milk. Preclinical and clinical studies have demonstrated that single-cell sources (algal and fungal) of long-chain polyunsaturated fatty acids are bioavailable. A balanced addition of fatty acids from these oils to preterm formula results in blood fatty acid concentrations in low birth weight infants comparable to those of infants fed human milk.

METHODS
In the present study the growth, acceptance (overall incidence of discontinuation, reasons for discontinuation, overall incidence and type of individual adverse events), and plasma fatty acid concentrations were compared in three groups of infants fed a long-chain polyunsaturated fatty acid-supplemented preterm infant formula, an unsupplemented control formula, or human milk. The study was prospective, double-blind (formula groups only), and randomized (formula groups only). Two hundred eighty-eight infants were enrolled (supplemented formula group, n = 77; control formula group, n = 78; human milk group, n = 133).

RESULTS
Anthropometric measurements at enrollment, at first day of full oral feeding, and at both 40 and 48 weeks postconceptional age did not differ between the formula groups, whereas the human milk-fed group initially grew at a lower rate. The incidence of severe adverse events was rare and not significantly different between formula groups. The groups fed either human milk or supplemented formula had long-chain polyunsaturated fatty acid concentrations higher than those in the control formula group.

The results of this study demonstrate the safety and efficacy of a preterm formula supplemented with long-chain polyunsaturated fatty acids from single-cell oils.

Evaluation of a long-chain polyunsaturated fatty acid supplemented formula on growth, tolerance, and plasma lipids in preterm infants up to 48 weeks postconceptional age.

The impact of prematurity on school performance was assessed in a 10 year prospective study of all 125 surviving infants ≤31 weeks' gestation born 7/1/85 to 6/30/86. Each preterm infant was matched at birth with a term infant for sex (57% male), race (86% Caucasian), and maternal age (25 ± 6 yr), education (12 ± 2 yr) and marital status (67% married). At 10 years, school performance was categorized for 120/125 preterm and 119/125 term children as either satisfactory (no grade retention, no special classroom help, normal achievement test scores in math, reading and spelling and teacher ratings of academic and intellectual functioning in the top 70% of peers) or poor (any above criteria not met). Preterm children were significantly less likely than term children to have satisfactory school performance (34% vs 61%, p<.001). Preterm children with satisfactory and poor school performance did not differ for neonatal variables including gestational age (28 ± 2 wk, both groups), severe IVH (5 vs 15%), BPD (34 vs 28%) or length of hospitalization (61 ±28 vs 67 ± 34 days). Preterm children reared in a stable family constellation (custodial make-up unchanged) and who experienced few moves were significantly more likely to have satisfactory school outcome: Table Preterm children with regular contact with both biological (or early adoptive) parents were twice as likely to have satisfactory school outcome (33/77, 43%) than were those with single parent contact (8/41, 20%; p<.01). The influence of family structure on school outcome was not significant for term children. In conclusion, while neonatal morbidities predict school outcome poorly, the family structure in which preterm children develop has a significant impact on school outcome at 10 years.

School Performance at Ten Years in Infants ≤ 31 Weeks' Gestational Age† 1263

A TWELVE MONTH MULTI-CENTER SAFETY AND EFFICACY TRIAL OF A PRETERM INFANT FORMULA SUPPLEMENTED WITH LONG CHAIN POLYUNSATURATED FATTY ACIDS (LCP)

Effect of preterm birth on pulmonary function at school age: a prospective controlled study.

Objective: To evaluate phospholipid response of a preterm infant formula supplemented with Arachidonic Acid (ARA) and Docosahexanoic Acid (DHA) from microbial fermentation oils.

A New Arachidonic Acid (ARA) and Docosahexanoic Acid (DHA) Supplemented Preterm Formula: Effect on Plasma and Erythrocyte Phospholipid Fatty Acids † 1376

A New Arachidonic Acid (ARA) and Docosahexanoic Acid (DHA) Supplemented Preterm Formula: Growth and Safety Assessment. † 1440

Background: Changes in survival, hospital morbidities and developmental outcome of extremely preterm infants were assessed prospectively by comparing the outcomes of two cohorts of infants born at 23-27 weeks' gestation.

Changes in Outcome for Extremely Preterm Infants at Age Four Years. 166

Adrenal steroidogenesis was evaluated in 25 sick premature infants with a gestational age of less than 30 weeks. ACTH stimulation tests were performed on the fourth day of life using synthetic ACTH (36 micrograms/kg). Considering the stress and degree of illness, preterm newborns had low basal cortisol levels (mean +/- SEM, 207.4 +/- 23.5 nmol/L), and their levels were similar to basal levels reported for healthy full-term newborns (170.7 +/- 26.8 nmol/L; P = 0.31; reference data from Endocrine Sciences, Inc., Calabasas Hills, CA). However, compared to term neonates, preterm infants had markedly elevated basal levels of 17-hydroxypregnenolone (54.3 +/- 11.2 nmol/L), 17-hydroxyprogesterone (19.7 +/- 4.0 nmol/L), and 11-deoxycortisol (19.1 +/- 3.3 nmol/L), which were 7-, 18-, and 8-fold higher, respectively, than values for term infants. The activity of 3 beta-hydroxysteroid dehydrogenase was not significantly reduced in extremely premature neonates (mean basal ratio of 17-hydroxypregnenolone/17-hydroxyprogesterone, 2.9 +/- 0.2; ACTH-stimulated ratio, 6.5 +/- 0.4). In contrast, the mean basal substrate/product ratio of 11-deoxycortisol was markedly elevated in the preterm infants (11.9 +/- 2.2, ratio x 10(-2) compared to that in the full-term infants (2.1 +/- 0.4, ratio x 10(-2); P < 0.001). These findings are consistent with decreased activity of 11 beta-hydroxylase (11 beta OH) in preterm infants born at less than 30 weeks gestation. Decreased 11 beta OH activity appears to be more prominent than the deficiency of 3 beta-hydroxysteroid dehydrogenase that has been found in infants with lesser degrees of prematurity, suggesting that 11 beta OH activity may be regulated during fetal development to increase during the latter part of gestation.

Adrenal steroidogenesis in very low birth weight preterm infants.

28 of 31 ECMO eligible infants born July, 1988 to March, 1992 with severe PPHN were assigned randomly when oxygenation index (OI) was ≥ 40 for four hours to be transported for ECMO (n=15, birthweight 3601 ± 622 g; OI 63 ± 28) or to receive conventional therapy at our center (n=13, birthweight 3403 ± 640 g; OI 60 ± 28). Fourteen of the 15 infants (93%) transported for ECMO survived to hospital discharge (including 3 who did not receive ECMO), while 7 of 13 (54%) conventionally treated infants survived (p<05). One ECMO infant died after hospital discharge at age 3 months of SIDS. Outcome for the survivors (mean ± SD):ECMO salvaged sicker neonates (mean OI at study entry for ECMO survivors was 60 ± 21 vs 44 ± 5 for conventionally treated survivors); nevertheless, transport for ECMO was not associated with worse neurodevelopmental outcome at 2 years. These data support the use of ECMO in term infants with severe respiratory distress.

86 PROSPECTIVE RANDOMIZED CONTROLLED TRIAL OF CONVENTIONAL TREATMENT OR TRANSPORT FOR ECMO IN INFANTS WITH SEVERE PERSISTENT PULMONARY HYPERTENSION (PPHN): TWO YEAR FOLLOW UP

Premature status and its relationship to ratings on behavior problem checklists

The impact of family structure and stability on developmental outcome was assessed in a 7 year prospective study of 121 of 125 surviving infants < 32 weeks' gestation (born 7/1/85 to 6/30/86) and 125 demographically matched term infants. Five preterm and four term children experienced the death of a parent. At 7 years, 66 (55%) preterm and 71 (59%) term children live with 2 parents (group I); 12 (10%) preterm and 13 (11%) term children live with 1 parent and have regular contact with the other parent (group II); 36 (30%) preterm and 34 (28%) term children live with a single parent and have no regular contact with the other parent (group III); and 7 (6%) preterm and 2 (2%) term children live in foster care (group IV). The preterm groups I - IV did not differ for gestational age (28.5 ± 2.1, 27.3 ± 2.4, 28.4 ± 1.9 and 27.1 ± 1.3 wk, respectively), birthweight (1187 ± 346, 1068 ± 394, 1208 ± 338, and 1019 ± 252 g) or NICU morbidities including mechanical ventilation, IVH or duration of hospitalization. Cognitive ability (McCarthy GCI) was significantly related to family structure in both preterm (groups I-IV: 96 ± 13, 90 ± 19, 87 ± 16, and 77 ± 15, respectively, p < .001) and term children (106 ± 13, 103 ± 12, 96 ± 12 and 81 ± 25, respectively, p < .001). One or more changes in family structure (marriage, divorce, custody) were more common in preterm (47%) than in term children (28%) (p < .01) and also were related to decreased I.Q. in preterm children (no change, 95 ± 14; single change, 93 ± 13; multiple changes, 80 ± 17, p < .001). Additionally, > 4 family moves occurred twice as often among preterm (30%) than among term children (17%) and was associated with poorer cognitive outcome in both groups (preterm children: 85 ± 16 vs 95 ± 14, p < .01; term children: 96 ± 14 vs 104 ±14, p < .05). Parents' reports of problematic behaviors (Child Behavior Checklist) were greatest for preterm children raised by single parents (p < .005), those with changes in family structure (p < .01) and preterm children with multiple moves (p < .05). Changes in family structure and stability occur more often for preterm than term children and impact significantly on their developmental outcome.

85 IMPACT OF FAMILY STRUCTURE AND STABILITY ON DEVELOPMENTAL OUTCOME IN PRETERM INFANTS

OBJECTIVE
To determine the relationship between transiently abnormal neurologic findings in preterm infants and subsequent cognitive outcome at 4 years of age.

DESIGN
Prospective 4-year follow-up.

SETTING
Regional perinatal center in Syracuse, NY.

One hundred thirty-one of 135 consecutively born infants of no more than 32 weeks of gestational age; 98% followed up from birth to 4 years of age.

None.

Based on neuromotor evaluations performed at 6 and 15 months of age, two groups of infants were identified. One group had abnormal neurologic findings at 6 months of age that had resolved by 15 months of age (transiently abnormal group). The other group had normal neuromotor findings at both 6 and 15 months of age (normal group). The transiently abnormal group had significantly poorer scores on the Bayley Mental scale at 6 months of age (90 +/- 15 vs 108 +/- 10; P < .001), 15 months (91 +/- 21 vs 105 +/- 12; P < .001), and 24 months (91 +/- 19 vs 101 +/- 17; P < .001). However, at 4 years of age, cognitive performance on the McCarthy Scales was similar for the transiently abnormal and normal groups (General Cognitive index, 93 +/- 13 and 95 +/- 14, respectively). The incidence of poor cognitive outcome (Cognitive index < 84) decreased from 39% at 2 years of age to 18% at 4 years of age in the group with a history of transient neurologic abnormalities but remained unchanged (16% to 18%) in the normal group.

Early neurologic abnormalities that are transient did not predict cognitive delays at 4 years of age in preterm infants.

Developmental outcome of preterm infants with transient neuromotor abnormalities.

One hundred twenty-four children who were born at 24 to 31 weeks' gestation and 124 term children matched in social background underwent serial developmental evaluations. The Bayley Mental Developmental Index at 6, 15, and 24 months and the McCarthy General Cognitive Index at 4 years were used to classify cognitive outcome for preterm children as normal (indices higher than 1 SD below the mean), mild-moderately delayed (indices between 1 and 2 SD below the mean), or severely delayed (indices > or = 2 SD below the mean). Classifications based on norms derived from the performance of the term control group were compared with those based on published standardized test scores. The control group had substantially higher mean (+/- SD) Bayley Mental Developmental Indices at 6 (111 +/- 11), 15 (114 +/- 13), and 24 months (115 +/- 21) than the published test mean (100 +/- 16). Consequently, significantly more preterm children were classified as normal when the Bayley test mean was used than when the performance of the control group was used to define the normal range (84% vs 52% at 6 months, 82% vs 49% at 15 months, and 70% vs 47% at 24 months). Severe cognitive delays were infrequent when defined by test mean (6% to 11%) but two to three times greater when the control group scores were used. In contrast, the control group had a mean McCarthy General Cognitive Index at 4 years (102 +/- 14) that was similar to the published test mean (100 +/- 16).(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of a matched term control group on interpretation of developmental performance in preterm infants.

Comparative efficacy of early day 4 versus late day 14 dexamethasone dex therapy in ventilator dependent infants with birthweight less than 1000 grams

All 133 surviving infants of gestational age less than or equal to 32 weeks born July 1, 1985, to June 30, 1986, as well as a socioeconomically matched full-term control group were observed prospectively for 2 years to determine the incidence of rehospitalization for respiratory illness. Perinatal and seasonal factors associated with increased risk for such hospitalizations were also examined. Forty-seven (36%) preterm infants were rehospitalized compared with 3 (2.5%) of 121 term infants (P less than .001). Preterm infants with and without rehospitalization were similar for mean birth weight (1104 +/- 329 g and 1188 +/- 360 g, respectively) and gestational age (28 +/- 2 weeks for both groups); however, infants who were subsequently rehospitalized had required more days of mechanical ventilation, supplemental oxygen therapy, and neonatal intensive care. While a history of bronchopulmonary dysplasia was a risk factor for rehospitalization (45% compared with 25% of those without bronchopulmonary dysplasia, P less than .05), preterm infants with no history of bronchopulmonary dysplasia still showed a 10-fold increase compared with control infants. Among the 43 infants who required no mechanical ventilation beyond the day of birth, 10 (23%) required rehospitalization.(ABSTRACT TRUNCATED AT 250 WORDS)

Rehospitalization for respiratory illness in infants of less than 32 weeks' gestation.

We evaluated the use of dexamethasone in preterm infants to decrease morbidity associated with bronchopulmonary dysplasia in a randomized, double-blind, placebo-controlled trial. Thirty-six preterm infants (birth weight, less than or equal to 1250 g and gestational age, less than or equal to 30 weeks) who were dependent on oxygen and mechanical ventilation at two weeks of age received a 42-day course of dexamethasone (n = 13), an 18-day course of dexamethasone (n = 12), or saline placebo (n = 11). The starting dose of dexamethasone was 0.5 mg per kilogram of body weight per day, and it was progressively lowered during the period of administration. Infants in the 42-day dexamethasone group, but not those in the 18-day group, were weaned from mechanical ventilation significantly faster than control infants (medians 29, 73, and 84 days, respectively; P less than 0.05), and from supplemental oxygen (medians 65, 190, and 136 days, respectively; P less than 0.05). No clinical complications of steroid administration were noted. Follow-up of all 23 survivors at 6 and 15 months of age showed good outcome (normal neurologic examinations and Bayley Developmental Indexes greater than or equal to 84) in 7 of the 9 infants in the 42-day dexamethasone group, but in only 2 of the 9 infants in the 18-day dexamethasone group and 2 of the 5 in the placebo group (P less than 0.05). We conclude that dexamethasone therapy for 42 days improves pulmonary and neurodevelopmental outcome in very-low-birth-weight infants at high risk for bronchopulmonary dysplasia.

A controlled trial of dexamethasone in preterm infants at high risk for bronchopulmonary dysplasia.

ABSTRACT: Cranial ultrasounds performed during the first 3 d of life on 211 infants of 24 to 40 wk gestational age were examined to determine the in utero development of the cingulate sulcus. The sulcus was identified between 24 and 28 wk of gestational age as fragmented echoes in the region between the thalamus and the anterior fontanelle. Over the next several weeks, these fragments coalesced into a single linear echo. Branches then appeared off of the primary cingulate sulcus, increasing in number until a complex pattern of branching was noted near term gestation. This maturational sequence was similar to postnatal cortical development determined from serial ultrasounds performed on 144 infants who were ≤ 32 wk of gestational age at birth. The timing of postconceptional cingulate sulcus development was independent of gestational age at birth. However, severe brain insult, defined as intraventricular hemorrhage complicated by ventriculomegaly or intraparenchymal extension or periventricular leukomalacia, was associated with significant delays in all stages of cingulate sulcus development. Cranial ultrasound examinations in preterm infants allow a noninvasive means of staging qualitative brain development during the early postnatal period.

Serial cultures of endotracheal tube aspirates were carried out in 94 neonates who were intubated and had been ventilated for longer than one week. A similar change in bacterial colonisation with duration of ventilation was seen in infants who subsequently developed sepsis and those who did not. In both groups, 177 aspirates (more than 90%) obtained during the first week of ventilation were sterile. Thereafter, colonisation with mixed Gram positive flora emerged followed by growth of Gram negative bacilli. For the infants who developed sepsis, the correlation between pathogens isolated from blood during the episodes of sepsis and those from previous endotracheal tube isolates was poor; in only five of the 26 cases of sepsis (19%) was the same single strain of organism isolated from culture of the blood and of the endotracheal tube aspirate. Other markers of infection such as endotracheal tube aspirate white blood cell counts and changes in bacterial flora were not useful in predicting systemic infection. Routine surveillance cultures of endotracheal tube aspirates in ventilated infants are not helpful in predicting the pathogens that are isolated from the blood during episodes of sepsis.

Routine endotracheal cultures for the prediction of sepsis in ventilated babies.

Effect of early low-volume enteral substrate on subsequent feeding tolerance in very low birth weight infants.

Bone mineralization in preterm infants fed human milk with and without mineral supplementation

Pulmonary function studies were performed in 11 neonatal intensive care survivors both during infancy and later in childhood. Lung function was compared with the respiratory support given in the neonatal period. The mean ± SE thoracic gas volume was 96 ± 4% predicted in infancy and rose to 122 ± 8% predicted during childhood (P < 0.005). The specific airway conductance (SGaw) in infancy was 57 ± 7% predicted and rose to 90 ± 8% predicted in childhood (P < 0.0025). Abnormalities in SGaw were found only in ventilated infants, and there was a negative logarithmic correlation between the treatment score in the neonatal period and the SGaw in both infancy and childhood. The data indicate a long‐term improvement in airway conductance of moderately affected infants with the development of mild hyperinflation in childhood possibly resulting from residual small airway abnormalities despite a symptomless clinical course. The residual abnormalities in prematurely born infants were in proportion to the intensity of treatment required in the neonatal period. Pediatr Pulmonol 1987; 3; 29–33.

Lung function in infancy and childhood following neonatal intensive care

Lung function was measured in nine infants, ages 15‐36 weeks, who had persistent wheezing, apparently following acute bronchiolitis, before and after 2 weeks of treatment with either inhaled nebulized beclomethasone dipropionate (BDP) or placebo in a randomized, double blind, crossover trial. The effect of nebulized albuterol (Salbutamol) was measured before and after the steroid treatment. Thoracic gas volume (TGV) and specific airway conductance (SGaw) were determined using a whole body plethysmograph, and forced expiratory flow at resting lung volume (VmaxFRC) was determined with a thoracoabdominal compression jacket. All infants had marked airways obstruction before treatment with mean ± SE VmaxFRC of 24 ± 4% predicted and SGaw of 37 ± 5% predicted. Two weeks of placebo treatment had no significant effect on lung function, but after 2 weeks of BDP inhalation there was a significant rise in SGaw to 61 ± 7% (P < 0.005). VmaxFRC increased to 42 ± 13% but the difference did not reach significance. Respiratory rate and clinical score for retractions and wheezing also fell significantly with BDP therapy (P < 0.01 and P < 0.001 respectively). Albuterol had no effect on lung function either before or during steroid therapy. Steroids may have a role in the management of persistent wheezing following bronchiolitis.

The functional response of infants with persistent wheezing to nebulized beclomethasone dipropionate

Vitamin E status in preterm infants fed human milk or infant formula.

Immunocytochemical study of human brain showed creatine kinase brain isoenzyme (CKBB) present in both neurons and astrocytes. Because creatine kinase brain isoenzyme is an intracellular enzyme that might be released with brain injury, its concentration in the CSF of newborns was measured using a radioimmunoassay. Infants who suffered a documented neurologic insult (a cerebroventricular hemorrhage or a CNS infection) were found to have a greater mean CSF creatine kinase brain isoenzyme concentration than those without a history of neurologic insult. Infants with a high concentration had a poor short-term outcome (death or neurologic abnormality when discharged) more frequently than did those with a lower concentration. Infants with a grade 3 or 4 cerebroventricular hemorrhage had a higher mean concentration than did those with a grade 1 or 2 hemorrhage. These data are consistent with the hypothesis that CSF creatine kinase brain isoenzyme is a metabolic indicator of brain damage in newborns.

Creatine kinase brain isoenzyme: relationship of cerebrospinal fluid concentration to the neurologic condition of newborns and cellular localization in the human brain.

Different developmental courses for very-low-birthweight infants differing in early head growth.

Bone mineral status was assessed in 20 healthy, appropriately grown infants <1600g birthweight assigned randomly to one of 2 diets: 1. Preterm human milk (PT milk) pooled by postpartum week and fed corresponding to infants postnatal age, providing calcium 22-26 mg/dl, phosphorus 13-17 mg/dl. 2. Supplemented PT milk, an equal mixture of premature infant formula and PT milk providing calcium 72-74 mg/dl, phosphorus 37-38 mg/dl. All infants were fed by gavage at 180 ml/kg/day and received 400 IU Vitamin D daily. Infants fed PT milk had significantly lower serum phosphorus levels at 4 and 5 wk (4.6±0.4 and 4.1±0.4 mg/dl) than infants fed supplemented PT milk (6.1±0.2 and 6.0±0.2 mg/dl), p<.005. They also had significantly higher serum alkaline phosphatase levels at 4 and 5 wk (569±81 and 824±127 IU/1) than the supplemented group (340±40 and 347±49 IU/1), p<.02. The serum differences were reflected in lower bone mineral content (BMC) of humerus by photon densitometry at 5 wk (PT milk, .084±.005 vs supplemented PT milk .107±.007 g/cm, p<.05). At 35-37 postconceptual wk, infants in both groups were discharged on standard infant formula (calcium 51 mg/dl, phosphorus 39 mg/dl). At 44 postconceptual weeks, infants initially fed either PT milk or supplemented PT milk, had similar serum phosphorus (6.7±0.2 and 7.2±0.2 mg/dl) and alkaline phosphatase (301±33 and 285±23 IU/1; BMC in both groups (.252±.021 and .246±.014 g/cm) was comparable to that of healthy term infants (.223±.006). Preterm infants fed unsupplemented PT milk show bone demineralization. BMC increases significantly after routine formula feeding irrespective of PT milk supplementation.

Follow-up of infants of <1500 gm birth weight with antenatal isoxsuprine exposure

My colleagues and I compared the biochemical status and rates of growth of three groups of preterm infants: one group was fed milk obtained early from mothers of preterm infants; one group received milk produced during the mature stage of lactation by mothers of term infants; and one group received a whey-based infant formula. Sixty healthy preterm infants with birth weights of 1600 g or less were randomly assigned to one of the three feedings groups. The 20 infants in each group were followed until they reached a weight of 1800 g. The mean (+/- S.E.M.) number of days required to regain birth weight was similar for infants receiving the formula (10.3 +/- 0.8) and those receiving milk from mothers of preterm infants (11.4 +/- 0.8); both were significantly less than the number (18.8 +/- 1.7) for infants receiving milk from mothers of term infants (P less than 0.001). Subsequent rates of weight gain were greater for the groups receiving formula (27.0 +/- 0.8 g per day) and milk from mothers of preterm infants (23.7 +/- 1.1) than for the group receiving milk from mothers of term infants (15.8 +/- 0.8) (P less than 0.001). Similarly, the average increments in crown-to-heel length and in the head circumference were significantly greater for the groups given formula and milk from mothers of preterm infants (P less than 0.005 and P less than 0.001, respectively). These data indicate that feeding with either milk from mothers of preterm infants or a whey-based infant formula results in more appropriate growth in preterm infants than feeding with milk from mothers of term infants.

Growth and biochemical response of preterm infants fed human milk or modified infant formula.

Follow-up of infants of less than 1500 gm birth weight with antenatal isoxsuprine exposure.

Effects of Acetylsalicylic-Acid Ingestion on Maternal and Neonatal Hemostasis

The predictive role of early head growth for subsequent outcome was evaluated in 85 infants with birth weight <1,500 g. On the basis of head circumference at birth and head growth between birth and age 6 weeks, infants were divided into four groups: (1) microcephalic at birth with less (< 3.5 cm) postnatal head growth (n = 9), (2) microcephalic at birth with more (≥3.5 cm) postnatal head growth (n = 12), (3) normocephalic at birth with less head growth (n = 32), and (4) normocephalic at birth with more head growth (n = 32). At both 6 and 15 months of age the two groups of infants with less postnatal head growth had an increased incidence of growth failure, whereas the two groups with more postnatal head growth had a low incidence, similar to that for a matched full-term group (n = 95). Major neurologic defects occurred significantly more frequently among infants who were microcephalic with less postnatal head growth; two thirds showed evidence of blindness, hydrocephalus, or spastic diplegia. This group also performed more poorly on the Bayley Scales than any of the other groups. Infants who were normocephalic with greater head growth were free of neurologic defects and had Bayley scores that did not differ from those for the healthy full-term infants. The two groups of infants with only one poor measure of head growth demonstrated intermediate scores at age 6 months. At age 15 months, the group with normocephaly and less postnatal head growth continued to have intermediate scores. The group with microcephaly and greater postnatal head growth, however, showed developmental catch-up; their scores did not differ from those of the group that was normocephalic with greater head growth or the full-term group. Less postnatal head growth was associated with an increased requirement for mechanical ventilation, patent ductus arteriosus, sepsis, delayed tolerance of feeding, and slower weight gain. These data suggest that early postnatal head growth may summarize the adverse effects of many perinatal risk factors and that head circumference at birth and head growth by six weeks are strong predictors of early developmental outcome in very low-birth-weight infants.

Head growth and developmental outcome in very low-birth-weight infants.

The life span of the term infant’s erythrocytes is approximately two-thirds that of the erythrocytes of normal adults.’ The red cells of premature infants have an even shorter life span than do the red cells of term infants.’ The mechanisms responsible for this accelerated senescence are unknown. Premature infants, at birth, are deficient in vitamin E. Deficiency of vitamin E, a naturally occurring antiperoxidant, can produce a shortening of red cell life span.3 The purpose of this investigation was to determine if the presence of vitamin E deficiency in the premature infant during the first week of life played a contributory role in the shortened red cell survival. In addition, since hyperbilirubinemia is, in part, secondary to red cell breakdown, we examined the influence of early vitamin E supplementation on bilirubinemia in preterm infants.

Controlled study of treatment for disseminated intravascular coagulation in the neonate.

Abstract In a case–control study, we evaluated the effects of maternal ingestion of acetylsalicylic acid (aspirin) within 10 days of delivery on maternal and neonatal hemostasis. Only one of 34 control maternal-neonatal pairs (3 per cent) had hemostatic abnormalities. In 10 pairs, when maternal aspirin ingestion occurred within five days of delivery, 6 of the 10 mothers and 9 of the 10 infants had bleeding tendencies. Seven maternal-neonatal pairs in which aspirin was ingested 6 to 10 days before delivery were free of clinical bleeding. Among seven other mothers who ingested aspirin in the immediate post-partum period four of the seven (57 per cent) also had impaired hemostasis. Neonatal hemostatic abnormalities included numerous petechiae over the presenting part, hematuria, a cephalhematoma, subconjunctival hemorrhage, and bleeding from a circumcision. Maternal bleeding was confined to excessive intrapartum or post-partum blood loss. We conclude that aspirin should be avoided during pregnancy. If ingest...

Effects of Acetylsalicylic Acid Ingestion on Maternal and Neonatal Hemostasis

In a case-control study, we evaluated the effects of maternal ingestion of acetylsalicylic acid (aspirin) within 10 days of delivery on maternal and neonatal hemostasis. Only one of 34 control maternal-neonatal pairs (3 per cent) had hemostatic abnormalities. In 10 pairs, when maternal aspirin ingestion occurred within five days of delivery, 6 of 10 mothers and 9 of the 10 infants had bleeding tendencies. Seven maternal-neonatal pairs in which aspirin was ingested 6 to 10 days before delivery were free of clinical bleeding. Among seven other mothers who ingested aspirin in the immediate post-partum period four of the seven (57 per cent) also had impaired hemostasis. Neonatal hemostatic abnormalities included numerous petechiae over the presenting part, hematuria, a cephalhematoma, subconjunctival hemorrhage, and bleeding from a circumcision. Maternal bleeding was confined to excessive intrapartum or post-partum blood loss. We conclude that aspirin should be avoided during pregnancy. If ingestion has occurred within five days of delivery, the neonate should be evaluated for the presence of bleeding.

Effects of Acetylsalicylic‐Acid Ingestion on Maternal and Neonatal Hemostasis

Argininosuccinic acidemia is an autosomal recessive disorder of the urea cycle caused by argininosuccinase deficiency. A 2 day old male developed seizures and respiratory distress, EEG showed status epilepticus pattern, and at 4 days of age he lapsed into coma. Blood amonia was 1800 μg/dl (normal 10-150), blood amino acids revealed argininosuccinic acid (ASA) 196.98 μmol/dl and anhydro ASA 174.12 μmol/dl. Urine ASA was 34.7 Gm/Gm creatinine and anhydro ASA was 39.5 Gm/Gm creatinine. A micro assay for argininosuccinase was developed, which showed no dectable activity in patient's RBC's while a control sample released 2.77 μmol (± 0.63) of ornithine/h/ml of whole blood.Treatment with exchange transufions and peritoneal dialysis reduced blood ammonia only slightly to 1100 μg/dl. Dramatic reduction of ammonia to 300 μg/dl occurred 24 h after intravenous therapy with 4 mM/Kg/day of arginine hydrochloride and 250 mg/Kg/day of sodium benzoate. The baby improved and his EEG became normal. At 9 months, the baby's height, weight, and head circumference are within the 50th percentile. Frequent developmental assesments have been within the normal range. Currently the baby is on 1.7 Gm/Kg of protein with arginine supplementation of 1 mM to 4 mM/Kg/day depending on the blood arginine levels. A biochemical and enzymic diagnosis of argininosuccinic acidemia can be made in the newborn period. Arginine therapy is superior to other forms of treatment in preventing hyperammonemia and neurological damage.

1159 DIAGNOSIS, TREATMENT AND FOLLOW UP OF NEONATAL ARGINOSUCCINIC ACIDEMIA

DIC was diagnosed in 31 newborns by the following laboratory criteria: platelet count <100,000/mm3, PTT >90 sec (nl <36 sec), PT ratio >1.5 (n1=1.0), and fibrinogen <150 mg/dl. Primary underlying diseases were identified and treated. Infants were assigned randomly to one of 3 treatment regimens: I. Exchange transfusion with CPD whole blood q 12 hr until coagulation improvement. II. Fresh frozen plasma (15 ml/kg) and platelets (1 unit) q 12 hr until coagulation improvement. III. No coagulation therapy. The 3 groups were similar for birthweight, gestational age, Apgar scores, underlying disease processes, and degree of abnormality of initial coagulation studies. Data indicate mean ± SD.There were no differences in rates of improvement in coagulation studies or survival in the 3 groups. Outcome was more dependent on success of treatment of underlying pathologic processes than on treatment specifically directed at the coagulopathy.

813 CONTROLLED STUDY OF TREATMENT FOR DISSEMINATED INTRAVASCULAR COAGULATION (DIC) IN THE NEWBORN

25 appropriately grown infants with birthweight <1600 gm were assigned randomly to one of 3 sources of nutrition from birth: 1. Cow's milk formula (67 kcal/dl, 2.0 gm/dl protein). 2. Preterm breast milk, obtained from donors 1-8 wk following preterm delivery, collected and pooled separately by postpartum week. Each week infants received milk corresponding to their postnatal age. Protein concentration decreased from 2.3 gm/dl (wk 1) to 1.2 gm/dl (wk 8). 3. Mature breast milk, obtained from donors >3 months following term delivery, containing 1.0 gm/dl protein. All infants were fed 180 ml/kg/day until achieving a wt of 1800 gm. Growth and biochemical measurements were made weekly. Data indicate mean ± SD.Mean values for BUN, serum sodium, protein, albumin, and blood pH were similar in the 3 groups. Infants fed preterm breast milk demonstrated similar growth and metabolic response as infants fed cow's milk formula.

559 GROWTH AND METABOLIC RESPONSE OF PRETERM INFANTS FED PRETERM AND MATURE BREAST MILK

Using a radioimmunoassay we measured [CKBB] in 130 CSF samples from 86 newborns. Infants with intraventricular hemmorhage(IVH) documented by computerized tomography(CT) had significantly higher [CKBB] in CSF than infants who had normal CT's or were not clinically suspected of having an IVH. [CKBB]'s are expressed in nanograms/ml.Patients with a definitely abnormal neurological exam prior to the LP had significantly higher [CKBB] in CSF than those with suspect or normal exams.All 15 infants with [CKBB]>25 ng/ml had suffered a severe neurological insult. (13 had an IVH and 2 had severe asphyxia.)CSF [CKBB] is a metabolic indicator of brain damage and is significantly elevated in CSF from infants with IVH and abnormal neurological exams.

1467 CREATINE KINASE BRAIN ISOENZYME CONCENTRATION CKBB IN CEREBROSPINAL FLUID(CSF) OF NEWBORNS

The influence of daily mechanical expression of breast milk on nutritional composition was examined by comparing expressed milk from 12 mothers who delivered preterm with milk from two groups of mothers delivering at term: nine mothers who mechanically expressed all milk and five mothers who nursed their infants at the breast. Collections were obtained at four-hour intervals over a period of 24 hours so that variability of constituents in milk of different mothers, as well as variability in the same mother over a 24-hour period, could be assessed. Preterm milk contained significantly higher concentrations of protein, sodium, and chloride, and lower concentrations of of lactose than the milk from either group of mothers delivering at term. The mean concentrations of protein, sodium, chloride, and potassium in early preterm milk were adequate to meet the estimated requirements for the preterm infant. However, there was large variability in nutritional composition of milk among mothers and among samples from the same mother.

Diurnal variation in nutritional composition of milk produced by mothers of preterm infants.

Nutritional composition of milk produced by mothers delivering preterm.

Large for gestational age (LGA) infants of insulin-dependent diabetic mothers (IDM), appropriate for gestational age (AGA) IDM, and infants of nondiabetic mothers were compared for the incidence of neonatal hyperbilirubinemia and related etiologic factors. At 60 hours of age, LGA IDM had significantly higher serum bilirubin concentrations (12.3 +/- 2.1 mg/100 ml) than AGA IDM (7.6 +/- 3.9 mg/100 ml) or control infants (7.8 +/- 2.8 mg/100 ml) (P < .001). Peak serum bilirubin concentrations were also significantly higher in LGA IDM (14.4 +/- 2.1 mg/100 ml) than in AGA IDM (8.4 +/- 3.7 mg/100ml) or control infants (8.6 +/- 3.3 mg/100 ml) (P < .001). Mean percent of carboxyhemoglobin was used as an indicator of hemolysis and showed a significant elevation in LGA IDM (1.51 +/- 0.19) when compared to AGA IDM (1.10 +/- 0.27) and control infants (1.19 +/- 0.33) (P < .05). No significant differences were found among the three groups with respect to mode of delivery, frequency of pitocin administration, 5-minute Apgar scores, incidence of isoimmunization, incidence of enclosed hemorrhage, hemoglobin concentration, bilirubin concentrations at 12 hours, and percent of weight loss. Our data suggest that only LGA IDM are at increased risk for hyperbilirubinemia and that increased heme turnover is a significant factor in the pathogenesis.

A study was designed to determine the effect of vitamin E on bilirubinemia in the preterm infant. Twenty infants with birth weight between 1,000 and 1,500 gm and 20 infants with birth weights between 1,501 and 2,000 gm were studied. Half the infants in each birth weight group received vitamin E administered intramuscularly in a total dose of 50 mg/kg during days 1 to 3 of life; the remaining infants served as controls. The administration of vitamin E produced significantly increased plasma tocopherol concentrations and normal hydrogen peroxide hemolysis tests by the end of the first week of life. Infants with birthweights less than or equal to 1500 gm who received vitamin E demonstrated a significant decrease in serum bilirubin on day 3 of life (6.5 +/- 2.2 vs 8.8 +/- 2.2 mg/dl) as well as a significant decrease in peak serum bilirubin during the first week of life (8.3 +/- 2.2 vs 10.6 +/- 2.6 mg/dl). The duration of phototherapy also was significantly less in the vitamin E-supplemented group (48 +/- 18 vs 107 +/- 31 hours). These differences were less pronounced in infants with birth weights more than 1,500 gm.

One hundred eighteen infants with birth weights of 2,000 g or less were evaluated for growth and development at approximately 5 years of age. Review of neonatal data indicated that head circumference less than the tenth percentile at birth and abnormal neurological examination in the newborn period were important predictors of outcome. Both of these factors were associated with poor growth, later microcephaly, and neurological deficit. In addition, neonatal microcephaly was substantially related to poor intellectual attainment. Other associations were seen between microcephaly at birth and intrauterine growth retardation, low Apgar score, and low socioeconomic status, factors that also correlated with poor outcome.

Newborn head size and neurological status. Predictors of growth and development of low birth weight infants.

A study was undertaken to determine whether the serum bilirubin level could be estimated by the light reflectance of skin. The reflectance of skin over the abdomen was measured at five wavelengths (λ = 629, 556, 511, 465, 424), and compared with reflectance of a white standard. A formula was derived which related measurements of skin reflectance with serum bilirubin level. Thirty Black and 14 Caucasian term infants were then prospectively studied with simultaneous spectral reflectance and serum bilirubin levels. All infants were less than one week of age, and none had received phototherapy. Serum bilirubin levels ranged from 1 mg/dl to 12 mg/dl and correlated with spectral reflectance estimates with a coefficient of 0.94. Agreement was within 2 mg/dl in all cases. Measurement of spectral reflectance of skin is an accurate and non-invasive screening method for estimation of serum bilirubin.

1009 ESTIMATION OF SERUM BILIRUBIN BY SPECTRAL REFLECTANCE OF THE SKIN

The effect of prenatal ASA ingestion on hemostasis was investigated in 59 maternal-neonate pairs. Group I consisted of 36 control pairs in whom a negative ASA drug history was substantiated by normal maternal and neonatal platelet aggregations and values for the prostaglandin byproduct malonyldialdehyde (MDA). Group II consisted of 16 pairs in whom a positive history for maternal ASA ingestion was confirmed by the expected abnormalities in platelet aggregations and MDA. Group III comprised 7 maternal-neonate pairs where maternal ASA ingestion occurred within 6 hours post partum. All groups were evaluated for hemostatic abnormalities. Maternal blood loss was considered excessive, if a drop of >10% between initial and discharge hemoglobin occurred (vaginal delivery), or >25% (C section). In Group I, no maternal hemostatic abnormalities were noted, although 1/34 neonates demonstrated facial ecchymoses. In 10/16 Group II pairs where maternal ASA ingestion had occurred 0-5 days prior to delivery, clinical evidence of bleeding occurred in 90% (9/10) of the infants, and 60% (6/10) of the mothers. In contrast, in 6/16 Group II pairs, where ASA ingestion had occurred 6-10 days prior to delivery, no abnormalities were found. Group III infants were normal, although 57% (4/7) mothers in this group bled abnormally. ASA ingested in the 5 days prior to delivery, or immediately post partum, is associated with hemostatic abnormalities in both mother and neonate.

667 THE EFFECT OF PRENATAL ACETYL SALICYLIC ACID (ASA) INGESTION ON MATERNAL AND NEONATAL HEMOSTASIS

A study was undertaken to determine if vitamin E deficiency contributed to the development of hyperbilirubinemia in the preterm infant. Ten appropriately grown infants of <36 weeks gestation received intramuscular vitamin E in a total dose of 50 mg/kg during days 1 to 3 of life and 10 infants served as controls. The two groups were matched for birthweight, gestational age, Apgar scores, and hemoglobin level at birth. Serum bilirubin levels were monitored during the first week of life and carboxyhemoglobin (%COHb) values were obtained as an index of hemolysis. A significant difference in bilirubin was observed by day 3 which persisted for the remainder of the first week. The highest bilirubin averaged 11.4 mg/100 ml in the control group and 7.9 mg/100 ml in the vitamin E supplemented group (p<0.01). There was no difference in the use of phototherapy between groups.The administration of vitamin E at a dose of 50 mg/kg resulted in a significant reduction in bilirubinemia associated with decreased hemolvsis during the first week of life.

Although it is recognized that vitamin E deficiency may be associated with a hemolytic anemia in premature infants at 6 to 10 weeks of age, no information is available to indicate if the vitamin E deficiency normally present at birth has hematologic consequences. A study was designed to determine if the presence of vitamin E deficiency during the first week of life played a contributory role in the shortened red cell lifespan observed in the premature infant. Carboxyhemoglobin values were used as an index of hemolysis. Ten healthy, preterm infants received intramuscular vitamin E in a total dose of 125 mg/Kg during days 3 to 7 of life and ten infants served as controls. The percent carboxyhemoglobin levels fell significantly from day 3 to day 8 in the treated sroup (1.03% to 0.78%) while the mean value remained unchanged at 0.96% in the control group. The administration of vitamin E during the first week of life appears to reduce, but not eliminate, the accelerated red cell destruction that is characteristic of the premature infant.

THE EFFECTS OF VITAMIN E ON HEMOLYSIS IN PREMATURE INFANTS DURING THE FIRST WEEK OF LIFE

A study was designed to determine if the presence of vitamin E deficiency during the first week of life played a contributory role in the shortened red cell life span observed in the premature infant. Carboxyhemoglobin values were used as an index of hemolysis. Ten infants received vitamin E administered intramuscularly in a total dose of 125 mg/kg during days 3 to 7 of life; ten infants served as controls. The mean percent carboxyhemoglobin level fell significantly from day 3 to day 8 in the treated group (1.08% to 0.78%) whereas the mean value remained unchanged at 0.96% in the control group. The administration of vitamin E appears to reduce but not eliminate the accelerated red cell destruction that characterizes the preterm infant.

Measurements of absolute neutrophil and band counts are now utilized with increasing frequency for the early diagnosis of infection in neonates. Unfortunately all the factors that may influence the absolute neutrophil count (ANC) during this period of life have not been elucidated. For this purpose ANC were de-determined at 3, 12-15, 48 and 72 hrs. of life in 4 groups of Caucasian premature infants who were appropriate weight for gestational age. One group did not develop respiratory distress syndrome (RDS), one group did, while a third group were born after their mothers received corticosteroids (CS) for 3 days prior to delivery - some of these infants developed RDS and others did not. The ANC (×103/mm3 ± ISD) in these infants are depicted below:These studies illustrate that the administration of CS to mothers significantly increases the ANC of their offspring if they do not develop RDS (p <.005). The CS had no effect in infants who developed RDS. The ANC in neonates is influenced by maternal CS therapy and may be of predictive value in identifying those CS treated patients who will develop RDS.

INFLUENCE OF MATERNAL CORTICOSTEROID (CS) ADMINISTRATION ON NEONATAL NEUTROPHIL COUNT

A study was designed to determine if the presence of vitamin E deficiency during the first week of life played a contributory role in the shortened red cell life span observed in the premature infant. Carboxyhemoglobin values were used as an index of hemolysis. Ten infants received vitamin E administered intramuscularly in a total dose of 125 mg/kg during days 3 to 7 of life; ten infants served as controls. The mean percent carboxyhemoglobin level fell significantly from day 3 to day 8 in the treated group (1.08% to 0.78%) whereas the mean value remained unchanged at 0.96% in the control group. The administration of vitamin E appears to reduce but not eliminate the accelerated red cell destruction that characterizes the preterm infant. Pediatrics, 59:995-997, 1677, VITAMIN E, HEMOLYSIS, PREMATURE INFANT, CARBOXYHEMOGLOBIN.

Inability to absorb oral iron is believed to be an extremely rare cause of therapeutic failure in the treatment of iron deficiency anemia. Six patients who had failed to respond to oral iron therapy were studied by a simple oral absorption test and contrasted with 25 patients with untreated iron deficiency anemia and 10 normal subjects. All six of the patients who were therapeutic failures demonstrated impaired iron absorption in the absence of other clinical evidence of gastrointestinal disease. In the 25 newly diagnosed patients with iron deficiency, 24 demonstrated elevated iron absorptions while 10 ironreplete normal subjects had minimal elevations in their serum iron values following the administration of the test dose of 1 mg of elemental iron per kilogram. When the therapeutic failures were treated with parenteral iron, all had a therapeutic response, In addition, after treatment the impaired absorption of iron improved transiently. All children who absorbed iron readily responded to oral iron therapy.

In its recent statement on iron,1 the Committee on Nutrition emphasized the value of iron-fortified, proprietary milk formulas for the prevention of iron-deficiency anemia of infancy. Despite this recommendation, the most recent marketing information available to the Committee shows that more than 70% of the proprietary formulas currently prescribed by physicians do not contain added iron.
 The reasons for continuing routine use of formulas not fortified with iron are not entirely clear. One reason may be that some physicians still believe iron additives increase the incidence of feeding problems or gastrointestinal disturbances. There is no documented evidence that this is a significant problem.
 The Committee strongly recommends when proprietary formulas are prescribed that iron-supplemented formulas be used routinely as the standard–that is, that this be the rule rather than the exception. There seems to be little justification for continued general use of proprietary formulas not fortified with iron. The Committee is fully aware that only a small percentage of American infants are fed proprietary formulas after 6 months of age. Fluid whole milk (available in bottle or carton ) or evaporated milk, both of which contain only trace amounts of iron, are substituted at the time of greatest iron need and highest prevalence of iron-deficiency anemia. The infant's diet is usually deficient in iron, unless other foods are carefully selected to insure adequate iron intake.
 Since the major dietary component during infancy is milk, two courses of action should be taken:
 (1) Pediatricians and other health professionals should engage in a program of public education to convince American mothers to provide their infants with a source of dietary iron.

The relationship between milk protein and iron content on hematologic values in infancy.

Objectives: To document in-hospital and 1-year mortality rates after high-energy pelvic fracture in patients 65 years of age or older as compared to a younger cohort. Design: Retrospective review. Setting: Urban Level 1 academic trauma center. Patients: Seventy consecutive patients 65 years of age and older treated for pelvic fracture resulting from high-energy mechanism from 2008 to 2011. A total of 140 patients 18–64 years of age were matched to the study population based on mechanism of injury and OTA Code 61 subtype for comparison. Intervention: Review of demographics, injury characteristics, hospital management, and mortality. Main Outcome Measurements: Mortality. Results: The overall inpatient mortality rate was 10%. The older cohort exhibited an inpatient mortality rate 3 times higher than the younger cohort (18.6% vs. 5.7%, P = 0.003). There was no difference in mortality 1 year post discharge (5.3% vs. 3.8%, P = 0.699). No significant differences in initial Glasgow Coma Scale or Injury Severity Score were identified (GCS 12.9 vs. 12.4, P = 0.363; ISS 24.7 vs. 23.4, P = 0.479). Multivariate analysis identified the Charlson Comorbidity Index (CCI) (P = 0.012) and Abbreviated Injury Scale (AIS)-chest (P = 0.005) as independent predictors of in-hospital mortality, and CCI (0.005) and AIS-abdomen (0.012) for 1-year mortality. Conclusions: After controlling for mechanism of injury and pelvic fracture classification, we found that adults ≥65 and those with multiple comorbidities were more likely to die in the hospital than younger adults. However, mortality within 1-year postdischarge was low and did not differ between groups. This is in sharp contrast to the high rates of postdischarge mortality observed in elderly patients with a hip fracture. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Mortality After High-Energy Pelvic Fractures in Patients of Age 65 Years or Older

Objective: To examine the potential benefits and risks associated with weight-bearing after intramedullary (IM) nailing of unstable tibial shaft fractures. Design: Randomized controlled trial. Setting: Two New York State level 1 trauma centers, one level 2 trauma center, and 1 tertiary care orthopaedic hospital in a large urban center in New York City. Patients/Participants: Eighty-eight patients with 90 tibial shaft fractures were enrolled. The following were used as inclusion criteria: (1) skeletally mature adult patients 18 years of age or older, (2) displaced fractures of tibial diaphysis (OTA type 42) treated with operative intervention, and (3) radiographs, including injury, operative, and completion of follow-up. Sixty-eight patients with 70 tibial shaft fractures completed follow-up. Intervention: All patients were treated with locked IM nailing. Patients were randomized to 1 of 2 groups: immediate weight-bearing-as-tolerated (WBAT) or non–weight-bearing for the first 6 postoperative weeks (NWB). Main Outcome Measures: Fracture union or treatment failure/revision surgery. Results: There was no statistical difference in the observed time to union between groups (WBAT = 22.1 ± 11.7 weeks vs. NWB = 21.3 ± 9.9 weeks; P = 0.76). Rates of complications did not statistically differ between groups. No fracture loss of reduction leading to malunion was encountered. Short Musculoskeletal Function Assessment scores for all domains did not statistically differ between groups. Conclusions: Immediate weight-bearing after IM nailing of tibial shaft fractures is safe and is not associated with an increase in adverse events or complications. Patients should be allowed to bear weight as tolerated after IM nailing of OTA subtype 42-A and 42-B tibial shaft fractures. Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Can Tibial Shaft Fractures Bear Weight After Intramedullary Nailing? A Randomized Controlled Trial

Arthroscopy has been advocated as a possible adjunct to the operative treatment of tibial plateau fractures. This review article provides a historical perspective on the development of the technique while focusing on its current role in the management of these injuries. Topics include the possible utility of employing arthroscopy in the diagnosis and management of associated soft tissue lesions and potential for arthroscopic assistance to facilitate achieving fracture reduction without an open arthrotomy. Pertinent literature is reviewed and discussed, with an emphasis on the data related to patient outcomes.

The Role of Arthroscopy in the Management of Tibial Plateau Fractures.

The Knee: Reconstruction, Replacement, and Revision Editor: Javad Parvizi, MD, FRCS

Positive predictive value of Carnett’s sign in differential diagnosis of chronic abdominal pain: a retrospective cohort study

We report the case of a woman in the third trimester of pregnancy who sustained an ankle fracture dislocation that could not be adequately closed reduced. After discussions with the patient, her obstetrician, and the anesthesiologists, she was indicated for surgical fixation. A heart tone monitor was used to assess fetal health during the procedure. During surgical incision, the fetus went into distress, and an emergency caesarian section was performed. After delivery of the infant and abdominal closer, surgery was completed. Due to a cohesive team effort, both the patient and her infant had excellent outcomes. There are many important considerations in the surgical management of the pregnant patient with traumatic orthopaedic injuries. Of especial importance to the orthopaedic surgeon is the impact of patient positioning on uteroplacental blood flow. This report discusses factors that should be taken into account by any orthopaedist who plans to operate on a pregnant patient.

Ankle Fracture Surgery on a Pregnant Patient Complicated by Intraoperative Emergency Caesarian Section

Recent resurgence in the interest of barbed suture has extended its application to wound closures in total joint surgery. Improved suture biomaterials and barb geometry has lead to consideration for its use in various orthopedic procedures including arthroplasty. The reported superior wound tensile stress distribution, no need for knots, and ability to close multiple layers with one suture make it an attractive option for deep wound closure after total joint surgery. However, inherent to the design of this suture are barbs that pose a risk of glove perforation and the potential for the transmission of blood borne pathogens. This study reports no increase in the incidence of glove perforation with use of barbed suture for deep wound closure after total joint arthroplasty.

Barbed sutures for arthroplasty closure--does it decrease the risk of glove perforation?

Surgical ligation clips of various materials were scanned in a water-filled phantom to determine what artifacts would be produced. Tantalum clips produced severe image degradation, while stainless steel clips produced less severe degradation. Minimal artifacts were observed with titanium clips. Clips molded from an absorbable polymeric material, polydioxanone, were visible on computed tomography (CT) scans and had the least effect on the CT image.

Computerized radiology : official journal of the Computerized Tomography Society

A prospective double-blind study was undertaken to compare computed tomography (CT) and conventional radiographic tomography (RT) in the staging of lung carcinoma. Seventy-five patients had CT and RT of the mediastinum and hilum prior to operation. The presence or absence of metastasis to lymph nodes documented at the time of operation was the standard applied to the studies. CT correctly predicted the presence or absence of mediastinal lymphadenopathy in most cases (sensitivity 91%, specificity 94%), while RT was less helpful (sensitivity 61%, specificity 86%). Metastatic mediastinal lymph nodes in those patients with false negative CT and RT studies averaged only 0.8 cm in diameter, probably accounting for the negative radiographic findings. Both CT and RT had poor predictive values in detecting hilar lymphadenopathy (sensitivity 73% and 47%, specificity 87% and 72%, respectively). The predictive value of CT in the evaluation of mediastinal lymphadenopathy equaled that of mediastinoscopy or mediastinotomy. When CT of the mediastinum demonstrates no lymphadenopathy, invasive staging can be deferred for definitive thoracotomy. Since false positive values were seen with both CT and RT scans of the mediastinum (4% and 8%, respectively), invasive staging will still be necessary in those patients with positive studies.

The value of radiographic and computed tomography in the staging of lung carcinoma.

The Value of Radiographic and Computed Tomography in the Staging of Lung Carcinoma

One hundred ten patients with proved bronchogenic carcinoma who were undergoing computed tomography (CT) of the thorax also underwent CT of the adrenals to determine the value of routine preoperative assessement of this gland. Sixteen adrenal masses were found in 11 patients. In five patients the adrenals were the only site of metastasis. CT of the adrenals should be performed routinely when the thorax is examined pre-operatively in patients with non-oat-cell bronchogenic carcinoma to improve patient selection for thoractomy.

Computed tomographic evaluation of the adrenal gland in the preoperative assessment of bronchogenic carcinoma.

Eleven patients presenting with thoracic aortic dissection were studied by computed tomography (CT). CT was usually performed with knowledge of the angiographic diagnosis. In eight cases, CT was definitive. This group included all six patients who received intravenous contrast material by bolus infusion. An algorithmic approach to patients with possible aortic dissection is suggested.

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A case of pseudocyst simulating the biliary ductal system is reported. Several CT findings indicate that the biliary system was not involved: (a) no dilatation of the more proximal intrahepatic biliary radicles; (b) the gallbladder was not distended; (c) lucency extending to the left at the level of the pancreas; (d) a position more medial and anterior than anatomic for the distal common bile duct.

Pancreatic pseudocyst simulating dilated biliary duct system on computed tomography.

Submitted for publication: May 16, 1979 Accepted for publication: May 23, 1979 * Department of Diagnostic Radiology, Henry Ford Hospital Address reprint requests to Dr. Eyler, Department of Diagnostic Radiology, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, Ml 48202 iagnostic radiological support for the urologist and his patient, confronted with a possible renal neoplasm, is still based on the scout radiograph of the abdomen and the excretory urogram including tomography, with the renal angiogram providing the final standard. As the use of tomography associated with excretory urograms increases, nephrotomography as a separate procedure is not used as often. However, the new modalities of ultrasound (US) and computed tomography (CT) dochallenge angiography in all cases and increasingly render angiography unnecessary. When a classical cyst can be demonstrated by CT or US, it can be followed either wfth serial examinations or it can be aspirated under ul t rasound, CT or convent ional f luoroscopic guidance. Fine needle aspiration biopsy of renal and pararenal areas with US or CT guidance is easily and safely performed.

Management of renal cell carcinoma: evaluation of renal masses by modern radiological techniques

The microtubule associated protein 4 (MAP4) sweeps organelles towards the nucleus by weakening the kinesin motor.

Significance Microtubules form a network spanning the interior of cells and serve as roads for molecular motor proteins that carry organelles and other cargo to where they are needed inside the cell. The function of molecular motors is regulated for proper delivery or distribution of cargo, failure of which is linked to myriad diseases. We discovered that the microtubule-associated protein 4, which is found in cells in all tissues, can determine whether mitochondria accumulate around the nucleus or distribute throughout the cell by controlling the kinesin motor’s ability to generate force, a novel mode of regulation. Our findings can guide therapeutic strategies for the paradoxical increased metastasis fueled by the spread of mitochondria in response to certain cancer treatments.

The ubiquitous microtubule-associated protein 4 (MAP4) controls organelle distribution by regulating the activity of the kinesin motor

Antimicrobial peptides (AMPs) have been extensively studied due to their vast natural abundance and ability to kill microbes. In an era critically lacking in new antibiotics, manipulating AMPs for therapeutic application is a promising option. However, bacterial pathogens resistant to AMPs remain problematic. To improve AMPs antimicrobial efficacy, their use in conjunction with other antimicrobials has been proposed. How might this work? AMPs kill bacteria by forming pores in bacterial membranes or by inhibiting bacterial macromolecular functions. What remains unknown is the duration for which AMPs keep bacterial pores open, and the extent to which bacteria can recover by repairing these pores. In this mini-review, we discuss various antimicrobial synergies with AMPs. Such synergies might arise if the antimicrobial agents helped to keep bacterial pores open for longer periods of time, prevented pore repair, perturbed bacterial intracellular functions at greater levels, or performed other independent bacterial killing mechanisms. We first discuss combinations of AMPs, and then focus on histones, which have antimicrobial activity and co-localize with AMPs on lipid droplets and in neutrophil extracellular traps (NETs). Recent work has demonstrated that histones can enhance AMP-induced membrane permeation. It is possible that histones, histone fragments, and histone-like peptides could amplify the antimicrobial effects of AMPs, giving rise to antimicrobial synergy. If so, clarifying these mechanisms will thus improve our overall understanding of the antimicrobial processes and potentially contribute to improved drug design.

Mechanical properties of cells are important features that are tightly regulated, and are dictated by various pathologies. Deformability cytometry allows for the characterization of mechanical properties of hundreds of cells per second, opening the way to differentiating cells via mechanotyping. A remaining challenge for detecting and classifying rare sub-populations is the creation of a combined experimental and analysis protocol that would assure classification accuracy approaching 100%. In order to maximize the accuracy, we designed a microfluidic channel that subjects each cell to repeated deformations and relaxations. We also track the shape dynamics of individual cells with high time resolution, and apply sequence-based deep learning models for feature extraction. HL60 cells with and without treatment with cytochalasin D (cytoD), a reagent previously shown to perturb the actin network, were used as a model system to understand the classification potential of our approach. Multiple recurrent and convolutional neural network architectures were trained using time sequences of cell shapes, and shown to achieve high classification accuracy based on cytoskeletal properties alone. The best model classified the two sub-populations of HL60 cells with an accuracy of 95%. This work establishes the application of sequence-based deep learning models to dynamic deformability cytometry.

Deep Learning Assisted Mechanotyping of Individual Cells Through Repeated Deformations and Relaxations in Undulating Channels

Cells drop a bomb on pathogens Lipid droplets (LDs) accumulate in cells to serve as lipid storage organelles. They are also an attractive source of nutrients for many pathogens. Bosch et al. show that various proteins involved in innate immunity form complexes on LDs in response to bacterial lipopolysaccharide (see the Perspective by Green). Upon activation, LDs became physically uncoupled from mitochondria, driving a shift in cells from oxidative phosphorylation to aerobic glycolysis. This work highlights the ability of LDs both to kill pathogens directly and to establish a metabolic environment conducive to host defense. This may inform future antimicrobial strategies in the age of antibiotic resistance. Science, this issue p. eaay8085; see also p. 294 Lipid droplets in cells act as host defense hubs. INTRODUCTION In all eukaryotic cells, lipid droplets (LDs) store and supply essential lipids to produce signaling molecules, membrane building blocks, and metabolic energy. The LD monolayer also accommodates proteins not obviously related to lipids, such as transcription factors, chromatin components, and toxic proteins. Common parasites (such as trypanosomes and Plasmodium falciparum), bacteria (such as mycobacteria and Chlamydia), and viruses (such as hepatitis C and dengue) induce and target LDs during their life cycles. The current view is that LDs support infection, providing microorganisms with substrates for effective growth. RATIONALE Successful innate defense is critical for survival, and host species have efficiently coevolved with pathogens to develop a plethora of immune responses. Multiple cues, including cellular stress and danger-associated molecular patterns such as lipopolysaccharide (LPS), induce LD formation. Thus, LD localization and dynamics may potentially be advantageous for organizing an intracellular host defense. We have investigated the possibility that mammalian LDs have a direct and regulated role in innate immunity. RESULTS We show that mammalian LDs are endowed with a protein-mediated antimicrobial capacity, which is up-regulated during polymicrobial sepsis and by LPS. Light and electron microscopy demonstrated specific association of LDs and bacteria in human macrophages, suggesting the existence of docking mechanisms that facilitate the engagement of antibacterial LD proteins with bacteria. A comparative mass spectrometry profiling of proteins differentially associated with LDs in response to LPS (LPS-LDs) revealed the profound remodeling of the organelle proteome. A stringent evaluation identified 689 proteins differentially regulated on LPS-LDs (317 enriched and 372 reduced). Ingenuity Pathway Analysis revealed an enrichment of innate immune system–related components and reduction of metabolism-related LD-resident proteins. Additional analyses suggested that LDs serve as innate immune hubs, integrating major intra- and extracellular immune responses. Among the five members of the perilipin family of LD surface proteins (PLINs), PLIN5 was the only one down-regulated on LPS-LDs. PLIN5 reduction promoted physical and functional disconnection of LPS-LDs and mitochondria, with a concomitant reduction of oxidative metabolism and ketogenesis. Forced PLIN5 reexpression increased the number of LD-mitochondria contacts, reducing LD-bacteria interactions and compromising the antimicrobial capacity of cells. By contrast, PLIN2 was the most up-regulated PLIN on LPS-LDs. Gene interaction analysis revealed that multiple immune proteins nucleated around PLIN2 in response to LPS. LPS-LDs accrued several interferon-inducible proteins such as viperin, IGTP, IIGP1, TGTP1, and IFI47. Furthermore, LPS-LDs also accumulated cathelicidin (CAMP), a broad-spectrum antimicrobial peptide with chemotactic properties. Cells overexpressing a LD-associated CAMP were more resistant to different bacterial species, including Escherichia coli, methicillin-resistant Staphylococcus aureus, and Listeria monocytogenes. CONCLUSION These results demonstrate that LDs form a first-line intracellular defense. They act as a molecular switch in innate immunity, responding to danger signals by both reprogramming cell metabolism and eliciting protein-mediated antimicrobial mechanisms. Mechanisms of LD trafficking and docking with phagocytic and parasitophorous membranes, observed here and described for several pathogens, may facilitate the delivery of immune proteins located on the LD surface. Intracellular LDs can provide infected cells with several biological benefits, serving as a location to attract pathogens as well as coordinating different immune systems that operate simultaneously against different classes of pathogens. LDs may also sequester cytotoxic compounds (such as antimicrobial peptides), reducing damage to other cellular organelles. In view of the widespread resistance to current antibiotics, this study helps decipher molecular mechanisms involved in antimicrobial defense that could be exploited for development of new anti-infective agents. LDs mediate innate immune defense. Serial blockface scanning electron microscopy data reconstruction showing an infected macrophage. Bacteria (blue) and LDs (green) in the three-dimensional dataset have been colored and projected onto a single image. LDs associate with the bacteria surface (black square). This interaction is proposed to bring a specific set of antipathogenic proteins in contact with the membrane-enclosing bacteria (inset). Lipid droplets (LDs) are the major lipid storage organelles of eukaryotic cells and a source of nutrients for intracellular pathogens. We demonstrate that mammalian LDs are endowed with a protein-mediated antimicrobial capacity, which is up-regulated by danger signals. In response to lipopolysaccharide (LPS), multiple host defense proteins, including interferon-inducible guanosine triphosphatases and the antimicrobial cathelicidin, assemble into complex clusters on LDs. LPS additionally promotes the physical and functional uncoupling of LDs from mitochondria, reducing fatty acid metabolism while increasing LD-bacterial contacts. Thus, LDs actively participate in mammalian innate immunity at two levels: They are both cell-autonomous organelles that organize and use immune proteins to kill intracellular pathogens as well as central players in the local and systemic metabolic adaptation to infection.

Mammalian lipid droplets are innate immune hubs integrating cell metabolism and host defense

Abstract Cellular cargos, including lipid droplets and mitochondria, are transported along microtubules using molecular motors such as kinesins. Our current understanding arises from experimental and computational studies of cargos with rigidly attached motors, in contrast to many biological cargos that have lipid surfaces that may allow surface mobility of motors. We develop a coupled-viscosity mechanochemical 3D computational model to compare different motor arrangements and mobilities. We find that surface mobility can resolve contradictions between recent reports that cargo attachment and transport initiation in vivo occur on 1-10s timescales, and expected slower behavior based on cargo rotation timescales of 102-103s at cytoplasmic viscosities. Further, we show that organizational changes can optimize for different objectives: Cargos with clustered motors are transported efficiently, but are slow to bind to microtubules, whereas those with motors dispersed rigidly on their surface bind microtubules quickly, but are transported inefficiently. Finally, cargos with freely-diffusing motors have both fast binding and efficient transport, although less efficient than clustered motors. These results suggest that experimentally observed changes in motor organization may be a control point for transport, modulated either by adaptor proteins or changes in lipid composition. Significance statement Many subcellular structures have fluid surfaces, meaning the molecules on their surface have the ability to rearrange, both randomly and under force. Transport of these subcellular cargos, which is driven by molecular motors, facilitates many fundamental biological processes, including cellular metabolism and pathways implicated in neuronal health. In this work, computational simulation is used to show how the fluidity of their surfaces results in new biophysical phenomena, including the ability to efficiently initiate transport. Since many previous experiments and simulations use rigid cargo, our work introduces a new paradigm for control points by which subcellular processes can be regulated.

Diffusion of kinesin motors on cargo can enhance intracellular transport

The rate at which antibiotics are discovered and developed has stagnated; meanwhile, antibacterial resistance continually increases and leads to a plethora of untreatable and deadly infections worldwide. Therefore, there is a critical need to develop new antimicrobial strategies to combat this alarming reality. One approach is to understand natural antimicrobial defense mechanisms that higher-level organisms employ in order to kill bacteria, potentially leading to novel antibiotic therapeutic approaches. Mammalian histones have long been reported to have antibiotic activity, with the first observation of their antibacterial properties reported in 1942. However, there have been doubts about whether histones could truly have any such role in the animal, predominantly based on two issues: they are found in the nucleus (so are not in a position to encounter bacteria), and their antibiotic activity in vitro has been relatively weak in physiological conditions. More recent studies have addressed both sets of concerns. Histones are released from cells as part of neutrophil extracellular traps (NETs) and are thus able to encounter extracellular bacteria. Histones are also present intracellularly in the cytoplasm attached to lipid droplets, positioning them to encounter cytosolic bacteria. Our recent work (Doolin et al., 2020, Nat Commun), which is discussed here, shows that histones have synergistic antimicrobial activities when they are paired with antimicrobial peptides (AMPs), which form pores in bacterial membranes and co-localize with histones in NETs. The work demonstrates that histones enhance AMP-mediated pores, impair bacterial membrane recovery, depolarize the bacterial proton gradient, and enter the bacterial cytoplasm, where they restructure the chromosome and inhibit transcription. Here, we examine potential mechanisms that are responsible for these outcomes.

A novel antibacterial strategy: histone and antimicrobial peptide synergy

Molecular motors like kinesin are critical for cellular organization and biological function including in neurons. There is detailed understanding of how they move and how factors such as applied force and the presence of microtubule-associated proteins can alter this single-motor travel. In order to walk, the cargo-motor complex must first attach to a microtubule. This attachment process is less studied. Here, we use a combination of single-molecule bead experiments, modeling, and simulation to examine how cargos with kinesin-1 bind to microtubules. In experiment, we find that increasing cargo size and environment viscosity both signficantly slow cargo binding time. We use modeling and simulation to examine how the single motor on rate translates to the on rate of the cargo. Combining experiment and modeling allows us to estimate the single motor on rate as 100 s−1. This is a much higher value than previous estimates. We attribute the difference between our measurements and previous estimates to two factors: first, we are directly measuring initial motor attachment (as opposed to re-binding of a second motor) and second, the theoretical framework allows us to account for missed events (i.e. binding events not detected by the experiments due to their short duration). This indicates that the mobility of the cargo itself, determined by its size and interaction with the cytoplasmic environment, play a previously underestimated role in determining intracellular transport kinetics.

Roles of motor on-rate and cargo mobility in intracellular transport

Phenotyping of Phagocytosing Neutrophil Populations using Deformability Cytometry

Mammalian histones facilitate antimicrobial synergy by disrupting the bacterial proton gradient and chromosome organization

Regulation of in vivo dynein force production by CDK5 and 14-3-3ε and KIAA0528

Cellular cargos, including lipid droplets and mitochondria, are transported along microtubules using molecular motors such as kinesins. In the cell, it is unclear how motors are coordinated to achieve transport outcomes that are cargo-specific. One possibility is that transport is modulated by differences in organization and mobility of motors on the cargo’s surface. We use mechanochemical 3D computational modeling to compare different motor anchoring modes, and find that organizational changes can optimize for different objectives. Cargos with clustered motors are transported efficiently, but are slow to bind to microtubules. Cargos with motors dispersed rigidly on their surface bind microtubules quickly, but are transported inefficiently. Cargos with freely-diffusing motors have both fast binding and efficient transport, although less efficient than clustered motors. These results point to a functional role for observed changes in motor organization on cargos, and suggest motor diffusivity as a control point for transport, either by modulation of adaptor proteins or changes in lipid composition. Author summary The molecular motors of the kinesin family are responsible for moving the parts of cells to their subcellular destinations, organizing the cell interior. Computational modeling has historically played an important role in understanding how these motors work. But, strikingly, most models assume the subcellular cargos have rigid surfaces. Simulating fluid surfaces is more challenging but more applicable to biological cargo. In this work, we build a computational model of molecular motor transport of cargo with fluid surfaces. Surface fluidity gives cargo transport new properties, like enhanced transport efficiency, and the ability to push against opposing forces. Because the effects of surface fluidity vary strongly with some of the properties of the cargo, like its size, our results hint at one of the ways that the same transport machinery can distinguish different cargo despite using the same motors.

Molecular motor organization and mobility on cargos can overcome a tradeoff between fast binding and run length

Cellular cargoes, including lipid droplets and mitochondria, are transported along microtubules using molecular motors such as kinesins. Many experimental and computational studies focused on cargoes with rigidly attached motors, in contrast to many biological cargoes that have lipid surfaces that may allow surface mobility of motors. We extend a mechanochemical three-dimensional computational model by adding coupled-viscosity effects to compare different motor arrangements and mobilities. We show that organizational changes can optimize for different objectives: Cargoes with clustered motors are transported efficiently but are slow to bind to microtubules, whereas those with motors dispersed rigidly on their surface bind microtubules quickly but are transported inefficiently. Finally, cargoes with freely diffusing motors have both fast binding and efficient transport, although less efficient than clustered motors. These results suggest that experimentally observed changes in motor organization may be a control point for transport.

Diffusion of kinesin motors on cargo can enhance binding and run lengths during intracellular transport

Conformational Space Annealing explained: A general optimization algorithm, with diverse applications

Combined Positive and Ne gative Feedback Allows Modulation of Neuronal Oscillation Frequency during Sensory Processing Graphical Abstract Highlights

Combined Positive and Negative Feedback Allows Modulation of Neuronal Oscillation Frequency during Sensory Processing.

Brownian Dynamics Simulation Reveals How Properties of the Cargo and its Environment Can Influence Multiple Motor Transport

Significance Eukaryotic cells use microtubule (MT)-based transport to control the distribution of cargos across their complex and crowded environment. Prior models of MT-based motility considered cargo behavior on single filaments or simple networks. However, numerous recent reports revealed surprisingly complex 3D MT networks and associated complex cargo motility in cells. Such phenomena could not be modeled in previous studies. We show (via a recently developed experimental approach and in silico modeling) that network geometry plays a significant role in MT-based motility: The 3D properties of a single intersection can determine cargo routing, depending on cargo properties (e.g., size), opening the possibility that tuning 3D network geometry allows for selective targeting of cargos around the cell. The eukaryotic cell’s microtubule cytoskeleton is a complex 3D filament network. Microtubules cross at a wide variety of separation distances and angles. Prior studies in vivo and in vitro suggest that cargo transport is affected by intersection geometry. However, geometric complexity is not yet widely appreciated as a regulatory factor in its own right, and mechanisms that underlie this mode of regulation are not well understood. We have used our recently reported 3D microtubule manipulation system to build filament crossings de novo in a purified in vitro environment and used them to assay kinesin-1–driven model cargo navigation. We found that 3D microtubule network geometry indeed significantly influences cargo routing, and in particular that it is possible to bias a cargo to pass or switch just by changing either filament spacing or angle. Furthermore, we captured our experimental results in a model which accounts for full 3D geometry, stochastic motion of the cargo and associated motors, as well as motor force production and force-dependent behavior. We used a combination of experimental and theoretical analysis to establish the detailed mechanisms underlying cargo navigation at microtubule crossings.

Geometry Matters for Cargos Navigating 3D Microtubule Intersections

Significance Members of the kinesin superfamily serve a wide variety of functions, and a dominant narrative for these molecular motors has been that each member of the superfamily is uniquely specialized to serve a very limited set of functions. However, it is now appreciated that many members of this group serve several distinct physiological roles, and it has been unclear how these kinesins accomplish this functional flexibility. In this report, we describe a posttranslational modification of the kinesin 5 family member Eg5 that dramatically alters its chemomechanical behavior to make it function much more efficiently under load and in ensembles. This work provides the biophysical context required to mechanistically understand the effects of modified Eg5 in dividing cells. Numerous posttranslational modifications have been described in kinesins, but their consequences on motor mechanics are largely unknown. We investigated one of these—acetylation of lysine 146 in Eg5—by creating an acetylation mimetic lysine to glutamine substitution (K146Q). Lysine 146 is located in the α2 helix of the motor domain, where it makes an ionic bond with aspartate 91 on the neighboring α1 helix. Molecular dynamics simulations predict that disrupting this bond enhances catalytic site–neck linker coupling. We tested this using structural kinetics and single-molecule mechanics and found that the K146Q mutation increases motor performance under load and coupling of the neck linker to catalytic site. These changes convert Eg5 from a motor that dissociates from the microtubule at low load into one that is more tightly coupled and dissociation resistant—features shared by kinesin 1. These features combined with the increased propensity to stall predict that the K146Q Eg5 acetylation mimetic should act in the cell as a “brake” that slows spindle pole separation, and we have confirmed this by expressing this modified motor in mitotically active cells. Thus, our results illustrate how a posttranslational modification of a kinesin can be used to fine tune motor behavior to meet specific physiological needs.

A posttranslational modification of the mitotic kinesin Eg5 that enhances its mechanochemical coupling and alters its mitotic function

Molecular Mechanisms of Dynein Force Persistence in Lipid Droplet Transport

The kinesin family proteins are often studied as prototypical molecular motors; a deeper understanding of them can illuminate regulation of intracellular transport. It is typically assumed that they function identically. Here we find that this assumption of homogeneous function appears incorrect: variation among motors’ velocities in vivo and in vitro is larger than the stochastic variation expected for an ensemble of “identical” motors. When moving on microtubules, slow and fast motors are persistently slow, and fast, respectively. We develop theory that provides quantitative criteria to determine whether the observed single‐molecule variation is too large to be generated from an ensemble of identical molecules. To analyze such heterogeneity, we group traces into homogeneous sub‐ensembles. Motility studies varying the temperature, pH and glycerol concentration suggest at least 2 distinct functional states that are independently affected by external conditions. We end by investigating the functional ramifications of such heterogeneity through Monte‐Carlo multi‐motor simulations.

Long-distance intracellular axonal transport is predominantly microtubule-based, and its impairment is linked to neurodegeneration. Here we review recent theoretical and experimental evidence that suggest that near the axon boundaries (walls), the effective viscosity can become large enough to impede cargo transport in small (but not large) caliber axons. Theoretical work suggests that this opposition to motion increases rapidly as the cargo approaches the wall. However, having parallel microtubules close enough together to enable a cargo to simultaneously engage motors on more than one microtubule dramatically enhances motor activity, and thus decreases the effects due to such opposition. Experimental evidence supports this hypothesis: in small caliber axons, microtubule density is higher, increasing the probability of having parallel microtubules close enough that they can be used simultaneously by motors on a cargo. For transport toward the minus-end of microtubules, e.g., toward the cell body in an axon, a recently discovered force adaptation system can also contribute to overcoming such opposition to motion.

To take advantage of the different chemical environments made possible by internal membrane bound sub-compartments, Eukaryotic cells heavily utilize active transport. Much of this involves moving distinct cargos along microtubules, perhaps to facilitate cargo-cargo interactions—e.g. to control transfer of lipids from lipid droplets to mitochondria as part of metabolism—or to allow function of extended cells such as neurons. There are 2 major families of microtubule molecular motors: the predominantly plus-end directed kinesin motors, and minus-end directed dynein, and evolutionarily they appear to have taken a different approach to modulating function. There are many kinesin-family members, and these appear to have been adapted to specific cellular functions. In contrast, there are typically only one or at most 2 genes for cytoplasmic dynein, and the multiple distinct functions of dynein are altered by functioning with the 2 large cofactor complexes, Dynactin and NudE/Lis1. Dynactin was originally discovered to increase dynein travel distances, and was later reported to also have a domain able to turn off dynein force production, suggesting multiple levels of potential regulation that have yet to be explored. The NudE/Lis1 system was identified to play an important role in development and disease, as mutations in the Lis1 protein result in a devastating developmental defect known as Miller-Dieker Syndrome, resulting from impaired neuronal migration due to impaired nuclear migration. Later studies in vitro showed that together with NudE, Lis1 modulates dynein force production, allowing the motor to better remain attached to microtubules when under load. By decreasing the motors’ detachment rate when exposed to opposing forces, this in turn allows multiple motors to better add their forces, resulting in improved ensemble function, and thus better ability to move cargos against opposition. While this in vitro study appeared to potentially explain the in vivo Miller-Dieker lissencephaly phenotype—neuronal migration requires transport of the cells’ nucleus down the axon, a dynein-dependent process likely facing serious opposition, and thus such migration is likely dependent on improved dynein function—a number of key questions remained. First, it was unknown whether cargo transport was relatively constant, and insensitive to local environmental factors, or whether there were in fact some local sensing and response, e.g., to impediments to motion. Second, it remained to be determined whether the NudE/Lis1 system altered dynein the same way in vivo as it did in vitro, given the more complicated in vivo environment. Third, the extent to which the NudE/Lis1 system was important for cargos other than nuclei remained an open question. Finally, whether—and how—the system worked in conjunction with the dynactin complex was unknown.

An Allosteric Gear Shift Mechanism in Eg5 Enhances Mechanochemical Coupling and Shifts the Force-Velocity Landscape

Load-induced enhancement of Dynein force production by LIS1–NudE in vivo and in vitro

Brownian Dynamics Simulation Reveals Freedom of Motors in the Cargo Membrane can Influence Cargo Dynamics

Conventional analysis of in vitro assays of motor proteins rests on the assumption that all proteins with the same chemical composition function identically; however molecule-to-molecule variation is often seen even in well-controlled experiments. In an effort to obtain a statistically meaningful set of time traces that simultaneously avoid any experimental artifacts, we performed quantum-dot labeled kinesin experiments on both surface and levitated microtubules. Similar to glassy systems, we found that mean velocities of individual kinesin motors vary widely from one motor to another, the variation of which is greater than that expected from the stochastic variation of stepping times. In the presence of heterogeneity, an ensemble-averaged quantity such as diffusion constant or randomness parameter is ill-defined. We propose to analyze heterogeneous data from single molecule measurements by decomposing them into homogeneous subensembles.

Time traces of individual kinesin motors suggest functional heterogeneity

Significance The kinesins are molecular motors that couple ATP binding to movement. Although crystallographic and cryo-EM methods have identified the structural changes that occur in several kinesins, the images they generate are static pictures that provide no insight into how dynamic these conformations are or how they are coupled together to generate force. We have addressed this through a novel combination of time-resolved fluorescence and transient-state kinetics to measure the conformational equilibria between two key domains in two functionally distinct kinesins: kinesin-1 and Eg5. Our results are significant because they provide a unique insight into how conformational dynamics vary between two kinesins with different functions, and explain the distinct enzymologies these two kinesins have. Kinesins perform mechanical work to power a variety of cellular functions, from mitosis to organelle transport. Distinct functions shape distinct enzymologies, and this is illustrated by comparing kinesin-1, a highly processive transport motor that can work alone, to Eg5, a minimally processive mitotic motor that works in large ensembles. Although crystallographic models for both motors reveal similar structures for the domains involved in mechanochemical transduction—including switch-1 and the neck linker—how movement of these two domains is coordinated through the ATPase cycle remains unknown. We have addressed this issue by using a novel combination of transient kinetics and time-resolved fluorescence, which we refer to as “structural kinetics,” to map the timing of structural changes in the switch-1 loop and neck linker. We find that differences between the structural kinetics of Eg5 and kinesin-1 yield insights into how these two motors adapt their enzymologies for their distinct functions.

The structural kinetics of switch-1 and the neck linker explain the functions of kinesin-1 and Eg5

AMPK activation promotes lipid droplet dispersion on detyrosinated microtubules to increase mitochondrial fatty acid oxidation

Control of intracellular transport is poorly understood, and functional ramifications of tubulin isoform differences between cell types are mostly unexplored. Motors' force production and detachment kinetics are critical for their group function, but how microtubule (MT) details affect these properties – if at all – is unknown. We investigated these questions using both a vesicular transport human kinesin, kinesin‐1, and also a mitotic kinesin likely optimized for group function, kinesin‐5, moving along either bovine brain or MCF7(breast cancer) MTs. We found that kinesin‐1 functioned similarly on the two sets of MTs – in particular, its mean force production was approximately the same, though due to its previously reported decreased processivity, the mean duration of kinesin‐1 force production was slightly decreased on MCF7 MTs. In contrast, kinesin‐5's function changed dramatically on MCF7 MTs: its average detachment force was reduced and its force–velocity curve was different. In spite of the reduced detachment force, the force–velocity alteration surprisingly improved high‐load group function for kinesin‐5 on the cancer‐cell MTs, potentially contributing to functions such as spindle‐mediated chromosome separation. Significant differences were previously reported for C‐terminal tubulin tails in MCF7 versus bovine brain tubulin. Consistent with this difference being functionally important, elimination of the tails made transport along the two sets of MTs similar.

Microtubule C‐Terminal Tails Can Change Characteristics of Motor Force Production

Pseudo-atomic model of microtubule-bound human kinesin-5 motor domain in the ADP.AlFx state, based on cryo-electron microscopy experiment.

Pseudo-atomic model of microtubule-bound human kinesin-5 motor domain in presence of adp.alfx (NECK-LINKER IN ITS DISCONNECTED CONFORMATION, based on cryo-electron microscopy experiment

There is an increasing interest in factors that can impede cargo transport by molecular motors inside the cell. Although potentially relevant (Yi JY, Ori‐McKenney KM, McKenney RJ, Vershinin M, Gross SP, Vallee RB. High‐resolution imaging reveals indirect coordination of opposite motors and a role for LIS1 in high‐load axonal transport. J Cell Biol 2011;195:193–201), the importance of cargo size and subcellular location has received relatively little attention. Here we address these questions taking advantage of the fact that mitochondria – a common cargo – in Drosophila neurons exhibit a wide distribution of sizes. In addition, the mitochondria can be genetically marked with green fluorescent protein (GFP) making it possible to visualize and compare their movement in the cell bodies and in the processes of living cells. Using total internal reflection microscopy coupled with particle tracking and analysis, we quantified the transport properties of GFP‐positive mitochondria as a function of their size and location. In neuronal cell bodies, we find little evidence for significant opposition to motion, consistent with a previous study on lipid droplets (Shubeita GT, Tran SL, Xu J, Vershinin M, Cermelli S, Cotton SL, Welte MA, Gross SP. Consequences of motor copy number on the intracellular transport of kinesin‐1‐driven lipid droplets. Cell 2008;135:1098–1107). However, in the processes, we observe an inverse relationship between the mitochondrial size and velocity and the run distances. This can be ameliorated via hypotonic treatment to increase process size, suggesting that motor‐mediated movement is impeded in this more‐confined environment. Interestingly, we also observe local mitochondrial accumulations in processes but not in cell bodies. Such accumulations do not completely block the transport but do increase the probability of mitochondria–mitochondria interactions. They are thus particularly interesting in relation to mitochondrial exchange of elements.

A Biophysical Analysis of Mitochondrial Movement: Differences Between Transport in Neuronal Cell Bodies Versus Processes

Calibration of optical tweezers for in vivo force measurements: how do different approaches compare?

Significance Kinesin regulation by autoinhibition has been extensively studied. However, it is known that cargo-bound kinesin motion can be altered by various signaling pathways. How are these kinesins regulated? Kinesin regulation by the signaling kinase casein kinase 2 (CK2) was previously reported to activate inactive kinesin at the level of the single motor head domain, but the mechanism was unknown. Here, using a multidisciplinary approach, we discover that kinesin inactivation involves a specific conformational change in the molecule’s neck linker, which controls microtubule affinity and is reversed by CK2. Kinesin is the canonical plus-end microtubule motor and has been the focus of intense study since its discovery in 1985. We previously demonstrated a time-dependent inactivation of kinesin in vitro that was fully reversible by the addition of purified casein kinase 2 (CK2) and showed that this inactivation/reactivation pathway was relevant in cells. Here we show that kinesin inactivation results from a conformational change that causes the neck linker to be positioned closer to the motor domain. Furthermore, we show that treatment of kinesin with CK2 prevents and reverses this repositioning. Finally, we demonstrate that CK2 treatment facilitates ADP dissociation from the motor, resulting in a nucleotide-free state that promotes microtubule binding. Thus, we propose that kinesin inactivation results from neck-linker repositioning and that CK2-mediated reactivation results from CK2’s dual ability to reverse this repositioning and to promote ADP release.

Axonal transport: how high microtubule density can compensate for boundary effects in small-caliber axons.

Starling's Law at Small Scale: Surprising Sub-Cellular Adaptation of Cargo Transport to Opposition to Motion

Autoregulatory Mechanism for Dynactin Control of Processive and Diffusive Dynein Transport

Dynamic Force Adaptation of Lipid Droplets in Sub-Cellular Transport

Significance Kinesins are a superfamily of ATP-dependent motors that are important for a wide variety of microtubule-based functions in eukaryotic cells. Kinesins have evolved to allow variable tuning of their motor properties, but the link between molecular variation and motor function is largely unknown. To understand this link, we have studied an essential mitotic kinesin, kinesin-5, which is the target of anticancer drugs. We used cryo-electron microscopy to visualize directly sequential conformational changes of structural elements during the motor ATPase cycle. We have identified the contribution of kinesin-5–specific variations to motor function indicating that kinesins indeed are precisely tuned according to cellular function. This insight will be important in designing kinesin-specific inhibitors in different disease contexts. Kinesins are responsible for a wide variety of microtubule-based, ATP-dependent functions. Their motor domain drives these activities, but the molecular adaptations that specify these diverse and essential cellular activities are poorly understood. It has been assumed that the first identified kinesin—the transport motor kinesin-1—is the mechanistic paradigm for the entire superfamily, but accumulating evidence suggests otherwise. To address the deficits in our understanding of the molecular basis of functional divergence within the kinesin superfamily, we studied kinesin-5s, which are essential mitotic motors whose inhibition blocks cell division. Using cryo-electron microscopy and determination of structure at subnanometer resolution, we have visualized conformations of microtubule-bound human kinesin-5 motor domain at successive steps in its ATPase cycle. After ATP hydrolysis, nucleotide-dependent conformational changes in the active site are allosterically propagated into rotations of the motor domain and uncurling of the drug-binding loop L5. In addition, the mechanical neck-linker element that is crucial for motor stepping undergoes discrete, ordered displacements. We also observed large reorientations of the motor N terminus that indicate its importance for kinesin-5 function through control of neck-linker conformation. A kinesin-5 mutant lacking this N terminus is enzymatically active, and ATP-dependent neck-linker movement and motility are defective, although not ablated. All these aspects of kinesin-5 mechanochemistry are distinct from kinesin-1. Our findings directly demonstrate the regulatory role of the kinesin-5 N terminus in collaboration with the motor’s structured neck-linker and highlight the multiple adaptations within kinesin motor domains that tune their mechanochemistries according to distinct functional requirements.

Comprehensive structural model of the mechanochemical cycle of a mitotic motor highlights molecular adaptations in the kinesin family

Lipid droplets (LDs) are ubiquitous dynamic organelles that store and supply lipids in all eukaryotic and some prokaryotic cells for energy metabolism, membrane synthesis, and production of essential lipid-derived molecules. Interest in the organelle’s cell biology has exponentially increased over the last decade due to the link between LDs and prevalent human diseases and the discovery of new and unexpected functions of LDs. As a result, there has been significant recent progress toward understanding where and how LDs are formed, and the specific lipid pathways that coordinate LD biogenesis.

Biogenesis of the multifunctional lipid droplet: Lipids, proteins, and sites

Dynamic Force Adaptation of Lipid Droplets during Intracellular Transport in Cos1 Cells

How intracellular transport controls the probability that cargos switch at intersections between filaments is not well understood. In one hypothesis some motors on the cargo attach to one filament while others attach to the intersecting filament, and the ensuing tug-of-war determines which filament is chosen. We investigate this hypothesis using 3D computer simulations, and discover that switching at intersections increases with the number of motors on the cargo, but is not strongly dependent on motor number when the filaments touch. Thus, simply controlling the number of active motors on the cargo cannot account for in vivo observations that found reduced switching with increasing motor number, suggesting additional mechanisms of regulation. We use simulations to show that one possible way to regulate switching is by simultaneously adjusting the separation between planes containing the crossing filaments and the total number of active motors on the cargo. Heretofore, the effect of filament-filament separation on switching has been unexplored. We find that the switching probability decreases with increasing filament separation. This effect is particularly strong for cargos with only a modest number of motors. As the filament separation increases past the maximum head-to-head distance of the motor, individual motors walking along a filament will be unable to reach the intersecting filament. Thus, any switching requires that other motors on the cargo attach to the intersecting filament and haul the cargo along it, while motor(s) engaged on the original filament detach. Further, if the filament separation is large enough, the cargo can have difficulty proceeding along the initial filament because the engaged motors can walk underneath the intersecting filament, but the cargo itself cannot fit between the filaments. Thus, the cargo either detaches entirely from the original filament, or must dip to the side of the initial filament and then pass below the crossing filament.

Filament-Filament Switching Can Be Regulated by Separation Between Filaments Together with Cargo Motor Number

Cell-to-Cell Heterogeneity in Lipid Droplets Suggests a Mechanism to Reduce Lipotoxicity

Acyl-CoA synthetase 3 is recruited early to lipid droplet assembly sites on the ER, where it is required for efficient lipid droplet nucleation and lipid storage.

Acyl-CoA synthetase 3 promotes lipid droplet biogenesis in ER microdomains

Significance Neuroinvasive herpesviruses cause diseases in humans ranging from cold sores to central nervous system infections. Unlike most icosahedral viruses, herpesvirus capsids are surrounded by protein layers that lack polyhedral architecture. The outer layers are critical for herpesvirus infectivity. Although the disorganized layers are visible by electron microscopy, the protein topography of these layers remains unclear. We fused fluorophores to virus proteins and pinpointed their positions within virions at nanometer resolution. The findings reveal a complex and variable asymmetric architecture, shed light on herpesvirus assembly, and provide a foundation for visualizing viral particle dynamics during herpesvirus infection. The herpesvirus virion is a multilayered structure consisting of a DNA-filled capsid, tegument, and envelope. Detailed reconstructions of the capsid are possible based on its icosahedral symmetry, but the surrounding tegument and envelope layers lack regular architecture. To circumvent limitations of symmetry-based ultrastructural reconstruction methods, a fluorescence approach was developed using single-particle imaging combined with displacement measurements at nanoscale resolution. An analysis of 11 tegument and envelope proteins defined the composition and plasticity of symmetric and asymmetric elements of the virion architecture. The resulting virion protein map ascribes molecular composition to density profiles previously acquired by traditional ultrastructural methods, and provides a way forward to examine the dynamics of the virion architecture during infection.

Differential protein partitioning within the herpesvirus tegument and envelope underlies a complex and variable virion architecture

Improved network community structure improves function prediction

Extraction of hidden information by efficient community detection in networks

We propose a modularity optimization method, Mod-CSA, based on stochastic global optimization algorithm, conformational space annealing (CSA). Our method outperforms simulated annealing in terms of both efficiency and accuracy, finding higher modularity partitions with less computational resources required. The high modularity values found by our method are higher than, or equal to, the largest values previously reported. In addition, the method can be combined with other heuristic methods, and implemented in parallel fashion, allowing it to be applicable to large graphs with more than 10,000 nodes.

Intracellular transport: Relating single-molecule properties to in vivo function

Microtubule‐based molecular motors often work in small groups to transport cargos in cells. A key question in understanding transport (and its regulation in vivo) is to identify the sensitivity of multiple‐motor‐based motion to various single molecule properties. Whereas both single‐motor travel distance and microtubule binding rate have been demonstrated to contribute to cargo travel, the role of single‐motor velocity is yet to be explored. Here, we recast a previous theoretical study, and make explicit a potential contribution of velocity to cargo travel. We test this possibility experimentally, and demonstrate a strong negative correlation between single‐motor velocity and cargo travel for transport driven by two motors. Our study thus discovers a previously unappreciated role of single‐motor velocity in regulating multiple‐motor transport.

We previously discovered histones bound to cytosolic lipid droplets (LDs); here we show that this forms a cellular antibacterial defense system. Sequestered on droplets under normal conditions, in the presence of bacterial lipopolysaccharide (LPS) or lipoteichoic acid (LTA), histones are released from the droplets and kill bacteria efficiently in vitro. Droplet-bound histones also function in vivo: when injected into Drosophila embryos lacking droplet-bound histones, bacteria grow rapidly. In contrast, bacteria injected into embryos with droplet-bound histones die. Embryos with droplet-bound histones displayed more than a fourfold survival advantage when challenged with four different bacterial species. Our data suggests that this intracellular antibacterial defense system may function in adult flies, and also potentially in mice. DOI: http://dx.doi.org/10.7554/eLife.00003.001

A novel role for lipid droplets in the organismal antibacterial response

Motor proteins move cargoes along microtubules, and transport them to specific sub-cellular locations. Because altered transport is suggested to underlie a variety of neurodegenerative diseases, understanding microtubule based motor transport and its regulation will likely ultimately lead to improved therapeutic approaches. Kinesin-1 is a eukaryotic motor protein which moves in an anterograde (plus-end) direction along microtubules (MTs), powered by ATP hydrolysis. Here we report a detailed purification protocol to isolate active full length kinesin from Drosophila embryos, thus allowing the combination of Drosophila genetics with single-molecule biophysical studies. Starting with approximately 50 laying cups, with approximately 1000 females per cup, we carried out overnight collections. This provided approximately 10 ml of packed embryos. The embryos were bleach dechorionated (yielding approximately 9 grams of embryos), and then homogenized. After disruption, the homogenate was clarified using a low speed spin followed by a high speed centrifugation. The clarified supernatant was treated with GTP and taxol to polymerize MTs. Kinesin was immobilized on polymerized MTs by adding the ATP analog, 5'-adenylyl imidodiphosphate at room temperature. After kinesin binding, microtubules were sedimented via high speed centrifugation through a sucrose cushion. The microtubule pellet was then re-suspended, and this process was repeated. Finally, ATP was added to release the kinesin from the MTs. High speed centrifugation then spun down the MTs, leaving the kinesin in the supernatant. This kinesin was subjected to a centrifugal filtration using a 100 KD cut off filter for further purification, aliquoted, snap frozen in liquid nitrogen, and stored at -80 °C. SDS gel electrophoresis and western blotting was performed using the purified sample. The motor activity of purified samples before and after the final centrifugal filtration step was evaluated using an in vitro single molecule microtubule assay. The kinesin fractions before and after the centrifugal filtration showed processivity as previously reported in literature. Further experiments are underway to evaluate the interaction between kinesin and other transport related proteins.

3D Simulation of Filament-Filament Switching in Intracellular Transport

(Dated: February 27, 2012)We propose a new modularity optimization method, Mod-CSA, based on stochastic global op-timization algorithm, conformational space annealing (CSA). Our method outperforms simulatedannealing in terms of both eﬃciency and accuracy, ﬁnding higher modularity partitions with lesscomputational resources required. The high modularity values found by our method are higherthan, or equal to, the largest values previously reported. In addition, the method can be combinedwith other heuristic methods, and implemented in parallel fashion, allowing it to be applicable tolarge graphs with more than 10000 nodes.I. INTRODUCTION

Mod-CSA: Modularity optimization by conformational space annealing

The spatial organization of the cell depends upon intracellular trafficking of cargos hauled along microtubules and actin filaments by the molecular motor proteins kinesin, dynein, and myosin. Although much is known about how single motors function, there is significant evidence that cargos in vivo are carried by multiple motors. While some aspects of multiple motor function have received attention, how the cargo itself —and motor organization on the cargo—affects transport has not been considered. To address this, we have developed a three-dimensional Monte Carlo simulation of motors transporting a spherical cargo, subject to thermal fluctuations that produce both rotational and translational diffusion. We found that these fluctuations could exert a load on the motor(s), significantly decreasing the mean travel distance and velocity of large cargos, especially at large viscosities. In addition, the presence of the cargo could dramatically help the motor to bind productively to the microtubule: the relatively slow translational and rotational diffusion of moderately sized cargos gave the motors ample opportunity to bind to a microtubule before the motor/cargo ensemble diffuses out of range of that microtubule. For rapidly diffusing cargos, the probability of their binding to a microtubule was high if there were nearby microtubules that they could easily reach by translational diffusion. Our simulations found that one reason why motors may be approximately 100 nm long is to improve their ‘on’ rates when attached to comparably sized cargos. Finally, our results suggested that to efficiently regulate the number of active motors, motors should be clustered together rather than spread randomly over the surface of the cargo. While our simulation uses the specific parameters for kinesin, these effects result from generic properties of the motors, cargos, and filaments, so they should apply to other motors as well.

How Molecular Motors Are Arranged on a Cargo Is Important for Vesicular Transport

Kinesin-1 is a plus-end microtubule-based motor, and defects in kinesin-based transport are linked to diseases including neurodegeneration. Kinesin can auto-inhibit via a direct head-tail interaction, but is believed to be active otherwise. Here we report a tail-independent inactivation of kinesin, reversible by the disease-relevant signaling protein, casein kinase 2 (CK2). The majority of initially active kinesin (native or tail-less) loses its ability to bind/interact with microtubules in vitro, and CK2 reverses this inactivation (~ 4-fold) without altering kinesin’s single motor properties. This activation pathway does not require motor phosphorylation, and is independent of head-tail autoinhibition. In cultured mammalian cells, reducing CK2 expression, but not kinase activity, decreases the force required to stall lipid droplet transport, consistent with a reduction in the number of active motors. These results provide the first direct evidence of a protein kinase up-regulating kinesin-based transport, and suggest a novel pathway for regulating the activity of cargo-bound kinesin.

Caveolin (CAV) is an essential component of caveolae, cholesterol‐enriched invaginations of the plasma membrane of most mammalian cells. However, CAV is not restricted to plasma membrane caveolae, and pools of CAV are present in myriad intracellular membranes. CAV proteins tightly bind cholesterol and contribute to regulation of cholesterol fluxes and distributions within cells. In this context, we recently showed that CAV1 regulates the poorly understood process controlling mitochondrial cholesterol levels. Cholesterol accumulates in mitochondrial membranes in the absence of CAV1, promoting the organelle's dysfunction with important metabolic consequences for cells and animals. In this article, we suggest a working hypothesis that addresses the role of CAV1 within the homeostatic network that regulates the influx/efflux of mitochondrial cholesterol.

Mitochondrial Cholesterol: A Connection Between Caveolin, Metabolism, and Disease

Caveolin-1 Deficiency Causes Cholesterol-Dependent Mitochondrial Dysfunction and Apoptotic Susceptibility

Casein Kinase 2 Reverses Tail-Independent Inactivation of Kinesin-1

Intracellular transport via the microtubule motors kinesin and dynein plays an important role in maintaining cell structure and function. Often, multiple kinesin or dynein motors move the same cargo. Their collective function depends critically on the single motors’ detachment kinetics under load, which we experimentally measure here. This experimental constraint—combined with other experimentally determined parameters—is then incorporated into theoretical stochastic and mean-field models. Comparison of modeling results and in vitro data shows good agreement for the stochastic, but not mean-field, model. Many cargos in vivo move bidirectionally, frequently reversing course. Because both kinesin and dynein are present on the cargos, one popular hypothesis explaining the frequent reversals is that the opposite-polarity motors engage in unregulated stochastic tugs-of-war. Then, the cargos’ motion can be explained entirely by the outcome of these opposite-motor competitions. Here, we use fully calibrated stochastic and mean-field models to test the tug-of-war hypothesis. Neither model agrees well with our in vivo data, suggesting that, in addition to inevitable tugs-of-war between opposite motors, there is an additional level of regulation not included in the models.

Mechanical stochastic tug-of-war models cannot explain bidirectional lipid-droplet transport

High-resolution particle tracking shows a specific role for the dynein regulatory factor LIS1 in high-load axonal transport of large vesicles but no evidence for mechanical activation of opposite-directed motors.

High-resolution imaging reveals indirect coordination of opposite motors and a role for LIS1 in high-load axonal transport

LIS1 and Nude Permit Multiple Dynein Motors to Cooperate to Transport High Loads

Casein Kinase 2 Reverses Tail-Independent Inhibition of Kinesin-1

Cytoplasmic Dynein Travel Cut Short by a Neurodegenerative Mutation in its Tail

Non-Monotonic Force-Dissociation Rate Relation Improves Ensemble Performance of Multiple Molecular Motors

LIS1 Converts Dynein to a Persistent-force State: A Molecular Model to Explain Lissencephaly

In recent years, progress in the study of the lateral organization of the plasma membrane has led to the proposal that mammalian cells use two different organelles to store lipids: intracellular lipid droplets (LDs) and plasma membrane caveolae. Experimental evidence suggests that caveolin (CAV) may act as a sensitive lipid‐organizing molecule that physically connects these two lipid‐storing organelles. Here, we determine the sequences necessary for efficient sorting of CAV to LDs. We show that targeting is a process cooperatively mediated by two motifs. CAV's central hydrophobic domain (Hyd) anchors CAV to the endoplasmic reticulum (ER). Next, positively charged sequences (Pos‐Seqs) mediate sorting of CAVs into LDs. Our findings were confirmed by identifying an equivalent, non‐conserved but functionally interchangeable Pos‐Seq in ALDI, a bona fide LD‐resident protein. Using this information, we were able to retarget a cytosolic protein and convert it to an LD‐resident protein. Further studies suggest three requirements for targeting via this mechanism: the positive charge of the Pos‐Seq, physical proximity between Pos‐Seq and Hyd and a precise spatial orientation between both motifs. The study uncovers remarkable similarities with the signals that target proteins to the membrane of mitochondria and peroxisomes

Adenovirus transport via direct interaction of cytoplasmic dynein with the viral capsid hexon subunit.

Stepping, Strain Gating, and an Unexpected Force-Velocity Curve for Multiple-Motor-Based Transport

Many biological machines function in discrete steps, and detection of such steps can provide insight into the machines' dynamics. It is therefore crucial to develop an automated method to detect steps, and determine how its success is impaired by the significant noise usually present. A number of step detection methods have been used in previous studies, but their robustness and relative success rate have not been evaluated. Here, we compare the performance of four step detection methods on artificial benchmark data (simulating different data acquisition and stepping rates, as well as varying amounts of Gaussian noise). For each of the methods we investigate how to optimize performance both via parameter selection and via prefiltering of the data. While our analysis reveals that many of the tested methods have similar performance when optimized, we find that the method based on a chi-squared optimization procedure is simplest to optimize, and has excellent temporal resolution. Finally, we apply these step detection methods to the question of observed step sizes for cargoes moved by multiple kinesin motors in vitro. We conclude there is strong evidence for sub-8-nm steps of the cargo's center of mass in our multiple motor records.

Intracellular transport along microtubules is often bidirectional, employing multiple plus‐ and minus‐end directed motors. How cells regulate such transport in time and space is a fundamental but unsolved question in cell biology. A recent paper presents a new modeling approach to predict how much of transport can be understood just from our knowledge of the motors involved. The model can generate strikingly complex patterns of motion, mimicking key aspects of cargo transport in vivo. Previous studies had inferred that plus‐end motors on bidirectional cargoes are usually turned off when the minus‐end motors are engaged “and vice versa…. In the model, such motor coordination can arise from motors competing in a tug‐of‐war, without help from additional regulators. This new theoretical framework should stimulate much research that will help unravel whether regulation of intracellular transport is dominated by higher‐order control mechanisms or is achieved simply by tuning basic properties of the motors themselves.

We recently proposed that regulating the single‐to‐multiple motor transition was a likely strategy for regulating kinesin‐based transport in vivo. In this study, we use an in vitro bead assay coupled with an optical trap to investigate how this proposed regulatory mechanism affects dynein‐based transport. We show that tau’s regulation of kinesin function can proceed without interfering with dynein‐based transport. Surprisingly, at extremely high tau levels – where kinesin cannot bind microtubules (MTs) – dynein can still contact MTs. The difference between tau’s effects on kinesin‐ and dynein‐based motility suggests that tau can be used to tune relative amounts of plus‐end and minus‐end‐directed transport. As in the case of kinesin, we find that the 3RS isoform of tau is a more potent inhibitor of dynein binding to MTs. We show that this isoform‐specific effect is not because of steric interference of tau’s projection domains but rather because of tau’s interactions with the motor at the MT surface. Nonetheless, we do observe a modest steric interference effect of tau away from the MT and discuss the potential implications of this for molecular motor structure.

Tuning Microtubule‐Based Transport Through Filamentous MAPs: The Problem of Dynein

Consequences of Motor Copy Number on the Intracellular Transport of Kinesin-1-Driven Lipid Droplets

Background A great deal of sub-cellular organelle positioning, and essentially all minus-ended organelle transport, depends on cytoplasmic dynein, but how dynein's function is regulated is not well understood. BicD is established to play a critical role in mediating dynein function—loss of BicD results in improperly localized nuclei, mRNA particles, and a dispersed Golgi apparatus—however exactly what BicD's role is remains unknown. Nonetheless, it is widely believed that BicD may act to tether dynein to cargos. Here we use a combination of biophysical and biochemical studies to investigate BicD's role in lipid droplet transport during Drosophila embryogenesis. Methodology/Principal Findings Functional loss of BicD impairs the embryo's ability to control the net direction of droplet transport; the developmentally controlled reversal in transport is eliminated. We find that minimal BicD expression (near-BicDnull) decreases the average run length of both plus and minus end directed microtubule (MT) based transport. A point mutation affecting the BicD N-terminus has very similar effects on transport during cellularization (phase II), but in phase III (gastrulation) motion actually appears better than in the wild-type. Conclusions/Significance In contrast to a simple static tethering model of BicD function, or a role only in initial dynein recruitment to the cargo, our data uncovers a new dynamic role for BicD in actively regulating transport. Lipid droplets move bi-directionally, and our investigations demonstrate that BicD plays a critical—and temporally changing—role in balancing the relative contributions of plus-end and minus-end motors to control the net direction of transport. Our results suggest that while BicD might contribute to recruitment of dynein to the cargo it is not absolutely required for such dynein localization, and it clearly contributes to regulation, helping activation/inactivation of the motors.

BicaudalD Actively Regulates Microtubule Motor Activity in Lipid Droplet Transport

Motor-based intracellular transport and its regulation are crucial to the functioning of a cell. Disruption of transport is linked to Alzheimer's and other neurodegenerative diseases. However, many fundamental aspects of transport are poorly understood. An important issue is how cells achieve and regulate efficient long-distance transport. Mounting evidence suggests that many in vivo cargoes are transported along microtubules by more than one motor, but we do not know how multiple motors work together or can be regulated. Here we first show that multiple kinesin motors, working in conjunction, can achieve very long distance transport and apply significantly larger forces without the need of additional factors. We then demonstrate in vitro that the important microtubule-associated protein, tau, regulates the number of engaged kinesin motors per cargo via its local concentration on microtubules. This function of tau provides a previously unappreciated mechanism to regulate transport. By reducing motor reattachment rates, tau affects cargo travel distance, motive force, and cargo dispersal. We also show that different isoforms of tau, at concentrations similar to those in cells, have dramatically different potency. These results provide a well defined mechanism for how altered tau isoform levels could impair transport and thereby lead to neurodegeneration without the need of any other pathway.

Noise is a major problem in analyzing tracking data of cargos moved by molecular motors. We use Bayesian statistics to incorporate what is known about the noise in parsing the trajectory of a cargo into a series of constant velocity segments. Tracks with just noise and no underlying motion are fit with constant velocity segments to produce a calibration curve of fit quality versus average segment duration. Fits to tracks of moving cargos are compared to the calibration curves with similar noise. The fit with the optimum number of constant velocity states has the least number of segments needed to match the fit quality of the calibration curve. We have tested this approach using tracks with known underlying motion generated by computer simulations and with a specially designed in vitro experiment. We present the results of using this parsing approach to analyze transport of lipid droplets in Drosophila embryos.

Studying molecular motor-based cargo transport: what is real and what is noise?

The Lipid-Droplet Proteome Reveals that Droplets Are a Protein-Storage Depot

from In Vivo Models Protein-Mediated Fatty Acid Uptake: Novel Insights

ABSTRACT Upon entering a cell, alphaherpesvirus capsids are transported toward the minus ends of microtubules and ultimately deposit virus DNA within the host nucleus. The virus proteins that mediate this centripetal transport are unknown but are expected to be either viral tegument proteins, which are a group of capsid-associated proteins, or a surface component of the capsid itself. Starting with derivatives of pseudorabies virus that encode a fluorescent protein fused to a structural component of the virus, we have made a collection of 12 mutant viruses that lack either the VP26 capsid protein or an individual tegument protein. Using live-cell fluorescence microscopy, we tracked individual virus particles in axons following infection of primary sensory neurons. Quantitative analysis of the VP26-null virus indicates that this protein plays no observable role in capsid transport. Furthermore, viruses lacking tegument proteins that are nonessential for virus propagation in cell culture were also competent for axonal transport. These results indicate that a protein essential for viral propagation mediates transport of the capsid to the nucleus.

The Herpesvirus Capsid Surface Protein, VP26, and the Majority of the Tegument Proteins Are Dispensable for Capsid Transport toward the Nucleus

Guidance of Bidirectional Motor Complexes by mRNA Cargoes through Control of Dynein Number and Activity

Molecular motors as cargo transporters in the cell—The good, the bad and the ugly

As our knowledge of biological processes advances, we are increasingly aware that cells actively position sub-cellular organelles and other constituents to control a wide range of biological processes. Many studies quantify the position and motion of, for example, fluorescently labeled proteins, protein aggregates, mRNA particles or virus particles. Both differential interference contrast (DIC) and fluorescence microscopy can visualize vesicles, nuclei or other small organelles moving inside cells. While such studies are increasingly important, there has been no complete analysis of the different tracking methods in use, especially from the practical point of view. Here we investigate these methods and clarify how well different algorithms work and also which factors play a role in assessing how accurately the position of an object can be determined. Specifically, we consider how ultimate performance is affected by magnification, by camera type (analog versus digital), by recording medium (VHS and SVHS tape versus direct tracking from camera), by image compression, by type of imaging used (fluorescence versus DIC images) and by a variety of sources of noise. We show that most methods are capable of nanometer scale accuracy under realistic conditions; tracking accuracy decreases with increasing noise. Surprisingly, accuracy is found to be insensitive to the numerical aperture, but, as expected, it scales with magnification, with higher magnification yielding improved accuracy (within limits of signal-to-noise). When noise is present at reasonable levels, the effect of image compression is in most cases small. Finally, we provide a free, robust implementation of a tracking algorithm that is easily downloaded and installed.

Tracking single particles: a user-friendly quantitative evaluation

ABSTRACT The molecular mechanisms responsible for long-distance, directional spread of alphaherpesvirus infections via axons of infected neurons are poorly understood. We describe the use of red and green fluorescent protein (GFP) fusions to capsid and tegument components, respectively, to visualize purified, single extracellular virions and axonal assemblies after pseudorabies virus (PRV) infection of cultured neurons. We observed heterogeneity in GFP fluorescence when GFP was fused to the tegument component VP22 in both single extracellular virions and discrete puncta in infected axons. This heterogeneity was observed in the presence or absence of a capsid structure detected by a fusion of monomeric red fluorescent protein to VP26. The similarity of the heterogeneous distribution of these fluorescent protein fusions in both purified virions and in axons suggested that tegument-capsid assembly and axonal targeting of viral components are linked. One possibility was that the assembly of extracellular and axonal particles containing the dually fluorescent fusion proteins occurred by the same process in the cell body. We tested this hypothesis by treating infected cultured neurons with brefeldin A, a potent inhibitor of herpesvirus maturation and secretion. Brefeldin A treatment disrupted the neuronal secretory pathway, affected fluorescent capsid and tegument transport in the cell body, and blocked subsequent entry into axons of capsid and tegument proteins. Electron microscopy demonstrated that in the absence of brefeldin A treatment, enveloped capsids entered axons, but in the presence of the inhibitor, unenveloped capsids accumulated in the cell body. These results support an assembly process in which PRV capsids acquire a membrane in the cell body prior to axonal entry and subsequent transport.

Heterogeneity of a Fluorescent Tegument Component in Single Pseudorabies Virus Virions and Enveloped Axonal Assemblies

Building Complexity: An In Vitro Study of Cytoplasmic Dynein with In Vivo Implications

Regulation of Lipid-Droplet Transport by the Perilipin Homolog LSD2

Neutrophil Migration in Opposing Chemoattractant Gradients Using Microfluidic Chemotaxis Devices

Molecular motors are responsible for active transport and organization in the cell, underlying an enormous number of crucial biological processes. Dynein is more complicated in its structure and function than other motors. Recent experiments have found that, unlike other motors, dynein can take different size steps along microtubules depending on load and ATP concentration. We use Monte Carlo simulations to model the molecular motor function of cytoplasmic dynein at the single-molecule level. The theory relates dynein's enzymatic properties to its mechanical force production. Our simulations reproduce the main features of recent single-molecule experiments that found a discrete distribution of dynein step sizes, depending on load and ATP concentration. The model reproduces the large steps found experimentally under high ATP and no load by assuming that the ATP binding affinities at the secondary sites decrease as the number of ATP bound to these sites increases. Additionally, to capture the essential features of the step-size distribution at very low ATP concentration and no load, the ATP hydrolysis of the primary site must be dramatically reduced when none of the secondary sites have ATP bound to them. We make testable predictions that should guide future experiments related to dynein function.

Active transport is critical for cellular organization and function, and impaired transport has been linked to diseases such as neuronal degeneration. Much long distance transport in cells uses opposite polarity molecular motors of the kinesin and dynein families to move cargos along microtubules. It is increasingly clear that many cargos are moved by both sets of motors, and frequently reverse course. This review compares this bi-directional transport to the more well studied uni-directional transport. It discusses some bi-directionally moving cargos, and critically evaluates three different physical models for how such transport might occur. It then considers the evidence for the number of active motors per cargo, and how the net or average direction of transport might be controlled. The likelihood of a complex linking the activities of kinesin and dynein is also discussed. The paper concludes by reviewing elements of apparent universality between different bi-directionally moving cargos and by briefly considering possible reasons for the existence of bi-directional transport.

Hither and yon: a review of bi-directional microtubule-based transport

Effective neutrophil chemotaxis is strongly influenced by mean IL-8 concentration.

Intracellular molecular motor-driven transport is essential for such diverse processes as mitosis, neuronal function, and mitochondrial transport. Whereas there have been in vitro studies of how motors function at the single-molecule level, and in vivo studies of the structure of filamentary networks, studies of how the motors effectively use the networks for transportation have been lacking. We investigate how the combined system of myosin-V motors plus actin filaments is used to transport pigment granules in Xenopus melanophores. Experimentally, we characterize both the actin filament network, and how this transport is altered in response to external signals. We then develop a theoretical formalism to explain these changes. We show that cells regulate transport by controlling how often granules switch from one filament to another, rather than by altering individual motor activity at the single-molecule level, or by relying on structural changes in the network.

Intracellular actin-based transport: how far you go depends on how often you switch.

The core structures of many viruses move within cells by association with host cytoskeletal motor proteins; however, the mechanisms by which intracellular viral particles are transported toward sites of replication or the cell periphery at distinct stages of infection remain to be understood. The regulation of herpesvirus directional transport in sensory neurons was examined by tracking individual viral capsids within axons at multiple frames per s. After entry into axons, capsids underwent bidirectional and saltatory movement to the cell body independently of endosomes. A comparison of entry transport to a previous analysis of capsid axonal transport during egress revealed that capsid targeting in and out of cells occurs by modulation of plus-end, but not minus-end, motion. Entry transport was unperturbed by the presence of egressing virus from a prior infection, indicating that transport direction is not modulated globally by viral gene expression, but rather directly by a component of the viral particle.

Local modulation of plus-end transport targets herpesvirus entry and egress in sensory axons.

Switching between Microtubule- and Actin-Based Transport Systems in Melanophores Is Controlled by cAMP Levels

A Determinant for Directionality of Organelle Transport in Drosophila Embryos

The organelles that inhabit a typical eukaryotic cell are restless bodies, usually in a state of motion from one part of the cell to another. One of the surprising things about this organelle motion is that, although the opposite-polarity molecular motors kinesin and dynein move unidirectionally with respect to their cytoskeletal tracks — towards the ‘plus’ or ‘minus’ end of a microtubule, respectively — many of the transported cargos move bidirectionally and frequently reverse course. Examples of such cargos include mRNA particles, mitochondria, endosomes, herpes virus particles and lipid droplets. This motion suggests that both classes of motors attach to the same organelle, and raises the question: how does a cargo that can go in either direction get to the right place? Obviously, net transport is controlled: ‘on average’ a nucleus-bound cargo spends more time employing a minus-end directed dynein than a plusend kinesin. This control might occur in two ways. First, opposite motors could be engaged in a tug-of-war, so that regulation could control the transport bias by determining who is likely to win the struggle. This could involve modulating either force production, by altering enzymatic activity, or the average number of active motor molecules of a particular type bound to the cargo. Second, motors might be coordinated, so that they do not interfere with each other’s function. In this case, because each motor could be turned ‘on’ or ‘off’ independently, regulation would control net transport simply by keeping one set of motors ‘on’ longer. Recent work on Drosophila showed that opposite polarity motors moving lipid droplets are indeed coordinated [1], but the mechanism by which this coordination is achieved was unclear. Deacon et al. [2] have now addressed this issue with a new study of bidirectional pigment granule motion in cultured Xenopus melanophores, cells which are specialized to aggregate or disperse pigment to allow the animal to rapidly change its coloration. They describe a molecular interaction that could lie at the heart of coordination between opposite polarity motors. Clarifying the ramifications of this interaction and establishing its generality should dramatically accelerate our understanding of bidirectional microtubule-based motion. Studies in diverse systems have provided evidence favoring the ‘coordination’ hypothesis. In cell culture systems and also in Drosophila neurons in the whole animal, function-blocking antibodies or genetic alterations affecting dynein or the dynein-regulatory complex dynactin were found to impair plus-enddirected, as well as minus-end-directed, motion [3–5]. Similarly, antibody or genetic impairment of the plusend-directed motor kinesin affected minus-enddirected as well as plus-end-directed transport [3,6]. In the tug-of-war scenario, impairment of minus-enddirected motion should lead to enhanced plus-enddirected motion, given the reduced opposition to the plus-end motor activity. This was not observed. Although these observations suggested motor coordination, an alternative interpretation was that the motors are not in fact coupled, but that the minus-end impairment indirectly causes plus-end impairment, and vice versa. For example, removal of motor function might cause a ‘traffic jam’, with the ‘stuck’ cargos blocking the motion of other cargos. Alternatively, the experimental manipulations might have led to aberrant motor function, with the ‘impaired’ motor(s) in a ‘locked-up’ state, tightly bound to the microtubules, and opposing motion in both directions. These concerns have been addressed in a recent study which examined the bidirectional transport of lipid droplets in early Drosophila embryos [1]. The authors found that, not only did alteration of minus-enddirected motor activity alter plus-end-directed motion, under some circumstances it did so when the minusend-directed stalling forces were normal, proving that the motors were not aberrantly ‘locked-up’. Because only droplets not interacting with other cargos were studied, there was no issue of non-specific ‘traffic-jam’ inhibition. Further, these experiments showed that the p150Glued subunit of the dynactin complex plays a role in this coordination. Taken together, these studies make a strong case for a model in which there is coordination between opposite motors on the same cargo. How such coordination could be achieved at a molecular level has, however, been an entirely open question. One possibility was that the two classes of motors might not bind to a single cargo at the same time, for instance, if there were a single receptor that can tether either kinesin or dynein to the cargo, but not both simultaneously. Then, the motors could not interfere with each other, because they would not be on the cargo at the same time. While this would be an elegant way of achieving coordination, evidence from a number of systems points against it. First, using fluorescence microscopy to observe GFP-tagged dynein in Dictyostelium, Ma and Chisholm [7] found that, when bidirectional cargos reverse course, the dynein stays bound. Current Biology, Vol. 13, R320–R322, April 15, 2003, ©2003 Elsevier Science Ltd. All rights reserved. DOI 10.1016/S0960-9822(03)00237-9

Dynactin: Coordinating Motors with Opposite Inclinations Dispatch

The importance of lattice defects in katanin-mediated microtubule severing in vitro.

Pseudorabies virus (PRV), an alpha-herpesvirus, is capable of spreading between synaptically connected neurons in diverse hosts. In this report, two lines of experimentation are summarized that provide insight into the mechanism of virus spread in neurons. First, techniques were developed to measure the transport dynamics of capsids in infected neurons. Individual viral capsids labeled with green fluorescent protein (GFP) were visualized and tracked as they moved in axons away from infected neuronal cell bodies in culture during egress. Second, the effects of three viral membrane proteins (gE, gI and Us9) on the localization of envelope, tegument, and capsid proteins in infected, cultured sympathetic neurons were determined. These three proteins are necessary for spread of infection from pre-synaptic neurons to post-synaptic neurons in vivo (anterograde spread). Us9 mutants apparently are defective in anterograde spread in neural circuits because essential viral membrane proteins such as gB are not transported to axon terminals to facilitate spread to the connected neuron. By contrast, gE and gI mutants manifest their phenotype because these proteins most likely function at the axon terminal of the infected neuron to promote spread. These two sets of experiments are consistent with a model for herpesvirus spread in neurons first suggested by Cunningham and colleagues where capsids and envelope proteins, but not whole virions, are transported separately into the axon.

Directional spread of an alpha-herpesvirus in the nervous system.

Many cellular components are transported using a combination of the actin- and microtubule-based transport systems. However, how these two systems work together to allow well-regulated transport is not clearly understood. We investigate this question in the Xenopus melanophore model system, where three motors, kinesin II, cytoplasmic dynein, and myosin V, drive aggregation or dispersion of pigment organelles called melanosomes. During dispersion, myosin V functions as a “molecular ratchet” to increase outward transport by selectively terminating dynein-driven minus end runs. We show that there is a continual tug-of-war between the actin and microtubule transport systems, but the microtubule motors kinesin II and dynein are likely coordinated. Finally, we find that the transition from dispersion to aggregation increases dynein-mediated motion, decreases myosin V–mediated motion, and does not change kinesin II–dependent motion. Down-regulation of myosin V contributes to aggregation by impairing its ability to effectively compete with movement along microtubules.

Interactions and regulation of molecular motors in Xenopus melanophores

Many cargoes move bidirectionally, frequently reversing course between plus- and minus-end microtubule travel. For such cargoes, the extent and importance of interactions between the opposite-polarity motors is unknown. In this paper we test whether opposite-polarity motors on lipid droplets in Drosophila embryos are coordinated and avoid interfering with each other's activity, or whether they engage in a tug of war. To this end we impaired the minus-end transport machinery using dynein and dynactin mutations, and then investigated whether plus-end motion was improved or disrupted. We observe a surprisingly severe impairment of plus-end motion due to these alterations of minus-end motor activity. These observations are consistent with a coordination hypothesis, but cannot be easily explained with a tug of war model. Our measurements indicate that dynactin plays a crucial role in the coordination of plus- and minus-end–directed motors. Specifically, we propose that dynactin enables dynein to participate efficiently in bidirectional transport, increasing its ability to stay “on” during minus-end motion and keeping it “off” during plus-end motion.

Alpha herpesviruses infect the vertebrate nervous system resulting in either mild recurrent lesions in mucosal epithelia or fatal encephalitis. Movement of virions within the nervous system is a critical factor in the outcome of infection; however, the dynamics of individual virion transport have never been assessed. Here we visualized and tracked individual viral capsids as they moved in axons away from infected neuronal cell bodies in culture. The observed movement was compatible with fast axonal flow mediated by multiple microtubule motors. Capsids accumulated at axon terminals, suggesting that spread from infected neurons required cell contact.

Herpesviruses use bidirectional fast-axonal transport to spread in sensory neurons

Cytoplasmic dynein is a microtubule-based motor with diverse cellular roles. Here, we use mutations in the dynein heavy chain gene to impair the motor's function, and employ biophysical measurements to demonstrate that cytoplasmic dynein is responsible for the minus end motion of bidirectionally moving lipid droplets in early Drosophila embryos. This analysis yields an estimate for the force that a single cytoplasmic dynein exerts in vivo (1.1 pN). It also allows us to quantitate dynein-mediated cargo motion in vivo, providing a framework for investigating how dynein's activity is controlled. We identify three distinct travel states whose general features also characterize plus end motion. These states are preserved in different developmental stages. We had previously provided evidence that for each travel direction, single droplets are moved by multiple motors of the same type (Welte et al. 1998). Droplet travel distances (runs) are much shorter than expected for multiple motors based on in vitro estimates of cytoplasmic dynein processivity. Therefore, we propose the existence of a process that ends runs before the motors fall off the microtubules. We find that this process acts with a constant probability per unit distance, and is typically coupled to a switch in travel direction. A process with similar properties governs plus end motion, and its regulation controls the net direction of transport.

Dynein-mediated cargo transport in vivo. A switch controls travel distance.

Developmental Regulation of Vesicle Transport in Drosophila Embryos: Forces and Kinetics

We describe the design and construction of two different types of multiple-beam optical tweezers, each equipped with nanometer-resolution position detectors. Multiple optical traps can be created either by splitting a laser beam in two parts, based on its polarization, or time-sharing a single beam among several different locations. The advantages and disadvantages of optical tweezers based on either scheme are discussed, along with details of specific implementations. Various ways to detect microscopic movements of an optically trapped object are presented and compared, including designs that are relatively insensitive to absolute location of a trapped particle within the field of view. Two of many possible applications for such instruments are illustrated: the detection of molecular steps by kinesin motor molecules, and determinations of the stiffness of single microtubules.

Construction of multiple-beam optical traps with nanometer-resolution position sensing

The mission of the New DEEL is to create an action oriented partnership dedicated to inquiry into the nature and practice of democratic ethical educational leadership through sustained processes of open dialogue, right to voice, community inclusion, and responsible participation toward the common good. They strive to create an environment to facilitate democratic ethical decision-making in educational theory and practice which acts in the best interests of all students. In this first episode of the New DEEL Community Podcast series, Dr. Joan Shapiro (Temple University), Dr. Steven Gross (Temple University), Kevin Peters, Dr. Susan Shapiro (Touro College), Dr. Taryn Conroy, and Jennifer Antoni explore relevant issues facing educational leaders today in light of COVID-19 affecting schools across the nation.

Applying Turbulence Theory to Educational Leadership in Challenging Times

Next Steps in Our Journey of Understanding and Applying Turbulence Theory

Orienting Yourself for the Journey Into a Turbulent Educational Landscape

The effectiveness of Google Classroom in the self-contained chemistry classroom

In the last decade war, social conflicts, and environmental catastrophes in Asia, the Middle East and Africa have contributed to an increased stream of refugees to Europe. Sweden was no exception and the increased number of asylum seekers made heavy demands on municipalities, including school systems. School leaders and teachers in Europe experienced increasing diversity followed by new and complex challenges (see Tuters & Portelli, 2017). This exploratory study takes place in Sweden and includes interviews with four principals whose schools received a variety influx of refugee students, many of whom arrived as unaccompanied minors, during fall 2015 through spring 2016. We use Turbulence Theory as our theoretical framework. The article’s purpose is to explore how school leaders managed to adjust their organization in order to fulfill their responsibilities concerning newly arrived students during that period.

Turbulent Ports in a Storm: The Impact of Newly Arrived Students upon Schools in Sweden.

Being an Ethical Leader Means Taking Responsibility for Students’ Academic and Social Success

Democratic Ethical Educational Leadership: Reclaiming School Reform

Maintaining a Commitment to Democracy (in Spite of High-Stakes Standardized Testing) DONNAN STOICOVY

Currently, educational reform has been narrowly defined to mean a combination of essentialism and market forces, thereby removing from our national dialogue other philosophical traditions, each having its own rich tradition and potential for guiding policy and practice. The purpose of this article is to problematize the concept of a monolithic definition of reform by providing multiple perspectives and thereby creating the basis for a robust debate among those holding opposing ways of seeking what they call educational reform. Specifically, I propose to accomplish in three ways. First, I briefly describe four philosophical traditions that have shaped education reform debates for the past century along with a newer force that has energized the debate. Second, I demonstrate the marriage between two of these traditions and how their ascendency now threatens to eclipse all other perspectives, thereby precluding a robust democratic debate about the future of education in America. Third, I conclude with suggestions to bring other reform philosophies back into our national debate so that we can return to a democratic national dialogue.

Where's Houdini when you Need Him? Breaking Out of the U.S. Educational Reform Straightjacket to Reclaim our Democracy

Introduction * Why Ethical Educational Leadership? Christopher M. Branson and Steven Jay Gross PART 1 : Issues and Perspectives * The Essence of Professionalism Sigurdur Kristinsson * Ethical Leadership: A Critical Transformative Approach Carolyn Shields * The Purpose of Education Robert J. Starratt * Socio-Political Awareness Steven Jay Gross * Leadership, Sustainability and Ethics Mike Bottery * Seeking Social Justice Rachel McNae * Leading with Empathy Qian Haiyan and Allan Walker * A Concern for Caring Lea Kuusilehto-Awale * The Prevalence of Silence Kjersti Lien Holte PART II : Developing Ethical Educational Leadership * An Ethical Leadership Developmental Framework Nancy Tuana * The Interplay of Values Ross Notman * The Power of Personal Values Christopher M. Branson * Ethical Decision Making Joan Poliner Shapiro, Jacqueline A. Stefkovich and Kathrine J. Gutierrez * Managing Ethical Dilemmas Neil Cranston, Lisa C. Ehrich and Megan Kimber * Using Turbulence Theory to Guide Actions Steven Jay Gross * Maintaining Moral Integrity Christopher M. Branson * An Insight into the Nature of Ethical Motivation Michael Bezzina and Nancy Tuana * De-Constructing Ethical Motivation Christopher M. Branson PART III : Examples from the Field * Holistic and Moral Development of Educational Leaders Pauline E. Leonard, Tammy Schilling and Anthony H. Normore * A Measure of Ethics Lyse Langlois and Claire Lapointe * Ethical Responses to Educational Policies Stephen Jay Gross and Joan Poliner Shapiro * The Ethical Perspectives of Turkish School Leaders Mualla Aksu and Gamze Kasalak * Preparation of Integrity William C. Frick and John F. Covaleskie * Striving for Moral Purpose Charles Burford and Michael Bezzina * The Ethical Demands of Multiculturalism Katarina Norberg and Olof Johansson Conclusion * If It Isn't Ethical, It Isn't Leadership Christopher M. Branson Contributing Authors

Ethical dilemmas and their possible resolution are a consistent issue facing educational leaders at all levels in today’s pre-K through graduate schools. While these dilemmas are serious, they are not all of the same magnitude, and the question often relates to the intensity of any given issue. It is in this vein that turbulence theory1 has been successfully applied as an aid in understanding and responding to challenges of ethical decision making in educational settings around the world. This chapter will examine the origins of turbulence theory, the four levels of turbulence, and the use of the turbulence gauge, the underlying dynamics that escalate and reduce levels of turbulence, and turbulence theory’s relevance to ethical decision making for educators.

Editorial Board: Paul Begley Nipissing University, Canada Paul Bredeson University of Wisconsin-Madison, USA Charles Burford Australian Catholic University, Aust Margaret Grogan Claremont Graduate School, USA Catherine Hands Brock University, Canada Olof Johansson Umea University, Sweden Kenneth Leithwood OISE/UT, Canada Pauline Leonard Louisiana Tech, USA Katarina Norberg Umea University, Sweden Anthony Normore California Lutheran University, USA James Ryan OISE/UT, Canada Allan Walker Hong Kong Institute of Education, China Lindy Zaretsky Geneva Centre for Autism, Canada AT THE CROSSROAD: VENTURE PHILANTHROPY OR A DEMOCRATIC ETHICAL VISION FOR EDUCATIONAL LEADERSHIP?

AT THE CROSSROAD: VENTURE PHILANTHROPY OR A DEMOCRATIC ETHICAL VISION FOR EDUCATIONAL LEADERSHIP?

The New DEEL (Democratic Ethical Educational Leadership) and the Work of Reclaiming a Progressive Alternative in Educational Administration from PreK-20.

While we often write about adolescents as full of turmoil and angst, focusing on `student voice' instead highlights ways in which young people can learn democratic principles by sharing their opinions and working to improve school conditions for themselves and others. This article examines the connection between the types of student voice initiatives desired and the contexts in which student voice is pursued. Drawing upon cases from the USA and Australia, we suggest that turbulence theory can influence the way that student voice is received at a school and its ability to achieve desired goals. Student voice can help to increase the tension and focus on pressing issues when needed; it also can help to calm turbulence occurring within individual adolescents and also in school contexts that need resolution.

Ethical Leadership in Higher Education Admission: Equality vs. Equity.

Leadership Mentoring: Maintaining School Improvement in Turbulent Times

The purpose of this article is to describe the emergence of the New DEEL (Democratic-Ethical Educational Leadership) and the role it is attempting to play in confronting the excesses of the current accountability movement typified by massive standardized testing and No Child Left Behind legislation in the United States. This article depicts the choice facing the field of educational leadership that pits a top-down control regime, modeled after corporations on the one hand against a progressive, democratic-ethical alternative on the other hand. A brief account of the historic traditions of the latter and its ties to the cause of social justice is also offered. Representing the democratic-ethical tradition in this era, The New DEEL movement, originating in university departments of educational leadership and policy studies in the US, Canada, Australia, is portrayed. This account includes the New DEEL’s mission, emerging set of educational leadership skills, and recent accomplishments.

IEJLL: International Electronic Journal for Leadership in Learning

(Re-) Constructing a Movement for Social Justice in Our Profession, 10(31)

Promises Kept: Sustaining School and District Leadership in a Turbulent Era

EVALUATING THE EDUCATIONAL IMPACT OF PRE- AND POST- VISIT ACTIVITIES ON ELEMENTARY STUDENTS FOLLOWING A FIELD TRIP TO A UNIVERSITY GARDEN

The purpose of this paper is to analyze recent publications on accountability in order to develop a deeper understanding of both the types of accountability that are being discussed in the literature, and to uncover the philosophical underpinnings which drive these discussions. We utilize varying conceptions of democracy in an attempt to discern the underlying assumptions on which various conceptions of accountability rest – assumptions regarding the role of various community members in the education of its children; assumptions about the role of the state in the educational process; and even assumptions about the nature of human beings and human interactions. In doing so, we provide a conceptual framework which allows for a more substantive and explicit debate regarding education, accountability, and their roles in the democratic process.

Deconstructing Accountability Through the Lens of Democratic Philosophies: Toward a New Analytic Framework

Abstract While establishing a successful school reform agenda is difficult, sustaining innovation after the departure of the founding leader is even more challenging. This article describes a mentoring programme for leadership succession instituted at a reforming high school in the United States. This relationship was officially sponsored by the school district, and involved the founding principal (mentor) and her successor (protégé), who agreed to speak daily on the telephone and meet formally for approximately 3 hours each month over a 3-year period. During the 1999-2000 academic year data were collected in the form of interviews and artifacts. Findings showed this relationship concentrated on the school's reform agenda, that the mentor used a five-stage problem-solving dialogue, and that the new principal was able to work at the encounter, accommodation and educational leadership stages of development. The possible meaning of this model for leadership succession in other school settings is discussed

Sustaining change through leadership mentoring at one reforming high school

Beyond their own walls, middle schools are having a profound effect on the entire range of American schooling, K–12. However, the recent indictments of student achievement at the middle level (TIMSS, NAEP) have increased attention on middle schools in general, and leadership in particular. What are the essential skills and knowledge that are necessary to effectively administer a middle school in the new millennium? The purpose of this research is dedicated to discovering and highlighting the qualities of effective leadership from the perspectives of the principals themselves—“in their own words.” As a result of the data analysis, a model of leadership grounded in the concept of “developmental responsiveness” has emerged. This new paradigm is examined within the context of school improvement and is compared to what the literature and professional organizations identify as necessary characteristics.

From the Desk of the Middle School Principal: Leadership Responsive to the Needs of Young Adolescents

Finding Your Way in the Legislation Maze: How To Pass Legislation in Your State.

Incorporation: the most effective way to reduce your federal taxes.

DEVELOPMENT OF A HANDBOOK FOR SECONDARY SCHOOL INTERNSHIP PROGRAMS

Crisis in the Family. Three Approaches. New York (Gardner) 1980.

Abstract This study tested two hypotheses concerning the nature of family rules about affect which were derived from the systems models of Satir (1967, 1972); Satir, Stachowiak and Taschman (1975); Turner and Gross (1976); and Umana, Gross and Turner (1978). The major hypotheses examined were: 1) family members share common rules about how they should handle their affect and 2) family rules about handling affect differentiate families according to their level of adjustment. Fifty-four family triads of father, mother and an adolescent child filled out questionnaires designed to measure how family members believed that they should behave (ideal) in affective situations and also how they perceived themselves behaving (actual) in the same situations. The results indicated support for the first hypothesis but not for the second. Alternative explanations of the data were offered including the idea that the questionnaire tapped social norms.

Families' Affective Rules and Their Relationship to the Families' Adjustment.

Abstract In today's society a continual question plaguing people involved in dying marriages is, “Are our children better off if we stay together or if we divorce?” As family counselors we have met with numerous parents struggling with this decision. Actually, the issue for them is not whether people should choose to stay together or divorce, but rather, how people choose to stay together or divorce.

A note on the confounding of personality and social class characteristics in research on premature termination. A reply to Garfield.

Families' perceptions of an adolescent member's psychiatric hospitalization1

A Note on A Developmental Model for Training Family Therapists Through Group Supervision

A classification scheme is proposed that integrates previous outcome studies in psychotherapy. Studies are classified into one of three frameworks according to the question addressed, the assumptions made, and the experimental designs used. Strengths and weaknesses of the three frameworks are examined within the context of specific studies of outcome. Evidence from the three frameworks suggests an alternative formulation of the question about outcome and a new experimental design. Specifically, the design involves evaluating the effectiveness of psychotherapy with respect to a population of patients deemed appropriate for psychotherapy. This design avoids random assignment of patient to psychotherapist and permits the investigator to address the question of whether psychotherapists are effective with patients whom they regard as appropriate for their particular type of therapeutic intervention.

A Research Strategy for Evaluating the Effectiveness of Psychotherapy

Confounding of personality and social class characteristics in research on premature termination.

Methods currently used to investigate interaction during marital conflict limit the validity and generalizability qf findings concerning the determinants and consequences of couples' interaction styles. The respective advantages and limitations of two research strategies-the questionnaire and simulation strategiesare critically evaluated. The assumptions made by each approach concerning the nature of interaction and the implications of such assumptions for studying how couples cope with conflict are discussed in detail. Several methodological guidelines for developing future research are suggested.

Marital Interaction and Marital Conflict: A Critical Evaluation of Current Research Strategies.

Teaching a course in clinical psy chology so as to foster development of problem solving skills and atti tudes and behaviors such as auton omy, creativity, and independent thinking is reported by faculty mem bers of Ohio State University. Schwebel: Associate Professor (B.A., Antioch College; M.S., Ph.D., Yale). Gross: Assistant Pro fessor (B.A., Brooklyn College; M.A., Ph.D., Cincinnati). Clarren: Research Associate, The Urban In stitute, Washington, D.C. (A.B., Oberlin College; M.A., Ph.D., Ohio State).

Influence of critical signal regularity, stimulus event matrix, and cognitive style on vigilance performance.

A major issue in evaluating innovative teaching methods has been the selection of outcome criteria. With a goal of developing students' process skills, the authors taught a clinical psychology course to undergraduates. To evaluate the course's effectiveness, Shostrom's Personal Orientation Inventory was utilized. There were significant changes in students' scores on 6 of the 12 scales. The implication of utilizing outcome measures consonant with the goals of a particular course was examined.

Evaluation with the Personal Orientation Inventory of a Problem-Solving Approach in Teaching an Undergraduate Psychology Course

Two methods of investigating human information processing, the one focusing on the manipulation of experimental tasks and the other emphasizing individual differences, were compared. The design utilized the experimental tasks of Treisman and Riley (1969) while examining for individual differences on the basis of Witkin's field-articulation dimension. The findings of Treisman and Riley were replicated, while no differences were found among Ss categorized on the individual-difference dimension, suggesting that task variables were most important in performance requiring selective attention.

The portable rod-and-frame test and the short-form embedded-figures test: A combined index of the field-dependence dimension

This study traces the process of ‘‘identity formation’’ among the Namasudras , one of the most numerous agrarian castes of eastern Bengal, having a very low ritual ranking in the Hindu caste hierarchy. Once mostly boatmen and ﬁshermen, they became, by the late nineteenth century, settled agriculturists, reclaiming vast swamps and forests. The ‘‘community consciousness’’, which their ﬁrst organized protest movement in 1872 reﬂected and also reinforced, had long been growing. A decisive role here was that of radical, deviant Vaisnava sects, sharply critical of caste hierarchy. To these sects belonged, in the late nineteenth century, most Namasudra converts to Vaisnava faith. This, however, did not lead to any organized deﬁance of the institutional forms of caste domination.Thisdeﬁance, ﬁrst in 1872 , argues Bandyopadhyay, had much to do with the growth of settled agriculture, providing for Namasudras a relatively stable subsistence, and even making possible the rise of a group of afﬂuent cultivators; the afﬂuence, making them more conscious of their lowly social position, prompted them to an organized protest against it.

The Buffalo Medical Journal and Monthly Review of Medical and Surgical Science

Female convict cichlids, Cichlasoma nigrofasciatum, typically develop orange ventral coloration which males do not. We investigated the behavioural significance of this sexual dichromatism using both live and dummy stimulus fish. In our experiments, males were insensitive to variation in ventral coloration. Females, however, appeared to use this colour pattern as a visual cue. Females directed significantly more behaviour, including aggressive behaviour, towards more brightly coloured stimulus fish, as well as towards dummies with orange ventral coloration compared with those without. Bright females displayed the least aggression towards an intruding female of intermediate coloration. Thus, sexual dichromatism in the convict cichlid is shown to affect intrasexual aggression among females. Copyright 1998 The Association for the Study of Animal Behaviour.

Sexual dichromatism in convict cichlids: the ethological significance of female ventral coloration

Hydrogel application for improving soil pore network in agroecosystems. Preliminary results on three different soils

Use of an aqueous solution containing hypochlorous acid (HOCl) with pH value between 2.5 and 8, which further contains a proportion of amorphous silicon dioxide (SiO2), as a disinfectant.

Using a disinfectant based on aqueous solutions containing? Hypochlorous acid.

It is a method for treating foodstuffs, in particular vegetable-based, such as vegetables, salad and / or fruit, proposed wherein the food is washed with an aqueous solution and disinfected. In order to ensure a proper and medically safe disinfection of food while avoiding the oxidative deterioration thereof, the inventive method provides the following steps: - providing a means of electrochemical activation (ECA) disinfectant obtained a dilute water / electrolyte solution; - contacting the food with the disinfectant in neat or diluted form; - providing a particular aqueous solution of at least one health acceptable reducing agent and / or anti-oxidation agent, wherein the reducing or anti-oxidant has a sufficient concentration to neutralize the oxidative effect of the disinfectant; and - contacting the food with the solution of reducing or antioxidant. Then the food for can. B. be dried and optionally wrapped.

A method for manufacturing a Desinfektionsmittels on the basis of an aqueous solution of hypochlorous acid (Hypochlorsaure, chlorine (I) acid, HClO) with an HClO concentration between 1 and 1000 mg / l, a pH between 2.7 and 4.0 and proposed a redox potential of at least 1240 mV. In order to provide in particular for a high stability of the disinfectant under minimizes the risk of outgassing of chlorine gas, the invention provides that a solution of at least one hypochlorite (OCl

A process for producing a disinfectant on the basis of an aqueous HClO solution

Disclosed is a disinfectant on the basis of an electrochemically activated, dilute water / electrolyte solution and a process for the preparation of such a disinfectant, a dilute water / electrolyte solution is electrochemically activated. In order also in case of the same the durability of such a disinfectant of a large surface, as z. Example, be in an order of the disinfectant on the surfaces of the case, to increase, the invention provides that the disinfectant further comprises a proportion of silicon dioxide (SiO This fraction can in particular be chosen in such a way to provide for an increase in viscosity to gelation. The invention is also directed to the use of such a disinfectant.

Disinfectants on the basis of electrochemically activated water / electrolyte solutions, processes for their preparation and use thereof

The invention relates to a method for treating drinking water for animals, especially livestock, z. B. factory farming, wherein the drinking water disinfected and is provided to the animals. According to the invention harmless to health, a depot effect exhibiting disinfectants in the form of a means of electrochemical activation (ECA) is provided a dilute water / electrolyte solution such as a sodium or potassium chloride solution, and this disinfectant is added in provided as drinking water water to give the disinfected drinking water. According to another aspect of the invention to provide a sanitary acceptable reducing agent or antioxidant, wherein the reducing or anti-oxidant has a sufficient concentration to neutralize the oxidative action of the disinfectant. The reduction or anti-oxidant is then added if necessary, the applied with the disinfectant drinking water to the oxidative effect of the disinfectant temporarily, eg. to prevent as for the purpose of vaccination of the animals by means of an added to the drinking water vaccine.

Heterogeneous Reactions of NO3 Radicals With Polycyclic Aromatic Hydrocarbons and Alkane Monolayers as Proxies for Particles in the Atmosphere

An analysis of microparticle size distributions and relationships with slope and particle coarseness factors

Statements on the Contribution by Grisold et al. from Issue 2/2022

PurposeProcess redesign refers to the intentional change of business processes. While process redesign methods provide structure to redesign projects, they provide limited support during the actual creation of to-be processes. More specifically, existing approaches hardly develop an ontological perspective on what can be changed from a process design point of view, and they provide limited procedural guidance on how to derive possible process design alternatives. This paper aims to provide structured guidance during the to-be process creation.Design/methodology/approachUsing design space exploration as a theoretical lens, the authors develop a conceptual model of the design space for business processes, which facilitates the systematic exploration of design alternatives along different dimensions. The authors utilized an established method for taxonomy development for constructing the conceptual model. First, the authors derived design dimensions for business processes and underlying characteristics through a literature review. Second, the authors conducted semi-structured interviews with professional process experts. Third, the authors evaluated their artifact through three real-world applications.FindingsThe authors identified 19 business process design dimensions that are grouped into different layers and specified by underlying characteristics. Guiding questions and illustrative real-world examples help to deploy these design dimensions in practice. Taken together, the design dimensions form the “Business Process Design Space” (BPD-Space).Research limitations/implicationsPractitioners can use the BPD-Space to explore, question and rethink business processes in various respects.Originality/valueThe BPD-Space complements existing approaches by explicating process design dimensions. It abstracts from specific process flows and representations of processes and supports an unconstrained exploration of various alternative process designs.

The Business Process Design Space for exploring process redesign alternatives

This report summarizes a large-scale online workshop series focusing on the connection between digital innovation and business process management (BPM). The motivation behind our format was to complement the primarily conceptual claims in this field of research with in-depth insights from organizational practice. The format covered four consecutive onehour workshops, each involving an average number of 120 practitioners and several academics. Each workshop shed light on specific aspects that appear important in the context of digital innovation and BPM. We collected data by means of discussions during the sessions, as well as from two surveys completed respectively before and after the workshop. Based on our findings, we identify three research directions to advance research on the intersection of digital innovation and BPM. We suggest (1) exploring the role of BPM in digital innovation, (2) scoping digital innovation activities within BPM projects, and (3) aligning organizational structures to support BPM-driven digital innovation activities. We point to several concrete avenues for future empirical research in this field.

Digital Innovation and Business Process Management: Opportunities and Challenges as Perceived by Practitioners

The Five Diamond Method for Explorative Business Process Management

Process mining is a widely used technique to understand and analyze business process executions through event data. It offers insights into process problems but leaves analysts barehanded to translate these problems into concrete solutions. Research on business process management discusses both process mining and improvement patterns in isolation. In this paper, we address this research gap. More specifically, we identify six categories of process problems that can be identified with process mining and map them to applicable best practices of business processes. We analyze the relevance of our approach using a thematic analysis of reports that were handed in to the Business Process Intelligence Challenges over recent years, and observe the dire need for better guidance to translate process problems identified by process mining into suitable process designs. Conceptually, we position process mining into the problem and solution space of process redesign and thereby offer a language to describe potentials and limitations of the technique.

Process Mining Supported Process Redesign: Matching Problems with Solutions

BPM has developed strong capabilities to support the management and improvement of business processes. For example, the BPM Cases book (vom Brocke & Mendling, 2018) provides practical evidence across organizations and industries. It has also been stated that BPM has a strong potential to support the innovation of processes (vom Brocke & Schmiedel, 2015), but only a few methods and cases are actually available to support the exploration of new innovation opportunities. The term ambidextrous BPM has been coined (Rosemann, 2014), specifically accounting for the need to extend exploitative approaches of BPM by explorative ones (Badakhshan, Conboy, Grisold, & vom Brocke, 2019; Groß et al., in press).

Class Notes: Teaching the Five-Diamond Method for Explorative BPM

Business Process Management (BPM) is an approach adopted by many organizations for improving their business processes in order to serve their customers more efficiently and effectively. Literature on BPM offers a plethora of methods used as a guide when improving business processes. Some are promoted as methods for process reengineering, while others as methods for improvement, redesign, or innovation. The number of BPM methods is overwhelming, such that organizations are faced with the challenge to select one that best fits their needs. In this paper, we follow a systematic literature review approach to investigate the characteristics of existing BPM methods. We find that the ambition, nature and perspective of the methods are important to determine whether they can be used for radical or incremental process change. Our findings point to the lack of research done on methods for radical process change.

Exploring Explorative BPM - Setting the Ground for Future Research

Researching Information Systems Methods using Method Mining - A Case Study on Process Improvement Methods

Organizations seek to change the design of their business processes in order to respond to a changing and challenging environment. A wide variety of business process improvement methodologies exist which aim to support practitioners in this effort. However, the selection of an appropriate approach is by no means trivial. Ideally, the characteristics of the methodology applied should fit the characteristics of the process improvement project in order to yield the best results. In this research proposal, we outline how the design science research methodology (DSRM) is adopted to develop, test, and evaluate a meta-methodology for the selection of an appropriate business process improvement methodology.

About the Selection of a Business Process Improvement Methodology

TRANSFORMATION: Constructivism, Design Thinking, and Elementary STEAM

Using a massive, five-year database of its own employment history, Marriott found that the cost of certain rewards was offset by lower turnover. And so it took a comprehensive look at its entire rewards program to align compensation and benefits with its associates' needs; improve attraction and retention; enhance productivity; and increase its return on the billions of dollars it invests annually in people. It did this while demonstrating the bottom-line impact of the resultant strategy. © 2003 Wiley Periodicals, Inc.

Marriott makes the business case for an innovative total rewards strategy

Business executives around the world agree that attracting, retaining and motivating employees globally is a key business objective in the 21st century. Organizations that can provide mean-ingful motivational rewards to employees across cultures stand to gain a competitive advantage through their human capital. This article dis-cusses the need for companies to take a much broader view of pay and rewards as they form global organizations. Although companies will approach the issues differently depending on their industry, their organizational hierarchy and their business life cycle, some common key factors characterize successful global pay programs.

Teams won't be effective unless the team roles and goals are clarified and team members and leaders support the process. Team development must involve a partnership of HR strategists, line managers, and team members. Otherwise, as experience shows, teams will most likely fail to meet expectations. Every team champion has to face the following teamwork design challenges: reward and recognition; management processes and systems; individual and team competencies; organization; team and job design; work processes and business systems; values and cultures; and leadership. In addition to tackling these issues, organizations must take a holistic approach to pay for teams-reconsidering what they pay for and how their pay is positioned.

teams should be linked to success in the employee’s regular job as well as team contributions, ( while the variable pay portion should include ( ’after-the-fact’ compensation (cash and noncash ( recognition awards) for team results.&dquo; I One network respondent, writing with refer¡ ence to full-time/permanent teams in a manufac1 turing setting, emphasized these transition steps: (1) design the teams, (2) develop problem-solving capabilities and work accountabilities, and (3) establish performance measures and collect data for measuring progress against performance goals. &dquo;Once teams are familiar and hopefully comfortable with the performance measurements, there will be a desire to move to group rewards based on how the group impacts performance. Where teams

Compensation for Teams: How to Design and Implement Team-Based Reward Programs

In the brave new corporate landscape, companies are asking their employees to organize themselves in a new way that emphasizes cooperation over specialization: teams. In today’s dynamic organizations, designing work around teams-using a lateral work flow-is often more efficient than shepherding projects through myriad departmental hierarchies. But the switch from narrow jobs to broader, cross-functional roles requires organizations to take a fresh look at how they pay team members. An effective team pay program rewards members for the right reasons. Attempting to

The experiences of a handful of major companies show that certain business conditions make success with variable pay much more likely.

Before deciding on a new variable compensation program, compensation managers should find out which program will be most compatible with the company environment.

The approach described in this step-by-step account of how a parent company designed a performance-oriented compensation plan for a new acquisition may be applied in other situations as well.

The 10 most common organizational problems: getting to their source.

FAS expression inversely correlates with PTEN level in prostate cancer and a PI 3-kinase inhibitor synergizes with FAS siRNA to induce apoptosis

2260 Fatty Acid Synthase (FAS), a key enzyme of the fatty acid biosynthetic pathway, has been shown to be overexpressed in various types of human cancer, and is therefore, considered to be an attractive target for anti-cancer therapy. However, relatively little is known about the regulatory mechanisms of the FAS gene in human tumor, and understanding these mechanisms is of paramount interest to design intervention of the FAS enzymatic pathway. Thus far, several factors including androgen, epidermal growth factor (EGF), PTEN and p53 have been demonstrated to modulate the expression of the FAS gene in vitro , however, none of these results have been validated in the clinical setting. In the present study, by immunohistochemical analysis of 81 prostate cancer specimens, we demonstrate that expression of the tumor suppressor gene PTEN has a significant inverse correlation with FAS expression in vivo . Furthermore, we used siRNA to inhibit the PTEN gene expression in vitro and found that knocking down the PTEN gene leads to overexpression of FAS in vitro . Together, these results suggest that the tumor suppressor gene, PTEN, negatively regulates the expression of the FAS gene. Our immunohistochemical analysis followed by Cox regression analysis also revealed that the combination of PTEN and FAS gene expression was an independent prognostic marker for prostate cancer. These data underscore the prognostic importance of combination of the FAS and PTEN genes, and also point toward the clinical relevance of the PTEN-FAS pathway in prostate tumorigenesis. As an initial trial for therapeutic targeting, we also used siRNA specific to the FAS gene in vitro . Our results indicated that the treatment of prostatic tumor cells with FAS siRNA leads to growth inhibition followed by apoptosis. Furthermore, in order to explore the possibility that the PTEN signaling pathway can be utilized to synergize the FAS siRNA mediated apoptosis, we introduced FAS siRNA and PI3K inhibitor into prostate cancer cells, and found that the PI3K inhibitor indeed synergized the effect of siRNA leading to tumor cell death. These results provide a strong rationale for exploring the therapeutic use of an inhibitor of the PTEN signaling pathway in conjunction with the FAS siRNA to inhibit prostate tumor growth.

FAS expression inversely correlates with the expression of PTEN and an Akt inhibitor synergizes with FAS siRNA to induce apoptosis in prostate cancer cells

PTEN (phosphatase and tensin homologue deleted on chromosome 10) has been shown to be inactivated in a wide variety of cancers, and the role of this gene as a tumor suppressor has been well established. On the other hand, results of recent animal studies as well as clinical evidence indicate that PTEN is also involved in tumor metastasis suppression. Although PTEN is known to play a key role in controlling cell growth and apoptosis, how PTEN exerts the metastasis suppressor function remains largely unknown. Recently, a microarray analysis identified the Drg-1 gene (differentiation related gene 1) as one of the potential targets of PTEN. The Drg-1 gene has been shown to suppress tumor metastasis in animal models of prostate and colon cancer, and the expression of this gene is significantly reduced with advancement of prostate and breast cancers in clinical setting. In this study, we explored the possibility that PTEN controls tumor metastasis by regulating the expression of the Drg-1 gene. Our results indicate that overexpression of PTEN significantly augments the endogenous expression of Drg-1 protein, whereas inhibition of PTEN by small interfering RNA decreases Drg-1 in a dose- and time-dependent manner. We also found that the control of the Drg-1 gene by PTEN seems to be at the transcriptional level, and that a phospho-Akt inhibitor restores the Drg-1 expression, indicating that PTEN controls Drg-1 by an Akt-dependent pathway. Consistent with these results, our immunohistochemical analysis revealed that PTEN expression correlates significantly with Drg-1 in both prostate and breast cancer cases. Furthermore, combination of the two markers, PTEN and Drg-1, emerged as a significantly better predictor of prostate and breast cancer patient survival than either marker alone.

PTEN Up-Regulates the Tumor Metastasis Suppressor Gene Drg-1 in Prostate and Breast Cancer

PTEN (phosphatase and tensin homologue deleted on chromosome 10) has been shown to be inactivated in a wide variety of cancers, and the role of this gene as a tumor suppressor has been well established. On the other hand, results of recent animal studies as well as clinical evidence indicate that PTEN is also involved in tumor metastasis suppression. Although PTEN is known to play a key role in controlling cell growth and apoptosis, how PTEN exerts the metastasis suppressor function remains largely unknown. Recently, a microarray analysis identified the Drg-1 gene (differentiation related gene 1) as one of the potential targets of PTEN. The Drg-1 gene has been shown to suppress tumor metastasis in animal models of prostate and colon cancer, and the expression of this gene is significantly reduced with advancement of prostate and breast cancers in clinical setting. In this study, we explored the possibility that PTEN controls tumor metastasis by regulating the expression of the Drg-1 gene. Our results indicate that overexpression of PTEN significantly augments the endogenous expression of Drg-1 protein, whereas inhibition of PTEN by small interfering RNA decreases Drg-1 in a doseand time-dependent manner. We also found that the control of the Drg-1 gene by PTEN seems to be at the transcriptional level, and that a phospho-Akt inhibitor restores the Drg-1 expression, indicating that PTEN controls Drg-1 by an Akt-dependent pathway. Consistent with these results, our immunohistochemical analysis revealed that PTEN expression correlates significantly with Drg-1 in both prostate and breast cancer cases. Furthermore, combination of the two markers, PTEN and Drg-1, emerged as a significantly better predictor of prostate and breast cancer patient survival than either marker alone.

Advances in Brief PTEN UpRegulates the Tumor Metastasis Suppressor Gene Drg-1 in Prostate and Breast Cancer

Role of the putative tumor metastasis suppressor gene Drg-1 in breast cancer progression

Drg-1 was previously identified (N. van Belzen et al., Lab. Investig., 77: 85–92, 1997) as a gene that was up-regulated by the induction of differentiation in a colon carcinoma cell line in vitro. Subsequently, this gene was found to be regulated by several factors including hypoxia, androgen, p53, and N-myc. Recently, Drg-1 has also been shown to be involved in tumor progression in animals, although the clinical significance of its involvement remains to be investigated. To clarify the functional role of Drg-1 in prostate cancer, we examined a clinical archive of cancer specimens for the expression of Drg-1 by immunohistochemistry. We found that the expression of Drg-1 had a significant inverse correlation with the Gleason grading and the overall survival rate of patients. In particular, the gene expression in patients with lymph node or bone metastasis was significantly reduced as compared with those with localized prostate cancer, suggesting that the function of Drg-1 is negatively involved in metastatic progression of the disease. To further clarify the function of this gene in the advancement of prostate cancer, a spontaneous metastasis assay was performed in a severe combined immunodeficient (SCID) mouse model. We found that Drg-1 almost completely inhibited lung colonization of highly metastatic prostate cancer cells without affecting the growth of the primary tumors. These results strongly suggest that Drg-1 is a candidate metastasis suppressor gene for prostate cancer and may serve as a useful prognostic marker.

Advances in Brief The Drg-1 Gene Suppresses Tumor Metastasis in Prostate Cancer

Focal adhesion kinase (FAK) and Src have been shown to be overexpressed in colon cancer. We have studied the role of these two kinases in resistance to apoptosis. Adenovirus-containing FAK-CD (Ad-FAK-CD), a dominant-negative, COOH-terminal portion of FAK, was used to inhibit FAK and cause apoptosis. Colon cancer cell lines were more resistant to Ad-FAK-CD-induced detachment and apoptosis than the breast cancer cell line, BT474. Colon cancer cell lines overexpressed highly active Src and FAK. Ad-FAK-CD-induced apoptosis was significantly increased by PP2, an inhibitor of Src family kinases. Activation of caspase-3, down-regulation of FAK, and Src and AKT activities were demonstrated in Ad-FAK-CD + PP2-treated colon cancer cells undergoing apoptosis. The results suggest that FAK and Src are both important survival factors, playing a role in protecting colon cancer cell lines from Ad-FAK-CD-induced apoptosis. Dual inhibition of these kinases may be important for therapies designed to enhance the apoptosis in colon cancers.

Simultaneous inhibition of focal adhesion kinase and SRC enhances detachment and apoptosis in colon cancer cell lines.

Drg-1 was previously identified (N. van Belzen et al., Lab. Investig., 77: 85-92, 1997) as a gene that was up-regulated by the induction of differentiation in a colon carcinoma cell line in vitro. Subsequently, this gene was found to be regulated by several factors including hypoxia, androgen, p53, and N-myc. Recently, Drg-1 has also been shown to be involved in tumor progression in animals, although the clinical significance of its involvement remains to be investigated. To clarify the functional role of Drg-1 in prostate cancer, we examined a clinical archive of cancer specimens for the expression of Drg-1 by immunohistochemistry. We found that the expression of Drg-1 had a significant inverse correlation with the Gleason grading and the overall survival rate of patients. In particular, the gene expression in patients with lymph node or bone metastasis was significantly reduced as compared with those with localized prostate cancer, suggesting that the function of Drg-1 is negatively involved in metastatic progression of the disease. To further clarify the function of this gene in the advancement of prostate cancer, a spontaneous metastasis assay was performed in a severe combined immunodeficient (SCID) mouse model. We found that Drg-1 almost completely inhibited lung colonization of highly metastatic prostate cancer cells without affecting the growth of the primary tumors. These results strongly suggest that Drg-1 is a candidate metastasis suppressor gene for prostate cancer and may serve as a useful prognostic marker.

Solidago virgaurea (goldenrod) has traditionally been used as an anti-inflammatory herbal medicine for the treatment of various symptoms, including prostatic diseases. The plant has also been reported to have antibacterial, spasmolytic, and carminative properties. During the course of our screening for antineoplastic activities in various herbal plants, we found that the extract of S. virgaurea exhibits strong cytotoxic activities on various tumor cell lines. The active component mostly resides in the leaves of the plant and is soluble in water. When the extract was fractionated by a Sephadex G-100 column, the active fraction corresponded to a molecular weight of ~40,000. This cytotoxic activity is effective on various tumor cell lines, including human prostate (PC3), breast (MDA435), melanoma (C8161), and small cell lung carcinoma (H520). To examine the effect of the cytotoxic activity on tumor cells in vivo, we used the rat prostate cell line (AT6.1) and an SCID mouse model. AT6.1 cells were injected into the flank of SCID mice, and then the G-100 fraction of S. virgaurea was administered intraperitoneally or subcutaneously every 3 days. The size of the tumor was measured for up to 25 days. The growth of the tumor was significantly suppressed by the G-100 fraction at 5 mg/kg without any apparent side effects. Therefore, S. virgaurea is considered to be promising as an antineoplastic medicine with minimal toxicities.

Antineoplastic Activity of Solidago virgaurea on Prostatic Tumor Cells in an SCID Mouse Model

Zelladhäsionsmoleküle involviert in die Invasion von Nierenkarzinomzellen in die extrazelluläre Matrix - Cell Adhesion Molecules Involved in Invasion of Renal Carcinoma Cells into the Extracellular Matrix -

Acquisition of metastatic ability by prostate cancer cells is the hallmark of their lethal trait and outcome. However, the genetic alterations underlying the clinical progression and pathogenesis of prostate cancer are not well understood. Several studies involving loss of heterozygosity (LOH) and comparative genomic hybridization analysis have identified distinctively altered regions on various human chromosomes, and genomic imbalance of chromosome 20 was implicated in progression and recurrence of prostate tumors. To examine the role of chromosome 20 in prostate neoplasms, we introduced this chromosome into highly metastatic rat prostate cancer cells using the microcell‐mediated chromosome transfer technique. Introduction of the chromosome resulted in significant suppression of the metastatic ability of the hybrid cells, by as much as 98%, without any interference with the in vivo growth rate or tumorigenicity of primary tumor in SCID mice. Our STS‐PCR analysis on 10 hybrid clones indicates that the suppressor activity of chromosome 20 is located in the p11.23‐12 region. Further examination of the hybrid clones by experimental metastasis assay and histologic analysis as well as Matrigel invasion assay suggests the involvement of the suppressor region at an early stage of invasion and extravasation. We also investigated the status of the chromosome 20 suppressor region in pathology specimens from human prostate cancer patients and detected the frequent loss of this region in high‐grade tumors. These results suggest the presence of a putative suppressor gene on human chromosome 20 that is functionally involved in development of prostate cancer metastases. © 2001 Wiley‐Liss, Inc.

Identification of tumor metastasis suppressor region on the short arm of human chromosome 20

KAI1 is a metastasis suppressor gene which is capable of inhibiting the processes of tumor metastasis without affecting tumorigenicity per se. We found that etoposide, a topoisomerase II inhibitor, is able to activate the expression of the KAI1 gene in a dose-dependent manner in human prostate cancer cell lines, ALVA, DU145, and PC-3 as well as in human lung carcinoma cell A549. The activation of the KAI1 gene was mainly mediated by the c-Jun gene in the PC-3 and DU145 cell lines, while it was mediated by both p53 and c-Jun genes in the A549 cell line. These results suggest that the augmentation of the KAI1 gene expression is independently controlled by p53 and c-Jun at the transcriptional level in the human cancer cell lines. Furthermore, treatment of these cell lines with etoposide resulted in significant reduction of cellular invasion measured by the Matrigel invasion chamber. Because etoposide has been shown to be effective on advanced prostate cancer when used in combination with other regimens, our results provide further rationale to use this drug as an antimetastatic agent.

Activation of the tumor metastasis suppressor gene, KAI1, by etoposide is mediated by p53 and c-Jun genes.

Differential inhibition of renal cancer cell invasion mediated by fibronectin, collagen IV and laminin.

Much of the lethality of malignant neoplasms is attributable directly to their ability to develop secondary growths in organs at a distance from the primary tumor mass, whereas few patients die from their primary neoplasm. Little is known about the molecular mechanism of tumor metastasis, however, which is controlled by a variety of positive and negative factors. In the search for metastasis suppressor genes, we have used the microcell‐mediated chromosome transfer method and a rat prostate tumor model in SCID mice. When human chromosome 2 was introduced into the highly metastatic rat prostatic tumor cell, AT6.1, the metastatic ability of this cell was significantly (>99%) decreased in animals. An STS‐based PCR analysis for 8 hybrid clones indicates that the suppressor activity is located in the p25–22 region of the chromosome. Furthermore, the AT6.1 cell with human chromosome 2 showed a reduced ability to invade Matrigel, suggesting that the suppressor activity is involved in the step of tumor invasion during the progression of prostate cancer. We have also examined the status of the suppressor region on chromosome 2 in human prostate cancer specimens and found that this region was often lost in high‐grade tumors. These results suggest that the putative suppressor gene on chromosome 2 is functionally involved in the progression of human prostate cancer. Genes Chromosomes Cancer 28:285–293, 2000. © 2000 Wiley‐Liss, Inc.

Localization of a novel tumor metastasis suppressor region on the short arm of human chromosome 2

Sequence and Functional Analysis of the 5′-Flanking Region of the Mouse Growth Inhibitory Factor Gene

Differential gene expression in experimental hepatocellular carcinoma induced by woodchuck hepatitis B virus.

The effect of a series of antisense oligodeoxyribonucleotide [oligo(dN)] on the expression of the surface antigen (HBsAg) gene of human hepatitis B virus (HBV) was examined using hepatocellular carcinoma cells that contain integrated HBV genomes. Of a number of antisense oligo(dN)s tested, synthetic 15-mers directed at the cap site of mRNA and regions of the translational initiation site of the HBsAg gene were found to be highly effective and inhibited viral gene expression by as much as 96%. The inhibition was specific to the HBsAg gene and appeared to be at the level of translation. These results suggest a therapeutic potential for antisense oligo(dN) in the treatment of patients who are chronically infected with HBV.

Antisense oligodeoxyribonucleotides inhibit the expression of the gene for hepatitis B virus surface antigen.

Comparative biochemistry and physiology. B, Comparative biochemistry

Organ-specific distribution of isozymes of 5'-nucleotide phosphodiesterase in mouse.

Identification and nucleotide sequence of the minimal replicon of the low-copy-number plasmid pBS2.

L'invention comprend des procedes pour isoler des cellules de myelome multiple ainsi que des procedes de traitement de patients suspectes d'avoir des maladies de cellules plasmatiques anormales.

Essai pour capturer et détecter des cellules de myélome multiple circulantes à partir de sang

Procede de traitement d'un mammifere souffrant d'hypotension generale induite par une production interne d'oxyde nitrique provoquee par des endotoxines ou des cytokines. Le procede consiste a administrer un agoniste adrenergique α1 et une certaine quantite d'un inhibiteur de formation d'oxyde nitrique a partir de l'arginine, permettant de retablir la sensibilite contractile vasculaire par rapport aux agonistes adrenergiques alpha. L'arginine utilisee de preference est l'arginine a substitution NG (dont au moins un hydrogene sur un groupe amino guanidino est remplace par une autre espece moleculaire ou atomique). L'inhibiteur est administre a un animal souffrant d'une hypotension generale ainsi induite. Des inhibiteurs de derives d'arginine presentent de preference une configuration L et comprennent des sels d'addition pharmaceutiquement acceptables. Il est egalement possible de traiter un patient souffrant d'hypotension generale induite par une chimiotheraphie effectuee a l'aide de modificateurs de reponse biologiques tels que le facteur de necrose tumorale ou l'Interleukine-2. Il est aussi possible de soigner un mammifere souffrant d'hypotension generale induite par une endotoxine ou d'autres toxines bacteriennes, par exemple provoquee par un choc septique, par l'intermediaire d'un traitement avec des agonistes adrenergiques α?1? et un inhibiteur tel qu'un derive d'arginine, qui permet de retablir la sensibilite contractile vasculaire par rapport aux agonistes adrenergiques α1.

Inhibiteurs de synthese d'oxyde nitrique servant a potentialiser l'action de vasopresseurs chez certains patients hypotendus

Building Resilience in Children and their Communities Following Disaster in a Developing Country: Responding to the 2010 Earthquake in Haiti

Building Effective, Self Sustaining Programs for Traumatized Children and Families: (517292011-023)

PLAY IS THE WAY is a games based methodology for teaching social and emotional learning. PLAY IS THE WAY uses guided play, classroom activities and an empowering language. It is a methodology that we use at Hackham East Primary to develop, improve and entrench the personal and social capabilities of students. Our aim is for the students at Hackham East Primary to become self-motivated, self regulated learners in charge of their own learning and behaviour.

The Classroom-Based Intervention emphasizes a specific theme each week to allow children to construct safe places to express their stories and develop coping strategies in a group environment.

Healing in familiar settings: support for children and youth in the classroom and community.

Phase II Archaeological Investigations: Proposed Social Security Administration Building, Jamaica, Queens County, New York

The objectives of this work were to take the initial steps needed to develop a field programmable gate array (FPGA)- based wideband digital radiometer backend (>500 MHz bandwidth) that will enable passive microwave observations with minimal performance degradation in a radiofrequency-interference (RFI)-rich environment. As manmade RF emissions increase over time and fill more of the microwave spectrum, microwave radiometer science applications will be increasingly impacted in a negative way, and the current generation of spaceborne microwave radiometers that use broadband analog back ends will become severely compromised or unusable over an increasing fraction of time on orbit. There is a need to develop a digital radiometer back end that, for each observation period, uses digital signal processing (DSP) algorithms to identify the maximum amount of RFI-free spectrum across the radiometer band to preserve bandwidth to minimize radiometer noise (which is inversely related to the bandwidth). Ultimately, the objective is to incorporate all processing necessary in the back end to take contaminated input spectra and produce a single output value free of manmade signals to minimize data rates for spaceborne radiometer missions. But, to meet these objectives, several intermediate processing algorithms had to be developed, and their performance characterized relative to typical brightness temperature accuracy re quirements for current and future microwave radiometer missions, including those for measuring salinity, soil moisture, and snow pack.

Digital microwave radiometers replace as much of the conventional analog circuitry in a radiometer as possible with an analog-to-digital converter followed by a high speed Digital Signal Processing (DSP) stage. Digital technology adds capabilities to a radiometer that would otherwise be much more difficult (and often cost prohibitive) to include. The quality of each of the performance enhancements enabled by digital radiometry (e.g. spectral resolution, RFI detectability threshold, and full Stokes polarization purity) is dependent on certain aspects of the digital technology (e.g. number of bits of digitization, digitization oversampling rate, length of transverse digital filters, number of internal bits utilized by the DSP algorithm, and core memory and logic block sizes in the DSP chip). These factors are examined and current and projected radiometer performance capabilities estimated given the current and projected state of the art in DSP technology.

The Radio frequency Interference Survey of Earth (RISE) is a new type of instrument used to survey and characterize the presence of Radio Frequency Interference (RFI) that can affect microwave radiometers. It consists of a combined microwave radiometer and kurtosis spectrometer with broad frequency coverage and high temporal and spectral resolution. A K-Band airborne version has been built and flown across southeast Michigan. A kurtosis detector is included in RISE to reliably detect the presence of RFI, even at very low levels, and to aid in its characterization. A radiometer is included to measure the impact of the RFI on observed brightness temperature.

K-Band Radio frequency Interference Survey of Southeastern Michigan

1. University of Michigan2455 Hayward St., Ann Arbor, MI, 48109-2143 USA734-764-6561(V), 734-936-0503 (F), cruf@umich.edu(E)2. University of Central Florida, 3. National Oceanic and Atmospheric Administration, 4. NASA Marshall Space Flight CenterAbstractThe Hurricane Imaging Radiometer (HIRAD) is an innovative radiometer which offers new and unique remotely sensed observations of both extreme oceanic wind events and strong precipitation. It is based on the airborne Stepped Frequency Microwave Radiometer (SFMR) [Uhlhorn and Black, 2004]. The HIRAD instrument advances beyond the current nadir viewing SFMR to an equivalent wide-swath SFMR imager using passive microwave synthetic thinned aperture radiometer (STAR) technology [Ruf et al., 1988]. This sensor operates over 4-7 GHz, where the required tropical cyclone remote sensing physics has been validated by both SFMR and WindSat radiometer [Bettenhausen et al., 2006; Brown et al., 2006]. HIRAD incorporates a new and unique array antenna design along with several technologies successfully demonstrated by the Lightweight Rain Radiometer instrument [Ruf et al., 2002; Ruf and Principe, 2003]. HIRAD will be a compact, lightweight, low-power instrument with no moving parts that will produce wide-swath imagery of ocean winds and rain in hurricane conditions. Accurate observations of surface ocean vector winds (OVW) with high spatial and temporal resolution are required for understanding and predicting tropical cyclones. The Hurricane Imaging Radiometer (HIRAD) is an innovative architecture which offers new and unique remotely sensed observations of both extreme oceanic wind events and strong precipitation. It is based on the airborne Stepped Frequency Microwave Radiometer (SFMR), which is a proven remote sensing technique for observing tropical cyclone (TC) ocean surface wind speeds and rain rates. The proposed HIRAD instrument advances beyond the current nadir viewing SFMR to an equivalent wide-swath SFMR imagerusing passive microwave synthetic thinned aperture radiometer (STAR) technology combined with a a unique array antenna design. The overarching design concept of HIRAD is to combine the multi-frequency C-band observing strategy of the SFMR with STAR technology to produce a wide-swath imager. Single frequency STAR technology

THE HURRICANE IMAGING RADIOMETER (HIRAD): INSTRUMENT STATUS AND PERFORMANCE PREDICTIONS

We report evidence for the emission of non‐thermal microwave radiation by a deep Martian dust storm. The observations were made using an innovative detector that can discriminate between radiation of thermal and non‐thermal origin by measuring the high order moments of its electric field strength. Measurements with this detector, installed in a 34 m radio telescope of the Deep Space Network (DSN), were made for about 5 hours a day over a dozen days between 22 May and 16 June 2006. Non‐thermal radiation was detected for a few hours only when a 35 km deep Martian dust storm was within the field of view of the radio telescope on 8 June 2006. The spectrum of the non‐thermal radiation has significant peaks around predicted values of the lowest three modes of the Martian Schumann Resonance (SR). The SR results from electromagnetic standing waves formed in the concentric spherical cavity between the Martian surface and its ionosphere and forced by large‐scale electric discharge. Thus, the non‐thermal radiation was probably caused by electric discharge in the Martian dust storm.

Emission of non‐thermal microwave radiation by a Martian dust storm

A new microwave radiometer detector has been developed that is capable of detecting low levels of Radio Frequency Interference (RFI) and of reducing its effect on the measured brightness temperatures. The Agile Digital Detector (ADD) digitizes the pre-detection radiometer signal, performs digital sub band filtering, and then measures the first four moments of the signal’s probability density function. The second moment reproduces the square law output of a conventional analog detector. The ADD can discriminate between RFI and natural thermal emission signals using higher order moments of the signal. The ADD uses spectral filtering methods to remove the RFI.

Detection and Mitigation of Radio Frequency Interference Using a Digital Kurtosis Spectrometer/Detector

The design, error budget, and preliminary test results of a 50-56-GHz synthetic aperture radiometer demonstration system are presented. The instrument consists of a fixed 24-element array of correlation interferometers and is capable of producing calibrated images with 1deg spatial resolution within a 17deg wide field of view. This system has been built to demonstrate a performance and a design which can be scaled to a much larger geostationary Earth imager. As a baseline, such a system would consist of about 300 elements and would be capable of providing contiguous full hemispheric images of the Earth with 1 K of radiometric precision and 50-km spatial resolution. An error budget is developed around this goal and then tested with the demonstrator system. Errors are categorized as either scaling (i.e., complex gain) or additive (noise and bias) errors. Sensitivity to gain and/or phase error is generally proportional to the magnitude of the expected visibility, which is high only in the shortest baselines of the array, based on model simulations of the Earth as viewed from geostationary Earth orbit. Requirements range from approximately 0.5% and 0.3deg of amplitude and phase uncertainty, respectively, for the closest spacings at the center of the array, to about 4% and 2.5deg for the majority of the array. The latter requirements are demonstrated with our instrument using relatively simple references and antenna models, and by relying on the intrinsic stability and efficiency of the system. The 0.5% requirement (for the short baselines) is met by measuring the detailed spatial response (e.g., on the antenna range) and by using an internal noise diode reference to stabilize the response. This result suggests a hybrid image synthesis algorithm in which long baselines are processed by a fast Fourier transform and the short baselines are processed by a more precise (G-matrix) algorithm which can handle small anomalies among antenna and receiver responses. Visibility biases and other additive errors must be below about 1.5 mK on average, regardless of baseline. The bias requirement is largely met with a phase-shifting scheme applied to the local oscillator distribution of our demonstration system. Low mutual coupling among the horn antennas of our design is also critical to minimize the biases caused by crosstalk of receiver noise. Performance is validated by a three-way comparison between interference fringes measured on the antenna range, solar transit observations, and the system model.

Initial Results of the Geostationary Synthetic Thinned Array Radiometer (GeoSTAR) Demonstrator Instrument

A new type of microwave radiometer detector has been developed that is capable of identifying high and low levels of radio-frequency interference (RFI) and of reducing or eliminating its effect on the measured brightness temperatures. High-level, localized RFI can be easily identified by its unnatural appearance in brightness temperature imagery. Low-level or persistent RFI can be much more difficult to identify and filter out. The agile digital detector (ADD) can discriminate between RFI and natural thermal emission signals by directly measuring higher order moments of the signal than the variance that is traditionally measured. After detection, the ADD then uses spectral filtering methods to selectively remove the RFI. ADD performance is experimentally verified in controlled laboratory tests and in the field near a commercial air traffic control radar. High-level RFI is easily identified and removed. Very low level RFI contamination, with power levels as low as the radiometric measurement uncertainty of the radiometer, is also shown to be reliably detected and removed.

RFI detection and mitigation for microwave radiometry with an agile digital detector

The design, error budget, and preliminary test results of a 50-56 GHz synthetic aperture radiometer demonstration system are presented. The instrument consists of a fixed 24-element array of correlation interferometers, and is capable of producing calibrated images with 0.8 degree spatial resolution within a 17 degree wide field of view. This system has been built to demonstrate performance and a design which can be scaled to a much larger geostationary earth imager. As a baseline, such a system would consist of about 300 elements, and would be capable of providing contiguous, full hemispheric images of the earth with 1 Kelvin of radiometric precision and 50 km spatial resolution.

Performance Evaluation of the Geostationary Synthetic Thinned Array Radiometer (GeoSTAR) Demonstrator Instrument

A prototype of the Geostationary Synthetic Thinned Array Radiometer (GeoSTAR) is presented. GeoSTAR is a concept for a Y-array of correlation interferometers operating in bands from 50 GHz to 180 GHz which will for the first time provide high spatial resolution, continuous soundings of the earths atmosphere from geosynchronous orbit. This paper presents preliminary data from a small (24-element) 50-55 GHz prototype system which has been built under NASA's Instrument Incubator Program to demonstrate the basic technology and calibration techniques needed for the larger (300 element) spaceborne system. Images are synthesized by Fourier transform of interferometric data, and it is essential that the spatial response of each antenna in the array be well characterized. This has been achieved using a novel variant of a Potter horn antenna which minimizes embedding effects in a closely packed array. The array electronics consists of low-power MMIC receivers, built by JPL, and a high speed digital correlator, built by the University of Michigan. Calibration circuits include a phase-switched correlated noise reference which is injected behind the antenna array; circuitry to modulate the receiver noise temperature and gain; and local oscillator phase shifters which are used to negate correlator offsets and quadrature imbalances. An outline of the data processing is presented, along with the first images from this system

Initial results of the GeoSTAR prototype (Geosynchronous Synthetic Thinned Array Radiometer)

An error budget is presented to meet 1 Kelvin radiometric accuracy in a geostationary atmospheric sounder with 50 km spatial resolution on the earth. The gain and phase errors are weighted by the magnitude of visibility versus antenna separation, and requirements range between approx.0.5% and 0.3 degrees of amplitude and phase, respectively, for the closest spacings at the center of the array, and about 5% and 3 degrees for the majority of the array. The latter requirement is met by our design without any special testing or stabilizations by reference signals. The former is met using an internal noise diode reference and by measuring the detailed antenna patterns on the antenna range. Biases and other additive errors in the raw visibility samples must be below about 2 mK on average, and this requirement is met by a phase shifting scheme applied to the local oscillator distribution. An outline of the data processing is presented, along with the first images from this system.

2006 IEEE International Symposium on Geoscience and Remote Sensing

Initial Results of the Geosynchronous Synthetic Thinned Array Radiometer (GeoSTAR)

The Geostationary Synthetic Thinned Radiometer (GeoSTAR) is a new concept for a microwave sounder intended for geostationary satellite applications. A small ground based proof-of-concept prototype has been developed at the Jet Propulsion Laboratory under the Instrument Incubator Program. The prototype, which is a fully functional 50-GHz temperature sounder, is now complete and has been undergoing testing at JPL and at the Goddard Space Flight Center, and the results have exceeded all expectations. The system is both accurate and extremely stable, and realistic and accurate radiometric images of natural scenes have been obtained for the first time with such an aperture synthesis system. This is a breakthrough achievement, which is expected to lead to a space based version within a decade, and GeoSTAR is likely to become one of the payloads on NOAA’s next-generation geostationary satellites, the GOES-R series. We present some of the latest test results.

The Geostationary Synthetic Thinned Aperture Radiometer, GeoSTAR, is a new concept for a microwave atmospheric sounder intended for geostationary satellites such as the GOES weather satellites operated by NOAA. A small but fully functional prototype has recently been developed at the Jet Propulsion Laboratory to demonstrate the feasibility of using aperture synthesis in lieu of the large solid parabolic dish antenna that is required with the conventional approach. Spatial resolution requirements dictate such a large aperture in GEO that the conventional approach has not been feasible, and it is only now, with the GeoSTAR approach, that a GEO microwave sounder can be contemplated. Others have proposed GEO microwave radiometers that would operate at sub-millimeter wavelengths to circumvent the large-aperture problem, but GeoSTAR is the only viable approach that can provide full sounding capabilities equal to or exceeding those of the AMSU systems now operating on LEO weather satellites and which have had tremendous impact on numerical weather forecasting. GeoSTAR will satisfy a number of important measurement objectives, many of them identified by NOAA as unmet needs in their GOES-R pre-planned product improvements (P3I) lists and others by NASA in their research roadmaps and as discussed in a white paper submitted to the NRC Decadal Survey. The performance of the prototype has been outstanding, and this proof of concept represents a major breakthrough in remote sensing capabilities. The GeoSTAR concept is now at a stage of development where an infusion into space systems can be initiated, either on a NASA sponsored research mission or on a NOAA sponsored operational mission. GeoSTAR is an ideal candidate for a joint "research to operations" mission, and that may be the most likely scenario. Additional GeoSTAR related technology development and other risk reduction activities are under way, and a GeoSTAR mission is feasible in the GOES-R/S time frame, 2012-2014.

A new type of microwave radiometer detector has been developed that is capable of identifying low level Radio Frequency Interference (RFI) and of reducing or eliminating its effect on the measured brightness temperature. The Agile Digital Detector (ADD) can discriminate between RFI and natural thermal emission signals by directly measuring higher order moments of the signal than the variance that is traditionally measured. After detection, the ADD then uses spectral and temporal filtering methods to selectively remove the RFI. ADD performance has been experimentally verified and its performance characterized while connected to an airborne C-Band radiometer (the NOAA/ETL PSR) installed on a NASA WB-57 flying over major urban centers. Index Terms—microwave radiometer, radio frequency interference

The Geostationary Synthetic Thinned Aperture Radiometer (GeoSTAR) is a new concept for a microwave sounder, intended to be deployed on NOAA's next generation of geostationary weather satellites, GOES-R. A ground based prototype has been developed at the Jet Propulsion Laboratory, under NASA Instrument Incubator Program sponsorship, and is now undergoing tests and performance characterization. With the aperture synthesis approach used by GeoSTAR it is possible to achieve very high spatial resolutions even in the crucial 50-GHz temperature sounding band without having to deploy the impractically large parabolic reflector antenna that is required with the conventional approach. The technology and system design required for GeoSTAR are rapidly maturing, and it is expected that a space demonstration mission can be developed before the first GOES-R launch. GeoSTAR will be ready for operational deployment 2-3 years after that. The prototype developed under IIP implements a small version of the temperature sounding component of GeoSTAR, is fully functional as a sounder and has all of the features and capabilities of an operational system with the exception of spatial resolution. It therefore represents a complete proof of concept as well as significant risk reduction for a space implementation.

Preliminary details of a 2-D synthetic aperture radiometer prototype operating from 50 to 55 GHz will be presented. The laboratory prototype is being developed to demonstrate the technologies and system design needed to do millimeter-wave atmospheric soundings with high spatial resolution from Geostationary orbit. The concept is to deploy a large thinned aperture Y-array on a geostationary satellite, and to use aperture synthesis to obtain images of the Earth without the need for a large mechanically scanned antenna. The laboratory prototype consists of a Y-array of 24 horn antennas, MMIC receivers, and a digital cross-correlation subsystem

IGARSS 2004. 2004 IEEE International Geoscience and Remote Sensing Symposium

Prototype development of a geostationary synthetic thinned aperture radiometer, GeoSTAR

Background Burst fractures are rare in the pediatric population. There is limited information available on the best treatment for these injuries. The aims of our study were to evaluate the risk of spinal cord injury (SCI) and the potential for neurologic recovery associated with pediatric burst fractures; to compare sagittal alignment between nonoperative and operative treatment; and to determine whether functional outcomes are improved after surgery. Methods All pediatric patients who sustained thoracic or lumbar burst fractures at 2 institutions between 1991 and 2005 were identified. The medical records were reviewed for patient demographics, injury, treatment, and outcomes. Health Survey data were collected from a subset of patients in both the operative and nonoperative groups. Results Thirty-seven patients met the inclusion criteria. There were 17 male patients and 20 female patients, with an average age of 14.6 years (range, 6 to 18 y). Nine patients were treated nonoperatively and 28 patients were treated operatively. The nonoperative group was treated with hyperextension casting or bracing and showed progression of kyphotic deformity from 16.1 degrees at injury to 23.1 degrees at final follow-up. In patients treated operatively, the kyphotic deformity improved from 17.1 degrees at presentation to 7.2 degrees at final follow-up. Twenty-four patients were neurologically intact at presentation, whereas 13 presented with neurologic deficit. Six of 13 patients with SCI had some improvement. The risk of SCI was highest in patients with thoracic-level fractures. The risk of SCI did not correlate with canal compromise. There were no significant differences in functional outcome between the 2 groups. Conclusions The risk of neurologic injury in pediatric burst fractures of the spine may be more closely related to the level of injury (thoracic) than the degree of spinal canal compromise. Prognosis for recovery of neurologic injury is related to the severity of the initial neurologic injury. Level of Evidence Prognostic level 2.

Burst Fractures of the Thoracic and Lumbar Spine in Children and Adolescents

We studied the disco-vertebral interface and the blood supply of the intervertebral disks L3-L4, L4-L5, and L5-S1 of 5 human adult columns. Moreover, in order to investigate the discal vasculature, infusion of Japanese ink was used in 2 other adult columns, as well as immuno-histological methods in the L5-S1 disk of 4 adults and 2 infants. Our study confirms the paucity of discal vasculature in adults, by contrast with that of infants, but shows numerous defects in the subchondral vertebral plate, which are filled by vascularised medullary soft tissue and are in contact with the cartilaginous discal end plate. By these contacts, nutrients could reach the intervertebral disk, as suggested by other works, and as is the case in other cartilaginous structures of the body.

[Lumbar intervertebral disk. Intervertebral disk-vertebral body pathways and discal vascularization].

The purpose of this paper is to review the main data on the structure of the intervertebral disc, which are illustrated by personal documents. Applications in understanding the degenerative pathology are highlighted. The nucleus pulposus is the "central" component of the disc, highly hydrophilic, deformable but remaining of constant volume. It can be compared to a hydraulic chamber within the disc, sealed by the annulus fibrosus, which is a dense peripheric ring of concentric fibrous lamellae. The cartilaginous end plates (cranial and caudal) separate the disc from the adjacent subchondral vertebral bone. (Their involvement in the discal metabolism as well as the blood supply of the disc are developed elsewhere (see our companion article)).

Isolated mitral valve prolapse (MVP) may represent one end of a spectrum of disease involving dysfunction of multiple cardiac valves. Eighty‐nine consecutive patients with MVP diagnosed by two‐dimensional echocardiography (2‐D echo) were prospectively studied specifically to determine the incidence of tricuspid valve prolapse (TVP) and its clinical correlations. Criteria for prolapse of the atrioventricular (A‐V) valves by 2‐D echo included extension of the valve leaflets behind an imaginary line defining the valve annulus.

Tricuspid valve prolapse: A common occurrence in the click‐murmur syndrome

Many a secured lender, upon learning his borrower has filed a bankruptcy petition, succumbs to wistful rumination over what might have been had he only foreclosed earlier when he was still at liberty to do so. However, envying secured creditors who completed foreclosure sales prepetition may be premature, because those creditors may yet be dragged back into their borrower's bankruptcy and reunited with those lenders who were not as quick to pull the foreclosure trigger. The statutory source of this reunification lies in the fraudulent conveyance provisions of the bankruptcy laws, which have been invoked by the courts in the last two years to justify the invalidation of prepetition foreclosure sales of real property. The primary purpose of fraudulent conveyance law, from the time of its enactment by the Parliament of Queen Elizabeth I of England, always has been to prevent the debtor from taking deliberate action to hinder, delay, or defraud his creditors.1 The debtor most typically has run afoul of that law when he has attempted to remove his assets from the reach of his creditors by transfering them without consideration into the safe hands of his friends and relatives. The law has not been confined under either the Bankruptcy Code, the old Bankruptcy Act, or the Uniform Fraudulent Conveyance Act to cases where the debtor's subjective intent is to defraud his creditors, but has extended to cases where the objective result of the transaction is detrimental to creditors, whether

Real Property Foreclosure as a Fraudulent Conveyance: Proposals for Solving the Durrett Problem

As nearly everyone knows by now, the Seventh Circuit held in Levit v. Ingersoll Rand Financial Corp. (In re V.N. Deprizio Construction Co.)1 that, where a payment is made by the debtor more than 90 days but less than one year before bankruptcy in respect of a loan guarantied by an insider, the bankruptcy trustee may avoid the payment as an insider preference and seek recovery from the lender even though the lender is not itself an insider.2 I will

Waiving Subrogation Rights and Conjuring Up Demons in Response to Deprizio

ACID-CATALYZED DEUTERIUM EXCHANGE OF THE INDOLE RING PROTONS IN TRYPTAMINE DERIVATIVES

Urinary peptides inhibit DNA synthesis in vitro in certain cultured neoplastic cells.

Acid-catalyzed deuterium exchange of the indole ring protons in tryptamine derivatives.

Urinary peptides in muscular dustrophy. 3. Studies on chick embryo fibroblast cultures.

Letter: Improved cation-exchange separation of asparagine and glutamine in the presence of other amino acids.

Letter: Dermatomyositis: urinary chromatographic findings by alkaline autoanalysis for peptides (one case).

Urinary amino acid and peptide excretion patterns in patients with muscular dystrophy (Duchenne). A preliminary study with the autoanalyzer.

AUTOMATED ANALYSIS OF PHOSPHORUS-CONTAINING COMPOUNDS IN BIOLOGICAL MATERIALS. II. ACID-SOLUBLE NUCLEOTIDES.

The biochemical transformation of the morphothebaine to the morphine ring system.

Administration and Policy in Mental Health and Mental Health Services Research

Clinical practica are essential to the training and socialization of future clinical and counseling psychologists. When training expectations are not met, however, students may not be candid about these gaps, instead opting to grin and bear it. A sample of 321 doctoral psychology students responded to a survey that qualitatively and quantitatively assessed their expectations and actual training experiences at practicum. Results indicated that although many students received what they expected, a large minority did not. in areas ranging from work responsibilities to primary supervision. Implications for students, practicum, graduate programs, and the profession are discussed.

Student perspectives on clinical and counseling psychology practica

Negotiating Risk: Knowledge and Use of HIV Prevention by Persons With Serious Mental Illness Living in Supportive Housing

Inadequate folic acid intakes are prevalent among young women with neural tube defects.

Forty-eight pharmacists from the New York area were selected for specialized training in consultant clinical services to skilled nursing home facilities. A skills curriculum was developed, and the pharmacists participated in 15 training sessions which included lectures by nationally recognized experts, audiovisual presentations, and on-site clinical workshops. Evaluations were based upon clinical preprogram v. clinical postprogram testing, comparisons with clinical pharmacy experts, and attitudinal pre- and postprogram testing. It was found that the training course did improve the skills of the trainees but they still performed at a level below recognized clinical pharmacy experts. Future programs should stress fewer topics, but in more detail, and should focus upon monitoring techniques, laboratory results, and more on-site experiences.

Evaluation of a training program to improve clinical competencies of pharmacists serving skilled nursing facilities.

Chasing Storage during Flood Events in a Small, Multi-Jurisdictional Urban Watershed

Mechanically Joined PVC Well Products–A 15-Year Retrospective and a Look Towards the Future

This study investigates the feasibility of utilizing natural ventilation through operable windows to provide ventilation and summer cooling for an existing university dormitory building in marine west coastal climate (warm summer and mild winter). A hybrid research approach is used to evaluate the performance of proposed natural ventilation schemes, featuring building energy modeling with fully integrated airflow network, onsite blower door tests, and building utility data analysis. Both ventilation and thermal comfort are studied during the investigation. Simulation results demonstrate great potential of relying on properly controlled operable windows to supply ventilation and maintain indoor thermal comfort.

A FEASIBILITY STUDY OF NATURAL VENTILATION IN A MIDRISE STUDENT DORMITORY BUILDING

The benefits of trenchless technology are well understood by all in our industry—more cost-effective and less disruptive to streets, driveways, and landscaping. However, what is often less clear to many engineers and city officials faced with a wide selection of materials and processes is just what type of pipe is best suited for a particular trenchless application. This paper will present the engineering considerations involved in selecting thermoplastic water distribution pipe for directional drilling projects, focusing on assembly considerations, structural and flow performance, pressure-handling capacity, joint integrity, and compatibility with existing systems. These concepts are illustrated by the experiences at the University of Denver, where trenchless technology was successfully utilized on an irrigation system in an area where conventional pipe installation techniques were determined to be unsatisfactory.

Trenchless Case History—University of Denver's Use of High-Performance Restrained-Joint Water Distribution Pipe

Trenchless Installation of Restrained-Joint PVC Wastewater Pipe in Broomfield Colorado County Park

It seems everywhere one looks today the international power development markets look incredibly large. 150,000 MWs are needed in China, 50,000 MWs are needed in India, 15,000 MWs are needed in Indonesia, 25,000 MWs are needed in Brazil. The list goes on and on and according to current IPP ``mythology`` these markets offer potential projects providing ``huge`` internal rates of return on investment. Unfortunately, against this favorable market backdrop remain some irrefutable facts; (1) There is not enough fabrication capacity in the world to meet the current capacity addition requirements, (2) There is not enough debt capital in the world to finance all the required MWs, further portfolio considerations reduce this on a country-by-country basis. (3) There are not enough qualified development and operational personnel to develop, construct and manage all of these projects. This paper will attempt to cover the broad mosaic of issues relative to the international development market. The authors illuminate the risks that will help optimize development funds, and human resources as well as the issues surrounding construction and operations.

Faculty Opinions recommendation of Computational model of dynein-dependent self-organization of microtubule asters.

Accumulation of protein 3‐nitrotyrosine (3‐NT) and oxidation of the NO synthase (NOS) cofactor, tetrahydrobiopterin (BH4), occur during the pathogenesis of atherosclerosis. This study sought to quantify 3‐NT accumulation and BH4 oxidation in organs of ApoE−/− atherogenic mice, and also determine the specific contribution of inducible NOS (iNOS) to these processes. Although protein 3‐NT accumulation and BH4 oxidation were low or undetected in the heart, lung, liver and kidney of 3‐week old ApoE−/− mice, robust accumulation was evident after 24 weeks on an atherogenic diet. Since 3‐NT accumulation was diminished in the heart, lung and liver of ApoE−/−iNOS−/− mice, iNOS‐derived species are involved in this reaction. iNOS deletion also protected against BH4 oxidation in the heart, lung and kidney of atherogenic ApoE−/− mice, but not the brain or liver. These findings demonstrate that iNOS‐derived species are increased in atherosclerotic ApoE−/− mice and contribute differentially to protein nitration and BH4 oxidation. Since BH4 oxidation can switch the predominant NOS product from NO to superoxide, we predict that progressive NOS uncoupling is likely to drive atherogenic vascular dysfunctions.

Contribution of inducible nitric oxide synthase to protein tyrosine nitration and biopterin oxidation in ApoE‐null mice

Nitric oxide (NO) modulates the activity of cyclooxygenase (COX) isoforms, thereby varying the biological levels of important cell signaling arachidonate‐derived eicosanoids. The complex chemistry of NO and NO‐derived species results in interactions with COX that either activates or suppresses its activity. We show that inducible NO synthase (iNOS) and COX‐1 co‐localize in atherosclerotic lesions from ApoE‐null mouse aortae. Tyr nitration in COX‐1 occurred in aortic lesions, but was markedly reduced in adjacent non‐involved tissue. The absence of 3‐NT in lesions from iNOS/ApoE double‐null mice confirmed that NO derived from iNOS is essential for 3‐NT modification of COX‐1. Mass spectrometric studies specifically identified Tyr385 in the active site as a 3‐NT modification site in purified COX‐1, following peroxynitrite exposure. Our findings indicate that COX‐mediated prostaglandin E2 synthesis is increased in cultured iNOS‐null versus iNOS‐expressing mouse aortic smooth muscle cells. These results indicate that NO derived from iNOS markedly suppresses COX activity in vascular cells. The extent to which iNOS‐dependent nitration of Tyr in COX‐1 contributes to perturbed eicosanoid biosynthesis in human atherosclerotic lesions awaits future investigations.

Inducible nitric oxide synthase mediates cyclooxygenase nitration and eicosanoid production

The mechanism by which the inflammatory enzyme cyclooxygenase‐1 (COX‐1) deactivates remains undefined. This study aimed to determine stabilizing parameters of COX‐1 and identify factors leading to COX‐1 modification and loss of function by peroxynitrite (ONOO−). Purified COX‐1 activity was improved when solubilized in β‐octylglucoside (rather than Tween‐20 or CHAPS) and reconstituted with hemin chloride (rather than hematin). Following ONOO− exposure, holoCOX‐1 (containing heme) could not metabolize arachidonic acid, whereas apoCOX‐1 (without heme) pre‐treated with ONOO− was fully active following heme reconstitution. ONOO−‐deactivation of holoCOX‐1 was manifested as heme loss, protein unfolding, aggregation and nitration. ONOO− compromised the structure in holoCOX‐1 rather than apoCOX‐1, since limited proteolysis exposed a peptide containing Tyr385 and proximal His388 only when heme was present. Tandem mass spectrometric analysis of denatured and fully digested COX‐1 following ONOO‐ treatment revealed nitration of Tyr385 in holoCOX‐1 but not in apoCOX‐1. Since nitration was targeted to Tyr385 and levels of nitration and multimer formation were increased in holoCOX‐1 compared to apoCOX‐1, we conclude that the heme plays a role in catalyzing these processes and in the demise of COX‐1.

Heme catalyzes tyrosine nitration and inactivation of cyclooxygenase‐1 by peroxynitrite

[Effect of pacing on the function of the cardiovascular system in ischemic heart disease and pathological bradycardia].

[Hemodynamic changes in patients with ischemic heart disease and functional disorders of the conduction system occurring with bradycardia].

[Pattern of various hemodynamic parameters in ischemic heart disease and hypertension].

 Introduction: Multiple myeloma (MM) develops from indolent stages monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Precursor conditions are incidentally diagnosed and require invasive bone marrow (BM) biopsies for complete characterization, highlighting the urgent need for improved early detection methods. Minimally invasive blood biopsies to measure circulating multiple myeloma cells (CMMCs) as markers of MM disease development are a promising solution to this unmet need. Here, we present our novel method CatchTheFISH, for whole genome sequencing (WGS) of CMMCs that enables genomic profiling and WGS based cytogenetic analyses from enriched liquid biopsy samples. Application of WGS in a cohort of 20 patients, revealed CMMCs were of tumor origin and able to faithfully match BM sequencing results and detect 100% of clinically reported events.
 Methods: Peripheral blood from 110 SMM patients from the PCROWD observational study (Dana-Farber Cancer Institute IRB #14-174) was collected and processed on CellSearch system (Menarini Silicon Biosystems), with enrichment and enumeration of CMMCs based on CD138+38+CD45-19- immunophenotype. In 20 patients, CMMCs and white blood cells were sorted for library construction, quantification and WGS on Illumina NovaSeq6000. Mutation analyses were performed with the cancer genome analysis pipelines of the Broad Institute.
 Results: CMMCs were detected in 84% of SMM patients enrolled in the study, with a median count of 13 CMMCs (range 0 to 43836). We first demonstrated the concordance of WGS results obtained from CMMCs with BM. In 100% of patients tested with paired BM and CMMCs (n = 8), we observed full agreement in structural event calling between our samples and clinical reports, including translocations and CNAs (trisomies, tetrasomy, monosomy 13 and 1q gain/amplification). Next, we showed WGS of CMMCs provided increased diagnostic yield compared to BM biopsy for the detection of structural events and MM-associated driver mutations. In 7 patients (88%) we detected additional aberrations not found by FISH. Unknown translocation events of IGH-MYC and t(14;20) were distinguished in two patients. Additionally, our method enabled detection of MM driver mutations. Three patients (38%) were found to harbor RAS mutations (KRAS and NRAS) in BM samples, which were also validated in matched CMMCs. Finally, we assessed a validation cohort of 12 SMM patients with CMMCs only. WGS detected comprehensive mutation data across all scales including clinically relevant translocations, trisomies, CNAs and mutations.
 Conclusion: Our findings provide proof of principle that capture and genomic profiling of CMMCs could be a robust surrogate to BM biopsy, allowing minimally invasive detection and monitoring of disease, unlocking the clinical potential of liquid biopsies for MM diagnostics.
 Citation Format: Ankit K. Dutta, Jean-Baptiste Alberge, Elizabeth D. Lightbody, Romanos Sklavenitis-Pistofidis, Cody J. Boehner, Tarek H. Mouhieddine, Anna Cowan, Nang Kham Su, Erica M. Horowitz, Andrew Dunford, Chip Stewart, Ziao Lin, Laura Hevenor, Hadley Barr, Amanda Cao, Ornkleaw Zepp, Thai Bui, Steve Gross, Daniel Auclair, Gad Getz, Irene M. Ghobrial. Genome sequencing of circulating multiple myeloma cells for minimally invasive molecular characterization of precursor disease pathology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 640.

Abstract 640: Genome sequencing of circulating multiple myeloma cells for minimally invasive molecular characterization of precursor disease pathology

Monitoring Plasma Cells and Clonal Emergence through Genome Sequencing of Circulating Tumor Cells for Minimally Invasive Molecular Characterization of Multiple Myeloma

 Introduction: Multiple Myeloma (MM) is an incurable hematologic malignancy characterized by the abnormal growth of clonal plasma cells in the bone marrow (BM). In most cases MM develops from early, asymptomatic disease stages known as Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM). Despite effective new therapies, most MM patients inevitably relapse and require further treatment, highlighting the need for better early detection methods for precursor patients and targeted interventions to prevent early disease from progressing.
 The initial diagnosis of MGUS/SMM remains an incidental process following the identification of increased clonal immunoglobulin in the blood. BM biopsy is the gold standard for diagnosis and monitoring of MM progression, but is intrusive, painful, and comes with possible secondary complications for patients. Consequently, repeated assessment is not a feasible option for MGUS and SMM patients who are asymptomatic. Here we tested the utility of circulating multiple myeloma cells (CMMCs) from non-invasive blood biopsy to accompany BM as a method to monitor disease development, by enumerating CMMCs from MGUS/SMM patients.
 Methods: Peripheral blood from 185 precursor patients (75 MGUS and 110 SMM) from the Dana-Farber Cancer Institute observational PCROWD study (IRB #14-174) was collected in CellRescue TM Preservative Tubes and processed on the CellSearch CellTracks Autoprep system using the CMMC assay kit using 4mL of blood. This assay employs the enrichment of CMMCs through the immunophenotype of CD138 +CD45 -19 -, and leukocyte exclusion based on CD45 +CD19 +. Nucleated cells were identified using DAPI staining. The CellTracks Analyzer II fluorescence microscope system was subsequently used to scan captured CMMC cartridges, with software allowing the automated scoring and enumeration of CMMCs. Additional molecular analyses were carried out on SMM patients. Briefly, minipools of CMMCs were sorted by DEPArray and underwent whole genome amplification using Ampli1 kit, PCR-free library construction, quantification and low pass whole genome sequencing (~0.5x) on the Illumina HiSeq2500. To assess whether molecular analyses can be performed to detect hyperdiploidy as a genomic biomarker of MM disease, ichorCNA analyses was performed to determine copy number variant (CNV) events and infer tumour fraction.
 Results: CMMCs were detected in 27% of MGUS patients collected, with a median count of 2 CMMCs (range 0 to 1328). Comparably, CMMCs were detected in 57% of SMM patients, with a median enumeration of 13 CMMCs (range 0 to 43836). Enumeration of CMMCs illustrated a correlation with clinical measure of disease including the International Myeloma Working Group 2/20/20 risk stratification model. A higher CMMC count was associated with increasing risk group based on the 3-risk factor model, with a median of 5, 29 and 59 CMMCs detected at low, intermediate, and high-risk SMM groups, respectively. CMMC counts were significantly increased at intermediate (P = 5.0 x 10 -4) and high-risk stages (P = 3.7 x 10 -3) compared to low-risk.
 While enumeration provides a correlative measure of CMMCs that may be of tumor origin, downstream molecular characterization can confirm MM-associated genetic alterations. At the precursor stages, a low tumour burden is evident clinically, thus both normal and malignant plasma cells are present. Therefore, to determine the concordance between bone marrow and peripheral blood CMMCs, we performed genomic analyses to identify arm level gain or loss events. Molecular analyses of CMMCs was carried out in patients who had matched BM and clinical fluorescent in situ hybridization (FISH) results. We showed that CMMCs can capture 100% of clinically annotated BM FISH CNV events. Furthermore, CMMC samples identified additional yield, with further CNVs identified that were not observed by FISH. In cases that did not have BM biopsy results, sequencing of CMMCs revealed the existence of genetic aberrations.
 Our results demonstrate clinical correlation and molecular characterization of CMMCs from MGUS/SMM patients. This study provides a foundation for non-invasive detection, enumeration and genomic interrogation of rare CMMCs from the peripheral blood of MGUS/SMM, illustrating the clinical potential of using liquid biopsies for monitoring and managing disease in the precursor setting of MM.
 
 Getz: IBM, Pharmacyclics: Research Funding; Scorpion Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

Non-Invasive Liquid Biopsy to Quantify and Molecularly Characterize Circulating Multiple Myeloma Cells in the Assessment of Precursor Disease Pathology

Background Immune checkpoint inhibition is effective in several cancers. Expression of programmed death-ligand 1 (PD-L1) on circulating tumor or immune effector cells could provide insights into selection of patients for immune checkpoint inhibition. Methods Whole blood was collected at serial timepoints from metastatic breast cancer patients and healthy donors for circulating tumor cell (CTC) and platelet PD-L1 analysis with a phycoerythrin-labeled anti-human PD-L1 monoclonal antibody (Biolegend clone 29E.2A3) using the CellSearch® assay. CTC PD-L1 was considered positive if detected on at least 1% of the cells; platelet PD-L1 was considered positive if ≥100 platelets per CellSearch frame expressed PD-L1. Results A total of 207 specimens from 124 metastatic breast cancer patients were collected. 52/124 (42%) samples at timepoint-1 (at or close to time of progressive disease) had ≥5 CTC/7.5ml whole blood. Of those, 21 (40%) had positive CTC PD-L1. In addition, platelet PD-L1 expression was observed in 35/124 (28%) at timepoint-1. Platelet PD-L1 was not detected in more than 70 specimens from 12 healthy donors. Platelet PD-L1 was associated with ≥5 CTC/7.5ml whole blood (p = 0.0002), less likely in patients with higher red blood cell counts (OR = 0.72, p<0.001) and a history of smoking tobacco (OR = 0.76, p<0.001). Platelet PD-L1 staining was not associated with tumor marker status, recent procedures or treatments, platelet-affecting drugs, or CTC PD-L1 expression. Conclusion PD-L1 expression was found in metastatic breast cancer patients on both CTC and platelets in an independent fashion. Inter-patient platelet PD-L1 expression was highly heterogeneous suggesting that it is a biological event associated with cancer in some but not all patients. Taken together, our data suggest that CTC and platelet PD-L1 expression could play a role in predicting which patients should receive immune checkpoint inhibition and as a pharmacodynamics biomarker during treatment.

PD-L1 expression on circulating tumor cells and platelets in patients with metastatic breast cancer

Blood-based gene expression signature associated with metastatic castrate-resistant prostate cancer patient response to abiraterone plus prednisone or enzalutamide

Background: Clonal evolution and heterogeneity are among the factors that make treatment of Multiple Myeloma (MM) challenging, and disease monitoring requires invasive bone marrow biopsies. Tumor heterogeneity has previously been demonstrated at copy-number level, showing patterns of recurring Copy-Number Alterations (CNA). Conversely, Loss-of-Heterozygosity (LoH) profiling has been investigated less extensively. Presence of genomic patterns of LoH has been associated with Homologous Recombination Deficiency (HRD) in MM, suggesting a role for therapy with PARP inhibitors. Here we report the genome-wide LoH profiling in single-CMMCs isolated from enriched peripheral blood of four different MM patients using a non-invasive approach that combines CellSearch® and DEPArray™ technology. Methods: CMMCs were obtained from peripheral blood of four MM patients using CellSearch for enrichment and DEPArray NxT for isolation. CMMCs enrichment was obtained using a custom kit with anti-CD138 or anti-CD138/CD38 antibody-conjugated ferrofluids for positive enrichment and CD38-PE, CD19/CD45-APC immunofluorescent staining for detection. After single cell isolation, Ampli1™ Whole Genome Amplification (WGA) kit was used to amplify single-cell genomic DNA. Whole genome sequencing libraries were prepared from WGA products using Ampli1™ LowPass kit and low-pass sequencing was performed on HiSeq 2500 Illumina® platform. Genome-wide single-cell Low-Pass Copy Number Alteration (LPCNA) analysis was performed using the cloud-based bioinformatic suite MSBiosuite. Single-cell genome-wide LoH profiles were obtained by a custom algorithm based on the ratio between mono- and bi-allelic loci in non-overlapping segments of uniform copy-number. Results: Out of 315 cells analyzed from the four MM patients, 244 (77%) showed LoH events. Extensive LoH regions were detected in all patients, with 231 cells showing copy-neutral LoH events and 121 showing LoH events in copy-gain regions. Globally, 460 copy-neutral LoHs, and 292 LoHs in copy-gain regions were detected. Two highly conserved copy-neutral events (9p; 16q) were detected in one of the patients analyzed, suggesting they are early events. Interestingly, the first of the 2 events includes CDKN2A, a tumor suppressor which has been implicated in predisposition to MM. Notably, in a second patient, chromosome 11 is associated both to a copy-neutral LoH and to an LoH event in a copy-gain segment including the CCND1 gene, whose amplification in MM has been associated with multidrug resistance expression. Conclusions: Here we present a non-invasive workflow for the molecular characterization of single CMMCs isolated from peripheral blood. Specifically, we reported the presence of chromosomal or sub-chromosomal LoH events in all MM patients, suggesting a pervasive phenomenon in MM which deserves to be further explored as potential therapy target. Citation Format: Claudio Forcato, Alberto Ferrarini, Genny Buson, Paola Tononi, Marianna Garonzi, Valentina del Monaco, Andrea Raspadori, Steven Gross, Francesca Fontana, Gianni Medoro, Mark Connelly, Nicolo Manaresi. Analysis of low-pass sequencing data reveals extensive loss-of-heterozygosity in circulating multiple myeloma cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2702.

Abstract 2702: Analysis of low-pass sequencing data reveals extensive loss-of-heterozygosity in circulating multiple myeloma cells

Abstract 2911: Genome-wide copy number profiling of single circulating multiple myeloma cells (CMMCs) reveals intra-patient convergent copy-number alterations (CNAs)

 Introduction: Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells. The high heterogeneity of MM cells is one of the major cause of disease relapse. Detection of circulating MM cells (CMMC) from peripheral blood is a useful procedure to investigate tumor heterogeneity and provides a painless alternative to the classic bone marrow biopsy to monitor disease progression. Here we demonstrate that the synergy between CellSearch® (CS) and DEPArray™ (DA) technologies can be used to identify, isolate and characterize at the genetic level single and pure CMMCs .
 Methods: 4.0 ml of peripheral blood samples were obtained from 3 patients with MM. Putative CMMCs were enriched with CS using anti-CD138 or anti-CD138/CD38 as positive selection marker and subsequently stained with CD38-PE, CD19/CD45-APC immunofluorescent probes. Cells detection and enumeration was performed based on the co-localization of nuclei DAPI staining and CD38-PE. Single CMMCs (CD38+/CD19- and CD45-/DAPI+) and White Blood Cells (WBCs: CD38-/CD19+ or CD45+/DAPI+) were then isolated using the DA NxT system. Single cells genomic DNA was amplified using Ampli1™ Whole Genome Amplification (WGA) kit and Illumina®-compatible libraries were obtained using Ampli1™ LowPass kit and a high-throughput, customized automated protocol using Hamilton STARLet Liquid handler. Highly-multiplexed, genome-wide single-cell Low-Pass Copy Number Alteration (LPCNA) analysis was performed using HiSeq 2500 Illumina® platform.
 Results: CS and DA workflow* enabled the isolation of 215 single CMMC, selected for LPCNA analysis. 42 single WBCs were also included as normal controls. Copy-number profiles of single CMMCs showed relevant gains and losses of chromosomal segments, as result of a high-level genomic instability. Notably, intra-patient CMMCs revealed overall conserved CNA patterns with subclonal alterations, suggesting a certain level of branched tumor evolution. Conversely, a higher degree of heterogeneity in CMMCs CNA profiles was observed among different patients. Interestingly, CNAs detected in all patients are located in regions containing genes involved in cell cycle regulation (MAPK, NOTCH pathways) and cell signaling (IL6R), which might be involved in proliferative processes and immuno-surveillance escape.
 Conclusion: The combination of CS and DA workflow* with a streamlined automated protocol allowed to obtain hundreds of genomic libraries from pure single CMMCs. The presented workflow constitutes a non-invasive, rapid and high-throughput approach for characterizing MM tumor heterogeneity and progression, suggesting a possible future implementation in clinical applications.
 *For Research Use Only. Not for use in diagnostic procedures.
 
 Raspadori: Menarini Silicon Biosystems: Employment. Forcato:Menarini Silicon Biosystems: Employment. Edoardo:Menarini Silicon Biosystems: Employment. Papadopulos:Menarini Silicon Biosystems: Employment. Ferrarini:Menarini Silicon Biosystems: Employment. Del Monaco:Menarini Silicon Biosystems: Employment. Terracciano:Menarini Silicon Biosystems: Employment. Morano:Menarini Silicon Biosystems: Employment. Gross:Menarini Silicon Biosystems: Employment. Bolognesi:Menarini Silicon Biosystems: Employment. Buson:Menarini Silicon Biosystems: Employment. Fontana:Menarini Silicon Biosystems: Employment. Connelly:Menarini Silicon Biosystems, Inc.: Employment, Other: Chief R&D Officer, USA. Simonelli:Menarini Silicon Biosystems: Employment. Medoro:Menarini Silicon Biosystems: Employment. Manaresi:Menarini Silicon Biosystems: Employment.

A High-Throughput Workflow for the Detection, Isolation and Genomic Analysis of Single Circulating Multiple Myeloma Cells

We have developed an automated assay to enumerate and characterize circulating multiple myeloma cells (CMMC) from peripheral blood of patients with plasma cell disorders. CMMC show expression of genes characteristic of myeloma and fluorescence in situ hybridisation results on CMMC correlated well with bone marrow results. We enumerated CMMC from over 1000 patient samples including separate cohorts of newly diagnosed multiple myeloma and high/intermediate risk smouldering multiple myeloma (SMM) with clinical follow‐up data. In newly diagnosed myeloma patient samples, CMMC counts correlated with other clinical measures of disease burden, including the percentage of bone marrow plasma cells, serum M protein, and International Staging System stage. CMMC counts decreased significantly from baseline when a remission was achieved due to treatment (P < 0·001). Patients with CMMC counts ≥100 at remission showed reduced survival relative to patients with CMMC counts <100. Patients with undetectable CMMC in remission showed further overall survival benefits. In the SMM cohort, there was a trend toward higher CMMC in patients with higher‐risk myeloma precursor states. Significantly higher CMMC counts were observed between intermediate/high risk SMM patients that progressed versus those without progression (P = 0·031). CMMC allow a non‐invasive means of monitoring tumour biology and may have use as a prognostic test for patients with plasma cell disorders.

Enumeration and characterization of circulating multiple myeloma cells in patients with plasma cell disorders

Background: Multiple myeloma (MM) is a bone marrow derived cancer of plasma cells, which remains an incurable disease. Because of the invasive and painful nature of bone biopsy, an alternate tumor monitoring strategy is needed. We have previously shown that Circulating Multiple Myeloma Cells (CMMCs) isolated by CellSearch® (CS) are prognostic and indicative of disease burden through remission and relapse. Here we report, for the first time, the molecular characterization of pure single CMMCs isolated from a multiple myeloma patient, by integrating CS and DEPArray™ (DA) NxT systems, providing access to copy-number alteration (CNA) profiling. Methods: 4.0ml of peripheral blood from a patient with multiple myeloma was tested. On CS, target CMMCs were enriched using anti-CD138 for cell capture, and stained immunofluorescently with CD38-PE, CD19 and CD45-APC. Nuclei were stained with DAPI and detected target cells counted. The enriched sample was then analyzed using the DA NxT system: single CMMCs (CD38+/CD19- and CD45-/DAPI+), along with some single White Blood Cells (WBCs: CD38-/CD19+ or CD45+/DAPI+), were isolated. The DNA of each single cell was amplified using the Ampli1™ WGA kit and used for highly-multiplexed, genome-wide single-cell CNA analysis using a Ampli1™ LowPass kit (LPCNA) on Illumina® MiSeq. Results: CS identified 128 CMMCs. From DA NxT we harvested 20 individual CMMCs for LPCNA analysis. Copy-number profiles of CMMCs confirmed their tumor origin, showing a high-level of genome instability with several gains and few losses of chromosomal segments. Moreover, an unsupervised hierarchical cluster analysis highlighted a conserved pattern of alterations, enabling the separation between CMMCs and WBCs groups. A pattern of copy-number gains shared by all CMMCs, coupled with gains and losses shared by a subset of CMMCs, suggests a branched evolution of different tumor subclones. WBC profiles were flat as expected. Conclusions: Cell enrichment by CS followed by individual cell sorting using DA NxT, enabled the isolation of single CMMCs with 100% purity. Ampli1™ single-cell analysis demonstrated CMMC molecular heterogeneity suggestive of tumor subclones presence. This platform combination provides a reliable and non-invasive method for MM characterization enabling translational research and future clinical application. Citation Format: Mario Terracciano, Claudio Forcato, Edoardo Petrini, Alberto Ferrarini, Valentina del Monaco, Andrea Raspadori, Carrie Morano, Steven Gross, Chiara Bolognesi, Genny Buson, Thai Bui, Francesca Fontana, Gianni Medoro, Mark Connelly, Nicolo Manaresi. An integrated workflow for liquid biopsy of circulating multiple myeloma cells (CMMCs) with single cell resolution reveals tumor heterogeneity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2198.

Abstract 2198: An integrated workflow for liquid biopsy of circulating multiple myeloma cells (CMMCs) with single cell resolution reveals tumor heterogeneity

Abstract 3736: Characterization of tumor cells and assessment of PD-L1 expression in pleural effusions of metastatic non-small cell lung cancer patients

Prognostic and predictive value of circulating tumor cells and CXCR4 expression as biomarkers for a CXCR4 peptide antagonist in combination with carboplatin-etoposide in small cell lung cancer: exploratory analysis of a phase II study

Introductory Sentence indicating purpose of study: Circulating tumor cell (CTC) clusters have been shown to have higher metastatic potential than single CTCs in breast, pancreatic, and other cancers, yet these clusters have not been extensively described in metastatic castrate-resistant prostate cancer (MCRPC). Here we sought to determine the feasibility of capturing and characterizing CTC clusters in prostate cancer patients. Description of Experimental Procedures: Fifty-five blood samples from 29 MCRPC patients, ages 50 to 81 (median age 68), were obtained prior to the patient starting or switching to androgen receptor inhibitor or 17 alpha lyase inhibitor therapies. Eighteen patients received enzalutamide and 11 received abiraterone. The majority of patients had a Gleason score > 7 (22; 75.9%), bone metastases (19; 65.5%), and an ECOG status of 0 (21; 72.4%). All patients had previously undergone, or were receiving at time of enrollment, androgen deprivation therapy. Eleven patients (37.9%) had been on a prior 2nd generation anti-androgen therapy. CTC single cells and clusters (2 or more cells together in one image) were enumerated using the CellSearch system and stained to detect expression of androgen receptor (AR), glucocorticoid receptor (GR), and neuroendocrine (NE) markers. Summary of Data: Five or more single CTCs, a measure which has previously been associated with an unfavorable prognosis, were detected in 13 of 29 patients (44.8%), and in 19 of 55 blood samples (34.5%). Altogether, a total of 282 CTC clusters was detected, with 1 or more clusters found in 10 patients (34.5%) and 13 samples (23.6%). The number of clusters per 7.5ml of blood ranged from 0-150, and clusters contained anywhere from 2 to 16 cells. Most CTC clusters (268; 95.0%) contained only CTCs and no leukocytes. Just over half the detected clusters (162; 57.4%) contained only 2 CTCs. Cluster staining patterns were fairly homogenous with 29.4% of clusters having uniform expression of either AR, GR, or NE markers, i.e., all CTCs in the cluster expressed the marker of interest. Most clusters (67.7%) were uniformly marker negative and the remaining 2.8% demonstrated a mix of marker positive and marker negative CTCs. Serum Chromogranin A levels, as determined by standard of care clinical blood testing, were found to be positively associated with the number of CTC clusters per 7.5ml of blood (p Statement of Conclusions: The capture and characterization of CTC clusters in the blood of MCRPC patients can be successfully performed using the CellSearch system. Further investigation into the clinical implications of these clusters is warranted, including whether cluster characteristics are associated with more aggressive disease. Citation Format: Samantha L. Savitch, Stephanie S. Yee, Devon Soucier, Denis Smirnov, Chandra Rao, Steve Gross, Ravi K. Amaravadi, David J. Vaughn, Naomi B. Haas, Erica L. Carpenter. Capture and characterization of circulating tumor cell clusters in patients with metastatic castrate-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 758. doi:10.1158/1538-7445.AM2017-758

Abstract 758: Capture and characterization of circulating tumor cell clusters in patients with metastatic castrate-resistant prostate cancer

Background Circulating tumor cells (CTCs) and chemokine (C-X-C motif) receptor 4 (CXCR4) expression in CTCs and tumor tissue were evaluated as prognostic or predictive markers of CXCR4 peptide antagonist LY2510924 plus carboplatin-etoposide (CE) versus CE in extensivestage disease small cell lung cancer (ED-SCLC). Methods This exploratory analysis of a phase II study evaluated CXCR4 expression in baseline tumor tissue and peripheral blood CTCs and in post-treatment CTCs. Optimum cutoff values were determined for CTC counts and CXCR4 expression in tumors and CTCs as predictors of survival outcome. Kaplan-Meier estimates and hazard ratios were used to determine biomarker prognostic and predictive values. Results There was weak positive correlation at baseline between CXCR4 expression in tumor tissue and CTCs. Optimum cutoff values were H-score ≥ 210 for CXCR4 tumor, ≥7%CTCs with CXCR4 expression (CXCR4 CTCs), and ≥6 CTCs/7.5 mL blood. Baseline H-score for CXCR4 tumor was not prognostic of progression-free survival (PFS) or overall survival (OS). Baseline CXCR4 CTCs ≥7%was prognostic of shorter PFS. CTCs ≥6 at baseline and cycle 2, day 1 were prognostic of shorter PFS and OS. None of the biomarkers at their respective optimum cutoffs was predictive of treatment response of LY2510924 plus CE versus CE. Conclusions In patients with ED-SCLC, baseline CXCR4 expression in tumor tissue was not prognostic of survival or predictive of LY2510924 treatment response. Baseline CXCR4 CTCs ≥7% was prognostic of shorter PFS. CTC count ≥6 at baseline and after 1 cycle of treatment were prognostic of shorter PFS and OS.

Prognostic and predictive value of circulating tumor cells and CXCR 4 expression as biomarkers for a CXCR 4 peptide antagonist in combination with carboplatin-etoposide in small cell lung cancer : exploratory analysis of a phase II study

There is an increasing interest in the ability to dynamically track disease burden and perform molecular subtyping of patients with plasma cell disorders without invasive bone marrow sampling. Circulating multiple myeloma cells (CMMC) have been detected in elevated numbers in the peripheral blood of patients with plasma cell disorders using flow cytometry or circulating cell enrichment platforms. We developed an automated CELLSEARCH® assay to enrich, enumerate, and perform a triplex FISH assay for t(4;14), t(14;16), and del 17p on CMMC (CD138+CD38+, CD45-CD19-) isolated from a 4 mL peripheral blood sample (Gross, et.al. Blood 2011; 118(21):1825). Here we present the enumeration and cytogenetic profiling of CMMC from separate cohorts of patients across the spectrum of plasma cell disorders. The first cohort consisted of newly diagnosed multiple myeloma patients enrolled in the CoMMpass study (ClinicalTrials.gov Identifier: NCT01454297). One or more CMMC per four ml blood were detected in 684/698 (98%) of newly diagnosed myeloma patients with median CMMC count of 413 per 4 mL of blood. CMMC counts decreased significantly from baseline when a remission was achieved due to treatment (p 100 at remission. CMMC FISH results (n = 57) showed overall agreement of 85%, 91% and 80% with bone marrow FISH results and 81%, 91%, and 95% agreement with bone marrow CNV/RNAseq results for the t(4;14), t(14;16), and del 17p assays, respectively. The second cohort of patients consisted of intermediate/high risk smoldering myeloma patients enrolled in a Phase 2 study of Siltuximab (ClinicalTrials.gov Identifier: NCT01484275). One or more CMMC per 4 mL blood was detected at baseline in 74/79 (94%) of intermediate/high risk smoldering myeloma patients with median CMMC count of 100 per 4 mL of blood. Significantly higher CMMC counts were observed between patients in the placebo arm that progressed versus those without progression (n = 34, p = 0.031). This is in contrast to standard metrics of percentage of bone marrow plasma cells and serum M protein levels where statistically significant differences were not seen between progressors and non-progressors in the placebo arm (p = 0.068 and p = 0.070, respectively). CMMCs were collected from a third cohort of 35 patients across the plasma cell disease spectrum with an emphasis on MGUS and SMM. CMMC counts were associated with the disease burden of patients within this cohort. CMMC may be a useful non-invasive tool for disease monitoring and characterization across the plasma cell disorder spectrum. In myeloma, CMMC may be a useful prognostic marker at remission to delineate those patients at risk for relapse. In SMM, CMMC may be useful for predictive patients at risk of progression to MM. Citation Format: Brad Foulk, Mike Schaffer, Steve Gross, Chandra Rao, Denis Smirnov, Shalini Chaturvedi, Manjula Reddy, Madeline Repollet, Claudia Rojas, Daniel Auclair, Mary DeRome, The MMRF CoMMpass Network, Brendan Weiss, A. Kate Sasser. Peripheral blood circulating multiple myeloma cells (CMMCs) correlate with disease burden and can be used to characterize high-risk cytogenetics in newly diagnosed and smoldering myeloma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3163.

Abstract 3163: Peripheral blood circulating multiple myeloma cells (CMMCs) correlate with disease burden and can be used to characterize high-risk cytogenetics in newly diagnosed and smoldering myeloma

Today, circulating tumor cells (CTCs) can provide important prognostic information about a patient. However, to one day help guide decisions for precision medicine, more and increasingly sophisticated information will have to be extracted from each patient blood sample. We describe a new microfluidic CTC isolation technology, the Harpoon CTC Isolator and Chip (Hrp Isolator). From a single sample the Hrp Isolator can enable the analysis of plasma components such as ctDNA, as well as the ability to enrich all circulating tumor cell types, regardless of their antigenic expression. To enrich the CTCs from 7.5 mL of whole blood, the Hrp Isolator removes the red blood cells and platelets based on their small size and the white blood cells by negative depletion using magnetic particles. The time required to process 7.5 mLs of blood is approximately 90 minutes. In contrast, the CELLSEARCH® CTC Test (CS), the only US FDA-cleared test, uses antigens expressed by CTCs to target the CTCs and positively select them out of blood. To enumerate CTCs from patient samples, the output from the Hrp Isolator was then loaded into and run on the CELLSEARCH® System using the CS test (Hybrid method). CTCs were enumerated from 37 breast and prostate cancer patients by CS and by the Hybrid method. At least 1 CTC was found in 23 (62%) patient samples by the Hybrid method versus 17 (46%) by CS. The product of the Hrp Isolator enrichment contained on average the same numbers of CTCs as were found by CS (mean = 13.3 ± 18 by CS versus 12.0 ± 16 by Hybrid) in patient samples having 75), the Hybrid method may have underestimated the total Hrp Isolator CTC count. An important feature of the Hrp Isolator is its ability to enrich CTCs that are negative or low expressers of epithelial cell adhesion molecule (EpCAM) or cytokeratin (CK). These cells could have been missed by positive-selection technologies such as CS and may not have been counted using the Hybrid method. CTC spiked samples were run on the Hrp Isolator and the CTC enriched product was spun onto microscope slides, stained, and examined using a Vectra Multispectral Imaging System (Hrp+Vec method). Using the Hrp+Vec method, 79% to 100% of spiked CTCs were recovered depending on the slide fixation method used. Also, using Hrp+Vec we confirmed the ability of the Harpoon Isolator to enrich EpCAM-/CK+ and EpCAM+/CK- CTCs from patient samples. This establishes the existence of “non-canonical” tumor cell types in circulation and adds to the biological diversity of the CTC population in circulation. These results emphasize the need to further characterize all tumor cell populations and to determine what, if any, clinical significance may be assigned to these diverse CTC types. Citation Format: David Chianese, Mark Connelly, Carrie Morano, Thai Bui, Steven Gross, Renouard Sanders, Tom Barber, Ravi Kapur, Shyamala Maheswaran, Mehmet Toner, Daniel Haber. Isolation of canonical and non-canonical circulating tumor cells (CTCs) by negative depletion using the Harpoon CTC Isolator and Chip. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2422.

Abstract 2422: Isolation of canonical and non-canonical circulating tumor cells (CTCs) by negative depletion using the Harpoon CTC Isolator and Chip

e18558 Background: CXCR4, highly expressed in SCLC, has been implicated in inducing tumor cell migration/invasion and shown to be prognostic of outcome. We evaluated CXCR4 expression in pretreatment CTCs and tumor tissue and post-carboplatin/etoposide (SOC) treatment CTCs in a phase 2 ED-SCLC study of a CXCR4 inhibitor (NCT 01439568). Methods: 89 pts were treated with 42 receiving SOC. CTCs were analyzed using CELLSEARCH CXC kit combined with a PE labelled anti-CXCR4 Ab. CXCR4 expression on CTCs was scored visually by an operator and with specialized software. Baseline tumor CXCR4 expression was quantified (H-score) by immunohistochemistry. Optimum cutoff values for CTC counts and CXCR4 expression on CTCs and tumor were determined from ROC curves. Kaplan Meier curves were used to assess cutoffs as PFS prognostic variables for SOC pts. Results: See Table. For all pts, baseline % CXCR4+CTCs correlated positively with tumor CXCR4 expression (r=0.423; p=0.001). The agreement between operator and software scor...

CXCR4 expression and circulating tumor cell (CTC) counts evaluated as prognostic markers in extensive disease small cell lung cancer (ED-SCLC) patients (pts).

Background Circulating plasma cells (PCs) have been identified as a prognostic factor in patients with myeloma precursor states (MGUS and SMM) and active multiple myeloma (MM). Enumeration of circulating PCs by available methods is not suitable for widespread use and does not provide molecular characterization. We developed and evaluated a novel method for enumeration and molecular characterization of circulating PCs (circulating multiple myeloma cells, “CMMC”), based on the CELLSEARCH® System (Janssen Diagnostics LLC, Raritan, NJ), an automated technology for the capture, enumeration and characterization of rare cells in the peripheral blood.

Methods We are performing a prospective study of patients with MGUS and SMM to evaluate CMMCs as biomarker for progression to active MM. Utilizing the CELLSEARCH® System CMMCs were captured by CD138 ferrofluid magnetic particles and identification was defined as CD38+ and CD19-, CD45-. Nonviable cells were excluded by DAPI. Isolated CMMCs were stored and FISH for t(4:14), t(14;16) and del17 was performed.

Results We have enrolled 16 patients, MGUS = 3, SMM = 11, and newly diagnosed MM = 2. The Mayo Risk stratification for MGUS patients was: low risk = 2, low-intermediate = 1. All SMM patients were low risk by Mayo Model incorporating serum free light chains. The median number of bone marrow plasma cells for MGUS patients was 7 (range 7-9) and for SMM patients was 15 (range 10-40). The median CMMCs for MGUS = 6 (range 2-55), median CMMCs for SMM = 31 (5-1918). The two patients with NDMM had 5870 and 5 CMMCs, respectively. A single patient with SMM progressed with a symptomatic solitary lumbar plasmacytoma and had CMMCs of 5 and 3 at baseline and progression, respectively. Abnormalities by FISH were detected in both bone marrow and CMMCs. Accrual is ongoing and additional data will be presented at the meeting.

Conclusions The CELLSEARCH® CMMC assay can detect, quantify and provide molecular characterization of circulating PCs in MGUS/SMM/MM; longer prospective follow-up is needed to test the prognostic value of CMMCs.

Disclosures Weiss: Janssen: Consultancy, Research Funding. Sasser: Janssen: Employment. Rao: Janssen: Employment, Equity Ownership. Foulk: Janssen: Employment. Gross: Johnson & Johnson: Employment, Equity Ownership. Cohen: Janssen: Membership on an entity's Board of Directors or advisory committees. Vogl: Celgene Corporation: Consultancy; Amgen: Consultancy; Millennium/Takeda: Research Funding; GSK: Research Funding; Acetylon: Research Funding. Stadtmauer: Janssen: Consultancy.

Circulating Multiple Myeloma Cells (CMMCs): A Novel Method for Detection and Molecular Characterization of Peripheral Blood Plasma Cells in Multiple Myeloma Precursor States

10616 Background: Circulating tumor cells (CTC) offer the potential for serially monitoring the molecular profile of a tumor. However, enrichment techniques provide a level of purity problematic for most molecular analysis methods, and do not readily provide for analysis of tumor cell heterogeneity. We evaluate the use of DEPArray (Silicon Biosystems), an automated system enabling image-based cell sorting with single-cell resolution, for CTC isolation and characterization from enriched blood samples.

METHODS
Experiments were carried out with healthy-donor blood (HB) collected in CellSave tubes, spiked with tumor cells (TC) and enriched on Veridex's AutoPrep with the CellSearch Epithelial Cell Kit. DEPArray system was used for detection and multiple recoveries of single TCs (or control WBCs) and 5 cell batches. A comparison of blind enumeration results with Veridex's CellTracks Analyzer II (CTAII) was carried out on replicate samples.

RESULTS
No TCs were detected among negative controls (n=10). TC count (normalized to sample volume analyzed) was compared sample-wise for each replicate (n=20): DEPArray/CTAII count was, on average, 100% (standard deviation = 52%). Enriched mixtures of Her2+ and Her2- TCs spiked in HB samples (n=5), were sorted by DEPArray and recovered into separate tubes. By phenotypical re-analysis no Her2+ cells were detected among the Her2- cell fraction and vice versa, neither were donor WBCs found (100% purity). KRAS-mutated, A549 cells spiked in HB were enriched and loaded on DEPArray. Individual fractions containing either 1 to 5 tumor cells or donor WBCs were sorted. Whole Genome Amplification (Ampli WGA, Silicon Biosystems), KRAS specific gene amplification and Capillary Electrophoresis sequencing were carried out. TCs successfully amplified showed only mutated KRAS, (WBCs were only wild-type).

DEPArray achieved 100% purity, eliminating all white blood cells (WBC), in the isolation of a mixed population of tumor cell lines downstream of CellSearch enrichment. This enabled molecular profiling of pure tumor cells from whole blood spiked tumor cell lines.

Use of the DEPArray platform to detect, isolate, and molecularly characterize pure tumor cells from peripheral blood samples enriched using the CellSearch system.

Abstract 1825 Detection of circulating Multiple Myeloma cells (CMMC) by flow cytometry is an indicator of active disease. In addition, circulating plasma cells can be detected in earlier stages of disease, including MGUS and Smoldering Multiple Myeloma, and appear to correlate with prognosis. The capture and characterization of these circulating plasma cells from peripheral blood may provide novel biomarkers for the management of Multiple Myeloma patients, particularly in monitoring minimal residual disease and in progression from MGUS or Smoldering Multiple Myeloma to active disease. The enumeration and characterization of circulating tumor cells (CTC) in patients with metastatic breast, prostate or colorectal cancer using the CellSearch ® technology, has been shown to provide clinically relevant prognostic and predictive information. Here we describe the development of an automated assay for detecting circulating normal plasma cells (CPC) and multiple myeloma cells (CMMC) in blood using CellSearch. Assay results from Multiple Myeloma, MGUS patients, and from an aged matched control population are presented. The CellTracks ® AutoPrep ® System and CellTracks Analyzer II ® systems were used to capture and enumerate CPC and CMMC. Magnetic particles conjugated to anti-CD138 are used to capture myeloma cells from 4.0mL of blood. Enriched cells are then stained with the nucleic acid dye DAPI and anti-CD38-Phycoerythrin (PE) antibody. Allophycocyanine (APC) conjugated anti-CD45 and anti-CD19 were used to exclude leukocytes and B-cells. In addition, FITC labeled anti-CD56 was added as a biomarker. The enriched and stained cells were transferred to a CellTracks ® cartridge and MagNest ® for magnetic mounting. The cartridge was scanned using the CellTracks Analyzer II ® . Individual images of cells were presented to the operator for review, and scored as CMMCs, based on fluorescence and cell morphology. In a model spike-in system the assay consistently recovered ∼60% of the cells from the Multiple Myeloma cell line H929 spiked into 4.0mL of blood from healthy donors. The assay was linear over the tested range of from 0 to 2000 spiked H929 cells (r 2 0.98, slope 0.50, intercept 10). The assay was validated using blood from age matched healthy donors (n=22) and patients with Multiple Myeloma (n=66) and MGUS (n=7). In 4.0mL blood from normal donors, 0 CPC were detected in 12/22 (55%) and low numbers (1–6 CPC) were detected in 10/22 (45%) samples. Interestingly, one CD56 positive CPC (CMMC?) was found in a normal donor. CMMC in Multiple Myeloma patients ranged from 0 – 17,000 /4.0mL blood. One or more CMMC were detected in 91% of the patients, > 5 in 68 % , > 10 in 58 % and > 100 in 35 % . Expression of CD56 was highly variable in the patient population. CMMC in MGUS patients ranged from 0 – 112 /4.0mL blood. One or more CMMC were detected in 6/7 of the patients, > 5 in 4/6, > 10 in 2/6 and > 100 in 1/6. To further characterize CMMC, and differentiate CPC from CMMC, an interphase fluorescent in situ hybridization (FISH) assay was developed to be used with the capture and detection system described above. A four color FISH probe was used to simultaneously detect high risk mutations including two recurrent translocations of the IgH locus (t(4;14)(p16;q32) and t(14;16)(q32;q23)) as well as deletion of the TP53 locus (Δ17p13). The FISH assay was verified on cell lines H929, MM1s, and U266, which showed mutations at t(4;14), t(14;16) and Δ17p13, respectively. The FISH assay was tested on 9 CMMC patient samples and 8 samples yielded evaluable results. Two samples showed t(4;14)fusions, 3 patients showed aberrant FISH signal patterns indicating aneuploidy of chromosome 4 or 14 and the remaining patients showed normal FISH patterns. Well controlled prospective clinical studies are needed to establish the prognostic and predictive value of the presence, and characteristics, of CMMC in multiple myeloma or MGUS. In addition, as with CTC, this automated CMMC assay should prove useful in evaluating the effectiveness of new treatments as well as the assessment of potential treatment targets on CMMC in this difficult disease. Disclosures: Gross: Johnson and Johnson: Employment, Equity Ownership. Foulk: Johnson and Johnson: Employment, Equity Ownership. Patel: Johnson and Johnson: Employment, Equity Ownership. Connelly: Johnson and Johnson: Employment, Equity Ownership. Mata: Johnson and Johnson: Employment, Equity Ownership.

Automated Enumeration and Characterization of Circulating Multiple Myeloma Cells in Blood

Multi-parameter method with high sensitivity for analysis of rare events in a biological sample

PURPOSE
Development of targeted therapeutic agents in colorectal cancer (CRC) is impeded by the lack of a noninvasive surrogate of drug effect. This pilot study evaluated the ability of immunomagnetic separation to isolate circulating tumor cells (CTCs) and of the fluorescent microscope system and flow cytometry to enumerate and characterize CTCs from patients with metastatic CRC.

Fifty patients with metastatic CRC contributed 50 mL of blood at treatment initiation and disease evaluation timepoints. Fresh tumor specimens were obtained from 17 patients for comparison of circulating and in situ tumor cell characteristics. Epithelial cells were magnetically isolated from whole blood targeting the antiepithelial cell adhesion molecule (EpCAM). Circulating tumor cells were defined as EpCAM isolated, cytokeratin positive, nuclear stain positive, and CD45 negative. Total RNA was isolated from EpCAM-enriched CTCs and multigene reverse-transcriptase polymerase chain reaction analyses were performed.

RESULTS
The median number of CTCs detected by flow cytometry was 2/7.5 mL blood. Mean change in cell count was significantly different for patients with tumor progression versus nonprogression (+6.7 vs. +0.2/7.5 mL; P = 0.001). A correlation was noted between mean fluorescence intensity (flow cytometry) of cytokeratin in CTC and matched tumor specimens (r = 0.79, P = 0.06). Nearly 80% (15 of 19) of samples with >or= 2 CTCs expressed >or= 1 epithelial marker gene (CK19, CK20, carcinoembryonic antigen, or epidermal growth factor receptor).

Isolating and characterizing CTCs from patients with metastatic CRC is feasible. Change in the CTC number might reflect clinical status, and flow cytometric and gene expression data suggest similarity of circulating and in situ tumor cells. Further evaluation of CTCs for pharmacodynamic and clinical monitoring in patients with CRC is warranted.

Isolation and characterization of circulating tumor cells in patients with metastatic colorectal cancer.

Circulating tumor cells predict survival in patients with metastatic prostate cancer.

Preliminary study of immunomagnetic quantification of circulating tumor cells in patients with advanced disease.

Circulating tumor cells (CTCs) represent a surrogate source of tissue and conceptually represent a "real-time" biopsy. We previously reported that the number of CTCs mirrors disease progression in hormone-refractory prostate cancer (HRPC). To improve characterization of CTCs we further investigated whether in vitro transcription-based multigene reverse transcription-PCR expression profiles could be obtained from CTCs in HRPC.

METHODS
We evaluated the expression of 37 genes with potential utility for epithelial cell characterization from antisense RNA libraries constructed from immunomagnetically enriched CTCs from 7.5-mL blood samples from healthy donors and patients with HRPC.

RESULTS
In the control group 13 of 37 genes were not expressed. The most notable of the genes expressed in CTCs of 23 blood specimens drawn from 9 patients with metastatic prostate cancer were prostate-specific antigen (20 of 23; 87%), prostate-specific membrane antigen (17 of 23; 74%), androgen receptor (16 of 23; 70%), human glandular kallikrein 2 (7 of 23; 30%), epidermal growth factor receptor (4 of 23; 17%), and prostate-specific gene with homology to G protein receptor (2 of 23; 9%). The number of CTCs in these samples ranged from 4 to 283 in 7.5 mL of blood (mean, 87; median, 89). Expression of some of the genes was low in the control samples and higher in the patient samples. In all 23 samples, cytokeratin 19, epithelial cell adhesion molecule, or mucin 1 was expressed. Because of background expression in the controls, expression of 13 of the 37 genes, including HER-2, p53, and BCL-2, could not be measured in CTCs.

Antisense RNA libraries can be constructed from CTCs and gene expression profiles of CTCs obtained from patients with HRPC. This could enhance the characterization of HRPC and facilitate the development of more effective therapies.

Multigene reverse transcription-PCR profiling of circulating tumor cells in hormone-refractory prostate cancer.

The prescence of circulating tumor cells (CTCs) in the peripheral blood of cancer patients and their frequency has been correlated with disease status.

Apoptosis of circulating tumor cells in prostate cancer patients

Nineteen breast cancer patients with measurable metastatic disease who were starting an initial or new line of therapy were evaluated for circulating epithelial cells (CECs) a minimum of 4 times over the course of treatment. In 7 of the 10 CEC+ patients, HER-2 expression was detected on the CECs. CECs expressing HER-2 varied among patients and in serial samples from the same patient including a shift from HER-2- to HER-2+ CECs. These results demonstrate that it is possible to quantify receptors essential for rationally designed therapy using CECs and that reliance on the immunophenotype of the primary tumor can be misleading.

Monitoring expression of HER-2 on circulating epithelial cells in patients with advanced breast cancer.

L'invention concerne des procedes et des reactifs mis en oeuvre pour analyser des cellules tumorales en circulation, des agregats, des fragments et des debris associes. L'analyse est effectuee au moyen d'un certain nombre de plates-formes, notamment une cytometrie de flux et le systeme d'imagerie par microscopie fluorescente CellSpotter®*. L'analyse de cellules endommagees s'est averee tres importante. Cependant, il y a deux sources de dommages: in vivo et in vitro. Des dommages in vivo sont causes par apoptose, necrose ou reponse immune. Des dommages in vitro apparaissent au cours de l'acquisition, de la manipulation, du transport, du traitement ou de l'analyse d'echantillons. Il est, par consequent, souhaitable de limiter, de reduire, d'eliminer ou au moins de qualifier des dommages in vitro, de maniere a empecher ceux-ci d'interferer dans l'analyse. L'invention concerne egalement des procedes de diagnostic, de surveillance et de balayage de maladie fondes sur des cellules rares en circulation, notamment une malignite telle que determinee par CTC, des agregats, des fragments et des debris, ainsi que des kits permettant de doser des specimens biologiques au moyen de ces procedes.

Analyse de cellules tumorales en circulation, de fragments et de debris associes

Changes in circulating carcinoma cells in patients with metastatic prostate cancer correlate with disease status.

Peripheral blood was examined for the presence of tumor cells at multiple time points over a one-year period in 45 patients with a history of surgical resection of breast carcinoma. The number of circulating epithelial cells in 8 of 8 patients with clinically active disease concurred or preceded changes in the disease activity. In 12 of 37 patients with no evidence of disease epithelial cells were found at least at one time point at a frequency larger than the control group. One patient had a recurrence of the breast cancer 4 weeks after circulating epithelial cells were detected in the blood.

Peripheral blood tumor cell load reflects the clinical activity of the disease in patients with carcinoma of the breast.

QUANTITATION OF THE CIRCULATING HEMATOGENOUS TUMOR CELL LOAD IN PROSTATE CANCER

Immunomagnetic selection of epithelial cells from peripheral blood was combined with flowcytometric or microscopic analysis to characterize and enumerate epithelium derived tumor cells in the circulation of patients with carcinoma of the breast. Highly significant differences in the number of circulating epithelial cells were found between normal controls and patients with breast cancer. In addition, significant differences in the number of circulating epithelial cells were found in patients in whom the tumor is confined to the primary tumor and those with metastatic disease to local lymphnodes or distant sites [1]. The malignant nature of the cells was demonstrated by their cytology and immunophenotype. In following up the number of epithelial cells in the blood of patients with metastatic carcinoma of the breast, it was shown that it was well correlated with the activity of the disease.

Flow cytometry--principles and feasibility in transfusion medicine. Enumeration of epithelial derived tumor cells in peripheral blood.

Flowcytometry ‐ Principles and Feasibility in Transfusion Medicine. Enumeration of Epithelial Derived Tumor Cells in Peripheral Blood

This packet contains the forms necessary to apply for disability benefits. It also addresses common questions about Disability claims. Please save this material for your future reference. For specific information about your Disability insurance coverage, refer to your group insurance certificate. The certificates are the ultimate authority for Disability claim decisions. If you need other information, please contact your employer’s benefit administrator or call our customer service line at 800.368.2859.

Distinct cAMP signaling microdomains differentially regulate melanosomal pH and pigmentation.

Novel genetically engineered mouse models for clear cell renal cell carcinoma

Differences in the effects of LKB1 loss in human versus murine lung adenocarcinoma are attributed to differential TPI1 regulation that leads to divergent metabolic liabilities and has implications for therapeutic targeting in cancer.

LKB1-Dependent Regulation of TPI1 Creates a Divergent Metabolic Liability between Human and Mouse Lung Adenocarcinoma

Mitochondrial diseases are a heterogeneous group of monogenic disorders that result from impaired oxidative phosphorylation (OXPHOS). As neuromuscular tissues are highly energy-dependent, mitochondrial diseases often affect skeletal muscle. Although genetic and bioenergetic causes of OXPHOS impairment in human mitochondrial myopathies are well established, there is a limited understanding of metabolic drivers of muscle degeneration. This knowledge gap contributes to the lack of effective treatments for these disorders. Here, we discovered fundamental muscle metabolic remodeling mechanisms shared by mitochondrial disease patients and a mouse model of mitochondrial myopathy. This metabolic remodeling is triggered by a starvation-like response that evokes accelerated oxidation of amino acids through a truncated Krebs cycle. While initially adaptive, this response evolves in an integrated multiorgan catabolic signaling, lipid store mobilization, and intramuscular lipid accumulation. We show that this multiorgan feed-forward metabolic response involves leptin and glucocorticoid signaling. This study elucidates systemic metabolic dyshomeostasis mechanisms that underlie human mitochondrial myopathies and identifies potential new targets for metabolic intervention.

A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy.

N6-methyladenosine (m6A) is a modified nucleotide found in mRNA, ribosome RNA (rRNA) and small nuclear RNA (snRNA). m6A in mRNA has important roles in regulating mRNA stability, splicing, and other processes. Numerous studies have described m6A as a dynamic modification using mass spectrometry-based quantification of m6A in mRNA samples prepared from different cellular conditions. However, these results have been questioned based on the finding that the mRNA purification protocols often result in varying levels of rRNA contamination. Additionally, mRNA purification protocols disproportionately enrich for the 3’ ends of mRNA, a region that is enriched in m6A. To address these problems, we developed the Phospho-tag m6A assay, a highly efficient method for quantifying m6A specifically from mRNA. In this assay, a series of selective RNase digestion steps is performed, which results in m6A from rRNA and snRNA being liberated as m6A monophosphate, while m6A from mRNA is mostly liberated as m6A nucleoside. m6A levels are normalized to transcript levels, using m7G monophosphate liberated by yDcpS decapping enzyme as a surrogate for mRNA levels. Notably, this approach uses total cellular RNA, rather than purified mRNA, which simplifies the steps for m6A detection and overcomes the 3’-end biases associated with mRNA purification. Overall, the Phospho-tag m6A provides a simple and efficient method for quantification of mRNA-derived m6A from total RNA samples.

Selective detection of m6A derived from mRNA using the Phospho-tag m6A assay

Research has shown extensive metabolic remodeling in clear cell renal cell carcinoma (ccRCC), with increased glutathione (GSH) levels. We hypothesized that activating transcription factor‐4 (ATF4) and the integrated stress response (ISR) induce a metabolic shift, including increased GSH accumulation, and that Vitamin A deficiency (VAD), found in ccRCCs, can also activate ATF4 signaling in the kidney. To determine the role of ATF4, we used publicly available RNA sequencing (RNA‐seq) data sets from The Cancer Genomics Atlas. Subsequently, we performed RNA‐seq and liquid chromatography–mass spectrometry‐based metabolomics analysis of the murine TRAnsgenic Cancer of the Kidney (TRACK) model for early‐stage ccRCC. To validate our findings, we generated RCC4 cell lines with ATF4 gene edits (ATF4‐knockout [KO]) and subjected these cells to metabolic isotope tracing. Analysis of variance, the two‐sided Student's t test, and gene set enrichment analysis were used (p < 0.05) to determine statistical significance. Here we show that most human ccRCC tumors exhibit activation of the transcription factor ATF4. Activation of ATF4 is concomitant with enrichment of the ATF4 gene set and elevated expression of ATF4 target genes ASNS, ALDH1L2, MTHFD2, DDIT3 (CHOP), DDIT4, TRIB3, EIF4EBP1, SLC7A11, and PPP1R15A (GADD34). Transcript profiling and metabolomics analyses show that activated hypoxia‐inducible factor‐1α (HIF1α) signaling in our TRACK ccRCC murine model also induces an ATF4‐mediated ISR. Notably, both normoxic HIF1α signaling in TRACK kidneys and VAD in wild‐type kidneys diminish amino acid levels, increase ASNS, TRIB3, and MTHFD2 messenger RNA levels, and increase levels of lipids and GSH. By metabolic isotope tracing in human RCC4 kidney cancer parental and ATF4 gene‐edited (ATF4‐KO) cell lines, we show that ATF4 increases GSH accumulation in part via activation of the mitochondrial one‐carbon metabolism pathway. Our results demonstrate for the first time that activation of ATF4 enhances GSH accumulation, increases purine and pyrimidine biosynthesis, and contributes to transcriptional and metabolic remodeling in ccRCC. Moreover, constitutive HIF1α expressed only in murine kidney proximal tubules activates ATF4, leading to the metabolic changes associated with the ISR. Our data indicate that HIF1α can promote ccRCC via ATF4 activation. Moreover, lack of Vitamin A in the kidney recapitulates aspects of the ISR.

Transcriptional and metabolic remodeling in clear cell renal cell carcinoma caused by ATF4 activation and the integrated stress response (ISR)

Valproic acid (VPA, valproate, Depakote) is a commonly used anti-seizure medication (ASM) in the treatment of epilepsy and a variety of other neurological disorders. While VPA and other ASMs are efficacious for management of seizures, they also increase the risk for adverse pregnancy outcomes, including neural tube defects (NTDs). Thus, the utility of these drugs during pregnancy and in women of childbearing potential presents a continuing public health challenge. Elucidating the underlying genetic or metabolic risk factors for VPA-affected pregnancies may lead to development of non-teratogenic ASMs, novel prevention strategies, or more targeted methods for managing epileptic pregnancies. To address this challenge, we performed unbiased, whole embryo metabolomic screening of E8.5 mouse embryos from two inbred strains with differential susceptibility to VPA-induced NTDs. We identified metabolites of differential abundance between the two strains, both in response to VPA exposure and in the vehicle controls. Notable enriched pathways included lipid metabolism, carnitine metabolism, and several amino acid pathways, especially cysteine and methionine metabolism. There also was increased abundance of ω-oxidation products of VPA in the more NTD-sensitive strain, suggesting differential metabolism of the drug. Finally, we found significantly reduced levels of hypotaurine in the susceptible strain regardless of VPA status. Based on this information, we hypothesized that maternal supplementation with L-carnitine (400 mg/kg), coenzyme A (200 mg/kg), or hypotaurine (350 mg/kg) would reduce VPA-induced NTDs in the sensitive strain and found that administration of hypotaurine prior to VPA exposure significantly reduced the occurrence of NTDs by close to one-third compared to controls. L-carnitine and coenzyme A reduced resorption rates but did not significantly reduce NTD risk in the sensitive strain. These results suggest that genetic variants or environmental exposures influencing embryonic hypotaurine status may be factors in determining risk for adverse pregnancy outcomes when managing the health care needs of pregnant women exposed to VPA or other ASMs.

Embryonic Hypotaurine Levels Contribute to Strain-Dependent Susceptibility in Mouse Models of Valproate-Induced Neural Tube Defects

Mitochondrial dysfunction and aberrant glycolysis are hallmarks of human clear cell renal cell carcinoma (ccRCC). Whereas glycolysis is thoroughly studied, little is known about the mitochondrial contribution to the pathology of ccRCC. Mitochondrial Ndufa4l2 is predictive of poor survival of ccRCC patients, and in kidney cancer cell lines the protein supports proliferation and colony formation. Its role in ccRCC, however, remains enigmatic. We utilized our established ccRCC model, termed Transgenic Cancer of the Kidney (TRACK), to generate a novel genetically engineered mouse model in which dox-regulated expression of an shRNA decreases Ndufa4l2 levels specifically in the renal proximal tubules (PT). This targeted knockdown of Ndufa4l2 reduced the accumulation of neutral renal lipid and was associated with decreased levels of the ccRCC markers carbonic anhydrase 9 (CA9) and Enolase 1 (ENO1). These findings suggest a link between mitochondrial dysregulation (i.e. high levels of Ndufa4l2), lipid accumulation, and the expression of ccRCC markers ENO1 and CA9, and demonstrate that lipid accumulation and ccRCC development can potentially be attenuated by inhibiting Ndufa4l2.

Mitochondrial Ndufa4l2 Enhances Deposition of Lipids and Expression of Ca9 in the TRACK Model of Early Clear Cell Renal Cell Carcinoma

These findings provide insights into the metabolic requirements of colorectal cancer and reveal a novel approach for its treatment. Serine is a nonessential amino acid generated by the sequential actions of phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT1), and phosphoserine phosphatase (PSPH). Increased serine biosynthesis occurs in several cancers and supports tumor growth. In addition, cancer cells can harness exogenous serine to enhance their metabolism and proliferation. Here we tested the relative contributions of exogenous and endogenous sources of serine on the biology of colorectal cancer. In murine tumors, Apc status was identified as a determinant of the expression of genes controlling serine synthesis. In patient samples, PSAT1 was overexpressed in both colorectal adenomas and adenocarcinomas. Combining genetic deletion of PSAT1 with exogenous serine deprivation maximally suppressed the proliferation of colorectal cancer cells and induced profound metabolic defects including diminished nucleotide production. Inhibition of serine synthesis enhanced the transcriptional changes following exogenous serine removal as well as alterations associated with DNA damage. Both loss of PSAT1 and removal of serine from the diet were necessary to suppress colorectal cancer xenograft growth and enhance the antitumor activity of 5-fluorouracil (5-FU). Restricting endogenous and exogenous serine in vitro augmented 5-FU–induced cell death, DNA damage, and metabolic perturbations, likely accounting for the observed antitumor effect. Collectively, our results suggest that both endogenous and exogenous sources of serine contribute to colorectal cancer growth and resistance to 5-FU. Significance: These findings provide insights into the metabolic requirements of colorectal cancer and reveal a novel approach for its treatment. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/81/9/2275/F1.large.jpg. Graphical Abstract

Exogenous and Endogenous Sources of Serine Contribute to Colon Cancer Metabolism, Growth, and Resistance to 5-Fluorouracil

Measurement of melanin metabolism in live cells by [U-13C]-tyrosine fate tracing using LC-MS.

Alcohol abuse reduces hepatic vitamin A (retinoids), reductions that are associated with progression of alcohol liver disease (ALD). Restoring hepatic retinoids through diet is contraindicated in ALD due to the negative effects of alcohol on retinoid metabolism. There are currently no drugs that can both mitigate alcohol‐driven hepatic retinoid losses and progression of ALD. Using a mouse model of alcohol intake, we examined if an agonist for the retinoic acid (RA) receptor β2 (RARβ2), AC261066 (AC261) could prevent alcohol‐driven hepatic retinoid losses and protect against ALD. Our results show that mice co‐treated with AC261 and alcohol displayed mitigation of ALD, including reduced macro, and microvesicular steatosis, and liver damage. Alcohol intake led to increases in hepatic centrilobular levels of ALDH1A1, a rate‐limiting enzyme in RA synthesis, and co‐localization of ALDH1A1 with the alcohol‐metabolizing enzyme CYP2E1, and 4‐HNE, a marker of oxidative stress; expression of these targets was abrogated in mice co‐treated with AC261 and alcohol. By RNA sequencing technology, we found that AC261 treatments opposed alcohol modulation of 68 transcripts involved in canonical retinoid metabolism. Alcohol modulation of these transcripts, including CES1D, CES1G, RBP1, RDH10, and CYP26A1, collectively favor hepatic retinoid hydrolysis and catabolism. However, despite this, co‐administration of AC261 with alcohol did not mitigate alcohol‐mediated depletions of hepatic retinoids, but did reduce alcohol‐driven increases in serum retinol. Our data show that AC261 protected mice against ALD, even though AC261 did not prevent alcohol‐mediated reductions in hepatic retinoids. These data warrant further studies of the anti‐ALD properties of AC261.

A retinoic acid receptor β2 agonist protects against alcohol liver disease and modulates hepatic expression of canonical retinoid metabolism genes

KRAS is the most frequently mutated oncogene in human lung adenocarcinomas (hLUAD) and activating mutations in KRAS frequently co-occur with loss-of-function mutations in the tumor suppressor genes, TP53 or STK11/LKB1. However, mutation of all three genes is rarely observed in hLUAD, even though engineered mutations of all three genes produces a highly aggressive lung adenocarcinoma in mice (mLUAD). Here we provide an explanation of this difference between hLUAD and mLUAD by uncovering an evolutionary divergence in regulation of the glycolytic enzyme triosephosphate isomerase (TPI1). Using KRAS/TP53 mutant hLUAD cell lines, we show that TPI1 enzymatic activity can be altered via phosphorylation at Ser21 by the Salt Inducible Kinases (SIKs) in an LKB1-dependent manner; this allows modulation of glycolytic flux between completion of glycolysis and production of glycerol lipids. This metabolic flexibility appears to be critical in rapidly growing cells with KRAS and TP53 mutations, explaining why loss of LKB1 creates a metabolic liability in these tumors. In mice, the amino acid at position 21 of TPI1 is a Cys residue which can be oxidized to alter TPI1 activity, allowing regulation of glycolytic flux balance without a need for SIK kinases or LKB1. Our findings reveal an unexpected role for TPI1 in metabolic reprogramming and suggest that LKB1 and SIK family kinases are potential targets for treating KRAS/TP53 mutant hLUAD. Our data also provide a cautionary example of the limits of genetically engineered murine models as tools to study human diseases such as cancers.

Non-conserved metabolic regulation by LKB1 distinguishes human and mouse lung adenocarcinoma

Noninvasive biomarkers of kidney allograft status can help minimize the need for standard of care kidney allograft biopsies. Metabolites that are measured in the urine may inform about kidney function and health status, and potentially identify rejection events. To test these hypotheses, we conducted a metabolomics study of biopsy-matched urine cell-free supernatants from kidney allograft recipients who were diagnosed with two major types of acute rejections and no-rejection controls. Non-targeted metabolomics data for 674 metabolites and 577 unidentified molecules, for 192 biopsy-matched urine samples, were analyzed. Univariate and multivariate analyses identified metabolite signatures for kidney allograft rejection. The replicability of a previously developed urine metabolite signature was examined. Our study showed that metabolite profiles can serve as biomarkers for discriminating rejection biopsies from biopsies without rejection features, but also revealed a role of estimated Glomerular Filtration Rate (eGFR) as a major confounder of the metabolite signal.

Kidney Allograft Function Is a Confounder of Urine Metabolite Profiles in Kidney Allograft Recipients

Abstract 3745: Exogenous and endogenous sources of serine contribute to colon cancer metabolism and growth

Accelerated transsulfuration metabolically defines a discrete subclass of amyotrophic lateral sclerosis patients

Neural tube closure is a critical early step in central nervous system development that requires precise control of metabolism to ensure proper cellular proliferation and differentiation. Dysregulation of glucose metabolism during pregnancy has been associated with neural tube closure defects (NTDs) in humans suggesting that the developing neuroepithelium is particularly sensitive to metabolic changes. However, it remains unclear how metabolic pathways are regulated during neurulation. Here, we used single-cell mRNA-sequencing to analyze expression of genes involved in metabolism of carbon, fats, vitamins, and antioxidants during neurulation in mice and identify a coupling of glycolysis and cellular proliferation to ensure proper neural tube closure. Using loss of miR-302 as a genetic model of cranial NTD, we identify misregulated metabolic pathways and find a significant upregulation of glycolysis genes in embryos with NTD. These findings were validated using mass spectrometry-based metabolite profiling, which identified increased glycolytic and decreased lipid metabolites, consistent with a rewiring of central carbon traffic following loss of miR-302. Predicted miR-302 targets Pfkp, Pfkfb3, and Hk1 are significantly upregulated upon NTD resulting in increased glycolytic flux, a shortened cell cycle, and increased proliferation. Our findings establish a critical role for miR-302 in coordinating the metabolic landscape of neural tube closure.

MiR-302 Regulates Glycolysis to Control Cell-Cycle during Neural Tube Closure

Radiation-induced adenosine production is identified as a barrier that limits radiotherapy-induced antitumor immune responses. Antibodies to CD73 that block adenosine generation could be used in combination with radiotherapy and immune checkpoint blockade to improve response to radiation therapy. The ability of focal radiotherapy to promote priming of tumor-specific CD8+ T cells and increase responses to immunotherapy is dependent on infiltration of the tumor by Batf3-dependent conventional dendritic cell type 1 (cDC1) cells. Such infiltration is driven by radiotherapy-induced IFN type I (IFN-I). Other signals may also modulate cDC1 infiltration of irradiated tumors. Here we found increased expression of adenosine-generating enzymes CD38 and CD73 in irradiated mouse and human breast cancer cells and increased adenosine in mouse tumors following radiotherapy. CD73 blockade alone had no effect. CD73 blockade with radiotherapy restored radiotherapy-induced cDC1 infiltration of tumors in settings where radiotherapy induction of IFN-I was suboptimal. In the absence of radiotherapy-induced IFN-I, blockade of CD73 was required for rejection of the irradiated tumor and for systemic tumor control (abscopal effect) in the context of cytotoxic T-lymphocyte–associated protein 4 blockade. These results suggest that CD73 may be a radiation-induced checkpoint, and that CD73 blockade in combination with radiotherapy and immune checkpoint blockade might improve patient response to therapy.

CD73 Blockade Promotes Dendritic Cell Infiltration of Irradiated Tumors and Tumor Rejection

Abstract An increasing number of studies have suggested a potential link between sugar consumption and cancer. However, a direct relationship between the two remains controversial. Here, we treated APC-mutant mice daily with a modest amount of high-fructose corn syrup (HFCS) via oral gavage to mimic sugar-sweetened beverage (SSB) consumption and evaluated the effects of SSBs on intestinal tumorigenesis. We observed a dramatic increase in tumor size and tumor grade in HFCS-treated mice despite no signs of obesity or metabolic syndrome. A bolus of HFCS spikes the level of fructose and glucose in the intestinal lumen and serum, respectively, allowing tumors to take up both sugars efficiently. Ketohexokinase (KHK) in tumors rapidly converts fructose to fructose-1-phosphate (F1P), lowering cytosolic ATP in the process. Consequently, this leads to the activation of glycolysis as ATP depletion relieves the allosteric inhibition of phosphofructokinase (PFK), the most critical regulatory enzyme in glycolysis. This accelerated glycolysis contributes to the increased de novo lipogenesis pathway that enhances tumor growth in HFCS-treated mice. Importantly, the deletion of KHK or fatty acid synthase (FASN) in APC-mutant mice abolishes the HFCS-induced metabolic changes and tumor growth. Overall, our results provide a mechanistic rationale for restricting SSB consumption to decrease the rate of growth of early stage colorectal cancers. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

SAT-LB057 High-Fructose Corn Syrup Enhances Intestinal Tumor Growth in Mice

Ethanol (EtOH) is a teratogen, but its teratogenic mechanisms are not fully understood. The alcohol form of vitamin A (retinol/ROL) can be oxidized to all-trans-retinoic acid (RA), which plays a critical role in stem cell differentiation and development. Using an embryonic stem cell (ESC) model to analyze EtOH's effects on differentiation, we show here that EtOH and acetaldehyde, but not acetate, increase differentiation-associated mRNA levels, and that EtOH decreases pluripotency-related mRNAs. Using reporter assays, ChIP assays, and retinoic acid receptor-γ (RARγ) knockout ESC lines generated by CRISPR/Cas9 and homologous recombination, we demonstrate that EtOH signals via RARγ binding to RA response elements (RAREs) in differentiation-associated gene promoters or enhancers. We also report that EtOH-mediated increases in homeobox A1 (Hoxa1) and cytochrome P450 family 26 subfamily A member 1 (Cyp26a1) transcripts, direct RA target genes, require the expression of the RA-synthesizing enzyme, aldehyde dehydrogenase 1 family member A2 (Aldh1a2), suggesting that EtOH-mediated induction of Hoxa1 and Cyp26a1 requires ROL from the serum. As shown with CRISPR/Cas9 knockout lines, the retinol dehydrogenase gene Rdh10 and a functional RARE in the ROL transporter stimulated by retinoic acid 6 (Stra6) gene are required for EtOH induction of Hoxa1 and Cyp26a1. We conclude that EtOH stimulates stem cell differentiation by increasing the influx and metabolism of ROL for downstream RARγ-dependent transcription. In stem cells, EtOH may shift cell fate decisions to alter developmental outcomes by increasing endogenous ROL/RA signaling via increased Stra6 expression and ROL oxidation.

Ethanol promotes differentiation of embryonic stem cells through retinoic acid receptor-γ

Antibody cross-reactivity accounts for widespread appearance of m1A in 5’UTRs

Ethanol (EtOH) is a teratogen that causes severe birth defects, but the mechanisms by which EtOH affects stem cell differentiation are unclear. Our goal here is to examine the effects of EtOH and its metabolites, acetaldehyde (AcH) and acetate, on embryonic stem cell (ESC) differentiation.

METHODS
We designed ESC lines in which aldehyde dehydrogenase (ALDH2, NCBI#11669) and acetyl CoA synthetase short chain family member 2 (ACSS2, NCBI#60525) were knocked out by CRISPR-Cas9 technology. We selected these genes because of their key roles in EtOH oxidation in order to dissect the effects of EtOH metabolism on differentiation.

RESULTS
By using kinetics assays we confirmed that AcH is primarily oxidized by ALDH2 rather than ALDH1A2. We found increases in mRNAs of differentiation-associated genes (Hoxa1, Cyp26a1, and RARβ2) upon EtOH treatment of WT and Acss2-/- ESCs, but not Aldh2-/- ESCs. The absence of ALDH2 reduced mRNAs of some pluripotency factors (Nanog, Sox2, and Klf4). Treatment of WT ESCs with AcH or 4-hydroxynonenal (4-HNE), another substrate of ALDH2, increased differentiation-associated transcripts compared to levels in untreated cells. mRNAs of genes involved in retinoic acid (RA) synthesis (Stra6 and Rdh10) were also increased by EtOH, acetaldehyde, and 4-HNE treatment. Retinoic acid receptor-γ (RARγ) is required for both EtOH- and AcH-mediated increases in Hoxa1 and Stra6, demonstrating the critical role of RA:RARγ signaling in AcH-induced ESC differentiation.

ACSS2 knockouts showed no changes in differentiation phenotype while pluripotency-related transcripts were decreased in ALDH2 knockout ESCs. We demonstrate that AcH increases differentiation-associated mRNAs in ESCs via RARγ. This article is protected by copyright. All rights reserved.

Different effects of knockouts in ALDH2 and ACSS2 on embryonic stem cell differentiation.

FTO controls reversible m6Am RNA methylation during snRNA biogenesis

A sweetener's not-so-sweet effects Obesity increases an individual's risk of developing many types of cancer, including colorectal cancer. One of the factors driving the rise in obesity rates is thought to be the use of high-fructose corn syrup (HFCS) as a sweetener in soft drinks. Goncalves et al. found that ingestion of HFCS promotes the growth of intestinal cancer even in the absence of obesity in mouse tumor models. An enzyme in tumors (ketohexokinase) converts fructose to fructose-1-phosphate, which alters tumor cell metabolism and leads to enhanced cell growth. Whether a similar process occurs in humans remains to be seen. Science, this issue p. 1345 Eating high-fructose corn syrup enhances growth of intestinal cancer in mice by altering tumor cell metabolism. Excessive consumption of beverages sweetened with high-fructose corn syrup (HFCS) is associated with obesity and with an increased risk of colorectal cancer. Whether HFCS contributes directly to tumorigenesis is unclear. We investigated the effects of daily oral administration of HFCS in adenomatous polyposis coli (APC) mutant mice, which are predisposed to develop intestinal tumors. The HFCS-treated mice showed a substantial increase in tumor size and tumor grade in the absence of obesity and metabolic syndrome. HFCS increased the concentrations of fructose and glucose in the intestinal lumen and serum, respectively, and the tumors transported both sugars. Within the tumors, fructose was converted to fructose-1-phosphate, leading to activation of glycolysis and increased synthesis of fatty acids that support tumor growth. These mouse studies support the hypothesis that the combination of dietary glucose and fructose, even at a moderate dose, can enhance tumorigenesis.

High-fructose corn syrup enhances intestinal tumor growth in mice

Combined Metabolomics and Genome-Wide Transcriptomics Analyses Show Multiple HIF1α-Induced Changes in Lipid Metabolism in Early Stage Clear Cell Renal Cell Carcinoma

Amyotrophic lateral sclerosis (ALS) is a disease characterized by progressive paralysis and death. Most ALS cases are sporadic (sALS) and patient heterogeneity poses a formidable challenge for the development of viable biomarkers and effective therapies. Applying untargeted metabolite profiling on 77 sALS patient-derived primary dermal fibroblast lines and 45 sex/age matched controls, we found that ∼25% of cell lines (termed sALS-1) are characterized by upregulated trans-sulfuration, where methionine-derived homocysteine is channeled into cysteine and glutathione synthesis. sALS-1 fibroblasts exhibit a growth defect when grown under oxidative conditions, that can be fully-rescued by N-acetylcysteine. [U-13C]-glucose tracing shows that activation of the trans-sulfuration pathway is associated with accelerated glucose flux into the TCA cycle. Based on four metabolites, we developed a support vector machine model capable of distinguishing sALS-1 with 97.5% accuracy. Importantly, plasma metabolite profiling identifies a systemic perturbation of cysteine metabolism as a hallmark of sALS-1. These results indicate that sALS patients can be stratified into distinct metabotypes, differently sensitive to metabolic stress, and provides new insights into metabolic biomarkers for personalized sALS therapy.

Accelerated trans-sulfuration metabolically defines a discrete subclass of ALS patients

Ethylmalonic Encephalopathy Protein 1 (ETHE1) is a sulfur dioxygenase that regulates cellular H2S levels. We previously demonstrated a significant increase of ETHE1 expression in "single-hit" colon epithelial cells from crypts of patients with Familial Adenomatous Polyposis (FAP). Here, we report elevated levels of ETHE1 expression and increased mitochondrial density occurring in-situ in phenotypically normal FAP colorectal mucosa. We also found that constitutive expression of ETHE1 increased aerobic glycolysis ("Warburg effect"), oxidative phosphorylation, and mitochondrial biogenesis in colorectal cancer (CRC) cell lines, thereby depleting H2S which relieved the inhibition of phosphodiesterase (PDE), and increased adenosine monophosphate (AMP) levels. This led to activation of the energy sensing AMP-activated protein kinase (AMPKp), Sirtuin1 (SIRT1) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), a master regulator of mitochondrial biogenesis. By contrast, shRNA silencing of ETHE1 reduced PDE activity, AMPKp/SIRT1/PGC1α levels and mitochondrial biogenesis. Constitutive expression of ETHE1 accelerated both CRC cell xenograft and orthotopic patient derived xenograft CRC cell growth in vivo. Overall, our data nominate elevated ETHE1 expression levels as a novel biomarker and potential therapeutic target for the prevention of CRC tumorigenesis.

ETHE1 overexpression promotes SIRT1 and PGC1α mediated aerobic glycolysis, oxidative phosphorylation, mitochondrial biogenesis and colorectal cancer

Untargeted Metabolite Profiling of Cerebrospinal Fluid Uncovers Biomarkers for Severity of Late Infantile Neuronal Ceroid Lipofuscinosis (CLN2, Batten Disease)

APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice

Sporadic amyotrophic lateral sclerosis (sALS) is a progressive motor neuron disease resulting in paralysis and death. Genes responsible for familial ALS have been identified, however the molecular basis for sALS is unknown. To discover metabotypic biomarkers that inform on disease etiology, untargeted metabolite profiling was performed on 77 patient-derived dermal fibroblast lines and 45 age/sex-matched controls. Surprisingly, 25% of sALS lines showed upregulated methionine-derived homocysteine, channeled to cysteine and glutathione (GSH). Stable isotope tracing of [U-13C]-glucose showed activation of the trans-sulfuration pathway, associated with accelerated glucose flux into the TCA cycle, glutamate, GSH, alanine, aspartate, acylcarnitines and nucleotide phosphates. A four-molecule support vector machine model distinguished the sALS subtype from controls with 97.5% accuracy. Plasma metabolite profiling identified increased taurine as a hallmark metabolite for this sALS subset, suggesting systemic perturbation of cysteine metabolism. Furthermore, integrated multiomics (mRNAs/microRNAs/metabolites) identified the super-trans-sulfuration pathway as a top hit for the sALS subtype. We conclude that sALS can be stratified into distinct metabotypes, providing for future development of personalized therapies that offer new hope to sufferers.

Identification of a Distinct Metabolomic Subtype of Sporadic ALS Patients

Rewiring of Glutamine Metabolism Is a Bioenergetic Adaptation of Human Cells with Mitochondrial DNA Mutations.

Suppressing glutaminolysis does not always induce cancer cell death in glutamine-dependent tumors because cells may switch to alternative energy sources. To reveal compensatory metabolic pathways, we investigated the metabolome-wide cellular response to inhibited glutaminolysis. We conducted metabolic profiling in the triple-negative breast cancer cell line MB-MDA-231, treated with different dosages of glutaminase inhibitor C.968 at multiple time points. We found that multiple molecules involved in lipid catabolism responded directly to glutamate deficiency as a presumed compensation for energy deficit. Accelerated lipid catabolism, together with oxidative stress induced by glutaminolysis inhibition, triggered autophagy. We therefore simultaneously inhibited glutaminolysis and autophagy, which induced cancer cell death. Our study emphasizes the potential of non-targeted metabolomics to characterize and identify metabolic escape mechanisms contributing to cancer cell survival under treatment. Our findings add to the increasing evidence that combined inhibition of glutaminolysis and autophagy may be effective in glutamine-addicted cancers.

Accelerated lipid catabolism and autophagy are cancer survival mechanisms under inhibited glutaminolysis

HSP90-incorporating chaperome networks as biosensor for disease-related pathways in patient-specific midbrain dopamine neurons

Accelerated lipid catabolism and autophagy are cancer survival mechanisms under inhibited glutaminolysis.

Small nuclear RNAs (snRNAs) are core spliceosome components and mediate pre-mRNA splicing. During their biogenesis, snRNAs acquire several constitutive nucleotide modifications. Here we show that snRNAs also contain a regulated and reversible nucleotide modification causing them to exist as two different methyl isoforms, m1 and m2, reflecting the methylation state of the adenosine adjacent to the snRNA cap. We find that snRNA biogenesis involves the formation of an initial m1-isoform with a single-methylated adenosine (2’-O-methyladenosine, Am), which is then converted to a dimethylated m2-isoform (N6,2’-O-dimethyladenosine, m6Am). The relative m1- and m2-isoform levels are determined by the RNA demethylase FTO, which selectively demethylates the m2-isoform. We show FTO is inhibited by endogenous metabolites, resulting in increased m2-snRNA levels. Furthermore, cells that exhibit high m2-snRNA levels show altered patterns of alternative splicing. Together, these data reveal that FTO has a central role in snRNA biogenesis and controls a previously unknown step of snRNA processing involving reversible methylation, thereby providing a potential link between reversible RNA modifications and mRNA splicing.

The RNA demethylase FTO targets m6Am in snRNA to establish distinct methyl isoforms that influence splicing

cal Reactivity of Nitric Oxide, J. Exp. Med., (1989) vol. 169, 1011-1020. Rees, D. D. et al., Role of Endothelium-Derived Nitric Oxide in the Regulation of Blood Pressure, Proc. Natl. Acad. Sci. U.S.A., (1989) vol. 86, 3375-3378. Aisaka, K. et al., NG-Methylarginine, An Inhibitor of Endothelium-Derived Nitric Oxide Synthesis, is a Po tent Pressor Agent in the Guinea Pig: Does Nitric Oxide Regulate Blood Pressure in vivo, Biochem. Bio phys. Res. Commun. (1989) 160:881-886. (List continued on next page.)

United States Patent ( 19 ) Gross et al . ( 54 ) NITRICOXIDE SYNTHESIS INHIBITORS FOR POTENTIATING THE ACTION OF PRESSORAGENTS IN CERTAIN HYPOTENSIVE PATIENTS

APOE4 INDUCES ENTORHINAL CORTEX HYPERMETABOLISM IN THE ABSENCE OF OVERT ALZHEIMER’S DISEASE PATHOLOGY

Blockade of alcohol escalation and “relapse” drinking by pharmacological FAAH inhibition in male and female C57BL/6J mice

Partitioning of One-Carbon Units in Folate and Methionine Metabolism Is Essential for Neural Tube Closure

Valproic acid (VPA) is prescribed therapeutically for multiple conditions, including epilepsy. When taken during pregnancy, VPA is teratogenic, increasing the risk of several birth and developmental defects including neural tube defects (NTDs). The mechanism by which VPA causes NTDs remains controversial and how VPA interacts with folic acid (FA), a vitamin commonly recommended for the prevention of NTDs, remains uncertain. We sought to address both questions by applying untargeted metabolite profiling analysis to neural tube closure (NTC) stage mouse embryos.

METHODS
Pregnant SWV dams on either a 2 ppm or 10 ppm FA supplemented diet were injected with a single dose of VPA on gestational day E8.5. On day E9.5, the mouse embryos were collected and evaluated for NTC status. Liquid chromatography coupled to mass spectrometry metabolomics analysis was performed to compare metabolite profiles of NTD-affected VPA-exposed whole mouse embryos with profiles from embryos that underwent normal NTC from control dams.

RESULTS
NTDs were observed in all embryos from VPA-treated dams and penetrance was not diminished by dietary FA supplementation. The most profound metabolic perturbations were found in the 10ppm FA VPA-exposed mouse embryos, compared with the other three treatment groups. Affected metabolites included amino acids, nucleobases and related phosphorylated nucleotides, lipids, and carnitines.

Maternal VPA treatment markedly perturbed purine and pyrimidine metabolism in E9.5 embryos. In combination with a high FA diet, VPA treatment resulted in gross metabolic changes, likely caused by a multiplicity of mechanisms, including an apparent disruption of mitochondrial beta-oxidation. Birth Defects Research 109:106-119, 2017. © 2016 Wiley Periodicals, Inc.

Metabolite profiling of whole murine embryos reveals metabolic perturbations associated with maternal valproate-induced neural tube closure defects.

Abstract Background: Metaplastic breast cancer is one of the most therapeutically challenging forms of breast cancer because of its highly heterogeneous and chemoresistant nature. We have previously demonstrated that ribosomal protein L39 (RPL39) and its gain-of-function mutation A14V have oncogenic activity in triple-negative breast cancer and this activity may be mediated through inducible nitric oxide synthase (iNOS). The function of RPL39 and A14V in other breast cancer subtypes is currently unknown. The objective of this study was to determine the role and mechanism of action of RPL39 in metaplastic breast cancer. Methods: Both competitive allele-specific and droplet digital polymerase chain reaction were used to determine the RPL39 A14V mutation rate in metaplastic breast cancer patient samples. The impact of RPL39 and iNOS expression on patient overall survival was estimated using the Kaplan-Meier method. Co-immunoprecipitation and immunoblot analyses were used for mechanistic evaluation of RPL39. Results: The RPL39 A14V mutation rate was 97.5% (39/40 tumor samples). High RPL39 (hazard ratio = 0.71, 95% confidence interval = 0.55 to 0.91, P = .006) and iNOS expression (P = .003) were associated with reduced patient overall survival. iNOS inhibition with the pan-NOS inhibitor NG-methyl-L-arginine acetate decreased in vitro proliferation and migration, in vivo tumor growth in both BCM-4664 and BCM-3807 patient-derived xenograft models (P = .04 and P = .02, respectively), and in vitro and in vivo chemoresistance. Mechanistically, RPL39 mediated its cancer-promoting actions through iNOS signaling, which was driven by the RNA editing enzyme adenosine deaminase acting on RNA 1. Conclusion: NOS inhibitors and RNA editing modulators may offer novel treatment options for metaplastic breast cancer.

Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer’s disease-like pathology

Fibroblast bioenergetics to classify amyotrophic lateral sclerosis patients

Untargeted metabolite profiling reveals that nitric oxide bioynthesis is an endogenous modulator of carotenoid biosynthesis in Deinococcus radiodurans and is required for extreme ionizing radiation resistance.

Nitration of tyrosine and other aromatic amino acid residues in proteins occurs in the setting of inflammatory, neurodegenerative, and cardiovascular diseases—importantly, this modification has been implicated in the pathogenesis of diverse diseases and the physiological process of aging. To understand the biological consequences of aromatic nitration in both health and disease, it is critical to molecularly identify the proteins that undergo nitration, specify their cognate modification sites and quantify their extent of nitration. To date, unbiased identification of nitrated proteins has often involved painstaking 2D-gel electrophoresis followed by Western Blotting with an anti-nitrotyrosine antibody for detection. Apart from being relatively slow and laborious, this method suffers from limited coverage, the potential for false-positive identifications, and failure to reveal specific amino acid modification sites. To overcome these shortcomings, we have developed a solid-phase, chemical-capture approach for unbiased and high-throughput discovery of nitrotyrosine and nitrotryptophan sites in proteins. Utilizing this method, we have successfully identified several endogenously nitrated proteins in rat brain and a total of 244 nitrated peptides from 145 proteins following in vitro exposure of rat brain homogenates to the nitrating agent peroxynitrite (1 mM). As expected, Tyr residues constituted the great majority of peroxynitrite-mediated protein nitration sites; however, we were surprised to discover several brain proteins that contain nitrated Trp residues. By incorporating a stable-isotope labeling step, this new Aromatic Nitration Site IDentification (ANSID) method was also adapted for relative quantification of nitration site abundances in proteins. Application of the ANSID method offers great potential to advance our understanding of the role of protein nitration in disease pathogenesis and normal physiology.

ANSID: A Solid-Phase Proteomic Approach for Identification and Relative Quantification of Aromatic Nitration Sites

Metabolomics enables precision medicine: “A White Paper, Community Perspective”

Treatment with celecoxib, a selective COX-2 inhibitor, reduces formation of premalignant adenomatous polyps in the gastrointestinal tracts of humans and mice. In addition to its chemopreventive activity, celecoxib can exhibit antimicrobial activity. Differing bacterial profiles have been found in feces from colon cancer patients compared with those of normal subjects. Moreover, preclinical studies suggest that bacteria can modulate intestinal tumorigenesis by secreting specific metabolites. In the current study, we determined whether celecoxib treatment altered the luminal microbiota and metabolome in association with reducing intestinal polyp burden in mice. Administration of celecoxib for 10 weeks markedly reduced intestinal polyp burden in APCMin/+ mice. Treatment with celecoxib also altered select luminal bacterial populations in both APCMin/+ and wild-type mice, including decreased Lactobacillaceae and Bifidobacteriaceae as well as increased Coriobacteriaceae. Metabolomic analysis demonstrated that celecoxib caused a strong reduction in many fecal metabolites linked to carcinogenesis, including glucose, amino acids, nucleotides, and lipids. Ingenuity Pathway Analysis suggested that these changes in metabolites may contribute to reduced cell proliferation. To this end, we showed that celecoxib reduced cell proliferation in the base of normal appearing ileal and colonic crypts of APCMin/+ mice. Consistent with this finding, lineage tracing indicated that celecoxib treatment reduced the rate at which Lgr5-positive stem cells gave rise to differentiated cell types in the crypts. Taken together, these results demonstrate that celecoxib alters the luminal microbiota and metabolome along with reducing epithelial cell proliferation in mice. We hypothesize that these actions contribute to its chemopreventive activity. Cancer Prev Res; 9(9); 721–31. ©2016 AACR.

Celecoxib Alters the Intestinal Microbiota and Metabolome in Association with Reducing Polyp Burden

The airway epithelium is a complex pseudostratified multicellular layer lining the tracheobronchial tree, functioning as the primary defense against inhaled environmental contaminants. The major cell types of the airway epithelium include basal, intermediate columnar, ciliated, and secretory. Basal cells (BCs) are the proliferating stem/progenitor population that differentiate into the other specialized cell types of the airway epithelium during normal turnover and repair. Given that cigarette smoke delivers thousands of xenobiotics and high levels of reactive molecules to the lung epithelial surface, we hypothesized that cigarette smoke broadly perturbs BC metabolism. To test this hypothesis, primary airway BCs were isolated from healthy nonsmokers (n = 11) and healthy smokers (n = 7) and assessed by global metabolic profiling by liquid chromatography-mass spectrometry. The analysis identified 52 significant metabolites in BCs differentially expressed between smokers and nonsmokers (P < 0.05). These changes included metabolites associated with redox pathways, energy production, and inflammatory processes. Notably, BCs from smokers exhibited altered levels of the key enzyme cofactors/substrates nicotinamide adenine dinucleotide, flavin adenine dinucleotide, acetyl coenzyme A, and membrane phospholipid levels. Consistent with the high burden of oxidants in cigarette smoke, glutathione levels were diminished, whereas 3-nitrotyrosine levels were increased, suggesting that protection of airway epithelial cells against oxidative and nitrosative stress is significantly compromised in smoker BCs. It is likely that this altered metabotype is a reflection of, and likely contributes to, the disordered biology of airway BCs consequent to the stress cigarette smoking puts on the airway epithelium.

Smoking-Associated Disordering of the Airway Basal Stem/Progenitor Cell Metabotype.

RATIONALE
Waterpipes, also called hookahs, are currently used by millions of people worldwide. Despite the increasing use of waterpipe smoking, there is limited data on the health effects of waterpipe smoking and there are no federal regulations regarding its use.

To assess the effects of waterpipe smoking on the human lung using clinical and biological parameters in young, light-use waterpipe smokers.

METHODS
We assessed young, light-use, waterpipe-only smokers in comparison with lifelong nonsmokers using clinical parameters of cough and sputum scores, lung function, and chest high-resolution computed tomography as well as biological parameters of lung epithelial lining fluid metabolome, small airway epithelial (SAE) cell differential and transcriptome, alveolar macrophage transcriptome, and plasma apoptotic endothelial cell microparticles.

Compared with nonsmokers, waterpipe smokers had more cough and sputum as well as a lower lung diffusing capacity, abnormal epithelial lining fluid metabolome profile, increased proportions of SAE secretory and intermediate cells, reduced proportions of SAE ciliated and basal cells, markedly abnormal SAE and alveolar macrophage transcriptomes, and elevated levels of apoptotic endothelial cell microparticles.

Young, light-use, waterpipe-only smokers have a variety of abnormalities in multiple lung-related biological and clinical parameters, suggesting that even limited waterpipe use has broad consequences on human lung biology and health. We suggest that large epidemiological studies should be initiated to investigate the harmful effects of waterpipe smoking.

Pulmonary Abnormalities in Young, Light-Use Waterpipe (Hookah) Smokers.

Introduction: Celecoxib is a chemopreventive agent that reduces adenomatous polyp number in the gastrointestinal tract of humans and mice and is thought to exert its effects exclusively through inhibition of COX-2. Bacteria have been shown to impact upon intestinal tumorigenesis in part by secretion of key metabolites. However, it is unknown whether celecoxib may be reducing polyp burden at least in part, through effects on the luminal microbiota or metabolome. This study tested whether celecoxib can alter the luminal microbiota and metabolome in association with reducing intestinal polyps in APCMin/+ mice, potentially providing a novel mechanism by which it exerts its chemopreventive effects. Methods: APCMin/+ and wild-type (WT) mice were co-housed for 2 weeks to normalize their microbiota, then individually housed and administered control or celecoxib-containing diet from 6 to 16 weeks of age. Feces were collected at 6, 11 and 16 weeks of age and ileal content and intestinal tissue (to quantify polyp burden) were collected at 16 weeks. Bacterial composition analysis on ileal content and feces was carried out using 16S rDNA sequencing and relative fecal metabolite levels were measured using UPLC/MS/MS and GC/MS. Results: As expected, administration of celecoxib for 10 weeks markedly reduced intestinal polyp burden in APCMin/+ mice. Concomitant with this effect, drug administration altered the luminal bacterial populations, a shift that also occurred in WT mice. These changes included increased Coriobacteriaceae and decreased Lactobacillaceae and Bifidobacteriaceae. Subsequent metabolomic analysis demonstrated that celecoxib caused a strong reduction in many fecal metabolites including glucose, amino acids, nucleotides and lipids. Ingenuity Pathway Analysis revealed that this change in metabolomic profile was associated with pathway perturbations that could contribute to reduced cell proliferation. Lastly, we showed that the observed changes were associated with a reduction in stem cell proliferation in normal intestinal crypts of APCMin/+ mice. Conclusions: These results demonstrate that celecoxib treatment profoundly altered the luminal microbiota and metabolome of mice and we hypothesize that these actions contribute to its chemopreventive activity. Further studies are warranted to confirm this hypothesis and assess whether our findings extend to humans and to other nonsteroidal anti-inflammatory drugs. Citation Format: David C. Montrose, Xi K. Zhou, Erin M. McNally, Erika Sue, Steven S. Gross, Nitai D. Leve, Edward D. Karoly, Lilan Ling, Eric G. Pamer, Andrew J. Dannenberg. Celecoxib alters the intestinal microbiota and metabolome in association with reducing polyp burden. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-302.

Abstract LB-302: Celecoxib alters the intestinal microbiota and metabolome in association with reducing polyp burden

Noninvasive diagnosis and prognostication of acute cellular rejection in the kidney allograft may help realize the full benefits of kidney transplantation. To investigate whether urine metabolites predict kidney allograft status, we determined levels of 749 metabolites in 1516 urine samples from 241 kidney graft recipients enrolled in the prospective multicenter Clinical Trials in Organ Transplantation-04 study. A metabolite signature of the ratio of 3-sialyllactose to xanthosine in biopsy specimen-matched urine supernatants best discriminated acute cellular rejection biopsy specimens from specimens without rejection. For clinical application, we developed a high-throughput mass spectrometry-based assay that enabled absolute and rapid quantification of the 3-sialyllactose-to-xanthosine ratio in urine samples. A composite signature of ratios of 3-sialyllactose to xanthosine and quinolinate to X-16397 and our previously reported urinary cell mRNA signature of 18S ribosomal RNA, CD3ε mRNA, and interferon-inducible protein-10 mRNA outperformed the metabolite signatures and the mRNA signature. The area under the receiver operating characteristics curve for the composite metabolite-mRNA signature was 0.93, and the signature was diagnostic of acute cellular rejection with a specificity of 84% and a sensitivity of 90%. The composite signature, developed using solely biopsy specimen-matched urine samples, predicted future acute cellular rejection when applied to pristine samples taken days to weeks before biopsy. We conclude that metabolite profiling of urine offers a noninvasive means of diagnosing and prognosticating acute cellular rejection in the human kidney allograft, and that the combined metabolite and mRNA signature is diagnostic and prognostic of acute cellular rejection with very high accuracy.

Urine Metabolite Profiles Predictive of Human Kidney Allograft Status.

Behavioural traits propagate across generations via segregated iterative-somatic and gametic epigenetic mechanisms

Reversible methylation of m6Am in the 5′ cap controls mRNA stability

A requirement for Gch1 and tetrahydrobiopterin in embryonic development

Getting all stressed out by vitamin C Few experimental cancer therapies have incited as much debate as vitamin C. Yet the mechanistic effect of vitamin C on cancer cells is still poorly understood. Yun et al. studied human colorectal cancer cells with KRAS or BRAF mutations and found that they “handle” vitamin C in a different way than other cells, ultimately to their detriment (see the Perspective by Reczek and Chandel). Because a certain receptor is up-regulated in the mutant cells, they take up the oxidized form of vitamin C (dehydroascorbate). This leads to oxidative stress, inactivation of a glycolytic enzyme required by the mutant cells for growth, and finally cell death. Whether the selective toxicity of vitamin C to these mutant cells can be exploited therapeutically remains unclear. Science, this issue p. 1391; see also p. 1317 Cancer cells with certain mutations take up the oxidized form of vitamin C, which fatally disrupts their metabolism. [Also see Perspective by Reczek and Chandel] More than half of human colorectal cancers (CRCs) carry either KRAS or BRAF mutations and are often refractory to approved targeted therapies. We found that cultured human CRC cells harboring KRAS or BRAF mutations are selectively killed when exposed to high levels of vitamin C. This effect is due to increased uptake of the oxidized form of vitamin C, dehydroascorbate (DHA), via the GLUT1 glucose transporter. Increased DHA uptake causes oxidative stress as intracellular DHA is reduced to vitamin C, depleting glutathione. Thus, reactive oxygen species accumulate and inactivate glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Inhibition of GAPDH in highly glycolytic KRAS or BRAF mutant cells leads to an energetic crisis and cell death not seen in KRAS and BRAF wild-type cells. High-dose vitamin C impairs tumor growth in Apc/KrasG12D mutant mice. These results provide a mechanistic rationale for exploring the therapeutic use of vitamin C for CRCs with KRAS or BRAF mutations.

Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH

COPD (chronic obstructive pulmonary disease) is defined by a fixed expiratory airflow obstruction associated with disordered airways and alveolar destruction. COPD is caused by cigarette smoking and is the third greatest cause of mortality in the US. Forced expiratory volume in 1 second (FEV1) is the only validated clinical marker of COPD, but it correlates poorly with clinical features and is not sensitive enough to predict the early onset of disease. Using LC/MS global untargeted metabolite profiling of serum samples from a well-defined cohort of healthy smokers (n = 37), COPD smokers (n = 41) and non-smokers (n = 37), we sought to discover serum metabolic markers with known and/or unknown molecular identities that are associated with early-onset COPD. A total of 1,181 distinct molecular ions were detected in 95% of sera from all study subjects and 23 were found to be differentially-expressed in COPD-smokers vs. healthy-smokers. These 23 putative biomarkers were differentially-correlated with lung function parameters and used to generate a COPD prediction model possessing 87.8% sensitivity and 86.5% specificity. In an independent validation set, this model correctly predicted COPD in 8/10 individuals. These serum biomarkers included myoinositol, glycerophopshoinositol, fumarate, cysteinesulfonic acid, a modified version of fibrinogen peptide B (mFBP), and three doubly-charged peptides with undefined sequence that significantly and positively correlate with mFBP levels. Together, elevated levels of serum mFBP and additional disease-associated biomarkers point to a role for chronic inflammation, thrombosis, and oxidative stress in remodeling of the COPD airways. Serum metabolite biomarkers offer a promising and accessible window for recognition of early-stage COPD.

Serum Metabolite Biomarkers Discriminate Healthy Smokers from COPD Smokers

Inhibition of iNOS as a novel effective targeted therapy against triple-negative breast cancer

493 Background: Clear cell renal cell carcinoma (ccRCC) is characterized by altered metabolism, including a shift from oxidative phosphorylation to glycolysis and lactate production (the Warburg effect). Here we evaluate human ccRCC tissue samples and kidney samples from the TRACK transgenic mouse model of ccRCC (that express constitutively active HIF1α in proximal tubule cells) [1] to characterize the effect of HIF1α on the renal cancer metabolome. Methods: We performed untargeted metabolomics analyses of 12 primary human ccRCCs and 10 TRACK kidney samples. In addition, we analyzed human ccRCC mRNA expression (Oncomine database) and performed RNA sequencing (RNAseq) on six TRACK kidney samples for expression of HIF1α target genes that regulate metabolism. Results: Analysis of RNA expression of HIF1α target genes in human ccRCCs and TRACK kidneys identified significantly increased transcript levels of genes responsible for mediating glucose uptake and glycolysis and suppressing the activity of the TCA cyc...

Analyses of the transcriptome and metabolome to elucidate the role of HIF1{alpha} in clear cell renal cell carcinoma metabolism.

Hypoxia inducible factor 1 alpha (HIF1α) is a transcription factor that is frequently stabilized and active in human clear cell renal cell carcinoma (ccRCC). We have found that constitutively active HIF1α is sufficient to cause neoplastic transformation in a murine model of ccRCC termed the TRACK model. RNA sequencing (RNAseq) and untargeted metabolomics analyses of samples from TRACK kidneys demonstrate that HIF1α activates the transcription of genes that cause increased glucose uptake, glycolysis, and lactate production, as well as a decrease in the flux of pyruvate entering the tricarboxylic acid (TCA) cycle and a decrease in oxidative phosphorylation; these changes are identical to those observed in human ccRCC samples. These studies show that a constitutively active HIF1α promotes tumorigenesis in TRACK mice by mediating a metabolic switch to aerobic glycolysis, i.e., the Warburg effect, and suggest that TRACK mice are a valid model to test novel therapies targeting metabolic changes to inhibit human ccRCC.

Analyses of the Transcriptome and Metabolome Demonstrate That HIF1α Mediates Altered Tumor Metabolism in Clear Cell Renal Cell Carcinoma

Huntingtin protein is essential for mitochondrial metabolism, bioenergetics and structure in murine embryonic stem cells.

Neural tube closure defects (NTDs) are among the most common congenital malformation in human, typically presenting in liveborns as spina bifida. At least 240 gene mutations in mouse are known to increase the risk of NTD. There is a growing appreciation that environmental factors significantly contribute to NTD expression, and that NTDs likely arise from complex gene-environment interactions. Because maternal folic acid supplementation reduces human NTD risk in some populations by 60 to 70%, it is likely that NTD predisposition is often associated with a defect in folate-dependent one-carbon metabolism. A comprehensive, untargeted metabolic survey of NTD-associated changes in embryo metabolism would provide a valuable test of this assumption. We sought to establish a metabolic profiling platform that is capable of broadly assessing metabolic aberrations associated with NTD-promoting gene mutations in early-stage mouse embryos.

METHODS
A liquid chromatography/mass spectrometry-based untargeted metabolite profiling platform was used to broadly identify significant differences in small molecule levels (50-1000 Da) in NTD-affected embryonic day (E) 9.5 mouse embryos (Lrp6(-) (/) (-) ) versus unaffected (Lrp6(+/+) ) control embryos.

RESULTS
Results provide proof-of-principal feasibility for the broad survey of the metabolome of individual E9.5 mouse embryos and identification of metabolic changes associated with NTDs and gene mutations. Levels of 30 different metabolites were altered in association with Lrp6 gene deletion. Some metabolites link to folate-dependent one-carbon transfer reactions, as anticipated, while others await structure elucidation and pathway integration.

Whole-embryo metabolomics offers the potential to identify metabolic changes in genetically determined NTD-prone embryos.

Birth defects research. Part A, Clinical and molecular teratology

Untargeted metabolite profiling of murine embryos to reveal metabolic perturbations associated with neural tube closure defects.

Although more than half of colorectal cancer patients have either KRAS or BRAF mutations, targeted therapies for these subgroups of cancer patients are still lacking. Here, we report that KRAS or BRAF mutant cells exhibit a significant increase in the uptake of oxidized vitamin C, dehydroascorbate (DHA), via the GLUT1 glucose transporter. Increased uptake of DHA in the mutant cell lines causes oxidative stress as intracellular DHA is immediately reduced back to vitamin C by reduced glutathione. Elevated reactive oxygen species inactivate GAPDH and thus divert glycolytic flux into the pentose phosphate pathway. Because KRAS or BRAF mutant cells are highly dependent on glycolysis, this altered glucose metabolism induced by vitamin C ultimately leads to an energy deficit in KRAS or BRAF mutant cells and thereby cell death. There are currently a growing number of clinical trials in phases I/II examining the effect of high dose vitamin C as a treatment for cancers, including colorectal cancers. Our results provide a rationale for the pharmacological use of vitamin C as a therapeutic agent to treat colorectal cancer patients with oncogenic KRAS or BRAF mutations. Citation Format: Jihye Yun, Adam Kavalier, Edouard Mullarky, Kaitlyn Bosch, Jatin Roper, Carlo Rago, Jihye Paik, John Asara, Steven Gross, Bert Vogelstein, Nickolas Papadopoulos, Lewis Cantley. Vitamin C is selectively toxic to cancer cells harboring KRAS or BRAF mutations by targeting GAPDH. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2951. doi:10.1158/1538-7445.AM2014-2951

Abstract 2951: Vitamin C is selectively toxic to cancer cells harboring KRAS or BRAF mutations by targeting GAPDH

The environmental toxin and carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) binds and activates the transcription factor aryl hydrocarbon receptor (AHR), inducing CYP1 family cytochrome P450 enzymes. CYP1A2 and its avian ortholog CYP1A5 are highly active arachidonic acid epoxygenases. Epoxygenases metabolize arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EETs) and selected monohydroxyeicosatetraenoic acids (HETEs). EETs can be further metabolized by epoxide hydrolases to dihydroxyeicosatrienoic acids (DHETs). As P450–arachidonic acid metabolites affect vasoregulation, responses to ischemia, inflammation, and metabolic disorders, identification of their production in vivo is needed to understand their contribution to biologic effects of TCDD and other AHR activators. Here we report use of an acetonitrile-based extraction procedure that markedly increased the yield of arachidonic acid products by lipidomic analysis over a standard solid-phase extraction protocol. We show that TCDD increased all four EETs (5,6-, 8,9-, 11,12-, and 14,15-), their corresponding DHETs, and 18- and 20-HETE in liver in vivo and increased 5,6-EET, the four DHETs, and 18-HETE in heart, in a chick embryo model. As the chick embryo heart lacks arachidonic acid–metabolizing activity, the latter findings suggest that arachidonic acid metabolites may travel from their site of production to a distal organ, i.e., heart. To determine if the TCDD–arachidonic acid–metabolite profile could be altered pharmacologically, chick embryos were treated with TCDD and the soluble epoxide hydrolase inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA). Cotreatment with AUDA increased hepatic EET-to-DHET ratios, indicating that the in vivo profile of P450–arachidonic acid metabolites can be modified for potential therapeutic intervention.

Increases in Levels of Epoxyeicosatrienoic and Dihydroxyeicosatrienoic Acids (EETs and DHETs) in Liver and Heart in Vivo by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) and in Hepatic EET:DHET Ratios by Cotreatment with TCDD and the Soluble Epoxide Hydrolase Inhibitor AUDA

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA

Triple negative breast cancer (TNBC) is an aggressive form of breast cancer with no effective targeted therapy. Inducible nitric oxide synthase (iNOS) is associated with poor survival in breast cancer patients by increasing tumor aggressiveness. This work aimed to investigate the potential of iNOS inhibitors as a targeted therapy for TNBC. We hypothesized that inhibition of endogenous iNOS would decrease TNBC aggressiveness by reducing metastasis through modulation of epithelial-mesenchymal transition (EMT)-inducing factors. We also propose an effective clinically relevant-targeted therapeutic regimen by re-purposing the iNOS inhibitor L-NMMA which has been extensively investigated in thousands of patients with cardiogenic shock.

Cell migration was determined in confluent MDA-MB-231 cells with a “wound healing assay” treated with different concentrations of the specific iNOS inhibitor 1400W (0, 0.0001, 0.001, 0.01, 0.1, 1, 2, 4 mM) in low serum conditions (1%) for 72h. EMT-inducing factors (Snail, Slug, Twist1, and Zeb1) were determined by Western blot in MDA-MB-231 cells. For in vivo studies, 3x106 MDA-MB-231 and SUM159 cells were injected in the right mammary fat pad of female SCID Beige mice (n=10/group). The clinically relevant dose regimen consisted on two cycles of docetaxel (20mg/kg, i.p, on day 0) twelve hours before being combined with L-NMMA (400mg/kg on day 1, and 200mg/kg for 4 additional days by oral gavage) and amlodipine on day 0 (10mg/kg, i.p, daily, for 6 days). Docetaxel alone, as well as saline (i.p) + sterile water (oral gavage) were used as controls.

Our results show that the specific iNOS inhibitor 1400W was able to diminish cell migration in vitro for all concentrations tested. Importantly, impact of iNOS inhibition on cell migration was further correlated with a dose-dependent decrease of the EMT transcription factors- Snail, Slug, and Twist1. Zeb1 was mainly affected at millimolar concentrations. In vivo, the combination of L-NMMA and docetaxel was able to decrease tumor growth in a MDA-MB-231 and SUM159 orthotopic models. Additionally, the combination with amlodipine did significantly prevent the L-NMMA-dependent increase of blood pressure. More importantly, this dose regimen also improved survival compared to docetaxel alone.

In conclusion, targeted therapy with iNOS inhibitor impacts cell migration and changes in epithelial-mesenchymal transition might influence metastatic events. Based on these findings, we have planned a phase Ib/II targeted therapeutic trial by re-purposing L-NMMA as an anti-cancer indication. Targeting TNBC with L-NMMA could significantly alter clinical practice for treatment of breast cancer in the near future.

Citation Format: Sergio M. Granados, Yi Liu, Bhuvanesh Dave, Melissa D. Landis, Steven S. Gross, Jenny C. Chang. iNOS inhibition increases survival in triple negative breast cancer by targeting metastasis and epithelial-mesenchymal transition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4024. doi:10.1158/1538-7445.AM2014-4024

Abstract 4024: iNOS inhibition increases survival in triple negative breast cancer by targeting metastasis and epithelial-mesenchymal transition

Complexes of solute transporters and potassium channels that reciprocally regulate each other may contribute to seizure susceptibility. Stopping Seizures The activity of potassium channels limits neuronal excitability, and mutations in the regulatory subunit (KCNE2), which promotes the activity of the potassium-conducting pore (KCNQ1), are associated with increased seizure susceptibility. Abbott et al. found that SMIT1, which transports the molecule myo-inositol, associated with KCNQ1 or KCNQ1-KCNE2 complexes. When complexed with KCNE2, KCNQ1 is constitutively active. SMIT1 activity was increased in the presence of KCNQ1 but was inhibited in the presence of KCNQ1-KCNE2. SMIT1 increased the activity of both KCNQ1 and KCNQ1-KCNE2 complexes. The increased seizure activity of mice deficient in KCNE2 was attenuated by administration of myo-inositol, suggesting that a decrease in SMIT1 activity or alterations in the activity of these molecular complexes may contribute to seizure susceptibility. Na+-coupled solute transport is crucial for the uptake of nutrients and metabolic precursors, such as myo-inositol, an important osmolyte and precursor for various cell signaling molecules. We found that various solute transporters and potassium channel subunits formed complexes and reciprocally regulated each other in vitro and in vivo. Global metabolite profiling revealed that mice lacking KCNE2, a K+ channel β subunit, showed a reduction in myo-inositol concentration in cerebrospinal fluid (CSF) but not in serum. Increased behavioral responsiveness to stress and seizure susceptibility in Kcne2−/− mice were alleviated by injections of myo-inositol. Suspecting a defect in myo-inositol transport, we found that KCNE2 and KCNQ1, a voltage-gated potassium channel α subunit, colocalized and coimmunoprecipitated with SMIT1, a Na+-coupled myo-inositol transporter, in the choroid plexus epithelium. Heterologous coexpression demonstrated that myo-inositol transport by SMIT1 was augmented by coexpression of KCNQ1 but was inhibited by coexpression of both KCNQ1 and KCNE2, which form a constitutively active, heteromeric K+ channel. SMIT1 and the related transporter SMIT2 were also inhibited by a constitutively active mutant form of KCNQ1. The activities of KCNQ1 and KCNQ1-KCNE2 were augmented by SMIT1 and the glucose transporter SGLT1 but were suppressed by SMIT2. Channel-transporter signaling complexes may be a widespread mechanism to facilitate solute transport and electrochemical crosstalk.

KCNQ1, KCNE2, and Na+-Coupled Solute Transporters Form Reciprocally Regulating Complexes That Affect Neuronal Excitability

Significance This manuscript describes the identification and characterization of two previously unidentified cancer genes, ribosomal protein L39 and myeloid leukemia factor 2, that play an important role in tumor initiation and metastasis. Knockdown of these genes in triple negative breast cancer (TNBC) models significantly reduces primary-tumor growth, as well as metastasis. Mutations in these genes are associated with worse survival in breast-cancer patients. Both genes are regulated by the nitric oxide signaling pathway. Identification of these two genes represents a significant breakthrough in our understanding of treatment resistance in TNBC. Targeting these genes could alter clinical practice for tumor metastasis in future and improve outcomes of patients with breast cancer. We previously described a gene signature for breast cancer stem cells (BCSCs) derived from patient biopsies. Selective shRNA knockdown identified ribosomal protein L39 (RPL39) and myeloid leukemia factor 2 (MLF2) as the top candidates that affect BCSC self-renewal. Knockdown of RPL39 and MLF2 by specific siRNA nanoparticles in patient-derived and human cancer xenografts reduced tumor volume and lung metastases with a concomitant decrease in BCSCs. RNA deep sequencing identified damaging mutations in both genes. These mutations were confirmed in patient lung metastases (n = 53) and were statistically associated with shorter median time to pulmonary metastasis. Both genes affect the nitric oxide synthase pathway and are altered by hypoxia. These findings support that extensive tumor heterogeneity exists within primary cancers; distinct subpopulations associated with stem-like properties have increased metastatic potential.

Targeting RPL39 and MLF2 reduces tumor initiation and metastasis in breast cancer by inhibiting nitric oxide synthase signaling

The ornithine decarboxylase inhibitor α-difl uoromethylornithine (DFMO) is a highly effective chemopreventive agent for colorectal cancer thought to act via polyamine depletion. However, in DFMO-treated patients, mucosal polyamine levels do not directly correlate with colorectal cancer risk. Untargeted metabolite profi ling was used to broadly survey DFMO actions on colon cancer cell metabolism. We found that DFMO treatment of Apc Min intestinal tumors and human colorectal cancer cells is associated with reduced levels of folate-dependent metabolites, including S-adenosylme-thionine (SAM), thymidine pools, and related pathway intermediates. We hypothesized that unrestrained SAM consumption/regeneration constitutes a futile DFMO-triggered cascade that can steal tetrahydro-folate from thymidylate synthase and thereby diminish thymidine pools. In accord with this hypothesis, DFMO treatment altered the folate cofactor balance and thymidine supplementation prevented DFMO-elicited cytostasis without restoring polyamine levels. These fi ndings suggest that thymidine metabolite pool insuffi ciency is a fundamental mechanism of DFMO cytostatic activity. SIGNIFICANCE: A previously unappreciated metabolic linkage between polyamine and thymidine biosynthesis is revealed, based on the competing requirement of these pathways for a limited pool of tetrahydrofolate cofactor. This study identifi es the fi rst shared mechanism for colorectal cancer chemoprevention and chemotherapy, suggesting a common metabolic target for both premalignant and malignant colon cells.

Unbiased Metabolite Profi ling Indicates that a Diminished Thymidine Pool Is the Underlying Mechanism of Colon Cancer Chemoprevention by Alpha-Difl uoromethylornithine

Offensives Against Vascular Injury Maintaining Equilibrium by Selective Targeting of Cyclooxygenase Pathways : Promising

Even though recent trends suggest a turn downward in both incidence and mortality, breast cancer remains the most common female cancer in the industrialized world. Development of resistance to a wide variety of drugs and metastatic spread of cancer cells to distant organs pose major challenge in successful treatment of breast cancer. Virtually all the roughly 40,000 annual breast cancer related deaths in the United States can be said to have occurred because the conventional therapy has failed. It is the second-leading cause of deaths from cancer in women. The survival rate for those with advanced, metastatic breast cancer has not changed significantly for decades. Recent robust evidence indicates that treatment resistance and metastasis arise from a subpopulation with stem-like properties within a heterogeneous primary cancer. These observations are consistent with subpopulations of chemoresistant cancer stem cells within the bulk tumor cells having the potential for self-renewal and metastases through different adaptive mechanisms. Thus despite apparently successful chemotherapy, the persistence of this unique sub-population of cancer stem cells may undergo epithelial-mesenchymal transition and can serve to re-initiate tumor growth and seed metastases.

Breast cancer stem cells (BCSCs) constitute a subpopulation of tumor cells that express stem cell-associated markers and have a high capacity for tumor generation in vivo. Identification of BCSCs from tumor samples or breast cancer cell lines has been based mainly on CD44+/CD24−/low or ALDH+ phenotypes. BCSCs isolation has allowed the analysis of the molecular mechanisms involved in their origin, self-renewal, differentiation into tumor cells, resistance to radiation therapy and chemotherapy, invasiveness and metastatic ability. Over the past few years, candidate cancer stem cells have been identified in a variety of human malignancies including leukemias and a number of solid tumors such as glioblastomas, medulloblastomas and carcinomas. Breast cancer is the first human carcinoma for which a putative cancer stem cell subpopulation has been isolated (Al-Hajj et. al, PNAS, 2003). Using in vitro-separated tumorigenic cells from malignant human breast cancer-derived pleural effusions, Al Hajj and colleagues isolated a cell population characterized by high CD44 expression and low or undetectable levels of CD24 (CD44+CD24−/low). These cells were highly tumorigenic when injected into immunocompromised NOD/SCID mice and shared classic features of normal stem cells, including the capacity for self-renewal and generation of heterogeneous progeny. The stem/progenitor cell phenotype of these cells was further refined by the Daidone group, who were able to grow mammospheres from single-cell suspensions obtained from the dissociation of primary breast tumors. Mammospheres are non-adherent spherical cell clusters obtained in selective culture conditions, which have been shown to be enriched in mammary stem/progenitor cells. The vast majority of cells in culture were CD44+CD24−/low, and 10 to 20% of these retained the ability to self-renew. Recently, three groups have independently provided unequivocal direct and functional evidence for the presence of cancer stem cells by lineage tracing experiments in glioblastomas (GBM), squamous skin tumors, and intestinal adenomas, suggesting the hierarchical nature of cancer (Chen J et.al, Nature, 2012, Schepers AG et. al, Science 2012; Driessens G et. al, Nature 2012). By genetic “lineage retracing," these independent groups confirm that only a fraction of cells within the bulk tumor had clonogenic potential, giving rise to the hierarchical growth of the tumor. In the GBM model, this restricted subpopulation responsible for tumor initiation was intrinsically resistant to chemotherapy.

To combat the impact of this common cancer among women and the disparities of ouotcomes observed, efforts have been directed towards the development of new approaches to early detection, chemotherapeutics, surgical and radiation treatments with promising results. We are one of the first groups to describe the breast cancer stem cells are intrinsically resistant to conventional therapy (Li X et. al. J Natl Cancer Inst, 2008; Creighton CJ et. al, PNAS, 2009). Since these initial observations, other groups have confirmed these findings following conventional chemotherapy or radiation therapy, and have supported our findings that an increase in these BCSCs is associated with poorer prognosis. This CSC model has fundamental clinical implications. The current development of cancer therapeutics is largely based on identifying agents with the ability to cause tumor regression in animal models or in clinical trials. Since tumor stem cells comprise only a small percent of the tumor bulk, focus on tumor regression may have produced agents capable of killing actively cycling or fully differentiated cells while sparing the tumor stem cell population. Thus, targeting BCSCs in combination with chemotherapy will be necessary to eliminate the heterogeneous populations within a tumor, particularly the fraction capable of tumor initiation and metastasis.

We previously published a tumorigenic signature derived from patient biopsies (Creighton CJ et. al, PNAS, 2009). Subsequently, we used a functional approach to identify novel targets for cancer stem cells. This screen was performed by shRNA knockdown of the 477 genes in our tumorigenic signature using high-throughput mammosphere formation efficiency (MSFE) assay. We identified top candidates that significantly reduced MSFE. This stringent screening yielded two potential candidates, namely RPL39 and MLF2, as the top candidate genes that affect BCSC self-renewal. Selective siRNA knockdown of RPL39 and MLF2 in patient-derived breast tumorgrafts showed reduced tumor volume and lung metastases with a concomitant decrease in BCSC markers. Thus, targeting BCSCs in combination with chemotherapy should eliminate the heterogeneous populations within a tumor. Additionally, next generation RNA-deep sequencing confirmed mutations in RPL39 and MLF2 in approximately 40% of lung metastases from breast cancer patients (n=53). Allele specific PCR confirmed damaging mutations in RPL39 and MLF2. Gain-of-function of these mutations was demonstrated by increase in proliferation, invasion, and self-renewal assays. In vitro and in vivo siRNA knockdown of RPL39 and MLF2 showed decrease in nitric oxide synthase, suggesting that these genes are driven by nitric oxide signaling. Because of the effect of RPL39 and MLF2 siRNA in reducing lung metastases in vivo, we tested the possibility that BCSC may have escaped the primary cancer to evolve in distant metastatic sites. The presence of these damaging mutations was found only in the stem cell (CD44+/CD24 low/−) subpopulation but not in non-BCSCs. These gain-of-function mutations in RPL39 (AV14) and MLF2 (R158W and D12H) were present in both ERα-positive and ERα-negative tumors, suggesting that BCSCs with these mutations may be capable of multilineage differentiation. Most importantly, the presence of these mutations was significantly associated with worse relapse-free survival and a shorter median time to relapse.

The role of BCSCs in the clinical outcome of breast cancer patients has been analyzed using different strategies, including targeting of membrane markers and transporters, interruption of intracellular signaling pathways, and alteration of the BCSCs microenvironment. Despite the success of some of those therapies in preclinical models; toxicology and pharmacokinetic studies are still required before human tests. We have shown for the first time in human breast cancer patients that residual tumors after chemotherapy are 1) enriched for the tumorigenic CD44+/CD24−/low population, 2) show enhanced mammosphere-forming efficiency (MSFE), and 3) display an increase in outgrowths in xenograft transplants in immunocompromised SCID/Beige mice, thus suggesting their increased tumorigenicity. The preclinical data showed that pharmacological inhibition of the Notch pathway with gamma secretase inhibitors (GSI) reduced the breast cancer stem cells in breast tumorgraft models. GSI enhanced the efficacy of docetaxel in preclinical studies. The clinical trial on 30 patients with advanced breast cancer showed feasibility of the combination of GSI and chemotherapy (Schott AF et. al, Clin Cancer Res., 2013).

In conclusion, the identification of breast cancer stem cell markers and an improved understanding of the molecular mechanism of BCSC phenotypes should lead to progress in cancer therapy and improved prognoses for patients with advanced breast cancer. Such emerging picture of the biological properties of BCSCs would contribute for devising innovative therapies for breast cancer, targeting the intrinsic and extrinsic factors that maintain the BCSCs.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN06-02.

Citation Format: Jenny C. Chang, Bhuvanesh Dave, Sergio Granados-Principal, Junhua Mai, Steven Gross, Haifa Shen, Vivek Mittal, Mauro Ferrari. Breast cancer stem cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr CN06-02.

The ornithine decarboxylase inhibitor α-difluoromethylornithine (DFMO) is a highly effective chemopreventive agent for colorectal cancer thought to act via polyamine depletion. However, in DFMO-treated patients, mucosal polyamine levels do not directly correlate with colorectal cancer risk. Untargeted metabolite profiling was used to broadly survey DFMO actions on colon cancer cell metabolism. We found that DFMO treatment of Apc(Min) intestinal tumors and human colorectal cancer cells is associated with reduced levels of folate-dependent metabolites, including S-adenosylmethionine (SAM), thymidine pools, and related pathway intermediates. We hypothesized that unrestrained SAM consumption/regeneration constitutes a futile DFMO-triggered cascade that can steal tetrahydrofolate from thymidylate synthase and thereby diminish thymidine pools. In accord with this hypothesis, DFMO treatment altered the folate cofactor balance and thymidine supplementation prevented DFMO-elicited cytostasis without restoring polyamine levels. These findings suggest that thymidine metabolite pool insufficiency is a fundamental mechanism of DFMO cytostatic activity.

A previously unappreciated metabolic linkage between polyamine and thymidine biosynthesis is revealed, based on the competing requirement of these pathways for a limited pool of tetrahydrofolate cofactor. This study identifies the fi rst shared mechanism for colorectal cancer chemoprevention and chemotherapy, suggesting a common metabolic target for both premalignant and malignant colon cells.

Unbiased metabolite profiling indicates that a diminished thymidine pool is the underlying mechanism of colon cancer chemoprevention by alpha-difluoromethylornithine.

S-sulfhydration/desulfhydration and S-nitrosylation/denitrosylation: a common paradigm for gasotransmitter signaling by H2S and NO.

Protein 3-nitrotyrosine (3-NT) formation is frequently regarded as a simple biomarker of disease, an irreversible posttranslational modification that can disrupt protein structure and function. Nevertheless, evidence that protein 3-NT modifications may be site selective and reversible, thus allowing for physiological regulation of protein activity, has begun to emerge. We have previously reported that cyclooxygenase (COX)-1 undergoes heme-dependent nitration of Tyr(385), an internal and catalytically essential residue. In the present study, we demonstrate that nitrated COX-1 undergoes a rapid reversal of nitration by substrate-selective and biologically regulated denitrase activity. Using nitrated COX-1 as a substrate, denitrase activity was validated and quantified by analytic HPLC with electrochemical detection and determined to be constitutively active in murine and human endothelial cells, macrophages, and a variety of tissue samples. Smooth muscle cells, however, contained little denitrase activity. Further characterizing this denitrase activity, we found that it was inhibited by free 3-NT and may be enhanced by endogenous nitric oxide and exogenously administered carbon monoxide. Finally, we describe a purification protocol that results in significant enrichment of a discrete denitrase-containing fraction, which maintains activity throughout the purification process. These findings reveal that nitrated COX-1 is a substrate for a denitrase in cells and tissues, implying that the reciprocal processes of nitration and denitration may modulate bioactive lipid synthesis in the setting of inflammation. In addition, our data reveal that denitration is a controlled process that may have broad importance for regulating cell signaling events in nitric oxide-generating systems during oxidative/nitrosative stress.

Characterization of a cellular denitrase activity that reverses nitration of cyclooxygenase.

Endothelial Cell Dysfunction (ECD) is a recognized harbinger of a host of chronic cardiovascular diseases. Using a mouse model of ECD triggered by treatment with L-Nω-methylarginine (L-NMMA), we previously demonstrated that renal microvasculature displays a perturbed protein profile, including diminished expression of two key enzymes of the Krebs cycle associated with a Warburg-type suppression of mitochondrial metabolism. We hypothesized that supplementation with L-glutamine (GLN), that can enter the Krebs cycle downstream this enzymatic bottleneck, would normalize vascular function and alleviate mitochondrial dysfunction. To test this hypothesis, mice with chronic L-NMMA-induced ECD were co-treated with GLN at different concentrations for 2 months. Results confirmed that L-NMMA led to a defect in acetylcholine-induced relaxation of aortic rings that was dose-dependently prevented by GLN. In caveolin-1 transgenic mice characterized by eNOS inactivation, L-NMMA further impaired vasorelaxation which was partially rescued by GLN co-treatment. Pro-inflammatory profile induced by L-NMMA was blunted in mice co-treated with GLN. Using an LC/MS platform for metabolite profiling, we sought to identify metabolic perturbations associated with ECD and offset by GLN supplementation. 3453 plasma molecules could be detected with 100% frequency in mice from at least one treatment group. Among these, 37 were found to be differentially expressed in a 4-way comparison of control vs. LNMMA both with and without GLN. One of such molecules, hippuric acid, an “uremic toxin” was found to be elevated in our non-uremic mice receiving L-NMMA, but normalized by treatment with GLN. Ex vivo analysis of hippuric acid effects on vasomotion demonstrated that it significantly reduced acetylcholine-induced vasorelaxation of vascular rings. In conclusion, functional and metabolic profiling of animals with early ECD revealed macrovasculopathy and that supplementation GLN is capable of improving vascular function. Metabolomic analyses reveal elevation of hippuric acid, which may further exacerbate vasculopathy even before the development of uremia.

Glutamine Supplementation Alleviates Vasculopathy and Corrects Metabolic Profile in an In Vivo Model of Endothelial Cell Dysfunction

Although more than half of colorectal cancer patients have either KRAS or BRAF mutations, targeted therapies for these subgroups of cancer patients are lacking. We previously showed that isogenic human colorectal cancer cell (CRC) lines harboring a KRAS or BRAF mutation up-regulate the expression of glucose transporter 1 (GLUT1), and increase glucose uptake and glycolysis. In this study, we go on to show that KRAS or BRAF mutant cells exhibit a significant increase in the uptake of vitamin C, mainly in its oxidized form, dehydroascorbic acid (DHA), relative to their wild-type counterparts through GLUT1. Notably, CRCs did not uptake vitamin C in its reduced form, possibly due to the fact that its known transporters, sodium vitamin C cotransporters (SVCTs) were generally not present in CRCs. Deletion of GLUT1 in mutant cells, overexpression of GLUT1 in wild-type cells and competition assays between glucose and DHA confirmed that GLUT1 is both necessary and sufficient for the uptake of vitamin C in CRCs. Both mutant and wild-type cells were able to grow in low glucose (1-2 mM) at a similar rate. In the same condition, we found vitamin C to be selectively toxic to KRAS and BRAF mutant cells, causing them to undergo apoptosis. In contrast, in high glucose levels (>10 mM), a similar concentration of vitamin C had no effect on the survival and growth of mutant cells. In addition, vitamin C significantly inhibited the growth of cancer cells with KRAS or BRAF mutations in vivo xenografts models. To find the mechanism by which vitamin C induces cell death in KRAS or BRAF mutant cells, we performed targeted metabolomics using LC/MS. Both unlabeled total metabolite analysis and flux analysis with C13-Glucose isotope strongly suggested that vitamin C re-routes glucose usage from aerobic glycolysis and non-oxidative pentose phosphate pathway (PPP) to the oxidative PPP to compensate for the lower levels of NADPH which was rapidly consumed to reduce GSSH to GSH. Having taken up exclusively DHA, the oxidized state of vitamin C, the mutant cells immediately use GSH to reduce Vitamin C, resulting in the accumulation of GSSH. Shunting glucose to the oxidative PPP reduces aerobic glycolysis, lowering ATP levels, and decreases glucose anabolism, disfavoring the synthesis of nucleic acids, lipid and amino acids, all needed for the survival and growth of mutant cells. Surprisingly the level of reactive oxidative stress (ROS) was largely unchanged following vitamin C treatment possibly because increased levels of vitamin C served as an anti-oxidant in mutant cells. There are currently more than three clinical trials phase I/II examining the effect of high dose vitamin C via intravenous administration in patients against lymphoma or solid cancers including CRCs. Our findings will provide proof of concept that KRAS or BRAF mutations in CRC can be predictive biomarkers for vitamin C therapy. Citation Format: Jihye Yun, Adam Kavalier, Jatin Roper, Steve Gross, Carlo Rago, Nickolas Papadopoulos, Bert Vogelstein, Lewis Cantley. Vitamin C inhibits the survival and growth of colorectal cancer cells with KRAS or BRAF mutations. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C60.

Abstract C60: Vitamin C inhibits the survival and growth of colorectal cancer cells with KRAS or BRAF mutations

Diabesity has become a popular term to describe the specific form of diabetes that develops late in life and is associated with obesity. While there is a correlation between diabetes and obesity, the association is not universally predictive. Defining the metabolic characteristics of obesity that lead to diabetes, and how obese individuals who develop diabetes different from those who do not, are important goals. The use of large‐scale omics analyses (e.g., metabolomic, proteomic, transcriptomic, and lipidomic) of diabetes and obesity may help to identify new targets to treat these conditions. This report discusses how various types of omics data can be integrated to shed light on the changes in metabolism that occur in obesity and diabetes.

Application of combined omics platforms to accelerate biomedical discovery in diabesity

Metabolomics, or global metabolite profiling, hails the lofty goal of establishing the identity and levels of all metabolites in a biological system, under a defined set of circumstances. A convergence of enabling technologies has recently made broad metabolite profiling a reality, providing a powerful new tool for defining disease mechanisms, identifying disease biomarkers and evaluating the efficacy of therapies. This overall goal of this educational session is to describe how global metabolite profiling technologies are being used to develop a systems-wide understanding of cancer cell metabolism and to discover the molecular basis for cancer chemopreventative drug therapies. Citation Format: Steven S. Gross, Qiuying Chen. Untargeted metabolite profiling as a powerful new tool in the armamentarium of cancer researchers. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr ED04-01.

Abstract ED04-01: Untargeted metabolite profiling as a powerful new tool in the armamentarium of cancer researchers

The serotonin transporter (SERT) is a major regulator of serotonergic neurotransmission and anxiety-related behaviors. SERT is expressed in two alternative polyadenylation forms that differ by an evolutionarily conserved element in the 3′ untranslated region of its mRNA. Expression of SERT mRNA containing the distal polyadenylation element is associated with decreased anxiety-related behaviors in mice and humans, suggesting that this element has behaviorally relevant modulatory effects on SERT expression. We have identified heterogeneous nuclear ribonucleoprotein K (hnRNPK), a protein known to integrate multiple signal transduction pathways with gene expression, as a SERT distal polyadenylation element binding protein. This interaction is functionally meaningful because genetic manipulation of hnRNPK alters expression of the SERT protein. Furthermore, the trophic factor S100β induces Src-family kinase-mediated tyrosine phosphorylation of hnRNPK and increased SERT expression. These results identify a previously unknown mechanism of regulated SERT expression and provide a putative mechanism by which the SERT distal polyadenylation element modulates anxiety-related behaviors.

Anxiety-associated alternative polyadenylation of the serotonin transporter mRNA confers translational regulation by hnRNPK

Endogenous nitric oxide production in the radioresistant bacterium deinococcus radiodurans determines lipid composition and is essential for rapid growth recovery after gamma-irradiation

To maintain homeostasis, cells employ intricate molecular machineries comprised of thousands of proteins programmed to execute well-defined functions. Dysregulation of these pathways, through protein mis-expression or mutation, provides biological advantages that confer the malignant phenotype. At the molecular level, this requires cells to invest energy in maintaining the stability and function of these proteins, and for this reason cancer cells co-opt molecular chaperones, including Hsp90. Hsp90 is recognized to play important roles in maintaining the transformed phenotype - the chaperone and its associated co-chaperones assist in the correct folding of cellular proteins, collectively referred to as “client proteins,” many of which are effectors of signal transduction pathways controlling cell growth, differentiation, the DNA damage response, and cell survival. Tumor cell addiction to these proteins (i.e. through mutations, aberrant expression, improper cellular translocation, etc) thus makes them critically reliant on Hsp90. While Hsp90 is expressed in all cells and tissues, it was shown that tumors preferentially contain Hsp90 that is in a higher order multi-chaperone complex with high affinity for certain Hsp90 inhibitors, while normal tissues harbor a latent, uncomplexed Hsp90 that has low affinity for these inhibitors. We here extend this model and propose that Hsp90 forms biochemically distinct complexes in cancer cells. In this view, a major fraction of cancer cell Hsp90 retains “house keeping” chaperone functions similar to normal cells, whereas a functionally distinct Hsp90 pool enriched or expanded in cancer cells specifically interacts with oncogenic proteins required to maintain tumor cell survival. Perhaps this Hsp90 fraction represents a cell stress specific form of chaperone complex that is expanded and constitutively maintained in the tumor cell context. Our data suggest that it may execute functions necessary to maintain the malignant phenotype. One such role is to regulate the folding of mutated (i.e. mB-Raf) or chimeric proteins (i.e. Bcr-Abl). We here also present experimental evidence for an additional role; that is, to facilitate scaffolding and complex formation of molecules involved in aberrantly activated signaling complexes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3029. doi:1538-7445.AM2012-3029

Abstract 3029: Biochemical evidence towards the existence of an oncogenic Hsp90 complex

We have recently documented the appearance of an anti-angiogenic peptide, endorepellin, in the urine of patients with chronic allograft dysfunction (CAD).

METHODS
Here, we analyzed using enzyme-linked immunosorbent assay the excretion of anti-angiogenic peptides endostatin, pigment epithelium-derived factor (PEDF) and Kruppel-like factor-2 (KLF-2), in healthy individuals, patients with stable graft function and patients with various degrees of CAD.

RESULTS
In healthy subjects and patients with CAD-0, endostatin, PEDF and KLF-2 excretions were at the level of detection. In contrast, there were significant differences between the patients with CAD-3 and CAD-0, CAD-1 and healthy controls for endostatin and CAD-0 versus CAD-3 for PEDF, but no differences in KLF-2 excretion. Receiver operating characteristic (ROC) curve analyses demonstrated a highly discriminative profile for all three biomarkers: the combination of these parameters offered 83% sensitivity and 90% specificity in distinguishing CAD-0 from CAD-1-3. The quality of these potential biomarkers of CAD was, however, highest in discriminating CAD status in biopsy-proven cases and dropped when CAD-0 was diagnosed based on clinical criteria.

In conclusion, these findings indicate the diagnostic potential of urinary detection of endostatin, PEDF and to lesser degree KLF-2 and suggest a mechanistic role played by anti-angiogenic substances in the developing vasculopathy and vascular rarefaction in patients with CAD.

Excretion of anti-angiogenic proteins in patients with chronic allograft dysfunction.

A major challenge in systems biology is integration of molecular findings for individual enzyme activities into a cohesive high-level understanding of cellular metabolism and physiology/pathophysiology. However, meaningful prediction for how a perturbed enzyme activity will globally impact metabolism in a cell, tissue or intact organisms is precluded by multiple unknowns, including in vivo enzymatic rates, subcellular distribution and pathway interactions. To address this challenge, metabolomics offers the potential to simultaneously survey changes in thousands of structurally diverse metabolites within complex biological matrices. The present study assessed the capability of untargeted plasma metabolite profiling to discover systemic changes arising from inactivation of xanthine oxidoreductase (XOR), an enzyme that catalyzes the final steps in purine degradation. Using LC-MS coupled with a multivariate statistical data analysis platform, we confidently surveyed >3,700 plasma metabolites (50–1,000 Da) for differential expression in XOR wildtype vs. mice with inactivated XOR, arising from gene deletion or pharmacological inhibition. Results confirmed the predicted derangements in purine metabolism, but also revealed unanticipated perturbations in metabolism of pyrimidines, nicotinamides, tryptophan, phospholipids, Krebs and urea cycles, and revealed kidney dysfunction biomarkers. Histochemical studies confirmed and characterized kidney failure in xor-nullizygous mice. These findings provide new insight into XOR functions and demonstrate the power of untargeted metabolite profiling for systemic discovery of direct and indirect consequences of gene mutations and drug treatments.

Untargeted Plasma Metabolite Profiling Reveals the Broad Systemic Consequences of Xanthine Oxidoreductase Inactivation in Mice

Abstract 1648 DLBCL is a molecularly heterogeneous disease usually treated with chemoimmunotherapy ultimately curing ∼65% of pts. In order to improve therapy for these pts, the identification of broadly relevant therapeutic targets is critical. One such target is HSP90. Tumor cells are enriched for a fraction of HSP90 found in higher-order multi-chaperone complexes. Tumor-enriched HSP90 (teHSP90) displays higher affinity for HSP90 inhibitors than normal tissues, which contain latent, uncomplexed HSP90. Many client proteins are depleted upon exposure to teHSP90 inhibitors. PU-H71 is a highly teHSP90 selective inhibitor with an excellent toxicity profile currently being tested for DLBCL in clinical trials. Combination therapies involving teHSP90 inhibitors may synergize with drugs targeting client proteins of teHSP90 by more powerfully inhibit survival pathways. Cell replication involves substantial metabolic demands and PU-H71-induced degradation of enzymatic client proteins may affect critical metabolic pathways. We hypothesized that by identifying PU-H71-induced metabolic changes, metabolomics could point to potential new targets for combinatorial therapeutic intervention. We therefore analyzed the global metabolic consequence of teHSP90 inhibition in DLBCL by PU-H71. The metabolome was analyzed in the serum of LY7 DLBCL xenografted mice treated with 75 mg/m2 of PU-H71 for 24 h (n=5) or vehicle (n=5) by HPLC/MS. Bioinformatic analysis revealed significant changes in 122 metabolites in PUH-71- vs. vehicle-treated mice; including significantly lower levels of xanthine, hypoxanthine, adenosine, xanthosine monophosphate (XMP), depletion of the guanine nucleoside pool, together with higher levels of inosine and inosine monophosphate (IMP). These metabolic changes pointed towards possible PU-H71 mediated inhibition of inosine monophosphate dehydrogenase (IMPDH). IMPDH catalyzes the NAD-dependent oxidation of IMP to XMP, which is the committed step in de novo guanosine nucleotide biosynthesis. This reaction is particularly important to lymphocytes, which depend on IMPDH activity to generate the guanosine nucleotide levels needed to initiate a proliferative response to antigen. Increased IMPDH activity has also been observed in leukemia and lymphoma, mostly as consequence of up-regulation of the IMPDH2 isoform. In order to determine whether IMPDH1/2 stability depends on teHSP90, we treated a panel of 6 DLBCL cell lines (including LY7) with the mean GI50 of PU-H71 (1 μM) for up to 24 h and checked for IMPDH1/2 abundance. We found a time-dependent decrease in IMPDH2 protein levels. Similar results were obtained with the chemically unrelated HSP90 inhibitor 17-DMAG. To confirm that IMPDH2 binds to teHSP90, we took advantage of an affinity-based PUH-71 pull-down method we recently developed. In this assay PU-H71-beads preferentially bind to teHSP90 complexes pecipitating cancer-related client proteins. By using this assay, we determined that IMPDH2 was indeed a teHSP90 client in DLBCL cells. We also found that PU-H71 (and 17-DMAG) inhibited the activity of IMPDH in DLBCL cells by shortening its half-live (IMPDH t1/2from 2 h to 45 min). To determine whether the combination of teHSP90 inhibitors will synergize with IMPDH inhibitors in killing DLBCL, we treated a panel of 10 DLBCL cell lines with the combination of PU-H71 and two IMPDH inhibitors in clinical use, mycophenolic acid (MPA, an uncompetitive inhibitor) and ribavirin (RIB, a competitive inhibitor). We found that most cell lines showed synergistic killing effect when treated with the combination of drugs compared to each drug alone (determined by isobologram method). This prompted us to test the combination in vivo. SCID mice were xenografted with LY7 and SUDHL6 and once tumor developed, they were treated with vehicle, PU-H71, mycophenolate mofetil (MMF, the pro-drug of MPA), RIB and the combination of PU-H71 and MMF or RIB. We found that mice treated with the combination of drugs exhibited greater effect that each drug alone (p=0.002 for SU-DHL6 and p>0.001 for LY7 for PU-H71+MMF, and p=0.01 for SU-DHL6 and p=0.02 for LY7 for PU-H71+RIB, all T-test day 10). There were no toxic effects. In sum, our work uses serum metabolomics to provide new insights into the pharmacological targets of a particular HSP90 inhibitor, and unveiled a critical survival pathway in DLBCL that was harnessed to develop a rationally combined targeted therapy. Disclosures: No relevant conflicts of interest to declare.

Serum Metabolomics Uncovers a New Therapeutic Target in Diffuse Large B Cell Lymphoma (DLBCL)

PP004-SUN GLUTAMINE SUPPLEMENTATION ALLEVIATES VASCULOPATHY AND ALTERS PLASMA METABOLOME IN AN IN VIVO MODEL OF ENDOTHELIAL CELL DYSFUNCTION

Most cancers are characterized by multiple molecular alterations, but identification of the key proteins involved in these signaling pathways is currently beyond reach. We show that the inhibitor PU-H71 preferentially targets tumor-enriched Hsp90 complexes and affinity captures Hsp90-dependent oncogenic client proteins. We have used PU-H71 affinity capture to design a proteomic approach that, when combined with bioinformatic pathway analysis, identifies dysregulated signaling networks and key oncoproteins in chronic myeloid leukemia. The identified interactome overlaps with the well-characterized altered proteome in this cancer, indicating that this method can provide global insights into the biology of individual tumors, including primary patient specimens. In addition, we show that this approach can be used to identify previously uncharacterized oncoproteins and mechanisms, potentially leading to new targeted therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1263. doi:1538-7445.AM2012-1263

Abstract 1263: Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90

Discovery and biological characterization of 1-(1H-indol-3-yl)-9H-pyrido[3,4-b]indole as an aryl hydrocarbon receptor activator generated by photoactivation of tryptophan by sunlight.

Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90.

Protein nitrotryptophan: formation, significance and identification.

Impaired amino acid metabolism in cells affected by the T8993G (NARP) mtDNA mutation: A potential novel therapeutic target

Development of a novel proteomic approach for the unbiased identification of nitrated proteins in Alzheimer's disease brains

Retraction of: NO suppresses while peroxynitrite sustains NF-κB: a paradigm to rationalize cytoprotective and cytotoxic actions attributed to NO.

PP005-MON GLUTAMINE SUPPLEMENTATION AMELIORATES THE PROFILE OF PLASMA METABOLOME AND RESTORES ENDOTHELIAL-MEDIATED VASORELAXATION IN AN IN VIVO MODEL OF ENDOTHELIAL CELL DYSFUNCTION (ED)

Erratum to: Retraction of ‘Angiotensin-II-induced oxidative stress elicits hypoadiponectinaemia in rats’

The scavenger receptor CD36 contributes to the neurotoxicity of bone marrow-derived monocytes through peroxynitrite production

GTP cyclohydrolase I (GTPCH) is the rate-limiting enzyme for biosynthesis of tetrahydrobiopterin (BH4), an obligate cofactor for NO synthases and aromatic amino acid hydroxylases. BH4 can limit its own synthesis by triggering decameric GTPCH to assemble in an inhibitory complex with two GTPCH feedback regulatory protein (GFRP) pentamers. Subsequent phenylalanine binding to the GTPCH·GFRP inhibitory complex converts it to a stimulatory complex. An N-terminal inhibitory peptide in GTPCH may also contribute to autoregulation of GTPCH activity, but mechanisms are undefined. To characterize potential regulatory actions of the N-terminal peptide in rat GTPCH, we expressed, purified, and characterized a truncation mutant, devoid of 45 N-terminal amino acids (Δ45-GTPCH) and contrasted its catalytic and GFRP binding properties to wild type GTPCH (wt-GTPCH). Contrary to prior reports, we show that GFRP binds wt-GTPCH in the absence of any small molecule effector, resulting in allosteric stimulation of GTPCH activity: a 20% increase in Vmax, 50% decrease in KmGTP, and increase in Hill coefficient to 1.6, from 1.0. These features of GFRP-stimulated wt-GTPCH activity were phenocopied by Δ45-GTPCH in the absence of bound GFRP. Addition of GFRP to Δ45-GTPCH failed to elicit complex formation or a substantial further increase in GTPCH catalytic activity. Expression of Δ45-GTPCH in HEK-293 cells elicited 3-fold greater BH4 accumulation than an equivalent of wt-GTPCH. Together, results indicate that the N-terminal peptide exerts autoinhibitory control over rat GTPCH and is required for GFRP binding on its own. Displacement of the autoinhibitory peptide provides a molecular mechanism for physiological up-regulation of GTPCH activity.

The N-terminal Peptide of Mammalian GTP Cyclohydrolase I Is an Autoinhibitory Control Element and Contributes to Binding the Allosteric Regulatory Protein GFRP*

The small molecule metabolome ( Citation Information: Cancer Prev Res 2010;3(12 Suppl):ED01-02.

Abstract ED01-02: Untargeted plasma metabolite profiling: Strategies and approaches for comprehensive characterization of gene mutations and drug actions

Tetrahydrobiopterin: An Essential Cofactor for Nitric Oxide Synthases and Amino Acid Hydroxylases

Prostaglandin biosynthesis is catalyzed by two spatially and functionally distinct active sites in cyclooxygenase (COX) enzymes. Despite the crucial role of COXs in biology, molecular details regarding the function and regulation of these enzymes are incompletely defined. Reactive nitrogen species, formed during oxidative stress, produce modifications that alter COX functionalities and prostaglandin biosynthesis. We previously established that COX-1 undergoes selective nitration on Tyr385 via a mechanism that requires the presence of bound heme cofactor. As this is a critical residue for COX-1 catalysis, nitration at this site results in enzyme inactivation. We now show that occupancy of the COX-1 active site with substrate protects against Tyr385 nitration and redirects nitration to alternative Tyr residues on COX-1, preserving catalytic activity. This study reveals a novel role for the substrate in protecting COX-1 from inactivation by nitration in pathophysiological settings.

Physical evidence for substrate binding in preventing cyclooxygenase inactivation under nitrative stress.

Neutral loss of isocyanic acid in peptide CID spectra: A novel diagnostic marker for mass spectrometric identification of protein citrullination

Triple-negative breast cancers (TNBCs) are defined by a lack of expression of estrogen, progesterone, and HER2 receptors. Because of the absence of identified targets and targeted therapies, and due to a heterogeneous molecular presentation, treatment guidelines for patients with TNBC include only conventional chemotherapy. Such treatment, while effective for some, leaves others with high rates of early relapse and is not curative for any patient with metastatic disease. Here, we demonstrate that these tumors are sensitive to the heat shock protein 90 (Hsp90) inhibitor PU-H71. Potent and durable anti-tumor effects in TNBC xenografts, including complete response and tumor regression, without toxicity to the host are achieved with this agent. Notably, TNBC tumors respond to retreatment with PU-H71 for several cycles extending for over 5 months without evidence of resistance or toxicity. Through a proteomics approach, we show that multiple oncoproteins involved in tumor proliferation, survival, and invasive potential are in complex with PU-H71-bound Hsp90 in TNBC. PU-H71 induces efficient and sustained downregulation and inactivation, both in vitro and in vivo, of these proteins. Among them, we identify downregulation of components of the Ras/Raf/MAPK pathway and G2-M phase to contribute to its anti-proliferative effect, degradation of activated Akt and Bcl-xL to induce apoptosis, and inhibition of activated NF-κB, Akt, ERK2, Tyk2, and PKC to reduce TNBC invasive potential. The results identify Hsp90 as a critical and multimodal target in this most difficult to treat breast cancer subtype and support the use of the Hsp90 inhibitor PU-H71 for clinical trials involving patients with TNBC.

Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models

A lofty goal of metabolomics is untargeted discovery of disease‐associated and drug‐induced changes in the expression of diverse small molecules in biological samples. Despite the enormous potential of metabolic profiling for translational biomedicine, effective analytical and informatic platforms remain to be established. This study sought to determine whether an untargeted metabolomics approach, utilizing accurate mass LC‐MS, feature profiling and unsupervised learning could effectively "discover" a purine metabolism defect in mice where xanthine oxidoreductase (XOR) is genetically‐deleted or pharmacologically‐inhibited. Untargeted profiling of XOR deficient mice conclusively revealed a marked decrease in the XOR product ureate (as predicted) in plasma and urine, as well as increases in purine metabolites upstream of XOR. Statistical methods, including principal component analysis and categorical clustering, demonstrated a remarkably similar metabolite profile in XOR‐inhibited and xor‐/‐ mice. Further, these methods revealed clear differences between the metabolite profiles of XOR deficient mice vs. xor+/+ and xor+/‐ mice. Together, the present studies provide proof‐of‐principle for the efficacy of untargeted metabolite profiling to discover altered biochemical pathways in diseases and in response to drug treatments.

Unbiased discovery of in vivo enzyme activities by metabolomic profiling of gene‐deleted mice: proof‐of‐principle using xanthine oxidoreductase

BIOL 152-Inducible nitric oxide synthase contributes to biopterin oxidation and protein tyrosine nitration during atherogenesis

Cardiovascular disease is the leading cause of death in most Western countries. Vascular abnormalities associated with cardiovascular disease are attributable to a variety of risk factors, including hypercholesterolemia, hypertension, hyperglycemia, lipotoxicity, obesity, aging, and tobacco smoke.1,2 Importantly, altered ·NO bioavailability is a major underlying mechanism linking each of these risk factors. Indeed, the endothelium is recognized as a pivotal regulator of vascular function by maintaining homeostatic levels of ·NO and prostanoids derived from arachidonic acid (AA) metabolism.3

Eicosanoids, synthesized from unsaturated fatty acids, are biologically active molecules that play a wide range of regulatory roles in the cardiovascular, renal, immune, and gastrointestinal systems.4 Alterations in their biosyntheses can promote hypertension, diabetes, and, in particular, atherosclerosis, an inflammatory disease characterized by the accretion of fat-laden plaques in the arterial wall that can lead to vasoocclusive events. During atherogenesis, eicosanoid production (from the cyclooxygenases [COXs], lipoxygenases [LOXs], and cytochrome P450s pathways) is altered by mechanisms that are not yet well understood. The dichotomous nature of eicosanoids requires that their balance is maintained, and, as such, these pathways are a relevant therapeutic target against cardiovascular disease.5 Thus, it is now appreciated that cardiovascular disease can be triggered by an absolute deficiency of ·NO and/or an imbalance between “beneficial” and “harmful” eicosanoids in the vasculature and that these pathways are mutually interactive. In this review we consider pharmacological therapies possessing the potential for greater safety and efficacy than nonsteroidal antiinflammatory drugs (NSAIDs) in the treatment of chronic vasoinflammatory conditions.

Fundamental physiological distinctions are now recognized for the structurally similar enzymes, COX-1 and COX-2. Constitutively expressed COX-1 is found in almost all of the tissues where it subserves diverse physiological functions. Basal expression of COX-2 is limited to the kidney, brain, and reproductive system4 but can be …

Maintaining equilibrium by selective targeting of cyclooxygenase pathways: promising offensives against vascular injury.

We present and validate tissue expression profile similarity searches (TEPSS), a computational approach to identify transcripts that share similar tissue expression profiles to one or more transcripts in a group of interest. We evaluated TEPSS for its ability to discriminate between pairs of transcripts coding for interacting proteins and non-interacting pairs. We found that ordering protein–protein pairs by TEPSS score produces sets significantly enriched in reported pairs of interacting proteins [interacting versus non-interacting pairs, Odds-ratio (OR) = 157.57, 95% confidence interval (CI) (36.81–375.51) at 1% coverage, employing a large dataset of about 50 000 human protein interactions]. When used with multiple transcripts as input, we find that TEPSS can predict non-obvious members of the cytosolic ribosome. We used TEPSS to predict S-nitrosylation (SNO) protein targets from a set of brain proteins that undergo SNO upon exposure to physiological levels of S-nitrosoglutathione in vitro. While some of the top TEPSS predictions have been validated independently, several of the strongest SNO TEPSS predictions await experimental validation. Our data indicate that TEPSS is an effective and flexible approach to functional prediction. Since the approach does not use sequence similarity, we expect that TEPSS will be useful for various gene discovery applications. TEPSS programs and data are distributed at http://icb.med.cornell.edu/crt/tepss/index.xml.

Beyond tissueInfo: functional prediction using tissue expression profile similarity searches

5,6,7,8-Tetrahydrobiopterin (BH(4)) is an essential cofactor of nitric oxide synthases (NOSs). Oxidation of BH(4), in the setting of diabetes and other chronic vasoinflammatory conditions, can cause cofactor insufficiency and uncoupling of endothelial NOS (eNOS), manifest by a switch from nitric oxide (NO) to superoxide production. Here we tested the hypothesis that eNOS uncoupling is not simply a consequence of BH(4) insufficiency, but rather results from a diminished ratio of BH(4) vs. its catalytically incompetent oxidation product, 7,8-dihydrobiopterin (BH(2)). In support of this hypothesis, [(3)H]BH(4) binding studies revealed that BH(4) and BH(2) bind eNOS with equal affinity (K(d) approximately 80 nM) and BH(2) can rapidly and efficiently replace BH(4) in preformed eNOS-BH(4) complexes. Whereas the total biopterin pool of murine endothelial cells (ECs) was unaffected by 48-h exposure to diabetic glucose levels (30 mM), BH(2) levels increased from undetectable to 40% of total biopterin. This BH(2) accumulation was associated with diminished calcium ionophore-evoked NO activity and accelerated superoxide production. Since superoxide production was suppressed by NOS inhibitor treatment, eNOS was implicated as a principal superoxide source. Importantly, BH(4) supplementation of ECs (in low and high glucose-containing media) revealed that calcium ionophore-evoked NO bioactivity correlates with intracellular BH(4):BH(2) and not absolute intracellular levels of BH(4). Reciprocally, superoxide production was found to negatively correlate with intracellular BH(4):BH(2). Hyperglycemia-associated BH(4) oxidation and NO insufficiency was recapitulated in vivo, in the Zucker diabetic fatty rat model of type 2 diabetes. Together, these findings implicate diminished intracellular BH(4):BH(2), rather than BH(4) depletion per se, as the molecular trigger for NO insufficiency in diabetes.

Ratio of 5,6,7,8-tetrahydrobiopterin to 7,8-dihydrobiopterin in endothelial cells determines glucose-elicited changes in NO vs. superoxide production by eNOS.

O89. Increased endothelial BH2:BH4 ratio as the explanation for NOS dysfunction in diabetes

The pathogenesis of progressive renal allograft injury, which is termed chronic allograft nephropathy (CAN), remains obscure and is currently defined by histology. Prospective protocol‐biopsy trials have demonstrated that clinical and standard laboratory tests are insufficiently sensitive indicators of the development and progression of CAN. The study aim was to determine if CAN could be characterized by urinary proteomic data and identify the proteins associated with disease. The urinary proteome of 75 renal transplant recipients and 20 healthy volunteers was analyzed using surface enhanced laser desorption and ionization MS. Patients could be classified into subgroups with normal histology and Banff CAN grades 2‐3 with a sensitivity of 86% and a specificity of 92% by applying the classification algorithm Adaboost to urinary proteomic data. Several urinary proteins associated with advanced CAN were identified including α1‐microglobulin, β2‐microglobulin, prealbumin, and endorepellin, the antiangiogenic C‐terminal fragment of perlecan. Increased urinary endorepellin was confirmed by ELISA and increased tissue expression of the endorepellin/perlecan ratio by immunofluoresence analysis of renal biopsies. In conclusion, analysis of urinary proteomic data has further characterized the more severe CAN grades and identified urinary endorepellin, as a potential biomarker of advanced CAN.

Running Title: A MOLECULAR EXPLANATION FOR HIGH GLUCOSE-ELICITED ENDOTHELIAL DYSFUNCTION

Protein 3-nitrotyrosine in complex biological samples: quantification by high-pressure liquid chromatography/electrochemical detection and emergence of proteomic approaches for unbiased identification of modification sites.

Diminished nitric oxide (NO) bioactivity and enhanced peroxynitrite formation have been implicated as major contributors to atherosclerotic vascular dysfunctions. Hallmark reactions of peroxynitrite include the accumulation of 3-nitrotyrosine (3-NT) in proteins and oxidation of the NO synthase (NOS) cofactor, tetrahydrobiopterin (BH(4)). The present study sought to 1) quantify the extent to which 3-NT accumulates and BH(4) becomes oxidized in organs of apolipoprotein E-deficient (ApoE(-/-)) atherosclerotic mice and 2) determine the specific contribution of inducible NOS (iNOS) to these processes. Whereas protein 3-NT and oxidized BH(4) were undetected or near the detection limit in heart, lung, and kidney of 3-wk-old ApoE(-/-) mice or ApoE(-/-) mice fed a regular chow diet for 24 wk, robust accumulation was evident after 24 wk on a Western (atherogenic) diet. Since 3-NT accumulation was diminished 3- to 20-fold in heart, lung, and liver in ApoE(-/-) mice missing iNOS, iNOS-derived species are involved in this reaction. In contrast, iNOS-derived species did not contribute to elevated protein 3-NT formation in kidney or brain. iNOS deletion also afforded marked protection against BH(4) oxidation in heart, lung, and kidney of atherogenic ApoE(-/-) mice but not in brain or liver. These findings demonstrate that iNOS-derived species are increased during atherogenesis in ApoE(-/-) mice and that these species differentially contribute to protein 3-NT accumulation and BH(4) oxidation in a tissue-selective manner. Since BH(4) oxidation can switch the predominant NOS product from NO to superoxide, we predict that progressive NOS uncoupling is likely to drive atherogenic vascular dysfunctions.

Profound biopterin oxidation and protein tyrosine nitration in tissues of ApoE-null mice on an atherogenic diet: contribution of inducible nitric oxide synthase.

Balancing reactivity against selectivity: the evolution of protein S-nitrosylation as an effector of cell signaling by nitric oxide.

Elucidation of post-translational mechanisms for regulation of GTP cyclohydrolase I

PREMATURE VASCULAR SENESCENCE IN METABOLIC SYNDROME: COULD IT BE PREVENTED AND REVERSED BY A SELENORGANIC ANTIOXIDANT AND PEROXYNITRITE SCAVENGER EBSELEN?

Unbiased identification of cysteine S-nitrosylation sites on proteins

AIMS
Previous studies suggested haemodynamic benefits and, possibly, mortality reduction with the use of nitric oxide synthase (NOS) inhibition in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS). We assessed preliminary efficacy and safety of four doses of l-n-monomethyl-arginine (l-NMMA), a non-selective NOS inhibitor, in patients with AMI complicated by CS despite an open infarct-related artery.

Patients (n = 79) were randomly assigned to a bolus and 5 h infusion of placebo or 0.15, 0.5, 1.0, or 1.5 mg/kg of l-NMMA. The primary outcome measure was absolute change in mean arterial pressure (MAP) at 2 h. Fifteen minutes after study drug initiation, mean change in MAP was -4.0 mmHg in the placebo group and 5.8 (P = 0.02), 4.8 (P = 0.02), 5.1 (P = 0.07), and 11.6 (P < 0.001) mmHg in the four l-NMMA groups, respectively (all vs. placebo). Mean change in MAP at 2 h was -0.4, 4.4, 1.8, -4.1, and 6.8 mmHg in the placebo and four l-NMMA groups, respectively (all P = NS).

l-NMMA resulted in modest increases in MAP at 15 min compared with placebo but there were no differences at 2 h.

Effect of nitric oxide synthase inhibition on haemodynamics and outcome of patients with persistent cardiogenic shock complicating acute myocardial infarction: a phase II dose-ranging study.

The mechanism by which the inflammatory enzyme prostaglandin H2 synthase-1 (PGHS-1) deactivates remains undefined. This study aimed to determine the stabilizing parameters of PGHS-1 and identify factors leading to deactivation by nitric oxide species (NOx). Purified PGHS-1 was stabilized when solubilized in β-octylglucoside (rather than Tween-20 or CHAPS) and when reconstituted with hemin chloride (rather than hematin). Peroxynitrite (ONOO−) activated the peroxidase site of PGHS-1 independently of the cyclooxygenase site. After ONOO− exposure, holoPGHS-1 could not metabolize arachidonic acid and was structurally compromised, whereas apoPGHS-1 retained full activity once reconstituted with heme. After incubation of holoPGHS-1 with ONOO−, heme absorbance was diminished but to a lesser extent than the loss in enzymatic function, suggesting the contribution of more than one process to enzyme inactivation. Hydroperoxide scavengers improved enzyme activity, whereas hydroxyl radical scavengers provided no protection from the effects of ONOO−. Mass spectral analyses revealed that tyrosine 385 (Tyr 385) is a target for nitration by ONOO− only when heme is present. Multimer formation was also observed and required heme but could be attenuated by arachidonic acid substrate. We conclude that the heme plays a role in catalyzing Tyr 385 nitration by ONOO− and the demise of PGHS-1.

Heme catalyzes tyrosine 385 nitration and inactivation of prostaglandin H2 synthase-1 by peroxynitrite Published, JLR Papers in Press, February 9, 2006.

O09. Development of a system for on-demand translocation of eNOS to desired subcellular loci

SNOSID, a proteomic method for identification of cysteine S-nitrosylation sites in complex protein mixtures.

Nitric oxide (NO) modulates the biological levels of arachidonate-derived cell signaling molecules by either enhancing or suppressing the activity of prostaglandin H(2) isoforms (PGHS-1 and PGHS-2). Whether NO activates or suppresses PGHS activity is determined by alternative protein modifications mediated by NO and NO-derived species. Here, we show that inducible NO synthase (iNOS) and PGHS-1 co-localize in atherosclerotic lesions of ApoE(-/-) mouse aortae. Immunoblotting and immunohistochemistry revealed Tyr nitration in PGHS-1 in aortic lesions but markedly less in adjacent nonlesion tissue. PGHS-2 was also found in lesions, but 3-nitrotyrosine incorporation was not detected. 3-Nitrotyrosine formation in proteins is considered a hallmark reaction of peroxynitrite, which can form via NO-superoxide reactions in an inflammatory setting. That iNOS-derived NO is essential for 3-nitrotyrosine modification of PGHS-1 was confirmed by the absence of 3-nitrotyrosine in lesions from ApoE(-/-)iNOS(-/-) mice. Mass spectrometric studies specifically identified the active site residue Tyr385 as a 3-nitrotyrosine modification site in purified PGHS-1 exposed to peroxynitrite. PGHS-mediated eicosanoid (PGE(2)) synthesis was more than fivefold accelerated in cultured iNOS(-/-) versus iNOS-expressing mouse aortic smooth muscle cells, suggesting that iNOS-derived NO markedly suppresses PGHS activity in vascular cells. These results further suggest a regulatory role of iNOS in eicosanoid biosynthesis in human atherosclerotic lesions.

Inducible nitric oxide synthase mediates prostaglandin h2 synthase nitration and suppresses eicosanoid production.

Electrospray tandem mass spectrometry analysis of S- and N-nitrosopeptides: Facile loss of NO and radical-induced fragmentation

P095. Elucidation of posttranslational mechanisms for regulation of GTPCH-GFRP: Relevance for control of NOS cofactor levels

Technology Insight: renal proteomics—at the crossroads between promise and problems

Room for both tyrosine nitration and cysteine nitrosylation to regulate NFκB activity, but perhaps only one modification at a time

RETRACTED ARTICLE: Angiotensin-II-induced oxidative stress elicits hypoadiponectinaemia in rats

Reply to Letter to the Editor Room for both tyrosine nitration and cysteine nitrosylation to regulate NFnB activity, but perhaps only one modification at a time

Prior studies have demonstrated that the substrate for NO synthesis, l-arginine, can be regenerated from the NOS co-product l-citrulline. This requires the sequential action of two enzymes, argininosuccinate synthetase (AS) and argininosuccinate lyase (AL). AS activity has been shown to be rate-limiting for high output NO synthesis by immunostimulant-activated cells and represents a potential site for metabolic control of NO synthesis. We now demonstrate that NO mediates reversible S-nitrosylation and inactivation of AS in vitro and in lipopolysaccharide-treated cells and mice. Using a novel mass spectrometry-based method, we show that Cys-132 in human AS is the sole target for S-nitrosylation among five Cys residues. Mutagenesis studies confirm that S-nitrosylation of Cys-132 is both necessary and sufficient for the inhibition of AS by NO donors. S-nitroso-AS content is regulated by cellular glutathione levels and selectively influences NO production when citrulline is provided to cells as a protosubstrate of NOS but not when l-arginine is provided. A phylogenetic comparison of AS sequences suggests that Cys-132 evolved as a site for post-translational regulation of activity in the AS in NOS-expressing species, endowing NO with the capacity to limit its own synthesis by restricting arginine availability.

Argininosuccinate Synthetase is Reversibly Inactivated by S-Nitrosylation in Vitro and in Vivo*

Although the accelerated atherosclerosis and premature aging of the cardiovascular system in patients with metabolic syndrome have been appreciated, the mechanisms of their development and potential therapeutic interventions remain unresolved. Our previous studies implicated advanced glycosylation end products in development of premature senescence preventable with a peroxynitrite scavenger, ebselen. Therefore, the effect of ebselen on endothelial senescence and vasculopathy in a model of metabolic syndrome—Zucker diabetic rats (ZDF)—was investigated. Ebselen decreased the abundance of 3-nitrotyrosine–modified proteins in ZDF rats. A 6-fold increase in the number of senescent endothelial cells in 22-week-old ZDF was prevented by ebselen. Development of vasculopathy, as collectively judged by the acetylcholine-induced vasorelaxation, NO production, angiogenic competence, and number of circulating microparticles, was almost completely prevented when ebselen was administered from 8 to 22 weeks and partially reversed when the treatment interval was 13 to 22 weeks. In conclusion, premature senescence of endothelial cells is progressively rampant in ZDF rats and is associated with the signs of severe vasculopathy. In addition, prevention of premature senescence of vascular endothelium through controlled decrease in nitrotyrosine formation was chronologically associated with the amelioration of vasculopathy, lending support to the idea of the pathogenetic role of premature senescence of endothelial cells in diabetic macrovasculopathy. (Circ Res. 2004;94:377-384.)

Measurement of NO Production by Aortic Rings and Primary Cultures of Endothelial Cells Obtained From ZL and ZDF Rats

Zucker diabetic fat (ZDF) rats with the metabolic syndrome and hyperlipidemia develop focal and segmental sclerosis. The role of oxidative and nitrosative stress in the nephropathy in ZDF was studied. Renal histology, function, and immunohistologic and biochemical parameters of oxidative and nitrosative stress were evaluated at 8 and 22 wk of age in ZDF and Zucker lean (ZL) rats and after chronic treatment with ebselen, an antioxidant and peroxinitrite scavenger. At 8 wk, ZDF rats showed hyperglycemia, no proteinuria or nephropathy, but higher levels of dihydrobiopterin and 3-nitrotyrosine (3-NT)-modified proteins compared with age-matched ZL rats. At 22 wk, ZDF rats developed focal and segmental sclerosis, proteinuria, decreased creatinine clearance, and renal tissue levels of glutathione and tetrahydrobiopterin with further elevation in dihydrobiopterin and 3-NT-modified proteins, in contrast to age-matched ZL rats. Renal immunohistologic expression of lipid peroxidation products and 3-NT-modified proteins also increased in 22-wk-old ZDF but not in ZL rats. Chronic ebselen treatment of ZDF rats restored renal tissue levels of glutathione and tetrahydrobiopterin; prevented significant accumulation of dihydrobiopterin, lipid peroxidation products, and 3-NT-modified proteins; and ameliorated focal and segmental sclerosis, proteinuria, and fall in creatinine clearance without affecting mean BP, body weight, and blood glucose, compared with the untreated ZDF rats. Chronic ebselen therapy also ameliorated vasculopathy with lipid deposits and tubulointerstitial scarring, inflammation, and upregulated alpha-smooth muscle actin expression. These findings suggest that ZDF rats develop a progressive nephropathy with glomerular, vascular, and tubulointerstitial pathology. Oxidative and nitrosative stress predates the nephropathy, which is improved by peroxinitrite scavenger ebselen, and thus considered its cause and not consequence.

Nephropathy in Zucker diabetic fat rat is associated with oxidative and nitrosative stress: prevention by chronic therapy with a peroxynitrite scavenger ebselen.

Despite growing evidence for a mitochondrial localization of nitric oxide (NO) synthase and a broadening spectrum of NO actions on mitochondrial respiration and apoptosis, the basis for interaction between the enzyme and the organelle remain obscure. Here we investigated mitochondrial localization of endothelial nitric oxide synthase (eNOS) in human umbilical vein endothelial cells and human embryonic kidney cells transfected or infected with eNOS expression vectors. Copurification of eNOS with mitochondria was observed in both human umbilical vein endothelial cells and eNOS-expressing human embryonic kidney cells. Immunodetectable eNOS was cleaved from mitochondria by proteinase K treatment, suggesting eNOS association with the outer mitochondrial membrane. Localization of eNOS to a proteinase K-cleavable site on the cytoplasmic face of the outer membrane was confirmed by immunogold labeling of non-permeabilized mitochondria. Markers for mitochondrial subfractions ruled out the possibility of eNOS association with an intramitochondrial site or inverted mitochondrial particles. Denaturation of eNOS did not attenuate association with mitochondria. Mutant eNOS lacking a pentabasic amino acid sequence within the autoinhibitory domain (residues 628–632 of the bovine eNOS) showed dramatically reduced binding to the mitochondrial but not to the plasma membrane, which was associated with increased oxygen consumption. Collectively, these findings argue in favor of eNOS localization to the outer mitochondrial membrane in endothelial cells and identify elements of a novel anchoring mechanism.

Docking of Endothelial Nitric Oxide Synthase (eNOS) to the Mitochondrial Outer Membrane

NO suppresses while peroxynitrite sustains NF-kappaB: a paradigm to rationalize cytoprotective and cytotoxic actions attributed to NO.

Inhibition of GTP cyclohydrolase I (GTPCH) has been used as a selective tool to assess the role of de novo synthesis of (6R)-5,6,7,8-tetrahydro-l-biopterin (BH4) in a biological system. Toward this end, 2,4-diamino-6-hydroxypyrimidine (DAHP) has been used as the prototypical GTPCH inhibitor. Using a novel real-time kinetic microplate assay for GTPCH activity and purified prokaryote-expressed recombinant proteins, we show that potent inhibition by DAHP is not the result of a direct interaction with GTPCH. Rather, inhibition by DAHP in phosphate buffer occurs via an indirect mechanism that requires the presence of GTPCH feedback regulatory protein (GFRP). Notably, GFRP was previously discovered as the essential factor that reconstitutes inhibition of pure recombinant GTPCH by the pathway end product BH4. Thus, DAHP inhibits GTPCH by engaging the endogenous feedback inhibitory system. We further demonstrate that l-Phe fully reverses the inhibition of GTPCH by DAHP/GFRP, which is also a feature in common with inhibition by BH4/GFRP. These findings suggest that DAHP is not an indiscriminate inhibitor of GTPCH in biological systems; instead, it is predicted to preferentially attenuate GTPCH activity in cells that most abundantly express GFRP and/or contain the lowest levels of l-Phe.

The Mechanism of Potent GTP Cyclohydrolase I Inhibition by 2,4-Diamino-6-hydroxypyrimidine

Abstract— Although the accelerated atherosclerosis and premature aging of the cardiovascular system in patients with metabolic syndrome have been appreciated, the mechanisms of their development and potential therapeutic interventions remain unresolved. Our previous studies implicated advanced glycosylation end products in development of premature senescence preventable with a peroxynitrite scavenger, ebselen. Therefore, the effect of ebselen on endothelial senescence and vasculopathy in a model of metabolic syndrome—Zucker diabetic rats (ZDF)—was investigated. Ebselen decreased the abundance of 3-nitrotyrosine–modified proteins in ZDF rats. A 6-fold increase in the number of senescent endothelial cells in 22-week-old ZDF was prevented by ebselen. Development of vasculopathy, as collectively judged by the acetylcholine-induced vasorelaxation, NO production, angiogenic competence, and number of circulating microparticles, was almost completely prevented when ebselen was administered from 8 to 22 weeks and partially reversed when the treatment interval was 13 to 22 weeks. In conclusion, premature senescence of endothelial cells is progressively rampant in ZDF rats and is associated with the signs of severe vasculopathy. In addition, prevention of premature senescence of vascular endothelium through controlled decrease in nitrotyrosine formation was chronologically associated with the amelioration of vasculopathy, lending support to the idea of the pathogenetic role of premature senescence of endothelial cells in diabetic macrovasculopathy.

Prevention and Reversal of Premature Endothelial Cell Senescence and Vasculopathy in Obesity-Induced Diabetes by Ebselen

Restoration of nitric oxide production by N-hydroxy-L-arginine in endothelial cells with NO deficiency triggered by elevated glucose

—Although the accelerated atherosclerosis and premature aging of the cardiovascular system in patients with metabolic syndrome have been appreciated, the mechanisms of their development and potential therapeutic interventions remain unresolved. Our previous studies implicated advanced glycosylation end products in development of premature senescence preventable with a peroxynitrite scavenger, ebselen. Therefore, the effect of ebselen on endothelial senescence and vasculopathy in a model of metabolic syndrome—Zucker diabetic rats (ZDF)—was investigated. Ebselen decreased the abundance of 3-nitrotyrosine–modified proteins in ZDF rats. A 6-fold increase in the number of senescent endothelial cells in 22-week-old ZDF was prevented by ebselen. Development of vasculopathy, as collectively judged by the acetylcholine-induced vasorelaxation, NO production, angiogenic competence, and number of circulating microparticles, was almost completely prevented when ebselen was administered from 8 to 22 weeks and partially reversed when the treatment interval was 13 to 22 weeks. In conclusion, premature senescence of endothelial cells is progressively rampant in ZDF rats and is associated with the signs of severe vasculopathy. In addition, prevention of premature senescence of vascular endothelium through controlled decrease in nitrotyrosine formation was chronolog-ically associated with the amelioration of vasculopathy, lending support to the idea of the pathogenetic role of premature senescence of endothelial cells in diabetic macrovasculopathy. ( Circ Res . 2004;94:377-384.) 0.05 was considered statistically significant. In vivo angiogenic competence was tested using a femoral artery ligation model in ZDF and ZL rats. Animals were studied 5 weeks postoperatively, when laser Doppler flowmetry/imaging of the cuta-neous circulation and immunohistochemical analysis of capillary density in the affected and contralateral quadriceps muscle were performed using endothelial-specific staining with RECA antibody.

Prevention and Reversal of Premature Endothelial Cell Senescence and Vasculopathy in Obesity-Induced Diabetes by Ebselen Integrative Physiology

GFRP tonically inhibits production of tetrahydrobiopterin and nitric oxide in marine endothelial cells

PURPOSE
Bladder outlet obstruction leads to histological and functional changes in the bladder over time. We investigated the role of inducible nitric oxide synthase (iNOS) in the progression of pathological changes of the bladder secondary to outlet obstruction in a rat and a mouse model.

To assess expression of iNOS in the bladder, polymerase chain reaction amplification of mRNA was done. Rats were subjected to sham operation or partial bladder outlet obstruction. They were given the iNOS inhibitor aminoguanidine in drinking water or unmodified water. After 2 weeks, awake cystometric evaluation was performed, the bladders were harvested and the degree of fibrosis was assessed. In another series of experiments mice deficient in the iNOS gene (iNOS -/-) were compared to WT mice for cystometric as well as histological changes in the bladder following partial bladder outlet obstruction or sham operation.

RESULTS
Partial bladder outlet obstruction induced the expression of iNOS mRNA in the mouse bladder. iNOS -/- mice showed a significantly smaller increase in bladder volume at 3 weeks compared with WT. Pharmacological inhibition of iNOS activity significantly attenuated the increase in bladder size and the number of spontaneous bladder contractions in obstructed rats at 2 weeks. Furthermore, genetic and pharmacological decreases in iNOS led to significantly less fibrosis of the bladder after partial bladder outlet obstruction in mice and rats, respectively.

Pharmacological or genetic decreases in iNOS resulted in amelioration of functional and fibrotic changes in the bladder after partial bladder outlet obstruction, suggesting that NO contributes to the pathophysiology of bladder outlet obstruction.

Inducible nitric oxide synthase promotes pathophysiological consequences of experimental bladder outlet obstruction.

Detection of cysteine S-nitrosylation and tyrosine 3-nitration in kidney proteins.

Renal hemodynamic and ureteral pressure changes in response to ureteral obstruction: the role of nitric oxide.

Premature endothelial cell (EC) senescence (SEN) and macrovasculopathy in obesity-induced diabetes are preventable by chronic treatment with a peroxynitrite scavenger ebselen.

The Redox Status of Bound Pterin Cofactor Determines Whether eNOS Produces NO or Superoxide Anion: [3H]-BH4 Binding Studies Provide Insights into Vascular Pathophysiology

Activation and inactivation of neuronal nitric oxide synthase: characterization of Ca(2+)-dependent [125I]Calmodulin binding.

Calmodulin-dependent activation of endothelial nitric-oxide synthase is generally considered to follow a transient increase in intracellular calcium levels. However, a number of physiological stimuli (e.g. endothelial shear-stress, insulin) are known to activate endothelial nitric oxide (eNOS) via a non-classical, “calcium-independent” pathway. Recent findings demonstrate that such stimuli elicit the phosphorylation of a C-terminal residue in eNOS (Ser1179 in the bovine isoform), rendering eNOS active at resting levels of intracellular calcium. However, the mechanistic basis for this mode of eNOS activation remains unknown. Protein modeling led us to consider that the C terminus of eNOS may fulfill an autoinhibitory function that can be disrupted by phosphorylation of serine 1179. To test this possibility we contrasted the phenotype of wild type bovine eNOS with that of a mutant lacking C-terminal residues 1179–1205 (CΔ27 eNOS). Despite no observed difference in calmodulin affinity, CΔ27 eNOS exhibited a 5-fold reduction in EC50 for calcium and a 2–4-fold increase in maximal catalytic activities. In these phenotypic properties, CΔ27 accurately mimics phospho-Ser1179 wild type eNOS. We conclude that the C terminus imposes a significant barrier to the activation of eNOS by calmodulin binding and that this barrier can be functionally disabled by Ser1179phosphorylation-elicited enzyme activation.

Disabling a C-terminal Autoinhibitory Control Element in Endothelial Nitric-oxide Synthase by Phosphorylation Provides a Molecular Explanation for Activation of Vascular NO Synthesis by Diverse Physiological Stimuli*

Diabetic vasculopathy is central to the development of diverse cardiovascular, renal, retinal, and neurological complications of diabetes. We previously demonstrated that growth of endothelial cells on glycated extracellular matrix proteins (collagen and matrigel) results in a significant decrease in cell proliferation. In the present study, we show that early-passage human umbilical vein endothelial cells (HUVECs) grown on glycated collagen (GC) express hallmarks of premature cell senescence, ie, increase in the proportion of cells expressing senescence-associated &bgr;-galactosidase activity, apoptotic rate, and p53 and p14AFR expression, but in contrast to replicative senescence, display neither attrition of telomeres nor decrease in telomerase activity. An increased frequency of prematurely senescent cells was similarly observed in vivo in aortae of young Zucker diabetic rats, compared with lean controls. NO production by HUVECs grown on GC was decreased, despite a 3-fold increase in eNOS expression and was associated with the increased nitrotyrosine-modified proteins. Development of premature senescence of HUVECs on GC could be prevented and reversed by treatments with the peroxynitrite scavenger, ebselen, eNOS intermediate N&ohgr;-hydroxy-l-arginine (NOHA), or superoxide dismutase mimetic Mn-TBAP. Concomitant with the reversal of senescence, ebselen, and NOHA each restored NO production to levels observed with HUVECs grown on unmodified collagen. Our findings indicate that diabetes mellitus in vivo and GC exposure in vitro elicit premature senescence of the vascular endothelium, a process with distinct pathogenetic mechanisms. Premature senescence of the vascular endothelium is hypothesized to be an important contributor to diabetic vasculopathy and a consequence of reduced NO availability, peroxynitrite, and/or superoxide excess.

Glycated Collagen I Induces Premature Senescence-Like Phenotypic Changes in Endothelial Cells

This article presents data linking eNOS function and nitric oxide (NO) generation or availability to vascular remodeling and signaling, hyperlipidemias, advanced glycated end products and hyperglycemia. These data should be viewed within the broader framework of endothelial cell dysfunction (ECD). It is possible that vascular dysfunctions are capable of triggering early preclinical forms of generalized ECD. Accordingly, it is important to learn more about simple noninvasive ways to assess the functional state of eNOS and the bioavailability of NO. Here we discuss the growing body of evidence--which suggests that disturbances of NO production or availability are major determinants of ECD--and the need for therapeutic efforts toward correction of eNOS activity and NO levels in blood vessels.

The ins and outs of endothelial dysfunction: much ado about NO-thing.

Nitric oxide (NO) is a free-radical product of mammalian cell metabolism that plays diverse and important roles in the regulation of cell function. Biological actions of NO arise as a direct consequence of chemical reactions between NO or NO-derived species and protein targets. Reactions of NO with transition metals in target proteins have garnered the most attention to date as the principal mechanism of NO signaling; nonetheless, S-nitrosylation of protein Cys residues is rapidly moving to center stage in importance. In general, however, there has been a delay in adequate appreciation of the role of S-nitrosylation in biological signaling by NO. This lag is attributed to a poor understanding of the basis for selective targeting of NO to particular thiols, and methodological limitations in accurately quantifying this modification--recent breakthroughs in concepts and methods diminish these barriers. Here, we consider the wheres and whys of protein S-nitrosylation and its basis for specificity. Protein S-nitrosylation potentially represents a ubiquitous and fundamental mechanism for posttranslational control of protein activity on a par with that of O-phosphorylation. Nitric oxide (NO) is a mammalian cell product that has been implicated in the control of essentially all cellular functions. Key to NO's bioactivity is its chemical reactivity. Recent studies suggest that a biologically important reaction of NO is with SH-groups on cysteine residues of proteins--this modification has been termed S-nitrosylation. Until recently, our appreciation of the importance of S-nitrosylation as a mechanism for posttranslational regulation of protein activity has been hindered by an inadequate understanding of how S-nitrosylation may be targeted to specific protein thiols and the lack of a simple method for identification of proteins that are S-nitrosylated in vivo. This review highlights emerging concepts and a new technique that may help to overcome these obstacles. A head-to-head comparison suggests that S-nitrosylation, like O-phosphorylation, may similarly play a fundamental role in the post-translational control of protein activity and cellular function.

S-Nitrosylation Is Emerging as a Specific and Fundamental Posttranslational Protein Modification: Head-to-Head Comparison with O-Phosphorylation

Endothelial dysfunction accompanies suboptimal glucose control in patients with diabetes mellitus. A hallmark of endothelial dysfunction is a deficiency in production or bioavailability of vascular nitric oxide (NO). Here we demonstrate that acute exposure of human endothelial cells to glucose, at levels found in plasma of diabetic patients, results in a significant blunting of NO responses to the endothelial nitric oxide synthase (eNOS) agonists bradykinin and A-23187. Monitoring of NO generation by purified recombinant bovine eNOS in vitro, using amperometric electrochemical detection and an NO-selective porphyrinic microelectrode, showed that glucose causes a progressive and concentration-dependent attenuation of detectable NO. Addition of glucose to pure NO solutions similarly elicited a sharp decrease in NO concentration, indicating that glucose promotes NO loss. Electrospray ionization-tandem mass spectrometry, using negative ion monitoring, directly demonstrated the occurrence of a covalent reaction involving unitary addition of NO (or a derived species) to glucose. Collectively, our findings reveal that hyperglycemia promotes the chemical inactivation of NO; this glucose-mediated NO loss may directly contribute to hypertension and endothelial dysfunction in diabetic patients.

NO production by the endothelial and neuronal isoforms of nitric oxide synthase (cNOS) is regulated on a moment-to-moment basis by calmodulin binding, triggered by transient elevations in intracellular-free calcium levels. Nonetheless, additional modes of cNOS regulation are implicit in the discoveries of stimuli that elicit a sustained increase in cNOS activity despite undetectable or transient increases in intracellular Ca2+ in endothelial cells; such stimuli include shear-stress, oestrogen, insulin or insulin-like growth factor treatment of endothelial cells. Recently, we identified a peptide insertion within the FMN-binding domain of mammalian NOSs that is unique to calcium-dependent isoforms, and not shared with inducible NOS or ancestral flavoproteins. Evidence suggests that this insertion serves as a fundamental control element, analogous to intrinsic autoinhibitory peptides that have been demonstrated to regulate activity of other calmodulin-dependent enzymes. Thus, the peptide insertion of cNOSs appears to function as structural element that is displaced upon calmodulin binding, resulting in dysinhibition of NO synthesis. Once displaced, the peptide may also be subject to transient chemical modifications and protein-protein interactions that modulate autoinhibitory function. Herein we summarize our present knowledge and speculate on mechanisms by which calmodulin and the autoinhibitory peptide conspire to regulate cNOS activity.

The autoinhibitory control element and calmodulin conspire to provide physiological modulation of endothelial and neuronal nitric oxide synthase activity.

The preferred source of arginine for high-output nitric oxide synthesis in blood vessels.

Dipyridinium use of compounds for treating diseases characterized by proliferating cells containing nitric oxide synthase

Tetrahydrobiopterin: An Essential Cofactor of Nitric Oxide Synthase with an Elusive Role

The use of a dipyridinium compound in the manufacture of a medicament for treating a patient with a disease characterized by pathologically proliferating cells containing selected nitric oxide synthase and restenosis, benign prostatic hyperplasia and pulmonary hypertension.

Using dipyridinium compounds to treat a disease characterized by proliferating cells containing nitric oxide synthase.

Adrenomedullin augments nitric oxide and tetrahydrobioptein synthesis in cytokine-stimulated vascular smooth muscle cells.

With the recent visit of Drs. Furchgott, Ignarro, and Murad to Nobel-land, the discovery of nitric oxide (NO) as a vascular signaling molecule achieved global appreciation. This elevates NO to the lofty status of hemoglobin (Hb), arguably the best-understood protein from a molecular structure/function viewpoint and one that has been recognized by the well-deserved award of the 1962 Nobel prize in Chemistry to Max Perutz. Nonetheless, there is trouble in paradise. At the intersection of NO and hemoglobin biochemistry lies an abyss in our understanding that is so fundamental and deep as to challenge the biological function of each molecule. This problem has been largely ignored, but it has been visited in a recent report by Gow et al. (1). 

Simply stated, the problem is that our dogmatic knowledge of chemical interactions of NO and hemoglobin predicts that ( i ) NO should not achieve a concentration in the vascular wall sufficient to elicit vasorelaxation, and ( ii ) nitrosylation of Hb, considered to be essentially irreversible, should result in the build-up of a complex that ultimately compromises life by interfering with tissue oxygenation. The obvious facts that endogenously produced NO is bioactive and Hb can deliver O2 indicate that the chemistry which actually occurs between NO and Hb needs major revision. Notably, this chemistry had been defined by in vitro experimentation using supraphysiological concentrations of NO under nonbiological conditions (2). Although correct, it fails to adequately describe the situation at normal physiological levels of NO (3), where interaction of NO would occur with only a single globin subunit, at most, per predominantly O2-saturated Hb tetramer. A growing body of evidence directs our attention to Hb allostery as the answer to this dilemma in adequately understanding NO/Hb chemistry.

It is well accepted that reaction with Hb is the major mechanism for …

Physiological reactions of nitric oxide and hemoglobin: a radical rethink.

Glycated proteins, including serum albumin, may be involved in the pathogenesis of diabetic vasculopathy. Recent evidence suggests that expression of inducible nitric oxide synthase (iNOS) in vascular smooth muscle cells (VSMC) may, in part, promote atherosclerosis by increasing local oxidative stress. We therefore investigated whether VSMC exposed to glycated human serum albumin (GHSA) produce nitric oxide (NO) by increasing iNOS expression through transcriptional activation of the iNOS gene and whether this process is dependent on nuclear factor kappaB (NF-kappaB) activation. Treatment of VSMC with GHSA causes activation of NF-kappaB and the iNOS promoter. Induction of NF-kappaB and the iNOS promoter by GHSA exhibited dose-dependent kinetics at concentrations ranging from 3 to 1000 microgram/ml. GHSA alone was a weak inducer of NO production in VSMC as measured by determining nitrite levels, and interferon-gamma alone was totally ineffective, whereas the combination of GHSA and interferon-gamma was a strong stimulus. This synergy for NO production corresponded to Northern blot analyses of iNOS mRNA expression. Thus, GHSA may promote atherosclerosis in part by activation of NF-kappaB and upregulation of iNOS, thereby fostering local inflammation and oxidative stress.

Glycated serum albumin-induced nitric oxide production in vascular smooth muscle cells by nuclear factor kappaB-dependent transcriptional activation of inducible nitric oxide synthase.

Appreciation of the role of nitric oxide (NO) in mammalian cell biology has toppled the paradigm that biological signaling is initiated exclusively by noncovalent, lock-and-key-type interactions with receptor proteins. Remarkably, nitric oxide is a free radical that signals by chemical reaction with its protein targets, resulting in covalent modifications and a stable alteration in protein structure and function. Although most proteins may be coerced to react with NO in vitro, the specific proteins that are functionally modified by NO within cells will depend on the concentration of NO and the composition of the intracellular milieu. A further level of complexity is introduced into NO signaling by the fact that reactions can occur with NO directly, or secondarily with NO-derived species. Much to the surprise of those who thought that reactive molecules are generated and act only under pathophysiological conditions (e.g., ischemia-reperfusion injury), NO has emerged as a prototype molecule that signals by chemistry in normal physiology. The unique attributes and importance of NO were recently recognized by the Nobel Prize Committee, with their decision to award the 1998 Prize in Medicine to Drs Furchgott, Ignarro, and Murad, pioneers in NO biology. This review surveys what we believe to be the most important mechanisms and targets of signaling by NO.

The vascular effects of carbon monoxide (CO) resemble those of nitric oxide (NO), but it is unknown whether the two messengers converge or exhibit reciprocal feedback regulation. These questions were examined in microdissected perfused renal resistance arteries (RRA) studied using NO-sensitive microelectrodes. Perfusion of RRA with buffers containing increasing concentrations of CO resulted in a biphasic release of NO. The NO response peaked at 100 nM CO and then declined to virtually zero at 10 microM. When a series of 50-s pulses of 100 nM CO were applied repeatedly (150-s interval), the amplitude of consecutive NO responses was diminished. NO release from RRA showed dependence on L-arginine but not D-arginine, and the responses to CO were inhibited by pretreatment with NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthases (NOS). CO (100 nM) also suppressed NO release induced by 100 microM carbachol, a potent agonist for endothelial NOS (eNOS). RRA from rats in which endogenous CO production from inducible HO was elevated (cobalt chloride 12 h prior to study) also showed suppressed responses to carbachol. Furthermore, responses consistent with these findings were obtained in juxtamedullary afferent arterioles perfused in vitro, where the vasodilatory response to CO was biphasic and the response to acetylcholine was blunted. Collectively, these data suggest that the CO-induced NO release could be attributed to either stimulation of eNOS or to NO displacement from a cellular storage pool. To address this, direct in vitro measurements with an NO-selective electrode of NO production by recombinant eNOS revealed that CO dose-dependently inhibits NO synthesis. Together, the above data demonstrate that, whereas high levels of CO inhibit NOS activity and NO generation, lower concentrations of CO induce release of NO from a large intracellular pool and, therefore, may mimic the vascular effects of NO.

Carbon monoxide induces vasodilation and nitric oxide release but suppresses endothelial NOS.

Immunostimulants trigger vascular smooth muscle cells (VSMC) to express the inducible isoform of NO synthase (iNOS) and increased arginine transport activity. Although arginine transport in VSMC is considered to be mediated via the y+ system, we show here that rat VSMC in culture express the cat-1 gene transcript as well as an alternatively spliced transcript of the cat-2 gene. An RT-PCR cloning sequence strategy was used to identify a 141-base nucleotide sequence encoding the low-affinity domain of alternatively spliced CAT-2A and a 138-base nucleotide sequence encoding the high-affinity domain of CAT-2B in VSMC activated with lipopolysaccharide (LPS) in combination with interferon-gamma (IFN). With this sequence as a probe, Northern analyses showed that CAT-1 mRNA and CAT-2B mRNA are constitutively present in VSMC, and the expression of both mRNAs was rapidly stimulated by treatment with LPS-IFN, peaked within 4 h, and decayed to basal levels within 6 h after LPS-IFN. CAT-2A mRNA was not detectable in unstimulated or stimulated VSMC. Arginine transporter activity significantly increased 4-10 h after LPS-IFN. iNOS activity was reduced to almost zero in the absence of extracellular arginine uptake via system y+. Induction of arginine transport seems to be a prerequisite to the enhanced synthesis of NO in VSMC. Moreover, this work demonstrates tissue expression of CAT mRNAs with use of a model of LPS injection in rats. RT-PCR shows that the expression of CAT-1 and CAT-2B mRNA in the lung, heart, and kidney is increased by LPS administration to rats, whereas CAT-2A mRNA is abundantly expressed in the liver independent of LPS treatment. These findings suggest that together CAT-1 and CAT-2B play an important role in providing substrate for high-output NO synthesis in vitro as well as in vivo and implicate a coordinated regulation of intracellular iNOS enzyme activity with membrane arginine transport.

Cationic amino acid transporter gene expression in cultured vascular smooth muscle cells and in rats.

The vascular effects of carbon monoxide (CO) resemble those of nitric oxide (NO), but it is unknown whether the two messengers converge or exhibit reciprocal feedback regulation. These questions were examined in microdissected perfused renal resistance arteries (RRA) studied using NO-sensitive microelectrodes. Perfusion of RRA with buffers containing increasing concentrations of CO resulted in a biphasic release of NO. The NO response peaked at 100 nM CO and then declined to virtually zero at 10 μM. When a series of 50-s pulses of 100 nM CO were applied repeatedly (150-s interval), the amplitude of consecutive NO responses was diminished. NO release from RRA showed dependence on l-arginine but notd-arginine, and the responses to CO were inhibited by pretreatment with N G-nitro-l-arginine methyl ester (l-NAME), an inhibitor of NO synthases (NOS). CO (100 nM) also suppressed NO release induced by 100 μM carbachol, a potent agonist for endothelial NOS (eNOS). RRA from rats in which endogenous CO production from inducible HO was elevated (cobalt chloride 12 h prior to study) also showed suppressed responses to carbachol. Furthermore, responses consistent with these findings were obtained in juxtamedullary afferent arterioles perfused in vitro, where the vasodilatory response to CO was biphasic and the response to acetylcholine was blunted. Collectively, these data suggest that the CO-induced NO release could be attributed to either stimulation of eNOS or to NO displacement from a cellular storage pool. To address this, direct in vitro measurements with an NO-selective electrode of NO production by recombinant eNOS revealed that CO dose-dependently inhibits NO synthesis. Together, the above data demonstrate that, whereas high levels of CO inhibit NOS activity and NO generation, lower concentrations of CO induce release of NO from a large intracellular pool and, therefore, may mimic the vascular effects of NO.

The first and rate‐limiting enzyme in tetrahydrobiopterin (BH4) biosynthesis is GTP cyclohydrolase (GTPCH). BH4 serves as the essential cofactor for aromatic L‐amino acid hydroxylases, such as tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH), as well as for nitric oxide synthase (NOS). We hypothesized that to provide access to the cofactor, a close association exists between BH4‐synthesizing and BH4‐dependent enzymes, and we determined the relationship among GTPCH, neuronal NOS (nNOS), and TH in rat brain and adrenal gland using immunohistochemistry and in situ hybridization. Analyses of adjacent sections revealed specific localization of GTPCH in TH‐containing cells of the substantia nigra, ventral tegmental area, hypothalamus, locus ceruleus, and adrenal medulla, and also in TPH‐containing cells of the dorsal raphe nucleus and pineal gland. Thus, BH4 can be synthesized in all monoaminergic cells and is readily available for the enzymes requiring it. In contrast, analysis of adjacent sections showed that nNOS was not colocalized with GTPCH. Scattered nNOS‐positive cells were found in the cortex, striatum, cerebellum, and olfactory bulb, all areas that receive monoaminergic innervation. The absence of GTPCH in nNOS cells suggests that nitric oxide‐producing cells may either obtain biopterin from monoamine‐containing processes which terminate in close proximity, or take up biopterin released into the blood. Double labelling of the same section for TH and nNOS revealed the TH nerve terminals connecting with the nNOS‐positive cell bodies, suggesting the possibility that the BH4‐containing nerve terminals may directly donate this cofactor to the nNOS‐containing cells. Synapse 28:140–153, 1998. © 1998 Wiley‐Liss, Inc.

Localization of GTP cyclohydrolase in monoaminergic but not nitric oxide‐producing cells

It has been proposed that Cys99 of human endothelial nitric oxide synthase (eNOS) is responsible for tetrahydrobiopterin (BH4) binding. To examine this possibility rigorously, we expressed rat neuronal NOS (nNOS) in Escherichia coli, with the homologous Cys331 to Ala mutation, and characterized structural and functional attributes of the purified, mutated enzyme. C331A-nNOS, as isolated, was catalytically incompetent. Upon prolonged incubation with l-arginine (l-Arg), not only BH4 binding but also catalytic activity could be restored. In contrast to wild-type nNOS (WT-nNOS), which exhibits an absorbance maximum at 407 nm that shifts immediately upon l-arginine addition to a high spin form, the C331A-nNOS mutant, as isolated, exhibited an absorbance maximum at 420 nm. C331A-nNOS, as isolated, did not bind detectable levels of either [3H]Nω-nitro-l-arginine or [3H]BH4, but [3H]BH4 binding was reinstated after extended incubation with excess l-arginine. On the other hand, C331A-nNOS and WT-NOS were identical with regard to imidazole binding affinity, CaM binding affinity, and rates of cytochrome cand 2,6-dichlorophenolindophenol reduction. EPR spectroscopy revealed conversion of low to high spin heme after extended incubation with high concentrations of l-arginine (0.1–10 mm). The estimated K d for l-arginine binding to C331A-nNOS was two orders of magnitude greater than WT-nNOS (>100 μm versus 2–3 μm). Here we propose that Cys331 plays an important role in stabilizingl-arginine binding to nNOS. Our findings suggest that the primary dysfunction in the C331A mutant of nNOS, as isolated, is disruption of the BH4-substrate binding interactions as broadcast from this mutated cysteine residue. Prolonged incubation withl-arginine appears to cause remodeling of the mutant protein to a form similar to that of WT-nNOS, allowing for normalized BH4 binding and nitric oxide synthetic activity.

The C331A Mutant of Neuronal Nitric-Oxide Synthase Is Defective in Arginine Binding*

Lipoteichoic acid (LTA), a component of the membrane of gram-positive bacteria, induces an isoform of nitric oxide (NO) synthase (iNOS) in vascular smooth muscle; this process may be associated with the vascular failure observed in gram-positive septic shock. The aim of the present work was to study the cellular mechanisms involved in the induction of NO synthesis by LTA from Staphylococcus aureus in cultured rat vascular smooth muscle cells. LTA induces the gene expression of iNOS and GTP cyclohydrolase I (GTPCH) as well as the formation of NO and tetrahydrobiopterin (BH4), effects which are synergistic with interferon-γ. 2,4-Diamino-6-hydroxypyrimidine (DAHP), a selective inhibitor of GTPCH, inhibits both the increase in cellular levels of BH4 as well as the concomitant formation of NO caused by LTA in combination with interferon-γ. This inhibition by DAHP is reversed by co-addition of sepiapterin which is a substrate for BH4 synthesis. Thus, BH4 synthesis is an absolute requirement for the induction of NO synthesis by LTA in vascular smooth muscle. Our findings also suggest that interrupting pterin synthesis may be an effective target for pharmacologic interventions aimed at limiting NO overproduction in gram-positive shock.

Induction of Nitric Oxide and Tetrahydrobiopterin Synthesis by Lipoteichoic Acid from Staphylococcus aureus in VascularSmooth Muscle Cells

Summary Cardiac myocytes are known to express the high-capacity inducible isoform of nitric oxide (NO) synthase (iNOS). Since tetrahydrobiopterin (BH4) is an essential cofactor for NO formation, we investigated whether BH4 synthesis is required for cytokine-induced NO production in cultutred rat cardiac myocytes. The total biopterin content of untreated cardiac myocytes was below our limit of detection. However, treatment with inter-leukin-1α. and interferon-γ (IL-1/IFN) caused a significant rise in biopterin levels and induced NO synthesis. iNOS mRNA and GTP cyclohydrolase I (GTPCH) mRNA were induced by IL-1/IFN in parallel. 2,4-Diamino-6-hydroxypyridine (DAHP), a selective inhibitor of GTPCH, inhibited both the increase in cellular levels of BH4 as well as the concomitant formation of NO caused by IL-1/IFN. This inhibition by DAHP was reversed by coaddition of sepiapterin which is a substrate for BH4 synthesis. Thus BH4 synthesis is an absolute requirement for induction of NO synthesis by cytokines in cardiac myocytes.

Tetrahydrobiopterin Synthesis in Rat Cardiac Myocytes; An Event Required for Cytokine-induced NO Generation

Nitric oxide (NO) is a key biosignaling molecule produced in both peripheral tissues and the central nervous system by a family of enzymes known as nitric oxide synthases (NOSs). NOSs convert L‐arginine to stoichiometric quantities of NO and L‐citrulline using molecular oxygen and NADPH as cofactors. Techniques for measurement of NO and NOS activity are essential to demonstrate the role of NO and NO‐derived species in biological systems. This unit describes two methods for detection of NO: a direct method employing chemiluminescent detection and one based on quantification of the stable oxidation products with detection using the Greiss reagent. Additionally, NOS activity can be quantified by measuring the conversion of radiolabeled L‐arginine to radiolabeled L‐citrulline.

2,4-Diamino-6-hydroxypyrimidine (DAHP) is considered to be a selective and direct-acting inhibitor of GTP cyclohydrolase I (GTPCH), the first and rate-limiting enzyme in the pathway for synthesis of tetrahydrobiopterin (BH4). Accordingly, DAHP has been widely employed to distinguish whether de novo BH4 synthesis is required in a given biological system. Although it has been assumed that DAHP inhibits GTPCH by direct competition with substrate GTP, this has never been formally demonstrated. In view of apparent structural homology between DAHP and BH4, we questioned whether DAHP may mimic BH4 in its inhibition of GTPCH by an indirect mechanism, involving interaction with a recently cloned 9.5-kDa protein termed GTPCH FeedbackRegulatory Protein (GFRP). We show by reverse transcription-polymerase chain reaction that GFRP mRNA is constitutively expressed in rat aortic smooth muscle cells and further induced by treatment with immunostimulants. Moreover, functional GFRP is expressed and immunostimulant-induced BH4 accumulates in sufficient quantity to trigger feedback inhibition of GTPCH. Studies with DAHP reveal that GFRP is also essential to achieve potent inhibition of GTPCH. Indeed, DAHP inhibits GTPCH by dual mechanisms. At a relatively low concentration, DAHP emulates BH4 and engages the GFRP-dependent feedback inhibitory system; at higher concentrations, DAHP competes directly for binding with GTP substrate. This knowledge predicts that DAHP would preferably target GTPCH in tissues with abundant GFRP.

GTP Cyclohydrolase I Inhibition by the Prototypic Inhibitor 2,4-Diamino-6-Hydroxypyrimidine

Molecular aspects of the three isoforms of nitric oxide synthase that uniquely suit them for no. production

OVEREXPRESSION OF GTP CYCLOHYDROLASE ACTIVITY IN VASCULAR SMOOTH MUSCLE: IMPACT ON HIGH-OUTPUT NO SYNTHESIS

Evidence for nitric oxide participation in down-regulation of CYP2B1/2 gene expression at the pretranslational level.

Nitric oxide synthases (NOSs) are classified functionally, based on whether calmodulin binding is Ca2+-dependent (cNOS) or Ca2+-independent (iNOS). This key dichotomy has not been defined at the molecular level. Here we show that cNOS isoforms contain a unique polypeptide insert in their FMN binding domains which is not shared with iNOS or other related flavoproteins. Previously identified autoinhibitory domains in calmodulin-regulated enzymes raise the possibility that the polypeptide insert is the autoinhibitory domain of cNOSs. Consistent with this possibility, three-dimensional molecular modeling suggested that the insert originates from a site immediately adjacent to the calmodulin binding sequence. Synthetic peptides derived from the 45-amino acid insert of endothelial NOS were found to potently inhibit binding of calmodulin and activation of cNOS isoforms. This inhibition was associated with peptide binding to NOS, rather than free calmodulin, and inhibition could be reversed by increasing calmodulin concentration. In contrast, insert-derived peptides did not interfere with the arginine site of cNOS, as assessed from [3H]N G-nitro-l-arginine binding, nor did they potently effect iNOS activity. Limited proteolysis studies showed that calmodulin’s ability to gate electron flow through cNOSs is associated with displacement of the insert polypeptide; this is the first specific calmodulin-induced change in NOS conformation to be identified. Together, our findings strongly suggest that the insert is an autoinhibitory control element, docking with a site on cNOSs which impedes calmodulin binding and enzymatic activation. The autoinhibitory control element molecularly defines cNOSs and offers a unique target for developing novel NOS activators and inhibitors.

An Autoinhibitory Control Element Defines Calcium-regulated Isoforms of Nitric Oxide Synthase*

Because tetra-hydrobiopterin (BH4) is an essential cofactor for nitric oxide (NO) formation, we investigated whether BH4 synthesis is required for cytokine-induced NO production in cultured rat cardiac myocytes. The total biopterin content of untreated cardiac myocytes was below our limit of detection. However, treatment with interleukin-1 alpha (IL-1 alpha) + interferon-gamma (IFN-gamma) caused a significant rise in biopterin levels and induced NO synthesis. 2,4-Diamino-6-hydroxypyrimidine (DAHP), a selective inhibitor of GTP cyclohydrolase I (the rate-limiting enzyme for de novo BH4 synthesis), completely abolished the elevation in biopterin levels induced by IL-1 alpha + IFN-gamma. DAHP also caused a concentration-dependent inhibition of (IL-1 alpha + IFN-gamma)-induced NO synthesis. Similarly, N-acetylserotonin, an inhibitor of the BH4 synthetic enzyme sepiapterin reductase, blocked increases in biopterin levels as well as NO synthesis induced by IL-1 alpha + IFN-gamma. Sepiapterin, substrate for BH4 synthesis via the pterin salvage pathway, prevented this inhibition by DAHP or N-acetylserotonin, and this effect was blocked by methotrexate. Sepiapterin and, to a lesser extent, BH4 dose dependently enhanced (IL-1 alpha + IFN-gamma)-induced NO synthesis, suggesting that the concentration of BH4 limits the rate of NO production. Inducible NO synthase mRNA and GTP cyclohydrolase I mRNA were induced by IL-1 alpha + IFN-gamma in parallel. We thus demonstrate that BH4 synthesis is an absolute requirement for induction of NO synthesis by cytokines in cardiac myocytes.

Induction of tetrahydrobiopterin synthesis in rat cardiac myocytes: impact on cytokine-induced NO generation.

I. General Biochemistry of NOSs and Cellular Actions of NO.- 1. The Biological Chemistry of NO.- 2. Role of NO and Nitrogen Intermediates in Regulation of Cell Functions.- 3. Nitric Oxide Synthases and Their Cofactors.- 4. Regulation of the NOS Gene Family.- 5. Role of NO in Cell Locomotion.- II. Renal Expression of NOSs and Production of NO.- 6. Metabolic Pathways and Cycles of L-Arginine Synthesis and Utilization.- 7. Distribution of NOSs in the Kidney.- III. NO and the Regulation of Renal Hemodynamics.- 8. Vascular Effects of NO.- 9. Role of NO in the Function of the Juxtaglomerular Apparatus.- 10. NOS in Mesangial Cells: Physiological and Pathophysiological Roles.- 11. Tubuloglomerular Feedback and Macula Densa-Derived NO.- 12. NO and the Renin System.- 13. NO and the Medullary Circulation.- IV. Role of NO system in Renal Pathophysiology.- 14. NO in Septic Shock.- 15. NO and Glomerulonephritis.- 16. NO in Acute Renal Failure.- 17. NO in Diabetic Nephropathy.- 18. NO and Hypertension.- 19. NO in Normal and Preeclamptic Pregnancy.- 20. Sickle Cell Disease and NO.- 21. A Putative Role of NO and Oxidant Injury in the Pathogenesis of Hemolytic Uremic Syndrome.- 22. Role of NO in Urinary Tract Infections.- 23. Role of the NO System in Urinary Tract Obstruction.

Nitric oxide (NO) is synthesized in wounds, but its exact role and cellular source are not known. Wound fibroblasts (WF) are phenotypically characterized by increased collagen synthesis and contractility. We hypothesized that WF may be also phenotypically altered during wound healing to synthesize NO. WF were isolated from polyvinyl alcohol sponges implanted in male Lewis rats and harvested 10 days later. Proliferation in response to 10% fetal bovine serum was assessed by [3H]thymidine incorporation in a microculture system. A fibroblast-populated collagen lattice was used for assaying contractility. Collagen synthesis was determined by measuring the collagenase-sensitive fraction of protein-incorporated [3H]proline. Fibroblasts were incubated in the presence or the absence of 0.5 mM S-methyl-isothio-uronium or 0.5 mM N-monomethyl-L-arginine, both competitive inhibitors of NO synthase. WF spontaneously synthesize and release NO (4.60 +/- 0.29 nmol nitrite/microg DNA/48 h). Normal dermal fibroblasts do not synthesize NO. WF NO synthesis was limited to the first and second passages postharvest and was inhibitable by S-methyl-isothio-uronium (96%) and N-monomethyl-L-arginine (84%). In vivo iNOS expression by WF was confirmed by in situ hybridization and immunohistochemistry. Inhibition of endogenous NO synthesis had no effect on fibroblast proliferation. However, fibroblast-mediated collagen contraction was enhanced (p < 0.01), and collagen synthesis was significantly decreased (p < 0.05) by inhibiting NO synthase. The data show that WF are phenotypically altered during the healing process to synthesize NO, which, in turn, regulates their collagen synthetic and contractile activities.

Nitric oxide, an autocrine regulator of wound fibroblast synthetic function.

CYS 331 of neuronal nitric oxide synthase is involved in L-arg binding rather than direct BH4 binding

Immunostimulants trigger vascular smooth muscle cells (VSMC) to express both the inducible isoform of NO synthase (iNOS) and argininosuccinate synthetase (AS). With constitutively expressed argininosuccinate lyase (AL), AS confers cells with an Arg/Cit cycle that can sustain NO production via continuous regeneration of the NOS substrate, l-arginine (Arg), from the NOS coproduct, l-citrulline (Cit). To assess whether NO synthesis can be rate-limited by Arg recycling, we tested whether AS-overexpressing cells have an enhanced capacity for immununostimulant-induced NO synthesis. Rat VSMC were stably transfected with human AS cDNA in a eukaryotic cell expression vector, driven by a strong viral promoter. AS activity in transfected VSMC exceeded that induced in untransfected cells treated for 24 h with a combination of bacterial lipopolysaccharide and interferon-γ (LPS/IFN). AS activity was predominantly associated with membranes but was also found in cytosol. Recombinant AS was purified from cytosol and possessed a specific activity exceeding that reported for native AS. Western blotting verified the basal expression of AS antigen in membranes from untreated AS-transfected VSMC and from untransfected VSMC after 24 h exposure to LPS/IFN. Epifluorescence histochemistry revealed a punctate distribution of AS antigen in transfected cells, consistent with a predominant membrane localization. Remarkably, on a per cell basis, LPS/IFN-induced NO production was 3–4-fold greater in AS-transfected cells than untransfected VSMC. In untransfected VSMC, maximal NO production during 48 h required millimolar Arg; notably, Cit was needed at ≈3-fold higher concentrations than Arg for a comparable NO synthesis rate. In contrast, AS-transfected VSMC utilized Arg and Cit equi-effectively and at much lower concentrations; 100 μm of either precursor supported a maximal rate of NO synthesis for 48 h. The enhanced ability of AS-transfected cells to produce NO, compared with untransfected cells, could not be ascribed to differences in iNOS protein content or LPS/IFN potency for immunoactivation. We conclude that transfection with AS provides a continuous flux of Arg which drives NO synthesis in immunoactivated VSMC. Arg regeneration by AS is rate-limiting to NO synthesis and apparently provides iNOS with a preferred cellular source of Arg. In accord with the reported “channeling” of substrates by urea cycle enzymes, we hypothesize that the Arg/Cit cycle sequesters a discrete pool of recyclable substrate that sustains high-output NO synthesis.

Argininosuccinate Synthetase Overexpression in Vascular Smooth Muscle Cells Potentiates Immunostimulant-induced NO Production*

Structural aspects of the isoforms of nitric oxide synthase which influence function

Microtiter plate assay for determining kinetics of nitric oxide synthesis.

Nitric oxide (NO) synthesis occurs during wound healing, but its role has not been defined. To study the effect of NO on wound repair, S-methyl isothiouronium (MITU, a competitive inhibitor of NO synthase) was administered at a dose of 10, 50, and 100 mg/kg body weight/day, using intraperitoneally implanted miniosmotic pumps. Groups of 10 male Balb/C mice underwent a dorsal skin incision and polyvinyl alcohol sponges were inserted subcutaneously. The animals were sacrificed 10 days postwounding and wound breaking strength and hydroxyproline content of sponges, an index of reparative collagen deposition, were determined. Some sponges were used to harvest wound fluid and infiltrating cells, which were then incubated overnight with or without 1 mM MITU. Nitrite and nitrate, stable end products of NO, were measured in wound fluid and in wound cell culture supernatants. Continuous intraperitoneal infusion of MITU significantly decreased wound fluid nitrite/nitrate concentrations in a dose dependent manner (P < 0.01). Inhibition of wound NO synthesis by 100 mg MITU/kg/day was paralleled by lowered wound collagen accumulation (P < 0.01) and wound breaking strength (P < 0.01). In vitro NO synthesis by wound cells obtained from animals treated with 100 mg MITU/kg/day was not significantly different from controls (12.6 +/- 1.2 vs 10.7 +/- 0.6 nmole NO2 + NO3/microgram DNA), reflecting the reversible inhibition of NO synthase by MITU. However, NO production was equally inhibited in wound infiltrating cells by the in vitro addition of MITU (83% vs 85%, respectively). These data suggest that nitric oxide synthesis is critical to wound collagen accumulation and acquisition of mechanical strength.

Understanding the structural aspects of neuronal nitric oxide synthase (NOS) using microdissection by molecular cloning techniques: molecular dissection of neuronal NOS.

NO in septic shock: good, bad or ugly? Learning from iNOS knockouts.

Bovine endothelial constitutive nitric oxide synthase (eNOS) was expressed in E. coli as a soluble, catalytically active enzyme using the pCW expression vector coexpressed with a plasmid, pGroELS, encoding the chaperonins groEL and groES. The E. coli BL21 cultures reproducibly synthesized 6-10 mg of recombinant enzyme per liter of culture. The eNOS protein was purified using 2'5'-ADP Sepharose 4B and appeared as a single band of apparent molecular mass 135 kDa on SDS/PAGE. The recombinant resting enzyme is predominantly high spin with an absorbance maximum at 406 nm. The dithionite-reduced, CO-bound form shows an absorbance maximum at 444 nm. The spectral properties of recombinant eNOS from E. coli are identical to those observed with eNOS from stably transfected HEK 293 cells or from baculovirus expression systems. Enzymatic activity of eNOS from E. coli ranged between 68-135 nmol product formed/min/mg at 25 degrees C, using hemoglobin-NO capture or L-citrulline formation assays. The enzyme is replete with heme and flavins and both activity and [3H]-nitroarginine binding were largely dependent on tetrahydrobiopterin. The heterologous expression of eNOS offers a number of advantages over tissue sources of the protein.

Characterization of bovine endothelial nitric oxide synthase expressed in E. coli.

Up-regulation of rat adrenomedullin gene expression by endotoxin: relation to nitric oxide synthesis.

Pyrrolidine dithiocarbamate inhibits immunostimulant-induced tetrahydrobiopterin synthesis in rat vascular smooth muscle.

Bacterial lipopolysaccharide (LPS) and other immunostimulants induce an isoform of NO synthase (iNOS) in vascular smooth muscle (VSM) which produces large quantities of NO and profound vasodilation; this process has been implicated as the cause of gram-negative septic shock. Although regulation of iNOS has been considered to occur at the level of transcription, it is unclear whether post-transcriptional events also contribute to changes in iNOS mRNA expression. We show that cycloheximide (CH), an inhibitor of protein synthesis, induces iNOS mRNA in VSM and potentiates the induction of iNOS mRNA caused by LPS. For many early-response genes, protein-synthesis inhibitors enhance mRNA levels by increasing mRNA stability. Since iNOS mRNA contains multiple copies of a consensus sequence (AUUUA) in common with these eary-response genes and responsible for mRNA destabilization, we tested whether CH induces iNOS mRNA by prolonging mRNA lifetime. In the absence of CH, iNOS mRNA decayed with biphagic kinetics and a half-life of 2 h. In the presence of CH, half-life was prolonged to approximately 7 h. Our observations indicate that in VSM the stability of iNOS mRNA may be under the control of a labile protein factor which awaits identification and characterization. Regulation of mRNA lifetime represents a novel site for control of iNOS gene expression.

Cycloheximide induces nitric oxide synthase mRNA in vascular smooth muscle cells by prolonging mRNA lifetime.

Since arginine is the only physiological substrate for the NO synthase reaction, regulation of arginine availability could determine the cellular rate of NO production. We investigated whether lipopolysaccharide (LPS) treatment in vivo would alter tissue expression of mRNAs for argininosuccinate synthetase (AS) and argininosuccinate lyase (AL), the net action of which is to convert citrulline to arginine. Concomitant with the induction of NO synthase mRNA, injection of LPS into the rats elicited an increase in AS and AL mRNA levels in the tissues. In contrast with modest increases in the abundance of AS and AL mRNA in lung and heart, a marked increase in levels of AS and AL mRNA in the kidney occurred. The liver, whether or not treated with LPS, contained high levels of mRNA for AS and AL which are components of the urea cycle. Findings suggest that an increase in the renal capacity to convert citrulline to arginine could play a key role in NO formation in vivo when arginine becomes limiting.

Effect of lipopolysaccharide treatment in vivo on tissue expression of argininosuccinate synthetase and argininosuccinate lyase mRNAs: relationship to nitric oxide synthase.

Recent evidence suggests that the production of nitric oxide (NO) may have important roles in the regulation of osteoblast and osteoclast metabolism. The present study was performed to investigate the effects of interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) on the expression of inducible NO-synthase (iNOS) and to measure high-output production of NO by primary rat osteoblasts and osteoblastic cell lines ROS 17/2.8, MC3T3-E1 and MG-63. In addition, we have investigated if NO may mediate some of the effects of these cytokines on osteoblast metabolism. Northern blots and immunocytochemistry revealed time-dependent iNOS messenger RNA and protein expression in primary rat osteoblasts in response to cytokine treatment. Reverse transcription polymerase chain reaction amplified an 807-base pair (bp) product from ROS 17/2.8 cells, which had a size and restriction enzyme-cut pattern identical to that predicted for authentic rat iNOS. Nitrite accumulation in culture medium was induced by IFN-gamma in a time- and dose-dependent manner and inhibited by cotreatment with inhibitors of NOS activity and by dexamethasone. IL-1 beta, TNF-alpha, and bacterial lipopolysaccharide were found to have weak stimulatory effects on nitrite production on their own. However, IL-1 beta and TNF-alpha showed strong synergy with IFN-gamma, but, surprisingly, lipopolysaccharide was found to exert potent inhibitory effects on IFN-gamma-induced nitrite synthesis. Basal production of nitrite and induction of its synthesis was similarly observed with primary rat osteoblasts as well as ROS 17/2.8, MC3T3-E1, and MG-63 cell lines. Cytokine-induced NO production significantly reduced osteoblast activity, as was evidenced by inhibition of DNA synthesis, cell proliferation, alkaline phosphatase activity, and osteocalcin production. The results provide evidence for a basal expression of iNOS activity and show that the iNOS messenger RNA, protein, and enzyme activity are all induced by cytokines across the species. The data further suggest that osteoblast-derived NO may have an important role in mediation of localized bone destruction associated with inflammatory bone diseases such as rheumatoid arthritis.

Cytokine-stimulated expression of inducible nitric oxide synthase by mouse, rat, and human osteoblast-like cells and its functional role in osteoblast metabolic activity.

Prior to the mid-1980s, nitric oxide (NO) was viewed as an environmental pollutant but not as a compound of physiological significance. Thus, it was a skeptical audience that first heard the pronouncement at a scientific meeting in 1986, that NO was the identity of the elusive endothelium-derived relaxing factor, a mediator of vasorelaxation in response to numerous endogenous stimuli. Since then, the simple gas NO has gone from obscurity to center stage, being identified as a key player in physiologic processes as diverse as blood pressure maintenance, neural transmission, and immunologic defense. In addition to its physiological roles, NO has been implicated in the pathogenesis of a multitude of disease states, many of which are of primary interest to the cardiovascular surgeon: circulatory shock, atherosclerosis, diabetes mellitus, and ischemia-reperfusion injury. Recent years has seen NO biology emerge as an exciting and extremely fertile area of biomedical investigation. To fully understand the molecular basis of many clinical problems facing the cardiovascular surgeon, appreciation of NO's involvement is essential.

Expression of NO synthase (NOS) in renal failure and hypertension

Lipid A and the lipid A analogue anti-tumour compound ONO-4007 induce nitric oxide synthase in vitro and in vivo.

Nitric oxide is a double-edged sword. Produced by mammalian cells at an appropriate magnitude and tempo, it serves as a key signaling molecule in physiological processes as diverse as host-defense, neuronal communication, and vascular regulation (for reviews, see 13 1 , 1 32, 172). On the other hand, excessive and unregulated NO synthesis has been implicated as causal or contributing to pathophysiological conditions induding many lethal and de­ bilitating diseases of humans: vascular shock, stroke, diabetes, neurodegenera­ tion, arthritis, and chronic inflammation. Contrary to conventional biosignaling molecules that act by binding to specific receptor molecules, NO manifests its biological actions via a wide range of chemical reactions. NO is a small, relatively stable, free-radical gas that readily diffuses into cells and cell mem­ branes where it reacts with molecular targets. The precise reactions, which are realized in any biological setting, depend on the concentration of NO achieved and often on subtle variations in the composition of the intraand extracellular milieu. This review summarizes the present knowledge of cellular events that lead to NO overproduction in mammalian systems and discusses reactions of NO that may contribute to cell damage or death. Our primary aim is to interpret rather than exhaustively summarize the large body of accumulated NO litera-

Nitric oxide (NO) produces rapid osteoclast detachment and contraction in vitro, and this effect is accompanied by a profound inhibition of bone resorption. Work by others has confirmed these findings in vivo: inhibition of NO synthase [NOS; L-arginine, NADPH: oxygen oxidoreductase (NO-forming), EC 1.14.13.39] in normal rats is followed by increased bone resorption reflected by a marked loss in bone mineral density. In our present study, immunocytochemistry and Northern blotting show the presence of the constitutive calcium-sensitive NOS isoform (cNOS) in normal rat osteoclasts and in the human preosteoclast cell line (FLG 29.1). The inducible NOS isoform (iNOS) was also clearly demonstrable in the rat cells especially after treatment with gamma interferon (IFN-gamma) and bacterial wall products [lipopolysaccharide (LPS)], while a basal level of transcript was detected in the untreated human preosteoclast line. However NADPH-diaphorase activity was intense only in neonatal rat osteoclasts attached to bone, perhaps reflecting either enhancement of cNOS activity by calcium or increased amounts of the inducible isoform in activated osteoclasts in situ compared with isolated neonatal rat osteoclasts. These actively resorb devitalized bone but the untreated cells contain relatively low levels of NOS; they are extremely sensitive to inhibition by NO. The iNOS inhibitor aminoguanidine markedly enhances in vitro resorption by activated NOS-rich chick osteoclasts and by normal rat osteoclasts treated with LPS or IFN-gamma. In contrast, the nonselective NOS inhibitor NG-monomethyl-L-arginine inhibits resorption by untreated neonatal rat osteoclasts. Thus, osteoclast function may require intermittent calcium-stimulated increases in NO production by cNOS against a basal inhibitory background activity of the iNOS isoform. However, bone resorption depends on precursor replication and on the activity of the mature cells, and we found that the NO donor 3-morpholinosydnonimine (SIN-1) (50 microM) profoundly depressed replication in the human preosteoclast line. Taken together, these results strongly suggest that NO maintains a central control of bone resorption in both avian and mammalian species by exerting a powerful tonic restraint of osteoclast numbers and activity. The presence of NOS in human cells implies a similar function in man and that conventional views of calcium homoeostasis and skeletal metabolism will need substantial revision. Since NO also influences behavior of the osteoblast, the bone-forming cell, in vitro, a similar effect in vivo might imply a general influence on bone remodeling.

Bidirectional regulation of osteoclast function by nitric oxide synthase isoforms.

A putative dihydrofolate reductase (DHFR) module has been identified in neuronal nitric oxide synthase, consisting of amino acids 558-721, and is proposed to be the site of tetrahydrobiopterin (BH4) binding. This polypeptide has been expressed in E. coli as a fusion protein with glutathione S-transferase (GST), using the plasmid pGEX-4T1. The protein binds N omega-nitro-L-arginine (NNA) tightly, but this binding is not stimulated by BH4. cDNAs for Module II (residues 220-557) and Module III (residues 220-721) have been expressed as fusion proteins with GST. Module II does not bind NNA. However, Module III does bind NNA and binding is significantly stimulated by BH4. These observations are taken as strong evidence that the DHFR module contains the L-arginine binding site and, presumably, the BH4 binding site by analogy to its homology with DHFR, but that tight binding of BH4 requires amino acids 220-577.

Modular structure of neuronal nitric oxide synthase: localization of the arginine binding site and modulation by pterin.

The neuronal nitric oxide synthase (nNOS) has been successfully overexpressed in Escherichia coli, with average yields of 125-150 nmol (20-24 mg) of enzyme per liter of cells. The cDNA for nNOS was subcloned into the pCW vector under the control of the tac promotor and was coexpressed with the chaperonins groEL and groES in the protease-deficient BL21 strain of E. coli. The enzyme produced is replete with heme and flavins and, after overnight incubation with tetrahydrobiopterin, contains 0.7 pmol of tetrahydrobiopterin per pmol of nNOS. nNOS is isolated as a predominantly high-spin heme protein and demonstrates spectral properties that are identical to those of nNOS isolated from stably transfected human kidney 293 cells. It binds N omega-nitroarginine dependent on the presence of bound tetrahydrobiopterin and exhibits a Kd of 45 nM. The enzyme is completely functional; the specific activity is 450 nmol/min per mg. This overexpression system will be extremely useful for rapid, inexpensive preparation of large amounts of active nNOS for use in mechanistic and structure/function studies, as well as for drug design and development.

High-level expression of functional rat neuronal nitric oxide synthase in Escherichia coli.

Nitric oxide (NO) is a messenger molecule that functions as a vasodilator and accounts for the biologic activity of endothelium-derived relaxing factor (EDRF). The enzyme responsible for NO production, NO synthase (NOS), exists in different isoforms. Some are expressed constitutively in various tissues, whereas others require induction by endotoxin and cytokines. There is evidence that NO plays an important role in the regulation of basal renal vascular resistance and in the tubuloglomerular feedback response. Specific antibodies to a constitutive NOS isolated from rat brain (B-NOS) and an inducible NOS isolated from rat aortic smooth muscle (VSM-NOS) were used to establish the cellular and subcellular distribution of NOS in the kidney. Kidneys from normal rats were preserved and processed for light and electron microscopic immunohistochemical studies using both a preembedding and a postembedding horseradish peroxidase technique. By light microscopy, strong immunostaining for B-NOS was observed in the juxtaglomerular apparatus, where it was located in cells of the macula densa. In contrast, immunostaining for VSM-NOS was specifically located in the terminal afferent arteriole and occasionally also in the initial efferent arteriole in the juxtaglomerular apparatus. In addition, faint immunostaining was present in the entire distal tubule. There was no labeling of arcuate or interlobular arteries. The injection of lipopolysaccharide was associated with increased immunostaining for VSM-NOS in the afferent arteriole but had no effect on B-NOS staining. By electron microscopy, B-NOS immunostaining was present throughout the cytoplasm of the macula densa cells, where it appeared to be associated mainly with small vesicles. Immunostaining for VSM-NOS in the afferent arteriole exhibited a patchy distribution in some cells, whereas other cells were stained throughout the cytoplasm. These results indicate that two distinct isoforms of NOS are present in the juxtaglomerular apparatus and support the hypothesis that NOS is involved in the regulation of tubuloglomerular feedback and glomerular capillary pressure.

Immunocytochemical localization of distinct isoforms of nitric oxide synthase in the juxtaglomerular apparatus of normal rat kidney.

Argininosuccinate synthetase mRNA and activity are induced by immunostimulants in vascular smooth muscle. Role in the regeneration or arginine for nitric oxide synthesis.

L-thiocitrulline. A stereospecific, heme-binding inhibitor of nitric-oxide synthases.

The effects of NG-methyl-L-arginine (L-NMA), an inhibitor of nitric oxide formation, were studied in dogs treated with interleukin-2 (IL-2). The administration of IL-2 to dogs resulted in hypotension within 3 days of treatment. The development of hypotension correlated with accumulation in the serum of nitrate, which is a stable breakdown product of nitric oxide. Administration of L-NMA decreased serum nitrate levels and increased the mean arterial pressure. The antihypotensive effect was dose dependent with a maximum effect observed at a dose of 20 mg/kg. Administration of a continuous infusion of L-NMA (5 mg.kg-1.h-1) maintained the mean arterial pressure for 48 h with concurrent administration of IL-2. Evaluation of IL-2-induced lymphokine-activated killer cell proliferation and tumoricidal activity toward a canine glioblastoma target cell line was unaffected by L-NMA. These studies imply that L-NMA may effectively ameliorate the dose-limiting hypotension associated with administration of IL-2 without adversely affecting the antitumor effects.

NG-methyl-L-arginine, an inhibitor of nitric oxide formation, reverses IL-2-mediated hypotension in dogs.

This study investigates the role of endogenous platelet-activating factor (PAF) in the production of nitric oxide (NO) by constitutive and inducible isoforms of NO synthase (NOS) in endotoxin shock. In anesthetized rats, 3 hours of endotoxemia resulted in a fall in mean arterial blood pressure (MAP) from 127 +/- 5 (control) to 61 +/- 7 mm Hg and a reduction of the pressor responses to norepinephrine (NE, 1 microgram.kg-1) from 33 +/- 3 (control) to 17 +/- 2 mm Hg. Endotoxemia for 3 hours also resulted in a significant reduction in the contractile effects of NE (10(-8) to 10(-6) mol/L) in thoracic aortas ex vivo. This hyporeactivity to NE was due to an enhanced formation of NO, for it was restored by the NOS inhibitor NG-nitro-L-arginine methyl ester. Animals pretreated with the PAF receptor antagonist WEB 2086 maintained higher MAP (MAP at 180 minutes, 98 +/- 6 mm Hg) and exhibited more pronounced pressor responses to NE at 180 minutes after LPS injection. Moreover, WEB 2086 attenuated by 58% the lipopolysaccharide (LPS)-induced hyporeactivity of the rat aortic rings ex vivo. At 3 hours after LPS injection, calcium-independent NOS activity was induced in the lung. The activity of inducible NOS was significantly lower (by 31%) in lungs of rats pretreated with WEB 2086. The hypothesis that WEB 2086 attenuates the induction of NOS in vivo was substantiated in vitro by the finding that pretreatment with WEB 2086 for 30 minutes inhibited the LPS-stimulated NO production in cultured murine macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)

Platelet-activating factor contributes to the induction of nitric oxide synthase by bacterial lipopolysaccharide.

Interleukin-1 contributes to the induction of nitric oxide synthase by endotoxin in vivo.

(LPS) andadiverse array ofother immunostimulants andcytokines suppress themetaboism ofendogenous andexogenous substances by reducing activity ofthehepatic cytochrome P450mixedfunction oxidase system. Although this effect ofimmunostimulants wasfirst described almost 40yrago, themechanism is obscure. Immunostimulants arenowknowntocause NO overproduction bycelis viainduction ofnitric oxide synthase. Wehaveinvestigated whether NOoverproduction isinvolved insuppressing hepatic metabolism byLPS.Invitro treatment ofhepatic microsomes withNO,produced bychemical decomposition of3-morpholinosydnonimnue orbynitric oxide synthase, substantially suppressed cytochrome P450-dependent oxygenation reactions. Thiseffect ofNOwasseen withhepatic microsomes prepared fromtwospecies (rat andchicken) and after exposure tochemicais thatinduce distinct molecular isoforms ofcytochromes P450(-naphthoflavone, 3-methylcholanthrene, andphenobarbital). Spectral studies indicate that NO reacts invitro withbothFe2+- andFe3+-hemes in microsomal cytochromes P450. Invivo, LPSdiminished the phenobarbital-induced dealkylation of7-pentoxyresorufin by ratliver microsomes andreduced theapparent P450content as measured byCO binding. These LPSeffects wereassociated withinduction ofNO synthesis; LPS-induced NO synthesis showeda strong positive correlation withtheseverity of cytochrome P450inhibition. Thedecrease inbothhepatic microsomal P450activity andCObinding caused byLPSwas largely prevented bytheselective NO synthase inhibitor N"nitro-L-arginine methyl ester. Ourrmdings implicate NOoverproduction asamajor factor mediating thesuppression of hepatic metabolism byimmunostimulants suchasLPS.

Nitric oxide isamediator ofthedecrease incytochrome P450-dependent metabolism caused byimmunostimulants

Tetrahydrobiopterin synthesis is induced by LPS in vascular smooth muscle and is rate-limiting for nitric oxide production.

Inducible nitric oxide synthase activity in hepatocytes is dependent on the coinduction of tetrahydrobiopterin synthesis.

Bacterial lipopolysaccharide (LPS) and a diverse array of other immunostimulants and cytokines suppress the metabolism of endogenous and exogenous substances by reducing activity of the hepatic cytochrome P450 mixed-function oxidase system. Although this effect of immunostimulants was first described almost 40 yr ago, the mechanism is obscure. Immunostimulants are now known to cause NO overproduction by cells via induction of nitric oxide synthase. We have investigated whether NO overproduction is involved in suppressing hepatic metabolism by LPS. In vitro treatment of hepatic microsomes with NO, produced by chemical decomposition of 3-morpholinosydnonimine or by nitric oxide synthase, substantially suppressed cytochrome P450-dependent oxygenation reactions. This effect of NO was seen with hepatic microsomes prepared from two species (rat and chicken) and after exposure to chemicals that induce distinct molecular isoforms of cytochromes P450 (beta-naphthoflavone, 3-methylcholanthrene, and phenobarbital). Spectral studies indicate that NO reacts in vitro with both Fe(2+)- and Fe(3+)-hemes in microsomal cytochromes P450. In vivo, LPS diminished the phenobarbital-induced dealkylation of 7-pentoxyresorufin by rat liver microsomes and reduced the apparent P450 content as measured by CO binding. These LPS effects were associated with induction of NO synthesis; LPS-induced NO synthesis showed a strong positive correlation with the severity of cytochrome P450 inhibition. The decrease in both hepatic microsomal P450 activity and CO binding caused by LPS was largely prevented by the selective NO synthase inhibitor N omega-nitro-L-arginine methyl ester. Our findings implicate NO over-production as a major factor mediating the suppression of hepatic metabolism by immunostimulants such as LPS.

Nitric oxide is a mediator of the decrease in cytochrome P450-dependent metabolism caused by immunostimulants.

Endothelium-derived relaxing factor/nitric oxide (EDRF/NO) is produced by the vascular wall and is a key modulator of vascular tone and blood pressure. NO is also produced by vascular smooth muscle (VSMC) where it can inhibit proliferation. Since cytokine-activated VSMC proliferation is a major event in the development of atherosclerosis, we investigated the influence of cholesterol (CE)-enrichment of VSMC on cytokine-induced NO synthesis. Treatment of VSMC with native LDL for one week did not promote CE-accretion or alter NO production following exposure to endotoxin (LPS). In contrast, CE-enrichment by cationized LDL augmented LPS-induction of NO synthesis 2-5-fold. While TNF-alpha promoted little NO synthesis in control VSMC, it was very potent after CE-enrichment. Similarly, CE-enrichment augmented IL-1 alpha-induced NO synthesis. However, CE-enrichment did not affect the synergistic induction of NO synthesis by cytokines in combination with IFN-gamma. Our findings suggest that CE-enrichment of VSMC upregulates signal transduction pathways which mediate cytokine and LPS induction of NO synthase activity.

Cholesterol enrichment of arterial smooth muscle cells upregulates cytokine-induced nitric oxide synthesis.

GTP cyclohydrolase I (GTPCH) is the first and rate-limiting enzyme for the synthesis of tetrahydrobiopterin (BH4), a cofactor of nitric oxide synthase (NOS). As the induction of NO synthesis by immunostimulants in vascular smooth muscle (VSM) cells requires de novo synthesis of BH4, we investigated whether immunostimulants enhance the expression of GTPCH mRNA. GTPCH mRNA and BH4 were measured in rat VSM cells after exposure to bacterial lipopolysaccharide (LPS) in combination with interferon-gamma (IFN). Reverse transcription polymerase chain reaction (RT-PCR) was used to amplify a predicted 372 bp fragment of GTPCH mRNA, deduced from the known nucleotide sequence of rat liver GTPCH cDNA. Dideoxynucleotide sequencing of the PCR fragment revealed 100% identity between LPS/IFN-induced GTPCH mRNA of VSM and the constitutive GTPCH mRNA of liver. Although BH4 was below our limit of detection in untreated VSM, low levels of GTPCH mRNA were detectable. LPS/IFN treatment triggered the appearance of BH4 and markedly increased GTPCH mRNA. Induction of GTPCH mRNA was apparent by 2 h, peaked at 4 h, and was sustained at high levels for at least 24 h. Induction of GTPCH mRNA by LPS/IFN was substantially enhanced by cycloheximide, suggesting that mRNA levels are depressed by a labile protein. Measurement of LPS/IFN-induced NOS mRNA by RT-PCR, demonstrated a timecourse of induction which mirrors that of GTPCH. Similarly, the timecourse of appearance of cytosolic NOS activity following exposure of VSM to LPS/IFN paralleled that of the increase in BH4 content. Our studies demonstrate that immunostimulants co-induce NOS and GTPCH gene expression: both events are necessary for induction of NO synthesis by VSM.

GTP cyclohydrolase I mRNA is induced by LPS in vascular smooth muscle: characterization, sequence and relationship to nitric oxide synthase.

We investigated the effect of the calcium channel antagonist nifedipine on the induction of nitric oxide synthase (NOS) by bacterial endotoxin (lipopolysaccharide; LPS) in J774.2 macrophages, in cultured rat aortic smooth muscle cells and in a rat model of endotoxin shock. Stimulation by LPS for 24 hr increased nitrite accumulation in the supernatant of both cell types. NOS induction accounts for this nitrite accumulation, as both NG-methyl-L-arginine and cycloheximide reduced nitrite production in both cell types. Dexamethasone inhibited LPS-stimulated nitrite production in macrophages, but not in rat aortic smooth muscle cells. Nifedipine inhibited the production of nitrite in these LPS-treated cell types, with a more pronounced effect on macrophages. However, nifedipine did not inhibit the production of nitrite in J774.2 cells in which NOS had already been induced by prior exposure to LPS, and any possible further induction was inhibited by cycloheximide. In anesthetized rats subjected to LPS, pretreatment with nifedipine or dexamethasone ameliorated the fall in mean arterial blood pressure and the vascular hyporeactivity to norepinephrine at 180 min after LPS injection. At 180 min after LPS, an increase in a calcium-independent (induced) NOS activity was measured in lung homogenates. This induced NOS activity was reduced in lungs from rats treated with nifedipine or dexamethasone before LPS. Thus, nifedipine inhibits the induction of NOS in response to LPS in cultured cells in vitro and in the anesthetized rat.

Nifedipine inhibits the induction of nitric oxide synthase by bacterial lipopolysaccharide.

Tetrahydrobiopterin synthesis. An absolute requirement for cytokine-induced nitric oxide generation by vascular smooth muscle.

Parenteral preparations containing amino acids to combat hypotension and related pathologies

Continuous production of endothelium-derived nitric oxide (NO) in peripheral vessels has been shown to modulate vascular resistance and blood pressure. NO is also formed in the brain upon activation of glutamate receptors, which are thought to mediate central autonomic reflexes. In the present study we assessed whether NO plays a role in central autonomic regulation. For this, we have investigated the effects of NG-methyl-L-arginine (NMA), a selective inhibitor of NO synthesis from L-arginine, on sympathetic renal nerve activity (RNA), blood pressure, and heart rate in the anesthetized rat. NMA elicited a dose-dependent sustained increase in blood pressure (approximately 20 and 30 mm Hg, 5 minutes after 10 and 50 mumol/kg i.v., respectively). Heart rate and RNA decreased transiently (15 beats per minute and 40%, respectively); RNA subsequently increased (100%) while blood pressure remained elevated. Baroreceptor deafferentation markedly altered these responses to NMA; the transient decreases in heart rate and RNA were abolished, whereas the increases in RNA and blood pressure were significantly potentiated. After spinal C-1-C-2 transection, there was no increase in RNA, and blood pressure increased to a smaller extent. L-Arginine blocked the NMA-induced increases in blood pressure and RNA. Thus, in addition to modulating vascular resistance by a peripheral action, NO may also play a role in the central regulation of sympathetic tone.

NG-methyl-L-arginine, an inhibitor of L-arginine-derived nitric oxide synthesis, stimulates renal sympathetic nerve activity in vivo. A role for nitric oxide in the central regulation of sympathetic tone?

BACKGROUND Interleukin-1-alpha (IL-1) is a cytokine with potentially therapeutic immunoproliferative and tumoricidal activities. Preliminary clinical studies suggest that use of IL-1 may be restricted by dose-limiting hypotension. PURPOSE The purpose of this study was to investigate the role of nitric oxide (NO.) as a possible mediator of this hypotension. METHODS Cytokine-treated rat aortic smooth muscle cells were assayed for nitrite production, a stable breakdown product of nitric oxide. Nitric oxide synthase from smooth muscle cells was partially characterized in cytosol preparations using a novel Fe(2+)-myoglobin method to test for nitric oxide production. To determine the role of NO. on the immunorestorative and antineoplastic activity of IL-1, N omega-amino-L-arginine (NAA) or N omega-monomethyl-L-arginine (NMA), inhibitors of nitric oxide synthase, were added to either cultures of IL-1-dependent T cells or A375 melanoma cells exposed to IL-1. To investigate the effects of NAA in vivo, pentobarbital anesthetized dogs, which were made hypotensive by administration of IL-1, received a single intravenous bolus dose of NAA. The effects of NAA were then reversed by the administration of L-arginine. RESULTS Our results show that cultured IL-1-activated rat aortic smooth muscle cells synthesize nitric oxide, a potent vasodilator. Induction of nitric oxide synthase is augmented by interferon-gamma and blocked by IL-1 receptor antagonist and by inhibitors of RNA or protein synthesis. Nitric oxide synthesis by IL-1-activated smooth muscle cells is inhibited by NAA, NMA, and N omega-nitro-L-arginine (NNA) with ED50 (i.e., effective dose for 50% inhibition) values of 20, 60, and 1000 microM, respectively; this rank order of inhibition is characteristic of an agonist-unregulated, inducible isoform of nitric oxide synthase. In smooth muscle cells, inhibition of NO. synthesis by NAA is reversed by excess L-arginine. Consistent with the induction of unregulated NO. synthesis in vascular smooth muscle in vivo, administration of IL-1 (50 micrograms/kg) to dogs caused a 33.5% decrease in systemic vascular resistance and a 28% decrease in blood pressure within 3 hours. Subsequent administration of NAA (20 mg/kg) rapidly and completely reversed the hypotension and increased systemic vascular resistance; these effects of NAA were reversed by L-arginine. Neither the immunoproliferative nor the tumoricidal activity of IL-1 was diminished by NAA. CONCLUSIONS Our results indicate that (a) vascular smooth muscle is a likely source as well as a target of IL-1-induced NO. synthesis, causing vasodilatation and hypotension, (b) nitric oxide synthase inhibitors can fully reverse this hypotension, and (c) the therapeutically useful properties of IL-1 are not diminished by nitric oxide synthase inhibitors. IMPLICATIONS Administration of inhibitors of nitric oxide synthase can reverse the pathological cardiovascular effects of IL-1 at concentrations that do not interfere with the potentially useful immunoproliferative or tumoricidal effects of this cytokine. In the context of the current clinical trials of IL-1, this finding would represent a very significant advantage.

Inhibition of Interleukin-1-α-Induced Nitric Oxide Synthase in Vascular Smooth Muscle and Full Reversal of Interleukin-1-α-Induced Hypotension by Nω-Amino-L-arginine

Tubular-fluid reabsorption by specialized cells of the nephron at the junction of the ascending limb of the loop of Henle and the distal convoluted tubule, termed the macula densa, releases compounds causing vasoconstriction of the adjacent afferent arteriole. Activation of this tubuloglomerular feedback response reduces glomerular capillary pressure of the nephron and, hence, the glomerular filtration rate. The tubuloglomerular feedback response functions in a negative-feedback mode to relate glomerular capillary pressure to tubular-fluid delivery and reabsorption. This system has been implicated in renal autoregulation, renin release, and longterm body fluid and blood-pressure homeostasis. Here we report that arginine-derived nitric oxide, generated in the macula densa, is an additional intercellular signaling molecule that is released during tubular-fluid reabsorption and counters the vasoconstriction of the afferent arteriole. Antibody to rat cerebellar constitutive nitric oxide synthase stained rat macula densa cells specifically. Microperfusion of the macula densa segment of single nephrons with N omega-methyl-L-arginine (an inhibitor of nitric oxide synthase) or with pyocyanin (a lipid-soluble inhibitor of endothelium-derived relaxation factor) showed that generation of nitric oxide can vasodilate the afferent arteriole and increase glomerular capillary pressure; this effect was blocked by drugs that prevent tubular-fluid reabsorption. We conclude that nitric oxide synthase in macula densa cells is activated by tubular-fluid reabsorption and mediates a vasodilating component to the tubuloglomerular feedback response. These findings imply a role for arginine-derived nitric oxide in body fluid-volume and blood-pressure homeostasis, in addition to its established roles in modulation of vascular tone by the endothelium and in neurotransmission.

Nitric oxide synthase in macula densa regulates glomerular capillary pressure.

REGULATION OF VASCULAR RESISTANCE BY L-ARGININE-DERIVED NITRIC OXIDE

We had reported that the systemic administration of N omega-methyl-L-arginine (L-NMA), a specific inhibitor of nitric oxide (NO) synthesis from L-arginine (ARG), raises arterial blood pressure (BP) while paradoxically enhancing central sympathetic outflow. Cervical spinal cord transection abolishes the increase in sympathetic outflow and attenuates the pressor effect of L-NMA. Thus, in addition to lowering BP by direct vasorelaxation, NO may also act in the central nervous system to reduce vascular sympathetic tone. To test this hypothesis we have injected L-NMA directly into the central nervous system in anesthetized rats. Intracisternally (i.c.), L-NMA elicited a small pressor response accompanied by a marked increase in sympathetic renal nerve activity (RNA). In contrast, the inactive stereoisomer N omega-methyl-D-arginine had neither pressor nor neural effects. The increases in RNA and BP elicited by i.c. L-NMA were abolished by spinal cord transection at C1 to C2 and by the i.v. administration of ARG. When administered i.c., ARG also abolished the increase in RNA elicited by i.v. L-NMA and significantly attenuated the pressor response. Thus, our findings indicate that L-NMA acts centrally by an ARG-reversible mechanism in the anesthetized rat to stimulate sympathetic nerve activity. Inasmuch as centrally synthesized NO has been postulated to play a second messenger and/or neurotransmitter role, our findings suggest that one such function would be the central regulation of sympathetic outflow and hence, BP.

A central nervous system action of nitric oxide in blood pressure regulation.

Interleukin-1-alpha (IL-1) is a cytokine with potentially therapeutic immunoproliferative and tumoricidal activities. Preliminary clinical studies suggest that use of IL-1 may be restricted by dose-limiting hypotension.

PURPOSE
The purpose of this study was to investigate the role of nitric oxide (NO.) as a possible mediator of this hypotension.

METHODS
Cytokine-treated rat aortic smooth muscle cells were assayed for nitrite production, a stable breakdown product of nitric oxide. Nitric oxide synthase from smooth muscle cells was partially characterized in cytosol preparations using a novel Fe(2+)-myoglobin method to test for nitric oxide production. To determine the role of NO. on the immunorestorative and antineoplastic activity of IL-1, N omega-amino-L-arginine (NAA) or N omega-monomethyl-L-arginine (NMA), inhibitors of nitric oxide synthase, were added to either cultures of IL-1-dependent T cells or A375 melanoma cells exposed to IL-1. To investigate the effects of NAA in vivo, pentobarbital anesthetized dogs, which were made hypotensive by administration of IL-1, received a single intravenous bolus dose of NAA. The effects of NAA were then reversed by the administration of L-arginine.

RESULTS
Our results show that cultured IL-1-activated rat aortic smooth muscle cells synthesize nitric oxide, a potent vasodilator. Induction of nitric oxide synthase is augmented by interferon-gamma and blocked by IL-1 receptor antagonist and by inhibitors of RNA or protein synthesis. Nitric oxide synthesis by IL-1-activated smooth muscle cells is inhibited by NAA, NMA, and N omega-nitro-L-arginine (NNA) with ED50 (i.e., effective dose for 50% inhibition) values of 20, 60, and 1000 microM, respectively; this rank order of inhibition is characteristic of an agonist-unregulated, inducible isoform of nitric oxide synthase. In smooth muscle cells, inhibition of NO. synthesis by NAA is reversed by excess L-arginine. Consistent with the induction of unregulated NO. synthesis in vascular smooth muscle in vivo, administration of IL-1 (50 micrograms/kg) to dogs caused a 33.5% decrease in systemic vascular resistance and a 28% decrease in blood pressure within 3 hours. Subsequent administration of NAA (20 mg/kg) rapidly and completely reversed the hypotension and increased systemic vascular resistance; these effects of NAA were reversed by L-arginine. Neither the immunoproliferative nor the tumoricidal activity of IL-1 was diminished by NAA.

Our results indicate that (a) vascular smooth muscle is a likely source as well as a target of IL-1-induced NO. synthesis, causing vasodilatation and hypotension, (b) nitric oxide synthase inhibitors can fully reverse this hypotension, and (c) the therapeutically useful properties of IL-1 are not diminished by nitric oxide synthase inhibitors.

Administration of inhibitors of nitric oxide synthase can reverse the pathological cardiovascular effects of IL-1 at concentrations that do not interfere with the potentially useful immunoproliferative or tumoricidal effects of this cytokine. In the context of the current clinical trials of IL-1, this finding would represent a very significant advantage.

Inhibition of interleukin-1-alpha-induced nitric oxide synthase in vascular smooth muscle and full reversal of interleukin-1-alpha-induced hypotension by N omega-amino-L-arginine.

Hypoxia is a potent coronary-vasodilating signal; its mechanisms are still controversial. We have assessed the possible role of nitric oxide (NO) in hypoxic coronary vasodilatation (HCVD) in isolated guinea pig hearts perfused at constant pressure. HCVD was elicited by a 1-minute 100% N2 exposure; coronary flow doubled within 1 minute of hypoxia (early phase) and returned to baseline within 40 seconds after reoxygenation (late phase). The early phase of HCVD was associated with a rapid approximately eightfold increase in cGMP overflow, an indication of NO release. The specific NO synthase inhibitor N omega-methyl-L-arginine (NMA, 0.1-1 mM) antagonized HCVD and the associated increase in cGMP spillover (maximum inhibition, approximately 65%); excess arginine (1.2 mM) prevented both effects. The late phase of HCVD was associated with an increase in adenosine overflow and was attenuated by the adenosine receptor antagonist BW A1433 (1 microM; maximum inhibition, approximately 45%). Indomethacin (10 microM) inhibited HCVD in spontaneously beating hearts by approximately 35% but had no effect in hearts paced at faster rates. NMA and BW A1433 were more effective in combination than alone (maximum inhibition, approximately 72%). However, irrespective of the concentrations used, there was no synergism among the anti-HCVD effects of NMA, BW A1433, and indomethacin, nor was HCVD completely inhibited by the antagonists, whether alone or in combination. Our findings indicate that NO is an important mediator of the early phase of HCVD, whereas additional mechanisms and/or factors, including adenosine and vasodilatatory prostaglandins, contribute to the late phase.

Nitric oxide is a mediator of hypoxic coronary vasodilatation. Relation to adenosine and cyclooxygenase-derived metabolites.

This study tested the effects on renal hemodynamics of blockage of nitric oxide (NO) synthesis from L-arginine with N G -methyl-L-arginine (L-NMMA) using both intact and isolated perfused rat kidneys. Infusion of L-NMMA into anesthetized rats increased the mean arterial pressure and reduced the glomerular filtration rate and renal plasma flow only when the renal perfucion pressure was maintained at control levels. In isolated kidneys, L-NMA increased vascular resistance; this was attenuated by coadministration of L-arginine.

Nitric oxide synthesis from L-arginine modulates renal vascular resistance in isolated perfused and intact rat kidneys

Histamine in Cardiovascular Function and Dysfunction: Recent Developments

The cofactor requirements of macrophage nitric oxide (NO·) synthase suggest involvement of an NADPH‐dependent flavoprotein. This prompted us to test the effect of the flavoprotein inhibitors diphenyleneiodonium (DPI), di‐2‐thienyliodonium (DTI), and iodoniumdiphenyl (ID) on the NO· synthases of macrophages and endothelium. DPI, DTI, and ID completely inhibited NO· synthesis by mouse macrophages, their lysates, and partially purified macrophage NO· synthase. Inhibition of NO· synthase by these agents was potent (IC50‘s 50–150 nM), irreversible, dependent on time and temperature, and independent of enzyme catalysis. The inhibition by DPI was blocked by NADPH, NADP+, or 2'5‘‐ADP, but not by NADH. Likewise, FAD or FMN, but not riboflavin or adenosine 5‐diphosphoribose, protected NO· synthase from inhibition by DPI. Neither NADPH nor FAD reacted with DPI. Once NO· synthase was inhibited by DPI, neither NADPH nor FAD could restore its activity. DPI also inhibited acetylcholine‐induced relaxation of norepinephrine‐preconstricted rabbit aortic rings (IC50 300 nM). Inhibition of acetylcholine‐induced relaxation persisted for at least 2 h after DPI was washed out. In contrast, DPI had no effect on norepinephrine‐induced vasoconstriction itself nor on vasorelaxation induced by the NO·‐generating agent sodium nitroprusside. These results suggest that NO∗ synthesis in both macrophages and endothelial cells depends on an NADPH‐utilizing flavoprotein. As a new class of NO· synthase inhibitors, DPI and its analogs are likely to prove useful in analyzing the physiologic and pathophysiologic roles of NO·.—Stuehr, D. J.; Fasehun, O. A.; Kwon, N. S.; Gross, S. S.; Gonzalez, J. A.; Levi, R.; Nathan, C. F. Inhibition of macrophage and endothelial cell nitric oxide synthase by diphenyleneiodonium and its analogs. FASEB J. 5: 98–103; 1991.

Inhibition of macrophage and endothelial cell nitric oxide synthase by diphenyleneiodonium and its analogs 1

Cytokine-activated endothelial cells express an isotype of nitric oxide synthase which is tetrahydrobiopterin-dependent, calmodulin-independent and inhibited by arginine analogs with a rank-order of potency characteristic of activated macrophages.

Bradyykinin-induced hypotension in the anesthetized guinea pig: resolution into nitric oxide- and prostaglandin-mediated phases

N alpha-benzoyl-L-arginine ethyl ester (BAEE) is a vasorelaxant which resembles an arginine-containing peptide; its action may be partially endothelium-dependent. Because L-arginine (ARG) has little potency as a vasorelaxant, it has been proposed that an arginine-containing peptide, rather than free ARG, is the immediate precursor of endothelium-derived relaxing factor/nitric oxide (EDRF/NO). In the present study we have characterized pharmacologically the vasorelaxant effect of BAEE and assessed the ability of BAEE to serve as a substrate for EDRF/NO synthesis. BAEE elicited a concentration-dependent vasorelaxation of guinea pig pulmonary artery (EC50 of 0.36 +/- 0.05 mM). This vasorelaxation was neither antagonized by -NG-methyl-L-arginine (100 microM), a competitive inhibitor of EDRF/NO synthesis from ARG, nor potentiated by superoxide dismutase (60 U/ml), a superoxide anion scavenger that prolongs EDRF lifetime. Additionally, compound LY 83583 (1 microM) and methylene blue (10 microM), inhibitors of soluble guanylyl cyclase, failed to block BAEE-induced vasorelaxation. Moreover, endothelium removal potentiated the vasorelaxant effect of BAEE 3-fold. Thus, BAEE-induced vasorelaxation is mediated by a direct action on vascular smooth muscle that is unrelated to EDRF/NO synthesis. Furthermore, ARG, but not BAEE, overcame the inhibition by NG-methyl-L-arginine of the acetylcholine-induced endothelium-dependent cyclic GMP accumulation in guinea pig aortic rings and of A23187-induced nitrite formation by cultured bovine aortic endothelial cells (nitrite is a convenient indicator of NO biosynthesis). Thus, BAEE cannot substitute for ARG as a substrate for EDRF/NO biosynthesis. Collectively, our findings support the notion that free ARG, rather than an arginine-containing peptide related to BAEE, is the immediate biosynthetic precursor of EDRF/NO.

L-arginine, but not N alpha-benzoyl-L-arginine ethyl ester, is a precursor of endothelium-derived relaxing factor.

Clinical assessment of the activity of tumor necrosis factor (TNF) against human cancer has been limited by a dose-dependent cardiovascular toxicity, most frequently hypotension. TNF is also thought to mediate the vascular collapse resulting from bacterial endotoxin. The present studies address the mechanism by which TNF causes hypotension and provide evidence for elevated production of nitric oxide, a potent vasodilator initially characterized as endothelium-derived relaxing factor. Nitric oxide is synthesized by several cell types, including endothelial cells and macrophages, from the guanidino nitrogen of L-arginine; the enzymatic pathway is competitively inhibited by NG-methyl-L-arginine. We found that hypotension induced in pentobarbital-anesthetized dogs by TNF (10 micrograms/kg, i.v., resulting in a fall in mean systemic arterial pressure from 124.7 +/- 7 to 62.0 +/- 22.9 mmHg; 1 mmHg = 133 Pa) was completely reversed within 2 min following administration of NG-methyl-L-arginine (4.4 mg/kg, i.v.). In contrast, NG-methyl-L-arginine failed to reverse the hypotensive response to an equivalent depressor dose of nitroglycerin, a compound that acts by forming nitric oxide by a nonenzymatic, arginine-independent mechanism. The effect of NG-methyl-L-arginine on TNF-induced hypotension was antagonized, and the hypotension restored, by administration of excess L-arginine (100 mg/kg, i.v.). Our findings suggest that excessive nitric oxide production mediates the hypotensive effect of TNF.

NG-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide.

Synthesis of L-Arginine-Derived Nitrogen Oxides by Macrophage Cytosol: Partial Characterization of the Enzyme System

Arginine antagonists to inhibit the systemic blood pressure in connection mitStickoxidbildung or endothelial derived relaxing factor

Glutathione depletion with buthionine sulfoximine does not attenuate acetylcholine-induced hypotension or basal production of endothelium-derived relaxing factor in the anesthetized guinea pig

Evidence that L-arginine is the biosynthetic precursor of vascular and cardiac nitric oxide

Arachidonic acid metabolism by dioxin-induced cytochrome P-450: a new hypothesis on the role of P-450 in dioxin toxicity.

Macrophage and endothelial cell nitric oxide synthesis: cell-type selective inhibition by NG-aminoarginine, NG-nitroarginine and NG-methylarginine.

Vasopressor effects of NG-substituted arginine analogs in the anesthetized guinea pig

Administration of cyclophosphamide at a dose which is lethal to 10% of control athymic nude mice resulted in sudden death within 3 h in all mice that had been pretreated with the glutathione synthesis inhibitor L-buthionine-SR-sulfoximine. In Fischer 344 rats pretreated with L-buthionine-SR-sulfoximine, the cyclophosphamide dose producing 100% acute toxicity was lowered from 500-150 mg/kg; cardiac monitoring revealed ventricular fibrillation to be the cause of death. These and additional studies reported demonstrate that cytoplasmic glutathione is an important protectant against the cardiac and skeletal muscle toxicity of cyclophosphamide and indicate that such toxicity may be substantially increased by glutathione depletion. Since diet and many drugs (including cyclophosphamide itself) are known to affect glutathione levels, the present studies suggest that cardiac and skeletal muscle glutathione content is likely to be a clinically significant determinant of the frequency and severity of the adverse drug interactions and systemic toxicity sometimes observed during cyclophosphamide therapy.

Glutathione protects cardiac and skeletal muscle from cyclophosphamide-induced toxicity.

Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis.

Sympatho-excitatory effect of a selective inhibitor of endothelium-derived nitric oxide synthesis, L-NG-methyl L-arginine, in anesthetized rats

U-46619, a stable epoxymethano analog of thromboxane A2 elicited a direct positive inotropic effect on guinea pig left atrium paced at a constant rate (EC50 = 2.5 nM). This novel observation contrasts with previous reports of a decrease in myocardial contractility by thromboxane mimetic compounds in coronary-perfused preparations, an action recognized as secondary to vasoconstriction. The positive inotropic effect of U-46619 was competitively antagonized by the specific thromboxane receptor blocker L-655,240 (pA2 = 8.02; identical to that reported in smooth muscle), but was unaffected by blockers of alpha 1-, beta 1-, and H1-receptors and by cyclooxygenase and lipoxygenase inhibitors. Increased tissue levels of inositol phosphates, but not cAMP, were associated with the positive inotropic action of U-46619, in analogy to the actions of alpha 1- and H1-receptor agonists. However, the inotropic effect of U-46619 and the concomitant increase in phosphoinositide breakdown were both selectively antagonized by L-655,240. Thus, U-46619 acts on specific thromboxane receptors in guinea pig left atrium and elicits a positive inotropic effect that probably results from an increase in phosphoinositide metabolism.

Positive inotropic effect of the thromboxane analog U-46619 on guinea pig left atrium: mediation by specific receptors and association with increased phosphoinositide turnover.

L-arginine-dependent synthesis of nitrite (NO2-) and nitrate (NO3-) by macrophages correlates with and is required for their execution of nonspecific cytotoxicity toward some tumor cells and microbes. However, the bioactive L-arginine metabolites responsible for cytotoxicity are unknown. Mammalian endothelial cells have recently been shown to release nitric oxide (NO.); we therefore determined if this reactive metabolite was synthesized by activated murine macrophages. Macrophage- derived NO. was detected by two independent methods: a bioassay for NO.- mediated relaxation of preconstricted rings of rabbit aorta; and a spectroscopic measurement of the reaction of NO. with clostridial ferredoxin, an Fe-S protein. After activation with IFN-gamma and LPS, macrophages continuously secreted a substance that relaxed rabbit aortic rings denuded of endothelium. Production of the vasorelaxant was enhanced by 0.5 mM L-arginine and inhibited reversibly by NG-methylated L-arginine analogs that block macrophage NO2-/NO3- synthesis. The vasorelaxant was scavenged by ferrous myoglobin, was labile, and was neither NO2- nor a cyclooxygenase metabolite. Activated M phi also secreted a substance that bleached Fd, a reaction carried out by NO. and NO2, but not NO2-. Macrophage bleaching of Fd correlated directly with time, cell number, and concomitant NO2-/NO3- production, required L-arginine, and was independent of reactive oxygen intermediates. Thus, activated murine M phi release NO. and/or a closely related, highly reactive nitrogen oxide such as NO2, during their conversion of L- arginine to NO2-/NO3-. NO. and NO2 may mediate L-arginine-dependent pathologic effects of M phi, as well as physiologic effects not previously considered for this widely distributed cell type.

Activated murine macrophages secrete a metabolite of arginine with the bioactivity of endothelium-derived relaxing factor and the chemical reactivity of nitric oxide

NG-methylarginine, an inhibitor of endothelium-derived nitric oxide synthesis, is a potent pressor agent in the guinea pig: does nitric oxide regulate blood pressure in vivo?

L-arginine availability determines the duration of acetylcholine-induced systemic vasodilation in vivo.

Synthesis of nitrogen oxides from L-arginine by macrophage cytosol: requirement for inducible and constitutive components.

Because histamine and adenosine are coreleased from the ischemic heart, we investigated the effects of their interaction on human myocardium. Surgical specimens of human right atrium (i.e., pectinate muscles) responded to histamine with increases in spontaneous rate and contractile force. Adenosine, and the A1-selective adenosine agonist N6-cyclopentyladenosine (CPA), reduced the spontaneous rate and suppressed the positive chronotropic and inotropic effects of histamine. CPA was more potent than adenosine in slowing the spontaneous rate and in suppressing histamine's positive chronotropic effect, suggesting that the responses to CPA and adenosine are A1-mediated. CPA was also more potent than adenosine in attenuating histamine's positive inotropic effect on human ventricular papillary muscle. The adenosine-induced suppression of histamine's effects on pectinate muscles was mimicked by carbachol, which like adenosine is known to attenuate H2-mediated histamine-induced adenylate cyclase activation. The H1-selective histamine antagonist pyrilamine potentiated histamine's chronotropic and inotropic responses, and inhibited the attenuation of these responses by adenosine or carbachol. In contrast, pyrilamine failed to modify the adenosine-induced attenuation of the cardiac stimulatory effects of dimaprit, an H2-selective histamine agonist. Our data suggest that adenosine-induced suppression of histamine's positive chronotropic and inotropic effects on human myocardium results both from an A1-mediated attenuation of H2-stimulatory effects and from the uncovering of H1 negative chronotropic and inotropic effects. Thus, the results of the histamine-adenosine interaction may exceed the "retaliatory" purpose of adenosine release and uncover H1-mediated myocardial depression.

Adenosine promotes histamine H1-mediated negative chronotropic and inotropic effects on human atrial myocardium.

Nitric oxide (NO) is a major endothelium-derived relaxing factor (EDRF) released in response to vasodilating amines, peptides, proteins, ionophores, and nucleotides. EDRF is an important regulator of smooth muscle tone and platelet aggregation and adhesion. Histamine and acetylcholine relax the intact norepinephrine-constricted guinea pig pulmonary artery by an EDRF-dependent mechanism in a medium free of amino acids. N omega-Monomethylarginine (N-MeArg; 0.25 mM) inhibited this relaxation by 64-73%. Inhibition by N-MeArg developed rapidly and was immediately and completely reversed by excess L-arginine but not by D-arginine or by citrulline. N-MeArg did not diminish relaxation induced by nitroprusside, an NO-generating agent, indicating that N-MeArg acts on endothelium rather than on smooth muscle. These observations strongly suggest that, in the intact guinea pig pulmonary artery, EDRF originates from enzymatic action on the guanido nitrogen(s) of an endogenous pool of arginine. This is strikingly similar to the origin of reactive nitrogen intermediates in activated macrophages.

Identification of arginine as a precursor of endothelium-derived relaxing factor.

The purpose of this study was to investigate the mechanism of histamine's H1-receptor-mediated positive inotropic effect, a response which is not associated with an increase in cyclic AMP levels. We found that the concentration-response curve for the positive inotropic effect of histamine on cavian left atrium was similar to that of the alpha-1 agonist phenylephrine, in terms of slope and maximum response. Additionally, both agents slightly prolonged time-to-peak tension and relaxation times. In contrast, the concentration-response relationship for the beta-agonist isoproterenol, whose positive inotropic effect is mediated by an increase in cyclic AMP, had a steeper slope and a much greater maximum. Furthermore, isoproterenol abbreviated time-to-peak tension and relaxation times. As reported previously for alpha-1 agonists, the development of the contractile response to a submaximal histamine concentration (10 microM) coincided with a rapid increase in left atrial tissue levels of inositol triphosphate. The concentration-response curves for histamine effects on contractility and phosphoinositide (PI) turnover were both unaffected by the H2-antagonist tiotidine, but were shifted markedly to the right by the H1-antagonist pyrilamine. High-performance liquid chromatography techniques were applied to resolve the various inositol mono-, di- and tri-phosphate isomers and to assess the possible production of higher phosphates (IP4, IP5 and IP6) in control and histamine-treated (10 microM) atria. Under both conditions IP products were qualitatively similar, but quantitatively greater after treatment with histamine; these products included inositol(1)phosphate, inositol(4)phosphate,inositol(1,4)diphosphate and inositol(1,4,5)triphosphate. No evidence of higher phosphate production was obtained.(ABSTRACT TRUNCATED AT 250 WORDS)

Positive inotropic effect of histamine on guinea pig left atrium: H1-receptor-induced stimulation of phosphoinositide turnover.

Peptidoleukotrienes induce an endothelium-dependent relaxation of guinea pig main pulmonary artery and thoracic aorta.

Histamine has been reported to attenuate adrenergic responses in cardiovascular tissues. In guinea pig atria preloaded with [3H]norepinephrine, histamine diminishes the field stimulation-induced efflux of radioactivity; this effect has been attributed to an inhibition of norepinephrine release from nerve endings. To assess the possible physiological relevance of these findings, we have reinvestigated the effects of histamine on cardiac sympathetic responses and on the release of endogenous norepinephrine in the guinea pig heart isolated with its intact sympathetic innervation. Heart rate, left ventricular contractile force, and perfusion pressure all increased with increasing frequencies of sympathetic nerve stimulation (2–8 Hz). Histamine (3 × 10−8 to 3 × 10−7 M) caused dose-dependent attenuation of the responses to sympathetic stimulation. The ability of histamine to modulate nerve stimulation-induced norepinephrine overflow into the coronary effluent was dependent on whether the heart had been preloaded with norepinephrine. Whereas histamine did not cause a significant reduction in nerve stimulation-induced norepinephrine overflow in hearts from untreated animals, histamine significantly reduced stimulation-induced norepinephrine overflow in hearts from guinea pigs that had been pretreated with norepinephrine before sacrifice. Histamine also attenuated the increases in left ventricular contractile force, perfusion pressure, and heart rate, which result from the intracardiac administration of norepinephrine (0.16-^g bolus injection). In this respect, histamine was as effective as it was in inhibiting the responses elicited by nerve stimulation. Thus, in normal animals, the negative modulatory effect of histamine on adrenergic responses can be attributed largely, if not totally, to a postjunctional mechanism. In contrast, a prejunctional action of histamine may contribute significantly to the negative modulation observed in norepinephrine-preloaded hearts. Since we have observed a large increase in the amount of endogenous histamine present in the coronary effluent after sympathetic stimulation (930 pg during the 30 seconds poststimulation vs. 240 pg during 30 seconds prestimulation), as well as a prolongation of nerve stimulation-induced cardiac responses in the presence of the H2 receptor antagonist tiotidine, we postulate that histamine plays a physiological role as a modulator of sympathetic responses in the heart.

Release of Histamine by Sympathetic Nerve Stimulation in the Guinea Pig Heart and Modulation of Adrenergic Responses: A Physiological Role for Cardiac Histamine?

Barrett’s esophagus requires surveillance to monitor for dysplasia and esophageal adenocarcinoma. New methods have been developed to detect dysplasia and esophageal adenocarcinoma. One of these methods, the wide area transepithelial sampling 3D brush biopsy (WATS 3D) is a computer-assisted brush-biopsy technique that uses an abrasive sampling instrument to detect dysplasia or esophageal adenocarcinoma compared to the standard four quadrant biopsy method. This case illustrates a patient with esophageal adenocarcinoma diagnosed by WATS 3D initially diagnosed as high-grade dysplasia and treated appropriately with HALO procedure during esophagogastroduodenoscopy. We aim to demonstrate the clinical utility of WATS 3D in Barrett’s surveillance.

The Role of Wide Area Transepithelial Sampling WATS 3D as an Adjunct to Standard Forceps Biopsy in Barrett's

Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA, Department of Medicine (Division of Hematology), Albert Einstein College of Medicine, Bronx, NY 10461, USA, Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA, and Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY 10461, USA

Structure of mutant human carbonmonoxy- hemoglobin C (bE6K) at 2.0 AÊ resolution

PP1140 Primary cirrhotic hepatocytes are more resistant to apoptosis than normal hepatocytes following NFkB inhibition

Impact of HIV on acute pelvic inflammatory disease in a Nairobi outpatient clinic

Acute pelvic inflammatory disease at an out-patient Clinic in Nairobi impact on HIV

P39 16 TP – PATTERN OF ATP-DISTRIBUTION IN HUMAN TUMOR-XENOGRAFTS

Abstract According to Clarke and Beck (C&B), the approximate number system (ANS) represents numbers. We argue that the ANS represents pure magnitudes. Considerations of explanatory economy favor the pure magnitudes hypothesis. The considerations C&B direct against the pure magnitudes hypothesis do not have force.

Linguistic intuitions are a central source of evidence across a variety of linguistic domains. They have also long been a source of controversy. This chapter aims to illuminate the etiology and evidential status of at least some linguistic intuitions by relating them to error signals of the sort posited by accounts of online monitoring of speech production and comprehension. The suggestion is framed as a novel reply to Michael Devitt’s claim that linguistic intuitions are theory-laden “central systems” responses rather than endorsed outputs of a modularized language faculty (the “Voice of Competence”). Along the way, it is argued that linguistic intuitions may not constitute a natural kind with a common etiology and that, for a range of cases, the process by which the intuitions used in linguistics are generated amounts to little more than comprehension.

Abstract Resource rationality may explain suboptimal patterns of reasoning; but what of “anti-Bayesian” effects where the mind updates in a direction opposite the one it should? We present two phenomena – belief polarization and the size-weight illusion – that are not obviously explained by performance- or resource-based constraints, nor by the authors’ brief discussion of reference repulsion. Can resource rationality accommodate them?

Can resources save rationality? “Anti-Bayesian” updating in cognition and perception

Probabilistic representations in perception: Are there any, and what would they be?

Abstract Impossible figures represent the world in ways it cannot be. From the work of M. C. Escher to any popular perception textbook, such experiences show how some principles of mental processing can be so entrenched and inflexible as to produce absurd and even incoherent outcomes that could not occur in reality. However, impossible experiences of this sort are mostly limited to visual perception; are there “impossible figures” for other sensory modalities? Here, we import a known magic trick into the laboratory to report and investigate an impossible experience for somatosensation—one that can be physically felt. We show that, even under full-cue conditions with objects that can be freely inspected, subjects can be made to experience a single object alone as feeling heavier than a group of objects that includes the single object as a member—an impossible and phenomenologically striking experience of weight. Moreover, we suggest that this phenomenon—a special case of the size-weight illusion—reflects a kind of “anti-Bayesian” perceptual updating that amplifies a challenge to rational models of perception and cognition.

“Impossible” Somatosensation and the (Ir)rationality of Perception

Theories of consciousness divide over whether perceptual consciousness is rich or sparse in specific representational content and whether it requires cognitive access. These two issues are often treated in tandem because of a shared assumption that the representational capacity of cognitive access is fairly limited. Recent research on working memory challenges this shared assumption. This paper argues that abandoning the assumption undermines post-cue–based ‘overflow’ arguments, according to which perceptual consciousness is rich and does not require cognitive access. Abandoning it also dissociates the rich/sparse debate from the access question. The paper then explores attempts to reformulate overflow theses in ways that do not require the assumption of limited capacity. Finally, it discusses the problem of relating seemingly non-probabilistic perceptual consciousness to the probabilistic representations posited by the models that challenge conceptions of cognitive access as capacity-limited. This article is part of the theme issue ‘Perceptual consciousness and cognitive access'.

Perceptual consciousness and cognitive access from the perspective of capacity-unlimited working memory

Does perceptual consciousness require cognitive access? Ned Block argues that it does not. Central to his case are visual memory experiments that employ post-stimulus cueing—in particular, Sperling's classic partial report studies, change-detection work by Lamme and colleagues, and a recent paper by Bronfman and colleagues that exploits our perception of ‘gist’ properties. We argue contra Block that these experiments do not support his claim. Our reinterpretations differ from previous critics' in challenging as well a longstanding and common view of visual memory as involving declining capacity across a series of stores. We conclude by discussing the relation of probabilistic perceptual representations and phenomenal consciousness.

Does Perceptual Consciousness Overflow Cognitive Access? The Challenge from Probabilistic, Hierarchical Processes

Zenon Pylyshyn argues that cognitively driven attentional effects do not amount to cognitive penetration of early vision because such effects occur either before or after early vision. Critics object that in fact such effects occur at all levels of perceptual processing. We argue that Pylyshyn’s claim is correct—but not for the reason he emphasizes. Even if his critics are correct that attentional effects are not external to early vision, these effects do not satisfy Pylyshyn’s requirements that the effects be direct and exhibit semantic coherence. In addition, we distinguish our defense from those found in recent work by Raftopoulos and by Firestone and Scholl, argue that attention should not be assimilated to expectation, and discuss alternative characterizations of cognitive penetrability, advocating a kind of pluralism.

Perceptual Consciousness, Short-Term Memory, and Overflow: Replies to Beck, Orlandi and Franklin, and Phillips

Is temporal representation constitutively necessary for perception? Tyler Burge argues that it is, in part because perception requires a form of memory sufficiently sophisticated as to require temporal representation. I critically discuss Burge's argument, maintaining that it does not succeed. I conclude by reflecting on the consequences for the origins of temporal representation.

Review of The Cognitive Penetrability of Perception (Zeimbekis and Raftopoulos, eds.)

1. lNrRODUCTION. This paper will address two questions: (I) What are the cognitive and syntactic principles that underlie the creation of grammatical systems like those we find among the world's creoles? (2) What are the principles that constrain the linguistic source of the lexical and grammatical forms that appear in the creole? In order to answer the first question, this paper takes the position that language contact phenomena such as creole formation involve the creation of an abstract composite grammar; that is, the grammatical frame that structures the surface constituents of the emerging language is largely made up of projections oflexical structure from the substrate and to a lesser extent from the superstrate. This notion of a composite grammar derives from the idea that lexical structure is composed of three levels (Abstract Level Model): (1) lexical-conceptual structure; (2) predicate-argument structure; (3) morphological realization patterns (Tai my 1985, Jackendoff 1990, Myers-Scotton & Jake 1995). Importantly, abstract lexical structure can be split and recombined so that parts of the lexical structure projecting the grammatical frame may come from different sources. This paper provides evidence for a composite grammar underlying creole formation. To answer the second question, this paper recognizes an asymmetry between lexical heads and functional heads in terms of both their properties and behavior in the syntax and in the level at which they are accessed in the production process. Furthermore, two types of functional heads are distinguished: conceptually-activated functional heads, those that are accessed early in the production process and selected by their lexical heads, and structurally-assigned functional elements, those that are accessed late in the production process and required by the syntax. Implicit in this distinction is that speakers engage in a morpheme sorting strategy during the production process. The asymmetry between lexical heads and early and late functional elements determines how the lexicon contributes to building the creole grammatical system.

This paper argues that whether an utterance of a vague term makes any contribution to propositional content is context-sensitive and that attention to this fact allows for an attractive solution to the sorites paradox.

Meaning Without Representation: Essays on Truth, Expression, Normativity, and Naturalism

Abstract Jim Hopkins (2012) defends a ‘straight’ (non-skeptical) response to Wittgenstein’s rule-following considerations, a response he ascribes to Wittgenstein himself. According to this response, what makes it the case that A means that P is that it is possible for another to (correctly) interpret A as meaning that P. Hopkins thus advances a form of interpretivist judgment-dependence about meaning. I argue that this response, as well as a variant, does not succeed.

Meaning Without Representation: Expression, Truth, Normativity, and Naturalism

Can one combine Davidsonian semantics with a deflationary conception of truth? A common worry has been that Davidsonian semantics apparently aims to explain meaning, or meanings, in terms of truth, while deflationism holds that the role of truth-talk is wholly expressive, never explanatory. But Michael Williams (1999) argues that this appearance is deceptive: Davidsonian semantics, contra Davidson himself, does not require truth-talk to play an explanatory role. If this is right, an incompatibilist must produce alternative grounds for doubt. Accordingly, Claire Horisk (2007) would have us shift our attention to the expressive role of ‘true’. She argues that, in any event, it disqualifies deflationary accounts—at least extant varieties—from combination with Davidsonian semantics: the deflationary accounts’ characterizations of the mechanisms by which they can fulfill their expressive function are incompatible with features Davidsonian semantics requires of them. She argues, in particular, that this is so for Quine’s disquotationalism, Horwich’s minimalism, and Brandom’s prosententialism.1 In what follows, I argue that Horisk fails to establish her claim in all three cases. This involves clarifying Quine’s understanding of a purely referential occurrence; explaining how Davidsonians can avail themselves of a syntactic treatment of lexical ambiguity; and correcting a common misreading of Brandom (answering along

Does the Expressive Role of ‘True’ Preclude Deflationary Davidsonian Semantics?

Fiona Macpherson (2012) argues that various experimental results provide strong evidence in favor of the cognitive penetration of perceptual color experience. Moreover, she proposes a mechanism for how such cognitive penetration occurs. We argue, first, that the results on which Macpherson relies do not provide strong grounds for her claim of cognitive penetrability; and, second, that, if the results do reflect cognitive penetrability, then time-course considerations raise worries for her proposed mechanism. We base our arguments in part on several of our own experiments, reported herein.

The Baltic International Yearbook of Cognition, Logic and Communication

Problems for the Purported Cognitive Penetration of Perceptual Color Experience and Macpherson’s Proposed Mechanism

Donald Davidson aims to illuminate the concept of meaning by asking: what knowledge would suffice to put one in a position to understand the speech of another, and what evidence sufficiently distant from the concepts to be illuminated could in principle ground such knowledge? Davidson answers: knowledge of an appropriate truth-theory for the speaker’s language, grounded in what sentences the speaker holds true, or prefers true, in what circumstances. In support of this answer, he both outlines such a truth-theory for a substantial fragment of a natural language, and sketches a procedure—radical interpretation—that, drawing on such evidence, could confirm such a theory. Bracketing refinements (such as those introduced to accommodate context-sensitivity), the truth-theory allows the derivation, from finite axioms, of theorems of the form “S is true in L iff p” for all sentences of the target language L, where “p” is replaced by a sentence that can be said to interpret the target sentence S. The radical interpreter confirms such a theory in application to some speaker if, while thus interpreting the speaker’s sentences, she can also attribute to the speaker attitudes that, given what sentences the speaker holds true in what circumstances, plausibly optimize her rationality and possession of true beliefs. Radical interpretation, Davidson maintains, underdetermines truth-theory. What is more, in his view, such underdetermination amounts to indeterminacy. The evidence available to a radical interpreter, given the constraints to which radical interpretation is subject, exhausts the relevant semantic facts, in the sense both of determining them and rendering them epistemically determinable. (Henceforth “(E)” for “exhaustion.”) Thus, truth-theories equally well confirmed by all the evidence equally well capture all the facts to be captured.1 This is so even if the truth-theories provide, for the same

Davidson, first-person authority, and the evidence for semantics

The main goal of the paper is to propose a methodology for the theory of reference in which experiments feature prominently. These experiments should primarily test linguistic usage rather than the folk’s referential intuitions. The proposed methodology urges the use of: (A) philosophers’ referential intuitions, both informally and, occasionally, scientifically gathered; (B) the corpus, both informally and scientifically gathered; (C) elicited production; and, occasionally, (D) folk’s referential intuitions. The most novel part of this is (C) and that is where most of the experimental work should be. The secondary goal of the paper is to defend my earlier paper “Experimental Semantics” from the criticisms of Machery, Mallon, Nichols, and Stich in “If Folk Intuitions Vary, Then What?” They charge that I have seriously misunderstood their goal in “Semantics, Cross-Cultural Style” and that many of my arguments are “largely irrelevant”. I argue that these charges are baseless.

Michael Devitt ([2006a], [2006b]) argues that, insofar as linguists possess better theories about language than non-linguists, their linguistic intuitions are more reliable. (Culbertson and Gross [2009]) presented empirical evidence contrary to this claim. Devitt ([2010]) replies that, in part because we overemphasize the distinction between acceptability and grammaticality, we misunderstand linguists’ claims, fall into inconsistency, and fail to see how our empirical results can be squared with his position. We reply in this note. Inter alia we argue that Devitt's focus on grammaticality intuitions, rather than acceptability intuitions, distances his discussion from actual linguistic practice. We close by questioning a demand that drives his discussion—viz., that, for linguistic intuitions to supply evidence for linguistic theorizing, a better account of why they are evidence is required. 1 Introduction 2 Acceptability and Grammaticality 3 Our Prima Facie Inconsistency 4 Our Experimental Results 5 Explaining why Intuitions are Evidence 1 Introduction 2 Acceptability and Grammaticality 3 Our Prima Facie Inconsistency 4 Our Experimental Results 5 Explaining why Intuitions are Evidence

This paper motivates two bases for ascribing propositional semantic knowledge (or something knowledgelike): first, because it’s necessary to rationalize linguistic action; and, second, because it’s part of an empirical theory that would explain various aspects of linguistic behavior. The semantic knowledge ascribed on these two bases seems to differ in content, epistemic status, and cognitive role. This raises the question: how are they related, if at all? The bulk of the paper addresses this question. It distinguishes a variety of answers and their varying philosophical and empirical commitments.

Who are the best subjects for judgment tasks intended to test grammatical hypotheses? Michael Devitt ([2006a], [2006b]) argues, on the basis of a hypothesis concerning the psychology of such judgments, that linguists themselves are. We present empirical evidence suggesting that the relevant divide is not between linguists and non-linguists, but between subjects with and without minimally sufficient task-specific knowledge. In particular, we show that subjects with at least some minimal exposure to or knowledge of such tasks tend to perform consistently with one another—greater knowledge of linguistics makes no further difference—while at the same time exhibiting markedly greater in-group consistency than those who have no previous exposure to or knowledge of such tasks and their goals. 1. Introduction2. Background and Clarification3. Previous Experiments4. Our Experiment5. The Context of Devitt's Claim and His Psychological Model Appendix Introduction Background and Clarification Previous Experiments Our Experiment The Context of Devitt's Claim and His Psychological Model Appendix

I consider whether the content of a speech act is best represented by a set of possible worlds or by an ordered set containing the individual and properties the speech act is about. I argue that there is nothing in such contents that an ordered set can represent that a set of worlds cannot. In particular, both can be used to capture what is distinctive about singular propositions. But a set of worlds better represents content in cases where the content concerns individuals that no longer exist. It is also better at representing how content can be expressed in different ways, and how assertion relates to the pursuit of truth. Finally, representing content by a set of worlds allows for a clearer view of the puzzle about logical omniscience, even though it is often taken to founder on that puzzle. Suppose Jones were to say something in assertively uttering (1). (1) Tony Blair is a proud father. Jones said things to be a certain way. A natural thought is that to report what Jones said one need only report how he said things to be: how things would be if things were as he said them to be. This natural thought supports a proposal about how we might represent what he said. Putting it picturesquely, we could represent what Jones said by a set of possible worlds: those where things are as he said them to be. I am inclined to think that this natural thought and the proposal it supports are right. But both are now almost universally rejected. All sides (or almost all) agree that whatever we use to represent what Jones said must determine that set of possible worlds. But most contend that this is not enough. There is, they claim, more to represent in what Jones said than is represented, or representable, by a set of possible worlds. According to one view, what Jones said can be better represented by an ordered set containing Tony Blair and the prop1 This proposal is familiar from the work of Robert Stalnaker. See the papers collected in (Stalnaker 1999). But it is also found, though less picturesquely, in Charles Travis’ work, especially (Travis 2000). What I say here, and especially in section 5, owes an important debt to their work.

Who are the best subjects for judgment tasks intended to test grammatical hypotheses? Michael Devitt ([2006a], [2006b]) argues, on the basis of a hypothesis concerning the psychology of such judgments, that linguists themselves are. We present empirical evidence suggesting that the relevant divide is not between linguists and non-linguists, but between subjects with and without minimally sufficient task-specific knowledge. In particular, we show that subjects with at least some minimal exposure to or knowledge of such tasks tend to perform consistently with one another—greater knowledge of linguistics makes no further difference—while at the same time exhibiting markedly greater ingroup consistency than those who have no previous exposure to or knowledge of such tasks and their goals.

Who are the best subjects for judgment tasks intended to test grammatical hypotheses ?

Cappelen and Lepore (2005) argue that "[s]peakers need not believe everything they sincerely say." I argue that their latest (2006a) defence of this claim proposes a problematic principle that does not yield their surprising conclusion.

Abstract In this note, I clarify the point of my paper “The Nature of Semantics: On Jackendoff's Arguments” (NS) in light of Ray Jackendoff's comments in his “Linguistics in Cognitive Science: The State of the Art.” Along the way, I amplify my remarks on unification.

Normal mature human language users arguably possess two kinds of knowledge of meaning. On the one hand, they possess semantic knowl-edge that rationalizes their linguistic behavior. This knowledge can be characterized homophonically, can be self-ascribed without adverting to 3rd-person evidence, and is accessible to consciousness. On the other hand, there are empirical grounds for ascribing to them knowledge, or cognition, of a compositional semantic theory. This knowledge lacks the three qualities listed above. This paper explores the possible relations among these two kinds of semantic knowledge. Is the former derived from the latter? Do these ascriptions in fact characterize the same states albeit in different ways? Special attention is paid to the varying philosophical and empirical commitments that different answers incur.

Can Empirical Theories of Semantic Competence Really Help Limn the Structure of Reality

Abstract Jackendoff defends a mentalist approach to semantics that investigates conceptual structures in the mind/brain and their interfaces with other structures, including specifically linguistic structures responsible for syntactic and phonological competence. He contrasts this approach with one that seeks to characterize the intentional relations between expressions and objects in the world. The latter, he argues, cannot be reconciled with mentalism. He objects in particular that intentionality cannot be naturalized and that the relevant notion of object is suspect. I critically discuss these objections, arguing in part that Jackendoff’s position rests on questionable philosophical assumptions.

:  According to cognitivist truth-theoretic accounts of semantic competence, aspects of our linguistic behavior can be explained by ascribing to speakers cognition of truth-theories. It's generally assumed on this approach that, however much context-sensitivity speakers’ languages contain, the cognized truth-theories themselves can be adequately characterized context-insensitively—that is, without using in the meta-language expressions whose semantic value can vary across occasions of utterance. In this paper, I explore some of the motivations for and problems and consequences of dropping this assumption.

Context-sensitive truth-theoretic accounts of semantic competence

This comment responds to some of the criticisms that MacSwan (2005) presents of the Matrix Language Frame (MLF) model of codeswitching (CS) in general and of Jake, Myers-Scotton and Gross (2002), in particular. The goal is to point out misunderstandings and misinterpretations that are the basis of MacSwan's critique. His attempt to show how the Minimalist Program can explain CS on its own fails. Theoretically, while either of the participating languages in CS could frame the bilingual CP, only one, the ML, does. That is, recognizing the construct of the ML as the source of the morpho-syntactic frame of each bilingual clause showing CS is necessary.

In a recent paper, Dean Pettit (2002) argues against the view that understanding a bit of language consists in the possession of propositional knowledge of its meaning-what he labels the epistemic view of linguistic understanding.' His objection to the epistemic view is that it entails that it is necessary to understand a bit of language that one possess propositional knowledge of its meaning, but this necessity claim is false: for linguistic understanding, unlike knowledge, does not fail in Gettier cases, does not require epistemic warrant, and does not require belief; in supplying cases demonstrating this, one supplies cases of linguistic understanding without such knowledge. Pettit's arguments, if successful, thus establish the falsity of a variety of weaker claims in addition to that of the epistemic view. They would establish, for example, the falsity of necessity claims as weak as the weakest modality allowing the possibility of his cases. Further, the third argument-that linguistic understanding does not require belief that the bit of language means such-and-such-establishes, if successful, the falsity of parallel claims concerning belief. Given the case Pettit appeals to in his third argument, this would include the falsity of the claim that belief about an expression's meaning is nomologically necessary for a human speaker to possess linguistic understanding of it. Pettit's case thus poses a challenge to prominent empirical accounts of semantic competence that advert to states with such propositional content.

The Biconditional Doctrine: Contra Kölbel on a “Dogma” of Davidsonian Semantics

A modest proposal: Explaining language attrition in the context of contact linguistics

When a debate seems intractable, with little agreement as to how one might proceed towards a resolution, it is understandable that philosophers should consider whether something might be amiss with the debate itself. Famously in the last Century, philosophers of various stripes explored in various ways the possibility that at least certain philosophical debates are in some manner deficient in sense. Such moves are no longer so much in vogue. For one thing, the particular ways they have been made have themselves undergone much critical scrutiny, so that many philosophers now feel that there is, for example, a Quinean response to Carnap, a Gricean reply to Austin, and a diluting proliferation of Wittgenstein interpretations.

Verdonk has written an engaging and highly accessible introduction to the field of stylistics. The book is organized along the lines of the Oxford introductions to language study series. Like the other volumes in the Oxford series, it contains four sections: a survey of the field, short readings extracted from the literature with study questions that address the issues presented in the survey section, a selection of annotated references, and a glossary of terms.

STYLISTICS.Peter Verdonk. Oxford: Oxford University Press, 2002. Pp. xiv + 124. $13.50 paper.

In this paper, we show how some proposals within the Minimalist Program are compatible with a model of codeswitching that recognizes an asymmetry between the participating languages, the Matrix Language Frame model. Through our discussion of an analysis of NPs in a Spanish–English corpus, we illustrate this compatibility and show how recent minimalist proposals can explain the distribution of nouns and determiners in this data set if they adopt the notion of Matrix Language as the bilingual instantiation of structural uniformity in a CP. We outline the central premises of the Matrix Language Frame model, and introduce the Uniform Structure Principle which requires that the structure of constituents be uniform at an abstract level. We then review previous applications of the Minimalist Program to codeswitching. Much recent research in minimalism has focused on issues related to feature checking. Earlier approaches to feature checking required matching of features in grammatical structures, although more recent proposals consider distinctions in the values of features and in types of matching. Because phi-features for grammatical gender in Spanish and English differ, an analysis of NPs in this corpus of naturally occurring Spanish–English conversations provides a test for minimalist applications to codeswitching. We present our general findings of the distribution of types of NP constituents and then consider explanations of these distributions in light of minimalist proposals. It is possible to explain these distributions in a recasting of the Matrix Language Frame model in minimalist terms, if the construct of the Matrix Language is maintained. The requirement that one language, the Matrix Language, provide an abstract grammatical frame in bilingual constituents corresponds to the type of uniformity that Chomsky (2001) suggests is necessary for the explanatory study of language and variation in language.

Making a minimalist approach to codeswitching work: Adding the Matrix Language

This powerfully iconoclastic book reconsiders the influential nativist position toward the mind. Nativists assert that some concepts, beliefs, or capacities are innate or inborn: "native" to the mind rather than acquired. Fiona Cowie argues that this view is mistaken, demonstrating that nativism is an unstable amalgam of two quite different-and probably inconsistent-theses about the mind. Unlike empiricists, who postulate domain-neutral learning strategies, nativists insist that some learning tasks require special kinds of skills, and that these skills are hard-wired into our brains at birth. This "faculties hypothesis" finds its modern expression in the views of Noam Chomsky. Cowie, marshaling recent empirical evidence from developmental psychology, psycholinguistics, computer science, and linguistics, provides a crisp and timely critique of Chomsky's nativism and defends in its place a moderately nativist approach to language acquisition. Also in contrast to empiricists, who view the mind as simply another natural phenomenon susceptible of scientific explanation, nativists suspect that the mental is inelectably mysterious. Cowie addresses this second strand in nativist thought, taking on the view articulated by Jerry Fodor and other nativists that learning, particularly concept acquisition, is a fundamentally inexplicable process. Cowie challenges this explanatory pessimism, and argues convincingly that concept acquisition is psychologically explicable. What's Within? is a clear and provocative achievement in the study of the human mind.

Drawing upon research in philosophical logic, linguistics and cognitive science, this study explores how our ability to use and understand language depends upon our capacity to keep track of complex features of the contexts in which we converse.

Essays on Linguistic Context Sensitivity and its Philosophical Significance

Book Review. Concepts: Where Cognitive Science Went Wrong Jerry Fodor

Vagueness in Context Steven Gross ( gross2@phil.upenn.edu ) Department of Philosophy; 433 Logan Hall; University of Pennsylvania Philadelphia, PA 19104 USA Abstract This paper argues that whether an utterance of a vague term makes any contribution to propositional content is context-sensitive and that attention to this fact allows for an attractive solution to the sorites paradox. Introduction A predicate is vague if it permits borderline cases such that it’s neither clear that the predicate does apply nor that it doesn’t. 1 What, for example, is the least number of hairs a man must have in order not to be bald? Vagueness is a pervasive feature of natural languages, but it has proven rather resistant to theoretical delineation. For any attempt to characterize the semantics of vague terms (what they mean) and their logic (what reasoning involving them is valid) must yield a compelling dissolution of the ancient sorites paradox, which is no easy matter. Here’s a version of the paradox using the predicate ‘bald’ 2 : Someone with no hairs is bald. But one hair can’t make the difference between being bald and not being bald. (That is, for any number n, if someone with n hairs is bald, then someone with n+1 hairs is bald.) So, someone with hairs is bald. Well-nigh unobjectionable premises seem to lead by well- nigh unobjectionable reasoning to an absurd conclusion. 3 What has gone wrong? The enormous literature logicians, philosophers, and semanticists have produced on vague language over the last few decades has generated a plethora of competing possible positions, each with its own well-known problems. 4 These discussions have succeeded in shedding much light on the phenomenon but have not generated anything remotely approaching a consensus on the relevant issues. So, let us proceed once more into the breach. In this paper, I defend an approach to vague language and the associated sorites paradox that emphasizes the context-sensitivity of vague terms. A term is context-sensitive if and only if its contribution to propositional content can vary across occassions of use without any change in the term’s standing meaning in the language. (Indexical expressions, such as the pronoun ‘I’, Previous provide standard examples.) 5 approaches have adverted to context-sensitivity in attempting to defang the sorites, 6 but they have assumed that vague terms always make some contribution to propositional content, whereas I stress how considerations of conversational coherence can affect whether, in a given context, the use of a vague term succeeds in contributing to content at all. My paper has three parts. I first put forward a necessary condition on the expression of a proposition and suggest that utterances of sentences containing vague predicates only sometimes satisfy it. Then, I argue that, in particular, the consideration of a sorites paradox can result in the violation of this condition. Finally, I briefly indicate some of the virtues embodied in this approach to vagueness. A Condition on the Expression of a Proposition 1 This characterization is somewhat rough, but (as it’s frequently noted in the literature) it’s difficult to characterize vagueness in a non-theory-laden manner. 2 It should be assumed throughout that the hairs on the person’s head are arranged in a manner optimal for non-baldness. 3 The reasoning used is simply Universal Instantiation and Modus Ponens. The latter alone suffices, if one replaces the universally quantified second premise with the appropriate conditionals. Note, in particular, that the principle of mathematical induction is not employed, though it (or some other sufficiently strong principle) would indeed be required to reach the conclusion that no one is bald. 4 Keefe and Smith (1997) is an excellent reader, the editors’ introduction providing a valuable survey of the field. Williamson (1994) is an indispensable monograph. The literature on vague concepts has been less well-developed and was until recently dominated by degree-theoretic approaches. But see Kamp and Partee (1995). 5 This use of the term ‘context sensitive’—common in semantics and pragmatics—should not be confused with its use in syntax to describe rules insensitive to surrounding syntactic context. 6 See, e.g., Kamp (1981), Bosch (1983), Raffman (1994), and van Deemter (1996).

Intentionality and the markedness model in literary codeswitching

This paper examines the structural consequences of the contact between Dutch overseers and Eastern Ij slaves during the seventeenth and eighteenth centuries on the formation of Berbice Dutch, an unusual creole because of its remarkably homogeneous substrate. Based on the assumption that the structure-building operations in language contact situations are governed by the relative accessibility of morphemes in production, various surface configurations in Berbice Dutch are explained in terms of the 4-M model. Although the 4-M model classifies morphemes as falling into four types, content morphemes and three types of system morphemes, its focus is on how morphemes are differentially elected in production. A second model, the Abstract Level model, views the structure of the abstract lemmas that support morphemes as internally complex. Considering how morphemes are elected and how abstract lexical structure is complex opens the door to an explanation for the surface configurations found in Berbice Dutch. Data from Berbice Dutch demonstrate that abstract lexical structure can be “split” and “recombined” in such a way that surface structure is projected by an underlying grammatical frame that is a composite of the abstract lexical structure of the linguistic varieties in contact. Perceptual saliency of morphological structure and the degree of homogeneity in the substrate play a crucial role in predicting what is and what is not possible in creole formation.

When two become one: Creating a composite grammar in creole formation

L'invention concerne un procede de traitement d'aliments, notamment a base vegetale, tels que les cereales, la salade, les fruits et analogues, lesdits aliments etant laves et desinfectes. L'objectif de l'invention est de permettre une desinfection des aliments irreprochable et sans inconvenient pour la sante, en evitant toute alteration oxydative. A cet effet, le procede selon l'invention consiste (a) a preparer une solution en particulier aqueuse d'un desinfectant a effet oxydant contenant de l'acide hypochloreux (HOCl) et/ou de l'hypochlorite (OCl-), (b) a preparer une solution en particulier aqueuse d'au moins un agent antioxydant et/ou de reduction sans inconvenient pour la sante, ledit agent antioxydant ou de reduction se trouvant en concentration suffisante pour neutraliser l'effet oxydant du desinfectant, (c) a mettre en contact les aliments avec le desinfectant sous forme diluee ou non diluee puis (d) a mettre en contact les aliments avec la solution d'agent antioxydant ou de reduction. Ensuite, les aliments peuvent etre p. ex. seches et eventuellement emballes.

L'invention concerne un procede de production d'un desinfectant par activation electrochimique de l'eau, procede selon lequel une solution electrolytique, en particulier une solution de sodium ou de chlorure de potassium, est ajoutee a l'eau a desinfecter puis l'eau soumise a l'action de cette solution electrolytique sous la forme d'une solution aqueuse/electrolytique diluee est soumise a l'action d'un courant electrique par application d'une tension continue aux electrodes dans un reacteur d'electrolyse presentant un compartiment cathodique pourvu d'une cathode et un compartiment anodique pourvu d'une anode et separe dans l'espace du compartiment cathodique, afin d'amener la solution aqueuse/electrolytique dans un etat metastable approprie a la desinfection. L'objectif de cette invention est de garantir un effet desinfectant fiable de l'eau activee electrochimiquement avec une haute reproductibilite. A cet effet, le pH de la solution aqueuse/electrolytique diluee est regle a une valeur comprise entre 2,5 et 3,5, en particulier a une valeur d'environ 3, dans le compartiment anodique du reacteur, de sorte que le potentiel de l'oxydation anodique est controle (oxydation anodique a potentiel controle). Cette invention concerne egalement un desinfectant ainsi produit et son utilisation.

Procédé de production d'un désinfectant par activation électrochimique de l'eau, désinfectant ainsi produit et son utilisation

Procédé de production d'un désinfectant par activation électrochimique de l'eau

L'invention concerne un systeme de gestion de flux de travaux qui fournit une approche integree a l'echange d'informations en temps reel et a la notification aux personnes responsables de delais atteints relatifs a une transaction donnee. Le systeme Web comprend un serveur comportant une base de donnees centrales de donnees de transaction, et au moins un systeme client facilite un procede de chargement de donnees de transaction proposees initiales, de notification a un souscripteur de la proposition telechargee, de telechargement d'un horaire de flux de travaux pour la transaction proposee et de notification aux personnes responsables que des actions destinees a des tâches sont dues conformement a l'horaire. Le systeme de gestion de flux de travaux est en outre concu pour limiter l'acces a la base de donnees aux utilisateurs autorises a visualiser la transaction et a lui apporter des mises a jour.

Forty-eight-hour ph monitoring increases sensitivity in detecting abnormal esophageal acid exposure

The Development and Testing of a New Multichannel, Shape-Locking Guide with Tip and Mid Body Articulation for Intragastric Endosurgery

A Next Generation Therapeutic Endoscope: Development of a Novel Endoluminal Surgery System with “Birds-Eye” Visualization and Triangulating Instruments

Abstract : Polyurethane adhesives are currently used in Apache aviator masks to secure polycarbonate lenses to a bromobutyl-natural rubber face piece. An alternative polyurethane adhesive packaged in a pre-measured assembly was investigated to determine its suitability for mask remanufacturing operations. Seventy-five prototype assemblies were prepared with the standard and alternative adhesive. The composite assemblies were then destructively tested on an Instron machine, in tension, to compare rupture strength of the polycarbonate-adhesive-rubber joint as a function of curing regime and surface preparation. Rupture load measurements indicate the alternative adhesive investigated is adequate for securing lenses within the aviator mask. Stress applied at joint failure ranged from 146 to 343 pounds per square inch. Prototypes cured at 63 degrees Celsius are approximately 38% stronger than ambient cured specimens.

Investigation of Polyurethane Adhesives for Use in the Apache Aviator NBC Protective Mask

An analytical approach is developed to evaluate the coefficients of thermal expansion (CTE) of textile reinforced composites. At the micro level, a cylindrical composite model is employed to model the fiber/matrix thermal and mechanical interactions. The effects of voids and fiber coating on the thermal expansion coefficients of composites are considered at this level. The cylindrical model was then embedded in a macro hybrid finite element solution structure to calculate the value of the CTE for textile composites. AS-4/epoxy balanced plain weave textile composites were manufactured. Five different fiber volume fractions were tested for CTE. Evaluation of the thermal expansion coefficients using the current model was compared to experimental data for in-plane and out-of-plane directions.

An analytical approach to evaluate the coefficients of thermal expansion of textile composite materials

Modern medical solutions to overcome disabilities and deseases tend to increasingly utilize implantable microelectronic systems, which are controlled and monitored from outside the body. One example is the electrical stimulation of nerves which have lost their natural functionality by an accident. This ASIC was developed as the central component in implantable, batteryless electro-neural stimulation systems. The first application being an implant for restoring basic movement abilities of a disabled hand, caused by a spinal cord injury. It allows stimulation of nerves with two independently controlled currents on one or more of 12 neural electrodes. The system is controlled and powered using an 80 kBit/s transcutaneous RF-telemetry link. The on-chip microcontroller was optimized to perform multi-tasking protocol handling and signal processing at a low-power level. The ASIC provides an 8-bit ADC to secure the integrity of the stimulation sub-system before activating, and a low speed load-shift keying RF-link to transfer protocol and measurement data to the external device.

Proceedings of the 27th European Solid-State Circuits Conference

A microcontroller embedded ASIC for an implantable electro-neural stimulator

A chip with selectable command rates up to 200 per second with error checking and command acknowledgment, using analog and I2L digital circuity, will be described. Backside argon gettering and a stratfied epitaxial layer have been used to provide 3μA operation.

1984 IEEE International Solid-State Circuits Conference. Digest of Technical Papers

A digital radio command link for implantable biotelemetry applications

The high electron emission resulting from low-work-function scandate-added dispenser cathodes has generated a great deal of interest and research since the late 1970s. Despite the reported high current density at low temperatures, scandate cathodes have not yet seen wide-scale industrial adoption due to poor emission uniformity, inadequate reproducibility, and short lifetimes. This lack of industrial adoption stemming from the above issues is likely due to insufficient fundamental understanding of the role that scandium plays in the emission process. Recent work by five research teams under the U.S. Defense Advanced Research Projects Agency Innovative Vacuum Electronics Science and Technology Program aims at advancing this fundamental understanding and the cathode manufacturing processing. Emission microscopy of model surfaces of adsorbed Ba–Sc–O on single crystal tungsten and detailed characterization techniques, such as Wulff shape analysis, are being used to understand the morphology, composition and phase of each of the species that comprise the cathode emitting surfaces. The structure of tungsten grains at the cathode surface of activated and unactivated scandate cathodes and the resulting emission performance are observed. 3-D printing is being investigated as an advanced manufacturing method to meet the demanding requirements of modern vacuum electron devices. Finally, density functional theory is being employed to study the work function of perovskite oxides as a novel class of alternative materials to tungsten dispenser cathodes.

The Defense Advanced Research Projects Agency funds leading-edge research that continually expands the capabilities of the military. Over the past several years, a number of US DoD research programs have focused on the electron beam generation and transport technologies that enable vacuum electronic devices capable of operating across the electromagnetic spectrum from G-band to x-rays. This paper will describe the program goals, discuss the electron sources, highlight selected breakthroughs, and preview potential new areas.

2013 26th International Vacuum Nanoelectronics Conference (IVNC)

Fuel Cell Development at Forschungszentrum Jülich with Special Emphasis on Mechanical Aspects

MICROMACHINED SWITCHES AND CANTILEVER ACTUATORS BASED ON PIEZOELECTRIC LEAD ZIRCONATE TITANATE (PZT)

In this paper discussed about the fabrication PbZrTiO/sub 3/ film for switch. This fabricated switches were tested and resonance frequency measurements also carried out.

61st Device Research Conference. Conference Digest (Cat. No.03TH8663)

A piezoelectric microelectromechanical switch actuated by lead zirconate titanate (PZT) is reported. A PZT unimorph cantilever actuator, fabricated on a sacrificial polysilicon layer and released using a xenon difluoride dry etch, was used to realize the switch. The PZT thin film was poled and driven with interdigitated electrodes to exploit the d33 coefficient for switching actuation. Preliminary dc and rf switching characteristics are reported. Measurements indicate a fast switching “on” time of 25 dB was achieved up to 100 MHz.

Lead-zirconate-titanate-based piezoelectric micromachined switch

The high piezoelectric effect of lead zirconate titanate (PZT) films enables improved performance in microelectromechanical systems (MEMS). The material's reliable integration into current and mainstream MEMS microfabrication processes is then of great interest. In this paper we report on high reliability fabrication processes that can be used for producing PZT based MEMS devices. Pattern definition and release of PZT, low stress silicon nitride, platinum, and/or zirconia structures via wet and dry chemical etching and ion beam etching, including their affects on the piezoelectric properties of PZT are reported. Ion beam etching results in appreciable imprint in the polarization - electric field hysteresis loop of the PZT, which can be ameliorated by annealing in ambient air at 450 degree(s)C. PZT on silicon nitride cantilever structures were defined and released by dry xenon difluoride silicon sacrificial etching. The advantages and difficulties of wet release etching versus xenon difluoride are also presented.

Reliable integration of piezoelectric lead zirconate titanate with MEMS fabrication processes

Electrostrictive coefficients, both the charge related (Q) and field related (M), were studied in electron irradiated P(VDF-TrFE) copolymer which exhibits a massive electrostrictive strain response. Although the M depends on the electric field which stems from the nonlinear dielectric behavior of the material, the Q is independent of the field. Considering the material is a 0-3 composite in nature, a simple model is proposed to understand the experimental phenomena that the Q increases with decreasing crystallinity. The mechanical load capability of the material was studied in both uniaxial and hydrostatic stresses. The experimental results demonstrate the material possesses high load capability. for example, the transverse strain for the film under a tensile stress of 45 MPa is nearly the same as that measured under stress free condition.

ISAF 2000. Proceedings of the 2000 12th IEEE International Symposium on Applications of Ferroelectrics (IEEE Cat. No.00CH37076)

Electrostrictive effect and load capability in electron irradiated P(VDF-TrFE) copolymer

Peizoelectric and electrostrictive polymers are widely used in many areas of electromechanical actuation and transduction. This paper summarizes the current status and recent works in this class of polymers. For the piezoelectric polymers, the electromechanical properties of poly(vinylidene fluoride-trifluoroethylene) copolymers (P(VDF-TrFE), which possess the best piezoelectric performance among the known piezopolymers, are presented. In order to improve the strain capability and other electromechanical properties, the large electrostrictive response and high electromechanical conversion efficient near a first order ferroelectric-paraelectric transition of P(VDF-TrFE) copolymer were exploited. It is shown that the copolymer, treated with high energy electron irradiation, exhibits high electrostrictive strains (-5% longitudinal strain under 150 MV/m and 3.5% transverse starin under 100 MV/m) with high strain energy density, high load capability and improved electromechanical coupling factor. For the comparison, the works related to the Maxwell stress induced strain response in soft polymers are also discussed.

In this letter, we show that the electric field induced strain in the electron irradiated poly(vinylidene fluoride-trifluoroethylene) copolymer can generate high strain even under a high mechanical stress. The observed change in strain with stress is due to the electrostrictive coupling of the local polarization with stress, and can be directly related to the change of the induced strain with temperature. The results indicate that the field induced strain observed in the films investigated is indeed from the local polarization regions in the material, and is electrostrictive in nature.

HIGH ELECTROSTRICTIVE STRAIN UNDER HIGH MECHANICAL STRESS IN ELECTRON-IRRADIATED POLY(VINYLIDENE FLUORIDE-TRIFLUOROETHYLENE) COPOLYMER

The high electric field induced strain response and elastic energy density recently observed in the electron irradiated P(VDF-TrFE) copolymer beckons its adoption in transducer applications. Due to its compliant nature however, concern exists over the effect of mechanical stress on the electrically induced strain. This paper investigates the electrostrictive strain-response of the irradiated copolymer in the longitudinal (parallel to the field) direction as a function of hydrostatic pressure and in the transverse direction as a function of tensile stress. The longitudinal strain was characterized via the development of an automated hydrostatic-pressure dilatometer specifically designed for compliant films. Various performance parameters of this bimorph-based strain sensor are analyzed including the noise, resolution and frequency response. The results are compared with similar data from axially stressed samples that corroborate the conclusion that this modified copolymer exhibits a high load capability.

1999 IEEE Ultrasonics Symposium. Proceedings. International Symposium (Cat. No.99CH37027)

Mechanical load effects on the electrostrictive strain of P(VDF-TrFE) copolymer and the development of a high-resolution hydrostatic-pressure dilatometer

The effect of hydrostatic pressure up to 1,361 atms on the dielectric properties of a segmented polyurethane elastomer (Dow 2103-80AE) is studied at temperatures from 0°C to 80°C. The experimental results show that the relaxation time for both the I-process, associated with the molecular motions in the hard segments, and the α-process, associated with the glass transition, increases with pressure, and this shift is more pronounced for the I-process. Besides the glass transition, it is found that the I-process can be described by the Vogel-Fulcher (V-F) and Williams-Landel-Ferry (WLF) relations. At atmospheric pressure, T g and T o for the I-process are 235.9 K and 4.2 × 10 3 K, respectively. Based on the V-F and WLF relations and experimental results, it is found that a parameter, C 1 , in the WLF relation is independent of the pressure. Thus, a method is introduced to determine the values of both the characteristic transition temperature (T g ) and activation energy (T o ) for the processes at different pressures. As the pressure increases from atmospheric to 1,361 atms, the increase of T g for the I-process is about 30°C. The results also show that, for both the I- and the α-processes, T o decreases with increasing pressure.

Pressure‐temperature study of dielectric relaxation of a polyurethane elastomer

Electro-Mechanical Properties of Electron Irradiated P(VDF-TrFE) Copolymers Under Different Mechanical Stresses

A Retinoic Acid Receptor β2 Agonist Attenuates Transcriptome and Metabolome Changes Underlying Non-Alcohol-Associated Fatty Liver Disease.

not available at the time of printing S15. Symposium: TRANSITION FROM PSYCHIATRIC IN PATIENT TO COMMUNITY CARE: A EUROPEAN PERSPECTIVE (Organised By The AEP Section On Epidemiology And Social Psychiatry)

The Editorial Board appreciates the help of all who have worked for The FASEB Journal during the last year. Below are the names of those who reviewed manuscripts submitted for publication. The work of such referees is indispensable in helping maintain the journal’s publication standards and ensuring clear and accurate reporting. Our sincere thanks to all of you. In turn, the Federation is grateful to the members of the Editorial Board who have served and whose names are recorded on the second page of the Table of

1997 PEDIATRIC ACADEMIC SOCIETIES ’ ANNUAL MEETING SPONSORED BY THE AMERICAN PEDIATRIC Socnrr S 0 cIE ’ rY FOR PEDIATRIC RESEARCH AND AMULATORY PEDIATRIC ASSOCIATION

The DARPA Millimeter Wave Digital Arrays (MIDAS) program is demonstrating the first element level digital millimeter wave phased arrays covering the 18–50 GHz band. The performers are leveraging compound semiconductors, CMOS and heterogeneous integration to meet the stringent size and power constraints while pushing the state-of-the-art in RF and mixed-signal design. The 4×4 element dual-polarized transceiver tile will be a building block to enable scalable arrays mobile-to-mobile ad-hoc networking and emerging proliferated low-earth orbit (LEO) satcom. Element-level digital beamforming has the potential to enable multi-beam operation for reduced network discovery time and increased network throughput.

2020 IEEE BiCMOS and Compound Semiconductor Integrated Circuits and Technology Symposium (BCICTS)

We have been developing a novel thermal-to-visible transducer (TVT), an uncooled thermal-IR imager that is based on a Fabry-Perot Interferometer (FPI). The FPI-based IR imager can convert a thermal-IR image to a video electronic image. IR radiation that is emitted by an object in the scene is imaged onto an IR-absorbing material that is located within an FPI. Temperature variations generated by the spatial variations in the IR image intensity cause variations in optical thickness, modulating the reflectivity seen by a probe laser beam. The reflected probe is imaged onto a visible array, producing a visible image of the IR scene. This technology can provide low-cost IR cameras with excellent sensitivity, low power consumption, and the potential for self-registered fusion of thermal-IR and visible images. We will describe characteristics of requisite pixelated arrays that we have fabricated.

Drucksensor-Modul, mit; einem Gehause; einem Drucksensor-Chip; einem oder mehreren eines Chips eines integrierten passiven Bauelements (IPD) und diskreten passiven Bauelementen; wobei der Drucksensor-Chip und einer oder mehrere des IPD-Chips und der diskreten passiven Bauelemente innerhalb des Gehauses angeordnet sind; und externe Kontaktelemente, die dazu ausgestaltet sind, an einer Leiterplatte befestigt zu werden und elektrische Verbindungen mit Kontaktelementen der Leiterplatte zu bilden, wobei die externen Kontaktelemente dazu ausgestaltet sind, mit einer metallischen Oberflache verschweist zu werden, und wobei die externen Kontaktelemente jeweils einen metallischen Korper aufweisen, wobei Abschnitte der Oberflache des metallischen Korpers von einer Materialschicht bedeckt sind, wobei das Material der Materialschicht dazu ausgestaltet ist, das Verschweisen der externen Kontaktelemente mit der metallischen Oberflache zu erleichtern.

Pressure sensor module with a sensor chip and passive components within a common housing

Vorrichtung, die folgende Merkmale aufweist: – ein Gehausesubstrat (102; 1000), das eine Anbringoberflache (112) auf demselben umfasst; – ein Druckerfassungselement (104), das an der Anbringoberflache angebracht ist; – eine Abdeckung (106), die dazu konfiguriert ist, das Gehausesubstrat in Eingriff zu nehmen, um eine Gehauseumhullung um das Druckerfassungselement herum zu bilden; – einen Fluidflusskanal (108), der in der Abdeckung angeordnet und dazu konfiguriert ist, das Druckerfassungselement in einen Umgebungskontakt mit einer auserhalb der Gehauseumhullung liegenden Umgebung zu bringen, wodurch ermoglicht wird, dass Fluid von der auseren Umgebung sowohl in die Gehauseumhullung eintritt als auch aus derselben austritt; wobei der Fluidflusskanal (108) ein Blockierbauglied (110) umfasst, das in dem Fluidflusskanal angeordnet und dazu konfiguriert ist, einen direkten physischen Kontakt zwischen einem Objekt von der auseren Umgebung und dem Druckerfassungselement zu verhindern.

Pressure sensing device and methods for manufacturing derselbigen

Objective: To examine differences among various test protocols on the fail rate at hospital discharge for infants in the well‐baby nursery (WBN) and neonatal intensive care unit (NICU) who received hearing screening through a universal newborn hearing screening demonstration project. Design: The outcomes of several screening protocols were examined. Two technologies were used: transient evoked otoacoustic emissions (TEOAEs) alone or in combination with the auditory brain stem response (ABR). The performance of test protocols in both nurseries within eight hospitals was examined over a 2‐ to 3‐yr period. In the WBN, six hospitals used a screening protocol of TEOAE technology first followed by an ABR (automated or conventional) technology screening for newborns who referred on TEOAE screening. Two hospitals used TEOAE only in the WBN. Seven hospitals used screening protocols in the NICU that used a combination of TEOAE and ABR technologies (TEOAE technology administered first or second, before or after TEOAE, or TEOAE and ABR tests on all infants). Only one hospital used TEOAE technology exclusively for hearing screening. Results: Significant differences among screening protocols were found across hospitals in the first, second, and third years of the program. The combination of TEOAE technology and ABR technology (a two‐technology screening protocol) resulted in a significantly lower fail rate at hospital discharge than the use of a single‐technology (TEOAE). Fail rates at discharge were twice as high using the one‐technology protocol versus two‐technology protocol, even when the best outcomes from program year 3 were considered exclusively. Results of two‐technology versus one‐technology protocols were similar in the NICU. Use of a second technology for screening TEOAE fails significantly reduced every hospital that used the protocol's fail rate at discharge. Conclusions: A two‐technology screening protocol resulted in significantly lower fail rates at hospital discharge in both the WBN and NICU nurseries than use of a single‐technology (TEOAE) hearing screening protocol.

New York State Universal Newborn Hearing Screening Demonstration Project: Effects of Screening Protocol on Inpatient Outcome Measures

Objective: To determine the ages of hearing loss identification, hearing aid fitting, and enrollment in early intervention through a multi‐center, state‐wide universal newborn hearing screening project. Design: Universal newborn hearing screening was conducted at eight hospitals across New York State. All infants who did not bilaterally pass hearing screening before discharge were recalled for outpatient retesting. Inpatient screening and outpatient rescreening were done with transient evoked otoacoustic emissions and/or auditory brain stem response testing. Diagnostic testing was performed with age appropriate tests, auditory brain stem response and/or visual reinforcement audiometry. Infants diagnosed with permanent hearing loss were considered for hearing aids and early intervention. Ages of hearing loss identification, hearing aid fitting, and enrollment in early intervention were investigated regarding nursery type, risk status, unilateral versus bilateral hearing loss, loss type, loss severity, and state regions. Results: The prevalence of infants diagnosed with permanent hearing loss was 2.0/1000 (85 of 43,311). Of the 85 infants with hearing loss, 61% were from neonatal intensive care units (NICUs) and 67% were at risk for hearing loss. Of the 36 infants fitted with hearing aids, 58% were from NICUs and 78% were at risk for hearing loss. The median age at identification and enrollment in early intervention was 3 mo. Median age at hearing aid fitting was 7.5 mo. Median ages at identification were less for infants from the well‐baby nurseries (WBNs) than for the NICU infants and for infants with severe/profound than for infants with mild/moderate hearing loss, but were similar for not‐at‐risk and at‐risk infants. Median ages at hearing aid fitting were less for well babies than for NICU infants, for not‐at‐risk infants than for at‐risk infants, and for infants with severe/profound hearing loss than for infants with mild/moderate hearing loss. However, median ages at early intervention enrollment were similar for nursery types, risk status, and severity of hearing loss. Conclusions: Early ages of hearing loss identification, hearing aid fitting, and enrollment in early intervention can be achieved for infants from NICUs and WBNs and for infants at risk and not at risk for hearing loss in a large multi‐center universal newborn hearing screening program.

The New York State Universal Newborn Hearing Screening Demonstration Project: Ages of Hearing Loss Identification, Hearing Aid Fitting, and Enrollment in Early Intervention

Objective: To investigate outpatient outcome measures of a multi‐center, state‐wide, universal newborn hearing screening project. Design: Eight hospitals participated in a 3‐yr, funded project. Each hospital designed its own protocol using common criteria for judging whether an infant passed a hearing screening. Infants were tested in the hospital, and those either failing the in‐hospital screening or who were not tested in the hospital (missed) were asked to return 4 to 6 wk after hospital discharge for outpatient rescreening. Those infants failing the outpatient rescreening were referred for diagnostic auditory brain stem response testing. Each hospital used its own audiological equipment and criteria to determine whether a particular infant had a hearing loss. All data were collected and analyzed for individual hospitals, as well as totaled across all hospitals. Data were analyzed in terms of year of program operation, nursery type, and geographic region. Results: Seventy‐two percent of infants who failed the in‐hospital screening returned for outpatient testing. The percentage of in‐hospital fails returning for retesting was significantly higher than the percentage of in‐hospital misses returning for retesting. The percentage of infants returning for retesting increased with successive years of program operation. Some differences were noted in the percentage of infants returning for retesting among hospitals and geographic regions of the state. Some differences in outpatient outcome measures also were noted between infants originally born into the neonatal intensive care unit (NICU) and the well‐baby nursery (WBN). The percentage of infants from the NICU who returned for retesting was slightly higher than that for infants from the WBN. The percentage of infants from the WBN passing the outpatient rescreening was higher than that for the NICU infants. The overall prevalence of hearing loss was 1.96/1000, with that in the NICU being 8/1000 and that in the WBN being 0.9/1000. Positive predictive value for permanent hearing loss based on inpatient screening was approximately 4% and based on outpatient rescreening was approximately 22%. Conclusions: Several outpatient outcome measures changed with successive years of program operation, suggesting that programs improve over time. Also, some outpatient outcome measures differ between NICU and WBN populations. The differences noted across regions of the state in the percentage of infants returning for outpatient retesting require further research to determine whether differences are due to demographic and/or procedural differences.

The New York State Universal Newborn Hearing Screening Demonstration Project: Outpatient Outcome Measures

Objective: To evaluate the feasibility of universal newborn hearing screening by examining inpatient outcome measures from 8 hospitals located in geographically diverse areas of New York State over a 3‐yr period. Design: Funding was provided by the New York State Department of Health to implement predischarge hearing screening programs in the neonatal intensive care units (NICUs) and well‐baby nurseries (WBNs) of eight hospitals. Various screening protocols including transient evoked otoacoustic emissions alone or in combination with conventional auditory brain stem response or screening auditory brain stem response were implemented by each site. Measured outcomes included rate of misses, refusals, and fails. Results were analyzed as a function of year of operation, nursery type, and geographic location. Results: Six out of eight hospitals successfully implemented universal hearing screening during the first year, and the remaining 2 hospitals implemented programs during the second year of the project. Over a period of 3 yr, 69,761 newborns were screened at the eight hospitals representing 96.9% of all live births. The overall fail rate (4.04%) combined with the miss rate (2.61%) resulted in 6.63% of infants referred for outpatient follow‐up. Mean data indicated that inpatient outcome measures improved with year of operation, with most individual hospitals also showing improvements. Both fail and miss rates were higher in the NICU than in the WBN and for hospitals located in New York City than in other regions of the state. Conclusions: Inpatient outcome measures of a universal newborn hearing screening project, which involved multiple centers across geographically diverse regions of New York State, were acceptable in terms of successfully screening a high percentage of live births and attaining low refer rates for outpatient screening. This study adds to the growing body of literature supporting the feasibility of screening all newborns before hospital discharge.

New York State Universal Newborn Hearing Screening Demonstration Project: Inpatient Outcome Measures

A 2-year-old male castrated Domestic Short-haired cat presented to the Ophthalmology Service at the Matthew J. Ryan Veterinary Hospital at the University of Pennsylvania for evaluation of chronic bilateral ocular discharge and blepharospasm. Initial ophthalmic examination revealed severe conjunctivitis and keratitis and the presence of upper eyelid distichiae bilaterally. Initial therapy for suspected feline herpesviral infection provided moderate, but not complete, resolution of the clinical signs. Over the subsequent year, the cat suffered from recurrent, severe, ulcerative keratitis in both eyes despite appropriate medical therapy. Approximately 13 months after the initial presentation, the distichiae were surgically removed using transconjunctival electrocautery, which resulted in complete resolution of the clinical signs. This report documents bilateral distichiasis in a cat, a condition that is considered rare in this species.

Successful treatment of distichiasis in a cat using transconjunctival electrocautery.

The clinical and morphological features of intraocular melanocytic masses that originated in the choroid of five dogs were compared. Two of the cases had been reported previously and the authors have examined the pathological material. Histologically, the choroidal melanocytic tumors had several features in common and appeared to be entities distinct from melanocytic tumors of the anterior uveal tract or the epibulbar region. The tumors were well-delineated with tapered edges. They occurred in the posterior quadrant and two tumors had infiltrated the optic nerve. The tumors contained plump, straplike polyhedral cells, with minimal nuclear anaplasia and no mitotic figures. The retina overlying the tumor mass was detached, and the retinal pigment epithelium in this area was swollen and contained intracytoplasmic autofluorescent lipopigment. In two cases, the basement membrane of the retinal epithelium was disrupted by the tumor and pigmented cells infiltrated into the retina, the subretinal space, and the posterior chamber. In one case, retinal detachment was complete and accompanied by intraocular hemorrhage. Melanocytic tumors of the canine choroid have features in common with choroidal nevus and melanocytoma in human eyes.

Nuclear cataracts were found in 2 groups of related Morgan horses. The cataracts were finely reticulated central spherical translucencies that sometimes extended to the region of the posterior "Y" suture. The cataracts were not associated with other ocular defects and did not impair vision. In 1 group of 8 horses, 5 were affected; in the other group, 6 of 8 were affected. Although a pattern of inheritance could not be determined, the familial distribution of the cataracts supported the conclusion that the defect was a heritable disorder.

Adult dogs occasionally become suddenly, totally and permanently blind. If examined soon after the onset of blindness, the dogs show no ophthalmologic evidence of disease sufficient to account for their problem and are usually in otherwise good health. The hallmark of this sudden, acquired retinal degeneration (SARD), that establishes it as a retinopathy, and distinguishes it from neurological disease, is the extinguished electroretinogram. The syndrome has been termed "Silent Retina Syndrome" and "Metabolic Toxic Retinopathy". Although uncommon, SARD has been diagnosed with increased frequency in recent years. Little retinal tissue has, however, become available for histopathologic characterization of the disease. This report reviews twenty six cases of SARD examined by the authors at the Veterinary Hospital, University of Pennsylvania (VHUP). The histopathology and ultrastructural morphology of four cases are described. Disciplines Eye Diseases | Medicine and Health Sciences | Ophthalmology | Veterinary Medicine Author(s) Gregory M. Acland, Nita L. Irby, Gustavo D. Aguirre, Stephen L. Gross, Susan F. Nitroy, and Kathleen L. Notarfrancesco This conference paper is available at ScholarlyCommons: http://repository.upenn.edu/vet_papers/114 SUDDEN ACQUIRED RETINAL DEGENERATION IN THE DOG: Clinical and Morphologic Characterization of the "Silent Retina" Syndrome G. M. ACLAND2,3 N. L. IRBY1 G. D. AGUIRRE2,3 s. GRoss4 · S. F. NITROY3 K, NOTARFRANCESC03 1: Section of Ophthalmology, School of Veterinary Medicine, University of Pennsylvania, Phila~elphia, PA 19104 2: Section ~f Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104 3: Scheie Eye Institute and School of Medicine, Universit of Pennsylvania, Philadelphia, PA 19104 4: Animal Medical C~nter, New York, NY

Sudden Acquired Retinal Degeneration in the Dog: Clinical and Morphologic Characterization of the "Silent Retina" Syndrome

Ischemie heart disease in systemic lupus erythematosus in the young patient: Report of six cases

To clarify the clinical spectrum of coronary arterial abnormalities in systemic lupus erythematosus, the data were reviewed on six patients who had a diagnosis of lupus at ages 15 to 29 years and who had ischemic heart disease before age 35. Two patients had coronary arteritis diagnosed on postmortem examination. In a third patient alterations in coronary arterial anatomy occurred with angiographic improvement temporally related to the initiation of steroid therapy. The other three patients had severe diffuse atherosclerotic coronary disease that was identified in two at postmortem examination. In the third patient the course of the disease strongly suggested coronary atherosclerosis, and eventually coronary bypass grafting was performed for relief of angina. In summary, clinically important extramural coronary arteritis and atherosclerosis both occur, although rarely, in young patients with lupus. Coronary artery disease may occur with or without coexisting active extracardiac lupus manifestations. Short-term steroid therapy and follow-up angiography for those with angina and in whom coronary arteritis is suspected warrant consideration. When stable coronary arterial anatomy is demonstrated on follow-up angiography, management is determined by the patient's symptoms irrespective of the prior history of lupus and, if indicated, cardiac surgery for symptomatic relief can be safely performed.

Ischemic heart disease in systemic lupus erythematosus in the young patient: report of six cases.

Systemic lupus erythematosus and ischemic coronary artery disease

Systemic diseases can present ocular manifestations. In some cases, the ocular lesions are present along with other generalized lesions characteristic of the disease. In a few cases, however, only ocular lesions are present. The interpretation of these ophthalmologic findings, together with the generalized signs exhibited by the patient, are important in establishing a differential diagnosis and prognosis for the patient. This article reviews selected systemic diseases and their ocular manifestations. A more exhaustive review of the diseases has been already presented. Disciplines Medicine and Health Sciences | Ophthalmology | Veterinary Medicine This journal article is available at ScholarlyCommons: http://repository.upenn.edu/vet_papers/48 t 144 Vol. JJ , N o.2 . Febnwl)" 198U Continuing Education Article # 6 Ocular Manifestations of Selected Systemic Diseases Gusta\,o D, Agu irre, VM D Stephen L. Gm 'S, VMD Section of Ophthal mology School of Ve terinary M dicine Fig 1\

Albumin and fibrinogen metabolism in heat- and cold-stressed rabbits.

The spleen is the largest single mass of lymphoid tissue in the body; however, unlike the other aggregates of this tissue which are inserted into the lymph stream, the spleen is interposed in the blood stream. The anatomic peculiarities of the spleen are reflected in the low incidence and unusual patterns of metastatic malignancy in that organ. It is the authors' purpose in this paper (1) to review the patterns of secondary cancer in the spleen, and (2) to correlate these with its structure. The spleen has a fibrous framework composed of a capsule and trabeculae. The capsule is thickened at the hilus of the organ where it is. attached to folds of peritoneum and where vessels enter and leave the viscus. The trabeculae are continuations of the capsule and penetrate deeply into the organ. The reticulum network together with the cells present comprise the splenic parenchyma. This is composed of white pulp, venous sinusoids, and pulp cords, the latter 2 together comprising the red pulp. The branches of the splenic artery enter the hilus and pass along the trabeculae, branching frequently and becoming smaller in caliber. When they reach a diameter of approximately 0.2 mm. they leave the trabeculae and become the central arterioles of the white pulp. The central arterioles give off numerous capillaries which nourish the white pulp and then pass into the red pulp. The arterioles continue to branch and when they reach a diameter of 40 to 50 M they, too, leave the white pulp and enter the red pulp. On entering the red pulp each divides into 2 to 6 straight branches, called penicillar arteries. These continue to divide and ultimately end up as arterial capillaries. Their exact mode of termination is unknown.

EXTRAMEDULLARY HEMATOPOIESIS AND METASTATIC CANCER IN THE SPLEEN.

The sebaceous cyst is a common lesion and in the vast majority of cases is regarded as a benign and harmless one. These growths are often disregarded, but when they cause the patient to seek medical advice they are frequently excised. In this study, an attempt has been made to correlate the clinical diagnosis of sebaceous cyst with the final pathological diagnosis. Most of these cases were designated sebaceous cysts by the clinicians, but a wide variety of terms, including steatoma, wen, pseudoatheroma, and epidermoid inclusion cyst, was used on occasion. All cases were included, regardless of exact terminology, if it could be ascertained that the clinician meant the lesion commonly called sebaceous cyst. The last 6,600 surgical specimens examined at the University Hospital of the New York University—Bellevue Medical Center were reviewed, and in 300 instances a clinical diagnosis of sebaceous cyst of the skin was made. Of these,

Sebaceous cysts; correlation of clinical and pathological diagnoses in three hundred cases.

Residual life assessment of the SSME/ATD HPOTP turnaround duct (TAD)

TABLE OF CONTENTSPageI. INTRODUCTION 1]I. BACKGROUND 1In'. TEST PROGRAM 3IV. ANALYSIS/EXPERIMENTAL CORRELATION 4V. TEST RESULTS 6A. Steady Strain Results 6B. Unsteady Strain Results 7C. Relationship Between Steady and Unsteady Loads 8VI. CONCLUSIONS 9REFERENCES 10APPENDIX A -INSTRUMENTATION 11APPENDIX B - TEST DATA 17

High Pressure Oxidizer Turbopump (HPOTP) inducer dynamic design environment

There were two main goals of the ATD HPOTP (alternate turbopump development)(high pressure oxygen turbopump). First, determine the steady and unsteady inducer blade surface strains produced by hydrodynamic sources as a function of flow capacity (Q/N), suction specific speed (Nss), and Reynolds number (Re). Second, to identify the hydrodynamic source(s) of the unsteady blade strains. The reason the aforementioned goals are expressed in terms of blade strains as opposed to blade hydrodynamic pressures is because of the interest regarding the high cycle life of the inducer blades. This report focuses on the first goal of the test program which involves the determination of the steady and unsteady strain (stress) values at various points within the inducer blades. Strain gages were selected as the strain measuring devices. Concurrent with the experimental program, an analytical study was undertaken to produce a complete NASTRAN finite-element model of the inducer. Computational fluid dynamics analyses were utilized to provide the estimated steady-state blade surface pressure loading needed as load input to the NASTRAN inducer model.

Steady and unsteady blade stresses within the SSME ATD/HPOTP inducer

An optimization methodology is presented for the selection of the end cross-sectional shape of composite torque tubes (drive shafts) with noncircular end geometries. In a typical application, metal inserts are adhesively bonded in the ends of the tubes to allow for torque transmission. The worst case scenario of bond failure with subse quent torque transmission via insert-tube contact is considered. Optimization of the tube end cross-sectional shape under this worst case situation is the goal of this study. Employ ing facets of elasticity and the finite element method, a two step methodology is estab lished to predict the failure torque of a tube with a range of selected end cross-sections. This methodology is verified through comparison with experimental data. Results ob tained from the analytical and experimental studies indicate a spline-like cross-sectional shape as the optimal design. Failure torques on the order of 70% of the circular cross- sectional failure torque are shown to be possible.

An Experimental and Analytical Investigation of Composite Drive Shafts with Non-Circular End Cross-Sections

Computationally efficient method for the solution of a singular integro-differential equation

A solution is presented for a non-Hertzian contact stress problem. The problem is reduced to a singular integro-differential equation which is solved numerically. Results are presented for the contact zones, and for the normal and tangential stresses at the plane-insert interface

Torsion of a Rigid Smooth Elliptic Insert in an Infinite Elastic Plane

The heat transfer characteristics of propane at subcritical and supercritical pressure were experimentally evaluated using electrically heated Monel K-500 tubes. A design correlation for supercritical heat transfer coefficient was established using the approach previously applied to supercritical oxygen. Flow oscillations were observed and the onset of these oscillations at supercritical pressures was correlated with wall-to-bulk temperature ratio and velocity. The critical heat flux measured at subcritical pressure was correlated with the product of velocity and subcooling. Long duration tests at fixed heat flux conditions were conducted to evaluate coking on the coolant side tube wall and coking rates comparable to RP-1 were observed.

Supercritical convection, critical heat flux, and coking characteristics of propane

Design, fabrication, test, and delivery of a high-pressure oxygen/RP-1 injector

Analysis of a unidirectional composite containing broken fibers and matrix damage

A sound data base was established by analytically and experimentally generating basic regenerative cooling, combustion performance, combustion stability, and combustion chamber heat transfer parameters for LOX/HC propellants, with specific application to second generation orbit maneuvering and reaction control systems (OMS/RCS) for the Space Shuttle Orbiter.

Combustion performance and heat transfer characterization of LOX/hydrocarbon type propellants

Stresses in a three-dimensional unidirectional composite containing broken fibers

The Wafra Second Eocene Heavy Oil Carbonate Reservoir, Partitioned Zone (PZ), Saudi Arabia and Kuwait: Reservoir Characterization, Modeling, and IOR/EOR Evaluation

Steamflood Pilot Design for the Wafra Field 2nd Eocene Reservoir in the Partitioned Zone (PZ), Saudi Arabia and Kuwait

This presentation summarises a workflow that was used in the appraisal of a heavy oil field discovered in the Pechora Sea during the 1990's. Reservoir flow properties were thought to be at least partly dependant on the presence of a connected fracture system. Therefore it was necessary to characterise the fracture system and model it's likely impact on deliverability. The work was carried out under a tight project deadline and using limited sub-surface data. Potential drilling strategies to optimise production were also explored.

Fracture Characterisation and Modeling in a Permo-Carboniferous Discovery in the Pechora Sea, NW Russia

Impact of Volumetric and Connectivity Uncertainty on Reservoir Management Decisions: Case Study from the Humma Marrat Reservoir, Partitioned Neutral Zone

Application of Design of Experiments to Expedite Probabilistic Assessment of Reservoir Hydrocarbon Volumes (OOIP)

Utilization of Sand Control and Mechanical Profile Control in Numbi Field Water Injection Wells

After a successful single-pattern field trial, an endeavor to apply seismic steamflood monitoring technology on a scale designed to meet the requirements of heat management programs has commenced in Duri Field, Central Sumatra - one of the largest heavy oil enhanced recovery projects in the world. A baseline 3-D seismic survey was acquired in April, 1995, just prior to the start of steam injection in a 31 pattern area. The first of four monitor 3-D seismic surveys was acquired 8 months later. Differences between the two seismic surveys were used to monitor steamflood evolution and optimize EOR and heat management processes. This paper will address a wide range of topics including expected economic benefits, planning, seismic acquisition and processing, modeling and analysis, and impact on EOR and heat management processes. A special emphasis will be given to value resulting from interdisciplinary synergy.

Large-scale Application of Seismic Steamflood Monitoring in Duri Field, Central Sumatra - Progress Report: ABSTRACT

Abstract The Duri Field, located in Riau province in central Sumatra, is currently the site of the largest steamflood project in the world. Roughly half of the field is currently being flooded in seven project areas. The older steamflood areas are in their mature stages, with the majority of patterns experiencing steam breakthrough. A reservoir simulation study was performed to optimize the operating strategies for these mature steamflood areas. A history-match of a mature steamflood area was developed using a three-dimensional, compositional, thermal reservoir simulator. A simple pattern-element, layer-cake (areally homogeneous and vertically heterogeneous) model was used, and an excellent match of six years of historical steamflood performance was obtained by making minor changes to the input parameters. The history-matched model was used to evaluate the effects on performance of terminating steam injection into the reservoir layers with steam breakthrough, and of using different rate reduction schemes. It was found that a combination of steam rate reductions and termination of injection into the breakthrough layers will yield the maximum value for the mature areas. The optimum timing for the initiation of rate reductions was found to be the time at which about one pore volume of steam has been injected. The results of a rate reduction field trial in a portion of a mature area agree well with the simulation results.

The Use of Reservoir Simulation to Optimize Operating Strategies for Mature Steamflood Areas in the Duri Field

The overall objective of reservoir management and development planning for the Duri field is to maximize project value. Key elements of Duri`s reservoir management practices include: injecting steam in new patterns at rates up to about 1.2 BCWEPD/NAF or the maximum rates achievable below fracture pressure; distributing the steam into reservoir layers in proportion to their h{phi}S{sub o}; maintaining these rates until steam breakthrough occurs in multiple wells in a pattern; then performing injector wellwork to shift steam out of the breakthrough layers while continuing initial rates into the non-breakthrough layers. The area-wide rate reduction schedule caused by these shifts resembles a heat balance (Vogel) rate reduction schedule. The steam that is shifted out of an old steamflood development area becomes the supply of steam for the start up of a new area. Key elements of Duri`s development planning practices include: obtaining sufficient reservoir information to be able to predict performance of all areas in the field; dividing the undeveloped parts of the field into steamflood areas that are logical and will fit the steam availability and construction scheduling constraints of the project; ranking the new projects by their profitability; and installing them at a schedule that matches the steammore » shifts out of the old areas with the ramp up of the new area so that steam plant capacity is fully utilized. This paper discusses the interrelationships between reservoir management practices, development planning, and the maximization of overall DSF project value.« less

Development planning and reservoir management in the Duri steam flood

Abstract The Rindu formation is the shallowest producing formation in the Duri Field. Its large original oil in place (OOIP) and low primary recovery (less than 6% of OOIP) leave a considerable target for enhanced oil recovery (EOR). Initial screenings have indicated that steamflooding is the most promising EOR technology for the Rindu. An aggressive program of data collection, reservoir characterization, simulation, and pilot steamflooding were undertaken to evaluate the steamflood potential of the Rindu reservoirs. Data collection efforts included an extensive coring and core analysis program to determine formation evaluation parameters and fluid flow properties, the collection and analysis of numerous oil samples, and step-rate testing and acoustical logging to establish the formation parting pressure. Following the data collection work, a pilot location was selected. A simulation model of the pilot area was built using a geostatistical distribution of reservoir properties to forecast the performance of the pilot. The favorable performance predictions led to the development of a pilot steamflood consisting of three 11 5/8 - acre inverted 7-spot patterns. Steam injection began in July 1994. The only consequence of the Rindu's shallow depth is a limitation on the steam injection pressure in order to prevent steam break out at the surface. The pilot response thus far has confirmed the simulation results, illustrating the importance of careful data collection and reservoir characterization in the evaluation of Rindu potential.

Evaluation of the Steamflood Potential of the Rindu Reservoirs in the Duri Field

Changes in static stress caused by 52 earthquakes of average mb 4.7 are modeled and compared to changes in the spatial distribution oi mostly smaller surrounding earthquakes recorded by the Central Aleutian Seismic Network. The comparisons have been used to evaluate possible fault failure criteria and background stress states appropriate for a subduction zone. Statistical measures were developed to assess the significance of changes in spatial distribution of seismicity. The significance of changes in the spatial distribution of seismicity occurring near the times of target earthquakes was evaluated by comparing them to changes occurring at other times in the same catalog. The most successful model includes background stresses caused by viscous drag forces exerted on the subducting plate as it moves through the mantle and assumes that surrounding seismicity occurs on strong faults in all orientations. This stress state suggests that the main thrust zone between the subducting and overriding plates is weak, because otherwise forces from the collision of the two plates would dominate the stress field. The best-fitting model is preferred over three other combinations of background stress state and fault friction which fit the data equally well because it more strongly correlates with seismicity near the larger earthquakes in more active areas.

Stress and the spatial distribution of seismicity in the central Aleutians

Sandstone reservoir rocks are not necessarily formed by random natural occurrences. These rocks are usually the result of an ordered series of depositonal events that may be represented by known depositional environments. A review of the geological literature has shown that these environments are well documented by modern examples. Sand bodies found in sandstone reservoirs may be broadly divided into regressive, transgressive, serrated, and homogeneous sequences. This paper discusses the results of a cross-sectional computer study on the depletion of an oil reservoir composed of the four basic depositional models. The studies indicate that recoveries under pressure depletion or water-drive conditions may be greatly affected by the type of sand body present in the reservoir. Geologists and engineers must be aware of the effect of depositional environment on ultimate recovery from oil reservoirs. This knowledge illustrates the usefulness of electric log and core analysis for furnishing an insight into the major flow paths in a reservoir. Additionally, the study shows how the depositional history of a reservoir may affect ultimate recovery.

ABSTRACT:This article analyzes a World War II-era Army field jacket and the principle of layering it represents as a technology of war. The M-1943 jacket, designed in military laboratories and issued to soldiers in the European Theater, represents a scientized approach to layering clothing developed on test expeditions and in new research and development laboratories run by the Quartermaster Corps. Drawing on both histories of technology and histories of design, this article shows how the M-43 jacket operated as part of a broader assemblage of testing facilities, institutions, and individuals. The debate within the Army about how best to equip soldiers points to the struggle to control the growing authority of scientific expertise in the military bureaucracy. The science of dress, more than personal or subjective experience, shaped how the American military equipped soldiers for war and contributed to the expansion of military research laboratories in the Cold War.

Layering for a Cold War: The M-1943 Combat System, Military Testing, and Clothing as Technology

This study has shown that laminated plate theory and kinematics can successfully predict the deflections generated by piezoceramic flexspar flight control surface actuators

Design and Testing of a Subsonic All-Moving Adaptive Flight Control Surface

A new type of very-low-stiffness super-active composite material is presented. This laminate uses shape-memory alloy (SMA) filaments which are embedded within a low-hardness silicone matrix. The purpose is to develop an active composite in which the local strains within the SMA actuator material will be approximately 1%, while the laminate strains will be at least an order of magnitude larger. This type of laminate will be useful for biomimetic, biomedical, surgical and prosthetic applications in which the very high stiffness and actuation strength of conventional SMA filaments are too great for biological tissues. A modified form of moment and force-balance analysis is used to model the performance of the super-active shape-memory alloy composite (SASMAC). The analytical models are used to predict the performance of a SASMAC pull - pull actuator which uses 10 mil diameter Tinel alloy K actuators embedded in a 0.10 thick, 25 Durometer silicone matrix. The results of testing demonstrate that the laminate is capable of straining up to 10% with theory and experiment in good agreement. Fatigue testing was conducted on the actuator for 1 000 cycles. Because the local strains within the SMA were kept to less than 1%, the element showed no degradation in performance.

The working principles and structural arrangements of several types of newly invented active flight control surfaces are detailed. The surfaces were built with graphite main spars around which mass-balanced aerodynamic shells were pivoted by active elements. These new designs used adaptive Flexspars to pitch the shells. Different actuator arrangements have yielded two main configurations: 1) the tip-joint Flexspar and 2) the shell-joint Flexspar. Estimations of aerodynamic shell pitch deflections are made using laminated plate theory and kinematics. The analytical estimations are compared to experimental test results which show static rotations in excess of +11° on a 3.3" chord by 4" span Flexspar specimen. A comparison of pitch deflection performance shows that the tip-joint Flexspar generates the highest deflections on small-scale surfaces while older designs like the piezoelectric torque-plates are well suited to larger control surfaces. Wind tunnel data on several arrangements showed that static changes in CL in excess of f0.43 may be achieved with the tip-joint Flexspars. In addition to generating high pitch deflections, these actuators demonstrated stable, gust resistant responses in a series of flight tests on a free-flight remotelypiloted vehicle and on a 113 scale TOW missile wind tunnel model.

DESIGN AND TESTING OF SUBSONIC ALL-MOVING SMART FLIGHT CONTROL SURFACES

A new type of very low stiffness super-active composite material is presented. This laminate uses shape-memory alloy (SMA) filaments which are embedded within a low Durometer silicone matrix. The purpose is to develop an active composite in which the local strains within the SMA actuator material will be approximately 1% while the laminate strains will be at least an order of magnitude larger. This type of laminate will be useful for biomimetic, biomedical, surgical and prosthetic applications in which the very high actuator strength of conventional SMA filaments is too great for biological tissues. A modified form of moment and force-balance analysis is used to model the performance of the super-active shape-memory alloy composite (SASMAC). The analytical models are used to predict the performance of a SASMAC pull-pull actuator which uses 10 mil diameter Tinel alloy K actuators embedded in a 0.10' thick, 25 Durometer silicon matrix. The results of testing demonstrate that the laminate is capable of straining up to 10% with theory and experiment in good agreement. Fatigue testing was conducted on the actuator for 1,000 cycles. Because the local strains within the SMA were kept to less than 1%, the element showed no degradation in performance.

Cementless femoral stems were placed into 12 normal greyhound femora. The implanted femora were divided into three groups by stem orientation and implant size and loaded in axial compression at a rate of 25 newtons (N) per second until failure. Rosette strain gauges were used to measure femoral principal strains at 500 N, 1,000 N, 1,500 N, and at maximum load. During maximum load, varus orientation of the femoral stem had significantly higher tensile hoop strains in the proximomedial cortex, whereas neutral orientation had higher tensile hoop strains along the cranial cortex. Femoral fractures occurred in these areas of peak tensile strain. There was no difference in maximum load between groups, therefore varus orientation did not predispose to fracture. Maximizing canal fill and implant fit increased implant stability.

The effects of implant orientation, canal fill, and implant fit on femoral strain patterns and implant stability during catastrophic testing of a canine cementless femoral prosthesis.

A new type of subsonic missile flight control surface using piezoelectric flexspar actuators is presented. The flexspar design uses an aerodynamic shell which is pivoted at the quarter-chord about a graphite main spar. The shell is pitched up and down by a piezoelectric bender element which is rigidly attached to a base mount and allowed to rotate freely at the tip. The element curvature, shell pitch deflection and torsional stiffness are modeled using laminated plate theory. A one-third scale TOW 2B missile model was used as a demonstration platform. A static wing of the missile was replaced with an active flexspar wing. The 1' X 2.7' active flight control surface was powered by a bi-morph bender with 5-mil PZT-5H sheets. Bench and wind tunnel testing showed good correlation between theory and experiment and static pitch deflections in excess of +/- 14 degree(s). A natural frequency of 78.5 rad/s with a break frequency of 157 rad/s was measured. Wind tunnel tests revealed no flutter or divergence tendencies. Maximum changes in lift coefficient were measured at (Delta) CL equals +/- .73 which indicates that terminal and initial missile load factors may be increased by approximately 3.1 and 12.6 g's respectively, leading to a greatly reduced turn radius of only 2,400 ft.

Twelve normal greyhound femora were divided into three groups. In group one, femoral stems were placed in neutral position with maximal fill. Group two had undersized femoral stems placed in neutral position. Group three had undersized femoral stems placed in varus position. Intact and implanted femora were loaded from 10 newtons (N) to 300 N in axial compression at a rate of 25 N/s for 10 replications. A strain gauge analysis showed that the strain distribution of all implanted femora were substantially different from intact femora, but femora with large implants placed in neutral position had the least amount of deviation from normal. An undersized stem in neutral position had significantly less compressive longitudinal strains along the proximomedial and proximocranial cortices. An undersized stem in varus position improved implant fit along the proximomedial and distolateral cortices, which resulted in increased tensile hoop strains. There were multiple significant correlations between the strain data and implantation variables (implant alignment, canal fill, and implant fit). Subsidence was significantly greater for the undersized implant in neutral position. There was not a difference in subsidence between the large neutral and varus groups. The most important variable that decreased subsidence was increased lateral implant fit (r = -0.86, P = .0003).

Femoral strain distribution and subsidence after physiological loading of a cementless canine femoral prosthesis: the effects of implant orientation, canal fill, and implant fit.

Ovarian folliculogenesis is characterized, in part, by the formation and expansion of the fluid-filled antrum. Development of this cavity requires water influx, which may occur by transcellular or pericellular transport mechanisms. To assess the contribution of these mechanisms to the water permeability of an antral follicle, the rate of (3)H(2)O and (14)C-inulin (a complex sugar restricted to the extracellular compartment) uptake into isolated follicles was determined. The rate of H(2)O movement was 3.5-fold greater than that of inulin, suggesting that water enters a follicle primarily by transcellular pathways. Preincubation of the follicles with 50 microM HgCl(2) [a nonspecific aquaporin (Aqp) inhibitor] decreased H(2)O movement to levels seen with inulin, indicating that transcellular water movement is mediated through Aqp. To demonstrate the functional presence of Aqp in granulosa cells, we show that swelling in response to a hypotonic insult is attenuated by preincubation with 50 microM HgCl(2). Flow cytometry demonstrated the presence of Aqps-7, -8, and -9, thus identifying candidate Aqp potentially mediating water movement into antral follicles. These results suggest that water permeability of antral follicles occurs primarily through transcellular mechanisms, which may be mediated by Aqps -7, -8, and/or -9 in granulosa cells.

Water permeability of an ovarian antral follicle is predominantly transcellular and mediated by aquaporins.

Abstract More than 99% of ovarian follicles are lost by a degenerative process known as atresia, a phenomenon characterized by apoptosis of granulosa cells. Uniquely, dying granulosa cells also greatly increase their progesterone biosynthesis while reducing estrogen production. Recent studies have documented a dramatic decrease in intracellular K+ concentration during apoptosis that plays an important role in regulating apoptotic enzymes. However, it is unclear whether this ionic change affects related processes such as the change in steroidogenesis in dying granulosa cells. To explore this question, granulosa cells were cultured in hypotonic medium, which initially swells the cells. The cells respond by extruding K+, which we have documented by fluorescence spectrophotometry. The K+ efflux osmotically draws water out the cell, returning it to a near normal volume (as measured by flow cytometry). The result is a cell of normal size with a decreased intracellular K+ concentration. FSH stimulation of these cells caused an increase in progesterone biosynthesis. This response was enhanced at higher doses of FSH, although basal progesterone production was not affected, suggesting that K+ levels may affect the gonadotropin-signaling pathway. No increase in steroidogenic acute regulatory or cholesterol side-chain cleavage cytochrome P450 mRNA was detected, although cAMP production was enhanced. These results suggest that the loss of intracellular K+ by apoptotic granulosa cells greatly facilitates FSH-stimulated progesterone production.

Decreased Intracellular Potassium Levels Underlie Increased Progesterone Synthesis During Ovarian Follicular Atresia1

Ophthalmologic manifestations of acquired immune deficiency syndrome-associated progressive multifocal leukoencephalopathy.

Aberrant innervational pattern in Duane's syndrome type II without globe retraction.

Aberrant Innervational Pattern in Duane??s Syndrome Type II Without Globe Retraction

Hepatocytes isolated from Sprague‐Dawley rats were incubated with various concentrations of either amiodarone or desethylamiodarone fro 0 to 69 hr. Both drugs produced a concentration‐dependent increase of lactate dehydrogenase release in the culture medium, which correlated well with cell death as measured by trypan blue exclusion test. Desethylamiodarone was more toxic than amiodarone in the cultured hepatocytes. Incubation with subtoxic concentrations of either amiodarone (7.6 μ) or desethylamiodarone (8 μM) for 24 hr resulted in the development of myelinoid inclusion bodies in the hepatocytes without any excess release of lactate dehydrogenase. In experimental protocols where the hepatocytes were exposed to either amiodarone or desethylamiodarone for up to 96 hr, there was an increase in lactate dehydrogenase and the percent volumedensity of multilamellar inclusion bodies with cumulative drug exposure with time. A linear correlation between hepatocyte drug concentration and multilamellar inclusion bodies was found for both amiodarone and desthylamiodarone. These results demonstrate that both amiodarone and its major metabolite, desethylamiodarone, induce lysosomal inclusions, which, under appropriate conditions, can be dissociated from cell death,. Withdrawal of the drug after 24 hr exposure did not result in disappearance of the inclusion bodies from the hepatocytes for up to 96 hr of tissue culture. The concentrations at which amiodarone‐ or desethylamiodarone‐induced electron microscopic changes and hepatotoxicity were only two to five times as high as the usual serum drug levels in patients given antiarrhythmic therapy with amiodarone. (HEPATOLOGY 1990; 11: 81–92.)

Amiodarone‐ and desethylamiodarone‐induced myelinoid inclusion bodies and toxicity cultured rat hepatocytes

Amiodarone, an antiarrhythmic agent, has proven to be unique in its capability to control arrhythmias unresponsive to conventional drugs. However, its association with many undesirable side effects after chronic usage has become just as clear. Chronic clinical toxicity with amiodarone is associated with intracellular lamellar or myelinoid inclusion bodies (onionoid bodies or corpora cepiformia) in various organs (i.e. skin, cornea, lung, liver, and lymph nodes). Previous study has demonstrated formation of these inclusion bodies in canine myocardium following multiple doses of amiodarone. The present study was designed to develop a more convenient animal model, and to measure the concentration of amiodarone, as well as desethylamiodarone (its major metabolite) in this rodent model. The direct role of desethylamiodarone in formation of lamellar inclusion bodies in rat myocardium was also investigated. Amiodarone (50 mg/kg) or desethylamiodarone (25 mg/kg) was injected intraperitoneally daily for a period of 14 days. Myocardial sections revealed the presence of lamellar inclusion bodies, round or oval in appearance, in the form of laminated or concentrically arranged membranes after either amiodarone or desethylamiodarone treatment. This is the first reference to the induction of these myelinoid inclusion bodies with desethylamiodarone. Myocardial tissue concentrations of amiodarone and desethylamiodarone exceeding plasma concentrations were found in the present study and indicate the capability of these compounds to easily distribute and accumulate in the myocardium.

Subcellular changes of rat myocardium after treatment with amiodarone or desethylamiodarone, studied with electron microscopy.

Adams et al. (1986) recently described their observation of more than three intracellular lamellar inclusions in the circulating neutrophils in their group 1 patients (n = 7, with unwanted side effects and higher plasma amiodarone (AM) and desethylamiodarone (DA) levels). They also found a significant association between the presence of multilamellar bodies and plasma AM levels in excess of 2 mg 1-1. Although their patients in group 2 did not appear to show the intracellular inclusion bodies, it was not clear whether or not this group had received drug therapy for a shorter duration as compared with the group 1 patients. Nor was it clear whether the patient with plasma AM above 4 mg 1-1 had intracellular inclusion bodies in the circulating neutrophils. Amiodarone is a class III antiarrhythmic drug with several unique pharmacokinetic and pharmacodynamic properties (Singh, 1983), including the reported systemic toxicity associated with intracellular myelinoid inclusions in various organs. Most of the published reports are case studies in which the patients received drug therapy for varying duration when they presented with signs and symptoms of toxicity. However, onset of these intracellular changes and whether or not they are pathognomonic of AM toxicity remain poorly understood. We have examined the correlation of serum and WBC drug concentration and electron microscopic changes in a group of patients given AM and our data (Somani et al., 1986) already showed that such inclusion bodies were detected in circulating neutrophils as early as day 10 of onset of therapy and were found in these cells in five out of five patients, four of whom had no signs or symptoms of systemic toxicity. We also reported that the concentration of AM and DA in WBCs was relatively high as compared with the plasma or RBCs and suggested that the WBC drug levels may correlate with the tissue drug levels. Additional data (Somani et al., 1987) in five patients undergoing myocardial biopsy 2 months after drug therapy was started showed that all five had the characteristic lamellar inclusion bodies in circulating neutrophils and in the myocardial cells (Figure 1). None of these patients had any signs or symptoms of clinical toxicity. Serun¶ AM (1.75 ± 0.21 s.e. mean, mg 1-) and DA (0.96 ± 0.17 s.e. mean, mg 1-1) levels were within low therapeutic range. Electron microscopic changes in the human myocardium were similar to those observed in the canine tissue after 8 days of AM treatment (Gross & Somani, 1986). The major question that needs to be resolved with chronic AM therapy in man is whether finding characteristic intracellular lamellar bodies carries any diagnostic or prognostic significance for toxicity. Our data suggest that inclusion bodies appear early, are seen in circulating neutrophils, basophils, and eosinophils as well as in the myocardium with low serum drug concentrations and in most cases are not associated with signs or symptoms of overt clinical toxicity.

Magnetic resonance imaging of optic tract involvement in multiple sclerosis.

Amiodarone-induced ultrastructural changes in canine myocardial fibers.

Suppression of ventricular premature beats by intravenous methylprednisolone in patients with acute myocardial infarction

Mural thrombi in myocardial infarctions. Prospective evaluation by two-dimensional echocardiography.

Mechanical failure (leaflet disruption) of a porcine aortic heterograft: rare cause of acute aortic insufficiency.

Development of Uncooled Micro-bolometer Arrays Based on Hole-doped Rare-Earth Manganites

The last time that you heard something break, you might have wondered whether the sound emitted is important to the fracture process. On reflection, you probably concluded that it is insignificant, since the sound emitted in the fracture of a brittle material is not very loud. Indeed, the energy contained in the sound wave makes up only a small percentage of the energy released during fracture (about 5% in glass).

A new type of subsonic missile flight control surface using piezoelectric flexspar actuators is presented. The flexspar design uses an aerodynamic shell which is pivoted at the quarter-chord about a graphite main spar. The shell is pitched up and down by a piezoelectric bender element which is rigidly attached to a base mount and allowed to rotate freely at the tip. The element curvature, shell pitch deflection and torsional stiffness are modeled using laminated plate theory. A one-third scale TOW 2B missile model was used as a demonstration platform. A static wing of the missile was replaced with an active flexspar wing. The 1 in 2.7 in active flight control surface was powered by a bimorph bender with 5 mil PZT-5H sheets. Bench and wind tunnel testing showed good correlation between theory and experiment and static pitch deflections in excess of . A natural frequency of 78.5 rad with a break frequency of 157 rad was measured. Wind tunnel tests revealed no flutter or divergence tendencies. Maximum changes in lift coefficient were measured at which indicates that terminal and initial missile load factors may be increased by approximately 3.1 and 12.6 g respectively, leading to a greatly reduced turn radius of only 2400 ft.

A new type of very-low-stiffness super-active composite material is presented. This laminate uses shape-memory alloy (SMA) filaments which are embedded within a low-hardness silicone matrix. The purpose is to develop an active composite in which the local strains within the SMA actuator material will be approximately 1%, while the laminate strains will be at least an order of magnitude larger. This type of laminate will be useful for biomimetic, biomedical, surgical and prosthetic applications in which the very high stiffness and actuation strength of conventional SMA filaments are too great for biological tissues. A modified form of moment and force-balance analysis is used to model the performance of the super-active shape-memory alloy composite (SASMAC). The analytical models are used to predict the performance of a SASMAC pull - pull actuator which uses 10 mil diameter Tinel alloy K actuators embedded in a 0.10" thick, 25 Durometer silicone matrix. The results of testing demonstrate that the laminate is capable of straining up to 10% with theory and experiment in good agreement. Fatigue testing was conducted on the actuator for 1 000 cycles. Because the local strains within the SMA were kept to less than 1%, the element showed no degradation in performance.

_______________________________________________________________i Acknowledgments _______________________________________________________iii List of Tables ___________________________________________________________v List of Figures __________________________________________________________vi

A Feasibility Study of Model-Based Natural Ventilation Control in a Midrise Student Dormitory Building

Repeated-measures counterbalanced design.

To determine the effect of rate of force application on anterior tibial displacement and anterior tibial stiffness when measured with the KT-2000 knee arthrometer.

Clinicians and researchers frequently use the KT-2000 to quantify anterior tibial displacement and stiffness. While many factors (ie, tibial rotation, alignment of the arthrometer, etc) have been identified to affect KT-2000 measurements, the effect of the rate of force application has not been studied.

METHODS AND MEASURES
Seventeen recreationally active males between the ages of 19 and 36 years (mean age +/- SD, 27.8 +/- 5.3 years) with no previous history of knee injury participated. With the knee in 25 degrees of flexion, the KT-2000 was applied to the participants' anterior tibia. While the distal femur was stabilized, the first author applied a posterior-to-anterior force at a fast and slow rate. Three trials for the slow and fast rates of force application were averaged and used for statistical analysis. Anterior tibial displacement (mm) was measured at 133 N and the related anterior tibial stiffness (N/mm) values were calculated between 89 and 133 N. Separate paired t tests with Bonferroni adjustment were used to determine if differences in displacement and stiffness between rates of force application were present.

RESULTS
Stiffness was significantly greater in the slow (mean +/- SD, 58 +/- 22 N/mm) as compared to the fast trials (mean +/- SD, 47 +/- 19 N/mm) (P = .005). Differences in displacement, however, were small and not significant (P = .132) between the slow (mean +/- SD, 3.9 +/- 1.5 mm) and fast (mean +/- SD, 4.0 +/- 1.6 mm) trials.

The rate of force application affects anterior tibial stiffness but not anterior tibial displacement when measured with the KT-2000. This suggests that to ensure reliable results when using the KT-2000, the rate of force application must be controlled when measuring stiffness between 89 and 133 N, but not when measuring anterior tibial displacement at 133 N.

Rate of force application during knee arthrometer testing affects stiffness but not displacement measurements.

Ameri Steel's experience with gainsharing demon-strates the effectiveness of using incentives to improve productivity within an organization. The advantages of gainsharing over profit sharing are two-fold: first, gainsharing distributes operating gains (as opposed to bottom-line profits), and, because it is easier to measure, can be paid out with a greater frequency than profit-sharing awards. The frequency of payouts is vital to the effectiveness of the plan, since there is a more immediate incentive with which to motivate employees. A further advantage of gainsharing is that, rather than basing rewards on total company profits, payouts can be based on the performance of plants, teams, or small work units. This struc-ture encourages employees to work together cohesively in a team environment. Companies with gainsharing programs are thus able to attract team-oriented risk-takers who are not afraid to bet the farm on their performance, while ensuring that excellence is rewarded with frequent and substantial payouts. Indeed, the Ameri Steel gain-sharing plan has helped the company generate an average of 8% annual improvements in productivity in the four years since management adopted this program, while employees have enjoyed average payouts equal to 46% of their base pay.

Purpose: To report atypical ocular findings of Rosai-Dorfman disease and to determine association with parvovirus 19. Design: The study is an observational case series of three patients that had atypical ocular presentations of Rosai-Dorfman disease. Methods: A multicenter, retrospective case series of 3 patients was evaluated for varied ocular complaints, including enlarging epibulbar masses and uveitis. Histologic specimens were examined retrospectively for parvovirus 19 antigen. Results: Patients presented with ocular findings prior to or concurrently with systemic findings, with and without associated lymphadenopathy. Two cases presented with epibulbar masses, one with the mass as the only sign of disease while the other exhibited multinodal involvement with bilateral epibulbar masses and anterior granulomatous inflammation. Parvovirus B19 antibody staining was negative in these cases. The final case exhibited bilateral anterior granulomatous inflammation and choroidal infiltrates. Conclusions: Ocular findings may be the sole or presenting complaint in Rosai-Dorfman disease prior to recognition of systemic disease and should be considered in the differential diagnosis of epibulbar masses as well as anterior and posterior granulomatous inflammation.

Intravenous nitroglycerin (IV-NTG) has gained wide use in the manage ment of critically ill patients, yet little is known regarding dose-response hemodynamics in man. Therefore, we studied 10 patients, all Class III or IV New York Heart Association Classification with pulmonary artery wedge pressures of 15 torr or greater. A special delivery system designed to prevent drug absorption Nitrostat® IV Infusion Kit was used and assessed. Multiple hemodynamic values were recorded before, during, and after the infusion. Administration of IV-NTG was started at 0.125 mcg/kg/min and was doubled every 15 minutes to a maximum dose of 2.0 mcg/kg/min. The infusion was stopped if the pulmonary artery wedge pressure dropped below 10 torr, or arterial pressure dropped below 90/60 torr, or if the mean artery pressure fell more than 10 torr, or if significant side effects occurred. Samples for blood levels were collected. Only one patient noted any untoward effects and he recovered quickly upon cessation of infusion. The mean infusion rate was 0.6125 mcg/kg/min. A significant drop in mean arterial blood pressure, mean pulmonary artery pressure, mean pulmonary artery wedge pressure, heart rate, and arterial oxygenation was noted. Cardiac output did not change significantly. Pulmonary vascular resistance index, as well as several other indices, decreased significantly in all patients. Nitrostat IV® appears to be very safe and to work by dilating preload capacitance vessels, followed by a drop in arterial pressure without an adverse lowering of cardiac output.

Effect of Intravenous Nitroglycerin on Hemodynamics of Congestive Heart Failure

Glaslöten - eine anspruchsvolle Fügetechnik nicht nur für die Hochtemperatur-Brennstoffzelle

Glaskeramische Materialien des Systems BaO-MgO-SiO2 zum Löten der Hochtemperatur-Brennstoffzelle

Aktivlöten von Keramik-Metall-Verbindungen durch mechanisches Beschichten der Keramik mit Titan

Es
wird ein Verfahren zur Desinfektion von Wasser durch elektrochemische
Aktivierung (ECA) vorgeschlagen, indem zumindest einem Teilstrom des
zu desinfizierenden Wassers eine Elektrolytlosung, insbesondere eine Natrium-
oder Kaliumchloridlosung,
zugesetzt und das mit der Elektrolytlosung beaufschlagte Wasser in
einem Elektrolysereaktor mit einem Kathodenraum mit einer Kathode
sowie mit einem von dem Kathodenraum raumlich getrennten Anodenraum
mit einer Anode durch Anlegen einer Gleichspannung an die Elektroden mit
einem elektrischen Strom beaufschlagt wird, um die Wasser-/Elektrolytlosung in
einen zur Desinfektion geeigneten Zustand zu versetzen. Um fur eine zuverlassige und reproduzierbare
Desinfektionswirkung des elektrochemisch eingesetzten Wassers zu
sorgen, welche insbesondere im wesentlichen unabhangig von
dem jeweils eingesetzten Wasser ist, ist erfindungsgemas vorgesehen,
das die
spezifische elektrische bzw. ionische Leitfahigkeit des elektrochemisch
zu aktivierenden Wassers vor Zusetzen der Elektrolytlosung auf
einen Wert von hochstens
350 µS/cm
eingestellt wird. Die Erfindung betrifft ferner ein Verfahren zur
Herstellung eines Desinfektionsmittels in Form einer solchen anodischen,
elektrochemisch aktivierten Wasser-/Elektrolytlosung, das Desinfektionsmittel
selbst sowie dessen Verwendung.

Verfahren zur Herstellung eines Desinfektionsmittels durch elektrochemische Aktivierung (ECA) von Wasser und Verfahren zur Desinfektion von Wasser mittels eines solchen Desinfektionsmittels

Untersuchungen zum Hochtemperaturlöten von Keramik-Metall-Verbindungen

Opposing effects of selectivity and invariance in peripheral vision

Most single units recorded from macaque secondary visual cortex (V2) respond with higher firing rates to synthetic texture images containing “naturalistic” higher-order statistics than to spectrally matched “noise” images lacking these statistics. In contrast, few single units in V1 show this property. Most single units recorded from macaque secondary visual cortex (V2) respond with higher firing rates to synthetic texture images containing “naturalistic” higher-order statistics than to spectrally matched “noise” images lacking these statistics. In contrast, few single units in V1 show this property. We explored how the strength and dynamics of response vary across the different layers of visual cortex by recording multiunit (defined as high-frequency power in the local field potential) and gamma-band activity evoked by brief presentations of naturalistic and noise images in V1 and V2 of anesthetized macaque monkeys of both sexes. As previously reported, recordings in V2 showed consistently stronger responses to naturalistic texture than to spectrally matched noise. In contrast to single-unit recordings, V1 multiunit activity showed a preference for images with naturalistic statistics, and in gamma-band activity this preference was comparable across V1 and V2. Sensitivity to naturalistic image structure was strongest in the supragranular and infragranular layers of V1, but weak in granular layers, suggesting that it might reflect feedback from V2. Response timing was consistent with this idea. Visual responses appeared first in V1, followed by V2. Sensitivity to naturalistic texture emerged first in V2, followed by the supragranular and infragranular layers of V1, and finally in the granular layers of V1. Our results demonstrate laminar differences in the encoding of higher-order statistics of natural texture, and suggest that this sensitivity first arises in V2 and is fed back to modulate activity in V1. SIGNIFICANCE STATEMENT The circuit mechanisms responsible for visual representations of intermediate complexity are largely unknown. We used a well validated set of synthetic texture stimuli to probe the temporal and laminar profile of sensitivity to the higher-order statistical structure of natural images. We found that this sensitivity emerges first and most strongly in V2 but soon after in V1. However, sensitivity in V1 is higher in the laminae (extragranular) and recording modalities (local field potential) most likely affected by V2 connections, suggesting a feedback origin. Our results show how sensitivity to naturalistic image structure emerges across time and circuitry in the early visual cortex.

Laminar Differences in Responses to Naturalistic Texture in Macaque V1 and V2

Ziemba CM, Freeman J, Simoncelli EP, Movshon JA. Contextual modulation of sensitivity to naturalistic image structure in macaque V2. J Neurophysiol 120: 409–420, 2018. First published April 11, 2018; doi:10.1152/jn.00900.2017.—The stimulus selectivity of neurons in V1 is well known, as is the finding that their responses can be affected by visual input to areas outside of the classical receptive field. Less well understood are the ways selectivity is modified as signals propagate to visual areas beyond V1, such as V2. We recently proposed a role for V2 neurons in representing the higher order statistical dependencies found in images of naturally occurring visual texture. V2 neurons, but not V1 neurons, respond more vigorously to “naturalistic” images that contain these dependencies than to “noise” images that lack them. In this work, we examine the dependency of these effects on stimulus size. For most V2 neurons, the preference for naturalistic over noise stimuli was modest when presented in small patches and gradually strengthened with increasing size, suggesting that the mechanisms responsible for this enhanced sensitivity operate over regions of the visual field that are larger than the classical receptive field. Indeed, we found that surround suppression was stronger for noise than for naturalistic stimuli and that the preference for large naturalistic stimuli developed over a delayed time course consistent with lateral or feedback connections. These findings are compatible with a spatially broad facilitatory mechanism that is absent in V1 and suggest that a distinct role for the receptive field surround emerges in V2 along with sensitivity for more complex image structure.

Sensory Processing Contextual modulation of sensitivity to naturalistic image structure in macaque V 2

The stimulus selectivity of neurons in V1 is well known, as is the finding that their responses can be affected by visual input to areas outside of the classical receptive field. Less well understood are the ways selectivity is modified as signals propagate to visual areas beyond V1, such as V2. We recently proposed a role for V2 neurons in representing the higher order statistical dependencies found in images of naturally occurring visual texture. V2 neurons, but not V1 neurons, respond more vigorously to “naturalistic” images that contain these dependencies than to “noise” images that lack them. In this work, we examine the dependency of these effects on stimulus size. For most V2 neurons, the preference for naturalistic over noise stimuli was modest when presented in small patches and gradually strengthened with increasing size, suggesting that the mechanisms responsible for this enhanced sensitivity operate over regions of the visual field that are larger than the classical receptive field. Indeed, we found that surround suppression was stronger for noise than for naturalistic stimuli and that the preference for large naturalistic stimuli developed over a delayed time course consistent with lateral or feedback connections. These findings are compatible with a spatially broad facilitatory mechanism that is absent in V1 and suggest that a distinct role for the receptive field surround emerges in V2 along with sensitivity for more complex image structure. NEW & NOTEWORTHY The responses of neurons in visual cortex are often affected by visual input delivered to regions of the visual field outside of the conventionally defined receptive field, but the significance of such contextual modulations are not well understood outside of area V1. We studied the importance of regions beyond the receptive field in establishing a novel form of selectivity for the statistical dependencies contained in natural visual textures that first emerges in area V2.

Contextual modulation of sensitivity to naturalistic image structure in macaque V2

Perceptual and neural deficits in processing naturalistic image structure in amblyopia

Significance The brain generates increasingly complex representations of the visual world to recognize objects, to form new memories, and to organize visual behavior. Relatively simple signals in the retina are transformed through a cascade of neural computations into highly complex responses in visual cortical areas deep in the temporal lobe. The representations of visual signals in areas that lie in the middle of this cascade remain poorly understood, yet they are critical to understanding how the cascade operates. Here, we demonstrate changes in the representation of visual information from area V1 to V2, and show how these changes extract and represent information about the local statistical features of visual images. As information propagates along the ventral visual hierarchy, neuronal responses become both more specific for particular image features and more tolerant of image transformations that preserve those features. Here, we present evidence that neurons in area V2 are selective for local statistics that occur in natural visual textures, and tolerant of manipulations that preserve these statistics. Texture stimuli were generated by sampling from a statistical model, with parameters chosen to match the parameters of a set of visually distinct natural texture images. Stimuli generated with the same statistics are perceptually similar to each other despite differences, arising from the sampling process, in the precise spatial location of features. We assessed the accuracy with which these textures could be classified based on the responses of V1 and V2 neurons recorded individually in anesthetized macaque monkeys. We also assessed the accuracy with which particular samples could be identified, relative to other statistically matched samples. For populations of up to 100 cells, V1 neurons supported better performance in the sample identification task, whereas V2 neurons exhibited better performance in texture classification. Relative to V1, the responses of V2 show greater selectivity and tolerance for the representation of texture statistics.

Many have proposed that peripheral vision operates by computing statistical summaries over local portions of the visual field, and that the loss of information associated with this process underlies the phenomenon of "crowding" (Parkes et. al. 2001; Pelli et. al. 2004; Greenwood et. al. 2009; Balas et. al. 2009; Freeman and Simoncelli, 2011). Here, we demonstrate another consequence of this hypothesis: that such statistical representation can either help or hinder visual discrimination performance depending on the observer's task. We created synthetic texture stimuli by matching a set of higher-order statistics measured from digitized photographs (Portilla and Simoncelli, 2001). The parameters include both the marginal statistics and pairwise correlations of the responses of V1-like filters selective for different spatial frequencies, orientations, and spatial positions. Observers were asked to discriminate stimuli presented simultaneously at three degrees eccentricity windowed within circular apertures. When stimuli differed in their statistics, performance increased with increasing patch diameter. This is expected since the parameters of the model converge to different values as the patch size increases. Interestingly, when observers discriminated between different samples matched for the same parameter settings, performance decreased with patch diameter. As the statistics converge to their matching values with increasing patch diameter, subjects were no longer able to utilize the local cues that enable high performance at small patch sizes. These opposing behaviors are analogous to those found for discrimination of auditory textures as a function of temporal window duration (McDermott et al., 2013), and suggest a general processing strategy for sensory systems. Meeting abstract presented at VSS 2015.

Opposing effects of summary statistics on peripheral discrimination.

Despite decades of study, we do not understand the fundamental processes by which our brain encodes and represents incoming visual information and uses it to guide perception and action. A wealth of evidence suggests that visual recognition is mediated by a series of areas in primate cortex known as the ventral stream, including V1 (primary visual cortex), V2, and V4 (Fig. 1A) (1). The earliest stages are to some extent understood; Hubel and Wiesel famously discovered, for example, that neurons in V1 respond selectively to the orientation and direction of a moving edge (2). However, a vast gulf remains between coding for a simple edge and representing the full richness of our visual world. David Hubel himself observed in 2012 that we still “have almost no examples of neural structures in which we know the difference between the information coming in and what is going out—what the structure is for. We have some idea of the answer for the retina, the lateral geniculate body, and the primary visual cortex, but that’s about it” (3). In PNAS, Okazawa et al. (4) make significant headway in this quest by uncovering and characterizing a unique form of neural selectivity in area V4.

Population representation of visual information in areas V1 and V2 of amblyopic macaques

Modulator relative spatial frequency M od ul at ed re sp on se (i ps ) Human observers are sensitive to "2nd-order" features, e.g., a horizontal edge defined by the change in contrast of a "1st-order" luminance pattern. One common psychophysical model of 2nd-order sensitivity comprises two stages: the 1st stage operates on the retinal image and responds to luminance variations; the 2nd stage operates on the output of the 1st, and responds in a spatial frequency (SF)and orientation-tuned way to contrast variations (Landy & Graham, 2004). This model can also serve as a physiological model of single-unit responses in primate V1/V2. There, a unit responds to contrast appearing within its classical receptive field (RF), and this response may be suppressed when contrast appears at certain sites in the surrounding extraclassical RF, imparting 2nd-order SF and orientation tuning (Tanaka & Ohzawa, 2009). Amblyopes show 2nd-order sensitivity deficits which cannot be explained as a simple consequence of reduced 1st-order sensitivity (Wong et al., 2001). We therefore wondered whether surround suppression of cortical responses in amblyopic macaques would be weaker than in normals. Introduction

Neural correlates of amblyopia in foveal and parafoveal visual cortex of amblyopic macaque monkeys

Amblyopia is a visual disorder associated with a disruption of conjugate binocular vision early in life, resulting in decreased visual performance in one eye. Previous studies have explored the neurophysiological basis of this disorder using single-unit recordings, but the results incompletely explain the perceptual deficits. New advances in recording techniques now allow us to simultaneously sample multiple sites over large areas of visual cortex. Introduction

Receptive field properties of V1 and V2 neurons in amblyopic macaque monkeys revealed with local spectral reverse correlation

Carving up the ventral stream with controlled naturalistic stimuli

A functional and perceptual signature of the second visual area in primates

It seems immediately obvious that the apple in my hand is the same apple I just picked up from the table. How can my brain recognize an object despite substantial variation in its location, size, and context? In a series of cortical areas known as the ventral stream, the brain performs sophisticated

Background: Many patients undergo two head computed tomography (CT) scans after mild traumatic brain injury (TBI). Radiographic progression without clinical deterioration does not usually alter management. Evidence-based guidelines offer potential for limited repeat imaging and safe discharge. This study characterizes patients who had two head CTs in the Emergency Department (ED), determines the change between initial and repeat CTs, and describes timing of repeat scans. Methods: This retrospective series includes all patients with head CTs during the same ED visit at an urban trauma center between May 1st, 2016 and April 30th, 2018. Radiographic interpretation was coded as positive, negative, or equivocal. Results: Of 241 subjects, the number of positive, negative, and equivocal initial CT results were 154, 50, and 37, respectively. On repeat CT, 190 (78.8%) interpretations were congruent with the original scan. Out of the 21.2% of repeat scans that diverged from the original read, 14 (5.8%) showed positive to negative conversion, 1 (.4%) showed positive to equivocal conversion, 2 (.88%) showed negative to positive conversion, 20 (8.3%) showed equivocal to negative conversion, and 14 (5.8%) showed equivocal to positive conversion. Average time between scans was 4.4 hours, and median length of stay was 10.2 hours. Conclusions: In this retrospective review, most repeat CT scans had no new findings. A small percentage converted to positive, rarely altering clinical management. This study demonstrates the need for continued prospective research to update clinical guidelines that could reduce admission and serial CT scanning for mild TBI.

Short Observation Period and Aggressive Discharge of Patients With Head Injury and Serial CT Scans

Neuroscientists apply a range of common analysis tools to recorded neural activity in order to glean insights into how neural circuits implement computations. Despite the fact that these tools shape the progress of the field as a whole, we have little empirical evidence that they are effective at quickly identifying the phenomena of interest. Here I argue that these tools should be explicitly tested and that artificial neural networks (ANNs) are an appropriate testing grounds for them. The recent resurgence of the use of ANNs as models of everything from perception to memory to motor control stems from a rough similarity between artificial and biological neural networks and the ability to train these networks to perform complex high-dimensional tasks. These properties, combined with the ability to perfectly observe and manipulate these systems, makes them well-suited for vetting the tools of systems and cognitive neuroscience. I provide here both a roadmap for performing this testing and a list of tools that are suitable to be tested on ANNs. Using ANNs to reflect on the extent to which these tools provide a productive understanding of neural systems—and on exactly what understanding should mean here—has the potential to expedite progress in the study of the brain.

Testing the Tools of Systems Neuroscience on Artificial Neural Networks

Biological neural networks adapt and learn in diverse behavioral contexts. Artificial neural networks (ANNs) have exploited biological properties to solve complex problems. However, despite their effectiveness for specific tasks, ANNs are yet to realize the flexibility and adaptability of biological cognition. This review highlights recent advances in computational and experimental research to advance our understanding of biological and artificial intelligence. In particular, we discuss critical mechanisms from the cellular, systems, and cognitive neuroscience fields that have contributed to refining the architecture and training algorithms of ANNs. Additionally, we discuss how recent work used ANNs to understand complex neuronal correlates of cognition and to process high throughput behavioral data.

Recent Advances at the Interface of Neuroscience and Artificial Neural Networks

Behavioral studies suggest that recurrence in the visual system is important for processing degraded stimuli. There are two broad anatomical forms this recurrence can take, lateral or feedback, each with different assumed functions. Here we add four different kinds of recurrence—two of each anatomical form—to a feedforward convolutional neural network and find all forms capable of increasing the ability of the network to classify noisy digit images. Specifically, we take inspiration from findings in biology by adding predictive feedback and lateral surround suppression. To compare these forms of recurrence to anatomically-matched counterparts we also train feedback and lateral connections directly to classify degraded images. Counter-intuitively, we find that the anatomy of the recurrence is not related to its function: both forms of task-trained recurrence change neural activity and behavior similarly to each other and differently from their bio-inspired anatomical counterparts. By using several analysis tools frequently applied to neural data, we identified the distinct strategies used by the predictive versus task-trained networks. Specifically, predictive feedback de-noises the representation of noisy images at the first layer of the network and decreases its dimensionality, leading to an expected increase in classification performance. Surprisingly, in the task-trained networks, representations are not de-noised over time at the first layer (in fact, they become ‘noiser’ and dimensionality increases) yet these dynamics do lead to de-noising at later layers. The analyses used here can be applied to real neural recordings to identify the strategies at play in the brain. Our analysis of an fMRI dataset weakly supports the predictive feedback model but points to a need for higher-resolution cross-regional data to understand recurrent visual processing..

Bio-inspired neural networks implement different recurrent visual processing strategies than task-trained ones do

Corrigendum: Attention in Psychology, Neuroscience, and Machine Learning

 Inspired by the brain, artificial neural networks are core to modern artificial intelligence. Grace Lindsay, author of Models of the Mind, explains concerns over the cognitive limits of these systems.

Deep learning is an approach to artificial intelligence (AI) centered on the training of deep artificial neural networks to perform complex tasks. Since the early 21st century, this approach has led to record-breaking advances in AI, allowing computers to solve complex board games, video games, natural language-processing tasks, and vision problems. Neuroscientists and psychologists have also utilized these networks as models of biological information processing to understand language, motor control, cognition, audition, and—most commonly—vision. Specifically, early feedforward network architectures were inspired by visual neuroscience and are used to model neural activity and human behavior. They also provide useful representations of the perceptual space of images. The extent to which these models match data, however, depends on the methods used to characterize and compare them. The limitations of these feedforward neural networks to account for, for example, simple visual reasoning tasks, suggests that feedback mechanisms may be necessary to solve visual recognition tasks beyond image categorization.

Artificial neural systems trained using reinforcement, supervised, and unsupervised learning all acquire internal representations of high dimensional input. To what extent these representations depend on the different learning objectives is largely unknown. Here we compare the representations learned by eight different convolutional neural networks, each with identical ResNet architectures and trained on the same family of egocentric images, but embedded within different learning systems. Specifically, the representations are trained to guide action in a compound reinforcement learning task; to predict one or a combination of three task-related targets with supervision; or using one of three different unsupervised objectives. Using representational similarity analysis, we find that the network trained with reinforcement learning differs most from the other networks. Through further analysis using metrics inspired by the neuroscience literature, we find that the model trained with reinforcement learning has a sparse and high-dimensional representation wherein individual images are represented with very different patterns of neural activity. Further analysis suggests these representations may arise in order to guide long-term behavior and goal-seeking in the RL agent. Our results provide insights into how the properties of neural representations are influenced by objective functions and can inform transfer learning approaches. ∗gracewlindsay@gmail.com †work done while employed by DeepMind 1 ar X iv :2 11 2. 02 02 7v 1 [ qbi o. N C ] 3 D ec 2 02 1

Divergent representations of ethological visual inputs emerge from supervised, unsupervised, and reinforcement learning

Abstract Convolutional neural networks (CNNs) were inspired by early findings in the study of biological vision. They have since become successful tools in computer vision and state-of-the-art models of both neural activity and behavior on visual tasks. This review highlights what, in the context of CNNs, it means to be a good model in computational neuroscience and the various ways models can provide insight. Specifically, it covers the origins of CNNs and the methods by which we validate them as models of biological vision. It then goes on to elaborate on what we can learn about biological vision by understanding and experimenting on CNNs and discusses emerging opportunities for the use of CNNs in vision research beyond basic object recognition.

Convolutional Neural Networks as a Model of the Visual System: Past, Present, and Future

Attention is the important ability to flexibly control limited computational resources. It has been studied in conjunction with many other topics in neuroscience and psychology including awareness, vigilance, saliency, executive control, and learning. It has also recently been applied in several domains in machine learning. The relationship between the study of biological attention and its use as a tool to enhance artificial neural networks is not always clear. This review starts by providing an overview of how attention is conceptualized in the neuroscience and psychology literature. It then covers several use cases of attention in machine learning, indicating their biological counterparts where they exist. Finally, the ways in which artificial attention can be further inspired by biology for the production of complex and integrative systems is explored.

One of the most fundamental organizational principles of the brain is the separation of excitatory (E) and inhibitory (I) neurons. In addition to their opposing effects on post-synaptic neurons, E and I cells tend to differ in their selectivity and connectivity. Although many such differences have been characterized experimentally, it is not clear why they exist in the first place. We studied this question in an artificial neural network equipped with multiple E and I cell types. We found that a deep convolutional recurrent network trained to perform an object classification task was able to capture salient distinctions between E and I neurons. We explored the necessary conditions for the network to develop distinct selectivity and connectivity across cell types. We found that neurons that project to higher-order areas will have greater stimulus selectivity, regardless of whether they are excitatory or not. Sparser connectivity is required for higher selectivity, but only when the recurrent connections are excitatory. These findings demonstrate that the differences observed across E and I neurons are not independent, and can be explained using a smaller number of factors.

Understanding the functional and structural differences across excitatory and inhibitory neurons

Selective visual attention modulates neural activity in the visual system in complex ways and leads to enhanced performance on difficult visual tasks. Here, we show that a simple circuit model, the stabilized supralinear network, gives a unified account of a wide variety of effects of attention on neural responses. We replicate results from studies of both feature and spatial attention, addressing findings in a variety of experimental paradigms on changes both in firing rates and in correlated neural variability. Finally, we expand this circuit model into an architecture that can perform visual tasks—a convolutional neural network—in order to show that these neural effects can enhance detection performance. This work provides the first unified mechanistic account of the effects of attention on neural and behavioral responses.

A unified circuit model of attention: Neural and behavioral effects

Many details are known about microcircuitry in visual cortices. For example, neurons have supralinear activation functions, they’re either excitatory (E) or inhibitory (I), connection strengths fall off with distance, and the output cells of an area are excitatory. This circuitry is important as it’s believed to support core functions such as normalization and surround suppression. Yet, multi-area models of the visual processing stream don’t usually include these details. Here, we introduce known-features of recurrent processing into the architecture of a convolutional neural network and observe how connectivity and activity change as a result. We find that certain E-I differences found in data emerge in the models, though the details depend on which architectural elements are included. We also compare the representations learned by these models to data, and perform analyses on the learned weight structures to assess the nature of the neural interactions.

Do Biologically-Realistic Recurrent Architectures Produce Biologically-Realistic Models?

Abstract Selective visual attention modulates neural activity in the visual system and leads to enhanced performance on difficult visual tasks. Here, we use an existing circuit model of visual cortex, known as the stabilized supralinear network, to demonstrate that many neural correlates of attention can arise from simple circuit mechanisms. Using different variants of the model we replicate results from studies of both feature and spatial attention. In addition to firing rate changes, we also replicate findings regarding how attention impacts trial-to-trial variability. Finally, we expand this circuit model into an architecture that can perform visual tasks in order to show that these neural effects can enhance detection performance. This work advances our understanding of the physical underpinnings of attention.

A simple circuit model of visual cortex explains neural and behavioral aspects of attention

Modeling the impact of internal state on sensory processing Grace Wilhelmina Lindsay Perception is the result of more than just the unbiased processing of sensory stimuli. At each moment in time, sensory inputs enter a circuit already impacted by signals of arousal, attention, and memory. This thesis aims to understand the impact of such internal states on the processing of sensory stimuli. To do so, computational models meant to replicate known biological circuitry and activity were built and analyzed. Part one aims to replicate the neural activity changes observed in auditory cortex when an animal is passively versus actively listening. In part two, the impact of selective visual attention on performance is probed in two models: a large-scale abstract model of the visual system and a smaller, more biologically-realistic one. Finally in part three, a simplified model of Hebbian learning is used to explore how task context comes to impact prefrontal cortical activity. While the models used in this thesis range in scale and represent diverse brain areas, they are all designed to capture the physical processes by which internal brain states come to impact sensory processing.

Author response: How biological attention mechanisms improve task performance in a large-scale visual system model

How does attentional modulation of neural activity enhance performance? Here we use a deep convolutional neural network as a large-scale model of the visual system to address this question. We model the feature similarity gain model of attention, in which attentional modulation is applied according to neural stimulus tuning. Using a variety of visual tasks, we show that neural modulations of the kind and magnitude observed experimentally lead to performance changes of the kind and magnitude observed experimentally. We find that, at earlier layers, attention applied according to tuning does not successfully propagate through the network, and has a weaker impact on performance than attention applied according to values computed for optimally modulating higher areas. This raises the question of whether biological attention might be applied at least in part to optimize function rather than strictly according to tuning. We suggest a simple experiment to distinguish these alternatives.

How biological attention mechanisms improve task performance in a large-scale visual system model

Complex cognitive behaviors, such as context-switching and rule-following, are thought to be supported by the prefrontal cortex (PFC). Neural activity in the PFC must thus be specialized to specific tasks while retaining flexibility. Nonlinear “mixed” selectivity is an important neurophysiological trait for enabling complex and context-dependent behaviors. Here we investigate (1) the extent to which the PFC exhibits computationally relevant properties, such as mixed selectivity, and (2) how such properties could arise via circuit mechanisms. We show that PFC cells recorded from male and female rhesus macaques during a complex task show a moderate level of specialization and structure that is not replicated by a model wherein cells receive random feedforward inputs. While random connectivity can be effective at generating mixed selectivity, the data show significantly more mixed selectivity than predicted by a model with otherwise matched parameters. A simple Hebbian learning rule applied to the random connectivity, however, increases mixed selectivity and enables the model to match the data more accurately. To explain how learning achieves this, we provide analysis along with a clear geometric interpretation of the impact of learning on selectivity. After learning, the model also matches the data on measures of noise, response density, clustering, and the distribution of selectivities. Of two styles of Hebbian learning tested, the simpler and more biologically plausible option better matches the data. These modeling results provide clues about how neural properties important for cognition can arise in a circuit and make clear experimental predictions regarding how various measures of selectivity would evolve during animal training. SIGNIFICANCE STATEMENT The prefrontal cortex is a brain region believed to support the ability of animals to engage in complex behavior. How neurons in this area respond to stimuli—and in particular, to combinations of stimuli (“mixed selectivity”)—is a topic of interest. Even though models with random feedforward connectivity are capable of creating computationally relevant mixed selectivity, such a model does not match the levels of mixed selectivity seen in the data analyzed in this study. Adding simple Hebbian learning to the model increases mixed selectivity to the correct level and makes the model match the data on several other relevant measures. This study thus offers predictions on how mixed selectivity and other properties evolve with training.

Hebbian Learning in a Random Network Captures Selectivity Properties of the Prefrontal Cortex

Covert visual attention has been shown repeatedly to enhance performance on tasks involving the features and spatial locations to which it is deployed. Many neural correlates of covert attention have been found, but given the complexity of the visual system, connecting these neural effects to performance changes is challenging. Here, we use a deep convolutional neural network as a large-scale model of the visual system to test the effects of applying attention-like neural changes. Particularly, we explore variants of the feature similarity gain model (FSGM) of attention---which relates a cell9s tuning to its attentional modulation. We show that neural modulation of the type and magnitude observed experimentally can lead to performance changes of the type and magnitude observed experimentally. Furthermore, performance enhancements from attention occur for a diversity of tasks: high level object category detection and classification, low level orientation detection, and cross-modal color classification of an attended orientation. Utilizing the full observability of the model we also determine how activity should change to best enhance performance and how activity changes propagate through the network. Through this we find that, for attention applied at certain layers, modulating activity according to tuning performs as well as attentional modulations determined by backpropagation. At other layers, attention applied according to tuning does not successfully propagate through the network, and has a weaker impact on performance than attention determined by backpropagation. This thus highlights a potential discrepancy between neural tuning and function.

Understanding Biological Visual Attention Using Convolutional Neural Networks

Complex cognitive behaviors, such as context-switching and rule-following, are thought to be supported by prefrontal cortex (PFC). Neural activity in PFC must thus be specialized to specific tasks while retaining flexibility. Nonlinear ‘mixed’ selectivity is an important neurophysiological trait for enabling complex and context-dependent behaviors. Here we investigate (1) the extent to which PFC exhibits computationally relevant properties such as mixed selectivity and (2) how such properties could arise via circuit mechanisms. We show that PFC cells recorded from male and female rhesus macaques during a complex task show a moderate level of specialization and structure that is not replicated by a model wherein cells receive random feedforward inputs. While random connectivity can be effective at generating mixed selectivity, the data shows significantly more mixed selectivity than predicted by a model with otherwise matched parameters. A simple Hebbian learning rule applied to the random connectivity, however, increases mixed selectivity and allows the model to match the data more accurately. To explain how learning achieves this, we provide analysis along with a clear geometric interpretation of the impact of learning on selectivity. After learning, the model also matches the data on measures of noise, response density, clustering, and the distribution of selectivities. Of two styles of Hebbian learning tested, the simpler and more biologically plausible option better matches the data. These modeling results give intuition about how neural properties important for cognition can arise in a circuit and make clear experimental predictions regarding how various measures of selectivity would evolve during animal training. Significance Statement Prefrontal cortex (PFC) is a brain region believed to support the ability of animals to engage in complex behavior. How neurons in this area respond to stimuli—and in particular, to combinations of stimuli (”mixed selectivity”)—is a topic of interest. Despite the fact that models with random feedforward connectivity are capable of creating computationally-relevant mixed selectivity, such a model does not match the levels of mixed selectivity seen in the data analyzed in this study. Adding simple Hebbian learning to the model increases mixed selectivity to the correct level and makes the model match the data on several other relevant measures. This study thus offers predictions on how mixed selectivity and other properties evolve with training.

Hebbian Learning in a Random Network Captures Selectivity Properties of Prefrontal Cortex

Parallel processing by cortical inhibition enables context-dependent behavior

Convolutional neural networks (CNNs) have proven effective for image processing tasks, such as object recognition and classification. Recently, CNNs have been enhanced with concepts of attention, similar to those found in biology. Much of this work on attention has focused on effective serial spatial processing. In this paper, I introduce a simple procedure for applying feature-based attention (FBA) to CNNs and compare multiple implementation options. FBA is a top-down signal applied globally to an input image which aides in detecting chosen objects in cluttered or noisy settings. The concept of FBA and the implementation details tested here were derived from what is known (and debated) about biological object- and feature-based attention. The implementations of FBA described here increase performance on challenging object detection tasks using a procedure that is simple, fast, and does not require additional iterative training. Furthermore, the comparisons performed here suggest that a proposed model of biological FBA (the "feature similarity gain model") is effective in increasing performance.

Hebbian-inspired rewiring of a random network replicates pattern of selectivity seen in PFC

Social Impact Games are created to address varied societal challenges. Future innovations in social impact game design are likely to come through the researchers and practitioners that not only make such games, but shape the way we design, develop, employ, and apply social impact games. This opinion piece emphasizes the idea that reactive research chases the future, but innovative research shapes it. It outlines threats to the practice, including antisocial impact games (contrasted with prosocial design), technological durability, and shifts in ludo literacy. It concludes with opportunities, based on historical contexts, to develop ethical standards for social impact game design, increase inclusivity and improved efficacy. From this perspective, the past indicates a future where the work of social impact matures out of research experiment toward everyday experiences among the milieux of interactive media.

Social Impact Games, a Probable Future Illuminated by Looking Back

Examining Misinformation and Disinformation Games Through Inoculation Theory and Transportation Theory

Discovery, Distribution, and Democracy: Key Considerations in the Next Generation of Research on AI and News

This chapter examines persuasive games through the dominant arguments
 made about the value of such designed play. Beyond the who,
 what, and where, there is the why. Why do researchers and practitioners
 want to persuade people through games? Why are games the right—or
 potentially wrong—medium for delivering persuasive messages? Why
 has public discourse come to need games as a vehicle for communicating
 and argumentation? Why has the design of such play grown into an
 increasingly media-rich environment that is seemingly adrift, unable to
 decant the real from its opposite?

This talk outlines the propensities of play to improve human computer interaction. Drawing from his experience addressing complex problems in journalism, misinformation, education, and more the talk outlines the theories that underpin applying play as interface. The idea is not merely the application of games to increase engagement or retention, but instead the integration of playful characteristics to improve problem solving and understanding of computing systems. Much like applying graphical user interfaces of old, playful interactions offer the opportunity to exploit innate characteristics of human interaction and accessibility with the scale and computation prowess of computing. Using play as interface can offer a next-gen solution to HCI problems. This means combining heuristics from game design but augmenting them with real world complexity and application. The talk combines case studies with suggestions for application in a wide variety of HCI challenges. It also champions the universal accessibility of the state of play, recognizing its cross-cultural value, pervasiveness and innate human utility.

Extended Abstracts of the 2021 Annual Symposium on Computer-Human Interaction in Play

Effective interpersonal and cross-cultural communication relies on pragmatics – knowing what to say to whom, and under what circumstances. Nevertheless, pragmatics is generally absent from formal second language instruction. The current effort describes a game designed to assess people's pragmatic ability. In the game, Awkward Annie, players are asked to intentionally select the most inappropriate things to say within conversations (i.e., be inappropriate and see what happens). Thus, players are able to escape from reality by being inappropriate. This work presents a between-subjects study designed to evaluate this twist using two versions of the game (selecting inappropriate versus appropriate responses). Participants in both conditions experienced the same content, but were provided with different goals (be inappropriate, be appropriate). The results indicate that users enjoyed both versions of game equally but performed better within the appropriate version of the game.

Proceedings of the 15th International Conference on the Foundations of Digital Games

While much research has been done on games as engaging strategies for assessment and education, little has been done to address the specific human computer interaction questions relating to the impact of player engagement in game experiences. This case study examines a section (284 adults) of a larger study on play preference of over 700 participants who were given four versions of an assessment game. While the content remained the same, the versions varied by their structure (rewarding players for acting either appropriately or inappropriately) and by play perspective aesthetics (direct or indirect character embodiment). The results indicate that player preference was for the aesthetics of indirect embodiment and the goals of negative behavior. While this is perhaps unsurprising to makers of commercial games, this is contrary to typical education assessment game design. The case study also demonstrates a difference in player character embodiment that should prove useful to those determining the perspective of their player environments.

Extended Abstracts of the 2020 CHI Conference on Human Factors in Computing Systems

The Effect of Positive and Negative Goal Orientation and Player Embodiment in Assessment Games

This research reports on heuristics in the design and implementation of games as polling systems. Adapting previous research in human computation games, this paper examines the opportunity to collect player opinion through game mechanics. The goal is to make more engaging experiences and exploit poll-taker as player instinct response. This case study describes the design, development and data collected through three playable polls focused on news sources and media literacy. This is a pilot analysis, outlining the propensities and limitations of using games as polling systems and reporting on the findings from a limited release involving 287 play sessions.

Pilot Case Study in Games as Polling Systems, Generating Knowledge about Fake News

This case study describes a game designed to serve as new literacy education tool, playful polling system for research audience perceptions. The game underwent two primary designer iterations. As a result of design changes and renewed political chatter about fake news, the game's second iteration gathered more than 500,000 plays. The data collected reveals useful patterns in understanding news literacy and the perception of play experiences. This data of more than 45,000 players, indicates that the older the person the better they are at identifying fake news, until the approximate age of 70. It also indicates that higher education correlates to better performance at identifying real news from fake, although the time it takes to do so varies. This case study demonstrates the potential for such game designs to collect data useful to non-game contexts.

Extended Abstracts of the 2019 CHI Conference on Human Factors in Computing Systems

Factitious: Large Scale Computer Game to Fight Fake News and Improve News Literacy

This paper collects a series of heuristics in game level design to articulate the relationship between designed experience, perceived experience, and the mechanics of play. This work aims simply to illuminate core concepts as a guide for framing the relationship between designer/author and player/participant. It is offered simply as a philosophical lens for perceiving and designing the dynamic between created works and their perception by players. It does so by offering the concept of nested narratives recursively experienced between the played narrative and the designed narrative. It is an adaptation of Derrida’s Hauntology, applied to the context of narratives in game design, at the scale and pace of 21st century game design. In short, games are always haunted by the ghosts of the author’s designed narrative, it’s manifestation in player’s actions, and the player’s self-authored explanation of their experience. This view can be used to design experiential, multi-narrative focused games and plays on the notion of games as penumbra. They are the penumbra which lay like ghosts in each new design.

10 Abstract—The current work describes efforts related to the evaluation of a game-based assessment called “Awkward Annie” which targets English language pragmatics by having players intentionally select the most awkward responses. Results are explored from 328 native English speaking adults collected through Amazon Mechanical Turk. This article explores a conceptual model of potential relations between individual differences, user experience, game performance, and English pragmatic skills. Specifically, results suggest that a foundational understanding of how to be inappropriate has significant implications for user experience and game performance, both of which are related to overall English pragmatics skills.

Measuring English Pragmatics Skills through Game-Based Performance

Can games be made at the pace of news? The Newsjam, an event held in Miami, Florida in November of 2017, aimed to investigate whether short, simple games about current topics could be made in less than two days. While the plethora of game jam events does demonstrate that such games can be made, the larger questions was by whom and how? The Newsjam event convened a mixture of media professionals and non-gamers to test the hypothesis that game-making tools have become so simple those who have never made a game previously could make a game in a single weekend. The results indicate that while it possible to make simple digital toys, the highest quality contemporary newsgames were made by teams that had previously existing experience in game making. 19 participants, produced 5 games in just over 36 hours. Their expertise ranged from first time game maker to seasoned independent developers.

Proceedings of the International Conference on Game Jams, Hackathons, and Game Creation Events

The format of conventional assessments (e.g., multiple-choice) can often make it difficult for students to be motivated or engaged, which can also make it difficult for students to perform to the best of their ability. Game-based assessments (GBA) are a new type of assessment that has been designed to address this issue. We conducted an in-depth investigation of four case studies of user experience during a GBA. The GBA was manipulated in order to investigate whether certain game features (length, feedback) impacted the user experience. The case studies revealed unique patterns in user experience for moment-to-moment changes in enjoyment and frustration. These patterns suggest that GBAs could be utilized to create both a more positive test-taking experience and offer the opportunity for students to perform to the best of their ability.

Awkward Annie: Game-Based Assessment of English Pragmatic Skills

Game Jam events are evolving at a rapid rate. The Global Game Jam, Ludum Dare, and the Nordic Game Jam are growing at record breaking rates, additional game jams are being introduced every year. The interest in game jams as an area of scientific study is also increasing. Events like this conference recognize the importance of game jams as an area for research, discourse and learning. We are on the forefront of this emerging research area. We are excited about the future.

Proceedings of the Second International Conference on Game Jams, Hackathons, and Game Creation Events

This paper outlines experiences and lessons learned in organizing a variety of digital art exhibits for small and large scale events. The perspective is provided as a cross-disciplinary set of heuristics, drawing on the decade long experience of the curator-artist and paying particular attention to playable electronic media (e.g. games and toys) as installation works in an art context. Lessons learned from exhibits organized or co-organized by the author in the United States, Europe and Asia are shared. These events were offered with support from the Smithsonian American Art Museum, Leuphana University, the University of Utah, Abertay University and others. Additional observations are provided as an artist who has exhibited at more than 40 events in the last decade. Formally the paper offers an ontology for defining distinguishing between exhibits, festivals and showcases. It is not the intention of the author to create a compendium of exhibition and curation practice. Instead the aim is to provide context and a starting point for the evolving intellectual examination of curatorial practices around digital games. It is hoped that these assertions support the growth of such work by providing a starting point for other practitioners.

Heuristics from Curating and Exhibiting Game Art in the 21st Century

This paper outlines two models for framing affection games as a contribution to the evolution of courtship rituals or as a matriculation through Maslow’s hierarchy of needs. It then frames the design of these games through two distinct lenses. The first is a game verb based framing, focusing on the affectionate actions designed to meet game goals. The second is an interaction dynamic framing, which describes digitally contained affection (affections remaining within the game), digitally facilitated affection (affections facilitated by the game) and digitally communicated affections (affection shared through the game). Continued research into affection games offers a peek into the softer side of digital play and gendered play. Its study unearths an intersection between sociological and psychological tendencies and technology. The work provides an update to previous published work in the domain of affection games by providing new data on affection games and the case study game.

Love, Lust, Courtship and Affection as Evolution in Digital Play

Striking a Balance: User-Experience and Performance in Computerized Game-Based Assessment

Video games are a popular technology adopted by educators to help teach ideas. The benefits are due to pedagogically beneficial characteristics of such games including their ability to adapt to the learner, allow failure, and entertain and engage players. However, designing a video game is a significant effort that takes time and may not even teach the desired learning objective(s). In this work, we provide a framework that can be used by educators to help determine if the effort needed to create a video game is worth it for a given learning objective(s). Our framework blends four pedagogical ideas so that educators can consider if their game is worth the design effort; these pedagogical tools/theories include: (1) Bloom's taxonomy; (2) the Substitution Augmentation Modification Redefinition (SAMR) Model; (3) Wiggins & McTighe course design approach and filter for learning objectives; (4) what we call, pedagogical logistics. With this framework, we analyze two games we have created, and we determine if the games we created were actually worth the effort. The overall goal is to create a framework and show how it can be used to help other researchers determine if their video game idea is worth creating.

A framework to help analyze if creating a game to teach a learning objective is worth the work

As early as 2001, digital newsgames offered a noteworthy opportunity to engage audiences and provide a new news consumption experience. Nearly 5 years later newsgames have not clearly delivered on their potential. With such promise, why didn‟t news presses give way to newsgame studios? This paper provides a simple case study in newsgame production, providing a set of lessons learned from an academic studio working with a variety of news organizations including one of the largest United States based daily newspapers. It does so to examine the contemporary opportunities and challenges in producing games for news organizations. The paper describes how the increased reliability of low cost, simple game-making software has afforded for the production of just-in-time newsgames. Such opportunity may facilitate a second wave of newsgames as lowered cost of production, increased distribution channels and growing ludic literacy of the general population facilitates their success. However three challenges remain obstacles to their growth: the pace of news; a misunderstanding of the rhetorical properties of games media, and an evolving ludoliteracy shaped by social currency and politics.

A Case Study in Newsgame Creation : Why Game Designers and Journalists are Still Learning to Work Together

This paper is the product of 12 months of intensive study applying game design to the challenges of journalism and news community management. After conducting interviews and site visits with a wide variety of leaders in major print, web, television and news organizations, primary observations were made. The goal was to understand how the increasingly challenged news media industry could benefit from the knowledge that has sustained the success of the game industry. Our findings indicate that the formal practice of game design offers three key foci that may likely prove useful to industries and practices concerned with improving their audience engagement strategies. These three foci are experience, agency and play. We suggest that these three elements are the key to engagement in non-game contexts and are a likely path to improving the struggles facing not only the news industry, but other domains like activism, social impact, and civic participation.

Proceedings of the 20th International Academic Mindtrek Conference

We have created a game called Culture Code that allows researchers and teachers to host online games where teams have asynchronous abilities. Inspired by the game Barnga [11], which is designed to "explore factors related to communication problems in intercultural situations", our game, Culture Code, takes Barnga's basic mechanics and extends them. In Barnga, some players enter a game where they do not know the game rules resulting in a disadvantage compared to others who already know the rules. This mechanic is meant to simulate the disadvantages of someone entering a culture where the rules aren't explained. We extend this idea into out frame-work in which players are divided into teams, and each team's capabilities can be uniquely defined. This framework can be used to create a wide variety of scenarios to facilitate experiments and teaching points related to cultural advantages and disadvantages.

A simple multi-player video game framework for experimenting and teaching cultural understanding

One of the many challenges facing the growth and proliferation of game jam communities is the ambiguity between game jams and allied activities including hackathons and other high intensity events. This research identifies the distinguishing characteristics of games jams and uniquely identifies the technical, cultural and experimental differences that define the game jam practices. The benefit of such understanding not only supports the continued growth of such act activities, it helps to disambiguate game jam activities from other productive practices.

In contrast to the trend toward large scale, immersive games that aspire toward the polish and experience of conventional commercial games, the authors offer a design case study for the potential of microgames and assessment. Microgames are designed to be small, pointed experiences more analogous to a single question than an entire exam. Instead of offering diverse mechanics, microgames are small punctuated play experiences. Microgames are rapidly developed games, targeting a relatively narrow set of skills. It is speculated that microgame based assessments can support contextualized, focused interaction that allows for situated decisions within a relatively short time frame. This paper outlines the design heuristics learned in a collaborative project to develop microgames for assessment between a major testing and assessment organization and their academic partner.

Proceedings of the 12th International Conference on Advances in Computer Entertainment Technology

Designing microgames for assessment: a case study in rapid prototype iteration

The specter of diversity in games continues to haunt the academic literature and evolving industry. The discussion of diversity in games often involves a focus on gender and race. Noticeably absent from the discussion is the mention of religion. Religion, it seems, is a taboo topic in the context of games. This tension comes from a few obvious sources. First, games are often relegated to the space of low value social artifacts, allowing them no opportunity to address serious issues. Second, they are often misidentified as child’s play, making it seemingly inappropriate to involve religion. Both of these perspectives are rich in fallacy. For the first issue, similarly relegated activities such as comics touch on religion frequently. Second, children’s activities often involve religious activities, from Sunday schools to animated programs such as Veggie Tales (Warren, 2005) and the variety of animated religious holiday specials. In short, there does not seem to be a good reason that games and religion have not been discussed more. Unpacking this reality hints at something more substantial. Games, as academic discipline, anthropological artifact, or social convention have been fighting for more than 75 years against one common misunderstanding—that they are the frivolous, dismissible activity of children. This notion is contested by Huizinga (1938/2014), Caillois (2001), and Sutton-Smith (1997/2009). In the many years of games research, this misunderstanding continues. Digital games in particular have wrestled with their understood value and significance in the larger society. The last decade has seen a marked increase in the critical acceptance of games as more than mere pleasure inducing virtual play. They have been understood as 21st century art (Jenkins, 2005), practical problem solver (Von Ahn, 2006), and a psycho-social, evolutionary essential (Brown, 2009). Enter, Playing with Religion in Digital Games. The book begins by highlighting the aforementioned tension. The book admonishes on its first few pages that “video games are not a ghetto of adolescent games” (p. 3). It is echoed in subsequent chapters that “the primary opposition at work is the idea that religion is ‘serious’ whereas games are ‘fun”’ (p. 193) and that “games strike us as pleasant distraction : : : religious activity : : : calls for the utmost seriousness” (p. 25). It is within this tension of seriousness and play that the book asserts the value of understanding religion in games. The authors view the barren landscape of research about religion in games as the product of four perspectives: the dismissal of games as young people’s entertainment, as an undervalued form of expression, as a secular technology, and as unreal. As previously mentioned, fighting the stereotype of games as childish is not new. It is the perpetual chorus of games scholars from every corner of the academic discipline. The notion

Review of: Playing with Religion in Digital Games, by H. Campbell and G. Grieve, eds.

This article examines attempts at game-based courses over the course of several semesters from the spring of 2014 to the spring of 2015 to discover how the fissure between gameful course plans and/or syllabi and the day to day operations of the classroom might be overcome. It examines the creation of teaching goals for gameful courses and how pedagogical methods must be constructed to meet curricular goals while creating a playful classroom atmosphere. Previous investigations argued that syllabi patterned after role playing game reward systems failed to capture student attention due to several factors; confusion about how to use the syllabus, the lack of game mechanics in the classroom experience, and the lack of intrinsic student motivation for exploring topics. This article proposes other, more directly interactive, gameplay structures to add to courses that create gameful learning environments for implementation at a variety of

Bug-fixing Game-like Syllabi: Evaluating Common Issues and Iterating New Pedagogical Mechanics

The continued interest in advertising and entertainment brings about important questions about the effectiveness of advertising when it is competing for attention with entertainment content. This research provides the results of an efficacy analysis of ingame advertising within the controlled environment of a race game, an environment in which advertising blends in naturally. The experiment was designed to understand the effectiveness of in-game advertising for both players and onlookers. It takes into account both the player’s retention and the onlooker’s attention as an inroads to understanding how in-game advertising works on those who participate in electronic entertainment and those who watch it. The results indicate that such advertising is more effective for onlookers than for players.

Persuasive Content: Understanding In-Game Advertising Retention in Players and Onlookers

VerilogTown is a game about cars, crashes and hardware design. The game is designed to help teach and practice the hardware description language, Verilog. The game uses the metaphor of traffic signals to help players understand and practice the code needed to implement combinational and sequential logic in digital circuits. Borrowing from the emerging space of human computation games, player solutions in the games can be directly transferred to embedded system for real world use.

This brief paper provides general context in the emerging mobile game type, affection games. Affection games require players to flirt, hug, or kiss to meet their goals in the game. To date, the largest subset of these games is kissing games. The paper provides a general analysis of the 10 most widely distributed kissing games in 2013 and 2014, which account for more than 3,000,0000 mobile game installations. To add detail to the overview, two case studies are provided which exemplify physical device kissing and virtual in-game kissing. The download activity, player comments, and history of the games are used to provide a simple overview of affection game characteristics as they relate to human-computer interaction and play. Such analysis provides a peek into the mildly taboo space of affection games and the ways in which mobile developers are effecting the genre.

This paper outlines a linguistic approach to understanding the content of games. Understanding game verbs as the fundamental unit of interaction within game environments it provides perspective on popular play experiences. The benefits of such analysis include a scalable view of the self reported content of games and the ways in which problems are being solved in games. The content of games is contrasted with the content of books for comparison. The findings indicate games are relatively limited in the diversity of verbs they use. The results also demonstrate greater emphasis on gender, and life or death in popular books than in popular mobile games. The occurrence of violent language like war and kill occur significantly more often in best-selling book descriptions than in best-selling mobile games. The most common game verbs from this research are use, touch, get, have, take, like, earn, try, create and make. Author

A linguistic analysis of games: Verbs and nouns for content estimation

Big Huggin‘ is an alternative interface game designed to critique the way we play. It is offered as part of the ongoing Critical Gameplay project. Instead of firing toy guns or gesturing abstractly, players must hug a large stuffed animal to win the game. The game has been played by more than 2000 people at 8 venues in North America, South America and Europe.

A Linguistic Analysis of Mobile Games : Verbs and Nouns for Content Estimation

Consider that uncomfortable moment in life when people discover a playful experience ceases to be worth playing. Just as an arm is broken on the playground, or a relationship can no longer be mended, there are explicit moments when art transgresses some unforeseen territory leaving us with fear of its potential. This paper explores the potential of taboo game design.

Discomfort Design: Critical Reflection through Uncomfortable Play

The effects of embedding advertising in digital games has been explored in only a few controlled studies. This research provides results of an efficacy analysis of in-game advertising within the controlled environment of a racing car game, an environment in which advertising blends in naturally. The experiment was designed to understand the effectiveness of in-game advertising for both players and onlookers. Examining players in both Europe and the United States, this study measured how in-game advertising works on those who participate in electronic entertainment and those who watch it. The results indicate that such advertising is more effective for onlookers than for players. Implications for designers and researchers is discussed.

Proceedings of the 11th Conference on Advances in Computer Entertainment Technology

Did you see that?: in-game advertising retention in players and onlookers

This case study outlines a methodology for adapting digital games from literature. The process maps key narrative events to human computer interactions via game verbs. Game verbs are distinct player actions that help the player accomplish their in-game goal. Through the use of tightly coupled narrative events and game verbs, the game engenders the spirit of Edgar Allen Poe's short story The Tell Tale Heart. Like the story's protagonist, players move from controlled actions to erratic behavior as they manipulate their device. Players are required to propel the narrative through accelerometer and touch-based actions. The resulting game's physicality is designed to match the narrative's drive toward madness.

CHI '14 Extended Abstracts on Human Factors in Computing Systems

This brief paper outlines the design and development challenges of a critical design affection game. Affection games require players to flirt, kiss, hug or make love to meet their goals. The game described, named Stolen Kisses, allows players to kiss a wider variety of individuals. The game is played by placing your lips on a mobile device and balancing long kisses with short kisses across one of eight gender and racially diverse characters. Author

Equal opportunity affection games, critical design in Stolen Kisses

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You is a game about play and the illusive pursuit of meaningful play. Each level of the game is about problem solving a space for You to meet objectives while making sense of the in-game content. Using the player character You, the player is both making meaning out of nonsense and finding meaning where it is absent. The game is designed as a light-hearted critical reflection on the intersection of narratology and ludology. Players must play with You, I and Them in the immutable structure of meaning making that forms the challenge of the game.

This paper describes the theory and implementation of a 2-tiered procedural rhetoric game. The game, Black Like Me, employs critical design to encourage players toward situational analysis instead of mere attribute matching. Players are presented with a color matching game at the surface, but the game is designed to reward players for holistically evaluating a scene and subverting the explicitly suggested game rules. The game is designed to train players toward perceiving ambiguity and employing alternative play strategies. Author

Black Like Me? Embedding 2-tiered procedural rhetoric in a critical game

The purpose of this research is to demonstrate how the pattern of play technologies follows the patterns of play types in developmental psychology. This research provides an overview of dominant theories in developmental psychology and offers evidence of its parallel in play modalities adopted by electronic game audiences. The fundamental benefit of such framing is the potential to offer a future facing understanding of the next generation of play technologies within a variety of environments. Here the researchers have chosen to demonstrate this evolution through the history of arcade game play. However, the researchers conclude with a brief demonstration of how similar developmental stages have been demonstrate in the evolution of portable game systems and home console game interfaces. This approach describes game design and player preference not as evolutionary, but as developmental. It demonstrates game design and player preference through a developmental framework, which mirrors the maturation of an individual. Players mature into new play modalities in much the way humans mature into play stages.

The psychology of play: Understanding digital game evolution through developmental psychology

In this paper, we propose a research direction that will allow the harnessing of human computation to be included in mainstream video games. Human computing resources are vastly different and superior in some cases compared to traditional computing machines. Previous findings in this domain showed that humans playing FoldIt, a protein folding video game, created new solutions to the problem that were previously unknown. Successes like these suggest that harnessing human computation through games can provide the world with a new computation resource, but existing games in this domain tend to be built around the problem. This means a large population of game players remains unharnessed. We, however, hypothesize that focusing research efforts on the synergy of understanding isomorphing problems, identifying problem solving behavior in mainstream video games, and an understanding of real-world problems is a direction that will allow us to merge harnessing human computation into these mainstream games.

Research Directions for Pushing Harnessing Human Computation to Mainstream Video Games

Affection games are ludic experiences in which players are required to express culturally recognized expressions of liking as a primary goal in the game. Interestingly, while the physical world of analog play has many such activities, the digital world has been relatively limited in affording players the ability to express affection as the primary game goal. Affection games in digital play exist as somewhat esoteric clusters across a variety of cultures and super genres. This paper defragments the diverse set of affection games, collecting, cataloging and describing the games in detail. The paper provides a content analysis of affection games and an overview of their preponderance on the web. This paper organizes affection games into a simple classification based on their game verbs. These are flirting, hugging, kissing, and sexual affection. The content analysis provides the attributes through which the affection games are clustered. Notable patterns from the content analysis include indications that kissing and sexual affection are most common, while hugging games are the rarest. There is also a strong coupling of targeted gender identification and the types of affection made playable. These patterns are indicated both in the spaces in which they are distributed and in their content. As the game industry and the academic research community look for new ways to understand and engage wider demographics, the lessons learned from studying affection games may prove useful. Affection games reveal cultural values, taboo, and may potentially expand the space of pro-social play.

Affection Games in Digital Play: A Content Analysis of Web Playable Games

Today the world of human computer interaction is an impersonal one. It is one where touch is mediated through glass and plastic. Where multi-touch means antiseptic sleek materials with little texture. Why isn't touch more personal? Why isn't touch more tactile? Big Huggin' is a game played with a 30 inch custom teddy bear controller. Players complete the game by providing several well-timed hugs. It is an experiment and gesture in alternative interface. Instead of firing toy guns at countless enemies or revving the engines of countless gas guzzling virtual cars, why not give a hug? The Big Huggin' game is designed to offer reflection on the way we play and the cultural benefit of alternative play.

CHI '13 Extended Abstracts on Human Factors in Computing Systems

Metaheuristic Entry Points for Harnessing Human Computation in Mainstream Games

Big Huggin' is a game designed for use with a custom teddy bear controller. Players complete the game by providing several well-timed hugs to a 30 inch teddy bear. It is an experiment and gesture in alternative interface and affection gaming. The game is designed around the action of hugging to support an onscreen character. If the players hug too much, their on screen bear will suffer. If they hug too little the player character will never reach its goal. This paper outlines the design, development and evaluation of the game by a wide demographic. The first section provides an outline of the history of affection gaming, providing the theoretical basis for the design of Big Huggin'. The second section describes the development, prototyping and pre-release of the game. The final section outlines the release to a community of pediatric patients and general play audience. The application of this game as a resource to promote pro-social exploration by players is addressed. The goal of this research is not merely to create an alternative play experience. It is envisioned as an opportunity to explore and critique the intersection of play and affection as practiced in digital games. This paper serves as an introduction to the history of such games, a case study and a post-mortem in the design and development of an affection

This paper discusses the critical gameplay design project and its newest evolution. After being exhibited in several international venues in 2009-2011, the project has evolved to employ a more pointed critique of game culture and how people play. The paper describes, Big Huggin', an affection game, Match, a game of procedural racism and Healer, and an unshooter about the Nanjing Massacre. These games continue to explore the notion of values in design.

Proceedings of the 20th ACM international conference on Multimedia

While motion control for gaming has grown in popularity, enjoyment of physical interaction continues to be a mainstay in digital games. Combining the benefits of several popular game interfaces, the researchers outline the design of an alternate game control interface called Swivel Pad. The Swivel Pad is a unique, stand-on interface for game playing. The game controller is designed to offer light exercise activity for young children and adults requiring rehabilitative practice in balance, cognition, and muscle memory KeywordsAlternative game interfaces, exergaming, game controllers, physical gaming

Despite the common tendency to understand computer games as a medium somewhere between film and traditional software, this paper argues for a more appropriate position amongst literature. This writing explores the opportunities in analogizing digital games not as art, but as literature. Within this framing new opportunities reveal themselves for innovative game design and more manageable archiving of games and their relationships. It should prove useful to media theorists, designers, and game librarians seeking a new way to frame the analysis and production of digital games.

Polyglot Cubed is an educational game to facilitate the learning of multiple languages. The game is an implementation of contemporary theories in motivation, education and entertainment. This document provides the results from a formal user evaluation of the game. This evaluation was designed to determine user defined difficulties in game experience and understand user interest in its solution. Preliminary results indicate favorable interest in the game as a tool for learning Mandarin Chinese and minor challenges in gameplay experience.

CHI '12 Extended Abstracts on Human Factors in Computing Systems

Expanding the bounds of digital educational games, this research describes the characteristics of games designed to modify player perspective, understanding, interests, activities or opinions. These persuasive play games include social impact games, games for change, and others games designed to persuade players. In summary the characteristics of 150 such games are reported through three broad categories of development, design and play experience. This summary of results focuses on digital play and proves effective at providing a topographical view of the state of play designed for extrinsic action and understanding. The focus of this research is the design and development characteristics of such games.

This chapter introduces critical gameplay design as a technique for creating digital games that offer alternative play. Critical gameplay provides the opportunity to explore game ethics through the way games are designed to be played. Since game designers outline the rules of play, game designs outline designer’s definitions of what is ethical and important. Taking the notion that, design is reflection of designer values, this chapter outlines methodologies for exposing the intrinsic values in play and creating gameplay models from alternative ethics and values. The chapter concludes with examples of critical gameplay games that have been demonstrated to international audience.

This paper introduces a novel concept in the use of game technology and education. Instead of employing gaming technology to create entertaining fictions or develop practical training environments, this paper introduces the concept and demonstrates the practical benefits of docugames for preservation. A docugame for preservation is a simulation that incorporates historical or culturally relevant artifacts to offer multiple perspectives on an historical or culturally relevant experience. Current trends in the growth of games, lowering production costs, and an increase in global collaborative production models have supported opportunities to employ games as a medium for preservation. As such, docugames for preservation demonstrate the promise of offering a 21st century educational experience for future learners. This research provides an analysis of existing docugames, overview of gamification principles and heuristics for improving the potential of docugames as a preservation medium.

Gamifying archives, a study of docugames as a preservation medium

Polyglot Cubed is an educational game to facilitate listening comprehension skills for a variety of languages. The modular language learning game works interchangeably with a variety of languages. The game relies on a matching mechanic intended to balance comprehension based language recognition with a casual game play mechanic. It is designed to entertain while enforcing language comprehension. The highly modular system was designed at the University of Illinois, Chicago and enhanced at Miami University. It works to aid in the retention of listening vocabulary with minimal training. 
 
The game is designed around 6 rooms of floating, cubicle tiles. Each tile is assigned a foreign language word or sound and a pictographic representation of that word. For teaching language, the cubes are clustered by topic, usage, or form of speech to encourage contextual recognition and aid visual memory. The player must match the spoken word with the cube that corresponds to it. 
 
The game has been demonstrated to a variety of international audiences and has been praised for its potential. It has been awarded at Michigan State University's Meaningful Play Conference (2008), recognized at the National Training Systems Association Serious Game Showcase (2009) and exhibited at the 5th ACM Advances in Computer Entertainment Conference (2009) and DevLearn (2009). 
 
Polyglot Cubed has been implemented for Mandarin Chinese and Portuguese Criolu. Experimental versions have also been created to teach the language of anatomy, music and chemistry (Grace, 2011). The tool offers a basic modification tool designed to aid researchers in the development of their own educational experiments.

Music Box is an artistic implementation of emergent behavior to create music. Music Box employs a flocking algorithm (Reynolds, 1999) to display animated notes that rise from a written score and move to create a flock-lead musical arrangement. The result is emergent sound; a musical composition directed by the visual representation of flocking. The experience is a pseudo-synesthetic application of visual rules to the creation of music. 
 
The philosophical goal of this creative exploration is to experiment with freeing the musical score from the prevalent model of composer, performer and listener. Instead the experience is more democratic. Here, the composer suggests, the performer follows a few loose rules, and the listener plays with the composition. As a performance, it attempts to conflate listener and composer, in much the same way author and player are combined in sandbox game narratives. This is accomplished through the development of artificial intelligence software that applies the visual rules of flocking behaviors to the algorithmic arrangement of musical tones.

How do games affect the way we problem solve, socialize, or even view the world? When we shoot, do we learn to destroy obstacles instead of work around them? Does the binary world of enemies and adversaries teach us to ignore the gray in the everyday? Do games encourage us to ignore consequences and wait for second chances at the same problems? Are we forgetting how to play with each other because playing against each other is more fun? 
 
Critical Gameplay is a collection of "strategically designed" video games. Each game asks what common game mechanics teach us. The games in the collection are designed to help reevaluate our perspective on gameplay experiences. Critical Gameplay seeks to offer alternate perspectives on the way we play.

In game advertising or IGA is an increasingly common means of promoting brands and products. This study seeks to understand the effectiveness of in game advertising by understanding player retention of brand messages. The researchers created a controlled environment and 3D car racing game, embedding in game advertising and measuring player performance and advertising retention. The study produces a highly detailed view of the relationship of brand retention, player ability, and engagement.

The paper explores the recent growth in critical gameplay, an application of critical design to the production of computer games. This paper outlines play pedagogy and game rhetoric, relating critical design practices to the creation of computer games. It attempts to explain the art practice of critical game design, providing a brief digital game history and identifying prominent creative works in this relatively new space.

This paper approaches the question about games as art from a fundamentally different perspective. Instead of asking questions of visual aesthetics and pursuing analogies to film or commercial arts, it demonstrates an even clearer analogy to poetic forms. Allying common practices in independent games in particular, this paper serves as an illustrative demonstration of the poetics of game design, emphasizing the poetic properties of independent game designs. It frames game design in terms of the rhetorical devices used to create an experience. Such framing is useful to independent game designers, developers of persuasive and critical gameplay, and archivists seeking an effective way to catalog digital games that is driven by structure instead of subject or play mechanic.

Polyglot Cubed is a language learning game designed to improve listening comprehension of unfamiliar vocabulary. As a system for the acquisition of Mandarin Chinese vocabulary, the game system has received international kudos. For educators, the application offers much more than previously documented. The game functions as a tool for the acquisition of various types of listened information, including music, other languages and specialized vocabulary. This game is worth the attention of a variety of educators that are interested in inspiring self-lead education among their students and themselves. This paper provides prototypical alternative uses for the Polyglot Cubed game in specific learning objectives.

Polyglot Cubed: a Multidisciplinary Listening Comprehension and Recognition Tool

As emphasis on Science, Technology, Engineering, and Math (STEM) initiatives increase, students are at a fragile point in their education. It is imperative that students learn core skills like computer programming and procedural logic necessary to living in today's increasingly digital society. Our new game Shapemaker solves these problems in game-based learning that incorporates an engaging augmented reality interface. ShapeMaker utilizes a table-based tactile interface that bridges physical actions with digital results, allowing players to learn basic concepts in programming by playing a card game. Shapemaker aims to transform the process of introducing new students to the world of programming and create a new, wider demographic of computer programmers. This article is a preliminary study of Shapemaker, documenting its concept, current design, and directions for development.

This paper serves as a postmortem for the game Third World Shooter. The game was completed as part of the Critical Gameplay project. The project endeavors to analyze common game mechanics and create games that demonstrate alternate ways to play. Third World Shooter was as a docugame employing critical gameplay. This paper illustrates how the design of Third World Shooter dovetails into the more successful designs of other critical gameplay games.

This paper discusses the critical gameplay design project and its newest developments. After being exhibited in five national and international venues in 2009--2010, the project has been reconstituted with 3 new games that critique specific aspects of standard gameplay. This short paper reflects on the experience of the exhibition and the design heuristics gathered from them. The paper discusses the three axes of creating Critical Gameplay Games, content, process and scale. It is provided as a resource for researchers making polemic games, including but not limited to persuasive games, advergames, and critical gameplay. It is also useful to people involved in game jams or other intensive, time restricted game-making activities.

Polyglot Cubed is an educational game to facilitate the learning of multiple languages. It is designed to entertain while enforcing language listening comprehension. The modular language learning game system works interchangeably with a variety of languages. The game relies on a matching mechanic intended to balance comprehension based language recognition with a simple gameplay mechanic. The game is an implementation of theories in motivation, education and entertainment. It takes as its motivation academic critique of existing educational video games and in particular pursues those areas where educational games fall short of the needs of post-secondary learners. This document outlines the research, design, implementation and fundamental evaluation of the educational video game.

Polyglot Cubed : The Design and Implementation of a Multi-Language Learning Game

The computer game software with which we interact on a daily basis not only entertains us, it trains us into specific patterns. Critical Gameplay is a design practice which endeavors to expose and redesign the patterns to which standard gameplay subscribes. The ongoing project seeks to identify the dominant values, philosophies and problem solving models reinforced by computer games and provides prototypical alternates to those standards.

CHI '10 Extended Abstracts on Human Factors in Computing Systems

This research proposes a method for producing music via visual composition in a computer-game like environment. This is accomplished through the development of artificial intelligence software that applies the visual rules of standard emergent behaviors to the algorithmic arrangement of musical tones. This research presents the proposed system, defining the algorithm and demonstrating its implementation.

2010 Third International Conference on Advances in Computer-Human Interactions

Studying the Philosophy of Software: A Framework for Examining How Digital Design Affects the Arts

Polyglot Cubed is an educational game to facilitate the learning of multiple languages. It is designed to entertain while enforcing language listening comprehension. The modular language learning game system works interchangeably with a variety of languages. The game relies on a matching mechanic intended to balance comprehension based language recognition with a simple gameplay mechanic. The game is an implementation of theories in motivation, education and entertainment. It takes as its motivation academic critique of existing educational video games and in particular pursues those areas where educational games fall short of the needs of post-secondary learners. This document outlines the design the comprised the educational video game system.

Proceedings of the International Conference on Advances in Computer Entertainment Technology

Music Box is an artistic implementation of emergent behavior and its use to create music. Music Box employs Craig Reynold's flocking algorithm to display animated notes that rise from a written score, then move to create a distinctive flock-lead musical arrangement. The result is emergent sound; a musical arrangement directed by the visual representation of flocking. The goal of this creative exploration is to free the musical score from the prevalent model of composer, performer and listener supported by standard models. Instead the experience is more democratic. Here the composer suggests, the performer follows a few loose rules, and the listener plays with the composition. This is accomplished through the development of artificial intelligence software that applies the visual rules of flocking behaviors to the algorithmic arrangement of musical pitches. Importantly, these visual rules are manipulated by the software user resulting in a dual performance and composition. The result is musical authoring based on the user model of computer video games.

How do games effect the way we problem solve, socialize, or even view the world? When we shoot do we learn to destroy obstacles instead of work around them? Does the binary world of enemies and adversaries teach us to ignore the gray in the everyday? Are we forgetting how to play with each other because playing against each other is more fun? Critical Gameplay is a collection of "strategically designed" video games. Each game asks what common game mechanics teach us. The four games in the collection are designed to help reevaluate our perspective on gameplay experiences. As Critical Cartography changes the way we perceive the world, Critical Gameplay seeks to offer alternate perspectives on the way we play. Critical Gameplay does not attempt to answer these questions. Instead it seeks to open the dialogue with demonstrative experiments in gameplay. It attempts to fill the space of what if, with something tangible - a game. What if that avatar did have a history before you destroyed it? What if you couldn't read the game world by stereotyping characters? Critical Gameplay is simply about raising questions that encourage critical reflection on gameplay experiences. A Critical Gameplay game is valued in intellectual profit.

This paper seeks to outline a set of fundamental observations about the instructive nature of video games. It stands as a resource when considering the content of games, the design intentions, and the games’ relationship to general society. It is, as asserted in this paper, true that games introduce fundamental approaches to problem solving and conflict resolution. These introductions serve as a kind of prescription which may be translated into philosophical approach. This paper outlines three instruction� related characteristics of video games. These are the games tendency to require learning for efficacy, understanding over recitation, and diagnosis the system. These three observations are then related to two solutions, the use of appropriate win

This paper describes the design, development and user study of a text-to-speech system for reviewing email messages. The system retrieves messages, converts them to audio files, and facilitates transferring the messages to a portable listening device. This study reviews the efficacy of such a system and compares the users' ability to comprehend spoken audio messages verses written messages. According to the study the system was successful, but the user interest in the design was only moderate.

2009 Second International Conferences on Advances in Computer-Human Interactions

gReader: A Universally Designed, Device-Independent Email Client

Enculturation is the act of passing cultural ideologies from one person to the other. It is what breeds innovation instead of new creation. It is the disease of derivation, instead of the birth of creativity. This chapter assumes the practical perspective of critical anthropological distance to understand the culture of art. Such critical evaluation should illuminate the distinct characteristics that encourage patterns. In the tradition of anthropological and sociological study of existing culture, this chapter seeks to illuminate the distinguishing characteristics of contemporary art production and offer perspective on the critical creative process. It takes new media art as its case study because it serves as a cross-cultural intersection of scientific invention and artistic innovation.

Automated Writing Evaluation systems have been developed to help students improve their writing skills through the automated delivery of both summative and formative feedback. These systems have demonstrated strong potential in a variety of educational contexts; however, they remain limited in their personalization and scope. The purpose of the current study was to begin to address this gap by examining whether individual differences could be modeled in a source-based writing context. Undergraduate students (n=106) wrote essays in response to multiple sources and then completed an assessment of their vocabulary knowledge. Natural language processing tools were used to characterize the linguistic properties of the source-based essays at four levels: descriptive, lexical, syntax, and cohesion. Finally, machine learning models were used to predict students’ vocabulary scores from these linguistic features. The models accounted for approximately 29% of the variance in vocabulary scores, suggesting that the linguistic features of source-based essays are reflective of individual differences in vocabulary knowledge. Overall, this work suggests that automated text analyses can help to understand the role of individual differences in the writing process, which may ultimately help to improve personalization in computer-based learning environments.

LAK21: 11th International Learning Analytics and Knowledge Conference

Automatic Student Writing Evaluation: Investigating the Impact of Individual Differences on Source-Based Writing

Background/ Objectives: This article reports on an e-learning readiness study that was carried out to determine the institutional, individual, and communication factors of the two major stakeholder groups (teachers and institutions) in the higher education universities in Saudi Arabia. Methods: A sample of 139 faculty members working in ten higher education universities in Saudi Arabia was surveyed in this cross-sectional study. A pre-validated survey questionnaire of e-learning was adopted to collect data from the participants\' between April and May 2019. Findings: The pre-validated survey tool of Teachers\' Readiness for Online Learning Measure (TROLM) of an 18 item scale has been explored in four factors: Communication self-efficacy, institutional support, self-directed learning, and learning-transfer self-efficacy. The findings of this study are instrumental in implementing successful e-learning resources (strategies) in Higher Education Institutions and will also benefit e-learning initiatives in similar institutions in other regions of Saudi Arabia and beyond. The Study demonstrated the supportive e-learning strategies Blackboard system that facilitated faculty members\' readiness to teach university students during the sudden transition from traditional methods to the e-learning platforms. Keywords: Faculty members\' readiness; higher education institutions; e-learning strategies; e-learning resources; information technology; institutional support

Faculty members' readiness implementing e-learning in higher education Saudi Universities: A cross-sectional study

Undergraduate Nursing Students’ Knowledge and Attitude: Care of Patients Of Mechanical Ventilators

This paper, drawing upon a mobile telecollaborative project, resonates with the rapid development of technology in language learning. We employed the instant messaging app WeChat to create an English telecollaborative environment for two groups of Chinese students to communicate within. Interview data were triangulated with students’ chat transcripts and comments from a teacher’s reflective journal. A mixed-methods approach, including quantitative descriptive analysis, thematic analysis and content analysis, was used to investigate the challenges and the linguistic performance by applying the community of inquiry framework to the students’ chats. The analysis illustrates some of the complexities and challenges of using online apps as a way of communicating in a second language: students expected more teacher support, they struggled to use the app due to their physical environments and they felt that they were not sufficiently well prepared for chatting in an English medium environment. Based on the findings, a conceptual model is proposed for consideration when encouraging students to engage in telecollaborative learning. Implications practice policy:

Challenges in a mobile English telecollaborative project: Towards a conceptual model

Critically ill COVID-19 patients display signs of generalized hyperinflammation. Macrophages trigger inflammation to eliminate pathogens and repair tissue, but this process can also lead to hyperinflammation and resulting exaggerated disease. The role of macrophages in dysregulated inflammation during SARS-CoV-2 infection is poorly understood. We inoculated and treated human macrophage cell line THP-1 with SARS-CoV-2 and purified, glycosylated, soluble SARS-CoV-2 spike protein S1 subunit (S1) to clarify the role of macrophages in pro-inflammatory responses. Soluble S1 upregulated TNF-α and CXCL10 mRNAs, and induced secretion of TNF-α from THP-1 macrophages. While THP-1 macrophages did not support productive SARS-CoV-2 replication or viral entry, virus exposure resulted in upregulation of both TNF-α and CXCL10 genes. Our study shows that extracellular soluble S1 protein is a key viral component inducing pro-inflammatory responses in macrophages, independent of virus replication. Thus, virus- or soluble S1-activated macrophages may become sources of pro-inflammatory mediators contributing to hyperinflammation in COVID-19 patients.

Proinflammatory Responses in SARS-CoV-2 and Soluble Spike Glycoprotein S1 Subunit Activated Human Macrophages

Understanding host-virus interactions is essential for the development of effective interventions against respiratory syncytial virus (RSV), a paramyxovirus that is a leading cause of viral pneumonia in infants. RSV induces autophagy following infection, although the viral factors involved in this mechanism are unknown. ABSTRACT Paramyxoviruses such as respiratory syncytial virus (RSV) are the leading cause of pneumonia in infants, the elderly, and immunocompromised individuals. Understanding host-virus interactions is essential for the development of effective interventions. RSV induces autophagy to modulate the immune response. The viral factors and mechanisms underlying RSV-induced autophagy are unknown. Here, we identify the RSV nonstructural protein NS2 as the virus component mediating RSV-induced autophagy. We show that NS2 interacts and stabilizes the proautophagy mediator Beclin1 by preventing its degradation by the proteasome. NS2 further impairs interferon-stimulated gene 15 (ISG15)-mediated Beclin1 ISGylation and generates a pool of “hypo-ISGylated” active Beclin1 to engage in functional autophagy. Studies with NS2-deficient RSV revealed that NS2 contributes to RSV-mediated autophagy during infection. The present study is the first report to show direct activation of autophagy by a paramyxovirus nonstructural protein. We also report a new viral mechanism for autophagy induction wherein the viral protein NS2 promotes hypo-ISGylation of Beclin1 to ensure availability of active Beclin1 to engage in the autophagy process. IMPORTANCE Understanding host-virus interactions is essential for the development of effective interventions against respiratory syncytial virus (RSV), a paramyxovirus that is a leading cause of viral pneumonia in infants. RSV induces autophagy following infection, although the viral factors involved in this mechanism are unknown. Here, we identify the RSV nonstructural protein 2 (NS2) as the virus component involved in autophagy induction. NS2 promotes autophagy by interaction with and stabilization of the proautophagy mediator Beclin1 and by impairing its ISGylation to overcome autophagy inhibition. To the best of our knowledge, this is the first report of a viral protein regulating the autophagy pathway by modulating ISGylation of autophagy mediators. Our studies highlight a direct role of a paramyxovirus nonstructural protein in activating autophagy by interacting with the autophagy mediator Beclin1. NS2-mediated regulation of the autophagy and ISGylation processes is a novel function of viral nonstructural proteins to control the host response against RSV.

Human Respiratory Syncytial Virus NS2 Protein Induces Autophagy by Modulating Beclin1 Protein Stabilization and ISGylation

Critically ill COVID-19 patients infected with SARS-CoV-2 display signs of generalized hyperinflammation. Macrophages trigger inflammation to eliminate pathogens and repair tissue, but this process can also lead to hyperinflammation and resulting exaggerated disease. The role of macrophages in dysregulated inflammation during SARS-CoV-2 infection is poorly understood. We used SARS-CoV-2 infected and glycosylated soluble SARS-CoV-2 Spike S1 subunit (S1) treated THP-1 human-derived macrophage-like cell line to clarify the role of macrophages in pro-inflammatory responses. Soluble S1 upregulated TNF-α and CXCL10 mRNAs, and induced secretion of TNF-α from THP-1 macrophages. While THP-1 macrophages did not support productive SARS-CoV-2 replication, virus infection resulted in upregulation of both TNF-α and CXCL10 genes. Our study shows that S1 is a key viral component inducing inflammatory response in macrophages, independently of virus replication. Thus, virus-infected or soluble S1-activated macrophages may become sources of pro-inflammatory mediators contributing to hyperinflammation in COVID-19 patients.

Proinflammatory responses in SARS-CoV-2 infected and soluble spike glycoprotein S1 subunit activated human macrophages

Concanavalin A (Con A)–induced injury is an established natural killer T (NKT) cell–mediated model of inflammation that has been used in studies of immune liver disease. Extracellular nucleotides, such as adenosine triphosphate, are released by Con A–stimulated cells and bind to specific purinergic type 2 receptors to modulate immune activation responses. Levels of extracellular nucleotides are in turn closely regulated by ectonucleotidases, such as CD39/NTPDase1. Effects of extracellular nucleotides and CD39 on NKT cell activation and upon hepatic inflammation have been largely unexplored to date. Here, we show that NKT cells express both CD39 and CD73/ecto‐5′‐nucleotidase and can therefore generate adenosine from extracellular nucleotides, whereas natural killer cells do not express CD73. In vivo, mice null for CD39 are protected from Con A–induced liver injury and show substantively lower serum levels of interleukin‐4 and interferon‐γ when compared with matched wild‐type mice. Numbers of hepatic NKT cells are significantly decreased in CD39 null mice after Con A administration. Hepatic NKT cells express most P2X and P2Y receptors; exceptions include P2X3 and P2Y11. Heightened levels of apoptosis of CD39 null NKT cells in vivo and in vitro appear to be driven by unimpeded activation of the P2X7 receptor. Conclusion: CD39 and CD73 are novel phenotypic markers of NKT cells. Deletion of CD39 modulates nucleotide‐mediated cytokine production by, and limits apoptosis of, hepatic NKT cells providing protection against Con A–induced hepatitis. This study illustrates a further role for purinergic signaling in NKT‐mediated mechanisms that result in liver immune injury. (HEPATOLOGY 2008.)

Natural killer T cell dysfunction in CD39‐null mice protects against concanavalin A–induced hepatitis

Extracellular nucleotides (e.g. ATP, UTP, ADP) are released by activated endothelium, leukocytes and platelets within the injured vasculature and bind specific cell-surface type-2 purinergic (P2) receptors. This process drives vascular inflammation and thrombosis within grafted organs. Importantly, there are also vascular ectonucleotidases i.e. ectoenzymes that hydrolyze extracellular nucleotides in the blood to generate nucleosides (viz. adenosine). Endothelial cell NTPDase1/CD39 has been shown to critically modulate levels of circulating nucleotides. This process tends to limit the activation of platelet and leukocyte expressed P2 receptors and also generates adenosine to reverse inflammatory events. This vascular protective CD39 activity is rapidly inhibited by oxidative reactions, such as is observed with liver ischemia reperfusion injury. In this review, we chiefly address the impact of these signaling cascades following liver transplantation. Interestingly, the hepatic vasculature, hepatocytes and all non-parenchymal cell types express several components co-ordinating the purinergic signaling response. With hepatic and vascular dysfunction, we note heightened P2- expression and alterations in ectonucleotidase expression and function that may predispose to progression of disease. In addition to documented impacts upon the vasculature during engraftment, extracellular nucleotides also have direct influences upon liver function and bile flow (both under physiological and pathological states). We have recently shown that alterations in purinergic signaling mediated by altered CD39 expression have major impacts upon hepatic metabolism, repair mechanisms, regeneration and associated immune responses. Future clinical applications in transplantation might involve new therapeutic modalities using soluble recombinant forms of CD39, altering expression of this ectonucleotidase by drugs and/or using small molecules to inhibit deleterious P2-mediated signaling while augmenting beneficial adenosine-mediated effects within the transplanted liver.

The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism.

FrontLine Physician is the official magazine of the Indiana Academy of Family Physicians and is published quarterly.

寒天平板上での土壌節足動物Folsomia candida(トビムシ目:ツチトビムシ科,オオフォルソムトビムシ)の飼育およびポンソーSでの蛋白質染色によるバイオマス推定

NHS Greater Glasgow and Clyde's Making the Most of Your Medicines service involves a more patient-centred approach to inpatient medication administration. A study explored patients' knowledge, experiences and views of the service.

But the male midwife is no new species: centuries of controversy.

Introduction: Gestational Diabetes Mellitus (GDM) is a condition potentially occurring during pregnancy. It is associated with adverse foetal and maternal outcomes and is particularly prevalent in South Asian women who comprised this study sample. Aim: To provide a critical analysis of the information on GDM risk that can be identified from screening using the Oral Glucose Challenge Test (OGCT-50 g). Materials and Methods: A prospective cohort study was conducted over eight months. Purposive sampling was used to collect demographic and clinical data {age; Body mass Index (BMI); parity; history of Diabetes Mellitus (DM) in a first degree relative and histories of GDM, polyhydramnious, macrosomia, birth congenital abnormalities and still birth} from 300 South Asian women in mid-trimester pregnancy who consented to undertake an OGCT-50g. Excluded were primigravidas, women with DM or other medical conditions, and women who were unwilling or unable to give informed written consent. Descriptive, comparative and multivariate logistic analyses were used to investigate strengths of correlation between OGCT outcomes and clinical/historical risk factors. Results: The OGCT were 107 (35.7%) positive and 193 (64.3%) negative. The threshold for body mass risk was identified as 27.5 kg/m2. Women with two or more risk factors were OGCT positive on 72.9% occasions whereas women with one or no risk factor were OGCT negative on 81.9% occasions. Approximately, 50% of women had a family history of DM as their only risk factor and 24% of them were OGCT positive. Conclusion: The BMI was the strongest determinant of a positive OGCT result. The logistic regression analysis demonstrated that using the lower BMI threshold of 27.5 compared to 30.0 [as per National Institute for Health and Care Excellence (NICE) guideline] improved agreement between risk factors profile was assessed and OGCT results.

Gestational Diabetes in Mid-trimester Pregnancy in South Asian Women Based on the Oral Glucose Challenge Test and Risk Factor Predictors: A Prospective Observational Study

Background: Nurses are the frontline health professional more likely to undergo various stressors during the pandemic Covid-19 situation The ongoing unprecedented crisis causes more stress, especially among nurses, as they are the most vulnerable group who predominantly get impacted while delivering comprehensive care Aim: This study explored the level of stress among nurses working in different healthcare settings Methods: A descriptive cross-sectional study among nurses from developed and developing countries between 7 February and 7 April 2020 was adopted for this research Sixty-four nurses working in different healthcare settings were included in the study A self-developed online questionnaire using google documents was used to collect data that comprised baseline data, Cohen Perceived stress scale, simplified coping items, and items of psychosocial perception Results: It was revealed that 75 64% of studied participants (N=64) had a high level of stress, with a mean anxiety score and Standard deviation of 3 52 +/- 1 084, during the Covid-19 pandemic situation A statistically significant association was found between the demographic variables such as experience and participation in the COVID-19 team at p&lt; 05, whereas gender, age, and working unit do not show any significant associations Conclusion: Heath institutions' effective and efficient protocols are required to enhance nurses' mental strength and alleviate their lack of coping strategies, particularly during a crisis

Healthcare Professionals (Nurses') Perceived Stress and Coping: Amid COVID-19

 The aim of this study was to survey student learning perspectives as measured by ‘student satisfaction’ following the rapid introduction of remote blended e-learning into the existing undergraduate nursing curriculum at Umm Al-Qura University, Saudi Arabia.
 
 National legislation resulting from the spread of Covid-19 required all theoretical and practical nurse training to move immediately to online provision using an unfamiliar e-learning environment and associated tools.
 
 The objective of this study was to use a validated satisfaction questionnaire developed elsewhere, but within a similar educational context involving both theoretical and practical components, for the purpose of checking that educational objectives were being satisfactorily achieved across five relevant domains of educational enquiry, and to use survey findings to improve the online delivery of the nursing program in future academic years.
 
 A validated 35 item questionnaire was circulated online to all male and female nursing students in their 2nd, 3rd and 4th years of study. The questionnaire content was subdivided into the five domains of ‘Interaction’, ‘Instruction’, ‘Instructor’, ‘Course Management’ and ‘Technology’. Descriptive and comparative statistics were used to compare levels of satisfaction between genders and among undergraduate years of study, and against findings from undergraduate information technology undergraduates.
 
 199 female and 84 male students completed the questionnaire (response rate 59.2%). Mean satisfaction scores for male and female nursing undergraduates were significantly greater than 3 (neutral score) in all domains of enquiry, indicating good satisfaction with blended e-learning (p<0.001). However, multivariate regressions of domain satisfaction scores taking gender and year of study as explanatory variables had poor resolving power. Domain scores were also significantly greater than those of a comparator study in three of the five domains (p<0.030) and similar in the domains of course management (p=0.717) and technology (p=0.677). Levels of satisfaction in males and females were similar in 80% of the survey questions, but in females, satisfaction was significantly lower in some questions concerning technology (p<0.003), willingness to interrupt the instructor (p=0.021), comparison of blended learning and face-to-face teaching (p=0.002) and timely feedback on tests and assignments (p=0.031). Fourth-year students showed the highest levels of satisfaction across all five domains.
 
 Undergraduate nursing students reported above-average satisfaction levels across all five domains of education provision. Despite an unfamiliar blended e-learning curriculum environment, they demonstrated compatible technological skills, satisfactory interaction with teachers and other students and engagement in the learning process. A number of recommendations identified in the literature as underlying a successful program of blended e-learning are recorded for the benefit of readers.

Undergraduate Nursing Students Endorse Education Standards in Blended e-Learning Theory Teaching during COVID-19 Pandemic

Sharp injuries are common reasons for the transmission of blood-borne diseases in acute care settings. Fear of sharp injuries and their consequences can expose nurses to high levels of stress (sharp injuries stress).

AIM AND OBJECTIVES
To examine the occurrence of sharp injuries and to assess their relationship with stress among nurses working in acute care settings.

DESIGN
This was a cross-sectional study.

METHODS
A total of 150 nurses working in 10 acute care settings in two selected hospitals in Alexandria, Egypt, were selected as the population of this study. Data on the occurrence of sharp injuries were collected using a sharp injuries circumstances questionnaire (including questions regarding number, instrument and reasons/procedures that caused sharp injuries, etc.), and two scales were used to measure sharp injuries stress (the Impact of Event Scale-Revised and the Post-Traumatic Stress Syndrome Questions Inventory).

RESULTS
More than 13% of nurses experienced sharp injuries, and 25% of injuries were caused by contaminated instruments. Sharp injuries stress scores were high in nurses, with 65% of nurses experiencing sharp injuries and 30.8% of nurses who did not experience sharp injuries having high Impact of Event Scale-Revised scores. In addition, 45% of nurses who experienced sharp injuries and 15.39% of nurses who did not experience sharp injuries had high Post-Traumatic Stress Syndrome Questions Inventory (PTSSQI) scores. There was a significant relationship between the occurrence of sharp injuries and stress scales at P < .05.

Nurses are exposed to sharp injuries, leading to sharp injury stress pre- and post-occurrence of injuries. Sharp injuries stress can make nurses prone to Post-Traumatic Stress Syndrome (PTSS).

RELEVANCE TO CLINICAL PRACTICE
Factors that lead to the occurrence of sharp injuries and sharp injuries stress should be investigated, and a psychological rehabilitation unit should be instituted to help nurses working in acute care settings deal with the sharp injuries-related stressors they are facing.

Sharp injuries and their relationship with stress among nurses working in acute care settings.

Objective: To explore the perception of undergraduate nursing students of second-year courses regarding e-learning experiences, competencies, interests, and values and obtain suggestions for improving such practices organized during the pandemic crisis of Covid-19. Methodology: The present crosssectional descriptive study design attempted to investigate the undergraduate nursing students’ experiences related to the quality dimensions of e-learning. Data were collected from 121 undergraduate students of a University in Saudi Arabia who completed a set of reflective questions. Findings: Four themes were generated; instructional immediacy, Self-confidence, Innovative navigation, High Versus Low Stakes Assignments, including the advantages, challenges, and recommendations, are also discussed. Novelty: The article demonstrates the domains of challenges that might impact students’ experiences during e-learning amid Covid-19. 
Keywords: Students experiences; E-learning; Covid-19; quality; generated themes

Generated Themes of E-learning: Exploration of Students’ Challenges During Covid-19

A novel coronavirus (COVID-19) is a newly discovered virus in 2019 in Wuhan, China Globally around the world, healthcare professionals (HCP), including nurses, are the front line health workers (FHW), considered as a vital member of the team trying to save several people's lives Although leading health organizations and scientific papers consistently addressed the HCP challenging role concerning multidisciplinary approaches and support systems, along with evidence-based research implications for delivering the best possible quality care, this review resulted in four primary categories, such as challenges, domains, support systems (code of ethics), and evidence-based synthesis of health policy A step further, this article will detail the tremendous role of brave healthcare workers, including nurses and pharmacists who proved themselves as health warriors, along with the key issues about the nurses' perspectives on the impact of COVID-19, and to debunk the mixed messages what is being reported every day is a virtual drive for nurses focusing on the significant domains of nursing practices as a motivating factor amid COVID-19

Health Professionals Dynamic Role Amid COVID-19: Nursing Perspectives

Abstract: Senior Charge Nurses (SCNs) are faced with an increasingly wide range of responsibilities as part of their workload and consequently devote less time to patient care. It is noted that Leadership and organizational management are also important, although adequate training, education, resources, and support to realize these ambitions lag needs. Design: A mixed-method focus group informed by a well-established leadership framework was used to explore senior clinical nurses' perceptions of their Leadership. Methods: Purposive sampling of SCNs working in Scotland was employed. Data sources included a small focus group and one to one face to face interview. 142 SCNs participated in this interview from 2000 to 2013. Results: Twelve main themes were identified: 'Patient-focused leadership and Organization focused leadership" These two themes were further described through domains of Leadership and capabilities that articulate confidence, quality improvement, and team performance.

Challenges in Everyday Leadership Capabilities Conversations with Senior Clinical Nurses

Background: Coronary artery bypass grafting (CABG) is a major surgical intervention to relieve symptoms and promote survival for individuals with coronary heart disease (CHD). The benefits of the intervention are thought to be improved when underlying risk factors of CHD are ameliorated. However in current health care systems the long-term follow-up of patients following CABG is not centralized to allow for the determination of survival trends and their optimization. The survival of study participants who underwent CABG is compared with age and gender matched individuals from the general population. Differences in rates of survival are interpreted in terms of lifestyle choices and the impact of risk factors of CHD.

Quantifying Relative Importance of Coronary Risk Factors on Patient Survival Following Coronary Artery Bypass Grafting: A Maximum Likelihood Analysis

 Background: Blended learning has recently been introduced as an addition to the existing teaching programme of nursing students at X University. The aim of this study is to assess student satisfaction with this change.Methods: A 35 item questionnaire was circulated to all male and female nursing students in their 2nd, 3rd and 4th years of study. The questionnaire was subdivided into the five domains of Interaction, Instruction, Instructor, Course Management and Technology.Results: Mean satisfaction scores for male and female nursing undergraduates was significantly greater than 3 (neutral score) in all domains of enquiry indicating good satisfaction with blended learning (p<0.001). Domain scores were also significantly greater than those of a comparator study in four of the five domains (p<0.030) and similar in the domain of Technology (p=0.677). Male and female levels of satisfaction were similar in 80% of the survey questions, but female satisfaction was significantly lower in some questions concerning technology (p<0.003), willingness to interrupt the instructor (p=0.021), comparison of blended learning and face-to-face teaching (p=0.002) and timely feedback on tests and assignments (p=0.031). Fourth year students showed highest levels of satisfaction across all five domains. Overall questionnaire reliability exceeded 90% and matched that of a comparable study elsewhere.Conclusion: Undergraduate nursing students reported high levels of satisfaction and demonstrated nascent technological skill, resilience and fortitude when presented with the immediate implementation of an unfamiliar e-learning blended curriculum environment.

Undergraduate Nursing Students’ Satisfaction with blended e-learning following the Covid-19 pandemic

Background: Survival after myocardial infarction (MI) is improving leading to increasing numbers of people dealing with heart health recovery, readjustment and re-investment in their future wellbeing and that of their family. Cardiac Rehabilitation (CR) aims to improve outcome by ensuring patients adopt recommended health maintenance strategies. This study explored the health maintenance needs of adults one to three years after an MI. The theoretical framework guiding the study was Leventhal’s Self Regulation Model. Data from the completion of different measures of health and illness representation are presented and the potential for measuring current health status and their explanatory factors is illuminated.

What are Adults’ Illness Representations, Mood and Quality of Life after Myocardial Infarction?

Older Woman, Diabetes Mellitus, Online Focus Group, Experiences, Challenges, Quality of Life

BACKGROUND Diabetes will occur at any age, but the presence of co-morbid conditions in the elderly population complicates its management. There are increasing concerns about managing the physical and emotional perspectives of older people whose functional and reasoning needs are on a decline. An older adult with diabetes is at increased risk of developing mental illness and is considered as one of the emerging widespread health issues of the twenty first century in India. Compliance with self-care behaviour is essential in developing a better outcome in glycaemic control and quality of life. This study aims to explore the self-care management experiences and challenges of older women with diabetes using online group discussion. Purposive sampling method was adopted to assign patients with diabetes from four semi-urban communities of India from different regions. Twenty-two women were employed to obtain data, and conduct group discussions a total of ten times through online sessions. Three themes were generated from the collected and analysed data such as body-mind voice perception, everyday challenges, including self-management accomplishment problems in exploring novel insights of their experiences and issues of older women with regard to self-care management of diabetes. Community healthcare multidisciplinary teams must be involved in providing health education to the needed population with diabetes to minimize patients’ anxiety and to develop more patient focused, high quality, competent and compassionate care. In addition to monitoring patients, more attention is needed on successful adaptation to maintain a better quality of life.

Self-Management Experiences and Challenges of Elderly Women with Type 2 Diabetes

International Journal of Trend in Scientific Research and Development

Systematic Review- Obstacles for Discontinuation of Breast-Feeding

Method: SF36 data and the presence of cardiac symptoms were collected from 44 women and 166 men prior to surgery and from consenting survivors at one and eight-year follow-ups. Survival data were collected from government records for 18 years post operation. Paired t-tests, Pearson correlation coefficients, chi-squared tests and the log-rank test were used to investigate connections between HRQoL and age, presence of angina/breathlessness and survival within and across genders.

Long Term Health Outcomes Following Coronary Artery Bypass Grafting: A Different Journey for Men and Women

Introduction: Health locus of control is a measure of an individual’s beliefs in factors that are thought to determine health experiences. Scores are generated and form a graduated linear scale from external to internal control, with respect to their views on health causality. Health locus of control has been considered to be a relatively stable entity. However, it is not clear if this status changes in the advent of serious health challenges, such as coronary artery bypass graft surgery. The aim of this study is to explore the variability of health locus of control and its association with postoperative health in this context. Methods: In a longitudinal cohort study of patients undergoing coronary artery bypass graft surgery, a purposive sample (n=215) were recruited from the waiting list and followed up postoperatively, at approximately one year and seven years later. Results: Patients undergoing coronary artery bypass graft surgery demonstrated marked fluctuations in health locus of control in their peri-operative and rehabilitative phases. Mean health locus of control became more external (often associated with poorer outcomes) peri-operatively, and more internal (generally associated with better health outcomes) in the rehabilitative period. Conclusions: Health locus of control scores were shown to be changeable during a major health care intervention, with possible consequences for patient outcomes and care needs. The significant health belief upheaval demonstrated in this cohort should be considered in assessing patients preoperatively, and managed as part of the patients’ clinical journey by both acute and rehabilitation staff. It is likely to have particular importance in individualised assessment and management of future prevention advice for patients.

Health locus of control in patients undergoing coronary artery surgery – changes and associated outcomes: a seven-year cohort study

A learning curve for nurse interns in clinical practice in Saudi Arabia

Background:Emerging evidence suggests that heart failure (HF) patients who have mild cognitive impairment (MCI) may experience greater difficulty with self-care. Objective:This article reports a systematic review that addressed the objective “What is the evidence for an association between MCI and self-care, measured in 1 or more of the self-care domains related to HF, in adults who have a diagnosis of chronic HF?” Method:We adopted Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for the review and synthesis of quantitative research studies that formally measured both cognitive function and self-care in HF patients and sought to describe the relationship between these factors. Results:Ninety-one potentially relevant studies were located; 10 studies (2006–2014) were included. Because of heterogeneity in the retrieved studies, meta-analysis was not possible. Narrative synthesis found growing evidence regarding the association between MCI and adverse effects on self-care in HF. Nine studies reported significant positive associations between MCI and self-care in HF, either specifically in relation to medication adherence or more generic measures of self-care activity. One study reported a significant, negative correlation between cognitive function and self-care, suggesting that worse cognitive function was associated with better self-care; however, this is partially explained by a small sample size and mixed methodology. Conclusions:These findings have implications for clinical practice. It is known that HF patients have difficulty with self-care, and the influence of cognitive function needs to be considered when providing professional support. Further research to determine the feasibility and acceptability of cognitive assessment in routine clinical care is recommended.

The Association Between Mild Cognitive Impairment and Self-care in Adults With Chronic Heart Failure: A Systematic Review and Narrative Synthesis

Background: The decision to seek professional help in the circumstances of acute myocardial infarction (AMI) is often delayed for too long. Aim: To explore the lived experience of three women in the decision phase prior to seeking professional care for a first AMI and provide justification for continuance of the study. Design: Hermeneutic phenomenology was used to explore for meaning, using in-depth, semi-structured interviews conducted in the homes of three participants purposively recruited for the pilot study from a cardiac centre situated in the West of Scotland. Results: Seven patterned themes were identified from hermeneutically analysed data: level of attunement, weighing up perception of urgency, ownership of decision, expressive language, family car, traditional perception of NHS services and relinquishing control. Conclusion: The pilot study exposed the complexity of the decision trajectory. Different ontological and social meanings were attached to women's decisions which require further explor...

An exploration of women's decision trajectories: seeking professional help for an AMI

Illness representations, mood and quality of life 1 to 3 years after a myocardial infarction

Nurses play a key role in leading and delivering cardiac rehabilitation within multidisciplinary teams, and continually face new challenges. However, one aspect of service delivery that remains a particular issue and challenge within many cardiac rehabilitation services is poor patient uptake of phase 3 cardiac rehabilitation programmes. Although there are a variety of factors that may affect uptake, it has been identified that despite efforts lack of equal access for sub groups of patients such as women, those from socio-economically deprived groups, ethnic minority groups and the elderly, remains an issue. This article provides a review of the literature exploring the existing issues affecting attendance within these groups, and offers some recommendations for local changes in service delivery to overcome some of the identified barriers to non- engagement or early drop out from programmes. The aim of the article is to discuss ways in which nurses can strengthen the person-centred approach to identify wa...

Review question/objective 
The objective of the review is to synthesise the best available evidence for an association between mild cognitive impairment and self-care activity in patients who have been diagnosed with chronic heart failure. 
 
The review question is: 
What is the evidence for an association between mild cognitive impairment and self-care activity, measured in one or more of the self-care domains related to heart failure in community dwelling adult patients who have a diagnosis of chronic heart failure? 
 
Inclusion criteria 
Types of participants 
Studies will include community dwelling adult patients (18 years and above) who have a diagnosis of chronic heart failure, at any stage of the New York Heart Association (NYHA) Classification of Heart Failure.35 Patients will be included regardless of gender, age, ethnic origin or any co-morbidity. 
 
Focus of the Review: 
The focus of the review is the epidemiological association between mild cognitive impairment (considered the presupposed risk factor) and self-care activity in the context of heart failure (considered the outcome). For the purposes of this review, mild cognitive impairment will be defined as evidence of impairment on a validated screening tool or diagnostic battery in individuals who do not have cognitive impairment that is severe enough to interfere with their basic activities of daily living. 
 
Studies that use validated instruments to measure cognitive function or impairment (as presupposed risk factor) will be considered for inclusion in this review. All included studies must also measure self-care capability or activities as outcomes of interest. This may be performed using validated tools, or more simple measures (such as percentage of missed medications). Self-care will include management of diet (including healthy diet, salt and fluid intake), medicines management, avoidance of risk factors for disease progression/deterioration, and symptom awareness and management.

The association between mild cognitive impairment and self‐care activity in community dwelling adult patients who have a diagnosis of chronic heart failure: a systematic review.

Locus of control in patients with chronic disease: the seven years following coronary artery surgery

Objective: This study examined whether involvement in a pre-surgical cardiac rehabilitation programme conferred a long-term survival benefit. Design: Patients randomly allocated to a pre-surgical cardiac rehabilitation programme intervention or a control group were tracked through national databases at a point approximately 12 years later, and all causes of mortality were identified from death records. Kaplan–Meier survival analyses based on involvement in a cardiac rehabilitation programme and known pre-surgical risk factors were carried out. Setting: Two health boards in the west of Scotland, referring to a single cardiothoracic tertiary centre. Subjects: Patients admitted to the waiting list for coronary artery bypass surgery. Interventions: Patients were randomly allocated to a control group (‘usual’ care) or an intervention group (nurse-led cardiac rehabilitation) in the pre-operative phase. They were followed up at 12 years post surgery. Main measures: The only outcome measure used for analysis was survival. Measures of anxiety and depression, and physiological and lifestyle risk factors were included as independent variables in analysis of death. Results: The initial study included 110 patients – none were lost to follow-up. Relative risk of death associated with inclusion in the cardiac rehabilitation programme was 0.814; risk of death increased with increasing pre-surgical depression (RR 1.07) and anxiety (RR 1.09). Conclusions: Undertaking pre-surgical cardiac rehabilitation confers a long-term survival advantage over patients not offered this service. Increased anxiety and depression in the pre-surgical phase are additional risk factors for increased mortality.

Patient mortality in the 12 years following enrolment into a pre-surgical cardiac rehabilitation programme

AbstractThe purpose of this study was to survey primary health care professionals’ perceptions of type 2 diabetes, an evaluation during a service redesign. Management of people with type 2 diabetes has been led by hospital based secondary care. The objective of the service redesign was to transfer the management of the majority of people with type 2 diabetes from secondary care to general practitioner (GP) led, multidisciplinary primary care (comprising the GP, practice nurses, dietitians and podiatrists) delivered closer to the patients. Prior to implementation, all primary health care professionals undertook accredited educational preparation and there was infrastructure development by the creation of new posts and streamlining of IT systems to support the planned change.The study aim was to examine health care professionals’ perspectives of diabetes, its management, the value of clinical guidelines and the impact of practice organisation.A cross-sectional survey design was used. Primary health care pro...

Professionals' perceptions of type 2 diabetes in primary care during a service redesign

Abstract Aim: The increasing incidence of type 2 diabetes challenges health care systems globally. This paper describes a mixed methods evaluation study and reports on key clinical outcomes during a change in service design for people with type 2 diabetes. Design: An evaluation mixed methods design was utilised. Methods: Both quantitative and qualitative approaches were utilised to address components of the study. Both professionals (N = 35) and people with diabetes (N = 136; N = 35) participated. Data was collected over 2 years. Results: A mixed methods approach derived rich data and findings. There was a statistically significant improvement in some clinical parameters including blood pressure (p < 0.001). Conclusions: Mixed methods research is appropriate for an evaluation study in primary care. People with type 2 diabetes are effectively managed in primary care.

An evaluation study using a mixed methods approach: Diabetes service redesign

Objectives. To evaluate changes in health related quality of life (HRQL) for individuals with Type 2 diabetes following the introduction of a new community-based model of care. Methods. A survey method was used in which HRQL, Problems Areas In Diabetes (PAID) and demographics were assessed before and 18 months after introducing the new service. Results. Overall HRQL and PAID scores were lower than published levels in individuals with diabetes but remained stable during the transition to the new model of care except for the bodily pain domain and deteriorating PAID scores for older patients. Four domains of SF36 health showed deterioration in the highest socio-economic groups. Deterioration was also observed in males, most notably mental health, in patients aged 54 years or less, 75 years or more and patients from socio-economic groups 1 and 2. HRQL was lowest at baseline and follow-up in socio-economic groups 6 & 7. Low levels of distress in patients across all deprivation categories was observed but remained stable over the transition. Conclusions. HRQL and distress associated with diabetes remained stable following the introduction of the new community-based model of care except for deterioration in the bodily pain domain and deteriorating PAID scores for older patients. Relevance for Practice. (i) Health related quality of life assessment is practical and acceptable to patients. (ii) In clinical governance terms it is good practice to monitor the impact of change in service delivery on the health of the patients in your care. (iii) Screening with health related quality of life tools such as generic and disease specific tools could help identify health problems otherwise undetected within current clinical care. Systematic identification of the most vulnerable groups with Type 2 diabetes should allow care to be better targeted.

Quality of Life in People with Type 2 Diabetes in Relation to Deprivation, Gender, and Age in a New Community-Based Model of Care

We sought to understand the barriers and facilitators to participation in research from the perspectives of South Asian people with asthma.

METHODS
Eight focus groups were conducted in the preferred language of participants. Sampling was purposeful to ensure inclusion of males and females from differing ethnic, linguistic and religious backgrounds.

RESULTS
The forming of trusting relationships was described as pivotal to the successful recruitment of minority ethnic groups into research; personalized approaches were likely to be better received than more impersonal written approaches. Notable barriers to participation included: the stigma of being labelled with asthma; concerns surrounding participation in pharmaceutical trials; major time or travel commitments and a failure to show respect by not making information available in minority ethnic languages. Flexibility, in terms of timing, location and respecting of cultural and religious sensitivities around gender segregation, together with the offer of incentives, were highlighted as key factors to promote participation.

The barriers to recruitment are largely surmountable, but these will necessitate the use of resource intensive and more personalized approaches than are commonly employed for the White European origin population. Our proposed model to enhance recruitment is likely to have transferability beyond the field of asthma.

Promoting recruitment of minority ethnic groups into research: qualitative study exploring the views of South Asian people with asthma.

Evaluation of the NHS Education for Scotland Advanced Practice Succession Planning Development Pathway

Aims. The primary aim of this study was to examine the needs of older people in relation to cardiac rehabilitation and to determine if these were currently being met. A secondary aim was to compare illness representations, quality of life and anxiety and depression in groups with different levels of attendance at a cardiac rehabilitation programme. Background. Coronary heart disease accounted for over seven million cardiovascular deaths globally in 2001. Associated deaths increase with age and are highest in those older than 65. Effective cardiac rehabilitation can assist independent function and maintain health but programme uptake rates are low. We have, therefore, focussed specifically on the older patient to determine reasons for the low uptake. Design. Mixed methods. Methods. A purposive sample of 31 older men and women (≥65 years) completed three questionnaires to determine illness representations, quality of life and anxiety and depression. They then underwent a brief clinical assessment and participated in a face-to-face audio-taped interview. Results. Quantitative: Older adults, who did not attend a cardiac rehabilitation programme, had significantly poorer personal control and depression scores (p < 0·01) and lower quality of life scores than those who had attended. Few achieved recommended risk factor reduction targets. Qualitative: The three main themes identified as reflecting the views and experiences of and attendance at the cardiac rehabilitation programme were: ‘The sensible thing to do’, ‘Assessing the impact’ and ‘Nothing to gain’. Conclusions. Irrespective of level of attendance, cardiac rehabilitation programmes are not meeting the needs of many older people either in terms of risk factor reduction or programme uptake. More appropriate programmes are needed. Relevance to clinical practice. Cardiac rehabilitation nurses are ideally placed to identify the rehabilitation needs of older people. Identifying these from the older person’s perspective could help guide more appropriate intervention strategies.

Coronary artery bypass grafting (CABG) is carried out for prognosis and symptomatic relief. Smoking is associated with increased postoperative complications, although its precise influence on long-term survival is unclear. We examined the influence of smoking and other risk factors on survival and myocardial ischaemia seven years after CABG.

METHODS
208 patients underwent elective CABG; 25 % were persistent smokers. 165 were alive at seven years. 128 (78 % of survivors) agreed to reexamination and 79 had thallium scans.

RESULTS
Angina and dyspnoea were reported by 52 % and 69 %, respectively, of survivors; these were associated with smoking ( P = 0.029 and 0.0 009) but with no other risk factors. Smokers had higher stress thallium scores ( P = 0.057) and ischaemia scores (10.6 +/- 6.5 vs. 6.8 +/- 6.0; P = 0.036); ejection fractions were equivalent. Obesity was prevalent and worsened in men. 33 patients (17 %) died during follow-up. Initially there was no survival difference between smokers and nonsmokers but as early as three years postoperation smoking was associated with an increased mortality ( P = 0.011; log-rank test).

Patients experienced almost universal improvement with the operation. However, persistent smoking completely removed the prognostic benefits of CABG by accelerating late mortality which was higher than previously reported. Higher indices of ischaemia in smokers were suggested by symptoms and confirmed by perfusion scans.

Smoking after coronary artery bypass: high three-year mortality.

This paper by David Cochrane, Janette Palmer, Grace Lindsay, Elizabeth Tolmie, Douglas Allan and Kay Currie describes a project that led to the formulation of an online educational needs assessment tool by drawing on national healthcare competencies in coronary heart disease. It discusses the merits of web-based data collection and concludes that web-based survey systems offer distinct advantages providing researchers proceed with care.

Formulating a web-based educational needs assessment questionnaire from healthcare competencies.

AIM AND OBJECTIVE
The accuracy with which patients recall their cardiac symptoms prior to aorta-coronary artery bypass grafting is assessed approximately one year after surgery together with patient-related factors potentially influencing accuracy of recall.

This is a novel investigation of patient's rating of preoperative symptom severity before and approximately one year following aorta-coronary artery bypass grafting.

DESIGN
Patients undergoing aorta-coronary artery bypass grafting (n = 208) were recruited preoperatively and 177 of these were successfully followed up at 16.4 (SD 2.1) months after surgery and asked to describe current and recalled preoperative symptoms using a 15-point numerical scale.

METHOD
Accuracy of recall was measured and correlated (Pearson's correlation) with current and past symptoms, health-related quality of life and coronary artery disease risk factors. Hypothesis tests used Student's t-test and the chi-squared test.

RESULTS
Respective angina and breathlessness scores were recalled accurately by 16.9% and 14.1% while 59% and 58% were inaccurate by more than one point. Although the mean preoperative and recalled scores for severity of both angina and breathlessness and were not statistically different, patients who recalled most accurately their preoperative scores had, on average, significantly higher preoperative scores than those with less accurate recall. Patients whose angina and breathlessness symptoms were relieved by operation had significantly better accuracy of recall than patients with greater levels of symptoms postoperatively.

Patient's rating of preoperative symptom severity before and one year following aorta-coronary artery bypass grafting was completely accurate in approximately one sixth of patients with similar proportions of the remaining patients overestimating and underestimating symptoms. The extent to which angina and breathlessness was relieved by operation was a significant factor in improving accuracy of recall.

Factors associated with accuracy of recall of symptoms provide useful insights for clinicians when interpreting patients' views of the effectiveness of aorta-coronary artery bypass grafting for the relief of symptoms associated with coronary heart disease.

Accuracy of patient recall of preoperative symptom severity (angina and breathlessness) at one year following aorta-coronary artery bypass grafting.

AIM
This article is a report of a study conducted to explore the perceptions of adults with type 2 diabetes towards the service redesign.

Diabetes is reaching epidemic proportions and the management of this chronic illness is changing in response to this challenge. In the United Kingdom, there is ongoing restructuring of healthcare services for people with chronic illnesses to ensure that their general health and clinical needs are met predominantly in primary care.

METHOD
An explorative qualitative approach was used. Eight focus groups were conducted with 35 people with type 2 diabetes in one urban location between 2003 and 2004. Five focus groups were conducted with people who had recently experienced the restructured service and three groups with people who had up to 2 years' experience of the new service. Concurrent data collection and thematic analysis were conducted by three researchers and credibility and verification sought by feedback to participants.

FINDINGS
Five main themes were identified: impact of living with diabetes; understanding diabetes; drivers for organizational change; care in context and individual concerns. Participants identified issues for ongoing development of the service.

People with type 2 diabetes appreciate their care management within the primary care setting where there has been investment in staff to deliver this care. Healthcare resources are required to support the development of staff and the necessary infrastructure to undertake management in primary care. Policy makers need to address the balance of resources between primary and secondary care.

Perceptions of a service redesign by adults living with type 2 diabetes.

Evaluation of the Succession Planning Development Pathway for Consultant Nurses, Midwives and Allied Health Professionals.

This study aimed to develop a valid and reliable questionnaire to measure primary health care professionals' (PHCP) views and perceptions of type 2 diabetes care. Management of type 2 diabetes within the UK is moving from secondary to primary led care. A need was identified to develop a tool to measure PHCP' views and perceptions of diabetes as studies have shown that these can have an impact on patient outcomes. There were four main stages in the development of the questionnaire that has used rare methodology. The first was an in-depth literature review of research databases, nationally recognized standards and professional literature. From this, criteria for the questionnaire were developed.The second stage involved a consultation with a national panel of diabetes experts. This utilized the nominal group technique consensus approach to determine ranked criteria. A sample of PHCP was interviewed on a one-to-one basis using the `talk through' technique for the third stage and was invited to make in-depth comments on each of the questions. The questionnaire was finally piloted with different professional groups working in community care. The developed questionnaire was used in a study evaluating the impact of the Glasgow Diabetes Project.

Development of a questionnaire to determine professionals' attitudes to type 2 diabetes

Coronary Artery Bypass Graft Operation: Patients' Experience of Health and Well-Being Over Time

An Evaluation of the Impact of the Glasgow Diabetes Project For Healthcare For Patients With Type 2 Diabetes

Is no evidence better than any evidence when controlled studies are unethical? 

Rigorous evidence on the health effects of social interventions is scarce1 2 despite calls for more evidence from randomised studies.3 One reason for the lack of such experimental research on social interventions may be the perception among researchers, policymakers, and others that randomised designs belong to the biomedical world and that their application to social interventions is both unethical and simplistic.4 Applying experimental designs to social interventions may be problematic but is not always impossible and is a desirable alternative to uncontrolled experimentation.3 However, even when randomised designs have been used to evaluate social interventions, opportunities to incorporate health measures have often been missed.5 For example, income supplementation is thought to be a key part of reducing health inequalities,6 but rigorous evidence to support this is lacking because most randomised controlled trials of income supplementation have not included health measures.5 Current moves to increase uptake of benefits offer new opportunities to establish the effects of income supplements on health. In attempting to design such a study, however, we found that randomised or other controlled trials were difficult to justify ethically, and our eventual design was rejected by funders.

#### Box 1 Attendance allowance

A pilot study carried out by one of us (RH) showed substantial health gains among elderly people after receipt of attendance allowance. We therefore decided to pursue a full scale study of the health effects of income supplementation. …

over the next 20 years it is anticipated that there will be a significant increase in those aged 75 and over, and a consequent increase in cardiovascular disease, cancer and chronic illness. As this shift takes effect, there will be an increased need for treatment strategies that are of known benefit to this age group and a consequent rise in demand for clinical trials that are conducted specifically with the older population. Because factors that motivate older individuals to participate in clinical trials may differ from those that influence younger adults, it is important to evaluate the strategies used to encourage recruitment and retention and to determine how appropriate these are.

AIM
evaluation of the reasons why subjects agree to participate in a controlled clinical trial of vascular disease prevention and the strategies used to improve compliance and protocol adherence.

SETTING
Scotland.

SUBJECTS
2,520 Prospective Study of Pravastatin in the Elderly at Risk participants, aged 70-82 with either pre-existing vascular disease or at least one major vascular risk factor (hypertension, cigarette smoking, or diabetes mellitus).

DESIGN OF STUDY
two-stage iterative survey. Stage I was exploratory.

RESULTS
curiosity, or an interest in finding out more about the study, 'a desire to support research', and anticipated personal benefits, such as health screening, were the most important motivators for generating initial interest in the trial. Ongoing health monitoring was the most important recruitment and retention motivator (P = 0.001).

curiosity, self interest and altruism may act as motivators at different points in the study time-line. However, fostering positive relationships between staff and recruits, and keeping recruits informed about the progress of the study are likely to maximise the retention of older subjects to long-term trials.

Understanding why older people participate in clinical trials: the experience of the Scottish PROSPER participants.

Experience of cardiac rehabilitation after coronary artery surgery: effects on health and risk factors.

Studies confirm the value of specialist nursing-led input in preventing patients having further coronary heart disease events. Interventions, targeted at effecting patient lifestyle changes, have been shown to be particularly successful in improving patients' diet and activity levels, reducing the incidence of subsequent events and mortality.

Nurse-led interventions contribute to cutting the risks for heart disease.

BRITISH ASSOCIATION FOR NURSING IN CARDIAC CARE (BANCC) Annual National Conference Wednesday, 30

Patients’ Perspectives on Statin Therapy for Treatment of Hypercholesterolaemia: A Qualitative Study

The distressing symptom complex known as angina pectoris is a key indicator of coronary heart disease. Obtaining an accurate clinical history and description of symptoms is an important part of the nurse's role in the care of these patients. A number of tests may be performed that will indicate the severity of the disease.

Emergency Nurse Practitioners (ENP) are increasingly managing minor injuries in Accident and Emergency departments across the United Kingdom. This study aimed to develop methods and tools that could be used to measure the quality of ENP-led care. These tools were then tested in a randomized controlled trial.

METHODS
A convenience sample of 199 eligible patients, over 16 years old, and with specific minor injuries was randomized either to ENP-led care (n = 99) or Senior House Officer (SHO)-led care (n = 100) and were diagnosed, treated, referred or discharged by this lead clinician. Following treatment, patients were asked to complete a patient satisfaction questionnaire related to the consultation. Clinical documentation was assessed using a 'Documentation Audit Tool'. A follow-up questionnaire was sent to all patients at 1 month. Return visits to the department and missed injuries were monitored.

RESULTS
Patients were satisfied with the level of care from both ENPs and SHOs. However, they reported that ENPs were easier to talk to (P = 0.009); gave them information on accident and illness prevention (P = 0.001); and gave them enough information on their injury (P = 0.007). Overall they were more satisfied with the treatment provided by ENPs than with that from SHOs (P < 0.001). ENPs' clinical documentation was of higher quality than SHOs (P < 0.001). No differences were found in recovery times, level of symptoms, time off work or unplanned follow-up between groups. Missed injuries were the same for both groups (n = 1 in each group).

The study was sufficiently large to demonstrate higher levels of patient satisfaction and clinical documentation quality with ENP-led than SHO-led care. A larger study involving 769 patients in each arm would be required to detect a 2% difference in missed injury rates. The methods and tools used in this trial could be used in Accident and Emergency departments to measure the quality of ENP-led care.

Evaluating Emergency Nurse Practitioner services: a randomized controlled trial.

Strategies to improve advice and relaxation for patients with acute myocardial infarction: some theoretical considerations

OBJECTIVE To evaluate the effectiveness of a nurse led shared care programme to improve coronary heart disease risk factor levels and general health status and to reduce anxiety and depression in patients awaiting coronary artery bypass grafting (CABG). DESIGN Randomised controlled trial. SETTING Community, January 1997 to March 1998. STUDY GROUPS 98 (75 male) consecutive patients were recruited to the study within one month of joining the waiting list for elective CABG at Glasgow Royal Infirmary University NHS Trust. Patients were randomly assigned to usual care (control; n = 49) or a nurse led intervention programme (n = 49). INTERVENTION A shared care programme consisting of health education and motivational interviews, according to individual need, was carried out monthly. Care was provided in the patients' own homes by the community based cardiac liaison nurse alternating with the general practice nurse at the practice clinic. OUTCOME MEASURES Smoking status, obesity, physical activity, anxiety and depression, general health status, and proportion of patients exceeding target values for blood pressure, plasma cholesterol, and alcohol intake. RESULTS Compared with patients who received usual care, those participating in the nurse led programme were more likely to stop smoking (25% v 2%, p = 0.001) and to reduce obesity (body mass index > 30 kg/m2) (16.3% v 8.1%, p = 0.01). Target systolic blood pressure improved by 19.8% compared with a 10.7% decrease in the control group (p = 0.001) and target diastolic blood pressure improved by 21.5% compared with 10.2% in the control group (p = 0.000). However, there was no significant difference between groups in the proportion of patients with cholesterol concentrations exceeding target values. There was a significant improvement in general health status scores across all eight domains of the 36 item short form health survey with changes in difference in mean scores between the groups ranging from 8.1 (p = 0.005) to 36.1 (p < 0.000). Levels of anxiety and depression improved (p < 0.000) and there was improvement in time spent being physically active (p < 0.000). CONCLUSIONS This nurse led shared care intervention was shown to be effective for improving care for patients on the waiting list for CABG.

Nurse led shared care for patients on the waiting list for coronary artery bypass surgery: a randomised controlled trial

Emergency Nurse Practitioners (ENPs) are being used in an increasing proportion of A&E departments across England and Wales. This paper reports the findings of a postal survey sent to all (94) A&E departments in Scotland including the smaller GP run units. The aim of the study was to document the extent and nature of ENP services in Scotland. Nurses were found to be practising as ENPs in 47% of Scottish A&E departments. The majority (70%) of nurses practising as ENPs had been educated for the role on courses for ENPs. Nurses working as ENPs were being paid at all grades ranging from the lowest grade for a staff nurse (D-grade) through to H-grade. ENPs are practising in all types of A&E department. Most ENPs have been formally trained for the role, however huge variation exists in educational preparation and in remuneration for this expanded nursing role.

The extent and nature of emergency nurse practitioner services in Scotland.

Coronary heart disease (CHD) risk factors are important to modify due to their association with CHD. Cardiac rehabilitation providing secondary prevention aims to reduce these CHD risk factors. This study was undertaken to explore the need for change in the management of secondary prevention in the patient admitted to hospital with angina pectoris and the patient's learning needs of the modifiable CHD risk factors. A small scale descriptive survey design was utilized using triangulation methodology with a convenience sample of 40 patients admitted with angina pectoris to a 12 bedded Coronary Care Unit (CCU) in Crosshouse Hospital, Kilmarnock. Ethical approval was granted from Ayrshire and Arran research ethics committee. A questionnaire was utilized for collecting quantitative data on the patient's modifiable CHD risk factors and a semi-structured interview schedule for collecting qualitative data on the patient's learning needs of their modifiable CHD risk factors.Results : Many patients with angina pectoris still have modifiable risk factors not yet modified just prior to discharge (n = 37; 92.5%). Many patients wish further information on how to modify these risk factors.Conclusion : There is potential to improve the modification of the CHD risk factors that patients with angina pectoris have when admitted to hospital. The patients themselves wish further information on how to modify these risk factors and cardiac rehabilitation can offer this.

Is there a need for cardiac rehabilitation for patients admitted to hospital with angina pectoris

OBJECTIVES To assess health status, level of social support, and presence of coronary artery disease risk factors before and after coronary artery bypass grafting (CABG); to assess symptomatic relief approximately 12 months postoperatively; and to examine the association between preoperative health status and recurrence of symptoms. DESIGN Observational study. SETTING Preoperatively, in hospital outpatient department (1995–1996); postoperatively, at home (1996–97). SUBJECTS AND METHODS Patients awaiting elective CABG were recruited one month before the expected date of operation. Preoperative assessment included severity of symptoms, coronary artery disease risk factors, short form 36 (SF-36) questionnaire, and social activities questionnaire. The presence and severity of angina and breathlessness were reported postoperatively (mean 16.4 months). Multiple regression analysis was used to identify factors associated with improved outcome following CABG. MAIN OUTCOME MEASURE Patient reported presence and severity of angina and breathlessness. RESULTS 183 patients were followed for a mean of 16.4 months after CABG. Angina and breathlessness were completely relieved in 55% and 36% of patients, respectively. In patients with residual symptoms, the severity was significantly reduced (angina p < 0.001; breathlessness, p = 0.02). Patients with low SF-36 scores and low social network scores preoperatively were less likely to be relieved of symptoms (p < 0.001). Health status and social support levels preoperatively were lower than in other reported coronary artery disease patients groups. Preoperatively, coronary artery disease risk factors were higher than recommended in current guidelines: 67.4% had raised plasma cholesterol, 39.0% were hypertensive, 80% were moderately obese, and 22.9% were smokers. CONCLUSIONS Recurrence of symptoms exceeded other published studies. Patients' perception of general health, symptoms, and social support influences outcome.

The influence of general health status and social support on symptomatic outcome following coronary artery bypass grafting

Assessment of changes in general health status using the short-form 36 questionnaire 1 year following coronary artery bypass grafting.

Emergency nurse : the journal of the RCN Accident and Emergency Nursing Association

Emergency nurse practitioner's documentation: development of an audit tool.

This prospective descriptive study has analysed 214 patient interviews before and 1 year after coronary artery bypass grafting (CABG). The preoperative interview explored issues related to the impact of coronary artery disease upon health and expectations of benefit from the patients' perspective. The postoperative interview examined patients' accounts of the experience of operation and its impact on their health. A thematic analysis of the interview data was undertaken. The main factors relating to health status preoperatively were described in terms of 'dependency' on others and medication, and 'impending doom' of some major life threatening event. Benefits to health postoperatively were viewed in terms of 'removal of a death sentence' and 'freedom of choice'. Expectations of benefit from operation were varied and included 'freedom and independence', 'hope, chance and uncertainty' and 'addition of years to life and life to years'. Undergoing the operation was described by themes of the 'enormity of the experience' and 'the importance of lay support'. These findings provide a greater understanding of the 'lived experience' of both coronary artery disease and undergoing coronary artery bypass grafting. Unrealistic expectations of the benefits of CABG highlights the need for improvement in the way patients are informed about risks and benefits of interventions. In addition, the views and insights suggest that CABG operation is regarded as a significant major life event; thus more information, advice and counselling might help support patients before, during and after surgery.

Coronary artery disease patients' perception of their health and expectations of benefit following coronary artery bypass grafting.

Detection of postoperative myocardial ischemia by bedside ST-segment analysis in coronary artery bypass graft patients.

Introduction: Coronary artery bypass graft (CABG) surgery is an important intervention for individuals with established coronary heart disease (CHD). Although its place as one of a range of therapeutic options has been established, outcome assessment is based almost exclusively on biomedical measures such as mortality and morbidity. Much less is understood about benefits to general health and well-being, broader life circumstances and the expectations of those undergoing this procedure, particularly the manner in which these factors influence the favourability of the outcome. The objective of this thesis was to investigate these issues.

The health and well-being of individuals before and after coronary artery bypass surgery

Exploring patients' perspectives of coronary heart disease: discerning methods and a review of the qualitative literature

A randomised controlled study of nurse-led shared care of patients awaiting coronary artery bypass surgery led to significant improvements in patients' care management. Here, we summarise the study's findings.

Coronary heart disease: pathology, epidemiology and diagnosis. Risk factor assessment. Cholesterol and lipoproteins. Hypertension. Lifestyle management: smoking. Lifestyle management: diet. Lifestyle management: exercise. Lifestyle management: behavioural change. Medical management of coronary heart disease. Lipid-lowering drug therapy. Anti-hypertensive therapy. Cardiac rehabilitation. Women and coronary heart disease. Prevention in practice: the role of the nurse in risk assessment.

Coronary heart disease prevention : a handbook for the health care team

A recent study has shown that the use of lipid-lowering drugs is a safe and effective way of reducing the risk of CHD. Allan Gaw and colleagues used this study to examine the role of practice nurses in screening.

Naveed Sattar and colleagues suggest public health strategies for tackling the problem of increased coronary heart disease in sub-continent Asians.

As the roles of practice nurses develop, methods of offering them continuing education are being examined. A postal survey of 94 practice nurses in the Glasgow area was conducted to gain an impression of their knowledge and needs related to coronary heart disease (CHD) prevention. On the basis of the responses, a series of study days was designed and implemented, and a biannual newsletter on CHD risk factor assessment published and distributed. Both initiatives have been welcomed and, the authors claim, fit in with the UKCC's requirements on continuing education.

The practice nurse in coronary heart disease screening: fitting the role.

Coronary heart disease telephone helpline: What the public want to know

This article describes how the first nurse-led national telephone helpline for the prevention of coronary heart disease (CHD) was set up and presents the results after the first year of operation. The free service was well received. Most callers were seeking advice on CHD prevention for the first time and traditional risk factors and general healthy lifestyle advice remained major areas of concern.

The authors have designed a computer-based health education programme introducing coronary heart disease (CHD) prevention to primary school children using the novel authoring system, Course Builder. To aid design of the programme, the basic knowledge of a randomly selected group of 90 children aged 8-11 years old from three city schools was assessed, using a questionnaire in storyline format. This surveyed children's understanding of the heart's basic function, the importance and prevalence of CHD, and perception of CHD as a preventable disease. The children's response after using the programme and their increased knowledge and awareness were evaluated, and the programme was deemed an overwhelming success.

This article considers the precedent set by the appointment of task-oriented workers in health care, and proposes that this cost-effective strategy will compromise the quality of patient care and threaten the role of the nurse.

Atherogenicity of Triglyceride-Rich Lipoproteins: Clinical Aspects

Background: Aberrant processing of the proIGF-II transcript produces proand big-IGF-II which are secreted in a range of cancers. Results: These induce potent receptor activation, cell proliferation and retard ternary complex formation with ALS and IGFBP-3 and 5. Conclusion: They elicit unique biological responses which can be completely different from IGF-II. Significance: Understanding the effects induced by these individual isoforms is crucial to elucidate their role in tumorigenesis.

Characterization of cancer-associated IGF-II isoforms. 1 Biochemical Characterization of Individual Human Glycosylated pro-IGF-II and big-IGF-II Isoforms Associated with Cancer.*

A detailed longitudinal examination of plasma lipoprotein subfraction concentrations and compositions in pregnancy was performed with the objective of discovering the pattern of change in lipoprotein subfractions. Plasma triglyceride, cholesterol, very low density lipoprotein (VLDL1), very low density lipoprotein (VLDL2), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and its subfractions (LDL-I, LDL-II, LDL-III), and high density lipoprotein-cholesterol (HDL cholesterol) were quantified in 10 normal pregnant women from 10 weeks of gestation and at 5 weekly intervals thereafter, until 35 weeks of gestation, together with circulating hepatic lipase (at 10 and 35 weeks) and serum estradiol concentration. Median concentrations of VLDL1 (19-109 mg/dL), VLDL2 (17-103 mg/dL) and IDL (26-124 mg/dL) increased in parallel (maximum increase around 5-fold) as plasma triglyceride increased with advancing gestation. This contrasts with observations in the normal non-pregnant female, where higher concentrations of plasma triglyceride are associated with preferentially higher VLDL1 concentrations. The rise in IDL was also remarkable as this does not normally accompany changes in plasma triglyceride. LDL mass increased by 70% (200-353 mg/dL) between 10 and 35 weeks, and in 6 of the 10 women studied, the LDL subfraction pattern was modified towards a smaller denser pattern in a manner suggestive of a "threshold" transition, with the proportion of LDL-III increasing at the expense of LDL-II, whereas in the other 4 women, LDL subfraction profile remained unchanged throughout pregnancy. Interestingly, this "threshold" transition, if it occurred, did so at varying gestational ages and triglyceride concentrations for different women. The likelihood of LDL subfraction change and the final concentration of small, dense. LDL-III were related to the 10-week triglyceride concentration (R2 = 36.7%, P = 0.063) and to the rate of change in triglyceride for a given increment in estrogen (R2 = 48.6%, P = 0.025). In addition, VLDL1 mass exceeded 100 mg/dL during pregnancy only in those individuals in whom LDL profile perturbation was evident (chi 2, P < 0.001). LDL profile change was evident at the lowest triglyceride concentrations in the 2 individuals with the highest increments in triglyceride corrected for estrogen. On the basis of these longitudinal observations, we conclude the following: 1) as plasma triglyceride increases in pregnancy, there are parallel rises in median concentrations of VLDL1, VLDL2 and IDL, around 5-fold; 2) as a result of this progressive increase in plasma triglyceride, in particular in VLDL1, the LDL profile is altered in some individuals towards smaller, dense particles; 3) in general, the higher the initial (booking) fasting plasma triglyceride concentration or the larger the rate of change in triglyceride for a given increment in estradiol, the greater the probability of change in LDL profile towards smaller denser species; 4) significantly, LDL subclass perturbation towards smaller denser species occurs not in a gradual and progressive manner but exhibits "threshold" behavior; and finally, 5) this threshold is achieved at differing gestational ages and triglyceride concentrations for different women.

Lipoprotein subfraction changes in normal pregnancy: threshold effect of plasma triglyceride on appearance of small, dense low density lipoprotein.

The effects of colestipol therapy alone (20 g/d) or combined with simvastatin (20 mg/d) were examined in a group of eight male patients with primary moderate hypercholesterolemia (total cholesterol > or = 6.5 mmol/L [> or = 250 mg/dL]) who had undergone coronary artery bypass grafting more than 3 months previously. Colestipol therapy decreased total cholesterol by 14% (P < .001) and LDL cholesterol (LDL-C) by 23% (P < .001), while dual therapy decreased total cholesterol by 38% and LDL-C by 52% (both P < .001 versus baseline). No significant changes were observed in plasma triglyceride, VLDL cholesterol, or HDL cholesterol levels. VLDL subfraction turnovers were conducted at baseline and again on each regimen. ApoB kinetic parameters derived from a multicompartmental model suggested that colestipol therapy resulted in an expansion of the total VLDL apoB pool (36%, P < .05) that was largely due to a fall in the clearance rate of VLDL1 apoB (49%), while the LDL apoB pool decreased 23% as a result of diminished direct LDL input. The model used also revealed that addition of simvastatin to the resin therapy caused increases in the fractional transfer rates of VLDL2 to IDL and IDL to LDL together with a 37% increment in the LDL apoB fractional catabolic rate. Compared with baseline, combined therapy generated falls in both IDL (35%, P = .01) and LDL (37%, P < .04) apoB pools due to enhanced clearance of IDL (214%, P < .03) and reduced total input of LDL (39%, P < .003).

Effects of colestipol alone and in combination with simvastatin on apolipoprotein B metabolism.

An analysis of apolipoprotein (apo) B turnovers conducted in subjects with moderate hypercholesterolemia was performed to discover relationships that may exist between apoB kinetic parameters and plasma lipid and lipoprotein levels. A group of 21 subjects with plasma cholesterol in the range 250-300 mg/dl and triglyceride < 265 mg/dl were injected with tracers of 131I-labeled very low density lipoprotein 1 (VLDL1, Sf 60-400) and 125I-labeled VLDL2 (Sf 20-60) prepared by cumulative flotation ultracentrifugation. The metabolism of apoB in these fractions was followed through intermediate density (IDL, Sf 12-20) to low density (LDL, Sf 0-12) lipoprotein. The most consistent feature giving rise to the higher apoB levels that occurred in VLDL2, IDL, and LDL in the hypercholesterolemic group was increased input of VLDL2 (787 +/- 607 (SD) mg/day vs. 349 +/- 213 in normals, P < 0.01). VLDL1 apoB input was variably affected and not significantly different from normal. However, the plasma residence time of this subfraction was increased (0.15 +/- 0.07 days vs. 0.08 +/- 0.03 days in normals, (P < 0.001) due to a decreased fractional rate of direct catabolism. Fractional transfer rates (FTR) down the delipidation cascade and other fractional rates of direct catabolism were, overall, not significantly different from normal. The plasma residence time of VLDL2 apoB and LDL apoB was similar in hypercholesterolemic and normal subjects, while that of IDL apoB was slightly increased. Variation in LDL apoB mass within the hypercholesterolemic group correlated with VLDL1 apoB input (r = 0.58, P = 0.006), the fractional rate of transfer from IDL to LDL (r = 0.61, P = 0.003), and direct LDL input (r = 0.64, P = 0.002). The proportion of LDL apoB mass derived by direct, i.e., VLDL-independent input, varied from 5 to 50% and was inversely correlated with plasma triglyceride (r = -0.53, P = 0.014) and positively with HDL2 (r = 0.66, P = 0.002). In addition, the amount of direct LDL input was related to the amount of VLDL1 removed by direct catabolism (r = 0.53, P = 0.013). The analysis indicated that moderate hypercholesterolemia arose principally from overproduction of small VLDL, while variation in VLDL1 input and the IDL to LDL conversion rate (presumably hepatic lipase-mediated) modulated the extent of the elevation in LDL apoB.

Overproduction of small very low density lipoproteins (Sf 20-60) in moderate hypercholesterolemia: relationships between apolipoprotein B kinetics and plasma lipoproteins.

The effects of combined therapy with acipimox (1250 mg/day) and cholestyramine (20 g/day) were examined in a group of 7 subjects with primary moderate hypercholesterolaemia (total cholesterol >=7 mmol/L). Radiolabeled VLDL subfraction turnovers were performed at baseline, during acipimox therapy and during combined therapy. Acipimox and combined therapies lowered plasma low density lipoprotein (LDL)-cholesterol by 20% (P<0.001) and 27% (P<0.001) respectively. The marked fall in LDL-cholesterol associated with acipimox therapy, was due to a reduced production rate of LDL (apolipoprotein) apoB. This is shown to be a result of reduced direct LDL apoB production, reduced IDL to LDL transfer consistent with inhibition of hepatic triglyceride lipase, and with a reduction in the overall throughput of VLDL1 apoB. With combined therapy both reduced production and increased catabolism of apoB containing LDL precursors and of LDL itself have to be invoked to explain the fall in plasma LDL-cholesterol.

Metabolism of apolipoprotein B in primary moderate hypercholesterolaemia: effects of acipimox and cholestyramine therapy.

This study investigated in a healthy population (n = 220) the association of the TaqI B restriction fragment length polymorphism (RFLP) in the cholesteryl ester transfer protein (CETP) gene with plasma high-density lipoprotein (HDL) cholesterol concentration and subfraction distribution. A raised HDL cholesterol level was found in B2B2 homozygotes (B2 cutting site absent) and was associated specifically with a 45% increase in HDL2 compared with B1B1 homozygotes (B1B1, 77 +/- 39 mg/100 mL, mean +/- SD; B2B2, 112 +/- 59 mg/100 mL; P < 0.01). Total plasma, very-low-density lipoprotein, and HDL triglyceride levels did not differ among the genotype groups, nor did plasma apolipoprotein AI levels (B1B1, 1.45 +/- 0.35 mg/mL, mean +/- SD; B2B2, 1.56 +/- 0.33 mg/mL). Thus, the genetic variation appeared to be independent of metabolic factors that are known to regulate HDL levels. Plasma CETP exchange activity was unlikely to be the cause of the association, since it did not differ between genotype groups and was not correlated with HDL2 concentration. Multivariate analysis demonstrated that the TaqI B polymorphism had an effect on HDL cholesterol and HDL2 that was independent of age, sex, body mass index, oral contraceptive use, exercise, alcohol consumption, and plasma triglycerides. In smokers, the presence of the B2B2 genotype did not result in increased HDL cholesterol or HDL2, whereas in obese subjects, the difference between B1B1 and B2B2 individuals was diminished. We conclude that the TaqI B RFLP is associated with a quantitatively significant effect on plasma HDL2 levels that is independent of plasma triglycerides and interacts with lifestyle factors.

Regulation of plasma HDL cholesterol and subfraction distribution by genetic and environmental factors. Associations between the TaqI B RFLP in the CETP gene and smoking and obesity.

Seven moderately hypercholesterolemic subjects were studied before and after 10 weeks of simvastatin therapy (20 mg/day). Therapy reduced low density lipoprotein (LDL) cholesterol by 39% (p < 0.001), whereas high density lipoprotein and very low density lipoprotein (VLDL) cholesterol were unchanged. Apolipoprotein (apo) B-containing lipoproteins were divided into VLDL1 (Sf 60-400), VLDL2 (Sf 20-60), intermediate density lipoprotein (IDL) (Sf 12-20), and LDL (Sf 0-12), and metabolic changes were sought in dual-tracer VLDL1 and VLDL2 turnover studies. VLDL1 apoB pool size was unaltered by therapy, as were its rates of synthesis, catabolism, and delipidation to VLDL2. Similarly, the VLDL2 apoB pool size was unchanged, but its metabolic fate was altered. The IDL pool size fell significantly (27%, p < 0.01) due entirely to an increased fractional catabolism of the lipoprotein. In our subjects, the circulating mass of LDL apoB decreased (49%, p < 0.01) primarily due to a reduction in its synthesis. Before therapy, 30% of the apoB entering the delipidation cascade in these hyperlipidemic subjects was converted to LDL. On therapy the input remained the same, but direct catabolism from VLDL2 and IDL was increased (p < 0.05), and as a result only 16% eventually appeared in LDL. These kinetic changes were associated with a fall in particle cholesteryl ester content throughout the delipidation cascade. We also observed a link between LDL kinetics and its subfraction distribution. Simvastatin influences the metabolism of LDL, IDL, and VLDL2 but not VLDL1.

Effects of simvastatin on apoB metabolism and LDL subfraction distribution.

The effect of smoking on high density lipoprotein concentration and cholesteryl ester transfer protein activity in a healthy population

Abstract. In a survey of a healthy population (n = 197), LDL cholesterol, plasma triglycerides and VLDL triglycerides were found to be substantially increased and plasma HDL cholesterol decreased in smokers. The lipid‐associated atherogenic risk in smokers as assessed by the LDL/HDL ratio was significantly higher [2.89 (SD 1.18, n= 63)] than in non‐smokers [2.38 (SD 0.98, n= 86) P < 0.01]. The lower HDL level found in smokers was explained by a lower HDL‐2 subfraction as determined by analytical ultracentrifugation. HDL 2b, 2a and 3a, measured by gradient gel electrophoresis, were all lower in the smokers but this was only significant for HDL 2a. Smoking had no effect on Lp(a) levels. HDL cholesterol and HDL‐2 were strongly negatively correlated whereas LDL cholesterol and LDL/HDL ratio were strongly positively correlated with the plasma triglyceride concentration. There was a small but significant reduction in plasma CETP activity [non‐smokers 49%t/μl (SD 17, n= 90), smokers 43%t/μl (SD 17, n= 66) P < 0.05] but CETP activity was not correlated with any measure of HDL in this population. Smoking was found to be an important independent contributor to the variation in plasma triglyceride, HDL, HDL‐2 and LDL/HDL ratio. After correcting for sex, age, BMI, alcohol consumption, oral contraceptive use and plasma triglycerides smoking was still found to be significantly associated with HDL and the LDL/HDL ratio. Upon adjustment for covariant factors the mean differences between smokers and non‐smokers for HDL cholesterol, HDL‐2 and LDL/HDL were 0.15 mM, 16 mg dl‐1 and 0.39 respectively. There appeared to be important sex differences in the influence of smoking on plasma lipoproteins. In women the main impact of smoking was on triglyceride levels and they in turn affected LDL and HDL. In contrast, in men, smoking had little impact on triglycerides and affected HDL more directly. We conclude that smoking cigarettes has an important effect on plasma lipoprotein metabolism through multiple mechanisms.

Smoking and plasma lipoproteins in man: effects on low density lipoprotein cholesterol levels and high density lipoprotein subfraction distribution

T4 replacement at 150 micrograms/day in a group of six hypothyroid subjects led to the development of a euthyroid state and produced a fall in the cholesterol content of plasma and low and high density lipoproteins (LDL and HDL). The effect of T4 on apolipoprotein-B (apoB) metabolism was followed using radioiodinated very low density lipoprotein1 (VLDL1; 60-400 Svedberg units) and VLDL2 (20-60 Svedberg units). The pretreatment plasma concentration of VLDL1 apoB and its rates of synthesis and catabolism were similar to those in normal subjects. VLDL2 apoB was synthesized at a supranormal rate in hypothyroid subjects, and this led to a doubling of its circulating mass. Treatment did not significantly alter the kinetics of apoB in either VLDL1 or VLDL2. The concentration of intermediate density lipoprotein (IDL) apoB in untreated hypothyroids was 170% of normal and fell during T4 treatment due to stimulation of conversion of LDL (from 0.46 +/- 0.14 to 0.91 +/- 0.30 pools/day; mean +/- SD; P < 0.01). Direct IDL apoB clearance was not altered by treatment, whereas the fractional catabolic rate of LDL increased 76% (from 0.17 +/- 0.06 to 0.27 +/- 0.07 pools/day), leading to a 36% decrement in LDL mass. The stimulation of IDL to LDL conversion during therapy was probably due to a 3-fold increase in hepatic lipase activity (P < 0.02). This change together with the known effects of T4 on LDL receptors largely explained the lipoprotein abnormality in hypothyroidism and the effects of replacement therapy.

Thyroid replacement therapy and its influence on postheparin plasma lipases and apolipoprotein-B metabolism in hypothyroidism.

The Reassembling of Things: Financialization, Value, and the Work of “Doing Gender” in the Contemporary Dutch University

On the Edge of All Dichotomies: Anarch@-Feminist Thought, Organization and Action, 1970-1983.

On the Edge of All Dichotomies: Anarch@-Feminist Thought, Process and Action, 1970-1983.

Moving beyond medical facility walls: opportunities, challenges and attitudes of midwives towards planned homebirth

Besides the risk of coronavirus disease 2019 (COVID-19) itself, the indirect and unprecedented effects of mitigation strategies including shelter-in-place orders and social distancing combined with the widespread COVID “infodemic” disseminated by media interacted synergistically to worsen already compromised mental health outcomes of Latino people living with HIV (PLWH). This funded project directly addresses the sources of health disparity in Miami Dade County: mental health and misinformation by developing a culturally tailored resilience and media literacy intervention for Latinos living with HIV. Extant research on resilience strategies and media literacy skills have documented their effectiveness in assisting individuals make realistic appraisals and informed decisions that could benefit their health outcomes and improve health-related challenges. We utilized a community-based approach by collaborating with two local community partners (Open Arms and Borinquen) and conducting 27 qualitative interviews with Latino PLWH, infectious disease providers, and community health workers who directly informed content of the Latino Unidos microgame intervention. This article describes the formative research process guiding the Latinos Unidos microgame intervention—a three-module gamified intervention. Study outcomes provide the foundation for media and educational strategies that increase adherence to health guidance and enhance mental health responses to adversity as a response to the COVID-19 pandemic.

Addressing COVID-19 Misinformation and Resiliency Among Latinos Living With HIV: Formative Research Guiding the Latinos Unidos Microgame Intervention

The temporal binding window between ICMS and vision depends on biological relevance of visual stimuli

Multi-channel intra-cortical micro-stimulation robustly evokes stable, somatosensory percepts; with reaction times significantly faster than natural occurring stimuli in a human participant

The responsiveness of primary somatosensory cortex (S1) to physical tactile stimuli is well documented but the extent to which it is modulated by vision is unresolved. Additionally, recent literature has suggested that tactile events are represented in S1 in a more complex, generalized manner than its long-established topographic organization. To better characterize S1 function, neural activity was recorded from a tetraplegic patient implanted with microelectrode arrays in S1 during 1s stroking touches to the forearm (evoking numb sensation) or finger (naturalistic sensation). Touch conditions included visually observed first person physical touches, physical touches without vision, and visual touches without physical contact which occurred either to a third person, an inanimate object, or the patient’s own body in virtual reality. Two major findings emerged from this dataset. The first was that vision strongly modulates S1 activity, but only if there is a physical element to the touch, suggesting that passive observation of touches is not sufficient to recruit S1 neurons. The second was that despite the location of the recording arrays in a putative arm area of S1, neural activity was able to represent both arm and finger touches in physical touch conditions. Arm touches were encoded more strongly and specifically, supporting the idea that S1 encodes tactile events primarily through its topographic organization, as well as in a more general manner encompassing larger areas of the body.

S1 represents multisensory contexts and somatotopic locations within and outside the bounds of the cortical homunculus

Somatosensory brain-machine-interfaces (BMIs) can create naturalistic sensations by modulating activity of neural populations in the brain. By utilizing different spatial or temporal patterns of intra-cortical micro-stimulation (ICMS) in primary sensory cortex (S1), human patients suffering somatosensory loss can experience both cutaneous and proprioceptive sensory feedback. As evidenced by motor deficits in deafferented patients, rapid somatosensory feedback is critical for dexterous motor ability, in part because visual feedback is much slower than naturally occurring somatosensory input. However, somatosensory BMI studies typically report significantly longer cognitive processing latencies for cortical electrical stimulation than for naturally occurring somatosensations or visual sensations. In this study, we show that multi-channel electrical stimulation patterns elicit naturalistic somatosensory percepts in a human tetraplegic participant. Crucially, somatosensations evoked by multi-channel ICMS are cognitively processed at comparable latencies to naturally evoked sensations and significantly faster than visual sensations, as measured via a simple reaction time test. Further investigation demonstrated multi-channel stimulation could significantly reduce minimum amplitude detection thresholds and such reductions in charge density resulted in more frequent natural sensation descriptors reported by the human participant. Multi-channel ICMS patterns also evoked percepts with highly stable somatotopic locations. While some single-channel ICMS patterns evoked sensations 20-80% of the time, most multi-channel patterns could evoke sensations with 100% repeatability, an important step in demonstrating BCI device reliability. These improvements are all significant advances towards state-of-the-art sensory BMIs. The addition of such low-latency artificial sensory feedback to motor BMIs is expected to improve movement accuracy and increase embodiment for human users.

Multi-channel intra-cortical micro-stimulation yields quick reaction times and evokes natural somatosensations in a human participant

Traditional brain-machine interfaces decode cortical motor commands to control external devices. These commands are the product of higher-level cognitive processes, occurring across a network of brain areas, that integrate sensory information, plan upcoming motor actions, and monitor ongoing movements. We review cognitive signals recently discovered in the human posterior parietal cortex during neuroprosthetic clinical trials. These signals are consistent with small regions of cortex having a diverse role in cognitive aspects of movement control and body monitoring, including sensorimotor integration, planning, trajectory representation, somatosensation, action semantics, learning, and decision making. These variables are encoded within the same population of cells using structured representations that bind related sensory and motor variables, an architecture termed partially mixed selectivity. Diverse cognitive signals provide complementary information to traditional motor commands to enable more natural and intuitive control of external devices.

Intracortical microstimulation (ICMS) in human primary somatosensory cortex (S1) has been used to successfully evoke naturalistic sensations. However, the neurophysiological mechanisms underlying the evoked sensations remain unknown. To understand how specific stimulation parameters elicit certain sensations we must first understand the representation of those sensations in the brain. In this study we record from intracortical microelectrode arrays implanted in S1, premotor cortex, and posterior parietal cortex of a male human participant performing a somatosensory imagery task. The sensations imagined were those previously elicited by ICMS of S1, in the same array of the same participant. In both spike and local field potential recordings, features of the neural signal can be used to classify different imagined sensations. These features are shown to be stable over time. The sensorimotor cortices only encode the imagined sensation during the imagery task, while posterior parietal cortex encodes the sensations starting with cue presentation. These findings demonstrate that different aspects of the sensory experience can be individually decoded from intracortically recorded human neural signals across the cortical sensory network. Activity underlying these unique sensory representations may inform the stimulation parameters for precisely eliciting specific sensations via ICMS in future work. SIGNIFICANCE STATEMENT Electrical stimulation of human cortex is increasingly more common for providing feedback in neural devices. Understanding the relationship between naturally evoked and artificially evoked neurophysiology for the same sensations will be important in advancing such devices. Here, we investigate the neural activity in human primary somatosensory, premotor, and parietal cortices during somatosensory imagery. The sensations imagined were those previously elicited during intracortical microstimulation (ICMS) of the same somatosensory electrode array. We elucidate the neural features during somatosensory imagery that significantly encode different aspects of individual sensations and demonstrate feature stability over almost a year. The correspondence between neurophysiology elicited with or without stimulation for the same sensations will inform methods to deliver more precise feedback through stimulation in the future.

The Neurophysiological Representation of Imagined Somatosensory Percepts in Human Cortex

Augmented manipulation ability in humans with six-fingered hands

We present a new deep multi-state Dynamic Recurrent Neural Network (DRNN) architecture for Brain Machine Interface (BMI) applications. Our DRNN is used to predict Cartesian representation of a computer cursor movement kinematics from open-loop neural data recorded from the posterior parietal cortex (PPC) of a human subject in a BMI system. We design the algorithm to achieve a reasonable trade-off between performance and robustness, and we constrain memory usage in favor of future hardware implementation. We feed the predictions of the network back to the input to improve prediction performance and robustness. We apply a scheduled sampling approach to the model in order to solve a statistical distribution mismatch between the ground truth and predictions. Additionally, we configure a small DRNN to operate with a short history of input, reducing the required buffering of input data and number of memory accesses. This configuration lowers the expected power consumption in a neural network accelerator. Operating on wavelet-based neural features, we show that the average performance of DRNN surpasses other state-of-the-art methods in the literature on both single- and multi-day data recorded over 43 days. Results show that multi-state DRNN has the potential to model the nonlinear relationships between the neural data and kinematics for robust BMIs.

Deep Multi-State Dynamic Recurrent Neural Networks Operating on Wavelet Based Neural Features for Robust Brain Machine Interfaces

Brain-machine interfaces (BMIs) can help spinal cord injury (SCI) patients by decoding neural activity into useful control signals for guiding robotic limbs, computer cursors, or other assistive devices. BMI in its most basic form maps neural signals into kinematics, then closes the loop to enable direct neural control of kinematics. Such systems have shown promise in helping SCI patients; however, improving performance and robustness of these systems remains challenging. Even for simple movements, such as moving a computer cursor to a target on a computer screen, decoding performance can be highly variable over time. Furthermore, most BMI systems currently run on high-power computer systems. Clinical translation of these systems will require decoders that can adapt to changing neural conditions, and which operate e ciently enough to run on mobile—even implantable—platforms. Recently, machine learning algorithms have shown promise in attaining high performance and robustness in BMIs. Therefore, to address a number of these challenges, we propose a deep multi-state Dynamic Recurrent Neural Network (DRNN) architecture. The DRNN is used for predicting Cartesian representation of kinematics from the open-loop neural data recorded from the posterior parietal cortex (PPC) of a human subject over 39 days in a BMI system. We design the algorithm to achieve a reasonable trade-o between performance, robustness, and to reduce the memory that is required to store the weights for hardware implementation. To achieve a better prediction performance and robustness, we generalize our model by feeding the predictions of the network back to the input. To solve the statistical distribution mismatch between the ground-truth and predictions, we apply a scheduled sampling approach to the model. By con guring the DRNN to operate without history, we reduce the number of memory accesses which has shown to consume the most signi cant power in neural network accelerators (Watmough et al., 2018). We compare our algorithm with the state-of-the-art methods in the literature to show that it performs favorably: DRNN achieves average correlation coe cients of (0.75, 0.88) for position (X, Y) and (0.74, 0.87) for velocity in X and Y directions. To the best of our knowledge, this is the rst demonstration of applying deep learning-based decoders to human PPC data. The results show that multi-state  Add to Itinerary

Brain-machine interfaces have shown promising results in providing control over assistive devices for paralyzed patients. In this work we describe a BMI system using electrodes implanted in the parietal lobe of a tetraplegic subject. Neural data used for the decoding was recorded in five 3-minute blocks during the same session. Within each block, the subject uses motor imagery to control a cursor in a 2D center-out task. We compare performance for four different algorithms: Kalman filter, a two-layer Deep Neural Network (DNN), a Recurrent Neural Network (RNN) with SimpleRNN unit cell (SimpleRNN), and a RNN with Long-Short-Term Memory (LSTM) unit cell. The decoders achieved Pearson Correlation Coefficients (ρ) of 0.48, 0.39, 0.77 and 0.75, respectively, in the Y-coordinate, and 0.24, 0.20, 0.46 and 0.47, respectively, in the X-coordinate.

Decoding Kinematics from Human Parietal Cortex using Neural Networks

Author response: Proprioceptive and cutaneous sensations in humans elicited by intracortical microstimulation

Objective. A primary control signal in brain–computer interfaces (BCIs) have been cortical signals related to movement. However, in cases where natural motor function remains, BCI control signals may interfere with other possibly simultaneous activity for useful ongoing movement. We sought to determine if the brain could learn to control both a BCI and concurrent overt movement execution in such cases. Approach. We designed experiments where BCI and overt movements must be used concurrently and in coordination to achieve a 2D centre out control. Power in the 70–90 Hz band of human electrocorticography (ECoG) signals, was used to generate BCI control commands for vertical movement of the cursor. These signals were deliberately recorded from the same human cortical site that produced the strongest movement related activity associated with the concurrent overt finger movements required for the horizontal movement of the cursor. Main results. We demonstrate that three subjects were able to perform the concurrent BCI task, controlling BCI and natural movements simultaneously and to a large extent independently. We conclude that the brain is capable of dissociating the original control signal dependency on movement, producing specific BCI control signals in the presence of motor related responses from the ongoing overt behaviour with which the BCI signal was initially correlated. Significance. We demonstrate a novel human brain–computer interface (BCI) which can be used to control movement concurrently and in coordination with movements of the natural limbs. This demonstrates the dissociation of cortical activity from the behaviour with which it was originally associated despite the ongoing behaviour and shows the feasibility of achieving simultaneous BCI control of devices with natural movements.

Concurrent control of a brain–computer interface and natural overt movements

Pioneering work with nonhuman primates and recent human studies established intracortical microstimulation (ICMS) in primary somatosensory cortex (S1) as a method of inducing discriminable artificial sensation. However, these artificial sensations do not yet provide the breadth of cutaneous and proprioceptive percepts available through natural stimulation. In a tetraplegic human with two microelectrode arrays implanted in S1, we report replicable elicitations of sensations in both the cutaneous and proprioceptive modalities localized to the contralateral arm, dependent on both amplitude and frequency of stimulation. Furthermore, we found a subset of electrodes that exhibited multimodal properties, and that proprioceptive percepts on these electrodes were associated with higher amplitudes, irrespective of the frequency. These novel results demonstrate the ability to provide naturalistic percepts through ICMS that can more closely mimic the body’s natural physiological capabilities. Furthermore, delivering both cutaneous and proprioceptive sensations through artificial somatosensory feedback could improve performance and embodiment in brain-machine interfaces.

Proprioceptive and cutaneous sensations in humans elicited by intracortical microstimulation

As Brain-computer interface (BCI) technology develops it is likely it may be incorporated into protocols that complement and supplement existing movements of the user. Two possible scenarios for such a control could be: the increasing interest to control artificial supernumerary prosthetics, or in cases following brain injury where BCI can be incorporated alongside residual movements to recover ability. In this study we explore the extent to which the human motor cortex is able to concurrently control movements via a BCI and overtly executed movements. Crucially both movement types are driven from the same cortical site. With this we aim to dissociate the activity at this cortical site from the movements being made and instead allow the representation and control for the BCI to develop alongside motor cortex activity. We investigated both BCI performance and its effect on the movement evoked potentials originally associated with overt execution.

Natural movement with concurrent brain-computer interface control induces persistent dissociation of neural activity

Mechanisms in natural and concurrent brain-computer interface motor control

To study body ownership and control, illusions that elicit these feelings in non-body objects are widely used. Classically introduced with the Rubber Hand Illusion, these illusions have been replicated more recently in virtual reality and by using brain-computer interfaces. Traditionally these illusions investigate the replacement of a body part by an artificial counterpart, however as brain-computer interface research develops it offers us the possibility to explore the case where non-body objects are controlled in addition to movements of our own limbs. Therefore we propose a new illusion designed to test the feeling of ownership and control of an independent supernumerary hand. Subjects are under the impression they control a virtual reality hand via a brain-computer interface, but in reality there is no causal connection between brain activity and virtual hand movement but correct movements are observed with 80% probability. These imitation brain-computer interface trials are interspersed with movements in both the subjects’ real hands, which are in view throughout the experiment. We show that subjects develop strong feelings of ownership and control over the third hand, despite only receiving visual feedback with no causal link to the actual brain signals. Our illusion is crucially different from previously reported studies as we demonstrate independent ownership and control of the third hand without loss of ownership in the real hands.

Ownership and Agency of an Independent Supernumerary Hand Induced by an Imitation Brain-Computer Interface

Background Evidence suggests that individuals may change adherence to public health policies aimed at reducing the contact, transmission, and spread of the SARS-CoV-2 virus after they receive their first SARS-CoV-2 vaccination when they are not fully vaccinated. Objective We aimed to estimate changes in median daily travel distance of our cohort from their registered addresses before and after receiving a SARS-CoV-2 vaccine. Methods Participants were recruited into Virus Watch starting in June 2020. Weekly surveys were sent out to participants, and vaccination status was collected from January 2021 onward. Between September 2020 and February 2021, we invited 13,120 adult Virus Watch participants to contribute toward our tracker subcohort, which uses the GPS via a smartphone app to collect data on movement. We used segmented linear regression to estimate the median daily travel distance before and after the first self-reported SARS-CoV-2 vaccine dose. Results We analyzed the daily travel distance of 249 vaccinated adults. From 157 days prior to vaccination until the day before vaccination, the median daily travel distance was 9.05 (IQR 8.06-10.09) km. From the day of vaccination to 105 days after vaccination, the median daily travel distance was 10.08 (IQR 8.60-12.42) km. From 157 days prior to vaccination until the vaccination date, there was a daily median decrease in mobility of 40.09 m (95% CI –50.08 to –31.10; P<.001). After vaccination, there was a median daily increase in movement of 60.60 m (95% CI 20.90-100; P<.001). Restricting the analysis to the third national lockdown (January 4, 2021, to April 5, 2021), we found a median daily movement increase of 18.30 m (95% CI –19.20 to 55.80; P=.57) in the 30 days prior to vaccination and a median daily movement increase of 9.36 m (95% CI 38.6-149.00; P=.69) in the 30 days after vaccination. Conclusions Our study demonstrates the feasibility of collecting high-volume geolocation data as part of research projects and the utility of these data for understanding public health issues. Our various analyses produced results that ranged from no change in movement after vaccination (during the third national lock down) to an increase in movement after vaccination (considering all periods, up to 105 days after vaccination), suggesting that, among Virus Watch participants, any changes in movement distances after vaccination are small. Our findings may be attributable to public health measures in place at the time such as movement restrictions and home working that applied to the Virus Watch cohort participants during the study period.

Tracking Changes in Mobility Before and After the First SARS-CoV-2 Vaccination Using Global Positioning System Data in England and Wales (Virus Watch): Prospective Observational Community Cohort Study

An interpretable machine learning framework for measuring urban perceptions from panoramic street view images

Objective Since the outbreak of COVID-19, public health and social measures to contain its transmission (e.g., social distancing and lockdowns) have dramatically changed people's lives in rural and urban areas globally. To facilitate future management of the pandemic, it is important to understand how different socio-demographic groups adhere to such demands. This study aims to evaluate the influences of restriction policies on human mobility variations associated with socio-demographic groups in England, UK. Methods Using mobile phone global positioning system (GPS) trajectory data, we measured variations in human mobility across socio-demographic groups during different restriction periods from Oct 14, 2020 to Sep 15, 2021. The six restriction periods which varied in degree of mobility restriction policies, denoted as “Three-tier Restriction,” “Second National Lockdown,” “Four-tier Restriction,” “Third National Lockdown,” “Steps out of Lockdown,” and “Post-restriction,” respectively. Individual human mobility was measured with respect to the time period people stayed at home, visited places outside the home, and traveled long distances. We compared these indicators across the six restriction periods and across socio-demographic groups. Results All human mobility indicators significantly differed across the six restriction periods, and the influences of restriction policies on individual mobility behaviors are correlated with socio-demographic groups. In particular, influences relating to mobility behaviors are stronger in younger and low-income groups in the second and third national lockdowns. Conclusions This study enhances our understanding of the influences of COVID-19 pandemic restriction policies on human mobility behaviors within different social groups in England. The findings can be usefully extended to support policy-making by investigating human mobility and differences in policy effects across not only age and income groups, but also across geographical regions.

Human mobility variations in response to restriction policies during the COVID-19 pandemic: An analysis from the Virus Watch community cohort in England, UK

Generative Adversarial Networks (GANs) are susceptible to bias, learned from either the unbalanced data, or through mode collapse. The networks focus on the core of the data distribution, leaving the tails - or the edges of the distribution - behind. We argue that this bias is responsible not only for fairness concerns, but that it plays a key role in the collapse of latent-traversal editing methods when deviating away from the distribution's core. Building on this observation, we outline a method for mitigating generative bias through a self-conditioning process, where distances in the latent-space of a pre-trained generator are used to provide initial labels for the data. By fine-tuning the generator on a re-sampled distribution drawn from these self-labeled data, we force the generator to better contend with rare semantic attributes and enable more realistic generation of these properties. We compare our models to a wide range of latent editing methods, and show that by alleviating the bias they achieve finer semantic control and better identity preservation through a wider range of transformations. Our code and models will be available at https://github.com/yzliu567/sc-gan

Self-Conditioned Generative Adversarial Networks for Image Editing

MDISN: Learning multiscale deformed implicit fields from single images

This paper studies a stochastic two-species Schoener's competitive model with regime switching. We first investigate the sufficient conditions for the existence of a unique stationary distribution of the model. Then we prove that the convergence of transition probability to the stationary distribution is exponentially under some mild assumptions. Moreover, we also introduce several numerical simulations to validate the model against the biological significance.

Stationary distribution of a stochastic two-species Schoener's competitive system with regime switching

Generative Adversarial Networks (GANs) are susceptible to bias, learned from either the unbalanced data, or through mode collapse. The networks focus on the core of the data distribution, leaving the tails — or the edges of the distribution — behind. We argue that this bias is responsible not only for fairness concerns, but that it plays a key role in the collapse of latent-traversal editing methods when deviating away from the distribution’s core. Building on this observation, we outline a method for mitigating generative bias through a self-conditioning process, where distances in the latent-space of a pre-trained generator are used to provide initial labels for the data. By fine-tuning the generator on a re-sampled distribution drawn from these self-labeled data, we force the generator to better contend with rare semantic attributes and enable more realistic generation of these properties. We compare our models to a wide range of latent editing methods, and show that by alleviating the bias they achieve finer semantic control and better identity preservation through a wider range of transformations. Our code and models will be available at https://github.com/yzliu567/sc-gan

Abstract Background: With the global spreading of Coronavirus disease (COVID-19), many primary care medical workers have been infected, particularly in the early stages of this pandemic. Although extensive studies have explored the COVID-19 transmission patterns and (non-) pharmaceutical intervention to protect the general public, limited research has analysed the measures to prevent nosocomial transmission based upon detailed interpersonal contacts between medical staff and patients. Aim: This paper aims to develop and evaluate proactive prevention measures to contain the nosocomial transmission of COVID-19. The specific objectives are (1) to understand the virus transmission via interpersonal contacts among medical staff and patients; (2) to define proactive measures to reduce the risk of infection of medical staff and (3) evaluate the effectiveness of these measures to control the COVID-19 epidemic in hospitals. Methods: We observed the operation of a typical primary hospital in China to understand the interpersonal contacts among medical staff and patients. We defined effective distance as the indicator for risk of transmission. Then three proactive measures were proposed based upon the observations, including a medical staff rotation system, the establishment of a separate fever clinic and medical staff working alone. Finally, the impacts of these measures are evaluated with a modified Susceptible-Exposure-Infected-Removed model accommodating the situation of hospitals and asymptomatic and latent infection of COVID-19. The case study was conducted with the hospital observed in December 2019 and February 2020. Findings: The implementation of the medical staff rotation system has the most significant impact on containing the epidemic. The establishment of a separate fever clinic and medical staff working alone also benefits from inhibiting the epidemic outbreak. The simulation finds that if effective prevention and control measures are not taken in time, it will lead to a surge of infection cases in all asymptomatic probabilities and incubation periods.

Measures to prevent nosocomial transmissions of COVID-19 based on interpersonal contact data

Pork is one of the most common foods causing microbial foodborne diseases. Since pork directly enters the market after slaughtering, the control of microbial contamination in the slaughtering processes is the key to ensuring the quality and safety of pork. The contamination level of Escherichia coli, a health-indicator bacterium, can reflect the risk level of potential pathogens. In order to assess the E. coli exposure risk of pork during slaughtering and to identify the key control points, we established an E. coli quantitative exposure assessment model for swine-slaughtering processes in slaughterhouses of different sizes. The model simulation data indicated the E. coli contamination pattern on the surfaces of swine carcasses during slaughtering. The changes in E. coli contamination were analyzed according to the simulation data of each slaughtering process. It was found that the number of E. coli after trimming in big and small slaughterhouses increased to the maximum values for the whole processes, which were 3.63 and 3.52 log10 CFU/100 cm2, respectively. The risk contribution of each slaughtering process to the E. coli contamination on the surface of terminal swine carcasses can be determined by correlation analysis. Because the absolute value of correlation coefficient during the trimming process was maximum (0.49), it was regarded as the most important key control point. This result can be further proved via the multilocus sequence typing of E. coli. The dominant sequence type before trimming processes was ST10. ST1434 began to appear in the trimming process and then became the dominant sequence type in the trimming and pre-cooling processes. The model can provide a theoretical basis for microbial hygiene supervision and risk control in swine-slaughtering processes.

Analysis of Key Control Points of Microbial Contamination Risk in Pork Production Processes Using a Quantitative Exposure Assessment Model

Abstract Background: Some evidence suggests that individuals may change adherence to public health policies aimed at reducing contact, transmission and spread of the SARS-CoV-2 virus after they receive their first SARS-CoV-2 vaccination. In this study, we aim to estimate the rate of change in average daily travel distance from a participant's registered address before and after SARS-CoV-2 vaccination. Method: Participants were recruited into Virus Watch starting in June 2020. Weekly surveys were sent out to participants and vaccination status was collected from January 2021 onwards. Between September 2020 and February 2021, we invited 13,120 adult Virus Watch participants to contribute towards our tracker sub-cohort which uses the Global Positioning System (GPS) to collect data on movement. We used segmented linear regression to estimate the median daily travel distance before and after the first self-reported SARS-CoV-2 vaccine dose. Results: We analysed the daily travel distance of 228 vaccinated adults. Between 157 days prior to vaccination until the day before vaccination, the median daily travel distance travelled was 8.9km (IQR: 3.50km, 24.17km). Between the day of vaccination and 100 days after vaccination, the median daily travel distance travelled was 10.30km (IQR: 4.11, 27.53km). Between 157 days prior to vaccination and the vaccination date, there was a daily median decrease in mobility of 40m (95%CI: -51m, -31m, p-value <0.001) per day. After the removal of outlier data, and between the vaccination date and 99 days after vaccination, there was a median daily increase in movement of 45.0m (95%CI: 25m, 65m, p-value = <0.001). Restricting the analysis to the 3rd national lockdown (4th of January 2021 to the 5th of April 2021), we found a median daily movement increase of 9m (95%CI: -25m, 45m, p = 0.57) in the 30 days prior to vaccination and the vaccination date, and a median daily movement increase of 10m (95%CI: -60m, 94m, p-value = 0.69) in the 30 days after vaccination. Conclusions: Our study demonstrates the feasibility of collecting high volume geolocation data as part of research projects, and the utility of these for understanding public health issues. Our results are consistent with both an increase and decrease in movement after vaccination and suggest that, amongst Virus Watch participants, any changes in movement distances post-vaccination are small.

Changes in mobility pre and post first SARS-CoV-2 vaccination: findings from a prospective community cohort study including GPS movement tracking in England and Wales (Virus Watch)

Theories of neural replay propose that it supports a range of different functions, most prominently planning and memory maintenance. Here, we test the hypothesis that distinct replay signatures relate to planning and memory maintenance. Our reward learning task required human participants to utilize structure knowledge for 'model-based' evaluation, while maintaining knowledge for two independent and randomly alternating task environments. Using magnetoencephalography (MEG) and multivariate analysis, we found neural evidence for compressed forward replay during planning and backward replay following reward feedback. Prospective replay strength was enhanced for the current environment when the benefits of a model-based planning strategy were higher. Following reward receipt, backward replay for the alternative, distal environment was enhanced as a function of decreasing recency of experience for that environment. Consistent with a memory maintenance role, stronger maintenance-related replay was associated with a modulation of subsequent choices. These findings identify distinct replay signatures consistent with key theoretical proposals on planning and memory maintenance functions, with their relative strength modulated by on-going computational and task demands.

Understanding the visual world is a constructive process. Whilst a frontal-hippocampal circuit is known to be essential for this task, little is known about the associated neuronal computations. Visual understanding appears superficially distinct from other known functions of this circuit, such as spatial reasoning and model-based planning, but recent models suggest deeper computational similarities. Here, using fMRI, we show that representations of a simple visual scene in these brain regions are relational and compositional – key computational properties theorised to support rapid construction of hippocampal maps. Using MEG, we show that rapid sequences of representations, akin to replay in spatial navigation and planning problems, are also engaged in visual construction. Whilst these sequences have previously been proposed as mechanisms to plan possible futures or learn from the past, here they are used to understand the present. Replay sequences form constructive hypotheses about possible scene configurations. These hypotheses play out in an optimal order for relational inference, progressing from predictable to uncertain scene elements, gradually constraining possible configurations, and converging on the correct scene configuration. Together, these results suggest a computational bridge between apparently distinct functions of hippocampal-prefrontal circuitry, and a role for generative replay in constructive inference and hypothesis testing.

Generative replay for compositional visual understanding in the prefrontal-hippocampal circuit

Background Differential exposure to public activities may contribute to stark deprivation-related inequalities in SARS-CoV-2 infection and outcomes but has not been directly investigated. We set out to investigate whether participants in Virus Watch—a large community cohort study based in England and Wales—reported differential exposure to public activities and non-household contacts during the autumn–winter phase of the COVID-19 pandemic according to postcode-level socioeconomic deprivation. Methods Participants (n=20 120–25 228 across surveys) reported their daily activities during 3 weekly periods in late November 2020, late December 2020 and mid-February 2021. Deprivation was quantified based on participants’ residential postcode using English or Welsh Index of Multiple Deprivation quintiles. We used Poisson mixed-effect models with robust standard errors to estimate the relationship between deprivation and risk of exposure to public activities during each survey period. Results Relative to participants in the least deprived areas, participants in the most deprived areas exhibited elevated risk of exposure to vehicle sharing (adjusted risk ratio (aRR) range across time points: 1.73–8.52), public transport (aRR: 3.13–5.73), work or education outside of the household (aRR: 1.09–1.21), essential shops (aRR: 1.09–1.13) and non-household contacts (aRR: 1.15–1.19) across multiple survey periods. Conclusion Differential exposure to essential public activities—such as attending workplaces and visiting essential shops—is likely to contribute to inequalities in infection risk and outcomes. Public health interventions to reduce exposure during essential activities and financial and practical support to enable low-paid workers to stay at home during periods of intense transmission may reduce COVID-related inequalities.

Deprivation and exposure to public activities during the COVID-19 pandemic in England and Wales

A ubiquitous feature of human decision making under risk is that individuals differ from each other, as well as from normativity, in how they incorporate reward and probability information. One possible explanation for these deviations is a desire to reduce the number of potential outcomes considered during choice evaluation. Although multiple behavioral models can be invoked involving selective consideration of choice outcomes, whether differences in these tendencies underlie behavioral differences in sensitivity to reward and probability information is unknown. Here we consider neural evidence where we exploit magnetoencephalography (MEG) to decode the actual choice outcomes participants consider when they decide between a gamble and a safe outcome. We show that variability in tendencies of individual participants to reinstate neural outcome representations, based on either their probability or reward, explains variability in the extent to which their choices reflect consideration of probability and reward information. In keeping with this we also show that participants who are higher in behavioral impulsivity fail to preferentially reinstate outcomes with higher probability. Our results suggest that neural differences in the degree to which outcomes are considered shape risk taking strategy, both in decision making tasks, as well as in real life.

Selective outcome reinstatement during evaluation drives heuristics in risky choice

Identifying and understanding road-constrained areas of interest (AOIs) through spatiotemporal taxi GPS data: A case study in New York City

Author response: Temporally delayed linear modelling (TDLM) measures replay in both animals and humans

Experiences Replay Accompanies Efficient Non-Local Learning: MEG Neurocomputational Dynamics

 Vaccination intention is vital to the success of any vaccination programme, alongside vaccine availability and access. Public intention to take a COVID-19 vaccine if offered is high in the UK, but evidence of disparities between ethnic, social and age groups has led to concern.
 
 Methods
 Online survey of prospective household community cohort study participants across England and Wales (Virus Watch). Vaccination intention was measured by individual participant responses to ‘Would you accept a COVID-19 vaccine if offered?’, collected in December 2020 and February 2021. Responses to a 13-item questionnaire collected in January 2021 were analysed using factor analysis to investigate psychological influences on vaccination intention.
 
 Results
 Survey response rate was 56% (20,785/36,998) in December 2020 and 53% (20,590/38,727) in February 2021, with 14880 adults reporting across both time points. Of participants reporting across both timepoints, 13,411 (90%) answered ‘Yes’ and 1,469 (10%) responded ‘No’ or ‘Unsure’ in December 2020. Of those answering ‘No’ or ‘Unsure’ in December 2020, 1,266 (86%) subsequently answered ‘Yes’ or ‘Already had a COVID-19 vaccine’ in February 2021. Vaccination intention increased across all ethnic groups and levels of social deprivation. Age was most strongly associated with vaccination intention, with 16–24-year-olds more likely to respond “Unsure” or “No” versus “Yes” than 65-74-year-olds in December 2020 (OR: 4.63, 95%CI: 3.42, 6.27 & OR 7.17 95%CI: 4.26, 12.07 respectively) and February 2021 (OR: 27.92 95%CI: 13.79, 56.51 & OR 17.16 95%CI: 4.12, 71.55). The association between ethnicity and vaccination intention has weakened, but not disappeared, over time. Both vaccine- and illness-related psychological factors were shown to influence vaccination intention.
 
 Four in five adults (86%) who were reluctant or intending to refuse a COVID-19 vaccine in December 2020 had changed their mind in February 2021 and planned to accept, or had already accepted, a vaccine.

Trends, patterns and psychological influences on COVID-19 vaccination intention: Findings from a large prospective community cohort study in England and Wales (Virus Watch)

Neural implicit functions have achieved impressive results for reconstructing 3D shapes from single images. However, the image features for describing 3D point samplings of implicit functions are less effective when significant variations of occlusions, views, and appearances exist from the image. To better encode image features, we study a geometry-aware convolutional kernel to leverage geometric relationships of point samplings by the proposed \emph{spatial pattern}, i.e., a structured point set. Specifically, the kernel operates at 2D projections of 3D points from the spatial pattern. Supported by the spatial pattern, the 2D kernel encodes geometric information that is crucial for 3D reconstruction tasks, while traditional ones mainly consider appearance information. Furthermore, to enable the network to discover more adaptive spatial patterns for further capturing non-local contextual information, the kernel is devised to be deformable manipulated by a spatial pattern generator. Experimental results on both synthetic and real datasets demonstrate the superiority of the proposed method. Pre-trained models, codes, and data are available at https://github.com/yixin26/SVR-SP.

Neural Implicit 3D Shapes from Single Images with Spatial Patterns

An emerging goal in neuroscience is tracking what information is represented in brain activity over time as a participant completes some task. Whilst EEG and MEG offer millisecond temporal resolution of how activity patterns emerge and evolve, standard decoding methods present significant barriers to interpretability as they obscure the underlying spatial and temporal activity patterns. We instead propose the use of a generative encoding model framework that simultaneously infers the multivariate spatial patterns of activity and the variable timing at which these patterns emerge on individual trials. An encoding model inversion allows predictions to be made about unseen test data in the same way as in standard decoding methodology. These SpatioTemporally Resolved MVPA (STRM) models can be flexibly applied to a wide variety of experimental paradigms, including classification and regression tasks. We show that these models provide insightful maps of the activity driving predictive accuracy metrics; demonstrate behaviourally meaningful variation in the timing of pattern emergence on individual trials; and achieve predictive accuracies that are either equivalent or surpass those achieved by more widely used methods. This provides a new avenue for investigating the brain’s representational dynamics and could ultimately support more flexible experimental designs in future. HIGHLIGHTS We introduce SpatioTemporally Resolved MVPA (STRM), an approach that explicitly models how successive stages of stimulus processing are distributed in both space and time in M/EEG data. We show that STRM is broadly applicable to diverse types of M/EEG data and outputs meaningful and interpretable maps of how neural representations evolve in space and time at millisecond resolution. The trial-specific deviations in activity pattern timings identified by STRM are not random, but vary systematically with inter-trial differences in behavioural, cognitive and physiological variables. These methods result in predictive accuracy metrics that are mostly equivalent to, or a modest improvement on, conventional methods.

Spatiotemporally resolved multivariate pattern analysis for M/EEG

Assessment of rural ecological environment development in China’s moderately developed areas: a case study of Xinxiang, Henan province

Differential replay of reward and punishment paths predicts approach and avoidance

Dynamic Spreading of COVID-19 Versus Community Mobility in Regions of England

Revealing spatiotemporal transmission patterns and stages of COVID-19 in China using individual patients’ trajectory data

A dual process model of popular support for Internet surveillance

Our brains at rest spontaneously replay recently acquired information, but how this process is orchestrated to avoid interference with ongoing cognition is an open question. We investigated whether replay coincided with spontaneous patterns of whole brain activity. We found, in two separate datasets, that replay sequences were packaged into transient bursts occurring selectively during activation of the default mode network (DMN) and parietal alpha network. These networks were characterized by widespread synchronized oscillations coupled to increases in ripple band power, mechanisms that coordinate information flow between disparate cortical areas. Our data show a tight correspondence between two widely studied phenomena of neural physiology and suggest the DMN may coordinate replay bursts in a manner that minimizes interference with ongoing cognition.

Replay bursts coincide with activation of the default mode and parietal alpha network

To make effective decisions we need to consider the relationship between actions and outcomes. They are, however, often separated by time and space. The biological mechanism capable of spanning those gaps remains unknown. One promising, albeit hypothetical, mechanism involves neural replay of non-local experience. Using a novel task, that segregates direct from indirect learning, combined with magnetoencephalography (MEG), we tested the role of neural replay in non-local learning in humans. Following reward receipt, we found significant backward replay of non-local experience, with a 160 msec state-to-state time lag, and this replay facilitated learning of action values. This backward replay, combined with behavioural evidence of non-local learning, was more pronounced in experiences that were of greater benefit for future behavior, as predicted by theories of prioritization. These findings establish rationally targeted non-local replay as a neural mechanism for solving complex credit assignment problems during learning. One Sentence Summary Reverse sequential replay is found, for the first time, to support non-local reinforcement learning in humans and is prioritized according to utility.

Considering context and dynamics: A classification of transit-orientated development for New York City

The human brain simulates the outcomes of actions to enable avoidance of danger. Harm avoidance is critical for survival, yet little is known regarding the neural mechanisms supporting avoidance in the absence of trial-and-error experience. Flexible avoidance may be supported by a mental model (i.e., model-based), a process for which neural reactivation and sequential replay have emerged as candidate mechanisms. During an aversive learning task, combined with magnetoencephalography, we show prospective and retrospective reactivation during planning and learning, respectively, coupled to evidence for sequential replay. Specifically, when individuals plan in an aversive context, we find preferential reactivation of subsequently chosen goal states. Stronger reactivation is associated with greater hippocampal theta power. At outcome receipt, unchosen goal states are reactivated regardless of outcome valence. Replay of paths leading to goal states was modulated by outcome valence, with aversive outcomes associated with stronger reverse replay than safe outcomes. Our findings are suggestive of avoidance involving simulation of unexperienced states through hippocampally mediated reactivation and replay.

Model-based aversive learning in humans is supported by preferential task state reactivation

There are rich structures in off-task neural activity. For example, task related neural codes are thought to be reactivated in a systematic way during rest. This reactivation is hypothesised to reflect a fundamental computation that supports a variety of cognitive functions. Here, we introduce an analysis toolkit (TDLM) for analysing this activity. TDLM combines nonlinear classification and linear temporal modelling to testing for statistical regularities in sequences of neural representations. It is developed using non-invasive neuroimaging data and is designed to take care of confounds and maximize sequence detection ability. The method can be extended to rodent electrophysiological recordings. We outline how TDLM can successfully reveal human replay during rest, based upon non-invasive magnetoencephalography (MEG) measurements, with strong parallels to rodent hippocampal replay. TDLM can therefore advance our understanding of sequential computation and promote a richer convergence between animal and human neuroscience research.

Measuring Sequences of Representations with Temporally Delayed Linear Modelling

Decision letter: Hippocampal replay of experience at real-world speeds

Abstract We discuss opportunities in applying the resource-rationality framework toward answering questions in emotion and mental health research. These opportunities rely on characterization of individual differences in cognitive strategies; an endeavor that may be at odds with the normative approach outlined in the target article. We consider ways individual differences might enter the framework and the translational opportunities offered by each.

Opportunities for emotion and mental health research in the resource-rationality framework

Representations of Sequence Identity and Position Consistently Precede Object Representations during Replay Events Are structural representations spontaneously reactivated at rest? To address this, we applied the trained position and sequence code classifiers to the MEG data from the second resting period. As with the stimulus code classifiers, each classifier produced a Cell 178, 1–13, July 25, 2019 7

Our everyday experience shapes how we represent the structure of the world. Retrieval of these experiences from memory is fundamental for informing our future decisions. To uncover the fine-grained neurophysiological mechanisms that support such retrieval we studied participants who first experienced unique multi-component episodes, and subsequently completed cued memory retrieval of these whilst undergoing magnetoencephalography (MEG). Successful retrieval was supported by sequential replay of episodes, with a temporal compression factor greater than 60. This sequential replay was stronger in those participants with weaker overall memories. Replay direction, forward or backward, was dependent on whether a participant’s goal was to retrieve elements of an episode that followed, or preceded, a retrieval cue. Our results demonstrate that memory-based decisions are supported by a rapid replay mechanism that flexibly shifts in direction.

Episodic memory retrieval is supported by rapid replay of episode content

ABSTRACT A geodemographic classification aims to describe the most salient characteristics of a small area zonal geography. However, such representations are influenced by the methodological choices made during their construction. Of particular debate are the choice and specification of input variables, with the objective of identifying inputs that add value but also aim for model parsimony. Within this context, our paper introduces a principal component analysis (PCA)-based automated variable selection methodology that has the objective of identifying candidate inputs to a geodemographic classification from a collection of variables. The proposed methodology is exemplified in the context of variables from the UK 2011 Census, and its output compared to the Office for National Statistics 2011 Output Area Classification (2011 OAC). Through the implementation of the proposed methodology, the quality of the cluster assignment was improved relative to 2011 OAC, manifested by a lower total within-cluster sum of square score. Across the UK, more than 70.2% of the Output Areas (OAs) occupied by the newly created classification (i.e. AVS-OAC) outperform the 2011 OAC, with particularly strong performance within Scotland and Wales.

A Principal Component Analysis (PCA)-based framework for automated variable selection in geodemographic classification

Rural Greenway Recreation Post-evaluation (POE) Study - A Case Study of Shentangyu Greenway in Huairou District, Beijing

ABSTRACT Plentiful studies have discussed the potential applications of contactless smart card from understanding interchange patterns to transit network analysis and user classifications. However, the incomplete and anonymous nature of the smart card data inherently limit the interpretations and understanding of the findings, which further limit planning implementations. Geodemographics, as ‘an analysis of people by where they live’, can be utilised as a promising supplement to provide contextual information to transport planning. This paper develops a methodological framework that conjointly integrates personalised smart card data with open geodemographics so as to pursue a better understanding of the traveller’s behaviours. It adopts a text mining technology, latent Dirichlet allocation modelling, to extract the transit patterns from the personalised smart card data and then use the open geodemographics derived from census data to enhance the interpretation of the patterns. Moreover, it presents night tube as an example to illustrate its potential usefulness in public transport planning.

Understanding public transit patterns with open geodemographics to facilitate public transport planning

This paper constructs a carbon financial development index to measure the development level of China’s various provinces and regions. It makes a comparative analysis of the general situation and trends of China’s carbon finance development to investigate the reasons for restricting the level of the development of carbon finance, then put forward suggestions in policy to improve the development level of China’s Carbon Finance.

An evaluation on regional differences in the level of carbon finance

Since the invention of the Smart Card in the late 1960s, this technology itself and its derivative applications have been increasingly benefiting and maturing in several industrial sectors, such as healthcare, banking, and government. In the public transit field, extensive researches that adopt data from the SCAFC system have been conducting accordingly, most of which are popularly categorised in the strategic-level study that aims primarily to understanding passengers’ travel pattern via characterisation and classification (Pelletier, Trépanier, and Morency, 2011). Understanding transit patterns can be beneficial to assess the performance of the transit network, more accurately forecast travel demand, adjust service arrangement which copes with the ridership varying from both space and time.

Characterising Passengers ’ Travel Patterns in London Public Transit

In the Funding section, there is a missing grant number for the National Natural Science Foundation of China. Please refer to the complete funding statement below: This study was funded by the National Basic Research Program of China (973 Program, 2014CB744600) and the National Natural Science Foundation of China (31300867, 31171004). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Correction: Spatial Attention Effects of Disgusted and Fearful Faces

Temporally delayed linear modelling ( TDLM ) measures replay in 1 both animals and humans 2 3

Abstract Schizophrenia is characterized by an abnormal resting state and default mode network brain activity. However, despite intense study, the mechanisms linking default mode network dynamics to neural computation remain elusive. During rest, sequential hippocampal reactivations, known as ‘replay’, are played out within default mode network activation windows, highlighting a potential role of replay-default mode network coupling in memory consolidation and model-based mental simulation. Here, we test a hypothesis of reduced replay-default mode network coupling in schizophrenia, using magnetoencephalography and a non-spatial sequence learning task designed to elicit off-task (i.e. resting state) neural replay. Participants with a diagnosis of schizophrenia (n = 28, mean age 28.2 years, range 20–40, 6 females, 13 not taking antipsychotic medication) and non-clinical control participants (n = 29, mean age 28.1 years, range 18–45, 6 females, matched at group level for age, intelligence quotient, gender, years in education and working memory) underwent a magnetoencephalography scan both during task completion and during a post-task resting state session. We used neural decoding to infer the time course of default mode network activation (time-delay embedding hidden Markov model) and spontaneous neural replay (temporally delayed linear modelling) in resting state magnetoencephalography data. Using multiple regression, we then quantified the extent to which default mode network activation was uniquely predicted by replay events that recapitulated the learned task sequences (i.e. ‘task-relevant’ replay-default mode network coupling). In control participants, replay-default mode network coupling was augmented following sequence learning, an augmentation that was specific for replay of task-relevant (i.e. learned) state transitions. This task-relevant replay-default mode network coupling effect was significantly reduced in schizophrenia (t(52) = 3.93, P = 0.018). Task-relevant replay-default mode network coupling predicted memory maintenance of learned sequences (ρ(52) = 0.31, P = 0.02). Importantly, reduced task-relevant replay-default mode network coupling in schizophrenia was not explained by differential replay or altered default mode network dynamics between groups nor by reference to antipsychotic exposure. Finally, task-relevant replay-default mode network coupling during rest correlated with stimulus-evoked default mode network modulation as measured in a separate task session. In the context of a proposed functional role of replay-default mode network coupling, our findings shed light on the functional significance of default mode network abnormalities in schizophrenia and provide for a consilience between task-based and resting state default mode network findings in this disorder.

Reduced coupling between offline neural replay events and default mode network activation in schizophrenia

Abstract Background and Hypotheses Hippocampal replay and associated high-frequency ripple oscillations are among the best-characterized phenomena in resting brain activity. Replay/ripples support memory consolidation and relational inference, and are regulated by N-methyl-D-aspartate receptors (NMDARs). Schizophrenia has been associated with both replay/ripple abnormalities and NMDAR hypofunction in both clinical samples and genetic mouse models, although the relationship between these 2 facets of hippocampal function has not been tested in humans. Study Design Here, we avail of a unique multimodal human neuroimaging data set to investigate the relationship between the availability of (intrachannel) NMDAR binding sites in hippocampus, and replay-associated ripple power, in 16 participants (7 nonclinical participants and 9 people with a diagnosis of schizophrenia, PScz). Each participant had both a [18F]GE-179 positron emission tomography (PET) scan (to measure NMDAR availability, VT) and a magnetoencephalography (MEG) scan (to measure offline neural replay and associated high-frequency ripple oscillations, using Temporally Delayed Linear Modeling). Study Results We show a positive relationship between hippocampal NMDAR availability and replay-associated ripple power. This linkage was evident across control participants (r(5) = .94, P = .002) and PScz (r(7) = .70, P = .04), with no group difference. Conclusions Our findings provide preliminary evidence for a relationship between hippocampal NMDAR availability and replay-associated ripple power in humans, and haverelevance for NMDAR hypofunction theories of schizophrenia.

Relationship Between Replay-Associated Ripples and Hippocampal N-Methyl-D-Aspartate Receptors: Preliminary Evidence From a PET-MEG Study in Schizophrenia

Theories of neural replay propose that it supports a range of functions, most prominently planning and memory consolidation. Here, we test the hypothesis that distinct signatures of replay in the same task are related to model-based decisionmaking (‘planning’) and memory preservation. We designed a reward learning task wherein participants utilized structure knowledge for model-based evaluation, while at the same time had to maintain knowledge of two independent and randomly alternating task environments. Using magnetoencephalography (MEG) and multivariate analysis, we first identified temporally compressed sequential reactivation, or replay, both prior to choice and following reward feedback. Before choice, prospective replay strength was enhanced for the current task-relevant environment when a model-based planning strategy was beneficial. Following reward receipt, and consistent with a memory preservation role, replay for the alternative distal task environment was enhanced as a function of decreasing recency of experience with that environment. Critically, these planning and memory preservation relationships were selective to pre-choice and post-feedback periods. Our results provide new support for key theoretical proposals regarding the functional role of replay and demonstrate that the relative strength of planning and memory-related signals are modulated by on-going computational and task demands. Significance statement The sequential neural reactivation of prior experience, known as replay, is considered to be an important mechanism for both future planning and preserving memories of the past. Whether, and how, replay supports both of these functions remains unknown. Here, in humans, we found that prior to a choice, rapid replay of potential future paths was enhanced when planning was more beneficial. By contrast, after choice feedback, when no future actions are imminent, we found evidence for a memory preservation signal evident in enhanced replay of paths that had been visited less in the recent past. The results demonstrate that distinct replay signatures, expressed at different times, relate to two dissociable cognitive functions.

Distinct replay signatures for prospective decision-making and memory preservation

The long-lasting global pandemic of Coronavirus disease 2019 (COVID-19) has changed our daily life in many ways and put heavy burden on our mental health. Having a predictive model of negative emotions during COVID-19 is of great importance for identifying potential risky population. To establish a neural predictive model achieving both good interpretability and predictivity, we have utilized a large-scale (n =542) longitudinal dataset, alongside two independent samples for external validation. We built a predictive model based on psychologically meaningful resting state neural activities. The whole-brain resting-state neural activity and social-psychological profile of the subjects were obtained from Sept. to Dec. 2019 (Time 1). Their negative emotions were tracked and re-assessed twice, on Feb 22 (Time 2) and Apr 24 (Time 3), 2020, respectively. We first applied canonical correlation analysis on both the neural profiles and psychological profiles collected on Time 1, this step selects only the psychological meaningful neural patterns for later model construction. We then trained the neural predictive model using those identified features on data obtained on Time 2. It achieved a good prediction performance (r =0.44, p =8.13 ×10-27). The two most important neural predictors are associated with self-control and social interaction. This study established an effective neural prediction model of negative emotions, achieving good interpretability and predictivity. It will be useful for identifying potential risky population of emotional disorders related to COVID-19. IEEE

Functional neuroimaging in psychiatry and the case for failing better

Impaired neural replay of inferred relationships in schizophrenia

Replay supports planning Learning from direct experience is easy—we can always use trial and error—but how do we learn from nondirect (nonlocal) experiences? For this, we need additional mechanisms that bridge time and space. In rodents, hippocampal replay is hypothesized to promote this function. Liu et al. measured high-temporal-resolution brain signals using human magnetoencephalography combined with a new model-based, visually oriented, multipath reinforcement memory task. This task was designed to differentiate local versus nonlocal learning episodes within the subject. They found that reverse sequential replay in the human medial temporal lobe supports nonlocal reinforcement learning and is the underlying mechanism for solving complex credit assignment problems such as value learning. Science, abf1357, this issue p. eabf1357 Reverse sequential replay supports nondirect reinforcement learning in humans and is prioritized according to utility. INTRODUCTION Adaptive decision-making requires assimilation of reward information to guide subsequent choices. However, actions and outcomes are often separated by time and space, rendering this difficult. In reinforcement learning, this problem can be solved using “model-based” inference, in which an agent leverages a learned model of the environment to link local reward to nonlocal actions; this process is known as experience replay. A potential neural substrate for this process is hippocampal “replay.” In rodents, cells in the hippocampus fire in an organized manner that recapitulates past or potential future trajectories during rest. A similar phenomenon has also been observed in humans during a post-task rest period. However, a direct connection between replay and nonlocal (i.e., model-based) learning has yet to be established. RATIONALE The question of how to achieve model-based learning in the service of adaptive behavior is central to understanding intelligence in both biological and artificial agents. We addressed this question by exploiting a normative model of replay based on reinforcement learning theory. This model makes specific predictions regarding how replay relates to nonlocal learning and about which information is more or less useful if replayed. To measure replay in humans, we used machine learning techniques in conjunction with magnetoencephalography (MEG) recordings of whole-brain neural activity. These techniques enabled us to ask whether and how neural replay contributes to nondirect learning in humans. In so doing, we address an outstanding question in reinforcement learning theory: how the brain forms links between disjoint actions and goals and uses these to inform better decisions in the future. RESULTS We designed a novel decision-making task to separate local from nonlocal learning—that is, learning from direct experience as opposed to indirect learning based on inference. Specifically, we developed a three-arm task, wherein each arm comprised two paths leading to distinct end states. Crucially, the two end states, reachable from each arm, are shared across all three arms. This design feature allows post-choice reward feedback to inform future choices not only in the chosen arm (local learning) but also in either of the other two arms (nonlocal learning). This work revealed the existence of backward neural replay of nonlocal experiences after reward receipt, with a 160-ms state-to-state time lag. In line with normative theory, such replay predominantly represents the path most useful for future behavior. This backward replay encoded nonlocal experience alone and was physiologically distinct from a faster forward replay (30-ms time lag), which was associated with power increase in a ripple band. Using computational modeling, we showed that the strength of this backward replay relates to efficient trial-by-trial within-subject learning of the same nonlocal experience, as well as a better overall task performance across subjects. This is consistent with our theoretical predictions and provides strong support for a reinforcement learning–based account of neural replay in decision-making. CONCLUSION Backward replay accompanies efficient nonlocal learning in humans and is prioritized according to its utility. These results connect several findings in human and rodent neuroscience and implicate experience replay in model-based reinforcement learning. Experience replay is associated with efficient nonlocal learning. Top left: The key element of the experimental design is a separation of local versus nonlocal learning. The chosen path (indicated by hand) reflects local experience; the other two paths leading to the same outcome state (the red £), but not directly experienced, are the nonlocal paths. Arrow direction indicates the order of actual experience; color indicates the arm identity. There are three arms, and outcomes are shared across the three arms. Top right: Nonlocal backward replay after reward receipt. There are two nonlocal experiences per trial. We found neural replay of these paths after reward receipt, consistent with a credit assignment account in reinforcement learning—an assignment of local reward information to nonlocal actions. Bottom: Consistent with reinforcement learning theory, replay was prioritized according to utility (need × gain) and was related to more efficient nonlocal learning. In the example, this is illustrated as stronger replay (double arrows) for the green path, because of its higher utility (0.32 versus 0.29) relative to the orange path. To make effective decisions, people need to consider the relationship between actions and outcomes. These are often separated by time and space. The neural mechanisms by which disjoint actions and outcomes are linked remain unknown. One promising hypothesis involves neural replay of nonlocal experience. Using a task that segregates direct from indirect value learning, combined with magnetoencephalography, we examined the role of neural replay in human nonlocal learning. After receipt of a reward, we found significant backward replay of nonlocal experience, with a 160-millisecond state-to-state time lag, which was linked to efficient learning of action values. Backward replay and behavioral evidence of nonlocal learning were more pronounced for experiences of greater benefit for future behavior. These findings support nonlocal replay as a neural mechanism for solving complex credit assignment problems during learning.

Experience replay is associated with efficient nonlocal learning

There are rich structures in off-task neural activity which are hypothesized to reflect fundamental computations across a broad spectrum of cognitive functions. Here, we develop an analysis toolkit – temporal delayed linear modelling (TDLM) – for analysing such activity. TDLM is a domain-general method for finding neural sequences that respect a pre-specified transition graph. It combines nonlinear classification and linear temporal modelling to test for statistical regularities in sequences of task-related reactivations. TDLM is developed on the non-invasive neuroimaging data and is designed to take care of confounds and maximize sequence detection ability. Notably, as a linear framework, TDLM can be easily extended, without loss of generality, to capture rodent replay in electrophysiology, including in continuous spaces, as well as addressing second-order inference questions, for example, its temporal and spatial varying pattern. We hope TDLM will advance a deeper understanding of neural computation and promote a richer convergence between animal and human neuroscience.

Temporally delayed linear modelling (TDLM) measures replay in both animals and humans

It combines nonlinear and linear temporal to test statistical regularities in sequences of sequence onset. All non-artefactual trials were baseline corrected at source level. We looked at the main effect of the initialization of sequence. 30 Non-parametric permutation tests were performed on the volume of interest to compute the multiple comparison (whole-brain corrected) P-values of clusters above 10 voxels, with the null distribution for this cluster size being computed using permutations (n = 5000 permutations).”

Temporally delayed linear modelling (TDLM): Measuring replay in both rodents and humans

Episodic memory retrieval success is associated with rapid replay of episode content

Replay bursts in humans coincide with activation of the default mode and parietal alpha networks

by retrieval P3). The current finding could help to further understand the cognitive mechanism underlying emotional memory enhancement effect.

Memory encoding, retention and retrieval of disgusting and fearful faces

Mechanisms for attentional modulation by threatening emotions of fear, anger, and disgust

Deficits in attentional processing of fearful facial expressions in schizophrenic patients

Neural correlates underlying impaired memory facilitation and suppression of negative material in depression

Perception of the duration of emotional faces in schizophrenic patients

Memory consolidation reconfigures neural pathways involved in the suppression of emotional memories

Worldwide racial prejudice is originated from in‐group/out‐group discrimination. This prejudice can bias face perception at the very beginning of social interaction. However, little is known about the neurocognitive mechanism underlying the influence of racial prejudice on facial emotion perception. Here, we examined the neural basis of disgust perception in racial prejudice using a passive viewing task and functional magnetic resonance imaging. We found that compared with the disgusted faces of in‐groups, the disgusted faces of out‐groups result in increased amygdala and insular engagement, positive coupling of the insula with amygdala‐based emotional system, and negative coupling of the insula with anterior cingulate cortex (ACC)‐based regulatory system. Furthermore, machine‐learning algorithms revealed that the level of implicit racial prejudice could be predicted by functional couplings of the insula with both the amygdala and the ACC, which suggests that the insula is largely involved in racially biased disgust perception through two distinct neural circuits. In addition, individual difference in disgust sensitivity was found to be predictive of implicit racial prejudice. Taken together, our results suggest a crucial role of insula‐centered circuits for disgust perception in racial prejudice. Hum Brain Mapp 36:5275–5286, 2015. © 2015 Wiley Periodicals, Inc.

Depression disorder is a mental disorder characterized by a pervasive and persistent low mood, and is accompanied by low self-esteem and by a loss of interest or pleasure in normally enjoyable activities. Biological, psychological, and social factors all play a role in inducing depression. In the last decades, the rapid growth of literatures on neuroimaging psychiatry has led to major advances in our understanding of affective disorder such as depression. However, it has also made it increasingly difficult to aggregate and synthesize neuroimaging findings to reach a conclusive agreement. We try to locate the core nerural mechanisms that are specific to depression disorder based on extant literature, by employing a newly developed automated brain-mapping framework—Neurosynth that uses text-mining, meta-analysis and machine-learning techniques to decode broad cognitive states from brain activity (i.e., reverse interference). The processing stream involves the following six steps: Activation coordinates are extracted from published neuroimaging articles using an automated parser. The full text of all articles is parsed, and each article is “tagged” with a set of terms that occur at a high frequency in that article. A list of several thousand terms that occur at high frequency in 20 or more studies are generated. For each term of interest (e.g., “depression”), the entire database of coordinates is divided into two sets: those that occur in articles containing the term and those that do not. A giant meta-analysis is performed comparing the coordinates reported for studies with and without the term of interest. In addition to producing statistical inference maps (i.e., z and p value maps), we also compute posterior probability maps, which display the likelihood of a given term being used in a study if activation is observed at a particular voxel. We repeat the series of steps for depression, anxiety as well as major depression. In sum, the meta-analysis suggests that amygdala, VMPFC and DLPFC are the core nerural mechanisms underlying depression disorder. Among them, differential anlysis indicates that the dysfunction of amygdala and VMPFC is also the key brain regions for other affective disorder such as anxiety, but the malfunction of DLPFC is most predictive and specific to depression disorder. The inability to down-regulate emotion reactions may be the key neural mechanism for this particular disorder. Thus, our study provides clues for future research on neural basis underlying depression disorder, with a special emphasis on DLPFC.

The Core Neural Mechanisms underlying Depression Disorder: A Meta-analysis of fMRI Studies

This study investigated the attention modulation of disgust in comparison with anger in a dot-probe task. Results indicated a two-stage processing of attention modulation by threats. When participants viewed the cues that were represented by Chinese faces (i.e. the in-group condition), it was found at the early processing stage that an angry face elicited a larger occipital P1 component whereas a disgusted face elicited a smaller P1 for validly than for invalidly cued targets. However, the result pattern was reversed at the later processing stage: the P3 amplitudes were larger for valid disgust cues but were smaller for valid angry cues, when both were compared with invalid cue conditions. In addition, when participants viewed the cues that were represented by foreign faces (i.e. the out-group condition), the attention modulation of disgust/anger diminished at the early stage, whereas enhanced P3 amplitudes were observed in response to validly cued targets in both disgusting and angry conditions at the later stage. The current result implied that although people can perceptually differentiate the emotional categories of out-group faces as accurately as in-group faces, they may still be not able to psychologically understand the subtle differences behind different categories of out-group facial expressions.

How disgust facilitates avoidance: an ERP study on attention modulation by threats.

Depressive states amplify both upward and downward counterfactual thinking.

Effective processing of threat-related stimuli is of significant evolutionary advantage. Given the intricate relationship between attention and the neural processing of threat-related emotions, this study manipulated attention allocation and emotional categories of threat-related stimuli as independent factors and investigated the time course of spatial-attention-modulated processing of disgusting and fearful stimuli. The participants were instructed to direct their attention either to the two vertical or to the two horizontal locations, where two faces and two houses would be presented. The task was to respond regarding the physical identity of the two stimuli at cued locations. Event-related potentials (ERP) evidences were found to support a two-stage model of attention-modulated processing of threat-related emotions. In the early processing stage, disgusted faces evoked larger P1 component at right occipital region despite the attention allocation while larger N170 component was elicited by fearful faces at right occipito-temporal region only when participants attended to houses. In the late processing stage, the amplitudes of the parietal P3 component enhanced for both disgusted and fearful facial expressions only when the attention was focused on faces. According to the results, we propose that the temporal dynamics of the emotion-by-attention interaction consist of two stages. The early stage is characterized by quick and specialized neural encoding of disgusting and fearful stimuli irrespective of voluntary attention allocation, indicating an automatic detection and perception of threat-related emotions. The late stage is represented by attention-gated separation between threat-related stimuli and neutral stimuli; the similar ERP pattern evoked by disgusted and fearful faces suggests a more generalized processing of threat-related emotions via top-down attentional modulation, based on which the defensive behavior in response to threat events is largely facilitated.

Appropriate processing of human voices with different threat-related emotions is of evolutionarily adaptive value for the survival of individuals. Nevertheless, it is still not clear whether the sensitivity to threat-related information is present at birth. Using an odd-ball paradigm, the current study investigated the neural correlates underlying automatic processing of emotional voices of fear and anger in sleeping neonates. Event-related potential data showed that the fronto-central scalp distribution of the neonatal brain could discriminate fearful voices from angry voices; the mismatch response (MMR) was larger in response to the deviant stimuli of anger, compared with the standard stimuli of fear. Furthermore, this fear–anger MMR discrimination was observed only when neonates were in active sleep state. Although the neonates' sensitivity to threat-related voices is not likely associated with a conceptual understanding of fearful and angry emotions, this special discrimination in early life may provide a foundation for later emotion and social cognition development.

Discrimination of fearful and angry emotional voices in sleeping human neonates: a study of the mismatch brain responses

Time perception has been shown to be altered by emotions. This study employed event-related potentials (ERPs) to examine the effects of two threat-related emotions on the judgment of time intervals in the range of 490–910 ms. We demonstrated that disgust and fear have distinct influences on time perception. At the behavioral level, disgusted faces were estimated longer and fearful faces were estimated shorter (i.e., the generalization gradient for the disgusted faces was shifted left while the generalization gradient for the fearful faces was shifted right) when compared with neutral faces. Accordingly, the contingent negative variation, an online ERP index of timing, displayed larger area in disgust and smaller area in fear conditions when compared with neutral condition (disgust = 1.94 ± 2.35 μV•s, neutral = 1.40 ± 2.5 μV•s, and fear = 1.00 ± 2.26 μV•s). These findings indicated that specific neural mechanisms may underlie the attention effects of different subtypes of threat-related emotions on timing; compared with neutral faces, fearful faces are likely to attract more attentional resources while disgusted faces may attract less attentional resources for emotional processing. The major contribution of the current study is to provide neural correlates of fear vs. disgust divergence in the aspect of time perception and to demonstrate beyond the behavioral level that the categorization of threat-related emotions should be refined so to highlight the adaptability of the human defense system.

The duration of disgusted and fearful faces is judged longer and shorter than that of neutral faces: the attention-related time distortions as revealed by behavioral and electrophysiological measurements

An important function of the brain is to scan one’s surroundings for the presence of biologically relevant features and grant them priority for attention and action. The significance of this function for an individual’s well-being and survival has given rise to the argument that specialized neural mechanisms for processing biologically salient stimuli may exist and that these mechanisms may require little, if any, experience for normal development. As evidenced by behavioral studies, the ontogeny of this network and associated cognitive capacities may emerge before the age of one year. With technological advances in recent years, researchers have been able to utilize electroencephalography, functional near-infrared spectroscopy, and functional magnetic resonance imaging to directly explore the early development of social-emotional brain mechanisms. In this paper, we systematically review three major aspects of early social and emotional development in infancy—facial expression, emotional voice, and early socialization. Based on empirical evidence, we describe the developmental process of the corresponding social and emotional neural network. We then discuss the impact of early social experience on the development of the social and emotional brain in terms of experience-expectant and experience-dependent mechanisms. We argue that the social-emotional neural network is not a congenital processing module that is independent of social experience. The core structure of the human social and emotional brain seems to reach anatomical maturity relatively early in development (zero to three months); however, the basic organization of the social-emotional network may be specified by an experience-expectant neural circuitry that emerges at five to seven months of age and is rapidly refined by exposure to universal features of social experience during a sensitive period of development. The network retains some plasticity throughout a person’s lifetime and can be fine-tuned by individual-specific experiences, i.e., experience-dependent development. Functional connectivity between emotion-processing networks and other prefrontal regulatory systems continues to develop into adolescence. Finally, based on the present study of the early development of the social and emotional brain, we indicate three promising directions for future research.

Neonatal seizures pose a high risk for adverse outcome in survived infants. While the prognostic value of amplitude-integrated electroencephalogram (aEEG) is well established in neonates with encephalopathy and asphyxia, neonatal seizure studies focusing on the direct correlation between early aEEG measurement and subsequent neurologic outcome are scarce. In this study, the prognostic value of aEEG features was systematically analyzed in 143 full-term neonates to identify prognostic indicators of neurodevelopmental outcome. Neonatal aEEG features of background pattern, cyclicity, and seizure activity, as well as the etiology of neonatal seizures, were significantly associated with neurodevelopmental outcome at one year of age. aEEG background pattern was highly associated with neurologic outcomes (χ2 = 116.9), followed by aEEG cyclicity (χ2 = 87.2) and seizure etiology (χ2 = 79.3). Multiple linear regression showed that the four predictors explained 71.2% of the variation in neurological outcome, with standardized β coefficients of 0.44, 0.24, 0.22, and 0.14 for the predictors of aEEG background pattern, cyclicity, etiology, and aEEG seizure activity, respectively. This clinically applicable scoring system based on etiology and three aEEG indices would allow pediatricians to assess the risk for neurodevelopmental impairment and facilitate an early intervention in newborns developing seizures.

The Prognostic Value of Amplitude-Integrated EEG in Full-Term Neonates with Seizures

The relationship between noise and human performance is a crucial topic in ergonomic research. However, the brain dynamics of the emotional arousal effects of background noises are still unclear. The current study employed meaningless speech noises in the n-back working memory task to explore the changes of event-related potentials (ERPs) elicited by the noises with low arousal level vs. high arousal level. We found that the memory performance in low arousal condition were improved compared with the silent and the high arousal conditions; participants responded more quickly and had larger P2 and P3 amplitudes in low arousal condition while the performance and ERP components showed no significant difference between high arousal and silent conditions. These findings suggested that the emotional arousal dimension of background noises had a significant influence on human working memory performance, and that this effect was independent of the acoustic characteristics of noises (e.g., intensity) and the meaning of speech materials. The current findings improve our understanding of background noise effects on human performance and lay the ground for the investigation of patients with attention deficits.

Low-Arousal Speech Noise Improves Performance in N-Back Task: An ERP Study

The present study examined the neural mechanisms of attention modulation on timing using ERP and sLORETA measurements in a dual-task paradigm. We parametrically varied the attention to the durations of a 1000-Hz pure tone and further localized the cortical regions that were sensitive to the attention modulation on timing. Results demonstrated that the attention modulation might happen at early stage, approximately 200 ms after stimulus presentation. The P2 component at frontal area served as an early neural correlate of attention effects on timing. More importantly, the contingent negative variation (CNV) appeared at fronto-central area was sensitive to the attention effect. In addition, the supplementary motor area (SMA) was assumed to be one of the key regions for selectively attending to and estimating time. These findings provide temporal and spatial correlates of attention-modulated time processing and potentially help to investigate the neural mechanisms of patients with time perception deficits.

The Attention Modulation on Timing: An Event-Related Potential Study

The incident wave pressure acting on the wall of the spherical charge in the rock and soil is an important factor affecting the size of the explosion cavity, and the pressure of the incident wave is related to the impedance of both the explosive and the rock and soil. In this paper, based on the quasi-static model of explosive spherical charge in rock and soil, the impact impedance was introduced to calculate the size of explosion cavity in rock and soil medium. Through the field underground explosion experiment, it is found that the calculation result of the impact impedance model is 6.15% higher than the original model, and the influence rule of several geotechnical medium parameters on the cavity size was also analyzed.

A Quasi-Static Model of Explosive Spherical Charge in Rock and Soil with Impulsive Impedance

Comparison of wear behavior of GCr15 bearing steel prepared by selective laser melting (SLM) and electron beam melting (EBM)

Single-layer angularly-stable bandpass frequency-selective surface with interdigital resonator

The energy coupling between the underground explosion and the medium and the wave propagation mechanism in the medium are important bases for understanding the physics of the underground explosion source. In order to study the law of the propagation and attenuation for the seismic wave energy of underground explosion, the composition of the radiated energy of underground explosion in viscoelastic medium was analyzed, and the formulas for calculating inflow energy, outflow energy, radiated kinetic energy, potential energy and dissipation energy in a limited observation region were given. Based on the theory of viscoelastic spherical wave in infinite medium, the theoretical solutions of velocity, displacement, stress and strain in the Laplace domain were given by using the exponential attenuation pressure model and the generalized Maxwell viscoelastic model. The numerical solutions of velocity, displacement, stress and strain were given by using the Laplace numerical inverse method, and the inflow energy, outflow energy, radiated kinetic energy, potential energy and dissipation energy were calculated by these numerical results. The numerical results of different components of seismic wave energy are consistent with the theoretical results, and the correctness of this method is proved. Using the dry loess as typical viscoelastic material, the radial stress and particle velocity at different radii were calculated, and the relationship between the inflow energy at different radii and the wave propagation distance was obtained. The spatial distributions of the radiated kinetic energy of seismic wave were calculated by using the spatial distributions of the radial particle velocity at different times, and the propagation law of the radiated kinetic energy was obtained. The changes of the inflow energy and the radiated kinetic energy with the propagation distance in the limited observation area were analyzed, and the results show as follows: (1) In a viscoelastic medium, the energy flowing into a sphere surface decreases gradually with the increase of radius. In an ideal elastic medium, the energy flowing into a sphere surface at the elastic radius of about several times can be stabilized to a constant value. (2) The potential energy and the dissipative energy tend to constant values when the observation time is long enough in a fixed limited observation region, and the radiated kinetic energy tends to zero. (3) When a limited observation area can hold the seismic waves with complete wave length, the steady-state value of the radiated kinetic energy of seismic waves decreases with the increase of the wave propagation distance. In general, exponential function and power function can be used for piecewise fitting of the attenuation law for the steady-state value of the radiated kinetic energy of the seismic wave.

Evolution of the radiated seismic wave energy of underground explosion in visco-elastic solids

We consider polygonal billiards and we show the uniqueness of coding of non-periodic billiard trajectories in polygons whose holes have non-zero minimal diameters, generalising a theorem of Galperi...

Computational microscopy for quantitative phase imaging and refractive index tomography using annular illumination

Preparation of molecularly imprinted polymers and application in a biomimetic biotin-avidin-ELISA for the detection of bovine serum albumin.

Objectives: To compare the accuracy of tumor cell type, tumor grade, and staging pre and postoperatively in patients with endometrial carcinoma. Materials and Methods: A retrospective analysis of 81 patients who were diagnosed with endometrial carcinoma and underwent hysterectomy at the 1st Affiliated Hospital of Chongqing Medical University from January 2015 to December 2016. Results: Endometrioid adenocarcinoma was the most common histological subtype with an agreement of 75.3% (61/81) on final pathology. The overall concordance rate between preand postoperative histological grade was 65.4% (53/81). 25.9% (21/81) patients had been upgraded while 8.6% (7/81) had been downgraded. The accuracy of clinical and surgical staging was 64.2% (52/81) with 22.2% (18/81) patients had been upstaged and 13.6% (11/81) down-staged. Conclusion: Tumor histology and grade, as well as the clinical staging, are only moderate predictors of the final surgical pathological outcome and surgical staging.

Preoperative Histopathological Grading and Clinical Staging Versus Surgico-Pathological Grading and Surgical Staging in Endometrial Carcinoma Patients: A Single Centre Retrospective Study

We consider polygonal billiards and we generalise a theorem from [1] on the uniqueness of coding of non periodic billiard trajectories to a wider class of polygons, which consists of non simply connected polygons with holes having non zero minimal diameter.

Study on the Bearing Fault Diagnosis based on Feature Selection and Probabilistic Neural Network

Comparison of Facial Expressions and Body Expressions: An Event-related Potential Study

Silicon carbide( Si C) with high surface area was prepared by a simple sol- gel process combined with carbothermal reduction method. This reaction involves the using of sodium silicate,sucrose and sulfuric acid as the silicon source,carbon source and catalyst respectively. The materials are characterized by X- ray powder diffraction( XRD),N2adsorption- desorption and field emission scanning electron microscope( FESEM). Studies here show that the as- prepared Si C samples are typical mesoporous materials and their textural properties can be effectively tuned and promoted by the simple controlling the adding amounts of sulfuric acid and sucrose. When the molar ratio of n( C) : n( Si) : n( S) is optimized and controlled as 3. 00: 1: 0. 44,tubular Si C with a high surface area of 235 m2·g- 1and pore volume of 0. 46 cm3·g- 1can be achieved.

Facile Synthesis and Characterization of Silicon Carbide with High Surface Area

Complex social environments are the primary selective pressure for the human brain. Mankind must evolve specialized brain networks to rapidly process social information (e.g., identification of social signals). However, the exact cognition mechanisms remain unclear. Social neuroscience is the burgeoning field that studies social behavior and underlying neural structures by applying an interdisciplinary, multilevel analysis. It has been fruitful and contributed to fields ranging from psychiatry to economics since its first appearance as a term in 1992. In this article, we systematically review four major aspects of social neuroscience: social perception, cognition, regulation and interaction. Based on that empirical evidence, we try to answer each core question of sub-domains: Is there any specialization for social perception? Is social cognition unique to humans? Is social regulation ability universal or sensitive to individual difference? We conclude that social perception is at least functionally specialized; the mentalizing system is unique to humans and social regulation ability is sensitive to individual difference. Besides, the brain-to-brain coupling may be the core mechanism of social interaction. Finally, based on the present studies and emerging techniques, we point out two broad directions for future research.

The main task of the Top Tracker detector of the neutrino reactor experiment Jiangmen Underground Neutrino Observatory (JUNO) is to reconstruct and extrapolate atmospheric muon tracks down to the central detector. This muon tracker will help to evaluate the contribution of the cosmogenic background to the signal. The Top Tracker is located above JUNO's water Cherenkov Detector and Central Detector, covering about 60% of the surface above them. The JUNO Top Tracker is constituted by the decommissioned OPERA experiment Target Tracker modules. The technology used consists in walls of two planes of plastic scintillator strips, one per transverse direction. Wavelength shifting fibres collect the light signal emitted by the scintillator strips and guide it to both ends where it is read by multianode photomultiplier tubes. Compared to the OPERA Target Tracker, the JUNO Top Tracker uses new electronics able to cope with the high rate produced by the high rock radioactivity compared to the one in Gran Sasso underground laboratory. This paper will present the new electronics and mechanical structure developed for the Top Tracker of JUNO along with its expected performance based on the current detector simulation.

Social dominance orientation, right‐wing authoritarianism, and political attitudes toward governmental performance during the COVID‐19 pandemic

JUNO is a multi-purpose neutrino observatory under construction in the south of China. This publication presents new sensitivity estimates for the measurement of the , , , and oscillation parameters using reactor antineutrinos, which is one of the primary physics goals of the experiment. The sensitivities are obtained using the best knowledge available to date on the location and overburden of the experimental site, the nuclear reactors in the surrounding area and beyond, the detector response uncertainties, and the reactor antineutrino spectral shape constraints expected from the TAO satellite detector. It is found that the and oscillation parameters will be determined to 0.5% precision or better in six years of data collection. In the same period, the parameter will be determined to about % precision for each mass ordering hypothesis. The new precision represents approximately an order of magnitude improvement over existing constraints for these three parameters.

Sub-percent precision measurement of neutrino oscillation parameters with JUNO

Over a billion people live in slums, with poor sanitation, education, property rights and working conditions having a direct impact on current residents and future generations. Slum mapping is one of the key problems concerning slums. Policymakers need to delineate slum settlements to make informed decisions about infrastructure development and allocation of aid. A wide variety of machine learning and deep learning methods have been applied to multispectral satellite images to map slums with outstanding performance. Since the physical and visual manifestation of slums significantly varies with geographical region and comprehensive slum maps are rare, it is important to quantify the uncertainty of predictions for reliable and confident application of models to downstream tasks. In this study, we train a U-Net model with Monte Carlo Dropout (MCD) on 13-band Sentinel-2 images, allowing us to calculate pixelwise uncertainty in the predictions. The obtained outcomes show that the proposed model outperforms the previous state-of-the-art model, having both higher AUPRC and lower uncertainty when tested on unseen geographical regions of Mumbai using the regional testing framework introduced in this study. We also use SHapley Additive exPlanations (SHAP) values to investigate how the different features contribute to our model’s predictions which indicate a certain shortwave infrared image band is a powerful feature for determining the locations of slums within images. With our results, we demonstrate the usefulness of including an uncertainty quantification approach in detecting slum area changes over time.

Uncertainty-Aware Interpretable Deep Learning for Slum Mapping and Monitoring

The physics potential of detecting 8 B solar neutrinos is exploited at the Jiangmen Underground Neutrino Observatory (JUNO), in a model independent manner by using three distinct channels of the charged-current (CC), neutral-current (NC) and elastic scattering (ES) interactions. Due to the largest-ever mass of 13 C nuclei in the liquid-scintillator detectors and the potential low background level, 8 B solar neutrinos would be observable in the CC and NC interactions on 13 C for the ﬁrst time. By virtue of optimized event selections and muon veto strategies, backgrounds from the accidental coincidence, muon-induced isotopes, and external backgrounds can be greatly suppressed. Excellent signal-to-background ratios can be achieved in the CC, NC and ES channels to guarantee the 8 B solar neutrino observation. From the sensitivity studies performed in this work, we show that one can reach the precision levels of 5%, 8% and 20% for the 8 B neutrino ﬂux, sin 2 θ 12 , and ∆ m 221 , respectively, using ten years of JUNO data. It would be unique and helpful to probe the details of both solar physics and neutrino physics. In addition, when combined with SNO, the world-best precision of 3% is expected for the 8 B neutrino ﬂux measurement.

Model Independent Approach of the JUNO $^8$B Solar Neutrino Program

To better guide microbial risk management and control, growth kinetic models of Salmonella with the coexistence of two other dominant background bacteria in pork were constructed. Sterilized pork cutlets were inoculated with a cocktail of Salmonella Derby (S. Derby), Pseudomonas aeruginosa (P. aeruginosa), and Escherichia coli (E. coli), and incubated at various temperatures (4–37 °C). The predictive growth models were developed based on the observed growth data. By comparing R2 of primary models, Baranyi models were preferred to fit the growth curves of S. Derby and P. aeruginosa, while the Huang model was preferred for E. coli (all R2 ≥ 0.997). The secondary Ratkowsky square root model can well describe the relationship between temperature and μmax (all R2 ≥ 0.97) or Lag (all R2 ≥ 0.98). Growth models were validated by the actual test values, with Bf and Af close to 1, and MSE around 0.001. The time for S. Derby to reach a pathogenic dose (105 CFU/g) at each temperature in pork was predicted accordingly and found to be earlier than the time when the pork began to be judged nearly fresh according to the sensory indicators. Therefore, the predictive microbiology model can be applied to more accurately predict the shelf life of pork to secure its quality and safety.

Establishment and Application of a Predictive Growth Kinetic Model of Salmonella with the Appearance of Two Other Dominant Background Bacteria in Fresh Pork

Bacterial Community Structures in Fresh Pork in Farmers’ Markets and Supermarkets During Different Seasons Determined by High-Throughput Sequencing Analysis

Assessing the value of user-generated images of urban surroundings for house price estimation

We present the detection potential for the diffuse supernova neutrino background (DSNB) at the Jiangmen Underground Neutrino Observatory (JUNO), using the inverse-beta-decay (IBD) detection channel on free protons. We employ the latest information on the DSNB flux predictions, and investigate in detail the background and its reduction for the DSNB search at JUNO. The atmospheric neutrino induced neutral current (NC) background turns out to be the most critical background, whose uncertainty is carefully evaluated from both the spread of model predictions and an envisaged in situ measurement. We also make a careful study on the background suppression with the pulse shape discrimination (PSD) and triple coincidence (TC) cuts. With latest DSNB signal predictions, more realistic background evaluation and PSD efficiency optimization, and additional TC cut, JUNO can reach the significance of 3σ for 3 years of data taking, and achieve better than 5σ after 10 years for a reference DSNB model. In the pessimistic scenario of non-observation, JUNO would strongly improve the limits and exclude a significant region of the model parameter space.

Prospects for detecting the diffuse supernova neutrino background with JUNO

A two-dimensional axisymmetric model of the underwater explosion is established in this paper. After verification by empirical formula, the variation law of the reflection coefficient of the shock wave with different boundary sizes under different boundary conditions is studied. The results show that the peak pressure of the near-field shock wave is relatively close to the empirical formula. The calculated value of the far-field shock wave peak pressure is smaller than the empirical value, and refining the mesh can make the near-field shock wave peak pressure closer to Cole’s empirical formula; when the “Flow-out” boundary condition is set, with the increase of the proportional boundary size, the boundary pressure decreases and the reflection coefficient increases. When the proportional boundary size reaches 5, the reflection coefficient of the boundary is the same as that without the “Flow-out” boundary, which is close to 90%.

Research on the Reflection Characteristics of the Shock Wave Boundary in the Numerical Simulation of Underwater Explosion

The parabolic reflector provides one of the common sound wave convergence methods in acoustic engineering. To reduce the difficulty of fabricating large-size reflectors and improve the convergence effect, this paper proposes a multi-segment linear reflector design method. Through the normal vibration radiation analysis of the flextensional transducer shell, the reflector interface reflection was optimized, the reflection effect was improved and the reflector size was reduced. The transmission theory was used to analyze the impact of different material parameters and sound wave frequency on the reflector transmission coefficient, and the gain effect of the multi-segment linear reflector was further tested. The research results show that the reflector has a significant gain effect in the test frequency band of 20∼100Hz, and the gain at 70Hz I reaches the maximum of 11.2dB.

Design Analysis and Experimental Research of Multi-Segment Linear Reflector

The dropping point of a projectile is an important parameter for evaluating the range weapon performance. A Bayesian jointed source location method by using seismic and acoustic observations is developed. This jointed method is to take advantage of signals in the atmosphere and seismic wave signals in the ground and reduce the influence of atmospheric factors, geological factors, topographical factors, and seismic phase identification factors on the location accuracy. Therefore, it is a high-precision location method. Firstly, this paper combined the four-element cross acoustic array and the single seismic measurement points to measure the acoustic signals/seismic waves of the surface explosion. Then, the paper obtained the azimuth information through sound arrays and signal arrival information through the seismic measurement points and performed an inversion of the explosive source location based on the Bayesian theory. The results show that the Bayesian location method has a high precision due to the full consideration of the error model and a-priori information. In addition, the Bayesian jointed source location method can provide more constraints on the location of the explosive source by integrating seismic wave data and acoustic data, which makes the probability density distribution of the explosive source more concentrated and the location result more robust.

Application of the Bayesian Source Location Using Seismic and Acoustic Observations in Inversion of Surface Explosion Source Locations

Atmospheric neutrinos are one of the most relevant natural neutrino sources that can be exploited to infer properties about Cosmic Rays and neutrino oscillations. The Jiangmen Underground Neutrino Observatory (JUNO) experiment, a 20 kton liquid scintillator detector with excellent energy resolution is currently under construction in China. JUNO will be able to detect several atmospheric neutrinos per day given the large volume. A study on the JUNO detection and reconstruction capabilities of atmospheric νe and νμ fluxes is presented in this paper. In this study, a sample of atmospheric neutrinos Monte Carlo events has been generated, starting from theoretical models, and then processed by the detector simulation. The excellent timing resolution of the 3” PMT light detection system of JUNO detector and the much higher light yield for scintillation over Cherenkov allow to measure the time structure of the scintillation light with very high precision. Since νe and νμ interactions produce a slightly different light pattern, the different time evolution of light allows to discriminate the flavor of primary neutrinos. A probabilistic unfolding method has been used, in order to infer the primary neutrino energy spectrum from the detector experimental observables. The simulated spectrum has been reconstructed between 100MeV and 10GeV, showing a great potential of the detector in the atmospheric low energy region.

Measuring low energy atmospheric neutrino spectra with the JUNO detector The JUNO Collaboration

JUNO is a multi-purpose underground neutrino observatory being constructed in the south of China. The main detector, with a 20 kton liquid scintillator target instrumented with about 18k 20” PMT and about 26k 3” PMT, will be strategically located 53 km from the Taishan and Yangjiang Nuclear Power Plants. Using reactor antineutrinos, JUNO will be able to measure several neutrino oscillation parameters with sub-percent precision as well as to determine the neutrino mass ordering to ∼3 σ over 6 years of operation. Furthermore, JUNO will have a broad physics program, ranging from studying neutrinos from other sources, such as solar and supernova neutrinos, to searching for BSM physics such as proton decay. This talk will give an overview on the JUNO’s broad physics potential.

Proceedings of 37th International Cosmic Ray Conference — PoS(ICRC2021)

An equivalent circuit model to explain the coupling between FSS (frequency selective surface) is presented in this paper. The proposed method of establishing equivalent circuit models is suitable for the modeling of multi-layer FSSs and has higher rationality and accuracy than the most existing methods that do not consider coupling. Meanwhile, empirical equations are proposed to build the relationship between the coupling coefficients and the distance between layers. By using the empirical equations, the transmission/reflection coefficients of the FSS structure can be obtained directly without full-wave simulations. Simulations show that these equations are still valid when the size of the unit cells is changed.

An Equivalent Circuit Model to Interpret The Coupling Between FSS Layers

In order to improve the radiation performance of low-frequency sound device, a design method for a long-stroke low-frequency sound device is proposed, which mainly involves the design of the drive structure and radiation structure and the drive structure is designed with an electric long stoke. The flat plate and conical structures of piston plate of radiation structure are compared, and a long-stroke radiation structure with a low-damping guide support motion pair uniformly distributed in the circumferential direction is proposed. The numerical simulation results show that, with six straight-line bearings circumferentially and uniformly distributed, the displacement and stress distribution of piston plate are better than those of piston plate with three straight-line bearings installed in the same manner. The sound device is further tested in the experiment, and it is found that the vibration displacement amplitude at the center of piston plate is 3.9 mm (20 Hz), and the maximum sound pressure level of 40 Hz is found at the location 10 m from the center of sound device along the axial direction, reaching 105.3 dB.

A novel closed-form expression for predicting the equivalent electromagnetic parameters of the honeycomb structure is proposed. It is obtained by approximating the correlation terms in the derivation of the strong fluctuation theory with the integral of the spherically symmetric function. Through several simulation examples, the calculation results of the formula are compared with the results of several traditional extraction methods and compared with the existing experimental data. Comparison of the extraction results of the formula with the simulation results and the experimental data shows good agreement, which proves the feasibility of the extraction expression, and this method does not require simulation as a prerequisite and can shorten the time for optimizing the design of the honeycomb absorbing structure.

A closed-form expression of effective permittivity with spherically symmetric function for honeycomb structure

In this work, we study the topological phases of the dimerized square lattice in the presence of an external magnetic field. The dimerization pattern in the lattice’s hopping amplitudes can induce a series of bulk energy gap openings in the Hofstadter spectrum at certain fractional fillings, giving rise to various topological phases. In particular, we show that at 12 -filling the topological quadrupole insulator phase with a quadrupole moment quantized to e2 and associated corner-localized mid-gap states exists in certain parameter regime for all magnetic fluxes. At 14 filling, the system can host obstructed atomic limit phases or Chern insulator phases. For those configurations gapped at fillings below 14 , the system is always in Chern insulator phases of various non-vanishing Chern numbers. Across the phase diagram, both bulk-obstructed and boundary-obstructed topological phase transitions exist in this model.

The design and sensitivity of JUNO’s scintillator radiopurity pre-detector OSIRIS

Prestress has a great bearing on the performance of flextensional transducer. In order to enhance the adjustability of prestress, a design method for the flextensional transducer with adjustable prestress was proposed in this study. Through the conversion design of rotational and rectilinear motions of the transition block, the clamping length of major axis of class IV flextensional transducer shell was changed, enabling the adjustment of prestress. Next, the related experiment was further carried out. The results show that the return displacement of adjustable transition block is slightly greater than the travel displacement, and both displacements show high overlap ratios in the two tests. Because of the prestress adjustment, the frequency response of flextensional transducer is reduced to some extent, within one frequency band (40-63 Hz), but its sound pressure level (SPL) substantially increases nearby the resonant frequency (about 75 Hz).

Damping signatures at JUNO, a medium-baseline reactor neutrino oscillation experiment

In this letter, the polar coordinate transformation numerical steepest descent path (PCT-NSDP) method is proposed to calculate the physical optics (PO) scattered field from concave or convex quadratic surfaces. In the proposed method, only three triangles integral domains are calculated, which avoids the complicated decomposition in the former NSDP methods. The PCT-NSDP method has a closed-form formula of the contribution of PO stationary phase point. Therefore, the calculation time can be much smaller. Moreover, the workload is frequency-independent. The numerical examples of the radar cross section of a quadratic convex surface demonstrate the high accuracy and efficiency of the PCT-NSDP method.

The Polar Coordinate Transformation Numerical Steepest Descent Path Method for Calculating Physical Optical Scattering Field of Quadric Concave or Convex Surfaces

In this letter, a shifted double-sided frequency selective surface (FSS) with miniaturized unit cells is proposed to achieve superior performance in angular insensitivity. Two identical FSS screens mounted on both sides of a thin substrate have lateral displacement relative to each other. We shed light into effect of shifting by investigating current and field distributions, and present the operating principles of the proposed FSS along with the equivalent circuit model. The whole structure has a lower profile (a thickness of 0.001λ, where λ represents the resonant wavelength in free space) as well as a small size (0.043λ × 0.043λ). This FSS as a bandpass spatial filter is stable with respect to different polarizations, polarized angles, and incident angles of the illuminating waves. A prototype of the proposed FSS is fabricated and tested. The measured frequency responses agree well with the simulated results.

Angularly Stable Frequency-Selective Surface Using Shifted Double-Sided Screens

 Bioretention, initially designed for treating discontinuous runoff pollution, faces considerable challenges in its trade-off between the hydraulic retention time (HRT) and its treatment capacity. In this study, six enhanced submerged media together with four HRTs were designed for bioretention cells to treat the highly nitrogenous river water in Tai lake basin in Yangtze River delta, China. Results revealed that bioretention with activated carbon has the highest removal of nitrate (NO3−-N) (93–96%) compared with surfactant-modified activated carbon (SMAC), surfactant-modified zeolite (SMZ), zeolite, fly ash and ceramsite. Although the SMAC had the best absorption for NO3−-N and could desorb NO3−-N when its concentration was low in the submerged layer, the desorbed surfactant could inhibit the growth of denitrifying bacteria, which leads to low removal efficiency (49–66%). The dynamic balancing of NO3−-N desorption and denitrifying system restrain in the SMAC device was observed and explained. The best activated carbon-gravel proportion in the submerged layer was 1:1 (150 mm). Such design could ensure the stable and efficient NO3−-N removal rate (93–94%) under high inflow concentration (28.9 mg/L) and high hydraulic loading (8.2 cm/h).

Design and operation of submerged layer in bioretention for enhanced nitrate removal

The present study introduces a weak magnetic field sensor that utilizes a laminated cantilever structure, consisting of a magnetostrictive layer, a piezoelectric layer, and a substrate layer. Consequently, the transformation from the magnetic signal to the electrical signal is accomplished through the consistent mechanical stress in both layers. A comprehensive theoretical model has been developed to evaluate the impact of key structural parameters on the magnetoelectric (ME) sensing performance, enabling the optimization of the device design. By incorporating vanadium (V) as a dopant element, a Zn-V-O film with a piezoelectric coefficient as high as 35 pm/V is fulfilled. Furthermore, the high piezomagnetic properties of Galfenol make it a suitable candidate as a magnetostrictive layer. Sensor prototypes were fabricated for experimental verification through the utilization of MEMS technology. The film was characterized using techniques, such as X-ray powder diffraction (XRD), transmission electron microscopy (TEM), and piezoelectric force microscopy (PFM). The ME testing experiments indicated that the magnetostrictive coefficient could achieve about 9.32 kV/(cm $\cdot $ Oe) at resonant frequencies for sensors with varying lengths and a 20- $\mu \text{m}$ -thick Si substrate. The proposed sensor exhibits promising potential for improving weak magnetic field detection performance.

Enhanced Performance of Weak Magnetic Field Sensor Based on Laminated Cantilever: Theoretical Analysis and Experimental Verification

Abstract: Green electricity (GE) is of great importance for effectively combating climate change and global Sustainable Development Goals (SDGs). The willingness-to-pay (WTP) for GE by end users has great influence on its widespread application, especially at the household level. Researchers have analyzed the mechanisms of residents' WTP and predicted how much they could afford for GE. However, most of these studies have focused on developed (affluent) countries and regions, and residents' WTP as well as the corresponding monetary amount of their WTP were not considered together in previous studies. In this study, we try to fill the gap of the inadequate research of residents' WTP in underdeveloped areas through an analysis of the WTP of urban residents in a small Chinese city (Anyang). A total of 274 household-scale samples were collected by face-to-face interviews in December 2019. We found that approximately 60% of respondents gave a positive response to WTP, with an average value of 8.39 yuan per month. Educational attainment, per capita disposable income in the household, the length of residents' time living in urban areas and the rate of neighbors' approval of WTP are all positively correlated with the tendency of the residents' positive response toward WTP. The three factors of per capita disposable income, the rate of neighbors' approval of WTP and the degree of residents' environmental concerns are positively correlated with the amount of residents' WTP. More importantly, we demonstrated the existence of a weak “Herd Effect” in residents' views of WTP. Finally, some suggestions for policymakers are given, such as raising household income through retraining and raising residents' environmental awareness through education and community advertisements. This study also highlights that the widespread application of GE at the household level will be of great assistance to the GE industry overall. Therefore, the rising economic cost of GE should not be shared by the households in the long term.

Who is More Willing to Pay for Green Electricity? a Case Study of Anyang City, China

Dehydration rates impact physiological, biochemical and molecular responses in desert moss Bryum argenteum

Abstract: The catering industry is an important industry related to the growth of the national economy and the needs of daily life. After 2012, the central government has successively introduced and implemented a series of policies to limit the official consumption and catering waste. These policies have had a huge impact on China's catering industry, especially the development of high-end catering. Based on expert scoring and interviews with government managers, the catering industry organizations, catering enterprises, researchers and consumers, this paper studies the impacts of the policies before and after 2012 on the sustainable development of the catering industry. The results show that: (1) Policies after 2012 have been very strong in their strength and duration, and this can ensure that the policies can effectively perform their restraint and management functions in the long term. (2) As affected by policies after 2012, the frequency and amounts of public expenditures in China have dropped significantly, and mass consumption is developing faster. (3) The impact of policies on income is quite controversial. On the whole, the policies have continued to promote the increasing of catering income after 2012, and have played a significant role in optimizing the catering structure and reducing food waste. However, the policies have had little effect on the improvement of industry standards and environmental protection. (4) The sustainable development of the catering industry requires the efforts of the government, industry organizations, restaurants and consumers. Steady income growth, a reasonable and healthy industry structure, sound industry standards, and low food waste are important standards and goals for the sustainable development of the catering industry.

Sustainable Development of the Catering Industry in China: Policy and Food Waste

Simulations for blood hydrodynamic problems have been still largely incomplete despite years of research, especially for the inlet of boundary conditions that served as an essential part in computational fluid dynamics simulations of blood flow in human arteries. In this paper, the four different velocities of inlet boundary conditions were tested and compared in the human arm arterial model developed by us previously. Based on the selected points of nine key areas in the blood model,[Formula: see text] we analyzed the calculation results of pressure and shear stress distributions in detail. Our results show that they are changeable in different [Formula: see text] (different peak velocities of inlet boundary). The results further show that the static pressure of the aortic tree is higher than the static pressure of the branch, while the shear stress of the aortic tree is lower than the shear stress of the branch. On the other hand, the velocities changed in different [Formula: see text], the vessel walls of max total deformation appear in the middle radial obviously, compared with the equivalent and shear stress show at the entrance and bifurcations. In all, the simulation results of the brachial arteries provide the wall deformation, pressure and shear stress characteristics in different [Formula: see text], and offer a new strategy to study the two-way coupling of hemodynamics in the arm arterial model.

ON THE DIFFERENT VELOCITIES OF INLET BOUNDARY CONDITIONS FOR HUMAN ARM ANALYSIS OF ARTERIAL FLOW USING ONE-WAY FLUID–SOLID COUPLING

This paper uses three data mining algorithms, support vector machine, decision tree and logical regression, to establish the stock classification prediction model. The paper compares and analyzes the prediction effect of the three models, and summarizes the relationship between the financial indicators of listed companies and their stock intrinsic investment value.The results show that: (1) among the three prediction models, logistic regression model has the best performance, followed by support vector machine model, and decision tree model has the worst performance.(2) The significant influencing factors of stock intrinsic investment value include the actual operation ability, profitability and the continuity and stability of operation. The conclusion of this paper can provide a basis for stock investors to make investment decisions.

Proceedings of the 2021 International Conference on Financial Management and Economic Transition (FMET 2021)

Application of SVM, Decision Tree and Logistic Regression Algorithm in Stock Classification and Prediction

To enhance the small cruise vehicle in the complex environment under the ice autonomous obstacle avoidance ability, the artificial potential field algorithm was improved in this paper. Firstly, the idea and principle of the traditional artificial potential field obstacle avoidance algorithm as well as its existing defects such as local minimum are analyzed. Then the local minimum defect of the traditional artificial potential field method is solved by optimizing the repulsive potential field function and adjusting the repulsive force component’s direction on the coordinate axis. Then, the improved artificial potential field obstacle avoidance algorithm is simulated by using MATLAB software. The experimental results show that the improved algorithm can make the cruiser safely and accurately sail to the target position without falling into the local minimum value, which proves that the improved artificial potential field obstacle avoidance algorithm can work safely and stably.

Research on Obstacle Avoidance of Small Cruise Vehicle Based on Improved Artificial Potential Field Method

Abstract: Currently, the topic of food waste and its environmental impacts is attracting increasing attention among academic researchers. Based on an investigation of restaurants in Beijing, this study analyzes the quantities, structures, characteristics and costs of the agricultural resources related to food waste in the catering industry in Beijing. The results show that: (1) The average food waste per capita per meal is about 75.02 g (raw) for food away from home among Beijing urban residents, which means that about 10.52% of the food is wasted. (2) According to the quantitative ranking of different categories of food waste, vegetable is the most wasted, followed by meat, aquatic products, and grains. The foods in the other categories are wasted much less. (3) Food waste is affected by the restaurant type, as well as the number, gender, age, education level, and consumption motivation of the consumers. (4) Based on the estimated food waste per capita, about 417.92 thousand tons of food is wasted annually at the consumption stage in the catering industry in Beijing. This food waste amount is equivalent to approximately 765.53 tons of cereals which are wasted, and this represents 79.66% of cereals production and 13.15% of cereals consumption in Beijing. Estimated by the required land use, this amount of food waste means that the total production of approximately 166.12 thousand ha of arable land is being wasted in Beijing.

ABSTRACT A comprehensive prediction model of sinter quality based on machine learning algorithm was proposed. First of all, the mass historical data of actual sintering production was collected, cleaned and integrated. On this basis, the drum index and screening index of sinter were analysed by cluster analysis, and the quality of sinter was evaluated synthetically by clustering results and iron grade of sinter. Then, the important characteristic variables related to sinter quality index were screened by Recursive feature elimination, stability selection and random forest selection. The comprehensive classification model of sinter quality and the regression model of sinter’s total iron content were established by using various machine learning algorithms. The results show that the prediction accuracy of the classification model and regression model established by the extra tree is the best, and the application effect of the model is verified by using the testing set. The F1-score of the comprehensive quality index classification model is 0.92 and the R 2 of the total iron content regression model is 0.882. This model has good learning and generalization ability, and the accurate prediction of sinter quality index is realized.

Synthetically predicting the quality index of sinter using machine learning model

Abstract: Grain production patterns are the basis of a nation's food security. Since China's reform and opening-up began in 1978, China's urbanization process, driven by rapid social and economic development, has accelerated steadily. During this time, the dietary structure of urban and rural Chinese has also changed significantly. Accordingly, grain production patterns have undergone major changes. First, traditional grain production patterns in the north and the south have changed, and the food production center has shifted toward the north. In 1980, the grain yield of southern provinces accounted for 60% of China's total, while that of northern provinces accounted for 40%. In 2015, the grain yield of southern provinces accounted for 56% of the total, while that of northern provinces accounted for 44%. Second, grain production by regions of the country is “shrinking in the east but expanding in the central regions,” meaning that grain production in eastern coastal provinces has decreased significantly, while that in the central region has expanded. The proportions of the nation's total grain production from the eastern, central and western regions were 38%, 36% and 26%, respectively, in 1980. These had changed to 27%, 46%, and 27%, respectively, in 2015. Third, the spatial centralization of grain production has increased. The total grain yield of 13 major grain-producing provinces and regions in the country accounted for 69.27% of nation's total in 1980, and it had reached 76.18% in 2015, showing that the impact of major grain-producing areas on national food security has increased. The influence of rapid urbanization on grain production areas shows remarkable regional differences. As the level of urbanization has increased, build-up land occupies a large number of high-quality farmland, especially in east coastal provinces and thus the grain planting area decreased obviously. The effect of dietary structure changes on grain production patterns was evident in two ways. On the one hand, as dietary diversity has increased, total grain consumption has decreased. The reduction in the proportion of planting area for grain crops to total crop planting area dropped from 82% in 1980 to 68% in 2015, making this change in total grain consumption evident. On the other hand, the ratio of grain for human consumption declined as the ratio of grain consumed by animals increased. The reduction in the proportion of rice and wheat grown and an increase in the proportion of feed grain production (mostly maize) from 20% in the 1980s to 36% in 2015 makes this change in grain production and consumption evident. In the future, with the establishment of national functional areas for grain production, the spatial pattern of grain production will return, while the demand for feed grains will continue to increase but with the space for expansion limited.

Changes in China's Grain Production Pattern and the Effects of Urbanization and Dietary Structure

Abstract The change regulations of the smelting parameters in a gas-injection blast furnace are investigated using theoretical calculations. The results show that when the volume of gas injected, the oxygen enrichment rate and the theoretical combustion temperature of tuyere are 600 m3/tHM, 10% and 1950~2200∘C, respectively, the conditions meet the smelting requirements of a blast furnace. With the increase of the oxygen enrichment rate, the required air volume decreases, the contents of CO and H2 in the top gas increase, and the content of CO2 first increases and then decreases.With an increase of the volume of gas injected, the coke rate decreases. In addition, when the oxygen enrichment rate and the volume of gas injected are 10% and 600 m3/tHM, respectively, the CO content of the top gas constantly increases with the increase of the coke rate, while the H2 and CO2 contents both decrease. With the increase of the H2 content in the gas, the direct reduction degree of iron gradually decreases and the volume shrinkage burden increases. Apparently, injecting gas into the blast furnace can prevent the theoretical combustion temperature from being too high and solve the contradiction between the upper cooling and lower heating of the blast furnace.

Study on the Appropriate Production Parameters of a Gas-injection Blast Furnace

Theoretical Logic and Value Elements of Good Governance in University

Efficient Preparation of Polydopamine Nanoparticles by Precipitation

Design and analysis of cloud platform for landslide monitoring in Heifangtai, Gansu province based on GPS and InSAR data

Induced pluripotent stem cells in dental tissue regeneration: effect and application

Comparison of applicability of remote sensing estimation model for grassland vegetation coverage

The Calculation Method and Performance Evaluation on SISA of New Generation BDS

: Food consumption is one of the most basic activities for human being ’ s survival and development. To develop a green lifestyle and promote the strategy of ecological civilization, we must first form a sustainable food consumption pattern and then implement it thereafter. At present, China ’ s enters a new food consumption period, which presents a significant change in the structure of food consumption and a diversification of people ’ s consumption pattern, etc. On the other side, great changes and challenges come hand-in-hand with each other during this period. For example, there are several bad trends such as health risks resulting from irrational consumption, serious food waste and frequent food- safety incidents, which to a large extent restricts the sustainable development of China's food consumption. Thus, it is recognized that food consumption, as one of the important part in the whole food safety, is of great importance for China ’ s social- economic development. The current study discusses the definition, principles and characteristics of sustainable food consumption, and then analyzes the similarities and differences between sustainable food consumption and other relevant concepts respectively. We further put forward the realization ways toward sustainable food consumption in China based on the system designing, program formulation, demonstration & extension, public guiding along with monitoring & evaluation orderly to build sustainable food consumption patterns. Additionally, in considering China's current national conditions, we would better select some aspects or cities as pilot areas before implementing the sustainable food consumption-related policies on a large scale. Therefore, we should highlight the big and medium- size cities, poor rural areas and other key regions, and focus on floating populations, students and other emphatic crowds, as well as households and catering industry, to find breakthroughs and explore food consumption patterns.

The connotation and realization way of sustainable food consumption in China

In recent years, dynamic reservoir monitoring technology using time-lapse microgravity method has been receiving much attention of researchers at home and abroad. As a result of the low signal to noise ratio (SNR) and weak signal in observation data, it is impossible to quantitatively interpret fluid migration in reservoirs using time-lapse microgravity data. In order to suppress observation noise and enhance weak signals, this article presents the regularized equivalent source downward continuation (RESDC) method, and derives the RESDC operator in the wavenumber domain. Besides, the iterative compensation algorithm is proposed to compensate for amplitude attenuation of the downward continuation field. With tests on synthetic data, this work further studies the wavenumber response of the filtering operators and the downward continuation operators of regularized equivalent layers at different depths. Results show that the downward continuation field of the RESDC method is more accurate and stable compared with the field from the Tikhonov downward continuation method. Applying the iterative compensation RESDC method to field data of a time-lapse microgravity survey verifies that the proposed method can effectively enhance weak signals and stably realizes large-depth downward continuation.

A study on gravity field downward continuation using the regularized equivalent-layer method

Abstract: Further utilization of global agricultural resources and the expansion of potential international cooperation space are necessary measures to promote a new level of China's national food security and optimize the structure of domestic food consumption. This study measured the global potential cultivated land area and national grain self-sufficiency. Based on the two-above measures, the authors made a classification of China's foreign agricultural cooperation countries and depicted the spatial pattern of cooperation based on the grain trades of those countries with China. The grain exporters include Australia, North America, South America, Eastern Europe and Central Asia; and the target countries for “going abroad” of Chinese grain enterprises are mainly located in Sub-Saharan Africa and northern Latin America. This study proposes that China's policy of cooperation on grain should be shifted to non-traditional partners alongside the “Belt and Road Initiative” region. Specifically, China could expand grain imports from Russia, Kazakhstan, Ukraine and other East European and Central Asian countries, and the direction for China's agricultural enterprises “going abroad” should shift to Sub-Sahara Africa.

A Study on the Spatial Distribution of China's Potential Foreign Cooperation on Grain from Geographical View

Precise Orbit Determination for the BDS IGSO Satellites Under the Yaw-steering Mode

Since the performance of pyramid Lucas-Kanade (LK) based optical flow algorithm would be influenced by different environments, this paper evaluates the simulation accuracy of the pyramid LK algorithm in cities, plains and mountains, respectively. The simulation results show that the LK algorithm can maintain high precision under the large motion, and the flight strategy of UAV under different environment is given according to the algorithm’s accuracy, In order to ensure the high accuracy of the optical flow sensor in different environments. For example, in the urban environment, when the UAV’s velocity is 12m/s-l5m/s, the best altitude is 80m-l50m. Simulation verification experiments are carried out in different environments. The simulation results show that the proposed UAV flight strategy is generally correct.

2018 IEEE CSAA Guidance, Navigation and Control Conference (CGNCC)

In order to improve the accuracy and efficiency of the size measurement of porous parts, this paper presents a high-precision measurement method base on Machine Vision. First of all, the Sobel operator was used to edge coarse positioning, and then the improved cubic spline interpolation algorithm with bilinear interpolation was used to locate the edge on higher precision. Experimental results showed that this method has the advantage of higher efficiency; it can reach the level of sub-pixel level in the measurement precision.

2017 12th IEEE Conference on Industrial Electronics and Applications (ICIEA)

Research on the size measurement of porous parts based on machine vision

The purposes of this paper are to investigate the effects of HIV Tat protein on miRNA-mediated epithelial anti-Cryptosporidium parvum defense. Using quantitative real-time PCR (qRT-PCR), Western blotting and luciferase assay, we demonstrated that HIV Tat decreased the expression of inducible nitric oxide synthase (iNOS) and induced epithelial expression of KH-type splicing regulatory protein (KSRP) (also known as KHSRP) through down regulation of selected miRNAs, such as miR-27b. As an RNA-binding protein, KSRP could recognize AU-rich element (ARE) within the 3'-untranslated region (3'-UTR) of iNOS mRNA and control their half-life time in the cytoplasm which impairs the defense of epithelial cell to C. parvum infection. Results from our studies could provide a rational basis for the implementation of new immunotherapeutic strategies for opportunistic infections in AIDS patients.

Investigation of Tat impairing anti-Cryptosporidium parvum defense mechanism

： The increasing complexity of oil flow within oil trade networks has become a key factor affecting oil supply security. Here ， we constructed China's oil trade network to analyze the overall features and patterns of oil flow using complex network theory. From 1990-2015 ， the influence of China on network trade partners gradually increased ， while exporting countries followed the opposite pattern. The transmission efficiency of China ’ s trade network followed a downward trend and then slightly increased. China's main oil import sources transferred from the Asia- Pacific region to the Middle East （ 51% ）， Africa （ 19% ）， Russia and Central Asia （ 15% ） and the Americas （ 13% ） in 2015. We estimated oil supply security from 1993-2015 using different evaluation models and found it was 23 in 1993 and 47 in 1999 ， peaking at 48 in 2004 before falling to 42 in 2015. The political risk rating of exporting countries was the most important factor affecting China's oil supply security. We simulated attenuation in supply security across China's oil trade network under two different attacks scenarios ： a random attack and targeted attack. We found that China's oil trade network is fragile to targeted attacks and would experience a rapid decline in oil supply security ； the network is robust to a random attack. Accordingly ， the key for China safeguarding its oil supply security is how to prevent a targeted attack. These findings have significant implications on the implementation of oil import diversification policy ， for example ， increasing oil imports from Russia ， Kazakhstan ， Azerbaijan and the Americas ， that are critical to assuring China's oil supply security in coming decades.

基于复杂网络理论的中国石油流动格局及供应安全分析@@@Spatial-temporal features of China's oil trade network and supply security simulation

Arteries in the upper limb play important roles in the circulation system of the human body. In particular, the radial artery has received considerable attention in traditional Chinese medicine for thousands of years. Here, a 3D model for the arm arteries has been created uncomplicated, in a Chinese adult's left hand, from the magnetic resonance imaging data, using professional modeling software to restore the basic structure of the arm artery in human body, before being imported to Ansys software for simulation. Blood model has been only simulated, and using the blood density of constant parameter and viscosity using the Carreau fluid model, and using viscous-laminar model of Fluent to obtain the velocity profile, static pressure and shear stress in the brachial, interosseous, ulnar, radial and palmar arch arteries. In particular, the brachial and bifurcations have the high pressure and velocity profiles. The simulation results obtained here are also validated by those published in the literature and proved the ulnar artery prevails over the radial artery as a blood supplier to the vessels in the wrist and hand.

Biomedical engineering : applications, basis, and communications

In order to solve the problem of low efficiency and accuracy in the control process of seeding robot, a vision measurement device based on ant colony algorithm and nonlinear circuit system is proposed in this paper. By scanning the trunks areas, border crossing points of the bottom of the tree and ground were detected, and these points were divided into two clusters on both sides based on neighbouring relationship. The simulation result is compared with artificial recognition in a two-orchard environment. The result shows that the proposed method is reliable, safe and can satisfy the moving request of seeding robot.

Design of Vision Measurement Device for Seeding Robot based on Ant Colony Algorithm and Nonlinear Circuit System

Abstract: In a world of climate change and socio-economic development, oil is the strategic resource that is closely intertwined and interdependent. Tracing the evolution of petroleum resources flow is fundamental to understanding petroleum supply and demand, and can also serve as the basis for assessing CO2 emissions from petroleum products. This paper aims to provide a petroleum products flow accounting framework that divides petroleum flow into four phases, three flows, three libraries, and two processes, and summarizes the approach to measure and analyze petroleum resources flows. It takes China as an example for empirical research, and finds that: ① China's petroleum production, consumption and import have significantly increased over the past two decades, and the combination of increasing demand and limited supply have created an urgent need for China to diversify its petroleum sources globally to ensure its oil security. ② Final consumption accounts for the use of most petroleum products and special attention should be paid to the losses in the petroleum refining process. ③ With the exception of crude oil, petroleum product flows among various sectors has changed greatly. Particularly, the flow of petroleum products into transport and residential consumption has trended upward significantly, whereas the flow to industry is trending downward. ④ CO2 emission data shows that CO2 emission amounts increased rapidly from 456Mt in 1993 to 1517Mt in 2013. Previously, the top three CO2 emitters were the industrial sector, the transport sector including the transport, storage and post segments, and the thermal power sector. Currently, the largest emitters are the transport sector, the industrial sector and the residential consumption sector. Finally, poorly demarcated system boundaries and incomplete databases and models constrain research on industry flows of petroleum resources for non-energy use.

A National Accounting Framework for the Petroleum Cycle: A Case Study of China

Recent years have seen increasing global interest in the study of food loss and waste, and their related environmental impacts. Wasted food creates carbon emissions throughout the duration of the food supply chain, from agricultural production, food processing, and distribution, to consumption and waste disposal. While it is widely known that the generation of food waste must be reduced, the lack of quantitative information on the production of household and catering food waste has led to the underestimation of waste volumes and hampered the development of proper policy

The carbon footprint of catering industry food waste: a Beijing case study

随着铁路未售住宅房屋设备老化日益严重,设备病害多发问题已经显得尤为突出,有些病害已经影响住户的正常使用.这不仅对房租的收费工作造成了一定影响,也会因病害得不到及时维修而产生住户上访问题.为了进一步解决未售住宅房屋维修管理中存在的主要问题,本文以北京局天津区域为例,从未售住宅房屋维修管理的现状、重要性及意义、管理特点及加强维修管理的几点建议方面,重点阐述了应如何加强未售住宅房屋维修管理.从而达到消除房屋倒塌危险、屋面漏雨、门窗破损、下水堵塞等病害,提升设备设施质量,确保未售住宅房屋的安全和正常使用.

国家地缘脆弱性探索——缅甸案例及对中国地缘战略启示@@@National geopolitical vulnerability: A Myanmar case and implications for China’s geopolitical policy

誘導結合プラズマ原子発光分光分析(ICP-AES)によるランタンガラス中のニオブ,ジルコニア,および酸化チタンの定量法を開発した。【JST・京大機械翻訳】

Objective 
To evaluate the incidence of and risk factors for esophageal fistula and fatal bleeding after intensity-modulated radiotherapy (IMRT) for esophageal cancer. 
 
Methods 
Clinical data were collected from 128 patients with esophageal cancer who received radical IMRT in our hospital from January 2012 to December 2014.According to the incidence of esophageal fistula and fatal bleeding, those patients were divided into control group (n=105) and severe complications group (n=23). In the severe complications group, 12 patients had esophageal fistula and 11 fatal bleeding. Between-group comparison was made by χ2 test. The Cox model was used for the multivariate analysis. 
 
Results 
Chest and back pain in the initial diagnosis, clinical stage cT4, tumor type (ulcerative), gross tumor volume (GTV)>50 cm3, and GTV maximum diameter>2.45 cm were risk factors for esophageal fistula and fatal bleeding after radiotherapy for esophageal cancer (P=0.042, 0.042, 0.019, 0.046, 0.002). The multivariate analysis showed that tumor type (ulcerative) and GTV maximum diameter were independent risk factors for esophageal fistula and fatal bleeding (P=0.010, HR=0.329, 95% CI: 0.142-0.763; P=0.009, HR=3.805, 95% CI: 1.404-10.312). 
 
The efficacy of IMRT is severely restricted by the incidence of esophageal fistula and fatal bleeding. For patients with an ulcerative type of esophageal cancer or a GTV max diameter of>2.45 cm, the chemoradiotherapy plan should be optimized to reduce the risk of severe complications. 
 
Key words: 
Esophageal neoplasms/intensity-modulated radiotherapy; Esophageal fistular; Bleeding

An analysis of risk factors for esophageal fistula and fatal bleeding after intensity-modulated radiotherapy for esophageal cancer

Effect of Chlorine on the High Temperature Metallurgical Properties of Coke in Blast-furnace

Predictive convection zone depth of chloride in concrete under chloride environment

Study on regional water quality difference and its influence on the heater life length

DHRUBA BIJAYA, G. C., Cheng SHENG-KUI, Gao QIJIE, Xu. ZENGRANG, Wang. LING-EN, Jyoti BHANDARI, Liu XIAOJIE, Gao LIWEI and Cao XIAOCHANG, 2015. Can community forestry play a major role in the socio-economic enhancement of poor users in Nepal? Bulg. J. Agric. Sci., 21: 378-383 Nepal is increasingly gaining world-wide recognition in participatory forestry and natural resource management, primarily through “Community Forestry” program which has a well documented history over three decades. This study was carried out in Tibrekot Community Forestry in Nepal focused on the local poor forest users with the objective to fi nd out the changes brought by the community forestry in the socio-economic enhancement of local forest users, to analyze the level of participation in community forestry management activities and to assess the ecological/economical aspects of the forest. The Participatory Rural Appraisal tools were used to collect the data from sampled households, key informants interview and interaction with different organizations involved in the forestry sectors in the study area. Data were collected using household interview, semi-structured questionnaires, interview schedule and checklists; and data were inserted and analyzed in MS Excel 2007 sheet and in SPSS 17 (Statistical Package for Social Sciences). The chi-square test at 5% level of signifi cant was applied as well. The fi ndings showed that the forest users’ participation in meetings and discussion and other activities like community forestry management, silvicultural operation related to community forestry was high. Likewise, it was found that the forest contributes 20% in the total income of the forest users. It also showed that the greenery has improved, water sources have restored back and environment of the surrounding has improved a lot after handing over the forest to the users in the study area.

Agricultural Academy CAN COMMUNITY FORESTRY PLAY A MAJOR ROLE IN THE SOCIO-ECONOMIC ENHANCEMENT OF POOR USERS IN NEPAL ?

Risto Herrala had an issue with the lack of a link in the model between the allocation of assets and the reasons underpinning that allocation. He cited the example of Norway where oil money flowing into the economy had the potential to be inflationary, which would affect the choice of where to allocate the assets. He thought the analysis was the motivation in the Chinese case, for example, whether there were long-term structural or cyclical reasons why they were allocating funds in the way the paper described.

Summary of General Discussion on “A Multiple-Goal Investment Strategy for Sovereign Wealth Funds: An Application to China”

Genetic analyses of floating Ulva prolifera in the Yellow Sea suggest a unique ecotype

Abstract: 
 Evaluation of the ecological effects of eco-compensation policies helps analyze policy rationality and feasibility and provides scientific and practical bases for perfecting eco-compensation systems. Taking the key ecological function area of the Loess Plateau, China as a case study, we have evaluated ecosystem responses to the Grain-for-Green Project that commenced in 1999. Six indicators were selected to assess changes in ecosystem structure, quality and function. The results showed that implementation of the Grain-for-Green Project has reduced sloping cropland by 1571 km2 and increased ecological land by 1337 km2. The increase in ecological land alters ecosystem structures across the study area and the decline in sloping cropland reduces farming activity interference; both of these are conducive to the restoration of natural vegetation. From 2000 to 2010, the vegetation cover of grassland, desert and forest ecosystems increased 10.89%, 8.34% and 4.24% respectively and average NPP rose 51%, with an average annual growth rate of around 5%. This indicates that eco-compensation has promoted the improvement of ecosystem quality. Total biomass of ecosystems increased two times on average from 2000 to 2010, meaning that the carbon sequestration capacity of ecosystems also increased. The reduction in the area of water loss and soil erosion and the increase in retained runoff by forests indicate an improvement in ecosystem function and services on the Loess Plateau.

Responses of Ecosystems to Ecological Compensation in a Key Ecological Function Area of the Loess Plateau

Effect of droperidol acupoint injection on postoperative nausea and vomiting in patients undergoing gynecological laparoscopic surgery.

Subsatellite point for geostationary satellite(GEO) needs to be retained based on the continual orbit maneuver, especially for GEO satellite of partial subsatellite point. How to recover orbit rapidly for GEO satellite based on short-arc tracking is the key factor to improve the service performance and usability of the navigation system. Due to its geostationary feature, GEO satellites orbit parameters are strongly correlated with the clock corrections parameters in precise orbit determination (POD) using L-band pseudorange data, which needs supports by the time synchronization technique. This paper presents an orbit rapid recovery method based on satellite clock offset and station clock offset. The satellite-ground time synchronization is realized by satellite-earth wireless two-way method, and the ground-ground time synchronization is realized by constellation combining orbit determination method. The precise orbit determination is realized based on pseudorange and phase data without clock offset. A new method of parameters decorrelation based on prior restriction and a short-arc orbit determination method based on the restriction by long-arc orbit determination are brought forward. The experiments based on ground data results indicate that the time of orbit recovery after maneuver is shortened from 24 h to 4 h. The 2-hour orbital prediction in radial component is better than 1 m, which is evaluated SLR data. User equivalent range error (UERE) is better than 1.5 m, and the precision is stable. The orbit recovery for GEO satellite of partial subsatellite point has come true.

Research on technique of orbit rapid recovery for GEO satellite of partial subsatellite point

随着我国经济的不断发展,人们对于汽车的需求日益强烈,汽车领域也得到了全面的生产和壮大,在这个过程中,人们对于汽车的整体舒适性和汽车本身的自动化要求变得越来越高,汽车的电子电器的设备占据着市场中很高的比例,本文针对汽车装配线领域中的电子电器检测系统的应用进行了系列的论述。

qi che zhuang pei xian ling yu dian zi dian qi jian ce xi tong de ying yong lun shu

This paper proposes an adaptive neural network backstepping tracking control method for the long-stroke reticle stage of lithography. The main feature of this method is that it can real-time online estimate the unknown model parameters of long-stroke reticle stage actuator under some nonlinear effects including load disturbance, force ripple and slot effect by radial basis function(RBF) neural network. First, in the study according to the actual system a nominal model of long-stroke reticle stage is established. Then, with this nominal model the derivation of the control method, the design of the adaptive law and the Lyapunov stability proof are made. From the results of the analysis above, it can be seen that this control method can sufficiently guarantee the convergence of the system's position and velocity errors. At last, this control method is verified by a simulation experiment. From the result of fifth-order S-curve tracking test, the tracking accuracy of the position and velocity can meet the design requirements well. Because it doesn't need to model the actual mechanical system and external uncertainties precisely, this method is very suitable for application in the field of ultra-precision manufacturing.

An adaptive neural network backstepping control method for reticle stage of lithography

Improvements in farmland surface roughness measurement by employing a new laser scanner

Web Applications are widely known as the building blocks of typical service oriented applications. Performance of such an application system is mainly dependent upon the components of web applications. Testing web application is nothing but to find out errors in its content, function, usability, navigability, performance, capacity, and security. Performance testing is used to determine the responsiveness, throughput, reliability and scalability of a system under a given workload. In recent years, various tools and techniques are developed for measurement and evaluation of quality of service of web applications. In this paper, two testing tools WAPT Pro and Apache JMeter are compared and implemented on a same website. The two tools WAPT Pro and Apache JMeter are compared in terms of their different performance metrics (parameters) results. Performance metrics results generated by these performance testing tools have been evaluated and analyzed. The same website has been tested for performance under these performance testing tools then differences in results of various performance metrics like average response time, bandwidth, error rate, throughput, memory and CPU utilization, median, standard deviation etc. are obtained.

Performance Evaluation and Comparison of Web Application Testing Tools: WAPT Pro and Apache JMeter

Erk1/2 signalling is involved in the differentiation of periodontal ligament stem cells to Schwann cells in dog.

In order to provide theory and decision-making basis for drought resisting and calamity reduction in Gansu Province,spatial and temporal patterns including intensity,frequency,spatial distribution and periodic feature are investigated by using the standardized precipitation index(SPI) based on the monthly precipitation from meteorological data of 52 stations during the period of 1951-2010.The results show that the performance of the standardized precipitation index(SPI) in different time scales in describing drought are different;the intensity and frequency of drought appear regular spatial and temporal patterns,and drought and flood appear inter-decadal variability significantly;the frequency of medium drought distributes between 26% and 60%,and the extreme drought frequency is in the range of 2.01% and 18.00%;drought intensity in dry season and wet season appear downward trend;the SPI varies with a primary period of 13a;Gansu Province suffers a gradual decreasing trend of drought from northwest to southeast spatially,and some local wet areas tend to be drought.

Multi-scale Temporal and Spatial Variation Comprehensive Analysis of Meteorological Drought in Gansu Province

The development of professional education is similar to biological evolution. Both of them are complicated system engineering. The development of professional education faces many challenges but also opportunities. In the paper it analyzes the enlightenment given by biological evolution to development of professional education by comparison and analysis on them taking advantage of general rules of biological evolution.

Study on the Development of Professional Education Based on Biological Evolution Theory

Non-destructive Detection of Saline-alkali Soil based on Differential of Microwave Dual-band in Western Jilin Province

Distinguishing morphologically similar Zostera species (Z. caespitosa and Z. marina) using microsatellite DNA markers on leaf fragments

Effective improvement of saline-alkali soil is very significant for the yield and the ecological environment, thus accurate parameters of different saline-alkali soils are deeply required. In this paper, the areas and perimeters of different soil cracks are detected in a non-contact, non-invasive online way by the three-dimensional laser imaging technology and several common texture feature measures are also derived from GLCMs of different soil crack images. Then the regression analysis among soil crack characteristics, soil conductivity, soil soluble sodium and SOM is studied and the result is very satisfactory which means soil conductivity, soil soluble sodium and SOM of saline soil can be referred very well through this method with the soil crack parameters.

Correlation between salinity and crack characteristic of saline soil in Songnen plain

Abstract: 
 There is growing global concern over food waste and its impacts on resources, environmental issues and food security, especially in developing countries. However, knowledge of food waste, in particular, the food wasted by consumers in restaurants, is entirely inadequate in China. Here, based on media reports and documents about food waste we provide an overview of food wasted by consumers in restaurants in China. We roughly estimated total food waste in order to uncover the seriousness of this large issue. We collected international literature referring to food waste and provided a detailed explanation of the resources and environmental costs associated with food waste. Ultimately we propose a conceptual diagram on research into catering food waste by consumers to evaluate resources and environmental costs based on life cycle assessment in China. This work will stimulate interdisciplinary research in this field.

An Overview of the Resources and Environmental Issues from Wasted Food in Urban Catering Across China

Objective To investigate the influence of dexmeditomidine on blood pressure and heart rate during conscious-sedative nasal intubation in patients with cervical movement limitation,thus to evaluate the safety and feasibility of dexmiditomidine in induced conscious-sedation with nasal-blind-intubation.Methods Sixty patients with cervical vertebral fracture scheduled for open reduction with internal fixation were randomly divided into four groups according to operation order: mucosal anesthesia group with lidocaine(Group L);dexmedetomidine and mucosal anesthesia group(Group DL);midazolam,sufentanil and mucosal anesthesia group(Group MSL);and dexmedetomidine,midazolam,sufentanil and mucosal anesthesia group(Group DMSL).Results There was significant elevation of BP during pharyngonasal mucosal anesthesia or intubation compared with pre-operative baseline in all the four groups(P0.01).BP was also significantly raised during intubation compared with that during mucosal anesthesia in Group L(P0.01).However,the BP were significantly suppressed in during intubation in Group DL and Group DMSL group,compared with that in Group L(P0.05).There were significant elevation of HR during pharyngonasal mucosal anesthesia or intubation Group L and MSL when comparing with baseline,with significantly further elevation during intubation when comparing with that during pharyngonasal mucosal anesthesia(P0.01).However,the HR was significantly suppressed during pharyngonasal mucosal anesthesia and intubation in Group DL and DMSL(P0.01).Furthermore,the HR were significantly lower during mucosal anesthesia in Group DL and DMSL than those in Group L and MSL(P0.01),with the lowest HR in Group DMSL.And the HR were significantly lower during intubation in Group DL,MSL and DMSL than that in Group L(P0.01),with the lowest HR in Group DMSL.Conclusion dexmedetomidine alleviates the BP and HR elevation during pharyngonasal mucosal anesthesia or intubation,which can be enhanced by low dose midazolam and sufentanil,providing feasible and safe anesthesia for intubation in patients with cervical vertebra movement limitation.

Influence of dexmeditomidine on blood pressure and heart rate during conscious-sedative nasal intubation in patients with cervical movement limitation

Objective To investigate the effects of repeated intrathecal cyclic AMP response elementbinding protein (CREB) antisense oligodeoxynucleotide (ODN) on the expression of NR2A in spinal cord in mice with neuropathic pain produced by chronic constrictive injury of the sciatic nerve (CCI).Methods Forty C57BL/6 male mice in which intrathecal catheter was successfully implanted were randomly divided into 4 groups ( n =10 each):normal saline group (group NS),CREB sense ODN group (group S),CREB missense ODN group (group M),and CREB antisense ODN group (group A).In groups NS,S,M and A,normal saline 5μl,sense ODN 5 μg/5 μl,missense ODN 5 μg/5 μl and antisense ODN 5 μg/5 μl were injected intrathecally once a day for 6 days,starting from the 1st day after CCI,respectively.Paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were measured on day 1 before CCI and on day 1,3,5 and 7 after CCI.Five mice from each group were sacrificed on day 7 and 14 after CCI and the lumbar segment of the spinal cord (L3-5 )was removed for determination of NR2A expression using Western blot and RT-PCR.Results Compared with the baseline value,no significant change was found in PWMT and PWTL on day 1-7 after CCI in group A ( P ＞0.05),while PWMT and PWTL were significantly decreased on day 1-7 after CCI in groups NS,S and M (P ＜0.05).Compared with groups NS,S and M,the expression of NR2A mRNA and protein was significantly downregulated on day 7 and 14 after CCI in group A ( P ＜ 0.05).The expression of NR2A mRNA and protein was significantly up-regulated on day 14 after CCI compared with that on day 7 after CCI in all the groups.Conclusion Intrathecal CREB antisense ODN during the development of neuropathic pain can attenuate neuropathic pain and inhibition of the expression of NR2A in mouse spinal cord may be involved in the mechanism. 
 
Key words: 
Oligonucleotides,antisense; Neuralgia; Receptors,N-methyl-D-aspartate

Effects of repeated intrathecal CREB antisense oligodeoxynucleotide on the expression of NR2A in spinal cord in a mouse model of neuropathic pain

Comparison of exogenous gene expression and insect-resistance ability of transgenic 741 poplars with single and double Bt genes.

A new approach for network security situation prediction based on the immune optimization theory

Electronic map data is of enormous importance for analyses of travel,urban congestion,etc.It is growing an important basic data of transportation research and widely employed in vehicle navigation system and intelligent transportation system.Of electronic map data,road network data is a fundamental part and often updated.As a result of a lot of expense of manpower and resources of traditional method,more and more research efforts have been made on extracting geometrical characteristics of road network from other data resources like LIDAR data.The wide use of mobile positioning devices makes it possible to obtain a large volume of vehicle trajectory data within a short period.These data are complete records of vehicles' movement and able to reflect geometrical characteristics of road network as well.By this means,vehicle trajectory data can be employed to figure out changes happening to the spatial extent of road networks as long as enough data are available,and then we can update the road network database.Since trajectory data integrate both spatial and temporal information and their volume is often huge,it is not straightforward to realize the aforementioned target.In view of this,the paper proposes a thinning-algorithm-based method to construct road network.Vehicle trajectory data are vector data,are first converted to raster data,then thinning method can be used to extract geometrical characteristics of road network.With this method,center lines of road networks can be extracted,network topology be maintained,and meanwhile redundant information be removed.A case study in Lujiazui,Shanghai with taxi trajectory data is conducted and the results are evaluated.

Geometrical Characteristics Extraction and Accuracy Analysis of Road Network Based on Vehicle Trajectory Data

Abstract: 
 Water quality evaluation is important because it could provide guidance when determining water utility. But many interacting impact factors are involved in water quality evaluation systems, making water quality evaluation difficult. Principal component analysis (PCA) is widely used in water quality evaluation because it can eliminate the correlation among factors. However, PCA ignores the degree of data dispersion, which is considered by information entropy (IE). To solve this problem, a model combined PCA and IE methods to obtain the weights of indicators is proposed in this paper, and the proposed model was applied to assess the reused water quality of Jinshui River in Zhengzhou City in 2009. The evaluation results were compared with those using PCA and IE methods for the same data. The results proved that the method is feasible and practical, and it can provide a theoretical basis and decision reference for the utility of unconventional water.

Water Quality Evaluation Model Based on Principal Component Analysis and Information Entropy: Application in Jinshui River

Objective To explore the use of traditional Chinese medicine pulse magnetotherapy instrument for children pneumonia combined with traditional Chinese medicine shop help clinical therapeutic effect.Methods The authoz retrospectived analysis of our hospital in October 2008 to January 2012 admitted to the pediatric pneumonia confirmed 200 cases of clinical data,according to different therapeutic methods are divided into two groups,100 cases in each group,the control group was given western medicine treatment,the observation group used traditional Chinese medicine pulse magnetotherapy instrument combined with traditional Chinese medicine auxiliary therapy.Observation of curative effect in two groups.Results All the patients were cured.Clinical observation of treating group cough,panting and disappearing rales,time,like changes were compared the control group to reduce,the indicators statistical treatment of the two groups had significant difference (P 0.05).Conclusion The traditional Chinese medicine pulse magnetotherapy instrument combined with traditional Chinese medicine shop help in treatment of infantile pneumonia to shorten the course of treatment,improve the cure rate.

Curative effect observation of traditional Chinese medicine pulse magnetic therapy instrument george pediatric pneumonia

The renewed focus on energy security is driven,to some degree,by the soaring energy price and the increasing pressure to reduce greenhouse gas emissions.Strengthening research on theories and methods of energy security is helpful not only in mastering the key elements and identify evolution trends of energy security,but also in laying a solid foundation for early warning and policy research.This article summarized the theories,methods and major progress of energy security,and found out the following results.(1) The quantitative study on energy security of China is very limited.There are very few quantitative empirical studies and a lack of consensus on the conceptual framework and evaluation model of energy security.(2) International evaluation models are mostly based on Shannon-Wiener Index and Herfindahl-Hirschman Index.At present,more representative evaluation models of energy security are developed by Joint Energy Security of Supply Working Group(JESS),Energy Research Centre of the Netherlands(ECN),International Energy Agency(IEA),The Asia Pacific Energy Research Centre.(3) Discussion and some perspectives in this paper imply that quantitative research on energy security should be improved from the aspects of temporal scale,spatial scale,contents,uncertainties and others.

Clinical Observation of Continuous Intravenous Morphine Pumping in Patients with Refractory Cancer Pain

Based on the energy and economy data from 1990 to 2008,this paper develops a model to evaluate China's energy security from both supply and demand perspectives and analyze its spatial-temporal evolution by using factor analysis,ArcGIS spatial analysis techniques and scenario analysis.The results are as follows:1)National energy security of China shows first a small and then a large inverted "U"-shaped trend during the past 20 years,and is currently at the downward stage of the pattern.2)The three scenarios for spatial-temporal evolution of regional energy security demonstrate significant differences.Scenario 1 considers only the stability of regional energy supply(α = 1;β = 0).The consequent regional energy security has improved significantly.The evolution of vulnerable regions of energy supply shows an "S"-shaped pattern,and stable regions shows a "Y"-shaped trend.Scenario 2 considers only the security of energy use(α = 0;β = 1).The consequent regional energy security has deteriorated rapidly.The security of regional energy supply and use are roughly in an inverted state.Scenario 3 prioritizes stability of energy supply than security of energy use(α = 0.9;β = 0.1).The consequent spatial distribution pattern of energy security reveals that regional energy security zones of China(sub-strong and strong area)are mainly distributed in the Yellow River Basin,northwestern,southwestern and northeastern parts of China,while vulnerability zones(sub-weak and weak areas)are mainly located in coastal areas.

Evaluation and Spatial-temporal Evolution of Energy Security in China

The concept of digital natives implies the theoretical presupposition on the smarter learner of the digital age. They believe that, there are some distinctions between digital natives and digital immigrants. For instance: the stronger learning ability, more talent to master new technique, handling multiple tasks simultaneously and so on. For these new learners, the educational change is to be effected. on the contrary, Through questionnaire survey and interview, the scholars consider the cognitive difference between digital natives and digital immigrants come into being mainly from the age differences rather than the application of IT. By analyzing the existing research literature, the show that there are three reasons: first, the different research background between the two sides; second, for lack of quantification study and realistic data, the parties are unable to persuade each other; third, for lack of future research to the teaching scene, issues essence can not be clarified. Moreover, there are some errors in the understanding of digital natives. The age should not be the sole criterion for digital natives. Digital natives not only live in computer network environment, but also have good skills in computer and network so that they are related closely with information degree of its environment.

2011 International Conference on Electrical and Control Engineering

Connected-Element Interferometry(CEI) was a passive angular tracking method with the merits of high phase precision,flexible network distribution and nearly real-time processing due to short length of baselines.Firstly,feasibility of ambiguity solution in CEI-based orbit determination for GEO was analyzed.Integer ambiguity must be primarily solved in the orbit determination for TDRS because of its low initial orbit precision.It could be calculated by the high precise range measurement if the master control station could obtain range measurement,while the method of parameter estimation by fixing integer ambiguity was used without high precise range measurement. The simulation results indicated that this method was effective when the systematic error was less than 1.0 m.The orbit determination precision for the satellite belt between 80°E and 140°E was gained,when the systematic error was 0.1 m,along-track positional error component of the 110°E satellite reached 25 m,while 82 m and 34 m respectively for the 80°E satellite and 140°E satellite.

For more reality in indoor training astronomic surveying,the real-time equal angles star map simulation was proposed in the paper.The relevant formulas as well as an improved method of circle field searching for searching view-field star were derived.Finally,the program of real-time equal angles star map simulation was developed with Visual C+ +,to implement the dynamic star map simulation in any time and station.The precision of the real time star map was given by analyzing the actually measured data.

The oxidation resistance of Si3N4/TiN multiphase ceramic prepared using iron tailing and high titanium slag as raw materi-als was investigated based on the thermodynamic analysis,and the dynamics of oxidation process was also analyzed.The oxidation process and the micro-morphology of the samples after oxidized were characterized by X-ray diffraction,scanning electron micro-scope and energy spectrum analysis.The dynamics of oxidation resistance of the Si3N4/TiN was investigated via the analysis of the constant temperature oxidation mass gaining curves.The results show that the oxidation process of Si3N4/TiN multiphase ceramic in air mainly consists of TiN,Si3N4 and O′-sialon oxidation.The section after oxidized at 1 100-1 240 ℃ involves three layers,namely,the out layer(the dense "protective coating" formed by melted oxides that mainly have Fe2TiO5,SiO2 and TiO2);the middle layer(solid oxides);the inner layer(the unoxidized body of Si3N4/TiN).The oxidation process follows a two-stage model that appears a linear model in the initial stage and a parabola model in the final stage.The apparent activation energies of the two-stage oxidation process are 1.350 × 105 J/mol in the initial stage and 1.896 × 105 J/mol in the final stage,respectively.

Oxidation Resistance Performance of Si_3N_4/TiN Multiphase Ceramic

As a new way of marine management,regional marine management was introduced to and implemented in China.But there are myraids of dilemmas in the implementation process,such as the mismatch between marine ecosystem area and marine administrative area,the discoordination and conflicting goals among marine management agencies,etc.The rational solution to these dilemmas is constructing an effective coordinating mechanism for regional marine management.

Dilemmas of and Solution to the Implementation of Regional Marine Management in China

[Objective] To provide a reference for dynamic regulation of the fermentation process.[Method] Using conditions for tylosin fermentation as feature vectors,final yield during the fermentation process was predicted using the Bayesian method.[Result] The Bayesian network which learned data of tylosin fermentation could better guide conditions of the fermentation process,and better prediction results were achieved.The yield of fermentation products could be effectively predicted using the obtained Bayesian network and could well guide the fermentation process.[Conclusion] Bayesian network has good predictive performance for microbial fermentation and has good practical yield and application prospects.

Migration of immiscible hydrocarbons recorded in calcite-hosted fluid inclusions, Ordos Basin: a case study from Northern China

The efficiency of the economics has been the core part of the economics performance and it has achieved the great attention by all the economists ever since 1960s. There is no doubt that the technology has played an important role in the process of the economic operation. Taking the Solow residual value into the analysis of the technological advancement for economic growth, this paper brings forward a new economic growth model, which aims analyzing the hereof technological advancement contribution for the economic growth. Based on the hereof advanced model, this paper reaches the conclusion that the technological advancement occupies the great part of the growth and determines the economic growth path. All the conclusions here mentioned have been confirmed by the empirical analysis of Heilongjiang province of China.

2011 International Conference on Business Management and Electronic Information

On the contribution of technological advancement of economic growth in Heilongjiang province

Aiming at the complexity and uncertainty of water quality evaluation and certain shortcomings of exiting models,a GIS-based variable fuzzy evaluation model on urban landscape water quality comprehensive evaluation is proposed in this paper.And then taking landscape water of Ruyi Lake artificial wetland system in Zhengzhou City for an example,the water quality and its spatial distribution are studied.The results show that the model is feasible and practical.Thus,it can provide theoretical basis and decision reference for non-conventional water usage and safety evaluation.

A GIS-based Variable Fuzzy Evaluation Model on Urban Landscape Water Quality

abstractThe Ryukyu Kingdom was once an independent kingdom situated at the Ryukyu Islands in the western Pacific Ocean.In 1372,it became a tributary state of the Ming Dynasty,China.This paper,basing on an outlined narration about the origin and changes of the Ryukyu Kingdom in the process of development,conducts a detailed combing and probing in the following respects,such as:the Ryukyu Kingdom's relation and communications with China,the relationship between the Ryukyu Kingdom and Japan,and the negation between China and Japan and on the ownership of the Ryukyu Kingdom after it was invaded and arbitrarily occupied by Japan. It is expected that this paper will provide us with and clearer and more meticulous explanation on many issues related to the Ryukyu Kingdom.

The Vicissitude of the Ryukyu Kingdom:Ryukyu Kingdom·China·Japan

Objective To retrospectively analyze the importance of preoperative ultrasound and D-dimer determination for patients with traumatic fractures so as to evaluate the value of vascular color Doppler ultrasound in diagnosing of vein thrombosis and the correlation between D-dimer level and lower extremity vein thrombosis. Methods The study involved 1000 in-patients with multiple traumatic fractures, femoral fractures, tibial fractures or tibiofibular fractures admitted from March 2008 to April 2009 who were prepared for open reduction surgery. There were 568 males and 432 females, at age range of 20-90 years ( average 54.8 years). Vein D-dimer was examined in the morning on the second day after admission. Vascular color Doppler ultrasound was performed on the lower extremity one day before operation (after the swelling faded away, about 4-10 days after fracture). Results The vascular color Doppler ultrasound on the lower extremity showed vein thrombosis of the lower extremity in 64 patients (6.4%) including 26 patients with iliac- femoral vein thrombosis, 10 with popliteal-tibial vein thrombosis and 28 with gastrocnemius or soleus muscle vein thrombosis. On the second day after operation, out of 736 patients (73.6%) with D-dimer above normal (324 μg/L), 56 patients (7.6%) developed thrombosis afterwards;of 264 patients (26.4%) with normal D-dimer, eight patients (3.03%) developed thrombsis. Incidence of thrombosis in patients with D-dimer above 650 μg/L was higher than that in patients with D-dimer below 650 μg/L (P＜0. 01). Conclusions Preoperative lower extremity vein Doppler ultrasound in traumatic fracture patients can lower the risk of fatal lung thrombosis caused by existing deep vein thrombosis.D-dimer above normal level indicates tendency of thorombosis. However, normal D-dimer still have the possibility to develop thrombosis, which deserves attention. 
 
Key words: 
Ulerasonography Doppler color; Fractures; Vein thrombosis; D-dimer

Importance of preoperative ultrasound and D-dimer determination for patients w:ith traumatic fractures

Through analyzing the current 2 years operational status of Beijing cardiovascular intervention quality control and improvement center, the experiences of quality management were summarized. By strengthening quality management, the concept of hospital quality control is emphasized and the technical progress of related subject is effectively promoted. Quality control center can help promoting subject development by management innovation.

The Exploration for promoting the subject development by means of management innovation in quality control center

Adapting for the requirement of personnel cultivation in high vocational institute, so to Cultivate undergraduates' innovative and practical ability, and to train their practical application ability, this paper is annotated deep into three aspects, the necessity of the instructional process optimized, how to optimize the instructional process and the implementation terms for optimizing instructional process. Then it promulgates the nature of teaching reform in E-commerce English instruction and the full view of practical process. It can be provided as the study reference on instructional process for achieving educational objectives by the educators in high vocational institutes.

2010 Second International Workshop on Education Technology and Computer Science

Notice of RetractionStudy on the Instructional Process of Cultivating the Undergraduates' Innovative and Practical Ability Instructional Process in E-Commerce English Teaching

The NbCP reinforced cast iron composite was prepared using in-situ reaction between cast iron and Nb wires at 1164 ℃ for 1 h. The Nb wires were uniformly fixed in the iron matrix through pouring molten iron. The microstructure and microhardness in the compound region were observed and measured,respectively. The results show that,the maximal microhardness in the compound region is 1930 HV0.05,and the average microhardness is 8～9 times as high as iron matrix. The wear-resistance of the composite is 2.71 times higher than the cast iron standard sample.

NbCP/Fe Composites In-situ Synthesized by Reaction Between Cast Iron and Nb Wires

Three-Dimensional Human Face Laser Scanning Based on Three-Line Structured Light

Under the background of the transformation of higher education system and the regionalization of economic development,regionalization of higher education and interactive development between higher education and regional economy has become a common understanding.Closely combined with regional economy,higher education in Hong Kong has been developing interactively with the society,which has set a successful example.Exploration of the successful experience of win-win interaction between higher education and regional economy in Hong Kong offers positive enlightenment and referential meaning to the construction of our construction of multidisciplinary university.

Enlightenment of Mode of Win-win Interaction Between Higher Education and Regional Economy in Hong Kong to Our Construction of Multidisciplinary University

Abstract: 
 In the 21st century. China is facing some challenges, e.g. population growth, rapid economy development, resources limitation and environmental vulnerability. Resource-use efficiency and the environmental impacts associated with growing resource utilization is a new challenge for both scientists and politicians, especially. In this paper, the concepts of resources and resource products flow is presented in order to analyze the environmental impacts that occur as a result of the resource flow process. We focus on forest resources, coal products and oil flows as these the main resources and products that are produced continuous severe and increasing environmental pressure. The data for domestic yield and exploitation, importation, exportation, and consumption, for various industries come from China's forest statistical yearbooks for the period 1949 to 2001, and China's energy statistical yearbooks for 1980 to 2006. We divided the resources flow process into key stages, such as harvest, exploitation, process or conversion and end consumption. Resources efficiency and environmental performance for each stage were evaluated. This study showed: resource-use efficiency improved and the structure of resources consumption has been optimized markedly in the past decades in China. However, the absolute quantities of resources consumption are still increasing, and the environment pressures originating from resource use became more severe.

The objective of the study is to investigate the effect of fasudil [1-(5-isoquinolinesulfonyl) homopiperazine] (HA1077, calcium antagonist vasodilator and an inhibitor of RhoA kinase) on expression of cytokeratin (CK), DNA multiplication, and synthesis of mesenchymal stem cells (MSC). After rats were killed, MSC were separated from rats and proliferated in culture medium. The cells were randomly divided into control group, HA1077 control group, induction group, and HA1077 group. The percentage of CK19+MSC, proliferating cell nuclear antigen (PCNA), and cell cycle were determined. The test was repeated for five times. SPSS 12 software was used to analyze all the data. A P value <.05 and P < .01were considered to be significant. The flow cytometry result showed that 1) the isolated MSC were uniformly positive for CD44, SSEA-1, CD105 but were negative for CD34, CD14, and CD45. 2) In the HA1077 control group, the percentage of CK19+MSC was similar to that in control group, which was lower than that in the induction group. In the HA1077 group, the percentage of CK19+MSC was higher than in the induction group (P < .01), in HA1077 control group (P < .01), and in control group (P < .01). 3) PCNA-positive rate in HA1077 group was highest among the groups. PCNA-positive rate of induction group was higher than that of control group and HA1077 control group. The cell cycle analysis showed that the quantity of MSC in S phase of HA1077 group was also highest. The quantity of MSC in S phase of induction group was higher than that of control group and HA1077 control group. There was no difference between the HA1077 control group and control group. HA1077 can repair burn wounds in future by promoting MSC differentiating into epidermal cell through DNA multiplication and synthesis.

HA1077 Enhances the Cytokeratin Expression of Mesenchymal Stem Cells

Process and analyze the point cloud after gaining the point cloud scan line of human body by non-contact measuring system, aiming to make the point cloud form a complete ring on the same horizontal plane. This is to lay a well foundation for the modeling of human body surface. Finally, taking the processed point cloud data is to reconstruct the model of human body surface by means of outline triangular meshing through one-on-one and one-on-multi.

A study on modeling of three-dimensional human body surface based on point clouds scan line

According to the subjects and strategies of life education that have existed in home and abroad,the author article tried to generally describe the methods and statement which are used to achieve life education,explore and analyse the matters that life education is facing and put forward some conceptions,so that it can provide some references for better life education.The ultimate goals are helping people to profoundly understand their life,better cherish and protect their life,more positive to pursue life values and its meanings.

Potential impacts of climate change on water quality and ecosystem, as a newly emerged problem and challenge, is of great concern by scientists and governments. However, scientific researches and practices are still facing big challenges in these issues because of their complexity and uncertainty. This paper reviews the most recent literatures on this topic at first, and proposes some research gaps between published results and what needs to be known in practice. Additionally, basing on our knowledge and results of some recent case studies of the two representative rivers which are Huai River and Hanjiang River in China, it should be addressed that if the impact of climate change on the water quality and ecosystem has been taken concern, water pollution and related water environmental problem caused by human activities and economic development must be addressed firstly. It has also been recognized that water quality and ecosystem can be significantly impacted by climate change under the condition of human activities. Climate change can alter water temperature and hydrological regimes and thus influence the water quality and ecosystem. Then, the contents and principles of adaptation options and adaptability construction are discussed. The present study is expected to make clear of conceptions and to give directions for further relevant researches.

Potential Impacts andChallenges of Climate Change onWater Quality andEcosystem: Case Studies inRepresentative Rivers inChina

Abstract: 
 Potential impacts of climate change on water quality and ecosystem, as a newly emerged problem and challenge, is of great concern by scientists and governments. However, scientific researches and practices are still facing big challenges in these issues because of their complexity and uncertainty. This paper reviews the most recent literatures on this topic at first, and proposes some research gaps between published results and what needs to be known in practice. Additionally, basing on our knowledge and results of some recent case studies of the two representative rivers which are Huai River and Hanjiang River in China, it should be addressed that if the impact of climate change on the water quality and ecosystem has been taken concern, water pollution and related water environmental problem caused by human activities and economic development must be addressed firstly. It has also been recognized that water quality and ecosystem can be significantly impacted by climate change under the condition of human activities. Climate change can alter water temperature and hydrological regimes and thus influence the water quality and ecosystem. Then, the contents and principles of adaptation options and adaptability construction are discussed. The present study is expected to make clear of conceptions and to give directions for further relevant researches.

Potential Impacts and Challenges of Climate Change on Water Quality and Ecosystem: Case Studies in Representative Rivers in China

The issue on screening for climate change adaptation is addressed. A screening approach is developed for assessing climate change impacts on water sector and integrating adaptation for water resource projects, and three phases for screening climate change adaptation are introduced that include the semi-quantitative & quantitative analysis, and the evaluation of different adaptation options on the water resources affected by climate change in China. According to different climatic regions facing different problems on water resource, four representative regions in China are chosen in the project; after setting up different objectives, this paper demonstrates the comprehensive research on climate change adaptation, and proposes new ideas, framework and methodologies on screening for climate change impacts and adaptation. This research provides the effective framework and methodology for the planning and risk management of the impacts of future climate change on water resource.

Screening for Climate Change Adaptation: Managing the Potential Impacts of Climate Change on Water Sector in China

Objective To observe the effects of human mesenchymal stem cells(MSCs) and HA1077 on indolent ulcer and wound healing.Methods Human MSCs were separated in vitro.Four wound patients with refractory 15 wounds were included.Control group(5 wounds) was treated only with routine dressing,HA1077 group was treated with routine dressing and HA1077 ,and cell transplant group was treated with MSCs and HA1077.3,7,and 14 days after treatment,wound cure index(WCI) was caculated.Results At 14d,WCI in cell transplant group was 36.32±9.92,significantly higher than that in control group.There was no difference in WCI between HA1077 group and control group.Conclusions HA1077 promotes MSCs to repair the refractory skin wounds.

This article take the Chinese hawthorn,the apple pear as the primary data,the process ferments add-on mixes by other supplementary materials develops the Chinese hawthorn apple pear vinegar drink,simultaneously discussed the Chinese hawthorn juice system to take the craft simply,and take fermented as the main object of study,through after affecting the fermentation result various factors(Chinese hawthorn apple pear acetic fermentation fluid,mother of vinegar,distiller's yeast,honey,xylose)performed the single factor experiment performs the orthogonal test,determined finally the Chinese hawthorn apple pear vinegar drink the best formula was:Chinese hawthorn apple pear acetic fermentation fluid 20%,mother of vinegar 8%,distiller's yeast 10%,honey 1%,xylose 0.12%.

Study on the production technology of vinegar beverage with Chinese hawthorn and apple pear.

Invisible Man is considered to be one of the best works since the Second World War.The paper concentrates on the work itself and studies it in terms of narratology and reveals some important internal structural features of the work.The narrative strategies such as the first-person narration,speech presentation and the narrator-narratee relationship help to develop the theme of Invisible Man,which exhibits the narrator’s development in his search for his identity,from blackness to light,from ignorance to enlightenment.

Due to the emergency critically ill patients in special condition and greater potential danger, the treatment effect of the hospital transfer has both opportunity and risk. Effective measures should be taken to maintain the stability of the vital signs of patients, reduce complications, ensure patient safety and smoothly reach the purpose section.

Discussion on the Security Transfer of Critically Ill Patients in Hospital

In the process of dynamic consolidation,some hammered spots and their surrounding exist large deformation,This paper analyzes the vibration of dynamic consolidation with the large deformation theory and uses LS-DYNA finite element program to modeling the process of dynamic consolidation.The velocity-time data acquired in the analysis are close to the actual data measured in dynamic consolidation.Using dimension analyzing method reasons a relational formula between vibration velocity and weight of the hammer.And the author uses the actual measured data to imitate the relationship of the vibration velocity.The formula provides a new method to forecast the vibration of dynamic compaction,which makes sense for the similar construction work to forecast the impact for adjacent buildings.

Detailed Pollution Map of an Area Highly Contaminated by Mercury Containing Wastewater from an Organic Chemical Factory in People's Republic of China

Relationship Between Leached Total Mercury and Leached Methylmercury from Soil Polluted by Mercury in Wastewater from an Organic Chemical Factory in the People’s Republic of China

The transient pulse testing is used in a commercial electric detonator to measure the electrothermal performance. The conventional inspection has the disadvantage of destruction with a number of detonators tested, while the transient pulse testing can give a dynamic electrothermal curve at a user's command. In addition, the transient pulse testing can be used to measure a passel of commercial matches one by one rather than by a statistical spot check. Unfortunately, a statistic spot check cannot provide the firing reliability of products efficiently. The other way round, the transient pulse testing may put an end to the possibility of loss for users absolutely. The reason that the transient pulse testing is not devastating for products is that these mixtures of a match have a required thermal stability, and then are simultaneously able to be responded reliably by a very small pulse current. We have determined that these bridge wires in air and under water electrothermal responsibility curves. Eletrothermal responsibility, calculation and simulation of electrothermal parameters are presented in this paper.

Mercury Distribution in Farmlands Downstream from an Acetaldehyde Producing Chemical Company in Qingzhen City, Guizhou, People’s Republic of China

Distribution of Methylmercury in an Area Polluted by Mercury Containing Wastewater from an Organic Chemical Factory in China

A total of 8 concrete model beams, which are made of concrete with different molding forms, either self compacting or vibro compacting, have been tested. The results indicate that the fatigue properties of two series of concrete beams are almost the same and the fatigue properties of the self compacting concrete beams are only a little bit better than those of the vibro compacting concrete beams, so that they can be analyzed in the same way.The fatigue life of a partially prestessed concrete beam should be decided by non prestressed longitudinal reinforcement rather than by the prestressing steel and concrete according to the results of the experiment and analysis, and the fatigue life of a beam can be predicted more accurately when the stress amplitude of tensile reinforcement under cyclic action is based on non linear analysis than based on the status of elasticity at early stage. And the calculated values agree well with the test ones.

Experimental study on fatigue properties of self-compacting prestreesed concrete beams

Elite soybean germplasm derived from the cross between G.max and G.soja which is faverable in more florets and pods,more branches and high protein content adopted from wild soybean,was used to make backcross with soybean cultivars (G.max) in order to broaden the genetic basis of soybean breeding and improve the agronomic traits,yield and quality of germplasm derived from interspecific crossing as well as soybean breeding for special purpose including exporting,sprouting,sauce making and food-treating.Breeding practice indicated that the utilization of new germplasm derived from wild and cultivated soybean is feasible and effective to broaden the genetic basis of soybean breeding and improve variety,especially to select soybean varieties or lines for special purpose.

Management with liabilities is one of the characteristics of modern enterprises. It has both advantages and disadvantages. On the one hand, it can help to accumulate capitals rapidly, makes up for the lack of capitals and thus benefits the enterprise; on the other hand, it endangers the enterprise in that when the management is not in good condition and investment can't be taken back to pay for due liabilities, the enterprise is likely to go bankrupt. So management with liabilities should be conducted on a moderate level, and the appropriate ratio of liabilities can be calculated through a comprehensive analysis of the enterprise's financial affairs and environment.

An interspecies conserved antigen ofPlasmodium falciparum containing clusters of asparagine residues

La moda : uomini costumi del secolo XIX da dipinti e incisioni del tempo

Medial and orbital frontal cortex in decision-making and flexible behavior

Activation and disruption of a neural mechanism for novel choice in monkeys

Animals learn from the past to make predictions. These predictions are adjusted after prediction errors, i.e., after surprising events. Generally, most reward prediction errors models learn the average expected amount of reward. However, here we demonstrate the existence of distinct mechanisms for detecting other types of surprising events. Six macaques learned to respond to visual stimuli to receive varying amounts of juice rewards. Most trials ended with the delivery of either 1 or 3 juice drops so that animals learned to expect 2 juice drops on average even though instances of precisely 2 drops were rare. To encourage learning, we also included sessions during which the ratio between 1 and 3 drops changed. Additionally, in all sessions, the stimulus sometimes appeared in an unexpected location. Thus, 3 types of surprising events could occur: reward amount surprise (i.e., a scalar reward prediction error), rare reward surprise, and visuospatial surprise. Importantly, we can dissociate scalar reward prediction errors—rewards that deviated from the average reward amount expected—and rare reward events—rewards that accorded with the average reward expectation but that rarely occurred. We linked each type of surprise to a distinct pattern of neural activity using functional magnetic resonance imaging. Activity in the vicinity of the dopaminergic midbrain only reflected surprise about the amount of reward. Lateral prefrontal cortex had a more general role in detecting surprising events. Posterior lateral orbitofrontal cortex specifically detected rare reward events regardless of whether they followed average reward amount expectations, but only in learnable reward environments.

Multiple systems in macaques for tracking prediction errors and other types of surprise

A Basal Forebrain-Cingulate Circuit in Macaques Decides It Is Time to Act

Mechanisms for novel multidimensional choices in prefrontal cortex

An immense reservoir of art history, Cairo's Museum of Egyptian Antiquities contains fabulous collections of relics from the Mediterranean's most mysterious and ancient civilization, the true cradle of western culture. From the creation of the first state on the banks of the Nile to its submission to the Roman empire, the millennial story of ancient Egypt is recounted here through the artistic masterpieces, the everyday objects, the spectacular jewels, and the magnificent remains from the tombs of the pharaohs, all remarkably assembled within the walls of a single institution.Structured as a guide, but fully illustrated with superb color photographs, this book suggests a simple but comprehensive itinerary through the museum, subdividing the tour into chapters devoted to the most important episodes in Egyptian history. Collected during the course of over a century of archaeological excavations, jewelry, tools, toys, models, religious objects, mummies, and monumental sculptures offer vivid glimpses of a formidable civilization. The rich funerary cache of Tutankhamun, the treasures of Tanis, and the jewels of Queen Ahhotep reflect the glory of the Egyptian monarchy, but there are insights too into the day-to-day lives of the more humble sections of society. Previously unpublished photographs and plans alongside texts prepared by the museum curators themselves help readers to penetrate the corridors and halls of the great museum in search of a heritage unique in its richness and variety, following in the footsteps of the great figures in Egyptian history: from the pharaohs, suspended between heaven and earth, to the archaeologists who, with their patient excavations, have helped to shed new light on the land of the pyramids.

Mechanical ventilation is one of the most widely used therapies in the ICU. However, despite broad application from anaesthesia to COVID-related life support, many injurious challenges remain. We frame these as a control problem: ventilators must let air in and out of the patient’s lungs according to a prescribed trajectory of airway pressure. Industrystandard controllers, based on the PID method, are neither optimal nor robust. Our data-driven approach learns to control an invasive ventilator by training on a simulator itself trained on data collected from the ventilator. This method outperforms popular reinforcement learning algorithms and even controls the physical ventilator more accurately and robustly than PID. These results underscore how effective data-driven methodologies can be for invasive ventilation and suggest that more general forms of ventilation (e.g., noninvasive, adaptive) may also be amenable.

Machine Learning for Mechanical Ventilation Control (Extended Abstract)

Responses to natural scenes are the business of the retina. We find primate ganglion cell responses to such scenes consistent with those to simpler stimuli. A biophysical model confirmed this and predicted ganglion cell responses with close to retinal reliability. Primate ganglion cell responses to natural scenes were driven by temporal variations in colour and luminance over the receptive field centre caused by eye movements, and little influenced by interaction of centre and surround with structure in the scene. We discuss implications in the context of efficient coding of the visual environment. Much information in a higher spatiotemporal frequency band is concentrated in the magnocellular pathway.

A quantitative description of macaque ganglion cell responses to natural scenes: the interplay of time and space

We consider the problem of controlling an invasive mechanical ventilator for pressure-controlled ventilation: a controller must let air in and out of a sedated patient's lungs according to a trajectory of airway pressures specified by a clinician. Hand-tuned PID controllers and similar variants have comprised the industry standard for decades, yet can behave poorly by over- or under-shooting their target or oscillating rapidly. We consider a data-driven machine learning approach: First, we train a simulator based on data we collect from an artificial lung. Then, we train deep neural network controllers on these simulators.We show that our controllers are able to track target pressure waveforms significantly better than PID controllers. We further show that a learned controller generalizes across lungs with varying characteristics much more readily than PID controllers do.

We present a fully open ventilator platform--The People's Ventilator: PVP1-- with complete documentation and detailed build instructions, and a DIY cost of $1,300 USD. Here, we validate PVP1 against key performance criteria specified in the U.S. Food and Drug Administration's Emergency Use Authorization for Ventilators. Notably, PVP1 performs well over a wide range of test conditions and has been demonstrated to perform stably for a minimum of 72,000 breath cycles over three days with a mechanical test lung. As an open project, PVP1 can enable both future educational, academic, and clinical developments in the ventilator space.

PVP1—The People’s Ventilator Project: A fully open, low-cost, pressure-controlled ventilator research platform compatible with adult and pediatric uses

The Synaptic Vesicle Priming Protein CAPS-1 Shapes the Adaptation of Sensory Evoked Responses in Mouse Visual Cortex.

Orientation Preference Maps in Microcebus murinus Reveal Size-Invariant Design Principles in Primate Visual Cortex

Peer review is the cornerstone of scholarly publishing and it is essential that peer reviewers are appointed on the basis of their expertise alone. However, it is difficult to check for any bias in the peer-review process because the identity of peer reviewers generally remains confidential. Here, using public information about the identities of 9000 editors and 43000 reviewers from the Frontiers series of journals, we show that women are underrepresented in the peer-review process, that editors of both genders operate with substantial same-gender preference (homophily), and that the mechanisms of this homophily are gender-dependent. We also show that homophily will persist even if numerical parity between genders is reached, highlighting the need for increased efforts to combat subtler forms of gender bias in scholarly publishing. DOI: http://dx.doi.org/10.7554/eLife.21718.001

Information processing in the nervous system requires the co-ordinated activity of neurons interacting in complex circuits. Despite effort to understand the design principles underlying most neuronal circuits, they remain one of the greatest challenges facing science because not all contributing neuronal circuit elements can be selectively manipulated. Here, I developed a new approach to modify the wiring diagram of neuronal circuits by constructing synthetic hybrid systems composed of simulated and living nerve cells in which key features of the wiring diagram can be artificially modified. I used the mammalian early visual system as a model pathway to perform a first connectomic structure-function study. This synthetic biology approach complements classical neurobiology, broadens our understanding of neuronal circuits, and extends the realm of questions that can be addressed experimentally.

The reconstitution of visual cortical feature selectivity in vitro

Growing neuronal islands on multi-electrode arrays using an accurate positioning-μCP device

The architecture of iso-orientation domains in the primary visual cortex (V1) of placental carnivores and primates apparently follows species invariant quantitative laws. Dynamical optimization models assuming that neurons coordinate their stimulus preferences throughout cortical circuits linking millions of cells specifically predict these invariants. This might indicate that V1’s intrinsic connectome and its functional architecture adhere to a single optimization principle with high precision and robustness. To validate this hypothesis, it is critical to closely examine the quantitative predictions of alternative candidate theories. Random feedforward wiring within the retino-cortical pathway represents a conceptually appealing alternative to dynamical circuit optimization because random dimension-expanding projections are believed to generically exhibit computationally favorable properties for stimulus representations. Here, we ask whether the quantitative invariants of V1 architecture can be explained as a generic emergent property of random wiring. We generalize and examine the stochastic wiring model proposed by Ringach and coworkers, in which iso-orientation domains in the visual cortex arise through random feedforward connections between semi-regular mosaics of retinal ganglion cells (RGCs) and visual cortical neurons. We derive closed-form expressions for cortical receptive fields and domain layouts predicted by the model for perfectly hexagonal RGC mosaics. Including spatial disorder in the RGC positions considerably changes the domain layout properties as a function of disorder parameters such as position scatter and its correlations across the retina. However, independent of parameter choice, we find that the model predictions substantially deviate from the layout laws of iso-orientation domains observed experimentally. Considering random wiring with the currently most realistic model of RGC mosaic layouts, a pairwise interacting point process, the predicted layouts remain distinct from experimental observations and resemble Gaussian random fields. We conclude that V1 layout invariants are specific quantitative signatures of visual cortical optimization, which cannot be explained by generic random feedforward-wiring models.

Random Wiring, Ganglion Cell Mosaics, and the Functional Architecture of the Visual Cortex

Background Multi-electrode arrays (MEAs) allow non-invasive multiunit recording in-vitro from cultured neuronal networks. For sufficient neuronal growth and adhesion on such MEAs, substrate preparation is required. Plating of dissociated neurons on a uniformly prepared MEA’s surface results in the formation of spatially extended random networks with substantial inter-sample variability. Such cultures are not optimally suited to study the relationship between defined structure and dynamics in neuronal networks. To overcome these shortcomings, neurons can be cultured with pre-defined topology by spatially structured surface modification. Spatially structuring a MEA surface accurately and reproducibly with the equipment of a typical cell-culture laboratory is challenging. New Method In this paper, we present a novel approach utilizing microcontact printing (μCP) combined with a custom-made device to accurately position patterns on MEAs with high precision. We call this technique AP-μCP (accurate positioning micro-contact printing). Comparison with existing Methods Other approaches presented in the literature using μCP for patterning either relied on facilities or techniques not readily available in a standard cell culture laboratory, or they did not specify means of precise pattern positioning. Conclusion Here we present a relatively simple device for reproducible and precise patterning in a standard cell-culture laboratory setting. The patterned neuronal islands on MEAs provide a basis for high throughput electrophysiology to study the dynamics of single neurons and neuronal networks.

Growing neuronal islands on multi-electrode arrays using an Accurate Positioning-µCP device

Submitted for the MAR14 Meeting of The American Physical Society Tunneling Currents through DNA Bases Tightly Constrained in a Fluid Channel1 LUKE A SOMERS, Rutgers University, MANUEL SCHOTTDORF, Max Planck Institute for Dynamics and Self-Organization, MENI WANUNU, Northeastern University, EVA Y. ANDREI, Rutgers University — Directing single-stranded DNA through a tunnel-junction is a strategy for rapid DNA sequencing. The main limiting factor in the viability of this method is coercing the ssDNA strand to pass only directly between the tunneling tips. This both ensures sequencing completely in order and minimizes the geometric effects on tunneling. We present such a device and results of tunneling through different bases. This device, employing graphene as a super-thin electrode, lies entirely in-plane rather than acting through a membrane. This geometry enables dense packing of devices with a minimum of fabrication. 1Supported by ICAM and NSF DMR 1207108 Luke A Somers Rutgers University Date submitted: 15 Nov 2013 Electronic form version 1.4

Tunneling Currents through DNA Bases Tightly Constrained in a Fluid Channel

Inferring retinal ganglion cell mosaics from measured orientation preference maps in cat V1

A Fluid Channel Coincident With Graphene Tunneling Leads for DNA sequencing

It has been argued that the emergence of roughly periodic orientation preference maps (OPMs) in the primary visual cortex (V1) of carnivores and primates can be explained by a so-called statistical connectivity model. This model assumes that input to V1 neurons is dominated by feed-forward projections originating from a small set of retinal ganglion cells (RGCs). The typical spacing between adjacent cortical orientation columns preferring the same orientation then arises via Moiré-Interference between hexagonal ON/OFF RGC mosaics. While this Moiré-Interference critically depends on long-range hexagonal order within the RGC mosaics, a recent statistical analysis of RGC receptive field positions found no evidence for such long-range positional order. Hexagonal order may be only one of several ways to obtain spatially repetitive OPMs in the statistical connectivity model. Here, we investigate a more general requirement on the spatial structure of RGC mosaics that can seed the emergence of spatially repetitive cortical OPMs, namely that angular correlations between so-called RGC dipoles exhibit a spatial structure similar to that of OPM autocorrelation functions. Both in cat beta cell mosaics as well as primate parasol receptive field mosaics we find that RGC dipole angles are spatially uncorrelated. To help assess the level of these correlations, we introduce a novel point process that generates mosaics with realistic nearest neighbor statistics and a tunable degree of spatial correlations of dipole angles. Using this process, we show that given the size of available data sets, the presence of even weak angular correlations in the data is very unlikely. We conclude that the layout of ON/OFF ganglion cell mosaics lacks the spatial structure necessary to seed iso-orientation domains in the primary visual cortex.

Can Retinal Ganglion Cell Dipoles Seed Iso-Orientation Domains in the Visual Cortex?

We present a model to describe the response of chip-based nanocavity sensors during extracellular recording of action potentials. These sensors feature microelectrodes which are embedded in liquid-filled cavities. They can be used for the highly localized detection of electrical signals on a chip. We calculate the sensor's impedance and simulate the propagation of action potentials. Subsequently we apply our findings to analyze cell-chip coupling properties. The results are compared to experimental data obtained from cardiomyocyte-like cells. We show that both the impedance and the modeled action potentials fit the experimental data well. Furthermore, we find evidence for a large seal resistance of cardiomyocytes on nanocavity sensors compared to conventional planar recording systems.

Frequency-dependent signal transfer at the interface between electrogenic cells and nanocavity electrodes.

We present a new nanocavity device for highly localized on-chip recordings of action potentials from individual cells in a network. Microelectrode recordings have become the method of choice for recording extracellular action potentials from high density cultures or slices. Nevertheless, interfacing individual cells of a network with high resolution still remains challenging due to an insufficient coupling of the signal to small electrodes, exhibiting diameters below 10 µm. We show that this problem can be overcome by a new type of sensor that features an electrode, which is accessed via a small aperture and a nanosized cavity. Thus, the properties of large electrodes are combined with a high local resolution and a good seal resistance at the interface. Fabrication of the device can be performed with state-of-the-art clean room technology and sacrificial layer etching allowing integration of the devices into sensor arrays. We demonstrate the capability of such an array by recording the propagation of action potentials in a network of cardiomyocyte-like cells.

Nanocavity electrode array for recording from electrogenic cells.

A nanochannel with an embedded transverse graphene tunneling electrode for molecular probing and as a future tool for DNA sequencing

Social anxiety disorder is a debilitating mental health condition characterized by intense fear of social situations that can significantly impair daily life if left untreated. Cognitive behavioral therapy (CBT) is an effective treatment, but many patients experience slow progress, possibly due to the heterogeneity of cognitive dysfunction contributing to the maintenance of the disease that is not adequately reflected in a typical one-size-fits-all CBT approach. In addition, many patients only seek treatment late, because human therapists can themselves constitute phobic stimuli. To address these challenges, we developed Alena, a digital CBT program based on the Clark and Wells model of social anxiety (Clark and Wells, 1995) that was reorganized to target the four key cognitive functions associated with the maintenance of social anxiety disorder in separate therapy modules: negative beliefs, self-directed attention, rumination, and avoidance behaviors. Here, we tested the safety, acceptability and efficacy of this therapy program. In a randomized controlled trial, primary outcomes showed the app to be safe and acceptable. Secondary endpoint analyses showed that SPIN scores were significantly reduced in the treatment compared to the control group, and a larger number of participants who completed the four-week digital CBT program showed a reliable reduction in their social anxiety scores compared to a waitlist control group. Our findings suggest that targeted digital CBT without therapist involvement was safe, acceptable and showed promising signs of rapid efficacy in the treatment of social anxiety disorder.

The Safety, Acceptability and Efficacy of Alena, a Modularized CBT-based Mobile App Intervention for Social Anxiety: a Randomised Controlled Trial

Task state representations in vmPFC mediate relevant and irrelevant value signals and their behavioral influence

The hippocampal-entorhinal system uses cognitive maps to represent spatial knowledge and other types of relational information, such as the transition probabilities between objects. However, objects can often be characterized in terms of different types of relations simultaneously, e.g. semantic similarities learned over the course of a lifetime as well as transitions experienced over a brief timeframe in an experimental setting. Here we ask how the hippocampal formation handles the embedding of stimuli in multiple relational structures that differ vastly in terms of their mode and timescale of acquisition: Does it integrate the different stimulus dimensions into one conjunctive map, or is each dimension represented in a parallel map? To this end, we reanalyzed functional magnetic resonance imaging (fMRI) data from Garvert et al. (2017) that had previously revealed an entorhinal map which coded for newly learnt statistical regularities. We used a triplet odd-one-out task to construct a semantic distance matrix for presented items and applied fMRI adaptation analysis to show that the degree of similarity of representations in bilateral hippocampus decreases as a function of semantic distance between presented objects. Importantly, while both maps localize to the hippocampal formation, this semantic map is anatomically distinct from the originally described entorhinal map. This finding supports the idea that the hippocampal-entorhinal system forms parallel cognitive maps reflecting the embedding of objects in diverse relational structures.

Parallel cognitive maps for short-term statistical and long-term semantic relationships in the hippocampal formation

Value representations in ventromedial prefrontal-cortex (vmPFC) are known to guide the choice between options. But the value of an option can be different in different task contexts. Goal-directed behavior therefore requires to know the current context and associated values of options, and to flexibly switch between value representations in a task-dependent manner. We tested whether task-relevant and -irrelevant values influence behavior and asked whether both values are represented together with context signals in vmPFC. Thirty-five participants alternated between tasks in which stimulus color or motion predicted rewards. As expected, neural activity in vmPFC and choices were largely driven by task-relevant values. Yet, behavioral and neural analyses indicate that participants also retrieved the values of irrelevant features, and computed which option would have been best in the alternative context. Investigating the probability distributions over values and contexts encoded in multivariate fMRI signals, we find that vmPFC maintains representations of the current context, i.e. task state, the value associated with it, and the hypothetical value of the alternative task state. Crucially, we show that evidence for irrelevant value signals in vmPFC relates to behavior on multiple levels, competes with expected value signals, and interacts with task state representations. Our results thus suggest that different value representations are represented in parallel and imply a link between neural representations of task states, their associated values and their influence on behavior. This sheds new light on vmPFC’s role in decision making, bridging between a hypothesized role in mapping observations onto the task states of a mental map, and computing value expectations for alternative states.

Representations of context and context-dependent values in vmPFC compete for guiding behavior

Contagion of Temporal Discounting Value Preferences in Neurotypical and Autistic Adults

Value representations in ventromedial prefrontal-cortex (vmPFC) are known to guide decisions. But how preferable available options are depends on one’s current task. Goal-directed behavior, which involves changing between different task-contexts, therefore requires to know how valuable the same options will be in different contexts. We tested whether multiple task-dependent values influence behavior and asked if they are integrated into a single value representation, or are co-represented in parallel within vmPFC signals. Thirty five participants alternated between tasks in which stimulus color or motion predicted rewards. Our results provide behavioral and neural evidence for co-activation of both contextually-relevant and -irrelevant values, and suggest a link between multi-variate neural representations and the influence of the irrelevant context and its associated value on behavior. Importantly, current task context could be decoded from the same region, and better context-decodability was associated with stronger (relevant) value representations. Evidence for choice conflicts was found only in the motor cortex, where the competing values are likely resolved into action.

Parallel representation of context and multiple context-dependent values in ventro-medial prefrontal cortex

The ability to appropriately generalise previously acquired knowledge to novel situations is a hallmark of human intelligence. A possible neural solution to this problem is to devote pools of neurons to represent the relations between entities in the environment explicitly, in a manner that is divorced from the entities themselves. Such an explicit representation can generalise to novel situations with the same relational structure. Grid cells, originally found in the entorhinal cortex, have been proposed as such an explicit representation of the relations between different locations in physical space. However, the neural representations underlying the generalisation of relational structures in abstract tasks remain poorly understood. Here we use fMRI in humans to show that the entorhinal cortex explicitly represents the relations between reward-predicting stimuli in a reinforcement learning task with different underlying correlation structures between the reward probabilities associated with different stimuli. Our results demonstrate that the same brain regions, perhaps with the same mechanisms, represent the relational structure of the task in both spatial and abstract decision-making tasks. This suggests that the brain uses a common coding framework for the structure of tasks across a wide range of domains.

The relational structure of a reinforcement learning task is represented and generalised in the entorhinal cortex

Entorhinal and ventromedial prefrontal cortices abstract and generalize the structure of reinforcement learning problems

Spatial codes beyond space: Mapping conceptual knowledge in the service of flexible behaviour

Alon B. Baram, Timothy H. Muller, Hamed Nili, Mona Garvert and Timothy EJ Behrens Summary Representing the relationships between entities in a task explicitly, i.e. in a manner that is divorced from the sensory particularities of the entities, is useful for generalising previous knowledge to new environments with the same relational structure – a key component of flexible behaviour. Theoretical work suggests that grid cells might encode such an explicit representation of the statistical structure of 2D space. In remapping experiments, grid cells indeed perform this kind of generalisation over environments. Importantly, in these experiments, there is always only a single relational structure: the structure of 2D space. Here, we look for such an explicit structural representation in a stimulus-outcome decision making task with an underlying correlation structure between the reward probabilities of the stimuli. Like in spatial remapping experiments, there were two different ‘environments’ with the same underlying structure. Importantly, we introduce a second pair of environments with a different underlying structure, allowing us to test for neural coding of the underlying structure, divorced from sensory particularities. Such neural coding can be thought of as remapping across structures/tasks. Preliminary results suggest that a network of regions previously shown to have gridlike coding properties explicitly encodes this abstract non-spatial task structure in a generalisable way. Additionally, we show that the hippocampus differentiates learning with and without structure, and that the orbitofrontal cortex is involved in assigning credit for rewards to their latent structural causes. Introduction. It is proposed that a cognitive map encoding the relationships between entities in the world supports flexible behaviour (Tolman 1948), including generalisation of previously learnt knowledge to novel situations. Most of the neural evidence for such a map comes from the spatial domain, most notably in the form of place (O’keefe & Nadel 1978) and grid cells (Hafting 2005). Whilst place cells remap across environments, grid cells maintain their covariance structure (relative phase relationships, Fyhn 2007), suggesting them as a substrate for generalisation (Behrens 2018). Furthermore, theoretical work suggests that grid cells explicitly encode the relationships between locations (i.e. structure) in 2D space (Dordek 2016; Stachenfeld 2017). However, representations that code similarly for different sensory instantiations of a particular task (like grid cells in 2D space; for non-spatial examples see Xie & Padoa-Schioppa 2016; Baldassano 2018), and also differentiate perceptually identical but structurally different tasks (i.e. remap across tasks/structures), have never been shown (Fig 1B). Task. We designed a task with a structure by stimulus factorial design. This can be viewed as two remapping (across stimuli) experiments, each with a different structure (rows in Fig 1B). In the first structure, participants performed a reversal learning task where the reward probabilities (probs) associated with two stimuli were anticorrelated. We also used a third, control stimulus, with an uncorrelated reward prob. Analogous to spatial remapping experiments, this correlation structure was instantiated with two different triplets of stimuli (Fig 1A, top two panels). In the second structure, the reward probs of the same two stimuli had a different correlation relationship – positive correlation (Fig 1A, bottom two panels). Subjects were pretrained on the correlations between stimuli (indexed by the images background colour).

Task remapping and generalisation of structure in reinforcement learning

The hippocampal–entorhinal system encodes a map of space that guides spatial navigation. Goal-directed behaviour outside of spatial navigation similarly requires a representation of abstract forms of relational knowledge. This information relies on the same neural system, but it is not known whether the organisational principles governing continuous maps may extend to the implicit encoding of discrete, non-spatial graphs. Here, we show that the human hippocampal–entorhinal system can represent relationships between objects using a metric that depends on associative strength. We reconstruct a map-like knowledge structure directly from a hippocampal–entorhinal functional magnetic resonance imaging adaptation signal in a situation where relationships are non-spatial rather than spatial, discrete rather than continuous, and unavailable to conscious awareness. Notably, the measure that best predicted a behavioural signature of implicit knowledge and blood oxygen level-dependent adaptation was a weighted sum of future states, akin to the successor representation that has been proposed to account for place and grid-cell firing patterns. DOI: http://dx.doi.org/10.7554/eLife.17086.001

A map of abstract relational knowledge in the human hippocampal–entorhinal cortex

Author response: A map of abstract relational knowledge in the human hippocampal–entorhinal cortex

Understanding how the human brain gives rise to complex cognitive processes remains one of the biggest challenges of contemporary neuroscience. While invasive recording in animal models can provide insight into neural processes that are conserved across species, our understanding of cognition more broadly relies upon investigation of the human brain itself. There is therefore an imperative to establish non-invasive tools that allow human brain activity to be measured at high spatial and temporal resolution. In recent years, various attempts have been made to refine the coarse signal available in functional magnetic resonance imaging (fMRI), providing a means to investigate neural activity at the meso-scale, i.e. at the level of neural populations. The most widely used techniques include repetition suppression and multivariate pattern analysis. Human neuroscience can now use these techniques to investigate how representations are encoded across neural populations and transformed by relevant computations. Here, we review the physiological basis, applications and limitations of fMRI repetition suppression with a brief comparison to multivariate techniques. By doing so, we show how fMRI repetition suppression holds promise as a tool to reveal complex neural mechanisms that underlie human cognitive function. This article is part of the themed issue ‘Interpreting BOLD: a dialogue between cognitive and cellular neuroscience’.

Repetition suppression: a means to index neural representations using BOLD?

Goal-directed behaviour is characterized by an ability to make inferences without direct experience. This requires a model of the environment and of ourselves, which is flexibly adjusted in light of new incoming information. This thesis uses representational functional magnetic resonance imaging (fMRI) techniques in combination with computational modelling to investigate (1) whether humans can construct models of other people’s preferences and whether this process influences their own value representation, and (2) how statistical relationships between discrete, non-spatial objects are combined into a model of the world. The first part of the thesis investigates how subjective values are computed in an intertemporal choice paradigm, and how these value computations are updated as a consequence of learning about the preferences of another. Critically, subjects’ own preferences shift towards those of the other when learning about their choices, suggesting that subjects incorporate new knowledge about others into a model of their own preferences. The underlying mechanism involves prediction errors, which introduce plasticity into subjects’ mPFC value representations, in turn resulting in a shift in subjects’ own preferences. The second part of this thesis investigates how relationships between arbitrary objects are represented in the brain. Relational knowledge is often considered analogous to spatial reasoning, where relationships are encoded in a hippocampal-entorhinal ‘cognitive map’. Here, I show that maps can also be extracted from the entorhinal cortex for discrete relationships between arbitrary stimuli, and in the absence of conscious knowledge. The representation of abstract knowledge in map-like structures suggests that inferences do not need to rely on direct experiences but can be computed anew from mapped knowledge. Together, these studies reveal how world models are represented and updated at the level of neural representations, providing a bridge between representational codes and cognitive computations.

Learning-Induced Plasticity in Medial Prefrontal Cortex Predicts Preference Malleability

The brain requires ∼20% of the body's total energy. When the body is deprived of energy, such as during hypoxia and in pathologies involving an altered energy metabolism, the brain's function can be severely and irreversibly disrupted. However, humans routinely cope with transient hypoxia, for

Managing multiple goals is essential to adaptation, yet we are only beginning to understand computations by which we navigate the resource demands entailed in so doing. Here, we sought to elucidate how humans balance reward seeking and punishment avoidance goals, and relate this to variation in its expression within anxious individuals. To do so, we developed a novel multigoal pursuit task that includes trial-specific instructed goals to either pursue reward (without risk of punishment) or avoid punishment (without the opportunity for reward). We constructed a computational model of multigoal pursuit to quantify the degree to which participants could disengage from the pursuit goals when instructed to, as well as devote less model-based resources toward goals that were less abundant. In general, participants (n = 192) were less flexible in avoiding punishment than in pursuing reward. Thus, when instructed to pursue reward, participants often persisted in avoiding features that had previously been associated with punishment, even though at decision time these features were unambiguously benign. In a similar vein, participants showed no significant downregulation of avoidance when punishment avoidance goals were less abundant in the task. Importantly, we show preliminary evidence that individuals with chronic worry may have difficulty disengaging from punishment avoidance when instructed to seek reward. Taken together, the findings demonstrate that people avoid punishment less flexibly than they pursue reward. Future studies should test in larger samples whether a difficulty to disengage from punishment avoidance contributes to chronic worry.

Humans perseverate on punishment avoidance goals in multigoal reinforcement learning

Correction: Humans perseverate on punishment avoidance goals in multigoal reinforcement learning

Background: Behavioral activation is an evidence-based treatment for depression. Theoretical considerations suggest that treatment response depends on reinforcement learning mechanisms. However, which reinforcement learning mechanisms are engaged by and mediate the therapeutic effect of behavioral activation remains only partially understood, and there are no procedures to measure such mechanisms. Objective: To perform a pilot study to examine whether reinforcement learning processes measured through tasks or self-report are related to treatment response to behavioral activation. Method: The pilot study enrolled 13 outpatients (12 completers) with major depressive disorder, from July of 2018 through February of 2019, into a nine-week trial with BA. Psychiatric evaluations, decision-making tests and self-reported reward experience and anticipations were acquired before, during and after the treatment. Task and self-report data were analysed by using reinforcement-learning models. Inferred parameters were related to measures of depression severity through linear mixed effects models. Results: Treatment effects during different phases

Components of Behavioral Activation Therapy for Depression Engage Specific Reinforcement Learning Mechanisms in a Pilot Study

Managing multiple goals is essential to wellbeing, yet we are only beginning to understand the computations by which we navigate this resource-demanding balancing act. Here, we sought to elucidate algorithms humans use to balance reward seeking and punishment avoidance goals, and to examine how these algorithms are affected in anxious individuals. To do so, we developed a novel multigoal pursuit task that includes trial-specific instructed goals to either pursue reward (without risk of punishment) or avoid punishment (without the opportunity for reward). Participants (n=192) in general were less flexible in avoiding punishment than in pursuing reward. Thus, when instructed to pursue reward, they often persisted in avoiding features that had previously been associated with punishment, even though at decision time these features were unambiguously benign. Participants also showed no significant downregulation of punishment avoidance when punishment avoidance goals became less abundant in the task. Importantly, individuals with chronic worry had particular difficulty disengaging punishment avoidance during instructed reward seeking. Taken together, the findings demonstrate that people avoid punishment less flexibly than they pursue reward, and this difference is pronounced in individuals with chronic worry.

Pavlovian Biases in Depression: From Choice to Thought and Therapy

A high pressure reactive evaporation process and a high pressure reactive sputtering process have been developed for the growth of high quality thin films of YBa2Cu307. Both techniques, when used with heated substrates, are effective in the formation of the 123 phase in-situ during the film growth. With reactive evaporation only a cooldown anneal in a higher pressure oxygen ambient is necessary to obtain good superconducting properties. For the reactive sputtering process, a brief, post growth, rapid thermal anneal step is required for best results. Fully epitaxial growth has been achieved with single crystal MgO substrates. The resultant films, which can be quite smooth and uniform, have been patterned to micron and submicron dimensions and the transport properties of these microstructures have been examined.

Cu 307 THIN FILMS GROWN BY HIGH PRESSURE REACTIVE EVAPORATION AND HIGH PRESSURE REACTIVE SPUTTERING

The superconductive weak link properties of microbridges formed in c-axis normal YBa2Cu307 -15 polycrystalline thin films containing a variable amount of large angle tilt boundaries have been studied. In the low critical current density limit these weak links have current-voltage (1V) characteristics that are accurately modeled by the resistively shunted junction model. The JV's are found to accurately follow a simple scaling law with the product of the critical current and weak link resistance Rn varying linearly with the weak link conductance.

We have investigated the nature of the in-situ growth of caxis normal Y BzyCu307 thin films on non-lattice-matched, vicinal, and polycrystalline MgO substrates, and on buffer layers of MgO. We find that the preparation of the MgO surface determines the structural and transport properties of the films. In particular, we are able to reproducibly grow films exhibiting either weak link behavior of very high critical current densities, We will discuss the variation of the thin film microstructure, oxygen content, and superconductive properties with the changes in the thin film crystal structure that result from the different growth situations.

GROWTH AND PROPERTIES OF YBa2Cu307 THIN FILMS ON NON- LATTICE-MATCHED AND POLY CRYSTALLINE SUBSTRATES

Can a digital clock that behaves erratically function as a flexible, open (random event generator-like) timing system to investigate purported communication with deceased individuals? If such theophysical effects exist, what implications do they have for mind-body and integrative medicine? Stimulated by research into spirit communication by Schwartz, Russek et al. (1999), Elayne Russek (ER) hypothesized that her deceased husband, noted cardiologist Henry I. Russek (HIR), might be influencing a digital clock that had become erratic. A repeated measures-within-subject experiment was designed such that daytime baseline data could be compared with the results of requests to slow or speed up the erratic clock during the night. Unfortunately, the AM-PM light was no longer functional, which meant that AM-PM information had to be inferred by applying an inference rule to the complete set of data. When this was done, a statistically significant effect was obtained. ER communicated to HIR that the experiment was inadequate because of the AM-PM defect and asked him for a "sign" that he was involved. She unexpectedly awoke in the middle of the night to find the AM-PM light flashing. The light became functional the following day, and subsequent data collection confirmed the inference rule. The combined empirical plus anecdotal nature of research in this area are considered, along with implications of the hypothesis for mind-body and integrative medicine.

A possible approach for researching purported spirit communication: an empirical-anecdotal investigation.

Mnemonic construction and representation of temporal structure in the hippocampal formation

The hippocampal-entorhinal region supports memory for episodic details, such as temporal relations of sequential events, and mnemonic constructions combining experiences for inferential reasoning. However, it is unclear whether hippocampal event memories reflect temporal relations derived from mnemonic constructions, event order, or elapsing time, and whether these sequence representations generalize temporal relations across similar sequences. Here, participants mnemonically constructed times of events from multiple sequences using infrequent cues and their experience of passing time. After learning, event representations in the anterior hippocampus reflected temporal relations based on constructed times. Temporal relations were generalized across sequences, revealing distinct representational formats for events from the same or different sequences. Structural knowledge about time patterns, abstracted from different sequences, biased the construction of specific event times. These findings demonstrate that mnemonic construction and the generalization of relational knowledge combine in the hippocampus, consistent with the simulation of scenarios from episodic details and structural knowledge.

Structuring time: The hippocampus constructs sequence memories that generalize temporal relations across experiences

An immersive first-person navigation task for abstract knowledge acquisition

Abstract Episodic memories are constructed from sequences of events. When recalling such a memory, we not only recall individual events, but we also retrieve information about how the sequence of events unfolded. Here, we focus on the role of the hippocampal–entorhinal region in processing and remembering sequences of events, which are thought to be stored in relational networks. We summarize evidence that temporal relations are a central organizational principle for memories in the hippocampus. Importantly, we incorporate novel insights from recent studies about the role of the adjacent entorhinal cortex in sequence memory. In rodents, the lateral entorhinal subregion carries temporal information during ongoing behavior. The human homologue is recruited during memory recall where its representations reflect the temporal relationships between events encountered in a sequence. We further introduce the idea that the hippocampal–entorhinal region might enable temporal scaling of sequence representations. Flexible changes of sequence progression speed could underlie the traversal of episodic memories and mental simulations at different paces. In conclusion, we describe how the entorhinal cortex and hippocampus contribute to remembering event sequences—a core component of episodic memory.

Investigating enthorinal maps for human memory using VR and fMRI

Remembering event sequences is central to episodic memory and presumably supported by the hippocampal-entorhinal region. We previously demonstrated that the hippocampus maps spatial and temporal distances between events encountered along a route through a virtual city (Deuker et al., 2016), but the content of entorhinal mnemonic representations remains unclear. Here, we demonstrate that multi-voxel representations in the anterior-lateral entorhinal cortex (alEC) — the human homologue of the rodent lateral entorhinal cortex — specifically reflect the temporal event structure after learning. Holistic representations of the sequence structure related to memory recall and the timeline of events could be reconstructed from entorhinal multi-voxel patterns. Our findings demonstrate representations of temporal structure in the alEC; dovetailing with temporal information carried by population signals in the lateral entorhinal cortex of navigating rodents and alEC activations during temporal memory retrieval. Our results provide novel evidence for the role of the alEC in representing time for episodic memory.

Mapping sequence structure in the human lateral entorhinal cortex

Time is memory: Temporal relationships shape memories in the hippocampal-enthorinal region

Hexadirectional coding of visual space in human entorhinal cortex

A framework for cognitive spaces Ever since Tolman's proposal of cognitive maps in the 1940s, the question of how spatial representations support flexible behavior has been a contentious topic. Bellmund et al. review and combine concepts from cognitive science and philosophy with findings from neurophysiology of spatial navigation in rodents to propose a framework for cognitive neuroscience. They argue that spatial-processing principles in the hippocampalentorhinal region provide a geometric code to map information domains of cognitive spaces for high-level cognition and discuss recent evidence for this proposal. Science, this issue p. eaat6766 BACKGROUND Ever since Edward Tolman’s proposal that comprehensive cognitive maps underlie spatial navigation and, more generally, psychological functions, the question of how past experience guides behavior has been contentious. The discovery of place cells in rodents, signaling the animal’s position in space, suggested that such cognitive maps reside in the hippocampus, a core brain region for human memory. Building on the description of place cells, several other functionally defined cell types were discovered in the hippocampal-entorhinal region. Among them are grid cells in the entorhinal cortex, whose characteristic periodic, six-fold symmetric firing patterns are thought to provide a spatial metric. These findings were complemented by insights into key coding principles of the hippocampal-entorhinal region: Spatial representations vary in scale along the hippocampal long axis, place cells remap to map different environments, and sequential hippocampal activity represents nonlocal trajectories through space. In humans, the existence of spatially tuned cells has been demonstrated in presurgical patients, and functional magnetic resonance imaging provides proxy measures for the noninvasive investigation of these processing mechanisms in human cognition. Intriguingly, recent advances indicate that place and grid cells can encode positions along dimensions of experience beyond Euclidean space for navigation, suggesting a more general role of hippocampal-entorhinal processing mechanisms in cognition. ADVANCES We combine hippocampal-entorhinal processing mechanisms identified in spatial navigation research with ideas from cognitive science describing a spatial representational format for cognition. Cognitive spaces are spanned by dimensions satisfying geometric constraints such as betweenness and equidistance, enabling the representation of properties and concepts as convex regions of cognitive space. We propose that the continuous population code of place and grid cells in the hippocampal-entorhinal region maps the dimensions of cognitive spaces. In these, each stimulus is located according to its feature values along the relevant dimensions, resulting in nearby positions for similar stimuli and larger distances between dissimilar stimuli. The low-dimensional, rigid firing properties of the entorhinal grid system make it a candidate to provide a metric or distance code for cognitive spaces, whereas hippocampal place cells flexibly represent positions in a given space. This mapping of cognitive spaces is complemented by the additional coding principles outlined above: Along the hippocampal long axis, cognitive spaces are mapped with varying spatial scale, supporting memory and knowledge representations at different levels of granularity. Via hippocampal remapping, spaces spanned by different dimensions can be flexibly mapped and established maps can be reinstated via attractor dynamics. The geometric definition of cognitive spaces allows flexible generalization and inference, and sequential hippocampal activity can simulate trajectories through cognitive spaces for adaptive decision-making and behavior. OUTLOOK Cognitive spaces provide a domain-general format for processing in the hippocampal-entorhinal region, in line with its involvement beyond navigation and memory. Spatial navigation serves as a model system to identify key coding principles governing cognitive spaces. An important question concerns the extent to which firing properties of spatially tuned cells are preserved in cognitive spaces. Technological advances such as calcium imaging will clarify coding principles on the population level and facilitate the translation to human cognitive neuroscience. Spatial navigation is mostly investigated in two dimensions and naturally limited to three dimensions; however, the processing of complex, multidimensional concepts is vital to high-level human cognition, and the representation of such high-dimensional spaces is an intriguing question for future research. Further, the role of brain networks acting in concert with the hippocampus, in navigation specifically and cognitive function in general, will provide insight into whether and how cognitive spaces are supported beyond the hippocampal-entorhinal region. Finally, the precise way in which cognitive spaces and trajectories through them are read out for behavior remains to be elucidated. Place and grid cells map cognitive spaces. Cognitive spaces are defined by dimensions satisfying geometric constraints. The example space (left) is spanned by the dimensions of engine power and car weight. Black dots show different vehicles whose positions reflect their feature combinations. Place cells (center; colored circles represent firing fields of different cells) and grid cells (right; circles illustrate firing pattern of one cell) provide a continuous code for cognitive spaces. The hippocampal formation has long been suggested to underlie both memory formation and spatial navigation. We discuss how neural mechanisms identified in spatial navigation research operate across information domains to support a wide spectrum of cognitive functions. In our framework, place and grid cell population codes provide a representational format to map variable dimensions of cognitive spaces. This highly dynamic mapping system enables rapid reorganization of codes through remapping between orthogonal representations across behavioral contexts, yielding a multitude of stable cognitive spaces at different resolutions and hierarchical levels. Action sequences result in trajectories through cognitive space, which can be simulated via sequential coding in the hippocampus. In this way, the spatial representational format of the hippocampal formation has the capacity to support flexible cognition and behavior.

Distance reproduction after rotation does not show a 60° modulation

Grid cells in the rodent and human entorhinal cortex are a critical component of the brain’s spatial coding system. In virtual-reality (VR) navigation tasks in humans, the fMRI BOLD signal in the entorhinal cortex exhibits hexadirectional modulations that may reflect population activity of grid cells. However, it remains unknown whether and how grid cell population activity specifically gives rise to this hexadirectional hemodynamic fMRI signal. Here we address this issue in two steps. First, we employed a VR navigation experiment using magnetoencephalography (MEG) in human participants and found hexadirectional signal modulations in the high-gamma band, source-localised to the medial temporal lobe. Next, we conducted analyses to test the relationship between grid cell activity and local field potential (LFP) recordings in freely moving rats. We found hexadirectional modulations in the same frequency band as in the human MEG navigation experiment. The orientation of this hexadirectional LFP modulation was aligned to the orientation of the hexagonally symmetric firing patterns of grid cells. Together, these findings describe new ways to measure grid cell population activity and their non-invasive source localisation using MEG. Crucially, we link grid cell activity to measures of population activity in rats and humans, thereby elucidating the physiological basis of non-invasive grid cell population measures previously revealed with fMRI. Since grid cell function is affected early in Alzheimer ’s disease, understanding how to measure their activity with non-invasive methods is of high clinical relevance.

Electrophysiological markers of grid cell population activity across species

Summary Episodic memories consist of event information linked to spatio-temporal context. Notably, the hippocampus is involved in the encoding, representation and retrieval of temporal relations that comprise a context [1–11], but it remains largely unclear how coding for elapsed time arises in the hippocampal-entorhinal region. The entorhinal cortex (EC), the main cortical input structure of the hippocampus, has been hypothesized to provide temporal tags for memories via contextual drift [12,13] and recent evidence demonstrates that time can be decoded from population activity in the rodent lateral EC[14]. Here, we use fMRI to show that the anterior-lateral EC (alEC), the human homologue region of rodent lateral EC [15,16], maps the temporal structure of events. Participants acquired knowledge about temporal and spatial relationships between object positions—dissociated via teleporters—along a fixed route through a virtual city. Multi-voxel pattern similarity in alEC changed through learning to reflect elapsed time between event memories. Furthermore, we reconstructed the temporal structure of object relationships from alEC pattern similarity change. In contrast to the hippocampus, which maps the subjective time between event memories in this task [1], the temporal map in alEC reflected the objective time elapsed between events. Our findings provide evidence for the notion that alEC represents the temporal structure of memories, putatively derived from slowly-varying population signals during learning. Further, our findings suggest a dissociation between objective and subjective temporal maps in EC and hippocampus; thereby providing novel evidence for the role of the hippocampal-entorhinal region in representing time for episodic memory.

Anticipating the future is a key motif of the brain, possibly supported by mental simulation of upcoming events. Rodent single-cell recordings suggest the ability of spatially tuned cells to represent subsequent locations. Grid-like representations have been observed in the human entorhinal cortex during virtual and imagined navigation. However, hitherto it remains unknown if grid-like representations contribute to mental simulation in the absence of imagined movement. Participants imagined directions between building locations in a large-scale virtual-reality city while undergoing fMRI without re-exposure to the environment. Using multi-voxel pattern analysis, we provide evidence for representations of absolute imagined direction at a resolution of 30° in the parahippocampal gyrus, consistent with the head-direction system. Furthermore, we capitalize on the six-fold rotational symmetry of grid-cell firing to demonstrate a 60° periodic pattern-similarity structure in the entorhinal cortex. Our findings imply a role of the entorhinal grid-system in mental simulation and future thinking beyond spatial navigation. DOI: http://dx.doi.org/10.7554/eLife.17089.001

The hippocampus has long been implicated in both episodic and spatial memory, however these mnemonic functions have been traditionally investigated in separate research strands. Theoretical accounts and rodent data suggest a common mechanism for spatial and episodic memory in the hippocampus by providing an abstract and flexible representation of the external world. Here, we monitor the de novo formation of such a representation of space and time in humans using fMRI. After learning spatio-temporal trajectories in a large-scale virtual city, subject-specific neural similarity in the hippocampus scaled with the remembered proximity of events in space and time. Crucially, the structure of the entire spatio-temporal network was reflected in neural patterns. Our results provide evidence for a common coding mechanism underlying spatial and temporal aspects of episodic memory in the hippocampus and shed new light on its role in interleaving multiple episodes in a neural event map of memory space. DOI: http://dx.doi.org/10.7554/eLife.16534.001

Proselfs depend more on model-based than model-free learning in a non-social probabilistic state-transition task

Although numerous studies have focused on brain functions related to inequity aversion, few have examined its genetic basis. Here, we show the association between estimated inequity aversion and polymorphisms in three genes associated with human sociality. Non-student adult participants took part in five economic game experiments on different days. Disadvantageous inequity aversion (DIA) and advantageous inequity aversion (AIA) were calculated from behavioural responses using Bayesian estimation. We investigated the association between genetic polymorphisms in the oxytocin receptor (OXTR rs53576), arginine vasopressin receptor 1A (AVPR1A RS3) and opioid receptor mu 1 (OPRM1 rs1799971) and inequity aversion. Regarding AVPR1A RS3, participants with the SS genotype had higher AIA than those with the SL or LL genotypes, but no association was found for DIA. Moreover, we observed no aversion associations for OXTR rs53576 or OPRM1 rs1799971. The results suggest that AVPR1A plays an important role in aversion when one's own gain is greater than that of others. Our findings may provide a solid theoretical basis for future studies on the relationship between genetic polymorphisms and inequity aversion.

Association between arginine vasopressin receptor 1A (AVPR1A) polymorphism and inequity aversion

Behavioral responses to unfair distribution have been measured mainly using the Ultimatum Game (UG). Recent studies examining the biological basis of behavioral responses to unfair distribution have focused attention on the role of the serotonin transporter gene. However, studies, to date, have been conducted on non-Asians, and it has not been confirmed whether similar results can be seen in other ethnic groups. It has also been shown that behavioral responses to unfair distribution are not only seen in the case of victims themselves but also in the case of third parties not directly affected. This study aimed to determine whether the results of the previous study would be replicated in an Asian population and whether the serotonin transporter gene would also be associated with behavior toward unfair distribution by third parties. We examined the association between polymorphisms (5-HTTLPR) of the serotonin transporter gene and participants’ behavior in the UG and the third-party punishment game (TPPG). The results did not show an association between punishment for unfair proposals in the TPPG and genetic polymorphisms, while participants with the SL/LL genotype were more likely to reject unfair offers in the UG than those with the SS genotype. These results indicate that 5-HTTLPR is associated with behavior when unfair intentions are directed at oneself.

Association Between Polymorphism (5-HTTLPR) of the Serotonin Transporter Gene and Behavioral Response to Unfair Distribution

The neuroanatomy of social trust predicts depression vulnerability

Macaque monkeys are prime animal models for studying the neural mechanisms of decision-making because of their close kinship with humans. Manipulation of neural activity during decision-making tasks is essential for approaching the causal relationship between the brain and its functions. Conventional manipulation methods used in macaque studies are coarse-grained, and have worked indiscriminately on mutually intertwined neural pathways. To systematically dissect neural circuits responsible for a variety of functions, it is essential to analyze changes in behavior and neural activity through interventions in specific neural pathways. In recent years, an increasing number of studies have applied optogenetics and chemogenetics to achieve fine-grained pathway-selective manipulation in the macaque brain. Here, we review the developments in macaque studies involving pathway-selective operations, with a particular focus on applications to the prefrontal network. Pathway selectivity can be achieved using single viral vector transduction combined with local light stimulation or ligand administration directly into the brain or double-viral vector transduction combined with systemic drug administration. We discuss the advantages and disadvantages of these methods. We also highlight recent technological developments in viral vectors that can effectively infect the macaque brain, as well as the development of methods to deliver photostimulation or ligand drugs to a wide area to effectively manipulate behavior. The development and dissemination of such pathway-selective manipulations of macaque prefrontal networks will enable us to efficiently dissect the neural mechanisms of decision-making and innovate novel treatments for decision-related psychiatric disorders.

Dissecting the Prefrontal Network With Pathway-Selective Manipulation in the Macaque Brain—A Review

Abstract The dorsolateral prefrontal cortex has been shown to be associated with prosocial behavior. However, the direction of this relationship remains controversial. To resolve inconsistencies in the existing literature, we introduced the concept of default prosociality preference and hypothesized that this preference moderates the relationship between gray matter volume in the dorsolateral prefrontal cortex and prosocial behavior. This study analyzed the data of 168 participants obtained from voxel-based morphometry, 4 types of economic games, and 3 different measures of social value orientation that represent default prosociality preference. Here we show that, in individuals who were consistently classified as proself on the 3 social value orientation measures, gray matter volume in the right dorsolateral prefrontal cortex was positively associated with prosocial behavior. However, in individuals who were consistently classified as prosocial, the direction of this association was vice versa. These results indicate that the right dorsolateral prefrontal cortex regulates default prosociality preference.

Right dorsolateral prefrontal cortex regulates default prosociality preference

Microendoscopic calcium imaging of the primary visual cortex of behaving macaques

Chemogenetic inactivation reveals the inhibitory control function of the prefronto-striatal pathway in the macaque brain

Whole brain Probabilistic Generative Model toward Realizing Cognitive Architecture for Developmental Robots

It has been reported that single-unit activity in the prefrontal cortex (PFC) and striatum represented visual stimulus and reward information. But how to encode these pieces of information is quite complex from the view of single-neuron activity. Different neurons represented stimulus or reward information in different task epochs with increasing or decreasing their activities relative to their baseline firing rates. The present paper was aimed to study whether population neurons in the two brain areas could stably encode task-relevant parameters in a whole trial period. We recorded single-unit activities in the lateral PFC (LPFC) and striatum while the monkey was performing a stimulus- reward prediction task, and analyzed the neuronal activities by the method of a multi-variable regression model and the linear support vector machine. The results showed that, although proportions of task-related neurons in the two areas varied largely in the whole trial period, LPFC population neurons encoded reward and stimulus information stably and reliably. Population neurons in the striatum encoded only reward information, not stimulus information. A group of neurons in the two areas represented combined information of stimulus and reward. Further analysis showed that LPFC neurons encoded reward information for a group of relevant stimuli, while striatal neurons encoded reward information for a specific stimulus. These results suggest that both LPFC and striatal population neurons are able to stably represent task-relevant information, but from different aspects of the task. The different strategies to encode information in the LPFC and striatum suggest their different contributions in reward-based decision making.

[Stimulus and reward information encoded by population neurons in the primate prefrontal cortex and striatum].

Molecular tools - such as chemogenetics, optogenetics, and calcium sensors – have been shown in small animals, e.g., mice, zebrafish, and flies, to be powerful tools for studying the mechanisms underlying brain function. The adoption of molecular tools in animals with larger brains has been more difficult than it initially seemed it might be. The purpose of this conference was to gather the leaders of the groups currently engaged in chemogenetic research with nonhuman primates, and experts in related disciplines, to facilitate the exchange of technical information and scientific results and catalyze future collaborative efforts. The dissemination of previously unpublished findings will allow other researchers in the field to avoid having to repeat costly, tedious experiments when data already exist elsewhere.

The cost of obtaining rewards enhances the reward prediction error signal of midbrain dopamine neurons

Abstract The Keio Twin Research Center (KoTReC) was established in 2009 at Keio University to combine two longitudinal cohort projects — the Keio Twin Study (KTS) for adolescence and adulthood and the Tokyo Twin Cohort Project (ToTCoP) for infancy and childhood. KoTReC also conducted a two-time panel study of self-control and psychopathology in twin adolescence in 2012 and 2013 and three independent anonymous cross-sectional twin surveys (ToTcross) before 2012 — the ToTCross, the Junior and Senior High School Survey and the High School Survey. This article introduces the recent research designs of KoTReC and its publications.

Psychosocial Twin Cohort Studies in Japan: The Keio Twin Research Center (KoTReC)

Oxytocin (OXT) is known to play an important role in trust, whereas the involvement of other peptide hormones has not been evaluated. In this study, we focused on microsatellite polymorphisms in the intron of the arginine-vasopressin receptor 1a (AVPR1a) gene and examined whether the association between the repeat lengths in the intron of AVPR1a is associated with trust and reciprocity in humans. Four-hundred and thirty-three participants played the trust game, answered the attitudinal trust question, and their buccal cells were collected. Results showed that men with a short form of AVPR1a tend to send more money to the opponent, even if there is a possibility of being betrayed by the opponent. Additionally, people with a short form of AVPR1a tended to return money to the opponent who trusts them. However, attitudinal trust was not associated with AVPR1a. These results indicate that arginine-vasopressin receptor 1a plays an important role in trust and reciprocal behaviors.

Association of Polymorphism of Arginine-Vasopressin Receptor 1A (AVPR1a) Gene With Trust and Reciprocity

Injection of Muscimol into Prefrontal Cortex Impairs Monkey’s Reward Transitive Inference

Abstract Previous studies have shown that genetic variations in rs53576, a common variant of the oxytocin receptor gene (OXTR) resulting from a single nucleotide polymorphism involving an adenine (A)/guanine (G) transition, are associated with attitudinal trust in men. However, the pathway from gene to behaviour has not been elucidated. We conducted the present study to determine whether amygdala volume mediates the association between OXTR rs53576 genotypes and attitudinal trust. Our results revealed that the left amygdala volume was significantly smaller in GG men than in AA and AG men, whereas it was significantly smaller in AA and AG women than in GG women. In addition, the left amygdala volume was negatively associated with attitudinal trust in men, whereas there was no such association in women. We also found a significant mediation effect of the left amygdala volume on the association between OXTR rs53576 genotypes and attitudinal trust in men. The results of our study suggest that the left amygdala volume plays a pivotal role in the association between OXTR rs53576 genotypes and attitudinal trust in men.

Association of the oxytocin receptor gene with attitudinal trust: role of amygdala volume

Herein, we investigated the characteristics of a backward wave oscillator using a dielectric discharge cold cathode (DDCC) in a weakly relativistic region with energies less than 100 keV. The DDCC comprises a copper disc electrode and a ceramic tube; the DDCC exhibited a circular burn pattern with a voltage less than about 30 kV. When a Marx generator was used as a high-voltage source, two microwave oscillations (first phase and second phase) were observed. Within 80 periods of the slow-wave structure, we observed microwave oscillation at the π-point with a voltage of about 30 kV and then detected a microwave signal of about 910 5500 mW.

Experimental Study on Backward Wave Oscillators Using Dielectric Discharge Cold Cathodes

Behavioural Differences and Neural Substrates of Altruistic and Spiteful Punishment

Significance Prosocial and proself predispositions dictate economic game players’ fast decisions but exert limited influence when game players take a longer time in making decisions. Prosocially predisposed individuals use the extended time to contemplate the risk of being exploited. Selfishly predisposed individuals are suggested to behave according to the immediate incentives of the games when they make decisions quickly and become behaviorally less selfish as they spend more time assessing the long-term strategic implications of always behaving according to immediate incentives. Different strategies are needed to promote prosocial behavior and to design institutions depending on the constitution of the population. Behavioral and neuroscientific studies explore two pathways through which internalized social norms promote prosocial behavior. One pathway involves internal control of impulsive selfishness, and the other involves emotion-based prosocial preferences that are translated into behavior when they evade cognitive control for pursuing self-interest. We measured 443 participants’ overall prosocial behavior in four economic games. Participants’ predispositions [social value orientation (SVO)] were more strongly reflected in their overall game behavior when they made decisions quickly than when they spent a longer time. Prosocially (or selfishly) predisposed participants behaved less prosocially (or less selfishly) when they spent more time in decision making, such that their SVO prosociality yielded limited effects in actual behavior in their slow decisions. The increase (or decrease) in slower decision makers was prominent among consistent prosocials (or proselfs) whose strong preference for prosocial (or proself) goals would make it less likely to experience conflict between prosocial and proself goals. The strong effect of RT on behavior in consistent prosocials (or proselfs) suggests that conflict between prosocial and selfish goals alone is not responsible for slow decisions. Specifically, we found that contemplation of the risk of being exploited by others (social risk aversion) was partly responsible for making consistent prosocials (but not consistent proselfs) spend longer time in decision making and behave less prosocially. Conflict between means rather than between goals (immediate versus strategic pursuit of self-interest) was suggested to be responsible for the time-related increase in consistent proselfs’ prosocial behavior. The findings of this study are generally in favor of the intuitive cooperation model of prosocial behavior.

Response time in economic games reflects different types of decision conflict for prosocial and proself individuals

Single-unit studies in monkeys have demonstrated that neurons in the prefrontal cortex predict the reward type, reward amount or reward availability associated with a stimulus. To examine contributions of pyramidal cells and interneurons in reward processing, single-unit activity was extracellularly recorded in prefrontal cortices of four monkeys performing a reward prediction task. Based on their shapes of spike waveforms, prefrontal neurons were classified into broad-spike and narrow-spike units that represented putative pyramidal cells and interneurons, respectively. We mainly observed that narrow-spike neurons showed higher firing rates but less bursty discharges than did broad-spike neurons. Both narrow-spike and broad-spike cells selectively responded to the stimulus, reward and their interaction, and the proportions of each type of selective neurons were similar between the two cell classes. Moreover, the two types of cells displayed equal reliability of reward or stimulus discrimination. Furthermore, we found that broad-spike and narrow-spike cells showed distinct mechanisms for encoding reward or stimulus information. Broad-spike neurons raised their firing rate relative to the baseline rate to represent the preferred reward or stimulus information, whereas narrow-spike neurons inhibited their firing rate lower than the baseline rate to encode the non-preferred reward or stimulus information. Our results suggest that narrow-spike and broad-spike cells were equally involved in reward and stimulus processing in the prefrontal cortex. They utilized a binary strategy to complementarily represent reward or stimulus information, which was consistent with the task structure in which the monkeys were required to remember two reward conditions and two visual stimuli.

Differences in reward processing between putative cell types in primate prefrontal cortex

Midbrain Dopamine Neurons Signal Belief in Choice Accuracy during a Perceptual Decision

Prefrontal cortex and striatum are two major areas in the brain. Some research reports suggest that both areas are involved in many advanced cognitive processes, such as learning and memory, reward processing, and behavioral decision. Single-unit recording experiments have found that neurons in the prefrontal cortex and striatum can represent reward information, but it remains elusive whether and how local field potentials (LFPs) in the two areas encode reward information. To investigate these issues, we recorded LFPs simultaneously in the prefrontal cortex and striatum of two monkeys by performing a reward prediction task (a large amount reward vs a small amount reward). Recorded LFP signals were transformed from the time domain to the time and frequency domain using the method of short-time Fourier transform (STFT). We calculated the power in each frequency and time, and examined whether they were different in the two reward conditions. The results showed that power of LFPs in both the prefrontal cortex and striatum distinguished one reward condition from the other one. And the power in small reward trials was greater than that in large reward trials. Furthermore, it was found that the LFPs better encoded reward information in the beta band (14-30 Hz) rather than other frequency bands. Our results suggest that the LFPs in the prefrontal cortex and striatum effectively represent reward information, which would help to further understand functional roles of LFPs in reward processing.

[Reward information encoded by power of local field potentials in the primate prefrontal cortex and striatum].

Characteristics of fast-spiking neurons in the striatum of behaving monkeys

To behave appropriately in a complex and uncertain world, the brain makes use of several distinct learning systems. One such system is called the "model-free process", via which conditioning allows the association between a stimulus or response and a given reward to be learned. Another system is called the "model-based process". Via this process, the state transition between a stimulus and a response is learned so that the brain is able to plan actions prior to their execution. Several studies have tried to relate the difference between model-based and model-free processes to the difference in functions of the lateral prefrontal cortex (LPFC) and the striatum. Here, we describe a series of studies that demonstrate the ability of LPFC neurons to categorize visual stimuli by their associated behavioral responses and to generate abstract information. If LPFC neurons utilize abstract code to associate a stimulus with a reward, they should be able to infer similar relationships between other stimuli of the same category and their rewards without direct experience of these stimulus-reward contingencies. We propose that this ability of LPFC neurons to utilize abstract information can contribute to the model-based learning process.

[Cognitive Functions in the Prefrontal Association Cortex; Transitive Inference and the Lateral Prefrontal Cortex].

Representation of economic preferences in the structure and function of the amygdala and prefrontal cortex

Functional connectivity between prefrontal cortex and striatum estimated by phase locking value

Causal Interaction Between Prefrontal Cortex and Striatum Estimated by Granger Causality

Significance Distributive justice is a highly controversial issue across many societies. Compared with the accumulation of various normative (“ought”) theories by philosophers over the centuries, our empirical (“is”) understanding of people’s distributive judgments remains insufficient. In a series of experiments, we show that the “maximin” concern (maximizing the minimum possible payoff) operates as a strong cognitive anchor in both distributive decisions for others and economic decisions for self, and that the right temporoparietal junction, associated with perspective taking, plays a key role in this linkage. Our approach illustrates how rigorous methods from behavioral, cognitive, and neural sciences can be combined to shed light on functional elements of distributive justice in our minds, and potential neural underpinnings shared by other nonsocial decisions. Distributive justice concerns the moral principles by which we seek to allocate resources fairly among diverse members of a society. Although the concept of fair allocation is one of the fundamental building blocks for societies, there is no clear consensus on how to achieve “socially just” allocations. Here, we examine neurocognitive commonalities of distributive judgments and risky decisions. We explore the hypothesis that people’s allocation decisions for others are closely related to economic decisions for oneself at behavioral, cognitive, and neural levels, via a concern about the minimum, worst-off position. In a series of experiments using attention-monitoring and brain-imaging techniques, we investigated this “maximin” concern (maximizing the minimum possible payoff) via responses in two seemingly disparate tasks: third-party distribution of rewards for others, and choosing gambles for self. The experiments revealed three robust results: (i) participants’ distributive choices closely matched their risk preferences—“Rawlsians,” who maximized the worst-off position in distributions for others, avoided riskier gambles for themselves, whereas “utilitarians,” who favored the largest-total distributions, preferred riskier but more profitable gambles; (ii) across such individual choice preferences, however, participants generally showed the greatest spontaneous attention to information about the worst possible outcomes in both tasks; and (iii) this robust concern about the minimum outcomes was correlated with activation of the right temporoparietal junction (RTPJ), the region associated with perspective taking. The results provide convergent evidence that social distribution for others is psychologically linked to risky decision making for self, drawing on common cognitive–neural processes with spontaneous perspective taking of the worst-off position.

Rawlsian maximin rule operates as a common cognitive anchor in distributive justice and risky decisions

To precisely understand how higher cognitive functions are implemented in the prefrontal network of the brain, optogenetic and pharmacogenetic methods to manipulate the signal transmission of a specific neural pathway are required. The application of these methods, however, has been mostly restricted to animals other than the primate, which is the best animal model to investigate higher cognitive functions. In this study, we used a double viral vector infection method in the prefrontal network of the macaque brain. This enabled us to express specific constructs into specific neurons that constitute a target pathway without use of germline genetic manipulation. The double-infection technique utilizes two different virus vectors in two monosynaptically connected areas. One is a vector which can locally infect cell bodies of projection neurons (local vector) and the other can retrogradely infect from axon terminals of the same projection neurons (retrograde vector). The retrograde vector incorporates the sequence which encodes Cre recombinase and the local vector incorporates the “Cre-On” FLEX double-floxed sequence in which a reporter protein (mCherry) was encoded. mCherry thus came to be expressed only in doubly infected projection neurons with these vectors. We applied this method to two macaque monkeys and targeted two different pathways in the prefrontal network: The pathway from the lateral prefrontal cortex to the caudate nucleus and the pathway from the lateral prefrontal cortex to the frontal eye field. As a result, mCherry-positive cells were observed in the lateral prefrontal cortex in all of the four injected hemispheres, indicating that the double virus vector transfection is workable in the prefrontal network of the macaque brain.

Double Virus Vector Infection to the Prefrontal Network of the Macaque Brain

Processing in Macaque Lateral Prefrontal Cortex Influence of Reward Expectation on Visuospatial

The brain contains multiple yet distinct systems involved in reward prediction. To understand the nature of these processes, we recorded single-unit activity from the lateral prefrontal cortex (LPFC) and the striatum in monkeys performing a reward inference task using an asymmetric reward schedule. We found that neurons both in the LPFC and in the striatum predicted reward values for stimuli that had been previously well experienced with set reward quantities in the asymmetric reward task. Importantly, these LPFC neurons could predict the reward value of a stimulus using transitive inference even when the monkeys had not yet learned the stimulus–reward association directly; whereas these striatal neurons did not show such an ability. Nevertheless, because there were two set amounts of reward (large and small), the selected striatal neurons were able to exclusively infer the reward value (e.g., large) of one novel stimulus from a pair after directly experiencing the alternative stimulus with the other reward value (e.g., small). Our results suggest that although neurons that predict reward value for old stimuli in the LPFC could also do so for new stimuli via transitive inference, those in the striatum could only predict reward for new stimuli via exclusive inference. Moreover, the striatum showed more complex functions than was surmised previously for model-free learning.

Contributions of distinct prefrontal neuron classes in reward processing

Two male Japanese monkeys were trained to perform a sequential conditional discrimination task with an asyrnrnetric reward, In this task the first cue A1 (or A2) was followed by cues B1 and B2, and the monkey made a saccadic eye movement to choose one of these two CBI or B2>, Aftcr this first choice the third cues, C1 and C2, were displayed and the monkey selected either. The two correct association chains were: Al, Bl, and Cl; and A2, B2, and C2. The asymmetric reward ru]e

2 P 30 Reward prediction responses in prefrontal . cortex ' matching-to-sample procedure in monkey using

Learning does not only depend on rationality, because real-life learning cannot be isolated from emotion or social factors. Therefore, it is intriguing to determine how emotion changes learning, and to identify which neural substrates underlie this interaction. Here, we show that the task-independent presentation of an emotional face before a reward-predicting cue increases the speed of cue–reward association learning in human subjects compared with trials in which a neutral face is presented. This phenomenon was attributable to an increase in the learning rate, which regulates reward prediction errors. Parallel to these behavioral findings, functional magnetic resonance imaging demonstrated that presentation of an emotional face enhanced reward prediction error (RPE) signal in the ventral striatum. In addition, we also found a functional link between this enhanced RPE signal and increased activity in the amygdala following presentation of an emotional face. Thus, this study revealed an acceleration of cue–reward association learning by emotion, and underscored a role of striatum–amygdala interactions in the modulation of the reward prediction errors by emotion.

Reward Prediction Error Signal Enhanced by Striatum–Amygdala Interaction Explains the Acceleration of Probabilistic Reward Learning by Emotion

Estimating causal interaction between prefrontal cortex and striatum by transfer entropy

To survive under changing circumstances, we have to make appropriate decisions on our behavior. For this purpose, the brain should recognize reward information from objects under a given circumstances. Recent experimental and theoretical studies have suggested that primates, including human beings, have at least 2 brain processes that calculate the reward value of objects. One is the process coding a specific reward value of a stimulus or response, depending on direct experience (e.g., classical conditioning and TD learning). The other enables us to predict reward based on the internal model of given circumstances without direct experience (e.g., categorization and inference). To clarify the neuronal correlates of the multiple processes on reward prediction, we have conducted 4 experiments: (1) single-unit recording from the caudate and lateral prefrontal cortex of a monkey, while it performed a memory-guided saccade task with asymmetric reward schedule; (2) human fMRI imaging during random-dot discrimination with asymmetric reward condition; (3) single-unit recording from the monkey dopamine neuron in the random-dot discrimination task with asymmetric reward schedule; and (4) simultaneous single-unit recording from the striatum and lateral prefrontal cortex of monkeys performing a reward inference task. Results suggest that the nigro striatal network and the prefrontal network have different functional roles for reward prediction (value generation). The former applies the model-free method (temporal-difference learning), while the latter uses the model-based method (category-based learning).

Categorization is a function of the brain that serves to group together items and events in our environments. Here we review the following important issues related to category representation and generalization: namely, where categories are presented in the brain, and how the brain utilizes categorical membership to generate new information. Accumulated experimental evidence shows that the prefrontal cortex (PFC) plays a critical role in category formation and generalization. We propose that prefrontal neurons abstract the commonality beyond individual stimuli, and categorize these based on their common meaning by ignoring their physical properties and learning to represent the boundaries between behaviorally significant categories. We also claim that a subgroup of prefrontal neurons simultaneously receives the category‐related information and specific property information (e.g. reward) associated with an exemplar, to form a category‐based representation of that property, and propagates it among stimuli of the same category, possibly reflecting a neural basis for category generalization in the PFC. These results suggest that the PFC is involved in representing abstract rules, and generating new information on the basis of previously acquired knowledge.

Category representation and generalization in the prefrontal cortex

The Performance Dip is a newly characterized behavioral phenomenon, where, paradoxically, a weaker task-irrelevant visual stimulus causes larger disturbances on the accuracy of a main letter identification task than a stronger stimulus does. Understanding mechanisms of the Performance Dip may provide insight into unconsciousness behavior. Here, we investigated the generalization of the Performance Dip. Specifically, we tested whether the Performance Dip occurs in a motion-related Simon task, and if so, whether the Performance Dip involves the same brain region, that is, the dorsolateral prefrontal cortex (DLPFC), previously implicated in the Performance Dip, or the supplementary motor area (SMA) and pre-SMA, implicated in a motion-related Simon Task. Subjects made manual directional responses according to the color of stochastic moving dots while ignoring the global direction of moving dots, which could be either congruent or incongruent to the response appropriate to the main task. We found that weak incongruent task-irrelevant stimuli caused a Performance Dip, in which the SMA and pre-SMA, rather than DLPFC, played critical roles. Our results suggest a possible common brain mechanism across different neural circuits, in which weak, but not strong, task-irrelevant information is free from inhibition and intrudes into neural circuits relevant to the main task.

Performance Dip in motor response induced by task-irrelevant weaker coherent visual motion signals.

Previous reports have described that neural activities in midbrain dopamine areas are sensitive to unexpected reward delivery and omission. These activities are correlated with reward prediction error in reinforcement learning models, the difference between predicted reward values and the obtained reward outcome. These findings suggest that the reward prediction error signal in the brain updates reward prediction through stimulus–reward experiences. It remains unknown, however, how sensory processing of reward-predicting stimuli contributes to the computation of reward prediction error. To elucidate this issue, we examined the relation between stimulus discriminability of the reward-predicting stimuli and the reward prediction error signal in the brain using functional magnetic resonance imaging (fMRI). Before main experiments, subjects learned an association between the orientation of a perceptually salient (high-contrast) Gabor patch and a juice reward. The subjects were then presented with lower-contrast Gabor patch stimuli to predict a reward. We calculated the correlation between fMRI signals and reward prediction error in two reinforcement learning models: a model including the modulation of reward prediction by stimulus discriminability and a model excluding this modulation. Results showed that fMRI signals in the midbrain are more highly correlated with reward prediction error in the model that includes stimulus discriminability than in the model that excludes stimulus discriminability. No regions showed higher correlation with the model that excludes stimulus discriminability. Moreover, results show that the difference in correlation between the two models was significant from the first session of the experiment, suggesting that the reward computation in the midbrain was modulated based on stimulus discriminability before learning a new contingency between perceptually ambiguous stimuli and a reward. These results suggest that the human reward system can incorporate the level of the stimulus discriminability flexibly into reward computations by modulating previously acquired reward values for a typical stimulus.

Stimulus-Dependent Adjustment of Reward Prediction Error in the Midbrain

Local inactivation of primate prefrontal cortex impairs reward prediction based on category inference

Differential representation of goal in monkey lateral prefrontal cortex in free- and instructed-choice

Five-year-old Japanese monkeys were tested on long-term visual recognition memory. The objects used were those that they had encountered daily during their first 2 years of life as to-be-remembered stimuli: persons, peers, and places. After a 3-year delay, we conducted a recognition test using the preferential looking paradigm where the monkeys were presented with pictures of these familiar stimuli in combination with those of novel stimuli. The monkeys looked relatively longer at pictures of familiar stimuli than at those of novel stimuli, while participants in the control group, who had never seen the stimuli in question, showed no discriminative preference. The monkeys thus recognized the familiar stimuli through the pictures, suggesting retention of visual information on real objects encountered in their lives even after a 3-year delay. Our present findings confirmed long-term visual recognition in monkeys, which might be essential to ecologically and socially significant behaviors such as individual identification.

Long-term visual recognition of familiar persons, peers, and places by young monkeys (Macaca fuscata).

Nonhuman primates, like humans, have demonstrated various physical intuitions. Cacchione and Krist (2004) examined chimpanzees' intuitions about support relations with the violation-of-expectation task. They reported that the chimpanzees possessed intuitions about support, but their intuitions differed from those of humans in part; they were sensitive to "contact/no-contact" and "amount of contact" but not "type of contact" rule. To further explore intuitions about support in nonhuman primates, we conducted similar experiments on monkeys (Japanese monkeys) and apes (chimpanzees). In three experiments, we presented physically possible and impossible events of different support relations to the participants and measured their looking times. The results reveal that the chimpanzees and monkeys detect the violations of "contact/no-contact" and "amount of contact" but not "type of contact" variable. Therefore, the apes and monkeys possess similar intuitions; however, these intuitions differ in part from those of humans. The present study provides new and corroborative evidence of intuitions about support in nonhuman primates. However, this again leads to the question of distinctive understanding about support relations among primate species.

Physical intuitions about support relations in monkeys (Macaca fuscata) and apes (Pan troglodytes).

Top-down signal from the frontal cortex regulates social value orientation

Emotional facial expression accelerates cue-reward association learning

Midbrain dopamine neurons respond to reward-predictive stimuli. In the natural environment reward-predictive stimuli are often perceptually complicated. Thus, to discriminate one stimulus from another, elaborate sensory processing is necessary. Given that previous studies have used simpler types of reward-predictive stimuli, it has yet to be clear whether and, if so, how dopamine neurons obtain reward information from perceptually complicated stimuli. To investigate this, we recorded the activities of monkey dopamine neurons while they were performing discrimination between two coherent motion directions in random-dot motion stimuli. These coherent directions were paired with different magnitudes of reward. We found that dopamine neurons showed reward-predictive responses to random-dot motion stimuli. Moreover, dopamine neurons showed temporally extended activity correlated with changes in reward prediction (i.e., reward prediction error) from coarse to fine scales between initial motion detection and subsequent motion discrimination phases. Noticeably, dopamine reward-predictive responses became differential in a later phase than previously reported. This response pattern was consistent with the time course of processing required for the estimation of expected reward value that parallels the motion direction discrimination processing. The results demonstrate that dopamine neurons are able to reflect the reward value of perceptually complicated stimuli, and suggest that dopamine neurons use the moment-to-moment reward prediction associated with environmental stimuli to compute a reward prediction error.

Temporally Extended Dopamine Responses to Perceptually Demanding Reward-Predictive Stimuli

SFS for feature selective maintenance, IPS for simple maintenance in visual working memory

Signal interaction between prefrontal cortex and striatum in reward prediction

An operant is a behavioral act that has an impact on the environment to produce an outcome, constituting an important component of voluntary behavior. Because the environment can be volatile, the same action may cause different consequences. Thus to obtain an optimal outcome, it is crucial to detect action–outcome relationships and adapt the behavior accordingly. Although prefrontal neurons are known to change activity depending on expected reward, it remains unknown whether prefrontal activity contributes to obtaining reward. We investigated this issue by setting variable relationships between levels of single-neuron activity and rewarding outcomes. Lateral prefrontal neurons changed their spiking activity according to the specific requirements for gaining reward, without the animals making a motor response. Thus spiking activity constituted an operant response. Data from a control task suggested that these changes were unlikely to reflect simple reward predictions. These data demonstrate a remarkable capacity of prefrontal neurons to adapt to specific operant requirements at the single-neuron level.

Causal interaction between lateral prefrontal cortex and striatum

Brain activity for monetary loss prediction based on ambiguous perception

To survive in changeable circumstances, we have to make appropriate decisions on our behavior. Recent studies have suggested that we have two brain processes to calculate reward values of objects. One is the process coding a specific reward value of a stimulus or event dependent on direct experience. The other enables us to predict reward based on the internal model of given circumstances, including societies, which doesn't necessarily require direct experience. The nigro-striatal network works for the model-free decision and the prefrontal network contributes to the model-based decision. These two networks are cooperative in one occasion and are competitive in another.

Subliminal and supraliminal stimulus value affects action selection separately in human brain

Reward prediction based on stimulus categorization in primate lateral prefrontal cortex

Human posterior parietal cortex maintains color, shape and motion in visual short-term memory

Tamagawa-Caltech Joint Workshop “ Neural Mechanisms of The Social Mind ”

Decision making—the field concerned with the processes by which animals choose between competing actions on the basis of the expected value, or utility, of their consequences—has long been a topic of interest in philosophy, psychology, economics, and ethology. Nevertheless, in recent years there has been considerable expansion in this field into new directions, particularly into neuroscience and machine learning, largely due to innovation, both in technology and in approach. Whereas classic theories tried to explain how a decision should be made under a stationary condition with sufficient knowledge of the problem, but without regard to the neural processes involved, recent decision-making research addresses how actual individuals learn to make decisions when faced with novel or uncertain situations, as well as which neural circuits and systems are involved during different types of decision and during different stages of learning. The maturation of neuroimaging techniques for studying brain functions in humans (e.g., functional magnetic resonance imaging) has played a key role in this development, but what characterizes the recent surge in decision-making research is convergence of different lines of research, including reinforcement learning theory, behavioral economics, focal lesions, and pharmacology. The field as it has developed is very broad, crossing traditional boundaries between areas of science and neuroscience in its investigation of multiple species and brain areas, and through its use of multiple approaches to research, particularly in the degree to which previously distinct procedures, protocols, and paradigms are combined to solve specific problems. This has been an exciting time of rapid, sometimes frenetic, or even chaotic, advances. Nevertheless, some broad themes have begun to emerge in recent years, and it was recognition of this fact that first prompted the thought that a collection of papers surveying contemporary research in decision making might be possible. In fact, the articles in this volume grew out of a series of talks and presentations given at a meeting held at the Lake Arrowhead Conference Center at the University of California, Los Angeles in June 2006 (see FIG. 1). The decision to hold that meeting itself came from a series of discussions between the editors of this volume, initiated first at the Okinawa Computational Neuroscience Course in July 2005 (OCNC2005), in which each of us participated that year, and that were carried forward to the Society for Neurosciences meeting in Washington D.C. in November 2005. We felt that there had been sufficient advance in the

Abstract:  The prefrontal cortex (PFC), particularly the lateral prefrontal cortex (LPFC), has an important role in cognitive information processing. The area receives projections from sensory association cortices and sends outputs to motor‐related areas. Neurons in LPFC code the behavioral significance of stimuli, which can be abstract precursors for complex motor commands and are structured hierarchically. Loss of these neurons leads to a lack of flexibility in decision making, such as seen in stereotyped behaviors. However, to make more appropriate decisions the code for behavioral significance has to reflect the subject's own desires and demands. Indeed, LPFC has connections with reward‐related areas, such as the orbitofrontal cortex (OFC), basal ganglia, and medial prefrontal cortex. Recently, many studies have reported reward modulation of neural codes of behavioral significance. Using an asymmetric reward paradigm, we can investigate the functional specificity of LPFC neurons that code both cognitive information and motivational information. In this review, we will discuss details of neuronal properties of LPFC neurons from the viewpoints of cognitive information processing and motivational information processing, and the question of how these two pieces of information are integrated. Abstract coding and contextual representations in the cognitive information processing are functional characteristics of LPFC. Such functional specificity in LPFC cognitive processes is supported by a long‐term scale of reward history in the motivational information processing. The integration enables us to make an elaborate decision with respect to goal‐directed behavior in complex circumstances.

Integration of Cognitive and Motivational Information in the Primate Lateral Prefrontal Cortex

Functional role of the ventrolateral prefrontal cortex in decision making

Reward Expectancy-Related Prefrontal Neuronal Activities: Are They Neural Substrates of “Affective” Working Memory?

Economic theories of decision making are based on the principle of utility maximization, and reinforcement-learning theory provides computational algorithms that can be used to estimate the overall reward expected from alternative choices. These formal models not only account for a large range of behavioral observations in human and animal decision makers, but also provide useful tools for investigating the neural basis of decision making. Nevertheless, in reality, decision makers must combine different types of information about the costs and benefits associated with each available option, such as the quality and quantity of expected reward and required work. In this article, we put forward the hypothesis that different subdivisions of the primate frontal cortex may be specialized to focus on different aspects of dynamic decision-making processes. In this hypothesis, the lateral prefrontal cortex is primarily involved in maintaining the state representation necessary to identify optimal actions in a given environment. In contrast, the orbitofrontal cortex and the anterior cingulate cortex might be primarily involved in encoding and updating the utilities associated with different sensory stimuli and alternative actions, respectively. These cortical areas are also likely to contribute to decision making in a social context.

Functional Specialization of the Primate Frontal Cortex during Decision Making

Impaired recognition of the facial expressions in patients with Parkinson's disease

The prefrontal cortex (PFC) appears to be important for processing both cognitive and motivational context information. Primate lateral PFC (LPFC) neurons are involved in cognitive context-dependent stimulus coding by responding differently to an identical stimulus according to the task situation. Such context-dependent LPFC activity appears to be supported by context-representing activity, observed also in LPFC neurons, in which the baseline activity differs as a function of the task. In LPFC, there are also neurons that code stimulus on the basis of motivational context. This motivational context is represented in differential baseline activity as a function of the reward context. In the orbitofrontal cortex (OFC), there are neurons that code stimuli depending on the motivational context as well as neurons that represent motivational context information. Furthermore, we found LPFC neurons that coded the stimulus depending on both the cognitive and motivational context, as well as LPFC neurons that represented both the cognitive and motivational context. For adaptive behavior, it is important to code the meaning of the environmental situation based on the context. While OFC is predominantly concerned with processing motivational context information, LPFC seems to play important roles in integrating the cognitive and motivational context for adaptive goal-directed behavior.

Integration of cognitive and motivational context information in the primate prefrontal cortex.

Functionally and temporally dissociable neural processes underlying social decision-making on faces

Perceptual ambiguity by luminance contrast and reward predictive activity in the brain

Prefrontal activities under a go/no-go conditional discrimination task

Functional differences between macaque prefrontal cortex and caudate nucleus during eye movements with and without reward

Attention enhances task-relevant signals while filtering task-irrelevant signals; however, this selection process is not perfect. It is generally assumed that the stronger the irrelevant signal, the more strongly performance is disrupted. The effect of irrelevant coherent motion signals on performance on a color-discrimination task was systematically examined. Motion direction was either congruent or incongruent with response selection. Performance was most impaired when motion signal strength was just above perceptual threshold and improved when the motion signal strength increased. These results suggest that distractors of higher strength increase attentional modulation and are filtered before they interfere with task performance.

Reward prediction responses in prefrontal cortex using matching-to-sample procedure in monkey(Summary of Awarded Presentations at the 24th Annual Meeting)

Influences of Rewarding and Aversive Outcomes on Activity in Macaque Lateral Prefrontal Cortex

Dual neural pathways for decision-making; from single neuron to neural network

Modeling Stimulus Equivalence with Multi Layered Neural Networks

Functional significance of delay-period activity of primate prefrontal neurons in relation to spatial working memory and reward/omission-of-reward expectancy

Encoding of behavioral significance of visual stimuli by primate prefrontal neurons: relation to relevant task conditions

Spatial selectivity of go/no-go neurons in monkey prefrontal cortex

Nihon seirigaku zasshi. Journal of the Physiological Society of Japan

Response selection and single unit activity in monkey prefrontal cortex: from the viewpoint of system neuroscience

The lateral prefrontal cortex (LPFC) has been implicated in visuospatial processing, especially when it is required to hold spatial information during a delay period. It has also been reported that the LPFC receives information about expected reward outcome. However, the interaction between visuospatial processing and reward processing is still unclear because the two types of processing could not be dissociated in conventional delayed response tasks. To examine this, we used a memory-guided saccade task with an asymmetric reward schedule and recorded 228 LPFC neurons. The position of the target cue indicated the spatial location for the following saccade and the color of the target cue indicated the reward outcome for a correct saccade. Activity of LPFC was classified into three main types: S-type activity carried only spatial signals, R-type activity carried only reward signals, and SR-type activity carried both. Therefore only SR-type cells were potentially involved in both visuospatial processing and reward processing. SR-type activity was enhanced (SR+) or depressed (SR-) by the reward expectation. The spatial discriminability as expressed by the transmitted information was improved by reward expectation in SR+ type. In contrast, when reward information was coded by an increase of activity in the reward-absent condition (SR- type), it did not improve the spatial representation. This activity appeared to be involved in gaze fixation. These results extend previous findings suggesting that the LPFC exerts dual influences based on predicted reward outcome: improvement of memory-guided saccades (when reward is expected) and suppression of inappropriate behavior (when reward is not expected).

Influence of reward expectation on visuospatial processing in macaque lateral prefrontal cortex.

Feature-Based Anticipation of Cues that Predict Reward in Monkey Caudate Nucleus

The prefrontal cortex is involved in acquiring and maintaining information about context, including the set of task instructions and/or the outcome of previous stimulus–response sequences. Most studies on context-dependent processing in the prefrontal cortex have been concerned with such executive functions, but the prefrontal cortex is also involved in motivational operations. We thus wished to determine whether primate prefrontal neurons show evidence of representing the motivational context learned by the monkey. We trained monkeys in a delayed reaction task in which an instruction cue indicated the presence or absence of reward. In random alternation with no reward, the same one of several different kinds of food and liquid rewards was delivered repeatedly in a block of ∼50 trials, so that reward information would define the motivational context. In response to an instruction cue indicating absence of reward, we found that neurons in the lateral prefrontal cortex not only predicted the absence of reward but also represented more specifically which kind of reward would be omitted in a given trial. These neurons seem to code contextual information concerning which kind of reward may be delivered in following trials. We also found prefrontal neurons that showed tonic baseline activity that may be related to monitoring such motivational context. The different types of neurons were distributed differently along the dorsoventral extent of the lateral prefrontal cortex. Such operations in the prefrontal cortex may be important for the monkey to maximize reward or to modify behavioral strategies and thus may contribute to executive control.

Coding and Monitoring of Motivational Context in the Primate Prefrontal Cortex

The primate brain is equipped with prefrontal circuits for interpreting visual information, but how these circuits deal with competing stimulus-response (S-R) associations remains unknown. Here we show different types of responses to task-irrelevant visual features in three functionally dissociated groups of primate prefrontal neurons. Two Japanese macaques participated in a go/no-go task in which they had to discriminate either the color or the motion direction of a visual target to make a correct manual response. Prior to the experiment, the monkeys had been trained extensively so that they acquired fixed associations between visual features and required responses (e.g., "green = go"; "downward motion = no-go"). In this design, the monkey was confronted with a visual target from which it had to extract relevant information (e.g., color in the color-discrimination condition) while ignoring irrelevant information (e.g., motion direction in the color-discrimination condition). We recorded from 436 task-related prefrontal neurons while the monkey performed the multidimensional go/no-go task: 139 (32%) neurons showed go/no-go discrimination based on color as well as motion direction ("integration cells"); 192 neurons (44%) showed go/no-go discrimination only based on color ("color-feature cells"); and 105 neurons (24%) showed go/no-go discrimination only based on motion direction ("motion-feature cells"). Overall, however, 162 neurons (37%) were influenced by irrelevant information: 53 neurons (38%) among integration cells, 71 neurons (37%) among color-feature cells, and 38 neurons (36%) among motion-feature cells. Across all types of neurons, the response to an irrelevant feature was positively correlated with the response to the same feature when it was relevant, indicating that the influence from irrelevant information is a residual from S-R associations that are relevant in a different context. Temporal and anatomical differences among integration, color-feature and motion-feature cells suggested a sequential mode of information processing in prefrontal cortex, with integration cells situated toward the output of the decision-making process. In these cells, the response to irrelevant information appears as a congruency effect, with better go/no-go discrimination when both the relevant and irrelevant feature are associated with the same response than when they are associated with different responses. This congruency effect could be the result of the combined input from color- and motion-feature cells. Thus these data suggest that irrelevant features lead to partial activation of neurons even toward the output of the decision-making process in primate prefrontal cortex.

Responses to task-irrelevant visual features by primate prefrontal neurons.

To examine the neural mechanism for behavioral inhibition, we recorded single-cell activity in macaque ventrolateral prefrontal cortex, which is known to receive visual information directly from the inferotemporal cortex. In response to a moving random pattern of colored dots, monkeys had to make a go or no-go response. In the color condition, green indicated go, whereas red indicated no-go, regardless of the motion direction; in the motion condition, upward indicated go, whereas downward indicated no-go, regardless of the color. Approximately one-half of the visual cells were go/no-go differential. A majority of these cells (64/73) showed differential activity only in the color condition; they responded nondifferentially in the motion condition, although the same set of stimuli was used. We classified these cells as “go type” (n = 41) and “no-go type” (n = 23) depending on the color for which they showed a stronger response. Interestingly, in both types of cells, the differential effects were observed only for the no-go-indicating color. Compared with the nondifferential responses in the motion condition, go-type cells in the color condition showed weaker responses to the no-go-indicating color, whereas their responses to the go-indicating color were similar; in contrast, no-go type cells showed stronger responses to the no-go-indicating color, whereas their responses to the go-indicating color were similar. Both types of cells did not show any activity change during the actual execution of the go or no-go response. These results suggest that neurons in ventrolateral prefrontal cortex contribute to stimulus–response association in complex task situations by inhibiting behavioral responses on the basis of visual information from the ventral stream.

A Code for Behavioral Inhibition on the Basis of Color, But Not Motion, in Ventrolateral Prefrontal Cortex of Macaque Monkey

To study the operation of selective attention in a conflict situation with automatic processes, we trained 4 Japanese macaques (Macaca fuscata) extensively on a manual go/no-go task. The monkey had to discriminate either the color, shape, motion direction, or location of a visual stimulus. In each trial, the behavioral meaning of the relevant feature (go or no-go) could either be congruent or incongruent with irrelevant features of the same stimulus. Reaction times were slowed, and error rates increased when irrelevant stimulus features were incongruent with the required response. The effects were obtained when the monkey attended to the color, shape, or motion direction, but not when it attended to the location of the stimulus. The effects were cumulative so that the interference from 1 incongruent feature was smaller than that from 2 incongruent features. We propose that the present paradigm provides a behavioral analogue of the human Stroop effect.

Interference from irrelevant features on visual discrimination by macaques (Macaca fuscata): a behavioral analogue of the human Stroop effect.

The hierarchical organization of decision making in the primate prefrontal cortex

Expectancy for the absence of the specific reward in primate prefrontal neurons

“Stroop effect” in the primate: Behavior and its neural correlate in the prefrontal cortex

Hierarchical processing of behavioral meaning of visual stimulus in monkey prefrontal cortex

Cross-dimensional encoding of behavioral connotation of visual stimuli by primate prefrontal neurons

Resting‐state functional magnetic resonance imaging (fMRI) is widely used for measuring functional interactions between brain regions, significantly contributing to our understanding of large‐scale brain networks and brain–behavior relationships. Furthermore, idiosyncratic patterns of resting‐state connections can be leveraged to identify individuals and predict individual differences in clinical symptoms, cognitive abilities, and other individual factors. Idiosyncratic connectivity patterns are thought to persist across task states, suggesting task‐based fMRI can be similarly leveraged for individual differences analyses.

Evaluating methods for measuring background connectivity in slow event‐related functional magnetic resonance imaging designs

A major question for the study of learning and memory is how to tailor learning experiences to promote knowledge that generalizes to new situations. In two experiments, we used category learning as a representative domain to test two factors thought to influence the acquisition of conceptual knowledge: the number of training examples (set size) and the similarity of training examples to the category average (set coherence). Across participants, size and coherence of category training sets were varied in a fully crossed design. After training, participants demonstrated the breadth of their category knowledge by categorizing novel examples varying in their distance from the category center. Results showed better generalization following more coherent training sets, even when categorizing items furthest from the category center. Training set size had limited effects on performance. We also tested the types of representations underlying categorization decisions by fitting formal prototype and exemplar models. Prototype models posit abstract category representations based on the category's central tendency, whereas exemplar models posit that categories are represented by individual category members. In Experiment 1, low coherence training led to fewer participants relying on prototype representations, except when training length was extended. In Experiment 2, low coherence training led to chance performance and no clear representational strategy for nearly half of the participants. The results indicate that highlighting commonalities among exemplars during training facilitates learning and generalization and may also affect the types of concept representations that individuals form. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Coherent category training enhances generalization in prototype-based categories.

The need to learn new concepts and categories persists through the lifespan, yet little is known about how aging affects the concept learning and generalization. Here, we trained young and older adults to classify typical and boundary category members, and then tested category generalization to new stimuli. During training, older adults had increased difficulty compared to young adults learning category labels for boundary items, but not typical items. At test, categorization performance that included new items at all levels of typicality was comparable across age groups, but formal categorization models indicated that older adults relied to a greater degree on generalized (prototype) category representations than young adults. These findings align with the proposal that older adults are able to form category representations based on central tendency even when they have difficulty learning and remembering individual category members. More broadly, the results contribute to our understanding of multiple categorization strategies and the limited strategy flexibility in older adults. They also highlight how reliance on preserved cognitive functions may sometimes help older adults maintain performance. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The effects of age on category learning and prototype- and exemplar-based generalization.

Resting-state functional MRI (fMRI) is widely used for measuring functional interactions between brain regions, significantly contributing to our understanding of large-scale brain networks and brain-behavior relationships. Furthermore, idiosyncratic patterns of resting-state connections can be leveraged to identify individuals and predict individual differences in clinical symptoms, cognitive abilities, and other individual factors. Idiosyncratic connectivity patters are thought to persist across task states, suggesting task-based fMRI can be similarly leveraged for individual differences analyses. Here, we tested the degree to which functional interactions occurring in the background of a task during slow event-related fMRI parallel or differ from those captured during resting-state fMRI. We compared two approaches for removing task- evoked activity from task-based fMRI: (1) applying a low-pass filter to remove task- related frequencies in the signal, or (2) extracting residuals from a general linear model (GLM) that accounts for task-evoked responses. We found that the organization of large-scale cortical networks and individual’s idiosyncratic connectivity patterns are preserved during task-based fMRI. In contrast, individual differences in connection strength can vary more substantially between rest and task. Compared to low-pass filtering, background connectivity obtained from GLM residuals produced idiosyncratic connectivity patterns and individual differences in connection strength that more resembled rest. However, all background connectivity measures were highly similar when derived from the low-pass filtered signal or GLM residuals, indicating that both methods are suitable for measuring background connectivity. Together, our results highlight new avenues for the analysis of task-based fMRI datasets and the utility of each background connectivity method.

Evaluating methods for measuring background connectivity in slow event-related functional MRI designs

A major question for the study of learning and memory is how to tailor learning experiences to promote knowledge that generalizes to new situations. Using category learning as a representative domain, the present study tested two factors thought to influence acquisition of conceptual knowledge: the number of training examples (set size) and the similarity of training examples to the category average (set coherence). Across participants, size and coherence of category training sets were varied in a fully-crossed design. After training, participants demonstrated the breadth of their category knowledge by categorizing novel examples varying in their distance from the category center. Results showed better generalization following more coherent training sets, even when categorizing items furthest from the category center. There was little effect of set size. We also tested the types of representations underlying categorization decisions by fitting formal prototype and exemplar models. Prototype models posit abstract category representations based on the category’s central tendency, whereas exemplar models posit that categories are represented by individual category members. We show that more subjects rely on a prototype strategy following high coherence training, suggesting that more coherent training sets facilitate extraction of the category average. Together, these results provide strong evidence for the benefit of training on examples that are similar to one another and to the category center.

Coherent category training enhances generalization and increases reliance on prototype representations

The ability to make inferences about related experiences is an important function of memory that allows individuals to build generalizable knowledge. In some cases, however, making inferences may lead to false memories when individuals misremember inferred information as having been observed. One factor that is known to increase the prevalence of false memories is the physical resemblance between new and old information. The extent to which physical resemblance has parallel effects on generalization and memory for the source of inferred associations is not known. To investigate the parallels between memory generalization and false memories, we conducted three experiments using an acquired equivalence paradigm and manipulated physical resemblance between items that made up related experiences. The three experiments showed increased generalization for higher levels of resemblance. Recognition and source memory judgments revealed that high rates of generalization were not always accompanied by high rates of false memories. Thus, physical resemblance across episodes may promote generalization with or without a trade-off in terms of impeding memory specificity.

Generalization and False Memory in an Acquired Equivalence Paradigm: The Influence of Physical Resemblance Across Related Episodes

Although we often are tasked with learning pieces of information that are related in some way in educational settings, the learning conditions that promote learning of and connections across related information are still poorly understood. In this thesis, I asked: Which instruction methods promote learning of and connections across (integration of) related information? In the two experiments in this thesis, participants were presented related information in two different formats, and we assessed their memory for related information, in addition to how well they could integrate related information to derive new knowledge. The two presentation formats incorporated the same number of exposures of related information, but the sequence with which information was presented was manipulated: In one presentation format (blocked) participants strongly learn one set of information, before being confronted with a related set of information, whereas participants learn related information in parallel in the other (interleaved). In Experiment 1, we found that blocked presentation enhanced both memory for and integration of related information. However, given potential effects of testing order on our results, we more closely examined memory for related information in Experiment 2. In Experiment 2, we no longer found a difference in overall memory for related information between the two presentation formats. In fact, we found evidence that presence of shared information enhanced learning of related information after interleaved presentation only. Regardless, the results of both experiments demonstrated that manipulating just the sequence with which information is presented, without increasing the number of exposures, can enhance learning, an impactful finding in an era of increased pressures to maximize instructional time.

The effect of learning condition on memory for and integration of related information

Category learning, learning to sort a set of stimuli into categories or groups, can induce category biases in perception such that items in the same category are perceived as more similar than items from different categories. To what degree category bias develops when learning goals emphasize individuation of each stimulus and whether the bias emerges spontaneously during learning itself rather than in response to task demands is unclear. Here, we used functional MRI (fMRI) during encoding to test for category biases in neural representations of individual stimuli during learning. Human participants (males and females) encountered face-blend stimuli with unique first names and shared family names that indicated category membership. Participants were instructed to learn the full name for each face. Neural pattern classification and pattern similarity analyses were used to track category information in the brain. Results showed that stimulus category could be decoded during encoding across many frontal, parietal, and occipital regions. Furthermore, two stimuli from the same category were represented more similarly in the prefrontal cortex than two stimuli from different categories equated for physical similarity. These findings illustrate that a mere presence of category label can bias neural representations spontaneously during encoding to emphasize category-relevant information, even in the absence of explicit categorization demands and when category-irrelevant information remains relevant for task goals. SIGNIFICANCE STATEMENT Entities belonging to the same category are perceived as being more similar than entities belonging to different categories. Here, we show that neural representations highlighting category-relevant information form spontaneously during encoding. Notably, the presence of a category label led to neural category bias although participants focused on remembering individual stimuli and category-irrelevant stimulus features remained important for explicit task goals. These results may inform our understanding of bias in general and suggest that bias may emerge when category information is present even when one's explicit focus is on individuals.

Category-Biased Neural Representations Form Spontaneously during Learning That Emphasizes Memory for Specific Instances

A classic study by Roediger and Karpicke (2006a) investigated the relative benefits of restudy versus retrieval practice, or “test”, on memory retention. Repeated studying was superior to repeated testing when memory was tested immediately (all study > multiple study/single test > single study/multiple tests). Strikingly, the pattern reversed when memory was tested after a days-long delay, with best performance in a single study/multiple tests condition. As each study period was minutes-long and contained repeated reading of a to-be-remembered text passage, we were interested whether the striking benefit for repeated testing at the expense of any restudy replicates when study opportunities are brief, akin to a single mention of a fact in a lecture. Participants encountered academically relevant facts a total of three times, each time either studied (S) or self-tested (T). Final test followed immediately or after a delay (Experiment 1: two days, Experiment 2: seven days). Partially replicating prior work, immediate memory benefited from repeated study (SSS > SST > STT), but the pattern did not reverse after a delay. Instead, memory was superior for facts the were restudied in addition to self-tested (SST > STT = SSS). We further investigated whether restudy after a test (STS) provides additional benefits compared to restudy before test (SST), but found comparably high delayed recall in both conditions. The results show that under some circumstances, balancing repetition and testing can allow for more information to be learned and retained long-term.

The need to learn new concepts and categories persists through the lifespan, yet little is known about how aging affects concept learning and generalization. Here, we trained young and older adults to classify typical and boundary category members and then tested category generalization to new stimuli. During training, older adults had increased difficulty compared to young adults learning category labels for boundary items, but not typical items. At test, categorization performance that included new items at all levels of typicality was comparable across age groups, but formal categorization models indicated that older adults relied to a greater degree on generalized (prototype) category representations than young adults. These findings align with the proposal that older adults are able to form category representations based on central tendency even when they have difficulty learning and remembering individual category members. More broadly, the results contribute to our understanding of multiple categorization strategies and the limited strategy flexibility in older adults. They also highlight how reliance on

The effects of age on prototype- and exemplar-based categorization

ABSTRACT Age deficits in memory for individual episodes are well established. Less is known about how age affects another key memory function: the ability to form new conceptual knowledge. Here we studied age differences in concept formation in a category-learning paradigm with face-blend stimuli, using several metrics: direct learning of category members presented during training, generalisation of category labels to new examples, and shifts in perceived similarity between category members that often follow category learning. We found that older adults were impaired in direct learning of training examples, but that there was no significant age deficit in generalisation once we accounted for the deficit in direct learning. We also found that category learning affected the perceived similarity between members of the same versus opposing categories, and age did not significantly moderate this effect. Lastly, we compared traditional category learning to categorisation after a learning task in which a category label (shared last name) was presented alongside stimulus-specific information (unique first names that individuated category members). We found that simultaneously learning stimulus-specific and category information resulted in decreased category learning, and that this decrement was apparent in both age groups.

Age effects on category learning, categorical perception, and generalization

There is a long-standing debate about whether categories are represented by individual category members (exemplars) or by the central tendency abstracted from individual members (prototypes). Neuroimaging studies have shown neural evidence for either exemplar representations or prototype representations, but not both. Presently, we asked whether it is possible for multiple types of category representations to exist within a single task. We designed a categorization task to promote both exemplar and prototype representations and tracked their formation across learning. We found only prototype correlates during the final test. However, interim tests interspersed throughout learning showed prototype and exemplar representations across distinct brain regions that aligned with previous studies: prototypes in ventromedial prefrontal cortex and anterior hippocampus and exemplars in inferior frontal gyrus and lateral parietal cortex. These findings indicate that, under the right circumstances, individuals may form representations at multiple levels of specificity, potentially facilitating a broad range of future decisions.

Tracking prototype and exemplar representations in the brain across learning

The brain utilizes distinct neural mechanisms that ease the transition through different stages of learning. Furthermore, evidence from category learning has shown that dissociable memory systems are engaged, depending on the structure of a task. This can even hold true for tasks that are very similar to each other, which complicates the process of classifying brain activity as relating to changes that are associated with learning or reflecting the engagement of a memory system suited for the task. The primary goals of these studies were to characterize the mechanisms that are associated with category learning and understand the extent to which different memory systems are recruited within a single task. Two studies providing spatial and temporal distinctions between learning-related changes in the brain and category-dependent memory systems are presented. The results from these experiments support the notion that exemplar memorization, rule-based, and perceptual similarity-based categorization are flexibly recruited in order to optimize performance during a single task. We conclude that these three methods, along with the memory systems they rely on, aid in the development of expertise, but their engagement might depend on the level of familiarity with a category.

Spatiotemporal Dynamics of Multiple Memory Systems During Category Learning

Age deficits in memory for individual episodes are well established. Less is known about how age affects another key memory function: the ability to form new conceptual knowledge. Here we studied age differences in concept formation in a category-learning paradigm with face-blend stimuli, using several metrics: direct learning of category members presented during training, generalization of category labels to new examples, and shifts in perceived similarity between category members that often follow category learning. Age deficits in categorization were compared to metrics of memory specificity (recognition, cued-recall) for the same set of stimuli. We found that older adults were impaired in direct learning of training examples, but there was no generalization deficit above-and-beyond the deficit in direct learning. We also found that category learning affected the perceived similarity between members of the same versus opposing categories, and age did not significantly moderate this effect. When comparing categorization to memory specificity, we found that categorization deficits were smaller than deficits in recall and comparable to deficits in recognition, showing that categorization deficits are smaller than some of the largest known age-related memory deficits. Lastly, we compared traditional category learning to categorization after a learning task in which a category label (shared last name) was presented alongside stimulus-specific information (unique first names that individuated category members). We found that simultaneously learning stimulus-specific and category information resulted in decreased category learning in both age groups, and that this decrement was not disproportionate in older adults.

Age effects on category learning and their relationship to deficits in memory specificity

Memory allows us to remember specific events but also combine information across events to infer new information. New inferences are thought to stem from integrating memories of related events during encoding but can be also generated on-demand, based on separate memories of individual events. Integrative encoding has been argued as dominant in the acquired equivalence paradigm, where people have a tendency to assume that when two faces share one preference, they also share another. A downside may be a loss of source memory, where inferred preferences are mistaken for observed ones. Here, we tested the predictions of integrative encoding across five data sets collected using small variations of the acquired equivalence paradigm. Results showed a statistically reliable but numerically small tendency to generalize preferences across faces, with stronger evidence for on-demand inferences at retrieval rather than spontaneous integration during encoding. Newly included explicit source memory test showed that participants differentiated learned from inferred preferences to a high degree, irrespective of whether they generalized preferences across faces. Overall, the results indicate that representations of individual events and retrieval-based processes may play a larger role in acquired equivalence than previously thought, informing current theories of generalization and knowledge representation.

Characterizing the impact of adversity, abuse, and neglect on adolescent amygdala resting-state functional connectivity

There has been a long-standing debate about whether categories are represented by individual category members (exemplars) or by the central tendency abstracted from individual members (prototypes). Across neuroimaging studies, there has been neural evidence for either exemplar representations or prototype representations, but not both. In the present study, we asked whether it is possible for individuals to form multiple types of category representations within a single task. We designed a categorization task to promote both exemplar and prototype representations, and we tracked their formation across learning. We found evidence for co-existing prototype and exemplar representations in brain in regions that aligned with previous studies: prototypes in ventromedial prefrontal cortex and anterior hippocampus and exemplars in inferior frontal gyrus and lateral parietal cortex. These findings show that, under the right circumstances, individuals may form representations at multiple levels of specificity, potentially facilitating a broad range of future memory-based decisions.

Model-based fMRI reveals co-existing specific and generalized concept representations

Author response: Tracking prototype and exemplar representations in the brain across learning

Building conceptual knowledge that generalizes to novel situations is a key function of human memory. Category-learning paradigms have long been used to understand the mechanisms of knowledge generalization. In the present study, we tested the conditions that promote formation of new concepts. Participants underwent 1 of 6 training conditions that differed in the number of examples per category (set size) and their relative similarity to the category average (set coherence). Performance metrics included rates of category learning, ability to generalize categories to new items of varying similarity to prototypes, and recognition memory for individual examples. In categorization, high set coherence led to faster learning and better generalization, while set size had little effect. Recognition did not differ reliably among conditions. We also tested the nature of memory representations used for categorization and recognition decisions using quantitative prototype and exemplar models fit to behavioral responses. Prototype models posit abstract category representations based on the category's central tendency, whereas exemplar models posit that categories are represented by individual category members. Prototype strategy use during categorization increased with increasing set coherence, suggesting that coherent training sets facilitate extraction of commonalities within a category. We conclude that learning from a coherent set of examples is an efficient means of forming abstract knowledge that generalizes broadly. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Training set coherence and set size effects on concept generalization and recognition.

Perceived similarity ratings predict generalization success after traditional category learning and a new paired-associate learning task

Concept learning, the ability to extract commonalities and highlight distinctions across a set of related experiences to build organized knowledge, is a critical aspect of cognition. Previous reviews have focused on concept learning research as a means for dissociating multiple brain systems. The current review surveys recent work that uses novel analytical approaches, including the combination of computational modeling with neural measures, focused on testing theories of specific computations and representations that contribute to concept learning. We discuss in detail the roles of the hippocampus, ventromedial prefrontal, lateral prefrontal, and lateral parietal cortices, and how their engagement is modulated by the coherence of experiences and the current learning goals. We conclude that the interaction of multiple brain systems relating to learning, memory, attention, perception, and reward support a flexible concept-learning mechanism that adapts to a range of category structures and incorporates motivational states, making concept learning a fruitful research domain for understanding the neural dynamics underlying complex behaviors.

Functional connectivity between memory and reward centers across task and rest track memory sensitivity to reward

The hippocampus contributes to both remembering specific events and generalization across events. Recent work suggests that information may be represented along the longitudinal axis of the hippocampus at varied levels of specificity: detailed representations in the posterior hippocampus and generalized representations in the anterior hippocampus. Similar distinctions are thought to exist within neocortex, with lateral prefrontal and lateral parietal regions supporting memory specificity and ventromedial prefrontal and lateral temporal cortices supporting generalized memory. Here, we tested whether functional connectivity of anterior and posterior hippocampus with cortical memory regions is consistent with these proposed dissociations. We predicted greater connectivity of anterior hippocampus with putative generalization regions and posterior hippocampus with putative memory specificity regions. Furthermore, we tested whether differences in connectivity are stable under varying levels of task engagement. Participants learned to categorize a set of stimuli outside the scanner, followed by an fMRI session that included a rest scan, passive viewing runs, and category generalization task runs. Analyses revealed stronger connectivity of ventromedial pFC to anterior hippocampus and of angular gyrus and inferior frontal gyrus to posterior hippocampus. These differences remained relatively stable across the three phases (rest, passive viewing, category generalization). Whole-brain analyses further revealed widespread cortical connectivity with both anterior and posterior hippocampus, with relatively little overlap. These results contribute to our understanding of functional organization along the long axis of the hippocampus and suggest that distinct hippocampal–cortical connections are one mechanism by which the hippocampus represents both individual experiences and generalized knowledge.

Differential Functional Connectivity along the Long Axis of the Hippocampus Aligns with Differential Role in Memory Specificity and Generalization

Building conceptual knowledge that generalizes to novel situations is a key function of human memory. Category-learning paradigms have long been used to understand the mechanisms of knowledge generalization. In the present study, we tested the conditions that promote formation of new concepts. Participants underwent one of six training conditions that differed in the number of examples per category (set size) and their relative similarity to the category average (set coherence). Performance metrics included rates of category learning, ability to generalize categories to new items of varying similarity to prototypes, and recognition memory for individual examples. In categorization, high set coherence led to faster learning and better generalization, while set size had little effect. Recognition did not differ reliably among conditions. We also tested the nature of memory representations used for categorization and recognition decisions using quantitative prototype and exemplar models fit to behavioral responses. Prototype models posit abstract category representations based on the category’s central tendency, whereas exemplar models posit that categories are represented by individual category members. Prototype strategy use during categorization increased with increasing set coherence, suggesting that coherent training sets facilitate extraction of commonalities within a category. We conclude that learning from a coherent set of examples is an efficient means of forming abstract knowledge that generalizes broadly.

Training set coherence and set size effects on concept generalization and recognition

Abstract Establishing links between neural systems and health can be challenging since there is not a one-to-one mapping between brain regions and psychological states. Building sensitive and specific predictive models of health-relevant constructs using multivariate activation patterns of brain activation is a promising new direction. We illustrate the potential of this approach by building two ‘neural signatures’ of food craving regulation (CR) using multivariate machine learning and, for comparison, a univariate contrast. We applied the signatures to two large validation samples of overweight adults who completed tasks measuring CR ability and valuation during food choice. Across these samples, the machine learning signature was more reliable. This signature decoded CR from food viewing and higher signature expression was associated with less craving. During food choice, expression of the regulation signature was stronger for unhealthy foods and inversely related to subjective value, indicating that participants engaged in CR despite never being instructed to control their cravings. Neural signatures thus have the potential to measure spontaneous engagement of mental processes in the absence of explicit instruction, affording greater ecological validity. We close by discussing the opportunities and challenges of this approach, emphasizing what machine learning tools bring to the field of health neuroscience.

Multivariate neural signatures for health neuroscience: assessing spontaneous regulation during food choice

Abstract Goal-directed behavior and lifelong well-being often depend on the ability to control appetitive motivations, such as cravings. Cognitive reappraisal is an effective way to modulate emotional states, including cravings, but is often studied under explicit instruction to regulate. Despite the strong prediction from Self-Determination Theory that choice should enhance task engagement and regulation success, little is known empirically about whether and how regulation is different when participants choose (vs are told) to exert control. To investigate how choice affects neural activity and regulation success, participants reappraised their responses to images of personally-craved foods while undergoing functional neuroimaging. Participants were either instructed to view or reappraise (‘no-choice’) or chose freely to view or reappraise (‘yes-choice’). Choice increased activity in the frontoparietal control network. We expected this activity would be associated with increased task engagement, resulting in better regulation success. However, contrary to this prediction, choice slightly reduced regulation success. Follow-up multivariate functional neuroimaging analyses indicated that choice likely disrupted allocation of limited cognitive resources during reappraisal. While unexpected, these results highlight the importance of studying upstream processes such as regulation choice, as they may affect the ability to regulate cravings and other emotional states.

The ability to flexibly combine existing knowledge in response to novel circumstances is highly adaptive. However, the neural correlates of flexible associative inference are not well characterized. Laboratory tests of associative inference have measured memory for overlapping pairs of studied items (e.g., AB, BC) and for nonstudied pairs with common associates (i.e., AC). Findings from functional neuroimaging and neuropsychology suggest the ventromedial prefrontal cortex (vmPFC) may be necessary for associative inference. Here, we used a neuropsychological approach to test the necessity of vmPFC for successful memory-guided associative inference in humans using an overlapping pairs associative memory task. We predicted that individuals with focal vmPFC damage (n = 5; 3F, 2M) would show impaired inferential memory but intact non-inferential memory. Performance was compared with normal comparison participants (n = 10; 6F, 4M). Participants studied pairs of visually presented objects including overlapping pairs (AB, BC) and nonoverlapping pairs (XY). Participants later completed a three-alternative forced-choice recognition task for studied pairs (AB, BC, XY) and inference pairs (AC). As predicted, the vmPFC group had intact memory for studied pairs but significantly impaired memory for inferential pairs. These results are consistent with the perspective that the vmPFC is necessary for memory-guided associative inference, indicating that the vmPFC is critical for adaptive abilities that require application of existing knowledge to novel circumstances. Additionally, vmPFC damage was associated with unexpectedly reduced memory for AB pairs post-inference, which could potentially reflect retroactive interference. Together, these results reinforce an emerging understanding of a role for the vmPFC in brain networks supporting associative memory processes. SIGNIFICANCE STATEMENT We live in a constantly changing environment, so the ability to adapt our knowledge to support understanding of new circumstances is essential. One important adaptive ability is associative inference which allows us to extract shared features from distinct experiences and relate them. For example, if we see a woman holding a baby, and later see a man holding the same baby, then we might infer that the two adults are a couple. Despite the importance of associative inference, the brain systems necessary for this ability are not known. Here, we report that damage to human ventromedial prefrontal cortex (vmPFC) disproportionately impairs associative inference. Our findings show the necessity of the vmPFC for normal associative inference and memory integration.

Ventromedial Prefrontal Cortex Is Necessary for Normal Associative Inference and Memory Integration

We tested the potential of task-based functional neuroimaging as a biomarker of emerging prefrontal brain changes in progranulin (GRN) mutations carriers. Five GRN mutation carriers free of frontotemporal dementia (FTD) and 11 non-carriers from families with FTD-GRN underwent functional MRI while solving matrix-reasoning problems. Mutation carriers displayed slower responses for more difficult problems and lower lateral prefrontal activation across all problems. Overall task-evoked posterior ventrolateral prefrontal activation predicted mutation status with 100% sensitivity and 91% specificity. Volumetric differences did not account for activation differences. Prefrontal activation may have utility as a biomarker in GRN mutation.

Decreased Prefrontal Activation during Matrix Reasoning in Predementia Progranulin Mutation Carriers.

Motivation enhances memory by increasing hippocampal engagement during encoding. However, whether such increased hippocampal activation reflects encoding of the value of highly rewarding events per se is less understood. Here, using a monetary incentive encoding task with a novel manipulation, we tested in humans whether the hippocampus represents abstract reward value, independent of perceptual content. During functional MRI scanning, men and women studied object pairs, each preceded by a monetary reward cue indicating the amount of money they would receive if they successfully remembered the object pair at test. Reward cues varied on both the level of reward (penny, dime, and dollar) and visual form (picture or word) across trials to dissociate hippocampal responses to reward value from those reflecting the perceptual properties of the cues. Behaviorally, participants remembered pairs associated with the high reward (dollar) more often than pairs associated with lower rewards. Neural pattern-similarity analysis revealed that hippocampal and parahippocampal cortex activation patterns discriminated between cues of different value regardless of their visual form, and that hippocampal discrimination of value was most pronounced in participants who showed the greatest behavioral sensitivity to reward. Strikingly, hippocampal patterns were most distinct for reward cues that differed in value but had similar visual appearance, consistent with theoretical proposals of hippocampal-pattern differentiation of competing representations. Our data illustrate how contextual representations within the hippocampus go beyond space and time to include information about the motivational salience of events, with hippocampal reward coding tracking the motivational impact on later memory. SIGNIFICANCE STATEMENT Motivation, such as the promise of future rewards, enhances hippocampal engagement during encoding and promotes successful retention of events associated with valuable rewards. However, whether the hippocampus explicitly encodes reward value, dissociable from sensory information, is unclear. Here, we show that the hippocampus forms abstract representation of valuable rewards, encoding conceptual rather than perceptual information about the motivational context of individual events. Reward representation within the hippocampus is associated with preferential retention of high-value events in memory. Furthermore, we show that hippocampal-pattern differentiation serves to emphasize differences between visually similar events with distinct motivational salience. Collectively, these findings indicate that hippocampal contextual representations enable individuals to distinguish the motivational value of events, leading to prioritized encoding of significant memories.

Abstract Representation of Prospective Reward in the Hippocampus

Memory function involves both the ability to remember details of individual experiences and the ability to link information across events to create new knowledge. Prior research has identified the ventromedial prefrontal cortex (VMPFC) and the hippocampus as important for integrating across events in the service of generalization in episodic memory. The degree to which these memory integration mechanisms contribute to other forms of generalization, such as concept learning, is unclear. The present study used a concept-learning task in humans (both sexes) coupled with model-based fMRI to test whether VMPFC and hippocampus contribute to concept generalization, and whether they do so by maintaining specific category exemplars or abstract category representations. Two formal categorization models were fit to individual subject data: a prototype model that posits abstract category representations and an exemplar model that posits category representations based on individual category members. Latent variables from each of these models were entered into neuroimaging analyses to determine whether VMPFC and the hippocampus track prototype or exemplar information during concept generalization. Behavioral model fits indicated that almost three-quarters of the subjects relied on prototype information when making judgments about new category members. Paralleling prototype dominance in behavior, correlates of the prototype model were identified in VMPFC and the anterior hippocampus with no significant exemplar correlates. These results indicate that the VMPFC and portions of the hippocampus play a broad role in memory generalization and that they do so by representing abstract information integrated from multiple events. SIGNIFICANCE STATEMENT Whether people represent concepts as a set of individual category members or by deriving generalized concept representations abstracted across exemplars has been debated. In episodic memory, generalized memory representations have been shown to arise through integration across events supported by the ventromedial prefrontal cortex (VMPFC) and hippocampus. The current study combined formal categorization models with fMRI data analysis to show that the VMPFC and anterior hippocampus represent abstract prototype information during concept generalization, contributing novel evidence of generalized concept representations in the brain. Results indicate that VMPFC–hippocampal memory integration mechanisms contribute to knowledge generalization across multiple cognitive domains, with the degree of abstraction of memory representations varying along the long axis of the hippocampus.

Abstract Memory Representations in the Ventromedial Prefrontal Cortex and Hippocampus Support Concept Generalization

Events with overlapping elements can be encoded as two separate representations or linked into an integrated representation, yet we know little about the conditions that promote one form of representation over the other. Here, we tested the hypothesis that the proximity of overlapping events would increase the probability of integration. Participants first established memories for house–object and face–object pairs; half of the pairs were learned 24 hr before an fMRI session, and the other half 30 min before the session. During scanning, participants encoded object–object pairs that overlapped with the initial pairs acquired on the same or prior day. Participants were also scanned as they made inference judgments about the relationships among overlapping pairs learned on the same or different day. Participants were more accurate and faster when inferring relationships among memories learned on the same day relative to those acquired across days, suggesting that temporal proximity promotes integration. Evidence for reactivation of existing memories—as measured by a visual content classifier—was equivalent during encoding of overlapping pairs from the two temporal conditions. In contrast, evidence for integration—as measured by a mnemonic strategy classifier from an independent study [Richter, F. R., Chanales, A. J. H., & Kuhl, B. A. Predicting the integration of overlapping memories by decoding mnemonic processing states during learning. Neuroimage, 124, 323–335, 2016]—was greater for same-day overlapping events, paralleling the behavioral results. During inference itself, activation patterns further differentiated when participants were making inferences about events acquired on the same day versus across days. These findings indicate that temporal proximity of events promotes integration and further influences the neural mechanisms engaged during inference.

Repeated encounters with the same event typically lead to decreased activation in the medial temporal lobe (MTL) and dopaminergic midbrain, a phenomenon known as repetition suppression. In contrast, encountering an event that overlaps with prior experience leads to increased response in the same regions. Such increased responding is thought to reflect an associative novelty signal that promotes memory updating to resolve differences between current events and stored memories. Here, we married these ideas to test whether event overlap significantly modulates MTL and midbrain responses—even when events are repeated and expected—to promote memory updating through integration. While undergoing high‐resolution functional MRI, participants were repeatedly presented with objects pairs, some of which overlapped with other, intervening pairs and some of which contained elements unique from other pairs. MTL and midbrain regions showed widespread repetition suppression for nonoverlapping pairs containing unique elements; however, the degree of repetition suppression was altered for overlapping pairs. Entorhinal cortex, perirhinal cortex (PRc), midbrain, and PRc—midbrain connectivity showed repetition‐related increases across overlapping pairs. Notably, increased PRc activation for overlapping pairs tracked individual differences in the ability to reason about the relationships among pairs—our behavioral measure of memory integration. Within the hippocampus, activation increases across overlapping pairs were unique to CA1, consistent with its hypothesized comparator function. These findings demonstrate that event overlap engages MTL and midbrain functions traditionally implicated in novelty processing, even when overlapping events themselves are repeated. Our findings further suggest that the MTL—midbrain response to event overlap may promote integration of new content into existing memories, leading to the formation of relational memory networks that span experiences. Moreover, the results inform theories about the division of labor within MTL, demonstrating that the role of PRc in episodic encoding extends beyond familiarity processing and item‐level recognition. © 2016 Wiley Periodicals, Inc.

Repetition suppression in the medial temporal lobe and midbrain is altered by event overlap

The ability to combine information acquired at different times to make novel inferences is a powerful function of episodic memory. One perspective suggests that by retrieving related knowledge during new experiences, existing memories can be linked to the new, overlapping information as it is encoded. The resulting memory traces would thus incorporate content across event boundaries, representing important relationships among items encountered during separate experiences. While prior work suggests that the hippocampus is involved in linking memories experienced at different times, the involvement of specific subfields in this process remains unknown. Using both univariate and multivariate analyses of high‐resolution functional magnetic resonance imaging (fMRI) data, we localized this specialized encoding mechanism to human CA1. Specifically, right CA1 responses during encoding of events that overlapped with prior experience predicted subsequent success on a test requiring inferences about the relationships among events. Furthermore, we employed neural pattern similarity analysis to show that patterns of activation evoked during overlapping event encoding were later reinstated in CA1 during successful inference. The reinstatement of CA1 patterns during inference was specific to those trials that were performed quickly and accurately, consistent with the notion that linking memories during learning facilitates novel judgments. These analyses provide converging evidence that CA1 plays a unique role in encoding overlapping events and highlight the dynamic interactions between hippocampal‐mediated encoding and retrieval processes. More broadly, our data reflect the adaptive nature of episodic memories, in which representations are derived across events in anticipation of future judgments. © 2014 Wiley Periodicals, Inc.

Recent research indicates that reward-based motivation impacts medial temporal lobe (MTL) encoding processes, leading to enhanced memory for rewarded events. In particular, previous functional magnetic resonance imaging (fMRI) studies of motivated learning have shown that MTL activation is greater for highly rewarded events, with the degree of reward-related activation enhancement tracking the corresponding behavioral memory advantage. These studies, however, do not directly address leading theoretical perspectives that propose such reward-based enhancements in MTL encoding activation reflect enhanced discrimination of the motivational context of specific events. In this study, a high-value or low-value monetary cue preceded a pair of objects, indicating the future reward for successfully remembering the pair. Using representational similarity analysis and high-resolution fMRI, we show that MTL activation patterns are more similar for encoding trials preceded by the same versus different reward cues, indicating a distributed code in this region that distinguishes between motivational contexts. Moreover, we show that activation patterns in hippocampus and parahippocampal cortex (PHc) that differentiate reward conditions during anticipatory cues and object pairs relate to successful associative memory. Additionally, the degree to which patterns differentiate reward contexts in dentate gyrus/CA2,3 and PHc is related to individual differences in reward modulation of memory. Collectively, these findings suggest that distributed activation patterns in the human hippocampus and PHc reflect the rewards associated with individual events. Furthermore, we show that these activation patterns-which discriminate between reward conditions--may influence memory through the incorporation of information about motivational contexts into stored memory representations.

Distributed hippocampal patterns that discriminate reward context are associated with enhanced associative binding.

Emerging evidence suggests that motivation enhances episodic memory formation through interactions between medial-temporal lobe (MTL) structures and dopaminergic midbrain. In addition, recent theories propose that motivation specifically facilitates hippocampal associative binding processes, resulting in more detailed memories that are readily reinstated from partial input. Here, we used high-resolution fMRI to determine how motivation influences associative encoding and retrieval processes within human MTL subregions and dopaminergic midbrain. Participants intentionally encoded object associations under varying conditions of reward and performed a retrieval task during which studied associations were cued from partial input. Behaviorally, cued recall performance was superior for high-value relative to low-value associations; however, participants differed in the degree to which rewards influenced memory. The magnitude of behavioral reward modulation was associated with reward-related activation changes in dentate gyrus/CA2,3 during encoding and enhanced functional connectivity between dentate gyrus/CA2,3 and dopaminergic midbrain during both the encoding and retrieval phases of the task. These findings suggests that, within the hippocampus, reward-based motivation specifically enhances dentate gyrus/CA2,3 associative encoding mechanisms through interactions with dopaminergic midbrain. Furthermore, within parahippocampal cortex and dopaminergic midbrain regions, activation associated with successful memory formation was modulated by reward across the group. During the retrieval phase, we also observed enhanced activation in hippocampus and dopaminergic midbrain for high-value associations that occurred in the absence of any explicit cues to reward. Collectively, these findings shed light on fundamental mechanisms through which reward impacts associative memory formation and retrieval through facilitation of MTL and ventral tegmental area/substantia nigra processing.

Reward Modulation of Hippocampal Subfield Activation during Successful Associative Encoding and Retrieval

Hippocampal and Ventral Medial Prefrontal Activation during Retrieval-Mediated Learning Supports Novel Inference

A critical aspect of inferential reasoning is the ability to form relationships between items or events that were not experienced together. This review considers different perspectives on the role of the hippocampus in successful inferential reasoning during both memory encoding and retrieval. Intuitively, inference can be thought of as a logical process by which elements of individual existing memories are retrieved and recombined to answer novel questions. Such flexible retrieval is sub-served by the hippocampus and is thought to require specialized hippocampal encoding mechanisms that discretely code events such that event elements are individually accessible from memory. In addition to retrieval-based inference, recent research has also focused on hippocampal processes that support the combination of information acquired across multiple experiences during encoding. This mechanism suggests that by recalling past events during new experiences, connections can be created between newly formed and existing memories. Such hippocampally mediated memory integration would thus underlie the formation of networks of related memories that extend beyond direct experience to anticipate future judgments about the relationships between items and events. We also discuss integrative encoding in the context of emerging evidence linking the hippocampus to the formation of schemas as well as prospective theories of hippocampal function that suggest memories are actively constructed to anticipate future decisions and actions.

The hippocampus and inferential reasoning: building memories to navigate future decisions

The cognitive neural underpinnings of prototype learning are becoming clear. Evidence points to 2 different neural systems, depending on the learning parameters. A/not-A (AN) prototype learning is mediated by posterior brain regions that are involved in early perceptual learning, whereas A/B (AB) is mediated by frontal and medial temporal lobe regions.

STUDY OBJECTIVES
To investigate the effects of sleep deprivation on AN and AB prototype learning and to use established prototype models to provide insights into the cognitive-processing locus of sleep-deprivation deficits.

DESIGN
Participants performed an AN and an AB prototype learning task twice, separated by a 24-hour period, with or without sleep between testing sessions.

Eighteen West Point cadets participated in the sleep-deprivation group, and 17 West Point cadets participated in a control group.

MEASUREMENTS AND RESULTS
Sleep deprivation led to an AN, but not an AB, performance deficit. Prototype model analyses indicated that the AN deficit was due to changes in attentional focus and a decrease in confidence that is reflected in an increased bias to respond non-A.

The findings suggest that AN, but not AB, prototype learning is affected by sleep deprivation. Prototype model analyses support the notion that the effect of sleep deprivation on AN is consistent with lapses in attentional focus that are more detrimental to AN than to AB. This finding adds to a growing body of work that suggests that different performance changes associated with sleep deprivation can be attributed to a common mechanism of changes in simple attention and vigilance.

The effects of sleep deprivation on dissociable prototype learning systems.

Episodic memory is characterized by rapid formation of new associations that bind information within individual episodes. A powerful aspect of episodic memory is the ability to flexibly apply and recombine information from past experience to guide new behavior. A critical question for memory research is how medial temporal lobe (MTL) and prefrontal cortex (PFC), regions implicated in rapid within-episode binding, further support cross-episode binding in service of mnemonic flexibility. We set to answer this question using an associative inference task in humans that required rapid binding of information across overlapping experiences (AB, BC) to enable successful transfer to novel test probes (AC). Within regions predicting subsequent associative memory for directly learned associations, encoding activation in MTL, including hippocampus and parahippocampal cortex, uniquely predicted success on novel transfer trials both within and across participants, consistent with an integrative encoding mechanism where overlapping experiences are linked into a combined representation during learning. In contrast, during retrieval, PFC activation predicted trial-by-trial transfer success while MTL predicted transfer performance across participants. Moreover, increased MTL-PFC coupling was observed during novel transfer trials compared with retrieval of directly learned associations. These findings suggest that inferential processes support transfer of rapidly acquired experiences to novel events during retrieval where multiple memories are recalled and flexibly recombined in service of successful behavior. Together, these results demonstrate distinct encoding and retrieval mechanisms that support mnemonic flexibility, revealing a unique role for MTL regions in cross-episode binding during encoding and engagement of interactive MTL-PFC processes during flexible transfer at test.

Flexible Memories: Differential Roles for Medial Temporal Lobe and Prefrontal Cortex in Cross-Episode Binding

Computational Models Inform Clinical Science and Assessment: An Application to Category Learning in Striatal-Damaged Patients.

Exemplar sequencing effects in incidental and intentional unsupervised category learning were investigated to illuminate how people form categories without an external teacher. Stimuli were perfectly separable into 2 categories based on 1 of 2 dimensions of variation. Sequencing of the first 20 training stimuli was manipulated. In the blocked condition, 10 Category A stimuli were followed by 10 Category B stimuli. In the intermixed condition, these 20 stimuli were ordered randomly. Experiment 1 revealed an interaction between learning mode and sequence, with better intentional learning for intermixed sequences but better incidental learning for blocked sequences. Experiment 2 showed that manipulating trial-to-trial variability along each dimension can impact intentional learning. Training sequences that emphasized variation along the category-relevant dimension resulted in better performance than sequences that emphasized variation along the category-irrelevant dimension. The results suggest that unsupervised category learning is influenced by the mode of learning and the order and nature of encountered exemplars.

Learning mode and exemplar sequencing in unsupervised category learning.

Military personnel often continue at high levels of performance despite being deprived of sleep. This article examines sleep deprivation effects on two forms of classification learning. In AN classification, participants are trained on one category and are then required to classify new items into the A or a previously unseen non-A category. In AB classification, participants are trained on A and B category members and are then required to classify new items into the A or B category. Preliminary results suggest that sleep deprivation impairs AN classification learning but leaves intact AB classification learning. Implications for military training are discussed.

Dissociable Processes in Classification: Implications From Sleep Deprivation

Previous research has presented a mixed picture of the cognitive and neural consequences of sleep deprivation on decision-making. Functional magnetic resonance imaging (fMRI) was used to examine the neural changes associated with simple and integrated decision-making under conditions of sleep deprivation. When rested, regions of the anterior prefrontal cortex (aPFC) were recruited to a greater degree for integrated decision-making (ID). After 24 hours of sleeplessness, there was minimal effect on simple decision-making but a clear vulnerability of ID to sleeplessness that was accompanied by a breakdown in task-specific neural activity in prefrontal cortex that, when rested, correlated with behavioral performance.

Decision-Making Under Conditions of Sleep Deprivation: Cognitive and Neural Consequences

The neural underpinnings of prototype learning are not well understood. A major source of confusion is that two versions of the prototype learning task have been used interchangeably in the literature; one where participants learn to categorize exemplars derived from two prototypes (A/B task), and one where participants learn to categorize exemplars derived from one prototype and noncategorical exemplars (A/non-A). We report results from an fMRI study of A/B and A/non-A prototype learning that allows for a direct contrast of the two learning methods. Accuracy in the two tasks did not correlate within subject despite equivalent average difficulty. The fMRI results revealed neural activation in a network of regions consistent with episodic memory retrieval for the A/B task while greater activation of a nondeclarative learning network was observed for the A/non-A task. The results demonstrate that learning in these two tasks is mediated by different neural systems and that recruitment of each system is dictated by the context of learning rather than the actual category structure.

Dissociable Prototype Learning Systems: Evidence from Brain Imaging and Behavior

The role of visuospatial and verbal working memory in perceptual category learning

Systematic reviews and meta-analyses have been increasingly recognized for their potential value in pre-clinical research, but their applications have not been extensively explored in behavioral neuroscience. In this work, we studied protein synthesis inhibition, a classic intervention used to disrupt fear learning, reconsolidation, and extinction in rodents, to explore how meta-analyses can identify potential moderators of its effect. We initially performed separate meta-analyses for different injection sites and target sessions to evaluate the effect of the intervention in various scenarios. Heterogeneity was further investigated by multilevel meta-regression models aggregating various sites, with article or research group as additional levels. We detected robust effects of protein synthesis inhibitors on training and reconsolidation, but not on extinction, possibly due to the lower number of studies on the latter. Our analyses identified some well-established moderators, such as intervention timing and reexposure duration. However, other factors proposed as boundary conditions for reconsolidation, such as memory age and training strength, were not associated with effect size. While our results point to the value of meta-analyses in consolidating findings from the literature, we believe that associations suggested by data synthesis should ideally be verified by well-powered, rigorous confirmatory experiments.

A meta-analysis of the effect of protein synthesis inhibitors on rodent fear conditioning

Introduction Preprints have been increasingly used in biomedical sciences, providing the opportunity for research to be publicly assessed before journal publication. With the increase in attention over preprints during the COVID-19 pandemic, we decided to assess the content of comments left on preprint platforms. Methods Preprints posted on bioRxiv and medRxiv in 2020 were accessed through each platform’s API, and a random sample of preprints that had received between 1 and 20 comments was analyzed. Comments were evaluated in triplicate by independent evaluators using an instrument that assessed their features and general content. Results 7.3% of preprints received at least 1 comment during a mean follow-up of 7.5 months. Analyzed comments had a median size of 43 words. Criticisms, corrections or suggestions were the most prevalent type of content, followed by compliments or positive appraisals and questions. Most critical comments regarded interpretation, data collection and methodological design, while compliments were usually about relevance and implications. Conclusions Only a small percentage of preprints posted in 2020 in bioRxiv and medRxiv received comments in these platforms. When present, however, these comments address content that is similar to that analyzed by traditional peer review. A more precise taxonomy of peer review functions would be desirable to describe whether post-publication peer review fulfills these roles.

Mapping the content of comments on bioRxiv and medRxiv preprints

Introduction: Previous studies about the replicability of clinical research based on the published literature have suggested that highly cited articles are often contradicted or found to have inflated effects. Nevertheless, there are no recent updates of such efforts, and this situation may have changed over time. Methods: We searched the Web of Science database for articles studying medical interventions with more than 2000 citations, published between 2004 and 2018 in high-impact medical journals. We then searched for replications of these studies in PubMed using the PICO framework. We evaluated whether replications were successful by the presence of a statistically significant effect in the same direction and by overlap of their effect sizes confidence intervals (CIs) with those of the original studies. We also analyzed evidence of effect size inflation and potential predictors or replicability. Results: We found a total of 89 eligible studies, of which 24 had valid replications. Of these, 21 (88%) had effect sizes with overlapping CIs. Of 15 highly cited studies with a statistically significant difference in the primary outcome, 13 (87%) had a significant effect in the replication as well. When both criteria were considered together, the replicability rate in our sample was 83%. When comparing effect sizes, there was little evidence of systematic inflation in these highly cited studies. Due to the small number of contradicted results, our analysis was underpowered to detect predictors of replicability. Conclusion: Although most studies did not have eligible replications, the replicability rate of highly cited clinical studies in our sample was higher than previous estimates, with little evidence of systematic effect size inflation.

Estimating the replicability of highly cited clinical research (2004-2018)

Diagnostic screening models for the interpretation of null hypothesis significance test (NHST) results have been influential in highlighting the effect of selective publication on the reproducibility of the published literature, leading to John Ioannidis’ much-cited claim that most published research findings are false. These models, however, are typically based on the assumption that hypotheses are dichotomously true or false, without considering that effect sizes for different hypotheses are not the same. To address this limitation, we develop a simulation model that overcomes this by modeling effect sizes explicitly using different continuous distributions, while retaining other aspects of previous models such as publication bias and the pursuit of statistical significance. Our results show that the combination of selective publication, bias, low statistical power and unlikely hypotheses consistently leads to high proportions of false positives, irrespective of the effect size distribution assumed. Using continuous effect sizes also allows us to evaluate the degree of effect size overestimation and prevalence of estimates with the wrong sign in the literature, showing that the same factors that drive false-positive results also lead to errors in estimating effect size direction and magnitude. Nevertheless, the relative influence of these factors on different metrics varies depending on the distribution assumed for effect sizes. The model is made available as an R ShinyApp interface, allowing one to explore features of the literature in various scenarios.

Are most published research findings false in a continuous universe?

Remembering is not a static process: when retrieved, a memory can be destabilized and become prone to modifications. This phenomenon has been demonstrated in a number of brain regions, but the neuronal mechanisms that rule memory destabilization and its boundary conditions remain elusive. Using two distinct computational models that combine Hebbian plasticity and synaptic downscaling, we show that homeostatic plasticity can function as a destabilization mechanism, accounting for behavioral results of protein synthesis inhibition upon reactivation with different reexposure times. Furthermore, by performing systematic reviews, we identify a series of overlapping molecular mechanisms between memory destabilization and synaptic downscaling, although direct experimental links between both phenomena remain scarce. In light of these results, we propose a theoretical framework where memory destabilization can emerge as an epiphenomenon of homeostatic adaptations prompted by memory retrieval.

Memory destabilization during reconsolidation: a consequence of homeostatic plasticity?

Thousands of systematic reviews are published every year. To conduct a systematic review,researchers spend hours of work extracting data from and about the individual papers that areincluded. This step often leads to the production of spreadsheets with structured data andmetadata about scientific publications, which are the basis for later steps in the project. Thesedatasets will often remain hidden in local folders and unavailable, despite the time invested inproducing them and their potential value. We argue that this is a great opportunity, where asmall amount of additional planning to make these intermediate datasets publicly available canbe valuable to the scientific community, while also allowing authors to be cited and recognized.

Scientists have increasingly recognised that low methodological and analytical rigour combined with publish-or-perish incentives can make the published scientific literature unreliable. As a response to this, large-scale systematic replications of the literature have emerged as a way to assess the problem empirically. The Brazilian Reproducibility Initiative is one such effort, aimed at estimating the reproducibility of Brazilian biomedical research. Its goal is to perform multicentre replications of a quasi-random sample of at least 60 experiments from Brazilian articles published over a 20-year period, using a set of common laboratory methods. In this article, we describe the challenges of managing a multicentre project with collaborating teams across the country, as well as its successes and failures over the first two years. We end with a brief discussion of the Initiative’s current status and its possible future contributions after the project is concluded in 2021.

Two years into the Brazilian Reproducibility Initiative: reflections on conducting a large-scale replication of Brazilian biomedical science

Aversive memories are at the heart of psychiatric disorders such as phobias and post-traumatic stress disorder (PTSD). Here, we present a new behavioral approach in rats that robustly attenuates aversive memories. This method consists of ‘deconditioning’ animals previously trained to associate a tone with a strong footshock by replacing it with a much weaker one during memory retrieval. Our results indicate that deconditioning-update is more effective than traditional extinction in reducing fear responses; moreover, such effects are long lasting and resistant to renewal and spontaneous recovery. Remarkably, this strategy overcame important boundary conditions for memory updating, such as remote or very strong traumatic memories. The same beneficial effect was found in other types of fear-related memories. Deconditioning was mediated by L-type voltage-gated calcium channels and is consistent with computational accounts of mismatch-induced memory updating. Our results suggest that shifting from fear to safety through deconditioning-update is a promising approach to attenuate traumatic memories.

The pressure for every research article to tell a clear story often leads researchers in the life sciences to exclude experiments that 'did not work' when they write up their results. However, this practice can lead to reporting bias if the decisions about which experiments to exclude are taken after data have been collected and analyzed. Here we discuss how to balance clarity and thoroughness when reporting the results of research, and suggest that predefining the criteria for excluding experiments might help researchers to achieve this balance.

Addressing selective reporting of experiments through predefined exclusion criteria

Comparing quality of reporting between preprints and peer-reviewed articles in the biomedical literature

Author response: Addressing selective reporting of experiments through predefined exclusion criteria

The Community of Open Scholarship Grassroots Networks (COSGN), includes 120 grassroots networks, representing virtually every region of the world and every research discipline. These networks communicate and coordinate on topics of common interest. We propose, using an NSF 19-501 Full-Scale implementation grant, to formalize governance and coordination of the networks to maximize impact and establish standard practices for sustainability. In the project period, we will increase the capacity of COSGN to advance the research and community goals of the participating networks individually and collectively, and establish governance, succession planning, shared resources, andcommunication pathways to ensure an active, community-sustained network of networks. By the end of the project period, we will have established a self-sustaining network of networks that leverages disciplinary and regional diversity, actively collaborates across networks for grassroots organizing, and shares resources for maximum impact on culture change for open scholarship.

NSF 19-501 AccelNet Proposal: Community of Open Scholarship Grassroots Networks (COSGN)

Meta‐analytic methods are powerful resources to summarize the existing evidence concerning a given research question and are widely used in many academic fields. Meta‐analyzes can also be used to study sources of heterogeneity and bias among results, which should be considered to avoid inaccuracies. Many of these sources can be related to study authorship, as both methodological heterogeneity and researcher bias may lead to deviations in results between different research groups. In this work, we describe a method to objectively attribute study authorship within a given meta‐analysis to different research groups by using graph cluster analysis of collaboration networks. We then provide empirical examples of how the research group of origin can impact effect size in distinct types of meta‐analyzes, demonstrating how non‐independence between within‐group results can bias effect size estimates if uncorrected. Finally, we show that multilevel random‐effects models using research group as a level of analysis can be a simple tool for correcting for authorship dependence in results.

Using collaboration networks to identify authorship dependence in meta‐analysis results

Background Preprint usage is growing rapidly in the life sciences; however, questions remain on the relative quality of preprints when compared to published articles. An objective dimension of quality that is readily measurable is completeness of reporting, as transparency can improve the reader’s ability to independently interpret data and reproduce findings. Methods In this observational study, we initially compared independent samples of articles published in bioRxiv and in PubMed-indexed journals in 2016 using a quality of reporting questionnaire. After that, we performed paired comparisons between preprints from bioRxiv to their own peer-reviewed versions in journals. Results Peer-reviewed articles had, on average, higher quality of reporting than preprints, although the difference was small, with absolute differences of 5.0% [95% CI 1.4, 8.6] and 4.7% [95% CI 2.4, 7.0] of reported items in the independent samples and paired sample comparison, respectively. There were larger differences favoring peer-reviewed articles in subjective ratings of how clearly titles and abstracts presented the main findings and how easy it was to locate relevant reporting information. Changes in reporting from preprints to peer-reviewed versions did not correlate with the impact factor of the publication venue or with the time lag from bioRxiv to journal publication. Conclusions Our results suggest that, on average, publication in a peer-reviewed journal is associated with improvement in quality of reporting. They also show that quality of reporting in preprints in the life sciences is within a similar range as that of peer-reviewed articles, albeit slightly lower on average, supporting the idea that preprints should be considered valid scientific contributions.

Aversive memories are at the heart of psychiatric disorders such as phobias and post-traumatic stress disorder (PTSD). Here, we present a new behavioral approach in rats that robustly attenuates aversive memories. This method consists of “deconditioning” animals previously trained to associate a tone with a strong footshock by replacing it with a much weaker one during memory retrieval. Our results indicate that deconditioning-update is more effective than traditional extinction in reducing fear responses; moreover, such effects are long lasting and resistant to renewal and spontaneous recovery. Remarkably, this strategy overcame important boundary conditions for memory updating, such as remote or very strong traumatic memories. The same beneficial effect was found in other types of fear-related memories. Deconditioning was mediated by L-type voltage-gated calcium channels and is consistent with computational accounts of mismatch-induced memory updating. Our results suggest that shifting from fear to safety through deconditioning-update is a promising approach to attenuate traumatic memories.

Shifting from fear to safety through deconditioning-update: a novel approach to attenuate fear memories

Freezing behavior is commonly used as a measure of associative fear memory. It can be measured by a trained observer, but this task is time-consuming and subject to variation. Commercially available software packages can also be used to quantify freezing; however, they can be expensive and usually require various parameters to be adjusted by the researcher, leading to additional work and variability in results. With this in mind, we developed Phobos, a freely available, self-calibrating software that measures freezing in a set of videos using a brief manual quantification performed by the user to automatically adjust parameters. To optimize the software, we used four different video sets with different features in order to determine the most relevant parameters, the amount of videos needed for calibration and the minimum criteria to consider it reliable. The results of four different users were compared in order to test intra- and interobserver variability in manual and automated freezing scores. Our results suggest that Phobos can be an inexpensive, simple and reliable tool for measurement of fear-related behavior, with intra- and interuser variability similar to that obtained with manual scoring.

A Freely Available, Self-Calibrating Software for Automatic Measurement of Freezing Behavior

Author response: Shifting from fear to safety through deconditioning-update

Decision letter: Four erroneous beliefs thwarting more trustworthy research

Meta-analytic methods are powerful resources to summarize the existing evidence concerning a given research question, and are widely used in many academic fields. However, meta-analyses can be vulnerable to various sources of bias, which should be considered to avoid inaccuracies. Many of these sources can be related to study authorship, as both methodological choices and researcher bias may lead to deviations in results between different research groups. In this work, we describe a method to objectively attribute study authorship within a given meta-analysis to different research groups by using graph cluster analysis of collaboration networks. We then provide empirical examples of how the research group of origin can impact effect size in distinct types of meta-analyses, demonstrating how non-independence between within-group results can bias effect size estimates if uncorrected. Finally, we show that multilevel random-effects models using research group as a level of analysis can be a simple tool for correcting biases related to study authorship.

Using collaboration networks to identify authorship bias in meta-analyses

Most efforts to estimate the reproducibility of published findings have focused on specific areas of research, even though science is usually assessed and funded on a regional or national basis. Here we describe a project to assess the reproducibility of findings in biomedical science published by researchers based in Brazil. The Brazilian Reproducibility Initiative is a systematic, multicenter effort to repeat between 60 and 100 experiments: the project will focus on a set of common methods, repeating each experiment in three different laboratories from a countrywide network. The results, due in 2021, will allow us to estimate the level of reproducibility of biomedical science in Brazil, and to investigate what aspects of the published literature might help to predict whether a finding is reproducible.

Decision letter: Releasing a preprint is associated with more attention and citations for the peer-reviewed article

Articles describing experimental data in the life sciences are meant to tell a clear story to the reader. This means that not every experimental attempt ends up published, as failed experiments and uninformative data are typically filtered out by researchers. Freedom to exclude data from an article, however, can lead to reporting bias when exclusion decisions are made after results are in. We discuss how to balance clarity and thoroughness in biomedical research reporting, and suggest that predefined criteria for experimental validity might help in solving this conflict.

Addressing selective reporting of experiments – the case for predefined exclusion criteria

Reconsolidation is a process in which re-exposure to a reminder causes a previously acquired memory to undergo a process of destabilisation followed by subsequent restabilisation. Different molecular mechanisms have been postulated for destabilisation in the amygdala and hippocampus, including CB1 receptor activation, protein degradation and AMPA receptor exchange; however, most of the amygdala studies have used pre-reexposure interventions, while those in the hippocampus have usually performed them after reexposure. To test whether the temporal window for destabilisation is similar across both structures, we trained Lister Hooded rats in a contextual fear conditioning task, and 1 day later performed memory reexposure followed by injection of either the NMDA antagonist MK-801 (0.1 mg/kg) or saline in order to block reconsolidation. In parallel, we also performed local injections of either the CB1 antagonist SR141716A or its vehicle in the hippocampus or in the amygdala, either immediately before or immediately after reactivation. Infusion of SR141716A in the hippocampus prevented the reconsolidation-blocking effect of MK-801 when performed after reexposure, but not before it. In the amygdala, meanwhile, pre-reexposure infusions of SR141716A impaired reconsolidation blockade by MK-801, although the time-dependency of this effect was not as clear as in the hippocampus. Our results suggest the temporal windows for CB1-receptor-mediated memory destabilisation during reconsolidation vary between brain structures. Whether this reflects different time windows for engagement of these structures or different roles played by CB1 receptors in destabilisation across structures remains an open question for future studies.

Different temporal windows for CB1 receptor involvement in contextual fear memory destabilisation in the amygdala and hippocampus

Prolonged increases in excitation can trigger cell‐wide homeostatic responses in neurons, altering membrane channels, promoting morphological changes, and ultimately reducing synaptic weights. However, how synaptic downscaling interacts with classical forms of Hebbian plasticity is still unclear. In this study, we investigated whether chronic optogenetic stimulation of hippocampus CA1 pyramidal neurons in freely moving mice could (a) cause morphological changes reminiscent of homeostatic scaling, (b) modulate synaptic currents that might compensate for chronic excitation, and (c) lead to alterations in Hebbian plasticity. After 24 hr of stimulation with 15‐ms blue light pulses every 90 s, dendritic spine density and area were reduced in the CA1 region of mice expressing channelrhodopsin‐2 (ChR2) when compared to controls. This protocol also reduced the amplitude of mEPSCs for both the AMPA and NMDA components in ex vivo slices obtained from ChR2‐expressing mice immediately after the end of stimulation. Finally, chronic stimulation impaired the induction of LTP and facilitated that of LTD in these slices. Our results indicate that neuronal responses to prolonged network excitation can modulate subsequent Hebbian plasticity in the hippocampus.

Chronic in vivo optogenetic stimulation modulates neuronal excitability, spine morphology, and Hebbian plasticity in the mouse hippocampus

Continuous excitation can trigger cell-wide homeostatic responses in neurons, altering membrane channels, promoting morphological changes and ultimately reducing synaptic weights. However, how synaptic downscaling interacts with classical forms of Hebbian plasticity is still unclear. In this study, we investigated whether chronic optogenetic stimulation of hippocampus CA1 pyramidal neurons in freely-moving mice could (a) cause morphological changes reminiscent of homeostatic scaling, and (b) lead to alterations in Hebbian plasticity. After 24 h of stimulation with 15-ms blue light pulses every 90 s, dendritic spine density was reduced in the CA1 region of mice expressing channelrhodopsin-2 (ChR2) when compared to controls. This protocol also impaired the induction of LTP and facilitated that of LTD in ex vivo slices obtained from ChR2-expressing mice immediately after the end of stimulation. Our results indicate that neuronal responses to prolonged network excitation can modulate subsequent Hebbian plasticity in the hippocampus.

Chronic in vivo optogenetic stimulation modulates Hebbian plasticity and spine density in the mouse hippocampus

With concerns over research reproducibility on the rise, systematic replications of published science have become an important tool to estimate the replicability of findings in specific areas. Nevertheless, such initiatives are still uncommon in biomedical science, and have never been performed at a national level. The Brazilian Reproducibility Initiative is a multicenter, systematic effort to assess the reproducibility of the country’s biomedical research by replicating between 60 and 100 experiments from Brazilian life sciences articles. The project will focus on a set of common laboratory methods, performing each experiment in multiple institutions across the country, with the reproducibility of published findings analyzed in the light of interlaboratory variability. The results, due in 2021, will allow us not only to estimate the reproducibility of Brazilian biomedical science, but also to investigate if there are aspects of the published literature that can be used to predict it.

The Brazilian Reproducibility Initiative: a systematic assessment of Brazilian biomedical science

Prolonged increases in excitation can trigger cell-wide homeostatic responses in neurons, altering membrane channels, promoting morphological changes and ultimately reducing synaptic weights. However, how synaptic downscaling interacts with classical forms of Hebbian plasticity is still unclear. In this study, we investigated whether chronic optogenetic stimulation of hippocampus CA1 pyramidal neurons in freely-moving mice could (a) cause morphological changes reminiscent of homeostatic scaling, (b) modulate synaptic currents that might compensate for chronic excitation, and (c) lead to alterations in Hebbian plasticity. After 24 h of stimulation with 15-ms blue light pulses every 90 s, dendritic spine density and area were reduced in the CA1 region of mice expressing channelrhodopsin-2 (ChR2) when compared to controls. This protocol also reduced the amplitude of mEPSCs for both the AMPA and NMDA components in ex vivo slices obtained from ChR2-expressing mice immediately after the end of stimulation. Lastly, chronic stimulation impaired the induction of LTP and facilitated that of LTD in these slices. Our results indicate that neuronal responses to prolonged network excitation can modulate subsequent Hebbian plasticity in the hippocampus.

Chronic in vivo optogenetic stimulation modulates neuronal excitability, spine morphology and Hebbian plasticity in the mouse hippocampus

Reconsolidation is a process in which re-exposure to a reminder causes a previously acquired memory to undergo a process of destabilisation followed by subsequent restabilisation. Different molecular mechanisms have been postulated for destabilisation in the amygdala and hippocampus, including CB1 receptor activation, protein degradation and AMPA receptor exchange; however, most of the amygdala studies have used pre-re-exposure interventions, while those in the hippocampus have performed them after re-exposure. To test whether the temporal window for destabilisation is similar across both structures, we trained Lister Hooded rats in a contextual fear conditioning task, and 1 day later performed memory re-exposure followed by injection of either the NMDA antagonist MK-801 (0.1 mg/kg) or saline in order to block reconsolidation. In parallel, we also performed local injections of either the CB1 antagonist SR141716A or its vehicle in the hippocampus or in the amygdala, either immediately before or immediately after reactivation. Infusion of SR141716A in the hippocampus prevented the reconsolidation-blocking effect of MK-801 when performed after re-exposure, but not before it. In the amygdala, meanwhile, pre-reexposure infusions of SR141716A impaired reconsolidation blockade by MK-801, although the time-dependency of this effect was not as clear as in the hippocampus. Our results suggest the temporal windows for CB1-receptor-mediated memory destabilisation during reconsolidation vary between brain structures. Whether this reflects different time windows for engagement of these structures or different roles played by CB1 receptors in destabilisation across structures remains an open question for future studies.

Different temporal windows for contextual fear memory destabilisation in the amygdala and hippocampus

Meta-analysis of protein synthesis inhibitors in fear conditioning

Supplementary Data: On the transdiagnostic nature of peripheral biomarkers in major psychiatric disorders: a systematic review

Proposals to increase research reproducibility frequently call for focusing on effect sizes instead of p values, as well as for increasing the statistical power of experiments. However, it is unclear to what extent these two concepts are indeed taken into account in basic biomedical science. To study this in a real-case scenario, we performed a systematic review of effect sizes and statistical power in studies using rodent fear conditioning, a widely used behavioral task to evaluate learning and memory. Our search criteria yielded 410 experiments comparing control and treated groups in 122 articles. Interventions with statistically significant differences had a mean effect size of 45.6%, and amnesia caused by memory-impairing interventions was nearly always partial. Mean statistical power to detect the average effect size observed in well-powered experiments (37.2%) was 65%, and was lower in studies with non-significant results. Only one article reported a sample size calculation, and our estimated sample size to achieve 80% power considering typical effect sizes and variances (15 animals per group) was reached in only 12.2% of experiments. Effect size correlated with textual descriptions of results only when findings were non-significant, and neither effect size nor power correlated with study quality indicators, number of citations or impact factor of articles. In summary, effect sizes and statistical power have a wide distribution in the rodent fear conditioning literature, but do not seem to have a large influence on how results are described or cited. Failure to take these concepts into consideration might limit attempts to improve reproducibility in this field of science.

Effect size and statistical power in the rodent fear conditioning literature – A systematic review

Retrieval of an associative memory can lead to different phenomena. Brief reexposure sessions tend to trigger reconsolidation, whereas more extended ones trigger extinction. In appetitive and fear cued Pavlovian memories, an intermediate “null point” period has been observed where neither process seems to be engaged. Here we investigated whether this phenomenon extends to contextual fear memory. Adult rats were subjected to a contextual fear conditioning paradigm, reexposed to the context 2 d later for 3, 5, 10, 20, or 30 min, with immediate injections of MK-801 or saline following reexposure, and tested on the following day. We observed a significant effect of MK-801 with the 3- and 30-min sessions, impairing reconsolidation and extinction, respectively. However, it did not have significant effects with 5-, 10-, or 20-min sessions, even though freezing decreased from reexposure to test. Further analyses indicated that this is not likely to be due to a variable transition point at the population level. In conclusion, the results show that in contextual fear memories there is a genuine “null point” between the parameters that induce reconsolidation and extinction, as defined by the effects of MK-801, although NMDA receptor-independent decreases in freezing can still occur in these conditions.

On the transition from reconsolidation to extinction of contextual fear memories

Resumo. A neurociencia e frequentemente usada como um argumento em diversos debates sobre saude mental, tais como a definicao de alguns comportamentos como patologicos. Para compreender como isto ocorre na midia brasileira, analisamos fatos neurocientificos mencionados em artigos sobre um diagnostico ainda controverso, a dependencia de jogos eletronicos e/ou internet. Dos 85 artigos localizados em 7 grandes veiculos de imprensa online, 25% faziam alusoes a neurociencia. A analise de dois fatos frequentemente mencionados (a similaridade das alteracoes cerebrais observadas nas dependencias de tecnologia e drogas e a liberacao de dopamina como mediador de recompensa e adicao a jogos eletronicos) demonstra inconsistencias entre as afirmacoes na midia e a evidencia empirica disponivel. No entanto, vieses semelhantes foram encontrados na propria literatura cientifica, sugerindo que interpretacoes relacionadas a existencia de um “cerebro dependente” em adicoes quimicas e comportamentais parecem ser favorecidas tanto entre jornalistas quanto entre cientistas. Palavras-chave. Dependencia; jogo eletronico; internet; neuroimagem; dopamina.

Constructing the dependent brain: an analysis of the Brazilian media and of the scientific literature on technology addiction

The concepts of effect size and statistical power are often disregarded in basic neuroscience, and most articles in the field draw their conclusions solely based on the arbitrary significance thresholds of statistical inference tests. Moreover, studies are often underpowered, making conclusions from significance tests less reliable. With this in mind, we present the protocol of a systematic review to study the distribution of effect sizes and statistical power in the rodent fear conditioning literature, and to analyze how these factors influence the description and publication of results. To do this we will conduct a search in PubMed for "fear conditioning" AND ("mouse" OR "mice" OR "rat" OR "rats") and obtain all articles published online in 2013. Experiments will be included if they: (a) describe the effect(s) of a single intervention on fear conditioning acquisition or consolidation; (b) have a control group to which the experimental group is compared; (c) use freezing as a measure of conditioned fear; and (d) have available data on mean freezing, standard deviation and sample size of each group and on the statistical significance of the comparison. We will use the extracted data to calculate the distribution of effect sizes in these experiments, as well as the distribution of statistical power curves for detecting a range of differences at a threshold of α=0.05. We will assess correlations between these variables and (a) the chances of a result being statistically significant, (b) the way the result is described in the article text, (c) measures to reduce risk of bias in the article and (d) the impact factor of the journal and the number of citations of the article. We will also perform analyses to see whether effect sizes vary systematically across species, gender, conditioning protocols or intervention types.

Protocol for a Systematic Review of Effect Sizes and Statistical Power in the Rodent Fear Conditioning Literature.

The search for biomarkers has been one of the leading endeavours in biological psychiatry; nevertheless, in spite of hundreds of publications, hardly any marker has proved useful in clinical practice. To study how biomarker research has progressed over the years, we performed a systematic review of the literature to evaluate (a) the most studied peripheral molecular markers in major psychiatric disorders, (b) the main experimental design features of studies in which they are proposed as biomarkers and (c) whether their patterns of variation are similar across disorders. An automated search revealed that, out of the six molecules most commonly present as keywords in articles studying plasmatic markers of schizophrenia, major depressive disorder or bipolar disorder, five (BDNF, TNF-alpha, IL-6, C-reactive protein and cortisol) were the same across the three diagnoses. An analysis of the literature on these molecules showed that, whilst 66% of original articles compared their levels between patients and controls, only 35% were longitudinal studies, and only 10% presented an evaluation of diagnostic efficacy, a pattern that has not changed significantly over two decades. Interestingly, these molecules varied similarly across the three disorders, suggesting them to be nonspecific systemic consequences of psychiatric illness rather than diagnostic markers. On the basis of this, we discuss how research fragmentation between diagnoses and publication practices rewarding positive findings may be directing the biomarker literature to nonspecific targets, and what steps could be taken to increase clinical translation in the field.

Promiscuity of peripheral molecular biomarkers in major psychiatric disorders: a transdiagnostic systematic review

Resumo. A divulgacao cientifica parece ser o instrumento ideal de comunicacao entre ciencia e sociedade. Com alto potencial para atrair o publico nao-especializado, busca-se diminuir a complexidade intrinseca do conhecimento cientifico. Contudo, ha um lado danoso do jornalismo cientifico, quando feito de forma descuidada ou sensacionalista. Neste artigo abordaremos as consequencias da ma divulgacao cientifica por meio da apresentacao de fatos e dados de pesquisas sobre o tema. Discutiremos alguns exemplos emblematicos de como pode ser nociva a circulacao de informacoes cientificas erroneas ou tendenciosas e abordaremos brevemente como minimizar estes problemas. Palavras-chave. Divulgacao cientifica; popularizacao da ciencia; divulgacao de neurociencias; ma divulgacao cientifica.

Effects of chronic optogenetic stimulation on Hebbian plasticity in the mouse hippocampus

On the transdiagnostic nature of peripheral biomarkers in major psychiatric disorders: A systematic review

Memory extinction involves the formation of a new associative memory that inhibits a previously conditioned association. Nonetheless, it could also depend on weakening of the original memory trace if extinction is assumed to have multiple components. The phosphatase calcineurin (CaN) has been described as being involved in extinction but not in the initial consolidation of fear learning. With this in mind, we set to study whether CaN could have different roles in distinct components of extinction. Systemic treatment with the CaN inhibitors cyclosporin A (CsA) or FK-506, as well as i.c.v. administration of CsA, blocked within-session, but not between-session extinction or initial learning of contextual fear conditioning. Similar effects were found in multiple-session extinction of contextual fear conditioning and in auditory fear conditioning, indicating that CaN is involved in different types of short-term extinction. Meanwhile, inhibition of protein synthesis by cycloheximide (CHX) treatment did not affect within-session extinction, but disrupted fear acquisition and slightly impaired between-session extinction. Our results point to a dissociation of within- and between-session extinction of fear conditioning, with the former being more dependent on CaN activity and the latter on protein synthesis. Moreover, the modulation of within-session extinction did not affect between-session extinction, suggesting that these components are at least partially independent.

Calcineurin inhibition blocks within-, but not between-session fear extinction in mice

The search for biological causes of mental disorders has up to now met with limited success, leading to growing dissatisfaction with diagnostic classifications. However, it is questionable whether most clinical syndromes should be expected to correspond to specific microscale brain alterations, as multiple low-level causes could lead to similar symptoms in different individuals. In order to evaluate the potential multifactoriality of alterations related to psychiatric illness, we performed a parametric exploration of published computational models of schizophrenia. By varying multiple parameters simultaneously, such as receptor conductances, connectivity patterns, and background excitation, we generated 5625 different versions of an attractor-based network model of schizophrenia symptoms. Among networks presenting activity within valid ranges, 154 parameter combinations out of 3002 (5.1%) presented a phenotype reminiscent of schizophrenia symptoms as defined in the original publication. We repeated this analysis in a model of schizophrenia-related deficits in spatial working memory, building 3125 different networks, and found that 41 (4.9%) out of 834 networks with valid activity presented schizophrenia-like alterations. In isolation, none of the parameters in either model showed adequate sensitivity or specificity to identify schizophrenia-like networks. Thus, in computational models of schizophrenia, even simple network phenotypes related to the disorder can be produced by a myriad of causes at the molecular and circuit levels. This suggests that unified explanations for either the full syndrome or its behavioral and network endophenotypes are unlikely to be expected at the genetic and molecular levels.

Multifactoriality in Psychiatric Disorders: A Computational Study of Schizophrenia.

A 66-year-old caucasian woman was admitted with a 40-day history of fatigue, anorexia, jaundice, itching and pale stools. She had undergone external percutaneous transhepatic drainage and had been treated for cholangitis with antibiotics. The patient had no palpable masses and her past medical history was unremarkable. Total bilirubin and liver enzymes were mildly elevated, and CBC was normal. Abdominal computed tomography showed a 4.0 x 0.5 cm tumor on the confluence of the right and left hepatic bile ducts with moderately dilated intrahepatic ducts. It also revealed a 2 cm tumor in the left kidney. Additional workup was negative for metastases. Laparotomy was performed and revealed a hardened mass involving the common bile duct from above the implantation of the cystic duct to the confluence of the right and left hepatic ducts. Resection of the biliary tree was then carried out from the supraduodenal portion of the common bile duct to the first 2 cm of the right and left hepatic ducts, with en-bloc regional lymphadenectomy. A Roux-en-Y jejunal loop was taken to the hepatic hilum and right, left and caudate bile ducts were sewn to a single jejunal loop. Macroscopic exam of the bile duct tumor revealed a 5.5x0.8cm surgical specimen that was firm and scirrhous tumor located on the confluence of the right and left hepatic ducts (Klatskin tumor). Bile duct confluence had a narrow lumen but no stones or mucin. Gallbladder had no stones or wall thickening. Pathology report revealed a poorly differentiated SRC hilar cholangiocarcinoma (UICC T4N0M0) with free proximal ABCDDV/1109 and distal margins and microscopically focally positive circumferential margins (Figure 1). Resected lymph nodes had no metastases.

Arquivos Brasileiros de Cirurgia Digestiva : ABCD = Brazilian Archives of Digestive Surgery

Established fear-related memories can undergo phenomena such as extinction or reconsolidation when recalled. Extinction probably involves the creation of a new, competing memory trace that decreases fear expression, whereas reconsolidation can mediate memory maintenance, updating, or strengthening. The factors determining whether retrieval will initiate extinction, reconsolidation, or neither of these two processes include training intensity, duration of the retrieval session, and age of the memory. However, previous studies have not shown that the same behavioral protocol can be used to induce either extinction or reconsolidation and strengthening, depending on the pharmacological intervention used. Here we show that, within an experiment that leads to extinction in control rats, memory can be strengthened if rolipram, a selective inhibitor of phosphodiesterase type 4 (PDE4), is administered into the dorsal hippocampus immediately after retrieval. The memory-enhancing effect of rolipram lasted for at least 1 week, was blocked by the protein synthesis inhibitor anisomycin, and did not occur when drug administration was not paired with retrieval. These findings indicate that the behavioral outcome of memory retrieval can be pharmacologically switched from extinction to strengthening. The cAMP/protein kinase A (PKA) signaling pathway might be a crucial mechanism determining the fate of memories after recall.

A phosphodiesterase 4-controlled switch between memory extinction and strengthening in the hippocampus

Memory labilization in reconsolidation and extinction – Evidence for a common plasticity system?

When 5-lipoxygenase (5-LO) is inhibited, roughly half of the CNS effect of the prototypic endocannabinoid anandamide (AEA) is lost. Therefore, we decided to investigate whether inhibiting this enzyme would influence physiological functions classically described as being under control of the endocannabinoid system. Although 5-LO inhibition by MK-886 reduced lipoxin A4 levels in the brain, no effect was found in the elevated plus maze (EPM), even at the highest possible doses, via i.p. (10 mg/kg,) or i.c.v. (500 pmol/2 µl) routes. Accordingly, no alterations in anxiety-like behavior in the EPM test were observed in 5-LO KO mice. Interestingly, aged mice, which show reduced circulating lipoxin A4 levels, were sensitive to MK-886, displaying an anxiogenic-like state in response to treatment. Moreover, exogenous lipoxin A4 induced an anxiolytic-like profile in the EPM test. Our findings are in line with other reports showing no difference between FLAP KO or 5-LO KO and their control strains in adult mice, but increased anxiety-like behavior in aged mice. We also show for the first time that lipoxin A4 affects mouse behavior. In conclusion, we propose an age-dependent relevancy of endogenous 5-LO derivatives in the modulation of anxiety-like behavior, in addition to a potential for exogenous lipoxin A4 in producing an anxiolytic-like state.

Age-Dependent Relevance of Endogenous 5-Lipoxygenase Derivatives in Anxiety-Like Behavior in Mice

P.1.j.024 Calcineurin inhibition has different effects on within- and between-session fear extinction in mice

TNF-α mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer's β-amyloid oligomers in mice and monkeys.

IN THE INTERVIEW WITH J. MERVIS (“ON TEACHing, tuition, and talent,” News Focus, 16 March, p. 1299), Association of American Universities (AAU) President Hunter Rawlings III puts forth the position that older faculty members should retire to make way for “the next generation to step forward.” His advocacy of “forced” retirement is out of step with reality. The socioeconomic model of retirement at 65 is no longer economically sustainable, and a substantial fraction of the “baby boom” generation have repeatedly indicated that they do not wish to retire. The scientifi c community should lead by example, demonstrating that people can and do make substantial contributions to their fi eld and to society even at an advanced age. The National Institutes of Health (NIH), AAU, and others should be concerned solely with funding the most promising projects. If there is a preponderance of support going to older researchers, it is hopefully because their projects appear to hold the most promise of signifi cant achievement and not simply because of the past track record of those applicants. NIH might also consider the possibility that the increasing average age of grant recipients simply refl ects the changing demographics of the United States in general. Simply forcing older investigators to retire will not ensure that younger investigators of greater or at least equal talent will replace them. NIH, AAU, and their partners should be focused on locating and promoting the most talented scientists, regardless of age or academic standing. ROY WILLIAMS

Journal impact factors have become an important criterion to judge the quality of scientific publications over the years, influencing the evaluation of institutions and individual researchers worldwide. However, they are also subject to a number of criticisms. Here we point out that the calculation of a journal’s impact factor is mainly based on the date of publication of its articles in print form, despite the fact that most journals now make their articles available online before that date. We analyze 61 neuroscience journals and show that delays between online and print publication of articles increased steadily over the last decade. Importantly, such a practice varies widely among journals, as some of them have no delays, while for others this period is longer than a year. Using a modified impact factor based on online rather than print publication dates, we demonstrate that online-to-print delays can artificially raise a journal’s impact factor, and that this inflation is greater for longer publication lags. We also show that correcting the effect of publication delay on impact factors changes journal rankings based on this metric. We thus suggest that indexing of articles in citation databases and calculation of citation metrics should be based on the date of an article’s online appearance, rather than on that of its publication in print.

The comments voiced by some scientists in response to Brian Nosek's project to systematically replicate studies in social psychology (“Psychology's bold initiative,” S. Carpenter, News Focus, 30 March, p. [1558][1]) are deeply worrisome. Reluctance to replicate data in a given field of science because it might harm the field's public image among other disciplines is symptomatic of a very dangerous logic. If such concerns are deemed valid, it seems natural to assume that scientists should also be worried about replicating their own labs' findings because of their standing among other laboratories, or that postdocs should not try to repeat experiments because it will make them look bad among their lab colleagues. The fact that this logic has spread among scientists is probably a large part of the reason why systematic replication studies have become so urgent in the first place. When the public image of a given field of science (or of science as a whole) becomes more important than establishing the truth of its findings in its value scale, one must conclude that something has gone awry along the way.

Transcriptional profiling of striatal neurons in response to single or concurrent activation of dopamine D2, adenosine A(2A) and metabotropic glutamate type 5 receptors: focus on beta-synuclein expression.

The processes of memory reconsolidation and extinction have received increasing attention in recent experimental research, as their potential clinical applications begin to be uncovered. A number of studies suggest that amnestic drugs injected after reexposure to a learning context can disrupt either of the two processes, depending on the behavioral protocol employed. Hypothesizing that reconsolidation represents updating of a memory trace in the hippocampus, while extinction represents formation of a new trace, we have built a neural network model in which either simple retrieval, reconsolidation or extinction of a stored attractor can occur upon contextual reexposure, depending on the similarity between the representations of the original learning and reexposure sessions. This is achieved by assuming that independent mechanisms mediate Hebbian-like synaptic strengthening and mismatch-driven labilization of synaptic changes, with protein synthesis inhibition preferentially affecting the former. Our framework provides a unified mechanistic explanation for experimental data showing (a) the effect of reexposure duration on the occurrence of reconsolidation or extinction and (b) the requirement of memory updating during reexposure to drive reconsolidation.

A Mismatch-Based Model for Memory Reconsolidation and Extinction in Attractor Networks

Scientific activity in Brazil has experienced an accelerated growth in the past decades, with an increase in productivity that greatly surpasses the international average. This growth has occurred mostly at the expense of centers of excellence in public universities, which account for the vast majority of the country's scientific output. The aim of this study was to evaluate the production of the Department of Biochemistry of a large public university in southern Brazil (Universidade Federal do Rio Grande do Sul), as well as to identify internal and external policies that have influenced this growing production profile. We have performed a historical analysis of the scientific output of this Department of Biochemistry, which accounts for a considerable share of the indexed scientific production at this university. By focusing on the temporal course of its growth and drawing correlations between scientific output and important events in the history of the Department of Biochemistry and of the Brazilian science policies, we concluded that internal factors (as the creation of a postgraduation program, collaboration among researchers, experienced abroad researchers, qualification of faculty members) and external factors (as investments in the postgraduate education, the establishment of national scientific policies, such as financial stimuli for productive researchers and evaluation systems) influence scientific productivity in Brazil.

37 years of scientific activity in a Biochemistry Department in Brazil: patterns of growth and factors leading to increased productivity.

Effects of low-dose d-serine on recognition and working memory in mice

Morphological changes in hippocampal astrocytes induced by environmental enrichment in mice

Molecular accounts of memory consolidation suggest that new learning generates persistent synaptic modifications through activation of an extensive set of neuronal receptors and intracellular signal transduction pathways, accompanied by RNA and protein synthesis. This traditional cellular consolidation theory has been challenged by evidence that reactivation of a previously consolidated memory might render this memory again susceptible to disruption by amnesic treatments, a process generally referred to as reconsolidation. Current evidence indicates that reconsolidation can be disrupted by administration of a variety of pharmacological agents after memory reactivation. Previous studies have indicated that the gastrin-releasing preferring type of bombesin receptor (GRPR) and the N-methyl-D-aspartate glutamate receptor (NMDAR) in the rat hippocampus are involved in consolidation of inhibitory avoidance (IA), a fear-related memory task. We show here that blockade of hippocampal GRPRs or NMDARs after memory reactivation temporarily disrupts memory retention. Post-retrieval intra-hippocampal infusion of the GRPR antagonist RC-3095 or the NMDAR antagonist aminophosphonopentanoic acid (AP5) produced an impairment of IA performance tested 2 days after training in rats. However, this impairment was transient and recovered to levels of control rats in a subsequent test 3 days after training. The drug effects were only present after memory reactivation and not in its absence. These findings provide evidence that GRPR or NMDAR inactivation after retrieval can impair fear memory.

Transient disruption of fear-related memory by post-retrieval inactivation of gastrin-releasing peptide or N-methyl-D-aspartate receptors in the hippocampus.

The gap between basic neuroscience and clinical psychiatry in the treatment of anxiety disorders has been steadily diminishing over recent years. Among the leading advances in this field of translation research is the application of knowledge on the neurobiology of fear memory to the treatment of anxiety disorders in humans. Animal studies have identified N-methyl-D-aspartate (NMDA) receptors as crucial in fear memory acquisition and consolidation, as well as in its extinction and reconsolidation. Based on this, the NMDA receptor partial agonist D-cycloserine, which facilitates fear extinction in rodents, has been shown to increase the effect of exposure therapy in psychiatric patients for conditions such as phobias, social anxiety and obsessive-compulsive disorder. In this article, we review current strategies for targeting the NMDA receptor in the treatment of fear-related disorders, analyzing experimental results, clinical data, and recent patents in the field, while also addressing potential new approaches to explore this field of drug discovery.

Plasma membrane diffusion of G protein-coupled receptor oligomers.

Duration of environmental enrichment influences the magnitude and persistence of its behavioral effects on mice

Detection of higher‐order G protein‐coupled receptor oligomers by a combined BRET–BiFC technique

The observation of memory recovery following post‐training amnestic interventions has historically caused controversy over the meaning of this finding, leading some authors to question the paradigm of a consolidation period for memories. Similarly, recent demonstrations of transient amnesia caused by interventions following memory reactivation have been used to question the existence of a retrieval‐driven reconsolidation process. The present work aims to approach the phenomenon of transient amnesia following disruptions of consolidation and reconsolidation, discussing how memory recovery might be explained within a framework of systems consolidation, persistent synaptic reinforcement, and multiple memory traces. With these concepts in mind, we propose that long‐term consolidation processes can underlie recovery from amnesia, demonstrating the feasibility of such a hypothesis in a two‐structure computational model of learning in which consolidation is dependent upon synaptic reentry reinforcement. On the basis of this, we suggest that prolonged consolidation can account for experimental findings of transient amnesia, in a way that explains differences between disruptions of consolidation and reconsolidation without the need to dwell into the discussion between storage‐ and retrieval‐based explanations for memory impairment. © 2008 Wiley‐Liss, Inc.

A synaptic reinforcement‐based model for transient amnesia following disruptions of memory consolidation and reconsolidation

Psychiatric disorders as social constructs: ADHD as a case in point.

Temporary inactivation of the dorsal hippocampus induces a transient impairment in retrieval of aversive memory

The series of disease mongering articles in the April 2006 issue of PLoS Medicine overall seem to define the term as “widening the boundaries of illness” [ 1] by “taking a normal function and implying that there's something wrong with it and that it should be treated” [ 2]. While there is undoubtedly a strong case to be made for this sort of practice by pharmaceutical companies, perhaps we should also question ourselves on what we mean by “disease boundaries.”

A simple webcam-based approach for the measurement of rodent locomotion and other behavioural parameters

Behavioral and genoprotective effects of Vaccinium berries intake in mice

Histoplasmosis of the central nervous system occurs in a significant percentage of patients with Histoplasma capsulatum infection, but has usually been described in association with immunosuppression and/or disseminated histoplasmosis. We aim to review the clinical and laboratory features of isolated histoplasmosis of the central nervous system in the immunocompetent host by presenting a series of 11 cases with this condition. Most of these patients presented with headache, meningeal irritation signs and mental status changes, comprising a somewhat different picture from that described in immunosuppressed patients. Moreover, almost all patients had signs of ventricular dilatation in neuroimaging studies, and 8 of the 11 patients had a ventriculoperitoneal shunt at the time of diagnosis, suggesting hydrocephalus to be an important feature of this condition and/or the possibility of shunt infection by the fungus. Immunodiffusion analysis of the cerebrospinal fluid appeared to be the most efficient way to reach the diagnosis and should be considered in immunocompetent patients with chronic lymphocytic meningitis, especially in those who have ventricular shunt or live in endemic areas of Histoplasma capsulatum.

Isolated central nervous system histoplasmosis in immunocompetent hosts: A series of 11 cases

Altered behavioural response to acute stress in mice lacking cellular prion protein

Eclampsia is defined as the occurrence of seizures and/or coma resulting from hypertensive encephalopathy on a background of preeclampsia (1). Eclampsia appears to be caused by a failure of the brain’s autoregulatory response to increases in blood pressure, leading to an increase in cerebral perfusion pressure with overperfusion injury similar to that observed in hypertensive encephalopathy (2)(3). Brain edema and hemorrhage ensue, as observed in imaging studies (4)(5), and there is evidence to suggest that these alterations can cause ischemia to brain cells. These events lead to neurologic symptoms (6), including seizures as well as cortical blindness, aphasia, limb weakness, psychosis, coma, and cerebrovascular accidents. Studies have analyzed various diagnostic methods, such as transcranial Doppler measurements, as a way to evaluate neurologic involvement in preeclampsia (3)(7). To date, however, there is no reliable laboratory marker to identify patients at risk for eclampsia or its related complications.

S100B is a 21-kDa protein physiologically produced and released primarily by astrocytes in the central nervous system (CNS), where it exerts neurotrophic and gliotrophic actions (8). Because ∼95% of S100B is located in the CNS, the results of several studies have suggested that an increase in S100B in blood and cerebrospinal fluid could be a potential marker of neural injury, indicating reactive gliosis, astrocytic death, and/or blood–brain barrier dysfunction. Accordingly, increased S100B concentrations in cerebrospinal fluid and/or blood have been reported in several pathologic conditions causing acute and chronic brain injury, such as head trauma (9), stroke (10), schizophrenia (11), and human T-lymphotropic virus type 1-associated myelopathy (12).

Some studies have also evaluated S100B as a marker of recent seizures. Although S100B has been shown to be increased in both cerebrospinal fluid and brain tissue of patients with temporal lobe epilepsy (13)(14), studies in which …

Serum S100B in pregnancy-related hypertensive disorders: a case-control study.

Changes in nucleotide hydrolysis in rat blood serum induced by pentylenetetrazol-kindling.

Benzodiazepines are among the most prescribed and consumed medication groups in the world. Although benzodiazepines are used in the treatment of several psychiatric and non-psychiatric disorders, and are generally safe and well-tolerated, the potential for misuse and abuse is considerable. This makes the study and regulation of benzodiazepine prescription and consumption an item of concern in public health around the world. Most developed countries have consistent data of benzodiazepine sales and consumption; however, data from developing countries is scarce, making health policies on the use of benzodiazepines a much tougher issue in these countries. This article aims to review the epidemiology of benzodiazepine use in Brazil, as well as to analyze how legislation, physician misinformation and economic factors might contribute to making benzodiazepine abuse a problem in the country.

Altered ATP Hydrolysis Induced by Pentylenetetrazol Kindling in Rat Brain Synaptosomes

Summary: Purpose: The physiologic role of the cellular prion protein (PrPc) is unknown. Mice devoid of PrPc develop normally and show only minor deficits. However, electrophysiologic and histologic alterations found in these mice suggest a possible role for PrPc in seizure threshold and/or epilepsy.

Increased Sensitivity to Seizures in Mice Lacking Cellular Prion Protein

( Discurso pronunciado durante la ceremonia de posesion como  Miembro Correspondiente Nacional de la Academia de  Historia de Santander, Bucaramanga, Mayo 13 de 2009). En 2006 paso casi desapercibido el cuadragesimo aniversario de la muerte de Jose Antonio Jacome Valderrama, una de las mentalidades medicas mas luminosas del pais en el siglo XX. Fallecido apenas al cumplir los 51 de su edad, su estrella brillo por 25 anos ascendiendo a las posiciones mas altas de la salud en Colombia. Por eso creimos, cuando se conmemoro el medio siglo del Colegio Medico de Santander, que nada hubiera sido mas oportuno que evocar la memoria de quien fuera no solo fundador y alto exponente de la Federacion Medica Colombiana (de la que recibio su maxima condecoracion en 1963) sino incondicional estandarte de su tierra, de sus valores y de su gente. Nacido en Bucaramanga el 16 de febrero de 1915, su madre fue una de esas nueve bellas mujeres que unieron sus genes con los de los varones mas ilustres y de mayor raigambre dentro de la sociedad santandereana. El mismo relato asi algunas de las circunstancias de su nacimiento :  “Soy hijo de Jose Domingo Jacome Niz y Matilde Valderrama de Jacome Niz, ambos ya fallecidos, a quienes debo tanto por la educacion que me dieron, por el ejemplo admirable que me ofrecieron, por la formacion moral con que forjaron mi espiritu y mi corazon y sobre todo por el amor entranable y cordial que hizo de nuestro hogar un sitio lleno de felicidad, a pesar de todas las vicisitudes que tuvimos que soportar” .1 1 Los Jacome Niz provenian de Ocana, ciudad que desde la colonia mantuvo vinculos con Bucaramanga, por el relativamente cercano acceso de ambas al rio Magdalena, en contraste con las fragorosas montanas que habia que cruzar desde cada una de ellas para llegar a Cucuta y a la frontera venezolana. En sus viajes entre una y otra, ya para finalizar el siglo XIX, los tres hermanos Jacome se dieron cuenta de la importancia que tenia la via fluvial para el comercio de importaciones o exportaciones a traves del Magdalena.

PATHOGENESIS OF HEPATIC ENCEPHALOPATHY - A ROLE FOR THE BENZODIAZEPINE RECEPTOR ?

Summary: Purpose: The physiologic role of the cellular prion protein (PrP') is unknown. Mice devoid of PrPC develop nor- mally and show only minor deficits. However, electrophysi- ologic and histologic alterations found in these mice suggest a possible role for PrP" in seizure threshold andor epilepsy. Methods: We tested the sensitivity of PrP" knockout mice to seizures induced by single convulsant or repeated subconvul- sant (kindling) doses of pentylenetetrazol (PTZ), and to status epilepticus (SE) induced by kainic acid or pilocarpine. Results: In PTZ kindling, seizure severity progressed faster in the PrP' knockout group, in which 92.8% reached stage 5 or death after 4 days of stimulation, as opposed to 38.4% in wild- type animals. After 10 injections, mortality was 85.7% among knockouts and 15.3% among controls. After a single PTZ in- jection (60 mgkg), overall mortality due to seizures was 91 % in knockout mice, but only 33% among wild-type animals. Pilocarpine-induced SE (320 mgkg) caused an 86.7% mortal- ity in knockouts, as opposed to 40% in wild-type animals. Finally, after kainic acid injections (10 mgkg), 70% of the knockouts developed at least one severe seizure, and 50% showed repetitive seizures, whereas

Rapid Communication Increased Sensitivity to Seizures in Mice Lacking Cellular Prion Protein

Dose-dependent impairment of inhibitory avoidance retention in rats by immediate post-training infusion of a mitogen-activated protein kinase kinase inhibitor into cortical structures

EFFECTS OF KINDLING ON PERFORMANCE AND RETENTION OF AN INHIBITORY AVOIDANCE TASK IN RATS

Anais do(a) Anais da Jornada Giulio Massarani de Iniciação Científica, Tecnológica, Artística e Cultural

Identificando Potenciais Preditores de Replicabilidade de Experimentos na Iniciativa Brasileira de Reprodutibilidade

Avalição do índice de resposta e informações obtidas por autores originais de experimentos na Iniciativa Brasileira de Reprodutibilidade

Avaliação do papel do fator de crescimento derivado de células gliais no aprendizado da tarefa de esquiva inibitória

Efeito facilitatório do MK-801 e propranolol sobre consolidação e reconsolidação da memória de reconhecimento de objeto em camundongos

Efeito de crises convulsivas agudas induzidas por pentilenetetrazol (PTZ) sobre as atividades de ectonucleotidases em soro de ratos adultos

Efeito do tratamento crônico com lítio nos níveis de beta-tubulina III no modelo de convulsão em ratos

Efeitos do knockout da proteína príon celular sobre a sensibilidade a convulsões em camundongos transgênicos

Efeitos da infusão intrahipocampal de Fibroblast growth factor sobre as memórias de curta e longa duração na tarefa de esquiva inibitória

Hepatic encephalopathy (HE) is a multifactorial syndrome in which the function of the central nervous system is impaired due to the metabolic consequences of liver disease. The two main components of liver pathology which lead to HE are the decrease in the number of functioning hepatocytes and the vascular rearrangement causing blood from the portal vein to bypass the liver. The symptoms of HE range from mild cognitive impairment to deep coma. Some degree of neuronal loss may be found in HE patients as a consequence of chronic cirrhosis and, in advanced HE, of brain edema; however, most of the HE syndrome is reversible with compensation of the liver disease. The pathogenesis of HE is not fully understood and  is likely to be multifactorial. The initial theories implicated accumulation of neurotoxins leading to an impairment of neuronal function. With better understanding of the physiology of neuroreceptors, abnormalities in several neurotransmission systems have been put forward as potential causes of HE, such as a reported increase in GABAergic neurotransmission. There is evidence that this enhancement is related to an increase in the potentiation of GABAergic action by ligands to the benzodiazepine receptor (BZR), which are known to be increased in liver disease. With this evidence in mind, therapy with the benzodiazepine antagonist flumazenil has been attempted in HE, yielding clinical benefit in a variable percentage of patients in recent studies. However, there is still a lack of evidence to support a causal relationship between increased levels of benzodiazepine agonist ligands and HE symptoms. It is feasible to think that this relationship exists in some but not all HE patients.

Patogênese da encefalopatia hepática: um papel para os receptores de benzodiazepínicos?

Avaliação do déficit de memória induzido pelo kindling por PTZ em ratos numa tarefa de esquiva inibitória

125  Estimating the replicability of highly cited clinical research between 2004 and 2018

Neuroscience is frequently used as an argument in various debates on mental health, such as the definition of some behaviors as pathological. To understand how this happens in the Brazilian media, we analyzed neuroscientific facts mentioned in articles about a controversial diagnosis: internet and or/video gaming addiction. Of 85 articles located in web searches of seven major press vehicles, 25% made allusions to neuroscience. The analysis of two frequently mentioned facts (the similarity between cerebral alterations observed in drug and technology addictions and the release of dopamine as a mediator of reward and addiction to video games) showed inconsistencies between media claims and the available empirical evidence. However, similar biases were already observable in the scientific literature itself, suggesting that the theory of a “dependent brain” in behavioral and chemical addictions seems to be favored by both journalists and scientists.

A construção do cérebro dependente: uma análise da mídia brasileira e da literatura científica sobre adição a tecnologias

O objetivo deste trabalho refere-se a um relato das atividades desenvolvidas pelos bolsistas, junto ao Programa de Iniciação à Docência (PIBID), do curso de Licenciatura em Física do Instituto Federal de Educação, Ciência e Tecnologia do Rio Grande do Norte – IFRN/Campus João Câmara. O trabalho se caracteriza como um relato de atividades, vivenciada por um grupo de licenciandos - bolsistas PIBID - buscando discutir as potencialidades do PIBID para a formação inicial de professores de Física. O desenvolvimento das atividades do PIBID partiu de um conhecimento do contexto escolar, seguido por observação de aulas de Física e, finalmente, intervenção em sala de aula, trazendo estratégias de ensino de maneiras diversificadas. Mostrando em sua fundamentação a importância do PIBID dentro do âmbito escolar, pois está convivendo com toda comunidade escolar, nos torna verdadeiros educadores dentro do ensino de Física.

Contribuições do PIBID para a formação inicial de professores de Física: aplicação da oficina projetor de celular

Resumo Neste artigo apresentamos o Centro de Memória da Paróquia de Nossa Senhora da Conceição e da Irmandade Nossa Senhora da Conceição, da Freguesia de Vassouras, a partir da organização dos livros de registros e processos de matrimônio e administrativos desta Freguesia criada em 1837. Justificamos a necessidade da criação deste espaço de pesquisa, devido ao número crescente de pesquisas científicas relacionadas ao Vale do Paraíba Fluminense nas duas últimas décadas, especialmente sobre a cidade de Vassouras-RJ. Para inclusão de documentos inéditos no Acervo, aplicamos a mesma metodologia desenvolvida pelo Centro de Documentação Histórica da Universidade Severino Sombra (CDH/USS), uma vez que a codificação da documentação já foi citada em trabalhos de pesquisa durante o tempo em que ficou no CDH e posteriormente no IPHAN. O principal embasamento teórico está em Michel Foucault e Jacques Le Goff, que “a partir do modo como se fez no século XX a crítica da noção do facto histórico, que não é um objeto que surge concluído visto resultar da construção do historiador, assim se faz hoje a crítica da noção de documento, que não é um documento bruto, objetivo e inocente, mas que exprime o poder da sociedade do passado sobre a memória e o futuro: o documento é um monumento”. E completam que “o próprio arquivo dos documentos sofreu uma revolução com o recurso ao computador”. Com principal resultado temos a disponibilização do acervo online e a garantia desse acesso para pesquisadores e interessados na história desta região do Vale do Paraíba Fluminense. Palavras-chave: Preservação. Metodologia de Organização de Acervo. Igreja Católica.

O presente artigo tem como objectivo analisar o impacto do Covid-19 no sector de Turismo, com incidência para o papel dos transportes aéreos nesse processo. O espaço escolhido para a análise é Moçambique, um país em desenvolvimento, situado na África Austral de onde se elegeu um recorte espacial constituído pelos municípios de Maputo, Inhambane, Vilanculos e Pemba. Para o alcance do objectivo proposto, a opção foi por uma metodologia mista quali-quantitativa, multi-escalar, tendo-se recorrido, para a recolha de dados a revisão bibliográfica e documental e a entrevista, segundo um guião elaborado para o efeito. Os resultados do estudo revelam que o sector de turismo foi muito afectado pela pandemia, tanto de forma directa, com uma redução drástica do número de visitantes como consequência directa da pandemia, mas e sobretudo pela redução do número de voos por decisão, tanto dos países emissores como, mais tarde pelas autoridades de Moçambique. Ora, reduzindo, ao mínimo as possibilidades de movimentação internacional e nacional, os empreendimentos turísticos (alojamento e restaurantes) vêem desaparecer a sua principal fonte de renda. Assim, assistiu-se ao encerramento ou a redução de actividades de muitos empreendimentos com impactos, económicos e sociais negativos percebidos por todos os actores ou agentes do turismo.

Os resultados do PISA demostram um baixo desempenho em relação ao ensino de matemática e, com o objetivo de melhoria, foi criada a OBMEP. Essa competição dispõe de problemas ricos em conceitos que, além de desafiadores, exigem bastante criatividade. Desse modo, pretendemos usar, neste artigo, uma Situação Didática Olímpica como proposta de ensino para a sala de aula, utilizando os pressupostos da Teoria das Situações Didáticas para ensinar geometria plana por meio de Problemas Olímpicos. Adotamos como teoria de ensino a Teoria das Situações Didáticas (TSD) aplicada a Problemas de Olimpíadas de Matemática, que se denomina como Situações Didáticas Olímpicas, além de contar com o auxílio do GeoGebra para as resoluções dos estudantes. A metodologia de pesquisa baseia-se em uma revisão bibliográfica a partir de autores, como Santos e Alves, Azevedo, Alves e Oliveira, Alves, Almouloud e Brousseau. Essa proposta de uma sequência didática com o uso de uma ferramenta tecnológica dará aos alunos subsídios para a construção do conhecimento e a possibilidade da dinamização e visualização dos conceitos, contribuindo em seu aprendizado e autonomia.
Palavras-chave: OBMEP; teoria das situações didáticas; situações didáticas olímpicas; problema olímpico; GeoGebra.

O artigo tem como objetivo analisar a produção científica internacional sobre o novo coronavírus (COVID-19) na perspectiva das ciências sociais e naturais, visando compreender as características das publicações científicas. Como procedimento metodológico foi realizado uma análise Bibliométrica, por meio de métodos bibliométricos como técnicas avaliativas, técnicas relacionais utilizando o programa VOSviewer. O protocolo de pesquisa consistiu em análise de artigos referentes às temáticas da COVID-19 no contexto das áreas de Ciências sociais e Naturais, a partir da base de dados Web of Science abrangendo o ano de 2020. Foram executadas duas etapas de filtragem. Na primeira optou-se por manter como tipos de documentos apenas artigos científicos no idioma inglês e, na segunda, procedeu-se a inclusão de áreas de pesquisa dentro do escopo da temática em estudo, totalizando, ao final, 379 artigos. A etapa seguinte constituiu-se de avaliação relacionada às áreas de pesquisa, periódicos, países, referências com maior número de citação e estudos mais relevantes do fator H (H-index). O uso do software VosViewer possibilitou a organização de grupos (cluster) baseados em cocitação e as redes de coocorrências de palavras-chave. Os resultados demonstram em termos avaliativos, que as instituições mais influentes nas pesquisas relacionadas a pandemia da COVID-19 estão concentradas em países como China (22,9%) do universo, seguidas por Itália, Estados Unidos, Inglaterra, Canadá, Austrália, Índia, Espanha, Brasil e Alemanha. Os periódicos mais relevantes em termos de publicação, dos 51 periódicos identificados, são: International Journal of Environmental Research and Public Health e Science of the Total Environment, A obra de referência é   Immediate Psychological Responses and Associated Factors during the Initial Stage of the 2019 Coronavirus Disease (COVID-19) Epidemic among the General Population in China‎. O mapa de palavras-chave apresentou o coronavírus como tema central do mapa seguido por termos como surto, confinamento, mortalidade, saúde pública, China, crise, risco, gestão, modelo, desempenho, comportamento, resiliência, incerteza, saúde metal, ansiedade, infecção, conhecimento, depressão, impacto psicológico e estresse. Além disso, também realizou-se uma análise nas obras consideradas referência na rede de citações, destacando os principais propósitos e/ou resultados de cada estudo. Evidenciando, portanto, a emergência e relevância do tema e como este vem sendo explorado.

A Tessitura Analítica Bibliométrica da Produção Internacional da COVID-19 no contexto das áreas de Ciências Sociais e Naturais

A procura crescente por alimentos seguros tem resultado em uma necessidade das indústrias se adequarem às normas estabelecidas para garantir produtos de qualidade que não ofereçam riscos à saúde dos consumidores. Diversos são os fatores que podem influenciar na qualidade do leite e podem torná-lo um produto impróprio para o consumo humano, como fatores físicos, químicos ou biológicos, os quais poderão contaminar o leite em decorrência de falhas na sua obtenção, no seu processamento ou expedição. Dessa forma, é essencial que estabelecimentos produtores/industrializadores de alimentos obtenham excelentes percentuais de conformidades no que diz respeito às Boas Práticas de Fabricação (BPF), as quais são medidas que devem ser implementadas por indústrias alimentícias com o intuito de garantir os requisitos necessários para a produção de alimentos seguros. O presente trabalho teve como objetivo avaliar a aplicação das BPF, em usinas de beneficiamento de leite caprino, na região do Cariri paraibano. Foram visitadas quatro usinas de beneficiamento, denominadas de A, B, C e D, sendo verificadas se estão de acordo com as normas de BPF´s. A partir da análise observacional realizada, foi constatado que, dos quatro estabelecimentos estudados apenas as usinas de beneficiamento A e C foram classificadas em grupo 1, sendo considerada de baixo risco à segurança alimentar, e as usinas B e D, por sua vez, foram enquadradas no grupo 2, as quais ofereciam médio risco à segurança alimentar. Foram observadas não conformidades em todos os cinco quesitos da lista, em todos os estabelecimentos, sendo descritas falhas nas edificações, falta de produtos relacionados a higiene pessoal, presença de pragas no interior da indústria, e principalmente, o não cumprimento de alguns Procedimentos de Operações Padronizados. O presente estudo demonstrou que as usinas B e D deverão melhorar seus níveis em relação as BPF’s, tanto para atender os requisitos da legislação vigente, como para oferecer produtos mais seguros aos seus consumidores, tendo em vista o grande número de não conformidades observadas nesses estabelecimentos. Também se faz necessária uma fiscalização mais efetiva dos órgãos competentes para garantir que os estabelecimentos se adequem a todos os quesitos das BPF’s, evitando assim o risco da veiculação de doenças alimentares aos consumidores, desperdícios de matéria-prima bem como prejuízos financeiros para o estabelecimento.

Análise de boas práticas de fabricação em usinas de beneficiamento de leite caprino no Cariri

O Brasil tem crescido bastante no segmento cervejeiro com as grandes fabricantes e com as cervejarias artesanais que surgem constantemente no mercado. Porem, o gasto de agua em uma industria cervejeira pode ser de 4a 10 vezes em relacao ao volume de cerveja produzida. Diante da grande quantidade de agua necessaria na producao de cerveja o trabalho teve como objetivo verificar se o uso da agua na producao de cerveja e sustentavel, tomando como parâmetro o preco implantado aos utilizadores e os custos pela utilizacao. Dois metodos de avaliacao foram adotados, a construcao de uma funcao de producao e a avaliacao da predisposicao a pagar pela agua na producao.Concluiu-se que ah um investimento em tecnologias pelas principais fabricas de cerveja para preservacao dos recursos naturais especialmente a agua e que a propensao a pagar pelo recurso e tratada a partir dos discursos dos representantes como ja sendo feito a partir dos investimentos em tecnologias para maior impactar no meio ambiente e diminuicao das externalidades negativas.

Custos da água na produção de cerveja: Uma análise econômica comparativa

A pesquisa foi desenvolvida na Escola Nossa Senhora da Soledade, Município de Moju-Pará, e propunha articular questões teóricas e ações sobre educação ambiental com lixo envolvendo a perspectiva dos (6rs) que são: reduzir, reutilizar, reciclar, repensar, recuperar, recusar. Procurou-se identificar que vertente teórica de educação ambiental se enquadra a Escola Nossa Senhora Da Soledade, e como professores e alunos têm desenvolvido suas ações na Escola pública da Zona rural de Moju. A metodologia constou de levantamento bibliográfico e documental sobre o tema Educação Ambiental e suas práticas; uso de geoprocessamento e sensoriamento remoto para elaboração de mapas de localização e contexto da Escola, além da aplicação de questionários para entrevista de funcionários e alunos para coletar dados sobre a viabilidade de aplicação de ações envolvendo os 6rs, e avaliar existe diálogo da Escola com os problemas ambientais estruturais na comunidade. O estudo é importante para que a visão do descarte do lixo seja feita de forma correta até o seu destino final. Conclui-se de maneira teórica que a educação ambiental desenvolvida na Escola é uma EA conservadora com crianças dentro do ambiente escolar, propondo ações individuais e comportamentais de forma a-histórica, a política, conteudista e normativa que não superariam o paradigma hegemônico. Apesar da proposição dos 6rs a Escola apresenta um contexto ambiental complexo com presença de lixão a céu aberto e contaminação dos recursos hídricos, sem estrutura alguma de eficiência do projeto uma vez que não existe nenhuma cooperativa de reciclagem e empresas interessadas no aproveitamento dos resíduos sólidos.

Anais do(a) Anais da Semana de Enfermagem: O trabalho em enfermagem no contexto de crise

A ENFERMAGEM FORENSE NO ATUAL CENÁRIO DA SAÚDE – UMA REVISÃO DA LITERATURA

O presente artigo realizou uma analise tecnica sobre uma area declarada de conflitos pelos usos de recursos hidricos, na bacia hidrografica do corrego dos Quatis, localizada no municipio de Itueta, Minas Gerais e teve como principal objetivo analisar o conflito pelo uso da agua identificado no local. A pesquisa foi embasada no documento de Analise de Conflito pelo Uso da Agua (ACUA) no 01/2019, cedido pelo Instituto Mineiro de Gestao das Aguas (IGAM), com informacoes relativas a usuarios outorgados e de usos insignificantes, vazoes da bacia, relacoes demanda x disponibilidade, e mapa de uso e ocupacao do solo. Os resultados obtidos pelo ACUA retornaram valores de deficit hidrico na relacao demanda x disponibilidade, alem de estarem apoiados no mapa de uso e ocupacao do solo com usos voltados principalmente a irrigacao; e as solucoes encontradas para o conflito ficaram relacionadas a instituicao de uma Comissao Gestora Local e a elaboracao do termo de alocacao de agua para a outorga coletiva. Por fim, alem das solucoes apontadas para minimizar ou resolver o conflito, foram indicadas outras iniciativas relacionadas a projetos ambientais para aumentar o potencial hidrico da regiao.

Conflitos na gestão de recursos hídricos no Estado de Minas Gerais: Estudo de caso da Bacia Hidrográfica do córrego dos Quatis, Itueta – Minas Gerais, Brasil

Resumo: Compreende-se que a geometria é de fundamental importância para o desenvolvimento de habilidades necessárias a percepção e a visualização do espaço no qual estamos inseridos. Além de possibilitar o desenvolvimento de conhecimentos relacionados a outras áreas, sejam elas próximas a matemática ou não, possuindo muitas aplicações no mundo real e sendo rica em possibilidades de exploração, representação e construção. Dentre os conteúdos da disciplina de matemática, a geometria é considerada de suma importância para a formação intelectual do educando, mas nem sempre assuntos relacionados a ela são abordados pelos docentes. Iniciativas como essas fazem com que os alunos sintam dificuldade na resolução de problemas relacionados à geometria em seu cotidiano. Motivado por tais convicções este trabalho tem como objetivo mostrar que o ensino nesta área pode ser aperfeiçoado, partindo do pressuposto de que as construções, proporcionadas pelo desenho geométrico, devem ser resgatadas em sala de aula. Também se propõe a investigar como a aprendizagem dos conceitos geométricos está sendo desenvolvida na escola de nível fundamental, considerando a construção histórica até os dias atuais, bem como as dificuldades enfrentadas no âmbito escolar para aplicação e trabalho com tais conceitos. Para tanto foi realizada uma pesquisa bibliográfica, com levantamento de literaturas que investigam tal temática. Frente à pesquisa desenvolvida, confirma-se a desvalorização do ensino da geometria e as dificuldades enfrentadas pelos alunos na tentativa de entenderem conceitos desvinculados da prática, sendo proposto o trabalho com construções realizadas a partir do resgate do desenho geométrico em sala de aula, como forma de incentivo ao trabalho com a geometria. Palavras Chave: Geometria, Aprendizagem da geometria, Desenho geométrico.

GEOMETRIA NA ESCOLA DE NÍVEL FUNDAMENTAL: DESENHO GEOMÉTRICO COMO UMA PROPOSTA DE ENSINO E APRENDIZAGEM

Uso dos recursos computacionais como ferramenta de apoio aos discentes da rede pública municipal de São João da Serra-PI

Visita domiciliar como estratégia de promoção da saúde na atenção primária à saúde: revisão integrativa (1a Edição)

Análise Econômica da Crise: A Corrida Pela Produção da Vacina Ante a Pandemia do Covid-19

Esse escrito tem o objetivo de apresentar uma Situação Didática Olímpica sob a perspectiva da Teoria das Situações Didáticas aos professores que ensinam matemática. Estruturamos nossa pesquisa com base nas etapas da Engenharia Didática, no entanto, por ter um direcionamento à formação inicial do professor de Matemática, utilizamos a terminologia Engenharia Didática de Formação. Além disso, a situação didática foi estruturada sob a perspectiva da Teoria da Situação Didáticas. A Experimentação ocorreu no curso de Matemática da Universidade Estadual Vale do Acaraú por intermédio da plataforma Google Meet, de modo Remoto, com professores licenciandos do curso de Matemática da Universidade Estadual Vale do Acaraú – UVA, Sobral, Ceará, Brasil e atuam como professores orientadores do Programa de Iniciação Científica Júnior – PIC. Os dados coletados foram baseados nas etapas da Teoria das Situações Didáticas e validadas por intermédio da Engenharia Didática de Formação, por intermédio do confronto da Análise a priori e Análise a posteriori (validação interna). Concluímos que o software GeoGebra foi bastante útil no auxílio à resolução da situação didática proposta, por meio da visualização e da dinamização da figura e que o problema permitiu aos licenciandos a vivenciarem as etapas da Teoria das Situações Didáticas percorrendo um caminho análogo ao de um matemático na construção do conhecimento.

Situação Didática Olímpica sob a perspectiva da Teoria das Situações Didáticas: uma aplicação com professores em formação inicial no Brasil

Este artigo apresenta uma discussao teorica que emergiu, sobretudo, das leituras da obra de Harari (2018), apoiado nos estudos de Santaella (2019), expostos em palestra durante o XII Simposio ABCiber, intitulada “Do Pos-humano ao Neo-humano: a setima revolucao comunicacional-cognitiva do sapiens” e de Morin (2018); alem das discussoes no Grupo de Estudos e Pesquisa em Informatica Educativa (GEPIED). O objetivo foi analisar, de acordo com o pensamento dos autores citados, os efeitos dos avancos tecnologicos sobre a vida das pessoas e como devemos estar atentos aos acontecimentos, no sentido de podermos nos educar para intervir sobre eles, de modo que o genero humano tenha relevância diante das transformacoes que poderao trazer riscos a propria existencia e a do planeta.

O sapiens frente ao colapso ideológico e as revoluções gêmeas da tecnologia da informação e da biotecnologia / Sapiens facing ideological collapse and the twin revolutions of information technology and biotechnology

RELATO DE EXPERIÊNCIA DO ESTÁGIO SUPERVISIONADO OBRIGATÓRIO EM QUÍMICA REALIZADO EM UMA ESCOLA DA REDE PÚBLICA DE ENSINO

EDUCAÇÃO A DISTÂNCIA: UMA APRENDIZAGEM COOPERATIVA NA IMPLANTAÇÃO DE ESCOLAS DE TEMPO INTEGRAL NO RECIFE.

Educação enquanto fenômeno social: Democracia e emancipação humana 3

CURRÍCULO E FORMAÇÃO DAS IDENTIDADES: UM ESTUDO SOBRE O PROJETO POLÍTICO PEDAGÓGICO DO CURSO DE MEDICINA DA UFRR

Resumo: O objetivo deste escrito foi apresentar dados parciais de uma investigação que trata do uso de Situações Didáticas Olímpicas (SDO) para o ensino de geometria plana. Destacamos que esses Problemas Olímpicos (PO), os quais possibilita o aluno agir, formular e validar os conhecimentos/saberes matemáticos, são denominados Situações Didáticas Olímpicas (SDO) e representados pela expressão SDO = PO + TSD. Utilizamos a metodologia Engenharia Didática de Formação (EDF) por ter como sujeitos licenciandos do curso de Matemática da Universidade Estadual Vale do Acaraú (UVA) e professores orientadores do Programa de Iniciação Científica Jr, os quais foram submetidos a Situações Didáticas Olímpicas (a proposta didática) em um ambiente de formação inicial e/ou continuada, pela plataforma Google Meet e por intermédio do ensino remoto devido à pandemia do coronavírus (COVID-19). Para a coleta de dados, baseamo-nos nas etapas da Teoria das Situações Didáticas e nos pressupostos da EDF. Os resultados parciais demostraram que a referida proposta pode ser utilizada para o ensino de conceitos de geometria plana em sala de aula, junto à contribuição do GeoGebra na visualização e dinamização das figuras e na formação dos sujeitos participantes.

Situações Didáticas Olímpicas (SDO): uma aplicação de Problemas Olímpicos (PO) à luz da Teoria das Situações Didáticas (TSD) com apoio do software GeoGebra

Resumo: Platão, no diálogo Sofista, argumenta que a vergonha tem a capacidade de fazer que um indivíduo mude sua opinião. Além disso, a vergonha não opera apenas uma mudança qualquer, mas o abandono de uma opinião falsa, retirando-a do caminho que leva ao conhecimento. Contudo, é argumentado que o erro intelectual é corrigido pelo ensino e não por um valor moral. Pretende-se explicar como a vergonha pode ter essa função de uma positiva mutação mental, contribuindo desta forma para a obtenção do conhecimento. A interação entre valor moral e capacidade cognitiva é possibilitada pelo conceito de imagem e fealdade.

Considerado o método de reaproveitamento mais aplicável para a fração orgânica de Resíduos Sólidos Urbanos (RSU), a compostagem – conversão biológica – atrai principalmente pelo baixo custo, portanto, o presente artigo discorre sobre a legislação referente aos resíduos sólidos no Brasil e os diferentes métodos de compostagem. O objetivo foi analisar os métodos de compostagem orgânica de baixo custo em zonas rurais como ferramenta de gestão de resíduos orgânicos para a geração de um composto orgânico estável e de qualidade para ser utilizado na agricultura. Para tanto, foi realizada uma revisão sistemática da literatura utilizando-se de estratégia bibliométrica no portal de Periódicos Capes, por meio de palavras-chave relacionadas ao tema. Constatou-se que, de fato, o método denominado aeração forçada se adapta melhor às possibilidades, tendo uma melhor decomposição de resíduos orgânico por meio da potencialização da ação de microorganismos ao longo do processo e recomenda-se que a propriedade rural identifique o melhor meio de utilizar e preservar, potencializando não só o desenvolvimento sustentável, como também o aumento da produtividade na propriedade.

Resíduos Orgânicos No Brasil: Métodos De Compostagem Para Pequenas Comunidades Rurais

IMPORTÂNCIA DO FARMACÊUTICO CLÍNICO NA DIMINUIÇÃO DAS INTERAÇÕES MEDICAMENTOSAS AO PACIENTE ONCOLÓGICO NA UNIDADE DE TERAPIA INTENSIVA

Diversidade, meio ambiente e o processo interdisciplinar na contemporaneidade

ELABORAÇÃO DE PLANO DE GERENCIAMENTO DE DADOS EPIDEMIOLÓGICOS NA ATENÇÃO BÁSICA: UM RELATO DE EXPERIÊNCIA

RELAÇÃO ENTRE A CAPACIDADE ABSORTIVA E A VANTAGEM COMPETITIVA EM REDES DE COOPERAÇÃO

MOTIVOS DE CANCELAMENTOS DE CIRURGIAS ELETIVAS: UM ESTUDO DE REVISÃO

O ESPECIALISTA EM EDUCAÇÃO ESPECIAL E INCLUSIVA COMO MEDIADOR DOS PROBLEMAS RELACIONADOS AO BULLYING COM ALUNOS COM DEFICIÊNCIA NAS ESCOLAS REGULARES

O presente artigo tem como objetivo principal demonstrar a extensao do impacto ambiental que o Rio Itabirito impoe a sub-bacia do Alto do Rio das Velhas

Expresso Chagas 21: Álbum fotográfico do conteúdo audiovisual para o compartilhamento de saberes em doença de Chagas

O PSICOPEDAGOGO COMO MEDIADOR: A ATUAÇÃO DO PSICOPEDAGOGO FRENTE AO BULLYING NAS ESCOLAS

Do curso de formação docente para indígenas ao curso de licenciatura indígena – UFAC

A educação desde sua origem apresenta-se como uma modalidade de acesso restrito, no qual nem todos tinham as mesmas oportunidades e direitos a aprendizagem. Com o passar do tempo surgiram documentos que salientavam um comprometimento maior com relação ao ensino à alunos com deficiências, reflexões e debates fizeram surgir políticas de incentivo e obrigatoriedade de uma educação agora chamada de inclusiva. O objetivo do presente estudo foi expor a partir das experiências vivenciadas no estágio, as dificuldades, bem como as possibilidades da prática pedagógica de Educação Física com alunos com diferentes deficiências e níveis de comprometimento da Associação de Pais e Amigos dos Excepcionais - APAE da cidade de Iguatu-CE. O estágio contribuiu de forma significativa tanto para os alunos quanto para os estagiários, havendo uma troca de conhecimento e experiências, possibilitando um crescimento pessoal, profissional e acadêmico, tornando-se de suma importância para o desenvolvimento do mesmo enquanto futuro docente.

Revista de Instrumentos, Modelos e Políticas em Avaliação Educacional

Possibilidades de avaliação e dificuldades na adequação da prática pedagógica para alunos com deficiência na Educação Física

Este artigo tem como objetivo demonstrar, a partir do diagnostico e planejamento do Plano de Acoes Articuladas (PAR), o processo de cooperacao tecnica firmado entre o Ministerio da Educacao e os municipios prioritarios da Baixada Cuiabana para entender a importância da formacao e a valorizacao dos profissionais da educacao inseridos no PAR. Demonstra tambem os pontos relevantes em relacao a legislacao e normas que tratam do processo de valorizacao e formacao dos profissionais da educacao, assim como algumas mudancas na politica publica educacional do pais. O processo historico apresentado neste artigo traz o periodo entre 1988, quando da promulgacao da Constituicao Federal ate o ano de 2007, com a publicacao do Decreto no 6.094, com a finalidade de esclarecer ao leitor a respeito das mudancas ocorridas na educacao brasileira por meio de suas principais legislacoes. Por fim apresenta o termo de cooperacao tecnica estabelecido individualmente entre o Ministerio da Educacao e os municipios do Estado de Mato Grosso: Planalto da Serra, Pocone e Rosario Oeste. Finalmente, com a efetivacao do diagnostico do PAR e planejamento das acoes a serem implementadas, dentre elas, as equipes destacaram como prioritarias a educacao, a formacao dos profissionais que laboram na execucao do plano, assim como as acoes definidas e contempladas em toda a estruturacao do PAR. Palavras-Chave: PAR; Formacao de Professores; Politicas Publicas Educacionais.

Resumo: A umidade causa nos pacientes com incontinencia urinaria e fecal um risco para o surgimento das ulceras por pressao, devido ao contato direto da urina e fezes com a pele. A etiologia da ulcera por pressao e predita pelas escalas de avaliacao, mas para sua aplicacao necessitam da habilidade do profissional enfermeiro. Este trabalho tem como objetivo revisar e compreender a relacao da incontinencia urinaria e fecal com o surgimento precoce de lesoes por pressao. Foi utilizado no estudo o metodo de revisao sistematica, constituido em cinco etapas, sendo eles o estabelecimento de criterios, categorizacao dos estudos e sintese do conhecimento produzido, analise dos dados e a interpretacao e discussao dos resultados. Sugere-se dentre os estudos analisados que a incontinencia urinaria e/ou fecal esta intimamente relacionada com lesoes precoces por pressao. Uma das principais caracteristicas dos pacientes criticos portadores de ulceras de decubito e a presenca da incontinencia miccional e/ou fecal, no qual, mostra a importância da assistencia de enfermagem no diagnostico precoce dos riscos e prevencao destas lesoes.

Lesões precoces por pressão em pacientes com incontinência miccional e fecal em unidade de terapia intensiva

Este trabalho relata a importância do PIBID na formação docente dos participantes do programa no curso de licenciatura em Química do IFPB-Campus Sousa. O programa é um incentivo para os graduandos em licenciatura, pois conta com bolsa que auxilia nas despesas e permanência nos cursos de licenciaturas que sofrem uma grande evasão, além de ajudar com conhecimentos e práticas docentes que serão de suma importância na futura profissão. O trabalho tem foco nas atividades realizadas belos bolsistas e como o programa incentiva a permanência no curso e no seu pensar docente sobre métodos pedagógicos. Essa é uma pesquisa de caráter qualitativo, na qual os resultados foram obtidos durante as apresentações das atividades através de depoimentos relatados pelos participantes do programa e dos alunos do curso técnico de agroindústria integrado ao ensino médio do IFPB. Foi possível constatar que o PIBID ajuda a melhorar as práticas docentes aprendidas em sala de aula, ressaltando ainda que os lúdicos e a experimentação são importantes para a compreensão dos conteúdos abordados.

A IMPORTÂNCIA DO PIBID NA FORMAÇÃO DOCENTE: ATIVIDADES LÚDICAS E EXPERIMENTAIS COMO FERRAMENTAS DE ENSINO

O presente artigo apresenta experiências didáticas realizadas no campo da Biologia Celular, em específico da Citologia, visando cumprir orientações da Lei de Diretrizes e Bases da Educação Brasileira (1996), que inseriu mudanças nos currículos escolares após a promulgação da Lei no 10.639/2003 – Educação das Relações Étnico-Raciais, História da África e da Cultura Afro-Brasileira. Nesse sentido, na formação inicial – primeiro semestre – de discentes do curso de Ciências Biológicas da Universidade Federal da Paraíba, foi utilizada uma metodologia com o propósito de aplicar de forma inovadora a referida Lei. Como resultado, tivemos a apresentação de 34 trabalhos por 120 discentes no formato de painel que foram apresentados à comunidade acadêmica, relacionados aos seguintes temas: preparação tecidual, Saúde da População Negra, personalidades negras e estruturas celulares. As atividades foram norteadas pelas perspectivas da Educação Antirracista e Colonialidade/Decolonialidade que propõem a descolonização dos currículos, buscando a superação do eurocentrismo que ainda está fortemente presente no sistema educacional brasileiro. 

Biologia celular, educação antirracista e currículo decolonial: experiências didáticas inovadoras na formação inicial no curso de Ciências Biológicas

O objetivo deste artigo é refletir sobre um importante e singular caso de diálogo transmidiático originado no cinema brasileiro, e que se estendeu às mídias televisão e histórias em quadrinhos. Esses produtos culturais foram abrigados sob o guarda-chuva da marca “Zé do Caixão”, personagem ficcional considerado um marco na cinematografia brasileira, em particular no gênero terror. Trata-se de um projeto cultural surgido há meio século atrás, momento em que o Brasil passava por severas mudanças sociais com o adensamento populacional dos centros urbanos e convulsões políticas desde 1964 que se traduziram em repressão à liberdade artística e de expressão. O país vivia sob o regime da ditadura militar, de valores conservadores e, mesmo assim, o triângulo formado pelos suportes audiovisuais e impressos difundiram esse personagem controverso em iniciativas que alcançaram sucesso comercial e repercussão em diversas camadas da sociedade brasileira da época.

A percepção de professores da educação infantil e do ensino fundamental I no tocante à discussão de gênero no espaço escolar

Santary sewage is the main source of contamination of water bodies, the volume released consititutes an expressive load of pathogenic organisms that are transmitted to man through direct ingestion of untreated water, ingestion of contaminated food or by infection resulting from skin contact contaminated water. Thus, in order to know the water quality situation of Joao Monlevade’s domestic sewers, the present work has emphasized the real need for the implementation and operation of the Sewage Treatment Station in the Cruzeiro Celeste neighborhood. The norms established by COPAM and CONAMA, in addition to conducting a mapping of sewage discharge points and opinion polls involving the riverside population of this region and high school students. The diagnosis of the sewage quality situation was carried out through chemical analysis, mapping using the GPS Trackmaker program and the opinion survey using a questionnaire and an interview. Based on the standards for monitoring water quality and chemical analyzes, the need for the implementation of a Sewage Treatment Plant was proven. The maps enabled the global visualization of the health system, producing information for the population and future research. The opinion poll showed the population’s lack of knowledge about the implementation and operation of the TEE. Thus, the greater the insertion of the community in aspects of public life, the greater the demand for more effective results.

Estudos da qualidade da água dos esgotos domésticos da Cidade de João Monlevade – MG, em relação às normatizações

Como um experimento de ciência cidadã, o presente artigo propõe a criação de um projeto envolvendo a participação de observadores de aves no levantamento, monitoramento e preservação das espécies que compõem a comunidade de aves da Lagoa Rodrigo de Freitas. Regulamentada como Área de Proteção Permanente em 2008, a Lagoa e o seu espaço circundante é considerado um dos principais pontos turísticos da cidade do Rio de Janeiro. A observação de aves (birdwatching) é uma atividade que vem crescendo ultimamente em diversos países e tem se constituído no principal alicerce da ciência cidadã. Pelo último levantamento aqui apresentado, a Lagoa possui um total de 39 espécies de aves pertencentes a 23 famílias. Desse total, 10 são aquáticas e 29 são terrestres. A proposta do artigo consiste em desenvolver um projeto particular de preservação das aves da Lagoa a partir da colaboração dos observadores de aves, os quais irão participar ativamente no levantamento, monitoramento e divulgação de informações. A primeira etapa do projeto será fazer uma atualização da lista de aves assinalando a presença sazonal das espécies conforme mostrada neste trabalho. As etapas posteriores envolvem a descrição de hábitos e comportamentos dos espécimens, marcação de pontos de melhor avistamento dos indivíduos e a divulgação periódica da situação do conjunto de aves do local. Os dados recolhidos poderão ser depositados em plataformas digitais como o Wiki Aves e o Táxeus. A ciência cidadã tem contribuído intensamente para a expansão do conhecimento científico permitindo a participação ativa dos cidadãos em atividades científicas, gerando experiência, compreensão e novos conhecimentos tanto para a ciência quanto para o cidadão participante.  

Birdwatching como uma proposta de valorização do espaço ecoturístico da Lagoa Rodrigo de Freitas, Rio de Janeiro (RJ)

ABSTRACT: The edaphic mesofauna consists of organisms between 0.2 and 2.0 mm in length. Among its members are the mites (Acari) and collemboli (Collembola), the diversity of these microarthropods is related to soil type and its physical and chemical characteristics. The objective of this research was to record data about the density and richness of the soil mesofauna in a permanent preservation area in the Alagoano forest. For this survey the modified Berlese-Tullgren funnel was used. Ten soil samples were collected from 3 meters away from each other, the dominant group was Acarina with 107 specimens, followed by the Collembola group with 79 specimens, suggesting that the mites have greater adaptability to the studied environment. 
KEYWORDS: Soil biodiversity, living organisms, microarthropods, bioindicators.

Levantamento da mesofauna do solo em área de preservação permanente da Vila Bananeiras, Arapiraca/AL

A AMAZÔNIA LEGAL, USO SUSTENTÁVEL E “SISTEMAS” DE VIGILÂNCIA AMBIENTAL: LEGADO HISTÓRICO E PERSPECTIVAS FUTURAS

Este trabalho apresenta uma introdução à química teórica e computacional e as inúmeras possibilidades de linhas de pesquisa que a área pode oferecer para o ingresso à iniciação científica no ensino básico e superior, por intermédio de um curso de extensão universitária ministrado na VIII Semana de Química e Meio Ambiente do Instituto Federal de Educação, Ciência e Tecnologia do Sertão Pernambucano – Campus Ouricuri. O minicurso teve duração de três dias, com carga horária total de 9 horas. Foram realizados estudos-piloto com ênfase nos aspectos práticos da modelagem molecular, onde os participantes tiveram a oportunidade de manipular softwares de química computacional, para o cálculo de propriedades geométricas e eletrônicas de moléculas orgânicas. As práticas possibilitaram uma ampla divulgação da área que, até então, ainda se encontra pouco difundida no meio acadêmico. O minicurso serviu como motivação para o registro de três projetos científicos voluntários na área de química computacional.

Oportunidades da Química Teórica e Computacional para a Iniciação Científica

ABSTRACT: Schistosomiasis Mansoni is endemic in approximately 76 countries and it currently affects 8 million Brazilian posing a serious threat to our country health system and population. The parasite Schistosoma Mansoni has the Biomphalaria Mollusc as its intermediate host and their infected larvae, is responsible for transmitting the disease to the population when they are released in the water. People in contact with water infested by larvae are prone to catch this dangerous disease. Our study was conducted in three different areas of lagoon do Retiro, nearby the city of Junqueiro- Al, Brazil. Molluscs were collected with the help of a special sieve, then kept in plastic containers identified by the area and sent to the State University of Alagoas( Uneal) laboratory, in Campus 1. There they were isolated and studied in a petri dish containing 10 ml of dechlorinated water and exposed to a 40 W incandescent lamp. For the molluscs that did not promptly test positive for the Schistosoma Mansoni, the exposure was repeated in the space if 7, 15 and 30 days, in order to rule out the possibility of infection. Out of the 3 areas studied in 2018 one tested positive with a total of 8 infected molluscs. The study therefore proved the lagoon is not safe to swim, bathe, or have its water used by the population and the public heath departament should alert the local population about this danger and health risc. 
KEYWORDS: Host species, Schistosomiasis mansoni, intermediate hosts, epidemiological importance.

Análise do caramujo Biomphalaria glabrata (Say, 1818) e identificação de áreas infectadas na lagoa do Retiro, Junqueiro/AL

O presente estudo propõe-se a discutir sobre a importância dos jogos no ensino da matemática nos ensinos fundamental e médio. De forma específica, procurar-se compreender a finalidade desses jogos a serem trabalhados em sala de aula, apresentando uma discussão acerca de como está sendo abordados dentro dos conteúdos propostos, a ser vivenciados, na prática pedagógica, e suas contribuições favoráveis ao processo de aprendizagem do ensino da matemática. Assim como, identificar os jogos e brincadeiras como elementos primordiais em uma visão contemporânea do professor no ensino fundamental e médio para, em seguida, identificar os fatores internos e externos que interferem nesse processo ensino aprendizagem dos conhecimentos matemáticos. Para tanto, serão analisados o que dizem os Parâmetros Curriculares Nacionais a respeito do uso de jogos, como recursos de aprendizagem, bem como, o papel do professor e a construção de saberes lógicomatemáticos vivenciados pelos alunos. Defende-se a hipótese de que a teoria e a prática sobre os jogos, quando incorporadas na formação e prática docente contribuem no ensino-aprendizagem. Nessa concepção, o jogo deve ser entendido como um instrumento no processo de aprendizagem significativa, através de uma reflexão crítica e social, uma vez que, uma das premissas da brincadeira consiste em trabalhar a prática das teorias das resoluções de problemas, neste sentido, o aluno tenta aprender de forma qualitativa, pois, o processo torna-se mais dinâmico formando leitores e, sobre lúdico-matemático com a autonomia do aluno no processo de ensino-aprendizagem. O estudo Fundamenta-se nos seguintes autores: Antunes (2006), Brasil (1998), Libâneo (2008), Piaget (1976) Starepravo (2009), Teixeira (2010) Vygotsky, (2003). Dentre outros que corroboram com a hipótese em questão.

Estudo do comportamento em fadiga de fios NiTi com memória de forma utilizando um analisador dinâmico-mecânico

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e inundações: Brasiléia, Acre

The textbook is still in the Brazilian educational reality a pedagogical tool widely used by teachers. Understanding the importance of this instrument, the present research aimed to analyze the conceptual approaches on sexuality, parenting and STI/AIDS in two didactic collections of Natural Sciences in the final years of Elementary School. For that, we used a qualitative research and the content analysis technique to elaborate inferences on the data collected. After data evaluation, it was noticed that the didactic collection of Natural Sciences textbook most acquired by Brazilian public schools, in the NTP of 2014, was identified with a conservative bias and, at times, aligned with the biologizing reductionism. On the other hand, the least acquired collection brings an approach corresponding to the current pedagogical and legal guidelines. Anyway, this finding led us to emphasize that biologizing approaches can lead to the impoverishment of the teaching of Natural Sciences.

South American Journal of Basic Education, Technical and Technological

ABORDAGENS CONCEITUAIS SOBRE SEXUALIDADE, PARENTALIDADE E IST/AIDS EM LIVROS DIDÁTICOS DE CIÊNCIAS NATURAIS

MORFOMETRIA DA BACIA HIDROGRÁFICA DO RIBEIRÃO DO LAGE, CARATINGA – MG

O USO DOS VÍDEOS EM UM CURSO NA MODALIDADE EDUCAÇÃO DISTÂNCIA ON-LINE: DESCOMPASSOS ENTRE O DISCURSO E A PRÁTICA.

Na envergadura do cenário atual, uma parcela da sociedade atribuiu a Paulo Freire o juízo de doutrinador, questionando suas ideias e supondo que suas obras possuem o intuito de reproduzir um comunismo apontado como chaga, motivo pelo qual este artigo posiciona-se politicamente em defesa deste educador. Mesmo porque, consoante a lógica freireana, o posicionamento é uma atitude política. Nesse intuito, apresentam-se dados que ratificam a preocupação de Paulo Freire com uma Pedagogia pautada em ideais de valorização do ser humano. O objetivo geral direciona-nos a discutir conceitos da Pedagogia Freireana a partir das sete palavras mais frequentes no livro Pedagogia da Autonomia. Com relação à metodologia, esta pesquisa enquadra-se no enfoque qualitativo com a utilização da modalidade de análise lexical, circunscrita ao método de análise de conteúdo. Os dados foram obtidos através da utilização do programa de análise qualitativa Nvivo®, por meio da investigação de frequência de palavras. Por fim, o exame dos dados permitiu-nos debater a dialogicidade entre os sujeitos, conhecimentos e práticas necessários à práxis pedagógica, bem como outros princípios pedagógicos discutidos por Freire. 

O alinhamento do pensamento freireano com o ser humano: análise de frequência de palavras do livro Pedagogia da Autonomia

A IMPORTÂNCIA DA SIMULAÇÃO CLÍNICA NOS CURSOS DE GRADUAÇÃO EM ENFERMAGEM

A geografia escolar tem como principal caracteristica a sintese, constitui-se num escopo teorico com conteudo variando da astronomia, geologia, agronomia, meteorologia, agregando seus proprios conceitos e categorias de analise: espaco geografico: paisagem, territorio e lugar. Entretanto, esse exercicio no contexto da sala de aula, ao longo dos anos, transformou a disciplina em excessivamente teorica, e pouco acessivel aos estudantes, entretanto, criou tecnicas especificas de reproducao dos conhecimentos fundamentadas na repeticao e memorizacao. Neste sentido, esse artigo propoe tratar de bases teoricas que apontam a relevância dos trabalhos de campo na consolidacao do processo de ensino – aprendizagem, adentrando a educacao basica e o ensino superior no âmbito do Programa Residencia Pedagogica de Geografia. A pesquisa foi desenvolvida por meio de experiencias praticas realizadas na Ilha do Combu com graduandos do curso de Geografia da Universidade Federal do Para, na Ilha de Caratateua com alunos do ensino fundamental e do ensino medio da Escola Bosque. Das teorias que fundamentam a investigacao, funcionando como suporte a analise dos dados obtidos, destacam-se a Teoria da Complexidade de Edgar Morin e a Teoria da Aprendizagem Significativa de David Ausubel, ambas relacionadas as novas perspectivas metodologicas de ensino aprendizagem da geografia. As experiencias praticas proporcionadas pelo trabalho de campo se revelam com grande potencial para a reversao do ensino tradicional e mecanicista que ainda persiste na area, estabelecendo uma compreensao mais complexa dos diversos sistemas estabelecidos pelos sujeitos locais, bem como um maior entendimento da relacao homem x ambiente nos estudos da geografia ambiental. 
 
PALAVRAS-CHAVE: Educacao Ambiental. Ensino. Geografia Escolar.

Bases teóricas para a compreensão do trabalho de campo como metodologia de ensino da Geografia e Educação Ambiental

A horta medicinal escolar pode ser um laboratorio vivo que possibilita o desenvolvimento de diversas atividades pedagogicas em educacao ambiental e saude, unindo teoria e pratica de forma contextualizada e interdisciplinar, auxiliando no processo de ensino-aprendizagem e na promocao do trabalho coletivo.

IMPLANTAÇÃO DE UMA HORTA MEDICINAL ESCOLAR COM APROVEITAMENTO DA ÁGUA EFLUENTE DE BEBEDOUROS: UMA PROPOSTA DE EDUCAÇÃO AMBIENTAL E RESGATE DE UMA CULTURA POPULAR

A IMPORTÂNCIA DOS PROJETOS SOCIAIS DESPORTIVOS PARA EVITAR A INSERÇÃO DO ADOLESCENTE NA CRIMINALIDADE

As tecnologias da informação e comunicação na formação inicial de professores de Matemática em Recife e região metropolitana

Trata-se de uma reflexão sobre conquistas do movimento indígena no Estado do Rio Grande do Norte na busca de uma educação e pelo direito de existir. Pretende-se refletir acerca de uma educação mediada como mecanismo de resistência. Para isso, os dados obtidos foram sistematizados a partir de estudos sobre a relação do Movimento Indígena Brasileiro com a educação diferenciada. No mais, utilizamos relatório de aula de campo à comunidade do Catu dos Eleotérios, a primeira comunidade indígena do referido estado a concretizar uma educação escolar indígena. Aqui, a escola indígena apresenta-se, portanto, como instrumento para a superação da invisibilidade, historicamente construída em diversos processos cumulativos de produção da inferioridade de populações indígenas.

Coisa de índio: Educação Escolar Indígena no Catu dos Eleotérios-RN

Neoplasia is a disorder in the cell growth caused by a set of acquired mutations that affect a single cell and its clonal progeny, the malignant neoplasm being referred to as cancer. In this context, the diagnosis and treatment of this pathology can interfere with the quality of the mental health of the affected. The objective of this study was to describe an activity carried out by medical school students who are members of the Liga de Saude Comunitaria do Cariri (Cariri Community Health League), a university extension program at the Federal University of Cariri, with adults and elderly people present at the NGO Casa Esperanca e Vida, an institution that assists people with cancer analyzing the impacts of diagnosis and cancer treatment on the mental health of this population through a reflection on their perspectives for the future. Initially, the participants were distributed in groups, and were given a sheet of A4 paper and a pencil for each member and they were oriented to draw their present moment. After the first drawing, a new sheet of paper was delivered for them to prepare engravings that represented their yearnings for the future. The activity stimulated the comparison between the present and the future of the participants through a mixed practice of speech with art therapy and obtained constructive reflections, is that all the participants believed in their statements that they would be able to cure their current condition. It was concluded that, despite the possibility of being affected by feelings such as sadness, helplessness, and disbelief, all participants were optimistic about their future, with a positive attitude towards these people's mental well-being.

RESUMO O envelhecimento é definido como uma fase natural de todo ser vivo, incluindo a fatores de envelhecimento biológico, psicológico e sociológico. O IBGE constatou que até 2030 a população brasileira será definida como uma população de idade avançada. Também se notou uma elevação na taxa de pessoas com sobrepeso e obesidade. O envelhecimento é influenciado diretamente por fatores genéticos e o modo de vida do indivíduo. Algumas teorias tentam analisar esse processo natural; a teoria das proteínas cruzadas, danos oxidativos, radicais livres e a teoria metabólica. Muito presente na população geriátrica, à sarcopenia é definida pela perda de peso significativa e da força e da funcionalidade muscular, levando a problemas de fragilidade do idoso. Com o aumento do sobrepeso e da obesidade, tem sido cada vez mais caracterizado a obesidade sarcopênica. O estresse oxidativo aumentado por quantidades altas de radicais livres é estimulado pelo aumento da massa gorda. Essa mudança na composição corporal leva a um dos principais processos do sistema imunológico que é a inflamação, que leva a mobilização proteíca. Esse tema engloba duas questões atuais que são o processo de envelhecimento da população brasileira e o crescente ganho de peso, a associação desses fatos traz como consequências o aumento da sarcopenia obesogênica e todas as alterações bioquímicas advindas desse processo. O objetivo desse trabalho foi compreender a gênese da sarcopenia obesogênica quando em idosos para o aparecimento ou comprometimento de doenças crônicas não transmissíveis.

Obesidade sarcopência em idosos: Um potencializador do estresse oxidativo e de biomarcadores inflamatórios. Complicadores e/ou promotores de doenças crônicas inflamatórias.

Tradicionalmente, a História das Ciências no Brasil recorre a exemplos clássicos como a disseminação das ideias darwinistas para exemplificar uma controvérsia científica nacional. O presente trabalho apresenta o desenrolar de uma controvérsia científica ocorrida na metade do século XIX entre consócios da Sociedade Vellosiana de Ciências Naturais do Rio de Janeiro em que os debatedores procuravam explicar as causas dos nevoeiros secos que cobriam a cidade entre os meses de agosto e setembro. Os debatedores eram personagens pouco conhecidos do cenário científico brasileiro, mas a participação do químico e naturalista Alexandre Vandelli chama a atenção. Vandelli era filho do professor de Química e História Natural de Coimbra, Domingos Vandelli, genro de José Bonifácio e professor de Ciências do jovem D. Pedro II. Os debatedores propuseram hipóteses surpreendentes para explicar a causa do fenômeno como as queimadas, erupções vulcânicas, terremotos e fatores astronômicos.  Produzido a partir de fontes da literatura científica, o presente trabalho traz aportes teóricos interessantes sobre a natureza das controvérsias científicas. Apesar da solução do tópico debatido estivesse ainda bem distante do alcance da ciência do século XIX, destaca-se o empenho dos estudiosos brasileiros nas argumentações mesmo diante de um tema complexo para a época. 

Uma Controvérsia Esquecida: A Querela dos Nevoeiros Secos do Rio de Janeiro nos Meados do Século XIX

Apresentacao de um projeto itinerante da DPU em parceria com a Diocese de Valenca para atendimento em nove municipios, com resultados positivos e possibilidade de aplicacao em todo o territorio nacional.

Ampliação da assistência jurídica gratuita prestada pela Defensoria Pública da União em parceria com a Diocese de Valença/ RJ: relato de uma experiência da Justiça Itinerante

O CONHECIMENTO SOBRE HOMEOPATIA DOS PROFISSIONAIS DE SAÚDE DE NiVEL SUPERIOR QUE ATUAM NAS USFs DO MUNICÍPIO DE LAJEDO – PE

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e inundações: Cacoal, Rondônia

Objective: investigates the use of persistent identifiers and Research Blogging by the Portuguese-language scientific blogosphere and their coverage by Altmetric through a survey of article citations in their posts.Methods: Starting from the list of blogs registered in the Scientific Blog Ring (Anel de Blogues Cientificos - ABC) portal, Google searches were made in order to identify blogs in Portuguese that cite in their posts articles with persistent identifiers such as DOI, PMID or ArXiv, or that integrate the Research Blogging initiative that links posts with research citations in academic journals.Results: The systematized data made it possible to consult Altmetric's website and verify its coverage. As a result, we found that of the 460 blogs listed on ABC, only 109 blogs cited with persistent identifiers, 35 participated in the Research Blogging initiative and 42 were mapped by Altmetric.Conclusions: Discussions about the representativeness of scientific blogs in Portuguese in scholarly communication were conducted based on the results obtained. The lack of standardization of blog citations was pointed as one of the factors responsible for the low coverage of Portuguese-language blogs by the Altmetric indicator. A possible action was also indicated to reduce this under-representation of the blogosphere in Portuguese.

Uso de Identificadores Persistentes e Research Blogging por Blogues Científicos em Língua Portuguesa e sua cobertura pela Altmetric

Engenharia Sanitária e Ambiental: Tecnologias para a Sustentabilidade 5

Introdução: considerando a importância e a relevância da educação em saúde com adolescentes, é essencial o uso de estratégias cada vez mais acolhedoras, dinâmicas, integradas e subjetivas. Assim, objetivou-se avaliar as estratégias de educação em saúde utilizadas com adolescentes, a partir das publicações existentes em revistas científicas. Desenvolvimento: trata-se de uma pesquisa descritiva, qualitativa, do tipo revisão integrativa. Foram critérios de inclusão: títulos em português, texto completo disponível gratuitamente, artigos e publicações nos últimos cinco anos (2012, 2013, 2014, 2015 e 2016). Foram excluídos os artigos repetidos ou em formato de revisão de literatura ou que não responderam à questão-problema pesquisada. Após a aplicação dos critérios de inclusão e exclusão, restaram 26 artigos, que foram lidos na íntegra e analisados na presente pesquisa. A região Nordeste destacou-se com dez publicações e a revista APS – Atenção Primária à Saúde possui o maior número de publicações. A maioria dos artigos utilizou a abordagem qualitativa. As oficinas educativas foram relatadas em 12 pesquisas, e abordou-se a temática saúde sexual e reprodutiva na maioria das ações. As escolas foram os cenários de maior escolha pelos pesquisadores. Em média, 69% dos artigos não utilizaram base metodológica para avaliar a efetividade das intervenções. Evidenciaram-se, ainda, limitações das publicações quanto às conclusões e avaliações das estratégias utilizadas. Conclusão: reforça-se a importância da pesquisa na área profissional, o que garante tanto a importância da busca de metodologias quanto da avaliação da estratégia usada, para melhor aplicabilidade, de forma dinâmica, afável e pessoal.

Participação de alunos do ensino médio em projetos científicos de grupos de pesquisa em química analítica

INFLUÊNCIAS DE CULTIVARES E SISTEMAS DE PRODUÇÃO SOBRE TEORES DE NUTRIENTES, PROTEÍNA, METILXANTINAS E TANINOS EM FOLHAS DE GUARANAZEIRO E POTENCIAL PARA A INDÚSTRIA

Este artigo apresenta elementos de ordem teórico-conceitual característicos de um design de investigação em Didática da Matemática com o escopo de assinalar uma discussão e a possibilidade do ganho de conhecimentos didático-metodológicos acerca do ensino de Geometria plana e visando o ensino por meio de Problemas Olímpicos retirados de provas de edições anteriores da OBMEP. Utilizou a Engenharia Didática dando ênfase as suas duas etapas iniciais: análises preliminares e análise a priori e a concepção da situação didática, com atenção especial dedicada à concepção e a modelização de uma situação-problema em complemento com a Teoria das Situações Didáticas e o software Geogebra como recurso tecnológico auxiliadora na visualização e modelização. Apresentou uma proposta através de uma SDO para os professores utilizarem em sala de aula ou em preparações para a OBMEP. Desse modo, espera-se que ela contribua para o planejamento e na diversidade metodológica aplicada no ambiente escolar

UMA ENGENHARIA DIDÁTICA APLICADA A OBMEP: SITUAÇÕES DIDÁTICAS OLÍMPICAS PARA O ENSINO DE GEOMETRIA PLANA

Este artigo abordou uma proposta de ensino cujo objetivo foi a apresentacao de uma metodologia de ensino com base na Teoria das Situacoes Didaticas (TSD). A proposta segue o modelo da TSD, com o uso de Problemas Olimpicos (PO) e o software GeoGebra, para a adaptacao desses problemas. A investigacao se estruturou na Engenharia Didatica (ED) em complemento com a TSD e o software GeoGebra, recurso tecnologico capaz de auxiliar o estudante na visualizacao e modelizacao das figuras. O relato de experiencia foi realizado com alunos do curso de Licenciatura em Matematica do Instituto Federal de Educacao, Ciencia e Tecnologia do Ceara (IFCE) e os dados foram coletados por meio de fotos, dialogos e escritos dos alunos. Os resultados foram satisfatorios no diz respeito ao uso do GeoGebra e a autonomia dos estudantes na construcao dos saberes matematicos. Concluimos que a proposta apresentada difere das metodologias tradicionais, nas quais o professor se posiciona como detentor do conhecimento, e nesse caso, o aluno se torna protagonista da sua aprendizagem.

SITUAÇÕES DIDÁTICAS OLÍMPICAS PARA O ENSINO DE GEOMETRIA PLANA NO CONTEXTO DA OBMEP: UMA EXPERIÊNCIA NO CURSO DE MATEMÁTICA DO IFCE

No presente trabalho, e meu proposito construir reflexoes sobre uma proposta de producao escrita do genero artigo de opiniao. Objetivo, mais especificamente, refletir sobre a implementacao de uma proposta pedagogica para o ensino da producao do artigo de opiniao que toma como ponto de partida orientacoes didatico-metodologicas da Olimpiada de Lingua Portuguesa. Como respaldo teorico, assumo pressupostos da abordagem dialogica da linguagem do Circulo de Bakhtin, assim como trabalhos de estudiosos que discutem o ensino de linguas como Antunes (2003); Barros (2015); Geraldi (2015); Schneuwly & Dolz (2004). Trata-se de um estudo em que adoto uma abordagem qualitativa e a metodologia da investigacao narrativa. Utilizo-me da producao do diario de aula como instrumento metodologico para reflexao da pratica educativa. A proposta de producao foi desenvolvida na 3a serie do ensino medio em uma escola publica no municipio de Marcelino Vieira-RN. Com base na reflexao realizada, percebo um efetivo avanco no ensino-aprendizagem do genero artigo de opiniao, visto a superacao de grande parte dos problemas encontrados durante todo o processo de desenvolvimento da proposta. Como conclusao, aponto um dialogo fecundo entre a proposta desenvolvida e as orientacoes da olimpiada para o ensino de escrita do genero artigo de opiniao.

PROPOSTA PEDAGÓGICA PARA O ENSINO DE ESCRITA DO GÊNERO ARTIGO DE OPINIÃO: ENTRE RELATOS E REFLEXÕES EM PERSPECTIVA DIALÓGICA

O acordo de não persecução penal foi introduzido no código de processo penal através da lei 13.964/19, com o intuito de aprimorar a justiça negociada e favorecer o atendimento das demandas a fim gerar punição mais efetiva. Contudo, uma problemática tomou voz, sendo ela a confissão como requisito à celebração do acordo entre Ministério Público e acusado, o que denota inconstitucionalidade para tanto, tendo em vista a sua notória desnecessidade, angariando eventual vantagem ao parquet em possível instauração da ação penal. Partindo do método bibliográfico e documental, o presente trabalho irá apresentar como ocorre a inconstitucionalidade material da confissão, partindo da análise da evolução histórica do processo penal à inserção do acordo no âmbito jurídico brasileiro, a fim de demonstrar o vício no requisito da confissão. Então, embora seja instituto inovador, a discussão é válida, tendo em vista que ocasionará efeitos jurídicos práticos ao longo do tempo.

Revista Acadêmica Escola Superior do Ministério Público do Ceará

Inconstitucionalidade material da confissão no acordo de não persecução penal

Este artigo apresenta elementos de ordem teórico-conceitual característicos de um design de investigação em Didática da Matemática com o escopo de assinalar uma discussão e a possibilidade do ganho de conhecimentos didático-metodológicos acerca do ensino de geometria Euclidiana plana por meio de Problemas Olímpicos (PO) retirados das provas da Olimpíada Brasileira de Matemática das Escolas Púbicas e Privadas (OBMEP). O objetivo é realizar uma Engenharia Didática (ED) visando a construção de uma Situação Didática Olímpica (SDO), com foco no ensino de geometria Euclidiana Plana, com o auxílio do software GeoGebra como recurso tecnológico com o intuito de possibilitar a percepção de novas estratégias aos estudantes por meio da movimentação e visualização das figuras apresentadas na situação-problema. Foi usada a metodologia Engenharia Didática (ED) pautado nas suas duas etapas iniciais: Análises preliminares e Concepção e Análise a priori da situação didática, com atenção especial dedicada à concepção e a modelização de uma situação-problema em complemento com a Teoria das Situações Didáticas (TSD) e o softwareGeoGebra como recurso tecnológico auxiliadora na visualização e modelização. Apresentou-se uma proposta através de uma SDO para os professores utilizarem em sala de aula ou em preparações para a OBMEP e com isso, espera-se que ela contribua para o planejamento e na diversidade metodológica aplicada no ambiente escolar.

Uma Engenharia Didática (ED) aplicada a Olimpíada Brasileira de Matemática das Escolas Públicas e privadas (OBMEP): Situações Didáticas Olímpicas (SDO) para o ensino de geometria Euclidiana plana

APLICABILIDADES DO MARKETING AOS CAFÉS ESPECIAIS DO PLANALTO DE VITÓRIA DA CONQUISTA/BA

AVALIAÇÃO DO TEOR DE MATÉRIA SECA DE CANA-DE-AÇÚCAR ADITIVADA COM DIFERENTES ADITIVOS E INOCULANTES BIOLÓGICOS

O abastecimento público de água e seus reflexos no cotidiano da população rural

Licenciatura indígena na formação de professores no Estado do Acre

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e inundações: Epitaciolândia, Acre

Este artigo objetiva compreender o uso do software educativo como instrumento pedagogico de aprendizagem. A informatica foi inserida na educacao inicialmente no seculo passado, no âmbito internacional, e que no Brasil somente se deu como discussao nas universidades e como politica publica somente na decada de 70 do seculo XX. A linguagem de programacao Logo, criada por Seymour Papert nos EUA foi a precursora na visao de que usar software como instrumento pedagogico poder-se-ia melhorar o ambiente de aprendizagem das criancas, torna-las mais autonomas. Esse pensamento vai de encontro com as ideias de Toffler, seguido de Sousa e Fino quando preconizam que a informatica pode vir a romper com o paradigma fabril, onde a escola estava mergulhada em pratica educativas centradas no ensino e nao na aprendizagem, o professor era o centro do saber. A tecnologia surge com essa possibilidade de mudar o olhar do ensino para o aprender, o aprender na pratica, incluindo as concepcoes do Construtivismo e Sociointeracionismo. Vale salientar que somente a tecnologia nao garante a inovacao, sendo preciso dedicacao do professor para esta mudanca, em sua formacao e adequacao a sua rotina diaria para fomentar aprendizagens. Para tanto buscamos referencias em Papert, Toffler, Fino, Sousa, Morin, Levy e outros estudiosos para contribuir em nossa discussao acerca da pratica pedagogica com as tecnologias, com o uso do software na escola e seus paradigmas.

A gestao publica e uma area voltada ao gerenciamento e controle dos recursos e bens publicos, contribuindo com o planejamento e o alcance de metas e acoes que promovam o interesse publico e o bem-estar social. Nesse contexto, o trabalho tem por finalidade analisar as praticas e as relacoes dos gestores publicos diante de questoes publico-privadas e seus impactos no desenvolvimento da gestao publica, sobretudo no municipio de Caraubas – PB. Esta pesquisa se justifica diante do instavel panorama social, politico, administrativo e economico em que se encontram as organizacoes publicas no pais. Para a concretizacao deste trabalho, foi realizada uma pesquisa de carater bibliografico e exploratorio, a partir de uma analise descritiva, de cunho quali-quantitativo, a qual envolveu a aplicacao de questionarios semiestruturados, por meio de entrevistas com 5 (cinco) grupos: funcionarios publicos municipais, funcionarios publicos estaduais, estudantes de ensino medio, estudantes de ensino superior e a sociedade civil. Na analise, buscou-se fazer um levantamento dos possiveis prejuizos causados pelas diversas praticas dos gestores publicos relacionadas a corrupcao, patrimonialismo, nepotismo e clientelismo, bem como demonstrar a perspectiva social ante essas questoes, os atores e as acoes no âmbito publico. Desse modo, considerou-se que a gestao publica local traz consigo acoes que retroalimentam comportamentos que dificultam o pleno funcionamento da maquina publica e obstaculizam sua eficiencia, eficacia e efetividade na implantacao de politicas publicas.

A gestão pública e suas práticas: um estudo sobre a relação público-privada no município de Caraúbas – PB

Licenciatura indígena no Acre: barreiras históricas, conhecimentos e perspectivas

Importância do farmacêutico clínico na diminuição das interações medicamentosas ao paciente oncológico na unidade de terapia intensiva/Importance of clinical pharmaceutical in reducing drug interactions to the oncological patient in the intensive care UNIT

Karla Denise Martins é, seguramente, umas das mais influentes estudiosas da religião na Amazônia. Historiadora de formação, com mestrado e doutorado desenvolvido na Universidade Estadual de Campinas (UNICAMP) com ênfase em História Cultural. Atualmente desempenha funções como professora na pós graduação do curso de História da Universidade Federal de Viçosa (UFV), no programa: Patrimônio Cultural, Paisagens e Cidadania; Seus interesses de pesquisa concentra-se em: Religião e Patrimônio, Métodos e Técnicas de Pesquisa, História da igreja católica e Pensamento Clerical.Suas contribuições são vultosas e ricas para o estudo e compreensão do universo religioso na Amazônia brasileira, mostrando assim seu amadurecimento intelectual, mas, alguns traços são comuns e fundamentais em seus escritos. Em primeiro lugar a compreensão do papel do catolicismo na formação da identidade civilizadora da Amazônia oitocentista e o desemborca das relações político-sociais no contexto amazônico sob a égide imperial. Por fim, suas reflexões voltaram-se para apreensão do patrimônio religioso. De certa forma, todos os temas que acompanharam/acompanham seu maturar intelectual e acadêmico irão ser abordados nesta entrevista que se segue. Nela buscamos, em um movimento ousado, apontar à uma só vez, os temas centrais dos escritos da Karla Denise e direcionar novos caminhos e problemáticas para pesquisa em religião para aqueles (a) que pretendem adentrar neste campo de pesquisa.  

ESTUDOS E PERSPECTIVAS DE PESQUISAS EM RELIGIÃO NA AMAZÔNIA, ENTREVISTA COM KARLA DENISE MARTINS

Anatomia da lâmina foliar de espécies de Mesosetum Steud. e afins (Poaceae, Arthropogoninae) e aplicações taxonômicas

Considerações para uma leitura das Diretrizes Gerais da Ação Evangelizadora da Igreja no Brasil, no tocante à Liturgia (2003-2006)

O presente artigo pretende proporcionar uma discussao sobre o modelo administrativo chamado de administracao sem papel, na tentativa de melhor atender toda a populacao, conectando-o a gestao publica. A pesquisa busca averiguar se tal modelo e adequado/viavel para as diversas esferas da administracao publica no Brasil, segundo estudiosos da area. Trata-se de um estudo de revisao de literatura, com suporte de uma analise documental. A elevada burocracia nos processos administrativos dos tres niveis (municipal, estadual e federal) e um dos maiores desafios para a sua eficiencia. Com o foco em atender melhor as necessidades da sociedade, os agentes do Estado e seus colaboradores vem aperfeicoando as praticas administrativas ao longo do tempo. Os antiquados processos manuais dificultam a vida dos funcionarios e dos cidadaos, fazendo com que os atos administrativos gerem custos extras para o governo. Na busca por resolver as disfuncoes do Estado burocrata (ineficiencia) fez com que o modelo gerencial viesse se consolidando pelas mudancas decorrentes nas estruturas organizacionais, reducao da maquina estatal, necessidade de reducao de custos, tendencia de descentralizacao dos servicos publicos, implementacao de agencias reguladoras, busca pela padronizacao dos processos para otimizacao de tempo e recursos, etc. O modelo de administracao sem papel parece vir ao encontro dessa realidade que busca a eficiencia, os resultados e a velocidade. Resta saber se a administracao publica esta preparada para as Tecnologias de Informacao e Comunicacao (TICs).

Administração sem papel: uma análise sobre a digitalização de documentos na administração pública

O conceito de beleza, tem mudado com o passar dos anos, sendo imposto pela sociedade a necessidade de estar por dentro do que e considerado belo, aumentando consideravelmente a procura por procedimentos esteticos. Criolipolise e um procedimento nao invasivo, que trata gordura localizada atraves do resfriamento das celulas adipocitas, que submetidas a baixas temperaturas, sofrem uma inflamacao, induzindo a apoptose destas celulas, sem danificar tecidos adjacentes. Objetivos: Atraves das pesquisas a literatura, identificar os parâmetros utilizados na criolipolise e seu mecanismo de acao. Metodologia: O artigo foi desenvolvido dos preceitos de estudos exploratorios, tratando-se de uma revisao sistematica, sobre o que ha de mais atual disponivel na literatura com explanacao sobre a criolipolise e analises da tecnica e seus efeitos terapeuticos. Para a coleta do artigo foram utilizados como Descritores: criolipolise, gorduras, estetica, equipamentos para estetica, modalidades de fisioterapia, fisioterapia, parâmetros nos seguintes bancos de dados: Google academico, Scielo, PubMed. Resultados e Discussao: No presente estudo encontrou-se 111 artigos dos quais 87 foram excluidos por se tratar de artigos de revisao, titulos repetidos alem de estudos que associaram a tecnica de Criolipolise a outros metodos de reducao da gordura localizada, resultando em 12 estudos que foram utilizados no projeto.

Criolipólise: análise da técnica e seus efeitos terapêuticos - revisão sistemática

O município de Campos dos Goytacazes, localizado na região Norte do Estado do Rio de Janeiro, destacou-se, até recentemente, como o maior receptor de rendas oriundas de royalties e participações especiais do país, cujo montante corresponderam a quase 2/3 de seu orçamento, em 2014. O objetivo deste artigo é observar, a partir da análise de indicadores econômicos e sociais, a contribuição do ciclo expansivo da indústria petrolífera na Bacia de Campos, no sentido de superar o subdesenvolvimento local e a promoção do desenvolvimento socioeconômico. O período de análise concentra-se no interstício 1999/2014 e engloba a quebra do monopólio do Petróleo no Brasil, ocorrida em 1997. A metodologia baseou-se em pesquisa bibliográfica sobre o comportamento socioeconômico de Campos dos Goytacazes no período 1999/2014, sendo, sempre que possível, relacionando com os municípios de Macaé e Niterói. Sendo a conclusão mais relevante do trabalho a de que, apesar do virtuoso ciclo do petróleo e das generosas receitas de royalties e participações especiais auferidos pelo município, observa-se que o subdesenvolvimento não só persiste, mas também se reproduz por conta da deterioração institucional.

Ciclo do Petróleo e Desenvolvimento Socioeconômico no Município de Campos dos Goytacazes – 1999/2014

The physical attributes of the soil allow us to monitor the areas that are impacted by agriculture. From this knowledge we can determine the management forms for each soil depending on its specificity, as they help in characterizing the soil type and way of working. This work aimed to characterize and describe the physical quality of a YELLOW RED ARGISSOL under different UVA and native forest use and management systems, evaluating its soil density and gravimetric humidity. The research was carried out in the property of Mr. Pedro located in São Vicente Férrer PE, located in the mesoregion of Agreste Pernambucano of the Middle Capibaribe, with altitude of 570m, average slope of the area of 15%. The experimental design of subdivided plots was used, where the main treatments were forms of land use under topossequence vine cultivation, and native forest and the secondary treatments were four soil layers (0.0-0.1 m; 0, 1-0.2 m, 0.2-0.3 m, and 0.3-0.4 m), using five repetitions. The treatments were: UCT: Grape and living ground cover in Topo; ECU: Grape and ground cover in Encosta; UCV: Grape and live ground cover in Várzea; MN: Native Forest. It was possible to observe that the native forest area presented the best results of soil density in the studied layers and gravimetric humidity, allowing to infer that the alteration of native forest in grape cultivation area, in any slope, promotes quality degradation. soil physics, since there is no proper management in the cultivated areas, making this soil degrading condition

ATRIBUTOS FÍSICOS DO SOLO SOB SISTEMA DE CULTIVO DA UVA EM TOPOSEQUENCIA E MATA NATIVA

O presente trabalho visa abordar o tema do Direito Canonico e sua evolucao ate os dias atuais. Desde sua origem, o Direito Canonico influenciou

Código de Direito Canônico: a era Francisco e suas mudanças nos processos de nulidade matrimonial

Setorização de áreas de alto e muito alto risco a movimentos de massa, enchentes e inundações: Paranatinga, Mato Grosso

Confunde-se, muitas vezes, comunicação litúrgica com técnica de comunicação, barulho e “movimentação de auditório”. Tal constatação levou o Autor a buscar o sentido latino de “communicare” e “comunicatio”, confirmando que estas palavras, traduzidas por “comungar” e “comunhão”, significam “por em comum”, “partilhar”. Pergunta-se, então: No jogo da divina Liturgia, o que é “posto em comum conosco e entre nós”, quando e como isso acontece, para que se possa falar em “comunicação litúrgica”? Responde o Autor: Deus, em seu imenso amor, coloca, hoje, à disposição dos seres humanos seu Sopro de vida “mediante sinais sensíveis” na celebração litúrgica, e o ser humano, por sua vez, acolhendo conscientemente a salvação que assim advém, corresponde-lhe com ação de graças, súplicas e vivência da caridade. Então, para que haja experiência de comunicação litúrgica, a possibilidade está em deixar que a própria Liturgia expresse a comunhão divino-humana no mistério do culto. E isso se dá, quando os agentes humanos da celebração litúrgica estiverem imbuídos do espírito da divina Liturgia e concentrados no mistério da ação celebrativa.Abstract: Liturgical communication is often confused with communication techniques, noise and the “movements of the public”. Recognition of this fact led the Author to seek the meaning of the Latin words “communicare” and “comunicatio”, confirming that these words, normally translated as “partaking of the communion” and “communion” actually mean “make common” or “share”. We ask then: in the game of the Divine Liturgy what is “made common with us and among us” and when and how this happens, so that we may speak of “liturgical communication”? The Author replies: God in his immense love, now places at the human beings’ disposal his breath of life “through sensitive signs” in the liturgical celebration, and the human being, in turn, consciously receiving the salvation that will come this way, corresponds Him with grace action, supplications and the experience of charity. Thus, in order to make sure that there is an experience of liturgical communication, the possibility is to let Liturgy itself express the divine-human communion in the mystery of the worship. And this happens when the human agents of the liturgical celebration are imbued by the spirit of the Divine Liturgy and concentrate on the mystery of the celebrative action.

A arborizacao urbana e toda vegetacao que compoe a paisagem urbana, sendo um dos componentes bioticos mais importantes das cidades, pois exercem inumeras funcoes importantes nos aspectos ecologicos, tais como as arvores que fornecem sombra, suavizam a temperatura e a poluicao sonora, e contribuem com o aumento da umidade relativa do ar, alem de melhorar sua qualidade. Este trabalho tem como objetivo elaborar o inventario e o diagnostico da arborizacao urbana, em suas principais vias de acesso ao Centro de Ouricuri (PE), no intuito de, futuramente, fornecer dados e informacoes para a organizacao do Plano Diretor de Arborizacao Urbana (PDAU) do Municipio. A metodologia baseou-se na revisao bibliografica do tema proposto (BIONDI, et al., 2006, 2011; GONCALVES, 2017; MILANO, 2000) e em atividades de campo no Centro de Ouricuri (PE), nas tres principais avenidas: Manuel Irineu de Araujo, Antonio Pedro da Silva e Fernando Bezerra. Procurou analisar e observar a presenca das plantas e avaliar as condicoes das arvores, do local de plantio - calcadas, levantar o numero de especies, de arvores e da identificar a necessidade de manejo. Os resultados mostraram uma predominância de especies exoticas compondo a arborizacao urbana do logradouro, em especial o Nim ( Azadirachta indica , A. Juss.) e Algaroba ( Proposis juliflora , Sw. DC) em detrimento das nativas, que representam apenas 35% de especies nativas. Paralelamente foram mensuradas as temperaturas na base da planta a partir de um sensor de temperatura com o intuito de confirmar a capacidade das arvores de climatizar e amenizar o ambiente. A taxa de diversidade de especies e pequena, trazendo efeito ecologico e estetico negativos, o que, de certa forma, favorece o desenvolvimento de doencas e pragas nas arvores. Foram identificados os seguintes problemas: raizes danificando calcadas, necessidade de manejo para nao causar problemas na rede eletrica e a predominância de especies exoticas.

Trata-se de um estudo que aponta para a analise juridica da greve dos caminhoneiros, de forma a se constatar quais os interesses que motivaram o seu desenvolvimento. Nesse sentido, o presente artigo alvitra para a necessidade de se compreender se o direito a greve foi legalmente exercido ou se foi ele usurpado por uma classe que nao possui legitimacao para realiza-lo. Assim, partiu-se de uma analise historica do direito a greve, de forma a se entender as lutas empreendidas para que a esse direito fosse realmente positivado e garantido pela Constituicao. Progressivamente, apresentaram-se as nuances principais da greve dos caminhoneiros, ocorrida em maio de 2018, de maneira a se poder vislumbrar toda a sua formacao e motivacao, atraves do metodo hipotetico-dedutivo, com a tecnica bibliografica de pesquisa. E por fim, percebeu-se a anomia legislativa existente no ordenamento juridico brasileiro concernente a pratica de uma greve convencionada entre empregados e empregadores.

 Diante de diversas tragédias ambientais ocorridas nos últimos anos, espera-se que voluntariamente as empresas relatem periodicamente como a organização está respondendo ao arcabouço de normativos vigente, qual o programa de sustentabilidade empresarial em vigor, como a empresa identifica riscos ambientais no seu negócio, o que está fazendo para melhor prevenir esses riscos, ou pelo menos detectá-lo mais cedo para tomar medidas corretivas. O contador é peça fundamental na garantia das organizações realizarem o alinhamento da estratégia da obtenção dos resultados econômico e financeiros com as obrigações socioambientais. A pesquisa apresentou que 97% dos contadores compreendem que eles são os responsáveis por promover a transparência das ações da empresa e 83% dos contadores informaram que concorda com o grande benefício que a informação contábil pode gerar para os usuários da informação sobre os impactos ambientais gerados pelo negócio o qual a organização esta inserida.

Responsabilidade social e meio ambiente: a contabilidade como ferramenta essencial ao desenvolvimento sustentável

Anais do(a) Anais do IV Colóquio Internacional de História da África e VIII Semana de Ciências Sociais

A reforma agrária como principio de amenização da desigualdade social na área rural: Análise do projeto no Assentamento Areias.

O Estado do Espirito Santo e o maior produtor de cafe Conilon do Brasil, porem a regiao produtora encontra-se em uma regiao onde existe restricao ao plantio, quanto a distribuicao de chuvas, requerendo assim, o uso de irrigacao complementar para garantir a produtividade das lavouras. A instabilidade das chuvas, nos ultimos anos, intensificou o uso de sistemas de irrigacao e vem promovendo mudancas comportamentais dos produtores quanto ao uso dos sistemas irrigacao. O objetivo deste estudo foi verificar o uso de irrigacao e as atitudes tomadas pelos produtores rurais por conta da proibicao de captacao de agua para fins de irrigacao no periodo da crise hidrica que afetou os produtores de cafe ao longo dos anos de 2015 a 2017 na regiao do Centro-Norte capixaba. O estudo foi direcionado para 590 produtores de cafe distribuidos em 28 municipios integrantes da regiao abrangida pela SUDENE no Espirito Santo. Como resultados, verificou-se que cerca de 97% dos entrevistados se utilizam de recursos hidricos para irrigar seus cafezais e, destes, aproximadamente 91% empregam os sistemas de baixo consumo de agua. Verificou-se, tambem, que a minoria dos entrevistados foi prejudicada pela proibicao de captacao ou irrigacao de suas lavouras porque foram selecionados para fiscalizacao pelos orgaos responsaveis. Para os poucos afetados pela fiscalizacao, as proibicoes de captacao ou irrigacao foram prejudiciais para a conducao de sua atividade cafeeira. O restante dos produtores rurais continuou irrigando suas lavouras normalmente ate que a escassez hidrica os impossibilitassem de fato.

DISTRIBUIÇÃO DOS SISTEMAS DE IRRIGAÇÃO NAS LAVOURAS DE CAFÉ NA REGIÃO DA SUDENE CAPIXABA

Engenharia e ciências ambientais: contribuições à gestão ecossistêmica

Coconut bagasse, an agricultural solid waste was used as biosorbent for the removal of hardness after alkalized treatment. The adsorption of Ca(II) was studied at pH 6.8. The analysis of the isotherms by the nonlinear model showed that the experimental data were best described by the Temkin model, with lower χ2 value was obtained. The maximum adsorption capacities by Langmuir model was 30.20 mg.g-1.The results using non linear and linear method shown low discrepancy between them to equilibrium study. The results show that the CHA adsorbent can be applied for the removal of Hardness from wastewater.

Modelagem de Equilíbrio e Cinética de Adsorção: Avaliação do Desempenho do Adsorvente no Abrandamento da Água para Irrigação e o Consumo de Animais

RESUMO A contabilidade aplicada ao setor publico no Brasil busca enquadrar-se aos padroes de convergencia as normas internacionais de contabilidade publica, tais como: a adocao da Demonstracao dos Fluxos de Caixa - DFC, composta por cinco quadros, um principal e quatro  acessorios, contendo informacoes sobre entrada e saida de caixa e equivalentes de caixa, conforme o Manual de Contabilidade Aplicada ao Setor Publico. O Objetivo da pesquisa foi conhecer se os municipios da microrregiao bragantina elaboraram a Demonstracao dos Fluxos de Caixa conforme ou nao conforme com as exigencias do MCASP, no ano de 2015. Os dados que serviram de base foram obtidos no site do Tribunal de Contas dos Municipios do Para – TCM/PA e no portal de transparencia dos municipios, no periodo de 02 de janeiro a 05 de fevereiro de 2017. Dados secundarios e aspecto exploratorio, do tipo bibliografico e documental e abordagem quantiqualitativa. Os resultados revelaram que os municipios de Peixe-Boi e Sao Francisco do Para estao em conformidade com o MCASP, elaborando a DFC de forma completa. Os municipios de Augusto Correa, Braganca, Capanema, Igarape Acu, Primavera e Tracuateua apresentaram apenas o quadro principal, deixando de demonstrar o detalhamento das informacoes contidas nos quatro quadros acessorios. O nivel de inadimplencia foi alto, onde 25% dos municipios apresentaram conformidade, enquanto 75% apresentaram nao conformidade em funcao de terem descumprido o manual. Palavras Chave: Municipios. Contabilidade - Setor Publico. MCASP. DFC.

Conformidade Municipal da Demonstração dos Fluxos de Caixa Frente ao Manual de Contabilidade Aplicada ao Setor Público

BIOMARCADORES PARA O MONITORAMENTO AMBIENTAL DE ECOSSISTEMAS AQUÁTICOS

Este artigo foi inspirado em parte da pesquisa de doutorado do autor, que investiga o uso das (TICs) no ensino basico na cidade de Manaus.

Uso de tics pelos professores do ambiente de mídias e laboratórios de informática das escolas estaduais da cidade de Manaus e aplicação na sala de aula

As Engenharias frente a Sociedade, a Economia e o Meio Ambiente 4

REMOÇÃO DE Cu(II) POR ADSORÇÃO EMPREGANDO CASCA DE COCO MODIFICADA COM FORMALDEÍDO POLIMERIZADO

Resumo Ao longo das últimas décadas, o conceito de família passou por muitas mudanças, divorciando-se do modelo nuclear tradicional. Embora a Constituição Federal tenha avançado quanto ao reconhecimento de novos núcleos familiares, ainda se omite na união homoafetiva, privando-a em termos de garantias e direitos. O objetivo deste artigo foi apontar a inexistência de preparação de estudantes e profissionais para lidar com casais homoafetivos e suas famílias. Trata-se de revisão narrativa respaldada por obras doutrinárias, legislação nacional pertinente, jurisprudência e documentos eletrônicos, como leis e normativas, que serviram de base para a elaboração do artigo científico. Com os avanços da sociedade e algumas recentes resoluções, hoje a união homoafetiva pode gozar de direitos semelhantes aos de casais heterossexuais quanto à reprodução medicamente assistida.

Planejamento para famílias homoafetivas: releitura da saúde pública brasileira

Este artigo analisa as “cidades na floresta”, criadas para atender aos grandes projetos ou “grandes objetos” economicos, implantados na Amazonia a partir da segunda metade do seculo XX; dando enfase as cidades e estas tambem chamadas de; Cidades dos notaveis, cidades-empresa, cidades rodoviarias e cidades tradicionais. A discussao e inspirada em reflexoes teoricas elaboradas por Henri Lefebvre, Berta Becker, Saint-Clair Cordeiro da Trindade Junior, Jose Aldemir de Oliveira, Milton Santos, pensarem uma teorizacao do espaco e, igualmente, ao proporem uma reflexao que de conta de compreender o territorio brasileiro em particular urbanizacao da Amazonia e os desafios de implementacao de politicas publicas.

O PROCESSO DE URBANIZAÇÃO NA AMAZÔNIA: DESTACANDO AS CIDADES DOS NOTAVÉIS, CIDADES-EMPRESAS, CIDADES RODOVIAS E AS CIDADES TRADICIONAIS

O presente trabalho tem o objetivo de identificar a perspectiva que a modalidade “salao parceiro” proporcionara a um determinado salao de beleza no que tange a analise de custos e, viabilidade financeira, auxiliando assim, a tomada de decisao. Buscou-se fazer um levantamento dos dados financeiros da empresa para que fosse possivel analisar as perspectivas que essa nova modalidade proporcionaria e, atraves da comparacao entre a forma tradicional e as novas perspectivas trazidas pela Lei. A elaboracao da demonstracao e uma ferramenta e a comparacao e a meta. Ficou constatado que o cenario atual vem apresentando prejuizos, enquanto que a comparacao feita sob a perspectiva do salao parceiro ficou evidenciado o lucro, pois, essa nova modalidade proporciona a reducao dos custos com mao de obra ja que o mesmo nessa modalidade sao as quotas pagas aos parceiros, bem como houve uma reducao do imposto (simples nacional) devido a base de calculo ser menor, consequencia da reducao da receita bruta ja que a mesma sera deduzida pelo valor das quotas dos parceiros.

“Salão parceiro”: uma nova perspectiva de custos para os salões de beleza

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e inundações: Santo Antônio do Leverger, Mato Grosso

Este trabalho de pesquisa foi desenvolvido buscando a producao de tecnologias 
limpas relacionadas a producao de biodiesel e biolubrificantes com perspectivas em 
aplicacoes industriais. Com esse objetivo, diversos materiais e bioprodutos foram 
obtidos, tais como a silica (MP1), proveniente da areia de praia, que permitiu a 
obtencao de um catalisador heterogeneo basico (SKS), utilizado com sucesso na 
sintese de bioprodutos atraves de reacao de transesterificacao de oleos vegetais. 
Alem disso, foram obtidos antioxidantes, a partir de extratos de Syzygium 
aromaticum, Punica granatum, Rosmarinus officinalis, Petroselinum crispum e 
Passiflora edulis para a avaliacao da estabilidade oxidativa dos bio-oleos 
sintetizados. O catalisador, o biodiesel, os biolubrificantes e os antioxidantes 
produzidos, foram caracterizados atraves das tecnicas de espectroscopia de 
infravermelho (FTIR),analises termicas (TG/DTG), Ressonância magnetica nuclear 
(RMN), Cromatografia gasosa com espectroscopia de massas (CG/MS), 
Difratometria de raios X (DRX), Microscopia eletronica de varredura (MEV), 
Espectroscopia de energia dispersiva (EDS), RANCIMAT, Espectrometria de 
fluorescencia de raios-X (FRX), Espectrometria de emissao optica por plasma 
acoplado indutivamente (ICP-OES). Os bio-oleos oxigenados, foram avaliados 
segundo Normas da American Oil Chemist’s Society (AOCS), American Society for 
Testing and Materials (ASTM) e European Standard (EN). Os biolubrificantes obtidos 
da reacao do oleo de algodao e dos alcoois, ciclohexanol (B1) e propilenoglicol (B2), 
apresentaram diversas propriedades fisico-quimicas dentro das normas, tais como, 
viscosidade, indice de viscosidade, corrosividade ao cobre, ponto de fluidez, que 
permitira a utilizacao como alternativas viaveis aos oleos lubrificantes comerciais, de 
fonte fossil, com o diferencial de serem renovaveis e nao agredirem o meio 
ambiente. A obtencao do biodiesel a partir da utilizacao do SKS nas condicoes cerca 
de 2,5 % m/m, 60 °C e 30 minutos, permitiu rendimentos de 90,01 %. O catalisador 
SKS foi reutilizado por cinco ciclos seguidos, para producao de biodiesel, com 
reducao de apenas 5 % de rendimento reacional, ao final do ciclo. Os bioprodutos 
(biodiesel e biolubrificantes) obtidos obedeceram as especificacoes das normas 
vigentes. Os antioxidantes naturais foram testados efetivamente nos bio-oleos, promovendo um aumento da estabilidade de oxidacao destes produtos, em cerca de 50% avaliado atraves do metodo Rancimat, segundo Norma EN 14112.

Produção de biodiesel e biolubrificantes: avaliação de novos catalisadores e antioxidantes naturais

Preparação de MOFs via eletroquímica e sua aplicação como fase estacionária para isolamento de voláteis pela técnica de headspace

FORMAÇÃO DE PROFESSORES NA PREFEITURA DE ARACAJU: REFLEXÃO-AÇÃO DAS TDIC NA EDUCAÇÃO

Setorização de áreas de alto e muito alto risco a movimentos de massa, enchentes e inundações: Santa Terezinha, Mato Grosso

Objetivo: Revisar as repercussões da reconstrução mamária na qualidade de vida das mulheres que foram submetidas à mastectomia. Metodologia: Estudo de revisão de literatura do tipo narrativa, realizada entre os meses de fevereiro a junho de 2019, foi incluído estudos de coorte que avaliaram a qualidade de vida em mulheres que foram submetidas à reconstrução mamária através dos instrumentos: EORTC QLQ-C30 e BR23 e WHOQOL-100. Resultados: De acordo com os resultados apresentados nessa revisão, sobre as repercussões da reconstrução mamária na qualidade de vida de mulheres mastectomizadas, foram considerados resultados positivos para a imagem corporal, função sexual, prazer sexual, funcionamento psicológico e perspectivas Conclusão: A cirurgia reconstrutiva de mama proporcionou benefícios as pacientes que realizaram reconstrução mamária, mas, não há evidências suficientes para afirmar que melhora a qualidade de vida, devido a pouca quantidade de amostras e a escassez de estudos com metodologia de ensaio clínico randomizado.

Impacto da reconstrução mamária na qualidade de vida de mulheres mastectomizadas

Em Os cativos, Plauto encena a tentativa de um pater familias de reaver seu filho, prisioneiro de guerra. A comédia é interpretada à luz do ius postliminium e o texto de Plauto é correlacionado com os esforços romanos de resgate de cativos da Segunda Guerra Púnica.

'Ius postliminium': 'Os cativos' de Plauto e da Segunda Guerra Púnica

Formação de professores para a educação básica: inovações, desafios e tensões

Formação Continuada de Professores e o Ambiente de Aprendizagem Colaborativo e-Proinfo

Setorização de áreas de alto e muito alto risco a movimentos de massa, enchentes e inundações: Barra do Bugres, Mato Grosso

Setorização de áreas de alto e muito alto risco a movimentos de massa, enchentes e inundações: Nova Olímpia, Mato Grosso

Para uma revisão dos 40 anos de aplicação da Constituição “Sacrosanctum Concilium” sobre a Sagrada Liturgia no Brasil – e quiçá em toda a América Latina –, o autor busca situar o documento no contexto histórico geral da liturgia. Primeiro verifica algumas características da liturgia no primeiro milênio da era cristã. Depois, constata como a liturgia foi tratada no segundo milênio, apontando alguns significativos deslocamentos de eixo na compreensão e vivência da mesma. A partir deste panorama histórico comparativo, pode-se entender o porquê da reforma litúrgica, proposta pelo Vaticano II, bem como as dificuldades que ela tem enfrentado em nosso país, não obstante as inúmeras realizações. Daí, enfim, emergem algumas perspectivas e desafios para o futuro.Abstract: In an attempt to examine the application of the Constitution “Sacrosanctum Concilium” on the Sacred Liturgy during the past 40 years in Brazil – and perhaps in Latin America as a whole – the author seeks to place the document in the general historical contexto of the Liturgy. As a first step, he identifies some characteristics of the Liturgy in the first millennium of the Christian Age. Next, he describes how it was dealt with in the second millennium, pointing to some significant deviations in the axle that influenced the way it was interpreted and practiced. With the help of this comparative historical panorama it becomes possible to understand why Vatican II proposed a liturgical reform, as well as the reasons for the difficulties the Liturgy has faced in our country despite its numerous achievements. From the above arguments, there finally emerge some new perspectives and challenges for the future.

“Sacrosanctum Concilium” e reforma litúrgica pós-conciliar no Brasil. Um olhar panorâmico no contexto histórico geral da liturgia: dificuldades, realizações, desafios

As moscas-das-frutas (Diptera: Tephritidae) sao pragas-chave na cultura da goiabeira Psidium guajava L., com diferentes especies de acordo com a regiao produtora no Brasil. Nesse sentido objetivou-se com esse trabalho conhecer a diversidade e analisar a fauna das moscas-das-frutas capturadas em um pomar de goiabeira, no municipio de Taquarana, Alagoas, situado no Nordeste brasileiro. As moscas-das-frutas foram coletadas diariamente, com auxilio de armadilhas McPhail, contendo atrativo. Foram registradas duas especies no pomar estudado: Ceratitis capitata e Anastrepha ssp. Todavia, a Anastrepha ssp foi a mais frequente, constante e dominante, considerada como uma praga invasiva, potencial em pomares de goiabeira.

O uso de armadilha para a coleta de moscas- das-frutas em pomar de goiabeira no município de Taquarana, Alagoas, Brasil.

Denaturalize modern science’s subject whiteness to de/re/construct the curriculum of history Resumo O artigo apresenta algumas reflexoes com intuito de propor uma via para a des/re/construcao do curriculo de historia, problematizando a relacao entre o sujeito, a ciencia moderna e a branquidade. Discute a intencao da ciencia moderna de produzir – a partir da Europa, das alvas luzes da razao e de uma cultura hegemonica (branca) – uma infalivel teoria do sujeito. Porem, com a proliferacao de diferentes teorias criticas e pos-criticas, chegou-se a desnaturalizacao e questionamento da branquidade como referencia superiorizada. Para des/re/construir o curriculo de historia, e fundamental colocar-se radicalmente a favor de outras historias e das epistemologias que lhes dao visibilidade. Palavras-chave: sujeito da ciencia moderna; branquidade; curriculo de historia. Abstract The paper presents some reflections aiming at proposing a way to de/re/construct the curriculum of history, problematizing the relationship between subject, modern science, and whiteness. It discusses the intention of the modern science of producing – from Europe, from the bright light of reason and a hegemonic (white) culture – an infallible theory of the subject. However, with the proliferation of different critical and post-critical theories, one has come to the denaturalization and questioning of whiteness as superior reference. To de/re/construct the curriculum of history, it is of utmost importance to put oneself radically in favor of other histories and epistemologies that give them visibility. Keywords: modern science’s subject; whiteness; history curriculum.

Desnaturalizar a branquidade do sujeito da ciência moderna para des/re/construir o currículo de história

Rompimento de aterros de estradas no município de Machadinho d’Oeste/RO: visita técnica

SILVA, J. D. D. A contribuicao das midias sociais na diminuicao da evasao escolar no ensino basico. 2019. 28 f. Trabalho de Conclusao de Curso (Graduacao em Administracao) - Universidade Estadual da Paraiba, Centro de Ciencias Exatas e Sociais Aplicadas, Patos, 2019.

A contribuição das mídias sociais na diminuição da evasão escolar no ensino básico

As aranhas são artrópodes distribuídos por todo o mundo, sendo sua abundância e diversidade diretamente ligadas à complexidade e estrutura do ambiente em que estão inseridas. O estudo teve como objetivo realizar um levantamento sistemático da araneofauna, em área remanescente de mata atlântica na Vila Bananeiras, em Arapiraca, Alagoas. O estudo foi realizado, no período de agosto de 2018 a julho de 2019, em quatro campanhas de amostragem, uma coleta a cada estação do ano. Para análise de variação temporal, considerou-se a coleta no início do mês de março – verão; no mês de maio – outono; na última semana de junho – inverno; e a coleta no mês de setembro - primavera. Utilizou-se duas metodologias para a coleta das aranhas: coleta manual e armadilhas-de-queda. Foram coletados 621 indivíduos, distribuídos em 10 famílias, dentre estas, 364 eram adultos e 257 jovens. Entre as famílias coletadas se destacam a Tetragnathidae, com 288 indivíduos; Araneidae, com 156 indivíduos e Theraphosidae, com 69 indivíduos. Referente à abundância de indivíduos por estação, verifica-se que durante o verão apresentou maior número de indivíduos, seguido pelo inverno e outono. O método da busca ativa foi mais eficaz ao ser comparado com a armadilha-de-queda. Conclui-se que a Mata Atlântica localizada na Vila Bananeiras apresenta uma diversidade em famílias de aranhas. Esta pesquisa possibilitou reduzir as lacunas existentes sobre o conhecimento da biodiversidade dos araneídeos, mas não é o suficiente, são necessárias novas pesquisas em outras localidades, no Estado de Alagoas. 
 
Diversidade de aranhas em área remanescente de Mata Atlântica, na vila Bananeira, zona rural de Arapiraca, agreste Alagoano

Índices nitrogenados, biomassa e produção de pimentão em SLAB associados a doses de nitrogênio via gotejamento

PRODUÇÃO CIENTÍFICA NA ÁREA DE SAÚDE COM FOCO NA PESSOA SURDA: UMA BIBLIOMETRIA

ASPECTOS JURÍDICOS E SOCIAIS DOS GRÊMIOS ESTUDANTIS ENQUANTO ESPAÇOS DE FORTALECIMENTO DAS JUVENTUDES NA FORMAÇÃO CIDADÃ

deva do do se a o de mais inteligente, as recebidas nas unidades, anônimas em maioria, do Disque-Denúncia, etc. 2013, triplicar o número de registros em comparação com o ano de um efetivo menor; disso, obtivemos um índice de confiabilidade nas denúncias de aproximadamente 50%, ou seja, a cada duas denúncias recebidas, se confirmou, resultando em um registro de ocorrência em uma delegacia circunscricional. Se ampliarmos essas denúncias para colaboradores, previamente acredito que seria mais um passo para otimização das ações de policiamento ostensivo Chegamos inclusive desenvolver

Geotecnologias na fiscalização ambiental: o uso de VANTS, SIG e mapas colaborativos para fins militares

Este artigo foi inspirado em parte da pesquisa de doutorado do autor, que investiga o uso das (TICs) nas aulas de matematica do ensino basico

Uso de tics pelos professores de matemática na cidade de Manaus e diretrizes para aplicação na sala de aula

Análises bioquímicas complementares a estudos de função da hemoglobina em bolsa de sangue

PROPOSTA DE ALTERAÇÕES EM UM GERADOR DE PULSOS ELÉTRICOS DE CÓDIGO ABERTO PARA CONTROLE DA SECREÇÃO DE INSULINA EM ILHOTAS DE LANGERHANS

The aim of this study was to study the phytosociology of weed species in areas of pasture cultivated with Brachiaria decumbens and Cynodon sp. (Tifton 85), in Ceará State, Brazil. The square inventory methodology was used in order to assess the weed community. Weed samples were quantified and classified by family, genus and species, using books and classification keys. The classification and quantification data of species allowed to calculate the following phytosociological variables: frequency (F), relative frequency (Fr), density (D), relative density (Dr), absolute dominance (DoA), relative dominance (DoR), importance value index (IVI), and similarity index (IS). The Amaranthaceae family was the one with the greatest intensity of species in both areas, represented mainly by Alternanthera tenera colla and Amaranthus viridis. In the area cultivated with B. decumbens, Cyperus rotundus presented higher results for frequency, density and abundance. In the Tifton 85 area, Nicandra physalodes presented higher values of density and abundance. The similarity of weed populations in pasture areas was 42.11%, with four species common to both areas.

Ervas daninha em pastagens: uma abordagem fitossociológica nas áreas do Ceará

O artigo analisa uma das políticas educacionais para a diversidade, a de Educação Escolar Indígena. O estudo foca em problemas na sua efetivação, permitindo-nos refletir sobre seu desenvolvimento no Acre. Aponta os embates na sua definição, destacando o papel dos agentes envolvidos desde a formulação até a execução nos contextos formais. Toma como base metodológica o Ciclo de Políticas. Das questões resultantes destacamos o fato das propostas e práticas de EEI no Acre terem transformado os direitos educativos indígenas em obrigações de Estado, mas perdendo seu caráter de produção coletiva e autônoma.

n. 41 - EDUCAÇÃO ESCOLAR INDÍGENA: O CENÁRIO DAS POLÍTICAS PÚBLICAS NO EXTREMO OCIDENTE DO BRASIL

DESENVOLVIMENTO DE UM SISTEMA WEB PARA GESTÃO DE EQUIPAMENTOS MÉDICOHOSPITALARES

RESUMO O artigo analisa uma das políticas educacionais para a diversidade, a de Educação Escolar Indígena. O estudo foca em problemas na sua efetivação, permitindo-nos refletir sobre seu desenvolvimento no Acre. Aponta os embates na sua definição, destacando o papel dos agentes envolvidos desde a formulação até a execução nos contextos formais. Toma como base metodológica o Ciclo de Políticas. Das questões resultantes destacamos o fato das propostas e práticas de EEI no Acre terem transformado os direitos educativos indígenas em obrigações de Estado, mas perdendo seu caráter de produção coletiva e autônoma.

O presente artigo pretende recolher os dados fundamentais, presentes no dialogo platonico A Republica, relativos as funcoes, objetos e partes da alma na teoria platonica da alma tripartite. A centralidade da chamada Teoria da Funcao Propria e o fator determinante para tal empresa.

FUNÇÃO PRÓPRIA, PARTES DA ALMA E VIRTUDE MORAL NA ÉTICA PLATÔNICA

Desenvolvimento de Materiais Nanoestruturados Baseados em Óxidos Metálicos e Avaliação da Respetiva Atividade Fotocatalítica em Substratos Sólidos

A DISCIPLINA METODOLOGIA DO ENSINO DA MATEMÁTICA III COMO ESPAÇO DE DISCUTIR EDUCAÇÃO MATEMÁTICA INCLUSIVA: UM RELATO DE EXPERIÊNCIA

ENSINO DE TEATRO E REINVENÇÕES DA REALIDADE: NOTAS SOBRE EXPERIÊNCIA ESTÉTICA, DOCÊNCIA E DESENVOLVIMENTO HUMANO

O The vine is a plant with great capacity to adapt to various edaphoclimatic factors. The name "rustic grapes" or "common grapes" is used in Brazil for all American grape cultivars (Vitis labrusca and Vitis bourquina), and hybrids of different species of Vitis. In conventional agriculture, due to the need to produce more in less time, it is common to use inputs and techniques aimed at increasing production, often negatively affecting the environment. The adoption of management and use practices that contribute to an increase in organic matter content can improve its physical qualities, increasing, for example, the water retention capacity, thus becoming an important strategy for the sustainable management of agricultural systems. The objective of this work was to evaluate the physical attributes of the soil in grape cultivation between rows, between plants and planting area, evaluating its soil density, particle density and gravimetric moisture. The research was developed in the property of Mr. Flávio located in São Vicente Férrer PE. The experimental design used was that of split plots, where the main treatments were three systems of use: Grape Cultivation between rows, plants and planting renewal area. And the secondary treatments were four layers of the soil profile: 0-10cm, 1020cm, 20-30cm and 30-40cm. In the results we can observe a higher value of soil density when we increased the depth, since the particle densities did not differ statistically, the soil moisture was higher in the most superficial soil layers, being explained by the higher organic material content and vegetation cover. present in areas between plants.

DEMOCRATIZAÇÃO DO CONHECIMENTO E VALORIZAÇÃO PROFISSIONAL: CAMINHOS PARA O DESENVOLVIMENTO TECNOLÓGICO E SOCIAL

AVALIAÇÃO DOS ATRIBUTOS FÍSICOS DO SOLO SOB SISTEMA DE CULTIVO DA UVA, ENTRE LINHAS, ENTRE PLANTAS E AREA DE RENOVAÇÃO MUNICÍPIO DE SÃO VICENTE FERRER-PE

Organizações não-governamentais voluntárias, globais e imprescindíveis.

A melhor catequese: uma liturgia bem celebrada. Elementos para reflexão pessoal e em grupos

As necessidades nutricionais apos a gastroplastia ocorrem devido a ingestao alimentar restrita ou a reducao das areas que ocorrem a absorcao dos nutrientes. O sucesso da cirurgia nao depende somente da reducao de peso ou tecnica escolhida, mas tambem da capacidade deste paciente em reorganizar e adaptar seus habitos alimentares pos bariatrica. O objetivo do estudo foi descrever as mudancas da microbiota intestinal relacionadas ao pos operatorio de gastroplastia. Foi realizado um estudo do tipo descritivo de natureza quantitativa, com analise de respostas de 36 pacientes submetidos a gastroplastia, com idade entre 20 a 70 anos. Participaram do estudo 32 pessoas do sexo feminino e 04 do sexo masculino. Os dados foram coletados por meio do sistema de pesquisa on line Survio, no periodo de 09 a 31 de maio de 2019. Ainda sao poucos os estudos relacionados ao uso de probioticos com a cirurgia bariatrica, no entanto, os resultados encontrados ate o momento indicam beneficios significativos, reduzindo inflamacoes efeitos colaterais entre outros. O resultado obtido nesse estudo teve inicio depois da avaliacao de 36 pacientes com idade variando entre 20 anos e 70 anos. Em relacao ao sexo, 91,7% era feminino e 8,3% era masculino. Dos que relataram ter feito uma dieta especial antes/depois da bariatrica, responderam Sim (88,9%) e Nao (11,1%). A microbioma intestinal contribui para o metabolismo dos alimentos, fatores essenciais de crescimento, que incentiva o sistema imunologico e protegem contra infeccoes por microrganismos fortemente virulentos. Sendo assim o uso de probioticos parece restringir sintomas gastrointestinais no pos operatorio.

MUDANÇAS NA MICROBIOTA INTESTINAL RELACIONADAS AO PÓS OPERATÓRIO DE GASTROPLASTIA

Os metais pesados tornaram-se responsaveis pela poluicao no ambiente, caracterizando assim um problema global. Um dos processos que tem se apresentado como alternativa viavel para o tratamento de efluentes que contem ions de metais pesados como Cu(II), Pb(II), Cr(II) e Zn(II) e a bioadsorcao, por ser de baixo custo, torna-se uma alternativa ecologica por utilizar residuos agricolas, que normalmente seriam descartados no meio ambiente. Neste trabalho foi feito um estudo de cinetica e mecanismo de difusao com solucoes sinteticas de concentracoes 100; 300 e 500 mg L -1 de Cu(II), utilizando casca de coco modificada com acido tartarico (CCAT). Foi empregada analise nao linear com modelo de Ho e Elovich para o estudo cinetico, e para estudo de difusao os modelos de Webber-Morris e Boyd.

Utilizando casca de coco quimicamente modificada para remoção de cobre (ii): estudo de cinética e mecanismo de adsorção

Estudo do comportamento de escolha com um novo programa de reforço de intervalo variável

A criminalidade feminina tem crescido significativamente ao longo dos anos, evidenciando a importância de se estudar esse fenomeno social. Como infelizmente muitas vezes a mulher ainda e vista como um ser docil e fragil, ocasiona-se uma “escassez” de conteudo acerca do tema. A maioria dos trabalhos academicos sao desenvolvidos com base na vitimizacao e nao na observacao da mulher enquanto delinquente. Deste modo, uma vez havendo um grande crescimento do encarceramento feminino, se faz necessario discutir questoes do genero, pois o genero feminino requer maior observacao as peculiaridades e especificidades que lhes sao inerentes. Neste caso, o presente trabalho busca analisar os motivos do crescimento da criminalidade feminina e as singularidades da mulher quando encarcerada, tanto no aspecto juridico quanto nos sociologicos e de politicas publicas. Considera ainda, os efeitos negativos do carcere feminino, uma vez que muitas destas detentas desligam-se do lado de fora da cela, deixando para tras a estrutura de um lar sem nenhuma seguranca de que voltara para casa ressocializada e que sera aceita tanto no âmbito social quanto no profissional.Para isto, foi realizada uma pesquisa de levantamento de producoes cientificas acerca do tema, sendo esta de teor bibliografico e levantamento documental. Os dados utilizados serao os ja existentes em outras pesquisas e os fornecidos no Infopen — Departamento Penitenciario Nacional (DEPEN), aconselhando, por fim, apresentacoes de estudos e pesquisas cientificas que incentivem a criacao de politicas publicas serias voltadas para as mulheres encarceradas como forma de garantir seus direitos, afim de que estes estejam assegurados e que sejam por fim respeitados.

Mulher, participação social e criminalidade: as peculiaridades do cárcere.

As propostas de Guerreiro Ramos e Frantz Fanon para superação da situação colonial

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e inundações: Marechal Thaumaturgo, Acre

Esta tese investiga a fotografia como elemento potencialmente pedagogico por suas caracteristicas de dialogo com a subjetividade humana. Essa relacao dialogica com a imagem ocorre desde o principio da humanidade e com o desenvolvimento tecnologico isso tem se intensificado e trazendo novas problematicas que o meio educacional nao acompanha de modo contextualizado com a vida do docente. A averiguacao da possibilidade do uso da imagem como alternativa de uma pedagogia imagetica se desenvolveu sob o conceito de iconologia desenvolvido por Erwin Panofsky. O historiador da arte elaborou uma leitura que privilegiava um aprofundamento alem dos elementos meramente formais e esteticos apresentados na imagem. O conceito usado por Erwin Panofsky inicialmente desenvolvido para leitura de obras pictoricas foi redirecionado a fotografia, ja que esse mecanismo imagetico esta estruturalmente fixado em um suporte que possibilitara sua concretizacao e visualizacao, utilizando alguns elementos composicionais analogos a arte pictorica. A concepcao de analise historico-social utilizada pelo teorico alemao se estrutura em tres etapas subsequentes numa crescente apropriacao das situacoes representadas na imagem. Estas tres etapas crescentes coincidem com o modo processual da construcao de conscientizacao elaborada por Paulo Freire como forma de uma compreensao do sujeito em relacao a sociedade e sua subjetividade. Portanto, buscamos na categoria de pensamento Conscientizacao, desenvolvida pelo grande educador brasileiro os elementos necessarios de relacao com o conceito de iconologia de Erwin Panofsky. Para aproximar e legitimar a relacao entre os dois conceitos e direciona-los a uma possibilidade pedagogica, recorremos ao pensamento do educador Francisco Gutierrez a perspectiva educacional voltada para o campo de uma Comunicacao Total, que privilegia uma educacao que incorpore todos os meios de comunicacao como totalidade necessaria para o desenvolvimento deste processo de conscientizacao.

Partindo de uma sugestiva reflexão sobre a divina Liturgia (o operar de Deus em favor da humanidade) que se manifesta e nos toca mediante sinais sensíveis, o autor leva em consideração o espaço sacramental (o santuário e outros) como manifestação viva do mistério de Cristo (memorial celebrativo da nossa fé em Cristo, celebração permanente desta fé) e, em seguida, contempla o lugar privilegiado da Palavra nesse contexto. Após tratar sobre o sentido teológico-litúrgico do santuário e da Palavra nele celebrada, o autor oferece sugestões práticas para a celebração e a vivência da fé nesse contexto.Abstract: Starting with a suggestive reflection on the divine liturgy (God’s operation in favour of humanity) that manifests itself and moves us through sensitive signs, the author considers the sacramental space (the sanctuary and others) as a live manifestation of Christ’s mystery (the celebrative memorial of our faith in Christ, a permanent celebration of this faith) and then examines the privileged place occupied by the Word in this context. Having dealt with the theological-liturgical meaning of the sanctuary and of the Word celebrated therein, the author offers practical suggestions for the celebration and experience of the faith in this context.

Celebração da fé em contexto de santuário memória e compromisso. Elementos teológico-litúrgicos

Efeitos da associação de estratégias de interferência de microRNAs na indução de apoptose mediada por citrato de ródio livre e associado à nanopartículas de maghemita em cultura de células de carcinoma mamário humano

A obesidade vem se tornando uma das maiores aflicoes da saude publica, por elevar a porcentagem de mortalidade e os riscos favoraveis para diabetes mellitus, hipertensao e disfuncao cardiaca. A predicao para 2025 sera de 2,5 bilhoes de cidadaos com sobre peso, podendo chegar a 700 milhoes de obesos. O objetivo da pesquisa foi apontar a influencia hormonal do excesso de carboidratos refinados e do meio ambiente no avanco da obesidade. O estudo do tipo ecologico foi desenvolvido por meio de aplicacao de questionario estruturado on-line, utilizando o software Survio, enviado aos participantes entre 15 e 55 anos, de ambos os sexos, no periodo de marco a novembro de 2018. A pesquisa foi desenvolvida nas regioes administrativas do Distrito Federal, em Santa Maria e no Gama, e composta por tamanho amostral igual a 108 respondentes. Para a construcao do referencial teorico foram feitas buscas nas plataformas especializadas Google academico, Pubmed, Scielo, Medline e livros. Com base no questionario aplicado, grande parte dos individuos encontram-se cientes dos riscos, que levam a obesidade. Dentre os entrevistados, cerca de 85% consomem carboidratos refinados em excesso, e 63% nao praticam atividade fisica. Este dado comprova porque o Brasil tem mais de 50% da populacao acima do peso. A presente pesquisa viabilizou entender como os fatores hormonais e ambientais podem conduzir diretamente a um quadro de obesidade e os recentes achados, envolvendo a obesidade, abrem novos campos de pesquisa para o controle dessa adversidade, essencialmente nos setores de nutricao e metabolismo.

INFLUÊNCIA HORMONAL DO EXCESSO DE CARBOIDRATOS REFINADOS E DO MEIO AMBIENTE NO AVANÇO DA OBESIDADE

Com o objetivo de avaliar o balanço hídrico da microbacia do Córrego Seco no município de Caratinga, MG, foram realizados os cálculos hidrológicos usando o método de Thornthwaite - Mather. Esta pesquisa tem uma natureza quantitativa se tratando especificamente de um estudo de caso. O resultado do balanço hídrico demonstrou que os meses de maior evapotranspiração, ou seja, acima de 100 mm, foram os meses de janeiro, agosto, setembro, outubro e dezembro. Entre os meses de março a novembro ocorreram os maiores déficits hídricos caracterizando a estação seca, contudo as maiores precipitações ocorreram entre os meses de dezembro a fevereiro, caracterizando uma estação chuvosa, mais úmida, demonstrando que a área estudada apresenta duas estações bem distintas e definidas.

Balanço hídrico da microbacia do Córrego Seco em Caratinga, Minas Gerais, sudeste do Brasil

Nesta pesquisa, aborda-se o tema ansiedade na performance musical (APM). 
Para o desenvolvimento desta pesquisa, foi definido como objetivo geral, investigar a 
prevalencia da ansiedade na performance musical e como objetivos especificos, a 
investigacao das situacoes, sintomas e observacao e analise de resultados dos exercicios 
de simulacao de performances musicais realizados pelos alunos da Escola de Musica da 
Universidade Federal do Rio Grande do Norte (EMUFRN) em sala de aula, como forma 
de treinamento de adversidade/enfrentamento da ansiedade na performance musical e 
dessensibilizacao de efeitos. As abordagens metodologicas adotadas para esta pesquisa 
foram a Quali- Quantitativa e a Experienci-Acao. O campo empirico foi constituido por 
134 alunos dos Cursos de Bacharelado e Tecnico em Musica da EMUFRN. A partir da 
aplicacao de questionarios ao publico citado, identificou-se a existencia da problematica 
pesquisada. Os procedimentos metodologicos para a coleta dos dados foram: 
levantamento bibliografico a respeito do tema; elaboracao e aplicacao de questionarios; 
delimitacao do universo de pesquisa a turma de Graduacao da disciplina „Preparacao 
para o palco e performance‟; aplicacao do Estudo das Sete Habilidades (GREENE, 
2001); observacao dos exercicios de simulacao de performance; filmagens de 
performances musicais e coleta de relatos. Os resultados possibilitaram: elencar os 
principais sintomas; apontar as situacoes de performance provocadoras de ansiedade 
entre os performers; alertar quanto ao uso de medicamentos, alcool e substâncias 
ilicitas; desenvolver o treinamento de adversidade (simulacoes de performances em 03 
situacoes), como estrategia de preparacao para a performance musical no palco, atraves 
da Experienci-Acao.

Ansiedade na performance musical - simulações de performance para constatação de efeitos: uma análise através da experiênci-ação no âmbito da Escola de Música da UFRN

ENGENHARIA DIDÁTICA PARA O ENSINO DA SEQUÊNCIA DE PADOVAN: UM ESTUDO DA EXTENSÃO PARA O CAMPO DOS NÚMEROS INTEIROS

Entre 1967 e 1969 Mojica e Lucchetti formaram uma parceria criativa que resultou em um dialogo multimidia sem precedentes ate entao no pais. O roteirista escreveu, sob o titulo de “O Estranho Mundo de Ze do Caixao” tres diferentes produtos culturais: um filme, um seriado televisivo e uma serie de quadrinhos. A partir da reflexao do dialogo entre as linguagens e tecnicas audiovisuais com a narrativa visual dos quadrinhos, pode-se tracar de que maneira se alterou a concepcao original do Ze do Caixao a partir do momento em que seu novo roteirista lhe trouxe uma nova abordagem. A analise tecnica dessa convergencia de midias que permitiu ao personagem se massificar, bem como do discurso e contexto historico-social dessas obras escritas por Lucchetti, expoe uma visao sobre a forma como o desenvolvimento tecnologico interage com atores-sociais dentro da industria cultural. O objetivo desta dissertacao e estudar como a versao do Ze do Caixao feita por Rubens Francisco Lucchetti contribuiu para sua manutencao junto ao publico do genero terror. Experiencia que transcendeu esse nicho e transformou o personagem em um icone tambem no imaginario popular brasileiro. Um produto cultural polemico e contestador que encontrou sua maior reverberacao multimi.

“O estranho mundo de Zé do Caixão” por R. F. Lucchetti: diálogos multimídia e hibridismo no terror brasileiro

Esse projeto apresenta uma analise do uso da tecnologia da informacao nas organizacoes, com aplicacoes utilizando a Internet das Coisas, Tudo em questao de tecnologia que existe hoje pode ser conectado, um telefone de ultima geracao a uma cafeteira expressa. A criacao do termo “internet das coisas” e ter processos pre-definidos, informacoes facilitando o cotidiano a qualquer momento com mais facilidade. O mundo conectado, mercados, cursos, palestras, agendas, horarios de transporte, tempo, o mundo mais dinâmico e mais organizado. 
A tecnologia da informacao esta cada vez mais junta das organizacoes e a Internet das Coisas vem ganhando cada vez mais atencao devido as varias funcionalidades e aplicacoes que pode fornecer para o ambiente de trabalho.

A utilização da tecnologia da informação nas organizações: o uso da internet das coisas (iot)

Dando continuidade a significativas considerações teológico-litúrgicas anteriores em torno da “celebração da fé em contexto de santuário” [cf. REB 66 (2006) 787-806], o autor reflete agora sobre o sentido e o lugar da celebração eucarística, da celebração da penitência, de outros sacramentos e sacramentais e da Liturgia das Horas, bem como sobre o sentido e o lugar das devoções e da piedade populares e da cultura nesse contexto. Não só reflete teológica e liturgicamente sobre as questões, mas oferece também sugestões práticas para a celebração da fé nos santuários.Abstract: Continuing the previous significant theological-liturgical considerations about “the celebration of the faith in a sanctuary context” [cf. REB 66 (2006) 787-806], the author now reflects on the meaning and on the place of the Eucharistic celebration, of the celebration of penitence, of other sacraments and sacramentals and on the Liturgy of the Hours. He also examines the meaning and the place of the popular devotions and piety and of the culture in that context. He does not only reflect in a theological and liturgical way about these issues but also offers practical suggestions for the celebration of the faith in the sanctuaries.

Celebração da fé em contexto de santuário: memória e compromisso. Elementos teológico-litúrgicos. (Continuação)

A celula e a menor particula viva que se encontra em nosso corpo e desempenha uma grande quantidade de funcoes. Todos os tecidos, orgaos e sistemas a possuem como base. E por este motivo, que o trabalho tem por objetivo analisar nos livros didaticos de ciencias do 8o ano do Ensino Fundamental aprovados pelo PNLD 2017, como vem sendo abordado o conteudo de Citologia. Tambem verificar a percepcao dos professores acerca dos desafios e limitacoes no uso desses livros em sala e a partir das mudancas feitas com a aprovacao da BNCC (Base Nacional Comum Curricular). A pesquisa e de cunho qualitativo e foi dividida em tres partes: analise de tres livros didaticos, entrevista semiestruturada com tres professores de tres escolas publicas da cidade de Sao Cristovao/SE e aplicacao de um questionario para estes mesmos professores. Diante de todos os resultados, e perceptivel que ha grandes desafios a serem enfrentados e superados na educacao e no ensino de Citologia.

Limites e possibilidades no ensino de citologia à luz dos livros didáticos de ciências aprovados pelo PNLD 2017 e da Base Nacional Comum Curricular

A Importância da Energia Solar para o Desenvolvimento Sustentável

GERENCIAMENTO DE REDES DE ENERGIA INTELIGENTES (REI) EMPREGANDO ANÁLISE POR MODELO PREDITIVO ATRAVÉS DE REDES MODULARES EXPANSÍVEIS DE INSTRUMENTAÇÃO

Plano de ação: aumento na participação do pré-natal das gestantes do bairro jardim progresso, em Mandaguari, Paraná

RESUMO: Objetivou-se com este trabalho comparar a eficacia da introducao dos experimentos simples nas aulas de ciencias com o ensino tradicional e sua influencia no processo de ensino aprendizagem, facilitando a comunicacao entre professor e aluno para a quebra das barreiras existentes no cotidiano escolar. A pesquisa foi realizada em duas turmas de 7o ano do ensino fundamental, de uma escola da rede publica municipal de Santana do Ipanema nas quais foram aplicadas um pre-teste e um pos- teste com questoes semiestruturadas que abordaram pontos referentes ao processo de metabolizacao dos fungos. O 7o ano “A” foi utilizado como a turma teste o 7o ano “B” como a turma controle. A turma controle consiste naquela onde o conteudo foi ministrado de forma tradicional com aula expositiva e a turma teste naquela onde foi aplicado um experimento simples sobre o conteudo debatido. Para a analise dos dados foi utilizado o teste do Qui-Quadrado, o qual consiste em um teste de hipoteses que avalia a associacao existente entre variaveis qualitativas. Os resultados revelaram que houve um avanco nos resultados em ambas as turmas, destacando um aumento de 38,46% no resultado da turma controle apos a apresentacao do conteudo e um aumento de 86,66% na turma teste apos a aplicacao da aula pratica. Os resultados obtidos a partir da pratica mostra a necessidade de buscar novos metodos que fornecam subsidios para a melhoria do ensino de ciencias, proporcionando assim o aprendizado dos alunos a partir da interacao entre teoria e pratica. PALAVRAS-CHAVE: aula pratica, aula expositiva, interacao. ABSTRACT: The aim of this study was to compare the effectiveness of the introduction of simple experiments in science classes with traditional teaching and its influence on the teaching and learning process, facilitating communication between teacher and student to break existing barriers in daily school life. The survey was conducted in two groups of 7 years of primary school, a school of public health system of Santana do Ipanema in which a pre-test were applied, and a post-test with semi-structured questions that addressed points regarding the process of metabolizing fungi. The 7th grade "A" was used as the test class the 7th grade "B" as the control group. The control class that is where the content was taught in the traditional manner with lecture and class test that where a simple experiment on the content discussed was applied. For data analysis, the chi-square, which consists of a hypothesis test that assesses the association between qualitative variables was used. The results revealed that there was an improvement in the results in both groups, highlighting an increase of 38.46% in the control group result after the presentation of content and an increase of 86.66% in the test group after application of classroom practice. The results from the practice shows the need to seek new methods that provide subsidies for the improvement of science education, providing student learning from the interaction between theory and practice. KEYWORD: classroom practice, lecture, interaction.

A Importância dos experimentos simples para as aulas de ciências e sua influência no processo de ensino aprendizagem

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e inundações: Teixeirópolis, Rondônia

O trabalho faz uma analise sobre a obra Analise de textos: fundamentos e praticas da autoria de Irande Antunes publicada pela Editora Parabola no ano de 2010.

Neste artigo, no qual se problematizam a hegemonia branca e o eurocentrismo, analisam-se representacoes de negros, indigenas e brancos no curriculo de um curso de Licenciatura em Historia. O curriculo esta sempre relacionado a representacoes de identidades etnico-raciais e, como os estudos etnico-raciais vem mostrando, sistematicamente ele contribui para reproduzir as representacoes hegemonicas, reforcando as hierarquias raciais construidas no periodo colonial. Examinou-se o projeto pedagogico do curso, realizaram-se observacoes de aulas inspiradas na etnografia, e fizeram-se entrevistas semiestruturadas com estudantes do curso. Conclui-se que as diferencas negras e indigenas necessitam ser mais visibilizadas e que o lugar da branquidade deve ser sistematicamente questionado para colocar em xeque as compreensoes estereotipadas que circulam na Licenciatura em Historia.

O currículo de uma Licenciatura em História e as representações de identidades étnico-raciais: tensões, manutenções e ambivalências

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e Inundações: Vale do Anari, Rondônia

Gênero, mulheres e masculinidades na história, literatura e no cinema

Setorização de áreas de alto e muito alto risco a movimentos de massa, enchentes e inundações: Cruzeiro do Sul, Acre

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e Inundações: Mirante da Serra, Rondônia

1Estudante Engenharia Agronômica Universidade Feder al de São João del-Rei, Sete Lagoas, Minas Gerais; 2 Pó doutorando em Fitopatologia, Embrapa Milho e Sorgo, Sete Lagoas, Minas Gerais; frederick.aguiar@colaborador.embrapa.br e briciolan za@gmail.com; Pesquisador(a), Embrapa Milho e Sorgo, Sete Lagoas, Minas Gerais, dagma.silva@embrapa.br e luci ano.cota@embrapa.br; Graduando em Engenharia Ambiental, Faculdades Santo Agostinho/ FASASETE, Sete Lagoas, Minas Gerais;

Agressividade do patógeno Phaeocytostroma ambiguum causando podridão de colmo em milho.

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e inundações: Bom Jesus, Santa Catarina

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e inundações: Alto Paraíso, Rondônia

O Ecoturismo e um segmento do turismo que vem crescendo ao longo dos anos. Esse segmento de atividade turistica utiliza de forma sustentavel o patrimonio natural e cultural, tendo como base o equilibrio harmonico entre a preservacao do meio ambiente, conservacao da cultura e desenvolvimento socioeconomico. O Camping do Magico e um empreendimento, voltado para a area de ecoturismo, localizado a cerca de 18 Km do municipio de Bonito-PE. O municipio de Bonito-PE possui um potencial ecoturistico relevante, direcionando o desenvolvimento em consonância com a conservacao ambiental. Esse estudo teve como base avaliar os impactos ambientais do ecoturismo no Camping do Magico, selecionando os indicadores que melhor apresentam os efeitos dos impactos nessa area, propondo implantar novas metas para melhor desenvolvimento ambiental. Na identificacao e caracterizacao dos impactos ambientais no Camping do Magico, analisou-se que existe uma correlacao entre os impactos as caracteristicas da visitacao e os visitantes. O ecoturismo e uma atividade turistica impossibilitada de nao gerar impactos. Visando isso, propoe-se medidas mitigadoras e de compensacao ambiental para os impactos negativos encontrados e estimulo para os impactos positivos.

Caracterização da visitação dos visitantes e avaliação de impactos ecológicos e recreativos no camping do mágico Bonito – PE

A atividade física promove benefícios da atividade física para a vida das pessoas, em qualquer faixa etária. O desenvolvimento motor adequado é um desses benefícios. Dessa maneira, tratando-se de área de atuação, esses temas são de interesse da Educação Física, uma área abrangente, onde cabem também as atividades recreativas. O objetivo deste trabalho foi verificar as possíveis relações entre as atividades recreativas e o desenvolvimento motor de crianças. Para isso, o presente trabalho dedicou-se a uma revisão bibliográfica sobre o tema, focando nos textos em língua portuguesa e utilizando palavras-chave na busca de artigos e livros em bases de dados como Periódicos Capes e Scielo Brasil. Diante dos achados, pode-se concluir que as atividades recreativas são recomendadas para a garantia do desenvolvimento motor de crianças. Porém, os efeitos positivos destas práticas são mais consideráveis quando a atividade é planejada e orientada de forma adequada. Diante dessas conclusões, considera-se o papel da Educação Física Escolar fundamental em todo esse processo.

ATIVIDADE RECREATIVA NO DESENVOLVIMENTO MOTOR INFANTIL – ESTUDO DE REVISÃO

SILVA, J. W. G. Solucoes algebricas de equacoes polinomiais de grau N com coeficientes que formam uma progressao geometrica. 2018. 94f. Trabalho de Conclusao de Curso (Graduacao em Matematica) - Universidade Estadual da Paraiba, Monteiro, 2019.

Soluções algébricas de equações polinomiais de grau N com coeficientes que formam uma progressão geométrica

The teaching of dance still presents itself as a major challenge for much of the 
physical education teachers. Starting from issues such as what to teach?, why 
teach? and how to teach?, we propose here to discuss the presence of dance as one 
of the contents of physical education. In this sense, this search, from the literature 
review, understand the social function of school and physical education to 
understand the importance of that content and build a solid proposal for its teaching. 
The text is divided into four topics, each dedicated to the deepening of a question (1. 
The construction of the school; 2. The school we want, 3. about physical education 
4. and dance in perspective). As theoretical orientation, appropriator of theories and 
critical conceptions of education, because we believe these are the most consistent 
with the needs of the public school. As a result, we chose to report one of our actions 
with this content under the PIBID (Institutional Program of Initiation to Teaching) in a 
public school in the interior of Pernambuco. After reflecting on difficulties of this 
experience, we conclude by highlighting the importance of a school (and physical 
education) focusing on active ownership of knowledge as a way to promote the 
emancipation of the subject.

Desenvolvimento de robô móvel a partir do conceito de cidades inteligentes

Avaliar o conhecimento dos profissionais de enfermagem do centro cirurgico quanto o desenvolvimento do protocolo de cirurgia segura. Metodo: Estudo transversal, de natureza exploratoria e abordagem quantitativa. Utilizou-se como criterios de elegibilidade profissionais de enfermagem que prestam assistencia direta ao paciente no centro cirurgico e que possuem vinculo empregaticio ha mais de tres meses no hospital. Resultados: Os dados apresentados mostram que 100% dos profissionais pesquisados referiram que conhecem o protocolo de Cirurgia segura, entretanto, apenas 66,7% destes, realizam a verificacao antes da inducao anestesica do prontuario do paciente, sitio cirurgico, procedimento a ser realizado, termo de consentimento assinado e 90% questionam se o paciente possui alguma alergia. O desenvolvimento do protocolo de cirurgia segura garante ao paciente a reducao de danos e eventos adversos proveniente dos cuidados em saude. Conclusao: O estudo possibilitou avaliar que os profissionais de enfermagem possuem um bom conhecimento sobre o desenvolvimento do protocolo de cirurgia segura, no entanto 
ficou evidente que deixam de seguir as diretrizes estabelecidas pelo Ministerio da 
Saude fazendo com que esse conhecimento seja fragilizando e insuficiente.

Cirurgia segura: conhecimento dos profissionais de enfermagem de um hospital privado do agreste Pernambucano.

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e Inundações: Buritis, Rondônia

Colar o adesivo na porta de casa é R$ 30. Se for bandeira, é mais de R$ 100. Quem promete votar e entrega o número do título de eleitor recebe R$ 40. Balançar bandeira durante visita do candidato na comunidade, R$ 40 ou R$ 50. Para vigiar das 8h às 17h30 as bandeiras na rua é mais ou menos R$ 500 pelo mês inteiro. Esses exemplos de compra de votos e de cabos eleitorais foram relatados à Pública por moradores da comunidade dos Coelhos, na região central de Recife. “[Os candidatos] Pegam o título, o povo fica com medo e vota mesmo. Eles dizem que vão olhar quantos votos tiveram na área”, contou uma jovem de 22 anos.

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e inundações: Campo Novo de Rondônia, Rondônia

A publicidade caracteriza-se por ser um eficaz meio de divulgacao dos produtos e servicos das 
empresas, mas deve observar limites impostos por lei, a fim de respeitar o consumidor, que 
ocupa uma posicao de vulnerabilidade frente ao fornecedor-anunciante. O objetivo do trabalho 
e analisar quais os limites da atividade publicitaria para que os anuncios nao se tornem perigo 
ao consumidor, quando na verdade deveriam possibilitar o conhecimento acerca do que esta 
sendo ofertado. Tal objetivo sera alcancado por meio da pesquisa bibliografica e exploratoria, 
buscando a familiarizacao com o tema da publicidade enganosa e abusiva frente a 
vulnerabilidade do consumidor; documental, utilizando-se da lei e de jurisprudencias 
pertinentes; alem da analise de casos praticos voltada a responsabilizacao dos sujeitos 
anunciantes quando nao respeitados os limites legais. Trata-se de pesquisa pura, com fins de 
ampliacao do conhecimento sobre a publicidade e seus limites, atraves de abordagem 
qualitativa e dedutiva para alcancar tais fins, alem de descritiva, descrevendo conceitos 
importantes sobre publicidade e seus limites frente a vulnerabilidade do consumidor. E de suma 
importância que o conhecimento acerca dos limites da publicidade seja difundido uma vez que 
grande parte dos consumidores desconhece seus direitos e a possibilidade de responsabilizacao 
dos causadores de danos provenientes da publicidade indevida. Assim, viabiliza-se que direitos 
sejam defendidos frente as inumeras ofensas sofridas todos os dias, seja a partir de campanhas 
de conscientizacao a respeito do consumo e dos direitos do consumidor, seja por meio de 
disciplinas curriculares obrigatorias desde o ensino infantil, com a mesma finalidade.

The Sport is one of the contents of the Physical Education school, and its approach is the 
responsibility of the Physical Education teacher, so it is essential that the teacher knows 
adequate teaching methods for students in each age group. This study aimed to point out some 
possibilities of teaching methods for the development of sports in Physical Education classes. 
Therefore, this work aims to analyze and point out which are the most appropriate teaching 
methods for each learning cycle of the Curricular Parameters of Physical Education in 
Pernambuco. To obtain the sources that supported this study, a review of the literature with 
articles available for free in the SCIELO and Google Academic databases between 1991 and 
2016 was used, as well as books that aided in the use of results. This research is exploratory 
due to the intention of presenting a greater familiarity to the topic discussed, treating its 
results through a qualitative approach, since it is concerned with pointing out the quality of 
teaching methods. The presented results were constructed by a discussion between the 
characteristics of the learning cycles and the phases of sports initiation of different authors. It 
was concluded in this study that for each learning cycle there are certain teaching methods 
suitable for Teaching-learning Collective Sports that respects the characteristics and age range 
of the students of each cycle.

Métodos de ensino dos esportes coletivos na iniciação esportiva escolar conforme os ciclos de aprendizagem dos Parâmetros Curriculares de Educação Física de Pernambuco

As Geotecnologias sao excelentes instrumentos para gestao ambiental pela sua capacidade de integracao de ferramentas e tecnicas de modelagem dos fenomenos ambientais. Tendo como base o conceito de Analise da Paisagem e possivel reconhecer os potenciais e as fragilidades de uma determinada area geografica. A Regiao Hidrografica VIII (RH-VIII), area de atuacao do Comite das Bacias Hidrograficas dos Rios Macae e das Ostras (CBH Macae/Ostras), apresenta alto grau de degradacao ambiental devido a ocupacao intensiva de terras improprias ao uso. A preocupacao com a gestao ambiental da regiao se manifesta a nivel nacional, pois alem do abastecimento publico suas aguas suprem boa parte das necessidades das industrias de petroleo instaladas na regiao. Os modulos de Analise de Multiplos Criterios (AMC) dos Sistemas de Informacoes Geograficas (SIG) se apresentam como uma ferramenta viavel em estudos de ordenamento territorial. Busca-se com a pesquisa fazer uma revisao da literatura visando adequar proposta metodologica para planejamento territorial da RH-VIII.

Análise da paisagem com o uso de geotecnologias: uma proposta metodológica para o planejamento territorial da região hidrográfica VIII - RJ.

Este estudo teve como objetivo analisar o cenário da violência escolar e do bulling na escola e quais suas consequências e formas de combate possíveis utilizando-se da pesquisa bibliográfica onde concluiu-se que a violência escolar e o bulling são ocorrências cada vez mais frequentes nas escolas, mas no momento em que a educação moral contribui com palestras, ensinamentos e muito dialogo, os alunos passam a entender que certas atitudes, ações e pensamentos não colocaram para o crescimento pessoal e social de cada um deles, muito pelo contrario os afasta de um cenário educacional positivo.

Educação Moral como Forma de Combater a Violência e o Bulling nas Escolas

Análise da estabilidade elástica em torres tubulares de aço para aerogeradores de eixo horizontal

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e inundações: São Domingos, Santa Catarina

Glossário Bilíngue (Libras-Português) das Disciplinas Sistemas Integrados de Produção Vegetal I e II do Curso Técnico de Agroecologia: Termos Técnicos do Território do Sisal

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e Inundações: Nova União, Rondônia

Al considerar la ensenanza de la lengua espanola en Brasil, el presente trabajo tiene como objetivo identificar las variedades linguisticas del espanol, presentes en un libro de texto aprobado por el Plan Nacional de Libro Didactico (PNLD), centrandose en los aspectos lexicos. Fue escogida para esta investigacion la Coleccion "Enlaces - Espanol para jovenes brasilenos, Volumen 1", incluida en el Plan Nacional del Libro Didactico 2012, con destino al bachillerato. Fueron tenidos en cuenta aspectos teoricos sobre el libro de texto y la ensenanza brasilena (MANTOVANI, 2009) y las variedades del idioma espanol (MORENO, 2010). Los autores de la coleccion son Soraia Osman, Neide Elias, Priscila Reis, Sonia. Izquierdo y Jenny Valverde. Como se trata de una investigacion biografica, se adelanto en primer lugar, una lectura de diversos materiales  como las resenas de libros en espanol del PNLD 2012, mas especificamente el volumen 1 de la coleccion Enlaces. Se descubrio que hay un predominio de la variante castellana en los libros de texto de los estudiantes europeos, dada su proximidad geografica con Espana. De los resultados, se plantearon algunas preguntas relacionadas con la ensenanza de las variantes del idioma espanol en el contexto brasileno.

Variedades do espanhol em livro didático aprovado pelo PNLD 2012

O livro Africanidades, afrobrasilidades e processo (des)colonizador: contribuicoes a implementacao da Lei 10.639/03 chegou em boa hora. Nesses tempos de tantos retrocessos que atingem os direitos das brasileiras e dos brasileiros, precisamos muito de producoes teoricas com esse teor e com as novidades das analises aqui presentes. Necessitamos de mais obras alicercadas em um conhecimento emancipatorio e descolonizador.

De acordo com os dados da Agencia Nacional de Aguas (ANA), no que se refere a recursos hidricos, o Brasil apresenta uma boa situacao em termos globais e tambem e no Brasil que se concentra grande parte da agua doce do mundo. Porem, o crescimento desenfreado, desordenado e por muitas vezes irregular das cidades, acompanhado pelo aumento da demanda hidrica e consequentemente pelo desperdicio desse bem finito, vem comprometendo o desenvolvimento urbano, industrial e agricola, afetando diretamente a qualidade de vida da populacao. Portanto, o aproveitamento de agua da chuva para fins nao potaveis e uma excelente alternativa para reduzir o desperdicio de agua e aumentar a eficiencia de seu uso. Assim, o presente trabalho trata do dimensionamento do aproveitamento de aguas pluviais em uma instituicao de ensino publica do Distrito Federal, com o intuito de reduzir gastos e o consumo de agua potavel para fins de irrigacao, e conscientizar a comunidade escolar da importância desse recurso natural finito. Para tal, foi realizado um diagnostico fisico da area de captacao na qual sera ligada aos reservatorios construidos com a tecnica de ferro-cimento, que apresentou custo menor quando comparado aos reservatorios convencionais, alem de calcular a demanda de agua para irrigacao das areas de cultivo utilizando o metodo de gotejamento, sendo que este, apresentou melhor eficiencia e menor consumo de agua. Os resultados foram satisfatorios devido ao aumento da oferta de agua obtida por meio da captacao de aguas pluviais e armazenando em reservatorios do tipo ferro-cimento. Desse modo, reduzindo o consumo de agua fornecida pela concessionaria de agua, contribuindo para diminuir a pressao sobre os recursos hidricos da regiao.

Estudo de caso: viabilidade do uso da água da chuva para irrigação de horta escolar

A presente pesquisa tem como objetivo identificar e compreender as dimensoes formativomusicais que norteiam as acoes educativas da ONG Ilha de Musica, localizada no bairro da 
Redinha, na comunidade da Africa, na Zona Norte do municipio de Natal - RN. Por meio da 
revisao bibliografica buscou-se compreender o papel da educacao musical nesses contextos e 
assim construir um percurso dialogico capaz de abarcar as idiossincrasias inerentes aos projetos 
sociais que usam a musica como um meio de insercao social. Configura-se como uma pesquisa 
de abordagem qualitativa, que por meio da modalidade estudo de caso busca fundamentar as 
relacoes entre educacao musical, musica e educacao. Considera-se a musica como um fenomeno 
que, sendo para fins educacionais, precisa atender aos significados de cada contexto. Buscando 
compreender a origem e finalidade do trabalho sociomusical que a Ilha de Musica realiza, o 
estudo apresenta uma contextualizacao da ONG, na qual sao discutidos aspectos inerentes a 
infraestrutura e qualidade de vida na comunidade da Africa. Nesse sentido, por meio de 
observacoes de campo e da realizacao de entrevistas, foram reveladas as concepcoes e praticas 
pedagogicas adotadas na instituicao. Os resultados demostram, alem da sincronia entre as falas 
dos entrevistados, um ensino de musica compromissado com a intuicao, com o conhecimento 
teorico e com a criatividade, bem como revelam que a etica, a socializacao, a diversidade, a 
oralidade nas transmissoes musicais, os significados das praticas musicais e o compromisso com 
o desenvolvimento da autonomia, foram caracteristicas das dimensoes formativas que se 
apresentaram de forma mais evidente.

Setorização de áreas de alto e muito alto risco a movimentos de massa, enchentes e inundações: Concórdia, Santa Catarina

Ação emergencial para delimitação de áreas em alto e muito alto risco a enchentes e movimentos de massa: Abelardo Luz, Santa Catarina

Esse artigo trata sobre os desafios e as possibilidades da Educacao Fisica na Educacao Infantil. A metodologia empregada realizou-se de uma pesquisa bibliografica, de uma abordagem do tipo qualitativo. A partir de alguns criterios de inclusao, foi analisado apenas artigos originais em lingua portuguesa, foi pesquisado na base de dados Scielo artigos que continham as palavras-chave: Educacao Fisica escolar na Educacao Infantil, Educacao Fisica escolar na infância, Brincadeiras infantis, Educacao Infantil. De acordo com os dados encontrados podemos dizer que os principais desafios para o trabalho da Educacao Fisica na Educacao Infantil foram: mudancas de humor das criancas, separacao de genero nas aulas, parte financeira, valorizacao dos professores e formacao. E as principais possibilidades giram em torno da necessidade de construcao de politicas publicas que deem subsidio ao professor de Educacao Fisica no que se refere ao conhecimento do curriculo desta disciplina, as interdisciplinaridades, rotina, brincadeiras e jogos.

A educação física na educação infantil: desafios e possibilidades

In the contemporary world environment, it is necessary to identify the weaknesses and potentialities of each region or city, aiming at the construction of macro policies that respect its territorial characteristics and diversities. In this context, the proposal to study development possibilities for the municipality of Ijuí (RS, Brazil) arose from the application of the Nation Brand. The study was elaborated, mainly, through bibliographical and documentary research about the municipality and related concepts, such as Marketing of Cities and Smart Cities. For this, data from the socioeconomic and cultural profile of the municipality and the Strategic Plan of COREDE-NORC were collected and analyzed. The results pointed out that the municipality should seek an identity and, from it, define a niche of action, through the identification of its attributes. In this way, it is expected that the work can contribute to the discussion about the development of Ijuí and region, and the current challenge of managers is to strengthen their capacities and skills, in order to be able to adapt to a environment.

O Nation Brand como vetor de desenvolvimento das cidades: o caso de uma cidade interiorana brasileira

O Presente estudo busca avaliar as interferencias da verticalizacao no conforto termico de Natal-RN, entre o periodo de 1984 ate 2013. Entendemos que o presente estudo e relevante visto que na atualidade a preocupacao com o tema da Climatologia Urbana esta em destaque no que tange as transformacoes no clima das cidades e suas consequencias para os habitantes da mesma. Delimitamos o recorte temporal a partir da disponibilidade dos dados meteorologicos, pelo Instituto Nacional de Pesquisas Espaciais (INPE) e dos dados sobre o quantitativo das construcoes de predios pela Secretaria Municipal de Meio Ambiente e Urbanismo (SEMURB). Com isso buscamos a priori entender o processo de verticalizacao que Natal sofreu nos ultimos 50 anos, tendo como foco a intensificacao ocorrida a partir da decada de 1980. Fazendo uso assim da divisao do periodo para possibilitar uma comparacao dos dois momentos vividos na Cidade, onde no primeiro momento (1984-1999) tivemos uma timida progressao do processo de verticalizacao ate chegar ao ano de 1995, onde estimulados pela implantacao do novo Plano Diretor de Natal (PDN) as empresas de construcao civil solicitaram um numero nunca antes visto de alvaras de construcao para se resguardar na Lei anterior menos restritiva. E no segundo periodo tivemos um crescimento de mais de 300% no quantitativo geral de construcoes de predios, com destaque no ano de 2007 em que impulsionados pelos subsidios do Programa de Aceleracao do Crescimento (PAC) para construcao de moradias para as mais diversas classes sociais, Natal passou por um “frenesi” onde em todas as zonas administrativas da cidade passaram pelo processo de verticalizacao. Quanto a relacao climatologica utilizamos dos metodos de Indice de Temperatura de Umidade (ITU) e Wind Chill Index (WCI) para avaliar atraves das variaveis meteorologicas se Natal apresentava condicoes de conforto ou desconforto termico a partir dos resultados obtidos. Por fim procuramos inter-relacionar o processo de urbanizacao, com enfoque na verticalizacao com os resultados dos metodos escolhidos para explicar se Natal ao se verticalizar afetou o seu conforto termico.

O Processo de verticalização e o conforto térmico em Natal-RN no período de 1984-2013

O artigo apresenta a implicacao da forca do eurocentrismo no espaco reservado as historias das populacoes negras e indigenas no curriculo de um curso de licenciatura em historia de uma universidade publica do estado do Parana. O projeto pedagogico do curso, observacoes em aulas das diferentes disciplinas e entrevistas com docentes e discentes trouxeram as questoes que foram analisadas. Afetadas pela superiorizacao da brancura e pelo eurocentrismo, historias indigenas e negras eram situadas como tematicas com menores relevâncias na formacao de professores de historia investigada, por causa do pouco espaco disponibilizado no curriculo para o estudo dessas historias. Entretanto, ocasionalmente, ocorrem algumas iniciativas de inserir debates a respeito da historia negra e indigena, mas tambem, consequentemente, acerca das relacoes etnico-raciais pelas quais o curriculo esta atravessado.

Implicação da força do eurocentrismo no currículo de um curso de licenciatura em História: que espaço é reservado à história negra e indígena?

Buscou-se com a pesquisa a producao do mapeamento indicativo de sensibilidade ambiental para o desenvolvimento regional da Regiao Hidrografica VIII (RH-VIII), no Estado do Rio de Janeiro, Brasil. O estudo desenvolveu-se com a utilizacao dos softwares SPRING 5.5.0 e QGIS 2.18.6. O metodo de pesquisa baseia-se na Analise por Multiplos Criterios (AMC), visando mapeamento de sensibilidade ambiental para o desenvolvimento regional da RH-VIII. O resultado revelou que 46% do territorio da RH-VIII apresenta alguma aptidao ao desenvolvimento enquanto mais 6% da area aponta extrema sensibilidade ambiental. A B S T R A C T The research was carried out to produce the mapping of environmental sensitivity for the regional development of Hydrographic Region VIII (RH-VIII), in the State of Rio de Janeiro, Brazil. The study was developed using the software SPRING 5.5.0 and QGIS 2.18.6. The research method is based on Multi Criteria Analysis (AMC), aiming at mapping environmental sensitivity for the regional development of RH-VIII. The result showed that 46% of the territory of RH-VIII has some developmental aptitude while another 6% of the area indicates extreme environmental sensitivity. Keywords: Geotechnology; Land use; Map Algebra; Environmental modeling.

Mapeamento de Sensibilidade Ambiental ao Desenvolvimento: estudo de caso na Região Hidrográfica VIII – RJ (Mapping of Environmental Sensitivity do Development: case study at Hydrographic Region VIII – RJ)

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e Inundações: Urupá, Rondônia

Atualmente o setor industrial que emprega o metal chumbo na sua producao, tais como fabricacao de forros para cabos, elemento de construcao civil, pigmentos, soldas suaves e municoes. Tem causado grande contaminacao em efluentes industriais. Diante desses problema, varios metodos vem sendo aplicado para reduzir a concentracao desse metal toxico. A adsorcao e um fenomeno de superficie que envolve a transferencia de uma especie quimica da solucao para a superficie do adsorvente. Tal processo tem sido empregado com sucesso na remocao de poluentes devido ao seu baixo custo de obtencao e manutencao (considerando seu reuso). O objetivo deste trabalho e obter um bioadsorbente de baixo custo com capacidade para remover ions Pb+2. A modificacao foi atraves de uma reacao de polimerizacao controlada em meio sulfurico empregando formaldeido como reagente de partida. No estudo cinetico aplicou-se os modelos cineticos de Pseudo Primeira Ordem, Pseudo Segunda Ordem e o modelo de Elovich. No estudo de mecanismo aplicou-se os modelo de Webber Morris e Boyd. No estudo de equilibrio foi empregado os modelos de Langmuir, Temkin e Freundlich.

Estudo de Cinética e Equilíbrio de Adsorçao Empregando a Casca do Coco Modificada Quimicamente para a Remoçao de Pb(II) de Banho Sintético

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e inundações: Ipuaçu, Santa Catarina

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e Inundações: Governador Jorge Teixeira, Rondônia

Pracas, parques, jardins publicos, ruas, passeios, entre outros, constituem equipamentos colectivos com grande importância para o lazer e a qualidade de vida das pessoas onde eles estao instalados. O aumento do tempo fora do trabalho e a crescente mobilidade dos cidadaos contribuem para a valorizacao destes elementos. Assim, a sua ausencia ou precariedade tem implicacoes negativas nas formas de convivencia social, na mobilidade e consequentemente na qualidade de vida das pessoas. Em Mocambique em geral e na cidade de Maputo, em particular, assiste-se a um processo acelerado de apropriacao desses espacos publicos. Trata-se de apropriacoes formais e informais. Constituem objetivos deste trabalho, por um lado, analisar a importância dos espacos publicos no lazer e na qualidade de vida das pessoas e, por outro lado, refletir sobre as consequencias da apropriacao desses equipamentos coletivos na qualidade de vida dos seus usuarios. Para o desenvolvimento da pesquisa, trabalhou-se segundo uma metodologia flexivel, que alguns autores denominam de “modelo artesanal de ciencia”. Assim, consistiu na producao de metodos necessarios para o trabalho, numa especie de “costura de diversos tipos de pesquisa disponiveis e publicos”. Os resultados da pesquisa, ainda que nao definitivos, indicam que a apropriacao ou privatizacao dos espacos publicos na cidade de Maputo, por um lado, e uma consequencia da mercantilizacao do lazer, processo com anuencia ou mesmo incentivado pelo poder publico; por outro lado, agora com ausencia ou com repressao do poder publico, constitui uma apropriacao que e consequencia da pobreza ou da luta pela sobrevivencia.

Prescrição de medicamentos que interferem na deambulação: Um preditor de queda para idosos hospitalizados

Maturidade do Data Governance em Portugal: elaboração de um instrumento de avaliação

A expansao dos cursos superiores a partir da decada de 1990 institui o Sistema Nacional de Avaliacao do Ensino Superior (Sinaes), atraves da lei 10.861, de 14 de abril de 2004, tendo como base a avaliacao de tres componentes principais: a avaliacao das instituicoes, avaliacao dos cursos e o desempenho dos estudantes. Esse sistema de avaliacao passa a aferir a qualidade e expansao de novos cursos e controlar a oferta de vagas. A analise desenvolvida nessa tese entende que esse sistema faz parte da expansao do projeto neoliberal na educacao, onde os Estados-nacoes passaram a reestruturar o ensino superior com o objetivo de atender a chamada Revolucao Tecnico-Cientifica. Este sistema foi implantado nas diferentes escalas geograficas, seguindo o modelo implantado na Europa, para colocar as universidades europeias no mesmo nivel de competicao das universidades norte-americanas, objetivando, medir a qualidade do ensino mediante metas de produtividade e eficiencia de cursos e instituicoes. Nesse sentido a analise da Tese e conduzida a partir do entendimento da inclusao da educacao no âmbito da logica do sistema neoliberal. O olhar geografico e fundante para o debate ao estabelecer a critica ao Sinaes como condutor do discurso do desenvolvimento regional, e como um instrumento de poder na regulacao do territorio para atender ao interesse da acao hegemonica do capital, apontando para uma politica condutora de um discurso de qualidade, imposto por atores sintagmaticos, que envolvidos na implementacao, discussao e embate contraditorio entre a necessidade de regulacao e controle, ordena o territorio e legitima a reproducao das desigualdades socioespaciais.

Sinaes : política de ordenamento para controle e poder do território

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e inundações: Theobroma, Rondônia

Based on the theoretical references that conceptualize and characterize blogs, we sought to understand their role in the field of science communication and its importance in the formation of scientific culture in contemporary society. In the current circuit of scientific productivity, the internet plays a central role, reinforcing institutionalized communicative processes and allowing other emitters to lead the information networks, creating new forms of interaction arising from the features that arise in the so-called web 2.0. The purpose of this study was to investigate the potential of the Brazilian scientific blogosphere in Portuguese language, specifically Brazilian, in order to presenting an overview of its evolution in the context of the popularization of science topics and identifying articulation among these tools with alternative metrics, which are progressively gaining prominence in the impact assessments of current scientific publications. An updated characterization of the scientific blogosphere based on surveys carried out in the Anel de Blogs Cientificos (ABC) is presented, emphasizing the quantitative aspect of accesses (rankings of views) and their connections with other sites, blogs and social networks through links, in addition to other considerations on the topic of blogs. It is a demonstrative, webometric and altmetric study because in addition to the general characterization data was collected on Altmetric.com to evaluate the visibility of Brazilian blogs in one of the most referenced altmetrics data aggregator. The investigation of blogs is extremely important to understand the extent to which re-articulations have taken place from their performance in order to communicate scientific information both to society in general and to academia.

Blogues científicos em língua portuguesa e sua atuação na interface entre a academia e a sociedade

A quimica esta presente em todo lugar e nao poderia ser diferente na matematica visto que o Ensino de Ciencias engloba diferentes vertentes e areas de estudo, e os correlaciona afim de encontrar solucoes de cunho politico, social e cultural. Mas, infelizmente, o Ensino de Ciencias nos ultimos anos de ensino fundamental ainda e muito tradicional e baseado no uso de apontamentos no quadro e resolucao de questionarios. Esse resumo tem por objetivo apresentar a experiencia vivenciada nos 9° anos da Escola Estadual Padre Lebretdurante o estagio supervisionado 1, do curso de licenciatura em quimica. A comemoracao ao dia Internacional da matematica foi feita com apresentacoes internas no formato de feira de conhecimento, onde, atraves desse projeto interdisciplinar os alunos conseguiram despertar e agucar o seu instinto para pesquisa. Inicialmente, a turma recebeu um embasamento teorico sobre misturas, proporcao, pH (com o uso do cha de repolho roxo, como indicador), acidez e basicidade. Em seguida, os alunos foram divididos em grupos de 4 e instruidos a pesquisarem o usodas substâncias que iriam misturare os impactosque elastrazem para sociedade, e com a ajuda do cha do repolho roxorealizaram testespara ver se as substâncias eram acidas ou basicas. Dentre essas substâncias tinhamos a agua, vinagre, limao, detergente, agua sanitaria, sal de cozinha, acucar, leite de magnesia, etc. Posteriormente aprenderam como calcular a massa molar do principio ativo de algumas substâncias ou apenas de sua molecula, como no caso da agua, para que pudessem apresentar no dia do evento. Como objetivo principal da turma era mostrar como a matematica esta inserida na quimica, eles apresentaram o calculo e mostraram qual o pH das substâncias, alem de comentarem sobre a utilidade, a forma de armazenagem, e os riscos a saude que essas substâncias poderiam trazer. Ao final do evento, os relatos da experiencia, em sua grande maioria foram de satisfacao por terem conseguido apresentar "conteudos quimicos", que ate entao era desvinculado da matematica na concepcao dos alunos.

QUIMICALIZANDO NO DIA INTERNACIONAL DA MATEMÁTICA: UMA EXPERIÊNCIA NO ESTÁGIO SUPERVISIONADO EM QUÍMICA

Atualmente, devido ao grande desenvolvimento das comunicações, a presença da cultura e das artes italianas no Brasil está em fase de crescente intensificação e a quantidade de obras italianas que circulam no Brasil é cada vez maior. Assim, a proposta desta comunicação é apresentar a descrição bibliográfica aplicada na construção de uma base de dados bibliográficos, resultante de mapeamento editorial da literatura italiana traduzida no Brasil a partir de 1951. Dá-se destaque aos elementos descritivos utilizados, ajustados para esta finalidade, com base também na necessidade dos pesquisadores envolvidos. Na descrição do projeto verifica-se a possibilidade de colaboração efetiva gerada entre as áreas de Biblioteconomia e de Letras. Também evidencia-se a contribuição que um método tradicional como a catalogação pode ser aplicada para subsidiar a construção de uma base bibliográfica da produção editorial para fins científicos.Palavras-chave: Catalogação. Descrição Bibliográfica. Literatura Italiana. Projeto de Pesquisa.Link: http://www.periodicos.ufpb.br/ojs/index.php/itec/article/view/38862/20154

O mapeamento da produção editorial italiana traduzida no brasil por meio da descrição bibliográfica

A gestao eficiente de dados agricolas e dependente de informacoes de diversos sistemas, equipamentos e tecnologias computacionais que nem sempre sao intercambiaveis. Esses dados estao distribuidos em sistemas e maquinas que tem formas diferentes de gerenciamento. Uma solucao para a padronizacao e melhoria na troca de dados, com a formalizacao das informacoes esta no uso de ontologias e metadados. Com isso, e possivel realizar o mapeamento dos principais processos 
na cadeia produtiva de determinada cultura. Uma aplicacao direta e utilizar os dados para a rastreabilidade e aumentar a seguranca nos produtos, pois e possivel determinar a origem e movimentacao dos produtos. Nesta pesquisa foi mapeado os processos de producao da erva-mate (Ilex Paraguariensis St. Hill.), por meio de uma ontologia de dominio, resultando em estruturas de informacao para intercâmbio e rastreabilidade de dados agricolas, melhorando os processos e gestao das informacoes. Para o processo de desenvolvimento da ontologia foi utilizada a Ferramenta Protege, aplicando a Metodologia Ontology Development 101. Como resultado e apresentado um sistema de representacao de conhecimento para a criacao de padrao de metadados contribuindo para a melhoria do processo de intercâmbio de dados para a cultura da erva-mate.

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e inundações: Ouro Verde, Santa Catarina

A discussao sobre o acesso a informacao esta costumeiramente presente na agenda das democracias representativas e seus governos. Esta pauta e importante, pois informacao e estrategia se articulam como subsidiadoras de poder. No Brasil, ha um arcabouco juridico relevante que ratifica esta compreensao no pais. Do ponto de vista politico, ha um orgao que desenvolve funcoes vitais na politica de acesso a infomacao: a Controladoria-Geral da Uniao, responsavel pelo monitoramento da Lei de Acesso a Informacao. Esta pesquisa tem entao por objetivo analisar esta importante organizacao publica, internamente, verificando se suas praticas correspondem aquilo que tem como funcao em âmbito nacional. Analisamos os relatorios de gestao do periodo 2011-2016, os sitios eletronicos do orgao, o Painel de Orcamento Federal e o Portal da Transparencia Publica, buscando atraves destes instrumentos compreender aspectos relacionados a aderencia entre os titulares da CGU e sua formacao; a existencia e manutencao efetiva de um programa de gestao de documentos; a avaliacao orcamentaria praticada no periodo; realizar um estudo sobre a forca de trabalho e das tecnologias/sistemas de informacao do orgao. Como resultados, observamos que a CGU vivencia problemas de ordem de gestao, como a grande maioria dos orgaos publicos brasileiros, mas mantem, ainda assim, estrutura parcialmente adequada frente ao seu papel relevante na politica informacional do pais.

The aim of this study was to identify the leaf and its part with greater sensitivity to detect P variation in the ‘Prata anã’ banana plant. The experiment was carried out in Montes Claros, Minas Gerais, in a clayey Oxisol. A randomized complete block design was used, with six P doses (0, 50, 100, 150, 200 and 250 g family-1 year-1 of P2O5) and four replications. In the plants beginning the emission of the bunch in the first, second and third cycle of the banana tree, the 3rd and the 7th leaves were collected from the apex, from where 10 cm of the center of the limbs were removed, eliminating the midrib, 10 cm of the petiole and 10 cm from the midrib and 10 cm from the 1 leaf limbs. The midrib of the third leaf showed greater sensitivity to detect the variation of the P content in the banana tree when the content of this nutrient varies in the soil, and can be indicated to be used in the diagnosis of P in the ‘Prata anã’ banana tree. The third leaf limb from the apex is not the part of the leaf indicated to perform the diagnosis of P in the banana ‘Prata anã’ as recommended in the literature.

Identificação da folha da bananeira ‘ Prata anã ’ para diagnóstico do nível de suficiência de fósforo

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e inundações: Monte Negro, Rondônia

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e inundações: Várzea Grande, MT

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e Inundações: Cajubim, Rondônia

Although Astronomy is part of everyday life of the people, peculiarities are little-known for an observer on the equator, as residents in Macapa-AP, located at Latitude Zero. So, this work aims to support physics teaching focusing on the correct diffusion of some physical phenomena which have an intrinsic relationship with Astronomy from the sight of an observer at latitude zero, highlighting the celestial sphere visualization and emphasizing which constellations are visible during an earth year, being proposed the elaboration of a planisphere to this latitude. It’s also discussed about the Solstices and, more specifically, about the Equinoxes and their particularities for an observer in latitude zero. The offered approach can help teachers of Physics and Science who work in regular education schools to explore these important astronomical phenomena.

Astronomia no Meio do Mundo: uma análise Física da visualização de constelações e dos equinócios e solstícios a partir da Latitude Zero

Leucism is the loss of melanin 
in the structures that cover the body of a certain species, so that the affected 
species possess white or grayish dermal structures, but the eyes remain with their 
normal colorations. The present note reports leucism cases in three bird species 
registered in the Zoobotanical Park of the National Institute of the Atlantic 
Forest (INMA), located in the municipality of Santa Teresa, mountainous region 
of the State of Espirito Santo. There were recorded leucistic specimens of the 
Brazilian chachalaca, Ortalis araucuan (Spix, 1825) (Order Galliformes), the 
rufous-bellied trush Turdus rufiventris (Vieillot, 1818), and the sparrow Passer 
domesticus (Linnaeus, 1865) (both of order Passeriformes). All three species observed had a partial leucistic anomaly in their plumages, with T. rufiventris 
having the highest area of leucism on its plumages. Factors leading to the 
occurrence of leucism in these species need to be better investigated.

Leucismo em três espécies de aves em um fragmento florestal da região serrana do Espirito Santo, sudeste do Brasil.

EXTRAÇÃO DO ÓLEO VEGETAL DE BURITI (MAURITIA FLEXUOSA), PRODUÇÃO E ANÁLISE DO BIODIESEL.

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e inundações: Faxinal dos Guedes, Santa Catarina

~ssor Titular apo­ responsável pelo I Pós-Graduação. Paulo aposenta­ Livre-Docente de Civil e de Direito )ireito da UFMG. o dos Advogados icano de Derecho sileira organizou recho Político y :iências Jurídicas onal de La Plata ::Jente do Instituto 1ado de la Nación ai de Derecho de )r da Associação Democratas. ltre as quais se io no Direito Pro­ r Constitucional; Do Recurso Ade­ Execução Fiscal; )refeito e o Muni­ ormação das Leis ,colaborações em

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e Inundações: Machadinho do Oeste, Rondônia

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e Inundações: Cacaulândia, Rondônia

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e inundações: Vargeão, Santa Catarina

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e inundações: Ponte Serrada, Santa Catarina

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e inundações: Passos Maia, Santa Catarina

Técnicas termoanalíticas aplicadas ao processo produtivo de painéis MDF: análises de fibras de madeira de eucalipto e resinas sintéticas termofixas

O Nucleo de Agroecologia Apete-Caapua (NAAC) e um coletivo de pesquisa e extensao universitaria da UFSCar, campus Sorocaba, que atua junto a agricultores, instituicoes publicas, privadas e movimentos sociais na Regiao Sorocabana, com o objetivo de promover uma agricultura de base ecologica e contribuir para que agricultores familiares tenham vida digna, saudavel, com bem-estar e renda, a partir dos principios da Agroecologia enquanto ciencia, pratica e movimento. Muitas acoes tem sido realizadas, como eventos regionais, campanhas, cursos, feiras, pesquisas cientificas e atividades de extensao, valorizando aspiracoes da populacao local. Desde 2009, alcancamos diversosobjetivos, aproximando a universidade com a realidade da agricultura familiar, semeando a Agroecologia como alternativa na producao de alimentos, alem da formacao tecnica e politica de membros do NAAC. A meta do nucleo e apoiar a transicao agroecologica no territorio e seu fortalecimento em redes, com atores que contribuam com troca de experiencia e aprendizado, a nivel regional e nacional. Por isso, trabalha-se em mutirao, no qual cada um contribui com seus conhecimentos e sentimentos.

O MUTIRÃO DE RELAÇÕES AGROOECOLÓGICAS DO NÚCLEO APÊTE-CAAPUÃ: TECENDO REDES NA REGIÃO SOROCABANA.

Esta monografia constitui-se em um estudo sobre a Banda de Musica Mestre Joao Roberto Paz e Uniao da cidade de Santa Cruz/RN – BMMJRPU, tendo como objetivo discutir a relevância do trabalho realizado pela BMMJRPU e relatar as suas praticas musicais, educacionais e sociais. Abordam-se aspectos historicos da cultura de bandas de musica no Brasil e no Rio Grande do Norte e a relacao da banda para a formacao pessoal dos individuos. Sao relatadas algumas consideracoes sobre a musica no processo educacional e a necessidade do reconhecimento da identidade musical a partir do que e realizado na banda: ensaios, apresentacoes e concertos. Quanto a metodologia, optou-se por desenvolver um estudo de caso atraves de uma abordagem com enfoque qualitativo. Os dados deste trabalho foram coletados atraves de questionario com os integrantes da banda, os pais e familiares dos integrantes, e tambem por meio de entrevistas semiestruturadas com o maestro da Banda e pessoas da comunidade representantes de instituicoes santa-cruzenses. Por meio deste estudo, foi possivel concluir que uma banda de musica pode proporcionar a formacao musical, profissional e pessoal de seus integrantes, configurando-se, assim, como uma acao social.

Banda de música Mestre João Roberto Paz e União de Santa Cruz/RN: um estudo sobre educação musical e o papel da banda na sociedade

As tecnologias da informacao e comunicacao vem a cada dia se inserindo em nosso 
cotidiano a ponto de sua ausencia gerar grande impacto em toda a sociedade, isso e 
perceptivel no mundo do trabalho, no consumo e nos habitos da populacao. Diante 
de tantos avancos tecnologicos, a saude e uma das areas que obtem beneficios atraves 
de sensores, atuadores, equipamentos, instrumentos, software e hardware voltados ao 
auxilio, prevencao, promocao a saude e qualidade de vida do individuo. A superlotacao 
dos Servicos de Emergencia Hospitalar e uma problematica que assola a saude no que 
diz respeito ao atendimento humanizado de paciente no âmbito das emergencias, fato 
que agrava-se devido ao elevado indice de acidentes e violencia. Com isso, destaca-se o 
baixo desempenho do sistema de saude como um todo, enfatizando principalmente 
a baixa qualidade assistencial e o atraso no diagnostico e tratamento, principalmente 
no âmbito das urgencias e emergencias. Diante disso, o objetivo desse trabalho foi o 
desenvolvimento de um sistema intitulado SOS Socorrista, que tem a finalidade de 
auxiliar a equipe de regulacao no processo de atendimentos de ocorrencias de urgencia e 
emergencia na tomada de decisao.OSOS Socorrista e multiplataforma responsivo e conta 
com o embasamento de E-Health e tecnicas de inteligencia artificial para representacao 
de conhecimento, util para processamento de informacoes e tomada de decisao. Os 
questionamentos levantados durante o decorrer desse trabalho, proporcionaram solucoes 
para a problematica aqui abordada, gerando assim conhecimentos cientificos. Alem 
disso, foi possivel verificar que o sistema apresentou desempenho satisfatorio no auxilio 
da equipe medica na tomada de decisao com uma taxa de acerto de 90%

Sos socorrista: sistemas para auxiliar equipe médica na tomada de decisão de emergência

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e Inundações: Rio Crespo, Rondônia

Na atualidade as organizacoes, estao inseridas em um ambiente de negocio globalizado e altamente competitivo, neste cenario, as empresas estao suscetiveis as transformacoes e variacoes da economia e politica interna e externa, das tecnologias que provocam alteracoes nos processos organizacionais, e da legislacao que rege e regulamenta o negocio, entre outros elementos que interferem no ambiente empresarial. Diante disso, surge a utilizacao dos cenarios economicos como ferramenta que possibilita se antecipar as incertezas que se tem quanto ao futuro e as suas tendencias. Posto isso, este artigo objetivou fazer um estudo comparativo, utilizando como parâmetro, os trabalhos realizados por Marques (1988) e o de Heinze et al . (2011). Os autores sugerem entre os elementos decisorios o mercado, tanto interno como externo, a imagem institucional ( marketing ), mensuracao da demanda atual e futura do mercado, o sistema de informacao gerencial, a concorrencia, a tecnologia de ponta e os seus produtos. Ja para a construcao do modelo de simulacao de cenarios para a empresa onde foi realizado o estudo de caso, aplicou-se o metodo Delphi . Atraves deste modelo Heinze et al. (2011) conseguiram fazer o correto direcionamento da pesquisa e obtiveram elementos essenciais que compoem o entendimento de um grupo de participantes, gestores da propria organizacao, as variaveis criticas, que para os autores esses sao elementos importantes e necessarios para dar o suporte estrategico adequado, e desta forma compor o modelo proposto. Os estudos de ambos os autores, contribuem para a tomada de decisao estrategica, ao possibilitar a avaliacao das probabilidades de acontecimentos futuro.

APLICAÇÃO DOS CENÁRIOS ECONÔMICOS NA GESTÃO DE NEGÓCIOS: UMA CONTRIBUIÇÃO TEÓRICA

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e inundações: Santa Rosa do Purus, Acre

Tito Livio de Castro (1864-1890) was a black Darwinian physician who lived in Rio de Janeiro in the 19th century and who passed away prematurely due to tuberculosis when he was only 26 years old. He was literate by his godfather, Manoel Paes, who created him when he was abondoned at his door at a young age. His formal education, on the other hand, began at Liceu Comercial, following to the renowned Colegio Pedro II, where he graduated in Languages (1883). In 1884, he began his higher education at the Faculty of Medicine of Rio de Janeiro, having graduated and finishing his doctorate in 1889. His doctoral thesis, developed next to the discipline of Psychiatry, Das allucinacoes e ilusoes, was very well received and praised, opening possibilities to occupy prominent jobs. Of his intellectual production, there are still two books that were published posthumously:  A mulher e a sociogenia (1893) and Questoes e problemas (1913). Considering these studies produced by Doctor Tito Livio, in this article, we aim at analyze his writings, showing that, although he was Darwinian and an epigone of Sylvio Romero, when he looked at the psychology of women, he sought to unveil female psyche, bringing an innovative interpretation of women, since the young physician chose to study female brain and not the female womb and her reproductive system, as usual at this time, which has demonstrated  the possibility of female evolution, if properly stimulated by Education. He also countered the stereotypes that saw them as people moved, above all, by emotion. For the development of this article, we have based ourselves on diversified documents about Tito Livio's life trajectory and, as mentioned before, regarding his intellectual production. Thus, we sought to provide information about social subjects, particularly Tito Livio, who has lived in the context of the last years of the century, explaining his protagonism in society, in which scientific racism has predominated and an extremely negative view of the black population.

DOUTOR TITO LIVIO DE CASTRO: NOVAS LUZES SOBRE A TRAJETÓRIA DE VIDA DE UM INESPERADO MÉDICO NEGRO NA CAPITAL DO BRASIL OITOCENTISTA

SILVA, J. W. da. Pilades e Orestes: o homoerotismo sob o veu da amizade romântica. 2018. 40f. Trabalho de Conclusao de Curso (Graduacao em Letras)- Universidade Estadual da Paraiba, Guarabira, 2018.

Pílades e Orestes: o homoerotismo sob o véu da amizade romântica

A pesquisa investiga o discurso da transparencia publica no contexto brasileiro, considerando a relacao informacao-poder, o direito a informacao e as relacoes politicas e economicas, uma vez que para Capurro e Hjorland (2007, p.149), o quarto pilar do desenvolvimento economico e a Informacao. Destacaremos o discurso de transparencia no pais, esvaziado de interesse pelo cidadao e centrado na ideologia capitalista. Adotamos o conceito de sociedade do espetaculo de Debord (1997, p.15), entendendo-o como o resultado e o projeto do modo de producao existente se esvaindo na fumaca da representacao. Esta determina o regime informacional que segundo Gonzalez de Gomez (2012, p.43), e o modo informacional dominante em uma formacao social, o qual define quem sao os sujeitos, as organizacoes, as regras e as autoridades informacionais e quais os meios e os recursos preferenciais de informacao. Utilizamos como marco empirico o Portal da Transparencia Publica e o Arquivo Nacional do pais, sobre os quais realizamos detalhada analise. O primeiro e um sitio eletronico de acesso livre, no qual o cidadao encontra informacoes sobre o uso do dinheiro publico e sobre a gestao publica do Brasil. O Portal tem sido aprimorado, contribuindo para uma pseudo-euforia de acesso informacional. O segundo experimenta significativo desprestigio politico, estando na periferia da politica informacional do pais. Resultados preliminares indicam a primazia do espetacular e a desvalorizacao de um dispositivo basilar, autentico e necessario para a organizacao da Informacao a efetiva politica de transparencia publica brasileira.

Transparência Pública no Brasil: o contexto ideológico à luz dos conceitos de Sociedade do Espetáculo e Regimes de Informação.

Estimativa de recarga e caracterização hidroquímica e isotópica das águas subterrâneas dos aquíferos da região do canal do Jurubatuba

Esta dissertacao compoe o conjunto de estudos realizados na Universidade Catolica do Salvador, no Mestrado em Politicas Sociais e Cidadania, na Linha de Pesquisa - Politicas Sociais Universais, Institucionalizacao e Controle. Tem como objeto de estudo o desenvolvimento de gestao participativa do Programa de Esporte e Lazer da Cidade (PELC), enquanto politica publica social de governo considerando uma analise das Diretrizes de 2011, 2012, 2013, 2014, e 2016. Problematiza os desafios e contradicoes que sao identificadas na proposta das Diretrizes que tratam de gestao participativa do Programa de Esporte e Lazer da Cidade (PELC), enquanto politica social. Responde uma pergunta cientifica especifica que diz respeito aos fundamentos do PELC, segundo os documentos oficiais, para identificar os limites na sua implementacao gestora. As fontes foram os documentos oficiais das Diretrizes do PELC nos anos de 2011, 2012, 2013, 2014 e 2016 do Ministerio do Esporte. Quanto ao metodo de pesquisa foram realizadas analise de conteudo dos documentos. Na analise foram destacados os fundamentos referentes as relacoes sociais estabelecidas - que orientam a gestao e participacao dos envolvidos com o PELC. Os dados foram expostos de forma descritiva atraves de quadros. A discussao dos dados analisados nos possibilitou apresentar contradicoes que existem no que esta escrito nos documentos. Para analisar as determinacoes e explicar as contradicoes e limites nos valemos da teoria que explica o que sao politicas publicas e como as relacoes sao estabelecidas em uma sociedade dividida em classes sociais como e o caso do Brasil. Concluimos que, apesar de ser anunciado um programa democratico, participativo, universalizante, para elevar o padrao cultural esportivo da populacao, existem limites estruturais, contradicoes e que inviabilizam muitas iniciativas de participacao e expansao, enquanto politica social. Isto decorre destas politicas estarem determinadas pela organizacao economica neoliberal que privilegia politicas assistencialistas, focais, compensatorias e nao politicas verdadeiramente democraticas e universais.

Política pública de governo do programa de esporte e lazer da cidade (PELC): desafios e contradições da gestão participativa - 2011 a 2016

Este trabalho apresenta consideracoes acerca das associacoes de bairro diante das problematicas de inefetividade de direitos e de ineficiencia de servicos publicos. Partindo-se do atendimento as condicoes da acao denominadas legitimidade e interesse de agir, especialmente no que tange a tutela de interesses transindividuais, a referida especie de entidade comunitaria figura como sendo detentora de capacidade juridica e processual para a canalizacao de demandas da sociedade. Assim, por meio do metodo bibliografico, elencam-se potenciais contribuicoes das associacoes de bairro em prol da concretizacao dos direitos fundamentais por meio das esferas judicial e extrajudicial.

LEGITIMIDADE E INTERESSE DE AGIR DAS ASSOCIAÇÕES DE BAIRRO NA TUTELA DE INTERESSES TRANSINDIVIDUAIS: BREVE ESTUDO SOBRE A EXISTÊNCIA POSSIBILIDADES DE CONTRIBUIÇÃO PARA A EFICIÊNCIA DOS SERVIÇOS PÚBLICOS E À EFETIVIDADE DE DIREITOS POR PARTE DE ENTIDADES COMUNITÁRIAS

O Trabalho de Conclusao de Curso tem por titulo: “A Terminologia Adotada no Brasil para o Conceito de Information Literacy: Pesquisa em Programas de Graduacao de Biblioteconomia” teve por objetivo principal analisar o conceito em estudo contrastivo com as diferentes traducoes e aproximacoes teoricas na lingua portuguesa: literacia, letramento informacional, alfabetizacao informacional, competencia informacional, competencia em informacao, proficiencia em informacao, assim como a adocao do termo original em Lingua Inglesa, utilizado por diferentes teoricos da Ciencia da Informacao. Quanto aos objetivos especificos, a pesquisa buscou relatar as evidencias que contribuem para o ensino e a pesquisa do conceito no Brasil. Em relacao a metodologia, a sondagem de campo seguiu a opcao pelo questionario (survey) com questoes fechadas e online, aplicado aos docentes e pesquisadores atuantes nos programas de graduacao em Biblioteconomia das diversas universidades do Brasil, como fonte de dados criados em complementacao a pesquisa bibliografica. A analise dos dados coletados foi feita mediante o conceito e os termos pelos quais e estudado no Brasil, apresentados no referencial teorico, verificando a polissemia em relacao ao termo e as aproximacoes com a Information Literacy. A questao de pesquisa denota quais autores e terminologias em Lingua Portuguesa tem sido utilizadas pelos docentes e adotadas nos programas de graduacao em Biblioteconomia no Brasil. Durante a pesquisa foi constatada a preferencia dos docentes pelo termo “Competencia Informacional” de autoria da Bernadete Campello, a qual faz frente em pesquisa e discussao no Brasil. Conclui que o termo IL vem sendo trabalhado ha muito tempo pelos estudiosos, contudo sem unanimidade sobre a sua traducao para a Lingua Portuguesa. Recomenda-se que a comunidade academica busque a adocao de um termo comum, para facilitar a mediacao da informacao aos graduandos da Ciencia da Informacao, assim como organize a producao cientifica da area, do ponto de vista da representacao tematica e indexacao

A terminologia adotada no Brasil para o conceito de information literacy : pesquisa em programas de graduação de biblioteconomia

O PROCESSO DE PRODUÇÃO DA CACHAÇA, O TURISMO RURAL E UMA AULA DE CAMPO NO ENGENHO TRIUNFO (PARAÍBA, NORDESTE DO BRASIL)

Introducao: Esta pesquisa tem como objetivo a analise do perfil das criancas e adolescentes em condicao de internacao no programa de desintoxicacao, oferecido pelo Hospital Universitario do Oeste do Parana (HUOP). Metodologia: O estudo consiste em uma pesquisa qualitativa e quantitativa, de carater exploratorio-descritivo. Como suporte para a analise, o estudo trata nao so da discussao bibliografica sobre criancas e adolescentes em situacao de uso de substâncias psicoativas, como tambem da normatizacao juridica, prevista pelo Estatuto da Crianca e Adolescente, e das diretrizes do SUS e do Ministerio da Saude. O presente estudo, tambem, adotou a analise documental para resgatar a historia da implantacao do Programa de Desintoxicacao do HUOP e suas atividades. Para efetuar analises estatisticas sobre os usuarios do programa, a pesquisa utilizou uma amostra de 400 prontuarios fisicos, contendo informacoes referentes aos pacientes. Todas as informacoes contidas nos prontuarios fisicos sao coletadas no dia do internamento do paciente, pela assistente social de plantao do HUOP, e todas as perguntas sao respondidas pelo proprio paciente e seu responsavel. Os prontuarios escolhidos sao do periodo de 2007 a 2016, e esse periodo foi escolhido pelo fato de a Ala de Desintoxicacao ter seu inicio de funcionamento em marco de 2007. As variaveis estudadas foram idade, sexo, escolaridade, evasao escolar, renda familiar, experimentacao, ordem cronologica de consumo de substâncias psicoativas, primeira substância, substâncias de maior uso, modo de obtencao da substância, ocupacao, participacao de programas sociais, composicao familiar, ordem de nascimento, membro familiar com dependencia, condicoes das moradias, procedencia, bem como envolvimento em atos infracionais, cumprimento em medidas socioeducativas, comportamento sexual, pacientes que ja engravidaram. Resultados: A maioria era do sexo masculino, com um percentual de 76,5%, enquanto o sexo feminino era de 23,5%. A media de idade dos pacientes variou entre oito e 17 anos, sendo que a maior faixa etaria e dos 15 aos 17 anos, concentrando-se na faixa etaria dos 15 anos. Quanto ao grau de escolaridade, observouse que os usuarios apresentavam algum grau de atraso escolar, 89,9% dos usuarios possuiam o ensino fundamental incompleto e 9% tinham o ensino medio incompleto, e no dia do internamento mais de 60% estavam fora da escola. A renda media dos familiares da populacao estudada e de um a dois salarios minimos. Quanto as caracteristicas do uso das substâncias psicoativas, constatou-se que muitos iniciaram o uso destas, tanto licitas como ilicitas, por influencia de amigos, irmaos, parentes e ate mesmo dos pais. O maior motivo que levou a experimentacao das substâncias psicoativas foi a curiosidade. E, como a primeira substância psicoativa mais consumida foi o alcool, com quase 50% seguido pelo tabaco, evoluido para a segunda, que foi a maconha. Todos, antes do internamento, faziam uso de mais de um tipo de substância, so que a mais consumida era a maconha, com 59,2%, seguida pelo crack. Ha tambem o uso de substâncias psicoativas entre os pais, chegando a 70,4%. O uso dessas substâncias pelos pacientes estava associado ao envolvimento com atividades ilegais para consegui-las, chegando a 92%. Havia o envolvimento em roubo, prostituicao e, sobretudo, a adesao ao trafico de substâncias psicoativas ilicitas. E 18,2% cumpriram medidas socioeducativas, 17,5% estavam em cumprimento de medida de prestacao de servico, 11,0%, em liberdade assistida, 2,6% estavam em cumprimento de medidas com privacao da liberdade. Com relacao a familia, observa-se que 70,5% fazem parte de um nucleo familiar parental/monoparental. E o numero de irmaos e pequeno, de dois a tres filhos. O relacionamento dos pacientes com a familia e uma relacao ruim ou conflituosa com algum membro, sendo o pai com quem ocorrem os maiores conflitos. A maior modalidade de internacao foi a involuntaria, em que sao trazidos pelos pais ou responsavel, seguida pela compulsoria. E 63,9% ja tinham recorrido a algum tratamento antes da internacao na ala. A mae e a principal pessoa que mais acompanha os filhos nos internamentos. O comportamento sexual esteve mais associado ao de risco, com inicio precoce de atividade sexual, cuja pratica e com parceiros diferentes, inclusive se prostituindo. E, da amostra dos 400 prontuarios, 40 eram meninas, e, destas, 12 ja tinham engravidado uma ou mais de uma vez.

Um estudo do perfil dos menores internados na ala de desintoxicação do Hospital Universitário do Oeste do Paraná - HOOP - e das políticas públicas relacionadas ao tema

Setorização de áreas em alto e muito alto risco a movimentos de massa, enchentes e inundações: Rio Branco, Acre

This work is treated of an empiric research accomplished with teachers of the Basic Education, that had as objective to identify the courses of profesional development accomplished by those professionals, as well as their formative needs and his/her influence in the formation of the identity and of the educational profesionality. It is an exploratory qualitative study, which is based on critical hermeneutics of Dilthey, Gadamer, Habermas and Ricoeur, as an epistemological foundation of analysis and discussion of the data. Was used as data collection instrument an online questionnaire with fifteen questions (twelve open and three closed) dealing on aspects of identity, professionalism, professional development and training needs. The link of the questionnaire was sent to a list of e- mails from early childhood education and elementary school teachers, two municipalities to be answered in Google Forms. The choice of the sample was performed from a personal contact list of the principal investigator , taking into account those who act as teachers in basic education . For purposes of analysis and discussion of the survey results, the most significant contributions were used, considering the viability of qualitative responses.

Os conceitos de desenvolvimento profissional, profissionalidade, necessidades formativas e identidade docente no discurso de professores da educação básica de dois municípios brasileiros

Importantes estudiosos da literatura brasileira, Silvio Romero (1852-1914) e Jose Verissimo (1857-1916), nao se importaram em somente periodizar as fases da literatura produzida no Brasil. Ocuparam-se, tambem, em identificar o inicio de uma literatura genuinamente brasileira, livre da influencia direta da producao portuguesa, e definir as caracteristicas do “modernismo” na producao intelectual nacional. As obras desses autores, declaradamente preocupados com a “evolucao literaria” brasileira, perpassam a mera critica literaria e nos fornecem um pano de fundo para discutir o papel atribuido a historia na construcao de uma identidade nacional apos a Proclamacao da Republica (1889). Buscamos nesse trabalho abordar as relacoes entre historia, literatura e a maneira como as obras dos autores mencionados definiram a ideia de um “modernismo” brasileiro no alvorecer do seculo XX.

As raízes do modernismo brasileiro: relações entre história e literatura nas obras Evolução da literatura brasileira (1905), de Silvio Romero, e História da literatura brasileira (1916), de José Veríssimo.

Law 10639/2003 completed 14 years in 2017. This public policy was regulated in 17 Brazilian states and generated a series of developments: new laws and resolutions, which have contributed both to the discussion of ethnic-racial relations and to the insertion of the black population in the world of work, through the reservation of vacancies. The text presents Biology as one of the areas of knowledge that can contribute to the debate on education related to race relations, thus, confirming a CNE proposal of 1996. This production presents the Ancient Egypt (Ta-netjeru), as well as the medical practice carried out by the remetu-kemi - especially the sangrias (Ith) -, as an activity carried out by other African peoples, which may enter the classroom, through an interdisciplinary action involving Biology and History.

CONQUISTA DE DIREITOS, ENSINO DE CIÊNCIAS/BIOLOGIA E A PRÁTICA DA SANGRIA ENTRE OS/AS REMETU-KEMI E POVOS DA REGIÃO CONGO/ANGOLA: UMA PROPOSTA DE ARTICULAÇÃO PARA A SALA DE AULA

O homem e um ser efetivamente historico. Relaciona-se com o seu meio empreendendo um significado e um objetivo a todas as suas acoes, conscientemente ou nao, em uma relacao entre o passado e o futuro. E um ser teleologico influenciado diretamente pelo meio social no qual se insere, ou seja, e impossivel falar do homem separando-o de seu meio social ou de sua “historicidade”. Tudo que se relaciona com o homem enquanto individuo esta ligado diretamente ao seu espaco social e as condicoes materiais e interpretacoes das mesmas herdadas por ele historicamente.

Cotidianamente, muitas pessoas enfrentam alguns obstáculos, barreiras ou dificuldades, seja na utilização de determinado produto, locomoção, comunicação ou até mesmo para obter informações. Neste contexto, esta análise promove uma discussão sobre o conceito de Design Universal, contemplando fatores que vão além de Acessibilidade, relacionados a evolução do termo para princípios ligados à qualidade de vida e bem-estar social de todos os indivíduos. O objetivo é sintetizar os dois termos, demonstrando as diferenças, seus avanços e complementaridades entre si, como forma de contribuir para a compreensão da abrangência do Design Universal para além da Acessibilidade. Nessa perspectiva, é realizado um levantamento exploratório bibliográfico sobre estes assuntos, juntamente com o Design Social e o questionável ideal do “homem padrão”.

DESIGN UNIVERSAL PARA ALÉM DA ACESSIBILIDADE: PARALELOS E CONFLITOS NA CONTEMPORANEIDADE

História da Escola Normal do Colégio Providência de Mariana – MG (1902 - 1930)

Ação emergencial para reconhecimento de áreas de alto e muito alto risco a movimentos de massa, enchente e inundação: Rolim de Moura, Rondônia

A certeza de Freud: consciência, subjetividade e afeto à luz da neuropsicanálise

Ação emergencial para reconhecimento de áreas de alto e muito alto risco a movimentos de massa, enchente e inundação: Costa Marques, Rondônia

Ação emergencial para reconhecimento de áreas de alto e muito alto risco a movimentos de massa e enchente e inundação: Ministro Andreazza, RO

Temos observado o crescimento da utilizacao da interacao natural nos mais diversos ambientes computacionais devido a facilidade de aprendizado e naturalidade de interacao oferecidas ao usuario. Dispositivos capazes de reconhecer os gestos humanos sao utilizados juntamente com tecnicas de reconhecimento de gestos para alcancar tal finalidade. O reconhecimento de gestos na maioria das vezes envolve aprendizagem de maquina ou algoritmos avancados de reconhecimento adicionando mais uma complexidade no desenvolvimento de uma aplicacao baseada em interacao natural. O nosso trabalho tem por objetivo a construcao de uma Linguagem Especifica de Dominio (DSL) capaz de descrever os gestos das maos, reduzindo consideravelmente os esforcos no desenvolvimento. Para o desenvolvimento da DSL, foi utilizada a linguagem de programacao C#, uma linguagem de proposito geral amplamente utilizada, a plataforma de desenvolvimento de jogos Unity3D e o Leap Motion, um sensor capaz de detectar movimentos das maos e dedos e os utilizar como comandos de entrada. O principal objetivo desta dissertacao e disponibilizar uma DSL que auxilie o desenvolvimento de aplicacoes que utilizem gestos naturais das maos como interacao. A proposta da DSL e tornar a especificacao de gestos mais simples atraves de uma notacao capaz de abstrair tais complexidades.

Uma linguagem de domínio específico para auxiliar o desenvolvimento de aplicações baseadas em gestos das mãos

A geração e desenvolvimento da automatização dos processos de triagens de resíduos e da automatização de pátios de compostagens orgânicas, incorporando inovações tecnológicas, vem sendo demandada pela sociedade, visando dar escala e qualidade no gerenciamento sustentável do ambiente e da qualidade de vida. Busca-se com esta pesquisa atender a política de gerenciamento integrado de resíduos sólidos brasileira e corroborar com a necessidade de aprimoramento nos processos tecnológicos e de automação, visando a destinação final adequada de resíduos e dos processos de triagem e reciclagem. É objetivo, ainda, a construção de uma maquete geográfica-arquitetônica dinâmica para simulação de processo de compostagem orgânica (em escala miniaturizada). Para isso, busca-se montar um sistema supervisório que controlará a planta por meio dos sinais obtidos pelos sensores. O dispositivo visa captar dados referentes ao composto orgânica (disposto em leiras) de temperatura, umidade, pH e nível de aeração. A partir da obtenção desses dados, poderá ser feita a inspeção e eventuais intervenções no sistema, como a ação de revolvimento, rega e aeração de forma programável. Busca-se, ainda, avaliar o estado atual da automatização dos processos de triagem de resíduos sólidos fazendo estudos e revisões epistemológicas das tecnologias já disponíveis e implementadas, no Brasil e em outros países, visando obter modelos e boas idéias para o aprimoramento e adequação de projetos de baixo custo. As pesquisas indicam que é possível desenvolver formatos mais simples de sistemas de prensagem e esteiras rolantes de separação, já que a automação possibilita uma gama enorme de possibilidades de melhorias dos processos. Esta pesquisa faz parte dos estudos de viabilidade para implementação do Centro DidáticoPedagógico para o Gerenciamento Integrado de Resíduos Sólidos e Inovação do IFFluminense – Campus Macaé (projeto-piloto no município de Macaé) que visa novas perspectivas na gestão dos resíduos sólidos, com a utilização de tecnologias para a gestão sustentável do ambiente e da qualidade de vida.

Automatização de Processos de Triagem e Compostagem de Resíduos Sólidos: Situação Atual e Perspectivas Futuras

Trabalho de Conclusao de Curso submetido ao Departamento de Matematica e Estatistica, da Fundacao Universidade Federal de Rondonia, Campus de Ji-Parana, como parte dos requisitos para obtencao do titulo de Bacharel em Estatistica.

Metodologia Box-Jenkins para previsão de temperatura média mensal da cidade de Cacoal (Rondônia) / José Ailton Alencar da Silva

Ação emergencial para reconhecimento de áreas de alto e muito alto risco a movimentos de massa, enchente e inundação: São Miguel do Guaporé, RO

Apesar do progresso recente da terminologia em diversas especialidades nas diversas areas de conhecimento, tem sido bastante reduzida a producao lexicografica relativamente a terminologia linguistica e gramatical, principalmente em lingua portuguesa, incluindo nesta carencia as boas traducoes que poderiam compensa-la. Para sanar em parte essa deficiencia em nossa terminologia linguistico-gramatical, esta em desenvolvimento o projeto do Dicionario Linguistico-gramatical da Lingua Portuguesa , de cujo corpus atualmente recolhido foi preparado o material que aqui se disponibiliza, consistente da coleta de dados registrados em dicionarios de linguistica e gramatica disponiveis em nossa biblioteca particular: Cândido de Oliveira, Celso Pedro Luft, David Crystal, Jean Dubois et alii, Joaquim Matoso Câmara Junior, Silvio Edmundo Elia, Tassilo Orpheu Sapalding, Walmirio de Macedo.  Naturalmente, a obra incluira a atualizacao baseada nas principais gramaticas atualmente recomendadas, como as de Ataliba T. de Castilho, Celso Cunha e Lindley Cintra, Evanildo Bechara, Jose Carlos de Azeredo, Rocha Lima, Mario Alberto Perini, Mario Vilela e Ingedore Villaca Koch, Maria Helena de Moura Neves, Marcos Bagno, Napoleao Mendes de Almeida e em outros dicionarios. Neste artigo, pretende-se alertar para a variedade de enfoques possiveis na definicao de termos linguisticos e gramaticais, considerando principalmente os termos mais comuns e de conhecimento aparentemente de dominio geral, apesar de surpreender ate mesmo os especialistas, quando se observam os diferentes pontos de vista pelos quais se pode ver cada um desses termos. Apesar de ser importante, as consideracoes historicas ou diacronicas nao serao consideradas aqui. Nas consideracoes finais, incluiremos uma breve lista de termos relativos a morfologia, os quais serao incluidos no referido dicionario.

O VERBETE DA MORFOLOGIA NOS DICIONÁRIOS DE LINGUÍSTICA E GRAMÁTICA

Sabemos que os textos ocupam um lugar central nas aulas de Historia e que a leitura e a interpretacao dos mesmos sao condicoes essenciais para a aprendizagem dos conteudos trabalhados em sala de aula. Entretanto, na pratica pedagogica de muitos professores, ainda observamos dificuldades em realizar um ensino de leitura realmente significativo, em que o sujeito leitor precisa compreender e identificar a importância e a funcao de um determinado texto, aprender a destacar e a selecionar as informacoes importantes, o que esta nas entrelinhas, a relacionar o texto lido com outros textos, aprender a ler com o objetivo de aprender, de memorizar. Considerando que essas sao estrategias importantes para a compreensao dos textos e facilitam a aprendizagem dos conteudos, o presente artigo tem como objetivo analisar como se desenvolve o processo de leitura e interpretacao de textos nas aulas de historia do 6o ano, do Ensino Fundamental, na Escola Municipal de Deputado Julio Monteles, em Santana do Maranhao - Ma.

ENSINO DE HISTÓRIA: UM ESTUDO DESCRITIVO DA LEITURA E DA INTERPRETAÇÃO DE TEXTOS NO ENSINO FUNDAMENTAL

Nosso objetivo e tracar a historia da circulacao da literatura italiana traduzida no Brasil no seculo XX e na primeira decada do seculo XXI, apontando para obras, autores, momentos, episodios em seu contexto de partida, mas sobretudo de chegada: ou seja, em suas relacoes com o ambiente em que surgiram, mas sobretudo com o ambiente que os acolhe. Nosso ponto de partida e a ideia de que o meio privilegiado com que um pais da as boas-vindas a uma obra e a traducao. Refletir sobre as traducoes em seu contexto de chegada significa tambem refletir sobre este mesmo contexto, isto e, sobre o sistema literario nacional. Entendemos que as literaturas traduzidas, concebidas como sistemas literarios especiais dentro dos polissistemas constituidos pelas literaturas nacionais (conforme a definicao de Even-Zohar), sofrem condicionamentos peculiares, de acordo com os diversos momentos atravessados pelos paises que as recebem. Para a otimizacao do levantamento de dados, sera dada continuidade ao Dicionario Bibliografico da Literatura Italiana Traduzida, que ja se encontra on-line: www.dlit.ufsc.br e www. usp.br/dlit. Nesta fase o projeto conta com a colaboracao da equipe da area de Biblioteconomia ECA-USP, responsavel pela revisao dos verbetes ja publicados e pela formulacao de novos criterios de catalogacao dos titulos do dicionario. Nosso objetivo, apos o levantamento dos titulos traduzidos e tendo formado um quadro da presenca e da importância das varias editoras ativas no mercado da literatura italiana traduzida, sera observar, na area da recepcao brasileira da literatura italiana a partir de 1900, os movimentos das ideias e as transformacoes no ambiente de chegada.

Mapeamento e dicionário da literatura italiana traduzida: projeto integrado

O termo lesao esportiva apresenta grande variacao de conceito na literatura, mas em geral, entende-se como afeccao musculoesqueletica, dor ou incapacidade para treinos e/ou competicoes. Este trabalho objetivou revisar na literatura a prevalencia de lesoes em praticantes de futebol recreacional. Trata-se de uma revisao sistematizada da literatura realizada nas bases de dados: medline, scielo, fonte academica, pubmed e academic search elite utilizando os descritores: futebol, atividades de lazer e medicina esportiva; e seus correspondente na lingua inglesa. Estes foram cruzados atraves de estrategia pre-definida por meio de operador booleano and, com a palavra-chave futebol recreacional sendo esta ultima tambem utilizada isoladamente. Apos analise dos criterios de elegibilidade, foram selecionados oito estudos para a analise combinada. Foi observado que o segmento com maior incidencia de lesoes em praticantes de futebol foi o do membro inferior, tendo como as lesoes que predominantes as entorses nos joelhos, lesoes musculares, contusoes, luxacoes e, menos frequente, as fraturas. Individuos mais jovens apresentaram maior incidencia destas lesoes do que os de maior faixa etaria, as caracteristicas intrinsecas do jogador e a sua posicao em campo durante a partida exercem grande influencia no desenvolvimento de lesoes, caracterizando os meio-campistas como os jogadores com maior predisposicao as lesoes. A prevencao se torna um eficiente instrumento na reducao o numero de novas lesoes. Mesmo que nao se possam impedi-las completamente, devido aos diferentes mecanismos que as geram, o conhecimento sobre as lesoes, o perfil do atleta e os mecanismos intrinsecos e extrinsecos, caracteriza-se como uma excelente ferramenta preventiva.

Silva J.D., Melo D.H.M., Costa J.A.G., Costa D.F., Silva R.B.S., Melo M.A., Azevedo S.S. & Alves C.J. 2017. [Visceral leishmaniasis in dogs from rural settlements.] Leishmaniose visceral em cães de assentamentos rurais. Pesquisa Veterinária Brasileira 37(11):1292-1298. Programa de Pós-Graduação em Medicina Veterinária, Universidade Federal de Campina Grande, Av. Universitária s/n, Santa Cecília, Patos, PB 58700-970, Brazil. E-mail: clebertja@uol.com.br In rural settlements there are higher concentrations of reservoirs and vectors of canine visceral leishmaniasis (CVL) due to environmental changes resulting from human action by occupation of the territory, however, there are no surveys in Brazil on epidemiological information of CVL in these areas. The aim of this study was to determine the seroprevalence of Leishmania sp. in dogs from rural settlements, as well as to identify the risk factors associated with infection. A total of 306 dogs were tested, and the serological diagnosis of CVL was performed by ELISA S7. Of the 306 dogs, 118 presented anti-Leishmania sp. antibodies., resulting in a frequency of 38.6%. The risk factors identified for CVL seropositivity were: age of 12-24 months (OR=2.97), age of 24-48 months (OR=4.83), age of 4-6 years (OR=4.40), age >6 years (OR=3.62), contact with poultry (OR=1.67) and gender (female) (OR=1.97). Dogs from rural settlements in the semiarid of Paraiba showed high anti-Leishmania sp. antibody frequency, what makes the population of those settlements susceptible to infection. This highlights for the need to alert the epidemiological surveillance agencies to stablish prevention and control methods for that zoonosis, including educational and health activities on these settlements, as they are located in areas with favorable characteristics for CVL installation.

Continuing teacher education is part of a continuing need for professional development, leading teachers to reflect critically on their own pedagogical practice. The present work aimed to investigate the contributions of the Institutional Program of Initiation Scholarships to Teaching (Pibid) in the continuous for mation of eight supervisors participating in the subprojects of the Faculty of Education, Sciences and Letters of Iguatu campi of the State University of Ceara (FECLI/UECE). This research is characterized as descriptive and exploratory, with a qualitative approach. Data were collected from a questionnaire and analyzed in a descriptive-interpretative manner. In view of the results, it was observed that the PIBID contributed in a positive and progressive way with regard to the continuous formation of supervising teachers, mainly in relation to the updating of the contents of the area, as well as the pedagogical methodologies and resources that can be inserted in their routine of living room. Thus, there is a teaching praxis in the face of the experiences shared with initiation scholarship students in the school, evolving them and qualifying their practice.

Contribuições do Programa Institucional de Bolsas de Iniciação à Docência na formação continuada de professores supervisores

Introdução O desenvolvimento do Serviço Nacional de Saúde (SNS) nos anos 80, depois dos primeiros passos dados na década anterior, levou a investimentos públicos muito significativos em infraestruturas e recursos humanos. A construção de dezenas de novos hospitais e centenas de centros de saúde, a assinatura de convenções e acordos com prestadores de cuidados e serviços privados, o aumento do número de médicos e enfermeiros, induziram, por outro lado, um aumento crescente da despesa do SNS, nomeadamente na rúbrica da despesa com medicamentos. Pela primeira vez, com duas décadas de atraso em relação aos países europeus mais desenvolvidos, os portugueses passaram a ter acesso a um serviço de saúde estruturado e com acesso universal, assim como a um sistema de comparticipação de medicamentos que abrangia toda a população. O mercado de medicamentos crescia entre 25 a 30% ao ano no final da década de oitenta, valores que mesmo tendo em conta a inflação registada à época eram muito elevados. Por outro lado, a percentagem dos gastos em saúde em relação ao PIB foi crescendo muito significativamente passando de 5,9% em 1980 para 9,2% em 2001, o que representa um aumento da preponderância das despesas em saúde na riqueza disponível de mais de 50% em cerca de duas décadas. Qual era no entanto a situação em Portugal na fase de adesão à Comunidade Económica Europeia (CEE) no que se refere à regulação do medicamento? A tutela da saúde esteve muitos anos na dependência do Ministério do Interior, cuja Direção-Geral da Saúde continha um serviço técnico de ”Exercício da farmácia e comprovação de medicamentos”. Com a reorganização em 1971 do Ministério da Saúde, o organismo de tutela dos medicamentos e da atividade farmacêutica continua a ser a Direção-Geral de Saúde (DGSaúde), que continha na sua estrutura orgânica uma Direção de Serviços de Farmácia e Medicamentos. A comprovação dos medicamentos fica na tutela do Instituto Nacional de Saúde Dr. Ricardo Jorge (INSA), onde também funcionava a Comissão Técnica dos Novos Medicamentos (CTNM), criada em 1957, que contava com o apoio de um novo laboratório de comprovação de medicamentos. O controlo dos medicamentos era também efetuado pela Comissão Reguladora de Produtos Químicos e Farmacêuticos (CRPQF), que tinha instalações laboratoriais próprias. O mercado de medicamentos crescia com o aumento do acesso e, consequentemente, da procura e instalam-se no país as grandes companhias internacionais, até aí representadas por empresas locais. Com o crescimento do mercado do medicamento as farmácias portuguesas melhoraram significativamente a sua rentabilidade. Por outro lado, os farmacêuticos, através da atuação das suas associações profissionais, investem na formação contínua, nas infraestruturas das farmácias, nomeadamente nos sistemas de informação e na melhoria qualitativa de recursos humanos, sendo também de realçar que o número de farmacêuticos por farmácia duplica no espaço de uma década.

Vinte e Cinco Anos de Evolução do INFARMED, I.P.: Os Atuais Desafios

Este artigo teve como objetivo a análise da influência da crise internacional, eclodida em 2008, sobre as finanças públicas municipais do Nordeste brasileiro, entre os anos de 2005/2012. A análise dos dados revelou que os municípios nordestinos após 2008 apresentaram desajustes fiscais, além de que paraibanos e pernambucanos foram mais responsáveis socialmente, porém, a totalidade desses municípios tiveram suas finanças públicas afetadas negativamente pelo contexto monetário realizado no Brasil, o qual foi refém do cenário de crise internacionalmente estabelecido. Palavras-Chave: Política Monetária; Finanças Públicas Municipais; Nordeste. ABSTRACT:

Crise financeira internacional e as finanças públicas municipais nordestinas: uma análise comparada

EXPERIÊNCIASCOM A UTILIZAÇÃO, EM SALA DE AULA, DE JOGOS MATEMÁTICOS

O presente trabalho foi realizado na comunidade PA Sao Francisco junto com a equipe do Nucleo de Pesquisa e Extensao em Ambiente, Socieconomia e agroecologia – NUPEAS. O Nucleo com esta acao visou conscientizar os moradores de como eles podem reutilizar os residuos agricolas, conservando o ambiente causando menos impactos no ecossistema. O trabalho teve inicio em 2016 no mes de abril, pelo NUPEAS em parceria com a comunidade PA Sao Francisco/Canutama no sul do Amazonas. O desenvolvimento do trabalho foi realizado em 4 etapas: A primeira foi na sala do NUPEAS com levantamentos bibliograficos e assunto relacionado ao tema e montagem do material. A segunda etapa foi na Comunidade no Projeto de Assentamento Sao Francisco – Canutama/AM. Foi feita uma oficina sobre todo aspecto da composteira: material usado, tipos de composteira, os fatores que afetem. Na terceira etapa foi feito a construcao da composteira que e o local onde acontece o processo de compostagem. Na quarta etapa foi feito a montagem das pilhas de compostagem onde foram montadas as camadas de acordo com a relacao carbono (C) e Nitrogenio (N) relacao C/N e tamanho da pilha. O processo de compostagem ficou pronto depois de 50 dias. A participacao na oficina teve envolvimento de aproximadamente 15 pessoas, entre eles comunitarios, equipe do NUPEAS, socios da associacao, homens, mulheres, jovens contribuiram com seus relatos, e que sejam multiplicadores para outras comunidades rurais do Sul do Amazonas, alem de incentiva-los ao processo da transicao agroecologica.

Formação de Composto no PA São Francisco - Canutama a Partir de Resíduos Agrícolas Oriundos na Comunidade.

O contato dos alunos com a pratica contribui significativamente para o aprendizado do que foi visto em sala de aula. Neste sentido, objetivou-se avaliar a importância das aulas praticas das disciplinas tecnicas do Curso de Agroecologia do IFAL, C ampus Piranhas. O trabalho foi desenvolvido por meio de um formulario de multipla escolha sobre o andamento das aulas praticas e metodologia adotada nessas. Uma segunda vertente do estudo foi sobre o estado de conservacao e diversificacao da horta escolar e autoavaliacao sobre o conhecimento das especies plantadas e do interesse dos alunos em relacao as aulas praticas. As aulas praticas atenderam parcialmente as expectativas dos alunos. Em media as aulas praticas foram consideradas essenciais para a complementacao e fundamentacao do ensino. A metodologia adotada pelos professores nas aulas foi considerada adequada. A horta foi considerada em condicao regular a boa, e diversificada em relacao as especies cultivadas. Na autoavaliacao os alunos relataram um bom conhecimento adquirido sobre as especies cultivadas na horta e interesse mediano em relacao as praticas desenvolvidas

Avaliação dos alunos do curso de agroecologia do IFAL, Campus Piranhas, sobre a importância das aulas práticas para sua formação

Ação emergencial para reconhecimento de áreas de alto e muito alto risco a movimentos de massa, enchente e inundação: Pimenta Bueno, Rondônia

With society’s growing concern about eating healthy foods, the food industry constantly seeks to develop less calorie products, associated with the presence of ingredients with functional properties. Thus, taking advantage of the wide acceptance of yogurt, the industry has been using it as a vehicle for inclusion of prebiotic compounds. Therefore, the objective of this work was the preparation and characterization, physicochemical and sensory, of light yogurts sweetened with honey and supplemented with prebiotics inulin and fructooligosaccharides. Three formulations were prepared: A (control – free of prebiotics), B (with addition of 3% inulin) and C (3% of fructooligosaccharides) that were submitted to physical and chemical analysis of moisture, ash, pH, titratable acidity and lipids; and sensory analysis of acceptance and purchase intent. The results were statistically similar for all physical and chemical parameters assessed, except moisture. Concerning the sensory analysis, it was observed that, statistically, the addition of prebiotics did not cause significant interference (p < 0.05) in the evaluated sensorial parameters, as all samples showed good acceptance with rates of over 70%, highlighting the similarity acceptance of samples supplemented with prebiotics in relation to the formulation control. Regarding the intention to purchase, formulation C stood out in a small numerical advantage, but not statistical, over the other formulations, being this the most viable for commercialization. Thus, it was possible to highlight the feasibility of including prebiotics in light yogurt sweetened with honey formulations in order to contribute to the diversification of the dairy sector and meet the population’s demands for healthy food.

ELABORAÇÃO E CARACTERIZAÇÃO FÍSICO-QUÍMICA E SENSORIAL DE IOGURTE LIGHT PREBIÓTICO ADOÇADO COM MEL

É por de mais conhecida a passagem 38a da Apologia de Sócrates de Platão onde Sócrates declara que “uma vida não examinada não vale a pena ser vivida”. Ainda nesta passagem, Sócrates afirma que o maior bem para o homem é discutir todos os dias sobre a virtude – a vida deve ser examinada todos os dias na totalidade do tempo em que estivermos vivos. Para demostrar isto, Sócrates precisa comparar seu modo de vida com aqueles considerados úteis à cidade. A medida que irá julgar qual dos dois modos é o melhor, segundo minha interpretação, é exatamente a relação de cada um deles com a morte.

Vida, morte e totalidade no tempo na apologia de Sócrates de Platão

Resumo O. dillenii é considerada uma espécie invasora por muitos autores, de grande distribuição no nordeste brasileiro. É registrada no semiárido da Paraíba, na Fazenda Agroecológica Gavião município de Picuí, local de realização do estudo. Diante disso, este trabalho avalia o desenvolvimento fenológico de O. dillenii em 180 dias de plantio. Com raquetes da Opuntia adulta foram realizados plantios em berços de 15 cm e em curva de nível distribuídos em três blocos formando 27 parcelas com um total de 432 plantas. Nesse estudo, utilizou-se o delineamento estatístico com fatorial 3x3x3 com três tratamentos: plantio com cladódio primárias, secundarias e terciárias, sobre os espaçamentos simples (ES) 0,5 x 0,5 m; o duplo (ED) 0,50 x 0,50 x 1,0 m e o triplo (ET) 0,40 x 0,40 x 040 x 0,80 m e três repetições com cladódio distribuídas aleatoriamente. Após o período de cultivo foram mensuradas a altura da planta, comprimento, largura, espessura e perímetro de cladódio de cada tratamento.

AVALIAÇÃO BIOMÉTRICA DE Opuntia dillenii PLANTADAS SOBRE DIFERENTES ESPAÇAMENTOS EM ÁREAS DEGRADADAS DO SERIDÓ PARAIBANO

This study analyzes the process of attending the Ombudsman's Office of the 
Worker's Agency of a municipality of the Metropolitan Region of Recife (RMR), with 
the perspective of making the public service more agile and efficient in presenting 
results to the user of the services of the Worker's Agency. To that end, the collection, 
organization, retrieval, interpretation and use of information in activities that sought to 
mediate conflicts and propose changes that benefited the best practices in service 
delivery had been studied. Currently, the procedures performed in the care of the 
agencies occur manually and do not have adequate control. With the analysis of the 
activities developed in the care of these agencies, through techniques based on 
process management and considering the importance of the Ombudsman's role in 
the relationship between Institution and population, the objective was to identify 
critical points in the execution of such activities and, consequently, Improvements.

Gestão de Processos na Ouvidoria da Agência do Trabalhador de Um Município da Região Metropolitana do Recife

Boletim técnico sobre ocorrência de eventos críticos em áreas de risco: erosão fluvial no Distrito de Nazaré, Porto Velho - RO

Ação emergencial para reconhecimento de áreas de alto e muito alto risco a movimentos de massa, enchente e inundação: Presidente Médici, RO

Uma grande parte do petroleo extraido hoje no Brasil e escoada para a costa, ou ate mesmo transportada para embarcacoes maiores, atraves de mangotes flutuantes, chamados de Floating Hoses . Essa operacao de descarregamento do petroleo e denominada de offloading , sendo de fundamental importância para o desempenho das unidades operacionais offshore . Essas unidades operacionais utilizam-se de sistemas de armazenamento e alivio de petroleo, que podem ser FSO (Unidade Flutuante de Estocagem e Transferencia) ou FPSO (Unidade Flutuante de Producao, Estocagem e Transferencia). Nesse cenario de transbordo do petroleo, os mangotes flutuantes tem papel primordial, pois sao eles os responsaveis por esta operacao. Os Floating Hoses , apos vida util, sao descartados. Como fazer o descarte ambientalmente correto desse residuo? O destino mais utilizado sao os aterros industriais classe 2 para residuos nao perigosos. Buscou-se com a pesquisa desenvolver tecnicas de destinacao adequadas para os Floating Hoses , de forma a obter uma maior valorizacao possivel dos materiais que os compoem, bem como apresentar os riscos em caso de estes serem acondicionados em um aterro, mesmo que seja um aterro controlado. Essa tecnica esta baseada em uma chamada Manufatura Reversa, todos os seus componentes sao reaproveitados e valorizados, tendo uma destinacao ambientalmente mais correta e economicamente viavel. A metodologia de pesquisa utilizada foi baseada em estudos empiricos de fundamentacao fenomenologica, envolvendo equipe operacional de uma empresa de porte medio que possui uma participacao ascendente no mercado de tratamento e destinacao de residuos no municipio de Macae. Evidenciou-se com a pesquisa que ha possibilidade de ganhos potenciais com a aplicacao das tecnicas de manufatura reversa dos mangotes, tanto em termos de reducoes de passivos ambientais, como com o retorno financeiro por meio da valorizacao dos materiais que os compoem.

Resíduos industriais - técnicas de destinação e valorização dos floating hoses: estudo de caso no município de Macaé, RJ

We will generalize a Maximum Principle at Infinity in the parabolic case given in paper A Maximum Principles at Infinity for surfaces with Constant Mean Curvature in Euclidean Space by Ronald F. de Lima and Ronaldo F. de Lima and William Meeks in paper Maximum Principles at Infinity for surfaces of Bounded Mean Curvature in R³ and H³ where we will now have hypersurfaces M₁ and M₂ of Rⁿ⁺¹ disjoints, with boundary (possibly empty) ∂M₁ e ∂M₂ of the bounded mean curvature and with Ideal Contact et Infinity, but now without restrictions on the Gaussian Curvature of any hypersurface. As geometric application we will present some results that extend for embedded hypersurfaces M₁ and M₂ in Rⁿ⁺¹ with empty boundaries a generalization of Hopf’s Maximum Principle for disjoint hypersurfaces that get close asymptotically. Once obtained these results, we inserted a structure of a weighted Riemannian Manifold in Rⁿ⁺¹ and obtained some generalizations of the results previously achieved under some hypothesis of the objects now found, such as f-mean curvature, f-Laplacian, f–parabolic weighted manifold, in the hypersurfaces M₁ and M₂ from Rfⁿ⁺¹ .

Um princípio do máximo para hipersuperfícies com um contato ideal no infinito e aplicações geométricas

Este artigo apresenta a politica de formacao em servico para o uso das TDIC na educacao municipal de Aracaju/SE. As transformacoes trazidas pelas tecnologias da informacao e comunicacao apresentam para a educacao, desafios muito grandes ao contribuirem com as profundas modificacoes na forma de ser e de pensar da humanidade. E uma pesquisa qualitativa com abordagem em analise de conteudos (os documentos), para apreciacao e reflexao. Constatou-se uma pratica de inclusao social via digital nas politicas de formacao em servico, quando os professores passaram a utilizar as tecnologias nos processos de aprendizagens.

FORMAÇÃO DE PROFESSORES NA PREFEITURA DE ARACAJU: REFLEXÃO-AÇÃO DAS TECNOLOGIAS DIGITAIS DE INFORMAÇÃO E COMUNICAÇÃO NA EDUCAÇÃO

Esta pesquisa traz a tona a discussao das relacoes entre a Biologia Educacional e a 
educacao, particularmente no que diz respeito aos fatores biologicos que podem vir a 
interferir na aprendizagem. Nesta empreitada, o objetivo geral e analisar as relacoes entre 
a Biologia e a Educacao, partindo dos fatores biologicos que podem interferir na 
aprendizagem. Em nivel de objetivos especificos, pretende-se: situar a Biologia no 
contexto brasileiro, sobretudo a partir da decada de 1930 ate a atualidade; estabelecer 
relacoes entre a Biologia e a educacao, recortando os fatores que subsidiam a 
aprendizagem. Questiona-se, sobretudo, quais sao as formas pelas quais ocorrem as 
relacoes entre a Biologia e a Educacao, e, sobretudo, de que modo os fatores biologicos 
podem interferir na aprendizagem. A perspectiva de analise que norteia este trabalho e 
a historia e cultural, por facilitar a compreensao das relacoes entre a Biologia e a 
educacao. A metodologia utilizada e a pesquisa bibliografica e documental, pelo fato de 
propiciar um olhar mais acurado ao tema estudado. Os resultados mostraram que e 
possivel estabelecer relacoes entre a Biologia e a Educacao, uma vez que a Biologia se 
constitui num corpus de conhecimento cientifico fundamental para subsidiar a Educacao 
e, prioritariamente, quanto aos fatores biologicos que interferem na aprendizagem. Ex : 
fatores geneticos e hereditarios, doencas congenitas, parasitas internos e externos, alem 
disso agentes quimicos e fisicos.

Biologia educacional: fatores que podem interferir na aprendizagem

O quadro pintado por volta de 1560 pelo artista Pieter Bruegel e um registo historico da forma de divertimento em pequenos povoados no periodo do Renascimento. Essa obra perpassou os tempos e continua a encantar pela riqueza dos detalhes e pelo seu contexto. Na atualidade, muito se discute a forma de interagir entre as pessoas desde as mais novas as mais velhas. No entanto, um problema pertinente, por questoes tecnologicas, as pessoas estao cada vez mais em frente de telas interativas e se esquecem de interagir entre elas no seu cotidiano. Em determinadas culturas, a presenca das representacoes do quadro “Jogos Infantis” e marcada pelo cunho folclorico, porem esta se perdendo aos poucos. No Rio Grande do Sul, entidades tradicionalistas preservam a cultura local e regional. A presenca das representacoes do quadro tambem esta presente na cultura Rio-grandense, pois as entidades tradicionalistas, alem de preservar a cultura do sul do pais, utilizam dos brinquedos, jogos e brincadeiras folcloricos e o ludico como um dos meios para atrair as novas geracoes a se integrarem nessas entidades. Dessa forma, faz-se necessario conhecer o trabalho desenvolvido pelos centros de tradicoes gauchas. A arte, o ludico, o folclore e a cultura como um todo, sao ferramentas que contribuem para a construcao do individuo com sua propria identidade, que pode ou podera se construir pelo ato de brincar, imaginar e criar.

Bruegel e a cultura rio-grandense: do passado ao presente, o folclore, o lúdico e o brincar

Confirma-se, nesta louvavel iniciativa, a preocupacao da Universidade de Brasilia com o aperfeicoamento das instituicoes politicas e juridicas do pais, constituindo um forum de permanente debate acerca das transformacoes da vida brasileira e das solucoes indicaveis aos grandes problemas nacionais. A convivencia democratica nao pode efetivamente prescindir do dialogo amplo, da discussao de alto nivel sobre as diversificadas questoes que enfrenta o desenvolvimento do pais. A presenca da Universidade, por seus mestres e estudantes, em tais debates, bem evidencia seus propositos de integracao nos esforcos nacionais por uma Patria livre, prospera e feliz.

A Experiência de desburocratização no Tribuna Federa de Recursos

Nesta segunda quinzena do seculo XXI, a Educacao busca estabelecer sintonia com as transformacoes culturais advindas da revolucao computacional iniciada nos anos 50. No atual contexto sociotecnico surgem duas tendencias, o Blended Learning e a Inteligencia Coletiva. O objetivo desta tese e investigar as contribuicoes da uniao entre Blended Learning e inteligencia coletiva para a aprendizagem individual e coletiva. A pesquisa tem carater qualitativo desdobrada em levantamento blibliografico e analise de dados provenientes de um curso Blended no âmbito da formacao judiciaria. Para enfrentar o problema, busquei aporte teorico em varias areas do conhecimento e autores. O norte teorico, entretanto, focou a Inteligencia Coletiva, especialmente os estudos de Pierre Levy, o Sociocontrutivismo, de Lev Vigotski, as investigacoes sobre Blended Learning realizadas por Michael B. Horn e Heather Staker, bem como minha pesquisa sobre operadores da Inteligencia Coletiva em ambiente de aprendizagem virtual conduzida em meu Mestrado. A analise dos dados validou o pressuposto de que a uniao entre o Blended Learning e a Inteligencia Coletiva favorece a aprendizagem por meio da criacao um espaco de aprendizagem mais rico em colaboracao, participacao, reflexao e autorregulacao do aprendizado. Amparado nesses resultados, proponho o Blended Learning Baseado na Inteligencia Coletiva (BLBIC).

Blended learning baseado na inteligência coletiva - BLBIC: análise de um curso de formação judiciária

O presente trabalho se propoe a apresentar um breve relato das experiencias de formacao continuada em servico, vivenciadas a partir da implantacao e implementacao do Programa de Formacao Continuada para professores da rede publica municipal de ensino de Teotonio Vilela/AL e os impactos dessa atividade no aperfeicoamento do fazer pedagogico docente e, consequentemente, nos resultados de aprendizagem dos estudantes. Ressalta-se a articulacao entre teoria e pratica na metodologia do programa ora mencionado com o intuito de dar maior significacao aos participantes. E conclui-se que atraves dessa formatacao, o processo de desenvolvimento profissional se torna eficaz, resultando na mudanca de reflexoes e posturas acerca dos caminhos para o desenvolvimento com qualidade de competencias e habilidades pelos estudantes.

A producao de bioenergia no Brasil vem revelando grandes oportunidades de negocios, uma delas e a producao de briquetes, que gera uma fonte de energia renovavel, que pode ser classificada como a capacidade de gerar trabalho atraves da alteracao da materia. O reaproveitamento energetico da biomassa residual de vegetais, gerados a partir de varias atividades da agricultura, por exemplo, pode ser uma forma de reduzir a pressao sobre os recursos naturais diretamente explorados como fonte de combustiveis renovaveis. Neste contexto, o aproveitamento da biomassa residual existente na microrregiao de Dourados no Estado do Mato Grosso do Sul-MS possui potencial para producao de um bioproduto como o briquete. As acoes empreendedoras voltadas para a bioenergia podem ser uma grande fonte de riqueza, visto que sao enormes a quantidade de energia demandadas atualmente, sendo o calor a energia mais intensamente utilizada, para atender e sustentar um processo de desenvolvimento socioeconomico. O trabalho de pesquisa teve como objetivo: Analisar a viabilidade tecnica para producao de bioproduto oriundo de biomassa residual na microrregiao de Dourados-MS. A pesquisa contou com uma metodologia qualitativa e quantitativa com caracteristicas exploratorias e pesquisa na base de dados do IBGE. Os dados da pesquisa demonstraram a viabilidade tecnica para um novo empreendimento. Desta forma a pesquisa contribuiu com a Producao Energetica na microrregiao de Dourados-MS.

DA BIOMASSA RESIDUAL AO BRIQUETE: VIABILIDADE TÉCNICA PARA PRODUÇÃO DE BRIQUETES NA MICRORREGIÃO DE DOURADOS-MS

A reuniao dos contos do autor dos Pontos de Gramatica Historica e uma importante contribuicao para o reconhecimento desse autor, quase totalmente desconhecido como poeta, contista e cronista. Depois de disponibilizado virtualmente o Espolio de Ismael de Lima Coutinho pelo CiFEFiL, interessantes trabalhos vem sendo realizados a partir de seus textos ate entao ineditos. Pretende-se mostrar aqui a contribuicao da critica textual na divulgacao de importantes trabalhos pouquissimo conhecidos, para a restauracao dos valores de autores que tanto contribuiram para o progresso da cultura intelectual em nosso pais, com as reflexoes sobre a edicao dos Contos Ingenuos, que Ismael de Lima Coutinho escreveu, sob o pseudonimo de Joao da Chagas.

Ação emergencial para reconhecimento de áreas de alto e muito alto risco a movimentos de massa, enchente e inundação: Parecis, Rondônia

Influência da velocidade da colhedora na qualidade fisiológica de sementes de arroz de terras altas

Ação emergencial para reconhecimento de áreas de alto e muito alto risco a movimentos de massa e enchente e inundação: Candeias do Jamari, Rondônia

Ação emergencial para reconhecimento de áreas de alto e muito alto risco a movimentos de massa, enchente e inundação: Alvorada D'oeste, Rondônia

Este artigo tem como objetivo aplicar a analise dos nucleos de significacao como instrumento para apreensao dos sentidos da escolha profissional para um adolescente. Foi realizada entrevista semiestruturada com base em dezessete perguntas norteadoras com a finalidade de identificar os principais aspectos relacionados a escolha profissional do jovem no final do ensino medio numa escola publica sob o vies contextualizado de um pequeno municipio no qual esta instalada uma grande industria. Foram debatidas no decorrer das fases da analise a ausencia da pratica da orientacao profissional e suas implicacoes. Seguiu-se o roteiro da elaboracao de quadros de pre-indicadores e indicadores, com a posterior analise intranucleos e internucleos, respeitando o metodo recomendado nas analises dos nucleos de significacao. Ao final entende-se que houve aproximacao das zonas de sentido contidas na fala do sujeito, dessa forma o instrumento utilizado mostrou-se relevante na analise dos significados.

APLICAÇÃO DOS NÚCLEOS DE SIGNIFICAÇÃO COMO MÉTODO DE ANÁLISE PARA ENTREVISTA: A ESCOLHA PROFISSIONAL DE UM ADOLESCENTE

ATRIBUTOS FÍSICOS DO SOLO: UMA ANÁLISE A PARTIR DAS ÁREAS DE CULTIVO DO IFPE-CAMPUS VITÓRIA DE SANTO ANTÃO

A banana destaca-se na primeira posição no ranking mundial das frutas, com uma produção de 106,5 milhões de toneladas. O Brasil produz sete milhões de toneladas, com participação de 6,9% nesse total VIEIRA (2015, apud IBGE, 2014). A banana é a segunda fruta mais consumida no planeta, com 11,4 kg/hab/ano, perdendo apenas para a laranja, com 12,2 kg/hab/ano. O continente americano é o maior consumidor, com 15,2 kg/habitantes/ano, destacando-se a América do Sul, com 20 kg/habitantes/ano e a América Central, com 13,9 kg/habitantes/ano VIEIRA (2015, apud FAO, 2013).

AVALIAÇÃO DOS ATRIBUTOS FISICOS DO SOLO NA ÁREA EXPERIMENTAL SOBRE CULTIVO DA BANANA (musa paradisíaca) NO IFPE-CAMPUS VITÓRIA DE SANTO ANTÃO

O reaproveitamento energetico da biomassa residual de vegetais gerados a partir de varias atividades da agricultura, por exemplo, pode ser uma forma de reduzir a pressao sobre os recursos naturais diretamente explorados como fonte de combustiveis renovaveis. Nesse contexto, o aproveitamento da biomassa residual existente na microrregiao de Dourados, no Estado do Mato Grosso do Sul (MS), possui potencial para a producao de um bioproduto como o briquete. O trabalho de pesquisa teve como objetivo analisar a viabilidade tecnica para producao de bioproduto, oriundo de biomassa residual na microrregiao de Dourados (MS). A pesquisa contou com uma metodologia qualitativa e quantitativa, com caracteristicas exploratorias e pesquisa na base de dados do IBGE. Os dados da pesquisa demonstraram a viabilidade tecnica para um novo empreendimento. Desta forma, a pesquisa contribuiu com a Producao Energetica na microrregiao de Dourados-MS.

Biomassa Residual Agrícola para Produção de Briquetes na Microrregião de Dourados-MS

As palmas forrageiras resistentes a cochonilha-do-carmim Dactylopius sp representadas 
pelas variedades Baiana, Sertânea ou Mao de Moca (Nopalea cochenillifera); Doce, 
Miuda ou Santa (Nopalea cochenillifera Salm-Dick) e Orelha de Elefante Mexicana 
(Opuntia tuna) podem ser enquadradas como lavouras xerofilas e bancos de energia e 
agua no âmbito do Semiarido brasileiro. Existe atualmente uma grande necessidade de 
repovoamento de areas onde ocorreu a extincao da variedade Gigante Opuntia ficusindica pela referida praga. No Projeto do Assentamento Ubaia localizado na municipio 
de Barra de Santa Rosa, Semiarido Paraibano foi formado um Grupo da Palma pelos 
assentados e implantado um campo de multiplicacao e pesquisa com a as variedades 
Orelha de Elefante Mexicana, Baiana e Miuda na area coletiva. Aos 12 meses apos 
plantio (MAP) foram realizadas medicoes da altura de plantas; numero de raquetes 
primarias, secundarias e terciarias; comprimento de raquetes primarias, secundarias e 
terciarias; largura de raquetes primarias, secundarias e terciarias; perimetro de raquetes 
primarias, secundarias e terciarias e peso de raquetes primarias, secundarias e terciarias. 
Os dados obtidos permitiram inferir que a variedade Orelha de Elefante Mexicana 
promoveu uma maior numero de raquetes primarias por area enquanto a variedade 
Baiana promoveu uma maior producao de massa verde por area sendo ligeiramente 
superior a variedede Orelha de Elefante Mexicana.

A PALMA FORRAGEIRA RESISTENTE A COCHONILHA - DO - CARMIM NO CURIMATAÚ PARAIBANO. O CASO DO ASSENTAMENTO UBAIA. BARRA DE SANTA ROSA

Ação emergencial para reconhecimento de áreas de alto e muito alto risco a movimentos de massa e enchente e inundação: Nova Brasilândia D'Oeste, Rondônia

O uso de antimicrobianos tem sido monitorado por varios meios e isso tem promovido uma atencao especial por parte dos profissionais de saude. Objetivos: avaliar as receitas de antimicrobianos dispensados em uma farmacia comunitaria no municipio de caucaia-ce, considerando-se o fato de que os antimicrobianos figuram entre os medicamentos mais prescritos e que seu uso irracional pode implicar em uma resistencia bacteriana, que pode acarretar em onus grave a saude dos pacientes. Materiais e metodos: foram analisadas 100 receitas de antimicrobianos, decorrentes do periodo de fevereiro de 2016. Resultados: a faixa etaria dominante da pesquisa foi entre 20-39 anos, tendo um percentual elevado de receitas com boa legibilidade e escritas a mao. A forma farmaceutica predominante em mais da metade das receitas foi em comprimido, sendo a classe terapeutica das quinolonas em primeiro lugar seguido das penicilinas. A especialidade do clinico geral se destacou isso provavelmente por ter uma maior visao do quadro clinico da populacao atendida e tambem um maior acesso a esse tipo de atendimento com sua identificacao completa na maior parte das receitas. Conclusao: o estudo verificou que as receitas dispensadas apresentaram as informacoes importantes para que o antimicrobiano fosse dispensado de maneira racional aos pacientes.

Avaliação das receitas de antimicrobianos dispensados em uma farmácia comunitária no município de caucaia – ceará.

Implantação de Sistema de Compostagem em Laboratório Didático de Resíduos

Over the past 30 years, financial market stakeholders have been following the involvement of large companies in frequent cases of accounting fraud. Emblematic corporate scandals such as Enron, WorldCom and Petrobras have prompted investors and professionals in the financial market to require companies to implement effective fraud detection tools. This work was developed from the model proposed by Cavusoglu and Raghunathan (2004), which deals with the programming of a risk management structure from the configuration of a software and seeks to establish a connection between the estimation of financial risk from software And the use of game theory. The proposed model was applied to a financial-accounting database of two Brazilian publicly traded companies with assets traded on BM & F BOVESPA, Mundial SA and Technos SA, which belong to the segment of fabrics, clothing and footwear (accessories). In the case of Mundial SA, there are convictions made on the basis of investigation procedures for accounting fraud by the Brazilian Securities and Exchange Commission (CVM) in Brazil. The results of the methodology developed here demonstrate that the estimates of risks of the company Mundial SA have been reached to a high power of detection of fraud with low probability of generating false warnings. Therefore, it was verified the effectiveness of the model in discriminating the two companies regarding the risk of fraudulent manipulation in their assets.

Uma metodologia na estimação de risco de auditoria baseada em softwares de detecção e na teoria dos jogos

A forma particular que o desenvolvimento capitalista assume na agricultura brasileira implica nao em transformar diretamente toda a producao, mas sim em se aproveitar das condicoes mais propicias para sua expansao, necessitando constantemente do amparo do Estado e da subordinacao ao capital comercial para efetivar tal transformacao, mesmo que de maneira lenta e desigual. Este trabalho pretendeu levantar alguns aspectos dessa problematica, centrando-se em dois pontos principais. Em primeiro lugar aborda a questao da concentracao de capitais que se verifica a partir do Estado de Sao Paulo ,especialmente no que se refere ao controle da propriedade da terra. A seguir procura mostrar a dependencia de outras regioes do pais em relacao a Sao Paulo quanto ao abastecimento de generos alimenticios basicos , tomando-a como reflexo das particularidades que assume tal desenvolvimento. Por tras desse processo procura-se ressaltar o papel do Estado, de um lado ao propiciar as condicoes para que se efetive tal desenvolvimento, e de outro ao acentuar suas contradicoes.

Ação emergencial para reconhecimento de áreas de alto e muito alto risco a movimentos de massa, enchente e inundação: Ariquemes, Rondônia

Trabajo en plataformas ferroviarias: acceso y seguridad = Work in railway platforms : access and security = Trabalho em plataformas ferroviárias: acesso e segurança

Ação emergencial para reconhecimento de áreas de alto e muito alto risco a movimentos de massa, enchente e inundação: Seringueiras, RO

Esse estudo tem como objetivo identificar o processo de aprendizagem do adulto, especificamente no exercicio do papel de pai, no contexto da escolha profissional do filho adolescente, e compreender os aspectos envolvidos nessa transformacao. Foram realizadas entrevistas abertas com tres adultos que estao passando pela experiencia de filhos adolescentes que estao em processo de escolha da profissao, ou que escolheram recentemente e estao cursando faculdades mediante as escolhas feitas.         Atraves das entrevistas houve a disponibilizacao de dados que foram trabalhados por meio da analise de conteudo. Em todos os casos foram identificados os processos de aprendizagens ocorridos com os pais, e foi possivel compreender alguns fatores que explicam como esse aprendizado ocorreu. Conclui-se nesse estudo que, a interface entre pais e filhos adolescentes em fase de processo de escolha profissional provoca a mudanca de postura dos pais no sentido de que eles deem conta de acompanhar esse processo de mudancas dos filhos. Essas mudancas na vida dos adultos foram entendidas como um processo de aprendizagem.

O adolescente e a escolha profissional: um processo de aprendizagem para os pais

Ação emergencial para reconhecimento de áreas de alto e muito alto risco a movimentos de massa, enchente e inundação: Primavera de Rondônia, RO

Boletim técnico sobre ocorrência de eventos críticos em áreas de risco: erosão fluvial nos bairros Triângulo e ramal para Comunidade Maravilha, Porto Velho - RO

Oportunidades de negócio e desenvolvimento económico em regiões de baixa densidade: o caso dos municípios do Alto Ave

Ação emergencial para reconhecimento de áreas de alto e muito alto risco a movimentos de massa, enchente e inundação: Santa Luzia D'Oeste, Rondônia

Produtos cerâmicos provenientes de suspensoes concentradas de Al2O3 necessitam que as mesmas sejam estabilizadas para que possam atender as crescentes exigencias de performance. As suspensoes estudadas neste trabalho sao, usualmente, empregadas na obtencao de folhas cerâmicas pelo processo de colagem de folhas cerâmicas (Tape Casting). Particulas, quando em suspensao, desenvolvem cargas superficiais. Quando estas particulas entram em choque umas com as outras pode acontecer o fenomeno da agregacao, gerando estruturas floculadas que aprisionam agua em seu interior, o que resultaria num produto final poroso e consequentemente de baixa resistencia mecânica e ate mesmo quimica. Estabilizar uma suspensao concentrada e fazer com que a resultante entre as forcas atrativas de van der Waals e as forcas repulsivas, entre duplas camadas eletricas igualmente carregadas ou decorrentes da adicao de material polimerico na superficie das particulas, seja repulsiva. Os parâmetros de avaliacao da estabilidade das suspensoes concentradas de Al2O3, aqui utilizados, foram o potencial zeta e a viscosidade. Foram, tambem, propostos novos parâmetros, a saber: 1) estruturas milimetricas, 2) microestrutura.

Com avanço econômico e tecnológico a sociedade vem acelerando a degradação ambiental e gerando quantidades excessivas de resíduos sólidos. Em decorrência disso, as consequências tem sido desastrosas para o ambiente e para a qualidade de vida da coletividade. Diante desse “cenário”, faz-se necessário buscar alternativas de gerenciamento de resíduos sólidos urbanos que busque sustentabilidade e resultados mais eficientes para recicláveis e não reciclareis. Buscou-se com esta pesquisa avaliar a viabilidade para implantação de um centro didático-pedagógico para triagem de resíduos sólidos urbanos no município de Macaé-RJ Instituto Federal Fluminense (Campus Macaé), visando promover inovação científica e o desenvolvimento de alternativas viáveis para o aprimoramento da gestão dos resíduos, na busca de políticas e estratégias metodológicas para planejamento e implementação de ações mais responsáveis e sustentáveis, para o setor (CORRÊA, SILVA, 2015). A obtenção de informações específicas, como o quantitativo de resíduos recicláveis gerados na área de estudo; suas características, tipologias e valor de mercado dos resíduos recicláveis. Esses dados e informações permitiram avaliar a viabilidade do empreendimento a dimensão da inclusão social, por meio da criação e funcionamento de uma cooperativa de catadores de recicláveis; estimar a geração de renda pelos cooperados e, ainda, a economia de recursos financeiros para o município de Macaé, na atividade de gestão de resíduos. A metodologia empregada baseou-se em entrevistas qualificadas; pesquisa de campo, realizada por amostragem, para efetuar a caracterização qualitativa e quantitativa dos resíduos gerados na área de estudo. A área pesquisada possui um total de 1.650 residências, podendo ser estimado que a produção mensal de resíduos recicláveis soma 27,69 toneladas. O valor de mercado dos resíduos sólidos recicláveis pode gerar um valor bruto mensal aproximado de R$14.639,00 (para 2015). Em síntese, foi possível concluir que a gestão integrada de resíduos sólidos, a partir da implantação de um Centro DidáticoPedagógico (com tais características) tende a promover a inclusão social por meio de cooperativa, que deve comportar cerca de oito associados, em condições dignas de trabalho. Assim, avalia-se viável a implementação de um Centro DidáticoPedagógico para o gerenciamento integrado de resíduos sólidos no município de Macaé Instituto Federal Fluminense – Campus Macaé, principalmente sob os aspectos da sustentabilidade ambiental e social.

Gestão de Resíduos Sólidos Urbanos: Estudo de Viabilidade para Implementação de Centro Didático-Pedagógico para Triagem de Resíduos no Município de Macaé-RJ.

Este artigo contribui para a discussao da relacao dos jovens com a escola de Ensino Medio da rede publica. Apresenta parte de uma pesquisa de natureza basica e descreve os sentidos atribuidos a escola e suas relacoes com o mundo do trabalho contemporâneo. Dentro de uma abordagem qualitativa, foi feito um estudo de caso em uma escola de Ensino Medio da rede publica do estado de Sao Paulo. A coleta de dados foi feita em 2015 atraves de questionarios. Os dados foram analisados pelo conjunto de tecnicas da Analise de Conteudo a luz da perspectiva teorica historico-cultural. O texto faz uma apresentacao da condicao do Ensino Medio no Brasil e dos sentidos que os jovens pesquisados atribuem a esse nivel de ensino. A guisa de conclusao, observa-se um sentido de preparacao para o futuro, de escola como instituicao responsavel pela formacao profissional ainda que esteja passando por crises de identidade e desafios de ordem social, economico e politico.

UM OLHAR JOVEM SOBRE A ESCOLA DE ENSINO MÉDIO: VIVENCIAR E SIGNIFICAR

O estuario Barra Grande, localizado no litoral de Icapui, extremo Leste do Ceara, e composto por sistemas ambientais de extrema importância socioeconomica para o litoral cearense. Esta inserido na diversidade de componentes geoambientais e ecologicos da planicie costeira, tendo o ecossistema manguezal como sintese das conexoes entre os componentes tipicamente costeiros (planicie de mare, laguna, dunas, falesias e praias), com os marinhos (delta de mare e bancos de algas). O objetivo da pesquisa foi realizar zoneamento ambiental da Area de Protecao Ambiental (APA) da Barra Grande, envolvendo os sistemas ambientais adjacentes para aprimorar os instrumentos de gestao. A gestao foi proposta atraves de zoneamento ambiental a partir de diagnostico e mapas tematicos. Foi possivel constatar os impactos ambientais (principalmente os relacionados com a carcinicultura e industria salineira), para a formulacao das zonas de diversidade de usos, de conservacao e de preservacao. Como resultado, foi realizado diagnostico geoambiental e proposta de zoneamento.

Área de Proteção Ambiental (APA) da Barra Grande em Icapuí-CE: Caminhos para a Sustentabilidade

O estudo do comportamento do cliente e do processo de decisao de compra possibilita que as empresas direcionem seus esforcos de marketing , para melhores resultados e satisfacao de necessidades dos clientes. A pesquisa fundamenta-se em uma pesquisa qualitativa que teve por objetivo mapear o processo de decisao de compra dos consumidores de aparelhos e jogos eletronicos de entretenimento da empresa Alphatoys, localizada na regiao serrana do estado do Rio Grande do Sul. Os dados foram obtidos atraves de entrevista semiestruturada com a utilizacao de amostragem nao probabilistica por conveniencia da populacao de clientes da empresa, durante o periodo de 30/09 a 11/10/2013. Para a analise dos resultados foi utilizado o modelo de Cinco Estagios do processo de decisao de compra descrito por Kotler (2006). Os resultados revelaram que os principais fatores de influencia centram-se no determinante social, nas variaveis, grupos de referencia e familia; e no determinante psicologico, nas variaveis percepcao e crencas e atitudes.

Processo de Decisão de Compra do Consumidor: O Caso de Uma Empresa Varejista

Neste trabalho serao estudadas duas construcoes do sistema dos numeros reais. A construcao do sistema dos numeros reais por cortes na reta ou seccoes no conjunto dos numeros racionais, avancada por Dedekind, e a construcao do numero real como classe de equivalencia de sucessoes fundamentais de numeros racionais, ideia protagonizada por Cantor. Relacionado com este tema, um capitulo deste trabalho sera dedicado a aplicacao da densidade dos numeros racionais e irracionais. Posteriormente, e de uma forma mais sintetizada do que nas anteriores, sao apresentadas outras construcoes, procurando tornar mais claro a ideia fundamental subjacente ao conceito de numero real. Por ﬁm, utiliza-se o metodo axiomatico com o intuito de mostrar a unicidade do sistema dos numeros reais, isto e, concluir ﬁnalmente que existe um corpo completo e ordenado, e apenas um a menos de um isomorﬁsmo, do conjunto dos numeros reais.

Purificação e caracterização de uma lectina antimicrobiana da raiz de Portulaca elatior

Este trabalho trata-se de uma discussao acerca da pratica e da formacao dos profissionais que atuam na modalidade da Educacao de Jovens e Adultos (EJA). Para tanto, foram feitas pesquisa bibliografica sobre os autores que tratam da EJA e suas especificidades, a exemplo de Paulo Freire, Machado e Gadotti. Nesse sentido, faz-se mister uma formacao inicial e continuada voltada para a EJA e que o professor nao so desenvolva e atualize os seus conhecimentos, mas trabalhe para trazer metodos mais significativos na sua pratica.

Prática e formação de educadores de Educação de Jovens e Adultos

Este artigo cientifico tem como objetivo identificar como um almoxarifado hospitalar deve se manter de forma que nao haja excesso e nem falta de materiais. Reposicao de materiais atraves de politicas de suprimento de estoque baseada em consumo, diario, semanal e mensal, sao preocupacoes relevantes para o fluxo logistico. Mantendo o estoque o mais baixo possivel com menor custo sem deixar de atender a demanda. Apresentar as normas e as leis vigentes para recebimento, armazenagem e distribuicao de materiais, com isso relacion-se a nocao de falta e excesso de materiais, identificando em que consiste fluxo logistico e como um estoque dever ser organizado.

Resumo Neste projeto buscou-se a construção de uma câmara de eletroforese em fluxo (FFE, acrônimo do termo em inglês free flow electrophoresis) para tratamento e preparo de amostras. Partes de poli(metil metacrilato) foram cortadas em uma cortadora a laser. Visou-se a otimização dos parâmetros geométricos da câmara para que se pudesse, em etapa posterior, aplicá-la a sistemas de remoção de íons interferentes em amostras complexas, em especial íons sódio e cloreto presentes em amostras de água marinha e fluidos biológicos sintéticos.

Desenvolvimento de um sistema de Eletroforese em Fluxo para Preparo de Amostras

Este trabalho tem como objetivo apresentar um estudo de caso, onde se investiga, em particular, as categorias de analise em didatica utilizadas pela autora para justificar que a sua proposta de trabalho final de mestrado implica em uma melhora do ensino de matematica na Educacao Basica. Como referencial teorico, para analisar as categorias utilizadas no TFM, utilizou-se os criterios de idoneidade didatica propostos pelo Enfoque Ontossemiotico. A analise mostra que a proposta esta pouco planejada e a justificativa se infere no uso, sobretudo, de argumentos, avaliacoes e reflexoes relacionados com o criterio de idoneidade ecologica que estao pouco relacionados com os outros criterios. Essa disparidade na profundidade dos criterios de idoneidade demonstra que nao se apresenta clareza sobre qual e a proposta e sobre qual e o grau de sua qualidade.

Estudo de caso sobre análise em didática realizado em um trabalho final do mestrado profissional PROFMAT

Ação emergencial para delimitação de áreas em alto e muito alto risco a movimentos de massa, enchente e inundação: Cabixi, RO

Fitossociologia de Plantas Daninhas em Cultivo de Duas Variedades de Mandioca

A inovacao e a geracao de conhecimento sao objeto de estudo em todos os setores da economia, dentre estes, o da saude. Neste sentido, este estudo buscou identificar as inovacoes na Atencao Primaria a Saude no municipio de Marau-RS. Para tanto foi efetivada uma pesquisa de cunho qualitativo, exploratorio, do tipo estudo de caso, aplicando-se como instrumento de coleta de dados uma entrevista semiestruturada, com perguntas abertas e fechadas baseadas no Manual de Oslo (2004), referencia na inovacao de produtos ou servicos, processos, marketing e gestao. A amostra de pesquisa foi constituida por oito gestores das unidades de Estrategia de Saude da Familia (ESF) do referido municipio. Sendo assim, tem-se como resultados finais que o municipio conta com a inovacao em seu sistema de saude publica, sao, no entanto, apenas inovacoes locais e este tem uma atitude reativa, passiva, quanto a inovacao. Dentre as inovacoes encontradas na saude publica do municipio, destacamos as inovacoes em marketing, como a Campanha de Vacinacao Hepatite B; as inovacoes em produtos e servicos, como a adequacao tecnologica da farmacia municipal para a dispensacao de medicamentos basicos, especiais e excepcionais e a promocao e adesao a programas como Saude no Interior e Saude na Estrada; inovacoes em processos, como a criacao do Grupo de Trabalho de Humanizacao e o Nucleo de Apoio a Saude da Familia e Inovacoes Organizacional ou de Gestao, destacando o remapeamento do municipio em funcao do elevado crescimento populacional e a criacao do cargo de coordenador dos ESFs.

Inovação na atenção primária à saúde : um estudo de caso no município de Marau - RS

Este estudo objetivou discutir a mobilidade urbana do pedestre na atualidade como resultado de um processo de expansao dos centros urbanos do pais a partir das ultimas decadas do seculo XX ate os dias atuais, colocando em evidencia a falta de um planejamento sistematizado na ocupacao e ordenamento dos espacos urbanos, o que ocorreu em grande parte de forma predatoria atraves de invasoes. Assim, na pesquisa bibliografica foram consultados varios artigos, simposio, tese de mestrado, programa governamental, legislacao de trânsito, norma da ABNT e o Plano Diretor do Municipio de Manaus, o que trouxe os pressupostos teoricos para responder aos questionamentos levantados e alcancar os objetivos propostos, no sentido de verificar as condicoes das calcadas e passeios publicos, explicar a responsabilidade do estado quanto ao espaco de caminhada e o direito de trânsito do pedestre. O estudo evidenciou que o Brasil priorizou o transporte motorizado particular em detrimento dos transportes nao motorizados e publicos, o que trouxe consequencias maleficas a maioria da populacao que faz uso do calcamento publico no seu deslocamento diario. Considerando a ocupacao do solo urbano desordenada e a omissao do estado no cuidado ao espaco do pedestre, foi constatado que as calcadas e passeios publicos foram deteriorados ao longo de algumas decadas, encontrando-se em pessimas condicoes de uso, impossibilitando ou dificultando a acessibilidade, principalmente das pessoas com deficiencia fisica ou com mobilidade reduzida. Outro dado revelado pelos autores referenciados e que o trânsito tornou-se a  primeira causa de morte violenta mundial nos paises em desenvolvimento, sendo o pedestre a principal vitima por ser o agente mais fragil na relacao de conflito. Desta forma, os autores foram unânimes em apontar a necessidade de gestores e planejadores publicos lancar um novo olhar a condicao de pedestre no sentido de qualificar os espacos de caminhada para garantir o acesso democratico e utilizacao de todas as areas, logradouros e equipamentos urbanos publico ou nao, sem restricao.

Desenvolvimento de uma metodología de avaliaçao da vulnerabilidade sísmica do edificado existente em Betao armado

A pesquisa tem como objetivo central investigar a influencia das caracteristicas dos empregados, fornecedores e clientes sobre o grau de endividamento das empresas. O tema estrutura de capital com o emprego de variaveis estrategicas e relativamente recente e tem despertado o interesse de diversos pesquisadores como decorrencia da importância da interacao entre a estrutura de capital das empresas, suas decisoes estrategicas e o seu relacionamento com os stakeholders nao financeiros. A metodologia aplicada foi um estudo em painel de dados estatico de efeitos fixos em uma amostra de 521 empresas de capital aberto do Reino Unido, abrangendo o periodo de 2005 a 2014. Sao realizados testes empiricos com oito subamostras estratificadas pelos segmentos de bens duraveis, bens nao duraveis e outros segmentos de negocios, para analisar de forma independente as interacoes das empresas com os seus empregados, fornecedores e clientes. Tambem sao testadas quatro proxies distintas para a mensuracao do grau de endividamento de modo a tentar capturar eventuais variacoes de comportamento e testar a robustez das variaveis dependentes. Os resultados empiricos, de modo geral, corroboram a existencia de correlacao, com significância estatistica, entre o grau de endividamento das empresas e as variaveis estrategicas que mensuram o seu inter-relacionamento com os empregados, fornecedores e clientes em nivel setorial. Porem, considerando as limitacoes da amostra e as restricoes do modelo econometrico aplicado, sao relatados alguns resultados divergentes aos esperados e suportados pela literatura pertinente ao tema. De qualquer forma, sao encontrados indicios de que as caracteristicas dos seus empregados, fornecedores e clientes sao variaveis explicativas relevantes da estrutura de capital das empresas, notadamente no segmento de bens duraveis para esta amostra e periodo analisado, e novos trabalhos sao necessarios para sua melhor compreensao.

As características dos fornecedores e clientes influenciam a estrutura de capital das empresas

This work studied the spatial dispersion of cases of fatal yellowing (FY) in an oil palm plantation in Acara, Para State, Brazil. Data were collected monthly from two areas, divided in 16 quadrants each, for a 24 month period (2012-2013). In each quadrant, 138 plants were evaluated. The number of diseased plants was counted in twenty planting lines, and the spatial pattern of the disease was analyzed. The following spatial analysis techniques were used: common sequences of “runs”, “doublets” and quadrants. We also determined the levels of disease aggregation in the sectors. Plants with FY had a spatial distribution aggregated in a lower line number when using the “run” analysis than when using the “doublets” method. Aggregation of FY cases was observed in 30% of the evaluated lines. The quadrant analysis confirmed the existence of case aggregation, with vertical and horizontal distribution. The existence of disease forming foci suggests that FY probably has biotic origin. Additional studies are required to confirm this hypothesis.

Distribuição espacial de casos de amarelecimento fatal em plantio orgânico de palma de óleo

Ação emergencial para reconhecimento de áreas de alto e muito alto risco a movimentos de massa, enchente e inundações: Vilhena, RO

Este artigo apresenta as politicas publicas de gestao educacional com apoio das tecnologias nos processos de aprendizagens e de informatizacao dos dados escolares na educacao municipal de Aracaju/SE. E uma pesquisa qualitativa com abordagem em analise das producoes dos dados obtidos em sites especificos das politicas de gestao, para analise e reflexao. A politica de gestao dos processos de aprendizagens por meio de aulas em slides construidas pelos professores e dispostas em um ambiente online, ha muito que se avancar, pois estao organizadas com modelo focado no ensino diretivo ao inves de colaborativo. E quanto a politica de gestao de organizacao dos dados (cadastros e diarios eletronico) necessita de aprimoramentos no que se refere a disposicao dos dados de programacao e para o registro dos conteudos programados.

O presente trabalho propoe-se compreender a modelagem de pontes no programa SAP 2000N. A pesquisa realizada foi exploratorio-descritiva, onde os dados foram extraidos do referencial teorico para estabelecimento de relacoes com os objetivos da pesquisa. A analise de dados, confrontando-se aspectos quantitativos e qualitativos das teorias e conceitos da AASHTO LRFD 2007 com a modelagem de uma ponte de vigas mestras no programa SAP2000N, Mostrou ser preciso um conhecimento minimo de recomendacoes da AASHTO LRFD 2007 para se obter expertise como o uso do programa para a modelagem de pontes, bem como e necessario conhecer as diferentes formas de analise que o programa oferece: “Static, Multistepstatic, Modal, Response spectrum, Time history, MovingLoad, Buckling, SteadState, Power spetral density, Hyperstatic”; para se ter o controle sobre o processamento do modelo gerado.

MODELAGEM DE ESTRUTURAS DE PONTES NO PROGRAMA SAP2000N: PRINCIPAIS RECOMENDAÇÕES DA AASHTO

Com a evolucao da Contabilidade, novas formas de gerenciamento sao constantemente estudadas e desenvolvidas para enfrentar o atual ambiente globalizado no qual as empresas estao inseridas. Neste cenario, surgiu o Balanced Scorecard (BS) como um importante sistema que influenciou diretamente a Contabilidade Gerencial moderna. E utilizado por empresas que pretendem ter exito com suas estrategias de curto, medio e longo prazo, melhorando assim sua situacao no futuro, revelando-se como uma ferramenta capaz de atender as novas exigencias de gerenciamento dentro dos cenarios economicos em constante mutacao. O BS complementa as medicoes baseadas apenas em indicadores financeiros, com outros tres componentes chamados de perspectivas: clientes, processos internos e aprendizado e crescimento. Ressalta-se que, a medida que foi sendo utilizado, o BS deixou de ser um sistema de medicao aperfeicoado para se transformar em um sistema gerencial essencial. O sistema de informacao gerencial deve contribuir como suporte as estrategias adotadas para que elas possam ser acompanhadas e venham a produzir retorno positivo para a empresa.

The building industry has occupied a prominent place in the Brazilian economy. However it may represent serious environmental impacts in the generation and improper disposal of waste from construction and demolition (C&D). The research aimed at evaluating the initiatives of public management of C&D in the county of Macae, RJ. It was based on the empirical-phenomenological methods, with individual descriptions and causal connections obtained from stakeholders, literature and documentary reviews, as well as qualified interviews (key informants) with local managers and specialists. Preliminary results have  allowed for an assessment of the current situation of management, legal instruments, environmental licensing, and irregular disposal of C&D.

Gestão dos resíduos da construção civil: estudo de caso no município de Macaé, RJ

Ação emergencial para reconhecimento de áreas de alto e muito alto risco a movimentos de massa, enchente e inundação: Cerejeiras, RO

Ação emergencial para delimitação de áreas em alto e muito alto risco a movimentos de massa, enchente e inundações: Cacoal, RO

Fazendo uma breve analise em torno da pessoa com necessidades educacionais especiais, percebe-se que seu trajeto perpassa pela historia da aquisicao dos direitos humanos. Nas observacoes a esse respeito, e que ja ultrapassam muitos anos, estas pessoas sempre foram observadas como partes distintas sem nenhum envolvimento enquanto seres sociais. Porem, marcos historicos e normativos foram se constituindo a medida que o respeito ao homem, o direito a igualdade de oportunidades e a participacao na sociedade, enquanto cidadaos, faria a diferenca, assim, a historia tomou um novo rumo. Nos dias atuais, buscam-se espacos organizados, a partir de politicas publicas governamentais e tambem da sociedade civil para a inclusao, com uma perspectiva e importância cada vez maior em atender as crescentes demandas e exigencias de uma sociedade em processo de transformacao para que desse modo se obtenha uma comunidade cada vez mais acolhedora, solidaria e humana. O presente artigo tem como objetivo mostrar, atraves da revisao bibliografica, que existem estudos e teorias disponiveis que demonstram a possibilidade de tornar a inclusao da pessoa com deficiencia, cada vez mais efetiva nas escolas regulares, no mercado de trabalho e na sociedade como um todo e que estes estudos estao alinhados aos preceitos e normas nacionais e internacionais para propiciar a melhoria da qualidade de vida, aumento da empregabilidade e formacao da cidadania.

Estudo do mecanismo de crescimento de nanobastões de ouro em sistemas coloidais através de cálculos de dinâmica molecular

COMERCIALIZAÇÃO DE CANUDOS INCREMENTADOS COM PALMA: INOVANDO EM FEIRAS LIVRES DA PARAÍBA

Ação emergencial para reconhecimento de áreas de alto e muito alto risco a movimentos de massa, enchente e inundação: Pimenteiras do Oeste, RO

O Estado deve operar, mediante seus tres Poderes, de maneira harmonica e, para este fim, ha a atividade de controle estatal, exercida por cada um deles reciprocamente. No entanto, existem hipoteses de controle controversas, tais como a circunstância de o Poder Judiciario fiscalizar os atos politicos emanados pelo Governo. A presente pesquisa visou discutir a viabilidade do exercicio do controle jurisdicional de atos politicos com a finalidade de proteger e aplicar os direitos fundamentais que possam ser por eles ameacados ou violados, a partir da interpretacao concretista da Constituicao. Para tanto, utilizou-se o metodo indutivo para abordar topicos referentes as funcoes politica e jurisdicional do Estado e ao dever que este tem de concretizar os direitos fundamentais. O trabalho resultou na constatacao da possibilidade do controle jurisdicional dos atos politicos quando prejudiciais aos direitos fundamentais.

O controle jurisdicional dos atos políticos: uma força entre a tirania e a judiciocracia

Esse estudo tem como objetivo apreender alguns aspectos do processo em que se da a evasao escolar, particularmente, entre o ensino fundamental e o ensino medio. A pesquisa se baseia em dados provenientes de censos recentes do Instituto Nacional de Pesquisas Educacionais Anisio Teixeira (INEP), do Instituto Brasileiro de Geografia e Estatistica (IBGE) e do Programa das Nacoes Unidas para o Desenvolvimento (PNUD). Essas fontes foram utilizadas por meio da Internet em seus respectivos sites oficiais. A microrregiao de Guaratingueta foi escolhida, como locus desse estudo, em virtude da consonância com os objetivos dos pesquisadores que desenvolvem atualmente outros trabalhos cientificos em municipios da regiao. A evasao escolar pode trazer, de forma implicita, uma serie de fatores sociais, culturais, economicos e ate religiosos, que, se bem trabalhados, tem a propriedade de definir, em certa medida, o perfil de uma sociedade. Diz-se isto, porque os motivos que levam uma crianca ou um jovem a desistir dos estudos antes de conclui-los, (no caso especifico da presente pesquisa, deixar de prosseguir no ensino medio, o que pode ser considerado o nivel minimo de formacao para um cidadao ter possibilidades de ingressar no mercado de trabalho atual) nao acontece sem que haja causas importantes. Este trabalho se propos a, a partir de indicadores educacionais de acesso publico, estabelecer relacoes de causa e efeito entre alguns indices, e analisa-los a fim de revelar relacoes causais que identifiquem alguns fatores que dificultam a permanencia de jovens na transicao do ensino fundamental para o ensino medio.

A evasão escolar na microrregião de Guaratinguetá.: Uma análise a partir de indicadores educacionais

As infeccoes parasitarias possuem relacao direta com os fatores socioeconomicos e habitos culturais de uma populacao e sao facilmente disseminadas de um local para outro. Consequentemente, o contagio de doencas infecciosas atraves da via indireta pelas maos e de extrema importância, especialmente em locais publicos e de aglomeracao humana como o transporte coletivo. Propoem-se pesquisar e identificar cistos de protozoarios e ovos de helmintos em transportes coletivos urbanos da cidade de Patos de Minas-MG. A coleta de amostras foi realizada em catracas, corrimoes e bancos de aproximadamente 30 onibus coletivos de diferentes zonas da cidade. Para isso, utilizou-se o metodo de Graham, onde fitas adesivas tipo durex foram fixadas a diferentes superficies do onibus e posteriormente coladas em lâminas de microscopia, e analisadas em objetivas de 10x e 40x. Nas amostras foram observados raros cistos de protozoarios e nenhum ovo de helminto. Apesar de nao ter apresentado significado estatistico, os resultados indicaram a contaminacao do meio de transporte e risco potencial para a populacao que utiliza este servico.

PESQUISA DE ENTEROPARASITAS EM MEIOS DE TRANSPORTE PÚBLICO URBANO DA CIDADE DE PATOS DE MINAS MG – BRASIL

Ação emergencial para delimitação de áreas de alto e muito alto risco a movimentos de massa, enchente e inundação: Castanheiras, RO

Nas ultimas decadas observou-se um significativo aumento da globalizacao do mercado mundial. Diversas empresas brasileiras enxergaram a oportunidade de se internacionalizar, na busca pela expansao de suas atividades, vislumbrando as possibilidades de vantagem competitiva e, ao mesmo tempo, os riscos associados ao investimento. Nesse contexto, o processo de internacionalizacao tornou-se objeto crescente de pesquisas academicas. Neste estudo, procurou-se identificar as principais teorias de base abordadas em pesquisas recentes sobre a internacionalizacao de empresas. A revisao bibliografica apresenta um breve panorama sobre o tema. Procurou-se identificar, pela analise de conteudo em dados secundarios, as principais teorias de base abordadas pelos pesquisadores, nos artigos apresentados nas edicoes 2013 e 2014 do EnANPAD. Foram identificados 8 e 22 artigos nesses dois ultimos eventos, respectivamente, totalizando 30 artigos a partir da palavra-chave de busca internacionalizacao . Este artigo contribui para o avanco do conhecimento do tema, ao mostrar as principais teorias de base abordadas nas pesquisas recentes no Brasil, dando continuidade, em parte, ao estudo realizado por Ferreira et al (2014), especificamente no que diz respeito aos dados identificados em pesquisas posteriores aquelas investigadas pelos autores. Como resultados, constatou-se a predominância da Estrategia de Inovacao, assim como tambem a incidencia da Perspectiva de Networks, da Visao Baseada em Recursos e do Empreendedorismo.

Produção acadêmica recente sobre internacionalização de empresas: uma análise das principais teorias de base apresentadas nas edições 2013 e 2014 do ENANPAD

Diante da importância da reciclagem de pneus inserviveis como meio de preservacao ambiental e reaproveitamento da borracha, o presente trabalho teve como objetivo analisar a viabilidade economica de uma usina de reciclagem, atraves da elaboracao de um plano de negocios. Para tal, utilizou-se o modelo proposto por Rosa (2007) e realizou-se um estudo de caso com pesquisa descritiva, coletando informacoes, via questionarios e entrevistas, com fornecedores, clientes e empresas que descartam os pneus. Mediante a identificacao que a Reciclanip, uma entidade sem fins lucrativos, mantem com ecopontos em praticamente todos os municipios da regiao de Marau e o levantamento de todos os custos e investimentos necessarios, passou-se a verificar a viabilidade de indicadores. Diante dos calculos que consideraram tres cenarios simulados, constatou-se que a usina apresentaria lucros. Em um cenario provavel, por exemplo, a mesma atingiria um lucro operacional de 46,14%, correspondente a R$ 36.278,33. Enquanto que em um cenario pessimista, cujo percentual de reducao de faturamento foi de 30%, mesmo assim ela teria um lucro de R$ 441,92, ou seja, 1,12%. Sendo assim, analisando-se os cenarios, mesmo o pessimista, pode-se constatar que seria viavel a implantacao de uma usina de reciclagem de pneus no municipio de Marau.

PLANO DE NEGÓCIOS PARA IMPLANTAÇÃO DE UMA USINA RECICLADORA DE PNEUS

Em razao da melhor expectativa de vida e do envelhecimento da populacao, consequentemente, a melhora dos avancos tecnicos e diagnosticos na Medicina, aliados a novas modalidades terapeuticas para doencas, cresce no mundo inteiro a transfusao de concentrados de hemacias, plaquetas e plasma fresco congelado. Assim, a fenotipagem eritrocitaria, tanto em receptores quanto em doadores de sangue, tem como finalidade reduzir o numero de reacoes transfusionais, prevenindo o aparecimento de anticorpos de forma mais tardia, principalmente naqueles receptores candidatos a politransfusao. Alem disso, a fenotipagem eritrocitaria e essencial na confirmacao dos aloanticorpos formados, alem de facilitar a identificacao de anticorpos que poderao ser constituidos no futuro. O estudo teve como objetivo analisar as frequencias dos principais antigenos de grupos sanguineos pertencentes aos sistemas ABO, Rh, Duffy, Kidd, MNS, e o antigeno K do sistema Kell, bem como estudar a associacao entre esses grupos e a distribuicao quanto a procedencia e o grupo racial autorreferido, por serem esses os principais sistemas envolvidos em reacao transfusional hemolitica e causarem a doenca hemolitica perinatal em todo o mundo. Foram analisadas 532 amostras de doadores de sangue do Hemocentro do Estado do Ceara, regional do Crato, e Hemocentro do Estado do Piaui (Teresina e Picos). As metodologias empregadas foram as tecnicas de tipagem sanguinea em tubo de hemolise, para fenotipagem ABO/Rh. Para a identificacao dos outros sistemas, utilizou-se a de gel-centrifugacao, com seus respectivos antissoros. Foram determinadas as frequencias absolutas e relativas das variaveis categoricas analisadas. A associacao entre os fenotipos dos grupos sanguineos e a regiao de procedencia ou a raca autorreferida dos doadores foram avaliadas pelo Teste de Qui-Quadrado. Foi adotado o P< 0,05. Neste trabalho, observou-se que, dos 532 doadores fenotipados, obteve-se a distribuicao de (68,80%) do sexo masculino e (31,20%) do sexo feminino. Quanto a frequencia dos sistemas sanguineos, os grupos mais frequentes foram: O (53,38%), Jk(a+b+) (52,26%), Fy(a-b+) (35,71%), M+N+S-s+ (21,05%), DCcee (35,54%) e o antigeno K negativo com (96,62%). Quanto aos fenotipos menos frequentes, foram encontrados os grupos: AB (2,26%), Jk(a-b-) (0,19%), Fy(a-b-) (8,65%), M-N+S-s- (0,19%), M+N-S-s- (0,19%), M+N+S-s- (0,56%), dCee (0,19%), DCCEe (0,38%) e DccEE (3,01%). Quanto a regiao de procedencia, notou-se que nao houve associacao entre todos os fenotipos analisados e a regiao de procedencia entre os doadores. Tambem nao foi constatada associacao entre as categorias de raca autorreferida e todos os fenotipos analisados. O estudo permitiu conhecer o perfil eritrocitario dos doadores da pesquisa com relacao aos grupos sanguineos estudados que constituem nos principais antigenos eritrocitarios de maior importância clinica, contribuindo com a melhoria da seguranca, qualidade e aprimoramento no exercicio da Medicina transfusional dos estados do Ceara e Piaui. O uso de hemacias fenotipadas, junto com a prova de compatibilidade, passa a ser meio fundamental para fomentar estrategia de estoque de sangue, refletindo na agilizacao do encontro de sangue ideal para cada receptor. Com suporte aos nossos dados, o encontro de unidades negativas para os principais antigenos eritrocitarios ira permitir o encontro de sangue com fenotipo raro na nossa populacao.

Fenotipagem eritrocitária em doadores de sangue no HEMOPI - PI (Teresina - Picos) e no hemocentro regional do Crato - CE

Esta pesquisa de abordagem qualitativa tem por objeto de estudo as praticas e narrativas no curriculo de uma escola municipal decorrente da implementacao de politicas publicas de inclusao no campo educacional natalense por meio dos CBRS – Complexos Bilingues de Referencias para Surdos. Com fundamento na abordagem socio-historica (FREITAS, 2003); e aporte em Bakhtin (1995), Vygotsky (1998) e nos Estudos Culturais (JOHNSON, 1999; MATTELART, NEVEU, 2004) com enfase nos Estudos Surdos (DORZIAT, 2009; 2011; SKLIAR, 2011; SA, 2011; 201?; LODI, MELO; FERNANDES, 2012). Como aportes teoricos tambem foram importantes as contribuicoes sobre o Curriculo Escolar (SILVA, 1995), Educacao de Surdos (LOPES, 2007; 2013) e Comunidade e Cultura Surda (SANCHEZ, 1990; LANE, 1997; SACKS, 2010). A pesquisa foi realizada entre o segundo semestre de 2014 e o primeiro semestre de 2015, em um dos CBRS da rede municipal de ensino de Natal/RN, tendo como objetivo geral a analise do curriculo da E. M. Luiz Maranhao por meio das acoes e enunciados de parte de seus profissionais envolvidos com a educacao de alunos surdos e como objetivos especificos identificar a concepcao de sujeito surdo na proposta dos Complexos e a finalidade da educacao desses sujeitos nesses espacos. Como instrumentos, foram utilizados o roteiro de entrevista e os questionarios e como procedimentos de pesquisas a observacao participante, as entrevistas coletivas e a analise documental. Os dados foram analisados com base na Analise de Conteudo (RAMPAZZO, 2002; FRANCO, 2005; BARDIN, 2011). A analise dos dados fez emergir as contradicoes e os descompassos nas narrativas e nas praticas curriculares. Diante dos dados analisados, concluimos que, nos anos iniciais no CBRS de Cidade Nova, Zona Oeste de Natal/RN, os fundamentos e as praticas manifestas vao de encontro a proposta de educacao bilingue do Movimento Surdo. A maioria dos colaboradores, como se pode constatar, concebe o sujeito surdo como deficiente e a educacao bilingue como mais um desdobramento da educacao de pessoas com necessidades especiais.

O complexo bilíngue de referência para surdos da zona oeste de Natal: fundamentos e práticas nos anos iniciais do ensino fundamental

Este estudo tem como objetivo apresentar o instrumento “pre-teste” como meio de calibracao e validacao do questionario elaborado para a coleta de dados em pesquisa cientifica, com fundamentacao na proposta de Gray (2012). A aplicacao do questionario pre-teste ocorreu numa escola publica estadual localizada num municipio do Vale do Paraiba Paulista. Houve a participacao de dezessete (17) sujeitos, sendo todos eles adolescentes e alunos do ensino medio. O questionario aplicado tem carater socio-economico e e composto de cinquenta e quatro (54) questoes fechadas com sua estrutura voltada para o tema da escolha profissional. Os dados coletados foram lancados em planilha eletronica e organizados em graficos e tabelas permitindo a analise e a discussao dos dados. Os resultados alcancados com o uso do pre-teste mostraram as potencialidades e fragilidades do questionario, bem como evidenciou as lacunas e as oportunidades de ajustes no questionario que refere-se a uma pesquisa em andamento. [1] Alem disso, foi possivel o aprofundamento no entendimento do objeto de pesquisa em andamento por meio dos dados coletados em pequena escala, mas que trouxeram clareza com relacao a relevância do tema estudado.

ESTUDO DO COMPORTAMENTO MECÂNICO E METALÚRGICO DE JUNTAS SOLDADAS DO AÇO ASTM A36 COM ARAMES DO TIPO METAL CORED E MACIÇO

Resenha: BRAGANÇA JÚNIOR, Álvaro Alfredo. A Fraseologia Medieval Latina. Vitória: DLL-UFES, 2012. 12 + 183 p.

A consideracao da sazonalidade do regime de ocorrencia das vazoes apresenta um potencial para o aumento da disponibilidade de uso dos recursos hidricos. Visando dar subsidios a otimizacao do uso da agua, neste trabalho avaliou-se o impacto da substituicao das vazoes minimas anuais pelas mensais na disponibilidade de agua ao longo da hidrografia de uma sub-bacia do rio Paracatu. Foi avaliado o impacto tanto na Q7,10 (vazao minima com sete dias de duracao associada a um periodo de retorno de dez anos) quanto na Q95 (vazao cuja frequencia de excedencia e de 95%). 
A utilizacao das vazoes mensais em substituicao as anuais tem um alto potencial para a melhoria das condicoes de uso dos recursos hidricos, sem incorrer em aumento do risco de desabastecimento. A utilizacao da Q7,10 mensal em substituicao a Q7,10 anual implica em aumentos na disponibilidade hidrica que variam de valores de cerca de 10% nos meses de menor disponibilidade ate valores que excedem os 200% nos meses de maior abundância dos recursos hidricos de superficie. A utilizacao da Q95 mensal em substituicao a Q95 anual implica em variacoes que oscilam de reducoes de ate 37% nos meses de maior restricao hidrica ate valores que excedem os 100% nos meses de maior abundância, logo, seu uso possibilita uma utilizacao mais racional e segura dos recursos hidricos.

IMPACTO DA SUBSTITUIÇÃO DAS VAZÕES MÍNIMAS ANUAIS PELAS MENSAIS NA DISPONIBILIDADE DOS RECURSOS HÍDRICOS

The objective of this work was to estimate nitrogen and potassium rates, in order to obtain maximum technical and economic efficiency and the critical levels of these two nutrients on leaves of irrigated 'Tahiti' lime tree, grown in a Typic Quartzipsamment soil in five crop seasons. A randomized complete block design was carried out with four replicates, in a 4x5 factorial arrangement, with four N rates (0, 25, 50, and 100 kg ha ‑1 ) and five K 2 O rates (0, 25, 50, 100, and 200 kg ha ‑1 ). The estimated rates to achieve the maximum technical efficiency were 90, 99, 69, 66, and 100 kg ha ‑1 N, and for the maximum economic efficiency, 85, 95, 67, 64, and 93 kg ha ‑1 N, for the first, second, third, fourth, and fifth crop seasons, respectively. The rates of K 2 O to obtain the maximum technical efficiency were 126, 116, 101, 98, and 95 kg ha ‑1 , and for maximum economic efficiency, 112, 105, 94, 90, and 88 kg ha ‑1 K 2 O, respectively, for the first, second, third, fourth, and fifth crops. The average, estimated critical levels for leaf contents are 25 g kg ‑1 N and 22 g kg ‑1 K, in five crop seasons.

Produção e nutrição de limoeiro 'Tahiti' em função da adubação com nitrogênio e potássio em cinco safras

Principios de Linguistica Descritiva, de Mario A. Perini, e uma introducao aos estudos linguisticos, dirigida em primeiro lugar a estudantes de graduacao, transmitindo um conjunto de conhecimentos e habilidades que o linguista deve adquirir antes mesmo de tomar contato com qualquer teoria linguistica. Perini apresenta, aqui, subsidios importantes para a preparacao do linguista consciente das escolhas teoricas que fizer, porque a visao pessoal dos fatos depende desse treinamento, sem a qual o iniciante fica a merce de ideias alheias, arriscando-se a nunca se conscientizar devidamente do carater empirico da linguistica e da fragilidade das teorias.

The article is a discussion about the strained relations of power between different cultures at the university. The academy and science become targets of questioning as they are questioned, especially by the active presence of blacks and indigenous inside while eurocentradas inventions conceived / conceive white cultures as the only sources and valid IDs for the production of knowledge and truth. We focus, first, the constituent elements of socio-cultural university and later show the impacts of the presence of blacks and indigenous people claiming spaces in universities. This presence as we will argue, reframes the university because the knowledge / power of black and indigenous groups infiltrate the hegemonic knowledge, placing the white hegemony in check.

A presença da diferença negra e indígena na educação superior e o processo de ressignificação da universidade brasileira

O presente trabalho versa sobre uma analise da concepcao de pobreza urbana e o uso do territorio do municipio de Uniao dos Palmares/AL no periodo contemporâneo, cujo objetivo e compreender como o territorio palmarino esta sendo usado no contexto da pobreza urbana. Desse modo, utilizou-se como recursos metodologicos uma pesquisa bibliografica, documental e de levantamento de dados, atraves de um questionario socioeconomico e subjetivo. Compreendeu-se que o fenomeno da pobreza em Uniao dos Palmares, sua intensificacao e influencia direta sao decorrentes da expansao urbana desestruturada e do uso diferenciado do espaco urbano, causados pelo descaso do poder publico que nao investe em politicas publicas em prol da populacao, na manutencao e aparelhamento do municipio, e tambem em razao do sistema capitalista normatizador, que funciona como regulador da vida economica, pois aumenta sua indispensabilidade, determina seu uso no espaco geografico e impoe a seletividade e a fragmentacao atraves da intensificacao das tecnicas no tecido social da referida cidade.  Por estas razoes, entende-se que, para isso, sao necessarias acoes energicas do gestor municipal, a saber: politicas publicas eficazes que sejam pensadas para os lugares, considerando sua totalidade para melhoria das condicoes de vida da populacao palmarina.

(RE) PENSANDO A POBREZA URBANA NO PERÍODO CONTEMPORÂNEO: UMA ANÁLISE A PARTIR DE UNIÃO DOS PALMARES-AL

Este trabalho tem o objetivo de mostrar como as artes no Brasil, em suas diversas manifestacoes, foram usadas para retratar o povo e as caracteristicas do Nordeste semiarido, mais especificamente as regioes de caatinga, como um lugar de sofrimento e personifica-los cheios de estereotipos que parecem resistir as mudancas do tempo, principalmente nas dimensoes socioculturais e economicas. A metodologia utilizada na pesquisa buscou referencias em obras da literatura, pintura, musica, no cinema, com destaque, para obras de Euclides da Cunha, Graciliano Ramos, Cândido Portinari, Luiz Gonzaga, Rachel de Queiroz, e em alguns trabalhos cientificos das ciencias sociais, escritos por Francisco de Oliveira, Durval Muniz e anonimos. Apos a pesquisa, concluiu-se que as mesmas artes que serviram para divulgar o Nordeste, tanto no Brasil como no exterior, tambem serviram para manter o contexto cultural tradicional de miseria e atraso que se completam na formacao do mesmo discurso e das mesmas relacoes de poder politico e social. Palavras-chave: Semiarido. Caatinga. Cultura. Artes. Literatura. Seca.

A producao de acerola orgânica nos Tabuleiros Litorâneos do Piaui garante bons resultados e rentabilidade. Este estudo teve como objetivo avaliar variedades de acerola para enxertia em pomar comercial nos Perimetros Irrigados dos Tabuleiros Litorâneos do Piaui. O estudo foi realizado de agosto a novembro de 2014. A area cultivada tem cerca de 2 hectares e plantas apresentavam idade de 6 anos em plena producao. Foram considerados quatro tratamentos para a analise: 13/2, 71, FP19 e Okinawa variedades, entre os quais foram selecionados aleatoriamente quatro plantas de cada variedade. Considerando os parâmetros avaliados neste estudo, as plantas da variedade 13/2 seriam as mais indicadas como matrizes para uso em enxertia.

Avaliação de variedades de acerola para enxertia em um pomar comercial orgânico do Perímetro Irrigado dos Tabuleiros Litorâneos do Piauí

Texto entregue como avaliacao parcial do componente curricular de Evolucao, segundo semestre-2016.

O presente estudo aborda os desafios enfrentados pelo Terceiro Setor, entidades sem fins lucrativos, preocupado com o desenvolvimento sustentavel, diante do largo crescimento economico e as necessidades sociais que dai surgiram.

O presente trabalho tem por objetivo demonstrar o estudo de caso sobre o Projeto de Extensao em Educacao Ambiental da Universidade do Sul de Santa Catarina – UNISUL. O intuito do Projeto foi oferecer uma palestra sobre os temas lixo, residuos solidos e reciclagem aos alunos, professores e funcionarios da Escola Alvaro Luis Nunes, em Sao Leopoldo (RS). Utilizou-se de muitas imagens, figuras, desenhos e gravuras que ilustraram a Educacao Ambiental como um todo, bem como alguns textos que explicavam melhor os assuntos da palestra. Com estes conhecimentos, sera possivel que aqueles que absorveram, pelo menos em parte, os assuntos abordados, contribuam significativamente para a disseminacao da cultura de sustentabilidade na Escola Alvaro Luis Nunes.

PROJETO DE EXTENSÃO EM EDUCAÇÃO AMBIENTAL: UM ESTUDO DE CASO NA UNIVERSIDADE DO SUL DE SANTA CATARINA – UNISUL

Interações intraguilda de noctuídeos-pragas na cultura do milho no Brasil e nos EUA

A agroecologia e os agrotoxicos sao antagonicos, pois o uso intensivo de produtos quimicos, como parte do conjunto de tecnologias associadas ao processo de modernizacao da agricultura, tem promovido diversos problemas de ordem ambiental, a saber: a contaminacao de alimentos, do solo, da agua e de animais, a intoxicacao de agricultores, a resistencia de patogenos, de insetos-praga e de plantas invasoras a diversos principios ativos. O objetivo do trabalho foi diagnosticar o uso de agrotoxicos e os impactos causados a saude dos trabalhadores rurais, decorrentes da agricultura tradicional praticada no Povoado Ermo, municipio de Carnauba dos Dantas, RN. Participaram do estudo 20 trabalhadores rurais que se encontravam em suas residencias e em suas propriedades (no campo). A coleta de dados deu-se por meio de questionario semiestruturado com perguntas abertas e fechadas. Os dados foram organizados e tabulados, utilizando-se a porcentagem para representar a proporcao dos mesmos No entanto situacoes desfavoraveis a saude dos trabalhadores rurais no Povoado Ermo, em contato com agrotoxicos, ressalta a necessidade de informacoes sobre os riscos do uso de produtos quimicos na agricultura sejam incorporadas em acoes de prevencao a saude.

Diagnóstico do uso de agrotoxicos por trabalhadores rurais no povoado do Ermo, município de Carnaúba dos Dantas Rio Grande do Norte

O tema proposto surgiu da necessidade de verificar a percepcao dos profissionais de secretariado executivo quanto a importância da cientificidade da area, tendo em vista que a area ainda nao e reconhecida como uma ciencia pelo Conselho Nacional de Desenvolvimento Cientifico (CNPq). A percepcao e o processo ativo de perceber a realidade e organiza-la em interpretacoes e visoes sensatas e ocorre por meio dos sentidos. Cientificidade e o que garante que uma profissao pertenca a uma area do conhecimento e para que tenha reconhecimento cientifico ela precisa de pressupostos basicos: um campo cientifico e essencialmente de um objeto de estudo. No caso do secretariado executivo, o campo cientifico e a ciencia da assessoria e o seu objeto de estudo se baseia na assessoria que envolve o saber e o fazer secretarial. Tendo como base a definicao de percepcao e cientificidade, surgiu o problema de pesquisa do presente artigo: como os profissionais de secretariado executivo percebem a importância da cientificidade da area? Por meio dos dados coletados e analisados, verificou-se que os profissionais de secretarios executivos percebem a importância da cientificidade. A metodologia aplicada foi a descritiva, enquanto na analise o metodo utilizado foi a pesquisa quantitativa e a abordagem foi realizada por meio de pesquisa de campo. O instrumento de pesquisa foi o questionario e ele foi aplicado aos profissionais atuantes na area. Obteve-se 30 respondentes, sendo 93% do sexo feminino e 7% do sexo masculino. Sugere-se o incentivo as pesquisas relacionadas a teoria pratica e conceitual do secretariado executivo. Palavras-chave: Ciencia; Percepcao; Secretariado Executivo.

A percepção dos profissionais de secretariado executivo quanto á importância da cientificidade da área

O presente trabalho objetiva apresentar a avaliacao tecnica e ambiental de um sistema de caldeira utilizado para incineracao de residuos de servicos de saude. Diversas tecnologias podem ser empregadas no tratamento de RSS, como a autoclavagem, a utilizacao de microondas ou a disposicao dos RSS em valas septicas em aterros sanitarios. O sistema de caldeira em estudo tem em sua composicao caracteristicas compativeis com o que preconiza a legislacao quanto ao tratamento termico de RSS.  Comumente, os sistemas de caldeira sao utilizados para geracao de agua quente e vapor, e neste estudo, o sistema utilizado, aproveita a troca de calor que ocorre na fornalha para favorecer a incineracao dos residuos com menor utilizacao de combustivel auxiliar. Como resultado, a utilizacao do sistema apresentou reducao massica dos volumes iniciais superior a 90%, e a implantacao dos equipamentos necessarios ao tratamento dos gases emitidos pela combustao, demonstrou eficiencia quanto aos padroes exigidos pela legislacao.

Estudo de viabilidade técnica e ambiental de utilização do sistema de caldeira para incineração de resíduos sólidos de serviços de saúde

A adolescencia e um periodo da vida do individuo caracterizado por intensas mudancas biopsicosociais. A escolha profissional e um evento que se soma as transicoes desta fase e que representa um desafio para o jovem, sua familia e a sociedade. No intuito de conhecer a producao cientifica sobre o tema, foi realizada busca simples nos acervos digitais da Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), da Scientific Eletronic Library (SciELO) e Google Academico. Com o descritor “adolescencia” foram localizadas 2.282 publicacoes, mas somente 5 eram relacionadas a escolha da profissao. A partir do termo descritor “escolha da profissao” a busca resultou em 89 publicacoes, das quais foram filtrados 9 relacionadas ao adolescente. Com a insercao do descritor “identidade” foram encontradas 77 publicacoes, das quais 3 versavam sobre o adolescente e a escolha profissional. Desse modo, entre artigos, dissertacoes e teses, foram localizadas 2.448 publicacoes, dentre as quais foram selecionadas 17. Apesar do numero de trabalhos selecionados representar menos de 1% do levantamento total, o material selecionado contempla conteudo rico sobre o tema, o que motiva a continuidade dos estudos nessa tematica.

A ESCOLHA PROFISSIONAL PARA ADOLESCENTES: PANORAMA DE ESTUDOS E PESQUISAS

Ação emergencial para reconhecimento de áreas de alto e muito alto risco a movimentos de massa e enchentes: Porto Velho, Rondônia

Data warehouse enriquecido com métodos de aprendizado de máquina para a família Geminiviridae

Epizootics and yellow fever epidemics in 2008 inBrazil, Paraguayand Argentinamarked a significant progression of the disease further south in the continent affecting non-vaccinated human populations. The state of Mato Grosso do Sul is located between the tropical endemic region and the subtropical epidemic region and, despite being an area recommended for vaccination since the 1980s, human and animal cases of the disease are still registered. The purpose of this study was to present the results of entomological surveys of probable sites of infection (PSI) geographically describing these areas regarding human cases and disease suspicion reported in 2008. Thirteen locations in nine municipalities were investigated. A total of 305 females of the genus Haemagogus and Sabethes and five specimens of Aedes albopictus were obtained. The genus Haemagogus was more abundant but Sabethes presented twice as many species (3 x 6) and higher distribution within the collection points. The most abundant species was Hg. janthinomys , with 102 individuals in one location. The other species found were: Hg. leucocelaenus, Hg. spegazzinii, Sa. albiprivus, Sa. belisarioi, Sa. chloropterus, Sa. glaucodaemun, Sa. intermedius and Sa. soperi . It was not possible to identify predominant species in relation to environmental and geographical characteristics of the collection points. Of the nine human cases, eight corresponded to persons not resident in the State, seven of them tourists. MS features a large diversity of rural and wildlife tourist attractions where the yellow fever vectors described in this work are present. In this sense, the monitoring of vaccination coverage and flow of non-vaccinated people through the area are crucial to controlling the disease.

ASPECTOS VETORIAIS EM ÁREAS DE RISCO PARA FEBRE AMARELA SILVESTRE NO ESTADO DO MATO GROSSO DO SUL, BRASIL

No contexto atual em que vivemos, a Tecnologia de Informacao (TI) esta cada vez mais inserida no ambiente empresarial, ja que esta sendo considerada um componente fundamental para a gestao das empresas. Se por um lado essa tecnologia aplicada com sucesso rende muitos beneficios para as empresas por outro traz grandes desafios para a administracao deste recurso, dos quais as empresas passam a ter elevada dependencia. Nesse mesmo periodo, as Unimeds passaram a atuar num cenario complexo, em virtude da lei dos planos de saude, que resultou em maior competitividade, melhoria da qualidade dos produtos e servicos oferecidos aos clientes. Dentro deste contexto, o presente artigo teve como objetivo investigar os investimentos estrategicos feitos em Tecnologia da Informacao, avaliando os impactos gerados na gestao de negocios do Sistema Unimed do Rio Grande do Sul. Para a realizacao da coleta de dados, foi realizada uma pesquisa de carater descritiva, atraves de um questionario. Foram enviados 58 questionarios as singulares. A pesquisa permitiu analisar que as Unimeds na sua grande maioria estao fazendo investimentos modestos, ou seja, ate 1% do faturamento anual, visando atender as determinacoes legais primeiramente e apos utilizando a TI como uma ferramenta para se obter vantagem competitiva.

TECNOLOGIA DA INFORMAÇÃO: UMA ESTRATÉGIA PARA OS NEGÓCIOS DO SISTEMA UNIMED DO RIO GRANDE DO SUL

Este estudo apresenta um projeto social idealizado e conduzido por uma Organizacao da Sociedade Civil de Interesse Publico (OSCIP), cuja finalidade e promover cursos de formacao basica para jovens em condicao socioeconomica vulneravel, para, com isso, promover a integracao entre empresa e comunidade. Por meio da construcao de projetos de vida, nos quais os jovens sao estimulados a aprender nao so a fazer uma escolha profissional, mas tambem aprender como fazer escolhas por toda a vida, os elementos estruturais sao a Orientacao Profissional e a perspectiva da Analise Institucional.

Modelo de apresentação dos artigos para a revista pubvet. O título (Fonte Times New Roman, estilo negrito, tamanho 16, somente a primeira letra da sentença em maiúscula, o mais breve possível- máximo 15 palavras)

O transporte rodoviario de cargas no Brasil, apesar de sua comprovada e grande importância na economia, muito pouco se conhece sobre suas reais caracteristicas, gerando dificuldades no setor, em virtude da escassez de informacoes. O mesmo apresenta essencial importância para eficiencia das empresas dos mais diversos setores existentes. Com o intuito de realizar esta compreensao, optou-se por realizar o estudo em uma Unidade transportadora localizada no centro-oeste do estado do Rio Grande do Sul, Brasil. O objetivo central deste trabalho e analisar qual dos fatores mais influencia o comportamento de compra dos consumidores organizacionais, no momento de decisao de solicitacao dos servicos de transporte de carga. Obteu-se como resultado final, o Fator Individual, que representou frente aos demais fatores com 38% de influencia sob o comportamento de compra dos clientes organizacionais da empresa. A tecnica utilizada na obtencao dos resultados foi de multicrititerio de apoio a decisao, a AHP. Sabendo que, a mesma auxilia na resolucao de problemas complexos, pois utiliza-se o desdobramento do objetivo em criterios e  subcriterios que englobam-o, chegando a indicacao de uma solucao apresentada como a mais satisfatoria para o que se refere.

TOMADA DE DECISÕES GERENCIAIS EM EMPRESAS DO SETOR DE TRANSPORTE DE CARGA: UTILIZAÇÃO DO MÉTODO DE ANÁLISE HIERÁRQUICA DE PROCESSOS (AHP) PARA DEFINIÇÃO DE FATORES DE INFLUÊNCIA

Diante de um cenario cada vez mais competitivo e acirrado pela concorrencia, e necessario que as organizacoes se tornem mais flexiveis e adaptaveis as mudancas. A pesquisa teve o objetivo de identificar as estrategias de crescimento intensivo na empresa pseudonima Caravaggio Tecnologias Ltda., atraves de pesquisa qualitativa com estudo de caso exploratorio. Os dados primarios foram obtidos por meio entrevistas semiestruturadas junto a area de vendas e os gestores da empresa. Tambem foram entrevistados dois especialistas externos do setor. Para a analise dos resultados foi utilizada a matriz de analise ambiental (SWOT), para classificacao dos dados e formulacao das estrategias, e a matriz de Expansao Produto-Mercado para a classificacao das estrategias de crescimento intensivo. Os resultados obtidos identificaram as estrategias de crescimento, desenvolvimento de mercado, desenvolvimento de produto e diversificacao.

XVI Mostra de Iniciação Científica, Pós-graduação, Pesquisa e Extensão

Avaliação de Estratégias de Crescimento: O Caso de Uma Empresa de Soluções em Informática da Serra Gaúcha

Ação emergencial para reconhecimento de áreas de alto e muito alto risco a movimentos de massa, enchente e inundação: Corumbiara, RO

Devido aos indices elevados de acidentes, incidentes e ocorrencias, qualquer um esta vulneravel e pode necessitar de informacoes sobre centros de saude mais proximos para o socorro. Na busca de reduzir o alto indice de ocorrencias fatais em acidentes e incidentes quaisquer, medidas tecnologicas passaram a ser empregadas para contatar rapidamente o socorro. O SOS movel e um sistema para auxiliar pessoas na solicitacao de socorro. O sistema faz reconhecimento de atividades, utiliza sensores moveis com sensibilidade ao contexto e um agente inteligente para deteccao de situacoes de risco e disparo de solicitacoes de socorro automaticas. O sistema e composto por uma parte web e uma movel. O aplicativo movel e utilizado ativamente pelo usuario, enquanto que a interface web e utilizada pelos familiares ou gestores da saude que podem monitorar o usuario e visualizar sua localizacao e alertas. Os experimentos com o SOS Movel foram realizados em um ambiente de simulacoes e permitiram concluir que esse apresentou desempenho satisfatorio ao detectar riscos e fazer o envio de solicitacoes de socorro automaticamente.

SOS Móvel: sistema para auxiliar pessoas na solicitação de socorro

Este estudo apresentou uma reflexao sobre a utilizacao de materiais manipulaveis como recurso para o ensino de Geometria. Resultado de pesquisas realizadas na area de educacao matematica tem revelado importantes questoes a respeito do processo de ensino e aprendizagem que merecem ser discutidas no âmbito da escola fundamental. A Geometria foi o foco de amplas discussoes, pois tratamos da questao da sua ausencia em sala de aula. Na tentativa de poder mudar esse quadro e buscar o desenvolvimento do processo de ensino e aprendizagem de Geometria 
surgem novas propostas e recursos vistos como uma alternativa para conferir 
qualidade e dinamismo ao ensino de Geometria. Fato que despertou a inquietacao de educadores e pesquisadores em compreender o descaso ao ato de ensinar e aprender. Uma das tendencias que vem ganhando destaque em educacao e o uso de materiais manipulaveis como recurso didatico para ensinar Matematica. O objetivo principal deste trabalho foi analisar a utilizacao dos materiais manipulaveis como recurso didatico para o ensino de Geometria. A presente discussao foi o resultado de uma pesquisa bibliografica composta por autores de obras importantes realizadas em educacao que tratam da Matematica e seu ensino, como Pavanello 
(1993), Lorenzato (1995), Fainguelernt (1999), Passos (1996), Rego e Silva (2012) Usiskin (1994), Dante (2005), Nacarato (1995) e Pais (2000). Atraves dos relatos dos varios autores consultados a pesquisa mostrou que a utilizacao de materiais manipulaveis pode ser uma ferramenta muito rica capaz de trazer muitas possibilidades e contribuicoes para a melhoria do ensino da Geometria e da Matematica de um modo geral.

Materiais Manipulativos: uma reflexão acerca desse recurso didático na aprendizagem de Geometria no Ensino Fundamental

O queijo Minas artesanal e elaborado a partir de leite cru com a adicao de culturas iniciadoras endogenas. Durante o processo de maturacao ha o crescimento de bacterias acido laticas (BAL) que sao essenciais para o sabor e contribuem beneficamente para a qualidade sanitaria do produto. As BAL tem demonstrado propriedades probioticas, como antagonismo contra patogenos. Porem, ha escassez de estudos que identifiquem a microbiota latica desse queijo ao nivel molecular e avaliem suas propriedades probioticas. Esse estudo objetivou identificar molecularmente BAL isoladas de queijo Minas artesanal da regiao de Araxa, Minas Gerais, durante sua maturacao por ate sessenta dias durante estacoes seca e chuvosa e avaliar suas propriedades probioticas in vitro. Ao todo, 263 amostras de BAL foram isoladas, 50 delas foram identificadas por sequenciamento do gene 16S rRNA. Foram identificadas bacterias dos generos Lactobacillus (74%), Enterococcus (24%) e Bacillus (2%). Dessas, dez amostras de Lactobacillus spp. foram selecionadas para testes in vitro do seu potencial probiotico. Somente L. plantarum (C0) foi sensivel a todos os antimicrobianos testados, as outras amostras foram resistentes a pelo menos um antimicrobiano. L. plantarum (E5) apresentou a mais elevada frequencia de resistencia a antimicrobianos (60%). Seis amostras foram tolerantes ao suco gastrico artificial, com destaque para L. brevis A6, que apresentou crescimento. Na avaliacao de resistencia aos sais biliares, L. brevis A6, L. casei B5 e L. plantarum E5 foram consideradas tolerantes, tendo a ultima apresentado o menor indice de inibicao, com 20,69%. Apenas L. brevis (E35) produziu peroxido de hidrogenio. Foi observada diferenca (p0,05) entre as medias dos halos de inibicao de Lactobacillus spp. contra duas bacterias reveladoras: Enterococcus faecalis ATCC 19433 e Lactobacillus plantarum C24. Todas as amostras de Lactobacillus spp. inibiram Escherichia coli ATCC 25922, Salmonella enterica var. Typhimurium ATCC 14028 e Shigella flexneri ATCC 25875 no teste de co-cultivo (p0,0001), exceto L. plantarum (C0) que nao inibiu S. flexneri ATCC 25875. Conclui-se que ha elevada frequencia de Lactobacillus spp. entre as BAL presentes no queijo Minas artesanal produzido na regiao de Araxa. A maioria delas demonstrou potencial probiotico in vitro. L. brevis (A6) foi selecionada para testes a fim de pesquisar seu potencial probiotico in vivo e utilizacao para a producao de queijos como micro-organismo benefico e preservando a identidade do produto

Identificação molecular de bactérias ácido-láticas e propriedades probióticas in vitro de Lactobacillus spp. isolados de queijo Minas artesanal de Araxá, Minas Gerais

PESQUISA E O PROCESSO CRIATIVO EM DESIGN: RELEITURA DE PERSONAGENS DE SÉRIE ANIMADO

Ação emergencial para reconhecimento de áreas de alto e muito alto risco a movimentos de massa, enchente e inundação: Chupinguaia, RO

As questões relacionadas com a saúde dos cidadãos europeus não foram, desde o início, consideradas na agenda da construção europeia. Em 1965 foi publicada uma diretiva que revelava preocupações com a segurança dos medicamentos e a harmonização dos critérios científicos de avaliação, visando a sua entrada no mercado. Tratava-se de uma resposta aos trágicos acontecimentos relacionados com os efeitos do medicamento talidomida e à necessidade de promover o desenvolvimento da indústria farmacêutica europeia, a qual, perante os Estados Unidos da América e o Japão, estava a perder importância. As questões gerais de saúde pública entram na agenda europeia com maior relevância na altura do Tratado de Maastricht (1991). O Tratado de Maastricht, tal como, posteriormente, o de Lisboa, consagram o princípio de que é necessário medir o impacto de todas as políticas europeias na saúde. O desenvolvimento dos sistemas nacionais de saúde passa, no entanto, à margem da construção europeia, tendo os diversos países sistemas de saúde muito diferentes, no que se refere ao acesso, à cobertura e ao sistema de financiamento. A característica comum entre eles é que o desenvolvimento foi feito com investimento maioritariamente público e os resultados, em termos de ganhos em saúde, são muito significativos nas últimas cinco décadas. No contexto europeu, nos últimos anos, os tratados longamente discutidos e posteriormente aprovados pelos governos ou parlamentos estão a ser convenientemente ignorados ou utilizados de forma seletiva, pondo em causa a construção de sistemas de proteção social, que são a grande marca diferenciadora da Europa. Pouco se fala na importância da saúde no desenvolvimento económico, tanto na perspetiva do bem-estar soPalavras-chave: Assistência à Saúde; Fatores Socioeconómicos; Portugal; Recessão Económica; Setor de Cuidados de Saúde; União Europeia.

Ação emergencial para reconhecimento de áreas de alto e muito alto risco a movimentos de massa, enchente e inundação: Colorado do Oeste, RO

O presente estudo consiste em analisar a atual situacao dos estoques e realizar a centralizacao das pecas de manutencao e sobressalentes de uma empresa do ramo alimenticio, sua reducao de estoques, de capital de giro e a logistica. Tambem foi avaliada a gestao de estoques buscando meios para administra-los com mais eficiencia, assunto esse de suma importância para empresas de qualquer dimensao. Com a realizacao de um controle apropriado, evitam-se desperdicios, perdas e ate mesmo excessos de materiais parados no estoque. Foram aplicados metodos de estudo de caso utilizando as seguintes formas de pesquisa: descritiva, exploratoria, documental, explicativa e qualitativa. Primeiramente, os dados foram coletados atraves de observacoes, entrevistas informais com os colaboradores e o administrador da unidade e, por fim, foram utilizados relatorios de controle e custos. Atraves dos dados obtidos, foi possivel calcular os indicadores de desempenho, entre eles a Curva ABC, estoque medio, giro de estoques e a cobertura de estoques. Por meio da ferramenta 5W1H, foram feitas as sugestoes de melhorias, sendo que, se os resultados encontrados forem testados e aplicados na empresa, poderao contribuir para a reducao dos custos de manutencao de estoque, aumentando o nivel de satisfacao dos gestores da empresa, proporcionando um acrescimo no capital de giro e, consequentemente, uma maior economia organizacional.

ANÁLISE DA CENTRALIZAÇÃO DOS ESTOQUES DE MANUTENÇÃO: O CASO DE UMA EMPRESA DE PRODUTOS ALIMENTÍCIOS

No periodo que se estende de 2002 a 2014, ou seja, durante os governos Lula e Dilma, ocorreu uma forte reducao da taxa de desemprego, em todos os indicadores que se propoe a avaliar a trajetoria do mercado de trabalho no Brasil. Contudo, como o Brasil apresenta um grande setor informal, essa queda da taxa de desemprego pode ter sido seguida de uma alta precarizacao e aumento da informalidade no mercado de trabalho. Assim, o objetivo deste artigo e observar se de fator isso ocorreu na economia brasileira. Para isso, parte da seguinte pergunta de pesquisa: a reducao da taxa de desemprego no Brasil ocorreu concomitante com o aumento do emprego informal? A hipotese de pesquisa e que ocorreu uma reducao da economia informal no Brasil, no entanto, existem outros fatores que contribuiram para reduzir a informalidade no pais.

Ação emergencial para delimitação de áreas em alto e muito alto risco a enchentes, inundações e movimentos de massa: Manoel Urbano, AC

Neste trabalho, faz-se um balanco geral macroeconomico do governo Fernando Henrique Cardoso, a partir de uma analise descritiva do comportamento das principais variaveis - objetivo das politicas economicas, indicadores de financas publicas e de vulnerabilidade externa. Conclui-se que os prejuizos para o pais, decorrentes da politica economica exclusivista de FHC, foram extremamente elevados, em face dos resultados alcancados em termos de estabilizacao monetaria, e que o seu grande legado ao sucessor foi uma crise economica dificil de administrar.

As propriedades rurais brasileiras de pequeno e medio porte representam a maior parte dos produtores rurais do pais, geralmente sao agricultores com pouca tecnologia, mao de obra familiar. Apesar da sua extrema importância, nao conseguem maiores incentivos e facilidades na obtencao de creditos. Portanto, a assistencia aos produtores menos favorecidos do Vale do Sao Francisco e de total importância, seus problemas mais frequentes estao ligados baixa produtividade, problemas ambientais como a salinizacao dos solos, o qual vem reduzindo a produtividade das culturas e ate mesmo provocando o abandono dessas areas. Entretanto, quando bem assistidos e com a devida orientacao e prevencao, esses agricultores podem melhorar sensivelmente suas producoes atraves de uma nova percepcao de sistema agricola sustentavel, evitando assim futuros prejuizos. De maneira geral o projeto promove de forma significativa a melhoria no sistema produtivo dos agricultores que se inserem no contexto de agricultura familiar, promovendo a conscientizacao dos pequenos agricultores sobre o uso adequado desses sistemas agricolas como uma forma de garantir o uso adequado do solo atraves de orientacoes sobre implantacoes de cultivos de especies vegetais que permitam uma condicao melhor em termos de retorno economico, mas tambem de praticas agricolas que permitam a conservacao do meio ambiente.

ESTUDO SOBRE SISTEMAS PRODUTIVOS AGRÍCOLAS: ADEQUAÇÕES E ORIENTAÇÕES DE PEQUENOS AGRICULTORES DOS MUNICÍPIOS DE JUAZEIRO-BA E PETROLINA-PE

Listeria monocytogenes e um bacilo que causa infeccao em humanos com maior incidencia durante a gestacao, em pacientes imunodeprimidos ou com alguma doenca de base grave, levando na maioria dos casos a meningite e bacteremia. A listeriose geralmente e assintomatica, mas pode levantar suspeita em gestantes com sintomas de gripe, febre e dores no corpo. Com este trabalho foi possivel concluir que a doenca pode levar a graves comprometimentos como: derrames serosos, natimorto, aborto e ate mesmo o obito, podendo ser transmitida para o homem atraves da ingestao de alimentos contaminados pela bacteria. Tornando-se evidente somente atraves de testes sorologicos e isolamento de cultura sanguinea.

LISTERIOSE NA GESTAÇÃO: incidência de infecção em gestantes devido à baixa imunidade

A solução adequada para os Resíduos Sólidos representa economia de recursos naturais, redução dos impactos negativos ao meio ambiente, aumento da vida útil do aterro, redução dos custos de tratamento deste material pelo poder público, geração de emprego e renda, a redução significativa do volume de resíduos gerados, além de contribuir para a mobilização da sociedade quanto a promoção do desenvolvimento sustentável. Em virtude disso, a implantação do Centro DidáticoPedagógico para o Gerenciamento Integrado de Resíduos Sólidos e Inovação do IFFluminense visa desenvolver tecnologias para a inclusão produtiva e social na implantação da política de gerenciamento integrado de resíduos sólidos, em consonância com a Lei 12.305, que institui a Política Nacional de Resíduos Sólidos. Soma-se a isso a capacitação de profissionais e equipes para trabalho em rede no atendimento as demandas tecnológicas para a solução do “lixo” e, também, promover a criação de Cooperativa de Catadores em escala piloto, no intuito de gerar oportunidades de trabalho e renda para trabalhadores do “lixo”, com condições dignas de segurança e qualidade de vida. A princípio, foi realizada coletas de dados por meio de pesquisa bibliográfica, levantamento e estudo da legislação no âmbito federal, estadual e municipal, entrevistas qualificada com representantes da Secretaria Municipal de Ambiente, Secretaria Municipal de Limpeza Pública e outros órgãos vinculados as ações e programas sobre o Gerenciamento de Resíduos Sólidos. Serão realizadas entrevistas e aplicação de questionários semiestruturados com o objetivo de obter subsídios para a realização de diagnóstico no local e bairros do entorno. A partir de então será possível dar início às ações de desdobramento do projeto analisando a sua viabilidade e adequações. Os benefícios ligados ao Centro Didático-Pedagógico são muitos: garantia institucional para a sustentabilidade dos negócios gerados, infraestrutura e pesquisa na temática do “lixo”, estudo de mercado e outros.

CENTRO DIDÁTICO-PEDAGÓGICO PARA O GERENCIAMENTO INTEGRADO DE RESÍDUOS SÓLIDOS E INOVAÇÃO DO IFFLUMINENSE – CAMPUS MACAÉ

The industrial processing of mango generates by-products such as kernel and peel that are usually discarded without proper utilization. The objective of this study was to investigate the physicochemical and functional properties of native and acidified starch separated from mango kernels of variety Tommy Atkins, searching for a new source of starch, ways to improve it and contribute to the utilization of residues from the food industry. Kernels were removed manually and starch was extracted. The native starch was acidified with hydrochloric acid and its chemical composition was -determined. Functional and paste properties of native and acidified starch was also determined. The chemical composition of the native starch consisted of 71.56% starch, 7.30% lipids and 5.6% protein. Native and acidified starches showed low resistance to high temperature, with maximum swelling at 75oC of 9.395 and 6.861 g/g, respectively. The solubility increased with temperature achieving the maximum of 48.03% for acidified starch. The native starch had greater capacity to absorb water and oil and greater paste clarity. It also showed the highest peak viscosity, hold on, breakdown, final viscosity, setback and paste temperature than the acidified starch. The native starch can be indicated to make dehydrated soups and meat products, while the acidified starch can be used in frozen and chilled food and candy industry.

Desenvolvimento vegetativo e produção do pinhão-manso em resposta à adubação fosfatada

Sistemática e biogeografia do género Rhagonycha Eschscholtz,1830 (Coleoptera, Cantharidae) como suporte à bioindicação de alterações ambientais na Península Ibérica

Apesar da sua insofismavel centralidade, a tematica dos direitos fundamentais nao conheceu, no conspecto da construcao europeia, um percurso delineativo linear, tendo o seu regime girado na confluencia de tres grandes vectores: os textos legais (Tratado da Comunidade Economica Europeia, Acto Unico Europeu, Tratado da Uniao Europeia, Carta dos Direitos Fundamentais da Uniao Europeia), as declaracoes politicas e a jurisprudencia comunitaria, com as inerentes interrogacoes que se foram suscitando ao longo do tempo. Apos alguns avancos e recuos, veio reconhecer-se, no âmbito do Tratado de Lisboa, forca juridica vinculante a Carta dos Direitos Fundamentais da Uniao Europeia. Despite its unmistakable centrality, the theme of fundamental rights hasn’t followed, in the context of European integration, a linear pathway, spinning its regime into the confluence of three main aspects: legal texts (Treaty on European Economic Community, Single European Act, Treaty on European Union, Charter of Fundamental Rights of the European Union), policy statements and community case law, thus with the inevitable questions that have been raising over time. After a few advances and retreats, it came to be recognized, in the context of the Lisbon Treaty, binding legal force to the Charter of Fundamental Rights of the European Union. Palavra-chaves / Keywords Carta dos direitos fundamentais da Uniao Europeia, Tratado de Lisboa. Charter of fundamental rights of the European Union, Treaty of Lisbon.

Os direitos fundamentais e a subsidiariedade na integração europeia

A crescente abstencao nas eleicoes para o Parlamento Europeu indicia indiferenca dos cidadaos comunitarios face ao processo de integracao europeia. A subsidiariedade, visando aproximar a decisao dos seus destinatarios, oferece duas vias para recuperar a confianca e a participacao dos cidadaos: Maior participacao dos niveis de poder mais proximos dos cidadaos no processo comunitario e simplificacao da legislacao comunitaria. The increased abstention in elections to the European Parliament suggests indifference of the citizens on the process of European integration. Subsidiarity, in order to approach the decision of its addressees, offers two ways to restore trust and citizens participation: Greater involvement of levels of government with more proximity to the citizens in the community and simplification of Community legislation. Palavras-chave / Keywords Subsidiariedade, Participacao, Eleicoes. Subsidiarity, Participation, Elections.

Um contributo para a abstenção eleitoral comunitária: a subsidiariedade

Monografia apresentada como requisito parcial para obtencao do titulo de Especializacao em Advocacia Empresarial, Contratos, Responsabilidade Civil e Familia no curso de Pos-Graduacao Lato Sensu do Instituto Brasiliense de Direito Publico-IDP.

Responsabilidade afetiva na relação conjugal: a traição como violação de cláusulas gerais no casamento

O aumento do consumo de drogas provoca efeitos destruidores a escala individual, estatal e global reclamando uma forte, eficaz e coordenada cooperacao dos Estados para reprimir a sua producao e trafico que o surgimento da Internet dificultou mais. A celebracao de acordos no âmbito da Organizacao das Nacoes Unidas e do Conselho da Europa, de natureza multilateral, regional e bilateral, a adopcao de normativos pela UE e a celebracao por Portugal de acordos multilaterais e bilaterais para o combate ao trafico ilicito podem constituir mecanismos capazes de aumentar a eficacia desse objectivo. Tal combate deve ser feito de forma integrada incluindo o crime organizado e o branqueamento de capitais. The increased consumption of drugs causes devastating effects on a individual and global scale, demanding a strong, effective and coordinated cooperation of States to suppress their production and trafficking that became more dificult with the appearance of Internet. The conclusion of bilateral, regional and multilateral agreements on the ONU and European Council auspicious, the adoption off rules by European Union and the celebration off multilateral and bilateral agreements by Portugal to combat illicit trafficking, are mechanisms that must increase the efficiency of this target. That combat must be done in a integrated way including the financial, economic andorganized crime and money laundering. Palavras-chave / Keywords Droga, Trafico, Crime organizado, Internet, Cooperacao internacional. Drugs, Trafficking, Organized crime, Internet, International cooperation.

Repressão ao narcotráfico, cooperação internacional e crime organizado

Cruzetas alternativas de Eucalyptus citriodora e Pinus elliottii impregnadas com resina poliuretana a base de óleo de mamona sobre manta geossintética: propriedades elétricas e mecânicas

Ação emergencial para delimitação para delimitação de áreas em alto e muito alto risco a enchentes, inundações e movimentos de massa: Ouro Preto d'Oeste, RO

O princípio da razoabilidade da lei - Limites da função legislativa

Ação emergencial para delimitação de áreas em alto e muito alto risco a enchentes, inundações e movimentos de massa: Ji-Paraná, RO

O livro de Habakkuk retrata um conflito entre a fe do profeta e sua realidade historica. Enquanto sua teologia descreve YHWH, seu Deus, como alguem que ve a opressao, ouve o clamor do oprimido e o liberta da opressao, a realidade de seus dias era de opressao e clamor por socorro divino, mas YHWH nao estava ouvindo o clamor, estava vendo a opressao, mas nao esta salvando o oprimido. O profeta nao consegue entender o que esta acontecendo. Finalmente, YHWH lhe responde, mas para anunciar o envio do imperio neobabilonico para punir os opressores que, a principio, sao pessoas dentre o proprio povo do profeta, ou seja, a elite governante judaita dos dias do rei Joaquim entre 608 e 598 a.C. O conflito do profeta aumenta, pois, com esta medida, YHWH apenas mudara a opressao de maos. O profeta insiste em seu clamor por uma intervencao de YHWH que resolva a questao da opressao tanto interna quanto externa. Entao a resposta vem. YHWH determinou um dia quando vai ajustar contas com todo tipo de impio, seja interno, seja externo. YHWH vai fazer com que suas impiedades se voltem sobre suas proprias cabecas. Esta resposta poe fim ao conflito do profeta. Finalmente, o Deus que ve a opressao, que ouve o clamor do oprimido e age para liberta-lo, esta novamente ativo em favor do seu povo. O livro revela que a teologia que move as queixas do profeta enderecadas a YHWH por causa do conflito entre sua fe e sua realidade historica, e a teologia do Exodo. O Exodo e a experiencia fundante da fe israelita. Assim, desde o principio, Israel conheceu YHWH como aquele que ouve o clamor do oprimido, ve sua opressao e age para liberta-lo de seus opressores. Quando a opressao esta reinando e YHWH nao esta agindo e, pior, quando o povo clama por ajuda e YHWH nao ouve, se instala o conflito entre a fe e a realidade historica conforme experimentada pelo profeta Habakkuk. O livro termina com um salmo que celebra o agir poderoso de YHWH que livra o seu povo e luta contra o impio. No fim o justo sabe que o seu Deus libertador esta ativo e nao o abandonou. Por isso, nao deve desistir. Deve sim, continuar lutando contra toda sorte de opressao apoiando sua fe incondicional em YHWH e submetendo-se a ele mesmo quando nao consegue entender seu modo de agir.

SUBVERSÃO E SUBMISSÃO EM HABAKKUK:A conversão do profeta ou duas teologias em conflito?

Este artigo tem o principal objetivo de identificar o comportamento dos gastos publicos em agricultura no estado de Minas Gerais, no periodo de 1985 a 2001. Constatou-se tendencia a diminuicao do volume desses gastos e a pulverizacao institucional destes, o que indica progressivo esvaziamento de tradicionais atribuicoes do Estado de apoio e fomento ao setor agricola, acompanhado de crescente superposicao de competencias para gastar a verba publica alocada na funcao agricultura e de sua consequente diluicao entre distintos sistemas operacionais da administracao publica. Se o padrao de distribuicao do gasto publico em agricultura em Minas Gerais representa bem o que ocorre no resto do pais, pode-se concluir que, no que concerne a intervencao do Estado na economia do setor agropecuario, o Brasil esta na contramao das tendencias atuais dos paises mais desenvolvidos, nos quais, cada vez mais, esse setor e enfocado num contexto holistico, envolvendo, de forma integrada, multiplos objetivos e politicas de preservacao do meio ambiente e das culturas autoctones, a seguranca alimentar, a inclusao social e a ocupacao do espaco nacional.

COMPORTAMENTO E DISTRIBUIÇÃO DO GASTO PÚBLICO EM AGRICULTURA EM MINAS GERAIS: MULTIFUNCIONALIDADE OU FRAGMENTAÇÃO?

Este estudo foi realizado na cidade de Carvalhopolis, Minas Gerais, com o intuito de verificar se o Programa Bolsa Familia esta atingindo os objetivos esperados ao exigir, na area da educacao, a condicionalidade da frequencia minima escolar. O cumprimento de tal condicionalidade acarretaria a reducao da defasagem idade-serie e evasao/conclusao. Os resultados foram positivos em relacao aos indicadores, mostrou uma forte associacao em tres fatores: frequencia, aprovacao e o local de moradia.

INFLUÊNCIA DO RECEBIMENTO DO AUXÍLIO BOLSA FAMÍLIA NO NÍVEL ESCOLAR: estudo para a cidade de Carvalhópolis.

Podridao do carvao de raizes de soja e causada pelo fungo Macrophomina phaseolina, podendo infectar centenas de especies vegetais. Considerou-se que um solo com alta atividade microbiana pudesse ter acao sobre a M. phaseolina. Este estudo teve como objetivo quantificar microesclerodios do fungo e determinar atividade microbiana. A atividade microbiana foi determinada pelo metodo de hidrolise de diacetato de fluoresceina em diferentes sistemas de cultivo. As amostras foram coletadas na Fazenda experimental da Coamo, Campo Mourao-PR (240 05? 89?? S, 520 21? 09?? O) em seis tratamentos em plantio direto e dois com sistema convencional. O delineamento experimental utilizado foi blocos ao acaso, com tres repeticoes. O fungo foi isolada no meio de cultura ?BDA+Rosa de Bengala? e incubada por 10 dias a 28oC. A menor contagem de propagulos do fungo foi o tratamento convencional aveia/soja. Os tratamentos com a melhor atividade foram T3 (milho safrinha/soja), T4 (aveia/soja), T6 (trigo/soja) e T8 (tremoco/milho). O plantio convencional com trigo/soja mostrou a pior atividade. Este estudo permitiu concluir que mesmo os tratamentos com menor e maior atividades nao mostraram diminuicao nos propagulos de M. phaseolina, significando, que nenhuma das enzimas (lipases, proteases e esterases) possui efeito deleterio sobre o fungo. Um numero minimo de anos faz-se necessario para determinar quais as sequencias de rotacao e sucessao de culturas sao mais uteis para a soja.

Quantificação de Macrophomina phaseolina e análise da atividade microbiana em áreas de soja com rotação de culturas.

Trata-se de um estudo de natureza de natureza descritiva, de carater exploratorio e de uma abordagem quantitativa, objetivando verificar, sob a visao psicanalitica, se as relacoes socioafetivas interferem no processo de aprendizagem das criancas timidas, numa escola publica do municipio de Aguiar, Estado da Paraiba. Ficou demonstrado que a timidez e um grande problema a ser vencido, principalmente, ainda na idade escolar, sendo por esta razao, necessario que o professor saiba identificar o aluno com problemas deste tipo. E, que no exercicio de suas funcoes, o educador pode ajudar seus alunos timidos a superarem esse problema. No entanto, o mais importante a ser colocado e que tanto os professores como as instituicoes educacionais tem inumeras possibilidades para auxiliaram na superacao dessa doenca. Quando a aplicacao dos questionarios junto aos alunos, pode-se comprovar que mais da metade dos entrevistados ressaltaram que sao timidos ou apresentam tracos de timidez. Desta forma, os resultados da presente pesquisa servirao para os professores da escola que serviu como campo de pesquisa, passem a olharem com mais atencao para seus alunos, identificando aqueles que apresentam algum tipo de timidez, direcionando, em seguida, uma atencao mais especial para esse alunos. Isto por que o educador, tambem, responsavel pela formacao da crianca. Palavras-chave : Timidez. Implicacoes na Aprendizagem. Visao Psicanalitica.

A timidez numa perspectiva psicanalítica: avaliando o problema numa escola pública

Urochloa ruziziensis plants constitute forage resource because its biomass production and chemical-bromatologic composition. Increments in these parameters can be obtained by improving the soil fertility and plant nutrition. In this sense, biofertilizers constitute an alternative source of organic fertilizer with potential application in the production of forage plants, enabling improvements in their production, morphogenic development and chemical-bromatologic composition. Thus, the aim of this study was to evaluate the effect of biofertilizer derived from goat droppings in the initial production of aerial biomass, in the chemical-bromatologic composition, structural and morphogenetic characteristics of Urochloa ruziziensis plants. We conducted the experiment in a completely randomized design with five doses of goat biofertilizer (0, 3, 5, 7 and 9 %) in six replicates. The application of goat biofertilizer as of 5 % provided greater accumulation of aerial dry biomass with improvement in dry matter, organic matter, neutral and acid detergent fiber. On the other hand, there was an opposite effect for mineral matter and hemicellulose. For the parameters of plant growth, the biofertilizer studied promoted increase (p<0.05) in sward height, with linear increase, greater foliar elongation and life duration at doses of 3 and 5 %, respectively. We conclude that the goat biofertilizer has potential for application in Urochloa ruziziensis plants, recommending the dose as of 5 %, having benefits for the biomass production and increases in morphogenic and chemical-bromatologic composition.

Biofertilizante caprino no desenvolvimento de Urochloa ruziziensis

The objective of this work was to estimate the K dose necessary to obtain the maximum physical efficiency of production and the critical foliar level of the nutrient, as well as to verify the relationship of soil application of K with the nutritional balance and the incidence of Panama disease ( Fusarium oxysporum ) in 'Prata Ana' (AAB) banana. The experiment was conducted during four production cycles in the semiarid region of the state of Minas Gerais, Brazil, in a clayey Oxisol, with 69 mg dm -1 available K. Treatments were distributed in a randomized complete block design in a 4×4 factorial arrangement, with four K rates (0, 250, 500, and 1,000 kg ha -1 K 2 O per year), four production cycles and six replicates. Soil application of K did not influence banana production in the first cycle. The mean rate of K 2 O to achieve maximum physical efficiency of production of 'Prata Ana' in the second, third, and fourth cycles was 880 kg ha -1 . The mean values of leaf concentrations of N, K, Ca, and Mg were similar between the production cycles. The mean critical foliar level of K, estimated in the three production cycles, was 28.9 g kg -1 . Fertilization with K increases the production and the tolerance of 'Prata Ana' banana to the Panama disease, in soil with average content of K.

Produção, nutrição e incidência do mal do Panamá em bananeira 'Prata Anã' adubada com potássio

Ação emergencial para delimitação de áreas em alto e muito alto risco a enchentes, inundações e movimentos de massa: Ariquemes, RO

Esse trabalho objetiva investigar a contribuiA§A£o das empresas transnacionais no processo de inovaA§A£o tecnolA³gica do Complexo Agroindustrial brasileiro. Para isso, construiu-se um A­ndice de internalizaA§A£o relativa da atividade tecnolA³gica (IRAT), a partir de informaA§Aµes de depA³sitos de patentes (invenA§A£o e modelo de utilidade) e registros de desenhos (desenhos e modelos industriais) no INPI. Foram analisados depA³sitos de 229 empresas, sendo 116 estrangeiras e 113 nacionais, agrupadas por setores especA­ficos e segmentos do CAI. Observou-se elevada concentraA§A£o de patentes nas empresas estrangeiras e baixa internalizaA§A£o tecnolA³gica no Complexo, para as patentes de invenA§A£o (0,061), e maior internalizaA§A£o nos modelos de utilidade e registros (0,71). Considerando-se que os modelos de utilidade e registros tAam teor tecnolA³gico mais baixo, concluiu-se que A© pouco significativa a contribuiA§A£o das empresas transnacionais para a inovaA§A£o tecnolA³gica no CAI. Verificou-se maior internalizaA§A£o na agricultura do que no segmento a sua montante, que A© mais sofisticado e intensivo no uso de tecnologias. Observou-se, tambA©m, que os setores de maior concentraA§A£o de empresas estrangeiras apresentaram menores A­ndices de internalizaA§A£o, e os de pequena participaA§A£o, maiores A­ndices de internalizaA§A£o tecnolA³gica. Assim, conclui-se que a presenA§a de empresas estrangeiras nos setores e segmentos do CAI estAi inversamente relacionada ao A­ndice de internalizaA§A£o da atividade tecnolA³gica.

Empresas transnacionais e internalizaÃ§Ã£o de atividades tecnolÃ³gicas no complexo agroindustrial brasileiro

I - Sentido e relevância da advocacia publica. II - O principio da legalidade. III - O principio da moralidade. IV - Conclusao.

Ação emergencial para delimitação de áreas em alto e muito alto risco a enchentes e movimentos de massa: Feijó, AC

O Programa Bolsa Familia (PBF) caracteriza-se por ser um programa de transferencia direta de renda com condicionalidades, principalmente em relacao a educacao. As familias atendidas pelo PBF aceitam o compromisso de manter as criancas e adolescentes de seis a 17 anos na escola (BRASIL, 2014). O PBF nao exerceu significativa influencia no indicador idade e serie cursada e no percentual de aprovacao na cidade de Andradas, porem no indicador permanencia na escola o PBF foi efetivo.

INFLUÊNCIA DO RECEBIMENTO DO AUXÍLIO BOLSA FAMÍLIA NO NÍVEL ESCOLAR: estudo para a cidade de Andradas

A mandioca tem grande expressao economica no Brasil e no mundo, pela sua importância alimentar. O Nordeste e a regiao que mais aumentou a producao dessa cultura no Brasil, porem, os produtores usam poucas tecnologias, acarretando em possiveis desenvolvimentos de doencas e queda na producao. A cultura sofre muitas perdas na producao pela acao de inumeros fitopatogenos, sendo os do solo os mais severos, o Fusarium solani e Scytalidium lignicola, ganham enfase por causarem doencas como a podridao radicular e negra da mandioca, respectivamente, afetando diretamente a parte comercial da planta, a tubera. Muitas pesquisas, apoiam o uso de praticas que viabilizem a producao e favorecam o ambiente, assim, a utilizacao de biocontroladores vem ganhando destaque, principalmente fungos do genero Trichoderma spp., por suas caracteristicas como antagonistas de uma gama de fitopatogenos. Todavia, ha poucas pesquisas que relatam os mecanismos fisiologicos que sao ativados pelas plantas, quando expostos a essa interacao, patogeno-planta-antagonista, como resposta vegetal a infeccao de doencas. Desse modo, objetivou-se verificar o potencial antagonico de dez Trichoderma spp. aos patogenos F. solani e S. lignicola, e avaliar a resposta fisiologica das plantas exposta a esse patossistema. Foi analisado, in vitro, a inibicao do crescimento micelial do F. solani e S. lignicola em meio batata-dextrose-agar, para selecionar o melhor Trichoderma com potencial antagonista direto a esses patogenos. Atraves do metodo da utilizacao de meio basal com quitina coloidal, sendo a unica fonte de carbono, foi utilizada para avaliar o melhor Trichoderma para producao de quitinase. Em casa de vegetacao, foi comparado os Trichoderma selecionados, contra o indutor de resistencia, in vivo, avaliando a inibicao das doencas infestadas nas plantas, apos 92 dias de crescimento. Em seguida, avaliou-se a producao de enzimas das plantas dos tratamentos in vivo, do complexo oxidativo (ascorbato peroxidase, catalase, peroxidase e polifeniloxidase). Todas as estirpes apresentaram inibicao do crescimento dos fitopatogenos. Porem, a melhor estirpe contra o F. solani foi o T. hamatum (6656), e para o S. lignicola foi o T. harzianum (3086), com valores de 88,91 e 80,78% de inbicao de crescimento micelial, respectivamente, sendo designados como os melhores candidatos para tratamentos em casa de vegetacao. Para a avaliacao de producao de quitinase, todos os Trichoderma testados foram positivos, destaque dado ao T. aureoviride (5158) por produzir 6,70 U mL-1, sendo selecionado para candidato da inibicao da severidade dos patogenos em casa de vegetacao. Todas os Trichoderma selecionados para teste in vivo contra as severidades das doencas, apresentaram eficiencia em comparacao ao controle com a presenca do patogeno. No entanto, o T. aureoviride (5158), foi a que apresentou valores contundentes para os dois patogenos. Dos resultados das enzimas das plantas, os tratamentos que detiveram a inoculacao dos Trichoderma apresentaram resultados satisfatorios, colaborando com a resposta em casa de vegetacao, contudo, novamente o tratamento com a estirpe (5158), foi a que apresentou melhores valores, com destaque a producao das enzimas ascorbato peroxidase e peroxidase. Portanto, conclui-se a efiencia do Trichoderma aureoviride (5158), para uso como biocontrolador da podridao radicular e da podridao negra da mandioca, pois induziu resistencia a planta aos fitopatogenos, colaborando com a producao das enzimas antioxidativas.

Produção de quitinase e antagonismo de Trichoderma spp. contra Fusarium solani e Scytalidium lignicola e atividades enzimáticas antioxidantes em mandioca

O objetivo deste artigo e tecer consideracoes hermeneuticas e filosoficas sobre etica, economia e meio ambiente, enfocando, especificamente, a relacao entre o imperativo categorico formulado por Kant e a questao do desenvolvimento sustentavel. Para isso, considerou-se como elemento de ligacao a perspectiva economica de Georgescu- Roegen. Embora a economia, a etica e a biologia constituam campos distintos de especializacao, o trabalho procurou mostrar as razoes pelas quais essa perspectiva pode ser vista como uma area de intersecao entre essas tres disciplinas. Conclui-se que as recomendacoes de Georgescu-Roegen, contidas no seu chamado “programa bioeconomico minimo”, estao de acordo com os preceitos fundamentais da etica kantiana, no que diz respeito a questao do desenvolvimento sustentavel.

O presente trabalho teve por objetivo validar metodos por espectrofotometria UV-Vis e por CLAE para a analise quantitativa de um derivado do tiofeno, o 2-[(3,4-dicloro-benzilideno)-amino]-5,6-diidro-4H-ciclopen-ta[b]tiofeno-3-carbonitrila (5CN05) e aplica-los no doseamento da molecula contida em microemulsoes. Os metodos propostos foram validados conforme a Resolucao 899/2003 da Agencia Nacional de Vigilância Sanitaria (ANVISA). O comprimento de onda de maxima absorcao do farmaco 5CN05 foi detectado em λmax= 387nm. O metodo espectrofotometrico validado mostrou-se seletivo, apresentando linearidade na faixa de 3 a 16 μg.mL-1, coeficiente de correlacao (r) igual a 0,9998 e limites de deteccao e quantificacao de 0,12 μg.mL-1 e 0,41 μg.mL-1, respectivamente. Para o metodo CLAE, observou-se linearidade na faixa de 0,1 a 3,0 μg.mL-1, r = 0,99915, limites de deteccao e quantificacao de 0,07 μg.mL-1 e 0,10 μg.mL-1 respectivamente. Para ambos os metodos, os parâmetros precisao, exatidao e robustez mostraram-se adequados para o uso pretendido. As metodologias propostas podem ser seguramente aplicadas para quantificacao do 5CN05 em produtos farmaceuticos como microemulsoes. 
 
Palavras-chave: Microemulsao. Derivado do tiofeno. Validacao espectrofotometria e por CLAE. 
 
ABSTRACT 
 
Development and validation of analytical methodologies for measurement of a tiophene derivative in microemulsion systems 
 
This study aims to validate methods of Uv-Vis) and HPLC for quantitative determination of a thiophene derivative, 2 - [(3,4-dichloro -benzylidene)-amino] -5,6-dihydro-4H-cyclopentyl-ta [b] thiophene-3- carbonitrile referred in this study as 5CN05, and apply them to quantify the 5CN05 in microemulsions. The proposed methods were validated according to the Resolution RE 899/2003 of the National Health Surveillance Agency (ANVISA). The 5CN05 was detected by UV-Vis at λmax= 387nm. The validated UVVis UVVis method proved to be selective, showing linearity in the range of 3-16 μg.mL-1, correlation coefficient (r) of 0.9998 and limits of detection and quantification of 0.12 μg.mL-1 and 0.41 μg.mL-1 respectively. For the CLAE method the linearity was observed in the range 0.1 to 3.0 μg.mL-1, r = 0.99915, limits of detection and quantification of 0.07 μg.mL-1 and 0.10 μg.mL-1 respectively. For both UV-Vis and CLAE methods, the precision parameters, accuracy and robustness were adequate for the intended use. The proposed methodologies can be safely applied to quantify the 5CN05 in pharmaceutical microemulsions products. 
 
Keywords: Microemulsion. Thiophene derivative. Validation spectrophotometry and HPLC.

Desenvolvimento e validação de metodologias analíticas para quantificação de um derivado tiofênico em sistemas microemulsionados

Ação emergencial para delimitação de áreas em alto e muito alto risco a enchentes, inundações e movimentos de massa: Plácido de Castro, AC

Políticas públicas de educação escolar indígena e a formação de professores indígenas no Acre

Ação emergencial para delimitação de áreas em alto e muito alto risco a enchentes, Inundações e movimentos de massa: Acrelândia, AC

No inferno e um romance de Armenio Vieira que representa uma dupla aventura por ele empreendida. Em primeiro lugar, observa-se a incursao do autor no universo da prosa, ambiente em que ele ja havia se arriscado com exito em O eleito do sol (1992) e, em segundo lugar, tem-se a composicao de um romance que, antes de tudo, reflete sobre a urdidura das grandes narrativas pertencentes a esse genero, a medida que traz a lume a recorrente figura de um homem que e obrigado, por determinadas conjunturas, a converter-se em romancista e embora se esforce para conceber algo que se distancie dos textos preteritos, depara-se sempre com a frustracao de perceber-se repetindo procedimentos narrativos e historias ja arquitetados por outrem. Protagonizado por um cabo-verdiano, o romance em questao reflete sobre os desafios que o processo de assimilacionismo cultural impoe aos habitantes das colonias portuguesas no continente africano. Analisar a maneira como tais reflexoes sao propostas e que se pretende com este trabalho.

“No inferno”: O despertar de Caliban na ficção de Arménio Vieira

Ação emergencial para delimitação de áreas em alto e muito alto risco a enchentes, inundações e movimentos de massa: Boca do Acre, AM

Crise política e sua solução institucional: reflexões sobre o controle político no Brasil

As comunidades quilombolas sao encontradas em todas as regioes brasileiras, porem a maior ocorrencia e na Regiao Nordeste. No estado da Paraiba, uma das sete unidades federativas dessa regiao apresenta 33 dessas comunidades, que estao distribuidas em 24 municipios. O artigo expoe algumas informacoes sobre os territorios quilombolas de Caiana dos Crioulos, Cruz da Menina e Mituacu, que apresentam um total de 1215 moradores/as, caracterizando-se pela grande presenca de criancas. Tem como objetivo fazer uma analise das condicoes de moradia, consumo e tratamento da agua e da saude.

CONDIÇÕES DE MORADIA E DE SAÚDE EM TRÊS COMUNIDADES QUILOMBOLAS DO ESTADO DA PARAÍBA

Nos anos de 1985 e 1986, foi conduzido, na UFV, urn experimento, visando avaliar o efeito do lactofen e do clopropoxydim sobre plantas daninhas e sobre a tokrancia da cebola semeada diretamente no campo, bem comp os efeitos pasecolheita dos pro- dutos sobre os bulbos armazenados. O lactofen foi eficiente no controle de erva-moura, vassoura, mentrasto, botao- de-ouro e caruru a partir da dose de 0,096 kg/ha e no controle do pica° e da poaia- do-campo a partir da dose de 0,192 kg/ha. O clopropoxydim mostrou-se eficiente no controle do capimecolchdo na dose de 1,08 kg/ha. O lactofen e o clopropoxydim mos- traramese fitotexicos para a cultura, que apresentou rapida recuperactio. 4 aumento das doses de ambos os herbicidas resultou na reducao do flamer° de plantas de cebola, entretanto nao afetou a producao de bulbos, provavelmente porque foi feito desbaste, para uniforrnizar o "stand". Houve decrescimo na percentagem de plantas florescidas quando se combinaram doses miximas de ambos Os herbicidas, enquanto a percenta- gem de bulbos mtiltiplos diminuiu corn o aumento das doses de clopropoxydim. A per- da de peso, a brotagao, a deterioracao e o tempo para emissdo de sizes na agua nab foe ram afetados por nenhum dos herbicides.

Controle químico de plantas daninhas na semeadura direta da cebola (Allium cepa L.)

A atual crise economica mundial esta contribuindo para desfazer equivocos do neoliberalismo. O momento e propicio para resgatar outras visoes teoricas. Entre estas, estao as que podem ser usadas para questionar a pregacao em prol da exploracao das potencialidades agropecuarias do Brasil, como estrategia de insercao na economia globalizada. Esse e o objetivo principal deste artigo. Nesse sentido, utilizou-se um modelo de “dois-setores” para identificacao e analise das consequencias macroeconomicas de mudancas em parâmetros do mercado agropecuario. Os resultados dos exercicios realizados serviram bem para mostrar, objetivamente, os equivocos contidos em certas visoes de grande presenca no debate economico brasileiro.

Ação emergencial para delimitação de áreas em alto e muito alto risco a enchentes, inundações e movimentos de massa: Sena Madureira, AC

Foram avaliados os efeitos de luz e temperatura sobre a percentagem de geniinag& de sementes de Solanum americanum provenientes de diferentes periodos de armazenamento, em expetitnento realizado em laboratOrio. A temperatura constante de 250C nao favoreceu a supernao da dormencia, corn excecio this sementes que foram armazenadas por 12 mares e colocadas pare germinar sob luz completa e vertnelha, evidenciando uma diminuicao da sensibilidade A temperatura ao longo do armazenamento. As sementes, em geral, mostraram um requerimento por temperaturas alternadas, sendo o regime tennico de 20 300C (16 11/8 h) o que apresentou maior genninagiio. Nas temperaturas alternadas, verificaram-se altos valores de germinagio de sementes submetidas a luz completa e verrnelha, enquanto as respostas a vermelho-distante e escura foram bastante variiveis, dependendo da temperature e da idade das sementes. Esser resultados evidenciam as grades possibilidades de gerrninagio de sementes de S. americanum no campo, quando submetidas a diferentes condigoes ariabientais, favorecendo a sue reinfestagio dents de urn dome' vegetal.

EFEITO DE FATORES AMBIENTALS SOBRE A GERMINAÇÃO DE SEMENTES DE SOLANUM AMERICANUM MILL

A investigacao pretende trazer a baila o conceito da “pulsao de morte” na obra “O quarto fechado” de Lya Luft, enfocando inicialmente as possibilidades dialogicas entre a literatura e a psicanalise, levando em conta a presenca daquela na construcao dos proprios conceitos freudianos. A “pulsao de morte”, mesmo evidente na obra, e pertinente para a analise, assim como um paciente no diva, a escrita literaria pode ser analisada sob a luz dos conceitos freudianos, evidenciando sua importância como objeto literario e de analise psicanalitica.

Ação emergencial para delimitação de áreas em alto e muito alto risco a enchentes, inundações e movimentos de massa: Capixaba, AC

A crise economica mundial resgatou o keynesianismo. As atuais tendencias da economia brasileira, no que tem sido chamado de “reprimarizacao”, tornam oportuno recolocar o estruturalismo em posicao de maior destaque no debate economico nacional. Esse e o objetivo principal deste artigo. Para isso, discute-se uma versao do modelo macroeconomico de “dois-setores”, mediante o qual se procurou mostrar sua pertinencia como guia de pensamento para uma serie de questoes socioeconomicas relevantes, especialmente para os paises do terceiro mundo. Procurou-se mostrar tambem sua consistencia com certas evidencias empiricas e como pode ser usado para fundamentar criticas objetivas a certas estrategias economicas que tem sido propostas para o Brasil.

CLASSIFICAÇÃO DIGITAL AUTOMÁTICA DE IMGESN DE SATÉLITE PARA IDENTIFICAÇÃO DE ESPÉCIES VEGETAIS BIOINDICADORAS: ESTUDO DE CASO NA RESTINGA DE JURUBATIBA – RJ*

Ação emergencial para delimitação de áreas em alto e muito alto risco a enchentes, inundações e movimentos de massa: Bujari, AC

Ação emergencial para delimitação de áreas em alto e muito alto risco a enchentes, inundações e movimentos de massa: Tarauacá, AC

SILVA, Jose Aroldo da. Direitos fundamentais sociais: uma analise da aplicacao do principio da reserva do possivel pelo tribunal de justica da paraiba. 2015. 53f. Trabalho de Conclusao de Curso (Graduacao de Direito) - Universidade Estadual da Paraiba, Campina Grande, 2015.

Direitos fundamentais sociais: uma análise da aplicação do princípio da reserva do possível pelo tribunal de justiça da Paraíba

A deficiencia de fosforo (P) e um dos principais responsaveis pela baixa producao agricola na maioria dos solos brasileiros. O objetivo desse trabalho foi avaliar a resposta do pinhao manso a adubacao fosfatado. O experimento foi realizado na Fazenda experimental da EPAMIG em Latossolo Vermelho Amarelode textura argilosa, no municipio de Montes Claros-MG, Brasil. As mudas de pinhao manso foram plantadas no espacamento de 4 mx 2 msob irrigacao. Utilizou-se o delineamento experimental de blocos casualizados com cinco doses de P 2 O 5 (0 - 100 - 200 - 400 e 800 kg ha -1 ano -1 ) e quatro repeticoes. O superfosfato triplo foi utilizado como fonte de P 2 O 5 . A adubacao fosfatada nao influenciou a altura das plantas, entretanto, aumentou o desenvolvimento dos ramos e do caule e elevou a producao de graos. A maxima eficiencia fisica do pinhao manso (798 kg ha -1 ano -1 ) foi obtida com aplicacao de 414 kg ha -1 ano -1 de P 2 O 5 .

Efeitos da substituição iônica por estrôncio na morfologia de cristais de fosfatos de cálcio e no polimorfismo da hidroxiapatita hexagonal e monoclínica

Ação emergencial para delimitação de áreas em alto e muito alto risco a enchentes, inundações e movimentos de massa: Assis Brasil, Acre

The objective of this research was to detect anomalies in the pricing of shares in IPOs in the Brazilian capital market. The methodology of the event study for the measurement of possible abnormal stock returns resulting from temporal periods (daily, monthly, semi-annual and annual) for a total of 91 IPOs conducted from 2007 to 2013 was applied. The empirical results presented evidence about recovery in stock prices resulting from the first day of trading, it was found an abnormal return of the 2.82% above the Bovespa index on average, which indicates the Underpricing. The cumulative average abnormal returns, excluding the return on day 1, were not observed for the survey period, it is suggested that, after the first day of trading, shares tend to maintain a consistent behavior with the Bovespa. These figures show significant gains in the value of stocks analyzed within one day's supply, provided that the investor perform the first day of trading on the stock market, both in purely economic terms and in their own level of statistical significance. Moreover, it is not characterized by robustness, statistically relevant, the phenomenon of underperformance in the period.

Ação emergencial para delimitação de áreas em alto e muito alto risco a enchentes, inundações e movimentos de massa: Jaru, RO

SENSIBILIDADE DE CULTIVARES DE CEBOLA (ALLIUM CEPA L.) IMPLANTADOS POR SEMEADURA DIRETA AO OXYFLUORFEN APLICADO EM DIFERENTES ESTÁDIOS DE DESENVOLVIMENTO DA PLANTA

Com a fmalidade de avaliar o controle de plantas daninhas e a tolerfincia das plan- tas de batatad-dote, cultivar Braziandia rosa, as combinagoes de eradicane e metribuzin, foi realizado um ensaio em campo, num Podzolico Vermelho Amarelo, fare tenni), muito argiloso, com 3,69% de materia organica. Foram avaliadas quatro doses de eradicane em primplantio incorporado, 0,00; 1,73; 3,46 e 5,19, e tres doses de metribuzin corn e sem incorporagio, 0,15; 0,30 e 0,45, ex- pressos em kg de ingrediente ativo por hectare, e uma testemunha capinada, em quatro rePetigOese A batata-doce apresentou boa tolerancia aos doffs produtos. A aplicarstio do metri- buzin aumentou a produtividade da cultura de batata-dote ao controlar eficientemente as plantas daninhas predominantes no local do ensaio, principalmente quando nab foi incorporado ao solo. Houve aumento linear do controle de plantas daninhas corn o aumento da dose de eradicane. Nenhuma das caracterfsticas avaliadas das *Was de batatas foi influenciada pelas doses do eradicane, o que indica uma boa tolerancia a cultura do produto.

EFEITO DO ERADICANE EM COMBINAÇÃO COM O METRIBUZIN, COM E SEM INCORPORAÇÃO, NO CONTROLE DE PLANTAS DANINHAS NA CULTURA DA BATATA-DOCE

Foram conduzidos dois experimentos no period° das "Aguas", um em Vicosa e outro em Coimbra, MG, e urn experimento no invemo, em Vicosa, coin o objetivo de avaliar a resposta de oito cultivares de fetid° de diferentes habitos de crescimento e ciclos biologicos a tits niveis de competicao corn plantas daninhas. O delineamento foi em blows ao acaso, corn parcelas subdivididas e quatro repetigoes. Nas parcelas colocaram-se os tre's graus de competigio corn plantas daninhas: controladas durante todo o ciao da cultura, controladas ate 30 dias apes a emergencia dos feijoeiros e nenhum controle durante todo o ciclo da cultura. Nos subparcelas foram colocados as seguintes cultivares de feijao: Manteigao Fosco I I, Preto Sessenta Dias, Diacol Cabala, Ouro, Rico 23, Negrito 897, Carioca e Ricopardo 896 Em Visa, nas "Aguas", as parcelas sem capinas apresentaram 179 plantas daninhas per m2, corn predomirLincia de monocotiledoneas, sobretudo tiririca; em Coimbra. nas "aquas"', a densidade foi de 402 plantas daninhas por m2, corn predominancia do capim-marmelada; em Vicosa, no inverno, a densidade foi de 323 plantas por m2, principalmente dicotiledoneas, clue pouco se desenvolveram. Concluiu-se o seguinte: 1) Os cultivares de feijab de maior produtividade, em condicees de ausencia de competicao corn plantas daninhas, foram os mais prejudicados quando submetidos forte competigab coin as invasoras. 2) Em geral, a manutencao da cultura livre da concorrOncia corn plantas daninhas, durante 30 dias ape's a emergencia dos feijoeiros, foi suficiente para se alcangar a maxima produtividades 3) Ocorreu a tendOncia de, quando em competicao corn a flora invasora. os feijoeiros darem menor cobertura vegetativa ao solo. 4) A competicado corn plantas daninhas nao afetou a altura dos feijoeiros, mar tendeu a diminuir-lhes o "stand" fmal e a qualidade comercial das sementes.

EFEITOS DA COMPETIÇÃO COM PLANTAS DANINHAS SOBRE A CULTURA DO FEIJÃO (PHASEOLUS VULGARIS L.)

As tecnologias da informação e comunicação no ensino deGeografia : formação e prática docente

O Programa Bolsa Familia (PBF) tem como objetivos na area escolar a inclusao e a permanencia dos alunos nas escolas. Ao exigir a frequencia, pressupoe-se que haja melhoria no desempenho academico e por consequencia diminuicao no tempo de conclusao da educacao basica. Propoe-se verificar se estes objetivos foram alcancados, em 2014, Poco Fundo/MG nas series finais das escolas publicas. Pode-se constatar que o PBF, nos indicadores observados produziu resultados satisfatorios.

IMPACTOS DO PROGRAMA BOLSA FAMÍLIA NA EVASÃO ESCOLAR, FREQUÊNCIA, APROVAÇÃO E DEFASAGEM IDADE-SÉRIE DOS ALUNOS DO MUNICÍPIO DE POÇO FUNDO/MG

Avalia-se com esta pesquisa o avanco das geotecnologias, em especial o sensoriamento remoto e dos servicos de imageamento por satelites nos mapeamentos ambientais para fins de monitoramento de especies vegetais bioindicadoras, visando a menor custo e maior eficiencia, quando comparado as tecnicas tradicionais. As especies nativas de restinga sao utilizadas como bioindicadores da qualidade ambiental. Busca-se identificar especies vegetais especificas por meio de classificacao digital automatica de imagens de satelites.

Classificadores Digitais Automáticos para Mapeamento de Bioindicadores Vegetais de Restingas: Estudo de Caso no PARNA da Restinga de Jurubatiba, RJ, Brasil

Ação emergencial para delimitação de áreas em alto e muito alto risco a enchentes, inundações e movimentos de massa: Senador Guiomard - AC.

Controle quimico de plantas daninhas na cultura da batata - doce ( ipomoea batatas ( l . ) lam . )

O aumento da geracao de residuos solidos surge em paralelo com o desenvolvimento economico. Por isso, o gerenciamento dos residuos solidos converge para uma importância crescente, sendo fundamental a coerencia ambiental, economica e social. Nesse sentido, o Centro Didatico-Pedagogico surge como alternativa para o gerenciamento dos residuos solidos no IFFluminense – Campus Macae, mas, vale considerar que tambem tende a promover a inclusao social, viabilizar ganhos sociais a partir da capacitacao profissional de pessoas de baixa renda, em escala piloto e conferir beneficios ambientais, a partir da destinacao correta dos residuos gerados, nao so para o IFFluminense – Campus Macae, como tambem para o municipio de Macae.

CENTRO DIDÁTICO-PEDAGÓGICO PARA O GERENCIAMENTO INTEGRADO DE RESÍDUOS SÓLIDOS: ESTUDO DE CASO PARA AVALIAÇÃO DE VIABILIDADE NO INSTITUTO FEDERAL FLUMINENSE - CAMPUS MACAÉ, RJ-BRASIL

A questao primordial abordada neste estudo objetiva uma tentativa de reflexao sobre a viabilidade de uma politica de informacao para a preservacao sustentavel da Reserva Biologica de Pedra Talhada, localizada no municipio de Quebrangulo/AL que vem sofrendo fortes impactos que acarretam desequilibrios ecologicos na referida regiao. Analisa-se ainda a questao da educacao ambiental como provedora de uma consciencia critica junto a comunidade local. A analise fundamentou-se em abranger quantitativamente atraves de um questionario estruturado, sendo considerado uma unica resposta por alternativa como instrumento de capitacao de dados que foram em seguida tabulados. Verificou-se atraves dos dados obtidos que ha necessidade de uma politica de informacao/comunicacao eficaz que conscientize a populacao local, de sua responsabilidade em fiscalizar e atuar no processo de preservacao da referida reserva. PALAVRAS-CHAVE: Biodiversidade. Comunicacao. Conservacao. COMMUNICATION AND ENVIRONMENTAL EDUCATION: A REFLECTION OF PEDRA TALHADA BIOLOGICAL RESERVE IN THE MUNICIPALITY OF QUEBRANGULO, ALAGOAS ABSTRACT This article aims to stimulate reflection on the viability of an information policy for the conservation of Pedra Talhada Biological Reserve, localized in the Municipality of Quebrangulo, Alagoas. This area has suffered severe impacts causing ecological imbalances. In addition, this article analyzes the environmental education as provider of a critical consciousness Community. Based on the analysis of survey questionnaires, quantitative methology that use a closed-ended question has the respondent pick an answer from a given number of options. Data  were  subsequently tabulated. The results showed the need for an effective information policy, in order to prepare political citizens concerned with Biological Reserve protection, through control and action aimed at preserving the Reserve. KEY-WORDS: Biodiversity. Communication. Conservation. COMUNICACION Y EDUCACION AMBIENTAL: UNA REFLEXION DE LA RESERVA BIOLOGICA PIEDRA TALLADA EN EL MUNICIPIO DE QUEBRANGULO, ALAGOAS RESUMEM La pregunta principal abordada en este estudio tiene como objetivo una tentativa de reflexion sobre la viabilidad de una politica de informacion para la conservacion sustentable de la Reserva Biologica Piedra Tallada, en el municipio de Quebrangulo, Alagoas; que viene sufriendo fuertes impactos que causan desequilibrios ecologicos en esa Region. Analiza tambien a la educacion ambiental como una herramienta para el desarrollo de una conciencia critica de la comunidad local. El analisis fue de caracter cuantitativo, atraves de un cuestionario estructurado de encuesta, considerada una unica respuesta por alternativa como instrumento de capitalizacion de datos, que posteriormente fueron tabulados. Se encontro a traves de los datos obtenidos que existe la necesidad de mantener una politica de informacion y comunicacion efectiva que concientice a la poblacion local de su responsabilidad de fiscalizar y actuar en el proceso de conservacion de la Reserva. Palabras-clave: Biodiversidad. Comunicacion. Conservacion.

COMUNICAÇÃO E EDUCAÇÃO AMBIENTAL: UMA REFLEXÃO PARA A RESERVA BIOLÓGICA DE PEDRA TALHADA NO MUNICÍPIO DE QUEBRANGULO/AL

SILVA, Josefa Erilene da Costa. Brinquedos e brincadeiras na educacao infantil. 2014. 38f. Trabalho de Conclusao de Curso (Graduacao em Pedagogia - PAFOR)- Universidade Estadual da Paraiba, Campina Grande, 2014.

O Projeto Sou Feliz ... ensino Educacao Fisica, desenvolvido no Inpar, instituicao centenaria que acolhe criancas e adolescentes oriundos da Cidade de Deus e bairros adjacentes, compreende vivencia profissional de alunos de Graduacao da UFRJ de forma integrada. Por meio da inter-relacao estabelecida com outros projetose disciplina de Graduacao, possibilita atuacao na area de Educacao Fisica Escolar, alem de interacao interdisciplinar,intra e interinstitucional. O objetivo deste trabalho e apresentar a visao dos bolsistas (Pibex e Especial I) da atuacao do Projeto como elemento transformador e formador em suas trajetorias de qualificacao profissional, ainda na Graduacao. Embora a avaliacao seja continua, depoimentos foram externados, por escrito, apos o primeiro semestre de 2015. Por integrar planejamento participativo, a estes sao acrescidas observacoes dos demais profissionais da instituicao onde o Projeto e desenvolvido, e de outras, onde algumas atividades vem sendo realizadas. O resultado subsidia o planejamento (inicial) do segundo semestre. Os depoimentos, elaborados individualmente, ou em duplas, destacaram o trabalho interdisciplinar, permitindo envolvimento de varias disciplinas, na abordagem de temas de relevância social. Destaque para a busca do desenvolvimento da autonomia dos alunos, assim como olhar critico e respeito ao proximo, essenciais para o convivio em sociedade. Com foco no processo ensino aprendizagem, possibilidade de experiencia e vivencia profissional na Educacao Escolar, promovendo atividades que visam contribuir tambem para o processo de escolarizacao, alfabetizacao e letramento. O estabelecimento de metodologia participativa, na identificacao de demandas e desdobramentos, agrega monitores e professores e gerencia opinioes, criticas, diferentes visoes. O aprimoramento dos planejamentos, desde a concepcao ate a elaboracao das atividades, que vao desde esportes tradicionais ate os menos conhecidos, ensinando e aprendendo diferentes culturas, possibilitando conhecer o repertorio corporal dos alunos. Enfim, a construcao de cidadaos criticos e evidente e o esporte e usado como ferramenta de abordagem durante as aulas. Alguns se posicionaram criticamente em relacao a aspectos institucionais e de relacionamento, que serao objeto de analise e avaliacao por toda a equipe.O Projeto Sou Feliz ... ensino Educacao Fisica, ao estabelecer inter-relacao com outros projetos, disciplinas e instituicoes permite a formacao plural de seus integrantes, externada nos depoimentos. Ainda cabe a experiencia em elaborar e realizar eventos, na area de Educacao Fisica Escolar e atletico-desportiva. Agrega interesses diversos, dos monitores-bolsistas, das criancas, adolescentes e alguns jovens atendidos, e das instituicoes. Cumpre, assim, funcao educativa-formativa, social e cultural. Destaque para a concessao de bolsas Pibex e Especial I (Edital Pro-Cultura 2015).

RELAÇÃO EXTENSÃO–FORMAÇÃO PROFISSIONAL NA GRADUAÇÃO: A EXPERIÊNCIA DO PROJETO SOU FELIZ ... ENSINO EDUCAÇÃO FÍSICA

Objective:to assert concerning the regulation of labor relations in nursing and to reflect on the legal aspects of working in nursing. Methodology: This is a reflective study that examined the working relationships of the nursing staff to focus on its workday with targeted legal aspects involving the theme. Results: The nursing staff has no specific legal protection about its workday, while developing essential work to life and to be present in almost all health institutions. The population is entitled to be served by healthy and competentprofessionals, in order that safe and quality care, and morally required, it is more economical because it prevents damage and reduces lawsuits against health services. For this discussion on the Draft Law 2295 /2000, which advocates a workload of 30 hours per week, reflecting a historic conquest of the nursing class, which it is based on biological, social and economic aspects. Conclusion: The reduction in working hours allows the provision of a safer care and represents nothing more than the realization of the current protectionist legal framework.

REFLEXÃO / REFLECTION / REFLECIÓN Legal aspects of work shift in nursing: theoretical reflection Aspectos jurídicos da jornada de trabalho em enfermagem: reflexão teórica Aspectos jurídicos de cambio de trabajo en enfermería: reflexión teórica

O Tratado de Roma apenas contemplou inicialmente instituicoes de representacao dos governos centrais dos Estados, nao incluindo organismos de representacao dos poderes regionais e locais. O presente artigo aborda a decisiva influencia da Politica Regional Comunitaria destinada a correccao dos desequilibrios de desenvolvimento regional, na criacao em 1992 pelo Tratado de Uniao Europeia do Comite das Regioes para assegurar a representacao dos poderes regional e local. The Treaty of Rome initially only contemplated institutions representing the central governments of the States, not including bodies representing the regional and local authorities. This article addresses the decisive influence of the Community Regional Policy destinated to redressing imbalances in regional development, on the creation of the Committee of the Regions in 1992 by the Treaty of the European Union to ensure the representation of regional and local authorities. Palavras-chave / Keywords Subsidiariedade, Regioes, Politica regional comunitaria, Participacao regional. Subsidiarity, Regions, Community regional policy, Regional participation.

Política regional comunitária, subsidiariedade e comité das regiões

Resquícios da antiga narrativa em Vila dos Confins de Mário Palmério

OBJETIVO: caracterizar as localidades hiperendemicas para esquistossomose no estado de Pernambuco quanto as condicoes de saneamento e recomendar medidas de intervencao ambiental que favorecam a sustentabilidade das acoes de enfrentamento da doenca. METODOS: trata-se de um estudo descritivo utilizando os dados obtidos no 'Relatorio das condicoes de saneamento das localidades hiperendemicas para a esquistossomose e geo-helmintiases em Pernambuco', elaborado pela Secretaria Executiva de Vigilância em Saude do estado de Pernambuco em 2012. RESULTADOS: das 119 localidades hiperendemicas identificadas, em 72 (60,5%) foi observada inexistencia de agua encanada, em 110 (92,4%) nao havia coleta de esgoto, e em 116 (97,5%), relatou-se ausencia de tratamento do esgoto. CONCLUSAO: as localidades hiperendemicas avaliadas apresentaram condicoes de saneamento basico precarias, que contribuem para as altas prevalencias da esquistossomose; por isso, torna-se necessaria a sensibilizacao dos gestores municipais para acoes efetivas de melhorias sanitarias que permitam garantir sustentabilidade no controle da esquistossomose.

Condições de saneamento básico em áreas hiperendêmicas para esquistossomose no estado de Pernambuco em 2012

Este artigo trata da influencia do Bolsa Familia em indicadores escolares como resultado, permanencia e genero. O programa auxilia milhoes de familias e proporciona uma melhoria na qualidade de vida da populacao. Para este projeto foram coletados os dados dos alunos de 9° ano, nas escolas de Alterosa e no CRAS (Secretaria de Educacao e Assistencia Social). Atraves da realizacao de calculos foi possivel indicar que o Bolsa Familia impacta positivamente no indice de genero.

IMPACTO DO BOLSA FAMÍLIA EM ÍNDICES ESCOLARES: estudo para a cidade de Alterosa

Este o artigo apresenta os resultados sobre o impacto do Programa Bolsa Familia (PBF) na evolucao escolar dos alunos do 9o ano do Ensino Fundamental e 3o ano do Ensino Medio do municipio de Areado/MG. Comparam tres indicadores educacionais: os indices de evasao escolar, o percentual de aprovacao/retencao e a razao de criancas e adolescentes com defasagem idade-serie. Espera-se que estas tres variaveis recebam interferencia direta da participacao ou nao do PBF, pois dentre as condicionalidades da educacao mais averiguadas estao a matricula e a frequencia de todos os beneficiarios em idade escolar. Conclui-se que esses indicadores estao correlacionados e apresentaram resultados satisfatorios.

INFLUÊNCIA DO RECEBIMENTO DO AUXÍLIO BOLSA FAMÍLIA NOS INDICADORES EDUCACIONAIS: estudo para o município de Areado/MG.

Análise bayesiana de um modelo linear generalizado misto: emprego no melhoramento de plantas

Anaerobic sewage treatment systems do not produce a good effluent quality and post-treatment is required. Aerobic systems can be used, but the excess sludge must be stabilized. We investigated the possibility of using the UASB both for the anaerobic pre-treatment and for stabilization of the post treatment sludge. The results of the investigation indicated that it was feasible to use the UASB simultaneously for the two purposes. However, the aerobic sludge mineralization was not complete and the indigestible part tended to be expelled from the UASB reactor because it had a much lower settleability than the anaerobic sludge. The undigested sludge accumulated in the treatment system until it was expelled in the effluent. For this reason aerobic-anaerobic systems in practice have serious operational problems. The solution of the problem is the separation of solids in the effluent of the UASB. Key-words: Sewage Treatment, UASB reactor , Aerobic post treatment, Aerobic Sludges stabilization. Estabilização de lodo de pós-tratamento aeróbio na unidade de pré-tratamento anaeróbio Anaerobic-aerobic treatment systems: Stabilization of aerobic sludge from the post treatment unit in the anaerobic pre treatment unit Data de entrada: 20/05/2013 | Data de aprovação: 22/07/2013 José de Anchieta da Silva Filho | Adrianus Cornelius van Haandel José de Anchieta da Silva Filho* Engenheiro Civil e Mestre em Saneamento pela Universidade Federal de Campina Grande. Atualmente trabalha na CETREL em Camaçari-Ba. Adrianus Cornelius van Haandel Professor na Universidade Federal de Campina Grande e consultor de projetos de sistemas de tratamento biológico de águas residuárias. *Endereço para correspondência: Departamento de Engenharia Civil da Universidade Federal de Campina Grande. Rua Aprígio Veloso 882 , Bodocongó, Campina Grande, PB Brasil. CEP: 58.429-350. E-mail: adrianusvh@gmail.com DOI: http://dx.doi.org/10.4322/dae.2014.006

Estabilização de Lodo de Pós Tratamento Aeróbio na Unidade de Pré Tratamento Anaeróbio

Este artigo mostra o processo de desconcentracao das atividades na economia brasileira, sobretudo no Nordeste, desde a implementacao da Sudene ao periodo mais recente. Esse processo continuou nas duas decadas depois da Sudene, seguido por um periodo de baixo dinamismo, quando predominaram as forcas do mercado, causando a inflexao do crescimento economico e, consequentemente, a desconcentracao da atividade e da renda. Contudo, no inicio dos anos 2000, a politica regional e o planejamento voltaram, principalmente, na segunda metade da decada. A economia brasileira inicia uma trajetoria de crescimento, levando consigo o Nordeste. Diante disso, algumas questoes emergem: essa dinâmica da economia brasileira tem sido acompanhada pela desconcentracao da renda? Qual a situacao do Nordeste dentro deste novo contexto? Diferente das ultimas duas decadas, o crescimento economico apresentado nos anos 2000 foi acompanhado pela desconcentracao da producao e, por conseguinte da renda, derivado da acao mais ativa do Estado em termos de politicas regionais. Assim, conclui-se que o Nordeste, dentro desse contexto, apresentou taxas de crescimento acima da media do Pais elevando a renda per capita da Regiao. Nesse sentido, esse crescimento foi acompanhado tambem pela melhora no padrao de vida da populacao, principalmente, devido a politica de transferencia de renda do Governo Federal.

Emprego da simulação na escolha do número de indivíduos no método "bulk" no melhoramento de plantas autógamas

Otimização do processo de purificação de óleo básico para formulação de biolubrificantes utilizando destilação molecular

Este trabalho visa abordar a importância do relativismo e do anacronismo na elaboracao de sentido da historia e sua funcao como orientadora para percepcao temporal. Desta forma procuraremos demonstrar que o relativismo e o anacronismo, por meio da linguagem, permite um dialogo entre o passado, o presente e o futuro, tornando outras experiencias de tempo compreensiveis para a Historia. Para tanto nao nos concentraremos em textos especificamente academicos, mas em duas narrativas historicas produzidas na cidade de Anapolis, interior goiano: Subsidios a historia de Anapolis , 1957, e Anapolis: um enfoque historico , 1975.

O oitavo pecado capital: anacronismo e construção de sentido em duas narrativas históricas sobre a cidade de Anápolis-GO

Ação emergencial para delimitação de áreas em alto e muito alto rico a enchentes, inundações e movimentos de massa: Tapauá, AM

A presente comunicacao pretende enunciar, problematizar e debater alguns dos aspetos mais  relevantes  que  temos  encontrado  na  realizacao  do  projeto  de  investigacao «Gestao  de  Pessoas  Nas  Organizacoes  Sem  Fins  Lucrativos:  Um  projeto-piloto  nos concelhos  da  Povoa  de  Varzim  e  Vila  do  Conde»,  sob  coordenacao  cientifica  da Professora Doutora Maria Ester Vaz (NID_RH, ESEIG-IPP). Esta comunicacao incidira sobre a recolha qualitativa de dados efetuado no periodo de maio  a junho de 2011, com  a  realizacao  de  quinze  entrevistas  seguindo  a  logica  sugerida  por  Ghiglione  e Matalon (1997: 64-65) – Semi-diretivas – onde «(…) o entrevistador conhece todos os temas sobre os quais tem de obter reacoes por parte do inquirido (…)», mas por outro lado  «(…)  a  pessoa  pode  dar  uma  resposta  tao  longa  quanto  desejar.  Cabe  ao entrevistador  obter  de  forma  fluida,  contributos  pertinentes  para  a  sua  investigacao.

Da comunidade para a academia: modelos de gestão em contexto Não Lucrativo

Ação emergencial para delimitação de áreas em alto e muito alto risco a enchentes, inundações e movimentos de massa: atualização, Porto Velho, RO

Subsurface stratigraphic analysis of Devonian strata in the Rio do Peixe Basin, newly recognized by palynological studies, has resulted in the identification of two new formations assembled in the newly established Santa Helena Group. These units were characterized using cores, sidewall and cuttings samples, conventional well logs, image log and 3D seismic data. The Piloes Formation, the lower unit, is composed mainly of dark mudstones and medium-to-very fine-grained sandstones, with minor conglomerates and breccias, and the Triunfo Formation, the upper unit, comprises whitish grey, kaolinitic, coarse-grained to conglomeratic, cross stratified sandstones and conglomerates, with interbedded mudstones and fine-grained sandstones. The Piloes Formation is represented by prodeltaic lagoonal-lacustrine facies, with lesser associated subaqueous talus, debrite and sandy turbidite lobe facies, part of fandelta and delta systems. The Triunfo Formation is interpreted as braided fluviodeltaic facies. The Santa Helena Group corresponds to the Lower Devonian tectono-sequence deposited in a NW-SE-trending graben during a transgressive-regressive cycle. With 343 m of thickness (isochore) in well 1-PIL-1-PB (Piloes 1), this sequence has a non-conformity at the lower boundary and its upper boundary is an angular unconformity that represents a hiatus of about 265 Myr, at the base of the Lower Cretaceous tectono-sequence (Rio do Peixe Group). Ignimbrites and co-ignimbrite breccias (Poco da Jurema volcanic breccia) were recognized at the northern margin of the Sousa half-graben. There is evidence that the pyroclastic event is coeval with the Lower Devonian graben filling. The results of this study indicate a polyhistorical tectono-volcano-sedimentary evolution of the basin. This lithostratigraphic update brings new perspectives for geological research in the Rio do Peixe Basin, as well as in other inland basins of the Northeast of Brazil.

Proposta de novas unidades litoestratigráficas para o Devoniano da Bacia do Rio do Peixe, Nordeste do Brasil.

A estrutura fundiaria brasileira e fruto de nossa submissao a Coroa Portuguesa. No entanto, sua consolidacao se deu nos periodos subsequentes com a Lei de Terras de 1850 e o poder das oligarquias rurais. Estas jamais permitiram a realizacao de uma reforma agraria autentica. Pautados em leituras bibliograficas procuramos nesse texto ressaltar como se deu a origem do latifundio no Brasil, destacando as consequencias advindas de sua consolidacao. O objetivo e mostrar como se deu a formacao da estrutura fundiaria injusta e desigual e como vivem aqueles que sao donos das terras e produzem para o capitalismo, bem como aqueles que dependem dos donos das terras. Os que veem a terra apenas como uma mercadoria, produzindo para suprir as necessidades do capital, e para isso expropriam o pequeno proprietario de suas terras; terras estas que para eles e mais que uma simples mercadoria, e a sua vida. Como nao tem forcas para lutar contra essa forca, em muitos casos sua unica opcao e tornar-se um trabalhador daquele que o expropriou ou migrar para a cidade em busca de melhores condicoes. Aqueles que resistem e decidem lutar pela extincao do latifundio, mais precisamente pela reforma agraria, ainda sao reprimidos com violencia. Enfim, o que percebemos e que o latifundio e um mal que necessita ser sanado da sociedade. O mesmo o latifundio deve ser combatido para que possamos contar com uma estrutura fundiaria em que o pequeno proprietario tambem possa dispor de terras para produzir e viver de maneira digna

Geração automática de dados de teste para programas concorrrentes com meta-heurística

O principal objetivo deste trabalho e verificar a presenca do oprimido como protagonista, dentro das caracteristicas postas por Paulo Freire, na literatura de Lima Barreto, alem dos desdobramentos que esse protagonismo pode oferecer como ato simbolico de insercao desses oprimidos num meio restrito a determinadas caracteristicas sociais de personagens. Os aspectos literarios que envolvem a criacao e a insercao do oprimido como protagonista serao mediados pelo conceito de estruturalismo genetico, proposto por LucienGoldmann como teoria literaria. O estudo do contexto historico e cultural sao de extrema importância para estabelecer as relacoes homologas da estrutura textual com a estrutura social. Por meio dessa perspectiva do oprimido como protagonista, estudaremos o principio de conscientizacao proposto por Paulo Freire, relacionando-o com os personagens de Clara dos Anjos. Os aspectos de relacionados a Educacao, simbolicamente trabalhados por Lima Barreto, serao estudos a luz dos conceitos do educador Paulo Freire.

Desfolha precoce e relações rendimento/qualidade na casta Loureiro (Vítis Vinífera L.) Região dos Vinhos Verdes

SILVA, J. E. F. da. Uma instituicao confessional masculina: o Diocesano Pio X e suas representacoes, praticas e cultura escolar dos anos 1894-1910. 2014. 33f. Trabalho de Conclusao de Curso (Graduacao em Historia) - Universidade Estadual da Paraiba, Campina Grande, 2014.

Uma instituição confessional masculina: o Diocesano Pio X e suas representações, práticas e cultura escolar dos anos 1894-1910

AS CONTRIBUIÇÕES DO INTÉRPRETE DE LIBRAS NA INCLUSÃO EDUCACIONAL DE ALUNOS SURDOS NA CIDADE DE MANAUS

Buscamos rastrear as formas como o processo de modernizacao foi interpretado e 
compreendido, entre as decadas de 1930 e 1950, no municipio de Anapolis-GO. Nosso intento 
nao visa propriamente narrar ou discutir o processo de urbanizacao e industrializacao o corrido 
na regiao, mas compreender, por meio dos discursos produzidos nesse contexto, a maneira 
como a modernizacao foi interpretada e utilizada como um modo de construcao de sentido das 
narrativas historicas locais. Com esse objetivo abordamos a maneira como a imprensa local se 
utilizou da categoria de progresso como forma de apropriacao e entendimento das mudancas 
pelas quais a cidade passava. Sob a otica do estrangeiro (individuos a principio estranhos ao 
horizonte cultural local), revisitamos o mesmo momento, com o intuito de verificar outras 
formas de construcao da imagem da cidade que se modificava. Por fim, recorremos a outras 
formas de interpretacoes construidas sobre este mesmo recorte temporal, desta vez, porem, na 
perspectiva das narrativas historicas desenvolvidas pelo periodismo local nao so durante o 
periodo analisado, mas tambem posteriormente, no decorrer da decada de 1970. Com isso 
visamos demonstrar como o processo de modernizacao se tornou nao so um evento historico 
vivenciado localmente, mas tambem uma forma de articulacao e compreensao da propria 
experiencia temporal.

O progresso como categoria de entendimento histórico: um estudo de caso sobre a modernização da cidade de Anápolis-GO (1930-1957)

Modelagem Multivariada para previsão de demanda de gasolina e óleo diesel no Brasil.

O inhame e reconhecidamente como uma das hortalicas mais cultivada no Brasil, em sistema de agricultura familiar, desempenhando importante papel no Nordeste do Brasil. Este trabalho teve por objetivo realizar um cadastramento fitossociologico das especies de plantas espontâneas encontradas em area de cultivo do inhame. O experimento foi conduzido no Distrito de Tabuleiro, Municipio de Bananeiras, microrregiao do Brejo paraibano. O levantamento fitossociologico foi realizado em uma area que totaliza 325m 2 . A amostragem da comunidade foi realizada no mes de Agosto de 2011. Na caracterizacao da comunidade foi utilizado o metodo do quadrado inventario. A partir da identificacao das especies, foi possivel realizar a classificacao em familia, genero, nome cientifico e comum, quando associada a contagem pode-se avaliar a Densidade relativa: DeR (%) Frequencia absoluta: FA Frequencia relativa: FR (%) Dominância relativa: DoR (%) Indice do valor de importância: IVI (%) Importância relativa: IR (%). Na area de producao estudada foram identificadas 11 especies, distribuidas em 10 generos e oito familias. As especies que apresentaram as maiores representatividades fitossociologicas foram Digitaria horizontalis, Croton lobatus e Richardia grandiflora.

Levantamento fitossociológico de plantas espontâneas na cultura do inhame sob produção orgânica

O estudo presente busca expor duas representacoes de mulher atraves da Literatura. Considerando a poesia, uma forma de experiencia de vida, um autoconhecer-se, evocamos Octavio Paz para dialogar com seus conceitos, pois este apresenta o espaco como um encontro do sujeito historico com o desejo da imaginacao, do sonho. E as duas poetisas que serao trabalhadas neste artigo, sao sujeitos que transformam o poema em um tecido vivo, cheio de historia e vida, uma historia que corrompe a do dominador e apresenta outra, a dos marginalizados. Atraves destas reflexoes sobre poesia e Historia, supomos que as autoras Conceicao Evaristo, brasileira, e Noemia de Sousa, mocambicana, construiram uma Literatura em que a mulher e colocada em evidencia, ou seja, e trabalhada, e dada a voz a ela. Duas mulheres que refletiram sobre os problemas da escravidao e do preconceito: questoes de raca e de genero. Sao poesias que apontam para uma realidade estampada em todos os lugares: a desigualdade de genero. Por mais que se tenha passado por um processo de valorizacao da mulher, ainda ha ideias de que a mulher pode dancar, cozinhar, cantar, mas escrever, nem pensar, lembrando Conceicao Evaristo. Noemia constroi sua poesia como um espaco para ecoar as vozes de uma identidade que foi por muito tempo sufocada, deformada e aniquilada. Em suas poesias, ressurge a mulher negra guerreira, lutadora, cheia de cultura e vida, e redesenhado um sujeito que foi apagado pela Historia e pela sociedade dominante. Atraves de autores como Stuart Hall, Michel Foucault, Octavio Paz e Homi Bhabha, tentaremos visualizar como Conceicao Evaristo e Noemia de Sousa representaram a mulher negra em suas poesias, perpassando pela Historia, colonizacao e identidade cultural.

REPRESENTAÇÕES IDENTITÁRIAS DA MULHER NEGRA NO BRASIL E EM MOÇAMBIQUE

Este artigo apresenta uma sintese de um Trabalho de Conclusao de Curso (TCC) de Graduacao em Musica, com o objetivo de realizar um mapeamento e analise das discussoes das revistas da ABEM e da ANPPOM no periodo de 2004 a 2014 sobre o uso das Tecnologias da Informacao e Comunicacao (TIC) na area de musica. Foi utilizada como metodologia a revisao bibliografica (LIMA; MIOTO, 2007) que implica na organizacao dos procedimentos de busca, visando solucionar um objeto de estudo proposto. Assim, foram sistematizados os dados para analise. A pesquisa mostrou que as discussoes das revistas apresentaram diversificadas proposicoes tematicas, aplicabilidade e uso das mais variadas ferramentas tecnologicas. Portanto, conclui-se que o estudo aqui apresentado fomenta reflexoes sobre esta diversidade de tematicas abordadas no âmbito da musica, e pontualmente, da educacao musical.

Música e tecnologia: discussões das revistas da ABEM e da ANPPOM no período de 2004-2014

O Projeto Arte na Escola foi um projeto de extensao executado no trienio 2011-2013 com fomento da Coordenacao de Aperfeicoamento de Pessoal Docente, no Programa Novos Talentos. Ele consistiu na oferta de oficinas de artesanato, danca e musica em tempo extracurricular para alunos do Câmpus Machado e escolas vizinhas. O objetivo foi levar cultura e lazer para a vivencia escolar, principalmente dos alunos internos no câmpus, contribuindo para a formacao integral dos adolescentes como cidadaos criativos.  A analise do projeto mostrou os resultados positivos nao so para os alunos mas tambem para a formacao de uma visao integrada do tecnico e cidadao no câmpus.

Ação emergencial para delimitação de áreas em alto e muito alto risco a enchentes, inundações e movimentos de massa: Lábrea, AM

Monografia (graduacao)—Universidade de Brasilia, Faculdade de Economia Administracao e Contabilidade, Departamento de Economia, 2013.

FU URN NAS S NA A R REGIÃO O S SUL L D DO O E ES ST TA AD DO O DE E M MAT TO O G GR RO OS SS SO

SILVA, J. A. Avaliacao Escolar: O que Reflete a Prova. 2014. 39f. Trabalho de Conclusao de Curso (Graduacao em Pedagogia PARFOR EAD)- Universidade Estadual da Paraiba, Monteiro, 2014.

Ação emergencial para delimitação de áreas em alto e muito alto risco a enchentes, inundações e movimentos de massa: Pauini, AM

As mudancas no cenario competitivo mundial tem dificultado a sobrevivencia das empresas, onde a previsao do futuro se torna inevitavel na atividade de planejamento. Desta forma, o estudo do futuro e a construcao de cenarios prospectivos estao diretamente relacionados a formulacao das estrategias organizacionais. Os estudos de cenarios nao visam adivinhar o que vai acontecer no futuro, e sim entender qual e o melhor caminho a ser tomado, qualificando a tomada de decisao. No caso dos arranjos produtivos locais, mais precisamente as redes de cooperacao, a identificacao dos eventos preliminares e a construcao de cenarios prospectivos sao os norteadores das estrategias competitivas e dos mecanismos de coordenacao das estrategias coletivas. Este estudo teve como objetivo identificar os futuros mais provaveis e os principais eventos responsaveis pela sua conducao, como forma de subsidiar a construcao estrategica da Associacao de Produtores Rurais dos Campos de Cima da Serra (APROCCIMA) para um horizonte temporal de cinco anos. O metodo utilizado foi uma pesquisa aplicada, exploratoria descritiva, e, quanto a abordagem do problema, a pesquisa pode ser classificada como qualitativa-quantitativa. Os dados foram obtidos junto aos produtores da rede APROCCIMA e especialistas com notorio saber na area. Foi adotado o metodo Grumbach na construcao dos cenarios e foi utilizado o software PUMA® para a modelagem. Os resultados obtidos com a metodologia empregada evidenciaram que a qualidade genetica do rebanho, a capacidade de trabalhar em grupo e de forma articulada, aumento da produtividade com uso da tecnologia e a melhoria da qualidade do produto final sao fatores indicam o cenario mais provavel para o intersticio temporal estipulado.

Cenários prospectivos em redes de cooperação : o caso da Associação dos Produtores Rurais dos Campos de Cima da Serra - APROCCIMA

Resumo A aprendizagem possui importância para os professores, pois influi diretamente no modo de trabalho (Barreto, 1986) e por percebem a existência de preferências estratégicas de aprendizagem dos seus alunos. Conhecer o estilo de aprendizagem pode prover estratégias pedagógicas ou métodos de ensino eficazes, facilitando a aprendizagem e o desenvolvimento de novas habilidades. O objetivo da pesquisa foi identificar o perfil e estilo de aprendizagem em 140 estudantes de Graduação em Administração em uma Instituição de Ensino Superior localizado na Serra Gaúcha, no Estado do Rio Grande do Sul. Para atingir o objetivo da pesquisa, utilizou-se o instrumento denominado ILS (Index of Learning Styles) de Felder e Soloman (1991) para identificação dos estilos de aprendizagem propostos por FelderSilverman (1988) como sendo uma pesquisa com abordagem quantitativa, com objetivo exploratório e descritivo. Os resultados identificaram que 55% dos estudantes de Administração possuem idade entre 18 e 25 anos, com predominância de estudantes do gênero masculino, no qual representam 68,6% do total pesquisado. Quanto ao estilo de aprendizagem, os estudantes de Graduação em Administração são em sua maioria classificados nas dimensões: ativos, verbais e globais, tendo uma preferência moderada por estas dimensões.

ESTILO DE APRENDIZAGEM ACADÊMICA: UMA ANÁLISE COM ESTUDANTES DE ADMINISTRAÇÃO DO ENSINO SUPERIOR

ABSTRACT. Fernandes M.F.T.S., Cavalcanti E.F.T.S.F., Silva J.G., Albuquerque P.P.F. & Moura A.P.B.L. [Search of sodium sulfite in ground beef sold in the city of Recife, Pernambuco, Brazil.] Pesquisa de sulfito de sodio em amostras de carne moida comercializadas na cidade do Recife, Pernambuco, Brasil. Revista Brasileira de Medicina Veterinaria, 36(1):42-44, 2014. Departamento de Medicina Veterinaria, Universidade Federal Rural de Pernambuco, Rua Dom Manuel de Medeiros s/n, Dois Irmaos, Recife, PE 52171-900, Brasil. E-mail: marcelasamico@hotmail.com The sodium sulfite is a prohibited additive from being used in fresh meat commercialized in butchers and supermarkets, since its use may mask incipient state of putrefaction and cause damage or adverse health effects. The objective was to identify the addition of sodium sulfite in samples of ground beef, purchased in public markets and supermarket chains in the city of Recife – PE. It was analyzed 32 ground beef samples in the Laboratorio de Inspecao de Carne e Saude Publica (LICASP), located at the Universidade Federal Rural de Pernambuco (UFRPE) in the Department of Veterinary Medicine, following the protocol of the Instituto Adolfo Lutz (2005). In all samples, was not detected the presence of sodium sulfite, indicating that the material analyzed met the standards established by Brazilian legislation.

PESQUISA DE SULFITO DE SÓDIO EM AMOSTRAS DE CARNE MOÍDACOMERCIALIZADAS NA CIDADE DO RECIFE, PERNAMBUCO, BRASIL

The use of silage sugar cane has a benefit that has aroused the interest of producers and researchers. However, some limitations mainly related to its fermentation pattern, has become the challenge for forage use. To evaluate the inclusion of manicoba on silage fermentation characteristics of sugar cane, it was prepared an experiment in a completely randomized design with four treatments (inclusion levels: 0, 20, 30 and 40% ) and six replications. After 90 days of the silos closing o were resoluted losses in the form of gases, total loss and recovery of dry matter production and effluent. The silos were opened and then obtained the aqueous extract of the silages, determined levels of organic acids (acetic, butyric, lactic and propionic), ethanol, NH3-N, NT and pH values. As the level of inclusion of manicoba was increased, it was observed a 67% reduction in the losses of gases and 23.3% in the effluent production, while the ethanol concentration was reduced from 25.6 to 2.7%. The maximum concentration of lactic acid (2.4%), acetic acid (2.2%) and propionic (0.03%) were found in silages containing 40% of manicoba, while for butyric acid it decreased linearly. In all silages the pH found was adequate to silage (range 3.4 to 3.7). The highest level of manicoba inclusion in sugar cane silages improves the fermentation of the silage and reduces fermentation losses.

Características fermentativas na ensilagem de cana-de-açúcar com maniçoba

Aiming to evaluate the growth and productive capacity of different sesame genotypes, submitted to irrigation depths, an experiment was conducted at the Experimental Station of Embrapa, in Barbalha, CE. Five depths of irrigation and three genotypes of sesame were studied. These combined factors resulted in 15 treatments. The experiment was arranged in strips with 4 replications, resulting in 60 experimental units. Destructive growth analysis was performed, with samplings at 15 days interval to estimate leaf area and biomass. The growth variables were studied in 10 plants in each plot. At the end of the cycle, the production and its components were evaluated. The highest values of yield components were obtained with the water depth of 1026.50 mm. The growth of genotypes was affected by different irrigation depths, with higher growth of BRS Seda, in the higher availability of water, and in the lowest availability the genotype 27561-ELAG09 was the best. The highest levels of oil and protein were obtained in higher water availability.

Crescimento e produção de genótipos de gergelim em função de lâminas de irrigação

RESUMO: No Estado democratico de Direito, a Administracao Publica cumpre a funcao de atender os interesses da coletividade. A busca pela consecucao do bem-estar comum resulta na luta juridico-politica do Estado pela democratizacao. O ordenamento juridico brasileiro dispoe atraves do texto da Carta Magna os principios norteadores da Administracao Publica. Para cumprir sua funcao o Estado desenvolve atividades de cooperacao com empresas do Sistema S, qual seja, empresas que prestam Servico Social Autonomo. O objetivo do presente estudo sera analisar a possivel subordinacao do Servico Social Autonomo aos ditames do Tribunal de Constas da Uniao embasado nos autores Hely Lopes Meireles, Maria Sylvia Zanella Di Prieto, Jose dos Santos Carvalho Filho, Nivea Carolina de Holanda Seresuela, Leila Cuellar, dentre outros, com o qual se buscou uma revisao de literatura a partir da leitura de fontes cientificas em livros, artigos online, artigos impressos, textos, sites da internet, bibliotecas virtuais, entre outros que tratam do tema. Espera-se que este estudo venha contribuir e melhorar a discussao sobre questoes controvertidas e analisar a vinculacao das Entidades do Sistema “S” as norma do Tribunal de Contas da Uniao

Os serviços sociais autônomos e a dúvida sobre a subordinação aos ditames do TCU.

The objective of this study was to evaluate the eff ects of cultivation of watermelon in different soil management systems on density and diversity of soil invertebra te macrofauna. In each system, 10 soil samples were collected at a depth of 0-20 cm for further evaluation of the chem ical characteristics. The macrofauna was collected by pitfall traps for invertebrates, two samples per study area. Macr ofauna data (x) were transformed into natural logar ithm (ln) x +1, and subjected to ecological analysis between the sy stems evaluated. Taxonomic groups identified in des cending order of density are: Hymenoptera, Coleoptera, Araneae, Diptera, Orthopte ra, Chilopoda, Diplopoda, Hemiptera, Isoptera, Dermaptera and Blattodae . The results of canonical correspondence analysis revealed that the chemical attributes were not considered sufficient to explain the variation in macrofauna composition, however, the organic system increased the content of soil nutrients in relation to other syst ems, as well as most abundance of invertebrates sampled.

Associação da diversidade de artrópodes com características do solo em diferentes plantios de melancia

O Programa de Pos-Graduacao em Design da Faculdade de Arquitetura, Artes e Comunicacao da UNESP, campus de Bauru, tem como nucleo de pesquisa o Desenho de Produto e suas relacoes entre o saber cientifico, tecnologico e o ensino. Tem como principio a reflexao sobre os processos envolvidos na construcao dos conhecimentos cientificos e tecnologicos, que conduzam para a producao de um corpus de conhecimentos filosoficos, cientificos, e tecnologicos, assim como os pedagogicos. Destina-se a formacao de docentes, pesquisadores e demais recursos humanos especializados na area, capacitando-os a: exercer acao didatica que esteja fundamentada em conhecimentos filosoficos, historicos, sociologicos, psicologicos, pedagogicos e tecnologicos, de maneira a desenvolver projetos coletivos que permitam estruturar conteudos, experiencias e curriculos para o ensino do Design, gerando condicoes institucionais que estimulem a disseminacao da cultura cientifica e tecnologica nesta area do conhecimento; vincular o Design a realidade e as necessidades da comunidade local e regional, criando caminhos que estimulem a democratizacao do conhecimento cientifico; e evidenciar as relacoes entre o trinomio ciencia/tecnologia/educacao e a qualidade de vida, bem como, possibilitar a compreensao das decisoes sobre projetos e estrategias projetuais que sao praticas adotadas no cotidiano do Design.

A pós-graduação em Design no interior paulista – o Programa de Pós-graduação da UNESP – campus de Bauru

Este trabalho teve como tematica o estudo sobre “Cultura e Mudancas Organizacionais: Como as organizacoes publicas mudam”, o que buscou conhecer a natureza tecnico-instrumental das organizacoes publicas em seu ambiente, tendo em vista sua cultura, suas resistencias e suas mudancas de ordem comportamental e funcional. Para isso, foram realizadas pesquisas e estudos exploratorios, com os dados coletados a partir de pesquisa bibliografica, o que levou a conclusao, sem o esgotamento do assunto, sobre como as organizacoes se gestam enquanto seus processos burocratico, de “jeitinho” e em sua estrutura de poder e inter-relacoes. O problema de pesquisa, para tal, se posta como um delimitador de questoes que buscam atingir seu objetivo geral, o qual compreende as especificidades de como as mudancas organizacionais dos orgaos e setores publicos vem se aculturando diante de problematicas como de resistencia, de implementacao, adequacao e contextualizacao, o que deve ser compreendido pela otica das mudancas globais e localizadas. Ainda a abordagem da pesquisa teve carater qualitativo, uma vez que buscou conhecer e desvelar, de forma aprofundada, dinâmica e holistica, como se constitui e se contextualiza a cultura e as mudancas nas e das organizacoes publicas, perfazendo tanto as definicoes mais comuns como as questoes de perspectivas fundadora e adaptativa, ja que a cultura organizacional se apresenta em muitas e varias formas de organizacoes coletivas, sejam elas institucionalizadas ou nao, formais e informais, as quais podem ser caracterizadas como estruturas rigidas e conservadoras, ou mesmo flexiveis e suscetiveis as mudancas e inovacoes.

Cultura e mudanças organizacionais: como as organizações públicas mudam

A questao ambiental nos ultimos anos, tornou-se uma das grandes preocupacoes da humanidade, tanto em relacao a extracao de insumos do ambiente natural, quanto em relacao aos efeitos dos modelos de producao e consumo baseados no aumento da demanda por produtos. Diante de tal, as empresas comecam a reconhecer a importância da preservacao ambiental e do uso racional dos recursos naturais, tendo as mesmas, o dever legal de reavaliar seus procedimentos operacionais a fim de reduzir os impactos ambientais negativos por elas causados. A gestao ambiental, surge como sendo um modelo administrativo voltado a reducao de impactos ambientais e constante busca pela sustentabilidade. No mote, o presente artigo tem por finalidade buscar conhecimento bibliografico, atraves de autores que versam sobre o assunto, abordando e analisando a importância da ISO 14000, norma que estabelece metas e diretrizes e certifica o compromisso das empresas com a questao ambiental.

O SISTEMA DE GESTÃO AMBIENTAL BASEADO NA ISO 14000: IMPORTÂNCIA DO INSTRUMENTO NO CAMINHO DA SUSTENTABILIDADE AMBIENTAL

Normal 0 21 false false false MicrosoftInternetExplorer4 O artigo faz uma analise das concepcoes de docentes de Historia da escolarizacao basica acerca das identidades negras. A perspectiva utilizada foi inspirada em Bauman (2001; 2007) e na vertente pos-estruturalista dos estudos culturais e pos-coloniais. A analise baseou-se na interpretacao de entrevistas com oito docentes de Historia atuantes em escolas publicas e privadas da cidade de Campo Grande/MS. Percebemos nessa leitura que as identidades negras, apesar de escaparem das identificacoes dos professores e irem alem, sao tambem provisoriamente solidificadas para fixacao de sentidos, indispensaveis para posicionamento politico e sociocultural. Os entrevistados tambem veem as dinâmicas complexas e constantes das diferenciacoes que tornam as identidades negras liquidas, apesar de seu empenho em identifica-las e defini-las.

DE SÓLIDAS PARA LÍQUIDAS, DE LÍQUIDAS PARA SÓLIDAS: AS CONCEPÇÕES DE PROFESSORES DE HISTÓRIA SOBRE OS PROCESSOS DE CONSTRUÇÃO DAS IDENTIDADES NEGRAS

This article is part of preliminaries research “The Integration of the black population in the city of Marechal Cândido Rondon-PR: Social Movement in the construction of Identity”. This study develops along the line of research Territory, History and Memory in the Master’s program at Society, Culture and Borders of UNIOESTE – Campus Foz do Iguacu. It objective is to analyze the Black Movement in the city of Marechal Cândido Rondon-PR, comprising the period 2008-2013. The research aims to answer by means of the analysis of the conditions of production, expressed in its manifestations, whether they allow to understand the construction of black identity.

MOVIMENTO NEGRO EM MARECHAL CÂNDIDO RONDON-PR: AS CONDIÇÕES DE PRODUÇÃO NA FORMAÇÃO DA IDENTIDADE

SILVA, J. D. da. Esquecida ou negligenciada: o arquivo pessoal de Anayde Beiriz. 2014. 48f. Trabalho de Conclusao de Curso (Graduacao em Arquivologia) - Universidade Estadual da Paraiba, Joao Pessoa, 2014. [Monografia]

The objective of this study was to evaluate different inclusion levels (0, 20, 40 and 60%) of old man saltbush in the fermentation dynamics of sugarcane silages. The experiment was carried out as a completely randomized design with four treatments and six replicates. After 90 days, with the opening of the silos, the levels of water soluble carbohydrates, ethanol, organic acids (lactic, acetic, propionic, butyric acid), crude protein (CP), mineral matter (MM), dry matter (DM), neutral detergent fiber ash free (NDFa), pH and buffer capacity were determined; and, the losses by gas, effluent and total of dry mater, density and dry matter recovery were estimated. Increasing levels of saltbush propitiated reduction in losses: by effluent and total dry matter, it also increased the concentration and recovery. The silages showed pH suitable for conservation (≤3.70) and mineral concentration increased. The ethanol concentrations were influenced (P<0.05) by the increase of saltbush, where reduction of 51.84% was observed, with 40% saltbush in sugarcane silage. The addition of saltbush reduces dry matter losses and ethanol production and, improves the quality of sugarcane silage.

Características fermentativas de silagens de cana-de-açúcar com erva-sal

As hepatites virais tem importância verificada nao so pelo grande numero de pacientes infectados, mas pela gravidade de suas complicacoes nas formas agudas e cronicas. Conflitos, acidentes ocasionais, catastrofes e combate ao terrorismo sao algumas das situacoes em que os militares das Forcas Armadas podem participar e serem expostos as enfermidades. Nesses casos as condicoes de contagio das hepatites sao exacerbadas em face a piora das condicoes sociais e higienicas locais e eventuais necessidades de hemotransfusoes emergenciais, em massa, decorrentes de traumas. Hepatites virais tambem contribuem para elevar os custos na area de saude atraves dos gastos vinculados ao seu tratamento prolongado e dispendioso, afastamento das atividades laborativas por longos periodos e consequente perda de produtividade. Mediante as adversidades, buscam-se no âmbito da Marinha do Brasil medidas para restringir os efeitos dessas infeccoes. Ha necessidade de solucionar esse desafio, atuando de forma preventiva, pois existe cobertura vacinal para hepatites A e B e entende-se que o diagnostico precoce das hepatites B e C permite o tratamento especifico no momento oportuno.

Hepatites virais: prevenção e diagnóstico precoce como política pública de saúde para militares da ativa na Marinha do Brasil

Universidade Estadual Paulista (UNESP), Faculdade de Engenharia (FEIS), Departamento de Fisica e Quimica, Ilha Solteira, SP, Brasil

Prática de mediação da aprendizagem com uma avaliação formativa na escola pública

William Douglas, doutor em direito (UFF), e juiz federal e professor universitario, com mais de meio milhao de livros vendidos e ja proferiu centenas e centenas de palestras. Nataniel Gomes, doutor em linguistica (UFRJ) e professor universitario, coordenador adjunto do curso de Letras da UEMS, especialista em linguas indigenas, membro do CiFEFiL, editor e autor de inumeros livros e artigos.

As dificuldades de adequacao, aplicacao e manutencao das estrategias de controle nos locais onde a malaria e endemica contribuem, em grande parte, para que a doenca seja considerada o maior flagelo da humanidade. Neste contexto, destaca-se o amplo desenvolvimento de resistencia dos plasmodios aos mais variados compostos que foram ou que ainda sao utilizados na terapeutica antimalarica, o que faz do tratamento efetivo dos casos um grande desafio a cada ano. Diante disso, torna-se inquestionavel a necessidade da descoberta de novas moleculas que possam, no futuro proximo, estar disponiveis para inclusao em medicamentos destinados a cura efetiva da infeccao. Este estudo investigou a atividade antiplasmodial de 10 moleculas sinteticas derivadas de quinolinas em cultura de P. falciparum, bem como sua atividade citotoxica em celulas HeLa e mononucleares do sangue periferico. Das 10 moleculas, 5 estao conjugadas a sulfonamidas enquanto as demais possuem em sua estrutura um grupo hidrazina. Independentemente do grupamento farmacoforico integrado ao anel quinolinico, nenhuma molecula foi citotoxica para celulas HeLa ou linfocito humano em baixas concentracoes. No que se refere a atividade antimalarica, 60% das moleculas foram altamente ativas contra P. falciparum (CI50 variando de 50µg/mL). Ao analisarmos o indice de seletividade das moleculas, somente dois compostos nao foram seletivos para o parasito (RMP103 e RMP107). Dentre as moleculas mais seletivas destacaram-se aquelas conjugadas ao grupo hidrazina, sobretudo RMP105 que foi >1800 vezes mais seletiva para plasmodio quando comparada a droga de referencia. Portanto, por apresentarem alta atividade antimalarica e baixa toxicidade em celulas humanas, com elevado indice de seletividade para os plasmodios, as moleculas testadas nesse estudo podem ser consideradas boas alternativas para se tornarem medicamentos antimalaricos e auxiliarem de maneira eficaz no combate a doenca.

Avaliação da ação antimalárica de compostos sintéticos derivados de quinolina em cultura de Plasmodium falciparum

The objective of this work was to evaluate the response of irrigated 'Prata Ana' banana (AAB) to soil application of phosphorus, in four production cycles. The experiment was carried out in the semiarid region of the north of the state of Minas Gerais, Brazil, in a clayey Oxisol, with very low available P (4.6 mg dm-3, Mehlich). A randomized complete block design was used, in a 5x4 factorial arrangement, with five doses of triple superphosphate (0, 50, 100, 200, and 300 g P2O5 per plant per year), four production cycles, and four replicates. In the first cycle, the soil application of P increased plant height, pseudostem diameter, weight and number of fruits per bunch of banana; however, banana plants did not respond to P application in the second, third, and fourth cycles. 'Prata Ana' banana, even when grown in soil with low P content, responds to the application of this nutrient only in the first production cycle.

Produção da bananeira 'Prata Anã' em função da aplicação de adubo fosfatado, em quatro ciclos

O uso de bioindicadores apresenta solucoes para problemas existentes na area de medicao de poluentes, conseguindo quantificar concentracoes muito pequenas destes. Por meio de alteracoes nesses bioindicadores ou pelo processo de bioacumulacao, pode-se usar os organismos vivos presentes no local para ajudar no monitoramento do ambiente. Uma solucao para diminuir altos custos para a identificacao desses bioindicadores e o uso de geotecnologias por meio de imagens de satelites. Uma vez que os padroes espectrais dessas imagens sejam associados as especies trabalhadas, acredita-se que sera possivel fazer um levantamento dessas populacoes vegetais com o uso de Sensoriamento Remoto (SR) e Sistema de Informacoes Geograficas (SIG). A area de estudo e o Parque Nacional da Restinga da Jurubatiba (RJ), reconhecido como reserva da biosfera pela UNESCO. E o primeiro parque dedicado a protecao da restinga, um dos ecossistemas mais impactados e pouco protegido pelo Sistema Nacional de Unidades de Conservacao (SNUC). Essa area se encontra sobre pressao do crescimento urbano e industrial das cidades vizinhas. Pretende-se com o resultado contribuir para o monitoramento da area, otimizando custos, e garantindo uma maior eficiencia e assim diminuir impactos ao ambiente e ao meio antropico. O objetivo da pesquisa e avaliar o uso do SR para identificacao de bioindicadores na referida regiao, por meio de imagens de satelites. A metodologia esta baseada no levantamento bibliografico, trabalho de campo, para coleta de dados, classificacoes digitais automaticas, supervisionadas e nao supervisionadas, da imagem de satelite, processos de edicao em tela dos mapas tematicos etc. Os aplicativos utilizados sao: IDRISI Taiga e ArcGis 10.1. Apos levantamento parcial da bibliografia sobre o tema, foi possivel detectar e avaliar a carencia de pesquisa sobre a tematica. Com o aumento da exploracao do petroleo em alto-mar e o impacto da industria do petroleo nas regioes produtoras se faz urgente e necessario a identificacao e o mapeamento de bioindicadores, como um dos recursos para mitigar impactos ambientais. Os bioindicadores podem ajudar na mitigacao desses impactos. O uso de geotecnologias associadas ao SR e SIG, pode agilizar o processo de identificacao e mapeamento destes bioindicadores. A validacao da metodologia para identificacao desses indicadores por imagens de satelites pode colaborar para proceder com os mapeamentos dessas especies biorremediaveis.

UTILIZAÇÃO DO SENSORIAMENTO REMOTO PARA MAPEAMENTO DE BIOINDICADORES: ESTUDO DE CASO NA RESTINGA DE JURUBATIBA – RJ

Ocupações Rurais Não-Agrícolas (ORNAs) Como Estratégia de Desenvolvimento Local: o pólo de confecção do município de Ceará-Mirim no Rio Grande do Norte

O texto traz uma leitura das representacoes de identidades negras por docentes de Historia da escolarizacao basica. Foram realizadas entrevistas semiestruturadas com oito professores que atuam em diferentes fases da escolarizacao (Ensino Fundamental e Ensino Medio) em escolas publicas e privadas de Campo Grande, MS. As entrevistas foram interpretadas com base em um conjunto de autores que argumentam que as identidades sao construcoes culturais e historicas, portanto, nao sao fixas e essenciais. Pela analise, foi possivel ver, nas representacoes dos professores, tensoes entre a perspectiva fixa, essencialista,  a-historica e a nao essencialista, historica, cultural e dinâmica da identidade negra. Palavras-chave: Identidade negra. Professores de Historia. Escolarizacao basica.

UMA LEITURA DAS REPRESENTAÇÕES DE IDENTIDADES NEGRAS POR DOCENTES DE HISTÓRIA DA ESCOLARIZAÇÃO BÁSICA

This thesis discusses the process of training teachers for the early years of Elementary School and aims to analyze the process of training students in the Pedagogy Major and its contribution to knowledge production, the construction of identity in teaching and the resizing of pedagogical practices. In research conducted under the parameters of a qualitative boarding, the study involved the participation of ten (10) graduated students, already working as teachers of basic education in Pedagogy of Centro de Formação de Professores da Universidade Federal de Campina Grande e do Centro de Educação da Universidade Federal da Paraíba, in addition to the coordinators of the two majors. Data collection was performed by the procedures of using semi-structured interviews since this technique allows the interviewee help in the investigation process with freedom and spontaneity without losing objectivity. The analysis was done by comparing the information and / or supporting the speech of the subjects interviewed with the theoretical framework adopted. The techniques of content analysis, defined by Laurence Bardin, were used for the interviews. The results shown in the course of the analysis of the speeches investigation showed that the training process experienced in Pedagogy majors in CFP and CE allows the acquisition of diverse knowledge and professional skills development and abilities required for the teaching practice. However, it has gaps that need to be met in order to promote the construction of teacher identity and the redefinition of their educational practices. It also shows that, without ignoring the importance and necessity of a solid theoretical foundation of professional education, one can argue, that in addition, only a systematic reflection and continuous production processes/knowledge mobilization in interface with the concrete conditions of teaching work exercise, makes it possible to explain the challenges and possibilities for resizing of pedagogical practices.

Formação, produção de saberes e da identidade docente: desafios e possibilidades de redimensionamento das práticas pedagógicas

Resistência de genótipos de soja Glycine max (L.) a Piezodorus guildinii (Westwood)(Hemiptera: Pentatomidae)

Estudo da hibridação e configuração de identidades culturais de imigrantes japoneses em Pirianito - (Uraí-Pr)

PRODUÇÃO E DEMANDA EM AGRONEGÓCIOS: UMA ANÁLISE DO MERCADO DA SOJA E DE PROTEÍNA ANIMAL

A determinacao do conteudo relativo de agua (CRA) e bastante empregada em laboratorios de pesquisa e oferece uma nocao do nivel de hidratacao das plantas. O presente trabalho descreve a elaboracao de uma aula pratica para alunos da disciplina de fisiologia vegetal com o objetivo de determinar o CRA em plantas coletadas no campus do curso de agronomia da UFCA. A elaboracao da aula pratica foi desenvolvida no laboratorio de Biologia da Universidade Federal do Cariri, Campus – Crato - CE, utilizando-se plantas adultas de hibiscus ( Hibiscus sabdariffa L . ) e de mandioca ( Manihot esculenta Crantz) , cultivadas sob sequeiro . As folhas retiradas de hibicus as 8:00 h encontravam-se com CRA de 47,3%, e quando coletados no horario de 13:00 h, considerado o horario mais quente do dia, o CRA foi reduzido para aproximadamente 35,6%. Ja para a cultura da mandioca as folhas retiradas do campo no horario de 8:00 h encontravam-se com um CRA bem maior do que a cultura anterior de 93,3%, e no horario de 13:00 h o CRA foi reduzido  para 83,3%. Conclui-se que, a determinacao do CRA pode ser utilizada como pratica para os estudantes de Agronomia da disciplina de fisiologia vegetal, por ser de facil execucao e nao requerem de equipamentos sofisticados.

ELABORAÇÃO DE UMA PRÁTICA DA DISCIPLINA DE FISIOLOGIA VEGETAL PARA DISCENTES DO CURSO DE AGRONOMIA

O presente artigo faz uma analise dos direitos fundamentais perpassando pelos direitos infanto-juvenis inseridos na CRFB/1988, procurando vincula-los ao principio republicano e federativo que tem como premissa dar guarida a protecao integral dos direitos das criancas e adolescente. Explicita conceituacao basilar do principio republicano procurando estabelecer enlaces entre seu significado e os direitos fundamentais. Identifica o federalismo como instrumento capaz de propiciar a criacao e implementacao de norma juridica e politicas publicas como referencia para a concretude dos direitos infanto-juvenis, pretendendo, portanto afirmar que os entes federativos possuem responsabilidade e obrigatoriedade juridica quanto a possibilidade de eficacia da doutrina da protecao integral que deve ser satisfeita a crianca e ao adolescente.

O PRINCÍPIO REPUBLICANO E FEDERATIVO NA EFETIVAÇÃO DOS DIREITOS INFANTO-JUVENIS NO BRASIL

Um novo metodo para deteccao e remocao de ruido impulsivo, baseado na juncao combinada de duas Redes Neurais Artificiais (RNA), e proposto. O algoritmo de treinamento das RNA baseia-se na tecnica da retropropagacao do erro (algoritmo backpropagation). A primeira RNA e utilizada para deteccao do ruido, conhecido como sal e pimenta e a segunda RNA e utilizada para remocao deste ruido. A tecnica consiste na deteccao do pixel ruidoso e substituicao do mesmo por um valor estimado pela RNA. Os resultados obtidos sao comparados com resultados da literatura para validacao da tecnica proposta.

Redes neurais aplicadas na redução de ruído impulsivo de imagens digitais

A Metapsicologia Freudiana e seus efeitos na desconstrução da Filosofia do Sujeito

Este trabalho tem como objetivo analisar e investigar as dificuldades dos alunos na transposicao dos enunciados de problemas envolvendo Equacoes do 1o grau para a Linguagem Algebrica. Apresenta embasamento teorico nos estudos apresentados por autores como Ponte (2005), Hoffmann (1992), entre outros estudiosos. Encontra-se tambem fundamentado nos PCN (BRASIL, 1998). Como escolha metodologica, realizamos pesquisa de campo na qual coletamos dados dos alunos do setimo ano do Ensino Fundamental II, de uma escola municipal, da cidade de Pianco, no estado da Paraiba. Atraves da observacao de duas aulas analisamos a abordagem do professor sobre o tema proposto, bem como as dificuldades encontradas pelos alunos na transposicao da linguagem natural para a linguagem algebrica, atraves da proposta de alguns problemas. A maioria respondeu com os dados presentes nos enunciados das proprias questoes, mas de forma desconexa; percebemos uma forte tendencia ao fazer uma associacao com a ordem das palavras, da esquerda para a direita e os alunos mostravam muitas vezes nao distinguir qual o papel que as letras estavam assumindo em determinadas situacoes. O estudo em questao contribuiu para refletirmos sobre as dificuldades que os estudantes tinham em entender os enunciados e assim fazer a transposicao para a forma algebrica, exigindo do professor uma postura participativa nesse processo.

As dificuldades dos estudantes na transposição de informações dos enunciados de problemas envolvendo equações do 1º grau para linguagem algébrica.

Este estudo realizado em uma industria da Serra Gaucha, a qual fabrica elementos de friccao para a linha leve e pesada de veiculos teve como objetivo apresentar uma sintese do processo de logistica reversa da empresa, apresentando algumas das vantagens competitivas geradas por este processo para a empresa. A pesquisa foi operacionalizada atraves de um estudo de caso, onde a coleta de da-dos foi efetivada a partir de entrevista realizada com dois gestores da empresa a partir de um roteiro de perguntas semiestruturado e observacao in loco. A entrevista possibilitou a identificacao da aplicacao dos conceitos relativos a logistica reversa e das respectivas vantagens competitivas adqui-ridas. Ja a observacao auxiliou na identificacao das dificuldades enfrentadas durante a implantacao do processo de logistica reversa na empresa Alfa S. A. e em como esse trabalho foi incorporado na cultura da empresa, contribuindo para a criacao de valor nos produtos e na imagem, bem como no seu potencial competitivo diante do mercado e dos seus concorrentes.

Logística Reversa na fabricação de elementos de fricção em indústria da Serra Gaúcha

O ensaio discute uma proposta para o trabalho com atividades interdisciplinares envolvendo a Fisica e a Arte das Revistas de Historias em Quadrinhos – HQs/Gibis, revista essa criada e desenvolvida pelo aluno ZUMBA e  Dr. Zanoni. Alem da discussao de aspectos historicos epistemologicos e culturais, fazendo uma ponte entre as duas culturas, e uma critica a educacao, considerada, segundo Paulo Freire, educacao bancaria, alienadora, adotada no Pais, por uma grande parte dos professores. O ensaio ressalta a importância da fisica na construcao de um dialogo inteligente com o mundo. Essa Fisica deve contemplar conteudos historicos, filosoficos e culturais do sujeito, mediados pela literatura de HQS. Alem de permitir uma forma alternativa de ensino, a ponte entre Fisica e Gibis pode contribuir para amenizar a crise e as dificuldades para a Interdisciplinaridade, assim como, para uma educacao problematizadora, dialogada, ate para a utilizacao dos temas geradores e contextualizacao, ferramentas, essas, que contribuem, desde que bem elaboradas, para uma educacao eficaz. O objetivo e contribuir para a divulgacao da ciencia levando informacao cientifica e tecnologica, unindo o ludico, o cientifico e a ficcao em uma abordagem diferenciada dos livros didaticos. Os textos literarios, imagem, ficcao, sonhos e desejos podem permitir um trabalho melhor com aqueles alunos que tem obstaculos epistemologicos e nao se sentem motivados ao estudo da Fisica. Essa revista passa a ser uma proposta de estudos e pesquisa inovadora.

Goats are important species of livestock for Brazil especially at the Northeast Region. Because of that Native goats breeds represent important genetic resources for conservation and breeding programs. Although there are some of infectious diseases that may affect to the conservation of this endangered breeds, particularly mastitis. The goal of this study study was to investigate the frequency and the etiology of mastitis in native goats and sheep born and raised in Brazilian semi-arid biom of Paraiba and Pernambuco state. A total of 480 fresh milk samples from of twelve native breeds of goat, from January to July 2012. All of the biological material were plated on Sheep blood supplemented with Agar Base, and incubated at 37oC for 72 h.Gram-staining followed by biochemical tests were made for identification of bacteria. The results of bacteriological examinations showed 13.54% (65/480) of positive samples and the most frequent microorganisms isolated and identified were Staphylococcus spp., followed by Micrococcus spp. This is the first report of isolation of bacteria that may produce mastitis in native goats and sheep from the northeast semiarid region of Brazil. The results obtained in this study will allow authorities to implement preventive measures for this disease.

Etiologia das Mastites em Cabras e Ovelhas de Raças Naturalizadas Criadas no Semiárido Nordestino (Etiology of Mastitis in native goats and sheeps born and raised in Brazilian semi-arid biom)

En este articulo presentamos parte de una investigacion que tiene como eje principal una reflexion critica del proceso de la creacion del Curso de Formacion de Docentes de los pueblos indigenas en el estado de Acre. Esta es una de las experiencias formativas de los docentes indigenas que se suma otras en Brasil y America Latina, dada la reciente inclusion de estes pueblos en diversos cursos de pregrado en el sistema educativo. La discusion se hace de las tensiones entre los organismos oficiales, los movimientos y las organizaciones no gubernamentales. El texto ofrece una breve analisis de la institucionalizacion de la educacion indigena en el estado de Acre, que culmino en un desafio a la voluntad de la formacion continua de profesores indigenas, que se incrementaron las demandas de mayor elemento de nivel de curso de formacion especifica que es objeto de este estudio. La aparicion de una educacion superior para los indigenas en la region occidental de Brasil es una experiencia de expansion de la capacidad de las comunidades para organizar su actividad en la educacion escolar. En medio de las luchas y los logros se da cuenta de que para muchas comunidades indigenas hicieron esto tambien significaba la posibilidad y garantizar una recuperacion de la cultura tradicional, mediante la construccion de un plan de estudios basado en el dialogo entre el conocimiento cientifico y las necesidades de esas comunidades. El estudio senala la necesidad urgente de reflexiones y acciones que deben llevarse a cabo para entender mejor la tarea que los pueblos indigenas y la sociedad en general se enfrentan al gran reto, pero no para integrar a vivir con la posibilidad de diferencias en todos los sectores de la sociedad, incluido el espacio academico.

DOCÊNCIA INDÍGENA NO EXTREMO OESTE BRASILEIRO: UMA EXPERIÊNCIA DE FORMAÇÃO EM ANDAMENTO

A IMPORTÂNCIA DA ATENÇÃO FARMACÊUTICA PARA ATLETAS DE ENDURANCE (NATAÇÃO) USUÁRIOS DE SUPLEMENTOS ALIMENTARES

The present study aims to evaluate the reverse flotation performance of iron ore, using collector (amine), in the presence and absence of chain extender (diesel oil) and emulsifier (sodium lauryl sulfate).Six tests were realized with duplicate. Tests using amine, diesel oil and sodium lauryl sulphate show the better results, with metallurgical recovery of 91.82% and the concentrate silica equal 1.68%. Thus, it is found that the use of emulsifier and chain extender together with the amine, shows better results in the flotation, in terms of metal recovery and selectivity, when compared to using only amine or amine and diesel oil.

Aplicação de extensor de cadeia e emulsificante na flotação de minério de ferro.

SILVA, J. D. C. da. Musica: uma ferramenta didatica ao letramento. 2011. 22f. Trabalho de Conclusao de Curso (Graduacao em Letras)- Universidade Estadual da Paraiba, Guarabira, 2011.

Música: uma ferramenta didática ao letramento / José Dayvid Carneiro da Silva

Este artigo tem como foco analisar o curriculo da Teologia e o fato de ela ter se tornado um curso de suma importância em diversas universidades espalhadas pelo Brasil. A teologia fica inicialmente dispensada de uma diretriz curricular no proprio ato de aprovacao do Conselho Nacional de Educacao, muito embora reconhecida, no mesmo parecer, como area de conhecimento e, portanto, consolidada como resultado de uma tradicao curricular.

As estruturas a base de carbono tem um papel de grande importância nos campos da ciencia e da tecnologia. Isso gracas a versatilidade do elemento carbono, pilar da quimica orgânica, que consegue formar uma diversidade de estruturas (cerca de 10 milhoes de compostos), alem de ser um constituinte basico de toda forma de vida conhecida. Dependendo das condicoes de formacao, este fenomenal elemento, pode se apresentar em diversas formas alotropicas: desde um material extremamente fragil, como o grafite, ate materiais incrivelmente resistentes como o diamante, nanotubos de carbono e o grafeno. Esses materiais grafiticos tem sido extensivamente estudados, apresentando propriedades unicas e grande potencial em aplicacoes tecnologicas. Dentre eles, o grafeno ocupa, atualmente, a posicao de maior destaque por possuir propriedades mecânicas e eletronicas diferenciadas. O oxido de grafeno e uma classe de estruturas grafiticas constituida basicamente de uma camada de grafeno decorada com grupos epoxido e hidroxila na superficie e grupos carboxilicos e carbonila nas bordas. A sua estequiometria depende fortemente do metodo de obtencao. Esse material, alem de ser uma das principais rotas para a obtencao em larga escala do grafeno, tambem apresenta diversas propriedades interessantes, que possibilitam, por exemplo, aplicacoes biologicas, uma vez que seus grupos funcionais o tornam bastante reativo alem de ser facilmente dispersado em agua. Muitas questoes relacionadas ao oxido de grafeno ainda nao estao bem esclarecidas, como sua propria estrutura, processo de formacao e mecanismos de interacao. Nesse sentido, foi utilizada, como principal ferramenta, a microscopia de forca eletrica (EFM) para estudar propriedades eletrostaticas de uma amostra de oxido de grafeno obtida utilizando-se um metodo de Hummer modificado. Por meio de um modelo simplificado, foi possivel desenvolver um metodo para analise das medicoes de EFM e assim determinar a presenca e o sinal da carga liquida da amostra. Alem de ser possivel esclarecer a origem do fenomeno de borda observado nos experimentos de EFM.

The quality of work life (QWL) is one of the most relevant topics in the middle when 
it comes to organizational productivity. The issue gained strength due to globalization and the 
need to recognize that the competitive advantage of new organizations, appropriate new 
market demands increasingly competitive; focuses on people. Understanding the perception of 
QWL, in view of the very employees of a public institution is the aim of this work, becoming 
a source of accurate and important decisions and investments aimed at increasing the levels of 
satisfaction and therefore productivity. Given the above, this research studied through the 
model proposed by Walton critical factors that influence the QWL in the 1st Special Court for 
civil Caruaru-PE. Through this research it became clear three critical factors for the Quality of 
Work Life (QWL) of the organization under study: Plan jobs and careers; Ergonomics and 
training as factors that need attention, for an improvement in employee satisfaction and 
consequently public services provided. How are items on the agenda of this claim of many 
classes of servers, we propose a broader discussion on the need to reform management of 
public organizations.

Qualidade de vida no trabalho: caso dos funcionários do 1º Juizado especial cível - Fórum - Caruaru-PE.

The effect of three rates of Diu ron and Prometryne (0.8, 1 .6, and 2.4 kg i.a./ha) alone orcombined, 
was tested in a hydromorphic soi1 during the years 1 984 and 1985. Treatments were imposed before the emergence of the upland rice. The prevalenl weeds were: Commelina beng halensis L., Paspalum notatum Fl ugge, and Cyperus rotu11dus L. The herbicides were applied with a coastal sprayer of 20 Jiters capaci ty and two nozzles 8004, fixed in a bar of0.50 m. Their efficiency was evaluated visually with an EWRC scale at 30, 60, and 90 days after sowing. The weeds were counted after 148 days after sowing with evaluation of the upland rice yield. There were no sign ificative differences between treatments al though phytoxicity by both herbicides was observed. The most phytotoxic herbiicide was Diuron (1.6 and 2.4 kg i.a. /ha). In spite of the fact that Prometryne, initia ll y caused damages, the symptoms decreased with time. The crop production and the n umber of panicles were red u ced, wi th both Diuron and Prometryne, even though the highest reduction was dueto Diuron. There was also significative reduction of other production components, except the weight of I00 seeds and the harvest index. 
 
KEY W ORDS: Prometryne - Diuron- weeds - ph ytoxicity - upland rice.

EMPREGO DE PROMETRYNE E DIURON NA CULTURA DO ARROZ DE SEQUEIRO, ORYZA SATIVA

Nosso interesse, neste trabalho, diz respeito aos tipos de justica encontrados na Republica de Platao. Para tanto, tomarei as consideracoes de Sachs e Vlastos sobre tal tema (principalmente Vlatos que admite que uma polis e justa somente se seus cidadaos sao justos). Afirmamos, ao contrarios destes pesquisadores, que existem cinco formas principais nesta obra, a saber: a justica nos elementos da alma; nas relacoes privadas, que sao comandadas pelos preceitos padroes da moralidade; nas relacoes publicas, grupo que exerce a maxima do fazer as coisas que lhe sao devidas na polis; nos elementos da polis; e por ultimo, o que Platao nao discutiu, mas fez mencao, as relacoes de uma cidade com outra. Concluimos que estas formas nao dependem uma da outra.

INTRODUCAO Os Sistemas de Informacao Geografica (SIG) sao ferramentas computacionais para Geoprocessamento. Eles permitem realizar analises complexas ao integrar dados de varias fontes e criar bancos de dados localizados espacialmente ou nao. Os dados fisiograficos, sao extraidas por meio de sensores remotos e estes sao classificados em ambiente SIG (CÂMARA e MEDEIROS, 2001). O Geoprocessamento e “um conjunto de conceitos, metodos e tecnicas erigido em torno do processamento eletronico de dados, que opera sobre registros de ocorrencia georreferenciados, analisando suas caracteristicas e relacoes geotopologicas para produzir informacao ambiental” (XAVIER-DA-SILVA, 2012). O Geoprocessamento auxilia a classificacao dos dados das feicoes em informacao espacial e, alem disso, possibilita avaliacoes e o monitoramento do uso e ocupacao das terras (WERNECK, 2010). Assim, o processo decisorio a cerca de uma regiao e conduzido de forma mais precisa e agil (XAVIER-DA-SILVA, 2001). A partir deste estudo foi delimitado o uso e ocupacao das terras e seus conflitos da regiao estuarina do rio Macae. Para tal, foi utilizada a edicao em tela do SIG ArcGis 9.3 apoiada por um mosaico de imagens google. Alem disso, foram gerados buffers dos corpos hidricos, mangues e brejos (Area de Preservacao Permanente Lei 12651/2012) para intercecao com as feicoes de uso e ocupacao, a fim de detectar os conflitos de uso.

USO DE GEOTECNOLOGIAS NA EDIÇÃO E AVALIAÇÃO DO MAPA DE USO E OCUPAÇÃO DAS TERRAS DO ESTUÁRIO DO RIO MACAÉ

SILVA, J. W. F. da. O espaco geografico como produto das manifestacoes socioculturais: o caso do sitio arqueologico Pedra de Santo Antonio municipio de Fagundes-PB. 2012. 53f. Trabalho de Conclusao de Curso (Graduacao em Geografia)- Universidade Estadual da Paraiba, Campina Grande, 2012.

O espaço geográfico como produto das manifestações socioculturais: o caso do sítio arqueológico Pedra de Santo Antônio município de Fagundes-PB

A analise de coeficiente de correlacao e uma importante ferramenta no estudo da associacao entre os caracteres de feijao-caupi e para avaliar a contribuicao de cada fator na produtividade desta cultura. Objetivou-se investigar as relacoes genotipicas entre a produtividade de graos em feijao-caupi e alguns componentes de producao e caracteristicas agronomicas, utilizando a analise de trilha para decompor as correlacoes em seus efeitos diretos e indiretos. O experimento foi realizado no periodo de maio a agosto de 2010. Foram utilizadas as cultivares BR8 Caldeirao, IPEAN V69, BRS Guariba e BR17 Gurgueia. Estimou-se as correlacoes genotipicas entre pares de caracteres e seus efeitos diretos e indiretos considerando os componentes de producao (numero de vagens.planta-1 e numero de sementes.vagem-1), caracteres agronomicos (altura da planta, area foliar e peso da materia seca da parte aerea) e a produtividade de graos. O diagrama de trilha com duas cadeias mostrou-se adequado em explicar as relacoes entre componentes primarios, secundarios e produtividade, considerando as altas estimativas dos coeficientes de determinacao (R2) e baixos efeitos residuais. O numero de vagens.planta-1 e a area foliar foram os caracteres mais correlacionados com a produtividade e se mostram eficientes em praticar-se selecao indireta, com  o intuito de obter ganhos geneticos sobre  o rendimento de graos. Tambem mostraram ser caracteres importantes sobre os efeitos indiretos do numero de sementes vagem-1, altura da planta e peso da materia seca da parte aerea.

Associações genotípicas entre componentes de produção e caracteres agronômicos em feijão-caupi

O processo de planeamento e escalonamento dos voos de uma companhia aerea e composto por varias fases, algumas das quais comecam a ser preparadas com varios meses de antecedencia. Contudo, e tao importante ter um planeamento otimo quanto conseguir mante-lo. Esta e uma tarefa bastante complicada devido a eventos inesperados (roturas) que ocorrem perto do dia da operacao. Tais problemas originam quebras no planeamento que podem levar a atrasos e/ou cancelamento de voos, se nada for feito para o prevenir.No Laboratorio de Inteligencia Artificial e Ciencia da Computacao (LIACC) esta a ser desenvolvido um projeto, denominado Multi-Agent System for Disruption Management (MASDIMA), em colaboracao com a TAP Portugal, no âmbito da negociacao automatica na Resolucao Distri- buida de Problemas em ambientes Cooperativos, aplicado ao cenario de Controlo Operacional das Companhias Aereas, atraves de um sistema multiagente de gestao de roturas.O objetivo desta dissertacao e o de incorporar, no sistema MASDIMA, uma camada de software suplementar, no conjunto de agentes responsaveis pela geracao, analise e decisao de novas solucoes, para que este sistema possa aprender com o passado. E assim estudada a possibilidade de o sistema gerar novas solucoes para os problemas atuais com base no seu conhecimento de situacoes similares ocorridas anteriormente.Para que esta implementacao seja uma realidade, utilizar-se-a a metodologia Case-based Reasoning (CBR), introduzindo desta forma a aprendizagem com o passado no apoio a negociacao automatica nos Centros de Controlo Operacionais, para obter a solucao final para a rotura do plano.Pretende-se, nesta dissertacao, que a introducao da aprendizagem com o passado, no sistema MASDIMA, mantenha, aproximadamente, a qualidade das solucoes apresentadas pelo sistema ao mesmo tempo que, por um lado, se diminui o tempo medio de resposta do sistema a um novo problema, e, por outro, se aumenta o nivel de confiabilidade do mesmo. A concretizacao destes objetivos sera analisada atraves da utilizacao de metricas como o tempo medio de resposta do sistema a um novo caso, e a determinacao da qualidade das solucoes propostas, em comparacao com as solucoes dadas pelo Centro de Controlo Operacional (CCO) da TAP Portugal, e com as produzidas pelas abordagens pre-existentes no sistema MASDIMA.

Aprender com o Passado: Apoio à Negociação Automática nos Centros de Controlo Operacionais

The objective of the present study were to estimate the rates of K to obtain the maximum physical and economic efficiency, determine the critical level of leaf K and to relate the nutritional balance of banana 'Prata Ana' with the incidence of plants with Panama disease in the 4th cycle. The experiment was conducted in an oxisol, medium texture, in the semi-arid region in the northern of the State of Minas Gerais, Brazil. The treatments consisted of four rates of K (0, 400, 800 and 1200 kg ha-1 yr-1 of K2O.) These were distributed in randomized blocks with five replications. Fertilization with K increased the production of banana in the 4th cycle. The maximum physical efficiency (31.0 Mg ha-1) and economic (30.5 Mg ha-1) were obtained with the application of 969 and 707 kg ha-1 yr-1 of K2O, respectively. The critical levels of leaf K obtained were 29.5 and 27.1g kg-1 for the maximum physical efficiency and economic, respectively. The increase in rates of K provided a better nutritional balance in the banana and reduced the percentage of plants infested with Panama disease.

Avaliação nutricional, produção e incidência do mal-do-panamá em bananeira 'Prata-Anã' (AAB) adubada com K, no quarto ciclo

This article was to focus on the Vatican and the laity in the Church, showing historical context, the ecclesial perspective in relation to the laity from Vatican II and relevant points when context as Lumen Gentium, Apostolicam Actuositatem, Gaudium et spes and Ad Gentes. Through a literature review has been studies and theories which served as a support for the conclusion of this article which showed that through the considerations made about positioning taken by the Church, from Vatican II, in relation to the laity, we can say that these are not only invited to the apostolate, but have, in addition to the right, the duty to participate in the Church’s evangelizing mission, by virtue of baptism that incorporates the Christ and the Church.

O presente trabalho trata da aplicabilidade das normas constitucionais da Constituição Brasileira, que é definida como constituição dirigente.

Aplicabilidade das normas constitucionais. Doi: 10.5020/2317-2150.1993.v02.n1.p07

Bottom of Pyramid, Fair Trade e Desenvolvimento Sustentável - Estudo Comparativo entre Setor Alimentar e Setor de Vestuário, a Partir de Análise Exploratória aos Websites das Empresas..

O trabalho prático como um dispositivo pedagógico no ensino e na aprendizagem da biologia e da geologia: Possibilidades e limitações.

Estudo da influência das resinas termofixas uréia formaldeído (UF) e melamina formaldeído (MF) nas características físicas e mecânicas de painéis MDF

A major difficulty the city manager is the Single Health System (SUS) is to monitor, audit and manage a large number of visits / procedures performed. Data from these visits, in most cases, are generated by systems that do not communicate, and or recorded on paper. In this context, the compiling of these data becomes inefficient, with common losses and inconsistencies. This article presents the experience of Maceio Municipal Health Department to consolidate and give the information transparency of its public health system through the BioSUS system. It is a web system that maintains centralized data, with the ability to compile and make available the informacoesregistradas. Such a system uses digital biometrics for verification and validation in real time, the services provided by the public health system.

BioSUS: uma ferramenta de tecnologia da informação e comunicação para a gestão do SUS em Maceió

O artigo aborda o caso para ensino em administracao como recurso pedagogico para ensinar a complexidade dos mais diversos problemas na gestao das organizacoes.O metodo de pesquisa se classifica em abordagem qualitativa, de natureza aplicada, como objetivo de pesquisa foi utilizado o estudo exploratorio e descritivo e como procedimento tecnico foi utilizado o levantamento bibliografico. Buscou-se levantar os seguintes aspectos do caso para ensino: a) conceituacao; b) historico; c) diferenca entre caso para ensino e estudo de caso; d) objetivos; e)tipos e; f) adequacao a realidade. Os resultados encontrados foram que o uso do caso para ensino como recurso pedagogico possibilita o estabelecimento de vinculos entre o ambiente de ensino e o mundo real das organizacoes, favorecendo o desenvolvimento de habilidades cognitivas nos estudantes atraves da analise, da sintese e do julgamento. Enfatiza-se a importância da participacao ativa de professores e alunos para o sucesso do metodo.Palavras-chave:caso para ensino, administracao, recurso pedagogico.

Apesar de ser uma atividade academica pouco valorizada ou reconhecida, inclusive no meio academico, a critica textual tem uma importância impar entre as diversas tarefas de quem valoriza e quer preservar a cultura de seu povo. Sabe-se que a transmissao do conjunto de ideias de um livro ou de um conjunto importante de documentos, com certeza nao se retransmite sem ruidos e interferencias durante muito tempo. Cabe ao filologo e ao critico textual a tarefa de reconstituir a autenticidade e a autoridade do texto, para que a cultura e a memoria do povo sejam preservadas para as novas geracoes. Isto porque a divulgacao de um texto deturpado pode mudar o rumo da historia e criar preconceitos dificilmente desfeitos posteriormente. Dependendo do destinatario, o editor critico escolhe o tipo de edicao mais adequada, desde a edicao atualizada a edicao interpretativa, a edicao critica e a genetica ou critico-genetica, sem contar que estas podem ter varios niveis, desde a mais conservadora e ortodoxa a mais atual e moderada. Hoje, a prioridade brasileira parece ser para as edicoes de textos nao literarios, apesar de ser bem grande tambem a producao da critica textual relativa aos textos literarios, porque ha apenas dois seculos que a imprensa foi legalizada entre nos. Ciente de que se comeca a reconhecer nossa producao cultural, estamos lancando, neste ano, a Colecao Critica Textual , que tem, desde a sua criacao, a macica contribuicao dos laboriosos e excelentes filologos baianos. Uma relacao bastante detalhada da producao em critica textual sera disponibilizada aos interessados a partir dessa comunicacao, com a ampliacao do livreto Para uma Bibliografia Brasileira de Critica Textual , preparado em 2007 e livremente disponibilizado na Internet. Trata-se de mais um volume da Colecao Critica Textual, a cargo da Editora Prismas e da Editora Appris. Palavras-chave: Critica Textual. Ecdotica. Edicao. Bibliografia.

Com o projeto de pesquisa busca-se realizar o mapeamento de atividades poluidoras e estudar o processo de licenciamento ambiental nos postos de combustiveis e oficinas automotivas no municipio de Macae. O crescimento da cidade, o aumento do numero de veiculos, entre outros fatores e a falta de planejamento e fiscalizacao gerou o descumprimento das normas estabelecidas. Assim sendo, nosso proposito consiste na verificacao dessas atividades e contribuicoes em solucoes. A metodologia utilizada no projeto baseia-se na leitura de uma serie de documentos importantes que tratam do licenciamento ambiental, gestao ambiental e a definicao da regulamentacao das atividades nos postos de combustiveis e aos produtos envolvidos. Tambem consiste no levantamento e observacao de mapas que situam esses estabelecimentos no municipio, alem de visitas tecnicas e analise da agua em ambientes proximos as atividades, dando enfoque ao perimetro urbano, onde se localiza a maior parte dos estabelecimentos. Com o resultado da pesquisa buscam-se instrumentos para que as autoridades possam criar metodos de fiscalizacao, onde os postos seriam regularizados, realizando o licenciamento ambiental dos mesmos, a partir do mapeamento das atividades poluidoras, ja que muitos postos se encontram na irregularidade, nao respeitando as normas ambientais e sem o licenciamento. A partir desse processo, os riscos ambientais seriam reduzidos, alem de eventuais impactos ao ambiente proximo as atividades. Macae possui varios postos de combustiveis e oficinas automotivas em atividade, alguns deles nao respeitam as normas ambientais vigentes. Faz-se importante o mapeamento e o licenciamento ambiental dessas atividades, com o objetivo de minimizar os impactos causados ao ambiente.

MAPEAMENTO DE ATIVIDADES POLUIDORAS E LICENCIAMENTO AMBIENTAL NO MUNICÍPIO DE MACAÉ-RJ: POSTOS DE COMBUSTÍVEIS E OFICINAS AUTOMOTIVAS

Este artigo tem como foco analisar a teologia, sua presenca e importância nas universidades, nao desejando versar completamente e de forma ampla sobre o tema, mas ao menos deixando neste estudo a relevância que a teologia adquiriu atraves dos tempos nas universidades de forma geral. Onde se pode concluir que no comeco a teologia era apenas ponto de debates nas universidades, mas tamanha foi sua importância que passou a disciplina e, posteriormente, a curso proprio e regulamentado, mostrando sua importância nas universidades.

RESENHA DO LIVRO:BOUISSAC, Paul. Saussure – Um guia para os perplexos.Traducao de Renata Gaspar Nascimento. Petropolis: Vozes, 2012. 260 p. il.http://www.vozes.com.br

Tomato is a water demanding crop, however water is a limited resource in the semiarid region, needing a suitable management which provides higher yield and better utilization of water resources. Therefore, the objective of this research was to evaluate the effect of replenishment levels of crop evapotranspiration (ETc) on production of tomato 'IPA Caline 6' grown in greenhouse. The experiment was carried out at experimental area at the State University of Paraiba. Five replenishment rates of crop water consumption (33, 66, 100, 133 and 166%) were studied in a completely randomized experimental design with eight replications each consisting of two plants. Productive characteristics and water use efficiency in tomato plants were evaluated in this research. The transverse and longitudinal diameter and fruit mass improved linearly with increase in the replenishment rates of ETc. The number of flowers, number of aborted flowers, number of fruits per plant, productivity and water use efficiency were higher when plants were irrigated with replenishment rates between 100 and 133% of crop water consumption. The tomato cultivar IPA Caline 6 can be grown in greenhouse with water levels between 100 and 133% of ETc.

Cultivo do tomateiro em ambiente protegido sob diferentes taxas de reposição da evapotranspiração

One of the ways of planning tourism is implementing tourism policies that promote the ordering of this activity where it occurs. In this way, the Ministry of Tourism has developed various tourism policies in Brazil. One of them is the Program of Regional Itinerary. This program was created with the intention of decentralizing this activity in all of the national territory. The purpose of this article is to know the institutional actions aimed to implement the “Serido’s Route” in Currais Novos/RN, identify the equipment used in its implementation, and which companies to sell and perform their official receptive. Then, we used the literature / electronic, documentary, interview and SWOT analysis. Thus, it was found that the “Serido’s Route” was developed by SEBRAE along with some private and public companies. It was found, in short, that it takes more investment in infrastructure, dissemination and monitoring of “Serido’s Route”.

This article has had a focus and objective look at the emergence of the concept of a layman in centuries I and II and the positioning of some Saints Priests, alluding to the laity, and the laity in the documents of the Magisterium of the Church. It is concluded that in documents of the Church and within your teaching the basic idea was the same that prevails even today that the layman should bring the Church to his experience of participation in the issues and challenges of his secular world, because it is precisely in this world who are called by God to exercise the mission assigned to them. The fundamental notes, therefore, is that the layman plays his evangelising mission, without leaving the world and its secular condition. He is engaged in the structure of this world and should play its mission, transforming the world, as the spirit of Christ. Concluding that the modern time is undoubtedly a challenge to evangelization; however, the Christian laity has as great mission to evangelise and seek to build the Kingdom of God in the world, dealing with the temporal and bringer of generating source of light, which is Jesus Christ.

O leigo no Magistério da Igreja: uma breve análise por meio dos seus documentos

Género, "raça" - etniae classe: a presença femenina em cursos de graduaçao na Universidade Federal da Paraíba

Projeto, desenvolvimento e implementação de um robô nadador de inspiração biológica

This paper presents a two-dimensional model of the human eye to investigate the evolution of temperature in transient state and the associated thermal damage in the layers of the eye and, especially in the choroidal melanoma. The computer modeling and simulation were performed for a patient with a choroidal melanoma, undergoing treatment by laser irradiation. To determine the temperature field, we developed a model that uses the Pennes Bioheat Transfer Equation (BHTE) that has a term of source/sink that responds to the heat transferred through the blood perfusion. The Birngruber model was used to determine the function of thermal damage during the laser transpupillary thermotherapy (TTT). The analysis was carried out from an ultrasound image of the patient. This type of examination provided the dimensions of the eye and the tumor. The CFD (Computational Fluid Dynamics) commercial software FLUENT&®, which uses the Finite Volume Method (FVM) was used in the analysis of the model. The temperatures, steady-state, were calculated for the normal eye, i.e, without laser irradiation and these results were used as initial condition for the simulation of transient state to the eye irradiated for 60 seconds with a diode laser (810 nm and output power of 178, 222, 400 and 500 mW) whose beam had a diameter of 2.0 to 3.0 mm and irradiance of 56,588 and 70,736 W/m2 on the cornea. To validate the model, the results of temperatures, in steady state to the eye not exposed to laser radiation, were compared with others showing a good agreement between them. The results of thermal damage and transient state, for the eye irradiated by the laser, show that the values of damage depth are in agreement with the literature.

Análise computacional do dano térmico no olho humano portador de um melanoma de coroide quando submetido à termoterapia transpupilar a laser

Ação emergencial para delimitação de áreas em alto e muito alto risco a enchentes, inundações e movimentos de massa: Porto Alegre, RS

Identificação de áreas prioritárias para preservação e recuperação da Apa do Sana-RJ

Essential oils are one of the most important groups of raw materials for various industries, especially the perfumery, food and pharmaceutical industries. Otacanthus azureus is an aromatic shrub, popularly known as herb-copal is a little studied species of great potential for obtaining oils, which can be used in the cosmetics industry, pharmacological and perfumery. In this context aimed to evaluate the effect of two brightness levels and fertilization for dry-matter accumulation and oil yield of plants Otacanthus azureus . The experiment was arranged in randomized 2x2x3 factorial, with two levels of light (50% and 100%) with two nitrogen levels (0 and 100 kg / ha). Treatment of irradiance herb-copal showed the highest growth response to 100% light, no effect of nitrogen fertilization on yield of oil.

Acúmulo de matéria seca e rendimento de óleo da planta Otacanthus azureus em função da luminosidade e adubação nitrogenada .

A preocupacao com o meio ambiente vem aumentando nas ultimas decadas, esse fato acontece devido a diversos fatores, tais como a necessidade de sobrevivencia do homem e a sua percepcao da limitacao dos recursos naturais. Diante desse cenario, uma das ferramentas que pode ser utilizadas pelas empresas para permitir conciliar lucratividade e responsabilidade social vem ser o chamado marketing verde ou ecologico, onde o mesmo leva informacoes sobre produto e produtor, alem de contribuir para adequacao das empresas junto aos orgaos responsaveis pela legislacao ambiental, e em relacao aos concorrentes servindo como uma variavel competitiva. Deste modo o estudo buscou identificar as acoes de marketing verde encontradas nos produtos que compoem a cesta basica, em duas grandes redes supermercadistas localizadas em Caruaru-PE. Atraves da pesquisa de campo foi possivel identificar oito produtos que continham acoes de marketing verde esses foram: Feijao, Arroz, Farinha, Pao Frances ou de Forma, Cafe em Po, Acucar, Oleo ou banha e Manteiga. Diante do explicitado, e possivel inferir que as empresas estao preocupadas com as acoes de marketing verde e comecam a usar em produtos basicos como os que compoem a cesta basica brasileira.

UTILIZAÇÃO DE AÇÕES DE MARKETING VERDE NOS PRODUTOS QUE COMPÕEM A CESTA BÁSICA BRASILEIRA

This paper aims at evaluating Brazil’s Biodiesel Production and Use Program (PNPB) in the period of 2004–2010. The purpose of PNPB is to implement a biodiesel commodity chain in Brazil, 
aiming to reduce diesel imports, diversify oilseed plants, and generate employment and income for family farmers. Although this is a recent public policy, it is possible to compare the available data with the program’s main objectives. The production of biodiesel has grown since 2005, but still has 
failed to halt the growth of diesel imports in Brazil. The number of family farmers participating in the program is significant, and the South Region holds more than half of these farmers. Diversification of oilseed plants also left much to be desired. Soybean accounts for more than 90% of the acquisitions made at auction in 2010, so that the diversification desired by PNPB has not occurred. Therefore, although PNPB has made Brazil the second largest world producer of biodiesel, this public policy needs some adjustments.

Avaliação do programa Nacional de produção e uso do biodiesel no Brasil – PNPB

O trabalho e uma tentativa de quantificar a pluriatividade das familias agricolas no Brasil com base nos microdados da Pesquisa Nacional por Amostra de Domicilios (PNAD) de 1995. Nossas estimativas mostram que a pluriatividade afetava 35% do conjunto de familias ligadas as atividades agropecuarias, proporcao essa que varia relativamente pouco em funcao da ocupacao principal do seu chefe, se empregador (44%) ou conta propria com acesso a terra (33%), ou se pertence a outras categorias de trabalhadores agricolas e/ou rurais sem acesso a terra(35%).

Os micro sistemas de analise total consistem de dispositivos da ordem de centimetros que tem como objetivo a integracao de varias etapas analiticas em um unico chip, tais como etapas de tratamento de amostra, separacao por eletroforese capilar, ou mesmo a integracao de sensores em canais microfluidicos. O poli(dimetilsiloxano), PDMS, e um dos polimeros mais adotados para a fabricacao destes microdispositivos, devido a suas propriedades elastomericas, transparencia optica, permeabilidade gasosa, biocompatibilidade, facil moldagem, relativa alta resistencia quimica e baixo custo de fabricacao, alem de poder ser facilmente moldado e selado, resultando em microcanais com boa resolucao. Alem disso, e possivel a fabricacao de canais por ablacao a laser sobre o polimero curado. Entretanto, a caracteristica altamente hidrofobica do PDMS faz com que sua aplicacao para solucoes aquosas seja problematica e analitos pouco polares possam sofrer forte adsorcao nas paredes do canal, tornando pobre a reprodutibilidade do processo. Neste sentido, estrategias para modificar o material nativo ou mesmo a superficie dos canais vem sendo estudadas. Neste trabalho, foi inicialmente estudada a modificacao estrutural do PDMS, que consiste na utilizacao de um reticulante (contendo funcao orgânica polar metacrilato ou amina) na formacao do substrato. Tambem foi realizada a modificacao da superficie do substrato de PDMS por reacao topologica, com a introducao de polietileno glicol, alem da modificacao do processo convencional de reticulacao do PDMS Sylgard 184, pela adicao do surfactante Silwet-L77 a este processo. O PDMS modificado foi avaliado quanto a sua hidrofobicidade, por medida do ângulo de contato com a agua, em relacao as propriedades do fluxo eletrosmotico gerado no microcanal e as modificacoes foram estudadas por metodos espectroscopicos. A reacao de modificacao de superficie do PDMS com divinil eter de polietileno glicol apresentou as melhores caracteristicas hidrofilicas dentre as modificacoes estudadas e mobilidade do fluxo eletrosmotico com valor de 3,6x10 cm V s. Em adicao, as modificacoes puderam ser caracterizadas por metodos de espectroscopia (IR e Raman), que se mostraram eficientes na avaliacao tanto da rota de modificacao quanto do produto final. 
Abstract

Modificação de poli(dimetilsiloxano) para aplicações em micro sistemas de análise total

O Diabetes esta diretamente relacionado a danos em varios orgaos e sistemas incluindo o sistema vascular. Os problemas vasculares representam a principal causa de morbidade e mortalidade no Diabetes. No entanto, os mecanismos envolvidos nas alteracoes vasculares associadas ao diabetes nao sao completamente esclarecidas. O objetivo deste estudo foi investigar as vias de sinalizacao envolvidas na disfuncao vascular em um modelo murino de diabetes tipo I induzida por streptozotocina. Metodo: Os experimentos funcionais foram conduzidos com a aorta toracica de camundongos C57BL/6 em um sistema de banho de orgaos. As correntes para Ca2+ foram medidas em celulas recem-dispersas utilizando a tecnica de patch-clamp na configuracao whole-cell. A expressao proteica foi medida atraves da tecnica de Western blot. A tecnica de antisense foi usada para diminuir agudamente (knockdown) a expressao da PI3Kd. Resultados: A resposta vasorelaxante nao foi diferente entre os grupos controle e diabeticos. No entanto, os vasos dos animais diabeticos apresentaram uma resposta contratil bastante aumentada em relacao ao controle quando estimulados com fenilefrina ou KCl. Os dados de Western blot mostraram um aumento da expressao dos canais para calcio dependentes de voltagem do tipo L (Cav1.2), da PI3Kd e da Rho na aorta dos animais diabeticos. Nos animais diabeticos tratados com antisense para a PI3Kd a expressao da Rho e dos Cav1.2 foi normalizada. A inibicao farmacologica ou com antisense para a PI3Kd normalizou a densidade de corrente atraves dos Cav1.2 para o nivel do controle. Os inibidores da RhoK, fasudil (10 mol/L) e Y27632 (5 mol/L) tambem foram efetivos em normalizar as correntes para Ca2+ atraves dos Cav1.2 nos animais diabeticos. Os efeitos da inibicao da PI3Kd e da RhoK sobre os Cav1.2 nao foram aditivos. Surpreendentemente, a nifedipina, bloqueador de Cav1.2, apesar de ter tido um efeito inibitorio mais pronunciado sobre a contracao dos animais diabeticos, nao restaurou completamente a resposta contratil ao nivel do animal controle. Estes resultados sugerem que o aumento de corrente para calcio atraves dos Cav1.2 nao e o unico mecanismo implicado no aumento da contratilidade vascular dos animais diabeticos. A PI3Kd e a RhoK devem agir tambem em outra via que controla o processo contratil, alem dos Cav1.2. A inibicao (farmacologica e com antisense) da PI3Kd normalizou a resposta contratil do animal diabetico sugerindo que todos os mecanismos envolvidos na alteracao contratil do diabetes envolvem a PI3Kd. A inibicao da RhoK com Y27632 praticamente aboliu a resposta contratil do animal controle e do animal diabetico, mostrando que esta via e fundamental no controle da contracao na aorta dos camundongos. Conclusoes e implicacoes: Os resultados mostram que no diabetes tipo 1 induzido por STZ ocorre uma remodelacao dos mecanismos moleculares envolvidos no controle da resposta contratil do musculo liso da aorta, incluindo o aumento da expressao da PI3Kd, Cav1.2 e Rho. No animal diabetico, a PI3Kd, via Rho/RhoK, promove um aumento das correntes para calcio atraves dos Cav1.2 e do grau de fosforilacao dos filamentos contrateis. Dessa forma, o bloqueio da PI3Kd pode representar um novo alvo terapeutico para o tratamento das disfuncoes vasculares em pacientes diabeticos.

Papel da PI3K8 no controle da contratilidade vascular no Diabetes Mellitus I: estudo funcional e eletrofisiológico

Preeclampsia is a disease specific to pregnancy, characterized by hypertension and proteinuria. HELLP Syndrome may be one of its complications, describing patients with hemolysis, anemia, elevated liver enzymes and low platelets count. Once the diagnosis is established, the most adequate treatment is the interruption of the pregnancy. The more interruption is postponed, the higher is the jeopardy to fetus and mother well-being. The clinical picture, as it was observed in this case, may not be completely established, albeit the syndrome is in progress, being detectable only by laboratory exams. Thus the authors emphasize the importance of routine investigation of HELLP Syndrome in every patient admitted with preeclampsia to preserve the fetal and maternal status in the most severe cases.

SÍNDROME HELLP: A IMPORTÂNCIA DA INVESTIGAÇÃO LABORATORIAL NA PRÉ-ECLAMPSIA

Neste artigo apresenta-se a tecnica de analise de Fourier utilizando o software de circuitos eletricos Proteus Isis para simulacao de sinais harmonicos em um sistema eletrico de potencia. Para tanto, faz-se um introdutorio sobre sistemas eletricos de potencia, harmonicos, series e transformada de Fourier.

A Análise de Fourier utilizando o software Proteus Isis: Um estudo de caso sobre as harmônicas

Objetivou-se quantificar em silagens de cana-de-acucar com diferentes niveis de inclusao de erva-sal (Atriplex nummularia Lindl.) os teores de carboidratos soluveis, producao de etanol, pH e poder tampao. Utilizou-se o delineamento inteiramente casualizado; os tratamentos consistiram de 0, 20, 40 e 60% de erva-sal em substituicao a cana-de-acucar com seis repeticoes cada. As forragens em suas proporcoes experimentais foram armazenadas em silos (baldes plasticos) de 25 litros adaptados com valvula do tipo Bunsen. Apos periodo de fermentacao de 90 dias, os silos foram abertos e coletaram-se amostras para obtencao do extrato aquoso, no qual foram determinados pH, poder tampao, teores de carboidratos soluveis (CHOSol) e etanol. A adicao de erva-sal proporcionou diminuicao (P<0,05) das concentracoes de etanol nas silagens avaliadas, onde se verificou reducao de 60,08%, considerando-se os niveis 0 e 40% de Atriplex sobre a silagem de cana-de-acucar. Observou-se ainda com o incremento de erva-sal, pH adequado a conservacao (≤ 3,7). A inclusao de erva-sal reduz a producao de etanol e melhora a qualidade fermentativa da silagem de cana-de-acucar. DOI:10.15528/2176-4158/rcpa.v14n2p173-176

Teores de Etanol e Carboidratos Solúveis de Silagens de Cana-de-Açúcar com Erva-Sal

MODELAGEM COMPUTACIONAL DOS EFEITOS DA TERMOTERAPIA TRANSPUPILAR EM TUMORES OCULARES ATRAVÉS DO MÉTODO DOS VOLUMES FINITOS EM MALHAS NÃO ESTRUTURADAS.

Função da proteína EnvZ na osmotolerância e fixação biológica de nitrogênio em Gluconacetobacter diazotrophicus

USO DE GEOTECNOLOGIAS NA RESOLUÇÃO DO CONFLITO TERRITORIAL DOS LIMITES GEOGRÁFICOS DA APA DO SANA - MACAÉ-RJ

SILVA, J. A. Manguezal do estuario Barra Grande em Icapui-CE: da degradacao ao processo de recuperacao e mudanca de atitude. 2012. 148 f. Dissertacao (Mestrado em Geografia) - Centro de Ciencias, Universidade Federal do Ceara, Fortaleza, 2012.

MANGUEZAL DO ESTUÁRIO BARRA GRANDE EM ICAPUÍ-CE: da degradação ao processo de recuperação e mudança de atitude

COSTA, Genira Pereira da. Housing Deficit and occupation in a risky área: Study of case of the housing complexes José da Silva Sobral, Vida Nova e Mazagão I e II Alagoa NovaPB. 70 pages. Monograph (graduation) Complete Degree Course in Geography. DG/UEPB, Campina Grande-PB, 2011. The aim of this essay is to identify the housing need in the town of Alagoa Nova-PB and the politics of use and occupation of the urban soil and its implications on the construction of the socioenvironmental risks. Based on the research, it was noticed that the living spaces build by the municipal government present high degrees of socioenvironmental vulnerability along with low academic levels and the absence of the basic infrastructure building equipments. To obtain the data was used a bibliographic research, which made possible the understanding of how ordered are the spacial elements and what were the objects of this study and how the reality of it is considered socially. In face of the reality presented on the spot at the three housing complexes Vida Nova, José da Silva Sobral e Mazagão I e II, were applied questionnaires to 45 families, corresponding to 43,28 % of the total. Those were fundamental to the study of the social and economic conditions of the local population, as well as to identify the environmental problems from the residents point of view. The study becomes an important tool to the analysis of the social housing politics on the shaping of exclusion and socioenvironmental segregation spaces, contributing to the insertion of families in risk areas, knowing that their homes are built with federal and local resources, having by aim to minimize the housing deficit and to answer the housing principles. KEY – WORDS: Housing Crisis; Socioenvironmental Segregation; Social Housing Politics; Socioenvironmental Vulnerability.

UNIVERSIDADE ESTADUAL DA PARAÍBA CENTRO DE EDUCAÇÃO DEPARTAMENTO DE GEOGRAFIA CURSO: LICENCIATURA EM GEOGRAFIA

Resumo: O artigo faz um excurso critico sobre os estudos filologicos, abordando a questao do metodo, indissociavel da historia da linguistica românica. Palavras-chave: Filologia. Metodo. Critica textual. Ecdotica.

A utilizacao de energia eletrica em massa vem sendo um dos grandes fatores geradores nao somente dos problemas ambientais, mas tambem financeiros. Isso se revelou em evidencia com a utilizacao de aparatos eletronicos que consomem quantidades elevadas de energia eletrica e que nao apresentam a capacidade esperada em edificacoes nao projetadas adequadamente conforme o clima onde o espaco geografico nao propicia o aproveitamento dos fatores ambientais na obtencao do conforto termico dos ocupantes. Em funcao disso, a arquitetura bioclimatica utiliza elementos arquitetonicos para aquisicao de bem-estar e busca a otimizacao do uso dos recursos naturais, baseando-se em quatro principios basicos: criacao de espacos em ambiente saudavel para os moradores e usuarios; eficiencia energetica e consideracao do ciclo de vida da estrutura edificada; minimizacao de desperdicios e uso de fontes renovaveis de energia e materiais que nao agridam o meio ambiente. Portanto, a arquitetura bioclimatica surgiu como alternativa para o conforto termico, atraves da aplicacao de seus metodos, construimos projetos arquitetonicos inteligentes e ecologicamente corretos; tendo em vista a especificidade climatica, evitando ao maximo o consumo de energia eletrica, diminuindo assim os  gastos e proporcionando um ambiente mais confortavel e funcional aos seus ocupantes.

Os benefícios da arquitetura bioclimática no conforto e na economia energética

Affonso Augusto Moreira Penna: duas vezes o criador da primeira Faculdade de Direito em Minas Gerais

O controle externo, funcao do Poder Legislativo, e exercido com o auxilio de outras entidades que podem ser tanto os Tribunais de Contas como as Auditorias ou Controladorias-Gerais. Tendo isso em vista, este artigo possui o objetivo de descrever os sistemas de controle externo mais utilizados no mundo atualmente – o Anglo-Saxonico e o Latino Americano – e confronta-los, a fim de explicitar as suas peculiaridades e tracar um paralelo entre as sistematicas utilizadas no Brasil, nos Estados Unidos e na Inglaterra. Antes, contudo, necessitou-se discorrer sobre quais as especies de controle existentes e alicercar o entendimento sobre o controle externo, tema central deste estudo. A pesquisa bibliografica e em sitios virtuais foi a ferramenta que impulsionou a realizacao do estudo que discorre sobre a realidade nas tres nacoes escolhidas. O resultado da pesquisa demonstra que cada modelo possui vantagens e deficiencias, mas que cabe a cada Pais escolher aquele que seja mais adequado para a sua realidade. Esta conclusao serve para demonstrar que nao existe um sistema melhor do que o outro, mas ha, sim, a necessidade de controlar os gastos dos gestores publicos por intermedio de qualquer modalidade, resguardando, desse modo, o Erario.

Sistemas de controle externo - abordagem sobre o sistemas anglo-saxão e latino-americano

Papel das citocinas e quimiocinas na resposta imunológica murina na infecção por Leptospira interrogans sorovar Copenhageni.

The purpose of this study was to evaluate the performance of varieties RB (Republic of Brazil) from sugar cane in relation to the attack of Diatraea spp. We used two cropping systems: rainfed and irrigated. The varieties studied were: RB72454, RB867515, RB971755, RB951541, RB931003, RB92579, RB863129 and RB93509. For irrigated crop, includes the RB98710. In both experiments, assessments were performed every 30 days. The damage caused by the borer were observed externally on all stems present in the sample and the percentage of intensity of external damage (% I.D.E.). The evaluation of the percentage of intensity of internal damage (% I.D.I.) was performed at harvest on 15 stems in each plot. In assessing the varieties together in the dryland cropping, it was found that the % I.D.E of Diatraea spp, was significantly greater in variety RB951541 compared with varieties RB863129, RB92579, RB867515, RB93509 and RB931003. Moreover, in irrigated crop, variety RB971755 stood out with greater %I.D.E. of Diatraea spp. when compared with the varieties RB72454, RB92579, RB867515, RB93509 and RB931003. As for the complex borer / rot at harvest, the varieties were similar. In both systems of cultivation, the %I.D.I. of Diatraea spp. and the agroindustrial parameters did not a positive correlation.

UNIVERSIDADE FEDERAL DE ALAGOAS CENTRO DE CIÊNCIAS AGRÁRIAS PROGRAMA DE PÓS-GRADUAÇÃO EM AGRONOMIA

Pretendo tratar do princípio que governa a tripartição da alma na República de Platão, ou melhor, o argumento necessário para fundamentar uma psique tripartite. Sabemos que Platão recorre ao Princípio de Não-Contradição para fundamentar a partição da alma, porém, não existe um argumento evidente que justifique uma tripartição. Entre as teses apresentadas por especialistas, trabalharei a que estabelece uma simetria entre a teoria do conhecimento platônica com sua teoria moral, a saber: a ciência é própria do elemento racional e a opinião dos irracionais (quando verdadeira, é própria do elemento irascível; quando falsa, do concupiscente); logo, tem-se uma alma tripartite. Reconheço existir problemas nesta interpretação, o que me faz apresentar uma hipótese interpretativa: a simetria entre as três formas de bens apresentada no início do Livro II com os elementos da alma. 
 
O princípio que fundamenta a tripartição da alma na República de Platão

Diagnostico de situacao utilizando metodologia cientifica de natureza exploratoria e descritiva (observacao participada com tratamento estatistico descritivo) com objectivo de identificar as praticas de enfermagem na area da promocao de saude durante uma consulta de enfermagem de saude infantil. Das 31 consultas observadas (n=31) a maioria das observacoes ocorreu em criancas com idade inferior a 2 anos sendo os temas mais abordados a alimentacao com utilizacao predominante de metodologia expositiva. Verificou-se ainda pouca utilizacao de suporte informacional e quando sao utilizados reportam-se aos temas seguranca e alimentacao. A maioria dos prestadores de cuidados colocou questoes e houve um reduzido registo da interaccao prestador/crianca existindo um dispendio medio de 23 minutos por consulta. Face aos resultados e reflexao sobre os mesmos destaca-se como intervencao a elaboracao de um manual de promocao de saude com integracao de aspectos teoricos e evidencia cientifica de boas praticas nesta area.

Observação participada da consulta de enfermagem de saúde infantil

Objetivou-se avaliar o efeito da adicao do residuo da vinificacao compostado (RVC) nas caracteristicas estruturais, morfogenicas e quimico-bromatologica de plantas de Brachiaria ruziziensis. Realizou-se experimento em delineamento inteiramente casualizado com cinco tratamentos de adicao de RVC (0, 3, 6, 9 e 12%), em seis repeticoes. A aplicacao do RVC proporcionou incremento nos teores de proteina bruta e materia mineral a partir da dose de 6% e na relacao perfilho/planta e taxa de aparecimento de folha a partir de 9%, em plantas de B. ruziziensis. Conclui-se que a aplicacao do residuo da vinificacao compostado em plantas de B. ruziziensis resulta em maior producao de biomassa aerea e teores de materia mineral e proteina bruta, alem de favorecer o aparecimento de folhas e aumentar a densidade de perfilhos por planta. DOI: 10.15528/2176-4158/rcpa.v14n1p46-49

Resíduo da Vinificação no Desenvolvimento e Composição Químico-Bromatológica de Plantas de Brachiaria ruziziensis

The objective of this work was to evaluate the effect of plant fertilization on the rooting of guarana cuttings. The experimental design was completely randomized in a 6x2 factorial arrangement, with five cultivars and one genotype of guarana, with or without fertilization. The experimental unit contained ten cuttings with four replicates. The fertilization was applied after pruning (January), after fruiting (April), and before the beginning of flowering (May). For rooting, the cuttings were kept in incubators at 50% irradiance and under intermittent mist. After 120 days in the incubator, the following characteristics were evaluated: rooted and dead cuttings; cutting length; and volume and dry weight of roots. Plant fertilization increased rooting in 11.15%, and reduced cutting mortality in 11.05%. The fertilization promoted a greater rooting in the cultivars BRS-Maues, BRS-CG882 and in the genotype CMU 381. Irrespective of the cultivar, the fertilization increases the number, volume and weight of root dry matter; however, it has no influence on root length.

Enraizamento de estacas de cultivares de guaranazeiro com adubação de plantas matrizes

Avaliação da atividade imunomoduladora de Propionibacterium acnes em animais submetidos à sepse letal e perfuração do ceco (CLP)

Em sua tese de doutorado, a Profa. Luisa Lessa desenvolveu uma pesquisa dialetologica a partir de investigacoes de campo realizada no Vale do Acre, considerando as duas atividades economicas basicas da regiao: o latex e a agricultura, utilizando-se a metodologia da geografia linguistica para delimitar as zonas e os pontos de inquerito para aplicar o questionario especifico, segundo as peculiaridades geograficas e linguisticas locais, que.

Contextualizar e problematizar e propor situacoes significativas para os alunos de forma que os conhecimentos quimicos auxiliem na compreensao e resolucao de problemas 1 . A quimica e caracterizada por grande parte dos alunos, como sendo uma ciencia “dificil” e “chata”. Desta forma, e fundamental que o professor de quimica utilize metodologias de ensino inovadoras que facilitem a aprendizagem de conceitos quimicos 2 . Os temas socio cientificos tem sido propostos como tentativa de contextualizar o conhecimento de quimica a partir das experiencias trazidas pelos alunos para a sala de aula, o que pode despertar um maior interesse dos estudantes para o aprendizado desta ciencia 3 . Este trabalho teve como objetivo analisar uma sequencia didatica sobre Tratamento de Agua (TA) para abordar o conteudo de misturas. A sequencia didatica 4 (SD) envolveu tres etapas: 1a Resolucao de questoes (Q1 a Q16) objetivas e subjetivas para identificar concepcoes previas e compreensao dos discentes sobre a tematica; 2a Visita a uma Estacao de Tratamento de Agua (ETA) em Caruaru-PE; 3o Resolucao de questoes (Q1 a Q16) apos a visita. A SD foi aplicada a 40 alunos do primeiro ano do Ensino Medio de uma Escola Publica da cidade de Caruaru-PE, com duracao total de 6 horas.

Abordagem do Conteúdo de Mistura envolvendo o Tratamento de Água: análise de uma proposta didática para o ensino de Química

O objetivo deste trabalho foi verificar os efeitos da aplicacao de nitrogenio (N) e boro (B) no solo sobre o desenvolvimento de mudas de bananeira Prata ana cultivadas em Latossolo Vermelho de textura argilosa (LV) e de Latossolo Vermelho-Amarelo de textura media (LVA). O experimento foi conduzido em casa de vegetacao na Empresa de Pesquisa Agropecuaria de Minas Gerais (EPAMIG), utilizando-se delineamento inteiramente casualizado, com quatro repeticoes, em esquema fatorial 5 x 4, correspondentes a cinco doses de B (0; 0,5; 1,0; 2,0 e 3,0 mg dm -3 de solo) e quatro doses de N (0, 100, 200 e 300 mg dm -3 de solo). As fontes de N e B foram ureia e acido borico, respectivamente. Os dados foram submetidos ao teste de Bartlett (p

Nitrogênio e boro em mudas de bananeira Prata Anã cultivadas em casa de vegetação

ABSTRACT The objective of this study was to verify appropiate N sources (ammonium sulfate, ammonium nitrate,calcium nitrate and urea) for banana and to determine the application rate for maximum physical andeconomic efficiency. The experiments were conducted in northern semiarid region of Minas Gerais inRed Latosol and Red-Yellow Latosol. The experimental design was in randomized blocks with 20 treatmentsand four repetitions. The treatments were arranged in (4 x 5) factorial, being four N sources (ammoniumsulfate, ammonium nitrate, calcium nitrate and urea) and five N rates (0, 100, 200, 400 and 800 kg ha -1 year -1 ). The N increased production in the 1 st cycle of banana grown in the Red-Yellow Latosol, where Nrates for maximum physical efficiency were 521, 471, 410, 424 kg ha -1 and to achieve maximumeconomic efficiency were 105, 204, 260 and 5 kg ha -1 for ammonium sulfate, ammonium nitrate, ureaand calcium nitrate, respectively, with urea being the most efficient source of nitrogen. In the 2

Adubação da bananeira 'Prata Anã' com diferentes doses e fontes de nitrogênio

Digital Storytelling em contexto de formação profissional: um estudo de caso

Introdução A obesidade é uma doença que vem crescendo nos últimos anos, não só no Brasil, mas no mundo todo. Caracteriza-se pelo excesso de gordura no tecido adiposo (gordura corporal) podendo tornar-se responsável pelo desenvolvimento de outros tipos de doenças. A obesidade está associada a diversas doenças crônicas, como resistência à insulina, esteatose hepática não alcoólica, síndrome dos ovários policísticos, hipertensão, dislipidemia, apnéia do sono, asma, trombose, infarto, acidente vascular cerebral, aterosclerose e a síndrome metabólica.

AVALIAÇÃO DE MARCADORES PLASMÁTICOS LIPÍDICOS E INFLAMATÓRIOS EM CRIANÇAS SOBREPESO E EUTRÓFICAS SUBMETIDAS A UM PROGRAMA DE ATIVIDADES CIRCENSES

Primação subliminar: uma ferramenta capaz de determinar o comportamento de escolha do consumidor?

This study reports development of a computational system to determine water availability in any specific stretch along a hydrographic basin network, and quantify the impact resulting from granting new rights for water use. The system is denominated as “Integrated System for Water Resources Management” (SINGERH). To estimate water availability, three discharge regionalization methods were implemented by using the programming tool ‘Borland Delphi 7.0’. The calculation of the impact from granting new rights for water use was done by considering the discharge to be granted, based on the section-estimated discharge, granting criteria of basin management agency and the discharges granted upstream the section under analysis. These data can be obtained by consulting users’ registers available at the state and federal managing agencies. SINGERH was applied to a specific section on the Preto River belonging to the Paracatu river basin to verify the functionality and potential of the system. The system allowed determination of the minimum and average discharge along the basin, providing inputs for decision making about granting process, through estimates of water availability at any section of the hydrography. Considering the granting criteria in Minas Gerais State, the SINGERH indicated that there was no possibility for granting new water use right during the period from May to September.

Nome dos autores: Salette Maria Barros Ferreira; Marcelo Santos Cruz; Viviane Tinoco Martins; Jose Leonardo da Silva; Juliana Sales, Bianca Valle; Thoya Lindner MosenaO presente trabalho tem o objetivo de descrever um projeto de pesquisa, financiado pela SENAD, em parceria com o PROJAD/IPUB, que tem como finalidade potencializar o Centro de Convivencia desta instituicao, atraves da difusao das tecnicas de oficinas terapeuticas para usuarios de alcool e outras drogas. As oficinas sao dispositivos clinicos que tem como caracteristica um fazer pautado em uma atividade, que proporciona uma interacao coletiva, promocao de autonomia, reconstruindo vinculos sociais muitas vezes perdidos. O projeto propoe: desenvolver as atividades de oficinas terapeuticas, seminarios internos semestrais junto aos alunos de graduacao e pos-graduacao, qualificando-os para a rede publica de assistencia; desenvolver acoes de capacitacao da rede de CAPS-ad, atraves de Work-shop e seminario; elaborar uma cartilha sobre o trabalho com oficinas terapeuticas para instrumentalizar a formacao dos profissionais da rede, a partir de uma abordagem interdisciplinar; implantar o Nucleo de Atividades Culturais (NAC) no Centro de Convivencia do PROJAD, atraves do dispositivo do Acompanhamento Terapeutico. O NAC pretende contribuir para a reinsercao social destes pacientes, atraves de atividades culturais extramuros (exposicoes, cinema, caminhadas, pontos turisticos, entre outros), promovendo a difusao dos espacos de cultura da cidade. Para isso, o projeto tambem conta com a elaboracao de um blog, possibilitando que esta populacao se aproxime do universo virtual tao presente na contemporaneidade. Essas atividades sao precedidas de reunioes com os pacientes e os acompanhantes, onde se recolhe os efeitos desse trabalho de circulacao, alem de construcao coletiva da proxima saida. Palavras-chave: toxicomania; oficinas terapeuticas; acompanhamento terapeuticoIntroducaoO Programa de Estudos e Assistencia ao Uso Indevido de Alcool e Outras Drogas (PROJAD) foi criado em 1996 para desenvolver atividades de pesquisa, ensino e atendimento a usuarios de alcool e outras drogas e tambem aos seus familiares. Este e um servico que esta inserido na rede de servicos do Municipio do Rio de Janeiro, trabalhando em parceria especialmente com os CAPS-Ads e com o Instituto Municipal Philippe Pinel. Sua principal especificidade e justamente atender aqueles sujeitos para os quais a toxicomania esta associada a comorbidades psiquiatricas (como as psicoses).Desde sua criacao, e em compatibilidade com resultados de pesquisas de outros servicos, nos deparamos com a dificuldade que esses pacientes apresentam de se manterem em tratamento. Alem disso, geralmente trata-se de sujeitos que estao de alguma forma a margem no territorio urbano, no mercado de trabalho e mesmo no convivio social e familiar, marcados que estao pelo uso de drogas. Entre os fatores que parecem contribuir para o agravamento desta situacao, encontram-se o desemprego, o emprego com vinculo instavel ou temporario e a ausencia de opcoes de atividades culturais e esportivas em suas comunidades de origem. Este conjunto de fatores torna esta populacao especialmente exposta aos riscos da convivencia com o trafico e o consumo prejudicial de alcool e outras drogas. Um dos objetivos dos servicos de assistencia, em consonância com as propostas da Reforma Psiquiatrica, e justamente favorecer a reinsercao e a reintegracao social e familiar desta populacao.Entre aqueles que procuram tratamento, mesmo quando se apresentam motivados, a dificuldade de insercao na rede de sociabilidade e o desemprego tornam a ociosidade um grave obstaculo ao sucesso do tratamento. Sabemos que as situacoes provocadas pelo uso indevido e dependencia de drogas provocam a fragilidade e/ou rompimento dos lacos sociais; no minimo, induzem a seu esgarcamento. Em estudo realizado anteriormente no servico e com o apoio da SENAD (SAAD, AC; COSTA, NR; BARBEITO, MM; CRUZ, MS. 2004) identificou-se que a parcela de usuarios de drogas mais jovens e com menor escolaridade e a que tem maior dificuldade de aderir ao tratamento.Para minimizar esta dificuldade, foi essencial a inclusao, entre os recursos oferecidos pelo PROJAD, de um Centro de Convivencia. Ha cerca de cinco anos ali se desenvolvem oficinas terapeuticas de musica, de mosaico, de culinaria, de comunicacao, de fotografia e, mais recentemente, de linhas (trico, croche, fuxico, etc). As oficinas caracterizam-se pela reuniao de um grupo de pessoas em torno de um fazer, com a producao de um objeto concreto de forma coletiva. As oficinas oferecem nao apenas uma alternativa de contato com outros, mas pode permitir o mapeamento de um outro percurso em relacao ao uso de drogas, constituindo estrategia que visa a uma maior implicacao do sujeito no seu tratamento. Alem disso, as oficinas oferecem como produto final producoes esteticas como exposicoes fotograficas, musicas, pecas de mosaico que podem conferir novos valores aos sujeitos, que podem experimentar o reconhecimento de um lugar social diferente, desta vez, como artistas.As direcoes apontadas pela politica de saude mental para o cuidado com a populacao em situacao de uso indevido de drogas, em curso desde o inicio de 2002 (BRASIL, 2002) dirigem a acoes assistenciais que privilegiem os espacos de sociabilidade e as alternativas de reinsercao, a exemplo tambem do que vem sendo construido no restante do campo da saude mental (BRASIL, 2002) e apontado pelas organizacoes internacionais. (OMS, 2001). Entretanto, os cursos de formacao na area da saude e afins nao se encontram ainda preparados para responder a demanda que suas acoes irao solicitar. Quando estas se referem ao campo de atencao ao uso abusivo de drogas, estas dificuldades se tornam ainda maiores (CRUZ, M., 2001).Ainda que as oficinas, enquanto dispositivo terapeutico, apontem para a possibilidade de seus participantes constituirem-se tambem “artistas”, sabemos que a real reinsercao social de pacientes no campo da saude mental e ainda um grande desafio para o nosso campo de atuacao. Partimos deste impasse para criar o Nucleo de Atividades Culturais do PROJAD.Material e metodologiaO Nucleo de Atividades Culturais (NAC) dirige-se aos pacientes do PROJAD. Trata-se de uma atividade de acompanhamento terapeutico realizado com um grupo de pacientes da instituicao que apresentem o desejo de passear pela cidade do Rio de Janeiro. Este grupo se encontra semanalmente no patio do IPUB (Instituto de Psiquiatria da UFRJ) para definir o local, percurso, data e horario do proximo passeio e para conversar sobre os efeitos do passeio realizado na semana anterior. Este Nucleo e desenvolvido por tres acompanhantes terapeuticos.Rompendo com a logica hospitalocentrica que predominou no campo da psiquiatria e da saude mental e, em especial, no campo das toxicomanias, o NAC inova em sua estrategia de intervencao por privilegiar os espacos extramuros de producao de novos sentidos e investir na insercao dos sujeitos toxicomanos no territorio da urbe.Resultados e discussoesDesde seu inicio, em fevereiro de 2011, ja realizamos saidas para uma serie de centros culturais do Rio de Janeiro, sempre considerando as propostas construidas coletivamente pelo grupo de pacientes e acompanhantes.Como primeiros efeitos destas atividades extramuros, observamos a partir das narrativas dos proprios integrantes do NAC um misto de surpresa, alegria e orgulho pelos novos e agora possiveis itinerarios percorridos. Alem disso, seus familiares tem reconhecido e testemunhado a importância dessa circulacao acompanhada pela cidade.Outros efeitos inicialmente observados sao as novas formas de enlace social a partir da experiencia coletiva de ampliacao do seu universo, o que vem produzindo efeitos tambem singulares e novas formas de andar a vida.ConclusaoAcredita-se que, ate o momento, os objetivos primeiramente tracados vem sendo atingidos em funcao do retorno dos pacientes e familiares anteriormente descrito. O projeto propoe-se a desenvolver as atividades de oficinas terapeuticas, seminarios internos semestrais junto aos alunos de graduacao e pos-graduacao, qualificando-os para a rede publica de assistencia; desenvolver acoes de capacitacao da rede de CAPS-ad, atraves de Work-shop e seminario; elaborar uma cartilha sobre o trabalho com oficinas terapeuticas para instrumentalizar a formacao dos profissionais da rede, a partir de uma abordagem interdisciplinar; implantar o Nucleo de Atividades Culturais (NAC) no Centro de Convivencia do PROJAD, atraves do dispositivo do Acompanhamento Terapeutico. A equipe possui supervisao semanal e seminario de pesquisa. REFERENCIAS BIBLIOGRAFICAS.BRASIL. Relatorio Final da III Conferencia de Saude Mental. Ministerio da Saude, Brasilia, 2002.BRASIL. A Politica do Ministerio da Saude para a atencao integral a usuarios de alcool e outras drogas. Brasilia, Ministerio da Saude, 2004.CRUZ. S. M. Formacao de profissionais para o atendimento a usuarios de drogas. Tese de Doutorado: Universidade Federal do Rio de janeiro, Instituto de Psiquiatria, 2001. (mimeo)CRUZ.S.M; EAST, L. A; COSTA, N; SILVA, O E; SILVA, S.T; BRAGA, R.M; INEM, L.C. MARTINS, T. V; RAMOS, A; FERREIRA, S.M.B. Criacao de um servico de atendimento a usuarios de drogas em ambulatorio do Instituto de Psiquiatria da UFRJ: experiencia de dois anos; em Informacao psiquiatrica, 18 (1) : 17-22, 1999.OMS. Relatorio sobre a Saude no Mundo – Saude Mental. 2001.SAAD, AC; COSTA, NR; BARBEITO, MM; CRUZ, MS. Abandono e adesao no tratamento para dependencia de drogas numa instituicao universitaria (PROJAD/IPUB/UFRJ). Revista Brasileira de Psiquiatria 26(supl II): 3, 2004.

NÚCLEO DE ATIVIDADES CULTURAIS: CONSTRUINDO UM ‘DE DENTRO PARA FORA’

O trabalho foi conduzido no ano de 2011, na Area Experimental do Setor de Melhoramento Genetico de Plantas do Centro de Ciencias Agrarias da Universidade Federal de Alagoas (SMGP-CECA-UFAL), com o objetivo de avaliar o desempenho de genotipos Alagoanos de milho em diferentes densidades de semeadura. Foram avaliados quatro genotipos de milho, sendo tres desenvolvidos pelo SMGP-CECA-UFAL (VICOSENSE, BRANCA e RIO LARGO) e um desenvolvido pela EMBRAPA (BRS 106), em tres densidades de semeadura: 50.000, 62.500 e 83.333 plantas.ha-1 . Foi usado o delineamento em blocos casualizados com tres repeticoes. As parcelas experimentais foram constituidas por cinco fileiras de 5,0 m de comprimento, sendo area util constituida pelas tres fileiras centrais. As variaveis avaliadas foram: Diâmetro do Colmo (DC), Altura de Insercao de Primeira Espiga (AIPE), Altura de Planta (AP), Porcentagem de Prolificidade (PROL), Porcentagem de Plantas Acamadas (PPA), Comprimento de Espiga (CE), Diâmetro de Espiga (DE), Numero de Fileiras de Graos (NFG), Peso de Cem Graos (PCG), Rendimento de Espigas com Palha (REP) e Rendimento de Graos (RG). Nao houve diferenca significativa entre os genotipos avaliados para as seguintes variaveis: DC, PPA, CE, DE, PCG, REP e RG. Por outro lado, houve diferenca significativa entre os genotipos avaliados para as seguintes variaveis: AIPE, AP, PROL e NFG. Os genotipos desenvolvidos pelo SMGP-CECA-UFAL: VICOSENSE, BRANCA e RIO LARGO apresentaram um excelente desempenho para todas as variaveis estudadas, especialmente no rendimento de graos, com uma produtividade media de 6.379,00 kg.ha-1. A densidade de semeadura de 83.333 plantas por hectare promoveu um maior rendimento de espigas com palha e rendimento de graos, respectivamente, 11.853,04 kg.ha-1 e 7.888,96 kg.ha-1.

Desempenho de genótipos alagoanos de milho (Zea mays L.) em diferentes densidades de semeaduras

A Fitorremediacao utiliza plantas para remediar solos e sistemas aquaticos contaminados por substâncias orgânicas e inorgânicas. Seus resultados sao satisfatorios e demonstram que certas especies de plantas com alto potencial genetico podem remover, degradar, metabolizar ou imobilizar uma serie de contaminantes, como metais pesados, petroleo, esgoto domestico e industrial, etc. Apesar de promissora a fitorremediacao tem encontrado problemas em descobrir novas plantas com capacidade para remediacao de ambientes contaminados. O proposito deste estudo prospectivo e a identificacao de plantas na regiao do Polo Industrial de Manaus (PIM), que possam acumular altos teores de metais pesados. As seguintes especies: Vismia guianensis (Aubl.) Choise, Diplasia karataefolia, Vismia japurensis, Annona, Alibertia edulis A. Rich, Poaceae (Capim coloniao), Lantana camara L., Araceae e Diffenbachia picta Schott, foram coletadas em tres fragmentos florestais, nas margens de igarapes do PIM. As plantas escolhidas foram submetidas a elevados niveis de contaminacao provenientes da poluicao dos igarapes. Amostras de solo dos fragmentos florestais foram coletadas e suas propriedades fisicas e quimicas determinadas por metodologias da EMBRAPA. As folhas de plantas foram separadas, digeridas com HNO3 concentrado a 60 ° C, e o conteudo de Zn, Fe, Mn, Cu, Co, Cd, Pb e Ni, determinado por espectrometria de absorcao atomica. Os resultados mostram que todas as plantas estudadas sao capazes absorverem niveis elevados de metais pesados em suas folhas. Como resultado, podemos afirmar que Vismia guianensis (Aubl.) Choise, Diplasia karataefolia, Vismia japurensis, Annona, Alibertia edulis A. Rich, Poaceae (Capim coloniao), Lantana camara L., Araceae e Diffenbachia picta Schott sao potencialmente fitorremediadoras.

Prospecção de plantas fitorremediadoras em solos contaminados por metais pesados

Este trabalho resultará do estudo da temática da fome, presente no romance Homens e Caranguejos, de Josué de Castro, relacionada com o mundo real. Através de uma pesquisa qualitativa serão consultados documentos de órgãos governamentais e não-governamentais, dados estatísticos, matérias de jornais e obras que tratam de questões como a fome, seca e o êxodo rural para subsidiar a análise dos excertos, retirados do corpus, pertinentes ao tema, os quais serão interpretados a partir do método dialético em associação com o método comparativo, sob o enfoque da Teoria do Romance de Georg Lukács, seqüenciada por estudiosos como Lucien Goldmann (Sociologia do romance), Roger Bastide (Arte e sociedade), Michel Zéraffa (Romance e sociedade), Fredric Jameson (O inconsciente político: a narrativa como um ato socialmente simbólico), Alfredo Bosi (História concisa da literatura brasileira) e Antonio Candido (Arte e Sociedade).

A representação da fome em Homens e Caranguejos de Josué de Castro

The Environmental Preservation Area (EPA) of Sana is a Municipal Conservation Unit with private and public lands in the rural area of Macae. This region has been densely occupied, due to the increase of tourism and urban rowth. This EPA has a Management Plan and Environmental Zoning to regulate nature conservation with sustainable use of local natural resources. As the Environmental Zoning is the most important tool to support decisions made by EPA, an evaluation of the cartographic adequacy of its limits was conducted in this study

Uso de Sistemas de Informação Geográfica na resolução da inadequação dos limites cartográficos da Área de Preservação Ambiental do Sana – Macaé, RJ

A atencao dispensada ao individuo com Sindrome de Down pode influenciar diretamente na sua qualidade de vida, uma vez que questoes bioquimicas, hematologicas, hormonais e imunologicas desempenham importante papel para o aumento da longevidade dos individuos possuidores dessa patologia. E necessaria a elucidacao de aspectos hematologicos que comprometem a qualidade de vida destes individuos; para tanto, realizou‑se pesquisa bibliografica acerca do estado da arte das referidas questoes, uma vez que uma fundamentacao teorica se torna indispensavel para o embasamento e compreensao do assunto em analise.

ALTERAÇÕES HEMATOLÓGICAS DE INDIVÍDUOS PORTADORES DA SÍNDROME DE DOWN

A agricultura familiar no Brasil, nos ultimos anos vem apresentando bom resultado,
sobretudo pela producao de alimentos destinados ao mercado interno, a atividade ocupa
75% da populacao economicamente ativa do setor agricola, e, e responsavel por 80% dos
alimentos consumidos no mercado interno Por suas caracteristicas relevantes e de suma
importância entender o processo de organizacao dessa categoria especialmente dos
agricultores remanescentes de quilombolas, assentamentos rurais ou arrendatarios de terras
publicas, nesse sentido o estudo ora apresentado tenciona investigar a organizacao
endogena dos arrendatarios do DNOCS do Acude Publico Epitacio Pessoa em BoqueiraoPB,
assim como identificar as tecnicas utilizadas por estes para alcancar o
desenvolvimento de suas propriedades. O trabalho justifica-se pela importância que a
atividade apresenta para a regiao que historicamente apresenta crescimento de escala.
Atualmente a producao pauta-se em culturas de subsistencia e mercadologicas de modo
que averiguar a viabilidade economica da producao, tendo em vistas a utilizacao dos
fatores, terra, capital e trabalho com uso eficiente dos recursos, capacidade de
investimentos, uso de tecnologias modernas e formacao de poupanca, relacao de demanda
agregada e decisao por que insumos utilizar sao fatores que se tornam eficientes na tomada
de decisoes quando sao analisados a partir dos elementos: VPL (Valor Presente Liquido),
TIR (Taxa Interna de Retorno), fluxo de caixa, funcao demanda e oferta, decisao pela
utilizacao de insumos na producao entre outros, ganham destaque na regiao o cultivo da
banana, do mamao e do maracuja sao as culturas que apresentam melhores retornos
economicos, tambem apresentam bons resultados o tomateiro e o pimentao, no que se
refere a culturas de consumo direto nas unidades produtivas, as mais importantes sao o
feijao e o milho. As mudancas ocorridas na pratica agricola em torno do acude atraves das
culturas desenvolvidas ocorrem provavelmente em funcao dos criterios de relacao de
propriedade da terra, os numeros de hectares destinados a cada cultura, tecnicas utilizadas
na producao, a mao de obra presente no campo, presenca de assistencia tecnica, formas de
comercializacao da producao e a renda anual auferida pelos irrigantes/pequenos produtores
capitalistas.

Analise de viabilidade econômica da agricultura familiar dosarrendatários do DNOCS no Açude de Boqueirão-PB

The Lake District (“Regiao dos Lagos”) in the State of Rio de Janeiro does not have a waste inventory or any systemized reliable data related to waste generation. Its municipalities also do not present combined management procedures in order to mitigate the enormous environmental liabilities due to solid waste disposal in inappropriate landfills. This paper aims to estimate and classify solid waste originated in the cities of Armacao dos Buzios, Arraial do Cabo, Cabo Frio, and Sao Pedro da Aldeia, by analyzing socio-economic data and considering local GDP.

Avaliação da produção e gestão dos resíduos sólidos de municípios da Região dos Lagos do estado do Rio de Janeiro

Erradicação da fome, o eixo central [entrevistado por Paulo Roque]

UNIVERSIDADE ESTADUAL DA PARAÍBA CAMPUS VII - GOVERNADOR ANTONIO MARIZ CENTRO DE CIENCIAS EXATAS E SOCIAIS APLICADAS CURSO DE GRADUAÇÃO BACHARELADO EM ADMINISTRAÇÃO

Valerio Caldas de Magalhaes (*06/09/1909 – †24/11/1964) nasceu em Boa Vista, no antigo municipio amazonense de Rio Branco, que posteriormente se transformou no territorio do Rio Branco, atual estado de Roraima, e foi casado com a senhora Alba Araujo Jorge Magalhaes, com quem teve quatro filhos: Ivete, Julio Cesar, Maria Herminia e Cesarina.

VALÉRIO CALDAS DE MAGALHÃES, PRIMEIRO ESBOÇO PARA A SUA BIOGRAFIA

This article aims to analyze the socio-spatial dynamics after the formation of the Itaipu Lake, in October 1982, with the consequent immersion of the Seven Falls (saltos das Sete Quedas). From the social and environmental impact due to the flooding, a new stage of development is going to be implemented in Guaira, since the natural attraction of the Seven Falls, for tourism, boosted the local economy. Through the master plans of 1980 and 1992, new guidelines for the development of the municipality were set, ordering a new socio-spatial reality. Data provided by public institutions also help methodologically the research. The present conditions point to a socioeconomic dynamic much more powerful than in the past, since the evidences of a new stage of development are represented in infrastructure works. As example we can mention the bridge over the Parana River which is a new economic source, increase of employment, and integration of the municipality of Guaira with other municipalities through inductive programs of regionalization.

Dinâmica socioespacial do município de Guaíra (PR) após o fim das Sete Quedas

Estratégias de referenciação em textos escritos em língua portuguesa por alunos indígenas da Comunidade Terena de Miranda – MS

Com a producao do Atlas Digital da VIII Regiao Hidrografica objetiva-se auxiliar as acoes de gestao das aguas nas bacias dos rios Macae e Das Ostras. A realizacao do projeto visa consolidar tecnologias para uma politica sustentavel no uso das aguas. O Atlas, elaborado para ser utilizado principalmente em midia eletronica, constitui de uma colecao sistematica de mapas com diversos formatos de dados, que apresentam propriedades espaciais e nao espaciais reunidas num mesmo ambiente. O desenvolvimento da pesquisa foi baseado no levantamento e discussao da tematica em estudo e compilacao da documentacao cartografica do formato analogico para o digital da area de abrangencia. Julgou-se necessario a realizacao de visitas tecnicas as areas de interesse para melhor compreensao da regiao e debate acerca da situacao hidrica de determinados pontos das bacias. A partir do Sistema de Informacoes Geograficas pode-se produzir uma serie de mapas tematicos, auxiliando didaticamente na leitura dos recursos naturais regionais como um todo. Para o tratamento das informacoes cartograficas e cruzamento dos bancos de dados foram utilizados os softwares ArcGis 9.2 e Corel Draw 12. A producao parcial do Atlas revelou uma regiao com distribuicao heterogenea dos recursos hidricos nos 04 municipios que a compoe. A area em estudo apresentou grande degradacao de seus corpos hidricos por ser uma regiao de intensas atividades industriais e uso inadequado do solo urbano, ligadas principalmente ao petroleo, tais atividades vem degradando os recursos hidricos da regiao. Medidas como a criacao de canais de drenagem serviram como fatores que aceleraram o processo de assoreamento dos corpos hidricos regionais, a exemplo da Lagoa de Imboassica que perdeu boa parte de sua totalidade por conta de tais processos, alem de gerar evidentes conflitos a respeito do uso das aguas. A realizacao do projeto possibilita o gerenciamento espacial da regiao, permitindo uma analise mais apurada dos recursos naturais e hidricos. O Atlas facilita o entendimento da regiao e possibilita vislumbrar melhores formas de utilizacao destes recursos, proporcionando o uso sustentavel das aguas.

ATLAS DIGITAL DA VIII REGIÃO HIDROGRÁFICA DO ESTADO DO RIO DE JANEIRO

O artigo relata a experiencia resultante do estagio de vivencia de um estudante de Medicina Veterinaria em quatro comunidades rurais nos Estados da Paraiba e Pernambuco. O estagiario realizou atividades socio-culturais e produtivas, auxiliando e interagindo com o quotidiano familiar e comunitario por um periodo de uma semana em cada comunidade. Manejo sanitario de animais, plantio de hortalicas, reunioes de associacao e sindicato, pescaria, visita as areas de manejo de caatinga foram as principais atividades. As maiores dificuldades foram: ausencia de sanitarios nas residencias, escassez de agua potavel, presenca de animais peconhentos, estradas em pessimas condicoes e falta de celular. Conclui-se que o estagio de vivencia e um momento de intenso aprendizado, a partir do quotidiano, propiciando um outro olhar para as questoes da agricultura familiar e que o poder publico deve investir para proporcionar melhores condicoes de vida e estrutura produtiva nas areas de assentamentos.

11919 - Estágio de vivência em assentamentos da Paraiba e Pernambuco

No contexto atual em que vivemos a Tecnologia de Informacao (TI) esta cada vez mais inserida no ambiente empresarial ja que esta sendo considerado um componente fundamental para a gestao das empresas. Se por um lado essa tecnologia aplicada com sucesso rende muitos beneficios para as empresas por outro traz grandes desafios para a administracao deste recurso, dos quais as empresas passam a ter elevada dependencia. Nesse mesmo periodo, as Unimeds passaram a atuar num cenario complexo, em virtude da lei dos planos de saude, que resultou em maior competitividade, melhoria da qualidade dos produtos e servicos oferecidos aos clientes. Dentro deste contexto o presente artigo teve como objetivo investigar os investimentos estrategicos feitos em Tecnologia da Informacao, avaliando os impactos gerados na gestao de negocios do Sistema Unimed do Rio Grande do Sul. Para a realizacao da coleta de dados foi realizada uma pesquisa de carater descritiva atraves de um questionario, onde foram enviados 58 questionarios as singulares. A pesquisa permitiu analisar que as Unimeds na sua grande maioria estao fazendo investimentos modestos, ou seja, ate 1% do faturamento anual, visando atender as determinacoes legais primeiramente e apos utilizando a TI como uma ferramenta para se obter vantagem competitiva. Observou-se tambem que seus CEOs foram classificados como de segundo nivel (1 – causal ou ad hoc) conforme o Modelo de Maturidade de Capacidade (CMM –Capability Maturity Model) definido por Humphrey (1989), ou seja, quando os executivos percebem que existe a necessidade de envolvimento, mas nao existe nenhum processo ou comportamento estabelecido para isto.

Tecnologia da Informação: Estratégia para os Negócios do Sistema Unimed do Rio Grande do Sul

The culture of coffee occupies a highly important role in agriculture and in the Brazilian economy, creating a major source of income for many rural families. In the state of Rondonia is the most widespread perennial crop, especially as the main producer in the Amazon region. However, to increase productivity is needed to plant healthy and vigorous seedlings. In this sense, vegetative propagation is an excellent option because the new plant has the genetic characteristics of the parent plant. To improve the rooting of the use of exogenous hormones is a technique widely used in this type of propagation. In this case, the hormones used are the indole-butyric acid (IBA) and indole acetic acid (IAA) and can also be obtained from other plants, which have higher concentrations of hormones in parts or organs. The sedge is difficult to control weed has high levels of IBA and IAA. The aim of this study was to evaluate different concentrations and immersion time of aqueous extract of purple nutsedge roots in coffee seedlings. The adopted experimental design, completely randomized design with four replicates and 10 cuttings per plot in a factorial scheme 4x2, with the factors: concentrations (0, 400, 800 and 1200 gL-1) and exposure time (20 seconds and 120 seconds). After 100 days of the piling were analyzed the following characteristics: volume and number of roots, plant height, number of leaves, and dry. The aqueous extract of C. rotundus showed no effect on the number and volume of roots, however the other features were stimulated or inhibited by concentrations of the extract. The time of immersion of the cuttings can induce growth of its features, but with 120 seconds of immersion showed symptoms of toxicity.

CRESCIMENTO DE MUDAS DE CAFEEIRO IMERSAS EM EXTRATO DE TIRIRICA 1

Universidade Estadual Paulista (UNESP), Faculdade de Engenahria (FEIS), Ilha Solteira, SP, Departamento de Biologia e Zootecnia

O óleo de fritura, o biodiesel e a educação ambiental em uma escola pública

Quando for empossado diretor-geral da Organizacao das Nacoes Unidas para a Alimentacao e a Agricultura (FAO) em janeiro, Jose Graziano da Silva tera meios para ampliar as estrategias de apoio a erradicacao da fome defendidas como representante da organizacao para a America Latina e o Caribe, cargo que ocupou desde 2006, e como coordenador do Programa Fome Zero, em 2001. Agora, porem, o exministro Extraordinario de Seguranca Alimentar e Combate a Fome trabalhara com um orcamento que equivale a menos da metade do que o do programa brasileiro no primeiro ano do governo Lula. “Por isso, a FAO precisa ser muito eficiente no uso dos recursos”, diz. Para esse agronomo formado pela USP e doutor em Ciencias Economicas pela Unicamp, ser o primeiro brasileiro a liderar a FAO e fruto da imagem que o Brasil inspira em outros paises para a efetiva reducao da fome e da miseria. Mesmo estimando que o atual cenario de crise economica dos paises desenvolvidos e a alta dos precos dos alimentos nao impactarao tanto no nivel de populacao faminta quanto em 2008, Graziano defende celeridade na criacao de um sistema de governanca da seguranca alimentar mundial mais efetivo. “O mundo ja produz alimentos suficientes; com poucas excecoes, a fome e um problema de acesso: falta dinheiro para comprar alimentos”, afirma.

Universidade Estadual Paulista (UNESP), Faculdade de Engenharia (FEIS), Departamento de Biologia e Zootecnia, Ilha Solteira, SP, Brasil

A reciclagem do óleo de fritura e as ciências para a educação para a saúde

E nossa sociedade a importância que e dada ao discurso midiatico e enorme e tal fato nao ocorre sem motivos. E corrente a formulacao de que a midia e o quarto poder e consideramos a imprensa um campo fertil de representacoes no que diz respeito a educacao. Nesse texto, fazemos uma discussao sobre artigos de jornal e reportagens enfocando essa tematica. Esse tipo de material, de acordo com (JEANNENEY, 2003), tem o seu ritmo: vida e morte e so se explica uma em relacao as outras. Tambem procuramos dar uma resposta a uma critica feita por Lima a um texto publicado anteriormente. Acreditamos que a reflexao sobre artefatos jornalisticos, envolvendo as mais variadas expressoes sobre a educacao, tem um papel importante para a reflexao sobre a imagem e as condicoes de trabalho do professor (a). O desdobramento de um texto de opiniao publicado no site do Observatorio da Imprensa a nosso ver merece alguma reflexao. Chamamos a atencao para o programa Profissao Reporter que foi ao ar em sete de dezembro de dois mil e dez. Utilizamos a propria chamada do portal G1 que explica o conteudo do programa:

A agricultura tem uma particularidade fundamental em relacao a industria: o meio de producao mais importante - a terra - nao e susceetivel de multiplicacao ao ar livre arbitrio do homem. A estrutura agraria torna-se, assim, o pano de fundo sobre o qual se desenrola o processo produtivo: compreender o que e a estrutura agraria significa, em outras palavras, entender o papel de um condicionamentos basicos da producao agricola.

The goal of this research, that belongs to the area of text linguistics, consists in characterizing the text, production of the National High School Exam (ENEM) as a genre, according to the point of view of the social action that involves the text and its development, the textual/discursive compositional structure and the New Rhetoric and its assumptions about the types according and the argumentative techniques. In order to accomplish this goal, we based this study on the conception of genre as a social action and as an action of rhetorical community (MILLER, 2009 [1984]), as well as on the methodological framework for genre analysis (BAZERMAN, 2011a), on the prototype of the argumentative sequence and on the text plan (ADAM, 1999; 2008), and on the types according and argumentative techniques (PERELMAN; OLBRECHTS-TYTECA, 2005). The corpus is composed by the analysis of one hundred text productions written in 2013 from all the Brazilian states, evaluated the maximum score (1000 marks) by brokers/assessors National High School Exam. These text productions were analysed following four different steps: a) description of the production conditions of the texts; b) characterization of the genre in internal and external aspects; c) systematization of the data about the textual/discursive compositional structure and d) survey of the types according and of the argumentative techniques. The data confirm that the text production of the National High School Exam as a genre has in its external characteristics aspects that pertain to the hierarchy of senses proposed by Miller (2009), which inserts the National High School Exam text production genre as a text that is typified in the sociodiscursive situation, in our corpus, the Drought Law. The external characterization also contemplates aspects such as: genre production, circulation and reception, mobilizing types of standardized enunciations which are determined by circumstances. On the other hand, the internal characterization presents a recurrent in all the macropropositions of the prototype of the argumentative sequence as well as in the text plan. The categories of Bakhtin show the text unit in the argumentative compositional construction, the formal written style of the Portuguese language, and the thematic content with a theme that concerns social problems. In the rhetorical analysis, the more recurrent argumentative techniques are those of the according type related to the real – fact – with arguments that are almost logic and based on the structure of the real, normally of a causal. These results allow us to state that production of National High School Exam has unique characteristics that differentiate it from other argumentative nature of texts.

UNIVERSIDADE FEDERAL DO CEARÁ CENTRO DE HUMANIDADES PROGRAMA DE PÓS-GRADUAÇÃO EM LINGUÍSTICA

Caracterização físico-química de casca de amêndoa para utilização como adsorvente natural

SILVA, Jose Glaucio da. Estudo dos modos normais de vibracao de cristais de DL-Leucina por meio de Espectroscopia Raman. 2011. 60 f. Dissertacao (Mestrado em Fisica) - Programa de Pos-Graduacao em Fisica, Departamento de Fisica, Centro de Ciencias, Universidade Federal do Ceara, Fortaleza, 2011.

Estudo dos modos normais de vibração de cristais de DL-Leucina por meio de Espectroscopia Raman

Editorial - Apresentação do número temático dedicado à «Construção da vida: Um paradigma para compreender a carreira no século XXI»

UNIVERSIDADE ESTADUAL DA PARAÍBA CENTRO DE HUMANIDADES - CAMPUS III DEPARTAMENTO DE LETRAS E EDUCAÇÃO CURSO DE LICENCIATURA PLENA EM LETRAS

Lowland soils of the state of Para, generally have good production capacity. However, we do not know the effect of liming on rice in rotational cultivation. In this sense, there was an experiment aiming to evaluate the residual effect of liming on the production of rice after cowpea cultivation. The work was conducted in a greenhouse at the Institute of Agricultural Sciences (ICA) of the Federal Rural University of Amazonia (UFRA) in Bethlehem, PA. Gleissolos samples collected in three floodplains of the Para River, in the 0 to 20 cm depth were used. The sites were: lowland UFRA, Bethlehem; floodplain near the Loop Road / Moju and floodplain Vigia. The experimental design was completely randomized with three soil samples and five doses of limestone, on a 3x5 factorial design, with four replications. The soil samples were subjected to doses of limestone in amounts equivalent to 0; 0.4; 0.8; 1.2 and 1.6 times the need for liming (NC) soil, determined based on the potential acidity to pH 7.0 (H + Al) and NC (t ha-1) = H + Al (cmol c dm-3). Seeds of rice cultivar BRS Jaburu were used. In smaller doses the residual effect of liming promoted increased dry mass of shoots of cultivated soils of UFRA Handle Road and plants. The maximum tillering was estimated at doses of 0.83 and 0.85 times the need for liming, soil of UFRA and Strap Road respectively. The residual effect of liming caused reduction in grain production of rice grown in soils of floodplains. Soil Strap Road had the highest potential for rice production, regardless of setting.

EFEITO RESIDUAL DA APLICAÇÃO DE CALCíRIO SOBRE A PRODUÇÃO DO ARROZ IRRIGADO EM SOLOS DE VíRZEA DO RIO PARí

Uma Leitura da produção de significados de estudantes para a Aritmética no Ensino Fundamental (TA)

Análise do acoplamento entre os núcleos de uma fibra de cristal fotônico dopada com germânio

The Environmental Preservation Area (EPA) in Sana, Macae, Rio de Janeiro State went through a historical process of deforestation resulting from agriculture and livestock production. Recently, this area has been occupied in unplanned ways, due to its tourist attractions and real estate speculation. A major negative impact in the region is forest fragmentation. Based on the concept of landscape management, we propose a study to identify the priority fragments to conservation and recovery in the EPA. Results of this project are essential support tools to assist the manager in the environmental planning of the EPA in its process of monitoring, inspection and management.

Phosphorus fertilization in banana ‘Prata ana’ (AAB) cultivated in two latosols Data on the effect of phosphorus on the development of banana are scarce. The objectives of this work were to evaluate the effect of the application of phosphorus on the development of banana “Prata Ana” growing in a Red Latosol (RL) and a Red-Yellow Latosol (RYL), as well as to determine the phosphorus critical level. The treatments were arranged in a randomized design , using a 8 x 2 in factorial arrangement, with three replications . The factors corresponded to eight phosphorus doses (0; 50; 100; 150; 300; 450; 600; 750 mg.dm -3 ) and the two soil types. The dry mass production of banana seedlings increased with phosphorus application to both soils. Phosphorus soil critical levels in RL and RYL were 18.9 and 40.2 mg dm -3 , respectively. The phosphorus critical levels in the leaves of banana seedlings growing in RL and RYL were 0.20 and 0.31 dag kg -1 , respectively. Phosphorus was used more efficiently by banana seedlings

Adubação fosfatada em mudas de bananeira 'Prata anã'(AAB), cultivadas em dois Latossolos

Priore, Mary Del. Condessa de Barral, a paixao do imperador. Rio de Janeiro: Objetiva, 2008.

Este trabalho foi realizado entre agosto de 2007 e julho de 2011, no Municipio de Itaborai, RJ, 
Brasil, e teve como objetivo identificar as especies de Calliphoridae existentes em uma area de 
mangue, quantificar as predominantes, destacando as proporcoes de machos e femeas, e tambem 
analisar a influencia de fatores abioticos, tais como temperatura, umidade do ar e fases lunares; e 
ainda relacionar a abundância, a riqueza, a diversidade e a similaridade entre os periodos de 
coletas, relacoes ecologicas entre as especies da entomofauna da mesma familia e a relacao 
ecologica entre Calliphoridae e Phoridae parasitoides dentro da Area de Protecao Ambiental de 
Guapi-Mirim (APA de Guapi-Mirim), em Itaborai. Durante 48 meses, foram realizadas 96 
coletas, uma a cada 15 dias. Em todas as capturas, foram utilizadas armadilhas confeccionadas 
em recipiente plastico com 35 cm de altura e 15 cm de diâmetro. Cada uma das quatro armadilhas 
foi suspensa a uma altura de 1,20 m do solo contendo 100g de isca de peixe (sardinha) em 
decomposicao por um periodo de 48 horas. Apos cada captura, todos os especimes foram mortos 
no interior das armadilhas por asfixia utilizando etanol 70%. Em seguida todos os individuos 
foram acondicionados em potes plasticos, contendo etanol a 70% e encaminhados ao Laboratorio 
de Transmissores de Leishmanioses (Setor de Entomologia Medica e Forense), IOC-FIOCRUZ, 
RJ, em seguida todos os especimes foram separados por dia de coleta, identificadas e 
quantificadas. Para tal procedimento utilizou-se um microscopio estereoscopico e chaves 
dicotomicas para a identificacao da familia e das especies. As analises estatisticas foram feitas 
utilizando o programa estatistico Statistica 7.1 (STATSOFT, 2005), atraves do teste de Kruskal- 
Wallis one way ANOVA, teste de qui- quadrado (χ2), Mann-Whitney e correlacao de Kendall 
Tau (p<0,05). Foram utilizados os indices de diversidade de Shannon-Wiener e similaridade de 
Bray-Curtis, assim como a Distância Euclidiana. Foram capturadas 4531 moscas pertencentes a 
dez (10) especies da familia Calliphoridae: Chrysomya megacephala (Fabricius, 1794) (86,40%), 
Chrysomya albiceps (Wiedemann,1819) (5,72%), Cochliomyia macellaria (Fabricius, 1775) 
(4,94%), Chrysomya putoria (Wiedemann, 1818) (2,10%), Lucilia eximia (Wiedemann, 1819) 
(0,30%), Cochliomyia hominivorax (Cocquerel, 1858) (0,22%), Chloroprocta idioidea 
(Robineau-Desvoidy, 1930) (0,20%), Hemilucilia segmentaria (Fabricius, 1805) (0,04%), 
Hemilucilia semidiaphana (Rondani, 1850) (0,04%), Lucilia cuprina (Wiedemann,1830) 
(0,04%). A especie C. megacephala foi aquela que apresentou a maior abundância, a primavera 
foi a estacao do ano em que todas as especies mostraram maior preferencia; as temperaturas 
compreendidas entre 30,5 e 32,40C e a umidade relativa do ar entre 56,8 e 61,7% foram 
consideradas aquelas onde houve frenesi de oviposicao; nas luas cheias e novas houve maior 
ocorrencia de moscas capturadas; Megaselia scalaris se utilizou de especies abundantes nas 
mesmas estacoes do anos em que ela ocorreu com maior frequencia, possibilitando assim maior 
dispersao de ovos; a maior disponibilidade de recursos alimentares resultantes da atividade 
poluidora temporaria ofereceram uma melhor condicao de sobrevivencia para as especies os 
Calliphoridae.

Diversidade da Calliphoridae em manguezal e a associação com Megaselia scalaris (Loew) (Diptera: Phoridae), Itaboraí, RJ, Brasil

The phytosociological assessment of pastures is an important support tool for management recommendations. The objective of this work was to make a phytosociological assessment of flooded low land in Autazes-Amazon, Brazil. The study was carried out in two areas that had been flooded in the past. The inventory square method was applied using a square frame of 1.0 m2, randomly thrown 31 times in each area of three hectares. In these two areas, 27,706 individuals were found, distributed in 12 families and 22 species. The most important families in number of species in the two areas were Poaceae (7) and Cyperaceae (4). Brachiaria subquadripara presented higher frequency, density, abundance and IVI values in both areas. The species B. subquadripara (118.45), Paspalum fasciculatum (51.25), Cynodon dactylon (46.99) and Lindernia crustacea (25.25) presented the highest IVI values in area 1 and the species B. subquadripara (111.66), C. dactylon (55.44), Acroceras zizanioides (33.70) and L. crustacea (24.91) the highest values in area 2. In both areas, the Poaceae family accounted for more than 90% of the total of the individuals found, and some species presented good forage potential.

Levantamento fitossociológico em pastagens de várzea no Estado do Amazonas

In the context we live in the Information Technology (IT) is increasingly embedded in the business environment is being considered as a fundamental component of corporate management. On the one hand successfully applied this technology yields many benefits for companies on the other brings great challenges for the management of this resource, which companies now have high dependence. In that same period, Unimeds started to act in a complex scenario, under the laws of health plans, resulting in increased competitiveness, improving the quality of products and services offered to customers. Within this context the present study aimed to investigate the strategic investments in information technology, evaluating the impacts on business management System Unimed Rio Grande of Sul. To perform the data collection was carried out a descriptive study through a questionnaire, which were sent questionnaires to 58 individuals. The research allowed us to analyze the Unimeds mostly modest investments are doing, or even 1% of annual revenues, to meet legal requirements and after first using IT as a tool to gain competitive advantage. It was also observed that their CEOs were rated as the second level (1 causal or ad hoc) as the Capability Maturity Model (CMM-Capability Maturity Model) defined by Humphrey (1989), when executives realize that there is need for involvement, but there is no process or behavior established for this.

TECNOLOGIA DA INFORMAÇÃO: ESTRATÉGIA PARA OS NEGÓCIOS DO SISTEMA UNIMED DO RIO GRANDE DO SUL INFORMATION TECHNOLOGY: STRATEGY FOR BUSINESS SYSTEM UNIMED RIO GRANDE OF SUL

Neste trabalho, Redes Neurais Artificiais (RNAs), usualmente denominadas redes neurais, sao aplicadas em conjunto com o Metodo Vetorial da Propagacao de Feixes (MVPF) na analise de acopladores direcionais baseados em fibras oticas. Os dados necessarios para treinamento da RNA foram obtidos a partir da analise modal e da aplicacao do MVPF como ferramenta de simulacao numerica. A rede neural obteve como saida a potencia nas duas fibras ao longo da distância de acoplamento.

Aplicação de Redes Neurais Artificiais em Conjunto com o Método Vetorial da Propagação de Feixes na Análise de um Acoplador Direcional Baseado em Fibra Ótica

A Area de Preservacao Ambiental (APA) do Sana (Macae-RJ) sofreu com o processo de desmatamento historico do Brasil e recentemente, vem sendo ocupada de forma desordenada. Um dos principais impactos negativos observados na regiao e a fragmentacao florestal que tem como consequencia a degradacao da paisagem em mosaicos floristicos inseridos em matrizes nao florestais. Com base no manejo de paisagem propoe-se um estudo de identificacao dos fragmentos prioritarios para a conservacao e recuperacao. O metodo adotado e de cruzamento do mapa de areas prioritarias com as restricoes de uso e manejo referentes ao zoneamento da APA, para retirada de fragmentos de interesse. Para gerar o mapa de areas prioritarias esta sendo elaborada uma base de dados que sera utilizada em uma Avaliacao Multicriterial, orientada por uma Media Ponderada Ordenada. O mapa de uso e cobertura das terras realizado parcialmente por meio de interpretacao de imagens do satelite IKONOS, por meio de digitalizacao em tela no ArcGIS 9.2. Os mapas tematicos e dos fatores serao produzidos a partir de cartas topograficas do IBGE (2011) e da atualizacao da base de dados ambientais do Laboratorio de Geomatica do IF Fluminense. A pesquisa e importante para o planejamento ambiental da APA do Sana nos processos de monitoramento, fiscalizacao e manejo que favorecam atividades agricolas para fortalecimento da economia local, alem de subsidiar a tomada de decisao na resolucao dos conflitos regionais baseados no uso das terras, com especial foco a formacao dos corredores ecologicos. O mapa de fragmentos florestais prioritarios para conservacao e recuperacao, com base no incremento da biodiversidade e um instrumento de apoio imprescindivel no auxilio as acoes dos gestores da APA do Sana.

IDENTIFICAÇÃO DE FRAGMENTOS PRIORITÁRIOS PARA CONSERVAÇÃO E RECUPERAÇÃO DA APA DO SANA-RJ

Production of banana tree cv. Prata ana (AAB) as a function of different doses and sources of potassium Among the nutrients required by the banana tree, the potassium (K) is what most influences the production of the crop. This study aimed to compare the effects of two K sources, potassium chloride (KCl) and potassium sulfate (K 2 SO 4 ) on production, and estimate the dose of K for maximum physical efficiency (MPE) and maximum economic efficiency (MEE), besides determine the critical levels of leaf K for the banana tree, cultivar Prata ana (AAB) irrigated, cultivated in the semi-arid region of northern Minas Gerais State, Brazil. The experiment was conducted in an oxisol, medium texture. The treatments were derived from the factorial (4 x 2), being four rates of K (0, 400, 800 and 1200 kg ha1 yr-1 of K 2 O) and two K sources (KCl and K 2 SO 4 ), resulting in eight treatments. These were distributed in randomized blocks with four replications. There were no differences among the effects of KCl and K 2 SO 4 on the production of banana. The KCl showed greater economic viability to be used as a source of K. The estimated doses for MPE of banana in the 2nd and 3rd production cycles using the KCl were 827 and 835 kg ha -1 yr -1 of K 2 O, respectively, while for MEE, doses were 157 and 670 kg ha -1 yr -1 of K 2 O, respectively. The critical levels of leaf K obtained in the 2nd and 3rd production cycles were 2.85 dag kg -1 for the MPE and for MEE, the values were 2.41 and 2.80 dag kg -1 , respectively.

Produção da bananeira 'Prata anã'(AAB) em função de diferentes doses e fontes de potássio

GARANTIZADO JUNIOR, Jose Olavo da Silva. Preliminares para a definicao da coerencia/coesao. 2011. 190f. – Dissertacao (Mestrado) – Universidade Federal do Ceara, Departamento de Letras Vernaculas, Programa de Pos-graduacao em Linguistica, Fortaleza (CE), 2011.

PRIORE, Mary Del. Condessa de Barral, a paixao do imperador. Rio de Janeiro: Objetiva, 2008.

O desenvolvimento distribuido de software (DSD) permite que as organizacoes aproveitem capital humano distribuido por todo o mundo. Entretanto a comunicacao, que e essencial para o desenvolvimento, e prejudicada pela imposicao da distância geografica. Para resolver esses problemas existem ferramentas que auxiliam na troca de informacoes eficientemente. Mas, estas ferramentas sao inflexiveis e criadas para agir em dominios especificos. Neste trabalho foi desenvolvida uma arquitetura extensivel que possibilita a identificacao dos especialistas em determinados assuntos utilizando diferentes algoritmos e que possibilite a adicao de novos metodos de recomendacao. Alem de permitir a extensibilidade a ferramenta abre espaco para extensoes que solucionem os problemas gerados pelas diferencas pessoais, culturais e temporais existentes em ambientes de DSD.

Uma arquitetura extensível para localização de especialistas em cenários de desenvolvimento distribuído de software

Este estudo destina-se a analisar, sob o enfoque multidisciplinar das areas do direito e da economia, a preservacao da empresa como objetivo principal da nova Lei de Falencias e Recuperacao de Empresas do Brasil. Apresenta um estudo de caso da recuperacao judicial da empresa Shellmar, para melhor compreensao das mudancas ocorridas na nova legislacao brasileira de falencias, principalmente no que se refere a reorganizacao e reestruturacao dos negocios, tendo como objetivo a preservacao da empresa

Uma análise multidisciplinar da preservação da empresa como objetivo da nova lei brasileira de falências e de recuperação de empresas: o caso da recuperação judicial da Shellmar

This article proposes to devise the territorial reorganization and environmental planning of the northern region of the Brazilian state of Rio de Janeiro, following the implementation of the Acu Port Industrial Complex and its impacts. Thus, we propose three guiding strategies of the urban and environmental planning: geomorphological analysis of the area under study; to rethink the macro drainage system; and the use of Geographical Information System as a support resource for the territory management.

Contribuições para o planejamento urbano-ambiental na região Norte Fluminense

Sentido e valoração nas práticas e no discurso do espectador sobre o cinema brasileiro: estudo sobre o subcampo do cinema e seu habitus narrativo

Este trabalho se insere na linha de pesquisa da Area de Concentracao de Politicas de Educacao e Sistemas Educativos, circunscrita ao Programa de Pos-Graduacao em Educacao da Universidade Estadual de Campinas. Trata-se de uma pesquisa de cunho qualitativo, cujo objetivo e analisar a politica educacional implementada na rede estadual de ensino do Estado de Sao Paulo no periodo de 1995-2002, apontando as possibilidades e os limites do trabalho do supervisor de ensino no Estado de Sao Paulo no fortalecimento dos diferentes espacos democraticos na escola publica e os reflexos da Reforma do Estado no trabalho do supervisor de ensino durante a gestao de Mario Covas/Alckmin. Investiga-se o modo como supervisores de ensino do sistema publico do Estado de Sao Paulo percebem e vivenciam a realidade do seu trabalho junto as escolas. Analisa-se a supervisao de ensino para melhor compreender o processo de organizacao da categoria dos supervisores educacionais e suas relacoes com o trabalho, retornando-se as raizes historicas, filosoficas e legais que a originaram. A cultura de participacao na escola foca a tensao, a correlacao de forcas e as contradicoes entre o que se escreve e o que se faz, bem como a revitalizacao da funcao politica do supervisor de ensino no fortalecimento do espaco democratico na escola publica. A partir de pesquisa qualitativa em duas escolas publicas estaduais da regiao bragantina apontam-se os limites e possibilidades da gestao democratica bem como a contribuicao do supervisor de ensino no fortalecimento dos espacos democraticos na escola publica, com vistas a superacao de praticas autoritarias, centralizadoras e verticalistas. Propoe-se desenvolver um projeto educativo democratico, nao apenas a partir do grau de democratizacao desenvolvido nas relacoes no interior da escola, mas, da articulacao da escola com o processo de democratizacao da sociedade. Mediante abordagem teorico-pratica este estudo aborda questoes referentes a singularidade do trabalho do supervisor como palco de contradicoes, instabilidades, precariedades e incertezas, no qual sao exigidas tomadas de decisoes, construidas e reconstruidas em virtude da tensao entre o que se pensa e o que se faz. 
 
Abstract

A supervisão de ensino e o fortalecimento do espaço democrático na escola pública

Foi desenvolvido e validado neste estudo um metodo analitico para quantificacao de diclofenaco de dietilamonio em pele humana por cromatografia liquida de alta eficiencia, segundo a Resolucao 899/2003 da Agencia Nacional de Vigilância Sanitaria (ANVISA). Empregou-se cromatografia em fase reversa com coluna C18 150 x 4,6 mm, 5 µm Shimpack®, a temperatura de 40 oC e fase movel, constituida por mistura de acetonitrila e tampao fosfato de sodio 20 mM pH 3,0 (70:30, v/v) com fluxo de 1,2 mL min-1. Os analitos foram detectados por UV a 280 nm e o metodo foi especifico, preciso, exato, robusto e linear no intervalo de 0,05 a 20 µg mL-1 (R2 = 0,998), mostrando que pode ser utilizado em estudos de penetracao cutânea in vitro tendo como modelo de membrana a pele humana. 
 
 Palavras-chave : Diclofenaco dietilamonio. Retencao cutânea. Validacao. 
 
 ABSTRACT Development and validation of an analytical method for quantitation of diclofenac diethylamine in human skin by high performance liquid chromatography 
An analytical method has been developed and validated for the quantitation of diclofenac diethylamine (DDA) in human skin by high performance liquid chromatography (HPLC), in accordance with Regulation 899/2003 of the National Sanitary Surveillance Agency (ANVISA). The HPLC column was a reversed-phase Shimpack® C18, with a 5 µm particle bed, measuring 150 x 4.6 mm i.d., eluted isocratically at 40C with 20 mM sodium phosphate buffer (pH 3.0):acetonitrile (30:70, v/v), the mobile phase flowing at 1.2 mL min-1. Analytes were measured by a UV detector set at 280 nm. The results revealed that the method was specific, precise, accurate, robust and linear (R2=0.998) in the range from 0.05 to 20 µg mL-1. Therefore, it can safely be used to assess DDA in vitro penetration of human skin in kinetic studies. 
 Keywords : Diclofenac diethylamine. Human skin retention. Validation.

Desenvolvimento e validação de método analítico para quantificação de diclofenaco de dietilamônio em pele humana por cromatografia líquida de alta eficiência

The value of the probably granted discharge is affected by the method used for its obtainment, and several methodologies are available to this purpose. The Integrated System for Water Resources Management (SINGERH) allows to obtaining water availability for any interesting section along the basin hydrographic net, as well as to quantify the impact from the granting of a new water right in this availability. So, it was used in this study in order to verify the impact of either grant criteria and the discharge regionalization methods upon the estimate of water availability in the basin of the Entre Rios creek. The data basis needed to the application of SINGERH was initially prepared. It consisted of digital elevation model of the minimum and medium discharges, regionalization equations of both the traditional method and that based on mass conservation and the cadastre of the basin water users. The results showed the impossibility of new grants for water using right until the end of the period under analysis. The accomplished simulations allowed to evaluate the way how variable water availability affects the water using right process, besides providing subsidies to the analysis of the different criteria adopted for the distribution of discharges to be granted.

SISTEMA INTEGRADO PARA A GESTÃO DE RECURSOS HÍDRICOS: ESTUDO DE CASO PARA A BACIA DO RIBEIRÃO ENTRE RIBEIROS

For nutritional diagnosis of the banana it is necessary to standardize the tissue sampling to be used, since the mineral composition changes with the plant age, sampled leaf, among the several parts of the leaf, besides ecological conditions, variety differences and seasonal fluctuations of the elements. Therefore, the possibility of mistake in the interpretation is considerable. The Method of International Sampling of Reference (MEIR) for banana recommends to collect the third leaf of plants with bunches that present all of the visible hands and no more than three hands of open masculine flowers, leaving the internal half of a central grade of the limbus, without the central rib. There is some difficulty in following such recommendation for banana tree 'Prata-Ana' cultivated in the North of Minas Gerais, because it possesses high load and very dense foliar rosette that confuses the location of the sampled leaf. Moreover, usually the samples are removed with width different from the recommended 10 cm. Due to the sampling difficulties of the 'Prata-Ana' banana and the fact that this cultivar, under irrigation, to be little studied when compared to those of the subgroup Cavendish, the present work aimed to determine the effect of the sampled leaf and the sample width on the mineral contents of the 'Prata-Ana' banana tree cultivated under irrigation in the North of Minas Gerais. In spite of the statistical variations, the foliar contents maintained themselves inside of the sufficiency grade, regardless of the sampled leaf position - 2nd, 3rd or 4th leaf - or of the sample size - 10, 20 or 30 cm of width. This suggests that the leaf collection in the position above (second) or below (fourth) of the third recommended leaf, in a foliar width from 10 to 30 cm, does not alter a lot the foliar contents in relation to the indication by the MEIR, thus being tolerated as a possible sample variation for the tested position and foliar width.

Tese de mestrado integrado. Engenharia Civil (Especializacao em estruturas). Faculdade de Engenharia. Universidade do Porto. 2010

Avaliação do comportamento sísmico de edifícios de betão armado dimensionados pelo EC 8

Este trabalho tem como objetivo discutir a gestao das aguas no Estado do Rio de Janeiro, suas realidades e perspectivas, visto que o manejo sustentavel dos recursos hidricos tem se apresentado como um dos maiores desafios do ultimo seculo. Para tanto, propoe-se o uso de novas tecnologias para o auxilio a gestao de aguas; neste caso, o Sistema de Informacoes Geograficas (SIG) tem o papel de ferramenta de apoio aos gestores das aguas.

O sistema de informações geográficas como ferramenta de apoio à gestão dos recursos hídricos no Estado do Rio de Janeiro

Um tema muito discutido atualmente no setor industrial refere-se a qualidade final do produto que envolve todo o processo de fabricacao. Nessa pesquisa se identificou no laboratorio de alimentos do IFRN – Currais Novos, a necessidade de implantar procedimentos operacionais padronizados que aperfeicoem o trabalho executado rotineiramente no laboratorio, garantindo assim a qualidade das analises e seguranca para os usuarios, tendo em vista a percepcao dos servidores do IFRN pesquisados. A pesquisa apresenta como metodologia um estudo de caso, o qual buscou por meio da aplicacao de questionarios aos servidores (docentes e tecnicos em laboratorio) que atuam e desempenham atividades no laboratorio de alimentos do Campus Currais Novos, obter informacoes relacionadas a implantacao de procedimentos operacionais padronizados (POP´s). Os resultados obtidos para uma real necessidade da implantacao de tais procedimentos, bem como o diagnostico de diversos beneficios oriundos de tal acao. Dessa forma, esse estudo apresenta o diagnostico da percepcao dos servidores pesquisados e tambem sugere procedimentos padronizados a serem implantados no ambiente analisado.

Percepção dos servidores quanto ao uso dos procedimentos operacionais padronizados no laboratório do IFRN - Campus Currais Novos: um estudo de caso

Este artigo tem como foco analisar a historia, o desenvolvimento e a relevância da teologia na humanidade, nao pretendendo esgotar o assunto, mas tendo como objetivo tornar claros estes pontos atraves de uma analise que utiliza a revisao bibliografica de livros e textos relevantes ao tema, para mostrar como a teologia se mostrou e mostra atraves dos tempos. Conclui-se que a teologia foi importante no momento em que o homem se deu conta da presenca e existencia de Deus. Logo, surge esta ciencia como forma de estudar mais a fundo os misterios da divindade e fatores relevantes a este contexto.

A pratica de esportes e uma via reconhecida de inclusao social. No contexto brasileiro, dentre as praticas esportivas, o futebol exerce grande influencia social e economica. Considerando a importância dos clubes de futebol nessa equacao, e relevante entender os fatores relacionados a profissionalizacao de sua gestao. O futebol tem desempenhado, no Brasil, papeis que vao do entretenimento popular maximo as aplicacoes menos nobres, como o seu emprego para beneficios pessoais dos dirigentes e para manobras politicas. Fundamentando-se na Teoria Institucional e, mais especificamente, na corrente do neo-institucionalismo (DIMAGGIO; POWELL, 1991), o estudo tem como objetivo identificar aspectos relativos ao campo organizacional do futebol que constituem obstaculos ou facilitadores do processo de profissionalizacao da gestao do futebol nos clubes brasileiros, por meio da melhor compreensao das relacoes entre os seus diferentes atores. Os resultados apontam que a necessidade de profissionalizacao da gestao do futebol dos clubes brasileiros e uma percepcao institucionalizada, e que sua efetivacao pode apresentar impactos sociais, economicos e financeiros positivos. Entretanto, este objetivo ainda enfrenta entraves praticos arraigados nos mais de cem anos de amadorismo, conservadorismo e pratica oligarquica.

FATORES INSTITUCIONAIS E ORGANIZACIONAIS QUE AFETAM A GESTÃO PROFISSIONAL DE DEPARTAMENTOS DE FUTEBOL DOS CLUBES: O CASO DOS CLUBES DE FUTEBOL NO BRASIL

POSSIBILIDADES PEDAGÓGICAS DE EDUCAÇÃO DAS RELAÇÕES ÉTNICO-RACIAIS

Faremos uma breve apresentacao dos progressos para a implementacaodo Acordo Ortografico em cada um dos outros paisesda Comunidade dos Paises de Lingua Portuguesa, antes de tratar especialmentede sua situacao no Brasil.Depois de tratar especificamente da implantacao do AcordoOrtografico no Brasil, daremos algumas noticias que me parecemtambem bastante animadoras.Vejamos como o processo de implementacao do Acordo se desenvolvenos diversos paises.

UMA AVALIAÇÃO DO PRIMEIRO ANO DE IMPLANTAÇÃO DO NOVO ACORDO ORTOGRÁFICO DA LÍNGUA PORTUGUESA

Based on analysis of Brazilian economic indicators in the period 1995-2010, this paper aims to establish a comparative evaluation between FHC and Lula governments. The results indicate that the main macroeconomic and social variables as well as public finance indicators and external financial situation of the country showed a more virtuous behavior during Lulaâ€™s government. It is noticed that, especially regarding to macroeconomic policies, Lula did not cause significant changes in relation to what was already being implemented at the end of FHC government. Therefore, most of the results should not be attributed to the superiority of management but to the fact that the international economic environment was more favorable to Brazil in the period of 2003-2010 than in 1995-2002. Considering the significant differences in the economic numbers, the paper presents some reasons why it is possible to say that both governments left much to be done in other aspects of Brazilian social and economic reality, mainly regarding the absence of a national strategic plan able to initiate a process of structural and institutional changes that can effectively put Brazil on a way already covered by developed countries.

Prevalência de lesões bucais cancerosas e cancerizáveis em pacientes ambulatoriais atendidos no FBHC de 2006 a 2007

This article presents discussions on the Water Resources Information System in Brazil , and evaluates new technologies for supporting integrated water resources management. The study also discusses the processes of generating, gathering, and analysing information using conceptual models with support of Geographical Information Systems.

In the present work three discharge regionalization were analyzed to estimate minimum discharge with a 7-day duration and a 10-year return period (Q7,10) for different sections of the Paracatu river basin. The regionalization methods used were: traditional; based on the proportionality of specific flows; and based on the conservation of mass. The Integrated System to the Water Resources Management (SINGERH) was carred out to estimated the Q7,10 to different sections. Was evidenced, in the obtained results, in some sections, expressive differences in the Q7,10 values for the three regionalization methods studied. The method based on the conservation of mass was the only that guaranteed the continuity of the flows in the whole area in study. The analysis allowed to verify a larger care in the choice of the regionalization method, because it can hamper the process of decision in the water resource management.

COMPARAÇÃO DOS VALORES DA Q7,10 ESTIMADOS POR DIFERENTES MÉTODOS DE REGIONALIZAÇÃO DE VAZÕES

Apesar de extremamente incompleta e ainda nao plenamenteatualizada, este trabalho pretende apresentar uma importante contribuicaopara os estudos diacronicos da lingua portuguesa, a partir doqual se poderao desenvolver numerosos e importantes trabalhos dehistoria da lingua portuguesa.Promete-se para brevemente, uma ampliacao e atualizacaodesse texto para que se possa ter uma boa bibliografia atualizada destaespecialidade dos estudos da lingua portuguesa: a sua historia (externae interna).Alem de outras fontes importantes que ainda nao foram consultadas,pretendemos completar esta pequena bibliografia com abusca de informacoes oferecidas pelos proprios autores na PlataformaLattes do CNPq e fazer uma revisao geral para uniformizar osverbetes, segundo as normas da ABNT para referencias bibliograficasem trabalhos academicos.Para este esboco, tres bases foram fundamentais: o relatorioda disciplina Historia da Lingua Portuguesa, da professora Maria TeresaBrocardo (2006), a Gramatica do Portugues Brasileiro, do professorAtaliba Teixeira de Castilho (2010) e a pagina de busca internado Circulo Fluminense de Estudos Filologicos e Linguisticos(http://www.filologia.org.br/buscainterna.html).

O Observatorio Ambiental Alberto Ribeiro Lamego tem como objetivo hospedar informacoes e disponibiliza-las a sociedade, oferecendo suporte as analises e avaliacoes ambientais na regiao de influencia do Instituto Federal de Educacao Ciencia e Tecnologia Fluminense (IF Fluminense). O presente projeto esta focado no crescimento do trabalho realizado pelo Observatorio Ambiental, visando sistematizar e desenvolver mecanismos de acesso as informacoes e conhecimentos gerados pela equipe de pesquisa. No desenvolvimento dos sistemas necessarios para melhorar o acesso as informacoes geradas no âmbito do Observatorio Ambiental, primeiramente foram geradas copias de seguranca dos dados existentes. A seguir, a equipe estudou e projetou a estrutura ideal para funcionamento do sistema de arquivo e disponibilizacao das informacoes. Finalmente, apos estudos sobre linguagens de programacao para web, foi construido. Simultaneamente ao desenvolvimento do website, os videos de educacao para o processo de gestao ambiental produzidos pelo Nucleo de Pesquisas em Petroleo, Energia e Recursos Naturais foram convertidos para disponibilizacao online. Ate o presente momento foram alcancados os seguintes objetivos: (a) Estruturacao dos sistemas de arquivamento e disponibilizacao da producao do Observatorio Ambiental; (b) Programacao do novo website de acordo com a estruturacao desenvolvida; (c) Conversao dos videos de educacao ambiental produzidos pelo NUPERN para disponibilizacao online. De acordo com os resultados obtidos, observa-se a viabilidade e importância da informatizacao e programacao de ferramentas com recursos para pesquisa na web para disseminacao das informacoes cientificas obtidas pelos trabalhos realizados pelo Observatorio Ambiental.

This article presents a thematic exploration of the environmental degradation in the Macae River Hydrographic Basin. The objective was to provide a cartographic base on relevant issues regarding the Basin, by doing environmental assessment with support of geoprocessing. This aims at providing assistance for public actions in environmental decisions, and suggest applications of data in local and/or regional plannings that may support the development of the Basin Plan. The AHP method – Hierarchic Analytical Process – was used. The resulting map shows the areas of potential environmental degradation, in which those with greater susceptibility are located at the top and middle sections of the river, and the less likely are found on its lower course.

Avaliação da susceptibilidade à degradação ambiental da Bacia Hidrográfica do Rio Macaé-RJ com apoio do Geoprocessamento

In the North of Minas Gerais it is cultivated basically banana 'Prata-Ana', cultivar that requires mainly Zn. The possibility of supply of zinc, without this nutrient gets in touch with the soil, it is important for the region, since several factors take to the low availability of the element supplied by the soil, as: elevated organic matter content on the surface (from cultural residues); maintenance of high pH of the soil - above 6,00 - as strategy contrary to the proliferation of the causal agent of the Fusarium Wilt; frequent fertilizations with potassium and magnesium that, besides converting the medium into base, they reduce the participation of Zn in the balance cation/anion of the soil, hindering the absortion of this micronutrient by the plant. For determining the distribution of biomass and minerals in the banana Prata-Ana, cultivated under irrigation in the North of Minas Gerais, when zinc supplied through thinned sprout, an experiment was carried out in the Irrigated Perimeter of Jaiba. The plants were fertilized with 0,00; 1,66 and 3,33 g.family-1 of Zn, through thinned sprout. One month after the fertilizations from October, 2007 and February, 2008, the production of fresh mass (FM) and dry mass (DM) were evaluated, the contents and meanings of minerals in all of the banana ''family'' bodies composed by mother-plant with bunch + tall daughter-plant + plant-granddaughter. The doses of Zn did not influence on the production of FM and DM of the plants in the first evaluation, while in the second evaluation positive effect of the treatment was observed just for MF accumulated in the inferior leaves, in the portions of the medium third and inferior of the pseudostem, and in the mother-plant's rhizome. As much the content as the accumulation of nutrients in the mother-plants presented the following decreasing order: K > N > Ca > Mg > P > S > Fe > Zn > B > Cu. The Zn contents were affected by the dose of that micronutrient in the most of the studied situations. The zinc supplied through thinned sprout increased in the mother-plant, and then it was redistributed in the banana's ''family''.

Distribuição da biomassa e minerais em "família" de bananeira 'prata-anã' adubada com zinco via broto desbastado

"Boom" agrícola e persistência da pobreza na América Latina: algumas reflexões 1

O bruxismo e uma atividade parafuncional do sistema mastigatorio que inclui apertar ou ranger os dentes, continuamente, durante o dia e/ou a noite, geralmente de maneira inconsciente, em intervalos de atividades nao funcionais do sistema estomatognatico. As criancas, por motivos variados, podem desenvolver esse habito, prejudicando o equilibrio entre funcao e desenvolvimento. A etiologia do bruxismo e multifatorial; assim como sao as formas de tratamento, pois essas devem ser individualizados. E, o grande aumento das forcas oclusais geradas por esse, resulta em cargas extras nao so na denticao, mas tambem em todo o sistema estomatognatico, podendo causar efeitos variados como danos a articulacao temporomandibular (ATM), aos musculos, ao periodonto e a oclusao. Apenas recentemente tem surgido o interesse do estudo desse fenomeno em criancas, provando que e um habito oral muito frequente na infância. Esse trabalho tem como objetivo descrever atraves da literatura a etiologia, a prevalencia, o diagnostico e a conduta a ser realizada frente aos comportamentos parafuncionais orais (AU) The bruxism is a parafunctional activity of masticatory system that includes tightening or gnash their teeth, continuously during the day and/or at night, usually so unconscious, at intervals of no functional activities of the stomatognathic system. The children, for various reasons, can develop that habit, jeopardizing the balance between function and development. The etiology of bruxism is multifactorial, as well as forms of treatment, as these must be individualized. And the big increase in occlusal forces generated by him, resulting in extra charges not only in the teeth, but also throughout the stomatognathic system and can cause various effects such as damage to the temporomandibular joint (TMJ), the muscles, the periodontal and occlusion . Only recently it has emerged the interest of the study this phenomenon in children, proving it is a very frequent oral habits in childhood. This paper aims to describe the etiology through literature, the prevalence, diagnosis and conduct to be held against the parafunctional oral behaviors

Bruxismo infantil: prevalência, etiologia, diagnóstico e tratamento - uma abordagem literária

Estudaremos uma tecnica de suavizacao de uma singularidade nua em um conifold chamada Brane Resolution Por um lado a singularidade aparece como uma solucao de brana de supergravidade contendo apenas termos do setor de Neveu-Schwarz Por outro lado podemos ver a singularidade do conifold como oriunda de um ponto fixo do grupo de simetria discreto responsavel pela geracao do conifold O conifold tem bastante importância no processo de compactificacao em teorias de cordas em particular nas chamadas transicoes conicas De fato existem diferentes tipos de espacos deCalabi-Yau que podem ser variedades internas Apesar de tais espacos terem caracteristicas to- pologicas distintas pode-se transformar um espaco no outro atraves das transicoes conicas Isso se faz atraves da geracao de singularidades no espaco de Calabi-Yau que surpreendentemente nao gera problemas quânticos. A tecnica consiste em acrescentar um termo topologico do setor de Ramond-Ramond a acao A inclusao de um termo de Chern-Simons responsavel pela interacao entre os campos do setor de Ramond-Ramond (Cn ), gera um fluxo dos campos H3 = dB2 e F3 = dC2 sobre a singularidade do conifold. A partir da equacao de movimento do campo pode-se, dado uma escolha adequada para a configuracao da metrica e dos campos, encontrar os fatores de warp que sao responsaveis pela retirada da singularidade O metodo tambem pode ser entendido topologicamente como a incisao de uma esfera no lugar da vizinhanca do nodo do cone O estudo do comportamento de campos sobre o conifold e feito no intuito de extender a correspondencia AdS-CFT originalmente a correspondencia foi proposta para o espaco AdS5 ×S 5 mas logo surgiram extensoes utilizando outras variedades como M4 × C6 Proximo a singula- ridade o espaco pode ser escrito como AdS5 × X 5 onde X 5 e o espaco base do conifold Geralmente toma-se o espaco base como um espaco homogeneo de Einstein Ricci-plana onde X 5 = SU (3)/SU (2) × SU (2). Contudo, para manter a invariância conforme da teoria de campos dual e necessario suavizar o conifold atraves de incisoes do tipo Eguchi-Hanson que podem ser de dois tipos: por uma 3-esfera S 3 e chamada deformation ou por uma 2-esfera S 2 e chamada resolution Recentemente foram propostas resolucoes do conifold em um cenario de teoria heterotica dotada de torcao Tal efeito e relevante em teorias onde solucoes do tipo buraco negro existem na variedade interna como as black branes e spinning branes esta ultima leva em conta o momento angular do buraco negro - spin - e e uma solucao do tipo Kerr A partir da transgressao da identidade de Bianchi para a 3-forma intensidade de campo de Kalb-Ramond oriundo de um termo de Gauss-Bonnet e de instanton podemos introduzir uma torcao e com isso um novo termo na conexao nao dependente da metrica. Estudaremos os efeitos de tais termos sobre a suavizacao de um conifold comparando com o caso sem torcao Alem disso buscamos estudar o efeito que um outro termo topologico tem sobre a resolucao de branas o termo BF Tal termo surgiu como uma extensao do termo de Chern-Simons para quatro dimensoes tendo como funcao gerar massa topologicamente para campos de calibre Nesse trabalho iremos modificar a acao da teoria heterotica de modo a obtermos o termo BF como um dos termos de anomalia e logo responsavel pelo fluxo que retira a singularidade Encontramos para um ansatz bastante conhecido uma configuracao onde o fluxo gerado pelo termo BF e o responsavel pela desingularizacao do espaco

Canine ehrlichiosis is a disease transmitted by ticks Rhipicephalus sanguineus and caused by Ehrlichia canis, obligatory intracellular bacteria. The present study examined the prevalence of anti-E. canis in 254 dogs from four administrative regions of Cuiaba, Mato Grosso, by indirect immunofluorescence assay. There was a prevalence of 42.5% (108/254) without significant difference between the studied regions. The variables age, breed, sex, habitat, access to rural and ticks were analyzed. The antibody titers ranged from 1:40 to 1:2,560. Only 32 (29.63%) seropositive dogs were infested with ticks, all R. sanguineus. The results confirm that do not have breed, sex or age predisposition to ehrlichiosis due E. canis, while the lowest occurrence of reactive dogs indoors probably related to low tick infestation, although no significant difference between dogs with or without infestation with the tick vector.

Soroprevalência de anticorpos anti-Ehrlichia canis em cães de Cuiabá, Mato Grosso

Melhoria da produtividade através da conclusão de acções de lean manufacturing em curso na Sidel Portugal S.A.

The need for developing research related principally to the nutritional requirements of essential native Amazonian forest species, such as mahogany, is urgent, since the exploration of highly valuable species is continually more frequent. With the objective of evaluating the growth and the nutritional requirement of mahogany plants, an experiment in a vegetation house with 14 treatments was undertaken. The experiment outline was of occasional blocks with 5 repetitions. The growth characteristics evaluated were: height of the aerial part, diameter of the bottom, dry material of the aerial part, root and total, relationship of root and aerial part, relationship and nutrient content of dry material of the aerial part. The results lead to the conclusion that: the conjoint correction of acidity and the fertility of the soil for acid soils and low natural fertility is necessary even if the content of the organic material is considered high; of the nutrients, P is the one which limits most the development of the plant, as well as the absorption of other nutrients; there is no need to add K for developing the plants when liming occurs.; addition of K is recommended when liming does not occur; and the nutritional requirement of mahogany in macronutrients obeys the decreasing order of P>S>K.N.

Exigências nutricionais e crescimento de plantas de mogno (Swietenia macrophylla King.)

Em condicoes tropicais os niveis de produtividade agricola sao afetados por uma serie de fatores bioticos e abioticos que interferem no desenvolvimento vegetal. O feijao-caupi tem capacidade de tolerar diversos estresses abioticos e manter bons niveis de fixacao biologica de nitrogenio (FBN) nestas condicoes. Esta caracteristica o torna uma especie estrategica para o estudo da FBN em condicoes de estresse. O objetivo do presente trabalho e a identificacao dos genes expressos em nodulos de feijao-caupi em resposta ao deficit hidrico e estresse termico. Foi conduzido um experimento em casa de vegetacao utilizando como substrato areia:vermiculita (2:1). Sementes de feijao-caupi foram inoculadas com a estirpe BR3267 de Bradyrhizobium japonicum no momento do plantio e aos 35 dias apos a germinacao foram submetidas a dois regimes de disponibilidade hidrica: Plena umidade e restricao hidrica por 48, 72 e 96 horas. Os nodulos foram removidos das raizes e utilizados para extracao de RNA total e sintese de cDNA. Para analise da expressao genica foi utilizada a tecnica de cDNA-AFLP, seguida pelo sequenciamento e analise de similaridade de sequencias dos fragmentos derivados de transcritos (FDTs). Foram isolados 54 FDTs diferencialmente expressos, sendo identificado o gene CPRD12, previamente induzido em folhas de feijao-caupi em condicoes de desidratacao progressiva. Este gene esta potencialmente envolvido na resposta do nodulo ao estresse hidrico, porem analises adicionais da expressao genica fazem-se necessarias para confirmar os resultados obtidos.

Prospecção de genes diferencialmente expressos em nódulos de feijão-caupi submetido ao estresse térmico e déficit hídrico

O crescimento da educacao a distância online e dos ambientes virtuais de aprendizagem (AVA), entre outros, indicam um acelerado movimento dos processos de ensino-aprendizagem em direcao a ciberespaco. Apesar do potencial deste para a producao de conhecimento em rede, as estrategias pedagogicas que visam mobilizar a inteligencia coletiva nos AVA nao sao, ainda, totalmente compreendidas. E neste contexto que se insere esta pesquisa, que teve por objetivo investigar quais seriam os elementos pedagogicos que fazem operar a inteligencia coletiva nos ambientes virtuais de aprendizagem. Para isso, buscamos aporte teorico nos estudos sobre cibercultura, na filosofia de Pierre Levy, no socioconstrutivismo, na cognicao distribuida e no conectivismo. Realizamos uma investigacao de carater qualitativo, apoiada em descricoes provenientes de um curso online colaborativo. A investigacao identificou quatros operadores que atuaram efetivamente como mobilizadores da inteligencia coletiva em AVA: o design instrucional, as midias de funcao pos-massiva, a interatividade e a comunidade virtual de aprendizagem

Operadores da inteligência coletiva em ambientes virtuais de aprendizagem

Apresenta este trabalho uma analise praticamente de
todas as modalidades de penas e de prisoes existentes na legislacao patria,
tidas como um dos requisitos para a obtencao do beneficio auxilioreclusao,
seja este decorrente de praticas de ilicitos criminais ou civis.
Por se tratar de um beneficio que objetiva a protecao
dos dependentes do segurado recluso, em razao da prisao deste, sao
examinados com circunspecao, o significado do enunciado dependentes e a
relacao taxativa de dependentes, bem como dissertado com proficuidade
sobre a existencia de excecoes nela constantes. Outros requisitos
normativos tambem sao analisados, como v.g., sujeitos, termo inicial, termo
final suspensao, cessacao, renda mensal inicial, abono, acumulacao, efeitos
da morte, ainda que presumida.
Como trabalho cientifico, fruto do ambiente academico
em ritmo acelerado e bem conjugado, de indagacoes sutis e de estimulos
intelectuais que o convivio no ambiente academico de pos-graduacao
 stricto sensu entre o corpo docente e discente, incitam ao pensamento e
provocam novos pensamentos e pesquisas, bem como fruto da experiencia
vivida no plano pratico da aplicacao do Direito das Relacoes Sociais,
incluindo a sub area do Direito Previdenciario, ele contem criticas,
incluindo inconstitucionalidade de normas e, sugestoes de mudancas
normativas (acrescimos e revisoes), sempre sob o pretexto de
aperfeicoamento do beneficio em comento

Benefício previdenciário:auxílio-reclusão(Regime Geral da Previdência Social)

O desenvolvimento de formulacoes para aplicacao na pele e uma estrategia interessante para transportar farmacos cuja acao e a propria pele, representando uma alternativa para superar aspectos indesejados relacionados as caracteristicas farmacocineticas e farmacodinâmicas dos farmacos. No entanto, a pele apresenta camadas que formam uma barreira a penetracao de farmacos. Desse modo, estrategias tem sido pesquisadas e os modernos estudos farmaceuticos apontam para o uso de metodos fisicos e quimicos, norteados no desenvolvimento de novas formas farmaceuticas, as quais devem apresentar propriedades fisico-quimicas e parâmetros farmacotecnicos adequados para o uso transdermico. 
 
 Palavras-chave: Novos Sistemas Transportadores de Farmacos. Pele. Administracao Cutânea. Transdermicos. 
 
 ABSTRACT Cutaneous administration of drugs: challenges and strategies for the development of transdermal formulations 
 
The development of formulations for skin application is a good strategy for the delivery of drugs whose target is the skin itself, which avoids some unwanted effects of treatment arising from the pharmacokinetic and pharmacodynamic properties of drugs. However, the skin has layers that resist the penetration of drugs. Thus, new strategies have been researched and the latest pharmaceutical studies point to the use of physical and chemical methods aimed at the development of new drug delivery systems, exhibiting physicochemical properties and pharmaceutical parameters suitable for transdermal administration. 
 
 Keywords: Drug Delivery Systems, New. Skin. Administration, Cutaneous. Transdermals.

Administração cutânea de fármacos: desafios e estratégias para o desenvolvimento de formulações transdérmicas

Este estudo analisa de que forma a experiencia profi ssional como empregado formal infl uencia o 
desenvolvimento do empreendedorismo. A pesquisa, de natureza qualitativa, abordou individuos residentes 
no Rio de Janeiro, com curso de graduacao completo e que tinham vivido, por pelo menos cinco anos, a 
situacao de empregados em organizacoes, antes de se tornarem empreendedores de seus proprios negocios, 
por intermedio da criacao de empresa, da autonomia ou da terceirizacao. Os resultados mostram que a 
experiencia na condicao de empregados propiciou aos individuos aprendizados importantes. Contudo, as 
condicoes organizacionais nem sempre favoreceram o desenvolvimento das competencias de que hoje 
necessitam. Percebe-se, tambem que, em parte, a motivacao para a mudanca foi gerada por insatisfacoes 
com o contexto vivido nas organizacoes.

With the advance of the information and communication technology and the recent changes in society, new forms of work relations have become popular, including telework. An example of telework arrangement is that in which the individual performs tasks from home, maintaining, however, a formal employment with an organization. This article focuses on such modality, aiming to identify individuals' perceptions about the consequences of telework for their personal and professional lives. The article presents a qualitative case study conducted at Shell Brazil, a company that has transferred some employees to the home-office scheme since the year of 2000. The methodology is comprised of interviews with individuals in that group. Results helped to identify a conceptual framework pointing to constraint and reference aspects that they use to evaluate their situation as home-office employees. Among the constraints, some aspects concern to: the individual, the organization, the resources available, the work tasks, the family, the home space and the characteristics of society. As reference elements, we can observe: the impacts on performance and the effects on career; the individual's relation with work; the quality of personal life and the relations in family and in society.

Percepções dos indivíduos sobre as consequências do teletrabalho na configuração home-office: estudo de caso na Shell Brasil

Este estudo propoe a elaboracao de um Atlas Hidrografico Digital que servira como um recurso de apoio a gestao dos recursos hidricos da IX Regiao Hidrografica do Estado do Rio de Janeiro. Nessa perspectiva, as condicoes degradantes dos recursos hidricos demandam uma mudanca de comportamento no manejo deste recurso, visando um uso racional, evitando problemas como a escassez, a ma qualidade da agua, assoreamentos, doencas e desequilibrio ambiental. O Atlas assumira importante papel na medida em que servira como recurso didatico-pedagogico, norteando acoes do Comite de Bacias Baixo Paraiba do Sul e Lagoa Feia.

ATLAS DIGITAL HIDROGRÁFICO COMO RECURSO DE APOIO À GESTÃO DOS RECURSOS HIDRICO: O EXEMPLO DA IX REGIÃO HIDROGRÁFICA-RJ

A equivalencia de estimulos, como area de estudos, tem contribuido no ensino de
repertorios academicos de diferentes areas do conhecimento, como a Matematica, a
Musica e a Lingua Portuguesa. Estas contribuicoes devem-se ao fato de pesquisas
sobre equivalencia de estimulos terem demonstrado resultados surpreendentes. A
partir dos resultados obtidos em tais pesquisas, defende-se que, com base nos
estudos sobre a equivalencia de estimulos, pode-se atuar tambem com o ensino de
arte.
O presente trabalho teve como objetivo implementar uma proposta de ensino de
arte pautada no modelo de equivalencia de estimulos, focalizando especificamente
a leitura de imagem, a qual constitui um conteudo fundamental para este ensino.
Teve-se como referencia o trabalho de Garcia e Aguayo (2005) no qual os autores
apoiam-se na proposta de equivalencia de estimulos para a formacao de categorias
de pinturas de arte. Os participantes deste estudo foram estudantes universitarios
que frequentavam um curso de Licenciatura em Artes Visuais na cidade de Sao
Paulo. Seis deles participaram de um pre-teste que avaliava o desempenho nas
relacoes EA, EB, EC e ED (reconhecimento dos nomes dos movimentos artisticos
Futurismo, Expressionismo, Fauvismo e Abstracionismo em imagens
representativas de tais movimentos). Dos seis, tres participaram das demais etapas,
quais sejam: ensino das relacoes AB, AC, AD (relacao entre duas imagens do
mesmo movimento), Teste de Emergencia de novas relacoes simetricas e transitivas
(BA, CA, DA, BC, CD e BD), ensino da relacao AE, Teste de Emergencia de
novas relacoes transitivas (BE, CE e DE), Pos-Teste (reaplicacao das relacoes EA,
EB, EC e ED do Pre-Teste) e Teste de Generalizacao, focando as relacoes EA, EB,
EC e ED com imagens nao trabalhadas durante o Pre-Teste e o ensino.
Os resultados mostraram que houve emergencia de novas relacoes para todos os
participantes assim como, no Pos-Teste, todos estabeleceram corretamente as
categorias de pintura em nivel maximo. No Teste de Generalizacao, os
desempenhos variaram: nas relacoes EA e EB obteve-se desempenho satisfatorio
(entre 80% e 100% de acertos) e nas relacoes EC e ED obteve-se desempenho
insatisfatorio (entre 60% e 79% de acertos).
A proposta da equivalencia de estimulos trata de conteudos atrelados ao universo
da linguagem, dos signos e simbolos, os quais o aprendiz aprende nao somente a
decodificar, mas tambem a compreender, fato que sinaliza a possibilidade de
trabalho com os repertorios academicos da area de Artes. Abrem-se, pois, novas
alternativas para a Arte/Educacao diante das contribuicoes reveladas a luz da
Abordagem Comportamental

A leitura de imagens no ensino de arte com uso de softwareeducativo: formação de categorias pictóricas por meio derelações de equivalência

A crise financeira repercutiu na economia mundial de uma forma nunca vista, desde a crise de 1229. A Lei de Responsabilidade Fiscal criou mecanismos para que o gestor publico possa enfrentar problemas como este. A fixacao de metas de resultados, o acompanhamento bimestral destas metas e a limitacao de empenho sao as principais ferramentas introduzidas pela Lei para que o gestor publico possa proteger as financas e assim manter o equilibrio entre as receitas e despesas. Este artigo avalia os efeitos da recente crise economica sobre as financas dos estados da federacao, mais precisamente sobre nas receitas, despesas e nos resultados primarios.

O impacto da crise econômica nas finanças dos governos estaduais. Uma análise das receitas, despesas e resultados primários

Universidade Estadual Paulista (UNESP), Departamento de Artes Cenicas, Educacao e Fundamentos da Comunicacao, Instituto de Artes de Sao Paulo

O presente estudo tem como objetivo demonstrar as contradicoes existentes no setor sucroalcooleiro com relacao direta entre capital e exploracao do trabalho humano na atual configuracao do sistema energetico brasileiro, principalmente em relacao a expansao do etanol produzido a partir da cana-de-acucar. O projeto analisa as varias problematicas que sao encontradas na cadeia produtiva do etanol, como as condicoes de trabalho dos boiasfrias, que sao obrigados a trabalharem em pessimas condicoes, com longas jornadas de trabalho, que em muitas das vezes ha ate ocorrencia de mortes. Para o desenvolvimento da pesquisa utilizou-se de metodos empirico e exploratorio com estagios de gabinete, onde foram feitos levantamentos de referenciais teoricos (livros, dissertacoes, teses e periodicos), sobre o tema em estudo, alem da analise de documentacao jornalistica dos ultimos anos. Na primeira etapa da pesquisa foram feitas discussoes teorico-metodologicas e a producao de textos. Na segunda etapa da pesquisa proceder-se-a com a aplicacao de questionarios semiestruturado junto aos trabalhadores boias-frias em canaviais no municipio de Campos dos Goytacazes-RJ com o objetivo de coletar dados que servirao de subsidios para a elucidacao das hipoteses sobre o trabalho degradante nos canaviais do referido municipio e regiao. Como resultado da analise aos referenciais, pode ser observado e compreendido que empleno sec. XXI ainda existe, no Brasil, trabalhadores boias-frias exercendo suas atividade nas lavouras de cana-de-acucar em condicoes de trabalho semelhante aos escravos do periodo colonial, assim como pode ser verificado que a escravidao atual tem duas faces, que e aquela condicionada a uma divida e a que explora a mao-de-obra atraves da demanda cada vez maior por produtividade no corte da cana, essas duas formas de escravidao ocorrem principalmente na Regiao Sudeste e Centro-sul. Portanto, nas pesquisas teoricas foram constados que os maiores focos do trabalho degradante no setor sucroalcooleiro encontra-se na Regiao Sudeste e Centro-Sul do pais. Essas sao as regioes onde esta havendo altos investimentos na producao e expansao do etanol, em contra partida, e a regiao que possui maiores indices de denuncias de trabalho degradante.

RECURSOS ENERGÉTICOS RENOVÁVEIS E A ECOLOGIA DO TRABALHO: O CASO DO ETANOL BRASILEIRO

Neste artigo apresenta-se a avaliacao do desempenho do modelo para estimativa do hidrograma de escoamento superficial em bacias hidrograficas apresentado por Silva et al. (2009). Monitorou-se uma bacia experimental localizada em Vicosa (MG), obtendo-se hidrogramas de escoamento superficial relativos a quatro eventos de precipitacao. O modelo desenvolvido foi capaz de prover boa estimativa do hidrograma de escoamento superficial para estes eventos. A comparacao destas estimativas com aquelas feitas por intermedio do Metodo Racional e do Metodo do Numero da Curva possibilitou evidenciar superioridade do modelo desenvolvido na estimativa da vazao maxima e da lâmina total escoada.

Modelo para a obtenção do hidrograma de escoamento superficial em bacias hidrográficas. 2. Avaliação - DOI:10.5039/agraria.v4i2a12

Ullrich Kothe propoe melhorias no calculo do tensor de estrutura, que serao apresentadas neste trabalho. Primeira, a taxa de amostragem e alterada, pois o metodo padrao para calculo desse tensor viola o teorema de amostragem de Shannon-Whittaker; segunda, usando um filtro nao-linear para calcular as entradas do tensor de estrutura, a integracao de informacao oriunda de fora da aresta e minimizada.

The central goal of this research was to increase the debating about efficacy from rules, legal actions and Corporate governance to protect the non qualified minority shareholders in the Brazilian IPOs (Initial Public Offering) programs. The theme has showed growing interest, because the number of personal investors and the Bovespas (Sao Paulo Stock Exchange) IPO market has been in progress strongly. The event study was the methodology used to measure the abnormal returns in the portfolios samples with between 23 and 98 shares from 106 IPOs going public in 2004-07, using de market price from January, 2004 to June, 2008. Further, four statistic tests were applied to detect if the speculative bubble dynamic affected the Bovespa from January, 1999 to June, 2008. The empiric results from event study evidenced the overpricing phenomenon measured from the offering price to the market price at the end of the first day of trading estimated between 4,80% and 9,26%, and a underpricing phenomenon in the sequel. The cumulative average abnormal returns, ruled out of the first day return, achieved -11,52% at the end of the 6 month, -16,60% at the end of the 12 month and -35,74% at the end of the 24 month, presented a underperfomance phenomenon with economic and statistic significance, widely documented by the academy, specially on the north American capital market. The empiric results from four statistic tests showed, with statistic significance, that speculative bubble dynamic affected the Ibovespa (Index of Sao Paulo Stock Exchange) in the period from January, 1999 to June, 2008. Thus, evidences were found of the minority shareholders that bought shares in the Bovespas IPOs programs in the studied period were induced by market anomalies to overpay the shares portfolios. Consequently, the research suggests that actions to improve the rules, legal actions and Corporate governance is necessary to protect of the non qualified minority shareholders in the Brazilian capital market%%%%Esta pesquisa teve como objetivo central ampliar as discussoes quanto a eficacia das normas, procedimentos e Governanca Corporativa na protecao dos acionistas minoritarios nao qualificados nos processos de IPOs (Initial Public Offering) ou abertura de capital das companhias no mercado de capitais brasileiro. O tema apresenta importância crescente em face do recente aumento do numero de investidores individuais e do forte incremento do mercado de IPOs na Bolsa de Valores de Sao Paulo (Bovespa). A metodologia empregada foi um estudo de evento para a identificacao da presenca de retornos anormais em carteiras compostas por uma amostra entre 23 e 98 acoes de um total de 106 IPOs realizados na Bovespa entre 2004 e 2007, abrangendo as cotacoes das acoes no periodo entre janeiro de 2004 e junho de 2008. Tambem foram realizados quatro testes estatisticos visando detectar indicios da presenca da dinâmica de bolha especulativa na Bovespa no periodo entre janeiro de 1999 e junho de 2008. Os resultados empiricos do estudo de evento demonstraram evidencias de…

Mercado de capitais brasileiro: discussão sobre a eficácia dos mecanismos de proteção dos acionistas minoritários não qualificados nos processos de IPO (Initial Public Offering) na Bovespa, no período de 2004 a 2007

The objective of this article is to relate the final results of several workshops conducted during 2008, which integrated the Course for social representations in the northern region of Rio de Janeiro State in hydrographic basins management. Rapid Participative Diagnosis was employed to evaluate environmental, social technical and political problems conflicts and potentialities related to the management of water resources in the Paraiba do Sul Basin estuary. The results, obtained during workshops realized with Basin Committee members of the Ninth Hydrographic Region of Rio de Janeiro State, Brasil (RH IX) pointed out the need for improving interinstitutional transescalars connections among Paraiba do Sul Basin's Federal Committee (CEIVAP) and State Committee (Low Paraiba do Sul River Committee), as well as stimulating collective consensus on reference conditions for the elaboration a The Basin Director Plan which contemplates Rio de Janeiro's representations' needs. It was also depicted that the valuing of environmental services, as well as implementation of integrated hydric resources monitoring systems can be regarded as important strategies for guiding Public Policies and improving environmental quality, not only for the RH IX, but also for all Rio de Janeiro's Hydrographic Regions. Flood control related emergency measures were picked out as priority.

Diagnóstico de bacias hidrográficas para a sustentabilidade - diagnóstico rápido participativo como estratégia de mobilização para a gestão integrada e participativa no Estado do Rio de Janeiro, com ênfase na região da Foz do Rio Paraíba do Sul

INTRODUCAO: Este trabalho propoe a producao do Atlas hidrografico da regiao hidrografica IX do Estado do Rio de Janeiro, que visa subsidiar a gestao das aguas na regiao. Material que servira como recurso de apoio didatico-pedagogico, auxiliando com a sua divulgacao maior discussao em torno das politicas de sustentabilidade dos recursos naturais e hidricos regionais, visando a manutencao do nicho ecologico, e a melhor compreensao  do contexto socioeconomico. Em meados do seculo XVIII a regiao foi ocupada para a producao de cana-deacucar, reorganizando e delineando os aspectos socio-economicos no espaco. A capacidade produtiva da cana se enfraqueceu com a descoberta do petroleo na bacia de campos, oferecendo novas oportunidades de empregos e servicos. A atividade petrolifera divide importância com outras existentes na regiao, que e o caso da agricultura, agropecuaria e comercio. Dessa maneira as ocupacoes irregulares em torno das bacias hidrograficas, o lancamento ilegal de esgotos e lixo domestico, causam grandes impactos comprometendo a utilizacao deste recurso. Com a criacao do Comite para a gestao das aguas o Atlas se constituira como uma ferramenta de auxilio e manejo sustentavel dos recursos hidricos regionais. METODOLOGIA: O metodo utilizado na viabilizacao da pesquisa e o empirico e o exploratorio de gabinete procedendo-se com o levantamento e discussao da literatura disponivel sobre a tematica em estudo e da compilacao da documentacao cartografica do formato analogico para o digital da area de abrangencia da pesquisa, visitas tecnicas as areas de interesse e relevância hidrica, teste piloto de modelagens de escalas cartograficas para representacao da area, capacitacao sobre os metodos e procedimentos de geoprocessamento para a producao do referido Atlas Hidrografico. Com o uso de Sistema de Informacoes Geograficas pode-se produzir uma serie de mapas tematicos em variadas escalas, dotados de informacoes, tendo como fins diferentes abordagens (levando em consideracao a Lei das Aguas do Estado do Rio de Janeiro) e auxiliando didaticamente na leitura dos recursos naturais regionais como um todo, assim como dos recursos hidricos. Para o tratamento das informacoes cartograficas e cruzamento dos bancos de dados foram utilizados os softwares ArcGis 9.2, VistaSaga 2007 e Corel Draw 12. RESULTADOS: A producao parcial do Atlas revelou uma regiao com distribuicao heterogenea dos recursos hidricos nos 22 municipios que a compoe. O acesso a agua de qualidade se dificulta a medida em que a regiao possui grande degradacao dos recursos naturais e intensas atividades industriais, agricolas e agropecuarias (que demandam grande quantidade de recursos hidricos). Medidas como a criacao de canais de drenagem serviram como fatores que aceleraram o processo de assoreamento dos corpos hidricos regionais, a exemplo da Lagoa Feia e da Lagoa de Cima, que perderam cerca de 30% de sua area total atraves dos processos citados e a geracao de conflitos sobre os usos das aguas. CONCLUSAO: A producao do Atlas como recurso didatico-pedagogico para abordagem dos temas relacionados a gestao dos recursos hidricos e ambientais pode auxiliar na tomada de decisoes pelos gestores na fiscalizacao e outorga dos recursos hidricos, favorecendo assim o seu uso sustentavel,  elhorando a qualidade de vida da comunidade regional. A finalizacao da producao das bases cartograficas que comporao o Atlas nos permitira vislumbrar a forma de utilizacao e distribuicao dos recursos hidricos, levando a uma gestao integrada em busca do uso democratico das aguas. Trabalho de Iniciacao Cientifica

ATLAS HIDROGRÁFICO DA REGIÃO HIDROGRÁFICA IX DO ESTADO DO RIO DE JANEIRO

1. A sede constitucional do tema está no art. 102, § 1, da Constituição de 1988, que assim dispõe: “A argüição de descumprimento de preceito fundamental decorrente desta Constituição será apreciado pelo Supremo Tribunal Federal, na forma da lei”. Ver-se-á que estamos diante de um caso especial de ação constitucional que, uma vez proposta, gera um tipo de processo constitucional. Significa isso que se trata de um instituto de direito processual constitucional. O texto fará considerações teóricas sobre a argüição de descumprimento de preceito fundamental decorrente da Constituição, como meio adequado de apreciar a constitucionalidade ou inconstitucionalidade de dispositivos legas, ilustrando essas considerações com a análise de artigos questionados da Lei complementar 101, de 4.5.2000. Só depois desse estudo prévio é que estaremos aptos a responder sinteticamente aos quesitos apresentados.

Arguição de descumprimento de preceito fundamental (sua doutrina em face de uma situação concreta)

In this work we present an analysis on the types of question from the first ten tests of the Brazilian Olympics of Astronomy and Astronautics (OBA). This paper examines the formulation of unique answer questions in the Astronomy issues, trying to point out elements for the elaboration of questions based on the rationalization of the answers, i.e. the linking of knowledge and not the simple placement of data to be substituted in previously memorized equations. The questions were classified according to closed problems or unique answer questions criteria, which are the basic skills necessary for students to use the time to resolve them. The ways to get the right result, the questions were classified as: direct knowledge (type 1), calculation (type 2), reasoning and knowledge (type 3), understanding (type 4) and questions of Science technology and society (type 5). It is observed through the editions of OBA that the types of questions tend to appear in all level tests. In each level the type 3 and type 4 questions, claims the same percentage, however, there is a percentage reduction on type 1. The number of questions that use the simple memorization of responses in High School has decreased over time as well. For example, in the I OBA questions of simple memorization there was a 32.4% and 53.3% in II OBA, but in the test of the IX OBA the percentage was 10% and there is still a reduction of 2.9% from the IX to the X OBA. The classification and the detailed of the results are presented showing that the questions of OBA, wherever possible, have converged to more questions of the 3 and 4 types and less on questions of type 1. In the initial series of tests, the percentage of simple memorization questions, or type 1 decreased from 77.8% in VII OBA to 35.7% in the X OBA. The largest difference in percentage occurred in the 5th to 8th series (eight years scheme) or 6th to 9th series (9 years scheme) of Elementary School, where the percentage reduced from 35.7% to 5.6%, since the VII to the X OBA.

Análise e classificação das questões das dez primeiras olimpíadas brasileiras de astronomia e astronáutica

Resumen pt: Neste artigo se apresenta avaliacao do desempenho do modelo para estimativa do hidrograma de escoamento superficial em bacias hidrograficas apresentado p...

Modelo para a obtenção do hidrograma de escoamento superficial em bacias hidrográficas. 2. Avaliação

A valorizacao social embutida nos programas e projetos de compensacao ambiental, tendo em vista a melhoria da qualidade de vida de populacoes menos favorecidas, tem se caracterizado como um importante mecanismo de inclusao, capaz de transformar os recursos disponiveis em beneficios para grande parte das populacoes afetadas pela intervencao humana na natureza. Partindo deste pressuposto, a presente pesquisa teve como objetivo analisar os efeitos socioeconomicos do Programa de Desenvolvimento Sustentavel do Gasoduto Coari-Manaus na comunidade Sao Pedro da Vila Lira, no municipio de Coari. A metodologia aplicada consistiu de uma pesquisa de campo, dividida em tres etapas. A primeira se deu a partir de uma detalhada pesquisa bibliografica e documental, tendo em vista a necessidade de entender o processo do Programa. Na segunda procedeu-se a pesquisa de campo propriamente dita por meio da observacao e coleta de dados socioeconomicos e ambientais. Nesta etapa, foram realizadas dez entrevistas semiestruturadas junto as familias locais e aplicados trinta formularios socioeconomicos, tendo em vista conhecer suas realidades antes e depois da implantacao dos projetos de compensacao; e quatro entrevistas com os gestores do Programa, sendo uma para cada instituicao, a saber: Secretaria de Meio Ambiente de Coari, Coordenacao da SDS em Coari, Coordenacao Geral do Programa em Manaus e o Coordenador do Programa pela PETROBRAS. A terceira e ultima etapa consistiu da analise dos dados e elaboracao do relatorio final. Diante dos resultados obtidos na ultima fase da pesquisa, observou-se que a Comunidade obteve beneficios socioeconomicos relacionados a educacao, com a construcao de uma escola; melhoria na renda a partir da geracao de emprego nas obras do gasoduto e melhoria tambem na facilitacao do acesso a energia eletrica (aquisicao de um gerador) e agua tratada por meio da construcao de uma estacao de tratamento para a agua captada na nascente de um igarape na propria Comunidade. A partir dos resultados obtidos na pesquisa, ficou evidente a necessidade da adocao de politicas publicas que permitam a melhoria continuada da infraestrutura e servicos basicos que atendam efetivamente as demandas locais, nao apenas por causa da construcao do gasoduto, mas, principalmente, porque e um direito de todos que habitam aquele lugar

Análise do programa de desenvolvimento sustentável do gasoduto Coari-Manaus na comunidade rural Vila Lira no município de Coari

O trabalho foi originalmente apresentado no Simposio "Constituinte em Debate", realizado pela Comissao de Constituicao e Justica da Assembleia Legislativa do Estado do Rio Grande do Sul em 1984, para tratar do tema da constituinte e da nova constituicao federal aos representantes dos mais diversos setores da sociedade. Nesse sentido, expoe a necessidade de uma nova constituicao, o equilibrio entre o poder estatal e os direitos fundamentais do homem e o equilibrio federativo, culminando com uma convocacao para instalacao da Assembleia Nacional Constituinte.

The practice of ethical Nursing care within health services, particularly in public hospitals of Education, comes as part of collective work in health, incorporating technical, managerial, educational, social and political. The ethical dimension of alterity of care in this work scene, assumes the configuration of an attitude of respect and welcome the other, and promotes a continous refletction and changing of attitude of nursing professionals. The aim of this study is to understand the design ethic of care in the daily experience of nursing in the University Public Hospital, with ethical discussion of radical alterity in Emmanuel Lévinas. Descriptive in nature, this study is based on the Hermeneutic-phenomenology, with a qualitative approach. The seizure of the empirical data was achieved with nine nurses of the hospital staff, using the technique of individual interview. The analysis revealed evidence of three areas: care, ethics and otherness of Nursing. Under such dimensions, the data analysis allowed us to identify the importance of ethics of alterity in nursing care, the search for the organization of the care and management, the training, the interdisciplinarity of the shares through the mobilization and articulation of knowledge, the ethical and responsible care, the attitude of understanding the importance of quality care, the commitment to the subjectivity of care, highlighted by the interviewees. However, these workers live, now, with the contradictions inherent in the process of their work, emphasizing the care model that persists in transit between the model and fully functional in form and curative hospital. The management model prints, even today, the characteristics of mechanistic and fragmented work, the multidisciplinary and its relationship with the hierarchy of care, rather than interdisciplinarity; the suffering occupational derivative inadequate working conditions; progressive deficit of the workforce and increased absenteeism, and change the current organizational structure to support the tension between the handle and manage. Because of this scenario, it can be concluded that the Nursing resist, so purposeful, to these challenges, with strong evidence on ethical alterity of care. This trend can express the reflection for the reinvention of the social practice of care, beyond the classical approach of partial care for the size of alterity ethics of care.

UNIVERSIDADE FEDERAL DO CEARÁ PRÓ-REITORIA DE PESQUISA E PÓS-GRADUAÇÃO MESTRADO EM POLÍTICAS PÚBLICAS E GESTÃO DA EDUCAÇÃO SUPERIOR

Cladonia clathrata (Cladoniaceae) e uma especie liquenica e varios extratos de especies de Cladonia sao utilizados como remedios na medicina popular. Para avaliar as acoes do extrato desse liquen, estudos foram realizados sobre as atividades antinociceptiva, anti-inflamatoria e antioxidante. O extrato hidroalcoolico da C. clathrata (EHCc) foi utilizado nos experimentos e produziu atividade inibitoria (p < 0,001) sobre o efeito do acido acetico no modelo de contorcoes abdominais nas doses de 100 (47,2%), 200 (47,2%) e 400 mg/Kg (86,4%), alem de reduzir o efeito da formalina na primeira (400 mg/Kg, p < 0,01) e segunda (200 e 400 mg/Kg, p < 0,01) 
fases da nocicepcao. A migracao de neutrofilos para a cavidade peritoneal induzida pela carragenina foi inibida pelo pre-tratamento dos animais com o EHCc na dose de 400 mg/Kg (p < 0,001). O EHCc reagiu com o radical DPPH e reduziu o mesmo em 25,76%, com um valor de CI50 de 77,39 ± 5,03 mg/mL de DPPH. O EHCc mostrou atividades antinociceptiva e anti-inflamatoria, com potencial antioxidante.

Avaliação das atividades antinociceptiva, anti-inflamatória e antioxidante do extrato hidroalcoólico do líquen Cladonia clathrata

Os processos de ocupacao espontânea nos centros urbanos dificultam o desenvolvimento harmonico da cidade. Tais processos levam a uma excessiva extensao do tecido urbano, inviabilizando a implantacao de infraestrutura e servicos basicos. Alem de contribuir para uma desintegracao funcional, a ocupacao espontânea dificulta o planejamento e a implementacao das ligacoes viarias. No municipio de Campos dos Goytacazes, cidade objeto de estudo neste projeto de pesquisa, tais ocupacoes, a exemplo de diversas cidades no Brasil, tambem ocorrem em diversas areas. Com o desenvolvimento da pesquisa, objetiva-se compreender esse fenomeno nas lagoas urbanas do municipio e, mais precisamente, na Lagoa do Vigario.

Estudo de Ocupação Espontânea na Lagoa do Vigário, no Município de Campos dos Goytacazes - RJ, propostas mitigadoras e amparo legal

No seculo VIII a Europa viu florescer uma marcante espiritualidade feminina, cujas representantes foram Lutgarda de Aywieres, Matilde de Magdeburgo, Matilde de Hatckeborn, Gertrudes de Helfta e Beatriz de Nazareth, abordada no relato. O autor parte de sua biografia e se concentra na obra "De septem modis sancti amoris " (Os sete modos do amor), um tratado pedagogico sobre Deus, com base na teologia biblica da "Image Dei".

O Rio Paraíba do Sul na IX Região Hidrográfica do Estado do Rio de Janeiro: impactos e possibilidades de uso.

Desenvolveu-se um modelo para obter o hidrograma de escoamento superficial em bacias hidrograficas considerando tanto o escoamento em encostas como em canais. O modelo usa a equacao de intensidade, duracao e frequencia na analise de eventos extremos ou o pluviograma correspondente ao evento em estudo na analise de eventos especificos e a equacao de Green-Ampt-Mein-Larson para estimar a taxa de infiltracao. A taxa de escoamento superficial e estimada considerando o modelo de ondas cinematicas, no qual o hidrograma para cada celula e obtido somando-se o hidrograma produzido na celula com os provenientes das celulas contribuintes. O modelo e mais sensivel a umidade de saturacao, umidade inicial, armazenamento superficial, potencial matricial na frente de umedecimento e condutividade hidraulica do solo e menos sensivel ao coeficiente de rugosidade e a interceptacao pela cobertura vegetal.

Modelo para a obtenção do hidrograma de escoamento superficial em bacias hidrográficas. 1. Desenvolvimento e análise de sensibilidade - DOI:10.5039/agraria.v4i1a13

O ensaio teorico em foco se detem na analise das teorias sociologicas elaboradas por Karl Marx, Emile Durkheim, Max Weber e Pierre Bourdieu com o proposito de averiguar como estes icones do pensamento sociologico, cada um a sua maneira, concebem o processo de formacao das ideias e representacoes dos individuos e o processo de formacao do sentido da acao social. Com a realizacao deste estudo, pode-se observar que o pensamento sociologico de Bourdieu resgata diversos aspectos da sociologia classica - Marx. Durkheim e Weber - e proporciona um fertil instrumental teorico para a compreensao da realidade social. Os conceitos de habitus e de campo elaborados por Bourdieu - na medida em que permitem uma compreensao relacional dos problemas sociais - possibilitam o resgate da teoria da praxis presente na obra de Marx e a recusa do estruturalismo-funcionalismo Durkheimiano e ate mesmo de aspectos subjetivistas da teoria Weberiana. Bourdieu, com sua terminologia propria, sugere que a pratica humana depende tanto das estruturas objetivas quando das estruturas subjetivas dos agentes sociais. Isto significa dizer que, a exemplo de Marx, Bourdieu entende que os homens fazem a sua historia, mas a faz dentro de certas condicoes.

A formação das idéias e representações e o sentido da ação social, segundo a sociologia clássica e contemporânea

Hidroxiapatita sintética nanoestruturada e esmalte dental aquecidos e irradiados por laser de Er, Cr: YSGG: caracterização por FTIR e por DRX

Mediação dos receptores ativados por proteases (PARs) em atividades biológicas da giroxina

Como cidadao brasileiro e como homo politicus, integrado ao universoda lusofonia, nesta “aldeia global”, em que a comunicacao circulasem fronteiras entre os usuarios dos mesmos codigos linguisticos, souplenamente favoravel ao Acordo Ortografico da Lingua Portuguesa.

Esta tese analisa as transformacoes em curso das formas de ocupacao e meios de reproducao social entre familias rurais, a partir do estudo de casos, que envolve o acompanhamento de uma decada de pesquisa entre familias na regiao serrana do estado do Rio de Janeiro, municipio de Nova Friburgo. O relato de historias reais de vida durante esse periodo da pesquisa, sob um mesmo grupo de familias, permitiu fazer uma leitura mais profunda da trajetoria de vida e de trabalho de seus membros, em um entorno rural diversificado. Pode-se, assim, compreender os distintos significados e pesos das rendas agricolas e nao-agricolas para a reproducao social dessas familias; as alteracoes nas formas de trabalho, no uso da terra e na propria agricultura provenientes dessa maior diversificacao inter-setorial, contribuindo assim, para o aprofundamento do debate sobre a pluriatividade no pais. O presente estudo demonstrou que a pluriatividade e uma forma de trabalho estavel e estrutural, e que tem permitido a manutencao dessas familias no campo com melhorias de renda e qualidade de vida 
Abstract

Novos contornos ocupacionais no meio rural fluminense : estudo sobre a pluriatividade entre agricultores familiares

Na literatura mais recente da gestao, observa-se o crescente discurso ressaltando a importância das pessoas para os resultados estrategicos da organizacao. Como consequencia, as empresas vem implementando politicas e praticas que visam a elevar o comprometimento e a produtividade de seus empregados. Entre essas ferramentas esta o Sistema de Gestao de Desempenho. O presente estudo tem como objetivo investigar a influencia dos Sistemas de Gestao de Desempenho no comprometimento dos individuos, com relacao as organizacoes e as metas estabelecidas. Em um estudo de campo com a utilizacao de questionarios, observou-se, por meio de analise quantitativa, que as variacoes nos niveis de comprometimento sao mais visiveis quando o individuo percebe esses sistemas propiciam ganhos para o funcionario, tais como oportunidades de crescimento profissional, maior conhecimento da estrategia da organizacao e maior autonomia de decisao. Os resultados tambem sugerem que tais praticas levam a formacao de um comprometimento normativo (quanto a organizacao e a meta) e, em menor escala, a um comprometimento afetivo com a organizacao.

A INFLUÊNCIA DOS SISTEMAS DE GESTÃO DE DESEMPENHO SOBRE O COMPROMETIMENTO DOS INDIVÍDUOS NO ATUAL CONTEXTO DAS ORGANIZAÇÕES

One of the challenges for organizational studies is that of trying to create their own language from knowledge generated in other sciences, often resulting in an oversimplified translation of concepts. In the case of organizational communication, this challenge is even more complex, as communication is traditionally viewed by hmaavnea gbeemene ndt ivtheersoirfiieesd .i nT hai sm tohreeo irnestticruaml eensstaaly paenrsaplyescetisv et,h ew hpiloes saipbpilirtoieasch oefs ainp portohxeirm aarteinags Management and Language Studies areas in order to develop research on organizational communication and help organizations solve their practical managerial problems. The source of inspiration are the experiences of an interdisciplinary research group that seeks an interdisciplinary approach based on the joint production of knowledge by researchers of obfo tcho nacreepatss, arantdh emr etthhaond so.n T thhee rcerfolescstiinogn so fp rdeissecinptleinda rsyh obwo utnhdaat roiens oanned hthane dm, eitr eis imnopto artlwataioyns easy to negotiate the investigative logics and tools used in the process; on the other hand, this exercise may facilitate the production of new knowledge in both areas, with practical relevance for the organizational context.

Comunicação organizacional: oportunidades para uma abordagem de pesquisa interdisciplinar entre a Administração e a área de Estudos da Linguagem

O ciberespaco e a cibercultura alteraram as formas de socializacao, de transmissao e de aquisicao de saberes. A conectividade permitida pelo ciberespaco trouxe o compartilhamento de ideias e a construcao de conhecimento em rede. 
A liberacao do polo da emissao, o principio da conexao em rede e a reconfiguracao de formatos midiaticos e praticas sociais favorecem a emergencia da Inteligencia Coletiva, cuja aplicacao na educacao podem ser percebida, por exemplo, em Comunidades Virtuais de Aprendizagem, as quais pressupoem um sujeito ativo e abandonam a pedagogia da transmissao, baseada na distribuicao de informacoes, na transmissao de conteudos e na memorizacao mecânica. A Inteligencia Coletiva no ciberespaco, na verdade, potencializa uma situacao ja existente: conceitos e ideias circulam entre nos e e dificil apontar a quem pertencem. Havera autoria exclusiva ou as ideias sao reconfiguracoes daquilo ja existentes e fruto de dialogismos? 
Palavras-chave: Inteligencia coletiva, educacao na cibercultura, comunidades virtuais de aprendizagem 
 Abstract: 
Abstract: The cyberspace and the cyberculture changed the ways of socializing, delivering and acquiring knowledge. The connectivity granted by the cyberspace allowed the sharing of thoughts and the construction of knowledge at network. 
The releasing of pole emission, the principle of net connectivity and the new configuration of media formats and social practices allow the establishment of Collective Intelligence, whose use on education could be noticed, for instance, in the virtual learning communities, which imply an active subject and renounce the transmission pedagogy set on sharing of information, transmission of contents and mechanic memorization. 
The Collective Intelligence on ciberspace, as a matter of fact, potentize an existing circumstance: concepts and ideas surround us and it is hard to disclose to whom they belong. Does exclusive authorship exist or the thoughts are new shapes of previous ideas and result of dialogism? 
Key-words: Collective Intelligence; cyberculture’s education; virtual learning communitie. 
Resumen: El ciberespacio y la cibercultura han cambiado las formas de socializacion, transmision y adquisicion de conocimientos. La conectividad ofrecida por el ciberespacio ha traido la posibilidad de compartir ideas y de construir conocimientos en red. 
La liberacion del polo de emision, el comienzo de la conexion en red, la reconfiguracion de formatos de los medios de comunicacion y practicas sociales, promueven la aparicion de la Inteligencia Colectiva, cuya aplicacion en la educacion se puede percibir, por ejemplo, en Comunidades Virtuales de Aprendizaje, las que presuponen un sujeto activo y abandonan la pedagogia de la transmision, basada en el reparto de informaciones, en la transmision de contenidos y en la memorizacion mecanica. 
La Inteligencia Colectiva en el ciberespacio, en verdad, mejora una situacion que ya existe: conceptos e ideas circulan entre nosotros y es dificil senalar a quienes pertenecen. ?Habra autoria exclusiva o las ideas son reconfiguraciones de lo existente y fruto del dialogo? 
Palabras clave: Inteligencia colectiva, educacion en cibercultura, comunidades virtuales de aprendizaje.

Educação na Cibercultura: comunidades de aprendizagem para mobilização da inteligência coletiva

Some of the most striking characteristics of recent discussions about labor relations are the reduction in formal employment and the growth in the discourse about flexibilization, which are translated into words like employability and into practices like outsourcing. This flexibilization, however, does not imply that organizations no longer expect their workers to be fully committed or that the wish to construct a solid and stable career has lost its meaning for professionals. This suggests that there are countless inherent ambiguities in current relations. This study investigates how such a context interferes in the expectations of the individuals who work as outsourced employees in the IT area in large companies, by observing the discourses that develop about their professional conditions and their careers.  The results indicate there are four types of discursive profile - the disillusioned, the ambivalent, the skeptical and the credulous. The possible implications of these profiles for individuals and for their employers are discussed in the conclusions.

The objective of this paper is to weave hermeneutic considerations and philosophies concerning ethics, economy and climate, with a specific focus on the relationship between Kant's categorical imperative and the question of improved sustainability. The economic perspective of Georgescu-Roegen has been considered, to this end. Although economy, ethics and biology constitute distinct fields of specialization, this work seeks to show reasons for which this perspective could be seen as an intersection between the three disciplines. The article concludes with the message of Georgescu-Roegan, held in his saying â€œminimal bioeconomic programâ€ in accordance with the fundamental precepts of the Kantian ethics, in respect to the question of sustainability.

This study approaches the reaches and limits of technological innovations produced by the Management System of Human Milk Banks - BLHWEB in the strategy of qualification and certification of the management of products and processes conducted under the responsibility of one Human Milk Bank - HMB. The BLHWEB is an information system specialized in the environment of action of 
HMB that internalizes procedures, technical guidelines, standards and scientifically based concepts to ensure the quality of products and processes under the responsibility of HMB. It was conceived with the perspective of configure itself in a strategy, more than one instrument, of qualification of these service units. The present study was raised under the perspective of evaluate how the innovations introduced by the system enable the qualification of the action of HMB. It was adopted as the guiding question, which are the technological innovations 
introduced by BLHWEB on the work environment of HMB and assumes that the qualification of the working processes of the HMB is a result of technological innovations produced by the system. 
The study was conducted supporting itself in the theoretical referencial that came from three areas of knowledge that comprise the field of construction of BLHWEB: the Human Milk Banks in the scenario of Public Health, the management of the quality of the processes, particularly in health and Information Technology applied in health management. The historical rescue of the construction process that culminated with the 
BLHWEB was carried through, trying to identify the innovations generated by the use of BLHWEB in processes conducted in a HMB in search of elements that allow to characterize the reaches and limits of the use of the system as strategical tool for qualification of the HMB in the scope of the RedeBLH in Brazil and abroad.

Inovações tecnológicas para uma estratégia de qualificação dos produtos e dos processos de trabalho em Bancos de Leite Humano: o sistema de gerenciamento BLHWEB

O crescimento do setor de servicos e a necessidade de informacoes que possam melhorar a qualidade da prestacao dos servicos, especificamente, no setor contabil, podem ser vistos, pelos interessados nas informacoes da contabilidade como um instrumento de grande importância dentro das empresas. Assim, devido ao grande numero de empresas prestadoras de servicos contabeis e de profissionais, torna-se essencial definir estrategias para maximizar o atributo da qualidade dos seus servicos como maneira de adquirir vantagem competitiva e permanencia no mercado. Dessa forma, a pergunta que motiva este estudo e a seguinte: Qual a percepcao dos gestores do setor de comercio da cidade de Sousa-PB, em relacao a satisfacao da qualidade dos servicos oferecidos pelos profissionais da area contabil? Como maneira de responder ao problema proposto foi realizada pesquisa de campo junto a 147 gestores, de um total de 525, do setor de comercio varejista de mercadorias em geral, da cidade de Sousa, PB. O procedimento estatistico foi composto por tecnicas da estatistica descritiva e da analise fatorial. Os resultados encontrados apontam 3 fatores criticos de sucesso, quais sejam: fator 1: Imagem e Credibilidade do Escritorio (com variância total explicada de 45,87%), Agilidade e Pontualidade na Prestacao dos Servicos (11,58% da variância explicada) e Desempenho e Percepcao dos Funcionarios (11,51% da variância total explicada). Os atributos encontrados com base nesses fatores criticos evidenciam as principais preocupacoes que podem estar sendo discutidas pelos contabilistas da cidade de Sousa, PB, como maneira de vislumbrar resultados mais satisfatorios para o auxilio do gerenciamento da prestacao dos servicos contabeis junto aos gestores. Como limitacao e sugestao para pesquisas futuras, entende-se que e necessario aumentar o tamanho da amostra utilizada.

Requisitos de Qualidade em Serviços Contábeis no Setor de Comércio

Tese de mestrado. Automacao, Instrumentacao e Controlo. Faculdade de Engenharia. Universidade do Porto. 2009

Sistema servo-hidráulico de ensaio dinâmico de estruturas : um caso de desenvolvimento

Análise de sistemas de controle de vibração em máquinas rotativas utilizando atuadores formados por ligas com memória de forma

Esse estudo tem por objetivo verificar quais as principais dificuldades enfrentadas pelos profissionais de contabilidade na cidade de Sousa-PB em relacao a prestacao do servico contabil. Para tanto, utilizou-se como metodologia a pesquisa exploratoria, descritiva e de campo, onde foram entrevistados 34 contabilistas de um total de 88 para obtencao destes dados. Utilizou-se de um questionario semi-estruturado com perguntas objetivas e subjetivas direcionados aos contadores e tecnicos de contabilidade da cidade de Sousa, PB. Os procedimentos estatisticos foram compostos pelo uso da estatistica descritiva e de testes nao parametricos (Teste Exato de Fisher e Qui-Quadrado). Observou-se que 76,5% dos contabilistas sao tecnicos, e 23,5% sao contadores. Constatou-se que a maioria dos escritorios e de pessoas fisicas e que atuam no mercado ha mais de 10 anos. No que se refere as dificuldades enfrentadas pelos profissionais na elaboracao das informacoes contabeis, detectou-se que 94,1% dos gestores segundo o entendimento do profissional contabil tem pouco conhecimento da importância da contabilidade, 91,2% nao tem interesse nas informacoes contabeis, 73,5% entendem que a falta de documentos para efetuar o registro dos fatos, 47,1% dizem que a sonegacao fiscal e um fator que dificulta a prestacao dos servicos contabeis e 41,2% dos profissionais nao estao interessados em elaborar as informacoes contabeis porque os honorarios contabeis sao baixos. Os resultados sinalizam para a conscientizacao dos profissionais contabeis da cidade de Sousa/PB na divulgacao da importância da contabilidade como ciencia social aplicada que busca atender a premissa de fornecer informacoes a sociedade para auxiliar no processo decisorio.

Dificuldades dos Profissionais de Contabilidade em Relação à Prestação dos Serviços Contábeis

O estado-da-arte da literatura em economia e gestão da inovação e tecnologia : um estudo bibliométrico

Dentro do conjunto da obra de Graciliano Ramos, considerado um autor de textos 
complexos e, portanto, de dificil acesso ao publico de um modo geral, a critica literaria 
tem abordado seus personagens infantis isoladamente, sem observar a relevância no 
conjunto de sua obra. De acordo com levantamento bibliografico para esta pesquisa, 
observou-se que o autor e pouco explorado nos livros didaticos do ensino fundamental e 
medio e o vies infantil nao e devidamente explorado pela critica literaria e/ou livros 
didaticos. Por esse motivo, este trabalho se propoe a trabalhar as seguintes narrativas: A 
terra dos meninos pelados (conto infantil: 1937); “Luciana” (1946) e “Minsk” (1945) 
(contos de Insonia), com objetivo de analisar a representacao do personagem infantil em 
Graciliano Ramos e examinar a recepcao desses contos em sala de aula, a partir das 
seguintes questoes: Qual a relevância do personagem infantil na obra do autor? Como 
alunos do ensino fundamental receberiam a expressao de sofrimento e exclusao infantil, 
apresentada por Graciliano Ramos? Partiu-se da hipotese de que a representacao do 
cotidiano, as ansiedades e expectativas, alem das dificuldades que os personagens 
infantis possuem de compreender a si mesmos e situarem-se historica e 
psicologicamente no meio social em que vivem, passando por momentos de descoberta e 
amadurecimento, possivelmente envolveriam o leitor “iniciante”, uma vez que os 
problemas desses sintetizam e projetam a experiencia humana infanto-juvenil. Com esse 
intuito, a experiencia pedagogica foi desenvolvida atraves de sequencia didatica, em uma 
escola publica. A principal fonte de dados foram as respostas, dos alunos-colaboradores, 
aos roteiros de leitura e as perguntas formuladas em sala de aula. Do ponto de vista 
teorico, para a analise dos contos, esta pesquisa fundamentou-se na vertente da 
hermeneutica, filiando-se, para isso, a autores como Bosi (2003a), Eco (1993), Eagleton 
(1983), entre outros. No que se refere ao ensino de literatura, apoiou-se na teoria da 
estetica da recepcao e do efeito, baseando-se nas propostas de Jauss (1994), Chartier 
(2001), Iser (1979), Zilberman (1989) e nas propostas metodologicas de Chiappini (2005), 
Cosson (2006) e Pinheiro (2003), entre outros. Embora, inicialmente, a pesquisa se 
voltasse a recorrencia do sofrimento dos personagens infantis na obra do autor, os 
alunos leram as narrativas por outro vies: o da diversao e brincadeira, ensinando a 
professora-pesquisadora a olhar os contos a partir de outra perspectiva. A pesquisa 
mostrou que ha varias leituras para um mesmo texto e que a experiencia do aluno deve 
ser levada em consideracao.

Compromisso e paixão: o universal e o singular na boa escola pública.

In a context of production and circulation of news in digital networks, news agencies are now facing an horizon with multiplicity of news sources and information such as internet and news channels by satellite TV. A few years ago, this was almost an exclusive domain of agencies. In a parallel with this framework, news agencies are constantly working to run and keep a continuous flow of news in a regular and stable dynamics, in order to keep its operation steady as a business model. This paper addresses an approach of news agencies flow of news, creating categories, typology and methodological procedures for analysis of news circulation in a more diverse and complex scenario of news circulation.

Problematizando o fluxo. Uma abordagem metodológica de caracterização do fluxo de notícias e informações nas agências de notícias

O objetivo deste trabalho e analisar a organizacao e a reorganizacao do espaco geografico do municipio de Guaira - PR relacionado com o desaparecimento das Sete Quedas, outubro de 1982. Com o desaparecimento das Sete Quedas abriu-se uma discussao sobre a bancarrota da economia de Guaira, entretanto, o municipio ampliou o horizonte de possibilidades economicas, refletindo tambem em novas formas espaciais. A economia da erva mate em Guaira sera a precursora de uma organizacao espacial que constituira elementos definidores da paisagem, considerando as suas caracteristicas produtivas. O fim das Sete Quedas representaram dois grandes impactos, o ambiental e o economico. O ambiental pela intervencao do homem na natureza e o economico pelo desmantelamento da atividade turistica e a perda de grandes porcoes de terras agricultaveis. As diretrizes da reorganizacao do espaco definiram-se por Planos Diretores, e em parte, pelo movimento da sociedade com suas novas demandas. Assim, considerou-se necessario, alem das observacoes e analise das novas formas espaciais, fazer uma analise dos indicadores economicos do municipio. Esta analise demonstrou que apesar das lamentacoes pela perda do atrativo turistico, Guaira encontrou uma nova matriz economica e apresenta resultados mais vigorosos que no passado. Praticamente todos os ramos de atividade, com poucas excecoes, apresentaram crescimento, bem como o numero de pessoas no mercado formal de trabalho, o numero de estabelecimentos comerciais, o PIB municipal e o PIB per Capita do municipio. Quanto as transformacoes espaciais, destacam-se as novas regionalizacoes que se apresentam em decorrencia da formacao do Lago de Itaipu, como o Conselho dos Municipios Lindeiros ao Lago de Itaipu, a chamada Costa Oeste e o Corredor da Biodiversidade. Tambem se evidencia a importância de Guaira na Mesoregiao Oeste Paranaense, a integracao com os municipios do Estado do Mato Grosso do Sul e com municipios do sudeste paraguaio. A expansao da ferrovia Ferroeste, passando por Guaira, fortalece a pujanca do municipio e, que, das Sete Quedas se guardara apenas a memoria de suas belezas naturais.

Antes e depois das Sete Quedas: o espaço geográfico de Guaíra PR

El presente estudio tuvo como objetivo evaluar los efectos del fortalecimiento muscular, en las fases neurogenica y miogenica, sobre el nivel de fuerza muscular y la autonomia funcional de una poblacion de mujeres mayores sanas y sedentarias. La muestra quedo constituida por 40 mujeres, subdivididas de manera aleatoria en: grupo experimental (GE, n = 12; 65,62±5,36 anos) y grupo control (GC, n = 11; 71,45±5,72 anos). Se utilizo el protocolo de una repeticion maxima (1RM) para la evaluacion de la fuerza muscular y la bateria de test del protocolo del Grupo de Desarrollo Latino Americano para la Madurez (GDLAM) para evaluar la autonomia funcional. Para el analisis estadistico fueron utilizadas las siguientes pruebas: Friedman (GE, en relacion a los 3 momentos) seguido de las comparaciones multiples de Wilcoxon (GC, en relacion a los 2 momentos) y Mann-Whitney por el ?% (comparacion inter-grupos). Los resultados en los niveles de fuerza muscular del GE, en la fase miogenica, revelaron ganancias significativas cuando fueron comparados con el pre-test (valores de p: EJ = 0,0001; FJD y FJE = 0,0001; SUP = 0,0001; ET = 0,0001) y en la fase neurogenica (valores de p: EJ = 0,0008; FJD y FJE = 0,0031; SUP = 0,0005; ET = 0,0073). Los tests de autonomia funcional obtuvieron mejoras significativas en el GE: Fase neurogenica (valores de p: IG = 0,0089; C10m = 0,0106; LPS = 0,0005; LPDV = 0,0061; LCLC = 0,0072; VTC = 0,0104) y fase miogenica (valores de p: IG = 0,0001; C10m = 0,0005; LPS = 0,0000; LPDV = 0,004; LCLC = 0,0059; VTC = 0,0003). Asi, se pudo concluir que el entrenamiento de la fuerza presento variaciones estadisticamente significativas en esta variable, solo en la fase miogenica; ademas se constataron tambien disminuciones estadisticamente significativas respecto al tiempo de ejecucion de los test de autonomia funcional en la fase neurogenica.

A influência de um programa de treinamento de força muscular, nas fases neurogênica e miogênica, sobre os níveis de IGF-1 em idosas sedentárias

O crescimento da terceirizacao tornou-se uma das caracteristicas mais marcantes das relacoes de trabalho nas ultimas decadas. Entre os trabalhadores mais qualificados, a categoria dos profissionais de Tecnologia da Informacao – TI – foi, talvez, uma das mais afetadas por esta pratica, uma vez que muitas organizacoes passaram a considerar as atividades destes profissionais como nao pertencentes ao seu core business. Uma das modalidades de terceirizacao mais popularizadas em TI e aquela em que os trabalhadores sao contratados por meio de uma empresa prestadora de servicos, mas atuam contratante. Sob a otica dos individuos, torna-se relevante entender, entao, como eles compreendem a relacao dupla de trabalho que se constitui em tais situacoes. O presente artigo aborda esta questao, investigando como essa dupla relacao influencia o contrato psicologico desses profissionais. O artigo focaliza tres casos de terceirizacao, utilizando-se de entrevistas com profissionais subcontratados e gestores de seus contratos. As conclusoes obtidas por meio da analise dos casos possibilitaram a proposicao de um quadro conceitual representativo da dinâmica de formacao e manutencao dos contratos psicologicos dos individuos que atuam neste tipo de modalidade.

TECNOLOGIA DA INFORMAÇÃO E GESTÃO DO CONHECIMENTO EM UMA ORGANIZAÇÃO MILITAR: UMA ABORDAGEM INTERPRETATIVA

A comparative analysis was carried out based on the detailed morphology of adults of seven genera: Caryedes Hummel, 1827, Ctenocolum Kingsolver & Whitehead, 1974, Gibbobruchus Pic, 1913, Meibomeus Bridwell, 1946, Merobruchus Bridwell, 1946, Penthobruchus Kingsolver, 1973, and Pygiopachymerus Pic, 1911, joined in the Merobruchus group. This group is included in Acanthoscelidina Bridwell, the largest subtribe of Bruchinae, and with imprecise limits. This study describes new characters, suggests a new hypothesis for the relationships among the genera, proposes diagnoses of the group and its genera, and provides a dichotomous key. It was also possible to record Caryedes godmani (Sharp, 1885) and Caryedes longifrons (Sharp, 1885) for the first time from Brazil and Dioclea virgata (Rich.) Amshoff (Papilionoideae) as a new host plant for C. godmani.

Morfologia comparada dos gêneros do grupo Merobruchus (Coleoptera: Chrysomelidae: Bruchinae): diagnoses e chave

Na hidroformilacao do linalol, foi usado o [Rh(COD)(OAc)]2 como precursor catalitico na presenca de trifenilfosfina ou varias difosfinas, que resultou, principalmente, em uma mistura de isomeros cis e trans de um hemiacetal decorrente da ciclizacao intramolecular de um hidroxi-aldeido formado primariamente. Foi observado um efeito inesperado do ligante de fosforo na velocidade da reacao. Com sistemas nao modificados, o linalol apresentou uma baixa reatividade sob as condicoes empregadas, provavelmente devido a quelacao do substrato no rodio. A introducao de (di)fosfinas e o aumento da sua concentracao levou a uma grande aceleracao da reacao que, nas condicoes otimizadas (40-50 oC e 20 atm de CO/H2), quase todo o linalol foi convertido em apenas 4-6 horas. Um bom controle da quimio- e da estereosseletividade foi conseguida atraves da escolha apropriada das variaveis de reacao. Cada um dos dois isomeros do hemiacetal pode ser obtido com cerca de 95% de quimiosseletividade e 85% de estereosseletividade. Neste trabalho tambem foram estudados a hidroformilacao de monoterpenos endociclicos, tais como 2-careno (1), 3-careno (2) e -pineno (3), catalisada por rodio na presenca de PPh3 ou varias difosfinas e fosfitos. O catalisador de Rh nao modificado promove uma intensa isomerizacao de ambos carenos, cuja hidroformilacao ocorre lentamente e resulta em uma mistura complexa de aldeidos e alcoois. A adicao de PPh3, difosfinas ou P(OPh)3, na elevada razao de P/Rh igual a 20, impede a isomerizacao, mas a atividade da hidroformilacao e drasticamente reduzida. Por outro lado, a utilizacao do ligante volumoso P(O-o-tBuPh)3, nao so reduz a isomerizacao, como aumenta significativamente a velocidade da hidroformilacao. Todas as tres olefinas estudadas (1-3) foram eficientemente hidroformiladas em condicoes de reacao relativamente brandas (80-100oC, 40-80 atm) resultando na formacao de um aldeido principal (2-formilcarano, 4-formilcarano, e 3-formilpineno, respectivamente) com boa quimio- e regiosseletividade e quase 100% de estereosseletividade para o isomeros trans. Tambem foi estudada a hidroformilacao do - e -terpineno utilizando um sistema catalitico rodio/trifenilfosfina. O estudo mostrou que dienos endociclicos podem ser hidroformilados em condicoes brandas somente se suas duplas ligacoes estiverem conjugadas. Uma escolha adequada das condicoes reacionais permite realizar a hidroformilacao rapida e seletiva do - e -terpineno, com seletividade conjunta para dois aldeidos principais proxima de 100%. Os resultados sugerem que a etapa lenta da reacao e a coordenacao do substrato ou sua insercao na ligacao metal hidreto. Nos dienos conjugados, o complexo 2-olefinico de rodio pode rapidamente se transformar no intermediario 3-alilico, mais estavel, o que confere as duplas ligacoes endociclica conjugada uma razoavel reatividade frente a hidroformilacao, enquanto as nao conjugadas permanecem praticamente intactas nas mesmas condicoes.

Hidroformilação de substratos monoterpênicos catalisada por complexos de ródio: síntese de produtos de interesse comercial e intermediários para a química fina

Resumo Sob o olhar das manifestacoes artisticas e culturais da Idade Media Ocidental, o texto a seguir visa a analisar a obra cinematografica intitulada O Setimo Selo (1957), dirigida pelo cineasta sueco Ingmar Bergman (1918-2007). Este filme consiste, pois, numa importante fonte para a compreensao da chamada crise do medievo na Baixa Idade media (seculos XIV e XV): as Cruzadas, a fome, a Inquisicao, a morte e a Peste Negra. A analise proposta se compoe, portanto, de tres partes principais. Em primeiro lugar, apos uma breve biografia de Ingmar Bergman e algumas informacoes sobre o filme, serao enfatizadas as referencias, feitas ao longo da obra, a passagens do Livro do Apocalipse, a musica Dies Irae e a Danca da Morte. Alem disto, serao igualmente observadas as influencias exercidas sobre o cineasta por Carmina Burana e pelas igrejas da sua cidade natal, Uppsala. Em seguida, sera proposto um estudo mais aprofundado do Livro do Apocalipse e de algumas de suas passagens com o intuito de expor as leituras que se fazia delas na epoca. A partir disto, sera realizada uma interpretacao sobre a maneira como essas mesmas leituras contribuiam para suscitar nas mentes dos individuos a ideia de um fim proximo e inevitavel. Por fim, conclui-se com uma indagacao, a partir do mesmo texto biblico, sobre a origem do medo da morte que permeava o imaginario medieval. Acredita-se que esse medo se devesse sobretudo a concepcao imaginaria de um Deus Pai, severo e dominador, cuja representacao estava intimamente associada aos conceitos de sancao e de imprevisibilidade. Palavras-chave: O Setimo Selo, Baixa Idade Media, Livro do Apocalipse Abstract Among artistic and cultural manifestations about the Occidental Middle Ages, the present text aims at analysing The Seventh Seal (1957), film directed by the Swedish film director Ingmar Bergman (1918-2007). It is an important source to comprehend the so-called medieval crisis in the Late Middle Ages (XIVth and XVth centuries): the Crusades, the famine, the Inquisition, the death and the Black Plague. Therefore, the analysis proposed comprehends three main parts. At first, after a brief biography of Ingmar Bergman and some informations about the film, the references, done during the work, to The Book of Apocalypse passages, to Dies Irae song and to the Dance of Death are going to be emphasized. Moreover, in the same way, the influences exercised on the film director by Carmina Burana and by the churches from his native city, Upsala, are going to be observed. Afterwards, a deeper study about The Book of Apocalypse and some of its passages are going to be proposed in order to expose the readings that were done of that in those days. Based on that, an interpretation are going to be realised about the manner as that same readings contribute to generate on individual minds the idea of a near and inevitable ending. At last, the text are going to be concluded with an enquiry, based on the same biblical text, about the origin of the fear of the death that used to permeate the medieval imaginary. It’s believed that this fear were explained above all by the imaginary conception of a God the Father, severe and domineering, whose representation was intimately associated to the concepts of sanction and imprevisibility. Keywords: The Seventh Seal, Late Middle Ages, The Book of Apocalypse

Densidade e tamanho populacional de aves endêmicas e ameaçadas dentro da IBA (Important Bird Area) MG06

Desenvolveu-se um programa computacional, denominado HidroBacia, que permite a aplicacao do modelo para estimativa do hidrograma superficial em bacias hidrograficas, desenvolvido por Silva (2002), em conjunto com Sistemas de Informacoes Geograficas. O programa estima o escoamento superficial por intermedio do balanco hidrico da bacia hidrografica, utilizando, alem de imagens relativas ao modelo digital de elevacao da bacia e suas direcoes de escoamento, imagens contendo a variacao espacial de caracteristicas da bacia hidrografica, tais como interceptacao pela cobertura vegetal, armazenamento superficial, coeficiente de rugosidade de Manning e parâmetros relativos a infiltracao de agua no solo.

Programa Computacional para Estimativa do Hidrograma de Escoamento Superficial em Bacias Hidrográficas

2 - Recursos hídricos: água no mundo, no Brasil e no Estado do Rio de Janeiro

In the latest years, it has increased the discussions on the emerging alternatives to the traditional model of career as a formal fulltime employee in organizations. In such context, the self-employment, or the condition of being a freelancer, has been a focus of special interest of research, considering the increasing number of individuals that voluntarily adhere to this kind of work relation, or are taken to migrate to it, in face of the organizations’ increasing policies of outsourcing and partnership, among other reasons.  However, the literature on such subject remains mainly focused on describing the characteristics of the self-employment condition, not dedicating the same attention to its implications for the individuals, in terms of how they cope with the new context of their professional lives. This paper aims to contribute to fulfill such gap, by analyzing how people which have a higher level of qualification and have turned to the self-employment cope with the dimensions of time and space.  The analysis about these two dimensions are based, respectively, on the conceptual frames proposed by Lewis e Weigert (1981) and Lefebvre (1991), as well as on other authors who have been also inspired by these same references. The study is based on interviews with individuals in different ages that have changed from being formal employees in organizations to the self-employment, and that have remained in such condition for distinct periods. The results suggest that the self-employment experience leads individuals to review the concepts and values that define their notion of temporality and their representations of space, as well as the way they perceive their embodied space and understand the dynamics of the family, the organization, and the life in society spaces.

PROFISSIONAIS QUALIFICADOS E EXPERIÊNCIA DE AUTO-EMPREGO: QUESTÕES DE TEMPO E ESPAÇO

O crescimento da terceirizacao tornou-se uma das caracteristicas mais marcantes das relacoes de  trabalho  nas  ultimas  decadas.  Entre  os  trabalhadores  mais  qualificados,  a  categoria  dos  profissionais  de  Tecnologia  da  Informacao  –  TI  –  foi,  talvez,  uma  das mais  afetadas  por  esta  pratica, uma vez que muitas organizacoes passaram a considerar as atividades destes profissionais  como  nao  pertencentes  ao  seu  core  business.  Uma  das  modalidades  de  terceirizacao  mais  popularizadas em TI e aquela em que os trabalhadores sao contratados por meio de uma empresa  prestadora  de  servicos,  mas  atuam  fisicamente  localizados  nas  instalacoes  da  empresa  contratante.  Sob  a  otica  dos  individuos,  torna-se  relevante  entender,  entao,  como  eles  compreendem  a  relacao  dupla  de  trabalho  que  se  constitui  em  tais  situacoes. O presente artigo  aborda esta questao, investigando como essa dupla relacao influencia o contrato psicologico desses  profissionais.  O  artigo  focaliza  tres  casos  de  terceirizacao,  utilizando-se  de  entrevistas  com  profissionais  subcontratados  e  gestores  de  seus  contratos.  As  conclusoes  obtidas  por  meio  da  analise dos casos possibilitaram a proposicao de um quadro conceitual representativo da dinâmica  de  formacao  e manutencao  dos  contratos  psicologicos  dos  individuos  que  atuam  neste  tipo  de  modalidade.

Casos de terceirização e a influência sobre o contrato psicológico de profissionais de TI

Por que as tarifas foram para os céus? : propostas para o setor elétrico brasileiro

SILVA, Jose Junior Alves da. Adsorcao de atomos alcalinos e halogenios em uma superficie de Grafeno: um estudo de primeiros principios. 2008. 85 f. Dissertacao (mestrado) - Programa de Pos-Graduacao em Fisica, Departamento de Fisica, Centro de Ciencias, Universidade Federal do Ceara, Fortaleza, 2008.

Adsorção de átomos alcalinos e halogênios em uma superfície de Grafeno: um estudo de primeiros princípios

Introducao: As principais operacoes para correcao da anomalia de Ebstein baseiam-se na reconstrucao da valva atrioventricular direita (AVD) em formato monovalvular, tendo resultados comprometidos pela necessidade de substituicao ou alta reincidencia de insuficiencia valvar. Uma nova tecnica foi desenvolvida, diferenciado-se das anteriores, pela correcao anatomica da valva AVD, resultando na coaptacao plena das valvulas no fechamento valvar. O objetivo deste estudo e avaliar a aplicabilidade dessa tecnica, estudando os seus efeitos na evolucao clinica, funcao da valva, restauracao do ventriculo direito funcional e remodelamento reverso do coracao no pos-operatorio imediato (POI) e no pos-operatorio em longo prazo (POL). Metodos: Estudo retrospectivo de 52 pacientes consecutivos, com idade media de 18,5±13,8anos, submetidos tecnica do cone para correcao da anomalia de Ebstein, entre novembro 1993 e dezembro de 2006, cujos principais detalhes cirurgicos sao: as valvulas anterior e posterior da valva AV direita sao mobilizadas das suas implantacoes anomalas no ventriculo direito (VD), a borda livre desse conjunto e rodada no sentido horario para ser suturada a, previamente mobilizada, borda septal da valvula anterior, formando um cone cujo vertice permanece fixo ao apice do VD e a base e suturada no nivel do anel atrioventricular verdadeiro, reduzido ao mesmo tamanho da base do cone. A valvula septal, sempre que possivel, e incorporada a parede do cone. A porcao atrializada do VD e reduzida por plicatura longitudinal. Os dados clinicos, ecocardiograficos e os indices cardiotoracicos, obtidos nos periodos pre-operatorio (PREOP) e pos-operatorio, foram analisados. Resultados: Houve dois obitos...(AU) Background: The main operations for Ebsteins anomaly repair are conceived to reconstruct the tricuspid valve (TV) in a monocusp format, but their results are restricted either by the need for valve replacement or by high incidence of postoperative valve regurgitation. A new surgical technique was developed, that performs an anatomical reconstruction of the tricuspid valve, realizing a leaflet-to-leaflet coaptation at the TV closure. The objective of this study is to access the feasibility of this technique, evaluating its effects in clinical outcome, tricuspid valve function, right ventricle (RV) morphology and reverse remodeling of the heart.Methods: Retrospective study on 52 consecutive patients, mean age of 18,5+- 13,8 years, treated with a new surgical technique for Ebsteins anomaly repair (the cone technique), between November 1993 and December 2006, which principal details are: a) the anterior and posterior tricuspid valve leaflets re mobilizedfrom their anomalous attachments in the RV, the free edge of this complex is rotated clockwise to be sutured to the septal border of anterior leaflet, creatind a cone which vertex remains fixed at RV apex and whose base is the sutured to a true tricuspid annulus, plicated to match it to base of said cone. The septal leaflet is incorporated into the cone wall ewhenever possible. The atrialized chamber is reduced by longitudinal placation. The clinical and echocardiographic data and the patients cardiothoracic ratios, collected at the preoperative, early and late postoperative periods, were analyzed. Results: There were two hospital deaths (3.8 %) and two more deaths in the long term followup.(AU)

Nova técnica cirúrgica para a correção da anomalia de Ebstein: resultados imediatos e em longo prazo

The effects of bean plant chemical desiccation on seed storage quality were evaluated in this research. Paraquat (400g a.i/ha) and paraquat + diquat (250g a.i/ha + 150g a.i/ha) were applied, at the dose of 2L/ha of c.p. at 26, 29, 33 and 36 days after flowering (DAF). During storage (70% and 10±1oC), germination (standard test), vigor (germination speed) and fungi occurrence were evaluated at zero, 60 and 120 days. No evidence of loss in the seed quality was found after the desiccation with paraquat and paraquat + diquat. In desiccation with seed moisture content of 37-26% (29-33 DAF) the stored seed high quality was maintained

Qualidade da semente de feijão armazenada após dessecação química das plantas, em quatro estádios de aplicação

The interpretant concept refers to the third element of the peircean triad of the sign concept. The other two elements are the representamem and the object . A sign is, according to Peirce, any thing that represents some other thing for anyone. But a thing only is capable to represent some other thing for anyone if, when it is perceived by this anyone, a third thing appears in his mind, as an effect produced by it. It is of this third thing that will be spoken in this work, without ignoring the other ones two. 
 
 Keywords: Sign. Interpretant. Representamem. Object. Interpretation.

O interpretante como aquilo que possibilita e, ao mesmo tempo, condiciona o processo interpretativo

Neste trabalho sao discutidos sete diferentes modelos de equacoes para o calculo das regressoes entre os diâmetros e as alturas das arvores. Foram medidas 64 arvores de pinheiro brasileiro ( Araucaria angustifolia (Bert.) ). Ktze.) de um povoamento de 17 anos de idade. A equacao calculada em funcao do logaritimo dos diâmetros e alturas apresentou o melhor ajustamento e o menor erro sistematico. Os modelos discutidos sao apresentados na Tabela 2 e os resultados na Tabela 3. E apresentada, tambem. uma analise sobre os erros casuais cometidos nas estinativas volumetricas de diferentes numeros de arvores, baseada na lei da propagacao dos erros. Para a estimativa dos volumes individuais foram estabelecidas relacoes entre o fator forma artificial, o verdadeiro fator forma e o quociente forma segundo o procedimento de Hohenadl. Abstract In this work are discussed differents models of equations to calculate the regressions between the diameters and heights of trees. Sixty-four trees of Parana Pine ( Araucaria angustifolia (Bert.) O. Ktze.) from a 17-year old stand were measured. A double logarithmic equation of diameters and heights showed the best results and the minimum systematic error. All discussed models are showed in Table 2 and the results in Table 3. Following and analysis is made, according to the law of error propagation, to investigate the random errors in volume, resulting from the estimations of differents numbers of trees. The interrelationships between the form factors and the form ratio according to Hohendl's'method were stablished for determination of individual volumes.

Relação entre diâmetro e altura e estimativa dos erros casuais em volume para um povoamento de Araucaria angustifólia (Bert.) O. Ktze

No presente trabalho procurou-se mostrar que para o planejamento de inventario e pesquisas biometricas deve-se estudar a forma e dimensao da parcela amostral mais coerentes com as caracteristicas do povoamento florestal. Para facilitar a selecao da melhor forma de parcela amostral, agruparam-se as amostras retangulares adjacentes em grupos distintos simulando-se novas amostras. O mesmo criterio nao pode ser aplicado as formas circulares. Como criterio de selecao, adotou-se o tempo dispendido na medicao de todas as parcelas e o coeficiente de variacao. Determinou-se que a parcela retangular de 0,04 ha (400 m 2 ) representa a melhor dimensao para as condicoes do povoamento de Pinus talda L. 
 
 Abstract 
 
In this study an attempt was made to demonstrate that for forestry inventory planning biometric work the shape and dimension of sample plots should be studied with general forest characteristis. In order to facilitate the selection of the best sample plot, the adjacent rectangular plots were grouped into different groups thus simulating new populations. The same criterion could not be applied to the circular shapes, however. The time spent in the measurement of the sample plots and the coefficient of variation were used as a criterion for plot selection. In this case, the best sample plot dimension was the rectangular plot of 0,04 ha (400 m 2 ) applied to Pinus talda L. stand.

Simulação para a escolha do tamanho das parcelas permanentes em experimentação florestal

UNIVERSIDADE FEDERAL DE PERNAMBUCO CENTRO DE FILOSOFIA E CIÊNCIAS HUMANAS PROGRAMA DE PÓS-GRADUAÇÃO EM CIÊNCIA POLÍTICA AS SEMENTES DA DISCÓRDIA: REGRAS E EXCEÇÕES DA INDISCIPLINA PARTIDÁRIA

O concreto betuminoso usinado a quente e uma mistura constituida de agregado graudo, agregado miudo, material de enchimento (filer) e ligante betuminoso, misturados a quente em usina apropriada, devendo ser espalhados e comprimidos a quente. O revestimento de concreto betuminoso consiste de uma ou mais camadas, construidas sobre uma base devidamente preparada para o seu recebimento. Este trabalho tem por objetivo gerar alternativas para a pavimentacao local, com a utilizacao de materiais regionais e nao convencionais na mistura asfaltica, em substituicao aos elementos tradicionais. Para tanto, utilizou-se o lodo, residuo gerado na Estacao de Tratamento de Agua ETA, da Ponta do Ismael, na cidade de Manaus/AM, responsavel pelo tratamento da agua do rio Negro, que abastece a cidade de Manaus. Atualmente, 
estes residuos sao lancados no igarape do Franco,ocasionando prejuizos ao meio ambiente. O residuo da ETA foi utilizado como filer no concreto asfaltico usinado a quente CBUQ, em substituicao ao material tradicionalmente usado nesta regiao, ou seja, o cimento Portland. Foi feita uma analise comparativa entre as misturas betuminosas, convencional e alternativa, com os dois tipos de fileres, utilizando o mesmo teor otimo da mistura com o CAP-50/70. Foram moldados corpos de prova de CBUQ e analisados os resultados concernentes a estabilidade Marshall, fluencia a 60 0C e compressao diametral uniaxial estatica, modulo de resiliencia e vida de fadiga, todos a 25 0C. Os resultados dos ensaios mostram desempenho adequado da mistura confeccionada com o lodo como filer, comparado a mistura convencional, confeccionada com cimento Portland.

Comportamento de misturas em concreto asfáltico tendo lodo da eta da Cidade de Manaus como Fíller.

Determinantes da anorexia nervosa em adolescentes: o caso do ambulatório de transtornos alimentares do núcleo de estudo da saúde do adolescente - NESA/HUPE/UERJ

O conhecimento de um fator capaz de converter o volume sobre casca em volume sem casca constitui uma importante pratica florestal, principalmente, quando se trata de estudos relativos a acacia negra ( Acacia spp.). Neste sentido, o fator de casca de MEYER, expresso por uma constante ao quadrado, tornou-se o meio ideal para avaliar o volume solido sem casca atraves de uma simples operacao de multiplicacao. A presente pesquisa procurou mostrar a relacao entre a dupla espessura de casca em arvores individuais de pinheiro brasileiro ( Araucaria angustifolia ) ao nivel do peito pela computacao do fator de casca, atraves de comparacoes entre algumas equacoes como a de KORSUN, LAAR, OSTLIN e outros, em IBM-1130. A equacao de KORSUN apresentou melhores resultados que as demais funcoes, obtendo uma correlacao de 0,5726 entre as variaveis (d) e (E). A introducao da idade (I) e da altura (H) para estimar a espessura de casca resultou em decrescimo de correlacao. Nessas condicoes, determinou-se um fator de casca para diâmetro igual a k = 0,8209 e para volumes igual k 2 = 0,6739 com um erro de aproximadamente igual a. 1,0%. A porcentagem de casca estimada por individuo foi de 32,60% e o rendimento 18,290 m 3 /ha/ano e 12,332 m 3 /ha/ano respectivamente, com casca e sob casca. 
 
 Abstract 
 
The knowledge about a tariff used for converting a volume over bark in volume under bark can be a very important practice, mainly if we deal with about some forest works aplied to comercial kinds like the Acacia spp. In this sense the MEYER bark factor, which is traduced by a square tariff, was used to avaluate the volume without bark on the field, only by a very simple operation, for exemple, a multiplication. The present research tried to show the relationship between the double thickness of bark in singular trees of Parana pine ( Araucaria angustifolia ) at breast height level by the comparison of some equations like .those presented by KORSON, LAAR, OSTLIN and others which were adjusted by computation in IBM - 1130 to field datas of this native specie. The KORSUN's equation demonstrated better results than the others equations, obtaining a correlation of 0,5726 between the variables (d) and (E). The introduction of age (I) and height (H) to estimate the thickness of bark did not show great results. In this work conditions, were determined a diameter bark factor of k = 0,8209 and a volume bark factor of k 2 - 0,6739 with a error closely equal to 1,0%. The individual bark percentage estimated was about 32,60% and the yield volume 18,290 m 3 /ha/ano and 12,322 m 3 /ha/ano respectively over and under bark.

Avaliação da dupla espessura de casca em árvores individuais de pinheiro brasileiro (Araucaria angustifolia (Bert.) O. Ktze.) Referente ao nível do DAP

The Township of Presidente Figueiredo, in the State of Amazonas, Brazil, was visited for three consecutive years, from 1996 to 1999, with the aim of acquiring botanical samples from the area, in order to carry out studies on the "Taxonomic Monographies and Revisions Preparation" Subproject for the purpose of preparing a survey of the flora. Collections pertaining to the present work are deposited at INPA's herbarium and, general information on the taxa studied here were complemented with those obtained from earlier collections conducted by other researchers. Twenty three (23) species and two varieties, distributed in four genera were identified for family Myristicaceae Br. R. Of these Iryanthera Warb. and Virola Aubl. stood out on account of their species diversity, being Iryanthera ulei Warb. and Virola calophylla (Spruce) Warb. var. calophylla the most collected ones. Family Monimiaceae Juss. is only represented by genus Mollinedia Ruiz & Pavon through species M. ovata Ruiz & Pavon, yet family Siparunaceae (A. DC.) Schodde is represented by genus Siparuna Aubl. with eight species, being S. cristata (Poepp. & Endl.) A. DC. the most collected one.

Estudos florísticos no município de Presidente Figueiredo, Amazonas, Brasil - II: famílias Myristicaceae, Siparunaceae e Monimiaceae

Para aplicar elevada quantidade de K no solo, e necessario que exista Mg em quantidade adequada, para evitar o aparecimento de disturbios fisiologicos na bananeira. O objetivo deste trabalho foi avaliar os efeitos da aplicacao de potassio (K), magnesio (Mg) e calcario sobre o desenvolvimento de mudas de bananeira 'Prata-ana' (AAB) cultivadas em casa de vegetacao. Os tratamentos foram distribuidos no delineamento de blocos casualizados, com quatro repeticoes em esquema fatorial (5x5x2), correspondentes a cinco doses de K (0; 200; 400; 800 e 1.600 mg dm-3), cinco doses de Mg (0; 30; 60; 90 e 180 mg dm-3) e duas doses de calcario dolomitico (0 e 2 t ha-1). A producao da massa da materia seca das mudas de bananeira aumentou com as aplicacoes de K e calcario no solo e reduziu com as doses de Mg. Para a producao maxima da massa da materia seca da parte aerea das mudas de bananeira, a relacao Ca: K: Mg no solo apresentou valores de 2,0: 0,3: 0,9, que correspondem a 62%, 9% e 28% da saturacao por base, respectivamente.

Aplicação de potássio, magnésio e calcário em mudas de bananeira 'Prata-anã' (AAB)

This article analyses the space (re) organization in the municipality of Guaira – PR after the formation of Itaipu Lake with consequent immersions of the “Sete Quedas”. Due to the socio-environmental impact caused by the flood, a new phase of development is going to be implemented in Guaira based on the Directory Plans of 1980 and 1992, reorganizing the geographic area of Guaira in a corollary way.

A (RE)ORGANIZAÇÃO DO ESPAÇO EM GUAÍRA APÓS O FIM DAS SETE QUEDAS

In order to reach high productivity, banana crops must be cultivated in places with favorable climatic factors that present soil with good chemical and physical properties. The present work has the objective to evaluate the chemical and physical properties of soil cultivated with Prata dwarf banana crops (AAB) in three levels of productivity. A total of 96 commercial banana crops were selected in the North of Minas Gerais. The banana crops were divided in three levels of productivity: low productivity ( 32 t ha-1 year-1). In each selected banana crop, soil samples were collected for chemical and physical analyses. Leaf samples of each banana crop were collected in 20 plants. In the foliares samples were determined the N, P, K, Ca, Mg, S, B, Cu, Fe, Mn and Zn proportions. It was verified that the content of Ca, K, P, organic matter, the values of electric conductivity, CTC, the percentage of saturation per bases (V%), and the amount of clay and silte present were significantly greater in the banana crops of high productivity soil. It was verified that in the banana crops of high productivity soil the amounts of Ca, K and Mg corresponded to 82%, 5% and 13% of the base saturation, respectively. There was no difference among the foliar contents of nutrients in the three banana crops levels of productivity.

Atributos químicos e físicos de solos cultivados com bananeiras 'Prata-Anã' (AAB), em três níveis de produtividade, no norte de Minas Gerais

O Estado brasileiro mudou substancialmente sua politica em relacao as fronteiras do pais – as amazonicas, em particular, deixando de encara-las tao somente como um problema de seguranca nacional. O que significou uma atualizacao, em face das novas configuracoes das instituicoes economicas que tem levado o Estado, nas duas ultimas decadas, a reelaborar que tem sido chave na sua atuacao como corpo politico. As fronteiras passaram a ser consideradas lugares que oportunizam a realizacao de negocios. No Amapa, o asfaltamento da BR-156, que atravessa o estado de norte a sul, e a construcao da ponte sobre o rio Oiapoque estao perfeitamente sintonizadas com o projeto da Iniciativa de Integracao de Infra-estrutura Regional Sul-Americana – IIRSA. Este trabalho procura evidenciar que tais empreendimentos favorecem fundamentalmente o alargamento do mundo do capital e das coisas, e que buscam garantir o acesso e o controle de territorios e dos recursos naturais da regiao ao grande capital. E o Oiapoque, na fronteira do Brasil com a Guiana Francesa, esta no meio desse turbilhao vivenciando o processo de integracao sul-americana, ainda que de forma marginalizada.

Globalização e Conflito nos processos de Integração na Fronteira Brasil x Guiana Francesa

Este articulo analiza la poblacion urbana y la poblacion ocupada de Guaira en el periodo de 1970 a 2000. Se considera que la poblacion economicamente activa desprovida de una vacancia en el mercado de trabajo, que es del orden de 23,56%, es muy elevada. Para colaborar con posibles acciones en el sentido de minorar el problema, el articulo presenta estrategias para promover el desarrollo y generacion de renta para tal poblacion. Las sugestiones presentadas encampan los sectores agricola y de turismo y/o actividades afines. Refuerza aun que Guaira, que ya habia sido pujante en el pasado, precisa recuperar el dinamismo de su economia para dar soporte a su poblacion que aun es muy proxima a la de 1970.

Time and space are concepts found in the essence of the constitution of society and of the being itself. For authors such as Giddens (1984) and Lefebvre (1991), sociological tradition has, however, dedicated greater attention to the time aspects of social reality, relegating space to a secondary role. This study aims to analyze how the notion of space and the dynamics of its production influence the manner in which individuals perceive organizational changes, assuming that the meaning of space affects their identities and subjectivities. The study is part of a research agenda which aims to understand the influence of time and space upon the production of organizational reality and on the meanings of work. The results, based on the experiences of 133 people in eight different organizations, reveal that changes are interpreted on grounds of the perceptions of spatial practices, representations of space and representational spaces, categories pointed out by Lefebvre (1991) as basic for the understanding of the production of social space. A reference framework for analyzing the influence of space in individuals' interpretations about organizational change is proposed.

A construção de um quadro analítico sobre as significações de espaço no contexto das mudanças organizacionais

The article has the purpose of analyzing as Alexis Tocqueville bases the political power and like him it explains the citizens’ participation in the political decisions. Along the discussions, the text tries to demonstrate that the political thought of Tocqueville – so much in theoretical-methodological terms, as in conclusive terms – it turns a differential one in relation to the political thought not only of the Old ones - Plato and Aristotle - but also of the Modern ones - Hobbes and Rousseau. With effect, the study reveals that while Tocqueville, through the method “ideal type”, tries to demonstrate as and because the American State appeared and which factors and processes condition the American citizens’ political participation, the other authors leave of beginnings general built in abstract to demonstrate as the State and the political participation should be.

O PODER POLÍTICO NA VISÃO DE TOCQUEVILLE: UM DIFERENCIAL ENTRE ANTIGOS E MODERNOS

Microssistemas analíticos com detecção condutométrica sem contato para monitorar interações em sistemas biomoleculares

Segismundo Spina lembra que o Pe. Antonio ";Vieira certa vez se queixou de que maior fruto produziam as satiras de Gregorio que os seus sermoes";. Por isto, acreditamos que o ";Boca do Inferno"; precisa ser conhecido tambem por esta faceta mistica e sacra, pela qual nao tem recebido a devida atencao. Nossa proposta e mostrar aos estudantes de Letras um outro poeta, pouco conhecido, mas extremamente rico em sua lirica sacra, impregnada de belas reflexoes cristas, segundo sua fe catolica. Palavras-chave: Gregorio de Matos; Sagrado; Barroco; Literatura

Fonte: Times New Roman - Tamanho 60 - Centralizado Negrito e espaçamento 1,5 entre linhas

Mesmo nao prevista expressamente no art. 5o(direitos e garantias fundamentais) da Constituicao Federal, a Revisao Criminal, esta embutida no § 2o do referido dispositivo, porque decorrente do regime e dos principios por ela adotados, como tambem daqueles oriundos da Convencao Americana de
Direitos Humanos de 1969 Pacto de San Jose da Costa Rica - da qual o Brasil e signatario, assim a revisao possui natureza de acao constitucional ,e, e apenas direito subjetivo individual do condenado, destinado a rescindir sentenca condenatoria definitiva, sempre em beneficio do reu. A Lei nao estabeleceu a hipotese da revisao criminal pro societate. Assim, considerando o principio da relatividade e historicidade dos direitos fundamentais, a luz da proporcionalidade materializada na tecnica da ponderacao de valores ou enunciados normativos validos quando em colidencia, propoe-se a alteracao da legislacao processual penal, para possibilitar o manejo da acao de revisao criminal pro societate, quando a absolvicao fundarse em documentacao comprovada falsa, a exemplo do caso de homicidio com a certidao de obito falsa; e quando apos a sentenca, se descobrirem provas de que foi prolatada por prevaricacao, concussao ou corrupcao do Juiz, desde que os tipos penais nao estejam fulminados pela prescricao. Ainda propoe-se seja outorgada legitimidade ao Ministerio Publico para ajuizar pedido revisional contra sentenca absolutoria, nas hipoteses aludidas e contra sentenca condenatoria nas hipoteses ja previstas ha legislacao. O metodo e dogmaticoanalitico da doutrina e legislacao nacionais e legislacao estrangeira bem como de dois julgados do STF. A dissertacao propoe, de lege ferenda, a adocao da revisao criminal pro societate, adotando como referencia o PL no 4.506/2001.

The application of vegetal wastes to soil have a beneficial effects on soil nutrient, physical conditions, biological activities and on the culture performance, the main objective of this study was to evaluate three kinds of vegetable byproducts: sugar cane bagasse, coffee chaff, and Buffel straw, regarding to the effect on the physical and chemical characteristics of custard apple (Annona squamosa L.).The experimental design used completely randomid plots with five repplications, and two plants per plot. The total fruit mass, the peel mass, the seed mass per fruit were evaluated. The pulp level of soluble solids was measured, as well as its pH. The presence of this mulching provided an increase in the fruit mass, thereby, increasing the commercial profit, as larger the fruit is, the greater the value per weight is. There was not a pH increase in the pulp, on the other hand the treatment using coffee chaff provided a greater level of soluble solids. Regarding to the other measured characteristics, no differences were found.

A influência da cobertura morta sobre características físicas e químicas de frutos da pinha (Annona squamosa L.)

Estagio realizado na BBT Termotecnologia Portugal, S. A. e orientado pela Eng.a Isabel Soares

Apoio à área de gestão de investimentos e recursos na BBT Termotecnologia Portugal S.A.

This is a contribution that presents a translation of the work "Terminology for Analytical Capillary Electromigration Techniques" by Riekkola and collaborators (Pure Appl. Chem., Vol. 76, No. 2, 443-451, 2004) from IUPAC© for the Portuguese Language. Additional terms that had not been defined in native Portuguese were included for the benefit of the local community. Additional notes were also included to clarify some important concepts and to highlight the differences between techniques.

Terminologia para as técnicas analíticas de eletromigração em capilares

O objetivo deste artigo e analisar a producao de acucar orgânico por intermedio de um estudo de caso no Estado do Parana no ano de 2006. A cana-de-acucar cultivada no sistema orgânico tem contribuido para a melhoria da renda do pequeno produtor, proporcionando beneficios sociais, economicos e ambientais, viabilizando a sua permanencia na propriedade rural, com melhor qualidade de vida para si e sua familia e para os consumidores. A analise economica da producao de acucar orgânico mostrou que, apesar das dificuldades de penetracao no mercado nacional e internacional pelas pequenas empresas, dos altos custos para certificacao e dos entraves burocraticos oriundos da propria certificadora, os resultados sao positivos e suficientes para a manutencao da atividade.

Este trabalho apresenta JFloat, uma implementacao de software do padrao IEEE-754 de aritmetica de ponto flutuante binaria. JFloat foi construida para prover algumas caracteristicas nao implementadas em Java, especificamente o suporte ao arredondamento direcionado. Esta caracteristica e de grande importância para o prosseguimento do projeto Java-XSC, em
desenvolvimento por esta linha de pesquisa. Apesar de programas escritos em Java, a principio, serem portaveis para qualquer arquitetura ao usar operacoes de ponto flutuante, principalmente porque IEEE-754 especifica que programas deveriam ter precisamente o mesmo comportamento em toda configuracao, observou-se que programas que usam tipos de ponto flutuantes nativos de Java podem ser dependentes da maquina e do sistema operacional. JFloat tambem se apresenta como uma possivel solucao para este problema

JFloat: uma biblioteca de ponto flutuante para a linguagem Java com suporte a arredondamento direcionado

In the same line of reflection, driven by the innovative expositions within the International Forum “Science, Religion and Consciousness”, here is also condensed the perspective of Science within the framework of a dialogue with Religion and, in a concrete manner, with Theology. The present text presents some of the seminal dogmas of the biblical Genesis tradition and confronts them with the most recent scientific acquisitions, keeping in mind the essential differences between these two ways of perceiving reality and the world. At the * Professor Catedrático Jubilado da Faculdade de Ciências da Universidade do Porto. Email: jfsilva@fc.up.pt

The recent changing scenario in public organizations tends to influence their employees' identification process. This is also the case of some science and technology institutions. This article identifies which aspects influence the identification of individuals with an S&T public organization, considering its frequent changes of direction and structure. The object of analysis is the case of Finep, a public agency which finances economic, social, scientific, and technological studies, researches, projects, and programs in Brazil. Based on documental data collection and interviews with 24 employees, the study has permitted the composition of two conceptual frameworks corresponding, respectively, to the aspects contributing positively (identification map) as well as negatively (frustration map) to the relation between individuals and the organization.

Identificação de funcionários com empresa pública no contexto de mudanças: o caso Finep

This article presents a conceptual framework which was developed as part of a research aimed at investigating management models adopted by firms in Brazil to conduct their social projects, how they fit project characteristics, and the implications for their effectiveness and sustainability. Firstly, the article shares the results of a wide-range review of the literature, undertaken to identify concepts and constructs which could support the building of the framework. The research also identifies the interaction of various factors that may have implications for project effectiveness and sustainability. Based on Kerlinger's (1973) recommendations regarding concept operationalization, a description is made of how the main constructs adopted in the research were defined. These were then broken down into dimensions, to which indicators were attributed. An explanation is given of how the resulting framework can be used to guide empirical research into social projects developed by firms in Brazil, and also its importance for project managers in their analyses of the fit between various intervening factors, in order to ensure the greater effectiveness and sustainability of results.

Projetos sociais de empresas no Brasil: arcabouço conceitual para pesquisas empíricas e análises gerenciais

Gestão de recursos hídricos e sistemas de informações geográficas: contribuições para a organização sócio-espacial do Pontal do Paranapanema-SP

Tese de mestrado. Redes e Servicos de Comunicacao. Faculdade de Engenharia. Universidade do Porto. 2006

A Unidade das Virtudes nos Diálogos Socráticos: uma questão de método

Resumen pt: Neste artigo, trata-se da formacao da Comunida- de Andina (CAN) e de sua importância no proces- so de integracao da America Latina. Nesse con- texto, enf...

A importância da Comunidade Andina para a economia da América Latina

TESTES DE EQUAÇÕES PARA PREDIZER A ESPESSURA DE CASCA E FATOR K PARA ACÁCIA NEGRA (Acacia mearnsii de Wild)

Diante dos perigos que as ideologias - enquanto sistemas de ideias que visam explicar o mundo social - particularmente, diante dos perigos que as ideologias politicas podem oferecer para a vida social - servir de justificativas para atrocidades cometidas por politicos “irresponsaveis”, no sentido weberiano do termo – o presente estudo teve o objetivo de analisar como Max Weber concebe o processo de producao de ideologias. Nas analises, pode-se observar certas ambiguidades no pensamento do autor: as vezes, ele tem o “carisma” de determinadas pessoas como condicao necessaria e suficiente para a producao de ideologias; as vezes ele considera que certos condicionamentos sociais interferem nao so na capacidade criadora das pessoas carismaticas, mas tambem no processo de difusao das visoes de mundo. O artigo pode demonstrar que, no pensamento de Weber, uma ideologia - produzida sob a inspiracao de “dons sobrenatural” ou por condicionamentos sociais - jamais poderia assumir o carater de uma verdade absoluta.

Este trabalho apresenta as informacoes mais recentes sobre as pessoas ocupadas em atividades agricolas, e principalmente das pessoas ocupadas em atividades nao-agricolas e residentes no meio rural. Os ocupados nao-agricolas mantem a tendencia observada nos anos 90, enquanto que os ocupados agricolas experimentam uma recuperacao em numero de pessoas ocupadas neste inicio de decada.

Nas ultimas duas decadas, especialmente apos a drastica reducao do credito rural subsidiado dos anos 70, observa-se um ciclo decenal de grandes reivindicacoes por parte dos produtores agricolas para equacionamento de suas dividas com o sistema financeiro. Em geral, esse movimento tem sido seguido pela adocao de amplas medidas por parte do governo federal, com a repactuacao destas dividas em melhores condicoes, alem de alongar seus prazos. Somente nos anos 90, entre outras medidas, ocorreram dois grandes programas de renegociacao (Securitizacao e PESA), com a transferencia do risco para a Uniao. Via de regra, o gasto para a rolagem dessas dividas tem sido maior que os gastos, por exemplo, com Pesquisa Agropecuaria ou Reforma Agraria. A despeito das condicoes vantajosas das renegociacoes mencionadas, os indicadores de gestao desses programas indicam um elevado indice de inadimplencia, mesmo nos anos de crescimento da renda agricola, o que implica em uma serie de consequencias negativas para o sistema nacional de credito rural. A partir de 2005, a questao voltou a cena politica e merece maior atencao por parte dos estudiosos da area.

A difícil institucionalização da política de extensão na universidade : um estudo de caso

ESTIMATIVA DOS ERROS SISTEMÁTICOS NA CUBAGEM DOS TRONCOS PELOS MÉTODOS DE HOHENALD E PRESSLER

Partindo de lineamentos filosoficos da concepcao do justo, o qual persegue a Justica, o presente trabalho procurou tracar o perfil do principio dispositivo puro, desde o seu nascedouro ate o estagio atual, unido, com grande esforco pelo legislador, ao principio inquisitivo. Com essa nova roupagem, os poderes do juiz fortalecem-se, notadamente os instrutorios, comprometidos com o signo publicistico do processo e a socializacao do direito, de modo a implicar, cada vez mais, na busca da verdade real dos fatos relevantes postos sob analise judicial, com a consequente realizacao pratica da chamada justica do caso concreto, visando a pacificacao social. De fato, com a ideia de que a administracao da justica e uma funcao integrante da soberania estatal, formou-se a conviccao de que o juiz, como orgao do Estado, nao deve mais assistir passivamente a disputa judicial entre as partes, como outrora ocorria, mas ha de participar da causa como forca viva e ativa. Sob essa otica, intensifica-se nas legislacoes processuais modernas, a participacao do juiz na etapa da atividade instrutoria. Embora subsistam as regras sobre o onus da prova, nao sao elas afetadas pelo poder do juiz de determinar ex officio a realizacao de quaisquer provas, por constituirem a ultima solucao para formacao de uma conviccao segura. Age com enorme equivoco quem ainda defende a tese de que se deve deixar as partes trazer ou nao as provas que quiserem e se nao as trazem e porque estao dispondo de um direito que lhes assiste. Ainda que elas possam dispor de seus direitos, nenhum poder de disposicao tem sobre o poder do juiz de averiguar os fatos relevantes da causa, eis que e funcao de quem julga, julgar bem, com justica e, para tanto, imprescindivel conhecer bem esses fatos. Contraria o espirito do Codigo e do processo civil moderno, o juiz julgar, conscientemente, contra a verdade real, por alegada falta de prova, sabendo da existencia dela, e sabendo, tambem, que so por ignorância ou desconhecimento, a parte nao a requereu em tempo habil

Princípio dispositivo e o papel do juiz: a procura de um equilíbrio

Measuring dendrometrias variables such as height (commercial and total), diameter and volume constitutes a basic and fundamental activity in forest inventory work. This work aims to obtain real measures of volumetric variables at a relatively low cost, reconciling them with the activities of collecting seeds, without the need to cut down the trees. 77 adult reproductive individuals, distributed in several decametric classes, belonging to seven native tree species occurring in the Atlantic Forest of eastern Minas Gerais state, Brazil were sampled. The hypsometric relation to all of the species showed a higher setting for individuals with small to medium diameters and showed a weak tendency to underestimate the heights of the trees in the class of 100 cm of CAP. Among the models tested to estimate the commercial height equations equation was selected No. 6 hc = (c / bo + b1 * c) 2, by presenting a higher coefficient of determination (R2 = 0.93), a lower standard error estimates (Syx = 3.35 m) and better graphical distribution of residuals. Also, if timed-time spent in measuring circumferences along the trunk, including the cleaning of the shaft, thus obtaining a relevant measure of the importance of forest inventory cost component.

CUBAGEM DE íRVORES EM PÉ E TEMPO DE MEDIÇÃO DE ESPÉCIES ARBÓREAS DA MATA ATLÂNTICA, USANDO-SE O ESCALADOR DE íRVORES1

Obtenção de mutantes no modelo Micro-Tom com o uso do agente químico EMS

Peco licenca para fazer neste artiguete um misto de biografiado naturalista baiano (de quem comemoramos os 250 anos no dia 27de abril) e de resenha da serie que a Kapa Editorial esta publicandodesde 2002 e que ja esta no decimo primeiro volume, cujo titulo e omesmo deste artigo, apresentando-lhes ainda uma amostra bibliograficados principais trabalhos surgidos a partir da decada de noventasobre esse ilustre desconhecido.

AVALIAÇÃO DA FUNÇÃO PULMONAR, MUSCULATURA RESPIRATÓRIA E DISTÂNCIA CAMINHADA DE PORTADORES DE FIBROSE CÍSTICA

O Municipio de Presidente Figueiredo, no Estado do Amazonas, foi visitado durante tres anos consecutivos, de 1996 a 1999, com o objetivo de se obter amostras botânicas da area, para estudos no Subprojeto "Elaboracao de Revisoes e Monografias Taxonomicas" com a finalidade de se elaborar uma Florula para o Municipio. As colecoes feitas neste periodo encontram-se depositadas no acervo do Herbario do INPA e as informacoes gerais sobre os taxa aqui estudados foram complementadas com as obtidas das colecoes feitas anteriormente por outros pesquisadores. Para a familia Annonaceae Juss. (Magnoliopsida) foram identificadas 39 especies distribuidas em 15 generos. Destes, Duguetia A. St. Hill., Guatteria Ruiz & Pavon, Annona L., Unonopsis R.E.Fries e Xylopia L.destacaram-se pela diversidade em especies, sendo os dois primeiros representados por oito e seis especies, respectivamente, e os tres ultimos, com quatro especies. A familia Gnetaceae Lindl. (Gimnospermae) esta representada no Municipio apenas pelo genero Gnetum L., com a especie G. leyboldii Tul.

Estudos florísticos no município de Presidente Figueiredo, Amazonas. Brasil: I. famílias Annonaceae e Gnetaceae

It was developed a methodology that allows obtaining the hydrograph of superficial flow and maxim flow of any position along a hillside and transversal sections of canals. The area of the hillside is divided in a matrix system having 100 lines and 100 columns. It was considered that the flux occurs in the direction of the hillside's slope and the flow of each pixel is the addition between its own flow and the flows that come from the pixels that contribute to the superficial flow in the pixel under analysis. In the canal the flow is taken as the addition of the hydrographs that come from the columns in the reticular system. By the new methodology the comparison of the total volume and maximum surface runoff flow values, obtained in two experimental conditions (hillside and hydrographic basin), allowed to conclude that the new model provided good performance when compared to the Rational Method and the Curve Number Method.

Metodologia para obtenção do hidrograma de escoamento superficial em encostas e canais. Parte I: desenvolvimento e avaliação

We report a case of intramedullary spinal cord metastasis from thyroid cancer in a 70-year-old woman complaining for three months an intense cervical pain, without motor or sensitive deficits. Six months before the onset of symptoms, the patient underwent total thyroidectomy for a thyroid cancer. Magnetic resonance imaging with gadolinium enhancement showed an intramedullary spinal cord lesion. A partial resection of the medullar tumor was performed and the pathological findings showed an metastatic adenocarcinoma. Post operatively the patient develloped a left crural monoplegia.

The present study deals with the development of an economic optimisation method for water supply systems, formed by the water distribution network together with the pumping station. The method takes into account the varia- tion of project boundary conditions during the time in which it is used. Flow variations, roughness of pipe walls and energy unitary cost are considered during the period of project exploitation. The method is based on a non-linear mathematical pro- gramming model, in order to obtain the minimum total cost of the pipe network/pumping station, taking into account the operational parameters variation over time. The opti- mum design solution was obtained by the algorithm of the Generalized Reduced Gradients (GRG2). The method was applied to the optimum water supply sys- tem design of the city of Itororo in the state of Bahia, Bra- zil. The design solutions obtained show that all the hydrau- lic restrictions had been taken into account. Despite the robustness of the optimisation model, with the variation of flows, head loss and energy unitary cost over time, the method proved to be practicable

Dimensionamento Econômico de Sistemas de Distribuição de Água, Considerando Variáveis as Condições de Contorno do Projeto

Estimative of maximum runoff flow rates are essential for the projects of hydraulic urban and rural basins. The difficulty in applying the available procedures to estimate the temporary variation of the flow rate and its maximum value is due to the inaccuracy of some methods that are usually used and to the big variability of results that can be obtained by different professionals that use the same procedures. Therefore, research of a method that produces trustworthy assessment of peak-flow rates and hydrographs is of great interest. This paper describes the development and sensitivity analysis of a software (HIDROGRAMA 2.1) that allows obtaining surface runoff hydrograph, peak flow rate and its time of occurrence, runoff maximum height, runoff velocity and runoff volume. The model presented great sensibility to precipitation return period, infiltration rate after long time of wetting and hillside and channel length.

Metodologia para obtenção do hidrograma de escoamento superficial em encostas e canais. Parte II: modelo computacional e análise de sensibilidade

A proposta deste trabalho e modelar, simular a dinâmica e estimar os parâmetros de uma mesa XY
aplicada em maquinas-ferramenta convencionais para permitir o controle usando estrategias adaptativas. Para
isto, o modelo dinâmico sera simulado atraves do metodo de Newmark e a estimacao dos parâmetros, parâmetros
modais e sinal de excitacao sera desenvolvida por tres metodos: minimos quadrados classico (LS), minimos
quadrados recursivo (RLS) e minimos quadrados estendido (ELS), para efeito de analise e comparacao da performance
dos resultados de estimacao.

SIMULAÇÃO DA DINÂMICA E IDENTIFICAÇÃO DE PARÂMETROS EM UMA MESA XY DE MÁQUINA-FERRAMENTA

The objective of this work was to establish the DRIS (diagnosis and recommendations integrated system ) norms for the 'Prata Ana' banana (AAB) cultivated in the semi-arid of the North of Minas Gerais state under irrigation. A total of 58 areas commercially cultivated with 'Prata Ana' banana were selected. In each area, leaves samples were collected in three successive cycles of banana production in the initial phase of emission of the bunch, except for six areas, in which the collections were performed only in two successive cycles, totaling 168 leaves samples, which were analyzed for determination of the nutrients (N, P, K, Ca, Mg, S, B, Cu, Fe, Mn and Zn). Banana's bunches of the plants marked with paint were harvested and weighted. The areas were divided in high-yielding population (HYP) (>30 t ha-1 year-1) and in low-yielding population (LYP) (< 30 t ha-1year-1). The results of the leaves analyses and yield of each area formed a database. The average, the variance and the variation coefficient for the relationship two to two among nutrients tenors were calculated for HYP and LYP. The Norms DRIS were established using the results of the leaves analyses of coming samples of HYP. 55 relationship were selected among nutrients tenors that presented the largest reasons between the variances of LYP and HYP (s2l/s2h ).

Estabelecimento de normas dris para bananeira 'Prata Anã' (AAB) sob irrigação

Este trabalho apresenta as informacoes mais recentes sobre as familias ligadas a agricultura, especialmente sobre as familias ligadas a agricultura familiar. Observou-se um forte crescimento destas familias com residencia urbana. As rendas nao-agricolas continuam a ter um papel fundamental na composicao da renda das familias rurais, juntamente com as transferencias de renda. Por fim, pela primeira vez, as populacoes das areas rurais do Norte do Pais foram abrangidas pela PNAD em 2004, e os resultados tambem expressam a presenca da pluriatividade nesta regiao.

Este artigo versa sobre a dor mental gravada na fronteira psicobiologica. A natureza da dor nao e compreensivel ao paciente, que sente uma grande dificuldade em descreve-la ao analista. Trata-se de algo quase fisico, relacionado a uma situacao de perda traumatica ocorrida em um momento em que ha uma tenue percepcao da separacao entre a mae e o bebe, acarretando a ma formacao da pele psiquica e a constituicao de uma segunda pele protetora que impede a desestruturacao psicotica. Varias situacoes clinicas sao apresentadas.(AU)

OBJETIVO: Relatar os resultados imediatos e tardios da operacao de Glenn bidirecional como segundo estagio do tratamento da Sindrome de Hipoplasia do Coracao Esquerdo (SHCE) e descrever a tecnica de miniesternotomia utilizada. METODO: Entre marco de 1998 e fevereiro de 2004, 15 pacientes com operacao de Norwood previa foram submetidos eletivamente a derivacao cavopulmonar. As idades variaram de 2 a 6 meses (media 3,46 ± 0,83 meses), sendo seis pacientes do sexo masculino. Foram realizadas miniesternotomias em 11 (73,3%) casos. Para adequada oxigenacao sanguinea inicial foi associado enxerto sistemico-pulmonar de 3 mm em nove casos e manutencao do enxerto VD-TP em um caso. Acompanhamento clinico e ecocardiografico foi realizado em todos os pacientes. RESULTADOS: A sobrevida hospitalar foi de 86,6%, ocorrendo um obito por sangramento e outro por hipoxia. O ecocardiograma imediato mostrava fluxo pelo enxerto de PTFE nos dez pacientes em que foi utilizado, ocorrendo seu fechamento no controle tardio. Ocorreram dois (13,3%) obitos tardios, um por complicacao de traqueostomia e outro por meningite bacteriana. Sete pacientes aguardam o terceiro estagio, estando assintomaticos. Quatro foram submetidos ao terceiro estagio com sucesso. O ecocardiograma dos 11 pacientes sobreviventes tardios mostra boa funcao do ventriculo direito, sem insuficiencia tricuspide e bom fluxo pela anastomose cavo-pulmonar, num seguimento medio de 2 anos e 5 meses. CONCLUSOES: A operacao de Glenn na SHCE apresenta baixa mortalidade hospitalar, com resultados satisfatorios em longo prazo, podendo ser realizada atraves de miniesternotomia A associacao de fluxo sistemico-pulmonar acessorio em criancas de baixa idade parece melhorar a saturacao de oxigenio.

Operação de Glenn bidirecional no tratamento estagiado da síndrome de hipoplasia do coração esquerdo: resultados imediatos e tardios

No sentido de maximizar o valor, um dos principais objetivos das empresas atualmente, tem se tornado constante a pratica de implementacao de Centros de Servicos Compartilhados (CSC) que concentrem as atividades de suporte administrativo das empresas, numa especie de terceirizacao interna, conduzida e gerenciada por membros da propria organizacao. Essa decisao estrategica, contudo, requer um sistema de monitoramento e gerenciamento constante da performance, onde a prestacao de servicos com elevados niveis de qualidade, dentro de prazos cada vez mais curtos, dada a velocidade da demanda informacional, e com custos especialmente competitivos ao mercado e exigencia basica dos clientes deste tipo de estrutura. A inter-relacao de indicadores qualitativos e quantitativos no processo de gerenciamento da performance em Servicos Compartilhados (SC) pode ser obtida atraves da metodologia Balanced Scorecard (BSC), que propicia clareza e objetividade na comunicacao das acoes necessarias em cada uma das expectativas definidas em um scorecard do CSC, quais sejam, o aprendizado e crescimento, os processos internos, os parceiros (clientes) e as financas, propiciando aos executivos desta unidade de negocio condicoes de gerenciamento do valor que se esta buscando criar.

A Prática dos Serviços Compartilhados no Processo de Criação de Valor e a Aplicação do Balanced Scorecard como Instrumento de Gerenciamento da Performance em Estruturas de Suporte Administrativo

The existence and nature of possible astronomic forcing of cyclicity in glacial sediments of the Itarare Group, Parana Basin, during the Eopermian, were studied in core and gamma ray log data from two wells drilled by CPRM (Companhiade Pesquisa de Recursos Minerais) to coal research, one in Santa Catarina and other in Rio Grande do Sul. The distance between the original location of the cores (about 380 km) made it possible to test the astronomic forcing in this deposits in different locations of the basin. Two methods of data sampling were used, according to data scaleand the possible forcing: the gamma ray logs were digitized and sampled at I em intervals, in order to test the presence of orbital forcing (20,000 to 400,000 years) or other forcing phenomena (3,000 to 10,000 years), and the cores were scanned in the intervals with rhythmites and transformed in gray scale data sampled equally (0,2538 mm), in order to search for annual to centennial cycles. The harmonic analysis showed cyclicity in both scales: orbital cycles ranging from about 17,000 to 100,000 years and solar cycles ranging from about 22 to 1,000 years. The accumulation time calculated for one well in log and core data (about 9,400 years for the scanned interval and about 12,600 years for the same intervalin log data) showed a very high correlation. The accumulation rates calculated for the log data, ranging from 5,2 to 9,3 cm/ka, are very similar to the Pleistocene ones. The analysis also showed that the complete sedimentary record of the Itarare Group for one of the wells corresponds to about half precession cycle (12,342 years). As both astronomic forcing phenomena detected, the solar and the orbital cycles, affect climate on a global scale, certainly their influence on sedimentation occurred in other locations of the basin.

CICLOESTRATIGRAFIA DO EOPERMIANO - ESTUDO DE CASO NO GRUPO ITARARÉ, BACIA DO PARANÁ (PARTE 2): EVIDÊNCIAS DE INDUÇÃO ASTRONÔMICA (ORBITAL E SOLAR) NO CLIMA E NA SEDIMENTAÇÃO

MEXIAS-SIMON, Maria Lucia; OLIVEIRA, Aileda de Mattos. [2004]. O nome do homem: Reflexoes em torno dos nomes proprios. [Rio de Janeiro]: H. P. Comunicacao. 175 p.

SILVA, Gustavo Adolfo Pinheiro da. 2005. Pragmatica: a ordem deitica do discurso (as representacoes do EU e seus efeitos de sentido). Rio de Janeiro: Enelivros, 208 p. (enelivros@terra.com.br e (21) 2568-6870)

O seculo XVII marca uma fase de intensa renovacao no Brasil,nao apenas do ponto de vista literario, mas tambem no aspectosocial e economico.A centuria anterior assistira ao apogeu de Pernambuco, tao ricocom os seus engenhos de acucar, que o padre Fernao Cardim, aover os cavalos com arreios enfeitados a ouro, ao contemplar as sedase os veludos com que se vestiam os nobres senhores de engenho, declarouque em Olinda e Recife havia mais luxo e vaidade do que emLisboa.

One of the most important issues in organizational change is its effect on individual identities, which becomes more complex when different cultures are involved, as has been happening in the privatization of state-owned companies in Brazil. This study analyses the discourse of two employees of a Brazilian company which was privatized and is now managed by a European group, trying to understand how they see the changing situation in terms of the insertion of foreigners in the organization's scene. The results show that, when talking about foreigners, individuals try to strengthen their own identities within a challenging context.

Identidades profissionais em contextos organizacionais 'glocais'

Objetivou-se com este trabalho avaliar o estado nutricional de bananeiras 'Prata Ana' (ABB) cultivadas no Norte de Minas Gerais, utilizando o metodo do sistema integrado de diagnose e recomendacao (DRIS). Foram realizadas as avaliacoes nutricionais de 168 amostras de folhas coletadas em 58 areas cultivadas com bananeira irrigada. O Cu e Mn foram os nutrientes que apresentaram teores deficientes em maiores frequencias de bananais e Ca, Mg e Mn apresentaram teores excessivos em maiores frequencias. Os teores de N e K apresentaram-se deficientes em 18% e 23% dos bananais, respectivamente. A frequencia de bananais com teor adequado de N foi maior naqueles da populacao de alta produtividade.Verificou-se a mesma frequencia com teor adequado de K entre os bananais de alta e baixa produtividade. Fatores de ordem nao nutricionais limitaram a producao das bananeiras da populacao de baixa produtividade.

Avaliação nutricional de bananeira 'Prata Anã' (AAB), sob irrigação no semi-árido do norte de Minas Gerais, pelo método DRIS

O ensino da Matemática passou por diversas mudanças significativas. Todavia, essas mudanças não foram suficientes para suprir as dificuldades enfrentadas pelos estudantes dessa disciplina. Vários são os fatores que dificultam a sua aprendizagem. Dentre eles, podemos destacar o conceito pré-formado de que a “Matemática é difícil”, a capacitação inadequada dos professores, a metodologia tradicional com ênfase excessiva ao cálculo, a busca inadequada a novos recursos pedagógicos, a falta de contextualização e a linguagem. A solução para essa problemática quanto à aprendizagem da Matemática passa, necessariamente, por uma disciplina lecionada de forma associada às necessidades da comunidade estudantil, a fim de capacitar os indivíduos para uma plena participação na vida social. Para isso, precisamos renovar o ensino. Essa renovação só é possível com a participação de todos os agentes sociais envolvidos. Isso ocorrerá, por exemplo, com uma constante reflexão de professores sobre sua prática, bem como, com a associação do que está sendo ensinado com sua origem histórica e com a sua aplicabilidade.

Refletindo sobre as dificuldades de aprendizagem na matemática: algumas considerações

Paulo Rogério da Silva Cosentino Químico Industrial pela Universidade Estadual da Paraíba (UEPB). Mestre em Engenharia Sanitária e Ambiental pela Universidade Federal da Paraíba (UFPB). Bolsista do CNPq – PROSAB. José de Anchieta da Silva Filho Engenheiro Civil (UFCG) e mestrando do Curso de Pós Graduação em Engenharia Civil/Engenharia Sanitária e Ambiental da UFCG. Adrianus C. van Haandel Professor do Departamento de Engenharia Civil do Centro de Ciências e Tecnologia da Universidade Federal de Campina Grande (UFCG). Paula Frassinetti Feitosa Cavalcanti Professora do Departamento de Engenharia Civil do Centro de Ciências e Tecnologia da Universidade Federal de Campina Grande (UFCG).

Estabilização de lodo de sistemas aeróbios em reatores do tipo UASB

A presente tese teve como questao central a discussao acerca de qual seja a perspectiva de futuro da pluriatividade no seio da agricultura familiar no Brasil. Por esta razao, privilegiou-se a analise sobre as duas macrorregioes do pais (Nordeste e Sul) que concentram quase 80% do total da agricultura familiar nacional. O estudo das especificidades da pluriatividade em si mesma nao foi o ponto central da tese, senao qual sera seu futuro no Brasil, particularmente nas duas regioes em foco. A conclusao mais geral consiste em que a pluriatividade, no Brasil, so tem perspectivas de crescimento em areas rurais de regioes pobres como o Nordeste. E, pior, nessas areas a pluriatividade cresce, mas sem contribuir para que os produtores familiares sejam alcados para cima da linha de pobreza estipulada (renda per capita familiar media de 1h salario minimo). Na regiao Nordeste, portanto, a pluriatividade cresce combinando proletarizacao com pobreza. Na regiao Sul, por seu lado, a pluriatividade apresenta uma tendencia (sentido estatistico) de declinio, juntamente com o conjunto da agricultura familiar da regiao. Defende-se que nessa regiao a pluriatividade so apresentara uma trajetoria de crescimento se houver politicas publicas que a promovam, e que essa promocao passa nao somente pelo fomento de oportunidades ocupacionais nao-agricolas nos entornos rurais, mas, sobretudo, pelo incentivo ao nao abandono das atividades agricolas "tradicionais" por parte dos inumeros pequenos produtores familiares que se veem alijados do processo acelerado de modernizacao das atividades agricolas. A tese mostra que na regiao Sul os pequenos produtores familiares agricolas e pluriativos estao se tomando, paulatinamente, em familias nao agricolas. Ou seja, nessa regiao a pluriatividade nao tem evitado o processo de proletarizacao completa de parcelas crescentes de pequenos produtores familiares. Esse processo fica mais patente a medida que o mercado, e nao o Estado, confirma-se como a instituicao privilegiada para organizar o setor agricola. 
Abstract

Como parte de um projeto mais amplo onde se pretende analisar como os diversos cientistas sociais concebem a producao de ideologias politicas, o presente artigo tem a pretensao de demonstrar como Pierre Bourdieu trata da questao em sua teoria sociologica. Por meio de pesquisa bibliografica, o artigo demonstra que a concepcao de Bourdieu acerca do processo de producao de discursos politicos, desmistifica a pretensao de se ter um discurso politico como verdade absoluta. Aos olhos de Bourdieu, o teor de um discurso politico depende das lutas simbolicas pelo poder simbolico que ocorrem entre os agentes do campo politico. Nessas lutas, os discursos politicos sao produzidos conforme as necessidades internas e conforme as necessidades externas do campo politico. Assim, o carater de verdade ou a legitimidade de um discurso politico dependem nao necessariamente de seu conteudo, mas de seu poder simbolico, portanto, de sua capacidade de conquistar adeptos e de ser por eles aceito como legitimo.

This study presents a methodology of data preparation for cyclostratigraphic analysis, using core and gamma ray log data from two wells drilled by CPRM (Companhia de Pesquisa de Recursos Minerais) to coal research, one in Santa Catarina state (7-RL-04-SC) and other in Rio Grande do Sui state (IB-93-RS). The wells sampled rocks from Lower Permian Itarare Group, Parana Basin, originally deposited in glacial, periglacial and marine environments. The distance between the original locations of the cores (about 380 km) made it possible to test, after ward (Cyclostratigraphy of Lower Permian - Case Study in Itarare Group, Parana Basin (PART II), in this same publication), the astronomic forcing in different locations of the basin. Two methods ofdata sampling were used, according to data scale and the possible forcing: the gamma ray logs were digitized and sampled at 1 em intervals, in order to test the presence oforbital forcing (20,000 to 400,000 years) or other forcing phenomena (3,000 to 10,000 years), and the cores were scanned in the intervals with rhythmites and transformed in gray scale data sampled equally (0.2538 mm), in order to search for annual to millenarian cycles. The process of core data preparation before scanning required a detailed elimination of small fractures and sedimentary structures as ripples, to avoid distortions in the final results

CICLOESTRATIGRAFIA DO EOPERMIANO - ESTUDO DE CASO NO GRUPO ITARARÉ, BACIA DO PARANÁ (PARTE 1): UMA METODOLOGIA PARA PREPARAÇÃO DE DADOS DE PERFIL E ROCHA

No atual cenario politico-economico mundial, que forca as empresas a elevarem os niveis de competitividade para sobreviverem, a busca pela criacao e gerenciamento do valor nunca esteve tao em alta. Nesse sentido, as organizacoes buscam percorrer caminhos, seja no plano estrategico, tatico ou operacional, que as leve ao maior estado de rentabilidade possivel. 
 
Uma das acoes que vem conquistando cada vez mais adeptos em funcao da geracao de valor que proporciona e a implementacao de Centros de Servicos Compartilhados que concentrem as atividades de apoio e retaguarda espalhadas atraves das empresas, transformando-as, de atividades secundarias ao negocio, em atividades primarias de unidades administrativo-financeiras compartilhadas. 
 
A decisao estrategica de concentrar o operacional exige atencao especial em relacao a consecucao de um sistema de comunicacao estrategica entre Servicos Compartilhados e demais unidades de negocio da empresa, alem do gerenciamento do desempenho do proprio Centro de Servicos Compartilhados. 
 
A metodologia Balanced Scorecard, atraves de suas relacoes de causa e efeito, propicia as empresas que decidem administrar suas estruturas de apoio e retaguarda de maneira compartilhada, clareza e objetividade na comunicacao da decisao de implementacao, pois liga as acoes minimas da unidade com sua estrategia final, que e atender as demais unidades de negocio da empresa em relacao as suas necessidades por produtos e servicos operacionais. Permite ainda estabelecer um conjunto de indicadores em quatro expectativas distintas, aprendizado e crescimento das pessoas, evolucao dos processos internos, parceiros (clientes) e financas, sendo que os resultados alcancados em cada uma destas expectativas influenciam as demais, formando, no todo, um unico sistema de indicadores integrados, que propicia aos executivos dos Servicos Compartilhados as condicoes de gerenciamento e tomada de decisoes com vistas ao estabelecimento de acoes que produzam valor sustentado.

Estudo da estratégia de implementação e mensuração do desempenho de um Centro de Serviços Compartilhados em indústria de bens de consumo imediato com a utilização do Balanced Scorecard

A historia da gramaticologia ocidental teve inicio na AntiguidadeGreco-Latina, com Platao, com Aristoteles e com Varrao, trazendonumerosas e indesculpaveis consequencias terminologicas absolutamentedistanciadas das diversas realidades linguisticas descritasou normatizadas.

Desde a revolucao industrial ate os dias de hoje, a poluicao do meio ambiente passou de um simples reflexo do progresso do homem, para ser um serio problema global. Atualmente, sao varias as legislacoes que tentam restringir essa poluicao, sendo esse fato o responsavel pelo urgimento de varias tecnologias para o tratamento previo dos residuos 
toxicos a serem lancados no meio ambiente. Uma dessas tecnologias e a hidrodescloracao catalitica. Dentro desse contexto, o objetivo do presente estudo e a avaliacao das condicoes experimentais para a hidrodescloracao do pentaclorofenol com catalisadores de paladio. Essa avaliacao foi realizada por meio de testes cataliticos com os catalisadores 5%Pd/C e 5%Pd/TiO2. Esses testes foram feitos de uma forma planejada, sendo que para tal empregou-se o planejamento fatorial fracionario 2 6/2. No que se refere aos catalisadores empregados, o solido 5%Pd/C e um catalisador comercial, enquanto o catalisador 5%Pd/TiO2 foi preparado via impregnacao a seco, partindo-se de uma solucao aquosa de PdCl2. Depois de impregnado e seco, esse solido foi dividido em duas partes: uma delas foi 
calcinada a 300 °C e a outra reduzida a mesma temperatura. Os resultados dos testes cataliticos revelaram que os catalisadores 5%Pd/C e 5%Pd/TiO2 reduzidos nao foram ativos para a hidrodescloracao do pentaclorofenol em fase liquida. Por outro lado, esses mesmos catalisadores, na sua forma oxidada, nao foram desativados durante o tempo de reacao em que foram avaliados. Alem disso, esses testes cataliticos tambem revelaram que o catalisador 5%Pd/C nao ativado e seletivo a cicloexanol, enquanto que o catalisador 5%Pd/TiO2 calcinado e seletivo a fenol 
Abstract

Tratamento de residuos organoclorados toxicos : avaliação das condições experimentais para a hidrodescloração do pentaclorofenol com catalisadores de paladio

1. O Ministerio Publico se tornou uma instituicao essencial na estrutura do Estado contemporâneo. Ha quem veja sua origem nos advogados e procuradores do rei que, antes do seculo XVI, eram apenas os representantes dos interesses privados do monarca perante os tribunais. O papel desses advogados e procuradores do rei foi gradativamente ampliando-se pari passu com o fortalecimento dos poderes dinasticos; e se tornaram assim agentes do poder publico junto aos Tribunais (Frederico Marques). Mais um passo adiante desprenderam dessa condicao para se transformarem num agente politico destinado a prover sobre a exata observância do direito objetivo, defesa dos direitos indisponiveis e do interesse publico.

O uso da avaliaçao de seu uso (acerca da avaliaçao da qualidade do ensino)

Estudo dos processos de admissão e exaustão utilizando ensaio experimental e simulação de um motor de combustão interna a etanol aspirado e turboalimentado

The effects of the irrigation using calcareous water on some chemical and physical properties of the soil, on the foliar nutrient content and on the productivity of  ‘Prata Ana’ (AAB) banana crops were evaluated. A total of 100 commercial banana crops were selected, being 50 commercial banana crops irrigated with calcareous water. It was verified that the banana crops irrigated with calcareous water presented greater foliar content of Ca, greater produtivity and the soils of these banana crops presented greater pH, eletric conductivity, Ca and organic matter content and smaller density in relation to those irrigated with non calcareous water.

Propriedades do solo, estado nutricional e produtividade de bananeiras 'prata anã' (aab) irrigadas com águas calcárias

The objective of this paper was to determine the phosphorus adsorption characteristics using the Langmuir isotherm and it is relation with some physical and chemical properties of soils. The study was carried out in the Soil and Plant Laboratory, of the National Institute for Amazon Research (INPA), Brazil, with surface (0-20 cm) samples from eight soils of the Amazonas State. Ample variation of the maximum phosphorus capacity factor (MPAC), adsorption energy and maximum phosphorus capacity factor (PmCF) were observed. The Plinthite soil showed the highest values of the MPAC and PmCF and the Yellow Oxisol 1 (LAx-1) showed the highest adsorption energy. The MPAC ranged from 0.297 to 0.888 mg P g-1 of soil, the adsorption energy with which the phosphorus is sorbed was between 0,230 and 0,730 L mg-1, and the PmCF. ranged from 137 to 593 mL g-1. The PmCF decreased from Plinthite (FTa) > Yellow Oxisol (LAx-1) > Yellow Oxisol (LAx-3) > Yellow Oxisol (LAx-6) > Yellow Oxisol (LAx-2) > Yellow Oxisol (LAx 4) > Yellow Ultisol (PAd) > Yellow Oxisol (LAx-5). The MPAC and the PmCF were positively correlated with clay content (r = 0,948** e r = 0,962** ) and exchangeable Al3+ (r = 0,688* e r = 0,666* ), and negatively correlated with base saturation (r = - 0,667* e r = - 0,761*), respectively. The adsorption energy was positively correlated with clay content (r = 0,783*) and negatively with base saturation (r = - 0,775*).

Características de adsorção de fósforo em alguns solos da Amazônia Central

OBJECTIVE: To assess the results of a technical modification of tricuspid valvuloplasty in Ebstein's anomaly. METHODS: From November 1993 to August 2002, 21 patients with Ebstein's anomaly of the tricuspid valve, with ages ranging from 20 months to 37 years (mean, 23 years), underwent a new technique of tricuspid valvuloplasty. This technique consisted of total or almost total detachment of the anterior tricuspid megaleaflet from the ventricular wall and valvular ring, transforming it into a cone, whose vertex remained fixed in the right ventricular tip, and the base was sutured to the tricuspid ring, after its plication, adjusting it to the size of the base of the cone (tricuspid ring), including the septal region. RESULTS: One (4.7%) patient with cardiomyopathy caused by chronic hypoxia died in the hospital due to low cardiac output. The mean follow-up lasted 4 years, and the recent echocardiograms showed good morphology of the right ventricle and tricuspid valve with mild or minimal insufficiency in 18 patients and moderate insufficiency in 2 patients. In 2 of the 3 patients with an anomalous bundle, it could be located and sectioned during surgery. No atrioventricular block occurred. CONCLUSION: The technique used was efficient in repairing tricuspid insufficiency and restoring right ventricular morphology, being applicable to all anatomic types of Ebstein's anomaly, except for Carpentier classification type D.

Anomalia de Ebstein: resultados com a reconstrução cônica da valva tricúspide

The article has the purpose of analyzing how Alexis of Tocqueville bases the political power -"legitimate monopoly of the use of the physical force" -and how he it explains the citizens' participation in the political decisions. The study could reveal that, to the eyes of Tocqueville, the political power -in the American case -was born from a social pact been celebrated among the Anglo-Americans, in the beginning of XVIIth century, with the purpose of promoting the well general of the English colonies and that the citizens' participation in the political is resulted of a confluence of factors such as social, political, economical, cultural and geographical.

A confirmacao diagnostica de leishmaniose visceral ou calazar e realizada atraves da deteccao do parasito por metodos diretos, atraves do encontro de formas amastigotas no interior de macrofagos ou monocitos, em aspirado esplenico, hepatico, medula ossea, histopatologico de linfonodo e esfregaco do sangue periferico, com ampla variacao de sensibilidade de acordo com o sitio pesquisado, constituindo-se o padrao-ouro a visualizacao de Leishmania sp. A pesquisa de anticorpos especificos para triagem diagnostica da leismaniose visceral atraves do ELISA, reacao de imunofluorescencia indireta e os testes de aglutinacao direta possuem sensibilidade alta e especificidade limitada pelas reacoes cruzadas com tripanosomatideos e micobacterias, incluindo-se tuberculose, hanseniase, doenca de Chagas, e ainda, leishmaniose tegumentar e histoplasmose. O teste intradermico de Montenegro e sempre negativo durante a fase ativa da doenca, e baseia-se na memoria imunologica dependente de linfocitos Th1. O ojetivo deste trabalho foi evidenciar a relevância do teste rapido para deteccao de anticorpo anti-leishmania chagasi utilizando o antigeno recombinante rK39 que apresentou sensibilidade de 99,2%. Foram realizados testes sorologicos pelo ELISA que apresentou sensibilidade de 80%, e a reacao de imunofluorescencia indireta para calazar com sensibilidade de 82%. O gold-standard diagnostico empregado para todos exames foi a pesquisa microscopica direta do parasito no aspirado de medula ossea e a positividade foi de 71%, em uma pesquisa realizada em hospitais terciarios de Fortaleza-CE. A reacao imunoenzimatica para teste rapido em fita contendo antigeno rK39 apresentou elevada sensibilidade e especificidade permitindo diagnostico imediato e inicio precoce do tratamento, alem de confirmar alta densidade de epitopos exclusivamente para o genero Leishmania, pois nao houve reacoes cruzadas dentre varias doencas testadas. Detectamos titulos de anticorpos IgG anti-leishmania chagasi persistentemente positivos em pacientes tratados adequadamente para calazar, corroborando com evidencias de que o rK39 nao define doenca em atividade e nem estabelece criterios de cura, fortalecendo que outras possibilidades diagnosticas sejam investigadas mediante um resultado positivo em individuo procedente de zona endemica para calazar, em paciente portador de hepatoesplenomegalia febril e pancitopenia. O teste rapido rk39 devera ter sua leitura imediatamente relizada e interpretada em ate no maximo 10 minutos, objetivando tomada de decisoes clinicas, e que sua implantacao como metodo auxiliar de diagnostico deveria fazer parte da rotina laboratorial, particularmente de servicos secundarios e terciarios de saude em regioes endemicas para leshmaniose visceral.

Estudo do teste rápido imunoenzimático através do antígeno recombinante rk39 para diagnóstico de leishmaniose visceral americana : correlação clínico-terapêutica

We report a rare case of spinal cord capillary hemangioma in a 79-year-old woman, presented with paraparesia that had progressed within 8 months. Radiologically, the lesion resemble other vascular spinal cord tumors. The patient underwent surgery and the outcome was good. Histologically, the lesion resembled capillary hemangioma of skin or soft tissue, composed of lobules of small capillaries with associated feeding vessels, all enveloped by a delicate fibrous capsule. A review of the published cases in the literature is provided as well as a discussion of the clinical, radiological and histological aspects of the lesion and the differential diagnosis. Knowledge of its existence may avoid misdiagnosis of this benign lesion.

Os inibidores foram isolados de TOI em sementes de Copaifera langsorffii, conhecida vulgarmente por Copaiba, uma arvore nativa do Brasil da subfamilia Caesalpinoideae da familia Leguminosae. A fracao TOI foi purificada a partir de precipitacao com sulfato de amonio, cromatografia em uma coluna de troca-ionica em OEAE-Sepharose e coluna de afinidade em Sepharose- Trypsina. TOI apresentou-se homogeneo em gel de poliacrilamida-SOS 12,5%, com uma massa molecular aparente de 24 kOa em condicoes nao reduzidas, e 12 kOa em condicoes reduzidas com OIT. A massa molecular relativa estimada por filtracao em gel em uma coluna Superdex-75, sistema FPLC, confirmou os resultados obtidos em PAGE-SOS. TOI tem um Ki de 1,2nM para a enzima tripsina bovina mostrando uma alta afinidade. No entanto, TOI nao mostrou atividade inibitoria para quimotripsina. O estudo da estequiometria do complexo TOI-tripsina revelou que este inibe tripsina na razao molar de 1: 1. O complexo TripsinaTOI foi eluido na cromatografia de filtracao em gel com um tempo de retencao equivalente a uma massa molecular relativa de 39 kOa. Evidenciou-se tambem que TOI e ativo na sua forma monomerica e nao na sua forma dimerica. A Focalizacao Isoeletrica de TOI revelou a presenca de duas bandas de proteinas, ambas coradas para inibidor de tripsina com pls de 6,45 e 7,35, indicando dois inibidores em TO!. Os inibidores de TOI, designadas por TOI-I e TOI-II, foram isoladas em coluna de fase reversa C18 /lBondapack, em Sistema HPLC Walters. Foi observado em gel de Tricina 16,5% uma diferenca minima na massa molecular aparente, sendo aproximadamente 12 e 10 kOa para TOI-I e TOI-1I respectivamente. O sequenciamento N-terminal dos inibidores de TOI revelou a presenca da sequencia consenso observada nos inibidores de tripsina tipo Kunitz para TOI-I, contudo, pesquisas nos banco de dados de proteinas nao revelou nenhuma homologia para TOI-II. TOI mostrou alta estabilidade para diferentes condicoes de pH, temperatura e concentracao de OTT, indicando um possivel numero elevado de pontes de dissulfeto na estrutura molecular. TOI nao foi degradado proteoliticamente na digestibilidade in vitro pelas proteases encontradas no intestino medio do gorgulho Callosobruchus maculatus, e demonstrou um efeito deleterio no desenvolvimento dos insetos, sugerindo que TOI atua como um fator antinutritivo e prejudica o desenvolvimento de Callosobruchus maculatus 
Abstract

Isolamento e caracterização bioquimica de inibidores de proteinases serinicas de sementes de Copaifera Iangsdorffii : estudo da resistencia contra o Callosobruchus maculatus

O objetivo desse trabalho e apresentar alguns textos de JoaquimMattoso Câmara Junior, a partir dos quais fique bastante clara aideia que esse grande linguista brasileiro tinha a respeito da Filologia.

The Deciduous Seasonal Forest of the Northeast region of the state of Goias is one of the few types of forest formations in the Cerrado biome, which may occur in areas of limestone outcrops. Generally it has a higher biomass of tree species than the contiguous cerrado. This study was carried out in an undisturbed area of forest (Flor Ermo Farm) and in others four areas of disturbed forests: Formosa, Tracadal, Manguinha and Conceicao Mocambo Farm. The study aimed to estimate the basal area and the sampling intensity needed to use Bitterlich´s relascope in the deciduous forests. Estimates of basal area of the plots ranged from 23 to 24 m²/ha in the disturbed forests up to a maximum of 29.3 m²/ha in the undisturbed one. Forests with high disturbance showed very small variation of the standard deviation curve for the sampled points when compared to the area with low disturbance level. For a confidence level of 95% estimate of the mean, 20 sampling points with the relascope can be enough to sample the basal area in this kind of vegetation.

Estimativas de área basal e uso do relascópio de Bitterlich em amostragem de Floresta Estacional Decidual.

The increase of weed infestation on agricultural systems cause damages to the crops, decreasing plant productivity by the direct competition or by alelopathy. This work have undertaken a survey and phytosociological analysis of some aspects of weed species that occur in agroforestry systems with cupuassu. The treatments consisted of three crops arrangements (cassava+fruit trees; annuals crops+fruit trees; passion fruit+fruit trees), and three fertilizer management (NPK+OM, with Phosphorus and Phosphorus+leguminous). Three harvests of weed plants were accomplished, being six samples of 0,25 m2 per plot. The identification of the species of the weed plants were carried out in the laboratory. The 55 weed species identified were distributed in 23 botanical families, being 43 of dicotyledonous species, 11 of monocotyledonous, and one of pteridophyta. The families Poaceae (monocotyledonous) and Asteraceae (dicotyledonous) were the most frequent and with large number of individuals. The most frequent species and with large number of plants per m2 were Paspalum conjugatum P.J. Bergius (area A) and Homolepis aturensis (Kunth) Chase (area B) of the Poaceae family; Ageratum conyzoides L. of the Asteraceae family, presented the largest density. The similarity coefficients varied among the areas studied, being the largest indexes observed in the treatments that received fertilizers with organic matter (NPK+OM), particularly in the system cassava+fruit trees. The agricultural practices and the soil and crops management systems, had a great influence to the flora composition and in the weed plants communities size in each local area. The number of monocotyledonous was smaller in the treatment with NPK+OM than in the other treatments.

Plantas invasoras em sistemas agroflorestais com cupuaçuzeiro no município de Presidente Figueiredo (Amazonas, Brasil)

Influência, coincidência e divergência constitucionais: Espanha/Brasil

Nitrogen, after potassium, is the chemical element most required by banana crop. This work evaluated the effect of nitrogen and potassium fertilization on irrigated banana crop (Prata-Ana, AAB) yield. Five rates of N (0 , 200 , 400 , 800 and 1600 kg ha-1 year-1) and five rates of K2O (0; 200; 400; 800 and 1600 kg ha-1 year-1), in a (5x5) factorial design were studied. The data were obtained during three yield cycles (second, third and four cycles), on an eutrofic Red-Yellow latosol, sandy-clay, in the North of Minas Gerais State, Brazil. The content of Mn have increased in the leaves with the increased amount of N applied in the soil. The banana yield reduced with the rise of the Mn content in the leaves, on the second and third cycle. The maximum yield was obtained with the application of 962,5 kg of K2O ha-1year-1, on the fourth cycle. No interaction between N and K was found.

Adubação com potássio e nitrogênio em três cíclos de produção da bananeira cv. prata-anã

The trinomial logistic models can be interpreted as a natural extension of the traditional binomial logistic model to situations in which the response allows only three possible results. We first introduce the trinomial logistic models and then some inferential aspects, such as estimation and hypothesis testing are discussed. Goodness-of-fit measures are also given. However, the aim of this work is the presentation of some diagnostic procedures for trinomial logistic models. We show that methods developed for binomial logistic models can adapted straightforward for trinomial models. The development of direct methods, even though possible, in general requires more complex calculation. Some of these direct methods, such as evaluation of residuals, measures of high leverage points, deletion methods and local influence are presented. Comparisons between adapted and direct methods are made via examples with real data.

Ceramic products obtained from concentrated suspensions of Al2O3need to be stabilized to meet the increasing demand for performance. The suspensions studied in this work are, usually, employed in the obtention of ceramic tapes by a ‘Tape Casting’ process. In a suspension, particles develop surface charges. When these particles collide with each other, this could cause aggregation, generating flocculated structures that consequently imprison water inside them, which will result in a higher porosity product with lower mechanical and even chemical resistance. To stabilize a concentrated suspension it isnecessary to make the difference of the attractive forces of Van der Waals and repulsive forces between double electric layers equally charged, or produced by the addition of polimeric material on the particle surface to be repulsive. Traditional parameters to evaluate the stability of concentrated suspensions, hereby used are the zeta potential and viscosity. We have proposed new additional parameters 1) suspension millimeter size structures, 2) microstructures, and 3) hysteresis of viscosity curves. Concentrated suspensions of Al2O3varying from 40 to 70% by volume, were tested. For each suspension, the concentration of the dispersing agent has been varied. Then, the stability of the suspension was evaluated using the parameters described above. To each sample, when we analyzed all parameters together, we perceived coherence among them. With each other however, one analysis based upon only one parameter probably is not sufficient to qualify the degree of stability of the suspension.

Reologia e microestrutura na estabilização de suspensões concentradas de Al2O3.

Many of the texts in change management literature approach the theme almost exclusively in a planning perspective, trying to find answers on issues as: how to make an organization being successful in its strategy for intentional change, promoting a cohesion of efforts and eliminating the supposed human resistances? Little attention has been dedicated, however, to individuals’ emotions, to the sense they attribute toorganizational change, and to their chances to become subjects in such context. This research, accomplished in five organizations in Rio deJaneiro, has the objective of trying to fill this kind of lack, by means of 75 interviews with employees that have participated in great changes facedby those organizations. The results point to the fragility of some of the myths about the concept of resistance, and suggest the possibility to turnorganizational change less traumatic for individuals, by means of the opportunities they find to constitute themselves as subjects and to makesense of their performance in the new context.

SENTIMENTOS, SUBJETIVIDADE E SUPOSTAS RESISTÊNCIAS À MUDANÇA ORGANIZACIONAL

Este trabalho enfoca o desenvolvimento turistico em areas rurais, atraves de um estudo de caso na regiao das Terras Altas da Mantiqueira (TAM) no sul do Estado de Minas Gerais, onde este processo esta sendo considerado como elemento essencial para o desenvolvimento regional e para a preservacao do meio ambiente. Destaca-se uma iniciativa de organizacao do setor privado, que procurou reunir os hoteleiros e atores afins, criar uma identidade regional e articular-se com o poder publico visando o desenvolvimento sustentavel do turismo na regiao e a dinamizacao economica regional impulsionada pela atividade turistica. A analise do processo de organizacao do turismo implementado pela Associacao Terras Altas de Mantiqueira (ATAM) revelou os exitos e as deficiencias de tal iniciativa. Os principais fatores que limitaram sua atuacao estao ligados a problemas de planejamento, gerenciamento e participacao, assim como ao contexto politico-institucional. Para que a atividade turistica se torne um fator de propulsao economica e desenvolvimento regional, sao necessarias politicas publicas que deem suporte ao processo de organizacao local e ao mesmo tempo fornecam incentivos ao planejamento e as parcerias com o setor privado

Perspectivas do desenvolvimento turistico em areas rurais : o caso das Terras Altas da Mantiqueira (MG)

Cruzetas para redes de distribuição de energia elétrica à base de polipropileno

Neste trabalho, faz-se um balanA§o geral macroeconA´mico do governo Fernando Henrique Cardoso, a partir de uma anAilise descritiva do comportamento das principais variAiveis - objetivo das polA­ticas econA´micas, indicadores de finanA§as pAoblicas e de vulnerabilidade externa. Conclui-se que os prejuA­zos para o paA­s, decorrentes da polA­tica econA´mica exclusivista de FHC, foram extremamente elevados, em face dos resultados alcanA§ados em termos de estabilizaA§A£o monetAiria, e que o seu grande legado ao sucessor foi uma crise econA´mica difA­cil de administrar.

Anisotropia do espaço percebido e paralaxe de movimento: uma análise da orientação espacial

O crescimento dos principais indicadores macroeconómico associados ao turismo português, se fazem das actividades que lhes estão associadas uma das principais especializações produtivas do país, vêm colocar a necessidade de uma reflexão estratégica sobre a inserção do turismo em contextos regionais. Este artigo, ao pretender responder a estas preocupações, começa por esboçar uma análise quantitativa da estrutura espacial das actividades turísticas em Portugal, através da construção de um índice de localização turística ponderado, cujo objectivo é o de analisar o protagonismo destas actividades no tecido produtivo das regiões portuguesas. Num segundo momento é desenvolvida uma tipologia qualitativa cujo objectivo é o de analisar o potencial de estruturação do turismo numa base regional. Finalmente equacionam-se os problemas nucleares e as áreas estratégicas de intervenção concordantes com a tipologia apresentada e baseados nos principais factores que delimitam o desenvolvimento turístico sustentável.

Inserção Territorial das Actividades Turísticas em Portugal – Uma Tipologia de Caracterização

Simulação por elementos finitos da propagação de feixes opticos em estruturas fotonicas

Caracterização espectroscópica de blendas condutoras de poli(anilina) e a sua aplicação para a proteção ativa contra a corrosão de metais

Sistematização e avaliação de técnicas de investigação aplicadas à caracterização e diagnóstico de área contaminada por hidrocarbonetos de petróleo

Information on peach palm (Bactris gasipaes Kunth, Palmae) mineral nutrition is scanty. This study was carried out in a greenhouse of the National Research Institute for Amazonia, Agronomy Department, to characterize the symptoms of nutrient deficiency and to identify the critical nutrient levels. Peach palm plants are cultivated in sand with 13 nutrient solutions: complete nutrient solution, minus nitrogen, phosphorus, potassium, calcium, magnesium, sulphur, iron, boron, copper, manganese, zinc, and molybdenum. The experimental design was completely randomized with 13 treatments and four replications. Nutrient deficiencies in the peach palm seedlings were easy identified and the analytical levels of adequacy and deficiency in the leaves were: N (g kg-1) 30.7 - 10.1; P (g kg-1) 3.4 - 1.0; K (g kg-1) 27.8 - 4.7; Ca (g kg-1) 12.7 -2.6; Mg (g kg-1) 3.5 - 0.9; Fe (mg kg-1) 175 - 191; Zn (mg kg-1) 33 - 41.

Caracterização de sintomas de carências nutricionais em mudas de pupunheira cultivadas em solução nutritiva

II-200 - ESTUDO CINÉTICO E DE EQUILÍBRIO DA ADSORÇÃO DE NÍQUEL EM ALGAS ARRIBADAS DA PRAIA DE JAGUARIBE - PE

O objetivo do presente artigo e resgatar o valor dos recursos oferecidos pela Cartografia e pelo Trabalho de Campo na Educacao Ambiental. A maior licao de cidadania de uma pessoa e estar preparada para entender o seu meio ambiente. Quem conhece o espaco aonde vive tem a possibilidade de transforma-lo. A Educacao Ambiental no ensino formal das escolas publicas, precisa de um direcionamento objetivo e uma resposta politica para que verdadeiramente seja viabilizada adequadamente.

CARTOGRAFIA E O TRABALHO DE CAMPO: INSTRUMENTOS DE EDUCAÇÃO AMBIENTAL

Uma das principais criticas que sao dirigidas a muitas das pesquisas que procuram obter uma melhor compreensao sobre o fenomeno da mudanca organizacional, tao presente em nossos dias, e o emprego de metodologias de investigacao que colocam um foco predominante sobre as iniciativas de natureza institucional para a gestao da mudanca, minimizando a importância do sentido atribuido pelas pessoas da organizacao. Assim tambem, as metodologias dominantes pouco tem contribuido para que se possa obter uma maior compreensao sobre o modo como as pessoas e equipes na organizacao lidam com os aspectos de natureza afetiva, psicologica e social envolvidos nas situacoes de mudanca. O presente trabalho tem como objetivo lancar um olhar mais atento sobre o emprego de uma metodologia de investigacao que procura resolver em parte algumas dessas questoes: a aplicacao da dinâmica de construcao de desenhos, que busca compreender o processo de criacao de sentido da mudanca. Para tanto, dois estudos que empregaram esse tipo de metodo de investigacao sao analisados de forma comparativa: um estudo realizado no Reino Unido por Vince e Broussine (1996) e outro realizado no Brasil, por Silva e Vergara (1999).

Análise comparativa acerca da utilização de desenhos na pesquisa sobre a criação do sentido da mudança organizacional

Investigações experimentais e modelo de Langevin da birrefringência magneto-ótica de fluidos magnéticos do tipo EDL

This technical note describes a new and simple electronic circuit for driving solenoid valves. The circuit is based on a single integrated circuit DRV103, which is able to drive resistive or inductive loads up to 1.5 A. Switching of 12-V loads can be controlled by TTLlevel signals in two distinct steps. Initially, 12 V is applied during 110 ms, followed by 4.2 VRMS until the end of the activation TTL pulse. This mode of operation is particularly suitable to drive solenoids, because it requires a higher voltage to start and a lower maintenance voltage. By using this circuit, power consumption and heating are reduced and the solenoid lifetime is enhanced. Moreover, this circuit is specially appropriated to build computercontrolled solenoid valves systems.

Dissertacao de Mestrado em Educacao Multimedia apresentada a Faculdade de Ciencias da Universidade do Porto

A Geometria dinâmica no âmbito do ensino / aprendizagem : Um Protótipo para o estudo do círculo no 9º ano do Ensino Básico

Nesta tese discute-se as alteracoes recentes no uso e ocupacao do solo rural, analisando-as como resultado do processo de urbanizacao e do consequente espraiamento da mancha urbana, a partir de um Estudo de Caso de Campinas e sua Area de Protecao Ambiental. Neste contexto, problematiza-se a abertura indiscriminada do territorio da metropole ao processo de urbanizacao, discutindo-se a possibilidade de que a dissolucao da especificidade do uso das areas rurais pode comprometer o desenvolvimento sustentavel. Alem disso, explicita-se uma contraposicao a ideia dominante de que as areas rurais, proximas aos grandes centros, nao tem outro destino possivel senao aguardar a chegada inexoravel da urbanizacao. Tambem sao analisados os conflitos de interesse articulados ao processo de incorporacao das areas rurais as cidades, que opoem segmentos do capital imobiliario - que exercem fortes pressoes pela urbanizacao-, e ambientalistas e moradores - que defendem a preservacao dos espacos rurais e de seus recursos naturais. Deriva-se das mudancas concretas de uso e ocupacao do solo nas areas rurais, assim como dos conflitos de interesse gerados nesse processo, a dificuldade de definicao e implementacao de instrumentos de regulacao e controle do processo de incorporacao das areas rurais as cidades, identificando a acao de "grupos de interesse" como um dos principais entraves a estruturacao e funcionamento de mecanismos de planejamento e gestao que garantam o desenvolvimento socioespacial sustentavel dessas areas. Identifica-se a apropriacao da maquina publica por esses grupos de interesse como mecanismo que instrumentaliza processos de definicao de normas de regulacao e controle do uso e ocupacao do solo e que, portanto, favorece a dinâmica de funcionamento do que se denomina, com apoio em autores classicos, de "circuito imobiliario especulativo". Demonstra-se no trabalho que o processo de incorporacao de areas rurais em Campinas, contempla fortes interesses do capital imobiliario local, em detrimento da realizacao de investimentos publicos de interesse coletivo. Os grupos imobiliarios, que tem grande poder organizacao, pressionam pela destinacao e abertura de areas na zona rural para ocupacao urbana, independentemente de sua capacidade de suporte, unindo-se nesta empreitada, tanto empreendedores imobiliarios, quanto proprietarios rurais, pelo proposito de valorizacao do seu patrimonio. Assim, os espacos rurais tornam-se objeto de um processo que pode ser visto apropriacao privada por segmentos do capital mercantil imobiliario, que e resultado da insercao de interesses particulares na definicao da regulacao do uso do solo. 
Abstract

A incorporação de areas rurais as cidades : um estudo de caso sobre Campinas, SP

There is little research regarding to tolerance of soil cover legumes to herbicides. Products that are selective to these plants and show satisfactory control of harmful plants are still scarce. This paper has the objective to evaluate the tolerance to herbicide of four legume plants. The experiment was installed in a greenhouse. The four legumes were sowed in a 2 kg plastic bag. The substratum was homogenized with two seeds of Pueraria phaseoloides, Desmodium ovalifolium, Mucuna aterrima and Mucuna cochinchinensis. The herbicides applied were 2,4-DB, in post-emergence and alachlor, imazaquin and pendimethalin in pre-emergence. The statistical experimental method used was completely randomized in a factorial experiment (4x4x5x4) with four legume species, four herbicides and five doses of each herbicide with four replications. Thirty six days after sowing, P. phaseoloides showed tolerance to the herbicides alachlor and imazaquin and susceptibility to 2,4-DB and pendimethalin. D. ovalifolium was susceptible to herbicides except the alachlor. M. aterrima showed tolerance to alachlor, imazaquin and pendimethalin and was susceptible to 2,4-DB. The herbicides alachlor and imazaquin were not phytotoxic to M. cochinchinensis. However, severe injury was observed with the use of 2,4-DB and pendimethalin.

BIOCENOSE DA ALGARONEIRA (PROSOPIS JULIFLORA (SW.) DC.) COM ÊNFASE NOS INSETOS FITÓFAGOS E SEUS PREDADORES

O objetivo deste texto é apresentar propostas de políticas, com base nas principais conclusões obtidas pelo Projeto Rurbano, que explora, fundamentalmente, os tipos de ocupações das pessoas; e as rendas das famílias residentes nas áreas rurais – agrícolas, pluriativas e não-agrícolas –, a partir dos dados das PNADs para o período 1992/99. Estamos iniciando a Fase III do referido projeto, que se prolongará até 2003, quando estaremos priorizando os estudos de caso e a análise dos dados do Censo Demográfico de 2000.

Velhos e novos mitos do rural brasileiro: implicações para as políticas públicas

Atualmente, o mercado farmaceutico dispoe de modernas drogas, como a cimetidina e a ranitidina, para o tratamento de ulcera peptica. Esta enfermidade se apresenta como uma area de escoriacao da mucosa, desenvolvida, de maneira aguda, sendo mais frequentemente localizada no estomago, mas podendo ocorrer no duodeno. A causa habitual da ulceracao peptica e um desequilibrio entre a velocidade de secrecao do suco gastrico e o grau de protecao oferecido pela barreira da mucosa gastroduodenal, bem como da neutralizacao do acido gastrico pelos sucos duodenais. (GUYTON, 1992; KOROLKOVAS, 1998; ROBBINS & COTRAN, 1983). De forma obscura, a ulcera peptica teve sua incidencia diminuida, nas ultimas decadas. Entretanto, simultaneamente a este fato, a sintomatologia resultante do quadro ulcerativo foi intensificada, provavelmente em decorrencia de uma maior exposicao a fatores que influenciam sua etiologia, tais como idade, sexo, grupo sanguineo, localizacao geografica, conflitos emocionais e competitivos, estresse, menopausa (para pacientes femininas), uso do tabaco, entre outros. (ROBBINS & COTRAN, 1983).

AVALIAÇÃO DA ATIVIDADE ANTIÚLCERA GÁSTRICA DA Egletes viscosa CASS. ("MARCELA")

This paper presents the main achievements of phases I and II of a thematic project named "Rurbano Project: Characterization of the Brazilian New Rural Sector, 1981/99", which aims at analyzing the main transformations occurring in the urban - rural relations in 11 Brazilian States. The research began in 1996 and currently is in its phase III. The phase I basically covered the types of occupation of rural residents and the phase II analyzed the income of agricultural multiple activities and non-agricultural families residing in rural areas. According to estimates, the number of rural workers and families devoted exclusively to agricultural activities has decreased rapidly, accompanied by an increase in the number of non-farming rural workers and families, that is, units where no members are engaged in agricultural activities. There was also a rapid increase in the number of rural families with unemployed and retired members. We also discuss the dynamics of occupation and income generation in the Brazilian rural areas and, finally, we propose groups of public policies that could improve the rural development, considering the new functions observed in the Brazilian rural areas. Key words: multiple activities, rural and agricultural occupations, non-agricultural activities, rural income, rural development policy.

Caracterização espectroeletroquímica da blenda polianilina (PANI)/POLI(sulfeto de fenilenamina)

• Magda Maria Marinho Almeida Quimica IndustrialUFC/CEMestre em Tecnologia de AlimentosUFC/CE. Divisao de Analises e Pesquisa da Superintendencia Estadual do Meio Ambiente-SEMACE. • Fernando Jose Araujo da Silva Engenheiro Civil UNIFOR. Mestre em Engenharia Civil , area de Engenharia Sanitaria e Ambiental-UFPB. Bolsista do CNPq • Rosa de Lisieux Urano de Carvalho Ferreira Biologa-UFC/CE.Especializacao em Saude, Trabalho e Meio Ambiente. Endereco: Rua Jaime Benevolo, 1400 B. de Fatima. Fortaleza CE. CEP. 60050-081. Fone: 085 2541866. FAX: 085 2541198. E-mail: camila@feq.unifor.br.

BALNEABILIDADE DAS PRAIAS DO LITORAL DE FORTALEZA, NORDESTE BRASILEIRO

SOBRE OS SISTEMAS LACUSTRES LITORÂNEOS DO MUNICÍPIO DE FORTALEZA

Inicialmente, a familia de ocupacoes 2614 da CBO-2002(Classificacao Brasileira de Ocupacoes) era constituida apenas de filologos,interprete e tradutores, na proposta inicial apresentada, masa discussao levou o grupo ao entendimento de que tambem os linguistasdevessem fazer parte da mesma familia, apesar de nao teremsido convidados para aquela etapa de trabalhos em que se discutiramestas definicoes.

A SITUAÇÃO OFICIAL BRASILEIRA DO FILÓLOGO E DO PROFESSOR DE FILOLOGIA NO MINISTÉRIO DO TRABALHO E EMPREGO

Repensando o recrutamento e a seleção de profissionais através da internet: o caso CEG-RJ

Entre os muitos assuntos tratados pela contabilidade no campo academico, esta a analise custo- volume- lucro, base de preocupacao constante para os administradores de empresa, devido sua a influencia direta no lucro. A combinacao dessas variaveis influencia diretamente o lucro da empresa, tornando-se indispensavel o seu controle, ja que o objetivo principal da empresa e maximizar o lucro do proprietario. As analises dessas variaveis, permitem aos administradores verificar o desempenho efetivo da empresa, de forma a medir a lucratividade , e se o realizado ocorreu de acordo com o planos iniciais da empresa. Esta seria a forma tradicional de medir o desempenho da empresa, associado a outras formas de avaliacao, como: rentabilidade do ativo, lucro por acao, valor patrimonial por acao, fluxo de caixa descontado, etc. Num outro enfoque procura-se mostrar tambem o novo conceito pela otica de custo - valor - preco, que sao os tres pilares do lucro. Por esse conceito, abordado de forma diferente, procura-se mostrar sua importância e as relacoes com os conceitos de valor agregado ou valor adicionado e as formas de distribuicao de riquezas. Por ultimo, apresenta-se a nova versao moderna do lucro, o EVA ? Economic Value Added, que significa valor economico agregado ou valor economico adicionado. Se a empresa agrega valor, o EVA sera positivo; caso contrario, sera negativo. Mostra-se ainda a formula de calculo do EVA para uma empresa e outros exemoplos, bem como algumas consideracoes sobre suas vantagens, limitacoes e problemas. Faz-se tambem uma pequena abordagem sobre o MVA- Market Value Added .

EVA (Economic Value Added) - A mais nova versão para medir o desempenho da empresa

Discovered in the Reserva A. Ducke, Manaus, Amazonas, Brazil, Sterculia duckei Taylor ex J. A. C. Silva et Μ. F. Silva, nov. sp., shows an affinity with S. pruriens differing from it by presenting stellate hairs and glands, scattered on its flowers from the apex down to the base of the calyx, lacking glandular hairs, and is recorded in the states of Amazonas and Para. This species is described and illustrated.

O presente trabalho foi conduzido em Coimbra, Mme, na "estacao chuvosa" da ano agricola dc I 995l96, para avaliar os efeitos da antecipacao da colheita, gela dessecacao quimica, c do citicirumentQ, na preseqa e ausencia ae chuva simulada sobre o rendimento e a q ua I i d ade da s sementes de tai, ao cv. Carioca. Ais 31 dias apos a florace , quando as sementes se apresentavam com 35% de uznidade, as plantas foram dessecadas cem paraquat (4(i0K ia./ha) e com mistura paraquat + diquat (250g iaiha + 150g i.aJlia). As colheitas loram realizadas aos 37, 41 e 45 dias apos a florae*. A qualidade fisiolegica das sementes aui avaliada geia teste de germinacao (TC), pela primeira contagem da TG e pele cvndutividaue eletrica, estes dois como indices de vigor. CJs tratamentos avaliados nao afetaram o rendimento das sementes. A dessecacâo quimica do feijoeiro proporcionou maiores porcentuais de sementes viaveis, independentemente cis regime de chuva simulada e do tipo de debulha realizada. O atraso na epoca de colheita reduziu o vigor idas sementes do feijao Carioca. O enleiramento de plantas prejudicou o vigor das sementes e seus efeitos foram agravados pela chuva simulada.

EFEITOS DE DESSECANTES, DA ÉPOCA DE COLHEITA, DO ENLEIRAMENTO E DA CHUVA SIMULADA NO RENDIMENTO E NA QUALIDADE FISIOLÓGICA DAS SEMENTES DE FEIJÃO / EFFECTS OF DESSICCANTS, HARVESTING TIME, WINDROWING AND SIMULATED RAINFALL ON DRY BEAN SEED YIELD AND QUALI

The present work was carried out at the Fazenda Experimental de Sooretama of the Instituto Capixaba de Pesquisa, Assistencia Tecnica e Extensao Rural - INCAPER, in Sooretama county, ES, over the period from November 22, 1996 to January 15, 1998. The soil of the area is a distrophic Yellow Red Latosol with a moderate A horizon. The objective was to study the effects of the interaction between the applied water depth and application frequencies upon the commercial production and production components of the papaya tree. A lineal growth of productivity was obtained with the increment in the applied water depth. However, it was verified that the largest productivity was obtained for irrigation frequency varying between three and five days. It was still observed that the average weight of the fruits was practically not affected by the interval among irrigations, but this effect was observed for the number of commercial fruits for plant, although both have grown with the increase of the applied water amount.

EFEITOS DE DIFERENTES LÂMINAS E FREQÜÊNCIAS DE IRRIGAÇÃO SOBRE A PRODUTIVIDADE DO MAMOEIRO (Carica papaya L.)

Blenda acrícila de polianilina para proteção à corrosão de ferro

The paper revise the difficulties encountered in measuring the problems of hunger and poverty in Brazil. The proposed methodology starts with the data for total income declared in the 1999 PNAD, adds the value estimated for the consumption of home-produced goods by agricultural families and discounts the values of rents and mortgages. The income thus obtained – denominated the available average family income per capita – is compared with the poverty line of US$ 1.08 per day adopted for the rural areas of the Northeast and corrected according to the regional costs of living indexes for the others areas of the country.

Detecção condutométrica sem contato (oscilométrica) para eletroforese capilar de zona e cromatografia micelar eletrocinética

Ate os anos 30, os problemas de abastecimento estavam associados a questao da oferta de alimentos para a populacao. Desse periodo ate o final dos anos 80, a fome passou a ser encarada como um problema de intermediacao e as politicas se voltaram para a regulacao de precos e controle da oferta. A partir dos anos 90, os problemas de abastecimento passaram a ser combatidos, supostamente, atraves da desregulamentacao do mercado na esperanca de que o crescimento economico pudesse proporcionar renda, emancipando as familias pobres e alcancando a cidadania.

We present an unusual case of thoracic constrictive arachnoiditis after pantopaque myelography, used 10 years before in the diagnosis of intradural arachnoid cyst.

Aracnoidite constritiva causada por pantopaque resultando em siringomielia e paraparesia: relato de caso

Estudo de cicloestratigrafia nos depósitos eopermianos do Grupo Itararé, Bacia do Paraná, nos Estados de Santa Catarina e Rio Grande do Sul, baseado em dados de testemunho e de perfis de raios gama

Estimativas das famílias potenciais beneficiárias de programas de assentamentos rurais no Brasil

in the context of great transformations wich organizations face today, many ideas have been proposed ini the various texts that focus on change management, trying to identify manners of dealing with difficulties and resistances that individuals and groups pose to the process. the focus of such approaches is, in general, to discover more effective ways to obtain from individuals an increasing level of effort and commitment to the change. But an important question to be consideres is: how can you get a higher level of commitment from individuals and groups without having a clearer view of what change really means to them? This paper intends to bring a better understanding to this issue, by using a participant methodology that tries to create a fertile field where the meaning of change can be more thoroughly debated by individuals involved in the process. At the same time, it uses interactive dynamics that favors a clearer manifestation of affective perceptions, as well as rational opinions about the process of change. The research was developed in an important Brazilian state-owned company in the power sector, wich is undergoing strong expectations related to an imminet process of privatization.

O significado da mudança: as percepções dos funcionários de uma empresa brasileira diante da expectativa de privatização

Os acumuladores de energia estacionarios devem ser periodicamente avaliados quanto a sua capacidade de carga, visando assegurar que sua energia acumulada podera ser prontamente utilizada, quando das falhas do sistema de alimentacao convencional. Normalmente, essas avaliacoes sao realizadas atraves dos testes de capacidade, que apresentam como principais desvantagens, o fato do banco de baterias permanecer indisponivel, durante a realizacao do teste, e o desperdicio da energia 
acumulada nas baterias. Neste trabalho a avaliada a potencialidade do metodo de espectroscopia de impedância eletroquimica como ferramenta na determinacao do estado-de-carga de baterias chumbo-acidas, atraves da analise das relacoes dos seus parâmetros eletroquimicos e sua quantidade de carga armazenada 
Abstract

Avaliação do estado de carga de baterias chumbo-acidas por espectroscopia de impedancia eletroquimica

AÇÕES DE POLÍTICAS PÚBLICAS PARA O NOVO RURAL BRASILEIRO SOB O ENFOQUE NO DESENVOLVIMENTO LOCAL

No cenario mundial atual, e crescente a preocupacao com a com servacao das florestas. Torna-se, portanto, indiscutivel a importância de se utilizar tecnicas de processamento que aumentem a resistencia e a longevidade do material madeira e que, consequentemente, venham resultar na diminuicao da pressao sobre as reservas naturais e em economia das florestas plantadas que ja apresentam preocupantes projecoes de deficit de materia-prima a medio e longo prazos.

Caracterização da prova de 400 metros livres em natação, tendo por base parâmetros técnicos e fisiológicos

Avaliação do risco de ocorrência de geadas no Estado de Santa Catarina

Os criterios para a separacao dos espacos urbano e rural tem sido questionados em razao da crescente ocorrencia no meio rural de atividades tipicamente urbanas, principalmente aquelas dos setores industriais e de servicos. Como resultado, esse corte perde relevância analitica e vem ganhando expressao, o enfoque no territorio, ou local para a formulacao de politicas. O local nao tem apenas uma conotacao fisica, mas representa um conjunto de relacoes economicas, sociais e culturais que lhe conferem caracteristicas individuais que diferenciam um local do outro. Neste trabalho, vao ser abordadas as principais politicas e tendencias que, no entender dos autores, fortalecem o local, como foco das estrategias e acoes de desenvolvimento. Entre as forcas estimuladoras desse processo, destacam-se a globalizacao, que privilegia a maior integracao socioeconomica entre regioes, a descentralizacao da administracao publica, as novas formas e mecanismos de gestao dos recursos naturais e a organizacao dos atores sociais, que garante a democratizacao das acoes de desenvolvimento local. Por fim, sao apresentadas propostas com o objetivo de incorporar as caracteristicas e tendencias discutidas nas iniciativas de desenvolvimento rural. LOCAL DEVELOPMENT AND DEMOCRATIZATION OF RURAL TERRITORY ABSTRACT Current criteria to separate urban from rural areas have been put in check because of the increasing incidence of typically urban activities in the rural milieu, especially those of the industrial and service sectors. As a consequence of this changing, the focus on the territory or the local has acquired importance and gave rise to new prospects for local development. The local is not defined on the basis of physical characters, but on all the specific social, economic and cultural relations, which differentiate each local from the others. In this paper we present the major policies and tendencies that we believe support the local on the premises for tactics and actions of rural development. Within the forces driving this process, emphasis is placed on globalization, which intensifies socio-economic integration among countries; decentralization of public administration; approaches and mechanisms for natural resource management; and organization of social actors, which assures the democratization to local development initiatives. Lastly, proposals are presented to incorporate those attributes and tendencies in rural development programs.

O presente estudo apresenta uma avaliação inicial da expansão da área urbana nas sub-bacias do Rio Tintiba e Córrego do Catonho através da fotointerpretação, acompanhada de uma proposta classificação do uso do solo..............

Análise da expansão urbana e das modificações no uso do solo nas sub-bacias do Rio Tintiba e do Córrego do Catonho, Jacarépagua, RJ e suas implicações sobre a erosão do solo

Europa dos medicamentos: objectivos sociais e interesses industriais

Todos nos temos, no correr de nossas vidas, momentos marcantes. Momentos que se erigem em simbolo de uma existencia, precisamente porque refletem, em si, a singularidade de uma personalidade, e sua propria realizacao, e denota a terceira dimensao do homem que Cassirer descreve como o sistema simbolico, porque nao se esta mais no universo meramente fisico, mas no universo simbolico, nao do homem apenas como animal racional, mas do homem simbolicum. E com esse pensamento, Senhor Presidente, que recebo o Colar do Merito Judiciario, que esse Tribunal me outorga. Aqui destaco que este e um momento marcante em minha vida, simbolico para mim, porque me foi conferido, ainda na gestao do Eminente Desembargador Dirceu de Melo, a quem saudo neste instante, ou seja, logo apos deixar a Secretaria de Seguranca Publica do Estado de

Discurso proferido pelo Prof. José Afonso da Silva por ocasião do recebimento do colar do mérito judiciário

O progresso tecnico na agricultura mineira: resultados e contradicoes da politica de modernizacao da decada de setenta

Separação de cátions metálicos dos grupos IA e IIA em presença de grande quantidade de sódio por eletroforese capilar com detecção oscilométrica

Microbiota fúngica e ocorrência de micotoxinas em grão de sorgo recém colhido e armazenado

We present two cases of mutism observed after resection of tumors of the cerebellum, in two children of the feminine sex, being in the first case of medulloblastoma and in the second of juvenile astrocytoma. In both patients there was pre-operative lesion of low cranial nerves. The pathophysiology of the mutism involves anatomical, vascular and emotional factors, being its essential characteristics discussed with base in revision of the literature.

I - Introducao. 2 - Cidadania e seus direitos. 3 - Acesso a Justica. 4 - Justica igual para todos. 5 - Acesso a Justica e organizacao judiciaria. 6 - Pontos da reforma judiciaria. 7. Conclusao.

1. Para Cappelletti todas as manifesta95es da justi9a constitucional podem reduzir-se a fungao de tutela e atuacao judiciaria dos preceitos da suprema lei constitucional. Para Hector Fix Zamudio, «a denominagao de jurisdigao constitucional deve reservarse, em sentido proprio, aos instrumentos de garantia ou de justiga constitucional que se conferem a organismos judiciais estritamente considerados, e com maior rigor ainda, quando os mesmo possuem carater especializados, isto e, quando sao tribunais constitucionais». 2. Para nos, a jurisdigao constitucional, em sentido estrito, consiste na entrega, aos orgaos do poder judiciario, da missao de solucionar os conflitos entre aos normas juridicas ordinarias (e complementares) e a constituigao. E, mais amplamente (sentido proprio), e a entrega ao poder judiciario da missao de solucionar conflitos constitucionais. E nesse sentido ampio que Frederico Marques, sempre com sua larga visao juridica, concebe a jurisdigao constitucional: «aplicac,ao de normas constitucionais pelo poder judiciario, a fim de compor conflitos litigiosos de interesse», e con-

Observação remota aérea da pluma de água turva na zona costeira da Barra da Ria de Aveiro

Trata-se de uma abordagem inovadora a respeito da agricultura familiar no Brasil, em que o autor demonstra grande conhecimento da realidade brasileira, fruto de profunda pesquisa de campo. Diante da progressiva desestruturacao das familias rurais que migram para as periferias das cidades, o autor conseguiu analisar o fenomeno a partir de uma perspectiva bastante moderna e original.

A PLURIATIVIDADE DA AGRICULTURA FAMILIAR NA INTEGRAÇÃO ENTRE O MEIO RURAL E O MEIO URBANO

MetodosOitenta e oito atletas (62 homens) que representaram o Brasil nos Jogos Olimpicos de Seul em 1988 dentro do Projeto SEUL/COB/AMIL. Foram analisados os seguintes fatores de risco: historia familiar de cardiopatia isquemica, hipercolesterolemia (colesterol-total e subfracoes), hipertensao arterial, intolerância a glicose, tabagismo e hipertrofia ventricular esquerda (HVE). As medias de colesterol-total, HDL-colesterol e da relacao colesterol-total/HDL-colesterol dos atletas masculinos e femininos foram comparadas pelo teste-t de Student para amostras independentes. A distribuicao da prevalencia do numero de fatores de risco por sexo foi analisada atraves do qui-quadrado.

I. Introducao a lei no tempo. I - ESTABILIDADE DOS DIREITOS SUBJETIVOS: 2. Seguranca das relacoes juridicas e lei no tempo. 3. Direito adquirido. 4. Ato juridico perfeito e direito adquirido. 5. Coisa julgada. II- NORMA CONSTITUCIONAL E DIREITO ADQUIRIDO. 6. Questao de ordem. 7. Poder constituinte originario e direito adquirido. 8. Poder de reforma e direito adquirido. 9. Norma de garantia e direito garantido. 10. Conclusao.

O objetivo do presente trabalho consiste em evidenciar o mecanismo de hedge em uma empresa produtora de ouro, utilizando variaveis contabeis, como Patrimonio liquido, Receita, Custo, Lucro bruto, Lucro operacional e Lucro liquido, resultando na apuracao de indicadores de margem de custo, margem operacional, margem liquida e rentabilidade do patrimonio liquido, que servirao de referencia para analise a que se pretende. No caso da industria de mineracao de ouro, as operacoes de hedge se fazem presentes dia-a-dia, onde as grandes empresas produtoras de ouro como Barrick Gold, Newmnont, Anglo American, Newcrest, WMC,etc., utilizam este mecanismo de forma a se defender contra as oscilacoes nos precos, provocadas pela instabilidade do mercado. Mostra-se ainda influencia do hedge na receita, custo, margens e sua contribuicao no lucro da empresa, enfocando a relacao entre essas variaveis, atraves de simulacoes (com premio e sem premio), mantendo-se os custos constantes.

O MECANISMO DO HEDGE E SEUS EFEITOS NA RECEITA, CUSTO, MARGENS E SUA CONTRIBUIÇÃO NO LUCRO DA EMPRESA ( INDÚSTRIA DO OURO)

Two cases of isolated fourth ventricle are reported, the first due to cerebellar haemorrhage, and the second due to congenital hydrocephalus with multiple shunt revisions and Dandy-Walker cyst. In our opinion, there are two basic treatment for isolated forth ventricle. The direct approach to the fourth ventricle is indicated when there is presence of an intraventricular cyst. The fourth ventricular shunting, independent of the supratentorial shunt, is the best treatments for patients with an isolated fourth ventricle without the presence of a cyst.

Uma proposta para utilização do computador no processo de ensino e aprendizagem dos primeiros números do sistema hindu-arábico

Analysis of nine patients with intracranial arachnoid cysts surgically treated from 1974 to 1995. The treatment consisted of cystoperitoneal shunt in seven patients and craniotomy with excision of cyst membrane in the other two cases. After surgery, bacterial meningitis and failure shunt device were observed in three cases. Both the infectious process and the shunt device were respectively treated and corrected at once. It has been observed total clinical improvement in all nine cases. A review of the literature has been made and some pathophysiological, diagnostic and therapeutic aspects are discussed.

1. Fundamento constitucional - 2. Pessoa humana - 3. Dignidade - 4. Protecao constitucional da dignidade humana - 5. Natureza da dignidade tutelada - 6. Conclusao.

Inserção internacional e financiamento da agricultura brasileira (1980-1996)

A evolução do emprego não agrícola no meio rural brasileiro - 1992-95

Caracterização do processo de dopagem secundária de polianilina por espectroscopia raman

Microbiota fúngica e ocorrência de micotoxinas em grãos de sorgo recém-colhido e armazenado no Brasil

O proposito deste texto e chamar a atencao para o que ha de novo no meio rural brasileiro. Procuramos mostrar algumas dessas dimensoes para o Brasil a partir dos dados das PNADs para 1981 e 1990. Concluimos que ja nao se pode caracterizar o meio rural brasileiro somente como agrario. E mais: o comportamento do emprego rural, principalmente dos movimentos da populacao residente nas zonas rurais, nao pode mais ser explicado apenas a partir do calendario agricola e da expansao/retracao das areas e/ou producao agropecuarias. Ha um conjunto de atividades nao-agricolas - tais como a prestacao de servicos (pessoais, de lazer ou auxiliares das atividades economicas), o comercio e a industria - que responde cada vez mais pela nova dinâmica populacional do meio rural brasileiro.

Agricultura, meio ambiente e sustentabilidade do cerrado brasileiro

O autor analisa as mudancas na distribuicao espacial e domiciliar da populacao do Estado do Mato Grosso, nas duas ultimas decadas. Vincula-as as transformacoes ocorridas nos padroes de ocupacao economica e de incorporacao dos varios espacos ao sistema economico nacional. Identifica padroes de localizacao bastante distintos, em sua genese e em seu curso, entre os varios subespacos mato-grossenses. Na maioria dos casos, porem, desses diferentes padroes resultaram deterioracao da capacidade de retencao populacional no campo e ate mesmo, principalmente na parte sul do Estado, forte liberacao da mao-de-obra outrora no setor primario. Nos anos 80, apenas a parte noroeste do Estado ainda se caracterizava como sendo uma area de prevalencia e atuacao de alguns fatores de atracao e retencao migratoria nos quadros rurais. 
 
The author analyses changes in the spatial distribution of Mato Grosso State's population in the last two decades. He associates such changes with transformations in the patterns of both economic occupation and absorption of the distinct spaces by the national economic system. He also identifies quite distinct localization patterns, both in their origin and in their development, among the various sub-regions in Mato Grosso. In most of the cases, however, these distinct patterns deteriorated the capacity of retaining population in the countryside and also, mainly in the south of the State, liberated workers previously employed in the primary sector. In the 1980s, only the Northwest of the State could be still characterized as an area of migration attraction and retention of rural population.

Dimensões da Indecisão da Carreira : Investigação com Adolescentes

Esta dissertacao apresenta as caracteristicas gerais da industria de mineracao e as especificidades da industria do ouro. Sao apresentados os diferentes tipos de depositos e de processos de producao, atraves dos quais o ouro e produzido, buscando ilustrar as variacoes que os elementos do custo de producao podem ter para cada situacao. Alem disso, sao apresentadas as principais variaveis endogenas e exogenas que influenciam o mercado, provocando oscilacoes nos precos. Em seguida, atraves dos dados dos balancos (ativo e passivo) e demonstrativos de resultados, e feita a analise economico-financeira comparativa para o periodo 1991-1995, de cinco empresas: Barrick Gold Corporation(Canada), Elandsrand Gold Mining Limited (Africa do Sul), Mineracao Morro Velho Ltda. (Brasil), Newcrest Mining Limited (Australia) e Newmont Mining Corporation (Estados Unidos), empresas que se dedicam exclusivamente a mineracao de ouro em paises com certa tradicao. Foram realizadas a analise convencional (vertical e horizontal) , tendo como referencia os indicadores de vendas brutas, custos, lucro liquido, liquidez corrente, grau de endividamento, rentabilidade do patrimonio liquido, retomo dos investimentos, margem operacional e margem liquida e a analise pelo modelo Fleuriet que enfoca o capital de giro, as necessidades do capital de giro, o saldo de tesouraria e o "efeito tesoura" . O estudo aponta em seu desenvolvimento que, das empresas selecionadas, o destaque de melhor desempenho, no aspecto economico e financeiro, esta associado a combinacao de baixo custo operacional e reservas com alto teor, caracteristicas intrinsecas ao deposito mineral e a existencia de programas de hedge para protecao contra as instabilidades adotada pela administracao da empresa. 
Abstract

Análise econômico-financeira comparativa de empresas produtoras de ouro

A questão regional na Argentina : origens, revisão critica do papel do estado no tratamento do problema e dilemas para o futuro

Antes de mais nada e preciso reconhecer que o Dr. Eliseu Alves continua sendo um grande estimulador de debates sobre temas relevantes da nossa agropecuaria. Nossos comentarios ao seu artigo obedecerao a sequencia com que os principais temas foram apresentados no texto original.

The authors report a case of cruciate hemiplegia associated with basilar impression, Chiari malformation and syringomyelia. The neuroanatomical controversy, the surgical treatment and the good outcome of the patient are discussed.

Hemiplegia cruzada associada a impressão basilar, malformação de Arnold-Chiari e siringomielia: relato de caso

O uso de instrumentos de trabalho de propriedade de terceiros, na execucao dos trabalhos agrarios, foi praticado em cerca de um milhao de estabelecimentos rurais, no Brasil, em 1985. A dispersao e evolucao das principais formas de acesso aos instrumentos de trabalho de terceiros foi avaliada atraves de tres Indices de Terceirizacao, calculados a partir das informacoes dos Censos Agropecuarios de 1980 e 1985, relativas as Grandes Regioes, estados, grupos de area total dos estabelecimentos rurais e tipo de trabalho agrario. Pelos resultados considera-se que a "terceirizacao parcial" constitui-se na denominacao que melhor complementa a caracterizacao do atual estagio da organizacao da producao agricola brasileira. Sobretudo, pela desigual incidencia, conjunta, das praticas de aluguel de forca de tracao e empreita de servicos que envolvem o emprego de maquinas e equipamentos, dado que foi relativamente mais concentrada na Regiao Centro Oeste e, em termos absolutos, nos estados de Minas Gerais, Parana e Bahia. Verifica-se que, tanto em termos absolutos como relativos, o uso temporario de instrumentos de trabalho de terceiros concentrou-se nos estabelecimentos de menor area total, no preparo do solo e na colheita. Essa ampla incidencia de unidades agricolas semi-estruturadas, em termos de instrumentos de trabalho, permite questionar a aplicabilidade de algumas concepcoes da economia politica, relacionadas com a transformacao da agricultura. Para tanto, avaliou-se alguns aspectos microeconomicos associados a decisao de suprimir, parcial ou totalmente, a funcao de reproducao do capital imobilizado em maquinaria pelo agricultor. Isto e, discute-se as implicacoes advindas da entrada de um terceiro tipo de agente economico, o prestador de servicos e proprietario dos instrumentos de trabalho. Nessa avaliacao, considerou-se a reducao dos custos operacionais: a importância do risco de safra para a estimativa do custo de oportunidade associado ao adiantamento de capital em maquinaria agricola; a reducao no montante do capital adiantado: a suplantacao da disparidade entre o tempo de producao e o de trabalho; e, a flexibilidade das unidades agricolas inseridas no mercado dos produtos das lavouras temporarias. Complementa a analise dos fatores associados a terceirizacao da execucao dos trabalhos agrarios a descricao, sumaria, do processo de producao agricola e do atual conjunto de inovacoes motomecânicas, assim como das politicas publicas dirigidas a agricultura, neste ultimo terco do seculo. A abordagem das politicas agricolas foi efetuada 
tendo-se como referencia de fundo a expressao empirica cio produtor simples de mercadoria (PSM), na producao de soja/trigo situada na regiao de modernizacao intensiva do estado do Parana. A coexistencia, na moderna producao de soja/trigo, de unidades de producao superavitarias e unidades de producao deficitarias quanto a capacidade operacional, que se inter-relacionam pela compra e venda de partes da vida util da maquinaria agricola, contudo, e visualizada como transitoria, na medida que a terceirizacao congrega dois movimentos distintos: o de diferenciacao economica e o de decomposicao social da categoria PSM. Prospectivamente, dado o continuo deslocamento da fronteira tecnologica, vislumbra-se a expansao desse processo de dissociacao entre a concentracao de capital fundiario e de acumulacao de capital na producao agricola e, consequente conformacao da producao agricola em rede. 
 
Abstract

A terceirização na agricultura : a dissociação entre a propriedade e o uso dos instrumentos de trabalho na moderna produção agricola paranaense

The autors report a case of acute neurogenic pulmonary edema in a 28-year-old woman who presented rupture of an internal carotid artery aneurysm and subarachnoid hemorrhage. The respiratory disorders started at the same time the patient's symptomatology aggravated. Some etiological and pathophysiological aspects on neurogenic pulmonary edema are revised.

A formacao de precos dos produtos agricolas: notas para discussao de uma abordagem alternativa

A formação de preços de produtos agrícolas: notas para uma discussão de uma abordagem alternativa

Polarografo tast de baixo custo para uso didatico, com operacao manual ou por microcomputador

To estimate the tolerance of three onion (Allium cepa L.) cultivars (Baia Periforme Super Precoce, Granex Ouro and Texas Grano 502 PRR), cultivated under direct drilled system, to Ioxynil and Oxyfluorfen, and the efficiency of these herbicides in weed control a trial was installed in Vicosa, State of Minas Gerais, Brazil. Three rates of each herbicide (0.125, 0.250, 0.372 kg/ha and 0.096, 0.192, 0.288 kg/ha) were applied 27 days after drilling, in a nested factorial design with four replications. Ioxynil was more selective than Oxyfluorfen, specially at higher rates. The lowest rate of Ioxynil did not provide effective control of most weeds present. Baia Periforme Super Precoce cultivar was more tolerant in relation to Texas Grano 502 PRR. The susceptibility of Texas Grano 502 PRR to Oxyfluorfen was expressed by significant decreases in final onion plant population and bulb yield.

Tolerância de três cultivares de cebola ao Ioxynil e Oxyfluorfen em semeadura direta

O exame psicologico e o cerne da actividade do psicologo clinico e a utilizacao das tecnicas projectivas constitui, seguramente, o seu momento mais fecundo. Todavia, para se atingir o objectivo a que nos propomos compreender a realidade psicologica do sujeito, a sua singularidade e necessario ter-se em conta uma serie de factores parasitas, como os que decorrem do contexto em que e efectuado o exame psicologico. E, ainda, necessario garantir uma conceptualizacao teorica precisa que determine a atitude do psicologo face ao examinando, que apoie com fiabilidade a interpretacao dos dados e que defina as regras de observacao e de intervencao, uma metodologia que suporte o raciocinio clinico, auxiliando a formular o(s) problema(s) e presidindo A escolha adequada das tecnicas de abordagem da personalidade, se tal for o caso. Concebido desta forma, o percurso da intervencao psicologica garante uma sintese integrativa coerente e rigorosa do ponto de vista metodologico, evitando-se o labirinto interpretativo eclectico e a generosidade semântica.

It is difficult to obtain an efficient mechanical and chemical control of wormwood (Artemisia verlotorum) because this weed has a great capacity to sprout and is tolerant to most herbicides. Natural areas infested with wormwood were treated with glyphosate and 2,4-D. Glyphosate was more efficient than 2,4-D on wormwood control. The application of 2,4-D did not cause significant differences on wormwood control 90 days after treatment. However, the glyphosate had prolonged effect, decreasing the number of living plants until 90 days after its application. Intermediary rates were more effecient than higher rates on wormwood control. Higher values of all studied characteristics of wheat crop were obtained with intermediary rates of both herbicides. Higher yield of wheat (3787 kg/ha) were obtained when 0,721 kg/ha of glyphosate associated with 1,152 kg/ha of 2,4-D was applied.

Aspectos juridicos do cooperativismo e das cooperativas de habitações no brasil

Circulação da água na Ria de Aveiro, contribuição para o estudo da qualidade da água

Modernização e diferenciação na bovinocultura de corte brasileira

A impressao basilar e malformacao frequentemente observada no Nordeste do Brasil. No periodo de 1971 a 1992 foram operados, em nosso Servico, 260 pacientes com malformacoes occipitocervicais, sendo 29 (11,1%) casos de impressao basilar pura, 18 (6,9%) com malformacao de Arnold-Chiari e 213 (81,9%) com impressao basilar associada a malformacao de Arnold-Chiari. Sao relatados os achados cirurgicos do plano osseo, da dura-mater, do tecido nervoso e dos vasos da fossa posterior.

Achados cirúrgicos em 260 casos de impressão basilar e/ou malformação de Arnold-Chiari

Adequação da força de trabalho rural na moderna agricultura da região de Ribeirão Preto

It is difficult to obtain an efficient mechanical and chemical control of wormwood (Artemisia verlotorum) because this weed has a great capacity to sprout and is tolerant to most herbicides. The rate of 1,662 kg/ha of 2,4-D reduced the number of living plants from 34 to 6 after 30 days application. However, glyphosate (0,856 kg/ha) reduced the number of living plants from 27 to 10 in field conditions. After 60 days application, the number of living plants was reduced from 34 to 18 by 0,811 kg/ha of glyphosate. However, no differences were found for application rates of 2,4-D at the same conditions. None of treatments showed satisfactory performance in relation to wormwood after 90 days application in field conditions. In greenhouse, glyphosate treatments reduced rhizome sprout, though, no differences were found for application rates of 2,4-D. The rates of 1,0 and 0,865 kg/ha of glyphosate resulted in lower dry matter weigth of aerial part of the wormwood and its rhizomes, respectively. Leaf area was reduced with glyphosate (0,983 kg/ha) at the same conditions.

Efeito do 2,4-D e do glifosate no controle da parte aérea e dos rizomas da losna

Desenvolvimento sustentavel : uma abordagem para as questões ambientais da Amazonia

Propostas de politica economica para a agricultura brasileira : (1960-1990)

ABSTRACTChemical control of wormwood in no -tillage wheat It is difficult to obtain an efficient mechanical andchemical control of wormwood (Artemisia verlotorum) be -cause this weed has a great capacity to sprout and is tolerantto most herbicides. Natural areas infested with wormwoodwere treated with glyphosate and 2,4 -D. Glyphosate wasmore efficient than 2,4 -D on wormwood control. The appl i-cation of 2,4 -D did not cause significant differences onwormwood control 90 days after treatment. However, theglyphosate had prolonged effect, decreasing the number ofliving plants until 90 days after its application. Intermediaryrates were more e ffecient than higher rates on wormwoodcontrol. Higher values of all studied characteristics of wheatcrop were obtained with intermediary rates of both herbi -cides. Higher yield of wheat (3787 kg/ha) were obtainedwhen 0,721 kg/ha of glyphosate associated with 1,152 kg/haof 2,4 -D was applied.Additional index words: perennial weeds, systemicherbicides, Artemisiaverlotorum.

du expert en ABSTRACT The author deals in this paper with the specific features of the psychological evaluation in the penal

Tolerâcia do alho (Allium sativum CV. gigante roxão) ao oxyfluorfen

Esta tese analisou o comportamento da economia no Nordeste, tomando por base a intervencao do Estado no periodo 1960 a 1980. Neste intervalo de tempo, o PIB cresceu a taxa media de 6,3%, provocando importantes transformacoes na economia da regiao: industrializacao e significativa escansao de sua intra-estrutura socioeconomica. No entanto, o processo de modernizacao da agricultura discriminou a maior parte do territorio nordestino, beneficiando quase que somente uma estreita faixa de terra compreendida pelo litoral, zona da mata e tabuleiros costeiros. Nos Estados mais ao Norte: Maranhao, Piaui, Ceara e Rio Grande do Norte, as areas onde se explora agricultura moderna sao verdadeiros oasis e se localizam em torno das capitais dos Estados e nas serras umidas. As condicoes de vida da populacao nao melhoraram significativamente, o Nordeste continuou sendo o maior bolsao de pobreza do Pais. As secas periodicas permaneceram gerando milhares de flagelados. A SUDENE, que ate 1964 era a esperanca para resolver os grandes problemas do Nordeste, transformou-se em mais uma agencia governamental - que cresceu exageradamente em termos de organizacao burocratica com acao de impacto apenas no que diz respeito a administracao dos incentivos fiscais 
Abstract

A SUDENE e o desenvolvimento agricola no nordeste no periodo 1960 a 1980

1. Introdução. 2. Conceito de eficácia e aplicabilidade. 3. Conceito de normas constitucionais. 4. Estrutura das normas constitucionais. 5. O problema da eficácia e da aplicabilidade das normas constitucionais. 6. A tríplice característica das normas constitucionais quanto à eficácia e aplicabilidade. 7. Normas constitucionais de eficácia plena. 8. Normas constitucionais de eficácia contida. 9. Normas constitucionais de eficácia limitada. 9.1. Normas constitucionais de princípio institutivo. 9.2. Normas constitucionais de princípio programático. 9.2.1. Conceito. 9.2.2. Localização das normas programáticas. 9.2.3. Normas programáticas e direitos sociais. 9.2.4. Normas programáticas e fins da ordem econômica e social. 9.2.5. Normas programáticas e princípios constitucionais. 9.2.6. Normas programáticas no sistema constitucional brasileiro. 9.2.7. Natureza dos direitos sociais. 9.2.8. Juridicidade. 9.2.9. Função e relevância. 9.2.10. Normas programáticas e regime político. 9.2.11. Normas programáticas e interpretação do Direito. 9.2.12. Normas programáticas e constitucionalidade das leis. 9.2.13. Normas programáticas e leis anteriores incompatíveis. 9.2.14. Condições gerais de aplicabilidade. 10. Instrumentos da eficácia constitucional.

Modernização, relações de trabalho e poder : um estudo das transformações recentes na agroindustria canavieira do Nordeste

14.00 Acutely conscious of the necessity of a real evaluation as to the historical and institutional process of aggression against the environment in our territory, the author addresses this article to all those who are interested in an environmental law. His idea is to compose a panel indicating the position of the municipality before the new fields (green, why not?), now open to law and to Public Administration. Normal 0 21 false false false PT-BR X-NONE X-NONE /* Style Definitions */ 
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O interesse maior que nos levou a realizacao dessa tese foi desvendar a logica mais geral da recriacao da parceria na agricultura irrigada do Nordeste, buscando entende-la, enquanto relacao de trabalho, dentro dos marcos de referencia da organizacao do trabalho na agricultura capitalista. Na conformacao do nosso objeto de estudo tomamos como pressuposto basico que a agricultura irrigada se constitua, em geral, numa atividade altamente tecnificada explicitando-se pelo seu carater de exploracao intensiva tanto em terra quanto em capital. Diante disso, o processo de trabalho tende a assumir formas mais evidentes de desqualificacao, principalmente pelas possibilidades que metodos de irrigacao apresentam a automacao do trabalho. No limite, a irrigacao permite, inclusive, atingir o ponto de prescindir do proprio trabalhador. De posse desse referencialp elaboramos como hipotese central que a parceria, pelo seu carater de transitoriedade e flexibilidade, tinha a sua presenca na agricultura irrigada do Nordeste relacionada a configuracao de um estagio de insuficiencia das forcas produtivas. Apos analisarmos as condicoes de ocorrencia da parceria em algumas experiencias de irrigacao no semi-arido nordestino, nos detivemos na regiao do Baixo-Acu, no Estado do Rio Grande do 
Norte. A conclusao mais geral a que chegamos e que a parceria se impoe porque o proprietario nao consegue o patamar necessario para estabelecer um processo especificamente capitalista baseado no trabalho assalariado. E que, no limite, a superacao desse 
estagio de insuficiencia das das forcas produtivas fica posta com a "automacao informatizada" 
Abstract

O dominio do processo de trabalho na agricultura irrigada do nordeste : a persistencia da parceria

Existe um amplo consenso em âmbitos empresariais, governamentais e academicos sobre a competitividade internacional do Complexo Florestal (reflorestamento e producao de celulose e papel); tambem citado como exemplo de dinamismo, em plena crise economica, e arquetipo de otimas relacoes de parceria com o Estado. Este trabalho propoe uma interpretacao sobre a constituicao do Complexo Florestal no Brasil, procurando identificar os principais fatores que contribuiram historicamente na sua configuracao estrutural e na determinacao da sua dinâmica. Da contribuicao de alguns autores neocorporatistas extraem-se elementos importantes para entender o processo de operacionalizacao das politicas publicas, e sugestoes para seu tratamento endogeno na analise economica...Observacao: O resumo, na integra, podera ser visualizado no texto completo da tese digital 
Abstract

Da industria de papel ao complexo florestal no Brasil : o caminho do corporatismo tradicional ao neocorporativismo

A tese demonstra que, a partir da segunda metade dos anos 60, houve uma politica agroindustrial no Brasil. Essa politica de modernizacao da agroindustria processadora permitiu estabelecer um novo elo junto a agricultura e ao setor a montante da mesma, dando uma forma definitiva ao que denominamos o grande Complexo Agroindustrial. A base dessa politica foram os fundos de financiamento, a principio indiscriminados para toda a agroindustria e, mais tarde, com a crise fiscal do Estado especificos para cada setor. O desenvolvimento da agroindustria processadora no periodo recente seguiu a conjugacao de dois elementos: a determinacao do Estado em promover setores da agroindustria e, a organizacao destes interesses setoriais e seu relacionamento com as agencias governamentais na elaboracao de suas politicas. Para entender como se deu a formulacao e implementacao destas politicas tomamos como base o enfoque neocorporatista. Tendo como referencial teorico esta abordagem, analisamos tres setores que consideramos caracteristicos desta politica agroindustrial: oleos vegetais, sucro-alcooleiro e celulose e papel 
Abstract

A incidencia da esquistossomose no Brasil continua alta, atingindo cerca de 10% da populacao. Desde o primeiro relato da neuroesquistossomose (NE) em nosso pais, ha mais de 4 decadas, seu comparecimento na literatura nacional tem mostrado acrescimo significativo. O presente trabalho tem como substrato o estudo de 5 casos de NE medular. Estes casos foram avaliados sob o ponto de vista clinico-laboratorial e submetidos a tratamento medicamentoso. Alem disso, e nosso proposito incentivar a pesquisa de novos casos, em portadores de quadros sugestivos desta patologia, sobretudo pelos resultados obtidos neste estudo.

Neuroesquistossomose medular avaliação clínico-laboratorial de 5 anos

Os autores descrevem sobre a Lei n.8080/90 e os criterios sobre os artigos da lei. Boa parte do que se propoe neste trabalho pode ser implementado na regulacao da lei. A ambivalencia da lei faculta nao so esse entendimento como tambem as transferencias venham a ser transparentes, regulares e automaticas. A transferencia pode ser assegurada atraves dos colegiados setoriais. Aregularidade depende, de vontade politica. E o automatismo decorrera da dispensa das exigencias de assinaturas de convenios e da analise de progrmas e projetos como pre-condicao para a definicao das cotas de cada unidade federada, na medida em que estas cotas sejam estabelecidas, exclusivamente, pela aplicacao de criterios

O financiamento da descentralizaçäo dos serviços de saúde: criterios para transfêrencias de recursos federais para estados e municipios

In order to test doses of metribu zin (0,0; 0,35; 0,70 and 1,05 kg a.i.ha 1) in weed control and yield of soybe an (Glycine max (L.) Merri ll, Uberaba), an experiment was conducted under field conditions in a clayey red yellow podzolic soil with 2,9% organic matter at Vicosa, MG, during the 1985 /86 growing season. Most of the monocotyledqns species present in the experimental area consisted of Cyperus rotundus L., Brachiaria plantaginea (Link) Hitch and Cynodon dactylon (L.) Pers. Reduction observed was only for Brachiaria plantaginea as metribuzin doses increased, the sa me occuring with dycot iledons species existent in the area except for Oxalis oxypt era Prop. wich was not controlled by the doses using. The avera ge of the tota l weed density minus Cyper us rotundus, Oxalis oxyptera and Cynodon da+-ylon was 141, 124, 62 and 59 plants.m2 for 0,0; 0,35; 0,70 and 1,05 kg a.i.ha-1 metribuzin, respectively. The lowest dose of metri buzin (0,35 kg a.i.ha-1) was as sufficient to promote reduction on weed shoot biomass at the highest did (1,05 kg a.i.ha-1). However, the mean of the total weed density was drastically recuded in the doses of 0,70 and 1,05 kg a.i.ha-1. The metribuzin caused damage to soybean plants at highest dose (1,05 kg a.i.ha-1) employed with a slight leaf injury '(chlorosis) until 25 days after emergence. After this period it was observed a total recovery of the plants treat ed with this dose. The yield and the harvest index were not affected by doses of metribuzin.

Efeito do metribuzin no controle das plantas daninhas e na produção de grãos em Glycine max (L ) merrill

Dois experimentos foram instalados em Vicosa, MG, em 1984/85 e 1985/86, compreendendo os seguintes tratamentos: manutencao da cultura do caupi ( Vigna unguiculata (L.) Walp.) em competicao com plantas daninhas durante 12, 24, 36, 48 e 60 dias apos a emergencia da cultura, eliminando-se em seguida as plantas invasoras; e permanencia da cultura livre da competicao durante 12, 24, 36, 48 e 60 dias, deixando, em seguida, que as plantas daninhas crescessem livremente. Acrescentaram-se, alem disso, mais dois tratamentos: ausencia da competicao com plantas daninhas durante todo o ciclo do caupi e competicao durante todo o ciclo. No ultimo tratamento, a densidade de plantas invasoras atingiu cerca de 800 por m 2 , representando 17 especies (no primeiro experimento) e 16 especies (no segundo), tanto de folhas estreitas como largas. Verificou-se que o periodo critico de competicao ocorre da emergencia do caupi ate 36 dias depois. A flora invasora, quando nao controlada, pode diminuir o rendimento da cultura de 70 a 90%. A competicao diminuiu o indice de colheita e aumentou a altura das plantas de caupi e seu acamamento.

Período crítico de competição entre plantas daninhas e a cultura do caupi

Development, assimlate partition and dry matter production in soybean (Glycine Max (L.) Merri ll, cv. Uberaba) plants treat ed with four metri buzin doses (0,0; 0,35; 0,70 and 1,05 kg i.a.ha-1) were studied in a field experiment. Metribuzin did not reduce the stand or alter ed significantly shoot /root ratio. Plants height average incre ased as the doses of metribuzin increased; maximum heights were 761, 784, 815 and 812 mm, for increasing metribuzin doses. Metribuzin did not alter the pattern of sequential dry matter partition in the plants. Metribuzin did not affect dry matter accumulation in pods (Wv); however, from initiation to the end of maturation of seeds the control presented greater Wv values than trea plants, due to its highest net assimilation rate after blooming. Pericarp dry matter (Wp) was decre ased from full development se eds to final harvest for all treatments, except for Wp of plant streated with 0,7 i.a.ha-l that was maintained practically. Constant on the other hand, seed dry matter increased accentuately, from formation to last harvest, for all doses employed.

Desenvolvimento, partição de assimilados e produção de matéria seca de plantas de soja (Glycine max (L.) merrill) submetidas a quatro doses de metribuzin

O crescimento e a eficiencia na conversao da energia solar foram estudados em soja (Glycine max (L.) Merri ll, cv. 'Uberaba'), cultivada em condicoes de campo, sob quatro doses de metribuzin (0, 0,35; 0,70 e 1,05 kg i.a.ha-1). O valor maximo da conversao da energia solar foi de 0,75%, para as plantas cultiva das na maior dose do herbicida. Os valores da conversao da energia solar media durante o ciclo da cultura foram 0,32 ; 0,31 ; 0,32 e 0,33%. em ordem crescente de dose do metribuzin. De modo geral, na fase vegetativa as plantas controle apresentaram valores inferiores em todos os valores de crescimento determinados, superando as tratadas com metribuzin somente na fase reprodutiva, mostrando que no periodo critico de competicao o dano causado pelas plantas daninhas e maior que a possivel fitotoxicida de causada pelo metribuzin.

Efeito de doses de metribuzin no crescimento e na conversão da energia solar em plantas de soja (Glycine max (L .) merrill)

The productivity growth due to technological adoption within the social relations of classes in capitalist systems is discussed. The relations between capital (private and social) and labor (working and non-working time) in agriculture and industry are analysed. Afterwards, attention is given to the especificities of the technical advancement in the primary sector, in which the biological processes, the natural conditions and the land as a production factor have their own particularities, turning the agricultural production processes into continuous, linked, interactive and restricted to specific conditions. At last, the role of technological innovations in agriculture is considered as to four innovations fields: mechanical, physical-chemical, biological and agronomic.

The aim of this article is to present an alternative methodology to calculate real exchange rate indexes. A brief discussion on real exchange rate and export competitiveness is introduced, including an evaluation of the most usual measures that have been used up to now. Then, the authors develop a multisector model to derivate an index of domestic prices of tradeable goods, which is applied to the Brazilian case. Finally, the real exchange rate behaviour for the period 1982-90 in Brazil is analyzed. Referências bibliográficas Braga, H. & Branco, F. Cambio e salários devem ser articulados. ConjunturaEconômica, 37(12): 85-7, 1983.

Controle de plantas daninhas com linuron, em pre e em pos - emergencia, na semeadura direta da cebola. (allium cepa l.)

Numero e constante de dissociacao dos receptores beta-adrenergicos na cardiopatia chagasica experimental em ratos

Análise financeira das empresas : os métodos convencionais de análise financeira de empresas : investimento operacional em Giro-IOG : fluxo de caixa (cash flow) e fluxo de recursos : a inflação e as demonstrações financeiras

Matriz extracelular da mama : caracterização histologica de fibras de colageno e quantificação de mastocitos

1. Democracia e Estado de Direito. 2. Estado liberal de Direito. 3. Estado social de Direito. 4. O Estado democratico. 5. Caracterizacao do Estado democratico de Direito. 6. A lei no Estado democratico de Direito. Z Os principios do Estado democratico de Direito. 8. Tarefa fundamental do Estado democratico de Direito.

Social and individual aspects of the adoption of new technologies were discussed, from epistemological viewpoint, and it was concluded that, in general, technologies are results of social and historic circunstances. A relexive analysis was made concerning falacious talk about alternative agriculture perspectives that, in addition to being the result of the capitalist system, is also a result of this production mode. Two ideological currents were evidenced, that dealt with technological innovations. One, that attributed the destruction of nature and of life itself, to the production relationships, stablished under the capitalist system, and another that, for question of convenience, forgets the correspondence between the production relationships and the development of the productive forces, that propose a "Green capitalism", with the objective of no longer submetting society to modern technologies. We conclude that, talking about alternative technologies in a capitalist system becomes impossible, since social transformations are the ones that introduce imediately the development of productive forces, and not the opposite. Technology process puts the small producer within intercapitalist competition, expelling him later, and thus, confirming the excluding characters of capitalist introduction in rural areas. This represents the loss of the campestral characteristics (proletarization), the "lumpenization" (loss of productive function of the families of the small producers).

Este trabalho visa detectar os principais "saltos tecnologicos" ocorridos nas culturas do milho, batata, soja, cafe, trigo, feijao e algodao. A metodologia empregada consistiu em, observado o padrao tecnologico utilizado nessas culturas, recuperar historicamente o seu processo de geracao. Na primeira parte procura-se dar um panorama do esforco global da pesquisa agropecuaria realizado pelo setor publico do Brasil. Na segunda parte analisam-se as inovacoes, principalmente as biologicas, ao nivel de cada um dos produtos. TECHNOLOGICAL INNOVATIONS AT THE LEVEL OF PRODUCTS IN THE STATE OF SAO PAULO Abstract The objective of this study is to detect the main "technological leaps" which have taken place in crops of corn, potatoes, soybean, coffee, wheat, beans and cotton. After observing the technological level utilized in these crops, the methodology employed consisted of a historical reconstruction of their cultivation process. In the first part an attempt was made to present a panorama of the global effort of agricultural research carried out by the public sector in Brazil. In the second part innovations are analyzed, principally those of biological nature, at each product level.

INOVAÇÕES TECNOLÓGICAS AO NÍVEL DE PRODUTOS NO ESTADO DE SÃO PAULO

The main objective of this work was to present actual information on the situation of the outstanding forest species in the Amazon Region, with the purpose to manage correctly its forest genetic resources. To obtain available data, questionnaires were sent to Research Institutions, Universities, Museums and IBDF`s Agencies (Brazilian Institute for Forest Development) settled in the Region. These questionnaries when filled in and returned gave conditions to analise and establish priority criteria on genetic conservation of endangered forest species. A strategy for "in situ" genetic conservation of this resource was suggested to preserve its genetic diversity.

ESTRATÉGIA PARA CONSERVAÇÃO GENÉTICA DE ESPÉCIES FLORESTAIS PRIORITÁRIAS NA AMAZÔNIA.

Foi desenvolvido um metodo para a determinacao de enxofre total em etanol usando-se a polarografia de pulso diferencial e a potenciometria direta com eletrodo ion-seletivo para sulfeto. Os compostos de enxofre sao reduzidos com a liga de Raney e apos a adicao de acido o H2S liberado e recolhido em solucao de NaOH 0,2 M e EDTA 0,02%. As determinacoes sao realizadas diretamente na solucao de recolhimento, por polarografia e potenciometria. As medicoes das correntes polarograficas utilizam o potencial de pico registrado em torno de -0,7V. Em amostras com concentracao de enxofre superior a 1,8 ppm: (mg/g) .0 desvio padrao relativo e de ± 4%. O metodo foi aplicado a determinacao de enxofre total em concentracoes superiores a 0,2 ppm em amostras de etanol. Foi realizado tambem o estudo do comportamento polarografico do ion sulfeto e do enxofre elementar em etanol usando-se NaOH e LiCl como eletrolitos de suporte, respectivamente. Os resultados obtidos com a aplicacao de va rias tecnicas polarograficas indicam o aparecimento de varias ondas e picos com o aumento da concentracao das substâncias eletroativas, sugerindo a formacao de filmes de produtos da reacao na superficie do eletrodo de mercurio gotejante. 
Abstract

Determinação de enxofre total em etanol por polarografia e potenciometria : estudo do comportamento polarografico doion sulfeto e do enxofre elementar em etanol

The present study attempts to analyze the mechanisms which have made viable the production of agricultural technology by the agroindustrial transformation complex. The first part consists of a brief diagnosis of the evolution and of the role of this agroindustrial sector in the Brazilian economy. In the second part, by means of several case studies of agroindustrial processors, an effort was made to determine how the private sector has created technology adequate to its needs. In the third part are analyzed some of the principal mechanisms by which these private firms obtain state financing to produce this technology. It was concluded that a private and independent agricultural research sector has not been developed in Brazil in the agroindustrial food and raw materials processing complex similar to that which occurred in other countries.

A GERAÇÃO DE TECNOLOGIA PELO SETOR PRIVADO: O CASO DA AGROINDÚSTRIA NO BRASIL

The study attemps to synthesize the principal indications of the case study for Brazil of the Project PROAGRO (Project Agricultural Research Organizations and Performance), aiming to interpret elements which lead to the development (or non-development) of a private agriculture research sector in this country. For this purpose, the evolution of the public research sector is discussed; a balance is presented of the private research institutions and of their technology production dynamic in the principal subsectors of production of inputs and machines for agriculture; and concluded that the fact that Brazil has not developed a private and autonomus sector of agricultural research of the size which was expected is due to the role which the state has assumed, that is to say, that once the state apparatus for creation of science and technology became completely subordinated to the interests and necessities of private enterprises-with mechanisms which even made possible the private appropriation of the results obtained -, it became unnecessary to set up a private, autonomus section for agriculture research.

A RELAÇÃO SETOR PÚBLICO - PRIVADO NA GERAÇÃO DE TECNOLOGIA AGRÍCOLA NO BRASIL

CAPM 'Capital Asset Pricing Model': o modelo de avaliação de ativos: uma revisão da literatura e dos testes empíricos

Emprego e relações de trabalho na agricultura brasileira : uma análise dos dados censitários de 1960, 1970 e 1975

O 'uso -da tradicional "análise de. balanço" é algo .que .tem-se cristalizado no decorrer do tempo, sendo uma ferramenta utilizada por investidores e emprestadores de dinheiro, bem como' por outras pessoas que objetivam uma medida de avaliação da "saúde" fínanceíra das empresas. Paralelamente, diversos estudiosos nas área de contabilidade e finanças dedicaram-se a pesquisa, observando sistematicamente o comportamento dos índices fínanceíros, tendo com finalidade descobrir se efetivamente esse instrumental é eficiente na predição deinsol. vências de empresas. Já em 1932, nOSEUA, Fitz Patrick selecionou 19 empresas que haviam falido no período de 1920 a 1929 e as comparou com 19 outras empresas bem-sucedidas, tendo confirmado a capacidade de previsão dos índices financeiros e concluído (para sua amostra) que os melhores indicadores foram patrimônio líquido sobre o passivo total e lucro líquido sobre patrimônio líquido. Posteriormente, vieram outras pesquisas, como as de Winakor e Srnith, de Merwin, Tamari e Beaver, por . exemplo. Em que pese à tentativa pioneira de Tamari, de usar um "composto ponderado" de vários índices, foi o trabalho de Edward Altman! em 1968 que serviu como uma espécie de "marco". Altman utilizou, em sua pesquisa, o instrumental estatístico denominado análise discriminante, o que lhe possibilitou a determinação do

The mechanical harvesting has been experimenting great technological evolution, in search of minimizing the losses that they can be avoided partially, being taken some tuning attentions. The objective of this work was to determine the losses of grain in the moment of the harvest in function of velocities, the reel of the harvester. An experiment was performed in the Abadiânia - Goias, following a completely randomized design, factorial scheme 4x4, four-speed operation Vo 1 = 2.6 km h -1 , Vo 2 = 3.3 km h -1 , Vo 3 = 5.0 km h -1 and Vo 4 = 6.4 km h -1 and four speeds of the reel, 9%, 16%, 23% and 29% higher than the speed of the machine, with three replications. Were determined to cut losses of the platform, internal mechanisms and total harvest. Seeds were harvested with moisture of 18% w.b. The results were submitted to analysis of variance at 5% probability and operated using the correspondence analysis (CA). The results concluded: i) the analyzed losses are close of the acceptable limit, ii) the interaction between the operation speed and of the reel interferes on the losses provoked by the court platform, and iii) the analysis for correspondence allowed to analyze the relation between the operation speed and of the reel of the harvesters, in the determination of the losses of grains.

Perdas de grãos na colheita mecanizada do arroz de terras altas em função das velocidades de deslocamento e do molinete

A case of basilar impression associated with Arnold-Chiari malformation and with trigeminal neuralgia is reported. The radiological examination of the skull showed marked asymmetry of the petrous bone with the tip of the odontoid apophysis located 30 mm above the McGregor line. Treatment consisted of craniectomy of the posterior fossa and cervical laminetomy (Ca to C3). The postoperative course was uneventful with total disappearance of the trigeminal neuralgia.

Impressão basilar como causa de neuralgia do trigêmeo: registro de um caso

A modernização dolorosa : estrutura agrária, fronteira agrícola e trabalhadores rurais no Brasil

A situação feminina em Portugal na segunda metade do século XVIII

Modelos para classificação de empresas com vistas a concessão de crédito

RESUMD o presente trabalho corresponde a uma síntese do inventá rio florestal realizado no Territõrio Federal de Roraima, no Norte do País, na região de influência do Rio Branco, numa área de aprox~ madamente 46.000 ha, pela Universidade Federal de Santa Maria. Procurou-se descrever os tipos florestais encontrados na região sob o ponto de vista ecolõgico e de estoque de madeira, efe tuando-se considerações sobre o potencial das florestas, o processo e o estágio de exploração em que se encontram e a vitalidade dostro.!! cos das diferentes espécies encontradas.

Estrutura e produção das florestas naturais ao longo do Rio Branco no Território Federal de Roraima

Three assays were carried out to evaluate the effectiveness of several herbicides on direct seeded tomato. The compounds metribuzin, napropamide, chloramben, diphenamid, pebulate and trifluralin aplied separatly, at the dosage of .35; 3.40; 2.50; 2.00; 3.60 and .67 kg/ha respectively, and combined each one with metribuzin at the same dose ge were evaluated in two assays, one at Vicosa, MG and the other at Domingos Martins, ES. One third assay was carried out at Vicosa, MG to evaluate the effectiveness of chloramben, napropamide, diphenamid and metr ibuzin at the dose of 3.40; 3.00; 5.00 and .70 kg/ha respectively, and pebulate at the dose of 4.32 and 1.76 kg/ha applied separated and combined with pebulate at mentioned dosages. All compounds showed some control of weeds, although the efficiency of each product was weed species dependant. Only pebulate was efficient on Cyperus rotundus control. Bachiaria plantaginea and Digitaria sanguinalis were better controled by chloramben, napropamide, diphenamid and trifluralin. Metribuzin gave excelent control of Bidens pilosa and Galinsoga parviflora. The mixtures of metr ibuzin or pebula te wi th each herbicide sudied increased the efficience of control and the number of species controled. All compounds were tolerated by the tomato plants. No visible injury were observed at the doses studied.

Controle químico de plantas daninhas na semeadura direta de tomate (Lycopersicon esculentum Mill.)

- A remuneracao de servico sob a forma de preco publico (tarifas) nao constitui receita publica, nem se incorpora ao orcamento do estado. - Integrado no sistema do Planasa, o fornecimento de agua em grosso, pela Sabesp, obedece a sistematica tarifaria sujeita a disciplina federal.

Apontamentos para a história da revolução do Minho em 1846 ou da Maria da Fonte

Neste trabalho realizamos uma revisao e discussao dos estudos concernentes a duas dimensoes inter-relacionadas da percepcao espacial: tamanho e distância. Como objetivo geral, enfatizamos os principais determinantes da tendencia evolutiva, ou seja, destacamos os fatores que influenciam no fenomeno da superconstância. Assim, discutimos a natureza do metodo, as instrucoes (objetivas e aparentes), o nivel de inteligencia e cognitivo, o erro do padrao, as variacoes na distância, a situacao experimental (campo aberto e laboratorio), a presenca ou ausencia de um estimulo-padrao e a amplitude das faixas etarias e outras variaveis. Alem disso, discutimos o fenomeno da superconstância em funcao dos expoentes obtidos atraves da funcao potencia ajustada pll.Ta diferentes faixas etarias. Em geral, a revisao nos possibilitou concluir os seguintes aspectos sobre a evolucao da percepcao de tamanho e de distância. Primeiro, que o desenvolvimento primario da constância de tamanho e de distância ocorre durante a infância. Segundo, que da infância ate a adolescencia ocorre um desenvolvimento secundario, de subconstância para superconstância. Terceiro, o grau de sub ou superconstância depende nao apenas de idade, mas tambem de distância. Quarto, as variaveis do procedimento e da situacao experimental, entre outras, influenciam essas estimativas. Quinto, nao ha uma unica funcao relacionando a distância fisica com a distância julgada ou tamanho fisico com o tamanho julgado, mas sim uma familia de funcoes, entre elas a funcao potencia, cujos parâmetros sao particularmente sensiveis a variaveis tais como as instrucoes, a natureza do objeto teste, a distância e o ambiente. Sexto, ha necessidade de varias outras pesquisas, com diversas classes etarias, diversas distâncias (maiores que IS metros), varios tipos de instrucoes e em diversas situacoes experimentais, para conclusoes mais fidedignas sobre a tendencia evolutiva de sub constância para superconstância.

Análise do fenômeno da superconstância e suas implicações para a psicologia do desenvolvimento e da percepção

A case of fronto-basal traumatism with isolated fracture of the left sphenoidal sinus is reported. Meningitis occured 5, 8 and 11 years, respectively, after injury. Cerebrospinal fluid cranio-nasal fistula was observed at the first time 8 years after injury and remained intermitent in the last 6 years. The surgical technic was accomphished according to the procedure devised by Dietz and consisted of plastics of the anterior floor of the skull accompanied by galea-periosteal junction taken out from the scalp.

Meningite e fistula liquorica recidivantes em traumatismo cranio-encefalico frontobasal: registro de um caso

1. Atividade urbanistica e conceito de propriedade. 2. Funcao social da propriedade. 3. Funcao publica do urbanismo. 4. Solo urbano e direito de construir.

A case of cryptococcal meningoencephalitis occurrying in a 26-year-old white man disclosing clinical as well radiological features of a expanding process localized in the right cerebral hemisphere is reported. A definitive diagnosis was established through histopathologic examination following right fronto-temporo-parietal exploratory and decompressive craniotomy. Cryptococcus neo-formans was easily demonstrated in the leptomeninges as well as in cystic spaces in the brain substance.

Meningencefalite criptocococica funcionando como processo expansivo: registro de um caso

As caracteristicas da populacao canina e felina de Belo Horizonte foram estudadas, atraves de amostragem nao probabilistica, em 543 residencias, sendo 339 casas e 204 apartamentos, localizados em 92 bairros. Os dados foram processados em computador BURROUGHS B-6700 do Centro de computacao da UFMG, utilizando o programa "Statistical Package for the Social Sciences - SPSS" da Universidade da California, Davis, USA. Os resultados revelaram a existencia de: 8,62 pessoas/cao, 48,27 pessoas/gato, 0,67 cao/residencia, 0,88 Cao/casa, 0,3l cao/apartamento, O,l2 gato/residencia, 0,l7 gato/casa, 0,024 gato/apartamento, l,56 caes machos/ femea, 3,9l caes nascidos/parto, 68,8% de caes sobreviventes a desmama, vacinacao anti-rabica canina de 67,3%, 52,5% das residencias sem caes, 33,3% com l cao, l0,3% com 2 caes, 2,4% com 3 caes e l,5% com 4 caes, 45,6% de caes em confinamento permanente, 34,3% em confinamento temporario e 20,1 % sem confinamento e 2,5 anos de idade mediana dos caes.

Características da população canina e felina de Belo Horizonte, Minas Gerais ­ Brasil

Progresso tecnico e relações de trabalho na agricultura paulista

Extracoes por fase unica (FU) em meio nitrico foram efetuadas no sistema agua/acetona/benzeno (10:100:25 v/v) com tenoiltrifluoroacetona (TTA) e fosfato de tri-n-butila (TBP) como complexantes, para os metais Fe, Cu, Co, Ni, Zn e U. Fe e Cu, com TTA, apresentam percentuais de extracao superiores a 99%. Para Co, Ni, Zn e U em extracoes por FU com misturas de TTA e TBP, nao foi evidenciada a presenca de sinergismo. O estudo espectroscopico (600-320 nm) do aduto sinergico UO2 (TTA)2TBP, obtido por extracao liquido-liquido convencional em benzeno e conduzido a fase unica, mostra a perda das caracteristicas espectrais basicas do aduto, indicando a sua decomposicao em FU. A curva de complexacao de Ni sofre algum tipo de interferencia, apresentando alta dispersao em seus pontos, enquanto a de Zn varia com o tempo. Os espectros de TTA em FU variam com a concentracao hidrogenionica, em comportamento analogo ao apresentado em solucoes aquosas. 
Abstract

Extração liquido-liquido por fase unica de Fe,Cu e estudo de sinergismo para CO,Ni,Zn e U : sistema agua-acetona-bezeno com tenoiltrifluoroacetona e fosfato de Tri-n-Butila

- Moderna concepcao do poder de policia. - Protecao de mananciais e poder de policia. - Atribuicao de competencia policial. - Exercicio de poder de policia por entidades paraestatais - Exercicio irregular de poder de policia e responsab.'lidaee civil.

The authors studied nine members of the same family; two among them received surgical treatment for basilar impression and Arnold-Chiari malformation. In the other members of the family, several signs and symptoms of central nervous disease were observed. All patients had the apex of the odontoid apophysis above Mc Gregory's line, 4 mm in the case 9, and 10 mm or more in the others.

Estrutura agrária e produção de subsistência na agricultura brasileira

Sendo metilisobutilcetona. (MIC) um solvente bastante empregado em extracoes liquido-liquido convencional, investiga-se no presente trabalho o comportamento do sistema MIC-etanol em relacao a tecnica de extracao liquido-liquido por Fase Unica. Os complexos formados no sistema de uma so fase liquida agua-MIC-etanol (fase unica), podem ser ertraidos quando esse sistema e separado, pela adicao de excesso de agua, em duas fases liquidas imisciveis. A complexacao e a extracao de varios ions metalicos, Fe(III), Co(II), Ni(II), Cu(II) e Pb(II), sao estudadas com relacao a tenoiltrifluoroacetona (TTA). Em meio fracamenta alcalino todos esses metais sao extraidos rapida e quantitativamente, para concentracoes de TTA na Fase Unica da ordem de 10 M. Em meio moderadamente acido apenas Fe (III) extrai completamente; Cu(II) extrai parcialmente e os demais metais nao sao extraidos. Foi possivel separar, pela tecnica de extracao por Fase Unica, Fe(III) de grandes quantidades de cobalto, niquel e chumbo (da ordem de mil vezes mais), separacoes essas normalmente nao conseguidas por extracao convencional com TTA. Estudou-se tambem a determinacao direta de Ni(II) e Pb(II) na fase orgânica, apos a separacao, por meio de espectrometria de absorcao atomica. E estudado ainda o problema da hidrolise parcial de Fe(III) na fase unica, que retarda sua complexacao com TTA; uma. modificacao na preparacao da fase unica foi introduzida, de maneira a se evitar essa inconveniencia da tecnica da Fase Unica. 
Abstract

Extração liquido-liquido por fase unica : sistema agua-etanol-metilisobutilcetona no estudo da separação de Fe, Co, Ni, Cu e Pb com tenoiltrifluoroacetona

Estudo comparativo dos niveis séricos de triiodotironina-'ANTPOT 125 I' ('T IND.3') e tiroxina-'ANTPOT 125 I' ('T IND.4') em bovinos das raças gir e nelore (Bos indicus)

I — O ESTADO E A TRIBUTACAO: 1. As atividades estatais e seus custos . 2. O poder do Estado para exigir contribuicoes. 3. Conceito juridico de tributo. II — LEGALIDADE DO FENOMENO TRIBUTARIO: 4. Os tributos como objeto do Direito. 5. O principio da legalidade tributaria. 6. O Estado-legislador e o Estado-fisco. 7. Relacao juridica tributaria. 8. Direito tributario e sua natureza. III — RELACOES DO DIREITO TRIBUTARIO COM AS DEMAIS DISCIPLINAS JURIDICAS: 9. Autonomia do Direito Tributario. 10. Relacoes do Direito Tributario com outros ramos do Direito Publico. 11. Relacoes do Direito Tributario com os ramos do Direito Privado. 12. Normas do direito positivo sobre as relacoes do Direito Tributario com outras disciplinas juridicas. IV — CONCLUSAO.

Urna das preocupaçôes predominantes nesta reuniâo justifica-se ampiamente e merece a gratidäo dos historiadores. Inventariar e dar a conhecer a informaçâo é urna tarefa prioritària. Nós sabemos por experiencia como é difícil obter essa informaçâo; vimo-nos forçados a reunir um certo número de dados para o 5o Congresso internacional de História económica que teve lugar em Leninegrado em 19701 e se tirámos algumas conclusoes sobre a realidade portuguesa2, nao publicamos esse dossier porque o considerámos insuficiente. Esperamos dá-lo a conhecer agora como um complemento às contribuiçôes fundamentáis de Joel S e r r á o. Porém ao risco de construir sobre urna informaçâo deficiente opóese um outro, de especializaçâo fediada. Nao sei até que ponto a informaçâo quantitativa inventariada näo dará lugar a sínteses que possam parecer definitivas a uns, excessivas a outros, provàvelmente exterilisantes. Deixemos o historiador encontrar na informaçâo particular resposta a perguntas que nascem doutros documentos. Corramos o risco de abundar numa orientaçâo contrària ao espirito da investigaçâo que se eré produtiva e respeita antes do mais «l'état de la connaissance sur le sujet à traiter»3. Acrescentemos enfim que quanto a Portugal, a contradiçâo actual entre o nivel baixíssimo da produçâo e a expatriaçâo da força de traballio nos parece dever orientar a investigaçâo (para näo falar aqui da acçâo que parece ainda tâo longe daquela). A História desse

A emigraçāo para a América nos séculos 19 e 20 e a História nacional

Uni or bilateral decompressive craniotomy was carried out in 30 patients bearing severe cerebral edema of etiology predominantly traumatic. Coma, midriasis and decerebrate state were the mostly commonly clinical features presented. The average survival in the series was 46.6%.

Craniotomia descompressiva no edema cerebral grave: a propósito de 30 casos operados

Sixty-seven cases of non-communicating hydrocephalus treated according to the Torkildsen's procedure are reported. The spinal fluid blockage was caused in 55 cases by supratentorial and in 10 cases by infratentorial tumors; in the remaining cases the spinal fluid interruption was due to non-tumoral causes. Ventriculography was the most important examination performed as far as the local diagnosis was concerned. 15 patients in this series disclosed lethal complications with signs of brain stem lesions. Patient survival was 3.9 years with variation ranging from 1 to 9 years. The following conclusions were drawn: 1) Ventriculocisternostomy is a valious method for the treatment of non-communicating hidrocephalus for it allows a more physiological drainage of the spinal fluid besides favouring the exploration of the posterior fossa in cases of doudtful pre-operative diagnosis. This procedure is of low cost and involves a relatively simple tecnique as compared with other procedures which demand the use of special valves. 2) According to the review of the pertinent literature the best results have been accomplished in cases where there is a non-tumoral aqueduct stenosis as well as in inoperable tumors of the third ventricle. 3) Bilateral drainage is mandatory in cases of bilateral obstruction of Monro's foramina. It has also been indicated in all cases as a precaution due to the possibility of occlusion of one catheter. 4) Ventriculocisternostomy should also be indicated as a prophylactic treatment of non-communicating hydrocephalus in cases of inoperable tumors of the sela or the basal ganglia with compression of the third ventricle but without completly blockage of the ventricle system. 5) Ventriculocisternostomy should be indicated with some reserve in cases of infratentorial tumors as well as in great supratentorial space-occupying lesions. It is however contra-indicated in cases of large tumors and in the inflammatory process involving the posterior fossa. 6) In the present series the obstruction of the draining-system was very uncommon being observed in only three patients. 7) No cases of spinal fluid fistula or meningitis were observed in the present study.

Ventriculocisternostomia de Torkildsen no tratamento do hidrocefalo não comunicante: resultados em 67 casos

The A. A. present 11 cases of rhinosporidiosis. The clinical, pathological and epidemiological aspects are studied. The pacients - a black man, a white woman and eight of brown color - were all of rural origin and the age ranged frorn 6 to 33 years. Nine were male. The duration of the disease varied frorn three months to four years and there was a case with three recurrences. The high prevalence of the disease in the State of Maranhao (Brazil) is emphasized.

Um caso de rinoentomoftorose — o terceiro ate agora descrito no Brasil e apresentado. Tratava-se de um paciente de cor preta de 26 anos, procedente do Estado do Maranhao, com tumoracâo ocupando seio maxilar e fossa nasal direita, produzindo obstrucao nasal e deformacao da face. Os achados histopatologicos consistiam de reacao inflamatoria cronica gigamohistiocitaria, muito rica em eosinofilos. O diagnostico baseou-se na presenca de hifas nao sentadas envolvidas por material eosinofilico.

The authors deal with the results accomplished by surgical procedure on 10 cases of fronto-basal trauma. X-Rays taken from the skull disclosed an involvement of bone structures of the fronto-basal region in all cases examined. The most outstanding clinical findings in these cases were: lesion of the olfactory nerve (7 cases), bacterial meningitis (3 cases), cerebrospinal fluid cranio-nasal fistula (3 cases). The surgical technic was accomplished according to the procedure devised by Dietz and consisted of plastics of the anterior floor of the skull accompanied by galea-periosteal junction taken out from the scalp. The authors did not find any post-operative complications in the cases registered.

Traumatismos crânio-encefálicos frontobasais: a propósito de 10 casos operados

A reforma agrária no Brasil : frustração camponesa ou instrumento de desenvolvimento?

A case of a metastatic cerebral chorioncarcinoma in the posterior aspect of the left frontal lobe of a 19-years-old woman is reported. After neurosurgical excision of the brain tumor a retrospective study of the patient was carried out as far as the gynecologic complaints were concerned. The patient complained only of little blood loss through the genitals started some weeks after the birth of a normal child four months ago. A smear vaginal preparation showed the presence of atypical epithelial cells (class V of Papanicolau). A total hysterectomy associated with bilateral anexectomy was performed. A small hemorrhagic tumor was detected within the uterus and a histological examination showed a chorioncarcinoma invading the miometrium. The clinico-pathological aspects of the chorioncarcinoma with special emphasis to cerebral metastases are discussed.

Coriocarcinoma manifestando-se inicialmente como um tumor cerebral

No presente trabalho, apresentamos dados relativos a inicia- cao sexual, sexo seguro, sexualidade de discentes de duas escolas publicas e algumas informacoes ligadas a educacao sexual presentes em tres colecoes trabalhadas no ensino fundamental, as quais fazem parte do PNLD 2014. Os percursos femininos e masculinos que os/as encaminham em direcao a sexarca sao marcados por diferencas ligadas ao genero, sendo que a entrada na sexualidade adulta ocorre aos 15,8 anos e 13,3 anos respectivamente. As adolescentes negras iniciam sua vida sexual, em media, um ano antes das brancas e que a iniciacao sexual sem o uso de preservativo e mais frequente entre as mocas do que entre os rapazes. No grupo pesquisado, nenhum dos/as estudantes soube conceituar corretamente o termo sexualidade, que era relacionado aos genitais, ao desenvolvimento do corpo ou a atividade sexual. Os livros avaliados sao marcados por um discurso biologico e naturalizante, o qual nao privilegia discussoes de cunho cultural.

Sexualidade e sexo (in)seguro entre adolescentes e jovens, dos anos finais, de duas escolas públicas de nível fundamental da cidade de João Pessoa/PB(Brasil)

The author presents a review of the present status of the possibilities to control Schisosomiasis in Brazil. Based on passed experiences on the matter in Brazil and in other countries, the description of a pilot project is given, aiming to start a new scale control program, adequately organized with a view to solve problems of a medical - social nature, not only favouring the agricultural development of the country, but also avoiding the spread of foci to non endemic areas. The basic purpose of the project is, of course, the interruption of transmission of the disease, utilizing the various methods for that, either alone or in combination, according to the various epidemiological conditions.

Abstract Context The COVID-19 pandemic challenged undertaking gradual educational activities for residency and fellowship trainees. However, recent technological advances have enabled broadening active learning opportunities through international online conferences. Objective The format of our international online endocrine case conference, launched during the pandemic, is introduced. The objective impact of this program on trainees is described. Methods Four academic facilities developed a semiannual international collaborative endocrinology case conference. Experts were invited as commentators to facilitate in-depth discussion. Six conferences were held between 2020 and 2022. After the fourth and sixth conferences, anonymous multiple-choice online surveys were administered to all attendees. Results Participants included trainees and faculty. At each conference, 3 to 5 cases of rare endocrine diseases from up to 4 institutions were presented, mainly by trainees. Sixty-two percent of attendees reported 4 facilities as the appropriate size for the collaboration to maintain active learning in case conferences. Eighty-two percent of attendees preferred a semiannual conference. The survey also revealed the positive impact on trainees’ learning regarding diversity of medical practice, academic career development, and confidence in honing of presentation skills. Conclusion We present an example of our successful virtual global case conference to enhance learning about rare endocrine cases. For the success of the collaborative case conference, we suggest smaller cross-country institutional collaborations. Preferably, they would be international, semiannually based, and with recognized experts as commentators. Since our conference has engendered multiple positive effects on trainees and faculty, continuation of virtual education should be considered even after the pandemic era.

The Impact of Multicultural Interfacility Video Case Conference: A Novel Education Model After the COVID Pandemic

Abstract Objective Although SARS-CoV2 vaccines have been developed with multiple novel technologies and rapidly disseminated worldwide, the full profile of adverse effects has not been known. Recently, there are sporadic but increasing reports of endocrinopathies in relation to SARS-CoV2 vaccination. Here, we report a rare case of hypophysitis with acute onset of diabetes insipidus after SARS-CoV2 vaccination. Case Report A 48-year-old female who had been in her usual state of health until she received the first SARS-CoV2 vaccine. Two days after the vaccination, she started to have flu-like symptoms including severe headache and myalgia as well as persistent headache, polydipsia and polyuria. On presentation, her vital signs were stable, with her pulse being 81 bpm, BP: 122/84 mm Hg, temperature: 98.6F. Her physical examination was unremarkable. Laboratory evaluation revealed normal values of the basic metabolic panel including sodium level of 142 mmol/L and normal complete blood count. Due to her prolonged and worsening headache, she underwent a brain MRI which revealed a 4 mm round shape of thickening pituitary stalk and partial empty sella. The polydipsia, polyuria, and the thickening of the pituitary stalk led to further pituitary work-up. She underwent the overnight water deprivation test followed by the desmopressin challenge test. Her overnight water deprivation test revealed hypernatremia (Na 147 mmol/L), elevated serum osmolarity (309 mmol/kg), and low urinary osmolarity (83 mmol/kg) which were compatible with diabetes insipidus. Her IGF1 level revealed low normal range (66 ng/mL). Her 250 mcg cosyntropin test showed appropriate response without adrenal insufficiency. DDAVP was started. 3 months after the vaccination, her symptoms have partially improved, and on repeating the MRI brain she has persistent pituitary stalk thickening. Discussion We report a rare case of diabetes insipidus from hypophysitis associated with SARS-CoV2 vaccine. Mechanisms of SARS-CoV2 vaccination-associated endocrinopathy is unknown. From our literature search, we found increasing numbers of the cases of endocrinopathy reported after the SARS- CoV2 vaccination. The thyroid seems the most frequently reported endocrine organ (83%), followed by the pituitary (11%) and adrenal (6%). Average onset is 1-5 days after the vaccinations and reported with all types of SARS-CoV2 vaccines. More mid-age (average age 46) female (78%) cases have been reported. Although associations are not confirmed, endocrinopathies may be underestimated in the post vaccinated population. Further studies are warranted to better understand SARS-CoV2 vaccinations and potential associations of endocrinopathy. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

PMON81 A Case of Hypophysitis Associated With SARS-CoV2 Vaccination

Abstract Introduction Coronavirus disease 2019 (COVID-19) pandemic brought not only physical and mental health problems but also negative impacts on social, economic and educational activities. Trainees, including medical students, residents, and clinical fellows had fewer opportunities to see and discuss patients with supervisors in person. In contrast, recent advances in technology have made it possible to review cases with overseas experts through online conferences. We launched a biannual inter-facility endocrine case review meeting in a video conference format during the pandemic of COVID-19. Here we present the format of our inter-facility online case conference and its impact on trainees. Methods The conference was organized by clinical faculty members from Japan, USA and Canada. For each conference, each facility prepared one to two cases in English. Four to five cases were presented and discussed with participants and guest commentators. After completion of the 4th conference, an anonymous multiple-choice online survey was administered to all attendees, and data was collected and analyzed by the committee members. Differences in responses before and after attendance were analyzed by paired t-test. Results Four conferences were held between July/31/2020, and Dec/10/2021 (CST). The facilities participating was as follows: University of Minnesota, Hokkaido Univ., University of Alberta, and Kobe Univ. Participants included medical students, residents, endocrine fellows, and faculty. Presenters were medical students (n=1), endocrine fellows (n=15), and neurosurgery faculty (n=1). Presented topics included the following: 11 cases with pituitary disorders, 3 cases with neuroendocrine tumors, 2 cases with adrenal disorders and 1 case of thyroid disorder. Sixty-two percent of the attendees stated that 3-4 facilities are an ideal size of the collaborations in inter-facility case conference, and 82% of the attendees felt twice a year is an appropriate frequency of the conference. Ninety-seven percent of the participants indicated their willingness to continue to attend. The survey results also revealed that the conference has a positive impact on trainees’ clinical practice and career development. Furthermore, the confidence in presenting skills in English significantly increased after the conference (p<0. 01). Conclusion Under the COVID-19 pandemic, we launched a new format of inter-institutional case review meeting using a video conferencing system that transcends national boundaries. This represents a new educational method for trainees. A small-scale (3-4 facilities) international collaboration in a video format may provide opportunities for learning rare endocrine cases, cultural diversity of endocrine care, enhanced active learning for trainees, and the opportunity for international presentation. This may lead to the development of a novel educational system in the future. Presentation: No date and time listed

ODP358 The effect of multi-cultural inter-facility endocrine video case conferencing – A novel model of education during the COVID pandemic

Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists

BEWARE OF LIVER MASSES IN DIFFERENTIATED THYROID CANCER PATIENTS: A CASE FOR CALCITONIN, CEA, AND MULTIDISCLIPLINARY EXPERTISE.

Thyroid nodules over 4 cm do not have higher malignancy or benign cytology false-negative rates

Importance Biotinylated antibodies and analogues, with their strong binding to streptavidin, are used in many clinical laboratory tests. Excess biotin in blood due to supplemental biotin ingestion may affect biotin-streptavidin binding, leading to potential clinical misinterpretation. However, the degree of interference remains undefined in healthy adults. Objective To assess performance of specific biotinylated immunoassays after 7 days of ingesting 10 mg/d of biotin, a dose common in over-the-counter supplements for healthy adults. Design, Setting, and Participants Nonrandomized crossover trial involving 6 healthy adults who were treated at an academic medical center research laboratory Exposure Administration of 10 mg/d of biotin supplementation for 7 days. Main Outcomes and Measures Analyte concentrations were compared with baseline (day 0) measures on the seventh day of biotin treatment and 7 days after treatment had stopped (day 14). The 11 analytes included 9 hormones (ie, thyroid-stimulating hormone, total thyroxine, total triiodothyronine, free thyroxine, free triiodothyronine, parathyroid hormone, prolactin, N-terminal pro-brain natriuretic peptide, 25-hydroxyvitamin D) and 2 nonhormones (prostate-specific antigen and ferritin). A total of 37 immunoassays for the 11 analytes were evaluated on 4 diagnostic systems, including 23 assays that incorporated biotin and streptavidin components and 14 assays that did not include biotin and streptavidin components and served as negative controls. Results Among the 2 women and 4 men (mean age, 38 years [range, 31-45 years]) who took 10 mg/d of biotin for 7 days, biotin ingestion–associated interference was found in 9 of the 23 (39%) biotinylated assays compared with none of the 14 nonbiotinylated assays (P = .007). Results from 5 of 8 biotinylated (63%) competitive immunoassays tested falsely high and results from 4 out of 15 (27%) biotinylated sandwich immunoassays tested falsely low. Conclusions and Relevance In this preliminary study of 6 healthy adult participants and 11 hormone and nonhormone analytes measured by 37 immunoassays, ingesting 10 mg/d of biotin for 1 week was associated with potentially clinically important assay interference in some but not all biotinylated assays studied. These findings should be considered for patients taking biotin supplements before ordering blood tests or when interpreting results. Trial Registration clinicaltrials.gov Identifier: NCT03034707

Association of Biotin Ingestion With Performance of Hormone and Nonhormone Assays in Healthy Adults

Indeterminate thyroid fine-needle aspiration (FNA) cytology, including atypia of undetermined significance (AUS/FLUS) and suspicious for follicular neoplasm (SFN), continues to generate uncertainty about the presence of malignancy, resulting in repeated follow-up, repeat FNA, or diagnostic surgery. Mutational panel testing may improve the malignancy risk prediction in indeterminate nodules, but the general application of such testing has not been investigated extensively.

METHODS
A retrospective review was performed of all patients undergoing thyroidectomy at a tertiary care facility over a two-year period. Mutational panel test results, when present, were analyzed relative to FNA cytologic result and surgical histopathologic diagnosis. Malignancy rates, sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV) and positive and negative likelihood ratios (LR) were calculated.

RESULTS
A total of 261 operated thyroid nodules had the following initial FNA cytology results: 2% non-diagnostic, 23% benign, 28% AUS/FLUS, 11% SFN, 9% suspicious for malignancy (SUSP), and 27% malignant. The histopathologic malignancy rate was 48%, subcategorized by cytology into benign 7%, AUS/FLUS 30%, SFN 38%, and SUSP 83%. Mutations were more frequent in indeterminate nodules that were histologically malignant versus benign (p < 0.0001) or versus adenoma (p = 0.001). Mutational analysis in 44 AUS/FLUS nodules resulted in a malignancy detection sensitivity of 85%, a specificity of 65%, a PPV of 50%, a NPV of 91%, and a positive LR of 2.4. In 12 SFN nodules analyzed with ThyroSeq(®) testing, sensitivity was 100%, specificity 57%, PPV 63%, NPV 100%, and LR 2.3. Performance of the seven-gene mutational panel was not significantly different from the ThyroSeq(®) panel in the AUS/FLUS group. The malignancy yield, comparing the mutation positive AUS/FLUS group with the untested AUS/FLUS surgical cohort, did not reach statistical significance (p = 0.17).

In a surgical cohort, a similar NPV but a lower PPV was found with the use of mutational panel testing compared to the published literature. Following the identification of a mutation, the prevalence of malignancy in the AUS/FLUS or SFN category was increased by nearly 15% to 45% and 53%, respectively. Further study is needed to confirm these results and to analyze clinical outcome subcategories relative to the utility of mutational testing.

Correlation Between Histological Diagnosis and Mutational Panel Testing of Thyroid Nodules: A Two-Year Institutional Experience.

Cull et al. recently discussed central diabetes insipidus (DI), in particular regarding its molecular and genetic abnormalities in patients with acute myelogenous leukemia (AML) [1]. We would like ...

Diabetes insipidus in myelodysplastic syndrome: what we learnt from a case regarding its diagnosis, pathophysiology and management

Guatemala has among the largest numbers of indigenous people living within its borders in Central America. With wealth coming from tourism and exports concentrated mainly around Guatemala City, descendants of the ancient Maya live in small, ethnically distinct villages where locals struggle to preserve their heritage. Isolated in the valleys between the Cuchumatanes Mountains, the Ixil Triangle is home to a unique community of Ixil people who have retained their ancient way of life. Men tend to be farmers, women weave using technologies passed down from generation to generation, and few have a strong grasp of Spanish as a second language. Yet despite the isolation, tensions and instability in modern-day Guatemala have struck this community hard. A startling number of the indigenous citizens of Guatemala, who make up 40% of the population, have no access to education, and many have no voice in the political process, as they lack the financial means to pay to become registered citizens. The Ixil also face economic pressures, as well as the repercussions of a bloody civil war that ended in 1996, taking an entire generation of men as casualties. Faced with the prospect of their disappearing culture, a small group of widows in the village of San Juan Cotzal have welcomed the help of European volunteers, and formed a weaving co-op. They take orders from distributors in more established tourist stops like Guatemala City and Antigua, utilizing age-old technologies to make carpets, bags, shawls, and other products that volunteers then deliver to stores around the country. Building upon the business skills they gain by maintaining the co-op, the widows are both politically and economically active, taking initiative on behalf of their community. Future projects include organizing fundraisers to equip each widow’s home with proper stoves and developing an improved outreach strategy to goods distributors in the larger cities. Defying heavy odds, the empowered women of Ixil are finding local ways to integrate their heritage into the global landscape.

We are interested in the metabolic response to ingested macronutrients and the interaction between macronutrients in meals. Recently, we have determined the insulin and glucose response to ingestion of lard, olive oil, or safflower oil, fat sources varying in fatty acid composition and carbohydrate (CHO), in the form of potato.

OBJECTIVE
Our aim was to determine the effect of these dietary fats ingested alone or with potato on glucagon, glucagon-like peptide-1 (GLP-1) (7-37 and 7-36 amide), and total and acyl-ghrelin concentrations.

METHODS
Healthy subjects ingested 25 g fat (lard, olive oil, or safflower oil), 50 g CHO (potato), 25 g fat with 50 g CHO, or water only. Glucagon, GLP-1 (7-37 and 7-36 amide), and total and acyl-ghrelin responses were determined over 4 h.

RESULTS
All fats when ingested alone increased glucagon. Glucagon increases were dramatically attenuated when fats were ingested with the potato. GLP-1 increased after all meals, but was greatest when fats were ingested alone. The fat-stimulated increase was completely negated when fats were ingested with potato. Both acyl and total ghrelin decreased when only fats were ingested, as expected. When potato was ingested with any of the fats, the fat-induced decrease in acyl-ghrelin response also was essentially negated. Paradoxically, ghrelin increased when potato alone was ingested.

The current data indicate that the glucagon, GLP-1 and ghrelin responses to ingested fats, varying in fatty acid composition, are significantly affected by co-ingestion of CHO. Overall, the interaction between ingested foods in general is likely to be complex.

The effect on glucagon, glucagon-like peptide-1, total and acyl-ghrelin of dietary fats ingested with and without potato.

Background: We are interested in the metabolic response to ingested macronutrients, and the interaction between macronutrients in meals. Previously, we and others reported that the postprandial rise in serum glucose following ingestion of 50 g carbohydrate, consumed as potato, was markedly attenuated when butter was ingested with the carbohydrate, whereas the serum insulin response was little affected by the combination. Objective: To determine whether a similar response would be observed with three other dietary fats considerably different in fatty acid composition. Design: Nine healthy subjects received lard, twelve received olive oil and eleven received safflower oil as a test meal. The subjects ingested meals of 25 g fat (lard, olive oil or safflower oil), 50 g CHO (potato), 25 g fat with 50 g CHO or water only. Glucose, C peptide, insulin, triacylglycerols and nonesterified fatty acids were determined. Results: Ingestion of lard, olive oil or safflower oil with potato did not affect the quantitative glucose and insulin responses to potato alone. However, the responses were delayed, diminished and prolonged. All three fats when ingested alone modestly increased the insulin concentration when compared to ingestion of water alone. When either lard, olive oil or safflower oil was ingested with the potato, there was an accelerated rise in triacylglycerols. This was most dramatic with safflower oil. Conclusions: Our data indicate that the glucose and insulin response to butter is unique when compared with the three other fat sources varying in their fatty acid composition.

The Degree of Saturation of Fatty Acids in Dietary Fats Does Not Affect the Metabolic Response to Ingested Carbohydrate

Viata medicala; revista de informare profesionala si stiintifica a cadrelor medii sanitare

[Role of hygienic measures in the dental care for pupils with incipient periodontopathies].

The nature of eye movements during visual search has been widely studied in psychology and neuroscience. Virtual reality (VR) paradigms provide an opportunity to test whether computational models of search can predict naturalistic search behavior. However, existing ideal observer models are constrained by strong assumptions about the structure of the world, rendering them impractical for modeling the complexity of environments that can be studied in VR. To address these limitations, we frame naturalistic visual search as a problem of allocating limited cognitive resources, formalized as a meta-level Markov decision process (meta-MDP) over a representation of the environment encoded by a deep neural network. We train reinforcement learning agents to solve the meta-MDP, showing that the agents’ optimal policy converges to a classic ideal observer model of search developed for simplified environments. We compare the learned policy with human gaze data from a visual search experiment conducted in VR, finding a qualitative and quantitative correspondence between model predictions and human behavior. Our results suggest that gaze behavior in naturalistic visual search is consistent with rational allocation of limited cognitive resources.

Positive and negative affective states are respectively associated with optimistic and pessimistic expectations regarding future reward. One mechanism that might underlie these affect-related expectation biases is attention to positive- versus negative-valence stimulus features (e.g., attending to the positive reviews of a restaurant versus its expensive price). Here we tested the effects of experimentally induced positive and negative affect on feature-based attention in 120 participants completing a compound-generalization task with eye-tracking. We found that participants' reward expectations for novel compound stimuli were modulated by the affect induction in an affect-congruent way: positive affect increased reward expectations for compounds, whereas negative affect decreased reward expectations. Computational modelling and eye-tracking analyses each revealed that these effects were driven by affect-congruent changes in participants' allocation of attention to high- versus low-value features of compound stimuli. These results provide mechanistic insight into a process by which affect produces biases in generalized reward expectations.

Affect-congruent attention drives changes in reward expectations

The central theme of this review is the dynamic interaction between information selection and learning. We pose a fundamental question about this interaction: How do we learn what features of our experiences are worth learning about? In humans, this process depends on attention and memory, two cognitive functions that together constrain representations of the world to features that are relevant for goal attainment. Recent evidence suggests that the representations shaped by attention and memory are themselves inferred from experience with each task. We review this evidence and place it in the context of work that has explicitly characterized representation learning as statistical inference. We discuss how inference can be scaled to real-world decisions by approximating beliefs based on a small number of experiences. Finally, we highlight some implications of this inference process for human decision-making in social environments. Expected final online publication date for the Annual Review of Neuroscience, Volume 44 is July 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

There are a number of well-accepted ways to measure risk sensitivity, with researchers often making conclusions about individual differences based on a single task. Even though long-standing observations suggest that how risky outcomes are presented changes people's behavior, it is unclear whether risk sensitivity is a unitary trait that can be measured by any one of these instruments. To directly answer this question, we administered three tasks commonly used to elicit risk sensitivity within-subject to a large sample of participants on Amazon Mechanical Turk. Our findings revealed high individual variability in each measure, with little evidence of consistency among different tasks: many participants who were classified as "risk-averse'' in one task were "risk-seeking'' in another, and we observed no significant correlations between continuous measures of risk sensitivity as measured in each of the tasks. Our results cast doubt on the pervasive assumption that risk paradigms measure a single underlying trait, and suggest instead that behavior in risky situations is the result of heterogeneous, interacting, and possibly task-dependent cognitive mechanisms.

Effective use of limited computational resources is a hallmark of intelligent systems. Here we explore how people make use of limited perceptual resources in a naturalistic visual search task. We hypothesize that people optimally trade off performance against the cost of sampling information. To formalize this hypothesis, we frame the problem of attention allocation in visual search as a meta-level Markov decision process (meta-MDP) and show that a classic Bayesian model of visual search can be interpreted as a heuristic policy for this meta-MDP. We test the heuristic policy against gaze data from 21 human participants in a virtual reality (VR) visual search study, finding that human gaze trajectories share qualitative structure with trajectories simulated from the model.

Modeling visual search in naturalistic virtual reality environments

Computational Mechanisms of Selective Attention during Reinforcement Learning

Real world reinforcement learning (RL) requires learning about stimuli composed of multiple features, only some of which are relevant to reinforcement. We investigated RL in a multi-feature task known as the Dimensions Task. Past work developed a computational model of this task, where the expected value of a stimulus comprises weights assigned to the stimulus’s features, hence the weights estimate the importance of each feature. We studies these weights and how they relate to human behavior. We found a sparse subset of features accrued much weight, and just 2 of 9 features exerted a significant influence on reaction time (RT), suggesting this pair of features mostly influences choice. These findings clarify that the Dimensions Task requires selectively attending to just a sparse subset of features while ignoring numerous irrelevant features, emphasizing its distinction from other recent multi-feature RL tasks that either require attending to all features or learning to treat feature conjunctions as objects. We next examined whether we could use the feature weights to develop a trial-wise marker of choice difficulty that related to individual differences. We found that high (vs. low) performing participants were better able to calibrate their responses based on variation in the standard deviation (SD) of the 2 features influencing RT. This suggests better-performing participants may be more responsive to the difference between the features. We discuss how this measure of trial-wise choice difficulty could be applied in experimental and translational research.

Measuring Trial-wise Choice Difficulty in Multi-feature Reinforcement Learning

Holistic Reinforcement Learning: The Role of Structure and Attention

To efficiently learn optimal behavior in complex environments, humans rely on an interplay of learning and attention. Healthy aging has been shown to independently affect both of these functions. Here, we investigate how reinforcement learning and selective attention interact during learning from trial and error across age groups. We acquired behavioral and fMRI data from older and younger adults (male and female) performing two probabilistic learning tasks with varying attention demands. Although learning in the unidimensional task did not differ across age groups, older adults performed worse than younger adults in the multidimensional task, which required high levels of selective attention. Computational modeling showed that choices of older adults are better predicted by reinforcement learning than Bayesian inference, and that older adults rely more on reinforcement learning-based predictions than younger adults. Conversely, a higher proportion of younger adults' choices was predicted by a computationally demanding Bayesian approach. In line with the behavioral findings, we observed no group differences in reinforcement-learning related fMRI activation. Specifically, prediction-error activation in the nucleus accumbens was similar across age groups, and numerically higher in older adults. However, activation in the default mode was less suppressed in older adults in for higher attentional task demands, and the level of suppression correlated with behavioral performance. Our results indicate that healthy aging does not significantly impair simple reinforcement learning. However, in complex environments, older adults rely more heavily on suboptimal reinforcement-learning strategies supported by the ventral striatum, whereas younger adults use attention processes supported by cortical networks. SIGNIFICANCE STATEMENT Changes in the way that healthy human aging affects how we learn to optimally behave are not well understood; it has been suggested that age-related declines in dopaminergic function may impair older adult's ability to learn from reinforcement. In the present fMRI experiment, we show that learning and nucleus accumbens activation in a simple unidimensional reinforcement-learning task was not significantly affected by age. However, in a more complex multidimensional task, older adults showed worse performance and relied more on reinforcement-learning strategies than younger adults, while failing to disengage their default-mode network during learning. These results imply that older adults are only impaired in reinforcement learning if they additionally need to learn which dimensions of the environment are currently important.

Intact Reinforcement Learning But Impaired Attentional Control During Multidimensional Probabilistic Learning in Older Adults

A growing literature has highlighted a role for selective attention in shaping representation learning of relevant task features, yet little is known about how humans learn what to attend to. Here we model the dynamics of selective attention as a memory-augmented particle filter. In a task where participants had to learn from trial and error which of nine features is more predictive of reward, we show that trial-by-trial attention to features measured with eye-tracking is better fit by the particle filter, compared to a reinforcement learning mechanism that had been proposed in the past. This is because inference based on a single particle captures the sparse allocation and rapid switching of attention better than incremental error-driven updates. However, because a single particle maintains insufficient information about past events to switch hypotheses as efficiently as do participants, we show that the data are best fit by the filter augmented with a memory buffer for recent observations. This proposal suggests a new role for memory in enabling tractable, resource-efficient approximations to normative inference.

A particle filtering account of selective attention during learning

Dynamic Interaction between Reinforcement Learning and Attention in Multidimensional Environments

Dynamic Interaction betw een Reinforcement Learning and Attention in Multidimensional Environments Highlights

Selective attention is thought to facilitate reinforcement learning (RL) in multidimensional environments by constraining learning to dimensions that are most relevant for the task at hand. But how would agents know what dimensions to attend to in the first place? Here we use computational modeling of human attention data to show that selective attention is sensitive to trial-by-trial dynamics of reinforcement. Twenty-five participants performed a decision-making task with multi-dimensional stimuli, while undergoing functional magnetic resonance imaging (fMRI) and eye-tracking. At any one time, only one of three stimulus dimensions (faces, houses or tools) was relevant to predicting probabilistic reward. Participants had to learn, through trial and error, which was the predictive dimension, and what feature within that dimension was the most rewarding. We chose this task design in order to capture real-world learning problems where only some dimensions in the environment consistently predict noisy reward. In previous work we showed that attention to different dimensions modulates learning in this task. To examine how subjects learn what to attend to, here we developed and compared different models that specify how attention changes trial-by-trial. Both the neural and eyetracking data were best explained by an RL model that tracks feature values learned through trial-and-error, and allocates dimensional attention in proportion to the highest-valued feature along each dimension. This model outperformed models that determined attention based on choice history alone, suggesting that attention dynamically changes as a function of recent reward history. To our knowledge, ours is the first explanation of how attention measured directly and simultaneously from neural data and eye-tracking is determined. Our results establish a bidirectional interaction between attention and RL: attention constrains what we learn about, and learned values determine what we attend to.

Reward-sensitive attention dynamics during human reinforcement learning

Predicting trial-by-trial attention dynamics during human reinforcement learning

Computational psychiatry applies advances from computational neuroscience to psychiatric disorders. A core aim is to develop tasks and modeling approaches that can advance clinical science. Special interest has centered on reinforcement learning (RL) tasks and models. However, laboratory tasks in general often have psychometric weaknesses and RL tasks pose special challenges. These challenges must be addressed if computational psychiatry is to capitalize on its promise of developing sensitive, replicable assays of cognitive function. Few resources identify these challenges and discuss strategies to mitigate them. Here, we first overview general psychometric challenges associated with laboratory tasks, as these may be unfamiliar to cognitive scientists. Next, we illustrate how these challenges interact with issues specific to RL tasks, in the context of presenting a case example of preparing an RL task for computational psychiatry. Throughout, we highlight how considering measurement issues prior to a clinical science study can inform study design.

Translating a Reinforcement Learning Task into a Computational Psychiatry Assay: Challenges and Strategies

It has been difficult to link synaptic modification to overt behavioral changes. Rodent models of DYT1 dystonia, a motor disorder caused by a single gene mutation, demonstrate increased long-term potentiation and decreased long-term depression in corticostriatal synapses. Computationally, such asymmetric learning predicts risk taking in probabilistic tasks. Here we demonstrate abnormal risk taking in DYT1 dystonia patients, which is correlated with disease severity, thereby supporting striatal plasticity in shaping choice behavior in humans. DOI: http://dx.doi.org/10.7554/eLife.14155.001

Reinforcement learning (RL) in complex environments relies on selective attention to uncover those aspects of the environment that are most predictive of reward. Whereas previous work has focused on age-related changes in RL, it is not known whether older adults learn differently from younger adults when selective attention is required. In 2 experiments, we examined how aging affects the interaction between RL and selective attention. Younger and older adults performed a learning task in which only 1 stimulus dimension was relevant to predicting reward, and within it, 1 "target" feature was the most rewarding. Participants had to discover this target feature through trial and error. In Experiment 1, stimuli varied on 1 or 3 dimensions and participants received hints that revealed the target feature, the relevant dimension, or gave no information. Group-related differences in accuracy and RTs differed systematically as a function of the number of dimensions and the type of hint available. In Experiment 2 we used trial-by-trial computational modeling of the learning process to test for age-related differences in learning strategies. Behavior of both young and older adults was explained well by a reinforcement-learning model that uses selective attention to constrain learning. However, the model suggested that older adults restricted their learning to fewer features, employing more focused attention than younger adults. Furthermore, this difference in strategy predicted age-related deficits in accuracy. We discuss these results suggesting that a narrower filter of attention may reflect an adaptation to the reduced capabilities of the reinforcement learning system. (PsycINFO Database Record

The effects of aging on the interaction between reinforcement learning and attention.

It has been difficult to link synaptic modification to overt behavioral changes. Rodent models of DYT1 dystonia, a motor disorder caused by a single gene mutation, demonstrate increased long-term potentiation and decreased long-term depression in corticostriatal synapses. Computationally, such asymmetric learning predicts risk taking in probabilistic tasks. Here we demonstrate abnormal risk taking in DYT1 dystonia patients, which is correlated with disease severity, thereby supporting striatal plasticity in shaping choice behavior in humans.

When confronted with many stimuli in a complex world, how does the aging brain learn where to focus attention? Previous work shows that older adults have more difficulty switching between different task-relevant dimensions. It remains unclear, however, whether and how the cognitive strategies they use differ from those employed by younger adults. Here we focus on age-related differences in the dynamics of representation learning, where participants learn which stimulus features are relevant to each task through trial and error. We compare the behavior of older and younger adults in a multidimensional reinforcement learning task designed to study how subjects update their representations on-line, and propose a series of models that implement various forms of selective attention. Model-based analysis of choice patterns shows that both younger and older adults employ attention during learning. However, older adults seem to maintain a narrower attentional filter, a cognitive strategy that might reflect an adaptation to changes in the interaction between the dopaminergic system and the prefrontal cortex.

The ability to use past experience to effectively guide decision making declines in older adulthood. Such declines have been theorized to emerge from either impairments of striatal reinforcement learning systems (RL) or impairments of recurrent networks in prefrontal and parietal cortex that support working memory (WM). Distinguishing between these hypotheses has been challenging because either RL or WM could be used to facilitate successful decision making in typical laboratory tasks. Here we investigated the neurocomputational correlates of age-related decision making deficits using an RL-WM task to disentangle these mechanisms, a computational model to quantify them, and magnetic resonance spectroscopy to link them to their molecular bases. Our results reveal that task performance is worse in older age, in a manner best explained by working memory deficits, as might be expected if cortical recurrent networks were unable to sustain persistent activity across multiple trials. Consistent with this, we show that older adults had lower levels of prefrontal glutamate, the excitatory neurotransmitter thought to support persistent activity, compared to younger adults. Individuals with the lowest prefrontal glutamate levels displayed the greatest impairments in working memory after controlling for other anatomical and metabolic factors. Together, our results suggest that lower levels of prefrontal glutamate may contribute to failures of working memory systems and impaired decision making in older adulthood.

Age-related differences in prefrontal glutamate are associated with increased working memory decay that gives the appearance of learning deficits

Age-related decline in prefrontal glutamate predicts failure to efﬁciently deploy working memory in the service of learning

A Unified Account of Adaptive Learning in Different Statistical Environments

not included. S45. DEFICITS IN INFORMATION-SEEKING BEHAVIOR IN SCHIZOPHRENIA: AN ALTERNATIVE MECHANISM OF AVOLITION James Waltz*,1, Dennis Hernaus2, Matthew Nassar3, Harrison Ritz3, Ziye Xu4, Michael Frank3, Rebecca Ruiz1, James Gold5 1Maryland Psychiatric Research Center; 2Maastricht University; 3Brown University; 4Duke University; 5University of Maryland School of Medicine Background: A wealth of data points to a role for deficient reward-seeking behavior in schizophrenia (SZ), as a mechanism of negative symptoms, in general, and avolition, in particular. Specifically, avolitional patients with SZ appear to experience reinforcers in a normative manner, but do not properly assign prospective value to rewards or actions that frequently lead to rewards. There are many forms of goal-directed behavior, however, with reward-seeking behavior being only one. A  second kind of goal-directed behavior is exploration: seeking out information about contingencies in the environment, so as to reduce uncertainty about available options. Successful navigation of the explore/exploit trade-off is critical to adaptive behavior. In several different studies, we have examined information-seeking behavior in individuals with SZ and matched controls, hypothesizing that reductions in goal-directed exploration make substantial contribution to avolition. Methods: We have used several different behavioral paradigms incorporating an explore/exploit trade-off in samples of SZ patients and matched controls. Two of these paradigms were forms of reversal learning tasks, where individuals learn to choose the most-frequently-rewarded of two or three stimuli, with reward contingencies changing after a certain number of consecutive correct choices. A third paradigm required participants to track the value of three slot machines across stable and volatile runs of trials (when reward contingencies changed suddenly, independent of performance). All of these paradigms were performed in conjunction with fMRI scanning, with single-subject MRI data being analyzed using parametric (amplitude-modulated) regressors constructed based on trial-wise estimates of expected value, certainty about value, and the degree to which choices were reward-seeking (choosing the slot machines with the highest EV) vs. information-seeking (driven by the exploration of unknown contingencies), from computational analyses. Results: In the context of reversal learning tasks, we have found that SZ patients show: 1) aberrant MRI signals in dorsolateral prefrontal cortex (dlPFC) and frontopolar cortex (FPC) in conjunction with responseset-shifting behavior; 2) a reduced ability to adjust learning rates in accordance with the volatility of the learning environment; and 3) that this behavioral deficit is accompanied by reduced connectivity between dorsomedial prefrontal cortex (dmPFC) and ventral striatum (VS). In the context of the Slot Machines task, individuals with SZ made fewer exploitative choices in the volatile condition (t=2.13, p=0.038), and required more trials to switch to the new-best machine following a reversal (t=2.99, p=0.004). Analyses of correlations among clinical symptoms and fMRI activations in brain regions-of-interest (ROIs) revealed that greater levels of avolition severity were associated with reduced reward tracking-related activity in right orbitofrontal cortex (OFC; r=-.41, p=0.05) and dmPFC (r=.57, p=0.01). Discussion: These results point to associations among behavioral and brain signals related to goal-directed learning and exploration and clinical measures of avolition in individuals along the psychosis spectrum. Specifically, they support a role for interactions among brain regions involved in reward-seeking behavior (VS and OFC), uncertainty processing (dmPFC), and information-seeking behavior (dlPFC and FPC) in motivated behavior and suggest alternative mechanisms for motivational deficits. Furthermore, even when reward-seeking behavior is intact, SZ patients may exhibit motivational deficits due to impairments in information-seeking behavior. S46. THE ROLE OF COGNITIVE FLEXIBILITY IN STIGMA AGAINST INDIVIDUALS WITH SCHIZOPHRENIA Rebecca De Los Santos*,1, Colin Carey1, Katelyn Challman1, Veronica Perez2 1Alliant International University; 2Alliant International University; University of California San Diego Background: The stigma faced by schizophrenia (SZ) patients leads to societal discrimination, reduced quality of life, and impaired social functioning. Prior research on efforts to decrease stigma against those with SZ is extensive, but the mechanisms of change remain unclear and reports are inconsistent. As such, the current study examined the efficacy of a novel combination of established anti-stigma interventions within the general public, and sought to identify whether malleable thinking, i.e., cognitive flexibility, could serve as a predictive indicator for individuals who would most benefit. Methods: Baseline stigma (Social Distance Scale (SDS)) and cognitive flexibility (Wisconsin Card Sorting Test (WCST), and Color-Word Interference Task (CWIT) and Verbal Fluency (VF) subtests of the Delis-Kaplan Executive Function System (DKEFS)) were assessed in D ow naded rom http/academ ic.p.com /schizophreniabrticle-abstract/45/Supplem ent_23/5434577 by gest on 15 M arch 2020

S44. ALTERED BRAIN RESPONSES TO NOVELTY, NEGATIVE EMOTIONAL AND TASK-DRIVEN SALIENCE IN ANTIPSYCHOTIC NAÏVE FIRST EPISODE PSYCHOSIS

knowledgeable informants. Interestingly, healthy individuals also generated reports of functioning that are related to mood states, wherein mild levels of dysthymia are associated with reduced over-estimation of functioning; this finding appears to be stronger in females than in males. In this study, we examine depression, gender, and psychiatric diagnoses as predictors of self-reported everyday functioning. Methods: 372 subjects were enrolled in this study, including 218 with SCZ and 154 healthy controls. Participants self-reported their everyday social functioning using the 31-item Specific Level of Functioning (SLOF) scale. All participants self-reported their depression with the BDI and their impressions of their social cognitive ability on the Observable Social Cognition Rating Scale (OSCAR). The resulting data was analyzed using linear regression models, predicting self-reported social functioning and social cognition with sex, diagnosis, and self-reported depression. Results: 64% of subjects were male and 36% were female. Schizophrenia patients reported more depression, poorer social functioning, and worse social cognition. Linear regression analyses revealed a significant corre- lation between self-reported social functioning and scores on the BDI: R2=.23. BDI scores also predicted self-reported social cognition on the OSCARS: R2=.30. There was no significant effect of sex on either self-reported social functioning or social cognition. Diagnosis accounted for 6% of the variance in OSCARS scores, but none for self-reported social functioning when depression was accounted for. Finally, when both the BDI and OSCARS were added to diagnosis and sex to predict self-reported social functioning, both depression, R2=.23, and OSCARS scores, R2=.06 predicted self-reported social functioning, with no impact of diagnosis or sex. Discussion: Self-reported interpersonal functioning is largely determined by levels of depression, with these influences being more important than sex or diagnosis of schizophrenia. Both healthy people and people with schizo- phrenia judge their social functioning by their level of depression, with the impact of sex not being statistically significant. Background: A wealth of data points to a role for deficient reward-seeking behavior in schizophrenia (SZ), as a mechanism of negative symptoms, in general, and avolition, in particular. Specifically, avolitional patients with SZ appear to experience reinforcers in a normative manner, but do not properly assign prospective value to rewards or actions that frequently lead to rewards. There are many forms of goal-directed behavior, how-ever, with reward-seeking behavior being only one. A second kind of goal-directed behavior is exploration: seeking out information about contingencies in the environment, so as to reduce uncertainty about available options. Successful navigation of the explore/exploit trade-off is critical to adaptive behavior. In several different studies, we have examined infor-mation-seeking behavior in individuals with SZ and matched controls, hypothesizing that reductions in goal-directed exploration make substan- tial contribution to avolition. Methods: We have used several different behavioral paradigms incorporat- ing an explore/exploit trade-off in samples of SZ patients and matched controls. Two of these paradigms were forms of reversal learning tasks, where individuals learn to choose the most-frequently-rewarded of two or three stimuli, with reward contingencies changing after a certain number of consecutive correct choices. A third paradigm required participants to track the value of three slot machines across stable and volatile runs of trials (when reward contingencies changed suddenly, independent of per- formance). All of these paradigms were performed in conjunction with fMRI scanning, with single-subject MRI data being analyzed using par-ametric (amplitude-modulated) regressors constructed based on trial-wise estimates of expected value, certainty about value, and the degree to which choices were reward-seeking (choosing the slot machines with the highest EV) vs. information-seeking (driven by the exploration of unknown contin-gencies), Therefore, measures of cognitive flexibility may to how issues of mental health are to the public. Background: Are people who are extraordinarily creative more likely to be mentally ill? Are all mentally ill people more creative? These are questions that have been asked for a very long time by scientists and philosophers. The link between creativity and mental illnesses has been hypothesized in varied ways. However, this link has not been properly es- tablished yet. Research from the last two decades has proposed that the problems in establishing such link or relationship is that it may only be present in certain specific mental illnesses, namely those with a psychotic component (e.g. bipolar disorder, schizotypal personality disorder) (Thys, Sabbe, & De Hert, 2014; Barrantes Vidal, 2004). We study this link using musical hallucinations (MH) as these are often being believed to be experienced as less disturbing than other types of hallucinations (e.g. auditory verbal, visual) (Shakenraad et al., 2006; Evers, 2006). Using MH in this study allowed to investigate the creativity-”madness” link in a more positive light. Methods: 76 participants were measured from a student population, who completed a series of tasks. We introduced a novel approach of measuring creativity (defined as the propensity to detect imaginary music), through a musical Signal Detection Task (SDT). During this SDT, bursts of au-dible pink noise were being played, sometimes mixed with music, and sometimes without. The participants also completed two questionnaires, related to hallucination proneness (LSHS-R) and schizotypy personality traits (SPQ-BR). Furthermore, the participants performed a series of computer tasks related to different ways of measuring

S45. DEFICITS IN INFORMATION-SEEKING BEHAVIOR IN SCHIZOPHRENIA: AN ALTERNATIVE MECHANISM OF AVOLITION

F9. REDUCED UNCERTAINTY-DRIVEN EXPLORATION AND ASSOCIATED NEURAL REWARD-RELATED SIGNALS RELATE TO MOTIVATIONAL DEFICIT SEVERITY

L'A. examine la these soutenue recemment par deux scientifiques de Harvard selon laquelle le niveau plus ou moins eleve d'intelligence d'une race est determine essentiellement par la genetique et non par l'environnement. La difference de quinze points entre blancs et noirs, donnee par un test de mesure du QI, est une donnee indiscutable. L'A. veut montrer que cette theorie se base sur une dangereuse ambiguite de fond, sur une confusion entre deux notions distinctes de l'heredite genetique et sur une accumulation de raisonnements errones

Race, gènes et QI : Un débat empoisonné par l'ambiguïté des concepts

Experiments suggest that conscious decisions to act may be initiated by unconscious neural events that precede the decision. Some have concluded that unconscious neural events are sufficient to cause both the decision to act and the action, so consciousness has no causal efficacy in producing the action. Here, I explain why this reasoning is fallacious in terms that apply to all mental events, using a variety of examples in which the conscious aspect of a mental event has a different and even an “opposite” effect on behavior from the unconscious aspect. These cases provide vivid illustrations of the distinct causal contributions of conscious and unconscious aspects of a mental event to behavior. One conclusion is that the neuroscience of decision has been overly focused on binary “go/no go” contents, obscuring the ways in which conscious and unconscious contents can make distinct contributions to decision and to action.

A central debate in philosophy and neuroscience pertains to whether PFC activity plays an essential role in the neural basis of consciousness. Neuroimaging and electrophysiology studies have revealed that the contents of conscious perceptual experience can be successfully decoded from PFC activity, but these findings might be confounded by postperceptual cognitive processes, such as thinking, reasoning, and decision-making, that are not necessary for consciousness. To clarify the involvement of the PFC in consciousness, we present a synthesis of research that has used intracranial electrical stimulation (iES) for the causal modulation of neural activity in the human PFC. This research provides compelling evidence that iES of only certain prefrontal regions (i.e., orbitofrontal cortex and anterior cingulate cortex) reliably perturbs conscious experience. Conversely, stimulation of anterolateral prefrontal sites, often considered crucial in higher-order and global workspace theories of consciousness, seldom elicits any reportable alterations in consciousness. Furthermore, the wide variety of iES-elicited effects in the PFC (e.g., emotions, thoughts, and olfactory and visual hallucinations) exhibits no clear relation to the immediate environment. Therefore, there is no evidence for the kinds of alterations in ongoing perceptual experience that would be predicted by higher-order or global workspace theories. Nevertheless, effects in the orbitofrontal and anterior cingulate cortices suggest a specific role for these PFC subregions in supporting emotional aspects of conscious experience. Overall, this evidence presents a challenge for higher-order and global workspace theories, which commonly point to the PFC as the basis for conscious perception based on correlative and possibly confounded information.

Does the Prefrontal Cortex Play an Essential Role in Consciousness? Insights from Intracranial Electrical Stimulation of the Human Brain

Reply to commentary by Naccache and colleagues (https://osf.io/zrqp8/) on our paper (Raccah et al., 2021) -https://www.jneurosci.org/content/41/10/2076.abstract

Subjective phenomena elicited by intracranial electrical stimulation challenge a global neuronal workspace hypothesis: A reply to objections raised by Naccache et al.

Computational models of visual processing aim to provide a compact, explanatory account of the complex neural processes that underlie visual perception and behavior. But what, if anything, do current modeling approaches say about how conscious visual experience arises from neural processing? Here, we introduce the reader to four commonly used models for understanding visual computations, neural activity, and behavior: signal detection theory, drift diffusion, probabilistic population codes, and sampling. In an attempt to bridge these modeling approaches with experimental and philosophical work on the neural basis of conscious visual perception, we lay out possible relationships between the components of the models and the contents of phenomenal visual experience. We find no unique relation between model components and phenomenal experience in any model; rather, there are multiple logically possible mappings from models to experience. Going forward, we suggest that there are scientific opportunities to develop models that predict and explain a variety of subjective reports and philosophical opportunities to consider what aspects of phenomenal experience are promising scientific targets.

What do models of visual perception tell us about visual phenomenology?

Do change-­‐blindness and inattentional blindness give rise to perceptual experiences that are so inattentive to be unreportable? Ned Block argues that they do, giving a powerful defense that has driven forward the debate about this central question in the philosophy and psychology of perception. 1 If Block is right, then we can ask whether the justificatory force traditionally accorded to perceptual experience really belongs to the subclass of attentive, reportable perceptual experiences. Your confidence that there's a hole in the ground, or a door in the fence, or a dog in your way often derives from the fact that you can plainly see these things. If you experienced these facts so inattentively that you couldn't report them, one might reasonably wonder whether your consciously seeing them still gives you reason to think they obtain. Does the reason you get from perceptual experience depend more on its attentiveness and reportability, or more on the mere fact that the experience is conscious? When phenomenal character comes apart from both attentiveness and reportability, does its justificatory force go with it? These are ways of asking what kinds of rational roles highly inattentive perceptual experiences can play. Our main goal is to explore the tenability of the view that attention is optional for perceptual justification – so much so that even largely inattentive perceptual experiences can provide it. This view is worth exploring, because on a widely held picture, perceptual experiences provide justification, when they do, partly in virtue of their phenomenal character. Whether or not one accepts the traditional identification of perceptual experiences per se as a provider of justification, one might wonder whether the existence of inattentive, unreportable experiences counts against it or not. We think it doesn't. After some preliminary clarification in section 1, sections 2-­‐3 formulate two main theses about the rational role of highly inattentive perceptual experiences, and sections 4-­‐5 defend the idea that such inattentive experiences are not disqualified from providing justification. We conclude in section 6 by discussing what positive epistemic roles attention might have. Throughout, our discussion of experience applies only to perceptual experiences. 2 The term " perceptual experience " is sometimes used to denote experiences one has while perceiving external things. But in our usage, perceptual experiences include hallucinations. They need not be cases of perceiving external things.

—0 —+1 Much of the battle over firstorder versus higherorder theories of conscious experience concerns intuitions concerning the word “consciousness”—or more charitably, the concept of consciousness. Firstorder perceptual repre sen ta tions are repre sen ta tions of the world, whereas higherorder repre sen ta tions are repre sen ta tions of one’s represen ta tions, including but not limited to firstorder repre sen ta tions. Firstorder theories of the sort I advocate locate conscious perception in interacting repre sen ta tions of the world and perhaps interactions between repre sen ta tions of the world and subcortical activations that do not represent anything. Advocates of higherorder theories focus on the founding intuition that a state that one is in no way conscious of being in is not a conscious state. In recent years, I have suggested that firstorder theories can accommodate this intuition via a sameorder account in which conscious states include a kind of awareness of themselves. I have also taken seriously the idea that the founding intuition is too superficial to give us any insight. We say that a song is something one sings, that a dance is something one dances, and a jump is something one jumps. These relations are superficial in that they do not provide any substantive insight into what singing, dancing, or jumping is. Similarly, saying a conscious state is one we are conscious of is a superficial relation. In some past writings I have focused on a bizarre feature of higherorder views, such as those of Rosenthal (2005) and Weisberg (2010), in which a conscious visual experience as of the green color of the grass on my lawn can occur without any firstorder visual repre sen ta tion of the green color of the grass (Block 2011a, 2011b). These authors are forced into this position by consideration of cases in which firstorder and higherorder repre sen ta tions disagree and cases in which there are no firstorder represen ta tions for the higherorder repre sen ta tions to be about. I have found discussions on this topic rather unproductive— even more so than most intuitionbased disagreements in philosophy. So I welcome that Hakwan Lau and Richard Brown have focused their discussion on actual cases that raise genuine empirical issues. By discussion of these and other real cases, we stand a better chance of adjudicating between firstorder and higherorder theories. 12 Empirical Science Meets HigherOrder Views of Consciousness: Reply to Hakwan Lau and Richard Brown

Empirical Science Meets Higher-Order Views of Consciousness: Reply to Hakwan Lau and Richard Brown

The success of the Bayesian perspective in explaining perceptual phenomena has motivated the view that perceptual representation is probabilistic. But if perceptual representation is probabilistic, why does normal conscious perception not reflect the full probability functions that the probabilistic point of view endorses? For example, neurons in cortical area MT that respond to the direction of motion are broadly tuned: a patch of cortex that is tuned to vertical motion also responds to horizontal motion, but when we see vertical motion, foveally, in good conditions, it does not look at all horizontal. The standard solution in terms of sampling runs into the problem that sampling is an account of perceptual decision rather than perception. This paper argues that the best Bayesian approach to this problem does not require probabilistic representation. This article is part of the theme issue ‘Perceptual consciousness and cognitive access'.

If perception is probabilistic, why does it not seem probabilistic?

—0 —+1 Michael Tye argues for an externalist version of repre sen ta tionism concerning the phenomenology of perception. Repre sen ta tionism on one version says that what it is for a percept to have a certain phenomenal character is for it to have a certain repre senta tional content. Tye wants to stay neutral on which form of repre sen ta tionism he is defending, but the kind of repre sen ta tionism he has advocated and I have criticized is externalist and reductionist. What it is to have an experience as of redness is to be in a state of nonconceptually representing an external world property redness. (Tye adds a functional condition to distinguish conscious from unconscious perception, and there are restrictions on the kind of content involved, but I won’t discuss those aspects of the view.) Tye’s view is distinct from what one might call a phenomenologyfirst view in which the property represented is phenomenal or in which there is an irreducible phenomenal mode of pre sen ta tion. It would be tempting to describe Tye’s view as a representationfirst view since he thinks there is nothing more to phenomenal character than repre sen ta tional content, but since Tye’s view is an identity theory (phenomenal character and the repre sen ta tional property are one and the same), it is better termed what Adam Pautz (2008, 263) calls a “nopriority” view. What is front and center in Tye’s chapter is not repre sen ta tionism per se but the putative historical dimension of externalist repre sen ta tion: the content of a repre senta tion that a subject has at noon depends constitutively (and not just causally) on what happened at previous times and even on the evolutionary history of the species. Although the official topic is repre sen ta tionism, the issues raised are also highly relevant to functionalism. The argument proceeds by comparing three dif fer ent science fiction examples: Groupsatellite brain: This case is descended from Hilary Putnam’s (1967) example of a swarm of bees that duplicates human functional organ ization. A large number of people communicating by satellite play the role of an external brain for a robot body. I used the nation of China as an example because of its large population (Block 1978), and that led to Searle’s Chinese Room argument two years later. (Searle told me at the time that he had read my paper.) The distributed brain and robot body together 34 Fading Qualia: A Response to Michael Tye

In their Review “What is consciousness, and could machines have it?” (27 October 2017, p. [486][1]), S. Dehaene et al. argue that the science of consciousness indicates that we are not on the verge of creating conscious machines. However, Dehaene et al. ask and answer the wrong questions.

To

Stringent Definitions : What Should Count as “ Unconscious ” and “ Perception ” ?

In our ASSC20 symposium, “Does unconscious perception really exist?”, the four of us asked some difficult questions about the purported phenomenon of unconscious perception, disagreeing on a number of points. This disagreement reflected the objective of the symposium: not only to come together to discuss a single topic of keen interest to the ASSC community, but to do so in a way that would fairly and comprehensively represent the heterogeneity of ideas, opinions, and evidence that exists concerning this contentious topic. The crux of this controversy rests in no small part on disagreement about what is meant by the terms of the debate and how to determine empirically whether a state is unconscious or not. 
 
These are issues that directly concern all of us who study consciousness, so it seems it would be in our best interest to strive for consensus. Given the conversation at ASSC20, we are pleased to have the opportunity to address some of the nuanced topics that arose more formally, and share some of the thinking we have done since the meeting. To reflect the heterogeneity of ideas and opinions surrounding this topic, we have organized this discussion into four distinct contributions.

Does unconscious perception really exist? Continuing the ASSC20 debate

In our ASSC20 symposium, “Does unconscious perception really exist?”, the four of us asked some difficult questions about the purported phenomenon of unconscious perception, disagreeing on a number of points. This disagreement reflected the objective of the symposium: not only to come together to discuss a single topic of keen interest to the ASSC community, but to do so in a way that would fairly and comprehensively represent the heterogeneity of ideas, opinions, and evidence that exists concerning this contentious topic. The crux of this controversy rests in no small part on disagreement about what is meant by the terms of the debate and how to determine empirically whether a state is unconscious or not. These are issues that directly concern all of us who study consciousness, so it seems it would be in our best interest to strive for consensus. Given the conversation at ASSC20, we are pleased to have the opportunity to address some of the nuanced topics that arose more formally, and share some of the thinking we have done since the meeting. To reflect the heterogeneity of ideas and opinions surrounding this topic, we have organized this discussion into four distinct contributions.

Abstract A recent fMRI study by Webb et al. (Cortical networks involved in visual awareness independent of visual attention, Proc Natl Acad Sci U S A 2016;113:13923–28) proposes a new method for finding the neural correlates of awareness by matching attention across awareness conditions. The experimental design, however, seems at odds with known features of attention. We highlight logical and methodological points that are critical when trying to disentangle attention and awareness.

SU M M A RY: The first aim of this paper is to remind the reader of a very original theory of meaning which in many aspects has not been surpassed by subsequent theories. The theory in question is Kazimierz Ajdukiewicz’s Directival Theory of Meaning. In the first section I present a version of this theory which, I trust, retains the gist of the original but loses its outdated language. In the second section I analyze some problematic consequences of the directival theory (specifically Tarski’s counterexample) and show how they can be addressed. The second aim of this paper is exploiting some of the similarities between the directival theory and later theories of meaning. In the third section I argue that using the directival theory as an interpretative tool enables us to create explications of some of the notoriously vague notions which contemporary theories of meaning employ.

Abstract One approach to the issue of a joint in nature between perception and cognition is to investigate whether the concepts of perception and cognition can be tweaked to avoid direct, content-specific effects of cognition on perception.

The Anna Karenina Principle and Skepticism about Unconscious Perception

This paper argues for a failure of correspondence between perceptual representation and what it is like to perceive. If what it is like to perceive is grounded in perceptual representation, then, using considerations of veridical representation, we can show that inattentive peripheral perception is less representationally precise than attentive foveal perception. However, there is empirical evidence to the contrary. The conclusion is that perceptual representation cannot ground what it is like to perceive.

If representationism is true, phenomenal precision is given by representational precision. But what if representationism is false as I claim? Can we make sense of phenomenal precision? Fink argues that there is a danger of trivialization of phenomenal precision and that the one way out may be incompatible with my view that consciousness overflows cognition. I try to say more about how to clarify phenomenal precision and its relation to my views on overflow.

Consciousness science: real progress and lingering misconceptions

I will discuss the issue of what we see, using the framework of Tyler Burge’s wonderful and monumental book Origins of Objectivity (Burge 2010). On Burge’s view, every percept is constituted by a “perceptual attributive” (that represents an attribute) and a singular element (that represents an individual). The format of a percept is map-like or iconic, and could be symbolized as “That F”. The most basic perceptual judgments and beliefs are conceptualized and propositionalized versions of percepts in which the attributive need not be bound to a time and place. What are the actual perceptual attributives? Vision science picks out a small set of basic low level attributives that are products of sensory transduction and are causally involved in the production of other visual attributives: shape, spatial relations (including position and size), geometrical motion, texture, brightness and color. Burge discusses a higher level attributive for objects (“integrated body”) and considers that there may be some higher level attributives for some biologically important properties like food, danger and shelter. However, he notes (and I agree) that probably there are no culture-specific higher level attributives for teacups and recessions (p. 101). Terminological note: I will abbreviate the list of low level environmental attributives with “color, shape and texture” and I will refer to all attributives that are not low level as “high level”.

Michael Tye's response to my “Grain” (Block 2012) and “Windows” (Block 2013) raises general metaphilosophical issues about the value of intuitions and judgments about one's perceptions and the relations of those intuitions and judgments to empirical research, as well as specific philosophical issues about the relation between seeing, attention and de re thought. I will argue that Tye's appeal to what is (§. 2) “intuitively obvious, once we reflect upon these cases” (“intuition”) is problematic. I will also argue that first person judgments can be problematic when used on their own as Tye does but can be valuable when integrated with empirical results.

Clark advertises the predictive coding (PC) framework as applying to a wide range of phenomena, including attention. We argue that for many attentional phenomena, the predictive coding picture either makes false predictions, or else it offers no distinctive explanation of those phenomena, thereby reducing its explanatory power.

I am grateful to Bradley Richards and J. H. Taylor for their thoughtful critiques and for the chance to clarify and re-think the main line of argument in ‘‘The Grain of Vision and the Grain of Attention’’ (Block 2013). My article concerned peripheral vision. Much of normal vision is peripheral. The fovea is the central area of the retina that is needed for fine discrimination, for example in reading. It subtends only 2◦ of visual angle, a bit more than the width of the thumbnail at arm’s length, so if you are looking at something the size of a hand at arm’s length, on any one fixation most of it is seen nonfoveally. All perception degrades in acuity in the periphery because cone cells in the retina decrease with eccentricity. But object-perception in the periphery suffers from more than a degradation in acuity; it suffers from crowding. Crowding is a phenomenon of peripheral vision in which ‘‘things . . . lose the quality of form . . . without losing crispness . . .’’ (Lettvin 1976). It is widely agreed that the explanation of crowding is that vision involves assigning features to objects; but there are minimal ‘‘windows of integration’’ within which the visual system cannot determine which features are to be bound to which objects. (Binding is the process by which the visual registration of a blue square and a red circle involves blueness being attributed to the square instead of the circle.) The windows of integration grow larger farther from the fixation point—that is, where the eyes are pointing. See Figure 1 for an indication of the size and shape of these windows. In the periphery, the windows can be large enough so that normally two or more objects are in the same window. I argued that there is conscious object-seeing without object-attention in a phenomenon that I called identity-crowding. Identity-crowding is the special case of crowding in which the crowded items are all the same so that there is no issue of determining which features are bound to which objects. See Figure 2 for an example. As Taylor and Richards note, my argument was that in identity-crowding, the subject consciously detects the crowded object (in the sense of distinguishing consciously between presence and absence), consciously differentiates the object from the background, consciously discriminates the crowded object from other objects and consciously identifies the crowded object, so it is difficult to see a rationale for denying that

Discussion of J. Kevin O’Regan’s “Why Red Doesn’t Sound Like a Bell: Understanding the Feel of Consciousness”

Often when there is no attention to an object, there is no conscious perception of it either, leading some to conclude that conscious perception is an attentional phenomenon. There is a well-known perceptual phenomenon—visuo-spatial crowding, in which objects are too closely packed for attention to single out one of them. This article argues that there is a variant of crowding—what I call “identity-crowding”—in which one can consciously see a thing despite failure of attention to it. This conclusion, together with new evidence that attention to an object occurs in unconscious perception, suggests there may be a double dissociation between conscious perception of an object and attention to that object, constraining the extent to which consciousness can be constitutively attentional. The argument appeals to a comparison between the minimal resolution (or “grain”) of object-attention and object-seeing.

Response to Kouider et al.: which view is better supported by the evidence?

I described an incoherence in one form of the higher order thought (HOT) theory that derives from its holding both that an appropriate higher order thought is sufficient for a conscious state and that being the object of an appropriate higher order thought is necessary for a conscious state. A (1) lone and (2) unconscious (i.e. not the object of another HOT) and (3) ''empty'' (i.e. reference-failing) higher order thought at t determines a conscious state at t, but – contrary to the necessary condition – there is no thought at t about that conscious state – unless the lone thought is about itself. But such self-reference would collapse the HOT theory into the rival same-order

or in terms of the existence of a conclusive justification for the proposition. I take this fragmentation of sentential apriority and knowability and different notions of propositional apriority and knowability to be perhaps the most interesting upshot of the original puzzle. In conclusion: if one accepts an orthodox semantics for 'actually' and an orthodox understanding of apriority, one must reject the orthodox view that p $ Ap is always a priori. Likewise, if one accepts the orthodox view that p $ Ap is always a priori, one must adopt an unorthodox semantics for 'actually' or an unorthodox understanding of apriority. The higher order approach to consciousness attempts to build a theory of consciousness from the insight that a conscious state is one that the subject is

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Author ' s personal copy Perceptual consciousness overflows cognitive access

The Anna Karenina theory says: all conscious states are alike; each unconscious state is unconscious in its own way. This paper argues that many components have to function properly to produce consciousness, but failure in any one of many different ones can yield an unconscious state in different ways. In that sense the Anna Karenina theory is true. But in another respect it is false: kinds of unconsciousness depend on kinds of consciousness.

American Philosophical Quarterly | Vol. 48 No. 4 | ARTICLE: Kevin Morris: Theoretical Identities as Explanantia and Explananda | PDF Document

Consciousness is a mongrel concept: there are a number of very different "consciousnesses." Phenomenal consciousness is experience; the phenomenally conscious aspect of a state is what it is like to be in that state. The mark of access-consciousness, by contrast, is availability for use in reasoning and rationally guiding speech and action. These concepts are often partly or totally conflated, with bad results. This target article uses as an example a form of reasoning about a function of "consciousness" based on the phenomenon of blindsight. Some information about stimuli in the blind field is represented in the brains of blindsight patients, as shown by their correct "guesses," but they cannot harness this information in the service of action, and this is said to show that a function of phenomenal consciousness is somehow to enable information represented in the brain to guide action. But stimuli in the blind field are BOTH accessunconscious and phenomenally unconscious. The fallacy is: an obvious function of the machinery of access-consciousness is illicitly transferred to phenomenal consciousness.

Much of recent philosophy of perception is oriented towards accounting for the phenomenal character of perception—what it is like to perceive—in a non-mentalistic way—that is, without appealing to mental objects or mental qualities. In opposition to such views, I claim that the phenomenal character of perception of a red round object cannot be explained by or reduced to direct awareness of the object, its redness and roundness—or representation of such objects and qualities. Qualities of perception that are not captured by what one is directly aware of or by representational content are instances of what Gilbert Harman has called “mental paint” (Block, 1990; Harman, 1990). The claim of this paper is that empirical facts about attention point in the direction of mental paint. The argument starts with the claim (later modified) that when one moves one’s attention around a scene while keeping one’s eyes fixed, the phenomenology of perception can change in ways that do not reflect which qualities of objects one is directly aware of or the way the world is represented to be. These changes in the phenomenology of perception cannot be accounted for in terms of awareness of or representation of the focus of attention because they manifest themselves in experience as differences in apparent contrast, apparent color saturation, apparent size, apparent speed, apparent time of occurrence and other appearances. There is a way of coping with these phenomena in terms of vague contents, but vague contents cannot save direct realism or representationism because the kind of vagueness required clashes wth the phenomenology itself.

For nearly thirty years, there has been a consensus (at least in English-speaking countries) that reductionism is a mistake and that there are autonomous special sciences. This consensus has been based on an argument from multiple realizability. But Jaegwon Kim has argued persuasively that the multiple realizability argument is flawed.1 I will sketch the recent history of the debate, arguing that much --but not all--of the anti-reductionist consensus survives Kim's critique. This paper was originally titled "Anti-Reductionism Strikes Back", but in the course of writing the paper, I came to think that the concepts used in the debate would not serve either position very well.

Marshall M. Weinberg Conference: The Future of Cognitive Science - Friday afternoon (Oct. 17, 2008) session: Christoph Koch and Ned Block

Abstract How can we disentangle the neural basis of phenomenal consciousness from the neural machinery of the cognitive access that underlies reports of phenomenal consciousness? We see the problem in stark form if we ask how we can tell whether representations inside a Fodorian module are phenomenally conscious. The methodology would seem straightforward: Find the neural natural kinds that are the basis of phenomenal consciousness in clear cases – when subjects are completely confident and we have no reason to doubt their authority – and look to see whether those neural natural kinds exist within Fodorian modules. But a puzzle arises: Do we include the machinery underlying reportability within the neural natural kinds of the clear cases? If the answer is “Yes,” then there can be no phenomenally conscious representations in Fodorian modules. But how can we know if the answer is “Yes”? The suggested methodology requires an answer to the question it was supposed to answer! This target article argues for an abstract solution to the problem and exhibits a source of empirical data that is relevant, data that show that in a certain sense phenomenal consciousness overflows cognitive accessibility. I argue that we can find a neural realizer of this overflow if we assume that the neural basis of phenomenal consciousness does not include the neural basis of cognitive accessibility and that this assumption is justified (other things being equal) by the explanations it allows.

Consciousness, accessibility, and the mesh between psychology and neuroscience

In his famous article advocating mind-body identity, J.J.C. Smart (1959) considered an objection (objection 3) that he says he thought was first put to him by Max Black. He says “...it is the most subtle of any of those I have considered, and the one which I am least confident of having satisfactorily met”. This argument, which is often called the Property Dualism Argument, has been mentioned often in one way or another in the literature but in my view, there has been no adequate rebuttal of it. This paper is aimed at elaborating and refuting the Property Dualism Argument—or rather a family of Property Dualism Arguments-and drawing some connections to related arguments.

This volume of Ned Block's writings collects his papers on consciousness, functionalism, and representationism. A number of these papers treat the significance of the multiple realizability of mental states for the mind-body problem -- a theme that has concerned Block since the 1960s. One paper on this topic considers the upshot for the mind-body problem of the possibility of a robot that is functionally like us but physically different -- as is Commander Data of Star Trek's second generation. The papers on consciousness treat such conceptual issues as phenomenal versus access consciousness, Dennett's theory of consciousness, and the function of consciousness, as well as such empirical matters as "How Not to Find the Neural Correlate of Consciousness," and (in an expanded version of a paper originally in Trends in Cognitive Sciences) an argument that there are distinct neural correlates for access consciousness and phenomenal consciousness. Turning to the mind-body problem, Block defends physicalism against Max Black's argument concerning phenomenal modes of presentation. The papers on representationism consider "mental paint" as well as the "Inverted Earth" thought experiment -- a world in which colors are reversed but there is a compensating reversal in the words that are used to describe them. Consciousness, Function, and Representation, bringing together papers that have appeared primarily in journals and conference proceedings, can be regarded as Block's most complete statement of his positions on consciousness.

Abstract In this response to 32 commentators, I start by clarifying the overflow argument. I explain why the distinction between generic and specific phenomenology is important and why we are justified in acknowledging specific phenomenology in the overflow experiments. Other issues discussed are the relations among report, cognitive access, and attention; panpsychic disaster; the mesh between psychology and neuroscience; and whether consciousness exists.

There are many problems of consciousness, but the most significant of them is: how is it possible to explain consciousness in terms of its neural basis? 
 
Keywords: 
 
consciousness; 
hard problem; 
deflationism; 
inflationism; 
reflexivity; 
neural

I. I find myself unable to share the reasoning set forth in paras. 184-199 of the Final Award in this case (the "Award") regarding the Claimant's direct expropriation claim, and the Award's final determination of such claim. For reasons set forth further below, I distance myself from the statement in para. 183 of the Award to the extent it limits the material benefits susceptible to expropriation under article VIII. 1 of the Canada-Ecuador Agreement for the Promotion and Reciprocal Protection of Investments of 29 April 1996 (the "Treaty") to acquired rights as characterized in the said paragraph. Unlike the Award, I am of the opinion that conduct attributable to Ecuador has expropriated EnCana's returns on its investments in Ecuador in breach of article VIII.l of the Treaty.

The merely verbal problem of consciousness Reply to Baars and Laureys

Representationism, 1 as I use the term, says that the phenomenal character of an experience just is its representational content, where that representational content can itself be understood and characterized without appeal to phenomenal character. Rep-resentationists seem to have a harder time handling pain than visual experience. (I say 'seem' because in my view, representationists cannot actually handle either type of experience successfully, but I will put that claim to one side here.) I will argue that Michael Tye's heroic attempt (this volume) at a representationist theory of pain, although ingenious and enlightening, does not adequately come to terms with the root of this difference. Representationism is in part an attempt to make an account of phenomenal character comport with G. E. Moore's diaphanousness intuition, the idea of which is that when I try to introspect my experience of the red tomato, I only succeed in attending to the color of the tomato itself, and not to any mental feature of the experience. The representationist thinks we can exploit this intuition to explain phenomenal character in nonphenomenal terms. To understand representationism, we need to know what to make of the phrase 'representational content' as applied to an experience. There is no clear pretheoretical notion of representational content as applied to an experience , certainly none that will be of use to the representationist. True, I can speak of seeing that and seeing as, and more generally of experiencing that and experiencing as. Looking at the gas gauge, I can say that I see that the tank is empty (Dretske 1995). And I can say that I experience my wound as a medical emergency. These (and other) pretheoretical ways of thinking of something that could be called the representational content of experience have little to do with phenomenology or with the kind of prop

Alexander of Aphrodisias 282-93 Mantissa (Book 2 of On the Soul) 282-93 Ethical Problems 284 and Academic Scepticism 287-9

The ASSC William James prize for contributions to the study of consciousness

One approach to the mind has been to avoid its mysteries by simply defining the mental in terms of the behavioral. This approach has been popular among thinkers who fear that acknowledging mental states that do not reduce to behavior would make psychology unscientific, because unreduced mental states are not intersubjectively accessible in the manner of the entities of the hard sciences. "Behaviorism", as the attempt to reduce the mental to the behavioral is called, has often been regarded as refuted, but it periodically reappears in new forms.

WHAT ELSE COMES TO MIND WHEN YOU THINK OF YOUR FATHER ? " If you type in " Everybody

T. H. Huxley famously said ‘How it is that anything so remarkable as a state of consciousness comes about as a result of irritating nervous tissue, is just as unaccountable as the appearance of Djin when Aladdin rubbed his lamp.’ We do not see how to explain a state of consciousness in terms of its neurological basis. This is the Hard Problem of Consciousness. The aim of this paper is to present another problem of consciousness. The Harder Problem as I will call it is more epistemological than the

Petrus Hispanus Lectures 2003. The harder problem of consciousness

(Kim, 1998), the Causal Exclusion Argument. The issue is whether it is a consequence of the Causal Exclusion Argument that all macro level causation (that is, causation above the level of fundamental physics) is an illusion, with all of the apparent causal powers of mental and other macro properties draining into the bottom level of physics. I will argue that such a consequence would give us reason to reject the Causal Exclusion Argument. But there is also a stronger challenge, the charge that, if there is no bottom level of physics, the Causal Exclusion Argument has the consequence that “causal powers would drain away into a bottomless pit and there wouldn’t be any causation

Brain-Wise Studies in Neurophilosophy. by Patricia Smith Churchland. MIT Press, Cambridge, MA, 2002. 486 pp., $65, £43.50. ISBN 0-262-03301-1. Paper, $25, £16.95. ISBN 0-262-53200-X. Churchland explores the implications of our current understanding of the brain for long-debated philosophical questions such as consciousness, free will, and morality.

The aim of this paper is to present another problem of consciousness. The Harder Problem as I will call it is more epistemological than the Hard Problem. A second difference: the Hard Problem could arise for someone who has no conception of another person, whereas the Harder Problem is tied closely to the problem of other minds. Finally, the Harder Problem reveals an epistemic tension or at least discomfort in our ordinary conception of consciousness that is not suggested by the Hard Problem, and so in one respect it is harder. Perhaps the Harder Problem includes the Hard Problem and is best thought of as an epistemic add-on to it. Or perhaps they are in some other way facets of a single problem. Then my point is that this single problem breaks into two parts, one of which is more epistemic, involves other minds, and involves an epistemic discomfort.

There are two concepts of consciousness that are easy to confuse with one another, access consciousness and phenomenal consciousness. However, just as the concepts of water and H2O are different concepts of the same thing, so the two concepts of consciousness may come to the same thing in the brain. The focus of this paper is on the problems that arise when these two concepts of consciousness are conflated. I will argue that John Searle’s reasoning about the function of consciousness goes wrong because he conflates the two senses. And Francis Crick and Christof Koch fall afoul of the ambiguity in arguing that visual area V1 is not part of the neural correlate of consciousness. Crick and Koch’s work raises issues that suggest that these two concepts of consciousness may have different (though overlapping) neural correlates—despite Crick and Koch’s implicit rejection of this idea. I will start with two quotations from Searle. You will see what appears to be a contradiction, and I will later claim that the appearance of contradiction can be explained if one realizes that he is using two different concepts of consciousness. I am not going to explain yet what the two concepts of consciousness are. That will come later, after I have presented Searle’s apparent contradiction and Crick and Koch’s surprising argument.

There is reason to believe that people of different gender, race or age differ in spectra that are shifted relative to one another. Shifted spectra are not as dramatic as inverted spectra, but they can be used to make some of the same philosophical points.

Money is a cultural construction, leukemia is not. In which category does phenomenal consciousness fit? The issue is clarified by a distinction between what cultural phenomena causally influence and what culture constitutes. Culture affects phenomenal consciousness but it is ridiculous to suppose that culture constitutes it, even in part.

The explanatory gap. Consciousness is a mystery. No one has ever given an account, even a highly speculative, hypothetical, and incomplete account of how a physical thing could have phenomenal states (Nagel 1974, Levine 1983). Suppose that consciousness is identical to a property of the brain-say, activity in the pyramidal cells of layer 5 of the cortex involving reverberatory circuits from cortical layer 6 to the thalamus and back to layers 4 and 6-as Crick and Koch have suggested for visual consciousness (Crick 1994). Still, that identity itself calls out for explanation! Proponents of an explanatory gap disagree about whether the gap is permanent. Some (e.g., Nagel 1974) say that we are like the scientifically naive person who is told that matter = energy, but does not have the concepts required to make sense of the idea. If we can acquire these concepts, the gap is closable. Others say the gap is unclosable because of our cognitive limitations (McGinn 1991). Still others say that the gap is a consequence of the fundamental nature of consciousness.

Is Experiencing Just Representing?@@@Ten Problems of Consciousness

There are two concepts of consciousness that are easy to confuse with one another, access-consciousness and phenomenal consciousness. However, just as the concepts of water and H2O are different concepts of the same thing, so the two concepts of consciousness may come to the same thing in the brain. The focus of this paper is on the problems that arise when these two concepts of consciousness are conflated. I will argue that John Searle's reasoning about the function of consciousness goes wrong because he conflates the two senses. And Francis Crick and Christof Koch fall afoul of the ambiguity in arguing that visual area V1 is not part of the neural correlate of consciousness. Crick and Koch's work raises issues that suggest that these two concepts of consciousness may have different (though overlapping) neural correlates – despite Crick and Koch's implicit rejection of this idea.

A MOTIVATIONAL PERSPECTIVE OF CONSCIOUS EXPERIENCE. AUTHOR'S REPLY

The distinction between phenomenal (P) and access (A) consciousness arises from the battle between biological and computational approaches to the mind. If P = A, the computationalists are right; but if not, the biological nature of P yields its scientific nature.

According to Conceptual Role Semantics ("CRS"), the meaning of a representation is the role of that representation in the cognitive life of the agent, e.g. in perception, thought and decision-making. It is an extension of the well known "use" theory of meaning, according to which the meaning of a word is its use in communication and more generally, in social interaction. CRS supplements external use by including the role of a symbol inside a computer or a brain. The uses appealed to are not just actual, but also counterfactual: not only what effects a thought does have, but what effects it would have had if stimuli or other states had differed. The view has arisen separately in philosophy (where it is sometimes called "inferential," or "functional" role semantics) and in cognitive science (where it is sometimes called "procedural semantics"). The source of the view is Wittgenstein (1953) and Sellars, but the source in contemporary philosophy is a series of papers by Harman (see his 1987) and Field (1977). Other proponents in philosophy have included Block, Horwich, Loar, McGinn and Peacocke (1992). In cognitive science, they include Woods (1981) and Miller and Johnson-Laird (1976). (See references in Block, 1987.)

Part 1 Stream of consciousness: the stream of consciousness, William James the Cartesian theatre and "filling in" the stream of consciousness, Daniel C. Dennett the robust phenomenology of the stream of consciousness, Owen Flanagan. Part 2 Consciousness, science and methodology: prospects for a unified theory of consciousness or, what dreams are made of, Owen Flanagan consciousness, folk psychology and cognitive science, Alvin I. Goldman can neurobiology teach us anything about consciousness?, Patricia Smith Churchland time and the observer -the where and when of consciousness in the brain, Daniel C. Dennett and Marcel Kinsbourne begging the question against phenomenal consciousness, Ned Block time for more alternatives, Robert Van Gulick. Part 3 The psychology and neuropsychology of consciousness: contrastive phenomenology - a thoroughly empirical approach to consciousness, Bernard J. Baars visual perception and visual awareness after brain damage - a tutorial overview, Martha J. Farah understanding consciousness - clues from unilateral neglect and related disorders, Edoardo Bisiach modularity and consciousness, Tim Shallice towards a neurobiological theory of consciousness, Francis Crick and Christof Koch. Part 4 Consciousness and content: consciousness and content, Colin McGinn externalism and experience, Martin Davies a representational theory of pains and their phenomenal character, Michael Tye sensation and the content of experience - a distinction, Christopher Peacocke. Part 5 Function of consciousness: conscious inessentialism and the epiphenomenalist suspicion, Owen Flanagan on a confusion about a function of consciousness, Ned Block the path not taken, Daniel C. Dennett availability - the cognitive basis of experience?, David J. Chalmers fallacies or analyses?, Jennifer Church two kinds of consciousness, Tyler Burge understanding the phenomenal mind - are we all just armadillos?, part 2 - the absent qualia argument, Robert Van Gulick. Part 6 Metaphysics of consciousness: the identity thesis, Saul A. Kripke reductionism and the irreducibility of consciousness, John R. Searle a question about consciousness, Georges Rey finding the mind in the neural world, Frank Jackson breaking the hold - silicon brains, conscious robots and other minds, John R. Searle the first-person perspective, Sydney Shoemaker. Part 7 Subjectivity and explanatory gap: what is it like to be a bat?, Thomas Nagel can we solve the mind-body problem?, Colin McGinn on leaving out what it's like, Joseph Levine. Part 8 The knowledge argument: understanding the phenomenal mind - are we all just armadillos?, part 1 - phenomenal knowledge and explanatory gaps, Robert Van Gulick what Mary didn't know, Frank Jackson knowing qualia - a reply to Jackson, Paul M. Churchland what experience teaches, David Lewis phenomenal states, Brian Loar. Part 9 Qualia: quining qualia, Daniel C. Dennett the inverted spectrum, Sydney Shoemkaer the intrinsic qualit

What is Functionalism? Functionalism is one of the major proposals that have been offered as solutions to the mind/body problem. Solutions to the mind/body problem usually try to answer questions such as: What is the ultimate nature of the mental? At the most general level, what makes a mental state mental? Or more specifically, What do thoughts have in common in virtue of which they are thoughts? That is, what makes a thought a thought? What makes a pain a pain? Cartesian Dualism said the ultimate nature of the mental was to be found in a special mental substance. Behaviorism identified mental states with behavioral dispositions; physicalism in its most influential version identifies mental states with brain states. Functionalism says that mental states are constituted by their causal relations to one another and to sensory inputs and behavioral outputs. Functionalism is one of the major theoretical developments of Twentieth Century analytic philosophy, and provides the conceptual underpinnings of much work in cognitive science.

The greatest chasm in the philosophy of mind -maybe even all of philosophydivides two perspectives on consciousness. The two perspectives differ on whether there is anything in the phenomenal character of conscious experience that goes beyond the intentional, the cognitive and the functional. A convenient terminological handle on the dispute is whether there are "qualia". Those who think that the phenomenal character of conscious experience goes beyond the intentional, the cognitive and the functional are said to believe in qualitative properties of conscious experience, or qualia for short. The debates about qualia have recently focused on the notion of representation, with issues about functionalism always in the background. All can agree that there are representational contents of thoughts, for example the representational content that virtue is its own reward. And friends of qualia can agree that experiences at least sometimes have representational content too, e.g. that something red and round occludes something blue and square. The recent focus of disagreement is on whether the phenomenal character of experience

Mental (or semantic) holism is the doctrine that the identity of a belief content (or the meaning of a sentence that expresses it) is determined by its place in the web of beliefs or sentences comprising a whole theory or group of theories. It can be contrasted with two other views: atomism and molecularism. Molecularism characterizes meaning and content in terms of relatively small parts of the web in a way that allows many different theories to share those parts. For example, the meaning of 'chase' might be said by a molecularist to be try to catch. Atomism characterizes meaning and content in terms of none of the web; it says that sentences and beliefs have meaning or content independently of their relations to other sentences or beliefs. One major motivation for holism has come from reflections on the natures of confirmation and learning. As Quine (1953) observed, claims about the world are confirmed not individually, but only in conjunction with theories of which they are a part. And typically, one cannot come to understand scientific claims without understanding a significant chunk of the theory of which they are a part. For example, in learning the Newtonian concepts of 'force', 'mass', kinetic energy' and 'momentum', one doesn't learn any definitions of these terms in terms that are understood beforehand, for there are no such definitions. Rather, these theoretical terms were all learned together in conjunction with procedures for solving problems. The major problem with holism is that it threatens to make generalization in psychology virtually impossible. If the content of any state depends on all others, it would be extremely unlikely that any two believers would ever share a state with the same content. Moreover, holism would appear to conflict with our ordinary conception of reasoning. What sentences one accepts influence what one infers. if i accept a sentence and then later reject it, i thereby change the inferential role of that sentence, so the meaning of what i accept wouldn't be the same as what i later reject. but then it would be difficult to understand on this view how one could rationally --or even irrationally!-- change one's mind. and agreement and translation are also problematic for much the same reason. holists have responded (1) by proposing that we should think not in terms of "same/different" meaning but in terms of a gradient of similarity of meaning, (2) by proposing "two factor" theories or (3) by simply accepting the consequence that there is no real difference between changing meanings and changing beliefs.

Abstract With some help from the commentators, a few adjustments to the characterizations of A-consciousness and P-consciousness can avoid some trivial cases of one without the other. But it still seems that the case for the existence of P without A is stronger than that for A without P. If indeed there can be P without A, but not A without P, this would be a remarkable result that would need explanation.

Abstract Consciousness is a mongrel concept: there are a number of very different “consciousnesses.” Phenomenal consciousness is experience; the phenomenally conscious aspect of a state is what it is like to be in that state. The mark of access-consciousness, by contrast, is availability for use in reasoning and rationally guiding speech and action. These concepts are often partly or totally conflated, with bad results. This target article uses as an example a form of reasoning about a function of “consciousness” based on the phenomenon of blindsight. Some information about stimuli in the blind field is represented in the brains of blindsight patients, as shown by their correct “guesses.” They cannot harness this information in the service of action, however, and this is said to show that a function of phenomenal consciousness is somehow to enable information represented in the brain to guide action. But stimuli in the blind field are both access-unconscious and phenomenally unconscious. The fallacy is: an obvious function of the machinery of accessconsciousness is illicitly transferred to phenomenal consciousness.

One characterization of functionalism that is probably vague enough to be acceptable to most functionalists is: each type of mental state is a state consisting of a disposition to act in certain ways and to have certain mental states, given certain sensory inputs and certain mental states. So put, functionalism can be seen as a new incarnation of behaviorism. Behaviorism identifies mental states with dispositions to act in certain ways in certain input situations. But as critics have pointed out (Chisholm, 1957; Geach, 1957; Putnam, 1963), desire for goal G cannot be identified with, say, the disposition to do A in input circumstances in which A leads to G, since, after all, the agent might not know that A leads to G and thus might not be disposed to do A. Functionalism replaces behaviorism's "sensory inputs ' with "sensory inputs and mental states '; and functionalism replaces behaviorism's "dispositions to act" with "dispositions to act and have certain mental states." Functionalists want to individuate mental states causally, and since mental states have mental causes and effects as well as sensory causes and behavioral effects, Functionalists individuate mental states partly in terms of causal relations to other mental states. One consequence of this difference between functionalism and behaviorism is that there are possible organisms that according to behaviorism, have mental states but, according to functionalism, do not have mental states.

This paper is about truth-conditional content from the point of view of a use theory of meaning. I shall be taking up the question of how a use theory of meaning should deal with cases where uses of words might be said to be the same, but truth conditions differ-specifically Putnam's 'twin earth' cases.' The background issue is whether there is a legitimate notion of meaning or content that is purely 'inside the head'-not dependent on the external context of things referred to or on the language community. This paper defends the legitimacy of this 'narrow content' conception in the following limited way: I argue that use theories of meaning must deal with truth conditions in a way that leaves room for narrow content.

There has been considerable debate among philosophers and psychologists about whether the internal representations of imagery represent in the manner of pictures or in the manner of language. One side, pictorialism, holds that an internal imagery representation of Reagan is like a picture of Reagan. The other side, descriptionalism, holds that an internal imagery representation of Reagan is more like a string of words denoting or describing Reagan. My aim here is to expose a widespread fallacy on the part of the descriptionalists. In the course of so doing, I try to clarify the pictorialist position, and show how it can undercut what appears to be a category of evidence for the other side.'

I et psychologism be the doctrine that whether behavior is intelligent behavior depends on the character of the internal information processing that produces it. More specifically, I mean psychologism to involve the doctrine that two systems could have actual and potential behavior typical of familiar intelligent beings, that the two systems could be exactly alike in their actual and potential behavior, and in their behavioral dispositions and capacities and counterfactual behavioral properties (i.e., what behaviors, behavioral dispositions, and behavioral capacities they would have exhibited had their stimuli differed)-the two systems could be alike in all these ways, yet there could be a difference in the information processing that mediates their stimuli and responses that determines that one is not at all intelligent while the other is fully intelligent. This paper makes two claims: first, psychologism is true, and thus a natural behaviorist analysis of intelligence that is incompatible with psychologism is false. Second, the standard arguments against behaviorism are inadequate to defeat this natural behaviorist analysis of intelligence or to establish psychologism. While psychologism is of course anathema to behaviorists,1 it also seems wrong-headed to many philosophers who would not classify themselves as behaviorists. For example, Michael Dummett says:

X, Y and Z conspired to murder Mr. Body. Seventeen years ago, in the gold fields of Uganda, X was Body’s partner... Last week, Y and Z conferred in a bar in Reading... Tuesday night at l1:17, Y went to the attic and set a time bomb... Seventeen minutes later, X met Z in the billiard room and gave him the lead pipe... Just when the bomb went off in the attic, X fired three shots into the study through the French windows...

Introduction. What Is Philosophy of Psychology? Ned Block Part One: Behaviorism Introduction: Behaviorism Harris Savin 1. The Logical Analysis of Psychology Carl G. Hempel 2. Brains and Behavior Hilary Putnam 3. Selections from Science and Human Behavior B. F. Skinner 4. A Review of B. F. Skinner's Verbal Behavior Noam Chomsky Part Two: Reductionism and Physicalism Materialism without Reductionism: What Physicalism Does Not Entail Richard Boyd 5. Mental Events Donald Davidson 6. Special Sciences, or The Disunity of Science as a Working Hypothesis Jerry A. Fodor 7. Philosophy and Our Mental Life Hilary Putnam 8. Excerpt from "Identity and Necessity" Saul A. Kripke 9. Identity, Necessity, and Events Fred Feldman 10. Anomalous Monism and Kripke's Cartesian Intuitions Cohn McGinn 11. What Is It Like to Be a Bat? Thomas Nagel Part Three: Functionalism Introduction: What Is Functionalism? Ned Block Functional Analysis 12. Functional Analysis Robert Cummins Functional Specification 13. The Nature of Mind D. M. Armstrong 14. Armstrong on the Mind Thomas Nagel 15. Psychophysical and Theoretical Identifications David Lewis 16. Mad Pain and Martian Pain David Lewis Functional State Identity Theory 17. The Nature of Mental States Hilary Putnam 18. Review of Putnam David Lewis 19. Physicalism and the Multiple Realizability of Mental States Jaegwon Kim 20. What Psychological States Are Not Ned Block and Jerry A. Fodor 21. Functionalism and Qualia Sydney Shoemaker 22. Troubles with Functionalism Ned Block Index

The IQ Controversy: Critical Readings.@@@Origins of Intelligence: Infancy and Early Childhood.

review of Julian Jaynes, Origin of Consciousness in the Breakdown of the Bicameral Mind

From the combination of knowledge and actions, someone can improve their skill and ability. It will lead them to live and work much better. This is why, the students, workers, or even employers should have reading habit for books. Any book will give certain knowledge to take all benefits. This is what this the iq controversy critical readings tells you. It will add more knowledge of you to life and work better. Try it and prove it.

Two doubtful philosophical doctrines have contributed strongly to the development of IQ tests, and now play a major role in defending IQ tests as measures of intelligence: they are operationism and fictionalism.

PSA: Proceedings of the Biennial Meeting of the Philosophy of Science Association

AS FAR as anyone knows, different organisms are often in psychological states of exactly the same type at one time or another, and a given organism is often in psychological states of exactly the same type at different times. Whenever either is the case, we shall say of the psychological states of the organism(s) in question that they are type identical. One thing that currently fashionable theories in the philosophy of mind often try to do is characterize the conditions for type identity of psychological states. For example, some varieties of philosophical behaviorism claim that two organisms are in typeidentical psychological states if and only if certain of their behaviors or behavioral dispositions are type identical. Analogously, some (though not all) varieties of physicalism claim that organisms are in type-identical psychological states if and only if certain of their physical states are type identical. In so far as they are construed as theories about the conditions for type identity of psychological states, it seems increasingly unlikely that either behaviorism or physicalism is true. Since

I shall argue against the claim' that teleological and mechanistic explanations of behaviour2 are logically incompatible. Teleological explanations are explanations which make essential use of such concepts as purpose, desire, want, and intention. Mechanistic explanations are implicitly characterized by Taylor and Malcolm as those which are " non-teleological ". Appearances to the contrary, defining 'mechanistic ' as ' non-teleological' does not beg the question of the incompatibility of the two types of explanation. For example, let an " automotive explanation " be an explanation which makes essential use of the notion of a car. Then' I was late because my car stalled ' is an automotive explanation, and 'I was late because I had difficulty getting here ' is a non-automotive explanation. But these two explanations of my being late are not incompatible. The incompatibility thesis has misled both teleologists (believers in some teleological theory of behaviour) and mechanists. Teleologists (e.g., Malcolm) have used the thesis to argue that mechanistic accounts could not be true, while mechanists (e.g., Hull) have used the thesis to argue that teleological accounts could not be true.

Are Mechanistic and Teleological Explanations of Behaviour Incompatible

If a sensory brain state plays an unusual functional role, does the phenomenology go with the role or the brain state? If the phenomenology goes with the functional role, that supports functionalism, which is the view that phenomenology just is the role. If it goes with the brain state, that supports physicalism, which is the view that phenomenology is what realizes or implements the role. I agree with Gray [1] as against Noë and Hurley [3] that the interest of the issues discussed by Hurley and Noë [2] lies in their relevance to the functionalism/physicalism debate. However, I do not think that Hurley and Noë have made it plausible that there are any cases in which phenomenology goes with role when role and realizer conflict. Gray [1] and Hurley and Noë [2,3] suppose that in Braille, visual cortex serves a tactile role and that the phenomenology is tactile too—so phenomenology goes with role rather than realizer. Objections: First, proficient Braille readers have an enlarged sensorimotor representation for the reading finger; and zapping the somatosensory cortex of blind subjects with TMS (transcranial magnetic stimulation) interferes with Braille reading. [4, 5] Hence, whatever tactile phenomenology there is in Braille may be a result of somatosensory activation rather than " visual " activation. Second, the talk of " visual " (or perhaps any modality-specific) cortex that Hurley and Noë depend on is seeming increasingly problematic. Many, perhaps most so-called " visual " areas are better thought of as multi-modal (or multi-sensory) and spatial rather than specifically visual. An fMRI study [6] on sighted subjects found both striate and extra-striate " visual " activation for tactile object recognition. Many different methodologies have located tactile shape recognition in the lateral occipital complex (a " visual " area), including a report of one patient who had both visual and tactile agnosia upon injury in the left occipital cortex. [7]. Tactile motion and visual motion appear to activate the same areas in macaques (viz., MT). [7] There is also evidence that superior occipital activation is necessary for some tactile discriminations from an experimental paradigm [7,8] that contrasted two kinds of tactile judgments of a grating: spacing width and orientation. When occipital sites were zapped with TMS, sighted subjects could still feel the grating and were unimpaired in detecting spacing, but they were impaired in recognition of orientation and also said they were unsure of orientation. However, when …

The computational theory of mind (CTM) is the theory that the mind can be understood as a computer or, roughly, as the 'software program' of the brain. It is the most influential form of 'functionalism', according to which what distinguishes a mind is not what it is made of, nor a person's behavioural dispositions, but the way in which the brain is organized. CTM underlies some of the most important research in current cognitive science, for example, theories of artificial intelligence, perception, decision making and linguistics. CTM involves a number of important ideas. (1) Computations can be defined over syntactically specifiable symbols (that is, symbols specified by rules governing their combination) possessing semantic properties (or 'meaning'). For example, addition can be captured by rules defined over decimal numerals (symbols) that name the numbers. (2) Computations can be analysed into 'algorithms', or simple step-by-step procedures, each of which could be carried out by a machine. (3) Computation can be generalized to include not only arithmetic, but deductive logic and other forms of reasoning, including induction, abduction and decision making. (4) Computations capture relatively autonomous levels of ordinary psychological explanation different from neurophysiology and descriptions of behaviour. 1 Syntax, semantics and algorithms Crucial to understanding computational theories of mind (CTM) is the distinction between the syntax and the semantics of a symbol system. How symbols may be combined comprises the syntax of a system and what the symbols mean or name comprises its semantics. For example, consider three different notational systems for numbers: decimal numerals ('1', '2', '3', These different types of numerals name the same numbers ('5' names the same number as 'V' and '101') but the rules for combining the numerals in calculations are very different. In other words, these systems each have a different syntax, but (approximately) the same semantics. When children learn arithmetic, they learn reliable rules, or 'algorithms', for computing syntactically with numerals (symbols) in ways that mirror their semantics (in particular, the arithmetical relations among the corresponding numbers). Children doing calculations with decimal numerals should get the same answers as a computer working in binary, but the algorithms each uses look very different. An algorithm is a 'mechanical' step-by-step procedure operating on syntactically well-defined symbols in a way that captures relations among the things the symbols represent. Alan Turing developed a general account of algorithms, conceiving what are called 'Turing machines', perfectly mechanical computing devices that …

* P erception plays a fundamental role in enabling us to think about objects and properties in the world around us. In particular , perception of objects and properties enables us to think demonstrative thoughts about them. 1 But what must perception be like in order to play this role? Normal human perception is conscious in the sense that there is something it is like for us to perceive. This raises a question about the role of consciousness, which is the target question of this paper. Must perception be conscious if it is to enable us to think demonstrative thoughts about the world around us? And if so, why? We can make the target question more vivid by considering examples of unconscious perception, such as blindsight. 2 Patients with blindsight are able to respond to stimuli that they do not consciously perceive. For example, when presented with a stimulus in the blind field and asked to guess whether it is an " X " or an " O, " they answer correctly with a high degree of reliability. What explains this reliable ability is the patient's unconscious perception of the stimulus. So we can ask: is it and an anonymous referee. Some of these ideas descend from my Ph.D. disserta-tion at New York University, so I also record earlier debts to Not all demonstrative thought is based on perception. For example, we can think demonstrative thoughts on the basis of memory and testimony, as well as perception. However, this paper is concerned only with demonstrative thought that is perceptually based, although this restriction is left implicit in the main text.

How do humans infer motion direction from noisy sensory signals? We hypothesized that motion direction is computed not only from velocity but also spatial orientation signals – a ‘streak’ created by moving objects. We implemented this hypothesis in a Bayesian model, which quantifies knowledge with probability distributions, and tested its predictions using psychophysics and fMRI. Using a probabilistic pattern-based analysis, we decoded probability distributions of motion direction from trial-by-trial activity in the human visual cortex. Corroborating the predictions, the decoded distributions had a bimodal shape, with peaks that predicted the direction and magnitude of behavioral errors. Interestingly, we observed similar bimodality in the distribution of the observers’ behavioral responses across trials. Together, these results suggest that observers use spatial orientation signals when estimating motion direction. More broadly, our findings indicate that the cortical representation of low-level visual features, such as motion direction, can reflect a combination of several qualitatively distinct signals.

Motion direction is represented as a bimodal probability distribution in the human visual cortex

Publisher Correction: Subjective confidence reflects representation of Bayesian probability in cortex

Subjective confidence reflects representation of Bayesian probability in cortex

Cortical activity can be difficult to interpret. Neural responses to the same stimulus vary between presentations, due to random noise and other sources of variability. This unreliable relationship to external stimuli renders any pattern of activity open to a multitude of plausible interpretations. We have previously shown that this uncertainty in cortical stimulus representations can be characterized using a probabilistic decoding algorithm, which inverts a generative model of stimulus-evoked cortical responses. Here, we improve upon this method in two important ways, which both target the precision with which the generative model can be estimated from limited, noisy training data. We show that these improvements lead to considerably better estimation of the presented stimulus and its associated uncertainty. Estimates of the presented stimulus are recovered with an accuracy that exceeds that of standard decoding methods (SVMs), and in some cases even approaches the behavioral accuracy of human observers. Moreover, the uncertainty in the decoded probability distributions better characterizes the precision of cortical stimulus information from trial to trial.

TAFKAP: An improved method for probabilistic decoding of cortical activity

Directing spatial attention towards a particular stimulus location enhances cortical responses at corresponding regions in cortex. How attention modulates the laminar response profile within the attended region, however, remains unclear. In this paper, we use high field (7T) fMRI to investigate the effects of attention on laminar activity profiles in areas V1-V3; both when a stimulus was presented to the observer, and in the absence of visual stimulation. Replicating previous findings, we find robust increases in the overall BOLD response for attended regions in cortex, both with and without visual stimulation. When analyzing the BOLD response across the individual layers in visual cortex, we observed no evidence for laminar-specific differentiation with attention. We offer several potential explanations for these results, including theoretical, methodological and technical reasons. Additionally, we provide all data and pipelines openly, in order to promote analytic consistency across layer-specific studies, improve reproducibility, and decrease the false positive rate as a result of analytical flexibility.

Investigation of layer specific BOLD in the human visual cortex during visual attention

Reported confidence is based on imprecision in visual cortical stimulus representations

Bimodal probability distributions decoded from human visual cortex reflect perception

Although confidence is commonly believed to be an essential element in decision making, it remains unclear what gives rise to one’s sense of confidence. Recent Bayesian theories propose that confidence is computed, in part, from the degree of uncertainty in sensory evidence. Alternatively, observers can use physical properties of the stimulus as a heuristic to confidence. In the current study, we developed ideal observer models for either hypothesis and compared their predictions against human data obtained from psychophysical experiments. Participants reported the orientation of a stimulus, and their confidence in this estimate, under varying levels of internal and external noise. As predicted by the Bayesian model, we found a consistent link between confidence and behavioral variability for a given stimulus orientation. Confidence was higher when orientation estimates were more precise, for both internal and external sources of noise. However, we observed the inverse pattern when comparing between stimulus orientations: although observers gave more precise orientation estimates for cardinal orientations (a phenomenon known as the oblique effect), they were more confident about oblique orientations. We show that these results are well explained by a strategy to confidence that is based on the perceived amount of noise in the stimulus. Altogether, our results suggest that confidence is not always computed from the degree of uncertainty in one’s perceptual evidence, but can instead be based on visual cues that function as simple heuristics to confidence.

Activity in human visual areas reflects the precision of motion perception

Improved methods for decoding sensory uncertainty from activity in the human visual cortex

How does the brain represent the reliability of its sensory evidence? Here, we test whether sensory uncertainty is encoded in cortical population activity as the width of a probability distribution, a hypothesis that lies at the heart of Bayesian models of neural coding. We probe the neural representation of uncertainty by capitalizing on a well-known behavioral bias called serial dependence. Human observers of either sex reported the orientation of stimuli presented in sequence, while activity in visual cortex was measured with fMRI. We decoded probability distributions from population-level activity and found that serial dependence effects in behavior are consistent with a statistically advantageous sensory integration strategy, in which uncertain sensory information is given less weight. More fundamentally, our results suggest that probability distributions decoded from human visual cortex reflect the sensory uncertainty that observers rely on in their decisions, providing critical evidence for Bayesian theories of perception. SIGNIFICANCE STATEMENT Virtually any decision that people make is based on uncertain and incomplete information. Although uncertainty plays a major role in decision-making, we have but a nascent understanding of its neural basis. Here, we probe the neural code of uncertainty by capitalizing on a well-known perceptual illusion. We developed a computational model to explain the illusion, and tested it in behavioral and neuroimaging experiments. This revealed that the illusion is not a mistake of perception, but rather reflects a rational decision under uncertainty. No less important, we discovered that the uncertainty that people use in this decision is represented in brain activity as the width of a probability distribution, providing critical evidence for current Bayesian theories of decision-making.

Probabilistic Representation in Human Visual Cortex Reflects Uncertainty in Serial Decisions

Abstract We disagree with Rahnev & Denison (R&D) that optimality should be abandoned altogether. Rather, we argue that adopting a normative approach enables researchers to test hypotheses about the brain's computational goals, avoids just-so explanations, and offers insights into function that are simply inaccessible to the alternatives proposed by R&D.

Optimality is critical when it comes to testing computation-level hypotheses

Confidence predicts variability but not biases in perceptual decisions

Uncertainty in cortical stimulus representations predicts serial dependence effects in orientation perception

Response variability is shared between similarly tuned neural populations

Visual orientation discrimination is known to improve with extensive training, but the mechanisms underlying this behavioral benefit remain poorly understood. Here, we examine the possibility that more reliable task performance could arise in part because observers learn to sample information from a larger portion of the stimulus. We used a variant of the classification image method in combination with a global orientation discrimination task to test whether a change in information sampling underlies training-based benefits in behavioral performance. The results revealed that decreases in orientation thresholds with perceptual learning were accompanied by increases in stimulus sampling. In particular, while stimulus sampling was restricted to the parafoveal, inner portion of the stimulus before training, we observed an outward spread of sampling after training. These results demonstrate that the benefits of perceptual learning may arise, in part, from a strategic increase in the efficiency with which the observer samples information from a visual stimulus.

A review of the mechanisms by which attentional feedback shapes visual selectivity

The cortical reinstatement hypothesis of memory retrieval posits that content-specific cortical activity at encoding is reinstated at retrieval. Evidence for cortical reinstatement was found in higher-order sensory regions, reflecting reactivation of complex object-based information. However, it remains unclear whether the same detailed sensory, feature-based information perceived during encoding is subsequently reinstated in early sensory cortex and what the role of the hippocampus is in this process. In this study, we used a combination of visual psychophysics, functional neuroimaging, multivoxel pattern analysis, and a well controlled cued recall paradigm to address this issue. We found that the visual information human participants were retrieving could be predicted by the activation patterns in early visual cortex. Importantly, this reinstatement resembled the neural pattern elicited when participants viewed the visual stimuli passively, indicating shared representations between stimulus-driven activity and memory. Furthermore, hippocampal activity covaried with the strength of stimulus-specific cortical reinstatement on a trial-by-trial level during cued recall. These findings provide evidence for reinstatement of unique associative memories in early visual cortex and suggest that the hippocampus modulates the mnemonic strength of this reinstatement.

Reinstatement of Associative Memories in Early Visual Cortex Is Signaled by the Hippocampus

Object-based selection is not mandatory: Perceptual load reduces the attentional boost of task-irrelevant features in the human visual cortex.

Less Is More: Expectation Sharpens Representations in the Primary Visual Cortex

Although practice has long been known to improve perceptual performance, the neural basis of this improvement in humans remains unclear. Using fMRI in conjunction with a novel signal detection-based analysis, we show that extensive practice selectively enhances the neural representation of trained orientations in the human visual cortex. Twelve observers practiced discriminating small changes in the orientation of a laterally presented grating over 20 or more daily 1 h training sessions. Training on average led to a twofold improvement in discrimination sensitivity, specific to the trained orientation and the trained location, with minimal improvement found for untrained orthogonal orientations or for orientations presented in the untrained hemifield. We measured the strength of orientation-selective responses in individual voxels in early visual areas (V1–V4) using signal detection measures, both before and after training. Although the overall amplitude of the BOLD response was no greater after training, practice nonetheless specifically enhanced the neural representation of the trained orientation at the trained location. This training-specific enhancement of orientation-selective responses was observed in the primary visual cortex (V1) as well as higher extrastriate visual areas V2–V4, and moreover, reliably predicted individual differences in the behavioral effects of perceptual learning. These results demonstrate that extensive training can lead to targeted functional reorganization of the human visual cortex, refining the cortical representation of behaviorally relevant information.

Perceptual Learning Selectively Refines Orientation Representations in Early Visual Cortex

In the early sensory and motor areas of the cortex, individual neurons transmit information about specific sensory features via a peaked response. This concept has been crystallized as “labeled lines,” to denote that axons communicate the specific properties of their sensory or motor parent cell. Such cells also can be characterized as being polarized, that is, as representing a signed quantity that is either positive or negative. We show in a model simulation that there are two important consequences when learning receptive fields using such signed codings in circuits that subtract different inputs. The first is that, in feedback circuits using labeled lines, such arithmetic operations need to be distributed across multiple distinct pathways. The second consequence is that such pathways must be necessarily dynamic, i.e., that synapses can grow and retract when forming receptive fields. The model monitors the breaking and growing of new circuit connections when their synapses need to change polarities and predicts that the rate of such changes should be inversely correlated with the progress of receptive field formation.

Dynamic Coding of Signed Quantities in Cortical Feedback Circuits

A prominent feature of signaling in cortical neurons is that of randomness in the action potential. The output of a typical pyramidal cell can be well fit with a Poisson model, and variations in the Poisson rate repeatedly have been shown to be correlated with stimuli. However while the rate provides a very useful characterization of neural spike data, it may not be the most fundamental description of the signaling code. Recent data showing γ frequency range multi-cell action potential correlations, together with spike timing dependent plasticity, are spurring a re-examination of the classical model, since precise timing codes imply that the generation of spikes is essentially deterministic. Could the observed Poisson randomness and timing determinism reflect two separate modes of communication, or do they somehow derive from a single process? We investigate in a timing-based model whether the apparent incompatibility between these probabilistic and deterministic observations may be resolved by examining how spikes could be used in the underlying neural circuits. The crucial component of this model draws on dual roles for spike signaling. In learning receptive fields from ensembles of inputs, spikes need to behave probabilistically, whereas for fast signaling of individual stimuli, the spikes need to behave deterministically. Our simulations show that this combination is possible if deterministic signals using γ latency coding are probabilistically routed through different members of a cortical cell population at different times. This model exhibits standard features characteristic of Poisson models such as orientation tuning and exponential interval histograms. In addition, it makes testable predictions that follow from the γ latency coding.

When spatial attention is directed toward a particular stimulus, increased activity is commonly observed in corresponding locations of the visual cortex. Does this attentional increase in activity indicate improved processing of all features contained within the attended stimulus, or might spatial attention selectively enhance the features relevant to the observer's task? We used fMRI decoding methods to measure the strength of orientation-selective activity patterns in the human visual cortex while subjects performed either an orientation or contrast discrimination task, involving one of two laterally presented gratings. Greater overall BOLD activation with spatial attention was observed in visual cortical areas V1–V4 for both tasks. However, multivariate pattern analysis revealed that orientation-selective responses were enhanced by attention only when orientation was the task-relevant feature and not when the contrast of the grating had to be attended. In a second experiment, observers discriminated the orientation or color of a specific lateral grating. Here, orientation-selective responses were enhanced in both tasks, but color-selective responses were enhanced only when color was task relevant. In both experiments, task-specific enhancement of feature-selective activity was not confined to the attended stimulus location but instead spread to other locations in the visual field, suggesting the concurrent involvement of a global feature-based attentional mechanism. These results suggest that attention can be remarkably selective in its ability to enhance particular task-relevant features and further reveal that increases in overall BOLD amplitude are not necessarily accompanied by improved processing of stimulus information.

Attention Improves Encoding of Task-Relevant Features in the Human Visual Cortex

Perceptual Learning Leads to Hemisphere-Specific Cortical Thickening

Attention improves decoding of stimulus orientation in early visual areas

A discrete-time feedback model can account for spike timing data in LGN

Neural correlates of perceptual learning in the human visual cortex

Attentional enhancement of orientation responses in human visual cortex depends on task

Biphasic neural response properties, where the optimal stimulus for driving a neural response changes from one stimulus pattern to the opposite stimulus pattern over short periods of time, have been described in several visual areas, including lateral geniculate nucleus (LGN), primary visual cortex (V1), and middle temporal area (MT). We describe a hierarchical model of predictive coding and simulations that capture these temporal variations in neuronal response properties. We focus on the LGN-V1 circuit and find that after training on natural images the model exhibits the brain's LGN-V1 connectivity structure, in which the structure of V1 receptive fields is linked to the spatial alignment and properties of center-surround cells in the LGN. In addition, the spatio-temporal response profile of LGN model neurons is biphasic in structure, resembling the biphasic response structure of neurons in cat LGN. Moreover, the model displays a specific pattern of influence of feedback, where LGN receptive fields that are aligned over a simple cell receptive field zone of the same polarity decrease their responses while neurons of opposite polarity increase their responses with feedback. This phase-reversed pattern of influence was recently observed in neurophysiology. These results corroborate the idea that predictive feedback is a general coding strategy in the brain.

Predictive Feedback Can Account for Biphasic Responses in the Lateral Geniculate Nucleus

The scalable mammalian brain: emergent distributions of glia and neurons

Interactions between higher and lower visual areas improve shape selectivity of higher level neurons—Explaining crowding phenomena

Computational modeling of the brain holds great promise as a bridge from brain to behavior. To fulfill this promise, however, it is not enough for models to be ‘biologically plausible’: models must be structurally accurate. Here, we analyze what this entails for so-called psychobiological models, models that address behavior as well as brain function in some detail. Structural accuracy may be supported by (1) a model's a priori plausibility, which comes from a reliance on evidence-based assumptions, (2) fitting existing data, and (3) the derivation of new predictions. All three sources of support require modelers to be explicit about the ontology of the model, and require the existence of data constraining the modeling. For situations in which such data are only sparsely available, we suggest a new approach. If several models are constructed that together form a hierarchy of models, higher-level models can be constrained by lower-level models, and low-level models can be constrained by behavioral features of the higher-level models. Modeling the same substrate at different levels of representation, as proposed here, thus has benefits that exceed the merits of each model in the hierarchy on its own.

Neural Models that Convince: Model Hierarchies and Other Strategies to Bridge the Gap Between Behavior and the Brain

Aboriginal Student Support & Community Relations Suggested list of resources Books, articles, sites For new staff members to advance their knowledge of aboriginal culture & history & health & wellness.

Trisomy 12 observed in chorionic villus sampling (CVS) may reflect generalized mosaicism or indicate mosaicism confined to only the placenta. In this report, four cases of trisomy 12 observed in CVS or cultured placental biopsies with varying outcomes are presented. Seven dinucleotide repeat polymorphisms for chromosome 12 were used to determine the chromosome 12 origins in the fetus or child and to delineate the mechanism(s) that gave rise to the trisomy. In two cases (cases A and C), the mosaicism was confined to the placenta, resulting in normal liveborns. Although, in one case, the molecular results suggested an apparent duplication of one paternal chromosome 12 in the placenta, normal biparental inheritance was found in the diploid fetal cell line in both cases. In two other cases (cases B and D), trisomy 12 was observed in both extraembryonic and fetal tissues. In one of these pregnancies, a child was born by Caesarean section at 37 weeks because of intrauterine growth retardation and oligohydramnios, and resulted in neonatal death. Molecular markers and fluorescence in situ hybridization (FISH) revealed low‐level trisomy 12 mosaicism in the spleen. In the fourth case, fetal abnormalities were detected on ultrasound and low‐level trisomy 12 mosaicism was observed in amniotic fluid cells using conventional cytogenetics and FISH. Molecular markers revealed a maternal meiosis I non‐disjunction of chromosome 12 in DNA from a cultured placental biopsy. Although predicting the outcomes of pregnancies involving confined placental mosaicism remains difficult, molecular techniques are valuable tools for distinguishing uniparental from biparental disomy and mechanisms of mosaicism.

In vitro, in silico studies of newly isolated tetrahydro-4-(7-hydroxy-10-methoxy-6, 14-dimethyl-15-m-tolylpentadec-13-enyl) pyran-2-one and isobutyryl acetate compounds from Alstonia boonei stem bark

Gastroenteritis is the inflammation of the stomach and
intestine, typically resulting from bacteria bacterial toxins or viral
infection and causing nausea, cramps, vomiting and diarrhea.

Infectious Gastroenteritis: Causes, Diagnosis, Treatmentand Prevention

Enterococcus faecalis , though opportunistic pathogen has emerged as one of the leading nosocomial pathogens and has been implicated in different human infections. The severity of the infections caused by this organism is largely due to its complex pathogenic process. The objective of this study was to determine the carriage of virulence factors and vanA gene among the strains of vancomycin-resistant E. faecalis isolated from hospitals. Standard methods were used for isolation, antibiotic susceptibility and detection of virulence factors in the isolates. A total of one hundred and twenty three (123) samples were screened out of which 69 (45.70 %) yielded E. faecalis . The highest percentage of the isolates was recovered from the environment followed by the clinical samples. Children surgical ward had the highest occurrence of the test organism followed by male surgical ward. All the isolates were resistant to both amoxycillin/clavulanic acid and ceftazidime, while 98.55%, 89.86% and 53.62% were resistant to ampicillin, cefuroxime and gentamicin respectively. Only twenty seven (39.13%) of the isolates were resistant to the vancomycin. Among the vancomycin-resistant isolates, haemolysin had the highest occurrence (60.29%) followed by caseinase (55.88%). A total of 16 (59.26%) were beta-lactamase positive while 8 (29.63%) out of the isolates (vancomycin-resistant) were non-biofilm former while vanA genes was detected in 9 (33.33%) of the isolates. This study gives an insight to antibiotic resistant pattern of circulating Enterococcus faecalis and also the isolate showed varying patterns of virulent factors.

Virulence factors and beta-lactamase production among vancomycin-resistant Enterococcus faecalis isolated from clinical samples and hospital environment

3-year outcomes from the prospective ‘MRIAS’ trial: A novel active surveillance protocol which incorporates multiparametric MRI to reduce frequency of biopsy in men with prostate cancer

E SSENTIAL SEGMENTAL myoclonus isolated to the extrinsic laryngeal muscleshasnot, toour knowledge, been described. We present the first case of this condition and call the phenomenon oscillating larynx. This is also the first report of levetiracetamresponsive segmental myoclonus. An otherwise healthy 47-yearold man described 15 years of involuntary movements of the larynx without ear clicks. He sought treatment because the movements were increasingly interfering with his ability to get to sleep. While sleep did not abolish the movements, they were visibly reduced according to next-of-kin. There was no disturbance of swallow, speech, or respiration. The movements were not suppressible.

Rasagiline enhances l-DOPA-induced contralateral turning in the unilateral 6-hydroxydopamine-lesioned guinea-pig

Present day university education in India has nothing to do with what was re­ garded as higher education in ancient India. We find references to the existence of a few famous universities in various ancient books, chief among them being Nalan­ da and Taxila. Except for some statements that they were very famous and very large. that they attracted students from countries outside India, and offered a large vari­ ety of subjects, we have no detailed knowledge about them. There is no line of con­ tinuity between that ancient past and the present.

Introduction Timber rivet connections have been used successfully in many structures over the past 30 years (Fig. 1). They are part of the U.S. (1) and Canadian (2) structural wood design codes, but unfortunately, there are few published design examples to aid designers (3-6). This paper is targeted to the connection designer and provides a short summary of the 2005 National Design Specification® (NDS®) for Wood Construction design process for timber rivet connections along with comments on design issues of common interest.

Timber Rivet Connections – Design Process for a Hanger Connection

Recent criticism of the bolted connection requirements in the Canadian wood design code CSA Standard O86 indicates that the code lacks consideration of the different modes of failure, particularly as they relate to multiple-bolt connections. A finite element model is proposed to predict loaddisplacement behaviour, stress distributions, ultimate strength, and mode of failure in single- and multiple-bolt connections. The three-dimensional (3-D) model uses anisotropic plasticity for the wood member and elastoplasticity for the bolt. The Weibull weakest link theory is used to predict failure at given levels of probability. Predictions for connection behaviour in Douglas-fir and laminated strand lumber (LSL) correspond to experimentally observed behaviour. The output from the 3-D model is used for a multiple-bolt connection spring model to illustrate many of the phenomena described in the literature.Key words: bolt, Douglas-fir, connection, model, plasticity, weakest link, wood.

This paper and recent papers by the same authors (Quenneville and Mohammad 2000; Mohammad and Quenneville 2001) present a tremendous amount of valuable laboratory data on the subject of bolted connection behaviour in timber. The observations of behaviour and failure mechanisms are particularly relevant. The authors present new design equations, based on failure mechanisms, to predict connection strength — an improvement on the current code requirements found in O86.1 (CSA 1994). These new equations were shown to produce improved results in the paper’s figures; however, the equations lack a detailed analytical basis. All bolted connections, regardless of the material, will develop a three-dimensional stress field — the magnitudes of the stresses depend on the connection geometry and material properties. The ductility in the steel connector also plays a role. In the wood member, the stress distribution is complicated by material orthotropy and nonlinear behaviour of wood in compression. The connection behaviour is further complicated by brittle failure of wood in tension and in shear. The authors provide between three and six equations to predict the connection strength for different connection con figurations loaded perpendicular-to-grain, when strength is governed by bearing. They provide only one additional equation to predict connection strength when splitting governs. The authors later conclude that, based on their tests, tension perpendicular-to-grain splitting was found to govern connection strength in most cases. From their conclusion, one would expect that their proposed equation for the prediction of brittle failures would have been developed using a rigorous analysis of the stresses in a bolted connection, rather than curve-fitting to an expression originally devel oped to predict the strength of timber rivets. Foschi and Longworth (1975) used a combination of material nonlinearity and the weakest link theory to predict the strength of timber rivets undergoing brittle failure. This work forms the basis of the current O86.1 rivet design procedure. Their one-dimensional finite element model predicted stresses around each rivet over a series of load steps. At each step, the stresses were analyzed to determine if the tension or shear stresses exceeded the allowable stresses according to the Weibull weakest link theory (Weibull 1939). The model also pinpointed the governing mode of failure (i.e., tension perpendicular-to-grain or shear). This model was specifically developed for timber rivets — the boundary conditions for the governing displacement field equations were chosen specifically for the rivet connection analyzed at that time. Quenneville and Mohammad modified Foschi’s (1973) governing equation but gave no direct indication that the original field equations can be applied to the design of multiple-bolt connections. There are a number of reasons to believe that recalibrating

DiscussionDesign method for bolted connections loaded perpendicular-to-grain: Discussion

Two case studies are summarized using anisotropic plasticity and the Weibull weakest link failure model to predict the behavior of wood and wood composites. The linear elastic orthotropic model normally used for wood is shown to be insufficient for the prediction of ultimate strength in wood. Non-linear, non-recoverable behavior in compression in each of the orthogonal material directions is of particular interest in cases where localized crushing governs the load-displacement behavior of wood. The anisotropic plasticity option in ANSYS was used to predict yielding and post-yield behavior for the wood composite used in this study because yield stresses in orthogonal directions were found to be in the ratio of 1:1.2:5. A user-programmable Fortran subroutine was developed for ANSYS to carry out the failure analysis (and to calculate the volume integration of the stresses) at each loadstep in post-processing. The model was verified using two cases: I) the ASTM D143 shear block test, and II) bolted connections. CASE I: A three-dimensional model of the ASTM D143 shear block was constructed. SOLID45 elements were used for the wood block and for the rigid steel surfaces. CONTAC49 elements were used on the interfaces between the steel loading platens and the wood block. Load-displacement results for three loading orientations and two block sizes agreed with experimental findings. CASE II: A three-dimensional model of a single-bolt connection was used to predict loaddisplacement behavior and ultimate strength. A three-dimensional analysis was required because experimental results have shown that non-uniform displacements occur through the thickness of the member due to bolt yielding and wood crushing near the member faces. SOLID45 elements were used for the bolt and wood with a friction contact interface of CONTAC49 elements. Bilinear kinematic hardening was assumed for bolt yielding behavior. Load-displacement curves of the connection compared well with experimental results.

ANISOTROPIC PLASTICITY AND FAILURE PREDICTION IN WOOD COMPOSITES

The American Society for Testing and Materials notched wood shear block specimen is revisited for use with laminated strand lumber. Shear block tests on fully oriented and randomly oriented panels were conducted to determine shear strength in each of the orthotropic planes. Nominal shear strengths are reported from experimental results. A three-dimensional finite element analysis was conducted to determine the ultimate shear strength of the shear blocks by accounting for the non-uniform stress distribution and stress concentrations developed in the blocks. The anisotropic plasticity material model accounts for non-linear behavior in compression. Brittle failure was predicted using the Weibull weakest link theory for each of the six tension and shear stresses. The model produced similar load-displacement results to the experiments and was compared against experimental ultimate strengths and failure modes. Model strength predictions were found to be approximately 1.7 times greater than the nominal shear stress determined for the assumed shear plane in experiments. This indicates conservative strength predictions from experiments. The model showed the stress concentration factor at the notch to be at least 2. The stress concentration, combined with the fact that a mixed failure mode exists (i.e., shear and tension perpendicular to the grain) results in poor estimates of the shear strength. The influence of shear modulus, G, on model-predicted results was investigated. It was shown that the load-displacement behavior for in-plane shear was least affected by the in-plane G, whereas G in the otherplanes only mildly influenced load-displacement, ultimate strength, and stress concentrations.

Constitutive and analytical models for structural composite lumber with applications to bolted connections

The note by Bakht and Jaeger examines the conventional wisdom that the incorporation of springs in stress-laminated wood decks is equivalent to reducing the stiffness of the prestressing system.

On the use of springs in stress-laminated wood decks: Discussion

INTRODUCTION............................................................................................ 392 I. NEURONS AND NARRATIVES .................................................................... 395 A. Brain-Computer Interfaces ................................................................ 396 1. What are they? ................................................................................ 396 2. How do they work? ......................................................................... 398 3. Limits of Available Consumer BCI Technology ............................ 401 B. Why Regulating BCIs is Challenging ................................................ 405 1. The Pacing Problem ........................................................................ 405 2. The Internet of Things Requires New Approaches to Data ............ 409 Protection ............................................................................................ 409 3. How the “Privacy Narrative” Influences BCI Risk Assessment .... 414 II. LEARNING FROM ROBOTS ....................................................................... 421 A. Of Robots and Humans (and Cyborgs): Bryan Casey and Mark A. Lemley’s Argument ................................................................................. 422 B. What’s in a Name? ............................................................................. 425 C. Affect: A Functional Criterion for BCIs (and Beyond?) ................... 428 CONCLUSION ............................................................................................... 431

MIND GAMES: HOW ROBOTS CAN HELP REGULATE BRAIN-COMPUTER INTERFACES

Harnessing the Power of Artificial Intelligence in Otolaryngology and the Communication Sciences

Generalizable spelling using a speech neuroprosthesis in an individual with severe limb and vocal paralysis

Decoding Speech from Cortical Surface Electrical Activity. Reply.

Technology to restore the ability to communicate in paralyzed persons who cannot speak has the potential to improve autonomy and quality of life. An approach that decodes words and sentences directly from the cerebral cortical activity of such patients may represent an advancement over existing methods for assisted communication.

METHODS
We implanted a subdural, high-density, multielectrode array over the area of the sensorimotor cortex that controls speech in a person with anarthria (the loss of the ability to articulate speech) and spastic quadriparesis caused by a brain-stem stroke. Over the course of 48 sessions, we recorded 22 hours of cortical activity while the participant attempted to say individual words from a vocabulary set of 50 words. We used deep-learning algorithms to create computational models for the detection and classification of words from patterns in the recorded cortical activity. We applied these computational models, as well as a natural-language model that yielded next-word probabilities given the preceding words in a sequence, to decode full sentences as the participant attempted to say them.

RESULTS
We decoded sentences from the participant's cortical activity in real time at a median rate of 15.2 words per minute, with a median word error rate of 25.6%. In post hoc analyses, we detected 98% of the attempts by the participant to produce individual words, and we classified words with 47.1% accuracy using cortical signals that were stable throughout the 81-week study period.

In a person with anarthria and spastic quadriparesis caused by a brain-stem stroke, words and sentences were decoded directly from cortical activity during attempted speech with the use of deep-learning models and a natural-language model. (Funded by Facebook and others; ClinicalTrials.gov number, NCT03698149.).

Neuroprosthesis for Decoding Speech in a Paralyzed Person with Anarthria.

Machine translation of cortical activity to text with an encoder–decoder framework

Real-time decoding of question-and-answer speech dialogue using human cortical activity

The emerging field of neural speech recognition (NSR) using electrocorticography has recently attracted remarkable research interest for studying how human brains recognize speech in quiet and noisy surroundings. In this study, we demonstrate the utility of NSR systems to objectively prove the ability of human beings to attend to a single speech source while suppressing the interfering signals in a simulated cocktail party scenario. The experimental results show that the relative degradation of the NSR system performance when tested in a mixed-source scenario is significantly lower than that of automatic speech recognition (ASR). In this paper, we have significantly enhanced the performance of our recently published framework by using manual alignments for initialization instead of the flat start technique. We have also improved the NSR system performance by accounting for the possible transcription mismatch between the acoustic and neural signals.

Characterizing the neural encoding of behavior remains a challenging task in many research areas due in part to complex and noisy spatiotemporal dynamics of evoked brain activity. An important aspect of modeling these neural encodings involves separation of robust, behaviorally relevant signals from background activity, which often contains signals from irrelevant brain processes and decaying information from previous behavioral events. To achieve this separation, we develop a two-branch State Space Variational AutoEncoder (SSVAE) model to individually describe the instantaneous evoked foreground signals and the context-dependent background signals. We modeled the spontaneous speech-evoked brain dynamics using smoothed Gaussian mixture models. By applying the proposed SSVAE model to track ECoG dynamics in one participant over multiple hours, we find that the model can predict speech-related dynamics more accurately than other latent factor inference algorithms. Our results demonstrate that separately modeling the instantaneous speech-evoked and slow context-dependent brain dynamics can enhance tracking performance, which has important implications for the development of advanced neural encoding and decoding models in various neuroscience sub-disciplines.

Modeling neural dynamics during speech production using a state space variational autoencoder

Author(s): Moses, David Aaron | Advisor(s): Chang, Edward F | Abstract: Recent research has explored the functional role of the human auditory and sensorimotor cortices in perceiving and producing speech. One key finding from these studies was the characterization of how phonetic features and phonemes, which are fundamental units of speech, are represented in the brain. In this thesis, I examine how these neural representations of speech can be used as the basis for decoding what individuals hear and say in real-time. This work leverages recent advances in human neurophysiology with epilepsy patients that have high-density electrocorticography arrays implanted on the surface of their brains as part of their clinical treatment, enabling collection of cortical activity at unprecedented spatiotemporal resolutions. Using these signals, I show that spatiotemporal feature vectors containing cortical activity in the high gamma frequency band can be used to decode speech sounds that listeners perceive by employing techniques from automatic speech recognition, contributing to an emerging field of research referred to as neural speech recognition (NSR). Next, I design and evaluate a real-time system capable of reliably classifying aurally presented sentences using phoneme-level models and spatiotemporal high gamma features. Finally, I demonstrate state-of-the-art real-time decoding of perceived and produced words and sentences in a naturalistic question-and-answer paradigm, illustrating the utility of NSR in a real-world interactive application. In addition to characterizing properties of speech that can be decoded from the human brain in real-time, these findings have practical implications for the design of speech neuroprostheses to aid patients who are unable to communicate due to paralysis.

Real-time decoding of perceived and produced speech from human cortical activity

Objective. Recent research has characterized the anatomical and functional basis of speech perception in the human auditory cortex. These advances have made it possible to decode speech information from activity in brain regions like the superior temporal gyrus, but no published work has demonstrated this ability in real-time, which is necessary for neuroprosthetic brain–computer interfaces. Approach. Here, we introduce a real-time neural speech recognition (rtNSR) software package, which was used to classify spoken input from high-resolution electrocorticography signals in real-time. We tested the system with two human subjects implanted with electrode arrays over the lateral brain surface. Subjects listened to multiple repetitions of ten sentences, and rtNSR classified what was heard in real-time from neural activity patterns using direct sentence-level and HMM-based phoneme-level classification schemes. Main results. We observed single-trial sentence classification accuracies of 90% or higher for each subject with less than 7 minutes of training data, demonstrating the ability of rtNSR to use cortical recordings to perform accurate real-time speech decoding in a limited vocabulary setting. Significance. Further development and testing of the package with different speech paradigms could influence the design of future speech neuroprosthetic applications.

Real-time classification of auditory sentences using evoked cortical activity in humans

Objective. The superior temporal gyrus (STG) and neighboring brain regions play a key role in human language processing. Previous studies have attempted to reconstruct speech information from brain activity in the STG, but few of them incorporate the probabilistic framework and engineering methodology used in modern speech recognition systems. In this work, we describe the initial efforts toward the design of a neural speech recognition (NSR) system that performs continuous phoneme recognition on English stimuli with arbitrary vocabulary sizes using the high gamma band power of local field potentials in the STG and neighboring cortical areas obtained via electrocorticography. Approach. The system implements a Viterbi decoder that incorporates phoneme likelihood estimates from a linear discriminant analysis model and transition probabilities from an n-gram phonemic language model. Grid searches were used in an attempt to determine optimal parameterizations of the feature vectors and Viterbi decoder. Main results. The performance of the system was significantly improved by using spatiotemporal representations of the neural activity (as opposed to purely spatial representations) and by including language modeling and Viterbi decoding in the NSR system. Significance. These results emphasize the importance of modeling the temporal dynamics of neural responses when analyzing their variations with respect to varying stimuli and demonstrate that speech recognition techniques can be successfully leveraged when decoding speech from neural signals. Guided by the results detailed in this work, further development of the NSR system could have applications in the fields of automatic speech recognition and neural prosthetics.

Neural speech recognition: continuous phoneme decoding using spatiotemporal representations of human cortical activity

Volitional control of neural activity lies at the heart of the Brain-Machine Interface (BMI) paradigm. In this work we investigated if subdural field potentials recorded by electrodes <; 1mm apart can be decoupled through closed-loop BMI learning. To this end, we fabricated custom, flexible microelectrode arrays with 200 μm electrode pitch and increased the effective electrode area by electrodeposition of platinum black to reduce thermal noise. We have chronically implanted these arrays subdurally over primary motor cortex (M1) of 5 male Long-Evans Rats and monitored the electrochemical electrode impedance in vivo to assess the stability of these neural interfaces. We successfully trained the rodents to perform a one-dimensional center-out task using closed-loop brain control to adjust the pitch of an auditory cursor by differentially modulating high gamma (70-110 Hz) power on pairs of surface microelectrodes that were separated by less than 1 mm.

Sub-mm functional decoupling of electrocortical signals through closed-loop BMI learning

Electrochemical Activation and Inhibition of Neuromuscular Systems through Modulation of Ion Concentrations with Ion-Selective Membranes

This article cites Robert Henryson's Fables in order to contextualise the history of the medieval notion that the world of imaginary, poetic fiction, needs justification; and examines the theological sources which served as the foundation of that debate and provided the validation for the use of fable animals as moral exemplars.

Lyrical liars, animal desires and figurative kinship: Robert Henryson's defence of poetry in the prologue to The Morall Fabillis

This volume is the inaugural edition of the ‘occasional series’ from the Neil Gunn Circle. It o¡ers an appraisal of Neil M. Gunn’s in£uence and relevance as perceived through his writings and involvement with Scottish nationalist politics. Its arrival is timely for those looking to the literary and cultural seeds of a more contemporary debate and it certainly allows Gunn readers to make more solid the links between his insights and contemporary notions of nationhood. This collection serves many: it will please the established Gunn-reading audience, yet will serve better to inform those interested in the roots of Scottish nationalism and its literary origins. Most of Gunn’s novels are still in print, and this edition is an ideal companion for those reading Gunn with a political eye. Alistair McCleery’s introduction sets out the historical context of Gunn’s essay writing and politics from 1930. From Gunn’s account in his diary McCleery draws comparison between the situation in 1931 and the present day to emphasise Gunn’s ‘crucial role in the creation of a single Nationalist political grouping’. He discusses what Gunn thought the consequences of self-government would be, including the arrest and reversal of social and economic decline and the ‘liberation of Scottish individuality’. Placing this in the context of other political models McCleery sees that Gunn’s nationalism ‘was a more humane, humanitarian and liberal philosophy than the contemporary alternatives of communism and fascism’. Gunn is famous for reinscribing Highland spiritual values, which are evident in his most gripping novels. This facet of Gunn’s writing is a strong theme running through the edition. It is the notion that native writers’ imaginations can deteriorate when writing on other matters, though thrive when using Scotland’s landscape as an arbiter of Scottishness. Gunn’s own reproduced essay, ‘Why are Writers Nationalists?’, delves brie£y but typically into the psychology of writing, the ‘vital experience’ required, and the need to release through literary expression a cultural identity suppressed and destructive to the body. Gunn likens Scotland to a ‘crashed airman su¡ering from shock’ which needs to be brought back to cultural and psychological health after the trauma of attempts to graft incompatible cultures together.

What a Boar! Animal Digression and Salvation in The Wedding of Sir Gawain and Dame Ragnelle

T HIS article explains in brief how, at a time of striking anticlericalism, religious figures in fourteenth-century English literature are often subtly criticized by the simple observation of their diet. The satirical representation of character types in medieval fiction very often depends upon those characters' indulging in the sinful acts which typify behaviour incompatible with their temporal functions and the spiritual symbolism oftheir earthly rank. Indeed, highlighting character voices which stand out as incongruent in a given context also assists in the identification of critical literary modes. These might be as direct as in William Langland's (c.1330-1387) satirical criticism of clerical figures within the allegory of Piers Plowman, or relatively lighthearted censures such as those ofGeoffrey Chaucer (c. 1343-1400) in TheCanterbury Tales, which depend upon the rhetoric ofirony. t Irony emerged in medieval rhetorical arts as a form ofallegory, in which the primary narrative level states quite the opposite to what the author means. While medieval allegories such as Piers Plowman consistently and directly spell out what they mean, an ineluctable difference between the two authors is that Chaucer as ironist does not. Rather, as Helen Cooper points out, interpretative tropes like irony require that 'judgment depends on the reader's picking up cues in the text, and some of them are deeply ambiguous.' 2 In other words, we are drawn into making judgments informed by the typecasting of an author who also warns against the danger of passing any judgement at all. Satire does, after all, hold up a mirror in which we find ourselves at fault and thus find ourselves imperfect to judge. Chauceralso follows the conventional modesty toposofdisavowing responsibility for his tales, indicating thatwe may

Soul Food and Eating Habits: What's at Steak in a Medieval Monk's Diet?

The increase in the rate of carrier of typhoid fever is on the increase in the recent time and this present a serious threat to the public health. Students in most cases are living in densely populated hostels with poor sanitary conditions. This coupled with poor hygienic practices constitute pre-disposing factors. This study investigates the carriage rate and antibiotic resistance profile of Salmonella among students in a tertiary institution who had suffered gastroenteritis and typhoid fever within one year of infection. Seventy four (74) stool samples were obtained from students in the university. Isolates were identified using standard methods, subjected to antimicrobial susceptibility by disc diffusion method. The incidence of the infection was found to be highest among participants of 20 - 24 years age group. Fifty-one (51) faecal samples were positive for enteric pathogens. Six (11.76%) Salmonella species were isolated from stool culture and all were Salmonella paratyphi B serotype. All the Salmonella paratyphi B showed hundred percent (100%) resistance to Ceftazidime, Ampicillin, Amoxicillin clavulanic acid and Cefuroxime but were susceptible to Ofloxacin and Ciprofloxacin. High carriage of Salmonella observed from this study calls for proactive action since most of the isolates were resistance to commonly prescribed antibiotic drugs.

Antibiotic Susceptibility and Carriage Rate of Salmonella Serotypes among Healthy Individuals with History of Salmonella Infection within One Year in a University Community in Nigeria

Occurrence of Antibiotic Resistance and Virulent Factors in Enterococcus faecalis Isolated from Bush Meat Roasted and Sold along Road Sides in Ekiti State

In 1999, the National Petroleum Council (NPC) stated that the resource base for meeting growing natural gas demands in the United States is adequate. A significant and increasing portion of natural gas production (8% by 2015) is expected to come from coal bed methane (CBM). The NPC cautions that for this to occur, certain factors, including compliance with environmental requirements, must be addressed. Numerous federal, state, and local programs address a variety of environmental issues, including water quality and quantity, air quality, wildlife, noise, and visibility. This paper examines existing and potential environmental regulatory requirements that could affect the timely development and production of CBM resources in the United States. Such an examination can help technology developers and policy makers target areas for research and development (R&D), demonstration, and implementation to help facilitate cost-effective CBM development and production to meet the nation's natural gas demands. It can also help identify R&D areas that will give rule-making bodies the information they need to incorporate more science into the regulatory development process.

Environmental regulatory drivers for coal bed methane research and development.

Many industrial, regulatory, and community leaders agree that the current U.S. environmental regulatory system imposes rigid requirements regardless of site-specific conditions, ignores the cross-media and multimedia environmental impacts that can result from these requirements, and lacks incentives for developing and using new technologies. For the foreseeable future, the U.S. petroleum refining industry, already challenged by thin profit margins and the need to manage releases of chemicals that can produce adverse impacts on the environment, will be required to produce higher quality fuels from poorer quality feedstocks. This paper describes two alternative environmental regulatory approaches to enhance environmental responsibility and maintain economic performance. These approaches are designed for existing petroleum refineries operating in the future. They differ from the current regulatory system in that they are multimedia in scope, provide for new technology development and use, and allow flexibility in how environmental goals are met. Various stakeholders, including industry representatives, regulators, local community groups, and national environmental organizations reviewed and critiqued early versions of the approaches. With minor modifications, the resulting approaches could be adapted for use by industries outside the refining sector. The submitted manuscript has been created by the University of Chicago as Operator of Argonne National Laboratory (“Argonne”) under Contract No. W-31-109-ENG-38 with the U.S. Department of Energy. The U.S. Government retains for itself, and others acting on its behalf, a paid-up, nonexclusive, irrevocable worldwide license in said article to reproduce, prepare derivative works, distribute copies to the public, and perform publicly and display publicly, by or on behalf of the Government.

Alternative future environmental regulatory approaches for petroleum refineries

Cooling water use patterns at US nonutility electric generating facilities

The drilling industry has developed several types of synthetic-based muds (SBMs) that combine the desirable operating qualities of oil-based muds with the lower toxicity and environmental impact qualities of water-based muds. SBMs offer operational advantages over WBMs and pollution prevention potential over OBMs in many situations, but the widespread use of SBMs has been inhibited by concerns that the discharged drill cuttings would not meet the ELGs requirement for no free oil. This article is based on a study performed by Argonne national Laboratory for the US Department of Energy (DOE), Office of Policy. The study was conducted through literature review and extensive communication with oil industry operators and drilling product supply companies. Much of the information on environmental impacts was previously published, but some of the key drilling performance and cost data were supplied directly by industry operators.

Synthetic-based muds can improve drilling efficiency without polluting

Consequences of proposed changes to clean water act thermal discharge requirements

Offshore oil and gas operators use specialized drilling fluids, referred to as {open_quotes}muds,{close_quotes} to help maintain well control and to remove drill cuttings from the hole. Historically, either water-based muds (WBMs) or oil-based muds (OBMs) have been used for offshore wells. Recently, the drilling industry has developed several types of synthetic-based muds (SBMs) that combine the desirable operating qualities of OBMs with the lower toxicity and environmental impact qualities of WBMs. This report describes the operational, environmental, and economic features of all three types of muds and discusses potential EPA regulatory barriers to wider use of SBMs.

Synthetic drilling fluids - a pollution prevention opportunity for the oil and gas industry

Building ventilation consumes about 5.8 exajoules of energy each year in the US The annual cost of this energy, used for commercial building fans (1.6 exajoules) and the heating and cooling of outside air (4.2 exajoules), is about $US 33 billion per year. Energy conservation measures that reduce heating and cooling season ventilation rates 15 to 35% in commercial and residential buildings can result in a national savings of about 0.6 to 1.5 exajoules ($US 3-8 billion) per year assuming no reduction of commercial building fan energy use. The most significant adverse environmental impact of reduced ventilation and infiltration is the potential degradation of the buildings indoor air quality. Potential benefits to the US from the implementation of sound indoor air quality and building ventilation reduction policies include reduced building-sector energy consumption; reduced indoor, outdoor, and global air pollution; reduced product costs; reduced worker absenteeism; reduced health care costs; reduced litigation; increased worker well-being and productivity; and increased product quality and competitiveness.

The role of the US Department of Energy in indoor air quality and building ventilation policy development

Macromodel for assessing residential concentrations of combustion-generated pollutants: Model development and preliminary predictions for CO, NO/sub 2/, and respirable suspended particles

In this era of stable to declining oil prices, the economic incentive for turning to alternative fuels for transportation has obviously decreased. Other incentives may lead to the use of alternative transportation fuels. This paper presents preliminary results of a study examining whether an inability of highway vehicles to comply fully with mobile source emission regulations might constrain the use of gasoline and diesel fuels, and thus catalyze penetration of alternative fuels into the transportation market. The study found that while compliance challenges exist, it is unlikely that they alone will force manufacturers to turn to alternative-fueled vehicles. Based on projected household and vehicle characteristics over the next 10 years, a forecast of alternative-fueled vehicle penetration and impact on national emissions has been developed under a set of optimistic but plausible assumptions about future availability and price of alternative fuels. It is estimated that by 1997 under 2% of personal vehicle miles driven could be in methanol-fueled cars and light trucks, the alternative-fueled vehicles most likely to penetrate first. This level of penetration would lead to a reduction of less than 1% in RHC and NO/sub x/ from all transportation sources in 1997.

Emerging environmental constraints on the use of gasoline and diesel fuel and tradeoffs associated with the use of alternative fuels

In the quest for measures to reduce ambient ozone and carbon monoxide levels to the degree required by revised State Implementation Plans (SIPs), non-attainment areas are investigating and committing to incentive programs for accelerated penetration of methanol- and flexible-fueled motor vehicles into the regional fleet. In this paper we examine if the premises for these commitments are sound; if, in fact, incontrovertible evidence is in hand to assure that the net air quality effect of replacing gasoline- and diesel-powered vehicles with methanol- and flexible-fuel units will be positive; and whether such positive effects, even if they can be proved, will occur in a time frame that will be useful or even relevant to the developers of SIP revisions. Our conclusions, based upon emission rate and failure mode information now available, are that optimism on either front (net positive air quality effect or availability of production methanol-compatible units in the near term) is premature, and that the case for methanol today should probably be founded on the desirability of national energy security, rather than on any assumed local or regional environmental benefit needed for SIP compliance. 7 refs., 1 tab.

An understanding of the basis for this difference in the cost estimates between the Environmental Protection Agency (EPA) and the manufactuers is the stimulus for this paper. The difference exists even though EPA conducted a reevaluation of its cost estimates for the regulatory impact analysis. This paper reports the results of a study in which EPA's, the manufacturers', and other particulate trap-oxidizer system cost estimates were analyzed and the reasons for the differences among the cost estimates documented. Because many papers and reports are available that discuss the viability (effectiveness, impact on engine performance) of specific systems in detail, this does not discuss these concerns except as they affect the cost estimates for trap-oxidizer systems.

Analysis of the costs of particulate trap-oxidizer systems for heavy-duty diesel vehicles

The potential for growth of natural gas vehicles (NGVs) and their different performance, emission, and safety characteristics prompted a DOE-sponsored study to document environmental concerns. The authors describe the vehicle technology and fueling system, then summarize the major findings of the study, which also examined regulatory considerations in the sale and use of natural gas as an automotive fuel. The results support continued evaluation of natural gas as an alternative fuel for transportation vehicles, but the conclusions are based on limited data that in some instances are out of date. The authors recommend additional research in each of the areas of the study. A full report was published earlier by Argonne National Laboratory. 10 references, 1 table.

State of knowledge of environmental concerns related to natural-gas-fueled vehicles

Vehicles powered by natural gas are currently used in the United States and other parts of the world. While the number of such vehicles in the US is small, the potential exists for substantial growth. For that reason and because natural gas-fueled vehicles have different performance, emission, and safety characteristics than do gasoline- or diesel-fueled vehicles, a study was conducted to document the environmental concerns related to natural gas vehicles. These concerns include those related to vehicle emissions and air quality regulations, safety hazards and regulations, natural gas supply, regulation of natural gas sales, and institutional impacts. This paper reports the results of that study, updated to include the results of several more recent analyses. The paper concludes in particular that while both the safety and emissions records of these vehicles appear satisfactory to date, a comprehensive data base exists in neither area.

Travel within urban areas accounted for about one-third of all the person miles of travel and about 5 Quads of energy in 1975. Two energy-saving strategies were designed for this sector that were aimed at minimal disruption to life-styles and the economy while achieving the reductions in aggregate energy, especially petroleum, consumption. These productive conservation strategies were tested in three typical cities; results were expanded to national urban totals and compared with results under a reference forecast of in-place policies. One strategy stressed group travel, whereas the other promoted individual travel. A scenario approach was used for projection of economic and social variables. Both strategies saved energy. Trips per person declined under the group travel strategy, which suggests that its greater energy savings were at the expense of some decrease in mobility. The impacts of environmental degradation and traffic fatalities were significantly different under the group travel strategy and were better than impacts under either the individual travel strategy or the in-place policy.

Technology assessment of productive conservation in urban transportation: an overview

Two strategies for saving energy in urban transportation were tested in three cities for their impact on the environment. The impacts of these strategies were contrasted to those occurring under the extension of policies in place in 1980. Key results included increased indirect energy use by transportation towards the end of this century; lack of impact on critical materials in building new, more fuel-efficient vehicles for urban travel; the dominance of fuel price increases in achieving the substantial energy savings projected by the year 2000; the differential impacts between fast growing and stable metropolitan areas; and the projection that both emissions and energy standards for urban vehicles can be met. Substantial energy savings were projected under all conditions; 40% savings were expected in the year 2000, relative to 1980, even under policies in place in 1980. The assumed rate of fuel price increase, from 3 to 5% per year depending upon the scenario, proved to be crucial in achieving these energy savings. Increased automotive fuel economy alone could not achieve energy savings in the long run. Further savings were achieved under each of the two strategies tested: Individual Travel, which promoted more fuel efficient automobiles than expected under In-Place Policies;more » and Group Travel, which promoted the use of transit systems by improved service and lower fares, and discouraged the use of autos by increased fuel taxes and parking taxes. Greater energy savings were achieved under Group Travel Strategy than under Individual Travel. In general, these energy savings were achieved without great cost to the environment or to specific social groups, even though impacts did vary by group.« less

ASSESSMENT OF NATIONAL ENERGY-SAVING POLICIES FOR TRANSPORTATION

Long-term trends, to the year 2000, of urban household travel were forecast for prototype metropolitan areas under several sets of energy prices, auto fuel economy, and emission standards. Dramatic improvements in air quality were forecast due to redistribution of travel and lowered emissions. The exception to this trend to rapidly growing cities, such as those in the west and southwest experiencing sprawl development that characterized many urbanized areas in the industrial northeast and midwest during the 1950's and 1960's. In one test city, where the rate of urbanization has slowed significantly, analysis indicated that relaxation of the light-duty-vehicle NO/sub x/ standard from 1.0 gm/mi to 2.0 gm/mi would not severely threaten attainment of the ambient NO/sub x/ standards by 1987 owing to redistribution of population and activities. The difference in total energy impacts was determined to be negligible, assuming moderate increase in petroleum prices through 1995 (3.1%/year). In another policy test, without changing emission standards, an increase in fuel price of 3.75%/year from 1980 to 2000 reduced travel and provided a 4% decrease in energy use and a corresponding decrease in CO, HC and NO/sub x/. Virtually all of the reduction in travel and emissions was due to non-work travel,more » which fell 9%. The price increase damped the increase in auto travel per person that would occur as autos become cheaper to operate and as household wealth increases, making the answer to the title a cautious yes, given steady or slowly rising fuel prices.« less

WILL CHEAP GAS AND EFFICIENT CARS IMPERIL AIR-QUALITY GOALS UNDER RELAXED EMISSION STANDARDS

Two strategies for the productive conservation of energy in urban transportation were compared to a reference situation in three typical cities in two plausible socio-economic scenarios; the reference case assumed as extension of transportation policies in place in 1980. Travel patterns, revenues and costs, and vehicle purchases were forecast; the resulting impacts on the physical environment, use of energy and materials, the economy, and health and safety were examined. The Group Travel Strategy, which included substantial additions to transit service, transit fare reductions, and gasoline and parking tax increases, yielded slightly higher energy savings than did the Individual Travel Strategy. The latter strategy raised average new car fuel economy steadily until the year 2000 and changed nothing else relative to the In-Place Policy. By 2000, assuming steady fuel price increases, the projected savings in total energy use under both strategies exceeded the savings projected under the In-Place Policy, where total energy use declined 16 to 34% from 1980 levels. The nature of the energy used for urban transportation changed significantly by 2000. In all situations, indirect energy use rose to about 40% of the total from the 1980 value of 24%. The environmental impacts varied by strategy, with Group Travelmore » Strategy impacts in general more benign.« less

TECHNOLOGY ASSESSMENT OF PRODUCTIVE CONSERVATION IN URBAN TRANSPORTATION--FINAL REPORT

The transportation sector directly consumes one quarter of the energy used in this country with auto passenger travel accounting for half of the transport sector's energy supply. Due to rapidly rising fuel prices and intermittent supply shortages, Federal, state, and local government have begun to introduce various strategies (combinations of policies and technologies) designed to conserve urban transportation energy while maintaining a productive economy. The environmental consequences of many of the conservation strategies have not been adequately assessed. As a result, a technology assessment project is underway. The project will concentrate on the effects of alternative conservation strategies for the efficient movement of people in urban areas. The goals of the project are to provide: a description of several alternative strategies promoting energy conservation in the urban passenger transportation sector; a better understanding of the environmental impacts of such strategies; and an identification of the constraints to the implementation of such strategies. After a brief discussion of conditions leading to the need for such a project, the process of defining and refining the study is presented. Objectives are then defined via examples followed by a presentation of the project structure and methodology. A short concluding statement presents the status of the major study elements. (ERA citation 06:023752)

STUDY DESCRIPTION: AN ENVIRONMENTAL COMPARISON OF FUTURE URBAN-TRANSPORTATION ALTERNATIVES

The US Department of Energy has developed a structured process to include National Environmental Policy Act of 1969 (NEPA) goals in RD and D planning. Argonne National Laboratory has been assisting in the implementation of the process for DOE transportation programs since its inception. The environmental evaluation process covers transportation technology RD and D projects up to commercialization or transportation system operation strategies implementation. An annual cycle planning process, resulting in an annual Environmental Development Plan, is the keystone of this approach. For it, each project is reviewed for potential environmental impacts and the additional research required to resolve or mitigate impacts is identified and scheduled, as are project-specific documents such as an Environmental Assessment or an Environmental Impact Statement. Two specific examples of how the process works are given: the off-gassing of electric vehicle lead acid batteries and the working fluid toxicity for a bottoming cycle. (ERA citation 06:024157)

ENVIRONMENTAL RESEARCH PLANNING AND ASSESSMENT OF DOE TRANSPORTATION TECHNOLOGY DEVELOPMENT

This programmatic plan identifies the ecosystem, resource, physical environment, health safety, and socio-economic issues associated with the DOE research, development, demonstration, and assessment of thirteen transportation technologies. These include the Stirling and gas turbine engines, constant speed accessory drive system, bottoming cycle for heavy duty trucks, continuously variable transmission, new hydrocarbons (brood-cut petroleum fuels), alcohol and synthetic fuels, hydrogen, electric and hybrid vehicles, pipeline bottoming cycle, and stratified-charge concept. The EDP presents a research and assessment strategy for resolving any potentially adverse environmental issues stemming from these technologies. The EDP process provides a framework for: incorporating environmental considerations into agency planning processes at the earliest stages; resolving environmental issues concurrently with energy technology development; and assuring that adverse environmental effects are mitigated through sound technological design and are at the same level of importance as technological, fiscal, and institutional issues in decision-making. Information contained in this EDP constitutes an inventory of the status of environmental problems and a plan for resolving these problems. (ERA citation 03:037534)

ENVIRONMENTAL DEVELOPMENT PLAN FOR THE DIVISION OF TRANSPORTATION ENERGY CONSERVATION, 1977

The Conservation Research and Technology (CONRT) EDP covers the environmental concerns related to CONRT technology R and D, whereas the end-use division EDPs cover the environmental concerns of system demonstrations and applications. After chapters on environmental strategy needs, objectives of this program, and technique for screening applicable projects, Chapter 4 characterizes middle-grade heat utilization, alternative fuels, 4.8-MW(e) fuel-cell power plant development, and first-generation systems development. Scientific desciplines that were investigated in Chapter 5 to point out environmental concerns were organic Rankine bottoming cycle, bi-phase system, resource assessment, wood-fired and waste-fired boilers, and fuel cells. The strategy for resolving environmental concerns is discussed in the final chapter. (MCW)

Environmental development plan for Conservation Research and Technology Program, 1977

This Environmental Development Plan (EDP) identifies the environmental concerns which include ecological, social/economic, health, safety, and resource impacts associated with the ERDA research, development, and demonstration (RD and D) of buildings and community energy systems and presents an environmental research and development strategy for resolving the concerns. The EDP process provides a framework for: incorporating environmental considerations into agency planning processes at the earliest stages; resolving environmental concerns concurrently with energy technology development; and assuring that adverse environmental effects are mitigated through sound technological design and are at the same level of importance as technological, economic, and institutional issues in decision making. Four technology thrusts covered in this Buildings and Community Systems program are: Architectural and Engineering Systems; Consumer Products and Technology; Urban Waste Technology; and Community Systems.

Environmental development plan for Buildings and Community Systems, 1977

This Environmental Development Plan (EDP) identifies the environmental, ecological, social/economic, health, safety and resource issues associated with ERDA research, development, and demonstration conducted in the Division of Industrial Energy Conservation (INDUS) and sets forth environmental RD and D strategies for resolving these issues. The approach taken in this EDP is to examine the environmental issues associated with each individual RD and D project. Emphasis is placed on currently active projects. In the present EDP, it is difficult to detect and programmatic environmental issues that are common to such diverse activities as poultry processing, blast furnace operation, and waste rubber recovery. Six air quality issues, one water quality and waste disposal issue, two occupational safety and health issues, and one public safety and health issue are identified and discussed.

Environmental development plan for Industrial Energy Conservation, 1977

32 p. transcript of an Elders conference conducted on August 27, 1980 . Tape number IH-OM.12, 12-1 ; transcript disc 85.

[A new formula of systematic preventive action with children: snow classes].

[Experience with the school at Vanves; a new educational system: half of the time for classroom work, the other half for athletics].

Topiramate is commonly used for treating epilepsy in both children and adults. Recent clinical data suggests that administration of topiramate to women during pregnancy increases the risk of oral clefts in their offspring. To better understand the potential effects of topiramate, we dosed adult female zebrafish with topiramate, and investigated the altered morphologies in adult females and their offspring. It showed that topiramate-treated female fish had reduced oocyte maturation, and the survival rates of their offspring were seriously decreased during embryogenesis. In addition, around 23% of offspring displayed cartilage malformation in the craniofacial area, such as loss of ceratobranchial cartilages as well as impaired ceratohyal, Meckel’s cartilage and ethmoid plate development. Moreover, mineralization of ceratohyal, Meckel’s cartilage, and vertebrae were downregulated during bone development. Taken together, we concluded that topiramate impaired oogenesis in the maternal reproductive system, and then caused offspring cartilage malformation or bone dysplasia.

Differential actinodin1 regulation in zebrafish and mouse appendages.

Independently verified structure of gp41-M-MAT, a membrane associated MPER trimer from HIV-1 gp41

Abstract Glial scars that consist predominantly of reactive astrocytes create a major barrier to neuronal regeneration after traumatic brain injury (TBI). In experimental TBI, Eph receptors and their ephrin ligands are upregulated on reactive astrocytes at injury sites and inhibit axonal regeneration, but very little is known about Eph receptors in the human brain after TBI. A better understanding of the functions of glial cells and their interactions with inflammatory cells and injured axons will allow the development of treatment strategies that may promote regeneration. We analyzed EphA4 expression and activation in postmortem brain tissue from 19 patients who died after acute closed head injury and had evidence of diffuse axonal injury and 8 controls. We also examined downstream pathways that are mediated by EphA4 in human astrocyte cell cultures. Our results indicate that, after TBI in humans, EphA4 expression is upregulated and is associated with reactive astrocytes. The expression was increased shortly after the injury and remained activated for several days. EphA4 activation induced under inflammatory conditions in vitro was inhibited using unclustered EphA4 ligand. These results suggest that blocking EphA4 activation may represent a therapeutic approach for TBI and other types of brain injuries in humans.

Expression and Activation of EphA4 in the Human Brain After Traumatic Injury

Neural progenitor cells reside in many regions of the adult brain. However, their capacity to generate new neurons relies on stem cell niches, consisting of stem cells, niche support cells, and basal lamina, which maintain stem cells and direct their differentiation and migration into tissue structures. Neurospheres are thought to expose neural progenitor cells to an environment reminiscent of the stem cell niche. We show that embryonic day 14.5 ventral mesencephalon neurospheres grafted into the midbrain of 6-hydroxydopamine lesioned mice express markers of mesenchymal cells, such as CD29 and CD44, and enclose a core of host-derived proliferating cells that express nestin, polysialic acid-neural cell adhesion molecule, βIII-tubulin, and neuron-specific nuclear protein. Laminin was expressed between the grafted cells and the core of proliferating host-derived cells. Further, infusion of the anti-mitotic agent β-d-arabinofuroside into the midbrain resulted in the loss of host-derived core cells that gradually returned over many days following β-d-arabinofuroside withdrawal. Together, these data suggest that a stem cell niche had been formed. Tyrosine hydroxylase (TH+) cells, ectopic to the usual midbrain locations, were present 4 weeks after grafting and increased in numbers up to 12 weeks after grafting, resulting in significantly more TH cells than control animals. These data provide evidence that cells within the midbrain are capable of acquiring a TH phenotype when exposed to the appropriate environment. Whether these cells are a result of neurogenesis or phenotypic shift remains unanswered.

Creating a ventral midbrain stem cell niche in an animal model for Parkinson's disease.

In this study, thermoresponsive xyloglucan hydrogel scaffolds were investigated as candidates for neural tissue engineering of the spinal cord. The hydrogels were optimized to provide similar mechanical properties to that of native spinal cord, although also being functionalized through the immobilization of poly-D-lysine to promote neurone adhesion and neurite outgrowth. Under 2D and 3D culture conditions, xyloglucan scaffolds supported the differentiation of primary cortical neurones. Furthermore, functionalization provided a means of controlling and optimizing the cell diameter, number, migration and the neurite density, and the direction of growth. The interaction of neural stem cells (NSCs) was also investigated on the xyloglucan scaffolds in vitro. The survival of the NSCs and the axonal extensions on the scaffolds were similar to that of the primary cortical neurones. These findings suggest that xyloglucan-based materials are suitable for providing a neurotrophic milieu.

Enhancing neurite outgrowth from primary neurones and neural stem cells using thermoresponsive hydrogel scaffolds for the repair of spinal cord injury.

By the time a patient first presents with symptoms of Parkinson’s disease at the clinic, a significant proportion (50-70%) of the cells in the substantia nigra (SN) has already been destroyed. This degeneration progresses until, within a few years, most of the cells have died. Except for rare cases of familial PD, the initial trigger for cell loss is unknown. However, we do have some clues as to why the damage, once initiated, progresses unabated. It would represent a major advance in therapy to arrest cell loss at the stage when the patient first presents at the clinic. Current therapies for Parkinson’s disease focus on relieving the motor symptoms of the disease, these unfortunately lose their effectiveness as the neurodegeneration and symptoms progress. Many experimental approaches are currently being investigated attempting to alter the progression of the disease. These range from replacement of the lost neurons to neuroprotective therapies; each of these will be briefly discussed in this review. The main thrust of this review is to explore the interactions between dopamine, alpha synuclein and redox-active metals. There is abundant evidence suggesting that destruction of SN cells occurs as a result of a self-propagating series of reactions involving dopamine, alpha synuclein and redox-active metals. A potent reducing agent, the neurotransmitter dopamine has a central role in this scheme, acting through redox metallo-chemistry to catalyze the formation of toxic oligomers of alpha-synuclein and neurotoxic metabolites including 6-hydroxydopamine. It has been hypothesized that these feed the cycle of neurodegeneration by generating further oxidative stress. The goal of dissecting and understanding the observed pathological changes is to identify therapeutic targets to mitigate the progression of this debilitating disease.

Fetal striatum- and ventral mesencephalon–derived expanded neurospheres rescue dopaminergic neurons in vitro and the nigro-striatal system in vivo

Murine embryonic EGF-responsive ventral mesencephalic neurospheres display distinct regional specification and promote survival of dopaminergic neurons

In Daniel Sack’s discussion of Nicola Gunn’s dramatic oeuvre, he finds a through line running between her works—one of self-reference and autofiction, a kind of playful knowledge of the self. In tracing this affinity between her pieces, in particular In the Sans Hotel, In Spite of Myself, Piece for Person and Ghetto Blaster, and Green Screen, Sack identifies the ways in which Gunn’s work speaks to both a contemporary moment in theater and the history of performance art, acknowledging the different baggage of the forms she references while coyly and fluently crossing between them. Sack sees in Gunn’s work the creation of heterotopias, places that open out onto an elsewhere, toward realities that simultaneously exist outside of the world and connect its disparate cultural manifestations together, from identity to ethics, politics to performance.

In “A Ride like Miss Johnson’s Wild Cat ”, a Keynote Address commissioned by the Indigenous Literary Studies Association to mark their First Gathering, “The Arts of Community”, at the Six Nations Polytechnic on the Six Nations of the Grand River Territory in October 2015, poet and playwright Daniel David Moses come home to explore the ‘meme’ of E. Pauline Johnson, the community’s historic ‘poetess’ and the sort of life in literature it suggests might be possible for indigenous artists in Canada.

Billions of Dollars Lost Along the Checkpoints? An Econometric Analysis of Labor Mobility, Economic Development, and Violence in the Israeli-Palestinian Conflict

Regulatory Elements, Protein Function and Evolution of the Actinodin Genes

The Influence of Key Adult Relationships on the Motivation and Achievement of Urban High School Students: A Qualitative Analysis

The emergent theatre of Native peoples offers theatre scholars and historians a unique opportunity to observe the fusion of cultures in the making. While contemporary postmodern theatre represents just one more link in a long chain of historical evolution that goes back two and a half millenia, contemporary Native playwrights are forced to work in a genre without direct antecedent in their culture—although theatrical elements are present, of course, in many aspects of traditional ritual and storytelling. In the best plays to emerge so far, the authors have successfully grafted the techniques of Euramerican postmodern theatre onto this traditional matrix of ritual and storytelling. The result is a theatre which shares all the surface aspects of Western postmodernism, but differs essentially in spirit. A comparative study of Tomson Highway's The Rez Sisters (1988) and Michel Tremblay's Les Belles-soeurs (1968) illustrates this point vividly, because of the exceptionally close parallels between these two sister plays. The parallels are immediately apparent on the levels of subject matter and dramatic techniques; there are also less apparent parallels with respect to the authors. Both Les Belles-soeurs and The Rez Sisters are first productions which catapulted their young authors, and with them the society they represent, into the spotlight of national and international attention; both plays marked the beginning of a new and original dramaturgy, the "nouveau théâtre québécois" in the case of Tremblay, Native Canadian theatre in that of Highway. Both plays focus exclusively on female characters. In both plays, these characters are closely related, as indicated by the respective titles. In both plays, the characters are struggling against poverty, as indicated by the respective

The research outlined in this paper explores two important issues relevant to understanding Latino identity and educational achievement: ethnic labels and educational injustices.

Mosquito Hall: Ethnic Labels and Social Injustices Within the Public School System

This catalogue for an exhibition of Niro’s work contains an artist’s statement, a poem by Daniel David Moses, and an essay by Gerald McMaster. McMaster describes each work and elaborates on the symbolism he discerns, relating it to his overarching theme: the spiritual core of humanity. He concludes that Niro’s reworking of the elements and motifs of Native culture contributes to the sovereignty of aboriginal peoples. List of works. Bio-bibliography 3 p.

In these linked plays, prize-winning playwright Daniel David Moses explores the frontier and discovers that the human face of the old West was more than cowboys and Indians.

Here we are: another meeting, another weekend of spinning words and being spun by them. That’s quite a title. I’m a playwright, among other things, and I have been invited (heck, I was part of the advisory committee) so I must also be a visible minority. I am the only registered Delaware Indian playwright I know.

Managing heterogeneous resources for dynamic energy-efficient sensing

This paper presents a new Q-value approximation algorithm for joint sensor scheduling and MAP state estimation in hidden Markov models. The proposed algorithm is motivated by the fact that energy-constrained embedded devices spend a significant amount of time in sleep modes. To develop an adaptive sensing-resource scheduling policy, the proposed base policy computes the exact value of sleeping over an infinite time horizon. This value is incorporated to rank sensing resources, trading off sensing quality with usage cost. As the base policy is independent of the sensing modalities, the proposed method is useful in applications where observation parameters such as SNR are time-varying, and when re-optimization is not practical. For applications with significant energy constraints, the proposed policy performs better than other heuristics and achieves near optimal performance/resource trade-off, as demonstrated in a long-term energy-constrained wildlife monitoring application.

2013 IEEE Global Conference on Signal and Information Processing

The value of sleeping: A rollout algorithm for sensor scheduling in HMMs

This paper proposes a low-power acoustic sensor built using off-the-shelf components. To reduce energy consumption, the ADC and the microphone's signal-conditioning circuit are replaced by a low-power analog comparator with adjustable thresholds. Although the SNR of the proposed sensor is reduced, we demonstrate how recent advancements in adaptive sensor scheduling can utilize this sensing modality at the right times to deliver high estimation performance in the presence of extremely stringent device-energy constraints. In a long-term acoustic wildlife monitoring application, energy consumption is reduced by a factor of up to 15× over the scheduling policy that does not utilize the proposed sensor. Furthermore, when device energy is extremely scarce, optimal sensor management can reduce error rate from nearly 40% to 8%.

Cheap noisy sensors can improve activity monitoring under stringent energy constraints

In many detection applications with battery powered or energy-harvesting sensors, energy constraints preclude the use of the optimal detector all the time. Optimal energy-performance trade-off is therefore needed in such situations. In many applications, the signal and noise power may vary greatly over time, and this can be exploited to constrain energy consumption while maintaining the best possible performance. A detector scheduling algorithm based on the signal and noise power information is developed in this work. The resulting algorithm is simple due to its threshold-test structure and can be easily implemented with almost no overhead. A detection system with two detectors using the proposed scheduling scheme is estimated to greatly reduce the energy consumption for a wildlife monitoring application.

Energy-efficient detection system in time-varying signal and noise power

Equipping everyday objects with sensing and computational capabilities creates the potential to achieve context and situational awareness through the detection of natural events. A major challenge in energy-constrained devices is that the detection of natural events generally demands sophisticated signal modeling and processing, along with continuous sensing. In this paper, we propose to use a cascade architecture to control signal-model complexity; this approach allows the device to sense continuously and trigger a more accurate signal model only when an event of interest is likely to be occurring. The sensitivity of the triggering affects detection performance and device energy consumption, so we formulate and solve the problem of optimal threshold allocation to control this sensitivity. We prove that for controlling signal-model complexity, triggering as often as possible maximizes detection performance; this seemingly intuitive result does not hold in other popular cascading techniques, most notably in low-power wakeup mechanisms. Our analysis leads to a simple threshold-tracking algorithm that can adjust to time-varying environmental conditions and energy supply. Combining a low-power MCU with controllable supply-voltage scaling, we present an acoustic wildlife monitoring system that exhibits 12× energy scalability from cascading detectors, and an additional 2× from synergistic hardware scaling on commercially available components. In practical scenarios, we demonstrate energy savings ranging from 3× to 20× with minimal loss in performance, compared to the conventional approach.

Sensing systems with multiple sensors and operating modes warrant active management techniques to balance estimation quality and measurement costs. Existing literature shows that in the joint sensor-scheduling and state-estimation problem for HMMs, estimator optimization can be done independently of the scheduler at each time step. We investigate the special case when a MAP estimator is used, and show how the joint problem can be converted to a standard Partially Observable MarkovDecision Process (POMDP), which in turn enables us to use POMDP solvers. As this approach is highly redundant, we derive a direct solution, which exploits the separability property while still utilizing standard solvers. When compared to standard techniques, the direct algorithm provides savings by a factor of the state-space dimension. Numerical results are given for an example motivated by wildlife monitoring.

A direct algorithm for joint optimal sensor scheduling and MAP state estimation for hidden Markov models

Current trends and popularity in embedded systems present an opportunity to modernize real-time digital signal processing (DSP) education. In this paper, we describe a hybrid real-time DSP laboratory course that starts with a fixed-point DSP processor to teach sample-by-sample processing, and then switches to the Google Nexus 7 tablet for block-based processing. This hybrid approach preserves the principles and components that embody real-time DSP education while spanning the full range of today's embedded signal processing applications.

2013 IEEE Digital Signal Processing and Signal Processing Education Meeting (DSP/SPE)

From fixed-point processors to android: A hybrid course for real-time DSP laboratory

Real-time detection of intermittent events requires continual monitoring and processing of sensor data. A battery-powered device that supports multiple sensing modalities and processing algorithms has the potential to save energy by using expensive sensors and algorithms only when the event of interest is most likely to occur. To develop a policy for sensing and processing management, we adopt maximum sequential information gain as an objective criterion for such energy-limited systems, which can be solved via dynamic programming. For binary hypothesis testing with two sensing options, the optimal management policy is a simple two-threshold test on the posterior belief. Detection of bird presence/absence in a wildlife monitoring application shows up to a 37% reduction in error rate over standard constant-duty-cycle sensing.

2012 IEEE International Conference on Acoustics, Speech and Signal Processing (ICASSP)

Practical sensor management for an energy-limited detection system

Low-power, scalable detection systems require aggressive techniques to achieve energy efficiency. Algorithmic methods that can reduce energy consumption by compromising performance are known as being energy-aware. We propose a framework that imposes energy-awareness on cascaded detection algorithms. This is done by setting the detectors' thresholds to make a systematic trade-off between energy consumption and detection performance. The thresholds are determined by solving our proposed energy-constrained version of the Neyman-Pearson detection criterion. Our proposed optimization method systematically determines the energy-optimal thresholds and dynamically adjusts to time-varying system requirements. This framework is applied to a two-stage cascade, and simulations show that our energy-aware cascaded detectors outperform an energy-aware detection algorithm based on incremental refinement. Finally, combining our framework with incremental refinement reveals a promising approach to the design of energy-efficient detection systems.

Nuclear safeguards considerations for pebble bed reactors (PBRs)

This report documents the detailed background information that has been compiled to support the preparation of a much shorter white paper on the design features and fuel cycles of Very High-Temperature Reactors (VHTRs), including the proposed Next-Generation Nuclear Plant (NGNP), to identify the important proliferation resistance and physical protection (PR&PP) aspects of the proposed concepts. The shorter white paper derived from the information in this report was prepared for the Department of Energy Office of Nuclear Science and Technology for the Generation IV International Forum (GIF) VHTR Systems Steering Committee (SSC) as input to the GIF Proliferation Resistance and Physical Protection Working Group (PR&PPWG) (http://www.gen-4.org/Technology/horizontal/proliferation.htm). The short white paper was edited by the GIF VHTR SCC to address their concerns and thus may differ from the information presented in this supporting report. The GIF PR&PPWG will use the derived white paper based on this report along with other white papers on the six alternative Generation IV design concepts (http://www.gen-4.org/Technology/systems/index.htm) to employ an evaluation methodology that can be applied and will evolve from the earliest stages of design. This methodology will guide system designers, program policy makers, and external stakeholders in evaluating the response of each system, to determine each system's resistance to proliferation threats and robustness against sabotage and terrorism threats, and thereby guide future international cooperation on ensuring safeguards in the deployment of the Generation IV systems. The format and content of this report is that specified in a template prepared by the GIF PR&PPWG. Other than the level of detail, the key exception to the specified template format is the addition of Appendix C to document the history and status of coated-particle fuel reprocessing technologies, which fuel reprocessing technologies have yet to be deployed commercially and have only been demonstrated in testing at a laboratory scale.

Very High-Temperature Reactor (VHTR) Proliferation Resistance and Physical Protection (PR&PP)

construction of a nuclear weapon, clandestine diversion of fissile materials by the host state for construction of a nuclear weapon, clandestine production of fissile materials in the facility by the host state, (4) abrogation by the host state of its participation in the Nuclear Nonproliferation Treaty and conversion of the facility to the production of nuclear weapons, and (5) radiological sabotage by subnational groups. Four safeguard challenges were examined. ABSTRACT People’s Republic of China (PRC) is operating a 10 MW(t) pebble-bed reactor (PBR) as a test reactor (the HTR-10) and is designing and building a prototypical PBR plant with two modular reactors (each 250 MW(t)) feeding steam to a single turbine generator. Because the prototype is a high-priority project for PRC, it will likely be the world’s first modular high-temperature reactor ready for commercial deployment. The plant design features multiple modular reactors feeding steam to a single turbine generator where the number of modules determines the plant output. The design and commercialization strategy are based on PRC strengths: (1) a rapidly growing electric market that will support low-cost mass production of modular reactor units and (2) a balance-of-plant system based on economies of scale that uses the same mass-produced turbine generator systems used in PRC coal plants. If successful, in addition to supplying the PRC market, this strategy could enable PRC to be the leading exporter of nuclear reactors to developing countries. The modular characteristics of the reactor match much of the need elsewhere in the world. PBRs have major safety advantages and a radically different fuel compared with current light-water reactors. The fuel, not the plant systems, is the primary safety system that prevents and mitigates the release of radionuclides under accident conditions. The fuel consists of small (6 cm) pebbles (spheres) containing coated-particle fuel in a graphitized carbon matrix. The fuel loading per pebble is small (~9 g of low-enriched uranium), and hundreds of thousands of pebbles are required to fuel a nuclear plant. The uranium concentration in the fuel is an order of magnitude less than in traditional nuclear fuels. These characteristics make the fuel significantly less attractive for illicit use (weapons production or dirty bomb), but its unusual physical form may require changes in the tools used for safeguards. This report describes PBRs, the differences between PBRs and other reactor types, and safeguards challenges. Safeguards are recommended based on the assumption that the reactor is commercialized successfully and is deployed widely.

Safeguards Challenges for Pebble-Bed Reactors Designed by People’s Republic of China

Recent reports by Department of Energy National Laboratories have discussed safeguards considerations for the low enriched uranium (LEU) fueled Pebble Bed Modular Reactor (PBMR) and the need for bulk accountancy of the plutonium in used fuel. These reports fail to account effectively for the degree of plutonium dilution in the graphitized-carbon pebbles that is sufficient to meet the International Atomic Energy Agency's (IAEA's) 'provisional' guidelines for termination of safeguards on 'measured discards.' The thrust of this finding is not to terminate safeguards but to limit the need for specific accountancy of plutonium in stored used fuel. While the residual uranium in the used fuel may not be judged sufficiently diluted to meet the IAEA provisional guidelines for termination of safeguards, the estimated quantities of {sup 232}U and {sup 236}U in the used fuel at the target burn-up of {approx}91 GWD/MT exceed specification limits for reprocessed uranium (ASTM C787) and will require extensive blending with either natural uranium or uranium enrichment tails to dilute the {sup 236}U content to fall within specification thus making the PBMR used fuel less desirable for commercial reprocessing and reuse than that from light water reactors. Also the PBMR specific activity of reprocessed uranium isotopic mixture and its A{sub 2} values for effective dose limit if released in a dispersible form during a transportation accident are more limiting than the equivalent values for light water reactor spent fuel at 55 GWD/MT without accounting for the presence of the principal carry-over fission product ({sup 99}Tc) and any possible plutonium contamination that may be present from attempted covert reprocessing. Thus, the potentially recoverable uranium from PBMR used fuel carries reactivity penalties and radiological penalties likely greater than those for reprocessed uranium from light water reactors. These factors impact the economics of reprocessing, but a more significant consideration is that reprocessing technologies for coated particle fuels encased in graphitized-carbon have not progressed beyond laboratory-scale demonstrations although key equipment that has been tested in the past (such as graphite burners and electrolytic disintegration/dissolution devices) are not listed on either the 'Trigger List' or the 'Dual Use List' for mandatory export controls. Finally, if gross burn-up determined from fission product gamma ray inspection of a discharged pebble cannot be correlated acceptably with predicted plutonium content of the pebble, development and testing may be required on detector concepts for more directly measuring the plutonium content in a discharged pebble to ensure that its placement in the spent fuel storage tanks is for an acceptable 'measured discard' of diluted plutonium.

Supplemental Report on Nuclear Safeguards Considerations for the Pebble Bed Modular Reactor (PBMR)

The Peoples Republic of China (PRC) is operating the HTR-10 pebble-bed reactor (PBR) and is in the process of building a prototype PBR plant with two modular reactors (250-MW(t) per reactor) feeding steam to a single turbine-generator. It is likely to be the first modular hightemperature reactor to be ready for commercial deployment in the world because it is a highpriority project for the PRC. The plant design features multiple modular reactors feeding steam to a single turbine generator where the number of modules determines the plant output. The design and commercialization strategy are based on PRC strengths: (1) a rapidly growing electric market that will support low-cost mass production of modular reactor units and (2) a balance of plant system based on economics of scale that uses the same mass-produced turbine-generator systems used in PRC coal plants. If successful, in addition to supplying the PRC market, this strategy could enable China to be the leading exporter of nuclear reactors to developing countries. The modular characteristics of the reactor match much of the need elsewhere in the world. PBRs have major safety advantages and a radically different fuel. The fuel, not the plant systems, is the primary safety system tomore » prevent and mitigate the release of radionuclides under accident conditions. The fuel consists of small (6-cm) pebbles (spheres) containing coatedparticle fuel in a graphitized carbon matrix. The fuel loading per pebble is small (~9 grams of low-enriched uranium) and hundreds of thousands of pebbles are required to fuel a nuclear plant. The uranium concentration in the fuel is an order of magnitude less than in traditional nuclear fuels. These characteristics make the fuel significantly less attractive for illicit use (weapons production or dirty bomb); but, its unusual physical form may require changes in the tools used for safeguards. This report describes PBRs, what is different, and the safeguards challenges. A series of safeguards recommendations are made based on the assumption that the reactor is successfully commercialized and is widely deployed.« less

Safeguards Challenges for Pebble-Bed Reactors (PBRs):Peoples Republic of China (PRC)

An accident, thermal fluids, and reactor physics phenomena identification and ranking process was conducted by a panel of experts on the next generation nuclear plant (NGNP) design (consideration given to both pebble-bed and prismatic gas-cooled reactor configurations). Safety-relevant phenomena, importance, and knowledge base were assessed for the following event classes: (1) normal operation (including some reactor physics aspects), (2) general loss of forced circulation (G-LOFC), (3) pressurized loss-of-forced circulation (P-LOFC), (4) depressurized loss-of-forced circulation (D-LOFC), (5) air ingress (following D-LOFC), (6) reactivity transients - including anticipated transients without scram (ATWS), (7) processes coupled via intermediate heat exchanger (IHX) (IHX failure with molten salt), and (8) steam/water ingress. The panel's judgment of the importance ranking of a given phenomenon (or process) was based on the effect it had on one or more figures of merit or evaluation criteria. These included public and worker dose, fuel failure, and primary (and other safety) system integrity. The major phenomena of concern that were identified and categorized as high importance combined with medium to low knowledge follow: (1) core coolant bypass flows (normal operation), (2) power/flux profiles (normal operation), (3) outlet plenum flows (normal operation), (4) reactivity-temperature feedback coefficients for high-plutonium-content cores (normal operation andmore » accidents), (5) fission product release related to the transport of silver (normal operation), (6)emissivity aspects for the vessel and reactor cavity cooling system (G-LOFC), (7) reactor vessel cavity air circulation and heat transfer (G-LOFC), and (8)convection/radiation heating of upper vessel area (P-LOFC).« less

Next Generation Nuclear Plant Phenomena Identification and Ranking Tables (PIRTs) Volume 2: Accident and Thermal Fluids Analysis PIRTs

As a follow-up to the phenomena identification and ranking table (PIRT) studies conducted recently by NRC on next generation nuclear plant (NGNP) safety, a study was conducted to identify the significant 'gaps' between what is needed and what is already available to adequately assess NGNP safety characteristics. The PIRT studies focused on identifying important phenomena affecting NGNP plant behavior, while the gap study gives more attention to off-normal behavior, uncertainties, and event probabilities under both normal operation and postulated accident conditions. Hence, this process also involved incorporating more detailed evaluations of accident sequences and risk assessments. This study considers thermal-fluid and neutronic behavior under both normal and postulated accident conditions, fission product transport (FPT), high-temperature metals, and graphite behavior and their effects on safety. In addition, safety issues related to coupling process heat (hydrogen production) systems to the reactor are addressed, given the limited design information currently available. Recommendations for further study, including analytical methods development and experimental needs, are presented as appropriate in each of these areas.

ASSUMPTIONSAND CRITERIA FOR PERFORMINGA FEASIBILITYSTUDY OF THE CONVERSIONOF THE HIGH FLUX ISOTOPE REACTORCORE TO USE LOW-ENRICHEDURANIUMFUEL

A computational study will be initiated during fiscal year 2006 to examine the feasibility of converting the High Flux Isotope Reactor from highly enriched uranium fuel to low-enriched uranium. The study will be limited to steady-state, nominal operation, reactor physics and thermal-hydraulic analyses of a uranium-molybdenum alloy that would be substituted for the current fuel powder--U{sub 3}O{sub 8} mixed with aluminum. The purposes of this document are to (1) define the scope of studies to be conducted, (2) define the methodologies to be used to conduct the studies, (3) define the assumptions that serve as input to the methodologies, (4) provide an efficient means for communication with the Department of Energy and American research reactor operators, and (5) expedite review and commentary by those parties.

Assumptions and Criteria for Performing a Feasability Study of the Conversion of the High Flux Isotope Reactor Core to Use Low-Enriched Uranium Fuel

The U.S.-Russian Joint Studies on Using Power Reactors to Disposition Surplus Weapons Plutonium as Spent Fuel

Plutonium disposition in the BN-600 fast-neutron reactor at the Beloyarsk nuclear power plant 1 Research sponsored by the Office of Fissile Materials Disposition, U.S. Department of Energy, under contract DE-AC05-96OR22464 with Lockheed Martin Energy Research Corp. 1

Accelerator-driven systems for fissile materials production have been proposed and studied since the early 1950s. Recent advances in beam power levels for small accelerators have raised the possibility that such use could be feasible for a potential proliferator. The objective of this study is to review the state of technology development for accelerator-driven spallation neutron sources and subcritical reactors. Energy and power requirements were calculated for a proton accelerator-driven neutron spallation source and subcritical reactors to produce a significant amount of fissile material--plutonium.

Proliferation Potential of Accelerator-Drive Systems: Feasibility Calculations

The Department of Energy (DOE) has proposed irradiation of mixed-oxide (MOX) fuel in existing commercial reactors as a disposition method for surplus plutonium from the weapons program. The burning of MOX fuel in reactors is supported by an extensive technology base; however, the infrastructure required to implement reactor-based plutonium disposition does not exist domestically. This report identifies and examines the actions required to qualify and license weapons-grade (WG) plutonium-based MOX fuels for use in domestic commercial light-water reactors (LWRs).

Fuel qualification issues and strategies for reactor-based surplus plutonium disposition

This paper describes safety goals that have been put into place to guide the emerging design of the Advanced Neutron Source (ANS) reactor.

A nuclear power plant is composed of many structures, systems, and components (SSCs). Examples include emergency core cooling systems, feedwater systems, and electrical systems. The design of a reactor consists of combining various SSCs (building blocks) into an integrated plant design. A new reactor design is the result of combining old SSCs in new ways or use of new SSCs. This report identifies, describes, and characterizes SSCs with passive and inherent features that can be used to assure safety in light-water reactors. Existing, proposed, and speculative technologies are described. The following approaches were used to identify the technologies: world technical literature searches, world patent searches, and discussions with universities, national laboratories and industrial vendors. 214 refs., 105 figs., 26 tabs.

Proposed and existing passive and inherent safety-related structures, systems, and components (building blocks) for advanced light-water reactors

This review journal covers significant developments in the field of nuclear safety. Its scope includes the analysis and control of hazards associated with nuclear energy, operations involving fissionable materials, and the products of nuclear fission and their effects on the environment. Primary emphasis is on safety in reactor design, construction, and operation; however, the safety aspects of the entire fuel cycle, including fuel fabrication, spent-fuel processing, nuclear waste disposal, handling of radioisotopes, and environmental effects of these operations, are also treated.

Nuclear Safety: 1959--1989, 30 years reviewing the nuclear world

The importance of the nuclear and neutronic properties of candidate space reactor materials to the design process has been acknowledged as has been the use of benchmark reactor physics experiments to verify and qualify analytical tools used in design, safety, and performance evaluation. Since June 1966, the Cross Section Evaluation Working Group (CSEWG) has acted as an interagency forum for the assessment and evaluation of nuclear reaction data used in the nuclear design process. CSEWG data testing has involved the specification and calculation of benchmark experiments which are used widely for commercial reactor design and safety analysis. These benchmark experiments preceded the issuance oflthe industry standards for acceptance, but the benchmarks exceed the minimum acceptance criteria for such data. Thus, a starting place has been provided in assuring the accuracy and uncertainty of nuclear data important to space reactor applications. (FI)

The role of integral experiments and nuclear cross section evaluations in space nuclear reactor design

Examination of the bases for proposed innovations in reactor safety technology

The Fort St. Vrain operating experience to be discussed here includes notable safety-related events which have occurred since late 1981 when ORNL was first contracted to provide technical assistance to AEOD. Earlier Fort St. Vrain operating experience through the time of successful full-power testing in November 1981 has been summarized by the licensee and the reactor vendor, GA Technologies, Inc. (GA), in papers presented at several different forums during 1982. In addition, extensive and very useful detailed evaluations of preoperational and startup testing and of the rise-to-power operating experience through completion of the first refueling outage in August 1979 have been compiled into a series of reports under the sponsorship of the Electric Power Research Institute (EPRI). Finally, the US Department of Energy's Fort St. Vrain Improvement Plan provides a summary of the major operational limits which have affected the plant since start-up. The events discussed here are categorized based on the major systems affected, namely, (1) primary system and reactor vessel, (2) electrical systems, and (3) the reactor building. In all cases to be discussed, the lessons to be learned are vigilance and prevention. These lessons translate into the need for the recognition and control of unexpected situations and more » of their potential for branching effects. At Fort St. Vrain, these lessons are found in the effects of moisture ingress, in the challenges experienced to the supply of essential electrical power, and in controlling the environment of the reactor building. 13 refs. « less

Analysis and evaluation of recent operational experience from the Fort St. Vrain HTGR

The effects of incorporating community supported agriculture on the profitability of farms in the Northeastern U.S.

Laboratory experiments were conducted to investigate the foraging responses of kangaroo rats (Dipodomys merriami) and pocket mice (Perognathus amplus) to aggregates of seeds which differed in size, depth, and degree of clumping. Kangaroo rats effectively used clumps of seeds, whereas the pocket mice did not differentially select clumps of seeds over a scattered distribution of seeds. In addition to distribution, clump size and depth were important criteria for both species in determining foraging efforts. These data, coupled with recent information which suggests wide arrays of seed distribution types in the desert, lead us to propose that rodents select seeds on the basis of spatial distribution of the resource. This is an attractive hypothesis because it can accommodate both of the primary mechanism previously suggested for desert rodent coexistence, seed size selection and habitat selection.

Selection of Seed Distribution Types by Dipodomys Merriami and Perognathus Amplus

A thesis submitted to the School of Post Graduate Studies, Ahmadu Bello University, Zaria in partial fulfillment of the requirement for the award of Master degree in Mass Communication, Faculty of Social Sciences Ahmadu Bello University, Zaria-Nigeria. DEPARTMENT OF MASS COMMUNICATION FACULTY OF SOCIAL SCIENCES AHMADU BELLO UNIVERSITY, ZARIA

Influence of Telecommunication Advertisements on Students’ Perception and Preference for GSM Services in Kogi State Tertiary Institutions

Studies of light charged particle emission from fission and ER reactions in the system 344 MeV 28Si+121Sb→149Tb (E∗=240 MeV)

Search for ternary fragmentation in the reaction 856 MeV 98Mo+51V: kinematic probing of intermediate-mass-fragment emissions

Coincidence Correlations Between Light Charged Particles in the Matched Reactions 905 and 1030 MeV121Sb + 27Al and 550 and 750 MeV 86Kr + 63Cu

Mechanisms of light-charged-particle emission in the matched reactions 905 and 1030 MeV 121Sb + 27A1 and 550 and 750 MeV 86Kr + 63Cu

The role of reversed kinematics and double kinematic solutions in nuclear reactions studies

Detailed coincidence studies of light-charged-particle evaporation in 485-MeV /sup 56/Fe+ /sup 197/Au reactions have recently been used to probe the features of fusion-like fission and deeply inelastic reaction mechanisms. We summarize here the average statistical properties which characterize the several identified groups of hot nuclear emitters. These properties are derived from comparisons of observed /sup 4/He//sup 1/H energy spectra and angular distributions with model calculations. The results demonstrate remarkably low effective evaporation barriers for the very heavy composite system produced here, consistent with the trends found previously for much lighter systems.

Light charged particle emission in 485 MeV 56Fe + 197Au reactions: Correlations with heavy fragments and relationships to spin and lifetime

Surprising Properties of the Nuclear Stratosphere Indicated by Energy Spectra and Large-Angle Correlations Between 4 He and 1 , 2 , 3 H or 4 He

Evaporation-like emission of light particles (n, H, He...) has been observed for many nuclear reactions that populate composite nuclei with temperatures of up to ≤ 5 MeV and spins as high as ≤ 150h. The measured average energies for the light charged particles are often significantly lower than calculations for evaporation from spherical nuclei. Detailed calculations have not been reported for the role of deformation in evaporative emission patterns, and thus the interpretation of such data has been severely limited. In this paper we describe a method for making evaporation calculations for deformed nuclei, and we present results for several systems. The trends of the calculated results are compared to those for spherical emitters in order to get a feeling for those effects peculiar to the deformations. The patterns of calculated spectra and angular distributions encourage the notion that such studies can give valuable clues to the shapes and surface properties of these very hot nuclei. Comparisons are made to experimental data for 1H-4He and 4He-4He correlations in the reaction 337 MeV 40Ar + natAg. These comparisons point out some novel features of the nuclear surface.

LARGE-ANGLE CORRELATIONS IN EVAPORATIVE PARTICLE EMISSION : SHAPE DISTORTION ? SURFACE EXPANSION ?

Particle spectra from reversed kinematics: Powerful probes of hot rotating nuclei

Fission reactions of 469-MeV56Fe+238U: Detection of4He/1H emission from pre- and post-fission sources

Multiplicities for evaporative4He emission in heavy ion reactions: Relationships to spin and lifetime expectancy of the composite nucleus

Mechanisms for emission of4He in the reactions of 334 MeV40Ar with238U

Light charged particle emission and fission in238U+238U collisions at 1,740 MeV

Exploratory Approach to Performance of Smart Components of Intelligent [Smart] Buildings

Advancement in the field of autonomous motion planning has enabled the realisation of fully autonomous unmanned vehicles. Sampling based motion planning algorithms have shown promising prospects in generating fast, effective and practical solutions to different motion planning problems in unmanned vehicles for both civilian and military applications. But the goal bias introduced by heuristic probability shaping to generate faster solution may result in local collisions. A simple, real-time method is proposed for goal direction by preferential selection of a state from a sampled pair of random state, based on the distance to goal. This limits the graph motions resulting in smaller data structure, making the algorithm optimised for time and solution length. This would enable unmanned vehicles to take shorter paths and avoid collisions in obstacle rich environment. The approach is analysed on a sampling based algorithm, rapidly-exploring random tree (RRT) which computes motion plans under constrain of time. This paper proposes an algorithm called ’goal directed RRT (GRRT)’ building on the basic RRT algorithm, providing an alternative to probabilistic goal biasing, thereby avoiding local collision. The approach is evaluated by benchmarking it with RRT algorithm for kinematic car, dynamic car and a quadrotor and the results show improvements in length of the motion plans and the time of computing.

Goal Directed Approach to Autonomous Motion Planning for Unmanned Vehicles

The issues of Monthly Weather Review would be mostly empty if it were not for the large number of high-quality submissions each year. To retain our position as one of the leading meteorological journals in the world, we need to attract and retain these valuable contributions. However, of the approximately 400 annual submissions, only 56.7% were eventually published in 2021. The percentage of papers being rejected has slowly increased from 33.7% in 2007 (Schultz 2010a) to 37.6% in 2021, with withdrawals and transfers making up the remaining few percent. Although some of those rejections are because the papers are off topic forMonthly Weather Review, most rejections are because the science does not meet our minimum standards or may need to be explained better. Defending the rejection of papers, the great fluid-mechanics scientist Batchelor (1981, p. 16), the founder and chief editor of the Journal of Fluid Mechanics, once wrote,

This editorial is the third in a series honoring Monthly Weather Review’s 150th volume.

Market Share Liability in DES Cases: The Unwarranted Erosion of Causation in Fact

Japan's Information Disclosure Law--Why a Law Full of Loopholes Is Better than No Law at All

L'invention concerne un procede de determination et de caracterisation de la photosynthese dans des parties vegetales d'une ou de plusieurs plantes qui consiste a capturer une pluralite d'images des parties vegetales de la ou des plantes a l'aide d'un capteur. La fluorescence des parties vegetales de la ou des plantes est mesuree par exemple par le stockage d'une image de capteur de la fluorescence observee. La lumiere absorbee par les parties vegetales de la ou des plantes est estimee par exemple par l'observation de la reflectance rouge et/ou infrarouge des parties vegetales. Une caracteristique de la photosynthese telle que le flux lineaire d'electrons dans des parties vegetales de la ou des plantes est derivee a l'aide de la fluorescence mesuree des parties vegetales, de la reflectance et de la lumiere absorbee par les parties vegetales, et/ou du modele tridimensionnel comprenant les parties vegetales de la ou des plantes.

Procédés d'estimation des caractéristiques photosynthétiques de couvertures végétales, et systèmes et appareil associés

Il est possible d'etudier la fluorescence de la chlorophylle en reponse a divers signaux ou conditions environnementaux en faisant croitre des microorganismes phototrophes sous eclairage actinique. Cet eclairage peut etre intermittent ou interrompu pour acquerir de l'information sur les proprietes ou les performances photosynthetiques de l'organisme phototrophe. L'invention concerne egalement des instruments ou des dispositifs pour mettre en œuvre le procede.

Systèmes de phénométrie végétale et procédés et dispositifs associés

L'invention concerne ici un systeme qui comprend un ou plusieurs reseaux modulaires de photobioreacteurs environnementaux, chaque reseau contenant deux ou plus de deux photobioreacteurs, ou le systeme est adapte pour surveiller chacun des photobioreacteurs et/ou moduler les conditions avec chacun des photobioreacteurs. Les photobioreacteurs sont aussi adaptes pour la mesure de multiples parametres physiologiques d'une biomasse qu'ils contiennent. Divers procedes pour la selection et la caracterisation de la biomasse sont aussi fournis. Dans une forme de realisation, la biomasse est constituee d'algues.

Système de réseau de photobioréacteur environnemental (epbra) et procédés apparentés

La presente invention concerne des procedes destines a mesurer un parametre photosynthetique. Ces procedes consistent (a) a eclairer une feuille de plante jusqu'a ce que la photosynthese se produise en regime continu, (b) a soumettre la feuille de plante eclairee a une periode d'obscurite, (c) a utiliser un spectrophotometre a cinetique ou un spectrophotometre/fluorimetre a cinetique afin de recueillir des donnees spectrales a partir de la feuille de plante traitee selon les etapes (a) et (b), et (d) a determiner un parametre photosynthetique a partir des donnees spectrales. Dans une autre realisation, l'invention concerne des procedes destines a determiner l'etat physiologique d'une plante.

Elimination des signaux parasites en résonance magnétique nucléaire

Vehicle tire pump system with speed sensor and use procedures for

Interoceptive fear conditioning and panic disorder: the role of conditioned stimulus-unconditioned stimulus predictability.

A Comparative Evaluation of Acceptance and Cognitive Restructuring Techniques for Coping with Acute Panicogenic Distress: An Experimental Evaluation in an Anxious Non-Clinical Sample

Research on the nature of emotional disorders points toward a common set of diatheses (underlying psychological vulnerabilities) and functionally (but not superficially) similar expression of pathological emotional responding (e.g., Barlow, 2002). Successful drug treatments for different emotional disorders are very similar, with selective serotonin reuptake inhibitors or related compounds in wide use. Successful psychological treatments, on the other hand, are currently specifically targeted to each individual disorder. Distilling common principles among existing empirically supported psychological treatments, and giving attention to new findings on emotion regulation and dysregulation from emotion science, we propose and describe a new unified psychological treatment for emotional disorders.

A New Unified Treatment Approach for Emotional Disorders Based on Emotion Science

L'invention porte sur des compositions d'asphalte comprenant de l'asphalte recupere et un agent de regeneration fonctionnel ester. L'invention porte egalement sur des compositions de liants regeneres. Les agents de regeneration rendent a l'asphalte recupere les proprietes les plus souhaitables de l'asphalte vierge. Des temperatures de debut de transition vitreuse reduites et une rigidite vis-a-vis du cheminement amelioree dans les liants regeneres se traduisent en une resistance a la fissuration a basse temperature amelioree dans l'asphalte. Les agents de regeneration communiquent un ramollissement souhaitable a un faible dosage, tout en maintenant egalement des valeurs de penetration acceptables. Des resultats de rheometrie de cisaillement dynamique demontrent que des criteres pour des compositions d'asphalte sous des conditions de temperature basse, intermediaire et elevee peuvent etre obtenus, et l'asphalte aura une bonne resistance a la fissuration a la fatigue et une prevention du defoncement. Les agents de regeneration reduisent la temperature necessaire pour compacter ou melanger des compositions d'asphalte, ce qui economise de l'energie et reduit les couts. Les compositions d'asphalte et de liants regeneres permettront une plus grande utilisation d'asphalte recupere, en particulier de revetement routier d'asphalte recupere, et aideront l'industrie de la construction routiere a reduire sa dependance vis-a-vis de materiaux vierges non renouvelables.

L'invention concerne des procedes et appareils permettant une selectivite et une translation de frequences, ainsi que leurs applications. Le procede consiste a filtrer un signal d'entree et a transposer le signal d'entree filtre. Les operations de filtrage et de transposition sont executees d'une maniere integree et unifiee. L'appareil concerne peut etre implante comme circuit integre (CI). Il peut egalement contenir un ou plusieurs modules de commande de gain.

Translation et selectivite de frequences integrees a fonctionnalite de commande de gain et applications associees

L'invention concerne des systemes et des procedes relatifs a l'utilisation de convertisseurs de frequence universels pour la detection de phase et/ou de frequence. La detection de phase et/ou de frequence peut servir a comparer un signal de reference haute frequence a un signal d'oscillateur local basse frequence. La detection de phase et/ou de frequence peut egalement servir au blocage de phase et/ou au verrouillage de frequence. Les systemes et procedes selon l'invention peuvent etre utilises pour convertir simultanement a la baisse un signal de reference destine a la comparaison de phase et/ou de frequence et/ou au verrouillage.

Utilisation de convertisseurs de frequence universels pour la detection de phase et/ou de frequence: procedes et systemes associes

Systeme de positionnement global (GPS) (20) dans lequel plusieurs satellites d'orbites terrestres transmettent des informations de position a des stations radio mobiles sur terre, ce systeme etant pourvu de canaux numeriques de diffusion de donnees de position par satellites-source separes et un ou plusieurs canaux de communication separes de services d'appel (selectionnes a partir d'une liaison de donnees avec support de telephone cellulaire terrestre (42) ou autres services (54) de donnees par paquet radio) pour faciliter a la station radio mobile l'acces aux informations de position provenant des satellites. Un controleur (22) est couple a la station radio mobile (55) pour assurer la connexion au canal de communication separe afin de sortir des donnees de position par satellite via le canal de communication separe. Le controleur (22) comprend un microprocesseur (30) qui traite les donnees de position par satellite afin de permettre a la station radio mobile de localiser et avoir acces rapidement aux informations de position provenant dudit satellite d'orbite terrestre.

John Trevisa's translation of Bartholomaeus Anglicus' De proprietatibus rerum.

Intramolecular and intermolecular effects of aromatic sticker residue strength on intrinsically disordered protein regions.

Hidden structure in disordered proteins is adaptive to changes in the cellular environment

Intrinsically disordered proteins and protein regions (IDPs) are essential to cellular function in all proteomes. Unlike folded proteins, IDPs exist in an ensemble of rapidly interchanging conformations. IDP sequences encode interactions that create structural biases within the ensemble. Such structural biases determine the three-dimensional shape of IDP ensembles and can affect their activity. However, the plasticity and sensitivity of IDP ensembles means structural biases, often measured in vitro, may differ in the dynamic and heterogeneous intracellular environment. Here we reveal that structural biases found in vitro in well-studied IDPs persist inside human-derived cells. We further show that a subset of IDPs are able to sense changes in cellular physical-chemical composition and modulate their ensemble in response. We propose that IDP ensembles can evolve to sense and respond to intracellular physicochemical changes, or to resist them. This property can be leveraged for biological function, be the underlying cause of IDP-driven pathology, or be leveraged for the design of disorder-based biosensors and actuators.

Structural biases in disordered proteins are prevalent in the cell

Intrinsically disordered protein biosensor tracks the physical-chemical effects of osmotic stress on cells

Sequence and Chemical Environment Determine the Global Dimension of Intrinsically Disordered Protein Ensembles

Intrinsically disordered protein regions (IDRs) are ubiquitous in all proteomes and essential to cellular function. Unlike folded domains, IDRs exist in an ensemble of rapidly changing conformations. The sequence-encoded structural biases in IDR ensembles are important for function, but are difficult to resolve. Here, we reveal hidden structural preferences in IDR ensembles in vitro with two orthogonal structural methods (SAXS and FRET), and demonstrate that these structural preferences persist in cells using live cell microscopy. Importantly, we demonstrate that some IDRs have structural preferences that can adaptively respond to even mild intracellular environment changes, while other IDRs may display a remarkable structural resilience. We propose that the ability to sense and respond to changes in cellular physicochemical composition, or to resist such changes, is a sequence-dependent property of IDRs in organisms across all kingdoms of life.

Hidden structure in disordered proteins is adaptive to intracellular changes

Intrinsically disordered proteins and protein-regions (IDRs) make up roughly 30% of the human proteome and play vital roles in a wide variety of biological processes. Given a lack of persistent tertiary structure, all of the residues in an IDR are, to some extent, solvent exposed. This extensive surface area, coupled with the absence of strong intramolecular contacts, makes IDRs inherently sensitive to their chemical environment. Despite this sensitivity, our understanding of how IDR structural ensembles are influenced by changes in their chemical environment is limited. This is particularly relevant given a growing body of evidence showing that IDR function is linked to the underlying structural ensemble. We develop and use a combined experimental, computational, and analytical framework for high-throughput characterization of IDR sensitivity we call solution space scanning. Our framework reveals that IDRs show sequence-dependent sensitivity to solution chemistry, with complex behavior that can be interpreted through relatively simple polymer models. Our results imply that solution-responsive IDRs are ubiquitous and can provide an additional layer of biological regulation.

Probing the Hidden Sensitivity of Intrinsically Disordered Proteins to their Chemical Environment

Tuning the Activity of Disordered Proteins by Changing Solution Conditions

Intrinsically disordered protein-regions (IDRs) make up roughly 30% of the human proteome and are central to a wide range of biological processes. Given a lack of persistent tertiary structure, all residues in IDRs are, to some extent, solvent exposed. This extensive surface area, coupled with the absence of strong intramolecular contacts, makes IDRs inherently sensitive to their chemical environment. We report a combined experimental, computational, and analytical framework for high-throughput characterization of IDR sensitivity. Our framework reveals that IDRs can expand or compact in response to changes in their solution environment. Importantly, the direction and magnitude of conformational change depend on both protein sequence and cosolute identity. For example, some solutes such as short polyethylene glycol chains exert an expanding effect on some IDRs and a compacting effect on others. Despite this complex behavior, we can rationally interpret IDR responsiveness to solution composition changes using relatively simple polymer models. Our results imply that solution-responsive IDRs are ubiquitous and can provide an additional layer of regulation to biological systems.

Revealing the Hidden Sensitivity of Intrinsically Disordered Proteins to their Chemical Environment.

Klaus G. Janda, Ane Gude Moralitie: Robert Henryson's Moral Fables and The Testament of Cresseid, 2nd edn

The Maitland Quarto: A New Edition of Cambridge, Magdalene College, Pepys Library MS 1408, ed. Joanna M. Martin

Robert Henryson's Moral Fabillis: ‘Exempill and similitude’, the animal as true Sign, and an argument from design

Thesis Advisor This project is a time capsule of the oil economy, created by entombing everyday objects made from and powered by petroleum into a landscape that spatially recreates the processes of drilling and fracking a contemporary oil well. It consists of two interrelated landscape systems. The first is a giant landform, a marker on the earth's surface commensurate with the scale of the second, a labyrinth of chambers carved out of a subterranean strata of rock. The site is an existing two square mile drill spacing unit on the edge of Williston, North Dakota, in the middle of one of the largest contemporary shale oil booms in the world. This thesis aspires to be a counter monument to the processes that create massive change on a territorial scale yet somehow remain hidden from the end consumers of those processes. By placing the objects of oil back underground in their place of origin, they become future sites of meditation on the ways that everyday consumption drives the economies of extraction. Their entombment takes place over a long period of future time: as objects and processes of the oil economy become obsolete, they are buried one by one, a long slow motion fracking of the site. Like most monuments, this one has been designed for a future public, hopefully one that wonders at the strangeness of us and our economies of frenzied extraction and consumption. The thesis is a way of saying that we as a culture at least contended with fracking and its innumerable consequences in way that was more substantial than simply worrying about the price of gas at the pump. Miho Mazereeuw, MArch, MLA Assistant Professor of Architecture and Urbanism Submitted to the Department of Architecture on May 21, 2015 in partial fulfillment of the requirements for the Master of Architecture degree Miho Thank you for going on this strange journey with me. Your trust in the project, and my ability to see it through, has been unwavering, and your guidance has been invaluable. It has been a true gift learning from and working with you during my time MIT. Arindam and Cristina Thank you for all the appropriate nudges. Your fresh takes on the project helped me see it clearly for what it was along the way. Barry and Aditya Thank you for the help at the ragged end before the final review, and for all your support before that too. My classmates All intellectual endeavors are of course carried out in dialogue with others. Thank you for being my sounding boards, coconspirators, snack buddies, and friends the last three and a half years. Mom and Dad I am finally finished! I will call home more often now, I promise. I would not be here if not for your constant love and support. Alison, My rock, I love you. Table of

Richard Holland, The Buke of the Howlat. Edited by Ralph Hanna. Scottish Text Society, Fifth Series. Boydell and Brewer: Woodbridge, 2014. 226 pp. £38 hardback. ISBN 9781897976395.

Mairi Cowan, Death, Life, and Religious Change in Scottish Towns, c. 1350–1560. Manchester University Press: Manchester, 2012. xi + 252 pp. £60.00 hardback. ISBN 9780719080234.

Fires and Evacuations • Always evacuate at the sound of the alarm. • If you discover a fire, pull the nearest fire alarm. • Collect your immediate belongings and exit by the nearest designated route. • Support those that may need assistance. • Persons requiring special assistance may be directed to the closest Area of Rescue Assistance then notify University Police or 911. • Close but DO NOT LOCK doors as you leave. • DO NOT USE ELEVATORS. • Proceed to your designated assembly area and report to the coordinator. • Do not return to the building until directed by University Police.

Audrey Beth-Fitch, The Search for Salvation: Lay Faith in Scotland, 1480–1560, John Donald: Edinburgh, 2009. 206 pp. £25 hardback. ISBN 9781906566036

Writing animals, speaking animals: the displacement and placement of the animal in medieval literature

Why is a Cow below a Lettuce? The Anomalous Placement of the Animal in Bartholomaeus Anglicus' De proprietatibus rerum

The author replies: To the Editor: The comments of Dr. Coelho are pertinent and the references quoted in his letter are important. In our review, Dr. Rao and I did not intend to present an exhaustive review of the literature. The concept of functional similarity between various anatomic malformations was expressed earlier by the undersigned. Among references to this concept are the following: EDWARDS JE: Functional pathology of certain cardiovascular malformations which may be treated surgically. Arch Surg 61: 1103, 1950 EDWARDS JE: Functional pathology of the pulmonary vascular tree in congenital cardiac disease. Circulation 15: 164,1957 Dr. Rao and I regret omission of the references cited by Dr. Coelho but this was without an attempt to disregard important work and concepts of others. JESSE E. EDWARDS, M. D. United Hospitals-Miller Division 125 W. College Avenue St. Paul, Minnesota

SUMMARY The chest X-ray, perfusion lung scan, and selective pulmonary arteriogram were independent-ly reviewed in 104 patients with suspected pulmonary embolism. Thirteen patients also had 133Xe ventilation studies. Of the 45 patients with angiographically-documented pulmonary emboli, 37 had perfusion scans interpreted as high probability of pulmonary embolism (82% sensitivity). Fifty of 59 patients without angiographic evidence of pulmonary embolism had perfusion scans interpreted as low probability of pulmonary embolism, other, or normal (85% specificity). Of the 41 patients with acute pulmonary embolism, only three had normal chest X-rays. In 26 (63%) the abnormality on perfusion scan was more extensive than that on chest X-ray. When both the scan and chest X-ray pointed strongly in the same direction, a correct diagnosis could usually be made, and accuracy was greater than when diagnosis was based on the perfusion scan alone. The lung scan was of limited value in patients with cardiomegaly or left heart failure. The differential role of the 133Xe ventilation study remains unclear. On the basis of the present and other data, guidelines for the selection of patients for pulmonary arteriography are proposed.

RADIOLOGY The Complementary Roles of Chest Radiography, Lung Scanning, and Selective Pulmonary Angiography in the Diagnosis of Pulmonary Embolism

Painless fibro-osseous lesion of the rib resembling osteoid osteoma: A report of six cases

A patient with severe Parkinson's disease experienced a syncopal attack due to skeletal muscle myopotential inhibition of an implanted ventricular demand pacemaker. The problem was diagnosed with the aid of Holter monitoring, and was corrected by noninvasively programming the pacemaker to a lower sensitivity.

Myopotential inhibition of a ventricular demand pacemaker in a patient with Parkinson's disease.

Effect of exercise training on cardiac function in patients with coronary artery disease.

In patients with trauma to the ureter, Ga-67 accumulation may represent a urinoma rather than abscess formation. Comparison with other radiologic studies may help to confirm this diagnosis.

We present two cases of myelomatous involvement of the skull. Correlative studies with routine radiography, angiography, and encephaloscintigraphy were performed. The areas of involvement of the skull were confirmed as autopsy. A mixed pattern of photon-deficient and photon-abundant lesions was noted. The clinician should be aware of such mixed patterns.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine

Hypervascular presentation of multiple myeloma involving the skull, demonstrated on encephaloscintigraphy.

A new triiodothyronine (T3) radioimmunoassay kit offers simplicity of method, short incubation time, specificity, and reproducibility. 125I-labeled T3 and unknown serum (or standard) are added to alkaline buffered (pH 12.4) Sephadex G-25 columns; the T3 is freed of proteins with an alkaline buffer wash, antiserum is added, and the columns are incubated at room temperature for 2 h. "Free" hormone (i.e., unbound to antiserum) remains on the column after a second wash. The radioactivity on the column is counted and related to the total activity added. The T3 standards produced a straight line on log-logit plot; reactivity of analytical-grade thyroxine was 0.6% on weight basis; and the analytical recovery of T3 added to a T3-free serum was complete. Euthroid, hyperthyroid, and hypothyroid ranges were 0.74-2.64, 2.91-7.52, and 0-1.21 mug/liter, respectively. These values correlated well with both the clinical status of patients and with values obtained by an established radioimmunoassay method. The procedure is simply done; results may be obtained in less than 4 h.

Simplified radioimmunoassay for triiodothyronine: evaluation of a new commercial kit.

This is a report of ectopic thyroid tissue in the neck, associated with a nodular colloid goiter, which recurred at least three times, beginning at age 24 years, in a woman in 12 years. The ectopic tissue appeared histologically benign and was identical to that found in the thyroid gland. Scintiscans of the neck and thyroid suppression tests showed that the tissue was initially unsuppressible and presumably autonomous in its function. Our conclusion is that the most reasonable explanation for this phenomenon is the intraoperative transmission of thyroid cells, probably benign and autonomous in function, to other sites in the neck.

We report the evaluation of a new T3 radioimmunoassay (RIA) kit (Ames Company) which offers the advantages of greater simplicity of methodology and shorter incubation time while at the same time providing accuracy and reproducibility. Iodine-125-labeled T3 and standard or unknown serum are added to a Sephadex G-205 column; the T3 is freed of protein in alkaline pH. After washing with bufer antiserum is added and incubation carried out at room temperature for 2 hours. The percent of free hormone remaining on the column was measured by radioactivity counting after an additional wash. Serum T3 values were determined by a standard curve. Sera of 15 volunteers 41 euthyroid 19 hyperthyroid 25 hypothyroid patients and 7 subjects who were pregnant or on oral contraceptives were assayed by the present method. Simultaneously 82 sera were assayed by an established method of RIA. The euthyroid hyperthyroid and hypothyroid ranges were 77-297 ng% 291-752 ng% and 0-121 ng% respectively. Pregnancy and treatement with oral contraceptives were associated with abnormally high serum T3 values. The hormone levels by the present method correlated well with the clinical status of the patients and the values obtained by the other method of RIA. Cross reactivity tested with analytical grade thyroxine was minimal (.6%) and probably related to the T3 in the thyroxine. The recovery of T3 added to hypothyroid serum was complete. Serial dilutions of a hyperthryoid serum established parallelism with the standard curve. Precision within run = 8% C.V. at a mean of 188 ng% and that between run = 13.6% C.V. at a mean of 127 ng%. The procedure was simple to carry out and the short incubation time allowed results to be obtained in less than 4 hours. The kit should be valuable for use in clinical laboratories.(Full text)

A simplified radioimmunoassay for triiodothyronine: evaluation of a new commercial kit. (Abstract only)

Abnormal liver scans in patients with alpha 1-antitrypsin deficiency.

Radiocholesterol adrenal images for the localization of pheochromocytoma.

Efficacy of radiocholesterol imaging of the adrenal glands in Cushing's syndrome.

High speed indexing of patient report data using the nuclear medicine computer

Lung Scanning and Angiography in Pulmonary Embolism: The authors reply

The chest X-ray, perfusion lung scan, and selective pulmonary arteriogram were independently reviewed in 104 patients with suspected pulmonary embolism. Thirteen patients also had 133Xe ventilation studies. Of the 45 patients with angiographically-documented pulmonary emboli, 37 had perfusion scans interpreted as high probability of pulmonary embolism (82% sensitivity). Fifty of 59 patients without angiographic evidence of pulmonary embolism had perfusion scans interpreted as low probability of pulmonary embolism, other, or normal (85% specificity).Of the 41 patients with acute pulmonary embolism, only three had normal chest X-rays. In 26 (63%) the abnormality on perfusion scan was more extensive than that on chest X-ray.When both the scan and chest X-ray pointed strongly in the same direction, a correct diagnosis could usually be made, and accuracy was greater than when diagnosis was based on the perfusion scan alone. The lung scan was of limited value in patients with cardiomegaly or left heart failure. The differential role of the 133Xe ventilation study remains unclear. On the basis of the present and other data, guidelines for the selection of patients for pulmonary arteriography are proposed.

The Complementary Roles of Chest Radiography, Lung Scanning, and Selective Pulmonary Angiography in the Diagnosis of Pulmonary Embolism

Changes in the position of the diaphragm with patient posture may explain apparent perfusion defects. Correct scan interpretation depends upon obtaining ventilation, perfusion, and radiographic studies with the patient in the same position.

The effect of patient posture on the position of the diaphragm. A cause of false-positive lung scans.

Regional cerebral circulation was evaluated in 25 patients using scintiphotos in the vertex projection during the initial passage of a bolus of intravenously administered sodium pertechnetate Tc 99m. These nuclear cerebral angiograms (NCA) and brain scans were compared to contrast angiograms. If the NCA was normal and the scan revealed a lesion that did not correspond to the area supplied by a major arterial distribution, the probability of a mass lesion was high. If the NCA showed decreased flow and the scan was normal or showed a lesion in a major arterial distribution, most probably the patient had cerebral vascular disease. If the NCA showed increased flow in the region of a scan abnormality, either a glioblastoma or an arteriovenous malformation was likely. In all cases the diagnosis was established by contrast angiography or surgery or both.

Nuclear cerebral angiography. Usefulness in the differential diagnosis of cerebrovascular disease and tumor.

To determine how often thyroid scanning correctly predicts the diagnosis of thyroid abnormalities, 59 patients who had thyroid surgery were examined with the scintillation camera shortly before operation. To improve the intrinsic resolution of the system, the thyroid gland was magnified two to three times normal size by using a pinhole collimator. With the higher-quality images, multinodular thyroids were correctly detected in 65% of the patients. Twenty-five were interpreted as solitary nodules; two were thought to be normal glands; one was diagnosed as diffuse hyperplasia. In only 39 (22%) of the patients with multinodular goiter were the nodules palpable. The remainder were diagnosed clinically as solitary nodules. Of 26 solitary nodules, 20 were seen in the images. When solitary nodules were not visible in the images, they were either small (

Improved methods for thyroid scanning. A correlation with surgical findings.

A small general-purpose computer interfaced with a gamma scintillation camera was used to compare the integrated counting rates measured over specific regions of the cerebral cortex from the time of intravenous injection of technetate up to the time of peak radioactivity. The initial slope describing the rate of arrival of the tracer at various regions of the cortex was also measured, and comparisons were made between corresponding regions over each cere-@ bral hemisphere. In 50 persons sensitivity method abstracts of exhibits are reviewed the 20th Annual Meeting. Abstracts of exhibits, large or small, are welcomed from members, nonmembers, and organizations. Exhibits supporting scientific papers are encouraged. View boxes for transilluminated material will be available. Abstract Format: Abstracts must be submitted on a special abstract form for scientific exhibits which is available from the Society of Nuclear Medicine, 21 1 E. 43rd Street, New York, New York 10017. Scientific Exhibit Awards: The Society is pleased to announce the presentation of Gold Medal, Silver Medal, and Bronze Medal awards for outstanding exhibits in each of the following categories: Clinical Nu clear Medicine; Instructional; and Biophysicsand Instrumentation. Judging is based on scientific merit, orig inality, display format, and appearance. Judging on the first full meeting day.

Quantitative cerebral circulation studies with sodium pertechnetate.

Regional cerebral blood flow estimation in the diagnosis of cerebrovascular disease.

The percentage changes in the cardiac output, stroke volume, and heart rate were determined in seven healthy habitual smokers after smoking, after glucose, and after smoking preceded by glucose. No significant changes occur after glucose. There is a significant increase in cardiac output, stroke volume, and heart rate after smoking. Pretreatment with glucose did not change the heart-rate response to smoking. Nevertheless, the cardiac-output response was diminished. This decrease is due to a block in the increase in stroke volume induced by smoking.

Glucose Blockage of the Increase in Stroke Volume Produced by Smoking

The relation of some morphological, physiological, and genetic dimensions to the cattell 16PF and T.A.T. scales

改良気管支拡張症重症度スコア(BSI)およびFACEDで測定した非嚢胞性線維症気管支拡張症の重症度と関連した緑膿菌:米国気管支拡張症およびNTM研究登録(BRR)研究【JST・京大機械翻訳】

La presente invention concerne un article qui comprend un substrat et une couche amorphe liee par covalence sur la surface du substrat. Le substrat peut consister en une ceramique cristalline et/ou peut comporter une surface presentant une premiere rugosite superficielle (Ra) superieure ou egale a 100 angstroms, et la couche amorphe liee par covalence presente une seconde rugosite superficielle (Ra) inferieure ou egale a 15 angstroms. Le substrat peut presenter une dimension superieure ou egale a 50 mm, et la couche amorphe liee par covalence peut presenter une epaisseur superieure ou egale a cinq micrometres. L'invention concerne egalement un procede de realisation d'un article. Le procede consiste a former par depot de plasma une couche amorphe liee par covalence sur la surface du substrat et, selon certains modes de realisation, a polir la couche amorphe liee par covalence jusqu'a obtenir une seconde rugosite superficielle (Ra) inferieure ou egale a 15 angstroms. La couche amorphe liee par covalence utilisee dans l'article et dans le procede comprend des atomes de silicium, d'oxygene, de carbone et d'hydrogene.

Substrat à couche amorphe liée par covalence et son procédé de réalisation

La presente invention porte sur des tampons de polissage, lesquels tampons comprennent une couche de polissage, la couche de polissage comprenant une surface de travail et une seconde surface opposee a la surface de travail. La surface de travail comprend au moins l'un d'une pluralite de corps de forme precise et d'une pluralite d'asperites de forme precise. La presente invention porte egalement sur un systeme de polissage, lequel systeme de polissage comprend le precedent tampon de polissage et une solution de polissage. La presente invention porte egalement sur un procede de polissage d'un substrat, lequel procede de polissage met en œuvre la disposition d'un tampon de polissage selon l'un quelconque des precedents tampons de polissage ; la disposition d'un substrat, la mise en contact de la surface de travail du tampon de polissage avec la surface du substrat, le deplacement du tampon de polissage et du substrat l'un par rapport a l'autre tout en maintenant un contact entre la surface de travail du tampon de polissage et la surface du substrat, le polissage etant effectue en presence d'une solution de polissage.

Tampons de polissage et leurs systèmes et leurs procédés de fabrication et d'utilisation

L'invention concerne un procede de fabrication de particules abrasives qui inclut l'exposition de particules ceramiques a un plasma derive d'organosilane forme a partir de composants comprenant un organosilane et de l'oxygene pour former des particules ceramiques modifiees par plasma; et la mise en contact d'un agent de couplage avec la seconde particule ceramique traitee au plasma pour fournir la particule abrasive. L'invention concerne egalement des particules abrasives pouvant etre preparees par le procede et des particules abrasives les contenant.

Particules abrasives, procédé de fabrication de particules abrasives et articles abrasifs

Materiau comprenant des particules sous-micrometriques dispersees dans une matrice polymere. Les materiaux selon l'invention sont utiles dans un article, par exemple, pour de nombreuses applications comprenant les applications d'affichage (par ex., ecrans a cristaux liquides (LCD), ecrans a diodes electroluminescentes (LED), ou ecrans plasma) ; l'extraction de lumiere ; le blindage contre les interferences electromagnetiques (EMI), les lentilles ophtalmiques ; les lentilles ou films de protection faciale ; les films pour fenetres ; les applications antireflets dans le domaine de la construction ; et autres applications dans le domaine de la construction ou les panneaux de signalisation.

La presente invention concerne des procedes de traitement des surfaces de substrats en matiere plastique contenant des microparticules inorganiques antimicrobiennes. Le procede comprend l'obtention d'un substrat en matiere plastique possedant une surface, le substrat contenant des microparticules inorganiques antimicrobiennes, et l'exposition de la surface du substrat a un plasma.

Procédé de fabrication d'articles en matière plastique présentant une surface antimicrobienne

L'invention concerne des articles nettoyables ayant des couvertures avec des surfaces avant hydrophiles et qui sont relies par siloxane a un element de corps sous-jacent. L'invention concerne egalement des procedes de fabrication et d'utilisation de tels articles.

Articles nettoyables et procédés de fabrication et d'utilisation de ces articles

La presente invention concerne une composition fluoree qui comprend : un polyfluoropolyethersilane represente par la formule : R fa O(CF(CF 3 )CF 2 O)pCF(CF 3 )CH 2 OZ 1 Si(Y 1 ) 3 ; et un polyfluoropolyethersilane represente par la formule : R fb [R 5 CH 2 OZ 2 Si(Y 2 ) 3 ] 2 
R fa represente un groupe perfluoroalkyle ayant de 1 a 12 atomes de carbone, facultativement substitue par au moins un atome d'oxygene catenaire ou un groupe -NR 8 -, ou R 8 represente un groupe perfluoroalkyle ; Z 1 represente -R 1 SR 2 -, -R 1 S(=O)R 2 -, ou -R 1 S(=O) 2 R 2 , ou R 1 et R 2 representent independamment des groupes alkylene ayant de 1 a 12 atomes de carbone ; chaque Y 1 represente independamment un groupe hydrolysable ; et p est un nombre dans un intervalle de 3 a 50 ; Z 2 represente independamment -R 3 SR 4 -, -R 3 S(=O)R 4 -, ou -R 3 S(=O) 2 R 4 , ou R 3 et R 4 representent independamment des groupes alkylene ayant de 1 a 12 atomes de carbone ; Y 2 represente independamment un groupe hydrolysable ; R fb represente un groupe perfluoroalkylene ayant au moins 3 atomes de carbone, facultativement substitue par au moins un atome d'oxygene catenaire ou un groupe -NR 6 -, ou R 6 represente un groupe perfluoroalkyle ; R 5 represente independamment une liaison covalente, ou -(OR 7 ) b -, et ou R 7 represente independamment un groupe perfluoroalkylene ramifie, et b represente independamment un nombre superieur ou egal a un.

Composition fluorée, procédé d'enduction de la composition, et article associé

L'invention porte sur un procede de fabrication d'une nanostructure, qui comprend l'application d'une couche de masquage discontinue aleatoire mince (105) sur une surface principale (103) d'un substrat (101) par depot chimique en phase de vapeur assiste par plasma. Le substrat (101) peut etre un polymere, un materiau inorganique, un alliage ou une solution solide. La couche de masquage (105) peut comprendre le produit de reaction du depot chimique en phase vapeur assiste par plasma effectue au moyen d'un gaz reactif comprenant un compose selectionne dans le groupe constitue par les composes d'organosilicium, les alkyles metalliques, les isopropylates metalliques, les acetylacetonates metalliques et les halogenures metalliques. Les parties (107) du substrat (101) non protegees par la couche de masquage (105) sont ensuite enlevees par gravure ionique reactive pour former les nanostructures.

La presente invention se rapporte a une composition destinee a modifier une surface d'un substrat, la composition comprenant : (a) un premier silane de polyfluoropolyether de la formule Ia: CF 3 CF 2 CF 2 O(CF(CF 3 )CF 2 O) p CF(CF 3 )-C(O)NH(CH 2 ) 3 Si(Y) 3 , chaque Y etant independamment un groupe hydrolysable et p etant compris entre 3 et 50 ; et (b) un second silane de polyfluoropolyether de la formule IIa: (Y') 3 Si(CH 2 ) 3 NHC(O)-CF 2 O(CF 2 O) m (C 2 F 4 O) q CF2-C(O)NH(CH 2 ) 3 Si(Y') 3 , chaque Y' etant independamment un groupe hydrolysable et m etant compris entre 1 et 50 et q etant compris entre 3 et 40. L'invention se rapporte egalement a un procede de fabrication d'un dispositif d'inhalation de medicaments ou a un composant d'un dispositif d'inhalation de medicaments comprenant une etape consistant a appliquer la composition sur au moins une partie d'une surface du dispositif ou du composant, respectivement.

L'invention concerne un procede continu pour la fabrication d'une surface nanostructuree comprenant (a) le positionnement d'un substrat comprenant un masque a nanoechelle sur une electrode cylindrique dans un recipient sous vide, (b) l'introduction d'un gaz de gravure dans le recipient a une pression predeterminee, (c) la generation de plasma entre l'electrode cylindrique et une contre-electrode, (d) la rotation de l'electrode cylindrique pour mettre le substrat en translation, et (e) la gravure anisotrope d'une surface du substrat pour fournir des elements anisotropes a nanoechelle sur la surface.

L'invention porte sur un article abrasif, tel qu'un article abrasif structure, que l'on peut traiter en le soumettant a un plasma grâce a quoi la surface externe peut etre erodee en exposant au moins une partie des particules abrasives dispersees a l'interieur d'un liant reticule formant les composites abrasifs. En fonction des conditions de procede pour le traitement par plasma, il est possible d'eroder seulement une petite fraction ou sensiblement la totalite du liant reticule a partir de la surface externe. Ainsi, la vitesse de coupe initiale de l'article abrasif peut etre controlee etant donne qu'il est possible de controler de facon precise le degre, la hauteur ou l'aire des particules abrasives exposees.

Détecteur chimique organique comprenant une couche microporeuse déposée par plasma, et procédé de fabrication et d'utilisation

La presente invention concerne un procede de formation de moule de travail comprenant le placement d'un substrat pres d'une electrode dans une chambre, le substrat (610) ayant au moins une premiere surface structuree (620), la fourniture d'energie a l'electrode pour creer un plasma, l'introduction d'une vapeur de molecules de silicone liquide dans le plasma, et le depot d'une couche anti-adherente (630), la couche anti-adherente (630) comprenant un polymere contenant du silicone, et etant deposee sur au moins une partie de la premiere surface structuree du substrat pour former le moule de travail.

Procédés de formation de moules et procédés de formation d'articles utilisant lesdits moules

Un article reflecteur multicouche optiquement sensible est forme par application d'une solution ou d'une suspension diluee de nanoparticules metalliques sur une couche de detection optiquement sensible. La solution ou la suspension est laissee a secher pour former une couche reflechissant la lumiere, semi-continue, permeable au liquide ou a la vapeur, qui permettra a un analyte sous forme liquide ou vapeur de traverser la couche reflechissant la lumiere pour provoquer un changement de sensibilite optique dans la couche de detection en presence de l'analyte.

Procédé de revêtement de contact d'un ensemble de micro-aiguille

Procede d'enrobage d'une matrice de micro-aiguilles par mise en contact

La presente invention concerne une couche de diffusion de gaz de pile a combustible comprenant une couche de surface hydrophile presentant une epaisseur inferieure ou egale a 1 micrometre, et, sous celle-ci, une seconde couche hydrophobe renfermant un fluoropolymere presentant une epaisseur d'au moins 5 micrometres. En outre, la presente invention concerne un procede destine a fabriquer une couche de diffusion de gaz de pile a combustible et consistant (a) a utiliser une structure en fibre de carbone, (b) a revetir au moins la surface superieure de la structure en fibre de carbone d'une composition renfermant un fluoropolymere, et (c) a exposer la surface superieure a au moins un plasma, tel qu'un plasma de silane, de maniere a generer une couche de surface hydrophile presentant une epaisseur inferieure ou egale a 1 micrometre. La presente invention concerne egalement un procede consistant a recouvrir partiellement la surface superieure d'un masque comportant des fenetres selon un motif donne de sorte que la couche de surface hydrophile soit appliquee conformement a ce motif. La presente invention concerne egalement un procede dans lequel on utilise la structure en fibre de carbone comme materiau en rouleau, l'etape d'exposition au plasma de la surface superieure etant realisee de maniere continue de rouleau a rouleau.

La presente invention concerne des systemes de detection et des procedes pour detecter des analytes biologiques cibles dans un echantillon de matiere, grâce a l'energie acousto-mecanique produite par un capteur. L'energie acousto-mecanique peut etre mise a disposition au moyen d'un capteur acousto-mecanique, par ex. un capteur d'onde acoustique de surface tel qu'un capteur d'onde acoustique de surface horizontale de cisaillement (par ex. un capteur LSH-SAW). L'invention a egalement pour objet differentes techniques pour modifier la masse reelle d'analytes biologiques cibles dans un echantillon de matiere, comprenant le fractionnement ou la separation des analytes biologiques cibles dans l'echantillon de matiere (par ex. lyse de l'analyte biologique cible) ; adjonction d'une masse detectable a l'analyte biologique cible ou amelioration du coulage de l'analyte biologique cible (par ex. par utilisation de particules magnetiques) ; exposition de l'echantillon de matiere a un reactif qui induit une modification d'au moins une propriete physique detectable dans l'echantillon de matiere si l'analyte biologique cible est present (par ex. une modification des proprietes de viscosite, d'elasticite, et/ou de viscoelasticite), etc.

Systemes de detection acousto-mecaniques, et procedes d'utilisation

Cette application concerne des procedes de traitement par plasma qui utilisent une gaine d'ions dans un systeme couple de maniere capacitive de facon a augmenter la capacite hydrophile d'articles poreux, y compris des articles microporeux dont la taille des pores est comprise entre 0,05 micrometre et 1,5 micrometre, tant sur leurs surfaces que dans leurs pores de sorte que les proprietes de mouillage dans la masse de ces articles soient ameliorees.

L'invention concerne des particules de phosphore encapsulees, et leur procede de fabrication. Chaque particule de phosphore electroluminescente est encapsulee dans un revetement d'oxynitrure metallique sensiblement transparent. Ce revetement permet de reduire la sensibilite des particules de phosphore a la degradation acceleree par l'humidite.

Particules de phosphore electroluminescentes encapsulees dans un revetement d'oxynitrure

Support (1) de circuit flexible comprenant au moins une couche de materiau (2) polymere dielectrique recouverte par au moins une couche de materiau conducteur (3), chaque couche possedant deux surfaces principales, au moins une desdites couches etant pourvue d'au moins une ouverture, au moins une partie d'au moins une couche etant revetue d'un materiau (4) possedant un module de Young de 100-200 GPa, une constante dielectrique (entre 45 MHz et 20 GHz) de 8-12 et une durete de Vickers de 2000 a 9000 kg/mm2 et consistant notamment en un carbone semblable a du diamant.

Structure améliorée d'une tête d'impression et son procédé de fabrication

Article abrasif a revetement de simili diamant a substrat en feuille presentant au moins une surface principale a laquelle adhere un revetement abrasif fait d'une multitude de particules abrasives et d'un liant organique, ainsi qu'une couche de carbone dur constituee par une pellicule de carbone simili diamant. La couche de carbone dur de l'article peut etre disposee en surface ou bien entre la couche abrasive et une couche de couverture de liant organique. L'invention porte egalement sur le procede de fabrication d'un tel article.

Article abrasif a revetement de simili diamant et procede associe

Schleifpartikel, verfahren zur herstellung der schleifpartikel und schleifartikel

A vehicle sensor system is described comprising an exterior surface; and a repellent composition disposed on the exterior surface, wherein the repellent composition exhibits an increase in haze according to the Dirty Water Spray Test of less than 5, 4, 3, or 2%. In typical embodiments, the repellent composition exhibits an advancing water contact angle from 90° to 125°. In some embodiments, the sensor system comprises a camera, a laser, a LIDAR sensor, a sonar sensor, or a radar sensor. The exterior surface is typically a windshield surface, a protective housing, or a lens surface. In some favored embodiments, the repellent composition exhibits a roll-off angle of no greater than 25, 20, 15, 10 or 5 degrees. Also described is a protective film, a repellent composition, a coating composition, and a method of evaluating repellency

Vehicle sensors comprising repellent surface, protective films, repellent coating compositions, and methods

(54) OXYNITRIDE ENCAPSULATED 5,500.279 A * 3/1996 Walter et al. ............... 428/213 ELECTROLUMNESCENT PHOSPHOR 5,856,009 A 1/1999 Nishio et al. ............... 428/404 PARTICLES 5,958,591 A * 9/1999 Budd ......................... 428/403 6,064,150 A 5/2000 Klinedinst et al. .......... 313/503 (75) Inventors: Kenton D. Budd; Moses M. David, 6,193.908 B1 * 2/2001 Hampden-Smith et al. 30 iii. both of Woodbury; Stephen L. Lieder, Wyoming; Kyung H. Moh, Woodbury, FOREIGN PATENT DOCUMENTS all of MN (US) EP O 928 826 7/1999 JP 8-176540 4/1996 (73) ASSignee: Many typerie Company, JP 9-104863 7/1997 . Paul, WO WO 99/00463 1/1999

Articles comprenant un substrat, une premiere couche constituee d'un materiau polymere avec des nanoparticules depassant d'une surface principale de ce dernier et, a l'ecart du substrat, une seconde couche dont une surface principale constitue une premiere nanostructure. Dans divers modes de realisation, ces articles conviennent pour des applications d'affichage, notamment a cristaux liquides (LCD), a diodes electroluminescentes (DEL) ou a plasma ; extraction de la lumiere ; blindage contre les interferences electromagnetiques (EMI) ; lentilles ophtalmiques ; masque ou film serre-tete ; films pour fenetres ; applications antireflets et constructions ; applications dans le bâtiment ou panneaux de la circulation.

A new random, anisotropic, nanostructure, contrast enhancement film (NCEF) with super low reflection broadband antireflection (BBAR) performance was developed by 3M Company using a wide web roll‐to‐roll process. The high performance BBAR NCEF film can be made from triacetate cellulose (TAC), polyester, polycarbonate, polymethyl methacrylate, or many other substrates commonly used for electronic display applications. At normal incidence, a TAC based BBAR NCEF exhibits an average reflectivity of 0.1% measured in the visible spectral range 400‐700 nm, and a total light transmission of > 97% is obtainable from single side nanostructured BBAR NCEF. Furthermore, BBAR NCEF film was shown to provide high light transmission at wide incidence angle with minimal optical loss making it well suited for viewing at wide viewing display angle. The roll format combined with the high performance characteristics of this BBAR NCEF film makes it an exceptional cost‐effective solution to be implemented on most electronic display modules.

52.5: Broadband Antireflection (BBAR) Nanostructure Contrast Enhancement (NCEF) Films For Electronic Optical Display Applications

A protective device comprising an enclosure including a gas inlet, a gas outlet and a multilayer indicator thin layer, wherein: A) the enclosure containing medium sorbent can sorb a vapor of interest flowing from the inlet to the exit; B) the multilayer indicator thin layer comprising: i) a porous layer detector whose optical thickness changes in the presence of steam, located between ii) a semi-reflective layer is viewable from outside the enclosure and iii) a permeable reflective layer steam; and C) the reflective layer is close enough to the medium so that in steady state vapor concentration applied between at least a portion of the medium and steam, the steam can pass from the medium by the reflective layer and to the detection layer and change the optical thickness of the detection layer sufficiently to produce a visibly discernible change in appearance of the indicator as viewed through the semireflective layer.

absorbent protective device organic vapors with indicator film and methods for manufacturing the device

Measurements of the surface resistance and conductivity of thin conductive films at frequency about 1 GHz employing dielectric resonator technique

We have developed a process to deposit a thin uniform layer of diamond-like film onto optical fibers. This UV-transparent film protects the fiber during the fiber grating inscription and maintains the geometry of the fiber so long length gratings can be fabricated.

Optical Fiber Communication Conference. Technical Digest Postconference Edition. Trends in Optics and Photonics Vol.37 (IEEE Cat. No. 00CH37079)

Diamond-like film encapsulated fibers for long-length fiber grating production

Indian journal of chemistry. Sect. A: Inorganic, physical, theoretical & analytical

SOLVENT EXTRACTION OF CADMIUM (II) WITH N-BENZOYL-N-PHENYLHYDROXYLAMINE INTO CYCLOHEXANE

A plurality of encapsulated particles, each of said encapsulated particles comprising: a phosphorus particle of an electroluminescent phosphor material showing a moisture accelerated decay; and a substantially transparent metallic oxynitride coating that sufficiently encapsulates said phosphorus particle to provide said phosphorus particle with a reduced sensitivity to moisture accelerated decay.

Electroluminiscent phosphortic particles encapsulated in oxinitride.

Improved print head structure and the manufacturing method thereof

SOLVENT EXTRACTION OF ZINC(II) WITH QUINALDIC ACID INTO BENZYL ALCOHOL

Light perfluorocarbons, such as carbon tetrafluoride, are produced or emitted from a variety of processes, including manufacture of aluminum and processing of semiconductor devices. At the same time, the long atmospheric lifetime and high global warming potential of such compounds makes them an environmental concern. A new process for the abatement of perfluorocarbon emissions using a carbon arc plasma was investigated. In particular, the conversion of CF{sub 4} to C{sub 2}F{sub 4} and higher fluorinated species, including poly(tetrafluoroethylene) (PTFE) was demonstrated. General features of the reaction chemistry are discussed, including primary reactions to form radicals and ions and secondary reactions to form C{sub 2}F{sub 4} and higher compounds. The conversion efficiencies and products obtained in the reported experiments indicate potential applicability of the process for point source emission control of high global warming potential perfluorocarbons.

The toxicity of mercury and its harmful effects on plants, animals and human beings are well documented1• It is apparent that a rapid and selective method for the separation of Hg11 from other elements is required. The reagent rhodamine B2 has been used for the extraction of wvi, MoV1, Zn11, Sc111 , ReVII and Tcv11• However, rhodamine B has not been used for the solvent extraction of Hgll. The present work describes a method for the solvent extraction and radiochemical separation ofHgll employing rhodamine B reagent. 203Hg was used as a tracer.

SOLVENT EXTRACTION OF MERCURY(II) WITH RHODAMINE B INTO NITROBENZENE

Substoichiometric extraction of metals and its application to the determination of heavy metals in environmental samples by neutron activation analysis

PURPOSE: To produce a thin film magnetic head assembly excellent in wear resistance at a low cost. CONSTITUTION: An insulating wear resistant layer 56 of diamondlike carbon is joined to an Al2 O3 -TiC substrate 52 contg. titanium carbide particles through a 1st joint accelerating layer 54 of amorphous silicon carbide and an electromagnetic circuit forming part 62 is stuck to the layer 56 through a 2nd joint accelerating layer 58 of amorphous hydrogenated silicon. The wear resistant layer 56 has increased hardness and surface finishing is made unnecessary.

Thin film magnetic head assembly with wear resistant thin layer, thin layer base and its production

Effect of diluent gases added during deposition on the etching characteristics of diamond-like carbon films

Abstract Diamond-like carbon films have been deposited in an RF plasma discharge from binary and ternary mixtures of butadiene, argon and hydrogen. These films have been etched in oxygen plasmas. The effect of the addition of argon and/or hydrogen to the precursor gas on the deposition and etch characteristics of the film has been determined. Optical emission from the plasma during deposition has been monitored and the changes in the emission intensity of the CH 431.2 nm line have been used to make several observations on the deposition mechanism.

Compounds Resistant to Carbon Adsorption in Municipal Wastewater Treatment

Simultaneous reduction and mercuration of disulfide bonds by monovalent mercury.

Experimental and statistical dry-fracture assessment of the CFRP-concrete interface bond

Innovations in manufacturing, analysis, design, and applications of fiber-reinforced polymer composites

INTERNATIONAL JOURNAL OF CIVIL ENGINEERING AND TECHNOLOGY (IJCIET)

STRUCTURAL DESIGN AND COST ANALYSIS OF A LEED-CERTIFIED BUILDING

Prototyping rail track for micro-people movers using additive manufacturing: Failure topology characterization

In this educational research study, a group of undergraduate students, under the supervision of Dr Boyajian and Dr Zirakian from California State University Northridge, introduce a designed fluid time-to-drainage model as part of the Senior Design undergraduate course. The model was chosen to be a time-to-drainage device due to the high resistance against pressure as well as being impervious to water. The main objective of this project is to experimentally examine the effects of using sharp and round edge orifices under different values of pressure, on the water flow rate and to inspire minority and international students in engineering to learn the effects of this pressure change and using different orifice geometries, on the fluid flow properties. This research endeavour is hoped to serve as a model for future generations of engineering students to better visualize difficult Fluid Mechanics concepts and thus enhance their overall comprehension of such important material..

Advances in Seismic Performance Assessment and Improvement of Structures

: This project involves modeling a water elevator in order to study its behavior and relate its mechanical advantages to various fluid mechanics properties. The reason that this small scale water elevator was constructed was to get a better understanding of such real world applications. As developing engineers, students have to grasp how to implement the theory they learn in the classroom. The properties of the water elevator were described with the energy equation, conservation of mass, volumetric flow rate, and hydrostatic pressure. After conducting various tests, theoretical and experimental values were compared and an analysis of the data was assembled allowing for the development of a more thorough understanding of fluid mechanics.

This research category paper is a work in progress that discusses the processes used to improve the service life estimation of steel culverts under roadways in the State of California. The service life of Corrugated Steel Pipe (CSP) culverts is largely dictated by the loss of wall section of pipe arising from corrosion. This corrosion is due to chemical and electrochemical processes based on two major factors: pH levels and the resistivity of the soil. Service life estimates are based on several additional factors: potential for culvert abrasion, changing soil moisture, temperature conditions, soil moisture content, presence of chloride in the soil, and proximity of lakes, wetlands, or marine environments. In addition to pH and resistivity, the CSUN Caltrans Research team has added culvert thickness loss, sulfate and chloride content, total dissolved solids (TDS), salinity, and land use. The thickness reader allows the CSUN Caltrans Research team to calculate the loss of metal from the CSP culverts’ nominal thickness. The goal of this research is to improve the existing service life equations which is currently used by the California Department of Transportation and its associated test methods. To this end, modern non-destructive instrumentation is being implemented in the field to measure CSPs’ thickness which is one of the key parameters under investigation throughout the State of California.

Distortional buckling of I-beams can occur in two lateral and restrained modes. Lateral-distortional mode of buckling is classified as local-global coupling which involves local changes in the cross-section geometry in addition to lateral displacement and twist. Restrained distortional mode of buckling, also, can occur due to applied restraints against rigid cross-sectional movements of one of the flanges. Compared to the two well-known local and lateraltorsional buckles, distortional buckling is relatively more complicated and less documented. Hence, further research work is still required to better understand and properly address this mode of buckling. This paper presents a review of some recently-published studies by the first author on the subject of distortional buckling of I-beams with the aim of providing some potential research avenues for fruitful future investigations.

In recent years, considerable attention has been paid to the development of effective structural control devices, with particular emphasis on improving the seismic response of buildings. Shape Memory Alloy (SMA) wires have shown that their superelastic characteristics are well suited for seismic applications. This is mainly due to their recentering and energy dissipating capabilities. When buildings are subjected to earthquakes, it is vital to dissipate the input energy through predetermined and well-designed mechanisms. This study investigates the effectiveness of using SMAs as reinforcements to single and coupled concrete shear walls. To this end, ABAQUS was used to model the behavior of the shear walls, and a User Implemented Material (UMAT) was programmed in FORTRAN to represent the uniaxial superelastic behavior of the SMA reinforcement. Time-history analyses were performed to evaluate the seismic performances of the structures subjected to two earthquake ground motion records. The results and findings of this study indicate that employment of a combination of SMA and conventional steel rebars can result in a cost-effective design to significantly reduce the residual deformation and enhance the seismic performance of such structural systems.

SMA Reinforcement for Seismic Performance Improvement of RC Shear Walls

Construction practices involving the rehabilitating, retrofitting, and reinforcing of concrete structures using fiber reinforced polymer (FRP) fabrics have been well documented. Experimental efforts to characterize the effectiveness of this technology, however, have included many large scale FRP-concrete tests for strength/stiffness evaluations which do not detect delamination effects; small-scale tests, on the other hand, only provide average interface strength properties that neither describe failure mechanisms nor provide fracture toughness data. In this paper, the experimental fracture mechanics specimen known as the single contoured-cantilever beam (SCCB) was used to obtain important quantitative results of FRP-concrete interfaces as subject to a host of conditions: dry, freezingthawing, wetting-drying, fatigue, and surface roughness effects on the integrity of the interface bond. The findings of this research effort demonstrate both the importance of surface preparation towards achieving an optimal bond as well as offering a means of gaging rates of degradation of the interface under a variety of commonly encountered construction environments.

Mechanical and Thermochemical Studies Using the Experimental FractureMechanics Single Contoured-Cantilever Beam Specimen

Construction companies face threats from competition and must be able to adjust to modern technology and changes in customer expectations. These issues require efficient risk management techniques. The success of construction companies running projects in international markets depends on how the risks arise from the host country conditions as well as the project specific risk factors. Successful management of risks requires identification of risks, construction of a risk model which can be used to assess the magnitude of risks, and implementation of response strategies so that an acceptable risk-return balance can be achieved. The project success usually depends on the combination of all risks, response strategies used to mitigate risks, and a company’s ability to manage them. There exists a need to develop risk models containing the risks of doing business in international markets and factors that affect manageability of these risks. One of the market’s critical challenges is scheduled management and the understanding and application of program management. This paper uses systematic risk identification, classification and analysis, and measurement and response methodologies to help international contractors quantify the risks of project development and accomplishment.

On the Application of IPRA Tool in Risk Assessment and Management of International Construction Projects

This research paper describes an SEE (Structural Engineering Encounter) Lab project. The paper reports on the development of a single-story, single-bay portal frame model as part of the AIMS (attract, inspire, mentor and support students) grant supported through the US DOE (Department of Education) summer research program at California State University, Northridge. This research effort is part of a comprehensive program to develop laboratory models of structures commonly encountered in civil engineering practice, which can serve the dual purpose of accomplishing engineering education and research in the areas of structural and earthquake engineering. The objective of the present study was to construct a physical model of the aforementioned frame to experimentally collect data due to the application of vertical and lateral loadings through instrumentation such as strain gages and an LVDT (linear variable differential transformer) displacement transducer, and also to make comparisons with theoretical and numerical predictions.

Statistical Characterization of Fracture in CFRP-Concrete Interfaces Due to Wet-Dry Cycling

Steel plate shear walls (SPSWs) are efficient lateral force-resisting systems which are used in new and retrofit construction. Based on the findings of the prior studies, it is believed that application of low yield point (LYP) steel with extremely low yield stress as well as high elongation properties can significantly improve the structural behavior and seismic performance of SPSW systems. However, widespread practical application of LYP steel plate shear wall systems requires rather comprehensive and systematic investigations and consequently development of reliable design and retrofitting guidelines. This study focuses on the seismic performance assessment of code-designed SPSW systems retrofitted by unstiffened LYP steel infill plates of various thicknesses. To this end, detailed numerical investigations are made on some key seismic response parameters of multi-story SPSW frames, including drift, acceleration, base shear, and web-plate ductility demands, under the action of earthquake ground motions. The results and findings of this study demonstrate the capabilities of SPSW systems in improving the seismic performance of structures, and particularly reveal the various advantages of use of LYP steel material in advancing the seismic design and retrofit of such lateral force-resisting and energy-dissipating structural systems. Assistant Professor, Department of Civil Engineering and Construction Management, California State University, Northridge, CA 91330 (email: tadeh.zirakian@csun.edu) Assistant Professor, Department of Civil Engineering and Construction Management, California State University, Northridge, CA 91330 (email: david.boyajian@csun.edu) Zirakian T, Boyajian D. Seismic Performance Assessment of Retrofitted SPSW Systems. Proceedings of the 11 National Conference in Earthquake Engineering, Earthquake Engineering Research Institute, Los Angeles, CA. 2018. Seismic Performance Assessment of Retrofitted SPSW Systems T. Zirakian and D. Boyajian

World Academy of Science, Engineering and Technology, International Journal of Civil, Environmental, Structural, Construction and Architectural Engineering

Study on Buckling and Yielding Behaviors of Low Yield Point Steel Plates

Steel plate shear walls (SPSWs) have been used as the primary or part of the primary lateral force-resisting system in design and retrofit of buildings. Development and use of low yield point (LYP) steel with considerably low yield stress and high elongation capacity nowadays provides the possibility to design SPSW systems with improved serviceability, structural performance, and enhanced energy absorption characteristics. This paper provides a review of recent studies performed by the first author on the seismic design and retrofit of SPSW systems using LYP steel material. The results and findings of these studies form the groundwork for future research in the design and detailing of cost-effective high-performing SPSW systems.

Steel plate shear walls (SPSWs) have been frequently used in seismic design and retrofit of buildings over the past three decades or so. Employment of infill plates made of low yield point (LYP) steel with considerably low yield stress and high elongation capacity is believed to provide the possibility in order to improve the structural and seismic characteristics of such lateral force-resisting systems. Among the various benefits is the early yielding of LYP steel infill plates, which can result in greater energy absorption capacity and limitation of the plastic deformation demand to the surrounding frame structure. On this basis, a case study is performed using numerical simulations and reported in this paper on the seismic retrofit of SPSWs using LYP steel infill plates of double thickness. It is shown that the retrofit of a steel shear wall using a LYP steel infill plate of double thickness can result in desirable plate-frame yielding sequence and interaction. Moreover, this retrofit strategy can improve the initial stiffness, buckling stability, and energy dissipation capacity of the existing SPSW system.

Case Study on Retrofit of Steel Plate Shear Walls Using Low Yield PointSteel Infill Plates

AbstractIn bridge engineering, laser-based measurement techniques show promise in assisting field tests due to their noncontact features. A case study of using laser-based remote sensing to help collect data during in situ testing for a bridge finite-element (FE) model validation is reported in this paper. The skewed two-span bridge in this study was constructed with nine high performance steel girders in two phases. A three-dimensional (3D) FE model of the bridge superstructure was developed based on the information provided by the design files. Various field tests were performed to validate the model: (1) light detection and ranging (LiDAR) scanning, (2) static truck load tests, and (3) laser Doppler vibrometer testing. The LiDAR scanner collected geometrical information of the actual bridge. It was also used to measure girder deflections during load testing. The fundamental frequency of the bridge vibration was obtained by using a laser Doppler vibrometer (LDV). In situ dynamic and static measurements ...

Laser-Based Field Measurement for a Bridge Finite-Element Model Validation

The single contour cantilever beam (SCCB) test method has been developed with the intent to capture Mode I opening failures of CFRP-reinforced concrete beams. Recent development in the method explores possible shifting damage into the concrete substrate by using the International Concrete Repair Institute (ICRI) Surface Profile Level Three (SP3) as the desired CFRP bonded interface to concrete. To validate and explain the interface fracture behavior, finite element analysis using special cohesive elements has been performed. The cohesive element allows separation of the concrete substrate from the CFRP. This paper presents the simulation of laboratory test results, where failure in the substrates has been successfully reproduced. The simulation results indicate that finite element method using cohesive elements can successfully replicate Mode I critical strain energy release rate and the peak capacity of the laboratory tests and may have the potential to simulate actual applications.

Finite Element Modeling of Mode I Failure of the Single Contoured Cantilever CFRP-Reinforced Concrete Beam

As the reinforced concrete infrastructure continues to decline, the engineering community is turning to rehabilitative methods as cost effective alternatives to replacement. One such method, that has gained popularity over the last few decades, is the use of wet-layup fiber reinforced polymers (FRP) adhered to the concrete surface. The application of FRP consists of a fibrous material (carbon, glass, Kevlar), which when impregnated by an epoxy, may then be bonded to the surface of a reinforced concrete structure. The experimental fracture mechanics approach known as the Single Contoured-Cantilever Beam (SCCB) was herein utilized to investigate the fatigue behavior of the bonded interface between the externally reinforcing CFRP composite member and the underlying concrete under Mode I failure. The research outcome made it possible to establish a modified Paris law relationship for the CFRP-concrete interface bond as a predictive means of ascertaining the expected mechanical life cycle of such externally reinforced structures.

Mode I fatigue of the carbon fiber-reinforced plastic—concrete interface bond

Baseline Model Establishment for a Bridge: II. Static Load Testing

The size and complexity of bridges make the analysis of such structures difficult. Load testing is a useful technique to test the performance of bridges and assess the presence of damage. Traditional techniques for measuring the response of bridges during load testing often necessitate physical contact with the bridge and thus restrict measurements to only the contact area. A 3D terrestrial light detection and ranging (LIDAR) scanner can provide highly accurate, noncontact measurements of bridge surface points. The scanner can obtain the geometric information of the entire bridge surface area within its scanning range, making it a powerful tool for bridge load test measurements. In this paper, the 3D scanner capability was demonstrated through the testing of a high-performance steel girder bridge in Iredell County, North Carolina. By comparing the changes of bridge surface scan data before and after a static load test, displacements of surface points were calculated. Also, the accuracy of the deflection measurement and a strain calculation technique using LIDAR scan data are discussed.

Application of 3D LIDAR Scan of a Bridge under Static Load Testing

Even before steel was a topic of formal study for structural engineers, the brilliant eighteenth century Swiss mathematician and physicist, Leonhard Euler (1707–1783), investigated the theory governing the elastic behaviour of columns, the results of which are incorporated into the American Institute of Steel Construction's (AISC's) Bible: the Steel Construction Manual. Each semester as the author teaches the introductory undergraduate ‘Structural Steel Design’ course, when arriving at the subject of compression members, he insists on first explaining in detail the mathematical contributions of Euler to the theory of elastic buckling, based on the subject of differential equations – the contents of which constitute this article – before commencing with issues pertaining to engineering design.

International Journal of Mathematical Education in Science and Technology

Closed-form solution for a cantilevered sectorial plate subjected to a twisting tip moment

A GIS-based data management system has been proposed for pavement management due to the spatial capability in organizing diverse geo-referenced information. The technology can be further enhanced by nondestructive distributed sensing. To target a wide study area, this research proposes a low-cost vibro-acousto passive sensing technique that embeds within roadways for long-term sensing. Using self-sustaining MEM sensors, the technology detects acoustic signals and use relative rating to assess pavement conditions. The detection technique echoes the traditional chain-drag technology in that the same sound detection is deployed. Coupling with previously established AMPIS pavement imaging and distress detection technique, the proposed system can evolve to be a more powerful new-generation GIS-PMS. This paper introduces the system concept and describes the philosophy behind the system and some of the challenges that we are currently attempting to solve.

Passive sensing and imaging for GIS-PMS: system concept and challenges

The fracture mechanics specimen known as the Single Contoured-Cantilever Beam (SCCB) – an experimental approach designed to ascertain both qualitative and quantitative information about the integrity of Fibre Reinforced Polymer (FRP) laminate-to-concrete interface bonds – has been used to assess the detrimental effects of subjecting concrete structures externally strengthened with Carbon Fibre Reinforced Polymer (CFRP) sheets to a combined thermo-chemical environment involving Freeze-Thaw (FT) cycling under a calcium chloride (CaCl2) solution. Quantitative fracture measurements in terms of the Mode I critical strain energy release rates (GIc) were recorded after 50, 100, 150, 200 and 300 cycles of alternate freezing and thawing; moreover, specimen weights and strains were measured initially and at the end of every 5th cycle. Considerable degradation of the interface bond integrity was found to have resulted, particularly for the latter-stage cycled beams.

Freeze-thaw cycling under a calcium chloride environment: effects on CFRP strengthened concrete structures

Analysis and testing of a bridge deck reinforced with GFRP rebars : final report, April 3, 2007.

The present project had two main objectives, to experimentally and analytically investigate a bridge deck reinforced with glass fiber reinforced polymer (GFRP) rebars, and to perform durability tests on four rebar types. An analytical investigation was performed using the finite element software ANSYS for both the actual bridge deck, and for the reduced size laboratory experiment. In addition, laboratory experiments were also performed on an 11-ft-long bridge deck model built inside the structures lab. Except for the length of the girder-deck model, the true scale was used for every other dimension. Three different tests were performed on the model, and the test data verified the analytical results. Once completed, this bridge located in Macon County was instrumented and tested using two loaded tandem trucks. For the durability testing, four different types of GFRP reinforcement provided by different rebar vendors were evaluated under exposure to an alkaline environment at different temperatures. For the moisture tests, a total of 96 specimens were monitored for changes in length, diameter, and weight. A total 128 unscathed samples and 64 “nicked” samples – simulating defects to the rebars that might occur on the field site – were tested in tension to determine the rate of degradation in tensile properties. Concrete cylinders were poured, and 168 pullout specimens were tested (84 at #5 rebar diameter and 84 at #8 rebar diameter).

Analysis and Testing of a Bridge Deck Reinforced with GFRP Rebars

A gamut of mathematical subjects and concepts are taught within a handful of courses formally required of the typical engineering student who so often questions the relevancy of being bound to certain lower-division prerequisites. Basic classes at the undergraduate level, in this context, include: Integral and Differential Calculus, Differential Equations, and Matrix (or Linear) Algebra. Focusing on but one sub-discipline within engineering, namely, Mechanics, the author attempts to expose the sheer pertinence of each of the aforementioned mathematical subjects as they unavoidably have materialized in various forms throughout his teaching experiences; specifically, an example is drawn from each of the following classes: Advanced Structural Analysis, Analysis of Plates and Shells, Fracture Mechanics and Fatigue, and Composite Materials. While comprehensiveness is not the aim of this article, the sampling of themes that are expounded upon – rudimentary to all disciplines of science and engineering – unearth such a commanding cross section of mathematical topics in their wake to warrant special consideration by every conscientious student.

The recently developed experimental fracture approach known as the Single Contoured-Cantilever Beam (SCCB) was used to characterize the interface bonds between concrete substrates and two varieties of FRP: glass and carbon (abbreviated GFRP and CFRP, respectively). Limited research has been performed concerning the FRP-concrete interface bond relative to three surface-roughness grades: low- ( 50 μm), to establish the optimal formation for bonding. By use of the SCCB approach, Mode I critical strain energy release rate results are measured and quantified. Finally, considering that a majority of externally strengthened FRP concrete structures involves bridges and girders that are subjected to repeated (as opposed to static) loads, a preliminary study is conducted on cyclically fatigued FRP-concrete interfaces under varying load-ratio and frequency effects.

Surface Roughness, Quasi-Static Fracture, and Cyclic Fatigue Effects on GFRP- and CFRP-Concrete Bonded Interfaces

Benchmarking Forensic Engineering practice — A Philosophical Discussion

Synopsis: Externally bonded GFRP fabrics are being increasingly used for seismic retrofit and rehabilitation of concrete structures, due to their high strength to weight ratio and low cost in comparison to carbon and aramid fibers. However, glass fibers are vulnerable to attack caused by harsh environmental weathering conditions such as freezing-thawing, wetting-drying, and exposure to alkaline and acidic environments. Concerned with durability, this study is based on fracture mechanics to evaluate the interface durability of GFRP bonded to Normal Concrete (NC) and High-Performance Concrete (HPC). Three types of specimens are evaluated: (1) newly bonded unconditioned specimens, (2) environmentally conditioned specimens, and (3) correspondingly base-line companion specimens. Two types of environmental ageing protocols are defined: (1) freeze-thaw cycling under in calcium chloride, used to simulate the deleterious effect of the deicing salts; and (2) alternate wetting and drying in sodium-hydroxide, used to simulate the alkalinity due to the presence of concrete pore water. Durability of the interface is characterized based on the critical strain energy release rate, under Mode-I loading, and weight and strain measurements. Considerable degradation of the interface bond is observed with increasing environmental cycling period.

SP-230: 7th International Symposium on Fiber-Reinforced (FRP) Polymer Reinforcement for Concrete Structures

A Fracture Mechanics Approach for Interface Durability of Bonded FRP to Concrete

Mode I fracture and durability of the CFRP -concrete interface bond

The influence of rainfall depth class and deciduous tree traits on stemflow production in an urban park

Tree canopy processes affect the volume and biogeochemistry of inputs to the hydrological cycle in cities. From June 2012 to November 2013, we studied stemflow production from 37 isolated deciduous park trees in a semi‐arid climate dominated by small precipitation events. To clarify the effects of canopy traits on stemflow metrics, we analysed branch angles, bark relief (one component of roughness), tree size, canopy and wood cover fraction, median leaf size, and branch and leader counts. High branch angles contributed to stemflow production in both single‐leader and multi‐leader trees. While bark relief was negatively correlated with stemflow rates in multi‐leader trees, it was positively correlated with rates for single‐leader trees, possibly reflecting the conducive role of linear furrows once bark of single‐leader trees is saturated. The association between numerous leaders, low stemflow initiation thresholds, and high rates deserves further study. Among meteorological variables, rain depth was strongly correlated with stemflow yields; rainfall inclination angle and wind speed were positively correlated with yields, while total intra‐storm break duration and vapour pressure deficit were inversely related. For rain depths <3 mm, greater stemflow was generally associated with leafless canopies. In support of integrated stormwater management, our results can inform climate‐sensitive selection and siting of urban trees with traits that tend to either promote or minimize stemflow, depending on infiltration potential. Copyright © 2015 John Wiley & Sons, Ltd.

Tree traits and meteorological factors influencing the initiation and rate of stemflow from isolated deciduous trees

The Quantitative Importance of Stemflow: a Synthesis and Evaluation of Past Research

Rainfall interception loss by forest canopies. In: Forest Hydrology and Biogeochemistry: Synthesis of Past Research and Future Directions

Forest hydrology and biogeochemistry : synthesis of past research and future directions

Throughfall associated with 34 rainfall events was measured from Year Day 1, 1999 to Year Day 184, 2001 within a pine‐oak stand of the central Sierra Madre Oriental mountain range of northeastern Mexico. Throughfall and canopy interception loss accounted for 83·6 ± 2·1% and 15·8 ± 1·8% (significance level, α, = 0·05) of the 691·8 mm cumulative rainfall input, respectively. A reformulated Gash analytical interception loss model and the Liu analytical model run with predetermined model parameters derived from the literature underestimated cumulative interception loss by 34·4%, and 37·1%, respectively. When the models were run with study period derived parameters the reformulated Gash model overestimated the observed interception by 3·0%, while the Liu model underestimated observed cumulative interception by 0·8%. Although good agreement between observed and estimated cumulative canopy interception loss was found using the analytical models with study period derived parameters, relatively poor agreement was found at the rainfall event scale. Although the analytical versions of the reformulated Gash and Liu models provided similar results, the Liu model is recommended for further application in the study area since it requires less data input and follows an exponential wetting of the canopy approach, something that the data collected during the study supports. Future work regarding the Liu model is discussed. Copyright © 2007 John Wiley & Sons, Ltd.

Modelling canopy interception loss from a Madrean pine‐oak stand, northeastern Mexico

Stemflow production within a red oak (Quercus rubra L.)–sugar maple (Acer saccharum Marsh.)–American beech (Fagus grandifolia Ehrh.) dominated stand in southern Ontario was evaluated during the growing season of 1995. For events that produced stemflow from all sampled tree boles (rainfall ≥ 4·3 mm), the geometric mean Herwitz (Earth Surf. Process. Landforms 11 (1986) 401) funnelling ratios were 7·3, 20·6, and 26·3 for oak, maple, and beech, respectively. Geometric mean funnelling ratios for these three species increased in a linear fashion with increasing rainfall depth for events ranging from 4·3 to 17·4 mm. However, funnelling ratios for the two larger rainfall events measured during the study (27·4 and 40·1 mm) were relatively small, suggesting that after a certain rainfall depth threshold has been reached, trees become less efficient at diverting intercepted rainfall to their boles. Significant (α = 0·10) positive linear relationships were found between stemflow production (l/tree) and beech basal area for all rainfall events ≥ 2·2 mm, while for oak and maple such relationships corresponded with only some relatively large rainfall events. Possible causes for the discrepancies in the funnelling efficiencies of the three tree species and between relatively small and large events are provided. Copyright © 2006 John Wiley & Sons, Ltd.

Growing‐season stemflow production within a deciduous forest of southern Ontario

Linking synchronization to self-assembly using magnetic Janus colloids

Method and apparatus for modulating a light beam for a two-dimensional image representation

Display device with one-dimensional fast grating light valve array

We investigated the effect of the angle orientation of the probe during Nd:YAG transscleral cyclophotocoagulation. We found, based on histologic evaluation of the ciliary processes and surrounding structures, that the angle at which the probe was placed on the eye was critical. A probe angulation as little as 15 degrees off the perpendicular destroyed sites less than optimal for achieving the goal of decreasing aqueous humor production.

Probe orientation in contact Nd:YAG laser cyclophotocoagulation.

A MANFIS-based geometric deviation prediction and optimal parameter selection for SPIF geometric accuracy improvement

A technique for visualizing an invertible, i.e. one-to-one, function graphically as a single one-way path with no branching is presented along with a simple procedure for obtaining the path of the inverse function.

Counting the number of paths in a graph is easily accomplished using powers of the adjacency matrix for the graph, while enumerating these paths is difficult. There appears to be only one technique, Floyd's algorithm [1], whose end result can be used, with a considerable amount of paper and pencil manipulation, to actually list in order the vertices that make up each path. Even so, Floyd's algorithm is used only to find shortest paths. This paper describes a technique in Maple that automatically prints out all paths of any desired length, along with the name of each vertex, proceeding in order from start (beginning vertex) to finish (ending vertex). This is accomplished by defining a new matrix multiplication that produces all paths, with the option of listing only the simple ones; can handle alphanumeric entries; and eliminates the clustering of parentheses and messy output obtained when using ordinary matrix multiplication with alphabetic entries.

The international business environment is always shifting, now more than ever. One of our main responsibilities and roles as international business educators is to help prepare students to work effectively in a variety of business environments and to provide them with the tools needed to operate in changing global circumstances. Those tools include a global mindset, a sense of global citizenship, and critical thinking skills. This article helps address this need by examining what makes international business education distinctive, then by outlining some exercises and assignments that can be useful in developing those necessary perspectives and skills.

Preparing Students for the “Next” Global: The Responsibilities and Tools of International Business Education

An increasing number of academic institutions provide short-term international study opportunities for their business students at both undergraduate and graduate levels. Some institutions even provide such experiences for faculty, to enhance their international background and to facilitate research and broader perspectives for the classroom. Since “the essence of pluralism is the recognition of the legitimate existence of alternative ideologies, frameworks, and references” [Reardon, (2009), p.2], the goals of the international study tour, the exposure to alternative perspectives it provides, and the dynamics it creates fit particularly well with the philosophy of diverse perspectives found in pluralism. We review the literature on short-term study abroad programmes and make the case for the value of short-term study tours as an experiential learning tool for international business students and faculty, noting the range of content and process gains in which such study tours enhance a pluralist view of the world, the global economy, the business curriculum, and even the student cohort.

Experiential pluralism: gains from short-term study abroad programmes in the business curriculum

The organizational communicator , The organizational communicator , مرکز فناوری اطلاعات و اطلاع رسانی کشاورزی

The mass media's capacity to create reality senes as the stimuli for rhetorical responses. Two categories of rhetorical activity are directly attributable to the influence of mass media: (1) that exacted by defects and problems in reality as it is created and shaped by media and (2) that exacted by sheer awareness on the part of the spokesmen and audiences that reality can be persuasively shaped, maintained, or altered by media. Each category of response poses special problems and dangers important to critics concerned with the functions of rhetoric and media.

THE ADVERSARIES: POLITICS AND THE PRESS. By William L. Rivers. Boston: Beacon Press, 1970; pp. xi+273. $730. THE LEFT‐LEANING ANTENNA: POLITICAL BIAS IN TELEVISION. By Joseph Keeley. New Rochelle, N. Y.: Arlington House, 1971; pp. 320. $8.95. PUBLIC OPINION AND FOREIGN POLICY. By James N. Rosenau. New York: Random House, 1961; pp. vii+118. Paper $1.35. PUBLIC OFFICIALS AND THE PRESS. By Delmer D. Dunn. Reading, Mass.: Addison‐Wesley, 1969; pp. vii+208. Paper $2.95.

Communicating with the people: The relationship between government and the press

An historian and rhetorician synthesize their interests in focusing on the process of psychological preparation for war, as demonstrated in New York papers after sinking of the “Maine.”

By tracing the relationship of the instrumental arts—rhetoric and education—to the master art of politics, the authors conclude that each serves a common function in promoting the ultimate Aristotelian good—the welfare of the community.

The relationship of rhetoric and education: An aristotelian view

The thematic analysis of discussion provides insight into the task process by describing themes in terms of their relationship to the task, duration of discussion, and contributing group member.

A thematic approach to the analysis of the task‐oriented, small group

A descriptive analysis of the distribution and duration of themes discussed by task‐oriented, small groups

The incidence of Candida species has increased among females of child bearing age over the years. There has also been an increase in the resistance of these Candida species to the antifungal drugs used to treat them. This study is aimed at detecting the prevalence of Candida species among patients with urinary tract infections (UTI) attending gynecological unit of Ekiti State University Teaching Hospital, Ado-Ekiti, Nigeria. The distribution of pathogenic factors and the antifungal resistance pattern of the isolates were also determined. A total of 61 subjects of different ages and socioeconomic status attending the health facility were enrolled in this study. Samples of high vaginal swab (HVS) were collected from each of the participant and screened. A total of 36 candidal isolates were recovered from the samples out of which 11 (30.5%) were predominantly Candida albican, 5 (13.9%) Candida krusei, 4 (11.1%) Candida glabrata, 2 (5.6%) Candida tropicalis and 14 (38.9%) were not identified beyond the genus level. Ten (27.8%) of the isolates were not able to produce biofilm. Out of those that produce biofilm 17 (47.2%) produced weak biofilm, 5 (8.2%) produced moderate biofilm, while 4 (11.1%) produced strong biofilm. Spectrophotometer was used to quantify those that produce biofilm 9 (25%) produced moderate biofilm while 16 (44.4%) produced strong biofilm. The isolates were subjected to various pathogenicity tests which include haemolysis, catalase, phospholipase and hydrolysis. This test shows that Candida species has the highest percentage to the entire test while none of C. glabrata produced haemolysin and phospholipase. Antifungal assay was then carried out on the entire organisms showed Candida albicans to have low resistance to the azoles drugs while the non-albican Candida shows higher resistance to it. Extremely high prevalence of Candida albicans and Candida species were documented in this study. These findings should be taken into account in further research concerning presence of Candida among patient with sexually transmitted disease in Nigeria.

Detection of virulence factors and antifungal resistant patterns of Candida species isolated from women with urinary tract infections

The incidence of fungal urinary tract infections has risen gradually and has thus constituted a public health challenge. The aim of this study was to determine the prevalence of urinary tract infections by fungi in two health centres in Ojo, Lagos. A total of 200 patients attending the health centers constituting 160 males’ urines and 40 females’ vaginal swabs were recruited for this study. Midstream urine samples and vaginal swabs were aseptically collected and processed using standard mycological techniques. Fungal isolates were identified based on cultural characteristics, lactophenol blue stain, chlamydospore formation, colony colour on CHROM agar Candida medium and API yeast identification. Antifungal susceptibility testing of the isolates was performed by using the Broth dilution and Kirby-Bauer disk diffusion methods using two of the most commonly used antifungal agents.  A total of 122 fungal isolates, of which 68 (55.7%) were Candida spp. and 54(44.3%) Aspergillus spp. were recovered. The Candida spp. included 64 (52.5%) C. albicans and 4(3.3%) C. glabrata while Aspergillus spp. included A. flavus, 20(16.4%), A. fumigatus, 24 (19.8%) and A niger, 10(8.2%). The most common fungal pathogens in the urinary tracts of the subjects were Candida albicans and Aspergillus fumigatus. Both C. albicans and A. fumigatus were highly susceptible to both fluconazole and amphotericin B in dimethyl sulphoxide and water (90-100%). Similarly, all Aspergillus spp. were susceptible to both antifungals except A. flavus which showed a slight resistance (10-15%), which appears to be emerging. Both fluconazole and amphotericin B still show high chances of therapeutic efficacy against fungal infections of the urinary tracts.

Antimicrobial resistance among fungi from patients with urinary tract infections in Ojo, Lagos, Nigeria

Studies on the mitochondrial, immunological and inflammatory effects of solvent fractions of Diospyros mespiliformis Hochst in Plasmodium berghei-infected mice

Incidence dandruff among students of a tertiary school was assessed in this study. A standard questionnaire was used to get demographic data while standard microbiological methods were used to identify organisms associated with the infection. Virulence factors and resistance of the isolates to different antifungal agents were also determined. Seventy-eight (65.55 %) out of 119 students sampled had dandruff while dermatophytes were isolated from only 32 (41.07 %). The highest occurrence of dandruff was observed among the age group of 21-25 years with 32 (71.11%) followed by 20 (60.61%) found among 31-35 age group. A total of 108 (90.76 %) of the subjects were single while 9.24 % (n=11) were married. Dry flakes with itching are the highest sign and symptoms among the subject with 71 (91.03 %). A total of 23 (29.29 %) used shampoo as an intervention for dandruff treatment. Two genera of dermatophytes were recovered in this study. The occurrence of Trichophyton was more than Microsporum.The isolates presented different virulence factors. None of the isolates was susceptible to clotrimazole while all Trichophyton were resistant to fluconazole. Nystatin followed by ketoconazole had good inhibitory effects on the isolates. The knowledge of the efficient screening, management, reduction, and treatment of the dermatophytic infection should be fruitful in the future

Virulence Factors and Antifungal Resistance in Dermatophytes Associated with Dandruff among University Students and a Tertiary Institution in Nigeria

Bioflocculants of microbial origin have the advantage of being safe, biodegradable and harmless to the environment. Production of bioflocculant by two fungi isolates and the factors affecting its production were investigated in this study. Primary screening of fungi for the production of bioflocculants, efficiencies and conditions for the optimum production of the bioflocculants were determined using standard microbiological and chemical methods. Aspergillus flavus MCB 271 and Aspergillus niger MCBF 08 were the best bioflocculant producers among the fourteen fungal isolates screened. Aspergillus flavus optimally produced bioflocculant with glucose and peptone as sole carbon and nitrogen sources respectively. Calcium ions (Ca2+) at 78.4% served as best cation sources for bioflocculant production with optimal pH of 7 and temperature of 40°C. Aspergillus niger MCBF 08 produced bioflocculant optimally when the media had peptone as a nitrogen source and maltose as a sole carbon source. The two species achieved the maximum flocculating activity of            97% (A. flavus MCBF 271) and 86% (A. niger MCBF 08) at pH values of 7 on the 3rd day of the study and caused a reduction in bacterial load of the wastewater samples by 58.73% and 60.85% respectively. These bioflocculants are thus potential replacement for synthetic flocculants conventionally used for wastewater treatment.

Characterisation of Fungal Bioflocculants and Its Application in Water Treatment

Disinfection of water is important in the control of waterborne diseases. It is used to kill or inactivate microorganisms in a gradual process that involves a number of physical–chemical and biochemical processes. The effects of sub-lethal gamma irradiation on survival and resistant pattern of two indicator organisms used in assessing water quality: Enterococcus faecalis and Escherichia coli were investigated in this study. Plate count agar and disc diffusion methods were used to determine the load and antibiotics susceptibility pattern of the test organisms respectively before and after exposure to different doses of gamma irradiation in sachet water samples. Survival pattern of the two indicator organisms to gamma- ray showed a decline in the populations of the organisms with time compared to the controls (non-radiated). The effect of the irradiation on the E. coli was dose dependent, it initially responded to the effects of the irradiation in the first 4 days of exposure compared to the control. On exposure to 4 and 5 gy gamma rays a minimum population was reached on the 7th day. At p

Effects of sub-lethal gamma irradiation on antibiotic susceptibility profile and population dynamics of Enterococcus faecalis and Escherichia coli in water

John Oludele Olanlokun, Andrew Fisayo Olotu, Oluwole Moses David, Thomas Oyebode Idowu, ElSayed Mahmoud Soliman and Olufunso Olabode Olorunsogo Laboratories for Biomembrane Research and Biotechnology, Department of Biochemistry, College of Medicine, University of Ibadan, Ibadan, Nigeria; Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, South Africa; Department of Microbiology, Faculty of Science, Ekiti State University, Ado-Ekiti, Nigeria; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Obafemi Awolowo, University, Ile-Ife, Nigeria; College of Pharmacy and Pharmaceutical Sciences, Florida Agricultural and Mechanical University, FAMU, Tallahassee, Florida, USA

A novel compound purified from Alstonia boonei inhibits Plasmodium falciparum lactate dehydrogenase and plasmepsin II

Background: Oral infection caused by Candida spp. is a major healthcare problem in dental and oral care. Treatment failure has been reported in cases of oral candidiasis as a result of resistance to common antifungals. 
Aim and Objective: In this study, the in vitro and in vivo activities of extract of Tithonia diversifolia against virulence factor-borne and antifungal resistant-Candida albicans were investigated. Candida albicans was isolated from the saliva of patients attending a tertiary hospital in Ekiti State. 
Methodology: Standard methods were used to determine the presence of virulence factors in the isolates. In vitro and in vivo anti-candidal activities of the hydro-ethanolic extract of T. diversifolia were also tested on the test fungus. 
Results: The virulence factors have varying percentage of occurrence in all the isolates with catalase having the highest. Itraconazole and nystatin were not effective against the isolates. Out of the six isolates selected (based on antifungal resistance) only three produced strong biofilm. The reduction in the population of the test organisms by the extract was time and concentration dependent. At the end of candidal challenge and treatment assays, extract of T. diversifolia has lower anti-candidal property compared to nystatin. 
Conclusion: This study has shown that C. albicans associated with the mouth carries virulence factors and are resistant to common antifungals. In this work, we noticed antifungal effects of hydro-alcoholic extract of T. diversifolia on C. albicans associated with oral infections.

Application of Hydro-ethanol Extract of Tithonia diversifolia (Hemsl) in the Treatment of Experimental Murine Oral Candidiasis

Listeria monocytogenes is an opportunistic food-borne pathogen causing listeriosis especially among immune-compromised persons. Its high rate of morbidity and mortality has classed the organism among the top watch list in foods. It is known to produce several virulence factors which aid its survival in harsh conditions and its dissemination within host cells. The pathogenicity of L. monocytogenes , isolated from cattle faeces in Ado-Ekiti, was determined in Wister albino rats for two weeks and the relative virulence was calculated. Rats were challenged with isolates producing listeriolysin O and phospholipase orally, intraperitoneally and subcutaneously. Biochemical parameters and haematoxylin and eosin (H and E) stained sections of selected organs were examined for significant changes ( p < .05) and histopathological effects post-experiment. Relative virulence was recorded at 0% with rats showing no signs of infection or death. However, significant changes in total protein, lipid profile and some selected antioxidant enzymes, as well as cytological changes in the examined H and E sections of organs showed that an infection had occurred. Bacteria may have however been eradicated by the immune-competent rats. This study therefore concludes that isolates may be pathogenic especially for persons tagged ‘high risk’ due to low immunity. Keywords:  L. monocytogenes , listeriosis, pathogenicity, histopathology, cattle feaces

Pathogenic potential of Listeria monocytogenes isolated from cattle faeces in Adoekiti

Plant protection is an important area which needs attention since most of the hazardous inputs added into agricultural systems are in form of synthetic chemicals. The inhibitory activity of partially purified enterocins (PPEs) produced by Enterococcus faecalis strains on plant pathogenic fungi was investigated in this study. The PPEs were preliminarily screened against bacteria using agar-well diffusion method. The active extracts were partially purified using ion exchange chromatography. The in vitro anti-fungal properties of the PPEs were determined using agar dilution and broth dilution techniques. The PPEs tested in this study inhibited the growth of Botryodiplodia theobromae, Aspergillus niger, Pythium ultimum, Penicillium expansum and Fusarium oxysporum. At different concentrations PPEs had varying inhibitory effects on the dry mycelial weight of Pythium ultimum and F. oxysporum. At the 96th hour of the experiment, enterocin UNAD 012 had higher percentage inhibition ranging between 37.63 and 84.11% than enterocin UNAD 046 with percentage inhibition ranging between 28.77% and 67.27% on the test fungi. This inhibitory activity of enterocins produced by E. faecalis on fungi makes them as potential biocontrol agents due to their ability in suppressing their growth. 
Keywords. Bacteriocin, enterocins, Enterococcus faecalis, fungi, phytopathogens.

Effect of Partially Purified Enterocins from Enterococcus faecalis Strains on the Growth of Some Phytopathogenic Fungi

Occurrence and Molecular Characterisation of Listeria Species in Some Fresh-cut Vegetables and Environmental Samples

In vitro antiplasmodial activity and prophylactic potentials of extract and fractions of Trema orientalis (Linn.) stem bark

Antimicrobial Activity, Safety and Acceptability of Formulated Ginger-fortified Hand Sanitizer Gel

Fungi are ubiquitous eukaryotic organisms and are transient flora in air. Their persistence and viability in air over time make them potentially pathogenic especially in environments like daycare facility (creches). The fungal load in fifty selected creches in Ado-Ekiti and the effectiveness of commonly used disinfectants on the fungi isolated were investigated. Fungi isolates were recovered from the air in creches facilities environments using sedimentation method and were identified using morphological and cultural methods. Their susceptibility to different disinfectants: Izal, Dettol, Z-Germicide and Nixoderm was evaluated using broth dilution method. A total of one hundred and sixty-four isolates belonging to 10 fungal genera: Alternaria, Candida, Cladosporium, Fusarium, Mucor, Nigrospora, Penicillium, Pullularia, Rhizopus and Trichoderma were recovered from creches. Alternaria sp. was the most predominant. It was also observed that the isolates exhibited varying levels of sensitivity to the different disinfectants. Z-germicide was the most effective though with fungicidal activities at, and above the manufacturer’s recommended in-use concentrations. However, the fungal isolates were observed to show resistant to all tested concentrations of Izal. The results of the present study clearly showed that airborne fungi of public health significance were present in creches and as such may pose threats to health of the babies. Proper hygiene should be practiced in creche environments to prevent fungal diseases among the babies.

Aeromycobiota survey of indoor and hygiene level of selected day care facilities in ekiti state, nigeria

Candida albicans infections are on the increase in the recent time and its resistance to most fungicides has been documented. We studied the effect of extracts of Sansevieria aethiopica (Thunb) on C. albicans ATCC 10231 and their possible mechanisms of actions were proposed. The minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) of the extracts were determined using macrobroth dilution method while the structural changes in the fungus after treatment with the extract was determined by electron microscope. Standard methods were used to determine the effects of the extracts on the proton pumping, internal pH and ergosterol synthesis. The MIC of the extracts ranged from 1.5625 to 3.125 mg/ml while extracts-treated cells showed alterations in the morphology; wrinkled surfaces, shrinkages, tears and holes. Proton pumping activity was lower in the treatment group compare to the control while the internal pH of test fungus ranged between 5.40 and 6.03. We observed a decreased in ergosterol content in the candidal cells treated with the plant extracts. At ½MIC of acetone, methanol and ethanol extracts of the plants the amount of 24(28)-dihydroergosterol to ergosterol were 0.0972/0.5128, 0.0939/0.3571 and 0.1032/0.3702 g/dry weight respectively. The extracts were able to inhibit the growth, affect the intracellular pH (by extension the membrane integrity) and interfere with the sterol metabolism in C. albicans ATCC 10231.

Anti-Candidal Activities of Leaf Extracts of Sansevieria aethiopica (Thunb): A Medicinal Plant Use in the Treatment of Oral Candidiasis in Eastern Cape of South Africa

In vitro susceptibility of selected pathogenic bacteria to leaf extracts and latex of Jatropha gossypiifolia (L) and Jatropha curcas (L)

Otitis is highly prevalent infection caused mainly by bacteria and frequently associated with secondary infections. It may lead to other permanent dysfunction in children, and multidrug-resistance has been reported in the implicated bacterial pathogens. The aim of this study is to evaluate the phytochemicals, toxicity and antibacterial potential of acetone leaf extract of Sansevieria aethiopica (Thunb.) against bacterial pathogens responsible for otitis. The phytochemical analyses of the acetone extract were determined using standard assay methods and the antioxidant activity was assessed using 2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic-acid (ABTS), 1,1diphenyl-2-picrylhydrazyl (DPPH), hydrogen peroxide (H2O2) and ferric reducing power. Brine shrimp lethality test was used to determine the cytotoxicity effect of the extract. Macrobroth dilution method was used for the determination of minimal inhibitory concentration (MIC). The amount of both phenolics and flavonoid in the extract were 19.69 mg tannic acid equivalent/gram and 7.198 mg quercetin equivalent/gram respectively. Flavonols and proathocyanidins concentrations in the extract were 4.351 mg quercetin equivalent/gram and 1.405 mg catechin equivalent/gram respectively. The extract expressed antibacterial effects on both Gram negative and Gram positive bacteria however the activity was more pronounced on Gram negative organisms. The extract has good antioxidant properties. Although, slightly toxic it has both bacteriostatic and bactericidal effects on the selected bacteria associated with otitis especially Gram negative.

Bioactivity Of Acetone Extract Of Sensevieria Aethiopica (Thunb) Leaf

Microbial and physicochemical properties of seven branded, seal tampered refrigerated fruit juices were carried out in this study using standard methods. Coliform counts ranged from 2.079 to3.093 log 10 cfu/ml over the storage period with pineapple juice and citrus juice having the highest and least coliform count respectively. Total bacteria count in the juice ranged from 7.009 to 8.243 log 10 cfu/ml. Citrus fruit juice however had the highest staphylococcal count while pineapple juice had the least (2.344 to 3.881log 10 cfu/ml). Also, osmophilic yeast count ranged from 2.017 to 3.903log 10 cfu/ml, having the highest load in orange fruit juice and lowest load in citrus fruit juice. The pH of the juice samples ranged from 2.9 to 4.2 during the period of refrigeration. Conductivity was highest in apple fruit juice and lowest in orange nectar pulp fruit juice. The total dissolved solids ranged from 0.29 to 1.95 over storage and was recorded highest in apple juice and lowest in orange nectar pulp fruit juice. Turbidity ranged from 5.8-200. These results indicate a reduction in the quality of fruit juices after 5 days of opening and thus reveals that both spoilage and pathogenic organisms could proliferate in juices despite refrigeration.

Microbiological and physicochemical properties of commercial seal tampered refrigerated fruit juices

Background: The recent global upsurge in antibiotic resistance among bacteria associated with wounds has contributed to high treatment failures in wound management. Enterocin are produced by enterococci and has been reported to inhibit the growth of many bacteria including those associated with wound infections. Objectives: In this study, antibacterial and physico-chemical properties of partially purified enterocin (PPE) from Enterococcus faecalis was determined. Also, the possible application of the enterocin in wound management was evaluated. Materials and Methods: Eight different enterocin were tested and that with highest antibacterial (E3) was partially purified using standard methods. The molecular weight of the PPE was determined by sodium dodecyl sulphate polyacrylamide gel electrophoresis after which the in vitro anti- Staphylococcus aureus potential of the PPE was determined. Results: Enterocin (E3) was effective against Staphylococcus aureus , Klebsiella pneumoniae , Enterobacter cloaca , Listeria monocytogenes and Proteus vulgaris . The activity of the E3 was very prominent at pH of 4 and 8. The molecular size of the isolated enterocin was 5.5 KDa. The photomicrograph of the skin tissue of the skin treated with partially purified enterocin for day 7showed epidermis covered by atrophic stratified squamous epithelium. A synergistic interaction was noticed when Eusol was used with the enterocin. Conclusions: From this study, enterocin from E. faecalis has a low molecular weight and inhibited bacteria isolates from wound and also aids physiological healing of wound.The antibacterial potency of this bacteriocin indicates that it is an alternative therapeutic agent that can be employed in wound care and management. Keywords: Enterocin, Enterococcus faecalis , wounds, bacteriocin, Staphylococcus aureus , skin

In vitro and in vivo antimicrobial activity of partially purified enterocin produced by Enterococcus faecalis and its application in wound healing

Molecular Detection of Panton Valentine Leukocidine Gene among Beta-lactamase Producing Staphylococcus aureus Isolated from Clinical Samples in Ondo State, Nigeria

The nutritional potential of oils extracted from different melon seeds and their fermented products‘ogiri’ was investigated. Diets composed with the oils were fed to experimental animals (albino rats) for seven weeks, while soybean oils served as control. Nutritional qualities were compared on the basis of the responses of body weight, organ weight, and biochemical parameters of the oils. The rats fed on diets with oil from fermented melon seeds gained more weight (28.30 – 43.24g) than those in the diet groups containing oil from unfermented seeds (27.74-31.98g). However, the differences were not significant at p<0.5. The relative weights of the hearts of rats fed on unfermented oil diets were higher than the corresponding fermented diet groups. The relative kidney and liver weights of the test diets were higher than the control diet, except diet containing oil from unfermented Citrullus lanatus (UCL). Both acid phosphates (ACP) and alkaline phosphates (ALP) in the test groups were higher than in the control group. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were reduced in the liver of the text groups in the group fed with diet containing oil of unfermented Cucumeropsis manii (UCM). AST increased in the hearts of the text groups except UCM. In summary, oils from fermented melon seeds were nutritionally better than oils from unfermented melon seeds.

Effect of fermentation on the nutritional potential of oils of melon seeds

One hundred and fifty Arbor acres broiler chickens aged four weeks were used in determining the effect of fermented rice husk meal diets on the performance and nutrient digestibility of finisher broiler chickens. They were allotted into five dietary treatments containing 0, 5, 10, 15 and 20 % rumen liquor fermented rice husk (RLFRH) meal, respectively. Each treatment was replicated three times with ten chickens each. The experiment was carried out using the completely randomized design. Feed and clean water were supplied ad libitum through the five weeks experimental period . Routine and standard management practices were strictly observed. Data on weight changes, feed intake and mortality were collected while feed conversion ratio was calculated. The results showed no significant (p>0.05) differences in live weight, feed intake, feed conversion ratio and mortality. However, the growth rate was influenced (p 0.05) influenced by the dietary treatments. The results from this study showed that diets containing RLFRH had no adverse effect on broiler chickens performance and nutrient digestibility at the finisher phase; as most of the performance parameters were not significantly different from the control diet. Twenty percent RLFRH inclusion level is recommended at this phase for improved growth rate. Keywords: Performance, rumen liquor, fermented, digestibility

Response of finishing broiler chickens to diets containing rumen liquor fermented rice husk meal.

Background: Fermented gruel ( Ogi ) has been reported to have high lactic acid bacteria (LAB) with proven probiotic properties. This fermented food has also has different therapeutic usages. Objective: The activities of fermented sorghum ( Ogi ) on induced hypercholesterolemia in albino rats were investigated. Materials and Methods: The LAB strains were isolated from traditionally fermented sorghum gruel Ogi. Also the ability of the isolates to tolerate bile and produced bile salt hydrolase was also determined. The hypolipidemic activity of fermented gruel ( Ogi ) with and without LAB strains in hypercholesterolemic rats was determined using standard methods. Results: The lactic acid bacteria (LAB) count in sorghum Ogi ranged between 5. 0792 log 10 CFU/g Original and 5.6990 log 10 while the average values of pH and titratable acidity (TTA) were 3.8 and 0.38 respectively. There was no significant difference between the weights of the animals in the control group (Basal Diet) and the experimental groups (at p<0.05). The mean values of the low density lipoproteins cholesterol (LDLC) in the rats were 188.60±7.27 mg/dl in the animals fed with HLF while the least value was recorded in the Basal diet supplanted with Ogi (BD+ Ogi ) (110.80±26.93 mg/dl). The mean high density lipoproteins cholesterol in the serum of the rats in cholesterol free feed supplemented with BD+ Ogi diet group was the highest (52.600 mg/dl). The amount of the total lipid in the animal fed with high lipid diet (HLF) was significantly higher than the amount in the organs of the animals feed with diets containing BD+ Ogi , HLF+ L. lactis and HLF+ L. brevis (at α = 0.05). In decreasing order, the amount of the glycerides in high lipid feed diets supplemented with Ogi , Lactobacillus lactis and L. brevis . The mean value of the Aspartate transaminase in the animals in Basal Diet group was higher at the commencement of the experiment (275.45±34.43 IU/L).while the level of the alanine transaminase was not significantly different (at p< 0.05). The histo-pathological micrograph of the various organs revealed the hypolipidemic potential activity of fermented sorghum. Conclusion: The diets supplemented with the fermented food showed better activity against hypercholesterolemia in the rat groups than their microbial isolates. It would therefore be safe to recommend these foods to individuals with this disease situation and those with incidence of coronary heart disease in Nigeria.

Hypolipidemic Activity of Fermented Sorghum (Sorghum bicolor L. Moench) Gruel (Ogi) in Hypercholesterolemic Rats (Rattus nervegicus)

The potential health risk associated with consumption of ready-to-eat (RTE) food sold in food outlets in and around Ekiti State University was investigated using standard techniques. The microbiological analysis of 96 food samples obtained randomly from 6 food outlets for a period of 12 months carried out. Antibiotic resistance of 379 Escherichia coli recovered from the samples was also determined using disk diffusion method. Results indicated that the total bacterial counts (TBC), total coliform counts (TCC) and total E. coli counts recorded for the food samples ranged between a mean value of 2.450±0.834 and 65.550±27.430x10 5 cfu/g; 0.050±0.022 and 12.250±6.735x10 5 cfu/g; and 0.033±0.021 and 5.333±2.809x10 5 cfu/g respectively. The values obtained for the TBC for rice, scotch egg, doughnut, semo and beans from all outlets were not significantly different (p<0.05). RTE Foods obtained from ST carried the highest number of E. coli with 21.1% of the total isolates, followed by food samples obtained from DKA with 20.3%. RTE foods from CJ had 18.5% of the total E. coli isolates, while 13.5% and 13.7% of the total E. coli isolates were recovered from foods from TTA and CCA respectively. Generally, the highest number of E. coli (61) was isolated from pounded yam while the least occurrence (26) was recovered from doughnut. Ofloxacin was the most effective antibiotic as only 2 (0.6%) of the E . coli isolates were resistant, while all the 379 isolates (100.0%) were resistant to augmentin and 80.2% and 65.7% of the isolates were resistant to ceftazidime and cefuroxime, respectively. Of the total E. coli recovered from this study, 73.1% were multiple antibiotic-resistant (MAR) with varying resistotypes. The highest percentage of MAR with 8 resistotypes was 0.3% of the E . coli isolates, while highest number (28%) had 4 resistotype with CXM-CRX-CAZ-AUG as the most common resistotype. The results of this study imply that there is need to improve on hygienic and good manufacturing practices in public food outlets in order to attain a relatively safe level in RTE foods for human consumption.

Multiple Antibiotic-resistant Escherichia coli in Ready-to-eat Foods from Food Outlets in Ekiti State University and Its Environ

The use of mobile phones in the clinical environment by health-care workers has become widespread. A swab of mobile phones of health-care personnel of several hospitals in Ekiti State were examined to evaluate the prevalence of Oxacillin resistant Staphylococcus aureus (ORSA), the resistance of ORSA to other commonly used antibiotics as well as the multiple resistant patterns of the recovered isolates. A total of 106 samples were screened yielding 100 S. aureus isolates. The antibiotics sensitivity profile to nine commonly used antibiotics revealed high levels of resistance amongst the isolates ranging from 47% resistance to Chloramphenicol to 100% resistance exhibited to cloxacillin with 55% of the isolates showed resistance to oxacillin while all isolates exhibited multiple resistance. Also, all 55 ORSA exhibited 100% resistance to erythromycin and cloxacillin but interestingly were very sensitive (99.9%) to gentamycin. The high recovery rate of bacteria from mobile phones revealed that cell phones may have notable roles in the transmission of multidrug resistant nosocomial pathogens, increasing the risk of cross-contamination posed to immunosuppressed patients by the heath care workers attending to them.

Epidemiology of oxacillin-resistant staphylococcus aureus from cell phones of health-care workers in Ekiti State

Methanolic extract of Alstonia boonei (De Wild) has been reported to be very effective against bacterial pathogens. Four solvents (hexane, chloroform, ethyl acetate and distilled water) were used to partition the concentrated crude methanolic extract. The fractions were further diluted by dimethyl sulphuroxide (DMSO). The concentrations used were 100, 50 and 25 mg/ml. Standard method was used to test the antibacterial properties of the fractions against nine clinically important pathogens. Hexane fraction showed no inhibition on Enterococcus faecalis but inhibit other test organisms at 25 mg/ml. Staphylococcus aureus was resistant to aqueous fraction at a very low concentration (25 mg/ ml). Shigella dysenteriae and Escherichia coli were most susceptible to aqueous fraction with zone of inhibition ranging between 18 and 5 mm. Chloroform fraction was the most effective out of the four fractions. Streptococcus sp, Staphylococcus aureus Proteus mirabilis and Escherichia coli were resistant to Ethyl acetate fraction at 25 mg/ml. Ethyl acetate had the least activity on the test organisms. The minimum inhibitory concentration (MIC) ranged between 0 and 25 mg/ml.

Antibacterial activity of partitioned methanolic extract of Alstonia boonei (De Wild) against some medically important pathogens

Evaluation of antioxidant activity, toxicity and antibacterial potential of extracts of Sensevieria aethiopica (Thunb) against bacteria associated with otitis.

Changes in the osmophilic yeast and psychrophilic bacterial counts, proximate and mineral composition of pasteu- rized and unpasteurized fruit juices refrigerated at 4 ± 2 o C were investigated using approved scientific methods. The osmophilic yeast count estimated in freshly prepared unpasteurized juice samples falls within the range of 1.4 x 10 2 cfu.ml -1 and 2.1 x 10 2 cfu.ml -1 . The highest bacterial count ranged between 3.4 x 10 4 cfu.ml -1 and 1.8 x 10 3 cfu.ml -1 in unpasteurized pineapple juice and pasteurized cashew juice respectively. The moisture contents of fresh juice samples were more than 80%. Crude protein, content of the food samples increased by 21.95% and 4.86% in pasteurized orange and unpasteurized cashew respectively. Cashew juice had the highest amount of vitamin C and pineapple juice containing the least. The concentration of iron and po- tassium were highest (11.93 and 5353.94 mg.kg -1 respectively) in fresh unpasteurized orange while calcium content was highest (226.67 mg.kg -1 ) in fresh pasteurized pineapple juice. Except for cashew juice, pasteurization reduces the mineral contents in the juice samples. There was an appreciable percentage reduction in the level of minerals with storage. The nutritional values of the juice samples reduce with the time of storage and the microbial loads also increased. Fruit juices stored at the refrigeration temperature could still pose consumers at risk of food-borne infections.

Nutritional and Microbiological Changes in Fresh Fruit Juices during Refrigeration

Enterococci have been implicated as an emerging important cause of several diseases and multiple antibiotic resistance. However, there is little information about the prevalence of pathogenic and/or antibiotic-resistant Enterococcus faecalis in ready-to-eat foods in Nigeria. Here we report the pathogenic potential of three selected antibiotic-resistant E. faecalis strains isolated from food canteens and food outlets with different virulence determinant genes, including EFC 12 (with gel+, esp+, cylA+, and asa1+), EFT 148 (with gel+, ace+, and asa1+), and EFS 18 (with esp+ and cylA+) in an animal model. Enterococcemia, hematological parameters, and histopathological changes in organ tissues were examined in experimental animals. The results showed differences in enterococcemia and hematological parameters between the control group and experimental animal group. Enterococcemia was observed for 7 days, and the animal group infected with EFC 12 showed the highest growth rate, followed by EFT 148, with the lowest growth rate seen in the EFS 18-infected group. White blood cell count, packed cell volume, and platelets were significantly reduced (P<0.05) in the experimental animals compared with the controls. White blood cells decreased drastically during the study period in rats challenged with EFC 12 (from 7,800 to 6,120 per mm3) but levels remained higher in the control group (from 9,228 to 9,306 per mm3). Histopathological changes included areas of pronounced hemorrhage, necrosis, and distortion in liver tissues, which were more marked in rats infected with EFC 12, followed by EFT 148, then EFS 18. The results of this study suggest the presence of potentially pathogenic E. faecalis strains in food canteens and food outlets; hence, there is a need for strict adherence to good hygiene practices in the study area owing to the epidemiological significance of foods.

Histopathological changes induced in an animal model by potentially pathogenic Enterococcus faecalis strains recovered from ready-to-eat food outlets in Osun State, Nigeria

The carriage of SalmonellaTyphi among Nigerian students is still very high due to very poor hygiene. In this study the prevalence, antibiotic susceptibility of SalmonellaTyphi from the stool of undergraduate students from a Nigeria university was investigated. Salmonella Typhi was isolated from stool samples from 510 subjects. Antibiotic susceptibility test of the isolates was carried out using disk diffusion method. The clinical data (Widal Test) from the University Health Centre records were also collected and analyzed in this study. Out of the isolates, 75.90 % were resistant to ceftazidime, 34.87 % to cefuroxime, 83.59 % to cefixime and 18.46 % to ofloxacin. SalmonellaTyphi isolated exhibited multiple resistance to at least three of the antibiotics tested. The carriage rate of the SalmonellaTyphi among undergraduate students of Ekiti State University, Ado-Ekiti was 33.86%. The clinical data showed the rate of the Salmonella infection among the undergraduate students to be 58.90%. From the clinical record of the University Health Centre, 935 (40.20%) and 1,391 (59.80%) of the students with symptoms of the enteric fever were male and females respectively and only 1370 tested positive to Salmonella antibody. There was a significant difference between the males and the females with the two tails, pvalue = 0.023, F=2.931. The needs for proper educated and the good hygiene cannot be overemphasized.

Prevalence and carriage status of Salmonella typhi among students of Ekiti State University, Ado-Ekiti, Nigeria

The study reports isolation and identification of Escherichia coli from the faecal samples of goats and rams in Ile- Ife, Nigeria. It also determines the antibiotic susceptibility profile, presence of plasmid DNA, resistance ( bla CTX , tetK , tetM ) and virulence ( Stx 1 , eae ) genes in the isolates. Four hundred rectal swabs were collected from goats and rams at three different locations in Ile-Ife. The susceptibility of the isolates to antibiotics was carried out by disk diffusion technique. The amplification of virulence ( eae and stx1 ) and resistance ( tetM , tetK and bla CTX (480 bp)genes in isolates was carried out by polymerase chain reaction. One hundred and sixty-six E. coli comprising rams (96) and goats (70) were recovered. Susceptibility of isolates to antibiotics varied greatly. The highest resistance was recorded against nitrofurantoin in E. coli from ram (97%) and goat (71%). The study revealed that Escherichia coli from rams (85.4%) and goats (87.1%) were multiple antibiotic resistant (MAR) types. The estimated molecular weight of plasmid DNA recovered from the MAR E. coli from rams and goats ranged from 9.41 to 30.84kb. Resistance genes ( tetK , tetM ) and virulence ( Stx 1 , eae ) genes were not harboured by the representative E. coli profiled. The bla CTX (480 bp) gene was detected in only three E. coli recovered from rams. The  incidence of multiple antibiotic resistance in E. coli isolated from apparently healthy goats and rams is high in the study area, hence, indiscriminate use of antibiotics in the animal husbandry sector should be discouraged. Keywords : Escherichia coli , ram, goat, antibiotic, resistant gene, virulence factors

Prevalence of antibiotic resistance and molecular characterization of Escherichia coli from faeces of apparently healthy rams and goats in Ile-Ife, Southwest, Nigeria

Bryophytes are poikilohydric in nature and the oldest known land plant. Their striking resistance to microbial attack suggests their inherent production of antibacterial compounds. The antibacterial activity of acetone, ethanol, methanol and hexane extracts of Calymperes erosum C. Mull and Bryum coronatum Schwaegr were investigated against twenty clinically important bacteria pathogens. Agar dilution method was used to assess the effectiveness of the extracts on the test organisms. The minimum inhibitory concentrations of the extracts of C. erosum were between ˂0.625 and ˃5.0 mg/ml. Klebsiella pneumoniae ATCC 10031, Enterococcus feacalis ATCC 29212, Bacillus pumilis ATCC 14884 and Enterobacter cloaca ATCC 13047 in decreasing order are most sensitive to the extracts while Proteus vulgaris KZN, Staphylococcus aureus OK2 and Shigella sonnei ATCC 29930 were resistant to the extracts. Ethanolic extract was the most effective among the extracts followed by acetone extract. B. coronatum had relatively lower activity. While the mosses screened proved to be promising sources of antimicrobial and biologically active compounds, their toxicity and action mechanism still needed to be investigated.

In Vitro Antibacterial Activity of Two Mosses: Calymperes erosum C. Mull and Bryum coronatum Schwaegr from South-Western Nigeria

Proximity, reliability and age long dependence on traditional medicine for health care delivery together with antibacterial resistance and high cost of antimicrobial drugs call for the validation of the efficacies of the medicinal plants. The effects of six Nigerian medicinal plants, which include Aspilia africana (Pers. C.D. Adams), Asystasia gangetica (L.) T. Anderson, Celosia laxa Schumach & Thonn, Cissus quadrangularis (L), Emilia coccinea (Sims) G.Don and Melanthera scandens (Schumach & Thonn), were investigated. The plants were tested against five bacteria commonly implicated in wound infections using standard methods. The minimum inhibitory concentrations (MICs) of the extracts ranged from 0.625 to 20.00 mg/ml. Extract of A. africana showed the least MIC values against Escherichia coli and Klebsiella pneumoniae (Gram-negative). The MIC of the extracts of C. laxa ranged between 1.25 and 20.00 mg/ml, it was 20.00 mg/ml for both Enterococcus faecalis and Pseudomonas aeruginosa. Staphylococcus aureus was the most susceptible organism to all the extracts of C. laxa. The MICs of ethanolic extract of E. coccinea for P. aeruginosa and S. aureus were 20.00 and 10.00 mg/ml respectively. Antibacterial activity of the plants was in the following increasing order: C. laxa, M. scandens, C. quadrangularis, A. africana, A. gangetica and E. coccinea. Ethanolic extract was the most effective of all the three extracts followed by petroleum ether. Aqueous extract has the least overall activity on the isolates. The inhibition of the common bacteria associated with wound infection by the extract preparations from the plants justifies the claims of the traditional healers in the study area.

In Vitro Antibacterial Assessment of Six Medicinal Plants Traditionally Used In Wound Care in South Western Nigeria

Antimicrobial Activities of Essential Oils fromHura crepitans (L.), Monodora myristica (GaertnDunal) and Xylopia aethiopica (Dunal A. Rich)Seeds

Stool samples from 2,200 patients with gastrointestinal tract (GIT) infections and 900 apparently healthy food vendors were collected in Lagos, Nigeria and examined to determine incidence and distribution of bacterial pathogens using standard microbiological methods. The isolates recovered were identified to belong to seven genera which include Salmonella, Shigella, Escherichia, Proteus, Klebsiella, Vibrio and Enterobacter. Salmonella typhi was the most prevalent, followed by Escherichia coli, while Klebsiella species was the least encountered. Most of the food vendors fell within the age range of 21 years and above constituting 78.4% of the food vendors examined. This study underscores the need to monitor the carriage of enteric pathogens among patients and apparently healthy food vendors. This study further implicates food vendors as a great threat to the health of the public since some of them were carriers of the pathogenic bacteria. Therefore, it is recommended that there should be enlightenment, training for, and vaccination of the vendors accordingly as well as periodic surveillance. 
 
 Key words: Enteric pathogens, patients, infections, food vendors, Salmonella species.

Distribution of enteric bacterial pathogens among patients with gastrointestinal tract infections and food vendors in Lagos, Nigeria

The incidence of methicillin-resistant Staphylococcus aureus (MRSA) in hospitalized patients and apparently healthy individuals was investigated in two western states of Nigeria using standard microbiological methods. One thousand and two hundred non-repeat isolates of S. aureus were recovered from the subjects. At varying degrees the isolates were resistant to cotrimoxazole (54.8%), augmentin (36.9%), pefloxacin (35.9%), gentamycin (28.3%), erythromycin (24.9%), vancomycin (10.3%), ofloxacin (5.2%) and ciprofloxacin (0.3%). One hundred and fifty six (13.0%) were resistant to methicillin out of which 4.8% and 8.2% were from healthy individuals and patients respectively. There was no correlation between prevalence of MRSA and age or sex (p < 0.05). There was no correlation between the antibiotic resistance pattern in MRSA from healthy volunteers and patients (P < 0.05). A total of 9.0%, 12.2% and 21.2% of the MRSA were resistant to 3, 4 and 5 antibiotics respectively. Antibacterial activities of five biocides examined using agar diffusion method showed that 38.5%, 53.2%, 59.6%, 61.5% and 71.8% of the MRSA were not inhibited by Izal®, Morigad®, Septol®, Dettol® and Purit® respectively, at concentrations two times higher than the in-use concentration. This finding points to the fact that MRSA occurs among patients and in the communities in the study areas, which calls for a public health concern and awareness.

Epidemiology of methicillin-resistant Staphylococcus aureus among hospitalized patients and apparently healthy individuals in Ekiti and Ondo States, Nigeria.

The quality of underground water is compromised by the indiscriminate dumping of waste in the environment and contamination by leachate. The effect of the dunghill leachate on the physicochemical and microbial quality of water samples  collected from closest wells to the municipal waste disposing sites were investigated using standard chemical and microbiological methods. Different antibiotics (amoxicillin, amoxicillin clavulanic acid, chloramphenicol, cloxacillin, cotrimoxazole, erythromycin, gentamicin, nalidixic, nitrofurantoin, ofloxacin, streptomycin and tetracycline) were screened against two indicator organisms ( Enterococcus faecalis and Escherichia coli ) isolated from water samples. The distances of the wells from the foot of the nearby dump sites ranges from 85.3 to 25.7 m. The pH values of the water samples ranged between 5.86 and 7.84. The turbidity of the water samples was also between 1.0 and 8.0 NTU. Five heavy metals were detected in the water samples with zinc having the highest value. The observed concentrations of metals in the wells water samples were presented as Zn˃Pb˃Cu˃Co˃Hg. The total bacterial count of the water samples from the well ranged between 2.2 × 10 1 cfu/ml and 2.51 × 10 2 cfu/ml while the coliform load ranged from 9.1 × 10 1 cfu/ml and 1.3 × 10 1 cfu/ml. Cloxacillin and tetracycline were not effective against the most of the E. faecalis isolates. Only 48 (71.66 %) and 53 (88.33 %) E. faecalis strains were sensitive to cloxacillin and tetracycline, respectively. Gentamicin was most effective on E. faecalis . Out of the eight antibiotics tested, ofloxacin was most effective against the pathogen. The quality of the water samples were below the tolerable level and unfit for domestic purposes.

Effect of Open Refuse Dumpsite on the Quality of Underground Water Used for Domestic Purposes in Ado-Ekiti, Nigeria - A Public Health Awareness Study

Nigerian bank notes like other currencies in the world pass through different hands and have been implicated in the carriage of medically important pathogens. This study was undertaken to determine the types of bacteria present on Nigerian currency in Ile-Ife, Osun State, with a view to determining the potential of naira notes as environmental vehicle for the transmission of potential pathogenic bacteria.  Standard microbiological methods were used to isolate, characterize and identify the bacterial isolates from different banknotes. Disc diffusion method was used to determine the sensitivity of the isolates to ten antibiotics. Representative multiple antibiotic resistant isolates were profiled for plasmid deoxyribonucleic acid (DNA). A total of three hundred and five comprising 216 Gram positive and 89 Gram negative bacteria were isolated from two hundred and five bank notes sampled; naira in mint condition was used as control. Thirteen bacterial genera namely Bacillus, Corynebacterium, Staphylococcus, Lactobacillus, Micrococcus, Aeromonas, C itrobacter, Edwardsiella, Klebsiella, Moraxiella, Pseudomonas, Enterobacter and Proteus were recovered. Resistance to antibiotics was generally high and varied among the isolates. Resistance ranged from 18.18% to 100% in Gram negative bacteria and 26.6% to 100% in Gram positive isolates. Enterobacter sp. and Edwardsiella sp. recovered were 100% resistant to all the antibiotics except septrin. All the isolates were resistant to more than one antibiotic. Multiple antibiotic resistant isolates harboured plasmids of various sizes, ranging from 1,356 bp to 17,367 bp in Gram- positive bacteria and 1815 to 23130 bp in Gram negative isolates. Nigerian currency harboured different types of multiple antibiotic resistant bacteria which can be implicated in human infections; hence constituting a potential public health hazard. Keywords : bacteria, multiple antibiotic resistance, currency, plasmids, pathogens, mint

Antibiotic Resistance and Public Health Perspective of Bacterial Contamination of Nigerian Currency

In vitro antimicrobial effects of aqueous, ethanolic and methanolic extracts of Albizia zygia dc leaf against some clinically important bacterial and fungal pathogens were reported. Following extraction of air dried A. zygia dc leaf by different solvents (water, ethanol and methanol), the filtrates were concentrated in vacuo using rotary evaporator. The antibacterial and antifungal activities were assayed by agar diffusion method on Muller-Hinton Agar (Himedia Laboratories Pvt. Ltd, Vadhani) and Potato dextrose agar (Oxoid, Ltd, Bashingstoke, Hampshire, England) plates, respectively. Standard methods were used to determine the time-kill assay of methanolic extract, the amount of protein and potassium ion leaked in the test bacteria. All the extracts (aqueous, ethanolic and methanolic) did not possess any antifungal property. The aqueous and ethanolic extracts were not active against the test bacteria.  Methanolic extract showed significant antibacterial effect on greater percentage of the test bacteria with diameter of zones of inhibition ranging from 3.0 to 21.12 mm at 30 mg/ml and 5.2 to 25.4 mm at 50 mg/ml of the extract. The minimum inhibitory concentration (MIC) of the methanolic extract ranged between 3.75 and 15.3 mg/ml. The methanolic extract of A. zygia leaf showed a significant bactericidal and bacteriostatic activity against Bacillus subtilis and Klebsiella pneumoniae over the time range (15-120 min) at different MIC concentrations. The time-kill assay of methanolic extract of A. zygia against K. pneumoniae was dose dependent. The amount of protein leaked was higher in B. subtilis than K. pneumoniae at 30 µg/ml ( P = 0.05). There was no significant difference in the level of  K + leaked at 15 µg/ml (1 X MIC) and 30 µg/ml (2 X MIC) of the extract. The methanolic leaf extract of A. zygia showed a considerable inhibitory effect on greater percentage of the test bacterial pathogens, but did not possess antifungal property. The antibacterial potential could be harnessed in the folklore management of infections caused by the susceptible test bacteria.

Evaluation of Antimicrobial Activities of Albizia zygia DC Leaf Extracts against Some Clinically Important Pathogens

Aims: Bark, leaves and gum of cashew (Anacardium occidentale L.) have been reported to be effective in curtailing the growing problems of resistance of bacterial pathogens. The in vitro activity of aqueous extracts of cashew apple peels was determined in this study against two clinically important pathogens. Place and Duration of Study: The work was conducted at the Department of Microbiology, Ekiti State University, Ado-Ekiti, Nigeria and processed immediately. This study was carried out between June, 2009 and January, 2010. Methodology: Bioautographic method was used to test the antibacterial activity of aqueous (cold and hot water) extracts of cashew apple peels on Escherichia coli O157:H7 and methicillin-resistant Staphylococcus aureus (MRSA). The zones of inhibition of the extracts were compared. Results: The activity of the fifth hour hot water extract was highest with zones of inhibition of 415.48 and 346.30 sq. mm against E. coli O157:H7 and MRSA respectively. E. coli O157:H7 was more susceptible to the extract with the zone of inhibition ranging between 176.79 and 283.53 sq. mm while that of MRSA was153.94 346.30 sq. mm. The 5 h extract of cold water was more potent on the test organisms with 615.75 and 490.87 sq. mm diameters of inhibition on E. coli O157:H7 and MRSA respectively. Cold water extracts produced more active compounds (13 biologically active spots) that inhibited the growth of the test organisms than the hot water extracts, with six spots. Conclusion: The extracts of the peels of the cashew apple against the test organisms Original Research Article European Journal of Medicinal Plants, 4(3): 284-291, 2014 285 are promising. However, the nature and mechanisms of action of the biologically active compounds in the extracts are still open to investigation.

In vitro antibacterial activity of aqueous extracts of cashew (Anacardium occidentale L.) fruit peels using bioautography method.

Enterococcus faecalis and Enterococcus gallinarum are part of enterococci that carry multiple antibiotic resistance genes. Their occurrence in animal and man has been documented. The occurrence, antibiotic resistance and the virulence factors of the organisms in the faecal samples of six farm animals in Ado-Ekiti, Nigeria was reported in this study. Microbiological methods were used in the isolation and the determination of the virulence factors of the isolates. The antibiotic resistant of the isolates was determined by disc diffusion method. The occurrence of E. faecalis (92.5 %) was higher than that of E. gallinarum (18.8 %) in all the samples. Compared to other virulence factors, the occurrence of gelatinase was highest in both E. faecalis and E. gallinarum. The total E. faecalis strains that expressed both cytolysin and gelatinase were 22 (30.1 %), with the highest among isolates from rabbits. Enterococcus gallinarum strains that produce both gelatinase and heamoagglutinase were only noticed in goat. Only nine (10.8 %) of the total E. faecalis isolates had all the three pathogenic factors. The enterococci isolates had the least resistance against gentamicin while tetracycline showed the least effects on the isolates. Comparatively, E. gallinarum strains were more resistant to antibiotics tested. The isolates were majorly resistant to first line antibiotics. The occurrence of antibiotic resistance among E. faecalis and E. gallinarum with virulence factor(s) is of public health concern.

Virulence factors and antibiotic resistance of Enterococcus faecalis and Enterococcus gallinarum strains isolated from farm animals in Ado-Ekiti, Nigeria.

Aims: The implication of Enterococcus faecalis in dental infections is rising and resistance to common antibiotics continues to rise globally as well. In this study, the association of E. faecalis with different forms of dental infections was investigated and the antibiotic resistance profile of the isolates was determined. Place and Duration of Study: The samples were collected from a tertiary health institution in Ekiti State, transferred to the Department of Microbiology, Ekiti State University, Ado-Ekiti, Nigeria and processed immediately. This study was carried out between June, 2009 and March, 2010. Methodology: Oral interview was conducted among the patients in order to collect relevant data while sterile culturette was used to collect the samples after proper diagnoses, plated and incubated appropriately using standard microbiological techniques. The susceptibility of the isolates to commonly and frequently used antibiotics was determined by the disc diffusion method on Muller-Hinton agar.

Association of Enterococcus faecalis with Different Forms of Dental Diseases among Patients Visiting a Tertiary Hospital in Ekiti State, Nigeria

Aim: Iru is a popular West Africa fermented soup condiment which is also consumed without cooking as snack. This product is mainly fermented by Bacillus species. The hypolipidemic activities of Bacillus spp. isolated from iru have not been documented hence the aim of this study. Place and Duration of Study: Iru sample was bought in an open market in Iworoko-Ekiti, Nigeria and transferred to the Laboratory of the Department of Microbiology, Ekiti State University, Nigeria where other studies were carried out. The study was conducted between January and June, 2012. Methodology: The properties and in vivo hypolipidemic potential of Bacillus species from iru were investigated using standard microbiological and haematological methods. Results: The cell free extracts of the Bacillus spp. did not produce significant inhibition on the selected Gram positive and Gram negative pathogens. Qualitative enzyme screening of the isolates showed all were haemolysin negative. Only respectively. The weights of hyper-cholesterolemia induced rats challenged with different species of Bacillus were relatively lower than those in the control group and also differ significantly from the control, at p˂ 0.05. The values of TC, TG, and LDL were highest in the control (saline) group while the values in the treatment group ranged between 121.3 ± 1.5 and 102.3 ± 6.8 mg/dl for TC. The treatment groups recorded lower values of values for TG (104.7 ± 1.6 - 117.4 ± 9.1 mg/dl) and LDL (42.6 ±7.4 - 59.0 ± 10.2 mg/dl) compared to the control. B. subtilis had the highest values of TC but least amount of LDL. TG in all the groups was higher than TC, HDL and LDL. The TC/HDL and the LDL/HDL of the animals in the iru group was higher than the other treatment groups but lower than the control. Conclusion: Compared to the control, hypolipidemic activities of B. lichenliformis was the best followed by B. subtilis. Iru had the least hypo-cholesterolemic effect.

In vivo evaluation of hypolipidemic potentials of Bacillus species isolated from fermented locust bean (Parkia fillicoides Welw) seeds (Iru).

Background: The presence of Cronobacter sakazakii in infant formula has been commonly reported in the recent time and has been implicated in infection of infants with high mortality rates. Aim: There is paucity of information the occurrence of C. sakazakii in infant formula in the study area hence this study. This work aimed at the determination of aerobic bacterial load and the susceptibility pattern of C. sakazakii isolated from the infant formula and to determine the factors that encourages bottle feeding. Materials and Methods: Standard microbiological methods were used to isolate and identify C. sakazakii and disc diffusion method was used to determine the susceptibility of the isolates to the tested antibiotics. Standard pre-test questionnaire was used to collect information on the pattern of infant formula feeding and breastfeeding among nursing mothers in the study area. Results: The total aerobic bacterial counts of ten different infant formula screened ranged from 1.1x10 2 to 8.0 x 10 3 cfu/g. The least counts occurred in brand CWG whiles the highest was recorded in brand DNN. Out of ten brands of infant formula

Pattern of breastfeeding and occurrence of Cronobacter sakazakii in infant formula sold in Ekiti State, Nigeria

Qualities of poultry feeds produced by local small-scale feed mills in Ekiti State, Nigeria: a public health and feed safety study.

The ability of fermented foods to inhibit the growth of human pathogenic bacteria has been reported. Effect of ogi (fermented maize gruel ) against pathogenic strains of Shigella dysenteriae was investigated ( in vivo ) using standard chemical and microbiological methods. The proximate composition of commercial feeds showed higher amount of total solid (85.82 %), crude protein (16.31 g/100g) and metabolizable energy (1355.09 KJ) than the ogi diet. However, ogi had higher concentrations of Fe, Ca and Mg than the commercial feeds. The commercial feed (CF) supported the growth of the animals better than ogi . The Packed cell volume (PCV) of all the animals ranged from 20.00 to 26.00 % while the challenged animals had lower WBC count than the infected animals. After 4 days of the experiment there was a decrease in the total bacterial count of the faecal materials of the animals compared to initial count, however, the difference was not significant at P˂0.05. Infected animals fed with commercial feeds had the highest microbial load when plated on Salmonella-Shigella agar. Ogi did not encourage the multiplication of Shigella dysenteriae JBA 010 in the animals. Compared to the control and the commercial feed, ogi offered a pronounced protection again the infection of the pathogen.

Effects of Fermented Maize Gruel (OGI) on the Haemato-biochemical Profile of Wistar Albino Rats Challenged with Shigella Dysenteriae JBA 010

Enterococci are lactic acid bacteria that are widespread in nature; they were initially grouped with the genus Streptococcus. Enterococcus species are Gram-positive cocci bacteria that have their applications in food, environment and health care. The presence of Enterococcus faecalis, in water for instance indicates faecal contamination and possible presence of pathogenic organisms. Oral application of probiotic enterococci confers health advantages while antihypertensive effect and amelioration of influenza infection by E. faecalis upon oral administration are beneficial to health. Improvement of intestinal ecosystem disturbed by antibiotic usage has been recorded. However, enterococci have ability to easily possess, amass and distribute genes that code for antibiotic resistance and pathogenic factors. They equally possess virulence factors among which are ability to hydrolyse gelatin, casein, haemoglobin and other bioactive peptides. They also cause agglutination and lyses of erythrocytes. The formation of biofilm on both biotic and abiotic surfaces is a universal survival strategy of enterococci. These organisms also induce the localization of cholesterol to phagosomes and also delay fusion upon infection. These negative attributes enable the organisms to acquire the potential to cause and inflict measurable harms in human. Furthermore, enterococci are intrinsically resistant to many antibiotics and possess ability to acquire and disseminate antibiotic resistance. They are of particular medical relevance because of their implication in both community- and hospital-acquired infections which could be transmitted through many sources. Therefore, man is still in a dilemma over the use of enterococci in food and other related industries owing to their ever increasing medical implications.

Quandary of Enterococci - their beneficial and detrimental roles in food, environment and medicine

The implications of fumonisin B1(FB1) on growth, pubertal development and egg quality of laying hens were studied in a 16-week experiment. 120 Isa-Brown Point-of-lay(POL) birds were divided into four groups. Four diets were prepared to contain 0.2, 5.2, 10.2 and 15.2 ppm of FB1 constituting diets 1(control), 2, 3 and 4 respectively. Each group was assigned to one diet in a completely randomised design .The age at which 50% of the birds on each diet began to lay was considered their pubertal age. Thirty eggs were selected per treatment every week for five weeks to assess egg quality. Results showed that daily feed intake, daily weight gain and feed conversion ratio of the birds were not significantly affected (p>0.05) . Statistically similar values(p>0.05) were obtained for the pubertal ages of the birds. FB1 did not exert any significant influence (p>0.05) on the egg quality traits investigated except the yolk colour of birds on diet 4 which was statistically superior (p<0.05) to those on other diets. Egg cholesterol and triglycerides were not significantly influenced(p>0.0) by FB1 levels. These imply that laying birds can tolerate dietary FB1 up to 15.2ppm without compromising their growth, nutritional and reproductive potentials of their eggs.

Growth performance and egg quality traits of laying hens fed graded levels of dietary fumonisin B 1

The therapeutic and prophylactic effects of fermented maize gruel (ogi) in protecting against and reducing the concentration of Salmonella typhi in rabbits were determined using standard methods. All the experimental animals were fed with commercial diet during the first feed trial. The control group was maintained only on the diet while the first treatment group fed with the commercial diet was later substituted with ogi in the third phase of the trial. The second treatment group was fed with ogi in both the second and third phases of the study. In the second feed trial, the treatment groups were challenged with Salmonella typhi. Infected rabbits that were fed with commercial diets showed high load of Salmonella typhi in the faeces and blood compared to those fed with ogi. The weights gained and food intakes of the animals in the control group were higher than the experimental group. The animals in the first treatment group recorded the least food intake while there was weight loss in the second treatment group. Bacteremia was established in the treatment groups. The level of white blood cells (WBCs) in the rabbits infected with Salmonella typhi but later maintained on ogi, decreased from 4900 mm3 to 4200 mm3. Similarly the WBC count decreased from 7300 mm3 to 6300 mm3 in rabbits that were initially infected (but fed on commercial diet) and later fed with ogi. It could be concluded that ogi could be potent in preventing Salmonella infection and the reduction of microbial load of Salmonella typhi in the blood of the mammals as shown by the microbial and haematological indices.

Evaluation of prophylactic and therapeutic properties of ogi in rabbits infected with Salmonella typhi.

Enterocins are small, heat stable and antimicrobial agents are directed against a broader spectrum of bacteria. Isolation, partial characterization and antibacterial activity of partially purified enterocin from Enterococcus faecalis form the aim of this study. The protein content of crude enterocin of the enterocin from highest producing strain was 16.6 mg/ml and its activity was 170 AU/ml. The antibacterial activity of crude enterocin produced by Enterococcus faecalis was tested on both Gram-positive bacteria which include Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus and Bacillus cereus, while Gram-negative bacteria were Klebsiella pneumoniae, Serratia marcescens, Pseudomonas aeruginosa, Proteus mirabilis, Listeria monocytogenes and Salmonella Typhi. The effect was pronounced on Gram-negative than Gram-positive pathogens. The enterocin was stable at 40, 50, 60 and 70oC and over a pH range between 4.0 and 8.5. It has bactericidal effect and cause rapid inhibition of the growth of the sensitive strains. No change was observed in the enterocin bioactivity after treatment with sodium chloride, magnesium chloride, sodium dodecyl chloride, ethylene diamine tetra-acetic acid and urea. In conclusion, since it can withstand a broad range of temperature and pH, it can be used as biocontrol of both pathogenic and spoilage organisms.

Property and Antibacterial Spectrum of Partially Purified Enterocin Produced by Entrocinogenic Enterococcus faecalis Isolated from the Gut of Cockroach

The study investigated the growth of Enterococcus faecalis in various fruit juice products, their resistance to antibiotics and their ability to be grown in the presence of most organic acids commonly employed as preservatives. E. faecalis strains were isolated from seven out of nine fruit juices using serial dilution and pour plate method. The total bacterial counts observed in the juice samples ranged between 20 to 460 colony forming unit per 100 ml (CFU/100 ml) with the highest and least values detected in fruit juice brands EXT and MNN respectively. The total coliform count in brand EXT exceeded those in all the other samples (275 CFU/100 ml) but enterococcal load in the fruit juices was within the range of 10 CFU/100 ml to 65 CFU/100 ml in MNN and LCS brands respectively. The isolates were all susceptible to vancomycin while resistance was observed to other antibiotics evaluated. Resistance was highest for erythromycin (93%); while penicillin and tetracycline exhibited less resistance (90%). E. faecalis strains isolated from brand TTT (EFTT) FAL (EFFA) and BST (EFBT) were all inhibited at higher concentrations of acetic acid (1.25 and 5.0% w/v) while lower concentrations (0.31% and below) could not effectively inhibit the growth of the isolates. The inhibitory effect of citric acid was pronounced in EFFA. At 0.31% w/v all the isolates were inhibited except EFFA. Benzoic acid had inhibitory effect on just two of the five strains, while formic acid showed no inhibition to all the isolates. EFFA and EFXT were also resistant to ethanoic acid at the different concentrations. Excellent manufacturing practices must be adopted during the production of commercial juice, as appropriate precautions will prevent contamination. Since most organic acids used for the preservation of most juice allow the survival of E. faecalis, there is a need to provide rational basis for designing interventions that are needed to assure the microbiological safety of final products.

Occurrence and implications of resistance to antibiotics and organic acids in Enterococcus faecalis isolated from fruit juices marketed in Ado-Ekiti

The proximate, energy, microbial load of two different owoh samples were determined using standard methods. The enzymatic, haematological and nutritional changes in rats fed owoh samples were also determined. The bacterial loads in the two owoh samples ranged between 4.5 × 106 and 7.5 × 107 cfu/g in Bacillus fermented owoh (BFO) and, 5.7 × 106 and 6.6 × 107 cfu/g in naturally fermented owoh (NFO), respectively. The microbial load in the samples reached the peak value at 72 h of fermentation. Rats fed on diet supplemented with BFO and NFO had average consumption of 10.42 and 8.05 g/rat/day, respectively, while the control (soy meal supplemented) groups recorded 8.49 g/rat/day. At the end of the feeding experiment, the test diets had lower body weight gain compared to the control; though the difference was not significant (p < 0.05). Compared with the control, the rats in the dietary groups had lower organ weight. NFO group had the least amount of packed cell volume (PCV), haemoglobin concentration and red blood cell (RBC) count with the values of 34%, 9.78 g/dl and 6.92 × 106/mm3, respectively. The alanine transaminase (ALT) and aspartate transaminase (AST) ratio were 0.05 and 0.91 for both NFO and BFO, respectively. Test groups had increased amount of AST compared with the control. The values recorded for BFO and NFO were not significantly different from the control. 
 
 Key words: Owoh, condiment, cotton seeds, transaminases, phosphatases, haematological parameters, proximate analyses.

Enzymatic and haematological changes in rats fed owoh : A Nigerian condiment from fermented cotton seeds

Bacteriological analysis of drinking water from streams, wells, taps and sachet water, from Ado-Ekiti using standard methods showed that most drinking water sources are contaminated with pathogenic bacteria. Bacterial species isolated include Escherichia coli (40.44%), Pseudomonas aeruginosa (13.30%), Klebsiella species. (9.02%), Proteus vulgaris (11.01%), Enterococcus faecalis (17.33%) and Citrobacter fruendii (8.89%). The isolates were highly susceptible to ofloxacin. The resistance of P. vulgaris and Klebsiella species were relatively low. Tetracycline, followed by cotrimoxazole, had the least antibacterial effects on the isolates. Escherichia coli and Pseudomonas aeruginosa have similar resistant pattern as did E. faecalis and Klebsiella species. The highest prevalences of resistance were observed with ampicillin, tetracycline, cotrimoxazole and augmentin. Multiple antibiotic resistance was observed in 10% and 12% of Klebsiella species. and E. faecalis respectively and were resistant to six antibiotics. The plasmid sizes in the pathogen ranged between 23130 and 1735bp.

Antibiotic Resistance and Plasmid Profile of Bacterial Pathogens isolated From Drinking Water In Ado-Ekiti, Nigeria

The antimicrobial efficacy of aqueous and ethanolic extracts of ten Nigerian chewing sticks was investigated using standard methods. These extracts were tested against six bacteria associated with dental infections; they are Actinomyces vercosus, Neisseria sicca, Streptococcus mutans, Staphylococcus aureus, Lactobacillus salivarius and Moraxella catarrhalis. Generally, ethanolic extract had higher activity on the test organisms than the aqueous extracts. The zone of inhibition of Viellaria paradoxical (Gaertn. F) ranged between 5 and 13 mm. M. catarrhalis was most susceptible bacterium to the extracts. A. vercosus was resistance to the extract of P. guineense (Schum & Thonn), A. indica (A. Juss) and M. accumunata (G. Don).  
 
 Key words: Chewing sticks, oral hygiene, pathogens, antibacterial activity

In vitro assessment of aqueous and ethanolic extracts of some Nigerian chewing sticks on bacteria associated with dental infections

INCIDENCE OF MULTIPLE ANTIBIOTIC RESISTANCE AND PLASMID CARRIAGE AMONG ENTEROCOCCUS FAECALIS ISOLATED FROM THE HANDS OF HEALTH CARE WORKERS IN SELECTED HOSPITALS IN EKITI, ONDO AND OSUN STATES, NIGERIA

Dissolved heavy metals concentration in water, sediment and tilapia from five fish ponds in Ado-Ekiti, were analysis using standard methods. The water from the fish ponds differed slightly in the concentrations metals. The amount of Fe and Mn in the ponds were not exceeded the recommended range for fish pond. The observed concentrations of metals in the ponds were presented as Zn > Pb > Mn > Cu > Cd. Co and Cr were not detected in all the samples. Mineral deposit in the catchment area of the studied ponds has moderate levels of trace element except Zn and Fe with 91.88 mg/100g and 74.66 respectively. Na was the most abundant mineral detected in the fish samples. It ranged between 243.8 mg/100g and 278.2 mg/100g. The Na/K of the fish from the ponds ranged between 1.01 and 1.29. Disc diffusion method was used to determine antibiotic sensitivity of Enterococcus spp. isolated from the water and the intestine of the fish samples. The resistant pattern of the enterococci isolates varied. The highest resistance was observed in penicillin while the isolates had the least resistance to gentamicin. Most of eisolates (74%) were resistant to more than one of the antibiotic tested. There was no significant difference in the resistance of the isolates from the water and the fish intestine (at p# 0.5). The implications of the results were also discussed.

Levels of heavy and other metals in Tilapia species raised in different ponds and resistant pattern of associated Enterococcus species.

Mycoflora of sundried plantain chips during storage and the effects of these fungi on the nutrient composition of chips were determined. Eight fungi: Aspergillus niger, A. flavus, A. fumigatus, Mucor sp., Neurospora sp., Fusarium sp., Rhizopus sp., and Penicillum sp were found associated with the sundried plantain chips in storage while the freshly prepared chip harbored A. niger, A. flavus, Mucor sp.and Fusarium sp. The various fungi were isolated using washing, direct and dilution methods. The fungal count was found to increase as the time of storage of increased. Moreover, the carbohydrate, crude protein, crude fat and crude fibre of the freshly prepared plantain chips were significantly higher than those of the stored ones. The moisture content, ash and Phosphorus content of the stored sundried plantain chips were significantly higher than the freshly prepared plantain chips. The increase in moisture content and the ash content with storage time may be due to the degradative activities of the fungi present on (and or in) the samples. All the minerals (Na, K, Ca, Mg, Zn, Fe, Mn, Co, Cu and P) assessed were found to be in high concentrations, in the freshly prepared plantain chips than in the stored samples except Phosphorus. 
 
 Key words: Fungi, plantain chips, stored product, minerals, proximate analysis.

Nutritional and mycoflora changes during storage of plantain chips and the health implications

*Corresponding author: Oludele Olanlokun, Laboratories for Biomembrane Research and Biotechnology, Department of Biochemistry, Faculty of Basic Medical Sciences, College of Medicine, University of Ibadan, Ibadan, Nigeria. Tel: 2348038014201 E-mail: jodel72000@yahoo.com All experimental procedures involving animals were conducted in accordance to National Institute of Health guide (#85-23, revised in 1985) and approved by the Department of Pharmacology and Toxicology Ethical Committee on Animal Experimentation. The journal implements double-blind peer review practiced by specially invited international editorial board members.

In vivo antiplasmodial activity of extract and fractions of Trema orientalis in P. berghei-induced malaria in mice

The aim of this experiment was to evaluate the efficacy of Neem seed extract (10% water solution) for tick control in goats in the Kilimanjaro area of Tanzania. Eighteen Small East African (SEA) and Toggenburg (TB) female goat kids between 2.5 and 4 months of age were used in the trial. Goats were divided into two similar groups according to age, body weight and breed composition. Ten treated kids (n = 6 SEA and n = 4 TB goats) and eight controls (n = 4 SEA and n = 4 TB goats) were housed in separate pens for shelter at night, but grazed/browsed together during the day on natural pastures infested with adult and immature ticks. The Neem-treated group was hand sprayed weekly (spot treatment) with a 10% aqueous solution of Neem seed extract to the following regions: perineum, udder, ears and sternum at a rate of 10 mL/kg body weight. The control animals were sprayed weekly with water (10 mL/kg body weight) to the same sites. Neem-treated goat kids recorded significantly lower tick numbers than the control animals, with significantly lower tick numbers and tick bite abscesses in the indigenous SEA goats compared to the goats of the exotic TB breed. Significantly higher tick infestations were recorded on both breeds of goats during the summer rainy season. It was concluded that Neem seed extract is effective in controlling ticks in goats. Further studies are necessary to fully understand the effect of Neem on ticks. Keywords: Ticks, Goats, Neem seed extract 
South African Journal of Animal Science Vol.33(2) 2003: 83-88

The efficacy of a 10% aqueous Neem (Azadirachta indica) seed extract for tick control in Small East African and Toggenburg female goat kids in Tanzania

The aim of this experiment was to evaluate the use of neem seed extract for controlling common cattle ticks of the Ixodidae species. Three bulls and three cows of the Tswana, Brahman and Simmentaler breeds were cleared of ticks using ether and hand-picking techniques. Each animal was then naturally infested with ticks. A 5% (w/v) water extract of neem seed kernel was applied at a rate of 5 g/kg body weight to various anatomical sites on the animals allocated to the experimental treatment, while the control treatment animals were sprayed with tap water. Treated and control animals grazed together and were mustered at weekly intervals for examination. Tick population densities on animals treated with neem seed extract were lower than on untreated animals. Indigenous Tswana cattle harboured fewer ticks during periods of tick abundance than Brahman or Simmentaler cattle. It was concluded that neem seed extract is effective in controlling ectoparasites on livestock.

The efficacy of neem seed extract (Azadirachta indica) to control tick infestation in Tswana, Simmentaler and Brahman cattle

An evaluation of lingering antimycotic effect of miconazole nitrate cream 2% was evaluated on the skin of 20-healthy subjects (16 male and 4 female) after a single dose of application. The test spots were covered with bandage. The tape strippings were taken at various intervals of time from the test area, and applied on the agar surface which was priorly inoculated with Trichophyton mentagrophytes isolated from a patient with the symptoms of onychomycosis. The lingering effect of miconazole nitrate was determined by the degree of inhibition of growth of the fungus under the tape. The test drug showed lingering effect from 36 to 48 hours.

In vitro evaluation of lingering antimycotic effect of 2% miconazole nitrate cream (citaderm) on human skin.

Efficacy of fenbendazole, at doses of 7.5 and 10.0 mg/kg of body weight, against inhibited early 4th-stage larvae of Ostertagia ostertagi and other nematodes of the abomasum and intestinal tract, was investigated in naturally infected yearling heifers in late May 1982. In Louisiana, this is near the end of the period (March to May) in which maximal numbers of inhibition-prone larvae are acquired. The mean numbers of O ostertagi in 10 untreated control cattle were: adults, 4,880; developing 4th-stage larvae, 12,546; and inhibited early 4th-stage larvae, 167,931. At the 7.5 mg/kg dose level (10% liquid suspension) in 10 cattle, percentage reduction of O ostertagi in comparison with controls was: adults, 95.7%; developing 4th stages, 91.1%; and inhibited 4th stage, 55.0%. Percentage reductions of other genera were as follows: abomasum--Trichostrongylus axei, 99.6%; Haemonchus sp, 95.1%; intestinal tract--Cooperia spp, 97.8%; Trichostrongylus colubriformis, 100.0%; and Oesophagostomum radiatum 4th stage and adults, 100.0%. At the 10.0 mg/kg dose (10% liquid suspension) in 11 cattle, the percentage reduction of O ostertagi in comparison with controls was: adults, 98.6%; developing 4th stages, 92.9%; and inhibited 4th stage, 80.0%. Percentage reductions of other genera were: abomasum--T axei, 99.9%; Haemonchus sp, 98.8%; intestinal tract--Cooperia spp, 99.3%; T colubriformis, 100.0%; and Oes radiatum 4th stage and adults, 100.0%. Variability of efficacy against inhibited larvae was observed, particularly at the 7.5 mg/kg dose; at this dose, 7 of the 10 heifers in the group yielded in excess of 54,000 surviving larvae.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of fenbendazole against inhibited larvae of Ostertagia ostertagi in yearling cattle.

Assessment of full and subsyndromal PTSD and quality of life of internally displaced older adults in northern Nigeria

Background: Psychoactive substance use is frequently encountered in hospitals' emergency departments (EDs). It accounts for major health-care problems frequently leading to accident and ED admissions, yet it is frequently unidentified. The aim of this study was to determine the prevalence and pattern of psychoactive substance use among patients presenting in the Accident and EDs and to compare the case detection rate of psychoactive substance use between self-report questionnaire and biochemical markers (e.g., urine toxicology). Methods: To achieve this, 200 consenting participants attending the accident and emergency unit of a tertiary hospital were consecutively enlisted into the study within 2 weeks. They were screened for psychoactive substance use with the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) and the urine drug test (UDT). Results: The lifetime prevalence of psychoactive substance use was 45.5%, while the past 3 months (recent use) prevalence was 27.0%. The pattern of psychoactive substance use revealed that alcohol was the predominant psychoactive substance use with a lifetime prevalence of 13.0% and recent use of 12.0%. The UDT significantly detected more patients who used psychoactive substance compared to self-report (P < 0.001). Conclusion: The prevalence of drug use recorded among attendees of the accident and emergency unit was high in this study. The UDT significantly detected more patients who used psychoactive substances compared to self-report (P < 0.001). Several patients with major health problems as a result of psychoactive substance use were identified with the aid of these screening tools.

Use of psychoactive substances among patients presenting at the emergency department of a tertiary hospital

The association between anxiety and cardiovascular events in patients with cardiovascular disease (CVD) has shown anxiety disorders to increase the risk of major cardiac events and mortality, anxiety disorders have also been linked to the onset, progression and prognosis of CVD. Therefore, this study was aimed to determine the prevalence and correlates of generalised anxiety disorder (GAD) in patients attending the cardiology clinic of Benue State University Teaching Hospital (BSUTH). It was part of a larger study conducted among 106 consenting participants within the period of June 2017 to August 2017. The result shows that 54(50.9%) of the respondents were female while 52 (49.1%) were male. Twenty-eight (26.4%) were married, 15(14.2%) were single while 63(59.4%) were previously married. Eight-two (77.4%) of the subjects were diagnosed with hypertension, Rheumatic heart disease was diagnosed in 8(7.5%) subjects, heart failure 3 (2.8%) and cardiomyopathy 9(8.5%). Thirty-two subjects were diagnosed with GAD representing a prevalence rate of 30.2%. Generalised anxiety disorder was significantly associated with female gender (p=0.001), marital status (p=0.008), unsatisfactory relationship with sexual partner (0.001), history of substance use (p=0.001), and low level of occupational status (p=0.026). However, there was no statistically significant association between GAD and body mass index -BMI (p=0.139), as well as the nature of a cardiovascular diagnosis (p=0.703). The authors, therefore, recommended a detail psychiatric/psychological evaluation of patients with CVD to enhance early detection and treatment for a better outcome and quality of life.

Generalised Anxiety Disorder and Cardiovascular Disease: A Study at a University Teaching Hospital in North-Central Nigeria

The prolonged Boko Haram crises in North-East Nigeria caused serious displacement and left the survivors with multiple psychological consequences such as Posttraumatic stress disorder (PTSD). A high prevalence rate of PTSD among Internally Displaced Persons (IDPs) has been reported across literatures. This study aimed to determine the factors that are associated with PTSD and its relationship with functional disability among IDPs in Yobe State, Nigeria. This was a cross sectional study of 450 respondents, recruited using a systematic sampling method. We used Harvard Trauma Questionnaire to screen for symptoms of PTSD and definite diagnosis made with WHO Composite International Diagnostic Interview (CIDI), PTSD Module. Hopkins Symptom Checklist was used for symptoms of depression and definite diagnosis made with CIDI Depression Module. The WHO Disability Assessment Schedule 2.0 was used to measure functional disability. There were 192 (45.5%) males and 230(54.5%) female respondents. The mean age of respondents was 39.4±18.50 years with range of 18-80 years. Significant PTSD symptoms were found among 159(37.7%) of the IDPs while Clinical interview gave a definite prevalence of 18.5%. Two hundred and forty-four (57.8%) of the respondents had disability scores in the mild range, 17.5% in the moderate range while 20.7% were in the severe range. Majority of those with disability scores in the severe range had PTSD. Factors significantly associated with PTSD were age, marital status, duration of displacement, type of abode, general living condition, self-reported general health, and disability score. A High prevalence rate of PTSD was found among IDPs and the severity of disability correlated well with having diagnosis of PTSD in the study.

Post-traumatic Stress Disorder and Functional Disability among Internally Displaced Persons in North-East Nigeria

Background: Alcohol related sexual assault is a growing epidemic world wide that affects mainly women. There is urgent need to empower women to identify behaviors and situations that may predispose them to sexual victimization. Objectives: The study was carried out to determine the relationship between binge drinking and sociodemographic factors. It also assessed the relationship between binge drinking and sexual assault. Methods: The cross-sectional descriptive study was carried out in Jos North Local Government Area from March to July, 2017. Multistage sampling technique was employed to select 272 participants aged 18 years and above who consented after obtaining ethical approval. Results: The total numbers of participants were 272 females with an age range of 18-60 years. The mean age was 28.8 ± 8.6 years. The socio-demographic variables significantly associated with binge drinking were marital status ( X 2 = 9.847, DF = 2, p = 0.007), educational status ( X 2 = 10.684, DF = 3, p = 0.014) and employment status ( X 2 = 5.122, DF = 1, p = 0.024). Binge drinking was significantly associated with sexual assault ( X 2 = 10.732, DF = 1, p = 0.001). Previously married were significantly more likely to binge drink compared with never married and married. Those with no formal education were more likely to binge drink compared to those with tertiary education while the unemployed were less likely to binge drink compared with the employed. The sexually assaulted (P = 0.01, OR = 2.429, CI = 1.419-4.157) were 2 times more likely to binge drink. Conclusion: There was a significant relationship between binge drinking with marital status, employment, lower level of education and sexual assault. Women should be provided with information about the safe level of alcohol consumption and the many consequences of heavy drinking including sexual assault. Keywords: Binge drinking, women, sexual assault, socio-demographic, Jos

Binge drinking and sexual assault among women in Jos Metropolis, Nigeria

Background: A large number of youth are often directly involved in armed-conflict, and therefore are at greater risk of developing a wide range of mental disorders including posttraumatic stress disorder (PTSD). However little is known about the prevalence of PTSD among youth who constitute a large work force. Objective: This study was carried out to assess the prevalence of posttraumatic stress disorder among Internally Displaced youth exposed to Boko Haram terrorism in North-Eastern Nigeria. It also assessed the socio-demographic factors associated with PTSD in this population. Method: A cross-sectional study that employed a consecutive sampling technique to select eligible subjects undergoing a Citizenship and leadership training at Citizenship and Leadership training institute Jos, Plateau State. The posttraumatic stress disorder module of Mini International Neuropsychiatric Interview was used to assess for current symptoms of PTSD. Results: The results show that more than two-third of the respondents were unemployed youth with secondary level of education and had low or no stable income. More than 63% of the respondents were diagnosed with PTSD. Educational status (p=0.002), marital status (p=0.001) and income before displacement (p=0.010) were the significant factors associated with PTSD. Conclusions: The results point to the importance of screening and treatment for traumatic armed conflict victims, with particular attention to youth who had low education and low income levels as well as being never married or widowed. Keywords: PTSD, sociodemographic factors, Bokoharam terrorism, North Eastern Nigeria

Posttraumatic stress disorder among internally displaced victims of Boko Haram terrorism in north-eastern Nigeria

A common factor in the development of mental disorders, including depression, is exposure to trauma. Boko Haram crisis has ravaged the North East part of Nigeria and has left indelible traumatic effect on the inhabitants especially the Internally Displaced People (IDPs) who fled their homes for survival. Previous studies reported high rates of depression and disability among IDPs. We set out to investigate the prevalence of depression, disability and correlates among the IDPs in two selected camps in Yobe state. We carried out a cross sectional study among 422 adult IDPs selected through a systematic sampling method. One hundred and ninety two (45.5%) were males. The mean age of the subjects was 39.4±18.50 years with range of 18-80 years. Of the 422 IDPs, 166(39.3%) had probable depression and 76(18.0%) had definite depression. Factors significantly associated with diagnosis of depression were; age (p=0.028), marital status (p=0.001), living condition (p=0.001), general health (p=0.001) and WHODAS 2.0 scores (p=0.001). Logistic regression revealed that age <20years (OR=8.4;p=0.001), being an IDP in the camp irrespective of the living condition (OR=3.6;p=0.001), being single/unmarried (OR=10.0;p=0.048) and comorbid PTSD predicted diagnosis of depression. Having a disability score in the severe range (OR=5.7;p=0.001) strongly correlated with having depression in the study. There is a high rate of depression among IDPs in North-east, Nigeria. Having a diagnosis of depression correlated well with the severity of disability in study. We recommend regular psychiatric services as part of routine medical services to IDPs as health cannot be complete without mental health.

Functional Disability and Depression among Internally Displaced Persons in North-East Nigeria

Long duration of hospitalisation has been associated with negative consequences of isolating the patients from their social network, initiating maladaptive patterns in the patients and worsening the burden of care on the relatives. In this particular study, we were interested in determining factors that correlate with length of stay on admission among in-patients receiving psychiatric services in North-Central Nigeria. The prospective study was part of a larger in-patients study conducted on 112 consenting patients admitted in the psychiatric wards of Benue State University Teaching Hospital Makurdi, Federal Medical Centre Makurdi and Jos University Teaching Hospital Jos during the study period. Patients who stayed on hospital admission for more than twenty-eight (28) days were classified as ‘long stay’, conversely, those who were discharged from admission after spending 28 days or less were referred to as ‘short stay’ patients. A total of 112 subjects were recruited for the study, 67(59.8%) were female while 45(40.2%) were male, the mean age was 36.98±11.09 years and 54(48.2%) subjects were still married at the time of the study. Forty-two representing 37.5% of the respondents stayed on admission for more than 28 days. The mean duration of stay was 28.8±24.5 days. Long duration of stay was found to be significantly associated with the quality of intimate partner relationship (p=0.001), years of completed education (p=0.021), age group (p=0.001), nature of psychiatric diagnosis (p=0.014), pharmacotherapy (p=0.001), comorbid physical condition (p=0.001), previous admission (p=0.001), defaulted treatment (p=0.001), frequency of previous episodes (p=0.001) and the number of years a patient has had the mental disorder (p=0.001). We concluded that, assessing duration of stay on admission among in-patients treatment for psychiatric disorders is very necessary.

Correlates of Psychiatric Inpatients Length of Stay in North-Central Nigeria

Depression has been consistently associated with cardiovascular disease (CVD), it is also known to play an essential role in the initiation and exacerbation of CVD. This study was aimed to determine the prevalence and correlates of depression among patients attending the cardiology clinic of the Benue State University Teaching Hospital (BSUTH), Makurdi. The study was conducted among one hundred and six (106) consenting patients attending the cardiology unit of BSUTH from June to August 2017. The result shows that, 52(49.1%) were males while the remaining 54(50.9%) were females. The mean age of the respondents was 53.48±14.77years, twenty-eighty respondents representing 26.4% were married at the time of the study, 15(14.2%) were single while the remaining 63(59.4%) were previously married. Thirty-seven (34.9%) of the study subjects had no formal education and eighty-two (77.4%) of the presentation at the clinic were having a diagnosis of hypertension, 8(7.5%) were being treated for Rheumatic Heart Disease (RHD), 9(8.5%) were diagnosed with cardiomyopathies, 3(2.8%) were diagnosed heart failure and 4 (3.8%) had other cardiovascular diseases. The prevalence of depression was found to be 45.3% in this study, there was a statistically significant relationship between the diagnoses of depression and gender status (p=0.001), marital status (p=0.01), partner relationship (p=0.001), substance abuse (p=0.001). No statistically significant relationship was found between depression and occupational status (p=0.167), level of educational attainment (p=0.401), respondents’ weight (p=0.06), and the nature of cardiovascular diagnoses (p=0.951). We recommended early detection and treatment of depression among patients with cardiovascular diseases.

A Cross-Sectional Descriptive Study of Depression among Patients Attending the Cardiology Clinic of a University Teaching Hospital in North-Central Nigeria

Armed-conflict and posttraumatic stress disorder among heads of households in Dogonahawa, North-Central Nigeria.

The patterns of alcohol consumption among females  is of enormous public health concerns, as harmful consumption poses danger to their health, welfare, children and to the civil society. The study objectives were to determine the current prevalence of alcohol use, the related socio-demographic factors and the patterns of alcohol consumption. It was a descriptive cross-sectional study in Jos North Local Government Area, carried out from March to July, 2017 after ethical clearance was obtained. A multistage sampling technique was employed to select the participants who were age 18 years and above. A total of 272 females with an age range of 18 to 60 years responded. The mean age was 28.8±8.6 years. Majority 112(41.2%) were in the age group of 25-34 years. Most of them were never married 168 (61.8%), protestants 151(55.4%) and had secondary education 97(35.7%). About half of them were employed (148(54.4%) with 167(61.4%) of them earned an average monthly income of 20,000 naira or less. One hundred and fifty nine (58.5%) use alcohol in the family. The estimated prevalence of life time use, current use and abstention were 79.4%, 41.2% and 20.6% respectively. Of the current users 35(31.1%) were low risk while hazardous, harmful and dependent users were 30(26.8%), 21(18.8%) and 26(23.2%) respectively. The sociodemographic variables associated with current alcohol use were history of family use (χ2 = 3.088, df = 1, p = 0.01) and educational status (χ2 = 8.797, df = 3, p = 0.03). These findings call for immediate advocacy and sensitization of awareness concerning prevention, treatment and rehabilitation to stem the tide of deleterious patterns of alcohol consumption among females in the community.

Patterns of Alcohol Consumption and Socio-Demographic Factors among Women in North Central Nigeria

Background: Over the last 45 years, mortality due to suicide has increased in some developed and developing countries among both adults and young people. Suicide has also been reported to be high for individuals with substance abuse, mood and personality disorders, and relatively low rates were reported for patients with anxiety disorders. This study was therefore to determine the socio-demographic and clinical factors associated with the risk of suicide among psychiatric in-patients in North-Central Nigeria. Objective: The aim of this study is to look at the socio-demographic and clinical correlates of having suicide risk among psychiatric in-patients. Method: This is a cross-sectional descriptive study conducted on 112 in-patients admitted in the psychiatric wards of BSUTH Makurdi, FMC Makurdi and JUTH Jos during the study period of July to September, 2017. Every consecutive in-patient who consented for the study was assessed with a proforma carefully designed by the authors to measure socio-demographic and clinical attributes. Suicide risk was determined using the 'Suicidality Module' of Mini International Neuropsychiatric Interview (M.I.N.I.). Results: Forty-five (40.2%) were males while 67(59.8%) were females. The mean age was 36.98 ±11.09 years, fifty- four (48.2%) subjects were still married at the time of the study. Eighty subjects representing 71.4% of the respondents reported having low (46), moderate (16) or high (18) suicide risk. Having a risk of suicide was significantly associated with the history of default ( p =0.001), previous episodes of illness ( p =0.005), co-morbid diagnosis ( p =0.001), long duration of illness ( p =0.001), and not having a good relationship with sexual partner ( p =0.002). Conclusion: The study justifies the need for the assessment of suicide risk among in-patients with high degree of suspicion. Keywords: Suicide risk, in-patient, correlates

Suicide risk among psychiatric in-patients in north-central Nigeria

Substance abuse and dependence are frequently encountered in emergency units of our hospitals, and it accounts for major health care problems frequently leading to accident and emergency department admission, though it is often missed or not diagnosed. The aim of this study was to estimate the prevalence of drug abuse and dependence among patients attending Accident and Emergency Hospitals and to determine the sociodemographic characteristics of these patients with substance use disorders. A total of 200 consented participants attending the accident and emergency unit of the hospital were recruited into the study consecutively over a 2-week period. They were screened for psychoactive substance use disorders (PSUD) with Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) and urine drug test (UDT) in the first phase and the Mini International Neuropsychiatric Interview (MINI) Instrument was used to make definitive diagnosis in the second stage. The result revealed that the prevalence of substance use disorders was 19.0% (13.0% for substance abuse and 6.0% for substance dependence). The study found that being male (p <0.001), widowed (p ≤0.012), and Christian (p ≤0.006) were associated with substance use disorders among patients presenting at accident and emergency units. The authors concluded that the prevalence of substance use disorders recorded in this study is higher compared to previous study conducted by Mustafa et al in Egypt with 11.5%.  The reason could be due to inclusion of biochemical test (urine drug test) in our screening, whereas only self-report questionnaires were used in their study.

Prevalence of Substance Use Disorders among Patients of Accident and Emergency Department of a University Teaching Hospital

Objective: The study was undertaken to examine the association between PTSD and Sociodemographic factors. It also determined the association between trauma exposure with and without PTSD and Alcohol Use Disorders.Method: The cross-sectional descriptive study was carried out from March to July, 2017. Multistage sampling technique was employed to select participants who consented aged 18 years and above after ethical clearance was obtained. The data was collected using Sociodemographic questionnaire, OSLO-3 social support scale, AUDIT and PTSD Modules of MINI.Results: A total of 272 females with an age range of 18 to 60 years responded. The mean age was 28.8 ± 8.6 years. Majority 112(41.2%) were in the age group of 25-34 years. Most of them were never married 168(61.8%), protestant 151(55.5%) and had secondary education 97(35.7%). About half of them were employed 148(54.4%) with 167(61.4%) of them on an average income of 20,000 naira or less. Perceived social support was reported as good by 133(41.5%) and poor by 159(58.5). fifty seven (21.0%) of participants fulfilled the criteria for PTSD. Majority 188(69.9%) reported at least one life time traumatic experience. Sociodemographic variables significantly associated with PTSD are; marital status (χ2=11.671, DF=2, P=0.003), educational level (χ2=11.485, DF=3, P=0.009) and social support (χ2=5.391, DF=1, P=0.020). Of those who reported exposure to traumatic event 131(69.7%) did not develop PTSD but 57(30.3%) developed PTSD. Sixty nine (36.2%) engaged in binge drinking and 68(36.2%) had alcohol use disorders; all were significantly associated with exposure to trauma with or without PTSD.Conclusion: Prevention and intervention efforts should be broadened to include those who are exposed to trauma with and without PTSD seeking treatment in the community and to screen for alcohol use disorders especially among women who were previously married with lower levels of education.

Trauma Exposure, Posttraumatic Stress Disorder and Alcohol Use Disorder among Females in Jos, North Central Nigeria

Background and Aim: Research has shown that 30% - 70% of people who have lived in war zones suffer from symptoms of depression, with exceptionally high rates documented among heads of households. Thus, this study aims to determine the prevalence and correlates of depression among victims of armed-conflict in Dogonahawa, North-Central Nigeria. Methods: A multistage sampling of households was employed to select 270 respondents aged ≥ 18 years. A face-to-face interview was conducted using the Revised Beck Depression Inventory-11 to collect data on depression. Results: The prevalence of depression was 38.5% in all respondents, 45.2% and 28.6% among heads of households and the dependants respectively. The odds of having depression was more than twice among heads of households with income below N20,000.00 compared to those earning above N50,000.00(OR = 3.02, P = 0.253), but was decreased among males, those engaged in professional jobs and those with household size of less than five members compared to females, being engaged in non professional jobs and having more than five household members respectively(OR = 0.198, P = 0.002; OR = 0.049 and OR = 0.199; P = 0.012 and OR = 0.193; P = 0.001 respectively). Conclusion: The results point to the importance of disaster preparedness generally and specifically, with particular attention to household heads who are females, non professionals, with low income and larger household size.

Armed Conflict and Depression among Heads of Households in Dogonahawa, North-Central Nigeria: Prevalence and Correlates

Background: Depression is one of the leading causes of disability including impairment in the subjective Quality of Life (QOL) of the patient. Unfortunately, only a fraction receives the correct diagnosis and treatment in general practice. This study aims to determine the subjective Quality of Life of depressed patients. Method: A representative sample of adults, 18 years and above (100 each for cases and controls), were assessed for QOL using the World Health Organization Quality of Life instrument (WHOQOL-BREF). Respondents were also evaluated for socio-demographic factors. Major depressive disorder was assessed using the Mini International Neuropsychiatric Interview. Severity of depression was measured using Hamilton’s Rating Scale for Depression and global functioning was assessed with the Global Assessment of Functioning scale. Results: Majority of the participants were females (62.0%) and young with a mean age of 39.11 ± 12.40 years. Overall subjective QOL (P P P P P P < 0.001) in depressed patients compared to healthy control. Conclusion: The finding of the study showed that depression is a serious illness that affects the patient’s perception of the quality of his/her life. It is therefore very necessary to innovate better treatment modalities to reduce its burden.

A Case Control Study of Subjective Quality of Life in Outpatients with Depression

Background : Survivors of mass violence are at high risk of developing a wide range of psychological disorders. Nevertheless, little is known about the impact of trauma in post conflict low-income countries where armed conflict abounds. Objective : This study was carried out to assess the prevalence of comorbid  depression among victims of armed- conflict in Dogonahawa, north-central Nigeria who developed posttraumatic stress disorder (PTSD) and those who did not. It also assessed the socio-demographic predictors for comorbid depression among those who developed PTSD. Method : A cross-sectional study that employed a multi stage sampling technique to select eligible subjects in Dogonahawa, north-central Nigeria. The PTSD module of Mini International Neuropsychiatric Interview (MINI) was used to assess for current symptoms of PTSD, while the Beck Depression Inventory-II (BDI-II) was used to assess for depression. Results : The results showed that 55.5% and 44.7% of the respondents had PTSD and PTSD with comorbid depression respectively. The difference in prevalence was statistically significant with adults diagnosed with PTSD in this community being significantly more likely to experience comorbid depression than those without PTSD (p< 0.001). Being a female gender and being the head of household were found to be the predictors for comorbid depression among respondents with PTSD. Conclusions : Mental health consequences of conflict continued to endure four years after the armed conflict. In the light of the above, mental health emergency  interventions after exposure to traumatic event need to be developed to enhance healing and recovery. KeyWords : PTSD, co-morbid depression, sociodemographic predictors, depression, Armed, Conflict, Dogonahawa

Sociodemographic predictors of depression among survivors of armed conflict with posttraumatic stress disorder in Dogonahawa, north central Nigeria

Background : Good level of functioning is an asset that individuals have used to create wealth and perform social activities. Depressive disorders, no matter how mild, have a negative toll on how individuals perform or enjoy such social or economic endowments. The study was aimed at determining the relationship between severity of depression and global functioning. Methods : The cross-sectional study included 100 depressed adult outpatients. A variety of measures including the Mini International Neuropsychiatric Interview (MINI) was used to diagnose depression while the Hamilton Rating Scale for Depression (HRSD) and Global Assessment of Functioning (GAF) scale were used to rate the severity of depression and measure the degree of functioning respectively. Results : Forty-two percent of the study participants were still depressed. Out of this number, 47.6% were in remission, 40.5% had mild symptoms while 7.1% and 4.8% had moderate and severe depressive symptoms respectively. Majority (93.1%) of those who had achieved full remission exhibited superior functioning compared to those who were still experiencing one symptom or the other. A statistically significant association (p<0.001) was found between severity of depression and level of functioning. Conclusion : Severe depression is associated with poor functioning among patients. Functional improvement should therefore be one of the targets of treatment by physicians. Key words : Functioning; Severity; Depressive disorders

Functional disability as a measure of severity in depressive disorders

Background :  Nonadherence with medications is a complex but significant problem that directly and indirectly affect psychiatric patients as well as the overall health care system. It is associated with increased symptoms, deterioration of functioning, suicide, violence and rehospitalisation. Methods : Patients attending psychiatric clinic at Jos University Teaching Hospital were consecutively recruited and interviewed using the Medication Adherence Rating Scale (MARS) and a patient questionnaire to obtain data on patient's adherence and attitude towards their medications. The study sampled 195 clients aged 18 years and above. Results : The study found a subjective adherence level of (32.8%) and objective adherence level of (49.7%) among psychiatric outpatients revealing a high rate of non-adherence. Factors relating to non-adherence included lack of finance, side effects and denial of the illness. Level of non-adherence for various diagnosis were; schizophrenia(65.5%), drug related cases(50.0%), Bipolar affective  disorder(36.5%), Major depressive disorder(38.1%) and anxiety disorders(33.3%). Seizure disorder(28.6%) and dementia(28.6%). Conclusion : High rate of non-adherence exists among patients with mental illness and is similar to other chronic illnesses. It is highly recommended that clinicians must take time to discuss the possible side effects of medications with their patients as this could reduce the rate of non-adherence. Key Words ; Jos, Medication, Adherence, Psychiatry, Patients

Medication adherence among psychiatry out patients in Jos University Teaching hospital

Background: Improving Quality of Life (QOL) is the ultimate goal of treatment for patients with depression. A large store of studies have shown that depression affects the overall quality of life of patients due to its negative impact on mood, energy and pleasure. Though the effects of depression is well documented, evidence also revealed that sociodemographic variables such as age, gender, education, income etc. may also predict quality of life. The aim of the study was to determine the impact of sociodemographic factors on the quality of life depressed patients and also to assess the predictors of patients' subjective QOL. The aim of this study is to determine the impact of sociodemographic factors on the quality of life of depressed patients, and also to determine the predictors of patients' subjective QOL. Methodology: This is a cross-sectional study of depressed outpatients over a period of 6 months. Sociodemographic variables was obtained using a self-reported questionnaire designed by the researchers. Diagnosis of depression as well as severity of depression were assessed with the Mini International Neuropsychiatric Interview questionnaire and Hamilton Rating Scale for depression respectively. Quality of life measures was assessed with the World Health Organization Quality of Life Brief Version (WHOQOLBREF). One hundred patients were recruited for the study. Results: As many as 64.0% of the subjects were females while 36.0% were males. The mean age of the subjects was 39.78 years (SD±13.36). Maximum income of subjects was N50,000.00 ($139.00) per month. Among the subject, 42.0% were still depressed with majority (61.9%) in remission, 26.2% in mild, 7.1% in moderate and 4.8% in severe stages of depression. Overall QOLwith respect to sociodemographic factors was statistically significant (P=0.001). Gender (P=0.001), age (P<0.001), marital status, (P<0.0010), and number of depressive episodes all yielded significant outcome. Conclusion: Depression is a debilitating illness which reduces general wellbeing. Improving social and economic factors which adds to further impair QOL as revealed by our study will reduces the added burden on the patient. Keywords: Major Depression,Quality of Life, Determinants

Sociodemographic determinants of quality of life among patients with major depressive disorders

Background: Survivors of mass violence are at high risk of developing a wide range of psychological disorders. Nevertheless, little is known about the impact of trauma in post conflict low-income countries where armed conflict abounds. Objective: This study was carried out to assess the prevalence of comorbid depression among victims of armedconflict in Dogonahawa, north-central Nigeria who developed posttraumatic stress disorder (PTSD) and those who did not. It also assessed the socio-demographic predictors for comorbid depression among those who developed PTSD. Method: A cross-sectional study that employed a multi stage sampling technique to select eligible subjects in Dogonahawa, north-central Nigeria. The PTSD module of Mini International Neuropsychiatric Interview (MINI) was used to assess for current symptoms of PTSD, while the Beck Depression Inventory-II (BDI-II) was used to assess for depression. Results: The results showed that 55.5% and 44.7% of the respondents had PTSD and PTSD with comorbid depression respectively. The difference in prevalence was statistically significant with adults diagnosed with PTSD in this community being significantly more likely to experience comorbid depression than those without PTSD (p< 0.001). Being a female gender and being the head of household were found to be the predictors for comorbid depression among respondents with PTSD. Conclusions: Mental health consequences of conflict continued to endure four years after the armed conflict. In the light of the above, mental health emergency interventions after exposure to traumatic event need to be developed to enhance healing and recovery.

overall. Previous findings suggest that symptoms of depression and PTSD in the aftermath of exposure to traumatic events may best be conceptualized as a single general traumatic stress

Background : Rape is common throughout the world. It is often under-reported by victims and their families for fear of social stigma and cultural sanctions. Several studies have revealed that majority of rape victims are females, with males being the most perpetrators. Objectives : The study was aimed at determining the prevalence of rape and to examine the psychological and social consequences as well as responses to rape by the victim, the family and society. Methods and Materials : The study was a cross-sectional descriptive study of 284 respondents from 4 communities in Jos, Plateau State Capital, Nigeria. A semi-structured socio-demographic questionnaire was used to collect participants’ socio-demographic data while a questionnaire on rape designed by the authors was used to enquire about rape and other associated factors. The Mini International Neuropsychiatric Interview (MINI) questionnaire was used to determine the psychological consequences of rape. Results : The result revealed a rape prevalence of 31.0% (28.2% in females and 2.8% among males). Rape was statistically associated with young victims (P<0.001). Majority (59.1%) of the victims were raped before 16 years of age. Rape by neighbors/family friends accounted for 50% of all cases involving female victims while that by strangers was 15%. A large proportion (63,6%) of the victims were raped once, 13.6% were raped more than thrice. All female victims were raped through the vagina (81.2% with penis and 18.8% by fingering). The male victims were raped with penis through anal orifice. Only 9.2% were gang raped. About two-thirds of the victims did not report to anyone, but, 36.4% did so. As high as 49.8% of the respondents believed there was no justification for anyone to rape another person just as others cited seductive dressing, substance abuse, and moral decadence as factors that contribute to the offence. Negative psychological and social consequences such as depression, anxiety, post –traumatic stress disorder, social isolation, loss of trust etc were found to be associated with rape. Conclusion : The study showed that rape is a serious problem in our community and therefore urgent measures must be put in place to deal with its increasing prevalence and consequences.

Prevalence and Psychosocial Consequences of Rape in Jos, North–Central Nigeria

CONTEXT
Posttraumatic stress disorder (PTSD) is the most common consequence of traumatic experiences. The North Central Nigeria to which Plateau State belongs has witnessed many ethno-religious crises. While previous studies suggested a high prevalence of PTSD among students, to the best of our knowledge, no such study has been reported in Nigeria.

AIMS
The study aimed to determine the prevalence and correlates of PTSD among medical students in a university.

Cross-sectional systematic random sampling was used to select 200 medical students. A two staged interview with questionnaire on sociodemographic variables, PTSD Checklist-Civilian Version, Impact of Event Scale, and Composite International Diagnostic Interview was carried out.

STATISTICAL ANALYSIS USED
SPSS Inc. Released 2007. SPSS for Windows, version 16.0. Chicago, SPSS Inc. was used for statistical analysis.

RESULTS
Prevalence of PTSD among the students was 23.5%. Previous childhood trauma and personal experiences during the crisis were significantly associated with having PTSD.

High prevalence rate of PTSD among medical students in Jos is an indicator of psychological consequences of the recurring crises on the inhabitants. There is a need for follow-up and counseling/trauma healing for those identified.

Prevalence and correlates of posttraumatic stress disorder among medical students in the University of Jos, Nigeria.

Substance abuse does not only increase susceptibility to HIV/AIDS through high risk Sexual behaviors but it also hastens the progression of the disease among infected persons than in those who do not abuse drugs. Furthermore, drug use impairs adherence to antiretroviral therapy (ART) leading to reduction in ART effectiveness and ultimately increased HIV-related mortality. In North Central Nigeria there is a dearth of information concerning the influence of substance abuse on adherence to ART which has substantially altered the fate of HIV-infected people. The objectives of this study therefore, were to determine the type of substances abused by HIV-infected patients attending clinic at Plateau State Specialists Hospital (PSSH) and to determine the effect of substance abuse and sociodemographic factors on adherence to ART among these patients. Ethical approval was obtained before the commencement of the study which was crosssectional in design. The study was carried out at the infectious disease unit of the Plateau State Specialists Hospital, Jos among 160 consecutive patients. The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) was used for the assessment of the types of substance abused and AIDS Clinical Trials Group(ACTG) adherence instrument was used to assess reasons for non- adherence. The results showed that 61.9% of the patients did not use any substance of abuse, 38.1% either abused one substance or a combination of substances. Substance abuse were ( p = 0.0001), alcohol abuse (p = 0.003) and educational status ( p = 0.0001) significantly associated with non-adherence to ART while, age ( p = 0.954), employment status ( p = 0.924) and marital status ( p = 0.466) were not. However, logistic regression revealed that only alcohol abuse (B = -1.383, df = 1, p  = .002) predicted non adherence to ART. We recommend the screening of patients on ART for substance abuse and a multi-disciplinary approach to the treatment of HIV/AIDS. Keywords: HIV, substance abuse, medication adherence

Substance abuse and adherence to antiretroviral therapy among patients attending clinic at a specialist hospital in Jos, Nigeria

Background : The peculiar characteristics of a military career, such as the specific professional military aims or tasks, working environment, strict subordination typical to military structures and formal and informal relationships, influence the type of coping strategies employed by individuals. The authors present the first study on coping strategies in a Nigerian military population. The study is aimed at determining the pattern of coping strategies employed by service personnel in the course of their duties and its correlation with socio-demographic parameters of this population. Methods : A cross sectional descriptive study carried out among 193 servicemen. Samples were drawn by stratified multistage sampling in which respondents were stratified according to gender, military units and rank. Data was collected using socio-demographic questionnaire and the full COPE scale. Results : Regarding specific coping strategies; 'turning to religion' (mean:- 14.09 ±2.551), was the most commonly used coping strategy, followed by planning (mean:- 12.6±3.059), positive re-interpretation and growth (mean:- 12.27±2.917) and then active coping (mean: - 12.11±2.896). Alcohol/drug use (mean:- 5.65 ±2.566) was the least used coping strategy among respondents. A statistically significant relationship was found between some coping strategies and gender (“Emotion Focussed Coping” greater among females, P= 0.017), educational status (“Denial”:- P=0.004, “Mental Disengagement ” : - P=0.038, “Behavioural Disengagement”:- P=0.000), and marital status (“Planning” highest among the divorced /separated group, P=0.019; “Suppression of Competing Activities” highest among single respondents, P=0.033; while “Humour” highest among the widowed, P=0.005), as well as the military ranks (emotion focused coping was greater among the lower ranks, P=0.042) of the service personnel. There was no statistically significant difference among the various age groups of the respondents with the various coping strategies. Conclusion : This study demonstrated that personnel of the Nigerian Army exhibited significant differences in their coping strategies associated with specific socio-demographic parameters. The authors recommend an intensification of army personnel training on the positive coping skills. Keywords : Military, Coping, Service, Northern Nigeria.

Coping strategies of Nigerian Military Service Personnel: A Survey of an Army Cantonment in Northern Nigeria.

Background: Developing countries health systems are bedeviled with numerous challenges including resource scarcity, high workload, unfavourable working conditions, Physical and Psychosocial stress. The Aim of this study was to assess the burden of burnout among primary care physicians working in such challenging environments with some level of postgraduate training programs. Methods: A cross-sectional study of primary care physicians was carried out using a Maslach Burnout Inventory human Services Survey (MBI-HSS) tool. Information was also collected about lifestyle and other demographic data. MBI-HSS scores were analysed in three dimensions of emotional exhaustion (EE), depersonalization (DP) and personal accomplishment (PA). Results: two hundred and twenty questionnaires were distributed and 155 were returned giving a response rate of 70.5%. In all, 54 doctors representing 34.8% (95% CI 27.4-42.9%) of the sample had high burnout in at least one of the three dimensions. There was statistically significant difference in the proportion of doctors with high burnout in the State Specialist Hospital when compared to those working in the Teaching Hospital (X 2 4.42; P =0.03). In respect of the three dimensions; 21.6% (33) of doctors scored high for DP (95% CI = 15.3 -28.91%), 15% (23) scored high for PA (95% CI = 9.8 -21.7%), 13.6% (21) for EE (95% CI = 8.6 -20.1%), a pattern that is the usually observed in burnout seen in academic work places. Having an excellent or good self-reported perceived health status was significantly associated with lower risk of developing high burn out (X 2 15.6; df 2, P < 0.01). Conclusion: Burnout is common among primary care physicians in this study and it is associated with the nature and type of working environment. Self-reported perceived health status of excellent or good health was associated with lower risk of high burnout. Keywords: Burnout, Primary Care Physicians, Perceived Health Status

Burnout among primary care physicians in Jos-Plateau, north-central Nigeria

High rates of psychotic disorder among special populations of homicide offenders, females, youth and the mentally disordered, have received much investigation. Personality disorder, especially antisocial personality disorder, augments the relative risk ratio of violence, especially in combination with substance use disorder. Few studies of these correlates of violence and especially homicide have been reported in low- and medium-income countries (LMIC). Using the structured clinical interview for DSM diagnosis (SCID), personality disorders were identified in a cross sectional study involving 546 homicide offenders in Jimma prison, Ethiopia. Predictors of personality disorder were determined using multivariate analysis of various demographic and clinical variables, for example, age, psychiatric history and substance use. Out of the 316 offenders who completed the SCID, only 16% fulfilled DSM IV criteria for personality disorder. The rationale for killing, self-defence, anger and revenge (52% of offenders), planning involved in offending (50%) and reasonably high level of relationship functioning (57% married) were different from most data from the high-income countries. Diagnostically relevant cultural factors in LMIC, not in play in high-income countries, may explain the differences in personality disorders similar to other mental disorders and the underlying mediators of homicide.

A developing world perspective on homicide and personality disorder

Over the past decade, a small extremist Islamic sect agitating against Western civilization has grown to become the biggest challenge to Nigerian internal security, a serious threat to international security and peace, and has earned the country the unenviable international reputation of a terrorist state. The radicalization of members of the group is driven majorly by extreme Middle-Eastern Islamic religious ideologies. In this study, 99 Nigerian participants (51 Christians and 48 Muslims) completed the Assessment and Treatment of Radicalization Scale (ATRS; Loza, 2007; formally the Belief Diversity Scale, BDS; Loza, 2007). The ATRS is a 33-item, six subscale instrument that is designed to quantitatively measure Middle-Eastern extremist ideologies in areas of risk reported in the literature. Results demonstrated reliability and validity of the ATRS as well as indicated the prevalence of Middle-Eastern extremistsi¯ ideologies among Nigerian Muslims. Current findings are consistent with those obtained from previous studies. These findings suggest that the ATRS could be used as an objective tool to measure Middle-Eastern religious extremism.

The Prevalence of Extreme Middle-Eastern Ideologies among Some Nigerians

Background : A considerable clinical attention has been received in recent years regarding the effects of psychological, social and behavioral factors in gastrointestinal (GI) diseases. The aim of this study is to assess correlates of anxiety disorder in patients referred for gastrointestinal endoscopy. Method : This cross-sectional descriptive study was part of a larger study conducted on one hundred and eleven (111) subjects referred for endoscopy at Jos University Teaching Hospital (JUTH) and Evangel Hospital in Jos between the periods of January 2008 to December, 2008. A proforma was designed to record demographic and clinical variables of subjects, and subsequently anxiety was measured using the Hospital Anxiety and Depression Scale (HADS). Results : A total of 111 subjects were studied, 42(37.8%) were males while 69(62.2%) were females, the age ranged from 19 to 80 years with a mean of 47.31±12.59 years. Forty-three (38.7%) were married while 68 (61.3%) were not married. Occupational classification of subjects revealed that 71(64.0%) belonged to low social clas. Findings at endoscopy showed that 61(55%) of subjects were found with Non-Ulcer Dyspepsia (NUD), 32 (28.8%) with peptic ulcer disease (PUD), 18 (16.2%) with other disorders like oesophageal varices, tumours, and inflammatory conditions. Anxiety was diagnosed in 48 patients representing a prevalence rate of 43.2%. Anxiety was significantly associated with being a female (p<0.001), low social class (p<0.001), educational attainment (p<0.001), not being married (p<0.000), duration of GI symptoms (p<0.001), diagnoses of NUD (p=0.025) and poor response to treatment (p=0.001). However, there was no significant association between anxiety and subject's age (p=0.618), place of residence (p=0.086), type of medication use (p=0.760) and present of other comorbid medical conditions (p=0.070). Conclusion : The significantly high rate of anxiety among these subjects has informed our recommendation of psychological assessment in patients presenting with gastrointestinal symptoms.

Anxiety disorder in Patients referred for Gastrointestinal Endoscopy: A Cross-sectional Descriptive Study in Jos, Nigeria

A study of psychiatry morbidity and co-morbid physical illness among convicted and awaiting trial inmates in Jos prison.

Background: The prevalence of psychiatric illness in correctional settings is significantly elevated, with higher than community rates reported in most mental disorders. The prison is a correctional institution in which inmates have limited liberty, autonomy, and communication with family and friends. This can be devastating to some inmates thereby leading to deterioration in their physical, psychological and social wellbeing. The study was aimed to determine the prevalence of axis 1 psychiatric disorders and associated factors among prison inmates in Jos, Nigeria. Method: This was a cross-sectional descriptive study carried out in Jos maximum security prison among 608 inmates. Two sets of data collection instruments were used namely (General Health Questionnaire) GHQ-28 and (Composite International Diagnostic Interview) CIDI. SPSS statistical software package for windows version 15.0 was used for data analysis and test of significance was set at P

Prevalence of psychiatric morbidity among inmates in Jos maximum security prison

Substance use in this country, among pregnant women, is a recent phenomenon as our women embrace western culture. More worrisome is the current finding showing no 'safe' level of alcohol exposure for possible adverse effect or harm to the developing child to occur.

AIMS AND OBJECTIVES
To determine what substances are used and the prevalence of substance use among pregnant women attending the antenatal clinic of the Jos University Teaching Hospital, Jos, Northcentral Nigeria.

DESIGN
Cross-sectional study.

SETTING
Jos University Teaching Hospital.

RESULTS
A total of 557 women were administered the pre-tested questionnaire. The mean age was 29.1 years, with a range of 15 to 48 years. The prevalence rate of substance used among the pregnant women was 43.8%. In all, 244 of the 557 women were taking one substance or the other. About 61.9% of the women abuse Kolanuts. There was no significant difference in the age group between those who sue it and those who do not (p-value 0.7411). Other substances were chlorpheniramine 10.6%, alcohol 8.6%, diazepam 4.5% and promethazine 2.5%, cigarettes/tobacco 2.9%, phenobarbitone 2.9%, cocaine 2.5%, codeine 2.0%, and marijuana 1.6%. A significant number 22.8% admit to using other substances in pregnancy. The commonest reason given for substance use is to control nausea and vomiting of early pregnancy.

Nigerian pregnant women use and abuse a wide variety of substances and drugs during pregnancy just as their counterparts in the developed world. The high prevalence observed in this study was largely due to the consumption of locally available substances.

Substance abuse among antenatal patients at jos university teaching hospital, north central Nigeria.

Depression is a common psychiatric disorder in primary health care throughout the world with increasing incidence and prevalence. It is often under-treated and under-diagnosed. Consequently, several studies have revealed that patients with depression are high utilizers of medical services.

The study was aimed at determining the frequency of consultation and the utilization of investigative procedures by the depressed and non-depressed patients in the last 12 months.

This was a cross-sectional descriptive study among 200 consecutive patients attending the General Out-Patient Department of the Jos University Teaching Hospital between November 2006 and March 2007. A semi-structured questionnaire was used to collect socio-demographic data and health services utilization indices. Structured Clinical Interview for DSM-IV axis-1 Disorders (SCID) was used for diagnosis of depression.

RESULTS
The study found that 51(25.5%) of the respondents met DSM-IV criteria for the diagnosis of major depression while 149 (74.5%) did not. Depressed patients significantly had more number of consultations with their doctors (P=0.000), had consulted more number of hospitals (P=0.000), stayed longer on admission (P=0.000) and had consumed more types of medicine (P=0.005) in the last 12 months compared with the non-depressed. The depressed patients also had significantly higher mean of different types of investigations compared with non-depressed; urinalysis (1.69 vs 0.55, P=0.000), chest X-ray (0.57 vs 0.21, P=0.000) and Widal test (1.92 vs 0.39, P=0.000). Others are HIV screening (0.39vs0.11, P=0.000) urine mcs (0.94 vs 0.18, P=0.000), stool mcs (1.24 vs 0.20, P=0.000).

The study demonstrated that patients who suffer from depression are higher utilizers of health care resources compared with the non-depressed. Therefore, it is recommended that general practitioners and other health workers need to be better equipped to deal with the diagnosis and management of depression.

Utilization of health care services by depressed patients attending the general out-patients department of the Jos University Teaching Hospital, Jos, Nigeria.

Authors Maigari Yusufu Taru, Moses David Audu, Davou Francis John, Tungchama Friday Philip, Suwa Goden. Goar Jos University Teaching Hospital (JUTH), Jos, Nigeria Corresponding Author Maigari Y Taru Department of Psychiatry, Jos University Teaching Hospital, Plateau state Nigeria Email: Tmaigariyusufu@yahoo.com, Tel: 2348036327951 ABSTRACT Survivors of mass violence are at high risk of developing psychological disorders. However, little is known about the impact of trauma in post conflict low income countries. This study assessed the prevalence of and socio-demographic risk factors for posttraumatic stress disorder among conflict survivors in North-Central Nigeria in comparison to a control group drawn from a population that was not exposed to armed-conflict. This is a cross-sectional study that employed a multi stage sampling technique to select respondents in both groups. The Mini international neuropsychiatric interview was used to assess for symptoms of posttraumatic stress disorder and their socio-demographic variables obtained with socio-demographic questionnaire. The results showed that 55.5% and 9.8% of the respondents in the conflict exposed group and the control were diagnosed with posttraumatic stress disorder. Respondents exposed to mass violence were significantly more likely to experience posttraumatic stress disorder compared to the control group (p< 0.001). Being a female was the consistent risk factor for the disorder in both groups, while being never married and having individual monthly income below N20,000.00 were also predictive of posttraumatic stress disorder in the group exposed to conflict. In conclusion, posttraumatic stress disorder prevalence was higher among the group exposure to armedconflict. Thus, an effective model for immediate and long-term mental health support for trauma victims needs to be developed in order to reduce the incidence of posttraumatic stress disorder among conflict survivors.

Post-Traumatic Stress Disorder in Dogonahawa and Zawan, North-Central Nigeria, Four-Years after Communal Violence: Prevalence and Risk Factors Prevalence of and risk factors for PTSD Authors

Background Among patients who have attempted suicide, the risk of later suicide is much increased and mortality due to suicide has continued to increase over the years both in developed and developing countries. Few studies in this environment have looked at the risk factors and psychiatric morbidity among patients with repeated suicidal attempts. Objective The objective of the study is to determine the risk factors for repeated suicidal attempts among patients with attempted suicide. Method This is a retrospective study of all patients that presented with a diagnosis of attempted suicide at the emergency unit of Jos University Teaching Hospital (JUTH) between January 2002 and January 2008. Results During a 6-year period, 57 patients presented with suicidal attempts. Sixteen were males and 41 were females, twenty-four have had at least one previous attempt of suicide. There was no statistically significant association between any of the sociodemographic variables studied i.e. marital status, occupation, recent problem with a sexual partner, family history of suicide and repetition of suicidal attempts. However, a statistically significant association was found between repeated suicidal attempts and depression ( 2لا =9.61, P= 0.008). Forty (70.2%) patients reported the use of  psychoactive substances notably alcohol but there was no statistically significant association between substance use and repeated suicidal attempts 2لا) =1.63, p=0.44). Conclusion This study revealed that psychiatric disorders are risk factors associated with repeated suicidal attempts. Therefore, early detection and treatment of such disorders is necessary in the management of patients with attempted suicide. Key words; Suicidal attempt, Risk factors

Risk factors for repeated suicidal attempts: a 6 –year retrospective study at Jos University teaching hospital, Jos.

Clinical depression is a common problem among patients who seek medical care, and diabetic patients with comorbid depression tend to have higher health care cost. A dearth of literature exists on depression among diabetics in Nigeria. The objectives of the study were to determine the prevalence of depression among diabetic patients and to determine the sociodemographic correlates of depression among diabetics.

METHODS
A cross-sectional descriptive study was conducted between December 2005 and April 2006 among patients who attend the diabetes clinic of Jos University Teaching Hospital (JUTH) with a laboratory and clinical evidence of diabetes mellitus. A semi-structured questionnaire was used to record the sociodemographic data of each consecutive patient followed by an interview by psychiatrists using the depression module of the Structured Clinical Interview for DSM-I V axis I disorder (SCID). Subsequently, the Hamilton Rating Scale for Depression (HDRS) was used to determine the severity of symptoms among subjects diagnosed with depression according to DSM-I V criteria.

RESULTS
Thirty-one of the 160 subjects fulfilled the DSM-IV criteria for the diagnosis of a major depressive episode giving a 1-year prevalence rate of 19.4%. Depression was significantly correlated with sex (P=0.001) with a female-to-male ratio of 3:1 and was also significantly associated with unmarried diabetics (P=0.002) and those who had a poor relationship with their partners (P=0.04). No significant association was found between depression and the respondents' age (P=0.216), educational qualifications (P=0.268), employment status (P=0.84), place of residence (P=0.80), household composition (P=0.77), and monthly income (P=0.110).

Depression is a common psychiatric disorder among diabetic subjects in this environment. It was suggested that diabetic patients be screened for depression to allow for early detection and treatment.

Depression among medical outpatients with diabetes: a cross-sectional study at Jos University Teaching Hospital, Jos, Nigeria.

The role of gender in psychiatry disorders is becoming increasingly important. This study is therefore, aimed at identifying gender pattern of admissions to a public mental health centre with regards to demographic characteristic, psychiatry diagnosis and length of stay on admission.

METHOD
In this retrospective study Hospital records of 388 patients admitted at the psychiatric section of the Federal Medical Centre (FMC) Makurdi, between January, 2004 and December, 2008 were studied for gender differences regarding demographic attributes, length of stay and psychiatry diagnoses.

RESULTS
Findings revealed that more men than women were admitted overall. Most men (56%) were less than 30 years old whereas 60.6% of women were within 30-59 years aged bracket. For men the main diagnosis was schizophrenia (30.5%), followed by substance related disorders (16.5%) then depression (14.0%); for women the main diagnosis was also schizophrenia (30.3%), this was followed by depression (24.5%), only one woman was diagnosed with substance related disorder. A statistically significant association was also found between having a personality disorder and being a male (p = 0.009). Most female were single and belong to the lowest occupational group. There was no significant difference in the gender distribution of patients with respect to length of stay on admission (p = 0.161).

The results revealed how psychiatry diagnosis is significantly influence by gender issues. We therefore recommend that; for a more effective psychiatry formulation, it is imperative to pay attention to gender issues that may affect the development of psychopathology.

Nigerian journal of medicine : journal of the National Association of Resident Doctors of Nigeria

Gender and psychiatric diagnosis: a 5-year retrospective study in a Nigerian Federal Medical Centre.

Background Studies on drinking behaviour in Nigeria have reported a preponderance of males, which makes it difficult to make any strong comparative assertion. Aims The aim of this study was to determine the types of alcoholic beverages commonly consumed by males and females, to compare the quantity and quality consumed, and to determine the time spent on drinking as well as to determine the mental and physical health problems encountered by both males and females. The study also sought to find out about their knowledge of health hazards associated with alcohol consumption. Method The modified version of the Obot’s 1993 Middle Belt general population survey questionnaire was randomly administered to respondents at various drinking places and offices. RESULTS Four hundred and fifty participants responded to the questionnaires (225 males and 225 females). Beer was the single most preferred alcoholic beverage by both males and females. Both men and women consumed similar quantity of alcoholic beverage but women spent more time drinking. Majority of both sexes had knowledge about the health hazards associated with drinking alcohol. Whereas men reported more mental health problems, both men and women equally experienced physical health problems. CONCLUSION The study reveals that both males and females have a similar drinking behaviour pattern in Jos and majority engaged in problem drinking despite awareness of the health problems associated with alcohol consumption. Hence there is dire need for deliberate Government policy to regulate the production, sale, and consumption of alcoholic beverages in view of the health, social, and economic consequences associated with problem drinking.

Pattern of alcohol consumption among males and females and associated health problems in Jos

Background
Most studies of psychiatric disorders associated with HIV/AIDS have been carried out in the USA and Europe in patients on anti-retroviral drugs. Few studies have looked at psychiatric disorders and substance use in Africa and a dearth of literature exists on HIV/AIDS and psychiatric morbidity in Nigeria.
Objectives 
The objectives of the study were:
1. To determine the rate of referral for psychiatric consultation among patients with HIV/AIDS
2. To determine the psychiatric diagnoses at referral
3. To determine the rate of substance use among referred patients.
Method
A retrospective chart review conducted among HIV/AIDS patients referred to an urban Teaching Hospital in Jos, Nigeria from January 2000 to December 2004. The case notes of patients who presented at the General Outpatient Department (GOPD) and Accident and Emergency Units or those who were treated at the medical, surgical, and psychiatric departments were retrieved from the records department and scrutinized.
A semi-structured questionnaire was used to record the sociodemographic data, the diagnoses, substance(s) used, and the anti-retroviral treatment taken. The cases referred for psychiatric assessment were compared with available records of clients who attended the hospital for HIV/AIDS-related illnesses. Cases treated at the specialist clinic for HIV/AIDS were excluded.
Results
Available record showed that a total of 420 confirmed cases of HIV/AIDS were treated within the study period. 247 were in WHO stages 111&1V while 177 were in WHO stages 1&11. 120 patients were referred for psychiatric consultation giving a referral rate of 25%. The rate of referral was significantly associated with less advanced stage of the disease process (p Highland Medical Research Journal Vol. 5 (1) 2007 pp. 54-60

Psychiatric morbidity in HIV/AIDS: a 5-year retrospective study in Jos, Nigeria.

Service on wheels: a developing country's perspective of home treatment service in psychiatry, a 4-year pilot experience

AIM
To study the brain-gut interaction and the effect of behavioral or psychiatric conditions on irritable bowel syndrome (IBS) in an African population.

METHODS
IBS was diagnosed using the Rome II diagnostic criteria. The entry of each patient was confirmed following detailed explanations of the questions. Four hundred and eighteen patients were studied. Subjects satisfying the Rome II criteria for IBS were physically examined and stool microscopy was done to identify the presence of "alarm factors". Depression was diagnosed using the symptom-check list adapted from the Research Diagnostic Criteria (DSM-IV) of the American Psychiatric Association.

RESULTS
Seventy-five (56.8%) of the 132 IBS patients were depressed whereas only 54 (20.1%) of the 268 non-IBS patients were depressed. There was a significant relationship between IBS and depression (chi2 = 54.29, Odds ratio = 5.21, 56.8 +/- 8.4 vs 20.1 +/- 5.2, P = 0.001). Even though constipation predominant IBS patients were more likely to be depressed, no significant relationship was found between the subtype of IBS and depression (chi2 = 0.02, OR = 0.95, P = 0.68).

IBS is significantly associated with major depression but not gender and bowel subtypes of the patients. Patients with IBS need to be evaluated for depression due to the highly significant relationship between the two conditions.

Depression in patients with irritable bowel syndrome in Jos, Nigeria.

Aims: The aim of the study was to determine the prevalence, demographic 
Characteristics of the study population and type of substance abused among children and adolescents below the age of 18 years. 
Method :1160 patients below the age of 18 years who had attended psychiatric care between December 1980 and November 1996 had their case notes scrutinized in details and records of substance abuse, demographic and clinical characteristics were noted. 
Results: 36(3.09%) patients presented with drug and alcohol related problems, at various stages of substance abuse. 32(88.89%) were males while 4(11.11%) were females. 
12(33.33%) patients had abused cannabis 9(25.00%) patients had abused more than one substance. 3(8.33%) patients used alcohol exclusively. 
1. People less than 18 yeas were less likely to use alcohol compare to illicit drugs 
2. Religious belief was not a determinant in the use of substance among children and adolescents below the age of 18 years. Highland Medical Research Journal Vol.1(3) 2003: 18-22

Alcohol and illicit Drug Abuse Among Children and Adolescence in Jos Nigeria

We examined the association between mental disorder and homicide in a developing country. Specifically, we studied culpable homicide offenders referred for psychiatric evaluation in Northern Nigeria, including their psychiatric diagnoses and their relationship with victims. A semi-structured questionnaire was used to collect forensic, demographic, and clinical information from 12,500 patients who underwent court-ordered psychiatric evaluations at the Jos University Teaching Hospital. Of all patients evaluated at the hospital, 1.3% had committed a homicide. Schizophrenia was the most common diagnosis among homicide offenders; there were relatively low rates of antisocial personality disorder and substance dependence. Most offenders knew their victims. The mean duration of time between arrest and psychiatric assessment was 24 months, with a range between 6 to 192 months. We discuss the implications of these findings with respect to motivations for homicide, the evaluation of offenders, and the need for treatment and follow-up of patients.

A Developing World Perspective on Homicide and Mental Disorder: An Eighteen-Year Retrospective Study (1980–1998) at Jos, Nigeria

Ecological risk assessment of potentially toxic elements in the bottom sediments of a stream in Oke-Ere, Kogi State, North Central Nigeria

In this work, dextrin was copolymerized with Concentrated Natural Rubber Latex (CNRL) to produce a polymeric product (Baby feeder teat) which is a dipping good. The chemical method of grafting was implored, and benzoyl peroxide was used as the initiator. The coagulant method of dipping was used in the production of the baby feeder teat. The effect of concentration of dextrin (A = 5.0 %, B = 7.5 %, C = 10.0 % and D = 12.5 %) was investigated by observing the mechanical properties such as weight, elongation at break and thickness of the samples. Also, comparison was made between samples produced from CNRL and grafted natural rubber latex (GNRL). The results for weight were: CNRL=1.992, GNRL A=2.427, GNRL B=2.560, GNRL C=2.594, GNRL D=3.313 while % elongation was 802.85%, 871.43%, 1000%, 1005% and 1100% for Pure NRL, Grafted sample A, B, C and D respectively. The thickness results: CNRL= 1.30 mm, 0.93 mm, 0.72 mm; GNRL A=1.44 mm, 1.15 mm, 0.91 mm; GNRL B= 1.67 mm, 1.45 mm, 1.34 mm; GNRL C=1.75 mm, 1.50 mm, 1.48 mm and GNRL D=1.84 mm, 1 73 mm, 169 mm) showed increase in the GNRL when compared to the CNRL as well as corresponding increase in GNRL with increased concentrations. From the results, it is obvious that the presence of dextrin in CNRL enhanced the properties of CNRL.

GRAFT COPOLYMERIZATION OF DEXTRIN ONTO CONCENTRATED NATURAL RUBBER FOR THE PRODUCTION OF BABY FEEDER TEAT.

ABSTRACT This study examined the levels of some heavy metals in soils of Oke-Ere mining area in Yagba West, Kogi State, Nigeria, aim at ascertaining the degree of pollution, and risk pose to the environment, and human health to the residents in the area. A total of 48 soil samples were analysed by using Inductively Coupled Plasma Mass Spectroscopy (ICP-MS). The mean concentrations (mg/kg) were As(1.92), Cd(< 0.004), Co(29.8), Cr(117), Mo(4.00), Ni(51.4), Pb(24.1), Sc(17.8), Sn(21.9), and Zn(85.8). Principal component analysis revealed significant anthropogenic contributions of Sc, Cr, Ni, and As in soils. Geochemical assessment evaluated based on models of geochemical load index (Igeo), enrichment factor (EF), contamination factor (Cf) and pollution load index (PLI), revealed that the soils were highly polluted by Sc, moderately polluted by Sn and non-polluted to slightly polluted by other metals. Enrichment factor shows significant enrichment by Sc, while Cr, Pb, Co, Mo and Sn were moderately enriched. The contamination factor indicated low contamination for most of the studied metals except Cu and Co which recorded considerable contamination. The values of pollution load index PLI > 1, signifies that the mining activities deteriorated soil quality. The total hazard index (HI) of the metals for adult and children, indicates HI < 1 which connotes a non-carcinogenic health risk effect. The cancer risk (CR) value for ingestion and dermal exposure pathways was higher than the permissible limits (1 x 10−6 to 1 × 10−4), which indicated adverse health risk to the local resident. This study suggested adequate attention be directed to detailed risk assessment of heavy metals in the study area.

Geochemical and health risk assessment of heavy metals concentration in soils around Oke-Ere mining area in Kogi State, Nigeria

Thermal and hydrothermal alkaline modification of kaolin for the adsorptive removal of lead(II) ions from aqueous solution

1 Principal Lecturer and Director of Research and Innovation, Eastern Polytechnic, Kenema, Eastern Sierra Leone. Corresponding Author‟s E-mail: saffabarbeemassaquoi@yahoo.com 2 Agricultural Education Senior Teacher Christ The King College Bo Southern Sierra Leone 3 Senior Lecturer, Former Dean of Education and Head of Agricultural Education and Home Economics Department, Njala University, Bo campus, Southern Sierra Leone.

Effects of the Ebola Crisis On Agricultural Productivity in Kakua and Bumpe Ngao Chiefdoms, Bo District, Southern Sierra Leone.

Predictors of OpenNotes use among Veterans receiving Mental Health Care

Cette invention concerne un ensemble essieu directeur. Cet ensemble comporte une poutre d'essieu definissant un bossage au niveau d'une extremite. Ce bossage definit un alesage concu pour recevoir une cheville d'attelage. Ce bossage definit egalement deux alesages supplementaires qui viennent intercepter l'alesage de la cheville d'attelage et qui sont concus pour recevoir des clavettes mobiles utilisees pour fixer solidement la cheville d'attelage a l'interieur de son alesage. Les clavettes mobiles sont toutes deux disposees sur un cote interieur de la cheville d'attelage. L'ensemble comprend egalement des ecrous disposes autour d'une extremite des clavettes mobiles, du meme cote que la poutre d'essieu. Le fait que les clavettes mobiles soient disposees sur un cote interieur et que les ecrous soient disposes du meme cote reduit le temps necessaire a l'assemblage de l'ensemble essieu directeur et permet de bloquer solidement la cheville d'attelage a l'interieur de l'alesage.

Dispositif de clavette mobile double servant a bloquer une cheville d'attelage d'essieu directeur

Problems that often occurred on PT. Mazebah Saroha are significant number 
of costs from defective products that resulting waste. This study aims to help the 
company in achieving standard quality that has already been defined and decrease 
waste from defective products. 
The method that has been used to increase the quality on PT. Mazebah 
Saroha is seven tools. There are 7 analysis tools in seven tools method, i.e, flow 
chart, check sheet, histogram, control chart, scatter diagram, pareto chart, fish-bone 
diagram. Flow chart serves to show production flow on PT. Mazebah Saroha so that 
the next analysis process can be facilitated. Check sheet and histogram serves to 
present comprehensive data of defective products based on their type of defects. 
Control chart scatter diagram serves to show whether some taken variables have 
connection on each other. Pareto chart serves to show which types of defective 
product are the most dominant so that some precaution can be done. Fish bone 
diagram serves to help find the factors that cause the occurrence of defective 
products. 
Control chart shows that there are 11 points outside the determined control 
limits. This can prove that there are still much needed improvements on PT. Mazeba 
Saroha’s quality control. Through pareto chart, improvements is done to defective 
products. Result from pareto chart shows that the most dominant type of defects on 
PT. Mazebah Saroha are striped and broken papers. If PT. Mazebah Saroha focus 
their quality improvements to both type of defects, it will indirectly improve overall 
product defects. The last one is find out what factors that are causing defective 
products on PT. Mazebah Saroha. The analysis result of fish-bone diagram using 
factor analysis found that there are 5 factors that are causing defective products on 
PT. Mazebah Saroha, i.e., professionalism, production support factors, a good 
working atmosphere, production process control, and production method. Factors 
that have been formed by the method of analysis factor is then compiled graphically 
using fish-bone diagram to ease the handling of defective products on PT. Mazebah 
Saroha.

ANALISIS PENGENDALIAN KUALITAS UNTUKMENGENDALIKAN PRODUK CACAT DENGANMENGGUNAKAN SEVEN TOOLS(Studi pada PT. Mazebah Saroha - Jakarta)

Objective
Consistent with the OpenNotes movement, the Veterans Health Administration (VHA) offers patients online access to their clinical notes through the Blue Button feature in its electronic patient health portal, My HealtheVet. We identified demographic, diagnostic, and knowledge-related predictors of viewing clinical notes among veterans receiving VHA mental health care who recently used My HealtheVet.

Three hundred and thirty-eight patients receiving mental health care from 1 VHA medical center who had logged into My HealtheVet in the prior 6 months completed self-report questionnaires assessing their viewing of clinical notes. Additional data were extracted from VHA's Patient Care Database. Multivariable logistic regression was used to examine predictors of viewing notes.

Results
Fifty percent of respondents reported having read their notes. In the final multivariable model, post-traumatic stress disorder (PTSD) diagnosis [odds ratio (OR) = 2.30 (1.31-4.07)], speaking with their mental health clinician about their ability to view notes [OR = 3.84 (1.69-8.72)], and being very or extremely confident in understanding the purpose and uses of Blue Button [OR = 9.80 (2.23-43.07) and OR = 13.36 (2.74-65.20), respectively] were associated with viewing notes.

Discussion
Patient recall of mental health clinicians speaking to them about their ability to view notes, and confidence in understanding the use and purposes of Blue Button, were stronger predictors of viewing notes than demographic variables. PTSD diagnosis was the only clinical characteristic associated with viewing notes.

The findings support the value of mental health clinicians openly discussing the availability of notes with patients if they wish to help them take advantage of their potential benefits.

Predictors of viewing progress notes among users of VA's electronic health portal who receive mental health care.

Prevalence and Risk Factors of Mycobacterium tuberculosis and Human immunodeficiency Virus Coinfection Among Patients on Antiretroviral Therapy in a Specialist Hospital, Lokoja

Porcine epidemic diarrhea virus papain-like protease 2 can be noncompetitively inhibited by 6-thioguanine

Disulfiram can inhibit MERS and SARS coronavirus papain-like proteases via different modes

Contact: davidadunade@gmail.com. The authors declare that they have no relevant or material financial interests that relate to the research described in this paper. Also, the authors declare that the submitted paper is their original work and that, upon publication, nothing contained in it will not constitute an infringement of any copyright. Paper received 15.04.2017. Approved 30.05.2017.This paper is licensed under the Creative Commons Attribution-Non Commercial-No Derives 3.0. License. This paper is published with Open Access at www.humsettlement.net.

SMART CITY STRATEGY AND SUSTAINABLE DEVELOPMENT GOALS FOR BUILDING CONSTRUCTION FRAMEWORK IN LAGOS

Globally, coinfection of human immunodeficiency virus (HIV) patients with Hepatitis B Virus (HBV) is associated with an accelerated progression of HIV disease and higher mortality resulting from complications of liver-related disease. Despite the public health importance, data are lacking on this subject in the study area. Therefore, we evaluated the prevalence and risk factors for HIV/HBV coinfection among HIV patients accessing antiretroviral treatment in Lokoja, Nigeria. In a cross-sectional study, sera from randomly selected 200 consenting HIV patients were screened for hepatitis B surface antigen (HBsAg) using The Commercial Rapid Immunoassay Test Kit. Demographic variables and putative risk factors of HBV transmission were obtained using structured questionnaire. HBsAg prevalence was 8.0% in the sampled group with higher seropositivity rate in the age group, 40-49 years, followed by those 20-29 years of age, whereas the other age groups had zero positivity rates each. The difference between seroprevalence rates in relation to patients' age and sex was not statistically significant (p > 0.05). Patients with no formal education, who were married and were housewives, had higher rates of HBV infection compared with others in the group. Although not statistically significant (p > 0.05), the likelihood of exposure to HBV was higher among patients who were engaged in multiple sexual behaviors, alcoholism, smoking, sharing of sharps, ear piercing, and had history of blood transfusion. Conclusively, HIV/HBV coinfection rate in our study is comparable to other localities and thus, affirm the endemicity in the study area. The need to strengthen health education of the masses to desist from risky behaviors is recommended to reduce the morbidity and mortality arising from HIV/HBV comorbidity.

Coinfection of Human Immunodeficiency Virus-Infected Patients with Hepatitis B Virus in Lokoja, North Central Nigeria.

Globally, infection of pregnant women by human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) pose a significant health challenge for not just the mothers but also the newborn infant. This study was undertaken to assess the prevalence of HIV, HCV, and HBV among pregnant women attending antenatal clinic in Kogi State University Teaching Hospital (KSUTH), Anyigba, Nigeria. Sera samples obtained from 200 consented pregnant women were screened for hepatitis B surface antigen (HBsAg), anti-HCV, and anti-HIV antibodies using commercially available immunoassay test kit. Demographic variables and obstetric characteristic were obtained using structured questionnaire. Of the 200 sera tested, the seroprevalence rates were 1.0%, 0.5%, and 8.5% for HBsAg, anti-HCV, and anti-HIV antibodies, respectively. Although 0.5% were coinfected with HIV/HCV, none was simultaneously infected by the three viruses. Age, marital status, trimester, and educational and occupational status did not significantly affect the prevalence of HIV, HCV, and HBV infections. However, factors such as history of abortion/miscarriage (p = 0.04), intravenous drug use (p = 0.001), and history of other sexually transmitted infection (p = 0.01) were significantly higher in relation to HIV seropositivity. In conclusion, findings from this study revealed high HIV seroprevalence and a clear decline of hepatitis C and B infection prevalence compared with previous epidemiological data. Reason for the latter could be attributed to the current efforts to reduce mother-to-child transmission and possible HBV vaccination programs. High burden of HIV infection in our study suggests the needs to strengthen the national prevention programs including education of the people on the risk factors of HIV transmission.

Seroprevalence of HBV, HCV, and HIV and Associated Risk Factors Among Apparently Healthy Pregnant Women in Anyigba, Nigeria.

Stoisk påvirkning på de greske grammatikere: En studie av hvorvidt Techne-tradisjonens behandling av ordklassen sundesmos viser påvirkning fra stoisk logikk

Evaluating the efficacy of rent control in Zambia)with particular reference to dwelling Houses)

Casting a Constitutional Controversy as a Nonjusticiable Political Question: Made in the USA Foundation v. United States

The virulence factors and antibiotic-resistance in enterococci isolated from the clinical samples and hospital environment were determined using standard microbiological methods. A total of 81 clinical samples and 35 environmental samples from a tertiary hospital in Ekiti State, Nigeria, were examined for the presence of Enterococcus spp. Species isolated were identified to include: Enterococcus faecalis (110), Enterococcus faecium (75), Enterococcus gallinarum (39), Enterococcus durans (37) and Enterococcus hirae (33). Enterococccus faecalis has the highest occurrence followed by E. faecium, while E. hirae had the least occurrence. The percentage prevalence of cytolysin (Cyt) was highest in E. gallinarum (74.4%) followed by E. faecalis (68.5%). A total of 49 (44.1%), 19 (48.7%) and 13 (17.3%) among E. faecalis, E. gallinarum and E. faecium, respectively, were positive for the combination of cytolysin (Cyt) and gelatinase (Gel). The presence of Gel with haemaglutinin (Hea) in the isolates was comparably lower than the Cyt and Gel combination. The occurrence of the three pathogenic factors is in this decreasing order: E. faecalis 20 (18.0%), E. faecium 8 (10.7%) and E. gallinarum 2 (5.1%). The susceptibility of isolates was tested against nine antibiotics. All the E. faecium isolates were resistant to cotrimoxazole, ampicillin and chloramphenicol while none was resistant to vancomycin. The highest resistance was observed against cotrimoxazole followed by erythromycin while the least was observed in vancomycin. The highest vancomycin resistance was found among E. faecalis (30.6%) followed by E. durans (18.2%). The resistance of Enterococcus spp. was minimal to vancomycin, ofloxacin and nitrofurantoin, in increasing order, among the tested antibiotics.

Virulence-Marker Distribution and Antibiotic Resistance in Enterococcus spp. Isolated from Tertiary Health Care Facility in Ekiti State, Nigeria

The influence of risk factors on the onset and outcome of psychosis: What we learned from the GAP study

The concept of coping is considered by the authors to be important to understanding the psychological outcomes of the stresses of military experiences in a developing multi -ethnic, multi-religious society with its problems of internal conflicts, growing infrast ructure and developing economy. Coping mechanisms/strategies play a role in psychological maladjustments in relation to occupational tasks particularly in the military o determine correlations, if any, between coping strategies and psychiatric morbidity and also to compare psychiatric outcomes among troops who use emotion focused coping and those who use problem focused coping. cross sectional descriptive study carri ed out among 193 servicemen. Samples were drawn by stratified multistage sampling in which respondents were stratified according to gender, military units and collected using a socio-demogra phic questionnaire, the full COP General Health Q uestionnaire (GHQ) 12 and interviewed with the Composite Inter national Diagnostic Interview (CIDI). Nine out of the domains had statistically significant correlations with morbidity. regression result showed that three coping strategies associated with psychiatric morbidity. We recommend a curriculum on coping skills training for the Army . The study found a significant relationship between coping styles and morbidity with emotion focused coping showing a greater positi ve correlation with morbidity.

Association of psychiatric morbidi ty and coping strategies among service personnel of an army formation in Nigeria , West Africa

Background: Mental health problems can affect any individual, but individuals with HIV/AIDS are more likely to experience psychological stresses such as anxiety, depression, and substance use over the course of their lives. Coping with these stresses is important in this group of individual so as to have good quality of life. Understanding how individuals cope with psychological stresses of HIV/AIDS is essentially for the development of an intervention with could improve their overall quality of life. The was study aimed to assess the impact of psychological distress and coping strategies among patients with HIV/AIDS in Jos. Methods: The study was a cross-sectional descriptive study carried out at a health centre in Jos, Plateau state, Nigeria. Two sets of data collection instruments were used namely symptom checklist – SCL 90 and the brief cope questionnaire. SPSS Statistical Software Package for windows version 17.0 was used for data analysis and test of significance was set at p < 0.05. Results: Two hundred patients with HIV/AIDS were recruited for the study. The study found the major coping strategies employed by respondents were turning to religion, active coping, and acceptance all of which are positive strategies which lead to adaptation and hastening recovery from distress. Paranoid ideation was found to have above normal mean score for the female sex, and a significant relationship was found on the hostility category between male and female sex (p = 0.002). Conclusion: Turning to religion, active coping and acceptance were the major coping strategies employed by respondents which are all positive coping strategies. The female gender was more hostile and had higher paranoid ideation than he male gender

Psychological distress and coping strategies among patients with HIV/AIDs in a comprehensive Health Centre in Jos, Nigeria

The World Health Organization (WHO) study entitled Suicide Trends in At-Risk Territories (START) is an international multisite initiative that aims to stimulate suicide research and prevention across different areas of the globe. A central component of the study is the development of registration systems for fatal and nonfatal suicidal behaviors.

AIMS
This paper provides an overview of the data collected on suicidal behaviors from the participating locations in the START study.

METHOD
Descriptive statistics on the data are presented in terms of age, sex, and method.

RESULTS
A greater proportion of suicide deaths occurred among males. In all areas except the Philippines more females than males engaged in nonfatal suicidal behaviors. Compared to Australia, Italy, New Zealand, the Philippines, and Hong Kong SAR, in the Pacific Islands suicide most often occurs in younger age groups. Results indicate notable variations between countries in choice of method. A greater proportion of suicides occurred by hanging in Pacific Islands, while inhalation of carbon monoxide, use of firearms, ingestion of chemicals and poisons, and drug overdose were the most frequent methods of choice in other areas.

The information drawn from this study demonstrates the enormous variation in suicidal behavior across the areas involved in the START Study. Further research is needed to assess the reliability of the established data-recording systems for suicidal behaviors. The baseline data established in START may allow the development of suicide prevention initiatives sensitive to variation in the profile of suicide across different locations.

The WHO START study: suicidal behaviors across different areas of the world.

PURPOSE
Simultaneous collection of PET and MR data for radiotherapy purposes are useful for, for example, target definition and dose escalations. However, a prerequisite for using PET/MR in the radiotherapy workflow is the ability to image the patient in treatment position. The aim of this work was to adapt a GE SIGNA PET/MR scanner to image patients for radiotherapy treatment planning and evaluate the impact on signal-to-noise (SNR) of the MR images, and the accuracy of the PET attenuation correction.

METHOD
A flat tabletop and a coil holder were developed to image patients in the treatment position, avoid patient contour deformation, and facilitate attenuation correction of flex coils. Attenuation corrections for the developed hardware and an anterior array flex coil were also measured and implemented to the PET/MR system to minimize PET quantitation errors. The reduction of SNR in the MR images due to the added distance between the coils and the patient was evaluated using a large homogenous saline-doped water phantom, and the activity quantitation errors in PET imaging were evaluated with and without the developed attenuation corrections.

RESULT
We showed that the activity quantitation errors in PET imaging were within ±5% when correcting for attenuation of the flat tabletop, coil holder, and flex coil. The SNR of the MRI images were reduced to 74% using the tabletop, and 66% using the tabletop and coil holders.

We present a tabletop and coil holder for an anterior array coil to be used with a GE SIGNA PET/MR scanner, for scanning patients in the radiotherapy work flow. Implementing attenuation correction of the added hardware from the radiotherapy setup leads to acceptable PET image quantitation. The drop in SNR in MR images may require adjustment of the imaging protocols.

Technical Note: Adapting a GE SIGNA PET/MR scanner for radiotherapy

A process for attenuation correction of a plurality of time-domain filtered PET images of a moving structure includes creating an ACF-matrix based on a base-MR image of the structure; developing a plurality of image transforms, each of said registered image transforms the base-MR image with an appropriate film-MR image of the moving structure; applying each of the image transformations to the ACF-matrix to generate a corresponding film ACF matrix; the Zeitkorrelieren each of the film-MR images and its corresponding film ACF matrix with one of the plurality of time-domain filtered PET data sets; and generating, from each of the time domain filtered PET data sets, an attenuation-corrected time domain filtered PET image a.

Method and apparatus for area-specific MR-based attenuation correction of the time domain filtered PET studies

Characterization of the impact to PET quantification and image quality of an anterior array surface coil for PET/MR imaging

Abstract: Magnetic resonance imaging (MRI) is emerging as a powerful tool for the diagnosis of breast abnormalities. Dynamic analysis of the temporal pattern of contrast uptake has been applied in differential diagnosis of benign and malignant lesions to improve specificity. Selecting a region of interest (ROI) is an almost universal step in the process of examining the contrast uptake characteristics of a breast lesion. We propose an ROI selection method that combines model-based clustering of the pixels with Bayesian morphology, a new statistical image segmentation method. We then investigate tools for subsequent analysis of signal intensity time course data in the selected region. Results on a database of 19 patients indicate that the method provides informative segmentations and good detection rates.

The purpose of this study was to evaluate the impact of spatial resolution on coronary calcium scoring by x-ray CT, to assess the scoring performance of different CT scanners as they are operated in the field and to correct for the effects of CT scanner spatial resolution on coronary calcium scoring. A phantom consisting of five aluminium wires of known diameter in water was used to measure spatial resolution and to assess scoring performance. Fourteen CT scanners (three helical, two dual, two electron-beam and seven multi-detector) from four manufacturers were evaluated, some under different operating conditions. One scanner was monitored over a 3 month period and again 6 months later. Both spatial resolution and image pixel size significantly affect calcium scoring results. Spatial resolution can be measured with a precision of about 2%. Scanner spatial resolution ranged from 1 to 1.7 mm full-width-half-maximum (FWHM), and pixel size from 0.25 to 0.86 mm. Spatial resolution differences introduce systematic scoring differences that range from 38% to 1100% depending on wire size. Significant temporal variations in spatial resolution were observed in the monitored scanner. By correcting all the scanners to the same target spatial resolution, the standard deviation of individual scanners with respect to a mean value (the spread) can be reduced by 25-70% for different wires. In conclusion, scanner spatial resolution significantly affects calcium scoring and should be controlled for. Scanner performance can change over time. Under ideal conditions, CT scanners should be operated with a standard spatial resolution for calcium scoring. When this is not possible, post-processing correction is a viable alternative.

Coronary calcium scoring: modelling, predicting and correcting for the effect of CT scanner spatial resolution on Agatston and volume scores.

Needle biopsies and other interventions done under MR Fluoroscopy sometimes do not show the target well, either because the rapid sequence does not have adequate contrast or because a contrast agent may have washed out of the target. In these cases, an image that shows the target can be saved and scaled to match the spatial parameters of the fluoroscopic sequence, and used as a virtual or ghost field upon which the fluoroscopic images are superimposed, thus providing a view of the target, useful for needle pre-localization and for monitoring its progress as it is inserted.

Magnetic Resonance Imaging (MRI) is emerging as a powerful tool for the diagnosis of breast abnormalities. Early investigation of contrast-enhanced MRI of the breast demonstrated that breast carcinoma consistently enhanced after the intravenous administration of contrast material (Gadolinium). However, many benign lesions also enhance reducing as a result MRI specificity- . Further characterization is necessary to differentiate benign from malignant lesions and analysis of the temporal pattern of contrast uptake has been applied to improve specificity. Selecting a Region-Of-Interest (ROI) is an almost universal step in the process of examining the contrast uptake characteristics of a breast lesion. A limitation of most ROI analysis procedures is that only subjectively selected regions are examined. We propose a ROI selection method based on techniques from multivariate data analysis and statistical image segmentation. In addition to the enhancement rate of the contrast material, we use other characteristics of the signal intensity to group areas of the breast with similar characteristics and then select the group which corresponds to a fast and strong enhancement. We then investigate tools for subsequent analysis of signal intensity time course data in the selected region in order to determine if the enhancing lesion is likely to be benign or malignant. We tested our procedure on cases for which the diagnosis was available. The results are promising and are consistent with the diagnosed nature of the lesions.

Region-Of-Interest Selection and Statistical Analysis of Dynamic Breast Magnetic Resonance Imaging Data

Ghost imaging for targeting breast masses with MR imaging: a phantom study.

A method was developed for separation of water and fat MR images in a single scan with correction of static field inhomogeneity. The imaging sequence uses a single radiofrequency (RF) echo that is „sandwiched”︁ between two gradient echoes. The gradient echoes are used to determine the Bo distribution and to produce out‐of‐phase images after phase correction using the field map. An algorithm was developed to unwrap the phase images for quantitating the Bo inhomogeneity. To account for differences in geometric distortion between the RF echo image and the gradient echo images due to the reversal of the read gradients, methods were developed to correct the images before the calculation of the final water and fat images. The proposed technique was implemented at .35 T. Both phantom and human images were acquired using the method. It is shown that water‐ and fat‐separated images can be obtained in a single scan using the „sandwich”︁ echoes in the presence of a relatively large Bo inhomogeneity.

Separation of water and fat MR images in a single scan at .35 T using „sandwich”︁ echoes

The authors investigated the possibility of making non-invasive temperature measurements using MRI. Excised samples of beef muscle and brain were imaged with sequences for rapidly measuring the T/sub 1/, T/sub 2/, and proton density as the tissue temperature was varied from 37/spl deg/C to 43/spl deg/C and above. The signal strength varied by as much as 1.7% per /spl deg/C. For the imaging protocol used, the minimum detectable temperature change (1/spl sigma/) in a 1 cm/sup 3/ voxel over a 6 minute time interval was 1/spl deg/C. Some improvement is expected if the measured dependencies of T/sub 1/, T/sub 2/, and proton density on temperature are used to design a sequence that maximizes the change in signal strength with temperature. The signal strength vs. temperature data show some hysteresis, even for samples held below 43/spl deg/C-the maximum temperature to which healthy tissue is generally raised in hyperthermia. If live tissue shows the same behavior, it may be impossible to do true thermometry based on changes in T/sub 1/, T/sub 2/, and density. There may remain the possibility of accurately measuring small temperature changes over a narrow range.<<ETX>>

1993 IEEE Conference Record Nuclear Science Symposium and Medical Imaging Conference

Acquisition of relaxation rate dispersion curves from magnetic resonance images was demonstrated on a clinical, whole-body imaging system. Study of the behavior of relaxation rates over a range of field strengths probes the structural environment of imaged hydrogen protons and reveals information about the composition of tissue. The authors determined relaxation rates in extremities and heads of healthy volunteers. The sensitivity of the measurement is sufficient to obtain a distinctive relaxation rate dispersion behavior for different tissues.

We describe the implementation of a field—cycling electromagnet in a whole—body clinical MRI system. A pulsed magnet is driven on during dead times of the NMR sequence and serves to increase the equilibrium magnetization induced in the patient Signal transmission and reception occurs only during the period when the electromagnet is turned off and does not otherwise influence the data collection. Applications of the technology include image quality enhancement for low field MRI and for in vivo localized relaxation rate measurements.

The 370 micron 3P2-3P1 fine-structure line of neutral carbon was detected in seven sources: OMC 1, NGC 2024, S140, W3, DR 21, M17, and W51. Simultaneous analysis of J = 2-1 data and available observations of the J = 1-0 line make it possible to deduce optical depths and excitation temperatures for these lines. These data indicate that both C I lines are likely to be optically thin, and that the ratio of C I to CO column densities in these clouds is typically about 0.1. 54 references.

Infrared Heterodyne Spectroscopy of Polyatomic Molecules in Circumstellar Envelopes.

Observations of the 809 GHz Fine Structure Line of Atomic Carbon in Dense Molecular Clouds

We have detected the 809 GHz 3P2-3P1 fine-structure line of neutral atomic carbon in four dense molecular clouds: M17, W51, W3, and DR 21(OH). These observations complement the published observations of the 492 GHz 3P1-3P0 line and allow the excitation temperature of the 3P levels along with the line optical depths to be determined. The results indicate excitation temperatures Tx approximately 30-60 K and optical depths of tau 10 < or approximately 1. This implies that the approximately 10(18) cm-2 lower limit to the C I abundance derived from 492 GHz observations is probably the actual abundance, which gives C I/CO approximately 0.1 in dense molecular clouds.

Circumstellar Dynamics Observed by Infrared Heterodyne Spectroscopy

Seven new lines in the 10 micron nu7 band of C2H4 have been detected in the highly obscured carbon star IRC + 10216. The line intensities cannot be well described by a single rotational temperature, in contrast to the lines of CH4 and SiH4 previously observed in this source. There are at least three interpretations: the line intensities are variable on a time scale of months and years, C2H4 lines are formed over a region less homogeneous than that of CH4 and SiH4, or ethylene is somewhat nonthermally excited. Regardless, the line intensities indicate an average rotational temperature of 100 K and a column density of about 4 x 10 to the 15th/sq cm, which is approximately 2 x 10 to the -5th times the CO abundance. A search was also made for infrared transitions of CH2, the methylene radical. No lines were detected, but the observational limits are compared with the abundance and radial distribution for CH2 predicted by a model invoking the photodissociation of CH4.

Silane has been detected in the gas surrounding IRC +10216. Thirteen absorption lines in the nu-4 band around 917/cm were observed at 0.2 km/s resolution. A lower limit to the radial column density is 2 x 10 to the 15th/sq cm, and the relative strengths of the transitions indicate an average rotational temperature of 173 K.

Experiences by orphaned children as learners at a Secondary School in the Maluti District of Education in the Eastern Cape

Dental disease is one of the leading causes of school absenteeism for children. This article describes the creation and evolution of the St. David's Dental Program, a mobile school-based dental program for children.

METHODS
The dental program is a collaboration of community partners in Central Texas that provides free dental care to low-income children in schools without relying on reimbursements or government funding.

RESULTS
Since 1998, the program has provided 132,791 screenings for oral health treatment needs and 38,634 encounters for sealants or treatment. In 2005, the program provided $2.1 million worth of services at a cost of $1.2 million (not including donated services). Factors important to the program's success included sustained funding for general operating costs; well-compensated clinicians to deliver care and experienced human service workers to manage program operations; the devotion of resources to maximize consent form return rates; and the development of strong relationships with school district and individual school staff.

By removing cost, time, transportation, and bureaucratic barriers, the program was able to reach more children than fixed-site clinics. The program was a merging of private and public health dentistries. This model can be useful to other communities in light of the unmet need for dental care and tighter federal, state, and local government budgets.

One teacher from each of the secondary schools and four special schools in Halton district completed a questionnaire in a semi-structured interview on sex education in their schools. The results showed that a variety of programmes took place but frequently teachers did not feel adequately prepared to teach this vital but difficult subject. Strengths of the programme included the popularity of parent's evenings to discuss sex education programmes, pastoral syllabuses followed by form tutors, 'student led' sex education programmes and the development of personal and social education courses. Difficulties encountered included a lack of on-going sex education programmes, a lack of sex education in the second year when teenage pregnancies were occurring and a lack of teacher training.

What a loss! exclaim these authors when schools fail to provide programs for artistically gifted young sters. They tell the reader how to identify talented students, how to select teachers for them, and how to utilize resources for such programs. All this and a glimpse at where successful programs are operating.

Citizen Participation - An Exercise in Futility: An Action Program for ASPA

A Portrait and Analysis of the New Left: Does the New Left Present a Viable Alternative to American Politics

Demonstration Center-Part One, Secondary School Programs for Gifted Students in English, Social Science, Mathematics and Science (The Demonstration Project for Gifted Children). Final Report.

INSERVICE EDUCATION - AN INTEGRAL PART OF THE ILLINOIS PLAN FOR PROGRAM DEVELOPMENT FOR GIFTED CHILDREN.

Q-TECHNIQUE, designed for the study of the traits or characteristics of individual cases, has been used increasingly since its development by Stephenson. (7) For many years sociologists and clinical psychologists have been concerned with the description of single cases. More recently, social psychologists, students of education, and others have increased their use of exploratory studies involving one or a few subj ects, seeking in this way to find a basis for the framing of hypotheses to be verified in investigations where generalizations are drawn from a sample to a population. Q-technique has been one tool seized upon for use in these exploratory investigations. Since these investigators are frequently concerned with the study of groups and social institutions, as well as with individuals, the heuristic value of Q-technique would seem to depend in part on the extent to which it may be used in the study of single groups or institutions as well as in the study of an individual person. It is the purpose of this paper to suggest certain modifications of Q-technique designed to increase its applicability to the study of group phenomena.

N connection with a study of teachers' and administrators' perceptions of core programs at the junior high school level, it was necessary to develop some means of measuring an individual's orientation toward one or the other of opposing curriculum theories: the theory upon which core programs are based or the theory basic to a curriculum organized as separate subjects. To meet the requirements of the study, the instrument designed for this purposel had to be administered in approximately thirty minutes, and scoring and analysis could not involve lengthy computations. The technique employed in developing the instrument is based upon Professor Stephenson's Q-methodology (4), but the methodology was adapted in this study for brevity and ease of administration and analysis.

Development of a Measure of Orientation toward Core and Subject Curriculum Theories

A thermoplastic shoulder member for a flexible thermoplastic tube container has a nozzle (13) with an orifice (14) therein, and is compression moulded to form on the internal side of the orifice (14) a surrounding inwardly projecting hollow spigot (21) which is formed by back extrusion during compression moulding. The shoulder member (12) may be formed from a laminate material which includes a barrier layer (23) which extends into the inwardly projecting spigot.

Mitochondrial Replacement Therapy is an ethically controversial procedure that allows women with genetically transmitted mutations in their mitochondria to have healthy children. Using this procedure, healthy mitochondria from a third party can be donated in the fertilization process to create a healthy child from three genetic “parents.” There is much concern about the safety and ethics of this procedure and presenting the Catholic and Jewish perspectives of Mitochondrial Replacement Therapy can offer insights into the morally complexity of the ethical issues surrounding this innovative medical procedure.

Mitochondrial Replacement Therapy, Jewish and Catholic Ethical Perspectives

Culturally competent medical care for the dying patient by families and health care professionals is a challenging task especially when religious values, practices, and beliefs influence treatment decisions for patients at the end of life. This article describes end-of-life guidelines for hospital health care professionals caring for Orthodox Jewish patients and their families. Religious perspectives on advance directives, comfort care and pain control, nutrition and hydration, do not resuscitate/do not intubate (DNR/DNI), and extubation are often unfamiliar to the American medical community.

DESIGN
The guidelines for the care of the dying Orthodox Jewish patient were mutually agreed upon by the authors, recognized authorities in medicine, ethics, and Jewish law, who presented their perspectives during a 1-day symposium and who participated in an active working-group session.

Care of the religious patient close to death is enormously complex especially when balancing religious obligations, the role of the rabbi, medical procedures, and personal preferences. These guidelines address from a religious perspective profound issues such as the definition of death, organ donation, and caring for the patient at life's end. The guidelines can be useful for any hospital that serves an Orthodox Jewish population.

The critical role of religion: caring for the dying patient from an Orthodox Jewish perspective.

Jewish Views on the Beginnings of Human Life and the Use of Medical Intervention to Produce Children

The potential use of stem cells in the treatment of a variety of human diseases has been a major driving force for embryonic stem cell research. Another productive area of research has been the use of human stem cells to reconstitute human organ systems in animals in an attempt to create new animal models for human diseases. However, the possibility of transplanting human embryonic brain cells or precursor brain cells into an animal fetus presents numerous ethical challenges. This paper examines, from a Jewish perspective on human dignity, several bioethical concerns related to the reconstitution of animal brains with human neurons.

Reconstituting a Human Brain in Animals: A Jewish Perspective on Human Sanctity

The potential use of stem cells in the treatment of a variety of human diseases has been a major driving force for embryonic stem cell research. Another productive area of research has been the use of human stem cells to reconstitute human organ systems in animals in an attempt to create new animal models for human diseases. However, the possibility of transplanting human embryonic brain cells or precursor brain cells into an animal fetus presents numerous ethical challenges. This paper examines, from a Jewish perspective on human dignity, several bioethical concerns related to the reconstitution of animal brains with human neurons. The two seminal papers (Shamblott et al. 1998; Thomson et al. 1998) that reported growing and maintaining human stem cells from embryos have stimulated numerous bioethical debates and discussions. A central theme in these debates is the status of a preimplanted embryo, an implanted embryo, and a fetus with respect to personhood (for reviews, see Rosner and Reichman 2002; Walters 2004). Yet, there are other issues that deserve analysis. In this article, we present a Jewish perspective on the following bioethical situation that has occupied the National Academy of Sciences (NAS 2005). What are the ethical considerations in transplanting embryonic human brain-stem cells into an animal embryo in an attempt to repopulate human nerve cells in the brain of an animal? Such an organism, composed of both human and animal cells is commonly called a chimera, a Greek name for a mythical beast that had a lion’s head, a goat’s body, and a serpent’s tail. Is such a being with human brain cells an animal? What if this organism speaks or expresses humanlike intelligence? Is it human? Here we propose a perspective rooted in the kennedy insTiTuTe of eThics JournaL • december 2008 [ 348 ] principles of Judaism1 on both the appropriateness of such experimentation and the bioethical challenges that emerge from this technology. Secular moral approaches published in the Kennedy Institute of Ethics Journal discuss various ethical concerns of this emerging technology (Karpowicz, Cohen, and van der Kooy 2005; Streiffer 2005). Some of the ethical concerns that this technology elicits include: (1) a moral taboo, (2) an effort contrary to nature, (3) a denigration of human dignity, (4) a violation of species integrity, and (5) an infringement of moral status. However, comparing a religious approach to a secular approach may provide another framework for assessing the moral impact of these types of experiments. Jewish religious philosophy often bases its principles on Biblical, Talmudic, and post-Talmudic rabbinical writings. From a Judaic perspective, the use of stem cells to reconstitute a human brain in an animal fetus raises several legal and philosophical concerns. We suggest that the two main ethical concerns related to this technology are the Bible’s identification of Homo sapiens as a unique species and its unwavering concern for human dignity. Although the Jewish perspective is to minimize animal suffering, animal experimentation is permitted and even encouraged when a technology can provide significant benefit to alleviate human suffering and disease (see Isserles 1954). Thus, the ethical issue of animal suffering is an important issue in Judaism but not as significant in this case. THE USE OF HUMAN-ANIMAL CHIMERAS IN RESEARCH AND MEDICINE Human-animal chimeras, organisms composed of a mixture of human and animal tissues, have been developed in medical centers around the world for several decades leading to significant medical applications (Nagy and Rossant 2001). Until recently, inserting small amounts of human tissue into animals rarely elicited ethical outcry. In the 1980s, Dr. Irving Weissman created one of the first human-mouse chimeras. He transplanted human bone marrow stem cells into a strain of mice that lacked its own immune system. The transplanted human stem cells from the bone marrow triggered the reconstitution of a human immune system in these mice. These mice serve as valuable animal models in studying a variety of human diseases, such as AIDS and hematological cancers (Shizuru et al. 2005). Since the HIV virus, which causes AIDS, does not normally infect mouse cells, these human-mouse chimeras enabled scientists to learn how the virus infects and replicates in human immune cells within a live animal. Humanized mice are also being used to study Loike and TendLer • a Jewish PersPecTive on human sancTiTy [ 349 ] the virus that causes hepatitis (Turrini et al. 2006). In addition, scientists have repopulated a mouse liver with human liver cells and are using this animal model to gain a better understanding of liver development and to examine drug metabolism within human livers (Meuleman et al. 2005). Chimeras eventually may be used to reproduce parts of the human body. Esmail Zanjani, at the University of Nevada, is taking advantage of the fact that about halfway through a sheep’s embryological development its immune system will not reject any transplantable foreign cell (AlmeidaPorada et al. 2004; Chamberlain et al. 2007). His group is examining whether human stem cells can be transplanted into an embryo of a sheep so that the stem cells will become incorporated into various organs, allowing the sheep’s organ to develop human cells. Once born, this sheep would have a liver composed primarily of human cells that are genetically compatible with the donor of the stem cells. The human liver developed in the sheep could then be transplanted into that stem cell donor with a minimal danger of organ rejection and without the need to provide lifelong anti-rejection drugs as are normally administered to most organ transplant patients. In addition, scientists reported in 2007 the capacity to repopulate 20 percent of adult and fetal mice with human hepatocytes enabling these mice to produce human liver proteins (Bissig et al. 2007). Another group (Chamberlain et al. 2007) is examining human-sheep chimeras as a potential animal model to reconstitute a human hematopoietic system. However, there are still many medical obstacles that must be overcome before this research enters the clinical testing. In other studies of human-animal chimeras, researchers have transferred whole human embryonic or fetal organs—stomachs, intestines, tracheas, and lungs—obtained from legal abortions into the bodies of nude mice (Angioi et al. 2002). Researchers also have inserted human blood and skin stem cells into postnatal mice (Kamel-Reid and Dick 1988; Dick et al. 2001; Raychaudhuri et al. 2001; Angioi et al. 2002). There are several reports of transplanting human embryonic stem cells or neural cells into animal embryos or fetuses. For example, Jitka Ourednik and colleagues (2001) transplanted human neural cells into the developing fetal brains of monkeys. Other groups have transplanted human embryonic stem cells into chicken embryos or human neural stem cells into fetal sheep (Goldstein et al. 2002; Almeida-Porada et al. 2004). Finally, several groups have reported transplanting neural-like human stem cells into the brains of neonatal rodents and found that they differentiated into both neurons and astrocytes (Brustle 1999; Zhang et al. 2001). kennedy insTiTuTe of eThics JournaL • december 2008 [ 350 ] Future research involving the transplantation of human brain stem cells (White 2007) or genetically integrating human neural-specific genes (Reiner et al. 2007) into animal fetuses could be designed to examine fundamental issues in biology and medicine. For example: (1) Developing human-animal chimeras with human brain cells might help scientists to better understand how the human brain is formed during embryological development. Although the prospect of studying human brain transplants is not foreseeable within the immediate future, scientists may use human-animal chimeras to understand how brain size is regulated and how human neural networks or circuits are formed during embryological development. Chimeras provide a novel model system for targeting many different kinds of human cell types that are mainly found in the human embryo and are necessary for the development of the brain. Identifying these cells and understanding how these diverse cell types regulate brain development in an animal environment could be scientifically valuable for understanding how the human brain develops normally. (2) Human-animal chimeras also could be used to study human neurological diseases. One could transplant human stem cells from an individual with a genetic predisposition to develop Alzheimer’s disease or Huntington’s disease into an animal fetus. Then, one could follow the progress of brain development from birth until old age to characterize neural degeneration within an animal model. Such an animal model could answer several important questions, including whether these diseases only develop later in life or whether there are early changes in the younger brains of these patients. Scientists also could use specific mice that develop Alzheimer’s disease to develop chimeras that express human brain cells such as microglial cells or astrocytes that are not nerve cells. Work at Columbia University College of Physicians and Surgeons (Wyss-Coray et al. 2003) and at other institutions have shown that microglial cells or astrocytes are critical for removing amyloid plaques that normally develop during aging. It is thought that in Alzheimer’s patients, these cells are less effective in removing these plaques. When the plaques build up, they trigger the destruction of surrounding neurons. Human-mouse chimeras could provide an animal model to examine whether reengineered human microglial cells or astrocytes could improve their capacity to prevent amyloid plaque build up, delay onset of the disease, or repair areas of the brain destroyed by Alzheimer’s disease. The more human-like the animal, the better research model it makes for testing drugs a

OBJECTIVE
Genital neonatal herpes simplex virus type 1 (HSV-1) infection was observed in a series of neonates after traditional Jewish ritual circumcision. The objective of this study was to describe neonate genital HSV-1 infection after ritual circumcision and investigate the association between genital HSV-1 after circumcision and the practice of the traditional circumcision.

METHODS
Eight neonates with genital HSV-1 infection after ritual circumcision were identified.

RESULTS
The average interval from circumcision to clinical manifestations was 7.25 +/- 2.5 days. In all cases, the traditional circumciser (the mohel) had performed the ancient custom of orally suctioning the blood after cutting the foreskin (oral metzitzah), which is currently practiced by only a minority of mohels. Six infants received intravenous acyclovir therapy. Four infants had recurrent episodes of genital HSV infection, and 1 developed HSV encephalitis with neurologic sequelae. All four mohels tested for HSV antibodies were seropositive.

Ritual Jewish circumcision that includes metzitzah with direct oral-genital contact carries a serious risk for transmission of HSV from mohels to neonates, which can be complicated by protracted or severe infection. Oral metzitzah after ritual circumcision may be hazardous to the neonate.

Neonatal genital herpes simplex virus type 1 infection after Jewish ritual circumcision: modern medicine and religious tradition.

In this age of rapid biotechnological discovery, we witness halakhic authorities responding to biomedical advances by examining basic definitions of the human experience. For example, the first success ful human heart transplant in the 1970's generated considerable debate concerning the halakhic definition of death.1 The birth of the first test tube babv, Louise Brown, in 1978, initiated halakhic discus sions regarding the definition of motherhood, the halakhic status of surrogate mothers, and whether babies born by way of in vitro fertil ization are included in the formal mitsva of reproduction.2 Today, bio medical research focusing on human cloning, embryonic stem cells, and the human genome project has prompted additional discussions, among them the fundamental question: How does halakha define a human being? In this article we begin by describing how scientists delineate species in general, and homo sapiens in particular. Next, we propose specific criteria for the halakhic definition of man and examine their application to new biotechnological advances. Within the context of a scientific definition of species we also show how the underlying charac teristics, so-called modern theories of human identity, were in fact foreshadowed hundreds or thousands of years ago in halakhic literature.

Ma adam va-teda-ehu: halakhic criteria for defining human beings.

Research in genomics, human cloning, and transgenic technology has challenged bioethicists and scientists to rethink the definition of human beings as a species. For example, should the definition incorporate a genetic criterion and how does the capacity to genetically engineer human beings affect the definition of our species? In considering these contemporary bioethical dilemmas, we revisit an ancient source, the Talmud, and highlight how it provides specific biological, cultural, and genetic criteria to define the human species.

The Judeo-Biblical perspective on organ donation: you shall choose life.

Alzheimer dementia: the Judaeo-Biblical perspective on patient care and genetic predestination or neurocalvinism.

The core of the text combines the theory and practice of brain death determination, history, and the development of clinical criteria of what brain death is. With incredible clarity, the author describes in the first five chapters the complex neurological evaluations and all the pitfalls that can be experienced: cultural beliefs, bioethical problems, discussions with family members, and many of the issues associated with organ procurement.

The article "Quality and Sanctity of Life in the Talmud and Midrash" (Tradition, 28:1 Fall, 1993), by Rabbi Moshe D. Tendier and Dr. Fred Rosner prompts several observations: 1. Aside from minor—though misleading—grammatical errors (e.g. "One" exception exists to the absolute "vote for life" rule when, of course, there are three which the subsequent quote from Maimonides makes clear) I am puzzled by the term the "sanctity of life. " Though this expression is often used today, I wonder where this term, which I would translate as kedushat hahaim, appears in early Jewish literature. The term "sanctity of life" has a foreign, almost Christian, ring to it. Surely life's sanctity is entirely a function of its liver. (Not the organ!) Life as such has no inherent sanctity unless sacred values are infused into life by the person who is entrusted with that life. Similarly, another contemporary notion, "death with dignity," has no status in halakhic sources. 2. Judaism teaches that innocent life's value is limitless and may not be liquidated under any circumstances. In terms of extinguish ing life, even the patient himself can make no compromising evalua tion of the quality of that life. Only insofar as deciding to allow death to supervene naturally would a patient's subjective agony be a relevant factor in permitting withholding or withdrawal of therapy. 3. The authors' disclaimer that "our analysis in this essay should not be interpreted or misconstrued as a final halakhic ruling" does little to moderate their demeaning categorization on the next page questioning whether "there [is] any validity in the claim of some rabbis that we are obligated to fight for the last breath of life?" The reader must consult the endnotes to find that these rabbis include such venerable and unquestioned authorities as Rabbi Eliezer Waldenberg and Rabbi Sholmo Zalman Auerbach. A review article—particularly one which renounces for itself a role as halakhic decisor—ought to present the views of all recognized authorities and should not imply that one view is normative by featuring it in the body of the text (in this case that of Rabbi Moshe Feinstein) while relegating other important opinions to the end-notes.

The talmudic maxim "to save one life is tantamount to saving a whole world" (Sanhedrin 37a) indicates that the value of human life is infinite. A fraction of infinity is stil infinity. Nothing in this world is of higher value or greater ethical import than human life. Even Torah commandments of the Holy One, blessed be He, must give way to the higher value of preserving human life. The biblical verse "You shall study and observe my laws and live thereby" (Lev. 18:5) is interpreted in the Talmud (Yama 8Sb) to mean that the saving of a life takes precedence over Sabbath observance. By inference, all other Torah laws must also be suspended to save a life since none are more important than the Sabbath laws. One exception exists to this absolute "vote for life." Rav Yohanan (Sanhedrin 84a) taught that the rabbinic consensus is that if someone's life is in danger, he should transgress all Torah laws to save his life. If, however, to save his life, he must transgress the laws of murder, idolatry or forbidden sexual relations such as adultery, he must rather forfeit his life. Maimonides explains that these three exceptions to the rule of "transgress and do not die" exist because of the duty to sanctify God's name:

Three diagnostic tests, Nitur, Urobact, and Uricult, were evaluated in the detection of bacteriuria in 865 pregnant women. As reference method agar culture was performed. Heavy growth (greater than 10(5) CFU/ml) of urinary tract bacteria was considered a true positive result and demonstrated in 58 (6.7%) of the women, 14 of whom had gram-negative rods. The sensitivity of the nitrite test was extremely low (0.13). The test gave negative results in eight of 17 specimens yielding heavy growth of Escherichia coli or Proteus mirabilis. Although the Urobact test was highly sensitive as regards gram-negative infection, it had an unacceptably low (0.27) predictive value in positive tests. The sensitivity of the Uricult test was low (0.35) in this study. The predictive value (0.50) of a positive test result may be acceptable, since just over half of the false positive results were explainable by moderate growth of urinary tract pathogens (10(4)-10(5) CFU/ml). It is argued that semi-quantitative urine culture may be preferable to the rapid diagnostic methods studied for the screening of bacteriuria in pregnant women.

he Chazol1 Ish wrote l that it is not an easy task to determine what the halacha is. First, one must be familiar with all the details of halacha, the normative Jewish law; secondly, and often more difficult. one must be able to analyze properly the case at hand in order to know which halacha "on the books" it is most similar to. Traditionally, halacha is determined by analogy: the pasek juxtaposes the particulars of his own case and various halachic precedents and principles, and thereby decides into which category his case falls. Then he must apply these precedents and principles to the situation at hand. However, the situation of a brain-dead individual is unique to our generation. Never has anything comparable existed in earlier generations. Bodily funcition can now be simulated by machines, and onsequently an ill person can linger in a kind of medical-legal limbo for a short period of time. Thus, it has become important to the medical profession to determine at what point a patient may be considered dead (both for terminating treatment and for possible organ transplantation). In turn, the new realities have given rise to the halachic need to determine the moment of death. The Talmud tells us1 that if someone is not breathing, he is dead. This conclusion is based on the verse in the Torah3 "Kal asher nishmat ruach chaim be-apov" "Whoever has the breath of

Rabbinic comment: The infant: right to privacy and patient's right to know.

To determine whether corticosteroids are efficacious in severe septic shock, we conducted a prospective study of 59 patients randomly assigned to a methylprednisolone, dexamethasone, or control group. Patients were treated 17.5 +/- 5.4 hours (mean +/- S.E.M.) after the onset of shock, and 55 patients required vasopressor agents. Early in the hospital course, reversal of shock was more likely in patients who received corticosteroids than in those who did not. Four (19 per cent) of 21 methylprednisolone-treated, 7 (32 per cent) of 22 dexamethasone-treated, and none of 16 control patients had reversal of shock 24 hours after drug administration (corticosteroid groups vs. control group, P less than 0.05). Patients treated with corticosteroids within four hours after the onset of shock had a higher incidence of shock reversal (P less than 0.05). At 133 hours after drug administration, 17 (40 per cent) of 43 corticosteroid-treated patients had died, and 11 (69 per cent) of 16 control patients had died (P less than 0.05). However, these differences in reversal of shock and survival disappeared later in the course. Overall, 16 (76 per cent) of 21 patients receiving methylprednisolone, 17 (77 per cent) of 22 patients receiving dexamethasone, and 11 (69 per cent) of 16 controls in the hospital died. We conclude that corticosteroids do not improve the overall survival of patients with severe, late septic shock but may be helpful early in the course and in certain subgroups of patients.

The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study.

Rabbinic comment: In vitro fertilization and extrauterine pregnancy ("test-tube" baby).

Gellman: The basic premise, as far as Jewish law is concerned, is that triage at all levels-societal or individual-is evil. Jewish law dictates, when confronted with the ordering of giving aid to people, be it medical or financial, that the ques­ tion is who gets help first. It is never a decision between someone getting help and someone else being left out. The classic example of two people in the desert-if they share the water and live today, they chance what is going to happen to­ morrow-applies not only to individuals but to society as well. It is very rare in Jewish practice that any community would say we're going to help one group of individuals and leave oth­ ers out.

New developments in the use and recognition of brain death in the united states and other countries.

To the Editor.— "Brain Death—An Opposing Viewpoint" by Byrne et al (242:1985, 1979) is an attempt to refute an article (238:1651, 1977) in which we developed scientific, theological, ethical, and legal support for use of the brain death concept. In our article we sustained the position that total and irreversible cessation of brain function as determined by the Harvard criteria (205:337, 1968) or their more recent modifications (237:982, 1977) is equivalent to total destruction of the brain and hence tantamount to functional or physiological decapitation, a condition that most lay and religious ethicists—and indeed most persons—can equate with death. The article by Byrne et al presents arguments that are weak at best and, in some instances, approach absurdity. It uses the language of science to plead a theological position against use of the brain death concept but fails to state clearly what can, with certainty, be equated with death, except

PART I of this article established the scientific validity of current clinical and laboratory criteria for determining complete destruction of the brain or brain death. It also showed that total destruction of the brain constitutes a determinant of death, which is in accord with secular philosophy and the three major Western religions. In part II, legal issues that arise from use of brain-related criteria to pronounce death are considered. NEED FOR STATUTORY RECOGNITION OF BRAIN DEATH The fact that physicians can recognize total and irreversible destruction of the brain on the basis of clinical and laboratory criteria is accepted and commonly utilized in many areas of the world. The need to make such pronouncements is based primarily on the requirement of society to respond appropriately to two recent advances in medical technology. The first is the hardware that can artificially maintain lung and heart action in the absence of spontaneous

Use of neurologic criteria to pronounce death, although accepted by many, has caused controversy among physicians, lawyers, legislators, philosophers, and theologians. The present work attempts to resolve this by accomplishing four objectives. (1) It summarizes scientific information that establishes the ability to determine the state of brain death with certainty on the basis of presently available clinical and laboratory criteria. (2) It shows that the concept of brain death is in accord with secular philosophy and the three major Western religions. (3) It documents the need for legislative recognition that death may be pronounced on the basis of neurologic criteria. (4) It reviews the present status of judicial and statutory law relating to the determination of death in the United States.

Brain death. I. A status report of medical and ethical considerations.

The use of a hydrophilic polymer as a permanent soft liner for dentures.

Effects of Temperature and Nutrition on Macromolecule Production by Thermophilic Eumycophyta

Our studies indicate that increased host resistance to irradiation is produced when M.B.T. or anthramycin is injected prior to exposure. The mechanism of protection with a therapeutic dose of M.B.T. or anthramycin is thought to be through stimulation of the hematopoietic and reticuloendothelial systems—usually sites of severe irradiation injury. Lysosome studies have been conducted on microscopic sections of liver and spleen of mice treated with M.B.T. and anthramycin 24 hours prior to lethal irradiation of 700 r and, in contrast, of control mice treated with saline and like irradiation. Immediately following irradiation and on day 7, 14, and 21 post total body exposure, the organs were removed and the animals sacrificed. The tissues were fixed and stained according to the method of Barka and Anderson.5 Microscopic examination was made of the prepared slides to determine evidence of stimulation of the hematopoietic or reticuloendothelial systems through this medium. To date, insufficient evidence is avail...

The radioprotective and anti-tumor effect of mixed bacterial toxins and anthramycin.

Summary Anthramycin toxicity to growth of the alga, E. gracilis, increases with decrease in pH and with incubation of cultures in the light instead of the dark. Anthramycin is a bleaching agent: it causes the production of permanently white colonies.

Clinical investigation of cancer chemotherapeutic agents for neoplastic disease.

‘Refuin’ : a Non-cytotoxic Carcinostatic Compound proliferated by a Thermophilic Actinomycete

Non-cytotoxic anti-tumor proteins proliferated by actinomycete. Abstr.

A total of 1,000 isolates of thermophilic actinomycetes representing two genera, Streptomyces and Thermoactinomyces, were studied. Media for cultivation and for physiological studies were designed. Differences between the two genera are noted and taxonomic criteria for the genus Thermoactinomyces are suggested. The importance of the nutritional environment to the thermophilic habit is noted.

Studies on the thermophilic actinomycetes. I. Methods of cultivation.

medical research focusing on human cloning, embryonic stem cells, and the human genome project has prompted additional discussions, among them the fundamental question: How does halakha define a human being? In this article we begin by describing how scientists delineate species in general, and homo sapiens in particular. Next, we propose specific criteria for the halakc definition of man and examine their application to new biotechnological advances. Withn the context of a scientific defition of species we also show how the underlying characteristics, so-called modern theories of human identity, were in fact foreshadowed hundreds or thousands of years ago in halakc literature.

Non-asbestiform elongate mineral particles and mesothelioma risk: Human and experimental evidence.

Abstract The potential toxic effects of short chrysotile and amphibole asbestos fibers with lengths <5 to ∼10 µm have been debated over the years. This stems from the large database of epidemiology, toxicology, and in-vitro studies, each of which often provides different information in understanding and differentiating the effects of short fibers. The epidemiology studies in which the cancer potency estimates were based upon relatively high exposure concentrations provide a conservative assessment that shorter fibers would have little if any effect, especially under controlled exposure or environmental conditions that may occur today. The QSAR models have shown that fiber aspect ratio and Mg content are excellent predictors of cancer potency and that short fibers/particles of amphibole would have no effect. The studies of motor vehicle mechanics and in particular workers who serviced chrysotile containing brakes with the majority of the fibers being short provides evidence that motor vehicle mechanics, including workers who were engaged in brake repair, are not at an increased risk of mesothelioma. Several inhalation toxicology studies clearly differentiated that short chrysotile and amphibole asbestos fibers did not produce a significant carcinogenic effect in the lung or pleural cavity. Because of dosing and lack of sensitivity to biosolubility, in vitro studies can be difficult to interpret; however, a number have differentiated short chrysotile and amphibole asbestos fibers from long fibers. Integral to understanding the importance of fiber length in determining possible health effects is an understanding of the biological and physiological function of the respiratory system. Short asbestos fibers, like innocuous dust, can be cleared through the tracheobronchial ciliated mucous transport, phagocytized by macrophages and cleared via the bronchial tree, and can also be removed through the lymphatic system. While the first two methods can remove them from the lung, with lymphatic transport through one-way valves, fibers are removed from the active area of the lung where the fiber-related disease has been shown to develop and can accumulate in lymphatic sumps and lymph nodes. While short asbestos fibers are present in most occupational or environmental exposures, the large body of studies strongly supports that they do not contribute to the health effects of asbestos exposure.

The health effects of short fiber chrysotile and amphibole asbestos

Evaluation of the dose-response and fate in the lung and pleura of chrysotile containing brake dust compared to chrysotile or crocidolite asbestos in a 28 day inhalation toxicology study

Standardized methods for preparation and bi-variate length & diameter counting/sizing of aerosol and tissue digestion fiber samples.

Evaluation of the fate and pathological response in the lung and pleura of brake dust alone and in combination with added chrysotile compared to crocidolite asbestos following short-term inhalation exposure.

Evaluation of the deposition, translocation and pathological response of brake dust with and without added chrysotile in comparison to crocidolite asbestos following short-term inhalation: interim results.

Purpose of review The word asbestos is a poorly attributed term, as it refers to two very different minerals with very different characteristics. One is the serpentine mineral of which the white asbestos, chrysotile, is the most common. The other is the amphibole asbestos, which includes the blue asbestos crocidolite and the brown asbestos amosite. Although today chrysotile is the only type used commercially, the legacy of past use of amphibole asbestos remains. This review clarifies the differences between the two mineral families referred to as asbestos and summarizes the scientific basis for understanding the important differences in the toxicology and epidemiology of these two minerals. Recent findings Biopersistence and sub-chronic inhalation toxicology studies have shown that exposure to chrysotile at up to 5000 times the current threshold limit value (0.1 fibers/cm3) produces no pathological response. These studies demonstrate as well that following short-term exposure the longer chrysotile fibers rapidly clear from the lung and are not observed in the pleural cavity. In contrast, short-term exposure to amphibole asbestos results quickly in the initiation of a pathological response in the lung and the pleural cavity. Summary Significant progress has been made in understanding the factors that influence inhalation toxicology studies of fibers and epidemiological studies of workers. Evaluation of the toxicology and epidemiology studies of chrysotile indicates that it can be used safely under controlled use. In contrast, even short-term exposure to amphibole asbestos can result in disease.

Summary Significant progress has been made in understanding the factors that influence inhalation toxicology studies of fibers and epidemiological studies of workers. Evaluation of the toxicology and epidemiology studies of chrysotile indicates that it can be used safely under controlled use. In contrast, even short-term exposure to amphibole asbestos can result in disease.

Abstract This review provides a basis for substantiating both kinetically and pathologically the differences between chrysotile and amphibole asbestos. Chrysotile, which is rapidly attacked by the acid environment of the macrophage, falls apart in the lung into short fibers and particles, while the amphibole asbestos persist creating a response to the fibrous structure of this mineral. Inhalation toxicity studies of chrysotile at non-lung overload conditions demonstrate that the long (>20 µm) fibers are rapidly cleared from the lung, are not translocated to the pleural cavity and do not initiate fibrogenic response. In contrast, long amphibole asbestos fibers persist, are quickly (within 7 d) translocated to the pleural cavity and result in interstitial fibrosis and pleural inflammation. Quantitative reviews of epidemiological studies of mineral fibers have determined the potency of chrysotile and amphibole asbestos for causing lung cancer and mesothelioma in relation to fiber type and have also differentiated between these two minerals. These studies have been reviewed in light of the frequent use of amphibole asbestos. As with other respirable particulates, there is evidence that heavy and prolonged exposure to chrysotile can produce lung cancer. The importance of the present and other similar reviews is that the studies they report show that low exposures to chrysotile do not present a detectable risk to health. Since total dose over time decides the likelihood of disease occurrence and progression, they also suggest that the risk of an adverse outcome may be low with even high exposures experienced over a short duration.

Consultant in Toxicology, Geneva, Switzerland, Faculty of Science, University of Sherbrooke, Sherbrooke, QC, Canada, Center for Toxicology and Environmental Health, Little Rock, Arkansas, USA, Toxicology Services, Rutland, UK, Academia Nacional de Medicina México, Mexico City, Mexico, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico, Independent Toxicologist, Haslemere, UK, and Llandough Hospital, Penarth, UK

Response to Murray M. Finkelstein, letter to the editor re Bernstein et al: Health risk of chrysotile revisited. Crit Rev Toxicol, 2013; 43(2): 154–183

Product stewardship and science: safe manufacture and use of fiber glass.

The marked difference in biopersistence and pathological response between chrysotile and amphibole asbestos has been well documented. This study is unique in that it has examined a commercial chrysotile product that was used as a joint compound. The pathological response was quantified in the lung and translocation of fibers to and pathological response in the pleural cavity determined. This paper presents the final results from the study. Rats were exposed by inhalation 6 h/day for 5 days to a well-defined fiber aerosol. Subgroups were examined through 1 year. The translocation to and pathological response in the pleura was examined by scanning electron microscopy and confocal microscopy (CM) using noninvasive methods. The number and size of fibers was quantified using transmission electron microscopy and CM. This is the first study to use such techniques to characterize fiber translocation to and the response of the pleural cavity. Amosite fibers were found to remain partly or fully imbedded in the interstitial space through 1 year and quickly produced granulomas (0 days) and interstitial fibrosis (28 days). Amosite fibers were observed penetrating the visceral pleural wall and were found on the parietal pleural within 7 days postexposure with a concomitant inflammatory response seen by 14 days. Pleural fibrin deposition, fibrosis, and adhesions were observed, similar to that reported in humans in response to amphibole asbestos. No cellular or inflammatory response was observed in the lung or the pleural cavity in response to the chrysotile and sanded particles (CSP) exposure. These results provide confirmation of the important differences between CSP and amphibole asbestos.

Quantification of the pathological response and fate in the lung and pleura of chrysotile in combination with fine particles compared to amosite-asbestos following short-term inhalation exposure.

The pathological response and translocation of a commercial chrysotile product similar to that which was used through the mid-1970s in a joint compound intended for sealing the interface between adjacent wall boards was evaluated in comparison to amosite asbestos. This study was unique in that it presents a combined real-world exposure and was the first study to investigate whether there were differences between chrysotile and amosite asbestos fibers in time course, size distribution, and pathological response in the pleural cavity. Rats were exposed by inhalation 6 h/day for 5 days to either sanded joint compound consisting of both chrysotile fibers and sanded joint compound particles (CSP) or amosite asbestos. Subgroups were examined through 1-year postexposure. No pathological response was observed at any time point in the CSP-exposure group. The long chrysotile fibers (L > 20 µm) cleared rapidly (T1/2 of 4.5 days) and were not observed in the pleural cavity. In contrast, a rapid inflammatory response occurred in the lung following exposure to amosite resulting in Wagner grade 4 interstitial fibrosis within 28 days. Long amosite fibers had a T1/2 > 1000 days and were observed in the pleural cavity within 7 days postexposure. By 90 days the long amosite fibers were associated with a marked inflammatory response on the parietal pleural. This study provides support that CSP following inhalation would not initiate an inflammatory response in the lung, and that the chrysotile fibers present do not migrate to, or cause an inflammatory response in the pleural cavity, the site of mesothelioma formation.

The pathological response and fate in the lung and pleura of chrysotile in combination with fine particles compared to amosite asbestos following short-term inhalation exposure: interim results

Chrysotile is a sheet silicate which is formed as a very thin rolled sheet as illustrated in Figure 1. The sheet is about 8 angstroms thick (0.8 nanometers thick). It is composed of a sandwich of magnesium and silica. In the lung, the acid environment of the macrophage scavenger cell quickly breaks apart the sheet structure causing the fiber to decompose into small pieces (Figure 2). These pieces can then be readily cleared from the lung. If the fiber is swallowed and ingested it is attacked by the even stronger acid environment (hydrochloric acid, pH 2) in the stomach.

In designing a study to evaluate the inhalation biopersistence of a chrysotile asbestos that was used as a component of a joint-compound, a feasibility study was initiated to evaluate the short-term biopersistence of the chrysotile alone and of the chrysotile in combination witht the sanded reformulated joint-compound. Two groups of Wistar rats were exposed to either 7RF3 chrysotile (Group 2) or to 7RF3 chrysotile combined with aerosolized sanded joint-compound (Group 3). In addition, a control group was exposed to filtered-air. The chrysotile used in the Ready Mix joint compound is rapidly removed from the lung. The chrysotile alone exposure group had a clearance half-time of fibers L > 20 μm of 2.2 days; in the chrysotile plus sanded exposure group the clearance half-time of fibers L > 20 μm was 2.8 days. However, across all size ranges there was approximately an order of magnitude decrease in the mean number of fibers remaining in the lungs of Group 3 as compared to Group 2 despite similiar aerosol exposures. Histopathological examination showed that the chrysotile exposed lungs had the same appearance as the filtered-air controls. This study uniquely illustrates that additional concurrent exposure to an aerosol of the sanded joint-compound, with large numbers of fine-particles depositing in the lungs, accelerates the recruitment of macrophages, resulting in a tenfold decrease in the number of fibers remaining in the lung. The increased number of macrophages in the chrysotile/sanded joint exposure group was confirmed histologically, with this being the only exposure-related histological finding reported.

A Biopersistence Study following Exposure to Chrysotile Asbestos Alone or in Combination with Fine Particles

In their work on human cancer, the International Agency for Research on Cancer have run a programme of «monographs» that evaluate carcinogenic risk of chemicals to man. The data collected provide considerable information on the risk from substances identified as carcinogens. However, this is largely unused in the IARC classification scheme in spite of the use of the term `risk' in the title and text of the monographs. Consequently, some governments and pressure groups use hazard identification to advance the cause for banning agents without conducting a risk assessment. Confusion and indiscriminate use of `hazard' and `risk' mean that the hazard data are commonly misrepresented as risk data. A common political response is to push regulatory action to extremes, citing the Precautionary Principle. Unfortunately, eliminating substances on the grounds of inherent hazard can deny major benefits to societies and undermine the sustainable developments. This is nowhere better illustrated than in the case of the minerals known collectively as asbestos. Evidence available clearly differentiates the hazards of chrysotile and amphibole asbestos, yet the current IARC classification does not make this distinction. This is in spite of the fact that amphibole asbestos produces orders of magnitude more diseases than chrysotile when used in the same way. The overwhelming weight of evidence available indicates that chrysotile can be used safely with low risk. Cement products such as water pipes and boards for housing provide are versatile products made at affordable cost for the developing countries which if not available would cost rather than save lives.

Misconceptions and Misuse of International Agency for Research on Cancer `Classification of Carcinogenic Substances'

Type 475 special-purpose glass fiber is rather unique among the family of synthetic mineral fibers. It is used not for insulation but for “high-end” filtration products designed for high and ultra-high purity filtration of air and liquids. The designation for these types of filters varies with country and includes HEPA, ULPA, EU 10–13, EN1822, and S3. In its evaluation, type 475 has been grouped together with E-glass another special-purpose fibre often with little distinction made in terms of its chemistry and corresponding toxicological response. The detailed review of the available toxicology data on type 475 glass fibers clearly shows that following inhalation of this fiber even at relatively high doses, which likely exceed that at which lung overload in the rat is known to occur, type 475 glass fibers are not fibrogenic and do not cause tumors. These data clearly show an important differentiation in potency between type 475 glass fibers and E-glass and support treating these two types of fibers independently and not equating them though the term “special-purpose fibers.” Analysis of the intraperitoneal studies taking into account fibre dimensions shows that at 109 fibers injected, there was a 0.3 tumor incidence. While these studies indicate according to the European Commission (EC) classification criteria that 475 should not be fully exonerated as a carcinogen, the results of the inhalation study fully support classification in category 3. The IP results are more difficult to interpret, however, the IP study itself provides no toxicological basis for determining what range of dose-response should correspond to EU category 3 or 2. Following the EC classification criteria, the toxicological data clearly indicate that 475 fibers are appropriately classified in EC category 3.

This review addresses the characteristics which differentiate synthetic vitreous fibers (SVFs, e.g., fiber glass, stonewool, slagwool, refractory ceramic fibers, etc.), how these influence the potential biopersistence and toxicity, the most recent epidemiological results and the integration of these findings into the health and safety regulations in Europe and the United States. Also presented is the historical basis for the European classification directive. The use and equivalence of the chronic inhalation toxicology and chronic intraperitoneal injection studies in laboratory rodents for evaluation of fiber toxicology is assessed as well as the impact of dose selection and design on the validity of the study. While synthetic vitreous fibers can span a wide range of chemistries, recognition and understanding of the importance of biopersistence (ability to persist in the lung) in fiber toxicity has led to the development of more and more biosoluble fibers (that break down rapidly in the lung). Still, the epidemiological data available which are largely based upon the use of fibers in past decades, indicate that the SVF do not present a human health risk at current exposure levels. The animal toxicology and biopersistence data provide a coherent basis for understanding and evaluating the parameters which affect SVF toxicity. The current regulations are based upon an extensive knowledge base of chronic studies in laboratory rodents which confirm the relationship between chronic adverse effects and the biopersistence of the longer fibers that can not be fully phagocytised and efficiently cleared from the lung. The amorphous structure of synthetic vitreous fibers facilitates designing fibers in use today with low biopersistence. Both the epidemiological data and the animal studies database provide strong assurance that there is little if any health risk associated with the use of SVFs of low biopersistence. IARC (2001) reclassified these fibers from Category 2b to Category 3 (with RCF and special purpose fibers remaining in 2b) an event which has not been common in the history of these monographs.

Synthetic Vitreous Fibers: A Review Toxicology, Epidemiology and Regulations

The health effects of chrysotile: current perspective based upon recent data.

Inhalation toxicology studies with chrysotile asbestos have in the past been performed at exceedingly high doses without consideration of fiber number or dimensions. As such, the exposures have exceeded lung overload levels, making quantitative assessment of these studies difficult if not impossible. To assess the cellular and pathological response in the rat lung to a well-characterized aerosol of chrysotile asbestos, a 90-day subchronic inhalation toxicology study was performed using a commercial Brazilian chrysotile (CA 300). The protocol was based on that established by the European Commission for the evaluation of synthetic vitreous fibers. The study was also designed to assess the potential for reversibility of any such changes and to permit association of responses with fiber dose in the lung and the influence of fiber length. Wistar male rats were randomly assigned to an air control group and to 2 CA 300 exposure groups at mean fiber aerosol concentrations of 76 fibers L > 20 μm/cm3 (3413 total fibers/cm3; 536 WHO fibers/cm3) or 207 fibers L > 20 μm/cm3 (8941 total fibers/cm3; 1429 WHO fibers/cm3). The animals were exposed using a flow-past, nose-only exposure system for 5 days/wk, 6 h/day, during 13 consecutive weeks (65 exposures), followed by a subsequent nonexposure period lasting for 92 days. Animals were sacrificed after cessation of exposure and after 50 and 92 days of nonexposure recovery. At each sacrifice, subgroups of rats were assessed for the determination of the lung burden; histopathological examination; cell proliferation response; bronchoalveolar lavage with the determination of inflammatory cells; clinical biochemistry; and for analysis by confocal microscopy. Through 90 days of exposure and 92 days of recovery, chrysotile at a mean exposure of 76 fibers L > 20 μm/cm3 (3413 total fibers/cm3) resulted in no fibrosis (Wagner score 1.8 to 2.6) at any time point. The long chrysotile fibers were observed to break apart into small particles and smaller fibers. In vitro modeling has indicated that these particles are essentially amorphous silica. At an exposure concentration of 207 fibers L > 20 μm/cm3 (8941 total fibers/cm3) slight fibrosis was observed. In comparison with other studies, chrysotile produced less inflammatory response than the biosoluble synthetic vitreous fiber CMS. As predicted by the recent biopersistence studies on chrysotile, this study clearly shows that at that at an exposure concentration 5000 times greater than the U.S. threshold limit value of 0.1 f(WHO)/cm3, chrysotile produces no significant pathological response.

The Toxicological Response of Brazilian Chrysotile Asbestos: A Multidose Subchronic 90-Day Inhalation Toxicology Study with 92-Day Recovery to Assess Cellular and Pathological Response

WORKING GROUP David Bernstein (Consultant, Geneva, Switzerland) Vince Castranova (National Institute for Occupational Safety and Health, Morgantown, West Virginia, USA) Ken Donaldson (University of Edinburgh Medical School, Edinburgh, UK) Bice Fubini (Interdepartmental Center “G. Scansetti” for Studies on Asbestos and other Toxic Particulates, University of Torino, Italy) John Hadley (Owens Corning Science and Technology Center, Granville, OH, USA) Tom Hesterberg (International Truck and Engine Corp., Warrenville, IL, USA) Agnes Kane (Brown University School of Medicine, Providence, RI, USA) David Lai (U.S. Environmental Protection Agency, Washington, DC, USA) Ernest E. McConnell (ToxPath, Inc., Raleigh, NC, USA) Hartwig Muhle (Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany) Gunter Oberdorster (University of Rochester School of Environmental Medicine, Rochester, NY, USA) Stephen Olin (ILSI Risk Science Institute, Washington, DC, USA) David B. Warheit (DuPont Haskell Laboratory for Health and Environmental Sciences, Newark, DE, USA)

The solubility of man-made mineral fibers in the lung in contrast to natural fibers

Calidria chrysotile asbestos, which is a serpentine mineral, has been shown to be considerably less biopersistent than the durable amphibole mineral tremolite asbestos, which persists once deposited in the lung. The initial results of this inhalation biopersistence study in rats that demonstrates this difference were reported in . This article presents the full results through 1 yr after cessation of the 5-day exposure. This study was based upon the recommendations of the European Commission (EC) Interim Protocol for the Inhalation Biopersistence of synthetic mineral fibers (). In addition, the histopathological response in the lung was evaluated following exposure. In order to quantify the dynamics and rate by which these fibers are removed from the lung, the biopersistence of a sample of commercial-grade chrysotile from the Coalinga mine in New Idria, CA, of the type Calidria RG144 and that of a long-fiber tremolite were studied. For synthetic vitreous fibers, the biopersistence of the fibers longer than 20 μm has been found to be directly related to their potential to cause disease. This study was designed to determine lung clearance (biopersistence) and the histopathological response. As the long fibers have been shown to have the greatest potential for pathogenicity, the aerosol generation technique was designed to maximize the number of long respirable fibers. The chrysotile samples were specifically chosen to have 200 fibers/cm3 longer than 20 μm in length present in the exposure aerosol. These longer fibers were found to be largely composed of multiple shorter fibrils. The tremolite samples were chosen to have 100 fibers/cm3 longer than 20 μm in length present in the exposure aerosol. Calidria chrysotile has been found to be one of the most rapidly cleared mineral fibers from the lung. The fibers longer than 20 μm in length are cleared with a half-time of 7 h. By 2 days postexposure all long fibers have dissolved/disintegrated into shorter pieces. The fibers between 5 and 20μm in length were cleared with a half-time of 7 days. This length range represents a transition zone between those fibers that can be fully phagocytosed and cleared as particles and the longer fibers that cannot be fully engulfed by the macrophage. The fibers/objects shorter than 5 μm in length were cleared with a half-time of 64 days, which is faster than that reported for insoluble nuisance dusts such as TiO2. By 12 months postexposure, 99.92% of all the remaining chrysotile was less than 5 μm in length. Following the 5 days of repeated exposure to more than 48,000 chrysotile fibers/cm3 (190 fibers L > 20 μm), histopathological examination revealed no evidence of any inflammatory reaction either after the cessation of the last exposure or at any time during the subsequent 12-mo period. This is in marked contrast to the amphibole tremolite, which was also investigated using the same inhalation biopersistence protocol. The long tremolite fibers, once deposited in the lung, remain over the rat's lifetime with essentially an infinite half-time. Even the shorter fibers, following early clearance, also remain with no dissolution or further removal. At 365 days postexposure, there was a mean lung burden was of 0.5 million fibers L > 20 μm and 7 million fibers 5–20 μm in length with a total mean lung burden of 19.6 million fibers. The tremolite exposed rats, even with exposure to 16 times fewer total fibers than chrysotile, showed a pronounced inflammatory response with the rapid development of granulomas as seen at day 1 postexposure, followed by the development of fibrosis characterized by collagen deposition within these granulomas and by 90 days even mild interstitial fibrosis. With the short exposure, this study was not designed specifically to evaluate pathological response; however, it is quite interesting that even so there was such a marked response with tremolite. These findings provide an important basis for substantiating both kinetically and pathologically the differences between chrysotile and the amphibole tremolite. As Calidria chrysotile has been certified to have no tremolite fiber, the results of the current study together with the results from toxicological and epidemiological studies indicate that this fiber is not associated with lung disease.

Comparison of Calidria Chrysotile Asbestos to Pure Tremolite: Final Results of the Inhalation Biopersistence and Histopathology Examination Following Short-Term Exposure

Chrysotile asbestos, a serpentine mineral, has been shown to be notably different from amphibole asbestos such as amosite, crocidolite, and tremolite in that chrysotile once inhaled is rapidly removed from the lung while the amphiboles persist. This has been demonstrated for three different chrysotile samples from Canada, the United States, and Brazil. The initial results of the inhalation biopersistence study on the Canadian chrysotile were reported earlier. This article presents the full results through 365 days after cessation of exposure. In order to fully understand the dynamics of the clearance of chrysotile from the lung, the study included a standardised inhalation biopersistence study following the recommendations of the European Commission (EC) Interim Protocol for the Inhalation Biopersistence of synthetic mineral fibers () in which the lungs were digested to evaluate fiber content remaining. In addition, confocal microscopy was used to examine lungs in three dimensions to determine where and what size the remaining fibers were in the lung tissue. The results showed that Canadian chrysotile is cleared from the lung with a clearance half-time of 11.4 days for the fibers longer than 20 μm. Canadian chrysotile clears in a range similar to that of glass and stone wools. It remains less biopersistent than ceramic and special purpose glasses and considerably less biopersistent than amphibole asbestos. At 1 yr after cessation of exposure, no long (L>20 μm) chrysotile fibers remained in the lung. In contrast, with amosite asbestos there were 4 × 105 long fibers (L>20 μm) remaining in the lungs at one year after cessation of exposure (). These results fully support the differentiation of chrysotile from amphiboles reported in recent evaluations of available epidemiological studies (; ).

The Biopersistence of Canadian Chrysotile Asbestos Following Inhalation: Final Results Through 1 Year After Cessation of Exposure

Recent publications have shown for synthetic mineral fibers that if a fiber dissolves rapidly and disappears from the lung, it does not cause a carcinogenic effect. With asbestos, chrysotile asbestos is often included with other asbestos materials. However, chrysotile is a serpentine mineral with markedly different mineralogical characteristics than amphibole asbestos (e.g. amosite, tremolite). These differences are mirrored in the differences in biopersistence between these two minerals. Chrysotile clears very rapidly from the lung with half-times ranging from 0.3 to 11 days and produces no inflammatory reaction. In contrast, the amphiboles clear with half-times in the range of 500 days or longer and produce a pronounced inflammatory response leading to mild interstitial fibrosis. These findings provide an important basis for substantiating both kinetically and pathologically the differences between chrysotile and amphiboles. In contrast to amphiboles, the toxicology of chrysotile can be understood in comparison to non-fibrous mineral dusts. These results fully support the differentiation of chrysotile from amphiboles reported in recent evaluations of available epidemiological studies.

Understanding Chrysotile Asbestos: A New Perspective Based Upon Current Data.

With the initial understanding of the relationship of asbestos to disease, little information was available on whether the two different groups of minerals that are called asbestos were of similar or different potency in causing disease. Asbestos was often described as a durable fiber that if inhaled would remain in the lung and cause disease. It has been only more recently, with the development of a standardized protocol for evaluating the biopersistence of mineral fibers in the lung, that the clearance kinetics of the serpentine chrysotile have been shown to be dramatically different from those of amphibole asbestos, with chrysotile clearing rapidly from the lung. In addition, recent epidemiology studies also differentiate chrysotile from amphibole asbestos. The biopersistence studies mentioned have indicated that chrysotile from Canada and California clear rapidly from the lung once inhaled. However, variations in chrysotile mineralogy have been reported depending upon the region. This is most likely associated with variations in the forces which created the chrysotile fibers centuries ago. In the present study, the dynamics and rate of clearance of chrysotile from the Cana Brava mine in central Brazil was evaluated in a comparable inhalation biopersistence study in the rat. For synthetic vitreous fibers, the biopersistence of the fibers longer than 20 μ m has been found to be directly related to their potential to cause disease. This study was designed to determine lung clearance (biopersistence) and translocation and distribution within the lung. As the long fibers have been shown to have the greatest potential for pathogenicity, the chrysotile samples were specifically chosen to have more than 450 fibers/cm3 longer than 20 μ m in length present in the exposure aerosol. For the fiber clearance study (lung digestions), at 1 day, 2 days, 7 days, 2 wk, 1 mo, 3 mo, 6 mo, and 12 mo following a 5-day (6 h/day) inhalation exposure, the lungs from groups of animals were digested by low-temperature plasma ashing and subsequently analyzed by transmission electron microscopy (at the GSA Corp.) for total chrysotile fiber number in the lungs and chrysotile fiber size (length and diameter) distribution in the lungs. This lung digestion procedure digests the entire lung with no possibility of identifying where in the lung the fibers are located. A fiber distribution study (with confocal microscopy) was included in order to identify where in the lung the fibers were located. At 2 days, 2 wk, 3 mo, 6 mo, and 12 mo postexposure, the lungs from groups of animals were analyzed by confocal microscopy to determine the anatomic fate, orientation, and distribution of the retained chrysotile fibrils deposited on airways and those fibers translocated to the broncho-associated lymphoid tissue (BALT) subjacent to bronchioles in rat lungs. While the translocation of fibers to the BALT and lymphatic tissue is considered important as in cases of human's with asbestos-related disease, there has been no report in the literature of pathological changes in the BALT and lymphatic tissue stemming from asbestos. Thus, if the fibers are removed to these tissues, they are effectively neutralized in the lung. Chrysotile was found to be rapidly removed from the lung. Fibers longer than 20 μ m were cleared with a half-time of 1.3 days, most likely by dissolution and breakage into shorter fibers. Shorter fibers were also rapidly cleared from the lung with fibers 5–20 μ m clearing even more rapidly (T1/2 = 2.4 days) than those < 5μ m in length (T1/2 weighted = 23. days). Breaking of the longer fibers would be expected to increase the short fiber pool and therefore could account for this difference in clearance rates. The short fibers were never found clumped together but appeared as separate, fine fibrils, occasionally unwound at one end. Short free fibers appeared in the corners of alveolar septa, and fibers or their fragments were found within alveolar macrophages. The same was true of fibers in lymphatics, as they appeared free or within phagocytic lymphocytes. These results support the evidence presented by that the chrysotile fibers are rapidly cleared from the lung in marked contrast to amphibole fibers which persist.

The Biopersistence of Brazilian Chrysotile Asbestos Following Inhalation

Ventilation of the cigarette was designed to allow dilution of the cigarette smoke and thereby reduce the dose delivered to the smoker. Following the toxicological principle of dose response, a lower concentration of cigarette smoke should be associated with a lower toxicological response. However, there have been many studies reporting on the phenomenon of compensation whereby the smoker increases puff volume and/or frequency in order to obtain higher volumes of smoke This article reviews studies of the particle size of cigarette smoke and examines, based on available literature, the associated differences in the tobacco smoke and smoking behavior and their relationship to deposition patterns in the lung. The data available indicate that particle size of the cigarette smoke does not significantly change as a function of cigarette type or smoking behavior. The cigarette smoke particle size is in the same range as the minimum deposition particle size in the lung. While varying concentrations of particles are taken into the mouth, the subsequent inhalation pattern has been reported as remaining constant and also does not appear to change significantly under different smoking types and conditions. The dynamics of what happens to the smoke in the short time it is retained in the mouth have not been studied, and this perhaps should be the subject of future investigations. The current data therefore suggest that the particle deposition pattern of the smoke within the lung would not change significantly if compensation occurs.

A Review of the Influence of Particle Size, Puff Volume, and Inhalation Pattern on the Deposition of Cigarette Smoke Particles in the Respiratory Tract

To the Editor: 

I read with interest the recent publication by Bergdahl etal. 1 on the increased mortality in chronic obstructive pulmonary disease (COPD) among construction workers exposed to inorganic dust. Within this publication, the authors stated that their “results corroborate those from previous studies, indicating an increased risk for COPD among workers exposed to dust, such as asbestos, man-made mineral fibres, mineral dust and concrete dust”.

The basis cited by Bergdahl et al. 1 for including fibre glass in the previous statement appears to be the article by Sixt et al. 2. The authors citing this article state that “increased elastic recoil pressure among workers exposed to man-made mineral fibres has …

Increased mortality in COPD among construction workers exposed to inorganic dust

Chrysotile asbestos is often included with other asbestos materials in evaluation and classification. However, chrysotile is a serpentine with markedly different physical and chemical characteristics in comparison to amphiboles (e.g., crocidolite, amosite, tremolite). In contrast to amphiboles, which are solid, rodlike fibers, chrysotile is composed like a rope of many fine fibrils, which tend to unwind. In order to quantify the dynamics and rate by which chrysotile is removed from the lung, the biopersistence of a sample of commercial chrysotile from the Eastern Townships area of Quebec, Canada, labeled QS Grade 3-F, which is the longest commercial grade intended for textile use, was studied. As the long fibers have been shown to have the greatest potential for pathogenicity, the chrysotile samples were specifically chosen to have more than 200 fibers/cm3 longer than 20 µm present in the exposure aerosol. This publication presents the results of this study through 3 mo postexposure. The study design included: (1) Fiber clearance (lung digestions): At 1 day, 2 days, 7 days, 14 days, 1 mo, 3 mo, and 12 mo (to be reported) following a 5-day (6 h/day) inhalation exposure, the lungs from groups of animals were digested by low-temperature plasma ashing and subsequently analyzed by transmission electron microscopy for total chrysotile fibers number in the lungs and chrysotile fiber size (length and diameter) distribution in the lungs. (2) Fiber distribution (confocal microscopy): This procedure was included in order to identify the location of the fibers in the lung. At 1 day, 2 days, 7 days, 14 days, 1 month, and 3 months (to be reported) postexposure, the lungs from groups of animals were analyzed by confocal microscopy to determine the anatomic fate, orientation, and distribution of the retained chrysotile fibrils deposited on airways and in the parenchymal region. Chrysotile was found to be rapidly removed from the lung. Fibers longer than 20 µm were cleared with T1/2 = 16 days, most likely by dissolution and disintegration into shorter fibers. The shorter fibers were also rapidly cleared from the lung, with fibers 5–20 µm clearing even faster (T1/2 = 29.4 days) than those <5 µm in length. The fibers <5 µm in length cleared at a rate (T1/2 = 107 days) that is within the range of clearance for insoluble nuisance dusts. The breaking apart of the longer fibers would be expected to increase the short fiber pool and therefore could account for this difference in clearance rates. The short fibers were not found clumped together but appeared as separate, fine fibrils, occasionally unwound at one end. Short free fibers appeared in the corners of alveolar septa, and fibers or their fragments were found within alveolar macrophages. The same was true of fibers in lymphatics, as they appeared free or within phagocytic lymphocytes. Neutrophil-mediated inflammatory response did not occur in the presence of chrysotile fibers at the time points examined. Taken in context with the scientific literature to date, this report provides new robust data that clearly support the difference seen epidemiologically between chrysotile and amphibole asbestos.

The Biopersistence of Canadian Chrysotile Asbestos Following Inhalation

This 3-mo inhalation study investigated the biological effects of a special-purpose glass microfiber (E-glass microfiber), the stone wool fiber MMVF21, and a new high-temperature application fiber (calcium-magnesium-silicate fiber, CMS) in Wistar rats. Rats were exposed 6 h/day, 5 days/wk for 3 mo to fiber aerosol concentrations of approximately 15, 50, and 150 fibers/ml (fiber length >20 µm) for E-glass microfiber and MMVF21. For the CMS fiber only the highest exposure concentration was used. During a 3-mo postexposure period, recovery effects were studied. In the highest exposure concentration groups, gravimetric concentrations were 17.2 mg/m 3 for E-glass microfiber, 37 mg/m 3 for MMVF21, and 49.5 mg/m 3 for the CMS fiber. After 3 mo of exposure, lung retention of fibers longer than 20 µm per lung was 17 × 10 6 for E-glass microfiber, 5.7 × 10 6 for MMVF21, and 0.88 × 10 6 for CMS. After 3 mo of recovery the concentration of the long fiber fraction was decreased to 38.4%, 63.9%, and 3.0% compared to original lung burden for the E-glass microfiber, MMVF21, and CMS, respectively. Biological effects measured included inflammatory and proliferative potential, histopathology lesions, and the persistence of these effects over a recovery period of 3 mo. Generally, observed effects were higher for E-glass microfiber when compared to MMVF21. The following clear dose-dependent effects on E-glass microfiber and MMVF21 exposure were observed as main findings of the study: increase in lung weight, in measured biochemical parameters and polymorphonuclear leukocytes (PMN) in the bronchoalveolar lavage fluid (BALF), in cell proliferation (BrdU-response) of terminal bronchiolar epithelium, and in interstitial fibrosis. The values observed in the proliferation assay on the carcinogenic E-glass microfiber indicate that this assay has an important predictive value with regards to potential carcinogenicity. Surprisingly, for the biosoluble CMS fiber, fibrogenic potential was detected in this study. The results of the CMS exposure group indicate that effects may be dominated by the presence of nonfibrous particles and that fibrosis may not be a predictor of carcinogenic activity of fiber samples, if the fiber preparation contains a significant fraction of nonfibrous particles. In summary, this study demonstrates the importance of fiber dust contamination by granular components. For future subchronic studies a longer posttreatment observation period would be advisable.

Calibration Study on Subchronic Inhalation Toxicity of Man-Made Vitreous Fibers in Rats

The differences between chrysotile asbestos, a serpentine mineral, and amphibole asbestos have been debated extensively. Many studies have shown that chrysotile is cleared from the lung more rapidly than amphibole. In order to quantify the comparative clearance of chrysotile and the amphibole asbestos tremolite, both fibers were evaluated in an inhalation biopersistence study that followed the European Commission recommended guidelines. In addition, the histopathological response in the lung was evaluated following the short-term exposure. This article presents the results of this study through 90 days after cessation of exposure. Following the termination of the study, a subsequent article will provide the complete results through 12 mo after cessation of exposure. In order to quantify the dynamics and rate by which these fibers are removed from the lung, the biopersistence of a sample of commercial grade chrysotile from the Coalinga mine in New Idria, CA, of the type Calidria RG144 and of a long-fiber tremolite were studied. For synthetic vitreous fibers, the biopersistence of the fibers longer than 20 µm has been found to be directly related to their potential to cause disease. This study was designed to determine lung clearance (biopersistence) and the histopathological response. As the long fibers have been shown to have the greatest potential for pathogenicity, the aerosol generation technique was designed to maximize the number of long respirable fibers. The chrysotile samples were specifically chosen to have 200 fibers/cm3 longer than 20 µm in length present in the exposure aerosol. These longer fibers were found to be largely composed of multiple shorter fibrils. The tremolite samples were chosen to have 100 fibers/cm3 longer than 20 µm in length present in the exposure aerosol. Calidria chrysotile fibers clear from the lung more rapidly (T1/2, fibers L>20 µm = 7 h) than any other commercial fiber tested including synthetic vitreous fibers. With such rapidly clearing fibers, the 5-day exposure would not be expected to result in any pathological change in the lung, and the lungs of animals that inhaled Calidria chrysotile showed no sign of inflammation or pathology and were no different than the lungs of those animals that breathed filtered air. Following this 5-day exposure to tremolite, the tremolite fibers once deposited in the lung parenchyma do not clear and almost immediately result in inflammation and a pathological response in the lung. At the first time point examined, 1 day after cessation of exposure, inflammation was observed and granulomas were already formed. By 14 days postexposure these microgranulomas had turned fibrotic, and by 90 days postexposure the severity of the collagen deposits had increased and interstitial fibrosis was observed in one of the rats. These findings provide an important basis for substantiating both kinetically and pathologically the differences between chrysotile and the amphibole tremolite. As Calidria chrysotile has been certified to have no tremolite fiber, the results of the current study together with the results from toxicological and epidemiological studies indicate that this fiber is not associated with lung disease.

Comparison of Calidria Chrysotile Asbestos to Pure Tremolite: Inhalation Biopersistence and Histopathology Following Short-Term Exposure

Chrysotile asbestos is often included with other asbestos materials in evaluation and classification. However, chrysotile is a serpentine with markedly different physical and chemical characteristics in comparison to amphiboles (e.g., crocidolite, amosite, tremolite). In contrast to amphiboles, which are solid, rodlike fibers, chrysotile is composed like a rope of many fine fibrils, which tend to unwind. In order to quantify the dynamics and rate by which chrysotile is removed from the lung, the biopersistence of a sample of commercial chrysotile from the Eastern Townships area of Quebec, Canada, labeled QS Grade 3-F, which is the longest commercial grade intended for textile use, was studied. As the long fibers have been shown to have the greatest potential for pathogenicity, the chrysotile samples were specifically chosen to have more than 200 fibers/cm3 longer than 20 micro m present in the exposure aerosol. This publication presents the results of this study through 3 mo postexposure. The study design included: (1) Fiber clearance (lung digestions): At 1 day, 2 days, 7 days, 14 days, 1 mo, 3 mo, and 12 mo (to be reported) following a 5-day (6 h/day) inhalation exposure, the lungs from groups of animals were digested by low-temperature plasma ashing and subsequently analyzed by transmission electron microscopy for total chrysotile fibers number in the lungs and chrysotile fiber size (length and diameter) distribution in the lungs. (2) Fiber distribution (confocal microscopy): This procedure was included in order to identify the location of the fibers in the lung. At 1 day, 2 days, 7 days, 14 days, 1 month, and 3 months (to be reported) postexposure, the lungs from groups of animals were analyzed by confocal microscopy to determine the anatomic fate, orientation, and distribution of the retained chrysotile fibrils deposited on airways and in the parenchymal region. Chrysotile was found to be rapidly removed from the lung. Fibers longer than 20 micro m were cleared with T(1/2) = 16 days, most likely by dissolution and disintegration into shorter fibers. The shorter fibers were also rapidly cleared from the lung, with fibers 5-20 micro m clearing even faster (T(1/2) = 29.4 days) than those <5 micro m in length. The fibers <5 micro m in length cleared at a rate (T(1/2) = 107 days) that is within the range of clearance for insoluble nuisance dusts. The breaking apart of the longer fibers would be expected to increase the short fiber pool and therefore could account for this difference in clearance rates. The short fibers were not found clumped together but appeared as separate, fine fibrils, occasionally unwound at one end. Short free fibers appeared in the corners of alveolar septa, and fibers or their fragments were found within alveolar macrophages. The same was true of fibers in lymphatics, as they appeared free or within phagocytic lymphocytes. Neutrophil-mediated inflammatory response did not occur in the presence of chrysotile fibers at the time points examined. Taken in context with the scientific literature to date, this report provides new robust data that clearly support the difference seen epidemiologically between chrysotile and amphibole asbestos.

The biopersistence of Canadian chrysotile asbestos following inhalation.

The carcinogenic potential in the intraperitoneal cavity of three newly developed biosoluble insulation glass wool fibers (M, P, and V) and one newly developed biosoluble insulation stone wool fiber (O) was investigated and compared to that of a previously developed soluble glass fiber (B). The in vitro dissolution coefficient of the three glass wool fibers ranged from 450 to 1037 ng/cm 2 × h and was 523 ng/cm 2 × h for the stone wool fiber. The in vitro dissolution coefficient of the B fiber was 580 ng/cm 2 × h. Groups of female Wistar rats (strain Crl: Wi BR) were exposed by repeated injections to doses of 0.5, 2, and 5 × 10 9 WHO fibers, which corresponds to between 41 mg to 724 mg fiber injected. In addition, 2 groups of crocidolite were used as positive controls at doses of 0.1 × 10 9 and 1 × 10 9 WHO fibers (0.5 and 5 mg). The in vitro dissolution coefficient of crocidolite is estimated to be ~1 ng/cm 2 × h. The protocol of the study and the size distribution of the test samples conformed to the European Commission Protocol EUR 18748 EN, and the study was executed under Good Laboratory Practice conditions. Two of the new insulation wools, fibers M and 0, showed no statistically significant tumorigenic response even at the very high dose of 5 × 10 9 WHO fibers injected. Fibers P and V showed a small tumorigenic response in the ip cavity similar in magnitude to the B fiber, which has been declared in the German fiber regulations as a noncarcinogenic fiber. The response to the soluble insulation fibers was notably different from that of the known carcinogen crocidolite, which produced 53% tumors at a comparatively low dose of 0.1 × 10 9 WHO fibers. The incidence of mesothelioma was found to be highly correlated to the incidence of intra-abdominal nodules and masses at different sites. The incidence of abdominal nodules and masses was highly correlated to the number of animals with ascites. The incidence of chronic peritonitis with fibrotic nodules at different organs also correlated with the incidence of mesotheliomas. Differences in etiology were observed between the massive doses of the highly soluble insulation wools when injected directly into the ip cavity and the lower doses of the extremely insoluble fiber crocidolite. The variability in this reaction and the impairment of animal health put into question the value of these massive doses in evaluating the carcinogenic response of soluble insulation wools. All of the fibers tested fulfilled the exoneration criteria with respect to carcinogenicity according to the European Directive 97/69/EC ("an appropriate intra-peritoneal test has not expressed signs of excessive carcinogenicity"). The dose as defined in the EC-Protocol EUR 18748 EN was 1 × 10 9 WHO fibers with a defined geometric spectrum. The influence of fiber dimensions on the ip tumor response and the difficulty in assessing the influence of the difference in background levels between this and previous studies make direct application of the German TRGS 905 criteria difficult; however, by comparison to fiber B, which in the TRGS 905 is considered as a noncarcinogenic fiber, all of the synthetic mineral fiber types tested in this study also appear to meet the intended German criteria for exoneration.

EXPERIENCE FROM A LONG-TERM CARCINOGENICITY STUDY WITH INTRAPERITONEAL INJECTION OF BIOSOLUBLE SYNTHETIC MINERAL FIBERS

It is generally accepted that the biopersistence of a synthetic vitreous fiber (SVF) is an important determinant of its biological activity. Experimental protocols have been developed to measure the biopersistence of an SVF from short-term inhalation experiments with rats. Clearance kinetics of long (>20 microm) fibers (those believed to have greatest biological activity) have been approximated by one- or two-pool models. Several measures or indices of biopersistence have been proposed in the literature of which three, the weighted half-time (WT(1/2)), the time required to clear 90% of long fibers (T(0.9)), and the so-called slow-phase half-time (T(2)), have been investigated in some detail. This paper considers both one- and two-pool models for long fiber clearance, characterizes the properties of these candidate indices of fiber biopersistence, identifies measures with potentially superior statistical properties, suggests possible cutoff values based on the relation between biopersistence and the outcome of chronic bioassays, and offers comments on the selection of efficient experimental designs. This analysis concludes that WT(1/2) and T(0.9) are highly correlated, are efficient predictors of the outcome of chronic bioassays, and have reasonable statistical properties. T(2), although perhaps attractive in principle, suffers from some statistical shortcomings when estimated using present experimental protocols. The WT(1/2) is shown to be directly proportional to the cumulative exposure (fiber days) after the cessation of exposure and also the mean residence time of these fibers in the lung.

Indices of fiber biopersistence and carcinogen classification for synthetic vitreous fibers (SVFs).

In December 1997 the European Commission (EC) adopted Directive 97/69/EC (O.J. L 343/19 of 13 December 1997), in which criteria were established for the classification and labeling of synthetic mineral fibers. This directive was derived based upon an extensive program evaluating current scientific knowledge on fiber pathogenicity and its relationship to the biopersistence of long fibers. Within this context, the biopersistence of fibers longer than 20 microm was found to be a good predictor of the lung burden and early pathological changes in chronic inhalation studies with fibers as well as of the tumor response in chronic intraperitoneal studies with fibers. The analysis that provided the scientific basis for the relationship of biopersistence to the chronic intraperitoneal (ip) results is presented in detail. Analysis of the relationship of biopersistence clearance half-times to ip tumor response shows a statistically significant relationship of ip tumor response to not only the number of fibers injected, but also the median length of the fibers injected and their solubility (clearance half-time). The results show that the biopersistence half-times as determined by intratracheal instillation (T(1/2) of WHO fibers or weighted T(1/2) of fibers with L > 20 microm) and as determined by inhalation (weighted T(1/2) of fibers with L > 20 microm) are equivalent predictors of the ip results. From these ip studies, fibers that can be exonerated from classification as carcinogens in Europe have a relative tumorigenic potency in the ip cavity of between 66 and 2500 times less than fibers that have been shown to produce a significant increase in tumors following chronic inhalation exposure. In addition, based upon the ip results, there is no statistical difference between the EC and the other fiber exoneration criteria, such as the German Gefahrstoffverordnung of 1999.

Biopersistence of synthetic mineral fibers as a predictor of chronic intraperitoneal injection tumor response in rats.

In December 1997 the European Commission (EC) adopted Directive 97/69/EC (O.J. L 343/19 of 13 December 1997) in which criteria were established for the classification and labeling of synthetic mineral fibers. This directive was derived based upon an extensive program evaluating current scientific knowledge on fiber pathogenicity and its relationship to the biopersistence of long fibers. Within this context, the biopersistence of fibers longer than 20 microm was found to be a good predictor of the lung burden and early pathological changes in chronic inhalation studies with fibers as well as of the tumor response in chronic intraperitoneal studies with fibers. The analysis that provided the scientific basis for the relationship of biopersistence to the chronic inhalation results is presented in detail. Proportional odds regression techniques were used to determine the relationship between both inhalation and intratracheal instillation biopersistence clearance half-times and the collagen deposition at the broncho-alveolar junction as determined following 24 mo in chronic inhalation toxicity studies. The results indicate all the indicators of biopersistence considered are equally good predictors of the early long-term change that occurs in the lung in response to more durable fibers. This change, the collagen deposition at the broncho-alveolar junction, is a precursor of interstitial fibrosis, which has been shown to be associated with tumor response in fiber-exposed animals. The results show that the clearance half-times set in the EC directive are within the baseline for this parameter.

Biopersistence of synthetic mineral fibers as a predictor of chronic inhalation toxicity in rats.

Fiber biopersistence as a major mechanism of fiber-induced pathogenicity was investigated. The lung biopersistence of 5 synthetic vitreous fibers (SVFs) and amosite asbestos was evaluated using the rat inhalation model. In contrast to several previous studies, this study examined fibers that dissolve relatively slowly in vitro at pH 7.4. Fisher rats were exposed for 5 days by nose-only inhalation to refractory ceramic fiber (RCF1a), rock (stone) wool (MMVF21), 2 relatively durable special application fiber glasses (MMVF32 or MMVF33), HT stonewool (MMVF34), amosite asbestos, or filtered air. Lung burdens were analyzed during 1 year post-exposure. Fiber aerosols contained 150-230 fibers/cc longer than 20 micrometer (>20 micrometer). On post-exposure Day 1, long-fiber lung burdens for the 6 test fibers were similar (12-16 x 10(5) fibers/lung >20 micrometer). After 1 year, the percentage of fibers >20 micrometer remaining in the lung was 0.04-10% for SVFs but 27% for amosite. Lung clearance weighted half-times (WT1/2) for fibers >20 micrometer were 6 days for MMVF34, 50-80 days for the other 4 SVFs, and >400 days for amosite. This study and 3 previous studies demonstrate a broad range of biopersistences for 19 different SVFs and 2 asbestos types. Ten of these fibers also have been (or are being) tested in chronic inhalation studies; in these studies, the very biopersistent fibers were carcinogenic (amosite, crocidolite, RCF1, MMVF32, and MMVF33), while the more rapidly clearing fibers were not (MMVF10, 11, 21, 22, and 34). These studies demonstrate the importance of biopersistence as an indicator of the potential pathogenicity of a wide range of fiber types.

Biopersistence of synthetic vitreous fibers and amosite asbestos in the rat lung following inhalation.

Summary Both inhalation and IT exposure provide estimates of the biopersistence of soluble fibres of similar magnitude. Inhalation systematically shows the faster clearance of longer fibres (L>20μm). For the one less soluble fibre evaluated in this study (RCF 1a), a large difference was observed between inhalation and IT exposure although as mentioned above this may be due to possible agglomeration in the bronchi following IT exposure. The results from both inhalation and IT studies were reproducible. Both methods require extensive controls to be valid. Inhalation exposure requires the aerosol to be rat respirable while IT requires confirmation of no agglomeration of fibres in the fibre suspensions used for injection and in the bronchi of the lungs following injection.

The Biopersistence of Fibres Following Inhalation and Intratracheal Instillation Exposure

Risk assessment of exposure to manmade vitreous fibres is a worldwide major concern, and has caused particular problems in the European Union, where consensus must be obtained between 15 member states. Two expert workshops have been held in Paris (Bignon, 1994; Bignon et al., 1995) and from these two primary issues have emerged: (1) the relationship between solubility and biopersistence; and (2) carcinogenic potential of MMVF in rodents. The German authorities (TRGS 905, 1994) disagree with most experts, because German experts believe that long-term inhalation tests in rodents are not sufficiently sensitive as a test of carcinogenic potential and that intraperitoneal injection (IP) tests are a safer basis for classification. The German authorities propose that MMVF should be classified using a formula reflecting biopersistence in terms of chemical composition:

The relationship between four methods of assessing clearance or toxicity of synthetic mineral fibres with chemical composition

AbstractThe biopersistence of nine fibers was evaluated using an inhalation model. The fibers studied were compositions with different in vitro acellular solubility. The commercial and new glass wool fibers were essentially sodium borosilicates and the commercial and new stone wools were essentially calcium modified silicates. Fischer 344 male rats were exposed to a well-defined rat respirable aerosol (mean diameter of ∼1 μm) at a concentration of 30 mg/m3, 6 h/day for 5 days with postexposure sacrifices at 1 h, 1 day, 5 days, 4 wk, 13 wk, and 26 wk. At sacrifice, the whole lung was removed, weighed, and frozen at -20°C for subsequent digestion by low-temperature plasma ashing. The number and bivariate size distribution of the fibers in the aerosol and lung were determined. At 1 h following the last exposure, the 9 fibers were found to have lung burdens ranging from 7.4 to 33 ° 106 fibers/lung with geometric mean diameters (CMD) of 0.40–0.54 μm. The range of initial lung burdens was found to reflect the d...

EVALUATION OF SOLUBLE FIBERS USING THE INHALATION BIOPERSISTENCE MODEL, A NINE-FIBER COMPARISON

Abstract Refractory ceramic fibers (RCF) are man-made vitreous fibers used primarily in industrial high-temperature applications, especially for insulation of furnaces and kilns. Because of their increasing use and potential for human exposure an in an effort to define the dose-response, as a follow up to a maximum tolerated dose [30 mg/m(3)] study in rats (Mast et al., 1995), a multiple dose chronic toxicity/carcinogenicity inhalation study was conducted in Fischer 344 (F344) rats. Four groups of 140 weanling male F344 rats were exposed via noseonly inhalation to either HEPA-filtered air (chamber controls) or 3, 9, or 16 mg/m(3)(approximately 36, 91, and 162 fibers/cm(3)) of kaolin-based "size-selected" RCF fibers (approximately 1 µm in diameter and approximately 20 µm in length) for 6 h/day, 5 days/wk for 24 mo. They were then held unexposed until approximately 20% survival and sacrificed (30 mo). Croups of 3-6 animals were sacrificed at 3, 6, 12, 18, and 24 mo to follow the progression of pulmonary lesions and to determine fiber lung burdens. Additional groups of 3-6 rats were removed from exposure at 3, 6, 12, and 18 mo and were held until sacrificed at 24 mo (recovery groups) for similar determinations. A dose-related increase in fiber lung burden was observed. Lung burdens at 24 mo ranged from 5.6 × 10(4) to 27.8 × 10(4) fibers/mg dry lung tissue. Significant increases in lung weights and lung to body weight ratios were seen in the high-dose group. Treatment-related lesions were restricted to the lungs. To some extent, all doses of RCF resulted in minimal to mild macrophage infiltration, bronchiolization of proximal alveoli, and microgranuloma formation by 12 mo of exposure. Interstitial fibrosis was observed at 12 mo in the 9 and 16 mg/m(3) groups but not in the low-dose group at any time point. A minimal amount of focal pleural fibrosis was first observed at 12 mo in the 9 and 76 mg/m(3) dose groups and progressed to a mild severity in the high-dose group by the end of the study. The incidence of pulmonary neoplasm's was well within the range typically reported in the male F344 rat. Neoplasm's (bronchoalveolar adenomas and carcinomas) were observed in all groups 10 mg/m(3) (air control), 1 of 129 (0.8%); 3 mg/m(3), 2 of 123 (1.6%); 9 mg/m(3), 5 of 127 (3.9%); 16 mg/m(3), 2 of 124 (1.6%)]. A single pleural mesothelioma was observed in an animal exposed to 9 mg/m(3) of kaolin RCF. The results of this study suggest that the dose response for primary lung neoplasms is steep, while that for mesothelioma may not be.

Multiple-dose chronic inhalation toxicity study of size-separated kaolin refractory ceramic fiber in male Fischer 344 rats.

AbstractKaolin-based refractory ceramic fiber (RCF) is a man-made vitreous fiber used primarily in industrial high-temperature applications, especially for insulation of furnaces and kilns. Because of its increasing use and potential for human exposure, a chronic toxicity/ carcinogenicity inhalation study was conducted in Syrian golden hamsters. Two groups of 140 weanling male hamsters were exposed via nose-only inhalation to either HEPA-filtered air (chamber controls) or 30 mg/m3 (-220 fibers/cm3) of “size-selected” RCF fibers (1 µm in diameter and -25 /jm in length) for 6 h/day, 5 dayslwk for 18 mo. They were then held unexposed until -20% survival (20 mo). A positive control group of 80 hamsters was exposed to 10 mg/m3 chrysotile asbestos (0.09 µm average diameter and 2.2 µm average length). Groups of 3 hamsters were sacrificed at 3, 6, 9, 12, 15, and 18 mo to follow the progression of lesions. Additional groups of 3 hamsters were removed from exposure at 3, 6, 9, and 12 mo and were held until 18 mo (r...

Chronic Inhalation Toxicity of a Kaolin-Based Refractory Ceramic Fiber in Syrian Golden Hamsters

Evaluation of the oncogenic potential of man-made vitreous fibres: the inhalation model.

AbstractThe biopersistence of three fibers was evaluated using an inhalation model. The fibers studied were man-made vitreous fiber (MMVF) 11, a commercially produced glass fiber; Fiber B, a relatively soluble glass fiber; and Fiber J, a synthetic stonewool with a high content of alkaline earth oxides. Fischer 344 male rats were exposed to a well-defined rat respirable aerosol (mean diameter of ≤1 μm) at a target concentration of 30 mg/m3, 6 h/day for 5 days. Following the end of the exposure period, subgroups were sacrificed at 1 h, 1 day, 5 days, 4 wk, 13 wk, 26 wk, and 52 wk. At sacrifice, the whole lung was removed, weighed, and immediately frozen at -20°C for subsequent digestion by low temperature plasma ashing. The number and bivariate size distribution of the fibers in the aerosol and lung were determined. At 1 h following the last exposure, the 3 fibers were found to have similar lung burdens ranging from 7.36-7.72 × 106 fibers/lung with geometric mean diameters of 0.42-0.54 μm. The three fibers ...

Evaluation of the Biopersistence of Commercial and Experimental Fibers Following Inhalation

This article describes the relationship between fiber biopersistence and the chronic toxicity of different chemical compositions of man-made vitreous fibers (MMVF) in the lung. Rats were exposed in "nose-only" inhalation chambers, 6 hr/day, 5 days/week, for 24 months to aerosol concentrations of 30 mg/m3 containing comparable fiber numbers and similar dimensions of fibrous glass (FG) or refractory ceramic fiber (RCF). Interim sacrifices were performed periodically to monitor fiber number and dimensions in the lung and the progression of pulmonary alterations. At each interim sacrifice, three to six recovery animals were removed from each exposure group and held until two years to determine the biopersistence of fibers after different exposure times. Fibers were recovered from the ashed lungs, counted, and measured using optical and scanning electron microscopy (SEM). Fiber chemistry was assessed in 91-week recovery lungs using energy dispersive spectroscopy (EDS) analysis. RCF induced lung fibrosis and an elevation in lung tumors and pleural mesotheliomas. FG exposure resulted in no lung fibrosis, no statistically significant increase in the lung tumor incidence, and no mesotheliomas. After two years of continuous exposure, the number of World Health Organization fibers per milligram dry lung recovered from RCF and FG exposed lungs was comparable. EDS analysis of recovery lungs showed that most of the alkalis and alkaline earths had leached from the FG fibers over time. A slight change in RCF chemistry was observed. These findings indicate that the change in the chemical composition of fibers may be an important determinant of the chronic toxicity of MMVFs.

Relationship between lung biopersistence and biological effects of man-made vitreous fibers after chronic inhalation in rats.

The biopersistence of fibers and minerals in the respiratory tract is an important parameter in the toxicity of those materials. The biopersistence of respirable synthetic fibers and minerals in man can be most closely evaluated in an animal model. While acellular and in vitro systems are important for initial evaluation of solubility and durability, they cannot simulate the dynamics of inhalation deposition and clearance and the subsequent systemic reaction to fibers and minerals that occurs in the animal. To evaluate the biopersistence of synthetic fibers, male rats were exposed to a well defined rat respirable aerosol of man-made vitreous fibers (MMVF), 6 hr/day for 5 days. Following exposure, subgroups were sacrificed at intervals ranging from 1 hr to 52 weeks. Following sacrifice, the lungs were removed, weighed, and immediately frozen at 20 degrees C for subsequent digestion by low temperature plasma ashing. The number, size distribution, and chemical composition of the fibers in the aerosol and lung were determined. With this animal model the role of biopersistence in altering the geometry and clearance of fibers can be systematically evaluated. The model also can be applied for the evaluation of the biopersistence of nonfibrous minerals.

An experimental approach to the evaluation of the biopersistence of respirable synthetic fibers and minerals.

Lifetime "nose-only" inhalation studies were conducted in rats using four types of refractory ceramic fibers (FCF), 1 micron in diameter x 22 to 26 microns length: High Purity, Kaolin, Zirconia, and After-Service; and on hamsters using Kaolin RCF. For comparison, animals also were exposed to chrysotile fibers. Rats were exposed 6 hr/day, 5 days/week for 24 months to concentrations ranging between 3 and 30 mg/m3. Time- and dose-dependent lesions in the rat included the development of interstitial fibrosis, pleural fibrosis, pulmonary tumors, and mesothelioma. Exposure to 3, 9 or 16 mg/m3 produced no excess lung tumors; no fibrosis was seen at 3 mg/m3. A significant increase in lung tumors and interstitial fibrosis was observed at 30 mg/m3. A single mesothelioma was observed in rats exposed to 9 mg/m3, while two occurred at 30 mg/m3. Hamsters were similarly exposed to 30 mg/m3 Kaolin RCF for 18 months; no lung tumors were induced, but pulmonary and pleural fibrosis were observed and there was a 42% incidence of mesothelioma. Multiple interim sacrifices together with recovery animals allowed detailed assessment of the lung burden of RCF, which was found to be dose related and, at the high doses, exceeded 10(5) fibers/mg of dry lung. During the various recovery periods there was a clear reduction in fiber burden. Mathematical modeling of these data for deposition, clearance, and retention and for species is currently underway.

Chronic inhalation and biopersistence of refractory ceramic fiber in rats and hamsters.

This study was initiated to determine the chronic biological effects in Fisher 344 rats of inhaled size-separated respirable fractions of fibrous glass (FG) having compositions representative of common building insulation wools. Rats were exposed using nose-only inhalation chambers, 6 hr/day, 5 days/week, for 24 months to three concentrations (3, 16, and 30 mg/m3) of two different compositions of FG (designated MMVF 10 and MMVF 11), or to filtered air (negative control). Fibrous glass findings were compared to those from a concurrent inhalation study of chrysotile asbestos and refractory ceramic fiber (RCF). The FGs used in this study were size selected to be largely respirable in the rat and the aerosol generation technique did not alter the dimensions of the fibers. Interim euthanizations took place at 3- to 6-month intervals to monitor progression of pulmonary changes. Fibers were recovered from digested lung tissue for determination of changes in fiber number and morphology. In animals exposed to 30 mg/m3 of MMVF 10 or MMVF 11, 4.2 +/- 0.9 x 10(5) and 6.4 +/- 3.1 x 10(5) fibers/mg dry lung tissue, respectively, were recovered after 24 months of exposure. Exposure to chrysotile asbestos (10 mg/m3) and to a lesser extent RCF (30 mg/m3) resulted in pulmonary fibrosis as well as mesothelioma and significant increases in lung tumors. FG exposure was associated with a nonspecific inflammatory response (macrophage response) in the lungs that did not appear to progress after 6-12 months of exposure. These cellular changes are reversible and are similar to the effects observed after inhalation of an inert dust. No lung fibrosis was observed in the FG-exposed animals. Further, FG exposure resulted in no mesotheliomas and no statistically significant increase in lung tumor incidence when compared to that of the negative control group. These findings, along with previous inhalation studies, suggest that respirable fibrous glass does not represent a significant hazard for fibrotic or neoplastic lung disease in humans.

Fundamental and applied toxicology : official journal of the Society of Toxicology

Chronic inhalation toxicity of size-separated glass fibers in Fischer 344 rats.

Evaluation of cutaneous responses and lung function from exposure to opiate compounds among ethical narcotics-manufacturing workers.

Chronic Inhalation Toxicity of Refractory Ceramic Fibers in Syrian Hamsters

Thirty-six employees who produced industrial enzymes from bio-engineered strains of bacteria and fungi were evaluated by skin prick testing and enzyme linked immunosorbent assays for specific IgE and IgG antibodies. The workers complained of asthma- and flu-like' symptoms which generally lessened away from work. The enzymes evaluated were {alpha}-amylase from A. niger (ind-AAN), B. licheniformis (ind-AAL) and B. subtilis (ind-AAS); purified {alpha}-amylase from B. subtilis (AAS) and A. niger (AAN); alkaline protease from B. licheniformis (ind-APL) and purified alkaline protease (APL); amylase glucosidase from A. niger (ind-AGN) and purified amylase glucosidase (AGN). Significantly positive skin tests were found for APL, AGN and ind-AAN. Significantly elevated specific IgE results were observed for AAN, AGN, and ind-AAN; elevated specific IgGs were observed for AAN, ind-AAN, ind-AAS, ind-AAL and ind-AGN. Radioimmunoassays of air filter samples (using sera with high Ab titers) for 4 of the ind-enzymes showed only ind-AAN at extremely high environmental levels. These results indicate that occupational exposure to some ind-enzymes causes immediate onset dermal hypersensitivity reactions. The results are equivocal as to whether these reactions are IgE mediated, as IgE titers were low. Contrary to this, IgG titers were extremely high and suggest that these biomarkers can be used asmore » indicators of both individual exposure and environmental analyses.« less

Positive dermal hypersensitivity and specific antibodies in workers exposed to bio-engineered enzymes

The potential carcinogenic effect of inhaled automobile exhaust emissions was examined in rodents. Both rats and hamsters were exposed to the emissions from (1) a gasoline engine, (2) a gasoline engine fitted with a three‐way catalytic converter, (3) a diesel engine and (4) a diesel engine with particle filtration. Exposures were for 16 hours per day, 5 days per week, for 2 years. All hamsters were sacrificed at the end of the 2 year exposure period, whereas the rats surviving after 2 years of exposure were maintained for a further 6 month observation period without additional exposure to emissions. Some of the hamsters in each treatment group were pretreated with diethylnitrosamine to induce respiratory tract tumours.

Tumours of the respiratory tract in rats and hamsters following chronic inhalation of engine exhaust emissions

Ventilation tower laboratory animals in modular construction for.

A number of studies have suggested that both the length and diameter of glass fibers are important parameters in determining their deposition and translocation in the lung and in the subsequent pathological response by the lung. However, the fibers used in these studies had broad size distributions and were often administered in a highly artificial manner. To better characterize the biological response to glass fibers, a study is being conducted to determine the translocation and ultimate fate of fibers of defined sizes after introduction into the respiratory tract of rats by both instillation and inhalation. The fibers have geometric mean diameters of 1.5 ..mu..m (sigma g = 1.11) and lengths of either 5 ..mu..m (sigma g = 1.49) or 60 ..mu..m (sigma g = 3.76). Serial sacrifices following intratracheal instillation of either 2 mg or 20 mg doses have shown differences in the response to the two sizes of fibers. The short fibers appear to lie primarily within mononuclear phagocytes in both the lung and lymph nodes. The majority of long fibers, however, cannot be totally engulfed by macrophages, nor are they cleared to the lymph nodes, although smaller fragments accompanying the long fibers may be so cleared. The longmore » fibers produce a striking foreign body reaction in the lung, particularly when impacted in the bronchi. Significant numbers of long fibers, but few, if any, short fibers are found in the plural cavity. A trachea only inhalation method was used to expose rats to approximately 500 fibers/cc for one hour. Between 30,000 to 50,000 fibers were deposited in the lung of each rat.« less

Translocation and fate of sized man-made mineral fibers following exposure by intratracheal instillation or inhalation in rats

The effects of inhaled benzene on primary and secondary antibody responses and the incidence of leukemia in mice are reported. Young adult mice were given 5, 12, or 22 exposures to 400 ppM benzene for 6 hrs/day 5 days/week. After the exposure periods, the mice were immunized with absorbed tetanus toxoid (APTT) and/or fluid tetanus toxid (FTT). Exposure to benzene increasingly suppressed primary antibody responses to both antigens. Secondary antibody responses to FTT were nearly normal in animals given 10, 15, or 20 exposures to 400 ppM benzene. Other groups of mice were exposed to either 200 ppM or 50 ppM benzene. Primary antibody responses elicited with FTT and/or APTT were nearly normal in all mice exposed to 50 ppM benzene and in mice exposed to 200 ppM benzene for 5 days. However, 10 and 20 exposures to 200 ppM benzene inhibited antibody production. The effects of chronically inhaled 300 ppM benzene on the time of onset and incidence of leukemia in 400 7-month-old female HRS/J mice were also studied. Two genotypes were used; the (hr/hr) hairless mice are leukemia-prone, whereas the (hr/+) haired mice are more resistant to leukemia. The exposure continued for a period of 6 months. Lymphoid, more » myeloid, and mixed (lymphoid and myeloid) leukemias were observed. Ninety percent of the (hr/hr) mice exposed to benzene died from leukemia as compared with 91% for the (hr/hr) air control group. Eighty-five percent of the (hr/+) mice exposed to benzene died from leukemia as compared with 81% for the (hr/+) air control group. Exposures to 300 ppM benzene did not alter the time of onset or the incidence of leukemia commonly expected in HRS/J mice. « less

Benzene inhalation effects upon tetanus antitoxin. Responses and leukemogenesis in mice

Variations in inhalation chamber temperature can produce alterations in animal physiology, metabolism of foreign compounds as well as the chemical interaction of pollutant aerosols. This report presents the results of an investigation of the different mechanisms of heat transfer in a 380 L inhalation chamber and discusses the relative effectiveness of various methods that may be used to maintain a uniform chamber temperature during animal exposures. The thermal characteristics of the inhalation chamber were studied using an array of 40 thermocouples, with and without rats in the chamber and with and without 5 cm fiber glass insulation surrounding the chamber. Temperature profiles were measured with different animal loadings and intake air temperatures. An effective heat transfer coefficient of 6.6 +/- 1.8 W/m2 degrees C was determined for the stainless steel walls of the chamber. Heat balance studies with rats in this chamber have shown that with room air intake at a flow rate of 100 L/min, the stainless steel chamber walls were effective at removing approximately ninety percent of the animal heat as compared to the airstream.

The major parameters affecting temperature inside inhalation chambers.

A number of studies have shown that glass fibers induce both malignant mesothelioma and fibrosis in rats and that these reactions may be primarily a function of the physical properties of the fiber. However, these studies were carried out with fibers having broad size distributions and used methods of administration which bear little resemblance to the way man is exposed. To better characterize the health effects of glass fibers, techniques have been developed to expose rats to glass fibers of defined sizes by intratracheal instillation of aqueous suspensions and by "nose only" inhalation exposure, and to determine the deposition, translocation, and ultimate fate of these fibers in the rat. The fibers have known size distributions with geometric mean diameters of 1.5 micrometers (sigma g = 1.1) and lengths of either 5 micrometers (sigma g = 1.49) or 60 micrometers (sigma g = 3.76). The fibers have been activated with neutron irradiation. Of the several resulting radionuclides, 65Zn appeared to be the most suitable for long-term clearance studies by use of in vivo whole body radioassay techniques. A fluidized bed aerosol generator has been developed to expose rats by "nose only" inhalation to approximately 500 fibers/cm3. The generator and exposure system permits reuse of fibers which pass through the exposure chamber and produces no significant alteration of the fiber size distribution. Rats were exposed by intratracheal instillations to 20 mg of the longer fibers and to equal numbers (2 mg) and equal mass (20 mg) of the shorter fibers. Through approximately 19 weeks little difference was observed in the whole rat clearance rate of long versus short fibers in the initial exposure group. Histopathology, however, showed differences at this time with the short fibers apparently successfully phagocytized by alveolar macrophages and cleared to the lymph nodes, while the long fibers were not. ImagesFIGURE 3.FIGURE 6.FIGURE 7.FIGURE 8.FIGURE 9.FIGURE 10.

Mass concentrations and size-mass distributions of the New York summer aerosol during July and August 1976 were determined by a variety of established and experimental techniques by several of the laboratories collaborating in the New York Summer Aerosol Study (NYSAS). All of the results to be presented and discussed here are based on samples collected, and/or measurements made, at the New York University Medical Center's rooftop sampling station, located at 30th Street near First Avenue, as described by Kneip et a1.l The objectives of this part of the summer aerosol study were to determine: 1. Temporal concentration patterns of total suspended particulates (TSP) , of accumulation mode suspended particulate (AMSP), and of sulfate ion, the most abundant single chemical species within the total suspended particulate. 2. The aerodynamic size distribution of the New York summer aerosol. 3. Sampler performances and reliabilities for the determination of suspended particulate concentrations. 4. Characteristic relations, if any, between the concentration indicated by direct-reading instruments and mass concentrations determined by gravimetric analyses of filter samples.

Airborne particulate matter was collected at rural High Point, New Jersey, during July and August 1976, as part of the New York Summer Aerosol Study (NYSAS). The effort involved the evaluation of the aerosol at this rural site, which is located approximately 55 miles west-northwest of New York City, and the examination of the upwind relationship between the High Point data and data obtained coincidently at the New York University Medical Center, New York City. The information in this paper characterizes the particulate matter collected throughout the period at High Point both chemically and physically. The general sources of the inorganic portions of thc particulates are indicated by the results from analysis of the aerosol during periods of elevated sulfate (SO,) and ozone (0,) concentrations, and high trace-element enrichment factors.

The size distributions and elemental compositions of the urban atmospheres are important parameters both for characterizing the aerosol itself and for understanding its relationship to sources and meteorology. In addition, these factors are essential for defining the composition of the fractions of the aerosol associated with health effects. The volume or mass distribution of the urban aerosol is often described by two or three log-normal modes. In New York City the two prevailing modes are the accumulation mode (mass-median aerodynamic diameter (MMAD) between approximately 0.1 and 2.5 pm) and the coarse-particle mode (MMAD greater than approximately 2.5 pm).' These two modes are generally attributed to different types of particle production.z In general, the fine-particle mode results from vapor phase to particle transformation, whereas the coarse-particle mode results from comminution processes. There is apparently little mixing between the two modes. To determine the elemental composition of the New York aerosol as a function of size, during the New York Summer Aerosol Study (NYSAS) in August 1976, three different types of size-selective samplers and one highvolume filter sampler were operated. The data obtained were used to achieve a better understanding of the sources and health hazard potential of the New York aerosol.

NEW YORK SUMMER AEROSOL STUDY: TRACE ELEMENT CONCENTRATIONS AS A FUNCTION OF PARTICLE SIZE

1. The nation's highest emission density of fossil fuel burning sources (electrical power generation and automobiles) within the city and surrounding areas; 2. High emission density of industrial sources near the city within the general urban area, which include refineries, chemical plants, scrap metals recovery and refining, etc. 3. The potential for transport of additional pollutants from sources in the highly urbanized and industrialized corridor Washington, D.C. to New York City to Boston on southwest winds, which occur frequently during the summer; 4. The potential for additional transport of sulfates and other small particles from the Midwest; 5 and 5 . The existence of a summertime photochemical smog problem that is significantly enhanced by long-range transport.'j

(1979). An electronic feedback constant flow controller for high volume samplers and air movers. American Industrial Hygiene Association Journal: Vol. 40, No. 9, pp. 835-837.

An electronic feedback constant flow controller for high volume samplers and air movers.

In order to characterize the aerosol generated within the New York Citynortheastern New Jersey Metropolitan Area, it was necessary to characterize the background, or upwind, aerosol that contributes to some fraction of the observed total suspended particulates (TSP) in New York City. A site in rural western N.J. at High Point State Park was chosen for the background site because of the predominance of westerly winds in this area. In Part 11 l of this characterization (see next paper), the aerosol composition will be discussed. In this paper, transport is examined. High Point is situated near the common border of New Jersey, New York, and Pennsylvania, and is 55 miles west-northwest of the New York city site, 60 miles northeast of the Allentown-Bethlehem area and approximately 50 miles east of Scranton (see FIGURE 1). The monitoring site (FIGURE 2) was situated on a 15-mile long north-south ridge at the 1640 ft. level. Immediately to the west and east, the elevation drops off rapidly to about 400-500 ft. The area surrounding High Point is sparsely populated, with a population density

CHARACTERIZATION OF AEROSOLS UPWIND OF NEW YORK CITY: I. TRANSPORT *

During July and August, 1976, participants from seven research laboratories undertook a collaborative study of the New York City aerosol. The study was designed to characterize both the chemical and physical properties of the upwind or background aerosol and the aerosol in New York City in the summer. This report presents in brief summary form a description of the New York Summer Aerosol Study (NYSAS) and the principal findings that have emerged to date.

This paper describes construction details and operating characteristics of a nebulizer developed by Sidney Laskin and used over a period of 30 yr in various laboratories to generate respirable aerosols for whole-animal inhalation exposure studies. Under the proper operating conditions, the device is capable of producing nearly monodisperse aerosols in the respirable size range (1.5 micron volume median diameter with a geometric standard deviation of 1.1) for long periods of time

An apparent effect of the oil embargo on total suspended particulate matter and vanadium in New York City air.

I cannot let Professor Lenihan's comment on the above in the February 1977 issue of Physics Bulletin (p59) go without comment. What the Professor says is of course absolutely correct but it needs saying much more often and as clearly but not to the converted.

A size selective particle sampler has been developed for continuous sampling of the urban aerosol over periods ranging from hours to weeks, providing relatively large sample weights. The system, which is now operating in New York City, uses a parallel array of two-stage samplers. The cyclones used as the first stage collectors have 50% particle retention at 3.5,2.5,1.5 and 0.5 µm aerodynamic diameter, respectively. Undersize particles which pass through the cyclones are captured on glass fiber filters. Equal intake velocities are assured by using flow equalizers on the inlets to the cyclones. Accurate control of the flow through the cyclones is obtained by the use of an integrated circuit pressure transducer in conjunction with a specially designed feedback control circuit. The collection efficiencies of the cyclone were calibrated using monodisperse ferric oxide test aerosols tagged with Tc-99m. Mass balances of the par-ticulates collected on the cyclones and filters are obtained for the five sampling st...

A High-Volume Sampler for the Determination of Particle Size Distributions in Ambient Air

Tissues obtained at autopsy of New York City residents have been analyzed for Cd, Cr, Cu, Fe, Mn, Ni, Pb and Zn. Tissue concentrations were determined for the right lung, hilar lymph nodes, kidney, liver, vertebrae and blood of each subject. Estimates of the deposition and clearance of the above trace metals in the human lung are predicted using a compartmental model. The coefficients of the differential equations have been determined using the data we have contained in conjunction with our results for the trace metal concentrations in the New York City aerosol. Comparison of the deposition and clearance coefficients is made with those proposed by the ICRP Task Group. 8 references, 4 figures, 3 tables.

Scattering of positrons by electrons has been investigated by bombarding a beryllium target with 200-Mev positrons and observing the recoil electrons in a diffusion cloud chamber located behind the target. The cloud chamber was in a magnetic field which permitted the yield of recoil electrons to be measured as a function of their energy W. The experiment covered the range 88<~W<~200 Mev. The positron beam also traversed the cloud chamber and the total number of incident positrons was determined by track-counting. 
 
The total electron yield for 88<~W<~200 Mev is (113±9)% below that predicted by the first-order Bhabha theory. This difference cannot be interpreted until radiative corrections to the theory have been evaluated. A calculation of these corrections which is valid for the conditions of this experiment is not available. The shape of the electron energy spectrum is in good agreement with the Bhabha theory, and inconsistent with the theory if annihilation terms are omitted.

I. Construction and Operation of a Diffusion Cloud Chamber. I. Bremsstrahlung Yield of High-Energy Electrons in Hydrogen.

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2 
Physics of Low Field Strength Operation 
 
3 
Magnets for Low-Field MRI 
 
4 
Sequencing for Low-Field Imaging 
 
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Sequences for Mid-Field Imaging 
 
6 
Signal-to-Noise Ratio and Field Strength 
 
7 
Discussion 
 
8 
Biographical Sketches 
 
True three-dimensional nuclear magnetic resonance zeugmatographic images of a human brain

Field Strength in Magnetic Resonance Imaging: Its Theoretical Basis

One-hundred and nineteen implants were imaged in an open-sided low-field magnetic resonance imaging system. Thirty-four of these implants were removed, and postoperative reports were made available. We found a variety of signs associated with the implants, including internal structures, loss of saline in double-lumen implants, intracapsular and extracapsular fluid accumulations, signal dropout regions most likely associated with calcifications, and debris and fluid in the silicone, as well as degradation of the silicone, disruptions of the capsule and bulging, and extracapsular silicone. Conclusions of intact versus ruptured were made on the basis of these findings and found to be confirmed in 32 of 34 cases, with 1 false-positive and 1 false-negative result. Based on MRI criteria for a broad sample of the population, 27 percent of the implants were considered ruptured. (Plast. Reconstr. Surg. 96: 852, 1995.)

In principle, tomographic imaging of breast implants provides the information needed to compute implant volume. We have investigated the reliability of this measurement as a means of diagnosing the loss of gel from the implant. We find that measurement errors, postimplantation changes of the implant, uncertainties in the patients' records, and lack of knowledge of the implant temperature in the body can lead to significant discrepancies, making this measurement unreliable as a diagnostic tool.

Measurement of Breast Implant Volume with Magnetic Resonance Imaging

RATIONALE AND OBJECTIVES.Low-field magnetic resonance imaging (MRI) evaluation of breast implants is described, with emphasis on the capabilities provided by different imaging sequences. METHODS.Open architecture MR images using a .064-T permanent magnet and three-dimensional Fourier transform and inversion recovery sequences were obtained. A breast coil was designed and built for this project. Symptomatic and asymptomatic patients with silicone, saline-silicone and saline implants, and phantoms were part of this study. Phase images were used to differentiate protons in silicone, water, and fat. RESULTS AND CONCLUSIONS.Low-field MRI permitted differentiation of silicone, water, and fat. Implant anatomy and surrounding pathology could be imaged and identified.

Characteristics of Magnetic Resonance Sequences Used for Imaging Silicone Gel, Saline, and Gel-Saline Implants at Low Field Strengths

5239266 MRI using variable imaging parameter(s) within a single image sequence

In disorders which involve the bone marrow, the fat/water ratio of the marrow is often an indicator of the progress of disease. A noninvasive method of monitoring this ratio in bone marrow could be clinically useful. We have investigated a method of bone marrow assessment, using magnetic resonance imaging at low field (0.064 Tesla). The method has been tested using calibrated phantoms; we also present results from normal human subjects.

A technique for assessment of bone marrow composition using magnetic resonance phase interference at low field

The authors address the problem of enhancing magnetic resonance (MR) images degraded by T2 effects and measurement noise in hybrid imaging process. Wiener filtering and the linear prediction (LP) techniques are utilized to perform global and local T2 corrections respectively. The effectiveness of this combined technique in correcting T2 distortions and reducing measurement noise is demonstrated.<<ETX>>

T2 restoration and noise suppression of hybrid MR images using Wiener and linear prediction techniques

PURPOSE: To allow the positioning of an operator and (or) a patient in a gantry chamber sealed integrally together with an MRI magnet, a console for observation and other components of an MRI system by using a continuously updated real time magnetic resonance imaging processing when an MR imaging area is displayed. CONSTITUTION: An MRI magnet assembly and a console for observation positioned near this assembly are both arranged in a sealed gantry chamber. A CRT display is used in a feeble magnetic field MRI system and a liquid crystal display in a ferromagnetic field MRI system. A stable RF shield is provided for RF separation of the console for observation, a power source and a video signal cable related thereto to monitor a relatively weak NMR signal which is released from an imaging area in the magnet assembly. A real time observation of an imaging area in the gantry chamber is performed simultaneously with the treatment of patients. COPYRIGHT: (C)1992,JPO

System and method for real time mr imaging system arranged in gantry chamber

We describe here an implementation of a pulse sequence in which one of the normally fixed scan parameters is varied through the scan. The image contrast that is normally obtained with long sequence repetition time TR, and consequently long scanning times, can be achieved with relatively shorter scan times by systematically varying TR during the data acquisition. By employing the longest TR only while collecting the data for the lowest spatial frequencies and using the shortest available TR elsewhere a flexible trade-off between image features (contrast and resolution) and scan time is possible. Examples of 2-D and 3-D FT MR images at low and middle field strength are presented with sequence details and some comparison scans of similar scan times.

A multisection, two‐dimensional, Fourier transform, doublegradient‐ echo magnetic resonance imaging sequence with partial flip‐angle excitation and section doubling by radiofrequency encoding approximately doubles the signal‐to‐noise ratio obtainable from a conventional spin‐echo sequence at low field strength, while maintaining essentially equivalent contrast.

Two‐Gradient‐Echo, TwoDimensional, Fourier Transform Multisection Imaging: Comparison with Spin‐Echo Imaging

Hybrid imaging techniques have been proposed as a means of decreasing imaging time without the cost and technical constraints of echo planar imaging. With this technique phase encoding measurements acquired at different echo times in more than one multiecho experiment are used to form a single image. This study analyzes the trade‐offs which occur in the selection of this technique over more conventional imaging in terms of signal/noise, contrast, resolution, imaging time, and efficiency. Hybrid imaging is shown to be advantageous when raw speed is essential such as in abdominal or pediatric imaging. When coverage rather than time becomes the important factor, hybrid imaging does not offer a significant advantage over conventional methods. T2 decay will also serve as a roll‐off filter which will reduce the spatial resolution, but not the noise, for short TE hybrid imaging.

Misregistration between section position and a feature of interest, such as a lesion, can result in loss of contrast on magnetic resonance images. Because the section direction typically has the poorest resolution, reduction of section misregistration can improve lesion contrast. Lesions occur at random sites; hence, to reduce misregistration, it is necessary to repeat imaging with a small amount of offset. This is impractical. Therefore, a reconstruction algorithm that yields offset sections was implemented, in which sections were produced with a zero- and a half-section shift. This algorithm was tested in 14 patients with multiple sclerosis. As expected, because of randomness associated with section placement relative to lesions, the half-shifted sections provided greater contrast as often as the zero-shifted sections. The combined set improved contrast significantly in 39% of lesions; improvement was greatest in lesions with lesser contrast. Signal-to-noise ratios were not affected by this process, which appears to be useful in magnetic resonance image reconstruction.

Three-dimensional Fourier transform (3-DFT) magnetic resonance imaging (MRI) offers advantages in terms of signal-to-noise (S/N) per unit of time for the case where a large number of slices is desired. This advantage is enhanced when the relaxation time, T/sub 1/, is short. Because time limitations in 3-DFT imaging force the use of short time intervals, TR, between excitations of a slice, lesion contrast is often undesirable at mid-and high-field strength even when the S/N is good. At low fields, where T/sub 1/ values are short, high S/N and contrast can both be achieved with 3-DFT MR images. The conceptual and analytical aspects of low-field 3-DFT MRI are presented and demonstrated at 640 G. >

Low-field 3-DFT MRI: conceptual, analytical, and experimental aspects

Surface descriptions are difficult to specify. Though image processing techniques are well established to generate nearly any planar or three-dimensionally curved surface, methods to describe such complex shapes are often disorienting. Even the best intentioned interface for surface description can confuse a seasoned user. This paper introduces a surface definition technique that is simple, accurate and intuitive for the needs of routine medical image analysis. We describe a procedure to define a curved surface based on surface intersection points in a series of parallel images. In this medical context, points selected describe a surface that contains pathology of diagnostic interest. Using this technique diagnostic views are generated that conform to natural anatomic shape, physicians are no longer restricted to orthogonal or even single curve surfaces. This user interface provides analytic descriptions to produce surface views that use a Fourier-shift technique for reconstruction. Surfaces through a volume are produced with resolution equal to that of the original data set. Example images are illustrated.

The authors developed a system for ultrafast magnetic resonance imaging (MRI) protocols at low field. The system design permits the acquisition of the raw data in the background while the reconstruction and display steps repeat as fast as they can in the foreground. The performance speeds depends partly on the desired use. By collecting raw data at a rate of 20 ms per echo with an echo delay of 9 ms, a complete data cycle for a 128*64 image takes 1.28 s. However, once half of that data is incorporated into the reconstruction, the image appears complete. Using this set of parameters the authors were able to get the rate of the recon/display loop to paint about two times per completed raw data cycle, showing an entirely new image at least once per second with an apparent frame rate of two per second. Interleaving of two or three orthogonal scans reduces the speed of update but provides better information. The authors discuss the system design for rapid scan/recon/display and demonstrate the image quality available at low field strength with scan times below one second. >

A total of 58 multiple sclerosis lesions from 16 patients were used to characterize the performance of a low field system for the detection of edematous (e.g., water‐elevating) brain lesions. Contrast, signal‐to‐noise, and their product (signal difference to noise) were measured for two‐dimensional and three‐dimensional Fourier transform techniques at low field strength (640 G) and compared to two‐dimensional sequences at mid field strength (3,500 G). The results showed numerically that low field‐strength magnetic resonance imaging can reliably detect multiple sclerosis lesions, and, by extension, other water‐elevating lesions, although with lower confidence levels.

Magnetic Resonance Imaging Characteristics of Multiple Sclerosis Plaques Imaged with Two‐dimensional and Three‐dimensional Fourier Transform Techniques at Low and Mid Field Strengths

It is shown how to generate oblique slices from a set of parallel slices. An algorithm that can produce planes or contours through the volume without any loss of the volume resolution of the original data set is presented. The algorithm uses the Fourier-shift theorem and is efficient for calculating large numbers of slices. Although the algorithm is general, it is particularly well suited for three-dimensional magnetic resonance images, as demonstrated with examples.<<ETX>>

Due to the nature of three-dimensional Fourier transform (3-DFT) data acquisition in magnetic resonance imaging (MRI), the spatial relation between a resolved volume element (a voxel) and the object can be manipulated easily. Those manipulations have practical consequences in terms of registering slice positions with respect to features of interest in producing oblique reformatted images where volume resolution is preserved, and in generating reformatted images that project the viewing plane onto a surface through the object that has an arbitrary shape.

Three-dimensional Fourier transform (3-DFT) magnetic resonance imaging (MRI) offers advantages in terms of signal-to-noise (S/N) per unit of time for the case where a large number of slices is desired. This advantage is enhanced when the relaxation time, T(1 ), is short. Because time limitations in 3-DFT imaging force the use of short time intervals, TR, between excitations of a slice, lesion contrast is often undesirable at mid-and high-field strength even when the S/N is good. At low fields, where T(1) values are short, high S/N and contrast can both be achieved with 3-DFT MR images. The conceptual and analytical aspects of low-field 3-DFT MRI are presented and demonstrated at 640 G.

Low-field 3-DFT MRI: Conceptual, Analytical And Experimental Aspects

A collection of modified procedures for setting rf transmitter levels using a three‐pulse sequence is described. Based on a geometrically weighted ratio of four signals, an estimate of the flip angle is calculated and used for an updating prescription. These techniques are designed to perform rapidly yet eschew systematic errors due to relaxation during the pulse sequence. © 1990 Academic Press, Inc.

Image Reconstruction A General Algorithm for Oblique Image Reconstruction

The authors developed a system for ultrafast magnetic resonance imaging (MRI) protocols at low field. The system design permits the acquisition of the raw data in the background while the reconstruction and display steps repeat as fast as they can in the foreground. The performance speeds depends partly on the desired use. By collecting raw data at a rate of 20 ms per echo with an echo delay of 9 ms, a complete data cycle for a 128x64 image takes 1.28 s. However, once half of that data is incorporated into the reconstruction, the image appears complete. Using this set of parameters the authors were able to get the rate of the recon/display loop to paint about two times per completed raw data cycle, showing an entirely new image at least once per second with an apparent frame rate of two per second. Interleaving of two or three orthogonal scans reduces the speed of update but provides better information. The authors discuss the system design for rapid scan/recon/display and demonstrate the image quality available at low field strength with scan times below one second.

Magnetic resonance (MR) imaging has proved beneficial in the evaluation of internal derangements of the knee. A limitation to general acceptance of MR imaging of the knee has been availability and cost. The recent introduction of low-field-strength MR imaging has shown promise in decreasing the cost and increasing the availability of this modality. High-resolution (pixel size, 0.7 mm2), three-dimensional Fourier transform (3DFT), thin-section (3.5 mm) imaging performed on a 0.064-T permanent magnet was used to evaluate 117 knees in 114 consecutive patients. The appearance of normal anatomy and internal derangements of the knee at low-field-strength imaging is described. Arthroscopic correlation was available for 28 knees. Findings from low-field-strength MR imaging and arthroscopy agreed in 79% of cases in the determination of meniscal tears. Partial-flip-angle techniques with 3DFT produced thin-section images of the knee of diagnostic quality. The authors conclude that in patients with internal derangements of the knee, low-field-strength (0.064-T) MR imaging may provide useful information.

Thin-section magnetic resonance imaging at low field strengths requires analysis of the relative merits of data collection techniques for direct three-dimensional versus multisection two-dimensional imaging. This analysis was done with specific emphasis on shortened relaxation times and the use of reduced magnetic field gradients. Three-dimensional Fourier transform techniques can provide thin-section images of good diagnostic quality when combined with partial flip-angle gradient-reversal techniques.

The cost of magnetic resonance imaging (MRI) is driven by magnetic field strength. Misperceptions as to the impact of field strength on performance have led to systems that are more expensive than they need to be. Careful analysis of all the factors that affect diagnostic quality lead to the conclusion that field strength per se is not a strong determinant of system performance. Freed from the constraints imposed by high-field operation, it is possible to exploit a varied set of opportunities afforded by low-field operation. In addition to lower costs and easier siting, we can take advantage of shortened T1 times, higher contrast, reduced sensitivity to motion, and reduced radiofrequency power deposition. These conceptual advantages can be made to coalesce onto practical imaging systems. We describe a low-cost MRI system that utilizes a permanent magnet of open design. Careful optimization of receiving antennas and acquisition sequences permit performance levels consistent with those needed for an effective diagnostic unit. Ancillary advantages include easy access to the patient, reduced claustrophobia, quiet and comfortable operation, and absence of a missile effect. The system can be sited in 350 sq ft and consumes a modest amount of electricity. MRI equipment of this kind can widen the population base than can access this powerful and beneficial diagnostic modality.

The signal-to-noise ratio (S/N) in magnetic resonance imaging is one of the variables that must be measured when comparing the relative performance of different techniques. Although various investigators and official groups have proposed different methods for measuring S/N, these are generally not practical for use by a physician working in a clinical situation. The authors present a simple method that should serve for estimating SIN in most cases.

Advances in Magnetice Resonance Imaging (MRI) techniques have recently made MRI the imaging modality of choice for many applications of clinical imaging. MRI provides the diagnosing clinician a non-invasive method for obtaining soft tissue differentiation with sub-millimeter resolution. Clinical MRI techniques include 3-dimensional imaging, spectroscopic imaging, arterial angiography and cardiac imaging. One MRI technique which has recently gained popularity is a class of protocols known as variable/partial flip angle MRI. Partial flip angle MRI techniques are useful because of their ability to vary contrast between tissues and/or maintain a particular level of contrast with a reduction in acquisition time [1]. Variable flip angle techniques differ from conventional MRI protocols in that the initial RF excitation/rotation pulse is not constrained to a 90 degree rotation of the longitudinal magnetization. Instead, the initial excitation flip angle is calculated to provide improved contrast between two tissues and/or maximize the intensity of a particular tissue. For tissues with reduced TR/T1 ratios, variable flip angle techniques may also be used to increase the image signal to noise within a localized region.

Tailored RF Pulse Modulation for RF Refocussed Variable Flip Angle MRI

The signal-to-noise ratio (S/N) in magnetic resonance imagining is one of the variables that must be measured when comparing the relative performance of different techniques. Although various investigators and official groups have proposed different methods for measuring S/N, these are generally not practical for use by a physician working in a clinical situation. The authors present a simple method that should serve for estimating S/N in most cases.

The efficiency and quality of three-dimensional Fourier transform (3DFT) magnetic resonance imaging were evaluated and compared with those of 2DFT imaging. For a fixed imaging time and number of sections, 3DFT imaging with conventional spin echoes always had a worse signal-to-noise ratio (S/N) than did 2DFT imaging, when both were optimized with respect to choice of repetition time (TR). With partial-flip magnetic resonance (MR) imaging, S/N was nearly equal for 2DFT and 3DFT imaging when both were optimized with respect to TR and flip angle. 3DFT imaging can have cross-section artifacts that exceed those of 2DFT imaging. For very thin sections these artifacts may be lessened, and 3DFT imaging can achieve this with smaller gradient pulses. Over-all, 3DFT imaging was found to be advantageous only for the very-thin-section imaging and in combination with partial-flip MR imaging.

Signal-to-noise ratio and section thickness in two-dimensional versus three-dimensional Fourier transform MR imaging.

The authors have developed techniques which may be performed on any standard clinical imager and produce complete data sets of 16 time frames in each of eight contiguous slices in a total acquisition time of 1024 heartbeats. The limits inherent in the acquisition procedure are outlined. The authors have found that 3.0 mm in-plane resolution is sufficient, and consequently, they need only perform 64 phase-encoding steps in a transaxial orientation and 128 in a coronal to produce a sufficiently large field of view to avoid aliasing in all but large patients. They have implemented these techniques using synchronous gating in both a spin echo (RF refocused) and a gradient reversal single pulse (gradient refocused) acquisition procedure. The former will suppress signal from flowing blood, thus producing a clean image of the cardiac anatomy, and that the latter will produce an image dominated by the inflowing blood due to flow related enhancement, possibly revealing variations in the flow due to abnormalities.<<ETX>>

Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society

Comparison of the RF refocused spin echo sequence experiment with the gradient reversal refocused spin echo sequence (for partial-flip-angle magnetic resonance imaging using sinc amplitude-modulated RF waveforms) has shown that the generally observed loss in enhancement of the signal at low flip angles for the RF refocused method can be attributed to the poor slice profile of the phase reversal pulse. Using a tailored RF refocusing pulse which improves the slice profile, the expected enhancement of signal at low flip angles has been improved to a level similar to that observed with gradient reversal sequences. This technique has important applications for partial flip imaging because it allows the use of RF refocused sequences, and the elimination of the intensity distortions that have hampered the clinical application of partial-flip-angle imaging with gradient refocusing.<<ETX>>

RF refocussed variable flip angle MRI using optimal pulse modulation

17 P ARTIAL flip angle and gradient meversal magnetic resonance (MR) imaging have recently attracted a great deal of attention. Although these techniques are used together, they involve two independent physical phenomena, and each brings complementary contributions to the imaging process. Although partial flip MR imaging does not replace conventional spin-echo procedures, it has proved to be a powerful adjunctive tool for specific applications. The ability to detect lesions with MR imaging is based on compositional differences among tissues and arises mostly from very simple effects. For a typical lesion, water content in the tissue increases, which mesults in correlated increases in relaxation times Ti and T2 and in hydrogen density, N(H). In a conventional spin-echo procedure, for any one set of imaging parameters (repetition time [TR]/echo time [TE]), the lengthening in Ti results in lowered signal intensity, while lengthened 12 and N(H) increase signal intensity. For medium to short TE values, there is a near cancellation of signal differences between the tissues, and contrast is poor. As TR lengthens, Ti ef-

Characteristics of partial flip angle and gradient reversal MR imaging.

4636728 Offset gradient fields in nuclear magnetic resonance imaging systems

Magnetic resonance (MR) is a new method for obtaining high quality tomographic images of potentially greater pathophysiologic specificity than conventional imaging methods. The basic concepts necessary for understanding MR instrumentation and image interpretation are outlined. A fundamental knowledge of MR is needed to appreciate future clinical applications.

Magnetic resonance (MR) gated cardiac imaging was performed in ten subjects using a prototype 0.15-T resistive magnet imaging system. Volume and planar imaging techniques utilizing saturation recovery, proton Tl-weighted relaxation time pulse sequences produced images of the heart and great vessels with exquisite anatomic detail that showed excellent correlation with cadaver sections of the heart. The left ventricular myocardial segments also showed excellent correlation with the thallium-201 cardiac single photon emission computed tomography images. Volume acquisition allowed postprocessing selection of tomographic sections in various orientations to optimize visualization of a particular structure of interest. The excellent spatial and contrast resolution afforded by MR volume imaging, which does not involve the use of ionizing radiation and iodinated contrast material, should assure it a significant role in the diagnostic assessment of the cardiovascular system.

Volume and planar gated cardiac magnetic resonance imaging: a correlative study of normal anatomy with thallium-201 SPECT and cadaver sections.

NMR IMAGING OF MESENCEPHALIC, HINDBRAIN AND CEREBELLAR ANATOMY–NORMAL AND ABNORMAL

NMR DEMONSTRATION OF ACUTE BRAIN INFARCTS IN PRIMATES FOLLOWING MIDDLE CEREBRAL ARTERY OCCLUSION

MOVEMENT OF PARAMAGNETIC STAINLESS STEEL ANEURYSM CLIPS IN A MAGNETIC FIELD

In order to determine the clinical usefulness of nuclear magnetic resonance (NMR) imaging, the investigators examined a variety of normal volunteers, patients with neoplastic lesions, and experimental animals. Preliminary results were obtained with the use of potential contrast agents. It was found that imaging applications of NMR in the vascular system, spine, brain, lung, and mediastinum offer certain advantages over other modalities. The absence of biological hazard as well as the ability to obtain unenhanced, noninvasive, gated images of the vascular system, as demonstrated in this study, make NMR particularly attractive. In addition to single-section capability, NMR makes it possible to obtain volume images of the spine and other organs which can be displayed in any desired plane or section thickness.

Preliminary experimental results in humans and animals with a superconducting, whole-body, nuclear magnetic resonance scanner.

Preliminary experimental results in humans and animals with a superconducting, whole-body nuclear magnetic resonance scanner

We report on the results of a collaboration between two independent research projects at the Buffalo and Stony Brook campuses of the State University of New York. At Buffalo we have been developing a software system for the detection and display of surfaces of organs and organ systems from three-dimensional reconstructions. At Stony Brook we have been developing hardware and software for the three-dimensional reconstruction of objects using nuclear magnetic resonance zeugmatographic imaging. The merging of these two modalities gives us a truly powerful tool for three-dimensional visualization. This is demonstrated by frames from movies illustrating the external and internal three-dimensional structure of organs, such as the brain and the heart, produced by applying the Buffalo display programs to the Stony Brook nuclear magnetic resonance reconstructions.

It is demonstrated that in some cases it is possible to reconstruct images of fields whose local values are not scalars but are instead anisotropic. The approach taken relies upon Fourier analysis of the angular dependence and separation of scalar and non-scalar contributions by symmetry, and is applicable to anisotropies that do not have even symmetry. Although there are only a limited number of cases in which the problem can be analytically solved, there appears to be a variety of applications for which good approximations are available. The proposed algorithm, a hybrid of well known image reconstruction techniques, has been applied to calculated projections of test patterns, local regions of which having been assigned either scalar or vector behavior or both.

On the Problem of Reconstructing Images of Non-Scalar Parameters from Projections. Application to Vector Fields

High resolution NMR zeugmatographic spectroscopy, 1. On the problem of image reconstruction of non scalar fields from projections, 2

Zeugmatographic high resolution nuclear magnetic resonance spectroscopy. Images of chemical inhomogeneity within macroscopic objects

The crude extracts obtained from two tropical moss species namely: Philonotis hastata (Duby) Wijk & Margad and Barbula lambaranensis C. Mull were analysed with a view to identifying the bioactive compounds present in them. The mosses were collected from their natural population and air dried at ambient temperature in the laboratory for fourteen days. The aqueous extracts were subjected to phytochemical analysis using standard methods while the n- hexane extracts were subjected to gas chromatography-mass spectrometry (GC-MS) analysis. The results of the phytochemical screening showed the presence of alkaloids (0.189mg/g), saponins (0.047mg/g) and flavonoids (22.35QE/g) in P. hastata while the alkaloids, saponins and flavonoids content in B. lambaranensis were 0.184mg/g, 0.037mg/g and 14.18QE/g respectively. Steroids and reducing sugars were also present in the two moss species. The results of the GC-MS analysis showed the presence of 23 compounds in P. Hastate with 9-Octadecenoic acid methyl ester, 9,12-Octadecadienoic acid (Z,Z)- methyl ester, cis-Vaccenic acid, Hexadecanoic acid methyl ester and 1- Phenanthrenecarboxylic acid, tetradecahydro-7-(2-methoxy-2-oxoethlidene)-1,4a,8-trimethyl-9-oxo-, methyl ester forming the major components while in B. lambaranensis, 31 compounds were present from which Hexadecanoic acid methyl ester, 9,12-Octadecadienoic acid methyl ester, 13-Tetradecenal, 9-Octadecenoic acid (Z)- methyl ester and Hexadecanoic acid, 2-hydroxy-1-(hydroxymethyl)ethyl ester formed the prominent components. Five compounds: Hexadecanoic acid methyl ester, n-Hexadecanoic acid, cis-Vaccenic acid, Octadecanoic acid and 9-Octadecanoic acid methyl ester were commonly identified in the two moss species. The identified compounds are considered to be biologically and pharmacologically important. Further investigation on the identified bioactive compounds from the studied moss species will be beneficial to formulate novel drugs for the treatment and management ...

Phytochemical Profiling and GC-MS Analysis of Extracts of Two Tropical Moss Species

Original Research Article This study was conducted to evaluate the efficiency of two digestion methods in determining heavy metal concentrations in a moss species. Samples of the moss Barbula lambaranensis were collected from seven major roadsides in Ado-Ekiti, Nigeria. In each location, three subsamples were collected and pooled to form a composite sample. Each was then divided into two parts. The moss samples were cleaned of extraneous material, oven dried at 50 0 C for 24 hrs and digested using two different digestion methods namely dry digestion and wet digestion to recommend the more efficient digestion method. Digested samples were analysed for six heavy metals namely iron (Fe), nickel (Ni), copper (Cu), chromium (Cr), lead (Pb) and cadmium (Cd) using atomic absorption spectrometry. Results revealed that both digestion methods gave similar and comparable results. Total mean concentrations (mg/kg) of Fe, Ni, Cu, Cr and Pb in the moss samples were 2758.57, 3.06, 18.93, 1.78 and 0.58 respectively using dry digestion method while mean concentrations of Fe (3409.05), Ni (3.56), Cu (20.37), Cr (2.21) and Pb (0.61) were observed in the moss samples using wet digestion method. Cadmium was below detection limits in both cases. Statistical analyses revealed that there were no significant differences between the concentrations of the heavy metals obtained by both digestion methods. This indicates that both digestion methods are equally precise and reliable for the preparation of moss samples for heavy metal analysis.

Comparative Study of Two Digestion Methods for Heavy Metal Analysis in a Moss Species Collected in Ado-Ekiti, Nigeria

This study determined the nutritional and anti-nutritional composition of leaves of Diplazium sammatii using standard methods. Fresh and matured leaves of the fern were plucked from healthy plants, air dried to constant weight and pulverised into powder using an electric blender. This was used for the analyses. Results of the proximate analysis showed that it contained 15.31% protein, 14.60% moisture, 13.33% ash, 9.76% crude fibre, 44.05% carbohydrate, 2.93% fat and energy value of 263.81 kcal/100 g. The leaves were also observed to contain 22.30 mg/100 g of Vitamin C. The mineral elements present included sodium (68.10 mg/100 g), potassium (2073.80 mg/100 g), manganese (4.19 mg/100 g), magnesium (105.30 mg/100 g), phosphorus (154.45 mg/100 g), iron (45.30 mg/100 g), calcium (1360.00 mg/100 g), zinc (8.30 mg/100 g) and copper (0.51 mg/100 g). Phytochemical screening revealed that alkaloids, tannins, phenols, saponins, flavonoids, steroids, cardiac glycosides and cyanogenic glycosides were present while terpenoids, anthraquinones and phlobatanins were not detected. The anti-nutritional compounds found included oxalate (0.53 mg/100 g), phytate (0.41 mg/100 g) and hydrogen cyanide (0.08 mg/100 g). The results of proximate analysis suggest that the leaves of Diplazium sammatii could be a good source of nutrients especially for human diet when supplemented. Relatively high flavonoid content of the leaf extracts suggest potential anti-oxidant property of the vegetable while extremely low levels of the anti-nutrients indicate that the consumption of this plant as vegetables may not pose any health problems to the consumers.

NUTRITIVE, MINERAL, PHYTOCHEMICAL AND ANTI-NUTRIENT COMPOSITION OF AN EDIBLE FERN, Diplazium sammatii (KUHN) C. CHR. GROWN IN EKITI STATE, NIGERIA

Original Research Article This study was conducted to determine the nutritional and anti-nutritional composition of the leaves of an edible and medicinal fern, Ceratopteris thalictroides using standard procedures. The phytochemical screening and GC-MS analysis of the leaf extracts were also carried out. GC-MS analysis was done using Agilent technologies Model 7890A coupled with a mass spectrometer Agilent technologies 6975. The results of proximate analysis revealed that the leaves contained 13.39% moisture, 13.36% protein, 10.18 % ash, 5.54% crude fibre, 54.34% carbohydrate, 3.21% fat and energy value of 299.69 kcal/100g. Vitamin C content of 6.09 mg/100g was also observed in the leaves. Minerals analysis revealed the occurrence of minerals such as sodium (85.20 mg/100g), potassium (1341.30 mg/100g), phosphorus (215.00 mg/100g), magnesium (107.00 mg/100g), calcium (434.00 mg/100g), manganese (6.44 mg/100g), iron (58.40 mg/100g), zinc (2.76 mg/100g) and copper (1.19 mg/100g). The anti-nutritional compounds found included oxalate (0.41 mg/100g), phytate (0.36 mg/100g) and hydrogen cyanide (0.15 mg/100g) which were much lower than reported safe limits. Results of phytochemical screening revealed the presence of alkaloids (0.02 mg/g ATE), saponins (0.01 mg/g), total phenol (14.51 mg/g GAE), tannins (4.29 mg/g TAE) and flavonoids (6.23 mg/g QE) while terpenoids, steroids, cyanogenic glycosides, cardiac glycosides, anthraquinones and phlobatanins were absent. The results of the GC-MS analysis revealed the presence of twelve compounds with documented therapeutic activities. The major phytocompounds included Benzene, (2-nitroethyl)(RT: 6.096; 40.75%), .gamma.-Sistosterol (RT: 23.154; 21.87%), n-Hexadecanoic acid (RT: 13.973; 5.96%) and Linalool (RT: 3.349; 4.04%). Others were present as minor compounds. The foregoing results revealed that the leaves of the investigated plant are good sources of essential nutrients. They also contain medicinally important compounds, having therapeutic potentials, thus they could be used as bio control agents.

Chemical Composition of the Leaves of Ceratopteris thalictroides (L.) Brongn

This study was conducted to evaluate the effect of refrigeration on the content of nutrients and anti-nutrients in an edible mushroom – P. sajor-caju consumed in Nigeria. Fresh and matured samples of the mushroom were purchased from Afe Babalola University, Ado Ekiti, Nigeria where it is being cultivated. This was shared into four equal groups. Three groups were subjected to storage in a refrigerator at 4°C for two weeks, four weeks and six weeks while the fourth group (fresh sample) served as the control. The samples were analysed for nutrients and anti-nutrients using standard methods. The results of the study revealed that increased storage time reduced most of the nutritional and anti-nutritional contents of the mushroom. Six weeks after refrigeration, moisture content increased by 3.77% while protein, fat, ash, crude fibre and carbohydrate contents reduced by 33.61%, 57.14%, 33.93%, 62.50% and 22.38% respectively; sodium, potassium, magnesium, phosphorus, iron, calcium, zinc and copper contents reduced by 14.09%, 12.08%, 27.91%, 13.01%, 21.28%, 20.14%, 39.68% and 42.00% respectively while manganese increased by 0.93%; vitamins A and C contents reduced by 36.00% and 52.51% respectively while phytate, oxalate and cyanide contents reduced by 26.67%, 23.33% and 25.00% respectively. The results of the present study suggest that refrigeration processing of less than two weeks could be the best time for the preservation of the nutritive value of the mushroom.

EFFECT OF REFRIGERATION ON THE NUTRITIONAL AND ANTI-NUTRITIONAL COMPOSITION OF AN EDIBLE MUSHROOM – PLEUROTUS SAJOR-CAJU CONSUMED IN NIGERIA

The present study was carried out to determine the phytochemical and anti nutritional composition of some selected edible mushrooms collected in Ekiti State, Nigeria such as Pleurotus sajor-caju, Termitomyces robustus, Lentinus squarosullus, Termitomyces microcarpous, Termitomyces clypeatus, Lentinus tuber-regium and Polyporus sp. The results of phytochemical analyses revealed the presence of phytochemicals such as alkaloids (0.03-0.17%), saponin (0.03-0.12%), total phenols (0.12-4.32%), flavonoids (0.20-6.04%) and tannins (0.04-2.60%). The least concentration of all the phytochemicals was found in Polyporus sp. Results of anti nutrient screening revealed the presence of phytate (0.17-0.34mg/g), oxalate (1.87-4.04mg/g) and cyanide (0.05-0.27mg/g). Furthermore, results revealed significant differences in the phytochemical as well as anti nutritional composition of the mushrooms though some species had similar compositions. The obtained values of phytochemicals and anti nutrients were significantly lower in all the mushroom species compared to their toxic levels according to World Health Organization stipulated safe limits. Thus, the study suggests that all the mushroom species are very safe for consumption while the presence of alkaloids, saponins, phenols and flavonoids indicate medicinal potentials. Hence, screening and characterization of the secondary metabolites are required.

Distribution of Phytochemicals and Some Anti-nutrients in Selected Edible Mushrooms in Ekiti State, Nigeria

DOI: 10.21276/haya.2018.3.10.4 Abstract: The effect of extraction solvents (water, ethanol and hexane) on the content of phytochemicals such as alkaloids, saponins, total phenols, tannins and flavonoids in three selected medicinal ferns (Nephrolepis cordifolia (L.) Presl, Nephrolepis biserrata (Sw.) Schott and Pneumatopteris afra (Christ) Holttum) in Ekiti State, Nigeria was investigated. Matured leaflets were collected from healthy plants in Ekiti State University, Ado Ekiti, Nigeria. Extracts from shade dried and powdered leaflets of each of the ferns were subjected to phytochemical screening using standard methods. The results showed the presence of total phenols, tannins and flavonoids in all the extracts of the ferns while saponin was present only in water extracts. Hexane was not able to extract alkaloids and saponins in the three ferns. The results showed that extraction solvents significantly affected the phytochemical composition of the ferns. The water and ethanol extracts had higher content of the phytochemicals than the hexane extracts. The diversity of phytochemicals found present suggests that the ferns could serve as sources of useful drugs.

Effect of Extraction Solvents on Phytochemical Composition of Selected Medicinal Ferns in Ekiti State, Nigeria

A survey on mushroom occurrence was carried out in Ado and Ikere local government areas of Ekiti State, Nigeria. The collected mushrooms were taxonomically identified. Out of a total of 109 samples, 19 species were obtained out of which 11 are edible while 8 are inedible. The edible ones include Schizophyllum commune Fr;Fr., Polyporus spp. P. Micheli ex Adans., Lentinus squarrosulus (Mont.), Termitomyces robustus (Beeli) Heim., Psathyrella candolleana Fr;Fr., Lactinus piperatus Linn., Lentinus tuber-regium (Fr) Singer, Termitomyces mammiformis F., Hydnochaete spp D. Davis., Agaricus campestris L. and Lentinus sajo-caju Fr. while the inedible ones are Auricularia spp Bull., Chlorophyllum spp (Massee)., Trichaptum biforme (Fr). , Ganoderma applanatum (Pers)., Coprinus nivenus Fr., Cyathus spp Haller., Geastrum spp Pers. and Stereum spp (Willd.) Pers. These mushrooms were distributed among different substrates which include soils, bark of trees, dead wood/trees and dead leaves. The cap size and stipe length of the mushrooms were also determined. The average cap size ranged from 3.00cm in Psathyrella candolleama to 24.9cm in Trichaptum biforme while the average stipe length ranged from 1.20cm in Hydnochaete spp to 15.60cm in Termitomyces mammiformis. Stipes were absent in Auricularia spp, Trichaptum biforme, Ganoderma applanatum and Geastrum spp. Variations were also observed in the cap colour, cap shape, stipe colour, stipe shape and gills of the mushrooms. Annulus was absent in all the mushrooms except Agaricus campestris. The rich diversity of mushrooms in the two local government areas of Ekiti State, Nigeria suggests huge socio-economic potential.

A Survey of Mushrooms in two Local Government Areas of Ekiti State, Nigeria

Phytochemical Constituents and Comparative in vitro Antibacterial Activity of Leaf and Stem Extracts of Pneumatopteris afra (Christ) Holttum

The effects of powders of two moss plants, Thuidum gratum (P. Beauv) and Barbula indica (Brid) on the survival of Callosobruchus maculatus (F.) was evaluated. The evaluations were aimed at generating natural products treatment suitable for post-harvest seed protection and as sustainable alternatives to synthetic insecticides in the control of the cowpea weevil, C. maculatus F. C. maculatus were obtained from the Department of Soil and Crop Sciences, Faculty of Agriculture, Ekiti State University Ado Ekiti, Nigeria. The insects were reared and bred in the laboratory of Plant Science Department, Ekiti State University Ado Ekiti. Cowpea seeds used in the study were kept in the freezer overnight to eliminate maculatus infestation coming from the Field. Powder of each moss plant were applied at the rate of 5.0, 7.5, 10.0 and 12.5% w/w with the cowpea seeds in petri dishes and five pairs of freshly emerging adults of C. maculatus were introduced into each petri dish including the control which has no powder. Each treatment was replicated three times. Mortality of adult C. maculatus at 24 hours interval after treatment was compared with the control. Results showed that all the treatments recorded higher mortality than the control and the differences were significant after 48hours of treatment (P< 0.05), but the level of mortality was independent of the concentrations applied. However, powders of these plants can be effectively used to store cowpea seeds. This innovative and sustainable information is critical to food security particularly the security of harvested and stored cowpea seeds.

Evaluation of the efficacy of moss plants:Thuidum gratum (P. Beauv) and Barbula indica (Brid) grown in the Southwestern ecological zone of Nigeria on the survival of Callosobruchus maculatus (F.) Coleoptera: Bruchidae

A laboratory experiment was conducted to investigate the insecticidal potential of aqueous and ethanol extracts of Barbula indica (a moss plant) on the survival of Callosobruchus maculatus F. a major storage pest of cowpea in Nigeria. Air dried plant materials were sieved to remove sandcrete materials. They were then ground into powder and portions of 1g, 2g,3g,and 4g each of the powder was suspended in 100ml of cold distilled water and ethanol separately for 24 hours. Each of these was filtered using a clean muslin cloth and the filtrates were used for the experiment. The effects of the extracts were tested on cowpea weevils. Percentage mortality of the weevils at 24, 48 and 72hours of treatment were recorded for these extracts at different concentrations.The results obtained indicated that the extracts caused significant reduction in the number of the weevils through contact killing, when compared with the control. Highest mortality was recorded in ethanol extract of the plant at 4% concentration. The plant can be used as an effective bio pesticide. (A.O. Adebiyi and P.O.Tedela. Pesticidal effects of extracts of Barbula indica on Callosobruchus maculatus ( Coleoptra Bruchidae). Nat Sci 2012;10(9):113-115). (ISSN: 1545-0740). http://www.sciencepub.net/nature . 15

Pesticidal effects of extracts of Barbula indica on Callosobruchus maculatus ( Coleoptra Bruchidae)

Chemical tests were carried out on the aqueous extracts of the air-dried powders of two tropical moss plants, Thidium gratum and Barbula indica using standard procedures, to identify the phytochemical constituents. The extracts were screened for the presence and quantities of alkaloids, flavonoids, phenols, saponins and steroids with a view to assess their therapeutic values in ethnomedicine. The results of the phytochemical screening revealed the presence of alkaloids, flavonoids, phenols, saponins and steroids in varying quantities in the two moss plants but there was absence of phenol in Barbula indica. These results suggest that the two moss plants can be veritable and potential source of useful drugs in treatment of ailments.

Phytochemical Screening of Two Tropical Moss Plants: Thidium gratum P. Beauv and Barbula indica Brid Grown in Southwestern Ecological Zone of Nigeria

This study investigated the effect of crude oil-contaminated soil on the germination and growth performance of Abelmoschus esculentus, a widely cultivated vegetable crop in Nigeria. The experiment was conducted in the Screen House, under controlled environmental conditions. The seedling emergence percentage, heights and girths were studied to determine the growth performance of the crop in crude oil-contaminated soil. The result of the investigation revealed that the crude oil-contaminated soil affects the growth performance of Abelmoschus esculentus L. as hindered germination, reduced heights and girths were observed in the crop planted in treated soil and this adversely and severely affects the crop agronomic growth and development and probably its yield. Therefore, contamination of agricultural soils with crude oil should be avoided and public awareness should be created on the detrimental effects of crude oil pollution in our terrestrial ecosystem. Innovative and environmental-friendly remediation strategies should be carried out on our agricultural soils that have been grossly polluted by crude oil exploitation and exploration.

Effect of Crude Oil-Contaminated Soil on Germination and Growth Performance of Abelmoschus esculentus L. Moench—A Widely Cultivated Vegetable Crop in Nigeria

This work was performed to determine the influence of heat treatment on sewage sludge and addition of zero valent iron (ZVI) on the degradation and decolourisation of an anthraquinone dye, reactive blue 2 (RB 2). A consortium of sulphate reducing bacteria (SRB) in a biosulphidogenic batch reactor with biodigester sludge was used. The latter supplied carbon and augmenting microorganisms. Reactors with heat treated sludge were outperformed by those with unheated sludge for the larger part of the reactor life span. A 75% decolourisation efficiency was achieved within 24 h of inoculation when 4 g ZVI/l were added in an SRB reactor with unheated sludge as opposed to 59% colour removal after four days in the same reactor without ZVI. However, decolourisation was also noted in the presence of ZVI alone, indicating existence of chemical reaction between ZVI and RB 2.

Decolourisation and degradation of reactive blue 2 by sulphate reducing bacteria (SRB) and zero valent iron in a biosulphidogenic reactor

Bacterial pathogens were isolated from some Nigerian packaged fruit juices. The isolates were characterized and identified as Bacillus licheniformis, Aeromonas hydrophila, Bacillus circulans, Proteus morganii, Pseudomonas cepacia, Bacillus alvei and Pseudomonas chlororaphis. The antibiotic susceptibility profile of the seven isolates was determined and it was discovered that 65% of the microorganisms isolated were resistance to the antibiotic used while 35% were sensitive. The effect of pH, benzoic acid and sodium chloride concentration on the growth rate of isolates was investigated. It was found that as the pH of the growth medium increased from 3 to 9, the rate of growth of most isolates also increased except for Pseudomonas cepacia, which had optimum growth at neutral pH 7. As the concentration of sodium chloride increased from 2 to 5%, the rate of growth of all the seven isolates decreased. It was also noted that as concentration of benzoic acid increased from 250 to 1000 mg L(-1) Bacillus licheniformis decreased from 1.330 to 0.167 nm, Aeromonas hydrophila decreased from 1.208 to 0.164 nm Bacillus circulans decreases from 1.158 to 0.299 nm, Proteus morganii decreases from 1.377 to 0.141 nm etc. The higher the concentration of Benzoic acid the lower the rate of growth of the isolates.

The effect of pH and chemical preservatives on the growth of bacterial isolates from some Nigerian packaged fruit juices.

Water borne bacterial pathogens were isolated from sachet water vended in Ogbomoso, Oyo State, Nigeria. The isolates were characterized and identified as Bacillus subtilis, Bacillus alvei, Pseudomonas putida, Pseudomonas fluorescens, Bacillus cereus, Enterobacter aerogenes and Proteus mirabilis. The antibiotic susceptibility profile of the seven isolates was determined and it was discovered that 59.3% was found sensitive to the commercial antibiotic disc used while 40.7% was resistant. The effect of temperature, pH and sodium chloride concentration on the growth rate of isolates was investigated. It was found that as temperature of incubation increased from 50 to 80°C, the rate of growth of all the isolate decreased and as the pH of the growth medium increased from 3 to 9, the rate of growth of all the isolates also increased. As the concentration of sodium chloride increased from 2 to 5%, the rate of growth of isolates also reduced. 
 
 Key words: Bacillus subtilis, Bacillus alvei, Pseudomonas putida, Pseudomonas fluorescens, Bacillus cereus, Enterobacter aerogenes and Proteus mirabilis,sachet water, pH, temperature and sodium chloride.

Microbiological analysis of some vended sachet water in Ogbomoso, Nigeria

Brain-computer interfaces (BCIs) can potentially restore lost function in patients with neurological injury. A promising new application of BCI technology has focused on speech restoration. One approach is to synthesize speech from the neural correlates of a person who cannot speak, as they attempt to do so. However, there is no established gold-standard for quantifying the quality of BCI-synthesized speech. Quantitative metrics, such as applying correlation coefficients between true and decoded speech, are not applicable to anarthric users and fail to capture intelligibility by actual human listeners; by contrast, methods involving people completing forced-choice multiple-choice questionnaires are imprecise, not practical at scale, and cannot be used as cost functions for improving speech decoding algorithms. Here, we present a deep learning-based “AI Listener” that can be used to evaluate BCI speech intelligibility objectively, rapidly, and automatically. We begin by adapting several leading Automatic Speech Recognition (ASR) deep learning models - Deepspeech, Wav2vec 2.0, and Kaldi - to suit our application. We then evaluate the performance of these ASRs on multiple speech datasets with varying levels of intelligibility, including: healthy speech, speech from people with dysarthria, and synthesized BCI speech. Our results demonstrate that the multiple-language ASR model XLSR-Wav2vec 2.0, trained to output phonemes, yields superior performance in terms of speech transcription accuracy. Notably, the AI Listener reports that several previously published BCI output datasets are not intelligible, which is consistent with human listeners.

Using Automatic Speech Recognition to Measure the Intelligibility of Speech Synthesized From Brain Signals

Losing the ability to speak due to brain injury or neurodegenerative diseases such as ALS can be debilitating. Brain-computer interfaces could potentially provide affected individuals a fast and intuitive way to communicate by decoding speech-related neural activity into a computer-synthesized voice. Current intracortical BCIs for communication using handwriting or point-and-click typing are substantially slower than natural speech and do not capture the full expressive range of speech. Recent studies have identified speech features from ECoG and sEEG recordings; however, intelligible speech synthesis has not yet been demonstrated. Our previous work has shown speech-related patterns in intracortical recordings from dorsal (arm/hand) motor cortex that enabled discrete word/phoneme classification. This motivates exploring an intracortical approach for continuous voice synthesis. Here, we present a neural decoding framework to synthesize speech by directly translating neural activity recorded from human motor cortex using intracortical multielectrode arrays into a low-dimensional speech feature space from which voice is synthesized.

Synthesizing Speech by Decoding Intracortical Neural Activity from Dorsal Motor Cortex

The Eighth International Brain-Computer Interface (BCI) Meeting was held June 7-9th, 2021 in a virtual format. The conference continued the BCI Meeting series' interactive nature with 21 workshops covering topics in BCI (also called brain-machine interface) research. As in the past, workshops covered the breadth of topics in BCI. Some workshops provided detailed examinations of specific methods, hardware, or processes. Others focused on specific BCI applications or user groups. Several workshops continued consensus building efforts designed to create BCI standards and increase the ease of comparisons between studies and the potential for meta-analysis and large multi-site clinical trials. Ethical and translational considerations were both the primary topic for some workshops or an important secondary consideration for others. The range of BCI applications continues to expand, with more workshops focusing on approaches that can extend beyond the needs of those with physical impairments. This paper summarizes each workshop, provides background information and references for further study, presents an overview of the discussion topics, and describes the conclusion, challenges, or initiatives that resulted from the interactions and discussion at the workshop.

Workshops of the Eighth International Brain-Computer Interface Meeting: BCIs: The Next Frontier.

Large-scale neural recordings with single neuron resolution using Neuropixels probes in human cortex

Recent advances in multi-electrode array technology have made it possible to monitor large neuronal ensembles at cellular resolution. In humans, however, current approaches either restrict recordings to only a few neurons per penetrating electrode or combine the signals of thousands of neurons in local field potential (LFP) recordings. Here, we describe a new probe variant and set of techniques which enable simultaneous recording from over 200 well-isolated cortical single units in human participants during intraoperative neurosurgical procedures using silicon Neuropixels probes. We characterized a diversity of extracellular waveforms with eight separable single unit classes, with differing firing rates, positions along the length of the linear electrode array, spatial spread of the waveform, and modulation by LFP events such as inter-ictal discharges and burst suppression. While some additional challenges remain in creating a turn-key recording system, high-density silicon arrays provide a path for studying human-specific cognitive processes and their dysfunction at unprecedented spatiotemporal resolution.

Large-scale neural recordings with single-cell resolution in human cortex using high-density Neuropixels probes

Neural Representation of Observed, Imagined, and Attempted Grasping Force in Motor Cortex of Individuals with Chronic Tetraplegia

Power-saving design opportunities for wireless intracortical brain–computer interfaces

Enhanced neural interactions between higher-order and primary motor areas have been observed during various types of motor learning, but the behavioral function of such interactions remains poorly understood. An intriguing possibility is that increased top-down interactions during learning reflect the development of signals that bias performance in real-time (i.e., by controlling moment-by-moment adaptive variation in motor output) in order to implement more adaptive behavioral variants. Here, we tested this possibility in adult songbirds during vocal learning, by measuring moment-by-moment interactions between a primary motor area (RA) which controls the production of song acoustic features and a higher order nucleus (LMAN) which contributes to the learning of song modifications. We quantified LMAN-RA interactions by measuring the cross-covariance between LMAN and RA spiking activity. The cross-covariance function exhibited an LMAN-leading peak, consistent with a top-down influence of LMAN on RA. The strength of LMAN-RA cross-covariance increased during learning. This increase was specific to behavioral features targeted for learning, including both its precise timing (sub-second) and sequential context. Moreover, analysis of interleaved song renditions revealed a moment-by-moment correlation between the strength of enhanced LMAN-RA cross-covariance and the expression of adaptive pitch changes. These results indicate that enhanced interactions between higher-order (LMAN) and primary motor (RA) circuitry reflect a real-time, top-down motor bias that implements adaptive modifications of song during performance.

III-70. Inter-area interactions encode real-time adaptive biasing of performance during motor skill learning

Objective. To evaluate the potential of intracortical electrode array signals for brain-computer interfaces (BCIs) to restore lost speech, we measured the performance of decoders trained to discriminate a comprehensive basis set of 39 English phonemes and to synthesize speech sounds via a neural pattern matching method. We decoded neural correlates of spoken-out-loud words in the ‘hand knob’ area of precentral gyrus, a step toward the eventual goal of decoding attempted speech from ventral speech areas in patients who are unable to speak. Approach. Neural and audio data were recorded while two BrainGate2 pilot clinical trial participants, each with two chronically-implanted 96-electrode arrays, spoke 420 different words that broadly sampled English phonemes. Phoneme onsets were identified from audio recordings, and their identities were then classified from neural features consisting of each electrode’s binned action potential counts or high-frequency local field potential power. Speech synthesis was performed using the ‘Brain-to-Speech’ pattern matching method. We also examined two potential confounds specific to decoding overt speech: acoustic contamination of neural signals and systematic differences in labeling different phonemes’ onset times. Main results. A linear decoder achieved up to 29.3% classification accuracy (chance = 6%) across 39 phonemes, while an RNN classifier achieved 33.9% accuracy. Parameter sweeps indicated that performance did not saturate when adding more electrodes or more training data, and that accuracy improved when utilizing time-varying structure in the data. Microphonic contamination and phoneme onset differences modestly increased decoding accuracy, but could be mitigated by acoustic artifact subtraction and using a neural speech onset marker, respectively. Speech synthesis achieved r = 0.523 correlation between true and reconstructed audio. Significance. The ability to decode speech using intracortical electrode array signals from a nontraditional speech area suggests that placing electrode arrays in ventral speech areas is a promising direction for speech BCIs.

Decoding spoken English from intracortical electrode arrays in dorsal precentral gyrus

Objective. Speech-related neural modulation was recently reported in ‘arm/hand’ area of human dorsal motor cortex that is used as a signal source for intracortical brain–computer interfaces (iBCIs). This raises the concern that speech-related modulation might deleteriously affect the decoding of arm movement intentions, for instance by affecting velocity command outputs. This study sought to clarify whether or not speaking would interfere with ongoing iBCI use. Approach. A participant in the BrainGate2 iBCI clinical trial used an iBCI to control a computer cursor; spoke short words in a stand-alone speech task; and spoke short words during ongoing iBCI use. We examined neural activity in all three behaviors and compared iBCI performance with and without concurrent speech. Main results. Dorsal motor cortex firing rates modulated strongly during stand-alone speech, but this activity was largely attenuated when speaking occurred during iBCI cursor control using attempted arm movements. ‘Decoder-potent’ projections of the attenuated speech-related neural activity were small, explaining why cursor task performance was similar between iBCI use with and without concurrent speaking. Significance. These findings indicate that speaking does not directly interfere with iBCIs that decode attempted arm movements. This suggests that patients who are able to speak will be able to use motor cortical-driven computer interfaces or prostheses without needing to forgo speaking while using these devices.

Speech-related dorsal motor cortex activity does not interfere with iBCI cursor control

Objective To evaluate the potential of intracortical electrode array signals for brain-computer interfaces (BCIs) to restore lost speech, we measured the performance of classifiers trained to discriminate a comprehensive basis set for speech: 39 English phonemes. We classified neural correlates of spoken-out-loud words in the “hand knob” area of precentral gyrus, which we view as a step towards the eventual goal of decoding attempted speech from ventral speech areas in patients who are unable to speak. Approach Neural and audio data were recorded while two BrainGate2 pilot clinical trial participants, each with two chronically-implanted 96-electrode arrays, spoke 420 different words that broadly sampled English phonemes. Phoneme onsets were identified from audio recordings, and their identities were then classified from neural features consisting of each electrode’s binned action potential counts or high-frequency local field potential power. We also examined two potential confounds specific to decoding overt speech: acoustic contamination of neural signals and systematic differences in labeling different phonemes’ onset times. Main results A linear decoder achieved up to 29.3% classification accuracy (chance = 6%) across 39 phonemes, while a recurrent neural network classifier achieved 33.9% accuracy. Parameter sweeps indicated that performance did not saturate when adding more electrodes or more training data, and that accuracy improved when utilizing time-varying structure in the data. Microphonic contamination and phoneme onset differences modestly increased decoding accuracy, but could be mitigated by acoustic artifact subtraction and using a neural speech onset marker, respectively. Significance The ability to decode a comprehensive set of phonemes using intracortical electrode array signals from a nontraditional speech area suggests that placing electrode arrays in ventral speech areas is a promising direction for speech BCIs.

Decoding spoken English phonemes from intracortical electrode arrays in dorsal precentral gyrus

Abstract Intracortical brain-computer interfaces (iBCIs) have the potential to restore hand grasping and object interaction to individuals with tetraplegia. Optimal grasping and object interaction require simultaneous production of both force and grasp outputs. However, since overlapping neural populations are modulated by both parameters, grasp type could affect how well forces are decoded from motor cortex in a closed-loop force iBCI. Therefore, this work quantified the neural representation and offline decoding performance of discrete hand grasps and force levels in two human participants with tetraplegia. Participants attempted to produce three discrete forces (light, medium, hard) using up to five hand grasp configurations. A two-way Welch ANOVA was implemented on multiunit neural features to assess their modulation to force and grasp. Demixed principal component analysis (dPCA) was used to assess for population-level tuning to force and grasp and to predict these parameters from neural activity. Three major findings emerged from this work: (1) force information was neurally represented and could be decoded across multiple hand grasps (and, in one participant, across attempted elbow extension as well); (2) grasp type affected force representation within multiunit neural features and offline force classification accuracy; and (3) grasp was classified more accurately and had greater population-level representation than force. These findings suggest that force and grasp have both independent and interacting representations within cortex, and that incorporating force control into real-time iBCI systems is feasible across multiple hand grasps if the decoder also accounts for grasp type.

The Neural Representation of Force across Grasp Types in Motor Cortex of Humans with Tetraplegia

We review recent progress in neural probes for brain recording, with a focus on the Neuropixels platform. Historically the number of neurons’ recorded simultaneously, follows a Moore’s law like behavior, with numbers doubling every 6.7 years. Using traditional techniques of probe fabrication, continuing to scale up electrode densities is very challenging. We describe a custom CMOS process technology that enables electrode counts well beyond 1000 electrodes; with the aim to characterize large neural populations with single neuron spatial precision and millisecond timing resolution. This required integrating analog and digital circuitry with the electrode array, making it a standalone integrated electrophysiology recording system. Input referred noise and power per channel is 7.5µV and <50µW respectively to ensure tissue heating <1°C. This approach enables doubling the number of measured neurons every 12 months.

The Neuropixels probe: A CMOS based integrated microsystems platform for neuroscience and brain-computer interfaces

Neural Population Dynamics Underlying Motor Learning Transfer Highlights

Neural prostheses are being developed to restore speech to people with neurological injury or disease. A key design consideration is where and how to access neural correlates of intended speech. Most prior work has examined cortical field potentials at a coarse resolution using electroencephalography (EEG) or medium resolution using electrocorticography (ECoG). The few studies of speech with single-neuron resolution recorded from ventral areas known to be part of the speech network. Here, we recorded from two 96- electrode arrays chronically implanted into the ‘hand knob’ area of motor cortex while a person with tetraplegia spoke. Despite being located in an area previously demonstrated to modulate during attempted arm movements, many electrodes’ neuronal firing rates responded to speech production. In offline analyses, we could classify which of 9 phonemes (plus silence) was spoken with 81% single-trial accuracy using a combination of spike rate and local field potential (LFP) power. This suggests that high-fidelity speech prostheses may be possible using large-scale intracortical recordings in motor cortical areas involved in controlling speech articulators.

2018 40th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC)

Decoding Speech from Intracortical Multielectrode Arrays in Dorsal “Arm/Hand Areas” of Human Motor Cortex

Speaking is a sensorimotor behavior whose neural basis difficult to study at the resolution of single neurons due to the scarcity of human intracortical measurements and the lack of animal models. We recorded from electrode arrays in the ‘hand knob’ area of motor cortex in people with tetraplegia. Neurons in this area, which have not previously been implicated in speech, modulated during speaking and during nonspeaking movement of the tongue, lips, and jaw. This challenges whether the conventional model of a ‘motor homunculus’ division by major body regions extends to the single-neuron scale. Spoken words and syllables could be decoded from single trials, demonstrating the potential utility of intracortical recordings for brain-computer interfaces (BCIs) to restore speech. Two neural population dynamics features previously reported for arm movements were also present during speaking: a large initial condition-invariant signal, followed by rotatory dynamics. This suggests that common neural dynamical motifs may underlie movement of arm and speech articulators.

Neural ensemble dynamics in dorsal motor cortex during speech in people with paralysis

Speaking requires coordinating articulator muscles with exquisite timing and precision. Understanding how the sensorimotor system accomplishes this requires studying its neural underpinnings. Neural measurements are also critical for identifying the causes of speech disorders and building brain-computer interfaces (BCIs) to restore speech. Speech is a uniquely human behavior, which makes electrophysiological investigations challenging. Previous direct neural recordings during speech have come from electrocorticography (ECoG)1 or single-unit (SUA) recordings from penetrating electrodes2 during clinical epilepsy treatment. Such studies have begun to characterize motor cortical dynamics underlying speech3, but not at the finer spatiotemporal scale uniquely afforded by high-density intracortical recordings often used in animal reaching studies4. We had the opportunity to study speech production at this detailed resolution by recording from multielectrode arrays previously chronically placed in human motor cortex as part of the BrainGate2 BCI clinical trial for people with paralysis5,6. The spiking rate of neurons in dorsal ‘arm areas’, where speech-related activity has not previously been reported, modulated during speaking. This finding challenges whether the conventional model of a ‘motor homunculus’ somatotopy7 extends to the single-neuron scale. It is, however, consistent with known links between hand and speech networks that may reflect hand-mouth coordination and an evolutionary relationship between manual and articulatory gestures8. Two neural population dynamics features previously reported for arm movements were also present during speaking: a large initial condition-invariant signal9, followed by rotatory dynamics4,5. This suggests that common neural dynamical motifs may underlie movement of arm and speech articulators. Lastly, spoken words and phonemes could be accurately decoded from single trials, demonstrating the potential utility of intracortical recordings for BCIs to restore speech.

The need for calcium imaging in nonhuman primates: New motor neuroscience and brain-machine interfaces

Objective. Making mistakes is inevitable, but identifying them allows us to correct or adapt our behavior to improve future performance. Current brain–machine interfaces (BMIs) make errors that need to be explicitly corrected by the user, thereby consuming time and thus hindering performance. We hypothesized that neural correlates of the user perceiving the mistake could be used by the BMI to automatically correct errors. However, it was unknown whether intracortical outcome error signals were present in the premotor and primary motor cortices, brain regions successfully used for intracortical BMIs. Approach. We report here for the first time a putative outcome error signal in spiking activity within these cortices when rhesus macaques performed an intracortical BMI computer cursor task. Main results. We decoded BMI trial outcomes shortly after and even before a trial ended with 96% and 84% accuracy, respectively. This led us to develop and implement in real-time a first-of-its-kind intracortical BMI error ‘detect-and-act’ system that attempts to automatically ‘undo’ or ‘prevent’ mistakes. The detect-and-act system works independently and in parallel to a kinematic BMI decoder. In a challenging task that resulted in substantial errors, this approach improved the performance of a BMI employing two variants of the ubiquitous Kalman velocity filter, including a state-of-the-art decoder (ReFIT-KF). Significance. Detecting errors in real-time from the same brain regions that are commonly used to control BMIs should improve the clinical viability of BMIs aimed at restoring motor function to people with paralysis.

Augmenting intracortical brain-machine interface with neurally driven error detectors

Accurate motor control is mediated by internal models of how neural activity generates movement. We examined neural correlates of an adapting internal model of visuomotor gain in motor cortex while two macaques performed a reaching task in which the gain scaling between the hand and a presented cursor was varied. Previous studies of cortical changes during visuomotor adaptation focused on preparatory and perimovement epochs and analyzed trial-averaged neural data. Here, we recorded simultaneous neural population activity using multielectrode arrays and focused our analysis on neural differences in the period before the target appeared. We found that we could estimate the monkey's internal model of the gain using the neural population state during this pretarget epoch. This neural correlate depended on the gain experienced during recent trials and it predicted the speed of the subsequent reach. To explore the utility of this internal model estimate for brain–machine interfaces, we performed an offline analysis showing that it can be used to compensate for upcoming reach extent errors. Together, these results demonstrate that pretarget neural activity in motor cortex reflects the monkey's internal model of visuomotor gain on single trials and can potentially be used to improve neural prostheses. SIGNIFICANCE STATEMENT When generating movement commands, the brain is believed to use internal models of the relationship between neural activity and the body's movement. Visuomotor adaptation tasks have revealed neural correlates of these computations in multiple brain areas during movement preparation and execution. Here, we describe motor cortical changes in a visuomotor gain change task even before a specific movement is cued. We were able to estimate the gain internal model from these pretarget neural correlates and relate it to single-trial behavior. This is an important step toward understanding the sensorimotor system's algorithms for updating its internal models after specific movements and errors. Furthermore, the ability to estimate the internal model before movement could improve motor neural prostheses being developed for people with paralysis.

Trial-by-Trial Motor Cortical Correlates of a Rapidly Adapting Visuomotor Internal Model

A central goal of systems neuroscience is to relate an organism’s neural activity to behavior. Neural population analysis often begins by reducing the dimensionality of the data to focus on the patterns most relevant to a given task. A major practical hurdle to data analysis is spike sorting, and this problem is growing rapidly as the number of neurons measured increases. Here, we investigate whether spike sorting is necessary to estimate neural dynamics. The theory of random projections suggests that we can accurately estimate the geometry of low-dimensional manifolds from a small number of linear projections of the data. We re-analyzed data from three previous studies and found that neural dynamics and scientific conclusions are quite similar using multi-unit threshold crossings in place of sorted neurons. This finding unlocks existing data for new analyses and informs the design and use of new electrode arrays for laboratory and clinical use.

Accurate Estimation of Neural Population Dynamics without Spike Sorting

Motor Cortical Visuomotor Feedback Activity Is Initially Isolated from Downstream Targets in Output-Null Neural State Space Dimensions

Corrigendum: Making brain-machine interfaces robust to future neural variability

theories of neural computation propose specific patterns of neural connectivity tied to the tuning properties of neurons. We propose an extension to traditional latent space models to uncover continuous hidden structure in these connectomes, such as the neural tuning property of a neuron and the function that determines neural connectivity. Our scalable model provides the flexibility to recover structure in both directed and undirected graphs. We demonstrate our model on synthetic connectomes and on the recently published mouse retinal connectome .

Sortfree : Using threshold crossings to evaluate scientific hypotheses in population analyses

Making brain–machine interfaces robust to future neural variability

ALS drug development faces many challenges that result in very high failure rates of tested therapies. Unfortunately, most ALS therapies that show encouraging results in the lab do not translate into effective treatments for people with ALS. One of the biggest challenges in ALS drug development is the lack of a mechanistic readout of drug efficacy in patients at early phases of clinical drug development. Our team at Mass General Hospital (MGH) is laser-focused on building these needed imaging mechanistic platforms.

Inspired by control theoretic approaches to studying motor control, we experimentally measured how a brain-machine interface (BMI) user responds to an unexpected perturbation. We randomly applied a step cursor position offset while a monkey controlled a BMI cursor using decoded motor cortical spiking activity. The subject was able to rapidly correct for these perturbations and (re)acquire the target regardless of when in the trial this cursor jump occurred. We observed a corrective neural response in motor cortex starting 115 ms after the cursor jump. At no time did the neural response to detecting this externally-induced error manifest itself (through the decoder) as a deleterious velocity change pushing the cursor away from the target. These results show that a user of a high-performance BMI can make rapid, accurate corrections to errors and that, insofar as the neural computations needed to counteract the error may involve motor cortex, these computations do not appear to interfere with BMI cursor control.

System identification of brain-machine interface control using a cursor jump perturbation

Brain machine interfaces (BMIs) aim to assist people with paralysis by increasing their independence and ability to communicate, e.g., by using a cursor-based virtual keyboard. Current BMI clinical trials are hampered by modest performance that causes selection of wrong characters (errors) and thus reduces achieved typing rate. If it were possible to detect these errors without explicit knowledge of the task goal, this could be used to automatically “undo” wrong selections or even prevent upcoming wrong selections. We decoded imminent or recent errors during closed-loop BMI control from intracortical spiking neural activity. In our experiment, a non-human primate controlled a neurally-driven BMI cursor to acquire targets on a grid, which simulates a virtual keyboard. In offline analyses of this closed-loop BMI control data, we identified motor cortical neural signals indicative of task error occurrence. We were able to detect task outcomes (97% accuracy) and even predict upcoming task outcomes (86% accuracy) using neural activity alone. This novel strategy may help increase the performance and clinical viability of BMIs.

2015 37th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC)

Auto-deleting brain machine interface: Error detection using spiking neural activity in the motor cortex

Brain machine interfaces (BMIs) aim to assist people with paralysis by increasing their independence and ability to communicate, e.g., by using a cursor-based virtual keyboard. Current BMI clinical trials are hampered by modest performance that causes selection of wrong characters (errors) and thus reduces achieved typing rate. If it were possible to detect these errors without explicit knowledge of the task goal, this could be used to automatically “undo” wrong selections or even prevent upcoming wrong selections. We decoded imminent or recent errors during closed-loop BMI control from intracortical spiking neural activity. In our experiment, a non-human primate controlled a neurallydriven BMI cursor to acquire targets on a grid, which simulates a virtual keyboard. In offline analyses of this closed-loop BMI control data, we identified motor cortical neural signals indicative of task error occurrence. We were able to detect task outcomes (97% accuracy) and even predict upcoming task outcomes (86% accuracy) using neural activity alone. This novel strategy may help increase the performance and clinical

Reprint of “Non-causal spike filtering improves decoding of movement intention for intracortical BCIs”

A goal of brain–computer interface research is to develop fast and reliable means of communication for individuals with paralysis and anarthria. We evaluated the ability of an individual with incomplete locked-in syndrome enrolled in the BrainGate Neural Interface System pilot clinical trial to communicate using neural point-and-click control. A general-purpose interface was developed to provide control of a computer cursor in tandem with one of two on-screen virtual keyboards. The novel BrainGate Radial Keyboard was compared to a standard QWERTY keyboard in a balanced copy-spelling task. The Radial Keyboard yielded a significant improvement in typing accuracy and speed—enabling typing rates over 10 correct characters per minute. The participant used this interface to communicate face-to-face with research staff by using text-to-speech conversion, and remotely using an internet chat application. This study demonstrates the first use of an intracortical brain–computer interface for neural point-and-click communication by an individual with incomplete locked-in syndrome.

Neural Point-and-Click Communication by a Person With Incomplete Locked-In Syndrome

Objective. Brain–machine interfaces (BMIs) seek to enable people with movement disabilities to directly control prosthetic systems with their neural activity. Current high performance BMIs are driven by action potentials (spikes), but access to this signal often diminishes as sensors degrade over time. Decoding local field potentials (LFPs) as an alternative or complementary BMI control signal may improve performance when there is a paucity of spike signals. To date only a small handful of LFP decoding methods have been tested online; there remains a need to test different LFP decoding approaches and improve LFP-driven performance. There has also not been a reported demonstration of a hybrid BMI that decodes kinematics from both LFP and spikes. Here we first evaluate a BMI driven by the local motor potential (LMP), a low-pass filtered time-domain LFP amplitude feature. We then combine decoding of both LMP and spikes to implement a hybrid BMI. Approach. Spikes and LFP were recorded from two macaques implanted with multielectrode arrays in primary and premotor cortex while they performed a reaching task. We then evaluated closed-loop BMI control using biomimetic decoders driven by LMP, spikes, or both signals together. Main results. LMP decoding enabled quick and accurate cursor control which surpassed previously reported LFP BMI performance. Hybrid decoding of both spikes and LMP improved performance when spikes signal quality was mediocre to poor. Significance. These findings show that LMP is an effective BMI control signal which requires minimal power to extract and can substitute for or augment impoverished spikes signals. Use of this signal may lengthen the useful lifespan of BMIs and is therefore an important step towards clinically viable BMIs.

A high performing brain–machine interface driven by low-frequency local field potentials alone and together with spikes

Brain-machine interface (BMI) systems convert neural signals from motor regions of the brain into control signals to guide prosthetic devices. The ultimate goal of BMIs is to improve the quality of life for people with paralysis by providing direct neural control of prosthetic arms or computer cursors. While considerable research over the past 15 years has led to compelling BMI demonstrations, there remain several challenges to achieving clinically viable BMI systems. In this review, we focus on the challenge of increasing BMI perfor- mance and robustness. We review and highlight key aspects of intracortical BMI decoder design, which is central to the conversion of neural signals into prosthetic control signals, and discuss emerging opportunities to improve intracortical BMI decoders. This is one of the primary research opportunities where information systems engineering can directly impact the future success of BMIs.

Brain-machine interface (BMI) systems convert neural signals from motor regions of the brain into control signals to guide prosthetic devices. The ultimate goal of BMIs is to improve the quality of life for people with paralysis by providing direct neural control of prosthetic arms or computer cursors. While considerable research over the past 15 years has led to compelling BMI demonstrations, there remain several challenges to achieving clinically viable BMI systems. In this review, we focus on the challenge of increasing BMI performance and robustness. We review and highlight key aspects of intracortical BMI decoder design, which is central to the conversion of neural signals into prosthetic control signals, and discuss emerging opportunities to improve intracortical BMI decoders. This is one of the primary research opportunities where information systems engineering can directly impact the future success of BMIs.

Information Systems Opportunities in Brain–Machine Interface Decoders

Non-causal spike filtering improves decoding of movement intention for intracortical BCIs

Objective. Neural prostheses, or brain–machine interfaces, aim to restore efficient communication and movement ability to those suffering from paralysis. A major challenge these systems face is robust performance, particularly with aging signal sources. The aim in this study was to develop a neural prosthesis that could sustain high performance in spite of signal instability while still minimizing retraining time. Approach. We trained two rhesus macaques implanted with intracortical microelectrode arrays 1–4 years prior to this study to acquire targets with a neurally-controlled cursor. We measured their performance via achieved bitrate (bits per second, bps). This task was repeated over contiguous days to evaluate the sustained performance across time. Main results. We found that in the monkey with a younger (i.e., two year old) implant and better signal quality, a fixed decoder could sustain performance for a month at a rate of 4 bps, the highest achieved communication rate reported to date. This fixed decoder was evaluated across 22 months and experienced a performance decline at a rate of 0.24 bps yr-1. In the monkey with the older (i.e., 3.5 year old) implant and poorer signal quality, a fixed decoder could not sustain performance for more than a few days. Nevertheless, performance in this monkey was maintained for two weeks without requiring additional online retraining time by utilizing prior days’ experimental data. Upon analysis of the changes in channel tuning, we found that this stability appeared partially attributable to the cancelling-out of neural tuning fluctuations when projected to two-dimensional cursor movements. Significance. The findings in this study (1) document the highest-performing communication neural prosthesis in monkeys, (2) confirm and extend prior reports of the stability of fixed decoders, and (3) demonstrate a protocol for system stability under conditions where fixed decoders would otherwise fail. These improvements to decoder stability are important for minimizing training time and should make neural prostheses more practical to use.

The best-performing brain-machine interfaces (BMIs) to date decode movement intention from intracortically recorded spikes, but these signals may be lost over time. A way to increase the useful lifespan of BMIs is to make more comprehensive use of available neural signals. Recent studies have demonstrated that the local field potential (LFP), a potentially more robust signal, can also be used to control a BMI. However, LFP-driven performance has fallen short of the best spikes-driven performance. Here we report a biomimetic BMI driven by low-frequency LFP that enabled a rhesus monkey to acquire and hold randomly placed targets with 99% success rate. Although LFP-driven performance was still worse than when decoding spikes, to the best of our knowledge this represents the highest-performing LFP-based BMI. We also demonstrate a new hybrid BMI that decodes cursor velocity using both spikes and LFP. This hybrid decoder improved performance over spikes-only decoding. Our results suggest that LFP can complement spikes when spikes are available or provide an alternative control signal if spikes are absent.

Hybrid decoding of both spikes and low-frequency local field potentials for brain-machine interfaces

Introduction The nucleus accumbens plays a central role in mediating reward and addiction. Based on its limbic connectivity, the nucleus accumbens is a logical candidate target for DBS for multiple neuropsychiatric disorders including addiction, obesity and depression. Here we use task-fMRI data mined from the Human Connectome Project to validate that activity in the nucleus accumbens changes in response reward cues during a gambling task. Methods Task and resting state fMRI data was obtained from 40 and 120 subjects respectively as described by the Human Connectome Project (http://humanconnectome.org). Task fMRI consisted of a gambling task as previously described by Delgado and Fiez. Group average task fMRI activity and resting state functional connectivity was processed and represented in grayordinate space as described by Woolrich and Van Essen. Results Group average task fMRI activity from 40 subjects revealed a significant increase in activity in the nucleus accumbens in the REWARD-PUNISHMENT contrast and a significant decrease in activity in the nucleus accumbens for the PUNISHMENT condition. In addition, resting state data from 120 subjects revealed signficant functional connectivity between the nucleus accumbens and the the anterior cingulate and medial prefrontal cortex. Conclusions Task fMRI data from subjects undergoing a gambling task show significant changes in activity in the nucleus accumbens associated with both reward and punishment. In addition, resting state fMRI data revealed significant functional connectivity between the nucleus accumbens and other limbic regions involved in reward processing such as the anterior cingulate and medial prefrontal cortex. The Human Connectome Project provides neurosurgeons with a robust data set to explore the correlation between behavior and functional and structural connectivity in order to confirm and identify candidate targets for DBS for various behavioral disorders. # 137: Tuesday, June 3, 2014, 11:16-11:26 am; PS #5 Screening the Human Connectome for Potential DBS Targets for the Treatment of Drug Addiction

Changes in the Nucleus Accumbens Associated with Reward Cues during a Gambling Task

The intraday robustness of brain-machine interfaces (BMIs) is important to their clinical viability. In particular, BMIs must be robust to intraday perturbations in neuron firing rates, which may arise from several factors including recording loss and external noise. Using a state-of-the-art decode algorithm, the Recalibrated Feedback Intention Trained Kalman filter (ReFIT-KF) [1] we introduce two novel modifications: (1) a normalization of the firing rates, and (2) a reduction of the dimensionality of the data via principal component analysis (PCA). We demonstrate in online studies that a ReFIT-KF equipped with normalization and PCA (NPC-ReFIT-KF) (1) achieves comparable performance to a standard ReFIT-KF when at least 60% of the neural variance is captured, and (2) is more robust to the undetected loss of channels. We present intuition as to how both modifications may increase the robustness of BMIs, and investigate the contribution of each modification to robustness. These advances, which lead to a decoder achieving state-of-the-art performance with improved robustness, are important for the clinical viability of BMI systems.

Investigating the role of firing-rate normalization and dimensionality reduction in brain-machine interface robustness

Recurrent neural networks (RNNs) are useful tools for learning nonlinear relationships in time series data with complex temporal dependences. In this paper, we explore the ability of a simplified type of RNN, one with limited modifications to the internal weights called an echostate network (ESN), to effectively and continuously decode monkey reaches during a standard center-out reach task using a cortical brain–machine interface (BMI) in a closed loop. We demonstrate that the RNN, an ESN implementation termed a FORCE decoder (from first order reduced and controlled error learning), learns the task quickly and significantly outperforms the current state-of-the-art method, the velocity Kalman filter (VKF), using the measure of target acquire time. We also demonstrate that the FORCE decoder generalizes to a more difficult task by successfully operating the BMI in a randomized point-to-point task. The FORCE decoder is also robust as measured by the success rate over extended sessions. Finally, we show that decoded cursor dynamics are more like naturalistic hand movements than those of the VKF. Taken together, these results suggest that RNNs in general, and the FORCE decoder in particular, are powerful tools for BMI decoder applications.

A recurrent neural network for closed-loop intracortical brain–machine interface decoders

Control of a robotic arm using intracortical motor signal by an individual with tetraplegia in the BrainGate2 trial

Continuous Control of the DLR Light-Weight Robot III by a Human with Tetraplegia Using the BrainGate2 Neural Interface System

Rewards are thought to influence future choices through dopaminergic reward prediction errors (RPEs) updating stored value estimates. However, accumulating evidence suggests that inference about hidden states of the environment may underlie much adaptive behaviour, and it is unclear how these two accounts of reward-guided decision-making should be integrated. Using a two-step task for mice, we show that dopamine reports RPEs using value information inferred from task structure knowledge, alongside information about recent reward rate and movement. Nonetheless, although rewards strongly influenced choices and dopamine, neither activating nor inhibiting dopamine neurons at trial outcome affected future choice. These data were recapitulated by a neural network model in which frontal cortex learned to track hidden task states by predicting observations, while basal ganglia learned corresponding values and actions via dopaminergic RPEs. Together, this two-process account reconciles how dopamine-independent state inference and dopamine-mediated reinforcement learning interact on different timescales to determine reward-guided choices.

Dopamine-independent state inference mediates expert reward guided decision making

Laboratory behavioural tasks are an essential research tool. As questions asked of behaviour and brain activity become more sophisticated, the ability to specify and run richly structured tasks becomes more important. An increasing focus on reproducibility also necessitates accurate communication of task logic to other researchers. To these ends, we developed pyControl, a system of open-source hardware and software for controlling behavioural experiments comprising a simple yet flexible Python-based syntax for specifying tasks as extended state machines, hardware modules for building behavioural setups, and a graphical user interface designed for efficiently running high-throughput experiments on many setups in parallel, all with extensive online documentation. These tools make it quicker, easier, and cheaper to implement rich behavioural tasks at scale. As important, pyControl facilitates communication and reproducibility of behavioural experiments through a highly readable task definition syntax and self-documenting features. Here, we outline the system’s design and rationale, present validation experiments characterising system performance, and demonstrate example applications in freely moving and head-fixed mouse behaviour.

Open-source, Python-based, hardware and software for controlling behavioural neuroscience experiments

Dopamine is thought to carry reward prediction errors (RPEs), which update values and hence modify future behaviour. However, updating values is not always the most efficient way of adapting to change. If previously encountered situations will be revisited in future, inferring that the state of the world has changed allows prior experience to be reused when situations are reencountered. To probe dopamine’s involvement in such inference-based behavioural flexibility, we measured and manipulated dopamine while mice solved a sequential decision task using state inference. Dopamine was strongly influenced by the value of states and actions, consistent with RPE signalling, using value information that respected task structure. However, though dopamine responded strongly to rewards, stimulating dopamine at the time of trial outcome had no effect on subsequent choice. Therefore, when inference guides choice, rewards have a dopamine-independent influence on policy through the information they carry about the world’s state.

Dopamine reports reward prediction errors, but does not update policy, during inference-guided choice

Latent learning occurs when associations are formed between stimuli in the absence of explicit reinforcement. Traditionally, latent learning in rodents has been associated with the creation internal models of space. However, increasing evidence points to roles of internal models also in non-spatial decision making. Whether the same brain structures and processes support the creation of spatially-anchored or non-spatial internal models via latent learning, is an open question. To address this question, we developed a novel operant box task that allows to test spatial and non-spatial versions of a flavour-based sensory preconditioning paradigm. We probed the role of the retrosplenial cortex, a brain area associated with spatial cognition and subjective value representation, in this task using precise, closed-loop optogenetic silencing during different task phases. We show that the retrosplenial cortex is necessary for both spatial and non-spatial latent learning in mice. We further demonstrate that the requirement of retrosplenial cortex is limited to the preconditioning phase of the task. Our results provide insight into the specific role of the retrosplenial cortex in latent learning, demonstrate that latent learning plays a general part in the creation of internal models, independent of spatial anchors, and provide a novel avenue for studying model-based decision making.

Retrosplenial cortex is necessary for spatial and non-spatial latent learning in mice

Complementary task representations in hippocampus and prefrontal cortex for generalizing the structure of problems

Working memory (WM), the capacity to briefly and intentionally maintain mental items, is key to successful goal-directed behaviour and impaired in a range of psychiatric disorders. To date, several brain regions, connections, and types of neural activity have been correlatively associated with WM performance. However, no unifying framework to integrate these findings exits, as the degree of their species- and task-specificity remains unclear. Here, we investigate WM correlates in three task paradigms each in mice and humans, with simultaneous multi-site electrophysiological recordings. We developed a machine learning-based approach to decode WM-mediated choices in individual trials across subjects from hundreds of electrophysiological measures of neural connectivity with up to 90% prediction accuracy. Relying on predictive power as indicator of correlates of psychological functions, we unveiled a large number of task phase-specific WM-related connectivity from analysis of predictor weights in an unbiased manner. Only a few common connectivity patterns emerged across tasks. In rodents, these were thalamus-prefrontal cortex delta- and beta-frequency connectivity during memory encoding and maintenance, respectively, and hippocampal-prefrontal delta- and theta-range coupling during retrieval, in rodents. In humans, task-independent WM correlates were exclusively in the gamma-band. Mostly, however, the predictive activity patterns were unexpectedly specific to each task and always widely distributed across brain regions. Our results suggest that individual tasks cannot be used to uncover generic physiological correlates of the psychological construct termed WM and call for a new conceptualization of this cognitive domain in translational psychiatry.

Highly task-specific and distributed neural connectivity in working memory revealed by single-trial decoding in mice and humans

Laboratory behavioural tasks are an essential research tool. As questions asked of behaviour and brain activity become more sophisticated, the ability to specify and run richly structured tasks becomes more important. An increasing focus on reproducibility also necessitates accurate communication of task logic to other researchers. To these ends we developed pyControl, a system of open source hardware and software for controlling behavioural experiments comprising; a simple yet flexible Python-based syntax for specifying tasks as extended state machines, hardware modules for building behavioural setups, and a graphical user interface designed for efficiently running high throughput experiments on many setups in parallel, all with extensive online documentation. These tools make it quicker, easier and cheaper to implement rich behavioural tasks at scale. As important, pyControl facilitates communication and reproducibility of behavioural experiments through a highly readable task definition syntax and self-documenting features. Resources Documentation: https://pycontrol.readthedocs.io Repositories: https://github.com/pyControl User support: https://groups.google.com/g/pycontrol

pyControl: Open source, Python based, hardware and software for controlling behavioural neuroscience experiments

Control of impulsivity by Gi-protein signalling in layer-5 pyramidal neurons of the anterior cingulate cortex

The brains of higher organisms are composed of anatomically and functionally distinct regions performing specialised tasks; but regions do not operate in isolation. Orchestration of complex behaviours requires communication between brain regions, but how neural activity dynamics are organised to facilitate reliable transmission is not well understood. We studied this process directly by generating neural activity that propagates between brain regions and drives behaviour, allowing us to assess how populations of neurons in sensory cortex cooperate to transmit information. We achieved this by imaging two hierarchically organised and densely interconnected regions, the primary and secondary somatosensory cortex (S1 and S2) in mice while performing two-photon photostimulation of S1 neurons and assigning behavioural salience to the photostimulation. We found that the probability of perception is determined not only by the strength of the photostimulation signal, but also by the variability of S1 neural activity. Therefore, maximising the signal-to-noise ratio of the stimulus representation in cortex relative to the noise or variability in cortex is critical to facilitate activity propagation and perception. Further, we show that propagated, behaviourally salient activity elicits balanced, persistent, and generalised activation of the downstream region. Hence, our work adds to existing understanding of cortical function by identifying how population activity is formatted to ensure robust transmission of information, allowing specialised brain regions to communicate and coordinate behaviour.

Perception and propagation of activity through the cortical hierarchy is determined by neural variability

A low-cost open-source 5-choice operant box system optimized for electrophysiology and optophysiology in mice

Experiments have implicated dopamine in model-based reinforcement learning (RL). These findings are unexpected as dopamine is thought to encode a reward prediction error (RPE), which is the key teaching signal in model-free RL. Here we examine two possible accounts for dopamine's involvement in model-based RL: the first that dopamine neurons carry a prediction error used to update a type of predictive state representation called a successor representation, the second that two well established aspects of dopaminergic activity, RPEs and surprise signals, can together explain dopamine's involvement in model-based RL.

Distinct roles for dopamine clearance mechanisms in regulating behavioral flexibility

Mechanisms for regulation of dopamine transmission are critical to its effects on behavior and vary by region. Recycling via the dopamine transporter (DAT) predominates in striatum, while degradation by catechol-O-methyltransferase (COMT) predominates in cortex. However, questions remain about whether and how each mechanism affects fast fluctuations in dopamine transmission in these regions and influences behavior. To address this issue, we used pharmacological blockade of each clearance mechanism to assess their roles in reward-guided decision making and in regulating sub-second dopamine transmission in striatum and cortex. We found that DAT and COMT selectively influence reward value updating in opposite directions, with DAT blockade impairing and COMT inhibition improving learning in a multi-step decision making task that requires mice to monitor changes in both optimal response strategy and reward probabilities. By contrast, neither drug influenced the speed of reversals following a change in action-state transition probabilities. In addition, DAT but not COMT influenced task engagement and motivation to work for reward in both the decision making task and a progressive ratio paradigm. Fast scan cyclic voltammetry recordings of evoked dopamine release in anesthetized mice revealed that DAT but not COMT blockade enhanced dopamine transients in nucleus accumbens. Unexpectedly, neither manipulation had an effect on evoked release in medial frontal cortex. Together, these data refine our understanding of how dopamine clearance mechanisms operate in different regions and at distinct timescales to shape aspects of reward-guided decision making. Significance Statement Dopamine transmission is tightly regulated by clearance mechanisms and these clearance mechanisms exhibit regional specificity. However, while we know a lot about how the activity of dopamine neurons relates to reward-guided behavior, the precise role of different clearance mechanisms in shaping these processes is much less understood. This is important, as dysfunctional clearance mechanisms have been implicated in many neuropsychiatric disorders. Here, we show specific and distinct roles for two clearance mechanisms – the dopamine transporter and catechol-O-methyltransferase – in reward value, but not action-state probability, updating during multi-step decision making, and in regulating striatal and cortical dopamine transients. Our findings demonstrate how regulation of dopamine transmission, over distinct timescales and in different brain regions, can influence multiple aspects of reward-guided behavior.

Distinct roles for DAT and COMT in regulating dopamine transients and reward-guided decision making

Midbrain dopamine activity is thought to represent reward prediction errors (RPEs) used to update the value of stimuli and/or actions. However, it remains unclear what sources of value information are available to dopamine neurons, and to what extent values derived from internal models inform dopaminergic RPEs. To assess how midbrain dopamine activity is influenced by internal models of task structure, we trained mice in a multi-step probabilistic decision-making task with changing reward contingencies, and performed photometry recordings from dopamine neurons in the ventral tegmental area (VTA) and dopamine axons in the nucleus accumbens (NAc) and dorsomedial striatum (DMS). Our results indicate that dopamine activity in VTA and NAc terminals is influenced by value information derived from models of task structure. By contrast, value information was absent from activity in DMS dopamine axons, which instead is strongly modulated when making choices towards the option contralateral to the recording site.

A 01-1 Large, invariable action potential amplitude in neocortical nerve terminals revealed by highresolution current-clamp recordings A. Ritzau-Jost1 , T. Tsintsadze2 ,3, M. Krueger4 , I . Bechmann4 , J . Ei lers1 , B. Barbour5, S. M. Smith2 ,3 , S. Hal lermann1 1University of Leipzig, Carl-Ludwig-Institute for Physiology, Faculty of Medicine, Leipzig, Germany 2Oregon Health & Science University, Department of Medicine, Division of Pulmonary & Critical Care Medicine, Portland, US 3VA Portland Health Care System, Section of Pulmonary & Critical Care Medicine, Portland, US 4University of Leipzig, Institute of Anatomy, Faculty of Medicine, Leipzig, Germany 5PSL Université Paris, Institut de biologie de l’Ecole normale supérieure (IBENS), Ecole normale supérieure, CNRS, INSERM, Paris, France

pyPhotometry: Open source Python based hardware and software for fiber photometry data acquisition

The ability to generalise previously learned knowledge to solve novel analogous problems relies on formation of representations that are abstracted from sensory states. Little is known about how the brain generalises abstract representations while maintaining the content of individual experiences. Here we present a novel behavioural paradigm for investigating generalisation of structural knowledge in mice and report electrophysiological findings from single neurons in hippocampus and prefrontal cortex. Mice serially performed a set of reversal learning tasks, which shared the same structure (e.g., one choice port is good at a time), but had different physical configurations and hence different sensory and motor representations. Subjects’ performance on novel configurations improved with the number of configurations they had already learned, demonstrating generalisation of knowledge. As in spatial remapping experiments, many hippocampal neurons responded differently in different configurations – here tasks rather than spatial environments. In contrast, prefrontal representations were more general and reflected different stages of the trial irrespective of the current physical configuration. Population analyses showed that although the structure of each task was represented strongly in both regions, different hippocampal neuronal assemblies participated in each task’s representation. In contrast, neuronal patterns in PFC generalised between different configurations.

Generalisation of structural knowledge in hippocampal – prefrontal circuits

A longstanding question in neuroscience is how animals and humans select actions in complex decision trees. Planning, the evaluation of action sequences by anticipating their outcomes, is thought to coexist in the brain with simpler decision-making strategies, such as habit learning and heuristics. Though planning is often required for optimal choice, for many problems simpler strategies yield similar decisions, making them difficult to disambiguate. The scarcity of behavioral tasks that can dissociate planning from other decision mechanisms while generating rich decision data has hindered our understanding of the neural basis of planning. We developed a novel navigation task in which mice navigate to cued goal locations in a complex maze. A targeted search through the large space of possible maze layouts in that environment maximizes the number of decisions that are informative about the use of planning. Over the course of training mice learn shorter paths to goals, and the individual decisions composing these paths are better accounted for by planning than vector navigation. With hundreds of informative decisions per behavioral session, this paradigm opens the door to the study of the neural basis of route planning.

Disambiguating planning from heuristics in rodent spatial navigation

Gamma-band oscillations are implicated in modulation of attention and integration of sensory information. The finding that cross-regional coherence varies with task and performance suggests a role for gamma oscillations in flexible communication among anatomically connected brain areas. How networks become entrained is incompletely understood. Specifically, it is unclear how the spectral and temporal characteristics of network oscillations can be altered on rapid timescales needed for efficient communication. We use closed-loop optogenetic modulation of principal cell excitability to interrogate the dynamical properties of hippocampal oscillations. Gamma frequency and amplitude can be modulated bi-directionally, and dissociated, by phase-advancing or delaying optogenetic feedback to pyramidal cells. Closed-loop modulation alters the synchrony rather than average frequency of action potentials, in principle avoiding disruption of population rate-coding of information. Modulation of phasic excitatory currents in principal neurons is sufficient to manipulate oscillations, suggesting that feed-forward excitation of pyramidal cells has an important role in determining oscillatory dynamics and the ability of networks to couple with one another.

Analogue closed-loop optogenetic modulation of hippocampal pyramidal cells dissociates gamma frequency and amplitude

This scientific commentary refers to ‘Selective impairment of goal-directed decision-making following lesions to the human ventromedial prefrontal cortex’, by Reber et al. 2017 (doi:10.1093/brain/awx105).

Oscillatory multiplexing of population codes for selective communication in the mammalian brain

Oscillatory dynamics in the hippocampus support dentate gyrus–CA3 coupling

Oscillatory synchronization of neuronal populations has been proposed to play a role in perceptual integration and attentional processing. However, some conflicting evidence has been found with respect to its causal relevance for sensory processing, particularly when using flickering visual stimuli with the aim of driving oscillations. We tested psychophysically whether the relative phase of gamma frequency flicker (60 Hz) between stimuli modulates well-known facilitatory lateral interactions between collinear Gabor patches (Experiment 1) or crowding of a peripheral target by irrelevant distractors (Experiment 2). Experiment 1 assessed the impact of suprathreshold Gabor flankers on detection of a near-threshold central Gabor target ("Lateral interactions paradigm"). The flanking stimuli could flicker either in phase or in anti-phase with each other. The typical facilitation of target detection was found with collinear flankers, but this was unaffected by flicker phase. Experiment 2 employed a "crowding" paradigm, where orientation discrimination of a peripheral target Gabor patch is disrupted when surrounded by irrelevant distractors. We found the usual crowding effect, which declined with spatial separation, but this was unaffected by relative flicker phase between target and distractors at all separations. These results imply that externally driven manipulations of gamma frequency phase cannot modulate perceptual integration in vision.

Does visual flicker phase at gamma frequency modulate neural signal propagation and stimulus selection?

Mammalian brains generate complex, dynamic structures of oscillatory activity, in which 
distributed regions transiently engage in coherent oscillation, often at specific stages in behavioural 
or cognitive tasks. Much is now known about the dynamics underlying local circuit 
synchronisation and the phenomenology of where and when such activity occurs. While 
oscillations have been implicated in many high level processes, for most such phenomena we 
cannot say with confidence precisely what they are doing at an algorithmic or implementational 
level. This thesis presents work towards understanding the dynamics and possible function of large 
scale oscillatory network activity. We first address the question of how coherent oscillatory activity 
emerges between local networks by measuring phase response curves of an oscillating network in 
vitro. The network phase response curves provide mechanistic insight into inter-region 
synchronisation of local network oscillators. Highly simplified firing models are shown to 
reproduce the experimental data with remarkable accuracy. We then focus on one hypothesised 
computational function of network oscillations; flexibly controlling the gain of signal flow between 
anatomically connected networks. We investigate coding strategies and algorithmic operations that 
support flexible control of signal flow by oscillations, and their implementation by network 
dynamics. We identify two readout algorithms which selectively recover population rate coded 
signal with specific oscillatory modulations while ignoring other distracting inputs. By designing a 
spiking network model that implements one of these mechanisms, we demonstrate oscillatory 
control of signal flow in convergent pathways. We then investigate constraints on the structures of 
oscillatory activity that can be used to accurately and selectively control signal flow. Our results 
suggest that for inputs to be accurately distinguished from one another their oscillatory modulations 
must be close to orthogonal. This has implications for interpreting in vivo oscillatory activity, and 
may be an organising principle for the spatio-temporal structure of brain oscillations.

Oscillatory mechanisms for controlling information flow in neural circuits

The ‘communication through coherence’ (CTC) hypothesis proposes that selective communication among neural networks is achieved by coherence between firing rate oscillation in a sending region and gain modulation in a receiving region. Although this hypothesis has stimulated extensive work, it remains unclear whether the mechanism can in principle allow reliable and selective information transfer. Here we use a simple mathematical model to investigate how accurately coherent gain modulation can filter a population-coded target signal from task-irrelevant distracting inputs. We show that selective communication can indeed be achieved, although the structure of oscillatory activity in the target and distracting networks must satisfy certain previously unrecognized constraints. Firstly, the target input must be differentiated from distractors by the amplitude, phase or frequency of its oscillatory modulation. When distracting inputs oscillate incoherently in the same frequency band as the target, communication accuracy is severely degraded because of varying overlap between the firing rate oscillations of distracting inputs and the gain modulation in the receiving region. Secondly, the oscillatory modulation of the target input must be strong in order to achieve a high signal-to-noise ratio relative to stochastic spiking of individual neurons. Thus, whilst providing a quantitative demonstration of the power of coherent oscillatory gain modulation to flexibly control information flow, our results identify constraints imposed by the need to avoid interference between signals, and reveal a likely organizing principle for the structure of neural oscillations in the brain.

Efficient “Communication through Coherence” Requires Oscillations Structured to Minimize Interference between Signals

Oscillations and Filtering Networks Support Flexible Routing of Information

We investigated the antiplasmodial activity of some pure compounds of Turreanthus africanus (Meliaceae), a plant that is used in traditional medicine to treat malaria in Southwest Cameroon. A phytochemical analysis of the methylene chloride: methanol (1:1) extract of the seeds of the plant yielded seven compounds. Four of them, which were oils, were subjected to in vitro bioassays on Plasmodium falciparum F 32, chloroquine sensitive strain. Compound 1 (16-oxolabda-8 (17), 12(E)-dien-15-oic acid), showed the highest antiplasmodial activity, two others (methyl-14,15-epoxylabda-8 (17), 12(E)-diene-16-oate, and turreanin A), had moderate activity and one was inactive. These findings are consistent with the use of T. africanus in the traditional treatment of P. falciparum malaria.

Antiplasmodial activities of some products from Turreanthus africanus (Meliaceae).

Theoretical prediction of the stereochemistry of the OH groups in turraesterodione

Chemical investigation of the stem bark of Turraeanthus africanus (Meliaceae) afforded a new pregnane derivative, 17α,20S-dihydroxypregn-4-ene-3,16-dione, named turraeasterodione, together with three known diterpenoids, methyl 14,15-epoxylabda-8(17),12E-dien-16-oate, 16-oxolabda-8(17),12E-dien-15-oic acid, and 16-acetoxy-12R,15-epoxylabda-8(17),13(16)-dien-15β-ol. Their structures were elucidated by spectroscopic and spectrometric methods. Methyl 14,15-epoxylabda-8(17),12E-dien-16-oate was found to exhibit anti-plasmodial activity against a chloroquine-resistant strain of Plasmodium falciparum.

A Pregnane Derivative and an Anti-plasmodial Labdane Diterpenoid from the Stem Bark of Turraenthus Africanus

Activated olefins of the types Ph2CCXY, R2CCXY, PhRCCXY, and RCHCXY (where X and Y are electronegative substituents or one of them is a hydrogen atom) have been reduced to the corresponding saturated compounds in excellent yields by treatment with zinc–copper couple in boiling methanol.

A convenient reduction of activated olefins by zinc–copper couple

A CONVENIENT REDUCTION OF ACTIVATED OLEFINS BY ZINC-COPPER COUPLE

Two labdane diterpenoids and a seco-tetranortriterpenoid from Turreanthus africanus.

The brain plans and executes volitional movements. The underlying patterns of neural population activity have been explored in the context of movements of the eyes, limbs, tongue, and head in nonhuman primates and rodents. How do networks of neurons produce the slow neural dynamics that prepare specific movements and the fast dynamics that ultimately initiate these movements? Recent work exploits rapid and calibrated perturbations of neural activity to test specific dynamical systems models that are capable of producing the observed neural activity. These joint experimental and computational studies show that cortical dynamics during motor planning reflect fixed points of neural activity (attractors). Subcortical control signals reshape and move attractors over multiple timescales, causing commitment to specific actions and rapid transitions to movement execution. Experiments in rodents are beginning to reveal how these algorithms are implemented at the level of brain-wide neural circuits. Expected final online publication date for the Annual Review of Neuroscience, Volume 45 is July 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Publisher Correction: Attractor dynamics gate cortical information flow during decision-making

Attractor dynamics gate cortical information flow during decision-making

Discrete attractor dynamics underlies persistent activity in the frontal cortex

Recent psychophysics data suggest that speech perception is not limited by the capacity of the auditory system to encode fast acoustic variations through neural γ activity, but rather by the time given to the brain to decode them. Whether the decoding process is bounded by the capacity of θ rhythm to follow syllabic rhythms in speech, or constrained by a more endogenous top-down mechanism, e.g., involving β activity, is unknown. We addressed the dynamics of auditory decoding in speech comprehension by challenging syllable tracking and speech decoding using comprehensible and incomprehensible time-compressed auditory sentences. We recorded EEGs in human participants and found that neural activity in both θ and γ ranges was sensitive to syllabic rate. Phase patterns of slow neural activity consistently followed the syllabic rate (4–14 Hz), even when this rate went beyond the classical θ range (4–8 Hz). The power of θ activity increased linearly with syllabic rate but showed no sensitivity to comprehension. Conversely, the power of β (14–21 Hz) activity was insensitive to the syllabic rate, yet reflected comprehension on a single-trial basis. We found different long-range dynamics for θ and β activity, with β activity building up in time while more contextual information becomes available. This is consistent with the roles of θ and β activity in stimulus-driven versus endogenous mechanisms. These data show that speech comprehension is constrained by concurrent stimulus-driven θ and low-γ activity, and by endogenous β activity, but not primarily by the capacity of θ activity to track the syllabic rhythm. SIGNIFICANCE STATEMENT Speech comprehension partly depends on the ability of the auditory cortex to track syllable boundaries with θ-range neural oscillations. The reason comprehension drops when speech is accelerated could hence be because θ oscillations can no longer follow the syllabic rate. Here, we presented subjects with comprehensible and incomprehensible accelerated speech, and show that neural phase patterns in the θ band consistently reflect the syllabic rate, even when speech becomes too fast to be intelligible. The drop in comprehension, however, is signaled by a significant decrease in the power of low-β oscillations (14–21 Hz). These data suggest that speech comprehension is not limited by the capacity of θ oscillations to adapt to syllabic rate, but by an endogenous decoding process.

θ-Band and β-Band Neural Activity Reflects Independent Syllable Tracking and Comprehension of Time-Compressed Speech

Short-term memories link events separated in time, such as past sensation and future actions. Short-term memories are correlated with selective persistent activity, which can be maintained over seconds. In a delayed response task that requires short-term memory, neurons in mouse anterior lateral motor cortex (ALM) show persistent activity that instructs future actions. To elucidate the mechanisms underlying this persistent activity we combined intracellular and extracellular electrophysiology with optogenetic perturbations and network modeling. During the delay epoch, both membrane potential and population activity of ALM neurons funneled towards discrete endpoints related to specific movement directions. These endpoints were robust to transient shifts in ALM activity caused by optogenetic perturbations. Perturbations occasionally switched the population dynamics to the other endpoint, followed by incorrect actions. Our results are consistent with discrete attractor dynamics underlying short-term memory related to motor planning.

Discrete attractor dynamics underlying selective persistent activity in frontal cortex

Author response: Speech encoding by coupled cortical theta and gamma oscillations

Neural Cross-Frequency Coupling: Connecting Architectures, Mechanisms, and Functions

Many environmental stimuli present a quasi-rhythmic structure at different timescales that the brain needs to decompose and integrate. Cortical oscillations have been proposed as instruments of sensory de-multiplexing, i.e., the parallel processing of different frequency streams in sensory signals. Yet their causal role in such a process has never been demonstrated. Here, we used a neural microcircuit model to address whether coupled theta–gamma oscillations, as observed in human auditory cortex, could underpin the multiscale sensory analysis of speech. We show that, in continuous speech, theta oscillations can flexibly track the syllabic rhythm and temporally organize the phoneme-level response of gamma neurons into a code that enables syllable identification. The tracking of slow speech fluctuations by theta oscillations, and its coupling to gamma-spiking activity both appeared as critical features for accurate speech encoding. These results demonstrate that cortical oscillations can be a key instrument of speech de-multiplexing, parsing, and encoding. DOI: http://dx.doi.org/10.7554/eLife.06213.001

Speech encoding by coupled cortical theta and gamma oscillations

Brain oscillations are dynamic entities, rapidly varying in time and frequency that are extensively recorded in the mammalian brain. In this thesis I investigated the role of cortical rhythms in human auditory cortex during speech perception, both with computational and experimental methods. We developed a neural microcircuit model of nested oscillations for early auditory processing, involving a fast Gamma rhythm (30-100 Hz) coupled to a slow Theta rhythm (3-8 Hz). The model is capable of parsing speech into its constituents (i.e. syllables) and extracting the syllabic information for latter categorization. We then analysed EEG signals from intracranial recordings in humans using cross-frequency coupling and Granger causality. We found that Bottom-up information is dominated by Gamma oscillations, while Top-Down flow is conveyed through Theta oscillations. Both flows fluctuate over time at a rate of ~1-3 Hz, suggesting that sensory information is conveyed using distinct frequencies and via discrete time windows.

The contribution of frequency-specific activity to hierarchical information processing in the human auditory cortex

Abstract The 35 commentaries cover a wide range of topics and take many different stances on the issues explored by the target article. We have organised our response to the commentaries around three central questions: Are Friston blankets just Pearl blankets? What ontological and metaphysical commitments are implied by the use of Friston blankets? What kind of explanatory work are Friston blankets capable of? We conclude our reply with a short critical reflection on the indiscriminate use of both Markov blankets and the free energy principle.

The Emperor Is Naked: Replies to commentaries on the target article

Smartphone use plays an increasingly important role in our daily lives. Philosophical research that has used first wave or second wave theories of extended cognition in order to understand our engagement with digital technologies has focused on the contribution of these technologies to the completion of specific cognitive tasks (e.g., remembering, reasoning, problem-solving, navigation). However, in a considerable number of cases, everyday smartphone use is task-unrelated. In psychological research, these cases have been captured by notions such as absent-minded smartphone use (Marty-Dugas et al., 2018) or smartphone-related inattentiveness (Liebherr et al., 2020). Given the prevalence of these cases, we develop a conceptual framework that can accommodate the functional and phenomenological characteristics of task-unrelated smartphone use. To this end, we will integrate research on second wave extended cognition with mind-wandering research and introduce the concept of ‘extended mind-wandering’. Elaborating the family resemblances approach to mind-wandering (Seli, Kane, Smallwood, et al., 2018), we will argue that task-unrelated smartphone use shares many characteristics with mind-wandering. We will suggest that an empirically informed conceptual analysis of cases of extended mind-wandering can enrich current work on digitally extended cognition by specifying the influence of the attention economy on our cognitive dynamics.

The concept of affordances is rapidly gaining traction in the philosophy of mind and cognitive sciences. Affordances are opportunities for action provided by the environment. An important open ques...

Abstract The free energy principle, an influential framework in computational neuroscience and theoretical neurobiology, starts from the assumption that living systems ensure adaptive exchanges with their environment by minimizing the objective function of variational free energy. Following this premise, it claims to deliver a promising integration of the life sciences. In recent work, Markov blankets, one of the central constructs of the free energy principle, have been applied to resolve debates central to philosophy (such as demarcating the boundaries of the mind). The aim of this paper is twofold. First, we trace the development of Markov blankets starting from their standard application in Bayesian networks, via variational inference, to their use in the literature on active inference. We then identify a persistent confusion in the literature between the formal use of Markov blankets as an epistemic tool for Bayesian inference, and their novel metaphysical use in the free energy framework to demarcate the physical boundary between an agent and its environment. Consequently, we propose to distinguish between “Pearl blankets” to refer to the original epistemic use of Markov blankets and “Friston blankets” to refer to the new metaphysical construct. Second, we use this distinction to critically assess claims resting on the application of Markov blankets to philosophical problems. We suggest that this literature would do well in differentiating between two different research programmes: “inference with a model” and “inference within a model.” Only the latter is capable of doing metaphysical work with Markov blankets, but requires additional philosophical premises and cannot be justified by an appeal to the success of the mathematical framework alone.

Review of Sanneke de Haan, Enactive Psychiatry, Cambridge: Cambridge University Press, 2020

In this commentary on Rietveld’s inaugural lecture, we exemplify with one of our design cases for project Expedition RWS 2050, how Rietveld’s and our method are complementary. Within this project, RWS invited us to contribute our design skills and make relevant future scenarios experienceable. To scaffold imaginative discussions about everyday life in 2050 with a cross-section of the Dutch population, we wrote seven short speculative stories and designed a set of physical discussion tools. When looking at this design case and the cases Rietveld describes in his inaugural lecture, one can see that we both are guided by and contributing to the development of ecological and enactive philosophy, which rejects the dichotomy between sensorimotor and higher cognition. In his approach, Rietveld pushes the boundaries of the affordances of the material during the making process, whereas we predominantly investigate the affordances of the things and practices which we have designed. Despite these differences, we are both pursuing engagement with philosophical practice through non-discursive means while imagining new sociomaterial practices.

Non-discursive philosophy by imagining new practices through design

We follow up on a prominent line of work in which principles of embodied cognition are employed to not only account for skilled coping but also for more intellectual activities such as remembering and imagination. Imagination then, is not a reflective activity an individual does by herself, but a shared and embodied activity scaffolded by tangible design. We present a case study in which we designed a toolkit to facilitate imagining the Netherlands in 2050. We wrote speculative stories of people living in 2050 and designed an assortment of objects. We held several workshops to use the toolkit for shared imagination for our client, Rijkswaterstaat. We analyze how, in the context of the workshops, the stories and objects provided affordances for shared imagination. We thereby hope to have demonstrated that it is possible to design for more intellectual activities in a tangible and embodied way.

We investigate the use of five postphenomenological concepts by bringing them to design practice and using them as a “generative lens” in design research. The use of these concepts in design research creates tension between the general and the particular. In a constructive design research process, we resolve this tension. We follow two complementary lines of inquiry: first, we design a ritual to support a postphenomenological analysis of the workplace. We discuss insights regarding ordering and formulation of the concepts, selecting a technological intermediary and assessing technologies. In the second, we use postphenomenology as a generative lens in designing the ritual. We discuss the iterative process in which the designer shapes specific uses by proposing different designs and reflecting on them using postphenomenological concepts. These reflections point to a responsibility of the designer to incorporate ways of being, ways of knowing and values on top of specific uses and utility.

Philosophy at work: Postphenomenology as a generative lens in design research and practice

Active inference introduces a theory describing action-perception loops via the minimisation of variational free energy or, under simplifying assumptions, (weighted) prediction error. Recently, act...

Predictions in the eye of the beholder: an active inference account of Watt governors

Abstract In this article, we investigate the foundations for a Gibsonian neuroscience. There is an increasingly influential current in neuroscience based on pragmatic and selectionist principles, which we think can contribute to ecological psychology. Starting from ecological psychology, we identify three basic constraints any Gibsonian neuroscience needs to adhere to: nonreconstructive perception, vicarious functioning, and selectionist self-organization. We discuss two previous attempts to integrate affordances with neuroscience: Reed’s ecological rendering of Edelman’s selectionism as well as Dreyfus’ phenomenological interpretation of Freeman’s neurodynamics. Reed and Dreyfus face the problem of how to account for “value.” We then show how the free-energy principle, an increasingly dominant framework in theoretical neuroscience, is rooted in both Freeman’s neurodynamics and Edelman’s selectionism. The free-energy principle accounts for value in terms of selective anticipation. The selection pressures at work on the agent shape its selective sensitivity to the relevant affordances in the environment. By being responsive to the relevant affordances in the environment, an agent comes to have grip on its interactions with the environment and can thrive in its ecological niche.

What’s Inside Your Head Once You’ve Figured Out What Your Head’s Inside Of

General ecological information supports engagement with affordances for ‘higher’ cognition

Abstract Objective: The current article set out to review all research conducted to date investigating prospective memory (PM) in autism. Method: All studies on PM in autism are first described, followed by a critical review and discussion of experimental findings within the multiprocess framework. PM in autism is then considered through an embodied predictive-coding account of autism. Results: Overall, despite somewhat inconsistent methodologies, a general deficit in PM in autism is observed, with evidence mostly in line with the multiprocess framework. That is, for tasks that are high in cognitive and attentional demand (e.g. time-based tasks; event-based cues of non-focality or low salience) PM performance of autistic participants is impaired. Building upon previous work in predictive-coding, and the way in which expected precision modulates attention, we postulate mechanisms that underpin PM and the potential deficits seen in autism. Furthermore, a unifying predictive-coding account of autism is extended under embodied predictive-coding models, to show how a predictive-coding impairment accounts not only for characteristic autistic difficulties, but also for commonly found differences in autistic movement. Conclusions: We show how differences in perception and action, core to the development of autism, lead directly to problems seen in PM. Using this link between movement and PM, we then put forward a number of holistic, embodied interventions to support PM in autism.

In this paper, we set out to develop a theoretical and conceptual framework for the new field of Radical Embodied Cognitive Neuroscience. This framework should be able to integrate insights from several relevant disciplines: theory on embodied cognition, ecological psychology, phenomenology, dynamical systems theory, and neurodynamics. We suggest that the main task of Radical Embodied Cognitive Neuroscience is to investigate the phenomenon of skilled intentionality from the perspective of the self-organization of the brain-body-environment system, while doing justice to the phenomenology of skilled action. In previous work, we have characterized skilled intentionality as the organism’s tendency toward an optimal grip on multiple relevant a↵ordances simultaneously. A↵ordances are possibilities for action provided by the environment. In the first part of this paper, we introduce the notion of skilled intentionality and the phenomenon of responsiveness to a field of relevant a↵ordances. Second, we use Friston’s work on neurodynamics, but embed a very minimal version of his free-energy principle in the ecological niche of the animal. Thus amended, this principle is helpful for understanding the embeddedness of neurodynamics within the dynamics of the system “brainbody-landscape of a↵ordances.” Next, we show how we can use this adjusted principle to understand the neurodynamics of selective openness to the environment: interacting action-readiness patterns at multiple timescales contribute to the organism’s selective openness to relevant a↵ordances. In the final part of the paper, we emphasize the important role of metastable dynamics in both the brain 1This paper was previously published as Bruineberg and Rietveld (2014).

Anticipating affordances : Intentionality in self-organizing brain-body-environment systems

This paper deals with the question of agency and intentionality in the context of the free-energy principle. The free-energy principle is a system-theoretic framework for understanding living self-organizing systems and how they relate to their environments. I will first sketch the main philosophical positions in the literature: a rationalist Helmholtzian interpretation (Hohwy 2013; Clark 2013), a cybernetic interpretation (Seth 2015) and the enactive affordance-based interpretation (Bruineberg and Rietveld 2014; Bruineberg et al. forthcoming) and will then show how agency and intentionality are construed differently on these different philosophical interpretations. I will then argue that a purely Helmholtzian is limited, in that it can account only account for agency in the context of perceptual inference. The cybernetic account cannot give a full account of action, since purposiveness is accounted for only to the extent that it pertains to the control of homeostatic essential variables. I will then argue that the enactive affordance-based account attempts to provide broader account of purposive action without presupposing goals and intentions coming from outside of the theory. In the second part of the paper, I will discuss how each of these three interpretations conceives of the sense agency and intentionality in different ways.

Beyond blanket terms: Challenges for the explanatory value of variational (neuro-)ethology: Comment on "Answering Schrödinger's question: A free-energy formulation" by Maxwell James Désormeau Ramstead et al.

formance, and do ‘the impossible’ – ‘to cheat’ (284), to break the rules and thereby inspire new ways of composing and performing. Overall, this is an accomplished collection that will be of interest to a wide range of readers. The variety of perspectives will appeal to students and teachers looking for an accessible entry into digital movement in performance, whilst experienced researchers and practitioners, working across dance, theatre and digital performance, will find it a highly valuable resource.

The anticipating brain is not a scientist: the free-energy principle from an ecological-enactive perspective

Even for simple perceptual decisions, the mechanisms that the brain employs are still under debate. Although current consensus states that the brain accumulates evidence extracted from noisy sensory information, open questions remain about how this simple model relates to other perceptual phenomena such as flexibility in decisions, decision-dependent modulation of sensory gain, or confidence about a decision. We propose a novel approach of how perceptual decisions are made by combining two influential formalisms into a new model. Specifically, we embed an attractor model of decision making into a probabilistic framework that models decision making as Bayesian inference. We show that the new model can explain decision making behaviour by fitting it to experimental data. In addition, the new model combines for the first time three important features: First, the model can update decisions in response to switches in the underlying stimulus. Second, the probabilistic formulation accounts for top-down effects that may explain recent experimental findings of decision-related gain modulation of sensory neurons. Finally, the model computes an explicit measure of confidence which we relate to recent experimental evidence for confidence computations in perceptual decision tasks.

In this paper, we set out to develop a theoretical and conceptual framework for the new field of Radical Embodied Cognitive Neuroscience. This framework should be able to integrate insights from several relevant disciplines: theory on embodied cognition, ecological psychology, phenomenology, dynamical systems theory, and neurodynamics. We suggest that the main task of Radical Embodied Cognitive Neuroscience is to investigate the phenomenon of skilled intentionality from the perspective of the self-organization of the brain-body-environment system, while doing justice to the phenomenology of skilled action. In previous work, we have characterized skilled intentionality as the organism's tendency toward an optimal grip on multiple relevant affordances simultaneously. Affordances are possibilities for action provided by the environment. In the first part of this paper, we introduce the notion of skilled intentionality and the phenomenon of responsiveness to a field of relevant affordances. Second, we use Friston's work on neurodynamics, but embed a very minimal version of his Free Energy Principle in the ecological niche of the animal. Thus amended, this principle is helpful for understanding the embeddedness of neurodynamics within the dynamics of the system “brain-body-landscape of affordances.” Next, we show how we can use this adjusted principle to understand the neurodynamics of selective openness to the environment: interacting action-readiness patterns at multiple timescales contribute to the organism's selective openness to relevant affordances. In the final part of the paper, we emphasize the important role of metastable dynamics in both the brain and the brain-body-environment system for adequate affordance-responsiveness. We exemplify our integrative approach by presenting research on the impact of Deep Brain Stimulation on affordance responsiveness of OCD patients.

Self-organization, free energy minimization, and optimal grip on a field of affordances

[Bespreking van: H. Dreyfus, C. Taylor (2017) Het realisme herwonnen]

Brede school Ekenrooi, gemeente Waalre : bureauonderzoek en inventariserend veldonderzoek, karterende fase door middel van boringen : Grontmij Archeologische Rapporten

herinrichting Voorste Stroom, gemeente Oisterwijk : bureauonderzoek : Grontmij Archeologische Rapporten

Proceedings of the Fifteenth International Conference on Tangible, Embedded, and Embodied Interaction

Efficient sensory processing requires the nervous system to adjust to ongoing features of the environment. In primary visual cortex (V1), neuronal activity strongly depends on recent stimulus history. Existing models can explain effects of prolonged stimulus presentation, but remain insufficient for explaining effects observed after shorter durations commonly encountered under natural conditions. We investigated the mechanisms driving adaptation in response to brief (100 ms) stimuli in L2/3 V1 neurons by performing in vivo whole-cell recordings to measure membrane potential and synaptic inputs. We find that rapid adaptation is generated by stimulus-specific suppression of excitatory and inhibitory synaptic inputs. Targeted optogenetic experiments reveal that these synaptic effects are due to input-specific short-term depression of transmission between layers 4 and 2/3. Thus, distinct mechanisms are engaged following brief and prolonged stimulus presentation and together enable flexible control of sensory encoding across a wide range of time scales.

Input-specific synaptic depression shapes temporal integration in mouse visual cortex

Cell-specific pharmaceutical technologies promise mechanistic insight into clinical drugs―those that treat, and often define, human disease. In particular, DART (drug acutely restricted by tethering) achieves genetically programmable control of drug concentration over cellular dimensions. The method is compatible with clinical pharmaceuticals and amenable to studies in behaving animals. Here, we describe DART.2, comprising three advances. First, we improve the efficiency of chemical capture, enabling cell-specific accumulation of drug to ∼3,000-times the ambient concentration in 15 min. Second, we develop tracer reagents, providing a behavior-independent measure of cellular target engagement in each animal. Third, we extend the method to positive allosteric modulators and outline design principles for this clinically significant class. We showcase the platform with four pharmaceuticals―two that weaken excitatory (AMPAR) or inhibitory (GABAAR) chemical neurotransmission, and two that strengthen these forms of synaptic communication. Across four labs, we tested reagents in the mouse cerebellum, basal ganglia, visual cortex, and retina. Collectively, we demonstrate robust, bidirectional editing of chemical neurotransmission. We provide for distribution of validated reagents, community design principles, and synthetic building blocks for application to diverse pharmaceuticals.

Distinct recruitment of feedforward and recurrent pathways across higher-order areas of mouse visual cortex

Feedforward mechanisms of cross-orientation interactions in mouse V1

Sensory neurons not only encode stimuli that align with their receptive fields but are also modulated by context. For example, the responses of neurons in mouse primary visual cortex (V1) to gratings of their preferred orientation are modulated by the presence of superimposed orthogonal gratings (“plaids”). The effects of this modulation can be diverse: some neurons exhibit cross-orientation suppression while other neurons have larger responses to a plaid than its components. We investigated whether these diverse forms of masking could be explained by a unified circuit mechanism. We report that the suppression of cortical activity does not alter the effects of masking, ruling out cortical mechanisms. Instead, we demonstrate that the heterogeneity of plaid responses is explained by an interaction between stimulus geometry and orientation tuning. Highly selective neurons uniformly exhibit cross-orientation suppression, whereas in weakly-selective neurons masking depends on the spatial configuration of the stimulus, with effects transitioning systematically between suppression and facilitation. Thus, the diverse responses of mouse V1 neurons emerge as a consequence of the spatial structure of the afferent input to V1, with no need to invoke cortical interactions.

Adaptation is a ubiquitous feature of sensory processing whereby recent experience shapes future responses. The mouse primary visual cortex (V1) is particularly sensitive to recent experience, where a brief stimulus can suppress subsequent responses for seconds. This rapid adaptation profoundly impacts perception, suggesting that its effects are propagated along the visual hierarchy. To understand how rapid adaptation influences sensory processing, we measured its effects at key nodes in the visual system: in V1, three higher visual areas (HVAs: AL, LM and PM), and the superior colliculus (SC) in awake mice of both sexes using single-unit recordings. Consistent with the feed-forward propagation of adaptation along the visual hierarchy, we find that neurons in layer 4 adapt less strongly than those in other layers of V1. Further, neurons in the HVAs adapt more strongly, and recover more slowly, than those in V1. The magnitude and time-course of adaptation was comparable in each of the HVAs and in the SC, suggesting that adaptation may not linearly accumulate along the feed-forward visual processing hierarchy. Despite the increase in adaptation in the HVAs compared to V1, the effects were similarly orientation specific across all areas. These data reveal that adaptation profoundly shapes cortical processing, with increasing impact at higher levels in the cortical hierarchy, and also strongly influencing computations in the SC. Thus, we find robust, brain-wide effects of rapid adaptation on sensory processing.

Magnitude, time-course and specificity of rapid adaptation across mouse visual areas.

Cortical visual processing transforms features of the external world into increasingly complex and specialized neuronal representations. These transformations arise in part through target-specific routing of information; however, within-area computations may also contribute to area-specific function. Here, we sought to determine whether higher-order visual cortical areas LM, AL, PM, and AM have specialized anatomical and physiological properties by using a combination of whole-cell recordings and optogenetic stimulation of V1 axons in vitro. We discovered area-specific differences in the strength of recruitment of interneurons through feed-forward and recurrent pathways, as well as differences in cell-intrinsic properties and interneuron densities. These differences were most striking when comparing across medial and lateral areas, suggesting that these areas have distinct profiles for net excitability and integration of V1 inputs. Thus, cortical areas are not defined simply by the information they receive, but also by area-specific circuit properties that enable specialized filtering of these inputs.

Distinct recruitment of feed-forward and recurrent pathways across higher-order areas of mouse visual cortex

Mouse Higher Visual Areas Provide Both Distributed and Specialized Contributions to Visually Guided Behaviors

Cortical parallel processing streams segregate many diverse features of a sensory scene. However, some features are distributed across streams, begging the question of whether and how such distributed representations contribute to perception. We determined the necessity of primary visual cortex (V1) and three key higher visual areas (LM, AL and PM) for perception of orientation and contrast, two features that are robustly encoded across all four areas. Suppressing V1, LM or AL decreased sensitivity for both orientation discrimination and contrast detection, consistent with a role for these areas in sensory perception. In comparison, suppressing PM selectively increased false alarm rates during contrast detection, without any effect on orientation discrimination. This effect was not retinotopically-specific, suggesting a distinct role for PM in the regulation of noise during decision-making. Thus, we find that distributed representations in the visual system can nonetheless support specialized perceptual roles for higher visual cortical areas.

Mouse higher visual areas provide both distributed and discrete contributions to visually guided behaviors

Attentional modulation of neuronal activity in sensory cortex could alter perception by enhancing the local representation of attended stimuli or its behavioral read-out downstream. We tested these hypotheses using a task in which mice are cued on interleaved trials to attend visual or auditory targets. Neurons in primary visual cortex (V1) that encode task stimuli have larger visually-evoked responses when attention is directed toward vision. To determine whether the attention-dependent changes in V1 reflect changes in representation or read-out, we decoded task stimuli and choices from population activity. Surprisingly, both visual and auditory choices can be decoded from V1, but decoding takes advantage of unique activity patterns across modalities. Furthermore, decoding of choices, but not stimuli, is impaired when attention is directed toward the opposite modality. The specific effect on choice suggests behavioral improvements with attention are largely due to targeted read-out of the most informative V1 neurons.

Separable codes for read-out of mouse primary visual cortex across attentional states

Neurons in primary visual cortex (V1) respond to simple visual features, such as orientation. These responses are read out by downstream areas to make perceptual decisions. How V1 responses are combined to make such decisions is unclear. One way to answer this question is to manipulate the responses of a subset of neurons activated during a perceptual task and ask how this manipulation affects judgments. Jin et al. used this approach to examine how mice perform an orientation discrimination task. Mice were trained to depress a lever, hold it during repeated presentations of a stimulus of a particular orientation, and release it when the orientation changed. The interval between stimulus presentations was varied to induce adaptation to the initial orientation on some trials, and the magnitude of the orientation change was varied to determine perceptual threshold. Adaptation selectively reduced the responses of neurons that were activated most strongly by (“preferred”) the initial orientation. At the behavioral level, adaptation significantly increased the perceptual threshold and reduced the number of times mice released the lever before the orientation changed (the false alarm rate). Two populations of V1 neurons are likely to be involved in this task: one that prefers the initial orientation and one that prefers the second. When the stimulus orientation changes, the activity of the first population should decrease while the activity of second population increases. An optimal decoder might therefore monitor the activity of both populations to determine when the orientation changes. Indeed, a linear regression trained on V1 population activity used this strategy. Unlike in mice, however, adaptation did not affect the discrimination threshold and false alarm rate for this decoder. Additional analyses suggested that the reason for this difference is that mice based their perceptual decision solely on the activity of neurons that prefer the second orientation. These data indicate that mice do not necessarily use all the information available in V1 to make perceptual choices. This does not mean that mice never use all available information, however. Whether mice use a different strategy for other tasks remains to be tested.

Neurons in the visual system integrate over a wide range of spatial scales. This diversity is thought to enable both local and global computations. To understand how spatial information is encoded across the mouse visual system, we use two-photon imaging to measure receptive fields (RFs) and size-tuning in primary visual cortex (V1) and three downstream higher visual areas (HVAs: LM (lateromedial), AL (anterolateral), and PM (posteromedial)) in mice of both sexes. Neurons in the visual system integrate over a wide range of spatial scales. This diversity is thought to enable both local and global computations. To understand how spatial information is encoded across the mouse visual system, we use two-photon imaging to measure receptive fields (RFs) and size-tuning in primary visual cortex (V1) and three downstream higher visual areas (HVAs: LM (lateromedial), AL (anterolateral), and PM (posteromedial)) in mice of both sexes. Neurons in PM, compared with V1 or the other HVAs, have significantly larger RF sizes and less surround suppression, independent of stimulus eccentricity or contrast. To understand how this specialization of RFs arises in the HVAs, we measured the spatial properties of V1 inputs to each area. Spatial integration of V1 axons was remarkably similar across areas and significantly different from the tuning of neurons in their target HVAs. Thus, unlike other visual features studied in this system, specialization of spatial integration in PM cannot be explained by specific projections from V1 to the HVAs. Further, the differences in RF properties could not be explained by differences in convergence of V1 inputs to the HVAs. Instead, our data suggest that distinct inputs from other areas or connectivity within PM may support the area's unique ability to encode global features of the visual scene, whereas V1, LM, and AL may be more specialized for processing local features. SIGNIFICANCE STATEMENT Surround suppression is a common feature of visual processing whereby large stimuli are less effective at driving neuronal responses than smaller stimuli. This is thought to enhance efficiency in the population code and enable higher-order processing of visual information, such as figure-ground segregation. However, this comes at the expense of global computations. Here we find that surround suppression is not equally represented across mouse visual areas: primary visual cortex has substantially more surround suppression than higher visual areas, and one higher area has significantly less suppression than two others examined, suggesting that these areas have distinct functional roles. Thus, we have identified a novel dimension of specialization in the mouse visual cortex that may enable both local and global computations.

Unique Spatial Integration in Mouse Primary Visual Cortex and Higher Visual Areas

Signal detection theory (SDT) is a widely used theoretical framework that describes how variable sensory signals are integrated with a decision criterion to support perceptual decision-making. SDT provides two key measurements: sensitivity (d′) and bias (c), which reflect the separability of decision variable distributions (signal and noise) and the position of the decision criterion relative to optimal, respectively. Although changes in the subject's decision criterion can be reflected in changes in bias, decision criterion placement is not the sole contributor to measured bias. Indeed, neuronal representations of bias have been observed in sensory areas, suggesting that some changes in bias are because of effects on sensory encoding. To directly test whether the sensory encoding process can influence bias, we optogenetically manipulated neuronal excitability in primary visual cortex (V1) in mice of both sexes during either an orientation discrimination or a contrast detection task. Increasing excitability in V1 significantly decreased behavioral bias, whereas decreasing excitability had the opposite effect. To determine whether this change in bias is consistent with effects on sensory encoding, we made extracellular recordings from V1 neurons in passively viewing mice. Indeed, we found that optogenetic manipulation of excitability shifted the neuronal bias in the same direction as the behavioral bias. Moreover, manipulating the quality of V1 encoding by changing stimulus contrast or interstimulus interval also resulted in consistent changes in both behavioral and neuronal bias. Thus, changes in sensory encoding are sufficient to drive changes in bias measured using SDT. SIGNIFICANCE STATEMENT Perceptual decision-making involves sensory integration followed by application of a cognitive criterion. Using signal detection theory, one can extract features of the underlying decision variables and rule: sensitivity (d′) and bias (c). Because bias is measured as the difference between the optimal and actual criterion, it is sensitive to both the sensory encoding processes and the placement of the decision criterion. Here, we use behavioral and electrophysiological approaches to demonstrate that measures of bias depend on sensory processes. Optogenetic manipulations of V1 in mice bidirectionally affect both behavioral and neuronal measures of bias with little effect on sensitivity. Thus, changes in sensory encoding influence bias, and the absence of changes in sensitivity do not preclude changes in sensory encoding.

Sensory information is encoded by populations of cortical neurons. Yet, it is unknown how this information is used for even simple perceptual choices such as discriminating orientation. To determine the computation underlying this perceptual choice, we took advantage of the robust visual adaptation in mouse primary visual cortex (V1). We first designed a stimulus paradigm in which we could vary the degree of neuronal adaptation measured in V1 during an orientation discrimination task. We then determined how adaptation affects task performance for mice of both sexes and tested which neuronal computations are most consistent with the behavioral results given the adapted population responses in V1. Despite increasing the reliability of the population representation of orientation among neurons, and improving the ability of a variety of optimal decoders to discriminate target from distractor orientations, adaptation increases animals' behavioral thresholds. Decoding the animals' choice from neuronal activity revealed that this unexpected effect on behavior could be explained by an overreliance of the perceptual choice circuit on target preferring neurons and a failure to appropriately discount the activity of neurons that prefer the distractor. Consistent with this all-positive computation, we find that animals' task performance is susceptible to subtle perturbations of distractor orientation and optogenetic suppression of neuronal activity in V1. This suggests that to solve this task the circuit has adopted a suboptimal and task-specific computation that discards important task-related information. SIGNIFICANCE STATEMENT A major goal in systems neuroscience is to understand how sensory signals are used to guide behavior. This requires determining what information in sensory cortical areas is used, and how it is combined, by downstream perceptual choice circuits. Here we demonstrate that when performing a go/no-go orientation discrimination task, mice suboptimally integrate signals from orientation tuned visual cortical neurons. While they appropriately positively weight target-preferring neurons, they fail to negatively weight distractor-preferring neurons. We propose that this all-positive computation may be adopted because of its simple learning rules and faster processing, and may be a common approach to perceptual decision-making when task conditions allow.

Neuronal Adaptation Reveals a Suboptimal Decoding of Orientation Tuned Populations in the Mouse Visual Cortex

The brain has evolved to transform sensory information in the environment into neural representations that can be used for perception and action. Higher-order sensory cortical areas, with their increasingly complex receptive fields and integrative properties, are thought to be critical nodes for this function. This is especially true in the primate visual cortex, in which functionally specialized areas are engaged in parallel streams to support diverse computations. Recent anatomical and physiological studies of the mouse visual cortex have revealed a similarly complex network of specialized higher-order areas. This structure provides a useful model for determining the synaptic and circuit mechanisms through which information is transformed across distinct processing stages. In this review, we summarize the current knowledge on the layout, connectivity, and functional properties of the higher visual areas in the mouse. In addition, we speculate on the contribution of these areas to perception and action, and how knowledge of the mouse visual system can inform us about the principles that govern information processing in integrated networks.

Optogenetic activation of axons is a powerful approach for determining the synaptic properties and impact of long-range projections both in vivo and in vitro. However, because of the difficulty of measuring activity in axons, our knowledge of the reliability of optogenetic axonal stimulation has relied on data from somatic recordings. Yet, there are many reasons why activation of axons may not be comparable to cell bodies. Thus we have developed an approach to more directly assess the fidelity of optogenetic activation of axonal projections. We expressed opsins (ChR2, Chronos, or oChIEF) in the mouse primary visual cortex (V1) and recorded extracellular, pharmacologically isolated presynaptic action potentials in response to axonal activation in the higher visual areas. Repetitive stimulation of axons with ChR2 resulted in a 70% reduction in the fiber volley amplitude and a 60% increase in the latency at all frequencies tested (10-40 Hz). Thus ChR2 cannot reliably recruit axons during repetitive stimulation, even at frequencies that are reliable for somatic stimulation, likely due to pronounced channel inactivation at the high light powers required to evoke action potentials. By comparison, oChIEF and Chronos evoked photocurrents that inactivated minimally and could produce reliable axon stimulation at frequencies up to 60 Hz. Our approach provides a more direct and accurate evaluation of the efficacy of new optogenetic tools and has identified Chronos and oChIEF as viable tools to interrogate the synaptic and circuit function of long-range projections.

High-fidelity optical excitation of cortico-cortical projections at physiological frequencies.

In mammals, the lateral geniculate nucleus (LGN) and the superior colliculus (SC) are the major targets of visual inputs from the retina. The LGN projects mainly to primary visual cortex (V1) while the SC targets the thalamus and brainstem, providing two potential pathways for processing visual inputs. Indeed, cortical lesion experiments in rodents have yielded mixed results, leading to the hypothesis that performance of simple visual behaviors may involve computations performed entirely by this subcortical pathway through the SC. However, these previous experiments have been limited by both their assays of behavioral performance and their use of lesions to change cortical activity. To determine the contribution of V1 to these tasks, we trained mice to perform threshold detection tasks in which they reported changes in either the contrast or orientation of visual stimuli. We then reversibly inhibited V1 by optogenetically activating parvalbumin-expressing inhibitory neurons with channelrhodopsin-2. We found that suppressing activity in V1 substantially impaired performance in visual detection tasks. The behavioral deficit depended on the retinotopic position of the visual stimulus, confirming that the effect was due to the specific suppression of the visually driven V1 neurons. Behavioral effects were seen with only moderate changes in neuronal activity, as inactivation that raised neuronal contrast thresholds by a median of only 14% was associated with a doubling of behavioral contrast detection threshold. Thus, detection of changes in either orientation or contrast is dependent on, and highly sensitive to, the activity of neurons in V1.

Mouse Primary Visual Cortex Is Used to Detect Both Orientation and Contrast Changes

Cortico-cortical projections in mouse visual cortex are functionally target specific

Network anatomy and physiology in the mouse visual cortex II: more function, bigger networks

Interneurons hyperpolarize pyramidal cells along their entire somatodendritic axis

Somatic inhibition, which is critical for determining the spike output of principal cells, is mediated by two physiologically distinct classes of GABAergic interneurons called basket cells. In the hippocampus, despite both targeting the somatic membrane of CA1 pyramidal cells, these two classes of basket cells are active at different times. Differential modulation of these two types of basket cells could hence be important for regulating the activity patterns of CA1 pyramidal cells at very specific periods during ongoing activity. Indeed, cannabinoids selectively suppress the output of one class of basket cell. Whether opioids, another major modulator of inhibition in the hippocampus, also selectively suppress somatic inhibition is not known. Here, we show that basket cells are selectively modulated by either opioids or cannabinoids, but not both. We also find that basket cells are integrated into specific inhibitory subnetworks that are themselves under differential control of opioids and cannabinoids. Furthermore, because the two interneuron types are activated at different times, opioids and cannabinoids suppress different epochs of inhibition. This cell-type specific sensitivity to neuromodulators allows for a fine control of the temporal structure of hippocampal activity.

Complementary Modulation of Somatic Inhibition by Opioids and Cannabinoids

The central nervous system is a crystalline-like structure which is constructed through the repeated assembly of stereotyped circuits. These circuits connect a relatively homogenous population of excitatory principal cells with a diverse population of inhibitory interneurons. One of the most striking features of the diversity of the interneurons is the specificity of their axonal arborizations. Each class of interneuron targets a specific subcellular compartment; for instance, different populations of interneurons mediate somatic and dendritic inhibition. However, in order to fully appreciate the implications of having different compartments under discrete inhibitory control we must know three things about each class of interneuron: its impact on the postsynaptic cell, the patterns of activity through which it is recruited, and its regulation by neuromodulators. We argue that these three properties will allow us to define the role of an inhibitory interneuron in the circuit. In order to investigate the roles of the diverse population of interneurons, we made intracellular recordings from identified interneurons in slices of the rat hippocampus. Through paired intracellular and extracellular recordings, we found that GABA release from both somatic and dendritic targeting interneurons results in the hyperpolarization of pyramidal cells. Within the groups of somatic and dendritic targeting interneurons there was additional diversity in their intrinsic properties, patterns of excitation, and modulation. By dividing the interneurons according to both the location of their axonal arborization (i.e. somatic or dendritic) and their intrinsic firing patterns (i.e. regular and fast spiking), we were able to define four relatively homogenous populations with distinct patterns of recruitment and impacts on their targets. In addition we found that neuromodulators could independently suppress the different classes of interneurons, suggesting that the network can actively regulate the timing and strength of inhibition. This work provides evidence for the precise roles of somatic and dendritically targeting interneurons in coordinating network activity. In addition, it proposes a methodology for understanding the role of the diverse population of inhibitory interneurons in the intact cortical circuit

Supralinear increase of recurrent inhibition during sparse activity in the somatosensory cortex

Distinct timing in the activity of cannabinoid-sensitive and cannabinoid-insensitive basket cells

At central synapses, P/Q-type Ca(2+) channels normally provide a critical Ca(2+) entry pathway for neurotransmission. Nevertheless, we found that nerve terminals lacking alpha(1A) (Ca(V)2.1), the pore-forming subunit of P/Q-type channels, displayed a remarkable preservation of synaptic function. Two consistent physiological changes reflective of synaptic homeostasis were observed in cultured hippocampal neurons derived from alpha(1A) (-/-) mice. First, the presynaptic response to an ionophore-mediated Ca(2+) elevation was 50% greater, indicating an enhanced Ca(2+) sensitivity of the release machinery. Second, basal miniature excitatory postsynaptic current frequency in alpha(1A) (-/-) neurons was increased 2-fold compared with WT neurons and occluded the normal response of presynaptic terminals to cAMP elevation, suggesting that the compensatory mechanism in alpha(1A) (-/-) synapses and the modulation of presynaptic function by PKA might share a final common pathway. We used cDNA microarray analysis to identify molecular changes underlying homeostatic regulation in the alpha(1A) (-/-) hippocampus. The 40,000 entries in our custom-made array included likely targets of presynaptic homeostasis, along with many other transcripts, allowing a wide-ranging examination of gene expression. The developmental pattern of changes in transcript levels relative to WT was striking; mRNAs at 5 and 11 days postnatal showed little deviation, but clear differences emerged by 22 days. Many of the transcripts that differed significantly in abundance corresponded to known genes that could be incorporated within a logical pattern consistent with the modulation of presynaptic function. Changes in endocytotic proteins, signal transduction kinases, and candidates for Ca(2+)-sensing molecules were consistent with implications of the direct physiological experiments.

Presynaptic homeostasis at CNS nerve terminals compensates for lack of a key Ca2+ entry pathway.

Olfactory receptor neurons (ORNs) convey sensory information directly to the CNS via conventional glutamatergic synaptic contacts in olfactory bulb glomeruli. To better understand the process by which information contained in the odorant-evoked firing of ORNs is transmitted to the brain, we examined the properties of glutamate release from olfactory nerve (ON) terminals in slices of the rat olfactory bulb. We show that marked paired pulse depression is the same in simultaneously recorded periglomerular and tufted neurons, and that this form of short-term plasticity is attributable to a reduction of glutamate release from ON terminals. We used the progressive blockade of NMDA receptor (NMDAR) EPSCs by MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-10-imine hydrogen maleate] and stationary fluctuation analysis of AMPA receptor (AMPAR) EPSCs to determine the probability of release (Pr) of ON terminals; both approaches indicated that Pr is unusually high (≥0.8). The low-affinity glutamate receptor antagonists γ-d-glutamylglycine and l-amino-5-phosphonovaleric acid blocked ON-evoked AMPAR- and NMDAR-mediated EPSCs, respectively, to the same extent under conditions of low and high Pr, suggesting that multivesicular release is not a feature of ON terminals. Although release from most synapses exhibits a highly nonlinear dependence on extracellular Ca2+, we find that the relationship between glutamate release and extracellular Ca2+ at ON terminals is nearly linear. Our results suggest that ON terminals have specialized features that may contribute to the reliable transmission of sensory information from nose to brain.

Sensory Neuron Signaling to the Brain: Properties of Transmitter Release from Olfactory Nerve Terminals

NiCo2O4 (NCO) films grown on MgAl2O4 (001) substrates have been studied using magnetometry and x-ray magnetic circular dichroism based on x-ray absorption spectroscopy and spin-polarized inverse photoemission spectroscopy with various thicknesses down to 1.6 nm. The magnetic behavior can be understood in terms of a layer of optimal NCO and an interfacial layer (1.2 ± 0.1 nm), with a small canting of magnetization at the surface. The thickness dependence of the optimal layer can be described by the finite-scaling theory with a critical exponent consistent with the high perpendicular magnetic anisotropy. The interfacial layer couples antiferromagnetically to the optimal layer, generating exchange-spring styled magnetic hysteresis in the thinnest films. The non-optimal and measurement-speed-dependent magnetic properties of the interfacial layer suggest substantial interfacial diffusion.

Interfacial and surface magnetism in epitaxial NiCo2O4(001)/MgAl2O4 films

Ultrasoft magnetorheological elastomers (MREs) offer convenient real-time magnetic field control of mechanical properties that provides a means to mimic mechanical cues and regulators of cells in vitro. Here, we systematically investigate the effect of polymer stiffness on magnetization reversal of MREs using a combination of magnetometry measurements and computational modeling. Poly-dimethylsiloxane-based MREs with Young’s moduli that range over two orders of magnitude were synthesized using commercial polymers Sylgard™ 527, Sylgard 184, and carbonyl iron powder. The magnetic hysteresis loops of the softer MREs exhibit a characteristic pinched loop shape with almost zero remanence and loop widening at intermediate fields that monotonically decreases with increasing polymer stiffness. A simple two-dipole model that incorporates magneto-mechanical coupling not only confirms that micrometer-scale particle motion along the applied magnetic field direction plays a defining role in the magnetic hysteresis of ultrasoft MREs but also reproduces the observed loop shapes and widening trends for MREs with varying polymer stiffnesses.

The effect of polymer stiffness on magnetization reversal of magnetorheological elastomers

Topological spin memory of antiferromagnetically coupled skyrmion pairs in Co/Gd/Pt multilayers

The effects of field history on magnetic skyrmion formation in [Pt/Co/Ir]3 multilayers

Persistent opto-ferroelectric responses in molecular ferroelectrics

With the realization of stress-induced perpendicular magnetic anisotropy, efficient spin-orbit torque switching, and room temperature topological Hall effect, interest in rare earth iron garnets has been revived in recent years for their potential in spintronic applications. In this study, we investigate the magnetic properties of micrometer-thick Bi and Ga substituted thulium iron garnets (BiGa:TmIG) grown by the liquid-phase epitaxy method. Above the magnetization compensation (MC) temperature, anomalous triple hysteresis is observed in BiGa:TmIG/Pt heterostructures by anomalous Hall effect measurements. X-ray magnetic circular dichroism and energy dispersive spectroscopy measurements reveal its origin as an internal exchange bias (EB) effect arising from inhomogeneities localized at the surface of the film. Possibly depending on the difference in thickness and defect realization of the EB layer, two types of magnetization reversal mechanisms, namely, the Stoner-Wohlfarth type and the reversible domain-wall motion type, are observed. Our results show that rich meta-magnetic phases exist in garnets close to MC, which can be robustly tuned by chemical composition engineering and conveniently probed by electrical transport measurements.

Probing exchange bias at the surface of a doped ferrimagnetic insulator

 Quantifying the resistance to heat flow across well-bonded, planar interfaces is critical in modern electronics packaging architectures, particularly as device length scales are reduced and power demands continue to grow unabated. However, very few experimental techniques are capable of measuring the thermal resistance across such interfaces due to limitations in the required measurement resolution provided by the characterization technique (i.e., Rth < 0.1 mm2·K/W in steady-state configurations) and restrictions on the thermal penetration depth that can be achieved as a result of the heating event that is typically imposed on a sample’s surface (for optical pump-probe thermoreflectance techniques). A recent numerical fitting routine for Frequency-domain Thermoreflectance (FDTR) developed by the authors1 offers a potential avenue to rectify these issues if the transducer’s geometry can be confined. This work utilizes numerical simulations to evaluate the sensitivity of FDTR to a range of thermal boundary resistance (TBR) values as a function of the thermal resistance of adjacent material layers. Experimental measurements are performed across a handful of different material systems to validate our computational results and to demonstrate the the extent to which confined transducer geometries can improve our sensitivyt to the TBR across so-called “buried” interfaces when characterized with FDTR.

ASME 2021 International Technical Conference and Exhibition on Packaging and Integration of Electronic and Photonic Microsystems

Confined Transducer Geometries to Enhance Sensitivity to Thermal Boundary Conductance in Frequency-Domain Thermoreflectance Measurements

Photoexcitation is well-known to trigger electronic metastable states and lead to phenomena like long-lived photoluminescence and photoconductivity. In contrast, persistent photo-response due to ionic metastable states is rare. In this work, we report persistent structural and ferroelectric photo-responses due to proton metastable states via a nuclear quantum mechanism in ferroelectric croconic acid, in which the proton-transfer origin of ferroelectricity is important for the ionic metastable states. We show that, after photoexcitation, the changes of structural and ferroelectric properties relax in about 1000 s, while the photoconductivity decays within 1 s, indicating the dominant ionic origin of the responses. The photogenerated internal bias field that survives polarization switching process suggests another proton transfer route and metastable state, in addition to the metastable states resulting from proton transfer along the hydrogen bonds proposed previously. Analysis based on Frank Condon principle reveals the quantum mechanical nature of the proton-transfer process both within the hydrogen bonds and out of the hydrogen bonds, where small mass of proton and significant change of potential landscape due to the excited electronic states are the key. The demonstration of persistent photo-responses due to the proton metastable states unveils a nuclear quantum mechanism for photo-tunability of materials, which is expected to impact many material properties sensitive to ionic positions.

Persistent Ionic Photo-responses and Frank-Condon Mechanism in Proton-transfer Ferroelectrics

We report tuning of the moduli and surface roughness of magnetorheological elastomers (MREs) by varying applied magnetic field. Ultrasoft MREs are fabricated using a physiologically relevant commercial polymer, SylgardTM 527, and carbonyl iron powder (CIP). We found that the shear storage modulus, Young’s modulus, and root-mean-square surface roughness are increased by ∼41×, ∼11×, and ∼11×, respectively, when subjected to a magnetic field strength of 95.5 kA m−1. Single fit parameter equations are presented that capture the tunability of the moduli and surface roughness as a function of CIP volume fraction and magnetic field strength. These magnetic field-induced changes in the mechanical moduli and surface roughness of MREs are key parameters for biological applications.

Magnetic field tuning of mechanical properties of ultrasoft PDMS-based magnetorheological elastomers for biological applications

Current methods to dynamically tune three-dimensional hydrogel mechanics require specific chemistries and substrates that make modest, slow, and often irreversible changes in their mechanical properties, exclude the use of protein-based scaffolds, or alter the hydrogel microstructure and pore size. Here, we rapidly and reversibly alter the mechanical properties of hydrogels consisting of extracellular matrix proteins and proteoglycans by adding carbonyl iron microparticles (MPs) and applying external magnetic fields. This approach drastically alters hydrogel mechanics: rheology reveals that application of a 4000 Oe magnetic field to a 5 mg/mL collagen hydrogel containing 10 wt % MPs increases the storage modulus from approximately 1.5 to 30 kPa. Cell morphology experiments show that cells embedded within these hydrogels rapidly sense the magnetically induced changes in ECM stiffness. Ca2+ transients are altered within seconds of stiffening or subsequent softening, and slower but still dynamic changes occur in YAP nuclear translocation in response to time-dependent application of a magnetic field. The near instantaneous change in hydrogel mechanics provides new insight into the effect of changing extracellular stiffness on both acute and chronic changes in diverse cell types embedded in protein-based scaffolds. Due to its flexibility, this method is broadly applicable to future studies interrogating cell mechanotransduction in three-dimensional substrates.

Dynamic Tuning of Viscoelastic Hydrogels with Carbonyl Iron Microparticles Reveals the Rapid Response of Cells to Three-Dimensional Substrate Mechanics.

The effects of processing method on conductivity and dielectric relaxations in PVDF blended with a zwitterionic copolymer

Magnetic Patterning: Magneto‐Driven Gradients of Diamagnetic Objects for Engineering Complex Tissues (Adv. Mater. 48/2020)

Engineering complex tissues represents an extraordinary challenge and, to date, there have been few strategies developed that can easily recapitulate native‐like cell and biofactor gradients in 3D materials. This is true despite the fact that mimicry of these gradients may be essential for the functionality of engineered graft tissues. Here, a non‐traditional magnetics‐based approach is developed to predictably position naturally diamagnetic objects in 3D hydrogels. Rather than magnetizing the objects within the hydrogel, the magnetic susceptibility of the surrounding hydrogel precursor solution is enhanced. In this way, a range of diamagnetic objects (e.g., polystyrene beads, drug delivery microcapsules, and living cells) are patterned in response to a brief exposure to a magnetic field. Upon photo‐crosslinking the hydrogel precursor, object positioning is maintained, and the magnetic contrast agent diffuses out of the hydrogel, supporting long‐term construct viability. This approach is applied to engineer cartilage constructs with a depth‐dependent cellularity mirroring that of native tissue. These are thought to be the first results showing that magnetically unaltered cells can be magneto‐patterned in hydrogels and cultured to generate heterogeneous tissues. This work provides a foundation for the formation of opposing magnetic‐susceptibility‐based gradients within a single continuous material.

Magneto‐Driven Gradients of Diamagnetic Objects for Engineering Complex Tissues

New directions in material applications have allowed for the fresh insight into the coordination of biophysical cues and regulators. Although the role of the mechanical microenvironment on cell responses and mechanics is often studied, most analyses only consider static environments and behavior, however, cells and tissues are themselves dynamic materials that adapt in myriad ways to alterations in their environment. Here, we introduce an approach, through the addition of magnetic inclusions into a soft poly(dimethylsiloxane) elastomer, to fabricate a substrate that can be stiffened nearly instantaneously in the presence of cells through the use of a magnetic gradient to investigate short-term cellular responses to dynamic stiffening or softening. This substrate allows us to observe time-dependent changes, such as spreading, stress fiber formation, Yes-associated protein translocation, and sarcomere organization. The identification of temporal dynamic changes on a short time scale suggests that this technology can be more broadly applied to study targeted mechanisms of diverse biologic processes, including cell division, differentiation, tissue repair, pathological adaptations, and cell-death pathways. Our method provides a unique in vitro platform for studying the dynamic cell behavior by better mimicking more complex and realistic microenvironments. This platform will be amenable to future studies aimed at elucidating the mechanisms underlying mechanical sensing and signaling that influence cellular behaviors and interactions.

Tunable and Reversible Substrate Stiffness Reveals a Dynamic Mechanosensitivity of Cardiomyocytes.

Thermal analysis of fully zwitterionic copolymers for safer electrochemical energy storage

The challenges in achieving a green and scalable integration of two dimensional (2D) materials with flexible polymer substrates present a major barrier for the application of 2D materials such as graphene, MoS2, and h-BN for flexible devices. Here, we create a sono-assisted surface energy driven assembly (SASEDA) method that can achieve foot-scale to micrometer-scale assembly of 2D materials, form a conductive network in as short as 10 seconds, and build hierarchical and hybrid flexible devices such as sensors, resistors, and capacitors by using water as the dispersion solvent. SASEDA highlights two counter-intuitive innovations. First, we use an "unfavorable" solvent (i.e. water) for both 2D materials (e.g. graphene, MoS2, h-BN) and polymer substrates (e.g. polydimethylsiloxane) to drive the assembly process. Second, we use a weak sono-field (0.3 W/cm2) generated by a regular sonication bath cleaner to enhance the assembly efficiency and reorganize and unify the assembly network. This method and its principle pave the way towards affordable large-scale 2D materials-based flexible devices.

Sono-assisted surface energy driven assembly of 2D materials on flexible polymer substrates: A green assembly method using water.

Fabrication of Sensitive MEMS-based Magnetometer for Biomagnetic Applications

Fabrication and characterization of ultra-soft PDMS based magnetorheological elastomers

Fabrication and characterization of magnetic-vortex microdiscs for applying force in mechanobiological systems

Interface Magnetism of Magnetic Multilayers with Interfacial Dzyaloshinskii-Moriya Interaction

Technical advances in electrochemical depo-sition using self-assembled colloidal polystyrene templates has resulted in eﬃcient and low-cost fabrication of large samples containing three-dimensional anti-sphere arrays (3DAAs). 3DAAs with periodic structure and high surface-to-volume ratio provide an ideal system for studying the eﬀect of dimensionality and morphology on magnetic properties. Micromagnetic simulations were performed using the object oriented micromagnetic framework (OOMMF) and mumax3 to study the magnetization reversal behaviors in a nickel 3DAAs structure with anti-sphere radii of 98nm and 252nm and varying sample thickness between 98nm-1.5 (cid:22) m. The simulation re-sults show that domain propagation dominates in the lowest quasi-continuous layer, whereas the reversal process becomes more localized in the void-heavy upper layers. As the structure thickness increases, the proportion of the quasi-continuous layer decreases and stronger pinning appears in the upper layers, resulting in a transition from a domain-growth reversal to a localized reversal.

Micromagnetic simulated magnetization reversal of nickel three-dimensional anti-sphere arrays

序論 脳の観点は心の観点に対して何を語るか 第１部 心の観点（古典的認知主義；状況と物質；民間心理学・思考・文脈；生物学的制約） 第２部 脳の観点（並列分散処理；情報論的全体論；心の多元性—古典的認知主義の限定的擁護；構造化された思考 ほか） エピローグ ハイレベルの建築家の寓話 付論 消去主義を超えて

For oral drugs, the formulator and discovery chemist have a tool available to them that can be used to navigate the risks associated with the selection and development of immediate release oral drugs and drug products. This tool is the biopharmaceutics classification system (giBCS). Unfortunately, no such classification system exists for inhaled drugs. The perspective outlined in this manuscript provides the foundational principles and framework for a classification system for inhaled drugs. The proposed classification system, an inhalation-based biopharmaceutics classification system (iBCS), is based on fundamental biopharmaceutics principles adapted to an inhalation route of administration framework. It is envisioned that a classification system for orally inhaled drugs will facilitate an understanding of the technical challenges associated with the development of new chemical entities and their associated new drug products (device and drug formulation combinations). Similar to the giBCS, the iBCS will be based on key attributes describing the drug substance (solubility and permeability) and the drug product (dose and dissolution). This manuscript provides the foundational aspects of an iBCS, including the proposed scientific principles and framework upon which such a system can be developed.

iBCS: 1. Principles and Framework of an Inhalation-Based Biopharmaceutics Classification System

The purpose of this review is to summarize essential pharmacological, pharmaceutical, and clinical aspects in the field of orally inhaled therapies that may help scientists seeking to develop new products. After general comments on the rationale for inhaled therapies for respiratory disease, the focus is on products approved approximately over the last half a century. The organization of these sections reflects the key pharmacological categories. Products for asthma and chronic obstructive pulmonary disease include β-2 receptor agonists, muscarinic acetylcholine receptor antagonists, glucocorticosteroids, and cromones as well as their combinations. The antiviral and antibacterial inhaled products to treat respiratory tract infections are then presented. Two “mucoactive” products—dornase α and mannitol, which are both approved for patients with cystic fibrosis—are reviewed. These are followed by sections on inhaled prostacyclins for pulmonary arterial hypertension and the challenging field of aerosol surfactant inhalation delivery, especially for prematurely born infants on ventilation support. The approved products for systemic delivery via the lungs for diseases of the central nervous system and insulin for diabetes are also discussed. New technologies for drug delivery by inhalation are analyzed, with the emphasis on those that would likely yield significant improvements over the technologies in current use or would expand the range of drugs and diseases treatable by this route of administration. Significance Statement This review of the key aspects of approved orally inhaled drug products for a variety of respiratory diseases and for systemic administration should be helpful in making judicious decisions about the development of new or improved inhaled drugs. These aspects include the choices of the active ingredients, formulations, delivery systems suitable for the target patient populations, and, to some extent, meaningful safety and efficacy endpoints in clinical trials.

This work is the second in a series of publications outlining the fundamental principles and proposed design of a biopharmaceutics classifications system for inhaled drugs and drug products (the iBCS). Here, a mechanistic computer-based model has been used to explore the sensitivity of the primary biopharmaceutics functional output parameters: (i) pulmonary fraction dose absorbed (Fabs) and (ii) drug half-life in lumen (t1/2) to biopharmaceutics-relevant input attributes including dose number (Do) and effective permeability (Peff). Results show the nonlinear sensitivity of primary functional outputs to variations in these attributes. Drugs with Do < 1 and Peff > 1 × 10–6 cm/s show rapid (t1/2 < 20 min) and complete (Fabs > 85%) absorption from lung lumen into lung tissue. At Do > 1, dissolution becomes a critical drug product attribute and Fabs becomes dependent on regional lung deposition. The input attributes used here, Do and Peff, thus enabled the classification of inhaled drugs into parameter spaces with distinctly different biopharmaceutic risks. The implications of these findings with respect to the design of an inhalation-based biopharmaceutics classification system (iBCS) and to the need for experimental methodologies to classify drugs need to be further explored.

iBCS: 2. Mechanistic Modeling of Pulmonary Availability of Inhaled Drugs versus Critical Product Attributes

The present COVID-19 pandemic caused by the SARSCoV-2 has resulted in massive disruption to the normal operation of societies worldwide. There is currently the prospect of a lengthy period of continued disease outbreak, associated with both serious morbidity and mortality, as well as the significant potential for further waves of infection as regulations regarding population mobility are relaxed. So far, the emphasis for pharmacological/biological agent-based therapies has been focused on agents that are administered by traditional routes, in particular injection. Yet, the location of initial infection (i.e., upper respiratory tract and central airways through direct surface contact or deposition of inhaled droplets) and the route of disease progression after initial infection are primarily through the respiratory system. Furthermore, the morbidity and mortality outcomes are manifested primarily in the respiratory tract, unless and until multiple organ failure occurs. Members of International Society for Aerosols in Medicine (ISAM), therefore, believe that there is an urgent need to accelerate the development of inhaled therapies for COVID-19. There are many examples of approved inhaled therapies for respiratory diseases, including for both viral and bacterial infections, for example, the use of inhaled ribavarin for respiratory syncytial virus infection and inhaled zanamivir for influenza infection, as well as the treatment of chronic conditions, such as asthma, chronic obstructive pulmonary diseases, pulmonary arterial hypertension, and cystic fibrosis. Furthermore, the use of inhaled measles vaccine in Mexico is an example of a preventative noninjectable strategy that is safe and efficacious. These inhaled therapies have proven to be both efficacious and safe by achieving high local concentrations at the sites of action in the lungs, while minimizing systemic exposure. Thus, the

Urgent Appeal from International Society for Aerosols in Medicine (ISAM) During COVID-19: Clinical Decision Makers and Governmental Agencies Should Consider the Inhaled Route of Administration: A Statement from the ISAM Regulatory and Standardization Issues Networking Group.

This review discusses how advances in formulation and device design can be utilized to dramatically improve lung targeting and dose consistency relative to current marketed dry powder inhalers (DPIs). Central to the review is the development of engineered particles that effectively bypass deposition in the upper respiratory tract (URT). This not only reduces the potential for off-target effects but it also reduces variability in dose delivery to the lungs resulting from anatomical differences in the soft tissue in the mouth and throat. Low-density porous particles are able to largely bypass URT deposition due to the fact that both the primary particles and their agglomerates are respirable. The low-density particles also exhibit dose delivery to the lungs that is largely independent of inspiratory flow rate across a range of flow rates that most subjects achieve with portable DPIs. Coupling this with delivery devices that are breath actuated, simple to operate (open-inhale-close), and have adherence-tracking capability enables drug delivery that is largely independent of how a subject inhales, with a user experience that is close to that of an "idealhaler."

Idealhalers Versus Realhalers: Is It Possible to Bypass Deposition in the Upper Respiratory Tract?

Local delivery of drugs to the lungs of newborn infant represents an unmet need as no drugs have been approved. Potential benefits could be large. Development of aerosol for delivery of drugs to infants and newborn offers huge potential for better therapy. Newborn infants present unique challenges with regard to aerosol therapy. Efficient deposition of aerosolized medications on the neonate airway surface is hampered by anatomical features such as small airway geometries and physiological features such as exquisitely small tidal volumes, rapid breathing and unfavorable inhalation:exhalation ratios.

METHODS
The selection of aerosol generators capable of delivering any more than a few percent of the nominal drug dose to the airways remains extremely limited with nebulizers and pressurized metered dose inhalers being predominantly used. Further hampering the development of bespoke high performance aerosol therapy for neonates is the as yet unknown ideal droplet size.

RESULTS
Droplet size is a critical determinant of the amount of aerosol that escapes the patient circuit, becoming available to the patient, and subsequently the location of deposition within the lung. It is assumed that smaller is better at traversing the tortuous path from aerosol generator to airway surface. To date, patient interface has been shown to have little effect with respect to delivered dose, but some may provide advantage with respect to ease of use and patient acceptance.

The present review iteratively describes the difficulties in achieving optimized aerosol drug delivery in neonates. We suggest possible technical solutions aimed at improving delivery and developing a platform for increased reliability and reproducibility of dosing such that new and existing medications may exploit the potential advantages of aerosol therapy in the neonate population.

The Impact of Inspiratory Flow Rate on Drug Delivery to the Lungs with Dry Powder Inhalers

Accessorized DPI: a Shortcut towards Flexibility and Patient Adaptability in Dry Powder Inhalation

Introduction. 1000 years of pharmaceutical aerosols: what remains to be done?

Deposition and clearance studies are used during product development and in fundamental research. These studies mostly involve radionuclide imaging, but pharmacokinetic methods are also used to assess the amount of drug absorbed through the lungs, which is closely related to lung deposition. Radionuclide imaging may be two-dimensional (gamma scintigraphy or planar imaging), or three-dimensional (single photon emission computed tomography and positron emission tomography). In October 2009, a group of scientists met at the "Thousand Years of Pharmaceutical Aerosols" conference in Reykjavik, Iceland, to discuss future research in key areas of pulmonary drug delivery. This article reports the session on "Deposition, imaging and clearance." The objective was partly to review our current understanding, but more importantly to assess "what remains to be done?" A need to standardize methodology and provide a regulatory framework by which data from radionuclide imaging methods could be compared between centers and used in the drug approval process was recognized. There is also a requirement for novel radiolabeling methods that are more representative of production processes for dry powder inhalers and pressurized metered dose inhalers. A need was identified for studies to aid our understanding of the relationship between clinical effects and regional deposition patterns of inhaled drugs. A robust methodology to assess clearance from small conducting airways should be developed, as a potential biomarker for therapies in cystic fibrosis and other diseases. The mechanisms by which inhaled nanoparticles are removed from the lungs, and the factors on which their removal depends, require further investigation. Last, and by no means least, we need a better understanding of patient-related factors, including how to reduce the variability in pulmonary drug delivery, in order to improve the precision of deposition and clearance measurements.

The objective of this study was to develop SEDS-engineered budesonide particles suitable for dry powder inhalation delivery and to evaluate their aerosol performance across a range of passive dry powder inhalers (DPI). SEDS budesonide powders were manufactured in Nektar's SCF manufacturing plant and compared to the micronized drug and commercial powder (Pulmicort Turbuhaler, AstraZeneca). Aerosol performance was evaluated by determining emitted dose (ED) by a variation of the USP method and fine particle fraction (FPF) using Andersen cascade impaction. The SCF powder dispersed best in the Turbospin and Eclipse devices, exhibiting high EDs (70%-80%) and relatively low variability (RSD 8%-13%). Regardless of the device, the SEDS material outperformed both the micronized drug and the commercial powder, while exhibiting good batch-to-batch reproducibility (RSD <5%). All powders exhibited flow rate-dependent ED, albeit for the SEDS material it was minimized at reduced fill weights. This was attributed to inadequate and variable powder clearance from the capsules at low inspiratory flow rates, which was more pronounced in the Eclipse and Cyclohaler. The results demonstrate that SEDS is an attractive particle-engineering process that may enhance pulmonary performance of budesonide and possibly facilitate development of other small molecule pulmonary products in passive DPI.

SCF-engineered powders for delivery of budesonide from passive DPI devices.

Evaluation of SCF-engineered particle-based lactose blends in passive dry powder inhalers.

Spray Dried Powders and Powder Blends of Recombinant Human Deoxyribonuclease (rhDNase) for Aerosol Delivery

La desoxyribonuclease humaine recombinante (rhDNase) est un nouveau medicament proteique destine a etre administre par voie respiratoire pour le traitement des affections avec expectorations purulentes a fort taux d'ADN dans les voies aeriennes. Ce travail decrit la caracterisation du nuage aerosol forme par pulverisation d'une solution aqueuse de rhDNase. Des differences importantes apparaissent dans la repartition de taille des gouttelettes produites par differents systemes d'administration. L'activite enzymatique et l'integrite structurale de la rhDNase sont preservees lorsque des aeroliseurs pneumatiques sont utilises pour la formation des aerosols

Assessment of aerosol delivery systems for recombinant human deoxyribonuclease

Cost-effectiveness of pharmaceutical strategies to prevent respiratory syncytial virus disease in young children: a decision-support model for use in low-income and middle-income countries

Background The risk of severe COVID-19 disease is known to be higher in older individuals and those with underlying health conditions. Understanding the number of individuals at increased risk of severe COVID-19 illness, and how this varies between countries may inform the design of possible strategies to shield those at highest risk. Methods We estimated the number of individuals at increased risk of severe COVID-19 disease by age (5-year age groups), sex and country (n=188) based on prevalence data from the Global Burden of Disease (GBD) study for 2017 and United Nations population estimates for 2020. We also calculated the number of individuals without an underlying condition that could be considered at-risk because of their age, using thresholds from 50-70 years. The list of underlying conditions relevant to COVID-19 disease was determined by mapping conditions listed in GBD to the guidelines published by WHO and public health agencies in the UK and US. We analysed data from two large multimorbidity studies to determine appropriate adjustment factors for clustering and multimorbidity. Results We estimate that 1.7 (1.0 - 2.4) billion individuals (22% [15-28%] of the global population) are at increased risk of severe COVID-19 disease. The share of the population at increased risk ranges from 16% in Africa to 31% in Europe. Chronic kidney disease (CKD), cardiovascular disease (CVD), diabetes and chronic respiratory disease (CRD) were the most prevalent conditions in males and females aged 50+ years. African countries with a high prevalence of HIV/AIDS and Island countries with a high prevalence of diabetes, also had a high share of the population at increased risk. The prevalence of multimorbidity (>1 underlying conditions) was three times higher in Europe than in Africa (10% vs 3%). Conclusion Based on current guidelines and prevalence data from GBD, we estimate that one in five individuals worldwide has a condition that is on the list of those at increased risk of severe COVID-19 disease. However, for many of these individuals the underlying condition will be undiagnosed or not severe enough to be captured in health systems, and in some cases the increase in risk may be quite modest. There is an urgent need for robust analyses of the risks associated with different underlying conditions so that countries can identify the highest risk groups and develop targeted shielding policies to mitigate the effects of the COVID-19 pandemic.

How many are at increased risk of severe COVID-19 disease? Rapid global, regional and national estimates for 2020

Background: National immunisation programmes globally are at risk of suspension due to the severe health system constraints and physical distancing measures in place to mitigate the ongoing COVID-19 pandemic. Our aim is to compare the health benefits of sustaining routine childhood immunisation in Africa against the risk of acquiring SARS-CoV-2 infections through visiting routine vaccination service delivery points. Methods: We used two scenarios to approximate the child deaths that may be caused by immunisation coverage reductions during COVID-19 outbreaks. First, we used previously reported country-specific child mortality impact estimates of childhood immunisation for diphtheria, tetanus, pertussis, hepatitis B, Haemophilus influenzae type b, pneumococcal, rotavirus, measles, meningitis A, rubella, and yellow fever (DTP3, HepB3, Hib3, PCV3, RotaC, MCV1, MCV2, MenA, RCV, YFV) to approximate the future deaths averted before completing five years of age by routine childhood vaccination during a 6-month Covid-19 risk period without catch-up campaigns. Second, we analysed an alternative scenario that approximates the health benefits of sustaining routine childhood immunisation to only the child deaths averted from measles outbreaks during the Covid-19 risk period. The excess number of infections due to additional SARS-CoV-2 exposure during immunisation visits assumes that contact reducing interventions flatten the outbreak curve during the Covid-19 risk period, that 60% of the population will have been infected by the end of that period, that children can be infected by either vaccinators or during transport and that upon child infection the whole household would be infected. Country specific household age structure estimates and age dependent infection fatality rates are then applied to calculate the number of deaths attributable to the vaccination clinic visits. We present benefit-risk ratios for routine childhood immunisation alongside 95% uncertainty range estimates from probabilistic sensitivity analysis. Findings: For every one excess Covid-19 death attributable to SARS-CoV-2 infections acquired during routine vaccination clinic visits, there could be 143 (38 - 576) deaths in children prevented by sustaining routine childhood immunisation in Africa. The benefit-risk ratio for the vaccinated children, siblings, parents or adult care-givers, and older adults in the households of vaccinated children are 58,000 (3,200 - 21,350,000), 52,000 (2,800 - 18,884,000), 2,000 (393 - 12,000), and 157 (41 - 652) respectively. In the alternative scenario that approximates the health benefits to only the child deaths averted from measles outbreaks, the benefit-risk ratio to the households of vaccinated children is 5 (1 - 21) under these highly conservative assumptions and if the risk to only the vaccinated children is considered, the benefit-risk ratio is 2,000 (131 - 839,000). Interpretation: Our analysis suggests that the health benefits of deaths prevented by sustaining routine childhood immunisation in Africa far outweighs the excess risk of Covid-19 deaths associated with vaccination clinic visits. However, there are other factors that must be considered for strategic decision making to sustain routine childhood immunisation in African countries during the Covid-19 pandemic. These include logistical constraints of vaccine supply chain problems caused by the Covid-19 pandemic, reallocation of immunisation providers to other prioritised health services, healthcare staff shortages caused by SARS-CoV-2 infections among the staff, decreased demand for vaccination arising from community reluctance to visit vaccination clinics for fear of contracting SARS-CoV-2 infections, and infection risk to healthcare staff providing immunisation services as well as to their households and onward SARS-CoV-2 transmission into the wider community.

Benefit-risk analysis of health benefits of routine childhood immunisation against the excess risk of SARS-CoV-2 infections during the Covid-19 pandemic in Africa

The last two decades have seen substantial expansion of childhood vaccination programmes in low and middle income countries (LMICs). Here we quantify the health impact of these programmes by estimating the deaths and disability-adjusted life years (DALYs) averted by vaccination with ten antigens in 98 LMICs between 2000 and 2030.Independent research groups provided model-based disease burden estimates under a range of vaccination coverage scenarios for ten pathogens: hepatitis B (HepB), Haemophilus influenzae type b (Hib), human papillomavirus (HPV), Japanese encephalitis (JE), measles, Neisseria meningitidis serogroup A (MenA), Streptococcus pneumoniae, rotavirus, rubella, yellow fever. Using standardized demographic data and vaccine coverage estimates for routine and supplementary immunization activities, the impact of vaccination programmes on deaths and DALYs was determined by comparing model estimates from the no vaccination counterfactual scenario with those from a default coverage scenario. We present results in two forms: deaths/DALYs averted in a particular calendar year, and in a particular annual birth cohort.We estimate that vaccination will have averted 69 (2.5-97.5% quantile range 52-88) million deaths between 2000 and 2030 across the 98 countries and ten pathogens considered, 35 (29-45) million of these between 2000-2018. From 2000-2018, this represents a 44% (36-57%) reduction in deaths due to the ten pathogens relative to the no vaccination counterfactual. Most (96% (93-97%)) of this impact is in under-five age mortality, notably from measles. Over the lifetime of birth cohorts born between 2000 and 2030, we predict that 122 (96-147) million deaths will be averted by vaccination, of which 58 (39-75) and 38 (26-52) million are due to measles and Hepatitis B vaccination, respectively. We estimate that recent increases in vaccine coverage and introductions of additional vaccines will result in a 72% (61-79%) reduction in lifetime mortality caused by these 10 pathogens in the 2018 birth cohort.Increases in vaccine coverage and the introduction of new vaccines into LMICs over the last two decades have had a major impact in reducing mortality. These public health gains are predicted to increase in coming decades if progress in increasing coverage is sustained.

Estimating the health impact of vaccination against 10 pathogens in 98 low and middle income countries from 2000 to 2030

Guidelines for multi-model comparisons of the impact of infectious disease interventions

Efficacy of live oral rotavirus vaccines by duration of follow-up: a meta-regression of randomised controlled trials

Mortality reduction benefits and intussusception risks of rotavirus vaccination in 135 low-income and middle-income countries: a modelling analysis of current and alternative schedules

Few methods exist to estimate vaccine efficacy and its decay following immunisation. Existing methods are largely based on survival analyses such as Poisson or Cox-regression, applied to individual-level data from randomised placebo-controlled trials (RCTs), however, such are often not easily available for analysing pooling evidence across trials. Hence, cumulative vaccine efficacy (VE), the commonly reported endpoint, is implicitly assumed a reasonable proxy for the instantaneous vaccine efficacy (iVE). This assumption is violated if the relative risk (RR) of vaccinated vs unvaccinated is not constant over time, i.e. if vaccine efficacy changes after immunisation. We propose a method to overcome this issue. We use estimates of VE stratified by time since completed immunisation, and estimate time-dependent iVE. We validate the method against simulated data for two forms of vaccine protection: all-or-nothing protection and leaky protection. We illustrate how VE estimates are biased by time-dependent effects in the baseline force of infection and in iVE. Our proposed method improves upon available iVE estimation techniques, particularly if the vaccine induced leaky-like protection and the disease outcome is rare.

Approximating instantaneous vaccine efficacy from cumulative vaccine efficacy

India has the highest burden of cervical cancer in the world. To estimate the consequences of delaying implementation of organized cervical cancer screening, we projected the avertable burden of disease under different implementation scenarios of a screening program. We used an individual‐based microsimulation model of human papillomavirus (HPV) infection and cervical cancer calibrated to epidemiologic data from India to project age‐specific cancer incidence and mortality reductions associated with screening (once‐in‐a‐lifetime among women aged 30–34 years) with one‐visit visual inspection with acetic acid (VIA) and one‐ and two‐visit HPV DNA testing. We then applied these reductions to a population model to project the lifetime cervical cancer cases and deaths averted under different implementation scenarios taking place from 2017 to 2026: (1) immediate implementation of screening with currently available screening tests (one‐visit VIA, two‐visit HPV testing); (2) immediate implementation of screening with currently available screening tests, with a switch to point‐of‐care one‐visit HPV testing in 5 years; and (3) 5‐year delayed implementation of screening with current screening tests or point‐of‐care HPV testing. Immediate implementation of two‐visit HPV testing with a switch to one‐visit HPV testing averted 574,100 cases and 382,500 deaths over the lifetimes of 81.4 million 30‐ to 34‐year‐old women screened once between 2017 and 2026. Delayed implementation with a one‐visit HPV test averted 209,300 cases and 139,100 deaths. Delaying implementation of screening programs in high‐burden settings will result in substantial morbidity and mortality among women beyond the age for adolescent HPV vaccination.

Health impact of delayed implementation of cervical cancer screening programs in India: A modeling analysis

To estimate the health impact, financial costs, and cost‐effectiveness of scaling‐up coverage of human papillomavirus (HPV) vaccination (young girls) and cervical cancer screening (women of screening age) for women in countries that will likely need donor assistance.

The health and economic impact of scaling cervical cancer prevention in 50 low‐ and lower‐middle‐income countries

Background Cervical cancer is the fourth leading cause of cancer death in women, with 85% of cases and deaths occurring in developing countries. While organized screening programs have reduced cervical cancer incidence in high-income countries through detection and treatment of precancerous lesions, the implementation of organized screening has not been effective in low-resource settings due to lack of infrastructure and limited budgets. Our objective was to estimate the cost of comprehensive primary and secondary cervical cancer prevention in low- and middle-income countries. Methods and Findings We performed a modeling analysis to estimate 1) for girls aged 10 years, the cost of 2-dose human papillomavirus (HPV) vaccination; and 2) for women aged 30 to 49 years, the cost of cervical cancer screening (with visual inspection with acetic acid (VIA), HPV testing, or cytology) and preventive treatment in 102 low- and middle-income countries from 2015 to 2024. We used an Excel-based costing and service utilization model to estimate financial costs (2013 US$) based on prevalence of HPV, prevalence of precancerous lesions, and screening test performance. Where epidemiologic data were unavailable, we extrapolated from settings with data using an individual-based microsimulation model of cervical carcinogenesis (calibrated to 20 settings) and multivariate regression. Total HPV vaccination costs ranged from US$8.6 billion to US$24.2 billion for all scenarios considered (immediate, 5-year, or 10-year roll-out; price per dose US$4.55-US$70 by country income level). The total cost of screening and preventive treatment ranged from US$5.1 billion (10-year roll-out, screening once at age 35 years) to US$42.3 billion (immediate roll-out, high intensity screening). Limitations of this analysis include the assumption of standardized protocols by country income level that did not account for the potential presence of multiple screening modalities or management strategies within a country, and extrapolation of cost and epidemiologic data to settings where data were limited. Conclusions The estimated cost of comprehensive cervical cancer prevention with 2-dose HPV vaccination of 10-year-old girls and screening of women aged 30 to 49 years ranges from US$13.7 billion to US$66.5 billion, depending on speed of roll-out, vaccine price per dose, and screening test and frequency. Findings demonstrate the substantial impact of vaccine price in middle-income countries that are not eligible for assistance from Gavi, the Vaccine Alliance. Replacing routine cytology with HPV-based screening may reduce total costs. Data on the health impact and relative cost-effectiveness of strategies are needed to determine the best value for public health dollars.

Resources Required for Cervical Cancer Prevention in Low- and Middle-Income Countries

Introduction of universal human papillomavirus vaccination of girls aged 11 years to the National Immunization Program in Brazil: a cost-effectiveness analysis

Evaluating the potential risks and benefits of infant rotavirus vaccination in England.

Griffiths, Ulla Kou; Clark, Andrew; Hajjeh, Rana; (2013) Cost-effectiveness of Haemophilus influenzae type b conjugate vaccine in lowand middle-income countries: regional analysis and assessment of major determinants. The Journal of pediatrics, 163 (1 Supp). S50-S59.e9. ISSN 0022-3476 DOI: https://doi.org/10.1016/j.jpeds.2013.03.031 Downloaded from: http://researchonline.lshtm.ac.uk/id/eprint/1012222/ DOI: https://doi.org/10.1016/j.jpeds.2013.03.031

Cost-effectiveness of Haemophilus influenzae type b vaccine in low- and middle-income countries: Regional analysis and assessment of major determinants

Cost-effectiveness of Haemophilus influenzae type b conjugate vaccine in low- and middle-income countries: regional analysis and assessment of major determinants.

Cost-Effectiveness Analysis of Incorporation of the HPV Vaccine to the National Immunization Program / NIP of Brazil

Background Hib vaccine has gradually been introduced into more and more countries during the past two decades, partly due to GAVI Alliance support to low-income countries. However, since Hib disease burden is difficult to establish in settings with limited diagnostic capacities and since the vaccine continues to be relatively expensive, some Governments remain doubtful about its value leading to concerns about financial sustainability. Similarly, several middle-income countries have not introduced the vaccine. The aim of this study is to estimate and compare the cost-effectiveness of Hib vaccination in a country relying on self-financing (Belarus) and a country eligible for GAVI Alliance support (Uzbekistan). Methods and Findings A decision analytic model was used to estimate morbidity and mortality from Hib meningitis, Hib pneumonia and other types of Hib disease with and without the vaccine. Treatment costs were attached to each disease event. Data on disease incidence, case fatality ratios and costs were primarily determined from national sources. For the Belarus 2009 birth cohort, Hib vaccine is estimated to prevent 467 invasive disease cases, 4 cases of meningitis sequelae, and 3 deaths, while in Uzbekistan 3,069 invasive cases, 34 sequelae cases and 341 deaths are prevented. Estimated costs per discounted DALY averted are US$ 9,323 in Belarus and US$ 267 in Uzbekistan. Conclusion The primary reason why the cost-effectiveness values are more favourable in Uzbekistan than in Belarus is that relatively more deaths are averted in Uzbekistan due to higher baseline mortality burden. Two other explanations are that the vaccine price is lower in Uzbekistan and that Uzbekistan uses a three dose schedule compared to four doses in Belarus. However, when seen in the context of the relative ability to pay for public health, the vaccine can be considered cost-effective in both countries.

Comparative Economic Evaluation of Haemophilus influenzae Type b Vaccination in Belarus and Uzbekistan

Global and regional risk of disabling sequelae from bacterial meningitis: a systematic review and meta-analysis.

WHO estimates that Haemophilus influenzae type b (Hib) caused over 8 million cases of serious disease and 376,000 deaths globally in the year 2000. The introduction of Hib vaccines has essentially eliminated Hib disease in countries where they are routinely used. Now, almost all Hib disease cases and deaths occur in countries where Hib vaccines is not incorporated in the routine immunization program.

PROCESS
The Hib and Pneumococcal subcommittee of National Technical Advisory Group on Immunization (NTAGI) in India met in April 2008. This paper focuses on the discussions regarding Hib vaccine introduction; the pneumococcal vaccine discussion is being published separately. The subcommittee reviewed the available published and unpublished literature as well as consulted prominent Hib experts to make an informed decision regarding the introduction of Hib vaccine into the routine Universal Immunization Program (UIP) in India.

The meeting was conducted with the objectives of reviewing the existing Indian, regional and global data on Hib disease (meningitis and pneumonia), the data on safety and immunogenecity of Hib vaccines manufactured in India, as well as the programmatic and operational requirements for the introduction of Hib vaccine in India, with the goal of making a recommendation on the introduction of Hib vaccine into the UIP.

The committee noted that Hib diseases burden is suffiently high in India to warrant prevention by vaccination. Hib vaccines have been demonstrated to be safe, both globally and in India, and extremely efficacious in all settings where they have been used. Hib vaccine fits into the UIP immunization schedule. Several Indian manufacturers are currently producing Hib vaccines, and a detailed analysis showed that supplier capacity would be sufficient to meet the present and future demand for India if given sufficient lead time to increase production. Recognizing that it is the poorest children that are most at risk, the Indian Academy of Pediatrics has already recommended this vaccine for routine use in India. This subcommittee strongly recommended that Hib vaccine should immediately be introduced in India's UIP.

NTAGI subcommittee recommendations on Haemophilus influenzae type B (Hib) vaccine introduction in India.

Timing of children's vaccinations in 45 low-income and middle-income countries: an analysis of survey data

Background: Since 2000, 72 countries with GNI per capita below $1,000 have had the opportunity to apply to GAVI for introduction of hepatitis B and Haemophilus influenzae type b (Hib) vaccines. While the large majority of countries relatively quickly applied for hepatitis B vaccine, only 17 of the countries had applied for Hib vaccine at the end of 2005. Reasons for hesitation towards Hib vaccine include limited knowledge of Hib disease burden and the relatively high costs of the vaccine. Since GAVI only offered to cover the full vaccine costs for the initial five years, countries were concerned about long-term sustainability. Objectives: (1) Development of a user-friendly decision analytic model for country-level assessment of the cost-effectiveness of Hib vaccine. (2) Use the model to compare the cost-effectiveness of Hib vaccine in Kenya, Indonesia and Moldova, and discuss reasons for differences between these countries. Methods: The model has been designed to provide a user-friendly environment for cost-effectiveness analysis at the country level. Vaccinated and unvaccinated cohorts are compared for a predefined duration, allowing streams of net costs and effects to be reported for a specific cohort. The user is able to specify future trends in coverage, vaccine price, access to health care and disease mortality, as well as consider the impact of rural/urban dimensions. Data on Hib disease incidence were collected in different ways in the three countries. In Kenya intensive hospital based surveillance before and after Hib vaccine introduction provided the evidence. In Indonesia data from a long-term randomized controlled probe study of Hib vaccine were used. In Moldova no long-term study on Hib disease burden has been carried out, so routine surveillance data and extrapolations from neighboring countries were used. In all three countries treatment cost data for meningitis and pneumonia were collected at a selection of health facilities. Results: The analysis illustrated that Hib disease epidemiology and treatment costs are markedly different in for the three countries. While Hib vaccination can be considered cost-effective in all three countries, the parameter values used for reaching this conclusion are different. Conclusion: The relatively simple modeling approach is well suited to give an understanding of the parameters affecting the cost-effectiveness ratio in different settings.

Decision Analytic Model for Evaluating the Cost-Effectiveness of Haemophilus Influenzae Type B Vaccine: Comparative Analysis in Kenya, Moldova and Indonesia

Comprehensive Global Cervical Cancer Prevention Costs and Benefits of Scaling up within a Decade

Over the course of three years, an M-reader supported extensive reading program at a small, private Japanese university grew from a tiny pilot into a fairly large-scale operation with over 2,000 participating students and approximately 60 teachers. Throughout the program, methods of implementation and assessment varied from class-to-class, as did student achievement. The researchers wanted to find out what methods and strategies were working well for both students and teachers in the program. Using data from M-reader in the form of word counts, participation rates, and number of quizzes taken, researchers identified and interviewed students achieving success in the program. Researchers also identified and interviewed teachers whose students were collectively outperform77 Characterizing Best Practices in an Extensive Reading Program Aaron P. CAMPBELL, Mami YOSHIDA, Midori TANIMURA, Andy H. CLARK, Rebecca CALMAN & Iain DAVEY ing other classes at similar levels in the program. From these interview results, researchers constructed profiles of students and teachers for whom the program was working well, highlighting the types of strategies and behaviors they had in common. Among these for students included a clear understanding of ER practices and the ability to integrate reading into their daily habits. Common practices amongst teachers were having students discuss their reading in pairs or small groups, and creating time for students to practice Silent Sustained Reading in class.

Hermawan, Andy. 2011. Students’ Mastery in Coordinating and Subordinating Conjunction of the Tenth Grade Students at SMAN 6 Banjarmasin Academic Year 2010/2011, Thesis, English Department, Tarbiyah Faculty, Advisor(1) Drs. Sa’adillah, M.Pd (2) Puji Sri Rahayu, M.A 
 
Conjunction has important function in the formulation of sentences to combine/related other words, phrase, and sentence in writing. Conjunctions are connecting words. They join words, phrases, and sentences in our writing and speech. Conjunction as part of grammar is an important aspect to the students to get knowledge and it can improve their ability. The students’ mastery in using coordinating and subordinating conjunction has to be mastered by the in learning process, especially the students at SMAN 6 Banjarmasin. 
This research is based on the result of the first observation at SMAN 6 Banjarmasin that the student have difficult in using coordinating and subordinating conjunction. Because that, the writer is interested in studying by writing a thesis entitles: Students’ Mastery in Using Coordinating and Subordinating Conjunction of the Tenth Grade Students of SMAN 6 Banjarmasin Academic Year 2010/2011. 
This research is aimed at knowing the level of students’ mastery in using coordinating and subordinating conjunction by tenth grade of SMAN 6 Banjarmasin and the factors that influence it. The population of this research are tenth grade students of SMAN 6 Banjarmasin. The total numbers of population are 215 students. The samples of this research are 54 students who take proportionally and randomly from each class. 
To collect the data, it is used achievement test to know students’ mastery in using coordinating and subordinating conjunction. Beside that the data are collected from questionnaire, interview and documentation to know the factors that influence it. 
Based on the result of this research, it is known that the total score of the students’ mastery in using coordinating and subordinating conjunction by tenth grades of SMAN 6 Banjarmasin is 3556 from 54 students as samples and its means score is 65,8. It can be concluding that the students’ mastery in using coordinating and subordinating conjunction by tenth grade students of SMAN 6 Banjarmasin are categorized by good category. There are many factors that influenced it, students learning activity, students’ interest to English subject, teacher guidance, means and infrastructure, and school environment.

Students’ Mastery in Coordinating and Subordinating Conjunction of the Tenth Grade Students at SMAN 6 Banjarmasin Academic Year 2010/2011

We present the first multimass velocity-map imaging data acquired using a new ultrafast camera designed for time-resolved particle imaging. The PImMS (Pixel Imaging Mass Spectrometry) sensor allows particle events to be imaged with time resolution as high as 25 ns over data acquisition times of more than 100 μs. In photofragment imaging studies, this allows velocity-map images to be acquired for multiple fragment masses on each time-of-flight cycle. We describe the sensor architecture and present bench-testing data and multimass velocity-map images for photofragments formed in the UV photolysis of two test molecules: Br(2) and N,N-dimethylformamide.

Multimass velocity-map imaging with the Pixel Imaging Mass Spectrometry (PImMS) sensor: an ultra-fast event-triggered camera for particle imaging.

Imaging mass spectrometry is a powerful technique that allows chemical information to be correlated to a spatial coordinate on a sample. By using stigmatic ion microscopy, in conjunction with fast cameras, multiple ion masses can be imaged within a single experimental cycle. This means that fewer laser shots and acquisition cycles are required to obtain a full data set, and samples suffer less degradation as overall collection time is reduced. We present the first spatial imaging mass spectrometry results obtained with a new time-stamping detector, named the pixel imaging mass spectrometry (PImMS) sensor. The sensor is capable of storing multiple time stamps in each pixel for each time-of-flight cycle, which gives it multi-mass imaging capabilities within each pixel. A standard velocity-map ion imaging apparatus was modified to allow for microscope mode spatial imaging of a large sample area (approximately 5 × 5 mm(2)). A variety of samples were imaged using PImMS and a conventional camera to determine the specifications and possible applications of the spectrometer and the PImMS camera.

The application of the fast, multi-hit, pixel imaging mass spectrometry sensor to spatial imaging mass spectrometry.

In this paper, we present the Pixel Imaging Mass Spectrometry (PImMS) sensor, a pixelated Time-of-Flight (TOF) sensor for use in mass spectrometry. The device detects any event which produces a signal above a programmable threshold with a timing resolution of 25ns. Both analogue and digital readout modes are available and all pixels can be individually trimmed to improve noise performance. The pixels themselves contain analogue signal conditioning circuitry as well as complex logic totalling more than 600 transistors. This large number can be achieved without any loss of quantum efficiency thanks to the use of the patented Isolated N-well Monolithic Active Pixels (INMAPS) process. In this paper, we examine the design of the PImMS 1.0 device and its successor PImMS 2.0, a significantly enlarged sensor with several added features. We will also present some initial results from mass spectrometry experiments performed with PImMS 1.0.

PImMS: A self-triggered, 25ns resolution monolithic CMOS sensor for Time-of-Flight and Imaging Mass Spectrometry

Direct detection of low-energy electrons (500-2000 eV) with a novel back-thinned CMOS active pixel sensor (APS) is reported in this paper. The sensor was installed in a JEOL 6400F scanning electron microscope to quantitatively test its linearity and spatial resolution by a focused electron beam. The obtained results show good linearity at electron beam energy values from 500 to 2000 eV. The full-width at half-maximum spatial resolution was around 2 pixels, a limit set by charge diffusion in the epilayer. These results show that this CMOS APS sensor is appropriate for low-energy electron detection providing the benefits of direct detection for many applications.

Direct Detection of Low-Energy Electrons With a Novel CMOS APS Sensor

PImMS, or Pixel Imaging Mass Spectrometry, is a novel high-speed monolithic CMOS imaging sensor tailored to mass spectrometry requirements, also suitable for other dark-field applications. In its application to time-of-flight mass spectrometry, the sensor permits ion arrival time distributions to be combined with 2D imaging, providing additional information about the initial position or velocity of ions under study. PImMS1, the first generation sensor in this family, comprises an array of 72 by 72 pixels on a 70 μm by 70 μm pitch. Pixels independently record digital timestamps when events occur over an adjustable threshold. Each pixel contains 4 memories to record timestamps at a resolution of 25 ns. The sensor was designed and manufactured in the INMAPS 0.18 μm process. This allows the inclusion of significant amounts of circuitry (over 600 transistors) within each pixel while maintaining good detection efficiency. We present an overview of the pixel and sensor architecture, explain its functioning and present test results, ranging from characterisation of the analogue front end of the pixel, to verification of its digital functions, to some first images captured on mass spectrometers. We conclude with an overview of the upcoming second generation of PImMS sensors.

PImMS, a fast event-triggered monolithic pixel detector with storage of multiple timestamps

We report on `proof of concept' experiments in Pixel Imaging Mass Spectrometry (PImMS) using an ultra-fast frame-transfer CCD camera and also describe an intelligent CMOS sensor which is being developed for this application by the PImMS collaboration in the UK. PImMS is a combination of traditional TOF mass spectrometry and ion imaging. Information provided by the ion imaging gives access to valuable structural information of the molecule under investigation, in addition to the normal mass spectrum. Recording of the 2D spatial information of the arriving ions allows to reconstruct the ion velocity distributions for separate ion masses and to correlate them to each other. The new PImMS sensor will be capable of time stamping up to four arriving ions per pixel during the 200 μsec acquisition cycle with 100 nsec resolution which should meet the demanding requirements of complete recording of mass spectra of complex organic molecules.

Pixel Imaging Mass Spectrometry with fast and intelligent Pixel detectors

The Large Area Sensor (LAS) is a 1350 times1350 array of active pixels on a 40 Im pitch fabricated in a 0.35 im CMOS process. Stitching technology is employed to achieve an area of 5.4 cm times5.4 cm. The sensor includes 'regions of reset', whereby three different integration times can be set on the array to achieve a large imaging range for static scenes. Characterization of the noise performance included temporal and fixed pattern sources. LAS was found to have a read noise of 62 e-, a full well capacity of 61 times103 e- and a conversion gain of 5 e- per digital number (DN). The fixed pattern noise (FPN) was evaluated at half saturation; within a single stitched section of the array, column-to-column FPN was found to be 0.6%, while the pixel-to-pixel FPN was 3%. Both FPN sources were found to be gain related and could be corrected via flat fielding. Based on the results of characterization, LAS was coupled to a structured CsI:Tl scintillator and included in an X-ray diffraction system developed for the analysis of breast biopsy samples. Data acquired with plastic test objects agrees with that acquired by a previous prototype sensor. It is demonstrated that an imaging output range of 140 dB can be achieved using integration times of 0.1 ms to record the transmitted X-ray beam and 2.3 s to record the lower intensity scattered radiation.

Characterization and Testing of LAS: A Prototype `Large Area Sensor' With Performance Characteristics Suitable for Medical Imaging Applications

A high frame rate active pixel sensor designed to track the position of up to six optically trapped objects simultaneously within the field of view of a microscope is described. The sensor comprises 520 x 520 pixels from which a flexible arrangement of six independent regions of interest is accessed at a rate of up to 20 kHz, providing the capability to measure motion in multiple micron scale objects to nanometer accuracy. The combined control of both the sensor and optical traps is performed using unique, dedicated electronics (a field programmable gate array). The ability of the sensor to measure the dynamic position and the forces between six optically trapped spheres, down to femtonewton level, is demonstrated paving the way for application in the physical and life sciences.

Dynamic position and force measurement for multiple optically trapped particles using a high-speed active pixel sensor.

Enhanced imaging in low dose electron microscopy using electron counting

A nanometre scale, picoNewton force probe based on advanced optical tweezers control of transparent microstructures will be presented. The probe will be applied to dynamic bio-molecular interactions in solution

2008 Conference on Lasers and Electro-Optics and 2008 Conference on Quantum Electronics and Laser Science

Floating micro-structured force probe for 3D imaging and force microscopy on the nanometre scale

The use of complimentary metal-oxide-semiconductor (CMOS) active pixel sensors (APS) in scientific applications is becoming increasingly widespread and as a result, attempts to quantify their absolute performance via the conversion gain parameter K(epsiv_/DN) are now common. The inherent non- linearity of CMOS APS response means that the gold standard "mean-variance" and "photon-transfer" methods for establishing sensor conversion gain cannot automatically be used. Recently, two alternative methods have been proposed for deriving the conversion gain of APS. These methods appear to produce good results but have yet to be directly compared using results from a single sensor. This paper uses a single data set from a prototype APS to provide an absolute comparison of the performance of these nonlinear methods with respect to each other, and to standard linear methods. It also proposes a measurement procedure to enable evaluation of any APS. The prototype APS "Vanilla" produced by the RC-UK MI-3 consortium was illuminated uniformly at 65 intensity levels between dark and saturation. Results for Vanilla from linear methods substantially overestimate the sensor full well capacity (p = 0.003) to be (94.1 plusmn 1.4) X 103e- and (91.2 plusmn 1.4) x 103e-, respectively, when compared to nonlinear analysis methods. They also slightly underestimate the sensor read noise (p = 0.016) to be 51.8 plusmn 0.7e_ and 52.3 plusmn 0.7e~, respectively. The results obtained from both nonlinear estimation (NLE) and nonlinear compensation (NLC) are in good agreement, predicting read noise of54.8plusmn0.3e- and 55.4 plusmn 0.2e- and full well capacity of (72.0 plusmn 0.3) x 103e- and (72.6 plusmn 0.3) X 103e-, respectively. Results indicate that nonlinear analysis should be performed for APSs.

Comparison of Methods for Estimating the Conversion Gain of CMOS Active Pixel Sensors

X-ray diffraction studies give material-specific information about biological tissue. Ideally, a large area, low noise, wide dynamic range digital x-ray detector is required for laboratory-based x-ray diffraction studies. The goal of this work is to introduce a novel imaging technology, the CMOS active pixel sensor (APS) that has the potential to fulfil all these requirements, and demonstrate its feasibility for coherent scatter imaging. A prototype CMOS APS has been included in an x-ray diffraction demonstration system. An industrial x-ray source with appropriate beam filtration is used to perform angle dispersive x-ray diffraction (ADXRD). Optimization of the experimental set-up is detailed including collimator options and detector operating parameters. Scatter signatures are measured for 11 different materials, covering three medical applications: breast cancer diagnosis, kidney stone identification and bone mineral density calculations. Scatter signatures are also recorded for three mixed samples of known composition. Results are verified using two independent models for predicting the APS scatter signature: (1) a linear systems model of the APS and (2) a linear superposition integral combining known monochromatic scatter signatures with the input polychromatic spectrum used in this case. Cross validation of experimental, modelled and literature results proves that APS are able to record biologically relevant scatter signatures. Coherent scatter signatures are sensitive to multiple materials present in a sample and provide a means to quantify composition. In the future, production of a bespoke APS imager for x-ray diffraction studies could enable simultaneous collection of the transmitted beam and scattered radiation in a laboratory-based coherent scatter system, making clinical transfer of the technique attainable. For more information on this article, see medicalphysicsweb.org

A CMOS active pixel sensor system for laboratory- based x-ray diffraction studies of biological tissue

A large area, 54 mm x 54 mm 1.8Megapixel CMOS image sensor was designed for scientific applications such as X-ray diffraction studies and direct medical X-ray imaging. Both applications have a requirement for large sensing area combined with a high dynamic range. The sensor was manufactured using stitching techniques in order to achieve a large, scalable design. The boundary between stitched sections is seamless, with no lost pixel space. Ten parallel outputs are used to enable a frame rate of up to 20 frames per second with full frame readout. Further increases in speed are possible by defining a region of interest.

A 54mm x 54mm — 1.8Megapixel CMOS image sensor for medical imaging

A UK consortium (MI3) has been founded to develop advanced CMOS pixel designs for scientific applications. Vanilla, a 520x520 array of 25&mgr;m pixels benefits from flushed reset circuitry for low noise and random pixel access for region of interest (ROI) readout. OPIC, a 64x72 test structure array of 30&mgr;m digital pixels has thresholding capabilities for sparse readout at 3,700fps. Characterization is performed with both optical illumination and x-ray exposure via a scintillator. Vanilla exhibits 34±3e- read noise, interactive quantum efficiency of 54% at 500nm and can read a 6x6 ROI at 24,395fps. OPIC has 46±3e- read noise and a wide dynamic range of 65dB due to high full well capacity. Based on these characterization studies, Vanilla could be utilized in applications where demands include high spectral response and high speed region of interest readout while OPIC could be used for high speed, high dynamic range imaging.

Optical and x-ray characterization of two novel CMOS image sensors

Characterisation of Vanilla—A novel active pixel sensor for radiation detection

Introduction Technology to manipulate and measure at the nanometre scale is a fundamental requirement to stimulate the new era of single molecule research in the areas of material science, biology and medicine. In response to this, the Central Laser Facility in partnership with the Technology Department, the Central Microstructure Facility, the Medical Research Council (MRC) and Oxford University are developing the Tweezers Nanoprobe Microscope, funded through the STFC Technology Partnership programme. The project builds upon STFC’s strengths in the areas of the optical tweezers, instrumentation and micro-structure fabrication.

Monolithic complementary metal oxide semiconductor (CMOS) active pixel sensors with high performance have gained attention in the last few years in many scientific and space applications. In order to evaluate the increasing capabilities of this technology, in particular where low dose high resolution x-ray medical imaging is required, critical electro-optical and physical x-ray performance evaluation was determined. The electro-optical performance includes read noise, full well capacity, interacting quantum efficiency, and pixels cross talk. The x-ray performance, including x-ray sensitivity, modulation transfer function, noise power spectrum, and detection quantum efficiency, has been evaluated in the mammographic energy range. The sensor is a 525 x 525 standard three transistor CMOS active pixel sensor array with more than 75% fill factor and 25 x 25 microm pixel pitch. Reading at 10 f/s, it is found that the sensor has 114 electrons total additive noise, 10(5) electrons full well capacity with shot noise limited operation, and 34% interacting quantum efficiency at 530 nm. Two different structured CsI:Tl phosphors with thickness 95 and 115 microm, respectively, have been optically coupled via a fiber optic plate to the array resulting in two different system configurations. The sensitivity of the two different system configurations was 43 and 47 electrons per x-ray incident on the sensor. The MTF at 10% of the two different system configurations was 9.5 and 9 cycles/mm with detective quantum efficiency of 0.45 and 0.48, respectively, close to zero frequency at approximately 0.44 microC/kg (1.72 mR) detector entrance exposure. The detector was quantum limited at low spatial frequencies and its performance was comparable with high resolution a: Si and charge coupled device based x-ray imagers. The detector also demonstrates almost an order of magnitude lower noise than active matrix flat panel imagers. The results suggest that CMOS active pixel sensors when coupled to structured CsI:Tl can be used for conventional and advanced digital mammography due to their low noise, high resolution performance.

Empirical electro-optical and x-ray performance evaluation of CMOS active pixels sensor for low dose, high resolution x-ray medical imaging.

It has been shown that CMOS imaging technology can be applied to digital autoradiography (AR) as a potential imaging alternative technology to using conventional film emulsion. In this work a thorough investigation on the performance of CMOS technology used in AR is presented. 3H is a particularly important radioisotope used in AR because it can label many sites on biomolecules and provides the highest resolution images due to its low energy and hence low particle range compared to other beta-emitting radioisotopes. In order to detect beta-particles from 3H beta decay a back-thinned CMOS sensor has been used. Back-thinning is a standard process in CCDs but it is not widely applied to CMOS sensors. In this paper the first results of imaging a calibrated 3H microscale and the first tritiated autoradiogram obtained with a back-thinned CMOS sensor at room temperature are presented.

Digital autoradiography imaging using CMOS technology: First tritium autoradiography with a back-thinned CMOS detector and comparison of CMOS imaging performance with autoradiography film

First evidence of phase-contrast imaging with laboratory sources and active pixel sensors

CCD (charged coupled device) and CMOS imaging technologies can be applied to thin tissue autoradiography as potential imaging alternatives to using conventional film. In this work, we compare two particular devices: a CCD operating in slow scan mode and a CMOS-based active pixel sensor, operating at near video rates. Both imaging sensors have been operated at room temperature using direct irradiation with images produced from calibrated microscales and radiolabelled tissue samples. We also compare these digital image sensor technologies with the use of conventional film. We show comparative results obtained with 14C calibrated microscales and 35S radiolabelled tissue sections. We also present the first results of 3H images produced under direct irradiation of a CCD sensor operating at room temperature. Compared to film, silicon-based imaging technologies exhibit enhanced sensitivity, dynamic range and linearity.

Digital autoradiography using room temperature CCD and CMOS imaging technology

A United Kingdom consortium MI3 is founded to develop advanced CMOS image sensors for scientific applications. "Vanilla," a 520520 array of active pixels with 25-m pitch is fabricated in the 0.35- m4 M2P4 metal, 2 poly CMOS process and uses a 3.3-V sup- ply. It has flushed reset circuitry to attain low reset noise and random pixel access for high-speed region-of-interest ROI readout. "OPIC" is a 6472 test structure array of digital pixels with 30-m pitch, fabricated in 0.25- m5 M1P5 metal 1 poly CMOS process with a 3.3/2.5-V sup- ply. It can perform thresholding via an in-pixel comparator for sparse readout at a high frame rate. Characterization of both sensors is per- formed under optical illumination and x-ray exposure. For x-ray charac- terization, both sensors were coupled to a structured thallium-doped ce- sium iodide CsI:Tl scintillator via a fiber optic plate. Vanilla has been found to exhibit 34±3eread noise and a spectral response of 225±5 mA/W at 500 nm and can read a 66 ROI at 24,395 frames/s. OPIC has 46±3eread noise and can perform sparse readout at up to 3700 frames/s. Based on these results, Vanilla could be employed for applications where only a small portion of the image contains relevant information, while OPIC is suited to high-speed imaging applications.

CMOS Monolithic Active Pixel Sensors (MAPS): New ‘eyes’ for science

Two active pixel sensor (APS) architectures have been evaluated for mammography. Firstly, a 525 times 525 APS array of 25 times 25 mum pixels with greater than 80% fill factor, on-pixel analogue buffer amplifier and column parallel 10-bit ADC has been optically coupled to a 115 mum thick CsI:Tl phosphor with columnar structure. Critical performance parameters such as photon transfer curves, MTF, and DQE have been measured. With a readout rate of 10 f/sec, the sensor has a read noise of 114 plusmn 2e- and suffers from read related column FPN. A DQE of 35 % close to zero frequency has been measured for this array. Secondly, a novel APS test structure with on-pixel ADC, i.e. On Pixel Intelligent CMOS (OPIC), has been designed to eliminate the above limitations. This sensor, a 72 times 64 array, is almost free of column FPN, reads at rates more than 3700 f/sec and exhibits 44 plusmn 5 e- read noise. Additionally, a "hit flag" can be set to select only pixels above a threshold for sparse readout. By adjusting the threshold, segmentation of different regions of the image can be performed. The time above threshold can also be recorded, offering a technique to eliminate over-exposed mammograms. Both sensors had 10% MTF at 9 cycles/mm when coated with the structured CsI:Tl. X-ray images displaying the sensors capabilities are also presented.

A Novel Active Pixel Sensor With On-Pixel Analog-to-Digital Converter for Mammography

CCD and CMOS imaging technologies can be applied to thin tissue autoradiography as potential imaging alternatives to using conventional film. In this work, we compare two particular devices; a CCD operating in slow scan mode and a CMOS-based active pixel sensor, operating at near video rates. Both imaging sensors have been operated at room temperature with images produced from calibrated microscales and radio-labelled tissue samples. We also compare these digital imaging technologies with the use of conventional film. We show first comparative results obtained with 14C calibrated microscales and 35S radiolabelled tissue sections. We also present first results of 3H images produced under direct irradiation of a CCD sensor operating at room temperature. Compared to film, silicon-based imaging technologies exhibit enhanced sensitivity, dynamic range and linearity.

Abstract : Scientific applications demand high performance CMOS Active Pixel Sensors. This paper will discuss where critical improvements are needed and describe how to achieve them. Our current drive in image sensor developments stem from the general needs of low-noise, high dynamic range, data sparsification (either on-chip or on-pixel), high rates, radiation hardness, sensor thickness and sensitive area.

Hepatocellular carcinoma (HCC) is one of the most common cancers, with high mortality. Chemotherapy is one of the main treatment options for HCC. However, the high toxicity and poor specificity of chemotherapeutic drugs have limited their clinical application. In this study, dual-ligand liposomes modified with glycyrrhetinic acid (GA) and cyclic arginine-glycine-aspartic acid (cRGD) (GA/cRGD-LP) were designed to target the GA receptor and αvβ3 integrin, respectively. The aim was to develop a highly selective targeted drug delivery system and further enhance the antitumor efficiency of drugs by targeting both hepatic tumor cells and vasculature. A novel lipid conjugate (mGA-DOPE) by coupling dioleoylphosphatidyl ethanolamine (DOPE) with methyl glycyrrhetinic acid (mGA) was synthesized, and its structure was confirmed. The targeting efficiency of GA/cRGD-LP by in vitro cellular uptake and ex vivo imaging was assessed. GA- and cRGD-modified doxorubicin-loaded liposomes (GA/cRGD-LP-DOX) were prepared, and their cytotoxicity in HepG2 and antitumor activity were evaluated. The results showed that the average particle size of the GA/cRGD-LP-DOX was 114 ± 4.3 nm, and the zeta potential was -32.9 ± 2.0 mV. The transmission electron microscopy images showed that the shapes of our liposomes were spherical. cGA/cRGD-LP-DOX displayed an excellent cellular uptake in both HepG2 and human umbilical vein endothelial cells. In the in vivo study, pharmacokinetic parameters indicated that cGA/cRGD-LP can prolong the circulation time of DOX in the blood. GA/cRGD-LP-DOX showed greater inhibition of tumor growth for HepG2-bearing mice than either the single-ligand-modified liposomes or nontargeted liposomes. GA/cRGD-LP-DOX displayed higher liver tumor localization than that of single-ligand-modified liposomes or free DOX. GA/cRGD-LP is a promising drug delivery system for liver cancer targeting and therapy and is worthy of further study.

Dual-Ligand-Functionalized Liposomes Based on Glycyrrhetinic Acid and cRGD for Hepatocellular Carcinoma Targeting and Therapy.

Myogenic tissue nanotransfection improves muscle torque recovery following volumetric muscle loss

Fabrication and use of silicon hollow-needle arrays to achieve tissue nanotransfection in mouse tissue in vivo

Bidirectional cell-cell communication involving exosome-borne cargo such as miRNA, has emerged as a critical mechanism for wound healing. Unlike other shedding vesicles, exosomes selectively package miRNA by SUMOylation of heterogeneous nuclear ribonucleoproteinA2B1 (hnRNPA2B1). In this work, we elucidate the significance of exosome in keratinocyte-macrophage crosstalk following injury. Keratinocyte-derived exosomes were genetically labeled with GFP reporter (Exoκ-GFP) using tissue nanotransfection and were isolated from dorsal murine skin and wound-edge tissue by affinity selection using magnetic beads. Surface N-glycans of Exoκ-GFP were also characterized. Unlike skin exosome, wound-edge Exoκ-GFP demonstrated characteristic N-glycan ions with abundance of low base pair RNA and were selectively engulfed by wound-macrophages (ωmϕ) in granulation tissue. In vitro addition of wound-edge Exoκ-GFP to proinflammatory ωmϕ resulted in conversion to a proresolution phenotype. To selectively inhibit miRNA packaging within Exoκ-GFP in vivo, pH-responsive keratinocyte-targeted siRNA-hnRNPA2B1 functionalized lipid nanoparticles (TLNPκ) were designed with 94.3% encapsulation efficiency. Application of TLNPκ/si-hnRNPA2B1 to murine dorsal wound-edge significantly inhibited expression of hnRNPA2B1 by 80% in epidermis compared to TLNPκ/si-control group. Although no significant difference in wound closure or re-epithelialization was observed, TLNPκ/si-hnRNPA2B1 treated group showed significant increase in ωmϕ displaying proinflammatory markers in the granulation tissue at day 10 post-wounding compared to TLNPκ/si-control group. Furthermore, TLNPκ/si-hnRNPA2B1 treated mice showed impaired barrier function with diminished expression of epithelial junctional proteins, lending credence to the notion that unresolved inflammation results in leaky skin. This work provides insight wherein Exoκ-GFP are recognized as a major contributor that regulates macrophage trafficking and epithelial barrier properties post-injury.

Exosome-Mediated Crosstalk between Keratinocytes and Macrophages in Cutaneous Wound Healing.

Neurogenic tissue Nanotransfection in the Management of Cutaneous Diabetic Polyneuropathy.

The difficulties associated with studying molecular mechanisms important in hemopoietic stem cell (HSC) function such as the problems of purifying homogeneous stem cell populations, have prompted us to adapt the murine ES cell system as anin vitro model of HSC generation and function. We now report that careful analysis of the time course of HSC generation in differentiating ES cells allows them to be used as a source of known and novel hemopoietic gene products. We have generated a subtracted library using cDNA from ES cells collected just prior to and just following the emergence of HSCs. Analysis of this library shows it to be a rich source of known hemopoietic and hemopoietic related gene products with 44% of identifiable cDNAs falling into these camps. We have demonstrated the value of this system as a source of novel genes of relevance to HSC function by characterizing a novel membrane protein encoding cDNA that is preferentially expressed in primitive hemopoietic cells. Intriguingly, further analysis of the known components of the subtracted library is suggestive of erythroid preconditioning of the ES cell-derived HSC. We have used dot-blot andin situ analysis to indicate that this erythroid preconditioning is probably restricted to primitive but not definitive HSC.

Differentiating Embryonal Stem Cells Are a Rich Source of Haemopoietic Gene Products and Suggest Erythroid Preconditioning of Primitive Haemopoietic Stem Cells*

This article practically applies Sherry-Lee Linkon’s ‘half-life of deindustrialisation’ thesis in examining a deindustrialising Scottish community. Linkon contends that, while the most visibly toxic impacts of deindustrialisation have dissipated over time, its lingering effects continue to cause harm in more subtle ways. Utilising qualitative research from a national study on the community impacts of organised crime, I consider the ways in which the long-term legacies of deindustrialisation and disinvestment manifest in the lived experiences of residents of Tunbrooke (pseudonym). I assess three areas where Linkon’s half-life can be observed in Tunbrooke: the physical environment; poverty, addiction and mental ill-health; and external stigmatisation. I argue that, for those living in Tunbrooke, these processes shape their day-to-day lives, along with the omnipresent threat posed by organised crime and regular episodes of violence. However, rather than passively accepting this, there is opposition to the external view of the locality as ‘a violent shithole’, with an emphasis on the kinship and solidarity through adversity. I argue that the responses of Tunbrooke residents are framed through a lasting communal working-class identity, which has been strengthened as the area experienced the fallout of the half-life of deindustrialisation and the recent impacts of political austerity.

‘People just dae wit they can tae get by’: Exploring the half-life of deindustrialisation in a Scottish community

Political discourse in contemporary Scotland increasingly revolves around the vision of a ‘New Scotland’, more prosperous and meritocratic than the rest of the United Kingdom. This has a convoluted relationship with Scotland’s industrial past, and specifically the social dislocation experienced through deindustrialisation. This article analyses the deployment of this narrative within regeneration efforts in former industrial communities in Lanarkshire and Inverclyde, West Central Scotland, before counterpoising it with the reflections of former industrial workers and their families. It does so through an analysis of monuments to the industrial past, comparing those erected as part of regeneration schemes by local authorities with community efforts to commemorate past struggles and industrial disasters. This examination is accompanied by the use of oral history narratives to argue that there are two distinct understandings of the nature of place, space, struggles over social justice and communal identities within these localities, which lean heavily on the memory of the industrial past in contrasting ways.

Voices of social dislocation, lost work and economic restructuring: Narratives from marginalised localities in the ‘New Scotland’

Networked territorialism: the routes and roots of organised crime

The collapse of the residential housing market in 2007 brought with it a wave of foreclosures. Subprime borrowers, who were once elated by loans they secured from lenders, suddenly found themselves strangled by the predatory terms of their newfound loans and ultimately became unable to pay their outstanding loan balance. Amidst a growing number of residential foreclosures, lenders discovered the financial downside of foreclosing on residential properties — though this realization often surfaced after the foreclosure proceeding had commenced — and began to delay, or halt, foreclosure sales altogether. These purposeful maneuvers by lenders resulted in borrowers’ continued legal liability for a residential property, a property which borrowers believed they had lost as a result of the lender’s foreclosure; in other words, a “zombie mortgage.”This Comment analyzes the different circumstances under which lenders can foster the creation of zombie mortgages. Particularly, this Comment focuses on stalled and incomplete residential foreclosure sales and failures to execute deeds of sale, tactics which serve to maintain legal liability of the mortgaged property on a borrower. Notwithstanding a lender’s right to foreclose on residential property to satisfy the obligations that it is owed under a promissory note, this Comment argues that strategic delays in completing a foreclosure sale entitle state courts and legislatures to either (1) force a lender to complete a sale or (2) divest a lender from both its right to foreclose and its security interest. Though some other solutions for zombie mortgages have been proposed, this Comment urges courts and legislatures to look outside criminal sanctions and nuisance abatement actions when developing strategies to eradicate zombie mortgages. Through judicial and legislative intervention, lenders would be incentivized to complete the foreclosure proceeding, or risk losing their security interests in the mortgaged property.

Amidst the Walking Dead: Judicial and Nonjudicial Approaches for Eradicating Zombie Mortgages

The Sutter Butte Flood Control Agency (SBFCA) Finance Committee Members, met on the above date at 1 p.m. at the SBFCA office, 1441 Garden Highway, Yuba City, California.

Containment in the City: Boundaries, Bodies, and the Politics of Urban Space

The organization of urban space accommodating the rapid movement of the automobile facilitates a kind of forgetting, through the act of driving, and creates a sense of containment, through the built environment itself. If this is so, how does this occur? What is the relationship between movement, memory, and containment? How do these kinds of material conditions reflect and reproduce the spatial segregation of different bodies? What are the implications of such spaces on the body and society, the body politic? Using Kansas City as a case study, these questions will be addressed in this project. In the spring of 2010, twenty-three interviews were conducted with urban planners, architects, developers, consultants, real estate agents, civic leaders, and community organizations, all of whom were asked to geographically define downtown and discuss urban redevelopment in Kansas City. Downtown was often defined by the highways that surround it, and streets, cars, parking, driving, and transit were unavoidable topics of discussion. What are the implications of the prevalence of highways in urban space for the body, movement, engagement, and society? I propose that as active, human agents orient to material boundaries in urban space, such as drivers on a highway, a sense of containment and passivity, even fear, is produced as

Containment in the city: Highways, boundaries, bodies, and the politics of urban space

1. Supernatant media from cultures of unstimulated human peripheral blood mononuclear cells contained one or more factors that increased by several hundred-fold the production of prostaglandin E by fibroblast-like cells derived from both inflamed and normal human gingival tissue. 2. This stimulation occurred in a dose-dependent manner and was completely inhibited by 14 microM-indomethacin. 3. Responsiveness to the factor declined as the age of the cell culture increased. 4. An increase in prostaglandin E production was first observed after a 2h exposure to the mononuclear cell factor(s) and could be prevented by cycloheximide. 5. Brief exposure (0.5 and 1.0 h) to mononuclear cell factor did not increase prostaglandin E production by the cells in a subsequent 72 h incubation in the absence of mononuclear cell factor. 6. Addition of arachidonate (10 microM and 15 microM) further enhanced stimulation of prostaglandin E production in response to mononuclear cell factor. 7. The stimulatory activity was resistant to digestion by trypsin, but was heat-labile, so that only 17% remained after treatment at 56 degrees C for 30 min.

Stimulation of production of prostaglandin E in gingival cells exposed to products of human blood mononuclear cells.

An assessment of erythrocyte migration times and serum cholesterol levels as indices in myocardial infarction.

Concerning nicotinic add. On the nutritional effects inhibiting factors in food. 6.

Concerning Nicotinic Acid. Article Six: On the Nutritional Effects of Inhibitory Factors in Food.

On the Individual Resistance of Animals to the Effects of Poisonous Food Plants.

Effects Arising from Inhibition of Cellular Activities. No. 3.-Selenium.

A preliminary note on the inhibitory effects of chronic poisoning by foods containing cyanic substances.

Climate, diet, and toxic substances in their association with adrenal condition.

Report on the effects of certain poisons contained in food-plants of West Africa upon the health of the native races.

The presence of a sapotoxin in Xanthosoma atrovirens, a tropical food-tuber.

17. On Local Inflammation in Certain Defined Conditions as Causes of Pulmonary Phthisis

An examination of the effects of feeding rats upon tannia, a member of the family arace˦

L'invention concerne un appareil et des procedes pour produire et administrer un medicament en phase vapeur. Un exemple d'appareil de l'invention comprend : une entree de gaz pour recevoir un gaz provenant d'une source de gaz mis sous pression ; une chambre pour recevoir un medicament liquide en son sein, la chambre etant en communication avec l'entree de gaz pour permettre l'entree et la dilatation du gaz dans la chambre en presence du medicament liquide pour produire le medicament en phase vapeur ; et une sortie de vapeur en communication avec la chambre pour administrer le medicament en phase vapeur.

Appareil et procédés pour produire et administrer un médicament en phase vapeur

La presente invention concerne un emballage a film flexible qui possede une ouverture refermable. L'emballage est compose d'un film flexible qui possede au moins une premiere couche de film et une seconde couche de film, avec un adhesif refermable dispose entre des parties de la premiere et de la seconde couche de film. Le film flexible definit au moins une partie d'une cavite interieure dans laquelle un contenu, comme des produits alimentaires distincts, peut etre stocke, et une ouverture de l'emballage permet d'acceder aux produits alimentaires distincts. De plus, l'emballage possede une ouverture segmentee munie d'une pluralite de fenetres d'ouverture separees par au moins un element transversal qui s'etend d'un cote de l'ouverture vers l'autre cote.

The alternative sigma factor SigL (Sigma-54) facilitates bacterial adaptation to the extracellular environment by modulating the expression of defined gene subsets. A homolog of the gene encoding SigL is conserved in the diarrheagenic pathogen Clostridioides difficile. To explore the contribution of SigL to C. difficile biology, we generated sigL-disruption mutants (sigL::erm) in strains belonging to two phylogenetically distinct lineages – the human-relevant Ribotype 027 (strain BI-1) and the veterinary-relevant Ribotype 078 (strain CDC1). Comparative proteomics analyses of mutants and isogenic parental strains revealed lineage-specific SigL regulons. Concomitantly, loss of SigL resulted in pleotropic and distinct phenotypic alterations in the two strains. Sporulation kinetics, biofilm formation, and cell surface-associated phenotypes were altered in CDC1 sigL::erm relative to the isogenic parent strain, but remained unchanged in BI-1 sigL::erm. In contrast, secreted toxin levels were significantly elevated only in the BI-1 sigL::erm mutant relative to its isogenic parent. We also engineered SigL overexpressing strains and observed enhanced biofilm formation in the CDC1 background, and reduced spore titers as well as dampened sporulation kinetics in both strains. Thus, we contend that SigL is a key, pleiotropic regulator that dynamically influences C. difficile’s virulence factor landscape, and thereby, its interactions with host tissues and co-resident microbes. Contribution to the Field Alternative sigma factors modulate bacterial gene expression in response to environmental and metabolic cues. C. difficile encodes multiple alternative sigma factors which mediate critical cellular processes. A Sigma-54 ortholog, SigL, is conserved across all sequenced strains, yet its function remains to be elucidated. We demonstrate that SigL dynamically influences C. difficile biology in fundamental, but distinct, ways in two strains representing two clinically-relevant C. difficile phylogenetic lineages (ribotypes). Loss of SigL results in changes in sporulation kinetics, biofilm formation, alterations in cell surface properties, and secreted toxin levels in a strain-specific manner. SigL overexpression, however, uniformly impedes sporulation. Thus, SigL plays a fundamental role in regulating the expression of C. difficile virulence factors and likely profoundly impacts pathogenesis in a strain-specific manner.

The Alternative Sigma Factor SigL Influences Clostridioides difficile Toxin Production, Sporulation, and Cell Surface Properties

Morbidity and mortality attributed to Clostridium difficile infection (CDI) have increased over the past 20 years. Currently, antibiotics are the only US FDA-approved treatment for primary C. difficile infection, and these are, ironically, associated with disease relapse and the threat of burgeoning drug resistance. We previously showed that non-toxin virulence factors play key roles in CDI, and that colonization factors are critical for disease. Specifically, a C. difficile adhesin, Surface Layer Protein A (SlpA) is a major contributor to host cell attachment. In this work, we engineered Syn-LAB 2.0 and Syn-LAB 2.1, two synthetic biologic agents derived from lactic acid bacteria, to stably and constitutively express a host-cell binding fragment of the C. difficile adhesin SlpA on their cell-surface. Both agents harbor conditional suicide plasmids expressing a codon-optimized chimera of the lactic acid bacterium’s cell-wall anchoring surface-protein domain, fused to the conserved, highly adherent, host-cell-binding domain of C. difficile SlpA. Both agents also incorporate engineered biocontrol, obviating the need for any antibiotic selection. Syn-LAB 2.0 and Syn-LAB 2.1 possess positive biophysical and in vivo properties compared with their parental antecedents in that they robustly and constitutively display the SlpA chimera on their cell surface, potentiate human intestinal epithelial barrier function in vitro, are safe, tolerable and palatable to Golden Syrian hamsters and neonatal piglets at high daily doses, and are detectable in animal feces within 24 h of dosing, confirming robust colonization. In combination, the engineered strains also delay (in fixed doses) or prevent (when continuously administered) death of infected hamsters upon challenge with high doses of virulent C. difficile. Finally, fixed-dose Syn-LAB ameliorates diarrhea in a non-lethal model of neonatal piglet enteritis. Taken together, our findings suggest that the two synthetic biologics may be effectively employed as non-antibiotic interventions for CDI.

An Engineered Synthetic Biologic Protects Against Clostridium difficile Infection

ABSTRACT Mesothelin is a glycosylphosphatidylinositol (GPI)-anchored membrane protein that shows promise as a target for antibody-directed cancer therapy. High levels of soluble forms of the antigen represent a barrier to directing therapy to cellular targets. The ability to develop antibodies that can selectively discriminate between membrane-bound and soluble conformations of a specific protein, and thus target only the membrane-associated antigen, is a substantive issue. We show that use of a tolerance protocol provides a route to such discrimination. Mice were tolerized with soluble mesothelin and a second round of immunizations was performed using mesothelin transfected P815 cells. RNA extracted from splenocytes was used in phage display to obtain mesothelin-specific antigen-binding fragments (Fabs) that were subsequently screened by flow cytometry and ELISA. This approach generated 147 different Fabs in 34 VH-CDR3 families. Utilizing competition assays with soluble protein and mesothelin-containing serum obtained from metastatic cancer patients, 10 of these 34 VH-CDR3 families were found to bind exclusively to the membrane-associated form of mesothelin. Epitope mapping performed for the 1H7 clone showed that it does not recognize GPI anchor. VH-CDR3 sequence analysis of all Fabs showed significant differences between Fabs selective for the membrane-associated form of the antigen and those that recognize both membrane bound and soluble forms. This work demonstrates the potential to generate an antibody specific to the membrane-bound form of mesothelin. 1H7 offers potential for therapeutic application against mesothelin-bearing tumors, which would be largely unaffected by the presence of the soluble antigen.

A new anti-mesothelin antibody targets selectively the membrane-associated form

Mo1676 Flagellar Glycosylation Influences Motility, Flagellar Assembly, and Toxin Production in Clostridium difficile

Mo1868 Role of Rpon (σ54) in the Regulation of Clostridium difficile Gene Expression and Growth

Sortase A is a transpeptidase expressed by Staphylococcus aureus (S. aureus) that covalently attaches with bacterial proteins encoded in a LPXTG motif to the pathogen surface. Sortase A functionally coats the pathogen with needed receptors and ligands that promote virulence of S. aureus. Although the majority of nosocomial infections are caused by S. aureus , there remain challenges in the clinical detection of the pathogen due to the non-specific methods used to diagnose these invasive infections. The development of pathogenspecific, non-invasive probes that target particular bacteria would provide a more effective alternative to diagnosing and monitoring clearance of S. aureus infections. Here we test whether a Forster resonance energy transfer (FRET) substrate containing a central LPXTG motif could be used to determine the presence or absence of the enzyme produced by dangerous pathogens in tissue biopsy samples. Initially, we expressed recombinant sortase A and compared the activity of our recombinant (sortase A)-His 6 with previous kinetic parameters for the enzyme. Analysis indicated our (sortase A)-His 6 had a K m of 10 µM for the LPXTG-containing FRET substrate, DABCYL-LPETGEDANS and its phenotypic enhancement in the presence of calcium ions. In a prelude to our in vivo experiments, we tested sortase A activity of lysates from several S. aureus strains to correlate the relative concentrations of sortase A produced by each S. aureus strain, namely Tager 104, RF122, and Xen29. As proof-of-principle for its use as a clinical diagnostic tool, an intramuscular infection of S. aureus Xen29 was established in albino C57BL/6 mice and tissue biopsies were performed. We determined the relative sortase A activity of whole tissue extracts isolated from the spleen, kidneys, and infection site of these animals and compared our results to control uninfected tissue. Our findings suggest that sortase A activity can be used as an indicator of the presence of S. aureus from tissue, which implies significant diagnostic potential.

Changes in expression of genes related to development of pulmonary arterial hypertension in lung tissue derived from a rat model of type 2 diabetes

Clostridium difficile infection is the leading cause of antibiotic- and healthcare-associated diarrhea, and its containment and treatment imposes a significant financial burden, estimated to be over $3 billion in the USA alone. Since the year 2000, CDI epidemics/outbreaks have occurred in North America, Europe and Asia. These outbreaks have been variously associated with, or attributed to, the emergence of Clostridium difficile strains with increased virulence, an increase in resistance to commonly used antimicrobials such as the fluoroquinolones, or host susceptibilities, including the use of gastric acid suppressants, to name a few. Efforts to elucidate C. difficile pathogenic mechanisms have been hampered by a lack of molecular tools, manipulatable animal models, and genetic intractability of clinical C. difficile isolates. However, in the past 5 y, painstaking efforts have resulted in the unraveling of multiple C. difficile virulence-associated pathways and mechanisms. We have recently reviewed the disease, its associated risk factors, transmission and interventions (Viswanathan, Gut Microbes 2010). This article summarizes genetics, non-toxin virulence factors, and host-cell biology associated with C. difficile pathogenesis as of 2011, and highlights those findings/factors that may be of interest as future intervention targets.

Transcriptional noise is known to play a crucial role in heterogeneity in bacteria and yeast. Mammalian macrophages are known to exhibit cell-to-cell variation in their responses to pathogens, but the source of this heterogeneity is not known. We have developed a detailed stochastic model of gene expression that takes into account scaling effects due to cell size and genome complexity. We report the results of applying this model to simulating gene expression variability in mammalian macrophages, demonstrating a possible molecular basis for heterogeneity in macrophage signalling responses. We note that the nature of predicted transcriptional noise in macrophages is different from that in yeast and bacteria. Some molecular interactions in yeast and bacteria are thought to have evolved to minimize the effects of the high-frequency noise observed in these species. Transcriptional noise in macrophages results in slow changes to gene expression levels and would not require the type of spike-filtering circuits observed in yeast and bacteria.

Transcriptional noise and cellular heterogeneity in mammalian macrophages

The cytokine tumour necrosis factor (TNF)α is a vital mediator of the innate immune response, and a pleiotropic regulator of cellular function. Its involvement in rheumatoid arthritis is illustrated by the clinical benefits of TNFα blockade. Post-transcriptional regulation (the control of mRNA stability and translation) appears to play a critical role in the regulation of TNFα expression by mitogen activated protein kinase signal transduction pathways and by anti-inflammatory agents. The aim of this article is to review some recent advances in our understanding of these processes, and to speculate on mechanisms of regulation of TNFα and other pro-inflammatory genes.

Commentary Post-transcriptional regulation of pro-inflammatory gene expression

Post-transcriptional regulation of pro-inflammatory gene expression

Transfer factor in Hodgkin's disease: a randomized clinical and immunological study.

Phosphonoformate (PFA; a pyrophosphate analogue) is an effective inhibitor of the reverse transcriptase enzyme in many animal retroviruses. In vitro studies have shown that PFA is also an effective inhibitor of HIV (HTLV III/LAV) at doses readily attainable in vitro. A pilot study was therefore performed with a 3-week intravenous infusion of PFA in 11 patients with AIDS and AIDS-related complex (ARC). Viral isolations were performed before and at regular intervals up to 3 months post-infusion on treated patients, as well as on four untreated control patients. Virus isolation was negative after therapy in eight patients, six of whom were negative throughout the follow-up period. Virus was isolated on 70% of attempts from the four control subjects and on 20% of attempts from treated subjects. Three patients showed an improvement in delayed hypersensitivity responses. No obvious improvement was seen in patients' OKT4 positive lymphocyte counts. Treatment was not limited by side-effects with the exception of one patient who developed an axillary vein thrombosis within 4 days of treatment via a subclavian line. Treatment was therefore discontinued following administration of only one dose and the patient was excluded from further study. A further patient had reversible renal dysfunction. Other side-effects were minor, consisting of headache or thrombophlebitis at the site of infusion. These results suggest that a further trial with PFA administered over a longer period and with a longer follow-up period in AIDS and ARC patients may be warranted, particularly if an oral preparation becomes available.(ABSTRACT TRUNCATED AT 250 WORDS)

Phosphonoformate (foscarnet): a pilot study in AIDS and AIDS related complex.

Mice were infected intraperitoneally with a low virulence strain of Toxoplasma gondii (TO) and transfer factor (TF) was prepared from the spleens of infected (TFT) and uninfected control mice (TFC). Three experimental groups of 12 mice were given either saline, TFC or TFT, by intraperitoneal injection. After 24 h half of each group of these animals were infected by intraperitoneal injection of TO cysts. In three separate experiments animals were killed at 11, 28 and 35 days and the flank and axillary nodes removed for histological examination. There was generalized lymph node enlargement with cortical and paracortical expansion. In most animals there was diffuse infiltration of the nodes by clusters of histiocytes. Administration of TFC alone led to a mild increase in node size at 11 and 28 days. Administration of TFT alone had a moderate stimulatory effect on the mouse lymph nodes with a significant increase in size at 11 days due predominantly to expansion of the paracortex. Administration of TFT and TFC followed by inoculation of TO led to an increased and more consistent histiocyte response and an increased number of paracortical T blasts compared with animals given TO alone. TFT and TFC had no demonstrable protective effect in experimental murine toxoplasmosis as assessed by quantitation of toxoplasma brain cysts. The effect of transfer factor was not antigen specific in this system.

The effect of transfer factor on lymph node morphology in murine toxoplasmosis.

Saliva was found to be a powerful and specific inhibitor of Neisseria gonorrhoeae. Although 28 other species of bacteria were tested, including Neisseria meningitidis, Neisseria pharyngis var flava, Neisseria lactamica, and Neisseria catarrhalis, we failed to find any others sensitive to saliva under similar conditions. The physical properties of the inhibitory substance indicated that it might be salivary alpha-amylase. To test this hypothesis alpha-amylase was extracted from saliva and was shown to have a high antigonococcal activity. Hog pancreas alpha-amylase also showed strong antigonococcal activity, thus the observations indicate that for the strains we tested alpha-amylase is inhibitory to gonococci. This observation indicates that either the gonococcal outer cell wall contains some unique lipopolysaccharides or that the gonococcus is unusually dependent on the integrity of these moieties. Whichever speculation proves to be true it indicates a need for a careful study of the gonococcal cell wall.

Coupling, Constitution and the Cognitive Kind: A Reply to Adam and Aizawa

# Sir John David Nunes Nabarro {#article-title-2}

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Former consultant physician Middlesex Hospital, 1954-81 ( b London 1915; q UCL 1938; MD, FRCS), d 28 April 1998. The son of a pathologist, he was an extremely good general physician combining clinical skills with a scientific approach. John quickly realised the possibilities for exploiting the development of radioimmunoassays for peptide hormones and techniques for measuring thyroid and steroid hormones. He trained a large number of endocrinologists, many of whom rose to positions of distinction in Britain and abroad. An incredible hard worker he set a pace that tested the juniors who were fortunate enough to work with him. He was pre-eminent in clinical endocrinology and made major contributions to the studies of the pituitary and the treatment of pituitary disease, to analysis of adrenal function and dysfunction, and to reproductive endocrinology. At the same time he made important contributions to the field of diabetes, particularly in the management of diabetic keto-acidosis and the use of oral hypoglycaemic agents and new insulins. When he retired he became director of the Institute of Clinical Sciences. John was chairman of the executive council of the British Diabetic Association—he persuaded the government to give free prescriptions for disposable syringes and blood glucose test strips—a senior vice president of the Royal College of Physicians, 1977-9, and chairman of the Joint Consultants Committee, 1979-82. This involved critical discussions with the Department of Health, and during his chairmanship important decisions were made about the training of junior doctors, not the least was persuading people that there had to be a closer balance between the numbers being trained and the opportunities at consultant level. One of his chief interests was philately, particularly of the Netherlands. He leaves a wife, Joan (also a doctor); two sons; and two daughters.

# Edoardo Parma {#article-title-3}

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General practitioner Milan ( b 1955; q Milan 1979), died from …

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Sir John David Nunes NabarroEdoardo ParmaMary Veronica Porter (n£e Burdett-Smith)Anthony Watson PurdieRory SadlerNorah Patricia SherlockMichael Edward SkinnerMark SticklandJohn WallaceWilliam Derek WylieStuart Young

This paper presents an active inference based simulation study of visual foraging. The goal of the simulation is to show the effect of the acquisition of culturally patterned attention styles on cognitive task performance, under active inference. We show how cultural artefacts like antique vase decorations drive cognitive functions such as perception, action and learning, as well as task performance in a simple visual discrimination task. We thus describe a new active inference based research pipeline that future work may employ to inquire on deep guiding principles determining the manner in which material culture drives human thought, by building and rebuilding our patterns of attention.

The Acquisition of Culturally Patterned Attention Styles Under Active Inference

Musical harmony is considered to be one of the most abstract and technically difficult parts of music. It is generally taught formally via abstract, domain-specific concepts, principles, rules and heuristics. By contrast, when harmony is represented using an existing interactive desktop tool, Harmony Space, a new, parsimonious, but equivalently expressive, unified level of description emerges. This focuses not on abstract concepts, but on concrete locations, objects, areas and trajectories.
 This paper presents a design study of a prototype version of Harmony Space driven by whole body navigation, and characterizes the new opportunities presented for the principled manipulation of chord sequences and bass lines. These include: deeper engagement and directness; rich physical cues for memory and reflection, embodied engagement with rhythmic time constraints; hands which are free for other simultaneous activities (such as playing a traditional instrument); and qualitatively new possibilities for collaborative use.

Running up Blueberry Hill: prototyping whole body interaction in harmony space

We describe the motivations behind the E-Sense project which will investigate augmented perception by building a range of novel tactile interfaces. As well as exploring the practical utility of these systems for real world tasks, we are particularly interested in the following question: how can we design tactile interfaces to mediate novel sensory information so that the user experiences the technology as an extension of themselves? Author Keywords E-Sense, extended mind, transparent technologies, tactile interface

Feel the force: Using tactile technologies to investigate the extended mind

What is the relation between the material, conventional symbol structures that we encounter in the spoken and written word, and human thought? A common assumption, that structures a wide variety of otherwise competing views, is that the way in which 10 these material, conventional symbol-structures do their work is by being translated into some kind of content-matching inner code. One alternative to this view is the tempting but thoroughly elusive idea that we somehow think in some natural language (such as English). In the present treatment I explore a third option, which I shall call the ‘‘complementarity’’ view of language. According to this third view the actual symbol 15 structures of a given language add cognitive value by complementing (without being replicated by) the more basic modes of operation and representation endemic to the biological brain. The ‘‘cognitive bonus’’ that language brings is, on this model, not to be cashed out either via the ultimately mysterious notion of ‘‘thinking in a given natural language’’ or via some process of exhaustive translation into another inner code. Instead, 20 we should try to think in terms of a kind of coordination dynamics in which the forms and structures of a language qua material symbol system play a key and irreducible role. Understanding language as a complementary cognitive resource is, I argue, an important part of the much larger project (sometimes glossed in terms of the ‘‘extended mind’’) of understanding human cognition as essentially and multiply hybrid: as involving 25 a complex interplay between internal biological resources and external non-biological resources.

 In 2015, while coring in the carbonate reservoir in the second appraisal well on an oil and gas discovery in the Barents Sea (386 m water depth), the drill string fell 2 meters and a total mud loss was experienced leading to a well control incident. As a result, since 2016, the operator has introduced and used the Controlled Mud Level (CML) system. To date this system has been used on seven wells including two further appraisal wells on the same field and five exploration wells in the area.
 In 2017 it was decided to drill a horizontal well in the same carbonate reservoir and to perform an extended production test in close proximity to the original loss well. Since it is not possible to predict where large voids (karsts) and natural fractures could be encountered, contingency to handle high losses, had to be implemented for the horizontal well. During the well planning, further risk reducing measures were implemented, including the use of wired drill pipe to improve the management of the wellbore pressure profile. This paper describes the planning processes leading up to the operation and the highlights of the operation itself together with the lessons learned. It elaborates on how wired pipe, used in combination with the CML system, added value to the operation. It shows how it was possible to drill the reservoir section with a low overbalance while managing severe losses associated with open karsts and natural fractures and still maintaining the fluid barrier. Despite the severe losses encountered it was possible to safely drill and complete the well without any well control event by use of the CML system.

Experience from Drilling a Horizontal Well in a Naturally Fractured and Karstified Carbonate Reservoir in the Barents Sea Using a CML MPD System

Microplastics are widespread contaminants in terrestrial environments but comparatively little is known about interactions between microplastics and common terrestrial contaminants such as zinc (Zn). In adsorption experiments fragmented HDPE bags c. one mm2 in size showed similar sorption characteristics to soil. However, when present in combination with soil, concentrations of adsorbed Zn on a per mass basis were over an order of magnitude lower on microplastics. Desorption of the Zn was minimal from both microplastics and soil in synthetic soil solution (0.01 M CaCl2), but in synthetic earthworm guts desorption was higher from microplastics (40-60%) than soil (2-15%), suggesting microplastics could increase Zn bioavailability. Individual Lumbricus terrestris earthworms exposed for 28 days in mesocosms of 260 g moist soil containing 0.35 wt % of Zn-bearing microplastic (236-4505 mg kg-1) ingested the microplastics, but there was no evidence of Zn accumulation, mortality, or weight change. Digestion of the earthworms showed that they did not retain microplastics in their gut. These findings indicate that microplastics could act as vectors to increase metal exposure in earthworms, but that the associated risk is unlikely to be significant for essential metals such as Zn that are well regulated by metabolic processes.

Plastic Bag Derived-Microplastics as a Vector for Metal Exposure in Terrestrial Invertebrates.

From the Proceedings of the 1998 Meetings of the Hydrology Section - Arizona-Nevada Academy of Science - April 18, 1998, Glendale Community College, Glendale, Arizona

The last two decades have seen a fundamental shift in the manufacturing, sourcing and operation of technology, which has raised concerns in state security agencies about the cybersecurity risk to government and critical infrastructure. Sophisticated cyber attacks continue to be launched by state actors worldwide, while the engineering practices in common use have failed to deliver a commensurate improvement in technology cyber security. Cyber attacks continue to be successful against commercial networks, leading the US Government to encourage government agencies to look towards models such as zero-trust networking and tailored trustworthy spaces. There has been progress in product engineering, with formal methodologies such as Correctness by Construction (CbyC) successfully producing commercial products with increased trustworthiness. However, the adoption of these techniques has been limited, and governments are now increasingly resorting to an approach of technology Balkanization, where import and use of products and components may be restricted based on their country of origin. Even in the early stages of this strategy, the effect upon the economy is significantly adverse. We propose an alternative to technology Balkanization by combining trustworthy engineering approaches with the use of a national security component we call a sanctum which together can deliver sovereign trust.

W3C has been working on the standardization of XML Encryption and released its specification as a W3C Proposed Recommendation in 2002. There are several implementations of the specification, all of which are implemented using DOM. However, it is commonly accepted that DOM has higher costs in time and space than other APIs. Also, even if SAX is used, with this kind of API, it is impossible to parse decrypted data both efficiently and correctly. Therefore, we thought of using the Xerces Native Interface (XNI) of Xerces2. Using this API, we prototyped a stream-based implementation of the specification. We also evaluated its performance. As compared with a DOM-based implementation, it achieves a 0.27%--26% reduction in processing time (i.e., 1.0x-1.3x performance) for encryption of XML documents with sizes larger than 2 KB, and 34%-88% (i.e., 1.5x-8.5x) for decryption of XML documents with any sizes.

A toolkit for configuring agent based applications is presented. Each agent comprises several components (some generic, some agent specific). All the components run as separate internal processes and communicate via an internal active message board component This indirect method of communication allows us to more easility mix and match components. The code for all the components that can be assembled into an agent are held on a code server. Standard or often used configurations of components can be symbolically described and stored with a suitable name in an agent library. Finally, an agent management platform allows a user to specify that a particular named type of agent should be launched on a particular machine. The platform will pull down the description for the agent library, pull down the code for the components for the code server, and launch the agent as an integrated set of component processes on the machine.

Title: Distinct tissue macrophage subsets regulate inflammation and provide a cellular and molecular mechanism for disease remission in rheumatoid arthritis. Abstract Treatment-refractory Rheumatoid Arthritis (RA) is a major clinical challenge. Drug-free remission is uncommon but provides proof-of-concept that articular immune-homeostasis can be reinstated. Here we identify active cellular and molecular mechanisms of sustained remission in RA. Single-cell transcriptomics (31,000 cells) identified phenotypic changes in synovial tissue macrophage (STM) populations spanning health, early/active RA, treatment-refractory RA, and RA in sustained remission. Each clinical state is characterised by different frequencies of 9 discrete phenotypes of 4 distinct STM populations with diverse homeostatic, regulatory and inflammatory functions. This cellular atlas combined with phenotypic and functional analyses of synovial biopsy FACS-sorted STM clusters reveal two STM subpopulations (MerTK/TREM2/TIM4 pos and MerTK/FOLR2/LYVE1 pos ) with unique remission transcriptomic signatures enriched in negative regulators of inflammation. In response to danger signals these cells are potent producers of inflammation-resolving lipid mediators, and engagement of their MerTK pathway restricts synovial fibroblasts activation. A low proportion of MerTK pos STMs of RA patients in remission is predictive of flare. Therapeutic modulation targeting MerTK pos STM-subsets could encourage resolution of inflammation and aberrant remodelling and reinstate synovial homeostasis in inflammatory arthritis. health, inflammation and disease remission and uncovered MerTK-dependent active mechanisms of remission driven by tissue resident STMs. This study provides a comprehensive description of the functional biology of human synovial tissue macrophages in health, autoimmune synovitis and sustained disease remission. This was based on integrated analysis of scRNAseq of >32,000 STMs from 25 synovial biopsies, FACS-phenotyping of STMs from 112 biopsies, and functional analysis of STMs from 47 biopsies. This spanned healthy homeostasis and early undifferentiated joint inflammation (UPA), treatment-naïve early RA, treatment-resistant RA and RA in sustained remission. Multiparameter flow cytometry uncovered that STMs consisted of two main populations; positive and negative for MerTK/CD206. ScRNAseq confirmed that these populations sit on distinct cell trajectory branches, and uncovered deep phenotypic and functional heterogeneity in both, revealing RA stage-specific mechanisms of pathogenesis and of remission. The MerTK/CD206 pos STMs are dominant in healthy tissue and RA in disease remission while MerTK/CD206 neg STMs are enriched in active RA. Their relative proportion in remission is predictive of persistent remission versus flare upon drug withdrawal. Patients disease remission STMs flare after treatment This can be linked to distinct functions of two populations. neg STMs alarmins. cells lipid controls stromal that intercellular cross-talk MerTK/CD206 pos and during maintain joint

Title: Distinct tissue macrophage subsets regulate inflammation and provide a cellular and molecular mechanism for disease remission in rheumatoid arthritis

Distinct tissue macrophage subsets regulate inflammation and provide a novel cellular and molecular mechanism for disease remission in rheumatoid arthritis

Background: We recently uncovered heterogeneity in human synovial tissue macrophages during inflammation and resolution of inflammation (remission) in rheumatoid arthritis (RA). The transcriptomic profiles of distinct macrophage subpopulations suggest distinct functions, ranging from inflammatory to regulatory. Prior studies propose reciprocal interactions between macrophages and synovial fibroblasts (FLS) exist in the joint; however, the exact contribution of these interactions to synovial pathology or resolution of inflammation remains unknown. Objectives: The aim of this study was to examine the functional interactions between different macrophage phenotypes and synovial fibroblasts. Methods: To model different macrophage phenotypes, monocyte-derived macrophages (MODM) were pre-stimulated (16h) with LPS (100ng/ml) to model inflammatory macrophages or with dexamethasone (Dex, 1μM) to model regulatory macrophages. After extensive washing, MODM were co-cultured with RA FLS for different periods of time. Prior to co-culture, FLS and MODM were labelled with CellTraceTM-Violet and CellTraceTM-Red, respectively. After 24 & 48 hours of co-culture, FLS and MODM were sorted based on positivity for CellTraceTM Violet (FLS) or Far Red (MODM) using FACS ARIA III, and expression of IL-6 and MMP1 in FLS analysed by ultrasensitive qPCR. In addition, the levels of IL-6 and MMP3 proteins were evaluated in co-culture supernatants by ELISA. To investigate the nature of the contact (40min meandering velocity) of individual MODMs on FLS monolayers was evaluated using Delta Vision fluorescence microscopy. Results: FLS co-cultured with MODM showed an increased mRNA expression of IL-6 at both 24 and 48h, and MMP1 at 48h, compared to FLS cultured alone. This expression pattern was decreased when MODM were pre-treated with Dex and significantly up regulated when MODM were pre-treated with LPS. Consistently with mRNA expression, IL-6 protein was significantly increased when FLS were co-cultured with MODM (1192±137pg/ml) as compared to FLS cultured alone (445±78pg/ml). This production was significantly augmented when MODM were pre-treated with LPS (1985±25 pg/ml) and decreased when MODM were pre-treated with Dex (729±62pg/ml). Similarly, MMP3 protein level was increased when FLS were co-cultured with MODM (256±10pg/ml) as compared to FLS cultured alone (123±1 pg/ml). This production was significantly augmented when MODM were pre-treated with LPS (1960±34pg/ml) and decreased when MODM pre-treated with Dex (164±2pg/ml). These distinct effects of MODM phenotypes on FLS function were associated with different dynamics of their interactions. Our preliminary data reveal that MODM are quiescent on FLS monolayers unless MODM are pre-treated with Dex, which induced a patrolling behaviour. Conclusion: Macrophages can actively increase or limit activation of FLS, depending on their inflammatory or regulatory phenotypes, respectively. These observations indicate the potential for different subsets of synovial tissue macrophages to drive or resolve synovial inflammation by influencing the stromal compartment. References [1] Elmesmari A, Alivernini S, et al., Synovial tissue of RA patients in remission contains a unique population of regulatory macrophages. Annals of the Rheumatic Diseases, 2017;76 (Suppl2) 138-139. Disclosure of Interests: Aziza Elmesmari: None declared, Robert Benson: None declared, Lucy MacDonald : None declared, Samuel Finlay : None declared, Andrew Filer: None declared, Stefano Alivernini Speakers bureau: BMS, Diane Vaughan: None declared, Barbara Tolusso: None declared, Elisa Gremese Consultant for: AbbVie, BMS, Celgene, Janssen, Lilly, MSD, Novartis, Sanofi, UCB, Roche, and Pfizer, Speakers bureau: BMS, Speakers bureau: Roche, Speakers bureau: AbbVie, BMS, Celgene, Janssen, Lilly, MSD, Novartis, Sanofi, UCB, Roche, and Pfizer, Iain McInnes Grant/research support from: AstraZeneca, Celgene, Compugen, Novartis, Roche, UCB Pharma, Consultant for: AbbVie, Celgene, Galvani, Lilly, Novartis, Pfizer, UCB Pharma, Andy Clark : None declared, Mariola Kurowska-Stolarska: None declared

AB0041 DO FUNCTIONAL INTERACTIONS BETWEEN MACROPHAGES AND SYNOVIAL FIBROBLASTS DRIVE SYNOVIAL PATHOLOGY OR RESOLUTION OF INFLAMMATION?

Detection and characterisation of bone destruction in murine rheumatoid arthritis using statistical shape models

Hillebrandt, David, Paul Richards, Andy Clark, and Dominique Jean. Zika virus advice for mountaineers: A UIAA Medcom consensus advice sheet. High Alt Med Biol. 17:70-71, 2016.-With the current media coverage of the spread of Zika virus from Africa and Asia to Central and South America and its possible relationship with fetal abnormalities, UIAA Medcom has produced an advice sheet for mountaineers visiting risk areas.

Zika Virus Advice for Mountaineers: A UIAA Medcom Consensus Advice Sheet.

Fitzgerald suggests that doctors who offer a telemedicine service should be regulated,1 but this could be difficult for doctors involved in remote practice.2 We write as a team of doctors who are active in offering telemedicine advice in the international field …

The U.S. Commission on Ocean Policy: Why You Should Care, and What You Can Do

The Internet of Things (IoT) is infiltrating many businesses. It provides simple means to collect and analyze technical system data to identify and optimize the performance of many things in our private and work lives. This technical revolution is also revealing new challenges and issues with our current IoT technologies. New solutions like Artificial Intelligence, Blockchain or 5G promise to overcome these challenges. Within this paper we discuss with leading experts the pros and cons of these technologies and what it means for the future IoT business.

A significant opportunity exists to apply information technology to better understand and more efficiently manage large complex manmade and natural systems. These systems often involve large-scale environmental, monitoring, and control systems, operating in harsh conditions with unreliable and low-bandwidth connections between a variety of heterogeneous devices. While there are many examples of these systems deployed, increasingly, there is a requirement to tightly integrate and couple these systems with more traditional core business applications and underlying infrastructure. This requirement is motivated by the desire for organizations to respond more quickly to new opportunities or threats, to gain deeper insight into the behavior of these systems, and to leverage existing investments in common tools, software stacks, programming models, and infrastructure. Deployment of such systems requires a pervasive messaging infrastructure to enable intercommunication of applications and devices. The publish/subscribe messaging paradigm has a number of characteristics that make it very attractive in this environment. These include scalability, efficiency, decoupling between publishing and subscribing entities, and the ability to integrate a wide variety of devices and systems. In this paper, we explore the application of the publish/subscribe messaging paradigm and a programming model to environmental, monitoring, and control systems, drawing on experience of projects from a variety of industries.

The application of publish/subscribe messaging to environmental, monitoring, and control systems

Digital exclusion refers to a lack of access to technological facilities, including the blossoming arena of social interaction. People without mobile phones or PCs cannot access email, SMS or social networking websites; this includes many groups, such as the elderly, who can become vulnerable without good social contact. These people could partake in such interactions if we could enable multimodal access to social networks through a wider variety of communication channels (for example, television and telephone). This poster describes how we have used methods from HCI and Social Theory to better understand social technology.

The digital divide refers to a lack of technological access, part of which involves exclusion from a blooming arena of social interaction. People without mobile phones or PCs cannot access email, SMS or social networking websites; this includes many groups, such as the elderly, who can become vulnerable without good social contact. By enabling multimodal access to a variety of communication channels, including ubiquitous ones such as televisions and home telephones, this set of people can be included in such interactions. This paper describes a prototype pervasive messaging infrastructure for multimodal communications, and how it can be used as an assistive environment. Our eventual aim is to create a social fabric, a pervasive infrastructure layer to support more complex social experiences in the future.

Social networking websites have become increasingly popular in recent times, and can be a source of fun and emotional support. However, a large chunk of society is excluded from this arena of social interaction: for example, in general elderly people face a range of obstacles to the uptake of technology. This paper describes our plans to use methods from a wide range of disciplines to better understand online social phenomena. This deeper understanding will allow us to provide social functions via novel and accessible communication channels. These might include televisions and telephones, alongside more unusual technologies such as digital photo frames and microprinters. We hope to provide the basis for a social fabric to improve technology access, and help a wider range of people benefit from social technologies.

Towards a Suite of Tools for Re-imagining Online Social Phenomena

Wireless sensor networks (WSNs) pose novel challenges compared with traditional networks. To answer such challenges a new communication paradigm, data-centric communication, is emerging. One form of data-centric communication is the publish/subscribe messaging system. Compared with other data-centric variants, publish/subscribe systems are common and wide-spread in distributed computing. Thus, extending publish/subscribe systems intoWSNs will simplify the integration of sensor applications with other distributed applications. This paper describes MQTT-S [1], an extension of the open publish/subscribe protocol message queuing telemetry transport (MQTT) [2] to WSNs. MQTT-S is designed in such a way that it can be run on low-end and battery-operated sensor/actuator devices and operate over bandwidth-constraint WSNs such as ZigBee-based networks. Various protocol design points are discussed and compared. MQTT-S has been implemented and is currently being tested on the IBM wireless sensor networking testbed [3]. Implementation aspects, open challenges and future work are also presented.

2008 3rd International Conference on Communication Systems Software and Middleware and Workshops (COMSWARE '08)

MQTT-S — A publish/subscribe protocol for Wireless Sensor Networks

Research into the retrieval and dissemination of mission-specific information across sensor networks is leading to the development of many novel new algorithms and the definition of new paradigms for configuring and enforcing communication flow policies amongst the various components. Testing the relative merits of such algorithms and policies, and exploring interoperability issues between them, is difficult unless they share a common test and validation framework. The wide variety of algorithms being developed (including ontological, mission scripting, resource allocation, network routing, data fusion algorithms, and policies) presents unique challenges to the development of such a framework and its subsequent instrumentation to provide experimental results. This work demonstrates a prototype of such framework (or "Fabric"), built on top of commercial off-the-shelf (COTS) components, used in a real-world sensor network deployment to experiment with the deployment of algorithms and gathering of live sensor data.

2008 IEEE Workshop on Policies for Distributed Systems and Networks

Policy Enabled ITA Sensor Fabric, A Distributed Framework for the Validation of Experimental Algorithms Using Real and Simulated Sensors

A standby power consumption limiting device is provided for connection between an electricity supply and an electrical appliance of the kind having a main on/off switch, two power supply input terminals and a standby mode control circuit operable, when the appliance is switched "on", to place the appliance in a reduced power standby mode. The device comprises a standby mode detection means 102 effective to detect and indicate that the appliance has gone into standby mode and a power switching means 104 having a first state in which the electricity supply is connected to the appliance via its power supply input terminals 91 and a second state in which the electricity supply is disconnected from the appliance. A power switch control means 107 responds to an indication from the standby mode detection means that the appliance has gone into standby mode, by switching the power switching means from its first state to its second state, thereby removing power from the appliance. At this point, a test signal generating means, 105 connected to one of the appliance input terminals by the power switching means when in its second state, generates a test signal of predetermined form, said test signal being returned, while the appliance main switch is in the "on" state, via the other appliance input terminal. A test signal detection means 106, connected to said other appliance input terminal by the power switching means when in its second state, is capable of detecting the test signal returned via said other terminal, when the appliance main switch is in its "on" state and of detecting a predetermined change in the returned test signal indicative of the appliance main switch having been turned to its "off' state. The power switch control means is responsive to an indication from the test signal detection means that the appliance main switch has turned been turned "off' to put the power switching means back into its first state thereby restoring power to the appliance which will then become active when its power switch is returned to the on position.

A simulation environment is very useful in analyzing sensor networks, but the development of a sensor simulation environment which can scale to a very large number of elements is hard to obtain using traditional simulation systems, or customized simulation environments. The desired level of scalability and high volumes are hard to achieve in customized simulation environments. One possible approach to obtain scalable simulation is by using commercially available messaging systems. Such messaging systems, e.g. IBM WebSphere MQ system or OSMQ, are designed to operate at a very high bandwidth of message transfers rate and number of interacting message queue end-points. However, the communications abstractions offered by message queue systems are very different from the communications abstractions required by sensor networks. In this paper, we describe an approach to map the communication abstractions of sensor network simulation systems to those of underlying message queue systems. We describe how issues related to message localization, propagation delays and error rates can be effectively handled, and a highly scalable infrastructure for message simulation be deployed.

Simulation of sensor networks using message queue infrastructure

The 1996 Atlanta Olympic Games were the rst to have an oocial Web site. This site had more than 60 Web server hosts, spread across 5 locations in 4 countries, and registered over 192 million hits during the 17 days of the games. This paper describes some of the challenges of building, operating and managing such a large distributed system. In particular, it outlines the use of novel TCP/IP technologies for sharing the load of HTTP requests across local and global servers. Using these technologies enabled us to build a scalable distributed Web server site that was able to comfortably support a huge demand. We also describe some of the management tools used for monitoring the system, logging HTTP requests, and providing secure access to system resources.

Load Distribution for Scalable Web Servers: Summer Olympics 1996 -a Case Study

Grid computing impacts directly on the experimental scientific laboratory in the areas of monitoring and remote control of experiments, and the storage, processing and dissemination of the resulting data.
We highlight some of the issues in extending the use of an MQ Telemetry Transport (MQTT) broker from facilitating the remote monitoring of an experiment and its environment to the remote control of an apparatus.
To demonstrate these techniques, an Intel-Play QX3 microscope has been "grid-enabled" using a combination of software to control the microscope imaging, and sample handling hardware built from LEGO Mindstorms. The whole system is controlled remotely by passing messages using an IBM WebSphere Message Broker.

The Combechem MQTT LEGO microscope: a grid enabled scientific apparatus demonstrator

By combining automatic environment monitoring with Java smartphones a system has
been produced for the real-time monitoring of experiments whilst away from the lab.
Changes in the laboratory environment are encapsulated as simple XML messages,
which are published using an MQTT compliant broker. Clients subscribe to the
MQTT stream, and produce a user display. An MQTT client written for the Java
MIDP platform, can be run on a smartphone with a GPRS Internet connection, freeing
us from the constraints of the lab. We present an overview of the technologies used,
and how these are helping chemists make the best use of their time.

Chemistry by Mobile Phone (or how to justify more time at the bar)

By combining automatic environment sensing and experimental data collection with broker based messaging middleware, a system has been produced far the real-time monitoring of experiments whilst away from the lab. Changes in the laboratory environment are encapsulated as simple messages, which are published using an MQTT compliant broker. Clients subscribe to the MQTT stream, and perform a data transform on the messages; this may be to produce a user display or to change the format of the message for republishing. For example, an MQTT client written for the Java MIDP platform can be run on a smart-phone with a GPRS Internet connection, freeing us from the constraints of the network. We present an overview of the technologies used, and how these are helping chemists make the best use of their time

First International Conference on e-Science and Grid Computing (e-Science'05)

We provide an overview of the design of a flood war ning system which uses a set of sensor nodes to collect readings of water level and communicates th e via an asynchronous reliable messaging infrastructure to a grid-based flood predictor mode l. The reporting frequency of sensor nodes is influenced by local conditions and also the flood p redictor model. This system is notable both for the adaptive sampling regime and the methodology ad opte in the design of the adaptive behaviour, which involved development of simulation t ols and very close collaboration with environmental experts.

FloodNet – Improving Flood Warning Times using Pervasive and Grid Computing

Open industrial standards in telemetry integration are important in creating a standard for open data transport and liberating data in a 3-tier architecture. Telemetry integration can be applied to many diverse applications such as pipeline (oil, gas, and water), energy and utilities (electricity, gas, oil, and water), process control, and factory automation. MQ telemetry is a protocol specification published and freely available on the Web. MQ telemetry, an "open" protocol jointly developed by IBM and Arcom Control Systems, is a lightweight wire transport for publish and subscribe over TCP/IP with various assurances of delivery. Security considerations in encryption, non-repudiation, entitlement, payload level, protocol level, and connection level should be carefully noted. MQ telemetry is currently working with a range of device and gateway manufacturers to enable products for the MQ telemetry transport.

Data processing apparatus for equation of the user load in a network

The ”ATLAS ITk Strip Sensor Collaboration” R&D group has developed a second iteration of single-sided n + -in-p type microstrip sensors for use in the tracker upgrade of the ATLAS experiment at the High-Luminosity (HL) LHC. The full size sensors measure approximately 97 x 97 mm 2 and are designed for tolerance against the 1 . 1 × 10 15 n eq / cm 2 ﬂuence expected at the HL-LHC. Each sensor has 4 columns of 1280 individual 23.9 mm long channels, arranged at 74.5 μ m pitch. Four batches comprising of 120 sensors produced by Hamamatsu Photonics were evaluated for their mechanical, and electrical bulk and strip characteristics. Optical microscopy measurements were performed to obtain the sensor surface proﬁle. Leakage current and bulk capacitance properties were measured for each individual sensor. For sample strips across the sensor batches, the inter-strip capacitance and resistance as well as properties of the punch-through protection structure were measured. A multi-channel probecard was used to measure leakage current, coupling capacitance and bias resistance for each individual channel of 100 sensors in three batches. The compiled results for 120 unirradiated sensors are presented in this paper, including summary results for almost 500’000 strips probed. Results on the reverse bias voltage dependence of various parameters and frequency dependence of tested capacitances are included for validation of the experimental methods used. Comparing results with speciﬁed values, almost all sensors fall well within speciﬁcation.

University of Birmingham Detailed Studies of Full-Size ATLAS12 Sensors

We compare a new CMOS Active Pixel Sensor (APS) to a Princeton Instruments PIXIS-XO: 2048B Charge Coupled Device (CCD) with soft X-rays tested in a synchrotron beam line at the Diamond Light Source (DLS). Despite CCDs being established in the field of scientific imaging, APS are an innovative technology that offers advantages over CCDs. These include faster readout, higher operational temperature, in-pixel electronics for advanced image processing and reduced manufacturing cost. The APS employed was the Vanilla sensor designed by the MI3 collaboration and funded by an RCUK Basic technology grant. This sensor has 520 x 520 square pixels, of size 25 μm on each side. The sensor can operate at a full frame readout of up to 20 Hz. The sensor had been back-thinned, to the epitaxial layer. This was the first time that a back-thinned APS had been demonstrated at a beam line at DLS. In the synchrotron experiment soft X-rays with an energy of approximately 708 eV were used to produce a diffraction pattern from a permalloy sample. The pattern was imaged at a range of integration times with both sensors. The CCD had to be operated at a temperature of -55°C whereas the Vanilla was operated over a temperature range from 20°C to -10°C. We show that the APS detector can operate with frame rates up to two hundred times faster than the CCD, without excessive degradation of image quality. The signal to noise of the APS is shown to be the same as that of the CCD at identical integration times and the response is shown to be linear, with no charge blooming effects. The experiment has allowed a direct comparison of back thinned APS and CCDs in a real soft x-ray synchrotron experiment.

The imaging of soft X-ray images is typically performed with charge coupled devices (CCDs). However, these can have limited readout speed, dynamic range and can also require significant cooling to obtain the required signal to noise ratio. Active pixel sensors (APS) are able to combine faster readout speeds and higher dynamic range with in-pixel intelligence to allow region of interest readout and adaptive gain. To obtain high detection efficiency and 100% pixel fill factor the sensor is back thinned and illuminated from the backside. We report on the characterization of a back-thinned APS (Vanilla); an array of 512 ? 512 pixels of size 25 ? 25 microns. The sensor has a 12-bit digital output for full frame mode, as well as being able to be readout in a fully programmable Region-Of-Interest (ROI) analogue mode. In full frame, the sensor can operate at a readout rate of more than 100 frames per second. Characterization of the detector was carried out through the analysis of photon transfer curves to yield measurements of the full well capacity, noise levels, gain constants and device linearity. Spectral response measurements were made to show the improvement in detection efficiency using a backthinned sensor. A typical synchrotron experiment was performed at the Diamond Light Source (DLS) using Soft X-rays ( ~ 700 eV) to produce a diffraction pattern from a permalloy sample. The pattern was imaged at a range of frame rates, up to 20Hz, and a range of temperatures for both a back-thinned Vanilla and a Princeton PIXIS-XO: 2048B CCD. The results of which are compared. The detection efficiency of the APS is shown to be comparable to the CCD for a given frame rate (0.1Hz), with similar noise levels. We suggest that the back-thinned APS are a viable technology choice for the direct detection of soft X-rays for synchrotron applications.

Characterisation of regional variations in a stitched CMOS active pixel sensor

Despite the continuing success of the charge couple device (CCD), the last 2 decades have seen APS devices become increasingly popular in their use as portable, low cost imagers. Despite suering from higher readout noise than the CCD, APS have a number of advantages. These include lower power consumption, lower cost, random access and selective readout. The possibility to incorporate on-chip functionality such as analogue-to-digital conversion (ADC), timing logic for thresholding and gain adjustment is driving an increased interest in these devices from the scientic community. In 2004, A UK consortium (MI3) was formed under an RC-UK Basic Technology Programme to develop CMOS active pixel sensors for a broad range of scientic applications including space science, particle physics and medical imaging. During the programme 6 APS’ were designed, fabricated and tested. Highlights from the project include: the LAS (Large Area Sensor), a novel stitched sensor designed for use in medical imaging; eLeNA (Low Noise), a test structure which develops a range of low noise pixels and OPIC (On Pixel Intelligent CMOS), a test structure designed for in-pixel intelligence including sparse read-out, ADC and storage in each pixel and thresholding. This paper reports on the results and conclusion from highlight of some of the 6 active pixel sensors produced by the MI3 consortium.

Preliminary investigations of active pixel sensors in Nuclear Medicine imaging

Characterisation of a monolithic active pixel sensor for electron detection in the energy range 10–20 keV

The Multidimensional Integrated Intelligent Imaging project (MI-3)

Optical and electrical characterization of a back-thinned CMOS active pixel sensor

Three CMOS active pixel sensors have been investigated to assess their potential application to Nuclear Medicine imaging. The first, Startracker, contained 525 × 525 pixels each 25 micron square and was coupled via a fiber optic stud to a 20mm × 20mm × 2mm thick segmented CsI(Tl) crystal. Imaging tests were performed using 99mTc sources which emit 140 keV gamma rays together with various lead collimators. The system was interfaced to a PC via an FPGA-based DAQ and optical link enabling imaging rates of 10 frames per sec. System noise was measured to be ≫100e but the majority of this noise was found to be fixed pattern in nature. The intrinsic spatial resolution was measured as ∼80 microns and the system spatial resolution measured with a slit was ≪1mm. The second sensor, OPIC, had 64 × 72 pixels each 40 micron square and was used to evaluate noise characteristics of these sensors and to develop a method of differentiation between fixed pattern and statistical noise. The third sensor, Vanilla, had 520×520 pixels each 25micron square and a measured system noise of ∼25e. This sensor was coupled directly to the segmented phosphor. Results show that even at this lower level of noise the signal from 140 keV gamma rays is small as the light from the phosphor is spread over a large number of pixels. Suggestions for the ‘ideal’ sensor are made.

Spectral characterisation and noise performance of Vanilla—an active pixel sensor

A Startracker CMOS monolithic active pixel sensor with 525times525 pixels each 25 microns/side has been coupled via a fibre optic stud to a CsI(Tl) crystal 2mm times 20mm times 20mm to form a test detector of gamma rays of energy between 60 keV and 200 keV. The crystal is segmented into 400 micron elements separated by 100 microns of filler. The system records images at 10 f/sec and is interfaced to a PC via an FPGA-based DAQ and optical link. Image acquisition is performed using a MatLab-based GUI. Noise is measured to be ~100 electrons with a temperature dependence of ~0.4%/C indicating that the majority of noise is reset related or fixed pattern in nature rather than statistical thermal noise. Images have been acquired using a Tc99m source placed directly onto the CsI(Tl) crystals as well as through several lead collimators. The structure of the CsI(Tl) scintillator is easy resolved once a noise image is subtracted and an intrinsic spatial resolution of 80-90 microns is measured. The system spatial resolution with a collimator is ~450 microns for 140keV photons. The results indicate that the present APS has too high a noise level for imaging low energy photons but a new device with ~25 electrons noise plus the potential to provide on-chip signal thresholding and cluster analysis could become part of a large-area intelligent gamma ray imager with a sub-mm spatial resolution at 140 keV.

The future of ground-based optical astronomy lies with advancements in adaptive optics (AO) to overcome the limitations that the atmosphere places on high resolution imaging. A key technology for AO systems on future very large telescopes are the wavefront sensors (WFS) which detect the optical phase error and send corrections to deformable mirrors. Telescopes with >30 m diameters will require WFS detectors that have large pixel formats (512 /spl times/ 512), low noise (<3 e/sup -//pixel) and very high frame rates (/spl sim/1 kHz). These requirements have led to the idea of a bare CMOS active pixel device (the Medipix2 chip) functioning in counting mode as an anode with noiseless readout for a microchannel plate (MCP) detector and at 1 kHz continuous frame rate. First measurement results obtained with this novel detector are presented both for UV photons and beta particles.

A high resolution, high frame rate detector based on a microchannel plate readout with the Medipix2 counting CMOS pixel chip

This paper summerises the first work on the characterization of a back-thinned Vanilla a 512x512 (25μm squared) active pixel sensor. Characterization of the detectors was carried out through the analysis of Photon Transfer Curves to yield a measurement of full well capacity, noise levels, gain constants and linearity. Spectral characterization of the sensors was also performed in the Visible and UV regions. A full comparison against non back-thinned front illuminated Vanilla sensors is included. Such measurements suggest that the Vanilla APS will be suitable for a wide range of applications including particle physics and biomedical imaging. 10th International Conference on Positional Sensitive Detectors Glasgow, Scotland

Optical & Electrical Characterization of a back-thinned CMOS Active Pixel Sensor

Expecting some action: Predictive Processing and the construction of conscious experience

Workplace Occupations in British Labour History: Rise, Fall, and Historical Legacies

The increasing level of attention being given to incremental learning is, we argue, fully justi ed. Although some view the process as something akin to an `e ciency hack', we argue that it is, in fact, a key cognitive process. The argument is based on a statistical observation. Learning, for most purposes, is all about acquiring the ability to generate appropriate outputs from given inputs, i.e., it is all about acquiring the ability to predict | or, in general, give a probability to | speci c bindings of output variables. Such predictions can be justi ed in two quite di erent ways by available training data (i.e., input/output examples). They can be justi ed directly, in virtue of being in 1-to-1 correspondence with probabilities (i.e., frequencies) directly observed in the training data. Or they can be justi ed indirectly, in virtue of being in 1-to-1 correspondence with probabilities observed in some re-coding of the data. Thus, where learning is driven by supplied training data, it must exploit some combination of these two types of justi cation. Since the space of indirectly observed probabilities is grounded in the space of possible re-codings (i.e., applicable Turing machines), searching through it is intractable. But we should not infer from this that learning does not (and cannot) make use of indirectly observed probabilities. As we show, learning problems whose solution necessarily entails exploiting such probabilities (or type-2 problems, as we call them) seem to be the norm in many realistic learning scenarios. We are thus left in need of an y The order of names is arbitrary.

Trading Spaces: Computation, Representation and the Limits of Learning

This article draws on research into three female-led occupations that occurred across central Scotland in 1981 and 1982. The actions at Lee Jeans, Lovable Bra and Plessey Capacitors were each in response to closure and relocation and, crucially in the context of this time period, were at least partly successful in opposing full closure. The piece considers the uses and limitations of mobilization theories in accounting for the collective action that emerged at the plants. Rejecting the individualistic frameworks that place extensive importance on injustice, it is suggested that the immediate impacts of manufacturing decline through the process of deindustrialization were a crucial factor in sustaining the action. Through an analysis of the statements made by the workers, their leaders and supporters at the time, along with an examination of oral-history interview narratives, the argument develops that these disputes were not localized actions at one site against one plant closure. By placing the factories and the workers within the social and economic contexts in which they took action, the research indicated that the process of collective action was dynamic and motivations were inevitably multiple, but that the detrimental impacts of deindustrialization - particularly as they related to the future of the localities - was crucial.

‘There Is Nothing There for Us and Nothing for the Future’: Deindustrialization and Workplace Occupation, 1981-1982

Among the exciting prospects raised by advocates of predictive processing [PP] is the offer of a systematic description of our neural activity suitable for drawing explanatory bridges to the structure of conscious experience (Clark, 2015). Yet the gulf to cross seems wide. For, as critics of PP have argued, our visual experience certainly doesn’t seem probabilistic (Block, 2018; Holton, 2016). While Clark (2018) proposes a means to make PP compatible with the experience of a determinate world, I argue that we should not rush to do so. Two notions of determinacy are conflated in the claim that perception is determinate: ‘univocality’ and ‘full detail’. The former, as Clark argues, is only to be expected in any PP agent that (like us) models its world for the purpose of acting on it. But as Husserl argued, and as perceptual psychology has borne out, we significantly overestimate the degree of detail with which we perceive a univocal world. This second form of indeterminacy is due not to the probabilistic nature of PP’s model, but rather to its hierarchical structure, with increasingly coarse-grained representations as we move further from the sensory periphery. A PP system may, or may not, deliver a univocal hypothesis at each of these levels. An action-oriented PP system would only be expected to do so only at the level needed for successful action guidance. A naïve reporter’s overestimation of the degree of determinate detail in their visual experience can thereby be accounted for with a more gradual version of the ‘refrigerator light’ effect: we experience determinate details just to the degree that they’re needed – immediately as they’re needed.

Visual experience in the predictive brain is univocal, but indeterminate

Despite frequent associations, deindustrialization features rarely in studies of organized crime, and organized crime is at best a spectral presence in studies of deindustrialization. By developing an original application of Linkon's concept of the "half-life," we present an empirical case for the symbiotic relationship between former sites of industry and the emergence of criminal markets. Based on a detailed case-study in the west of Scotland, an area long associated with both industry and crime, the paper interrogates the environmental, social, and cultural after-effects of deindustrialization at a community level. Drawing on 55 interviews with residents and service-providers in Tunbrooke, an urban community where an enduring criminal market grew in the ruins of industry, the paper elaborates the complex landscapes of identity, vulnerability, and harm that are embedded in the symbiosis of crime and deindustrialization. Building on recent scholarship, the paper argues that organized crime in Tunbrooke is best understood as an instance of "residual culture" grafted onto a fragmented, volatile criminal marketplace where the stable props of territorial identity are unsettled. The analysis allows for an extension of both the study of deindustrialization and organized crime, appreciating the "enduring legacies" of closure on young people, communal identity, and social relations in the twenty-first century.

Damaged hardmen: Organized crime and the half-life of deindustrialization.

Correction to: Networked territorialism: the routes and roots of organised crime

George Soros is one of the best traders of all time. That is the general consensus. While Soros gladly accepts that compliment he frequently also expressed his frustration that he failed as a philosopher. Specifically, he admits that he was unable to formulate his philosophy of reflexivity from its original abstractions. More importantly, reflexivity—which informed his successful trading—did not get the academic recognition that Soros’s track record suggests it deserves. This paper will discuss the reasons for this, the key one being that reflexivity points to the elephant in economics’s room. This will be highlighted by explaining reflexivity, from its original abstractions, in novel terms provided by cognitive science. In particular, via philosophy of mind this paper will argue why Soros is not a failed philosopher. This leads to the submission that reflexivity deserves proper recognition as an early contribution to the emerging field of cognitive economics, for which the Market Mind Hypothesis is a standard bearer. Moreover, the issues discussed are relevant in the wider context of our economic predicament.

Reflexivity and the Market Mind Hypothesis: Why George Soros is Not a Failed Philosopher (and What it Means for Economics, the Economy, and Investing)

For many years, the dominant theoretical framework guiding research into the neural origins of perceptual experience has been provided by hierarchical feedforward models, in which sensory inputs are passed through a series of increasingly complex feature detectors. However, the long‐standing orthodoxy of these accounts has recently been challenged by a radically different set of theories that contend that perception arises from a purely inferential process supported by two distinct classes of neurons: those that transmit predictions about sensory states and those that signal sensory information that deviates from those predictions. Although these predictive processing (PP) models have become increasingly influential in cognitive neuroscience, they are also criticized for lacking the empirical support to justify their status. This limited evidence base partly reflects the considerable methodological challenges that are presented when trying to test the unique predictions of these models. However, a confluence of technological and theoretical advances has prompted a recent surge in human and nonhuman neurophysiological research seeking to fill this empirical gap. Here, we will review this new research and evaluate the degree to which its findings support the key claims of PP.

Evaluating the neurophysiological evidence for predictive processing as a model of perception

The Predictive Processing (PP) framework casts the brain as a probabilistic prediction engine that continually generates predictions of the causal structure of the world in order to construct for itself, from the top down, incoming sensory signals. Conceiving of the brain in this way has yielded incredible explanatory power, offering what many believe to be our first glimpse at a unified theory of the mind. In this paper, the picture of the mind brought into view by predictive processing theories is shown to be embodied, deeply affective and nicely poised for cognitive extension. We begin by giving an overview of the main themes of the framework, and situating this approach within embodied cognitive science. We show perception, action, homeostatic regulation and emotion to be underpinned by the very same predictive machinery. We conclude by showing how predictive minds will increasingly be understood as deeply interwoven with, and perhaps extended into, the surrounding social, cultural and technological landscape. This article is categorized under: Philosophy > Foundations of Cognitive Science Psychology > Emotion and Motivation Philosophy > Action.

Does language change what we perceive? Does speaking different languages cause us to perceive things differently? We review the behavioral and electrophysiological evidence for the influence of language on perception, with an emphasis on the visual modality. Effects of language on perception can be observed both in higher-level processes such as recognition and in lower-level processes such as discrimination and detection. A consistent finding is that language causes us to perceive in a more categorical way. Rather than being fringe or exotic, as they are sometimes portrayed, we discuss how effects of language on perception naturally arise from the interactive and predictive nature of perception.

Recent work in cognitive and computational neuroscience depicts the human brain as a complex, multi-layer prediction engine. This family of models has had great success in accounting for a wide variety of phenomena involving perception, action, and attention. But despite their clear promise as accounts of the neurocomputational origins of perceptual experience, they have not yet been leveraged so as to shed light on the so-called “hard problem” of consciousness—the problem of explaining why and how the world is subjectively experienced at all, and why those experiences seem just the way they do. To address this issue, I motivate and defend a picture of conscious experience as flowing from “generative entanglements” that mix predictions about the world, the body, and (crucially) our own reactive dispositions.

ABSTRACT ‘Predictive Processing’ (PP) is an emerging paradigm in cognitive neuroscience that depicts the human mind as an uncertainty management system that constructs probabilistic predictions of sensory signals. Such accounts apply very naturally to perception and have plausible extensions to motor control. But desires and motivations can seem to pose a much greater puzzle, appearing especially resistant to reconstruction by a processing story that appeals to predictions alone. I examine several versions of this worry and show that it is fundamentally misplaced. Desires and motivations are fluently accommodated within the unifying PP schema, where they emerge as webs of prior ‘beliefs’ that sculpt probabilistic predictions, some of which become positioned (as we shall see) so as to bring about actions. Importantly, a single construct here plays the role of belief and desire. But what results is, perhaps surprisingly, a potentially richer landscape within which to think about agency, control, and choice.

That the brain matches its environment is no more surprising than the matching of the two ends of a broken stick.
 W. Ross Ashby
 First of all, heartfelt thanks to Liz Irvine, Matteo Colombo, and Mog Stapleton: thanks for coming up with the idea of this volume, and for somehow making it actually happen....

Correction to: Happily entangled: prediction, emotion, and the embodied mind

Visions of the Roman North: Art and Identity in Northern Roman Britain

Between 2013 and 2016, Edinburgh’s Eidyn research centre hosted the AHRC-funded Extended Knowledge (AH/J011908/1) project (http://www.extended-knowledge.ppls.ed.ac.uk/). The papers presented in this volume are the direct or indirect products of workshops, conferences, and impact events held at the University of Edinburgh under that umbrella. The project’s main team consisted of the present editors, but the project itself comprised an international, interdisciplinary network spanning epistemology, philosophy of mind, cognitive science, cognitive and social psychology, computer science, Web science, and cybernetics. The goal was to provide, for the first time, a systematic exploration of the various ways of “externalizing” knowledge....

Current understandings of worker mobilisation against factory closure and capital migration in Britain are dominated by the perspectives of male industrial workers. The narratives of displaced miners, shipbuilders and steel workers are prominent in the historiography and collective memories of deindustrialisation. There is considerably less understanding of the response of female manufacturing workers to these processes and the ways in which women mobilised in opposition to the free movement of capital. This article presents the testimony of Margaret Robertson, shop steward at the Lee Jeans factory in Greenock, Scotland, where the predominantly female workforce conducted a successful seven-month occupation in opposition to proposed closure beginning in February 1981. The contribution highlights the specific gendered challenges encountered by women workers. The occupation occurred in a period of accelerated factory closure in Britain, yet supporting female unionists resisting job loss was not a priority for the male-dominated union executive.

‘We Were the Ones Really Doing Something About It’: Gender and Mobilisation against Factory Closure

Recent work in cognitive and computational neuroscience depicts the brain as in some (perhaps merely approximate) sense implementing probabilistic inference. This suggests a puzzle. If the processing that enables perceptual experience involves representing or approximating probability distributions, why does experience itself appear univocal and determinate, apparently bearing no traces of those probabilistic roots? In this paper, I canvass a range of responses, including the denial of univocality and determinacy itself. I argue that there is reason to think that it is our conception of perception itself that is flawed. Once we see perception aright, as the slave of action, the puzzlement recedes. Perceptual determinacy reflects only the mundane fact that we are embodied, active, agents who must constantly engage the world they perceptually encounter.

Beyond the ‘Bayesian Blur’: Predictive processing and the nature of subjective experience

The present volume explores the topic of socially extended knowledge. This is a topic of research at the intersection of epistemology and philosophy of mind and cognitive science. The core idea of socially extended epistemology is that epistemic states such as beliefs, justification, and knowledge can be collectively realized by groups or communities of individuals. Typical examples that are being studied in the literature include collective memory in old partners, problem-solving by juries, and the behaviors of hiring committees, scientific research teams, and intelligence agencies. This volume attempts to further our understanding of socially extended knowledge while also exploring its potential practical and societal impact by inviting perspectives not just from philosophy but from cognitive science, computer science, Web science, and cybernetics too. Contributions to the volume mostly fall within two broad categories: (i) foundational issues within socially extended epistemology (including elaborations on, defences and criticisms of core aspects of socially extended epistemology), and (ii) applications and new directions, where themes in socially extended epistemology are connected to these other areas of research. The volume is accordingly divided into two parts corresponding to these broad categories. The topics themselves are of great conceptual interest, and wider interdisciplinary perspectives suggest many connections with social concerns and policy-making.

One of the most important research programs in contemporary cognitive science is that of extended cognition. In this area of study, features of a subject’s cognitive environment can, in certain conditions, become constituent parts of the cognitive process itself. The aim of this volume is to explore the epistemological ramifications of this idea. The book brings together papers written by a range of distinguished and emerging academics, from a variety of different perspectives, to investigate the very idea of an extended epistemology. The first part of the volume explores foundational issues with regard to an extended epistemology as well as from a critical perspective. The second part of the volume examines the applications of this idea, and the new theoretical directions that it might take us. These include the relevance of Chinese philosophy, the ethical ramifications of extended epistemology, and its import to the epistemology of education, moral ethics, and emerging digital technologies.

This chapter focuses on extended cognition, a concept that invites the possibility of extended knowledge—i.e., knowledge that results from the close coupling of agents’ biological and technological equipment. It examines what is minimally required for such forms of technologically extended (and distributed) agents to be sufficiently justified and it asks whether existing and future technologies can allow for such forms of epistemic extension. Critical examination of the relevant literature at the intersection of philosophy of mind and epistemology suggests a positive response. Given this possibility, the chapter finally explores some of the ensuing transformations in the ethical obligations and rights of the resulting socio-technical systems and “new humans.”

A nice surprise? Predictive processing and the active pursuit of novelty

Priors and prejudices: Comments on Susanna Siegel’s The Rationality of Perception

INTRODUCTION. The brain fascinates because it is the biological organ of mindfulness itself. It is the inner engine that drives intelligent behavior. Such a depiction provides a worthy antidote to the once-popular vision of the mind as somehow lying outside the natural order. But it is a vision with a price. For it has concentrated much theoretical attention on an uncomfortably restricted space; the space of the inner neural machine, divorced from the wider world which then enters the story only via the hygienic gateways of perception and action. Recent work in neuroscience, robotics and psychology casts doubt on the effectiveness of such a shrunken perspective. Instead, it stresses the unexpected intimacy of brain, body and world and invites us to attend to the structure and dynamics of extended adaptive systems -ones involving a much wider variety of factors and forces. Whilst it needs to be handled with some caution, I believe there is much to be learnt from this broader vision. The mind itself, if such a vision is correct, is best understood as the activity of an essentially situated brain: a brain at home in its proper bodily, cultural and environmental niche. 1. SOFTWARE. Humans, dogs, ferrets -these are, we would like to say, mindful things. Rocks, rivers and volcanoes are not. And no doubt there are plenty of cases in between (insects, bacteria ...). In the natural order, clear cases of mindfulness always involve creatures with brains. Hence, in part, the fascination of the brain: understanding the brain looks crucial to the project of understanding the mind. But how should such an understanding proceed? An early sentiment -circa 1970 and no longer much in vogue -was that understanding the mind depended rather little on understanding the brain. The brain, it was agreed, was in some sense the physical medium of cognition. But everything that mattered about the brain qua mind-producing engine turned not on the physical details but on the computational and information-processing strategies that the neural stuff (merely) implemented. There was something importantly right about this view, but something desperately wrong as well. What was right was the observation that understanding the physical workings was not going to be enough; that we would need also to understand how the system was organized at a higher level in order to grasp the roots of mindfulness in the firing of neurons. This point is forcefully made by the cognitive scientist Brian Cantwell Smith who draws a parallel with the project of understanding ordinary computer systems. With respect to e.g., a standard PC running a tax-calculation program, we could quite easily answer all the "physiological" questions (using source code and wiring diagrams) yet still lack any real understanding of what the program does or even how it works. To really understand how mental activity yields mental states, many theorists believe, we must likewise understand something of the computational/information-processing organization of the brain. 1 See B.C. Smith (1996), p. 148. Note that Smith’s worry, at root, concerns the gap between physiological and semantic or intentional questions.

Recent work in computational and cognitive neuroscience depicts the brain as an ever-active prediction machine: an inner engine continuously striving to anticipate the incoming sensory barrage. I briefly introduce this class of models before contrasting two ways of understanding the implied vision of mind. One way (Conservative Predictive Processing) depicts the predictive mind as an insulated inner arena populated by representations so rich and reconstructive as to enable the organism to ‘throw away the world’. The other (Radical Predictive Processing) stresses the use of fast and frugal, action-involving solutions of the kind highlighted by much work in robotics and embodied cognition. But it goes further, by showing how predictive schemes can combine frugal and more knowledge-intensive strategies, switching between them fluently and continuously as task and context dictate. I end by exploring some parallels with work in enactivism, and by noting a certain ambivalence concerning internal representations and their role in the predictive mind.

According to an emerging vision in computational cognitive neuroscience, perception (rich, full-blooded, world-presenting perception of the kind we humans enjoy) depends heavily on prediction. To visually perceive, if this schema is correct, is to meet incoming visual information with a set of matching top-down predictions that track the evolving visual signal across multiple spatial and temporal scales. In this chapter I first introduce this general explanatory schema. I then display some recent evidence for the schema, and discuss to what extent it marks a radical departure from previous (‘featuredetection based’) models of perception. I end by exploring some implications of the schema for questions concerning multi-modal and cross-modal effects in sensory processing, and for our understanding of the deep and fundamental relations between perception, imagination, and understanding. 1. Perceiving as Predicting 1.1 Predictive Coding A familiar view depicts perception as essentially a process of ‘bottom-up’ feature detection. Thus, in the case of vision, detected colors, edges, and shapes might act as the building blocks for detected objects (cats, dogs) and states of affairs (dogs chasing a cat, perhaps). Scientific versions of the paradigm depict early perception as building towards a complex world model by a feedforward process of evidence accumulation. Visual cortex, to take the most-studied example, is thus “traditionally viewed as a hierarchy of neural feature detectors, with neural population responses being driven by bottom-up stimulus features” (Egner et al 2010 p. 16601). This is a view of the perceiving brain as passive and stimulus-driven, taking energetic inputs from the senses and turning them into a coherent percept by a kind of step-wise build-up moving from the simplest features to the more complex. From pixel intensities up to lines and edges and on to complex meaningful shapes (like teacups), accumulating structure and complexity along the way in a kind of Lego-block fashion. In

According to one prominent view in contemporary epistemology, the correct application of one’s cognitive abilities in believing truly is necessary and sufficient for a kind of credit that is, in turn, necessary for knowledge. Epistemologists who hold this view typically take the cognitive abilities concerned to be based in states and processes that are spatially located inside the head of the knowing subject. Enter the hypothesis of extended cognition (henceforth ExC). According to ExC, the physical machinery of mind sometimes extends beyond the skull and skin. The present chapter will explore what happens when the credit condition on knowledge is brought into contact with ExC. Via discussions of (a) empirical psychological work on the adaptive character of technologically augmented memory and (b) thought experiments from the extended cognition and extended knowledge literatures, conclusions will be drawn for our understanding of ‘knowledge in the wild’.

Knowledge , Credit , and the Extended Mind , or what Calvisius Sabinus got Right

Hohwy (Hohwy 2016, Hohwy 2017) argues there is a tension between the free energy principle and leading depictions of mind as embodied, enactive, and extended (so-called ‘EEE1 cognition’). The tension is traced to the importance, in free energy formulations, of a conception of mind and agency that depends upon the presence of a ‘Markov blanket’ demarcating the agent from the surrounding world. In what follows I show that the Markov blanket considerations do not, in fact, lead to the kinds of tension that Hohwy depicts. On the contrary, they actively favour the EEE story. This is because the Markov property, as exemplified in biological agents, picks out neither a unique nor a stationary boundary. It is this multiplicity and mutability– rather than the absence of agent-environment boundaries as such that EEE cognition celebrates.

How to Knit Your Own Markov Blanket: Resisting the Second Law with Metamorphic Minds

Biological brains are increasingly cast as ‘prediction machines’: evolved organs whose core operating principle is to learn about the world by trying to predict their own patterns of sensory stimulation. This, some argue, should lead us to embrace a brain-bound ‘neurocentric’ vision of the mind. The mind, such views suggest, consists entirely in the skull-bound activity of the predictive brain. In this paper I reject the inference from predictive brains to skull-bound minds. Predictive brains, I hope to show, can be apt participants in larger cognitive circuits. The path is thus cleared for a new synthesis in which predictive brains act as entry-points for ‘extended minds’, and embodiment and action contribute constitutively to knowing contact with the world.

Busting Out: Predictive Brains, Embodied Minds, and the Puzzle of the Evidentiary Veil

Howhy (Hohwy 2016, Hohwy 2017) argues there is a tension between the free energy principle and leading depictions of mind as embodied, enactive, and extended (so-called ‘EEE cognition’). The tension is traced to the importance, in free energy formulations, of a conception of mind and agency that depends upon the presence of a ‘Markov blanket’ Andrey Markov demarcating the agent from the surrounding world. In what follows I show that the Markov blanket considerations do not, in fact, lead to the kinds of tension that Howhy depicts. On the contrary, they actively favour the EEE story. This is because the Markov property, as exemplified in biological agents, picks out neither a unique nor a stationary boundary. It is this multiplicity and mutability– rather than the absence of agent-environment boundaries as such - that EEE cognition celebrates.

explorations reveal the power and promise of hierarchical predictive coding as a bridge linking basic forms of sensorimotor engagement with the emergence of higher and higher forms of abstraction and control. Prediction-based learning yields representational forms, at higher processing levels, that act to summarize, compress, and control, activity at lower levels.

The University of Edinburgh From the SelectedWorks of Mirko Farina 2013 The Extended Mind Thesis

Editorial to the special issue on perspectives on human probabilistic inference and the ‘Bayesian brain'

'Not our jobs to sell' : workforce mobilization, deindustrialisation and resistance to plant closure : Scottish female factory occupations, 1981-1982

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Supersizing The Mind Embodiment Action And Cognitive Extension Andy Clark

Practicing clinicians wishing to obtain a graduate degree benefit from synchronous online classes available in the evenings. Clinicians wish to obtain a Master's degree for career advancement, updating best practices, or lifelong learning. The use of the synchronous virtual classroom as a vehicle for providing evening courses allows professionals to participate in their educational objectives from home, after work, in an environment that simulates the traditional classroom. An anonymous survey of graduate students in a distance delivered, synchronous program was done to evaluate benefits/drawbacks of synchronous versus asynchronous learning and the delivery of course content online. Additional survey items included questions regarding hybrid programming and cohorts. The survey was designed, refined and piloted through qualitative methods with faculty who teach both synchronously and asynchronously. The anonymous survey was launched through Survey Monkey™, sans identifiers or IP address, password protected and only accessible to authorized personnel. This research is considered exempt from IRB review. Opening screens contained disclosures and consent was obtained upon entry into the survey. Survey results were collected from 27% of the total student population sampled (n=53). The response rate is consistent with rates for anonymous emailed surveys. Likert scale responses ranged from 1= “Very Poor” to 6= “Excellent”. The results included a strong positive experience with synchronous delivery of course content through the virtual classroom (μ=4.7). The average rating of asynchronous delivery through discussion boards or electronic correspondence was not as favorable (μ=3.2). Qualitative, open ended questions revealed several emergent themes, using grounded theory. Strengths of real time, synchronous delivery of graduate level nutrition content, with mandatory virtual classroom attendance included: 1. Fostering of relationships, rapport, meaningful interactions 2. Real time interactions, participation, discussion, clarification and feedback 3. Convenience, flexibility, ease, planning and utilization of resources 4. Improved commitment, consistency, connectivity, networking and access 5. Enhanced goal setting, task completion, tracking, understanding, focus and learning. Limitations of real time, synchronous delivery included: 1. Limitations of time, availability, scheduling, and flexibility. 2. Technical or connectivity issues, time zone differences, technological capabilities 3. Limitations to engagement, participation or personal characteristics that prohibit interactions. Other strengths and weaknesses of asynchronous delivery, hybrid programming, and cohort enrollment were explored. The authors conclude that there is research that corroborates our findings that synchronous online environments enhance learning of advanced nutrition and dietetics content in a population of practicing nutrition clinicians.

Synchronous Classrooms: Teaching Practicing Nutrition Clinicians through Distance Technologies

TOC: 
 
Introduction to Special Issue of American Philosophical Quarterly Varieties of Externalism: Epistemic, Content, Vehicle ii 
J. Adam Carter, Andy Clark, Jesper Kallestrup, S. Orestis Palermos, and Duncan Pritchard 
Know-wh Does Not Reduce to Know-That 109 
Katalin Farkas 
The Dual Concepts Objection to Content Externalism 123 
Bryan Frances 
The Sound of Music: Externalist Style 139 
Luke Kersten and Robert A. Wilson 
Access Internalism and the Guidance Deontological Conception of Justification 155 
Ram Neta 
Embodied Knowledge, Conceptual Change, and the A Priori; or, Justification, Revision, and the Ways Life Could Go 169 
Robert D. Rupert 
Semantic Deference versus Semantic Coordination 193 
Laura Schroeter and Francois Schroeter

Special Issue of American Philosophical Quarterly: Varieties of Externalism: Epistemic, Content, Vehicle [Guest Editors]

Strange inversions occur when things work in ways that turn received wisdom upside down. Hume offered a strangely inverted story about causation, and Darwin, about apparent design. Dennett suggests that a strange inversion also occurs when we project our own reactive complexes outward, painting our world with elusive properties like cuteness, sweetness, blueness, sexiness, funniness, and more. Such properties strike us as experiential causes, but they are (Dennett argues) really effects—a kind of shorthand for whole sets of reactive dispositions rooted in the nuts and bolts of human information processing. Understanding the nature and origins of that strange inversion, Dennett believes, is thus key to understanding the nature and origins of human experience itself. This paper examines this claim, paying special attention to recent formulations that link that strange inversion to the emerging vision of the brain as a Bayesian estimator, constantly seeking to predict the unfolding sensory barrage.

Strange Inversions: Prediction and the Explanation of Conscious Experience

Introduction to special issue of American Philosophical Quarterly Varieties of Externalism: Epistemic, content, vehicle

Abstract Firestone & Scholl (F&S) bracket many attentional effects as “peripheral,” altering the inputs to a cognitive process without altering the processing itself. By way of contrast, I highlight an emerging class of neurocomputational models that imply profound, pervasive, nonperipheral influences of attention on perception. This transforms the landscape for empirical debates concerning possible top-down effects on perception.

Michael Madary’s visionary and incisive commentary brings into clear and productive focus some of the deepest, potentially most transformative, implications of the Predictive Processing (PP) framework. A key thread running through the commentary concerns the active and “organism-relative” nature of the inner states underlying perception and action. In this Reply, I pick up this thread, expanding upon some additional features that extend and underline Madary’s point. I then ask, What remains of the bedrock picture of inner states bearing familiar representational contents? The answer is not clear-cut. I end by suggesting that we have here moved so far from a once-standard complex of ideas concerning the nature and role of the inner states underlying perception and action that stale old debates concerning the existence, nature, and role of “internal representations” should now be abandoned and peace declared.

Clark, A. (2015). Predicting Peace: The End of the Representation Wars-A Reply to Michael Madary

Versions of the “predictive brain” hypothesis rank among the most promising and the most conceptually challenging visions ever to emerge from computational and cognitive neuroscience. In this paper, I briefly introduce (section 1) the most radical and comprehensive of these visions—the account of “active inference”, or “action-oriented predictive processing” (Clark 2013a), developed by Karl Friston and colleagues. In section 2, I isolate and discuss four of the framework’s most provocative claims: (i) that the core flow of information is top-down, not bottom-up, with the forward flow of sensory information replaced by the forward flow of prediction error; (ii) that motor control is just more top-down sensory prediction; (iii) that efference copies, and distinct “controllers”, can be replaced by top-down predictions; and (iv) that cost functions can fruitfully be replaced by predictions. Working together, these four claims offer a tantalizing glimpse of a new, integrated framework for understanding perception, action, embodiment, and the nature of human experience. I end (section 3) by sketching what may be the most important aspect of the emerging view: its ability to embed the use of fast and frugal solutions (as highlighted by much work in robotics and embodied cognition) within an over-arching scheme that includes more structured, knowledge-intensive strategies, combining these fluently and continuously as task and context dictate.

According to an emerging vision in computational cognitive neuroscience, perception (rich, full-blooded, world-presenting perception of the kind we humans enjoy) depends heavily on prediction. To visually perceive, if this schema is correct, is to meet incoming visual information with a set of matching top-down predictions that track the evolving visual signal across multiple spatial and temporal scales. In this chapter I first introduce this general explanatory schema. I then display some recent evidence for the schema, and discuss to what extent it marks a radical departure from previous (‘feature-detection based’) models of perception. I end by exploring some implications of the schema for questions concerning multi-modal and cross-modal effects in sensory processing, and for our understanding of the deep and fundamental relations between perception, imagination, and understanding.

Can what we know change what we see? Does language affect cognition and perception? The last few years have seen increased attention to these seemingly disparate questions, but with little theoretical advance. We argue that substantial clarity can be gained by considering these questions through the lens of predictive processing, a framework in which mental representations—from the perceptual to the cognitive—reflect an interplay between downward-flowing predictions and upward-flowing sensory signals. This framework provides a parsimonious account of how (and when) what we know ought to change what we see and helps us understand how a putatively high-level trait such as language can impact putatively low-level processes such as perception. Within this framework, language begins to take on a surprisingly central role in cognition by providing a uniquely focused and flexible means of constructing predictions against which sensory signals can be evaluated. Predictive processing thus provides a plausible mechanism for many of the reported effects of language on perception, thought, and action, and new insights on how and when speakers of different languages construct the same “reality” in alternate ways.

In this ground-breaking work, philosopher and cognitive scientist Andy Clark turns a common view of the human mind upside down. In stark opposition to familiar models of human cognition, Surfing Uncertainty explores exciting new theories in neuroscience, psychology, and artificial intelligence that reveal minds like ours to be prediction machines—devices that have evolved to anticipate the incoming streams of sensory stimulation before they arrive. This keeps minds like ours a few steps ahead of the game, poised to respond rapidly and apparently effortlessly to threats and opportunities as (and sometimes even before) they arise. 
 
Creatures thus equipped are more than simple response machines. They are knowing agents deep in the business of understanding their worlds. Such agents cope with changing and uncertain worlds by combining sensory evidence with informed prediction. Remarkably, the learning that makes neural prediction possible can itself be accomplished by the ceaseless effort to make better and better predictions. A single fundamental trick (the trick of trying to predict your own sensory inputs) thus enables learning, empowers moment-by-moment perception, and installs a rich understanding of the surrounding world. 
 
Action itself now appears in a new and revealing light. For action is not so much a 'response to an input' as a neat and efficient way of selecting the next 'input'. As mobile embodied agents we are forever intervening, actively bringing about the very streams of sensory information that our brains are simultaneously trying to predict. This binds perception and action in a delicate dance, a virtuous circle in which neural circuits animate, and are animated by, the movements of our own bodies. Some of our actions, in turn, structure the physical, social, and technological worlds around us. This moves the goalposts by altering the very things we need to engage and predict. 
 
Surfing Uncertainty brings work on the predictive brain into full and satisfying contact with work on the embodied and culturally situated mind. What emerges is a bold new vision of what brains do that places circular causal flows and the active structuring of the environment, center-stage. In place of cognitive couch potatoes idly awaiting the next sensory inputs, Clark's journey reveals us as proactive predictavores, skilfully surfing the waves of sensory stimulation.

Sensory substitution devices are a type of sensory prosthesis that (typically) convert visual stimuli transduced by a camera into tactile or auditory stimulation. They are designed to be used by people with impaired vision so that they can recover some of the functions normally subserved by vision. In this chapter we will consider what philosophers might learn about the nature of the senses from the neuroscience of sensory substitution. We will show how sensory substitution devices work by exploiting the cross-modal plasticity of sensory cortex: the ability of sensory cortex to pick up some types of information about the external environment irrespective of the nature of the sensory inputs it is processing. We explore the implications of cross-modal plasticity for theories of the senses that attempt to make distinctions between the senses on the basis of neurobiology.

Digital technologies play an increasingly important role in shaping the profi le of human thought and action. In the few short decades since its invention, the World Wide Web, for example, has transformed the way we shop, date, socialize, and undertake scientifi c endeavors. 1 We are also witnessing an unprecedented rate of technological innovation and change, driven, at least in part, by exponential rates of growth in computing power and performance. 2 Th e technological landscape is thus a highly dynamic one—new technologies are being introduced all the time, and the rate of change looks set to continue unabated. In view of all this, it is natural to wonder about the eff ects of new technology on both ourselves and the societies in which we live. When it comes to the social impacts of new technology, an interesting debate has emerged regarding the extent to which technologies are, on occasion, incorporated into the fabric of society (e.g., Smart and Shadbolt 2014 ). Consider, for example, the case of the Web. Th e fi rst uses of the Web did not yield a sudden change in the organization and operation of society; rather, the Web served as something of a technological add-on to an existing set of social practices and conventions. At this point, the project to create

Emerging Digital Technologies : Implications for Extended Conceptions of Cognition and Knowledge

Getting ahead: forward models and their place in cognitive architecture

Super A.I's Won't Take Over the World (Unless They Get Culture First)

We present some initial forays into the questions that underlie the philosophy of the Web around the notions of representation, enactive search, the extended mind, and collective intelligence.

Towards a Philosophy of the Web: Representation, Enaction, Collective Intelligence

'And the next thing, the chairs barricaded the door' : The Lee Jeans factory occupation, trade unionism and gender in Scotland in the 1980s

Much ink has lately been spilled in the name of Embodied Cognition. Mind itself, we are now frequently told, is an intrinsically embodied and environmentally embedded phenomenon. But there is a prima facie tension, or so I shall argue, between two strands of thought prominent in this recent literature. One of those strands depicts the fine details of a creature’s embodiment as a major constitutive constraint on the nature of its mind: a kind of new–wave body–centrism. The other depicts the body as just one element in a kind of equal–partners dance between brain, body and world, with the nature of the mind fixed by the overall balance thus achieved: a kind of extended functionalism (now with an even broader canvas for multiple realizability than ever before). Where some theorists of embodiment see the contribution of the flesh as both special and at least partially constitutive of certain mental states, some theorists of embedding see the contribution as instrumental, with the body acting as the contingent bridge to new forms of extended functional (computational and representational) organization. The main goal of the present paper is to display this subterranean tension. Along the way, I isolate some specific cases for which a constitutive relation between embodiment and mentality seems most plausible, and begin to scout the space of possible ways of reconciling the two approaches. More positively, but rather speculatively, the paper ends by depicting the body itself as whatever plays a certain role in a (possibly extended) functional organization. This delivers a clear account of why the body matters, but may require some revisions in our common understanding of the space of possible embodied intelligences.

Pressing the Flesh: Exploring a Tension in the Study of the Embodied, Embedded Mind*

In this paper we present a ﬁnite diﬀerence method for solving two-dimensional viscoelastic unsteady free surface ﬂows governed by the single equation version of the eXtended Pom-Pom (XPP) model. The momentum equations are solved by a projection method which uncouples the velocity and pressure ﬁelds. We are interested in low Reynolds number ﬂows and, to enhance the stability of the numerical method, an implicit technique for computing the pressure condition on the free surface is employed. This strategy is invoked to solve the governing equations within a Marker-and-Cell type approach while simultaneously calculating the correct normal stress condition on the free surface. The numerical code is validated by performing mesh reﬁnement on a two-dimensional channel ﬂow. Numerical results include an investigation of the inﬂuence of the parameters of the XPP equation on the extrudate swelling ratio and the simulation of the Barus eﬀect for XPP ﬂuids.

Brains, it has recently been argued, are essentially prediction machines. They are bundles of cells that support perception and action by constantly attempting to match incoming sensory inputs with top-down expectations or predictions. This is achieved using a hierarchical generative model that aims to minimize prediction error within a bidirectional cascade of cortical processing. Such accounts offer a unifying model of perception and action, illuminate the functional role of attention, and may neatly capture the special contribution of cortical processing to adaptive success. This target article critically examines this "hierarchical prediction machine" approach, concluding that it offers the best clue yet to the shape of a unified science of mind and action. Sections 1 and 2 lay out the key elements and implications of the approach. Section 3 explores a variety of pitfalls and challenges, spanning the evidential, the methodological, and the more properly conceptual. The paper ends (sections 4 and 5) by asking how such approaches might impact our more general vision of mind, experience, and agency.

Whatever next? Predictive brains, situated agents, and the future of cognitive science.

The target article sketched and explored a mechanism (action-oriented predictive processing) most plausibly associated with core forms of cortical processing. In assessing the attractions and pitfalls of the proposal we should keep that element distinct from larger, though interlocking, issues concerning the nature of adaptive organization in general.

Are we predictive engines? Perils, prospects, and the puzzle of the porous perceiver.

The extended mind thesis (EMT) claims that the cognitive processes that make up the human mind can reach beyond the boundaries of individual to include as proper parts aspects of the individual’s physical and sociocultural environment. Proponents of the extended mind story thus hold that even quite familiar human mental states (such as states of believing that so-and-so) can be realized, in part, by structures and processes located outside the human head. Such claims go far beyond the important, but less challenging, assertion that human cognizing leans heavily on various forms of external scaffolding and support. Instead, they paint mind itself (or better, the physical machinery that realizes some of our cognitive processes and mental states) as, under humanly attainable conditions, extending beyond the bounds of skin and skull. Extended cognition in its most general form occurs when internal and external resources become fluently tuned and deeply integrated in such a way as to enable a cognitive agent to solve problems and accomplish their projects, goals, and interests. Consider, for instance, how technological resources such as pens, paper, and personal computers are now so deeply integrated into our everyday lives that we couldn’t accomplish many of our cognitive goals and purposes without them. The extended mind thesis claims that technological resources have become so thoroughly enmeshed with our internal cognitive machinery that they now count as part of the machinery of thought itself. Underlying (but distinct from) the extended mind thesis is a commonplace observation thatintelligent problem solving of the kind we find in adult humans isn’t something the naked brain can achieve all on its own, but is instead the outcome of the brain and body operating together in an environmental and often technologically loaded setting. As humans, we possess the kinds of high-level cognitive skills and abilities we do in no small part because of the many tools we use for thinking. The extended mind thesis goes further, however, by claiming that it is mere prejudice to suppose that all cognition must take place within the confines of the organism’s skin and skull. Cognitive science, it is then claimed, shouldn’t only concern itself with the more or less enduring processes taking place inside the heads of cognitive agents. Cognitive scientists should also investigate, on a kind of equal footing, temporary, soft-assembled wholes that mesh the problem-solving contributions of the brain and nervous system with the body and physical and sociocultural environment.

This paper advocates explicitness about the type of entity to be considered as contentbearing in connectionist systems; it makes a positive proposal about how vehicles of content should be individuated; and it deploys that proposal to argue in favour of representation in connectionist systems. The proposal is that the vehicles of content in some connectionist systems are clusters in the state space of a hidden layer. Attributing content to such vehicles is required to vindicate the standard explanation for some classificatory networks’ ability to generalise to novel samples their correct classification of the samples on which they were trained. Content and Its Vehicles in Connectionist Systems

structuring knowledge from the data. The central trick, as we just saw, is to use the data itself in a kind of multi-stage manner. First the data is used to learn priors that encode expectations concerning the large-scale shape of the domain (what Tenenbaum et al. (op cit) call the ‘form of structure’ within the domain). expectations, learning about more detailed regularities becomes possible. In this way, HBMs actively unearth the abstract structural expectations that enable them to use raw data to learn finer and finer grained models (supporting finer grained sets of expectations).

Expecting the World: Perception, Prediction, and the Origins of Human Knowledge

Chapter 1 Introduction Tillmann Vierkant, Julian Kiverstein, and Andy Clark Part I: The Zombie Challenge Chapter 2 The Neuroscience of Volition Adina L. Roskies Chapter 3 Beyond Libet: Long-term Prediction of Free Choices from Neuroimaging Signals John-Dylan Haynes Chapter 4 Vetoing and Consciousness Alfred R. Mele Chapter 5 Determinism & Predictability Richard Holton Part II: The Sense of Agency Chapter 6 From the Fact to the Sense of Agency Manos Tsakiris and Aikaterini Fotopoulou Chapter 7 Ambiguity in the Sense of Agency Shaun Gallagher Chapter 8 There's Nothing Life Being Free: Default Dispositions, Judgments of Freedom, and the Phenomenology of Coercion Fabio Paglieri Chapter 9 Agency as a Marker of Consciousness Tim Bayne Part III: The Function of Conscious Control: Conflict Resolution, Emotion, and Mental Actions Chapter 10 Voluntary Action and the Three Forms of Binding in the Brain Ezequiel Morsella, Tara C. Dennehy, and John A. Bargh Chapter 11 Emotion Regulation and Free Will Nico H. Frijda Chapter 12 Action Control by Implementation Intentions: The Role of Discrete Emotions Sam J. Maglio, Peter M. Gollwitzer, and Gabriele Oettingen Chapter 13 Mental Action and the Threat of Automaticity Wayne Wu Chapter 14 Mental Acts as Natural Kinds Joelle Proust Part IV: Decomposed Accounts of the Will Chapter 15 Managerial control and free mental agency Tillmann Vierkant Chapter 16 Recomposing the Will: Distributed Motivation and Computer Mediated Extrospection Lars Hall and Petter Johansson Chapter 17 Situationism and Moral Responsibility: Free Will in Fragments Manuel Vargas

An appreciation of the many roles of “precision-weighting” (upping the gain on select populations of prediction error units) opens the door to better accounts of planning and “offline simulation,” makes suggestive contact with large bodies of work on embodied and situated cognition, and offers new perspectives on the “active brain”. Combined with the complex affordances of language and culture, and operating against the essential backdrop of a variety of more biologically basic ploys and stratagems, the result is a maximally context-sensitive, restless, constantly self-reconfiguring architecture.

The many faces of precision (Replies to commentaries on “Whatever next? Neural prediction, situated agents, and the future of cognitive science”)

Although predictive coding may offer a computational principle that unifies perception and action, states with different directions of fit are involved (with indicative and imperative contents, respectively). Predictive states are adjusted to fit the world in the course of perception, but in the case of action the corresponding states act as a fixed target towards which the agent adjusts the world. Main Text One of the central insights motivating Clark’s interest in the potential for predictive coding to provide a unifying computational principle is the fact that it can be the basis of effective algorithms in both the perceptual and motor domains (Eliasmith 2007, 380). That is surprising because perceptual inference in natural settings is based on a rich series of sensory inputs at all times, whereas a natural motor control task only specifies a final outcome. Many variations in the trajectory are irrelevant to achieving the final goal (Todorov and Jordan 2002), a redundancy that is absent from the perceptual inference problem. Despite this disanalogy, the two tasks are instances of the same general mathematical problem (Todorov 2006). Clark emphasises the “deep unity” between the two problems, which is justified but might serve to obscure an important difference. In the perceptual task a prediction error is used to change expectations so as to match the input whereas, as Clark notes, in the motor task the prediction error is used to drive motor behaviour that changes the input. In perception, prediction error is minimised by changing something internal (expectations) whereas in action prediction error is minimised by changing something external (acting on the world so as to alter sensory input). Although it is true in one sense that there is a common computational principle

Commentary Title Perception Vs Action: the Computations May Be the Same but the Direction of Fit Differs Author Information

We suggest that the hierarchical predictive processing account detailed by Clark can be usefully integrated with narrative psychology by situating personal narratives at the top of an individual’s knowledge hierarchy. Narrative representations function as high-level generative models that direct our attention and structure our expectations about unfolding events. Implications for integrating scientific and humanistic views of human experience are discussed.

Personal narratives as the highest level of cognitive integration

How to Qualify for a Cognitive Upgrade: Executive Control, Glass Ceilings and the Limits of Simian Success

This chapter introduces some recent developments in the areas of human reasoning and decision making. Regarding decision making, the chapter focuses on decision-under-risk, using problems which are explicitly described in linguistic or symbolic terms. Human common-sense reasoning is far more sophisticated than any current artificial intelligence models can capture; yet people's performance on, for example, simple conditional inference, while perhaps explicable in probabilistic terms, is by no means effortless and noise-free. It may be that human reasoning and decision making function best in the context of highly adapted cognitive processes such as basic learning, deploying world knowledge, or perceptuomotor control. Indeed, what is striking about human cognition is the ability to handle, even to a limited extent, reasoning and decision making in novel, hypothetical, verbally stated scenarios, for which our past experience and evolutionary history may have provided us with only minimal preparation.

Philosophical Explorations: An International Journal for the Philosophy of Mind and Action

Does the material basis of conscious experience extend beyond the boundaries of the brain and central nervous system? In Clark 2009 I reviewed a number of ‘enactivist’ arguments for such a view and found none of them compelling. Ward (2012) rejects my analysis on the grounds that the enactivist deploys an essentially world-involving concept of experience that transforms the argumentative landscape in a way that makes the enactivist conclusion inescapable. I present an alternative (prediction-and-generative-model-based) account that neatly accommodates all the positive evidence that Ward cites on behalf of this enactivist conception, and that (I argue) makes richer and more satisfying contact with the full sweep of human experience.

Dreaming the Whole Cat: Generative Models, Predictive Processing, and the Enactivist Conception of Perceptual Experience

According to the thesis of extended cognition, cognitive processes do not need to be fully located inside the skin of the cognizing agent. Humans routinely engage their wider artifactual environment to extend the capacities of their naked brain. They often rely extensively on external aids (notebooks, watches, and smartphones) and the latter may (under certain conditions) become a proper part of the cognizing mind. The thesis of extended cognition has been influential in the philosophy of mind, cognitive science, linguistics, informatics, and ethics, but, surprisingly, not in contemporary epistemology. The discipline concerned with one of the most remarkable products of human cognition – viz., knowledge – has largely ignored the suggestion that its main object of study might be produced by cognitive processes outside the human skin. The purpose of this volume is therefore to examine the ramifications of extended cognition for epistemology – which, as it turns out, are quite profound. The authors of the first five articles in the volume – Ken Aizawa, Fred Adams, Adam Green, Michael Kirchhoff & Will Newsome, and Tom Roberts – are all concerned principally with the relationship between extended cognition and contemporary virtue/credit theories of knowledge. Ken Aizawa, in his paper ‘Distinguishing virtue epistemology and extended cognition’, engages with Pritchard’s (2010) suggestion that there is a ‘snug fit’ between the ability condition in virtue epistemology and extended cognition. Regarding the famous ‘Otto’ case put forward by Clark and Chalmers (1998), for instance, Pritchard argues that Otto’s systematic use and maintenance of his notebook represents a great deal of epistemic virtue on his part; in light of that, putative cases of extended cognition do not seem to threaten the intuitive link between ability/virtue and knowledge. Aizawa, now, offers two lines of thought to motivate the charge that Pritchard overestimates the fit between virtue epistemology and extended cognition: (i) two agents may be in the same epistemic situation, yet differ in the extendedness of their cognition, a fact which shows that epistemic matters are orthogonal to matters of the realization base of cognitive processes; (ii) the particular formulation of extended cognition Pritchard homes in on (namely that offered by Clark and Chalmers 1998) gives a misleading impression of the affinity between extended cognition and virtue epistemology. Fred Adams argues in his article, ‘Extended cognition meets epistemology’, that extended cognition poses a problem for certain theories of knowledge (namely credit/

The Iterated Learning Explanation of Structured Language (Language As An Adaptive System: Humans As Hosts): What is your favourite deep, elegant or beautiful explanation?

Part I Complexity and the Animal Mind Introduction 3 Maggie McGonigle-Chalmers 1 Relational and Absolute Discrimination Learning by Squirrel Monkeys: Establishing a Common Ground with Human Cognition 12 Barry T. Jones 2 Serial List Retention by Non-Human Primates: Complexity and Cognitive Continuity 25 F. Robert Treichler 3 The Use of Spatial Structure in Working Memory: A Comparative Standpoint 38 Carlo De Lillo 4 The Emergence of Linear Sequencing in Children: A Continuity Account and a Formal Model 55 Maggie McGonigle and Iain Kusel 5 Sensitivity to Quantity: What Counts across Species? 80 Sarah T. Boysen and Anna M. Yocom

Hubert L. Dreyfus and Stuart E. Dreyfus Making a Mind Versus Modeling the Brain: Artificial Intelligence Back at a Branchpoint

Although predictive coding may offer a computational principle that unifies perception and action, states with different directions of fit are involved (with indicative and imperative contents, respectively). Predictive states are adjusted to fit the world in the course of perception, but in the case of action the corresponding states act as a fixed target towards which the agent adjusts the world.

In his engaging and important essay, John Banja (2011) mounts a powerful (and for the most part successful) assault on an argumentative strategy that he dubs “virtue essentialism.” Virtue essentialists treat moral and ethical discourse as conducted using constructs and categories that assume the existence, hence availability to discovery, of determinate, context-independent, facts: facts about the “correct” meaning of such contested descriptions as “woman” (as in the case of the athlete Semenya, who has female external genitalia, no uterus or ovaries, and a highly elevated [for a woman athlete] level of testosterone). Banja, by contrast, argues for a nonessentialist approach in which terms such as “woman” name fluid, multidimensional feature complexes. Relative to such high-dimensional feature complexes, the question of what features matter on a given occasion elicits a context-dependent reaction, and one that may be quite properly pushed around by attempts to reframe the context, or in virtue of different initial biases. This latter picture of much “on-the-hoof” debate and discussion is mandated, as Banja notes, by work in cognitive science that depicts human concepts as prototype-based cognitive constructs. Such constructs deliver the statistical central tendency of a large number of concrete exemplars, many of which may differ in important ways (and along an unlimited number of possible dimensions) from the others. The instances are nonetheless proper instances, despite the variation. And the central tendency may not even be exemplified in a single concrete exemplar. The upshot, according to Banja, is that:

Book Symposium on Supersizing the Mind: Embodiment, Action, and Cognitive Extension (Oxford University Press, NY, 2008)

Predictive Coding: What scientific concept would improve everybody's cognitive toolkit?

Précis of Supersizing the mind: embodiment, action, and cognitive extension (Oxford University Press, NY, 2008)

Perception, action, and experience: unravelling the golden braid*

Knowing what we can do: actions, intentions, and the construction of phenomenal experience

There seems to be a distinction bet:ween primary and secondary properties; some philosophers defend the view rhat properties like colours and values are secondary, while others criticize ie The distinction is usually introduced in terms of essence; roughly, secondary properties essentially involve mental states, while prirnary properties do noL In part because this does not seem very illuminating, philosophers have produced different reductive analyses in modal terms, metaphysic al' episternic. Here 1 will argue, firstly, that some weU-known examples fail, and also that there are deep reasoos why such approaches should do so. Secondly, 1 wiJI argue that it 1s acceptable to remaio satisfied ;vith the nonreductive account in terrns of essence. To that end, I will indicare how such an explication could be put ro use to support the claim that properties like colours and values are secondary. In a series of recent writings, Kit Fine has argued that essence cannor be reductively analysed in modal terms. Fine offers sorne examples to motivare his dairn. 1 suggest that the primary/secondary distinction constitutes a philosophically interesting i!lustratioo.

Listening to Philosophy Amidst the clatter and din of contemporary philosophy—a cacophony that winds in and around and through language—Jean-Luc Nancy pauses to ask if philosophy is capable of listening. Listening, of course, takes as its object sound, and sound, as the material vehicle for arbitrary symbolic tokens, is basic to the process of signification upon which language and philosophy are based. Nancy, however, is interested in sound not as object but as sense, and in listening not as the first step in a process of signification but as an activity prior to signification. For philosophy to be capable of listening, then, it must seize sound as sense, not as sign. This thought brings Nancy to music, for although sounds permeate our existence (as their resonance permeates Nancy’s Listening), it is in music that sound—sound that shapes time and space without referring to either—becomes a substantive worthy of a more comprehensive contemplation. Listening, then, leads philosophy past sound and past resonance to music as the place where sound and resonance become complete. In the course of following this path along its various twists and turns Nancy comes face to face with one of the originary moments of phenomenology: Husserl’s analysis of time, in which the philosopher uses as his model the act of listening to a melody. Here Nancy follows and adapts Gerard Granel’s critique of Husserl, and together they note that, in his analysis, Husserl has perpetuated a ‘forgetting of being,’ which occurs “to the very extent that he does not concentrate his ear on musical resonance but rather converts it ahead of time into the object of an intention that configures it. Sound (and/or sense) is what is not at first intended. It is not first “intentioned”: on the contrary, sound is what places its subject, which has not preceded it with an aim, in tension, or

In her excellent and thought-provoking essay "Searching for the Source of Executive Attention" Catherine Stinson argues that many accounts of executive attention threaten to involve some kind of conceptual confusion. While agreeing with many of the key criticisms, I explore some possible responses, which retain some of the flavor of the notion of executive attention. In the excellent and thought-provoking essay, "Searching for the Source of Executive Attention," Catherine Stinson argues that many accounts of executive attention threaten to involve some kind of conceptual confusion. Such confusion threatens when executive attention is thought of as involving some kind of supervisory control over what gets attended to and when, and often involves what Stinson (p. 5) describes as the problematic "assumption that there is an ultimate origin of executive control to be found somewhere in the brain, probably in prefrontal cortex. " What makes that assumption problematic is, she argues, its dangerous liaison with a kind of hallucinated, over-endowed, inner homunculus. Concerning this kind of worry in general she states, " The homunculus problem could more generally be attached to any explanation of how a mechanism achieves a given ability that involves the assumption that some part of the mechanism has the ability " (p. 7). The worry, thus, is that by effectively assuming the ability in question, such " explanations " merely assume that which they set out to explain. Stinson is right to warn us that many accounts that mention executive attention and supervisory control and so forth, may place too much unexplained power in some over-endowed black box. Stinson argues, in addition, that there is something in the way * This commentary was prepared thanks to support from the AHRC, under the ESF Eurocores CNCC scheme, for the CONTACT (Consciousness in Interaction) project, AH/E511139/1

: According to the thesis of the ‘extended mind’ (Clark and Chalmers (1998)), the physical systems that realize some of our mental states and processes are not always confined to the brain. Neil Levy (2007a, 2007b) supports the extended mind thesis, and argues that it has ethical implications which have thus far been largely overlooked. We agree with Levy, but we emphasise the difference between the claim that the mind is extended and the claim that the mind is merely embedded, and suggest that the former may be associated with more significant ethics implications than the latter. We consider how the extended mind thesis has implications for strategies of cognitive rehabilitation, and for our understanding of cognitive impairment itself. We conclude with an exploration of the relationship between the boundaries of the mind and the boundaries of moral agency.

1. The Situation in Cognition The situated cognition movement in the cognitive sciences, like those sciences themselves, is a loose-knit family of approaches to understanding the mind and cognition. While it has both philosophical and psychological antecedents in thought stretching back over the last century (see Gallagher, this volume, Clancey, this volume,), it has developed primarily since the late 1970s as an alternative to, or a modification of, the then predominant paradigms for exploring the mind within the cognitive sciences. For this reason it has been common to characterize situated cognition in terms of what it is not, a cluster of "anti-isms". Situated cognition has thus been described as opposed to Platonism, Cartesianism, individualism, representationalism, and even

Is consciousness all in the head, or might the minimal physical substrate for some forms of conscious experience include the goings on in the (rest of the) body and the world? Such a view might be dubbed (by analogy with Clark and Chalmers’s (1998) claims concerning ‘the extended mind’) ‘the extended conscious mind’. In this article, I review a variety of arguments for the extended conscious mind, and find them flawed. Arguments for extended cognition, I conclude, do not generalize to arguments for an extended conscious mind.

Spreading the Joy? Why the Machinery of Consciousness is (Probably) Still in the Head

Genesis Machines: The New Science of Biocomputing. Martyn Amos (2006, Atlantic Books, London.) xiii + 353. £19, $30 (hardcover), £10 (paper), xiii + 353 pages. There is (as George Orwell assured us, and Martyn Amos, in this informative and engaging treatment, reminds us) a statue inside every block of stone. The trick is just getting it out. Much the same principle turns out to be at work in recent attempts to use operations upon strands of DNA as a means of computation. At first sight, the idea seems bizarre. We read, for example, of Len Adleman (a pioneer in the field) starting a computation running by adding, to a soup of strands of DNA ‘‘a fiftieth teaspoon of water, plus various other enzymes and salts’’ (p. 120) then awaiting the answer, self-assembled among the strands within a fraction of a second (but still hidden somewhere among all the resulting strands of DNA—the trick really was in getting it out ). To call this whole process computation sounds strange to a generation steeped in silicon-based electronic computing. But is in fact no stranger, fundamentally, than the idea of using any other kind of physical matter and process (siliconbased machines or networks of neurons and neurotransmitters) as a means both of representing data (or problems) and of implementing computational operations apt to the data thus represented. In each case the theorist, or Mother Nature, needs to find a way to represent some problem using the materials at hand, then to define operations that can be applied automatically to the problem encoded in that format: operations that will terminate (if they terminate at all) in a representation, in the same format, of a solution to the problem. In the sub-eponymous ‘‘new science of biocomputing’’ the representational medium is strands of DNA (or sometimes RNA) and the operations performed by enzymes or by the use of other bench techniques able to act upon different strands in different (but reliable enough) ways. Take, for example, the Hamiltonian path problem (a variant of the traveling salesman problem): ‘‘given a set of cities connected by a set of one-way roads, does there exist a path that allows a traveler to start a journey at one particular city, visit each intermediate city only once and end at another particular city?’’ (p. 112). The problem is interesting in that it belongs to the class of problems that are said to be NP-complete—that is, to involve search spaces that grow very rapidly as the number of variables (in this case, cities) increases—and that seem to offer no way of reliably finding a solution except by the brute force method of trying out each candidate solution to see if it works. [The class includes (p. 163) sudoku puzzles, games such as tetris and minesweeper, identifying new computer viruses, predicting how proteins will fold, and classroom scheduling so as to avoid timetable clashes.] To solve such problems using DNA computing, Adleman, Amos, and others implemented various versions of what is probably the most basic computational strategy of them all: generate and test. That is, find a way to generate lots and lots of candidate solutions, then test each candidate to see if it works. If you are able to generate and test every possible candidate solution, you are guaranteed to find a solution, assuming one exists. Natural selection exploits a complex and interesting variant: Generate a variety of forms and structures, then see which ones pass the test of survival and reproduction. Natural selection, however, does not have to worry about finding any one correct solution from a combinatorially explosive haystack of candidates. Not so with the Hamiltonian path problem, or any of its NP-complete cousins. In these kinds of cases, the solution or solutions (if there are any) lie buried deep in the pile of candidates. The question, as with the statue, is how to get them out.

Genesis Machines: The New Science of Biocomputing. Martyn Amos (2006, Atlantic Books, London.) xiii + 353. 19, $30 (hardcover), 10 (paper), xiii + 353 pages

Introduction: Mind Embodied, Embedded, Enacted: One Church or Many?

After offering a brief account of how we understand the shared circuits model (SCM), we divide our response into four sections. First, in section R1, we assess to what extent SCM is committed to an account of the ontogeny and phylogeny of shared circuits. In section R2, we examine doubts raised by several commentators as to whether SCM might be expanded so as to accommodate the mirroring of emotions, sensations, and intransitive actions more generally. Section R3 responds to various criticisms that relate to the account of social-learning Hurley proposes in the target article. We conclude in section R4 by responding to a number of commentators who argued for the limitation of control theory as a framework for studying social cognition. Introduction: Stirring the science “Shared circuits” was Susan Hurley’s last grand project. It set the agenda that might, in another possible world, have allowed Susan and her commentators to begin to converge on a unified and integrated understanding of something quite fundamental to human thought and reason: our ability to know the minds of others, and of ourselves. Susan’s goal was to show one possible way in which a shared basic information space for perception and action might be bootstrapped, function by function, into a grip on self and other, thus providing the essential entrance ticket to the rich realm of social cognition. This project would close the circle, showing that the issues concerning embodiment and dynamics (Hurley 1998) were never that far away from those concerning social cognition, policy, and the possibility of responsibility (Hurley 1989; 2003; 2006a). Susan died before she could see this project into print. But had she been able to do so, she would have been truly delighted by the wide array of thoughtful, challenging, and constructive commentaries that her shared circuits model (SCM) has elicited. One special source of delight would have been the sheer interdisciplinary diversity of the responses. For Susan believed very strongly that a proper understanding of minds, persons, and reasons would emerge only from tough, cooperative, interdisciplinary work drawing on psychology, philosophy, neuroscience, social science, and cognitive science. One measure of the success of SCM is thus its capacity to stir that larger scientific pot. In that, the treatment (as we see) succeeds wonderfully. Moreover, there seems to be significant agreement concerning many of the finer details of the story. In our response, we try to do three things: First, we briefly clarify the nature of the story on offer; second, we highlight (and where possible respond to) the main critical issues raised by the commentators; and third, we showcase the exciting range of new suggestions (and additional mechanisms) that the commentary phase has uncovered. In suggesting the responses that follow, we are acutely aware of our own shortcomings as surrogate respondents. Some of the issues raised simply exceeded our grasp of the subject area, the target material, or both. Where this has arisen, we have simply remained silent, and beg the readers’ (and the commentators’) forbearance. R1. The nature of the beast One of the challenges facing an embodied and situated approach to cognitive science is to map out a path that might have taken humans from the basic kinds of capacities for on-line adaptive response we share with robots and nonhuman animals to distinctively human cognitive abilities, such as the capacity for rational deliberation and the ability to make sense of the purposeful behaviour of other agents. The shared circuits model Response/Hurley: The shared circuits model BEHAVIORAL AND BRAIN SCIENCES (2008) 31:1 41 (SCM) contributes to meeting this challenge. It describes a set of mechanisms that might have taken humans and their evolutionary ancestors from active perception to imitation, mindreading, and deliberative, strategic thinking. Each of the model’s five layers is given a functional description, which deliberately abstracts away from details of neural implementation. This is not to say that the model is silent about implementation issues – it predicts a common coding for perception and action implemented by the mirror system, for instance (see sect. 2.2 of the target article). However, it leaves the details of how each layer might be neurally implemented as open questions for further investigation. At least one commentator (Preston) took the lack of detail at the neuroanatomical/functional level to be a weakness of the model. Notice, however, that any explanation of how the layers of the model are implemented in the brain will itself most likely be a functional explanation. Preston concedes as much in referring to a neuroanatomical/ functional level of description. Consider, for instance, a putative explanation of how layer 3 could be implemented in the mirror system. Such an explanation will identify a widely distributed neural system that includes amongst other regions the temporal lobe, the rostral inferior parietal lobule, and the ventral premotor cortex. In virtue of what do these separate neural regions form parts of a single neural system that implements a mirror system? Arguably, disparate neural regions form a part of a single distributed system because of what they do – because the cells at these regions have activation profiles that make a contribution to realising a particular task. It is true that SCM doesn’t tell us which parts of the brain coalesce to form the different layers of the model, but it does purport to describe what sub-tasks these parts of the brain must perform if they are to contribute to realising a capacity for action understanding. In this spirit, we propose interpreting SCM as having two objectives. First, it offers a task-level description of action understanding. Second, it identifies possible mechanisms that could do the work of accomplishing each of these tasks. Action understanding is a multi-faceted capacity, including the abilities to learn novel behaviours by copying, to predict and explain other’s behaviour, and to think strategically about one’s social interactions. Hurley decomposes each of these complex capacities into more basic sub-tasks. The different layers of SCM describe possible mechanisms that could perform these sub-tasks. Consider SCM’s layer 3 as an example. Layer 3 identifies a mechanism for mirroring – the kind of behavioural priming that occurs in us when we observe an action performed by another person. Our observing the other’s action makes us more likely to perform an action of the same type, ourselves. Hurley argues that our capacity for action understanding is facilitated by this tendency to copy behaviours. As the behaviours we can copy become more complex, so also does the repertoire of actions we can potentially understand. Copying behaviour is therefore a sub-task one has to be capable of performing if one is to get into the business of understanding the goaldirected behaviour of others. Now consider the mechanism SCM introduces to explain an animal’s ability to copy behaviour. The mechanism is not new to layer 3 but has already been introduced at the previous layer to explain amongst other things the motor system’s execution of fast, fluent sensorimotor behaviours. Thus, an explanation is being given of one aspect of action understanding in terms of the same mechanisms used to control sensorimotor behaviour. Often, sensorimotor behaviour will require sensory feedback to be made available faster than the sensory systems can supply. A way around this problem would be for the motor system to employ its learned associations between motor outputs and the sensory consequences of those outputs to make predictions about what will happen when a given motor command is executed. In control theory, these predictive models are called forward models. At layer 3, forward models are run in reverse, so that a system can, instead of predicting the sensory consequence of an action, work out from an observed action the motor commands that were the cause of this action. Running a forward model in reverse thus produces a motor command. Whether the system then carries out this motor command is a further question. Most of the time, the execution of motor commands arrived at exogenously from observing the actions of others will be inhibited. This makes good evolutionary sense, as Makino (and indeed Hurley) notes: A creature that copied the behaviour of an approaching predator would not be long of this world. How does this mechanism of running forward models in reverse explain an animal’s ability to copy behaviour? When a forward model is run in reverse, the outcome of this process will be the production of a motor command. This explains why, when we observe another acting, we are automatically primed to perform the same or similar action ourselves. We have this standing disposition because running a forward model backwards produces in us the same motor plan that initiated the action in the other person. We can also see now what Hurley means when she claims that a shared information space for perception and action can also function as a shared information space for self and other. Perception and action share a common information space in part because perceiving another agent acting causes our motor system to produce the same or similar motor commands that were the causes of that agent’s actions. This information space can also be deployed in action understanding. Say I perceive another person reach for and answer their mobile phone. My motor system will now run a forward model in reverse and produce the same or similar motor plan that led the other person to reach and pick up their ringing handset. This motor plan is now available to be used by other subpersonal systems (layer 4 of SCM) to make sense of the other person’s action and its causes. However, the information my motor system makes available doesn’t distinguish between motor plans

Much recent work stresses the role of embodiment and action in thought and reason, and celebrates the power of transmitted cultural and environmental structures to transform the problem-solving activity required of individual brains. By apparent contrast, much work in evolutionary psychology has stressed the selective fit of the biological brain to an ancestral environment of evolutionary adaptedness, with an attendant stress upon the limitations and cognitive biases that result. On the face of it, this suggests either a tension or, at least, a mismatch, with the symbiotic dyad of cultural evolution and embodied cognition. In what follows, we explore this mismatch by focusing on three key ideas: cognitive niche construction; cognitive modularity; and the existence (or otherwise) of an evolved universal human nature. An appreciation of the power and scope of the first, combined with consequently more nuanced visions of the latter two, allow us to begin to glimpse a much richer vision of the combined interactive potency of biological and cultural evolution for active, embodied agents.

The Cambridge Handbook of Situated Cognition: How to Situate Cognition

Forward: By David Chalmers / Acknowledgements / Introduction: BRAINBOUND versus EXTENDED / I: From Embodiment to Cognitive Extension - 1. The Active Body: 1.1 A Walk on the Wild Side 1.2 Inhabited Interaction 1.3 Active Sensing 1.4 Distributed Functional Decomposition 1.5 Sensing for Coupling 1.6 Information Self-Structuring 1.7 Perception, Qualia, and Sensorimotor Expectations 1.8 Time and Mind 1.9 Dynamics and (Soft) Computation. 1.10 Out from the Bedrock 2. The Negotiable Body: 2.1 Where the Rubber Meets the Road 2.2 What's in an Interface? 2.3 New Systemic Wholes 2.4 Substitutes 2.5 Incorporation Vs Use 2.6 Towards Cognitive Extension 2.7 Three Grades of Embodiment 3. Material Symbols: 3.1 Language as Scaffolding 3.2 Augmenting Reality 3.3 Sculpting Attention 3.4 Hybrid Thoughts? 3.5 From Translation to Coordination 3.6 Second-order Cognitive Dynamics 3.7 Self-made Minds. 4. World, Incorporated: 4.1 Cognitive Niche Construction: A Primer 4.2 Cognition in the Globe: A Cameo 4.3 Thinking Space 4.4 Epistemic Engineers 4.5 Exploitative Representation and Wide Computation 4.6 Tetris: The Update 4.7 The Swirl of Organization 4.8 Extending the Mind 4.9 BRAINBOUND versus EXTENDED: The Case So Far. II. Boundary Disputes - 5. Mind Re-bound?: 5.1 EXTENDED Anxiety 5.2 Pencil Me In 5.3 The Odd Coupling 5.4 Cognitive Candidacy 5.5 The Mark of the Cognitive? 5.6 Kinds and Minds 5.7 Perception and Development 5.8 Deception and Contested Space 5.9 Folk Intuition and Cognitive Extension 5.10 Asymmetry and Lopsideness 5.11 Similarity vs Complementarity 5.12 Hippo-World 6. The Cure for Cognitive Hiccups (HEMC, HEC, HEMC): 6.1 Rupert's Challenge 6.2 HEC versus HEMC 6.3 Parity and Cognitive Kinds (Again) 6.4 The Persisting Core 6.5 Cognitive Impartiality 6.6 A Brain Teaser 6.7 Thoughtful Gestures 6.8 Material Carriers 6.9 Loops as Mechanisms 6.10 Anarchic Self-Stimulation 6.11Autonomous Coupling 6.12 Why the HEC? 6.13 The Cure 7. Rediscovering the Brain: 7.1 Matter into Mind 7.2.Honey, I Shrunk the Representations 7.3 Change Spotting: The Sequel 7.4 Thinking about Thinking: The Brain's Eye View.: 7.5 Born-Again Cartesians? 7.6 Surrogate Situations 7.7 Plug Points 7.8 Brain Control 7.9 Asymmetry Arguments 7.10 Extended in a Vat 7.11 The (Situated) Cognizer's Innards III: The Limits of Embodiment - 8. Painting, Planning, and Perceiving: 8.1 Enacting Perceptual Experience 8.2 The Painter and the Perceiver 8.3 Three Virtues of the Strong Sensorimotor Model 8.4 A Vice: Sensorimotor (Hyper) Sensitivity 8.5 What Reaching Teaches 8.6 (Tweaked)Tele-Assistance 8.7 Sensorimotor Summarizing 8.8 Virtual Content, Again 8.9 Beyond the Sensorimotor Frontier 9. Disentangling Embodiment: 9.1 Three Threads 9.2 The Separability Thesis 9.3 Beyond Flesh-eating Functionalism. 9.4 Ada, Adder, and Odder 9.5 A Tension Revealed 9.6 What Bodies Are 9.7 Participant Machinery and Morphological Computation 9.8 Quantifying Embodiment 9.9 The Heideggerian Theatre / 10. Conclusions: Mindsized Bites / Appendix: The Extended Mind (Andy Clark and David Chalmers)

Mind, it is increasingly fashionable to assert, is an intrinsically embodied and environmentally embedded phenomenon. But there is a potential tension between two strands of thought prominent in this recent literature. One of those strands depicts the body as special, and the fine details of a creature’s embodiment as a major constraint on the nature of its mind: a kind of new-wave body-centrism. The other depicts the body as just one element in a kind of equal-partners dance between brain, body and world, with the nature of the mind fixed by the overall balance thus achieved: a kind of extended functionalism (now with an even broader canvas for multiple realizability than ever before). The present paper displays the tension, scouts the space of possible responses, and ends by attempting to specify what the body actually needs to be, given its complex role in these recent debates.

Pressing the Flesh: A Tension in the Study of the Embodied, Embedded Mind?*

I offer here a new theory of moral agency ‐why people are ethical, why they are not, and how to get them to be more ethical. I look broadly at evidence from the new brain sciences, systems theory, and Spinoza’s philosophy to address the question. Spinoza’s vision of the infinitely expansive boundaries of the self as we progressively take in and embrace the world, and also extrude ourselves into the universe, forms the basis for rethinking moral agency and moral psychology. His vision opens up a broader swathe of the evidence coming out of both the theory of complex adaptive systems and also out of the new brain sciences than is usually thought of as relevant to exploring and understanding what makes us moral beings. It points us toward the pertinence of understanding moral agency in terms of nested complex adaptive systems.

The Self Beyond Itself: Further Reflection on Spinoza's Systems Theory of Ethics

172 words): This article is a contribution to a recent debate in the philosophy of perception between Alva Noë and Sean Kelly. Noë (2004) has argued that the perspectival part of perception is simultaneously represented along with the non-perspectival part of perception. Kelly (2004) argues that the two parts of perception are not always simultaneously experienced. Here I focus on specular highlights as an example of the perspectival part of perception. First I give a priori motivation to think that specular highlights are experienced at the same time as nonperspectival properties, which challenges Kelly’s position. Then I discuss psychophysical work by Andrew Blake and Heinrich Bülthoff (1990) which seems to show that specular highlights are not represented in the way that Noë (2004) would suggest. In the third section I suggest a compromise between Noë and Kelly: specular highlights are not represented, but rather play an evidentiary role in the representation of perspective independent properties, like gloss and shape. I conclude with some thoughts about how this study can generalize to other kinds of experience. Words: 4391 Words including footnotes: 5231 Specular highlights are the perspective dependent shiny spots appearing on glossy surfaces. Our visual experiences are filled with them. One can notice them on automobiles, leaves, liquid, food, metals, and many other surfaces. Philosophers of perception have not paid much attention to specular highlights, as far as I can tell. But scientists working in computer rendering have studied specular highlights extensively, and have developed some advanced mathematical techniques for calculating the locations of highlights in artificial scenes (Watt and Watt 1992, for example). Here I show how specular highlights are relevant for contemporary issues in the philosophy of perception. 1 This article takes material from my doctoral dissertation which was supervised by Radu Bogdan for Tulane University. I thank the following people for helpful comments: Harald Atmanspacher, Radu Bogdan, Bruce Brower, Andy Clark, Sean Kelly, Alva Noë, and two anonymous referees. I especially benefited from discussing this material with the late Susan Hurley. Finally, I received helpful comments when presenting this material at the Bristol PPNB conference in March 2007, for which I am grateful. 2 In the computer vision literature, they are sometimes called ‘specularities,’ ‘highlights,’ or ‘specular reflections.’ 3 They might be implicit in some of Edmund Husserl’s writings, and Maurice Merleau-Ponty was sensitive to the way in which the surface of an object affects our color experience of that object. More recently, Alva Noë has mentioned specular highlights (2004: 125). 4 I understand the philosophy of perception to be a part of the philosophy of mind which focuses on perception using both empirical evidence and a priori description. For example, some live issues in the philosophy of perception involve whether there is more than one type of perceptual content (Noë 2004, chapter 5), whether perceptual content is fully representational (Tye 2000, chapter 4), and whether perceptual content is partly non-conceptual (Gunther 2003).

Bio of Dr. Clark: Dr. Andy Clark is a professor of philosophy and chair in logic and metaphysics at the University of Edinburgh in Scotland. Previously, he taught at Washington University at St. Louis and the University of Sussex in England. Clark is one of the founding members of the Contact collaborative research project, whose aim is to investigate the role environment plays in shaping the nature of conscious experience. Dr. Andy Clark research interests include philosophy of mind, artificial intelligence, including robotics, artificial life, embodied cognition, and mind, technology and culture. Dr. Clark's papers and books deal with the philosophy of mind and he is considered a leading scientist in mind extension. He has also written extensively on connectionism, robotics, and the role and nature of mental representation.

This newsletter is published twice each year, in spring and fall issues, by the Cognitive Science Program at Lehigh University. Its purpose is to inform faculty and students about the interdisciplinary and growing field of cognitive science and to report the activities of Lehigh’s Program. The newsletter is distributed free of charge in the United States and Canada to academic programs and individuals interested in cognitive science. Anyone who would like to be added to the mailing list should simply notify the Production Editor. The Editorial Staff welcomes readers’ comments and solicits materials dealing with cognitive science. We are especially pleased to consider course syllabi, short essays, brief descriptions of scholarship and research in progress, extended ab stracts of doctoral dissertations, book reviews, and original art work (e.g., cartoons, line-drawings, computer-generated images). Address all submissions, comments, and subscription requests to: John B. Gatewood, CogSci News, Lehigh University, 681 Taylor St., Bethlehem, PA 18015-3169. Send electronic mail to jbg1@Lehigh.edu or to gdb0@Lehigh.edu. Towards a Cognitive Science of the Embodied Mind

Sentence Processing Disorders in Aphasia : Theory and Treatment 1

Our apparently simple and basic sense of our own location is, I argue, the fruit of an ongoing project. It is a construct formed by our implicit awareness of our current set of potentials for action, social engagement and intervention. Nonetheless, most attempts at technologically supported telepresence seem shallow and unsatisfying. In what follows, I explore the potential of richer and more varied technologies to impact our fundamental sense of location.

Abstract Can we really make sense of the idea (implied by Block's treatment) that there can be isolated islets of experience that are not even potentially available as fodder for a creature's conscious choices and decisions? The links between experience and the availability of information to guide conscious choice and inform reasoned action may be deeper than the considerations concerning (mere) reportability suggest.

Recent advances in cognitive science and cognitive neuroscience open up new vistas for human enhancement. Central to much of this work is the idea of new human-machine interfaces (in general) and new brain-machine interfaces (in particular). But despite the increasing prominence of such ideas, the very idea of such an interface remains surprisingly under-explored. In particular, the notion of human enhancement suggests an image of the embodied and reasoning agent as literally extended or augmented, rather than the more conservative image of a standard (non-enhanced) agent using a tool via some new interface. In this essay, I explore this difference, and attempt to lay out some of the conditions under which the more radical reading (positing brand new integrated agents or systemic wholes) becomes justified. I adduce some empirical evidence suggesting that the radical result is well within our scientific reach. The main reason why this is so has less to do with the advancement of our science (though that certainly helps) than with our native biological plasticity. We humans, I shall try to show, are biologically disposed towards literal (and repeated) episodes of sensory re-calibration, of bodily re-configuration and of mental extension. Such potential for literal and repeated re-configuration is the mark of what I shall call "profoundly embodied agency," contrasting it with a variety of weaker (less philosophically and scientifically interesting) understandings of the nature and importance of embodiment for minds and persons. The article ends by relating the image of profound embodiment to some questions (and fears) concerning converging technologies for improving human performance.

Re-inventing ourselves: the plasticity of embodiment, sensing, and mind.

A cognitive model of axiom formulation and reformulation with application to AI and software engineering

What is the role of conscious visual experience in the control and guidance of human behaviour? According to some recent treatments, the role is surprisingly indirect. Conscious visual experience, on these accounts, serves the formation of plans and the selection of action types and targets, while the control of ‘online’ visually guided action proceeds via a quasi-independent non-conscious route. In response to such claims, critics such as (Wallhagen [2007], pp. 539–61) have suggested that the notions of control and guidance invoked are unacceptably vague, and that that the image of ‘zombie systems’ guiding action fails to take account of the possibility that there is genuine but unconceptualized, unnoticed, and/or unreportable experience taking place and guiding or controlling the actions. I address both sets of concerns. I try to show that refining and clarifying the key notions of control and guidance leaves the original argument intact, as does the appeal to unconceptualized, unnoticed, or unreportable experiences. The exercise serves, however, to highlight an important complex of considerations concerning the relations between control, agency, and experience. Better understanding these relations is, I suggest, an important source of insights concerning the nature of phenomenal experience.

What Reaching Teaches: Consciousness, Control, and the Inner Zombie

Recent advances in Cognitive Science and Cognitive Neuroscience open up new vistas for human enhancement. Central to much of this work is the idea of new Human-Machine interfaces (in general) and new Brain-Machine interfaces (in particular). But despite the increasing prominence of such ideas, the very idea of such an interface remains surprisingly under-explored. In particular, the notion of human enhancement suggests an image of the embodied and reasoning agent as literally extended or augmented, rather than the more conservative image of a standard (non-enhanced) agent using a tool via some new interface. In this essay, I explore this d ifference, and attempt to lay out some of the conditions under which the more

Reinventing Ourselves: The Plasticity of Embodiment, Sensing, and Mind*. Short title: Reinventing Ourselves

What is the relation between the material, conventional symbol structures that we encounter in the spoken and written word, and human thought? A common assumption, that structures a wide variety of otherwise competing views, is that the way in which these material, conventional symbol-structures do their work is by being translated into some kind of content-matching inner code. One alternative to this view is the tempting but thoroughly elusive idea that we somehow think in some natural language (such as English). In the present treatment I explore a third option, which I shall call the “complementarity” view of language. According to this third view the actual symbol structures of a given language add cognitive value by complementing (without being replicated by) the more basic modes of operation and representation endemic to the biological brain. The “cognitive bonus” that language brings is, on this model, not to be cashed out either via the ultimately mysterious notion of “thinking in a given natural language” or via some process of exhaustive translation into another inner code. Instead, we should try to think in terms of a kind of coordination dynamics in which the forms and structures of a language qua material symbol system play a key and irreducible role. Understanding language as a complementary cognitive resource is, I argue, an important part of the much larger project (sometimes glossed in terms of the “extended mind”) of understanding human cognition as essentially and multiply hybrid: as involving a complex interplay between internal biological resources and external non-biological resources.

Introduction Advanced biological brains are by nature open-ended opportunistic controllers. Such controllers compute, pretty much on a moment-tomoment basis, what problem-solving resources are readily available and recruit them into temporary problem-solving wholes. Neural

That lonesome whistle: a puzzle for the sensorimotor model of perceptual experience

In Action in Perception Alva Noe develops and presents a sensorimotor account of vision and of visual consciousness. According to such an account seeing (and indeed perceiving more generally) is analysed as a kind of skilful bodily activity. Such a view is consistent with the emerging emphasis, in both philosophy and cognitive science, on the critical role of embodiment in the construction of intelligent agency. I shall argue, however, that the full sensorimotor model faces three important challenges. The first is to negotiate a path between two prima facie unsatisfactory readings of the central claim that conscious perceptual experience is constituted by knowledge of patterns of sensorimotor dependence. The second is to convince us that the sensorimotor contribution, in such cases, is actually constitutive of perceptual experience rather than merely causally implicated in the origination of such experience. 2 And the third is to respond to the important challenge raised by what I will dub 'sensorimotor summarizing' models of the relation between conscious experience and richly detailed sensorimotor routines. According to such models 3 conscious perceptual experience only rather indirectly reflects the rich detail of our actual sensorimotor engagements, which are instead lightly sampled as a coarse guide, optimized for planning and reasoning, and geared and filtered according to current needs and purposes.

Vision as Dance? Three Challenges for Sensorimotor Contingency Theory

ABSTRACT What is the relation between perceptual experience and the suite of sensorimotor skills that enable us to act in the very world we perceive? The relation, according to ‘sensorimotor models’ (O'Regan and Noe 2001, Noe 2004) is tight indeed. Perceptual experience, on these accounts, is enacted via skilled sensorimotor activity, and gains its content and character courtesy of our knowledge of the relations between (typically) movement and sensory stimulation. I shall argue that this formulation is too extreme, and that it fails to accommodate the substantial firewalls, dis-integrations, and special-purpose streamings that form the massed strata of human cognition. In particular, such strong sensorimotor models threaten to obscure the computationally potent insensitivity of key information-processing events to the full subtleties of embodied cycles of sensing and moving.

I—Andy Clark: Cognitive Complexity and the Sensorimotor Frontier

Connectionism and classicism, it generally appears, have at least this much in common: both place some notion of internal representation at the heart of a scientific study of mind. In recent years, however, a much more radical view has gained increasing popularity. This view calls into question the commitment to internal representation itself. More strikingly still, this new wave of anti-representationalism is rooted not in 'armchair' theorizing but in practical attempts to model and understand intelligent, adaptive behavior. In this paper we first present, and then critically assess, a variety of recent anti-representationalist treatments. We suggest that so far, at least, the sceptical rhetoric outpaces both evidence and argument. Some probable causes of this premature scepticism are isolated. Nonetheless, the anti-representationalist challenge is shown to be both important and progressive insofar as it forces us to see beyond the bare representational / nonrepresentational dichotomy and to recognize instead a rich continuum of degrees and types of representationality.

Sensorimotor skills and perception. Cognitive complexity and the sensorimotor frontier: I - Andy Clark

Clark and Chalmers (1998) defend the view that the human mind need not be in the human head. To speak more carefully, they defend the view that the material vehicles 1 of cognition can be spread out across brain, body and certain aspects of the physical environment itself. Critics of this view (which has become known as the ‘extended mind hypothesis’, henceforth EM) have pointed to the supposedly intrinsic nature of the contents carried by inner biological vehicles. External, non-biological vehicles, such critics claim, are not (at least in any typical human case) similarly endowed, and thus fail to exhibit one of the key ‘marks of the cognitive’ (Adams and Aizawa 2001: 48). I shall argue that this response is mistaken. First, though I shall not dwell upon this, it is unclear that there is any such thing as intrinsic content anyway. Second, in so far as the notion is intelligible at all, there is no reason to believe that external, non-biological structures are incapable of supporting such content. And third, even if they were incapable of so doing, this would not actually compromise the case for the extended mind. The worry about intrinsic content, I conclude, is multiply fatally flawed. Despite all this, there are some related and legitimate worries that may well be informing the unease expressed by Adams, Aizawa and others. 2 The paper ends by briefly discussing these worries, pointing to a possible solution, and then gesturing at the larger picture of the extended mind and its place in nature. The original argument for EM took the form of some thought experiments, a principle meant to command rational assent, and a battery of

Material Symbols: From Translation to Co-ordination in the Constitution of Thought and Reason Andy Clark (andy.clark@ed.ac.uk) School of Philosophy, Psychology and Language Sciences Edinburgh University, Scotland, UK How, if at all, can embodied and ‘representation-lite’ approaches deal with traditionally cognitive phenomena? One key move may be to take very seriously the role of human activity and human-built structures in altering the way difficult problems are presented and solved. Our best practices and artifacts, on this view, enable many of the same basic strategies to tackle perception, action and high-level reason. An important challenge to this view depicts practices of ‘higher-level reasoning’ as themselves requiring the use of new forms of ‘de- coupled’ internal representation (for a sophisticated version, see Kim Sterelny’s Thought in a Hostile World) I explore this issue, with special attention to the cognitive role of words and public symbols. De-coupled ways of knowing, I conclude, do not demand de-coupled internal representations in addition to the resources provided by, respectively, standard perceptually-based knowledge and representations (internal and external) of the words and symbols themselves. In this way, de-coupled knowing is itself a kind of global skill, and one that is partially constituted by our activities with a variety of cognitive artifacts including words and symbols.

Material Symbols: From Translation to Co-ordination in the Constitution of Thought and Reason

Review: Thought in a Hostile World: The Evolution of Human Cognition

How does language (spoken or written) impact thought? One useful way to approach this important but elusive question may be to consider language itself as a cognition-enhancing animal-built structure. To take this perspective is to view language as a kind of self-constructed cognitive niche.

Word, Niche and Super-Niche: How Language Makes Minds Matter More

What do linguistic symbols do for minds like ours, and how (if at all) can basic embodied, dynamical, and situated approaches do justice to high-level human thought and reason? These two questions are best addressed together, since our answers to the first may inform the second. The key move in scaling up simple embodied cognitive science is, I argue, to take very seriously the potent role of human-built structures in transforming the spaces of human learning and reason. In particular, in this article I look at a range of cases involving what I dub surrogate situations. Here, we actively create restricted artificial environments that allow us to deploy basic perception-action-reason routines in the absence of their proper objects. Examples include the use of real-world models, diagrams, and other concrete external symbols to support dense looping interactions with a variety of stable external structures that stand in for the absent states of affairs. Language itself, I finally suggest, is the most potent and fundamental form of such surrogacy. Words are both cheap stand-ins for gross behavioral outcomes, and the concrete objects that structure new spaces for basic forms of learning and reason. A good hard look at surrogate situatedness thus turns the standard skeptical challenge on its head. But it raises important questions concerning what really matters about these new approaches, and it helps focus what I see as the major challenge for the future: how, in detail, to conceptualize the role of symbols (both internal and external) in dynamical cognitive processes.

Language learning : an interdisciplinary perspective : papers from the 2004 AAAI Symposium, March 22-24, Stanford, California

In the movie, Memento, the hero, Leonard, suffers from a form of anterograde amnesia that results in an inability to lay down new memories. Nonetheless, he sets out on a quest to find his wife’s killer, aided by the use of notes, annotated polaroids, and (for the most important pieces of information obtained) body tattoos. Using these resources he attempts to build up a stock of new beliefs and to thus piece together the puzzle of his wife’s death. At one point in the movie, a character exasperated by Leonard’s lack of biological recall, shouts:

Andy Clark is one of the few professional philosophers worth reading. Unlike the vast majority of his colleagues, he writes clearly, about important issues, and is scientifically literate. His latest book, however, is a disappointment. In Natural-born Cyborgs, Clark revisits philosophical territory that he has already mapped in great detail elsewhere. In earlier works, such as the excellent Being There (MIT Press, 1997), Clark constructed a robust defence of the idea that the mind supervenes on more than just the bare biological brain. According to this view, which sometimes goes by the name of ‘situated cognition’, tools need not always remain mere peripherals which the mind uses, but can actually come to form an integral part of the mind. As the psychologist Nicholas Humphrey has put it, a man with a hammer is not just handier—he is also in an important sense cleverer. The problem with the new book is that it does not add anything to this already wellworked thesis except more examples. True, the examples themselves are fascinating, and provide a kind of whirlwind tour of some of the most exciting developments in cognitive technology from the past decade. But while brain–machine interfaces, multi-agent-based modelling and telerobotics may be interesting technologies in their own right, they add nothing to Clark’s earlier claims except by way of providing new and vivid illustrations. Given that Clark himself admits this at several points in the book, one is left wondering why he bothered to dress up the technology in the garb of philosophical analysis. After all, it is clearly the cool technology he discusses that really excites him, not the tired old claims about ‘embodiment’. You get the feeling that Clark really wishes he was an engineer, but feels constrained to make some kind of gesture towards his philosophical training. The book also suffers from a peculiar inconsistency. Most of the new technologies Clark waxes lyrical about are novel interfaces that will allow us to interact with computers in ways that we find more ‘natural’ than the ‘narrow and demanding channels of keyboard and mouse’. These include ‘tangible user interfaces’ (TUIs), in which the user manipulates physical icons (‘phicons’), and other such devices that ‘take digital abstractions and data-flows and make them as solid and manipulable as rocks and stones’. Clark calls these new interfaces ‘transparent technologies’ because they allow the user to forget the tool and concentrate on the task at hand, unlike the ‘opaque technologies’ we currently have, such as desktop computers with keyboards that are ‘nasty, clumsy, fragile, and slow’.

Fodor's theory makes thinking prior to doing. It allows for an inactive agent or pure reflector, and for agents whose actions in various ways seem to float free of their own conceptual repertoires. We show that naturally evolved creatures are not like that. In the real world, thinking is always and everywhere about doing. The point of having a brain is to guide the actions of embodied beings in a complex material world. Some of those actions are, to be sure, more recondite-than others. But in every case the contents of thoughts still look to depend, in some non-unique but vitally important way, on the kinds of doings they support.

Putting concepts to work: Some thoughts for the twentyfirst century. Author's reply

Philosophical Issues in Brain Theory and Connectionism ( Revised Version , 2002 )

A suitable project for the new Millenium is to radically reconfigure our image of human rationality. Such a project is already underway, within the Cognitive Sciences, under the umbrellas of work in Situated Cognition, Distributed and De-centralized Cogition, Real-world Robotics and Artificial Life1. Such approaches, however, are often criticized for giving certain aspects of rationality too wide a berth. They focus their attention on on such superficially poor cousins as “adaptive behaviour”, “ecologically sound perception-action routines”, “fast and frugal heuristics” and “fast, fluent real-time real-world action control”2. Is this robbery or revelation? Has 'embodied, embedded' cognitive science simply lost sight of the very phenomena it was meant to explain? Or are we finally seeing rationality aright, as fully continous with various forms of simpler, ecologically situated, adaptive response? I distinguish two ways of developing the 'embodied, embedded' approach. The first, which does indeed threaten to lose sight of the key targets, is fully committed to a doctrine of biological cognitive incrementalism according to which full-scale human rationality is reached, rather directly, by some series of tweaks to basic biological modes of adaptive response. The second depicts human capacities for advanced reason as at best the indirect products of such a process. Such capacities, it is argued, depend heavily upon the effects of a special kind of hybridization in which human brains enter into an increasingly potent cascade of genuinely symbiotic relationships with knowledge-rich artifacts and technologies. This latter approach, I finally suggest, does better justice to our peculiar profile, which combines deep biological continuity with an equally deep cognitive discontinuity. 1. For an overview of all these developments, see Clark (1997a) 2 See, for example Brooks (1991), Beer (1995), Gigerenzer and Todd (1999) and Clark (1997a).

Reasons , Robots and the Extended Mind ( Rationality for the New Millenium ) *

Abstract This article is about using research from a practitioner perspective. It tells the stories of four teachers and a researcher, who were part of a collaborative project focused on connecting research and practice in relation to Education for Sustainable Development. The project started with a small advertisement placed in a practitioner newsletter, and ended with a publication launch at the House of Commons. In this article, the authors look back at how they came to be involved in this venture, what the highs and lows were along the way, and what they now feel they got out of the experience. In sharing their experiences, they hope that they might encourage and inform others who are wondering what on earth research has got to do with them. To this end, the article concludes with some brief ‘take-away points’ for practitioners and researchers.

Is language special? Some remarks on control, coding, and co-ordination

In Natural-Born Cyborgs, Clark argues that what makes humans so different from other species is our capacity to fully incorporate tools and supporting cultural practices into our existence. Technology as simple as writing on a sketchpad, as familiar as Google or a cellular phone, and as potentially revolutionary as mind-extending neural implants - all exploit our brains' astonishingly plastic nature. Our minds are primed to seek out and incorporate nonbiological resources, so that we actually think and feel through our best technologies. Drawing on his expertise in cognitive science, Clark demonstrates that our sense of self and of physical presence can be expanded to a remarkable extent, placing the long-existing telephone and the emerging technology of telepresence on the same continuum. He explores ways in which we have adapted our lives to make use of technology (the measurement of time, for example, has wrought enormous changes in human existence), as well as ways in which increasingly fluid technologies can adapt to individual users during normal use. Bio-technological unions, Clark argues, are evolving with a speed never seen before in history. As we enter an age of wearable computers, sensory augmentation, wireless devices, intelligent environments, thought-controlled prosthetics, and rapid-fire information search and retrieval, the line between the user and her tools grows thinner day by day. "This double whammy of plastic brains and increasingly responsive and well-fitted tools creates an unprecedented opportunity for ever-closer kinds of human-machine merger," he writes, arguing that such a merger is entirely natural.

Natural-Born Cyborgs: Minds, Technologies, and the Future of Human Intelligence

This excellent and absorbing collection – a special issue of the Journal of Consciousness Studies, edited by Alva Noë, now published in separate book form – comprises fourteen papers dealing with responses to certain very striking recent discoveries about the limitations of visual attention. A cluster of experiments on “Change Blindness”, “Inattentional Blindness” and associated phenomena appear to demonstrate extremely counter intuitive results. According to one plausible characterisation, these results show that we consciously take in far less of the visual world than it seems we are aware of. It is worth briefly summarising the results of two recent sets of experiments, in order to give a flavour of this work. In ‘Gorillas in our Midst’ (Simons, D. and Chabris, C., Perception, 1999, 28), subjects were asked to perform a task that involved watching a video of a casual basketball game that lasts for about a minute. The task involves counting the number of consecutive passes between members of the one of the teams. While the basketball is being thrown from player to player, something unexpected takes place: a person dressed in a black gorilla-suit walks through the play, stops briefly in the centre of the picture, thumps his chest, and then walks off. Although most subjects correctly record the number of passes made by the team, at least half of these subjects fail to notice the gorillasuited interloper, who is visible for about nine seconds. When shown the video sequence a second time they are amazed to observe what they had previously overlooked. In Change Blindness experiments, a picture is displayed of a couple in the foreground with a number of buildings in the background. A brief flicker interrupts the display, which then returns with one substantial change – a large building in the background is no longer visible. This display remains visible for a second or so, and then again the flicker occurs and the switch is made, returning to the original picture. It may take many such alternations between images before the subject finally notices the large scene change not previously attended to; again, this produces surprise on the part of the subjects, when they realise they have overlooked an apparently obvious change. What is agreed by all theorists is that the phenomena of Change and Inattentional Blindness, etc, are well established. These experiments provide strong evidence about the limits of attention. What is less

Chapter 13. Artificial Intelligence and the Many Faces of Reason

Beer’s (2003) paper is a tour de force of detailed dynamical modeling, and provides a concrete sample of the kinds of understanding dynamicists may realistically hope to achieve. The analysis is thus, as Beer states, a “tool for building intuition”, and in this it succeeds brilliantly. But it is also an attempt to show that dynamical approaches can get a foothold in the explanation of “minimally cognitive behaviors”; that is to say, behaviors that seem, on the surface at least, good contenders for more traditional forms of problem decomposition and analysis. In these brief comments, I want to focus on one important question that I think remains unanswered, and that bears rather directly on this enterprise of “scaling up”. The question concerns the notion of an integrated dynamical explanation itself. The point about such explanations, as I understand it, is to provide a kind of integrated window on the production of behavior. By an “integrated window” I mean a perspective that treats bodily, neural, and environmental factors and forces in a kind of common dynamical currency (a single mathematical language of trajectories, bifurcations, parameters, state variables, etc., and ultimately, perhaps, of differential or difference equations). In the opening comments on the more general notion of “situatedness”, Beer suggests that “on this view, situated action is the fundamental concern and cognition is ... one resource among many that can be brought to bear as an agent encounters its world”. In the worked example of an agent that approaches circles and avoids diamonds, we see direct evidence of this in the claim that a certain three-dimensional projection provides a potent analytic tool. For this projection happens to be one that involves one environmental state variable (vertical object position), one body state variable (horizontal position relative to the object) and one neuronal state variable (output of interneuron 9). By dispensing with talk of representations and their contents, and restricting the depiction of the inner realm to a depiction of inner state alone (section 9.3), the dynamicist makes it easy to treat all three factors (bodily, neural and environmental) at once and on an even par, thus allowing projections based on any combinations that the theorist suspects might pay explanatory or predictive dividends. But can we really afford to buy this flexibility by ignoring the apparently special role of some of these factors and forces in the production of intelligent behavior? Here is a very simple example of what I

The study of Cognitive Technology is, in a very real sense, the study of ourselves. Who we are, what we are, and even where we are, are all jointly determined by our biological natures and the web of supporting (and constraining) technologies in which we live, work and dream. But what general principles and concepts will allow us to make systematic sense (indeed, to make a science) of the bio-technological mind? I offer a brief, personal sketch of the underappreciated intimacy of human organisms and technological scaffoldings, and then rehearse 7 questions that such a science needs urgently to address.

We seem, or so it seems to some theorists, to experience a rich stream of highly detailed information concerning an extensive part of our current visual surroundings. But this appearance, it has been suggested, is in some way illusory. Our brains do not command richly detailed internal models of the current scene. Our seeings, it seems, are not all that they seem. This, then, is the Grand Illusion. We think we see much more than we actually do. In this paper I shall (briefly) rehearse the empirical evidence for this rather startling claim, and then critically examine a variety of responses. One especially interesting response is a development of the so-called ‘skill theory’, according to which there is no illusion after all. Instead, so the theory goes, we establish the required visual contact with our world by an ongoing process of active exploration, in which the world acts as a kind of reliable, interrogable, external memory (Noe, Pessoa and Thompson (2000), Noe (2001). The most fully worked-out versions of this response ( Noe and O’Regan (2000), O’Regan and Noe 2001) tend, however, to tie the contents of conscious visual experience rather too tightly to quite low-level features of this ongoing sensorimotor engagement. This (I shall argue) undervalues the crucial links between perceptual experience, reason and intentional action, and opens the door to a problem that I will call ‘sensorimotor chauvinism’: the premature welding of experiential contents to very specific details of our embodiment and sensory apparatus. Drawing on the dual visual systems hypothesis of Milner and Goodale (1995), I sketch an alternative version of the skill theory, in which the relation between conscious visual experience and the low-level details of sensorimotor engagement is indirect and non-constitutive. The hope is thus to embrace the genuine insights of the skill theory response, while depicting conscious visual experience as most tightly geared to knowing and reasoning about our world.

Dennett depicts human minds as both deeply different from, yet profoundly continuous with, the minds of other animals and simple agents. His treatments of mind, consciousness, free will and human agency all reflect this distinctive dual perspective. There is, on the one hand, the (in)famous Intentional Stance, relative to which humans, dogs, insects and even the lowly thermostat (e.g. Dennett (1998)

That Special Something: Dennett on the making of Minds and Selves

1.1 ANDY CLARK ON COGNITION AND REPRESENTATION 2.1 MINDS, BRAINS, AND TOOLS 3.1 HAUGELAND ON REPRESENTATION AND INTENTIONALITY 4.1 CUMMINS - OR SOMETHING ISOMORPHIC TO HIM 5.1 BRIAN CANTWELL SMITH 6.1 HUGH CLAPIN

What are minds, that they are both essentially mental yet inextricably intertwined with body (and world)?

Peter Carruthers correctly argues for a cognitive conception of the role of language. But such a story need not include the excess baggage of compositional inner codes, mental modules, mentalese, or translation into logical form (LF).

Anchors not inner codes, coordination not translation (and hold the modules please)

Commentary on J.K O’Regan and A Noe: A sensorimotor account of vision and visual consciousness

Introduction How should we characterize the functional role of conscious visual experience? In particular, how do the conscious contents of visual experience guide, bear upon, or otherwise inform our ongoing motor activities? According to an intuitive and (I shall argue) philosophically influential conception, the links are often quite direct. The contents of conscious visual experience, according to this conception, are typically active in the control and guidance of our fine-tuned, real-time engage- ments with the surrounding three-dimensional world. But this idea (which I shall call the Assumption of Experience-Based Control) is hos- tage to empirical fortune. It is a hostage, moreover, whose safety is in serious doubt. Thus Milner and Goodale (1995) argue for a deep and abiding dissociation between the contents of conscious seeing, on the one hand, and the resources used for the online guidance of visuo- motor action, on the other. This "dual visual systems" hypothesis, which finds many echoes in various other bodies of cognitive scientific research, poses a prima facie challenge to the Assumption of Experi- ence-Based Control. More importantly, it provides (I shall argue) fuel for an alternative and philosophically suggestive account of the func- tional role of conscious visual experience.

A suitable project for the new Millenium is to radically reconfigure our image of human rationality. Such a project is already underway, within the Cognitive Sciences, under the umbrellas of work in Situated Cognition, Distributed and Decentralized Cognition, Real-world Robotics and Artificial Life. 1 Such approaches, however, are often criticized for giving certain aspects of rationality too wide a berth. They focus their attention on such superficially poor cousins as 'adaptive behaviour', 'ecologically sound perception-action routines', fast and frugal heuristics' and 'fast, fluent real-time real-world action control'. 2 Is this robbery or revelation? Has 'embodied, embedded' cognitive science simply lost sight of the very phenomena it was meant to explain? Or are we finally seeing rationality aright, as fully continuous with various forms of simpler, ecologically situated, adaptive response? I distinguish two ways of developing the embodied, embedded' approach. The first, which does indeed threaten to lose sight of the key targets, is fully committed to a doctrine of biological cognitive incrementalism according to which full-scale human rationality is reached, rather directly, by some series of tweaks to basic biological modes of adaptive response. The second depicts human capacities for advanced reason as at best the indirect products of such a process. Such capacities, it is argued, depend heavily upon the effects of a special kind of hybridization in which human brains enter into an increasingly potent cascade of genuinely symbiotic relationships with knowledge-rich artifacts and technologies. This latter approach, I finally suggest, does better justice to our peculiar profile, which combines deep biological continuity with an equally deep cognitive discontinuity.

Sensorimotor Chauvinism?” Commentary on O'Reagan, J. Kevin and Noë, Alva, “A Sensorimotor account of vision and Visual Consciousness”

Phenomenal Immediacy and the doors of Sensation: Comments on Humphreys

Neural organization raises, in an especially clear way, a major problem confronting contemporary cognitive science. The problem (the “big issue” of my title) is: What is the relation between the strategies used to solve basic problems of perception and action and those used to solve more abstract or “cognitive” problems? Is there a smooth, incremental route from what Arbib et al. call “instinctual schemas” to higher-level kinds of cognitive prowess? I argue that, despite some suggestive comments, Arbib et al. do not resolve this issue.

Abstract Recent work in cognitive science highlights the importance of exemplar-based know-how in supporting human expertise. Influenced by this model, certain accounts of moral knowledge now stress exemplar-based, non-sentential know-how at the expense of rule-and-principle based accounts. I shall argue, however, that moral thought and reason cannot be understood by reference to either of these roles alone. Moral cognition—like other forms of ‘advanced’ cognition—depends crucially on the subtle interplay and interaction of multiple factors and forces and especially (or so I argue) between the use of linguistic tools and formulations and more biologically basic forms of thought and reason.

Word and Action: Reconciling Rules and Know-How in Moral Cognition

Ranging across both standard philosophical territory and the landscape of cutting-edge cognitive science, Mindware: An Introduction to the Philosophy of Cognitive Science, Second Edition, is a vivid and engaging introduction to key issues, research, and opportunities in the field.Starting with the vision of mindware as software and debates between realists, instrumentalists, and eliminativists, Andy Clark takes students on a no-holds-barred journey through connectionism, dynamical systems, and real-world robotics before moving on to the frontiers of cognitive technologies, enactivism, predictive coding, and the extended mind. Throughout, he highlights challenging issues in an effort to engage students in active debate. Each chapter opens with a brief sketch of a major research tradition or perspective, followed by concise critical discussions dealing with key topics and problems.

Mindware: An Introduction to the Philosophy of Cognitive Science (Second Edition)

Figure 1: Cameras occupy literal points of view with respect to their subjects…….…35 Figure 2: Pictures have as part their representational content relations that the viewer would bear to the subject………………………………………………….……………36 Figure 3: Figures 3a and 3b are drawn in vanishing-point perspective, thus positioning the viewer in front of the first and second houses, respectively. Figure 3c is drawn in oblique perspective and thus does not specify a point of view in front of any particular house……………………………………………………………………………………37 v Acknowledgments

OBJECTIVE SUBJECTIVITY : ALLOCENTRIC AND EGOCENTRIC REPRESENTATIONS IN THOUGHT AND EXPERIENCE

Block (1995) famously warns against the confusion of ‘access-conscious-ness’ and ‘phenomenal consciousness’. Access consciousness occurs whenthe content of a mental state is poised for the control of rational action, forverbal report and for use in reasoning. Phenomenal consciousness, bycontrast, involves the harder-to-deﬁne presence of experiential properties,of there being ‘something it is like’ to see red, to hear a distant bell, and soon. It is the explanation of phenomenal consciousness that constitutes the‘hard problem’ of consciousness highlighted in Chalmers 1996. Block, likeChalmers, believes that many attempted explanations of phenomenalconsciousness are really just explanations of (various forms of) access-consciousness, and that the two notions are conceptually quite distinct(Block 1995: §3, Chalmers 1996: ch. 1). I shall argue, however, that thereis at least one kind of case in which facts about access seem to imply thepresence of full-blown phenomenal consciousness – a kind of case, that is,in which given the facts about access it is impossible to conceive of theabsence of phenomenal consciousness.Consider a system (being, organism, whatever) capable of perceptuallydetecting a variety of differences between stimuli. And suppose also thatthis system can be interrogated about its own acts of perceptual difference-detection. Take a particular incident in which the system detects, for exam-ple, the colour difference between two visually presented stimuli.Interrogated about this act of detection, the system must (I suggest) say oneof two things. It must say

Like those famous nations divided by a single tongue, my paper (this volume) and Professor P.M. Churchland's deep and engaging reply offer different spins on a common heritage. The common heritage is, of course, a connectionist vision of the inner neural economy a vision which depicts that economy in terms of supra-sentential state spaces, vector-to-vector transformations, and the kinds of skillful patternrecognition routine we share with the bulk of terrestrial intelligent lifeforms. That which divides us is, as ever, much harder to isolate and name. Clearly, it has something to do with the role of moral talk and exchange, and something to do with the conception of morality itself (and, correlatively, with the conception of moral progress). Most of this Reply will be devoted to clarifying the nature of the disputed territory. First, though (as a prophylactic against misunderstanding), I shall rehearse some points of agreement concerning moral talk and progress. Professor Churchland and I agree that words, talk, moral labels, and the whole collective infrastructure of moral texts, rules, traditions, tools and practices matter. We agree, indeed, that it is this speciesspecific overlay that gives human thought and reason (in science, morals, and elsewhere) much of its distinctive power and character. Thus, Churchland recognizes and emphasizes "the genuine novelty represented by the evolutionary emergence of language and the cultural emergence of discursive rules," and depicts this novelty as something that "extends the reach and elevates the quality of the original nondiscursive cognition." Furthermore, we agree that words, texts and technologies are, taken alone, cognitively and morally inert, so that "even when that external machinery does get deployed, it is the original

The last ten years have seen an increasing interest, within cognitive science, in issues concerning the physical body, the local environment, and the complex interplay between neural systems and the wider world in which they function. “Physically embodied, environmentally embedded” approaches thus loom large on the contemporary cognitive scientific scene. Yet many unanswered questions remain, and the shape of a genuinely embodied, embedded science of the mind is still unclear. I begin by sketching a few examples of the approach, and then raise a variety of critical questions concerning its nature and scope. A distinction is drawn between two kinds of appeal to embodiment: ‘simple’ cases, in which bodily and environmental properties merely constrain accounts that retain the focus on inner organization and processing, and more radical appeals, in which attention to bodily and environmental features is meant to transform both the subject matter and the theoretical framework of cognitive science. Things of the Flesh Cognitive science is bringing the body out of the closet. Talk of embodiment, and situatedness looms increasingly large in philosophy, psychology, neuroscience, robotics, education, cognitive anthropology, linguistics, and in dynamical systems approaches to behavior and thought. Something is afoot. But it is surprisingly – and frustratingly – hard to get a firm grip on exactly what it is. What is “embodied cognitive science” and how far can it take us? We can begin by illustrating some of the varied roles that embodiment can play. Fish Consider first the swimming know-how of the Bluefin Tuna. The Bluefin Tuna is a swimming prodigy, but its aquatic capacities – its ability to turn sharply, to move off quickly, and to reach such high speeds – have puzzled biologists. Physically speaking, so

Recent work in "embodied, embedded" cognitive science links mental contents to largescale distributed effects: dynamic patterns implicating elements of (what are traditionally seen as) sensing, reasoning and acting. Central to this approach is an idea of biological cognition as profoundly "action-oriented" geared not to the creation of rich, passive inner models of the world, but to the cheap and efficient production of real-world action in real-world context. A case in point is Hurley's (1998) account of the profound role of motor output in fixing the contents of conscious visual awareness an account that also emphasizes distributed vehicles and long-range dynamical loops. Such stories can seem dramatically opposed to accounts, such as Milner and Goodale (1995), that stress relatively local mechanisms and that posit firm divisions between processes of visual awareness and of visuomotor action. But such accounts, I argue, can be deeply complimentary and together illustrate an important lesson. The lesson is that cognition may be embodied and action-oriented in two distinct but complimentary ways. There is a way of being embodied and action-oriented that implies being closely geared to the fine-grained control of low level effectors (hands, arms, legs and so on). And there is a way of being embodied and action-oriented that implies being closely geared to gross motor intentions, current goals, and schematic motor plans. Human cognition, I suggest, is embodied and actionoriented in both these ways. But the neural systems involved, and the size and scope of the key dynamic loops, may be quite different in each case.

Connectionism, Concepts, and Folk Psychology: The Legacy of Alan Turing, Volume Ii

There is a definite challenge in the air regarding the pivotal notion of internal representation. This challenge is explicit in, e.g., van Gelder, 1995; Beer, 1995; Thelen & Smith, 1994; Wheeler, 1994; and elsewhere. We think it is a challenge that can be met and that (importantly) can be met by arguing from within a general framework that accepts many of the basic premises of the work (in new robotics and in dynamical systems theory) that motivates such scepticism in the first place. Our strategy will be as follows. We begin (Section 1) by offering an account (an example and something close to a definition) of what we shall term Minimal Robust Representationalism (MRR). Sections 2 & 3 address some likely worries and questions about this notion. We end (Section 4) by making explicit the conditions under which, on our account, a science (e.g., robot ics) may claim to be addressing cognitive phenomena.

The Legacy of Alan Turing, Volumes 1 and 2. Volume 1: Machines and Thought

Some recent cognitive-scientific research suggests that a considerable amount of intelligent action is generated not by the systematic activity of internal representations, but by complex interactions involving neural, bodily, and environmental factors. Following an analysis of this threat to representational explanation, we pursue an analogy between the role of genes in the production of biological form and the role of neural states in the production of behaviour, in order to develop a notion of genic representation. In both cases an appeal to normal ecological context is used to balance multi-factoral, interactive causal determination against the intuition that certain aspects of the causal nexus play a special role in promoting adaptive success. Certain worries abut this vision help us to get a better grip on the concept of genic representation itself. We end with a puzzle concerning the relation between cognition and representation.

Intelligence and understanding are rooted not in the presence and manipulation of explicit, language-like data structures, but in something more earthy: the tuning of basic responses to a real world that enables an embodied organism to sense, act and survive . . . it is now increasingly clear that the alternative to the `̀ disembodied explicit data manipulation'' vision of AI is not to retreat from hard science; it is to pursue some even harder science. It is to put intelligence where it belongs: in the coupling of organisms and the world that is at the root of daily, fluent action. (p. 4)

Being There : Putting Philosopher , Researcher and Student Together Again

Rethinking Innateness (henceforth RI) is a remarkable book, and a substantial contribution to that most persistent and elusive of debates, the controversy over innate knowledge. As befits a book composed by six co-authors, RI displays a diverse body of evidence and analysis, ranging from developmental observation, to computational (connectionist) modelling, to hard neuroscientific detail. It includes a first-rate introduction to the basic ideas of connectionist modelling and a nicely accessible account of some of the basics of neural development. It is chock full of conceptually pregnant examples, models and illustrations and will make rewarding reading for anyone seriously concerned with the nature of mind and adaptive success. Such merits aside, the major goal of the book is (positively) to stress the importance of organism/ environment interactions in explaining biological form and behaviour and (negatively) to argue against the view that posits innate higher-level knowledge: a view the authors term 'representational nativism'. It is this negative argument, I suspect, that will attract the most attention. For it is presented in bold opposition to a number of influential research programmes that posit, for example, innate knowledge of grammar, physics, theory of mind and more. The argument seems to go like this:

Where does the mind stop and the rest of the world begin? The question invites two standard replies. Some accept the intuitive demarcations of skin and skull, and say that what is outside the body is outside the mind. Others are impressed by arguments suggesting that the meaning of our words "just ain't in the head", and hold that this externalism about meaning carries over into an externalism about mind. We propose to pursue a third position. We will advocate an externalism about mind, but one that is in no way grounded in the debatable role of external reference in fixing the contents of our mental states. Rather, we advocate an *active externalism*, based on the active role of the environment in driving cognitive processes.

In his new commentary, Damper re-emphasises his claim that parity is not a generalisation problem. But when proper account is taken of the arguments he puts forward, we find that the proposed conclusion is not the only one that can be drawn.

Mind, it has recently been argued 1 , is a thoroughly temporal phenomenon: so temporal, indeed, as to defy description and analysis using the traditional computational tools of cognitive scientific understanding. The proper explanatory tools, so the suggestion goes, are instead the geometric constructs and differential equations of Dynamical Systems Theory. I consider various aspects of the putative temporal challenge to computational understanding, and show that the root problem turns on the presence of a certain kind of causal web: a web that involves multiple components (both inner and outer) linked by chains of continuous and reciprocal causal influence. There is, however, no compelling route from such facts about causal and temporal complexity to the radical anticomputationalist conclusion. This is because, interactive complexities notwithstanding, the computational approach provides a kind of explanatory understanding that cannot (I suggest) be recreated using the alternative resources of pure Dynamical Systems Theory. In particular, it provides a means of mapping information flow onto causal structure -- a mapping that is crucial to understanding the distinctive kinds of flexibility and control characteristic of truly mindful engagements with the world. Where we confront especially complex interactive causal webs, however, it does indeed become harder to isolate the syntactic vehicles required by the computational approach. Dynamical Systems Theory, I conclude, may play a vital role in recovering such vehicles from the burgeoning mass of real-time interactive complexity.

Cognitive science is in some sense the science of the mind. But an increasingly influential theme, in recent years, has been the role of the physical body, and of the local environment, in promoting adaptive success. No right-minded cognitive scientist, to be sure, ever claimed that body and world were completely irrelevant to the understanding of mind. But there was, nonetheless, an unmistakeable tendency to marginalize such factors: to dwell on inner complexity whilst simplifying or ignoring the complex inner-outer interplays that characterize the bulk of basic biological problem-solving. This tendency was expressed in, for example, the development of planning algorithms that treated real-world action as merely a way of implementing solutions arrived at by pure cognition (more recent work, by contrast, allows such actions to play important computational and problem-solving roles). It also surfaced in David Marr's depiction of the task of vision as the construction of a detailed threedimensional image of the visual scene. For possession of such a rich inner model effectively allows the system to ‘throw away’ the world and to focus subsequent computational activity on the inner model alone.

Word power Of course, words aren't magic. Neither are sextants, compasses, maps, slide rules and all the other paraphernalia which have accreted around the basic biological brains of Homo sapiens . In the case of these other tools and props, however, it is transparently clear that they function so as either to carry out or to facilitate computational operations important to various human projects. The slide rule transforms complex mathematical problems (ones that would baffle or tax the unaided subject) into simple tasks of perceptual recognition. The map provides geographical information in a format well suited to aid complex planning and strategic military operations. The compass gathers and displays a kind of information that (most) unaided human subjects do not seem to command. These various tools and props thus act to generate information, or to store it, or to transform it, or some combination of the three. In so doing, they impact on our individual and collective problem-solving capacities in much the same dramatic ways as various software packages impact the performance of a simple PC. Public language, I shall argue, is just such a tool – it is a species of external artefact whose current adaptive value is partially constituted by its role in re-shaping the kinds of computational space that our biological brains must negotiate in order to solve certain types of problems, or to carry out certain complex projects. This computational role of language has been somewhat neglected (not un-noticed, but not rigorously pursued either) in recent cognitive science, due perhaps to a (quite proper) fascination with and concentration upon, that other obvious dimension: the role of language as an instrument of interpersonal communication.

Current Issues in Philosophy of Mind: Embodiment and the Philosophy of Mind

Artificial intelligence and cognitive science : conceptual issues

Cognitive architectures in artificial intelligence : the evolution of research programs

As a longtime reader of American comic books, I have always been averse to those WHAT IF? treatments in which well-worn characters are depicted in alternative realities, in strange groupings, and sometimes with morphed views and personalities to boot. In this engaging but similarly disturbing counterfactual conceit, John Casti pits philosopher Ludwig Wittgenstein against computer scientist Alan Turing on the question “Can a machine think?” The literary device is to imagine a lively but urbane dinner party held one stormy night in Cambridge, in postwar England, in 1949. The novelist and science advisor C.P. Snow has, at the behest of His Majesty’s Government, invited a stellar list of guests to a sumptuous (by postwar standards) meal, whose intended by-product is the discovery of whether machines have the potential to exhibit intelligent behavior. The spur, we soon learn, is the work of Turing and his group in Manchester, work rooted in wartime cryptography and now continuing as an investigation into general-purpose automated problemsolving and the theory of computation. The direct (perhaps too direct) counterpoint to Turing’s optimistic vision of genuinely intelligent machines emerges, in Casti’s treatment, as Wittgenstein. Or rather, the enemy of that idea emerges as an unholy cross between Wittgenstein and more contemporary dissenters such as the philosopher John Searle. Casti’s crucial move makes the book lively, intriguing, and at the same time somewhat distressing. He allows his historical characters to invent and discuss numerous views and positions that were actually developed in subsequent decades. Thus Wittgenstein is allowed to invent and defend Searle’s Chinese Room argument against the sufficiency of computational profile—demonstration that some rule-based program is running, whatever its material basis—as proof of the presence of real thought. Turing, in his turn, is depicted as linking his ideas about computation to a Chomskian vision of a universal grammar shared by all human languages. This trick certainly makes for some interesting and powerful exchanges. But it exacts a matching penalty in terms of academic comfort—a point to which I shall return later. The eponymous quintet is completed by the addition of physicist Erwin Schrödinger and J.B.S. Haldane, geneticist and popular science writer. Although not as intellectually central to Casti’s treatment as Turing and Wittgenstein, these characters are well-rendered and make distinctive contributions to the proceedings. Haldane, for instance, plays a kind of academic Everyman, dividing his attention equally between the argument and the convivial succession of sherry, soup, fish, beef, salad, flummery (a Scottish dessert based on fruit, oatmeal, and whisky), brandy, and cigars—a succession that Casti also employs to divide the chapters and introduce breaks and new topics as required. In the gastronomic lulls, Haldane interjects rough but reasonable summaries of the points and arguments, as well as something of his own views concerning the crucial role of sensory-motor environmental interactions in endowing inner syntactic states with genuine content or meaning. The central exchange, however, is between Turing and Wittgenstein. Turing introduces the idea that cognition might depend purely on the computational organization of the brain, and not on the specific wet stuff of which it is built. He also develops his famous test, in which success in fooling a verbal interlocutor for the duration of a topic-unbounded conversation is asserted to suffice to demonstrate genuine intelligence in a machine. Thus primed, the conversation ricochets off the usual walls: isn’t the test too behavioristic? Don’t machines only do what they are programmed to? Is all human behavior really rule-governed? What about Gödel’s proof (that any self-consistent mathematical system will contain truths unprovable within that system)? And so on. But the conversation quickly takes a social/linguistic turn. This is initiated by Wittgenstein, who draws the group’s attention to the intimate relations between thought and language, and between language and the social settings in which it functions. The dominant objection to machine intelligence then emerges as something like this: human concepts get their meanings from the way the words function in our form of life; no machine can share our form of life; so no machine can ever understand human language; so—given the intimacy of language and thought—no machine can think like us. But this argument is never (to my mind) properly criticized. Just what must you share to share a form of life? How is this argument meant to relate to the earlier points about the inadequacy of syntax for semantics (the Chinese room argument, here cast as the “Hieroglyphic Room”)? And why the sudden focus on thinking just like us when the initial topic looked to be, “Can machines exhibit real intelligence and solve a wide and strategically important, range of problems?”. No small book can, of course, hope to tackle all aspects of such a pregnant question as “Can a machine think?” But I did feel that somehow, even within its natural confines, The Cambridge Quintet sometimes lost its way, drifting a little too readily into the discussion of language and society, and losing sight of the driving question about the general prospects for machine intelligence. One reason for this is, as just remarked, the textual tendency to focus on the question of whether a machine can think “like us” (whatever that means), rather than whether there could be real thought supported by alternatively implemented computational processes. I should confess, finally (and in line Too intelligent, or too artificial, or both?

Twisted Tales: Causal Complexity and Cognitive Scientific Explanation

Some regularities enjoy only an attenuated existence in a body of training data. These are regularities whose statistical visibility depends on some systematic recoding of the data. The space of possible recodings is, however, infinitely large – it is the space of applicable Turing machines. As a result, mappings that pivot on such attenuated regularities cannot, in general, be found by brute-force search. The class of problems that present such mappings we call the class of “type-2 problems.” Type-1 problems, by contrast, present tractable problems of search insofar as the relevant regularities can be found by sampling the input data as originally coded. Type-2 problems, we suggest, present neither rare nor pathological cases. They are rife in biologically realistic settings and in domains ranging from simple animat (simulated animal or autonomous robot) behaviors to language acquisition. Not only are such problems rife – they are standardly solved! This presents a puzzle. How, given the statistical intractability of these type-2 cases, does nature turn the trick? One answer, which we do not pursue, is to suppose that evolution gifts us with exactly the right set of recoding biases so as to reduce specific type-2 problems to (tractable) type-1 mappings. Such a heavy-duty nativism is no doubt sometimes plausible. But we believe there are other, more general mechanisms also at work. Such mechanisms provide general (not task-specific) strategies for managing problems of type-2 complexity. Several such mechanisms are investigated. At the heart of each is a fundamental ploy – namely, the maximal exploitation of states of representation already achieved by prior, simpler (type-1) learning so as to reduce the amount of subsequent computational search. Such exploitation both characterizes and helps make unitary sense of a diverse range of mechanisms. These include simple incremental learning (Elman 1993), modular connectionism (Jacobs et al. 1991), and the developmental hypothesis of “representational redescription” (Karmiloff-Smith 1979; 1992). In addition, the most distinctive features of human cognition – language and culture – may themselves be viewed as adaptations enabling this representation/computation trade-off to be pursued on an even grander scale.

Informed learning and conceptual structure : Putting the “ birdness ” back in the bird

Language and Meaning in Cognitive Science: Cognitive Issues and Semantic Theory

Why should wait for some days to get or receive the consciousness and emotion in cognitive science conceptual and empirical issues book that you order? Why should you take it if you can get the faster one? You can find the same book that you order right here. This is it the book that you can receive directly after purchasing. This consciousness and emotion in cognitive science conceptual and empirical issues is well known book in the world, of course many people will try to own it. Why don't you become the first? Still confused with the way?

Consciousness and Emotion in Cognitive Science: Conceptual and Empirical Issues

Trading spaces: Computation, representation, and the limits of uninformed learning

We argue that existing learning algorithms are often poorly equipped to solve problems involving a certain type of important and widespread regularity that we call “type-2 regularity.” The solution in these cases is to trade achieved representation against computational search. We investigate several ways in which such a trade-off may be pursued including simple incremental learning, modular connectionism, and the developmental hypothesis of “representational redescription.”

Recent studies such as Thelen and Smith (1994), Kelso, (1995), Van Gelder, (1995), Beer, (1995), and others have presented a forceful case for a dynamical systems approach to understanding cognition and adaptive behavior. These studies call into question some foundational assumptions concerning the nature of cognitive scientific explanation and (in particular) the role of notions such as internal representation and computation. These are exciting and important challenges. But they must be handled with care. It is all too easy, in this debate, to lose sight of the explanatorily important issues and to talk at cross-purposes, courtesy of the (surprisingly) various ways in which different theorists often conceive the key terms. The primary goal of the present paper is thus a modest one: to begin to clarify just what is at issue and to highlight some of the most central and pressing concerns. In so doing, we may hope to develop a constructive framework for future debate. In addition, I try to open up a space of intermediate options—ways in which dynamical and representational/computational understandings may sometimes afford complementary (rather than competing) perspectives on adaptive success.

From text to process: connectionism's contribution to the future of cognitive science

The old opposition of matter versus mind stubbornly persists in the way we study mind and brain. In treating cognition as problem solving, Andy Clark suggests, we may often abstract too far from the very body and world in which our brains evolved to guide us. Whereas the mental has been treated as a realm that is distinct from the body and the world, Clark forcefully attests that a key to understanding brains is to see them as controllers of embodied activity. From this paradigm shift he advances the construction of a cognitive science of the embodied mind.

Introduction 1. Learning and Conceptual Change: The View from the Neurons 2. Remarks on the Paradigms of Connectionism 3. Remarks on the Impact of Connectionism on our Thinking about Concepts 4. Causation in the Philosophy of Mind 5. Altered States and Virtual Beliefs 6. The Relation between Philosophical and Psychological Theories of Concepts 7. How Simple is the Simple Account? 8. Modularity and Logical Cognitivism 9. Folk Learning and Naive Physics 10. Why Concept Learning is a Good Idea 11. Analogy-Making, Fluid Concepts, and Brain Mechanisms 12. Encoding Psychological Knowledge 13. Does Belief Exist?

Language, according to Jackendoff, is more than just an instrument of communication and cultural transmission. It is also a tool which helps us to think. It does so, he suggests, by expanding the range of our conscious contents and hence allowing processes of attention and reflection to focus on items (such as abstract concepts and steps in chains of reasoning) which would not otherwise be available for scrutiny. I applaud Jackendoff s basic vision, but raise some doubts concerning the argument. In particular, I wonder what it is about public language that uniquely fits it to play the functional role which Jackendoff isolates — why couldn't expression in a private inner code induce the same computational benefits? I suggest a weaker position in which the communicative role of public language moulds it into a suitably expressive resource, such that natural language emerges as the logically and technologically contingent filler of a functional role which could, in principle, be filled by other means. I also compare and contrast Jackendoff's position with some related ideas due to Daniel Dennett and others, concluding with a sketch of my own view of language as an external artifact whose computational properties complement those of the basic biological brain.

The essays in this anthology deal with the growing interconnections between moral philosophy and research that draws upon neuroscience, developmental psychology, and evolutionary biology. This cross-disciplinary interchange coincides, not accidentally, with the renewed interest in ethical naturalism. In order to understand the nature and limits of moral reasoning, many new ethical naturalists look to cognitive science for an account of how people actually reason. At the same time, many cognitive scientists have become increasingly interested in moral reasoning as a complex form of human cognition that challenges their theoretical models. The result of this collaborative, and often critical, interchange is an exciting intellectual ferment at the frontiers of research into human mentality. Sections and Contributors: Ethics NaturalizedOwen Flanagan, Mark L. Johnson, Virginia Held Moral Judgments, Representations, and PrototypesPaul M. Churchland, Andy Clark, Peggy DesAutels, Ruth Garrett Millikan Moral EmotionsRobert M. Gordon, Alvin I. Goldman, John Deigh, Naomi Scheman Agency and ResponsibilityJames P. Sterba, Susan Khin-Zaw, Helen E. Longino, Michael E. Bratman A Bradford Book

Introduction. 1. Externalism and Experience M. Davies. 2. Conceptual Analysis and the Connectionist Account of Concepts W. Ramsey. 3. Of Norms and Neurons A. Clark. 4. Skepticism, Lucid Content and the Metamental Loop K. Lehrer. 5. Evading the Slingshot J. Perry. 6. Reference Without Sense: An Examination of Putnam's Semantic Theory A.G. Suarez. 7. Attitudes, Content and Identity: A Dynamic View J.J. Acero. 8. Conceptual Spaces as a Basis for Cognitive Semantics P. Gardenfors. 9. The Cognitive Impact of Diagrams K. Stenning. 10. What's Happening? Elements of Commonsense Causation K. Konolige. 11. Principles of Uncertain Reasoning J. Pais, A. Vencovska. Authors' Index. Subject Index.

Philosophy and cognitive science : categories, consciousness, and reasoning : proceedings of the Second International Colloquium on Cognitive Science

Connectionism, Moral Cognition, and Collaborative Problem Solving

Introduction 1. Subcognition and the Limits of the Turing Test 2. Turing's Test and Conscious Thought 3. The Turing Test: AI's Biggest Blind Alley? 4. The Intentional Stance and the Imitation Game 5. Machine as Mind 6. Minds, Machines, and Godel: A Retrospect 7. Human versus Mechanical Intelligence 8. The Church-Turing Thesis: Its Nature and Status 9. Measurement and Computational Description 10. Beyond Turing Equivalence 11. The Demise of the Turing Machine in Complexity Theory 12. A Grammar-Based Approach to Common-Sense Reasoning 13. Chaos: Its Past, its Present, but Mostly its Future 14. The Hierarchies of Knowledge and the Mathematics of Discovery

,Artificial Life' names a very broad church indeed. The banner encompasses work on colonies of simple simulated organisms, all kinds of 'synthetic biology', studies of real-world robots and autonomous agency, and much else besides. (For a representative sampling, see the variety of papers in volume 1 of the journal Artificial Life.) Underlying this surface variety, h~wever, are a few relatively central and recurrent themes. Two such (related) themes are (1) the unfolding of patterns over time and (2) the emergence of interesting or adaptive features from clever couplings between agents and environments (including other agents). The present chapter focuses on these key themes as they appear in work on Autonomous Agents, Dynamic Systems Theory, and systems-level neuroscientific conjecture. Attention to this range of example cases can, I believe, help us to . assess the more general role of explanations of emergent phenomena in' cognitive science. Such a project seems worth while for at least two reasons. First, because an emphasis on emergent phenomena is highly characteristic of much of the most recent, challenging and exciting work in Cognitive Science (from, for example, Mitchel Resnick's work on collective, decentralized behaviour (Resnick 19940), to Luc Steels's work on behaviour systems (Steels 1994), to Harvey, Husbands, and Cliff's work on evolutionary robotics (Harvey et al. 1994». But second, because some of the most basic questions about the explanation of emergent properties remain unresolved. Such questi9ns include: how to define emergenc~ itself; what general explanatory framework is best able to account for emergent features (is dynamic systems theory, for example, a better bet than classical component-based analysis?); and do such novel modes of explanation merely augment or radically displace more familiar styles of Cognitive Scientific understanding?

Moving Minds: Situating Content in the Service of Real-Time Success

A guide to locating scholarships for all calibre of athletes, this book uncovers information on where and how to get grants in all types of sports from alpine skiing to wrestling.

Athletic Scholarships: Thousands of Grants-And over $400 Million-For College-Bound Athletes

Artificial Intelligence and the Simulation of Behaviour Quarterly

The Cognizer's Innards: a Philosophical and Psychological Perspective on the Development of Thought

Part 1 Melting the inner code: computational models, syntax, and the folk solids connectionism, code, and context what networks know what networks don't know concept, category and prototype. Part 2 From code to process: the presence of a symbol the role of representational trajectories the cascade of significant virtual machines associative learning in a hostile world the fate of the folk associative engines - the next generation.

Associative Engines: Connectionism, Concepts, and Representational Change

Department of Philosophy, Washington University, Saint Louis, Missouri FRIDAY, April 8 SATURDAY, April 9 Welcome: Roger Gibson University

En reponse a tous les commentaires qu'a suscites leur article «The Cognizer's Innards», les AA. se proposent de delimiter et de preciser les themes majeurs du debat sur la redescription representationnelle, en se referant a Dennett

The Varieties of Eliminativism: Sentential, Intentional and Catastrophic

A travers l'analyse du comportement cognitif des enfants, l'A. etudie le processus de redescription representative qui semble indissociable des modeles connexionnistes complexes ou d'un systeme connexionniste-symbolique

The cognizer's innards: A psychological and philosophical perspective on the development of thought.

Abstract The image of the presence of symbols in an inner code pervades recent debates in cognitive science. Classicists worship in the presence. Connectionists revel in the absence. However, the very ideas of code and symbol are ill understood. A major distorting factor in the debates concerns the role of processing in determining the presence or absence of a structured inner code. Drawing on work by David Kirsh and David Chalmers, the present paper attempts to re-define such notions to begin to reflect the inextricability of code and process.

Systematicity, Structured Representations and Cognitive Architecture: A reply to Fodor and Pylyshyn

A competence model describes the abstract structure of a solution to some problem. or class of problems, facing the would-be intelligent system. Competence models can be quite derailed, specifying far more than merely the function to be computed. But for all that, they are pitched at some level of abstraction from the details of any particular algorithm or processing strategy which may be said to realize the competence. Indeed, it is the point and virtue of such models to specify some equivalence class of algorithms/processing strategies so that the common properties highlighted by the chosen class may feature in psychologically interesting accounts. A question arises concerning the type of relation a theorist might expect to hold between such a competence model and a psychologically real processing strategy. Classical work in cognitive science expects the actual processing to depend on explicit or tacit knowledge of the competence theory. Connectionist work, for reasons to be explained, represents a departure from this norm. But the precise way in which a connectionist approach may disturb the satisfying classical symmetry of competence and processing has yet to be properly specified. A standard ‘Newtonian’ connectionist account, due to Paul Smolensky, is discussed and contrasted with a somewhat different ‘rogue’ account. A standard connectionist understanding has it that a classical competence theory describes an idealized subset of a network's behaviour. But the network's behaviour is not to be explained by its embodying explicit or tacit knowledge of the information laid out in the competence theory. A rogue model, by contrast, posits either two systems, or two aspects of a single system, such that one system does indeed embody the knowledge laid out in the competence theory.

The Stuff of ConsciousnessMind, Brain and the Quantum.The Emperor's New Mind

Abstract The paper considers two recent accounts of the difference between human and animal thought. One deflationary account, due to Daniel Dennett, insists that the only real difference lies in our ability to use words and sentences to give artificial precision and determinacy to our mental contents. The other, due to Paul Smolensky, conjectures that we at times deploy a special purpose device (the Conscious Rule Interpreter) whose task is to deal with public, symbolically coded data and commands. Both these accounts make a crucial error. They offer what is in effect an extra top‐level processor to soothe our realist/classical prejudices. But in each case the extra ingredient turns out to be explanatorily hollow. Appealing to language use and language processing alone mistakes a cognitive effect for a cognitive cause. I argue instead that we need to seek a more profound architectural condition which may ground our conscious linguistic abilities but also explains a variety of deeper facts. I sketch a pic...

Considers the adoption of customer care by both public and private sector organizations as a means of gaining a longer‐term competitive edge. Examines ways of avoiding “charm‐school training”, the concept of the internal customer, the challenges of quality service, and a total approach to quality. Summarizes that if the “total approach” is compatible with business style, short‐term enthusiasm can be converted into long‐term and sustainable results.

Building a Culture of Quality and Service: A Strategic Approach to Success through Customer Service

Explaining Behaviour@@@Explaining Behaviour: Reasons in a World of Causes.

A review of: “Simple Minds” D. Lloyd, 1989 London, MIT Press ISBN 0-262-12140-9, xiv + 266 pp., £22.50

Introduction: what the brain's-eye view tells the mind's-eye view. Part 1 The mind's-eye view: classical cognitivism situation and substance folk psychology, thought, and context biological constraints. Part 2 The brain's-eye view: parallel distributed processing informational holism the multiplicity of mind - a limited defence of classical cognitivism structured through reassembling the jigsaw. Epilogue: The parable of the high-level architect. Appendix: Beyond eliminativism.

Microcognition: Philosophy, Cognitive Science, and Parallel Distributed Processing

Philosophy/Neuroscience/Psychology Program Department of Philosophy Washington University St. Louis, MO 63130 e-mail: andy@twinearth.wustl.edu * What follows is an amended version of material that first appeared in A. Clark, Microcognition: Philosophy, Cognitive Science, and Parallel Distributed Processing (MIT Press, Cambridge, MA, 1989), Ch. 1, 2, and 6. Thanks to MIT Press for permission to re-use this material here.

Microfunctionalism: Connectionism and the Scientific Explanation of Mental States

DOES mental imagery involve the same cognitive processes and operations as visual perception? In a previous paper (Clark [2]) I argued that it does not. In support of this claim, which goes counter to a fairly strong tradition in the literature on mental imagery (see e.g. Metzler and Shepherd [2], Kosslyn et al. [3]), I suggested a simple thought experiment designed to show that the operations we can perform on an image differ in functionally significant ways from those we can perform when actually perceiving a real object. The thought experiment, which I shall not repeat in detail here, involved comparing the ill-fated attempt to trace an imagined picture on a blank page, and the successful attempt to trace around the edges of a real picture. The picture used for the experiment was one of Superman flying through the air, hence the title of this piece. Gordon and Bringsjord (above) both dispute the validity of the thought experiment. Both argue, in effect, that the task demands differ significantly in the case where the subject is required to 'trace' the image and that the difference in task demands invalidates the comparison between the two cases. Gordon says that 'Clark's example assumes without argument that his case is one of essential similarity to physical tracing' but insists that in reality '[the imagetracer] has been presented with a task of substantially greater

Abstract Cognitive Science, it is argued, comprises two distinct projects. One is an Engineering project whose goal is understanding the in‐the‐head computational activities which ground intelligent behaviour. The other is a Descriptive project whose goal is the mapping of relations between thoughts as ascribed using the (sentential) apparatus of the propositional attitudes. Some theorists (e.g. Fodor, 1987) insist that the two projects are (in a sense to be explained) deeply related. This view is contested, and the consequences of its abandonment examined. Such consequences are seen to include (i) the irrelevance of scientific arguments for Eliminative Materialism, (ii) a view concerning the proper roles of classical and connectionist work in Artificial Intelligence and (iii) the failure of an allegedly damning argument against connectionism (the so‐called systematicity argument)

The notion of folk-psychology as a primitive speculative theory of the mental is called into question. There is cause to believe that folk-psychology has more in common with a naive physics than with early speculative physical theorising. The distinction between these is elaborated. The conclusion drawn is that commonsense ascription of psychological content, though not a suitable finishing point for cognitive science, should still provide a more reliable source of data than some contemporary theorists are willing to admit.

Christopher Hookway, ed. , Minds, Machines and Evolution: Philosophical Studies . Reviewed by

Sub-Saharan Africa has the highest rate of cervical cancer cases and deaths worldwide. Kenya introduced a quadrivalent HPV vaccine (GARDASIL, hereafter referred to as GARDASIL-4) for ten-year-old girls in late 2019 with donor support from Gavi, the Vaccine Alliance. As Kenya may soon graduate from Gavi support, it is important to evaluate the potential cost-effectiveness and budget impact of the current HPV vaccine, and potential alternatives.

METHODS
We used a proportionate outcomes static cohort model to evaluate the annual budget impact and lifetime cost-effectiveness of vaccinating ten-year-old girls over the period 2020-2029. We included a catch-up campaign for girls aged 11-14 years in 2020. We estimated cervical cancer cases, deaths, disability adjusted life years (DALYs), and healthcare costs (government and societal perspective) expected to occur with and without vaccination over the lifetimes of each cohort of vaccinated girls. For each of the four products available globally (CECOLIN©, CERVARIX©, GARDASIL-4©, and GARDASIL-9 ©), we estimated the cost (2021 US$) per DALY averted compared to no vaccine and to each other. Model inputs were obtained from published sources, as well as local stakeholders.

RESULTS
We estimated 320,000 cases and 225,000 deaths attributed to cervical cancer over the lifetimes of the 14 evaluated birth cohorts. HPV vaccination could reduce this burden by 42-60 %. Without cross-protection, CECOLIN had the lowest net cost and most attractive cost-effectiveness. With cross-protection, CERVARIX was the most cost-effective. Under either scenario the most cost-effective vaccine had a 100 % probability of being cost-effective at a willingness-to-pay threshold of US$ 100 (5 % of Kenya's national gross domestic product per capita) compared to no vaccination. Should Kenya reach its target of 90 % coverage and graduate from Gavi support, the undiscounted annual vaccine program cost could exceed US$ 10 million per year. For all three vaccines currently supported by Gavi, a single-dose strategy would be cost-saving compared to no vaccination.

HPV vaccination for girls is highly cost-effective in Kenya. Compared to GARDASIL-4, alternative products could provide similar or greater health benefits at lower net costs. Substantial government funding will be required to reach and sustain coverage targets as Kenya graduates from Gavi support. A single dose strategy is likely to have similar benefits for less cost.

Impact, cost-effectiveness, and budget implications of HPV vaccination in Kenya: A modelling study.

Mozambique has one of the highest rates of cervical cancer in the world. Human papillomavirus (HPV) vaccination was introduced in 2021. This study evaluated the health and economic impact of the current HPV vaccine (GARDASIL® hereafter referred to as GARDASIL-4) and two other vaccines (CECOLIN® and CERVARIX®) that could be used in the future. A static cohort model was used to estimate the costs and benefits of vaccinating girls in Mozambique over the period 2022–2031. The primary outcome measure was the incremental cost per disability-adjusted life-year averted from a government perspective. We conducted deterministic and probabilistic sensitivity analyses. Without cross-protection, all three vaccines averted approximately 54% cervical cancer cases and deaths. With cross-protection, CERVARIX averted 70% of cases and deaths. Without Gavi support, the discounted vaccine program costs ranged from 60 million to 81 million USD. Vaccine program costs were approximately 37 million USD for all vaccines with Gavi support. Without cross-protection, CECOLIN was dominant, being cost-effective with or without Gavi support. With cross-protection and Gavi support, CERVARIX was dominant and cost-saving. With cross-protection and no Gavi support, CECOLIN had the most favorable cost-effectiveness ratio. Conclusions: At a willingness-to-pay (WTP) threshold set at 35% of Gross Domestic Product (GDP) per capita, HPV vaccination is cost-effective in Mozambique. The optimal vaccine choice depends on cross-protection assumptions.

Impact and Cost-Effectiveness of Alternative Human Papillomavirus Vaccines for Preadolescent Girls in Mozambique: A Modelling Study

The potential cost-effectiveness of HPV vaccination among girls in Mongolia

ABSTRACT While current live, oral rotavirus vaccines (LORVs) are reducing severe diarrhea everywhere, their effectiveness is lower in high burden settings. Alternative approaches are in advanced stages of clinical development, including injectable next-generation rotavirus vaccine (iNGRV) candidates, which have the potential to better protect children, be combined with existing routine immunizations and be more affordable than current LORVs. In an effort to better understand the real public health value of iNGRVs and to help inform decisions by international agencies, funders, and vaccine manufacturers, we conducted an impact and cost-effectiveness analysis examining 20 rotavirus vaccine use cases. We evaluated several currently licensed LORVs, one neonatal oral NGRV (oNGRV), one iNGRV, and one iNGRV-DTP (iNGRV comprising part of a DTP-containing combination) over a ten-year timeframe in 137 low- and middle-income countries. The most promising use case identified was a high efficacy iNGRV-DTP, predicted to have the lowest vaccine program cost (US$1.4 billion), the highest vaccine benefit (750,000 rotavirus deaths averted, 13 million rotavirus hospital admissions averted, US$ 2.7 billion health-care cost averted), and most favorable cost-effectiveness (cost-saving). iNGRV-DTP vaccine remained the most affordable, safe, and cost-effective option even when it was assumed to have equivalent efficacy to the current LORVs. This study shows that while the development of iNGRVs with superior efficacy to currently licensed LORVs would be ideal, iNGRVs with similar efficacy to LORVs would offer substantial public health value. It also highlights the economic value of accelerating the development of DTP-based combination vaccines that include iNGRV to provide rotavirus protection.

Potential impact and cost-effectiveness of injectable next-generation rotavirus vaccines in 137 LMICs: a modelling study

Objectives To evaluate the cost-effectiveness of alternative rotavirus vaccines in Niger, using UNIVAC, a proportionate outcomes model. Setting The study leverages global, regional and local data to inform cost-effectiveness modelling. Local data were collected as part of a clinical trial taking place in the Madarounfa district, Maradi region, Niger. Participants The study models impact of infants vaccination on rotavirus gastroenteritis in children under 5 years of age. Interventions We compared the use of ROTARIX (GlaxoSmithKline, Belgium), ROTAVAC (Bharat Biotech, India) and ROTASIIL (Serum Institute, India) to no vaccination and to each other over a 10-year period starting in 2021. Results We estimated that ROTARIX, ROTAVAC and ROTASIIL would each prevent 13 million cases and 20 000 deaths of children under 5 years over a 10-year period in Niger. Compared with no vaccination, the cost to avert a disability-adjusted life-year was US$146 with ROTARIX, US$107 with ROTASIIL and US$76 with ROTAVAC from the government perspective. ROTAVAC dominated ROTARIX and ROTASIIL (eg, provided similar or higher benefits at a lower cost) and had 90% chance to be cost-effective at a US$100 willingness-to-pay threshold. Conclusions This study can inform decision-making around rotavirus vaccination policy in Niger, demonstrating that ROTAVAC is likely the most cost-effective option. Alternative products (ROTASIIL and ROTARIX) may also be considered by decision-makers if they are priced more competitively, or if their cold chain requirements could bring additional economic benefits.

Impact and cost-effectiveness of rotavirus vaccination in Niger: a modelling study evaluating alternative rotavirus vaccines

Background: Diarrhea remains a major cause of morbidity and mortality amongst children under five years of age in low- and middle-income countries. This study aimed to estimate the direct and indirect costs of acute diarrhea in children under five years old treated in both outpatient and inpatient care settings in Indonesia. 
 
Methods: Direct medical cost data were extracted retrospectively for 1050 children under five years old with acute diarrhea receiving inpatient care across 45 health facilities in seven Indonesian provinces during 2017-2020. Direct medical costs for children treated in outpatient settings were estimated by collecting unit costs associated with standard diarrhea case management in children. A structured interview of 240 inpatients’ caregivers was also conducted retrospectively to estimate direct non-medical costs as well as indirect costs from caregiver income loss. We did not estimate non-medical or indirect costs for outpatient clinic visits. 
 
Results: The weighted average direct medical cost per case of inpatient and outpatient diarrhea across all health facility types was US$99·8±56·8 (35% room costs, 29% professional fees, 26% medication costs, 10% diagnostic costs) and US$7·6±4·3 (34% diagnostic costs, 28% medication costs, 27% professional fees, 10% registration fees), respectively. The average direct non-medical household costs and indirect costs for a diarrheal admission were US$4·90 and US$9·90, respectively. 
 
Conclusion: This study highlighted essential details on the direct and indirect economic burden acute diarrhea represents for Indonesia in both inpatient and outpatient settings. 
 
Funding: This work was supported by the Murdoch Children’s Research Institute (MCRI), PATH, and the Indonesian Technical Advisory Group on Immunization (ITAGI). 
 
Declaration of Interest: None to declare. 
 
Ethical Approval: The study was approved by the Medical and Research Ethics Committee of the Faculty of Medicine, Public Health, and Nursing Universitas Gadjah Mada, Indonesia (No. KE/FK/0348/EC/2019) and the Royal Children’s Hospital Melbourne Human Research Ethics Committee, Australia.

Direct and Indirect Costs of Acute Diarrhea in Children Under-Five Years Old in Indonesia

Estimating the health impact of vaccination against ten pathogens in 98 low-income and middle-income countries from 2000 to 2030: a modelling study

Cost-effectiveness of rotavirus vaccination in the Philippines: A modeling study

The projected cost-effectiveness and budget impact of HPV vaccine introduction in Ghana.

Background: Vaccination is one of the most effective public health interventions. We investigate the impact of vaccination activities for Haemophilus influenzae type b, hepatitis B, human papillomavirus, Japanese encephalitis, measles, Neisseria meningitidis serogroup A, rotavirus, rubella, Streptococcus pneumoniae, and yellow fever over the years 2000–2030 across 112 countries. Methods: Twenty-one mathematical models estimated disease burden using standardised demographic and immunisation data. Impact was attributed to the year of vaccination through vaccine-activity-stratified impact ratios. Results: We estimate 97 (95%CrI[80, 120]) million deaths would be averted due to vaccination activities over 2000–2030, with 50 (95%CrI[41, 62]) million deaths averted by activities between 2000 and 2019. For children under-5 born between 2000 and 2030, we estimate 52 (95%CrI[41, 69]) million more deaths would occur over their lifetimes without vaccination against these diseases. Conclusions: This study represents the largest assessment of vaccine impact before COVID-19-related disruptions and provides motivation for sustaining and improving global vaccination coverage in the future. Funding: VIMC is jointly funded by Gavi, the Vaccine Alliance, and the Bill and Melinda Gates Foundation (BMGF) (BMGF grant number: OPP1157270 / INV-009125). Funding from Gavi is channelled via VIMC to the Consortium’s modelling groups (VIMC-funded institutions represented in this paper: Imperial College London, London School of Hygiene and Tropical Medicine, Oxford University Clinical Research Unit, Public Health England, Johns Hopkins University, The Pennsylvania State University, Center for Disease Analysis Foundation, Kaiser Permanente Washington, University of Cambridge, University of Notre Dame, Harvard University, Conservatoire National des Arts et Métiers, Emory University, National University of Singapore). Funding from BMGF was used for salaries of the Consortium secretariat (authors represented here: TBH, MJ, XL, SE-L, JT, KW, NMF, KAMG); and channelled via VIMC for travel and subsistence costs of all Consortium members (all authors). We also acknowledge funding from the UK Medical Research Council and Department for International Development, which supported aspects of VIMC's work (MRC grant number: MR/R015600/1). JHH acknowledges funding from National Science Foundation Graduate Research Fellowship; Richard and Peggy Notebaert Premier Fellowship from the University of Notre Dame. BAL acknowledges funding from NIH/NIGMS (grant number R01 GM124280) and NIH/NIAID (grant number R01 AI112970). The Lives Saved Tool (LiST) receives funding support from the Bill and Melinda Gates Foundation. This paper was compiled by all coauthors, including two coauthors from Gavi. Other funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Lives saved with vaccination for 10 pathogens across 112 countries in a pre-COVID-19 world

COVID-19's lost generation of unvaccinated children – Authors' reply

Evaluating the potential economic and health impact of rotavirus vaccination in 63 middle-income countries not eligible for Gavi funding: a modelling study

Introduction The Palestinian Ministry of Health (MOH) started a routine rotavirus immunization program with ROTARIX in May 2016, with support for vaccine procurement and introduction provided through a global development organization. In 2018, financial responsibility for rotavirus vaccine procurement was transferred to the Palestinian government, which elected to shift to ROTAVAC vaccine because of its lower price per dose. This study aims to assess the cost, impact, and cost-effectiveness of rotavirus vaccination, specifically evaluating the economic implications of the change in vaccine product, accounting for the different characteristics of each rotavirus vaccine used. Methods We conducted primary and secondary data collection to assess the introduction, procurement, supply chain, and service delivery costs related to each vaccine. We used the UNIVAC model to project costs and benefits of rotavirus vaccination over a 10-year period comparing the use of ROTARIX versus no vaccination; ROTAVAC versus no vaccination; and ROTAVAC versus ROTARIX. We undertook scenario and probabilistic analyses to capture uncertainty in some of the study parameters. We used a 3% discount rate, and all costs are in 2018 US$. Results The cost to deliver one dose was lower for ROTAVAC than ROTARIX (US$2.36 versus $2.70), but the total cost per course, excluding vaccine cost, favored ROTARIX ($7.09 versus $5.39). Both vaccines had high probability of being cost-effective interventions in Palestine compared to no vaccine. Because of lower vaccination program costs for ROTAVAC, however, switching from ROTARIX to ROTAVAC was cost-saving. Conclusion National decision-makers should consider systematically assessing multiple criteria beyond vaccine price when comparing the health and economic value of several products in order to fully account for all characteristics including product presentation, number of doses per course, cold chain volume, cost of delivery, and wastage.

Introduction of rotavirus vaccination in Palestine: An evaluation of the costs, impact, and cost-effectiveness of ROTARIX and ROTAVAC

Economic evaluation of the introduction of rotavirus vaccine in Hong Kong.

Global, regional, and national estimates of the population at increased risk of severe COVID-19 due to underlying health conditions in 2020: a modelling study

Corrigendum to "Cost-effectiveness of introducing a domestic pneumococcal conjugate vaccine (PCV7-TT) into the Cuban national immunization programme" [Int. J. Infect. Dis. 97 (2020) 182-189].

Cost of illness for childhood diarrhea in low- and middle-income countries: a systematic review of evidence and modelled estimates

Cost-effectiveness of introducing a domestic pneumococcal conjugate vaccine (PCV7-TT) into the Cuban national immunization programme.

Routine childhood immunisation during the COVID-19 pandemic in Africa: a benefit–risk analysis of health benefits versus excess risk of SARS-CoV-2 infection

Abstract Background In some countries that have introduced oral rotavirus vaccines, a small but elevated risk of intussusception—a rare bowel disorder—has been reported. Updated estimates on the global epidemiology of intussusception are needed to help predict the potential number of intussusception cases that could be caused by the vaccine in different settings. Methods We estimated incidence rates, age distributions and case-fatality ratios (CFRs) for intussusception hospital admissions among children aged <5 years, before the introduction of rotavirus vaccines. We included all articles identified in a systematic review between January 2002 and January 2018, and contacted authors for more granular unpublished data on age distributions. Results We identified 128 articles containing 227 country datasets (61 age distributions, 71 incidence rates and 95 CFRs). The median age of intussusception ranged from 29 weeks in Africa (83% of cases in the first year of life) to 70 weeks in the Western Pacific region (35% of cases in the first year of life). The median (range) annual incidence of intussusception hospital admissions per 100 000 aged <1 year ranged from 34 (13–56) in Africa to 90 (9–380) in the Western Pacific region. We found extreme differences between the CFRs in Africa (1 death in every 10 hospital admissions) and the rest of the world (fewer than 1 death in every 100–2000 hospital admissions). Conclusion Intussusception epidemiology varies by country and region. Understanding and recognizing these differences will be important when assessing the potential number of intussusception cases associated with rotavirus vaccines.

Update on the global epidemiology of intussusception: a systematic review of incidence rates, age distributions and case-fatality ratios among children aged <5 years, before the introduction of rotavirus vaccination

Cost-effectiveness analysis for rotavirus vaccine decision-making: How can we best inform evolving and complex choices in vaccine product selection?

Cost-effectiveness analysis of the implementation of a National Immunization Program for rotavirus vaccination in a country with a low rotavirus gastroenteritis-related mortality: A South Korean study.

Abstract We sought datasets with granular age distributions of rotavirus-positive disease presentations among children <5 years of age, before the introduction of rotavirus vaccines. We identified 117 datasets and fit parametric age distributions to each country dataset and mortality stratum. We calculated the median age and the cumulative proportion of rotavirus gastroenteritis events expected to occur at ages between birth and 5.0 years. The median age of rotavirus-positive hospital admissions was 38 weeks (interquartile range [IQR], 25–58 weeks) in countries with very high child mortality and 65 weeks (IQR, 40–107 weeks) in countries with very low or low child mortality. In countries with very high child mortality, 69% of rotavirus-positive admissions in children <5 years of age were in the first year of life, with 3% by 10 weeks, 8% by 15 weeks, and 27% by 26 weeks. This information is critical for assessing the potential benefits of alternative rotavirus vaccination schedules in different countries and for monitoring program impact.

Global Review of the Age Distribution of Rotavirus Disease in Children Aged <5 Years Before the Introduction of Rotavirus Vaccination

Projected impact, cost-effectiveness, and budget implications of rotavirus vaccination in Mongolia

Re-evaluating the potential impact and cost-effectiveness of rotavirus vaccination in 73 Gavi countries: a modelling study

Potential effect of age of BCG vaccination on global paediatric tuberculosis mortality: a modelling study

Potential health impact and cost-effectiveness of bivalent human papillomavirus (HPV) vaccination in Afghanistan

With social policies increasingly directed toward enhancing equity through health programs, it is important that methods for estimating the health and economic benefits of these programs by subpopulation be developed, to assess both equity concerns and the programs' total impact. We estimated the differential health impact (measured as the number of deaths averted) and household economic impact (measured as the number of cases of medical impoverishment averted) of ten antigens and their corresponding vaccines across income quintiles for forty-one low- and middle-income countries. Our analysis indicated that benefits across these vaccines would accrue predominantly in the lowest income quintiles. Policy makers should be informed about the large health and economic distributional impact that vaccines could have, and they should view vaccination policies as potentially important channels for improving health equity. Our results provide insight into the distribution of vaccine-preventable diseases and the health benefits associated with their prevention.

The Equity Impact Vaccines May Have On Averting Deaths And Medical Impoverishment In Developing Countries.

Introduction Beyond their impact on health, vaccines can lead to large economic benefits. While most economic evaluations of vaccines have focused on the health impact of vaccines at a national scale, it is critical to understand how their impact is distributed along population subgroups. Methods We build a financial risk protection model to evaluate the impact of immunisation against measles, severe pneumococcal disease and severe rotavirus for birth cohorts vaccinated over 2016–2030 for three scenarios in 41 Gavi-eligible countries: no immunisation, current immunisation coverage forecasts and the current immunisation coverage enhanced with funding support. We distribute modelled disease cases per socioeconomic group and derive the number of cases of: (1) catastrophic health costs (CHCs) and (2) medical impoverishment. Results In the absence of any vaccine coverage, the number of CHC cases attributable to measles, severe pneumococcal disease and severe rotavirus would be approximately 18.9 million, 6.6 million and 2.2 million, respectively. Expanding vaccine coverage would reduce this number by up to 90%, 30% and 40% in each case. More importantly, we find a higher share of CHC incidence among the poorest quintiles who consequently benefit more from vaccine expansion. Conclusion Our findings contribute to the understanding of how vaccines can have a broad economic impact. In particular, we find that immunisation programmes can reduce the proportion of households facing catastrophic payments from out-of-pocket health expenses, mainly in lower socioeconomic groups. Thus, vaccines could have an important role in poverty reduction.

Poverty reduction and equity benefits of introducing or scaling up measles, rotavirus and pneumococcal vaccines in low-income and middle-income countries: a modelling study

Infant rotavirus vaccines have led to substantial reductions in rotavirus gastroenteritis (RVGE) hospital admissions and costs, but some studies have reported an elevated risk of intussusception, a rare bowel disorder, in vaccinated infants. The aim of this thesis is to quantify the potential mortality benefits and intussusception risks of alternative rotavirus vaccination schedules in 135 low- and middle-income countries (LMICs). The thesis begins with an introduction to the topic and background to the literature and concludes with some final reflections on the research and its relevance for informing national decisions about vaccine safety and optimal scheduling of rotavirus vaccines. The main body of the thesis includes a series of research papers which address specific topics relevant to the estimation of mortality benefits and intussusception risks. These include methods for estimating: RVGE deaths <5 years of age; RVGE age distributions <5 years; vaccine coverage and timeliness; rotavirus vaccine efficacy and waning; and, intussusception incidence, age distributions, and case fatality ratios in children <5 years of age. The final research paper brings together this evidence and uses a national-level vaccine decision support model to estimate the potential rotavirus mortality benefits (averted RVGE deaths <5 years of age) and risks (excess intussusception deaths <5 years of age) of 18 possible vaccination schedules in 135 LMICs. Scenarios with and without age restrictions are evaluated. Rotavirus vaccines are found to have a favourable benefit-risk profile in LMICs. Mortality benefits and intussusception risks are estimated to vary considerably by country and choice of rotavirus vaccination schedule. Schedules involving birth and booster doses could further increase benefits and reduce risks, but more research is needed to assess their feasibility, safety and impact.

Mortality benefits and intussusception risks of rotavirus vaccination in low- and middle-income countries

Re-evaluating the cost and cost-effectiveness of rotavirus vaccination in Bangladesh, Ghana, and Malawi: A comparison of three rotavirus vaccines

Impact and cost-effectiveness of rotavirus vaccination in Bangladesh

Potential impact and cost-effectiveness of rotavirus vaccination in Afghanistan

Background Rotavirus is a leading cause of diarrhoeal mortality in children but there is considerable disagreement about how many deaths occur each year. Methods and findings We compared CHERG, GBD and WHO/CDC estimates of age under 5 years (U5) rotavirus deaths at the global, regional and national level using a standard year (2013) and standard list of 186 countries. The global estimates were 157,398 (CHERG), 122,322 (GBD) and 215,757 (WHO/CDC). The three groups used different methods: (i) to select data points for rotavirus-positive proportions; (ii) to extrapolate data points to individual countries; (iii) to account for rotavirus vaccine coverage; (iv) to convert rotavirus-positive proportions to rotavirus attributable fractions; and (v) to calculate uncertainty ranges. We conducted new analyses to inform future estimates. We found that acute watery diarrhoea was associated with 87% (95% CI 83–90%) of U5 diarrhoea hospitalisations based on data from 84 hospital sites in 9 countries, and 65% (95% CI 57–74%) of U5 diarrhoea deaths based on verbal autopsy reports from 9 country sites. We reanalysed data from the Global Enteric Multicenter Study (GEMS) and found 44% (55% in Asia, and 32% in Africa) rotavirus-positivity among U5 acute watery diarrhoea hospitalisations, and 28% rotavirus-positivity among U5 acute watery diarrhoea deaths. 97% (95% CI 95–98%) of the U5 diarrhoea hospitalisations that tested positive for rotavirus were entirely attributable to rotavirus. For all clinical syndromes combined the rotavirus attributable fraction was 34% (95% CI 31–36%). This increased by a factor of 1.08 (95% CI 1.02–1.14) when the GEMS results were reanalysed using a more sensitive molecular test. Conclusions We developed consensus on seven proposals for improving the quality and transparency of future rotavirus mortality estimates.

Estimating global, regional and national rotavirus deaths in children aged <5 years: Current approaches, new analyses and proposed improvements

Abstract Objective To estimate the economic impact likely to be achieved by efforts to vaccinate against 10 vaccine-preventable diseases between 2001 and 2020 in 73 low- and middle-income countries largely supported by Gavi, the Vaccine Alliance. Methods We used health impact models to estimate the economic impact of achieving forecasted coverages for vaccination against Haemophilus influenzae type b, hepatitis B, human papillomavirus, Japanese encephalitis, measles, Neisseria meningitidis serogroup A, rotavirus, rubella, Streptococcus pneumoniae and yellow fever. In comparison with no vaccination, we modelled the costs – expressed in 2010 United States dollars (US$) – of averted treatment, transportation costs, productivity losses of caregivers and productivity losses due to disability and death. We used the value-of-a-life-year method to estimate the broader economic and social value of living longer, in better health, as a result of immunization. Findings We estimated that, in the 73 countries, vaccinations given between 2001 and 2020 will avert over 20 million deaths and save US$ 350 billion in cost of illness. The deaths and disability prevented by vaccinations given during the two decades will result in estimated lifelong productivity gains totalling US$ 330 billion and US$ 9 billion, respectively. Over the lifetimes of the vaccinated cohorts, the same vaccinations will save an estimated US$ 5 billion in treatment costs. The broader economic and social value of these vaccinations is estimated at US$ 820 billion. Conclusion By preventing significant costs and potentially increasing economic productivity among some of the world’s poorest countries, the impact of immunization goes well beyond health.

Estimated economic impact of vaccinations in 73 low- and middle-income countries, 2001–2020

Over 20,000 rabies deaths occur annually in India, representing one-third of global human rabies. The Indian state of Tamil Nadu has pioneered a “One Health” committee to address the challenge of rabies in dogs and humans. Currently, rabies control in Tamil Nadu involves postexposure vaccination of humans after dog bites, whereas potential supplemental approaches include canine vaccination and sterilization. We developed a data-driven rabies transmission model fit to human rabies autopsy data and human rabies surveillance data from Tamil Nadu. Integrating local estimates for canine demography and costs, we predicted the impact of canine vaccination and sterilization on human health outcomes and evaluated cost-effectiveness according to the WHO criteria for India, which correspond to thresholds of $1,582 and $4,746 per disability-adjusted life-years (DALYs) for very cost-effective and cost-effective strategies, respectively. We found that highly feasible strategies focused on stray dogs, vaccinating as few as 7% of dogs annually, could very cost-effectively reduce human rabies deaths by 70% within 5 y, and a modest expansion to vaccinating 13% of stray dogs could cost-effectively reduce human rabies by almost 90%. Through integration over parameter uncertainty, we find that, for a cost-effectiveness threshold above $1,400 per DALY, canine interventions are at least 95% likely to be optimal. If owners are willing to bring dogs to central point campaigns at double the rate that campaign teams can capture strays, expanded annual targets become cost-effective. This case study of cost-effective canine interventions in Tamil Nadu may have applicability to other settings in India and beyond.

Evidence-based decision-making for vaccine introductions: Overview of the ProVac International Working Group's experience.

Cost-effectiveness analysis of introducing universal human papillomavirus vaccination of girls aged 11 years into the National Immunization Program in Brazil.

Cost-effectiveness analysis of 10- and 13-valent pneumococcal conjugate vaccines in Peru.

Cost-effectiveness of pneumococcal conjugate vaccination in Georgia.

ProVac Global Initiative: a vision shaped by ten years of supporting evidence-based policy decisions.

Cost-effectiveness of pneumococcal conjugate vaccination in Croatia.

Cost-effectiveness analysis of pneumococcal conjugate vaccine introduction in Paraguay.

Estimated impact and cost-effectiveness of rotavirus vaccination in Senegal: A country-led analysis.

Cost-effectiveness of rotavirus vaccination in Kenya and Uganda.

Investment case for improving maternal and child health: results from four countries

Impact and cost-effectiveness of Haemophilus influenzae type b conjugate vaccination in India.

TRIVAC decision-support model for evaluating the cost-effectiveness of Haemophilus influenzae type b, pneumococcal and rotavirus vaccination.

Establishing a regional network of academic centers to support decision making for new vaccine introduction in Latin America and the Caribbean: the ProVac experience.

Supporting local planning and budgeting for maternal, neonatal and child health in the Philippines

SUMMARY Global coverage of infant Haemophilus influenzae type b (Hib) vaccination has increased considerably during the past decade, partly due to GAVI Alliance donations of the vaccine to low-income countries. In settings where large numbers of children receive only one or two vaccine doses rather than the recommended three doses, dose-specific efficacy estimates are needed to predict impact. The objective of this meta-analysis is to determine Hib vaccine efficacy against different clinical outcomes after receiving one, two or three doses of vaccine. Studies were eligible for inclusion if a prospective, controlled design had been used to evaluate commercially available Hib conjugate vaccines. Eight studies were included. Pooled vaccine efficacies against invasive Hib disease after one, two or three doses of vaccine were 59%, 92% and 93%, respectively. The meta-analysis provides robust estimates for use in decision-analytical models designed to predict the impact of Hib vaccine.

Dose-specific efficacy of Haemophilus influenzae type b conjugate vaccines: a systematic review and meta-analysis of controlled clinical trials

With the recent postlicensure identification of an increased risk of intussusception with rotavirus vaccine, the 14 Latin American countries currently using rotavirus vaccine must now weigh the health benefits versus risks to assess whether to continue vaccination. To inform policy considerations, we estimated excess intussusception cases and mortality potentially caused by rotavirus vaccine for each of the 14 countries and compared these estimates to hospitalizations and deaths expected to be averted through vaccination.

METHODS
We used regional rotavirus disease burden and rotavirus vaccine efficacy data, global natural intussusception and regional rotavirus vaccine-related risk estimates, and country-specific diphtheria, tetanus, and pertussus vaccination coverage rates to estimate rotavirus vaccine coverage rates. We performed a probabilistic sensitivity analysis to account for uncertainty in these parameters.

RESULTS
For an aggregate hypothetical birth cohort of 9.5 million infants in these 14 countries, rotavirus vaccine would annually prevent 144 746 (90% confidence interval [CI], 128 821-156 707) hospitalizations and 4124 deaths (90% CI, 3740-4239) due to rotavirus in their first 5 years of life but could cause an additional 172 hospitalizations (90% CI, 126-293) and 10 deaths (90% CI, 6-17) due to intussusception, yielding benefit-risk ratios for hospitalization and death of 841:1 (90% CI, 479:1 to 1142:1) and 395:1 (90% CI, 207:1 to 526:1), respectively. In an uncertainty analysis using 10 000 simulations of our probabilistic parameters, in comparing rotavirus disease averted to intussusception events caused, the hospitalization ratio was never below 100:1, and our death ratio fell below 100:1 only once.

The health benefits of vaccination far outweigh the short-term risks and support continued rotavirus vaccination in Latin America.

Potential intussusception risk versus health benefits from rotavirus vaccination in Latin America.

Eliana Jimenez Soto and colleagues describe the Investment Case framework, a health systems research approach for planning and budgeting, and detail the implementation of the framework in four Asian countries to improve maternal, newborn and child health.

Developing and Costing Local Strategies to Improve Maternal and Child Health: The Investment Case Framework

Performing Country-led Economic Evaluations to Inform Immunization Policy: ProVac Experiences in Latin America and the Caribbean.

A modeling analysis conducted by Manish Patel and colleagues predicts the possible number of rotavirus deaths prevented, and number of intussusception deaths caused, by use of an unrestricted rotavirus schedule in low- and middle-income countries.

Removing the Age Restrictions for Rotavirus Vaccination: A Benefit-Risk Modeling Analysis

Strengthening the technical capacity at country-level to make informed policy decisions on new vaccine introduction: lessons learned by PAHO's ProVac Initiative.

Cost-effectiveness analysis of the 10- and 13-valent pneumococcal conjugate vaccines in Argentina.

Broadening the age restriction for initiating rotavirus vaccination in regions with high rotavirus mortality: benefits of mortality reduction versus risk of fatal intussusception.

There are plans to introduce the oral rotavirus vaccine Rotarix (GlaxoSmithKline), 1 of 2 recently developed vaccines against rotavirus, in Peru.

METHODS
We modeled the cost-effectiveness of adding a rotavirus vaccine to the Peruvian immunization program under 3 scenarios for the timing of vaccination: (1) strictly according to schedule, at 2 and 4 months of age (on time); (2) distributed around the target ages in the same way as the actual timings in the program (flexible); and (3) flexible but assuming vaccination is not initiated for infants >12 weeks of age (restricted). We assumed an introductory price of US $7.50 per dose, and varied the annual rate of price decrease in sensitivity analyses.

RESULTS
The discounted cost per disability-adjusted life-year averted for restricted, flexible, and on-time schedules was $621, $615, and $581, respectively. For each of the 3 scenarios, the percentage reduction in deaths due to rotavirus infection was 53%, 66%, and 69%, respectively. The cost per disability-adjusted life-year averted for alternative "what-if" scenarios ranged from $229 (assuming a 1-dose schedule, administered on time) to $1491 (assuming a 2-dose schedule, with half the baseline vaccine efficacy rates and a restricted timing policy).

On the basis of current World Health Organization guidelines, rotavirus vaccination represents a highly cost-effective intervention in Peru. Withholding the vaccine from children who present for their first dose after 12 weeks of age would reduce the number of deaths averted by approximately 20%. A single dose may be more cost-effective than 2 doses, but more evidence on the protection conferred by a single dose is required.

Getting it to communities at highest risk of mortality from diarrhoeal disease is the greatest challenge

OBJECTIVE
Estimates of vaccination costs usually provide only point estimates at national level with no information on cost variation. In practice, however, such information is necessary for programme managers. This paper presents information on the variations in costs of delivering routine immunization services in three diverse districts of Peru: Ayacucho (a mountainous area), San Martin (a jungle area) and Lima (a coastal area).

METHODS
We consider the impact of variability on predictions of cost and reflect on the likely impact on expected cost-effectiveness ratios, policy decisions and future research practice. All costs are in 2002 prices in US dollars and include the costs of providing vaccination services incurred by 19 government health facilities during the January-December 2002 financial year. Vaccine wastage rates have been estimated using stock records.

FINDINGS
The cost per fully vaccinated child ranged from 16.63-24.52 U.S. Dollars in Ayacucho, 21.79-36.69 U.S. Dollars in San Martin and 9.58-20.31 U.S. Dollars in Lima. The volume of vaccines administered and wastage rates are determinants of the variation in costs of delivering routine immunization services.

This study shows there is considerable variation in the costs of providing vaccines across geographical regions and different types of facilities. Information on how costs vary can be used as a basis from which to generalize to other settings and provide more accurate estimates for decision-makers who do not have disaggregated data on local costs. Future studies should include sufficiently large sample sizes and ensure that regions are carefully selected in order to maximize the interpretation of cost variation.

Variation in the costs of delivering routine immunization services in Peru.

Molecules that bind DNA via threading intercalation show high binding affinity as well as slow dissociation kinetics, properties ideal for the development of anticancer drugs. To this end, it is critical to identify the specific molecular characteristics of threading intercalators that result in optimal DNA interactions. Using single-molecule techniques, we quantify the binding of a small metal-organic ruthenium threading intercalator (Δ,Δ-B) and compare its binding characteristics to a similar molecule with significantly larger threading moieties (Δ,Δ-P). The binding affinities of the two molecules are the same, while comparison of the binding kinetics reveals significantly faster kinetics for Δ,Δ-B. However, the kinetics is still much slower than that observed for conventional intercalators. Comparison of the two threading intercalators shows that the binding affinity is modulated independently by the intercalating section and the binding kinetics is modulated by the threading moiety. In order to thread DNA, Δ,Δ-P requires a "lock mechanism", in which a large length increase of the DNA duplex is required for both association and dissociation. In contrast, measurements of the force-dependent binding kinetics show that Δ,Δ-B requires a large DNA length increase for association but no length increase for dissociation from DNA. This contrasts strongly with conventional intercalators, for which almost no DNA length change is required for association but a large DNA length change must occur for dissociation. This result illustrates the fundamentally different mechanism of threading intercalation compared with conventional intercalation and will pave the way for the rational design of therapeutic drugs based on DNA threading intercalation.

Reshaping the Energy Landscape Transforms the Mechanism and Binding Kinetics of DNA Threading Intercalation.

Role of Threading Moiety Size and Chirality in Determining the DNA Binding Characteristics of Threading Intercalators

Significance of Steric Bulk in DNA Threading Intercalation Revelaed through Force-Dependent Kinetics

The Role of the Threading Moiety in DNA Threading Intercalation by Ruthenium Dimer Complexes

Threading Moieties Play a Significant Role in Determining the DNA Binding Properties of Binuclear Ruthenium Complexes

W e have observed hypotension (mean arterial pressure [MAP] , 60 mm Hg) and/or bradycardia (heart rate [HR] , 40 bpm) shortly after IV heparin loading for cardiopulmonary bypass (CPB) in several patients undergoing cardiac surgery. Serum electrolytes after these episodes of cardiovascular instability (CVI, defined as MAP , 60 mm Hg and/or HR , 40 bpm) often showed relative hyperkalemia. Hyperkalemia has been reported with chronic heparin administration (1–6), but only after several days of treatment, and has not been reported to occur acutely. The purposes of this report were to review the characteristics of the cases of CVI and to compare the cases of CVI with a control group.

Cardiovascular Instability Requiring Treatment after Intravenous Heparin for Cardiopulmonary Bypass

Rapid enzyme kinetic assays of individualDrosophila and comparisons of field-caughtD. melanogaster andD. simulans

Hydrostatically balanced gradient-formers: programming of gradients.

Affinity chromatography of rat plasma albumin on bromosulfophthalein-glutathione conjugate covalently linked to sepharose 4-B.

A rapid chromatographic technique for the detection of dye-binding.

1. The substrate kinetic properties of cerebral hexokinases (mitochondrial and cytoplasmic) were studied at limiting concentrations of both glucose and MgATP(2-). Primary plots of the enzymic activity gave no evidence of a Ping Pong mechanism in three types of mitochondrial preparation tested (intact and osmotically disrupted mitochondria, and the purified mitochondrial enzyme), nor in the purified cytoplasmic preparation. 2. Secondary plots of intercepts from the primary plots (1/v versus 1/s) versus reciprocal of second substrate of the mitochondrial activity gave kinetic constants which differed from those obtained directly from the plots of 1/v versus 1/s or of s/v versus s, although the ratios of the derived constants were consistent. The kinetic constants obtained with the cytoplasmic enzyme from primary and secondary plots were consistent. 3. Deoxyglucose, as alternative substrate, inhibited cytoplasmic hexokinase by competition with glucose, but did not compete when MgATP(2-) was the substrate varied. The K(i) for deoxyglucose when glucose concentrations were varied was 0.25mm. 4. A range of ATP analogues was tested as potential substrates and inhibitors of hexokinase activity. GTP, ITP, CTP, UTP and betagamma-methylene-ATP did not act as substrates, nor did they cause significant inhibition. Deoxy-ATP proved to be almost as effective a substrate as ATP. AMP inhibited but did not act as substrate. 5. N-Acetyl-glucosamine inhibited all preparations competitively when glucose was varied and non-competitively when MgATP(2-) was varied. AMP inhibition was competitive when MgATP(2-) was the substrate varied and non-competitive when glucose was varied. 6. The results are interpreted as providing evidence for a random reaction mechanism in all preparations of brain hexokinase, cytoplasmic and mitochondrial. The kinetic properties and reaction mechanism do not change on extraction and purification of the particulate enzyme. 7. The results are discussed in terms of the participation of hexokinase in regulation of cerebral glycolysis.

Cerebral-cortex hexokinase. Elucidation of reaction mechanisms by substrate and dead-end inhibitor kinetic analysis.

A model is presented that accounts for all types of reversible inhibition by a single inhibitor molecule in bimolecular rapid-equilibrium random-order enzyme systems. The characterization of inhibition mechanisms by graphical methods is examined, and a system of nomenclature is suggested.

Reversible inhibition in bimolecular rapid equilibrium random order enzyme systems. The effect of substrate-substrate and inhibitor-substrate interactions.

How do intelligent agents spawn and exploit integrated processing regimes spanning brain, body, and world? The answer may lie in the ability of the biological brain to select actions and policies in the light of counterfactual predictions — predictions about what kinds of futures will result if such-and-such actions are launched. Appeals to the minimization of ‘ counterfactual prediction errors ’ (the ones that would result under various scenarios) already play a leading role in attempts to apply the basic toolkit of the neurocomputational theory known as ‘ predictive processing ’ to higher cognitive functions such as policy selection and planning. In this paper, I show that this also leads naturally to the discovery and use of extended processing regimes de ﬁ ned across heterogeneous mixtures of biological and non-biological resources. This solves a long-standing puzzle concerning the ‘ recruitment ’ of the right non-neural processing resources at the right time. It reveals how (and why) human brains spawn and maintain extended human minds.

Parking enforcement in Westminster is briefly described, including occasions when enforcement may be difficult or controversial, emergencies and special events. For covering abstract see ITRD E110293.

of a Dissertation Submitted to the Graduate School of The University of Southern Mississippi in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy

Comparing Mississippi's Public University Graduation Rates for Community College Completers and Non-Completers

The purpose of this study was to analyze the effects of teacher autonomy on student achievement levels in public education. The research includes findings that answer the questions, “Is teacher autonomy perceived differently between two high schools in the same district?” “Do prescribed programs work as a means to increase test scores?” The research was conducted using an anonymous survey done through the use of Google Docs and was given to both high school Communication Arts departments in the Park Hill School District in suburban Kansas City, Missouri.. The findings were analyzed by Chi-Square through Microsoft Excel and A Statistical Program (ASP) software. Findings indicate that there is a difference between the level of teacher autonomy between the two schools. Both schools, while high achieving, do vary in the performance level on state End of Course Exams for both 9 and 10 grade. Teacher Autonomy-3 INTRODUCTION Background Issues and Concerns: Educators are constantly trying to find their stride in teaching. One of the biggest areas of focus and debate amongst teachers and administrators is a feeling of autonomy from the administration for teachers to adequately, and by using their own resources, educate their students. This project will involve research and a survey of information to determine if teacher autonomy has a positive effect on student learning. Practice Under Investigation: This practice under investigation is the effect of teacher autonomy on student learning. School Policy to be Informed by Study: The school district in focus has two high schools with varying opinions and methods which support teaching autonomy. Each high school has roughly the same number of students with the same number of teachers. Each building also has 5 administrators to supervise its teachers. These high schools both serve students grades 912 with approximately 1600 students. Conceptual Underpinning: Both state and national governments implement mandated testing that districts are required to administer to their students. As standards for performance raise to even higher levels, schools are determining the best way to meet these goals. One such method has Teacher Autonomy-4 been to deprive teachers of autonomy and force them to a set curriculum and “teach to the test.” While this practice is usually looked down upon by teachers, some schools have seen results with a more set curriculum. Either way, standardized testing scores are effecting the level of teacher autonomy in the classroom. In theory, an increase in teacher autonomy would increase student achievement as a number of factors come into play. Teacher autonomy allows teachers to take ownership of their work and allows them to do what they do best: teach. In theory, if a teacher is consistently concerned with getting through a prescribed curriculum with materials which have been provided for them, it leaves them very little room to modify or make improvements in their teaching practices. Secondly, teacher burnout is becoming an increasing problem. And as the brightest crop of new teachers are graduating from universities and colleges, schools need to make an effort to make keep them in the profession. If they are being forced to teach a certain way, it gives them very little ownership and allows them little room to practice the art of teaching which they learned in their respective college and university. Therefore, entrusting teachers to make adequate and appropriate instructional decisions, provides them a greater sense of ownership of their classroom and decreasing the amount of burnout which would work to increase student achievement. Statement of Problem: The current deprivation of teacher autonomy in the classroom is preventing students from a beneficial educational experience and increasing teacher burnout rates. Teacher Autonomy-5 Purpose of the Study: To determine if building climate affects the perceptions of teacher autonomy. Research questions: RQ1: Is there a difference of opinion regarding teacher autonomy between two high schools in the same school district? RQ2: Is NCLB and other state level initiatives preventing teachers from exploring more creative and innovative teaching strategies and practices? Null hypothesis: There is no significant difference between perceptions of teacher autonomy between the two high schools in the same district. Anticipated benefits of the study: The benefits of this study will be for both teacher and student. This will require a reflection and analysis of teaching practices from the teacher. From the student perspective, they will benefit from a different approach to teaching which requires more interaction between not only student and teacher, but students with other students. Teacher Autonomy-6 Definition of terms: AYP: Annual Yearly Progress. Each public school is assessed in Comm Arts and Math. The school is required to reach a certain achievement level in these areas. Since this program began with the implementation of No Child Left Behind, each year the number of schools making this goal has decreased. NCLB: No Child Left Behind. Education legislation created by the George W. Bush administration and put into effect in 2002. It is designed to set benchmarks for each child in Comm Arts and Math and is assessed each year. Autonomy: being self governing. Ability and freedom to make own professional choices regarding curriculum and content. DESE: Missouri Department of Education IEP: Individual Education Plan. Plan created on a student by student basis to address needs of special education students. These plans consist of accommodations and modifications for classroom teachers to follow to ensure that the needs of special education students are being met. Summary: PHSD is a suburban district based in Kansas City, MO. Each high school has roughly the same number of students with the same number of teachers. Each building also has the same number of administrators to supervise its teachers. These high schools both serve students grades 9-12 with approximately 1600 students. The research investigates the level of teacher autonomy in the classroom and then will compare this level to the success of its students on standardized test scores. Teacher Autonomy-7 REVIEW OF LITERATURE In a keynote address, University of Northern Kentucky Professor Doug Feldmann said, “I submit that those going into the education field in contemporary times are no longer overly concerned with traditional discouragements such as low salaries; rather, what appears to be desired today by teachers—both novice and veteran—is the freedom to make reasonable curricular and instructional choices, and the administrative support to enact such choices” (Feldmann 2011, p.2). This is, in fact the overwhelming issue teachers face in public education. Feldman (2011) will go on to argue that the lack of teacher autonomy has led to an increase in teacher attrition rates as well as a more compartmentalized view of public education. However, with the increase in emphasis in standardized test scores, policy makers have, what they feel to be, a more defined curriculum that teachers and public schools should subscribe to leaving the teacher with little freedom. It is publicly acknowledged that there is much good to come from a child’s education that extends beyond their standardized test scores. However, what cannot be determined is what should be achieved beyond theses scores. Feldmann (2011) speculates that if this could be determined, and the teachers were left alone from policy makers and the general public to achieve these goals, America would see a drastic increase in the performance of public education. Furthermore, common syllabi and curriculum do not foster higher levels of achievement in teachers causing them to become complacent or leave the profession altogether. Similar to Feldmann’s thoughts on teacher autonomy, the discussion also comes around about high stakes testing and the teacher response to the increase in this type of Teacher Autonomy-8 assessment. Reich and Bally (2010) speculate through research that this sort of high stakes testing which determines levels of state funding for schools as well as public knowledge of which schools reach No Child Left Behind (NCLB) or Annual Yearly Progress (AYP) force teachers to abandon their own teaching strategies and practices and resort to “teaching to the test”. This often times requires teachers to teach a list of terms or ideas that may be too extensive to cover in such a short period of time. The other negative impact of high stakes testing on teaching practices is the abandonment of teaching actual content and students effectively learning information. Rather teachers are informing students on testing strategies for a particular test. Therefore, the question must be asked that if students are simply learning terms or testing strategies for a particular test at a particular time, are they actually learning skills that will make them effective and contributive members of an ever changing 21 century society? Both the Feldmann (2011) and Reich and Bally (2010) articles speculate that what needs to be improved in public schools is a renewed faith in the educators to achieve holistic common goals and an improvement in teaching practices—not a quick fix to what teachers should teach and what students should know. Reich and Bally (2010) write, “What often happens is that the sense of urgency for the achievement of better results, that is, higher test scores, places tremendous strain on teachers and administrators alike. Paradoxically, as the pressure for higher achievement cascades down the institutional hierarchy, conditions are created that make higher achievement less likely to occur” (p.181). In their article, “Following the Script” authors Parsons and Harrington (2009) evaluate the desire of inner city schools to raise reading levels of younger students and Teacher Autonomy-9 that added pressure that N

A SURVEY OF HIGH SCHOOL ENGLISH TEACHERS IN THE PARK HILL SCHOOL DISTRICT ON PERCEPTIONS OF TEACHER AUTONOMY IN SCHOOLS

American higher education, according to the authors, is facing a financial crisis that can be alleviated only by drastic, increased federal support to the educational system. Presented in this document is a review of the financial history of American colleges and universities, a look at the present situation, and a preview of the future picture of higher education. Following the past, present, and future review is a discussion of whether a federal role in financing is implied, how much aid should be appropriated, and what form this aid should take It is suggested that the federal government adopt a financial aid program that would combine institutional and student aid. An institutional grant and student loan program is offered as one major alternative. (Hs)

The Financial Crisis in Hi her Education : Past , Present , and Future

EDITORIAL Representation, Development and Situated Connectionism

Introduction The synovial membrane is the main site of inflammation in rheumatoid arthritis (RA). Here several subsets of fibroblasts and macrophages, with distinct effector functions, have been recently identified. The RA synovium is hypoxic and acidic, with increased levels of lactate as a result of inflammation. We investigated how lactate regulates fibroblast and macrophage movement, IL-6 secretion and metabolism via specific lactate transporters. Methods Synovial tissues were taken from patients undergoing joint replacement surgery and fulfilling the 2010 ACR/EULAR RA criteria. Patients with no evidence of degenerative or inflammatory disease were used as control. Expression of the lactate transporters SLC16A1 and SLC16A3 on fibroblasts and macrophages was assessed by immunofluorescence staining and confocal microscopy. To test the effect of lactate in vitro we used RA synovial fibroblasts and monocyte-derived macrophages. Migration was assessed via scratch test assays or using trans-well inserts. Metabolic pathways were analysed by Seahorse analyser. IL-6 secretion was determined by ELISA. Bioinformatic analysis was performed on publicly available single cell and bulk RNA sequencing datasets. Results We show that: i) SLC16A1 and SLC16A3 which regulate lactate intake and export respectively, are both expressed in RA synovial tissue and are upregulated upon inflammation. SLC16A3 is more highly expressed by macrophages, while SLC16A1 was expressed by both cell types. ii) This expression is maintained in distinct synovial compartments at mRNA and protein level. iii) Lactate, at the concentration found in RA joints (10 mM), has opposite effects on the effector functions of these two cell types. In fibroblasts, lactate promotes cell migration, IL-6 production and increases glycolysis. In contrast macrophages respond to increases in lactate by reducing glycolysis, migration, and IL-6 secretion. Discussion In this study, we provide the first evidence of distinct functions of fibroblasts and macrophages in presence of high lactate levels, opening new insights in understanding the pathogenesis of RA and offering novel potential therapeutic targets.

Differential effect of lactate on synovial fibroblast and macrophage effector functions

Glucocorticoids potently inhibit expression of many inflammatory mediators, and have been very widely used to treat both acute and chronic inflammatory diseases for more than seventy years. However, they can have several unwanted effects, amongst which immunosuppression is one of the most common. Here we investigated effects of the synthetic glucocorticoid dexamethasone on the responses of primary mouse bone marrow-derived macrophages to the pro-inflammatory agonist lipopolysaccharide (LPS). At the mRNA level, dexamethasone inhibited the LPS-induced expression of more than 100 genes that are involved in cell-intrinsic defence against viral pathogens. Expression of most of the corresponding proteins was also reduced by dexamethasone. This antiviral disarmament occurred at two distinct levels. First, dexamethasone strongly and dose-dependently inhibited the expression of the type I interferon IFNβ by LPS-activated macrophages. IFNβ mediates an autocrine positive feedback loop in LPS-treated macrophages, promoting the expression of antiviral genes and other interferon-stimulated genes. Hence reduction of IFNβ expression contributes to impaired expression of antiviral genes. Dexamethasone also acted downstream of IFNβ to inhibit expression of a subset of interferon-regulated genes. We tested a number of hypotheses based on previous publications, but found that no single mechanism could account for more than a small fraction of the broad suppressive impact of dexamethasone on macrophage type I interferon signaling, underlining the complexity of this pathway. Preliminary experiments indicated that dexamethasone exerted similar inhibitory effects on primary human monocyte-derived or alveolar macrophages.

The glucocorticoid dexamethasone impairs the expression of anti-viral mediators in activated macrophages by inhibiting both expression and function of interferon β

Mitochondria are major energy-producing organelles that have central roles in cellular metabolism. They also act as important signalling hubs, and their dynamic regulation in response to stress signals helps to dictate the stress response of the cell. Rheumatoid arthritis is an inflammatory and autoimmune disease with high prevalence and complex aetiology. Mitochondrial activity affects differentiation, activation and survival of immune and non-immune cells that contribute to the pathogenesis of this disease. This review outlines what is known about the role of mitochondria in rheumatoid arthritis pathogenesis, and how current and future therapeutic strategies can function through modulation of mitochondrial activity. We also highlight areas of this topic that warrant further study. As producers of energy and of metabolites such as succinate and citrate, mitochondria help to shape the inflammatory phenotype of leukocytes during disease. Mitochondrial components can directly stimulate immune receptors by acting as damage-associated molecular patterns, which could represent an initiating factor for the development of sterile inflammation. Mitochondria are also an important source of intracellular reactive oxygen species, and facilitate the activation of the NLRP3 inflammasome, which produces cytokines linked to disease symptoms in rheumatoid arthritis. The fact that mitochondria contain their own genetic material renders them susceptible to mutation, which can propagate their dysfunction and immunostimulatory potential. Several drugs currently used for the treatment of rheumatoid arthritis regulate mitochondrial function either directly or indirectly. These actions contribute to their immunomodulatory functions, but can also lead to adverse effects. Metabolic and mitochondrial pathways are attractive targets for future anti-rheumatic drugs, however many questions still remain about the precise role of mitochondrial activity in different cell types in rheumatoid arthritis.

Mitochondria as Key Players in the Pathogenesis and Treatment of Rheumatoid Arthritis

Fibroblast-like synoviocytes (FLS) play an important role in maintaining joint homeostasis and orchestrating local inflammatory processes. When activated during injury or inflammation, FLS undergo transiently increased bioenergetic and biosynthetic demand. We aimed to identify metabolic changes which occur early in inflammatory disease pathogenesis which might support sustained cellular activation in persistent inflammation. We took primary human FLS from synovial biopsies of patients with very early rheumatoid arthritis (veRA) or resolving synovitis, and compared them with uninflamed control samples from the synovium of people without arthritis. Metabotypes were compared using NMR spectroscopy-based metabolomics and correlated with serum C-reactive protein levels. We measured glycolysis and oxidative phosphorylation by Seahorse analysis and assessed mitochondrial morphology by immunofluorescence. We demonstrate differences in FLS metabolism measurable after ex vivo culture, suggesting that disease-associated metabolic changes are long-lasting. We term this phenomenon ‘metabolic memory’. We identify changes in cell metabolism after acute TNFα stimulation across disease groups. When compared to FLS from patients with early rheumatoid arthritis, FLS from patients with resolving synovitis have significantly elevated mitochondrial respiratory capacity in the resting state, and less fragmented mitochondrial morphology after TNFα treatment. Our findings indicate the potential to restore cell metabotypes by modulating mitochondrial function at sites of inflammation, with implications for treatment of RA and related inflammatory conditions in which fibroblasts play a role.

Spontaneously Resolving Joint Inflammation Is Characterised by Metabolic Agility of Fibroblast-Like Synoviocytes

Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis

Phytomedicine : international journal of phytotherapy and phytopharmacology

Enhanced therapeutic efficacy of a novel colon-specific nanosystem loading emodin on DSS-induced experimental colitis.

Fibroblasts are ubiquitous stromal cells, with populations found in all organs. The traditional role of fibroblasts was thought to be mainly structural; making and modifying extracellular matrix. Taken together the ability of fibroblasts to produce and respond to many factors involved in the immune system indicates the degree to which they are involved in orchestrating the inflammatory response in rheumatoid arthritis (RA). This level of involvement demonstrates the importance of fibroblasts in inflammation and indicates the shift from transient to chronic inflammation in RA could be facilitated in part by synovial fibroblasts. This chapter explores the role of fibroblasts in RA.

Chronic obstructive pulmonary disease (COPD) is a progressive disease that causes significant mortality and morbidity worldwide and is primarily caused by the inhalation of cigarette smoke (CS). Lack of effective treatments for COPD means there is an urgent need to identify new therapeutic strategies for the underlying mechanisms of pathogenesis. Tristetraprolin (TTP) encoded by the Zfp36 gene is an anti‐inflammatory protein that induces mRNA decay, especially of transcripts encoding inflammatory cytokines, including those implicated in COPD.

Enhancing tristetraprolin activity reduces the severity of cigarette smoke‐induced experimental chronic obstructive pulmonary disease

I094 Tristetraprolin (TTP) and dual specificity phosphatase 1 (DUSP1) cooperate to prevent inflammatory arthritis

Pre-receptor metabolism and signalling of glucocorticoids between macrophages and fibroblasts

Protein phosphatase 2A as a therapeutic target in inflammation and neurodegeneration

Key Points MK2/3 are the only LPS-induced kinases for S52 and S178 of TTP. TNF regulation by MK2/3 is not restricted to TTP phosphorylation at S52 and S178. The MK2/3/TTP signaling axis contributes to sepsis in vivo. Visual Abstract Tristetraprolin (TTP) is an RNA-binding protein and an essential factor of posttranscriptional repression of cytokine biosynthesis in macrophages. Its activity is temporally inhibited by LPS-induced p38MAPK/MAPKAPK2/3–mediated phosphorylation, leading to a rapid increase in cytokine expression. We compared TTP expression and cytokine production in mouse bone marrow–derived macrophages of different genotypes: wild type, MAPKAP kinase 2 (MK2) deletion (MK2 knockout [KO]), MK2/3 double deletion (MK2/3 double KO [DKO]), TTP-S52A-S178A (TTPaa) knock-in, as well as combined MK2 KO/TTPaa and MK2/3 DKO/TTPaa. The comparisons reveal that MK2/3 are the only LPS-induced kinases for S52 and S178 of TTP and the role of MK2 and MK3 in the regulation of TNF biosynthesis is not restricted to phosphorylation of TTP at S52/S178 but includes independent processes, which could involve other TTP phosphorylations (such as S316) or other substrates of MK2/3 or p38MAPK. Furthermore, we found differences in the dependence of various cytokines on the cooperation between MK2/3 deletion and TTP mutation ex vivo. In the cecal ligation and puncture model of systemic inflammation, a dramatic decrease of cytokine production in MK2/3 DKO, TTPaa, and DKO/TTPaa mice compared with wild-type animals is observed, thus confirming the role of the MK2/3/TTP signaling axis in cytokine production also in vivo. These findings improve our understanding of this signaling axis and could be of future relevance in the treatment of inflammation.

The Role of TTP Phosphorylation in the Regulation of Inflammatory Cytokine Production by MK2/3

Glucocorticoids (GCs) are steroids with profound anti-in-flammatory and immunomodulatory activities. Synthetic GCs are widely used for managing chronic inflammatory and auto-immune conditions, as immunosuppressants in transplanta-tion, and as anti-tumor agents in certain hematological cancers. However, prolonged GC exposure can cause adverse effects. A detailed understanding of GCs’ mechanisms of action may enable harnessing of their desirable actions while minimizing harmful effects. Here, we review the impact on the GC biology of microRNAs, small non-coding RNAs that post-transcription-ally regulate gene expression. Emerging evidence indicates that microRNAs modulate GC production by the adrenal glands and the cells’ responses to GCs. Furthermore, GCs influence cell proliferation, survival, and function at least in part by regulating microRNA expression. We propose that the beneficial effects of GCs may be enhanced through combination with reagents targeting specific microRNAs.

University of Birmingham The role of microRNAs in glucocorticoid action

All organisms are exposed constantly to a variety of infectious and injurious stimuli. These induce inflammatory responses tailored to the threat posed. While the innate immune system is the front line of response to each stimulant, it has been considered traditionally to lack memory, acting in a generic fashion until the adaptive immune arm can take over. This outmoded simplification of the roles of innate and acquired arms of the immune system has been challenged by evidence of myeloid cells altering their response to subsequent encounters based on earlier exposure. This concept of ‘innate immune memory’ has been known for nearly a century, and is accepted among myeloid biologists. In recent years other innate immune cells, such as natural killer cells, have been shown to display memory, suggesting that innate immune memory is a trait common to several cell types. During the last 30 years, evidence has slowly accumulated in favour of not only haematopoietic cells, but also stromal cells, being imbued with memory following inflammatory episodes. A recent publication showing this also to be true in epithelial cells suggests innate immune memory to be widespread, if under‐appreciated, in non‐haematopoietic cells. In this review, we will examine the evidence supporting the existence of innate immune memory in stromal cells. We will also discuss the ramifications of memory in long‐lived tissue‐resident cells. Finally, we will pose questions we feel to be important in the understanding of these forgotten cells in the field of innate memory.

Glucocorticoids (GCs) are steroids with profound anti-inflammatory and immunomodulatory activities. Synthetic GCs are widely used for managing chronic inflammatory and autoimmune conditions, as immunosuppressants in transplantation, and as anti-tumor agents in certain hematological cancers. However, prolonged GC exposure can cause adverse effects. A detailed understanding of GCs' mechanisms of action may enable harnessing of their desirable actions while minimizing harmful effects. Here, we review the impact on the GC biology of microRNAs, small non-coding RNAs that post-transcriptionally regulate gene expression. Emerging evidence indicates that microRNAs modulate GC production by the adrenal glands and the cells' responses to GCs. Furthermore, GCs influence cell proliferation, survival, and function at least in part by regulating microRNA expression. We propose that the beneficial effects of GCs may be enhanced through combination with reagents targeting specific microRNAs.

IL‐33 is an IL‐1‐related cytokine that can act as an alarmin when released from necrotic cells. Once released, it can target various immune cells including mast cells, innate lymphoid cells and T cells to elicit a Th2‐like immune response. We show here that bone marrow‐derived mast cells produce IL‐13, IL‐6, TNF, GM‐CSF, CCL3 and CCL4 in response to IL‐33 stimulation. Inhibition of the p38 MAPK, or inhibition or knockout of its downstream kinases MK2 and MK3, blocked the production of these cytokines in response to IL‐33. The mechanism downstream of MK2/3 was cytokine specific; however, MK2 and MK3 were able to regulate TNF and GM‐CSF mRNA stability. Previous studies in macrophages have shown that MK2 regulates mRNA stability via phosphorylation of the RNA‐binding protein TTP (Zfp36). The regulation of cytokine production in mast cells was, however, independent of TTP. MK2/3 were able to phosphorylate the TTP‐related protein Brf1 (Zfp36 l1) in IL‐33‐stimulated mast cells, suggesting a mechanism by which MK2/3 might control mRNA stability in these cells. In line with its ability to regulate in vitro IL‐33‐stimulated cytokine production, double knockout of MK2 and 3 in mice prevented neutrophil recruitment following intraperitoneal injection of IL‐33.

IL‐33 regulates cytokine production and neutrophil recruitment via the p38 MAPK‐activated kinases MK2/3

University of Dundee IL-33 regulates cytokine production and neutrophil recruitment via the p 38 MAPK-activated kinases MK 2 / 3 McCarthy

MAPK p38 regulates inflammatory gene expression via tristetraprolin: Doing good by stealth

Metabolomic studies of body fluids show that immune‐mediated inflammatory diseases such as rheumatoid arthritis (RA) are associated with metabolic disruption. This is likely to reflect the increased bioenergetic and biosynthetic demands of sustained inflammation and changes in nutrient and oxygen availability in damaged tissue. The synovial membrane lining layer is the principal site of inflammation in RA. Here, the resident cells are fibroblast‐like synoviocytes (FLS) and synovial tissue macrophages, which are transformed toward overproduction of enzymes that degrade cartilage and bone and cytokines that promote immune cell infiltration. Recent studies have shown metabolic changes in both FLS and macrophages from RA patients, and these may be therapeutically targetable. However, because the origins and subset‐specific functions of synoviocytes are poorly understood, and the signaling modules that control metabolic deviation in RA synovial cells are yet to be explored, significant additional research is needed to translate these findings to clinical application. Furthermore, in many inflamed tissues, different cell types can forge metabolic collaborations through solute carriers in their membranes to meet a high demand for energy or biomolecules. Such relationships are likely to exist in the synovium and have not been studied. Finally, it is not yet known whether metabolic change is a consequence of disease or whether primary changes to cellular metabolism might underlie or contribute to the pathogenesis of early‐stage disease. In this review article, we collate what is known about metabolism in synovial tissue cells and highlight future directions of research in this area.

Review: Synovial Cell Metabolism and Chronic Inflammation in Rheumatoid Arthritis

Priming in response to pro-inflammatory cytokines is a feature of adult synovial but not dermal fibroblasts

Macrophage responses to lipopolysaccharide are modulated by a feedback loop involving prostaglandin E2, dual specificity phosphatase 1 and tristetraprolin

The NLRP3 inflammasome is a central regulator of inflammation in many common diseases, including atherosclerosis and type 2 diabetes, driving the production of pro-inflammatory mediators such as IL-1β and IL-18. Due to its function as an inflammatory gatekeeper, expression and activation of NLRP3 need to be tightly regulated. In this study, we highlight novel post-transcriptional mechanisms that can modulate NLRP3 expression. We have identified the RNA-binding protein Tristetraprolin (TTP) as a negative regulator of NLRP3 in human macrophages. TTP targets AU-rich elements in the NLRP3 3′-untranslated region (UTR) and represses NLRP3 expression. Knocking down TTP in primary macrophages leads to an increased induction of NLRP3 by LPS, which is also accompanied by increased Caspase-1 and IL-1β cleavage upon NLRP3, but not AIM2 or NLRC4 inflammasome activation. Furthermore, we found that human NLRP3 can be alternatively polyadenylated, producing a short 3′-UTR isoform that excludes regulatory elements, including the TTP- and miRNA-223-binding sites. Because TTP also represses IL-1β expression, it is a dual inhibitor of the IL-1β system, regulating expression of the cytokine and the upstream controller NLRP3.

The RNA-binding protein Tristetraprolin (TTP) is a critical negative regulator of the NLRP3 inflammasome

ABSTRACT The mRNA-destabilizing factor tristetraprolin (TTP) binds in a sequence-specific manner to the 3′ untranslated regions of many proinflammatory mRNAs and recruits complexes of nucleases to promote rapid mRNA turnover. Mice lacking TTP develop a severe, spontaneous inflammatory syndrome characterized by the overexpression of tumor necrosis factor and other inflammatory mediators. However, TTP also employs the same mechanism to inhibit the expression of the potent anti-inflammatory cytokine interleukin 10 (IL-10). Perturbation of TTP function may therefore have mixed effects on inflammatory responses, either increasing or decreasing the expression of proinflammatory factors via direct or indirect mechanisms. We recently described a knock-in mouse strain in which the substitution of 2 amino acids of the endogenous TTP protein renders it constitutively active as an mRNA-destabilizing factor. Here we investigate the impact on the IL-10-mediated anti-inflammatory response. It is shown that the gain-of-function mutation of TTP impairs IL-10-mediated negative feedback control of macrophage function in vitro. However, the in vivo effects of TTP mutation are uniformly anti-inflammatory despite the decreased expression of IL-10.

Gain-of-Function Mutation of Tristetraprolin Impairs Negative Feedback Control of Macrophages In Vitro yet Has Overwhelmingly Anti-Inflammatory Consequences In Vivo

Tryptophan-Mediated Interactions between Tristetraprolin and the CNOT9 Subunit Are Required for CCR4-NOT Deadenylase Complex Recruitment.

Explorer Regulation of cyclooxygenase 2 mRNA stability by the mitogen-activated protein kinase p 38 signaling cascade

Asthma is an allergic airway disease (AAD) caused by aberrant immune responses to allergens. Protein phosphatase‐2A (PP2A) is an abundant serine/threonine phosphatase with anti‐inflammatory activity. The ubiquitin proteasome system (UPS) controls many cellular processes, including the initiation of inflammatory responses by protein degradation. We assessed whether enhancing PP2A activity with fingolimod (FTY720) or 2‐amino‐4‐(4‐(heptyloxy) phenyl)‐2‐methylbutan‐1‐ol (AAL(S)), or inhibiting proteasome activity with bortezomib (BORT), could suppress experimental AAD.

Targeting PP2A and proteasome activity ameliorates features of allergic airway disease in mice

Preventing virally induced liver disease begins with an understanding of the host factors that define susceptibility to infection. Hepatitis C virus (HCV) is a global health issue, with an estimated 170 million infected individuals at risk of developing liver disease including fibrosis and hepatocellular carcinoma. The liver is the major reservoir supporting HCV replication and this hepatocellular tropism is defined by HCV engagement of cellular entry receptors. Hepatocytes are polarized in vivo and this barrier function limits HCV entry. We previously reported that activated macrophages promote HCV entry into polarized hepatocytes via a TNF-α-dependent process; however, the underlying mechanism was not defined. In this study, we show that several TNF superfamily members, including TNF-α, TNF-β, TWEAK and LIGHT, promote HCV entry via NF-κB-mediated activation of myosin light chain kinase (MLCK) and disruption of tight junctions. These observations support a model where HCV hijacks an inflammatory immune response to stimulate infection and uncovers a role for NF-κB-MLCK signalling in maintaining hepatocellular tight junctions.

TNF superfamily members promote hepatitis C virus entry via an NF-κB and myosin light chain kinase dependent pathway

Gain-of-function mutation of tristetraprolin impairs negative feedback control of macrophages , yet has overwhelmingly anti-inflammatory consequences .

Objectives Tristetraprolin (TTP), a negative regulator of many pro-in ﬂ ammatory genes, is strongly expressed in rheumatoid synovial cells. The mitogen-activated protein kinase (MAPK) p38 pathway mediates the inactivation of TTP via phosphorylation of two serine residues. We wished to test the hypothesis that these phosphorylations contribute to the development of in ﬂ ammatory arthritis, and that, conversely, joint in ﬂ ammation may be inhibited by promoting the dephosphorylation and activation of TTP. Methods The expression of TTP and its relationship with MAPK p38 activity were examined in non-in ﬂ amed and rheumatoid arthritis (RA) synovial tissue. Experimental arthritis was induced in a genetically modi ﬁ ed mouse strain, in which endogenous TTP cannot be phosphorylated and inactivated. In vitro and in vivo experiments were performed to test anti-in ﬂ ammatory effects of compounds that activate the protein phosphatase 2A (PP2A) and promote dephosphorylation of TTP. Results TTP expression was signi ﬁ cantly higher in RA than non-in ﬂ amed synovium, detected in macrophages, vascular endothelial cells and some ﬁ broblasts and co-localised with MAPK p38 activation. Substitution of TTP phosphorylation sites conferred dramatic protection against in ﬂ ammatory arthritis in mice. Two distinct PP2A agonists also reduced in ﬂ ammation and prevented bone erosion. In vitro anti-in ﬂ ammatory effects of PP2A agonism were mediated by TTP activation. Conclusions The phosphorylation state of TTP is a critical determinant of in ﬂ ammatory responses, and a tractable target for novel anti-in ﬂ ammatory treatments.

Treatment of in ﬂ ammatory arthritis via targeting of tristetraprolin, a master regulator of pro-in ﬂ ammatory gene expression

Tristetraprolin (TTP) is an RNA binding protein that negatively regulates the expression of many inflammatory mediators, including TNF, IL-1, IL-6, IL-17, IL-23 and cyclooxygenase 2. Moreover, the control of pro- inflammatory gene expression by the mitogen-activated protein kinase (MAPK) p38 is achieved via the phosphorylation of TTP. We present evidence that direct targeting of TTP itself, rather than the upstream signalling cascades, might be used to treat inflammatory arthritis. Disclosure statement: The author has declared no conflicts of interest.

I55 Targeting Tristetraprolin as a New Approach to the Treatment of Rheumatoid Arthritis

ABSTRACT Autocrine or paracrine signaling by beta interferon (IFN-β) is essential for many of the responses of macrophages to pathogen-associated molecular patterns. This feedback loop contributes to pathological responses to infectious agents and is therefore tightly regulated. We demonstrate here that macrophage expression of IFN-β is negatively regulated by mitogen- and stress-activated kinases 1 and 2 (MSK1/2). Lipopolysaccharide (LPS)-induced expression of IFN-β was elevated in both MSK1/2 knockout mice and macrophages. Although MSK1 and -2 promote the expression of the anti-inflammatory cytokine interleukin 10, it did not strongly contribute to the ability of MSKs to regulate IFN-β expression. Instead, MSK1 and -2 inhibit IFN-β expression via the induction of dual-specificity phosphatase 1 (DUSP1), which dephosphorylates and inactivates the mitogen-activated protein kinases p38 and Jun N-terminal protein kinase (JNK). Prolonged LPS-induced activation of p38 and JNK, phosphorylation of downstream transcription factors, and overexpression of IFN-β mRNA and protein were similar in MSK1/2 and DUSP1 knockout macrophages. Two distinct mechanisms were implicated in the overexpression of IFN-β: first, JNK-mediated activation of c-jun, which binds to the IFN-β promoter, and second, p38-mediated inactivation of the mRNA-destabilizing factor tristetraprolin, which we show is able to target the IFN-β mRNA.

Beta Interferon Production Is Regulated by p38 Mitogen-Activated Protein Kinase in Macrophages via both MSK1/2- and Tristetraprolin-Dependent Pathways

Activating protein phosphatase 2A (PP2A) enhances tristetraprolin (TTP) anti-inflammatory function in A549 lung epithelial cells.

Objectives Tristetraprolin (TTP), a negative regulator of many pro-inflammatory genes, is strongly expressed in rheumatoid synovial cells. The mitogen-activated protein kinase (MAPK) p38 pathway mediates the inactivation of TTP via phosphorylation of two serine residues. We wished to test the hypothesis that these phosphorylations contribute to the development of inflammatory arthritis, and that, conversely, joint inflammation may be inhibited by promoting the dephosphorylation and activation of TTP. Methods The expression of TTP and its relationship with MAPK p38 activity were examined in non-inflamed and rheumatoid arthritis (RA) synovial tissue. Experimental arthritis was induced in a genetically modified mouse strain, in which endogenous TTP cannot be phosphorylated and inactivated. In vitro and in vivo experiments were performed to test anti-inflammatory effects of compounds that activate the protein phosphatase 2A (PP2A) and promote dephosphorylation of TTP. Results TTP expression was significantly higher in RA than non-inflamed synovium, detected in macrophages, vascular endothelial cells and some fibroblasts and co-localised with MAPK p38 activation. Substitution of TTP phosphorylation sites conferred dramatic protection against inflammatory arthritis in mice. Two distinct PP2A agonists also reduced inflammation and prevented bone erosion. In vitro anti-inflammatory effects of PP2A agonism were mediated by TTP activation. Conclusions The phosphorylation state of TTP is a critical determinant of inflammatory responses, and a tractable target for novel anti-inflammatory treatments.

Treatment of inflammatory arthritis via targeting of tristetraprolin, a master regulator of pro-inflammatory gene expression

Strain dependent differences in glucocorticoid-induced bone loss between C57BL/6J and CD-1 mice

Twenty years ago, the first description of a tristetraprolin (TTP) knockout mouse highlighted the fundamental role of TTP in the restraint of inflammation. Since then, work from several groups has generated a detailed picture of the expression and function of TTP. It is a sequence-specific RNA-binding protein that orchestrates the deadenylation and degradation of several mRNAs encoding inflammatory mediators. It is very extensively post-translationally modified, with more than 30 phosphorylations that are supported by at least two independent lines of evidence. The phosphorylation of two particular residues, serines 52 and 178 of mouse TTP (serines 60 and 186 of the human orthologue), has profound effects on the expression, function and localisation of TTP. Here, we discuss the control of TTP biology via its phosphorylation and dephosphorylation, with a particular focus on recent advances and on questions that remain unanswered.

The control of inflammation via the phosphorylation and dephosphorylation of tristetraprolin: a tale of two phosphatases

Autocrine or paracrine signaling by beta interferon (IFN) is essential for many of the responses of macrophages to pathogen-associated molecular patterns. This feedback loop contributes to pathological responses to infectious agents and is therefore tightly regulated. We demonstrate here that macrophage expression of IFNis negatively regulated by mitogenand stress-activated kinases 1 and 2 (MSK1/2). Lipopolysaccharide (LPS)-induced expression of IFNwas elevated in both MSK1/2 knockout mice and macrophages. Although MSK1 and -2 promote the expression of the anti-inflammatory cytokine interleukin 10, it did not strongly contribute to the ability of MSKs to regulate IFNexpression. Instead, MSK1 and -2 inhibit IFNexpression via the induction of dual-specificity phosphatase 1 (DUSP1), which dephosphorylates and inactivates the mitogen-activated protein kinases p38 and Jun N-terminal protein kinase (JNK). Prolonged LPS-induced activation of p38 and JNK, phosphorylation of downstream transcription factors, and overexpression of IFNmRNA and protein were similar in MSK1/2 and DUSP1 knockout macrophages. Two distinct mechanisms were implicated in the overexpression of IFN: first, JNKmediated activation of c-jun, which binds to the IFNpromoter, and second, p38mediated inactivation of the mRNA-destabilizing factor tristetraprolin, which we show is able to target the IFNmRNA.

University of Dundee Beta Interferon Production Is Regulated by p 38 Mitogen-Activated Protein Kinase in Macrophages via both MSK 1 / 2-and Tristetraprolin-Dependent Pathways

The phosphorylated form of FTY720 activates PP2A, represses inflammation and is devoid of S1P agonism in A549 lung epithelial cells

Dual-specificity phosphatase (DUSP) 1 dephosphorylates and inactivates members of the MAPK superfamily, in particular, JNKs, p38α, and p38β MAPKs. It functions as an essential negative regulator of innate immune responses, hence disruption of the Dusp1 gene renders mice extremely sensitive to a wide variety of experimental inflammatory challenges. The principal mechanisms behind the overexpression of inflammatory mediators by Dusp1−/− cells are not known. In this study, we use a genetic approach to identify an important mechanism of action of DUSP1, involving the modulation of the activity of the mRNA-destabilizing protein tristetraprolin. This mechanism is key to the control of essential early mediators of inflammation, TNF, CXCL1, and CXCL2, as well as the anti-inflammatory cytokine IL-10. The same mechanism also contributes to the regulation of a large number of transcripts induced by treatment of macrophages with LPS. These findings demonstrate that modulation of the phosphorylation status of tristetraprolin is an important physiological mechanism by which innate immune responses can be controlled.

Dual-Specificity Phosphatase 1 and Tristetraprolin Cooperate To Regulate Macrophage Responses to Lipopolysaccharide

Dual-speciﬁcity phosphatase (DUSP) 1 dephosphorylates and inactivates members of the MAPK superfamily, in particular, JNKs, p38 a , and p38 b MAPKs. It functions as an essential negative regulator of innate immune responses, hence disruption of the Dusp1 gene renders mice extremely sensitive to a wide variety of experimental inﬂammatory challenges. The principal mechanisms behind the overexpression of inﬂammatory mediators by Dusp1 2 / 2 cells are not known. In this study, we use a genetic approach to identify an important mechanism of action of DUSP1, involving the modulation of the activity of the mRNA-destabilizing protein tristetraprolin. This mechanism is key to the control of essential early mediators of inﬂammation, TNF, CXCL1, and CXCL2, as well as the anti-inﬂammatory cytokine IL-10. The same mechanism also contributes to the regulation of a large number of transcripts induced by treatment of macrophages with LPS. These ﬁndings demonstrate that modulation of the phosphorylation status of tristetraprolin is an important physiological mechanism by which innate immune responses can be controlled. The Journal of Immunology , 2015, 195: 000–000.

LipopolysaccharideMacrophage Responses to Tristetraprolin Cooperate To Regulate Dual-Specificity Phosphatase 1 and

In myeloid cells, the mRNA-destabilizing protein tristetraprolin (TTP) is induced and extensively phosphorylated in response to LPS. To investigate the role of two speciﬁc phosphorylations, at serines 52 and 178, we created a mouse strain in which those residues were replaced by nonphosphorylatable alanine residues. The mutant form of TTP was constitutively degraded by the proteasome and therefore expressed at low levels, yet it functioned as a potent mRNA destabilizing factor and inhibitor of the expression of many inﬂammatory mediators. Mice expressing only the mutant form of TTP were healthy and fertile, and their systemic inﬂammatory responses to LPS were strongly attenuated. Adaptive immune responses and protection against infection by Salmonella typhimurium were spared. A single allele encoding the mutant form of TTP was sufﬁcient for enhanced mRNA degradation and underexpression of inﬂammatory mediators. Therefore, the equilibrium between unphosphorylated and phosphorylated TTP is a critical determinant of the inﬂammatory response, and manipulation of this equilibrium may be a means of treating inﬂammatory pathologies. The Journal of Immunology , 2015, 195: 265–276. of gene cells of stability (1–4). and mediators

Destabilizing Protein Tristetraprolin Targeted Mutation of the mRNA Dominant Suppression of Inflammation via

Cytokines drive many inflammatory diseases, including asthma. Understanding the molecular mechanisms responsible for cytokine secretion will allow us to develop novel strategies to repress inflammation in the future. Harnessing the power of endogenous anti-inflammatory proteins is one such strategy. In this study, we investigate the p38 MAPK-mediated regulatory interaction of two anti-inflammatory proteins, mitogen-activated protein kinase phosphatase 1 (MKP-1) and tristetraprolin (TTP), in the context of asthmatic inflammation. Using primary cultures of airway smooth muscle cells in vitro, we explored the temporal regulation of IL-6 cytokine mRNA expression upon stimulation with TNF-α. Intriguingly, the temporal profile of mRNA expression was biphasic. This was not due to COX-2-derived prostanoid upregulation, increased expression of NLRP3 inflammasome components, or upregulation of the cognate receptor for TNF-α-TNFR1. Rather, the biphasic nature of TNF-α-induced IL-6 mRNA expression was regulated temporally by the RNA-destabilizing molecule, TTP. Importantly, TTP function is controlled by p38 MAPK, and our study reveals that its expression in airway smooth muscle cells is p38 MAPK-dependent and its anti-inflammatory activity is also controlled by p38 MAPK-mediated phosphorylation. MKP-1 is a MAPK deactivator; thus, by controlling p38 MAPK phosphorylation status in a temporally distinct manner, MKP-1 ensures that TTP is expressed and made functional at precisely the correct time to repress cytokine expression. Together, p38 MAPK, MKP-1, and TTP may form a regulatory network that exerts significant control on cytokine secretion in proasthmatic inflammation through precise temporal signaling.

American journal of physiology. Lung cellular and molecular physiology

Temporal regulation of cytokine mRNA expression by tristetraprolin: dynamic control by p38 MAPK and MKP-1.

Basal protein phosphatase 2A activity restrains cytokine expression: role for MAPKs and tristetraprolin

Introduction Regions of the arterial tree exposed to unidirectional laminar flow, which exerts high shear stress, are protected from endothelial cell (EC) activation, inflammation and atherosclerosis. Pro-inflammatory mediators (e.g. lipopolysaccharide (LPS)) activate p38 and JNK mitogen-activated protein (MAP) kinases by phosphorylation, which induce pro-inflammatory molecules including VCAM-1 in EC. We assessed whether regions of the arterial tree exposed to high shear were protected from pro-inflammatory activation by suppression of p38 and JNK. Methods Wild-type C57BL/6 and MAP kinase phosphatase-1 -/- (MKP-1 -/- ) mice were studied. Expression levels of VCAM-1 and phosphorylated forms of p38 and JNK in EC were measured by en face staining in a region of the murine aorta that is exposed to relatively low shear and is pre-disposed to atherosclerosis (lesser curvature of arch) and in a region that is exposed to high shear and is protected (greater curvature). The expression of MKP-1 was assessed in human umbilical vein EC (HUVEC) exposed to high shear stress or to static conditions by comparative real-time PCR, immunofluorescence staining and Western blotting. Results We observed that phosphorylation of p38 and JNK and expression of VCAM-1 in EC occurs constitutively and can be enhanced by LPS treatment in the lesser curvature in wild-type mice. By contrast, p38 and JNK activities and VCAM-1 expression were suppressed in the greater curvature. We observed using cultured EC that high shear (12 dynes/cm 2 for 24h) induced MAP kinase phosphatase-1 (MKP-1), a molecule that inactivates p38/JNK by dephosphorylation. Similarly, MKP-1 was expressed at high levels in EC exposed to high shear in the greater curvature of the aorta but at relatively low levels in the lesser curvature. We examined the function of MKP-1 in aortic EC using MKP-1 -/- mice. En face staining revealed that EC in the greater curvature of MKP-1 -/-mice were sensitive to LPS treatment as p38 and JNK were phosphorylated and VCAM-1 was induced. Conclusion MKP-1 is expressed by EC in protected regions of the aorta where it suppresses EC activation. Our findings reveal a novel mechanism to explain protection from vascular inflammation and atherosclerosis in arteries exposed to high shear. vessel wall the EC at atheroprotected sites. Our findings suggest that the mechanism by which high shear protects arteries from inflammation relies on the establishment of persistent endothelial expression of MKP-1 which suppresses cellular activation by inhibiting the activities of p38 and JNK. Further work is required to examine whether MKP-1 protects arteries from atherogenesis in response to hypercholesterolemia. Our findings complement previous studies demonstrating that EC at atheroprotected regions express reduced levels of pro-inflammatory Toll-like receptors and NF- κ B transcription factors 17, 38 . Thus the novel findings presented herein and those from previous studies 17, 38 suggest that regions of the arterial tree exposed to high shear are protected from pro-inflammatory activation by suppression of both MAPK and NF-κ B signalling pathways.

MAP KINASE PHOSPHATASE 1 SUPPRESSES PRO-INFLAMMATORY ACTIVATION OF ENDOTHELIAL CELLS IN REGIONS OF THE ARTERIAL TREE THAT ARE RESISTANT TO ATHEROSCLEROSIS

In myeloid cells, the mRNA-destabilizing protein tristetraprolin (TTP) is induced and extensively phosphorylated in response to LPS. To investigate the role of two specific phosphorylations, at serines 52 and 178, we created a mouse strain in which those residues were replaced by nonphosphorylatable alanine residues. The mutant form of TTP was constitutively degraded by the proteasome and therefore expressed at low levels, yet it functioned as a potent mRNA destabilizing factor and inhibitor of the expression of many inflammatory mediators. Mice expressing only the mutant form of TTP were healthy and fertile, and their systemic inflammatory responses to LPS were strongly attenuated. Adaptive immune responses and protection against infection by Salmonella typhimurium were spared. A single allele encoding the mutant form of TTP was sufficient for enhanced mRNA degradation and underexpression of inflammatory mediators. Therefore, the equilibrium between unphosphorylated and phosphorylated TTP is a critical determinant of the inflammatory response, and manipulation of this equilibrium may be a means of treating inflammatory pathologies.

Dominant Suppression of Inflammation via Targeted Mutation of the mRNA Destabilizing Protein Tristetraprolin

Glucocorticoids (GC) are often used as anti-inflammatory agents in the treatment of inflammatory disorders. However, long term use of GC in all chronic inflammatory diseases may produce unwanted secondary side effects such as GC induced osteoporosis (GIO). Experimental models of GIO are well established in the Swiss and CD1 mice, nonetheless most genetically modified mice are on C57BL/6 background.

Experimental glucocorticoid-induced bone loss in mice is strongly influenced by the strain

Nonclassical Ly6C(-) monocytes drive the development of inflammatory arthritis in mice.

Role of mitogen-activated protein kinase phosphatase-1 in corticosteroid insensitivity of chronic oxidant lung injury

Tissue factor (TF) (CD142) is a 47 kDa transmembrane cell surface glycoprotein that triggers the extrinsic coagulation cascade and links thrombosis with inflammation. Although macrophage TF expression is known to be regulated at the RNA level, very little is known about the mechanisms involved. Poly(adenosine 5'-diphosphate [ADP]-ribose)-polymerase (PARP)-14 belongs to a family of intracellular proteins that generate ADP-ribose posttranslational adducts. Functional screening of PARP-14-deficient macrophages mice revealed that PARP-14 deficiency leads to increased TF expression and functional activity in macrophages after challenge with bacterial lipopolysaccharide. This was related to an increase in TF messenger RNA (mRNA) stability. Ribonucleoprotein complex immunoprecipitation and biotinylated RNA pull-down assays demonstrated that PARP-14 forms a complex with the mRNA-destabilizing protein tristetraprolin (TTP) and a conserved adenylate-uridylate-rich element in the TF mRNA 3' untranslated region. TF mRNA regulation by PARP-14 was selective, as tumor necrosis factor (TNF)α mRNA, which is also regulated by TTP, was not altered in PARP-14 deficient macrophages. Consistent with the in vitro data, TF expression and TF activity, but not TNFα expression, were increased in Parp14(-/-) mice in vivo. Our study provides a novel mechanism for the posttranscriptional regulation of TF expression, indicating that this is selectively regulated by PARP-14.

PARP-14 combines with tristetraprolin in the selective posttranscriptional control of macrophage tissue factor expression.

Oral abstracts 7: Molecular mechanisms of disease—osteoarthritisS1. Identification of novel osteoarthritis genes using zebrafish

The p38 mitogen-activated protein kinase (MAPK) signaling pathway has been strongly implicated in many of the processes that underlie the pathology of rheumatoid arthritis (RA). For many years it has been considered a promising target for development of new anti-inflammatory drugs with which to treat RA and other chronic immune-mediated inflammatory diseases. However, several recent clinical trials have concluded in a disappointing manner. Why is this so, if p38 MAPK clearly contributes to the excessive production of inflammatory mediators, the destruction of bone and cartilage? We argue that, to explain the apparent failure of p38 inhibitors in the rheumatology clinic, we need to understand better the complexities of the p38 pathway and its many levels of communication with other cellular signaling pathways. In this review we look at the p38 MAPK pathway from a slightly different perspective, emphasising its role in post-transcriptional rather than transcriptional control of gene expression, and its contribution to the off-phase rather than the on-phase of the inflammatory response.

OBJECTIVE
Bone formation and destruction are usually tightly linked; however, in disorders such as rheumatoid arthritis, periodontal disease, and osteoporosis, elevated osteoclast activity leads to bone destruction. Osteoclast formation and activation are controlled by many signaling pathways, including p38 MAPK. Dual-specificity phosphatase 1 (DUSP-1) is a factor involved in the negative regulation of p38 MAPK. The purpose of this study was to examine the effect of Dusp1 deficiency on bone destruction.

METHODS
Penetrance, onset, and severity of collagen-induced arthritis were recorded in DUSP-1+/+ and DUSP-1-/- mice. Bone destruction was assessed by histologic and micro-computed tomographic examination of the joints. The in vitro formation and activation of osteoclasts from DUSP-1+/+ and DUSP-1-/- precursors were assessed in the absence or presence of tumor necrosis factor (TNF).

RESULTS
The formation and activation of osteoclasts in vitro in the presence of TNF were enhanced by Dusp1 gene disruption. DUSP-1-/- mice exhibited higher penetrance, earlier onset, and increased severity of experimental arthritis, accompanied by greater numbers of osteoclasts in inflamed joints and more extensive loss of bone. A DUSP-1-/- mouse colony of mixed genetic background also demonstrated striking spontaneous osteolytic destruction of distal phalanges.

DUSP-1 is a critical regulator of osteoclast activity and limits bone destruction in an experimental model of rheumatoid arthritis. Defects in the expression or activity of DUSP1 in humans may correlate with a propensity to develop osteolytic lesions in arthritis.

Dual-specificity phosphatase 1-null mice exhibit spontaneous osteolytic disease and enhanced inflammatory osteolysis in experimental arthritis.

It is thought that the anti‐inflammatory effects of glucocorticoids (GCs) are largely due to GC receptor (GR)‐mediated transrepression of NF‐κB and other transcription factors, whereas side effects are caused by activation of gene expression (transactivation). Selective GR modulators (SGRMs) that preferentially promote transrepression should retain anti‐inflammatory properties whilst causing fewer side effects. Contradicting this model, we found that anti‐inflammatory effects of the classical GC dexamethasone were partly dependent on transactivation of the dual specificity phosphatase 1 (DUSP1) gene. We wished to determine whether anti‐inflammatory effects of SGRMs are also mediated by DUSP1.

Anti‐inflammatory effects of selective glucocorticoid receptor modulators are partially dependent on up‐regulation of dual specificity phosphatase 1

Maps and legends: the quest for dissociated ligands of the glucocorticoid receptor.

Abstract Objective Tissue glucocorticoid (GC) levels are regulated by the GC-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). This enzyme is expressed in cells and tissues arising from mesenchymal stromal cells. Proinflammatory cytokines dramatically increase expression of 11β-HSD1 in stromal cells, an effect that has been implicated in inflammatory arthritis, osteoporosis, obesity, and myopathy. Additionally, GCs act synergistically with proinflammatory cytokines to further increase enzyme expression. The present study was undertaken to investigate the mechanisms underlying this regulation. Methods Gene reporter analysis, rapid amplification of complementary DNA ends (RACE), chemical inhibition experiments, and genetic disruption of intracellular signaling pathways in mouse embryonic fibroblasts (MEFs) were used to define the molecular mechanisms underlying the regulation of 11β-HSD1 expression. Results Gene reporter, RACE, and chemical inhibitor studies demonstrated that the increase in 11β-HSD1 expression with tumor necrosis factor α (TNFα)/interleukin-1β (IL-1β) occurred via the proximal HSD11B1 gene promoter and depended on NF-κB signaling. These findings were confirmed using MEFs with targeted disruption of NF-κB signaling, in which RelA (p65) deletion prevented TNFα/IL-1β induction of 11β-HSD1. GC treatment did not prevent TNFα-induced NF-κB nuclear translocation. The synergistic enhancement of TNFα-induced 11β-HSD1 expression with GCs was reproduced by specific inhibitors of p38 MAPK. Inhibitor and gene deletion studies indicated that the effects of GCs on p38 MAPK activity occurred primarily through induction of dual-specificity phosphatase 1 expression. Conclusion The mechanism by which stromal cell expression of 11β-HSD1 is regulated is novel and distinct from that in other tissues. These findings open new opportunities for development of therapeutic interventions aimed at inhibiting or stimulating local GC levels in cells of mesenchymal stromal lineage during inflammation.

Inflammatory regulation of glucocorticoid metabolism in mesenchymal stromal cells

The role of dual specificity phosphatase 1 (DUSP1) in inducible nitric oxide synthase (iNOS) expression in A549 human pulmonary epithelial cells, J774 mouse macrophages and primary mouse bone marrow-derived macrophages (BMMs) was investigated. iNOS expression was induced by a cytokine mixture (TNF, IFNγ and IL-1β) in A549 cells and by LPS in J774 cells, and it was inhibited by p38 MAPK inhibitors SB202190 and BIRB 796. Stimulation with cytokine mixture or LPS enhanced also DUSP1 expression. Down-regulation of DUSP1 by siRNA increased p38 MAPK phosphorylation and iNOS expression in A549 and J774 cells. In addition, LPS-induced iNOS expression was enhanced in BMMs from DUSP1(−/−) mice as compared to that in BMMs from wild-type mice. The results indicate that DUSP1 suppresses iNOS expression by limiting p38 MAPK activity in human and mouse cells. Compounds that enhance DUSP1 expression or modulate its function may be beneficial in diseases complicated with increased iNOS-mediated NO production.

Dual Specificity Phosphatase 1 Regulates Human Inducible Nitric Oxide Synthase Expression by p38 MAP Kinase

IL-10 plays a central nonredundant role in limiting inflammation in vivo. However, the mechanisms involved remain to be resolved. Using primary human macrophages, we found that IL-10 inhibits selected inflammatory genes, primarily at a level of transcription. At the TNF gene, this occurs not through an inhibition of RNA polymerase II (Pol II) recruitment and transcription initiation but through a mechanism targeting the stimulation of transcription elongation by cyclin-dependent kinase (CDK) 9. We demonstrated an unanticipated requirement for a region downstream of the TNF 3′ untranslated region (UTR) that contains the nuclear factor κB (NF-κB) binding motif (κB4) both for induction of transcription by lipopolysaccharide (LPS) and its inhibition by IL-10. IL-10 not only inhibits the recruitment of RelA to regions containing κB sites at the TNF gene but also to those found at other LPS-induced genes. We show that although IL-10 elicits a general block in RelA recruitment to its genomic targets, the gene-specific nature of IL-10’s actions are defined through the differential recruitment of CDK9 and the control of transcription elongation. At TNF, but not NFKBIA, the consequence of RelA recruitment inhibition is a loss of CDK9 recruitment, preventing the stimulation of transcription elongation.

IL-10 inhibits transcription elongation of the human TNF gene in primary macrophages

Developing sympathetic neurons depend on NGF for survival. When sympathetic neurons are deprived of NGF in vitro, a well documented series of events, including c-Jun N-terminal kinase (JNK) pathway activation, release of cytochrome c from the mitochondria, and caspase activation, culminates in the death of the neuron by apoptosis within 24–48 h. This process requires de novo gene expression, suggesting that increased expression of specific genes activates the cell death program. Using rat gene microarrays, we found that NGF withdrawal induces the expression of many genes, including mkp1, which encodes a MAPK phosphatase that can dephosphorylate JNKs. The increase in mkp1 mRNA level requires the MLK-JNK-c-Jun pathway, and we show that Mkp1 is an important regulator of JNK-dependent apoptosis in sympathetic neurons. In microinjection experiments, Mkp1 overexpression can inhibit JNK-mediated phosphorylation of c-Jun and protect sympathetic neurons from apoptosis, while Mkp1 knockdown accelerates NGF withdrawal-induced death. Accordingly, the number of superior cervical ganglion (SCG) neurons is reduced in mkp1−/− mice at P1 during the period of developmental sympathetic neuron death. We also show that c-Jun and ATF2 bind to two conserved ATF binding sites in the mkp1 promoter in vitro and in chromatin. Both of these ATF sites contribute to basal promoter activity and are required for mkp1 promoter induction after NGF withdrawal. These results demonstrate that Mkp1 is part of a negative feedback loop induced by the MLK-JNK-c-Jun signaling pathway that modulates JNK activity and the rate of neuronal death in rat sympathetic neurons following NGF withdrawal.

Mkp1 Is a c-Jun Target Gene That Antagonizes JNK-Dependent Apoptosis in Sympathetic Neurons

Elucidation of factors regulating glucocorticoid (GC) sensitivity is required for the development of "steroid-sparing" therapies for chronic inflammatory diseases, including rheumatoid arthritis (RA). Accumulating evidence suggests that macrophage migration inhibitory factor (MIF) counterregulates the GC-induction of anti-inflammatory mediators, including mitogen-activated protein kinase phosphatase 1 (MKP1), a critical mitogen-activated protein kinase signaling inhibitor. This observation has yet to be extended to human disease; the molecular mechanisms remain unknown. We investigated NURR1, a GC-responsive transcription factor overexpressed in RA, as a MIF signaling target. We reveal abrogation by recombinant MIF (rMIF) of GC-induced MKP1 expression in RA fibroblast-like synoviocytes (FLS). rMIF enhanced NURR1 expression, artificial NBRE (orphan receptor DNA-binding site) reporter transactivation, and reversed GC-inhibition of NURR1. NURR1 expression was reduced during experimental arthritis in MIF-/- synovium, and silencing MIF reduced RA FLS NURR1 mRNA. Consistent with NBRE identification on the MKP1 gene, MKP1 mRNA was reduced in FLS that ectopically express NURR1, and silencing NURR1 enhanced MKP1 mRNA in RA FLS. rMIF enhanced NBRE binding on the MKP1 gene, and the absence of the NBRE prevented NURR1-repressive effects on basal and GC-induced MKP1 transactivation. This study defines NURR1 as a novel MIF target in chronic inflammation and demonstrates a role for NURR1 in regulating the anti-inflammatory mediator, MKP1. We propose a MIF-NURR1 signaling axis as a regulator of the GC sensitivity of MKP1.

Identification of NURR1 as a mediator of MIF signaling during chronic arthritis: effects on glucocorticoid-induced MKP1.

Objective—Atherosclerosis is a focal disease that occurs predominantly at branches and bends of the arterial tree. Endothelial cells (EC) at atherosusceptible sites are prone to injury, which can contribute to lesion formation, whereas EC at atheroprotected sites are resistant. The c-Jun N-terminal kinase (JNK) is activated constitutively in EC at atherosusceptible sites but is inactivated at atheroprotected sites by mitogen-activated protein kinase phosphatase-1 (MKP-1). Here, we examined the effects of JNK activation on EC physiology at atherosusceptible sites. Methods and Results—We identified transcriptional programs regulated by JNK by applying a specific pharmacological inhibitor to cultured EC and assessing the transcriptome using microarrays. This approach and subsequent validation by gene silencing revealed that JNK positively regulates the expression of numerous proapoptotic molecules. Analysis of aortae of wild-type, JNK1−/−, and MKP-1−/− mice revealed that EC at an atherosusceptible site express proapoptotic proteins and are primed for apoptosis and proliferation in response to lipopolysaccharide through a JNK1-dependent mechanism, whereas EC at a protected site expressed lower levels of proapoptotic molecules and were protected from injury by MKP-1. Conclusion—Spatial variation of JNK1 activity delineates the spatial distribution of apoptosis and turnover of EC in arteries.

c-Jun N-Terminal Kinase Primes Endothelial Cells at Atheroprone Sites for Apoptosis

Anti-inflammatory effects of SGRMs: are they dependent on DUSP1?

OBJECTIVE
Aurothiomalate is a disease-modifying antirheumatic drug that suppresses inflammation and retards cartilage degradation and bone erosion in arthritis. The molecular mechanisms of action of aurothiomalate are not known in detail. MAPK pathways are major signaling pathways in inflammation that regulate the production of many inflammatory and destructive factors in arthritis. The purpose of the present study was to investigate the effects of aurothiomalate on the activity of p38 MAPK and on the expression of MAPK phosphatase 1 (MKP-1), cyclooxygenase 2 (COX-2), matrix metalloproteinase 3 (MMP-3), and interleukin-6 (IL-6) in immortalized murine H4 chondrocytes and in intact human and murine cartilage.

METHODS
Protein expression was examined by Western blotting or by enzyme-linked immunosorbent assay, and messenger RNA (mRNA) expression was examined by real-time reverse transcription-polymerase chain reaction analysis. The mediator role of MKP-1 was investigated by using small interfering RNA (siRNA) methods to down-regulated MKP-1 expression in chondrocytes in culture and by comparing the responses in intact cartilage from MKP-1-deficient and wild-type mice. The effects of aurothiomalate were also confirmed in human rheumatoid cartilage by using tissue samples obtained at the time of total knee replacement surgery.

RESULTS
Aurothiomalate inhibited IL-1beta-induced COX-2 expression and prostaglandin E(2) production by destabilizing COX-2 mRNA, as did the p38 MAPK inhibitor SB203580. Interestingly, aurothiomalate also increased the expression of MKP-1 and reduced the IL-1beta-induced phosphorylation of p38 MAPK. Knockdown of MKP-1 by siRNA significantly impaired the ability of aurothiomalate to inhibit the phosphorylation of p38 MAPK and the expression of COX-2, MMP-3, and IL-6. Likewise, aurothiomalate reduced COX-2, MMP-3, and IL-6 expression in articular cartilage from patients with rheumatoid arthritis, as well as in articular cartilage from wild-type mice but not from MKP-1(-/-) mice.

Our findings indicate a novel mechanism for the antiinflammatory and antierosive actions of aurothiomalate, through increased expression of MKP-1, which leads to reduced activation of p38 MAPK and suppressed expression of COX-2, MMP-3, and IL-6. The results suggest that manipulation of MKP-1 levels is a promising new mechanism to be directed in the search and development of novel antiinflammatory and antierosive compounds that have the good efficacy of gold compounds but not their toxicity.

Aurothiomalate inhibits cyclooxygenase 2, matrix metalloproteinase 3, and interleukin-6 expression in chondrocytes by increasing MAPK phosphatase 1 expression and decreasing p38 phosphorylation: MAPK phosphatase 1 as a novel target for antirheumatic drugs.

Tristetraprolin (TTP) directs its target AU-rich element (ARE)-containing mRNAs for degradation by promoting removal of the poly(A) tail. The p38 MAPK pathway regulates mRNA stability via the downstream kinase MAPK-activated protein kinase 2 (MAPKAP kinase 2 or MK2), which phosphorylates and prevents the mRNA-destabilizing function of TTP. We show that deadenylation of endogenous ARE-containing tumor necrosis factor mRNA is inhibited by p38 MAPK. To investigate whether phosphorylation of TTP by MK2 regulates TTP-directed deadenylation of ARE-containing mRNAs, we used a cell-free assay that reconstitutes the mechanism in vitro. We find that phosphorylation of Ser-52 and Ser-178 of TTP by MK2 results in inhibition of TTP-directed deadenylation of ARE-containing RNA. The use of 14-3-3 protein antagonists showed that regulation of TTP-directed deadenylation by MK2 is independent of 14-3-3 binding to TTP. To investigate the mechanism whereby TTP promotes deadenylation, it was necessary to identify the deadenylases involved. The carbon catabolite repressor protein (CCR)4·CCR4-associated factor (CAF)1 complex was identified as the major source of deadenylase activity in HeLa cells responsible for TTP-directed deadenylation. CAF1a and CAF1b were found to interact with TTP in an RNA-independent fashion. We find that MK2 phosphorylation reduces the ability of TTP to promote deadenylation by inhibiting the recruitment of CAF1 deadenylase in a mechanism that does not involve sequestration of TTP by 14-3-3. Cyclooxygenase-2 mRNA stability is increased in CAF1-depleted cells in which it is no longer p38 MAPK/MK2-regulated.

MAPKAP Kinase 2 Blocks Tristetraprolin-directed mRNA Decay by Inhibiting CAF1 Deadenylase Recruitment

We determined the role of p38 mitogen-activated protein kinase (MAPK) in the increased airway smooth muscle (ASM) contractile responses following ozone and modulation by corticosteroids. Mice were exposed to air or ozone (3 ppm for 3 h) and isometric contractile responses of bronchial rings to acetylcholine (ACh) were measured using a myograph in the presence of p38 MAPK inhibitor, SB239063 (10−6 M) or dexamethasone (10−6 M). Because MAPK phosphatase (MKP)-1 is a negative regulator of p38 MAPK, we also studied these effects in MKP-1-/- mice. Bronchial rings from ozone-exposed wild-type and MKP-1-/- mice showed increased contractile responses, with a leftward shift of the dose–response curve in MKP-1-/- mice. SB239063 inhibited bronchial contraction equally in air- and ozone-exposed C57/BL6 and MKP-1-/- mice. Dexamethasone inhibited ACh-induced bronchial contraction in both air- and ozone-exposed C57/BL6 mice, but not in air- or ozone-exposed MKP-1-/- mice. ACh-stimulated p38 MAPK and heat shock protein (HSP)27 phosphorylation, as measured by Western blotting, and this effect was suppressed by SB239063 in C57/BL6 and MKP-1-/- mice, but not by dexamethasone in either air- or ozone-exposed MKP-1-/- mice. p38 MAPK plays a role in maximal ACh-induced isometric contractile responses and increased contractility induced by ozone. Dexamethasone inhibits ACh-induced ASM contraction through phosphorylation of p38 MAPK and HSP27.

Inhibition of p38 MAPK-dependent bronchial contraction after ozone by corticosteroids

Purpose: Aurothiomalate is a disease modifying antirheumatic drug that suppresses inflammation and retards cartilage degradation and bone erosion in arthritis. The molecular mechanisms of action of aurothiomalate are not known in detail. Mitogen-activated protein kinase (MAPK) pathways are major signaling pathways in inflammation, which regulate the production of many factors known to mediate inflammation and cartilage destruction in OA and RA. In the present study we investigated the effects of aurothiomalate on the activity of p38 MAPK and expression of MAPK phosphatase 1 (MKP-1), COX-2, MMP-3 and IL-6 in chondrocytes and intact cartilage. Methods: Cartilage tissue was obtained from the leftover pieces of total knee replacement surgery from patients with OA and RA and from MKP-1-/and wild type mice. Immortalized H4 murine chondrocytes* were used in cell culture experiments. Results: Aurothiomalate inhibited IL-1β -induced COX-2 expression and prostaglandin E2 (PGE2) production by destabilizing COX-2 mRNA, as did the p38 MAPK inhibitor SB203580. Interestingly, aurothiomalate also increased the expression of MKP-1 and reduced IL-1β -induced phosphorylation of p38 MAPK. Knockdown of MKP-1 by siRNA significantly impaired the ability of aurothiomalate to inhibit the phosphorylation of p38 MAPK and the expression of COX-2, MMP-3 and IL-6. Likewise, aurothiomalate reduced COX-2, MMP-3 and IL-6 expression in human rheumatoid arthritis (RA) and osteoarthritis (OA) cartilage, and in articular cartilage from wild type mice but not in cartilage from MKP-1-/mice. Conclusions: The results provide a novel mechanism for the antiinflammatory and anti-erosive action of aurothiomalate through increased MKP-1 expression, reduced p38 MAPK activation and suppressed expression of COX-2, MMP-3 and IL-6. MKP-1 may therefore be a promising novel target for the development of disease modifying drugs for RA and OA. *Murine H4 chondrocyte cell line was kindly provided by Peter van der Kraan, Laboratory of Experimental Rheumatology, University Medical Center Nijmegen, Netherlands.

Osteoarthritis and Cartilage Vol . 17 , Supplement 1 S 143 260 DMARD AUROTHIOMALATE INHIBITS COX-2 , IL-6 AND MMP-3 EXPRESSION IN CHONDROCYTES BY INCREASING MKP-1 EXPRESSION AND DECREASINGP 38 PHOSPHORYLATION

To the Editor: A recent report by Damjanov et al (1) described nonsignificant therapeutic effects of a selective p38 MAPK inhibitor in patients with rheumatoid arthritis (RA), and a recent editorial by Genovese (2) discussed the disappointing outcomes of several clinical trials of p38 inhibitors in RA and in other chronic inflammatory diseases. Blockade of this signaling pathway has consistently had little or no clinical benefit and has resulted in only transient suppression of markers of inflammation. It has been argued that the lack of efficacy of p38 inhibitors “must lie in one or more biologic adaptations that allow escape from this pathway” (2). Therefore, “to best understand the failure of this class of therapies, we need to better understand this biologic adaptation” (2). MAPK p38 inhibitors were first discovered using simple in vitro screens for compounds that blocked production of tumor necrosis factor (TNF) and interleukin-1 (IL-1) in myeloid cells stimulated with lipopolysaccharide (LPS). Since that initial identification of p38 as a promising therapeutic target, many increasingly potent and specific inhibitors have been generated. Together with genetic and molecular approaches, these compounds have been used in investigations to determine exactly what p38 does, and how. It was soon recognized that p38 not only promotes expression of proinflammatory cytokines but is also activated by them. This potential feed-forward loop creates the danger of selfamplifying, runaway inflammatory responses. Such an outcome is prevented, in part, by p38-dependent antiinflammatory mechanisms. For example, the p38 pathway controls the expression of important antiinflammatory factors that limit inflammation and contribute to its resolution; consequently, long-term blockade of the pathway may have little net benefit. It also participates in crosstalk that constrains the activity of other proinflammatory pathways, with the result that p38 inhibitors may enhance other proinflammatory processes. To use a crude metaphor, p38 has one foot on the gas and one foot on the brake. An awareness of this characteristic may help us to understand the disappointing outcomes of clinical trials of p38 inhibitors. Inflammatory stimuli (e.g., IL-1, TNF, or ligands of the Toll-like receptors) engage their diverse receptors, and all promote activation of the transforming growth factor –activated kinase 1 (TAK1) signaling complex (Figure 1). TAK1 then activates MKKs and IKK, which is responsible for the activation of the transcription factor NFB. The MKKs phosphorylate and activate both p38 and JNK, another member of the MAPK family. (There are 4 isoforms of p38: , , , and . Herein we generally refer to p38 , the major ubiquitous isoform and the most important regulator of inflammatory responses. Most, although not all, inhibitors are active against p38 and p38 .) Once phosphorylated and activated, p38 phosphorylates its own substrates, which include downstream kinases such as MAPKAPK2 (MK2). Together, the NFB, JNK, and p38 pathways regulate the expression of inflammation mediators, including cytokines and chemokines, cyclooxygenase 2, and many other proteins. Both transcriptional and posttranscriptional effects of p38 are critical to this coordinated response. Many inflammatory effectors are encoded by messenger RNA (mRNA) that contain destabilizing AUUUA motifs. The RNA binding protein tristetraprolin (TTP) recognizes these sequence motifs and directs mRNA for rapid degradation (3). The antiinflammatory function of TTP is well illustrated by the erosive arthritis found in TTP / mice, which is largely caused by overexpression of TNF. When activated by p38, MK2 phosphorylates and inactivates TTP, allowing accumulation and translation of mRNA for TNF and other inflammatory cytokines. Figure 1 illustrates antiinflammatory mechanisms that are controlled by the p38 pathway. First, the expression of IL-10, a powerful antiinflammatory cytokine with an important role in the resolution of inflammation, is strongly dependent on p38 (4,5). Ironically, p38 inhibitors could have also been identified by screening for compounds that blocked IL-10 expression. Second, blockade of p38 signaling can reduce expression of TTP and interrupt the normal “off” phase of inflammatory gene expression that involves the degradation of mRNA encoding mediators of inflammation (6,7). Third, inhibiting p38 may augment JNK activity by reducing the expression of MAPK phosphatase 1. This enzyme dephosphorylates and inactivates both p38 and JNK, and hence restrains inflammatory responses (8–10). Finally, in a similar way, p38 inhibitors can prevent the negative feedback control of TAK1 activity and thus enhance activity of JNK and NFB pathways (11). In clinical trials, “escape” from, or lack of, antiinflammatory effects may involve disruption of one or more of these antiinflammatory mechanisms. It is likely that therapeutic targeting of kinase pathways will often run the risk of perturbing negative feedback and crosstalk mechanisms, whose function is to constrain cellular responses. It might be worth considering whether the endogenous feedback mechanisms are disturbed in chronic diseases such as RA, in which mediators of inflammation continue to be expressed in the absence of a recognizable stimulus. If the breakdown of negative feedback loops contributes to chronicity, it may be possible to exert antiinflammatory effects by repairing or reinforcing these natural “off” mechanisms, rather than by simply blocking the p38 pathway.

The p38 MAPK pathway mediates both antiinflammatory and proinflammatory processes: comment on the article by Damjanov and the editorial by Genovese.

260 DMARD AUROTHIOMALATE INHIBITS COX-2, IL-6 AND MMP-3 EXPRESSION IN CHONDROCYTES BY INCREASING MKP-1 EXPRESSION AND DECREASINGP38 PHOSPHORYLATION

Anti-inflammatory effects of glucocorticoids (GCs) are partly mediated by up-regulation of DUSP1 (dual specificity phosphatase 1), which dephosphorylates and inactivates mitogen-activated protein kinases. We identified putative GC-responsive regions containing GC receptor (GR) binding site consensus sequences that are well conserved between human and mouse DUSP1 loci in position, orientation, and sequence (at least 11 of 15 positions identical) and lie within regions of extended sequence conservation (minimum 65% identity over at least 100 bp). These were located ∼29, 28, 24, 4.6, and 1.3 kb upstream of the DUSP1 transcription start site. The homology-based approach successfully identified four cis-acting regions that mediated transcriptional responses to dexamethasone. However, there was surprising interspecies divergence in site usage. This could not be explained by variations of the GR binding sites themselves. Instead, variations in flanking sequences appear to have driven the evolutionary divergence in mechanisms of regulation of mouse and human DUSP1 genes. There was a good correlation between the ability of cis-acting elements to respond to GC in transiently transfected reporter constructs and their ability to recruit GR in the context of intact chromatin. We propose that divergence of gene regulation has involved the loss or gain of binding sites for accessory transcription factors that assist in GR recruitment. Finally, a novel GC-responsive region of the human DUSP1 gene contains a highly unusual element, in which three closely spaced GR half-sites are required for potent transcriptional activation by GC.

Glucocorticoid Regulation of Mouse and Human Dual Specificity Phosphatase 1 (DUSP1) Genes

Eukaryotic cells must continuously sense their environments, for example their attachment to extracellular matrix and proximity to other cells, differences in temperature or redox conditions, the presence of nutrients, growth factors, hormones, cytokines or pathogens. The information must then be integrated and an appropriate response initiated by modulating the cellular programme of gene expression. The mitogen-activated protein kinase (MAPK) signaling pathways play a critical role in this process. Decades of research have illuminated the many ways in which MAPKs regulate the synthesis of mRNA (transcription) via phosphorylation of transcription factors, cofactors, and other proteins. In recent years it has become increasingly clear that the control of mRNA destruction is equally important for cellular responses to extracellular cues, and is equally subject to regulation by MAPKs. This review will summarize our current understanding of post-transcriptional regulation of gene expression by the MAPKs and the proteins that are involved in this process.

Post-transcriptional gene regulation by MAP kinases via AU-rich elements.

The p38 MAPK pathway inhibits tristetraprolin‐directed decay of interleukin‐10 and pro‐inflammatory mediator mRNAs in murine macrophages

Atherosclerosis is a chronic inflammatory disease of arteries. It is triggered by proinflammatory mediators which induce adhesion molecules (eg, vascular cell adhesion molecule [VCAM]-1) in endothelial cells (ECs) by activating p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinases by phosphorylation. Blood flow influences atherosclerosis by exerting shear stress (mechanical drag) on the inner surface of arteries, a force that alters endothelial physiology. Regions of the arterial tree exposed to high shear are protected from endothelial activation, inflammation, and atherosclerosis, whereas regions exposed to low or oscillatory shear are susceptible. We examined whether MAP kinase phosphatase (MKP)-1, a negative regulator of p38 and JNK, mediates the antiinflammatory effects of shear stress. We observed that expression of MKP-1 in cultured ECs was elevated by shear stress, whereas the expression of VCAM-1 was reduced. MKP-1 induction was shown to be necessary for the antiinflammatory effects of shear stress because gene silencing of MKP-1 restored VCAM-1 expression in sheared ECs. Immunostaining revealed that MKP-1 is preferentially expressed by ECs in a high-shear, protected region of the mouse aorta and is necessary for suppression of EC activation at this site, because p38 activation and VCAM-1 expression was enhanced by genetic deletion of MKP-1. We conclude that MKP-1 induction is required for the antiinflammatory effects of shear stress. Thus, our findings reveal a novel molecular mechanism contributing to the spatial distribution of vascular inflammation and atherosclerosis.

Increased Endothelial Mitogen-Activated Protein Kinase Phosphatase-1 Expression Suppresses Proinflammatory Activation at Sites That Are Resistant to Atherosclerosis

The powerful anti-inflammatory effects of glucocorticoids (GCs) have been known for more than sixty years, but their molecular mechanisms are still incompletely understood and hotly debated. The GC receptor (GR) was cloned in 1985 and shown to be a transcription factor. Initially, the anti-inflammatory actions of GCs were explained in terms of genes that were up-regulated by the receptor. However, none of these putative mediators seemed able to account for the spectrum of anti-inflammatory responses to GCs. The discovery of a negative regulatory function of GR then shifted the focus away from GC-induced genes as anti-inflammatory mediators. In recent years, attention has begun to move back toward the idea that the anti-inflammatory response to GCs is partially dependent on the positive regulation of gene expression by GR.

Role of Dual Specificity Phosphatases in Biological Responses to Glucocorticoids*

Map kinase phosphatase-1 suppresses endothelial activation in regions of the arterial tree that are resistant to atherosclerosis

Identification of target mRNAs regulated by both p38 MAPK and tristetraprolin in murine macrophages

The Zfp36l1 gene encodes a zinc finger‐containing mRNA binding protein implicated in the posttranscriptional control of gene expression. Mouse embryos homozygous for a targeted mutation in the Zfp36l1 locus died mid‐gestation and exhibited extraembryonic and intraembryonic vascular abnormalities and heart defects. In the developing placenta, there was a failure of the extraembryonic mesoderm to invaginate the trophoblast layer. The phenotype was associated with an elevated expression of vascular endothelial growth factor (VEGF)‐A in the embryos and in embryonic fibroblasts cultured under conditions of both normoxia and hypoxia. VEGF‐A overproduction by embryonic fibroblasts was not a consequence of changes in Vegf‐a mRNA stability; instead, we observed enhanced association with polyribosomes, suggesting Zfp36l1 influences translational regulation. These data implicate Zfp36l1as a negative regulator of Vegf‐a gene activity during development. Developmental Dynamics 235:3144–3155, 2006. © 2006 Wiley‐Liss, Inc.

The RNA binding protein Zfp36l1 is required for normal vascularisation and post‐transcriptionally regulates VEGF expression

ABSTRACT The p38 mitogen-activated protein kinase (MAPK) signaling pathway, acting through the downstream kinase MK2, regulates the stability of many proinflammatory mRNAs that contain adenosine/uridine-rich elements (AREs). It is thought to do this by modulating the expression or activity of ARE-binding proteins that regulate mRNA turnover. MK2 phosphorylates the ARE-binding and mRNA-destabilizing protein tristetraprolin (TTP) at serines 52 and 178. Here we show that the p38 MAPK pathway regulates the subcellular localization and stability of TTP protein. A p38 MAPK inhibitor causes rapid dephosphorylation of TTP, relocalization from the cytoplasm to the nucleus, and degradation by the 20S/26S proteasome. Hence, continuous activity of the p38 MAPK pathway is required to maintain the phosphorylation status, cytoplasmic localization, and stability of TTP protein. The regulation of both subcellular localization and protein stability is dependent on MK2 and on the integrity of serines 52 and 178. Furthermore, the extracellular signal-regulated kinase (ERK) pathway synergizes with the p38 MAPK pathway to regulate both stability and localization of TTP. This effect is independent of kinases that are known to be synergistically activated by ERK and p38 MAPK. We present a model for the actions of TTP and the p38 MAPK pathway during distinct phases of the inflammatory response.

Posttranslational Regulation of Tristetraprolin Subcellular Localization and Protein Stability by p38 Mitogen-Activated Protein Kinase and Extracellular Signal-Regulated Kinase Pathways

The Zfp36l1 gene encodes a zinc ﬁnger-containing mRNA binding protein implicated in the posttranscriptional control of gene expression. Mouse embryos homozygous for a targeted mutation in the Zfp36l1 locus died mid-gestation and exhibited extraembryonic and intraembryonic vascular abnormalities and heart defects. In the developing placenta, there was a failure of the extraembryonic mesoderm to invaginate the trophoblast layer. The phenotype was associated with an elevated expression of vascular endothelial growth factor (VEGF)-A in the embryos and in embryonic ﬁbroblasts cultured under conditions of both normoxia and hypoxia. VEGF-A overproduction by embryonic ﬁbroblasts was not a consequence of changes in Vegf-a mRNA stability; instead, we observed enhanced association with polyribosomes, suggesting Zfp36l1 inﬂuences translational regulation. These data implicate Zfp36l1 as a negative regulator of Vegf-a gene activity during development. Developmental Dynamics 235:3144–3155, 2006.

The RNA Binding Protein Zfp36l1 Is Required for Normal Vascularisation and Post-Transcriptionally Regulates VEGF Expression o

ABSTRACT The mitogen-activated protein kinase (MAPK) p38/MAPK-activated protein kinase 2 (MK2) signaling pathway plays an important role in the posttranscriptional regulation of tumor necrosis factor (TNF), which is dependent on the adenine/uridine-rich element (ARE) in the 3′ untranslated region of TNF mRNA. After lipopolysaccharide (LPS) stimulation, MK2-deficient macrophages show a 90% reduction in TNF production compared to the wild type. Tristetraprolin (TTP), a protein induced by LPS, binds ARE and destabilizes TNF mRNA. Accordingly, macrophages lacking TTP produce large amounts of TNF. Here, we generated MK2/TTP double knockout mice and show that, after LPS stimulation, bone marrow-derived macrophages produce TNF mRNA and protein levels comparable to those of TTP knockout cells, indicating that in the regulation of TNF biosynthesis TTP is genetically downstream of MK2. In addition, we show that MK2 is essential for the stabilization of TTP mRNA, and phosphorylation by MK2 leads to increased TTP protein stability but reduced ARE affinity. These data suggest that MK2 inhibits the mRNA destabilizing activity of TTP and, in parallel, codegradation of TTP together, with the target mRNA resulting in increased cellular levels of TTP.

Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 Regulates Tumor Necrosis Factor mRNA Stability and Translation Mainly by Altering Tristetraprolin Expression, Stability, and Binding to Adenine/Uridine-Rich Element

Glucocorticoids (GCs), which are used in the treatment of immune-mediated inflammatory diseases, inhibit the expression of many inflammatory mediators. They can also induce the expression of dual specificity phosphatase 1 (DUSP1; otherwise known as mitogen-activated protein kinase [MAPK] phosphatase 1), which dephosphorylates and inactivates MAPKs. We investigated the role of DUSP1 in the antiinflammatory action of the GC dexamethasone (Dex). Dex-mediated inhibition of c-Jun N-terminal kinase and p38 MAPK was abrogated in DUSP1−/− mouse macrophages. Dex-mediated suppression of several proinflammatory genes (including tumor necrosis factor, cyclooxygenase 2, and interleukin 1α and 1β) was impaired in DUSP1−/− mouse macrophages, whereas other proinflammatory genes were inhibited by Dex in a DUSP1-independent manner. In vivo antiinflammatory effects of Dex on zymosan-induced inflammation were impaired in DUSP1−/− mice. Therefore, the expression of DUSP1 is required for the inhibition of proinflammatory signaling pathways by Dex in mouse macrophages. Furthermore, DUSP1 contributes to the antiinflammatory effects of Dex in vitro and in vivo.

Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1

Dual specificity phosphatase-1 (DUSP-1) - A novel mediator of the anti-inflammatory effects of glucocorticoids?

The rapid induction of interferon-gamma (IFN-gamma) by innate cytokines such as interleukin 12 (IL-12) and IL-18 is critical for immunity against infectious pathogens. We investigated the molecular mechanisms underlying this response. IL-12 and IL-18 rapidly and synergistically induced the secretion of IFN-gamma by freshly purified human peripheral blood lymphocytes. At early time points, IFN-gamma was expressed almost exclusively by natural killer cells and in both CD56bright and CD56dim subpopulations. Mitogen-activated protein kinase p38 was activated strongly by IL-18 and weakly by IL-12 in natural killer cells but was not activated by either cytokine in T cells. The expression of IFN-gamma mRNA and protein was dose-dependently blocked by SB203580, a specific inhibitor of mitogen-activated protein kinase p38, which also caused a dramatic destabilization of IFN-gamma mRNA. The 3' untranslated region (UTR) of IFN-gamma mRNA conferred p38 responsiveness to a heterologous reporter mRNA. Therefore, the synergistic induction of IFN-gamma by IL-12 and IL-18 in natural killer cells is mediated at least in part by p38-dependent and 3' UTR-mediated stabilization of IFN-gamma mRNA.

Stabilization of IFN-γ mRNA by MAPK p38 in IL-12– and IL-18–stimulated human NK cells

Stabilization of IFN-gamma mRNA by MAPK p38 in IL-12- and IL-18-stimulated human NK cells.

Posttranscriptional regulation is important for tumor necrosis factor alpha (TNF- a ) expression in mono-cytes and macrophages, and an AU-rich element (ARE) in the 3 * untranslated region (UTR) of TNF- a mRNA is implicated in control of its translation and mRNA stability. Regulation of mRNA turnover is thought to be mediated by trans -acting proteins, which bind the ARE and stabilize or destabilize the transcript. However, with the exception of the destabilizing factor tristetraprolin, the identity and function of the proteins binding the TNF- a mRNA ARE have not been established. To identify other proteins involved in the posttranscriptional control of TNF- a , the subcellular location of TNF- a mRNA was determined in the macrophage-like cell line RAW 264.7. TNF- a mRNA was located in the pellet following centrifugation of cytoplasm at 100,000 3 g (P100 fraction). This fraction also contained proteins which formed two distinct ARE-speciﬁc complexes with the TNF- a mRNA 3 * UTR in electrophoretic mobility shift assays (EMSAs). A protein present in these two complexes was puriﬁed and identiﬁed by peptide mass mapping and tandem mass spectrometry as HuR. In EMSAs both complexes were supershifted by an anti-HuR antibody, while Western blotting also demonstrated the presence of HuR in the P100 extract. A HeLa cell tetracycline-regulated reporter system was used to determine the effect of HuR on mRNA stability. In this system, overexpression of HuR resulted in stabilization of an otherwise unstable reporter-mRNA containing the TNF- a ARE. These results demonstrate that the TNF- a ARE is a target of the mRNA-stabilizing factor HuR.

The 3′ Untranslated Region of Tumor Necrosis Factor Alpha mRNA Is a Target of the mRNA-Stabilizing Factor HuR

Erratum: The 3′ untranslated region of tumor necrosis factor alpha mRNA is a target of the mRNA-stabilizing factor HuR (Molecular and Cellular Biology (2001) 21:3 (721-730))

Tristetraprolin (TTP) is an mRNA-destabilizing protein that negatively regulates the expression of proinflammatory mediators such as tumor necrosis factor α, granulocyte/macrophage colony-stimulating factor, and cyclooxygenase 2. Here we investigate the regulation of TTP expression in the mouse macrophage cell line RAW264.7. We show that TTP mRNA is expressed in a biphasic manner following stimulation of cells with lipopolysaccharide and that the second phase of expression, like the first, is dependent on mitogen-activated protein kinase (MAPK) p38. MAPK p38 acts through a downstream kinase to stabilize TTP mRNA, and this stabilization is mediated by an adenosine/uridine-rich region at the 3′-end of the TTP 3′-untranslated region. Hence TTP is post-transcriptionally regulated in a similar manner to several proinflammatory genes. We also demonstrate that TTP is able to bind to its own 3′-untranslated region and negatively regulate its own expression, forming a feedback loop to limit expression levels.

The Stability of Tristetraprolin mRNA Is Regulated by Mitogen-activated Protein Kinase p38 and by Tristetraprolin Itself*

The rapid induction of interferon- (cid:1) (IFN- (cid:1) ) by innate cytokines such as interleukin 12 (IL-12) and IL-18 is critical for immunity against infectious pathogens. We investigated the molecular mechanisms underlying this response. IL-12 and IL-18 rapidly and synergistically induced the secretion of IFN- (cid:1) by freshly puriﬁed human peripheral blood lymphocytes. At early time points,IFN- (cid:1) wasexpressedalmostexclu-sively by natural killer cells and in both CD56 bright and CD56 dim subpopulations. Mitogen-activated protein kinase p38 was activated strongly by IL-18 and weakly by IL-12 in natural killer cells but was not activated by either cytokine in T cells. The expression of IFN- (cid:1) mRNA and protein was dose-dependently blocked by SB203580, a speciﬁc inhibitor of mitogen-activated protein kinase p38, which also caused a dramatic destabilization of IFN- (cid:1) mRNA. The 3 (cid:1) untranslated region (UTR) of IFN- (cid:1) mRNAconferred p38 responsiveness to a heterologous reporter mRNA. Therefore, the synergistic induction of IFN- (cid:1) by IL-12 and IL-18 in natural killer cells is mediated at least in part by p38-dependent and 3 (cid:1) UTR-mediated stabilization of IFN- (cid:1) mRNA. (Blood. 2005;105: 282-288)

Stabilization of IFN- (cid:1) mRNA by MAPK p38 in IL-12– and IL-18–stimulated human NK cells

The involvement of AU-rich element-binding proteins in p38 mitogen-activated protein kinase pathway-mediated mRNA stabilisation.

COX-2 (cyclo-oxygenase-2) mRNA is degraded rapidly in resting cells, but is stabilized by the mitogen-activated protein kinase p38 signalling pathway in response to pro-inflammatory stimuli. A conserved ARE (AU-rich element) of the COX-2 3' untranslated region, CR1 (conserved region 1), acts as a potent instability determinant, and mediates stabilization in response to p38 activation. A detailed structural and functional analysis of this element was performed in an attempt to identify RNA-binding proteins involved in the regulation of COX-2 mRNA stability. Destabilization of a beta-globin reporter mRNA was dependent upon two distinct AREs within CR1, each containing three copies of the sequence AUUUA. CR1 was shown to bind AUF-1 [ARE/poly(U)-binding/degradation factor-1] and/or AUF-2, HuR (Hu antigen R), TTP (tristetraprolin) and FBP1 (far-upstream-sequence-element-binding protein 1), yet these factors did not appear to account for the effects of CR1 upon mRNA stability. Mutant sequences were identified that were incapable of destabilizing a reporter mRNA, yet showed unimpaired binding of FBP1 and AUF-1 and/or -2. TTP was absent from the HeLa cell line used in this analysis. Finally, RNA interference experiments argued against a prominent role for HuR in the CR1-mediated regulation of mRNA stability. We conclude that at least one critical regulator of COX-2 mRNA stability is likely to remain unidentified at present.

Structural and functional dissection of a conserved destabilizing element of cyclo-oxygenase-2 mRNA: evidence against the involvement of AUF-1 [AU-rich element/poly(U)-binding/degradation factor-1], AUF-2, tristetraprolin, HuR (Hu antigen R) or FBP1 (far-upstream-sequence-element-binding protein 1).

Crosstalk between glucocorticoids and mitogen-activated protein kinase signalling pathways.

The expression of genes involved in the inflammatory response is controlled both transcriptionally and post-transcriptionally. Primary inflammatory stimuli, such as microbial products and the cytokines interleukin-1 (IL-1) and tumour necrosis factor alpha (TNF alpha), act through receptors of either the Toll and IL-1 receptor (TIR) family or the TNF receptor family. These cause changes in gene expression by activating four major intracellular signalling pathways that are cascades of protein kinases: namely the three mitogen-activated protein kinase (MAPK) pathways, and the pathway leading to activation of the transcription factor nuclear factor kappa B (NF kappa B). The pathways directly activate and induce the expression of a limited set of transcription factors which promote the transcription of inflammatory response genes. Many of the mRNAs are unstable, and are stabilized by the p38 MAPK pathway. Instability is mediated by clusters of the AUUUA motif in the 3' untranslated regions of the mRNAs. Control of mRNA stability provides a means of increasing the amplitude of a response and allows rapid adjustment of mRNA levels. Not all mRNAs stabilized by p38 contain AUUUA clusters; for example, matrix metalloproteinase-1 and -3 mRNAs lack these clusters, but are stabilized. Inflammatory gene expression is inhibited by glucocorticoids. These suppress MAPK signalling by inducing a MAPK phosphatase. This may be a significant mechanism additional to that by which the glucocorticoid receptor interferes with transcription factors.

Synthetic glucocorticoids (GCs) potently inhibit the expression of pro-inflammatory genes and are widely used in the treatment of inflammatory diseases. However, some patients are resistant to the therapeutic effects of GCs, and many suffer deleterious side effects from these drugs. Furthermore, the precise mechanisms by which GCs inhibit pro-inflammatory gene expression remain unclear. A number of recent papers report that GCs induce the sustained expression of MAP kinase (MAPK) phosphatase 1 (MKP-1), a negative regulator of MAPK signal transduction pathways. The potential relevance of MKP-1 to some of the biological effects of GCs is discussed.

MAP kinase phosphatase 1: a novel mediator of biological effects of glucocorticoids?

Post‐transcriptional regulation of gene expression by mitogen‐activated protein kinase p38

p 38 Phosphatase-Mediated Inhibition of MAPK Kinase ( MAPK ) Phosphatase 1 and Expression of Mitogen-Activated Protein Dexamethasone Causes Sustained

Control of stability of mRNA of inflammatory response proteins by p38 MAP kinase

ABSTRACT The stress-activated protein kinase p38 stabilizes a number of mRNAs encoding inflammatory mediators, such as cyclooxygenase 2 (Cox-2). In HeLa cells the anti-inflammatory glucocorticoid dexamethasone destabilizes Cox-2 mRNA by inhibiting p38 function. Here we demonstrate that this effect is phosphatase dependent. Furthermore, in HeLa cells dexamethasone induced the sustained expression of mitogen-activated protein kinase phosphatase 1 (MKP-1), a potent inhibitor of p38 function. The inhibition of p38 and the induction of MKP-1 by dexamethasone occurred with similar dose dependence and kinetics. No other known p38 phosphatases were induced by dexamethasone, and other cell types which failed to express MKP-1 also failed to inhibit p38 in response to dexamethasone. The proinflammatory cytokine interleukin 1 (IL-1) induced MKP-1 expression in a p38-dependent manner and acted synergistically with dexamethasone to induce MKP-1 expression. In HeLa cells treated with IL-1 or IL-1 and dexamethasone, the dynamics of p38 activation mirrored the expression of MKP-1. These observations suggest that MKP-1 participates in a negative-feedback loop which regulates p38 function and that dexamethasone may inhibit proinflammatory gene expression in part by inducing MKP-1 expression.

Dexamethasone Causes Sustained Expression of Mitogen-Activated Protein Kinase (MAPK) Phosphatase 1 and Phosphatase-Mediated Inhibition of MAPK p38

The AU-rich element (ARE) is an important instability determinant for a large number of early-response-gene mRNAs. AREs also mediate the stabilization of certain pro-inflammatory mRNAs, such as tumour necrosis factor (TNF)-alpha and cyclo-oxygenase-2 (COX-2), in response to inflammatory stimuli. To understand how AREs control mRNA stability, it is necessary to identify trans-acting factors. We have purified a new ARE-binding protein and identified it as CArG box-binding factor-A (CBF-A). The amino acid sequence of CBF-A is highly similar to that of the ARE-binding protein AUF1. Recombinant CBF-A bound the COX-2 and TNF-alpha AREs, but not a non-specific control RNA. In contrast, in an electrophoretic-mobility-shift assay (EMSA) of crude RAW 264.7 macrophage-like cell extracts, an antiserum that recognizes both AUF1 and CBF-A failed to supershift complexes formed on the TNF-alpha ARE, but did supershift a complex specific for the COX-2 ARE. CBF-A exists as two isoforms, p37 and p42, that differ by a 47-amino-acid insertion close to the C-terminus. By expressing epitope-tagged isoforms of CBF-A it was shown that the p42 isoform binds the COX-2 ARE in EMSA of crude cell extracts. In a HeLa-cell tetracycline-regulated reporter system, overexpression of the p42 CBF-A isoform resulted in stabilization of a COX-2 ARE reporter mRNA. Epitope-tagged p42 CBF-A expressed in HeLa cells co-immunoprecipitated with endogenous COX-2 mRNA, but not glyceraldehyde-3-phosphate dehydrogenase mRNA, as shown by reverse-transcription PCR. The similarity between CBF-A and AUF1 suggests that CBF-A could be re-named AUF2.

Identification of a novel AU-rich-element-binding protein which is related to AUF1.

ABSTRACT Posttranscriptional regulation is important for tumor necrosis factor alpha (TNF-α) expression in monocytes and macrophages, and an AU-rich element (ARE) in the 3′ untranslated region (UTR) of TNF-α mRNA is implicated in control of its translation and mRNA stability. Regulation of mRNA turnover is thought to be mediated bytrans-acting proteins, which bind the ARE and stabilize or destabilize the transcript. However, with the exception of the destabilizing factor tristetraprolin, the identity and function of the proteins binding the TNF-α mRNA ARE have not been established. To identify other proteins involved in the posttranscriptional control of TNF-α, the subcellular location of TNF-α mRNA was determined in the macrophage-like cell line RAW 264.7. TNF-α mRNA was located in the pellet following centrifugation of cytoplasm at 100,000 ×g (P100 fraction). This fraction also contained proteins which formed two distinct ARE-specific complexes with the TNF-α mRNA 3′ UTR in electrophoretic mobility shift assays (EMSAs). A protein present in these two complexes was purified and identified by peptide mass mapping and tandem mass spectrometry as HuR. In EMSAs both complexes were supershifted by an anti-HuR antibody, while Western blotting also demonstrated the presence of HuR in the P100 extract. A HeLa cell tetracycline-regulated reporter system was used to determine the effect of HuR on mRNA stability. In this system, overexpression of HuR resulted in stabilization of an otherwise unstable reporter-mRNA containing the TNF-α ARE. These results demonstrate that the TNF-α ARE is a target of the mRNA-stabilizing factor HuR.

ABSTRACT Signal transduction pathways regulate gene expression in part by modulating the stability of specific mRNAs. For example, the mitogen-activated protein kinase (MAPK) p38 pathway mediates stabilization of tumor necrosis factor alpha (TNF-α) mRNA in myeloid cells stimulated with bacterial lipopolysaccharide (LPS). The zinc finger protein tristetraprolin (TTP) is expressed in response to LPS and regulates the stability of TNF-α mRNA. We show that stimulation of RAW264.7 mouse macrophages with LPS induces the binding of TTP to the TNF-α 3′ untranslated region. The p38 pathway is required for the induction of TNF-α RNA-binding activity and for the expression of TTP protein and mRNA. Following stimulation with LPS, TTP is expressed in multiple, differentially phosphorylated forms. We present evidence that phosphorylation of TTP is mediated by the p38-regulated kinase MAPKAPK2 (MAPK-activated protein kinase 2). Our findings demonstrate a direct link between a specific signal transduction pathway and a specific RNA-binding protein, both of which are known to regulate TNF-α gene expression at a posttranscriptional level.

Mitogen-Activated Protein Kinase p38 Controls the Expression and Posttranslational Modification of Tristetraprolin, a Regulator of Tumor Necrosis Factor Alpha mRNA Stability

ABSTRACT The stability of cyclooxygenase 2 (Cox-2) mRNA is regulated positively by proinflammatory stimuli acting through mitogen-activated protein kinase (MAPK) p38 and negatively by anti-inflammatory glucocorticoids such as dexamethasone. A tetracycline-regulated reporter system was used to investigate mechanisms of regulation of Cox-2 mRNA stability. Dexamethasone was found to destabilize β-globin–Cox-2 reporter mRNAs by inhibiting p38. This inhibition occurred at the level of p38 itself: stabilization of reporter mRNA by a kinase upstream of p38 was blocked by dexamethasone, while stabilization by a kinase downstream of p38 was insensitive to dexamethasone. Inhibition of p38 activity by dexamethasone was observed in a variety of cell types treated with different activating stimuli. Furthermore, inhibition of p38 was antagonized by the anti-glucocorticoid RU486 and was delayed and actinomycin D sensitive, suggesting that ongoing glucocorticoid receptor-dependent transcription is required.

Dexamethasone Destabilizes Cyclooxygenase 2 mRNA by Inhibiting Mitogen-Activated Protein Kinase p38

ABSTRACT A tetracycline-regulated reporter system was used to investigate the regulation of cyclooxygenase 2 (Cox-2) mRNA stability by the mitogen-activated protein kinase (MAPK) p38 signaling cascade. The stable β-globin mRNA was rendered unstable by insertion of the 2,500-nucleotide Cox-2 3′ untranslated region (3′ UTR). The chimeric transcript was stabilized by a constitutively active form of MAPK kinase 6, an activator of p38. This stabilization was blocked by SB203580, an inhibitor of p38, and by two different dominant negative forms of MAPK-activated protein kinase 2 (MAPKAPK-2), a kinase lying downstream of p38. Constitutively active MAPKAPK-2 was also able to stabilize chimeric β-globin–Cox-2 transcripts. The MAPKAPK-2 substrate hsp27 may be involved in stabilization, as β-globin–Cox-2 transcripts were partially stabilized by phosphomimetic mutant forms of hsp27. A short (123-nucleotide) fragment of the Cox-2 3′ UTR was necessary and sufficient for the regulation of mRNA stability by the p38 cascade and interacted with a HeLa protein immunologically related to AU-rich element/poly(U) binding factor 1.

Regulation of Cyclooxygenase 2 mRNA Stability by the Mitogen-Activated Protein Kinase p38 Signaling Cascade

Regulation of tumour necrosis factor α mRNA stability by the mitogen‐activated protein kinase p38 signalling cascade

p38 mitogen-activated protein kinase (MAPK) is activated by inflammatory stimuli such as bacterial lipopolysaccharide (LPS), interleukin-1, and tumor necrosis factor. We have previously shown that the pyridinyl imidazole SB 203580, which inhibits it, blocks the interleukin-1 induction of cyclooxygenase-2 (COX-2) and matrix metalloproteinase 1 and 3 mRNAs in fibroblasts. Here we explore the role of p38 MAPK in the response of human monocytes to LPS. 0.1 μm SB 203580 significantly inhibited the LPS induction of COX-2 and tumor necrosis factor protein and mRNAs. The activity of MAPK-activated protein kinase-2 (a substrate of p38 MAPK) in the cells was commensurately reduced. Some isoforms of c-junN-terminal kinase (which is also activated by LPS) are sensitive to SB 203580; the inhibitor had little effect on monocyte c-junN-terminal kinases up to 2 μm. We investigated the mechanism of inhibition of COX-2 induction. Transcription (measured by a nuclear run-on assay) was 60% inhibited by SB 203580 (2 μm). Importantly, we found that p38 MAPK was essential for stabilizing COX-2 mRNA: when cells stimulated for 4 h with LPS were treated with actinomycin D, COX-2 mRNA decayed slowly. Treatment of stimulated cells with 2 μm SB 203580 caused a rapid disappearance of COX-2 mRNA, even with actinomycin D present. We conclude p38 MAPK plays a role in the transcription and stabilization of COX-2 mRNA.

p38 Mitogen-activated Protein Kinase Regulates Cyclooxygenase-2 mRNA Stability and Transcription in Lipopolysaccharide-treated Human Monocytes*

A p38 MAP kinase inhibitor regulates stability of interleukin‐1‐induced cyclooxygenase‐2 mRNA

A deletion analysis of the human insulin gene extending to 2 kb upstream of the transcription start site provided evidence of regulatory sequences located upstream of the insulin-linked polymorphic region (ILPR). Within this ILPR-distal region is a sequence (Ink, for insulin kilobase upstream) which contains three potential nuclear hormone-receptor half-sites, closely matching the consensus sequence AGGTCA. These sequences are arranged as a palindromic element with zero spacing over-lapping a direct repeat with 2 bp spacing. The Ink sequence was used in electrophoretic mobility-shift assays within nuclear extracts from COS-7 cells overexpressing the vitamin D, thyroid hormone or retinoic acid receptors, or from an insulin-expressing hamster cell line, HIT-T15. These studies suggest that the insulin-expressing cell line contains thyroid hormone and retinoic acid receptors at least, and that these receptors are able to recognize the Ink sequence. Three copies of the Ink sequence were placed upstream of the thymidine kinase promoter and firefly luciferase reporter gene. In COS-7 cells expressing the appropriate nuclear hormone receptor, this construct was responsive to both thyroid hormone (18-fold) and all-trans-retinoic acid (31-fold). In HIT-T15 cells the same construct responded to all-trans-retinoic acid, but not to thyroid hormone. Within the context of a 2 kb insulin gene fragment, the Ink sequence was shown to be activated by retinoic acid and by the retinoic acid receptor, but acted as a negative element in the presence of both retinoic acid and the retinoic acid receptor. Mutagenesis studies demonstrated that the palindromic sequence was important for the retinoic acid response, and for binding of complexes containing retinoic acid receptor. In human islets of Langerhans, retinoic acid was shown to stimulate insulin mRNA levels. These results demonstrate that a functional nuclear hormone-receptor-response element is located upstream of the human ILPR. As retinoic acid and thyroid hormone are frequently involved in developmental regulatory processes, it is possible that this element may be important in the process of islet cell differentiation.

Identification and characterization of a functional retinoic acid/thyroid hormone-response element upstream of the human insulin gene enhancer.

A negative regulatory element (NRE) is located between positions -279 and -261 relative to the transcription start site of the human insulin gene. The NRE contains at least three distinct overlapping binding sites for several nuclear proteins. These proteins may be distinguished by their interaction with mutant variants of the NRE. Mutagenesis of two of these protein-binding sites within an insulin gene fragment containing sequences from position -361 to position +112 attenuated the negative activity of the NRE, confirming the importance of these sites in the function of the NRE. When placed in isolation upstream of the herpes-simplex-virus thymidine-kinase promoter, the NRE exhibited stimulatory activity in non-beta (BHK) and beta (HIT) cells. The positive activity within the NRE was mapped to a sequence that resembled the binding site for the ubiquitous factor Oct-1. These results indicated that the negative activity of the NRE was dependent on its interaction with other regulatory sites within the insulin gene. Thus, the NRE exhibited negative activity in transfected HIT cells when placed upstream of an insulin gene fragment (positions -261 to +112). However, its activity was modulated in a positive manner by inclusion of additional sequences from position -279 to -341. This region contains the CT3 box that binds the homeodomain protein IUF1 (insulin upstream factor 1). The NRE resembled a silencer, being at least partly independent of precise location and orientation, and being able to operate upon a variety of promoters. The role of the NRE is unclear, although it may be involved in restricting expression of the insulin gene to cells of the islets of Langerhans.

A silencer and an adjacent positive element interact to modulate the activity of the human insulin promoter.

The β cell of the islets of Langerhans contributes along with other factors to glucose homeostasis by sensing changes in the plasma glucose concentrations and adjusting the rate of insulin production and release. Over short periods of time, insulin production is controlled principally through translation of pre‐existing mRNA. Over longer periods, insulin mRNA levels are modulated through effects on the rate of transcription of the insulin gene, and also through changes in the rate of decay of insulin mRNA. These long‐term effects may be important in allowing the β cell to adapt to changes in diet or periods of fasting. Several mechanisms involved in the control of the rate of translation of insulin mRNA have been described. Effects of glucose metabolism on the turnover of insulin mRNA have yet to be characterized in detail. At the level of transcription, cis‐acting DNA elements and trans‐acting factors involved in the transient response of the insulin gene to changes in intracellular cAMP levels, or to signals generated as a result of glucose metabolism, have been identified.— Docherty, K., Clark, A. R. Nutrient regulation of insulin gene expression. FASEB J. 8: 20‐27; 1994.

How is the developmental timing and tissue-specificity of insulin gene expression controlled?

Human insulin gene enhancer‐binding proteins in pancreatic α and β cell lines

Two important sequence elements, designated insulin enhancer binding site 1 (IEB1) or NIR and IEB2 or FAR, are involved in regulating expression of the rat insulin I gene. These elements bind a helix-loop-helix transcription factor, insulin enhancer factor 1 (IEF1). The IEB1 site is highly conserved among insulin genes but the IEB2 site is not conserved. To investigate the factors binding at the equivalent IEB1 and IEB2 sites in the human insulin gene enhancer, electrophoretic mobility shift assays were performed using a variety of cell extracts and probes specific for the homologous IEB1 and IEB2 sites. The results indicate that a factor with similar tissue distribution and binding characteristics to those of IEF1 binds to the IEB1 site in the human insulin gene, but that a separate factor, identified as the adenovirus major late transcription factor [MLTF, or upstream stimulating factor (USF)] binds to the IEB2 site.

The helix-loop-helix transcription factor USF (upstream stimulating factor) binds to a regulatory sequence of the human insulin gene enhancer.

Electrophoretic mobility shift assays were performed using oligonucleotides corresponding to known protein binding sites within the human insulin gene enhancer and nuclear extracts from mouse pancreatic alpha and beta cell lines. The results demonstrate that a previously described factor, IUF-1, binds to three sites at -82 (the CT1 box), -215 (the CT2 box), and -319 (the CT3 box) in the human insulin gene enhancer. IUF-1 was present only in beta but not in alpha cells, while all other DNA-binding proteins were present in both cell lines. IUF-1 may therefore be an important determinant of insulin gene beta cell-specific expression.

Human insulin gene enhancer-binding proteins in pancreatic alpha and beta cell lines.

Cell-specific gene expression in the islets of Langerhans: E boxes and TAAT boxes.

The first stages of the study of eukaryotic gene expression revolved around the identification of positively acting transcription factors and the investigation of their function. It has since become clear that negative regulation of transcription is an equally vital process, in some way participating in the control of more or less all genes so far studied (for recent reviews, see [1-4]). Transcriptional repression is required for the establishment of the temporally and spatially complex patterns of gene expression which are characteristic of eukaryotes, and is also frequently involved in the modulation of gene expression in response to changes in the micro-environment of the cell. In this review we briefly discuss several mechanisms of negative regulation, before addressing the variety of cellular processes in which these mechanisms are involved.

The regulation of insulin production by pancreatic p cells is mediated by a number of circulating nutrients and hormones, of which glucose is the predominant physiological stimulus. Over short periods of 1-2 h glucose regulates. insulin biosynthesis mainly at the level of translation (Permutt & Kipnis, 1972). This is in keeping with the requirement to rapidly replenish insulin stores, secreted in response to elevated circulating glucose levels following food intake. In addition to the acute effect on translation, glucose also affects insulin mRNA production and stability over longer periods (Brundstedt & Chan, 1982; Nielsen et al. 1985; Welsh et al. 1985). Here we will describe some recent experiments, which have increased our understanding of how these transcriptional and translational processes respond to external stimuli.

Two proteins act as the IUF1 insulin gene enhancer binding factor

Positive and negative regulation of the human insulin gene by multiple trans-acting factors.

Dutch Contributions to the Thirteenth International Congress of Slavists, Ljubljana August 15-21, 2003: Linguistics by J.s>SchaekenP. HoutzagersJ. Kalsbeek (review)

Exciting fresh perspectives on Edward I as man, king and administrator. The reign of Edward I was one of the most important of medieval England, but the king's activities and achievements have not always received the full attention they deserve. The essays collected here offer fresh insights into Edward's own personality as well as developments in law, governance, war and culture. Edward the man emerges in chapters on his early life, his piety and his family, while the administrator king is discussed in evaluations of his two great ministers, his handling of the crucial issue of law and order and the way he managed the realm from abroad through his correspondence. Edward's nobles, both in England and Scotland, naturally appear as vital to understanding the reign, while his rule is set in a British and European context. Overall, the book aims to move the debate on the reign beyond K.B. McFarlane's hugely influential judgement that "Edward I preferred masterfulness to the arts of political management", by highlighting his skills -- and failings -- as a politician and manager.

VOLITIONAL MOOD IN SOUTH SLAVIC WITH A FOCUS ON BULGARIAN: A PARADIGMATIC VIEW In this paper, we survey some of the inflected and periphrastic volitional mood paradigms in South Slavic with a focus on Bulgarian data. Our review confirms typological observations in the literature that volitional mood paradigms tend to ‘fracture’, in that the cross-categorisation with different person/number features leads to systematic associations with different meanings and, typologically, frequent associations with different forms. This makes it difficult to argue that non-existent inflected forms are gaps in the inflected paradigm. Because of this periphrastic volitional mood forms that exist alongside inflected forms have to be seen as independent (syntactic) paradigms, rather than forms that fill missing cells in inflected paradigms, i.e. the product of feature intersection. Like more canonical periphrases, however, syntactic volitional mood forms are non-compositional and exhibit an organisation akin to the content-form paradigm organisation of inflected paradigms developed in certain inferential-realizational approaches to morphology. Following some recent formalisations, we suggest a tentative analysis of the most productive periphrastic volitional mood forms in Bulgarian based on the assumption that their properties are constrained partially by the morphology and partially in the syntax.

Uninflectedness: Uninflecting, Uninflectable and Uninflected Words, or the Complexity of the Simplex

Exploring the phenomenon of 'mixed categories', this book is the first in-depth study of the way in which languages can use a noun, as opposed to an adjective, to modify another noun. It investigates noun-adjective hybrids - adjectives and adjective-like attributive forms which have been derived from nouns and systematically retain certain nominal properties. These rarely-discussed types of mixed category raise a number of important theoretical questions about the nature of lexemic identity, the inflection-derivation divide, and more generally, the relationship between the structure of words and their phrasal syntax. The book proposes a new formal framework that models cross-linguistic and cross-constructional variation in noun modification constructions. The framework it offers enables readers to explicitly map word structure to syntactic structure, providing new insights into, and impacting upon, all current theoretical models of grammar.

The chapter presents an overview of phenomena which pose important problems of description and analysis. I focus on the inflectional system, which has undergone severe attrition and shows idiosyncrasies typical of such systems. For nominals I describe the personal pronoun paradigm and the ‘possessive -s’ clitic/phrasal affix. The controversial categorial status of adverbs in -ly is discussed, while for verbs, all the subcategories prove to be highly problematical. For instance, only 50 irregular verbs distinguish past tense from past participle (e.g. wrote/written), so it is not even clear whether the past participle category is a highly restricted subcategory, with the vast majority of verbs showing past tense/past participle syncretism, or whether this is a case of ‘overdifferentiation’, like the forms am, are, were of the verb BE. On the other hand, the polyfunctionality of the completely regular -ing suffix, which derives verb, noun, and adjective forms, also poses serious unresolved problems. Auxiliary verbs and related phenomena alternate between periphrastic, clitic, and genuinely morphological (affixal) constructions. The chapter concludes with consideration of those aspects of derivational morphology which seem to be indisputably productive, hence part of the grammar, including (certain types of) event nominalization, some cases of double object alternation, and morphosemantic mismatches of the kind electrical engineering ⇒ electrical engineer.

Interpretation and Memorialization at the Sand Creek Massacre National Historic Site

The term productivity most commonly applies to word formation, but in principle it can be applied to any linguistic process. A process is said to be productive if it applies without restriction to give rise to novel expressions, for instance, new words. Ideally, speakers apply productive processes without conscious deliberation and in principle they can be applied by any and all competent native speakers. Creative coining of words, by contrast, is typically a one-off intentional act (nonce word creation), often of one individual, and often with the aim of drawing attention to the coined word for the purposes of advertising, humor, and so on. Creative coining often involves extra-grammatical processes which cannot be described deterministically, unlike bona fide linguistic rules. However, many productive processes are restricted in various ways, and some of the extra-grammatical devices are very frequent, so the distinction between productive, grammatical word formation and (nonce) word creation is blurred.

The Nature of Productivity (Including Word Formation Versus Creative Coining)

The chapter contrasts the still popular traditional approach to morphology, based on the classical morpheme concept, with contemporary approaches which significantly modify that concept (Distributed Morphology, Construction Morphology) or reject it altogether (Paradigm Function Morphology, Network Morphology). I extend the scope of the latter, ‘lexeme-and-paradigm’, models by introducing types of morphology intermediate between inflection and derivation: argument-structure alternations and transpositions (such as deverbal participles), together with other problematic phenomena such as clitics, light verbs, periphrasis. The chapter ends with a discussion of derivational morphology as a subtype of lexemic relatedness, briefly outlining the principal theoretical issues facing approaches to lexemic relatedness and lexical representation: ‘blocking’, semantic primitives, lexical semantics, and derivation.

ABSTRACT Oscar Wilde's short story “The Portrait of Mr. W. H.” is the story of a small group in search of the identity of the person to whom William Shakespeare famously (and enigmatically) dedicated his collection of sonnets, a man known only as Mr. W. H. Scholars have debated for centuries the man's true name, and Oscar Wilde jumped into that conversation in 1889 with the publication of his story. In this paper, I argue that Wilde’s story is not as much about identifying Mr. W. H. as it is about preserving his own authorial legacy for future generations. In pursuing this argument, I offer a close reading of the text filtered through the lens of Roland Barthes’ “The Death of the Author,” and conclude that Wilde sought to perpetuate his name through the facilitation of academic debate about his collected works.

“Immortal Children of Undying Fame”: Preserving a Personal Legacy in Oscar Wilde’s “The Portrait of Mr. W. H.”

Adjectives and compounds at the interface Heinz J. Giegerich, Lexical Structures: Compounding and the Modules of Grammar

Lexicalist models of syntax share with lexeme-and-paradigm models of morphology the assumption that the primary unit of the lexicon is the lexeme, an abstract representation of properties unifying a set of inflected word forms. Lexicalist syntactic models (such as Headdriven Phrase Structure Grammar, henceforth HPSG, and Sign-Based Construction Grammar, henceforth SBCG) distinguish modelled linguistic objects from descriptions of objects. A description, but not an object, can be a partial (underspecified) representation. However, a lexeme is by definition only partially specified, being underspecified for all those morphosyntactic properties that its word forms realize (the lexeme dog realizes neither singular nor plural, unlike the word forms dog, dogs). This implies that lexemes are descriptions, not objects, which is incompatible with assumptions about the type hierarchy for signs and the lexicon in HPSG/SBCG. If we relax the definition of full specification to admit lexemes as objects then the question arises as to how many properties can be left unspecified. I argue for a maximally underspecified model. Even the declaration of properties for which the given class of lexemes inflects (the ‘morpholexical signature’, morsig) is underspecified to the extent that its contents are predictable. This entails that an inflected word form of a lexeme can be defined only after the morsig attribute is specified. Derivation, a lexeme-to-lexeme mapping, can therefore be defined over the same maximally underspecified lexical representations, whose inflection is then typically governed by a different morpholexical signature (e.g. when the derivation changes word class). All such specifications are given by default statements, which are overridden for irregular items. Verb-to-adjective transpositions (participles) are members of the verb’s paradigm yet inflect according to the adjectival paradigm (the ‘adjectival representation’ of a verb). This gives the effect of a ‘lexeme-within-a-lexeme’, posing a challenge for lexeme-and-paradigm models. I present an analysis in which the definition of the participle is driven by a feature representation. This (re-)defines the morsig attribute, creating a representation which is identical to that of an adjective, while remaining part of the verb’s paradigm. I discuss some of the implications of this analysis for lexical relatedness, the lexical type hierarchy of SBCG and the morphology-syntax interface.

The case of Margot Macomber is, taken at face value, a pretty simple one. As we are told, “Mrs. Macomber, in the car, had shot at the buffalo with the 6.5 Mannlicher as it seemed about to gore Macomber and had hit her husband about two inches up and a little to one side of the base of his skull” (36). And that is all there is to it. Margot Macomber shot and killed her husband. There is no argument to the contrary, no surprise twist that will cause the whole case to unravel and point a guilty finger at another party who was the heretofore unknown trigger man. But there is a nagging question that remains, one that has caused more than one Hemingway scholar to argue with more than one other such scholar: Namely, did she intend to kill her husband as Wilson seems to suggest? Or, if Margot’s tears and apparent sorrow are to be believed, was it an unfortunate accident resulting from her attempts to save her husband’s life? Was this a case of murder or just a horrible accident? Although a cursory reading of the story leaves the answer to that question frustratingly ambiguous, Hemingway was sprinkled his story with clues that, through a careful analysis, suggest that the true nature of the shooting is anything but ambiguous. Margot Macomber shot her husband with intent to kill. That is to say, Margot murdered her husband. The African cape buffalo like the one Macomber was hunting that fateful day can weigh up to 2,000 pounds. In bulls of that size, the shoulder height can measure up to five-and-a-half feet in height (Estes). Wilson said of the buffalo after the shooting that it was a “hell of a good bull” (36), so it can be assumed that the buffalo in question was at the high-end of the size range. This is important information, given that Wilson told Francis, “When a buff comes he comes with his head high and thrust straight out. The boss of the horns covers any sort of brain shot. The only shot is straight into the nose. The only other shot is into his chest or, if you’re to one side, into the neck or

Beyond a Reasonable Doubt: Mathematical Proof of the Unequivocal Guilt of Margot Macomber in Ernest Hemingway’s THE SHORT HAPPY LIFE OF FRANCIS MACOMBER

History will see advertising as one of the real evil things of our time. It is stimulating people constantly to want things, want this, want that.Malcolm MuggeridgeAt its most utilitarian level, advertising has as its purpose to facilitate the promotion and sale of particular commodities. However, as Judith Williamson argues, "[Advertising] has another function, which I believe in many ways replaces that traditionally fulfilled by art or religion. It creates structures of meaning" (Williamson 11). Those structures of meaning, as the above quote from Malcom Muggeridge suggests, may be perceived as having nefarious motivations; specifically advertising's aim is to keep us constantly wanting more. This suggests that in addition to being a cultural institution in the United States, advertising is a powerful force that we as consumers willingly enable in its efforts to exploit us. Advertising encourages us to constantly desire and, in order to fulfill those desires, to constantly acquire more and more commodities. As a result of this perpetual desiring and the resultant quest for satisfaction, those within a capitalist economic system find themselves enslaved by the system. Consumers work in order to purchase commodities that they believe will satisfy their desires. However, they soon discover that material goods do not deliver on their promises, and the desire for a new commodity appears. As there is no other option available to a consumer within a capitalist structure but to assimilate to this exploitative system, assimilation to the never-ending cycle is inevitable.It is this theme of voluntary exploitation and forced assimilation that is at play in John Steinbeck's The Grapes of Wrath, the canonical American novel of Dust Bowl-era migrants looking for work and a better life. What they find, however, is that they are victims of the system, both as consumers and as commodities. The Joads are uneducated and unfamiliar with the oftentimes exploitive techniques incorporated into early twentieth-century advertising, and they fall prey to advertisements that exploit their human desires. Because of their ignorance of the darker motivations behind advertising, the Joads willingly allow themselves to be exploited by capitalism and the system's lieutenants that use them up and then cast them aside as disposable commodities.In his discussion of The Grapes of Wrath, Morris Dickstein writes,The plight and migration of the Joads [...], the Dust Bowl, the loss of a family home, the trek in search of work, the awful conditions for migrant farm labor, the struggle to keep the family together, became a metaphor for the Depression as a whole. This portrayal aroused sympathy and indignation that transcended literature and became part of our social history, as if Steinbeck had been reporting on a real family, which in a sense he was.(Dickstein 112)It was the moral outrage from the general American public that the novel elicited that, according to Dickstein and countless other Steinbeck scholars, earned the author the mantle of anticapitalist protest writer. And nowhere in his collected writings is his criticism of the capitalist system more apparent than in The Grapes of Wrath. As Dickstein suggests, Steinbeck's ability to verbally transport his reader to the time and place in the novel does tempt readers into accepting that the writer's pathos-laden tale of the Joad family is a story about the human cost of the environmental and economic catastrophe wrought by the Dust Bowl. That suffering and misery was intensified by the commercial culture that permeated the United States at the turn of the twentieth century, a culture that itself was fueled by advertising. And it is that culture that was the target of much of Steinbeck's social criticism in the novel.Born in Salinas, California, in 1902, Steinbeck was the third of four children born to middleclass parents. His mother was a former school teacher and his father worked as a manager in a flour mill at the time of John's birth. …

Voluntary Exploitation and Forced Assimilation: John Steinbeck's Critique of American Advertising in The Grapes of Wrath

Adventures of Huckleberry Finn is, this article argues, a novel that attacks the very premise of racial hierarchies through Twain's satirical presentation of those who so willingly endorse the practice of subjugating those of nonwhite races. Through a close reading of the text and an examination of Twain's own experiences with African Americans (and his writings about those experiences), it demonstrates how Twain uses various characters throughout the novel—including the widow Douglas and Miss Watson, Pap Finn, the king and duke, and others—to serve as negative examples of those who cling to racist ideologies. Reading through the lens of critical race theory, a new approach to teaching the novel as an attack on the foundations of racism emerges. In the end, this article argues that Twain was focused on dismantling the "fiction of law and custom" that he knew racial hierarchies to be.

"A Fiction of Law and Custom": Mark Twain's Interrogation of White Privilege in Adventures of Huckleberry Finn

Many languages have morphological devices to turn a noun into an adjective. Often this morphology is genuinely derivational in that it adds semantic content such as ‘similar-to-N’ (similitudinal), ...

One of Anderson’s many contributions to morphological theory is the claim that morphology is split between syntactically mediated inflection and lexically mediated derivation. In Minimalist morphosyntax all morphology is syntax. This means that the split morphology proposal is not meaningful for that model. In lexicalist models, however, the split morphology hypothesis manifests itself as a distinction between direct accessibility to syntactic representations (inflection proper) and lack of accessibility. However, there are construction types which bring the inflection-derivation distinction into question. One of these is the transposition, as illustrated by the ubiquitous deverbal participle. This is a mixed category, being at once a form of a verb yet having the external syntax of an adjective. It is thus unclear which side of the split participles fall. Similarly, participles seem to be an embarrassment for the Word-and-Paradigm models of inflection which have become dominant since Anderson first introduced them to contemporary theorizing. This is because they seem to require us to define a “paradigm-within-a-paradigm” (or “quasi-lexeme-within-a-lexeme”).

Chapter 18 Split-morphology and lexicalist morphosyntax : The case of transpositions

With the beginning of Roman influence over Britain in the late Iron Age, and direct political and administrative control from A.D. 43 onwards, Britain underwent dramatic transformations in both social structures and ideologies. The remains of prehistoric constructions in the landscape may have been an integral part of these transformations, used as anchors of stability in a rapidly changing and expanding world. Over the past two decades, there have been a number of publications which have highlighted the ways in which later interactions with certain prehistoric funerary sites could be linked with a sense of respect or reverence of the past, focusing on the way in which later interactions could be used to manipulate the perceptions of a society in order to achieve certain goals, such as legitimising inequalities between certain social groupings. A group of studies, presented as papers to the Theoretical Roman Archaeology Conference in Leicester in 2003, discussed aspects of ephemeral and experienced landscapes and the roles which prehistoric monuments may have assumed during the late Iron Age and Roman periods. This research attempts to build upon those papers and looks at the evidence for later interactions with prehistoric monuments, or earthworks, during the period in which Mediterranean-centred material culture influenced the development of the landscape and social structures in the British Isles. It correlates a sample of the archaeological evidence regarding the repurposing of both singular features and wider landscapes from the end of the 2nd century BC, through to the beginning of the 5th century AD, in order to establish if any significant patterns of interaction can be ascertained.

The past in the past : patterns of interaction with prehistoric landscape features in Late Iron Age and Roman Britain

I argue in favour of the notions ‘word (form)’, ‘lexeme’, ‘paradigm’ against Distributed Morphology claims that lexical roots are indexed only by their form. That approach entails there can be no suppletion in lexical items. In addition to the obvious counterexamples I point out more subtle cases such as Russian prefixed verbs. Following Spencer (2013) I propose that a lexical entry is identified with a unique lexemic index. Transpositions, such as participles, preserve their base verb’s lexemic index (cf inflected forms). They contrast with transpositional lexemes such as prepositional or participle-form adjectives such as interesting . They share their semantic content with their base verb yet they are distinct lexemes, hence, are furnished with a distinct lexemic index.

The first part of the handbook covers the fundamental building blocks of inflectional form and content: morphemes, features, and means of exponence. Part 2 focuses on what is arguably the most characteristic property of inflectional systems, paradigmatic structure, and the non-trivial nature of the mapping between function and form. The third part deals with change and variation over time, and the fourth part covers computational issues from a theoretical and practical standpoint. Part 5 addresses psycholinguistic questions relating to language acquisition and neurocognitive disorders. The final part is devoted to sketches of individual inflectional systems, illustrating a range of typological possibilities across a genetically diverse set of languages from Africa, Asia and the Pacific, Australia, Europe, and South America.

How well do library and information professionals use Twitter to engage with conferences in Australasia? (or "A little birdie told me...")

This paper addresses the issue of phonologically null elements in HPSG by providing an 
analysis of the construction exemplified by NPs such as ˋthe rich', ˋthe beautiful', ˋthe
unemployed', which lack an overt noun. The properties of this construction are explored in
detail, and a number of approaches described: in particular approaches which posit a
phonologically empty noun, and constructional approaches. It is shown that a
constructional approach is empirically superior. This is interesting, theoretically,
because empirical differences between such approaches have proved elusive hitherto.

Proceedings of the International Conference on Head-Driven Phrase Structure Grammar

Hungarian pronominal case and the dichotomy of content and form in inflectional morphology

I examine some of the rich set of transpositional process in the Samoyedic language Selkup, focussing on denominal adjectives. Selkup provides evidence that (i) some case inflections add semantic content to the lexical representation in addition to realizing a morphosyntactic feature, (ii) transpositions can be defined over already inflected word forms (in this case, nouns inflected for case and possessor agreement). In each case the morphology provides forms of a lexeme, it doesn’t create a new lexeme. This is in contrast to genuine cases of denominal adjectival derivation in the language such as privative/proprietive adjectives. I provide an analysis of the transpositions in the framework of Generalized Paradigm Function Morphology.

Selkup Denominal Adjectives: A Generalized Paradigm Function Analysis

I TAKE ‘PERIPHRASIS’ TO REFER TO A SYNTACTIC (multiword) construction, typically expressing some set of grammatical properties, and which in certain senses behaves like a morphological construction. In the prototypical cases the periphrasis actually realizes a cell in an otherwise synthetic morphological paradigm (Sadler and Spencer 2001).1 However, periphrases are syntactic in form (by definition) and so the question arises whether they are to be treated as just a special form of syntax, or whether their status intermediate between ‘true’ syntax and morphology calls for special treatment in grammatical theory. In most discussions of periphrasis, the construction type is taken as expressing the kinds of morphosyntactic properties that are normally associated with functional categories (or inflection) in the language under discussion. This can leave us with a problem: function words typically arise from lexical words as the result of a process of grammaticalization. However, it is not always entirely clear when a grammaticalization process has reached completion and there are often unclear cases where it is difficult to know whether we have, say, a weakly demonstrative adjective/determiner or a nascent definite article, or whether we have lexical verb with some rather general modal meaning or a modal auxiliary verb. One category that is (usually!) less controversial is sentential or clausal negation. It is difficult to imagine a language without this category, and it is difficult to imagine sentential negation as anything other than a grammatical, functional category. Whenever a construction is expressed by a function word, we are entitled to investigate whether or not that construction might be a periphrase, so clearly, whenever negation is expressed by means of a construction with a function word we have a plausible candidate for a periphrastic construction. This chapter surveys a number of constructions associated with the expression of sentential or clausal negation (which I take to be the negation of

1. Introduction: Words and paradigms 2. The lexical entry 3. Lexical relatedness 4. Paradigm Function Morphology 5. Lexical entries and the generalized paradigm function 6. Representing lexical relatedness 7. The form and function of argument structure representations 8. Further instances of transposition 9. Lexical relatedness in Selkup 10. Conclusions References Index

Chapter Title English Unit 1 Spelling Unit 2 Alphabetising Unit 3 Comprehension Unit 4 Grammar Unit 5 Punctuation Unit 6 Formal letter writing Maths Unit 7 General mathematics Unit 8 Basic operations Unit 9 Decimals Unit 10 Fractions Unit 11 Percentages Unit 12 Measurement conversions Unit 13 Earning wages Unit 14 Squaring numbers Unit 15 Vouchers Unit 16 Deals Unit 17 Reading, interpreting and understanding information in tables and Charts Unit 18 Practice written exam for the Hospitality and Catering Industry industry

Maths & English for hospitality and catering : graduated exercises and practice exam

In most languages we find 'little words' which resemble a full word, but which cannot stand on their own. Instead they have to 'lean on' a neighbouring word, like the 'd, 've and unstressed 'em of Kim'd've helped'em ('Kim would have helped them'). These are clitics, and they are found in most of the world's languages. In English the clitic forms appear in the same place in the sentence that the full form of the word would appear in but in many languages clitics obey quite separate rules of placement. This book is the first introduction to clitics, providing a complete summary of their properties, their uses, the reasons why they are of interest to linguists and the various theoretical approaches that have been proposed for them. The book describes a whole host of clitic systems and presents data from over 100 languages.

Possession and modification - a perspective from Canonical Typology

Edmund Gussmann, The phonology of Polish. Oxford and New York: Oxford University Press, 2007. xiii + 367pp. ISBN 978–0-19–926747-7.

There are a number of constructions in various languages which occupy a problematic position between morphology and syntax. Though they are made up of more than one word and are phrasal in nature, they also occupy a place in the morphological paradigm. We can illustrate this with an example from Russian. In Russian verbs are either of perfective, or of imperfective aspect. All verbs have synthetic past tense forms. The imperfective but not the perfective verb has a present tense form. In the future tense, however, perfective verbs have a synthetic form, whereas imperfective verbs have a phrasal, or periphrastic form (see the table below):

THIS PAPER AROSE FROM OUR INTEREST IN PERIPHRASES—complex linguistic expressions that serve as exponents of grammatical features and values and are often integrated in morphological paradigms.1 Elsewhere, in co-operation with others, we have written in more detail about how such expressions can be defined, recognized, and distinguished from other linguistic phenomena (Brown et al., in press). We will recap some of this below. Our main interest here, however, is in how periphrases within a single grammatical system are related to each other and how their relatedness is best expressed. In particular, we are interested in those cases where it appears that a periphrase is embedded within another complex periphrastic expression. We think that assuming certain relationships between periphrases (for example, seeing one periphrase as being derived from another, or one being embedded within another) can be linked to the distribution of forms within them. Here, we draw conclusions about relatedness on the basis of the distribution of various forms of an auxiliary verb within the paradigm. Our views of relatedness between periphrases depend to some extent on our views of the phenomenon itself and our views of paradigms. We explain these below. The data included in this paper come primarily from Bulgarian. Apart from our familiarity with the language, it is a good source of material because of the unusually rich verbal paradigm which combines synthetic and analytic forms and in which many of the analytic forms appear to have similar composition. We will not be able to cover all the constructions that could be considered part of the verbal paradigm in the language. Rather, we have selected a

Introduction Scholars from diverse linguistic traditions have observed that the behaviour of clitics is neither that of an independent word nor that of an affix, but enjoys what Klavans (1982) calls ‘dual citizenship’. Among the classical studies on clitic phenomena, two oft-cited and influential papers stand out, namely Wackernagel (1892) and Zwicky (1977). In Section 3.2 we offer a summary of these studies, which represent two early attempts at identifying and classifying the idiosyncrasies of clitic placement. Section 3.3 offers a descriptive overview of a number of well-documented (though not necessarily uncontroversial) placement patterns. Having surveyed the meaning and function of clitics in the previous chapter, we look in somewhat more detail at the distributional properties of clitics and the various positions within which clitics occur cross-linguistically. We first briefly introduce the notion of clitic cluster and then explore the way that clitics or clusters of clitics are positioned within their domain (the clause, the noun phrase, occasionally the verb phrase). Placement patterns vary significantly: while some clitics may show a strong preference for the second position in the clause, others are banned from the edge of the sentence, and yet others must be adjacent to a specific word category. We will also show that even a concept such as ‘second position’ can mean different things in different languages. Clitics very often express functional properties akin to (or even identical to) inflectional categories in a language, which in practice means inflectional properties of nouns and of verbs. A clitic's linear positioning usually associates it in some way with the noun or verb whose properties it expresses, and so the noun and verb serve to define domains for clitic placement. In Section 3.4 we examine these domains. On the other hand, a good many clitics express properties of entire clauses or, in the case of discourse clitics, of utterances. Section 3.5 is devoted to such clause-domain clitics.

The book is a collection of contributions which applies Western theoretical constructs to an understanding of heritage tourism and development in South-east Asia. This precipitously encouraged a juxtaposition of the two worlds which led to a confirmation or rejection of commonly held views in Western society regarding conflicts between governmental development agendas and the preservation of authentic identity. This well written and edited text is carefully anchored by the editors through the use of an overview which frames heritage and heritage tourism in its context and also through a conclusive chapter on heritage futures. The substance of the text is however contained in the contributions of chapters 2–12 which address specific locales and initiatives in South-east Asia. Kathleen M. Adams presents a useful discourse on the local politics surrounding the emergence of a UNESCO World Heritage Site in Indonesia. The political process surrounding the selection of a culturally authentic symbol in Toraja, Sulawesi, extends the discussion of authenticity but also reinforces that the emergence of heritage sites is not a ‘natural’ process but one that involves significant competition between many stakeholders. In particular, where there is a quest for World Heritage Site status, the competitive and collaborative landscape becomes more complex as this will now involve, in addition to local residents and governments, input from external international bodies. The key element here is that the notion of what is truly authentic is significantly influenced by internationally accepted ideas of what is true about the community’s identity. The reconstruction of identity is further highlighted by Mami Yushimura and Geoffrey Wall who focus on the heritage of the Atayal in Taiwan. Their emphasis on reconstructed identity is somewhat different from the previous authors in that they discuss this construct in light of colonial suppression of authentic culture and the need to redefine identity and heritage in the tourism context. Colonialism and Neo-colonialism are analysed in terms of how they have shaped the post-colonial history and contemporary tourism development of the country. The key argument here is that multiple facets of culture are attributed to the colonizers and this makes it particularly difficult to recreate an identity and product that is worthy of consumption by tourists and more importantly that is real. The introduction of the tourism development debate is extended by Michael Hitchcock and Nick Stanley who articulate from the position of nation-building that there are some gaps in the approaches taken to development. The struggle between the need to offer ‘pure education’ and at the same time ensuring that tourists are sufficiently entertained presents significant challenges. The emergent ‘edutainment’ which typically provides a snapshot of tangible and intangible elements of culture may be paralleled to Western notions of ‘staged authenticity’. This calls for a need for greater coherence in governance, politics, policies and ethno-cultural

Book review: Hitchcock, Michael, King, Victor T. and Parnwell, Michael, editors, 2010: Heritage Tourism in Southeast Asia

The Oxford Handbook of Compounding surveys a variety of theoretical and descriptive issues, presenting overviews of compounding in a number of frameworks and sketches of compounding in a number of languages. Much of the book deals with Germanic noun–noun compounding. I take up some of the theoretical questions raised surrounding such constructions, in particular, the notion of attributive modification in noun-headed compounds. I focus on two issues. The first is the semantic relation between the head noun and its nominal modifier. Several authors repeat the argument that there is a small(-ish) fixed number of general semantic relations in noun–noun compounds (‘Lees's solution’), but I argue that the correct way to look at such compounds is what I call ‘Downing's solution’, in which we assume that the relation is specified pragmatically, and hence could be any relation at all. The second issue is the way that adjectives modify nouns inside compounds. Although there are languages in which compounded adjectives modify just as they do in phrases (Chukchee, Arleplog Swedish), in general the adjective has a classifier role and not that of a compositional attributive modifier. Thus, even if an English (or German) adjective–noun compound looks compositional, it isn't.

What's in a compound? Review article on Lieber and Štekauer (eds) 2009. 'The Oxford Handbook of Compounding'

Based on the notion of a lexicon with default inheritance, I address the problem of how to provide a
template for lexical representations that allows us to capture the relatedness between inflected
word forms and canonically derived lexemes within a broadly realizational-inferential model of
morphology. To achieve this we need to be able to represent a whole host of intermediate types of
lexical relatedness that are much less frequently discussed in the literature. These include
transpositions such as deverbal participles, in which a word's morphosyntactic class changes
(e.g. verb ⇒ adjective) but no semantic predicate is added to the semantic representation and the
derived word remains, in an important sense, a "form" of the base lexeme (e.g. the 'present
participle form of the verb'). I propose a model in which morphological properties are inherited by
default from syntactic properties and syntactic properties are inherited from semantic properties,
such as ontological category (the Default Cascade). Relatedness is defined in terms of a Generalized
Paradigm Function (perhaps in reality a relation), a generalization of the Paradigm Function of
Paradigm Function Morphology (Stump 2001). The GPF has four components which deliver respectively
specifications of a morphological form, syntactic properties, semantic representation and a lexemic
index (LI) unique to each individuated lexeme in the lexicon. In principle, therefore, the same
function delivers derived lexemes as inflected forms. In order to ensure that a newly derived lexeme
of a distinct word class can be inflected I assume two additional principles. First, I assume an
Inflectional Specifiability Principle, which states that the form component of the GPF (which
defines inflected word forms of a lexeme) is dependent on the specification of the lexeme's
morpholexical signature, a declaration of the properties that the lexeme is obliged to inflect for
(defined by default on the basis of morpholexical class). I then propose a Category Erasure
Principle, which states that 'lower' attributes are erased when the GPF introduces a non-trivial
change to a 'higher' attribute (e.g. a change to the semantic representation entails erasure of
syntactic and morphological information). The required information is then provided by the Default
Cascade, unless overridden by specific declarations in the GPF. I show how this model can account
for a variety of intermediate types of relatedness which cannot easily be treated as either
inflection or derivation, and conclude with a detailed illustration of how the system applies to a
particularly interesting type of transposition in the Samoyedic language Sel'kup, in which a noun is
transposed to a similitudinal adjective whose form is in paradigmatic opposition to case-marked noun
forms, and which is therefore a kind of inflection.

I discuss the problem of the morphological and semantic properties of transpositions, forms of lexical relatedness such as deverbal participles or action nominalizations which retain many of the properties of the base while still exhibiting a change in morphosyntactic category. I pay particular attention to deverbal nominalizations based on the infinitive form of verbs in languages such as German, Italian and others. I argue that such nominalizations are not true derivation because they remain, in an important sense, forms of the base verb. At the same time they are not ‘pure’ transpositions because they often involve added subtle semantic nuances (which, however, are not of the same kind as the added semantic predicates found in true derivation). I analyse these types of lexical relatedness within an approach to lexical relatedness I have called Generalized Paradigm Function Morphology.

Many languages have morphological devices to turn a noun into an adjective. Often this morphology is genuinely derivational in that it adds a semantic predicate such as ‘havingN’ (proprietive), ‘lacking-N’ (caritive’), ‘similar-to-N’ (similitudinal) and so on. In other cases the denominal adjective expresses some vaguely defined notion of possession as in Russian Ivan-ovo (detstvo) ‘Ivan’s (childhood)’, or is purely relational as in prepositional phrase (cf. the synonymous preposition phrase). In some languages and in some constructions the resulting adjective retains some of the noun-related properties of its base. For example, the base can be modified by an attribute as though it were still a syntactically represented noun (as in the English proprietive [short sleev]ed shirt), giving rise to what we call ‘syntagmatic category mixing’. We contrast classes of syntactic and lexical approaches to such constructions. On syntactic approaches the derivational affix takes scope over a syntactic phrase because the affix itself is introduced in the syntax. We argue that there are cases which cannot be handled in this manner, because the affix lacks crucial syntactic properties we would otherwise expect, such as taking wide scope over coordinated hosts, and because the syntactic approach cannot account for some of the syntactic properties of the derived modifier. For these cases we argue for a lexical approach based on the idea that the morphological, syntactic and semantic dimensions of a lexical representation are in principle independent and can be fractionated. We then define lexical type hierarchies on the basis of these fractionated lexical entries. This permits us to express the idea that a denominal adjective can have the external syntax of an adjective, for instance, agreeing with its head noun, while retaining the internal syntax of a noun, for instance, by still taking attributive modifiers of its own. We identify six principal types of denominal modifiers defined in terms of whether they exhibit category mixing and if so what kind. These are canonical derivation, canonical transposition (change of morphosyntactic category but no additional semantic content – relational adjectives in Russian and many other languages), mixed derivation (with syntagmatic mixing – proprietive adjectives in Tungusic), mixed transposition (transposition with syntagmatic mixing – possessive adjectives in Upper Sorbian, Chukchi possessive and relational adjectives), mixed inherent inflection (semantically contentful inflection with syntagmatic mixing – Selkup similitudinal forms), and mixed contextual inflection (Suffixaufnahme based on genitive case forms – Daghestanian/Cushitic). We show how each type represents a different fractionation of the lexical entry of the derived modifier.

The value of imperial virtutes in the Tabula siarensis and the Senatus consultum de Cn. Pisone patre

In a transposition (e.g. deverbal participle) we don’t create a new lexeme, but we do change the morphosyntactic word class (while preserving a variety of verbal properties). How do we account for transpositions in a lexicalist framework? Proposal: Spencer (1999) proposes to define transpositions in terms of argument structure representations, making use of the ‘semantic function roles’, ‘R’ for nouns, ‘E’ for events. E.g. a deverbal nominalization ((NP’s) shooting (of) the lions) has the a-structure: shoot >>. The ‘E’ role licenses (limited) verbal properties, the ’R’ role licenses nominal properties. However, what is the semantic function role of an adjective? What kind of representation would we need to account for deverbal/denominal adjectives (participles/relational adjectives)?

I argue that case markers in Hungarian are best thought of as ‘fused postpositions’. There is no need to set up a separate syntactic or morphological [Case] attribute as such. Rather, we just need a morphological principle stating that nominals (including pronouns) have a special form, the traditional case form. In this respect Hungarian is crucially different from languages such as Latin (which requires both a morphological and a syntactic [Case] feature) or Finnish (which requires at least a syntactic [Case] feature). I discuss certain typological issues arising from this analysis, arguing that when grammarians refer to Hungarian ‘cases’, they are really referring to a rather more general notion of ‘canonical grammatical function markers on dependents’.

This handbook provides a comprehensive account of current research on case and the morphological and syntactic phenomena associated with it. Scholars from all over the world provide overviews of current theoretical, typological, diachronic, and psycholinguistic research and assess cross-linguistic work on case and case-systems.

Review of R. M. W. Dixon and A. Y. Aikhenvald (2004) 'Adjective classes. A Cross-linguistic Typology'

The possessum-agreement construction or `Does Albanian have a genitive case?'

In this chapter, the term case is taken in its traditional meaning of inflectional category-system (and the individual categories or values of that system) expressing dependency relations involving NPs.1 A spatial relation involves two percepts, a Figure (or Theme, or Trajector) and a Ground (or Location, or Landmark), the Figure being perceived as located or in motion relative to the Ground.2 A spatial case is an inflected form of nouns or NPs distinct from the absolute form available for the extra-syntactic function of pure designation, and apt to fulfill one of the following functions without the addition of an adposition: – non-verbal predicate, or predicative complement of a copula, specifying the location of an entity, – verb satellite specifying the location of an event, – argument of motion verbs specifying the source, path, or destination of the movement. It may happen that the same case form has some uses corresponding to this definition along with non-spatial uses (see sections 4 and 5). Some authors have advocated that all cases can be viewed as locative expressions (see in particular Hjelmslev 1935, Hjelmslev 1937, Anderson 1971, Cook 1989). Since we are concerned with cases that have concrete spatial meanings (and not with cases having only non-spatial uses derivable from abstract locative meanings) this question will not be further developped here.

Ellen Brandner & Heike Zinsmeister (eds.),New perspectives on case theory (CSLI Lecture Notes 156). Stanford, CA: Center for the Study of Language and Information, 2003. Pp. ix+373.

A paradigm function account of ‘mesoclisis’ in European Portuguese

Marit Julien , Syntactic heads and word formation (Oxford Studies in Comparative Syntax). Oxford: Oxford University Press, 2002. Pp. viii+407.

Masculine Image of Cleopatra VII: A Connotative Symbasis in Literature and the Visual Arts

We argue that Russian has a lexical category of stative middles, comparable to those of English, French or German, in which a verb in the reflexive form ascribes a potential state to the subject. Moreover, these stative middle forms are derived in the lexicon, and are not simply the result of interpreting an eventive predication generically. We provide a semantic analysis of the construction, demonstrating that it corresponds to more familiar stative middles, and show also that it is lexically restricted (unlike the straightforward generic or habitual interpretation associated with the imperfective aspect). In addition, we find that verbs used in the stative middle sense fail to license a deverbal nominalization. This shows that middles pattern with other statives in Russian, which overwhelmingly lack nominalizations. This behaviour contrasts strikingly with that of generics, where a deverbal nominalization is extremely productive and regular. We argue that the existence of such middle verbs is of significance for our understanding of the notion of the lexeme, and the role of verbal aspect in the lexical and grammatical system of Russian.

The German noun phrase generally reflects a straightforward four-way case distinction (nominative, accusative, genitive, dative), but this is most clearly realized on the determiner. Nouns show a depleted case system: genitive is only marked specifically on masculine/neuter nouns in the singular. There are several contexts which require genitive case: possessor NPs and objects of certain verbs and prepositions as well as complements to deverbal nominalizations. However, certain forms of proper names obligatorily fail to realize their genitive case in genitive contexts. Moreover, there are contexts in which even an unambiguously marked genitive singular noun is inadequate on its own and has to be accompanied by an inflected (not indeclinable!) modifier. This complex pattern of behaviour is difficult for current LFG approaches to case to handle because there is a many-many relationship between syntactic case specification and morphological case marking. I propose a realizational analysis, in which it is only NP/DPs in c-structure which are given syntactic CASE attributes. A set of fto c-structure mapping rules define the distribution of these attributes, effectively capturing statements such as ‘transitive SUBJECT is realized by ergative’, ‘POSSESSOR is realized by genitive’ and so on. The syntactic CASE attributes are not part of lexical structure but are mapped onto morphological case-marked forms. Thus, syntactic CASE GEN is by default realized by a noun marked [Case: Gen], but not always, and not all [Case: Gen] marked elements realize CASE GEN (much less POSS).

Laurie Bauer , Morphological productivity . Cambridge: Cambridge University Press, 2001. Pp. xiii+245.

Russian adjectives, especially participles, can be used as nouns denoting people, e.g. bol′noj/bol′naja ‘(male/female) patient’ from bol′noj ‘sick’, učaščijsja/učaščajasja ‘(boy/girl) pupil’, participle from the verb učit′sja ‘to learn, study’. These are unusual in that they formally reflect the sex of their referent by means of inflectional morphology. Moreover, many surnames inflect like adjectives and they, too, inflect for gender: Mr. Puškin, Čexov, Tolstoj, Dostoevskij but Ms. Puškina, Čexova, Tolstaja, Dostoevskaja. Lexemes such as ‘patient, pupil’ are genuine nouns and not just adjectives modifying null nouns. The latter type do exist and have different properties from converted nouns. Converted nouns and adjectival surnames thus form systematic gender pairs which are forms of a single lexeme. However, gender is not conventionally regarded as an inflection category of the kind which induces word forms of lexemes in this way, rather it is an inherent ‘classificatory’ property of nouns. The paper discusses the peculiar nature of this type of inflectional marking and provides an explicit analysis of the construction. On the semantic side, nouns such as bol′noj, učaščijsja have a similar representation to that of a phrase person who is sick/studies and we effectively have an instance of the poorly researched phenomenon of de-phrasal word formation. On the morphosyntactic side, the lexical entry of the deadjectival noun or surname shares crucial properties with 3rd person pronouns. The analysis raises questions about the nature of lexical categories (especially ‘mixed categories’) and the structure of lexical entries generally.

just adjectives modifying null nouns. The latter type do exist and have different properties from converted nouns. Converted nouns and adjectival surnames thus form systematic gender pairs which are forms of a single lexeme. However, gender is not conventionally regarded as an inflection category of the kind which induces word forms of lexemes in this way, rather it is an inherent 'classificatory' property of nouns. The paper discusses the peculiar nature of this type of inflectional marking and provides an explicit analysis of the construction. On the semantic side, nouns such as bol'noj, uca6iljsja have a similar representation to that of a phrase person who is sick/studies and we effectively have an instance of the poorly researched phenomenon of de-phrasal word formation. On the morphosyntactic side, the lexical entry of the deadjectival noun or surname shares crucial properties with 3rd person pronouns. The analysis raises questions about the nature of lexical categories (especially 'mixed categories') and the structure of lexical entries generally.

I provide an analysis of the Bulgarian clitic cluster within the framework of Greg Stump’s theory of Paradigm Function Morphology. I treat the basic clitic cluster as essentially a string of affixes generated by paradigm functions. In this way I formalize the notion of ‘phrasal affix’. The placement of the cluster is determined by the interaction of syntactic and prosodic constraints, whose interaction is mediated by Optimality Theory. The notorious question clitic, li , is treated as an enclitic to the leftmost stressed element in its domain. The clitic itself is generated as a member of the basic cluster but without any linear precedence. Its final placement is thus decided by OT constraints. I briefly consider the closely related Macedonian system, in which the clitic cluster is affixed by the paradigm function not to the root of the lexeme, but to a word form which has already undergone a layer of inflection.

New updated! The latest book from a very famous author finally comes out. Book of handbook of morphology, as an amazing reference becomes what you need to get. What's for is this book? Are you still thinking for what the book is? Well, this is what you probably will get. You should have made proper choices for your better life. Book, as a source that may involve the facts, opinion, literature, religion, and many others are the great friends to join with.

Ingo Plag, Morphological Productivity. Structural Constraints on English Derivation. Berlin/New York: Mouton de Gruyter, 1999.

A particular set of Slavic auxiliary-participle constructions (based on the ‘l-participle’) exhibit a number of characteristic ‘deviations from agglutination’ of a type commonly found in inflectional morphology, such as cumulation, extended exponence and zero exponence. The participle itself cannot be given a unitary meaning. I present an analysis of these constructions within the paradigm-based approach of Ackerman and Webelhuth (1998), in which the principles of inferential–realisational (Stump 2001) or ‘word-and-paradigm’ models (Robins 1959) are applied to multiword combinations which realise functional categories.

Christopher Lyons,Definiteness. Cambridge: Cambridge University Press, 1999. Pp. xx+380.

I argue for an extension of Clahsen's psycholinguistic paradigm to well-known languages with more complex morphological systems. This would help to address conceptual questions such as the nature of defaults and the way in which syncretisms are coded in the brain.

We argue that a large class of Russian prefixed verbs has essentially the same semantic structure as resultative constructions in English of the type paint the door green. We analyze both phenomena as instances of lexical subordination : although it is syntactically a secondary predicator, green expresses the primary (core ) semantic predication, while paint is a secondary subordinated semantic predicate. The expression therefore means cause to become green by painting. In the Russian vyteret' stol (wipe down the table, literally out-wipe table), the prefix vy- is semantically primary and the verb stem is subordinated. By virtue of this shared semantic structure, Russian prefixation can only access internal arguments (objects, or subjects of unaccusatives) and Russian prefixed verbs may support fake or unselected object constructions, akin to English resultatives such as drink the pub dry or sing oneself hoarse. From pisat' (write) we have ispisat' rucku (out-write pen, to run out of ink (of a pen)), in which the direct object pen is not selected by pisat' (write). Since these unselected objects are arguments of the prefixed verb complex, we conclude (with Goldberg 1995, against Levin and Rappaport Hovav 1995) that unselected objects in English resultatives are also arguments (of the construction). We extend our analysis to the steal/rob alternation and offering an explanation of why in some languages, verbs of manner of motion (e.g. run) behave like unergative verbs while the same verbs with directional complements/adjuncts (e.g. run into the room) behave like unaccusative verbs. We discuss the repercussions for the interpretation of notions such as complex predicate and construction

A morphomic account of a syncretism in Russian deverbal nominalizations

Bringing together scholarly sources and media coverage, Martin Murray has provided a detailed, informative and compelling account of the events over the decade leading to South Africa's first democratic election. It is imperative reading as much for those who are concerned with South Africa's future as for those concerned with its past. For the blow-by-blow account of apartheid's demise also serves to reveal the extent to which many of the forces for a fundamental break with the inequalities and inequities of the past have been dissipated. Hence the title—The revolution deferred. Murray's subtitle—The painful birth of postapartheid South Africa—is equally apt. For the white elite has been all too reluctant to hand over any aspect of their hold over economic and political power. This is true both of the neo-fascist Afrikaners and of politicians, government officials, and the liberally minded captains of industry and finance. The only differences in this respect are in what they have to lose and the lengths to which they are prepared to go to defend it. As the elections drew close, white supremacists bombed and killed as a last act of defiance against the inevitable. Yet, as Murray amply demonstrates, this random and futile violence was merely the tip of an iceberg that all the rest were only then prepared to condemn. The protracted negotiations before the election, and earlier, had seen a bund eye and supporting hand turned towards organized white violence through the police and armed and secret services. In addition, financial and training support by the apartheid government was provided to black opposition to the ANC to undermine the latter's bargaining and organizational strength, with Buthelezi's Inkatha Freedom Party to the fore as the regime's favoured fomenter. The violence that has ensued has taken on a life and rhythm of its own, intricately and deeply entrenched within the segregated landscape of South African society and the struggle for power, privilege and survival at each and every level. Ultimately, the National Party came to a settlement despite the success of this divideand-prevaricate strategy as its own political support began to wither—it was satisfying neither liberals nor racists amongst the white population by prolonging negotiations. But the negotiations themselves were fundamentally characterized by an intense centralization of the political process, even if hastened and pressured by the mass action on the streets and the violence in the townships. The process of coming to a settlement for a government of national unity, both in principle and in its details, was one in which all but a few were effectively excluded from active participation. Nor is it possible to doubt, as Murray documents, that huge compromises were made on both sides, even though from very unequal starting points. In particular, the wealth and privileges of the white population have been left untouched—a heavy price to pay for limited democratization in which monopoly power over the economy and secure employment and working conditions for the civil service have been guaranteed. Given the devastation of the economy over the past decade, the new government's prospects of room for manoeuvre in providing the basic needs of the majority, and hence social stability, remain bleak. Yet, this situation must be compared with a decade ago when the apartheid regime was running a strategy of partial reform for a minority and repression for the majority. The passage over the decade to democratic elections seems to have been unimaginably fraught with dangers and difficulties. It is not only luck that has brought about this outcome. The alliance between the ANC, COSATU and the SACP— and its commitment to a unified South Africa, to tactical violence where necessary, to nonracialism and to democratic principles—have all been crucial, and are too easily taken for granted, even if not fully realized in practice. These principles had to be fought for and won, both against the apartheid regime and amongst its opponents. None the less, the extraordinary and troublesome passage to democratic elections should not blind us to the limited progress that has been made in the journey to eradicate the heritage of apartheid. For the cost of victory has been high, not only in the struggle itself but also in the political and economic conditions that have been inherited. The prospects for fundamental change remain positive but confined to the long term. And there is the nagging doubt that, but for a few blacks in government and business, it is whites who have gained the most, if only they are prepared to abandon the most extreme and overt forms of racial prejudice. It is Murray's merit to have opened up these issues, if not to have resolved them. That is for the future to decide, which will in turn cast new light on the transition to democracy in the context of what the majority is able to achieve for itself. The tortuous passage to South Africa's first democratic election, the pain, fragility, and joy in avoiding major civil war, should not delude us into ignoring what has been sacrificed along the way nor into exaggerating what has been more broadly achieved.

R. M. W. Dixon: Ergativity . (Cambridge studies in Linguistics, no. 69.) xxii, 271 pp. Cambridge University Press, 1994. £37.50 (paper £12.95).

existing theoretical knowledge can be used to improve lexica and how the needs of lexica may drive theoretical research and vice versa. I found particularly interesting the articles by Annie Zaenen and Elizabeth Engdahl and by Charles Fillmore and B. T. S. Atkins. These articles clearly show why lexicography and theoretical linguistics can benefit from each other by offering working examples of a combined approach to lexical matters. They also investigate the consequence of such an approach. Exactly this kind of work is important and timely today. The last section, Section 4, consists of articles that address methodological issues in specified domains of lexicography and explain how the use of computers improves both several aspects of lexicographic work and the quality of the output. The time lag between the Pisa Summer School and this publication means that the articles in this section are interesting mainly when they describe specific methodological problems rather than when they propose solutions. An important topic that has not found its way into this book is that of the formal issues that arise when one tries to structure lexical knowledge. It is generally accepted that a well-organized (computational) lexicon exploits certain generalizations to avoid the redundant encoding of facts. The diversity of lexical information makes this task extremely complex and challenging. Although lots of research has been done (and is currently being done) in this area, there is no article in the book reporting on it. The book offers a reasonably informative overview of a dynamic field, a field that brings together computer science, lexicography and theoretical linguistics in an attempt to obtain better results in a number of tasks such as lexicography, language teaching, translation, natural language processing and literature study. As such, and given the very attractive way that many of the chapters are written, it will function as a reference book for courses on the topics listed above and as a good source of general information about the field of CLL.

Aaron Halpern, On the placement and morphology of clitics. Center for the Study of Language and Information, Stanford, CA: CSLI Publications, 1995. Pp. xii+250.

This book (TSL) is a survey of the extant Slavonic languages (including Cassubian), two extinct languages (Old Church Slavonic and Polabian), and Proto-Slavonic, together with chapters on Slavonic languages in emigration, on alphabets and transliteration systems and an introduction by the editors, which gives a very clear overview of the group. The language chapters are all written according to a tight scheme skilfully devised by the editors, which facilitates cross- referencing between languages. Each language is given full status in its own right. The chapters follow the pattern: introduction, phonology, morphology, syntax, lexis and dialects. There is a detailed index (41 pp. long). Cyrillic examples are all transliterated, so the book can be used by non-Slavicists.In the past the main source for the Slavonic languages in English (or any language) was De Bray's 1951 Guide (second edition 1980), a remarkable one-man production of considerable scope. That book is the obvious point of comparison with TSL. Not surprisingly, TSL wins hands down, for important reasons. First, each chapter is written by an acknowledged expert - no individual could hope to cover the whole language group nowadays. Second, the format imposed by the editors is informed by developments in contemporary linguistics. This is not so

Bernard Comrie & Greville G. Corbett (eds.), The Slavonic languages. London: Routledge, 1993. Pp. xiii + 1078.

in a letter to his publisher, Flann O’Brien wrote “time is a great Xat motionless sea. Time does not pass; it is we who pass. With this concept taken as basic, fantastic but coherent situations can easily be devised, and in eVect the whole universe be torn up in a monstrous comic debauch.”1This statement compounds a claim made in “Cruiskeen Lawn,” copying a similar claim by the English physicist Eddington, that because there are fewer than a thousand people in the world who really understand Einstein’s theory of relativity, then most or all physics professors must necessarily be teaching theories of the universe which are based on inadmissible premises.2At the time when O’Brien was making these claims, scientiWc theory was, indeed, undergoing a revolution following work by Einstein, Planck, and others in the Welds of relativity theory and quantum mechanics. For an author fascinated by paradox and the counterintuitive, it is clear that the new Wndings were to provide a fruitful basis for humor. This is the basic concept mentioned by O’Brien above. In fact, O’Brien was remarkably upto-date on the state of research. He explains,

Many Worlds: The New Physics in Flann O’Brien’s The Third Policeman

Noun Incorporation in Chukchi is shown to exhibit many of the characteristics that would be expected on a syntactic analysis of incorporation (e.g. Baker 1988): it is productive, the incorporated element may be referential, subjects can only be incorporated from unaccusative verbs, and noun incorporation feeds a process of Dative Shift, just as predicted on Baker's syntactic account. However, several properties are incompatible with this. In particular, Chukchi freely allows incorporation of adjuncts (which would violate the ECP on Baker's account). In addition, nouns incorporate their modifiers/specifiers, in a way not predicted by a syntactic (head movement) theory. Moreover, Chukchi permits incorporation of aspectual/ temporal elements, which contradicts even the much weaker version of Baker's thesis proposed by Rivero 1992 to handle adverb incorporation in Greek. The data are, however, broadly compatible with a lexical analysis along the lines of Rosen 1989.*

This volume is the first of a series of monographs on the phonologies of individual languages edited by Jacques Durand. The aim of the series is to present descriptions which are theoretically informed, so as to constitute both a reference text for the language and a contribution to current theoretical debate. The book consists of nine chapters, a very clearly presented Conclusion, and a helpful summary of all the 60-odd phonological rules (though not the allomorphy rules, for some reason). The first part sketches the theoretical background and then presents two sizeable 'theory-neutral' chapters on the phonology and morphology of the language, an extremely useful addition to the sparse literature on Slovak in English. Rubach is obliged to describe a rather conservative variety in which a (/se/) is not neutralized with e (/e/), otherwise many of the alternations wouldn't work. The main body of the monograph treats palatalizations, vowel-zero alternations ('yers'), various lengthenings and shortenings and syllable structure. Then comes briefer discussion of the postcyclic and postlexical rules. Rubach does a very skilful job of presenting an overview of Slovak lexical (and some postlexical) phonology and using this corpus to defend a particular theoretical viewpoint, in particular, mounting a defence of the Lexical Phonology paradigm. The book displays considerable scholarship and attention to detail and is written in Rubach's characteristically clear and unfussy style. or assumptions he adopts are:

Jerzy Rubach, The lexical phonology of Slovak . Oxford: Clarendon Press, 1993. Pp. xvi + 312.

List of Figures.List of Tables.Preface.Acknowledgements.List of Abbreviations and Symbols.1. Preliminaries to Phonology. 2. Phonological Processes. 3. Syllables and Syllabification. 4. Distinctive Features. 5. Rules and Domains. 6. Postlexical Processes in English. 7. Stress and Rhythm. 8. Stress and Rhythm in English. Notes.References.Language Index.Subject Index.

This paper presents a review of a number of recent issues in the field of generative morphology, with their implications for the description of English. After an introduction to the field two types of question are considered. First, 1 examine the nature of word structure and illustrate two competing approaches, one of which assurnes that words have a constituent structure (much like the phrase structure of syntax) and the other of which rejects this assumption. Then we look at the way morphologicai structure interacts with syntax. We examine the extent to which syntactic principles can account for the behaviour of certain types of compounds and aiso the expression of syntactic arguments in nominaiizations.

Those who knew Perlin while he was a student at SOAS some twenty years ago and many who have known him since then will be delighted by this volume of his essays; new readers will discover an original and challenging historian. The present is the first of what will be a two-volume set. It consists of three long papers of which the earliest, ' State formation reconsidered', was first published in Modern Asian Studies in 1985 and the latest, ' Financial institutions and business practices' appeared in an edited collection of 1990; two shorter papers were published between those two, and the introductory essay, 'Traces of the ancient "city"' , was written for the present volume. Of these several papers, the first mentioned concentrates on India, offering a bold, revisionist formulation on the pre-colonial state and providing a framework for his other discussions on monetary subjects which are the technical base of the volume and its argument. Of his monetary papers, the most impressive, and one for which he is justly commended by many scholars of South Asia, is his 100-page, 'Money-use in late precolonial South Asia', originally published in 1987; it serves with ' State formation reconsidered' to set out Berlin's complex understanding of the advanced state of the political economy of India prior to colonial subjugation and enlists him to the side of those who argue for a significant degree of continuity that marked the passage to colonialism. These two essays together, in their length, elaborate documentation, scope and importance would constitute a quality monograph for any of the rest of us. But Perlin offers so much more. The other essays are comparative discussions of immense range; the readings that he has canvassed are prodigious, and his judgements about them, in richly informing footnotes, repay close attention. Apart from the astonishing range of secondary sources which he presents to construct his complex arguments, Perlin is an assiduous framer of the crucial issues he investigates. Each of the five essays opens with a statement of the problem to be addressed, the problematic within which it has previously been essayed by others, and his own theorizing of the subject. Thus, each discussion is accompanied by an epistemological and methodological prolegomena; the reader can be in no doubt of Perlin's reasons for raising the questions he does, nor of their importance. Take the main theme of the volume— monetary processes and systems in India and the world during the seventeenth and eighteenth centuries: Perlin skilfully marshalls the thin foundation of knowledge that exists on Indian monetary history, sets out the framing discourses that have been developed by economic historians of Europe during the same period and then opens the whole to the complex interactions between Europe and Asia for nearly four centuries. The central argument in these various papers is adumbrated in his brief introductory chapter: there was a world system of exchange knit together by commercial as well as political processes that united the Eurasian land mass and its connecting seas, and that this system and its processual ligaments can be likened to the social form which we call ' the city—as an image of a certain kind of complexity of organisation'. However, the metaphorical, or ' other' city i s ' invisible', an implicate structure, a ' metropolitan conglomerate of taxonomical systems and terms running unbroken right across Euro-Asia....'; this ' " o t h e r " city was the precondition permitting merchants to travel to distant, exotic markets, use "alien" local measures and moneys, and thereby deal in commodities.' (pp. 11-12) This discussion places Perlin in the ambit of world-system theorists like Immanuel Wallerstein as well as that of Asian generalists like K.N. Chaudhuri, in his earlier formulations of The trading world of Asia and the East India Company, and, with respect to these two scholars and others, Perlin offers important critical judgements that enrich the comparative sensibility that pervades these essays. Perlin differs from these two predecessors and others who write on similar comparative questions, such as Andre Gunder Frank and Professor Chaudhuri, in his recent Braudel-inspired Asia before Europe, by his alertness to another kind of comparative analysis, that within current social sciences, and particularly between historical and anthropological explanations about society and change. This intellectual selfreflexivity has always been a mark of Perlin's scholarship and one of its most valuable. One has no difficulty imagining the making of a second volume of equal merit, for Perlin's scholarship has always been impressive, and many of us want to see more, much more, of it. The anticipated volume 2 will contain a subject index we are told, and that is welcomed, for the present volume is incomplete without one; in a writer of such sweep and attentiveness to the work of others as Perlin, the present author index can be no more than minimally adequate.

Robert H. Robins and Eugenius M. Uhlenbeck (ed.): Endangered languages . xiv, 273 pp. Oxford: Berg Publishers, 1991. £24.50.

This book is an extension and revision of the research programme initiated by Sadock (I985) (for introductions to the theory see Spencer, I99I: 435-44I; Carstairs-McCarthy, 1992: I48-I5I). The central concern of autolexical syntax is mismatches between structural descriptions at different levels of linguistic representation. Sadock argues that we must often provide two (or more) structures for a single expression, and that the linearprecedence and immediate-domination relations of each structure may be different. This, of course, is not new: it characterizes the transformation of a D-structure into an S-structure in classical transformational grammar. However, Sadock argues that the two structures must be represented simultaneously, without appear to the temporal, procedural metaphor implicit in a derivational model. Moreover, many of the more puzzling structural mismatches arise at the interface between morphology and syntax. Therefore, Sadock posits a separate morphological 'module', whose representations can be accessed simultaneously with representations from syntax and semantics (and, presumably, phonology). This defines a nonhierarchical organization, hence, a different type of theory from that in which morphological rules apply only after syntactic rules have applied (that is, in which morphology is a 'component' in the sense of Grimshaw, I986). He stresses that a module in this sense is different from the notion of module in Government-Binding (GB) syntax. For him, each of the modules, morphology, syntax, semantics, is an 'autonomous grammar' (io), not a set of principles which can apply at several or all levels of representation (such as GB's Binding theory). There are two types of construction which abound in the world's languages and which engender structural mismatches: these are cliticization and incorporation, and they form a dual focal point for autolexical syntax.

Current Morphology@@@Morphology (2nd Edn.)@@@Morphological Theory

The article examines vowel alternations in Slavic languages on the basis of Polish CVC - CC alternations mostly involving the vowel 'e'. It links the phenomenon to prosodic structures of Slavic languages and tries to resolve the issue by employing a concept of lexical syllabicity within the frameworks of post-generative and government phonologies.

There is a widespread assumption within the Government–Binding theory as it has developed from the Barriers model (Chomsky 1986) that functional categories, that is, categories which play a role in establishing dependencies between parts of a sentence, as opposed to lexical categories, should be represented as heads projecting X-bar phrases. I shall refer to this as the Full Functional Projection Hypothesis (FFPH), stated informally in (1). (i) Full Functional Projection Hypothesis Any morphophonosyntactic formative which corresponds to a functional category in a given language is syntactically the head of a maximal projection.

Gazdar, G. (1979). Pragmatics: implicalure, presupposition, and logical form. New York: Academic Press. Givon, T. (ed.) (1983). Topic continuity in discourse: a quantitative cross-language study. Amsterdam & Philadelphia: John Benjamins. Givon, T. (1984). Syntax: a functional typological introduction, vol. 1. Amsterdam: John Benjamins. Green, G. (1988). Pragmatics and natural language understanding. Hillsdale, NJ: Lawrence Erlbaum. Haiman, J. (1985). Natural syntax. Cambridge: Cambridge University Press. Haiman, J. (ed.) (1985). Iconicity in syntax. Amsterdam & Philadelphia: John Benjamins. Hawkins, J. A. (1978). Definiteness and indefiniteness. London: Croom Helm. Leech, G. N. (1983). Principles of pragmatics. London & New York: Longman. Levinson, S. C. (1983). Pragmatics. Cambridge: Cambridge University Press. Loftus, E. (1979). Eyewitness testimony. Cambridge MA: Harvard University Press. Lyons, J. (1977). Semantics (2 vols). Cambridge: Cambridge University Press. Prince, E. (1981). Toward a taxonomy of given-new information. In Cole, P. (ed.), Radical Pragmatics. New York: Academic Press. 233-256. Rumelhart, D. E. & McClelland, J. L. (eds) (1986). Parallel distributed processing. Explorations in the microstructures of cognition (2 vols): Foundations. Cambridge MA: MIT Press. Schank, R. (1982). Dynamic memory: a theory of reminding and learning in computers and people. Cambridge: Cambridge University Press. Sperber, D. & Wilson, D. (1986). Relevance: communication and cognition. Oxford: Basil Blackwell.

Jolanta Szpyra, The phonology-morphology interface. Cycles, levels and words. (Croom Helm Linguistics Series.) London & New York: Routledge, 1989. Pp. xiii + 270.

Preface. Abbreviations. Part I: Preliminaries. 1. The Domain of Morphology. Word Structure. Morphemes, Morphs and Allomorphy. Types of Morphological Operation:. Inflection and Derivation. Morphemes: Things or Rules?. Morphological Formatives: Morphemes as Things. Morphological Formatives: Morphemes as Rules. Summary. Functions of Morphology -- Morphosyntax. Summary. 2. Basic Concepts and Pre--Generative Approaches. Introduction. Morphological Typology. Morphemes, Words and The Lexicon:. Morphemes and Allomorphy. The Nature of Words. The Lexicon. Structuralist Theories. The Three Models. Morphophonemics. Summary. Exercises. 3. Early Generative Approaches. Phonology and Syntax in the Standard Theory:. The Standard Theory in Outline. The SPE Model of Phonology. Morphosyntax in the Standard Theory. Chomskya s a Remarks on Nominalizationa : Lexicalist Grammar:. Generative Semantics and Lexical Transformations. Lexicalism. Concluding Remarks on a Remarksa . Hallea s a Prolegomenaa . Siegela s Level Ordering Hypothesis. Aronoffa s Word Formation in Generative Grammar:. The Model in Outline. The Form and Function of WFRs. Justifying the Model. The a Classicala Model of Generative Morphology: Conclusions. Exercises. Part II: The Morphology--Phonology Interface. 4. Approaches to Allomorphy. Introduction. The SPE Model. Natural Generative Phonology. Lexical Phonology:. Kiparskya s Alternation Condition. Cyclic Phonology and Lexical Phonology. Lexical Phonology: Summary. Morpholexical Phonology. Allomophy in Natural Morphology. Zwigya s Shape Conditions. Summary. Exercises. 5. Nonlinear Approaches to Morphology. Introduction. The Autosegmental Approach to Morphology:. McCarthya s Theory. Some Theoretical Consequences of McCarthya s Approach. Reduplication. Further Applications of Nonconcantenative Morphology:. Alternations Affecting Melody Elements. Alternations Affecting the CV Skeleton. Tones as Morphemes. Prospect. Summary. Exercises. Part III: The Morphology--Syntax Interface. 6. Later Generative Theories. Introduction. Basic Issues:. Problems with Level Ordering. Constituent Structure in Morphology. Argument Structure. The Nature of Inflection. The Constituent Structure of Words:. Psg Approaches. Liebera s a Organization of the Lexicona . Syntactic Affixation. Template Morphology. Approaches to Inflection:. Basic Issues. Andersona s a Extended Word--and--Paradigma Theory. Paradigms as Systems. Paradigm Economy. Summary. Exercises. 7. Grammatical Relations. Introduction. Overview of the Phenomena. Theoretical Preliminaries:. Representing Grammatical Relations. Transformational Theories of Passive. The Unaccusative Hypothesis. Matantza s Theory:. Introduction. Affix--Mediated Alternations. Morphological Merger: Causatives. Morphological Merger: Applied Verbs. Bakera s Incorporation Theory:. The Basic Principles. PF Identification. Causatives. Applicatives (Applied Verbs). Passives and Antipassives. Conclusions. Lexical Approaches to Valency Alternations:. Valency Alternations in the Llexicon. Williamsa s Theory. Excursus on Adjectival Passives (Levin and Rappaport). Conclusions: Syntactic and Lexical Approaches. Exercises. 8. Compounds. Introduction. Overview of Compound Types:. Basic Concepts. Compounding in Turkish. Root Compounds. English Synthetic Compounds:. Introduction. Roeper and Siegel (1978). Selkirk (1982). Lieber (1983). Di Sciullo and Williams (1987). Syntactic Approaches. Fabb (1984). Sproat (1985a). Roeper (1988). Postscript on Inheritance. Roeper (1987). Semantically Based Accounts of Inheritance. Summary and Conclusions. Exercises. 9. Clitics. Introduction. Four Case Studies:. Serbo--Croat. Macedonian. Portuguese. Polish. Resume. Definitions of Clitics. Cliticization and Agreement. Summary and Conclusions. Exercises. Part IV: The Word in Generative Grammar. 10. Bracketing Paradoxes. Introduction: The Phenomena. Bracketing Paradoxes in Lexical Phonology. A Prosodic Approach (Aronoff and Sridhar). Williamsa s Theory of a Lexical Relatednessa . Pesetskya s a Morphological QRa . Sproata s Mapping Principle. Bracketing Paradoxes and Paradigmatic Word Formation. Appendix: Sproata s Formalism. Exercises. 11. The Place of Morphology. Introduction. Di Sciullo and Williamsa s Definition of Worda . The Separation Hypothesis. Zwickya s a Interface Programa . Autolexical Syntax. Post--Syntactic Compounding in Japanese. Parallel Morphology. Conclusions. Notes. References. Subject Index. Name Index. Language Index.

Morphological Theory: An Introduction to Word Structure in Generative Grammar

9. A Linguist's Reflections on ‘Phonological Awareness’and Literacy

Lieber (1980) provided a theory of the organization of the lexicon which has been extremely influential within current theories of morphology. However, one of her central suggestions, concerning the nature of phonological rules in the lexicon, has been largely ignored. Lieber (1980, 1982) considers allomorphic variation induced by relationships which are not true phonological rules, in that they refer to lexical or morphosyntactic features but which none the less seem to be statable in phonological terms. These constitute the bulk of morphologically conditioned alternations, particularly those which have the prime function of signalling morphological relationships. Such rules have been dubbed ‘morpholexical’ rules in the structuralist literature, and Lieber adopts this term, giving it a specialist technical interpretation within the Lexicalist theory she develops.

In so-called 'Bracketing Paradoxes', it seems to be necessary to assign two incompatible constituent structures to a single expression. The paper outlines empirical and conceptual difficulties with three main current approaches and discusses in detail the problem of 'paradoxical' expressions relating to people, such as transformational grammarian, theoretical linguist, serial composer, and Southern Dane. It is shown that such expressions can be formed productively by means of a process of analogical backformation defined strictly over existing entries in the permanent lexicon, a novel type of productive word formation process.*

This paper expands on Lieber's (1980) claim that certain instances of allomorphy must be determined before word-formation processes apply. Her notion of 'morpholexical rule' is reinterpreted as a structure-building lexical-redundancy rule. Such rules are triggered by morpholexical or morphosyntactic features assigned to lexical entries. The morpholexical rules specify phonological structure which is predictable, either from general principles or from morpholexical class membership. It is argued that in certain cases the lexical representations so constructed resemble the structures of nonconcatenative morphologies, in that they are multiplanar, with separate tiers corresponding to different morphosyntactic or morphophonological categories. Linguistic and psycholinguistic evidence is presented in support of these claims.

This book is a collection of 18 papers, all but one (McCarthy's) the result of a Workshop organized in Holland by the editors with Anneke Neijt in 1983. The blurb stresses that the papers were actually written up in 1984, the implication being that the volume will not be too dated. The book inevitably invites comparison with van der Hulst and Smith (1982 a, b). Overall subject matter is very similar, and there is a clear and helpful update by the editors of their earlier overview. Also included are short summaries of each of the papers. (Unfortunately, the central claim of McCarthy's paper on Speech Disguise in Amharic is reversed in the summary (51): what McCarthy shows is that the (consonantal part of the) phonemic melody is unchanged in the language game while the CV tier is altered.) But in some respects this book suffers from the comparison. Unlike its predecessors, which were heavily dominated by American contributions (mostly from very well established figures in the field), 'Advances' only includes three authors working in the USA, and of the 22 contributors no less than 17 were working in Holland at the time of publication. Moreover, contributions to The structure of phonological representations were invited by the editors while the present volume is, in effect, published conference proceedings. We are presented, then, with a comparatively parochial collection of papers which on the whole deal with individual research problems rather than presenting global theoretical statements. While this has the advantage of broadcasting to an international audience some of the extremely vigorous and interesting research being conducted in Holland (a number of the papers seem to be revisions of papers originally published in Dutch), it does mean that many of the contributions are of specialist interest and will not be useful to the reader wishing simply to keep abreast of general trends in phonological theory. Rather than discuss each paper, or even a selection of them, I shall try to point out some of the recurrent themes tackled by the contributors. The book falls into three sections headed' Stress and accent',' Prosodic categories', and 'Autosegmental phonology'. Conspicuously absent are papers on tone. Inevitably, the categories are somewhat arbitrary. Gussenhoven's paper, for instance, comes in the first section, though it is actually about intonation and is an overview of his influential autosegmental theory. Several of the papers are primarily about syllables and syllabification. Current theories of word stress seem to divide into three broad camps: metrical tree theorists, metrical grid theorists, and trees-cum-grid theorists. None of the papers in this section adopts a grid-only stance. Interestingly, two papers (van Zonneveld & Hoeksema) suggest that the old SPE numbering notation may be sufficient. Hoeksema's paper is especially interesting because he attempts a properly formal characterization of stress theory, and

H. van der Hulst and N. Smith (eds), Advances in nonlinear phonology . Dordrecht: Foris Publications, 1984. Pp. 396.

This is a collection of eleven well-selected, well-written, carefully thought-out papers all concerned with the relationship between phonology and morphology. Six are by Polish scholars, five of them on Polish data. Some of the eleven tackle specific descriptive problems; others raise more general questions about grammatical theory. Geert Booij discusses the way phonological rules can appeal to prosodic domains, thus eliminating the potential for spurious use of boundary symbols in rules, and solving the problem sandhi rules pose in the Natural Generative Phonology framework, Steven Strauss argues for a root-formation component distinct from a word-formation component in NOT being sensitive to prosodic (e.g. syllable or foot) structure. Edmund Gussmann shows that even an apparently 'low-level' rule of vowel lengthening in Icelandic is morphologically conditioned. He appeals to a rule changing a • boundary to a + boundary, which I presume Booij would disapprove of. Wolfgang Dressier compares the (essentially phonological) allomorphy of Austrian dialect definite articles with the morphologically denned allomorphy of Italian definite articles. Kristjan Arnason argues that Icelandic U-umlaut is a morphological, not phonological process. Theo Venneman returns to Siever's Law in Gothic, which he claims is an example of a morphological change (levelling) contingent on earlier phonological change. The five papers on Polish data are all written broadly within a Cyclic Phonology framework (cf. now Rubach, 1984). Bogdan Szymanek raises interesting questions around intermorphemic extensions (e.g. the -uof'aspectual') suggesting they are introduced after word formation rules but before phonology. Elzbieta Gorska provides a very careful analysis of the palatalizations induced by the suffix -arnia in Polish, finally plumping for what looks exactly like one of Szymanek's extension rules. Neither author refers to the other, however. Anna MalickaKleparska has an interesting discussion of the way the distinction between the permanent lexicon and the conditional lexicon can shed light on a vexatious problem of Polish diminutive allomorphy. Jerzy Rubach uses Polish imperatives to illustrate the use of Aronoffs (1976) Allomorphy Rules, in a slightly more detailed version of Rubach (1984: 85 ff.). Barbara Nykiel-Herbert tackles another vexed problem: vowel-zero alternations in Polish prefixed forms. She wavers between an exception feature analysis and a constituent structure solution. (Rubach (1984: 187) accounts for these alternations in terms of last cyclic prefixation.)

Edmund Gussmann (ed.), Phono-morphology. Studies in the interaction of phonology and morphology . Lublin: Redakcja Widawnictw Katolickiego Uniwersytetu Lubelskiego, 1985. Pp. 231.

Gussmann (1980) has presented an analysis of Polish morphophonemics within the framework of SPE (Chomsky & Halle, 1968). His treatment appeals extensively to underlying representations containing segments which never appear in surface representations. He justifies this use of absolute neutralization with the claim that other rules of Polish phonology appeal to such underlying forms. Rubach (1984) has reanalysed much of Gussmann's description within the framework of Kiparsky's (1982) Lexical Phonology, retaining the analysis of the neutralized segments and even adding to the inventory of abstract elements. The arguments presented by both scholars are a paradigm of elegance and ingenuity, representing generative phonological analysis at its best. However, the considerable reliance they put on abstract underlying representations, morphologically conditioned rules, extrinsic rule ordering and other devices which give rise to a high degree of opacity arouses suspicion. For this reason I have sought to re-examine some of their material within a more ‘concrete’ interpretation of Lexical Phonology, making use of recent ideas from theories of non-linear phonology and theories of allomorphy.

ABSTRACT The feature [lateral] has a very limited morphophonemic or classificatory role which makes its presence in the universal phonetic feature inventory questionable. A mode of elimination is suggested which involves (i) treating all laterals as [+ distributed]; (ii) limiting [distributed] as a distinctive feature to continuants; (iii) redefining [anterior] in terms of [labial], [apical] and [dental]; (iv) analysing approximant rhotics as glides (Kahn, 1976); (v) adopting Halle and Stevens' re-analysis of [coronal]. This also provides a natural characterization of retroflex sounds and of sibilants. A conceptual problem in child phonology is discussed in the light of the above proposals.

This book is about the way that nouns can serve as attributive modifiers to other nouns. Many languages have productive morphology which turns nouns into adjectives, i.e. words whose canonical grammatical function is to act as an attributive modifier to a nominal head. In some cases the denominal adjective retains a number of nominal properties, so that it may even take noun-oriented modifiers and specifiers, while still itself serving as an attributive modifier. →e will call these elements ‘noun–adjective hybrids’. Noun–adjective hybrids constitute a type of ‘mixed category’. In such cases the adjectival affix seems to attach to an already modified noun, thus giving rise to the appearance of an adjective being formed on a whole syntactic phrase. It is rather difficult to determine what the lexical category of such adjectives is, if syntactic distribution is the only diagnostic criterion, and the literature contains rather little discussion of how syntax of these constructions is to be represented (Spencer, 2013, 4). The well-known phenomenon of Suffixaufnahme (see Plank (1995b) for an introduction to this notion) is also often an instance of categorial mixing. The prototypical example of Suffixaufnahme is found when a dependent noun inflected for, say, genitive case acquires the case marking of its head, yielding structures of the form father-GEN-INSTR spear-INSTR ‘with father’s spear’. In these structures, genitive case-marked nouns agree with the head in case. As case-marked elements such words are nouns, but as agreeing modifiers they are adjectives. ↑arious other kinds of mismatch can occur in the nominal phrase, and their examination raises a number of general questions about the nature of word classes. The first goal of this book is to bring together cross-linguistic evidence for categorial mixing in adnominal modifiers and to discuss the variety of intermediate types, concentrating specifically on how certain classes of denominal adjective (DNA) and adjective-like forms are related to their base noun, to nouns generally, and to the canonical adjective class.

Un procede et un dispositif destines a regler la balance des blancs sont decrits aux presentes. Le procede peut comprendre la generation (202) de donnees representant une image avec et sans l'utilisation d'un flash stroboscopique (114). La contribution du flash stroboscopique (114) et la contribution de la lumiere ambiante sur les donnees sont calculees (214, 216). Sur la base, en partie, des contributions de la lumiere ambiante et du flash stroboscopique (114), une ponderation est calculee (222). La ponderation est appliquee aux donnees afin de regler la balance des blancs (224).

Herein is a method and an apparatus for adjusting a white balance are disclosed. The method may comprise generating data representing an image, with and without the use of a strobe. The contribution of the strobe and the contribution of ambient light to the data are calculated. Based in part on the contributions of the ambient light and strobe weighting is calculated. The weighting is applied to the data to adjust the white balance.

Elektronische Kamera, die folgende Merkmale aufweist: eine Batterie (112); ein eingebettetes Bildverarbeitungssystem (104), das mit der Batterie (112) gekoppelt ist, um Leistung von derselben zu empfangen; einen entfernbaren nichtfluchtigen Speicher (108), der mit dem eingebetteten Bildverarbeitungssystem (104) gekoppelt ist, zum Speichern von Bildern; wobei das Bildverarbeitungssystem (104) eine Firmware zum Durchfuhren einer anfanglichen Komprimierung (206) und zum Durchfuhren einer fortgeschrittenen Verarbeitung (218, 230) von Bildern aufweist; wobei das Bildverarbeitungssystem (104) eine Firmware zum Sichern von anfanglich komprimierten (206) und einer fortgeschrittenen Verarbeitung (218, 230) unterzogenen Bildern in dem nichtfluchtigen Speicher (108) aufweist; und wobei die Kamera eine Firmware zum Schatzen einer Zeit bis zu einem Sichern von Bildern in dem entfernbaren nichtfluchtigen Speicher (108) und zum Anzeigen, an einen Benutzer, das die Kamera beginnt, in den entfernbaren nichtfluchtigen Speicher (108) zu schreiben, aufweist.

To delay user interface for digital camera having a non-volatile memory for storing intermediate data for advanced processing and is able to slow down during advanced processing conditions of a depleting battery and / or suspend

This article describes an approach to fast image generation that uses a high-speed serial scan converter, a somewhat slower frame buffer, and a pixel cache to match the bandwidth between the two. Cache hit rates are improved by configuring the cache to buffer either 4 × 4 or 16 × 1 tiles of frame memory, depending on the type of operation being performed. For line drawing, the implenmention discribed can process 300,000 30-pixel vectors per second. For shaded polygons, the system can fill 16,000 900-pixel polygons per second. In addition to buffering pixel intensity data, the pixel cache also buffer z (depth) values, improving the performance of the z-buffer hidden-surface algorithm. By utilizing z-value caching, the system can process 5800 900-pixel shaded polygons per second with hidden-surface removed.

Tree coding of speech has been investigated by several workers. Virtually all of these investigations have involved incremental tree coding in that no matter how deep the tree is searched, only a single path map symbol is released at a time. As noted by Gray, even if a good long-term fit is found, the first step in the fit may be a poor one, thus yielding large sample distortions. Hence, it is important to stay on a path long enough to achieve the promised long-term distortion value. The relative frequency of path switching for the single symbol release rule is investigated for the (M,L) and truncated Viterbi tree search algorithms, various search depths, and different code generators. In addition, two multiple symbol release rules are investigated. One rule releases a fixed number of path symbols at a time, while the other rule releases a variable number of path symbols, the exact number depending on how many symbols are required for the average sample distortion to be less than or equal to the L -depth path average distortion. Speech sources are considered exclusively.

Complex systems are simulated by engineers without extensive computer experience. Analyst uses free-form engineering-oriented language to input "black box" description. System Time Domain (SYSTID) Simulation Program generates appropriate algorithms and proceeds with simulation. Program is easily linked to postprocessing routines. SYSTID program is written in FORTRAN IV for batch execution and has been implemented on UNIVAC 1110 under control of EXEC 8, Level 31.

Optimal estimation algorithms for the identification of the predictor coefficients for both undistorted and distorted speech are developed by first specifying appropriate state space message and observation models. Those portions of the models and the algorithms which impede their utility are discussed. A technique for identifying the predictor coefficient vector single-stage state transition matrix is derived, and experimental results using speech data are presented.

Tree coding of speech using variable length symbol release techniques

Recurrent neural networks (RNNs) based on model neurons that communicate via continuous signals have been widely used to study how cortical neurons perform cognitive tasks. Training such networks to perform tasks that require information maintenance over a brief period (i.e., working memory tasks) remains a challenge. Critically, the training process becomes difficult when the synaptic decay time constant is not fixed to a large constant number for all the model neurons. Here, we show that introducing random noise to the RNNs not only speeds up the training but also produces stable models that can maintain information longer than the RNNs trained without internal noise. Importantly, this robust working memory performance induced by internal noise during training is attributed to an increase in synaptic decay time constants of a distinct subset of inhibitory units, resulting in slower decay of stimulus-specific activity critical for memory maintenance.

Random noise promotes slow heterogeneous synaptic dynamics important for robust working memory computation

Probing population codes and circuit dynamics of probabilistic learning

Visual inputs are often highly structured, and statistical regularities of these signals can be used to guide future visuomotor associations and thus optimize behavior. Through a recurrent neural network (RNN) model, human psychophysics, and electroencephalography (EEG), we probed the neural mechanisms for processing probabilistic structures of visual signals to guide behavior. We first constructed and trained a biophysically constrained RNN model to perform a series of probabilistic visual discrimination tasks similar to paradigms designed for humans. Specifically, the training environment was probabilistic such that one stimulus was more probable than the others. We showed that both humans and RNNs successfully learned the stimulus probability and integrated this knowledge into their decisions and task strategy in a new environment. Performance of both humans and RNNs varied with the degree to which the stimulus probability of the new environment matched the formed expectation. In both cases, this expectation effect was more prominent when the strength of sensory evidence was low, suggesting that like humans, the RNNs placed more emphasis on prior expectation (top-down signals) when the available sensory information (bottom-up signals) was limited, thereby optimizing task performance. By dissecting the trained RNNs, we demonstrated how competitive inhibition and recurrent excitation form the basis for neural circuitry optimized to perform probabilistic visual processing.

Probabilistic visual processing in humans and recurrent neural networks.

Abstract Dynamic functional brain connectivity facilitates adaptive cognition and behaviour. Abnormal alterations within such connectivity could result in disrupted functions observed across various neurological conditions. As one of the most common neurological disorders, epilepsy is defined by the seemingly random occurrence of spontaneous seizures. A central but unresolved question concerns the mechanisms by which extraordinarily diverse propagation dynamics of seizures emerge. Here, we applied a graph-theoretical approach to assess dynamic reconfigurations in the functional brain connectivity before, during and after seizures that display heterogeneous propagation patterns despite sharing similar cortical onsets. We computed time-varying functional brain connectivity networks from human intracranial recordings of 67 seizures (across 14 patients) that had a focal origin—49 of these focal seizures remained focal and 18 underwent a bilateral spread (focal to bilateral tonic-clonic seizures). We utilized functional connectivity networks estimated from interictal periods across patients as control. Our results characterize network features that quantify the underlying functional dynamics associated with the observed heterogeneity of seizure propagation across these two types of focal seizures. Decoding these network features demonstrate that bilateral propagation of seizure activity is an outcome of the imbalance of global integration and segregation in the brain prior to seizure onset. We show that there exist intrinsic network signatures preceding seizure onset that are associated with the extent to which an impending seizure will propagate throughout the brain (i.e. staying within one hemisphere versus spreading transcallosally). Additionally, these features characterize an increase in segregation and a decrease in excitability within the brain network (i.e. high modularity and low spectral radius). Importantly, seizure-type-specific differences in these features emerge several minutes prior to seizure onset, suggesting the potential utility of such measures in intervention strategies. Finally, our results reveal network characteristics after the onset that are unique to the propagation mechanisms of two most common focal seizure subtypes, indicative of distinct reconfiguration processes that may assist termination of each seizure type. Together, our findings provide insights into the relationship between the temporal evolution of seizure activity and the underlying functional connectivity dynamics. These results offer exciting avenues where graph-theoretical measures could potentially guide personalized clinical interventions for epilepsy and other neurological disorders in which extensive heterogeneity is observed across subtypes as well as across and within individual patients.

Brain network dynamics codify heterogeneity in seizure evolution

Recurrent neural networks (RNNs) based on model neurons that communicate via continuous signals have been widely used to study how cortical neurons perform cognitive tasks. Training such networks to perform tasks that require information maintenance over a brief period (i.e., working memory tasks) remains a challenge. Critically, the training process becomes difficult when the synaptic decay time constant is not fixed to a large constant number for all the model neurons. We hypothesize that the brain utilizes intrinsic cortical noise to generate a reservoir of heterogeneous synaptic decay time constants optimal for maintaining information. Here, we show that introducing random, internal noise to the RNNs not only speeds up the training but also produces stable models that can maintain information longer than the RNNs trained without internal noise. Importantly, this robust working memory performance induced by incorporation of internal noise during training is attributed to an increase in synaptic decay time constants of a sub-population of inhibitory units.

Internal noise promotes heterogeneous synaptic dynamics important for working memory in recurrent neural networks

Since their development, social media has grown as a source of information and has a significant impact on opinion formation. Individuals interact with others and content via social media platforms in a variety of ways but it remains unclear how decision making and associated neural processes are impacted by the online sharing of informational content, from factual to fabricated. Here, we use EEG to estimate dynamic reconfigurations of brain networks and probe the neural changes underlying opinion change (or formation) within individuals interacting with a simulated social media platform. Our findings indicate that the individuals who changed their opinions are characterized by less frequent network reconfigurations while those who did not change their opinions tend to have more flexible brain networks with frequent reconfigurations. The nature of these frequent network configurations suggests a fundamentally different thought process between intervals in which individuals are easily influenced by social media and those in which they are not. We also show that these reconfigurations are distinct to the brain dynamics during an in-person discussion with strangers on the same content. Together, these findings suggest that brain network reconfigurations may not only be diagnostic to the informational context but also the underlying opinion formation. Author Summary Distinctive neural underpinnings of opinion formation and change during in-person and online social interactions are not well understood. Here, we analyze EEG recordings of the participants interacting with a simulated social media platform and during an in-person discussion using a network-based analysis approach. We show that the structure of network reconfigurations during these interactions is diagnostic of the opinion change and the context in which information was received.

Intermittent brain network reconfigurations and the resistance to social media influence

Brain activity is a highly nonlinear phenomenon, and as such, dynamical relationships between neurons and expressed behaviors have been described on low dimensional attractor manifolds mostly through dimensionality reduction techniques. These range from simple principal component analysis to sophisticated sequential recurrent variational autoencoders such as LFADS. These low dimensional representations i.e. the principal components of PCA or factors of a variational autoencoder, are a dimensionally reduced representation of the original high dimensional activity of thousands of observed neurons. Although these low dimensional manifolds offer unifying views of global brain activity the principal components of PCA reduced or factors of variational autoencoders are not experimentally tractable. For example with PCA, it is not possible to experimentally manipulate the factional amount of the activity of a particular neuron(e.g. 0.7 of neuron1, 0.9 of neuron 2, 0.3 of neuron 3 etc. . . ) that corresponds to its projection on a principal component. Thus although these low dimensional manifolds provide appealing explanatory power, it is ultimately difficult if not impossible to address these experimentally. To solve this problem, here, we propose an algorithm grounded in dynamical systems theory that generalizes manifold learning from a global state representation, to a network of local interacting manifolds – termed a Generative Manifold Network (GMN). Manifolds are discovered using the convergent cross mapping (CCM) causal inference algorithm which are then compressed into a reduced redundancy network. The representation is a network of manifolds embedded from observational data where each orthogonal axis of a local manifold is an embedding of a individually identifiable neuron or brain area that has exact correspondence in the real world. As such these can be experimentally manipulated to test hypotheses derived from theory and data analysis. Here we demonstrate that this representation preserves the essential features of the brain of a fly. In addition to accurate nearterm prediction, the GMN model can be used to synthesize realistic time series of whole brain neuronal activity and locomotion viewed over the long term. Thus, as a final validation of how well GMN captures essential dynamic information, we show that the artificially generated time series can be used as a training set to predict out-of-sample observed fly locomotion, as well as brain activity in out of sample withheld data not used in model building. Remarkably, the artificially generated time series show realistic novel behaviors that do not exist in the training data, but that do exist in the out-of-sample observational data. This suggests that GMN captures inherently emergent properties of the network. We suggest our approach may be a generic recipe for mapping time series observations of any complex nonlinear network into a model that is able to generate naturalistic system behaviors that identifies variables that have real world correspondence and can be experimentally manipulated.

Experimentally testable whole brain manifolds that recapitulate behavior

Dynamic functional brain connectivity facilitates adaptive cognition and behavior. Abnormal alterations within such connectivity could result in disrupted functions observed across various neurological conditions. As one of the most common neurological disorders, epilepsy is defined by the seemingly random occurrence of spontaneous seizures. A central but unresolved question concerns the mechanisms by which extraordinarily diverse dynamics of seizures emerge. Here, we apply a graph-theoretical approach to assess dynamic reconfigurations in the functional brain connectivity before, during, and after seizures that display heterogeneous propagation patterns despite sharing similar origins. We demonstrate unique reconfigurations in globally-defined network properties preceding seizure onset that predict propagation patterns of impending seizures, and in locally-defined network properties that differentiate post-onset dynamics. These results characterize quantitative network features underlying the heterogeneity of seizure dynamics and the accompanying clinical manifestations. Decoding these network properties could improve personalized preventative treatment strategies for epilepsy as well as other neurological disorders.

Brain network dynamics codify heterogeneity in seizure propagation

Understanding Motor Abnormalities in Psychiatric Disorders as Altered Sensorimotor Processing

Author(s): Rungratsameetaweemana, Nuttida | Advisor(s): Serences, John T | Abstract: Our visual world is full of ambiguous sensory signals, from which we have to extract relevant and meaningful information in order to guide optimal actions. To maximize the efficiency of this process, our visual system relies on foreknowledge to prioritize the processing of relevant or expected features. Knowledge of statistical regularities in the environment can lead to faster detection and recognition of objects when they are encountered in an expected context (e.g., a bird in a backyard) than when they are encountered in unlikely context (e.g., a bird in a washing machine). In addition, knowledge about the current task goals can also support faster and more accurate processing of relevant over irrelevant items--a mechanism referred to as selective attention. In what manner do these “top down” modulatory factors individually and jointly affect visual sensory processing, decision making, and behavior? In three studies, we examined how perceptual decision making is modulated by prior expectation about stimulus probabilities alone and in the context where knowledge about the current behavioral goals were available. We examined these effects both neurally via electroencephalography (EEG) and behaviorally through psychophysics and also in amnesic patients in relation to age-matched controls. To this end, we first devised an experimental paradigm where prior expectation and selective attention could be individually manipulated. The behavioral readouts from this paradigm were continuous which made it possible for the temporal evolution of the effects of expectation and attention on decision process to be probed both behaviorally and in relation to the continuous neural (EEG) measures. We first demonstrated that prior expectation improves decision processes by primarily affecting post-perceptual operations such as initiation and execution of motor responses, instead of directly improving the efficiency of early sensory processing. This finding confirms an idea that has been put forth by traditional theoretical framework that prior expectation affects decision making by preferentially modulating motor responses that correspond to sensory inputs with high probability of occurring. Further, we showed that while both expectation and attention improved behavior, the underlying neural mechanisms that give rise to these effects differed: while attention operates on the early processing of sensory inputs, expectation affects the late stage of decision making by biasing motor responses towards the most likely decision choice. These differential temporal dynamics of expectation and attention were observed bot h behaviorally and neurally. Finally, we demonstrated that an ability to utilize knowledge about current task goals and to form expectation based on statistical regularities of the sensory environment can be independent of a declarative memory system.

Neural dynamics of probabilistic perceptual decision making in the human brain

A chimera state is a spatiotemporal pattern of broken symmetry, where synchrony (coherent state) and asynchrony (incoherent state) coexist. Here, we report chimera states in electrocorticography recordings preceding, by several hours, each of seven seizures in one patient with epilepsy. Before the seizures, the onset channels are not synchronized, while the remaining channels are synchronized. During the seizures, this pattern of behavior flips and the nononset channels show a more asynchronous behavior. At a seizure offset, synchrony can be observed that might facilitate termination.

Significance The hippocampus is important for many kinds of learning and memory. We explored the role of the hippocampus in the learning of statistical regularities. We administered a motion discrimination task where expectation about stimulus regularities, the degree of attention afforded to the relevant stimulus, and the amount of available sensory information were manipulated. Although modestly slower overall, patients with bilateral damage to the hippocampus performed similar to controls, exhibiting a normal tendency to respond faster and more accurately when the motion direction was more probable, when the stimulus was better attended, and when more sensory evidence was present. These findings show that the ability to acquire expectations based on regularities of a sensory environment can be independent of the hippocampus. Prior knowledge about the probabilistic structure of visual environments is necessary to resolve ambiguous information about objects in the world. Expectations based on stimulus regularities exert a powerful influence on human perception and decision making by improving the efficiency of information processing. Another type of prior knowledge, termed top-down attention, can also improve perceptual performance by facilitating the selective processing of relevant over irrelevant information. While much is known about attention, the mechanisms that support expectations about statistical regularities are not well-understood. The hippocampus has been implicated as a key structure involved in or perhaps necessary for the learning of statistical regularities, consistent with its role in various kinds of learning and memory. Here, we tested this hypothesis using a motion discrimination task in which we manipulated the most likely direction of motion, the degree of attention afforded to the relevant stimulus, and the amount of available sensory evidence. We tested memory-impaired patients with bilateral damage to the hippocampus and compared their performance with controls. Despite a modest slowing in response initiation across all task conditions, patients performed similar to controls. Like controls, patients exhibited a tendency to respond faster and more accurately when the motion direction was more probable, the stimulus was better attended, and more sensory evidence was available. Together, these findings demonstrate a robust, hippocampus-independent capacity for learning statistical regularities in the sensory environment in order to improve information processing.

Preserved capacity for learning statistical regularities and directing selective attention after hippocampal lesions

Dissociating the impact of attention and expectation on early sensory processing.

The hippocampus has long been recognized as important for the formation of long-term memory. Recent work has suggested that the hippocampus might also be important for certain kinds of spatial operations, as in constructing scenes, shifting perspective, or perceiving the geometry of scenes and their boundaries. We explored this proposal using a task similar to one used previously that related hippocampal activity to scenes and their boundaries. In our study, participants viewed scenes from above that displayed walls and towers. After viewing each scene, participants saw a scene from ground level and judged whether it was the same as or different from the scene just presented. The number of towers and walls in each scene was manipulated so that it was possible to assess how the structure of the scene affected performance. Patients with hippocampal lesions performed similarly to controls in all task conditions and had no special difficulty as a function of the layout of a scene and its boundaries. In contrast, a patient with large medial temporal lobe (MTL) lesions was impaired. Taken together, our findings suggest that the hippocampus is not needed for scene construction, shifts in perspective, or perceiving the geometry of scenes. The impairment associated with large MTL lesions may result from damage in or near parahippocampal cortex.

Preserved capacity for scene construction and shifts in perspective after hippocampal lesions

Two factors play important roles in shaping perception: the allocation of selective attention to behaviorally relevant sensory features, and prior expectations about regularities in the environment. Signal detection theory proposes distinct roles of attention and expectation on decision-making such that attention modulates early sensory processing, whereas expectation influences the selection and execution of motor responses. Challenging this classic framework, recent studies suggest that expectations about sensory regularities enhance the encoding and accumulation of sensory evidence during decision-making. However, it is possible, that these findings reflect well documented attentional modulations in visual cortex. Here, we tested this framework in a group of male and female human participants by examining how expectations about stimulus features (orientation and color) and expectations about motor responses impacted electroencephalography (EEG) markers of early sensory processing and the accumulation of sensory evidence during decision-making (the early visual negative potential and the centro-parietal positive potential, respectively). We first demonstrate that these markers are sensitive to changes in the amount of sensory evidence in the display. Then we show, counter to recent findings, that neither marker is modulated by either feature or motor expectations, despite a robust effect of expectations on behavior. Instead, violating expectations about likely sensory features and motor responses impacts posterior alpha and frontal theta oscillations, signals thought to index overall processing time and cognitive conflict. These findings are inconsistent with recent theoretical accounts and suggest instead that expectations primarily influence decisions by modulating post-perceptual stages of information processing. SIGNIFICANCE STATEMENT Expectations about likely features or motor responses play an important role in shaping behavior. Classic theoretical frameworks posit that expectations modulate decision-making by biasing late stages of decision-making including the selection and execution of motor responses. In contrast, recent accounts suggest that expectations also modulate decisions by improving the quality of early sensory processing. However, these effects could instead reflect the influence of selective attention. Here we examine the effect of expectations about sensory features and motor responses on a set of electroencephalography (EEG) markers that index early sensory processing and later post-perceptual processing. Counter to recent empirical results, expectations have little effect on early sensory processing but instead modulate EEG markers of time-on-task and cognitive conflict.

Expectations Do Not Alter Early Sensory Processing during Perceptual Decision-Making

Decisions made about identical perceptual stimuli can be radically different under changing task demands. For example, the need to make a fast decision undermines the accuracy of that decision, a well-documented effect termed the speed-accuracy tradeoff (SAT). Models of the SAT are generally based on theories of decision making in which responses are triggered only after sensory evidence accumulation terminates at a set threshold. Within this accumulate-to-bound framework, speed pressure operates by lowering the response threshold, allowing for faster responses at the expense of accumulated sensory evidence. To empirically examine the mechanisms necessary for adaptively adjusting the speed and accuracy of decisions, we used an event-related potential that indexes sensory evidence accumulation in the human brain. Instead of lowering response thresholds, we found that speed pressure adaptively shifts responses to occur close to where the rate of evidence accumulation peaks. Moreover, responses are not triggered automatically by the termination of the accumulation process, as sensory evidence continues to build after speeded decisions. Together these results suggest that response processes adaptively access accumulating sensory evidence depending on task demands and support parallel over serial models of decision making.

The speed-accuracy tradeoff reveals flexible access to accumulating sensory evidence during human decision making

Task-irrelevant contextual expectation impairs orientation discrimination performance

Top-down factors such as attention and expectation have been shown to modulate visual discrimination by improving the quality of sensory processing. However, few studies have investigated these factors within the same experiment to determine if they operate via similar or independent mechanisms (Kok et al., 2012; Jiang et al., 2013). To address this question, subjects viewed a display containing flickering and randomly oriented lines, half of which were blue and half of which were red. On each trial, some percentage of the lines were rendered at the same orientation, either clockwise or counterclockwise relative to the vertical meridian. We manipulated attention (behavioral relevance) by cueing subjects to monitor either the red or blue lines (focused attention) or to monitor both (divided attention). Expectation of the target-defining orientation was also manipulated by varying the ratio between target orientations presented in a given block of trials. Finally, we examined interactions between the strength of sensory evidence and attention/expectation by manipulating the number of iso-oriented lines in the target display across two levels (low and high coherence). At high coherence levels, there is no main effect of attention or expectation on accuracy, but both factors lead to faster response times (RTs). In contrast, at low coherence levels, there is a robust effect of expectation on accuracy such that expected orientations are more likely to be correctly discriminated. However, this expectation effect is primarily observed in the divided-attention condition, suggesting that focused attention dampens the effects of expectation. In addition, at low coherence levels, there is a main effect of attention on RTs but little effect of expectation. Taken together, these results suggest that the effects of attention and expectation on behavioral performance during orientation discrimination are dissociable depending on the amount of relevant sensory information available in the display. Meeting abstract presented at VSS 2015.

Dissociable effects of attention and expectation during orientation discrimination.

Over the last several decades, spatial attention has been shown to influence the activity of neurons in visual cortex in various ways. These conflicting observations have inspired competing models to account for the influence of attention on perception and behavior. Here, we used electroencephalography (EEG) to assess steady-state visual evoked potentials (SSVEP) in human subjects and showed that highly focused spatial attention primarily enhanced neural responses to high-contrast stimuli (response gain), whereas distributed attention primarily enhanced responses to medium-contrast stimuli (contrast gain). Together, these data suggest that different patterns of neural modulation do not reflect fundamentally different neural mechanisms, but instead reflect changes in the spatial extent of attention.

Changing the Spatial Scope of Attention Alters Patterns of Neural Gain in Human Cortex

12 In liquid state machines with generic cortical microcircuits, synaptic plasticity 13 can be optimized by reward-modulated Hebbian learning, eliminating the need 14 for supervised learning (Hoerzer, Legenstein, and Maass, 2014). Reward15 modulated Hebbian learning can thus lead to autonomous emergence of task16 specific working memory during the learning of computational rules. However, 17 in Hoerzer, Legenstein, and Maass (2014), reward-modulated Hebbian learning 18 was modeled with an all-or-none modulatory signal that permitted synaptic 19 weight change only above a criterion level of learning. We use liquid computing 20 models to investigate working memory emergence via Hebbian learning with 21 non-binary modulatory signals. We implement a nonbinary, but discrete 22 modulatory signal and an analog signal. In doing so, we model physiological 23 conditions of tonic and phasic output of reward-mediating systems like the 24 dopaminergic system. We find that the effects of analog modulatory signals on 25 working memory emergence improve reward-modulated Hebbian learning in 26 liquid state machines. We propose that reward-modulated Hebbian learning in 27 generic microcircuits of neurons can abstractly model general cognitive 28 processes. 29 30

Modification of a Reward-Modulated Hebbian 2 Learning Rule as a Model of Working Memory 3 Emergence 4 5 6

Alzheimer’s disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive and stereotyped accumulation of protein aggregates, but the underlying molecular and cellular mechanisms driving AD progression and vulnerable cell populations affected by disease remain coarsely understood. The current study harnesses single cell and spatial genomics tools and knowledge from the BRAIN Initiative Cell Census Network to understand the impact of disease progression on middle temporal gyrus cell types. We used image-based quantitative neuropathology to place 84 donors spanning the spectrum of AD pathology along a continuous disease pseudoprogression score and multiomic technologies to profile single nuclei from each donor, mapping their transcriptomes, epigenomes, and spatial coordinates to a common cell type reference with unprecedented resolution. Temporal analysis of cell-type proportions indicated an early reduction of Somatostatin-expressing neuronal subtypes and a late decrease of supragranular intratelencephalic-projecting excitatory and Parvalbumin-expressing neurons, with increases in disease-associated microglial and astrocytic states. We found complex gene expression differences, ranging from global to cell type-specific effects. These effects showed different temporal patterns indicating diverse cellular perturbations as a function of disease progression. A subset of donors showed a particularly severe cellular and molecular phenotype, which correlated with steeper cognitive decline. We have created a freely available public resource to explore these data and to accelerate progress in AD research at SEA-AD.org.

Single cell transcriptomic studies have identified a conserved set of neocortical cell types from small post-mortem cohorts. We extend these efforts by assessing cell type variation across 75 adult individuals undergoing epilepsy and tumor surgeries. Nearly all nuclei map to one of 125 robust cell types identified in middle temporal gyrus, but with varied abundances and gene expression signatures across donors, particularly in deep layer glutamatergic neurons. A minority of variance is explainable by known factors including donor identity and small contributions from age, sex, ancestry, and disease state. Genomic variation was significantly associated with variable expression of 150-250 genes for most cell types. Thus, human individuals display a highly consistent cellular makeup, but with significant variation reflecting donor characteristics, disease condition, and genetic regulation. One-Sentence Summary Inter-individual variation in human cortex is greatest for deep layer excitatory neurons and largely unexplainable by known factors.

Inter-individual variation in human cortical cell type abundance and expression

Variation in cortical cytoarchitecture is the basis for histology-based definition of cortical areas, such as Brodmann areas. Single cell transcriptomics enables higher-resolution characterization of cell types in human cortex, which we used to revisit the idea of the canonical cortical microcircuit and to understand functional areal specialization. Deeply sampled single nucleus RNA-sequencing of eight cortical areas spanning cortical structural variation showed highly consistent cellular makeup for 24 coarse cell subclasses. However, proportions of excitatory neuron subclasses varied strikingly, reflecting differences in intra- and extracortical connectivity across primary sensorimotor and association cortices. Astrocytes and oligodendrocytes also showed differences in laminar organization across areas. Primary visual cortex showed dramatically different organization, including major differences in the ratios of excitatory to inhibitory neurons, expansion of layer 4 excitatory neuron types and specialized inhibitory neurons. Finally, gene expression variation in conserved neuron subclasses predicts differences in synaptic function across areas. Together these results provide a refined cellular and molecular characterization of human cortical cytoarchitecture that reflects functional connectivity and predicts areal specialization.

Transcriptomic cytoarchitecture reveals principles of human neocortex organization

Multimodal assays such as Patch-seq that simultaneously profile molecular and cellular phenotypes of cells enable the identification of molecular underpinnings of electrophysiological response patterns in neurons. Here we analyzed Patch-seq measurements of thousands of mouse interneurons to identify subclass-specific genes associated with different electrophysiological features. We found extensive subclass specificity: even for the same ephys feature, largely unique sets of genes are associated with that feature in different subclasses. Well established ephys genes such as Reln demonstrated subclass specificity that was previously not reported. Surprisingly, we found that ion channels explained significantly less variation in ephys response across interneurons compared to other genes; in particular, gene sets enriched in cell adhesion genes were amongst the most associated. We found our gene sets associated with action potential dV/dt measurements explained significant heritability of Schizophrenia risk, suggesting a novel role of single neuron electrophysiology in Schizophrenia risk. Finally, we observed significant ephys function switching of cell adhesion molecules across subclasses; the same adhesion molecule was observed to associate with different functional ephys measurements in distinct subclasses and co-express with different genes, suggesting re-purposing of adhesion molecules in different subclasses. Overall, our results yield novel insight into the specificity of roles that individual genes and adhesion molecules play in both single neuron ephys response and Schizophrenia risk.

Cell adhesion molecules play subclass-specific roles in electrophysiological response and Schizophrenia risk

Multi-modal single cell RNA assays capture RNA content as well as other data modalities, such as spatial cell position or the electrophysiological properties of cells. Compared to dedicated scRNA-seq assays however, they may unintentionally capture RNA from multiple adjacent cells, exhibit lower RNA sequencing depth compared to scRNA-seq, or lack genome-wide RNA measurements. We present scProjection, a method for mapping individual multi-modal RNA measurements to deeply sequenced scRNA-seq atlases to extract cell type-specific, single cell gene expression profiles. We demonstrate several use cases of scProjection, including the identification of spatial motifs from spatial transcriptome assays, distinguishing RNA contributions from neighboring cells in both spatial and multi-modal single cell assays, and imputing expression measurements of un-measured genes from gene markers. scProjection therefore combines the advantages of both multi-modal and scRNA-seq assays to yield precise multi-modal measurements of single cells.

Projecting clumped transcriptomes onto single cell atlases to achieve single cell resolution

Human cortical interneurons have been challenging to study due to high diversity and lack of mature brain tissue platforms and genetic targeting tools. We employed rapid GABAergic neuron viral labeling plus unbiased Patch-seq sampling in brain slices to define the signature morpho-electric properties of GABAergic neurons in the human neocortex. Viral targeting greatly facilitated sampling of the SST subclass, including primate specialized double bouquet cells which mapped to two SST transcriptomic types. Multimodal analysis uncovered an SST neuron type with properties inconsistent with original subclass assignment; we instead propose reclassification into PVALB subclass. Our findings provide novel insights about functional properties of human cortical GABAergic neuron subclasses and types and highlight the essential role of multimodal annotation for refinement of emerging transcriptomic cell type taxonomies. One Sentence Summary Viral genetic labeling of GABAergic neurons in human ex vivo brain slices paired with Patch-seq recording yields an in-depth functional annotation of human cortical interneuron subclasses and types and highlights the essential role of multimodal functional annotation for refinement of emerging transcriptomic cell type taxonomies.

Signature morpho-electric properties of diverse GABAergic interneurons in the human neocortex

Conserved cell types with divergent features in human versus mouse cortex

scAlign: a tool for alignment, integration, and rare cell identification from scRNA-seq data

Complex systems are characterized by intricate interactions between entities that evolve dynamically over time. Accurate inference of these dynamic relationships is crucial for understanding and predicting system behavior. In this paper, we propose Regulatory Temporal Interaction Network Inference (RiTINI) for inferring time-varying interaction graphs in complex systems using a novel combination of space-and-time graph attentions and graph neural ordinary differential equations (ODEs). RiTINI leverages time-lapse signals on a graph prior, as well as perturbations of signals at various nodes in order to effectively capture the dynamics of the underlying system. This approach is distinct from traditional causal inference networks, which are limited to inferring acyclic and static graphs. In contrast, RiTINI can infer cyclic, directed, and time-varying graphs, providing a more comprehensive and accurate representation of complex systems. The graph attention mechanism in RiTINI allows the model to adaptively focus on the most relevant interactions in time and space, while the graph neural ODEs enable continuous-time modeling of the system's dynamics. We evaluate RiTINI's performance on various simulated and real-world datasets, demonstrating its state-of-the-art capability in inferring interaction graphs compared to previous methods.

Inferring dynamic regulatory interaction graphs from time series data with perturbations

While numerous methods have been proposed for computing distances between probability distributions in Euclidean space, relatively little attention has been given to computing such distances for distributions on graphs. However, there has been a marked increase in data that either lies on graph (such as protein interaction networks) or can be modeled as a graph (single cell data), particularly in the biomedical sciences. Thus, it becomes important to find ways to compare signals defined on such graphs. Here, we propose Graph Fourier MMD (GFMMD), a novel distance between distributions and signals on graphs. GFMMD is defined via an optimal witness function that is both smooth on the graph and maximizes difference in expectation between the pair of distributions on the graph. We find an analytical solution to this optimization problem as well as an embedding of distributions that results from this method. We also prove several properties of this method including scale invariance and applicability to disconnected graphs. We showcase it on graph benchmark datasets as well on single cell RNA-sequencing data analysis. In the latter, we use the GFMMD-based gene embeddings to find meaningful gene clusters. We also propose a novel type of score for gene selection called"gene localization score"which helps select genes for cellular state space characterization.

Although data diffusion embeddings are ubiquitous in unsupervised learning and have proven to be a viable technique for uncovering the underlying intrinsic geometry of data, diffusion embeddings are inherently limited due to their discrete nature. To this end, we propose neural FIM, a method for computing the Fisher information metric (FIM) from point cloud data - allowing for a continuous manifold model for the data. Neural FIM creates an extensible metric space from discrete point cloud data such that information from the metric can inform us of manifold characteristics such as volume and geodesics. We demonstrate Neural FIM's utility in selecting parameters for the PHATE visualization method as well as its ability to obtain information pertaining to local volume illuminating branching points and cluster centers embeddings of a toy dataset and two single-cell datasets of IPSC reprogramming and PBMCs (immune cells).

Neural FIM for learning Fisher Information Metrics from point cloud data

Diffusion-based manifold learning methods have proven useful in representation learning and dimensionality reduction of modern high dimensional, high throughput, noisy datasets. Such datasets are especially present in fields like biology and physics. While it is thought that these methods preserve underlying manifold structure of data by learning a proxy for geodesic distances, no specific theoretical links have been established. Here, we establish such a link via results in Riemannian geometry explicitly connecting heat diffusion to manifold distances. In this process, we also formulate a more general heat kernel based manifold embedding method that we call heat geodesic embeddings. This novel perspective makes clearer the choices available in manifold learning and denoising. Results show that our method outperforms existing state of the art in preserving ground truth manifold distances, and preserving cluster structure in toy datasets. We also showcase our method on single cell RNA-sequencing datasets with both continuum and cluster structure, where our method enables interpolation of withheld timepoints of data. Finally, we show that parameters of our more general method can be configured to give results similar to PHATE (a state-of-the-art diffusion based manifold learning method) as well as SNE (an attraction/repulsion neighborhood based method that forms the basis of t-SNE).

A Heat Diffusion Perspective on Geodesic Preserving Dimensionality Reduction

Cells communicate with one another through a variety of signaling mechanisms. Exchange of information via these mechanisms allows cells to coordinate their behaviour and respond to environmental stress and other stimuli. To facilitate quantitative understanding of complex spatiotemporal signaling activity, we developed Geometric Scattering Trajectory Homology, a general framework that encapsulates time-lapse signals on a cell adjacency graph in a low-dimensional trajectory. We tested this framework using computational models of collective oscillations and calcium signaling in the Drosophila wing imaginal disc, as well as experimental data, including in vitro ERK signaling in human mammary epithelial cells and in vivo calcium signaling from the mouse epidermis and visual cortex. We found that the geometry and topology of the trajectory are related to the degree of synchrony (over space and time), intensity, speed, and quasi-periodicity of the signaling pattern. We recovered model parameters and experimental conditions by training neural networks on trajectory data, showing that our approach preserves information that characterizes various cell types, tissues and drug treatments. We envisage the applicability of our framework in various biological contexts to generate new insights into cell communication.

Capturing Spatiotemporal Signaling Patterns in Cellular Data with Geometric Scattering Trajectory Homology

In this work we introduce CUTS (Contrastive and Unsupervised Training for Segmentation), the first fully unsupervised deep learning framework for medical image segmentation to better utilize the vast majority of imaging data that is not labeled or annotated. Segmenting medical images is a critical task for facilitating both patient diagnoses and quantitative research. A major limiting factor is the lack of labeled data, as obtaining expert annotations for each new set of imaging data or task can be expensive, labor intensive, and inconsistent across annotators. Thus, we utilize self-supervision from pixels and their local neighborhoods in the images themselves. Our unsupervised approach optimizes a training objective that leverages concepts from contrastive learning and autoencoding. In contrast to prior work, our framework segments medical images with a novel two-stage approach without relying on any labeled data at any stage. The first stage involves the creation of a"pixel-centered patch"that embeds every pixel along with its surrounding patch, using a vector representation in a high-dimensional latent embedding space. The second stage utilizes diffusion condensation, a multi-scale topological data analysis approach, to dynamically coarse-grain these embedding vectors at all levels of granularity. The final outcome is a series of coarse-to-fine segmentations that highlight image structures at various scales. We show successful multi-scale segmentation on natural images, retinal fundus images, and brain MRI images. Our framework delineates structures and patterns at different scales which may carry distinct information relevant to clinical interpretation. As we tackle the problem of segmenting medical images at multiple meaningful granularities without relying on any label, we demonstrate the possibility to circumvent tedious and repetitive manual annotations in future practice.

CUTS: A Fully Unsupervised Framework for Medical Image Segmentation

Transformer-based protein generation with regularized latent space optimization

The development of powerful natural language models have increased the ability to learn meaningful representations of protein sequences. In addition, advances in high-throughput mutagenesis, directed evolution, and next-generation sequencing have allowed for the accumulation of large amounts of labeled ﬁtness data. Leveraging these two trends, we introduce Regularized Latent Space Optimization (ReLSO), a deep transformer-based autoencoder which features a highly structured latent space that is trained to jointly generate sequences as well as predict ﬁtness. Through regularized prediction heads, ReLSO introduces a powerful protein sequence encoder and novel approach for eﬃcient ﬁtness landscape traversal. Using ReLSO, we explicitly model the sequence-function landscape of large labeled datasets and generate new molecules by optimizing within the latent space using gradient-based methods. We evaluate this approach on several publicly-available protein datasets, including variant sets of anti-ranibizumab and GFP. We observe a greater sequence optimization eﬃciency (increase in ﬁtness per optimization step) by ReLSO compared to other approaches, where ReLSO more robustly generates high-ﬁtness sequences. Furthermore, the attention-based relationships learned by the jointly-trained ReLSO models provides a potential avenue towards sequence-level ﬁtness attribution information.

ReLSO: A Transformer-based Model for Latent Space Optimization and Generation of Proteins

Brain activity as measured with functional magnetic resonance imaging (fMRI) gives the illusion of intractably high dimensionality, rife with collection and biological noise. Nonlinear dimensionality reductions like PCA, UMAP, tSNE, and PHATE have proven use-ful for high-throughput biomedical data, but have not been extensively used in fMRI, which is known to reﬂect the redundancy and co-modulation of neural population activity. Here we take the manifold-geometry preserving method PHATE and extend it for use in brain activity timeseries data in a method we call temporal PHATE (T-PHATE). We observe that in addition to the intrinsically lower dimensionality of fMRI data, it also has signiﬁcant autocorrelative structure that we can exploit to faithfully denoise the signal and learn brain activation manifolds. We empirically validate T-PHATE on three fMRI tasks and show that T-PHATE manifolds improve visualization ﬁdelity, stimulus feature classiﬁcation, and neural event segmentation. T-PHATE demonstrates impressive im-provements over previous cutting-edge approaches to understanding the nature of cognition from fMRI and bodes potential applications broadly for high-dimensional datasets of temporally-diffuse processes.

Temporal PHATE: A multi-view manifold learning method for brain state trajectories

The scattering transform is a multilayered, wavelet-based transform initially introduced as a mathematical model of convolutional neural networks (CNNs) that has played a foundational role in our understanding of these networks’ stability and invariance properties. In subsequent years, there has been widespread interest in extending the success of CNNs to data sets with non-Euclidean structure, such as graphs and manifolds, leading to the emerging field of geometric deep learning. In order to improve our understanding of the architectures used in this new field, several papers have proposed generalizations of the scattering transform for non-Euclidean data structures such as undirected graphs and compact Riemannian manifolds without boundary. Analogous to the original scattering transform, these works prove that these variants of the scattering transform have desirable stability and invariance properties and aim to improve our understanding of the neural networks used in geometric deep learning. In this paper, we introduce a general, unified model for geometric scattering on measure spaces. Our proposed framework includes previous work on compact Riemannian manifolds without boundary and undirected graphs as special cases but also applies to more general settings such as directed graphs, signed graphs, and manifolds with boundary. We propose a new criterion that identifies to which groups a useful representation should be invariant and show that this criterion is sufficient to guarantee that the scattering transform has desirable stability and invariance properties. Additionally, we consider finite measure spaces that are obtained from randomly sampling an unknown manifold. We propose two methods for constructing a data-driven graph on which the associated graph scattering transform approximates the scattering transform on the underlying manifold. Moreover, we use a diffusion-maps based approach to prove quantitative estimates on the rate of convergence of one of these approximations as the number of sample points tends to infinity. Lastly, we showcase the utility of our method on spherical images, a directed graph stochastic block model, and on high-dimensional single-cell data.

The development of powerful natural language models have increased the ability to learn meaningful representations of protein sequences. In addition, advances in high-throughput mutagenesis, directed evolution, and next-generation sequencing have allowed for the accumulation of large amounts of labeled ﬁtness data. Leveraging these two trends, we introduce Regularized Latent Space Optimization (ReLSO), a deep transformer-based autoencoder which is trained to jointly generate sequences as well as predict ﬁtness. Using ReLSO, we explicitly model the underlying sequence-function landscape of large labeled datasets and optimize within latent space using gradient-based methods. Through regularized prediction heads, ReLSO introduces a powerful protein sequence encoder and novel approach for efﬁcient ﬁtness landscape traversal

High-throughput high-dimensional data is now being generated in massive quantities in many fields including biology, medicine, chemistry, finance and physics. Researchers have successfully used manifold learning in order to gain insight from such data, particularly in biomedical and single cell data. One such technique, data diffusion geometry, has been useful in understanding manifold intrinsic distances, density, and major non-linear axes or paths through the data. However, a relatively unstudied feature of high-dimensional data is curvature. While curvature is well-defined and easy to compute in low dimensions, it poses computational and conceptual difficulties in high dimensions. Here, we present two techniques to estimate curvature from high-dimensional data starting from data diffusion probabilities. The first technique, diffusion curvature, uses the spread or conversely laziness of a random walk to estimate curvature pointwise in data. The second technique, deep diffusion curvature, trains a neural network to estimate pointwise curvature. Since these techniques are scalable, we anticipate that they can be used to describe and compare datasets as well as find points in data that represent transitional entities.

Prediction of Death after Terminal Extubation, the Machine Learning Way

The manifold scattering transform is a deep feature extractor for data defined on a Riemannian manifold. It is one of the first examples of extending convolutional neural network-like operators to general manifolds. The initial work on this model focused primarily on its theoretical stability and invariance properties but did not provide methods for its numerical implementation except in the case of two-dimensional surfaces with predefined meshes. In this work, we present practical schemes, based on the theory of diffusion maps, for implementing the manifold scattering transform to datasets arising in naturalistic systems, such as single cell genetics, where the data is a high-dimensional point cloud modeled as lying on a low-dimensional manifold. We show that our methods are effective for signal classification and manifold classification tasks.

The Manifold Scattering Transform for High-Dimensional Point Cloud Data

Diffusion condensation is a dynamic process that yields a sequence of multiscale data representations that aim to encode meaningful abstractions. It has proven effective for manifold learning, denoising, clustering, and visualization of high-dimensional data. Diffusion condensation is constructed as a time-inhomogeneous process where each step first computes and then applies a diffusion operator to the data. We theoretically analyze the convergence and evolution of this process from geometric, spectral, and topological perspectives. From a geometric perspective, we obtain convergence bounds based on the smallest transition probability and the radius of the data, whereas from a spectral perspective, our bounds are based on the eigenspectrum of the diffusion kernel. Our spectral results are of particular interest since most of the literature on data diffusion is focused on homogeneous processes. From a topological perspective, we show diffusion condensation generalizes centroid-based hierarchical clustering. We use this perspective to obtain a bound based on the number of data points, independent of their location. To understand the evolution of the data geometry beyond convergence, we use topological data analysis. We show that the condensation process itself defines an intrinsic condensation homology. We use this intrinsic topology as well as the ambient persistent homology of the condensation process to study how the data changes over diffusion time. We demonstrate both types of topological information in well-understood toy examples. Our work gives theoretical insights into the convergence of diffusion condensation, and shows that it provides a link between topological and geometric data analysis.

Exciting advances in technologies to measure biological systems are currently at the forefront of research. The ability to gather data along an increasing number of omic dimensions has created a need for tools to analyze all of this information together, rather than siloing each technology into separate analysis pipelines. To advance this goal, we introduce a framework called the Single-Cell Multi-Modal GAN (scMMGAN) that integrates data from multiple modalities into a unified representation in the ambient data space for downstream analysis using a combination of adversarial learning and data geometry techniques. The framework’s key improvement is an additional diffusion geometry loss with a new kernel that constrains the otherwise over-parameterized GAN network. We demonstrate scMMGAN’s ability to produce more meaningful alignments than alternative methods on a wide variety of data modalities, and that its output can be used to draw conclusions from real-world biological experimental data. We highlight data from an experiment studying the development of triple negative breast cancer, where we show how scMMGAN can be used to identify novel gene associations and we demonstrate that cell clusters identified only on the scRNAseq data occur in localized spatial patterns that reveal insights on the spatial transcriptomic images.

Single-Cell Multi-Modal GAN (scMMGAN) reveals spatial patterns in single-cell data from triple negative breast cancer

We introduce a new intrinsic measure of local curvature on point-cloud data called diffusion curvature. Our measure uses the framework of diffusion maps, including the data diffusion operator, to structure point cloud data and define local curvature based on the laziness of a random walk starting at a point or region of the data. We show that this laziness directly relates to volume comparison results from Riemannian geometry. We then extend this scalar curvature notion to an entire quadratic form using neural network estimations based on the diffusion map of point-cloud data. We show applications of both estimations on toy data, single-cell data, and on estimating local Hessian matrices of neural network loss landscapes.

Diffusion Curvature for Estimating Local Curvature in High Dimensional Data

We present a method called Manifold Interpolating Optimal-Transport Flow (MIOFlow) that learns stochastic, continuous population dynamics from static snapshot samples taken at sporadic timepoints. MIOFlow combines dynamic models, manifold learning, and optimal transport by training neural ordinary differential equations (Neural ODE) to interpolate between static population snapshots as penalized by optimal transport with manifold ground distance. Further, we ensure that the flow follows the geometry by operating in the latent space of an autoencoder that we call a geodesic autoencoder (GAE). In GAE the latent space distance between points is regularized to match a novel multiscale geodesic distance on the data manifold that we define. We show that this method is superior to normalizing flows, Schr\"odinger bridges and other generative models that are designed to flow from noise to data in terms of interpolating between populations. Theoretically, we link these trajectories with dynamic optimal transport. We evaluate our method on simulated data with bifurcations and merges, as well as scRNA-seq data from embryoid body differentiation, and acute myeloid leukemia treatment.

Manifold Interpolating Optimal-Transport Flows for Trajectory Inference

We propose a new graph neural network (GNN) module, based on relaxations of recently proposed geometric scattering transforms, which consist of a cascade of graph wavelet filters. Our learnable geometric scattering (LEGS) module enables adaptive tuning of the wavelets to encourage band-pass features to emerge in learned representations. The incorporation of our LEGS-module in GNNs enables the learning of longer-range graph relations compared to many popular GNNs, which often rely on encoding graph structure via smoothness or similarity between neighbors. Further, its wavelet priors result in simplified architectures with significantly fewer learned parameters compared to competing GNNs. We demonstrate the predictive performance of LEGS-based networks on graph classification benchmarks, as well as the descriptive quality of their learned features in biochemical graph data exploration tasks. Our results show that LEGS-based networks match or outperforms popular GNNs, as well as the original geometric scattering construction, on many datasets, in particular in biochemical domains, while retaining certain mathematical properties of handcrafted (non-learned) geometric scattering.

In modern relational machine learning it is common to encounter large graphs that arise via interactions or similarities between observations in many domains. Further, in many cases the target entities for analysis are actually signals on such graphs. We propose to compare and organize such datasets of graph signals by using an earth mover’s distance (EMD) with a geodesic cost over the underlying graph. Typically, EMD is computed by optimizing over the cost of transporting one probability distribution to another over an underlying metric space. However, this is inefficient when computing the EMD between many signals. Here, we propose an unbalanced graph EMD that efficiently embeds the unbalanced EMD on an underlying graph into an L1 space, whose metric we call unbalanced diffusion earth mover’s distance (UDEMD). Next, we show how this gives distances between graph signals that are robust to noise. Finally, we apply this to organizing patients based on clinical notes, embedding cells modeled as signals on a gene graph, and organizing genes modeled as signals over a large cell graph. In each case, we show that UDEMD-based embeddings find accurate distances that are highly efficient compared to other methods.

Embedding Signals on Graphs with Unbalanced Diffusion Earth Mover’s Distance

Biology has become a data-intensive science. Recent technological advances in single-cell genomics have enabled the measurement of multiple facets of cellular state, producing datasets with millions of single-cell observations. While these data hold great promise for understanding molecular mechanisms in health and disease, analysis challenges arising from sparsity, technical and biological variability, and high dimensionality of the data hinder the derivation of such mechanistic insights. To promote the innovation of algorithms for analysis of multimodal single-cell data, we organized a competition at NeurIPS 2021 applying the Common Task Framework to multimodal single-cell data integration. For this competition we generated the first multimodal benchmarking dataset for single-cell biology and defined three tasks in this domain: prediction of missing modalities, aligning modalities, and learning a joint representation across modalities. We further specified evaluation metrics and developed a cloud-based algorithm evaluation pipeline. Using this setup, 280 competitors submitted over 2600 proposed solutions within a 3 month period, showcasing substantial innovation especially in the modality alignment task. Here, we present the results, describe trends of well performing approaches, and discuss challenges associated with running the competition.

Multimodal single cell data integration challenge: results and lessons learned

The genome of the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), the pathogen that causes coronavirus disease 2019 (COVID-19), has been sequenced at an unprecedented scale leading to a tremendous amount of viral genome sequencing data. To assist in tracing infection pathways and design preventive strategies, a deep understanding of the viral genetic diversity landscape is needed. We present here a set of genomic surveillance tools from population genetics which can be used to better understand the evolution of this virus in humans. To illustrate the utility of this toolbox, we detail an in depth analysis of the genetic diversity of SARS-CoV-2 in first year of the COVID-19 pandemic. We analyzed 329,854 high-quality consensus sequences published in the GISAID database during the pre-vaccination phase. We demonstrate that, compared to standard phylogenetic approaches, haplotype networks can be computed efficiently on much larger datasets. This approach enables real-time lineage identification, a clear description of the relationship between variants of concern, and efficient detection of recurrent mutations. Furthermore, time series change of Tajima's D by haplotype provides a powerful metric of lineage expansion. Finally, principal component analysis (PCA) highlights key steps in variant emergence and facilitates the visualization of genomic variation in the context of SARS-CoV-2 diversity. The computational framework presented here is simple to implement and insightful for real-time genomic surveillance of SARS-CoV-2 and could be applied to any pathogen that threatens the health of populations of humans and other organisms.

Population Genomics Approaches for Genetic Characterization of SARS-CoV-2 Lineages

Understanding the dynamics and reactions of cells from population snapshots is a major challenge in single-cell transcriptomics. Here, we present Geodesic Sinkhorn, a method for interpolating populations along a data manifold that leverages existing kernels developed for single-cell dimensionality reduction and visualization methods. Our Geodesic Sinkhorn method uses a heat-geodesic ground distance that, as compared to Euclidean ground distances, is more accurate for interpolating single-cell dynamics on a wide variety of datasets and significantly speeds up the computation for sparse kernels. We first apply Geodesic Sinkhorn to 10 single-cell transcriptomics time series interpolation datasets as a drop-in replacement for existing interpolation methods where it outperforms on all datasets, showing its effectiveness in modeling cell dynamics. Second, we show how to efficiently approximate the operator with polynomial kernels allowing us to improve scaling to large datasets. Finally, we define the conditional Wasserstein-average treatment effect and show how it can elucidate the treatment effect on single-cell populations on a drug screen.

Geodesic Sinkhorn: optimal transport for high-dimensional datasets

12 Discovery of effective therapies for neurodegeneration represents a major obstacle, in part due to challenges in 13 disease monitoring and drug access to the central nervous system (CNS). Age-related macular degeneration 14 (AMD) is a neurodegenerative disease of the CNS, affecting the retina, where anti-VEGF therapy is the only 15 effective intervention. Due to commonalities in disease progression and pathophysiology, AMD may represent a 16 uniquely accessible model to investigate therapies for other neurodegenerative diseases, leading us to examine 17 whether pathways of disease progression are shared across neurodegenerative conditions. We used single-nucleus 18 RNA sequencing to profile lesions from the macula of 17 retinas with varying degrees of AMD pathology as 19 well as controls. To identify populations of cells implicated in disease, we created a robust computational 20 pipeline, which first identified subsets of cells enriched in particular phases of disease progression and then 21 created signatures of disease pathogenesis in a cell type specific manner. By applying this pipeline to single-cell 22 profiling of human AMD lesions, we identified activated microglial and astrocyte populations that are enriched 23 in the early phase of disease. Examining single-cell data generated from Alzheimer’s disease and progressive 24 multiple sclerosis, we found a similar activation profile in transcriptional populations enriched in the early phases 25 of these neurodegenerative diseases. In late-stage AMD, our pipeline identified a microglia-to-astrocyte signaling 26 axis mediated by IL-1β which drives VEGFA expression and angiogenesis characteristic of disease pathogenesis. 27 We validated this mechanism using in vitro and in vivo assays, identifying a possible new therapeutic target for 28 AMD and possibly other neurodegenerative conditions. Thus, due to the shared glial states across diseases, the 29 retina provides a novel human system for investigating therapeutic approaches in multiple neurodegenerative 30 diseases. 31

Multigranular single-cell analysis reveals inflammatory interactions driving

Multiple-manifold Generation with an Ensemble GAN and Learned Noise Prior

Traditional Generative Adversarial Networks (GANs) sample from a continuous stochastic noise distribution, and then treating that sample as a constant, optimize the parameters of a generator network on the average loss over the sample. In other words, the generator must take samples from a continuous input distribution, and on average, match a non-continuous target distribution (the training data). The result is that, as the generator transitions from one realistic image to another, some regions of the noise space correspond to relatively high quality images and other regions correspond to relatively low quality images. To avoid these relatively low quality areas, and allow the generator to optimize the shape of its noise distribution in a data-aware way, we present a novel sampling procedure: alternating (a) the traditional approach of optimizing the generator while holding the noise space sample constant, but then also (b) moving points in the noise space to improve the loss, using the direction of the gradient, while holding the generator parameters constant. We demonstrate that this procedure, which we call noise space optimization, improves the overall quality of samples obtained from an identical model without it on a wide array of canonical datasets and training paradigms.

Generative Adversarial Networks (GANs) learn generating functions that map a random noise distribution $Z$ to a target data distribution. Usually, little attention is paid to the form of $Z$, resulting in nearly all models assuming $Z$ follows a convenient parametric form (almost always $Z\ \sim \ Normal (0,1)$ or $Z\ \sim\ Uniform(-1,1))$. However, we observe that image-conditional generators, such as those used in the CycleGAN, produce better quality generation than comparable single domain GANs can currently achieve. This is true even when the images being conditioned upon are substantially different from the target images. We hypothesize these models benefit from input which already has the general structure of images, even if their semantic content is different. As a result, we propose the Canvas GAN: using just a small handful of real images (“canvases”), we create random input for an image-conditional generator by randomly cropping, flipping along either or both axis, coloring, and resizing the canvas. These diverse samples allow the generator to edit an input that already exhibits natural image structure, as opposed to having to generate it from scratch from independent white noise.

We propose a new fast method of measuring distances between large numbers of related high dimensional datasets called the Diffusion Earth Mover's Distance (EMD). We model the datasets as distributions supported on common data graph that is derived from the affinity matrix computed on the combined data. In such cases where the graph is a discretization of an underlying Riemannian closed manifold, we prove that Diffusion EMD is topologically equivalent to the standard EMD with a geodesic ground distance. Diffusion EMD can be computed in $\tilde{O}(n)$ time and is more accurate than similarly fast algorithms such as tree-based EMDs. We also show Diffusion EMD is fully differentiable, making it amenable to future uses in gradient-descent frameworks such as deep neural networks. Finally, we demonstrate an application of Diffusion EMD to single cell data collected from 210 COVID-19 patient samples at Yale New Haven Hospital. Here, Diffusion EMD can derive distances between patients on the manifold of cells at least two orders of magnitude faster than equally accurate methods. This distance matrix between patients can be embedded into a higher level patient manifold which uncovers structure and heterogeneity in patients. More generally, Diffusion EMD is applicable to all datasets that are massively collected in parallel in many medical and biological systems.

Fixing Bias in Reconstruction-based Anomaly Detection with Lipschitz Discriminators

Exploring the Geometry and Topology of Neural Network Loss Landscapes

We propose a method called integrated diffusion for combining multimodal datasets, or data gathered via several different measurements on the same system, to create a joint data diffusion operator. As real world data suffers from both local and global noise, we introduce mechanisms to optimally calculate a diffusion operator that reflects the combined information from both modalities. We show the utility of this joint operator in data denoising, visualization and clustering, performing better than other methods to integrate and analyze multimodal data. We apply our method to multi-omic data generated from blood cells, measuring both gene expression and chromatin accessibility. Our approach better visualizes the geometry of the joint data, captures known crossmodality associations and identifies known cellular populations. More generally, integrated diffusion is broadly applicable to multimodal datasets generated in many medical and biological systems.

Multimodal data visualization, denoising and clustering with integrated diffusion

Functional magnetic resonance imaging (fMRI) data is collected in millions of noisy, redundant dimensions. To understand how different brains process the same stimulus, we aim to denoise the fMRI signal via a meaningful embedding space that captures the data's intrinsic structure as shared across brains. We assume that stimulus-driven responses share latent features common across subjects that are jointly discoverable. Previous approaches to this problem have relied on linear methods like principal component analysis and shared response modeling. We propose a neural network called MRMD-AE (manifold-regularized multiple- decoder, autoencoder) that learns a common embedding from multi-subject fMRI data while retaining the ability to decode individual responses. Our latent common space represents an extensible manifold (where untrained data can be mapped) and improves classification accuracy of stimulus features of unseen timepoints, as well as cross-subject translation of fMRI signals.

2022 IEEE 32nd International Workshop on Machine Learning for Signal Processing (MLSP)

Although existing deep learning models perform remarkably well at predicting physicochemical properties and binding affinities, the generation of new molecules with optimized properties remains challenging. Inherently, most GNNs perform poorly in whole-graph representation due to the limitations of the message-passing paradigm. Furthermore, step-by-step graph generation frameworks that use reinforcement learning or other sequential processing can be slow and result in a high proportion of invalid molecules with substantial post-processing needed in order to generate valid molecules. To address these issues, we propose a representation-first approach to molecular graph generation. We guide the latent representation of an autoencoder by capturing graph structure information with the geometric scattering transform and apply penalties that organize the representation by molecular properties. We show that this highly structured latent space can be directly used for molecular graph generation by the use of a GAN. We demonstrate that our architecture learns meaningful representations of drug datasets and provides a platform for drug synthesis using publicly available ZINC and BindingDB datasets.

We propose a new graph neural network (GNN) module, based on relaxations of recently proposed geometric scattering transforms, which consist of a cascade of graph wavelet filters. Our learnable geometric scattering (LEGS) module enables adaptive tuning of the wavelets to encourage band-pass features to emerge in learned representations. The incorporation of our LEGS-module in GNNs enables the learning of longer-range graph relations compared to many popular GNNs, which often rely on encoding graph structure via smoothness or similarity between neighbors. Further, its wavelet priors result in simplified architectures with significantly fewer learned parameters compared to competing GNNs. We demonstrate the predictive performance of LEGS-based networks on graph classification benchmarks, as well as the descriptive quality of their learned features in biochemical graph data exploration tasks.

2021 IEEE 31st International Workshop on Machine Learning for Signal Processing (MLSP)

Biomolecular graph analysis has recently gained much attention in the emerging field of geometric deep learning. Here we focus on organizing biomolecular graphs in ways that expose meaningful relations and variations between them. We propose a geometric scattering autoencoder (GSAE) network for learning such graph embeddings. Our embedding network first extracts rich graph features using the recently proposed geometric scattering transform. Then, it leverages a semi-supervised variational autoencoder to extract a low-dimensional embedding that retains the information in these features that enable prediction of molecular properties as well as characterize graphs. We show that GSAE organizes RNA graphs both by structure and energy, accurately reflecting b istable R NA s tructures. A lso, the model is generative and can sample new folding trajectories.

Uncovering the Folding Landscape of RNA Secondary Structure Using Deep Graph Embeddings

It is increasingly common to encounter data from dynamic processes captured by static cross-sectional measurements over time, particularly in biomedical settings. Recent attempts to model individual trajectories from this data use optimal transport to create pairwise matchings between time points. However, these methods cannot model continuous dynamics and non-linear paths that entities can take in these systems. To address this issue, we establish a link between continuous normalizing flows and dynamic optimal transport, that allows us to model the expected paths of points over time. Continuous normalizing flows are generally under constrained, as they are allowed to take an arbitrary path from the source to the target distribution. We present TrajectoryNet, which controls the continuous paths taken between distributions to produce dynamic optimal transport. We show how this is particularly applicable for studying cellular dynamics in data from single-cell RNA sequencing (scRNA-seq) technologies, and that TrajectoryNet improves upon recently proposed static optimal transport-based models that can be used for interpolating cellular distributions.

TrajectoryNet: A Dynamic Optimal Transport Network for Modeling Cellular Dynamics

Functional magnetic resonance imaging (fMRI) is a crucial technology for gaining insights into cognitive processes in humans. Data amassed from fMRI measurements result in volumetric data sets that vary over time. However, analysing such data presents a challenge due to the large degree of noise and person-to-person variation in how information is represented in the brain. To address this challenge, we present a novel topological approach that encodes each time point in an fMRI data set as a persistence diagram of topological features, i.e. high-dimensional voids present in the data. This representation naturally does not rely on voxel-by-voxel correspondence and is robust towards noise. We show that these time-varying persistence diagrams can be clustered to find meaningful groupings between participants, and that they are also useful in studying within-subject brain state trajectories of subjects performing a particular task. Here, we apply both clustering and trajectory analysis techniques to a group of participants watching the movie 'Partly Cloudy'. We observe significant differences in both brain state trajectories and overall topological activity between adults and children watching the same movie.

Uncovering the Topology of Time-Varying fMRI Data using Cubical Persistence

While neural networks are good at learning unspecified functions from training samples, they cannot be directly implemented in hardware and are often not interpretable or formally verifiable. On the other hand, logic circuits are implementable, verifiable, and interpretable but are not able to learn from training data in a generalizable way. We propose a novel logic learning pipeline that combines the advantages of neural networks and logic circuits. Our pipeline first trains a neural network on a classification task, and then translates this, first to random forests, and then to AND-Inverter logic. We show that our pipeline maintains greater accuracy than naive translations to logic, and minimizes the logic such that it is more interpretable and has decreased hardware cost. We show the utility of our pipeline on a network that is trained on biomedical data. This approach could be applied to patient care to provide risk stratification and guide clinical decision-making.

Interpolating optimal transport barycenters of patient manifolds

Graph neural networks (GNNs) in general, and graph convolutional networks (GCN) in particular, often rely on low-pass graph filters to incorporate geometric information in the form of local smoothness over neighboring nodes. While this approach performs well on a surprising number of standard benchmarks, the efficacy of such models does not translate consistently to more complex domains, such as graph data in the biochemistry domain. We argue that these more complex domains require priors that encourage learning of band-pass and high-pass features rather than oversmoothed signals of standard GCN architectures. Here, we propose an alternative GNN architecture, based on a relaxation of recently proposed geometric scattering transforms, which consists of a cascade of graph wavelet filters. Our learned geometric scattering (LEGS) architecture adaptively tunes these wavelets and their scales to encourage band-pass features to emerge in learned representations. This results in a simplified GNN with significantly fewer learned parameters compared to competing methods. We demonstrate the predictive performance of our method on several biochemistry graph classification benchmarks, as well as the descriptive quality of its learned features in biochemical graph data exploration tasks. Our results show that the proposed LEGS network matches or outperforms popular GNNs, as well as the original geometric scattering construction, while also retaining certain mathematical properties of its handcrafted (nonlearned) design.

Functional magnetic resonance imaging (fMRI) is a crucial technology for gaining insights into cognitive processes in humans. Data amassed from fMRI measurements result in volumetric data sets that vary over time. However, analysing such data presents a challenge due to the large degree of noise, and person-to-person variation in how information is represented in the brain. To address this challenge, we present a novel topological approach that encodes each time point in an fMRI data set as a persistence diagram of topological features, i.e. high-dimensional voids present in the data. This representation naturally does not rely on voxel-by-voxel correspondence and is robust towards noise. We show that these time-varying persistence diagrams can be clustered to find meaningful groupings between participants, and that they are also useful in studying within-subject brain state trajectories as each subject is performing a task, for example. Here, we apply both clustering and trajectory analysis techniques to a group of participants watching the movie ‘Partly Cloudy’. We note that there are marked differences in both brain state trajectories and overall topological features between adults and children watching the same movie. Equal contribution. †These authors jointly directed this work. Department of Biosystems Science and Engineering, ETH Zurich, Switzerland SIB Swiss Institute of Bioinformatics, Switzerland Department of Psychology, Yale University, New Haven, CT, USA Department of Mathematics & Statistics, Université de Montréal, Montréal, QC, Canada Mila – Quebec AI Institute, Montréal, QC, Canada Department of Computer Science, Yale University, New Haven, CT, USA Department of Genetics, Yale University, New Haven, CT, USA. Correspondence to: Bastian Rieck <bastian.rieck@bsse.ethz.ch>, Nicholas Turk-Browne <nicholas.turk-browne@yale.edu>, Smita Krishnaswamy <smita.krishnaswamy@yale.edu>. Presented at the ICML 2020 Workshop on Computational Biology (WCB). Copyright 2020 by the author(s).

Author Correction: Visualizing structure and transitions in high-dimensional biological data

Unsupervised image-to-image translation consists of learning a pair of mappings between two domains without known pairwise correspondences between points. The current convention is to approach this task with cycle-consistent GANs: using a discriminator to encourage the generator to change the image to match the target domain, while training the generator to be inverted with another mapping. While ending up with paired inverse functions may be a good end result, enforcing this restriction at all times during training can be a hindrance to effective modeling. We propose an alternate approach that directly restricts the generator to performing a simple sparse transformation in a latent layer, motivated by recent work from cognitive neuroscience suggesting an architectural prior on representations corresponding to consciousness. Our biologically motivated approach leads to representations more amenable to transformation by disentangling high-level abstract concepts in the latent space. We demonstrate that image-to-image domain translation with many different domains can be learned more effectively with our architecturally constrained, simple transformation than with previous unconstrained architectures that rely on a cycle-consistency loss.

Image-to-image Mapping with Many Domains by Sparse Attribute Transfer

While generative models such as GANs have been successful at mapping from noise to specific distributions of data, or more generally from one distribution of data to another, they cannot isolate the transformation that is occurring and apply it to a new distribution not seen in training. Thus, they memorize the domain of the transformation, and cannot generalize the transformation out of sample. To address this, we propose a new neural network called a Neuron Transformation Network (NT-Net) that isolates the signal representing the transformation itself from the other signals representing internal distribution variation. This signal can then be removed from a new dataset distributed differently from the original one trained on. We demonstrate the effectiveness of our NTNet on more than a dozen synthetic and biomedical single-cell RNA sequencing datasets, where the NTNet is able to learn the data transformation performed by genetic and drug perturbations on one sample of cells and successfully apply it to another sample of cells to predict treatment outcome.

2020 IEEE 30th International Workshop on Machine Learning for Signal Processing (MLSP)

Learning General Transformations of Data for Out-of-Sample Extensions

Big data often has emergent structure that exists at multiple levels of abstraction, which are useful for characterizing complex interactions and dynamics of the observations. Here, we consider multiple levels of abstraction via a multiresolution geometry of data points at different granularities. To construct this geometry we define a time-inhomogemeous diffusion process that effectively condenses data points together to uncover nested groupings at larger and larger granularities. This inhomogeneous process creates a deep cascade of intrinsic low pass filters on the data affinity graph that are applied in sequence to gradually eliminate local variability while adjusting the learned data geometry to increasingly coarser resolutions. We provide visualizations to exhibit our method as a “continuously-hierarchical” clustering with directions of eliminated variation highlighted at each step. The utility of our algorithm is demonstrated via neuronal data condensation, where the constructed multiresolution data geometry uncovers the organization, grouping, and connectivity between neurons.

Coarse Graining of Data via Inhomogeneous Diffusion Condensation

Interest in image-to-image translation has grown substantially in recent years with the success of unsupervised models based on the cycle-consistency assumption. The achievements of these models have been limited to a particular subset of domains where this assumption yields good results, namely homogeneous domains that are characterized by style or texture differences. We tackle the challenging problem of image-to-image translation where the domains are defined by high-level shapes and contexts, as well as including significant clutter and heterogeneity. For this purpose, we introduce a novel GAN based on preserving intra-domain vector transformations in a latent space learned by a siamese network. The traditional GAN system introduced a discriminator network to guide the generator into generating images in the target domain. To this two-network system we add a third: a siamese network that guides the generator so that each original image shares semantics with its generated version. With this new three-network system, we no longer need to constrain the generators with the ubiquitous cycle-consistency restraint or any other autoencoding regularization. As a result, the generators can learn mappings between more complex domains that differ from each other by more than just style or texture. We demonstrate our model by mapping between high-resolution, arbitrarily chosen classes from the Imagenet dataset completely without pre-processing such as cropping, centering, or filtering unrepresentative images.

TraVeLGAN: Image-To-Image Translation by Transformation Vector Learning

Anomaly detection is of great interest in fields where abnormalities need to be identified and corrected (e.g., medicine and finance). Deep learning methods for this task often rely on autoencoder reconstruction error, sometimes in conjunction with other penalties. We show that this approach exhibits intrinsic biases that lead to undesirable results. Reconstruction-based methods can sometimes show low error on simple-to-reconstruct points that are not part of the training data, for example the all black image. Instead, we introduce a new unsupervised Lipschitz anomaly discriminator (LAD) that does not suffer from these biases. Our anomaly discriminator is trained, similar to the discriminator of a GAN, to detect the difference between the training data and corruptions of the training data. We show that this procedure successfully detects unseen anomalies with guarantees on those that have a certain Wasserstein distance from the data or corrupted training set. These additions allow us to show improved performance on MNIST, CIFAR10, and health record data. Further, LAD does not require decoding back to the original data space, which makes anomaly detection possible in domains where it is difficult to define a decoder, such as in irregular graph structured data. Empirically, we show this framework leads to improved performance on image, health record, and graph data.

We propose a novel approach for clustering the vertices of a graph. The method, Vertex-Frequency Clustering (VFC), considers the local harmonic content of one or many graph signals, forming partitions based on spectral features in the input signal. The method can be related to spectral clustering, and the length scale over which frequencies are considered is tunable. This allows one to cluster data based on intrinsic graph geometry in the context of signal dynamics. VFC is useful for unravelling active regions in a signal, collecting sets of similar observations, or detecting anomalies. We demonstrate the utility of VFC in synthetic and biological data, and show how VFC can be used to identify observations with similar feature sets and signal profiles.

As high dimensional biological data becomes more easily available, there is a pressing need for visualization tools that reveal the structure and emergent patterns of data in an intuitive form. Potential of Heat-diffusion for Affinity-based Transition Embedding (PHATE) [3] is a visualization method that captures both local and global nonlinear structure in data by an information-geometry distance between data points. The advantage of PHATE over many other visualization methods is its ability to reveal branching structures that commonly exist in differentiation systems. For example, PHATE can faithfully visualize the underlying trajectories in a newly generated scRNA-seq dataset of human germ layer differentiation. Here, PHATE reveals a dynamic picture of the main developmental branches in unparalleled detail.

Extracting Progressions in Biological Data by Identifying Branches in Potential of Heat-diffusion for Affinity-based Transition Embedding

Archetypal analysis is a type of factor analysis where data is fit by a convex polytope whose corners are "archetypes" of the data, with the data represented as a convex combination of these archetypal points. While archetypal analysis has been used on biological data, it has not achieved widespread adoption because most data are not well fit by a convex polytope in either the ambient space or after standard data transformations. We propose a new approach to archetypal analysis. Instead of fitting a convex polytope directly on data or after a specific data transformation, we train a neural network (AAnet) to learn a transformation under which the data can best fit into a polytope. We validate this approach on synthetic data where we add nonlinearity. Here, AAnet is the only method that correctly identifies the archetypes. We also demonstrate AAnet on two biological datasets. In a T cell dataset measured with single cell RNA-sequencing, AAnet identifies several archetypal states corresponding to naive, memory, and cytotoxic T cells. In a dataset of gut microbiome profiles, AAnet recovers both previously described microbiome states and identifies novel extrema in the data. Finally, we show that AAnet has generative properties allowing us to uniformly sample from the data geometry even when the input data is not uniformly distributed.

Protein docking using constrained self-adaptive differential evolution algorithm

Unsupervised domain mapping has attracted substantial attention in recent years due to the success of models based on the cycle-consistency assumption. These models map between two domains by fooling a probabilistic discriminator, thereby matching the probability distributions of the real and generated data. Instead of this probabilistic approach, we cast the problem in terms of aligning the geometry of the manifolds of the two domains. We introduce the Manifold Geometry Matching Generative Adversarial Network (MGM GAN), which adds two novel mechanisms to facilitate GANs sampling from the geometry of the manifold rather than the density and then aligning two manifold geometries: (1) an importance sampling technique that reweights points based on their density on the manifold, making the discriminator only able to discern geometry and (2) a penalty adapted from traditional manifold alignment literature that explicitly enforces the geometry to be preserved. The MGM GAN leverages the manifolds arising from a pre-trained autoencoder to bridge the gap between formal manifold alignment literature and existing GAN work, and demonstrate the advantages of modeling the manifold geometry over its density.

Generating and Aligning from Data Geometries with Generative Adversarial Networks

Diffusion maps are a commonly used kernel-based method for manifold learning, which can reveal intrinsic structures in data and embed them in low dimensions. However, as with most kernel methods, its implementation requires a heavy computational load, reaching up to cubic complexity in the number of data points. This limits its usability in modern data analysis. Here, we present a new approach to computing the diffusion geometry, and related embeddings, from a compressed diffusion process between data regions rather than data points. Our construction is based on an adaptation of the previously proposed measure-based Gaussian correlation (MGC) kernel that robustly captures the local geometry around data points. We use this MGC kernel to efficiently compress diffusion relations from pointwise to data region resolution. Finally, a spectral embedding of the data regions provides coordinates that are used to interpolate and approximate the pointwise diffusion map embedding of data. We analyze theoretical connections between our construction and the original diffusion geometry of diffusion maps, and demonstrate the utility of our method in analyzing big datasets, where it outperforms competing approaches.

2019 13th International conference on Sampling Theory and Applications (SampTA)

Single-cell RNA-sequencing (scRNA-seq) is a powerful tool to quantify transcriptional states in thousands to millions of cells. It is increasingly common for scRNA-seq data to be collected in multiple experimental conditions, yet quantifying differences between scRNA-seq datasets remains an analytical challenge. Previous efforts at quantifying such differences focus on discrete regions of the transcriptional state space such as clusters of cells. Here, we describe a continuous measure of the effect of an experiment across the transcriptomic space. First, we use the manifold assumption to model the cellular state space as a graph (or network) with cells as nodes and edges connecting cells with similar transcriptomic profiles. Next, we create an Enhanced Experimental Signal (EES) that estimates the likelihood of observing cells from each condition at every point in the manifold. We show that the EES has useful properties and information that can be extracted. The EES can be used to identify how gene expression is affected by a given perturbation, including identifying non-monotonic changes from only two conditions. We also show that we can use both the magnitude and frequency of the EES, using an algorithm we call vertex frequency clustering, to derive subsets of cells at appropriate levels of granularity (tailored to areas that change) that are enriched in the experimental or control conditions or that are unaffected between conditions. We demonstrate both algorithms using a combination of biological and synthetic datasets. Implementations are provided in the MELD Python package, which is available at https://github.com/KrishnaswamyLab/MELD.

Quantifying the effect of experimental perturbations in single-cell RNA-sequencing data using graph signal processing

Quantifying the differences in gene expression and cellular composition between single-cell RNA-sequencing (scRNA-seq) data sets presents an analytical challenge due to biological and technical noise. To facilitate analysis of multiple scRNA-seq experiments, we developed MELD: Manifold Enhancement of Latent Dimensions. MELD leverages tools from graph signal processing to learn the underlying, or latent, dimension within the data corresponding to the differences between data sets. We call this dimension the Enhanced Experimental Signal (EES). MELD learns the EES by ﬁltering the categorical experimental label in the graph frequency domain to recover a smooth signal with continuous values. We also present a novel clustering algorithm combing the graph Fourier transform with the EES to identify cells that are transcriptionally similar and exhibit uniform response to a perturbation via an adapted vertex frequency clustering. Together, these methods can be used to identify signature genes that vary strongly between conditions, characterize clusters of cells with similar responses to the experiment, and quantify the degree to which each cluster is affected by a given perturbation. We demonstrate the advantages of MELD analysis using a combination of biological and synthetic data sets. MELD is implemented in Python and code is available at https://github.com/KrishnaswamyLab/MELD.

Enhancing experimental signals in single-cell RNA-sequencing data using graph signal processing

Anomaly detection is a problem of great interest in medicine, finance, and other fields where error and fraud need to be detected and corrected. Most deep anomaly detection methods rely on autoencoder reconstruction error. However, we show that this approach has limited value. First, this approach starts to perform poorly when either noise or anomalies contaminate training data, even to a small extent. Second, this approach cannot detect anomalous but simple to reconstruct points. This can be seen even in relatively simple examples, such as feeding a black image to detectors trained on MNIST digits. Here, we introduce a new discriminator-based unsupervised Lipschitz anomaly detector (LAD). We train a Wasserstein discriminator, similar to the ones used in GANs, to detect the difference between the training data and corruptions of the training data. We show that this procedure successfully detects unseen anomalies with guarantees on those that have a certain Wasserstein distance from the data or corrupted training set. Finally, we show results of this system in an electronic medical record dataset of HIV-positive veterans from the veterans aging cohort study (VACS) to establish usability in a medical setting.

We propose a novel framework for combining datasets via alignment of their intrinsic geometry. This alignment can be used to fuse data originating from disparate modalities, or to correct batch effects while preserving intrinsic data structure. Importantly, we do not assume any pointwise correspondence between datasets, but instead rely on correspondence between a (possibly unknown) subset of data features. We leverage this assumption to construct an isometric alignment between the data. This alignment is obtained by relating the expansion of data features in harmonics derived from diffusion operators defined over each dataset. These expansions encode each feature as a function of the data geometry. We use this to relate the diffusion coordinates of each dataset through our assumption of partial feature correspondence. Then, a unified diffusion geometry is constructed over the aligned data, which can also be used to correct the original data measurements. We demonstrate our method on several datasets, showing in particular its effectiveness in biological applications including data fusion and batch effect removal.

Biological data often contains measurements of dynamic entities such as cells or organisms in various states of progression. However, biological systems are notoriously difficult to describe analytically due to their many interacting components, and in many cases, the technical challenge of taking longitudinal measurements. This leads to difficulties in studying the features of the dynamics, for examples the drivers of the transition. To address this problem, we present a deep neural network framework we call Dynamics Modeling Network or DyMoN. DyMoN is a neural network framework trained as a deep generative Markov model whose next state is a probability distribution based on the current state. DyMoN is well-suited to the idiosyncrasies of biological data, including noise, sparsity, and the lack of longitudinal measurements in many types of systems. Thus, DyMoN can be trained using probability distributions derived from the data in any way, such as trajectories derived via dimensionality reduction methods, and does not require longitudinal measurements. We show the advantage of learning deep models over shallow models such as Kalman filters and hidden Markov models that do not learn representations of the data, both in terms of learning embeddings of the data and also in terms training efficiency, accuracy and ability to multitask. We perform three case studies of applying DyMoN to different types of biological systems and extracting features of the dynamics in each case by examining the learned model.

Modeling Dynamics of Biological Systems with Deep Generative Neural Networks

We propose a novel framework for combining datasets via alignment of their intrinsic geometry. This alignment can be used to fuse data originating from disparate modalities, or to correct batch effects while preserving intrinsic data structure. Importantly, we do not assume any pointwise correspondence between datasets, but instead rely on correspondence between a (possibly unknown) subset of data features. We leverage this assumption to construct an isometric alignment between the data. This alignment is obtained by relating the expansion of data features in harmonics derived from diffusion operators defined over each dataset. These expansions encode each feature as a function of the data geometry. We use this to relate the diffusion coordinates of each dataset through our assumption of partial feature correspondence. Then, a unified diffusion geometry is constructed over the aligned data, which can also be used to correct the original data measurements. We demonstrate our method on several datasets, showing in particular its effectiveness in biological applications including fusion of single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) data measured on the same population of cells, and removal of batch effect between biological samples.

Proceedings of the ... SIAM International Conference on Data Mining. SIAM International Conference on Data Mining

It is increasingly common in many types of natural and physical systems (especially biological systems) to have different types of measurements performed on the same underlying system. In such settings, it is important to align the manifolds arising from each measurement in order to integrate such data and gain an improved picture of the system. We tackle this problem using generative adversarial networks (GANs). Recently, GANs have been utilized to try to find correspondences between sets of samples. However, these GANs are not explicitly designed for proper alignment of manifolds. We present a new GAN called the Manifold-Aligning GAN (MAGAN) that aligns two manifolds such that related points in each measurement space are aligned together. We demonstrate applications of MAGAN in single-cell biology in integrating two different measurement types together. In our demonstrated examples, cells from the same tissue are measured with both genomic (single-cell RNA-sequencing) and proteomic (mass cytometry) technologies. We show that the MAGAN successfully aligns them such that known correlations between measured markers are improved compared to other recently proposed models.

Deep neural networks can learn meaningful representations of data. However, these representations are hard to interpret. For example, visualizing a latent layer is generally only possible for at most three dimensions. Neural networks are able to learn and benefit from much higher dimensional representations but these are not visually interpretable because neurons have arbitrary ordering within a layer. Here, we utilize the ability of a human observer to identify patterns in structured representations to visualize higher dimensions. To do so, we propose a class of regularizations we call Graph Spectral Regularizations that impose graph structure on latent layers. This is achieved by treating activations as signals on a predefined graph and constraining those activations using graph filters, such as low pass and wavelet-like filters. This framework allows for any kind of graphs and filters to achieve a wide range of structured regularizations depending on the inference needs of the data. First, we show a synthetic example where a graphstructured layer reveals topological features of the data. Next, we show that a smoothing regularization imposes semantically consistent ordering of nodes when applied to capsule nets. Further, we show that the graph-structured layer, using wavelet-like spatially localized filters, can form local receptive fields for improved image and biomedical data interpretation. In other words, the mapping between latent layer, neurons and the output space becomes clear due to the localization of the activations. Finally, we show that when structured as a grid, the representations create coherent images that allow for image processing techniques such as convolutions.

Graph Spectral Regularization for Neural Network Interpretability

Manifold learning-based methods for analyzing single-cell RNA-sequencing data

Handling the vast amounts of single-cell RNA-sequencing and CyTOF data, now being generated in patient cohorts, presents a computational challenge due to the noise, complexity, sparsity and batch effects present. Here, we propose a unified deep neural network approach to automatically process and extract structure from these massive datasets. Our unsupervised architecture, called SAUCIE (Sparse Autoencoder for Unsupervised Clustering, Imputation, and Embedding), simultaneously performs several key tasks for single-cell data analysis including 1) clustering, 2) batch correction, 3) visualization, and 4) denoising/imputation. SAUCIE is trained to recreate its own input after reducing its dimensionality in a 2-D embedding layer which can be used to visualize the data. Additionally, it uses two novel regularizations: (1) an information dimension regularization to penalize entropy as computed on normalized activation values of the layer, and thereby encourage binary-like encodings that are amenable to clustering and (2) a Maximal Mean Discrepancy penalty to correct batch effects. Thus SAUCIE has a single architecture that denoises, batch-corrects, visualizes and clusters data using a unified representation. We show results on artificial data where ground truth is known, as well as mass cytometry data from patients undergoing immunotherapy, dengue-infected patients, and single-cell RNA-sequencing data from embryonic mouse brain. Citation Format: Matthew Amodio, Krishnan Srinivasan, David van Dijk, Hussein Mohsen, Kristina Yim, Rebecca Muhle, Kevin Moon, Ruth Montgomery, James Noonan, Guy Wolf, Smita Krishnaswamy. SAUCIE: Sparse autoencoder for unsupervised clustering, imputation, and embedding [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5306.

Abstract 5306: SAUCIE: Sparse autoencoder for unsupervised clustering, imputation, and embedding

Many generative models attempt to replicate the density of their input data. However, this approach is often undesirable, since data density is highly affected by sampling biases, noise, and artifacts. We propose a method called SUGAR (Synthesis Using Geometrically Aligned Random-walks) that uses a diffusion process to learn a manifold geometry from the data. Then, it generates new points evenly along the manifold by pulling randomly generated points into its intrinsic structure using a diffusion kernel. SUGAR equalizes the density along the manifold by selectively generating points in sparse areas of the manifold. We demonstrate how the approach corrects sampling biases and artifacts, while also revealing intrinsic patterns (e.g. progression) and relations in the data. The method is applicable for correcting missing data, finding hypothetical data points, and learning relationships between data features.

The objective of protein docking is to achieve a relative orientation and an optimized conformation between two proteins that results in a stable structure with the minimized potential energy. Constrained self-adaptive differential evolution (Cons_SaDE) algorithm is used to find the minimum energy conformation using proposed constraints such as boundary surface complementary interactions, non-bonded inter-atomic allowed distances and finding of interaction and non-interaction sites. With these constraints, Cons_SaDE is efficient enough to explore the promising solutions by gradually self-adapting the strategies and parameters learned from their previous experiences. Modified sampling scheme called rotate only representation is used to represent a docking conformation. GROMOS53A6 force field is used to find the potential energy. To test the performance of this algorithm, few bound and unbound complexes from Protein Data Bank (PDB) and few easy, medium and difficult complexes from Zlab Benchmark 4.0 are used. Buried surface area, root-mean-square deviation (RMSD) and correlation coefficient are some of the metrics applied to evaluate the best docked conformations. RMSD values of the best docked conformations obtained from five popular docking Web servers are compared with Cons_SaDE results, and nonparametric statistical tests for multiple comparisons with control method are implemented to show the performance of this algorithm. Cons_SaDE has produced good-quality solutions for the most of the data sets considered.

Complex high dimensional stochastic dynamic systems arise in many applications in the natural sciences and especially biology. However, while these systems are difficult to describe analytically, "snapshot" measurements that sample the output of the system are often available. In order to model the dynamics of such systems given snapshot data, or local transitions, we present a deep neural network framework we call Dynamics Modeling Network or DyMoN. DyMoN is a neural network framework trained as a deep generative Markov model whose next state is a probability distribution based on the current state. DyMoN is trained using samples of current and next-state pairs, and thus does not require longitudinal measurements. We show the advantage of DyMoN over shallow models such as Kalman filters and hidden Markov models, and other deep models such as recurrent neural networks in its ability to embody the dynamics (which can be studied via perturbation of the neural network) and generate longitudinal hypothetical trajectories. We perform three case studies in which we apply DyMoN to different types of biological systems and extract features of the dynamics in each case by examining the learned model.

Modeling Global Dynamics from Local Snapshots with Deep Generative Neural Networks

Many generative models attempt to replicate the density of their input data. However, this approach is often undesirable, since data density is highly affected by sampling biases, noise, and artifacts. We propose a method called SUGAR (Synthesis Using Geometrically Aligned Random-walks) that uses a diffusion process to learn a manifold geometry from the data. Then, it generates new points evenly along the manifold by pulling randomly generated points into its intrinsic structure using a diffusion kernel. SUGAR equalizes the density along the manifold by selectively generating points in sparse areas of the manifold. We demonstrate how the approach corrects sampling biases and artifacts, while also revealing intrinsic patterns (e.g. progression) and relations in the data.

Markov processes, both classical and higher order, are often used to model dynamic processes, such as stock prices, molecular dynamics, and Monte Carlo methods. Previous works have shown that an autoencoder can be formulated as a specific type of Markov chain. Here, we propose a generative neural network known as a transition encoder, or \emph{transcoder}, which learns such continuous-state dynamic processes. We show that the transcoder is able to learn both deterministic and stochastic dynamic processes on several systems. We explore a number of applications of the transcoder including generating unseen trajectories and examining the propensity for chaos in a dynamic system. Further, we show that the transcoder can speed up Markov Chain Monte Carlo (MCMC) sampling to a convergent distribution by training it to make several steps at a time. Finally, we show that the hidden layers of a transcoder are useful for visualization and salient feature extraction of the transition process itself.

While neural networks can be trained to map from one specific dataset to another, they usually do not learn a generalized transformation that can extrapolate accurately outside the space of training. For instance, a generative adversarial network (GAN) exclusively trained to transform images of black-haired men to blond-haired men might not have the same effect on images of black-haired women. This is because neural networks are good at generation within the manifold of the data that they are trained on. However, generating new samples outside of the manifold or extrapolating "out-of-sample" is a much harder problem that has been less well studied. To address this, we introduce a technique called neuron editing that learns how neurons encode an edit for a particular transformation in a latent space. We use an autoencoder to decompose the variation within the dataset into activations of different neurons and generate transformed data by defining an editing transformation on those neurons. By performing the transformation in a latent trained space, we encode fairly complex and non-linear transformations to the data with much simpler distribution shifts to the neuron's activations. We motivate our technique on an image domain and then move to our two main biological applications: removal of batch artifacts representing unwanted noise and modeling the effect of drug treatments to predict synergy between drugs.

We propose a novel framework for combining datasets via alignment of their associated intrinsic dimensions. Our approach assumes that two datasets are sampled from a common latent space, i.e., they measure equivalent systems. Thus, we expect there to exist a natural (albeit unknown) alignment of the data manifolds associated with the intrinsic geometry of these datasets, which are perturbed by measurement artifacts in the sampling process. Importantly, we do not assume any individual correspondence (partial or complete) between data points. Instead, we rely on our assumption that a subset of data features have correspondence across datasets. We leverage this assumption to estimate relations between intrinsic manifold dimensions, which are given by diffusion map coordinates over each of the datasets. We compute a correlation matrix between diffusion coordinates of the datasets by considering graph (or manifold) Fourier coefficients of corresponding data features. We then orthogonalize this correlation matrix to form an isometric transformation between the diffusion maps of the datasets. Finally, we apply this transformation to the diffusion coordinates and construct a unified diffusion geometry of the datasets together. We show that this approach successfully corrects misalignment artifacts and enables data integration.

Advances in intelligent data analysis. International Symposium on Intelligent Data Analysis

Interpretable Neuron Structuring with Graph Spectral Regularization

Recovering Gene Interactions from Single-Cell Data Using Data Diffusion

New technologies such as single-cell RNA sequencing and mass cytometry are measuring cellular populations in high dimensions, offering unparalleled insights into cellular behavior and enabling new scientific discoveries. However, when these measurements are applied to multiple samples or experimental conditions, the resulting systematic variations, or batch effects, confound biological variation and create a vexing problem in comparing cellular populations. Moreover, these batch effects, which arise as a result of changed environmental condition, instrument variation, machine calibration, or human handling differences, can be complex and highly non-linear transformations. Despite their ubiquity, there are few computational tools designed to correct generally for such effects while maintaining biological differences. The ones that exist hold strong assumptions (such as linear shifts between batches). 
Here, we propose an entirely novel approach to disentangling biological from batch variation where we take a specific subpopulation of cells as a control between the batches. This subpopulation can be an unchanged population (known via prior biology) or a repeatedly measured spike-in. We use an autoencoder to model the variation in the control, and then interfere with neuron activations on inference to correct for these differences on the entire sample. This technique, which we term neuron interference, is unique in its ability to generalize a batch effect learned on a subpopulation to the entire population.

Journal of the American Academy of Child and Adolescent Psychiatry

5.8 Mapping Regulatory Networks of Autism Risk at Cellular Resolution during Neurodevelopment

Exploring single-cell data with deep multitasking neural networks

With the advent of high-throughput technologies measuring high-dimensional biological data, there is a pressing need for visualization tools that reveal the structure and emergent patterns of data in an intuitive form. We present PHATE, a visualization method that captures both local and global nonlinear structure in data by an information-geometric distance between datapoints. We perform extensive comparison between PHATE and other tools on a variety of artificial and biological datasets, and find that it consistently preserves a range of patterns in data including continual progressions, branches, and clusters. We define a manifold preservation metric DEMaP to show that PHATE produces quantitatively better denoised embeddings than existing visualization methods. We show that PHATE is able to gain unique insight from a newly generated scRNA-seq dataset of human germ layer differentiation. Here, PHATE reveals a dynamic picture of the main developmental branches in unparalleled detail, including the identification of three novel subpopulations. Finally, we show that PHATE is applicable to a wide variety of datatypes including mass cytometry, single-cell RNA-sequencing, Hi-C, and gut microbiome data, where it can generate interpretable insights into the underlying systems.

Visualizing Structure and Transitions for Biological Data Exploration

In recent years, dimensionality reduction methods have become critical for visualization, exploration, and interpretation of high-throughput, high-dimensional biological data, as they enable the extraction of major trends in the data while discarding noise. However, biological data contains a type of predominant structure that is not preserved in commonly used methods such as PCA and tSNE, namely, branching progression structure. This structure, which is often non-linear, arises from underlying biological processes such as differentiation, graded responses to stimuli, and population drift, which generate cellular (or population) diversity. We propose a novel, affinity-preserving embedding called PHATE (Potential of Heat-diffusion for Affinity-based Trajectory Embedding), designed explicitly to preserve progression structure in data.

PHATE provides a denoised, two or three-dimensional visualization of the complete branching trajectory structure in high-dimensional data. It uses heat-diffusion processes, which naturally denoise the data, to compute cell-cell affinities. Then, PHATE creates a diffusion-potential geometry by free-energy potentials of these processes. This geometry captures high-dimensional trajectory structures, while enabling a natural embedding of the intrinsic data geometry. This embedding accurately visualizes trajectories and data distances, without requiring strict assumptions typically used by path-finding and tree-fitting algorithms, which have recently been used for pseudotime orderings or tree-renderings of cellular data. Furthermore, PHATE supports a wide range of data exploration tasks by providing interpretable overlays on top of the visualization. We show that such overlays can emphasize and reveal trajectory end-points, branch points and associated split-decisions, progression-forming variables (e.g., specific genes), and paths between developmental events in cellular state-space. We demonstrate PHATE on single-cell RNA sequencing and mass cytometry data pertaining to embryoid body differentiation, IPSC reprogramming, and hematopoiesis in the bone marrow. We also demonstrate PHATE on non-single cell data including single-nucleotide polymorphism (SNP) measurements of European populations, and 16s sequencing of gut microbiota.

PHATE: A Dimensionality Reduction Method for Visualizing Trajectory Structures in High-Dimensional Biological Data

Single-cell RNA-sequencing is fast becoming a major technology that is revolutionizing biological discovery in fields such as development, immunology and cancer. The ability to simultaneously measure thousands of genes at single cell resolution allows, among other prospects, for the possibility of learning gene regulatory networks at large scales. However, scRNA-seq technologies suffer from many sources of significant technical noise, the most prominent of which is ‘dropout’ due to inefficient mRNA capture. This results in data that has a high degree of sparsity, with typically only ~10% non-zero values. To address this, we developed MAGIC (Markov Affinity-based Graph Imputation of Cells), a method for imputing missing values, and restoring the structure of the data. After MAGIC, we find that two- and three-dimensional gene interactions are restored and that MAGIC is able to impute complex and non-linear shapes of interactions. MAGIC also retains cluster structure, enhances cluster-specific gene interactions and restores trajectories, as demonstrated in mouse retinal bipolar cells, hematopoiesis, and our newly generated epithelial-to-mesenchymal transition dataset.

MAGIC: A diffusion-based imputation method reveals gene-gene interactions in single-cell RNA-sequencing data

With the advent of high-throughput technologies measuring high-dimensional biological data, there is a pressing need for visualization tools that reveal the structure and emergent patterns of data in an intuitive form. We present PHATE, a visualization method that captures both local and global nonlinear structure in data by an information-geometry distance between datapoints. We perform extensive comparison between PHATE and other tools on a variety of artificial and biological datasets, and find that it consistently preserves a range of patterns in data including continual progressions, branches, and clusters. We show that PHATE is applicable to a wide variety of datatypes including mass cytometry, single-cell RNA-sequencing, Hi-C, and gut microbiome data, where it can generate interpretable insights into the underlying systems. Finally, we use PHATE to explore a newly generated scRNA-seq dataset of human germ layer differentiation. Here, PHATE reveals a dynamic picture of the main developmental branches in unparalleled detail.

Visualizing Transitions and Structure for Biological Data Exploration

Clustering algorithms play an integral role in exploratory analysis of single cell data. The aim of these analyses is to find population structures that often exist at multiple scales. Previous approaches are limited to finding clusters in data, and these clustering methods come with serious limitation for exploration of this structure. For instance, they require commonly missing knowledge about the structure of the data such as the granularity or even the number of clusters. We propose a novel scalable diffusion-based data contracting process, that learns the shape of the data and contracts datapoints iteratively towards a diffusion-based data potential function. In each iteration, datapoints move to the center of gravity of their local neighbors as defined by a graph diffusion process, and this in turn alters the graph diffusion to reflect the new data positions. This process is carried forward by a non-homogenous Markov process representing the changing affinities between datapoints, along with changing granularities, and eventually collapses all data to a single point. However, each intermediate step in this process is a clustering at a particular granularity or abstraction level. Therefore, this process can naturally uncover a continual hierarchy of clusters.

A Diffusion-based Condensation Process for the Multiscale Analysis of Single Cell Data

Narrative Economic is the study of the spread and dynamics of the collective verbal output of a society in order to understand economic fluctuations. Many reasons motivate individuals to focus on and propagate specific narratives from the many they come across. Each narrative originates in the mind of an individual before starting its evolutionary course through time. The Kermack-McKendrick (1927) SIR Model lends itself well to representing the spread of a narrative over time. An individual at a given point in time either has or has not been exposed to specific narrative. If this person has not come across a narrative, she is susceptible to coming across it for the first time. Otherwise, she is either infected (she will pass pass the narrative along to another susceptible individual) or recovered (she will not pass the narrative along to another susceptible individual). Given that more infected individuals implies a more powerful social epidemic, we hypothesize that narratives of certain valences should evoke aggregate market responses that manifest themselves as measurable economic fluctuations.

Crystal structure of YagE, a KDG aldolase protein in complex with 2-Keto-3-deoxy gluconate

Protein structure prediction using diversity controlled self-adaptive differential evolution with local search

Crystal structure of 0.5M urea unfolded YagE, a KDG aldolase protein in complex with Pyruvate

The structure of DLP12 endolysin exhibits likely active and inactive conformations.

Crystal structure of YagE, a KDG aldolase protein, in complex with aldol condensed product of pyruvate and glyoxal

Crystal Structure of YagE, a KDG aldolase protein in complex with Magnesium cation coordinated L-glyceraldehyde

Significance Activation of T lymphocytes by the rearranged T-cell receptor (TCR) conditions essentially all aspects of their differentiation and function, and variations in the efficacy of signal transduction condition pathogen resistance and autoimmune deviation. We explored the defects in signal transduction downstream of the TCR in diabetes-susceptible nonobese diabetic (NOD) mice using mass cytometry and computational processing of single-cell data. We found that small initial differences in the efficacy of triggering at the apex of the cascade result in much more profound differences downstream, with the system being set to amplify the discriminating power of initial sensing to arrive at more marked response/no response decisions within T cells. Signaling from the T-cell receptor (TCR) conditions T-cell differentiation and activation, requiring exquisite sensitivity and discrimination. Using mass cytometry, a high-dimensional technique that can probe multiple signaling nodes at the single-cell level, we interrogate TCR signaling dynamics in control C57BL/6 and autoimmunity-prone nonobese diabetic (NOD) mice, which show ineffective ERK activation after TCR triggering. By quantitating signals at multiple steps along the signaling cascade and parsing the phosphorylation level of each node as a function of its predecessors, we show that a small impairment in initial pCD3ζ activation resonates farther down the signaling cascade and results in larger defects in activation of the ERK1/2–S6 and IκBα modules. This nonlinear property of TCR signaling networks, which magnifies small initial differences during signal propagation, also applies in cells from B6 mice activated at different levels of intensity. Impairment in pCD3ζ and pSLP76 is not a feedback consequence of a primary deficiency in ERK activation because no proximal signaling defect was observed in Erk2 KO T cells. These defects, which were manifest at all stages of T-cell differentiation from early thymic pre-T cells to memory T cells, may condition the imbalanced immunoregulation and tolerance in NOD T cells. More generally, this amplification of small initial differences in signal intensity may explain how T cells discriminate between closely related ligands and adopt strongly delineated cell fates.

Single-cell mass cytometry of TCR signaling: Amplification of small initial differences results in low ERK activation in NOD mice

In the IC industry, chip design cycles are becoming more compressed, while designs themselves are growing in complexity. These trends necessitate efficient methods to handle late-stage engineering change orders (ECOs) to the functional specification, often in response to errors discovered after much of the implementation is finished. Past ECO synthesis algorithms have typically treated ECOs as functional errors and applied error diagnosis techniques to solve them. However, error diagnosis methods are primarily geared towards finding a single change, and moreover, tend to be computationally complex. In this paper, we propose a unique methodology that can systematically incorporate human intuition into the ECO process. Our methodology involves finding a set of directly substitutable points known as functional correspondences between the original implementation and the new specification by using name-preserving synthesis and user hints, to diminish the size of the ECO problem. On average, our approach can reduce the size of logic changes by 94% from those reported in current literature. We then incorporate our logic ECO changes into an incremental physical synthesis flow to demonstrate its usability in an industrial setting. Our ECO synthesis methodology is evaluated on high-performance industrial designs. Results indicate that post-ECO worst negative slack (WNS) improved 14% and total negative slack (TNS) improved 46% over pre-ECO.

2013 Design, Automation & Test in Europe Conference & Exhibition (DATE)

Modern synthesis flows apply a series of technology independent optimization steps followed by mapping algorithms which bind the optimized network to a specific technology library. As the exact solution of the mapping problem is computationally intractable, algorithms used in practice use heuristic, typically tree-based approaches. The application of these algorithms results in mapped but suboptimal networks. In this work, we present a novel, efficient, and effective optimization algorithm for mapped networks which can be considered a generalization of SAT-sweeping. Our algorithm searches for alternative, more efficient implementations of each net in the network. Candidate support nets for reimplementation are selected using simulation signatures and verified using Boolean satisfiability. We report experimental results on the quality of our algorithm obtained from an implementation of the approach using the logic synthesis system ABC.

With the growing complexity of synthetic biological circuits, robust and systematic methods are needed for design and test. Leveraging lessons learned from the semiconductor and design automation industries, synthetic biologists are starting to adopt computer-aided design and verification software with some success. However, due to the great challenges associated with designing synthetic biological circuits, this nascent approach has to address many problems not present in electronic circuits. In this session, three leading synthetic biologists will share how they have developed software tools to help design and verify their synthetic circuits, the unique challenges they face, and their insights into the next generation of tools for synthetic biology.

Joint DAC/IWBDA special session design and synthesis of biological circuits

Proceedings of the 20th symposium on Great lakes symposium on VLSI

Session details: Algorithms and architectures for emerging technologies

The impact of physical synthesis on design performance is increasing as process technology scales. Current physical synthesis flows generally perform a series of individual netlist transformations based on local timing conditions. However, such optimizations lack sufficient perspective or scope to achieve timing closure in many cases. To address these issues, we develop an integrated transformation system that performs multiple optimizations simultaneously on larger design partitions than existing approaches. Our system, SPIRE, combines physically-aware register retiming, along with a novel form of cloning and register placement. SPIRE also incorporates a placement-dependent static timing analyzer (STA) with a delay model that accounts for buffering and is suitable for physical synthesis. Empirical results on 45nm microprocessor designs show 8% improvement in worst-case slack and 69% improvement in total negative slack after an industrial physical synthesis flow was already completed.

2010 IEEE/ACM International Conference on Computer-Aided Design (ICCAD)

SPIRE: A retiming-based physical-synthesis transformation system

State elements are increasingly vulnerable to soft errors due to their decreasing size, and the fact that latched errors cannot be completely eliminated by electrical or timing masking. Most prior methods of reducing the soft error rate (SER) involve combinational redesign, which tends to add area and decrease testability, the latter a concern due to the prevalence of manufacturing defects. Our work explores the fundamental relations between the SER of sequential circuits and their testability in scan mode, and appears to be the first to improve both through retiming. Our retiming methodology relocates registers so that [1] registers become less observable with respect to primary outputs, thereby decreasing overall SER, and [2] combinational nodes become more observable with respect to registers (but not with respect to primary outputs), thereby increasing scan testability. We present experimental results which show an average decrease of 42% in the SER of latches, and an average improvement of 31% random pattern testability.

Improving testability and soft-error resilience through retiming

During the IC design process, functional specifications are often modified late in the design cycle, after placement and routing are completed. However, designers are left either to manually process such modifications by hand or to restart the design process from scratch - a very costly option. In order to address this issue, we present DeltaSyn, a method for generating a highly optimized logic difference between a modified high-level specification and an implemented design. DeltaSyn has the ability to locate boundaries in implemented logic within which changes can be confined. Delta-Syn demarcates the boundary in two phases. The first phase employs fast functional and structural analysis techniques to identify equivalent signals forming the input-side boundary of the changes. The second phase locates the output-side boundary of the changes through a novel dynamic algorithm that detects matching logic downstream from the changes required by the ECO. Experiments on industrial designs show that together these techniques successfully implement ECOs while preserving an average of 97% of the existing logic. Unlike previous approaches, the use of bit-parallel logic simulation and fast SAT solvers enables high performance and scalability. DeltaSyn can process and verify a typical ECO for a design of around 10K gates in about 200 seconds or less.

2009 IEEE/ACM International Conference on Computer-Aided Design - Digest of Technical Papers

DeltaSyn: An efficient logic difference optimizer for ECO synthesis

We explore the use of signatures, i.e., partial truth tables generated via bit-parallel functional simulation, during soft error analysis and logic synthesis. We first present a signature-based CAD framework that incorporates tools for the logic-level analysis of soft error rate (x) and for signature-based design for reliability (SiDeR). We observe that the soft error rate (SER) of a logic circuit is closely related to various testability parameters, such as signal observability and probability. We show that these parameters can be computed very efficiently (in linear time) by means of signatures. Consequently, AnSER evaluates logic masking two to three orders of magnitude faster than other SER evaluators while maintaining accuracy. AnSER can also compute SER efficiently in sequential circuits by approximating steady-state probabilities and sequential signal observabilities. In the second part of this paper, we incorporate AnSER into logic synthesis design flows aimed at reliable circuit design. SiDeR identifies and exploits redundancy already present in a circuit via signature comparison to decrease SER. We show that SiDeR reduces SER by 40% with only 13% area overhead. We also describe a second signature-based synthesis strategy that employs local rewriting to simultaneously improve area and decrease SER. This technique yields 13% reduction in SER with a 2% area decrease. We show that combining the two synthesis approaches can result in further area-reliability improvements.

IEEE Transactions on Computer-Aided Design of Integrated Circuits and Systems

Soft errors, once only of concern in memories, are beginning to affect logic as well. Determining the soft error rate (SER) of a combinational circuit involves three main masking mechanisms: logic, timing and electrical. Most previous papers focus on logic and electrical masking. Here, we develop static and statistical analysis techniques to estimate timing masking through the error-latching window of each gate. Our SER analysis algorithms incorporating timing masking are 10 - 100x faster than comparable evaluators and can be used in synthesis and layout. We show that 62% of gates identified as error-critical using timing masking would not be identifiable by considering only logic masking. Furthermore, hardening the top 10% of error-critical gates leads to a 43% reduction in the SER. We also propose to decrease the error-latching window of each gate by relocating it such that path lengths to primary outputs are equalized. Our results show that this technique yields 14% improvement in SER with no area overhead.

We propose the probabilistic transfer matrix (PTM) framework to capture nondeterministic behavior in logic circuits. PTMs provide a concise description of both normal and faulty behavior, and are well-suited to reliability and error susceptibility calculations. A few simple composition rules based on connectivity can be used to recursively build larger PTMs (representing entire logic circuits) from smaller gate PTMs. PTMs for gates in series are combined using matrix multiplication, and PTMs for gates in parallel are combined using the tensor product operation. PTMs can accurately calculate joint output probabilities in the presence of reconvergent fanout and inseparable joint input distributions. To improve computational efficiency, we encode PTMs as algebraic decision diagrams (ADDs). We also develop equivalent ADD algorithms for newly defined matrix operations such as eliminate_variables and eliminate_redundant_variables, which aid in the numerical computation of circuit PTMs. We use PTMs to evaluate circuit reliability and derive polynomial approximations for circuit error probabilities in terms of gate error probabilities. PTMs can also analyze the effects of logic and electrical masking on error mitigation. We show that ignoring logic masking can overestimate errors by an order of magnitude. We incorporate electrical masking by computing error attenuation probabilities, based on analytical models, into an extended PTM framework for reliability computation. We further define a susceptibility measure to identify gates whose errors are not well masked. We show that hardening a few gates can significantly improve circuit reliability.

Probabilistic transfer matrices in symbolic reliability analysis of logic circuits

While circuit density and power efficiency increase with each major advance in IC technology, reliability with respect to soft errors tends to decrease. Current solutions to this problem such as TMR require high area and power overhead. In this work, soft-error reliability is improved with minimal area overhead by careful, localized circuit restructuring. The key idea is to increase logic masking of errors by taking advantage of conditions already present in the circuit, such as observability don't-cares. We describe two circuit modification techniques to improve reliability: don't-care-based resynthesis and local rewriting. A key feature of these techniques is fast, on-the-fly estimation of soft error rate (SER) using our reliability evaluator AnSER. This tool is compared against prior SER evaluators and found to run orders of magnitude faster. We show empirically that our reliability-driven synthesis methods can reduce SER by 29-40% with only 5-13% area overhead.

Enhancing design robustness with reliability-aware resynthesis and logic simulation

The diverse nature of the faults and defects that may occur at nanoscale ranges necessitates new techniques for ATPG. This article proposes an efficient technique that relies on a probabilistic approach to detect and diagnose nontraditional faults and defects.

Most recent works on soft errors only address circuit reliability under single gate errors caused by SEUs. In this paper, we compare the probabilities of single and multiple errors. We formulate a criterion based on gate error probabilities for considering multiple gate errors in circuit reliability. Gate error probabilities are increased by technology trends such as the down-scaling of device features and process variation. The probability of multiple errors is generally higher when there is correlation between gate errors. We discuss several examples of correlated errors such as systematic errors and SEUs with a common radiation source. The correlation decreases the number of error combinations to be considered, thereby making multiple gate errors easier to simulate and analyze. We conclude by briefly discussing methods to model multiple errors.

Soft errors are an increasingly serious problem for logic circuits. To estimate the effects of soft errors on such circuits, we develop a general computational framework based on probabilistic transfer matrices (PTMs). In particular, we apply them to evaluate circuit reliability in the presence of soft errors, which involves combining the PTMs of gates to form an overall circuit PTM. Information, such as output probabilities, the overall probability of error, and signal observability, can then be extracted from the circuit PTM. We employ algebraic decision diagrams (ADDs) to improve the efficiency of PTM operations. A particularly challenging technical problem, solved in our work, is to extend simultaneously tensor products and matrix multiplication in terms of ADDs to non-square matrices. Our PTM-based method enables accurate evaluation of reliability for moderately large circuits and can be extended by circuit partitioning. To demonstrate the power of the PTM approach, we apply it to several problems in fault-tolerant design and reliability improvement.

Accurate reliability evaluation and enhancement via probabilistic transfer matrices

Transient faults are becoming an increasingly serious concern for logic circuits. They can be caused by thermal neutrons, present at all altitudes, and by other types of ionizing radiation, especially in aerospace applications and nuclear engineering. In this paper we examine issues related to detection of transient errors. The difficulty in testing for transient errors is that they are not always present. Test vectors need to be repeated a number of times in order to detect a fault. We show how to compute a measure for the detectability of transient faults with respect to specific test vectors. This is done using a matrix-based gate-fault model known as the probabilistic transfer matrix model. Using this detectability measure we derive methods to generate multisets of tests to verify probability distributions of faults and detect abnormalities in circuit behavior. Applications of this method include detection of increased atmospheric radiation in terms of its impact on circuits, and testing for process variation that increases the susceptibility of a circuit to transient errors.

Plant growth-promoting rhizobacteria (PGPR) effects on plant yield are highly variable under field conditions due to competition with soil microbiota. Previous research determined that many Bacillus velezensis PGPR strains can use pectin as a sole carbon source and that seed inoculation with PGPR plus pectin-rich orange peel (OP) can enhance PGPR-mediated increases in plant growth. Because the previous studies used a single soybean cultivar, the objective of this research was to test the effect of PGPR plus OP inoculation on plant responses in a wide range of soybean cultivars. Preliminary screening with 20 soybean cultivars in the greenhouse showed that the PGPR plus OP produced a positive increase in all plant growth parameters when all cultivar data was averaged. However, when the inoculation response was examined cultivar by cultivar there was a range of cultivar response from a 60% increase in growth parameters to a 12% decrease, pointing to the presence of a cultivar-PGPR specificity. Further greenhouse and field experiments that studied cultivars with contrast responses to synbiotic inoculation revealed that the environment and/or the molecular interactions between the plant and microorganisms may play an important role in plant

As device features continue to scale, traditional circuit optimizations targeting area and delay have to be closely monitored for their effect on reliability. Yet, existing reliability analysis algorithms suffer from poor scalability and technology-dependent approaches which are unable to efficiently guide synthesis optimizations. Therefore, we present a new reliability analysis framework known as Analysis of Soft Error Rate (AnSER) that runs in linear time and outperforms state-of-the-art by two to three orders of magnitude. Moreover, our algorithms are amenable to uses in logic synthesis due to their technology independence and scalability.

AnSER : A Lightweight Reliability Evaluator for use in Logic Synthesis

Patient-derived organoids (PDOs) can model personalized therapy responses, however current screening technologies cannot reveal drug response mechanisms or study how tumor microenvironment cells alter therapeutic performance. To address this, we developed a highly-multiplexed mass cytometry platform to measure post translational modification (PTM) signaling in >2,500 colorectal cancer (CRC) PDOs and cancer-associated fibroblasts (CAFs) in response to clinical therapies at single-cell resolution. To compare patient- and microenvironment-specific drug responses in thousands of single-cell datasets, we developed Trellis — a highly-scalable, hierarchical tree-based treatment effect analysis method. Trellis single-cell screening revealed that on-target cell-cycle blockage and DNA-damage drug effects are common, even in chemorefractory PDOs. However, drug-induced apoptosis is patient-specific. We found drug-induced apoptosis does not correlate with genotype or clinical staging but does align with cell-intrinsic PTM signaling in PDOs. CAFs protect chemosensitive PDOs by shifting cancer cells into a slow-cycling cell-state and CAF chemoprotection can be reversed by inhibiting YAP. Highlights >2,500 single-cell PTM signaling, DNA-damage, cell-cycle, and apoptosis responses from drug-treated PDOs and CAFs. Trellis: hierarchical tree-based treatment effect method for single-cell screening analysis. PDOs have patient-specific drug responses that align with cell-intrinsic PTM signaling states. CAFs chemoprotect PDOs by altering PDO cell-state via YAP signaling.

Trellis Single-Cell Screening Reveals Stromal Regulation of Patient-Derived Organoid Drug Responses

INTRODUCTION: The median survival for glioblastoma multiforme (GBM) has only improved by 4.6 months in more than 100 years, underlying the need for innovative methods for understanding this devastating tumor. Spatial transcriptomics is a new method of whole-transcriptome assessment which allows for simultaneous visualization of mRNA expression in situ with histopathology. METHODS: We applied spARC to 25,517 Unique Molecular Identifiers from 10 surgically resected human IDH-mutant astrocytic gliomas (Grade II (n = 3) and Grade III (n = 3)) and GBMs (n = 4). spARC uses manifold learning, graph filters, data diffusion and diffusion filtration to enable discovery of gene-gene relationships, spatial co-localization of genes, and receptor-ligand interactions applicable across a variety of spatial transcriptomic methods. A Neuropathologist annotated whole-slide images blind to our computational analysis and we used in-situ hybridization and immunohistochemistry to demonstrate that spaRC imputation recovery of gene expression is superior to raw expression. RESULTS: We demonstrate that spARC can identify spatially restricted tumor niches of dense tumor, leading edge, infiltration/high tumor burden, hemoglobin, and vasculature with high specificity. These clusters can be identified with genes including CD44, VIM, LDHA (dense tumor); SNAP25, UCHL1, OLMF1 (leading edge); OLIG2, MBP, PDGFRA (Infiltrating/High Tumor Burden). In our assessment of ligand-receptor interactions we found that GBM samples were enriched for SPP1-CD44 signaling. We validated this using GBM TCGA data stratifying patients based on expression of SPP1 and CD44 genes and found that high expression conferred lower survival at 12 months. CONCLUSIONS: Spatial transcriptomics paired with graph-based machine learning methods applied to human GBMs is a powerful technique able to uncover signaling networks relevant to patient survival and may aid in developing new therapeutic strategies.

157 Identifying Spatial Transcriptomics Signaling Networks in Human Glioblastoma Using Graph-Based Machine Learning

While single-cell technologies have allowed scientists to characterize cell states that emerge during cancer progression through temporal sampling, connecting these samples over time and inferring gene-gene relationships that promote cancer plasticity remains a challenge. To address these challenges, we developed TrajectoryNet, a neural ordinary differential equation network that learns continuous dynamics via interpolation of population flows between sampled timepoints. By running causality analysis on the output of TrajectoryNet, we compute rich and complex gene-gene networks that drive pathogenic trajectories forward. Applying this pipeline to scRNAseq data generated from in vitro models of breast cancer, we identify and validate a refined CD44hiEPCAM+CAV1 + marker profile that improves the identification and isolation of cancer stem cells (CSCs) from bulk cell populations. Studying the cell plasticity trajectories emerging from this population, we identify comprehensive temporal regulatory networks that drive cell fate decisions between an epithelial-to-mesenchymal (EMT) trajectory, and a mesenchymal-to-epithelial (MET) trajectory. Through these studies, we identify and validate estrogen related receptor alpha as a critical mediator of CSC plasticity. We further apply TrajectoryNet to an in vivo xenograft model and demonstrate it’s ability to elucidate trajectories governing primary tumor metastasis to the lung, identifying a dominant EMT trajectory that includes elements of our newly-defined temporal EMT regulatory network. Demonstrated here in cancer, the TrajectoryNet pipeline is a transformative approach to uncovering temporal molecular programs operating in dynamic cell systems from static single-cell data.

Learning transcriptional and regulatory dynamics driving cancer cell plasticity using neural ODE-based optimal transport

Single-cell analysis reveals inflammatory interactions driving macular degeneration

PD-1 maintains CD8 T cell tolerance towards cutaneous neoantigens.

Herpes simplex virus type 2 (HSV-2) coinfection is associated with increased HIV-1 viral loads and expanded tissue reservoirs, but the mechanisms are not well defined. HSV-2 recurrences result in an influx of activated CD4+ T cells to sites of viral replication and an increase in activated CD4+ T cells in peripheral blood. We hypothesized that HSV-2 induces changes in these cells that facilitate HIV-1 reactivation and replication and tested this hypothesis in human CD4+ T cells and 2D10 cells, a model of HIV-1 latency. HSV-2 promoted latency reversal in HSV-2–infected and bystander 2D10 cells. Bulk and single-cell RNA-Seq studies of activated primary human CD4+ T cells identified decreased expression of HIV-1 restriction factors and increased expression of transcripts including MALAT1 that could drive HIV replication in both the HSV-2–infected and bystander cells. Transfection of 2D10 cells with VP16, an HSV-2 protein that regulates transcription, significantly upregulated MALAT1 expression, decreased trimethylation of lysine 27 on histone H3 protein, and triggered HIV latency reversal. Knockout of MALAT1 from 2D10 cells abrogated the response to VP16 and reduced the response to HSV-2 infection. These results demonstrate that HSV-2 contributes to HIV-1 reactivation through diverse mechanisms, including upregulation of MALAT1 to release epigenetic silencing.

HSV-2 triggers upregulation of MALAT1 in CD4+ T cells and promotes HIV latency reversal

Multiscale geometric and topological analyses for characterizing and predicting immune responses from single cell data.

Moore, Bhaskar, Gao, et al. combine live imaging of the mouse epidermis and machine learning to study the role and regulation of calcium signaling within the stem cell layer. They find that cells in G2 are necessary for coordinated tissue-wide communication and reveal a feedback loop between cell cycle and calcium signaling.

Cell cycle controls long-range calcium signaling in the regenerating epidermis

Modeling uniquely human gene regulatory function via targeted humanization of the mouse genome

Checkpoint inhibitors (CPIs) targeting programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have revolutionized cancer treatment but can trigger autoimmune complications, including CPI-induced diabetes mellitus (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti–PD-L1 but not anti–CTLA-4 induced diabetes rapidly. RNA sequencing revealed that cytolytic IFN-γ+CD8+ T cells infiltrated islets with anti–PD-L1. Changes in β cells were predominantly driven by IFN-γ and TNF-α and included induction of a potentially novel β cell population with transcriptional changes suggesting dedifferentiation. IFN-γ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti–IFN-γ and anti–TNF-α prevented CPI-DM in anti–PD-L1–treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway resulted in transcriptional changes in β cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication.

Immune cells and their inflammatory mediators modify β cells and cause checkpoint inhibitor–induced diabetes

The landscape of pioneer factor activity reveals the mechanisms of chromatin reprogramming and genome activation.

Key Points • Integrated transcriptome analyses identify putative precancerous circulating clonal CD4+ T-cell populations in patients with CTCL.• The study results reveal promising therapeutic strategies via targeting of CD82 and JAK kinases.

Integrated transcriptome and trajectory analysis of cutaneous T-cell lymphoma identifies putative precancer populations

Tissue repair requires a highly coordinated cellular response to injury. In the lung, alveolar type 2 (AT2) cells act as stem cells and can replace both themselves and alveolar type 1 cells (AT1); however, the complex orchestration of AT2 stem cell activity following lung injury is poorly understood owing to the inability of tracking individual stem cells and their dynamic behavior over time. Here, we apply live time lapse imaging to ex vivo mouse precision cut lung slice (PCLS) culture and in vivo mouse lung to track individual GFP-labeled AT2 cells following induction of alveolar injury by bleomycin. We observe highly dynamic movement of AT2 cells, including migration within and between alveoli. To map the dynamic evolution of AT2 cell behavior, we introduce Live Cell Encoder (LCE-PHATE), a novel method for converting static snapshots from time lapse imaging into single points representative of entire, dynamic cellular trajectories. Applying LCE-PHATE, we observe the emergence of at least three distinct morphokinetic AT2 cell states associated with AT2 stem cell injury response. Finally, small molecule-based inhibition of Rho-associated protein kinase (ROCK) pathway significantly reduced motility of AT2 stem cells following injury and reduced expression of Krt8, a marker of intermediate progenitor cells. Together, our results uncover motility of alveolar stem cells as a new injury response mechanism in the lung and reveal properties of stem cell motility at high cellular resolution.

Spatiotemporal coordination of stem cell behavior following alveolar injury

Thousands of long intergenic non-coding RNAs (lincRNAs) are transcribed throughout the vertebrate genome. A subset of lincRNAs enriched in developing brains has recently been found to contain cryptic open reading frames and are speculated to encode micropeptides. However, systematic identification and functional assessment of these transcripts have been hindered by technical challenges caused by their small size. Here we show that two putative lincRNAs (linc-mipep and linc-wrb) encode micropeptides with homology to the vertebrate-specific chromatin architectural protein, Hmgn1, and demonstrate that they are required for development of vertebrate-specific brain cell types. Specifically, we show that NMDA receptor-mediated pathways are dysregulated in zebrafish lacking these micropeptides and that their loss preferentially alters the gene regulatory networks that establish cerebellar cells and oligodendrocytes – evolutionarily newer cell types that develop postnatally in humans. These findings highlight the power of screening for unexplored micropeptide functions by revealing a key missing link in the evolution of vertebrate brain cell development and illustrating a genetic basis for how some neural cell types are more susceptible to chromatin disruptions, with implications for neurodevelopmental disorders and disease.

linc-mipep and linc-wrb encode micropeptides that regulate chromatin accessibility in vertebrate-specific neural cells

Abstract Phenotypic plasticity describes the ability of cancer cells to undergo dynamic, nongenetic cell state changes that amplify cancer heterogeneity to promote metastasis and therapy evasion. Thus, cancer cells occupy a continuous spectrum of phenotypic states connected by trajectories defining dynamic transitions upon a cancer cell state landscape. With technologies proliferating to systematically record molecular mechanisms at single-cell resolution, we illuminate manifold learning techniques as emerging computational tools to effectively model cell state dynamics in a way that mimics our understanding of the cell state landscape. We anticipate that “state-gating” therapies targeting phenotypic plasticity will limit cancer heterogeneity, metastasis, and therapy resistance. Significance: Nongenetic mechanisms underlying phenotypic plasticity have emerged as significant drivers of tumor heterogeneity, metastasis, and therapy resistance. Herein, we discuss new experimental and computational techniques to define phenotypic plasticity as a scaffold to guide accelerated progress in uncovering new vulnerabilities for therapeutic exploitation.

Mapping Phenotypic Plasticity upon the Cancer Cell State Landscape Using Manifold Learning

Patient-derived organoids (PDOs) model personalized cancer therapy responses. How- ever, existing bulk PDO screening technologies cannot reveal drug response mechanisms or model how cells of the tumor microenvironment alter therapy performance. To address this, we developed a highly-multiplexed thiol-reactive organoid barcoding in situ (TOB is ) mass cytometry platform to perform single-cell post translational modification (PTM) sig- naling analysis of colorectal cancer (CRC) PDOs and cancer-associated fibroblasts (CAFs) in response to clinical therapies. To compare patient- and microenvironment-specific treatment effects in thousands of single-cell PTM datasets, we developed Trellis — a 21 highly-scalable, hierarchical tree-based treatment effect analysis method. Trellis analysis of > 2,500 single-cell PTM PDO-CAF organoid cultures revealed that on-target cell-cycle blockage and DNA-damage drug effects are common, even in chemorefractory PDOs. 24 However, drug-induced apoptosis is patient-specific. We found drug-induced apoptosis 25 does not correlate with genotype or clinical staging, but does align with cell-intrinsic PTM 26 signaling in PDOs. We observe that CAFs protect chemosensitive PDOs by shifting can- 27 cer cells into a slow-cycling cell-state in a patient-specific manner and show that CAF 28 chemoprotection can be reversed by inhibiting YAP. These results reveal that PTM sig- 29 naling flux is a major determinant of chemosensitivity and demonstrate CAFs regulate 30 patient-specific drug responses by altering cancer cell-state. 31 normalizing by their own controls. TOB is mass cytometry and Trellis revealed PDO-specific drug response PTM signaling and demonstrated CAFs protect CRC cells from chemotherapy by shifting epithelial cell- state. CAF chemoprotection could be rationally reversed using insights from single-cell PTM data, demon- strating the utility of PTM-focused drug screening for overcoming therapy resistance. These results illustrate the functional intertumoral heterogeneity of patient-specific drug response mechanisms and suggest TME cells should be included in future PDO models. manner and PTM signaling data can be used to overcome CAF protection. We propose single-cell analysis as a powerful alternative to traditional bulk viability analysis of PDOs and suggest TME cells should be considered in future precision medicine models. of the Quadtree construction but can be applied to higher dimensions.

Cancer-Associated Fibroblasts Regulate 1 Patient-Derived Organoid Drug Responses 2

Deep learning for quality assessment of optical coherence tomography angiography images

 Herpes simplex virus 2 (HSV-2) infection is a major factor driving the global HIV epidemic, leading to increased HIV plasma viral loads (PVLs) and transmission. Previous studies which focused on mucosal responses cannot explain the observed effects of HSV-2 on HIV PVLs. We sought to determine mechanisms by which HSV-2 increases HIV PVLs. CD4 T cells are recruited to sites of HSV-2 lesions and HSV-2 can infect these cells. Phenotyping of CD4 cells infected with HSV-2 in vitro suggested a preference for T follicular helper cells, an HIV latent reservoir. HSV infection of latently infected Jurkat-2D10 cells resulted in a 10-fold increase in HIV ltr expression. After exposing CD4 cells from HIV+ donors to HSV-2, HIV p24 was detected only in cells expressing HSV-2 glycoprotein B (gB), a marker of productive HSV-2 infection. Bulk and single cell RNAseq on FACS-purified, HSV-infected and uninfected CD4 cells demonstrated reduced expression of HIV restriction factors in HSV+ cells; HSV exposed but uninfected cells exhibited higher expression of interferon response genes, potentially explaining their resistance to HIV reactivation. HSV+ cells exhibited increased expression of the lncRNA MALAT1, which may promote HIV reactivation through epigenetic modification, and HSV infection of 2D10 and CD4 cells led to decreased histone deacetylase activity. Transfection of 2D10 cells with HSV protein VP16 resulted in significantly increased HIV ltr and MALAT1 gene expression, and reduced epigenetic silencing marks. HIV proteins were also increased by proteomic analyses. These findings identify several mechanisms by which HSV-2 directly triggers HIV reactivation, such as the up-regulation of the lncRNA MALAT1.
 Supported by grants from the NIH (R01 AI134367, T32 AI007501, T32 GM007288)

Skin epidermal homeostasis is maintained via constant regeneration by stem cells, which must communicate to balance their self-renewal and differentiation. A key molecular pathway, Ca2+ signaling has been implicated as a signal integrator in developing and wounded epithelial tissues[1, 2, 3, 4]. Yet how stem cells carry out this signaling across a regenerative tissue remains unknown due to significant challenges in studying signaling dynamics in live mice, limiting our understanding of the mechanisms of stem cell communication during homeostasis. To interpret high dimensional signals that have complex spatial and temporal patterns, we combined optimized imaging of Ca2+ signaling in thousands of epidermal stem cells in living mice with a new machine learning tool, Geometric Scattering Trajectory Homology (GSTH). Using a combination of signal processing, data geometry, and topology, GSTH captures patterns of signaling at multiple scales, either between direct or distant stem cell neighbors. Here we show that epidermal stem cells display dynamic intercellular Ca2+ signaling among neighborhoods of up to 10 cells that is surprisingly coordinated and directed through time across a pool of thousands of stem cells. We find that this collective coordination is an emergent property of the stem cell compartment, distinct from excitatory quiescent neuronal tissues. We demonstrate that cycling stem cells, specifically G2 cells, govern homeostatic patterns of Ca2+ signaling. Stem cells in different cell cycle stages dynamically regulate localization of the gap junction component Connexin43 (Cx43). Lastly, we uncouple global from local communication and identify Cx43 as the molecular mediator necessary for connectivity between local signaling neighborhoods. This work provides resolution in how stem cells at different stages of the cell cycle communicate and how that diversity of phases is essential for tissue wide communication and signaling flow during epidermal regeneration. Our approach provides a framework to investigate stem cell populations and their signaling dynamics, previously not possible.

G2 stem cells orchestrate time-directed, long-range coordination of calcium signaling during skin epidermal regeneration

 Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States. Various epidemiologic studies have shown that obesity increases the risk of PDAC. With rising rates of obesity worldwide, it is imperative that we understand the mechanisms by which obesity promotes PDAC progression. Therefore, to study the effect of obesity on PDAC, we combined a well-established genetic model of obesity (Lepob/ob) with a faithful oncogenic Kras-driven pancreatic cancer model (KC: Pdx1-Cre; KrasLSL-G12D/+) and showed that obese mice had both increased tumor burden and shortened survival compared to their lean counterparts. Strikingly, weight loss (via AAV-leptin rescue or caloric restriction), decreased tumor development, demonstrating that the tumor-promoting effects of obesity can be reversed. Bulk-RNA sequencing of tumors from obese mice exhibited aberrant expression of islet beta-cell genes, including those coding for the peptide hormones cholecystokinin (CCK) and amylin (Iapp). Single-cell RNA sequencing of islet beta-cells from wild-type, high fat diet-fed, and Lepob/ob mice revealed a trajectory of beta-cell adaptation to obesity with dysregulated hormone expression, including downregulation of insulin expression and upregulation of CCK and Iapp, concordant with loss of beta-cell identity transcription factors and beta-cell dysfunction. In silico analyses using dynamic optimal transport (TrajectoryNet) demonstrate that CCK-expressing beta-cells arise from pre-existing insulin low-expressing beta-cells, arguing for baseline beta-cell heterogeneity as a determinant of aberrant hormone expression. Lastly, transgenic expression of CCK or Iapp in beta-cells was sufficient to promote oncogenic Kras-driven pancreatic tumorigenesis, while converse beta-cell ablation impeded tumor progression in mice. Together, these results uncover a novel mechanism of obesity driven PDAC by local hormonal signaling between endocrine islets and exocrine acinar cells and reveal pancreatic endocrine adaptations that could be targeted to halt exocrine tumorigenesis.
 Citation Format: Cathy C. Garcia, Lauren Lawres, Sherry Agabiti, Jaffarguriqbal Singh, Alex Tong, Aarthi Venkat, Daniel B. Burkhardt, Rebecca Cardone, Richard G. Kibbey, Smita Krishnaswamy, Mandar D. Muzumdar. Elucidating mechanisms of endocrine-exocrine signaling in obesity-driven pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C050.

Abstract C050: Elucidating mechanisms of endocrine-exocrine signaling in obesity-driven pancreatic cancer

Biological networks operate within architectural frameworks that influence the state and function of cells through niche-specific factors such as exposure to nutrients and metabolites, soluble signaling molecules, and direct cognate cell-cell communication. Spatial omics technologies incorporate environmental information into the study of biological systems, where the spatial coordinates of cells may directly or indirectly encode these micro-anatomical features. However, they suffer from technical artifacts, such as dropout, that impede biological discovery. Current methods that attempt to correct for this fail to adequately integrate highly informative spatial information when recovering gene expression and modelling cell-cell dynamics in situ. To address this oversight, we developed spatial Affinity-graph Recovery of Counts (spARC), a data diffusion-based filtration method that shares information between neighboring cells in tissue and related cells in expression space, to recover gene dynamics and simulate signalling interactions in spatial transcriptomics data. Following validation, we applied spARC to 10 IDH-mutant surgically resected human gliomas across WHO grades II-IV in order to study signaling networks across disease progression. This analysis revealed co-expressed genes that border the interface between tumor and tumor-infiltrated brain, allowing us to characterize global and local structure of glioma. By simulating paracrine signaling in silico, we identified an Osteopontin-CD44 interaction enriched in grade IV relative to grade II and grade III astrocytomas, and validated the clinical relevance of this signaling axis using TCGA.

spARC recovers human glioma spatial signaling networks with graph filtering

Single-cell multi-modal GAN reveals spatial patterns in single-cell data from triple-negative breast cancer

A major challenge in embedding or visualizing clinical patient data is the heterogeneity of variable types including continuous lab values, categorical diagnostic codes, as well as missing or incomplete data. In particular, in EHR data, some variables are missing not at random (MNAR) but deliberately not collected and thus are a source of information. For example, lab tests may be deemed necessary for some patients on the basis of suspected diagnosis, but not for others. Here we present the MURAL forest – an unsupervised random forest for representing data with disparate variable types (e.g., categorical, continuous, MNAR). MURAL forests consist of a set of decision trees where node-splitting variables are chosen at random, such that the marginal entropy of all other variables is minimized by the split. This allows us to also split on MNAR variables and discrete variables in a way that is consistent with the continuous variables. The end goal is to learn the MURAL embedding of patients using average tree distances between those patients. These distances can be fed to nonlinear dimensionality reduction method like PHATE to derive visualizable embeddings. While such methods are ubiquitous in continuous-valued datasets (like single cell RNA-sequencing) they have not been used extensively in mixed variable data. We showcase the use of our method on one artificial and two clinical datasets. We show that using our approach, we can visualize and classify data more accurately than competing approaches. Finally, we show that MURAL can also be used to compare cohorts of patients via the recently proposed tree-sliced Wasserstein distances.

MURAL: An Unsupervised Random Forest-Based Embedding for Electronic Health Record Data

The genome of the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), the pathogen that causes coronavirus disease 2019 (COVID-19), has been sequenced at an unprecedented scale, leading to a tremendous amount of viral genome sequencing data. To understand the evolution of this virus in humans, and to assist in tracing infection pathways and designing preventive strategies, we present a set of computational tools that span phylogenomics, population genetics and machine learning approaches. To illustrate the utility of this toolbox, we detail an in depth analysis of the genetic diversity of SARS-CoV-2 in first year of the COVID-19 pandemic, using 329,854 high-quality consensus sequences published in the GISAID database during the pre-vaccination phase. We demonstrate that, compared to standard phylogenetic approaches, haplotype networks can be computed efficiently on much larger datasets, enabling real-time analyses. Furthermore, time series change of Tajima’s D provides a powerful metric of population expansion. Unsupervised learning techniques further highlight key steps in variant detection and facilitate the study of the role of this genomic variation in the context of SARS-CoV-2 infection, with Multiscale PHATE methodology identifying fine-scale structure in the SARS-CoV-2 genetic data that underlies the emergence of key lineages. The computational framework presented here is useful for real-time genomic surveillance of SARS-CoV-2 and could be applied to any pathogen that threatens the health of worldwide populations of humans and other organisms.

Data-driven approaches for genetic characterization of SARS-CoV-2 lineages

In modern relational machine learning it is common to encounter large graphs that arise via interactions or similarities between obser-vations in many domains. Further, in many cases the target entities for analysis are actually signals on such graphs. We propose to compare and organize such datasets of graph signals by using an earth mover’s distance (EMD) with a geodesic cost over the underlying graph. Typically, EMD is computed by optimizing over the cost of transporting one probability distribution to another over an underlying metric space. However, this is inefﬁcient when computing the EMD between many signals. Here, we propose an unbalanced graph EMD that efﬁciently embeds the unbalanced EMD on an underlying graph into an L 1 space, whose metric we call unbalanced diffusion earth mover’s distance (UDEMD) . Next, we show how this gives distances between graph signals that are robust to noise. Finally, we apply this to organizing patients based on clinical notes, embedding cells modeled as signals on a gene graph, and organizing genes modeled as signals over a large cell graph. In each case, we show that UDEMD-based embeddings ﬁnd accurate distances that are highly efﬁcient compared to other methods.

Embedding Signals on Knowledge Graphs with Unbalanced Diffusion Earth Mover's Distance

Abstract LT013: Endocrine-exocrine signaling is a driver of obesity-associated pancreatic ductal adenocarcinoma

Description Tumor-specific CD8+ T cells in stable tumor-draining lymph node reservoir are clonally and developmentally related to those in tumors. A niche in the node The presence of “stem-like” TCF1+ CD8+ T (TSL) cells in tumors correlates with better patient outcomes after immunotherapy. TSL cells undergo terminal differentiation and exhaustion in the tumor microenvironment; therefore, how a stem-like population is maintained throughout tumor development is unclear. Using a mouse model of lung adenocarcinoma programmed to express neoantigens, Connolly et al. identified a stable reservoir of tumor-specific TSL cells in the tumor-draining lymph node (dLN). TSL cells migrated from the dLN to the tumor, where they became terminally differentiated as the tumor microenvironment shifted from “hot” to “cold.” These findings suggest that therapeutic strategies directed at tumor-specific T cells in the dLN may be a promising approach to treat patients with cold tumors. “Stem-like” TCF1+ CD8+ T (TSL) cells are necessary for long-term maintenance of T cell responses and the efficacy of immunotherapy, but, as tumors contain signals that should drive T cell terminal differentiation, how these cells are maintained in tumors remains unclear. In this study, we found that a small number of TCF1+ tumor-specific CD8+ T cells were present in lung tumors throughout their development. Yet, most intratumoral T cells differentiated as tumors progressed, corresponding with an immunologic shift in the tumor microenvironment (TME) from “hot” (T cell inflamed) to “cold” (non–T cell inflamed). By contrast, most tumor-specific CD8+ T cells in tumor-draining lymph nodes (dLNs) had functions and gene expression signatures similar to TSL from chronic lymphocytic choriomeningitis virus infection, and this population was stable over time despite the changes in the TME. dLN T cells were the developmental precursors of, and were clonally related to, their more differentiated intratumoral counterparts. Our data support the hypothesis that dLN T cells are the developmental precursors of the TCF1+ T cells in tumors that are maintained by continuous migration. Last, CD8+ T cells similar to TSL were also present in LNs from patients with lung adenocarcinoma, suggesting that a similar model may be relevant in human disease. Thus, we propose that the dLN TSL reservoir has a critical function in sustaining antitumor T cells during tumor development and in protecting them from the terminal differentiation that occurs in the TME.

A reservoir of stem-like CD8+ T cells in the tumor-draining lymph node preserves the ongoing antitumor immune response

Here we focus on understanding mechanisms that drive dynamic changes in gene expression and epigenetic marks that enable triple negative breast cancer cells to change states, and to thereby invade tissues and seed secondary tumors. The epithelial-to-mesenchymal transition (EMT) facilitates invasion and migration away from the primary tumor site. However, it is increasingly apparent that the reverse process, the mesenchymal-to-epithelial transition (MET), enhances metastatic colonization and growth via reacquisition of the epithelial phenotype. With no therapies currently available to stop metastatic tumor growth, we aim to uncover the mechanisms driving the MET towards identifying novel anti-metastatic therapies. We use the 3D in vitro mammosphere model system where single tumor-initiating cells residing in a partial-EMT state develop into a 3D organoid over 30 days. We sampled cells at 5 time points and performed scRNA-seq and scATAC-seq to analyze cell states. We develop a novel computational model of cellular development based on the theory of dynamic optimal transport (OT) and continuous normalizing flows. Our model TrajectoryNet is a neural ODE (ordinary differential equation) network that models the gradient of cell state with respect to time continuously over the input space and over time from cross-sectional single-cell data. TrajectoryNet interpolates between collected timepoints and learns a continuous realistic progression that describes cellular evolution in terms of gene expression and chromatin accessibility. Key to TrajectoryNet is a unique regularization to penalize the magnitude of the gradient over the flow. We prove this results in dynamic OT, thereby discouraging the neural network from taking circuitous or unrealistic paths. In contrast to TrajectoryNet, pseudotime, and RNA velocity are best at analyzing within a particular timepoint and do not handle large gaps in timepoints. We compare TrajectoryNet to RNA velocity and static OT and show that TrajectoryNet achieves better trajectories in terms of predicting withheld timepoints. Using TrajectoryNet, we identify a continuous ordering of events that occur during MET that show when and how the epithelial cell states begin to emerge. Such a continuous ordering can give rise to causal associations that can be inhibited to alter MET mechanisms. We also differentiate between trajectories that show self-renewal and maintenance of the tumor-initiating cells, and trajectories that revert to an epithelial state. Further we find that only ~10% of the initial seeded cells develop into mammospheres and identify which initial cells have the potential to seed secondary tumors. Hence, we can refine features (gene and epigenetic states) that define aggressive tumor-initiating cells in triple negative breast cancer, as well as their dynamics through the MET in order to find therapeutic targets. Citation Format: Alexander Tong, Beatriz P. San Juan, Brandon Zhu, Christine L. Chaffer, Smita Krishnaswamy. Understanding the mesenchymal-to-epithelial transition and its drivers in triple-negative breast cancer with continuous normalizing flows [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2839.

Abstract 2839: Understanding the mesenchymal-to-epithelial transition and its drivers in triple-negative breast cancer with continuous normalizing flows

Regenerative processes in the mammalian skin require coordinated cell-cell communication. Ca2+ signaling can coordinate tissue-level responses in developing and wounded epithelia in tissue explants and invertebrates. However, its role in the homeostatic, regenerative basal layer of the skin epithelium is unknown due to significant challenges in studying signaling dynamics in a spatially complex tissue context in live mice. Here we combine in vivo imaging of dynamic Ca2+ signaling at the single cell level across thousands of cells with a novel computational approach, Geometric Scattering Trajectory Homology (GSTH). GSTH models Ca2+ as signals over a cell adjacency graph and uses a multi-level wavelet-like transform (called a scattering transform) to extract signaling patterns from our high dimensional in vivo datasets. We discover local Ca2+ signaling patterns are orchestrated so that signals flow in a coordinated and directed manner across the tissue, distinct from topographically uncoordinated Ca2+ signaling in excitatory tissues. Directed Ca2+ signaling is regulated by the major gap junction protein in the epidermal stem cell layer, Connexin 43 (Cx43). Cx43 gap junctions are dissociated as cells progress through the cell cycle out of G1 and play an essential role in the progression of stem cells from G2 towards mitosis. Finally, G2 cells display related signaling patterns and are essential for tissue-level signaling coordination. Together, our results provide insight into how such a ubiquitous signaling pathway regulates highly specific behaviors and outcomes at a tissue-wide level to maintain proper homeostasis.

Tissue-wide coordination of calcium signaling regulates the epithelial stem cell pool during homeostasis

1-deoxysphingolipids bind to COUP-TF to modulate lymphatic and cardiac cell development.

A novel topological machine learning approach applied to single-nucleus RNA sequencing from human retinas with age-related macular degeneration identifies interacting disease phase-specific glial activation states shared with Alzheimer’s disease and multiple sclerosis. 2 Abstract Neurodegeneration occurs in a wide range of diseases, including age-related macular degeneration (AMD), Alzheimer’s disease (AD), and multiple sclerosis (MS), each with distinct inciting events. To determine whether glial transcriptional states are shared across phases of degeneration, we sequenced 50,498 nuclei from the retinas of seven AMD patients and six healthy controls, generating the first single-cell transcriptomic atlas of AMD. We identified groupings of cells implicated in disease pathogenesis by applying a novel topologically-inspired machine learning approach called ‘diffusion condensation.’ By calculating diffusion homology features and performing persistence analysis, diffusion condensation identified activated glial states enriched in the early phases of AMD, AD, and MS as well as an AMD-specific proangiogenic astrocyte state promoting pathogenic neovascularization in advanced AMD. Finally, by mapping the expression of disease-associated genes to glial states, we identified key signaling interactions creating hypotheses for therapeutic intervention. Our topological analysis identified an integrated disease-phase specific glial landscape that is shared across neurodegenerative conditions affecting the central nervous system.

Topological analysis of single-cell data reveals shared glial landscape of macular degeneration and neurodegenerative diseases

We propose a method called integrated diffusion for combining multimodal data, gathered via different sensors on the same system, to create a integrated data diffusion operator. As real world data suffers from both local and global noise, we introduce mechanisms to optimally calculate a diffusion operator that reflects the combined information in data by maintaining low frequency eigenvectors of each modality both globally and locally. We show the utility of this integrated operator in denoising and visualizing multimodal toy data as well as multi-omic data generated from blood cells, measuring both gene expression and chromatin accessibility. Our approach better visualizes the geometry of the integrated data and captures known cross-modality associations. More generally, integrated diffusion is broadly applicable to multimodal datasets generated by noisy sensors collected in a variety of fields.

Multimodal Data Visualization and Denoising with Integrated Diffusion

Topological Analysis of Single-Cell Hierarchy Reveals Inflammatory Glial Landscape of Macular Degeneration

Generating hard-to-obtain information from easy-to-obtain information: Applications in drug discovery and clinical inference

Neural network predicts need for red blood cell transfusion for patients with acute gastrointestinal bleeding admitted to the intensive care unit

“Stem-like” TCF1+ CD8+ T cells (TSL) are necessary for long-term maintenance of T cell responses and the efficacy of immunotherapy but, as tumors contain signals that should drive T-cell terminal-differentiation, how these cells are maintained in tumors remains unclear. We found that a small number of TCF1+ tumor-specific CD8+ T cells were present in tumors throughout development. Yet, most intratumoral T cells differentiated as tumors progressed, corresponding with an immunologic shift in the tumor microenvironment (TME) from “hot” to “cold”. By contrast, most tumor-specific CD8+ T cells in tumor-draining lymph nodes (dLNs) had functions and gene expression signatures similar to TSL from chronic LCMV infection and this population was stable over time, despite the changes in the TME. dLN T cells were the precursors of their more-differentiated intratumoral counterparts, and maintenance of TCF1 by intratumoral T cells required continuous migration from dLNs. Finally, TSL CD8 T cells were also present in LNs from lung adenocarcinoma patients, suggesting this population is also relevant in human disease. Thus, we propose that the dLN TSL reservoir has a critical function during tumor development in sustaining antitumor T cells during tumor development and protecting them from the terminal differentiation that occurs in the TME.

A reservoir of stem-like CD8 T cells in the tumor-draining lymph node maintains the ongoing anti-tumor immune response

The biomedical community is producing increasingly high dimensional datasets, integrated from hundreds of patient samples, which current computational techniques struggle to explore. To uncover biological meaning from these complex datasets, we present an approach called Multiscale PHATE, which learns abstracted biological features from data that can be directly predictive of disease. Built on a continuous coarse graining process called diffusion condensation, Multiscale PHATE creates a tree of data granularities that can be cut at coarse levels for high level summarizations of data, as well as at fine levels for detailed representations on subsets. We apply Multiscale PHATE to study the immune response to COVID-19 in 54 million cells from 168 hospitalized patients. Through our analysis of patient samples, we identify CD16hi CD66blo neutrophil and IFNγ+GranzymeB+ Th17 cell responses enriched in patients who die. Further, we show that population groupings Multiscale PHATE discovers can be directly fed into a classifier to predict disease outcome. We also use Multiscale PHATE-derived features to construct two different manifolds of patients, one from abstracted flow cytometry features and another directly on patient clinical features, both associating immune subsets and clinical markers with outcome.

Multiscale PHATE Exploration of SARS-CoV-2 Data Reveals Multimodal Signatures of Disease

Publisher Correction: MLL-AF9 initiates transformation from fast-proliferating myeloid progenitors

The genus Flavivirus contains many mosquito-borne human pathogens of global epidemiological importance such as dengue virus, West Nile virus, and Zika virus, which has recently emerged at epidemic levels. Infections with these viruses result in divergent clinical outcomes ranging from asymptomatic to fatal. Myriad factors influence infection severity including exposure, immune status and pathogen/host genetics. Furthermore, pre-existing infection may skew immune pathways or divert immune resources. We profiled immune cells from dengue virus-infected individuals by multiparameter mass cytometry (CyTOF) to define functional status. Elevations in IFNβ were noted in acute patients across the majority of cell types and were statistically elevated in 31 of 36 cell subsets. We quantified response to in vitro (re)infection with dengue or Zika viruses and detected a striking pattern of upregulation of responses to Zika infection by innate cell types which was not noted in response to dengue virus. Significance was discovered by statistical analysis as well as a neural network-based clustering approach which identified unusual cell subsets overlooked by conventional manual gating. Of public health importance, patient cells showed significant enrichment of innate cell responses to Zika virus indicating an intact and robust anti-Zika response despite the concurrent dengue infection.

Single cell immune profiling of dengue virus patients reveals intact immune responses to Zika virus with enrichment of innate immune signatures

IL-7 receptor alpha defines heterogeneity and signature of human effector memory CD8+ T cells in high dimensional analysis.

Structural and developmental principles of neuropil assembly in C. elegans

We have profiled cerebrospinal fluid T cells in healthy individuals and patients with MS using single-cell RNA and TCR sequencing. Cerebrospinal fluid snapshot The central nervous system (CNS) features mechanisms to protect against untoward inflammation yet allowing immune surveillance for pathogens. Pappalardo et al. profiled T cells in the cerebrospinal fluid (CSF) of healthy individuals and patients with multiple sclerosis (MS) using single-cell RNA and TCR sequences to define CNS immune homeostasis in both healthy donors and patients with MS. In healthy individuals, clonally expanded CSF T cells are largely distinct from those found in the blood with effector, IFNγ, and tissue adaptation signatures, whereas CSF T cells from patients with MS differ from healthy controls with a gene expression signature consistent with elevated activation and cytotoxicity. These findings provide insight into the unique immune environment in the CSF under normal and disease-associated conditions. T cells provide critical immune surveillance to the central nervous system (CNS), and the cerebrospinal fluid (CSF) is thought to be a main route for their entry. Further characterization of the state of T cells in the CSF in healthy individuals is important for understanding how T cells provide protective immune surveillance without damaging the delicate environment of the CNS and providing tissue-specific context for understanding immune dysfunction in neuroinflammatory disease. Here, we have profiled T cells in the CSF of healthy human donors and have identified signatures related to cytotoxic capacity and tissue adaptation that are further exemplified in clonally expanded CSF T cells. By comparing profiles of clonally expanded T cells obtained from the CSF of patients with multiple sclerosis (MS) and healthy donors, we report that clonally expanded T cells from the CSF of patients with MS have heightened expression of genes related to T cell activation and cytotoxicity.

Transcriptomic and clonal characterization of T cells in the human central nervous system

Dissecting alterations in human CD8+ T cells with aging by high-dimensional single cell mass cytometry.

The evolution of uniquely human traits likely entailed changes in developmental gene regulation. Human Accelerated Regions (HARs), which include transcriptional enhancers harboring a significant excess of human-specific sequence changes, are leading candidates for driving gene regulatory modifications in human development. However, insight into whether HARs alter the level, distribution and timing of endogenous gene expression remains limited. We examined the role of the HAR HACNS1 (HAR2) in human evolution by interrogating its molecular functions in a humanized mouse model. We find that HACNS1 maintains its human-specific enhancer activity in humanized mice and that it modifies expression of Gbx2, which encodes a homeobox transcription factor, during limb development. Using single-cell RNA-sequencing, we demonstrate that Gbx2 is upregulated in the chondrogenic mesenchyme of humanized limbs, supporting that HACNS1 alters gene expression in cell types involved in skeletal patterning. Our findings illustrate that humanized mouse models provide mechanistic insight into how HARs modified gene expression in human evolution.

Modeling uniquely human gene regulatory function in humanized mice

Abstract Morphological innovations that arose during human evolution are ultimately encoded in genetic changes that altered development. Human Accelerated Regions (HARs), which include developmental enhancers that harbor a significant excess of human-specific sequence changes, are leading candidates for driving novel physical modifications in humans. Here we examine the role of the HAR HACNS1 (also known as HAR2) in human limb evolution by directly interrogating its cellular and developmental functions in a humanized mouse model. HACNS1 encodes an enhancer with human-specific activity in the developing limb in transgenic mouse reporter assays, and exhibits increased epigenetic signatures of enhancer activity in the human embryonic limb compared to its orthologs in rhesus macaque and mouse. Here we find that HACNS1 maintains its human-specific enhancer activity compared to its chimpanzee ortholog in the mouse embryonic limb, and that it alters expression of the transcription factor gene Gbx2 during limb development. Using single-cell RNA-sequencing, we demonstrate that Gbx2 is upregulated in humanized limb bud chondrogenic mesenchyme, implicating HACNS1-mediated Gbx2 expression in early skeletal patterning. Our findings establish that HARs direct changes in the level and distribution of gene expression during development, and illustrate how humanized mouse models provide insight into regulatory pathways modified in human evolution.

The Human Accelerated Region HACNS1 modifies developmental gene expression in humanized mice

Visualizing structure and transitions in high-dimensional biological data

Quantifying the effect of experimental perturbations at single-cell resolution

MLL-AF9 initiates transformation from fast-proliferating myeloid progenitors

Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how and when obesity contributes to PDAC progression is not well understood. Leveraging an autochthonous mouse model, we demonstrate a causal and reversible role for obesity in early PDAC progression, showing that obesity markedly enhances tumorigenesis, while genetic or dietary induction of weight loss intercepts cancer development. Bulk and single cell molecular analyses of human and murine samples define microenvironmental consequences of obesity that promote tumor development rather than new driver gene mutations. We observe increased inflammation and fibrosis and also provide evidence for significant pancreatic islet cell adaptation in obesity-associated tumors. Specifically, we identify aberrant islet beta cell expression of the peptide hormone cholecystokinin (CCK) in tumors as an adaptive response to obesity. Furthermore, beta cell CCK expression promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Our studies argue that PDAC progression is driven by local obesity-associated changes in the tumor microenvironment – rather than systemic effects – and implicate endocrine-exocrine signaling beyond insulin in PDAC development. Furthermore, our demonstration that these obesity-associated adaptations are reversible supports the use of anti-obesity strategies to intercept PDAC early during progression.

Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma

Archetypal analysis is a data decomposition method that describes each observation in a dataset as a convex combination of ”pure types” or archetypes. These archetypes represent extrema of a data space in which there is a trade-off between features, such as in biology where different combinations of traits provide optimal fitness for different environments. Existing methods for archetypal analysis work well when a linear relationship exists between the feature space and the archetypal space. However, such methods are not applicable to systems where the feature space is generated non-linearly from the combination of archetypes, such as in biological systems or image transformations. Here, we propose a reformulation of the problem such that the goal is to learn a non-linear transformation of the data into a latent archetypal space. To solve this problem, we introduce Archetypal Analysis network (AAnet), which is a deep neural network framework for learning and generating from a latent archetypal representation of data. We demonstrate state-of-the-art recovery of ground-truth archetypes in non-linear data domains, show AAnet can generate from data geometry rather than from data density, and use AAnet to identify biologically meaningful archetypes in single-cell gene expression data.

High‐expression alleles of macrophage migration inhibitory factor (MIF) are linked genetically to the severity of systemic lupus erythematosus (SLE). The U1 small nuclear RNP (snRNP) immune complex containing U1 snRNP and anti–U1 snRNP antibodies, which are found in patients with SLE, activates the NLRP3 inflammasome, comprising NLRP3, ASC, and procaspase 1, in human monocytes, leading to the production of interleukin‐1β (IL‐1β). This study was undertaken to investigate the role of the snRNP immune complex in up‐regulating the expression of MIF and its interface with the NLRP3 inflammasome.

Macrophage Migration Inhibitory Factor Regulates U1 Small Nuclear RNP Immune Complex–Mediated Activation of the NLRP3 Inflammasome

Cellular regulatory networks are not static, but continuously reconfigure in response to stimuli via alterations in protein abundance and confirmation. However, typical computational approaches treat them as static interaction networks derived from a single time point. Here, we provide methods for learning the dynamic modulation of relationships between proteins from static single-cell data. We demonstrate our approach using TGFß induced epithelial-to-mesenchymal transition (EMT) in murine breast cancer cell line, profiled with mass cytometry. We take advantage of the asynchronous rate of transition to EMT in the data and derive a pseudotime EMT trajectory. We propose methods for visualizing and quantifying time-varying edge behavior over the trajectory, and a metric of edge dynamism to predict the effect of drug perturbations on EMT.

Learning time-varying information flow from single-cell epithelial to mesenchymal transition data

Type 1 diabetes (T1D) is most likely caused by killing of β cells by autoreactive CD8+ T cells. Methods to isolate and identify these cells are limited by their low frequency in the peripheral blood. We analyzed CD8+ T cells, reactive with diabetes Ags, with T cell libraries and further characterized their phenotype by CyTOF using class I MHC tetramers. In the libraries, the frequency of islet Ag–specific CD45RO+IFN-γ+CD8+ T cells was higher in patients with T1D compared with healthy control subjects. Ag-specific cells from the libraries of patients with T1D were reactive with ZnT8186–194, whereas those from healthy control recognized ZnT8186–194 and other Ags. ZnT8186–194-reactive CD8+ cells expressed an activation phenotype in T1D patients. We found TCR sequences that were used in multiple library wells from patients with T1D, but these sequences were private and not shared between individuals. These sequences could identify the Ag-specific T cells on a repeated draw, ex vivo in the IFN-γ+ CD8+ T cell subset. We conclude that CD8+ T cell libraries can identify Ag-specific T cells in patients with T1D. The T cell clonotypes can be tracked in vivo with identification of the TCR gene sequences.

Identification and Analysis of Islet Antigen–Specific CD8+ T Cells with T Cell Libraries

Abstract Previously, the effect of a drug on a cell population was measured based on simple metrics such as cell viability. However, as single-cell technologies are becoming more advanced, drug screen experiments can now be conducted with more complex readouts such as gene expression profiles of individual cells. The increasing complexity of measurements from these multi-sample experiments calls for more sophisticated analytical approaches than are currently available. We develop a novel method called PhEMD (Phenotypic Earth Mover’s Distance) and show that it can be used to embed the space of drug perturbations on the basis of the drugs’ effects on cell populations. When testing PhEMD on a newly-generated, 300-sample CyTOF kinase inhibition screen experiment, we find that the state space of the perturbation conditions is surprisingly low-dimensional and that the network of drugs demonstrates manifold structure. We show that because of the fairly simple manifold geometry of the 300 samples, we can accurately capture the full range of drug effects using a dictionary of only 30 experimental conditions. We also show that new drugs can be added to our PhEMD embedding using similarities inferred from other characterizations of drugs using a technique called Nystrom extension. Our findings suggest that large-scale drug screens can be conducted by measuring only a small fraction of the drugs using the most expensive high-throughput single-cell technologies—the effects of other drugs may be inferred by mapping and extending the perturbation space. We additionally show that PhEMD can be useful for analyzing other types of single-cell samples, such as patient tumor biopsies, by mapping the patient state space in a similar way as the drug state space. We demonstrate that PhEMD is highly scalable, compatible with leading batch effect correction techniques, and generalizable to multiple experimental designs. Altogether, our analyses suggest that PhEMD may facilitate drug discovery efforts and help uncover the network geometry of a collection of single-cell samples.

Embedding the single-cell experimental variable state space to reveal manifold structure of drug perturbation effects in breast cancer

Single-cell data are now being collected in large quantities across multiple samples and gene profiling runs. This introduces the need for computational methods that can compare and stratify samples that are represented themselves as complex, high-dimensional objects. We introduce PhEMD as an analytical approach that can be used for this purpose. PhEMD uses Earth Mover’s Distance (EMD), a distance between probability distributions that is sensitive to differences at multiple levels of granularity, in order to compute an accurate measure of dissimilarity between single-cell samples. PhEMD then generates a low-dimensional embedding of the samples based on this dissimilarity. We demonstrate the utility of the PhEMD sample embedding by using it to subtype melanoma and clear-cell renal cell carcinomas based on their immune cell profiles. These analyses reveal sources of inter-sample heterogeneity that have potentially clinically actionable implications, given the recent adoption of immunotherapy as an effective treatment for these cancers. We also apply PhEMD to a newly-generated 300-sample CyTOF drug screen experiment, where the effects of 233 kinase inhibitors are measured at the single-cell resolution in 33 protein dimensions. In doing so, we find that PhEMD reveals novel insights into the effects of small-molecule inhibitors on breast cancer cell subpopulations undergoing epithelial-to-mesenchymal transition. Finally, by leveraging the Nystrom extension method for diffusion maps, we demonstrate that the results of PhEMD can be integrated with other data sources and data types to predict the single-cell phenotypes of samples not directly profiled. Our analyses demonstrate that PhEMD is highly scalable and compatible with leading batch effect correction techniques, allowing for the simultaneous comparison of many single-cell samples.

Embedding the single-cell sample manifold to reveal insights into cancer pathogenesis and disease heterogeneity

Previously, the effect of a drug on a cell population was measured based on simple metrics such as cell viability. However, as single-cell technologies are becoming more advanced, drug screen experiments can now be conducted with more complex readouts such as gene expression profiles of individual cells. The increasing complexity of measurements from these multi-sample experiments calls for more sophisticated analytical approaches than are currently available. We developed a novel method called PhEMD (Phenotypic Earth Mover’s Distance) and show that it can be used to embed the space of drug perturbations on the basis of the drugs’ effects on cell populations. When testing PhEMD on a newly-generated, 300-sample CyTOF kinase inhibition screen experiment, we find that the state space of the perturbation conditions is surprisingly low-dimensional and that the network of drugs demonstrates manifold structure. We show that because of the fairly simple manifold geometry of the 300 samples, we can accurately capture the full range of drug effects using a dictionary of only 30 experimental conditions. We also show that new drugs can be added to our PhEMD embedding using similarities inferred from other characterizations of drugs using a technique called Nystrom extension. Our findings suggest that large-scale drug screens can be conducted by measuring only a small fraction of the drugs using the most expensive high-throughput single-cell technologies—the effects of other drugs may be inferred by mapping and extending the perturbation space. We additionally show that PhEMD can be useful for analyzing other types of single-cell samples, such as patient tumor biopsies, by mapping the patient state space in a similar way as the drug state space. We demonstrate that PhEMD is scalable, compatible with leading batch effect correction techniques, and generalizable to multiple experimental designs. Altogether, our analyses suggest that PhEMD may facilitate drug discovery efforts and help uncover the network geometry of a collection of single-cell samples.

Embedding single-cell experimental conditions to reveal manifold structure of cancer drug perturbation effects

Airway diseases affect over 7% of the U.S. population and millions of patients worldwide. Asthmatic patients have wide variation in clinical severity with different clinical and physiologic manifestations of disease that may be driven by distinct biologic mechanisms. Further, the immunologic underpinnings of this complex trait disease are heterogeneous and treatment success depends on defining subgroups of asthmatics. Because of the limited availability and number of cells from the lung, the active site, in‐depth investigation has been challenging. Recent advances in technology support transcriptional analysis of cells from induced sputum. Flow cytometry studies have described cells present in the sputum but a detailed analysis of these subsets is lacking. Mass cytometry or CyTOF (Cytometry by Time‐Of‐Flight) offers tremendous opportunities for multiparameter single cell analysis. Experiments can now allow detection of up to ∼40 markers to facilitate unprecedented multidimensional cellular analyses. Here we demonstrate the use of CyTOF on primary airway samples obtained from well‐characterized patients with asthma and cystic fibrosis. Using this technology, we quantify cellular frequency and functional status of defined cell subsets. Our studies provide a blueprint to define the heterogeneity among subjects and underscore the power of this single cell method to characterize airway immune status. © 2016 International Clinical Cytometry Society

Multiparameter Single Cell Profiling of Airway Inflammatory Cells

Abstract 977: Phenotypic analysis of single-cell breast cancer inhibition data reveals insights into EMT

Cellular regulatory networks are not static, but continuously reconfigure in response to stimuli via alterations in gene expression and protein confirmations. However, typical computational approaches treat them as static interaction networks derived from a single experimental time point. Here, we provide a method for learning the dynamic modulation, or rewiring of pairwise relationships (edges) from a static single-cell data. We use the epithelial-to-mesenchymal transition (EMT) in murine breast cancer cells as a model system, and measure mass cytometry data three days after induction of the transition by TGFβ. We take advantage of transitional rate variability between cells in the data by deriving a pseudo-time EMT trajectory. Then we propose methods for visualizing and quantifying time-varying edge behavior over the trajectory and use these methods: TIDES (Trajectory Imputed DREMI scores), and measure of edge dynamism (3DDREMI) to predict and validate the effect of drug perturbations on EMT.

Immunotherapies targeting the immune checkpoint receptor programmed cell death protein 1 (PD-1) have shown remarkable efficacy in treating cancer. CD4+CD25hiFoxP3+ Tregs are critical regulators of immune responses in autoimmunity and malignancies, but the functional status of human Tregs expressing PD-1 remains unclear. We examined functional and molecular features of PD-1hi Tregs in healthy subjects and patients with glioblastoma multiforme (GBM), combining functional assays, RNA sequencing, and cytometry by time of flight (CyTOF). In both patients with GBM and healthy subjects, circulating PD-1hi Tregs displayed reduced suppression of CD4+ effector T cells, production of IFN-γ, and molecular signatures of exhaustion. Transcriptional profiling of tumor-resident Tregs revealed that several genes coexpressed with PD-1 and associated with IFN-γ production and exhaustion as well as enrichment in exhaustion signatures compared with circulating PD-1hi Tregs. CyTOF analysis of circulating and tumor-infiltrating Tregs from patients with GBM treated with PD-1-blocking antibodies revealed that treatment shifts the profile of circulating Tregs toward a more exhausted phenotype reminiscent of that of tumor-infiltrating Tregs, further increasing IFN-γ production. Thus, high PD-1 expression on human Tregs identifies dysfunctional, exhausted Tregs secreting IFN-γ that exist in healthy individuals and are enriched in tumor infiltrates, possibly losing function as they attempt to modulate the antitumoral immune responses.

PD-1 marks dysfunctional regulatory T cells in malignant gliomas.

Palladium-based mass tag cell barcoding with a doublet-filtering scheme and single-cell deconvolution algorithm

Introduction Cellular circuits sense the environment, process signals, and compute decisions using networks of interacting proteins. Emerging high-dimensional single-cell technologies such as mass cytometry can measure dozens of protein epitopes simultaneously in millions of individual cells. With thousands of individual cells, each providing a point of data on co-occurring protein states, it is possible to infer and quantify the functional forms of the relationships between proteins. However, in practice these underlying relationships are typically obscured by statistical limitations of the data, hence rendering the analysis and interpretation of single-cell data challenging. We developed computational methods, tailored to single-cell data, to more completely define the function and strength of signaling relationships. Quantitative characterization of T cell signaling. (A) The pCD3ζ-pSLP76 signaling interaction shown as (I) a scatterplot, (II) a kernel density estimate, and (III) by using a conditional DREVI method. (IV) Shape features are extracted and quantified. (B) DREVI plots of a signaling cascade downstream of TCR show the time-varying nature of edge shapes and strengths. (C) Edge strengths are quantified by use of conditional DREMI. Rationale We demonstrate the utility of our methods using single-cell data collected from T cells. Although T cell subpopulations are phenotypically delineated into several cell subsets—such as regulatory, effector, and memory—and are thought to have similarly wired signaling networks, their responses to activation differ in ways that are not understood. Results We used mass cytometry to measure the abundance of 20 internal and surface protein epitopes, at 13 time points, after two different types of TCR activation in T cells of B6 mice—resulting in more than 2 million data points. To study TCR signaling, we developed conditional-Density Resampled Estimate of Mutual Information (DREMI) to quantify the strengths of the influence that a protein X has on protein Y, and conditional-Density Rescaled Visualization (DREVI) to visualize and characterize the edge-response function underlying their molecular interaction. A key conceptual shift in DREMI and DREVI is our use of the conditional probability of Y | X rather than the joint probability of X and Y. We show that the consensus Y-response for each value of X is much easier to identify in the conditional density estimate, especially when the joint density is concentrated in a narrow range, which is typical of such data (Fig. 1A). We used DREMI to characterize the rapid dynamics of signaling interactions upon TCR activation (Fig. 1B) and show that the strength of signal transfer peaks in canonical pathway order (Fig. 1C). We compared edges in naive and antigen-exposed CD4+ T cells and identified differential signal transmission along a key signaling cascade that starts at pCD3ζ and continues through pSLP76, pERK, and pS6. At each stage in this cascade, more information (higher DREMI) is transferred downstream from one protein to another, over a longer time period, in naïve cells than in antigen-exposed cells. We validated our characterization in mice lacking the extracellular-regulated mitogen-activated protein kinase (ERK2), demonstrating stronger influence of pERK on pS6 in naive cells, as predicted. Conclusion DREMI solves a challenging problem: quantifying the strength of the underlying complex relationships between proteins from noisy data. Our approach reveals how signaling is fine-tuned between T cell subpopulations: The differences we identified between naïve and antigen-exposed T cells suggest that naïve cells more sensitively transmit upstream signaling inputs along a key signaling cascade. In contrast, trained effector or memory cells seem poised for fast responses upon repeated exposure. DREVI and DREMI are broadly applicable across biological systems and single-cell technologies. As single-cell data become more abundant, our methods will enable the construction of quantitative models of cellular signaling and comparison between healthy and diseased cells. Cite this article as: S. Krishnaswamy et al., Science 346, 1250689 (2014). DOI: 10.1126/science/1250689 Cellular circuits sense the environment, process signals, and compute decisions using networks of interacting proteins. To model such a system, the abundance of each activated protein species can be described as a stochastic function of the abundance of other proteins. High-dimensional single-cell technologies, such as mass cytometry, offer an opportunity to characterize signaling circuit-wide. However, the challenge of developing and applying computational approaches to interpret such complex data remains. Here, we developed computational methods, based on established statistical concepts, to characterize signaling network relationships by quantifying the strengths of network edges and deriving signaling response functions. In comparing signaling between naïve and antigen-exposed CD4+ T lymphocytes, we find that although these two cell subtypes had similarly wired networks, naïve cells transmitted more information along a key signaling cascade than did antigen-exposed cells. We validated our characterization on mice lacking the extracellular-regulated mitogen-activated protein kinase (MAPK) ERK2, which showed stronger influence of pERK on pS6 (phosphorylated-ribosomal protein S6), in naïve cells as compared with antigen-exposed cells, as predicted. We demonstrate that by using cell-to-cell variation inherent in single-cell data, we can derive response functions underlying molecular circuits and drive the understanding of how cells process signals. A computational method quantifies information flow in T cells. Deciphering information flow in T cells We can now measure the activation state of multiple components of biochemical signaling pathways in single cells. This ability reveals how information flows through such cellular regulatory pathways and how it is altered in disease. Krishnaswamy et al. applied statistical techniques to overcome the complexity and variation (or noise) in such single-cell measurements. They used these techniques to quantify information transfer between proteins that participate in antigen recognition in cells of the immune system. The methods should prove useful in analysis of other signaling circuits to enhance basic understanding and reveal potential therapeutic targets to fight disease. Science, this issue 10.1126/science.1250689

Conditional density-based analysis of T cell signaling in single-cell data

Mass cytometry uses atomic mass spectrometry combined with isotopically pure reporter elements to currently measure as many as 40 parameters per single cell. As with any quantitative technology, there is a fundamental need for quality assurance and normalization protocols. In the case of mass cytometry, the signal variation over time due to changes in instrument performance combined with intervals between scheduled maintenance must be accounted for and then normalized. Here, samples were mixed with polystyrene beads embedded with metal lanthanides, allowing monitoring of mass cytometry instrument performance over multiple days of data acquisition. The protocol described here includes simultaneous measurements of beads and cells on the mass cytometer, subsequent extraction of the bead‐based signature, and the application of an algorithm enabling correction of both short‐ and long‐term signal fluctuations. The variation in the intensity of the beads that remains after normalization may also be used to determine data quality. Application of the algorithm to a one‐month longitudinal analysis of a human peripheral blood sample reduced the range of median signal fluctuation from 4.9‐fold to 1.3‐fold. © 2013 International Society for Advancement of Cytometry

Eukaryotic cells have complex regulatory systems that sense adversity (e.g. DNA damage, heat shock, external deathinduction signals) and respond by invoking programmed celldeath or apoptosis. Cancer cells have evolved the ability to thwart such sensory information and associated regulation. As biologists begin to understand cells in circuit-like terms, we can also begin to derive and simulate druggable targets of cellular networks that cause a cancerous cell to kill its self. Towards this goal, we have performed preliminary experiments that test the impact of siRNA (RNA silencing) on diverse cellular signaling pathways, at unprecedented single-cell resolution. We propose ways in which a CAD system can process such data to automatically derive drug targets.

viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia

There are many ways to compute value. For instance, animals can compute value by learning from the past or by imagining future outcomes, but it is unclear if or how these computations interact. We used high-throughput training to collect statistically powerful datasets from 240 rats performing a temporal wagering task with hidden reward states. Rats adjusted how quickly they initiated trials and how long they waited for rewards across states, balancing effort and time costs against expected rewards. Statistical modeling revealed that animals computed the value of the environment differently when initiating trials versus when deciding how long to wait for rewards, even though these decisions were only seconds apart. This work reveals that sequential decisions use parallel value computations on single trials.

Rats rapidly switch between retrospective and inferential value computations

The process by which sensory evidence contributes to perceptual choices requires an understanding of its transformation into decision variables. Here, we address this issue by evaluating the neural representation of acoustic information in auditory cortex-recipient parietal cortex while gerbils either performed an auditory discrimination task or while they passively listened to identical acoustic stimuli. During task performance, decoding performance of simultaneously recorded parietal neurons reflected psychometric sensitivity. In contrast, decoding performance during passive listening was significantly reduced. Principal component and geometric analyses each revealed the emergence of decision-relevant, linearly separable manifolds, but only during task engagement. Finally, using a clustering analysis, we found subpopulations of neurons that may reflect the encoding of separate segments during task performance: stimulus integration and motor preparation or execution. Taken together, our findings demonstrate how parietal cortex neurons integrate and transform encoded auditory information to guide sound-driven perceptual decisions.

Transformation of acoustic information to sensory decision variables in the parietal cortex

Tracking self-performance in the prefrontal cortex: It’s layered

Parietal Cortex Is Required for the Integration of Acoustic Evidence

Explorer Prefrontal Cortex HCN 1 Channels Enable Intrinsic Persistent Neural Firing and Executive Memory Function

In many cortical neurons, HCN1 channels are the major contributors to Ih, the hyperpolarization-activated current, which regulates the intrinsic properties of neurons and shapes their integration of synaptic inputs, paces rhythmic activity, and regulates synaptic plasticity. Here, we examine the physiological role of Ih in deep layer pyramidal neurons in mouse prefrontal cortex (PFC), focusing on persistent activity, a form of sustained firing thought to be important for the behavioral function of the PFC during working memory tasks. We find that HCN1 contributes to the intrinsic persistent firing that is induced by a brief depolarizing current stimulus in the presence of muscarinic agonists. Deletion of HCN1 or acute pharmacological blockade of Ih decreases the fraction of neurons capable of generating persistent firing. The reduction in persistent firing is caused by the membrane hyperpolarization that results from the deletion of HCN1 or Ih blockade, rather than a specific role of the hyperpolarization-activated current in generating persistent activity. In vivo recordings show that deletion of HCN1 has no effect on up states, periods of enhanced synaptic network activity. Parallel behavioral studies demonstrate that HCN1 contributes to the PFC-dependent resolution of proactive interference during working memory. These results thus provide genetic evidence demonstrating the importance of HCN1 to intrinsic persistent firing and the behavioral output of the PFC. The causal role of intrinsic persistent firing in PFC-mediated behavior remains an open question.

Prefrontal Cortex HCN1 Channels Enable Intrinsic Persistent Neural Firing and Executive Memory Function

A Direct Line in the Brain For decades, neuroscientists have assumed that there is a “canonical microcircuit” in the neo cortex, in which information is transformed as excitation spreads serially along connections from thalamus, to cortical layer 4, then to layers 2/3, to layers 5/6, and finally to other brain regions. Each cortical layer is thought to transform sensory signals to extract behaviorally relevant information. Now, Constantinople and Bruno (p. 1591) challenge this dogma. In vivo whole-cell recordings revealed that sensory stimuli activate neurons in deep cortical layers simultaneously to those in layer 4 and that a large number of thalamic neurons converge onto deep pyramidal neurons, possibly allowing sensory information to completely bypass upper layers. Temporary blockade of layer 4 revealed that synaptic input to deep cortical layers derived entirely from the thalamus and not at all from upper cortical layers. This thalamically derived synaptic input reliably drove pyramidal neurons in layer 5 to discharge action potentials in the living animal. These deep layer neurons project to numerous higher-order brain regions and could directly mediate behavior. A direct pathway is used to evoke sensory responses in neurons in multiple layers of the rat barrel cortex. The thalamocortical (TC) projection to layer 4 (L4) is thought to be the main route by which sensory organs communicate with cortex. Sensory information is believed to then propagate through the cortical column along the L4→L2/3→L5/6 pathway. Here, we show that sensory-evoked responses of L5/6 neurons in rats derive instead from direct TC synapses. Many L5/6 neurons exhibited sensory-evoked postsynaptic potentials with the same latencies as L4. Paired in vivo recordings from L5/6 neurons and thalamic neurons revealed substantial convergence of direct TC synapses onto diverse types of infragranular neurons, particularly in L5B. Pharmacological inactivation of L4 had no effect on sensory-evoked synaptic input to L5/6 neurons. L4 is thus not an obligatory distribution hub for cortical activity, and thalamus activates two separate, independent “strata” of cortex in parallel.

Supplementary Video for Subcortical Inputs Governing Cortical Network Activity

Effects and Mechanisms of Wakefulness on Local Cortical Networks

Voltage‐gated potassium channels that are composed of Kv3 subunits exhibit distinct electrophysiological properties: activation at more depolarized potentials than other voltage‐gated K+ channels and fast kinetics. These channels have been shown to contribute to the high‐frequency firing of fast‐spiking (FS) GABAergic interneurons in the rat and mouse brain. In the rodent neocortex there are distinct patterns of expression for the Kv3.1b and Kv3.2 channel subunits and of coexpression of these subunits with neurochemical markers, such as the calcium‐binding proteins parvalbumin (PV) and calbindin D‐28K (CB). The distribution of Kv3 channels and interrelationship with calcium‐binding protein expression has not been investigated in primate cortex. We used immunoperoxidase and immunofluorescent labeling and stereological counting techniques to characterize the laminar and cell‐type distributions of Kv3‐immunoreactive (ir) neurons in macaque V1. We found that across the cortical layers ≈25% of both Kv3.1b‐ and Kv3.2‐ir neurons are non‐GABAergic. In contrast, all Kv3‐ir neurons in rodent cortex are GABAergic (Chow et al. [ 1999 ] J Neurosci. 19:9332–9345). The putatively excitatory Kv3‐ir neurons were mostly located in layers 2, 3, and 4b. Further, the proportion of Kv3‐ir neurons that express PV or CB also differs between macaque V1 and rodent cortex. These data indicate that, within the population of cortical neurons, a broader population of neurons, encompassing cells of a wider range of morphological classes may be capable of sustaining high‐frequency firing in macaque V1. J. Comp. Neurol. 516:291–311, 2009. © 2009 Wiley‐Liss, Inc.

Quantitative analysis of neurons with Kv3 potassium channel subunits, Kv3.1b and Kv3.2, in macaque primary visual cortex

Parvalbumin (PV)-expressing GABAergic neurons of the basal forebrain (BFPVNs) were proposed to serve as a rapid and transient arousal system. While they have a well-documented role in the regulation of sleep-wake states, whether and how BFPVNs participate in mediating awake behaviors is not known. To address this, we performed bulk calcium imaging and recorded single neuronal activity from the horizontal band of the diagonal band of Broca (HDB) while mice were performing an associative learning task. Genetically identified BFPVNs of the HDB responded with a distinctive, phasic activation to punishment. In contrast, reward only elicited slow and delayed responses, while stimuli predicting behavioral reinforcement (reward or punishment) were followed by a gradual increase of HDB BFPVN firing rates. Optogenetic inhibition of HDB BFPVNs during punishment impaired the formation of cue-outcome associations, suggesting a causal role of these neurons in associative learning. Mapping the input-output connectivity of HDB BFPVNs by anterograde and mono-transsynaptic retrograde tracing experiments showed that these neurons received strong inputs from the hypothalamus, the septal complex and the median raphe region, while they synapsed on diverse cell types in key structures of the limbic system including the medial septum, the retrosplenial cortex and the hippocampus. Bulk calcium imaging performed in these termination regions indicated that HDB BFPVNs broadcast information about aversive stimuli to multiple downstream targets. We propose that the arousing effect of BFPVNs is recruited by aversive stimuli to serve crucial associative learning functions during awake behaviors.

Parvalbumin-expressing basal forebrain neurons mediate learning from negative experience

COPYRIGHT © 2023 Hangya and Varga. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Editorial: The medial septum as a smart clock: New aspects of its function beyond pacemaking

Editorial: The medial septum as a smart clock: New aspects of its function beyond pacemaking

Studying animal models furthers our understanding of Parkinson’s disease (PD) pathophysiology by providing tools to investigate detailed molecular, cellular and circuit functions. Different versions of the neurotoxin-based 6-hydroxydopamine (6-OHDA) model of PD have been widely used in rats. However, these models typically assess the result of extensive and definitive dopaminergic lesions that reflect a late stage of PD, leading to a paucity of studies and a consequential gap of knowledge regarding initial stages, in which early interventions would be possible. Additionally, the better availability of genetic tools increasingly shifts the focus of research from rats to mice, but few mouse PD models are available yet. To address these, we characterize here the behavioral, neuronal and ultrastructural features of a graded-dose unilateral, single-injection, striatal 6-OHDA model in mice, focusing on early-stage changes within the first two weeks of lesion induction. We observed early onset, dose-dependent impairments of overall locomotion without substantial deterioration of motor coordination. In accordance, histological evaluation demonstrated a partial, dose-dependent loss of dopaminergic neurons of substantia nigra pars compacta (SNc). Furthermore, electron microscopic analysis revealed degenerative ultrastructural changes in SNc dopaminergic neurons. Our results show that mild ultrastructural and cellular degradation of dopaminergic neurons of the SNc can lead to certain motor deficits shortly after unilateral striatal lesions, suggesting that a unilateral dose-dependent intrastriatal 6-OHDA lesion protocol can serve as a successful model of the early stages of Parkinson’s disease in mice. Highlights - Unilateral striatal 6-OHDA injection caused an early onset dose-dependent behavioral deficit in mice - Behavioral deficit manifested as mild impairment of locomotion and locomotive movement initialization - Behavioral changes were accompanied by moderate, dose-dependent loss of SNc dopaminergic neurons - Behavioral changes were paralleled by ultrastructural alterations of SNc dopaminergic neurons

Behavioral, neural and ultrastructural alterations in a graded-dose 6-OHDA mouse model of early-stage Parkinson’s disease

ABSTRACT Traumatic events can immediately lead to debilitating symptoms collectively called Acute Stress Disorder (ASD), however the mechanisms of ASD are poorly understood. Using a rodent model of ASD here we identify a crucial communication bottleneck between the brainstem and the forebrain, the calretinin-positive neurons in the paraventricular thalamus (PVT/CR+), that controls ASD. We show that following a single acute stress event, the pre-sleep behavior of the mice is altered for several days in parallel with a persistent increase in the firing rate of PVT/CR+ cells. Optogenetic inhibition of PVT/CR+ neuronal activity after the stress event for one hour was sufficient to rescue both the ASD symptoms and the prolonged increase in PVT/CR+ firing rate. Inhibition applied 5 days later was still able to ameliorate some of the symptoms. These data suggest that post-stress activity of PVT/CR+ neurons play a critical role in mediating the acute forms of stress-related affective dysfunctions. One-Sentence Summary Post-stress inhibition of paraventricular thalamic neurons prevents the emergence of acute stressed phenotype.

Persistently increased post-stress activity of paraventricular thalamic neurons is essential for the emergence of stress-induced maladaptive behavior

Abstract Model selection is often implicit: when performing an ANOVA, one assumes that the normal distribution is a good model of the data; fitting a tuning curve implies that an additive and a multiplicative scaler describes the behavior of the neuron; even calculating an average implicitly assumes that the data were sampled from a distribution that has a finite first statistical moment: the mean. Model selection may be explicit, when the aim is to test whether one model provides a better description of the data than a competing one. As a special case, clustering algorithms identify groups with similar properties within the data. They are widely used from spike sorting to cell type identification to gene expression analysis. We discuss model selection and clustering techniques from a statistician’s point of view, revealing the assumptions behind, and the logic that governs the various approaches. We also showcase important neuroscience applications and provide suggestions how neuroscientists could put model selection algorithms to best use as well as what mistakes should be avoided.

Navigating the Statistical Minefield of Model Selection and Clustering in Neuroscience

Microglia modulate cerebral blood flow (CBF) through complex purinergic actions, which are mediated by dynamic, P2Y12 receptor-driven interactions with the vasculature. Microglial actions are partially independent of nitric oxide. Microglial dysfunction leads to impaired CBF response during neurovascular coupling, hypercapnia-induced vasodilation and cerebral hypoperfusion.

Microglia modulate blood flow, neurovascular coupling, and hypoperfusion via purinergic actions

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Approximately 50% of AD patients show anxiety and depressive symptoms, which may contribute to cognitive decline. We aimed to investigate whether the triple-transgenic mouse (3xTg-AD) is a good preclinical model of this co-morbidity. The characteristic histological hallmarks are known to appear around 6-month; thus, 4- and 8-month-old male mice were compared with age-matched controls. A behavioral test battery was used to examine anxiety- (open field (OF), elevated plus maze, light-dark box, novelty suppressed feeding, and social interaction (SI) tests), and depression-like symptoms (forced swim test, tail suspension test, sucrose preference test, splash test, and learned helplessness) as well as the cognitive decline (Morris water maze (MWM) and social discrimination (SD) tests). Acetylcholinesterase histochemistry visualized cholinergic fibers in the cortex. Dexamethasone-test evaluated the glucocorticoid non-suppression. In the MWM, the 3xTg-AD mice found the platform later than controls in the 8-month-old cohort. The SD abilities of the 3xTg-AD mice were missing at both ages. In OF, both age groups of 3xTg-AD mice moved significantly less than the controls. During SI, 8-month-old 3xTg-AD animals spent less time with friendly social behavior than the controls. In the splash test, 3xTg-AD mice groomed themselves significantly less than controls of both ages. Cortical fiber density was lower in 8-month-old 3xTg-AD mice compared to the control. Dexamethasone non-suppression was detectable in the 4-month-old group. All in all, some anxiety- and depressive-like symptoms were present in 3xTg-AD mice. Although this strain was not generally more anxious or depressed, some aspects of comorbidity might be studied in selected tests, which may help to develop new possible treatments.

Investigation of Anxiety- and Depressive-like Symptoms in 4- and 8-Month-Old Male Triple Transgenic Mouse Models of Alzheimer’s Disease

Basal forebrain cholinergic neurons (BFCNs) play an important role in associative learning, suggesting that BFCNs may participate in processing sensory stimuli that predict future outcomes. However, little is known about how BFCNs respond to outcome-predictive sensory cues and the impact of outcome probabilities on BFCN responses has not been explored. Therefore, we performed bulk calcium imaging and recorded spiking output of identified cholinergic neurons from the basal forebrain of mice performing a probabilistic Pavlovian cued outcome task that allowed us to control the predictive strength of cue stimuli. BFCNs responded strongly to sensory cues predicting likely reward, while little response was observed for cues that were rarely paired with reward. Reward delivery led to the activation of BFCNs, with less expected rewards eliciting a stronger response, while air puff punishments also evoked positive-going responses from BFCNs. We propose that BFCNs differentially weigh predictions of positive and negative reinforcement, reflecting divergent relative salience of forecasting appetitive and aversive outcomes, in accordance with a simple reinforcement learning model of a weighed, unsigned prediction error. Finally, the extent of cholinergic activation after cue stimuli predicted subsequent decision speed, suggesting that the expectation-gated cholinergic firing is instructive to reward-seeking behaviors.

Cholinergic neuronal responses to probabilistic outcome-predicting stimuli follow a weighed, unsigned prediction error model and anticipate behavioral responses

Cholinergic activity reflects reward expectations and predicts behavioral responses

Two-photon GCaMP6f imaging of infrared neural stimulation evoked calcium signals in mouse cortical neurons in vivo

Training protocol for probabilistic Pavlovian conditioning in mice using an open-source head-fixed setup

Episodic learning and memory retrieval are critically dependent on a hippocampal 4-12 Hz oscillatory ‘clock’ signal, the theta oscillation. This clock is largely externally paced, by a network of GABAergic neurons in the medial septum (MS). Theoretical studies suggested a range of hypotheses how this network may achieve theta synchrony; however, experimental evidence is still lacking. By recording multiple single MS neurons and hippocampal local field potential oscillations simultaneously, with both acute and chronically implanted silicon probes, we show that MS pacemaker units oscillate at individual frequencies within the theta range in rodents. Synchronization of MS neuron frequencies, accompanied by an elevation of firing rates, was found to parallel hippocampal theta formation in multiple rodent model systems. This suggests a general mechanism for theta synchronization, akin to the synchronization of weakly coupled pendulum clocks observed by Huygens in the 17th century. We optogenetically identified the MS pacemaker units as parvalbumin-expressing GABAergic neurons, while the previously enigmatic MS glutamatergic neurons were mostly theta-activated non-rhythmic cells. Our data were consistent with a network model of partially connected single-compartment inhibitory pacemaker neurons, in which synchronization and de-synchronization in the frequency domain upon waxing and waning tonic excitatory drive was sufficient to toggle MS network output between theta and non-theta states. These results provide experimental and theoretical support to a frequency-synchronization mechanism for pacing hippocampal theta, which may serve as an inspirational prototype for the countless examples of synchronization processes in the central nervous system from Nematoda to Anthropoda to Chordate and Vertebrate phyla.

Huygens synchronization of medial septal pacemaker neurons generates hippocampal theta oscillation

Microglia, the main immunocompetent cells of the brain regulate neuronal function in health and disease, but their contribution to cerebral blood flow (CBF) remained elusive. Here we identify microglia as important modulators of CBF both under physiological conditions and during hypoperfusion. We show that microglia establish direct purinergic contacts with cells in the neurovascular unit that shape cerebral perfusion in both mice and humans. Surprisingly, the absence of microglia or blockade of microglial P2Y12 receptor (P2Y12R) substantially impairs neurovascular coupling in the barrel cortex after whisker stimulation. We also reveal that hypercapnia, which is associated with acidification, induces microglial adenosine production, while depletion of microglia reduces brain pH and impairs hypercapnia-induced vasodilation. Furthermore, the absence or dysfunction of microglia markedly impairs adaptation to hypoperfusion via P2Y12R after transient unilateral common carotid artery occlusion, which is also influenced by CX3CR1-mediated actions. Thus, our data reveal a previously unrecognized role for microglia in CBF regulation with broad implications for common neurological diseases.

Microglia control cerebral blood flow and neurovascular coupling via P2Y12R-mediated actions

Distinct synchronization, cortical coupling and behavioral function of two basal forebrain cholinergic neuron types

The ventral pallidum (VP) is a major hub interfacing striatopallidal and limbic circuits, conveying information about salience and valence crucial to adjusting behavior. However, how neuron populations of the VP with different firing properties represent these variables is not fully understood. Therefore, we trained mice on auditory Pavlovian conditioning and recorded the activity of VP neurons while mice were performing the task. Many VP neurons responded to punishment (51%) and reward (44%), either by firing rate increase or decrease. Additionally, 20% of cells responded to outcome-predicting auditory stimuli, showing larger responses to reward-predicting cues compared to those that signaled likely punishment. We found that a large subset of VP neurons showed burst firing based on their auto-correlograms, while a small population exhibited fast rhythmic discharge in the beta/gamma frequency range. Some bursting neurons exhibited distinct response properties of their bursts and single spikes, suggesting a multiplexed coding scheme in the VP. However, non-bursting, non-rhythmic neurons were the most sensitive to reward and punishment. Finally, we demonstrate the presence of synchronously firing neuron assemblies in the VP. Neurons participating in such assemblies were particularly responsive to reinforcing stimuli. This suggests that a synchronous, non-bursting, non-rhythmic neuron population of the VP is responsible for the lion’s share of ventral pallidal salience representation, likely important for reinforcement learning. Significance statement The ventral pallidum (VP) is a subcortical brain area that participates in regulating motion and emotion by processing information related to appetitive and aversive stimuli. However, how these stimuli are represented by VP neural circuits is not well understood. Therefore, we investigated how VP neuron populations defined by their firing properties respond to reward and punishment during Pavlovian conditioning. We found that a distinct, non-bursting-non-rhythmic group of neurons was responsible for most responses to reward and punishment in the VP. Neurons of this group formed co-active cell assemblies and multiplexed different types of information via different firing patterns, revealing flexible and plastic neuronal representation strategies in the VP during associative learning.

Non-bursting non-rhythmic neurons of the ventral pallidum form cell assemblies and respond to reward and punishment during Pavlovian conditioning

Review for "Cholinergic modulation of Up‐Down states in the mouse medial entorhinal cortex in vitro"

Cartographers of the Cognitive Map: Locus Coeruleus Is Part of the Guild

In vivo localization of chronically implanted electrodes and optic fibers in mice

Efficient training of mice on the 5-choice serial reaction time task in an automated rodent training system

Publisher Correction: Distinct synchronization, cortical coupling and behavioral function of two basal forebrain cholinergic neuron types

Differential recruitment of ventral pallidal e-types by behaviorally salient stimuli during Pavlovian conditioning

Electrophysiology provides a direct readout of neuronal activity at a temporal precision only limited by the sampling rate. However, interrogating deep brain structures, implanting multiple targets or aiming at unusual angles still poses significant challenges even for expert operators, and errors are only discovered by post-hoc histological reconstruction. Here, we propose a method combining the high-resolution information about bone landmarks provided by micro-CT scanning with the soft tissue contrast of the MRI, which allowed us to precisely localize electrodes and optic fibers in mice in vivo. This enables arbitrating the success of implantation directly after surgery with a precision comparable to the gold standard histological reconstruction. Adjustment of the recording depth with electrode microdrives or early termination of unsuccessful experiments saves many working hours, while fast 3-dimensional feedback helps surgeons to avoid systematic errors. Increased aiming precision will allow more precise targeting of small or deep brain nuclei and multiple targeting of specific cortical layers.

Acetylcholine (Ach) is released by the cholinergic basal forebrain (CBF) throughout the cortical mantle and is implicated in behavioral functions ranging from arousal to attention to learning. Yet what signal ACh provides to cortex remains unresolved, hindering our understanding of its functional roles. Here we demonstrate that the CBF signals unsigned reinforcement prediction error, in contrast to dopamine (DA) neurons that encode reward prediction error. We show that both CBF neuronal activity and acetylcholine (ACh) release at cortical targets signal reinforcement delivery, acquire responses to predictive stimuli and show diminished responses to expected outcomes, hallmarks of a prediction error. To compare ACh with DA, we simultaneously monitored the activity of both neuromodulators during a serial reversal learning task. ACh tracked learning as swiftly as DA during acquisition but lagged slightly during extinction, suggesting that these neuromodulators play complementary roles in reinforcement as their patterns of innervation, cellular targets, and signaling mechanisms are themselves complementary. Through retrograde viral tracing we show that the cholinergic and dopaminergic systems engage overlapping upstream circuits, accounting for their coordination during learning. This predictive and valence-free signal explains how ACh can proactively and retroactively improve the processing of behaviorally important stimuli, be they good or bad.

Basal forebrain-derived acetylcholine encodes valence-free reinforcement prediction error

Experiments aiming to understand sensory-motor systems, cognition and behavior often require animals trained to perform complex tasks. Traditional training protocols require lab personnel to move the animals between home cages and training chambers, to start and end training sessions, and in some cases, to hand-control each training trial. Human labor not only limits the amount of training per day, but also introduces several sources of variability and may increase animal stress. Here we present an automated training system for the 5-choice serial reaction time task (5CSRTT), a classic rodent task often used to test sensory detection, sustained attention and impulsivity. We found that fully automated training without human intervention greatly increased the speed and efficiency of learning, and decreased stress as measured by corticosterone levels. Introducing training breaks did not cancel these beneficial effects of automated training, and mice readily generalized across training systems when transferred from automated to manual protocols. Additionally, we validated our automated training system with mice implanted with wireless optogenetic stimulators, expanding the breadth of experimental needs our system may fulfill. Our automated 5CSRTT system can serve as a prototype for fully automated behavioral training, with methods and principles transferrable to a range of rodent tasks.

Rapid learning of the 5-choice serial reaction time task in an automated rodent training system

Single cell electrophysiology remains one of the most widely used approaches of systems neuroscience. Real-time feedback during electrophysiology experiments is important to guide experimental decisions that eventually determine the quality of recording, duration of the project and value of the collected data. We present an open-source tool that enables flexible online visualization of action potential alignment to external events, called the peri-event or peristimulus time histogram (OPETH). Based on the Open Ephys open source data acquisition system, we developed a Python interface for real-time plotting of neuronal spike times and evoked waveforms with respect to external events represented by digital logic signals. These digital inputs may signal photostimulation time stamps for in vivo optogenetic identification of cell types or the times of behaviorally relevant events during in vivo behavioral neurophysiology experiments. Therefore, OPETH allows real-time identification of genetically defined neuron types or behaviorally responsive populations. By allowing ‘hunting’ for neurons of interest, OPETH may significantly increase the efficiency of experiments that combine in vivo electrophysiology with behavior or optogenetic tagging of neurons.

OPETH: Open Source Solution for Real-Time Peri-Event Time Histogram Based on Open Ephys

An array of neuromodulators, including monoamines and neuropeptides, regulate most behavioural and physiological traits. In the past decade, dramatic progress has been made in mapping neuromodulatory circuits, in analysing circuit dynamics, and interrogating circuit function using pharmacogenetic, optogenetic and imaging methods. This review will focus on several distinct neural networks (acetylcholine/GABA/glutamate; histamine/GABA; orexin/ glutamate; and relaxin-3/GABA) that originate from neural hubs that regulate wakefulness and related attentional and cognitive processes, and highlight approaches that have identified dual transmitter roles in these behavioural functions. Modulation of these different neural networks might be effective treatments of diseases related to arousal/sleep dysfunction and of cognitive dysfunction in psychiatric and neurodegenerative disorders.

2-1-2018 Dual-Transmitter Systems Regulating Arousal , Attention , Learning and Memory

Understanding how the brain controls behavior requires observing and manipulating neural activity in awake behaving animals. Neuronal firing is timed at millisecond precision. Therefore, to decipher temporal coding, it is necessary to monitor and control animal behavior at the same level of temporal accuracy. However, it is technically challenging to deliver sensory stimuli and reinforcers as well as to read the behavioral responses they elicit with millisecond precision. Presently available commercial systems often excel in specific aspects of behavior control, but they do not provide a customizable environment allowing flexible experimental design while maintaining high standards for temporal control necessary for interpreting neuronal activity. Moreover, delay measurements of stimulus and reinforcement delivery are largely unavailable. We combined microcontroller-based behavior control with a sound delivery system for playing complex acoustic stimuli, fast solenoid valves for precisely timed reinforcement delivery and a custom-built sound attenuated chamber using high-end industrial insulation materials. Together this setup provides a physical environment to train head-fixed animals, enables calibrated sound stimuli and precisely timed fluid and air puff presentation as reinforcers. We provide latency measurements for stimulus and reinforcement delivery and an algorithm to perform such measurements on other behavior control systems. Combined with electrophysiology and optogenetic manipulations, the millisecond timing accuracy will help interpret temporally precise neural signals and behavioral changes. Additionally, since software and hardware provided here can be readily customized to achieve a large variety of paradigms, these solutions enable an unusually flexible design of rodent behavioral experiments.

Open Source Tools for Temporally Controlled Rodent Behavior Suitable for Electrophysiology and Optogenetic Manipulations

Spatial learning, including encoding and retrieval of spatial memories as well as holding spatial information in working memory generally serving navigation under a broad range of circumstances, relies on a network of structures. While central to this network are medial temporal lobe structures with a widely appreciated crucial function of the hippocampus, neocortical areas such as the posterior parietal cortex and the retrosplenial cortex also play essential roles. Since the hippocampus receives its main subcortical input from the medial septum of the basal forebrain (BF) cholinergic system, it is not surprising that the potential role of the septo‐hippocampal pathway in spatial navigation has been investigated in many studies. Much less is known of the involvement in spatial cognition of the parallel projection system linking the posterior BF with neocortical areas. Here we review the current state of the art of the division of labour within this complex ‘navigation system’, with special focus on how subcortical cholinergic inputs may regulate various aspects of spatial learning, memory and navigation.

Cholinergic modulation of spatial learning, memory and navigation

Understanding how the brain controls behavior requires observing and manipulating neural activity in awake behaving animals. Neuronal firing is timed at millisecond precision. Therefore, to decipher temporal coding, it is necessary to monitor and control animal behavior at the same level of temporal accuracy. However, commonly available processors are not designed for this task and it is challenging to deliver sensory stimuli and reinforcers as well as to read the behavioral responses they elicit with millisecond precision. We present here a set of tools that offer affordable solutions to achieve these goals, including a physical environment to train head-fixed animals, means of providing calibrated sound stimuli and technical details of delivering sensory cues, fluid reward and air puff punishment with measured latencies. Combined with electrophysiology and optogenetic manipulations, the millisecond timing accuracy will help interpret temporally precise neural signals and behavioral changes. Additionally, since software and hardware provided here can be readily customized to achieve a large variety of paradigms, these solutions enable an unusually flexible design of rodent behavioral experiments.

Open source toolkit for temporally controlled rodent behavior suitable for electrophysiology and optogenetic manipulations

Dual-transmitter systems regulating arousal, attention, learning and memory

Some neurons are more equal than others: neuroscience relies heavily on the notion that there is a division of labor among different subtypes of brain cells. Therefore, it is important to recognize groups of neurons that participate in the same computation or share similar tasks. However, what the best ways are to identify such collections is not yet clear. Here, we argue that monitoring the activity of genetically defined cell types will lead to new insights about neural mechanisms and improve our understanding of disease vulnerability. Through highlighting how central cholinergic neurons encode reward and punishment that can be captured by a unified framework of reinforcement surprise, we hope to provide an instructive example of how studying a genetically defined cell type may further our understanding of neural function.

Monitoring the Right Collection: The Central Cholinergic Neurons as an Instructive Example

Signatures of a Statistical Computation in the Human Sense of Confidence

Central Cholinergic Neurons Are Rapidly Recruited by Reinforcement Feedback

A subcortical inhibitory signal for behavioral arrest in the thalamus

Decision confidence is a forecast about the probability that a decision will be correct. Confidence can be framed as an objective mathematical quantity the Bayesian posterior probability, providing a formal definition of statistical decision confidence. Here we use this definition as a starting point to develop a normative statistical framework for decision confidence. We analytically prove interrelations between statistical decision confidence and other observable decision measures. Among these is a counterintuitive property of confidence that the lowest average confidence occurs when classifiers err in the presence of the strongest evidence. These results lay the foundations for a mathematically rigorous treatment of decision confidence that can lead to a common framework for understanding confidence across different research domains, from human behavior to neural representations.

Representations in Brain Stem and Thalamus Temporal Frequency of Whisker Movement. I.

Recent interest in the neural bases of spatial navigation stems from the discovery of neuronal populations with strong, specific spatial signals. The regular firing field arrays of medial entorhinal grid cells suggest that they may provide place cells with distance information extracted from the animal's self-motion, a notion we critically review by citing new contrary evidence. Next, we question the idea that grid cells provide a rigid distance metric. We also discuss evidence that normal navigation is possible using only landmarks, without self-motion signals. We then propose a model that supposes that information flow in the navigational system changes between light and dark conditions. We assume that the true map-like representation is hippocampal and argue that grid cells have a crucial navigational role only in the dark. In this view, their activity in the light is predominantly shaped by landmarks rather than self-motion information, and so follows place cell activity; in the dark, their activity is determined by self-motion cues and controls place cell activity. A corollary is that place cell activity in the light depends on non-grid cells in ventral medial entorhinal cortex. We conclude that analysing navigational system changes between landmark and no-landmark conditions will reveal key functional properties.

Independence of landmark and self-motion-guided navigation: a different role for grid cells

From circuit motifs to computations: mapping the behavioral repertoire of cortical interneurons

GABA-A receptors (GABA-ARs) are typically expressed at synaptic or nonsynaptic sites mediating phasic and tonic inhibition, respectively. These two forms of inhibition conjointly control various network oscillations. To disentangle their roles in thalamocortical rhythms, we focally deleted synaptic, γ2 subunit-containing GABA-ARs in the thalamus using viral intervention in mice. After successful removal of γ2 subunit clusters, spontaneous and evoked GABAergic synaptic currents disappeared in thalamocortical cells when the presynaptic, reticular thalamic (nRT) neurons fired in tonic mode. However, when nRT cells fired in burst mode, slow phasic GABA-AR-mediated events persisted, indicating a dynamic, burst-specific recruitment of nonsynaptic GABA-ARs. In vivo, removal of synaptic GABA-ARs reduced the firing of individual thalamocortical cells but did not abolish slow oscillations or sleep spindles. We conclude that nonsynaptic GABA-ARs are recruited in a phasic manner specifically during burst firing of nRT cells and provide sufficient GABA-AR activation to control major thalamocortical oscillations.

Phasic, Nonsynaptic GABA-A Receptor-Mediated Inhibition Entrains Thalamocortical Oscillations

Sense organs are often actively controlled by motor processes and such active sensing profoundly shapes the timing of sensory information flow. The temporal coordination between different active sensing processes is less well understood but is essential for multisensory integration, coordination between brain regions, and energetically optimal sampling strategies. Here we studied the coordination between sniffing and whisking, the motor processes in rodents that control the acquisition of smell and touch information, respectively. Sniffing, high-frequency respiratory bouts, and whisking, rapid back and forth movements of mystacial whiskers, occur in the same theta frequency range (4–12 Hz) leading to a hypothesis that these sensorimotor rhythms are phase locked. To test this, we monitored sniffing using a thermocouple in the nasal cavity and whisking with an electromyogram of the mystacial pad in rats engaged in an open field reward foraging behavior. During bouts of exploration, sniffing and whisking showed strong one-to-one phase locking within the theta frequency range (4–12 Hz). Interestingly, we also observed multimode phase locking with multiple whisks within a sniff cycle or multiple sniffs within a whisk cycle—always at the same preferred phase. This specific phase relationship coupled the acquisition phases of the two sensorimotor rhythms, inhalation and whisker protraction. Our results suggest that sniffing and whisking may be under the control of interdependent rhythm generators that dynamically coordinate active acquisition of olfactory and somatosensory information.

Multiple Modes of Phase Locking between Sniffing and Whisking during Active Exploration

Distinct behavioural and network correlates of two interneuron types in prefrontal cortex

Ascending and descending information is relayed through the thalamus via strong, “driver” pathways. According to our current knowledge, different driver pathways are organized in parallel streams and do not interact at the thalamic level. Using an electron microscopic approach combined with optogenetics and in vivo physiology, we examined whether driver inputs arising from different sources can interact at single thalamocortical cells in the rodent somatosensory thalamus (nucleus posterior, POm). Both the anatomical and the physiological data demonstrated that ascending driver inputs from the brainstem and descending driver inputs from cortical layer 5 pyramidal neurons converge and interact on single thalamocortical neurons in POm. Both individual pathways displayed driver properties, but they interacted synergistically in a time-dependent manner and when co-activated, supralinearly increased the output of thalamus. As a consequence, thalamocortical neurons reported the relative timing between sensory events and ongoing cortical activity. We conclude that thalamocortical neurons can receive 2 powerful inputs of different origin, rather than only a single one as previously suggested. This allows thalamocortical neurons to integrate raw sensory information with powerful cortical signals and transfer the integrated activity back to cortical networks.

Convergence of Cortical and Sensory Driver Inputs on Single Thalamocortical Cells

Repetitive one-per-day seizures induced in otherwise normal rats by the volatile convulsant flurothyl decrease the accuracy of locating a hidden goal without changing the mean location of goal selection. We now show that an 8-d series of such seizures degrades the spatial signal carried by the firing of hippocampal pyramidal cells and specifically reduces the information conveyed by the place cell subset of pyramidal cells. This degradation and a concomitant slowing of the hippocampal theta rhythm occur over time courses parallel to the development of the behavioral deficit and plausibly account for the impairment. The details of how pyramidal cell discharge weakens are, however, unexpected. Rather than a reduction in the precision of location-specific firing distributed evenly over all place cells, the number of place cells decreases with seizure number, although the remaining place cells remain quite intact. Thus, with serial seizures there is a cell-specific conversion of robust place cells to sporadically firing (<0.1 spike/s) “low-rate” cells as opposed to gradual loss of place cell resolution. This transformation occurs in the absence of significant changes in the discharge rate of hippocampal interneurons, suggesting that the decline in the number of place cells is not a simple matter of increased inhibitory tone. The cumulative transformation of place cells to low-rate cells by repetitive seizures may reflect a homeostatic, negative-feedback process.

Repetitive Convulsant-Induced Seizures Reduce the Number But Not Precision of Hippocampal Place Cells

Cortical electrical activity during nonrapid eye movement (non-REM) sleep is dominated by slow-wave activity (SWA). At larger spatial scales (∼2–30 cm), investigated by scalp EEG recordings, SWA has been shown to propagate globally over wide cortical regions as traveling waves, which has been proposed to serve as a temporal framework for neural plasticity. However, whether SWA dynamics at finer spatial scales also reflects the orderly propagation has not previously been investigated in humans. To reveal the local, finer spatial scale (∼1–6 cm) patterns of SWA propagation during non-REM sleep, electrocorticographic (ECoG) recordings were conducted from subdurally implanted electrode grids and a nonlinear correlation technique [mutual information (MI)] was implemented. MI analysis revealed spatial maps of correlations between cortical areas demonstrating SWA propagation directions, speed, and association strength. Highest correlations, indicating significant coupling, were detected during the initial positive-going deflection of slow waves. SWA propagated predominantly between adjacent cortical areas, albeit spatial noncontinuities were also frequently observed. MI analysis further uncovered significant convergence and divergence patterns. Areas receiving the most convergent activity were similar to those with high divergence rate, while reciprocal and circular propagation of SWA was also frequent. We hypothesize that SWA is characterized by distinct attributes depending on the spatial scale observed. At larger spatial scales, the orderly SWA propagation dominates; at the finer scale of the ECoG recordings, non-REM sleep is characterized by complex SWA propagation patterns.

Complex Propagation Patterns Characterize Human Cortical Activity during Slow-Wave Sleep

The exact timing of cortical afferent activity is instrumental for the correct coding and retrieval of internal and external stimuli. Thalamocortical inputs represent the most significant subcortical pathway to the cortex, but the precise timing and temporal variability of thalamocortical activity is not known. To examine this question, we studied the phase of thalamic action potentials relative to cortical oscillations and established correlations among phase, the nuclear location of the thalamocortical neurons, and the frequency of cortical activity. The phase of thalamic action potentials depended on the exact frequency of the slow cortical oscillation both on long (minutes) and short (single wave) time scales. Faster waves were accompanied by phase advancement in both cases. Thalamocortical neurons located in different nuclei fired at significantly different phases of the slow waves but were active at a similar phase of spindle oscillations. Different thalamic nuclei displayed distinct burst patterns. Bursts with a higher number of action potentials displayed progressive phase advancement in a nucleus-specific manner. Thalamic neurons located along nuclear borders were characterized by mixed burst and phase properties. Our data demonstrate that the temporal relationship between cortical and thalamic activity is not fixed but displays dynamic changes during oscillatory activity. The timing depends on the precise location and exact activity of thalamocortical cells and the ongoing cortical network pattern. This variability of thalamic output and its coupling to cortical activity can enable thalamocortical neurons to actively participate in the coding and retrieval of cortical signals.

Phase Advancement and Nucleus-Specific Timing of Thalamocortical Activity during Slow Cortical Oscillation

Earlier work on freely moving rats classified neurons in Ammon's horn as pyramidal cells (including place cells) or interneurons (previously called “theta cells”) based on temporal discharge correlates and waveform configurations, but the anatomical and biochemical diversity of interneurons suggests they may have other distinguishing characteristics. To explore this possibility, we made extracellular recordings as rats foraged for food in an open space, used accepted criteria to identify interneurons, and found two additional categorization methods. First, interneurons were separated into theta-modulated and theta-independent groups using spike autocorrelograms. Second, theta-modulated interneurons were further separated into four groups by the phase of the ∼8 Hz theta rhythm at which firing was most rapid. These phase groups resemble the four phase peak groups of five anatomically identified interneuron types (two with the same preferred phase) recorded during the slow (∼4 Hz) theta rhythm in urethane-anesthetized rats. We suggest that the similar number of peak phase groups in walking rats and urethane-anesthetized rats and the partial agreement between peak phase values reflect a similar organization of theta rhythm in both states, so that the discharge properties of anatomically identified interneurons can be described in freely moving rats. Interestingly, the average spatial firing precision of the interneuron classes does not differ significantly, suggesting that the strong location-specific firing of place cells may be due to segregated high- and low-precision interneuron ensembles rather than to one or more dedicated high-precision classes.

Theta Phase Classification of Interneurons in the Hippocampal Formation of Freely Moving Rats

The hippocampal formation plays a pivotal role in representing the physical environment. While CA1 pyramidal cells display sharply tuned location‐specific firing, the activity of many interneurons show weaker but significant spatial modulation. Although hippocampal interneurons were proposed to participate in the representation of space, their interplay with pyramidal cells in formation of spatial maps is not well understood. In this study, we investigated the spatial correlation between CA1 pyramidal cells and putative interneurons recorded concurrently in awake rats. Positively and negatively correlated pairs were found to be simultaneously present in the CA1 region. While pyramidal cell–interneuron pairs with positive spatial correlation showed similar firing maps, negative spatial correlation was often accompanied by complementary place maps, which could occur even in the presence of a monosynaptic excitation between the cells. Thus, location‐specific firing increase of hippocampal interneurons is not necessarily a simple product of excitation by a pyramidal cell with a similarly positioned firing field. Based on our observation of pyramidal cells firing selectively in the low firing regions of interneurons, we speculate that the location‐specific firing of place cells is partly determined by the location‐specific decrease of interneuron activity that can release place cells from inhibition.

The more we anticipate a response to a predictable stimulus, the faster we react. This empirical observation has been confirmed and quantified by many investigators suggesting that the processing of behaviorally relevant stimuli is facilitated by probability-based confidence of anticipation. However, the exact neural mechanisms underlying this phenomenon are largely unknown. Here we show that performance changes related to different levels of expectancy originate in dynamic modulation of delta oscillation phase. Our results obtained in rhythmic auditory target detection tasks indicated significant entrainment of the EEG delta rhythm to the onset of the target tones with increasing phase synchronization at higher levels of predictability. Reaction times correlated with the phase of the delta band oscillation at target onset. The fastest reactions occurred during the delta phase that most commonly coincided with the target event in the high expectancy conditions. These results suggest that low-frequency oscillations play a functional role in human anticipatory mechanisms, presumably by modulating synchronized rhythmic fluctuations in the excitability of large neuronal populations and by facilitating efficient task-related neuronal communication among brain areas responsible for sensory processing and response execution.

Phase Entrainment of Human Delta Oscillations Can Mediate the Effects of Expectation on Reaction Speed

Subcortical Network Regulation Subcortical neuromodulatory centers dominate the motivational and emotional state–dependent control of cortical functions. Control of cortical circuits has been thought to involve a slow, diffuse neuromodulation that affects the excitability of large numbers of neurons relatively indiscriminately. Varga et al. (p. 449) describe a form of subcortical control of cortical information processing whereby strong, spatiotemporally precise excitatory input from midbrain serotonergic neurons produces a robust activation of hippocampal interneurons. This effect is mediated by a synaptic release of both serotonin and glutamate and impacts network activity patterns. A form of subcortical control of cortical information processing is mediated by a synaptic release of serotonin and glutamate. Cortical information processing is under state-dependent control of subcortical neuromodulatory systems. Although this modulatory effect is thought to be mediated mainly by slow nonsynaptic metabotropic receptors, other mechanisms, such as direct synaptic transmission, are possible. Yet, it is currently unknown if any such form of subcortical control exists. Here, we present direct evidence of a strong, spatiotemporally precise excitatory input from an ascending neuromodulatory center. Selective stimulation of serotonergic median raphe neurons produced a rapid activation of hippocampal interneurons. At the network level, this subcortical drive was manifested as a pattern of effective disynaptic GABAergic inhibition that spread throughout the circuit. This form of subcortical network regulation should be incorporated into current concepts of normal and pathological cortical function.

Information processing in the hippocampus critically relies on its reciprocal interaction with the medial septum (MS). Synchronization of the septo-hippocampal system was demonstrated during both major hippocampal activity states, the regular theta rhythm and the large amplitude irregular activity. Previous experimental and modeling data suggest that the MS provides rhythmic drive to the hippocampus, and hippocampo-septal feedback synchronizes septal pacemaker units. However, this view has recently been questioned based on the possibility of intrahippocampal theta genesis. Previously, we identified putative pacemaker neurons expressing parvalbumin (PV) and/or the pacemaker hyperpolarization-activated and cyclic nucleotide-gated nonselective cation channel (HCN) in the MS. In this study, by analyzing the temporal relationship of activity between the PV/HCN-containing medial septal neurons and hippocampal local field potential, we aimed to uncover whether the sequence of events during theta formation supports the classic view of septal drive or the challenging theory of hippocampal pacing of theta. Importantly, by implementing a circular statistical method, a temporal lead of these septal neurons over the hippocampus was observed on the course of theta synchronization. Moreover, the activity of putative hippocampal interneurons also preceded hippocampal local field theta, but by a shorter time period compared with PV/HCN-containing septal neurons. Using the concept of mutual information, the action potential series of PV/HCN-containing neurons shared higher amount of information with hippocampal field oscillation than PV/HCN-immunonegative cells. Thus, a pacemaker neuron population of the MS leads hippocampal activity, presumably via the synchronization of hippocampal interneurons.

GABAergic Neurons of the Medial Septum Lead the Hippocampal Network during Theta Activity

The medial septum (MS) is an indispensable component of the subcortical network which synchronizes the hippocampus at theta frequency during specific stages of information processing. GABAergic neurons exhibiting highly regular firing coupled to the hippocampal theta rhythm are thought to form the core of the MS rhythm‐generating network. In recent studies the hyperpolarization‐activated, cyclic nucleotide‐gated non‐selective cation (HCN) channel was shown to participate in theta synchronization of the medial septum. Here, we tested the hypothesis that HCN channel expression correlates with theta modulated firing behaviour of MS neurons by a combined anatomical and electrophysiological approach. HCN‐expressing neurons represented a subpopulation of GABAergic cells in the MS partly overlapping with parvalbumin (PV)‐containing neurons. Rhythmic firing in the theta frequency range was characteristic of all HCN‐expressing neurons. In contrast, only a minority of HCN‐negative cells displayed theta related activity. All HCN cells had tight phase coupling to hippocampal theta waves. As a group, PV‐expressing HCN neurons had a marked bimodal phase distribution, whereas PV‐immunonegative HCN neurons did not show group‐level phase preference despite significant individual phase coupling. Microiontophoretic blockade of HCN channels resulted in the reduction of discharge frequency, but theta rhythmic firing was perturbed only in a few cases. Our data imply that HCN‐expressing GABAergic neurons provide rhythmic drive in all phases of the hippocampal theta activity. In most MS theta cells rhythm genesis is apparently determined by interactions at the level of the network rather than by the pacemaking property of HCN channels alone.

The presence of pacemaker HCN channels identifies theta rhythmic GABAergic neurons in the medial septum

Histamine is a well-known inflammatory mediator exerting various immunomodulatory effects and affecting the development of antigen-specific immune responses. Dendritic cells (DCs) are the most potent antigen-presenting cells specialized for capture, uptake, transport, processing and presentation of antigens to T cells. Using a genetically histamine-free [histidine decarboxylase knockout (HDC-/-)] mouse model, we examined the effects of histamine on DC-mediated antigen presentation. Applying an in vitro antigen presentation assay, we found that spleen DCs, derived from HDC-/- mice, display a higher efficiency in antigen presentation compared with wild-type cells. Flow cytometric characterization of DCs disclosed that this difference was not due to an altered distribution of DCs between or within the major functional sub-populations (assessed by CD11b and CD4 as myeloid and CD8alpha and DEC205 as lymphoid DC markers) or major changes in the co-stimulatory molecule profile (CD40, CD80, CD86). However, real-time PCR analysis of in vivo CFA-induced IL-12p35, IFNgamma, IL-10 and IL-4 expression showed that DCs matured in a histamine-free environment exhibit significantly elevated levels of IL-12p35 and IFNgamma mRNA. In vitro investigations confirmed that isolated DCs, developed in the absence of histamine, exhibit indeed a predominantly T(h)1-polarized cytokine pattern, as they show elevated levels of IFNgamma mRNA upon LPS stimulation. Similar difference was found at the protein level by ELISA, as well. Our study demonstrates that histamine interferes with antigen presentation and alters the cytokine profile of DCs.

Increased antigen presentation and T(h)1 polarization in genetically histamine-free mice.

Chidamide with Azacitidine and CHOP Treatment Plus Autologous Transplantation, Followed By Maintenance with Chidamide for Patients with Newly Diagnosed Peripheral T-Cell Lymphoma (PTCL): Interim Analysis of a Prospective,Single Center, Single-Arm, Phase 2 Trial

Efficacy and Safety of Polatuzumab Vedotin in Combination with Rituximab Plus Bendamustine in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Single Center Analysis of Pola Compassionate Use Program (CUP) in China

Characterization of porcine sapelovirus prevalent in western Jiangxi, China

Conventionally, Porcine teschovirus (PTV) consists of 13 genotypes (PTV 1-13, which belong to Teschovirus A); however, several novel members including PTV 14-22 have been discovered recently. PTV 21 was identified as a novel Teschovirus species named Teschovirus B. In this study, almost all 22 reported PTV genotypes except PTV 6, 7, 12, and 20 were identified in the pig populations of western Jiangxi, China, which reflects a high genotype diversity. Moreover, to the best of our knowledge, the nearly complete genome of PTV 22-JiangX1 was first sequenced in the present study. The homology comparison of the polyprotein genes showed that PTV 22-JiangX1 shared a relatively high nucleotide and deduced amino acid sequence identities ranging from 78.3% to 82.0% and 84.6% to 89.3%, respectively, with PTV 19 and 21. Additionally, the PTV strain of JiangX1 represents genotype 22 with the PTV 19, and 21 strains proved to be members of Teschovirus B based on the phylogenetic and evolutionary divergence analyses. Finally, we determined that the novel Teschovirus B species comprises at least three PTV genotypes.

Novel species of Teschovirus B comprises at least three distinct evolutionary genotypes.

Identification of novel genotypes belonging to the species Teschovirus A from indigenous pigs in western Jiangxi, China

Five hundred and eighty four strains of yeasts were isolated from the soil of the tropical rain forest in Xishuangbanna,in which 539 strains were identified to belong to Cryptococcus,Debaryomyces,Candida,Saccharomyces,Pichia,Torulaspora,Trichosporon,Rhodotorula,Geotrichum,Sporidiobolous,Williopsis,Zygosaccharomyces ,and 45 strains were not able to be identified to any genera.

A study on yeasts of Yunnan.I.Yeasts of tropical rain forest, Xishuangbanna

Two typical yeasts were isolated from China Xuanwei ham, by which the complex fermentative process of ham may be accomplished fully and satisfactorily. Both of the vegetative cells are spheroidal or ellipsoidal and asexual reproduction is by multilateral budding on malt extract agar. The strain S86121 forms asci and one to four hat-shaped ascospores in each ascus on sporulated medium. The strain S86107 produce asci which contain one to three (ofter 1-2)hat-shaped ascospores in each ascus. The two strains, fermentating glucose and assimilating nitrate, are identified into the genus of Hansenula H.et P. Sydow according to the direction of Kreger^s yeasts monograph(1984). Further, The distinctions between ham yeasts and their related species Hansenula holstii of the genus have been compared, the strain S86121 differs markedly from the strain S86107 and H. holstii in the fermentation of lactose, raffinose. The distinctions between the strain S86107 and H.holstii are the assimilation of lactose, raffinose, erythrole, melibiose. The strains S86107 and S86121 differ from all of the known species of the genus by their physiological, biochemical and ecological characteristics. Therefore,...

Iterative stencils are used widely across the spectrum of High Performance Computing (HPC) applications. Many efforts have been put into optimizing stencil GPU kernels, given the prevalence of GPU-accelerated supercomputers. To improve the data locality, temporal blocking is an optimization that combines a batch of time steps to process them together. Under the observation that GPUs are evolving to resemble CPUs in some aspects, we revisit temporal blocking optimizations for GPUs. We explore how temporal blocking schemes can be adapted to the new features in the recent Nvidia GPUs, including large scratchpad memory, hardware prefetching, and device-wide synchronization. We propose a novel temporal blocking method, EBISU, which champions low device occupancy to drive aggressive deep temporal blocking on large tiles that are executed tile-by-tile. We compare EBISU with state-of-the-art temporal blocking libraries: STENCILGEN and AN5D. We also compare with state-of-the-art stencil auto-tuning tools that are equipped with temporal blocking optimizations: ARTEMIS and DRSTENCIL. Over a wide range of stencil benchmarks, EBISU achieves speedups up to 2.53x and a geometric mean speedup of 1.49x over the best state-of-the-art performance in each stencil benchmark.

Proceedings of the 37th International Conference on Supercomputing

General Purpose Graphics Processing Units (GPGPU) are used in most of the top systems in HPC. The total capacity of scratchpad memory has increased by more than 40 times in the last decade. However, existing optimizations for stencil computations using temporal blocking have not aggressively exploited the large capacity of scratchpad memory. This work uses the 2D Jacobian 5-point iterative stencil as a case study to investigate the use of large scratchpad memory. Unlike existing research that tiles the domain in a thread block fashion, we tile the domain so that each tile is large enough to utilize all available scratchpad memory on the GPU. Consequently, we process several time steps inside a single tile before offloading the result back to global memory. Our evaluation shows that our performance is comparable to state-of-the-art implementations, yet our implementation is much simpler and does not require auto-generation of code.

Proceedings of the 15th Workshop on General Purpose Processing Using GPU

Exploiting Scratchpad Memory for Deep Temporal Blocking: A case study for 2D Jacobian 5-point iterative stencil kernel (j2d5pt)

—Iterative memory-bound solvers commonly occur in HPC codes. Typical GPU implementations have a loop on the host side that invokes the GPU kernel as much as time/algorithm steps there are. The termination of each kernel implicitly acts as the barrier required after advancing the solution every time step. We propose a scheme for running memory-bound iterative GPU kernels: PERsistent KernelS (PERKS). In this scheme the time loop is moved inside a persistent kernel, and device-wide barriers are used for synchronization. We then reduce the trafﬁc to device memory by caching a subset of the output in each time step in registers and shared memory to be used as input for the following time step. PERKS can be generalized to any iterative solver: they are largely independent of the solver’s implementation. We explain the design principle of PERKS and demonstrate the effectiveness of PERKS for a wide range of iterative 2D/3D stencil benchmarks (geometric mean speedup of 2 . 29 x in small domains and 1 . 53 x in large domains), and a Krylov subspace solver (geometric mean speedup of 4 . 67 x in smaller SpMV datasets from SuiteSparse and 1 . 39 x in larger SpMV datasets, for conjugate gradient).

Over the last three decades, innovations in the memory subsystem were primarily targeted at overcoming the data movement bottleneck. In this paper, we focus on a specific market trend in memory technology: 3D-stacked memory and caches. We investigate the impact of extending the on-chip memory capabilities in future HPC-focused processors, particularly by 3D-stacked SRAM. First, we propose a method oblivious to the memory subsystem to gauge the upper-bound in performance improvements when data movement costs are eliminated. Then, using the gem5 simulator, we model two variants of LARC, a processor fabricated in 1.5 nm and enriched with high-capacity 3D-stacked cache. With a volume of experiments involving a board set of proxy-applications and benchmarks, we aim to reveal where HPC CPU performance could be circa 2028, and conclude an average boost of 9.77x for cache-sensitive HPC applications, on a per-chip basis. Additionally, we exhaustively document our methodological exploration to motivate HPC centers to drive their own technological agenda through enhanced co-design.

At the Locus of Performance: A Case Study in Enhancing CPUs with Copious 3D-Stacked Cache

Iterative memory-bound solvers commonly occur in HPC codes. Typical GPU implementations have a loop on the host side that invokes the GPU kernel as much as time/algorithm steps there are. The termination of each kernel implicitly acts the barrier required after advancing the solution every time step. We propose an execution model for running memory-bound iterative GPU kernels: PERsistent KernelS (PERKS). In this model, the time loop is moved inside persistent kernel, and device-wide barriers are used for synchronization. We then reduce the traffic to device memory by caching subset of the output in each time step in the unused registers and shared memory. PERKS can be generalized to any iterative solver: they largely independent of the solver's implementation. We explain the design principle of PERKS and demonstrate effectiveness of PERKS for a wide range of iterative 2D/3D stencil benchmarks (geomean speedup of 2.12x for 2D stencils and 1.24x for 3D stencils over state-of-art libraries), and a Krylov subspace conjugate gradient solver (geomean speedup of 4.86x in smaller SpMV datasets from SuiteSparse and 1.43x in larger SpMV datasets over a state-of-art library). All PERKS-based implementations available at: https://github.com/neozhang307/PERKS.

PERKS: a Locality-Optimized Execution Model for Iterative Memory-bound GPU Applications

Matrix engines or units, in different forms and affinities, are becoming a reality in modern processors; CPUs and otherwise. The current and dominant algorithmic approach to Deep Learning merits the commercial investments in these units, and deduced from the No. 1 benchmark in supercomputing, namely High Performance Linpack, one would expect an awakened enthusiasm by the HPC community, too. Hence, our goal is to identify the practical added benefits for HPC and machine learning applications by having access to matrix engines. For this purpose, we perform an in-depth survey of software stacks, proxy applications and benchmarks, and historical batch job records. We provide a cost-benefit analysis of matrix engines, both asymptotically and in conjunction with state-of-the-art processors. While our empirical data will temper the enthusiasm, we also outline opportunities to “misuse” these dense matrix-multiplication engines if they come for free.

2021 IEEE International Parallel and Distributed Processing Symposium (IPDPS)

Matrix Engines for High Performance Computing: A Paragon of Performance or Grasping at Straws?

The dedicated memory of hardware accelerators can be insufficient to store all weights and/or intermediate states of large deep learning models. Although model parallelism is a viable approach to reduce the memory pressure issue, significant modification of the source code and considerations for algorithms are required. An alternative solution is to use out-of-core methods instead of, or in addition to, data parallelism.We propose a performance model based on the concurrency analysis of out-of-core training behavior, and derive a strategy that combines layer swapping and redundant recomputing. We achieve an average of 1. 52x speedup in six different models over the state-of-the-art out-of-core methods. We also introduce the first method to solve the challenging problem of out-of-core multi-node training by carefully pipelining gradient exchanges and performing the parameter updates on the host. Our data parallel out-of-core solution can outperform complex hybrid model parallelism in training large models, e.g. Megatron-LM and Turning-NLG.

SC20: International Conference for High Performance Computing, Networking, Storage and Analysis

Scaling Distributed Deep Learning Workloads beyond the Memory Capacity with KARMA

GPUs are playing an increasingly important role in general-purpose computing. Many algorithms require synchronizations at different levels of granularity in a single GPU. Additionally, the emergence of dense GPU nodes also calls for multi-GPU synchronization. Nvidia’s latest CUDA provides a variety of synchronization methods. Until now, there is no full understanding of the characteristics of those synchronization methods. This work explores important undocumented features and provides an in-depth analysis of the performance considerations and pitfalls of the state-of-art synchronization methods for Nvidia GPUs. The provided analysis would be useful when making design choices for applications, libraries, and frameworks running on single and/or multi-GPU environments. We provide a case study of the commonly used reduction operator to illustrate how the knowledge gained in our analysis can be useful. We also describe our micro-benchmarks and measurement methods.

2020 IEEE International Parallel and Distributed Processing Symposium (IPDPS)

A Study of Single and Multi-device Synchronization Methods in Nvidia GPUs

(1) Background: DNA sequence alignment process is an essential step in genome analysis. BWA-MEM has been a prevalent single-node tool in genome alignment because of its high speed and accuracy. The exponentially generated genome data requiring a multi-node solution to handle large volumes of data currently remains a challenge. Spark is a ubiquitous big data platform that has been exploited to assist genome alignment in handling this challenge. Nonetheless, existing works that utilize Spark to optimize BWA-MEM suffer from higher overhead. (2) Methods: In this paper, we presented PipeMEM, a framework to accelerate BWA-MEM with lower overhead with the help of the pipe operation in Spark. We additionally proposed to use a pipeline structure and in-memory-computation to accelerate PipeMEM. (3) Results: Our experiments showed that, on paired-end alignment tasks, our framework had low overhead. In a multi-node environment, our framework, on average, was 2.27× faster compared with BWASpark (an alignment tool in Genome Analysis Toolkit (GATK)), and 2.33× faster compared with SparkBWA. (4) Conclusions: PipeMEM could accelerate BWA-MEM in the Spark environment with high performance and low overhead.

PipeMEM: A Framework to Speed Up BWA-MEM in Spark with Low Overhead

Heterogeneous parallel computing accelerated iterative subpixel digital image correlation

The rapid development of NGS (Next Generation Sequencing) leads to the explosive increase of genome data. Massive data pose a great challenge to post-sequencing genomic data analysis process and put forward higher requirements for the performance and pipeline optimization of genome analysis tools. In this paper, we present CloudGT, a high performance genome analysis toolkit leveraging pipeline optimization based on Apache Spark. CloudGT accelerates genome analysis process by implementing parallelization of multi-core and multi-node using Spark framework. In order to improve the performance of genome analysis process, a pipeline optimization strategy based on Parquet storage is presented to reduce the storage space and I/O overhead throughout the process. Three main tools including CloudBWAMem, CloudDuplicateMark and CloudHaplotypeCaller to support read aligning, duplicate marking and variant calling are optimized and implemented which adapt to the pipeline optimization and further improve the overall performance. In our whole genome sequencing experiments, CloudGT is evaluated on a 10-node cluster and achieves high performance and scalability. The optimized pipeline totally reduces 80.95% storage space and 14.32% runtime than the unoptimized and is 26.6%-74.9% faster than state-of-the-art toolkits and approaches based on cluster with higher accuracy.

2018 IEEE International Conference on Bioinformatics and Biomedicine (BIBM)

CloudGT: A High Performance Genome Analysis Toolkit Leveraging Pipeline Optimization on Spark

High accuracy digital image correlation powered by GPU-based parallel computing

The endophytic fungi and the rhizosphere fungi of Diphylleia sinensis, which grow in Zhongdian county, Yunnan province, were isolated. As a result, 25 fungal isolates,belonging to 8 genera, 5 families, were isolated from the rhizomes of Diphylleia sinensis. Meanwhile, 19 fungal isolates, belonging to 6 genera, 5 families, were obtained from the rhizosphere soil of this plant. The results show the diversity of the two kinds of fungi respectively. The correlation between endophytic fungi and rhizosphere fungi, and the origin of endophytic fungi were studied, too.

Diversity and Correlation of Endophytic Fungi and Rhizosphere Fungi Isolated from Diphylleia sinensis

首次报道从长春花Catharanthus roseus (L.) G.Don 茎的韧皮部中分离出尖孢镰刀菌Fusarium oxysporu m,为该植物的一种内生真菌,并用TLC和HPLC对该菌的97CG3菌株培养物进行了分析,初步结果表明该真菌能产生抗癌药长春新碱成分.

Preliminary Study on the Isolation of Endophytic Fungus of Catharanthus roseus and Its Fermentation to Produce Products of Therapeutic Value

A preliminary study on nutrition physiological characteristics of Thelephora ganbajun Zang mycelia

Object To select the endophytic fungi which produce vincristine by isolating fungi from the leaves of Catharanthus roseus (L.) G. Don. Methods The endophytic fungi were isolated from the leaves of C. roseus and the zymotic extracts were analyzed by TLC and HPLC. Results An endophytic fungus which is Mycelia sterilia 97CY_3 can produce vincristine. The content of vincristine in the fungus was determined as 0.205 μg/L by HPLC. Conclusion Some endophytic fungi isolated from C. roseus can produce the anticancer substance vincristine which is the same as that of host plant producing.

Preliminary study of a vincristine-producing endophytic fungus isolated from leaves of Catharanthus roseus

In this paper, we define different ansatz equations to study two classes of high‐order nonlinear Schrödinger equations. The concrete forms of soliton solutions of these two classes of equations are obtained by using this equation. This paper briefly summarizes and explains the method used and applies it to two classes of specific equations. Finally, the concrete form of solutions and the necessary conditions for the existence of solutions are obtained, and pictures are added to assist understanding.

Soliton solution of high‐order nonlinear Schrödinger equation based on ansatz method

This paper deals with estimation of semi-varying coefficientmodels with correlated random errors. The estimations of the function coefficients are are given by the use of generalized weighted least squares. The theorem of Gauss-Markov was very well known, but moreover we present an estimation of parameter � 2 .

ON PARAMETER ESTIMATION OF SEMI-VARYING COEFFICIENT MODELS WITH CORRELATED RANDOM ERRORS

A linearized three‐level difference scheme on nonuniform meshes is derived by the method of the reduction of order for the Neumann boundary value problem of a nonlinear parabolic system. It is proved that the difference scheme is uniquely solvable and second‐order convergent in L∞‐norm. A numerical example is given. © 2003 Wiley Periodicals, Inc. Numer Methods Partial Differential Eq 20: 230–247, 2004

A second‐order linearized difference scheme on nonuniform meshes for nonlinear parabolic systems with Neumann boundary value conditions

Comparison of Green's Functions for a Family of Multipoint Boundary Value Problems☆

ASYMPTOTIC METHOD FOR ANALYSIS OF NONLINEAR SYSTEMS WITH TWO PARAMETERS

Hypermobile Patients with Femoroacetabular Impingement Syndrome can be Effectively Treated Utilizing Hip Arthroscopy with Periportal Capsulotomy Closure: A Matched Cohort Analysis Compared to Patients without Joint Hypermobility.

Editorial Commentary: Hip Arthroscopy in Patients With Early Degeneration Who Receive Intra-Articular Bone Marrow Aspirate Concentrate Can Achieve Outcomes Similar to Nonarthritic Patients.

Editorial Commentary: Rates of 5-Year Secondary Surgery After Hip Arthroscopy May Be Higher Than Reported: The Highs and Lows of the Administrative Database Study.

Leukocyte-Poor Platelet-Rich Plasma Injections Improve Cartilage T1ρ and T2 and Patient-Reported Outcomes in Mild-to-Moderate Knee Osteoarthritis

Postless Tape Augmentation for Posterior Cruciate Ligament Reconstruction

Postless Tape Augmentation for Anterior Cruciate Ligament (ACL) Reconstruction

The Use of Multiple Imaging Studies Before Shoulder Stabilization Surgery Is Increasing

Orthopaedic Sleep and Novel Analgesic Pathway (OSNAP): A prospective randomized controlled trial to advance recovery after shoulder arthroplasty.

Editorial Commentary: Quadratus Lumborum Analgesia for Hip Arthroscopy: The New Kid on the (Nerve) Block.

Utilization of Autologous Chondrocyte Implantation in the Knee is Increasing While Reoperation Rates Are Decreasing Despite Increasing Pre-Operative Comorbidities.

Physical Examination of the Hip: Assessment of Femoroacetabular Impingement, Labral Pathology, and Microinstability

Complications and re-operations after extensor mechanism repair surgery in a large cross-sectional cohort: females and tobacco-users at highest risk for adverse outcomes

Correction to: Complications and re‑operations after extensor mechanism repair surgery in a large cross‑sectional cohort: females and tobacco‑users at highest risk for adverse outcomes

Lateral T-Capsulotomy with Hip Arthroscopy for Access and Excision of Posterior Intra-Articular Mass

Complications after high tibial osteotomy and distal femoral osteotomy are associated with increasing medical comorbidities and tobacco use

Pre-existing Mental Health Diagnoses Are Associated with Higher Rates of Postoperative Complications, Readmissions, and Reoperations Following Arthroscopic Rotator Cuff Repair.

Arthroscopic Single-Portal Suprapectoral Biceps Tenodesis With All-Suture Anchor

Background: Nonoperative and operative treatment modalities have been used for symptom management of adhesive capsulitis, but neither has been shown to significantly alter the long-term natural history. Purpose/Hypothesis: The purpose was to evaluate the current trends in resource and treatment strategy utilization for patients with adhesive capsulitis. It was hypothesized that (1) patients with idiopathic adhesive capsulitis will primarily undergo nonoperative treatment and (2) patients with systemic medical comorbidities will demonstrate relatively higher utilization of nonoperative therapies. Study Design: Cross-sectional study; Level of evidence, 3. Methods: We searched the Mariner/PearlDiver database for Current Procedural Terminology and International Classification of Diseases codes to identify patients with adhesive capsulitis from 2010 to 2020 and to track their usage of diagnostic and therapeutic modalities, including radiography, magnetic resonance imaging (MRI), physical therapy, surgery, opioids, and injection. Patients with active records 1 year before and 2 years after initial diagnosis of adhesive capsulitis were eligible. Excluded were patients with secondary causes of adhesive capsulitis, such as fracture, infection, prior surgery, or other intra-articular pathology. Results: The median age of this 165,937-patient cohort was 58 years, with 67% being women. There was a high prevalence of comorbid diabetes (44.2%), thyroid disorder (29.6%), and Dupuytren contracture (1.3%). Within 2 years of diagnosis of adhesive capsulitis, diagnostic and therapeutic modality utilization included radiography (47.2%), opioids (46.7%), physical therapy (43.1%), injection (39.0%), MRI (15.8%), arthroscopic surgery (2.7%), and manipulation under anesthesia (2.5%). Over 68% of the diagnostic and therapeutic modalities were rendered from 3 months before to 3 months after diagnosis. Patients with diabetes, thyroid disorders, tobacco use, and obesity had greater odds for treatment with physical therapy, opioids, radiography, and injection when compared with patients without these comorbidities (odds ratio [OR] range, 1.05-2.21; P < .0001). Patients with diabetes and thyroid disorders had decreased odds for surgery (OR range, 0.88-0.91; P ≤ .003). Patients with Dupuytren contracture had increased odds for all therapeutic modalities (OR range, 1.20-1.68; P < .0001). Conclusion: Patients with adhesive capsulitis underwent primarily nonoperative treatment, with a high percentage utilizing opioids. The most active periods for treatment were from 3 months before diagnosis to 3 months after, and patients with medical comorbidities were more likely to undergo nonoperative treatment.

Evaluating Utilization Trends in Adhesive Capsulitis of the Shoulder: A Retrospective Cohort Analysis of a Large Database

Perioperative Thromboprophylaxis Is Associated With Lower Risk of Venous Thromboembolism After Knee Arthroscopy.

Younger Patients are More Likely to Undergo Arthroscopic Meniscal Repair and Revision Meniscal Surgery in a Large Cross-sectional Cohort.

Background: Postoperative biomechanics after hip arthroscopy for femoroacetabular impingement syndrome (FAIS) are an outcome of interest, but correlation with patient-reported outcomes (PROs) remains unclear. Purpose/Hypothesis: The purpose of this study was to assess the correlation between changes in hip biomechanics in FAIS patients after hip arthroscopy and changes in PRO scores. We hypothesized that gait analysis would demonstrate significant correlations between pre- and postoperative changes in biomechanics and changes in PRO scores. Study Design: Descriptive laboratory study. Methods: FAIS patients without dysplasia or arthritis who underwent primary hip arthroscopy for labral repair and femoroplasty underwent preoperative and 1-year postoperative 3-dimensional motion tracking and biomechanical testing during normal gait. Joint kinematics calculated included flexion/extension (sagittal plane), abduction/adduction (frontal plane), and internal/external rotation (transverse plane). Peak hip angles and moments were compared between baseline and 1-year postoperative measures. At baseline, 1-year, and 2-year postoperatively, patients completed the following PRO surveys: 12-Item Short Form Health Survey (SF-12), modified Harris Hip Score (mHHS), and Hip disability and Osteoarthritis Outcome Score (HOOS). Joint kinematics that significantly improved 1 year after surgery were assessed for correlations with PRO scores. Results: A total of 10 patients (12 hips) were enrolled prospectively. PROs significantly improved at 1 and 2 years postoperatively compared with baseline values for HOOS, mHHS, and SF-12 Physical Component Score, with all patients achieving the minimal clinically important difference (MCID) on the HOOS Sport/Recreation and Quality of Life subscales. From preoperatively to 1-year postoperatively, significant improvements were seen in peak hip abduction angle (from −2.3° ± 1.8° to −4.6° ± 1.8°; P = .0058) and peak hip extension moment (from −1.03 ± 0.19 to −0.85 ± 0.20 N·m/kg; P = .014); however, there were no significant correlations between these changes and the pre- to postoperative changes on any PRO scores. Conclusion: Gait analysis of FAIS patients after hip arthroscopy demonstrated small, albeit significant, changes in postoperative hip kinetics and kinematics; however, these changes did not correlate with the large, clinically significant improvements in PROs at 1 year after surgery. Clinical Relevance: The results of this study suggest that the degree of improvement in short-term PROs after hip arthroscopy for FAIS may not be related to small changes in biomechanics postoperatively.

Correlating Biomechanical Gait Analysis With Patient-Reported Outcomes After Hip Arthroscopy for Femoroacetabular Impingement Syndrome

Objectives: We sought to identify pre-operative physical exam findings, imaging findings, and surgical management trends associated with humeral avulsion of the glenohumeral ligament (HAGL) lesions by utilizing a large, multicenter orthopedic outcomes database. Methods: Patients with anterior shoulder instability who underwent surgical management from 2012 to 2020 at 11 orthopedic centers were prospectively enrolled. Patients with a HAGL lesion identified intra-operatively were compared to patients without a HAGL lesion; patients with isolated posterior HAGL lesions were excluded from data analysis. Pre-operative patient demographics, physical examination, and imaging findings were collected; intra-operative findings and surgical procedures performed were also recorded. Student’s T-test, Fisher Exact test and Chi Square test were used to compare groups and determine risk factors. Logistic regression analysis was performed to determine independent risk factors associated with need for an open stabilization procedure, and odds ratio (OR) and 95% confidence interval (95% CI) were calculated. Significance was set at p<0.05. Results: From 2012 to 2020, 22 HAGL lesions were identified in 1002 patients (2.2%). Baseline demographics, including age, gender, BMI, and number of lifetime shoulder dislocations, were similar between the HAGL and non-HAGL groups. As compared to non-HAGL patients, HAGL patients were less likely to have a Hill Sachs lesion (51.8% vs. 27.3%, p=0.02) or an anterior labral tear (81.7% vs. 63.6%, p=0.03) on pre-operative MRI. On pre-operative physical examination, HAGL patients demonstrated increased external rotation when their affected arm was positioned in 90° of abduction as compared to non-HAGL patients (90° vs. 85°, p=0.01). The most common procedure performed amongst all patients was an arthroscopic Bankart repair (45.5% of the HAGL patients and 78.9% of the non-HAGL group); however, HAGL patients were more likely than non-HAGL patients to undergo an open stabilization procedure (68.2% vs. 10.7%, p<0.001) and less likely to undergo an arthroscopic stabilization procedure (72.7% vs. 94.7%, p<0.001). Additionally, HAGL lesions were independently associated with an increased risk of undergoing an open stabilization procedure (OR 31.3, 95% CI 11.0 – 88.9, p<0.001). Conclusions: Patients with anterior shoulder instability and a HAGL lesion are less likely to exhibit classic pre-operative imaging findings associated with anterior shoulder instability, such as Hill Sachs lesions or anterior labral pathology. Increased external rotation at 90° of shoulder abduction on pre-operative physical exam may suggest presence of a HAGL lesion. Other demographic factors, including age, gender, BMI, and number of lifetime shoulder dislocations, do not differ significantly between patients with and without HAGL lesions. Patients with HAGL lesions undergo open stabilization procedures more frequently than patients without HAGL lesions.

Paper 73: Patient Factors Associated with Humeral Avulsion of Glenohumeral Ligament (HAGL) Lesions: An Analysis of the MOON Shoulder Instability Cohort

Arthroscopic Treatment Yields Lower Reoperation Rates than Open Treatment for Native Knee but Not Native Shoulder Septic Arthritis

Background Femoroacetabular impingement (FAI) frequently leads to acetabular chondral delamination. Early identification and treatment of these cases is crucial to prevent further damage to the hip. Purpose To evaluate the accuracy of morphological signs of cartilage acetabular delamination in non-arthrographic magnetic resonance imaging (MRI) using intra-articular arthroscopic findings in patients undergoing FAI surgery. Material and Methods All hip MRI scans were assessed individually by three independent radiologists. Images were assessed for signs of delamination including the presence of a linear area of bright signal intensity along the acetabular subchondral bone and an area of darker tissue at the surface of the acetabular cartilage. All FAI patients underwent surgery; arthroscopy served as the standard of reference. Results The mean age of participants was 36.1±10.9 years with 36 (48.6%) women. In the FAI group, arthroscopic surgery showed acetabular chondral delamination in 37 hips. In all hips (including the controls), MRI signs of acetabular cartilage delamination showed an average sensitivity across the three raters of 73.0% with a specificity of 71.0%. In a separate analysis of only the FAI patients, a slightly higher sensitivity (77.7%) but lower specificity (66.7%) was demonstrated. The interrater reliability showed a moderate agreement (average [k]) across the raters (0.450). Conclusion Performance of non-arthrographic MRI in diagnosing acetabular chondral delamination showed good results, yet inter-observer reproducibility among different radiologists was only moderate. Our results suggest that an increased level of awareness, for signs of delamination using MRI, will be helpful for detecting chondral delamination in patients with a history of FAI.

Acetabular cartilage delamination: performance of MRI using arthroscopy as the standard of reference

Incidence of Venous Thromboembolism after Hip Arthroscopy is Low with or without Prophylaxis but Risk Factors Include Oral Contraceptive Use, Obesity and Malignancy.

Patient Reported Outcome Surveys for Femoroacetabular Impingement Syndrome Demonstrate Strong Correlations, High MCID Agreement and Large Ceiling Effects.

Hip arthroscopy is often associated with postoperative pain, requiring opioid analgesia. We describe our use of the pericapsular nerve group (PENG) block as a rescue analgesia for hip arthroscopy. This block was used for 3 patients at an ambulatory surgery center. All patients exhibited good pain control without clinically significant quadriceps weakness and were able to go home the same day. This case report illustrates the possibility of using the PENG block as an alternative to more conventional regional nerve blocks, such as a fascia iliaca block, femoral nerve block, or lumbar plexus block.

Rescue Pericapsular Nerve Group Block for Hip Arthroscopy: A Report of 3 Cases.

Background: Surgical treatment options for proximal humeral fractures include hemiarthroplasty (HA), reverse shoulder arthroplasty (RSA), and open reduction and internal fixation (ORIF). The objectives of this study were to analyze the trends in surgical treatment of proximal humeral fractures across a decade and to compare complications, reoperation rates, and readmission rates between ORIF and RSA. Methods: The PearlDiver MUExtr Database was used to identify patients with proximal humeral fractures who were treated with ORIF, HA, or RSA between 2010 and 2019 and analyze yearly trends. Complications, revision procedures, demographic characteristics, comorbidities, and emergency room visits and hospital readmissions within 90 days of the surgical procedure were compared between ORIF and RSA cohorts for patients who had at least 2-year follow-up data. Results: In this study, 384,158 patients with proximal humeral fractures were identified in the 10-year period between 2010 and 2019. There was a significant increase in the frequency of RSA and a decrease in the frequency of ORIF and HA over time (p < 0.0001). Compared with patients who underwent ORIF or HA, patients who underwent RSA were more likely to be older (p < 0.0001), to be female, and to have a higher Charlson Comorbidity Index. Patients who underwent ORIF had higher complication rates (23.03% compared with 18.62%; p < 0.0001) and higher reoperation rates (20.3% compared with 10.3%; p < 0.0001) than patients who underwent RSA. Patients who underwent RSA had higher emergency room visit rates (20.0% compared with 16.7%; p < 0.001) and hospital readmission rates (12.9% compared with 7.3%; p < 0.0001) within 90 days of the surgical procedure compared with patients who underwent ORIF. Conclusions: There has been an increasing trend in RSA utilization for the surgical treatment of proximal humeral fractures, along with a decreasing trend in HA and ORIF, over time. Patients who underwent ORIF for a proximal humeral fracture had higher complication and reoperation rates compared with patients who underwent RSA. Patients who underwent RSA had higher emergency room visit and hospital readmission rates within 90 days of the surgical procedure compared with patients who underwent ORIF, which may be attributable to the RSA cohort being older and having more comorbidities. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Trends in Surgical Treatment of Proximal Humeral Fractures and Analysis of Postoperative Complications Over a Decade in 384,158 Patients

Risk for recurrent instability and reoperation following arthroscopic and open shoulder stabilization in a large cross-sectional population

Objectives: Incidence of venous thromboembolism (VTE) after knee arthroscopy is reportedly low, but rates vary significantly across literature. Current guidelines recommend against routine perioperative thromboprophylaxis, but prescribing practices and VTE risk factors are poorly understood. Methods: Medical records for patients ≥18 years of age were queried from the Pearl Diver database using CPT codes for arthroscopic knee procedures. Patients with a previous diagnosis of VTE or hyper-coagulable disorder were excluded from analyses. Procedures were grouped by rehabilitation protocols, with restrictive procedures requiring a period of non-weightbearing or postoperative immobilization. Patients who received perioperative thromboprophylaxis were identified. Patients diagnosed with VTE, including pulmonary embolism and/or deep vein thrombosis, within 90 days of surgery were identified using International Classification of Diseases (ICD) codes. Multivariable logistic regression models were utilized to identify VTE risk factors and likelihood of thromboprophylaxis prescription. Covariates included age, restrictive rehabilitation protocols, oral contraceptive pill (OCP) use, and medical comorbidities. Results: A total of 718,289 patients underwent knee arthroscopy from 2011 to 2020. 10,769 patients (1.5%) received perioperative thromboprophylaxis, including aspirin (n=5,353, 0.7%), low molecular weight heparin (n=4,563, 0.6%) and factor Xa inhibitors (n=947, 0.1%). A total of 7,618 patients (1.1%) experienced VTE. Perioperative prophylaxis was associated with decreased odds of experiencing VTE (adjusted odds ratio [aOR] = 0.64, 95% confidence interval [CI] = 0.51 to 0.79) (Table 1). Restrictive procedure type was associated with increased odds of experiencing VTE (aOR =1.42, 95% CI = 1.34 to 1.50) and receiving prophylaxis (aOR=1.95, 95% CI = 1.87 to 2.05). OCP use (aOR = 1.63, 95% CI = 1.37 to 1.91), renal disease (aOR = 1.33, 95% CI = 1.18 to 1.50) and congestive heart failure (aOR = 1.30, 95% CI = 1.13 to 1.49) were associated with increased odds of VTE. Tobacco use was associated with increased odds of VTE (aOR = 1.12, 95% CI 1.03 to 1.22), but decreased odds of receiving perioperative prophylaxis (aOR = 0.84, 95% CI 0.78 to 0.91). Malignancy was associated with increased odds of receiving prophylaxis (aOR = 1.18, 95% CI 1.09 to 1.29) but not with increased odds of VTE. Conclusions: Procedures with restrictive rehabilitation protocols, OCP use, renal disease, and congestive heart failure are associated with increased odds of VTE following knee arthroscopy. Conversely, the use of perioperative thromboprophylaxis is associated with significantly lower odds of VTE. Risk factors for postoperative VTE are not always correlated with increased likelihood of receiving perioperative thromboprophylaxis. Patients with a tobacco use history may be an at-risk population that can be better selected for thromboprophylaxis when clinically appropriate. Table 1. Multivariable Logistic Model of VTE and Perioperative Thromboprophylaxis Odds

Poster 222: Venous Thromboembolism Risk factors and Prophylaxis Patterns in Knee Arthroscopy: A Large Database Study

Delayed ACL reconstruction increases rates of concomitant procedures and risk of subsequent surgery

High Rate of Overlapping Question Content Among Commonly Used Patient-Reported Outcome Measurements for Anterior Cruciate Ligament Injury

Hip Arthroscopy Volume and Reoperations in a Large Cross-sectional Population: High Rate of Subsequent Revision Hip Arthroscopy in Young Patients and Total Hip Arthroplasty in Older Patients.

Background: There is much debate in the current literature with regard to the most appropriate hip-specific patient-reported outcome (PRO) measurement for assessment of femoroacetabular impingement syndrome (FAIS) and outcomes after surgical treatment. Despite systematic reviews assessing the validity of classic hip-specific PROs as well as newer PROs developed to target the young, active population, there lacks a direct comparison of the question content between each PRO. Purpose: To compare the question composition and degree of overlap between commonly used PROs for FAIS. Study Design: Cross-sectional study Methods: A literature review yielded the 6 most commonly cited PROs for assessment of FAIS: modified Harris Hip Score (mHHS), Hip disability and Osteoarthritis Outcome Score (HOOS), Copenhagen Hip and Groin Outcome Score (HAGOS), Nonarthritic Hip Score (NAHS), international Hip Outcome Tool (iHOT-33), and Hip Outcome Score (HOS). Questions from each PRO were classified as identical, similar, or unique after pooled comparison, and the number of overlapping (identical or similar) questions between each PRO was determined. Questions were then classified into 5 domains: pain, symptoms, functional activities, sports, and quality of life, and variations in questions assessing each domain based on PRO were analyzed. Results: Analysis of 164 total questions from 6 PROs showed that 87 questions (53%) were identical between 2 or more PROs, 39 (24%) were similar, and 38 (23%) were unique. The iHOT-33 contained the highest number of unique questions, with 13 of 33 (39.4%), while the HOOS contained the lowest number of unique questions, with 3 of 40 (7.5%). The HOOS, HAGOS, and iHOT-33 contained questions assessing all 5 domains of patient outcomes; the NAHS did not evaluate quality of life; the mHHS only assessed pain, symptoms, and functional activities; and the HOS only assessed functional activities and sports. Conclusion: As there is a high percentage of overlapping (identical or similar) questions between the most commonly used hip-specific PROs for FAIS, multiple tests may be appropriate for use. The iHOT-33, HOOS, and HAGOS are well suited for the general population as they offer comprehensive assessments across all domains, while the HOS provides added focus to sports/activity assessments for athletes and highly active patients.

Comparing Patient-Reported Outcome Measurements for Femoroacetabular Impingement Syndrome

Teres Minor Muscle Hypertrophy is Negative Predictor for Outcomes after Reverse Total Shoulder Arthroplasty: An Evaluation of Pre-Operative MRI and Post-Operative Implant Position.

Background: The association between activity level after anterior cruciate ligament (ACL) reconstruction (ACLR) and development of posttraumatic osteoarthritis (PTOA) remains unclear. This study investigated the relationship of patient-reported outcomes and progressive cartilage degenerative changes at 3 years after ACLR. Hypothesis: Higher activity levels, as measured by Marx scores, are significantly correlated with early cartilage degeneration after ACLR. Study Design: Cohort study; Level of evidence, 2. Methods: A total of 35 patients (16 women; mean age, 31.0 ± 7.6 years) with isolated ACLR and without pre-existing arthritis were prospectively enrolled. Patients reported Marx activity scores and Knee injury and Osteoarthritis Outcome Score (KOOS) scores and underwent T1ρ magnetic resonance imaging (MRI) preoperatively, 6 months, 1 year, 2 years, and 3 years after ACLR with soft tissue graft (22 autograft). The change in cartilage relaxation times between preoperative and 3-year imaging was used to identify cartilage degeneration, defined as an increase in T1ρ values by 14.3%. Correlation between Marx activity levels, KOOS scores, and T1ρ degeneration was performed with the Spearman rank test. The Fisher exact test was used to test for association between Marx activity score cutoffs and degeneration. The Student t test was used to compare Whole-Organ Magnetic Resonance Imaging Score (WORMS) and T1ρ relaxation times. Significance was defined as P < .05. Results: Sixteen patients (45.7%) showed evidence of cartilage degeneration at 3 years, most frequently in the medial compartment (n = 12; 34%). Higher Marx activity scores at 3 years correlated with cartilage degeneration in the medial femur (rho = 0.34; P = .045), and medial tibia (rho = 0.43; P = .01). A Marx score of 11 or greater at 3 years was significantly associated with medial compartment degeneration (P = .03), with a positive predictive value of 52.6%. No Marx score cutoff at years 1 or 2 predicted future cartilage degeneration. The KOOS Quality of Life score was inversely correlated with cartilage degeneration (rho = 0.38; P = .02). WORMS did not correlate with degeneration of the medial compartment. Conclusion: Increased activity at 3 years after ACLR was significantly associated with increased risk of medial compartment PTOA. While further research is needed to fully define these relationships, patients may be counseled that return to Marx activity levels of greater than 11 may be associated with a higher risk of medial compartment cartilage degeneration.

Patient-Reported Activity Levels Correlate With Early Cartilage Degeneration After Anterior Cruciate Ligament Reconstruction

Background: There is a lack of research investigating current practice trends in the treatment of anterior cruciate ligament (ACL) tears as well as common concomitant procedures and reoperations associated with ACL reconstruction (ACLR). Purpose: To analyze current practice patterns for ACLR as well as the frequency of concomitant and revision procedures with respect to patient characteristics in a cross-sectional population of the United States. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Patient data between 2010 and 2017 were queried using the Mariner PearlDiver database. International Classification of Diseases, Ninth Revision (in 2010-2014) and Tenth Revision (ICD-10; in 2015-2017), diagnosis codes were used to identify ACL tears, and Current Procedural Terminology codes were used to identify ACLR and concomitant surgical procedures. Patient characteristics were stratified by sex and age. Cases of subsequent knee surgery and conversion to total knee arthroplasty (TKA) within 2 years after ACLR were tracked using ICD-10 codes between 2015 and 2017 to ensure ipsilateral laterality. Results: Of 229,295 patients identified with an ACL tear diagnosis during the study period, 75% underwent ACLR. In patients aged 10 to 39 years, 84% to 92% underwent ACLR, while patients aged 50 to 59 (50%) and 60 to 69 (28%) years were less likely to have surgery after an ACL tear. Female and male patients underwent ACLR at a similar rate (75%). Within the patients who underwent ACLR, 44% underwent concomitant meniscal debridement as compared with 11% with concomitant meniscal repair. Male patients were more likely to undergo meniscal debridement (48% vs 40%; P < .0001). The frequency of meniscal repair increased from 9% in 2010 to 14% in 2017, while the frequency of meniscal debridement decreased from 47% to 41% (P < .0001). Within 2 years of ACLR, 6% of patients underwent revision ACLR; 4%, subsequent meniscal debridement; 1%, meniscal repair; and 1%, conversion to TKA. Conclusion: The frequency of ACLR for ACL tears has remained relatively stable in recent years and was similar between female and male patients in this cross-sectional population. The majority of patients aged 10 to 39 years underwent ACLR, while less than half of patients >50 years underwent surgery.

Contemporary Practice Patterns for the Treatment of Anterior Cruciate Ligament Tears in the United States

Femoroacetabular impingement (FAI) consists of abnormal bony morphology of the femoral head/neck junction (cam morphology) and/or acetabulum (pincer morphology), which can lead to articular cartilage and labral injury as well as clinical symptoms from altered mechanical loading of the hip joint in some patients. Although some have considered FAI (and the cam morphology, more specifically) to be modern phenomena [7], there is evidence that this is not the case [12]. Regardless, there seems to be some evidence that environmental factors matter, since participation in high-intensity and high-impact sports during skeletal maturation appears to be associated with the development of FAI [10]. Multiple studies have shown radiographic findings consistent with FAI in high-level adolescent and young adult male athletes [3, 8-10]. Another study of 63 women collegiate athletes (soccer, track/field, volleyball) showed 48% of hips had radiographic findings for cammorphology [6]. Based on data from these and other similar studies, researchers generally believe that elite athletes in high-intensity/impact sports have increased risk for FAI because of factors associated with their training and with sports that alter physeal growth during skeletal development [10]. To further evaluate the development of FAI during skeletal maturation, one research team prospectively followed a cohort of elite pre-professional adolescent male soccer players from the Netherlands over 5 years and found that cam morphology in plain radiographs developed in 73% of players by skeletal maturity at age 18 [1, 11]. The current study by Hanke et al. [5] sheds additional light on this process. They shared findings from a prospective, longitudinal MRI analysis about the development of cam morphologies in adolescent ice hockey players. Performing baseline, 1.5-year, and 3-year follow-up MRIs on players beginning at age 12 to 13 years, the authors found that 12 of 23 (52%) players developed a cam morphology within 3 years. They also found a correlation between physeal extension of the proximal femoral physis and higher alpha angle, indicating an underlying growth disturbance may be associated with cam development. The authors conclude that cam morphology develops during the early phase of the final growth spurt of the proximal femur between ages 13 to 16 years. This is important because understanding that cam morphology develops from a growth plate disturbance during a specific period of skeletal development will help to direct future research focused on prevention of this phenomenon. Surgeons caring for young athletes might also consider thorough counseling of this pathology for their patients as well as close clinical examination to survey for signs and This CORR Insights is a commentary on the article “A Cam Morphology Develops in the Early Phase of the Final Growth Spurt in Adolescent Ice Hockey Players: Results of a Prospective MRI-based Study” by Hanke and colleagues available at: DOI: https://doi. org/10.1097/CORR.0000000000001603. The author certifies that neither he, nor any members of his immediate family, has funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research editors and board members are on file with the publication and can be viewed on request. The opinions expressed are those of the writer, and do not reflect the opinion or policy of CORR or The Association of Bone and Joint Surgeons. A. L. Zhang ✉, Department of Orthopaedic Surgery, University of CaliforniaSan Francisco, 1500 Owens Street, Box 3004, San Francisco, CA 94158, USA, Email: Alan. zhang@ucsf.edu A. L. Zhang, Associate Professor, Department of Orthoapedic Surgery, University of CaliforniaSan Francisco, San Francisco, CA, USA

CORR Insights®: A Cam Morphology Develops in the Early Phase of the Final Growth Spurt in Adolescent Ice Hockey Players: Results of a Prospective MRI-based Study.

Patients Aged 50 Years and Older Have Greater Complication Rates After Anterior Cruciate Ligament Reconstruction: A Large Database Study

Editorial Commentary: Arthroscopic Treatment for Diminutive Hip Labral Size: Go Big or Go Home?

Introduction: Shoulder arthroplasty has become popular in the treatment of degenerative shoulder conditions in the United States. Shoulder arthroplasty usage has expanded to younger patients with increased surgical indications. Methods: Reverse total shoulder arthroplasty (RTSA) and TSA patient records with the 1-year follow-up between 2015 and 2018 were queried from the nationwide PearlDiver Mariner Shoulder Database using International Classification of Disease-10 codes. Chi-square analysis was done to compare the demographics, surgical complications, and revision procedures between RTSA and TSA. Results: From 2010 to 2018, there was an increase in shoulder arthroplasty cases because of RTSA. The overall surgical complication and revision procedure rates were 2.26% and 3.56% for RTSA, and 6.36% and 2.42% for TSA. Patients older than 50 years had statistically lower surgical complications after RTSA than TSA (2.25% versus 3.94%, P < 0.05), whereas no statistical difference between RTSA and TSA for patients younger than 50 years (10.06% versus 7.45%, P = 0.19). Male patients had higher RTSA complication rates (3.12% versus 2.28%, P < 0.05), whereas female patients had higher TSA (4.86% versus 5.92%, P < 0.05). History of tobacco, depression, and obesity were risk factors for higher complications. Conclusion: RTSA has become more commonly done than TSA in the United States. Older patients who underwent shoulder arthroplasty had lower surgical complication. TSA had a higher surgical complication rate than RTSA for patients older than 50 years.

Surgical Complications After Reverse Total Shoulder Arthroplasty and Total Shoulder Arthroplasty in the United States

Abstract Background Patients undergoing revision total shoulder arthroplasty (TSA) typically achieve smaller improvements in outcome measurements than those undergoing primary TSA. The minimum clinically important difference (MCID) in the American Shoulder and Elbow Surgeons (ASES) questionnaire for primary shoulder arthroplasty ranges from 13.6-20.9, but the MCID for revision shoulder arthroplasty remains unclear. This study aims to define the MCID in ASES score for revision TSA and ascertain patient factors that affect achieving the MCID threshold. Methods Patients were identified from an institutional shoulder arthroplasty database. Prospective data collected included demographic variables, prior shoulder surgeries, primary and revision implants, indication for revision, and pre- and post- operative ASES scores. All patients provided informed consent to participate. An anchor-based method was used with a binary answer choice. The MCID was calculated using the receiver-operator curve (ROC) method, and the sensitivity, specificity, and area under the curve were obtained from the ROC. MCID values were compared between groups using Student's t-test. Multivariate logistic regression modeling was used to determine significant predictors for reaching MCID. Significance was defined as p Results A total of 46 patients underwent revision TSA with minimum two-year follow-up. The MCID using ROC method was 16.7 with 71% sensitivity and 62% specificity. There was a trend towards males being more likely to reach MCID after revision arthroplasty (p=0.058). There were also trends towards increased forward flexion and abduction range of motion in patients who met MCID (p=0.08, p=0.07). Multivariate logistic regression modeling demonstrated male sex to be associated with achieving MCID (p=0.03), while younger age and fewer prior shoulder surgeries demonstrated a trend to association with achieving MCID (p=0.06, p=0.10). Conclusion The MCID for ASES score in patients undergoing revision shoulder arthroplasty is similar to previously reported MCID values for patients undergoing primary shoulder arthroplasty. Younger, male patients with fewer prior shoulder surgeries were more likely to achieve MCID after revision TSA. Level of Evidence Level III

Minimum clinically important difference for the American Shoulder and Elbow Surgeons score after revision shoulder arthroplasty

Arthroscopic Glenoid Reconstruction With Iliac Crest Bone Block Transfer in the Beach Chair Position

Arthroscopic Rotator Cuff Repair Results in Lower Two-Year Reoperation Rates Compared With Open Rotator Cuff Repair in a Large Cross-sectional Cohort

Biceps Tenodesis Demonstrates Lower Reoperation Rates Compared to SLAP Repair for Treatment of SLAP Tears in a Large Cross-sectional Population.

A Systematic Approach to Arthroscopic Femoroplasty With Conservative Management of the Hip Capsule

Background: Depression and related psychiatric diagnoses are common in patients undergoing hip arthroscopy for femoroacetabular impingement syndrome (FAIS). The effects of depression on postoperative complications, readmissions, and additional ipsilateral hip surgery are not well studied. Hypothesis: Patients with preoperative depression who undergo hip arthroscopy for FAIS would experience higher rates of 90-day postoperative complications and readmissions, with an increased risk of additional ipsilateral hip procedures, as compared with patients without depression. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective cohort study between 2010 and 2019 was performed using the Mariner/PearlDiver database. Current Procedural Terminology and International Classification of Diseases codes were used to compare patients with and without preexisting depression who underwent hip arthroscopy for FAIS. Patients were matched at a 1:1 ratio based on age, sex, Charlson Comorbidity Index, body mass index, and tobacco use. Patients undergoing shoulder or knee arthroscopy were also identified to compare lifetime preoperative depression prevalence amongst groups. Results: The lifetime preoperative depression prevalence was significantly higher in patients undergoing hip arthroscopy as compared with patients undergoing shoulder or knee arthroscopy (25.4% vs 22.2% vs 19.8%; P < .001). When compared with the patients without depression, patients with preoperative depression had higher rates of 90-day readmissions (2.4% vs 1.5%) and complications, including urinary tract infection (36.2% vs 28.9%), pneumonia (12.9% vs 9.1%), hematoma formation (3.1% vs 1.9%), acute kidney injury (4.0% vs 2.6%), deep venous thrombosis/pulmonary embolism (2.6% vs 1.7%), and superficial infection (4.9% vs 2.8%; P < .01 for all comparisons). Preoperative depression was associated with significantly higher odds of undergoing revision hip arthroscopy within 2 years (6.3% vs 2.4%; P < .001). Conclusion: Patients with preexisting depression experienced higher rates of 90-day postoperative complications and hospital readmissions after elective hip arthroscopy for FAIS and were more likely to undergo revision hip arthroscopy within 2 years of the index procedure.

Association Between Comorbid Depression and Rates of Postoperative Complications, Readmissions, and Revision Arthroscopic Procedures After Elective Hip Arthroscopy

Background : The utilization of reverse total shoulder arthroplasty (RTSA) for the treatment of proximal humerus fractures in the elderly is increasing. Recent results support the use of RTSA for this indication over hemiarthroplasty or open reduction internal fixation (ORIF). However there are limited data on the outcomes of RTSA for fracture or fracture sequelae as compared to RTSA for cuff tear arthropathy (CTA). We hypothesized that patients undergoing RTSA for fracture or fracture sequelae would have worse outcomes compared to patients undergoing RTSA for CTA. Methods : This was a retrospective analysis of a prospectively collected outcomes database of all patients undergoing shoulder arthroplasty at a single institution between 2008 and 2019. Patients were included if they underwent primary RTSA for a diagnosis of acute fracture, fracture nonunion or malunion, failed hemiarthroplasty or ORIF for proximal humerus fracture, or rotator cuff arthropathy. The primary outcome was American Shoulder and Elbow Surgeons (ASES) score at the most recent follow-up, with minimum 1-year follow-up. Secondary outcomes included range of motion (ROM) at most recent follow-up, patient satisfaction with surgery, and revision or reoperation rates. Analysis of variance (ANOVA) was used to compare continuous variables between the groups, while chi-square or Fisher's exact test were used to compare categorical variables. Linear regression analysis was used to perform multivariable analysis. Prosthesis survival rates were calculated using Kaplan Meier survival analysis. Significance was defined as p Results : There were 287 patients included in the final cohort, including 62 with fracture and 225 with CTA. Sex, diagnosis, increasing patient comorbidities, and diagnosis (malunion/nonunion and failed prior surgery) were associated with worse ASES scores on univariate analysis (p 0.05). Outcomes of delayed RTSA for malunion/nonunion and hemiarthroplasty/ORIF were significantly worse than those for acute fracture/CTA (p Conclusion : Treatment of acute proximal humerus fractures with RTSA leads to similar improvements in patient outcomes compared to elective treatment for CTA, but outcomes of delayed RTSA for fracture are considerably worse. These findings provide further guidance to clinicians counselling patients on treatment options and outcomes for proximal humerus fractures Level of Evidence : Level III.

Outcomes of Acute but Not Delayed Reverse Total Shoulder Arthroplasty for Proximal Humerus Fracture Are Equal to Those for Rotator Cuff Arthropathy

Changes in Hip Capsule Morphology after Arthroscopic Treatment for Femoroacetabular Impingement Syndrome with Periportal Capsulotomy are Correlated with Improvements in Patient-Reported Outcomes.

The Effects of Non-Steroidal Anti-Inflammatory Medications After Rotator Cuff Surgery: A Randomized Double-Blinded Placebo-Controlled Trial.

Defining Recovery Trajectories after Shoulder Arthroplasty: A Latent Class Analysis of Patient Reported Outcomes.

Journal of hand therapy : official journal of the American Society of Hand Therapists

Patient outcomes and costs after isolated flexor tendon repairs of the hand.

Impact of fatty degeneration on the functional outcomes of 38 patients undergoing surgical repair of gluteal tendon tears

Abstract Background : Golf is a common sporting activity that patients continue to participate into older age, including after joint replacement surgery. The influence of shoulder replacement on golf performance remains unclear. We hypothesized that patients undergoing anatomic total shoulder arthroplasty (TSA) would have significantly better return to play rates and better performance metrics, including handicap, driving distance, and 7-iron distance, after shoulder replacement relative to those treated with reverse total shoulder arthroplasty (RTSA). Methods : Patients were retrospectively surveyed after anatomic TSA and RTSA with regards to return to golf and golf performance before and after shoulder replacement. Patients reported if they were able to return to golf after shoulder replacement, timing of return to golf, and driving distance, 7-iron distance, handicap, and difficulty with specific shot types upon returning to golf. Significance was defined as p Results : The survey was completed by 31 patients with a total of 37 replaced shoulders (68.0 ± 8.1 years; 87% male) out of 44 patients who indicated they played golf. The overall return to golf rate was 74%. Patients undergoing anatomic TSA returned at a significantly higher rate relative to patients treated with RTSA (93% [14 of 15] vs 56% [9 of 16], p = 0.037). There was no difference between groups with regards to drive distance, 7-iron distance, and handicap. There were also no difference between preoperative and postoperative values for patients who were able to return to golf. Overall, patients played golf less frequently afterwards than they did prior to shoulder replacement (p = 0.013). Conclusion : Patients are able to return to golf after shoulder replacement, at an overall rate of 74%, including a rate of 93% for patients with anatomic TSA and 56% for patients with RTSA. Golf performance was similar before and after shoulder replacement surgery for both groups amongst those who were able to return to play, though overall frequency was decreased after shoulder replacement. Level of Evidence : Level III; Retrospective Comparative Study

Return to golf and golf-specific performance after anatomic total shoulder arthroplasty and reverse total shoulder arthroplasty

Background: Cell-based cartilage restoration with autologous chondrocyte implantation (ACI) is a safe and effective treatment for symptomatic cartilage lesions. Many patients undergoing ACI have a history of prior surgery, including bone marrow stimulation (BMS). There is mounting evidence that a history of prior BMS may impede healing of the ACI graft. Purpose/Hypothesis: The purpose of this study was to compare the failure rates of primary ACI with ACI after prior BMS. We hypothesized that ACI after BMS would have a significantly higher failure rate (defined as reoperation, conversion to arthroplasty, and/or imaging-based failure) compared with primary ACI. Study Design: Systematic review; Level of evidence, 4. Methods: A literature search was performed by use of PubMed and Embase databases for relevant articles published through October 2, 2020, to identify studies evaluating outcomes and failures rates of ACI after prior BMS in the knee. Results: Included were 11 studies comprising 1479 ACI procedures. The mean age at surgery ranged from 18.3 to 39.1 years, and the mean follow-up ranged from 3 to 20.6 years. All studies reported failure rates. The overall failure rate was significantly higher in the patients who underwent ACI after BMS, at 26.4% compared with 14.8% in the ACI group (P < .001). Meta-analysis demonstrated an increased risk of failure in patients with a history of prior BMS (log odds ratio = –0.90 [95% confidence interval, –1.38 to –0.42]). Conclusion: This systematic review demonstrated that failure rates were significantly higher for patients treated with ACI after BMS relative to patients undergoing ACI without prior BMS. This finding has important implications when considering the use of BMS for defects that are amenable to cell-based restoration and when determining treatment options after failed BMS. Registration: PROSPERO (CRD42020180387).

Prior Bone Marrow Stimulation Surgery Influences Outcomes After Cell-Based Cartilage Restoration: A Systematic Review and Meta-analysis

Do glenoid retroversion and humeral subluxation affect outcomes following total shoulder arthroplasty?

Equivalent Mid-Term Results of Open vs Endoscopic Gluteal Tendon Tear Repair Using Suture Anchors in Forty-Five Patients.

Objectives: Patients with posterior shoulder instability often present with significant differences in history of injury and complaints compared to anterior instability that can lead to challenges in diagnosis and treatment. These patients may have bone and cartilage lesions in addition to caspulolabral injuries, though the risk factors for these intra-articular lesions are unclear. The purpose of this study was to describe intraoperative incidence of glenohumeral bone and cartilage lesions in a cohort of patients undergoing primary posterior stabilization using data from a prospectively collected, multicenter shoulder instability cohort. We hypothesized that patients with traumatic posterior instability with greater number of instability events would have higher rate of bone and cartilage injuries compared to those without fewer instability episodes. Methods: Data from the Multicenter Orthopaedic Outcomes Network (MOON) Shoulder Group instability patient cohort was utilized for this study. This is a multi-center study encompassing a prospective evaluation of patients ages 12 to 99 years of age undergoing primary surgical treatment for shoulder instability by 24 orthopedic surgeons at 11 sites in the United States. Demographic data and specifics regarding the patient’s instability history were recorded, including patient age, sex, body mass index (BMI), history of smoking, and Beighton score. The number of instability events was classified as 0, 1, 2 to 5, or more than 5. The duration of symptoms was classified as <1 month, 1-3 months, 4-6 months, 7-12 months, or greater than 1 year. The glenohumeral joint was evaluated by the treating surgeon at the time of surgical treatment for bone and cartilage injuries, and patients were classified as having a bone or cartilage lesion (BCL) if there was any grade 3 or 4 glenoid or humeral cartilage lesion, reverse Hill-Sachs lesion, bony Bankart lesion, or glenoid bone loss. The effects of number of instability events on the presence of BCLs was investigated using Fisher’s exact tests. Multivariate analysis using logistic regression modeling was performed to investigate the independent contributions of demographic variables and injury-specific variables to the likelihood of having a BCL. Significance was defined as p<0.05. Results: There were 271 patients identified for analysis. Bone and cartilage lesions were identified in 59 patients (21.8%) at the time of surgical treatment (Table 1). The most common lesion was a glenoid cartilage injury, which was identified in 28 patients (10.3%). Patients with BCLs were significantly older and had significantly higher BMI relative to patients without BCLs (Table 2). There was a significant difference between the number of instability events and the presence of BCLs (p = 0.035), with the highest rate observed in patients with 2-5 instability events (33.9%) (Figure 1). Through multivariate logistic regression modeling, increasing age (p=0.002), increasing BMI (p=0.012), and 2 to 5 reported instability events (p=0.001) were significant independent predictors of the presence of BCLs. Conclusion: Bone and cartilage lesions are seen significantly more frequently with increasing patient age, increasing BMI, and patients with 2-5 instability events. Early surgical stabilization for posterior instability may be considered to potentially limit the extent of associated intra-articular injury. Table 1. Frequency of Bone and Cartilage Lesions Identified in Patients Undergoing Primary Surgery for Posterior Instability Intra-Articular Lesion N % Glenoid cartilage injury* 28 10.3% Humeral cartilage injury* 20 7.4% Reverse Hill-Sachs 16 5.9% Glenoid bone loss 11 4.1% Bony Bankart 8 3.0% Any bone or cartilage lesion 59 21.8% *Indicates Outerbridge Grade 3 or 4 lesions Table 2. Comparison of Patients With and Without Bone and Cartilage Lesions No Bone/Cartilage Lesion (N = 212) Bone/Cartilage Lesion (N = 59) Mean or N Standard Deviation or % Mean or N Standard Deviation or % P Value Age (Years) 22.8 7.7 26.1 9.6 0.025 Body Mass Index (kg/) 26.3 4.6 28.6 5.2 0.0014 Male Sex (N) 173 81.6% 50 84.8% 0.70 Smoker (N) 7 3.3% 4 6.8% 0.26 Hyperlax (Beighton >4) 52 24.5% 9 15.3% 0.16 Pre-Operative Kerlan-Jobe Score 49.3 21.8 42.4 18.3 0.094 Pre-Operative WOSI Score 43.6 18.4 38.9 17.7 0.11 Pre-Operative SAS 13.0 4.5 14.1 4.2 0.13 WOSI: Western Ontario Shoulder Instability; SAS: Shoulder Activity Score Figure 1.

Risk Factors for Intra-Articular Bone and Cartilage Lesions in Patients Undergoing Surgical Treatment for Posterior Instability

OBJECTIVE. The purpose of this study is to describe postoperative MRI findings after femoroacetabular impingement surgery in correlation with pain changes and surgical findings. SUBJECTS AND METHODS. We prospectively enrolled 42 patients (43 hips) who were scheduled for FAI surgery. Pre- and postoperative MR images were obtained using a 3-T MRI system. Changes in pain scores were assessed using the hip dysfunction and osteoarthritis outcome score. MR images were evaluated for the presence of acetabuloplasty or femoroplasty, presence of chondral and labral repair surgery, bone marrow edema, subchondral cysts, chondral defects, labral tears, capsular defects, and effusion. The optimal orientation to detect these changes was noted. Imaging findings were compared with pain score changes using linear regression analysis. Sensitivity and specificity were assessed using surgical correlation as the reference standard. RESULTS. Increased acetabular bony débridement length was associated with decreased improvement in pain scores (coefficient, -2.07; 95% CI, -3.53 to -0.62; p = 0.008), whereas other imaging findings were not significantly different. Femoroplasty and capsular alterations were best detected on oblique axial sequences; acetabuloplasty and cartilage and labral repair were best seen on sagittal sequences. MRI showed excellent sensitivity (100%) and specificity (100%) for detecting labral repair and excellent sensitivity for detecting femoroplasty (98%). Sensitivity and specificity were lower for detecting acetabuloplasty (83% and 80%, respectively) and chondral repair (75% and 54%, respectively). CONCLUSION. Arthroscopic acetabuloplasty showed a greater association with postoperative pain than did other aspects of surgical correction for femoroacetabular impingement. Femoroplasty and labral repair were reliably diagnosed on 3-T MRI; however, limitations were found in the evaluation of acetabular chondral repair.

Postoperative MRI Findings and Associated Pain Changes After Arthroscopic Surgery for Femoroacetabular Impingement.

Purpose: To evaluate research listed as “Submitted” on orthopaedic surgery residency applications for eventual publication rates and quality. Significance: As the orthopaedic surgery residency selection process becomes increasingly competitive, the number of research publications listed on applications continually increases. However, the utility of using publications listed as “Submitted” in the applicant evaluation process remains unknown. Methods: Demographic and publication data were retrospectively collected from 1303 applications to an orthopaedic surgery residency program. The PubMed database was used to verify “Submitted” publications for (1) publication fruition or (2) publication mismatch, defined as discordance between the listed journal of submission and the eventual journal of publication. Results: A total of 594 applications (45.6%) listed ≥1 publication as “Submitted.” Out of 1636 “Submitted” publications, 565 were unverifiable (32.5%). Of the 1071 verified publications, 362 (33.8%) experienced publication mismatch. Within this subgroup, a significant difference existed between the mean impact factors of the listed journal of submission and the eventual journal of publication (1.5 ± 2.7 versus 3.0 ± 2.5, P < 0.01). Demographic data were not predictive of having an unverified publication. Conclusion: Publications listed as “Submitted” in orthopaedic surgery residency applications frequently remain unpublished or are published in less impactful journals than originally intended.

The Outcomes of “Submitted” Publications From Applicants to Orthopaedic Surgery Residency Programs: A Retrospective Review of 1303 Residency Applications

A randomized single-blinded trial of early rehabilitation versus immobilization after reverse total shoulder arthroplasty.

Background: Patients experience varying degrees of pain and symptoms during the early recovery period after hip arthroscopy for femoroacetabular impingement (FAI). Some “fast starters” report minimal discomfort and are eager to advance activities, while “slow starters” describe severe pain and limitations. The relationship between these early postoperative symptoms and 2-year outcomes after hip arthroscopy is unknown. Purpose: To analyze the relationship between early postoperative pain and 2-year patient-reported outcomes (PROs) after hip arthroscopy for FAI. Study Design: Cohort study; Level of evidence, 2. Methods: Patients without arthritis or dysplasia who were undergoing primary hip arthroscopy for FAI were prospectively enrolled and completed validated PROs. Scores for visual analog scale (VAS) for pain were collected preoperatively and at 1 week, 6 weeks, and 2 years postoperatively. Scores for the modified Harris Hip Score (mHHS), Hip disability and Osteoarthritis Outcome Score (HOOS), and 12-Item Short Form Health Survey (SF-12) were collected preoperatively and 2 years postoperatively. Paired t tests were used to evaluate PRO score changes, and correlation analyses were used to assess relationships between early postoperative pain and 2-year postoperative outcomes. Results: A total of 166 patients were included (55% female; mean ± SD age, 35.29 ± 9.6 years; mean body mass index, 25.07 ± 3.98 kg/m2). Patients demonstrated significant improvements in PRO scores (VAS, SF-12 Physical Component Score, mHHS, and all HOOS subscales) at 2 years after hip arthroscopy for FAI (P < .001). There was a significant correlation between lower 1-week VAS pain level (fast starters) and lower 2-year VAS pain level (R = 0.31; P < .001) as well as higher 2-year PRO scores (SF-12 Physical Component Score, mHHS, and all HOOS subscales: R = −0.21 to −0.3; P < .001). There was no correlation between 1-week VAS pain and 2-year SF-12 Mental Component Score (P = .17). Preoperative VAS pain levels showed positive correlations with 1-week postoperative pain scores (R = 0.39; P < .001) and negative correlations with 2-year patient outcomes (R = −0.15 to −0.33, P < .01). There was no correlation between 6-week postoperative pain scores and 2-year PRO scores. Conclusion: Fast starters after hip arthroscopy for FAI experience sustained improvements in outcomes at 2 years after surgery. Patient pain levels before surgery may delineate potential fast starters and slow starters.

Fast Starters and Slow Starters After Hip Arthroscopy for Femoroacetabular Impingement: Correlation of Early Postoperative Pain and 2-Year Outcomes

Treatment of Labral Calcification in the Setting of Femoroacetabular Impingement Syndrome with Arthroscopic Calcification Excision, Labral Repair and Osteoplasty Improves Outcomes.

Background: Orthopaedic sports medicine fellowship positions are increasing in popularity, as evidenced by the increasing number of applicants to these programs. As positions have become more competitive, greater emphasis has been placed on an applicant’s research experience. However, there has been a lack of research evaluating the accuracy of self-reported publications from fellowship applications. Purpose: To evaluate the accuracy of self-reported research publications and the outcomes of studies submitted for publication by applicants to an Accreditation Council for Graduate Medical Education (ACGME)–accredited sports medicine fellowship in the United States (US). Study Design: Cross-sectional study. Methods: Demographic and research publication data were retrospectively collected from 435 applications to an ACGME-accredited orthopaedic sports medicine fellowship program at a single high-volume academic institution from 2013 to 2017. All self-reported manuscript publications and studies in progress were analyzed with a minimum 2-year follow-up. “Submitted” publications were reviewed by searching the originally submitted journal and all publicly available sources. Publications were verified on PubMed, MEDLINE, and other open access journals. Journal impact factors were collected through use of InCites Journal Citation Reports. Results: Only 5.7% (85/1504) of papers reported as “completed” were inaccurately self-reported, with 44 (51.8%) remaining unverified and 41 (48.2%) reporting discordant authorship, in which the published study listed a different author order than reported on the application. Further, 28.3% (197/696) of papers self-reported as “submitted” remained unpublished, 21.8% (152/696) were published in a different journal than originally reported, and 7.6% (53/696) were published with a different authorship order than reported. Among 95 applicants whose papers were published in different journals than originally reported, the mean impact factor of the final accepting journal was significantly lower than that of the journal of original submission (0.97 ± 0.13 vs 3.91 ± 0.79, respectively; 95% CI of the difference, 1.34-4.54; P < .01). Univariate analysis showed no significant relationships between variables of interest (age, sex, US Medical Licensing Examination Step 1 score, American Orthopaedic Association membership, medical school ranking, and advanced degree) and the presence of an inaccuracy. Conclusion: There is a low rate of inaccurate self-reporting of “completed” publications on applications for orthopaedic sports medicine fellowships. The majority of papers listed as “submitted” on these applications were not published in the journals to which they were originally submitted.

An Evaluation of Self-Reported Publications in Orthopaedic Sports Medicine Fellowship Applications

Patellar tendon reconstruction with hamstring autograft for the treatment of chronic irreparable patellar tendon injuries.

Background: Rotator cuff fatty infiltration has been correlated with poorer radiographic and clinical outcomes in supraspinatus and infraspinatus tendon repairs, but this has not been well-studied in subscapularis tendon repairs. Purpose: To evaluate the influence of preoperative rotator cuff fatty infiltration on postoperative outcomes for patients undergoing arthroscopic subscapularis tendon repair. Study Design: Cohort study; Level of evidence, 3. Methods: Patients who underwent arthroscopic subscapularis repair between 2010 and 2016 were retrospectively identified, and demographic data and surgical findings were recorded. The extent of fatty infiltration was determined on preoperative magnetic resonance imaging by the Fuchs modification of the Goutallier classification. At the most recent follow-up, patients completed the Patient-Reported Outcomes Measurement Information System for Upper Extremity (PROMIS-UE) computer adaptive test and a postoperative visual analog scale for pain. The distribution of fatty infiltration was compared between patients undergoing subscapularis tendon repair versus subscapularis tendon repair combined with a posterior cuff repair. Outcomes were compared for patients using Goutallier grade 0-1 versus grade ≥2 changes in each rotator cuff muscle. Multivariate linear regression analysis was performed to evaluate the influence of muscle quality, as well as demographic factors, on PROMIS-UE scores. Significance was defined as P < .05. Results: There were 140 shoulders included (mean age, 61.8 years; 42.1% female; mean follow-up, 51.7 months). The prevalence of Goutallier grade 2 changes or higher was significantly greater in patients with multitendon repair relative to isolated subscapularis tendon repair. For the overall group of all patients undergoing subscapularis tendon repair, whether in isolation or as part of a multitendon repair, PROMIS-UE scores were significantly lower for patients with infraspinatus muscle grade 2 or higher Goutallier changes relative to grade 0 or 1. After adjustment for age, body mass index, patient sex, and fatty infiltration in other rotator cuff muscles, poor infraspinatus muscle quality remained the only significant predictor for lower PROMIS-UE scores. Conclusion: Patients undergoing arthroscopic subscapularis tendon repair with poor infraspinatus muscle quality had worse patient-reported outcomes. This was true whether subscapularis tendon repair was isolated or was performed in conjunction with supraspinatus and infraspinatus tendon repairs.

Do Outcomes of Arthroscopic Subscapularis Tendon Repairs Depend on Rotator Cuff Fatty Infiltration?

The relationship between morphological characteristics of the hip capsule and patient symptoms in the setting of femoroacetabular impingement (FAI) is undefined. In this study, patients with symptomatic FAI prospectively underwent 3T magnetic resonance (MR) imaging of the affected hip and completed the hip disability and osteoarthritis outcome score (HOOS) to determine the correlation between hip capsule anatomy and patient symptoms. Anterior hip capsule volume, posterior capsule volume, anterior‐posterior capsule volume ratio, and proximal‐distal volume ratio in the anterior capsule were quantified and measured using axial‐oblique intermediate‐weighted 3D fast spin echo MR images. A total of 35 patients (35 hips) were included for analysis (mean age: 30.6 years; mean body mass index [BMI]: 24.9 kg/m2; 57% male). The mean alpha angle was 62.2° ± 4.7°, the mean anterior hip capsule volume was 1705.1 ± 450.3 mm3, the mean posterior hip capsule volume was 1284.8 ± 268.5 mm3, the mean anterior to posterior capsule volume ratio was 1.1 ± 0.39, and the mean proximal to distal volume ratio of the anterior capsule was 0.65 ± 0.28. There was no correlation between age, gender, or BMI, and any hip capsule characteristics. Worse scores on the HOOS pain scale were correlated with increased anterior to posterior volume ratio (r = −.38; 95% confidence interval: −0.06 to −0.63). In conclusion, hip capsule morphology correlates with patient symptoms in the setting of FAI as increased anterior capsular volume, relative to posterior capsular volume, is associated with greater patient pain.

Correlation of hip capsule morphology with patient symptoms from femoroacetabular impingement

Background: Patients who have undergone shoulder instability surgery are often allowed to return to sports, work, and high-level activity based largely on a time-based criterion of 6 months postoperatively. However, some believe that advancing activity after surgery should be dependent on the return of strength and range of motion (ROM). Hypothesis: There will be a significant loss of strength or ROM at 6 months after arthroscopic Bankart repair with remplissage compared with Bankart repair alone. Study Design: Cohort study; Level of evidence, 2. Methods: A total of 38 patients in a prospective multicenter study underwent arthroscopic Bankart repair with remplissage (33 males, 5 females; mean age, 27.0 ± 10.2 years; 82% with ≥2 dislocation events in the past year). Strength and ROM were assessed preoperatively and at 6 months after surgery. Results were compared with 104 matched patients who had undergone Bankart repair without remplissage, although all had radiographic evidence of a Hill-Sachs defect. Results: At 6 months, there were no patients in the remplissage group with anterior apprehension on physical examination. However, 26% had a ≥20° external rotation (ER) deficit with the elbow at the side, 42% had a ≥20° ER deficit with the elbow at 90° of abduction, and 5% had persistent weakness. Compared with matched patients who underwent only arthroscopic Bankart repair, the remplissage group had greater humeral bone loss and had a greater likelihood of a ≥20° ER deficit with the elbow at 90° of abduction (P = .004). Risk factors for a ≥20° ER deficit with the elbow at 90° of abduction were preoperative stiffness in the same plane (P = .02), while risk factors for a ≥20° ER deficit with the elbow at the side were increased number of inferior quadrant glenoid anchors (P = .003), increased patient age (P = .02), and preoperative side-to-side deficits in ER (P = .04). The only risk factor for postoperative ER weakness was preoperative ER weakness (P = .04), with no association with remplissage (P = .26). Conclusion: Arthroscopic Bankart repair with remplissage did not result in significant strength deficits but increased the risk of ER stiffness in abduction compared with Bankart repair without remplissage at short-term follow-up.

What Are the Effects of Remplissage on 6-Month Strength and Range of Motion After Arthroscopic Bankart Repair? A Multicenter Cohort Study

Background: Although patients have experienced significant improvements after hip arthroscopy for femoroacetabular impingement (FAI), prior studies suggest that women have worse outcomes than men. These previous studies lack comparisons of patient-reported outcome (PRO) scores based on gender with respect to clinical significance measurements, including the minimal clinically important difference (MCID) and patient acceptable symptom state (PASS). Purpose: To evaluate outcomes after hip arthroscopy for FAI based on patient gender by prospectively assessing changes in PRO scores, MCID, and PASS. Study Design: Cohort study; Level of evidence, 2. Methods: Women and men undergoing hip arthroscopy for FAI were prospectively enrolled, and preoperative radiographic and intraoperative findings were collected. Patients completed the following PRO surveys before surgery and 2 years postoperatively: modified Harris Hip Score (mHHS), Hip disability and Osteoarthritis Outcome Score (HOOS), and 12-Item Short Form Health Survey. Mean scores and percentage of patients reaching MCID and PASS were analyzed. Results: A total of 131 hips were included (72 women, 59 men). Women had smaller preoperative alpha angles (59.1° vs 63.7°, respectively; P < .001) and lower acetabular cartilage injury grade (6.9% vs 22.0% with grade 4 injury, respectively; P = .013). Both women and men achieved equivalent significant improvements in PRO scores after surgery (scores increased 18.4 to 45.1 points for mHHS and HOOS). Women and men reached PASS for mHHS at similar rates (76.4% and 77.2%, respectively; P = .915). MCID was also achieved at similar rates between women and men for all scores (range, 61.4%-88.9%) except the activities of daily living subscale of the HOOS, in which a greater percentage of women reached MCID compared with men (79.2% vs 62.7%, respectively; P = .037). Additional stratification by age group using the median cohort age of 34 years showed no significant differences in PRO improvement based on age group for each gender. Conclusion: Women can achieve clinically meaningful improvements in PRO scores after hip arthroscopy for FAI. Compared with men, women demonstrated equivalent high rates of achieving MCID and PASS at 2 years after surgery.

Is There a Gender Gap in Outcomes After Hip Arthroscopy for Femoroacetabular Impingement? Assessment of Clinically Meaningful Improvements in a Prospective Cohort

The aim of this study was to develop an automatic segmentation method for hip abductor muscles and find their fat fraction associations with early stage hip osteoarthritis (OA) cartilage degeneration biomarkers. This Institutional Review Board approved, Health Insurance Portability and Accountability Act compliant prospective study recruited 61 patients with evidence of hip OA or Femoroacetabular Impingement (FAI). Magnetic resonance (MR) images were acquired for cartilage segmentation, T1ρ and T2 relaxation times computation and grading of cartilage lesion scores. A 3D V‐Net (Dice loss, Adam optimizer, learning rate = 1e−4, batch size = 3) was trained to segment the three muscles (gluteus medius, gluteus minimus, and tensor fascia latae). The V‐Net performance was measured using Dice, distance maps between manual and automatic masks, and Bland‐Altman plots of the fat fractions and volumes. Associations between muscle fat fraction and T1ρ, T2 relaxation times values were found using voxel based relaxometry (VBR). A p < 0.05 was considered significant. The V‐Net had a Dice of 0.90, 0.88, and 0.91 (GMed, GMin, and TFL). The VBR results found associations of fat fraction of all three muscles in early stage OA and FAI patients with T1ρ, T2 relaxation times. Using an automatic, validated segmentation model, the associations derived between OA biomarkers and muscle fat fractions provide insight into early changes that occur in OA, and show that hip abductor muscle fat is associated with markers of cartilage degeneration.

Automatic hip abductor muscle fat fraction estimation and association with early OA cartilage degeneration biomarkers

Tailoring opioid prescriptions to inpatient use after orthopaedic procedures may effectively control pain while limiting overprescription but may not be common in the current orthopaedic practice.

METHODS
A retrospective review identified opioid-naïve patients admitted after any orthopaedic procedure. Daily and total prescription quantities as well as patient-specific factors were collected. The total opioids used the day before discharge was compared with the total opioids prescribed for the day after discharge. Refill rates were then compared between patients whose daily discharge prescription regimen far exceeded or approximated their predischarge opioid consumption.

RESULTS
Six hundred thirteen patients were included (ages 18 to 95 years). The total opioids prescribed for the 24 hours after discharge significantly exceeded the opioids consumed the 24 hours before discharge for each orthopaedic subspecialty. The excessive-prescription group (409 patients) received greater daily opioid (120 oral morphine equivalents [OMEs] versus 60 OMEs; P < 0.01) and total opioid (750 OMEs versus 512.5 OMEs; P < 0.01) at discharge but was more likely to refill their opioid prescription within 30 days of discharge (27.6% versus 20.1%; P = 0.043).

Opioid regimens prescribed after an orthopaedic surgery frequently exceed inpatient opioid use. Opioid regimens that approximate inpatient use may help curb overprescription and are not associated with higher refill rates compared with more excessive prescriptions.

Level III, Retrospective Cohort Study.

A Review of Inpatient Opioid Consumption and Discharge Prescription Patterns After Orthopaedic Procedures.

Background There are limited data on the effect of glenoid retroversion in clinical outcomes following reverse total shoulder arthroplasty (RTSA). The purpose of this study was to evaluate if surgical correction of retroversion affects outcomes following RTSA. Methods An institutional database was utilized to identify 177 patients (mean age: 68.2 ± 10.1 years) with minimum 2-year follow-up after primary RTSA. Glenoid version was measured on preoperative and postoperative radiographs. American Shoulder and Elbow Surgeons (ASES) scores and range of motion were collected before and after RTSA. Change in retroversion was determined by comparing preoperative and postoperative glenoid retroversion on radiographs using paired Wilcoxon signed-rank test. Spearman’s rank correlation was used to investigate relationships between ASES scores and glenoid retroversion. Results The mean postoperative ASES composite score (75.5 ± 22.7) was significantly higher than preoperative (36.8 ± 19.2; P < .0001). The mean preoperative glenoid retroversion was 9.1 ± 6.7° compared to 6.5 ± 5.1° postoperatively (P < .0001). There was no correlation between postoperative ASES scores and preoperative retroversion (r = .014, P = .85) or postoperative retroversion (r = −.043, P = .57). There was no statistical relationship between postoperative retroversion and range of motion, though there is a risk of inadequate power given the sample size. Conclusions Patient-reported outcomes and range of motion measurements following RTSA at short-term follow-up appear to be independent of either preoperative or postoperative glenoid retroversion.

Do Preoperative and Postoperative Glenoid Retroversion Influence Outcomes After Reverse Total Shoulder Arthroplasty?

Do patient outcomes and follow-up completion rates after shoulder arthroplasty differ based on insurance payor?

Background: The use of hip arthroscopic surgery in the treatment of femoroacetabular impingement (FAI) is increasing, but it is universally known as a technically demanding procedure with a “steep” learning curve. There are limited data investigating the correlation between surgeon experience and patient-reported outcomes (PROs) as well as procedure and traction times. Purpose: To prospectively evaluate the relationship between surgeon experience and PROs after hip arthroscopic surgery for the treatment of FAI. Study Design: Cohort study; Level of evidence, 2. Methods: A total of 190 patients undergoing primary hip arthroscopic surgery for FAI were prospectively enrolled during a sports medicine fellowship–trained surgeon’s first 36 months of practice. A radiographic evaluation as well as PRO surveys including the 12-Item Short Form Health Survey (SF-12), the modified Harris Hip Score (mHHS), and the Hip disability and Osteoarthritis Outcome Score (HOOS) were administered preoperatively and at 2 years postoperatively. Logistic regression as well as analysis of variance was performed to evaluate for correlations between surgical experience and PROs, procedure time, and traction time. Results: Of the 190 patients, 168 (88%; mean age, 35.3 ± 9.6 years; mean body mass index, 25.07 ± 3.98) completed a 2-year follow-up and were included for analysis. The mean procedure time was 91.5 ± 23.9 minutes, and the mean traction time was 54.0 ± 17.7 minutes. Patients demonstrated significant improvements at 2 years after surgery for all PRO scores (mHHS, HOOS, and SF-12 physical component summary; P < .001), except the SF-12 mental component summary, which had no change (P = .43). The procedure time significantly decreased after 70 cases, while the traction time continued to decrease until 110 cases (R 2 = 0.99; P < .0001). There was no correlation between increasing case volume and 2-year PRO scores (P > .2 for mHHS, HOOS, and SF-12). There was also no difference with increasing case volume and amount of improvement from preoperative to 2-year postoperative PRO scores for the SF-12 and HOOS. Case volume did not affect the complication rate, as this cohort experienced 4 minor cases of neurapraxia. Conclusion: Surgical efficiency in hip arthroscopic surgery for the treatment of FAI was maximized after 110 cases in this cohort. However, significant PRO improvements can be achieved early in a surgeon’s practice prior to maximizing surgical efficiency.

The Learning Curve for Hip Arthroscopic Surgery: A Prospective Evaluation With 2-Year Outcomes in Patients With Femoroacetabular Impingement

Objectives: Although patients have been found to have significant improvements after hip arthroscopy for femoroacetabular impingement (FAI), prior studies suggest women have worse outcomes compared to men. These previous studies lack comparisons of patient reported outcome (PRO) scores based on gender with respect to clinical significance measurements, including the minimal clinically important difference (MCID) and patient acceptable symptom state (PASS). Therefore, the purpose of this study is to evaluate outcomes following hip arthroscopy for FAI based on patient gender by prospectively assessing changes in PRO scores, MCID, and PASS. Methods: Women and men undergoing hip arthroscopy for FAI were prospectively enrolled and preoperative radiographic and intra-operative findings were collected. The cohort was stratified based on self-identified patient gender so the term gender as well as the terms women and men were used to describe the patients as opposed to sex and the terms female and male. Patients completed the following PRO surveys before surgery and 2-years postoperatively: modified Harris Hip Score (mHHS), Hip disability and Osteoarthritis Outcome Score (HOOS), and the 12-Item Short Form Health survey (SF-12). Mean scores and the percentage of patients reaching MCID and PASS were analyzed. An a priori power calculation was performed which determined 42 hips in each group were needed to adequately power the study to 95%. Results: A total of 131 hips, from 72 women and 59 men were included. The mean ± SD age for women and men was 34.2 ± 9.5 vs 35.8 ± 10.3 years, respectively; P= .347 and body mass index (BMI) of 24.9 ± 4.4 vs 25.5 ± 3.3 kg/m2, respectively; P= .379. Women had smaller preoperative alpha angles (59.1 vs 63.7, respectively; P< 0.001) and lower acetabular cartilage injury grade (6.9% vs 22.0% with grade 4 injury, respectively; P= 0.013). Both women and men achieved equivalent significant improvements in PRO scores after surgery (PRO scores increased 18.4 to 45.1 points for mHHS and HOOS). Women and men reached PASS for mHHS at similar rates (76.4% and 77.2%, respectively; P=0.915). MCID was also achieved at similar rates between women and men for all scores (ranged 61.4% to 88.9%) except HOOS-ADL in which a higher percentage of women reached MCID compared to men (79.2% vs 62.7%, respectively; P= .037). Additional stratification by age group using the median cohort age of 34 showed no significant differences in PRO improvement based on age group for each gender. Conclusions: Women can achieve clinically meaningful improvements in patient reported outcomes scores after hip arthroscopy for FAI. Compared to men, women demonstrated equivalent high rates of achieving MCID and PASS at 2 years following surgery. Table 4. Comparison of the percentage of patients reaching PASS and MCID between Women and Men PRO survey Womena Mena P Valueb mHHS (PASS=74) 76.4 (55/72) 77.2 (44/57) 0.915 mHHS (MCID=8) 70.8 (51/72) 61.4 (35/57) 0.259 HOOS   Symptoms (MCID=9) 68.1 (49/72) 69.5 (41/59) 0.860   Pain (MCID=9) 70.8 (51/72) 62.7 (37/59) 0.325   ADL (MCID=6) 79.2 (57/72) 62.7 (37/59) 0.037   Sports (MCID=10) 86.1 (62/72) 74.1 (43/58) 0.085   QoL (MCID=11) 88.9 (64/72) 82.8 (48/58) 0.314 aData are provided as a percentage and number of patients out of total eligible. ADL, activities of daily living; HOOS, Hip disability and Osteoarthritis Outcome Score; MCID, minimally clinical important difference; mHHS, modified Harris Hip Score; PASS, patient acceptable symptomatic state; PRO, patient-reported outcome; QoL, Quality of Life. bChi-Square Test. Bold indicates P<.05

Is there a gender gap in outcomes after hip arthroscopy for femoroacetabular impingement? Assessment of clinically meaningful improvements in a prospective cohort

Background: The Latarjet procedure is growing in popularity for treating athletes with recurrent anterior shoulder instability, largely because of the high recurrence rate of arthroscopic stabilization, particularly among contact athletes with bone loss. Purpose: (1) To evaluate return of strength and range of motion (ROM) 6 months after the Latarjet procedure and (2) to determine risk factors for failure to achieve return-to-play (RTP) criteria at 6 months. Study Design: Case-control study; Level of evidence, 3. Methods: A total of 65 athletes (83% contact sports, 37% overhead sports; mean ± SD age, 24.5 ± 8.2 years; 59 male, 6 female) who enrolled in a prospective multicenter study underwent the Latarjet procedure for anterior instability (29% as primary procedure for instability, 71% for failed prior stabilization procedure). Strength and ROM were assessed preoperatively and 6 months after surgery. RTP criteria were defined as return to baseline strength and <20° side-to-side ROM deficits in all planes. The independent likelihood of achieving strength and motion RTP criteria at 6 months was assessed through multivariate logistic regression modeling with adjustment as needed for age, sex, subscapularis split versus tenotomy, preoperative strength/motion, percentage bone loss, number of prior dislocations, preoperative subjective shoulder function (American Shoulder and Elbow Surgeons and Western Ontario Shoulder Instability Index percentage), and participation in contact versus overhead sports. Results: Of the patients, 55% failed to meet ≥1 RTP criteria: 6% failed for persistent weakness and 51% for ≥20° side-to-side loss of motion. There was no difference in failure to achieve RTP criteria at 6 months between subscapularis split (57%) versus tenotomy (47%) (P = .49). Independent risk factors for failure to achieve either strength or ROM criteria were preoperative American Shoulder and Elbow Surgeons scores (per 10-point decrease: adjusted odds ratio [aOR], 1.61; 95% CI, 1.14-2.43; P = .006), Western Ontario Shoulder Instability Index percentage (per 10% decrease: aOR, 0.61; 95% CI, 0.38-0.92; P = .01), and a preoperative side-to-side ROM deficit ≥20° in any plane (aOR, 5.01; 95% CI, 1.42-21.5; P = .01) or deficits in external rotation at 90° of abduction (per 10° increased deficit: aOR, 1.64; 95% CI, 1.06-2.88; P = .02). Conclusion: A large percentage of athletes fail to achieve full strength and ROM 6 months after the Latarjet procedure. Greater preoperative stiffness and subjective disability are risk factors for failure to meet ROM or strength RTP criteria.

Are Patients Who Undergo the Latarjet Procedure Ready to Return to Play at 6 Months? A Multicenter Orthopaedic Outcomes Network (MOON) Shoulder Group Cohort Study

Short term outcomes of hip arthroscopy on hip joint mechanics and cartilage health in patients with femoroacetabular impingement syndrome.

Postoperative MRI findings after arthroscopic surgery for femoroacetabular impingement

Preoperative IDEAL (Iterative Decomposition of Echoes of Asymmetrical Length) magnetic resonance imaging rotator cuff muscle fat fractions are associated with rotator cuff repair outcomes.

Response to McLaughlin et al regarding: "Multimodal analgesia decreases opioid consumption after shoulder arthroplasty: a prospective cohort study".

Outcomes for Surgical Treatment of Femoroacetabular Impingement in Adults

The effects of transmuscular quadratus lumborum blocks on postoperative pain in arthroscopic hip surgery: a cohort analysis

The Impact of Body Mass Index on Complications After Shoulder Arthroscopy: Should Surgery Eligibility Be Determined by Body Mass Index Cutoffs?

Background: Positive-pressure air arthrography and venting of the hip capsule are techniques used to decrease the traction forces needed for joint distraction during hip arthroscopic surgery. Little is known about the effects that these techniques have on postoperative pain. Hypothesis: Positive-pressure air arthrography and venting during hip arthroscopic surgery will decrease patient-reported pain and narcotic requirements in the acute postoperative setting. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective cohort analysis was conducted to analyze 35 patients who underwent positive-pressure air arthrography and venting to aid joint distraction during hip arthroscopic surgery versus a group with similar demographics, pathologies, and treatments who did not undergo air arthrography. Numeric pain rating scale (NPRS) scores and medication administration including narcotic and nonnarcotic analgesia in the postanesthesia care unit (PACU) were tracked and compared. Results: The maximum (7.17 vs 4.97, respectively), minimum (2.43 vs 1.09, respectively), and mean (5.15 vs 3.11, respectively) NPRS scores were all higher in the control group compared with the air arthrogram group (P < .001, P = .007, and P < .001, respectively). The administration of oral morphine equivalents (OMEs) during the PACU stay was significantly lower in the air arthrogram group, with a mean of 36.75 ± 11.37 OMEs, compared with 44.53 ± 16.06 OMEs in the control group (P = .023). There was no difference in postoperative nonopioid medications, such as ketorolac or acetaminophen, given between groups. Conclusion: Patients undergoing hip arthroscopic surgery with air arthrography and venting used to aid distraction had significantly less postoperative pain and required a lower total dosage of opioids during their PACU stay when compared with patients who underwent hip arthroscopic surgery without air arthrography.

Use of Air Arthrograms to Aid in Joint Distraction During Hip Arthroscopic Surgery Decreases Postoperative Pain and Opioid Requirements

Background: The treatment of patellar instability in the setting of trochlear dysplasia is challenging. Purpose/Hypothesis: The purpose of this study was to evaluate outcomes for the treatment of recurrent patellar dislocations due to trochlear dysplasia using anteromedialization tibial tubercle osteotomy combined with medial patellofemoral ligament (MPFL) imbrication. We hypothesized that the treatment of patellar instability with tibial tubercle osteotomy and MPFL imbrication would result in improved patient satisfaction and decrease patellar instability events in patients with prior instability and trochlear dysplasia. Study Design: Case series; Level of evidence, 4. Methods: We performed a retrospective analysis of patients who underwent MPFL imbrication and concomitant anteromedialization tibial tubercle osteotomy for recurrent patellofemoral instability at a single institution. The minimum follow-up was 1 year. Patient demographic information including age at the time of surgery, sex, body mass index (BMI), tibial tubercle–trochlear groove (TT-TG) distance, and grade of trochlear dysplasia was collected along with relevant operative data. Postoperatively, recurrent dislocation events as well as Knee injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index, and Kujala scores were collected, and satisfaction was ascertained by asking patients whether they would undergo the procedure again. Results: A total of 37 knees from 31 patients (23 female) with a mean follow-up of 3.8 years (range, 1-8.9 years) were included. The mean patient age was 28.8 years (range, 14-45 years), the mean BMI was 24 kg/m2 (range, 20-38 kg/m2), and the mean preoperative TT-TG distance was 18.9 mm (range, 8.4-32.4 mm). Two knees were classified as low-grade trochlear dysplasia (Dejour A) and 35 as high-grade trochlear dysplasia (Dejour B-D). At final follow-up, patients reported mean KOOS subscale scores of 86.5 (Pain), 79.8 (Symptoms), 93.9 (Activities of Daily Living), 74.3 (Sports/Recreation), and 61.9 (Quality of Life), as well as a mean Kujala score of 81.3. Mean patient satisfaction was 8.3 of 10. The majority of knees (86.5%; 32/37) remained stable without recurrent instability after this procedure, while 13.5% (5 knees) suffered a recurrent dislocation, with 2 requiring revision surgery. Eight knees (21.6%) underwent subsequent hardware removal. Conclusion: Anteromedialization tibial tubercle osteotomy with MPFL imbrication can improve recurrent patellofemoral instability and provide significant clinical benefit to patients with trochlear dysplasia.

Tibial Tubercle Osteotomy and Medial Patellofemoral Ligament Imbrication for Patellar Instability Due to Trochlear Dysplasia

Cutibacterium (formerly Propionibacterium) acnes13, 16 is a slow growing, gram-positive bacteria that is naturally found in higher concentrations as skin flora on the chest and back, as well as in other areas with greater numbers of hair follicles.25, 37 Most of the reported cases of C. acnes shoulder girdle infection follow arthroplasty surgery,18, 20, 26, 27, 32, 35 which then often requires debridement, administration of intravenous antibiotics, and surgical revision of the implanted device.12, 15, 21, 28-30 In a recent study, 56% of 193 shoulder revisions had a positive culture, 70% of which grew C. acnes.30 Despite the relatively common presumed association of C. acnes humeral osteomyelitis with prosthetic infection, infection of the scapula or clavicle secondary to C. acnes is rare.4, 23, 36 Osteomyelitis of the clavicle involving any organism is also an uncommon event that can arise spontaneously via presumed hematogenous spread, or secondary to open fractures or internal fixation.6, 33 The most commonly found organism in clavicular osteomyelitis is Staphylococcus aureus.9 We here report two cases of clavicular infection secondary to C. acnes that were not associated with implants.

Cutibacterium (formerly Propionibacterium) acnes clavicular infection

Objectives: Following surgical reconstruction of the anterior cruciate ligament (ACL), the tendon graft undergoes a remodeling process of ligamentization. Collagen within the ACL graft becomes organized along the long-axis of the ligament and the proteoglycan content increases. Quantitative imaging sequences, specifically T2 and T1rho, allow for a non-invasive assessment of collagen orientation and proteoglycan content, respectively. The purpose of this study was to investigate the longitudinal progression of T2 and T1rho relaxation times of the graft after ACL reconstruction and the relationship between these quantitative imaging markers and patient-reported outcome measures. We hypothesized that T2 and T1rho would decrease significantly over time, reflecting improved collagen organization and ncreased proteoglycan content, and that T2 and T1rho relaxation times would be inversely correlated with Knee Osteoarthritis Outcome Scores (KOOS). Methods: Thirty-two patients (mean age 29.4±8.2 years, 12 females) were followed prospectively after arthroscopic ACL reconstruction with hamstring autograft. Patients provided informed consent and all procedures were IRB-approved. Exclusion criteria included allograft reconstruction, other ligamentous injury, meniscal tear requiring repair, prior knee surgery, or history of arthritis. Post-operative MR imaging was obtained for 31 patients at 6 months, 30 patients at 12 months, 26 patients at 24 months, and 23 patients at 36 months after surgery. T2 and T1rho relaxation times were simultaneously acquired with a combined 3D sagittal sequence using a 3 T MR system (GE Healthcare) with a 1Tx/8Rx knee coil. The intra-articular ACL graft was identified on a fat-suppressed sagittal high-resolution 3D fast spin echo images and manually segmented. The T2 and T1rho relaxation times for the graft were recorded. Patients completed the KOOS at each imaging time point. Repeated measures analysis of variance (ANOVA) tests with Tukey corrections were used to compare T2 and T1rho relaxation times between time points. The relationship between KOOS and T2 and T1rho values at 2 years post-operative was investigated with Spearman’s rank correlation. Significance was defined as p<0.05. Results: The T2 relaxation times of the ACL graft were significantly higher at 6 months relative to 12 months (p<0.001), 24 months (p<0.001,) and 36 months (p<0.001) after ACL reconstruction, as well as significantly higher at 12 months relative to 36 months (p<0.001) (Figure 1A). The T1rho relaxation times of the ACL graft were significantly higher at 6 months relative to 12 months (p<0.001), 24 months (p<0.001), and 36 months (p<0.001) (Figure 1B). The two-year T2 relaxation times and T1rho relaxation times were significantly correlated with the KOOS Sports, Pain, Symptoms, and Activities of Daily Living sub-scores. Conclusion: We observed significant changes in the tendon graft over time following ACL reconstruction with hamstring autograft, reflecting a higher concentration of proteoglycan and more longitudinally-organized collagen structure over time. Improved collagen organization (lower T2 values) and increased proteoglycan content (lower T1rho values) were correlated with better outcomes based on KOOS scores. Quantitative T2 and T1rho relaxation times of ACL graft may offer a non-invasive method for monitoring graft maturation that correlates with patient-reported knee function after ACL reconstruction. Figure 1. The mean T2 relaxation time (A) and mean T1ρ relaxation time (B) is shown for patients following ACL reconstruction with hamstring autograft at four post-operative time points following ACL reconstruction. * indicates p<0.001 relative to 12, 24, and 36 months. # indicates p<0.001 relative to 36 months. Table 1: Correlations between two-year post-operative KOOS scores and two-year T2 and T1ρ relaxation times of ACL graft following autograft hamstring ACL reconstruction Two-Year Post-Operative KOOS Sub-Scores Imaging Sequence Sports Pain Symptoms ADLs Quality of Life T2 Spearman’s Correlation -0.73 -0.62 -0.63 -0.41 -0.31 P Value <0.001 <0.001 <0.001 0.04 0.13 T1ρ Spearman’s Correlation -0.72 -0.64 -0.61 -0.43 -0.26 P Value <0.001 <0.001 <0.001 0.03 0.21

ACL Graft Signal Characteristics Measured by Quantitative MRI Are Significantly Correlated with Patient Reported Outcomes Two-Years after Hamstring Autograft ACL Reconstruction

Periportal Capsulotomy: A Technique for Limited Violation of the Hip Capsule During Arthroscopy for Femoroacetabular Impingement

Objectives: Advanced fatty infiltration is correlated with poor outcomes after rotator cuff repair, and high-grade fatty infiltration is considered a contraindication for repair. The influence of lower levels of fatty infiltration on outcomes after rotator cuff repair remains unclear. Quantitative magnetic resonance (MR) imaging sequences, specifically IDEAL imaging (iterative decomposition of water and fat with echo asymmetry and least-squares estimation), has been recently applied to measuring fatty infiltration of the rotator cuff muscles. Our purpose was to evaluate the relationship between rotator cuff intramuscular fat and patient-reported outcome measures after rotator cuff repair. We hypothesized that higher pre-operative fat content would be negatively correlated with post-operative outcomes. Methods: We retrospectively identified patients who underwent arthroscopic rotator cuff repair with pre-operative MRI scan with sagittal-oblique IDEAL imaging. All procedures were approved by our Institutional Review Board. Pre-operative tear size, tendon involvement, and tendon retraction were measured by a musculoskeletal radiologist. Image segmentation was performed manually on four consecutive slices with perimuscular fat excluded. Patients completed the Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extremity computer adapted survey at a minimum of two years after repair. Correlations between intramuscular fat measurements and PROMIS scores were determined with Spearman’s rank correlation coefficient. Patients were grouped by PROMIS scores above and below 50, as 50 represents population mean. Mann-Whitney U tests were used to compare fat fractions between patients with high PROMIS scores (at or above 50) or low PROMIS scores (less than 50). Multivariate linear regression was performed with PROMIS score as the dependent variable, and individual muscle fat fractions, age, BMI, sex, and total tear size as independent predictors. Significance was defined as p<0.05. Results: A total of 80 patients were included (Table 1). Mean follow-up was 42.5 ±10.7 months. Post-operative PROMIS scores were significantly correlated with the infraspinatus fat fraction (rho = -0.25, p = 0.02) and subscapularis fat fraction (rho = -0.29, p = 0.009). The infraspinatus fat fraction for patients with a low PROMIS score (N=31) was significantly higher relative to those with a PROMIS score above 50 (N=49) (7.2±4.9% vs. 5.2 ±3.0%; p=0.046) (Figure 1). The subscapularis fat fraction was significantly higher for patients with a low PROMIS score relative to those with a PROMIS score above 50 (10.4 ±5.1% vs. 8.2 ±5.0%; p=0.001). In controlling for age, BMI, sex, and total tear size, multivariate regression modeling identified infraspinatus fat fraction (beta = -0.68, p = 0.029) as the only significant independent predictor of post-operative PROMIS score. Conclusion: We observed significant relationships between infraspinatus and subscapularis muscle quality and post-operative patient-reported outcomes after rotator cuff repair. Infraspinatus fat fraction was the only significant predictor when accounting for demographics and rotator cuff tear size. Importantly, these patients were selected for rotator cuff repair and therefore excluded patients with advanced fatty infiltration. Even in patients with lower degrees of muscle degeneration, small differences in muscle quality may impact outcomes after tendon repair. Table 1. Demographics Mean Standard Deviation Age (years) 62.3 7.5 BMI (kg/m2) 26.7 4.9 Tear Size (mm) 16.3 14.1 Retraction (mm) 15.9 14.5 Supraspinatus Fat Fraction (%) 8.53 5.34 Infraspinatus Fat Fraction (%) 5.99 3.96 Subscapularis Fat Fraction (%) 9.04 5.14 Teres Minor Fat Fraction (%) 6.55 6.03 Post-Operative PROMIS-UE 51.29 7.33 Figure 1. Box plots for the pre-operative fat fractions for suprapinsatus, infraspinatus, subscapularis, and teres minor are shown for patients with PROMIS-UE scores at two years post-operatively less than 50 (N = 31) and PROMIS-UE at two years post-operatively greater than or equal to 50 (N = 49). * indicates p = 0.046, # indicates p = 0.001 through Mann-Whitney U tests.

Pre-Operative Quantitative MRI-Based Rotator Cuff Muscle Fat Fractions Are Associated with Patient-Reported Outcomes Following Rotator Cuff Repair

Periportal Capsulotomy: Technique and Outcomes for a Limited Capsulotomy During Hip Arthroscopy.

Editorial Commentary: The Truth about Peripheral Nerve Blocks and Hip Arthroscopy.

Hip joint muscle forces during gait in patients with femoroacetabular impingement syndrome are associated with patient reported outcomes and cartilage composition.

T1ρ and T2 magnetic resonance imaging (MRI) may allow for a noninvasive assessment of ligamentization after anterior cruciate ligament (ACL) reconstruction. We hypothesized that ACL graft T1ρ and T2 relaxation times would decrease over time, that T1ρ and T2 relaxation times would be inversely correlated with Knee Osteoarthritis Outcome Scores (KOOS), and that T1ρ and T2 values would be lower for autograft relative to allograft reconstruction. Thirty‐nine patients (age: 30.5 ± 8.2 years) were followed prospectively after ACL reconstruction with hamstring autograft (N = 27) or soft‐tissue allograft (N = 12). Magnetic resonance (MR) imaging and KOOS surveys were completed at 6, 12, 24, and 36 months after surgery. ACL graft was segmented to define T1ρ and T2 relaxation times. Relaxation times were compared between time points with ANOVA tests. Log‐transformed autograft and allograft relaxation times were compared with the Student t tests. The relationship between KOOS and relaxation times at 24 months was investigated with Spearman's rank correlation. ACL graft T1ρ relaxation times were significantly higher at 6 months relative to 12 months (P = .042), 24 months (P < .001), and 36 months (P < .001). ACL graft T2 relaxation times were significantly higher at 6 months relative to 12 months (P = .036), 24 months (P < .001), and 36 months (P < .001). T1ρ and T2 relaxation times were significantly lower for autograft reconstruction vs allograft reconstruction at 24 months postreconstruction. Two‐year KOOS Sports, Pain, and Symptoms were significantly inversely correlated with T1ρ and T2 relaxation times. T1ρ and T2 sequences may offer a noninvasive method for monitoring ACL graft maturation that correlates with patient‐reported knee function after ACL reconstruction.

Quantitative imaging of anterior cruciate ligament (ACL) graft demonstrates longitudinal compositional changes and relationships with clinical outcomes at 2 years after ACL reconstruction

Arthroscopic Primary Bundle-Specific Posterior Cruciate Ligament Repair with Transosseous Fixation

Patient-Reported Outcomes After Isolated and Combined Arthroscopic Subscapularis Tendon Repairs.

Introduction: Despite growing rates of fragility fractures, there has been a lack of research investigating the risk and characteristics of recurrent fragility fractures. Methods: The Medicare Standard Analytic Files database was used to identify patients from 2005 to 2009 who were older than 65 years, had a diagnosis of osteoporosis or osteopenia, and sustained a fragility fracture of the proximal humerus, distal radius, hip, ankle, or vertebral column. The incidence and type of recurrent fragility fracture were tracked over a 36-month period. Results: A total of 1,059,212 patients had an initial fragility fracture from 2005 to 2009. Of these patients, 5.8% had a subsequent fragility fracture within 1 year for their initial fracture, 8.8% within 2 years, and 11.3% within 3 years. At 3-year follow-up, hip fractures were the most common type of subsequent fracture, regardless of the initial fracture type (6.5%, P < 0.001). Vertebral compression and proximal humerus fractures (13.8% and 13.2%, respectively) were most likely to be associated with a recurrent fragility fracture. Conclusion: Patients who have any type of fragility fracture have a notable risk of subsequent fractures within 3 years, especially hip fractures. These patients should be evaluated and treated for underlying risks factors, including osteoporosis and/or osteopenia. Level of Evidence: Retrospective, level III

Outcomes of revision arthroplasty for shoulder periprosthetic joint infection: a three-stage revision protocol.

Body Mass Index Screening in Knee Arthroscopy: An Analysis Using the National Surgical Quality Improvement Database.

Cross-sectional analysis.

Hip joint loading in persons with hip osteoarthritis (OA) is not well-studied and its associations with symptoms and lesions are unknown.

To determine whether hip joint loading differs between subjects with and without radiographic hip OA and to identify its associations with patients' symptoms and cartilage morphology.

METHODS
Forty-eight subjects (28 males, age 56.0 ± 12.2 years) with hip OA and 95 controls (40 males, age 43.2 ± 13.6 years) participated. Pelvic radiographs, questionnaires, magnetic resonance (MR) imaging, and gait analysis were administrated. Hip disability and OA Outcome Scores (HOOS) were used to assess symptoms. Cartilage morphology was graded on MR images using Scoring Hip OA with MR imaging grading (SHOMRI). Biomechanical variables included peak external hip joint moment (Nm/kg) and moment impulses (Nm⋅ms/kg) in all planes. Generalized Estimating Equations were used to compare the biomechanical characteristics between groups. In the subjects with OA, associations of moment impulses with HOOS and SHOMRI were assessed with partial correlation.

RESULTS
OA group exhibited higher peak external hip flexion and adduction moments (P<.001), and higher hip flexion, adduction, and external rotation moment impulses (P=.001~.039). Increased hip flexion moment impulses were correlated with worse HOOS subscores (r=-0.361~0.424, P<.05) and worse femoral SHOMRI grades (ρ=0.256~0.315, P<.05). Increased hip external rotation moment impulses were correlated with worse femoral SHOMRI grades (ρ=0.283~0.372, P<.05).

Persons with hip OA exhibited abnormally high hip joint loads during walking, and high loads were associated with worse self-reported symptoms and cartilage morphology. J Orthop Sports Phys Ther, Epub 14 Oct 2019. doi:10.2519/jospt.2019.8945.

Abnormal Joint Loading During Gait in Persons With Hip Osteoarthritis is Associated With Symptoms and Cartilage Lesions.

Correlation of PROMIS with Orthopaedic Patient-Reported Outcome Measures.

The influence of preoperative opioid use on inpatient opioid requirements and discharge prescriptions after primary shoulder arthroplasty.

Background: Hip arthroscopic surgery is a rapidly growing procedure, but it may be associated with a steep learning curve. Few studies have used patient-reported outcome (PRO) surveys to investigate the relationship between surgeon experience and patient outcomes after the arthroscopic treatment of femoroacetabular impingement (FAI). Hypothesis: Patients undergoing hip arthroscopic surgery for the treatment of FAI in the early stages of a surgeon’s career will have significantly worse outcomes and longer procedure times compared with patients treated after the surgeon has gained experience. Study Design: Cohort study; Level of evidence, 2. Methods: Patients undergoing hip arthroscopic surgery for FAI and labral injuries were prospectively enrolled during a sports medicine fellowship–trained surgeon’s first 15 months of practice. Patients were stratified into an early group, consisting of the first 30 consecutive cases performed by the surgeon, and a late group, consisting of the second 30 consecutive cases. Radiographic and physical examinations were performed preoperatively and postoperatively. PRO surveys, including the 12-item Short Form Health Survey (SF-12), the modified Harris Hip Score (mHHS), and the Hip disability and Osteoarthritis Outcome Score (HOOS), were administered preoperatively and at a minimum of 1 year postoperatively. Results: There was no difference between the early and late groups for patient age (37.2 ± 11.5 vs 35.3 ± 10.8 years, respectively; P = .489), body mass index (25.6 ± 4.0 vs 25.1 ± 4.5 kg/m2, respectively; P = .615), or sex (P = .465). There was a significantly increased procedure time (119.3 ± 21.0 vs 99.0 ± 28.6 minutes, respectively; P = .002) and traction time (72.7 ± 21.4 vs 59.0 ± 16.7 minutes, respectively; P = .007) in the early group compared with the late group. Mean postoperative PRO scores significantly improved in both groups compared with preoperative values for all surveys except for the SF-12 mental component summary. No differences were found in PRO score improvements or complication rates between the early and late groups. Conclusion: The total procedure time and traction time decrease after a surgeon’s first 30 hip arthroscopic surgery cases for FAI and labral tears, but patient outcomes can similarly improve regardless of surgeon experience in the early part of his or her career.

Hip Arthroscopic Surgery for Femoroacetabular Impingement: A Prospective Analysis of the Relationship Between Surgeon Experience and Patient Outcomes

Editorial Commentary: The Rise of Hip Arthroscopy: Temporary Trend or Here to Stay?

Background: There is no standard method for the surgical treatment of acromioclavicular (AC) joint separations. Current techniques have associated complications, including need for device removal, coracoid fracture, and inadequate reduction. Purpose: To evaluate the clinical outcomes of an internal splint technique without graft augmentation or rigid fixation to treat acute Rockwood type IV and V AC joint injuries. Study Design: Case series; Level of evidence, 4. Methods: A retrospective analysis was performed of 26 patients who underwent a novel internal splint fixation technique between 2011 and 2016. Patients had type IV (n = 2) and type V (n = 24) acute AC separations. The mean time to surgery was 13.7 days (range, 1-28 days). The surgical technique included an open approach with coracoclavicular suture and tape fixation and AC suture fixation. Range of motion, strength, and radiographs were evaluated after surgery. Patient follow-up included the DASH (Disabilities of the Arm, Shoulder and Hand) questionnaire at a mean 3.3 years postoperatively (range, 6 months–8.6 years). DASH questionnaires were obtained for all patients via email. Patients were also surveyed on cosmetic appearance and willingness to undergo the operation again. Results: All patients regained full strength and range of motion following surgery. All postoperative radiographs demonstrated well-maintained reduction of the AC joint. The mean DASH score was 3.4 at final follow-up, and 23 of 26 respondents were satisfied with their postoperative shoulder appearance. There were no reoperations, and all patients stated that they would have the operation again given the same circumstances. Conclusion: The results of this study demonstrate a reliable new technique for acute fixation of type IV or V AC joint injuries via an internal splint construct. This technique enables reduction in the coronal and sagittal planes without the need for graft augmentation or a rigid implant, allowing healing of the coracoclavicular and AC ligaments.

Acute Fixation of Type IV and V Acromioclavicular Separations: An Internal Splint Technique

Background: Although overlapping surgery is used to maximize efficiency, more empirical data are needed to guide patient safety. We conducted a retrospective cohort study to evaluate the safety of overlapping inpatient orthopaedic surgery, as judged by the occurrence of perioperative complications. Methods: All inpatient orthopaedic surgical procedures performed at 5 academic institutions from January 1, 2015, to December 31, 2015, were included. Overlapping surgery was defined as 2 skin incisions open simultaneously for 1 surgeon. In comparing patients who underwent overlapping surgery with those who underwent non-overlapping surgery, the primary outcome was the occurrence of a perioperative complication within 30 days of the surgical procedure, and secondary outcomes included all-cause 30-day readmission, length of stay, and mortality. To determine if there was an association between overlapping surgery and a perioperative complication, we tested for non-inferiority of overlapping surgery, assuming a null hypothesis of an increased risk of 50%. We used an inverse probability of treatment weighted regression model adjusted for institution, procedure type, demographic characteristics (age, sex, race, comorbidities), admission type, admission severity of illness, and clustering by surgeon. Results: Among 14,135 cases, the frequency of overlapping surgery was 40%. The frequencies of perioperative complications were 1% in the overlapping surgery group and 2% in the non-overlapping surgery group. The overlapping surgery group was non-inferior to the non-overlapping surgery group (odds ratio [OR], 0.61 [90% confidence interval (CI), 0.45 to 0.83]; p < 0.001), with reduced odds of perioperative complications (OR, 0.61 [95% CI, 0.43 to 0.88]; p = 0.009). For secondary outcomes, there was a significantly lower chance of all-cause 30-day readmission in the overlapping surgery group (OR, 0.67 [95% CI, 0.52 to 0.87]; p = 0.003) and shorter length of stay (e&bgr;, 0.94 [95% CI, 0.89 to 0.99]; p = 0.012). There was no difference in mortality. Conclusions: Our results suggest that overlapping inpatient orthopaedic surgery does not introduce additional perioperative risk for the complications that we evaluated. The suitability of this practice should be determined by individual surgeons on a case-by-case basis with appropriate informed consent. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Safety of Overlapping Inpatient Orthopaedic Surgery: A Multicenter Study

Surgical stabilization for first-time shoulder dislocators: a multicenter analysis.

Background: Global acetabular retroversion is classically treated with open reverse periacetabular osteotomy. Given the low morbidity and recent success associated with the arthroscopic treatment of femoroacetabular impingement (FAI), there may also be a role for arthroscopic treatment of acetabular retroversion. However, the safety and outcomes after hip arthroscopic surgery for retroversion need further study, and the effect of impingement from the anterior inferior iliac spine (subspine) in patients with retroversion is currently unknown. Hypothesis: Arthroscopic treatment for global acetabular retroversion will be safe, and patients will have similar outcomes compared with a matched group undergoing arthroscopic treatment for focal pincer-type FAI. Study Design: Cohort study; Level of evidence, 2. Methods: Patients undergoing hip arthroscopic surgery for symptomatic global acetabular retroversion were prospectively enrolled and compared with a matched group of patients undergoing arthroscopic surgery for focal pincer-type FAI. Both groups underwent the same arthroscopic treatment protocol. All patients were administered patient-reported outcome (PRO) measures, including the 12-item Short-Form Health Survey (SF-12) Physical Component Summary (PCS) and a Mental Component Summary (MCS), modified Harris Hip Score (mHHS), Hip disability and Osteoarthritis Outcome Score (HOOS), and visual analog scale (VAS) for pain preoperatively and at 1 year postoperatively. Results: There were no differences in age, sex, or body mass index between 39 hips treated for global acetabular retroversion and 39 hips treated for focal pincer-type FAI. There were no major or minor complications in either group. Patients who underwent arthroscopic treatment for global acetabular retroversion demonstrated similar significant improvements in postoperative PRO scores (scores increased by 17 to 43 points) as patients who underwent arthroscopic treatment for focal pincer-type FAI. Patients treated for retroversion who also underwent subspine decompression had greater improvement than patients who did not undergo subspine decompression for the HOOS-Pain (33.7 ± 15.3 vs 22.5 ± 17.6, respectively; P = .046) and HOOS–Quality of Life (49.7 ± 18.8 vs 34.6 ± 22.0, respectively; P = .030) scores. Conclusion: Arthroscopic treatment for acetabular retroversion is safe and provides significant clinical improvement similar to arthroscopic treatment for pincer-type FAI. Patients with acetabular retroversion who also underwent arthroscopic subspine decompression demonstrated greater improvements in pain and quality of life outcomes than those who underwent arthroscopic treatment without subspine decompression.

Arthroscopic Treatment of Acetabular Retroversion With Acetabuloplasty and Subspine Decompression: A Matched Comparison With Patients Undergoing Arthroscopic Treatment for Focal Pincer-Type Femoroacetabular Impingement

There is currently no widely accepted classification system of intra‐articular damage in the setting of femoroacetabular impingement (FAI). The goal of this study is to correlate the Scoring Hip Osteoarthritis with Magnetic Resonance Imaging (SHOMRI) system with arthroscopic findings in symptomatic FAI patients to justify its use in this setting. Symptomatic FAI patients scheduled for hip arthroscopy were prospectively enrolled. Prior to surgery, radiographs, and an MRI were obtained of the affected hip and all patients completed the Hip disability and Osteoarthritis Outcome Score (HOOS) questionnaire. Each MRI was graded using the SHOMRI system. Intraoperatively, cartilage and labral injury grades were recorded. SHOMRI scores were then correlated with the intraoperative cartilage and labral grades as well as preoperative radiographic findings and HOOS scores. Forty‐three patients were analyzed (mean age 35.7 years, 58.1% male). SHOMRI total scores correlated with intraoperative femoral cartilage grade (ρ = 0.42; p = 0.002), acetabular cartilage grade (ρ = 0.30; p = 0.046), and labral tear grade (ρ = 0.42; p = 0.003) as well as with preoperative Tönnis grade (ρ = 0.37, p = 0.013), HOOS pain score (ρ = −0.33; p = 0.039), HOOS ADL score (ρ = −0.39; p = 0.007), and HOOS sports score (ρ = −0.30; p = 0.037). In conclusion, total scores from the SHOMRI system showed significant correlation with arthroscopic findings as well as radiographic gradings and clinical symptoms in patients with FAI. Use of this quantitative system to assess the burden of chondrolabral damage in FAI appears valid. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:3064–3070, 2018.

Using the Scoring Hip Osteoarthritis with Magnetic Resonance Imaging (SHOMRI) system to assess intra‐articular pathology in femoroacetabular impingement

Mental health, preoperative disability, and postoperative outcomes in patients undergoing shoulder arthroplasty.

Background: Femoroacetabular impingement (FAI) can lead to labral and articular cartilage injuries as well as early osteoarthritis of the hip. Currently, the association of patient symptoms with the progression of labral and articular cartilage injuries due to FAI is poorly understood. Purpose: To evaluate the correlation between patient-reported outcome (PRO) scores and cartilage compositional changes seen on quantitative magnetic resonance imaging (MRI) as well as cartilage and labral damage seen during arthroscopic surgery in patients with FAI. Study Design: Cohort study; Level of evidence, 3. Methods: Patients were prospectively enrolled before hip arthroscopic surgery for symptomatic FAI. Patients were included if they had cam-type FAI without radiographic arthritis. All patients completed PRO scores, including the Hip disability and Osteoarthritis Outcome Score (HOOS) and a visual analog scale for pain. MRI with mapping sequences (T1ρ and T2) on both the acetabular and femoral regions was performed before surgery to quantitatively assess the cartilage composition. During arthroscopic surgery, cartilage and labral injury grades were recorded using the Beck classification. Pearson and Spearman correlation coefficients were then obtained to evaluate the association between chondrolabral changes and PRO scores. Results: A total of 46 patients (46 hips) were included for analysis (mean age, 35.5 years; mean body mass index [BMI], 23.9 kg/m2; 59% male). Increasing BMI was correlated with a more severe acetabular cartilage grade (ρ = 0.37; 95% CI, 0.08-0.65). A greater alpha angle was correlated with an increased labral tear grade (ρ = 0.59; 95% CI, 0.37-0.82) and acetabular cartilage injuries (ρ = 0.61; 95% CI, 0.42-0.80). With respect to PRO scores, increasing femoral cartilage damage in the anterosuperior femoral head region, as measured on quantitative MRI using T1ρ and T2 mapping, correlated with lower (worse) scores on the HOOS Activities of Daily Living (r = 0.35; 95% CI, 0.06-0.64), Symptoms (r = 0.32; 95% CI, 0.06-0.57), and Pain (r = 0.31; 95% CI, 0.06-0.55) subscales. There was no correlation between PRO scores and acetabular cartilage damage or labral tearing found on quantitative MRI or during arthroscopic surgery. Conclusion: Femoral cartilage damage, as measured on T1ρ and T2 mapping, appears to have a greater correlation with clinical symptoms than acetabular cartilage damage or labral tears in patients with symptomatic FAI.

Correlation of Patient Symptoms With Labral and Articular Cartilage Damage in Femoroacetabular Impingement

UPDATE
This article was updated on April 26, 2018, because of a previous error. On pages 1 and 14, the author name that had read "Alan Z. Zhang, MD" now reads "Alan L. Zhang, MD."

Biomechanical Consequences of Meniscal Tear, Partial Meniscectomy, and Meniscal Repair in the Knee.

Overlapping Surgery-Perspectives From the Other Side of the Table.

Effects of cemented versus press-fit primary humeral stem fixation in the setting of revision shoulder arthroplasty.

Friday, September 28, 2018 3:00 PM–4:00 PM abstracts: the gravity of obesity: 229. Risk factors for readmission and complications in obese and severely obese patients undergoing elective posterior lumbar spine fusion

What We Already Know about This TopicHip arthroscopy is a surgical procedure growing in popularityThe optimal approach to postoperative analgesia has not been identified What This Article Tells Us That Is NewThe addition of preoperative fascia iliaca block using ropivacaine to the intraarticular injection of ropivacaine did not improve early postoperative pain scoresThe fascia iliaca blocks also did not improve most secondary endpoints, although they did cause quadriceps weakness Background: Ambulatory hip arthroscopy is associated with postoperative pain routinely requiring opioid analgesia. The potential role of peripheral nerve blocks for pain control after hip arthroscopy is controversial. This trial investigated whether a preoperative fascia iliaca block improves postoperative analgesia. Methods: In a prospective, double-blinded trial, 80 patients scheduled for hip arthroscopy were randomized to receive a preoperative fascia iliaca block with 40 ml ropivacaine 0.2% or saline. Patients also received an intraarticular injection of 10-ml ropivacaine 0.2% at procedure end. Primary study endpoint was highest pain score reported in the recovery room; other study endpoints were pain scores and opioid use 24 h after surgery. Additionally, quadriceps strength was measured to identify leg weakness. Results: The analysis included 78 patients. Highest pain scores in the recovery room were similar in the block group (6 ± 2) versus placebo group (7 ± 2), difference: −0.2 (95% CI, −1.1 to 0.7), as was opioid use (intravenous morphine equivalent dose: 15 ± 7mg [block] vs. 16 ± 9 mg [placebo]). Once discharged home, patients experienced similar pain and opioid use (13 ± 7 mg [block] vs. 12 ± 8 mg [placebo]) in the 24 h after surgery. The fascia iliaca block resulted in noticeable quadriceps weakness. There were four postoperative falls in the block group versus one fall in the placebo group. Conclusions: Preoperative fascia iliaca blockade in addition to intraarticular local anesthetic injection did not improve pain control after hip arthroscopy but did result in quadriceps weakness, which may contribute to an increased fall risk. Routine use of this block cannot be recommended in this patient population.

Preoperative Fascia Iliaca Block Does Not Improve Analgesia after Arthroscopic Hip Surgery, but Causes Quadriceps Muscles Weakness: A Randomized, Double-blind Trial

Clinical measurements versus patient-reported outcomes: analysis of the American Shoulder and Elbow Surgeons physician assessment in patients undergoing reverse total shoulder arthroplasty

Validation of scoring hip osteoarthritis with MRI (SHOMRI) scores using hip arthroscopy as a standard of reference

Background: Hip arthroscopy for femoroacetabular impingement (FAI) has been shown to improve patient outcomes, especially for returning to sport. Although previous studies often evaluated outcomes 2 years after hip arthroscopy, there has been no analysis of the progression of patient improvement over time or with respect to achieving the minimal clinically important difference (MCID). Hypothesis/Purpose: The purpose was to prospectively evaluate changes in patient-reported outcome (PRO) scores during the first 2 years after hip arthroscopy for FAI and to analyze when the MCID is achieved. It was hypothesized that clinically significant changes will be reached by 1 year after surgery. Study Design: Case series; Level of evidence, 4. Methods: Patients undergoing hip arthroscopy for FAI were prospectively enrolled, and they completed the 12-Item Short Form Health survey (SF-12), modified Harris Hip Score, and Hip disability and Osteoarthritis Outcome Score (HOOS) at preoperative baseline and 3 months, 6 months, 1 year, and 2 years after surgery. Mean scores and the percentage of patients reaching the MCID at each time point were analyzed via analysis of variance and Cochrane-Armitage trend tests. Results: A total of 129 hips from 122 patients were evaluated, revealing significant improvements after hip arthroscopy for FAI (PRO scores increased 19 to 45 points) with 95.8%, 93.6%, and 84.8% of patients achieving the MCID for HOOS-Sports, HOOS–Quality of Life (QoL), and HOOS-Pain, respectively, at 2-year follow-up. Analysis of PRO change showed that for all scores, the greatest improvement occurred from presurgery to postoperative 3 months, with lesser improvements at subsequent 6-month, 1-year, and 2-year time points (P < .001). The SF-12 physical component score, HOOS-Sports, and HOOS-QoL continued to show statistically significant improvements through 2 years, while other scores plateaued after 3 months. The percentage of patients achieving the MCID for HOOS-Sports, HOOS-QoL, and HOOS-Pain continued to increase over 2 years, but the percentage achieving the MCID did not increase after 3 months for all other scores. Conclusion: Hip arthroscopy for FAI yields significant improvements in patient outcomes within 2 years of surgery. The majority of improvement occurs within 3 months after surgery, but certain outcomes, such as returning to sport, QoL, and pain, can continue to improve through 2 years.

When Do Patients Improve After Hip Arthroscopy for Femoroacetabular Impingement? A Prospective Cohort Analysis

Bariatric surgery before elective posterior lumbar fusion is associated with reduced medical complications and infection.

Intra-arthroscopic evaluation of scoring hip osteoarthritis with MRI (SHOMRI)

Do younger patients have better results after reverse total shoulder arthroplasty?

Background: Intra-articular glenohumeral joint changes frequently occur after shoulder instability events. Purpose: (1) To compare demographic characteristics, baseline patient-reported outcomes, and intraoperative findings for patients undergoing primary or revision shoulder stabilization surgery and (2) to determine the incidence of glenohumeral bone and cartilage lesions in this population while identifying factors independently associated with these lesions. Study Design: Cross-sectional study; Level of evidence, 3. Methods: The Multicenter Orthopaedic Outcomes Network (MOON) Shoulder Group shoulder instability database was used to identify all prospectively enrolled patients undergoing shoulder stabilization surgery for anterior instability between October 2012 and September 2016. Any patient who underwent surgery for posterior or multidirectional shoulder instability or concomitant rotator cuff repair surgery was excluded. Patient demographic characteristics, preoperative patient-reported outcomes, and intraoperative findings, including glenohumeral bone and cartilage lesions, were compared for patients undergoing primary and revision shoulder stabilization surgery. Additionally, patients with and without glenohumeral bone and cartilage lesions were compared and independent associations determined using multivariate analysis. Results: There were 545 patients available for analysis (461/545 [84.6%] primary; 84/545 [15.4%] revision). Patients undergoing revision surgery were older (P = .001), were more frequently smokers (P = .022), had a greater number of instability events before surgery (P = .047), more frequently required reduction assistance (P < .001), and had lower Short Form–36 (SF-36) Mental Component Summary (P = .020) and Western Ontario Shoulder Instability Index (WOSI) (P = .026) scores preoperatively. Additionally, patients undergoing revision surgery had a higher frequency of bone and cartilage lesions than those undergoing primary surgery (47.6% vs 18.4%, respectively; P < .001). Male sex, revision surgery, black race, increasing body mass index, increasing patient age, and lower preoperative SF-36 Physical Component Summary score were independently associated with the presence of glenohumeral bone and cartilage lesions at the time of shoulder stabilization surgery. Revision surgery was strongly associated with the presence of glenohumeral bone and cartilage lesions (odds ratio [OR], 4.381 [95% CI, 2.591-7.406]) and glenoid bone loss greater than 10% (OR, 9.643 [95% CI, 5.128-18.134]) or 20% (OR, 13.076 [95% CI, 5.113-33.438]) of the glenoid width. Conclusion: Glenohumeral bone and cartilage lesions are common at the time of shoulder stabilization surgery, occurring more frequently in patients undergoing revision surgery as compared with primary surgery. On the basis of these findings, future prospective studies should aim to compare the clinical outcomes in these 2 groups.

The Incidence of Glenohumeral Bone and Cartilage Lesions at the Time of Anterior Shoulder Stabilization Surgery: A Comparison of Patients Undergoing Primary and Revision Surgery

Multimodal analgesia decreases opioid consumption after shoulder arthroplasty: a prospective cohort study.

Early Effects of HIP Arthroscopy on Articular Cartilage Composition in Femoroacetabular Impingement Patients

Bariatric Surgery Prior to Elective Posterior Lumbar Fusion Significantly Reduces Medical Complications and Infection

The effect of patient gender on outcomes after reverse total shoulder arthroplasty.

Background Although venous thromboembolic (VTE) events are known to develop after lower extremity surgery, there is little research on the risk of VTE after upper extremity surgery. The aim of this study is to identify the risk factors for VTE in patients undergoing open shoulder surgery. Methods We used International Classification of Diseases, 9th Revision, Clinical Modification procedure codes to identify patients in the Nationwide Inpatient Sample (NIS) from 1998 to 2011 who underwent open shoulder surgery. Patients were tracked to determine the incidence of VTE after surgery and stratified by demographics, comorbidities, and hospital characteristics. Risk factors were analyzed using multivariate analysis. Results A total of 315 423 open shoulder procedures were identified in the NIS from 1998 to 2011, of which 1420 (0.45%) carried a diagnosis of VTE, with 873 (0.27%) cases of pulmonary embolism, and 976 (0.31%) cases of deep vein thrombosis. The VTE incidence was similar in common shoulder surgeries, including total shoulder replacement (0.28%), partial shoulder replacement (0.51%), open reduction internal fixation of humerus (0.73%), and open rotator cuff repair (0.28%). Patients with VTE were older, male, African-American, and had a longer hospital stay (14.0 days compared with 3.2 days for patients without VTE). Comorbidities associated with higher risk of VTE included hypercoagulability (odds ratio [OR]: 5.62, P < .001), cancer (OR: 2.51, P < .001), congestive heart failure (OR: 2.01, P < .001), electrolyte abnormalities (OR: 2.1, P < .001), and obesity (OR: 1.46, P < .001). Conclusions There is a low overall risk of VTE after open shoulder surgery. Risk factors for VTE in this population should be used in conjunction with current guidelines to update recommendations for postoperative prophylactic treatment.

Incidence and Risk Factors for Venous Thromboembolic Events After Open Shoulder Surgery

Background: Anterior shoulder instability can be a disabling condition for the young athlete; however, the best surgical treatment remains controversial. Traditionally, anterior shoulder instability was treated with open stabilization. More recently, arthroscopic repair of the Bankart injury with suture anchor fixation has become an accepted technique. Hypothesis: No systematic reviews have compared the rate of return to play following arthroscopic Bankart repair with suture anchor fixation with the Bristow-Latarjet procedure and open stabilization. We hypothesized that the rate of return to play will be similar regardless of surgical technique. Study Design: Systematic review; Level of evidence, 4. Methods: We performed a systematic review and meta-analysis focused on return to play following shoulder stabilization. Inclusion criteria included studies in English that reported on rate of return to play and clinical outcomes following primary arthroscopic Bankart repair with suture anchors, the Latarjet procedure, or open stabilization. Statistical analyses included Student t tests and analyses of variance. Results: Sixteen papers reporting on 1036 patients were included. A total of 545 patients underwent arthroscopic Bankart repair with suture anchors, 353 with the Latarjet procedure, and 138 with open repair. No significant difference was found in patient demographic data among the studies. Patients returned to sport at the same level of play (preinjury level) more consistently following arthroscopic Bankart repair (71%) or the Latarjet procedure (73%) than open stabilization (66%) (P < .05). Return to play at any level and postoperative Rowe scores were not significantly different among studies. Recurrent dislocation was significantly less following the Latarjet procedure (3.5%) than after arthroscopic Bankart repair (6.6%) or open stabilization (6.7%) (P < .05). Conclusion: This systematic review demonstrates a greater rate of return to play at the preinjury level following arthroscopic Bankart repair and the Latarjet procedure than open stabilization. Despite this difference, >65% of all treated athletes returned to sport at their preinjury levels, with other outcome measures being similar among the treatment groups. Therefore, arthroscopic Bankart repair, the Latarjet procedure, and open stabilization remain good surgical options in the treatment of the athlete with anterior shoulder instability.

Return to Play Following Shoulder Stabilization: A Systematic Review and Meta-analysis

Background Rotator cuff fatty infiltration and atrophy are risk factors for worse outcomes after total shoulder arthroplasty (TSA). The purpose of this study is to evaluate the prevalence of preoperative fatty infiltration and atrophy in TSA patients compared to control patients without glenohumeral osteoarthritis. Methods We retrospectively identified 30 patients undergoing TSA for primary glenohumeral arthritis who had preoperative magnetic resonance imaging. TSA patients were matched by age and sex with control patients without arthritis or full-thickness rotator cuff tears. Blinded observers graded fatty infiltration of the 4 rotator cuff muscles and measured supraspinatus atrophy by the occupation ratio. A multivariate analysis was used to correlate arthritis, age, sex, and body mass index with rotator cuff atrophy and fatty infiltration. Results Goutallier grade ≥ 2 fatty infiltration was seen in at least one muscle for 13/30 (43%) TSA patients and 1/30 (3%) control patients (P < .01). The average supraspinatus fossa occupation ratio was 0.72 ± 0.24 in the TSA group compared to 0.92 ± 0.23 for controls (P < .01). Moderate to severe supraspinatus muscle atrophy (occupation ration < 0.6) was observed in 10/30 (33%) TSA patients and 0/30 (0%) controls. Glenohumeral arthritis was an independent predictor of atrophy and fatty infiltration (P < .01). Age, sex, and body mass index were not significantly correlated with atrophy or fatty infiltration. Conclusion Glenohumeral arthritis is associated with rotator cuff atrophy and fatty infiltration. In the absence of rotator cuff tendon tearing, glenohumeral arthritis may contribute to the pathophysiology of rotator cuff muscle degeneration.

Prevalence of Rotator Cuff Atrophy and Fatty Infiltration in Patients Undergoing Total Shoulder Arthroplasty

Background The coexistence of cervical disease and shoulder pathology is not uncommon. The purpose of this study is to evaluate the early complication rates and outcomes after shoulder arthroplasty in patients with prior cervical arthrodesis. Methods A retrospective analysis was performed on a prospectively collected cohort at a single institution. Shoulder arthroplasty (TSA or RTSA) patients with prior cervical fusion (cervical arthrodesis-shoulder arthroplasty [CASA]) were identified and age-matched to controls without cervical fusion from 2012 to 2015. Early (<90-day) complications, visual analog scale (VAS) pain scores, and hospital length of stays were analyzed. Active shoulder range of motion (ROM) and American Shoulder and Elbow Surgeon (ASES) scores preoperatively, 6-week, 6-month, and 1-year postoperatively were compared. Results Seventeen CASA patients were matched to 34 controls. Patients were similar in gender, American Society of Anesthesiologist score, body mass index, opioid use, and arthroplasty procedure (TSA vs RTSA). CASA patients had similar postoperative VAS pain scores (4.6 vs 4.0), hospital length of stay (2.3 vs 2.5), and 90-day complications (3/17 vs 3/34) when compared to controls. Active shoulder ROM and ASES preoperatively and postoperatively at 6-week, 6-month, and 1-year were similar between the 2 groups. CASA patients had similar improvements in ASES scores at 1-year from preoperative scores when compared to controls (25.8 ± 24.3 vs 35.8 ± 21.4, P = .25). Conclusion Prior cervical fusion does not appear to be a risk factor for increased perioperative complications or poorer patient reported outcomes in patients undergoing shoulder arthroplasty.

Effects of Prior Cervical Fusion on Patient Outcomes After Shoulder Arthroplasty

In this study, quantitative magnetic resonance based measurements were used to evaluate T1ρ and T2 mapping and heterogeneity in femoroacetabular impingement (FAI) patients with acetabular cartilage delamination and to determine the ability of these quantitative MR‐based measurements in detecting delamination. Unilateral hip joint MR‐scans of 36 FAI patients with arthroscopically‐confirmed acetabular cartilage delamination and 36 age, gender, and BMI matched controls were obtained. T1ρ and T2 mapping and heterogeneity of the hip joint articular cartilage were assessed in both groups using voxel‐based relaxometry (VBR). Quantitative MR‐based measurements were compared using statistical parametric mapping (SPM). Receiver operating characteristic (ROC) analysis was used to assess the ability of these quantitative measurements in detecting delamination by calculating the area under the curve (AUC). Pearson partial correlations (r) were used to assess for associations between T1ρ and T2 radial heterogeneity with the alpha angle in FAI patients. T1ρ and T2 global acetabular values were significantly higher in FAI patients with a focal increase within the posterior acetabular cartilage. FAI patients exhibited increased anterior superior acetabular T1ρ and T2 heterogeneity and both of these measures demonstrated a strong ability to detect acetabular cartilage delamination (T1ρ AUC: 0.96, p < 0.001; T2 AUC: 0.93, p < 0.001). FAI patients with a larger alpha angle exhibited increased anterior superior acetabular T1ρ (r = 0.48, p = 0.02) and T2 (r = 0.42, p = 0.03) heterogeneity. T1ρ and T2 heterogeneity within the anterior superior acetabular cartilage was shown to be a sensitive measure in detecting delamination and may prove beneficial to clinicians in determining optimal interventions for FAI patients. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:971–978, 2018.

A novel mr‐based method for detection of cartilage delamination in femoroacetabular impingement patients

T1ρ Radial heterogeneity is a distinctive feature of cartilage delamination in femoroacetabular impingement patients

The James A. Rand Young Investigator's Award: Administrative Claims vs Surgical Registry: Capturing Outcomes in Total Joint Arthroplasty.

Study Design: Retrospective cohort analysis of a national database between 2005 and 2011. Objective: To investigate the current usage of neuromonitoring in patients undergoing multilevel thoracolumbar spine surgery. We hypothesize that the use of neuromonitoring would be associated with a reduced incidence of postoperative neurological injuries. Summary of Background Data: Intraoperative neuromonitoring is a common technique utilized in spine surgery to improve safety and reduce neurological injuries. However, the literature remains unclear in defining the populations that benefit from the use of neuromonitoring. Methods: The PearlDiver Medicare database was queried to identify patients undergoing multilevel thoracolumbar spine instrumentation (defined as >3 thoracolumbar levels) from 2005 to 2011. The use of neuromonitoring was identified by Current Procedural Terminology codes. Neurological injuries were identified by codes from the International Classification of Diseases, Ninth Revision. Results: Within 15,032 patients, the postoperative rate of neurological injury diagnosis was higher when neuromonitoring was used at both 1 week (1.3% vs. 1.0%, P=0.06) and 6 months (5.9% vs. 4.6%, P=0.0005). However, a lower incidence of neurological injury was associated with neuromonitoring in patients undergoing specifically anterior fusion of 4–7 levels, posterior fusion of 7–12 levels, and in adults below 65 years old (P=0.0266, 0.0458, 0.032). Conclusion: Within the total Medicare cohort, the use of neuromonitoring was not associated with a decreased rate of neurological injury in multilevel thoracolumbar instrumentation procedures. This is likely due to the possible selection and detection bias of utilizing neuromonitoring when there is an increased risk of neurological injury based on patient-specific pathology and/or surgical procedure. However, despite the overall potential bias, it was appreciated that in subgroups: age below 65 years old, anterior fusion of 4–7 segments, and posterior fusion of 7–12 segments, there was a statistically significant reduction in the incidence of neurological injuries with neuromonitoring. Level of Evidence: Level III.

Intraoperative Use of Neuromonitoring in Multilevel Thoracolumbar Spine Instrumentation and the Effects on Postoperative Neurological Injuries

Abnormal Joint Moment Distributions and Functional Performance During Sit‐to‐Stand in Femoroacetabular Impingement Patients

The perioperative effects of chronic preoperative opioid use on shoulder arthroplasty outcomes.

Axial traction magnetic resonance imaging (MRI) of the glenohumeral joint in healthy volunteers: initial experience.

Introduction Upper extremity hand dominance greatly impacts the functional ability to perform activities of daily living. No studies have evaluated the effects of hand dominance on patient outcomes and postoperative range of motion (ROM) after reverse total shoulder arthroplasty (rTSA). Methods From 2009 to 2014, functional data and patient-reported outcomes were prospectively collected from patients who underwent rTSA at a single institution. Baseline characteristics were assessed and patients were stratified based on whether surgery was performed on the dominant extremity. A repeated-measures ANOVA was performed to determine differences in outcomes between cohorts. Results Eighty-seven rTSAs were performed on the patients’ dominant (DO) shoulder and 53 on the nondominant (ND) shoulder. Both groups had similar age, hospital length of stay, body mass index, and Charlson Comorbidity Index. Prior to surgery, the ND group had significantly lower active forward elevation (FE) (68°) compared to the DO group (87°, P = .04). Both groups had significant increases in FE ROM at both 1 and 2 years compared to preoperatively (P < .001). At 2 years, both groups had equivalent FE but the ND group gained significantly more than the DO group (67° vs 43°) (P = .005), mainly due to the preoperative FE. This finding was similar for shoulder abduction. Both groups had significant improvements in American Shoulder and Elbow Surgeons scores (P < .001) and Visual Analog Scale pain scores (P < .001) at 1 and 2 years postoperatively, with no significant differences between the groups. Conclusion rTSA is a reliable operation which consistently improves patient ROM, function, and pain scores at 2 years. However, baseline FE is higher in patients undergoing surgery for the DO extremity, which indicates an inability to tolerate as much functional deficiency compared to the ND extremity.

Effect of Hand Dominance on Range of Motion and Outcomes Following Reverse Total Shoulder Arthroplasty

Posterior Shoulder Instability in Athletes: An Analysis of the MOON Shoulder Stabilization Cohort

Background: Femoroacetabular impingement (FAI) is a morphological abnormality of the hip joint that results in functional impairments during various activities of daily living (ADL) such as walking. Purpose/Hypothesis: The purpose of this study was to determine if lower extremity joint loading differed between patients with FAI and controls and to determine whether these altered biomechanical parameters were associated with intra-articular abnormalities. It was hypothesized that patients with FAI would exhibit altered lower extremity joint loading during walking when compared with healthy controls and that these altered joint loading patterns would be associated with intra-articular abnormalities. Study Design: Controlled laboratory study. Methods: Lower extremity kinetics was assessed during walking at a self-selected speed in 15 presurgical patients with FAI and 34 healthy controls matched for age and body mass index. All participants underwent unilateral hip magnetic resonance imaging (MRI) to assess hip joint abnormalities. Hip joint abnormalities were assessed using a semiquantitative MRI-based scoring system. Self-reported outcomes of pain and function were obtained using the Hip disability and Osteoarthritis Outcome Score (HOOS), and physical performance was measured using the 6-minute walk test (6MWT). Group differences were assessed using an independent t test and analysis of variance. In the patients with FAI, associations of joint kinetics with HOOS subscores and intra-articular abnormalities were assessed using the Pearson (r) and Spearman (ρ) correlation coefficients, respectively. Results: Compared with the control group, the FAI group exhibited a significantly increased severity of acetabular (FAI: 1.87 ± 1.55; control: 0.47 ± 0.79; P < .001) and femoral (FAI: 3.27 ± 2.79; control: 1.21 ± 1.55; P = .002) cartilage abnormalities, increased levels of pain (FAI: 65.0 ± 18.8; control: 98.2 ± 3.4; P = .001), and reduced function (FAI: 67.2 ± 21.5; control: 98.9 ± 3.4; P < .001) but similar walking speeds (FAI: 1.55 ± 0.19 m/s; control: 1.63 ± 0.22 m/s; P = .20) and 6MWT performance (FAI: 628.0 ± 91.2 m; control: 667.2 ± 73.4 m; P = .13). The FAI group demonstrated increased hip flexion moment impulses (FAI: 0.14 ± 0.04 N·m·s/kg; control: 0.11 ± 0.03 N·m·s/kg; P = .03), peak ankle dorsiflexion moments (FAI: 1.64 ± 0.16 N·m/kg; control: 1.46 ± 0.31 N·m/kg; P = .04), and ankle dorsiflexion moment impulses (FAI: 0.39 ± 0.07 N·m·s/kg; control: 0.31 ± 0.07 N·m·s/kg; P = .01) compared with the control group. Within the FAI group, an increased hip flexion moment impulse during walking was significantly correlated with increased pain (r = −0.60, P = .03), decreased ADL (r = −0.57, P = .04), and increased severity of acetabular cartilage abnormalities (ρ = 0.82, P < .01). Conclusion: Patients with FAI exhibited altered hip and ankle joint loading patterns during walking. These data suggest that patients with FAI demonstrate both local and distal joint alterations during walking and that hip joint loading is directly related to hip joint abnormalities. Clinical Relevance: The results of this study suggest that the hip flexion moment impulse may be an important biomechanical parameter to understand FAI, as the hip flexion moment impulse during walking was shown to be directly related to hip joint abnormalities on MRI.

Joint Loading in the Sagittal Plane During Gait Is Associated With Hip Joint Abnormalities in Patients With Femoroacetabular Impingement

Is Obesity a Risk Factor for Adverse Events After Knee Arthroscopy?

The practice of a surgeon performing procedures in two operating rooms during overlapping time frames has been described as concurrent surgery if critical portions occur simultaneously, or overlapping surgery if they do not. Although recent media reports have focused on the potential adverse effects of these practices, to our knowledge, there has been no previous research investigating outcomes of overlapping procedures in orthopaedic surgery.

METHODS
A retrospective review of an institutional clinical database from 2012 to 2015 was utilized to collect data from all surgical cases (including sports medicine, hand, and foot and ankle) performed at an ambulatory orthopaedic surgery center. Patient demographic characteristics, types of procedures, operating room time, procedure time, and 30-day outcomes including complications, unplanned hospital readmissions, unplanned reoperations, and emergency department visits were collected. The amount of overlap time between cases was also analyzed. Pearson chi-square tests, Student t tests, and logistic regression were used for statistical analysis.

RESULTS
Of 3,640 cases performed, 68% were overlapping procedures and 32% were non-overlapping. There was no difference in the mean age, sex, body mass index, American Society of Anesthesiologists rating, or Charlson Comorbidity Index between patients who had overlapping procedures and those who did not. Comparison of overlapping surgery cases and non-overlapping surgery cases revealed no difference in the mean procedure time (70.7 minutes compared with 72.8 minutes; p = 0.116) or total operating room time (105.4 minutes compared with 105.5 minutes; p = 0.949). Complications were tracked for 30 days after procedures and yielded a rate of 1.1% for overlapping surgeries and 1.3% for non-overlapping surgeries (p = 0.811). Stratification based on subspecialty surgery also demonstrated no difference in complications between the cohorts. Fifty percent of overlapping cases overlapped by <1 hour of operating room time, but 7% overlapped by >2 hours. The rate of complications was found to have no association with the amount of overlap between cases (p = 0.151).

Overlapping surgery yields equivalent patient operating room time, procedure time, and 30-day complication rates as non-overlapping surgery in the ambulatory orthopaedic setting. Further investigation is warranted for inpatient orthopaedic procedures and across all orthopaedic subspecialties.

Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Plate fixation of midshaft clavicular fractures: patient-reported outcomes and hardware-related complications.

Distal biceps tendon ruptures are uncommon events in the adult population and exceedingly rare in the adolescent population. To the best of our knowledge, this is the first and only report of a distal biceps tendon rupture in an adolescent with a history of chronic corticosteroid suppression. We present a case of a 17-year-old male on chronic corticosteroid suppression who underwent a successful distal biceps tendon repair after an acute rupture following weightlifting. At the 1-year follow-up, the patient reports full range of motion and strength, and is able to return to his preinjury activity level with sports and weightlifting. Acute distal biceps ruptures are uncommon injuries in the pediatric population, but may occur in conjunction with chronic corticosteroid use. Anatomic repair, when possible, can restore function and strength. Level of Evidence: level IV, case report

Acute distal biceps rupture in an adolescent weightlifter on chronic steroid suppression: a case report

ABSTRACT Intra-articular injection of corticosteroid and anesthetic (CSI) is a useful diagnostic tool for hip pain secondary to labral tears or femoroacetabular impingement (FAI). However, the effectiveness of CSI as a stand-alone treatment for hip pain in adolescents is unknown. The purpose of this study is to evaluate the use of CSI for the treatment of hip pain and determine factors that may affect outcomes after injection. Retrospective analysis of 18 patients and 19 hips that underwent fluoroscopic guided hip injection for the treatment of pain at a single institution from 2012 to 2015 was carried out in this study. Mean age at the time of injection was 15.1 years (range 13–17) with mean follow-up of 29.4 months. Fifty-two percent (10/19 hips) went on to surgery after the injection. Average time to surgical conversion was 12.8 months after CSI. Cam or pincer morphologies were present in 90% (9/10 hips) of the operative group. Patients with FAI were more likely to need surgery than patients without bony abnormalities (RR= 10, 95% CI 1.6–64.2, P = 0.0001). There was no difference in the presence of labral tears in the operative and non-operative groups (100% versus 89%, P = 0.47). For adolescents without bony abnormalities, 90% improved with CSI alone and did not require further treatment within 2.4 years. Fluoroscopic guided corticosteroid hip injection may have limited efficacy for the treatment of hip pain secondary to FAI in adolescents. However, for patients without osseous deformity, CSI may offer prolonged improvement of symptoms even in the presence of labral tears.

Outcomes of intra-articular corticosteroid injections for adolescents with hip pain

The Effects of Patient Obesity on Early Postoperative Complications After Shoulder Arthroscopy.

Outcomes of Intra-articular Corticosteroid Injections for Adolescents with Hip Pain

Preoperative patient-reported scores can predict postoperative outcomes after shoulder arthroplasty.

Background: Concussion injuries have been highlighted to the American public through media and research. While recent studies have shown increased traumatic brain injuries (TBIs) diagnosed in emergency departments across the United States, no studies have evaluated trends in concussion diagnoses across the general US population in various age groups. Purpose: To evaluate the current incidence and trends in concussions diagnosed across varying age groups and health care settings in a large cross-sectional population. Study Design: Descriptive epidemiological study. Methods: Administrative health records of 8,828,248 members of a large private-payer insurance group in the United States were queried. Patients diagnosed with concussion from years 2007 through 2014 were stratified by year of diagnosis, age group, sex, classification of concussion, and health care setting of diagnosis (eg, emergency department vs physician’s office). Chi-square testing was used for statistical analysis. Results: From a cohort of 8,828,248 patients, 43,884 patients were diagnosed with a concussion. Of these patients, 55% were male and over 32% were in the adolescent age group (10-19 years old). The highest incidence of concussion was seen in patients aged 15 to 19 years (16.5/1000 patients), followed by those aged 10 to 14 years (10.5/1000 patients), 20 to 24 years (5.2/1000 patients), and 5 to 9 years (3.5/1000 patients). Overall, there was a 60% increase in concussion incidence from 2007 to 2014. The largest increases were in the 10- to 14-year (143%) and 15- to 19-year (87%) age groups. Based on International Classification of Disease–9th Revision classification, 29% of concussions were associated with some form of loss of consciousness. Finally, 56% of concussions were diagnosed in the emergency department and 29% in a physician’s office, with the remainder in urgent care clinics or inpatient settings. Conclusion: The incidence of concussion diagnosed in the general US population is increasing, driven largely by a substantial rise in the adolescent age group. The youth population should be prioritized for ongoing work in concussion education, diagnosis, treatment, and prevention. Clinical Relevance: The rise of concussions in the adolescent age group across the general population is concerning, and clinical efforts to prevent these injuries are needed.

Poor Agreement on Classification and Treatment of Subscapularis Tendon Tears.

Quantitative MRI (QMRI) of the hip with sequences such as T1ρ and T2 mapping has been utilized to detect early changes in cartilage matrix composition. However, QMRI has not been performed in the presence of intra‐articular contrast. Thus the purpose of this study was to evaluate the feasibility and use of QMRI during MR‐arthrography (MRA) in femoracetabular impingement (FAI) patients.

Quantitative magnetic resonance arthrography in patients with femoroacetabular impingement

Proximal humerus fragility fractures: recent trends in nonoperative and operative treatment in the Medicare population.

Clinical, Radiographic, and Surgical Presentation of Subscapularis Tendon Tears: A Retrospective Analysis of 139 Patients.

Accuracy of MRI evaluation of meniscus tears in the setting of ACL injuries.

Altered Joint Loading During Gait is Associated with Hip Joint Abnormalities in FAI Patients

The cost-effectiveness of meniscal repair versus partial meniscectomy: A model-based projection for the United States.

Objectives: Concussion injuries have been correlated with significant long-term deleterious effects on patients. While recent studies have shown increased traumatic brain injuries (TBI) diagnosed in U.S. emergency departments, no studies have evaluated trends in concussion diagnoses across the general U.S. population in various age groups. The objective of this study is to evaluate the current incidence and trends in concussions diagnosed across varying age groups and healthcare settings in a large cross-sectional population. Methods: Administrative health records of 8,828,248 members of a large private payer insurance group in the United States were queried. Patients diagnosed with concussion from years 2007 through 2014 were stratified by year of diagnosis, age group, gender, classification of concussion, and healthcare setting of diagnosis (e.g. ED vs. physician’s office). Chi-square testing was used to for statistical analysis. Results: From a cohort of 8,828,248 patients, 43,884 patients were diagnosed with a concussion. Fifty-five percent of concussion patients were male and over 32% were in the adolescent age group (10-19 years old). The highest incidence of concussion was seen in the 15-19 age group (16.5 cases per 1000 patients) followed by the 10-14 (10.5 per 1000), 20-24 (5.2 per 1000) and 5-9 (3.5 per 1000) age groups. Overall there was a 160% increase in concussion incidence from 2007 to 2014. The largest increases were in the 10-14 (243%) and 15-19 (187%) age groups. Based on ICD-9 classification, 29% of concussions were associated with some form of loss of consciousness. Finally, 56% of concussions were diagnosed in the ED and 29% in a physician’s office, with the remainder in urgent cares or inpatient settings. Conclusion: The incidence of concussion diagnosed in the general population in the United States is increasing, driven largely by a substantial rise in the adolescent age group. The youth population should be prioritized for ongoing work in concussion education, diagnosis, treatment and prevention.

Study Design: Retrospective cohort study. Objective: To investigate the relationship between cervical spine (C-spine) and rotator cuff (RTC) pathology. Summary of Background Data: Cervical spine and RTC pathology cause significant shoulder pain in isolation and in tandem, but there is limited information about the relationship between these 2 entities. Methods: Patients with a diagnosis of C-spine and/or RTC pathology between 2005 and 2011 were identified using a large national database composed of private payer as well as Medicare patient records. Patients with concomitant C-spine and RTC diagnoses were then stratified by age group and sex. Patients with lumbar spine (L-spine) and RTC pathology were used as a comparative group, and multivariate logistic regression was used for statistical analysis. Results: Concomitant C-spine and RTC diagnoses were identified in 86,928 patients representing 13% of 679,112 patients with a RTC diagnosis and 16% of 531,177 patients with a C-spine diagnosis. The association between C-spine and RTC pathology increased significantly with age as RTC diagnoses were present in 13% of patients with C-spine pathology younger than 60 years old but increased to 25% in C-spine patients older than 60 years (P<0.0001). For patients over 60 years old who developed a new C-spine diagnosis, 11% would develop a new RTC diagnosis or undergo an operation for a RTC disorder within 5 years. Lumbar diagnosis codes (2,297,480 patients) were over 4 times more common than C-spine codes but RTC pathology had a significantly higher correlation with C-spine pathology than L-spine pathology (odds ratio, 2.32) and patients with C-spine pathology were more likely to develop new rotator cuff pathology (odds ratio, 1.53). Conclusions: The association between cervical spine and RTC pathology is significantly greater than that between L-spine and RTC pathology and increases substantially with patient age. Further studies are needed to elucidate the cause of this relationship.

The Association Between Cervical Spine Pathology and Rotator Cuff Dysfunction

Objectives: The rate of hip arthroscopy has increased dramatically in the past 5 years but there is a lack of information regarding patient demographics in a large cross-sectional population. The purpose of this study was to evaluate recent trends in hip arthroscopy from a large private payer population in the United States. Methods: We performed a retrospective analysis using the Pearldiver private insurance patient record database from 2007 through 2011. A search was performed for hip arthroscopy procedures including newly introduced codes such as osteochondroplasty of Cam and Pincer lesions and labral repair. Hip arthroscopy incidence, growth over time, and conversion rates to total hip arthroplasty (THA) were stratified by age. Chi-square analysis was used for statistical comparison. Conversion to THA was evaluated using Kaplan-Meier analysis with logrank and Wilcoxon tests. Results: From 2007 through 2011, 15,532,426 outpatient procedure records were analyzed. Hip arthroscopy was performed in 8,237 patients with females comprising 63% of cases. The number of hip arthroscopies increased over 250% from 981 cases in 2007 to 2,507 cases in 2011 (p<0.0001). Patients in age group 40-49 underwent the most number of hip arthroscopies, comprising 28% of cases followed by 30-39 (22%), 50-59 (19%), 20-29 (14%), 10-19 (12%) and 60-69 (5%). Patients under 30 years of age showed the greatest increase in incidence from 2007 to 2011 (335%) but patients over 60 still had over a 200% increase. Chondroplasty/labral debridement was the most common procedure, present in 6,031 cases and approximately 1.6 procedural codes were billed for every case performed. Older patients were more likely to receive labral debridement instead of repair. Within 24 months of hip arthroscopy, 17% of patients older than 50 years old required conversion to THA compared to less than 1% of patients under 30 years old (p<0.0001). Conclusion: Hip arthroscopy procedures are increasing in popularity across all age groups with patients aged 40-49 having the highest incidence in this population. A high rate of conversion to THA within 2 years of hip arthroscopy in patients over 50 suggests a need to better specify appropriate indications.

Age-Related Trends in Hip Arthroscopy: A Large Cross-Sectional Analysis.

The Cost-Effectiveness of Meniscal Repair Versus Partial Meniscectomy: A Model-Based Projection of Clinical Outcomes And Costs In The United States Healthcare System

OBJECTIVE
Imaging of hip cartilage is challenging because of its limited thickness and complex geometry and therefore requires advanced MRI techniques. However, cartilage abnormalities are found in a number of disease entities, and their diagnosis may impact patient management. This article will provide pertinent information about the motivation to image hip cartilage, which imaging techniques to use, and how to analyze cartilage; finally, we will discuss disease entities with regional cartilage lesions, including the typical MRI findings.

Because the detection and quantification of regional cartilage abnormalities are critical for guidance of operative and nonoperative management of hip disorders, radiologists should be familiar with imaging and analysis techniques for assessing hip cartilage.

Management of deep postoperative shoulder infections: is there a role for open biopsy during staged treatment?

Tibiofemoral contact pressures in radial tears of the meniscus treated with all-inside repair, inside-out repair and partial meniscectomy.

Background: Scapular notching is a radiographic finding of unknown clinical significance following reverse total shoulder arthroplasty (RTSA). The purpose of this study was to determine how baseplate position affects the incidence of scapular notching and measure the clinical outcomes. Hypothesis: We hypothesized that low base plate position on the glenoid and new prosthesis design with a higher humeral inclination angle would decrease the incidence of notching at 2 years follow-up. Materials and methods: A total of 54 patients with an average follow-up of 30 months met inclusion criteria and underwent radiographic analysis of scapular notching and radiographic measures to determine glenoid component placement. Clinical measures including visual analog score, American Shoulder and Elbow Surgeons (ASES) scores, and range of motion (ROM) were prospectively collected. Results: Thirty-nine of the 54 patients had no notching. 7 had Grade 1 notching, 7 had Grade 2 notching, one had Grade 3, and one had Grade 4 notching. Notching was associated with higher placement of the glenoid component as measured by peg-glenoid rim distance and base plate distance. All patients with no evidence of notching at 1-year, continued to have no notching after multi-year follow-up. Clinical outcome measures including ASES scores, ROM, and visual analog pain scores were improved at follow-up. Conclusion: We concluded that lower neck-shaft angle and low baseplate positioning led to a low incidence of significant scapular notching as only 6 out of 57 (16%) patients had notching Grade 2 and above. At short-term follow-up, this RTSA results in excellent clinical outcomes and a significantly lower scapular notching rate than traditional techniques.

Decreased scapular notching with lateralization and inferior baseplate placement in reverse shoulder arthroplasty with high humeral inclination

Hospital Readmissions After Surgical Treatment of Proximal Humerus Fractures: Is Arthroplasty Safer Than Open Reduction Internal Fixation?

Abnormal origins of the long head of the biceps tendon can lead to rotator cuff pathology: a report of two cases

Arthroscopic versus open shoulder stabilization: current practice patterns in the United States.

Analysis of rotator cuff repair trends in a large private insurance population.

Knee arthroscopy to address meniscus tears is among the most common orthopedic procedures performed, and technical advances in the treatment of meniscus tears have affected the treatment options available to orthopedic surgeons. The purpose of this study was to perform a large cross-sectional analysis of orthopedic patients to investigate trends in arthroscopic meniscectomy and meniscus repair in the United States. Patients who underwent arthroscopic meniscectomy (Current Procedural Terminology codes 29881 and 29880) and arthroscopic meniscus repair (Current Procedural Terminology codes 29882 and 29883) were identified using the PearlDiver Patient Record Database, which is a national database of insurance records. The authors identified 187,607 arthroscopic medial or lateral meniscectomies and repairs performed between 2004 and 2009. Ninety-six percent of patients underwent meniscectomy and 4% underwent repair. No change occurred in the incidence of medial or lateral meniscectomy. The incidence of medial meniscus repair decreased from 5.3 cases per 10,000 patients in 2004 to 3.8 in 2009 (P<.001), although no significant change occurred in the incidence of lateral meniscus repair. Medial meniscectomy was most commonly performed in patients aged 50 to 59 years, whereas lateral meniscectomy demonstrated a bimodal age distribution. Conversely, meniscus repairs were most frequently performed in patients aged 10 to 19 years. Sex differences were more pronounced with meniscus repair (63% male vs 37% female) compared with meniscectomy (53% male vs 47% female). A high frequency of meniscus debridement can be expected in arthroscopic knee surgery. Despite advances in meniscus repair techniques and devices, no increase occurred in the performance of meniscus repair compared with meniscectomy.

Cross-sectional analysis of trends in meniscectomy and meniscus repair.

Background: Treatment of superior labral anterior posterior (SLAP) tears remains controversial, particularly in older age groups. Repair, debridement, biceps tenodesis, tenotomy, and observation have been recommended depending on patient characteristics, but there have not been any large epidemiologic studies investigating treatment trends. Purpose: To investigate current trends in SLAP repair across time, gender, age, and regions in the United States. Study Design: Descriptive epidemiology study. Methods: Patients who underwent arthroscopic SLAP repair (Current Procedural Terminology [CPT] code 29807) were identified using a publicly available national database of insurance records (PearlDiver Patient Records Database) during years 2004 through 2009. Factors identified for each patient included gender, age group, and region in the United States. Logistic regression analysis and the chi-square test were used for statistical measures. Results: From 2004 to 2009 there were 25,574 cases of arthroscopic SLAP repair identified, of which 75% were male patients and 25% were female patients. There was a significant rise in cases of SLAP repair from 2004 to 2009 as the incidence of SLAP repair increased from 17.0 for every 10,000 patients with an orthopaedic International Classification of Diseases, Ninth Revision (ICD-9) or CPT code in 2004 to 28.1 in 2009 (P < .0001). Age analysis revealed the highest incidence in the 20-29–year (29.1 per 10,000) and 40-49–year (27.8 per 10,000) age groups. Men (37.3 per 10,000) had a significantly higher incidence of repairs than did women (10.7 per 10,000). The West (24.6 per 10,000) and South (24.4 per 10,000) regions also demonstrated a higher incidence than the Midwest (20.5 per 10,000) and Northeast (20.1 per 10,000) regions (P < .0001). Conclusion: Our analysis illustrates that surgeons are performing significantly more arthroscopic SLAP repairs each year. The highest incidence of repair is in the 20-29– and 40-49–year age groups, and a significant gender difference exists, with men having a threefold higher incidence of repair.

Demographic Trends in Arthroscopic SLAP Repair in the United States

Background: The reverse total shoulder replacement has become a popular treatment option for cuff tear arthropathy and other shoulder conditions requiring arthroplasty in the setting of a deficient rotator cuff. Despite a revision rate of as much as 10%, to date, there are few reports of reverse replacement conversion to hemiarthroplasty, and none specifically examining shoulder function. Materials and Methods: Six patients with a reverse replacement that was dislocated, infected or loose were revised an average of 9.2 months after the reverse replacement. Two of the three patients that were dislocated also had a known deep infection. Patients with known infection were treated with explant of the reverse prosthesis and conversion to a preformed antibiotic spacer hemiarthroplasty. In three cases with gross loosening of the glenosphere without infection, treatment was performed with removal of glenosphere only, bone grafting of glenoid with allograft and conversion of humeral stem to hemiarthroplasty. Patients were evaluated with outcome scores and physical examination an average of 26.5 months after removal of the reverse prosthesis. Results: The average range of motion postoperatively was forward elevation 42.5 degrees and external rotation 1.7 degrees. The VAS pain score was 2.42 (range 0–6); simple shoulder test was 3.17 (range 1–5); and ASES score was 52.1 ± 8.5. There were no reoperations to date, and five patients had anterosuperior escape. Conclusions: Safe removal of a reverse replacement and conversion to hemicement spacer or hemiarthroplasty can provide pain relief in those patients with a dislocated or infected reverse replacement. However, the shoulder will likely have very poor function and anterosuperior escape postoperatively. Further studies are needed to determine the optimal treatment for the failed reverse shoulder replacement. Level of Evidence: Therapeutic Level IV.

Shoulder function and pain level after revision of failed reverse shoulder replacement to hemiarthroplasty

Removal for the reverse total shoulder prosthesis can present a unique set of challenges even to the most experienced shoulder surgeon. Although there have been many early cases of failure from infection and instability, the first cycle of long-term reverse prosthesis failures because of aseptic loosening and polyethylene wear have yet to occur. Despite the known high complication rate, there has been very little written about the proper management of a reverse replacement that has failed because of infection, instability, and loosening. The purpose of this study is to describe the surgical technique used to safely extract a failed reverse total shoulder prosthesis and also to highlight the extraction methods and salvage options unique to each manufacturer. After removal of the reverse replacement and conversion to hemiarthroplasty or preformed spacer, pain is routinely low, but shoulder function is poor with severe anterosuperior escape.

Background: Progressive genu varum with disturbance of medial tibial physeal growth (classic Blount disease) is a well-studied phenomenon, and in rare cases, genu varum can occur because of medial distal femoral physeal growth disturbance (so-called femoral Blount disease). To our knowledge, progressive genu valgum caused by disturbance of lateral distal femoral physeal growth has not been described. Methods: This article presents the history, clinical findings, imaging studies, results of surgical treatment, and speculation regarding the etiology of this disorder in 2 girls. Results: Both patients were overweight girls without a history of injury or prior medical disorder who presented with relatively rapid progression of knock-kneed deformity. Magnetic resonance imaging studies demonstrated unusual circular peglike disturbances of the lateral distal femoral physes. Treatments in both cases included corrective distal femoral osteotomy and epiphysiodesis to prevent further deformity. Conclusions: Obesity and repetitive microtrauma, superimposed on genetic factors (physis that is sensitive to compressive forces), may contribute to the etiology of this rare disorder. Level of Evidence: Therapeutic, level IV.

Progressive Genu Valgum Resulting From Idiopathic Lateral Distal Femoral Physeal Growth Suppression in Adolescents

Background Fixation strength of metal and bioabsorbable interference screws has not been evaluated while varying the anterior cruciate ligament graft tension angle. Hypothesis There is no difference in fixation strength between 2 types of interference screws for anterior cruciate ligament graft fixation while the graft tension angle is varied relative to the femoral tunnel. Study Design Controlled laboratory study. Methods Forty-eight anterior cruciate ligament reconstructions were performed using immature porcine femurs stripped of soft tissue and doubled-over porcine flexor digitorum profundus tendon grafts. Specimens were randomized to bioabsorbable or titanium interference screw fixation. Specimens were randomized to one of three pull angles (0°, 30°, 60°) representing loading at different knee flexion angles (n = 8/group). Reconstructed ligaments were tensioned to 10 N followed by 200 loading cycles between 10 and 150 N and a final failure test. Construct elongation (mm) at 100 and 200 cycles and failure load (N) were analyzed using a 2-way analysis of variance (P < .05). Results Screw material interacted significantly with graft tension angle, as the bioabsorbable screw specimens demonstrated significantly greater fixation strength when tensioned at greater angles. Specimens fixed with bioabsorbable screws showed significantly less elongation at both 100 and 200 cycles and significantly greater failure load compared with titanium screws. Conclusion Bioabsorbable interference screws acutely have increased fixation strength compared with titanium interference screws for anterior cruciate ligament grafts loaded at greater tension angles. Clinical Relevance The strength of anterior cruciate ligament reconstruction fixation increases with increasing divergence between the tension angle and femoral tunnel, a condition seen when the knee approaches full extension.

Biomechanical Analysis of Femoral Tunnel Pull-out Angles for Anterior Cruciate Ligament Reconstruction with Bioabsorbable and Metal Interference Screws

The filamentous fungus producing aroma of bone were isolated from iris rhizome. Irone production from fresh iris rhizome obtained by solid fermentation with fungi was analysed by thin-layer chromatography and GC/ MS analysis. The result showed that Rhizopus oryzae 94Y-01 was the best strain producing aroma of irone. Physical and chemical characters of the irone product from fresh iris rhizome fermentation are proved to be all alike to those of traditional one. Medium compound,culture temperature and fermentation character of the strain were also studied.

ISOLATION, DETERMINATION AND AROMA PRODUCT CHARACTERIZATION OF FUNGUS PRODUCING IRONE

Numerical Simulation of Collision Process of Reactive Flame Sprayed Particles with Substrate

Abstract Stommel's two-box model of thermohaline circulation is generalized to incorporate 1) either mixed or Newtonian thermal and saline boundary conditions; 2) temperature-dependent evaporation, including a simple coupled air-sea model; and 3) a nonlinear flow law for meridional overturning. The authors prove that under steady forcing, the generalized model cannot exhibit self-driven oscillations. If the saline adjustment time is larger than the thermal, then 1) there is one and only one, stable “saline” equilibrium state corresponding to evaporation-driven sinking and 2) “thermal” equilibrium states corresponding to sinking in cooling zones may or may not exist. If they do, they come in pairs, one saddle and one stable node or spiral. A nonlinear “wiggly” flow law may lead to more than one such pair.

Qualitative behavior and nonoscillation of Stommel's thermohaline box model

Inferring Restricted Regular Expressions with Interleaving from Positive and Negative Samples

The advantages offered by the presence of a schema are numerous. However, many XML documents in practice are not accompanied by a (valid) schema, making schema inference an attractive research problem. The fundamental task in XML schema learning is inferring restricted subclasses of regular expressions. Most previous work either lacks support for interleaving or only has limited support for interleaving. In this paper, we first propose a new subclass Single Occurrence Regular Expressions with Interleaving (SOIRE), which has unrestricted support for interleaving. Then, based on single occurrence automaton and maximum independent set, we propose an algorithm iSOIRE to infer SOIREs. Finally, we further conduct a series of experiments on real datasets to evaluate the effectiveness of our work, comparing with both ongoing learning algorithms in academia and industrial tools in real-world. The results reveal the practicability of SOIRE and the effectiveness of iSOIRE, showing the high preciseness and conciseness of our work.

Proceedings of the 23rd International Database Applications & Engineering Symposium

An effective algorithm for learning single occurrence regular expressions with interleaving

Recommender systems are mostly well known for their applications in e-commerce sites and are mostly static models. Classical personalized recommender algorithm includes item-based collaborative filtering method applied in Amazon, matrix factorization based collaborative filtering algorithm from Netflix, etc. In this article, we hope to combine traditional model with behavior pattern extraction method. We use desensitized mobile transaction record provided by T-mall, Alibaba to build a hybrid dynamic recommender system. The sequential pattern mining aims to find frequent sequential pattern in sequence database and is applied in this hybrid model to predict customers' payment behavior thus contributing to the accuracy of the model.

Recommender systems are mostly well known for their applications in e-commerce sites and are mostly static models. Classical personalized recommender algorithm include collaborative filtering method applied in Amazon, matrix factorization algorithm from Netflix, etc. In this article, we hope to combine traditional model with behavior pattern extraction method. We use desensitized mobile transaction record provided by T-mall, Alibaba to build a hybrid dynamic recommender system. The sequential pattern mining aims to find frequent sequential pattern in sequence database and is applied in this hybrid model to predict customers' payment behavior thus contributing to the accuracy of the model.

Frequency sweeping interferometry (FSI) is an attractive absolute distance measurement (ADM) method because of the advantages of large unambiguity range, simple structure and excellent flexibility. By using a reference interferometer (RI), the calibration of the frequency sweeping range in FSI can be avoided, and the complexity and cost of the system can be further reduced. Then, the measurement accuracy is associated with the accuracy of phase demodulation, the range of frequency sweeping and the compensation of target drift. In this paper, ADM using FSI with large swept range and target drift compensation is presented. A frequency stabilized HeNe laser that travels along the same optical path with the swept source laser was employed to monitor the target drifts of the measurement interferometer and RI. Interference phases of the corresponding interferometers were extracted simultaneously using phase generated carrier demodulation technique, and an accuracy better than 1° was verified by nanometer displacement measurement. Comparative experiments of ADM at a distance of ∼4.5 m with different swept ranges before and after target drift compensation were carried out, and the results demonstrated that larger swept range and target drift compensation could greatly improve the stability and accuracy of measurement.

Absolute distance measurement using frequency sweeping interferometry with large swept range and target drift compensation

This study aimed to develop an effective treatment for diabetes and diabetic complications, based on the advantage complementary strategy of drug–drug salt, by designing and synthesizing the multicomponent molecular salts containing metformin (MET) and rhein (RHE). Finally, the salts of MET–RHE (1:1), MET–RHE–H2O (1:1:1), MET–RHE–ethanol–H2O (1:1:1:1), and MET–RHE–acetonitrile (2:2:1) were obtained, indicating the polymorphism of salts formed by MET and RHE. The structures were analyzed by the combination of characterization experiments and theoretical calculation, and the formation mechanism of polymorphism was discussed. The obtained results of in vitro evaluation showed that MET–RHE had a similar hygroscopicity with metformin hydrochloride (MET·HCl), and the solubility of the component of RHE increased by approximately 93 times, which laid a foundation for improving the bioavailability of MET and RHE in vivo. The evaluation of hypoglycemic activity in mice (C57BL/6N) indicated that MET–RHE exhibited better hypoglycemic activity than the parent drugs and the physical mixtures of MET and RHE. The above findings demonstrate that this study achieved the complementary advantages of MET and RHE through the multicomponent pharmaceutical salification technique, and provides new possibilities for the treatment of diabetic complications.

Versatile Solid Modifications of Multicomponent Pharmaceutical Salts: Novel Metformin–Rhein Salts Based on Advantage Complementary Strategy Design

Introduction: To investigate biventricular structural and functional abnormalities in pre-dialysis patients across stages of chronic kidney disease (CKD) by cardiac magnetic resonance (CMR).
Methods: Fifty-one CKD patients with CMR exams were retrospectively analyzed. Patients were divided into three groups according to estimated glomerular filtration rate (eGFR): CKD 1 group (patients with normal eGFR≥90ml/min/1.73m2, n=20), CKD 2-3 group (patients with eGFR< 90 to ≥30ml/min/1.73m2, n=14) and CKD 4-5 group (patients with eGFR<30ml/min/1.73m2, n=17). Twenty-one age- and sex-matched healthy controls were recruited. CMR derived left ventricular (LV) and right ventricular (RV) structural and functional measures were compared. Association between CMR parameters and clinical measures were assessed. 
Results: There was a increase trend in RV mass index (RVMi) and LV mass index (LVMi) with the occurrence and development of CKD from HC group to CKD 4~5 group although no significant difference was observed between CKD 1 group and HC group. LV global radial strain (LVGRS) and LV global circumferential strain (LVGCS) dropped and native T1 value elevated significantly in CKD 4-5 group compared with the other three groups (all p<0.05), while RV strain measures, RV ejection fraction and LV ejection fraction showed no significant difference among 4 groups (all p>0.05). Elevated LV end-diastolic volume index (β=0.356, p=0.016) and RV end-systolic volume index (β=0.488, p=0.001) were independently associated with RVMi. Increased systolic blood pressure (β=0.309, p=0.004), LV end-systolic volume index (β=0.633, p<0.001) and uric acid (β=0.261, p=0.013) were independently associated with LVMi. Meanwhile, serum phosphorus (β=0.519, p=0.001) was independently associated with native T1 value.
Conclusion: In pre-dialysis CKD patients, left and right ventricular remolding has occurred. RVMi and LVMi were the first changed CMR indexes in the development of CKD when eGFR began to drop. Because fluid volume overload was the independent risk factor for RVMi and LVMi increase, reasonable controlling fluid volume overload may slow down the progression of biventricular remolding and may reduce related cardiovascular disease risk.

Defining biventricular abnormalities by cardiac magnetic resonance in pre-dialysis patients with chronic kidney disease

Determination of monophenolase activity based on backpropagation neural network analysis of three-dimensional fluorescence spectroscopy.

Background: Idiopathic achalasia (AC) may be affected by anxiety and/or depression; however, reliable evidence is still lacking. The present retrospective cohort study aimed to explore the influence of psycho-mental factors on the severity of AC. Methods: All patients in the AC database of the Tianjin Medical University General Hospital from 2012 to 2020 were divided into two subgroups, intervention (n = 202) and medication (n = 84), according to previous treatments. Healthy people (n = 300) who underwent gastrointestinal endoscopy comprised the control group. The severity of symptoms and the anxiety and depression score of AC patients and controls were monitored by telephone and compared before and during COVID-19. In addition, the factors of AC symptoms during the COVID-19 were discussed by multiple linear regression. Results: During COVID-19, the anxiety and depression levels of AC patients and healthy individuals were deteriorated. For AC patients, before and after COVID-19, symptoms, anxiety, and depression scores in the medication group were more serious than those in the intervention group. Furthermore, previous therapy, depression, and gender were found to be significantly related to the severity of AC symptoms during COVID-19. Conclusions: The outbreak of COVID-19 made AC patients and healthy people anxious and depressed. Depression rather than anxiety might worsen the AC symptoms. Interventional therapy might protect AC patients against psychological abnormalities during COVID-19.

Influence of Anxiety and Depression on the Symptoms of Achalasia Patients: A Retrospective Cohort Study in China during COVID-19

Engineering nanointerfaces of Cu-based catalysts for balancing activity and stability of reverse water-gas-shift reaction

Genesis of the world-class Dachang gold deposit, Northern Qinghai-Tibet Plateau: A multiproxy approach

Complexation-Assisted Polymerization for the Synthesis of Functional Silicon Oxycarbonitride with Well-Dispersed Ultrafine CoS as High-Performance Anode for Lithium-Ion Batteries

Renewable Energy Use Under Electricity Supply Guarantee Rates: The Impact of Two Incentive Policies

Pore Space Partition Approach of ZIF-8 for pH Responsive Codelivery of Ursolic Acid and 5-Fluorouracil

A biosensor for glucose early-warning system application is developed using patterned Janus fabrics and non-enzymatic compositions with strong catalytic activity.

High-performance sensing, breathable, and biodegradable integrated wearable sweat biosensors for a wireless glucose early warning system

Existing point-based, sparse voxel-based, or hybrid point cloud processing methods require time-consuming neighborhood searches or sparse 3D convolutions, which consume a lot of time and computational resources. Therefore, it is difficult to run at high speed in real time on mobile devices. To this end, we reconstructed the internal structure based on RangeNet++1 and designed an efficient and lightweight network named AMBrnet, still using the encoder-decoder architecture. An asymmetric multi-branch aggregation module is designed to directly aggregate the input information and provide rich information for subsequent step encoding. The dual-branch structure is introduced to combine with the encoder and decoder to strengthen the information encoding and decoding capabilities of the network. Weighted cross-entropy loss combined with Lovász-Softmax loss2 is used to directly optimize the Jaccard index (IoU). In the network inference stage, structural reparameterization is introduced to ensure that the inference speed is improved based on the same accuracy, reducing the number of network parameters. We evaluate the proposed model on the SemanticKITTI dataset. The prediction accuracy is better than most existing networks, notably its inference speed is up to 43.9 Hz. Experimental data show that AMBrnet is well suited for real-time high-speed point cloud processing on outdoor mobile devices.

AMBrnet: asymmetric multi-branch residual network for LiDAR semantic segmentation

A microscopic diffusion-induced discrete element model for swellable particles

Light entrains the endogenous circadian clocks of organisms to synchronize their behavioral and physiological rhythms with the natural photoperiod. The presence of artificial light at night disrupts these photoperiodic cues and is currently considered to be a major threat to key fitness-related behaviors, including sleep disruption and physiological stress. Research on the ecological influence of forest pest and their natural enemies is lacking. The wood-boring insects significantly damage forest and urban forest ecosystem functions. The parasitic beetles, Dastarcus helophoroides is an important natural enemy of wood-boring insects, especially those in the Cerambycidae family. However, the effect of artificial light at night on the locomotor rhythms and oviposition capacity of D. helophoroides has received little attention. To address this gap, diel changes in the locomotor activity and number of eggs laid by female D. helophoroides was analyzed under different light-dark (LD) cycles and temperatures. The results showed that the 24-h rhythmic of locomotor activity in these beetles was elevated in darkness and reduced under illumination, indicating that they are nocturnal insects. This activity has two major peaks, the evening (1–8 h after lights off) and morning (3.5–12.5 h after lights off) components, reflecting that light mediate regular changes in locomotor activity. Moreover, the circadian rhythms and active percentage were influenced by the illumination duration and temperature, especially constant light and 40°C. Females laid more eggs under the 16 L: 8 D cycles at 30°C than under the other combinations of photoperiod (including constant light and darkness) and temperature. Finally, the potential influence of exposure to four ecologically relevant intensities of artificial light at night (0, 1, 10 or 100 lx) on oviposition capacity was studied. The results showed that lifetime exposure to bright artificial light (1–100 lx) at night decreased the number of eggs laid relative to those laid with no lighting at night. These results demonstrate that chronic exposure to bright artificial light at night may influence the locomotor activity and oviposition capacity of this parasitic beetle.

Exposure to artificial light at night mediates the locomotion activity and oviposition capacity of Dastarcus helophoroides (Fairmaire)

Wuzang Wenyang Huayu Tang Promoting Learning-memory Ability in Vascular Dementia Rats via Brain-gut-microbiome Axis

Deubiquitinase OTUD6A in macrophages promotes intestinal inflammation and colitis via deubiquitination of NLRP3

CT ventilation image-guided helical Tomotherapy at sparing functional lungs for locally advanced lung cancer: analysis of dose-function metrics and the impact on pulmonary toxicity

Acute myeloid leukemia (AML) with a nucleophosmin 1 (NPM1) mutation is a unique subtype of adult leukemia. Recent studies show that NPM1-mutated AML has high autophagy activity. However, the mechanism for upholding the high autophagic level is still not fully elucidated. In this study, we first identified that tumor protein p53 inducible nuclear protein 2 (TP53INP2) was highly expressed and cytoplasmically localized in NPM1-mutated AML cells. Subsequent data showed that the expression of TP53INP2 was upregulated by fat mass and obesity-associated protein (FTO)-mediated m6A modification. Meanwhile, TP53INP2 was delocalized to the cytoplasm by interacting with NPM1 mutants. Functionally, cytoplasmic TP53INP2 enhanced autophagy activity by promoting the interaction of microtubule-associated protein 1 light chain 3 (LC3) - autophagy-related 7 (ATG7) and further facilitated the survival of leukemia cells. Taken together, our study indicates that TP53INP2 plays an oncogenic role in maintaining the high autophagy activity of NPM1-mutated AML and provides further insight into autophagy-targeted therapy of this leukemia subtype.

Cytoplasmic Expression of TP53INP2 Modulated by Demethylase FTO and Mutant NPM1 Promotes Autophagy in Leukemia Cells

Simultaneously enhanced flame retardancy and smoke suppression properties of flexible polyvinyl chloride with the incorporation of modified Mg(OH)2 and Sb2O3

Chronic kidney disease (CKD), one of the common clinical urological diseases, is increasingly more prevalent in recent years and has emerged as a major concern of public health around the globe. The continuous recurrence of CKD caused by renal function impairment leads eventually to irreversible renal failure and severe systemic complications, which causes severe negative impact on the quality of life of the patient. As an essential component of human microbiome, oral microbiota plays a major role in maintaining health, and there has been research suggesting close association between oral dysbiosis and CKD. It is therefore of great clinical significance to understand the correlation between CKD and oral microbiota. Herein, we reviewed the characteristics of oral microbiota of CKD patients, the possible mechanisms of oral microbiota's involvement in the pathogenesis and development of CKD, and the latest research findings on oral dysbiosis and CKD, with a view to finding new approaches to early prevention and control of CKD through oral microbial targets.

Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition

[Research Progress in the Correlation Between Oral Microbiota and Chronic Kidney Disease].

Drone monitoring plays an irreplaceable and significant role in forest firefighting due to its characteristics of wide-range observation and real-time messaging. However, aerial images are often susceptible to different degradation problems before performing high-level visual tasks including but not limited to smoke detection, fire classification, and regional localization. Recently, the majority of image enhancement methods are centered around particular types of degradation, necessitating the memory unit to accommodate different models for distinct scenarios in practical applications. Furthermore, such a paradigm requires wasted computational and storage resources to determine the type of degradation, making it difficult to meet the real-time and lightweight requirements of real-world scenarios. In this paper, we propose an All-in-one Image Enhancement Network (AIENet) that can restore various degraded images in one network. Specifically, we design a new multi-scale receptive field image enhancement block, which can better reconstruct high-resolution details of target regions of different sizes. In particular, this plug-and-play module enables it to be embedded in any learning-based model. And it has better flexibility and generalization in practical applications. This paper takes three challenging image enhancement tasks encountered in drone monitoring as examples, whereby we conduct task-specific and all-in-one image enhancement experiments on a synthetic forest dataset. The results show that the proposed AIENet outperforms the state-of-the-art image enhancement algorithms quantitatively and qualitatively. Furthermore, extra experiments on high-level vision detection also show the promising performance of our method compared with some recent baselines.

Particle locations determine the whole structure of a granular system, which is crucial to understanding various anomalous behaviors in glasses and amorphous solids. How to accurately determine the coordinates of each particle in such materials within a short time has always been a challenge. In this paper, we use an improved graph convolutional neural network to estimate the particle locations in two-dimensional photoelastic granular materials purely from the knowledge of the distances for each particle, which can be estimated in advance via a distance estimation algorithm. The robustness and effectiveness of our model are verified by testing other granular systems with different disorder degrees, as well as systems with different configurations. In this study, we attempt to provide a new route to the structural information of granular systems irrelevant to dimensionality, compositions, or other material properties.

Estimation of Particle Location in Granular Materials Based on Graph Neural Networks

 Prostate cancer is the second most common cause of cancer-related deaths in American men. About 20-40% of patients with localized castration-sensitive prostate cancer (CSPC) eventually progress, requiring androgen deprivation therapy (ADT). However ADT inevitably fails, giving rise to castration-resistant prostate cancer (CRPC), which is incurable and fatal. A significant fraction of patients undergoing ADT die of treatment-accelerated cardiovascular disease. Pre-existing metabolic dysfunction has been implicated in PC disease incidence, higher rates of prostatectomy failure, and accelerated progression to CRPC. Thus, there is an unmet need to counter the adverse sequelae of ADT through alternative CSPC treatments that do not exacerbate metabolic syndrome but prevent PC progression. Few studies have evaluated whether targeting the metabolic dysfunction associated with early-stage PC can prevent progression and thus the need for ADT. In a recent clinical trial spearheaded by Dr. Bilusic, metformin, an affordable and well-tolerated insulin-sensitizing diabetes drug, has recently shown promise as monotherapy in biologically-recurrent CSPC, preventing PSA rise in about 40% of high-risk patients. To identify the molecular mechanisms and biomarkers of positive response to metformin in PC patients, we performed preliminary cytokine profiling of responder vs non-responder patient sera. We found that mitigation of inflammatory factors implicated in cardiovascular disease as well as markers of pro-apoptotic response are associated with positive metformin response. We also found that metformin responders exhibited pre-treatment cytokine signatures associated with inflammatory metabolic diseases, including diabetes and hyperinsulinemia, which are conditions known to benefit from metformin treatment. We have been able to model the variability of metformin treatment response in two well-characterized CSPC cell lines, LNCaP (highly responsive) and LAPC4 (minimally responsive). Metformin induced cell death in LNCaP but not in LAPC4, which possesses mutant p53 and high Bcl-2 levels. LAPC4 instead showed markers of senescence, which is associated with an inflammatory phenotype. Metformin also elevated levels of damaging high-potency (short-lived) ROS in LNCaP to a greater extent than in LAPC4. LAPC4 instead exhibited elevated levels of hydrogen peroxide upon metformin treatment, a ROS associated with inflammation. Thus the cell models show congruence with factors of positive response seen in patients. Our findings shed light on the potential mechanism of positive response to metformin in CSPC patients, and lay the groundwork for further investigation, while insight into biomarkers predicting positive response could be immediately useful in the clinic.
 Citation Format: Philip Gregory, Beatriz Mateo-Victoriano, Ling Zhang, Cassie Due, Marijo Bilusic, Priyamvada Rai. Repurposing metformin in early-stage high risk prostate cancer to avoid ADT-induced cardiovascular toxicity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4335.

Abstract 4335: Repurposing metformin in early-stage high risk prostate cancer to avoid ADT-induced cardiovascular toxicity

Developing low cost and excellent performance of oxygen evolution reaction (OER) and urea oxidation reaction (UOR) electrocatalysts is critically important for hydrogen production through electrochemical water splitting. Herein, ultrasmall NiFe-LDH...

Ultrafast Preparation of NiFe Nanoclusters/Graphene Heterojunction Catalyst for Oxygen Evolution Reaction and Urea Oxidation Reaction

Efficient preparation of phenol-enriched bio-oil using cobalt-modified montmorillonite K-10 catalyst

Maternal exposure to regulated disinfection by-products (DBPs) during pregnancy has been linked with adverse birth outcomes. However, no human studies have focused on drinking water nitrosamines, a group of emerging unregulated nitrogenous DBPs that exhibits genotoxicity and developmental toxicity in experimental studies. This cohort study included 2457 mother-infant pairs from a single drinking water supply system in central China, and maternal trimester-specific and entire pregnancy exposure of drinking water nitrosamines were evaluated. Multivariable linear and Poisson regression models were used to estimate the associations between maternal exposure to nitrosamines in drinking water and birth outcomes [birth weight (BW), low birth weight (LBW), small for gestational age (SGA) and preterm delivery (PTD)]. Elevated maternal N-nitrosodimethylamine (NDMA) exposure in the second trimester and N-nitrosopiperidine (NPIP) exposure during the entire pregnancy were associated with decreased BW (e.g., β = -88.6 g; 95% CI: -151.0, -26.1 for the highest vs. lowest tertile of NDMA; p for trend = 0.01) and increased risks of PTD [e.g., risk ratio (RR) = 2.16; 95% CI: 1.23, 3.79 for the highest vs. lowest tertile of NDMA; p for trend = 0.002]. Elevated maternal exposure of N-nitrosodiethylamine (NDEA) in the second trimester was associated with increased risk of SGA (RR = 1.80; 95% CI: 1.09, 2.98 for the highest vs. lowest tertile; p for trend = 0.01). Our study detected associations of maternal exposure to drinking water nitrosamines during pregnancy with decreased BW and increased risks of SGA and PTD. These findings are novel but require replication in other study populations.

Maternal exposure to nitrosamines in drinking water during pregnancy and birth outcomes in a Chinese cohort.

Clinicodemographic correlates of psychotic features in bipolar disorder – a multicenter study in China

A convolutional Transformer-based truncated Gaussian density network with data denoising for wind speed forecasting

Recent advancements in combining MOFs and natural compounds for cancer therapy

Abstract Purpose To explore the pathological mechanism of Toll-like receptor 4 (TLR4) mediating neovascular age-related macular degeneration (nAMD) and the potential role of the TLR4 coreceptor myeloid differentiation protein 2 (MD2). Methods In the study, we inhibited MD2 with the chalcone derivative L2H17 and we utilized a laser-induced choroidal neovascularization (CNV) mouse model and Tert-butyl hydroperoxide (TBHP)-challenged rhesus choroid-retinal endothelial (RF/6A) cells to assess the effect of MD2 blockade on CNV. Results Inhibiting MD2 with L2H17 reduced angiogenesis in CNV mice, and significantly protected against retinal dysfunction. In retina and choroid/retinal pigment epithelium (RPE) tissues, L2H17 reduced phospho-ERK, phospho-P65 but not phospho-P38, phospho-JNK, and reduced the transcriptional levels of IL-6, TNF-α, ICAM-1 but not VCAM-1. L2H17 could protect RF/6A against TBHP-induced inflammation, oxidative stress, and apoptosis, via inhibiting the TLR4/MD2 signaling pathway and the following downstream mitogen-activated protein kinase (MAPK) and nuclear transcription factor-κB (NF-κB) activation. Conclusions Inhibiting MD2 with L2H17 significantly reduced CNV, suppressed inflammation, and oxidative stress by antagonizing TLR4/MD2 pathway in an MD2-dependent manner. MD2 may be a potential therapeutic target and L2H17 may offer an alternative treatment strategy for nAMD.

MD2 Inhibits Choroidal Neovascularization via Antagonizing TLR4/MD2 Mediated Signaling Pathway

Early embryonic arrest is one of the causes of assist reproduction technology (ART) failure. We have previously reported that the first sperm-derived genetic factor, ACTL7a mutations, could lead to early embryonic arrest. However, whether there are other male genetic factors associated with early embryonic arrest remains elusive. Here, we reported bi-allelic mutations in PLCZ1, a well-known causal gene of total fertilization failure, in four infertile males. Among these mutations, p.403_404del, p.I489S, and p.W536X were newly reported in this study. Histological and Western blotting analysis of the patients’ sperm indicated these variants as loss-of-function mutations. These patients manifested normal conventional semen parameters and ultra-structures in sperm heads. However, among four in vitro fertilization (IVF) cycles, 81.8% (18/22) of the oocytes were polyspermic fertilized, which was rarely reported in PLCZ1-related male patients. In the following six ICSI cycles, artificial oocyte activation (AOA) was applied and successfully rescued the fertilization failure and polyspermy phenotypes, with 31.3% (15/48) of the MII oocytes normally fertilized. However, 60.0% (9/15) of these normally fertilized zygotes were arrested at 2–5-cell stage, with one failing to cleave, indicating that PLCZ1 was not only necessary for fertilization, but also crucial for early embryonic development. However, these rescued zygotes showed a lower potential in developing into blastocysts when cultured in vitro. Thus, fresh cleavage transfer was tried and two live births were successfully achieved thereafter. In conclusion, this study provided novel mutations in PLCZ1 gene to expand the pathogenic mutational spectrum in male infertility and demonstrated that PLCZ1 was a crucial sperm-related genetic factor for early embryonic arrest. We also proposed that cleavage transfer after ICSI and AOA treatment could be a potential treatment method for male patients carrying bi-allelic mutations in PLCZ1.

Novel mutations in PLCZ1 lead to early embryonic arrest as a male factor

Concurrent multipath quantum entanglement routing based on segment routing in quantum hybrid networks

Diversity of Wolbachia infection and its influence on mitochondrial DNA variation in the diamondback moth, Plutella xylostella.

Effect of single and dual voids on lateral capacity of large-diameter monopiles in marine clay

Prenatal and postnatal decoration in residence are associated with childhood allergies and respiratory diseases: A 10-year repeated retrospective observational study

Exploring the Impact of New Commercial Complexes on Surrounding House Prices Based on a Time-Varying DID Method

Rheumatoid arthritis (RA) is one of the most widespread chronic immune-mediated inflammatory diseases characterized by continuous erosion of bone and cartilage by synovial hyperplasia. Telotristat Etiprate is an inhibitor of tryptophan hydroxylase, a rate-limiting enzyme in the biosynthesis of serotonin. Telotristat Etiprate can be used in the treatment of carcinoid syndrome. The purpose of this study was to explore the effect of Telotristat Etiprate on RA and its mechanism. We investigated Telotristat Etiprate in collagen-induced arthritis (CIA) model mice and in rheumatoid arthritis synovial fibroblasts (RASFs). Results showed that Telotristat Etiprate had anti-inflammatory effects both in vitro and in vivo, can inhibit the invasion and migration of cells, inhibit the formation of pannus, and induce cell apoptosis. Transcriptome sequencing (RNA-seq) and mass spectrometry analysis showed that Galectins-3 (LGALS3) could be a newly identified target of Telotristat Etiprate, affecting the phosphorylation of the MAPK signaling pathway through UBE2L6, thereby improving RA.

Telotristat Etiprate alleviates rheumatoid arthritis by targeting LGALS3 and affecting MAPK signaling.

Identification of GPI-anchored protein LYPD1 as an essential factor for odontoblast differentiation in tooth development

Promoting the reduction reactivity of magnetite by introducing trace-K-ions in hydrogen direct reduction

N 6-methyladenosine modification contributes to respiratory syncytial virus infection.

Impact mechanisms of urbanization processes on supply-demand matches of cultivated land multifunction in rapid urbanization areas

Screening, characterization and specific binding mechanism of aptamers against human plasminogen Kringle 5.

Design and analysis of a pulsed coil power supply for the DIII-D tokamak

Objective This study evaluated the treatment outcomes of agomelatine on anhedonic state, anxiety/somatic symptoms, and sexual function in Chinese patients with major depressive disorder (MDD). Method In total, 93 adult patients with MDD were enrolled, and 68 of them were included in a prospective, open-label, multicenter clinical study. All patients received agomelatine monotherapy during a 9-week treatment phase. The effectiveness of the treatment was reflected by the improvement of anhedonia and somatic symptoms based on the 17-item Hamilton Depression Rating Scale (HAMD-17). In addition, the Arizona Sexual Dysfunction Scale (ASEX), Sheehan Disability Scale (SDS), and Short Form of Quality-of-Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF) were administered to all participants at baseline and at the 3-, 6-, and 9-week follow-ups. Results After 9 weeks of treatment with agomelatine, the response and remission rates were 73.5% and 39.7%, respectively. Somatic symptoms significantly improved at week 9 (p < 0.001), and significant effects were also observed on the HAMD anhedonia items (p < 0.001). The patients exhibited lower levels of disease severity (the SDS score dropped from 15.52 ± 4.7 to 7.09 ± 5.62 at week 9; the ASEX score dropped from 21.89 ± 4.06 to 16.19 ± 4.79, p < 0.001) and higher levels of QOL (the Q-LES-Q-SF score dropped from 41.02 ± 5.99 to 50.49 ± 8.57, p < 0.001) during the follow-up. Furthermore, treatment with agomelatine improved depressive symptoms without causing serious adverse events. Conclusion These analyses indicate that agomelatine is a treatment option for improving anhedonic status, anxiety/somatic symptoms, and sexual dysfunction in MDD patients.

Agomelatine in the treatment of anhedonia, somatic symptoms, and sexual dysfunction in major depressive disorder

Micromorphological and Physiological Responses of Two Contrasting Centipedegrass (Eremochloa ophiuroides (Munro) Hack.) Genotypes in Response to Aluminum Toxicity

Post-transplantation cyclophosphamide as GVHD prophylaxis in allogenic hematopoietic stem cell transplantation: Recent advances and modification.

Efforts have been made to pursue multifunctional electrode materials, and their practical applications have been promoted in energy storage and conversion equipment. At present, constructing composite materials has been considered...

In situ hollow nanoarchitectonics of MIL-88A@Co(OH)2 composites for supercapacitor and oxygen evolution reaction

Clinical diagnosis of epilepsy significantly relies on identifying interictal epileptiform discharge (IED) in electroencephalogram (EEG). IED is generally interpreted manually, and the related process is very time-consuming. Meanwhile, the process is expert-biased, which can easily lead to missed diagnosis and misdiagnosis. In recent years, with the development of deep learning, related algorithms have been used in automatic EEG analysis, but there are still few attempts in IED detection. This study uses the currently most popular convolutional neural network (CNN) framework for EEG analysis for automatic IED detection. The research topic is transferred into a 4-labels classification problem. The algorithm is validated on the long-term EEG of 11 pediatric patients with epilepsy. The computational results confirm that the CNN-based model can obtain high classification accuracy, up to 87%. The study may provide a reference for the future application of deep learning in automatic IED detection.

Automatic interictal epileptiform discharge (IED) detection based on convolutional neural network (CNN)

To evaluate the efficacy and safety of fractional 1064 nm picosecond Nd:YAG laser (FPNYL) in the treatment of post‐acne erythema (PAE) of adult Chinese.

Evaluation of the safety and efficacy of a fractional picosecond 1064 nm laser for post‐acne erythema in adult Chinese patients

In-situ characterization of silicate slag crystallization by electrical impedance spectroscopy: Construction of continuous cooling transformation diagram

A Tri-Training method for lithofacies identification under scarce labeled logging data

Improvements of adhesion strength of water-based epoxy resin on carbon fiber reinforced polymer (CFRP) composites via building surface roughness using modified silica particles

Combinations of ivermectin with proteasome inhibitors induce synergistic lethality in multiple myeloma.

Enzymatic colorimetric method for turn-on determination of l-lactic acid through indicator displacement assay.

Graphite tailings were used as the raw materials for the preparation of foamed ceramics via a high-temperature self-foaming method. The residual carbon in the tailings acted as the foaming agent and no additional foaming agents were required. The residual carbon reacted with Fe2O3 and produced gas that was wrapped by the liquid phase to form a porous structure. The effects of sintering temperature, holding time, carbon content, flux on the bulk density, water absorption, and mean pore size of the foamed ceramics were investigated. The bulk density, compressive strength, thermal conductivity, and water absorption of the foamed ceramic prepared using the optimal sample D100 (100 wt% graphite tailings) and sintered at 1200 °C for 20 min were 1.36 g/cm3, 0.35%, 12.03 MPa, and 0.51 W/(m·K), respectively. The raw material contained CaO, Fe2O3, and SiO2, which formed augite with a low fusibility point. In contrast, the molten decomposition products of potassium feldspar and CaSiO3 ions formed anorthite, which has a high fusibility point. Therefore, potassium feldspar is not recommended for use as a flux in tailing systems with high calcium content. Foamed ceramics were prepared using up to 100 wt% graphite tailings. This is a new approach for the economical disposal of graphite tailings.

Preparation of Foamed Ceramics from Graphite Tailings Using A Self-Foaming Method

Fast and accurate prediction of air temperature and velocity field in non-uniform indoor environment under complex boundaries

The lipoxygenase OsLOX10 affects seed longevity and resistance to saline-alkaline stress during rice seedlings

Accurately predicting the Remaining Useful Life (RUL) of lithium-ion batteries is the key to the battery health management system. However, problems of unstable model output and extensive calculation limit the prediction accuracy. This article proposes a Particle Swarm Optimization Random Forest (PSO-RF) prediction method to improve the RUL prediction accuracy. First, the battery capacity extracted from the lithium-ion battery data set of the National Aeronautics and Space Administration (NASA) and the University of Maryland Center for Advanced Life Cycle Engineering (CALCE) is set as the battery life health factor. Then, a PSO-RF prediction model is established based on the optimal parameters for the number of trees and the number of random features to split by the PSO algorithm. Finally, the experiment is verified on the NASA and CALCE data sets. The experiment results indicate that the method predicts RUL with Mean Absolute Error (MAE) less than 2%, Root Mean Square Error (RMSE) less than 3%, and goodness of fit greater than 94%. This method solves the problem of parameter selection in the RF algorithm.

Remaining useful life prediction of Lithium-ion batteries based on PSO-RF algorithm

Microwave dielectric ceramics with permittivity (εr) ∼ 20 play an important role in massive multiple-input multiple-output (MIMO) technology in 5G. Although fergusonite-structured materials with low dielectric loss are good candidates for 5G application, tuning the temperature coefficient of resonant frequency (TCF) remains a problem. In the present work, smaller V5+ ions (rV = 0.355 Å, with coordination number (CN) = 4) were substituted for Nb5+ (rNb = 0.48 Å with CN = 4) in the Nd(Nb1-xVx)O4 ceramics, which, according to in situ X-ray diffraction data, lowered the fergusonite-to-scheelite phase transition (TF-S) to 400 °C for x = 0.2. The thermal expansion coefficient (αL) of the high-temperature scheelite phase was +11 ppm/°C, whereas for the low-temperature fergusonite phase, it was + 14 < αL < + 15 ppm/°C. The abrupt change in αL, the associated negative temperature coefficient of permittivity (τε), and the minimum value of εr at TF-S resulted in a near-zero TCF ∼ (+7.8 ppm/°C) for Nd(Nb0.8V0.2)O4 (εr ∼ 18.6 and Qf ∼ 70,100 GHz). A method to design near-zero TCF compositions based on modulation of τε and αL at TF-S is thus demonstrated that may also be extended to other fergusonite systems.

Novel Method to Achieve Temperature-Stable Microwave Dielectric Ceramics: A Case in the Fergusonite-Structured NdNbO4 System.

Detection of H
 2
 S in Living Cells Using Escape Lysosome Technology Based on the Swelling Effect of Polymeric Nanomicelles

An automatic identification method of imbalanced lithology based on Deep Forest and K-means SMOTE

Non-metallic carbon-based catalysts are one of the most promising catalysts for electrocatalytic oxygen reduction (ORR). However, the controlled synthesis of the pore structures of carbon-based catalysts and the determination of catalytic sites still remains to be further explored. Based on this, two nitrogen-doped carbon-based catalysts with microporous and mesoporous structures were prepared in this paper. The two catalysts had different pore structures and nitrogen-doped species. The experimental results showed that the carbon-based catalyst (PC-NH3) rich in microporous structure and pyridine nitrogen doping had better catalytic performance, the electrocatalytic oxygen reduction performance of the catalyst was comparable to that of the platinum catalyst, and it had excellent methanol resistance and stability. This study provided important guidance for the application of porous carbon materials in oxygen reduction.

Preparation of multistage microporous and mesoporous nitrogen-doped carbon nanospheres and study on electrocatalytic oxygen reduction

Multiparametric cardiac magnetic resonance reveals persistent myocardial inflammation in patients with exertional heat illness.

Green and Edible Cyclodextrin Metal-Organic Frameworks Modified Polyamide Thin Film Nanocomposite Nanofiltration Membranes for Efficient Desalination

Ultrathin and Flexible ANF/APP/PRGO Composite Films for High-Performance Electromagnetic Interference Shielding and Joule Heating

Efficacy and safety of prophylactic use of benzhexol after risperidone treatment

Diagnostic Value Of Prognostic Nutritional Index For Venous Thromboembolism In Lung Cancer Patients: A Novel Nomogram

As a neurodegenerative disease, Alzheimer’s disease (AD) is characterized by synaptic loss, extracellular plaques of amyloid accumulation, hyperphosphorylation of tau, and neuroinflammation. Various biological processes are affected by epitranscriptomic modifications, which regulate the metabolism of mRNA in cells and regulate the expression of genes. In response to changes in m6A modification levels, the nervous system becomes dysfunctional and plays a significant role in the development of Alzheimer’s disease. As a result of recent research, this paper reviews advances in the understanding of the regulatory mechanisms of m6A modification in the occurrence and development of AD. In addition, the article discusses recent research techniques related to animal models of m6A and AD. Furthermore, it discusses the possibility of studying the pathogenesis of AD at the level of the epitranscriptome, identifying early diagnostic markers, and screening for effective treatment options.

Preliminary Development and Verification of a Openfoam-Based Multi-Physics Coupling Safety Analysis Code for Lead-Based Reactor

Correction: Concurrent multipath quantum entanglement routing based on segment routing in quantum hybrid networks

Retraction notice to “Extended ocular delivery of latanoprost from niosome-laden contact lenses: In vitro characterization and in vivo studies” [J. Drug Deliv. Sci. Technol. 68 (2021) 103044]

High‐κ materials that exhibit large permittivity and band gaps are needed as gate dielectrics to enhance capacitance and prevent leakage current in downsized technology nodes. Among these, monoclinic ZrO2 (m‐ZrO2) shows good potential because of its inertness and high‐κ with respect to SiO2, but a method to produce ultrathin single crystal is lacking. Here, the controllable preparation of ultrathin m‐ZrO2 single crystals via the in situ thermal oxidation of ZrS2 is achieved. As‐grown m‐ZrO2 presents an equivalent oxide thickness of ≈0.29 nm, a high dielectric constant of ≈19, and a breakdown voltage (EBD) of ≈7.22 MV cm−1. MoS2 field effect transistor (FET) by using m‐ZrO2 as a dielectric layer shows comparable mobility to that using SiO2 dielectric. The ultraclean interface of m‐ZrO2/MoS2 and high crystalline quality of m‐ZrO2 lead to negligible hysteresis in transfer curves. Single crystal m‐ZrO2 dielectric shows potential application in digital complementary metal oxidesemiconductor (CMOS) logic FET.

Controllable Oxidation of ZrS2 to Prepare High‐κ, Single‐Crystal m‐ZrO2 for 2D Electronics

Increased risk of respiratory and allergic diseases in preschoolers from building envelope dampness exposure: Repeated cross-sectional surveys in multicity China

As people’s awareness of the special functions of selenium continues to deepen, the development of selenium-rich food continues to develop, and selenium-rich places have been vigorously developing this resource-based industry. The development of selenium-rich agriculture is of great significance to improve people’s quality of life and promote agricultural, rural and regional economic development. This paper analyzes the factors affecting consumers’ willingness to purchase selenium-rich agricultural products in detail through questionnaire survey data of some consumers in Jiangxi, Ensh, Hubei and Ankang, Shaanxi, using three analytical methods of descriptive statistical analysis, factor analysis and logistic regression analysis with SPSS software. The research results show that consumers’ attitude toward selenium-rich agricultural products, price concerns, consumers’ family characteristics, health and environmental protection motives, gender and other factors have certain influence on consumers’ willingness to purchase selenium-rich agricultural products, among which the attitude factor and family characteristics have the greatest influence. Finally, the market prospect of selenium-rich agricultural products in China is analyzed and prospected, and the measures and suggestions for developing selenium-rich food are proposed in response to the problems of developing selenium-rich food in China.

Study on the Influence of Consumers’ Purchase Intention of Selenium-Rich Agricultural Products

Electrochemical carbon dioxide (CO2) reduction for C2 products has been studied on a series of supported Cu-based catalysts; however, the charge-promotion effects from the substrates for the selectivity of CO2 reduction are still unclear. Here we localize nanosized Cu2O on three carbon-based substrates that provide different charge-promotion effects: positively charged boron-doped graphene (BG), negatively charged nitrogen-doped graphene (NG), and weak negatively charged reduced graphene oxide (rGO). We demonstrate that the charge-promotion effects lead to an increase in faradaic efficiency (FE) for C2 products with an order of rGO/Cu < BG/Cu < pure Cu < NG/Cu and an FEC2/FEC1 ratio from 0.2 to 7.1. By performing in situ characterization, electrokinetic investigations, and density functional theory (DFT) calculations, we reveal that the negatively charged NG is favorable for stabilizing Cu+ species under CO2 reduction, which strengthens CO* adsorption to further boost C-C coupling for C2 products. As a result, we achieve a high C2+ FE of ∼68% at high current densities of 100-250 mA cm-2.

Effect of Charge on Carbon Support on the Catalytic Activity of Cu2O toward CO2 Reduction to C2 Products.

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy

An efficient fluorescence reversible regulation strategy with single labelled oligonucleotide HEX-OND successively triggered by Hg(II) and Cysteine: The application and mechanism

Recently, few-shot learning (FSL) has exhibited great potential in the hyperspectral image (HSI) classification due to its promising performance under a few training samples. Although existing FSL methods have achieved great success, some limitations can still be witnessed. On the one hand, current methods mainly rely on a single metric to identify, which cannot effectively represent the class distribution with few labeled samples. On the other hand, existing methods usually only use the last deep feature of the feature extractor, which may lead to the under-utilization of scarce labeled samples. To overcome the above issues, a novel multistage relation network with dual-metric (DM-MRN) is proposed for few-shot HSI classification. First, a sample recombination strategy is designed to increase the variety of classification tasks in the training period. Second, an embedding module is employed to extract deep features of the input image patches. Third, we propose two relation modules: image-to-class (I2C) block and image-to-image (I2I) block. The I2C block is designed to compute the I2C-level relation score between second-order features, and the I2I block is conceived to generate the I2I-level relation score between first-order features. Finally, DM-MRN is constructed by integrating one embedding module, two I2C blocks, and one I2I block. In addition, an adaptive weighting strategy is designed to fuse the obtained relation scores, and classification can be achieved by assigning each query sample to the class with the highest value of the fused relation score. Extensive experiments carried out on five popular HSI datasets demonstrate that the proposed method outperforms other traditional and advanced models under few training samples in terms of classification accuracy and generalization performance, i.e., the performance improvement in terms of OA is around 0.30%–27.98% under ten labeled samples per class.

Multistage Relation Network With Dual-Metric for Few-Shot Hyperspectral Image Classification

Insights into the hydrophobic surface promoting electrochemical CO2 reduction to ethylene

Physical exercise effectively alleviates chronic pain associated with complex regional pain syndrome type-I. However, the mechanism of exercise-induced analgesia has not been clarified. Recent studies have shown that the specialized pro-resolving lipid mediator resolvin E1 promotes relief of pathologic pain by binding to chemerin receptor 23 in the nervous system. However, whether the resolvin E1-chemerin receptor 23 axis is involved in exercise-induced analgesia in complex regional pain syndrome type-I has not been demonstrated. In the present study, a mouse model of chronic post-ischemia pain was established to mimic complex regional pain syndrome type-I and subjected to an intervention involving swimming at different intensities. Chronic pain was reduced only in mice that engaged in high-intensity swimming. The resolvin E1-chemerin receptor 23 axis was clearly downregulated in the spinal cord of mice with chronic pain, while high-intensity swimming restored expression of resolvin E1 and chemerin receptor 23. Finally, shRNA-mediated silencing of chemerin receptor 23 in the spinal cord reversed the analgesic effect of high-intensity swimming exercise on chronic post-ischemic pain and the anti-inflammatory polarization of microglia in the dorsal horn of the spinal cord. These findings suggest that high-intensity swimming can decrease chronic pain via the endogenous resolvin E1-chemerin receptor 23 axis in the spinal cord.

High-intensity swimming alleviates nociception and neuroinflammation in a mouse model of chronic post-ischemia pain by activating the resolvin E1-chemerin receptor 23 axis in the spinal cord

Hyphantria cunea (Drury) is a globally important forest pest. We found that the Serratia marcescens Bizio strain SM1 had insecticidal activity against H. cunea, but the transcriptomic response of H. cunea to SM1 were not clear. Therefore, we performed full-length sequencing of the transcriptomes of H. cunea larvae infected with SM1 and the control group. A total of 1,183 differentially expressed genes (DEGs) were identified by comparing the group infected with SM1 and the control group, including 554 downregulated genes and 629 upregulated genes. We found many downregulated genes in metabolic pathways. Furthermore, some of these downregulated genes were involved in cellular immunity, melanization, and detoxification enzymes, which showed that SM1 weakened H. cunea immunity. In addition, genes in the juvenile hormone synthesis pathway were upregulated, which was detrimental to the survival of H. cunea. This research analyzed the transcriptomic response of H. cunea to SM1 by high-throughput full-length transcriptome sequencing. The results provide useful information to explore the relationship between S. marcescens and H. cunea, and theoretical support for the application of S. marcescens and the control of H. cunea in the future.

The transcriptomic response of Hyphantria cunea (Drury) to the infection of Serratia marcescens Bizio based on full-length SMRT transcriptome sequencing

Supramolecular interaction enabled preparation of high-strength water-based adhesives from polymethylmethacrylate wastes

In recent years, the microneedle radiofrequency (MRF) has been widely used for skin rejuvenation, but histological studies on the immediate trauma caused by different parameters of non‐insulated RF microneedles

Histological damage characteristics and quantitive analysis of porcine skin with non‐insulated microneedle radiofrequency

Self‐Powered Te/Wse
 2
 Van Der Waals Heterojunction Photodetectors With High Light On/Off Ratio And Fast Response

Fe
 3
 O
 4
 /g‐C
 3
 N
 4
 Nanozyme for Production of L‐DOPA as Mimetics of Tyrosine Hydroxylase

Inversion of extinction coefficient and refractive index of variable transparency solid–solid phase change material based on a hybrid model under real climatic conditions

A Pyrrole-Tricyanofuran-Based Probe for the Detection of Bisulfite and Viscosity in Lysosomes of Living Cells and Zebrafish

Data-driven methods based on samples from a supervisory control and data acquisition system have been widely applied in water-supply-network burst detection to save unexpected economic and labor costs. However, the class imbalance problem in actual on-site monitoring needs to be revised to improve the performance of data-driven methods. In this study, we proposed a domain adaptation method to generate minor-category samples (pipeline-burst samples in general) of arbitrary pipe networks utilizing theoretical hydraulic models. The proposed method transferred pipeline-burst data generated from a random water supply network with theoretical hydraulic models to an actual imbalanced dataset. Accordingly, we established a machine learning model exploring a mapping matrix between two domains for minority-category data transfer. The experimental validation first verified the effectiveness and reliability of the proposed method between two customized water supply networks in terms of their bust recognition accuracy, model parameter sensitivity and time efficiency. Then, an actual monitoring dataset from a working water supply network was used to prove the suitability and compatibility of the proposed method. A bust-point location method was also provided based on the detection results of pipeline-bursting events. The validations show the superiority of our proposed approach for the imbalance data problem in pipe burst detection.

Pipeline-Burst Detection on Imbalanced Data for Water Supply Networks

Effect of aging route on the precipitation behavior and thermal stability of Al-Cu-Mg-Ag alloy

Suppression of ETI by PTI priming to balance plant growth and defense through a MPK3/MPK6-WRKYs-PP2Cs module.

ABSTRACT Introduction of primary COVID-19 vaccination has helped reduce severe disease and death caused by SARS-CoV-2 infection. Understanding the protection conferred by heterologous booster regimens informs alternative vaccination strategies that enable programmatic resilience and can catalyze vaccine confidence and coverage. Inactivated SARS-CoV-2 vaccines are among the most widely used vaccines worldwide. This review synthesizes the available evidence identified as of May 26, 2022, on the safety, immunogenicity, and effectiveness of a heterologous BNT162b2 (Pfizer-BioNTech) mRNA vaccine booster dose after an inactivated SARS-CoV-2 vaccine primary series, to help protect against COVID-19. Evidence showed that the heterologous BNT16b2 mRNA vaccine booster enhances immunogenicity and improves vaccine effectiveness against COVID-19, and no new safety concerns were identified with heterologous inactivated primary series with mRNA booster combinations.

Evidence synthesis and pooled analysis of vaccine effectiveness for COVID-19 mRNA vaccine BNT162b2 as a heterologous booster after inactivated SARS-CoV-2 virus vaccines

Research progress of graphene for the adsorption, enrichment and analysis of environmental pollutants

Regular expression, or regex, is widely used to extract critical information from a large corpus of formatted text by finding patterns of interest. In tasks like log processing, the speed of regex matching is crucial. Data scientists and developers regularly use regex libraries that implement optimized regular expression matching using modern automata theory. However, computing state transitions in the underlying regex evaluation engine can be inefficient when a regex query contains a multitude of string literals. This inefficiency is further exasperated when analyzing large data volumes. This paper presents BLARE, Blazingly Fast Regular Expression, a regular expression matching framework that is inspired by the mechanisms that are used in database engines, which use a declarative framework to explore multiple equivalent execution plans, all of which produce the correct final result. Similarly, BLARE decomposes a regex into multiple regex and string components and then creates evaluation strategies in which the components can be evaluated in an order that is not strictly a left-to-right translation of the input regex query. Rather than using a cost-based optimization approach, BLARE uses an adaptive runtime strategy based on a multi-armed bandit approach to find an efficient execution plan. BLARE is also modular and can be built on top of any existing regex library. We implemented BLARE on four commonly used regex libraries, RE2, PCRE2, Boost Regex, and ICU Regex, and evaluated it using two production workloads and one open-source workload. BLARE was 1.6× to 3.7× faster than RE2 and 3.4× to 7.9× faster than Boost Regex. PCRE2 did not finish on one of the workloads, but on the remaining two workloads, BLARE improved the performance of PCRE2 by 3.1× to over 100×. For the open-source dataset, BLARE provided a speed up of 61.7× for ICU Regex. BLARE code is publicly available at https://github.com/mush-zhang/Blare.

The saturable absorber of niobium diselenide (NbSe2), with a wide working bandwidth and excellent nonlinear optical response, was prepared using liquid-phase exfoliation. Its saturation intensity and modulation depth were 5.35 MW/cm2 and 6.3%, respectively. Stable mode-locking with a center wavelength of 1558.7 nm of an erbium-doped fiber laser based on a NbSe2 saturable absorber was successfully achieved. The maximum average output power of the mode-locked laser was 6.93 mW, with a pulse width of 1.3 ps and a repetition rate of 25.31 MHz at a pump power of 550 mW. The results show that NbSe2 is a promising photoelectric modulation material owing to its excellent nonlinear optical properties.

Development of a Mode-Locked Fiber Laser Utilizing a Niobium Diselenide Saturable Absorber

Enhanced Built-In Self-Diagnosis and Self-Repair Techniques for Daisy-Chain Design in MEDA Digital Microfluidic Biochips

With the popularity of mobile devices and the advent of the Internet era, social media data has received widespread attention as a new disaster data source. Based on Twitter data, this paper constructs a research framework for storm and flood public response and disaster detection and monitors the spatio-temporal changes in public sentiment and driving factors. The following conclusions were obtained: (1) There is a strong correlation between the activity of public response to heavy rainfall and flooding on social media and the amount of rainfall, which proves the interconnectedness between the two. (2) Public sentiment changes in a "U" shape and reaches its lowest value during the most severe rainfall and flooding. (3) The public's response to heavy rainfall and flooding is concentrated around the more severely affected areas such as Sydney and the Gold Coast.

Application of GIS in disaster management: a case study of the 2021 Australian flood

Geometric Correction of Luojia 1-01 Nighttime Light Image based on Road Network

Molecular phylogeny and inflorescence evolution of Prunus (Rosaceae) based on RAD-seq and genome skimming analyses

Ag/TiO2/muscovite (ATM) composites were prepared by the sol–gel method and the effects of Ag modification on the structure and photocatalytic performance were investigated. The photocatalysts were characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Brunauer–Emmett–Teller surface area (BET), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectra (FTIR), photoluminescence spectra (PL) and ultraviolet–visible diffuse reflectance spectra (DRS). The photocatalytic activity of the obtained composites was evaluated by taking 100 mL (10 mg/L) of Rhodamine B (RhB) aqueous solution as the target pollutant. The muscovite (Mus) loading releases the agglomeration of TiO2 particles and the specific surface area increases from 17.6 m2/g (pure TiO2) to 39.5 m2/g (TiO2/Mus). The first-order reaction rate constant increases from 0.0009 min−1 (pure TiO2) to 0.0074 min−1 (150%TiO2/Mus). Ag element exists in elemental silver. The specific surface area of 1-ATM further increases to 66.5 m2/g. Ag modification promotes the separation of photogenerated electrons and holes and increases the visible light absorption. 1%Ag-TiO2/Mus (1-ATM) exhibits the highest photocatalytic activity. After 100 min, the rhodamine B (RhB) degradation degrees of PT, 150%TiO2/Mus and 1-ATM are 10.4%, 48.6% and 90.6%, respectively. The first-order reaction rate constant of 1-ATM reaches 0.0225 min−1, which is 25 times higher than that of pure TiO2.

Effect of Ag Modification on the Structure and Photocatalytic Performance of TiO2/Muscovite Composites

Spectrum Sharing Towards Delay Deterministic Wireless Network: Delay Performance Analysis

Three novel umami peptides derived from the alcohol extract of the Pacific oyster (
 Crassostrea gigas): Identification, characterizations and interactions with T1R1/T1R3 taste receptors

An Evidence-Based Multimodal Fusion Approach for Predicting Review Helpfulness with Human-Ai Complementarity

Tumor-infiltrating CD36+CD8+T cells determine exhausted tumor microenvironment and correlate with inferior response to chemotherapy in non-small cell lung cancer

Handwriting Chinese Character Recognition (HCCR) is the foundation of document digitization. It is a challenging subject in the field of image classification and recognition for a series of reasons such as the large number of Chinese characters, the diversification of writing style and numerous similar characters. To solve the above problems, this paper designs a four-channel convolution recognition model based on MobileNetV2. First, the input image is sent to four-channel convolution with different receptive fields, and feature maps of different scales are extracted respectively to improve the accuracy of the model. Then the feature maps are combined to enrich the diversity of features. Afterwards, the combined features are weighted by SE Block, and more useful feature maps are screened by this means to accelerate the model convergence. Finally, the lightweight network mobilenetv2 is used to classify the weighted features. The experimental results show that the recognition accuracy of the four-channel convolution recognition model based on mobilenetv2 on the offline handwritten Chinese character set CASIA-HWDB1.1 has reached 96.05%, and the convergence speed of the model is extremely fast. Also, the memory occupation and parameter quantity are far lower than other Chinese handwriting character recognition models.

Four-channel convolutional Chinese handwriting recognition based on MobileNetV2

This paper presents a fast lock-in time clock frequency multiplier without using traditional clock generation circuits such as PLLs and DLLs. We propose a novel technique based on capacitive finite impulse response (FIR) filters to generate clock phases while reducing the input clock phase noise at the same time. A new delay line circuit is also proposed for improving power supply rejection. In addition, to improve the matching quality as well as the end-effects tolerance of the on-chip capacitors, a single-value series/parallel algorithm is proposed. Designed in a 0.18 μm digital CMOS process, with a 20 MHz input clock frequency, the multiplier achieves a multiplication factor of 5 with a lock-in time of less than 4 clock cycles. The input clock jitter is reduced from 7ns RMS to 153 ps RMS after frequency multiplication.

A Fast Lock-In Time, Capacitive FIR-Filter-Based Clock Multiplier with Input Clock Jitter Reduction

A ferroptosis-related prognostic model with excellent clinical performance based on the exploration of the mechanism of oral squamous cell carcinoma progression

Genomic characterization of a novel torradovirus infecting Arctium lappa L. in China

One of the key challenges for future fusion research is to mitigate the high steady-state heat load on the divertor target plates, and divertor detachment offers a promising solution. The Experimental Advanced Superconducting Tokamak (EAST) has developed several feedback control methods for divertor detachment. However, when an off-normal event momentarily disturbs the main plasma, impurity seeding may still be conducted by these methods for detachment, which probably drives the main plasma further away from its stable equilibrium or even causes the disruption. These off-normal events include excessive impurity seeding, loss of heating and dust droplets, which are not rare in current tokamak experiments, especially in long-pulse operation. To compensate for the drawbacks of these methods, we propose and develop a module of stored-energy monitoring to ensure stable plasmas in long-pulse operation. The stored energy usually decreases when the main plasma is away from its stable equilibrium, which is suitable for monitoring the state of the main plasma. Once the stored energy falls below a certain threshold, the module actively switches off the impurity seeding system. Without impurity seeding, the main plasma can recover with the increase in the stored energy. Only when the stored energy exceeds another threshold does the module switch on the impurity seeding to continue the detachment operation. The module function has been verified during the EAST radiative divertor experiments in the newly-upgraded lower tungsten divertor. A typical ∼20 s discharge in grassy-ELM H-mode regime with ∼5 MW source heating power is demonstrated with divertor partial detachment and good energy confinement by active impurity seeding (50% neon, 50% D2). The energy confinement factor is maintained at a high level, i.e. H98,y2∼1.1. The electron temperature in the core region only has a slight change after the impurity seeding, while the electron density has a ∼10% increase. Furthermore, the ion temperature near the axis also has a remarkable increase. These achievements provide an important demonstration of the actively controlled radiative divertor mitigating the heat loads with good core confinement, which is an essential step toward steady-state operation of fusion reactors.

Long-pulse H-mode operation with stored-energy monitoring for detachment feedback control with a new lower tungsten divertor in EAST

Cytotoxic sesquiterpene aryl esters from Armillaria gallica 012m

A Promising Composite Solid Electrolyte of Garnet-Type Llzto and Succinonitrile in Thermal Polyurethane Matrix for All-Solid-State Lithium-Ion Batteries

Simultaneous removal of phosphate, calcium, and ammonia nitrogen in a hydrogel immobilized reactor with bentonite/lanthanum/PVA based on microbial induced calcium precipitation.

Venetoclax combined with daunorubicin and cytarabine (2 + 6) as induction treatment in adults with newly diagnosed acute myeloid leukemia: a phase 2, multicenter, single-arm trial

The Application of the Easily-Obtained Expanded Graphite Synergized with Environment-Friendly Oxalic Acid Under Uv Irradiation in the Hazardous Cr(Vi) Removal

Abstract: Due to the problems of more noise and lower contrast in X-ray tomography images of the honeycomb lung, and the poor generalization of current medical segmentation algorithms, the segmentation results are unsatisfactory. We propose an automatic segmentation algorithm MCSC-UTNet based on SepViT with contextual feature fusion for honeycomb lung lesions to address these problems. Firstly, a Multi-scale Channel Shuffle Convolution (MCSC) module is constructed to enhance the interaction between different image channels and extract the local lesion feature at different scales. Then, a Separable Vision Transformer (SepViT) module is introduced at the bottleneck layer of the network to enhance the representation of the global information of the lesion. Finally, we add a context-aware fusion module to relearn the encoder feature and strengthen the contextual relevance of the encoder and decoder. In comparison experiments with eight prevalent segmentation models on the honeycomb lung dataset, the segmentation metrics of this method, Jaccard coefficient, mIoU, and DSC are 90.85%, 95.32%, and 95.07%, with Jaccard coefficient improving by 3.56% compared with that before. Compared with medical segmentation models such as TransUNet, Sharp U-Net, and SETR, this paper's method has improved results and segmentation performance.

Proceedings of the 2023 2nd Asia Conference on Algorithms, Computing and Machine Learning

MCSC-UTNet: Honeycomb lung segmentation algorithm based on Separable Vision Transformer and context feature fusion

As the essential tissue for sperm maturation and storage, the epididymis secretes a number of tissue-specific proteins to exert its functions. Among these proteins, epididymal lipocalins have been intensively studied because of their epididymis-specific expression pattern and clustered genomic organization. In this study, rLcn13, a member of the rat epididymal lipocalin family, is identified and elaborately characterized. The cDNA sequence of rLcn13 consists of 719 nucleotides and encodes a 176 amino-acid protein with a predicted N-terminal signal peptide of 19 amino acids. rLcn13 shares a similar genomic structure and predicted 3D protein structure with other lipocalin family members. A recombinant rLCN13 mature peptide of 157 amino acids is expressed and purified, which is used to raise a polyclonal antibody against rLCN13 with high specificity and sensitivity. Northern blot, western blot, and immunohistochemistry assays reveal that rLcn13 is an epididymis-specific gene which is expressed predominantly in the initial segment and proximal caput epididymis and influenced by androgen. The rLCN13 protein is modified by N-glycosylation and secreted into the epididymal lumen, and then binds to the acrosome region of the sperm. Our data demonstrate that rLcn13 exhibits a specific temporospatial expression pattern and androgen dependence, indicating its potential roles in sperm maturation.

Identification, characterization and expression analysis of rLcn13, an epididymal lipocalin in rats

Based on the important role of antibiotic treatment in the research of the interaction between Wolbachia and insect hosts, this study aimed to identify the most suitable antibiotic and concentration for Wolbachia elimination in the P. xylostella, and to investigate the effect of Wolbachia and antibiotic treatment on the bacterial community of P. xylostella. Our results showed that the Wolbachia-infected strain was plutWB1 of supergroup B in the P. xylostella population collected in Nepal in this study; 1 mg/mL rifampicin could remove Wolbachia infection in P. xylostella after 1 generation of feeding treatment and the toxic effect was relatively low; among the 29 samples of adult P. xylostella in our study (10 WU samples, 10 WA samples, and 9 WI samples), 52.5% of the sequences were of Firmicutes and 47.5% were of Proteobacteria, with the dominant genera being mainly Carnobacterium (46.2%), Enterobacter (10.1%), and Enterococcus (6.2%); Moreover, antibiotic removal of Wolbachia infection in P. xylostella and transfer to normal conditions for 10 generations no longer significantly affected the bacterial community of P. xylostella. This study provides a theoretical basis for the elimination method of Wolbachia in the P. xylostella, as well as a reference for the elimination method of Wolbachia in other Wolbachia-infected insect species, and a basis for the study of the extent and duration of the effect of antibiotic treatment on the bacterial community of the P. xylostella.

Effects of Antibiotic Treatment on the Development and Bacterial Community of the Wolbachia-Infected Diamondback Moth

 Background:
 There are known associations between sex-specific reproductive health factors such as reproductive lifespan and stroke risk. The relation of endogenous sex hormones, specifically sex hormone binding globulin (SHBG), to stroke risk remains uncertain, however, despite some data showing an inverse association between SHBG and stroke. We conducted a pilot case-control study to evaluate SHBG as a stroke risk factor, to report SHBG levels in the period immediately after acute ischemic stroke (AIS), and to demonstrate the feasibility of collecting data on sex hormones and reproductive history in this study population.
 
 Methods:
 In STOP STROKE, postmenopausal women were enrolled from a single large healthcare system in the northeast between July 2020 and May 2022. Case participants were postmenopausal women ≥50 years old newly admitted with AIS to a large stroke center; controls were postmenopausal women without a history of stroke recruited from an outpatient clinic in the same healthcare system. Among others, exclusion criteria included use of menopausal hormone therapy within 10 years, prior stroke, surgical menopause, and history of hormone-related cancers. We ascertained data on stroke risk factors and collected blood samples between 24 and 72 hours after stroke onset or at the time of enrollment for controls. Serum SHBG was measured using enzyme-linked immunosorbent assays. Following descriptive analyses, age- and BMI-adjusted SHBG levels were compared between cases and controls using multiple linear regression. Multiple logistic regression was then performed to assess associations between SHBG, clinical risk factors, and the outcome of AIS, with covariates chosen
 a priori
 based on prior literature.
 
 Results:
 In total, 32 cases and 30 controls were enrolled; median age was 69.0 years (IQR 64.5-82.0) for cases vs. 62.0 (IQR (59.0-68.0) for controls. The mean SHBG of AIS cases was 68.8 (SD 36.1) nmol/L compared to 56.6 (SD 30.0) nmol/L among controls (p=0.16). In models adjusted for age and body mass index (BMI), SHBG was similar between cases and controls (beta = 3.0, 95%CI -15.0 - 21.1, p=0.74). Adjusted for age, BMI, history of hypertension, history of diabetes, and age at menarche and menopause, there was a positive association between SHBG and AIS (OR 1.04, 95%CI 1.004-1.071, p=0.03).
 
 Conclusions:
 Our pilot study demonstrates the feasibility of enrolling newly admitted AIS patients and controls among postmenopausal women in the catchment area of our comprehensive stroke center. To understand initial findings of a positive association between SHBG and AIS, work is ongoing to measure estrogens and androgens at study baseline and all hormones in follow-up specimens (3-6 months post stroke).

Abstract P474: Sex-Specific Prevention of Stroke Through Reproductive Risk Factors and Sex Hormone Effects (STOP STROKE): Preliminary Findings

This paper proposes a two-level stress correction method to overcome the limitations of the element stress average method that is typically used to calculate the nodal stress in finite element analyses and increase the fatigue life evaluation accuracy at the stiffness mutation positions of large-scale structure. In the first stage, a standard-deviation-weighted stress smoothing method is used to address the high element stress dispersion at the stiffness mutation point. The second stage involves a stress gradient correction method established based on the theory that the nodal stress is affected by other nodal stresses on the stress gradient path. The nodal stresses of the key points of an 80 tons gondola car body are extracted using the two-level stress correction method, and the fatigue life of the key points is evaluated considering the load spectrum of the Daqin coal line. The fatigue lives corresponding to the measured stress spectrum at the key points are compared with the simulated values. Compared with that obtained by the traditional method, the fatigue life of the key joints obtained by the proposed method is closer to the actual fatigue life. Additionally, the nodal stress at the stiffness mutation position obtained by the proposed method is more accurate. Therefore, the two-level stress correction method is a promising platform for the fatigue life evaluation of large-scale structures.

Research and application of nodal stress correction at stiffness mutation position for fatigue life evaluation

ABSTRACT Cholangiocarcinoma (CCA) is an aggressive biliary epithelial tumor with limited therapeutic options and poor prognosis. Curcumin is a promising active natural compound with several anti-cancer properties, though its clinical uses remain hindered due to its poor bioavailability. We recently synthesized curcumin analogs with multifunctional pharmacological and bioactivities with enhanced bioavailability. Among these novel curcumin analogs, WZ26 is a representative molecule. However, the anti-tumor effect of WZ26 against CCA is unclear. In this study, we evaluated the anti-tumor effect of WZ26 in both CCA cells and CCA xenograft mouse model. The underlying molecular anti-cancer mechanism of WZ26 was also studied. Our results show that WZ26 significantly inhibited cell growth and induced mitochondrial apoptosis in CCA cell lines, leading to significant inhibition of tumor growth in xenograft tumor mouse model. Treatment of WZ26 increased reactive oxygen species (ROS) generation, subsequently decreased mitochondrial membrane potential and inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3), thereby inducing G2/M cell cycle arrest and cell apoptosis. Pretreatment of N-acetyl cysteine (NAC), an antioxidant agent, could fully reverse the WZ26-induced ROS-mediated changes in CCA cells. Our findings provide experimental evidence that curcumin analog WZ26 could be a potential candidate against CCA via enhancing ROS induction and inhibition of STAT3 activation.

Curcumin analog WZ26 induces ROS and cell death via inhibition of STAT3 in cholangiocarcinoma

Remimazolam Compared to Propofol During Hysteroscopy: A Safety and Efficacy Analysis

As one of the most important geophysical methods for detecting the lunar underground structure of the Moon, the lunar penetrating radar (LPR) is applied to the Chang’e-4 (CE-4) mission to explore the Von Kármán crater on the far side of the Moon. With the Yutu-2 rover continuing to move toward the Zhinyu crater at the west, radar will likely detect the fractures created by the impact that formed the Zhinyu crater. Therefore, the establishment of a comprehensive lunar subsurface structure model with fracture, random media, and fractal terrain is crucial for the LPR data processing and the understanding of the lunar geological impact process. In addition, the method that can image the radar data with fractures well has great significance to the interpretation of the LPR data. In this article, we establish a comprehensive lunar subsurface structure model first, and the considering factors, including fractures, random media, fractal terrain, and the radar response, are calculated through forward modeling. Second, according to the high resolution and the sensitive to inhomogeneities of LPR data, we design a set of processing flow, including plane-wave destruction (PWD), velocity analysis based on the focusing analysis method, and migration imaging based on the velocity continuation. Finally, the results, including simulation data and Antarctic fracture data, are used to verify the effectiveness of imaging method.

Simulation of Lunar Comprehensive Substructure With Fracture and Imaging of Later LPR Data From Chang’e-4 Mission

Continuous Allocation of Carbon Emission Quota Considering Different Paths to Carbon Peak: Based on Multi-Objective Optimization

Thermal behavior and performance of shallow-deep-mixed borehole heat exchanger array for sustainable building cooling and heating

Hollow Carbon Dual-Decorated with MnO2 Shielding Layer and Carbon Nanotube as a Sulfur Host for Li-S Batteries

Reinforcement Mechanism of Silica Surface Hydroxyl: The Opposite Effect

Objective The goal of this study was to simplify the smoking rationalization belief (SRB) scale among Chinese male smokers and provide a convenient measuring tool with good reliability and validity to promote the assessment and further intervention of SRB among smokers. Methods Through purposive sampling, a questionnaire survey was conducted among adult male smokers in three districts in Shanghai, and 1,307 valid questionnaires were collected. Exploratory factor analysis was used to analyze the simplified scale, and Pearson correlation analysis, multiple linear regression, and Cronbach’s α were used to test the reliability and validity of the simplified scale. Results The SRB scale was simplified from 26 items to 8 items and had good overall reliability (Cronbach’s α = 0.757). There was a strong correlation between the simplified scale and the original scale (P < 0.001, r = 0.911), and the scores of SRB measured by the two scales were both negatively associated with a willingness to quit smoking (P < 0.001), which reflected the practical effectiveness of the simplified version. Conclusion The simplified version of the SRB scale showed good reliability and validity among Chinese smokers, which facilitates smoking cessation-related research and practice.

Development of a simplified version of the smoking rationalization belief scale for Chinese male smokers

Evaluating disparities and convergence of financial support efficiency for resource recycling industry in China

Field and laboratory experiments on performance of double-pile substructure of bridge along slope strike

Enhanced Piezo-Catalytic H2o2 Production Over Bi0.5na0.5tio3 Via Piezoelectricity Enhancement and Surface Engineering

Biocrystal-encased manganese ferrite coupling with peroxydisulfate: Synergistic mechanism of adsorption and catalysis towards tetracycline removal

Simple and Mild Method for the Recycling of Carbon-Fiber-Reinforced Bismaleimide Resin Composite Waste

Abstract Cancer is a very heterogeneous disease, and uncontrolled cell division is the main characteristic of cancer. Cancerous cells need a high nutrition intake to enable aberrant growth and survival. To do so, cancer cells modify metabolic pathways to produce energy and anabolic precursors and preserve redox balance. Due to the importance of metabolic pathways in tumor growth and malignant transformation, metabolic pathways have also been given promising perspectives for cancer treatment, providing more effective treatment strategies, and target-specific with minimum side effects. Metabolism-based therapeutic nanomaterials for targeted cancer treatment are a promising option. Numerous types of nanoparticles (NPs) are employed in the research and analysis of various cancer therapies. The current review focuses on cutting-edge strategies and current cancer therapy methods based on nanomaterials that target various cancer metabolisms. Additionally, it highlighted the primacy of NPs-based cancer therapies over traditional ones, the challenges, and the future potential.

Recent progress in the development of nanomaterials targeting multiple cancer metabolic pathways: a review of mechanistic approaches for cancer treatment

3D Objects Detection And Tracking Using Solid-State LiDAR And RGB Camera

Banks play an important role in the economic and social development of a country, and bank failures can have numerous adverse effects on businesses and individuals. However, the frequency of international bank failures is so high that the analysis and prediction of the causes of international bank failures has received a lot of attention from many managers and academic researchers. This article selects data on 64 indicators of existing or failed banks in Poland from 2017 to 2021, and proposes a bank efficiency evaluation and bankruptcy analysis model in order to analyze the efficiency of bank failures in the context of studying the inputs and outputs of each bank, after which the five most important causes of failure are selected, based on which a failure risk prediction model is developed, through which representative banks are selected and specifically applied to other banks. Based on the principal component analysis method previously done, fuzzy component analysis was introduced for specific evaluation, while for the data of these banks to be used for the prediction of the risk of other banks, a banking system was created in this paper and a risk contagion model was introduced. Finally, specific calculations were performed for the time series model, and cluster analysis was performed using its residuals as the discriminant criterion to determine whether they came from the same bank. The research in this paper is more accurate in predicting the possibility of bank failures, and the approach used in this paper is more risk-averse than current techniques, minimizing losses from bank failures and providing more effective protection for citizens' property.

Aim Appraise the clinical features and influencing factors of the hospitalization times and length of stay in bipolar disorder (BD) patients. Methods This is a multicenter, observational, cohort study of patients diagnosed of type I or type II bipolar disorder. Five hundred twenty outpatients in seven hospitals from six cities in China were recruited from February 2013 to June 2014 and followed up using a continuous sampling pattern. The research included a retrospective period of 12 months and the prospective period of 9 months. The demographic and clinical features of the patients were collected. The influencing factors that could affect the length of stay (number of days spent in the hospital in the prospective period) were analyzed by poisson's regression and the hospitalization times (times of hospitalization in the prospective and retrospective period) was analyzed by general linear model. The selected variables included gender, age, years of education, occupational status, residence status, family history of mental disease, comorbid substance abuse, comorbid anxiety disorder, times of suicide (total suicide times that occurred in the retrospective and prospective period), polarity of the first mood episode, and BD type(I/II). Results Poisson's regression analysis showed that suicide times [Incidence Rate Ratio (IRR) = 1.20, p < 0.001], use of antipsychotic (IRR = 0.62, p = 0.011), and use of antidepressant (IRR = 0.56, p < 0.001) were correlated to more hospitalization times. Linear regression analysis showed that BD type II (β = 0.28, p = 0.005) and unemployment (β = 0.16, p = 0.039) which might mean longer duration of depression and poor function were correlated to longer length of stay. However, patients who experienced more suicide times (β = −0.21, p = 0.007) tended to have a shorter length of stay. Conclusion Overall, better management of the depressive episode and functional rehabilitation may help to reduce the length of stay. BD patients with more hospitalization times were characterized by higher risk of suicide and complex polypharmacy. Patients at high risk of suicide tended to have inadequate therapy and poor compliance, which should be assessed and treated adequately during hospitalization. Clinical trial registration www.ClinicalTrials.gov, Identifier: NCT01770704.

Factors associated with hospitalization times and length of stay in patients with bipolar disorder

Contemporary estimates of heart failure (HF) prevalence in Japan are scarce. We aimed to estimate HF prevalence and trends in Japan using nationally representative, large administrative claims databases.

Trends in heart failure prevalence in Japan 2014–2019: a report from healthcare administration databases

Myocardial protection is essential in cardiac surgery with cardiopulmonary bypass The Del Nido cardioplegia which was initially used in pediatric cardiac surgery, has been increasingly used in adult cardiac surgery recently. However, no literature has reported the efficacy of DNC in hypertrophic obstructive cardiomyopathy.

METHODS
This retrospective study involved elective patients who underwent extended surgical myectomy with or without concomitant cardiac surgical procedures between September 2017 and June 2022. Patients were distributed into two groups, the DNC and the CBC group. The primary outcome was high-sensitivity cardiac troponin I (hs-TnI) and creatine kinase-MB (CK-MB) levels at the 0, 1, and 2 postoperative days. The secondary outcomes contained: intraoperative LVEF, return to spontaneous rhythm; postoperative myocardial infarction, worsening or deteriorating of EF, mechanical circulatory support; new-onset atrial fibrillation; mechanical ventilation duration; intensive care unit hours; in-hospital days.

RESULTS
Fifty-nine patients were included and divided into the CBC (n = 15) and the DNC group (n = 44). There was no statistical difference in patients' demographics and preoperative parameters between the two groups. No in-hospital mortality. The total cardioplegia volume [21.93(18.36,26.07) vs. 25.68(23.17,37.12), p = 0.012] and infusion times [1(1,1) vs. 2(2,3), p = 0.000] were less and the incidence of return to spontaneous rhythm after declamping was higher in the DNC group [97.7% vs. 73.3%, p = 0.013]. Postoperative hs-TnI and CK-MB levels were comparable between the two groups. A longer DNC infusion interval was associated with higher levels of CK-MB on postoperative day 1 and day 2 (p = 0.009 and p = 0.011, respectively).

The use of DNC in extended surgical myectomy procedure was as safe and effective as CBC. However, DNC infusion interval over 60 minutes was associated with increased postoperative CK-MB levels.

Del nido versus conventional blood cardioplegia in patients with obstructive hypertrophic cardiomyopathy.

Bicyclol Alleviates Streptozotocin-induced Diabetic Cardiomyopathy By Inhibiting Chronic Inflammation And Oxidative Stress

An Endoplasmic Reticulum-Targeted Ratiometric Fluorescent Probe for Hypochlorite Bioimaging Based on Aggregation-Induced Ratiometric Emission

Accelerated Peridynamic Computation on GPU for Quasi-static Fracture Simulations

A Fourth-Order Cese Scheme for 3d Mhd Simulations with Parallel Computing

Preparation of Buffered Nano-Submicron Hierarchical Structure Hollow Siox@C Anodes for Lithium-Ion Battery Materials with Carboxymethyl Chitosan

Enhanced Hydrolysis of Aluminum Nitride from Secondary Aluminum Dross Through Combination of Wet-Stirred Milling and Alkaline Leaching

An approach for upgrading behavior and bio-oil production using CO2-assisted cellulose pyrolysis in cobalt-based Ce/Fe/Mg composite catalyst

White clover (Trifolium repens L.) is an important perennial legume forage and ornamental plant, and is widely distributed and cultivated in the world. Recently, white clover plants showing symptoms of leaf mosaic and redding were observed in Hohhot, Inner Mongolia of China. In this work, flexuous filamentous viral particles of about 700 × 13 nm in size were observed in the symptomatic leaf samples. The infection of clover yellow vein virus (ClYVV) was confirmed by small RNA sequencing and RT-PCR validation. Mechanical inoculation assays showed that this ClYVV isolate (ClYVV-IM) can infect a range of herbaceous species, including Nicotiana benthamiana, N. occidentalis, Chenopodium quinoa, C. amaranticolor, Vicia faba, Vigna unguiculata, and Solanum lycopersicum, causing various symptoms. The complete genome sequence of ClYVV-IM consists of 9565 nt and shared sequence identities, ranging from 83.05% to 96.30%, with those of the other ClYVV isolates published in GenBank. Phylogenetic analyses based on the polyprotein nucleotide and amino acid sequences clustered 15 ClYVV isolates into two groups and ClYVV-IM located in Group I. Two potential recombination events located at 914–2970 nt and 5153–5694 nt were detected in the genome of ClYVV-IM. To our knowledge, this is the first report of occurrence and complete genome of ClYVV infecting white clover in China.

Biological and Molecular Characterization of Clover Yellow Vein Virus Infecting Trifolium repens in China

Hormonal and inflammatory signatures of different mood episodes in bipolar disorder: a large-scale clinical study

Insights into the multirole CoAl layered double hydroxide on boosting photoelectrochemical activity of hematite: Application to hydrogen peroxide sensing.

Optimization of Flexible Nacre-Like Cellulose Nanofiber Films by a Covalent Overlapping Method: Excellent Thermal Conductivity and Superior Flame Resistance

Exploring the Roles and Impact of Women in Executive Leadership: A Comprehensive Analysis of Gender Diversity in Top Corporate Management

Simultaneous exfoliation and functionalization of black phosphorus by sucrose-assisted ball milling with NMP intercalating and preparation of flame retardant polyvinyl alcohol film

Time-dependent cardiac structural and functional changes after kidney transplantation: a multi-parametric cardiac magnetic resonance study

Make the invisible visible: Valuation of the hidden cost of particulate-filtering facemask use against air pollution in China

Uncertainty assessment of a semi-empirical output voltage model for proton exchange membrane fuel cells

Direct Reductive Amination from Ketones, Aldehydes to Synthesize Amines Using N, S-Dual Doped Co/C Catalyst

Unique Work Hardening Rate of a Heterogeneous Structured High Purity Ti Subjected to Laser Surface Treatment

Grafting provides a way to improve tolerance to low phosphorus (P) stress for plants, and has been extensively applied in commercial cultivars grafted onto appropriate rootstocks. However, little literature is available concerning the scion-mediated effect on P efficiency in grafted plants. In this study, three different Camellia oleifera Abel. scion cultivars (G8, G83-1, and W2) were grafted onto the same rootstock (W2) under controls (0.5 mM) and low-P (0 mM) availability for eight months. The results showed that the scions significantly affected root-to-shoot weight ratios, the root morphology with a diameter larger than 1 mm, P accumulation, and the P utilization efficiency (PUE) of the root. A higher increase in the root-to-shoot weight ratio under the low-P supply was observed in the G83-1/W2 (26.15%) than in the G8/W2 (0%) and the W2/W2 (5.32%). Root PUE of the scion G8, G83-1, and W2 was improved by up to 113.73%, 45.46%, and 20.97% under the low-P supply. Moreover, G8/W2 exhibited higher shoot P accumulation and the highest root PUE under the low-P supply, indicating a high capability to tolerate P deficiency by maximizing the cost-effectiveness of P remobilization to photosynthetic organs. This suggested the vigorous variety of G8 could be a promising scion to improve grafted C. oleifera tolerance to low-P stress. Our results would have important implications for exploration and identification of a superior scion variety to enhance the ability of resistance concerning P deficiency stress in C. oleifera.

Effects of Scion Variety on the Phosphorus Efficiency of Grafted Camellia oleifera Seedlings

Associations of IFT20 and GM130 protein expressions with clinicopathological features and survival of patients with lung adenocarcinoma

Exosomal long non-coding RNAs (lncRNAs) have emerged as a cell-free biomarker for clinical evaluation of cancers. However, the potential clinical applications of exosomal lncRNAs in acute myeloid leukemia (AML) remain unclear. Herein, we attempted to identify plasma exosomal lncRNAs as prospective biomarkers for AML. In this study, plasma exosomes were first successfully extracted from AML patients and healthy donors (HD). Subsequently, the downregulated plasma exosomal lncRNAs (LINC00265, LINC00467, and UCA1) and the upregulated plasma exosomal lncRNA (SNHG1) were identified in AML patients (n=65) compared to HD (n=20). Notably, individual exosomal LINC00265, LINC00467, UCA1, or SNHG1 had a capability for discriminating AML patients from HD, and their combination displayed better efficiency. Furthermore, exosomal LINC00265 and LINC00467 were increased expressed in patients achieving complete remission after chemotherapy. Importantly, there was upregulation of exosomal LINC00265 and downregulation of exosomal SNHG1 upon allogeneic hematopoietic stem cell transplantation. Additionally, these lncRNAs were high stability in plasma exosomes. Exosomal LINC00265, LINC00467, UCA1, and SNHG1 may act as promising cell-free biomarkers for AML diagnosis and treatment monitoring and provide a new frontier of liquid biopsy for this type of cancer.

Circulating plasma exosomal long non-coding RNAs LINC00265, LINC00467, UCA1, and SNHG1 as biomarkers for diagnosis and treatment monitoring of acute myeloid leukemia

Sulfur‐Doped Hydrogen‐Bonded Organic Framework for Improved Oxygen Evolution Reaction

MilR3, a unique SARP family pleiotropic regulator in Streptomyces bingchenggensis

A sensitive photoelectrochemical sensor based on hematite decorated with nickel hydroxide for the detection of glucose

Rivers are important sites for nitrogen (N) cycling processes. N removal is thought to occur predominantly in the benthic zone and the role of the water column is frequently neglected. Here, we find that the water‐air and sediment‐water fluxes of N2 and N2O decreased, while the water column production increased with stream order through 4‐year observations across six river networks in China. The water column contribution increased with stream order and accounted for more than 50% in rivers above fifth order. The increase in the contact area of suspended sediment (SPS)‐water caused by higher SPS concentrations and river depths resulted in the shift as river size increased. N removal and N2O emissions would be underestimated approximately by 50% if neglecting water column processes for the six river networks. This study highlights the necessity and provides a pathway to incorporate water column processes into models to balance the global N budget.

The Dominant Role of the Water Column in Nitrogen Removal and N2O Emissions in Large Rivers

Agriculture provides a basis for social and economic development. It is therefore crucial for society and the economy to stabilize agricultural prices. Recent large increases and decreases in Chinese agricultural commodity prices have increased production risks, heightened fluctuations in the domestic agricultural supply, and impacted the stability of the global agricultural market. Meanwhile, big data technology has advanced quickly and now serves as a foundation for the investigation of time series bubbles. Identifying agricultural price bubbles is important for determining agricultural production decisions and policies that control agricultural prices. Using weekly agricultural price data from 2009 to 2021, this paper identifies agricultural price bubbles, pinpoints their time points, and examines their causes. According to our research, prices for corn, hog, green onions, pork, and ginger all have bubbles, but garlic do not. The quantity, length, time distribution, and type of bubbles differ significantly among corn, ginger, green onion, hog, and pork. The main causes for ginger and green onion price bubbles are speculation and natural disasters. Price bubbles for hog and pork are influenced by animal disease and rising costs. Conflicts between supply and demand and changes in price policy cause corn price bubbles to form. This paper advises that the government adopt various regulatory actions to stabilize agricultural prices depending on the characteristics and causes of the various types of agricultural price bubbles, it should also improve the early warning system and response mechanism for agricultural price bubbles and focus on how policies and market processes work together.

Study on Price Bubbles of China’s Agricultural Commodity against the Background of Big Data

Polygonati rhizoma (Huangjing in Chinese) is a traditional and classic dual-purpose material used in food and medicine. Herbalists in China and Japan have noticed several different rhizome types in Huangjing with different qualities. Rhizome of Polygonatum cyrtonema Hua and P. sibiricum Red. is divided into five types: “Jitou-type” Polygonati rhizoma (JTPR), atypical “Jitou-type” Polygonati rhizoma (AJTPR), “Jiang-type” Polygonati rhizoma (JPR), “Cylinder-type” Polygonati rhizoma (CPR), and “Baiji-type” Polygonati rhizoma (BJPR). This study observed the microstructure and histochemical localization of polysaccharides, saponins, and proteins in Huangjing. Nutritional and medicinal component data and antioxidant capacity (DPPH and ABTS) were analyzed to evaluate the quality of different types of Huangjing. The results showed that the comprehensive quality of the rhizomes, BJPR and JTPR, was better, regardless of their nutritional or medicinal values. Altogether, these results could recommend future breeding efforts to produce Huangjing with improved nutritional and medicinal qualities.

An Evaluation of Traits, Nutritional, and Medicinal Component Quality of Polygonatum cyrtonema Hua and P. sibiricum Red.

A radiomics-based model can predict recurrence-free survival of hepatocellular carcinoma after curative ablation.

Solution‐processed quasi‐2D Ruddlesden‐Popper perovskites are being considered as a promising optical gain medium in lasing applications, owing to their outstanding optoelectronic properties and inherent stability. However, the development of quasi‐2D perovskites for lasers with low threshold and high optical gain is still lagging far behind 3D‐perovskites. This work proposes an anti‐solvent treatment strategy to regulate the phase components and surface morphology of quasi‐2D PEA2(CsPbBr3)n−1PbBr4 thin films. Furthermore, an additional poly(methyl methacrylate) coating is introduced to reduce the surface defects of perovskite films and suppress the non‐radiative recombination. Due to the phase engineering and surface passivation, excellent amplified spontaneous emission (ASE) is obtained with a low threshold of 11.7 µJ cm−2 and a high net model gain of 622 cm−1. In addition, under 800 nm femtosecond laser excitation, two‐photon‐pumped ASE is also successfully observed with a low threshold of 7.2 mJ cm−2.

Amplified Spontaneous Emission with a Low Threshold from Quasi‐2D Perovskite Films via Phase Engineering and Surface Passivation

Texturing In-Situ: N/F Dual-Doped hollow porous carbon nanospheres for advanced Li-S batteries

Engineering miniature gold nanorods with tailorable plasmonic wavelength in NIR region via ternary surfactants mediated growth

Oil-based drug delivery systems have been studied in different aspects. The present study proposes a new application for an oil-based delivery system, focusing on controlled release until the drug reaches the later part of the small intestine. Bulk surfactants and interfacial surfactants were added into the oil formulation to provide a better mechanistic understating of the lipolysis. Validation of the modified in vitro method shows the overall conversion from medium-chain triglyceride oil (MCT oil) to free fatty acids (FFA) of 100 ± 4% in five replicates. This fully converted level and high reproducibility are fundamental for the following investigations where any retarding effect can be distinguished from the experimental errors. The results show that viscosity and thermodynamic activity have limited retardation. Furthermore, the former may change the kinetics of lipolysis, while the latter changes the equilibrium level. The gel-forming retarder (ethylcellulose) displayed a strong effect. Whereas the lipolysis was significantly retarded (>50%) when the retarders altered the interfacial composition (poloxamer 407), degradable interfacial surfactants did not have the same effect. However, surface-active, lipolysis-resistant retarders with a high CMC did not show a retarding effect.

Oil-Based Delivery Control Release System Targeted to the Later Part of the Gastrointestinal Tract—A Mechanistic Study

Objective: To investigate the clinicopathological features, immunophenotypic and molecular genetic characteristics and differential diagnosis of fibrous hamartoma of infancy (FHI). Methods: Thirty-three cases of surgically removed FHI were collected from the Department of Pathology, Henan Provincial People's Hospital from October 2011 to December 2020, the clinical and pathologic data with follow-up were collected and analyzed. Next-generation sequencing (NGS) and quantitative real time polymerase chain reaction (q-PCR) were used to study the molecular genetics. Results: The FHI cases occurred in 21 males and 12 females (mean age 16.7 months, range 6 months to 6 years). The sites included trunk (n=21), limb (n=11), and neck (n=1). All patients had painless solitary superficial soft tissue masses, the size was 1.5-9.0 cm (mean 3.8 cm). Microscopically, they were composed of mature adipose tissue, fibroblast/myofibroblast bundle and primitive mesenchymal cells in different proportions; giant cell fibroblastoma-like areas were seen in 14 cases. Immunohistochemistry showed variable expression of EGFR in the spindle cells and primitive mesenchymal components. In most cases, the spindle cells were positive for CD34 and SMA; giant cell fibroblastoma-like areas were strongly positive for CD34; and S-100 protein was expressed by adipocytes in all cases. Ki-67 labeling index ranged 1%-5%. There were recurrent somatic EGFR exon 20 insertion/duplication mutations in six cases tested by NGS, and there were three different mutation types: p.Asn771_His773dupAsnProHis, p.Pro772_His773insProProHis, and p.His773_Val774insThrHis. All the above 6 and another 15 tested cases showed EGFR exon 20 insertion/duplication mutations by q-PCR. Conclusions: FHI is a rare benign fibroblast/myofibroblast tumor. The characteristic histologic feature is organoid triphasic morphology, and the molecular feature is somatic mutation of EGFR exon 20 (insertion/duplication).

[Fibrous hamartoma of infancy: a clinicopathological and molecular genetic analysis of 33 cases].

Reinforcement Mechanism of Silica Surface Hydroxyl: Janus Effects

A “Turn-On” Chalcone-Based Probe for Hydrogen Sulfide and Imaging Applications in Lysosomes of Living Cells and Zebrafish

Five Cocrystal Forms of Antitumor Drug Temozolomide with p-Hydroxybenzoic Acid: Structure, Computational Analysis, Characterizations, Stability, and Transformation

Background: Laryngeal squamous cell carcinoma (LSCC) is one of the most common malignant tumors of the head and neck, and it has shown increasing incidence and mortality. The mechanistic target of rapamycin complex 1 (mTORC1) is frequently dysregulated in LSCC, but its underlying mechanisms remain unclear. Methods: Establishment of a novel LSCC cell line using primary LSCC tumor tissues with dysregulated mTORC1 activity and then stable knockdown of Raptor (an mTORC1 specific component) in this cell line. Transcriptomic sequencing, quantitative real-time PCR, western blot analysis, and immunofluorescence assays were used to identify the crucial downstream effector of mTORC1. A series of experiments were conducted to investigate the functions and underlying mechanisms of the mTORC1 target gene in LSCC progression. Clinical LSCC samples were used to evaluate the association of mTORC1 and its downstream targets with clinicopathological features and patient prognosis. Finally, the influence on cisplatin (CDDP) sensitivity upon depletion of the mTORC1 target gene was assessed using a cell culture system, a cell line-derived xenograft (CDX) model, and a patient-derived xenograft (PDX) model. Results: We successfully established a novel LSCC cell line with hyperactivated mTORC1 activity and then identified integrin subunit alpha 5 (ITGA5) as a novel functional downstream effector of mTORC1 in the progression of LSCC. Elevated ITGA5 promotes LSCC progression through augmentation of ephrin-B2 (EFNB2). Clinical data analysis indicated that the activation of the mTORC1-ITGA5-EFNB2 signaling pathway is associated with malignant progression and poor prognosis of LSCC patients. Inhibition of ITGA5 significantly sensitized LSCC cells to CDDP. Conclusions: Our findings highlight a novel molecular mechanism for the tumorigenesis driven by deregulated mTORC1 signaling in LSCC, suggesting that the ITGA5-EFNB2 axis may be a therapeutic target for the treatment of mTORC1-related LSCC.

Elevated ITGA5 facilitates hyperactivated mTORC1-mediated progression of laryngeal squamous cell carcinoma via upregulation of EFNB2

The construction of aromatic skeleton structures by the Diels–Alder reaction is a synthetic route to obtain substitutes for petrochemical products using biomass as a raw material.

Synergistic Fe(Iii) and Acid Sites in Siw@Mil-100(Fe) Catalyst Prompt the Synthesis of P-Xylene from Biomass Derivatives

Spatial identification and trade-off analysis of land use functions improve spatial zoning management in rapid urbanized areas, China

The circular RNA circHMGB2 drives immunosuppression and anti-PD-1 resistance in lung adenocarcinomas and squamous cell carcinomas via the miR-181a-5p/CARM1 axis

Highly N-Doped and Flexible Carbon Nanofiber Membrane as Cathode Host for Li-Se Batteries

The matching between the wire material and the base metal has an extremely important influence on the performance of the welded joint. In this work, the effects of two welding materials THQ440‐NQ‐II and ER50‐6 with different compositions on the microstructure, mechanical properties and corrosion resistance of bridge weathering steel Q345qDNH were investigated. Although the mechanical properties of the two welded joints are lower than those of the base metal, the yield strength, elongation after fracture, impact toughness at 20 °C and −40 °C of THQ440‐NQ‐II welded joints are 6.8 %, 23.5 %, 13.7 %, 18 % higher than those of ER50‐6 welds, respectively. THQ440‐NQ‐II welds are ductile fractures and quasi‐cleavage fractures at 20 °C and −40 °C, respectively; while ER50‐6 welds are quasi‐cleavage fracture and cleavage fracture at 20 °C and −40 °C, respectively, the ductile‐brittle transition temperature of ER50‐6 weld is higher than that of THQ440‐NQ‐II weld. Comparing the corrosion resistance in 3.5 % sodium chloride (NaCl) solution, THQ440‐NQ‐II weld is better than the base metal, while ER50‐6 welds are lower than the base metal. This is because the nickel, chromium, copper elements contained in the THQ440‐NQ‐II welding wire can inhibit the formation of Widmanstätten structure and upper bainite during the welding process, refine the structure, increase the content of acicular ferrite, and reduce the ductile‐brittle transition temperature of welding joint, improves the corrosion resistance of the weld.

Effect of welding material on microstructure and properties of welded joints of bridge weathering steel Q345qDNH

Photocatalytic conversion of methane selectively into oxygenated products in the presence of chloride ions

Development of an Intelligent MOF-Based Binary Heterojunction for Intensive Chemodynamic/Starvation Synergistic Tumor Ablation

The interactions of Ce and P on microstructure, mechanical properties in as-cast pure copper were investigated by utilising the OM, SEM and TEM techniques, combined with tensile tests. The results reveal that the micron-scale CeP precipitates are distributed along grain boundaries (GBs), leading to an obvious reduction of grain size and a significant improvement in mechanical properties, compare with pure copper. In addition, the fracture mechanism transformed from microvoid coalescence fracture to quasi-cleavage failure due to the formation of grain boundary precipitates CeP.

The interactions of Ce-P on microstructure and mechanical properties in pure copper

Compared with gold and silver, cheap copper has attracted more attention and can potentially be applied in non-enzymatic electrochemical sensors due to its excellent conductivity and catalytic activity. In this paper, copper nanoplates were rapidly synthesized using copper bromide as the copper precursor, polyethyleneimine as the stabilizer, and ascorbic acid as a reducing agent in the presence of silver nanoparticles at a reaction temperature of 90 °C. The Cu nanoplates with an average side length of 10.97 ± 3.45 μm were obtained after a short reaction time of 2 h, demonstrating the promoting effect of an appropriate amount of silver nanoparticle on the synthesis of Cu nanoplates. Then, the electrochemical dopamine sensor was constructed by modifying a glass carbon electrode (GCE) with the Cu nanoplates. The results obtained from the test of cyclic voltammetry and chronoamperometry indicated that the Cu-GCE showed a significant electrochemical response for the measurement of dopamine. The oxidation peak current increased linearly with the concentration of dopamine in the range of 200 µmol/L to 2.21 mmol/L, and the corresponding detection limit was calculated to be 62.4 μmol/L (S/N = 3). Furthermore, the anti-interference test showed that the dopamine sensor was not affected by a high concentration of ascorbic acid, glucose, uric acid, etc. Therefore, the constructed Cu-GCE with good selectivity, sensitivity, and stability possesses a high application value in the detection of dopamine.

Preparation of Copper Nanoplates in Aqueous Phase and Electrochemical Detection of Dopamine

Background This study investigated the correlation between cardiac function parameters by cardiac computed tomography (CT) and the clinical outcomes of heart failure patients with preserved ejection fraction (HFpEF) to provide experimental data for the diagnosis of HFpEF. Methods A total of 157 HFpEF patients admitted to our hospital from January 2017 to January 2019 were retrospectively analyzed. The patients were divided into event and non-event groups according to the occurrence or absence of adverse events. Cardiac function parameters, such as the left ventricular (LV) end-diastolic volume (LVEDV) and LV end-diastolic volume index (LVEDVI), were obtained via CT scan. Also, the N-terminal-pro hormone b-type natriuretic peptide (NT-proBNP) levels in patients’ serum were measured using an enzyme linked immunosorbent assay (ELISA) kit, and echocardiographic parameters such as LV posterior wall thickness (LVPWT) were also recorded. Further, Cox regression was employed to analyze factors associated with the clinical outcomes. Results Compared with patients in the non-event group, the left ventricular end-diastolic mass (LVM), LVEDVI, left ventricular end-systolic volume index (LVESVI), left atrial end-diastolic volume index (LAEDVI), and left atrial end-systolic volume index (LAESVI) were significantly increased, and the left ventricular total emptying fraction (LVTEF) and left atrial total emptying fraction (LATEF) were markedly decreased in the event group patients. Also, the E/e’ and LAEDVI were related factors affecting the clinical outcomes of HFpEF patients. The above indicators displayed a significant predictive for the clinical outcomes of HFpEF patients. Conclusions Several cardiac function measures, including LAEDVI, are factors associated with the clinical outcomes of HFpEF patients.

A retrospective study on the clinical significance of cardiac computed tomography in heart failure patients with preserved ejection fraction

Angiomyofibroblastoma (AMF) is a rare benign myofibroblastic tumor that mainly occurs in the genital tract of middle-aged female patients. However, it can also arise in the scrotum, spermatic cord, and bladder. We described, herein, a case of a 42-year-old patient who was admitted to our hospital with a left scrotal mass. Imaging examinations showed that the mass had abundant vessels and displayed obvious progressive intensification on enhanced MRI. The following histopathological and immunohistochemical studies led to the diagnosis of AMF. Here, we describe the magnetic resonance imaging findings of a case of scrotal AMF. We hope that the information can help radiologists to identify AMF.

Case Report: Magnetic Resonance Imaging Features of Scrotal Angiomyofibroblastoma (AMF) With Pathologic Correlation

Supercapacitor represents an important electrical energy storage technology with high-power performance and superior cyclability. However, currently commercialized supercapacitors still suffer limited energy densities. Here we report an unprecedentedly respiring supercapacitor with chlorine gas iteratively re-inspires in porous carbon materials, that improves the energy density by orders of magnitude. Both electrochemical results and theoretical calculations show that porous carbon with pore size around 3 nm delivers the best chlorine evolution and adsorption performance. The respiring supercapacitor with multi-wall carbon nanotube as the cathode and NaTi2(PO4)3 as the anode can store specific energy of 33 Wh/kg with negligible capacity loss over 30,000 cycles. The energy density can be further improved to 53 Wh/kg by replacing NaTi2(PO4)3 with zinc anode. Furthermore, thanks to the extraordinary reaction kinetics of chlorine gas, this respiring supercapacitor performs an extremely high-power density of 50,000 W/kg.

High Power- and Energy-density Supercapacitors through the Chlorine Respiration Mechanism.

Two-Stage Multi-Objective Evolution Strategy for Constrained Multi-Objective Optimization

A new perchlorate-based hybrid ultramicroporous material with rich bare oxygen atoms for high C2H2/CO2 separation

Department of Ophthalmology of the General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China Department of Radiotherapy of the General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China Correspondence to: Ling Zhang. Depar tment of Radiotherapy of the General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China. zhangling71@163.com Received: 2022-01-19 Accepted: 2022-07-20

Optical coherent tomography angiography observation of macular subinternal limiting membrane hemorrhage in CO poisoning: a case report.

Airborne aerosol is believed to be an important pathway for infectious disease transmissions like COVID-19 and influenza. However, the effects of dust event days on influenza have been rarely explored, particularly in arid environments. This study explores the effects of ambient particulate matter (PM) and dust events on laboratory-confirmed influenza in a semi-arid city. A descriptive analysis of daily laboratory-confirmed influenza (influenza) cases, PM (PM10 and PM2.5), meteorological parameters, and dust events were conducted from 2014 to 2019 in Lanzhou, China. The case-crossover design combined with conditional Poisson regression models was used to estimate the lagging effects of PM and dust events on influenza. In addition, a hierarchical model was used to quantitatively evaluate the interactive effect of PM with ambient temperature and absolute humidity on influenza. We found that PM and dust events had a significant effect on influenza. The effects of PM10 and PM2.5 on influenza became stronger as the cumulative lag days increased. The greatest estimated relative risks (RRs) were 1.018 (1.011,1.024) and 1.061 (1.034,1.087), respectively. Compared with the non-dust days, the effects of dust events with duration ≥ 1 day and with duration ≥ 2 days on influenza were the strongest at lag0 day, with the estimated RRs of 1.245 (95% CI: 1.061–1.463) and 1.483 (95% CI: 1.232–1.784), respectively. Subgroup analysis showed that pre-school children and school-aged children were more sensitive to PM and dust events exposure. Besides, we also found that low humidity and temperature had an interaction with PM to aggravate the risk of influenza. In summary, ambient PM and dust events exposure may increase the risk of influenza, and the risk of influenza increases with the dust events duration. Therefore, more efforts from the government as well as individuals should be strengthened to reduce the effect of PM on influenza, particularly in cold and dry weather.

Effects of Dust Event Days on Influenza: Evidence from Arid Environments in Lanzhou

Nanoporous metals possess excellent catalytic and optical properties that are related with surface morphology. Here, we modulated the ligament surface of nanoporous gold (NPG) by controlling electrochemical dealloying and obtained NPG with an improved enhancement of its surface-enhanced Raman scattering (SERS) property. We found that both high-density atomic steps and kinks on the curved surfaces and high-content silver atoms close to the ligament surface contributed to the high SERS ability. The presented strategy will be useful for the fabrication of nanoporous metal with an excellent surface that is needed for sensing, conversion, and catalytic.

Surface Defects Improved SERS Activity of Nanoporous Gold Prepared by Electrochemical Dealloying

BACKGROUND Safe and effective analgesia strategy remains one of the priorities for pediatric inguinal hernia treatment. AIM To explore safety and efficacy of dexmededomidine monotherapy for postoperative analgesia in children who received laparoscopic unilateral internal inguinal ring ligation. METHODS This randomized single-center controlled trial included 390 children (aged 1-3 years, ASA grade I-II), randomly divided into a dexmededomidine group (D group), a dexmededomidine + sufentanil group (DS group), and a sufentanil group (S group). The primary endpoint was percentage of children with the Face, Legs, Activity, Cry, and Consolability (FLACC) score ≤ 3 points 2 h after surgery. RESULTS The comparisons of the FLACC scores at 2, 4, 6, 8, 12, and 24 h were not significantly different among the three groups (P > 0.05). The sedative effects in the D group were significantly better than those in the S group (P > 0.05), but not significantly different from those in the DS group. The incidence of nausea and vomiting was significantly lower in the D group than in the S group and DS group (P > 0.05). CONCLUSION Analgesic effects of dexmededomidine monotherapy are comparable to those of sufentanil alone or in combination with dexmededomidine for children who underwent laparoscopic unilateral internal inguinal ring ligation, with better sedative effects and a lower incidence of adverse events.

Dexmededomidine in pediatric unilateral internal inguinal ring ligation

Analysis of suppression switching overvoltage for CRAFT power supply

A Web-GIS hazards information system of the 2008 Wenchuan Earthquake in China

Purpose There is a lack of rigorous experimental evidence to verify the effects of bubble tea on body weight and mental health, especially whether it is an addictive thing. Materials and methods Male adult C57BL/6 mice were randomly assigned to two groups, including the bubble-tea and the control group. The change in their body weight was calculated. Behavior tests include novel object recognition test (NORT), elevated plus maze test (EPMT), forced swim test (FST), tail suspension test (TST), conditioned place preference (CPP). Results There was a significant time effect on weight change of the two groups (F = 36.83, P < 0.01). The bubble tea-treated mice spent significantly less time in the open arms, indicating an increase in anxiety (t = 2.39, P = 0.03). In FST, bubble tea treatment produced a significantly increased immobility time (186.58 ± 29.67 s) as compared to pure water treated group (112.50 ± 46.67 s) (t = −3.79, P < 0.01). Similarly, the immobility time in the TST was also significantly increased by bubble tea treatment (437.63 ± 27.72 s) compared to the treatment with pure water (340.24 ± 77.22 s) (t = −3.36, P < 0.01). We investigated the rewarding effects of bubble tea, using the CPP paradigm, which measures the rewarding properties of abused drugs. Independent-samples t-test revealed no significant difference between the two groups (t = −0.47, P = 0.65). Conclusion In conclusion, we showed that long-term administration of bubble tea could not induce addictive behavior in mice. Meanwhile, the long-term effects of bubble tea on weight were also very limited. However, long-term consumption of bubble tea can lead to anxiety and depression-like behaviors and impair cognitive function in mice.

Effects of chronic bubble tea administration on behavior and cognition in C57BL/6 mice

Bottlebrush Polymer-Functionalized Graphene Oxide-Based Multifunctional Poly(vinyl alcohol) Nanocomposite Films with Exceptional Performance

Tenoxicam (TNX) is a new non-steroidal anti-inflammatory drug that shows a superior anti-inflammatory effect and has the advantages of a long half-life period, a fast onset of action, a small dose, complete metabolism, and good tolerance. Some compounds often have tautomerism, and different tautomers exist in different crystalline forms. TNX is such a compound and has three tautomers. TNX always exists as the zwitterionic form in cocrystals. When the salt is formed, TNX exists in the enol form, which exhibits two conformations depending on whether a proton is gained or lost. Currently, the crystal structure of the keto form is not in the Cambridge Structural Database (CSD). Based on the analysis of existing crystal structures, we derived a simple rule for what form of TNX exists according to the pKa value of the cocrystal coformer (CCF) and carried out validation tests using three CCFs with different pKa values, including p-aminosalicylic acid (PAS), 3,5-dinitrobenzoic acid (DNB), and 2,6-dihydroxybenzoic acid (DHB). The molecular surface electrostatic potential (MEPS) was combined with the pKa rule to predict the interaction sites. Finally, two new cocrystals (TNX-PAS and TNX-DNB) and one salt (TNX-DHB) of TNX were obtained as expected. The differences between the cocrystals and salt were distinguished by X-ray diffraction, vibration spectra, thermal analysis, and dissolution measurements. To further understand the intermolecular interactions in these cocrystals and salt, the lattice energy and energy decomposition analysis (EDA) were used to explain them from the perspective of energy. The results suggest that the melting point of the CCF determines that of the cocrystal or salt, the solubility of the CCF itself plays an important role, and the improvement of the solubility after salt formation is not necessarily better than that of API or its cocrystals.

Insight into the Formation of Cocrystal and Salt of Tenoxicam from the Isomer and Conformation

Improvement of Thermal Stability of Al-Cu-Mg-Ag Alloy by Over-Aging

Syndrome (Zheng in Mandarin Chinese) is the induction of disease attributes in the theory of traditional Chinese medicine (TCM). This is often used to explain why patients with the same disease show different symptoms. Cold and heat represent the two basic tendencies of a syndrome; therefore, the identification of cold and heat syndromes is key to the diagnosis and treatment of rheumatoid arthritis (RA) according to TCM. However, a traditional thinking model of cold and heat syndromes identifies a reliance on the clinical manifestations, which is inevitably affected by the subjectivity of doctors. It is important to identify objective biomarkers to improve accuracy in the identification of cold and heat syndromes of RA. Previous studies have identified differences in gene expression and function between cold and heat syndromes of RA, suggesting that different syndromes possess a unique biological basis.1,2 However, the biological basis is large and complex; therefor constructing a “disease– syndrome– biomaker” network using modern technology to preserve the characteristics of TCM and also improve the objectivity and applicability in syndrome identification is challenging DNA hydroxymethylation is an epigenetic marker that has attracted increasing attention recently. As a bridge between methylation and demethylation, DNA hydroxymethylation drives demethylation, indicating the reactivation of gene transcriptional expression.3 More importantly, DNA hydroxymethylation is sensitive to environmental stimuli, the state of DNA hydroxymethylation modification is able to change under different environmental stimuli, resulting in phenotypic differences.4 This regulatory mechanism is consistent with the concept of TCM, whereby “environmental differences can break the balance between cold and heat, causing differences in external clinical symptoms in patients with RA”, inferring that it is feasible to explore the epigenetic biomarkers of cold and heat syndromes of RA from DNA hydroxymethylation and gene transcription. The aim of our study was to identify epigenetic biomarkers of cold and heat syndromes of RA by combining DNA hydroxymethylation sequencing and transcriptome sequencing. Our study was approved through ethical review by the First Affiliated Hospital of Yunnan University of Traditional Chinese Medicine (ethical batch number: the scientific research [2020] Ethical Review [005]02). The study was conducted as follows. Ten patients with RA cold syndrome and 10 with heat syndrome were recruited according to the Guideline for Diagnosis and Treatment of Rheumatoid Arthritis Based on TCM Syndromes.5 We also included 10 healthy participants. The general situation of these groups is shown in Table 1. Next, 10 mL peripheral venous blood was extracted from each participant to isolate peripheral blood mononuclear cells; DNA and RNA were further extracted. Hydroxymethylated DNA fragments were obtained through DNA hydroxymethylation immunoprecipitation (hMeDIP), and mRNA was obtained through enzyme digestion. The Illumina highthroughput sequencing platform was used to generate the library, in addition to hMeDIP sequencing (hMeDIPseq) and mRNA sequencing (mRNAseq). Bioinformatics analysis was used to compare the changes in DNA hydroxymethylation and transcriptional expression between cold and heat syndrome genes. Remarkably altered genes at DNA hydroxymethylation were used in Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes pathway enrichment. Genes significantly altered at both the DNA hydroxymethylation and transcription expression levels were identified as epigenetic biomarkers of cold and heat syndromes of RA and the correlation was preliminarily analyzed. Results demonstrated that genomes with significant hydroxymethylation alteration tended to have a higher hydroxymethylation level (Figure S1A). Among 754 differential genes screened, 737 genes showed upregulation (logFC ≥ 1, P < 10−4), involved in 32 pathways including the Wnt signaling pathway, T helper type 17 cell differentiation pathway, and neuroactive ligandreceptor interaction (Figure S1B). The expression of 17 genes was downregulated (logFC ≤ −1, P < 10−4) and related to African trypanosomiasis, Malaria, and Axonal guidance pathways (Figure S1C). There were 125 genes with significant hydroxymethylated changes from patients with heat syndrome (Figure S1D). Among which, 64 genes indicated upregulated expression (logFC ≥ 1, P < 10−4) and enriched Arginine and proline metabolism (Figure S1E). The remaining 61 genes with

Epigenetic biomarkers of cold and heat syndromes of rheumatoid arthritis: Combining DNA hydroxymethylation and mRNA‐sequencing

As an intermediate state between normal aging and dementia, mild cognitive impairment (MCI), especially amnestic MCI (aMCI), is a key stage in the prevention and intervention of Alzheimer’s disease (AD). Whether dancing could increase the hippocampal volume of seniors with aMCI remains debatable. The aim of this study was to investigate the influence of aerobic dance on hippocampal volume and cognition after 3 months of aerobic dance in older adults with aMCI. In this randomized controlled trial, 68 elderly people with aMCI were randomized to either the aerobic dance group or the control group using a 1:1 allocation ratio. Ultimately, 62 of 68 participants completed this study, and the MRI data of 54 participants were included. A specially designed aerobic dance routine was performed by the dance group three times per week for 3 months, and all participants received monthly healthcare education after inclusion. MRI with a 3.0T MRI scanner and cognitive assessments were performed before and after intervention. High-resolution three-dimensional (3D) T1-weighted anatomical images were acquired for the analysis of hippocampal volume. A total of 35 participants (mean age: 71.51 ± 6.62 years) were randomized into the aerobic dance group and 33 participants (mean age: 69.82 ± 7.74 years) into the control group. A multiple linear regression model was used to detect the association between intervention and the difference of hippocampal volumes as well as the change of cognitive scores at baseline and after 3 months. The intervention group showed greater right hippocampal volume (β [95% CI]: 0.379 [0.117, 0.488], p = 0.002) and total hippocampal volume (β [95% CI]: 0.344 [0.082, 0.446], p = 0.005) compared to the control group. No significant association of age or gender was found with unilateral or global hippocampal volume. There was a correlation between episodic memory and intervention, as the intervention group showed a higher Wechsler Memory Scale-Revised Logical Memory (WMS-RLM) score (β [95% CI]: 0.326 [1.005, 6.773], p = 0.009). Furthermore, an increase in age may cause a decrease in the Mini-Mental State Examination (MMSE) score (β [95% CI]: −0.366 [−0.151, −0.034], p = 0.002). In conclusion, 3 months of aerobic dance could increase the right and total hippocampal volumes and improve episodic memory in elderly persons with aMCI. Clinical Trial Registration: This study was registered on the Chinese Clinical Trial Registry [www.chictr.org.cn], identifier [ChiCTR-INR-15007420].

Effect of 3-Month Aerobic Dance on Hippocampal Volume and Cognition in Elderly People With Amnestic Mild Cognitive Impairment: A Randomized Controlled Trial

Effects of Comprehensive Swallowing Intervention on Obstructive Sleep Apnea and Dysphagia After Stroke: A Randomized Controlled Trial.

Intensified reactive extraction of 4-hydroxypyridine with di(2-ethylhexyl) phosphoric acid in 1-octanol by using tributyl phosphate

Hyaluronan-Based Theranostic Nanomicelles for Breast Cancer-Targeting and Anticancer Drug Delivery

Exosomal circZNF451 restrains anti-PD1 treatment in lung adenocarcinoma via polarizing macrophages by complexing with TRIM56 and FXR1

Photophysical properties and sensing mechanism of fluorescent coumarin–chalcone hybrid for biothiols: A theoretical study

CDK16 promotes the progression and metastasis of triple-negative breast cancer by phosphorylating PRC1

Sleep problems have become one of the most serious health problems facing college students all over the world. This paper is to describe and investigate the phenomenon of sleep disturbances among Chinese college students in Wenzhou Kean University (WKU). This research adopted the descriptive-correlational design, made use of the method of cross-sectional study. Administering the researcher-developed Sleep Disturbances Survey questionnaire to 275 students (131 male and 144 female) in WKU, the sampling technique being used is random sampling method. The data collection will base on the participants’ answers to the questionnaire. Their answers will be truthfully recorded and used for further analysis, discussion and research. The study found that WKU students generally have insufficient sleep duration and sleep deprivation, and more than half of them suffer from sleep disturbances, in which long-term or short-term insomnia accounts for a large proportion. The gender difference of sleep disturbances among students is not significant. In addition, the study found that ways to improve sleep quality vary from person to person, but drinking milk, exercising and listening to music are widely used.

Survey of Sleep Disturbances among Wenzhou-Kean University (WKU) Students

Thyroid eye disease (TED) is the most common orbital disease in adults. Targeting expanded orbital adipose tissue (OAT) removed by surgery has therapeutic potential. However, drugs targeting OAT are unavailable because of the lack of deciphering features of OAT. Here, we aimed to investigate the mechanism underlying OAT expansion and identify a drug targeting OAT in TED. We found an increasing number of adipocytes with smaller size in TED-derived OATs as compared with controls, indicating that hyperplasia rather than hypertrophy contributed to OAT enlargement in TED. Typically smaller-sized adipocytes in TED patient-derived OATs were noted to localize surrounding vessels. RNA sequencing revealed enriched vascular endothelial growth factor receptor (VEGFR) genes in adipocytes differentiated from preadipocytes of TED-derived stromal vascular fraction (SVF). Similarly, OATs in patients with TED also expressed a higher level of VEGFR-1 and -2. We induced adipogenesis in TED-derived SVF with or without Lenvatinib, an FDA-approved small-molecule VEGFR inhibitor. Lenvatinib significantly suppressed lipid accumulation in a dose-dependent manner. In conclusion, our study revealed the potential anti-adipogenic effect of Lenvatinib on the OAT of TED-affected patients. In addition to proposing a drug for TED treatment, this study shows the therapeutic potential of anti-adipogenesis drugs targeting the VEGF pathway.

Repurposing Lenvatinib as A Potential Therapeutic Agent against Thyroid Eye Disease by Suppressing Adipogenesis in Orbital Adipose Tissues

Generally, a high quality surface-enhanced Raman spectroscopy (SERS) substrate often requires a highly-tailorable electromagnetic (EM) field generated at nanoparticle (NP) surfaces by the regulation of the morphologies, components and roughness of NPs. However, most recent universal approaches are restricted to single components, and integrating these key factors into one system to achieve the theoretically maximum signal amplification is still challenging. Herein, we design a triple SERS signal amplification platform by the coordination of spiky Au NPs with rich-tip nanostructures, controllable silver nanoshell, as well as tailorable surface roughness into one nano-system. As a result, the theoretical electromagnetic field of the interfacial self-assembled 2D substrate can be improved by nearly 5 orders of magnitude, and the ideal tracing capability for the model SERS molecule can be achieved at levels of 5 × 10-11 M. Finally, diverse analytes in pesticide residues, environmental pollutants as well as medically diagnose down to 10-11 M and can be fingerprinted by the proposed SERS nano-platform. Our integrated triple amplification platform not only provides an effective SERS sensing strategy, but also makes it possible to simultaneously achieve high sensitivity, stability as well as universality into one plasmonic-based SERS sensing system.

Etched-spiky Au@Ag plasmonic-superstructure monolayer films for triple amplification of surface-enhanced Raman scattering signals.

Lattice vibrational characteristics and structure-property relationships of SrWO4- x wt.% LiF (x = 0.5–3.0) microwave dielectric ceramics

Co-pyrolysis of corn stalk and coal fly ash: A case study on catalytic pyrolysis behavior, bio-oil yield and its characteristics

Early‐life neglect has irreversible emotional effects on the central nervous system. In this work, we aimed to elucidate distinct functional neural changes in medial prefrontal cortex (mPFC) of model rats.

Distinct neuronal excitability alterations of medial prefrontal cortex in early‐life neglect model of rats

Marine environmental pollution, aquatic products trade and marine fishery Economy——An empirical analysis based on simultaneous equation model

Study on the Relationship Between Migration of Desensitizer and Combustion Performance of a Double-Base Propellant

In recent years, abnormal endoplasmic reticulum stress (ERS) response, as an important regulator of immunity, may play a vital role in the occurrence, development, and treatment of glioma. Weighted correlation network analysis (WGCNA) based on six glioma datasets was used to screen eight prognostic-related differentially expressed ERS-related genes (PR-DE-ERSGs) and to construct a prognostic model. BMP2 and HEY2 were identified as protective factors (HR < 1), and NUP107, DRAM1, F2R, PXDN, RNF19A, and SCG5 were identified as risk factors for glioma (HR > 1). QRT-PCR further supported significantly higher DRAM1 and lower SCG5 relative mRNA expression in gliomas. Our model has demonstrated excellent performance in predicting the prognosis of glioma patients from numerous datasets. In addition, the model shows good stability in multiple tests. Our model also shows broad clinical promise in predicting drug treatment effects. More immune cells/processes in the high-risk population with poor prognosis illustrate the importance of the tumor immunosuppressive environment in glioma. The potential role of the HEY2-based competitive endogenous RNA (ceRNA) regulatory network in glioma was validated and revealed the possible important role of glycolysis in glioma ERS. IDH1 and TP53 mutations with better prognosis were strongly associated with the risk score and PR-DE-ERSGs expression in the model. mDNAsi was also closely related to the risk score and clinical characteristics.

A Composite Bioinformatic Analysis to Explore Endoplasmic Reticulum Stress-Related Prognostic Marker and Potential Pathogenic Mechanisms in Glioma by Integrating Multiomics Data

Ling Zhang Zhejiang Provincial People's Hospital Li-mei Wu Zhejiang Provincial People's Hospital Qiong-xiao Huang Zhejiang Provincial People's Hospital Meng-xia Ji Zhejiang Provincial People's Hospital Shi-shi Li Zhejiang Provincial People's Hospital Lin Zhang Zhejiang Provincial People's Hospital Zhen Jin Zhejiang Provincial People's Hospital Yi-er Zhou Zhejiang Provincial People's Hospital Chong-yi Shu Zhejiang Provincial People's Hospital Jing Shu (  shujing@hmc.edu.cn ) Zhejiang Provincial People's Hospital Wei-hai Xu Zhejiang Provincial People's Hospital

A Retrospective Analysis on the Clinical E ciency of Dual Trigger During Vitro Fertilization and Embryo Transfer (IVF-ET) Treatment for Women with Diminished Ovarian Reserve

A novel AIRE-based fluorescent ratiometric probe with endoplasmic reticulum-targeting ability for detection of hypochlorite and bioimaging.

Thermally Responsive Electroactive Gel for Switchable Electroanalysis

The semantic segmentation technology of remote sensing image refers to labeling the semantic information of pixel-level of the image to complete the classification, namely, terrain classification. It is widely used in intelligent maps, smart cities and other aspects. With the increase of satellite image resolution and the development video communication moonlet, its application and scenes are greatly broadened. The traditional remote sensing image semantic segmentation method mainly uses statistical machine learning methods, which cannot take into account the spectral features and the context semantic relationship of pixels, and has a bottleneck in improving the accuracy of classification. In deep learning method, Using the convolutional neural networks to extract features can achieve classification results of remote sensing images with higher classification accuracy. Aiming at the problems of existing deep learning methods in multi-spectral image semantic segmentation, to make full use of the information of multi-spectral images, this paper proposes a semantic segmentation algorithm for multispectral remote sensing images based on deep learning and verified the method on open data sets.

Research on semantic segmentation algorithm of multispectral remote sensing image based on deep learning

Beyond universal attack detection for continuous-variable quantum key distribution via deep learning

Rapid detection of nerve agents in environmental and biological samples using a fluorescent probe.

The measurement of cosmic-ray individual spectra provides unique information regarding the origin and propagation of astro-particles. Due to the limited acceptance of current space experiments, protons and nuclei around the “knee” region (∼ 1 PeV) can only be observed by ground based experiments. Thanks to an innovative design, the High Energy cosmic-Radiation Detection (HERD) facility will allow direct observation up to this energy region: the instrument is mainly based on a 3D segmented, isotropic and homogeneous calorimeter which properly measures the energy of particles coming from each direction and it will be made of about 7500 LYSO cubic crystals. The read-out of the scintillation light is done with two independent systems: the first one based on wave-length shifting fibers coupled to Intensified scientific CMOS cameras, the second one is made of two photo-diodes with different active areas connected to a custom front-end electronics. This photo-diode system is designed to achieve a huge dynamic range, larger than 107, while having a small power consumption, few mW per channel. Thanks to a good signal-to-noise ratio, the capability of a proper calibration, by using signals of both non-interacting and showering particles, is also guaranteed. In this paper, the current design and the performance obtained by several tests of the photo-diode read-out system are discussed.

Development of the photo-diode subsystem for the HERD calorimeter double-readout

Development of an intelligent heterojunction fenton catalyst for chemodynamic/starvation synergistic cancer therapy

Seasonality of hospitalization for schizophrenia and mood disorders: A single-center cross-sectional study in China.

In order to solve the problem of undershoot and non-monotonicity in the envelope fitting applied to frequency spectrum analysis, this paper proposed an improved envelope fitting algorithm based on linear interpolation. The improved algorithm performs envelope fitting on the non-stationary region of the original signal by combining the method of finding extreme values and linear interpolation, and rejects the non-monotonic extreme points to ensure the monotonicity of the envelope. For the stationary signal regions, the envelope can tightly wrap the original signal and retain the characteristics of the original signal. The simulation results shows that the method proposed in this paper can effectively fit the envelope of the original signal without undershoot regions.

2022 IEEE MTT-S International Microwave Workshop Series on Advanced Materials and Processes for RF and THz Applications (IMWS-AMP)

An Improved Envelope Fitting Algorithm for Frequency Spectrum Analysis

A2AR Regulate Apoptosis and Inflammation Through PKA/ NF-κB Signaling Pathways in Intervertebral Disc Degeneration

Human induced pluripotent stem cell (hiPSC)-derived cardiomyocyte modelling of cardiovascular diseases for natural compound discovery.

2022 International Applied Computational Electromagnetics Society Symposium (ACES-China)

Effect of esophageal muscle fibrosis on prognosis of per-oral endoscopic myotomy (POEM) in achalasia patients

Pathogen Analysis of Superficial Mucocutaneous Mycosis in a Tertiary A-level Hospital from 2007 to 2018

DNA hydroxylation catalyzed by Tet dioxygenases occurs abundantly in neurons in mammals. However, effects of ten-eleven translocation methylcytosine dioxygenase 1 (TET1) expression and hydroxymethylation status on neuron injury remain unclear. This study was designed to explore the effects of TET1 and TET2 expression in the inflammatory pain of rats induced by complete Freund’s adjuvant (CFA). Mechanical paw withdrawal threshold (PWT) and thermal withdrawal latency (TWL) were detected to assess pain behavior. The expression of TET1 and TET2 were measured in the dorsal root ganglion (DRG) with western blotting analysis. Immunofluorescence staining is employed to detect the expression and co-location of TRPV1 with TET1. Intrathecal administration of Bobcat339 was used to inhibit TET1 function in dorsal root ganglion. The paw withdrawal threshold and thermal withdrawal latency of rats were significantly reduced after CFA Injection. Western blot results showed that the expression of TET1 was significantly increased at 3 days after CFA injection, but TET2 had no statistical difference. Immunofluorescence results showed that TET1 was co-localized with TRPV1. Intrathecal administration of Bobcat339 improved mechanical and thermal pain threshold in CFA rats. Our findings highlight the role of TET1 in chronic inflammatory pain model. The expression of TET1 was increased in CFA rats, and suppression of TET1 will ameliorate inflammatory pain.

Increased ten-eleven translocation methylcytosine dioxygenase one in dorsal root ganglion contributes to inflammatory pain in CFA rats

Significant Improvement in the Flame Retardancy and Thermal Conductivity of the Epoxy Resin via Constructing a Branched Flame Retardant Based on SI-ATRP Initiated by Dopamine-Modified Boron Nitride

Sepsis-induced acute lung injury (ALI) is mostly attributed to an outbreak of reactive oxygen species (ROS), which makes leukocytes infiltrate into the lung and results in lung hypoxia. Nitroreductase (NTR) is significantly upregulated under hypoxia, which is commonly regarded as a potential biomarker for assessing sepsis-induced acute lung hypoxia. Increasing evidence shows that NTR in the Golgi apparatus could be induced in sepsis-induced ALI. Meanwhile, the prolyl hydroxylase (PHD) inhibitor (dimethyloxalylglycine, DMOG) attenuated sepsis-induced ALI through further increasing the level of Golgi NTR by improving hypoxia inducible factor-1α (HIF-1α) activity, but as yet, no Golgi-targetable probe has been developed for monitoring and assessing treatment response of sepsis-induced ALI. Herein, we report a Golgi-targetable probe, Gol-NTR, for monitoring and assessing treatment response of sepsis-induced ALI through mapping the generation of NTR. The probe displayed high sensitivity with a low detection limit of 54.8 ng/mL and good selectivity to NTR. In addition, due to the excellent characteristics of Golgi-targetable, Gol-NTR was successfully applied in mapping the change of Golgi NTR in cells and zebrafish caused by various stimuli. Most importantly, the production of Golgi NTR in the sepsis-induced ALI and the PHD inhibitor (DMOG) against sepsis-induced ALI were visualized and precisely assessed for the first time with the assistance of Gol-NTR. The results demonstrated the practicability of Gol-NTR for the precise monitoring and assessing of the personalized treatment response of sepsis-induced ALI.

Precise Monitoring and Assessing Treatment Response of Sepsis-Induced Acute Lung Hypoxia with a Nitroreductase-Activated Golgi-Targetable Fluorescent Probe.

Progress in mesenchymal stem cell mitochondria transfer for the repair of tissue injury and treatment of disease.

Microstructure Evolution and Properties of High-Strength and High-Conductivity Cu-(1~6wt.%) Ag Alloy

Most Surface-enhanced Raman scattering (SERS) substrates enhance all the Raman signals in a relative broad spectral range. The substrates enhance both the interested and background signals together. To improve the identification of target molecules from numerous background ones, substrates with multi high-quality (Q) factor resonance wavelengths can be designed to achieve the selective enhancement of specific Raman transitions. When the resonance frequencies are modulated to match the excitation and Raman scattering frequencies, the detection of the target molecule can be more effective. In this paper, we design a tunable high-Q SERS substrate with periodic silver bowtie nanoholes on silica spacer and silver film. The substrate possessed three high-Q and high electric field resonance modes, which resulted from the interaction of the localized surface plasmon resonance (LSPR) of the bowtie nanoholes, the surface plasmon polariton (SPP) of the period bowtie nanoholes and the Fabry–Perot (FP) resonance between the bowtie and silver film bottom. The interaction between these resonance modes resulted in not only a higher quality (Q) factor, but also a higher electric field, which can be employed to realize a potential substrate in high-sensitivity and selective-detection fields.

Tunable High-Q Factor Substrate for Selectively Enhanced Raman Scattering

In recent years, droplet-based triboelectric nanogenerator (TENG) have triggered intense research interests as self-powered devices for the capability to harvest energy of water droplets efficiently. To make the droplet-based TENGs...

An integrally underwater self-healable droplet-based triboelectric nanogenerator.

Vanadium(V)-substituted cerium niobate [Ce(Nb1-xVx)O4, CNVx] ceramics were prepared to explore their structure-microwave (MW) property relations and application in C-band dielectric resonator antennas (DRAs). X-ray diffraction and Raman spectroscopy revealed that CNVx (0.0 ≤ x ≤ 0.4) ceramics exhibited a ferroelastic phase transition at a critical content of V (xc = 0.3) from a monoclinic fergusonite structure to a tetragonal scheelite structure (TF-S), which decreased in temperature as a function of x according to thermal expansion analysis. Optimum microwave dielectric performance was obtained for CNV0.3 with permittivity (εr) of ∼16.81, microwave quality factor (Qf) of ∼41 300 GHz (at ∼8.7 GHz), and temperature coefficient of the resonant frequency (TCF) of ∼ -3.5 ppm/°C. εr is dominated by Ce-O phonon absorption in the microwave band; Qf is mainly determined by the porosity, grain size, and proximity of TF-S; and TCF is controlled by the structural distortions associated with TF-S. Terahertz (THz) (0.20-2.00 THz, εr ∼ 12.52 ± 0.70, and tan δ ∼ 0.39 ± 0.17) and infrared measurements are consistent, demonstrating that CNVx (0.0 ≤ x ≤ 0.4) ceramics are effective in the sub-millimeter as well as MW regime. A cylindrical DRA prototype antenna fabricated from CNV0.3 resonated at 7.02 GHz (|S11| = -28.8 dB), matching simulations, with >90% radiation efficiency and 3.34-5.93 dB gain.

Design and Fabrication of a C-Band Dielectric Resonator Antenna with Novel Temperature-Stable Ce(Nb1-xVx)NbO4 (x = 0-0.4) Microwave Ceramics.

EDTA–Fe2+ Complex-Functionalized Fe3O4 Nanozyme as Tyrosine Hydroxylase Mimics for the Production of l-DOPA

A DAC-CLGD-Danet network based method for defaced image segmentation

An image analysis-based Reflection Coefficient (RC) estimation method of femtosecond laser surface processing for the blackening of X-ray imaging sensor shell is proposed. The Support Vector Regression (SVR) is used for RC computation and both an offline and an online steps are considered in this method. Regarding offline step, the typical laser process parameters are set to perform surface processing and Scanning Electron Microscope (SEM) images are recorded. Then a series of image features are computed and both the computed image features and typical laser parameters are used to train SVR: the training dataset includes the laser line space, laser beam diameter, natural logarithm of laser power divided by laser frequency, and image features of Gray-Level Co-occurrence Matrix (GLCM); the supervising data are laser ablation diameters. As for online step, when SEM image data are recorded after laser processing, the trained SVR is used to predict laser ablation diameter and then the RC can be computed by laser ablation model. Many experiment results have verified the effectiveness of our proposed method, and the RC estimation accuracy can be better than 90.0%.

Reflection Coefficient Estimation of Femtosecond Laser Surface Processing Using Support Vector Regression

The Simple and Efficient Photoreduction Removal of High-Toxic Cr(Vi) by the Easily-Obtained Expanded Graphite Synergized with Environment-Friendly Oxalic Acid

Effects of LiF additive on crystal structures, lattice vibrational characteristics and dielectric properties of CaWO4 microwave dielectric ceramics for LTCC applications

Promoting knowledge transfer and developing students' complex problem-solving skills are important goals in today's education. The use of immersive virtual reality in teaching and learning has shown great potential to achieve this goal. This study used a quasi-experimental research method, with a video group as the control group, to investigate the effect of the immersive virtual reality learning environment on learners' conceptual and procedural knowledge transfer. The results found that learners in the immersive virtual reality learning environment scored significantly higher than those in the video group on the conceptual knowledge transfer and procedural knowledge transfer test. These results suggest that immersive virtual reality is more advantageous than video learning in facilitating knowledge transfer.

2022 Eleventh International Conference of Educational Innovation through Technology (EITT)

Investigating the Effect of Immersive VR on Conceptual Knowledge and Procedural Knowledge Transfer

3d Simulation of Positive Corona Effect On the Upward Leader Initiation of Tall Building

Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment

Dual U-Net based feature map algorithm for automatic projection alignment of synchrotron nano-CT

Populus euphratica is mainly distributed in desert environments with dry and hot climate in summer and cold in winter. Compared with other poplars, P. euphratica is more resistant to salt stress. It is critical to investigate the transcriptome and molecular basis of salt tolerance in order to uncover stress-related genes. In this study, salt-tolerant treatment of P. euphratica resulted in an increase in osmo-regulatory substances and recovery of antioxidant enzymes. To improve the mining efficiency of candidate genes, the analysis combining both the transcriptome WGCNA and the former GWAS results was selected, and a range of key regulatory factors with salt resistance were found. The PeERF1 gene was highly connected in the turquoise modules with significant differences in salt stress traits, and the expression levels were significantly different in each treatment. For further functional verification of PeERF1, we obtained stable overexpression and dominant suppression transgenic lines by transforming into Populus alba × Populus glandulosa. The growth and physiological characteristics of the PeERF1 overexpressed plants were better than that of the wild type under salt stress. Transcriptome analysis of leaves of transgenic lines and WT revealed that highly enriched GO terms in DEGs were associated with stress responses, including abiotic stimuli responses, chemical responses, and oxidative stress responses. The result is helpful for in-depth analysis of the salt tolerance mechanism of poplar. This work provides important genes for poplar breeding with salt tolerance.

Transcriptome Analysis of Populus euphratica under Salt Treatment and PeERF1 Gene Enhances Salt Tolerance in Transgenic Populus alba × Populus glandulosa

Research on the impact of green finance and abundance of natural resources on China's regional eco-efficiency

The role of TELO2‐interacting protein 1 (TTI1) in the progression of several types of cancer has been reported recently. The aim of this study was to estimate the expression and potential value of TTI1 in non‐small‐cell lung cancer (NSCLC) patients. The expression of TTI1 and its prognostic value in NSCLC from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database were analyzed. To verify the bioinformatics findings, a tissue microarray containing 160 NSCLC and paired peritumoral tissues from NSCLC patients was analyzed by immunohistochemistry for TTI1. Subsequently, the roles of TTI1 in NSCLC cells were investigated in vivo by establishing xenograft models in nude mice and in vitro by transwell, CCK‐8, wound healing, and colony formation assays. In addition, quantitative real‐time polymerase chain reaction and western blot were applied to explore the underlying mechanism by which TTI1 promotes tumor progression. Finally, the relationship between TTI1 and Ki67 expression level in NSCLC was probed, and Kaplan–Meier and Cox analyses were performed to assess the prognostic merit of TTI1 and Ki67 in NSCLC patients. We found that the expression of TTI1 was significantly upregulated in NSCLC tissues compared to paired peritumoral tissues, which coincides with the bioinformatics findings from the TCGA and GEO databases. TTI1 was highly expressed in NSCLC patients with large tumors, advanced tumor stage, and lymphatic metastasis. In addition, the prognostic analysis identified TTI1 as an independent indication for poor prognosis of NSCLC patients. In vitro, upregulation of TTI1 in NSCLC cells could facilitate cell invasion, metastasis, viability, and proliferation. Mechanistically, our study verified that TTI1 could regulate mTOR activity, which has a pivotal role in human cancer. Consistently, the expressions of TTI1 and Ki67 had a positive relationship in NSCLC cells and tissues. Notably, patients with overexpression of TTI1 or Ki67 had a shorter overall survival rate and a higher disease‐free survival rate compared to patients with low expression of TTI1 or Ki67, and the combination of TTI1 and Ki67 was an independent parameter predicting the prognosis and recurrence of NSCLC patients. We conclude that TTI1 promotes NSCLC cell proliferation, metastasis, and invasion by regulating mTOR activity, and the combination of TTI1 and Ki67 is a valuable molecular biomarker for the survival and recurrence of NSCLC patients.

TTI1 promotes non‐small‐cell lung cancer progression by regulating the mTOR signaling pathway

The extreme weather conditions in Northwest China, especially in Xinjiang, are relatively complex and easily have an adverse impact on power grid safety, especially on high-voltage transmission lines, among which the impact of icing is the most prominent. This study analyzed the five forms of wire icing: rime, wet snow, mixed icing and frost. It was concluded that the main types of wire icing in Xinjiang were rime, and the extreme value appears to be highest in March. Variation characteristics of wire icing: the maximum thickness of wire icing in Xinjiang was generally between 21–66 mm, mostly between 30–45 mm. The distribution characteristics of rime and snow songs in Xinjiang were that the mountain area was more than the plain, and the wet area was more than the dry area. According to the extreme value I-type distribution, the recurrence level of the maximum icing thickness at 30 years, 50 years and 100 years was estimated, the ice area was divided, and the data were corrected by altitude, line diameter, special terrain and other parameters.

Efficient CO2/CO separation through channel confinements in an amino-coordinated metal-organic framework

A novel indene-chalcone-based fluorescence probe with lysosome-targeting for detection of endogenous carboxylesterases and bioimaging.

Primary coenzyme Q10 deficiency-6 (COQ10D6), as a rare autosomal recessive disease caused by COQ6 mutations, is characterized by progressive infantile-onset nephrotic syndrome resulting in end-stage renal failure and sensorineural hearing loss. Here, we report two Chinese siblings with COQ10D6 who primarily presented with severe metabolic acidosis, proteinuria, hypoalbuminemia, growth retardation, and muscle hypotonia and died in early infancy. Using whole-exome sequencing and Sanger sequencing, we identified two rare recessive nonsense mutations in the COQ6 gene segregating with disease in affected family members: c.249C > G (p.Tyr83Ter) and c.1381C > T (p.Gln461Ter), resulting in two truncated protein products. Both mutations are located in a highly conserved area and are predicted to be pathogenic. Indeed, the death of our patients in early infancy indicates the pathogenicity of the p.Tyr83Ter and p.Gln461Ter variants and highlights the significance of the two variants for COQ6 enzyme function, which is necessary for the biosynthesis of coenzyme Q10. In conclusion, we discovered a novel compound heterozygous pathogenic variant of the COQ6 gene as a cause of severe COQ10D6 in the two siblings. Based on the clinical history and genetic characteristics of the patients, our cases expand the genotypic spectrum of COQ10D6 and highlight the heterogeneity and severity of clinical features associated with COQ6 mutations. For patients with clinical manifestations suggestive of COQ10D6, early testing for COQ6 mutations is beneficial for disease diagnosis and therapeutic interventions as well as disease prevention in future generations.

A Family Segregating Lethal Primary Coenzyme Q10 Deficiency Due to Two Novel COQ6 Variants

Monophenolase assay using excitation-emission matrix fluorescence and ELMAN neural network assisted by whale optimization algorithm.

Five-parameter grain boundary character distribution of gold nanoparticles based on three dimensional orientation mapping in the TEM

The intrinsic sluggish kinetics of the oxygen evolution reaction (OER) limit the improvement of hydrogen evolution reaction (HER) performance, and substituting the anodic oxidation of biomass materials is an alternative approach, given its lower oxidation potential and higher added value compared to those of OER. In this study, a Ni3 S2 -MoS2 nanoheterojunction catalyst with strong electronic interactions is prepared. It exhibits high efficiency for both the HER and the electrooxidation of 5-hydroxymethylfurfural (HMF). In a two-electrode cell with Ni3 S2 -MoS2 serving as both the anode and cathode, the potential is only 1.44 V at a current density of 10 mA cm-2 , which is much lower than that of pure water splitting. Density functional theory calculations confirm that the strong chemisorption of H and HMF at the interface leads to outstanding electrocatalytic activity. The findings not only provide a strategy for developing efficient electrocatalysts, but also provide an approach for the continuous production of high value-added products and H2 .

Construction of Synergistic Ni3 S2 -MoS2 Nanoheterojunctions on Ni Foam as Bifunctional Electrocatalyst for Hydrogen Evolution Integrated with Biomass Valorization.

Tunable Selectivity on Copper–Bismuth Bimetallic Aerogels for Electrochemical Co2 Reduction

Outstanding Reviewers for International Journal of Geotechnical Engineering 2021

Fine identification of the supply–demand mismatches and matches of urban green space ecosystem services with a spatial filtering tool

A method of band selection of remote sensing image based on clustering and intra-class index

Objective: This study aims to evaluate the effectiveness of health education in diabetes. 
Methods: This study investigated 40 diabetic patients treated in a tertiary A hospital from February 2022 to May 2022 through convenient nearby sampling. Eligible patients were evaluated by the general basic information questionnaire, diabetes self-behavior management scale through the number of lectures. 
Results: Through the questionnaire survey, it was found that the average self-behavior management score of patients who have been in diabetes care group was 63.3, which was much higher than the 41.3 points for patients without group education. And patients participating in diabetes group education scored higher than those who did not participate in group education in terms of diet, exercise, and foot care. 
Conclusion: Group education can improve the self-behavior management ability of diabetic patients.

Active Zn species in Cu-based methanol synthesis catalysts have not been clearly identified yet due to their complex nature and dynamic structural changes during reactions. Herein, atomically dispersed Zn on ZrO2 support is established in Cu-based catalysts by separating Zn and Zr components from Cu (Cu-ZnZr) via the double-nozzle flame spray pyrolysis (DFSP) method. It exhibits superiority in methanol selectivity and yield compared to those with Cu-ZnO interface and isolated ZnO nanoparticles. Operando X-ray absorption spectroscopy (XAS) reveals that the atomically dispersed Zn species are induced during the reaction due to the strengthened Zn-Zr interaction. They can suppress formate decomposition to CO and decrease the H2 dissociation energy, shifting the reaction to methanol production. This work enlightens the rational design of unique Zn species by regulating coordination environments and offers a new perspective for exploring complex interactions in multi-component catalysts.

Probing the Nature of Zinc in Copper-Zinc-Zirconium Catalysts by Operando Spectroscopies for CO2 Hydrogenation to Methanol.

Evolution of the Microstructure and Mechanisms of Performance Degradation in Eb-Pvd Ysz Thermal Barrier Coatings Corroded by Volcanic Ash at 1150°C

Focusing on the issue that the accuracy of object detection is reduced when the foreground target moves slowly and there is interference in the background, a moving object detection method based on weighted kernel norm and saliency constraint RPCA is proposed. In the new method, the weighted kernel norm is used to restore a relatively clean background, which is helpful to separate the slow moving target from the background. The l 1 norm is used to constrain the sparsity of moving objects, and the Frobenius norm is used to detect noise, and a saliency constraint is introduced to detect slow-moving objects. Experiments show that this method can effectively deal with the problems of slow foreground motion and background interference. Compared with the suboptimal algorithm, the average measured value F of the proposed algorithm is improved by 15%.

Moving Object Detection Based on Weighted Kernel Norm and Saliency Constrained RPCA

Objectives Real-world clinical outcome data of patients with an above-normal estimated glomerular filtration rate (eGFR) and increasing eGFR over time (eGFR slope) are scarce. Although eGFR is commonly recorded, eGFR slopes are rarely used for adverse outcome risk categorisation in clinical practice. We investigated the association of above-normal/below-normal eGFR ranges and increasing/declining eGFR slopes with clinical outcomes in Japan. Design Observational cohort study. Setting Primary and acute care hospitals; 423 centres. Participants 57 452 patients aged ≥16 years with ≥3 eGFR values (latest available January 2013–December 2016) from the Japanese Medical Data Vision database were stratified into six index eGFR and six eGFR slope groups (slopes calculated using a linear mixed model). Primary and secondary outcome measures Time-to-event analyses of cardiovascular mortality, all-cause mortality (ACM), all-cause hospitalisation (ACH) and cardiovascular and major kidney events. eGFR and slope groups were analysed by Cox proportional hazard models with multivariable adjustment, using normal eGFR/little-to-no slope groups as reference. Results Higher risk of clinical outcomes was observed with declining eGFR slope groups versus the reference group; the HR (95% CI) for slope ≤−5 mL/min/1.73 m2/year: cardiovascular events 1.8 (1.4 to 2.2), ACH 1.8 (1.5 to 2.1), and ACM 2.8 (1.9 to 4.2) and was non-significant for kidney events 1.5 (0.9 to 2.5). A similar, but non-significant, pattern was observed with increasing slope groups (slope >3 mL/min/1.73 m2/year HR (95% CI): cardiovascular events 1.2 (0.9 to 1.5), ACH 1.1 (0.9 to 1.4) and ACM 1.5 (0.9 to 2.3)). Above-normal and below-normal eGFR groups were associated with poorer outcomes versus the reference group, but kidney events were associated with below-normal eGFR only. Conclusion Poorer clinical outcomes were observed not only for below-normal eGFR and declining eGFR slope groups but also for certain above-normal eGFR and increasing slope groups. eGFR and eGFR slope may, therefore, be useful for identifying patients at high risk of adverse clinical outcomes.

Analysis of eGFR index category and annual eGFR slope association with adverse clinical outcomes using real-world Japanese data: a retrospective database study

Study on the multitime scale rolling optimization operation of a near-zero energy building energy supply system

Enhanced Cd adsorption by red mud modified bean-worm skin biochars in weakly alkali environment

Hemodialysis is an important means to maintain life in patients with end-stage renal disease (ESRD). Approximately 76.8% of patients who begin hemodialysis do so through catheters, which play vital roles in the delivery of hemodialysis to patients. During the past decade, the materials, structures, and surface-coating technologies of catheters have constantly been evolving to ameliorate catheter-related problems, such as recirculation, thrombosis, catheter-related infections, and malfunction. In this study, based on the commercial GDK catheter, six catheter models (GDK, GDK1, GDK2, GDK3, GDK4, and GDK5) with different lumen diameters and different geometric features of side holes were established, and computational flow dynamics (CFD) were used to measure flow rate, shear stress, residence time (RT), and platelet lysis index (PLI). These six catheters were then printed with polycarbonate PC using 3D printing technology to verify recirculation rates. The results indicated that: (1) the catheter with a 5.5 mm outer diameter had the smallest average shear stress in the arterial lumen and the smallest proportion of areas with shear stress > 10 pa. With increasing catheter diameter, the shear stress in the tip volume became lower, the average RT increased, and the PLI decreased due to larger changes in shear stress; (2) the catheters with oval-shaped side holes had smaller shear stress levels than those with circular-shaped holes, indicating that the oval design was more effective; (3) the catheter with parallel dual side holes had uniformly distributed flow around side holes and exhibited lower recirculation rates in both forward and reverse connections, while linear multi-side holes had higher shear stress levels due to the large differences in flow around side holes. The selection of the material and the optimization of the side holes of catheters have significant impacts on hemodynamic performances and reduce the probability of thrombosis, thus improving the efficiency of dialysis. This study would provide some guidance for optimizing catheter structures and help toward the commercialization of more efficient HD catheters.

Hemodynamic Analysis of the Geometric Features of Side Holes Based on GDK Catheter

By introducing multiple molecule/intermolecular dynamic reversible hydrogen bonds into the polydimethylsiloxane elastomer system, the solid polymeric electrolyte with high ion conductivity (2.5×10-4 Scm-1) and stable electrochemical window (> 5 V)...

Fast self-healing solid polymer electrolyte with high ionic conductivity for Lithium metal batteries

Acoustic purely imaginary metamaterials (PIMs) slabs can support the coexistence of coherent perfect absorption and laser modes and are used to achieve negative refraction. Previous works have focused on a pair of different PIM slabs, one operating in CPA mode and the other in laser mode. However, this structure has restrictions on the incident wave direction, specifically the wave can only be incident from the CPA side. In this paper, we derive the analytical expressions for the parameters required for the coexistence of CPA and laser modes in acoustic PIM slabs. Numerical simulation results show that such PIM slab can freely switch states between the coherent complete absorber and the laser depending on the incidence direction. On this basis, by using a pair of identical PIM slabs, bidirectional negative refraction and planar focusing can be achieved. In addition, the parameters in the appropriate range can be found by adjusting the mode order, which facilitates the experimental verification. So far, the required acoustic purely imaginary metamaterials (PIMs) have not been experimentally demonstrated, and the results presented in the manuscript are theoretical speculations on their existence, so practical applications may require more sophisticated design and engineering.

Bidirectional Acoustic Negative Refraction Based on a Pair of Identical Purely Imaginary Metamaterials Slabs

Quantum network is one of the important development directions of network in the future. Consideration should be given to the unique physical properties of quantum. In quantum networks with relatively limited resources (such as quantum memory), decoherence will lead to qubits loss, which restricts the time that data qubits can be stored in memory before use. Therefore, transmitting data qubits as soon as possible is very important to realize the network function. In order to ensure timeliness, this paper proposes a multipath concurrent entanglement routing scheme based on virtual circuit in quantum networks. Compared with the single path method, this scheme has obvious advantages in reducing the time required to establish the quantum entanglement channel and to transmit the measurement outcomes.

2022 4th International Conference on Advances in Computer Technology, Information Science and Communications (CTISC)

Multipath concurrent entanglement routing in quantum networks based on virtual circuit

Turn Wastes into Valuables: Supuramolecular-Interaction Enabled Preparation of Super-Strong Water-Based Adhesives from Polymethylmethacrylate Wastes

A deep asymmetric Laplace neural network for deterministic and probabilistic wind power forecasting

In this study, the authors developed a three-dimensional (3D) numerical model for the diffusion of positive corona charges based on a 2D model with a uniform grid to explore the characteristics of corona discharge at a building tip during a thunderstorm in the presence of wind. The variable-grid meshing method is used to solve the problems of implementing a large simulation domain for thunder clouds (kilometer-scale) and the minute calculations of corona discharge at the tip (centimeter scale) in the 3D numerical simulation. The proposed model has advantages in terms of the acquisition of the parameters of corona charges and the spatial distribution of the electric field (E-field) in the environment. We used positive corona discharge at the tip of a building under a negative thunderstorm, along with three wind fields (horizontal wind, updraft, and downdraft with wind speeds of 10 m/s) as an example. The presence of the wind increased the density of corona charges at the tip, where the horizontal wind was the most beneficial for its occurrence. Moreover, the characteristics of distortion of the electric field around the tip were significantly different, owing to the different directions of the wind. Downdraft led to the maximum enhancement in the E-field above the tip, and updraft prompted the minimum increase in it, by only 1.19 times. However, the opposite results were obtained for the enhancement in the spatial range of the charges: The updraft led to the greatest increase in it, and the downdraft caused the smallest. Corona charges had an apparent shielding effect on the E-field below the tip and can even change the polarity of the E-field in a small area close to it. The strongest shielding effect on the ground E-field occurred in the case of the downdraft, which decreased the E-field to 0.36 times compared with that without the corona charges. On the contrary, corona discharge had the weakest shielding ability on the ground when it met the updraft. The horizontal wind had the largest range of shielding on the ground, of up to 14,699.36 m2, while the updraft had the lowest, at only 6,170.91 m2.

3D Corona Discharge Model and Its Use in the Presence of Wind During a Thunderstorm

The switching overvoltage due to the operation of the switching device is considered to be one of the important research contents during the design phase of a high-power supply system based on thyristor rectifier topology in the comprehensive research facility for fusion technology (CRAFT). Switching peak overvoltage is suppressed by resistors–capacitors (RC) snubber circuit generally; however, the traditional RC design often relies on some simple empirical formulas and blind amplification margins, which is unable to meet the precision requirements of engineering design. All the work that has been done is based on the cophase counter parallel connection structure of the converter module, and a new strategy is proposed to optimize the RC snubber circuit in order to suppress the operating peak overvoltage better. First, the no-load transformer breaking overvoltage is analyzed, then RC parameters are designed based on a new strategy. Compared with traditional methods, the RC parameters selected by this strategy are more accurate, which meets the accuracy requirements of engineering design and suppresses switching better than before.

The Optimization Design for Suppression of CRAFT TF Magnet Power Converter Switching Overvoltage

How does establishing a branch office affect audit quality? Evidence from China

Surface-enhanced Raman scattering (SERS) technology can amplify the Raman signal due to excited localized surface plasmon (LSP) from SERS substrates, and the properties of the substrate play a decisive role for SERS sensing. Several methods have been developed to improve the performance of the substrate by surface modification. Here, we reported a surface modification method to construct carbon-coated nanoporous gold (C@NPG) SERS substrate. With surface carbon-assistant, the SERS ability of nanoporous gold (NPG) seriously improved, and the detection limit of the dye molecule (crystal violet) can reach 10−13 M. Additionally, the existence of carbon can avoid the deformation of the adsorbed molecule caused by direct contact with the NPG. The method that was used to improve the SERS ability of the NPG can be expanded to other metal structures, which is a convenient way to approach a high-performance SERS substrate.

Carbon-Assistant Nanoporous Gold for Surface-Enhanced Raman Scattering

Power converters utilizing SiC MOSFETs have attracted significant interest from the automotive industry due to their improved efficiency and power density. In this paper, a SiC lateral-channel trench (LT) MOSFET is proposed to reduce the conduction losses compared to the state-of-the-art designs. With the help of an additional lateral trench channel, the specific on-state resistance (RDS, ON) is dramatically decreased by over 40%. Under extensive simulations, the device's blocking capability and short circuit robustness are maintained, and the device capacitance is also analyzed to verify this design.

A 650V Hybrid-Channel SiC Trench MOSFET with Improved On-State Performance

Liposomal co-delivery system encapsulating celastrol and paclitaxel displays highly enhanced efficiency and low toxicity against pancreatic cancer

Third International Conference on Electronics and Communication; Network and Computer Technology (ECNCT 2021)

Research on adaptive differential protection methods for smart distribution networks in the framework of 5G communication

Three unusual diterpenes with rare sarsolenane and capnosane skeletons, namely mililatensols A–C (1–3), were isolated from the South China Sea soft coral Sarcophyton mililatensis, leading to the first record of sarsolenane and capnosane diterpenes from the title animal. The structures of compounds 1–3 were established by extensive spectroscopic analysis and comparison with the literature data. Moreover, the absolute configuration of 2 was determined by TDDFT ECD calculations. In an in vitro bioassay, none of the isolated compounds showed obvious anti-inflammatory activity on LPS-induced TNF-α release in RAW264.7 macrophages. In the preliminary virtual screening of inhibitory potential against SARS-CoV-2 by molecular docking, the results showed these three diterpenes were potential SARS-CoV-2 Mpro inhibitors.

Mililatensols A–C, New Records of Sarsolenane and Capnosane Diterpenes from Soft Coral Sarcophyton mililatensis

Engineering of Bi2O2CO3/Ti3C2Tx heterojunctions co-embedded with surface and interface oxygen vacancies for boosted photocatalytic degradation of levofloxacin

How to reduce the radiation dose received from full-body CT scans during the follow-up of lymphoma patients is a concern.

OBJECTIVE
To investigate the image quality and radiation dose of reduced-dose full-body computerized tomography [CT] in lymphoma patients during follow-up.

METHODS
121 patients were included and divided into conventional CT group [group 1, 120-kVp, n = 61] or reduced-dose CT group [group 2, 100-kVp combined dual-energy CT [DECT], n = 60]. 140-kVp polychromatic images and 70-keV monochromatic images were reconstructed from DECT. The abdominal virtual non-enhanced [VNE] images were reconstructed from monochromatic images. Two radiologists rated the overall image quality with a five-point scale and graded the depiction of lesions using a four-point scale. The objective image quality was evaluated using image noise, signal-to-noise ratio, contrast-to-noise ratio. The radiation dose and image quality were compared between groups.

RESULTS
The comparable subjective image quality was observed between 70-keV and 120-kVp images in the neck, while 120-kVp images showed better objective image quality. 70-keV images showed better objective image quality in the chest. While the subjective image quality of abdominal VNE images was inferior to that of true non-enhanced images, the improved objective image quality was observed in VNE images. In the abdominal arterial phase, similar subjective image quality was observed between groups. Abdominal 70-keV images in the arterial phase showed improved objective image quality. Similar image quality was obtained in the abdominal venous phase between groups. The effevtive radiation dose in group 2 showed a significant reduction.

The application of reduced-dose full-body CT can significantly reduce the radiation dose for lymphoma patients during follow-up while maintaining or improving image quality.

Background: Factors such as variations in thyroid carcinoma (THCA) gene characteristics could influence the clinical outcome. Ferroptosis and immunity have been verified to play an essential role in various cancers, and could affect the cancer patients’ prognosis. However, their relationship to the progression and prognosis of many types of THCA remains unclear. Methods: First, we extracted prognosis-related immune-related genes and ferroptosis-related genes from 2 databases for co-expression analysis to obtain prognosis-related differentially expressed immune-related ferroptosis genes (PR-DE-IRFeGs), and screened BID and CDKN2A for building a prognostic model. Subsequently, multiple validation methods were used to test the model’s performance and compare its performance with other 4 external models. Then, we explored the mechanism of immunity and ferroptosis in the occurrence, development and prognosis of THCA from the perspectives of anti-tumor immunity, CDKN2A-related competitive endogenous RNA regulatory, copy number variations and high frequency gene mutation. Finally, we evaluated this model’s clinical practice value. Results: BID and CDKN2A were identified as prognostic risk and protective factors, respectively. External data and qRT-PCR experiment also validated their differential expression. The model’s excellent performance has been repeatedly verified and outperformed other models. Risk scores were significantly associated with most immune cells/functions. Risk score/2 PR-DE-IRFeGs expression was strongly associated with BRAF/NRAS/HRAS mutation. Single copy number deletion of CDKN2A is associated with upregulation of CDKN2A expression and worse prognosis. The predicted regulatory network consisting of CYTOR, hsa-miRNA-873-5p and CDKN2A was shown to significantly affect prognosis. The model and corresponding nomogram have been shown to have excellent clinical practice value. Conclusion: The model can effectively predict the THCA patients’ prognosis and guide clinical treatment. Ferroptosis and immunity may be involved in the THCA’s progression through antitumor immunity and BRAF/NRAS/HRAS mutation. CYTOR-hsa-miRNA-873-5p-CDKN2A regulatory networks and single copy number deletion of CDKN2A may also affect THCA′ progression and prognosis.

Identification of immune-related ferroptosis prognostic marker and in-depth bioinformatics exploration of multi-omics mechanisms in thyroid cancer

Synthesis of As-Cast WCu Composite Containing Micro- and Nano-Size Tungsten Particles Using Aluminothermic Reduction

Although learning-based methods have shown their potential for image shadow detection, video shadow detection is still a challenging problem. It is due to the absence of large-scale, temporally consistent annotated video shadow detection dataset. To this end, we propose a semi-supervised video shadow detection method by seeking the assistance of the existing labeled image dataset to generate pseudo-labels as the additional supervision signals. Specifically, we first introduce a novel image-assisted video pseudo-label generator with a spatio-temporally aligned network (STANet). It generates high-quality and temporally consistent pseudo-labels. Then, with these pseudo-labels, we propose an uncertainty-guided semi-supervised learning strategy to reduce the impact of noise from them. Moreover, we also design a memory propagated long-term network (MPLNet), which produces video shadow detection results with long-term consistency in a light-weight way by using the memory mechanism. Extensive experiments on ViSha and our collected real-world video shadow detection dataset RVSD show that our approach not only achieves superior performance in the benchmark dataset but also generalizes well in more practical applications, which demonstrates the effectiveness of our method.

Proceedings of the 30th ACM International Conference on Multimedia

Semi-supervised Video Shadow Detection via Image-assisted Pseudo-label Generation

Photocatalytic Conversion of CO2 to Acetic Acid by CuPt/WO3: Chloride Enhanced C-C Coupling Mechanism

Sensitive photoelectrochemical sensing of glucose using hematite decorated with NiAl-layered double hydroxides.

A Novel Fluorescence Aggregation-Induced Emission Active Chemosensor for Sequential Determination of Cu2+ and S2− in an Almost Neat Aqueous Solution

As an essential regulator of photosynthesis and hormone signaling, light
plays a critical role in leaf senescence and yield gain in crops.
Previously, numerous studies have shown that the narrow-wide-row
planting pattern, especially under intercropping systems, is more
beneficial for crops to enhance light interception, energy conversion,
and yield improvement. However, the narrow-wide-row planting pattern
inevitably leads to a heterogeneous light environment for crops (i. e.,
maize in maize-based intercropping systems) on both sides of the plant.
The mechanism by which it affects leaf senescence and yield of maize
under a narrow-wide-row planting pattern is still unclear. Therefore, in
this study, we compared the leaf senescence and yield formation process
of maize under homogeneous (normal light, NL and full shade, FS) and
heterogeneous (partial light, PL) light conditions. Results revealed
that partial light treatment influenced the homeostasis of growth and
senescence hormones by regulating the expression of ZmPHYA and ZmPIF5.
Compared to normal light and full shade treatments, partial light
delayed leaf senescence by 3.6 and 5.9 days with 2.2 and 3.3 more green
leaves and 1.1 and 1.4 fold nitrogen uptake, respectively. Partial light
reduced oxidative stress by enhancing antioxidant enzyme activities of
PS (shade side of partial light) leaves, which improved photosynthetic
assimilation, balanced sucrose, and starch ultimately maintaining the
similar maize yield to NL. Overall, these results are important for
understanding the mechanism of leaf senescence in maize, especially
under heterogeneous light environments, which maize experienced in
maize-based intercropping systems. Furthermore, these findings are
providing proof of getting a high yield of maize with less land in
intercropping systems. Thus, we can conclude that maize-based
intercropping systems can be used for obtaining high maize yields
maintained under the current climate change scenario.

Heterogeneous light delayed leaf senescence and ensure yield in maize

Simple Summary Rosai–Dorfman disease (RDD) was a benign histiocytic proliferative disorder rather than a neoplastic process. Emergent molecular studies have shown recurrent somatic gain-of-function mutations in genes of the MAPK pathway (e.g., NRAS, KRAS, MAP2K1, and ARAF) in a subset of RDD, suggesting a clonal histiocytic proliferative process. This review encompasses clinical characteristics, updated subclassification, diagnostic approaches, and treatment strategies, with an emphasis on the molecular profiles of RDD. This study includes the latest international consensus on diagnosing and managing this disease. This review will provide novel insights on the latest discoveries in RDD. Abstract Rosai–Dorfman disease (RDD) is a rare myeloproliferative disorder of histiocytes with a broad spectrum of clinical manifestations and peculiar morphologic features (accumulation of histiocytes with emperipolesis). Typically, the patient with RDD shows bilateral painless, massive cervical lymphadenopathy associated with B symptoms. Approximately 43% of patients presented with extranodal involvement. According to the 2016 revised histiocytosis classification, RDD belongs to the R group, including familial and sporadic form (classical nodal, extranodal, unclassified, or RDD associated with neoplasia or immune disease). Sporadic RDD is often self-limited. Most RDD needs only local therapies. Nevertheless, a small subpopulation of patients may be refractory to conventional therapy and die of the disease. Recent studies consider RDD a clonal neoplastic process, as approximately 1/3 of these patients harbor gene mutations involving the MAPK/ERK pathway, e.g., NRAS, KRAS, MAP2K1, and, rarely, the BRAF mutation. In addition to typical histiocytic markers (S100/fascin/CD68/CD163, etc.), recent studies show that the histiocytes in RDD also express BCL-1 and OCT2, which might be important in pathogenesis. Additionally, the heterozygous germline mutation involving the FAS gene TNFRSF6 is identified in some RDD patients with an autoimmune lymphoproliferative syndrome type Ia. SLC29A3 germline mutation is associated with familial or Faisalabad histiocytosis and H syndrome.

A superlattice composite of Zn-Fe layered double hydroxide and graphene oxide was fabricated on the titanium surface and showed lamellar morphology. It was found for the first time that this superlattice composite could inhibit cell adhesion and proliferation, and cause cell death of the cholangiocarcinoma cell line RBE cells in vitro and show tumor inhibition effect in vivo.

A superlattice composite of Zn-Fe layered double hydroxide and graphene oxide for antitumor application.

A high-performance fluorescent probe 2,5-dimercapto-1,3,4-thiadiazole copper nanoparticles (DMTD-CuNPs) was synthesized by hydrothermal method based on monovalent copper (Cu(I)) and 2,5-dimercapto-1,3,4-thiadiazole (DMTD), and it can effectively detect cysteine (Cys) in plasma. Experiments show that DMTD can reduces band gap of Cu(I) in DMTD-CuNPs, promote charge transfer transition from DMTD to Cu(I) and significantly enhance fluorescence intensity of DMTD-CuNPs at 515 nm. The large Stokes shift of DMTD-CuNPs is 315 nm, which can reduce the self-quenching of probe fluorescence and improves detection accuracy of the probe. In the presence of Cys, fluorescence of DMTD-CuNPs at 515 nm is significantly quenched because Cys reacts with Cu(I) in DMTD-CuNPs through Cu-S bond to form reduced charge transfer, which can be successfully used for the detection of Cys. Linear range and detection limit for Cys detection are 25-65 µM and 50 nM, respectively. Furthermore, feasibility of detecting Cys in plasma using DMTD-CuNPs probe was evaluated by standard addition method, and the absolute recovery is 96-99%. Such a DMTD-CuNPs probe shows high sensitivity, good selectivity and low detection limit for Cys, which is expected to be used for the practical analysis of Cys in plasma.

A high-performance fluorescent probe for detection of cysteine in plasma constructed by combining Cu(I) and 2,5-dimercapto-1,3,4-thiadiazole.

Parallel Dense Merging Network with Dilated Convolutions for Semantic Segmentation of Sports Movement Scene

International Journal of Environmental Technology and Management

Evaluation method of ecotourism carrying capacity of popular scenic spots based on set pair analysis

An efficient strategy for photocatalytic hydrogen peroxide production over oxygen-enriched graphitic carbon nitride with sodium phosphate

Numerical analysis of die filling with a forced feeder using GPU-enhanced discrete element methods.

Chemotherapy is still an important and effective clinical treatment for cancer. However, individual drugs hardly achieve precise controlled release and targeted therapy, thus resulting in unavoidable side effects. Fortunately, the emergence of drug carriers is expected to solve the above problems. In this work, the MOF-on-MOF strategy was adopted to encapsulate DOX into double-layer NH2-MIL-88B to fabricate a core-shell-structured DOX@NH2-MIL-88B-On-NH2-MIL-88B (DMM) and then realize the pH and GSH dual-responsive controlled DOX release. Because of the core-shell structure, the drug-loading capacity of DMM reached 14.4 wt %, which was nearly twice that of DOX@NH2-MIL-88B (DM), and the controlled release performance of DMM was also improved at the same time, greatly improving the kinetics equilibrium time of DOX from 2 h (DM) to 16 h (DMM) at pH 5.0. Moreover, we found that DMM also possessed peroxidase-like catalytic activity under acidic conditions, which could catalyze H2O2 to produce •OH, exhibiting the potential chemodynamical treatment of cancer. Cell experiments showed that DMM had a significant inhibitory effect against 4T1 cancer cells, and the survival rate of 4T1 cells was less than 20% at 100 ppm.

Hierarchical MOF-on-MOF Architecture for pH/GSH-Controlled Drug Delivery and Fe-Based Chemodynamic Therapy.

Acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutations exhibits distinct biological and clinical features, accounting for approximately one-third of AML. Recently, the N6-methyladenosine (m6A) RNA modification has emerged as a new epigenetic modification to contribute to tumorigenesis and development. However, there is limited knowledge on the role of m6A modifications in NPM1-mutated AML. In this study, the decreased m6A level was first detected and high expression of fat mass and obesity-associated protein (FTO) was responsible for the m6A suppression in NPM1-mutated AML. FTO upregulation was partially induced by NPM1 mutation type A (NPM1-mA) through impeding the proteasome pathway. Importantly, FTO promoted leukemic cell survival by facilitating cell cycle and inhibiting cell apoptosis. Mechanistic investigations demonstrated that FTO depended on its m6A RNA demethylase activity to activate PDGFRB/ERK signaling axis. Our findings indicate that FTO-mediated m6A demethylation plays an oncogenic role in NPM1-mutated AML and provide a new layer of epigenetic insight for future treatments of this distinctly leukemic entity.

Mutant NPM1-Regulated FTO-Mediated m6A Demethylation Promotes Leukemic Cell Survival via PDGFRB/ERK Signaling Axis

To investigate the effects of intense pulsed light (IPL) and ablative 2.940 nm erbium‐doped yttrium aluminum garnet (Er: YAG) laser on dynamic changes in collagen by quantitative analysis of type I collagen (Col I) and type III collagen (Col III), transforming growth factor (TGF), and matrix metalloproteinases (MMPs) in the dermis of rabbits.

Quantitative analysis of collagen after intense pulsed light and erbium‐doped yttrium aluminum garnet laser treatment on rabbit skin

Soil moisture (SM) is critical in maintaining the balance of Earth’s environment and climate system. Existing machine learning based SM estimation methods mainly belong to single model, which may be unstable and are probably lack of adaptability when switching to other sites. In addition, the in-situ observations are usually inadequate, deteriorating the generalization performance of single model. To overcome the above issue, we design two novel ensemble learning models based on Gaussian process regression (GPR) for SM retrieval. One is bagging embedded with GPR (BAGGPR), which is a parallel algorithm designed by randomly selecting multiple data subsets to train an ensemble of GPR models. The other is gradient boosting embedded with GPR (GBGPR), which is a sequential algorithm built by iteratively learning the residual between previous prediction and its true value. In GBGPR, we also propose an improved Huber loss function by applying square loss on different residuals. The proposed methods greatly enhance the stability, adaptability, and generalization performance of a single GPR model. Experiments are conducted in the continental U.S. (CONUS) between April 2015 and March 2016, where BAGGPR and GBGPR are tested to estimate SM based on eleven multi-source remote sensing features. The results demonstrate that our proposed methods outperform other state-of-the-art models including thirteen single models and three ensemble models, with R of 0.8958 and 0.9047, and RMSE of 0.0513 cm3/cm3 and 0.0490 cm3/cm3, respectively for BAGGPR and GBGPR. Moreover, the proposed methods can well capture spatial dynamics, and they have higher consistent with the in-situ measurements, better generalization performance in terms of training data, and higher adaptability to different in-situ networks.

Ensemble Learning Embedded with Gaussian Process Regression for Soil Moisture Estimation: A Case Study of the Continental U.S.

PURPOSE
The spatiotemporal index (STI) is a widely used approach for measuring speech pattern stability across multiple repetitions of a stimulus. In this study, we examine how methodological choices in the implementation of the STI (including the number of repetitions, length of stimuli, and parsing procedure) can affect its value.

METHOD
To evaluate how each methodological decision affects the STI, we use a synthetic data framework that allows for the generation of random productions of the template phrase "Buy Bobby a Puppy" at different stability levels. Within this framework, we conduct three experiments: Experiment 1 investigates the effects of the number of repetitions, Experiment 2 investigates the effects of stimulus length, and Experiment 3 investigates the effects of parsing errors.

RESULTS
In Experiment 1, we observed that STI values based on fewer repetitions will systematically underestimate larger repetition estimates. Experiment 2 showed that STI values will tend to be higher when calculated on longer (multimovement) stimuli independent of any differences in the stability of the underlying speech patterns. Finally, in Experiment 3, we showed that even minor parsing errors (≈ 10 ms) increase the value of the STI.

The results of this study illustrate that even minor choices in the implementation of the STI can have a noticeable impact on the resulting value. These findings highlight the care that needs to be taken when designing studies and comparing STI values across studies to ensure that different STI values are capturing real differences in motion pattern stability rather than trivial methodological variation.

Influences of Methodological Decisions on Assessing the Spatiotemporal Stability of Speech Movement Sequences.

. The present study was carried out to evaluate the effects of dietary yam polysaccharide (YPS) supplementation on growth performance, intestinal morphology, digestive enzyme activities and intestinal microflora of growing geese. A total of 400 Huoyan geese (28 days old, sex-balanced) were allotted to four groups (control, YPS100, YPS500 and YPS1000, according to initial body weight), and their diets included 0, 100, 500 and 1000 mg of YPS per kg of basal diet. Each group consisted of 5 replicates, 20 geese each, and the feeding experiment lasted from 28 to 56 days of age. The results showed that compared to the control group, the YPS500 group had higher final body weight, average daily gain, villus height, villus height to crypt depth ratio, amylase and trypsin activity, while lower feed to gain ratio and lipase activity in the small intestine ( P < 0.05). In addition, all experimental groups had a higher number of Lactobacillus and Bifidobacterium , and a lower number of Escherichia coli in the caecal content of growing Huoyan geese ( P < 0.05). The results indicated that dietary supplementation with 500 mg/kg YPS improved growth performance by regulating digestive enzyme activities, small intestine morphology and intestinal microflora in growing Huoyan geese.

Effects of dietary yam polysaccharide on growth performance and
intestinal microflora in growing Huoyan geese

In this paper, a region iterative correction algorithm is proposed to improve the performance of Multi-State Constraint Kalman Filter (MSCKF) based visual-inertial navigation system in large-scale long-distance scenarios. To improve the real-time performance of the algorithm, traditional MSCKF uses a sliding window to constrain the state. However, for the long-distance landmarks, the relatively small sliding window capacity is inable to provide sufficient baseline and accurate disparity calculation for high accuracy landmark estimation. Meanwhile, in order to keep the consistency of the systematic observations, MSCKF maintains an initial nullspace containing the landmark estimation to constrain the system transfer matrix with the observability constrained (OC) method. As a result, poor landmark estimation leads to the constructed initial nullspace deviating from the true value, and keeping the wrong correction direction for a long time makes the system performance degraded. To address the above problem, this paper proposes a landmark estimation algorithm based on region iterative correction. The algorithm forms a region judgment logic based on sliding window by setting a time threshold constraint and monitoring the initial frame change in window. When the logic determines that the carrier moves into a new region, iterative estimation of landmarks is realized with the combination of the current region observation. The joint correction of multi-level regions can effectively avoid the degradation of system performance caused by the error of nullspace constraints. The results based on Airsim virtual scenario indicate that the region iterative correction algorithm can effectively overcome the drawback of incorrect correction directions caused by poor initial landmark estimation and improve the positioning accuracy of visual-inertial navigation system in large scale, long-distance and long-time tracking environments.

Region Iterative Correction Algorithm in Visual-Inertial Navigation System

In this paper, we present a neural network-based framework to compensate for the nonlinear distortion of high-speed continuous variable quantum key distribution (CV-QKD) systems. In practice, the nonlinear impairment of imperfect devices could bring interference to the measured quadrature values and thus compromise the parameter estimation procedure and the secure key rate. Specifically, for a high-speed CV-QKD system, the balanced homodyne detector (BHD) and the following analog-to-digital converter are the primary sources of nonlinear impairment. The nonlinear distortion effect will be more pronounced as the pulse repetition rate increases. We propose an autoencoder-based network to learn the inner patterns of distorted data and then compensate the quadrature measurements in real-time at the receiver’s side. The numerical simulation demonstrates that the excess noise induced by nonlinear impairment is reduced to the $10^{-3}$ level in the shot noise unit. Consequently, such a software approach has the ability to significantly boost the bandwidth efficiency of the BHD and the secure key bit rate.

Neural Network-Powered Nonlinear Compensation Framework for High-Speed Continuous Variable Quantum Key Distribution

Mechanical Analysis of Frost Heaving of Weakly Cemented Soft Rock Tunnel in Cold Regions

Ritter-type amination of C(sp3)-H bonds enabled by electrochemistry with SO42−

This paper conducts a research on the wavelet construction and application of image edge detection. Taking the image edge detection algorithm based on wavelet modulus maxima as the research subject, this paper discusses the problem of dislocation phenomenon, threshold selection, multi-scale edge fusion and evaluation criterion in the algorithm, and proposes an improved self-adaptive hierarchical threshold algorithm based on information amount and vanishing moment. From the angle of wavelet symmetry, filter composition and vanishing moment, the influence of wavelet property on image edge detection is studied, and the construction requirements of wavelet filter banks for image edge detection are proposed. The constant-length compactly supported biorthogonal wavelet parameterized construction method is used to construct the biorthogonal wavelet featuring odd symmetry for high-pass decomposition filter and unidirectionality for filter sequence, and the improved algorithm of wavelet construction and threshold is applied to the simulation of image edge detection of concrete cracks in ultra-high arch dam.

Multi-Scale Edge Detection of Crack in Extra-High Arch Dam Based on Orthogonal Wavelet Construction

Objective The purpose of this study was to observe the relationship between physical performance and mild cognitive impairment (MCI) in the presence or absence of type 2 diabetes in elderly hemodialysis patients. Methods In this multicenter cross-sectional study, 396 clinically stable and aged ≥60 years hemodialysis patients (255 men; mean age: 68.3 ± 5.9 years) were included from seven dialysis units in Shanghai, China. The Chinese version of the Modified Mini-Mental State Examination (MMSE) and the Instrumental Activities of Daily Living (IADL) scale were utilized to assess MCI. The performance-based assessments consisted of three physical tests, grip strength (GS), Timed Up and Go Test (TUGT), and 4-m walking test, which respectively represent muscle strength, mobility, and walking speed (WS). Logistic regression and multivariate linear regression were used for analysis. Results Hemodialysis patients with diabetes had a high prevalence of MCI (20.6%). The odds ratio (OR) of MCI for the interacted items [(TUGT) * (diabetes) and (WS) * (diabetes)] was significant (p < 0.05). In diabetes patients, TUGT was positively associated with MCI, and WS was negatively associated with MCI after adjusting covariates [OR = 0.129; 95% confidence interval (CI) = 0.028–0.704, p = 0.021]. However, no significant association was found between physical performance and MCI in the non-diabetes hemodialysis patients (p > 0.05). Further analysis showed that TUGT was negatively associated with attention and calculation and language. WS was positively associated with recall and language in diabetic hemodialysis patients. Conclusions Physical performance was associated with MCI in diabetic hemodialysis patients rather than the non-diabetes group. Whether increasing mobility or WS can positively influence MCI in individuals with type 2 diabetes requires further study.

Relationship between physical performance and mild cognitive impairment in elderly hemodialysis patients is modified by the presence of diabetes: A multicenter cross-sectional study

Authenticity, psychological ownership and tourist commitment in heritage tourism: the moderating effect of cultural intelligence

Ensemble probabilistic wind power forecasting with multi-scale features

PbS/CdS quantum dots (QDs) have attracted much attention in the applications of photonic devices owing to their excellent saturable absorption properties. Here, highly monodisperse and perfect crystalline PbS/CdS QDs with...

Generation of Q-switched and mode-locked pulses based on PbS/CdS saturable absorber in an Er-doped fiber laser

A total of 49 patients with cerebellopontine angle cholesteatoma from the Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University between January 2013 and January 2021 were recruited. All patients were evaluated by MRI scan before surgery and tumor resection was performed under microscope via retrosigmoid sinus approach. Then residual tumor was searched with 0°and 30°neuroendoscopy, and tumor resection was performed.Residual tumors were foundand resectedin 38 cases under theneuroendoscopy after routine microsurgery.Total and subtotalresections were performed in 44 cases and 5 cases, respectively. Complications included aseptic meningitis (n=8), cerebrospinal fluid leakage (n=1) and intracranial hematoma (n=2). Follow-up[42±3(6-72)months] was available in all patients. During follow-up, 45 cases (91.8%) had a Kar-nofsky Performance Status (KPS)score ≥80.Neuroendoscopy-assisted microsurgery for cerebellopontine angle cholesteatomas helps enhance the total resection rate and decrease the operative risk.

[Neuroendoscopy-assisted microneurosurgery for cerebellopontine angle cholesteatoma].

Currently, redundant data affects the speed of intrusion detection, many intrusion detection systems (IDS) have low detection rates and high false alert rate. Focusing on these weakness, a new intrusion detection model based on rough set and random forest (RSRFID) is designed. In the intrusion detection model, rough set (RS) is used to reduce the dimension of redundant attributes; the algorithm of decision tree(DT) is improved; a random forest (RF) algorithm based on attribute significances is proposed. Finally, the simulation experiment is given on NSL-KDD and UNSW-NB15 dataset. The results show: attributes of different types of datasets are reduced using RS; the detection rate of NSL-KDD is 93.73%, the false alert rate is 1.02%; the detection rate of NSL-KDD is 98.92%, the false alert rate is 2.92%.

Three new polyketide dimers named huoshanmycins A‒C (1–3) were isolated from a plant endophytic Streptomyces sp. HS-3-L-1 in the leaf of Dendrobium huoshanense, which was collected from the Cultivation base in Jiuxianzun Huoshanshihu Co., Ltd. The dimeric structures of huoshanmycins were composed of unusual polyketides SEK43, SEK15, or UWM4, with a unique methylene linkage. Their structures were elucidated through comprehensive 1D-/2D-NMR and HRESIMS spectroscopic data analysis. The cytotoxicity against MV4-11 human leukemia cell by the Cell Counting Kit-8 (CCK8) method was evaluated using isolated compounds with triptolide as positive control (IC50: 1.1 ± 0.4 μM). Huoshanmycins A and B (1, 2) displayed moderate cytotoxicity with IC50 values of 32.9 ± 7.2 and 33.2 ± 6.1 μM, respectively.

Huoshanmycins A‒C, New Polyketide Dimers Produced by Endophytic Streptomyces sp. HS-3-L-1 From Dendrobium huoshanense

Targeted activation of GPER enhances the efficacy of venetoclax by boosting leukemic pyroptosis and CD8+ T cell immune function in acute myeloid leukemia

Spatiotemporal pattern and influencing factors of green efficiency of water resources in the Yangtze River Economic Belt

Autophagy is one of the degradation pathways to remove proteins or damaged organelles in cells that plays an important role in neuroprotection. Different stages of autophagy are regulated by autophagy‐related genes, and many molecules such as transcription factor EB (TFEB) are involved. The complete autophagy process plays an important role in maintaining the dynamic balance of autophagy and is crucial to the homeostasis of intracellular substance and energy metabolism. Autophagy balance is disrupted in neurodegenerative diseases, accounting for a variety of degeneration disorders. These impairments can be alleviated or treated by the regulation of autophagy through molecules such as TFEB.

Autophagy and autophagy‐related molecules in neurodegenerative diseases

In recent years, computer vision technology has been widely applied in various fields, making super-resolution (SR), a low-level visual task, a research hotspot. Although deep convolutional neural network has made good progress in the field of single-image super-resolution (SISR), its adaptability to real-time interactive devices that require fast response is poor due to the excessive amount of network model parameters, the long inference image time, and the complex training model. To solve this problem, we propose a lightweight image reconstruction network (MSFN) for multi-scale feature local interaction based on global connection of the local feature channel. Then, we develop a multi-scale feature interaction block (FIB) in MSFN to fully extract spatial information of different regions of the original image by using convolution layers of different scales. On this basis, we use the channel stripping operation to compress the model, and reduce the number of model parameters as much as possible on the premise of ensuring the reconstructed image quality. Finally, we test the proposed MSFN model with the benchmark datasets. The experimental results show that the MSFN model is better than the other state-of-the-art SR methods in reconstruction effect, computational complexity, and inference time.

Lightweight Image Super-Resolution Based on Local Interaction of Multi-Scale Features and Global Fusion

Impact of high temperature on road injury mortality in a changing climate, 1990-2019: A global analysis.

Emerging photodynamic/sonodynamic therapies for urological cancers: progress and challenges

Solvent-assisted grinding (SAG) and solution slow evaporation (SSE) methods are generally used for the preparation of cocrystals. However, even by using the same solvent, active pharmaceutical ingredient (API), and cocrystal coformer (CCF), the cocrystals prepared using the two methods above are sometimes inconsistent. In the present study, in the cocrystal synthesis of praziquantel (PRA) with polyhydroxy phenolic acid, including protocatechuic acid (PA), gallic acid (GA), and ferulic acid (FA), five different cocrystals were prepared using SAG and SSE. Three of the cocrystals prepared using the SAG method have the structural characteristics of carboxylic acid dimer, and two cocrystals prepared using the SSE method formed cocrystal solvates with the structural characteristics of carboxylic acid monomer. For phenolic acids containing only one phenolic hydroxyl group (ferulic acid), when preparing cocrystals with PRA by using SAG and SSE, the same product was obtained. In addition, the weak molecular interactions that were observed in the cocrystal are explained at the molecular level by using theoretical calculation methods. Finally, the in vitro solubility of cocrystals without crystal solvents and in vivo bioavailability of PRA-FA were evaluated to further understand the influence on the physicochemical properties of API for the introduction of CCF.

Cocrystals of Praziquantel with Phenolic Acids: Discovery, Characterization, and Evaluation

Heart failure (HF) is a clinical syndrome of cardiac insufficiency caused by abnormalities in cardiac structure and function that arise for various reasons, and it is the final stage of most cardiovascular diseases’ progression. Total flavonoid extract from Dracocephalum moldavica L. (TFDM) has many pharmacological and biological roles, such as cardioprotective, neuroprotective, anti-atherogenic, antihypertensive, anti-diabetic, anti-inflammatory, antioxidant, etc. However, its effect on HF and its molecular mechanism are still unclear. In this study, we used systems pharmacology and an animal model of HF to investigate the cardioprotective effect of TFDM and its molecular mechanism. Eleven compounds in TFDM were obtained from the literature, and 114 overlapping genes related to TFDM and HF were collected from several databases. A PPI network and C-T network were established, and GO enrichment analysis and KEGG pathway analysis were performed. The top targets from the PPI network and C-T network were validated using molecular docking. The pharmacological activity was investigated in an HFpEF (heart failure with preserved ejection fraction) mouse model. This study shows that TFDM has a protective effect on HFpEF, and its protective mechanism may be related to the regulation of proinflammatory cytokines, apoptosis-related genes, fibrosis-related genes, etc. Collectively, this study offers new insights for researchers to understand the protective effect and mechanism of TFDM against HFpEF using a network pharmacology method and a murine model of HFpEF, which suggest that TFDM is a promising therapy for HFpEF in the clinic.

Systems Pharmacology-Based Strategy to Investigate Pharmacological Mechanisms of Total Flavonoids in Dracocephalum moldavica on Chronic Heart Failure

The emergence of tissue engineering technology provides an option for the treatment of early organ and tissue lesions by combination of biomimetic scaffolds and stem cells. Stereoscopic projection lithography is utilized broadly in varied application areas due to its high-precision, resolution, and efficiency features. It can be used to fabricate and manufacture complex scaffolds with hierarchical construct, which are highly suitable for advanced tissue engineering application. In current work, gelatin methacrylate (GelMA) was synthesized and fabricated to bioactive scaffold because of its excellent biocompatibility and biodegradability by using stereoscopic projection lithography based 3D printer (YC-M3D-10). The scaffold displayed multilayered micro structures that supported stem cell growth and promoted cell proliferation. The results demonstrated that the cells proliferated significantly on the printed GelMA scaffold after 6 days. Moreover, GelMA scaffolds can promote cell proliferation and show great prospects in future tissue engineering applications.

Stereoscopic projection lithography based 3D printing with high precision for advanced tissue engineering application

Mortality among psychiatric inpatients in China: A national survey.

This study aimed to deal with the problems that current intrusion detections have poor classification ability toward small sets of samples. A new intrusion detection model based on coordinative immune and random antibody forest (CIRAFID) is proposed. The vaccination mechanism of coordinative immune algorithm is designed to increase the fitness of poor antibodies, a kind of random antibody detection forest model is given to detect anomalies, and to classify attacks. The experimental results show: the proposed model has higher detection rate, classification accuracy, classification ability and lower false positives rate.

Intrusion detection model based on coordinative immune and random antibody forest

Fe3O4/g‐C3N4 nanozyme for production of L‐DOPA as mimetics of tyrosine hydroxylase

Transcriptome Sequencing and Bioinformatic Analysis of Eucalyptus cloeziana Terminal Buds

Located in the south of Jiangxi Province, Poyang Lake is China’s largest freshwater lake directly connected to the Yangtze River. In the wet seasons, the water area of the lake can reach more than 3000 km2 and in the dry seasons, it can drop to lower than 800 km2. As one of the important lakes in the mainstream of Yangtze River, it plays an important role in flood storage, biodiversity protection and the economic development of the watershed. Based on high-frequency MODIS data, we obtained series of Poyang Lake coastlines in wet and dry seasons during 2000–2020. When compared with two visual interpretation results in wet and dry seasons, the overall accuracy of this dataset is higher than 85%. This dataset can delineate the tempo-spatial dynamics of the lake inundations and can serve as scientific data for the research on ecological protection and water resource management in the watershed of Poyang Lake.

A dataset of the Poyang Lake coastlines in dry and wet seasons during 2000–2020

Aptasensing a class of small molecules based on split aptamers and hybridization chain reaction-assisted AuNPs nanozyme.

BACKGROUND Cervical cancer is a gynecological malignancy common in middle-aged and older patients, with a high mortality rate. Spondin-2 is an extracellular matrix protein that involved in innate and acquired immune responses. Herein, we investigated the relationship between serum Spondin-2 expression, tumor invasion and infiltration, and immune response in patients with cervical cancer and provided a theoretical basis for clinical practice. AIM To investigate the relationship between serum Spondin-2 expression and cervical cancer-related indicators. METHODS Overall, 147 patients with cervical cancer who were admitted to our institution between January 2019 and August 2019 were assigned to the cervical cancer group, and 92 patients with benign uterine lesions and 86 healthy individuals were assigned to the benign and control groups, respectively. In each group, serum Spondin-2 expression was measured, and the receiver operating characteristic (ROC) curve was determined. Patients with cervical cancer were classified into high or low Spondin-2 groups depending on the Spondin-2 threshold value used for diagnosing cervical cancer. Patient’s clinical data were collected to compare the clinicopathologic characteristics, immune cytokine levels, and prognosis of patients with varying Spondin-2 expression levels. RESULTS The expression level of serum Spondin-2 was significantly higher in the cervical cancer group than in the benign and control groups (P < 0.05). According to the ROC curve, the cutoff value of Spondin-2 used in the diagnosis of cervical carcinoma was 25.68 ± 7.11 μg/L. The proportion of patients with Federation of Gynecology and Obstetrics stage III, nerve invasion, vascular invasion, and lymph node metastasis was higher in the high Spondin-2 group than in the low Spondin-2 group (P < 0.05). Interleukin-5 (IL-5) and IL-4 Levels were higher in the high Spondin-2 group than in the low Spondin-2 group. In contrast, IL-2 and tumor necrosis factor-α levels were lower in the high Spondin-2 group than in the low Spondin-2 group (P < 0.05). After 3 years of follow-up, progression-free survival and overall survival were significantly shorter in the high Spondin-2 group than in the low Spondin-2 group (P < 0.05). CONCLUSION The expression of serum Spondin-2 is upregulated in patients with cervical carcinoma and is related to tumor invasion and infiltration, antitumor immune response, and prognosis.

Serum Spondin-2 expression, tumor invasion, and antitumor immune response in patients with cervical cancer

Sifting scheme for continuous-variable quantum key distribution with short samples

Purpose Adolescence has always been a period prone to behavior problems. Some studies have shown that left-behind experience, social support, and sleep quality are all crucial factors influencing behavior problems, but the mechanisms of how they are influenced are unclear. This cross-sectional study investigated the prevalence of behavior problems among school-aged adolescents and explored the mediating role of social support and sleep quality in the association between left-behind experience and behavior problems. Patients and Methods A total of 738 school adolescent students completed this questionnaire. We collected basic information about the participants using a general demographic scale and assessed their sleep quality, social support, and behavioral problems using the Pittsburgh Sleep Quality Index scale, Social Support Rating Scale, and Strengths and Difficulties Questionnaire. The multiple mediating effects of sleep quality and social support were examined by path analysis. Results Among 738 school-aged adolescent students who completed the survey, a total of 198 students had behavior problems, with an overall prevalence of 26.8%. In the multiple mediation model, the mediation effect of social support and sleep quality on left-behind experience to behavior problems was 56.7% (direct effect: standardized estimate=0.946, indirect effect: standardized estimate=1.239). The model was a saturated model, and fit was no longer considered. Conclusion We found that social support and sleep quality had a series of multiple mediating effects in the pathway from left-behind experience to behavior problems, and both significantly moderated behavior problems. Therefore, we suggest that we should pay more attention to students’ psychological status and improve their use of social support for left-behind adolescents, in addition to giving more external social support. And paying attention to their sleep problems to reduce the occurrence of behavior problems, considering that their psychological development is not mature.

Left-Behind Experience and Behavior Problems Among Adolescents: Multiple Mediating Effects of Social Support and Sleep Quality

The State Grid actively promotes the development of a new power system. The internet of things for power transmission and transformation equipment, for example, is a significant way to open up the "last mile" of power grid communication. In this paper, we design a sensor terminal serial communication module to meet the internet of things business requirements for power transmission and transformation equipment while also realizing sensor data collection and reporting functionality. The results of the tests show that the serial communication module designed in this paper can help the sensing terminal and reliably report sensing data to the upper-layer access node.

Design of a sensor terminal serial communication module for power transmission and distribution equipment based on data protocol of sensors in Internet of Things

The metropolitan circle is the basic unit of regional competition. Enhancing the connection between cities in the metropolitan circle and optimizing the spatial layout of the metropolitan circle is one of the goals of regional high-quality development in the new era. Therefore, it is of great significance to analyze the spatial network structure of the metropolitan circle. Taking Hangzhou metropolitan circle as an example, this study used web crawler technology to obtain data in multiple Internet big data platforms; used centrality analysis, flow data model, and social network analysis to construct the network connection matrix of human flow, goods flow, capital flow, information flow, and traffic flow; and explored the spatial network structure of the metropolitan circle. The results showed that the node intensity of the metropolitan circle presented a distribution pattern of strong in the east and weak in the west. The network connections of each county under the action of different element flows were different, and the skeleton of the integrated flow network connections showed a starfish-shaped feature. Hangzhou, Jiaxing, Huzhou, and Shaoxing cities had strong group effects in goods flow and traffic flow, while Quzhou and Huangshan cities had relatively independent cohesive subgroups in human flow and information flow. This study can provide useful references for regional development and spatial planning implementation.

Exploring Spatial Network Structure of the Metropolitan Circle Based on Multi-Source Big Data: A Case Study of Hangzhou Metropolitan Circle

The geometric unscented Kalman filter (GUF) is an effective method for state estimation due to its advantages of high precision, reasonable efficiency, and good stability. In order to further improve the filtering performance of GUF, multiple rotation matrices are first designed by optimizing the rotation angles of their corresponding sampling points with maximum likelihood estimation, leading to a novel sampling strategy, namely, rotating geometric unscented sampling (RGUS). Then, applying RGUS to the GUF framework generates a rotating geometric unscented Kalman filter (RGUF). Since observable measurements are generally corrupted by non-Gaussian noise, RGUF may suffer from performance degradation due to the used minimum mean square error (MMSE) criterion. To improve the robustness of RGUF against non-Gaussian noises, we propose a novel maximum correntropy rotating geometric unscented Kalman filter (MCRGUF) using the maximum correntropy criterion (MCC). Finally, a Cramér–Rao lower bound (CRLB) of MCRGUF is introduced as a performance indicator. Simulations on three examples validate the high filtering accuracy and strong robustness of MCRGUF in the presence of non-Gaussian noise.

Robust State Estimation With Maximum Correntropy Rotating Geometric Unscented Kalman Filter

Since early 2019, the Lunar Penetrating Radar (LPR) onboard Chang'e‐4 (CE‐4)’s Yutu‐2 rover has been gathering data relating to the subsurface structure of the Von Kármán crater within the South Pole‐Aitken Basin (SPA) on the lunar farside. Low‐frequency radar data have the potential of carrying geological information of about 300 m worth of strata below the traversed path. Forty‐two days’ data have revealed a bifurcated structure within the layered structure beneath the CE‐4 surveying area for the first time, affecting the overlying reflectors between 90 and 310 m. This study suggests that, based on the morphological characteristics, thickness, depth (timing sequence) and direction of the newly found structure, its origin might be linked to the deposition of ejecta from the Schrödinger impact. The local stratigraphy is interpreted as consisting of distinct geological layers, corresponding to the superposition of ejecta from different impact craters, paleo‐regolith, and basaltic lava flows.

From Schrödinger to Von Kármán: An Intriguing New Geological Structure Revealed by the Chang'e‐4 Lunar Penetrating Radar

Trends in Worldwide Research in Cryoablation of Atrial Fibrillation Over the Period 2002-2022: A Bibliometric Analysis

Understanding different cultural ecosystem services: An exploration of rural landscape preferences based on geographic and social media data.

Polycystic ovary syndrome (PCOS) is a disease in which endocrine metabolic abnormalities coexist with reproductive system abnormalities, with the main clinical manifestations including abnormal menstruation, hirsutism, acne, infertility, and obesity, and it is also a high risk for the development of many pregnancy complications, gynecological malignancies and other diseases. Therefore, timely intervention to prevent the progression of PCOS is of great significance for improving the quality of life of most female patients. Insulin resistance (IR) is one of the most common endocrine disorders in PCOS patients, with approximately 75% of PCOS patients experiencing varying degrees of IR. It is now believed that it is mainly related to the PI3K signaling pathway. The role of autophagy and apoptosis of ovarian granulosa cells (GCs) in the pathogenesis of PCOS has also been gradually verified in recent years. Coincidentally, it also seems to be associated with the PI3K signaling pathway. Our aim is to review these relevant studies, to explore the association between the IR, cellular autophagy and apoptosis in PCOS patients and the PI3K pathway. We summarize some of the drug studies that have improved PCOS as well. We have also found that proteomics holds great promise in exploring the pathogenesis of PCOS, and we have published our views on this.

Insulin resistance, autophagy and apoptosis in patients with polycystic ovary syndrome: Association with PI3K signaling pathway

Preclinical and clinical studies have suggested a neuroprotective effect of remote ischemic conditioning (RIC), which involves repeated occlusion/release cycles on bilateral upper limb arteries; however, robust evidence in patients with ischemic stroke is lacking.

Objective
To assess the efficacy of RIC for acute moderate ischemic stroke.

This multicenter, open-label, blinded-end point, randomized clinical trial including 1893 patients with acute moderate ischemic stroke was conducted at 55 hospitals in China from December 26, 2018, through January 19, 2021, and the date of final follow-up was April 19, 2021.

Eligible patients were randomly assigned within 48 hours after symptom onset to receive treatment with RIC (using a pneumatic electronic device and consisting of 5 cycles of cuff inflation for 5 minutes and deflation for 5 minutes to the bilateral upper limbs to 200 mm Hg) for 10 to 14 days as an adjunct to guideline-based treatment (n = 922) or guideline-based treatment alone (n = 971).

The primary end point was excellent functional outcome at 90 days, defined as a modified Rankin Scale score of 0 to 1. All end points had blinded assessment and were analyzed on a full analysis set.

Results
Among 1893 eligible patients with acute moderate ischemic stroke who were randomized (mean [SD] age, 65 [10.3] years; 606 women [34.1%]), 1776 (93.8%) completed the trial. The number with excellent functional outcome at 90 days was 582 (67.4%) in the RIC group and 566 (62.0%) in the control group (risk difference, 5.4% [95% CI, 1.0%-9.9%]; odds ratio, 1.27 [95% CI, 1.05-1.54]; P = .02). The proportion of patients with any adverse events was 6.8% (59/863) in the RIC group and 5.6% (51/913) in the control group.

Among adults with acute moderate ischemic stroke, treatment with remote ischemic conditioning compared with usual care significantly increased the likelihood of excellent neurologic function at 90 days. However, these findings require replication in another trial before concluding efficacy for this intervention.

Trial Registration
ClinicalTrials.gov Identifier: NCT03740971.

Effect of Remote Ischemic Conditioning vs Usual Care on Neurologic Function in Patients With Acute Moderate Ischemic Stroke: The RICAMIS Randomized Clinical Trial.

Seismic P‐wave first arrival picking is one of the critical problems in seismic source research. At present, the picking of seismic P‐wave first arrival mainly relies on the combination of traditional methods and manual picking. However, traditional algorithms have poor picking performance and low manual picking efficiency, which cannot meet the needs of research and application. Based on the deep learning network InceptionResNet‐V2, this paper proposes an improved network (EQK‐IncResNet) that can be used for seismic P‐wave first arrival picking. Compared with traditional methods, this model does not need to set the threshold manually and only needs to input the three‐component data of the seismic waveform data to intelligently identify the first‐arrival of the seismic P‐wave. This model has a lightweight structure and excellent feature extraction capabilities, which can effectively identify low signal‐to‐noise ratio data. The experimental results show that within the error thresholds of 0.1, 0.3, and 0.5 s, the hit rate of this method is 74.45%, 96.79%, and 98.68%, respectively. The average picking error is 0.031 s, which is better than the traditional methods such as AR‐AIC + STA/LTA and the mainstream deep learning methods such as GRU.

Seismic P‐wave first‐arrival picking model based on EQK‐IncResNet

Objective Hyperhomocysteinemia (HHcy), as an important risk factor for Alzheimer’s disease (AD), would aggravate cognitive dysfunction. This study aimed to investigate whether and to what degree the homocysteine (Hcy) levels in blood and cerebrospinal fluid (CSF) were elevated in AD patients compared with healthy controls and to explore the factors related to the elevated Hcy levels in AD patients. Methods PubMed and Embase databases were searched to identify eligible studies, and study quality was evaluated using the Newcastle-Ottawa Quality Assessment Scale. Ratio of mean (RoM) Hcy concentrations was used as a measure of fold-change between AD patients and healthy control subjects. Results We identified 35 eligible studies, consisting a total of 2172 patients with AD and 2289 healthy controls. The pooled results showed that patients with AD had a significantly higher blood level of Hcy (RoM, 1.32; 95% CI, 1.25–1.40; p<0.001) than controls did, with large heterogeneity across studies (I2=81.4%, p<0.001). Hcy level in CSF did not differ significantly between patients with AD than controls (RoM, 1.12; 95% CI, 0.90–1.39, p=0.293; I2=69.4%, p=0.02). A random effects meta-regression analysis revealed that there was an inverse correlation between the blood levels of Hcy and folate (p=0.006). There was no link found between the blood levels of vitamin B12, or the Mini-Mental Status Examination scores reflecting the degree of cognitive impairment, and blood levels of Hcy. Conclusion Regardless of dementia severity, there is an approximate one-third increase in blood Hcy in AD patients, which is robustly associated with a decreased level of blood folate in AD, but not with that of blood vitamin B12 nor the degree of dementia. Future investigation on the cause-and-effect link between Hcy and folate is warranted to clarify this issue.

Blood and CSF Homocysteine Levels in Alzheimer’s Disease: A Meta-Analysis and Meta-Regression of Case–Control Studies

Left ventricular strain derived from computed tomography feature tracking: Determinants of failure and reproducibility.

Noble-metal free Ce-Fe-Zr ternary oxides with synergistic dual active sites for accelerating NO reduction

Low sintering temperature, temperature-stable scheelite structured Bi[V1-x (Fe1/3W 2/3)x]O4 microwave dielectric ceramics

Abrupt Topographic Depression at the Eastern End of the Himalayan Arc: Insights from Geodetic Analyses1

The growing complexity and size of integrated circuits has made functional verification a huge challenge. As the control center of integrated circuit hardware design, any design errors in the Instruction Pipeline Control Unit (IPCU) will put the entire chip at significant risk. Verification of the IPCU has accordingly become a substantial challenge for test engineers. Taking a 32-bit VLIW DSP as the research goal, this paper proposes a directional random verification method for IPCU based on the instruction reordering strategy (InstRO). First, according to the symmetry of input and output of the instruction pipeline, this method considers several functional components as a whole and establishes a high-level reference model based on the instruction reordering strategy (InstRO-Model), thereby both shielding the complex logic inside the hardware design and reducing the complexity of the verification model. Second, by automatically generating random test stimuli, the constraints of which can be adjusted in a particular direction, effective intensive testing of different functional points of the design under test (DUT) is realized, and code coverage and functional coverage are both improved. Finally, the test stimuli are input into the InstRO-Model and the DUT at the same time. As the input and output of the InstRO-Model also have symmetry with the input and output of the DUT, an automatic comparison of the verification results is realized via assertions. This approach greatly reduces the manpower and time required for verification and improves the verification efficiency. Experiments and practical application results show that this method can increase the code coverage to more than 99%. In particular, efficient directional random verification can be carried out for the weak points in the instruction pipeline control verification and the function points that are difficult to manually simulate and traverse, which greatly improves the verification efficiency and verification integrity of the IPCU.

A 32-Bit DSP Instruction Pipeline Control Unit Verification Method Based on Instruction Reordering Strategy

Designing metal-organic framework (MOF)-based catalysts with superior oxygen evolution reaction (OER) activity and robust durability simultaneously is highly required yet very challenging due to the limited intrinsic activity and their elusive evolution under harsh OER conditions. Herein, a steady self-reconstructed MOF heterojunction is constructed via redox electrochemistry and topology-guided strategy. Thanks to the inhibiting effect from hydrogen bonds of Ni-BDC-1 (BDC=1,4-benzenedicarboxylic acid), the obatained MOF heterojunction shows greatly improved OER activity with low overpotential of 225 mV at 10 mA cm-2, relative to the totally reconstructed Ni-BDC-3 (332 mV). Density function theory calculations reveal that the formed built-in electric field in the MOF heterojunction remarkably optimizes the ad/desorption free energy of active Ni sites. Moreover, such MOF heterojunction shows superior durability attributed to the shielding effect of the surface-evolved NiOOH coating.

Self-Reconstructed Metal-Organic Framework Heterojunction for Switchable Oxygen Evolution Reaction.

Watersheds are the basic unit of Earth's terrestrial systems and are therefore ideal units for the study of critical zones (CZs). However, grand challenges remain regarding the observation, modeling, and management of CZs and watershed systems. We synthesize the progress and breakthroughs associated with watershed science and CZ research in the Heihe River basin (HRB), a large‐scale endorheic river basin with unique mountain cryosphere‐oasis‐desert landscapes and prominent human‐nature competition for water resources. The HRB observation system consists of mountain cryosphere, agricultural oasis, and natural oasis observatories and is promoted by large‐scale comprehensive experiments to achieve multiscale observations. A watershed system model that couples ecohydrological models with socioeconomic models is developed to investigate the complex interactions among water, ecology, and socioeconomics in the HRB. The model is embedded in a decision support system to bridge science and decision‐making and to better serve river basin sustainability. Significant progress and breakthroughs have been made in CZ and watershed process research (e.g., cryospheric hydrological processes, ecological and hydrological interactions, and surface‐groundwater interactions) in the HRB. Nevertheless, observation and modeling of geochemical and geomorphological processes in the CZ have not been well addressed in integrated watershed studies of the HRB. In the future, new observation technologies, agent‐based models, machine learning, and data assimilation will benefit both watershed science and CZ science and help to address complexity and dynamics in the CZ at the river basin scale. Overall, the HRB has successfully demonstrated how an experimental river basin can link CZ science with watershed science.

Linking Critical Zone With Watershed Science: The Example of the Heihe River Basin

Linear Frequency Modulation Continuous Wave (LFMCW) radar is widely used for automotive applications as its high range resolution and frequency resolution. In this article, a multiple target detection radar is presented to monitor aircraft docking. The proposed radar adopts FMCW+CW mode and two receiving antennas to calculate the range, velocity and angle of the multiple targets. This method was verified by simulation and measurements.

A multiple target detection radar for monitoring aircraft docking

Elevated circASCC3 limits antitumor immunity by sponging miR-432-5p to upregulate C5a in non-small cell lung cancer.

A coumarin/cyanoacetamide-derived lysosome-targeting probe for detecting bisulfite and viscosity changes in living cells and zebrafish

Organic-inorganic hybrid perovskite materials have recently attracted considerable interests owing to their excellent optoelectrical properties, good environmental stability and variety of applications. The quasi-2D perovskite is also expected to have...

Mode-locking operation of Er-doped fiber laser with (PEA)2(CsPbBr3)n-1PbBr4 perovskite saturable absorber

Tuning the electrocaloric effect by tailoring phase fraction in BaTiO3-based ferroelectrics

ABSTRACT This study explored the influence of COVID-19 on vocational hospitality and tourism students’ career choices. 31 interviewees were approached through purposive and snowball sampling. This study found that students’ attitudes toward working in the hospitality and tourism industry are changed by COVID-19 pandemic. Theoretically, this study developed a framework of the influence of COVID-19 on vocational hospitality and tourism students’ career choices at three stages, including before COVID-19, during COVID-19 outbreak, and after COVID-19 outbreak. Practically, this study provided useful suggestions for government and employers to attract students to work in the hospitality and tourism industry after COVID-19 outbreak.

The Influence of COVID-19 on Vocational Hospitality and Tourism Students’ Career Choices

As the third generation of neural network after Artificial Neural Network, Spiking Neural Network (SNN) has the advantages of low energy consumption and high computing efficiency. However, due to the complex neurons and non-differentiable characteristics of SNN, the current results mostly stay in the software simulation stage, focusing on tasks with relatively simple processes such as image classification, and less achievements in Object Detection (OD) tasks with more application value. At present, the OD based on SNN mostly uses frequency coding, but the regression problem requires high precision and requires a large number of timesteps, resulting in a long time-consuming inference of a picture and a large overall power consumption. In this regard, based on Two-stage OD network, this paper decouples its detection process classification and localization, and proposes a multi-patch classification with localization network, which is completed by using a classification SNN. And take the drone shot by the infrared camera as the dataset, the OD as the application scene. The OD network is deployed on the neuromorphic chip PAICORE1.0 of Peking University, which proves the feasibility of applying our method to real-world neuromorphic chip and facilitates the development of SNN OD and its neuromorphic chip deployment.

2022 IEEE 16th International Conference on Solid-State & Integrated Circuit Technology (ICSICT)

Multi-patch localization Spiking Neural Network for Object Detection

Hematite decorated with nanodot-like cobalt (oxy)hydroxides for boosted photoelectrochemical water oxidation.

With the gradual improvement of space launch sites image communication system construction, Visual command is increasingly demanding video image retrieval. The previous keyword retrieval method can not meet the requirements of new generation space mission network communication, content-based retrieval need to be developed. In view of the problem that video information is unstructured and cannot be quickly previewed, this paper studies the video key frame extraction algorithm and propose a video key frame extraction algorithm based on convolutional neural network.

Research on key frame extraction algorithm based on deep convolutional neural network in video catalogue

Metformin, a well-known antidiabetic drug, exhibits anticancer effect in a variety of cancers, including liver cancer. Plantamajoside (PMS), a phenylethanoid glycoside compound isolated from Plantago asiatica, is proved to possess anticancer effects, too. In our study, we hypothesized that PMS might promote metformin mediated anticancer effects on liver cancer. The half maximal inhibitory concentration (IC50) of metformin was evaluated by cell viability assay. The influence of PMS on proliferation, migration, invasion and apoptosis of metformin-treated cells was evaluated by BrdU incorporation assay, flow cytometry, western blot, wound scratch healing assay, transwell cell migration assay and immunofluorescence. A fasting/feeding mouse model was built to evaluate the influence of PMS on metformin sensitivity in vivo. PMS (2.5, 10 or 40 μg/mL) treatment reduced the IC50 of metformin under different glucose concentrations. PMS (10 μg/mL) promoted metformin (5 mm) induced apoptosis and autophagy, and inhibition on proliferation, migration and invasion of HepG2 and HuH-7 cells. In the fasting/feeding mouse model, PMS (50 mg/kg) promoted metformin (200 mg/kg) induced proliferation arrest and apoptosis in vivo. Meanwhile, PMS reduced the level of pAkt(ser473) and GSK3β(ser9) in HepG2 and HuH-7 cells. Restoration of Akt/GSK3β signaling by a constitutively activated myr-Akt1 abrogated the effects of PMS on metformin-treated liver cancer cells. Our results demonstrated that PMS promoted the anticancer effects of metformin on liver cancer in vitro and in vivo.

Plantamajoside promotes metformin-induced apoptosis, autophagy and proliferation arrest of liver cancer cells via suppressing Akt/GSK3β signaling

Topological Field-Effect Transistor Based on Quasi-Two-Dimensional Tellurium Flakes

Tetrandrine (Tet), derived from the traditional Chinese herb Fangji, is a class of natural alkaloids with the structure of bisbenzylisoquinoline, which has a wide range of physiological activities and significant pharmacfological effects. However, studies and clinical applications have revealed a series of drawbacks such as its poor water solubility, low bioavailability, and the fact that it can be toxic to humans. The results of many researchers have confirmed that chemical structural modifications and nanocarrier delivery can address the limited application of Tet and improve its efficacy. In this paper, we summarize the anti-tumor efficacy and mechanism of action, anti-inflammatory efficacy and mechanism of action, and clinical applications of Tet, and describe the progress of Tet based on chemical structure modification and nanocarrier delivery, aiming to explore more diverse structures to improve the pharmacological activity of Tet and provide ideas to meet clinical needs.

Progress on structural modification of Tetrandrine with wide range of pharmacological activities

Soil moisture (SM) is a critical parameter in maintaining the balance of water cycle and energy budgets between climate system and the Earth's environment. Generalized regression neural network (GRNN) has been substantially verified as a powerful model for SM estimation due to the ability of capturing complex, non-linear relationships between predictors and responses. However, GRNN builds a full adjacency matrix using Gaussian kernel, which is computationally expensive and may ignore the local structure. In addition, it is laborious to optimize the “spread” parameter. To overcome the above issues, we propose an enhanced generalized regression neural network (EGRNN) for SM estimation, where two main adaptations are made. On the one hand, the City block distance instead of the Euclidean distance is used for building Gaussian kernel. On the other hand, k-nearest neighbors (k-NN) is adopted to yield an empirically sparse adjacency matrix. As the key advantage, the proposed EGRNN weakens the sensitivity to outliers since large differences are weighted more heavily by using Euclidean distance than City block distance. Another advantage is that EGRNN models more local and discriminant information in the pattern layer since only the data points within neighbors are connected by using k-NN. Experiments conducted in the Qinghai-Tibet Plateau (QTP) demonstrate that; 1) EGRNN outperforms the other four neural network models, with R = 0.9485 and RMSE = 0.0325 cm3/cm3; 2) It can well capture spatial-temporal dynamics and has higher consistent with the in-situ measurements; 3) It adapts well to different in-situ networks and has better generalization performance.

IEEE Journal of Selected Topics in Applied Earth Observations and Remote Sensing

Enhanced Generalized Regression Neural Network for Soil Moisture Estimation Over the Qinghai-Tibet Plateau

Abstract Zygophyllum kansuense Y. X. Liou is a localized species and endemic to China. In this study, the complete chloroplast genome of Z. kansuense was sequenced and described. The length of complete chloroplast genome was 105,383 base pairs (bp) for Z. kansuense, the genome with 33.8% GC content, containing a large single-copy (LSC) of 79,594 bp, a small single-copy (SSC) of 17,061 bp, and a pair of inverted repeats (IRs) of 4,364 bp. The genome contains 112 genes, including 75 protein-coding genes, 33 tRNA genes, and four rRNA genes. The phylogenetic analysis indicated that Z. kansuense and others of Zygophyllum clustered into one clade with a high support value.

The complete chloroplast genome sequence of Zygophyllum kansuense Y. X. Liou (Zygophyllaceae)

As a by-product of wheat planting, wheat straw is an abundant agricultural residue with the highest cellulose content of all agricultural fibers. Its resourceful utilization contributes to alleviating the environmental problems it caused. In this study, cellulose from wheat straw (WS) is used as a dispersing agent to prepare a novel multi-walled carbon nanotube-modified nickel foam (NF) electrode. The new electrode is investigated for electrochemical properties relevant to supercapacitors. The 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) oxidation is chosen to produce cellulose nanofibers (CNF) from wheat straw. The prepared CNF is used to facilitate the uniform dispersion of multi-walled carbon nanotubes (MWCNT) and favor the formation of a stable CNF-CNTs membrane on the nickel foam skeleton. The influence of dispersing materials and content of CNF on the electrochemical performance of electrodes is investigated. It is revealed that the incorporation of CNF can improve the electrochemical stability of electrodes. Moreover, it also exhibits optimum capabilities (70.2% capacitance retention from 1 to 40 mA cm−2) when CNF:MWCNT = 1:0.7. The areal capacity of the CNF-MWCNT/NF electrode for a scanning rate of 5 mV s−1 is twice that of the MWCNT/NF electrode and 30 times that of the NF electrode, indicating it is a promising candidate to ensure the synchronization of a green environment and energy development.

Isolation and Characterization of Cellulose Nanofibers from Wheat Straw and Their Application for the Supercapacitor

Non-Clay Bricks with High Compressive Strength Made from Secondary Aluminum Dross and Waste Glass

Reduced inhibitory and excitatory input onto parvalbumin interneurons mediated by perineuronal net might contribute to cognitive impairments in a mouse model of sepsis-associated encephalopathy

Cangzhou-Hengshui-Nangong subsidence, located in the southeast of North China Plain, has become the largest subsidence bowl with the maximum rates of subsidence and influenced regions in North China Plain. We employ PSInSAR and SBAS algorithms to retrieve deformation time series of Cangzhou-Hengshui-Nangong subsidence area, in order to research its spatial-temporal distribution characteristic of subsidence. Meanwhile, we discuss the correlation between groundwater depth, groundwater funnel areas and land subsidence and the deep-confined groundwater overexploitation bring about large-scale subsidence.

Research on spatial and temporal distribution and mechanism of large-scale subsidence funnel of North China Plain using InSAR time series

Ancient glass products are prone to weathering, resulting in the exchange of elements, which affects the identification of glass products. In order to solve the problem of determining the significance of surface weathering related factors and predicting the chemical composition before and after weathering, chi-square test was performed after data preprocessing, and the P-value was used to determine whether the relevant factors were significant according to the cross-thermal map.Then, with the help of the bar chart, the characteristics of the data before and after weathering of high potassium and lead and barium were visualized, and the relevant statistical rules were obtained by comparison.According to the mean values of weathering points before and after weathering, the prediction formula was constructed to calculate the content of chemical components before and after weathering, and the rationality was tested.

Analysis and identification of ancient glass components based on statistical methods

Inorganic nanomaterials with enzyme-like activity have been attracting much attention due to their low cost, favorable stability, convenient storage, and simple preparation. Herein, Co3O4 nanoplates with a uniform nanostructure were prepared by the thermolysis of cobalt hydroxide at different temperatures, and the influence of the annealing temperature on the performance of the mimetic enzyme also was reported for the first time. The results demonstrated that Co3O4 nanoplates obtained at an annealing temperature of 200 °C possessed strong oxidase activity and efficiently catalyzed the oxidation of 3,3′,5,5′-tetramethylbenzidine (TMB) without the addition of hydrogen peroxide to generate the blue color product ox-TMB. Once the annealing temperature was increased to 500 °C and 800 °C, the oxidase activity of Co3O4 decreased rapidly, and was even inactivated. This might be attributed to the relatively large specific surface area of Co3O4 annealed at 200 °C. Besides this, based on the TMB-Co3O4 nanoplate system, a colorimetric analysis method was developed to detect dopamine with a limit of 0.82 μmol/L in a linear range from 1.6 μmol/L to 20 μmol/L.

Synthesis of Co3O4 Nanoplates by Thermal Decomposition for the Colorimetric Detection of Dopamine

Climate factors affect N2O emissions by influencing the migration and transformation of nonpoint source nitrogen in an agricultural watershed.

Extracellular vesicles (EVs) are natural nanoparticles secreted by cells in the body and released into the extracellular environment. They are associated with various physiological or pathological processes, and considered as carriers in intercellular information transmission, so that EVs can be used as an important marker of liquid biopsy for disease diagnosis and prognosis. EVs are widely present in various body fluids, among which, urine is easy to obtain in large amount through non-invasive methods and has a small dynamic range of proteins, so it is a good object for studying EVs. However, most of the current isolation and detection of EVs still use traditional methods, which are of low purity, time consuming, and poor efficiency; therefore, more efficient and highly selective techniques are urgently needed. Recently, inspired by the nanoscale of EVs, platforms based on nanomaterials have been innovatively explored for isolation and detection of EVs from body fluids. These newly developed nanotechnologies, with higher selectivity and sensitivity, greatly improve the precision of isolation target EVs from urine. This review focuses on the nanomaterials used in isolation and detection of urinary EVs, discusses the advantages and disadvantages between traditional methods and nanomaterials-based platforms, and presents urinary EV-derived biomarkers for prostate cancer (PCa) diagnosis. We aim to provide a reference for researchers who want to carry out studies about nanomaterial-based platforms to identify urinary EVs, and we hope to summarize the biomarkers in downstream analysis of urinary EVs for auxiliary diagnosis of PCa disease in detail.

Nanomaterials-Based Urinary Extracellular Vesicles Isolation and Detection for Non-invasive Auxiliary Diagnosis of Prostate Cancer

An accurate dynamic model is a prerequisite for realizing precise control of industrial robots. The dynamics research of multi-degree of freedom (DOF) robots is relatively unexplored and needs to be solved urgently. In this paper, a dynamic modeling method of multibody system of 6-DOF robot is proposed based on the screw theory. The established dynamic model has a more concise and unified mathematical form, and the modular matrix expression is convenient for the control of the robot. In order to ensure that the screw method is suitable for motion in a wide range of angles, quaternions are used as generalized angular coordinates, and the model established thereby eliminates singularities and improves computational efficiency. The correctness and accuracy of the screw method is verified by the simulation example, and the modeling theory and method can provide a theoretical basis for the precise control of the robot.

Dynamic Modeling Method of Multibody System of 6-DOF Robot Based on Screw Theory

Fire behavior and transparent properties of polyvinyl chloride film with different plasticized systems

The utility model discloses a new type of flat vehicle for emergency patient transfer, comprising a support frame, a bed board, an infusion stand and a transfer assembly; the transfer assembly comprises a trapezoidal base fixed on the upper part of the support frame, and a trapezoid mounted on the bottom or side of the bed board. A sliding sleeve, a limit pin, a fixing cylinder and a spring; the trapezoidal sliding sleeve is matched on the trapezoidal base, a pin shaft hole is arranged on the trapezoidal base, the fixing cylinder is fixed on the trapezoidal sliding sleeve, and the limit pin is sleeved in the fixing cylinder, The bottom of the limit pin protrudes from the trapezoidal sliding sleeve, and the upper part is provided with a traction rod; the spring is sleeved on the traction rod, and a limiting plate is arranged at intervals on both sides of the trapezoidal base, and the limiting plate is wrapped in the trapezoidal sliding sleeve. The outer end: by setting the transfer component, the bed board is allowed to be fixed, slid and completely disengaged from the support frame, which is convenient for transferring the bed board together with the patient on it during the patient transfer process. It provides convenience for medical staff.

Head and neck squamous cell carcinoma (HNSCC or HNSC) is the sixth most common cancer worldwide. Placenta-specific 1 (Plac1) belongs to the cancer testis antigen family and is highly expressed in malignant cells in HNSC. However, the biological function and prognostic value of plac1 in HNSC are still unclear. In the current research, we performed a comprehensive analysis of plac1 using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) bulk RNA sequencing databases as well as a single-cell sequencing dataset. We constructed a 15-gene prognostic signature through screening plac1-related immunomodulators and validated its efficiency and accuracy in immunotherapy cohorts and a pancancer database. We found that plac1 expression level is a prognostic predictor of poor overall survival in patients with HNSC. Plac1 is associated with epithelial–mesenchymal transition and tumor invasion. Plac1 has a “dual immunosuppressive function” on tumor microenvironment. On one hand, plac1-positive cells promote extracellular matrix formation and suppress immune cell infiltration. On the other hand, plac1-positive cells enhance the interaction between dendritic cells and macrophages, which further suppresses antitumor immunity. Finally, we constructed a 15-gene prognostic signature, the efficiency and accuracy of which were validated in immunotherapy cohorts and a pancancer database. In conclusion, plac1 is a promising candidate biomarker for prognosis, a potential target for immunotherapy, and a novel point for studying the immunosuppressive mechanisms of the tumor microenvironment in HNSC.

Plac1 Remodels the Tumor Immune Evasion Microenvironment and Predicts Therapeutic Response in Head and Neck Squamous Cell Carcinoma

Nomogram based on MRI for preoperative prediction of Ki-67 expression in patients with intrahepatic mass cholangiocarcinoma

Background Adolescents are at high risk of Internet addiction (IA). Previous studies have shown that the occurrence of IA may be associated with childhood trauma and social support to varying degrees. This study aimed to investigate the pathogenesis of IA in adolescents. Further, to explore the potential mediating role of social support in childhood trauma and IA. This study provides theoretical support for future interventions targeting IA in adolescents. Methods This study used a descriptive cross-sectional design. The Childhood Trauma Questionnaire (CTQ), Social Support Rating Scale (SSRS), and Young’s Internet Addiction Test (IAT) were used to conduct an anonymous questionnaire survey among randomly selected adolescents aged less than 18 years old in two cities in southern Anhui Province. Descriptive statistics and correlation analysis were used to test the correlation between IA and other variables. A binary logistic regression model was used to explore the influencing factors of IA. Multiple regression models were examined with process macro and bootstrapping to confirm significant mediating effects. Results A total of 844 adolescents, equally divided between males and females, participated in this study, and the prevalence of IA in the region was 23.0%. Through the mediation test, the direct effect of childhood trauma on IA was 0.20 (95% CI [0.12, 0.27], p < 0.001), and the mediating effect of social support on childhood trauma and IA was 0.09 (95% CI [0.06, 0.14]). Conclusion The study showed that childhood trauma significantly affected the incidence of IA in adolescents. Social support had a significant mediating effect on childhood trauma and IA and attenuated its negative effects.

The relationship between Internet addiction and childhood trauma in adolescents: The mediating role of social support

The Couple-Group Consensus of Heterogeneous Multi-Agent Systems with Different Leaders Under Markov Switching in Cooperative-Competitive Networks

New polycatenated coordination polymers for the selective detection of folic acid

Multi-functional extracellular vesicles: Potentials in cancer immunotherapy.

Background: Colorectal cancer is a malignant tumor second only to lung and breast cancer in the West. The liver is the main target organ for colorectal cancer metastasis, affecting the prognosis and survival. Surgical treatment has made great progress in colorectal cancer liver metastasis , including radiofrequency ablation (RFA), high-intensity focused ultrasound (HIFU) ablation. Object: Clinical treatments for colorectal cancer liver metastases are not the same. In order to clarify the impact of surgical resection, RFA and HIFU, we provided a decision-making basis for the clinical treatment of colon cancer liver metastasis through systematic reviews and network meta-analysis (NMA). Methods: We systematically searched the Chinese and English databases: PubMed, Embase, CENTRAL, CINAHL, Web of Science, CNKI, CBM, VIP, Wan Fang. Literature screening, data extraction, and quality evaluation were carried out by two researchers, and finally, use Stata to carry out meta-analysis. Results: This study is ongoing and the results will be submitted to a peer-reviewed journal for publication. Protocol registration number: INPLASY202150044.

Comparison of prognosis among patients with colorectal cancer liver metastases treated by surgical resection, radiofrequency ablation and HIFU: A protocol for network meta-analysis

Some bounds of the generalized μ-scrambling indices of primitive digraphs with d loops

Simple interpolation algorithm and its application in power parameter estimation

Recent advances in the development of multivariate analysis methods have led to the application of multivariate pattern analysis (MVPA) to investigate the interactions between brain regions using graph theory (functional connectivity, FC) and decode visual categories from functional magnetic resonance imaging (fMRI) data from a continuous multicategory paradigm. To estimate stable FC patterns from fMRI data, previous studies required long periods in the order of several minutes, in comparison to the human brain that categories visual stimuli within hundreds of milliseconds. Constructing short-time dynamic FC patterns in the order of milliseconds and decoding visual categories is a relatively novel concept. In this study, we developed a multivariate decoding algorithm based on FC patterns and applied it to magnetoencephalography (MEG) data. MEG data were recorded from participants presented with image stimuli in four categories (faces, scenes, animals and tools). MEG data from 17 participants demonstrate that short-time dynamic FC patterns yield brain activity patterns that can be used to decode visual categories with high accuracy. Our results show that FC patterns change over the time window, and FC patterns extracted in the time window of 0∼200 ms after the stimulus onset were most stable. Further, the categorizing accuracy peaked (the mean binary accuracy is above 78.6% at individual level) in the FC patterns estimated within the 0∼200 ms interval. These findings elucidate the underlying connectivity information during visual category processing on a relatively smaller time scale and demonstrate that the contribution of FC patterns to categorization fluctuates over time.

Rapidly Decoding Image Categories From MEG Data Using a Multivariate Short-Time FC Pattern Analysis Approach

A randomised, double-blind, placebo-controlled study to evaluate the safety and efficacy of lamotrigine in the maintenance treatment of Chinese adult patients with bipolar I disorder

Objects on the earth are subject to gravity due to universal gravitation. This paper systematically studies the influence factors, including latitude, altitude, depth inside the earth, surrounding stars, on gravitational acceleration of object near the earth. The results show that latitude has a relatively large impact on gravitational acceleration; depth and altitude have the greatest impact on gravitational acceleration. The orbit and the position of the object (dayside or nightside of the earth) have little effect on the gravitational acceleration of the object. Our work can offer reference for accurate calculation of gravity acceleration.

Proceedings of the International Online Conference on Hybrid Materials and Optoelectronic Devices

Predictions of moiré excitons in twisted 2D organic–inorganic halide perovskites

Atomic Structures and Mechanical Properties of Magnetron Co-Sputtered Zr-V-N Coatings

Acceptance and Use of Mobile-Assisted Language Learning for Vocational College Students

As an important branch of array signal processing, robust adaptive beamforming (RAB) has been widely used in many fields. In the conventional robust adaptive beamformers, a common problem is that the estimated manifold vector of the signal of interest (SOI) may converge to the interference subspace. By using the data dependent constraints, such problem can be mitigated. In this paper, first we reconstruct the covariance matrices for the desired signal. Then a novel RAB is proposed in which the data dependent constraints are formed on the basis of the reconstructed signal covariance matrices. Moreover, the optimal solution to the proposed RAB can be found by the Lagrange multiplier methodology and the semi-definite generalized eigen- decomposition. Simulation results demonstrate the effectiveness of our proposed RAB.

2021 IEEE 6th International Conference on Signal and Image Processing (ICSIP)

Robust Interference Cancellation Beamforming Based on Signal Covariance Matrix Reconstruction

Flavokawain B alleviates LPS-induced acute lung injury via targeting myeloid differentiation factor 2

Extended ocular delivery of latanoprost from niosome-laden contact lenses: In vitro characterization and in vivo studies

Beamforming technology is mainly applied to increase the energy utilization efficiency in wireless communication, and to enlarge signal transmission range via multiantenna technology. The beamforming technology presented in this paper is distributed collaborative beamforming (DCBF) technology, which is a branch of cooperative communication. In this paper, we propose a phase synchronization algorithm to achieve DCBF in a distributed array. The proposed algorithm consists of two steps. First, in order to improve the convergent speed of the phase alignment, we traverse all N possible initial phases of each node to determine a local optimum iteration point. Then we perform two-bit feedback iteration to ensure that the normalized received signal strength (NRSS) reaches the threshold of cooperative beamforming. Numerical results demonstrate that proposed algorithm offers better phase synchronization performance compared with the classical one-bit feedback method and two-bit feedback method.

Two-step Phase Synchronization Algorithm for Distributed Collaborative Beamforming

Integrated analysis of lncRNA–miRNA–mRNA ceRNA network and the potential prognosis indicators in sarcomas

Background Chordoma is a rare malignant bone tumor with high recurrence and metastasis rates. Little is known about the mutational process of this incurable disease. The aim of our research was to explore the potential driver genes and signal pathways in the pathogenesis of chordoma and provide a new idea for the study of molecular biological therapy of chordoma. Methods We performed whole-exome-sequencing (WES) on 8 sacrum chordoma tissue samples (matched to peripheral blood samples that had been drawn from patients before surgery) to identify genetic alterations in Chinese patients. We analyzed the sequencing data from known driver genes, pathway enrichment analysis and significantly mutated genes (SMGs) after quality control of sequencing, comparison of reference genomes, analysis of mutations and identification of somatic mutations. Immunohistochemistry staining, Sanger sequencing and GeneChip were used to verify the related genes obtained from the analysis of sequencing data. Results The driver genes Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA), Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1), and Phosphatase And Tensin Homolog (PTEN) were enriched in the Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway and could be potential therapeutic targets for the treatment of sacrum chordoma. The significantly mutated gene Claudin 9 (CLDN9) may play a critical role in the development and progression of sacrum chordoma. Conclusions Collectively, our results identified the genetic signature of sacrum chordoma and could be used to develop a potential promising therapeutic strategy for the treatment of sacrum chordoma in Chinese patients.

Clinical and molecular features of sacrum chordoma in Chinese patients

Intelligent Proximate Analysis of Coal Based on Near-Infrared Spectroscopy

The important direction of information hiding is digital watermarking technology. The traditional digital watermarking is advantage to against general attacks, but it is difficult to the geometrial distortions. This paper proposes a novel digital watermarking based on discrete cosine transform and support vector machine. Firstly, the block discrete cosine transformation is used for watermarking embedding, then the trained support vector machine is used to roughly correct the geometric parameters and the template matching method is used to correct the existing errors. Experiments show that the purposed algorithm is not only against traditional attacks such as noise, filtering and clipping, but also better robustness against geometrial distortions.

2021 IEEE 4th International Conference on Automation, Electronics and Electrical Engineering (AUTEEE)

Background There has been an increase in research on the potential adverse effects on children’s mental health, especially depression and anxiety, during the coronavirus disease 2019 (COVID-19) pandemic over the past few months. Therefore, the aim of the present study was to investigate depression and anxiety symptoms among children in shelter hospitals during the 2022 Shanghai lockdown. Methods A total of 98 infected children aged 7–12 years were enrolled in this study between April 19 and June 4, 2022. The Children’s Depression Inventory (CDI), Anxiety Scale for Children-Autism Spectrum Disorder (ASC-ASD), and Anxiety Scale or Children-Autism Spectrum Disorder Parent Form (ASC-ADS-P) were used to assess children’s depression and anxiety symptoms. Children’s guardians completed the survey by verbally asking their child/children the questions. The guardians additionally completed the ASC-ASD-P. Results The prevalence of depression and anxiety was 12.2% and 13.3%, respectively. A total of 66 respondents reported no physical symptoms. Linear regression showed that myalgia [7.198, 95% confidence interval (CI): 3.163–11.232], headache (7.189, 95% CI: 3.842–10.535) coryza (5.362, 95% CI: 2.654–8.070), and number of quarantine days (4.378, 95% CI: 3.409–5.348) were significantly correlated with higher levels of depression, whereas chills (14.337, 95% CI: 9.799–18.875), coryza (9.309, 95% CI: 6.467–12.152), headache (7.193, 95% CI: 3.182–11.204), myalgia (5.571, 95% CI: 0.684–10.459), number of quarantine days (3.190, 95% CI: 1.796–4.584), and gender (male) (−4.137, 95% CI: −6.609 to 1.665) were associated with anxiety scores. Persistent fever was correlated with depression (P=0.007), whereas physical discomfort, such as persistent fever, cough, sore throat, headache, myalgia, and coryza were correlated with anxiety (all P<0.05). Conclusions The findings of the present study indicated a moderate prevalence of depression and anxiety among infected children in a shelter hospital during the 2022 Shanghai lockdown. Therefore, the findings of this study could provide scientific basis for the development of targeted psychological intervention. It could be helpful for policy-makers to focus on psychological health among infected children and help to optimize future interventions.

Mental health status of infected children between 7 to 12 years old in Fangcang Shelter Hospital during the COVID-19 Shanghai lockdown in 2022: a cross-section study

Geothermal resource is indispensable as a clean, renewable, stable and cheap resource. Nowadays in China, the Gonghe Basin, located in northeastern Qinghai Province, has been thought to be a promising geothermal area. To explore geothermal energy potential in and around the Gonghe Basin, geophysical means including magnetic and gravity methods were used to plot distribution. Firstly, we inversed Moho depth and Curie point depth in and around the basin using gravity and magnetic data, respectively, through an improved Parker–Oldenburg algorithm. Secondly, seven different thermal models were established, considering radiogenic heat, basement depth, anomalous heat source and simulated corresponding temperature field and heat flow. These were analyzed numerically and we found the high heat flow in the Gonghe Basin co‐acted with radiogenic heat, an anomalous heat source and conductive heat. The distribution of seismic activities indicates that the Langshan–Wuwei–Gonghe Fault might have provided channels for transporting heat effectively.

Heat Flow Distribution and Thermal Mechanism Analysis of the Gonghe Basin based on Gravity and Magnetic Methods

Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease characterized by synovitis and symmetrical joint destruction. RA has become one of the key diseases endangering human health, but its etiology is not clear. Therefore, identifying the immunopathogenic mechanisms of RA and developing therapeutic drugs to treat autoimmune diseases have always been difficult. This article mainly reviews the immunopathogenic mechanism of RA and advances in the study of anti-inflammatory drugs in order to provide a reference for the treatment of RA and drug development in the future.

Immunopathogenic mechanisms of rheumatoid arthritis and the use of anti-inflammatory drugs.

Interstitial free steels with various grain sizes and textures were prepared by cold-rolling followed by an annealing process. The effect of grain size, crystallographic orientations and stored energy on corrosion behavior of interstitial free steel was investigated. It was found that the deformed microstructure and dislocation boundaries were consumed by recrystallizing grains during annealing. The average grain size increase ranging from 0.61 μm to 11 μm and the volume fraction of recrystallized grains was about 96% after annealing for 64 h; meanwhile, the γ fiber was the dominated recrystallized texture component. The stored energy gradually decreased due to the reduction in dislocation density by annealing. The potentiodynamic polarization and Nyquist plots show that the corrosion potential exhibits a more positive shift and depressed capacitive semicircle radius increase with rising annealing time. The 64 h annealed specimens had the biggest depressed semicircle in the Nyquist plots and the highest positive corrosion potential, which indicates the enhancement of corrosion resistance. Such an improvement of corrosion resistance is attributed to the increase in the volume fraction of the γ fiber and decrease in the stored energy.

Effect of Annealing on Microstructure and Corrosion Behavior of Interstitial Free Steel

Research progress on occurrence characteristic and toxicity of microplastics in marine organisms

OBJECTIVE
To explore the application of serum peptidomics in the early diagnosis of pancreatic ductal adenocarcinoma (PDAC).

METHODS
The serum specimens from 176 patients with PDAC and 158 healthy control patients were subjected to matrix-assisted laser desorption ionization time-of-flight mass spectrometry to obtain serum peptide profiles. Next, a classification model by differentiated peptides was established and verified to distinguish the 2 groups. Finally, the peptides were identified by tandem mass spectrometry.

RESULTS
A classification model was established by 13 peptides. For patients with PDAC in the early stage, the sensitivity and specificity of the model reached 100% and 96.7%, respectively. The amino acid sequences of the 13 peptides were then determined and the types of proteins were identified, including platelet basic protein, fibrinogen alpha, complement C3, and secreted frizzled-related protein 4. Some of the 13 peptides could be potential PDAC biomarkers.

Serum peptidomics may have potential application in the early diagnosis of PDAC.

MALDI-TOF-MS Analysis in the Discovery and Identification of the Serum Peptide Pattern of Pancreatic Ductal Adenocarcinoma.

: This case study of Zhejiang Geely Holding Group Co., Ltd ( (hereinafter referred to as Geely)), China's first automotive multinational enterprise, analyzes how a latecomer in an emerging country, in a disadvantaged position, continuously seeks to surpass itself despite its own lack of innate resources and technological conditions, uses cross-border M&A as a lever to leapfrog its capabilities, dynamically integrates and utilizes internal and external resources , which has evolved from a locally based enterprise to a global enterprise and successfully caught up with the industry leaders in some fields, using internal and external resources to cross the technological innovation gap and promote strategic transformation.

Puerarin Attenuated Excessive Extracellular Matrix Accumulation in Diabetic Nephropathy Through Inhibiting Glomerular Mesangial Cells Ferroptosis

AbstractGeopolymers and alkali-activated materials (AAM) have emerged as a promising sustainable alternative to ordinary Portland cement (OPC). Although much effort has recently been devoted to a w...

Crack Self-Healing in NaOH-Activated Slag-Based Composites Incorporating Calcium Hydroxide

Adequate time and effective training facilities are essential for undergraduate dental students participating preclinical dental practice to ensure them providing safe treatment for patients in the future. The study aimed to explore the current status of preclinical dental training in China in relation to the curriculum setting and students' feedback of pre-clinical training in different dental schools and thus provide information for further standardize curricula.

MATERIALS AND METHOD
An online questionnaire was distributed electronically to undergraduates in 44 Chinese dental schools of different levels according to China Discipline Ranking (CDR). The questionnaire collected information in relation to the training hour and student to facility ratio of four main dental courses (cariology and endodontics, periodontology, prosthodontics and oral surgery), as well as the application and effect of virtual reality (VR) simulator in preclinical dental practice in different schools. Students' feedback was also collected.

RESULTS
565 valid questionnaires were recruited. Results of this cross-sectional survey show that training hour of periodontology course was the lowest, and oral surgery course showed most prominent shortage of facilities. The application of VR simulator among schools is uneven. Students from A and A+ level schools showed higher satisfaction with their pre-clinical courses and reported a more positive attitude toward the use of VR simulator than other students. (p<0.05).

Pre-clinical dental training in China remained imperfect in insufficient training time, training facility and students didn't have access to standard pre-clinical training and quality assurance. VR technique has potential values in preclinical dental practice in China.

European journal of dental education : official journal of the Association for Dental Education in Europe

Curriculum setting and students' feedback of pre-clinical training in different dental schools in china- A national-wide survey.

Background Post-stroke depression (PSD) is a common complication after stroke. Ganoderic acid A (GAA), one of the main bioactive Ganoderma triterpenoids, exerts preventive and therapeutic effects in many diseases. However, the function of GAA in PSD has not been well studied. Methods PSD model was established via stimulating rats with chronic unpredictable mild stress stimulations (CUMS) after middle cerebral artery occlusion (MCAO). Rats were treated with GAA before CUMS. Depressive-like behaviors were investigated by body weight alteration, open field test (OFT), and sucrose preference test (SPT). Neuronal damage was evaluated by hematoxylin and eosin (HE) staining and Western blotting. Inflammation was detected by enzyme-linked immunosorbent assay (ELISA) and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Microglial polarization was analyzed via qRT-PCR and Western blotting. The extracellular signal-regulated kinase (ERK)/cAMP-response element-binding protein (CREB) pathway was analyzed by Western blotting, and inactivated by the inhibitor PD98059 (PD). Results GAA attenuated PSD-induced depressive-like behaviors in rats. GAA mitigated PSD-induced neuronal damage and reduced BDNF and NGF levels in the cerebral hippocampus. GAA weakened PSD-induced inflammatory response in the cerebral hippocampus. GAA prevented pro-inflammatory (M1) polarization and promoted anti-inflammatory (M2) polarization, as indicated by decreased iNOS and CD86 levels and increased Arg-1 and CD206 levels. GAA restored the PSD-induced inactivation of the ERK/CREB pathway. GAA regulated M1/M2 microglial polarization by activating the ERK/CREB pathway. Conclusion GAA alleviated the depressive-like behaviors and brain inflammation in PSD rats, indicating its potential for PSD therapy.

Ganoderic Acid A-Mediated Modulation of Microglial Polarization is Involved in Depressive-Like Behaviors and Neuroinflammation in a Rat Model of Post-Stroke Depression

miR-29a-3p inhibits endometrial cancer cell proliferation, migration and invasion by targeting VEGFA/CD C42/PAK1

Abstract Ovarian cancer is a common and complex malignancy with poor prognostic outcome. Most women with ovarian cancer are diagnosed with advanced stage disease due to a lack of effective detection strategies in the early stage. Traditional treatment with cytoreductive surgery and platinum-based combination chemotherapy has not significantly improved prognosis and 5-year survival rates are still extremely poor. Therefore, novel treatment strategies are needed to improve the treatment of ovarian cancer patients. Recent advances of next generation sequencing technologies have both confirmed previous known mutated genes and discovered novel candidate genes in ovarian cancer. In this review, we illustrate recent advances in identifying ovarian cancer gene mutations, including those of TP53, BRCA1/2, PIK3CA, and KRAS genes. In addition, we discuss advances in targeting therapies for ovarian cancer based on these mutated genes in ovarian cancer. Further, we associate between detection of mutation genes by liquid biopsy and the potential early diagnostic value in ovarian cancer.

Cellular Mechanism of Gene Mutations and Potential Therapeutic Targets in Ovarian Cancer

Evaluation of Roasting Conditions as an Attempt to Improve Bioactive Compounds and Antioxidant Activities of Pine Nut Shell and Skin

Construction and comprehensive analysis of a ceRNA network to reveal potential prognostic biomarkers for lung adenocarcinoma

Nowadays, the emerging photoelectrochemical (PEC) bioanalysis has drawn intensive interest due to its numerous merits. As one of its core elements, functional nanostructured materials play a crucial role during the construction of PEC biosensors, which can not only be employed as transducers but also act as signal probes. Although both chemical composition and morphology control of nanostructured materials contribute to the excellent analytical performance of PEC bioassay, surveys addressing nanostructures with different dimensionality have rarely been reported. In this review, according to classification based on dimensionality, zero-dimensional, one-dimensional, two-dimensional, and three-dimensional nanostructures used in PEC bioanalysis are evaluated, with an emphasis on the effect of morphology on the detection performances. Furthermore, using the illustration of recent works, related novel PEC biosensing patterns with promising applications are also discussed. Finally, the current challenges and some future perspectives in this field are addressed based on our opinions.

Recent Advances of Nanostructured Materials for Photoelectrochemical Bioanalysis

Land subsidence monitoring in mining areas is one of the main applications of surface deformation monitoring, which is of great significance for safety production. Using the IPTA (Interferometric Point Target Analysis) time-series InSAR (Interferometry Synthetic Aperture Radar) method, land subsidence data of the new exploration area in the Weizhou mining area were analyzed and compared with static GPS (Global Positioning System) monitoring data from 2017 to 2020. Gray-Markov model was established by combining the gray prediction model with the Markov model to predict the surface subsidence of the mining area. The results show that <xref rid="deqn1" ref-type="disp-formula">(1)</xref> InSAR data has high accuracy and application potential in prediction of long-term surface deformation in mining areas; <xref rid="deqn2" ref-type="disp-formula">(2)</xref> The Gray-Markov model can better reflect the volatility and practicality of subsidence data in mining areas; <xref rid="deqn3" ref-type="disp-formula">(3)</xref> The prediction results have high accuracy, and the Gray-Markov model can serve as an effective guide for long-term surface deformation monitoring and safety management.

Application of Gray-Markov Model to Land Subsidence Monitoring of a Mining Area

Chinese hamster ovary cells are the predominant cell lines used for bio-therapeutic production. Real-time quantitative PCR (RT-qPCR) and transcriptomics are powerful tools to understand and optimize the Chinese hamster ovary cells for higher productivity or better control of product qualities. Reliable reference genes, which were proved to be experiment-specific, are critical yardsticks. In this study, we compared expression stability of 20 candidate reference genes at mRNA level, including commonly used housekeeping genes, previous literature reported genes in Chinese hamster ovary cells producing an intact antibody, and new candidates suggested by our RNA-seq transcriptomic database, in RT-qPCR reactions in Fc-fusion protein-producing Chinese hamster ovary cells with various productivity during long-term cultivation and fed-batch cultures at 26 different conditions. geNorm, NormFinder, BestKeeper, and ΔCt programs and methods were utilized to analyze the gene expression stability and gave an overall ranking. Akr1a1, Gpx1, and Aprt in long-term cultivation and Akr1a1, Rps16 in fed-batch culture, which have not been reported previously, exhibited the highest stability of gene expression, while Pabpn1, Hirip3, and Actb in both sets of experiments together with Atp5f1 in long-term passage process showed the weakest stability. The results were then validated using GLP1-Fc (Glucagon-like peptide-1 Fc fusion protein) gene as the target with determined expression level which were doubly confirmed by both absolute RT-qPCR and confocal microscopy. These new references should be considered for the investigations on Chinese hamster ovary cells in related research. Impact statement In order to reveal potential genotype-phenotype relationship, RT-qPCR reactions are frequently applied which require validated and reliable reference genes. With the investigation on long-term passage and fed-batch cultivation of CHO cells producing an Fc-fusion protein, four new reference genes–Akr1a1, Gpx1, Aprt, and Rps16, were identified from 20 candidates with the aid of geNorm, NormFinder, BestKeeper, and ΔCt programs and methods. This article provided more verified options in reference gene selection in related research on CHO cells.

Validation and identification of reference genes in Chinese hamster ovary cells for Fc-fusion protein production

Thyroid ultrasonography is widely used to diagnose thyroid nodules in clinics. Automatic localization of nodules can promote the development of intelligent thyroid diagnosis and reduce workload of radiologists. However, besides the ultrasound image has low contrast and high noise, the thyroid nodules are diverse in shape and vary greatly in size. Thus, thyroid nodule detection in ultrasound images is still a challenging task.

OBJECTIVE
This study proposes an automatic detection algorithm to locate nodules in B ultrasound images and Doppler ultrasound images. This method can be used to screen thyroid nodules and provide a basis for subsequent automatic segmentation and intelligent diagnosis.

METHODS
We develop and optimize an improved YOLOV3 model for detecting thyroid nodules in ultrasound images with B-mode and Doppler mode. Improvements include (1) using the high-resolution network (HRNet) as the basic network for gradually extracting high-level semantic features to reduce the missed detection and misdetection, (2) optimizing the loss function for single target detection like nodules, and (3) obtaining the anchor boxes by clustering the candidate frames of real nodules in the dataset.

RESULTS
The experimental results of applying to 8000 clinical ultrasound images show that the new method developed and tested in this study can effectively detect thyroid nodules. The method achieves 94.53% mean precision and 95.00% mean recall.

CONCLUTIONS
The study demonstrates a new automated method that enables to achieve high detection accuracy and effectively locate thyroid nodules in various ultrasound images without any user interaction, which indicates its potential clinical application value for the thyroid nodule screening.

Automated location of thyroid nodules in ultrasound images with improved YOLOV3 network.

To examine the results of raloxifene for prevention of periprosthetic bone loss around the femoral stem in patients undergoing total hip arthroplasty (THA).

Raloxifene Prevents Early Periprosthetic Bone Loss for Postmenopausal Women after Uncemented Total Hip Arthroplasty: A Randomized Placebo‐Controlled Clinical Trial

Accelerators have been widely used in SoC systems as an effective method to improve computing power. There are many ways of which CPU is coupled with accelerator. In this paper, we design a matrix-matrix multiplication accelerator and couple the accelerator with RISC-V CPU in two different forms - independent accelerator and instruction accelerators. Then we evaluate the performance of independent accelerator and new instruction accelerator. The matrix independent accelerator achieves up to 19.6x speedup to the Rocket CPU. And the matrix instruction accelerator achieves up to 44.5x speedup to the Rocket CPU. The instruction accelerator is 2.26x faster than independent accelerator.

2020 IEEE 2nd International Conference on Circuits and Systems (ICCS)

Design Space Exploration for Heterogenous SoC Integrated with Matrix Accelerator

Preparation and Certification of a New Salvianolic Acid A Reference Material for Food and Drug Research

Skeleton-based action recognition has attracted considerable attention since the skeleton data is more robust to the dynamic circumstances and complicated backgrounds than other modalities. Recently, many researchers have used the Graph Convolutional Network (GCN) to model spatial-temporal features of skeleton sequences by an end-to-end optimization. However, conventional GCNs are feedforward networks for which it is impossible for the shallower layers to access semantic information in the high-level layers. In this paper, we propose a novel network, named Feedback Graph Convolutional Network (FGCN). This is the first work that introduces a feedback mechanism into GCNs for action recognition. Compared with conventional GCNs, FGCN has the following advantages: (1) A multi-stage temporal sampling strategy is designed to extract spatial-temporal features for action recognition in a coarse to fine process; (2) A Feedback Graph Convolutional Block (FGCB) is proposed to introduce dense feedback connections into the GCNs. It transmits the high-level semantic features to the shallower layers and conveys temporal information stage by stage to model video level spatial-temporal features for action recognition; (3) The FGCN model provides predictions on-the-fly. In the early stages, its predictions are relatively coarse. These coarse predictions are treated as priors to guide the feature learning in later stages, to obtain more accurate predictions. Extensive experiments on three datasets, NTU-RGB+D, NTU-RGB+D120 and Northwestern-UCLA, demonstrate that the proposed FGCN is effective for action recognition. It achieves the state-of-the-art performance on all three datasets.

Feedback Graph Convolutional Network for Skeleton-Based Action Recognition

The current quality of system routing available in wireless sensor network mainly provides assurance for traffic flow, with little consideration on full use of network resource, like bandwidth. Aiming at solving these problems, this article proposes a quality of system routing method based on neighborhood interference detection and mitigation. First, the algorithm uses a sink node as root node to establish a minimum spanning tree for the network to obtain the depth of each node. Then, each node dynamically updates its interference degree by contiguous iterations during neighboring nodes communication. Finally, the interference degree, packet level, residual energy, and node depth are combined to establish a multipath route to enhance the network bandwidth and thus improve the quality of system. Experimental results show that the algorithm can not only effectively balance the network load but also reduce the network packet delay and improve the network throughput. It also has a good network lifetime; thus, it can effectively improve the quality of system of wireless sensor network.

A quality of system routing based on neighborhood interference detection and mitigation in wireless sensor network

Frontispiece: Recent Progress in Precious Metal‐Free Carbon‐Based Materials towards the Oxygen Reduction Reaction: Activity, Stability, and Anti‐Poisoning

Corncob and Graphene oxide were used to prepare and characterize corncob/graphene oxide (GO/CC) composites. The adsorption performance of GO/CC on dye wastewater was studied, and the factors affecting the adsorption effect were investigated. The results showed that GO/CC had rich functional groups which could provide sufficient binding sites for Congo red. It could remove Congo red solution strongly, and the removal rate was as high as 80%. GO/SP was endothermic in the process of Congo red adsorption. The reaction was mainly based on chemical adsorption.

Synthesis of Graphene Oxide/Corn Cob Composites and investigation of their adsorption performance of Dye

ABSTRACT Considering the vulnerability of cultural heritage site from over-tourism, this paper develops a resilience evaluation index system to evaluate a cultural heritage site for sustainable tourism development. The system consists of 3 Level I sub-systems, socio-cultural, economic, and ecological ones, and 19 Level II indicators. Using Jiangwan town in China as a case, we calculate the resilience evaluation index during 2010–2014 and investigate the factors explaining the variation of this index over time. The results indicate that the degree of cultural inheritance and protection level of value characteristics are the main resilience determinants. Lastly, specific implications are proposed.

Developing a resilience evaluation index for cultural heritage site: case study of Jiangwan Town in China

Screening, Characterization and Evaluation of Mangiferin Polymorphs

Because of the influence of clutter and interference, intelligent detection is of great importance for high-frequency surface wave radar (HFSWR) in complex environment. In this paper, we propose a cascade HFSWR target detection strategy based on semi-supervised self-distillation (<inline-formula> <tex-math notation="LaTeX">$\sf S^{3}D$ </tex-math></inline-formula>) learning algorithm. First, based on the results of constant false alarm rate (CFAR) detection, the <inline-formula> <tex-math notation="LaTeX">$\sf S^{3}D$ </tex-math></inline-formula> algorithm proposed in this paper further classifies the real and other targets. Moreover, the non-maximum suppression (NMS) is combined to remove redundant target boxes, in order to achieve accurate location. For supervised learning, the classification needs to label all the samples, which is extremely difficult and time consuming, especially for HFSWR data under complex environment. While the <inline-formula> <tex-math notation="LaTeX">$\sf S^{3}D$ </tex-math></inline-formula> algorithm can make use of both labeled and unlabeled samples. For labeled data, labels are directly used to restrict both the deep and shallow layers of the network, so that both layers represent the same semantic categories. For unlabeled data, the pseudo-label is retained only if the deepest layer produces a high-confidence prediction. The deep and shallow layers are then updated to predict the pseudo-label when fed a strongly augmented version of the same unlabeled samples. The above multiple consistency regularization methods can improve the generalization performance of the network effectively. Finally, the simulations conducted across public datasets show that compared with other semi-supervised learning methods, <inline-formula> <tex-math notation="LaTeX">$\sf S^{3}D$ </tex-math></inline-formula> can better improve the performance of network generalization. Besides, the <inline-formula> <tex-math notation="LaTeX">$\sf S^{3}D$ </tex-math></inline-formula>-based HFSWR target detection method can significantly improve the vessel detection performance by using only a minority of sample labels.

Numerical Simulation of Gas-Particle Two-Phase Chemical Reactions and Key Structure Optimization in the Lead Flash Smelting Furnace

Abstract Rationale: Mixed gonadal dysgenesis is a rare disorder of sex development, and typically contains a mosaic 45,X/46,XY karyotype. Patient concerns: We reported here a case of a 42-year-old man with infertility for 6 years and inability to ejaculate during intercourse. Diagnosis: Physical examination confirmed that the external genitalia was male. The right testis of this patient was resected and the left testis had intrascrotal calcification. Hormone test showed that the level of follicle-stimulating hormone was 20.14 IU/L (normal range, 1.27–19.26 IU/L). No deletion or mutation was found on the sex-determining region Y. H&E staining revealed seminiferous tubule dysgenesis. The karyotyping in peripheral blood and testicular tissue was 45,X/46,XY and 45,X/47,XYY/46,XY, respectively. Based on these results, the patient was diagnosed with 45,X/46,XY or 45,X/47,XYY/46,XY mosaicism and gonadal dysgenesis. Interventions: In vitro fertilization and embryo transfer technology were used to help his wife to achieve pregnancy. Outcomes: A normal baby boy was born at 36 weeks of gestation with a karyotype 46, XY. Lessons: We reported a rare case of a karyotype 45,X/46,XY in blood cells and 45,X/47, XYY/46,XY in testicular tissue. In vitro fertilization and embryo transfer technology can help to achieve pregnancy.

Successful surgical sperm retrieval from a patient with 45,X/46,XY mosaicism followed by in vitro fertilization pregnancy

A plagiarism detection approach for Chinese documents based on semantic textual similarity

Data on rotary die filling performance of various pharmaceutical powders

ABSTRACT Chu, P.; Zhang, L.; Huo, W.; Wang, K., and Chen, Y., 2020. Analysis of high-resolution underwater acoustic imaging technology in multi-subarray beam domain. In: Gong, D.; Zhang, M., and Liu, R. (eds.), Advances in Coastal Research: Engineering, Industry, Economy, and Sustainable Development. Journal of Coastal Research, Special Issue No. 106, pp. 518–521. Coconut Creek (Florida), ISSN 0749-0208. The development of ocean resources and the research of ocean engineering are inseparable from the acquisition and mastery of underwater scene information, and the most important way to obtain this information is underwater acoustic imaging technology. This paper is divided into two parts: theoretical research and model simulation. In the theoretical research, the principle of traditional the split-beam phase detection method and the basic principle of cross-correlation detection technology of the phase center in beam domain are analyzed. Then, the signal model is established, and the conclusion that the number of subarray elements is positively correlated with the resolution of the system is obtained. Finally, the simulation model of the seabed is established to verify the algorithm of multi-subarray beam domain seabed detection and the high-resolution underwater acoustic imaging system.

Analysis of High-Resolution Underwater Acoustic Imaging Technology in Multi-Subarray Beam Domain

Abstract E-waste, also known as waste electrical and electronic equipment, has become one of the fastest growing waste streams worldwide. As the world’s largest e-waste processing country, China’s e-waste management practice is facing multiple barriers to meet the requirement of sustainability from the economic, environmental and social perspectives. With an empirical study on the e-waste management practice of a major province in Western China, this paper develops an integrated planning approach for evaluating and managing the barriers which have mutual influence on their impact on the e-waste management practice. In consideration of interactive relationships of the barriers, a barrier assessment process is developed to assess the direct and indirect impacts of the barriers on the sustainable e-waste management practice in terms of economic, environmental and social sustainability criteria. A strategic planning process is proposed to categorise the barriers into four planning zones based on their overall impact and mitigation level. This paper contributes to e-waste management research by providing a structured approach for managing interactive barriers to achieve sustainable e-waste management. The proposed approach represents a methodological contribution to multicriteria evaluation research involving sustainability criteria and interactive alternatives.

Evaluating and managing interactive barriers for sustainable e-waste management in China

Transplantation of Mesenchymal Stromal Cells Expressing the Human Preproenkephalin Gene Can Relieve Pain in a Rat Model of Neuropathic Pain

Assessing the renewable energy investment risk factors for sustainable development in Turkey

Abstract Bioactivity modification helps polymethylmethacrylate (PMMA) bone cement to reinforce its interfacial adhesion to bone tissues through the chemical bonding of apatite. Since Si-OH groups combined with Ca2+ ions have succeeded in inducing apatite formation, more combinations of functional groups and active ions are being explored. In this study, Bis[2-(methacryloyloxy)ethyl] phosphate (B2meP) containing phosphate (=PO4H) groups and Ca(CH3COO)2 supplying Ca2+ ion were adopted to investigate the feasibility of equipping PMMA bone cement with apatite-forming ability in vitro, more effects under designed contents on setting behavior, injectability, contact angle, cytotoxicity and mechanical strength were also investigated. Results showed B2meP copolymerized with MMA and became one section of PMMA chains, surface = PO4H groups and released Ca2+ ions pushed spherical apatite individuals nucleating and agglomerating into layer horizontally, Increasing B2meP content lowered the contact angle and the peak temperature, enhanced the cell viability of MC3T3-E1, but prolonged apatite forming period. Injectability rate performed a similar trend to setting time. Lower adding content and deposited apatite layer contributed to reduce the strength loss in soaking. Taking biological performance and other properties into balance, cement added with B2meP of 10 wt% in MMA and Ca(CH3COO)2 of 20 wt% in PMMA performed better.

Setting behavior, apatite-forming ability, mechanical strength of polymethylmethacrylate bone cement through bioactivity modification of phosphate functional groups combined with Ca2+ ions

Objective To investigate the clinical manifestations of infectious mononucleosis in children of different ages. Methods Clinical data from pediatric patients with infectious mononucleosis admitted from May 2015 to April 2019 were retrospectively analyzed. Patients were stratified into three groups (age 1–3 years, 4–6 years, and 7–14 years) for analysis of clinical and laboratory results. Results Data from 61 patients (male:female ratio 1.18:1) aged 5.15 ± 2.93 years (mean ± standard deviation; range: 1–14 years) were analyzed. Infectious mononucleosis occurred throughout the year and the main clinical manifestations were fever (98.3%), tonsillitis (100%), tonsillar white exudate (83.6%), cervical lymphadenopathy (98.3%), hepatomegaly (37.7%), splenomegaly (42.6%), eyelid edema (41.0%), and nasal obstruction (49.2%). Disease onset was most common during early childhood (37.7%) and at preschool age (37.7%). Younger children had more obvious symptoms of nasal obstruction and older children had more significant elevations of alanine aminotransferase and higher percentages of atypical lymphocytes. Conclusion The clinical manifestations of infectious mononucleosis in children differed by age. These associations required attention for clinical decision making.

Clinical manifestations and laboratory results of 61 children with infectious mononucleosis

The Influence of Referral Cognition on Referral Intention Among Outpatient Patients: An Empirical Research

Plug-and-play unidimensional continuous-variable quantum key distribution

Transcriptomic analysis of resistant and susceptible banana corms in response to infection by Fusarium oxysporum f. sp. cubense tropical race 4

The occurrence and development of congenital microtia are the result of multiple factors and mechanisms, including genetic factors, living environment and lifestyle, etc. However, genetics is the key to understand the etiology of congenital microtia. In this paper, the genetics of microtia was reviewed in the aspects of epigenetics, gene polymorphism, chromosomal change, genetic change and signal pathway. The etiology of microtia was discussed and summarized. 
 
Key words: 
Congenital microtia; Genetics; Etiology

Specification of floral organ identity is critical for floral morphology and inflorescence architecture. Floral organ identity in plants is controlled by floral homeotic A/B/C/D/E-class genes. Although multiple genes regulate floral organogenesis our understanding of the regulatory network remains fragmentary. Here, we characterized rice floral organ gene KAIKOUXIAO (KKX), mutation of which produces an uncharacteristic open hull, abnormal seed, and semi-sterility. KKX encodes a putative LEUNIG-like (LUGL) transcriptional co-repressor. OsLUGL is preferentially expressed in young panicles and its protein can interact with OsSEU, which functions were reported as an adaptor for LEUNIG. OsLUGL-OsSEU functions together as a transcriptional regulatory complex to control organ identity specification through regulation of MADS-box genes. During this process, SEP3 (such as OsMADS8) and AP1 (such as OsMADS18) serve as the DNA-binding partner of OsLUGL-OsSEU complex. Further studies indicated that OsMADS8 and OsMADS18 could bind the promoter of OsGH3-8 and regulate its expression. The altered expression of OsGH3-8 caused the increased auxin level and the decreased expression of OsARFs. Overall, our results demonstrate a possible pathway whereby OsLUGL-OsSEU-OsAP1-OsSEP3 complex as a transcriptional regulator by targeting the promoter of OsGH3-8 directly, affecting auxin level, OsARFs expression level and thereby influencing floral development. These findings provide a valuable insight into the molecular functions of OsLUGL in rice floral development. Highlight OsLUGL through forming OsLUGL-OsSEU-OsAP1-OsSEP3 complex regulate OsGH3-8 expression, and regulate auxin level and OsARFs expression indirectly. This work is a new insight to floral development molecular mechanism.

OsLUGL involved in floral development through regulating auxin level and OsARFs expression in rice (Oryza sative L.)

Gastightness testing plays an increasingly important role in ensuring the quality and performance of sealed products and the safety of their use. In this paper, a gas tightness detection scheme based on carbon dioxide gas sensor is proposed. The adaptive weighted fusion algorithm is used to fuse the weighted data collected by multiple carbon dioxide sensors to compensate for the error of single sensor test. The method is applied to leak detection of tracer gas, with high detection accuracy and wide range to meet production demand.

Application of Weighted Fusion Algorithm in Air Tightness Detection Device

As the flagship species of biodiversity conservation in China, the giant panda has significant ecological protection value and plays an important demonstrative role for conservation. Sichuan Province has the largest area of giant panda habitat, making its protected areas the most important for the conservation of this species. However, the habitats of the giant panda are shrinking due to human disturbance through land encroachment for agriculture and other forms of resource exploitation. Reducing these pressures requires assessing current land use and the causes of fragmenting giant panda habitats. This paper reports on changes in land-use patterns and socio-economic development in typical counties with giant panda habitats in Sichuan in 2003 and 2015, with a focus on giant panda protection areas and human pressures in the surrounding lands. We found that road construction, industrial infrastructure, and other forms of economic development have led to increases in human populations and fragmentation of the giant panda habitats, such that that the population of this species has been significantly reduced in some counties. Improving the protection of giant panda requires designing regional economic development activities based on scientific principles to provide benefits to both the local people and the giant pandas. For example, when making land use plans, the local government should consider the impact of the development of the communities surrounding the giant panda areas on the giant pandas’ habitat.

The Landscape Patterns of the Giant Panda Protection Area in Sichuan Province and Their Impact on Giant Pandas

Effects of Hydrothermal Time on the Properties, Morphology and Photocatalytic Activity of Rose‐Like Microspheres ZnIn
 2
 S
 4

The Cu–3%Ag alloy was prepared by continuous unidirectional solidification technique. The composition distribution of continuous unidirectional solidification Cu–3%Ag alloy was analyzed. The effect of different mold temperatures on the composition distribution of alloy was studied. The results show that when the mold temperature is low, continuous unidirectional solidification Cu–3%Ag alloy has surface segregation. The morphology of segregation phase mainly presents stripe and water drop shape. When the mold temperature is high, the surface segregation begins to decrease and eventually disappear.

Effect of Mold Temperature on Surface Segregation of Continuous Unidirectional Solidified Cu-Ag Alloy

A Convolutional Neural Network Model Based on Improved Softplus Activation Function

High-strength, multiphase steels consisting of pearlite surrounded by tempered martensite were prepared by pre-quenching and ultrafast tempering heat treatment of high-carbon pearlitic steels (0.81% C). The microstructures were analyzed by scanning electron microscopy, electron backscatter diffraction, and transmission electron microscopy. With an increasing quenching temperature from 120 °C to 190 °C, the quenched martensite variants nucleated via autocatalytic nucleation along the interface. Furthermore, the tempered nodules exhibited a distinct symmetrical structure, and the tempered martensite and pearlitic colonies in the group also showed a symmetrical morphology. In addition, a reasonable model was formulated to explain the transformation process from quenching martensite to the multiphase microstructure. When the quenching temperature was set to 120 °C, followed by ultrafast heating at 200 °C/s to 600 °C and subsequent isothermal treatment for 60 s, the multiphase structure showed highest strength, and the pearlite volume fraction after tempering was the lowest. The microhardness softening mechanism for the tempered structures consisted of two stages. The first stage is related to martensitic sheets undergoing reverse transformation and the nucleation of cementite on dislocations. The second stage involves the transformation of austenite into pearlite and continued carbide coarsening in the martensitic matrix.

Microstructure Transformation on Pre-Quenched and Ultrafast-Tempered High-Strength Multiphase Steels

This paper presents a new strategy of handwritten digit recognition based on the improved VGG16 model that aims at the lack of texture features, the large differences between handwritings, and the difficulty of extracting effective information. In order to maximize the efficiency of the improved VGG16 model, an automatic drop-based learning rate scheduling is proposed to improve the SGD algorithm in the learning procedure. And automatic adaptation technique of the SGD optimizer's learning rate parameter according to the changes of accuracy rate in the previous training iterations is utilized for the training of the model, which not only apparently improves the learning results, but also speeds up the training convergence. The improved VGG16 model was evaluated on the extended MNIST dataset, achieving a high recognition accuracy rate of 99.97%. Experimental results demonstrate that the improved VGG16 model has obviously higher recognition accuracy than traditional classifiers, has stronger feature extraction ability and can meet the requirements of handwritten digits classification and recognition.

Advances in adaptive modulation techniques have fueled the growth of classic communication recently, and the modulation format identification (MFI) has been extensively studied in the field of wireless communication, but in order to make Alice and Bob smoothly enter post-processing and develop toward an adaptive network, the MFI concept is worth reviewing for a continuous-variable quantum key distribution (CV-QKD) system. This paper proposes a constellation MFI scheme based on the density-based spatial clustering of applications with noise (DBSCAN) machine learning algorithm, and the MFI process is set at the receiving end of the CV-QKD system. The proposed MFI scheme for 4-QAM, 16-QAM, 64-QAM, and 256-QAM signals can reach high accuracy (>99%) when the signal-to-noise ratio (SNR) is greater than or equal to 23 dB. The simulation results show that using the DBSCAN unsupervised machine learning algorithm can achieve good identification performance. The proposed MFI scheme can be further improved at lower SNR by optimizing the algorithm and increasing the number of samples.

Blind modulation format identification using the DBSCAN algorithm for continuous-variable quantum key distribution

Molecular detection and identification of phytoplasmas in a novel 16SrI subgroup in sunflowers and cocklebur weeds

Efficient terahertz and photoelectron emission were observed from nano-porous gold (NPG) films deposited on an intrinsic gallium arsenide (GaAs) semiconductor substrate stimulated by femtosecond laser with pulse width of 60 fs. Time-domain THz emission and reflection spectroscopy confirmed that the free charges accelerated by irradiated femtosecond laser pulses transferred from the NPG films into the GaAs substrates. Accordingly, charges accumulation was reduced in the NPG films, resulting in a stronger emission of THz pulse than that from NPG films deposited on SiO2 substrate. Charges injected into the GaAs substrate enforced an observable decrease of the THz refractive index proportional to the intensity of incident light. In comparison, for NPG deposited on glass substrates, laser induced free charges were accumulated in the NPG films, and femtosecond laser pulses irradiating on the NPG films made no changes of the THz refractive index of the glass substrates.

Terahertz and Photoelectron Emission from Nanoporous Gold Films on Semiconductors

The fungus Colletotrichum fructicola (a species of C. gloeosporioides complex) causes devastating anthracnose in strawberry. Like other species of the genus Colletotrichum, it uses a composite strategy including both the biotrophic and necrotrophic processes for pathogenesis. Host-derived hormones are central regulators of immunity, among which salicylic acid (SA) is the core defense one against biotrophic and hemibiotrophic pathogens. However, the manner and timing of pathogen manipulation of SA are largely elusive in strawberry. To achieve better understanding of the early challenges that SA-mediated defense experiences during strawberry/C. fructicola interaction, dynamic changes of SA levels were followed through the high-performance liquid chromatography method. A very early burst of free SA at 1 h postinoculation (hpi) followed by a fast quenching during the next 12 h was noticed, although rhythm variations were present in two hosts. Transcriptional characterization of genes related to SA pathway in two varieties on C. fructicola inoculation revealed that these genes were differentially expressed, although they were all induced at different time points. At the same time, three types of genes encoding homologous effectors interfering with SA accumulation were found to be first inhibited but sequentially activated during the first 24 hpi. Furthermore, subcellular localization analysis suggests that CfShy1 is a weapon of C. fructicola for strawberry invasion. Based on these results, we propose that the infection strategy that C. fructicola utilizes on strawberry is specialized, which is implemented through the optimized expression of a specific set of effector genes. Transcriptional characterization of host genes supports that de novo SA biosynthesis and the free SA release from methyl salicylate might contribute equally to the intricate control of SA homeostasis in strawberry. C. fructicola manipulation of SA-dependent resistance in strawberry might be closely related to multihormonal interplay among SA, jasmonic acid, abscisic acid, and cytokinin.

Fast Quenching the Burst of Host Salicylic Acid Is Common in Early Strawberry/Colletotrichum fructicola Interaction.

Phase diversity technique (PD) is a widely known method to estimate wave-front aberration of optical imaging system and to obtain reconstructed high-resolution image after degradation. However, when detecting weak or low light object in space, Poisson noise, as the main source of noise, has a serious impact on the accuracy of the PD’s two main function. Hence, we firstly propose a modified PD combined with Non-local Means (NLM) algorithm to reduce the sensitivity of PD towards the Poisson noise. The numerical simulations demonstrate that our approach compared with the traditional PD has a significant improvement in terms of both the wave-front residual root-mean-square error (RMS) and the structural similarity index metrics (SSIM). The wave-front residual RMS decreases by approximately 51% across the Poisson noise levels ranging from 24.48 dB to 61.02 dB. The overall decline range of SSIM significantly decreases from 47% to 17%, and the average of SSIM increases from 84% to 91%. The modified PD would be useful in the AO system with active Poisson noise.

Modified phase diversity technique to eliminate Poisson noise for reconstructing high-resolution images

Phase Estimation and Compensation for Continuous-Variable Quantum Key Distribution

MM-SIS: Model for multiple information spreading in multiplex network

Feature screening in ultrahigh-dimensional varying-coefficient Cox model

Sparse emission source microscopy (ESM) is an efficient method to identity radiating sources. With the purpose to minimize the number of required measurement points, the presented work investigates how numerical properties of sparse ESM affects the quality of source reconstruction. A simulation model of a simple printed circuit board was used instead of measurements to isolate the observed effect of the two-dimensional (2-D) discrete Fourier transformation (DFT) and the plane wave spectrum's numerical properties. The paper shows that sub-Nyquist is achievable and suggests uniform sampling is superior to nonuniform, in contrast to other reported uses of microwave imaging. Finally, the study shows that if the source reconstruction is based on uniform 2-D DFT care should be taken with the previously suggested intelligent selection of sparse samples based on real-time observation of the measured field.

Analysis of the Effect on Image Quality of Different Scanning Point Selection Methods in Sparse ESM

Role of miR-200c in early diagnosis of gastric cancer: Current status and prospects

Deep Learning gets a new research direction of machine learning. After years of deep learning development, researchers have put forward several types of neural network built on the Auto-encoder. In this article, firstly, the origins and basic concepts of deep learning, automatic encoders, deep belief networks, and convolutional neural networks are introduced. The principle of deep neural networks based on Auto-encoders is described, and the application of hybrid neural networks in various types is introduced. Finally, the problems existing in the current stage of deep neural network based on Auto-encoders and the future prospects of it are described.

Exploring Factors That Impact Instructional Adaptations to Address Learner Variability in U.S. Middle School Classrooms

Although deep neural networks (DNNs) have led to many remarkable results in cognitive tasks, they are still far from catching up with human-level cognition in antinoise capability. New research indicates how brittle and susceptible current models are to small variations in data distribution. In this letter, we study the stochasticity-resistance character of biological neurons by simulating the input-output response process of a leaky integrate-and-fire (LIF) neuron model and proposed a novel activation function, rand softplus (RSP), to model the response process. In RSP, a scale factor η is employed to mimic the stochasticity-adaptability of biological neurons, thereby enabling the antinoise capability of a DNN to be improved by the novel activation function. We validated the performance of RSP with a 19-layer residual network (ResNet) and a 19-layer visual geometry group (VGG) on facial expression recognition data sets and compared it with other popular activation functions, such as rectified linear units (ReLU), softplus, leaky ReLU (LReLU), exponential linear unit (ELU), and noisy softplus (NSP). The experimental results show that RSP is applied to VGG-19 or ResNet-19, and the average recognition accuracy under five different noise levels exceeds the other functions on both of the two facial expression data sets; in other words, RSP outperforms the other activation functions in noise resistance. Compared with the application in ResNet-19, the application of RSP in VGG-19 can improve a network's antinoise performance to a greater extent. In addition, RSP is easier to train compared to NSP because it has only one parameter to be calculated automatically according to the input data. Therefore, this work provides the deep learning community with a novel activation function that can better deal with overfitting problems.

Improving the Antinoise Ability of DNNs via a Bio-Inspired Noise Adaptive Activation Function Rand Softplus

Structural analysis of lunar regolith not only provides important information about lunar geology but also provides a reference for future lunar sample return missions. The Lunar Penetrating Radar (LPR) onboard China’s Chang’E-3 (CE-3) provides a unique opportunity for mapping the subsurface structure and the near-surface stratigraphic structure of the regolith. The problem of rock positioning and regolith-basement interface highlighting is meaningful. In this paper, we propose an adaptive rock extraction method based on local similarity constraints to achieve the rock location and quantitative analysis for regolith. Firstly, a processing pipeline is designed to image the LPR CH-2 A and B data. Secondly, we adopt an f-x EMD (empirical mode decomposition)-based dip filter to extract low-wavenumber components in the two data. Then, we calculate the local similarity spectrum between the filtered CH-2 A and B. After a soft threshold function, we pick the local maximums in the spectrum as the location of each rock. Finally, according to the extracted result, on the one hand, the depth of regolith is obtained, and on the other hand, the distribution information of the rocks in regolith, which changes with the path and the depth, is also revealed.

Rock Location and Quantitative Analysis of Regolith at the Chang'e 3 Landing Site Based on Local Similarity Constraint

The litters of Bt corn would go into the soil through straw returning and field ploughing after cultivation. To clarify whether the leaf litter decomposition rate and the non-target soil Collembola were influenced by the Bt protein or other litter properties in leaf litters of Bt corn in Northeast China, leaf litterbags of Bt-506, its near isoline Zheng 58 and a local type Zhengdan 958 were used in the field in Northeast China. The leaf decomposition rate, the leaf properties and the collembolan community in litterbags were investigated later. After seven months, only 43.5 ng/g Bt protein in Bt-506 leaf litter was left. All the investigated indices were not significantly different between Bt-506 and its near isoline Zheng 58. But when compared with local type Zhengdan 958, Bt-506 and its near isoline Zheng 58 contained lower non-structural carbohydrate content but higher total nitrogen content, and had lower litter decomposition rate and less abundance of Collembola. Collembolan abundance and litter decomposition rate were both significantly correlated with the non-structural carbohydrate and total nitrogen contents of the leaf litters. Field study results revealed Bt protein did not affect the leaf litter decomposition rate and the collembolan community in leaf litterbags in short term. The significant differences of these investigated indices among corn types were caused by the different non-structural carbohydrate and total nitrogen contents in leaf litter.

Field decomposition of Bt-506 corn leaf and its effect on Collembola in the black soil region of Northeast China

Proceeding of the 24th International Conference on Industrial Engineering and Engineering Management 2018

Patent Quality Evaluation Model Based on Hesitant Fuzzy Soft Set

Growth behaviors of AlN on hexagonal configuration hole-type and truncated-cone-pillar-type nano-patterned sapphire substrates (NPSSs) have been investigated.

Realization of low dislocation density AlN on a small-coalescence-area nano-patterned sapphire substrate

Excess noise induced by the phase drifts is a serious impairment for the continuous-variable quantum key distribution with locally generated local oscillator scheme, which is recently proposed to avoid the side channel attacks due to the transmitted local oscillator. Theoretical and experimental studies on the phase estimation have been widely reported, while two frequency-locked laser sources are indispensable to achieve quantum coherent detection. Moreover, the self-referenced phase estimation scheme requires to propagate the strong reference pulse through optical fiber, which opens a security loophole through the manipulation of the reference pulse amplitude. Based on the theoretical security and Bayes' theorem, we propose a phase estimation protocol, which does not require propagating the strong reference pulse for performing phase estimation. Compared to the other related work, the protocol can avoid the security problem caused by strong reference pulse. Moreover, this algorithm is an iterative progress for each of experiment to obtain the phase estimation and its uncertainty. We hope the proposed scheme could further promote the performance of continuous-variable quantum key distribution.

Phase noise estimation using Bayesian inference for continuous-variable quantum key distribution.

Abstract. To bridge the gap between large-scale GCM (global climate model) outputs and
regional-scale climate requirements of hydrological models, a
spatiotemporally distributed downscaling model (STDDM) was developed. The
STDDM was done in three stages: (1) up-sampling grid-observations and GCM
simulations for spatially continuous finer grids, (2) creating the mapping
relationship between the observations and the simulations differently in
space and time, and (3) correcting the simulation and producing downscaled
data to a spatially continuous grid scale. We applied the STDDM to
precipitation downscaling in the Poyang Lake watershed using the MRI-CGCM3
(Meteorological Research Institute Coupled Ocean–Atmosphere General
Circulation Model 3), with an acceptable uncertainty of ≤ 4.9 %.
Then we created future precipitation changes from 1998 to 2100 (1998–2012 in
the historical scenario and 2013–2100 in the RCP8.5 scenario). The
precipitation changes increased heterogeneities in temporal and spatial
distribution under future climate warming. In terms of temporal patterns, the
wet season become wetter, while the dry season become drier. The frequency of
extreme precipitation increased, while that of the moderate precipitation
decreased. Total precipitation increased, while rainy days decreased. The
maximum continuous dry days and the maximum daily precipitation both
increased. In terms of spatial patterns, the dry area exhibited a drier
condition during the dry season, and the wet area exhibited a wetter
condition during the wet season. Analysis with temperature increment showed
precipitation changes can be significantly explained by climate warming, with
p<0.05 and R≥0.56. The precipitation changes indicated that the
downscaling method is reasonable, and the STDDM could be successfully applied
to the basin-scale region based on a GCM. The results implied an increasing
risk of floods and droughts under global warming, which were a reference for
water balance analysis and water resource planning.

Precipitation projections using a spatiotemporally distributed method: a case study in the Poyang Lake watershed based on the MRI-CGCM3

Background The aim was to develop a diagnostic questionnaire for damp phlegm pattern and blood stasis pattern in coronary heart disease patients (CHD-DPBSPQ). Methods The standard procedures of questionnaire development were carried out to develop and assess CHD-DPBSPQ. The patients were assessed using the CHD-DPBSPQ, CHD-DPPQ, and CHD-BSPQ. Four methods were used to select the items on the CHD-DPBSPQ in a pilot study based on data from a Guizhou tertiary grade A hospital. Cronbach's alpha and the split-half reliability, test-retest reliability, content validity, criterion validity, construct validity, and convergent validity were determined in a validation study using a nationwide sample. Results After item selection, the CHD-DPBSPQ contained 15 items in two domains: the phlegm domain (9 items) and the blood stasis domain (6 items). For the CHD-DPBSPQ, the alpha coefficient was 0.88, the split-half coefficient was 0.90, and the intraclass correlation coefficient was 0.83. The range of the item-level content validity index (I-CVI) was 0.71 to 1.0 and that of the scale-level content validity index/average (Scale-CVI/Ave) was 0.97. The domain scores on the CHD-DPBSPQ were in close relation to the scores on a questionnaire for damp phlegm pattern in coronary heart disease patients (CHD-DPPQ) and a questionnaire for blood stasis pattern in coronary heart disease patient (CHD-BSPQ) (P < 0.01). The root mean square error of approximation (RMSEA) was equal to 0.05 (90% CI: 0.044, 0.059). Convergent validity was demonstrated with a moderate correlation. Conclusion The CHD-DPBSPQ is a reliable and valid instrument.

Development of a Diagnostic Questionnaire for Damp Phlegm Pattern and Blood Stasis Pattern in Coronary Heart Disease Patients (CHD-DPBSPQ)

Urban vitality provides an important basis for evaluating urban development and spatial balance. In the era of big data, the quantitative analysis of urban vitality has become a research hotspot in the field of urban sustainability and planning research. However, time variation characteristics are often neglected, which leads to one-sidedness in the pattern analysis of urban vitality. In this paper, a method for extracting vitality areas and integrating spatiotemporal features clustering is proposed. The method is used to divide urban space into multiple vitality areas scientifically. The spatial and temporal distribution patterns of urban vitality areas are found, and the driving factors of various vitality patterns are analyzed by combining points of interest (POI)-based land use characteristics. To illustrate this method, this paper takes Nanjing city as an example. One week's worth of mobile phone data indicated that Nanjing has 10 and 8 vitality areas on weekdays and weekends, respectively. The spatial and temporal distribution patterns of the vitality areas and their correlation with land use were analyzed, which proved that POI density and entropy have strong correlations with urban vitality.

Urban Vitality Area Identification and Pattern Analysis from the Perspective of Time and Space Fusion

Molecular detection and identification of Brassica juncea phyllody and witches’ broom-associated phytoplasmas of group 16SrVI-A in Inner Mongolia, China

Abstract Background: Stapedotomy has been proved to be one of the most efficient procedure to treat otosclerosis, various factors contribute to the diversity of the outcomes and controversial results exist from previous studies. Objectives: We evaluated clinical characteristics and outcomes of stapedotomy, as well as possible predictive factors of a successful outcome. Materials and methods: This retrospective study evaluated 58 ears from 48 patients with demographic data, plus short-term follow-up of hearing outcomes of 28 ears, and evaluated variables using univariate general linear regression analyses. Results: The average operation age was 41.54 years. A total of 87.5% (42/48) patients presented with bilateral otosclerosis. 39.66% (23/58) ears had CT finding before the surgery. Patients with persistent tinnitus accounted for 53.45% (31/58) and the average preoperative ABG of the 58 ears was 32.22 dB. We achieved good postoperative air-bone gaps (ABGs) overall but poor ABG closure at 4 kHz. No predictive factors were identified in the 28 ears that were followed up. Conclusions and significance: Delayed surgery may be attributable to insufficient recognition of otosclerosis. The fenestration size could be the reason for poor ABG closure at high frequency. However, more cases and longer follow-ups are required to confirm our findings.

The clinical characteristics of otosclerosis and benefit from stapedotomy: our experience of 48 patients (58 ears)

Accurate recognition of gestures based on surface EMG signals is of very importance in the study of human prosthetic interaction. In this paper, multi-feature combination and adaptive AdaBoost algorithm are used to identify nine kinds of fine gestures. First, in order to adaptively set the threshold for extracting the active segment, the algorithm for detecting the active segment of the surface myoelectric signal is improved, and the effective active segment value is obtained by rejecting the invalid active segment. Second, a fine gesture classification method based on multi-feature combination is proposed. In this paper, the recursive feature elimination algorithm based on cyclic feature selection is used to screen out the feature set with the top classification effect, and the feature set selected by eight experimental objects is counted, and the optimal feature combination is obtained according to the experimental analysis. Finally, nine fine gesture actions are identified through a weak classifier constructed by combining the AdaBoost algorithm and the single-layer decision tree. The experimental results show that the proposed algorithm can achieve an average recognition rate of 98.56 (±1.44)% for nine fine gestures.

Research on Recognition of Nine Kinds of Fine Gestures Based on Adaptive AdaBoost Algorithm and Multi-Feature Combination

Improved closed-loop subspace identification based on principal component analysis and prior information

The main frame is the primary load-bearing component of a mapping camera system. As the critical structure of the system, the main frame determines the mechanical properties of a camera system. The main frame design is hindered by its large size, complicated interface, as well as high-stability, high-frequency requirement, and lightweight requirements. During the launching process, the main frame should be able to withstand the mechanical action of the active section without affecting the performance of the camera system. This paper describes the design scheme of the main frame. The modal analysis, static analysis and frequency response analysis of the main frame are performed. The simulation analysis results prove that the natural frequency of the mapping camera system satisfies the design requirements and the main frame satisfies the required safety margin in the linear overload in X-, Y-, and Z-directions. Moreover, under condition of the frequency response in X-, Y-, and Z-directions, the main frame has excellent structural stiffness, which provides a proper mechanical environment for the camera system. The design scheme of the main frame is reasonable and feasible.

Structural design and simulation analysis of the carbon fiber-reinforced polymer main frame of a mapping camera system

As one of the important scientific instruments of lunar exploration, the Lunar Penetrating Radar (LPR) onboard China’s Chang'E-3 (CE-3) provides a unique opportunity to image the lunar subsurface structure. Due to the low-frequency and high-frequency noises of the data, only a few geological structures are visible. In order to better improve the resolution of the data, band-pass filtering and empirical mode decomposition filtering (EMD) methods are usually used, but in this paper, we present a mathematical morphological filtering (MMF) method to reduce the noise. The MMF method uses two structural elements with different scales to extract certain scale-range information from the original signal, at the same time, the noise beyond the scale range of the two different structural elements is suppressed. The application on synthetic signals demonstrates that the morphological filtering method has a better performance in noise suppression compared with band-pass filtering and EMD methods. Then, we apply band-pass filtering, EMD, and MMF methods to the LPR data, and the MMF method also achieves a better result. Furthermore, according to the result by MMF method, three stratigraphic zones are revealed along the rover's route.

Application of Mathematical Morphological Filtering to Improve the Resolution of Chang'E-3 Lunar Penetrating Radar Data

Background: No optimal regimen exists for the LPNYL (long-pulsed 1,064-nm neodymium:yttrium-aluminum-garnet laser) for treating onychomycosis. Objective: To establish an optimal LPNYL treatment regimen for onychomycosis caused by Trichophyton rubrum (OCTr). Patients and Methods: First, 511 infected nails of 177 patients were treated using LPNYL with orthogonally designed regimens according to various energy densities, spot sizes, pulse widths, and treatment times. The optimal treatment regimen was established by multivariate analysis. Next, 69 patients with 221 infected nails were randomized to receive oral itraconazole (drug group) and the optimal regimen of LPNYL treatment (laser group). The clinical efficacy (CE) and mycological efficacy (ME) were evaluated at 6 and 12 months following the start of treatment, and adverse reactions were recorded in both groups. Results: Both CE and ME were significantly correlated with the energy density (p < 0.05) and treatment times (p < 0.05), but not with the spot size (0.071 < p < 0.083) or pulse width (0.051 < p < 0.060), at 6 or 12 months. There were no significant differences at 6 or 12 months (p > 0.05), and no significant difference was observed in CE at 12 months between the two groups (p > 0.05). At 6 months, the CE in the laser group was significantly higher than that in the drug group (p < 0.001). Conclusions: LPNYL is effective and safe for treating OCTr. The energy density and treatment times are the main factors that affect the efficacy. The optimal regimen for LPNYL is an energy density of 45 J/cm2, pulse width of 35 ms, spot size of 4 mm, frequency of 1 Hz, and 6 treatments with 1-week intervals. Laser treatment has rapid clinical recovery.

The Energy Density and Treatment Times Are the Main Factors That Affect the Efficacy of Long-Pulsed 1,064-nm Nd:YAG Laser Treatment for Onychomycosis Caused by Trichophyton rubrum

Multiple genetic tools for editing the genome of Riemerella anatipestifer using a counterselectable marker

miR-24 inhibited the killing effect of natural killer cells to colorectal cancer cells by downregulating Paxillin.

The emergence of adaptive immunity in jawed vertebrates depended on the appearance of variable immune receptors, BCRs and TCRs, which exhibit variable-J–constant (VJ-C)–type Ig superfamily folds. Hitherto, however, the structures of IgV-J-IgC–type molecules had never been characterized in invertebrates, leaving the origin of BCR/TCR-type molecules unknown. Using x-ray crystallography, the structure of a VJ-C2 molecule, named AmpIgVJ-C2, was determined in amphioxus (Branchiostoma floridae). The first domain shows typical V folding, including the hydrophobic core, CDR analogs, and eight conserved residues. The second domain is a C2-type Ig superfamily domain, as defined by its short length and the absence of β-strand D- and C1-typical motifs. AmpIgVJ-C2 molecules form homodimers, using “three-layer packing dimerization,” as described for TCRs and BCRs. The AmpIgVJ-C2 V domain harbors a diglycine motif in β-strand G and forms a β-bulge structure participating in V–V intermolecular interaction. By immunohistochemistry, AmpIgVJ-C2 molecules were primarily found in mucosal tissues, whereas PCR and sequence analysis indicated considerable genetic variation at the single-gene level; these findings would be consistent with an immune function and a basic ability to adapt to binding different immune targets. Our results show a BCR/TCR-ancestral like molecule in amphioxus and help us to understand the evolution of the adaptive immune system.

Discovery and Analysis of Invertebrate IgVJ-C2 Structure from Amphioxus Provides Insight into the Evolution of the Ig Superfamily

Simulating the dynamic characteristics of a PN junction at the microscopic level requires solving the Poisson's equation at every time step. Solving at every time step is a necessary but time-consuming process when using the traditional finite difference (FDM) approach. Deep learning is a powerful technique to fit complex functions. In this work, deep learning is utilized to accelerate solving Poisson's equation in a PN junction. The role of the boundary condition is emphasized in the loss function to ensure a better fitting. The resulting I-V curve for the PN junction, using the deep learning solver presented in this work, shows a perfect match to the I-V curve obtained using the finite difference method, with the advantage of being 10 times faster at every time step.

2019 Joint International Symposium on Electromagnetic Compatibility, Sapporo and Asia-Pacific International Symposium on Electromagnetic Compatibility (EMC Sapporo/APEMC)

Solving Poisson's Equation using Deep Learning in Particle Simulation of PN Junction

Abstract Nontarget soil fauna in fields planted with transgenic Bt crops may be influenced by the Bt protein following crop establishment. Here, we investigated the effects of transgenic Cry1Ac corn Bt-799 on soil Collembola using both taxonomic and trait-based approaches in an experimental field in northeast China from 2014 to 2015. The relationship between the collembolan community and environmental variables (including corn type) was investigated using redundancy analysis (RDA). In May 2015, we found that collembolan species richness, Shannon–Wiener's index, and all trait values examined in transgenic Cry1Ac corn (Event Bt-799, Bt corn) were lower than in its near isoline (Zheng 58, non-Bt corn). However, this significant influence did not persist in the subsequent corn growth period. For all other sampling periods over 2-yr study, all indices based on taxonomic (abundance, species richness, and Shannon–Wiener's index) and trait-based (number of ocelli, body size, pigmentation, furcula development, and antennae length) approaches in Bt corn were not significantly different from non-Bt corn. The results showed no significant difference between the two corn types in the repeated-measures analysis of variance (ANOVA). Moreover, redundancy analysis (RDA) showed that corn type only explained 1% of the variation in the collembolan community. These results suggested that Bt corn did not affect collembolan community characteristics in the short term.

Use of Taxonomic and Trait-Based Approaches to Evaluate the Effects of Transgenic Cry1Ac Corn on the Community Characteristics of Soil Collembola

As an important weak target detection method, Duffing oscillator is very effective in detecting signals with very low signal-to-noise ratio. However, the accurate discrimination between chaotic and periodic states is a crucial problem and that is the prerequisite for using the Duffing oscillator. Conventionally, the Lyapunov exponent is used as an index to identify different states, but as this indicator has the problem of heavy computation cost, slow convergence rate, and requires a mass of data, its application becomes seriously limits. To solve this problem, a novel method for state identification of the Duffing oscillator based on extreme learning machine (ELM) is proposed. The feature data, as the input of ELM, are extracted from the phase diagram and the time series of the Duffing oscillator. Three effective features are extracted in this letter, i.e., ratio of points in and out of the closed region, average distance, and power spectrum. Computer simulations are presented to validate the proposed method and demonstrate that the state classification performance is superior to other related methods with higher computation efficiency, faster convergence rate, and better accuracy.

State Identification of Duffing Oscillator Based on Extreme Learning Machine

Natural products are the important source of drugs including the small molecule drugs, large molecules drugs and the traditional medicines. Now, in the area of drug research and development, the drug discovery based on the drug screening mainly focus on the compounds even there are a lot of synthetic compounds. The traditional As the compounds isolated from traditional medicines. The characteristics of traditional medicines, such as the traditional Chinese Medicines, are with a lot of information about clinical knowledge and experiences. So, discover new drugs by the modern screening techniques, such as high throughput screening, high contents screening etc., from natural products need to design strategy. The strategy for determination of candidate from the multi-bioactivity compounds. A large numbers of natural compounds has been reported with varieties bioactivities. The druggable evaluation for these compounds are very complex and the pharmacological evaluation is the key procedures. e.g. pinocembrin. The strategy of traditional information analysis. As we know that the clinical information of traditional medicines is quite different from the modern medical and medicinal theories. The purpose to analysis the traditional literatures is to find the valuable signals for drug discovery especially the druggable information for components, e.g. salvianolic acid A. The strategy of therapeutic theory should be rethink based on the traditional medicinal theory. As the most of diseases are not with single target, so the drugs act on one targets should not be exert the full therapeutic effects. In the other hand, most of the natural compound with multi-bioactivities and act on multiple targets. So, the another strategy is to design and find compound act on multiple targets and these targets match the disease. Based on the pathological and physiological change during disease, established a disease elated targets

Drug Discovery form Natural Products and Traditional Medicine, Strategy and Applications

Abstract. In recent, the trajectory data of moving objects is getting bigger and bigger, and it has become a very important part of the social big data. Its compression is an indispensable operation of data processing, and also it is the basis of the data storage, analysis and mining of moving objects. In the related research, there are two kinds of methods for the trajectory compression. One is to compress trajectory data based on its own spatial-temporal characteristics, another kind of methods is the map-matched trajectory compression. However, for offline trajectory compression, methods based on spatial-temporal characteristics do not take the road network constraints into account. If road networks are considered, the map matching is needed first, and it will greatly affect the efficiency of trajectory compression. Therefore, this paper proposes a new trajectory compression algorithm that combines the spatial-temporal characteristics from trajectories themselves and structural characteristics from road networks to improve the compression precision and efficiency.

The International Archives of the Photogrammetry, Remote Sensing and Spatial Information Sciences

Experimental study and performance evaluation of a PV-blind embedded double skin façade in winter season

Background : An increasing number of miRNAs were confirmed to be involved in the initiation and progression of colorectal cancer (CRC) by acting as cancer suppressor genes and oncogenes. The purpose of this study was to uncover the role of miR-449b in CRC and its underlying mechanisms. Methods : The expression profile of miR-449b in human CRC tissues and cell lines was determined using quantitative real-time polymerase chain reaction (qRT-PCR) analysis. The effect of miR-449b on CRC was assessed by CRC cell migration and invasion as determined using a transwell assay. A luciferase reporter assay was also carried out to explore the interaction between MMP2 3′UTR and miR-449b. Results : The current study revealed that the relative expression of miR-449b was decreased significantly in human CRC tissues and cell lines; meanwhile, miR-449b in metastatic CRC tissues was significantly lower than that in non-metastatic CRC tissues. We also observed that the forced miR-449b in CRC cells significantly restrained cell migration and invasion in vitro . In contrast to miR-449b, our study found that both the MMP-2 mRNA and protein levels were increased in CRC cells. MiR-449b negatively regulated MMP2 in CRC cells, and the result was corroborated by luciferase reporter assay. Most importantly, overexpression of MMP2 significantly reversed the miR-449b-mediated inhibition on the invasion and migration of CRC cells. Conclusion : Our data provided encouraging evidence that miR-449b possessed a strong inhibitory effect on CRC cell migration and invasion by negative regulation of MMP2. Keywords : Colorectal cancer; MiR-449b; MMP2; Migration; Invasion

MiR-449b inhibits the migration and invasion of colorectal cancer cells through the negative regulation of MMP2

Identification and evaluation of resistance to Fusarium oxysporum f. sp. cubense tropical race 4 in Musa acuminata Pahang

Inverse packet matrix reasoning model-based the intelligent dynamic separation and acquisition of educational information

Lunar Penetrating Radar (LPR) is one of the important scientific systems onboard the Yutu lunar rover for the purpose of detecting the lunar regolith and the subsurface geologic structures of the lunar regolith, providing the opportunity to map the subsurface structure and vertical distribution of the lunar regolith with a high resolution. In this paper, in order to improve the capability of identifying response signals caused by discrete reflectors (such as meteorites, basalt debris, etc.) beneath the lunar surface, we propose a compressive sensing (CS)-based approach to estimate the amplitudes and time delays of the radar signals from LPR data. In this approach, the total-variation (TV) norm was used to estimate the signal parameters by a set of Fourier series coefficients. For this, we chose a nonconsecutive and random set of Fourier series coefficients to increase the resolution of the underlying target signal. After a numerical analysis of the performance of the CS algorithm, a complicated numerical example using a 2D lunar regolith model with clipped Gaussian random permittivity was established to verify the validity of the CS algorithm for LPR data. Finally, the compressive sensing-based approach was applied to process 500-MHz LPR data and reconstruct the target signal’s amplitudes and time delays. In the resulting image, it is clear that the CS-based approach can improve the identification of the target’s response signal in a complex lunar environment.

A Compressive Sensing-Based Approach to Reconstructing Regolith Structure from Lunar Penetrating Radar Data at the Chang'E-3 Landing Site

Variable speed control moment gyros (VSCMGs) are powerful attitude control actuators for their combined functionality providing both reaction wheel mode and control moment gyro mode. Four VSCMGs in a pyramid configuration are used to control the attitude of an agile satellite aiming at earth-scanning observation. A strategy for roll maneuver together with its steering law of the VSCMG cluster, is proposed. Performance of the strategy and the steering law is examined through numerical simulation. The results show that the scanning mission is well implemented within the constraints of physical limits, and the errors are acceptable.

Attitude Control for an Agile Satellite using Four Variable Speed Control Moment Gyros

Photocatalytic cellulose reformation is regarded as a potential and affordable route for sustainable H2 evolution. However, direct photoreformation still suffers from challenges such as the limited solubility of cellulose and the dependence on the catalytic activity of noble metals. Herein, we report a new photoreformation of cellulose into H2 over TiO2 that is modified with nickel sulfide (Nix Sy ) and chemisorbed sulfate species (SO42- ) by a one-pot approach. A significant elevation in the photocatalytic hydrogen evolution rate is achieved with a maximal value of 3.02 mmol g-1  h-1 during the first 3 h, which is almost 76-fold higher than that of P25 and comparable to that of Pt-P25. Aided by systematic investigation, it is proposed that nickel sulfide and sulfate modification contribute synergistically to the remarkably increased efficiency of biomass transformation. Specifically, Nix Sy acts as a cocatalyst for photocatalytic H2 production, and we infer that SO42- ions promote cellulose hydrolysis and the consequent accessibility of the biomass to catalysts. Further, the accumulated formate intermediates have a poisoning effect on the catalysts, the desorption of which can be controlled by tuning the aqueous alkalinity. Overall, our strategy for the modification of TiO2 with SO42- and Nix Sy provides a new perspective for the concurrent acceleration of cellulose hydrolysis and increase of the number of hydrogen evolution sites for the efficient photocatalytic reformation of cellulose into H2 .

Facile Modification of Titania with Nickel Sulfide and Sulfate Species for the Photoreformation of Cellulose into Hydrogen.

A fluorine-modified tetracarboxylic acid ligand, namely, 2'-fluoro-[1,1':4',1''-terphenyl]-3,3'',5,5''-tetracarboxylic acid (H4FTPTC), with suitable triplet energy excited state, was designed and applied to construct the luminescent lanthanide metal-organic frameworks (LnMOFs) for cryogenic temperature sensing. With the lanthanides codoping strategy, we developed a new Tb3+/Eu3+ mixed LnMOF system Tb1- xEu xFTPTC ( x = 0.05, 0.1, 0.2), which feature excellent linear responses to temperature with high relative sensitivity in the cryogenic range of 25-125 K. It was found that the relative sensitivity of such mixed LnMOF could readily be tuned by adjusting the incorporation amount of Eu3+ ions in the host framework. In addition, the energy transfer efficiency between the Tb3+ and Eu3+ ions in the framework with different Tb3+/Eu3+ ratios are also investigated and discussed.

Cryogenic Luminescent Tb/Eu-MOF Thermometer Based on a Fluorine-Modified Tetracarboxylate Ligand.

Practical security analysis of continuous-variable quantum key distribution with jitter in clock synchronization

A digital microfluidic biochip is an attractive platform for revolutionizing immunoassays, clinical diagnostics, drug discovery, DNA sequencing, and other laboratory procedures in biochemistry. A recent generation of biochips uses a microelectrode-dot-array (MEDA) architecture, which provides finer controllability of droplets and seamlessly integrates microelectronics and microfluidics using CMOS technology. In order to simplify the wiring problem for MEDA biochips, all microelectrodes and their control registers are daisy-chained together. Therefore, chain diagnosis and fault tolerance are critical for MEDA biochips. We propose the first daisy-chain design that can perform self-diagnosis and repair the detected faults. In our design, every microelectrode cell is fully controlled, and faults in the daisy chain can be detected and repaired in a timely manner. Moreover, the proposed design can be used in both online and off-line modes. Experimental results demonstrate the effectiveness of the proposed daisy-chain design.

Built-In Self-Diagnosis and Fault-Tolerant Daisy-Chain Design in MEDA Biochips*

Silk fibroin possesses good cytocompatibility and biodegradability, was a potential material for wound haemostasis. Ca2+ acts as a coagulation factor in cascade pathway for thrombin generation, it can be chelated to silk fibroin molecule. We used three neutral salt solvents (CaCl2, Ca(NO3)2 and LiBr) to dissolve silk fibers and prepare regenerated silk fibroin materials, preliminarily explored blood compatibility. Results showed that the regenerated silk fibroin materials prepared by calcium salt dissolving could shorten thrombin time and plasma recalcification time, compared with non-calcium salt reagent LiBr.

Preliminary Blood Compatibility Comparison of Silk Fibroin Dissolved by different Solvents

Ascorbic acid (AA), which is a well-known antioxidant, reacts with reactive oxygen species (ROS) inside the human body. It is crucial for the proper functioning of living organisms, however, the sensing of AA is still a huge challenge. Herein, a mixed Ce/Eu metal–organic framework [ZJU-136-Ce1−xEux (x = 0.24, 0.36)] is designed and synthesized. Due to the specific redox reaction between the enediol group of AA and Ce4+, the fluorescence intensity of the ligand increases significantly with a simultaneous fluorescence quenching of Eu ions, resulting in a ratiometric fluorescent probe for detecting AA. It is worth noting that the ZJU-136-Ce1−xEux (x = 0.24, 0.36) exhibited good luminescence properties and ratiometric fluorescence for AA determination. Furthermore, the regeneration cycle test shows that the mixed Ce/Eu metal–organic framework can be used as a potential ratiometric sensor for AA determination.

Ratiometric luminescence sensing based on a mixed Ce/Eu metal–organic framework

It has been proven that integrating prior information into subspace identification methods (SIMs) can improve the accuracy of model identification. In this study, a new closed-loop SIM integrating prior information is proposed based on principal component analysis (PCA) and column weighting. Compared with the conventional SIMs based on PCA, the constrained least square (CLS) approach is used to incorporate prior information into the impulse response after the PCA procedure. Then the system matrices can be extracted from the estimated impulse response parameters. The simulation results demonstrate that the proposed method is more accurate and stable for model identification.

2018 14th IEEE International Conference on Signal Processing (ICSP)

Improved Closed-Loop Subspace Identification with Prior Information Using Principal Component Analysis and Column Weighting

Insight into the molecular mechanism of yeast acetyl-coenzyme A carboxylase mutants F510I, N485G, I69E, E477R, and K73R resistant to soraphen A

Continuous-Variable Quantum Key Distribution with Orthogonal Frequency Division Multiplexing Modulation

Abstract The paxillin and M2 macrophage are all involved in cell proliferation and tumor progression, and this study aims to explore the interaction between them in colon cancer and the role of paxillin in cancer progression. Expression of mRNAs and proteins was determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot, separately. Endogenous expression of genes was modulated by recombinant plasmids and cell transfection. The levels of cytokines were determined by enzyme-linked immunosorbent assay (ELISA). The cell viability, invasion and migration were detected using the MTT assay, the transwell assay and the wound-healing cell migration assay, respectively. A nude mouse model for human colon cancer was constructed for tumor orthotopic expression. Paxillin was up-regulated in tumor-associated macrophages (TAMs). Paxillin was up-regulated in process of M2 macrophage polarization. M2 macrophage polarization was inhibited with paxillin suppressed. Down-regulated paxillin inhibited cell proliferation and invasion in colon cancer through suppressing M2 macrophage polarization. PI3k/Akt inhibitor repressed M2 macrophage polarization through down-regulating paxillin. PI3k/Akt inhibitor inhibited the function of the macrophage in promoting cell proliferation and invasion of colon cancer through down-regulating paxillin. Down-regulated paxillin in macrophages inhibited tumor growth of colon cancer. With the PI3K/AKT pathway inhibited, down-regulated paxillin suppressed colon cancer cell proliferation and invasion by inhibiting the M2 macrophage polarization, thereby restraining the tumor progression.

Down-regulated paxillin suppresses cell proliferation and invasion by inhibiting M2 macrophage polarization in colon cancer

Correct lateralization of temporal lobe epilepsy (TLE) is critical for improving surgical outcomes. As a relatively new noninvasive clinical recording system, magnetoencephalography (MEG) has rarely been applied for determining lateralization of unilateral TLE. Here we propose a framework for using resting-state brain-network features and support vector machine (SVM) for TLE lateralization based on MEG. We recruited 15 patients with left TLE, 15 patients with right TLE, and 15 age- and sex-matched healthy controls. The lateralization problem was then transferred into a series of binary classification problems, including left TLE versus healthy control, right TLE versus healthy control, and left TLE versus right TLE. Brain-network features were extracted for each participant using three network metrics (nodal degree, betweenness centrality, and nodal efficiency). A radial basis function kernel SVM (RBF-SVM) was employed as the classifier. The leave-one-subject-out cross-validation strategy was used to test the ability of this approach to overcome individual differences. The results revealed that the nodal degree performed best for left TLE versus healthy control and right TLE versus healthy control, with accuracy of 80.76% and 75.00%, respectively. Betweenness centrality performed best for left TLE versus right TLE with an accuracy of 88.10%. The proposed approach demonstrated that MEG is a good candidate for solving the lateralization problem in unilateral TLE using various brain-network features.

Automatic Lateralization of Temporal Lobe Epilepsy Based on MEG Network Features Using Support Vector Machines

Considering the ocean water's optical attenuation and the roughness of the sea surface, we analyze the security of continuous-variable (CV) quantum key distribution (QKD) based air-to-water channel. The effects of the absorption and scattering on the transmittance of underwater quantum channel and the maximum secure transmission distance are studied. Considering the roughness of the sea surface, we simulate the performance bounds of CV QKD with different wind speeds using the Monte Carlo method. The results show that even if the secret key rate gradually reduces as the wind speed increases, the maximum transmission distance will not be affected obviously. Compared to the works regarding short-distance underwater optical communication, our research represents a significant step towards establishing secure communication between air platform and submarine vehicle.

Security Simulation of Continuous-Variable Quantum Key Distribution over Air-to-Water Channel Using Monte Carlo Method

This paper deals with a channel-parameter estimation for continuous-variable quantum key distribution (CV-QKD) over a satellite-to-submarine link. In particular, we focus on the channel transmittances and the excess noise which are affected by atmospheric turbulence, surface roughness, zenith angle of the satellite, wind speed, submarine depth, etc. The estimation method is based on proposed algorithms and is applied to low-Earth orbits using the Monte Carlo approach. For light at 550 nm with a repetition frequency of 1 MHz, the effects of the estimated parameters on the performance of the CV-QKD system are assessed by a simulation by comparing the secret key bit rate in the daytime and at night. Our results show the feasibility of satellite-to-submarine CV-QKD, providing an unconditionally secure approach to achieve global networks for underwater communications.

Channel-parameter estimation for satellite-to-submarine continuous-variable quantum key distribution

Fe-based electrocatalysts are elegant due to their better performance towards the oxygen reduction reaction. Nevertheless, they commonly contain different moieties, for example Fe-Nx , Fe, Fe3 C and N-doped carbon, primarily the debatable assistance of these components towards ORR electrocatalysis, specifically for intermediate peroxide reduction reactions (PRR). In this paper, to explore the role of Fe-Nx centres for PRR, a Fe-N-C electrocatalyst rooted in nitrogen-doped carbon nanotubes with mesoporous structures was synthesized from a Fe/Zn-dicyanoimidazolate framework. The use of dicyanoimidazole coordinated with iron can introduce the Fe-Nx active sites as well as directional N-doped carbon nanotubes, which is good for enhancing electronic conductance of the catalyst. The attained electrocatalyst shows tremendous enactment to ORR, being comparable to the activity of Pt/C in acidic and better in alkaline electrolytes. This study also reveals that Fe-Nx active centres are responsible for less H2 O2 production. Though the Fe-Nx moieties and Fe3 C/Fe particles encapsulated N-doped carbon, both are active centres for ORR, however, Fe-Nx sites are more active than others for peroxide reduction reaction. These perceptions suggest rational methodologies for more active and consequently further durable Fe-N-C catalysts.

Exploring Fe-Nx for Peroxide Reduction: Template-Free Synthesis of Fe-Nx Traumatized Mesoporous Carbon Nanotubes as an ORR Catalyst in Acidic and Alkaline Solutions.

ABSTRACT Critique is a central feature in the discipline of apparel design and product development. Thus, this study examined student-generated responses regarding their learning experiences with three different critique methods: (a) group critique, (b) peer critique and (c) desk critique with instructor. A convenient sample of 40 students enrolled in an introductory design studio at a Midwest university participated in each critique session in the course of three projects throughout the semester. An online survey with closed and open-ended questions was conducted followed by each critique. Content analysis and descriptive statistics were conducted for data analysis. Results showed that students’ perceived learning experiences, work improved and motivation increased through critiques with honest feedback. The findings confirm the importance of both instructor-led and student-led critiques. Strategically, instructors can integrate the efficacy of each critique method into course projects, thus, incorporating activity theory into the curriculum.

International Journal of Fashion Design, Technology and Education

Parameter estimation of the lunar regolith not only provides important information about the composition but is also critical to quantifying potential resources for lunar exploration and engineering for human outposts. The Lunar Penetrating Radar (LPR) onboard China’s Chang’E-3 (CE-3) provides a unique opportunity for mapping the near-surface stratigraphic structure and estimating the parameters of the regolith. In this paper, the electrical parameters and the iron-titanium content of regolith are estimated based on the two sets of LPR data. Firstly, it is theoretically verified that the relative dielectric constant can be estimated according to the difference of the reflected time of two receivers from a same target. Secondly, in order to verify the method, a parameter estimation flow is designed. Subsequently, a simple model and a complex model of regolith are carried out for the method verification. Finally, on the basis of the two sets of LPR data, the electrical parameters and the iron-titanium content of regolith are estimated. The relative dielectric constant of regolith at CE-3 landing site is 3.0537 and the content of TiO2 and FeO is 14.0127%. This helps us predict the reserves of resources at the CE-3 landing site and even in the entire Mare Imbrium.

Parameter Estimation of Lunar Regolith from Lunar Penetrating Radar Data

Polarization-Multiplexed Quadrature Amplitude Modulation for Continuous-Variable Quantum Key Distribution

Dysregulation of the neddylation pathway is related to various cancers. However, the specific role of the neddylation pathway in human hepatocellular carcinoma (HCC) remains largely unclear. In this study, the neddylation pathway in HCC and adjacent noncancerous liver (ANL) tissues was evaluated by immunohistochemistry (IHC), Western blotting, and qRT‐PCR (quantitative real‐time polymerase chain reaction). The results showed that the entire neddylation pathway, including NEDD8 (the IHC staining of NEDD8 represents the global‐protein neddylation), E1 NEDD8‐activating enzymes (NAE1 and UBA3), E2 NEDD8‐conjugating enzymes (UBE2F and UBE2M), E3 NEDD8‐ligases (MDM2, RBX1 and RNF7), and deneddylation enzymes (COPS5, UCHL1 and USP21), was overactivated in HCC. Furthermore, the upregulation of NEDD8 in HCC was correlated with aggressive characteristics and was an independent risk factor for overall survival (OS) and recurrence‐free survival (RFS) in patients with HCC after hepatectomy. The upregulation of NAE1, UBE2M, and UCHL1 in HCC was associated with aggressive characteristics and poor OS and RFS in patients with HCC after hepatectomy. In conclusion, our research reveals that the entire neddylation pathway is overactivated in HCC and associated with clinical characteristics and prognosis of patients with HCC.

Overactivated neddylation pathway in human hepatocellular carcinoma

This paper proposes an approximate message passing cooperative localizer (AMP-CL) for wireless sensor networks (WSNs) with angle-of-arrival (AOA) ranging measurements and unknown orientation angles. At first, an incremental localizer is developed to provide initial position estimations. Subsequently, orientation angles of WSN nodes are separately estimated based on current node position estimations and AOA observations by maximum-likelihood (ML) method. Based on the current orientation estimations, cooperative localization problem is converted as a generalized linear mixing problem, and resolved by AMP algorithm. Finally, AMP-CL will iterate between AMP-based positioning recovery and ML orientation angle estimation until convergence conditions are satisfied. It is featured on low-computational complexity, and distributed implementation manner. Simulation results also validate the state-of-the-art positioning performance and cooperative gains of AMP-CL after comparing itself with some main-stream localizers under different communication ranges and noise contaminations.

IEEE INFOCOM 2018 - IEEE Conference on Computer Communications Workshops (INFOCOM WKSHPS)

Message-passing cooperative localization in sensor networks with AOA measurements

How to balance the relationship between stretchability, sensitivity, and optical transmittance remains an obstacle for the realization of high‐performance wearable strain sensors. Here, a highly stretchable, sensitive, and transparent strain sensor is presented by using a binary hybrid network consisting of hierarchical multiscale metal nanowires. Small‐sized silver nanaowire (AgNW) network is demonstrated to have considerable sensitivity but very limited sensing range. The introduction of the highly continuous gold nanowire backbone network can not only improve the stretchability by bridging the detached AgNW regions, but also provide excellent sensitivity in large strain range. As a result, the rationally designed hybrid network based strain sensor demonstrates a wide sensing range up to 90%, high gauge factor values from 12 at 5% to 2370 at 70%, high transmittance of 86%, and prominent cyclical stability (1000 times). The highly flexible strain sensor can be conformally attached to human body and succeeds in detecting a series of activities. Both of the outstanding sensing and optical performance endow the hybrid network based sensor great potential as invisible human‐monitoring device.

A Highly Stretchable, Sensitive, and Transparent Strain Sensor Based on Binary Hybrid Network Consisting of Hierarchical Multiscale Metal Nanowires

Depth Image-Based Rendering (DIBR) is an approach to generate a 3-D image by the original 2-D color image with the corresponding 2-D depth map. Although DIBR is a quite convenient to convert 2D images to 3D ones, there is a disadvantage in DIBR system that it cannot reach real-time processing due to the computing time. Against this, this paper proposes a method which is based on discrete wavelet transform and adaptive edge-oriented smoothing process, to speed up the computing of the system. The proposed method still preserves the original texture and thus the proposed method not only preserves the vertical texture but also reduces at least 60% of the computing time of the DIBR system.

Wavelet-Based Technique for Mobile Device with Low Resolution Depth Image-Based Rendering

Inverse P-augmented matrix method-based the dynamic findings of unknown information

In Eurocrypt’2009, Wu et al. (2009) presented an important primitive named the asymmetric group key agreement (AGKA) protocol. In such a primitive, a group of users generate a common public encryption key, and each user only holds his own secret decryption key. Authenticated asymmetric group key agreement (AAGKA) protocols are a kind of AGKA protocol that can be secure against active attacks. AAGKA protocols in certificateless public key cryptography (CL-PKC) have some preponderance than those in identity-based cryptography and PKI cryptography. However, existing AAGKA protocols in CL-PKC only consider security against normal type adversaries, the weakest adversaries considered in CL-PKC literature. To solve this problem, an improved security model that considers security against super adversaries and a provably secure certificateless AAGKA protocol under the improved security model are proposed. Efficiency comparison shows that the proposed protocol is more efficient.

A Strongly Secure and Efficient Certificateless Authenticated Asymmetric Group Key Agreement Protocol

Strain Sensors: A Highly Stretchable, Sensitive, and Transparent Strain Sensor Based on Binary Hybrid Network Consisting of Hierarchical Multiscale Metal Nanowires (Adv. Mater. Technol. 6/2018)

Evaluating WEEE recycling innovation strategies with interacting sustainability-related criteria

Finite-size analysis of eight-state continuous-variable quantum key distribution with the linear optics cloning machine

Security analysis of orthogonal-frequency-division-multiplexing–based continuous-variable quantum key distribution with imperfect modulation

Deep learning for image-based cancer detection and diagnosis - A survey

Quantifying the spatio-temporal heterogeneities in the downscaling process is of great importance for future projections of climate change, especially for regional water resources adaptive management. The spatiotemporally distributed downscaling model (STDDM) proposed in this manuscript is of certain significance for statistical downscaling methodology, which could improve the simulation effects of climate variables at different spatial and temporal scales. However, the results, conclusions and discussion presented in current manuscript is not clear, concise, and well structured. The manuscript in current form needs a major revision before acceptance. Specific com-

Interactive comment on “ Variations of future precipitations in Poyang Lake Watershed under the global warming using a spatiotemporally distributed downscaling model ” by Ling Zhang et al

The application of implantable medical devices (IMDs), which solves the problems of geographical distance limitation and real-time health monitoring that plague patients and doctors, has caused great repercussions in the medical community. Despite the great potential of wide application, it also brings some security and privacy issues, such as the leakage of health data and unauthorized access to IMDs. Although a number of authentication and key agreement (AKA) schemes have been developed, we find that some subtle attacks still remain to be addressed. Then we propose an improved AKA scheme which achieves strong security features including user anonymity and known key security. It is formally proved to be secure under the Real-or-Random model. Moreover, a comprehensive security analysis shows that our scheme can resist various attacks and satisfy the desired requirements. Finally, the performance analysis shows the superiority of our protocol which is suitable for the implantable medical system.

Trusted Authority Assisted Three-Factor Authentication and Key Agreement Protocol for the Implantable Medical System

A pulse waveform profiling algorithm is introduced for processing real-time photoplethysmography (PPG) data in mobile applications. The real PPG waveform is discriminated from artifacts based on rules of probability distribution and physiological significance. The swift background is removed through a two-step method to minimize its effect on the final waveform analysis: interpolating the midpoint of the amplitude of the PPG AC part and then interpolating the minimum of each pulse period. The pulse waveform features are extracted from the stratified PPG wave data. The implementation of the proposed algorithm in a real-time mobile application demonstrated its high efficiency and robustness with a sensitivity of around 96% and a positive specificity of 100%. The potential applications of these extracted features are discussed in terms of long-term trends in physiology such as circadian and arrhythmia real-time monitoring.

Real-Time Pulse Waveform Profiling Algorithm for Wearable Applications

Objective 
The study compared the clinical outcomes among cleavage stage embryo transfer, two-step embryo transfer and blastocyst transfer in frozen-thawed cycles. To provide the clinical guidance for the patients with repeated implantation failure(RIF) to make a appropriate embryo transfer protocol. 
 
Methods 
In this retrospective study, a total of 252 patients with RIF were undergoing the frozen-thawed embryo transfer (FET) treatment. They were divided into cleavage stage embryo transfer group (group A) , two-step embryo transfer group (group B) and blastocyst transfer group (group C) according to the transfer protocols. Groups were compared including implantation rate, clinical pregnancy rate, live birth rate, miscarriage rate, multiple pregnancy rate and ectopic pregnancy rate. 
 
Results 
⑴ There were no significant differences among three groups in age, infertility duration, infertility type , endometrial preparation protocols and embryo resuscitation rate. The rate of optimal embryo after resuscitation of group B was lower than that of group A (72.46% vs 81.50%), showing significant differences (P′ 0.0125). ⑵ The implantation rate of embryos in group C was significantly higher than that in group A (38.46% vs 21.61%) (P′ 0.05). No case of ectopic pregnancy occurred in group B and group C, while in the group A, there were 7 cases of ectopic pregnancy. 
 
For RIF patients, two-step embryo transfer and blastocyst transfer are relatively safe and effective transplants in frozen-thawed cycles compared to cleavage embryo transfer. 
 
Key words: 
Embryo transfer; Reproductive techniques, assisted; Freezing; Pregnancy rate; Treatment failure

Comparison of clinical outcomes of different embryo transfer protocols in patients with repeated implantation failure in frozen-thawed cycles

Dissecting Brain Networks Underlying Alcohol Binge Drinking Using a Systems Genomics Approach

Four-dimensional data coupled to alternating weighted residue constraint quadrilinear decomposition model applied to environmental analysis: Determination of polycyclic aromatic hydrocarbons.

Streamflow estimates are substantially important as fresh water shortages increase in arid and semi-arid regions where evapotranspiration (ET) is a significant contribution to the water balance. In this regard, evapotranspiration data can be assimilated into a distributed hydrological model (SWAT, Soil and Water Assessment Tool) for improving streamflow estimates. The SWAT model has been widely used for streamflow estimations, but the applications combining SWAT and ET products were rare. Thus, this study aims to develop a SWAT-based evapotranspiration data assimilation system. In particular, SWAT is gridded at Hydrologic Response Unit (HRU) level to incorporate gridded ET products acquired from the remote sensing-based ETMonitor model. In the modeling case, Gridded SWAT (GSWAT) shows a good agreement of streamflow modeling with the original SWAT. Such a scant margin between them is due to the modeling domain mismatch caused by different HRU delineations. In the ET assimilation case, we carry out a synthetic data experiment to illustrate the state augmentation Direct Insertion (DI) method and a real data experiment for the upper Heihe River Basin. The results demonstrate the benefits of the ET assimilation for improving hydrologic processes representations. In the future, more remotely sensed data can be assimilated into the data assimilation system to provide more reliable hydrological predictions.

Development of an Evapotranspiration Data Assimilation Technique for Streamflow Estimates: A Case Study in a Semi-Arid Region

To solve the problem of estimating and verifying stream flows without direct observation data; we extend existing techniques for estimating stream flows in ungauged zones, coupling a hydrological model with a hydrodynamic model, using the Poyang Lake basin as a test case. We simulated stream flows in the land covered area of the ungauged zone by building a SWAT model for the entire catchment area covering gauged stations and the land covered area; then estimated stream flows in the water covered area of the ungauged zone using the simplified water balance equation. To verify the results, we built two scenarios (original and adjusted scenarios) using the Delft3D model. In this study, the original scenario did not take stream flows in the ungauged zone into consideration, unlike the adjusted scenario that accounts for the ungauged zones. Experimental results show there was a narrower discrepancy between the stream flows observed at the outlet of the lake and the simulated stream flows in adjusted scenario. Using our technique, we estimated that the ungauged zone of Poyang Lake produces stream flows of approximately 180 billion m 3 ; representing about 11.4 % of the total inflow from the entire watershed. We also analysed the impact of the stream flows in ungauged zone on the water balance between inflow and outflow of the lake. These results, incorporating the estimated stream flow in ungauged zone, significantly improved the water balance as indicated by R 2 with higher value and percent bias with lower value, as compared to the results when the stream flows in the ungauged zone were not taken into account, R 2 with lower value and percent bias with higher value. The method can be extended to other lake, river, or ocean basins where observation data is unavailable.

Stream flow simulation and verification in ungauged zones by coupling hydrological and hydrodynamic models: a case study of the Poyang Lake ungauged zone

A novel active contour model for image segmentation using local and global region-based information

Three-Way Dicision Community Detection Algorithm Based on Local Group Information

In this paper, we proposed a novel approach called Hybrid Orientation Filter which deploys a combination of the information filter and the complementary filter to achieve accurate heading estimation. Base on this approach, a Hybrid Orientation Filter aided pedestrian dead reckoning system with utilization of the visual gyroscope is proposed and implemented on a smartphone, offering real-time indoor tracking for pedestrians without map information or infrastructure. Experiment results show that the proposed dead reckoning system achieves typically sub-meter accuracy in position over 207 meters, and an average error of 2.55 degrees in heading over 1800 degrees.

2017 13th IEEE International Conference on Control & Automation (ICCA)

Hybrid orientation filter aided indoor tracking for pedestrians using a smartphone

Suppression of tungsten accumulation during ELMy H-mode by lower hybrid wave heating in the EAST tokamak

Variable forgetting factor mechanisms for diffusion recursive least squares algorithm in sensor networks

An Improved OFDM Timing Synchronization Algorithm with Variable Length of Cyclic Prefix

Expression analysis of argonaute, Dicer-like, and RNA-dependent RNA polymerase genes in cucumber (Cucumis sativus L.) in response to abiotic stress

Shadow removal for videos is an important and challenging vision task. In this paper, we present a novel shadow removal approach for videos captured by free moving cameras using illumination transfer optimization. We first detect the shadows of the input video using interactive fast video matting. Then, based on the shadow detection results, we decompose the input video into overlapped 2D patches, and find the coherent correspondences between the shadow and non‐shadow patches via discrete optimization technique built on the patch similarity metric. We finally remove the shadows of the input video sequences using an optimized illumination transfer method, which reasonably recovers the illumination information of the shadow regions and produces spatio‐temporal shadow‐free videos. We also process the shadow boundaries to make the transition between shadow and non‐shadow regions smooth. Compared with previous works, our method can handle videos captured by free moving cameras and achieve better shadow removal results. We validate the effectiveness of the proposed algorithm via a variety of experiments.

Video Shadow Removal Using Spatio‐temporal Illumination Transfer

A design method of finite dimensional nonlinear disturbance observer based control (NLDOBC) is proposed for a class of nonlinear dissipative partial differential equation (PDE) systems, where the disturbance is modeled by an exosystem of nonlinear ordinary differential equations (ODEs). Motivated by the fact that the dominant structure of the dissipative PDE is usually characterized by a finite number of degrees of freedom, the modal decomposition technique is initially applied to the PDE system to give a slow subsystem of low dimensional nonlinear ODEs. By using the nonlinear slow subsystem and exosystem, a nonlinear disturbance observer (NLDO) is constructed to estimate the disturbance. Then, on the basis of NLDO, an NLDOBC method is proposed in terms of linear matrix inequality (LMI) to ensure the exponential stability of the closed-loop PDE system in the presence of the modeled disturbance. Finally, the simulation results on control of one dimensional Fisher diffusion-reaction system show the effectiveness of the proposed method.

Nonlinear disturbance observer based control for nonlinear dissipative PDE systems

The high frequency surface wave radar (HFSWR) with detection capability of hundreds of kilometers plays an important role in marine surveillance [1]–[8]. Nevertheless, HFSWR has low azimuth measurement accuracy, which causes great deviation of target location and tracking [9]. Meanwhile, the miniaturization of radar arrays leads to the limitation of antenna length, which further causes severe decline of azimuth accuracy. Moreover, the interference from external environment also decreases the azimuth accuracy, making the accurate tracking of vessels difficult. In recent years, the 2-HFSWR multisensor surveillance system has become a hot spot, because it only requires parameters of distance and velocity without using the azimuth measurement when tracking vessels. The 2-HFSWR multisensor surveillance system consists of two independent radars implementing the target location and tracking task by detecting the radial distance and velocity, respectively. The 2-HFSWR multisensor surveillance system can ensure the detection accuracy without azimuth measurement, which is advantageous to the miniaturization of HFSWR. However, there are still certain complicated cases to be solved for continuous tracking of vessels, for example sudden change in motion state, an inaccurate model, and unknown priori statistical properties of noise.

Adaptive maneuvering target tracking with 2-HFSWR multisensor surveillance system

Drainage systems are important components in cartography and Geographic Information Systems (GIS), and achieve different drainage patterns based on the form and texture of their network of stream channels and tributaries due to local topography and subsurface geology. The drainage pattern can reflect the geographical characteristics of a river network to a certain extent. To preserve the drainage pattern during the generalization process, this article proposes a solution to deal with many factors, such as the tributary length and the order in river tributary selection. This leads to a multi‐objective optimization problem solved with a Genetic Algorithm. In the multi‐objective model, different weights are used to aggregate all objective functions into a fitness function. The method is applied on a case study to evaluate the importance of each factor for different types of drainage and results are compared with a manually generalized network. The result can be controlled by assigning different weights to the factors. From this work, different weight settings according to drainage patterns are proposed for the river network generalization.

A Genetic Algorithm for Tributary Selection with Consideration of Multiple Factors

The accurate detection of T-wave characteristic points is the basis of the morphology judging, which plays a great role in the diagnosis of heart diseases, especially in the arrhythmia diagnosis. Recently, the method based on the sliding area has received increasing interest due to its stable robustness. In this study, we aim to evaluate the performance of T-wave detection based on the sliding area method. Firstly, we constructed a systematic evaluation scheme by using records from the QT database and records chosen were separated into 10 groups, randomly. Then, the sliding area method was evaluated on each group. The sensitivity, specificity, accuracy and F1 measure were used as the evaluation indexes. Additionally, the tolerance window for determining a correct segmentation was 100ms. In this study, 1371 beats were used to detect the T-wave onsets. And for 1371 beats, the values of Se, P+, Acc and F1 measure were 54.70%, 54.70%, 37.66%, 54.70% for signals of first channel and were 54.05%, 54.05%, 37.03%, 54.05% for signals of second channel. Besides, 3542 beats were used to detect the T-wave offsets. And for 3542 beats, the values of Se, P+, Acc and F1 measure were 87.83%, 87.83%, 78.30%, 87.83% for signals of first channel and were 86.73%, 86.73%, 76.57% 86.73% for signals of second channel. Values of index aforementioned were smaller than 90%, which illustrated that the performance of the sliding area method depends on its different parameters combination and it adaptability needs to be verified further.

Performance evaluation for the sliding area-based T wave detection method on the QT database

Optical transceiver modules are commonly used in telecommunication and data communication systems, and are among the most troublesome electromagnetic interference (EMI) problems for regulatory compliance at their operation frequencies and/or harmonics. In this study, simulations and measurements are performed on an optical subassembly module, including the silicon photonics submodule assembly, in order to identify and characterize the EMI coupling paths. The total radiated power is measured and computed. Through simulation and corroborating measurements, the dominant EMI coupling paths at high frequencies above 10 GHz are identified and characterized, and currents on the silicon photonic subassembly conductor housing and optical fiber connection ferrule are a dominant radiating source. EMI mitigation methods are developed and shown to be effective in reducing the radiated emissions from real product hardware.

EMI Coupling Paths and Mitigation in Optical Transceiver Modules

A perennial problem in structure from motion (SfM) is visual ambiguity posed by repetitive structures. Recent disambiguating algorithms infer ambiguities mainly via explicit background context, thus face limitations in highly ambiguous scenes which are visually indistinguishable. Instead of analyzing local visual information, we propose a novel algorithm for SfM disambiguation that explores the global topology as encoded in photo collections. An important adaptation of this work is to approximate the available imagery using a manifold of viewpoints. We note that, while ambiguous images appear deceptively similar in appearance, they are actually located far apart on geodesics. We establish the manifold by adaptively identifying cameras with adjacent viewpoint, and detect ambiguities via a new measure, geodesic consistency. We demonstrate the accuracy and efficiency of the proposed approach on a range of complex ambiguity datasets, even including the challenging scenes without background conflicts.

2017 IEEE Conference on Computer Vision and Pattern Recognition (CVPR)

Distinguishing the Indistinguishable: Exploring Structural Ambiguities via Geodesic Context

An Improved MAC Protocol Design in VHF Data Exchange System (VDES) For Internet of Vessels

An Evolutionary Vulnerability Detection Method for HFSWR Ship Tracking Algorithm

Auto white balance algorithms can correct color conveniently, but not accurately. For some stationary video scenes that need accurate color information, we present a precise color correction algorithm. The algorithm needs to place the standard white or gray card in the application scene as a reference. The cards will be detected automatically by the algorithm. After the detection, the color information on the cards will be used to correct the color of the entire image. Experiment demonstrates that, this algorithm can correct the color precisely in real-time, far better than other white balance algorithms.

2017 10th International Congress on Image and Signal Processing, BioMedical Engineering and Informatics (CISP-BMEI)

A precise color correction algorithm for stationary video systems

We achieved a low-cost and small-sized Rb optical frequency standard based on 85Rb 5S1/2 → 6P3/2 transition with 10-15 stability, which is comparable with that of the best 532 nm I2 optical frequency standards. In this system, we directly lock the 420 nm diode laser on the 5S1/2 F = 3 → 6P3/2 F' = 4 hyperfine transition line without an additional Pound-Drever-Hall pre-locking system. The signal-to-noise-ratio reaches as high as 350 000 when the averaging time is at 1 s. Eventually by the fluctuation of the residual error signal after locking, the preliminary stability of the optical frequency standard reaches 1.2×10-14/τ, decreasing to 2.1 × 10-15 at 80 s. It shows potential in stability performance, experimental cost, and system volume compared with the 532 nm I2 optical frequency standard as a wavelength standard. It also opens a door for the achievement of wavelength standards by using higher excited states of alkalies.

Graph-based segmentation of abnormal nuclei in cervical cytology

In this paper, underwater near field sources separation and tracking method based on hydrophone array technique is proposed. Based on the acoustic wave propagation model in near field, the multiple signal classification and minimum variance beamforming method are applied. According to the maneuvering target detection strategy, an algorithm for source separation and tracking is proposed based on spatial domain filtering combined with neighborhood search method for improved tracking accuracy and low computational cost. Simulation results show that the proposed algorithm can separate near field multiple signal sources and track the definite target effectively.

Underwater near field sources separation and tracking with hydrophone array based on spatial filter

In this work, we propose a substrate-supported rapid evaporation crystallization (SSREC) method to rapidly self-assemble microbelts of 4-N,N-dimethylamino-4′-N′-methyl-stilbazolium tosylate (DAST), a benchmark organic nonlinear optical (NLO) crystal. The DAST microbelts formation depends very largely on substrate property and surfactant, and millimetre-long microbelts can be fabricated in less than one minute. The self-assembly driving forces are presumed to be the coulombic interactions which originate from DAST's ionic molecular structure and the large dipole moment of DAST nanocrystals. The DAST microbelt has a second harmonic generation active crystal structure and exhibits featured absorption and fluorescent properties. We believe that all these findings will facilitate applications of DAST in a very broad range of areas such as integrated light modulation, lasing etc. Furthermore, the simplicity of the SSREC may open new avenues in the area of organic NLO one-dimensional materials fabrication.

One-minute self-assembly of millimetre-long DAST crystalline microbelts via substrate-supported rapid evaporation crystallization

Singlet oxygen‐responsive micelles for enhanced photodynamic therapy

This paper proposed a moving vehicles segmentation approach combined two kinds of classifiers which are Gaussian mixture model and spatiotemporal saliency map. We extracted new spatial and temporal saliency features and improved spatiotemporal consistency optimization model to calculate more exact saliency map and to speed up the processing. Because misclassification appears when Gaussian background cannot be correctly updated on time, we combined saliency map and Gaussian mixture model foreground to solve the problem. Experimental results showed that, compared to current methods, our approach had higher efficiency and accuracy.

2017 International Conference on Machine Learning and Cybernetics (ICMLC)

Vehicles segmentation via spatiotemporal saliency improvement in crossroads monitoring

Coronal Mass Ejections detection using multiple features based ensemble learning

AbstractTo determine the route choice behavior of a driver under a scenario with multiple-source travel information, the features of subjective travel time prediction were analyzed, and then a conc...

Simulation Study on Route Choice Behavior under Multi-Source Travel Information

A method is proposed to predict the worst case shielding effectiveness of a board level shield (BLS). This method estimates the shielding effectiveness (SE) of the shield below and above the first resonance of a cavity formed by the BLS. The apertures of the BLS are modelled as antennas with known radiation efficiency. The estimation of the maximum field inside the cavity is used to calculate the magnetic currents driving the antennas above the first resonance of the cavity. Below the first resonance the field inside the cavity is estimated using the resonant LC circuit model. An approximated formula for the radiation of the uniformly placed apertures is developed. The worst case prediction is validated by the full wave simulation and also in measurement on a real BLS.

2017 IEEE International Symposium on Electromagnetic Compatibility & Signal/Power Integrity (EMCSI)

Worst case prediction of shielding effectiveness of board level shields

Moderate halophilic bacteria are of halophilic bacteria whose suitable growth of NaCl is 5-10%. When the moderate halophilic bacteria response to high osmotic stress, the intracellular will synthesize small organic molecule compatible solutes. Ectoine, which is the major synthetic osmotic compatible solutes for moderate halophilic bacteria, can help microbial enzymes, nucleic acids and the whole cell resist to hypertonic, high temperature, freezing and other inverse environment. In order to increase the Ectoine production of Moderate halophilic bacteria Halomonas sp. H02, the Ectoine fermentation medium component was optimized by Plackett-Burman (PB) and Response Surface Methodology (RSM) based on the principle of non-complete equilibrium The results of PB experiments showed that the three main influencing factors of Moderate halophilic bacteria Halomonas sp. H02 synthesis Ectoine culture medium were C5H8NNaO4 concentration, NaCl concentration and initial pH. According to the center point of the steepest climbing experiment, the central combination design experiment was used to show that the model is consistent with the actual situation. The optimum combination of three influencing factors were C5H8NNaO4 41 g/L, NaCl 87.2 g/L and initial pH 5.9, and the predicted amount of Ectoine was 1835.8 mg/L, increased by 41.6%.

Response surface method optimization of ectoine fermentation medium with moderate halophilic bacteria Halomonas sp. H02

Chapter 6 – Computer-Aided Molecular Design and Property Prediction

Emission source microscopy (ESM) technique can be utilized for the localization of electromagnetic interference sources in complex and large systems. This paper presents a sparse and nonuniform sampling technique for ESM. Compared with the traditional way of acquiring abundant and uniformly distributed scanning points on the scanning plane using a robotic scanning system, the proposed method is much more time-efficient in identifying the major radiation sources, even though the image quality is sacrificed. The feasibility of sparse sampling is mathematically proved, and it is shown that increasing number of scanning points increases the signal-to-noise ratio of reconstructed images. Besides, a nearest neighbor interpolation method is applied in the real-time processing to estimate the radiated power through the scanning plane. Thus, back-propagated images and estimated radiated power can be obtained in the real-time measurement process, which can efficiently and instantaneously provide the locations and the radiation strength of the most significant emission sources.

Sparse Emission Source Microscopy for Rapid Emission Source Imaging

This work discusses the concurrent applications of data collection and reconfiguration, and proposes a novel reconfiguration scheme during data collection. The proposed scheme incorporates the advantages of both proactive and reactive protocols into one system: using proactive protocol to collect continuous data and reactive protocol to reconfigure each remote node of the network. In addition, three methods with suppression mechanism are proposed in which two using the topology information as hints and one using simple flooding. Finally, we propose a cost-saving and reliable reconfiguration scheme during data collection to efficiently combine the table-driven data collection tree and three reconfiguration methods. The results of simulation show the effectiveness of the scheme.

Reconfiguration during data collection for many-to-one routing in wireless sensor networks

Local structural characteristics of Sb2Te3 films studied by reverse Monte Carlo modeling

Detection of Coronal Mass Ejections Using Multiple Features and Space–Time Continuity

The Accuracy on the Common Pan-Tompkins Based QRS Detection Methods Through Low-Quality Electrocardiogram Database

Association of the DISC1 and NRG1 genetic polymorphisms with schizophrenia in a Chinese population.

Tremendous underground exploitation as subway tunneling, functional facilities excavation in inner-city environments caused potential damages to buildings and bridges over the construction zone. PSInSAR technique and high resolution SAR data provides a powerful tool for slightly surface deformation in recent years. Till now, it is time to use PSInSAR as an operational and mature technique for geodesy and geodetic purposes. In this work we presented the monitoring of subsidence over subway tunnels and along high speed railway in Beijing city by interferometric time series analysis based on nearly 46 scenes of TerraSAR-X data over the past 4 years. The resulted velocity map described the extent and magnitude of subsidence along the subway lines due to the different ground excavation method. It demonstrated that the total subsidence of PSs over the tunnels caused by open-cutting method is up to 70-80 mm and that caused by tunneling method is only 15-25mm in the full construction cycle of subway tunnels. The subsidence extent is distinguished different relying on the excavation method as well as the load of ground buildings. Under the same condition the subsidence over the built up area is more significant than that over the general area.

2016 IEEE International Geoscience and Remote Sensing Symposium (IGARSS)

Beijing subway tunnelings and high-speed railway subsidence monitoring with PSInSAR and TerraSAR-X data

Tool presetting method for gear grinding based on the worst angles of tooth space edges

Based on P-augmented matrices theory, this paper put forwards the concepts of the dynamic internal segmentation of internal P-augmented matrix, the dynamic outer segmentation of outer P-augmented matrix, and the dynamic internal-outer segmentation of P-augmented matrix, and gives the segmentation structures and attribute relationships; then based on the concepts above, the concepts of internal P-augmented matrix reasoning, outer P-augmented matrix reasoning and P-augmented matrix reasoning, as well as their structures are proposed; finally, the intelligent acquisition theorems and acquisition criterion of P-information are presented, moreover, based on dynamic internal segmentation and dynamic internal P-augmented matrix reasoning, an application on the intelligent acquisition of internal P-information is shown.

The dynamic segmentation characteristics of P-augmented matrix and the dynamic intelligent acquisition of P-information

UCA1 overexpression predicts clinical outcome of patients with ovarian cancer receiving adjuvant chemotherapy

Underexposed video enhancement aims at revealing hidden details that are barely noticeable in LDR video frames with noise. Previous work typically relies on a single heuristic tone mapping curve to expand the dynamic range, which inevitably leads to uneven exposure and visual artifacts. In this paper, we present a novel approach for underexposed video enhancement using an efficient perception-driven progressive fusion. For an input underexposed video, we first remap each video frame using a series of tentative tone mapping curves to generate an multi-exposure image sequence that contains different exposed versions of the original video frame. Guided by some visual perception quality measures encoding the desirable exposed appearance, we locate all the best exposed regions from multi-exposure image sequences and then integrate them into a well-exposed video in a temporally consistent manner. Finally, we further perform an effective texture-preserving spatio-temporal filtering on this well-exposed video to obtain a high-quality noise-free result. Experimental results have shown that the enhanced video exhibits uniform exposure, brings out noticeable details, preserves temporal coherence, and avoids visual artifacts. Besides, we demonstrate applications of our approach to a set of problems including video dehazing, video denoising and HDR video reconstruction.

Underexposed Video Enhancement via Perception-Driven Progressive Fusion

How to manage increasing population and consumption with the earth’s finite resources. How can we do this while at the same time increasing equity and eradicating poverty? In order to reconcile this difficult balance, we construct two models to measure the sustainable capacity of a country. Defines the method to distinguish more sustainable countries and policies from less sustainable ones.Based on many factors impose impact on the sustainable development, choose PCA (principal component analysis) method to simplify the operation. Improve and optimize the TOP-SIS Model to calculate the relative closeness degree. Base on the conclusion development into five stages, the corresponding closeness of which is used as the standard to measure the sustainable development of a country. 1.Introduction How to manage increasing population and consumption with the earth’s finite resources. How can we do this while at the same time increasing equity and eradicating poverty? In order to reconcile this difficult balance, the concept of sustainable development was introduced in the 1980’s. Sustainable development is development that meets the needs of the present without compromising the ability of future generations to meet their own needs. It contains within it two key concepts:the concept of needs, in particular the essential needs of the world’s poor, to which overriding priority should be given; and the idea of limitations imposed by the state of technology and social organization on the environment’s ability to meet present and future needs. In order to define when and how a county is sustainable or unsustainable clearly,we develop two models to measure the sustainable capacity of a country. 2.Two Models for The Sustainability of a Country When obtaining the main indicators as the influence factor, we found too many factors were involved and not convenient for analysis. Therefore, we apply the Principal Components Analysis(PCA)methodfor evaluation. 2.1 Model1:TOPSIS TOPSIS is based on the concept that the chosen alternative should have the shortest geometric distance from the positive ideal solution and the longest geometric distance from the negative ideal solution Considering the discrepancy between all the countries and their indicators,firstly,we establish a judging matrix. Then we standardize the judging matrix to unify the data unit and their order of magnitude,and obtain the standard matrix V . The indicator of “the bigger,the better”, we use formula ) min( ) max( ) min( j j ij ij ij x x x x v − − = (1) The indicator of “the smaller,the better”, we use formula 3rd International Conference on Education, Management and Computing Technology (ICEMCT 2016) © 2016. The authors Published by Atlantis Press 1046 ) min( ) max( ) min( j j ij j ij x x x x v − − = (2) For sake of define the impact of indicators to the degree of sustainable development,we calculate weighted decision matrix R. The weighted value formulate ij j ij v w r ⋅ = (3) Where the indicator weighted value is calculated by Entropy Weight Method. We utilize Euclidean Distance Formula to define the degree of sustainable disparity between the actual value and the ideal value.Computing relative closeness degree. We can measure the level of a country’s sustainable development.With the increase of relative closeness degree.the sustainable development ability enhances as well. In order to make our simulation suitable for all of countries,we measure 28 countries in different degree of sustainable development to define the relationship between relative closeness degree and the countries’ sustainability.The consequence is shown in figure: These results divide sustainability into 6 stages as,shown in the table as bellow: 2.2 The Phil Haas Model-Based Forecas In order to test the rationality of our model, we made an analog emulation to use BP neural network model with Particle Swarm with randomly , choosing 20 countries as analog training samples, and using the remaining 8 countries as analogs, we got the following result:

Detection of coronal mass ejections using AdaBoost on grayscale statistic features

Using RADARSAT-2 satellite images from January 2012 to October 2015, this paper employ the PSInSAR(Permanent Scatterer InSAR) technique to acquire coastal lowland subsidence in Zhejiang province. In the Hangzhou Bay Region, the widely distributed silt deposition leads to the entire ground sinking slowly, with 10~20mm/a in rate. Conversely, the ground subsidence distribution of the Eastern Coastal Region appear be funnel-shaped. Its involving area is small, while the settlement gradient of settlement center is comparatively large, whose maximum is more than 20mm/a. It is clear that the over-exploitation groundwater may be the main force in pace with the growth of factories and plenty of population. However, the distribution characteristic of ground subsidence in distinct regions could be determined by different geological structure. Therefore the environmental capacity of Zhejiang's coast is relatively vulnerable, and the ground subsidence is extremely prominent. Nowadays, the main undertaking is to vigorously restrict groundwater extraction and make seawater dilute in order to keep a comfortable environment to live in.

PSInSAR technique to monitor coastal lowland subsidence along the Eastern Coast of China - a case study in Zhejiang coast

Optical transceiver modules are commonly used in telecommunication and data communications systems. These modules, which are located in the optical I/O ports at the front-end of switches and routers, are a dominating source of electromagnetic interference (EMI) problems at their operation frequency and/or harmonics. In this study, a simulation model is used to investigate the EMI coupling physics and performance of the silicon optical sub-assembly (OSA) module. Total radiation power (TRP) measurement has also been performed in a mode-stirred reverberation chamber (RC) to support the radiation mechanism analysis. The connector between the module circuit board to flex cable has been identified as the major EMI source above 15 GHz in the OSA module. This conclusion can help provide insight to EMC design engineers about the potential EMI problems in the OSA package.

2016 IEEE International Symposium on Electromagnetic Compatibility (EMC)

In recent years, as commercial banks' non-performing loans continue to rise, commercial banks have paid increasing attention to post-evaluation of loan project. This paper is based on the concept of social responsibility and draw lessons from the existing literature results, then designs an index system of post-evaluation of loan project from six aspects, and by using AHP to determine the weight of various indicators in order to comprehensively and systematically reflect problems of commercial banks' credit management, to promote the decision-making and management level of credit departments, and to improve the quality of loans. At the same time, promoting commercial banks to enhance the social sense of responsibility and consciously maintain the sustainable development of society and the environment. Keywords—Commercial Banks, Post-Evaluation of Loan Project, Index System, AHP

Establishment of Index System of Commercial Banks’ Post-Evaluation of Loan Project Based on the AHP

Abstract. As an important part of the scenic area infrastructure services, signage guiding system plays an indispensable role in guiding the way and improving the quality of tourism experience. This paper proposes an optimal method in signage location selection and direction content design in a scenic area based on geographic analysis. The object of the research is to provide a best solution to arrange limited guiding boards in a tourism area to show ways arriving at any scenic spot from any entrance. There are four steps to achieve the research object. First, the spatial distribution of the junction of the scenic road, the passageway and the scenic spots is analyzed. Then, the count of scenic roads intersection on the shortest path between all entrances and all scenic spots is calculated. Next, combing with the grade of the scenic road and scenic spots, the importance of each road intersection is estimated quantitatively. Finally, according to the importance of all road intersections, the most suitable layout locations of signage guiding boards can be provided. In addition, the method is applied in the Ming Tomb scenic area in China and the result is compared with the existing signage guiding space layout.

ISPRS - International Archives of the Photogrammetry, Remote Sensing and Spatial Information Sciences

A GEOGRAPHIC ANALYSIS OF OPTIMAL SIGNAGE LOCATION SELECTION IN SCENIC AREA

This paper presents a wearable signal acquisition system, which can measure physiological signs, i.e., electrocardiogram (ECG) and photoplethysmogram (PPG). The system is comprised of two parts: (1) an ECG sensor implemented in the master board which will be mounted on the chest and, (2) a combined PPG and motion sensor implemented in the slave board which will be worn around the neck area. The single-lead ECG, the single-channel PPG, and the 3-channel accelerometer signals are all sampled at 200Hz, and transmitted to an Android app through Bluetooth® low energy (BLE) in real time. The system is powered by a 3.7V lithium polymer battery, with an average current consumption of 10mA. In addition to giving an overview of the system design and implementation decisions, we summarize the finding of a PPG test region study based on our system, which indicates that the highest PPG stability is in the mid-throat region over the thyroid gland, and the PPG in the lower throat region is an excellent choice for respiration rate extraction with an average error less than 5%. With the assistance of the motion sensor, an obvious swallow motion can also be easily identified.

A wearable signal acquisition system for physiological signs including throat PPG

In this work, we present the low-complexity variable forgetting factor (VFF) technique for the diffusion recursive least squares (RLS) algorithm. In particular, we adopt the VFF mechanism that rely on time-averages of the posteriori error signal and incorporate it into the diffusion RLS (DRLS) algorithm to yield the low-complexity correlated time-averaged VFF diffusion RLS (LCTVFF-DRLS) algorithm. We develop detailed analyses in terms of mean and mean square performance for the proposed algorithm, and derive mathematical expressions to compute the mean square deviation (MSD) and the excess mean square error (EMSE). The simulation results show that the proposed LCTVFF-DRLS algorithm outperforms the existing DRLS algorithm with the fixed forgetting factor, and demonstrate a good match between our proposed analytical expressions and simulated results.

2016 IEEE Sensor Array and Multichannel Signal Processing Workshop (SAM)

Low-complexity correlated time-averaged variable forgetting factor mechanism for diffusion RLS algorithm in sensor networks

Abstract. As the received radar signal is the sum of signal contributions overlaid in one single pixel regardless of the travel path, the multipath effect should be seriously tackled as the multiple bounce returns are added to direct scatter echoes which leads to ghost scatters. Most of the existing solution towards the multipath is to recover the signal propagation path. To facilitate the signal propagation simulation process, plenty of aspects such as sensor parameters, the geometry of the objects (shape, location, orientation, mutual position between adjacent buildings) and the physical parameters of the surface (roughness, correlation length, permittivity)which determine the strength of radar signal backscattered to the SAR sensor should be given in previous. However, it's not practical to obtain the highly detailed object model in unfamiliar area by field survey as it's a laborious work and time-consuming. In this paper, SAR imaging simulation based on RaySAR is conducted at first aiming at basic understanding of multipath effects and for further comparison. Besides of the pre-imaging simulation, the product of the after-imaging, which refers to radar images is also taken into consideration. Both Cosmo-SkyMed ascending and descending SAR images of Lupu Bridge in Shanghai are used for the experiment. As a result, the reflectivity map and signal distribution map of different bounce level are simulated and validated by 3D real model. The statistic indexes such as the phase stability, mean amplitude, amplitude dispersion, coherence and mean-sigma ratio in case of layover are analyzed with combination of the RaySAR output.

This paper presents a new four poles dual-mode of the triangular microstrip filter with asymmetrical input and output filter feed. Cameron theory is applied to synthesize coupling matrix and design the filter. The filter is optimized by using the Cauchy's method, which is used in the S band with 200MHz pass-band filters of orders two and four are successfully designed. The results show that the insertion loss is less than 2 dB, the return loss is more than 20dB, even no higher order mode interference in the pass-band. The improved structure has a better band rejection performance. The designed filter is now being fabricated.

2016 IEEE International Conference on Microwave and Millimeter Wave Technology (ICMMT)

Design of triangular microstrip dual mode filter based on the coupling matrix synthesis method

The extension of onshore high-frequency surface wave radar (HFSWR) to shipborne HFSWR has the advantage of extended monitoring area and high application flexibility. However, additional modulation on the echo signal introduced by the forward movement and six-degree-of-freedom (6-DOF) ship motion may increase the surface current measurement error. Considering the radar array position on the ship, six-DOF ship motion, forward movement velocity, first-order Bragg scatter, and background noise, this paper models the backscattered Doppler spectrum of shipborne HFSWR. Based on this model, the performance of surface radial current measurement is analyzed, with the adoption of the MUltiple SIgnal Classification (MUSIC) to estimate the azimuth of the sea patches. Simulation results show that, rotation, sway and forward movement of the ship all have significant impacts on the surface radial current measure error. Nevertheless, if the ship sails at relative low speed and keeps its sailing direction (with small yaw amplitude), shipborne HFSWR may provide a better result than onshore HFSWR.

Ocean Surface Current Measurement Using Shipborne HF Radar: Model and Analysis

City sustainability evaluation using multi-criteria decision making with objective weights of interdependent criteria

Long-term efficacy of implantable cardiac resynchronization therapy plus defibrillator for primary prevention of sudden cardiac death in patients with mild heart failure: an updated meta-analysis

High Resolution Microendoscopy (HRME) is a new imaging method which based on high resolution fiber and molecular imaging technology and it is possible to organize real-time imaging. After design and optimization of excitation light conduction part, fluorescent image transfer unit, optical fast switching unit and image capture unit, we constructe a HRME imaging system. We make an imaging observation of animal gastrointestinal tract by using HRME system and the results show that the feasibility of virtual pathology of HRME which lay the foundation for further clinical research. As an instant histopathological imaging method, HRME is expected to become a new immediate diagnosis model.

Zhongguo yi liao qi xie za zhi = Chinese journal of medical instrumentation

[Construction and Preliminary Application of High Resolution Microendoscopy Imaging System].

Compared with traditional patch-based sparse representation, recent studies have concluded that group-based sparse representation (GSR) can simultaneously enforce the intrinsic local sparsity and nonlocal self-similarity of images within a unified framework. This article investigates an accelerated split Bregman method (SBM) that is based on GSR which exploits image compressive sensing (CS). The computational efficiency of accelerated SBM for the measurement matrix of a partial Fourier matrix can be further improved by the introduction of a fast Fourier transform (FFT) to derive the enhanced algorithm. In addition, we provide convergence analysis for the proposed method. Experimental results demonstrate that accelerated SBM is potentially faster than some existing image CS reconstruction methods.

Accelerated Split Bregman Method for Image Compressive Sensing Recovery under Sparse Representation

Optical flow-aided navigation for UAV: A novel information fusion of integrated MEMS navigation system

Family characteristics and the use of maternal health services: a population-based survey in Eastern China

In this research, the optimal estimation for networked control system with multiplicative noises (MN), one-step random delays and multiple packet dropouts is studied. Both the sensor-to-estimator and controller-to-actuator channels are affected by MN. The one-step random delays and packet dropouts are characterised by a series of Bernoulli variables. By state augmentation, the random circumstances in channels are transformed into random parameters, and the optimal estimators are derived utilising projection theory. For systems without MN, random delays or packet dropouts, the corresponding estimators can be derived as particular cases of the proposed algorithm. Then a sufficient existence condition of steady-state estimators is derived. Some numerical examples are given to validate the proposed estimation algorithms.

Optimal estimation for systems with multiplicative noises, random delays and multiple packet dropouts

The drainage pattern of a river network is the arrangement in which a stream erodes the channels of its network of tributaries. It can reflect the geographical characteristics of a river network to a certain extent because it depends on the topography and geology of the land and as such should be considered during the river network generalization process. There are many methods for river network generalization in tributary selection but most do not explicitly consider the network pattern. Validation of the generalized result is performed visually by an expert and may not be done systematically. An automatic validation technique may help to better understand the results obtained with each method and check whether the pattern has been preserved. This paper proposes an approach to evaluate the quality of a generalized river network by assessing how well its original drainage pattern is preserved. The membership to a drainage pattern is evaluated by a set of geometric indicators, making use of a fuzzy logic approach which allows for a compromise between different criteria depending on the membership values. Three tributary selection methods are tested in this work: selection by stroke and length, catchment area, and a manually generalized network. Assessing the quality of a generalization is done by comparing pattern memberships before and after generalization. This research provides a quantitative indicator to assess the generalized river network in preserving geographical information.

Evaluation of River Network Generalization Methods for Preserving the Drainage Pattern

Research on Cost-Sensitive Method for Boundary Region in Three-Way Decision Model

IBIS-L ground based SAR is able to provide accurate and long-term measurements over relative large areas by combining of stepped frequency continuous wave, synthetic aperture radar and interferometric technique. To measure displacements of an open pit slope in Beizhan iron mine, a novel environmental correction method is presented to perform the atmospheric distortion correction of GB-InSAR. GB-InSAR results show that, the entire working area is mainly on a stable condition, only two remarkable displacement areas with the maximum displacement over -15mm locate in the upper and lower parts of quarry rock face, respectively. Considering the displacement evolutions of selected pixels at different sectors, the quarry rock face should be impossible to produce larger geological disasters.

Using GB-SAR technique to monitor displacement of open pit slope

As China’s economic development continues, people’s living standard improves, and the development pace of the logistic industry in China has gradually accelerated, but the development level of the logistics industry in various regions still needs a detailed analysis. This paper collected in 2014 13 indicators from China’s 31 provinces which reflected the development level of the logistics industry; it then conducts a thorough analysis, using the factor and cluster analysis method to understand more about the development level of China’s logistics industry. Finally, a comprehensive evaluation is offered.

A Development-Level Evaluation on China’s Logistics Industry Based on Factor and Cluster Analysis

AbstractHeart failure is a public health problem and a great economic burden for patients and healthcare systems. Suppression of the renin–angiotensin system (RAS) by angiotensin-converting enzyme (ACE)-inhibitors remains the mainstay of treatment for heart failure. However, the abundance of ACE inhibitors makes it difficult for doctors to choose.We performed this network meta-analysis of ACEIs in patients with heart failure in order to address this area of uncertainty.We searched PubMed, Embase, CENTRAL, and Medline.Any randomized controlled trial evaluating the efficacy and safety of captopril, enalapril, lisinopril, ramipril, or trandolapril or combined interventions of 2 or more of these drugs.Two reviewers extracted the data and made the quality assessment. At first, we used Stata software (version 12.0, StataCorp, College Station, TX) to make traditional pairwise meta-analyses for studies that directly compared different interventions. Then, network meta-analysis was performed using WinBUGS (version 1.4.3, MRC Biostatistics Unit, Cambridge, UK).A total of 29 studies were included. Lisinopril was associated with a higher rate of all-cause mortality compared with placebo (odds ratio 65.9, 95% credible interval 1.91 to 239.6) or ramipril (14.65, 1.23 to 49.5). Enalapril significantly reduced systolic blood pressure when compared with placebo (standardized mean differences −0.6, 95% credible interval −1.03 to −0.18). Both captopril (odds ratio 76.2, 95% credible interval 1.56 to 149.3) and enalapril (274.4, 2.4 to 512.9) were associated with a higher incidence of cough compared to placebo.Some important outcomes such as rehospitalization and cardiac death were not included. The sample size and the number of studies were limited, especially for ramipril.Our results suggest that enalapril might be the best option when considering factors such as increased ejection fraction, stroke volume, and decreased mean arterial pressure. However, enalapril was associated with the highest incidence of cough, gastrointestinal discomfort, and greater deterioration in renal function. Trandolapril ranked first in reducing systolic and diastolic blood pressure. Ramipril was associated with the lowest incidence of all-cause mortality. Lisinopril was the least effective in lowering systolic and diastolic blood pressure and was associated with the highest incidence of all-cause mortality.

Comparison of the Efficacy and Safety of Different ACE Inhibitors in Patients With Chronic Heart Failure

Early detection of the high-risk lesions such as thin-cap fibroatheroma (TCFA) is highly desired in the clinic. Our group recently addressed the task of prediction of future TCFAs based on baseline virtual histology intravascular ultrasound (VH-IVUS) data with prediction performance not sufficient for routine clinical use. To achieve clinical relevance of our TCFA prediction, an improved strategy is presented here that introduces a spatial context between adjacent IVUS-frame locations and uses a 3-frame TCFA definition. We compared performance of four types of feature set (VH-based, IVUS-based, biomarkers, and combined features), two feature selection approaches (support vector machine recursive feature elimination [SVM RFE] and mutual information [MI]), and two classifiers (SVM and random forests [RF]) when analyzing 24 baseline-follow-up patient datasets. The experimental results indicated that the best prediction performance achieved nearly 10% improvement compared to our previous context-free method — AUC = 0.86, sensitivity=82.6%, specificity=82.1%.

2016 IEEE 13th International Symposium on Biomedical Imaging (ISBI)

Location-specific prediction of vulnerable plaque using IVUS, virtual histology, and spatial context

Application of Online Acidizing Technology Without Pulling String in Tight Reservoir

In this paper, considering the mobility of the sensor network, a novel mobility aware medium access control protocol is discussed, which applies to the problem of utilizing mobile nodes to collect data from underwater sensor networks. The proposed underwater mobility aware medium access (UW-MMAC) protocol, based on a hybrid of random and deterministic access, can be divided into two phases. The first phase is restructuring, which is based on random access to re-cluster with the mobile node as the cluster head. The second is data transfer phase, based on the Improved Time Division Multiple Access (ITDMA) protocol, which doesn't require strict time synchronization and makes full use of the long propagation delay. The cluster head calculates the delay of every sensor node to decide when to transmit data according to the updated cluster and assigns slots by sending a broadcast frame. And the length of allocated guard time of every sensor node depends on the distance between the sensor node and the mobile one. Besides, a personalized time compensation scheme is designed for every sensor node according to the maximum variety of predicted distance, which is caused by the movement of mobile node in the current cycle. The restructuring phase and the data transfer phase automatically switch in turns along with the process of moving. Simulation results demonstrate that the personalized time compensation mechanism in our UW-MMAC can improve the protocol throughput and reduce the packet collision rate in the process of moving.

A novel mobility aware medium access control protocol for underwater sensor networks

Detailed and precise information of land-use and land-cover (LULC) in rural area is essential for land-use planning, environment and energy management. The confusion in mapping residential and industrial areas brings problems in energy management, environmental management and sustainable land use development. However, they remain ambiguous in the former rural LULC mapping, and this insufficient supervision leads to inefficient land exploitation and a great waste of land resources. Hence, the extent and area of residential and industrial cover need to be revealed urgently. However, spectral and textural information is not sufficient for classification heterogeneity due to the similarity between different LULC types. Meanwhile, the contextual information about the relationship between a LULC feature and its surroundings still has potential in classification application. This paper attempts to discriminate settlement and industry area using landscape metrics. A feasible classification scheme integrating landscape metrics, chessboard segmentation and object-based image analysis (OBIA) is proposed. First LULC map is generated from GeoEye-1 image, which delineated distribution of different land-cover materials using traditional OBIA method with spectrum and texture information. Then, a chessboard segmentation of the whole LULC map is conducted to create landscape units in a uniform spatial area. Landscape characteristics in each square of chessboard are adopted in the classification algorithm subsequently. To analyze landscape unit scale effect, a variety of chessboard scales are tested, with overall accuracy ranging from 75% to 88%, and Kappa coefficient from 0.51 to 0.76. Optimal chessboard scale is obtained through accuracy assessment comparison. This classification scheme is then compared to two other approaches: a top-down hierarchical classification network using only spectral, textural and shape properties, and lacunarity based hierarchical classification. The distinction approach proposed is overwhelming by achieving the highest value in overall accuracy, Kappa coefficient and McNemar test. The results show that landscape properties from chessboard segment squares could provide valuable information in classification.

Discrimination of Settlement and Industrial Area Using Landscape Metrics in Rural Region

This paper investigates a multi-cell system powered by a micro-grid (MG), where the conventional generators (CGs), energy storage devices (ESDs) and renewable energy generators (REGs) are scheduled to supply electricity to base stations (BSs) at different prices respectively. Under this energy schedule model, we study the efficiency aspect of the MG-powered multi-cell systems from the economical perspective, and propose a new concept of efficiency, which is referred to as cost efficiency (CE). Specifically, we consider the ratio of the sum rate for all BSs to the total energy cost that the system spends in providing electricity for BSs. Assuming that the zero-forcing (ZF) beamforming scheme is employed by the BSs, our goal is to maximize the CE by jointly scheduling energy in the MG and allocating the transmit power at the BSs. We apply the Lagrange duality decomposition technique and Dinkelbach method to address the established CE optimization problem. Simulations are provided to validate the effectiveness of the proposed algorithm.

Cost Efficiency Optimization for Multi-Cell Systems Powered by Micro-Grids

Hybrid facial image feature extraction and recognition for non-invasive chronic fatigue syndrome diagnosis

Based on the quantitative analysis in Kano model, this paper proposes a model for improving tourism industry service quality from customer satisfaction and cost budget constraints perspectives. Relevant evaluation information is obtained by employing the questionnaire survey and the relationships between customer satisfaction and the fulfillment of service quality elements is determined in Kano model through processing the obtained evaluation information. Then based on the relationship functions, considering the budget constraints, the optimization model of improving tourism industry service quality to maximize the customer satisfaction is constructed, and the budget allocation is determined by solving the optimization model. Finally, a case study is provided to illustrate the feasibility and availability of the proposed method.

A decision method for improving tourism industry service quality under budget constraints.

Objective To evaluate the effectiveness of tooth guide trainer software (TGT) on the teaching of shade matching to dental students. Methods Forty undergraduate students were included in this study. All of the students learned theory knowledge of shade matching firstly and then were divided into two groups with 12 boys and 8 girls in each group. Students in one group accepted shade matching training with TGT. The other group didn't accept the TGT training. Then the shade matching ability of students in each group was evaluated by an experienced clinician. Results ANOVA analysis showed that both TGT training and gender of the students significantly affected the shade matching ability of students. The group with TGT software training had significant higher score in shade matching than that of the group without TGT training (P<; 0.05). The scales of girls were significantly higher than those of boys (P <; 0.05). Conclusion The use of TGT training can promote the study on shade match of dental students.

2015 7th International Conference on Information Technology in Medicine and Education (ITME)

Use of Tooth Guide Trainer on Dental Students' Training of Shade Matching

Nash equilibrium strategies for a defined contribution pension management

Phase assemblages of the K–Fe–Se ternary system (xK < 33.3 %) and the metastability of superconducting phase in this area

IBR (Internet Background Radiation) traffic identification is significant for malicious behavior detection. This paper presents a novel IBR traffic identification method since traditional methods depend on tough conditions, such as full bi-direction traffic or unassigned IP address space. We firstly explored the traffic source distribution of each destination IP on a traffic dataset, and found that the traffic sources of active IPs are relatively certain but that of inactive IPs are relatively uncertain. Secondly, based on this exploration results, we present a method to identify IBR traffic. It utilizes the presented metric to evaluate the certainty of traffic sources of a destination IP, so as to identify inactive IPs. Then it detects IBR traffic according to some heuristics built according to malicious traffic behavior patterns. We carried out several experiments to evaluate our method on real traffic datasets, and results show that it obtains 99% precision and 0.1% omission rate on detecting IPv4 IBR traffic. The detected IBR traffic includes the traffic that sent to assigned IPs besides unassigned IPs, which is more valuable and practical for detecting the malicious traffic in real networks.

Identifying Internet background radiation traffic based on traffic source distribution

The notable features of guarantee program differing from traditional project are high degree of information asymmetry and risk uncertainty. The evaluation for credit insurance risk is the key to insurance organization. In this paper, limitations of the traditional NPV evaluation method are proposed. A credit risk pricing model of the guarantee project is put forward based on the real options, which can reflect the value of the project more accurately and therefore enhance the feasibility and rationality of investment decision due to its consideration of the option value of flexible valuation. By using of the pricing model of the guarantee project based on Black - Scholes option risk model proposed in this paper, the investor can make a decision according to internal and external environment, so as to ensure the realization of the guarantee project and to optimize the enterprise value.

2015 12th International Conference on Service Systems and Service Management (ICSSSM)

A credit risk pricing model of guarantee business based on the real options

Canopy structural parameters and light radiation are important for evaluating the light use efficiency and grain yield of crops. Their spatial variation within canopies and temporal variation over growth stages could be simulated using dynamic models with strong application and predictability. Based on an optimized canopy structure vertical distribution model and the Beer-Lambert law combined with hyperspectral remote sensing (RS) technology, we established a new dynamic model for simulating leaf area index (LAI), leaf angle (LA) distribution and light radiation at different vertical heights and growth stages. The model was validated by measuring LAI, LA and light radiation in different leaf layers at different growth stages of two different types of rice (Oryza sativa L.), i.e., japonica (Wuxiangjing14) and indica (Shanyou63). The results show that the simulated values were in good agreement with the observed values, with an average RRMSE (relative root mean squared error) between simulated and observed LAI and LA values of 14.75% and 21.78%, respectively. The RRMSE values for simulated photosynthetic active radiation (PAR) transmittance and interception rates were 14.25% and 9.22% for Wuxiangjing14 and 15.71% and 4.40% for Shanyou63, respectively. In addition, the corresponding RRMSE values for red (R), green (G) and blue (B) radiation transmittance and interception rates were 16.34%, 15.96% and 15.36% for Wuxiangjing14 and 5.75%, 8.23% and 5.03% for Shanyou63, respectively. The results indicate that the model performed well for different rice cultivars and under different cultivation conditions.

Exploring the Vertical Distribution of Structural Parameters and Light Radiation in Rice Canopies by the Coupling Model and Remote Sensing

Rechargeable dental adhesive with calcium phosphate nanoparticles for long-term ion release.

Graph pattern matching is a hot spot in the big data era, which is to find answer graphs matching a given query graph in a data graph of graph databases. “Matching” means two graphs satisfy some relation, such as isomorphism, simulation, bisimulation, etc. Since there are seldom algorithms for the subgraph bisimulation, our work commits to solve the graph pattern matching problem involving bisimulation relations through the model checking technology. We characterize query graphs by modal formulas. By model checking the formulas in the data graphs, the answer graphs bisimilar to the query graphs can be discovered. We add * to basic modal logic language resulting in ML + * language, and add r* to form ML + * formulas. Then a theorem which states that ML + * formulas characterize finite directed graphs modulo bisimulation is put forward. Furthermore, we list steps to find answer graphs bisimilar to a query graph.

2015 8th International Conference on Database Theory and Application (DTA)

Incorporating Prepositional Phrase Classification Knowledge in Prepositional Phrase Identification

Reliable segmentation of abnormal nuclei in cervical cytology is of paramount importance in automation-assisted screening techniques. This paper presents a general method for improving the segmentation of abnormal nuclei using a graph-search based approach. More specifically, the proposed method focuses on the improvement of coarse (initial) segmentation. The improvement relies on a transform that maps round-like border in the Cartesian coordinate system into lines in the polar coordinate system. The costs consisting of nucleus-specific edge and region information are assigned to the nodes. The globally optimal path in the constructed graph is then identified by dynamic programming. We have tested the proposed method on abnormal nuclei from two cervical cell image datasets, Herlev and H and E stained liquid-based cytology (HELBC), and the comparative experiments with recent state-of-the-art approaches demonstrate the superior performance of the proposed method.

Improved segmentation of abnormal cervical nuclei using a graph-search based approach

In this paper, we present a novel shadow removal system for single natural images as well as color aerial images using an illumination recovering optimization method. We first adaptively decompose the input image into overlapped patches according to the shadow distribution. Then, by building the correspondence between the shadow patch and the lit patch based on texture similarity, we construct an optimized illumination recovering operator, which effectively removes the shadows and recovers the texture detail under the shadow patches. Based on coherent optimization processing among the neighboring patches, we finally produce high-quality shadow-free results with consistent illumination. Our shadow removal system is simple and effective, and can process shadow images with rich texture types and nonuniform shadows. The illumination of shadow-free results is consistent with that of surrounding environment. We further present several shadow editing applications to illustrate the versatility of the proposed method.

Shadow Remover: Image Shadow Removal Based on Illumination Recovering Optimization

In this paper, the river network is divided into sub-networks forming a hierarchy of drainage systems following the Horton order. Then, drainage systems are rearranged based on their pattern to obtain more homogeneous drainage systems which do not necessarily follow the Horton order. Such reorganization facilitates the description of the network system. Such organization can be useful for terrain analysis as it can help provide a qualitative description of the terrain or for generalization as river selection can be adapted to the type of network.

P-information Law Models and the Separation-Discovery of Unknown Information Law

 The 2014 dengue outbreak, the largest one in the last ten years in China, resulted in 13,800 hospitalized patients and more than 300 severe dengue cases in Guangzhou. Both of the viral strain and the host immune background may contribute to severe dengue. Here we report the monocyte response in dengue fever (DF) and severe dengue (SD) during the acute infection of seven dengue patients (DF n=4 and SD n=3) using multiparameter flow-cytometry with a panel of 9-surface markers. We also compared dengue specific IgG, IgM and NS1 in serum at the same time points for each patient. Six of the seven patients were diagnosed as secondary DENV1 infection, while one DF diagnosed as primary DENV1 infection. NS1 was nearly cleared in all patients when the serum IgG and IgM reached the high level at day 8-10 from the onset of fever. Obvious monocyte expansion was observed in both of DF and SD groups, frequently companied with the expansion of CD14++CD16+ subset. But the pattern of the response in the two groups was different at the recovery phase. The monocyte expansion in DF group maintained at a high level at day 7-10. Interestingly, the SD group underwent a second wave of monocyte expansion, in parallel with clinical course, starting from day 7 to day 10, especially the CD16+CD64+ monocyte subset. The characteristics of monocyte responses in DF and SD groups will advance our understanding of human dengue pathogenesis and may implicate the potential targets for early therapy.

A second wave of monocyte expansion may contribute to the severe dengue in 2014 outbreak in China (HUM4P.272)

The normal accident prediction models can't predict the occurrence of major accidents very well, so the cusp catastrophe model of major accidents is set up on the base of ideas of black swan and catastrophe theory. In the model, the main factors of major accidents are regarded as the controls parameters and the functional status of the system as the state parameter. The model has filled up the blank field of studying emergency in the black area. It is well explained by the model that the project state depends on the interaction between human factors and material factors. In the further step, the mechanism of major accidents can be generalized. The model is applied in the case of port engineering. To avoid major accidents, the corresponding measures would be taken according to different states of the port engineering. Through the application, the model is proved to be useful in the engineering practice.

The Cusp Catastrophe Model of Major Accidents Based on Ideas of Black Swan and Its Application in Port Road Projects

Face to face hand-holding is the main Inheritance method of traditional Chinese medical science (TCMS). But famous traditional-Chinese doctors are very rare, it's almost impossible to learn face-to-face for the youth who are thirsty for traditional Chinese diagnosis. In order to resolve the contradiction, this paper develops a video recording system to record the diagnostic procedure of famous traditional Chinese doctors, in which full views have been recorded as mp4 files which would be played again and again and stored forever in Weblib server. Also a mechanism for reliable recording and synchronization is proposed and implemented in the system.

A PV inverter Grid-Connected system based on SVPWM is designed here, which is consisted of DC/DC circuit, TMS320F2812 , optical isolating circuit and driver circuit, three-phase inverter bridge, Grid signal acquisition circuit. Besides,program of the system is built with CCS3.3. SVPWM, MPPT, Grid-Connected, control comes true with the help of C language. Improved variable step size perturbation and observation method is applied in MPPT, which saves time of searching maximum power point and avoids oscillation generated. The experimental results show that the system can not only meet the design requirements, the Grid-Connect effect is also ideal.

The Design and Implementation of PV Inverter for Grid-Connected System Base on SVPWM

Aiming to solve the problems of lacking quality element dynamics prediction in Kano model, considering the advantages of grey theory in coping with irregular data, a quality element dynamics prediction method based on GM(1,1) model is proposed. In view of the strong subjectivity of traditional Kano model, propose a fuzzy Kano model to classify the quality elements more objectively. Furthermore, for GM(1,1) model's ability to deal with small data, inadequate information and high prediction precision, it is widely used to study the dynamics prediction of Kano quality elements. Finally, an empirical study in express industry is provided to illustrate the feasibility and availability of the proposed method.

2014 11th International Conference on Service Systems and Service Management (ICSSSM)

Research on the dynamic of quality elements classification based on GM(1,1) model

This paper uses a double bounded dichotomous choice(DBDC) contingent valuation method(CVM) to estimate the willingness to pay(WTP) for water quality improvement of the Yangtze River in Nanjing in China. To improve the validity, special attention is paid to the issue of zero responses, and a Spike model that allowed for a non-zero probability of zero WTP is applied. Results indicate that there are significant positive values derived from the water quality improvement in Nanjing city, China. With protest responses being excluded, the WTP for each household is CNY260.7 (USD38.2) per year. Aggregating over the whole target population, it yields a benefit of CNY524.0 million (USD76.8 million) per year. If protest responses are treated as true zeros, estimation yields a WTP of CNY118.1, coupled with an aggregated benefit of CNY237.4 million (USD37.8 million) per year. At the practical level, considering the heterogeneous acceptability and the burden of water expenditure, special attention needs to be paid to the low-income families.

2014 International Conference on Behavioral, Economic, and Socio-Cultural Computing (BESC2014)

Value estimates of water quality improvement using the double bounded dichotomous choice contingent valuation format: A case study for Yangtze River, China

In this paper, MUltiple SIgnal Classification (MUSIC) algorithm is applied to determine the Direction of Arrival (DoA) of ocean surface current by shipborne High-Frequency (HF) radar moving with a constant velocity, based on principles of broadened first-order Bragg peaks. The velocity of the signal in DoA is compared with that of platform in the same direction, from which the radial velocity of currents can be obtained. As the platform moves forward, the currents are observed at different locations, thus obtaining the ocean surface vector currents. Simulation results show that the algorithm performs well in the overlapping areas.

Measurements of ocean surface currents using shipborne High-Frequency radar

In this study, poly-β-hydroxybutyrate (PHB) was synthesized by moderately halophilic bacteria Halomonas venusta and identified by 1H-NMR. The effects of different carbon sources, salt concentration, initial carbon nitrogen quality ratio, initial phosphate concentration were studied on the synthesis of PHB. The optimum conditions of the PHB synthesis were detemined. Glucose was as carbon source with the concentration of 80 g/L and salt concentration, initial carbon nitrogen ratio, initial phosphate concentration was 3%, 15 and 1.9 g/L respectively. Under the above conditions, a two-phase synthesis system of PHB was constructed. The PHB synthesis amount and yield of cell dry weight was reached up to 1.5 g/L and 69.19 wt.%, respectively. The efficient synthesis of PHB was realized.

The Synthesis of Poly-β-Hydroxybutyrate by Moderately Halophilic Bacteria Halomonas venusta

Based on the assumption that low-resolution image is sampled from an original scene approximated by piecewise polynomial surface, this paper proposes two different constraints to make the fitting surface of the original scene preserve the image's edge characteristics. We first construct a cubic parametric curve to approximate the edge in each local area and obtain an auxiliary pixel set by re-sampling the curve, then introduce a weight function to accord pixels different degrees of effects on surface reconstruction. By re-sampling the constructed surface, the enlarged image can be easily obtained. Extensive experimental results on various types of low-resolution images demonstrate that our method produces generally better results both in terms of quantitative evaluation and subjective visual quality.

In order to meet the demands of operation monitoring of large scale, autoscaling, and heterogeneous virtual resources in the existing cloud computing, a new method of live virtual machine (VM) migration detection algorithm based on the cellular neural networks (CNNs), is presented. Through analyzing the detection process, the parameter relationship of CNN is mapped as an optimization problem, in which improved particle swarm optimization algorithm based on bubble sort is used to solve the problem. Experimental results demonstrate that the proposed method can display the VM migration processing intuitively. Compared with the best fit heuristic algorithm, this approach reduces the processing time, and emerging evidence has indicated that this new approach is affordable to parallelism and analog very large scale integration (VLSI) implementation allowing the VM migration detection to be performed better.

Global Detection of Live Virtual Machine Migration Based on Cellular Neural Networks

A coordination strategy among a large cellular MIMO network is presented in this paper. With clustered linear precoding and dynamic frequency reservation techniques, JDFR-BDGMD (Joint Dynamic Frequency Reservation and Block Diagonalization precoding with Geometric Mean Decomposition precoding scheme) greatly mitigates intra-cluster interference as well as inter-cluster interference in the downlink OFDMA networks. Furthermore, the coordination is based on decision tree classification which categorizes users into coordinative users and non-coordinative users. It is noteworthy that we pick a capacity-based subchannel from system available resources for coordinative users. Finally, an equal power allocation algorithm is utilized to distribute power. Simulation results show that our proposed scheme can significantly improve the performance of multi-cell networks.

Network MIMO with decision tree classification in downlink OFDMA networks

Applying visual perception information for detection analysis and automatic extraction of breast mass in mammograms

Aiming at the problem of serious deformation and failure of the surrounding rock of the main roadways in diabase zone in west wing on-500m leve in Dongbaowei Coal Mine and roof caving occurring several times, the rupture characteristics of roadway roof rock was observed in this paper. And the observation result shows that the rupture of the roof rock of the roadways in diabase zone has obvious zoning characteristics, and the roadway roof rock is divided into three zones: fragmentation zone, fissure zone and intact rock zone. According to this, this paper introduced a new concept of controlling roadway roof subsidence and redesigned the support parameters of the roof of the roadway in diabase zone. The deformation monitoring of the testing roadway roof rock was carried out, and the monitoring result shows that the anchor supporting scheme which was based on the “three zones” of roadway roof could control the roof rock deformation better. This indicates that roadway anchor support design method which is based on the “three zones” of roadway roof is correct and feasible.

Roadway Anchor Support Design Method Based on the “Three Zones” of Roadway Roof

The Journal of China Universities of Posts and Telecommunications

The detection capability of the high frequency surface wave radar (HFSWR) is severely limited due to the strong interference from the sea/ground and the ionospheric clutter, etc. Since the ionospheric clutter occupies a lot of range and Doppler cells with strong echo energy in the range-Doppler (R-D) spectrum, the target is submerged in the clutter region, which seriously affects the target detection capability of HFSWR. In this paper, an ionospheric clutter region extraction method is proposed based on the morphological analysis of the ionospheric clutter region distribution characteristics in the R-D spectrum image. Furthermore, to overcome the weakening of the target echo strength induced by the ionospheric clutter, the peak detection method is applied to improve the target detection ability of HFSWR. Finally, the proposed method is validated by the field data of HFSWR, which shows that the new detection method can effectively identify the ionospheric clutter region on the R-D spectral image with higher target detection precision comparing with the traditional image processing method combining with the constant false alarm rate (CFAR) target detection results.

2014 IEEE International Conference on Communiction Problem-solving

Ionospheric clutter extraction in HFSWR based on range-doppler spectral image processing

A common single-nucleotide polymorphism identified in the 5'-untranslated region of the leptin gene (LEP -2548 G/A polymorphism) may be associated with obesity, but the existing research findings are inconsistent, so we conducted this meta-analysis.

METHODS
Medline, Embase and ISI Web of Science databases were searched to identify relevant studies. Meta-analysis of the total and subgroup populations was conducted using allelic, additive, dominant and recessive models, and odds ratios and their 95% confidence intervals were calculated in a fixed-effect model if no heterogeneity (evaluated as I(2) statistic) existed. Otherwise, a random-effects model was adopted. Subgroup analysis was performed by ethnicity. Meta-regression and the HETRED analysis were used to explore the potential sources of between-study heterogeneity. Egger's test and influence analysis were conducted to evaluate the publication bias and study power, respectively.

RESULTS
The final selection enrolled 9 studies, including 2,988 subjects (1,372 obese subjects and 1,616 controls). No significant association was identified between the LEP -2548 G/A polymorphism and obesity for all genetic models in the overall population and Caucasians. We found a significant association with allelic, additive and dominant models for subjects of mixed race from South America. Notwithstanding, this significance should be treated cautiously for it is based on a rather small sample (788 involved subjects).

In total, the combined analysis of data from current and published studies suggested that the LEP -2548 G/A polymorphism does not contribute to the development of obesity, despite the fact that a significant association exists in a small subgroup from South America. Further studies are needed to elucidate the relationship. .

Association of leptin gene -2548 G/A polymorphism with obesity: a meta-analysis.

In this paper, a global and local scheme based on graph cuts approach is proposed to segment cervical cells in images with a mix of healthy and abnormal cells. For cytoplasm segmentation, on the A* channel enhanced image, the multi-way graph cut is performed globally, which can effectively extract cytoplasm boundaries when image histograms present non-bimodal distribution. For nucleus especially abnormal nucleus segmentation, we propose to use graph cut adaptively and locally, which allows the combination of intensity, texture, boundary and region information together. Two concave-based approaches are integrated to split the touching-nuclei. On 21 cervical cell images with non-ideal imaging condition and pathology, our segmentation method achieved a 93% accuracy for cytoplasm, and a 88.4% F-measure for abnormal nuclei, both outperformed state of the art works in terms of accuracy.

2014 IEEE 11th International Symposium on Biomedical Imaging (ISBI)

Automated segmentation of abnormal cervical cells using global and local graph cuts

The explosive growth of high-data-rate multimedia services, with diverse quality-of-service (QoS) requirements, in wireless networks will lead to enormous energy consumption. Thus, the main challenge in designing recent wireless networks is to utilize network resources as efficiently as possible while ensuring the QoS for users. In this paper, we investigate the energy-efficient power allocation with QoS considered in the downlink of wireless multimedia networks with orthogonal frequency division multiple access (OFDMA). Firstly, energy-efficient power allocation problem is molded as the maximization of energy efficiency (EE) under different QoS requirements. Subsequently, an energy-efficient power allocation algorithm with chaotic particle swarm optimization (CPSO) is proposed. Finally, simulation results show that the proposed algorithm can converge much faster, compared with water-filling power allocation (WFPA), but both of them improve the EE greatly, compared with equal-power power allocation (EPPA).

2014 International Symposium on Wireless Personal Multimedia Communications (WPMC)

Energy-efficient power allocation with QoS guarantee in OFDMA wireless networks

This paper considers a continuous-time mean-variance asset-liability management problem with incompletely observable information. An investor can only observe the prices of the asset and liability and the dynamics 
of the unobservable states of the underlying financial market is described by a hidden Markovian 
chain. The price of the risky asset is assumed to be governed by a hidden Markovian 
regime switching geometric Brownian motion and the liability is assumed to follow a hidden 
Markovian regime switching Brownian motion with drift, respectively. The appreciation rates of 
the risky asset and the liability are modulated by the hidden Markovian chain. By using the 
separation principle, the filtering-estimation problem and the mean-variance asset-liability 
management problem are discussed. The explicit expressions for the optimal asset-liability 
management strategy and the mean-variance efficient frontier are determined by using the 
stochastic maximum principle.

Continuous-Time Mean-Variance Asset-Liability Management with Hidden Markovian Regime Switching

As the stochastic and time-varying underwater acoustic channels with serious multipath delays, energy loss and distortion factors, making the modeling and estimation of the underwater acoustic channel have been difficult problems in academic circles. As to the multiple-input multiple-output (MIMO) underwater acoustic communication, the system model with multiplicative noise is proposed to characterize the stochastic and time-varying underwater acoustic channels. Symbols are estimated based on the optimal recursive filtering algorithm in the sense of linear minimum variance, which can overcome the intersymbol interference and noise pollution efficiently. The system with multiplicative noise model established in this paper can characterize the underwater acoustic channels with complicated factors such as time-varying, energy attenuation, etc. The corresponding optimal channel estimation algorithm is computed recursively, which is calculation-efficient and can track the random variation of the underwater channel gain dynamically.

Symbol estimation for MIMO underwater acoustic communication based on multiplicative noise model

When dynamic network exhibits extremely complex behavior and keeps on changing all the time, the energy efficiency is the most important key-point of routing algorithm. Many empirical measurements are inadequate to represent dynamic networks. However, the quotient space theory is an in-depth treatment of hierarchical problem solving, and powerful abilities of representation with different granularities. In this paper, we present a novel approach based on quotient space theory to reduce the computation complexity of routing algorithm in the dynamic network. Firstly, we analyze the structure of dynamic network and use community-based multi-granular representation to represent the network. Then we develop a routing algorithm based on multi-granular spaces. Finally, we compare the proposed algorithm with several alternative methods and the results show that our algorithm clearly outperforms the comparison methods in the road network

Aiming at solving the subjectivity and uncertainty of service quality elements classification in Kano model and combining with fuzzy theory which is effective to cope with uncertainty and ambiguity, a Kano model based on fuzzy theory is proposed. This study will apply an approach of fuzzy questionnaires to modify Kano questionnaires which considered as subjective. Furthermore, this study will also develop a mathematical calculation performance according to the quality classification of fuzzy Kano model. It's more objective than traditional Kano model to realize the service quality elements classification. With this method, the accurate mentality can be fully reasonable reflected in unknown circumstances. Finally, an empirical study in Xuzhou Construction Machinery Group Co., Ltd, the largest manufacturing industry in China, to testify its feasibility and validity.

Classification of service quality elements based on Fuzzy Kano model: An empirical study in Chinese machinery industry

In recent years, the research on the resources sharing has made great progress in education area. But it is far from reaching the needs of teachers and students because of the great investment, poor management and service, low intelligence and poor scalability of present Basic Education Resources Sharing Model. With full use of the advantages of cloud computing, such as super computing ability, high reliability, high scalability, on-demand service, low cost, this paper intends to adopt cloud computing technology to design the model of basic education resources sharing platform and expatiate it's realization mechanism. The platform will offer a new solution for Basic Education Resources Sharing, which can save human, material and financial resources on repetition development and provide more high quality learning resources and references for teachers and students. The platform will also promote the integration of information technology with curricula and improve the imbalanced education development and gradually elevate the overall quality of education.

Research on the basic education resources sharing model based on cloud computing

In this paper, we propose a coordinated scheduling scheme in downlink multi-cell Orthogonal Frequency Division Multiplexing Access (OFDMA) networks. Firstly, a novel decision tree algorithm is introduced to categorize users according to certain attribute parameters to improve system performance. To suppress inter-cluster interference, a filter is used at the receive. To mitigate intra-cluster interference and enhance system performance, we jointly form precoding matrix (using Block Diagonalization precoding) and distribute power for coordinative users. Considering the fact that there is a constraint on number of coordinative users simultaneously served on one resource slot and there may be a large number of users needing coordinative transmission, it is necessary to allocate proper resource slots to them, seeking a tradeoff between coordinative user sum rate and system total capacity. Thus, a performance-based slot distribution is utilized. What needs to be pointed out is that our power control is a per BS power constraint. Simulation results show that our proposed scheme can significantly improve the performance of multi-cell networks.

Macrocells may suffer serious interference induced by the deployment of co-channel femtocells. To mitigate the cross-interference, we design a novel price-based power control method, with each femtocell user's delay quality-of-service (QoS) provisioning, in uplink OFDMA two-tier femtocell networks. Assuming that the macrocell base station (MBS) protects itself by pricing the interference from femtocell users (FU), a Stackelberg game is formulated with a goal to reach the joint utility maximization of the macrocell and the femtocells subject to a maximum tolerable interference power at the MBS. The Nash Equilibrium (NE) of its non-cooperative subgame is found with optimization theory firstly, and then a particle swarm optimization (PSO) aided power allocation (PSO-PA) algorithm is proposed to achieve the final Stackelberg Equilibrium (SE). Simulation results show that our proposed power allocation algorithm can converge quite fast and bring much higher effective capacity (EC) at FU side.

Price-based power control with statistical delay QoS guarantee in two-tier femtocell networks

Fatigue may lead to potential accidents, but its diagnosis is difficult so it is easy to be delayed or missed. In this paper, a novel 3D facial-image-based fatigue detection method is presented. There are three steps involved: First, 3D surface curvature-based methods are combined with some 2D image-based methods to locate the position of facial fatigue feature points on the facial 3D image-based model, which is reconstructed based on a pair of binocular facial images. Secondly, facial fatigue features, such as eye blink, gaze direction, mouth morphology, and facial expressions are extracted from the facial 3D image-based model by the corresponding extraction methods. Finally, together with N-times sampling data, the attribute value of each facial fatigue feature is calculated, and then integrated together to recognize fatigue by linear discriminant analysis (LDA) algorithm. The following experimental results show that compared with only 2D image-based method, the accurate location of facial feature points, attribute value's calculation, and fatigue's fusion detection are obviously improved using the method presented in this paper.

Fatigue detection with 3D facial features based on binocular stereo vision

The limited sensor node energy and the large number of nodes with dynamic network topology information have always been the important design concerns in Wireless Sensor Networks (WSN). Node clustering is an effective way to tackle with the two issues by grouping the nodes into hierarchies in order to reduce communication distance and the amount of message. This paper mainly focuses on the unification of the node energy consumption in WSN. The distributions of the energy consumption for various scenarios in the hierarchical network are analyzed for the first time and two main reasons are found leading to the asymmetry of the energy consumption among nodes. One is the energy consumption from the communications between nodes and base station, and the other is that from the cluster head for receiving data from other nodes. It is concluded that the probability of the node acting as cluster head should depend on the distribution of the head's energy consumption, and a variable sampling space oriented to the potential number of cluster heads is established thereafter. Furthermore, a new clustering algorithm, the Segment Equalization Clustering based on Cluster Head Energy Consumption (SECHEC) algorithm is proposed, which can effectively improve the network lifetime and ensure the availability of the system within its entire lifespan.

s: Decision making problems always puzzled managers and decision makers in enterprises or organizations. There are many useful soft operation research methods could solve the complicated problem. The paper raises two classic approaches ANP (Analytical network process) and FCM (Fuzzy cognitive map). Those two methods have some similarities and differences. In thus, according to different decision problems, people could compare the two approaches’ characteristics and choose the best tool to deal with the problems. At the end of the paper, a case study has been given for us.

The analytic network processes method & fuzzy cognitive map method in decision making: a comparative study

Background: A common single-nucleotide polymorphism identified in the 5′-untranslated region of the leptin gene (LEP -2548 G/A polymorphism) may be associated with obesity, but the existing research findings are inconsistent, so we conducted this meta-analysis. Methods: Medline, Embase and ISI Web of Science databases were searched to identify relevant studies. Meta-analysis of the total and subgroup populations was conducted using allelic, additive, dominant and recessive models, and odds ratios and their 95% confidence intervals were calculated in a fixed-effect model if no heterogeneity (evaluated as I2 statistic) existed. Otherwise, a random-effects model was adopted. Subgroup analysis was performed by ethnicity. Meta-regression and the HETRED analysis were used to explore the potential sources of between-study heterogeneity. Egger's test and influence analysis were conducted to evaluate the publication bias and study power, respectively. Results: The final selection enrolled 9 studies, including 2,988 subjects (1,372 obese subjects and 1,616 controls). No significant association was identified between the LEP -2548 G/A polymorphism and obesity for all genetic models in the overall population and Caucasians. We found a significant association with allelic, additive and dominant models for subjects of mixed race from South America. Notwithstanding, this significance should be treated cautiously for it is based on a rather small sample (788 involved subjects). Conclusions: In total, the combined analysis of data from current and published studies suggested that the LEP -2548 G/A polymorphism does not contribute to the development of obesity, despite the fact that a significant association exists in a small subgroup from South America. Further studies are needed to elucidate the relationship.

Association of Leptin Gene -2548 G/A Polymorphism with Obesity: A Meta-Analysis

Anti-proteolytic capacity and bonding durability of proanthocyanidin-biomodified demineralized dentin matrix

In this paper, we are interested in a series of sub-hierarchies of the KP hierarchy introduced by Date et al. in [4], which we call the ℬ𝒞r-KP hierarchy for r ∈ ℤ≥0. In a unified way, we construct additional symmetries of the ℬ𝒞r-KP hierarchy and show that all of them form a -algebra. Then, we introduce the constrained ℬ𝒞r-KP hierarchy, and construct its additional symmetries and show that all of them form a Witt algebra.

Effects of hepatitis B immunization on prevention of mother-to-infant transmission of hepatitis B virus and on the immune response of infants towards hepatitis B vaccine.

Quotient Space Based Problem Solving provides an in-depth treatment of hierarchical problem solving, computational complexity, and the principles and applications of multi-granular computing, including inference, information fusing, planning, and heuristic search. Explains the theory of hierarchical problem solving, its computational complexity, and discusses the principle and applications of multi-granular computing Describes a human-like, theoretical framework using quotient space theory, that will be of interest to researchers in artificial intelligence. Provides many applications and examples in the engineering and computer science area. Includes complete coverage of planning, heuristic search and coverage of strictly mathematical models.

Quotient Space Based Problem Solving: A Theoretical Foundation of Granular Computing

Characterized by small volume, low cost, and low power, MEMS inertial sensors are widely concerned and applied in navigation research, environmental monitoring, military, and so on. Notably in indoor and pedestrian navigation, its easily portable feature seems particularly indispensable and important. However, MEMS inertial sensor has inborn low precision and is impressionable and sometimes goes against accurate navigation or even becomes seriously unstable when working for a period of time and the initial alignment and calibration are invalid. A thought of adaptive neuro fuzzy inference system (ANFIS) is relied on, and an assistive control modulated method is presented in this paper, which is newly designed to improve the inertial sensor performance by black box control and inference. The repeatability and long-time tendency of the MEMS sensors are tested and analyzed by ALLAN method. The parameters of ANFIS models are trained using reasonable fuzzy control strategy, with high-precision navigation system for reference as well as MEMS sensor property. The MEMS error nonlinearity is measured and modulated through the peculiarity of the fuzzy control convergence, to enhance the MEMS function and the whole MEMS system property. Performance of the proposed model has been experimentally verified using low-cost MEMS inertial sensors, and the MEMS output error is well compensated. The test results indicate that ANFIS system trained by high-precision navigation system can efficiently provide corrections to MEMS output and meet the requirement on navigation performance.

Performance Analysis of Adaptive Neuro Fuzzy Inference System Control for MEMS Navigation System

A bacterium capable of simultaneous heterotrophic nitrification and aerobic denitrification at high concentrations of ammonia-nitrogen was screened and identified and the denitrification property was investigated in this paper. The strain was isolated from aeration tank of wastewater disposed by activated sludge and analyzed and identified by 16S rDNA. The effects of different carbon sources and carbon and nitrogen mass ratios on denitrification rate were studied. The changes of various forms of ammonia-nitrogens during the simultaneous heterotrophic nitrification and aerobic denitrification process were characterized. A strain capable of simultaneous heterotrophic nitrification and aerobic denitrification at 600 mg/L nitrogen concentration has been isolated and screened. Comparison of its 16S rDNA sequence showed 100% similarity to Bacillus licheniformis strain Lr124/6. The strain was named as Bacillus sp. A22. The optimal conditions for degradation of ammonia-nitrogen by Bacillus sp. A22 were trisodium citrate as carbon source and carbon and nitrogen mass ratios of 10. The denitrification rate was 98.2% after 96 h of culture under the optimal conditions and there was hardly any intermediates accumulation in the denitrification process. It has practical applications that the denitrification can be performed efficiently at high concentrations of ammonia-nitrogen by method of simultaneous heterotrophic nitrification and aerobic denitrification by Bacillus sp. A22 in nitrogen purification treatment of wastewater with high concentrations of ammonia-nitrogen.

Screening and Characterization of a Bacterium Capable of Simultaneous Heterotrophic Nitrification and Aerobic Denitrification at High Concentrations of Ammonia-Nitrogen

In this paper, a novel resource allocation with QoS guarantee and fairness (RAQF) scheme is considered for orthogonal frequency division multiple access (OFDMA) two-way relay networks. Multiple source nodes exchange information with the assistance of an amplify-and-forward (AF) relay node (RN) in the presence of an eavesdropper. A joint power allocation, subchannel allocation and subchannel pairing scheme is proposed, aiming to maximize the secrecy capacity for legitimate users, and fulfill the diverse quality of service (QoS) requirements for different users and guarantee the fairness. RAQF scheme formulates the optimization problem into a mixed integer programming problem, and then solve it with constrained particle swarm optimization (CPSO), binary CPSO (B CPSO) and classic Hungarian algorithm. Simulations are conducted to assess the effectiveness of the proposed strategies.

2014 IEEE Wireless Communications and Networking Conference (WCNC)

Joint resource allocation in secure two-way relay networks with QoS guarantee and fairness

The most important limiting factor of conventional D-InSAR method is strongly atmospheric wet delay during monitoring small landslides located at rainy and mountainous area. The wet delay phase could even cover deformation field of test site sometimes. In this paper, we found the wet delay phase over Shuping landslide was not only closely related with elevation, but also was a function of distance along radar azimuth or range direction. Therefore, based on least-square method, best-fit-polynomial correction models about wet delay filed over Shuping landslide could be established. By removing the wet delay phase field simulated from unwrapping phase, the deformation field of Shuping landslide could appear immediately. The result showed that this correction method could effectively remove the wet delay phase from differential interferograms, and it will have an important significance for monitoring slowly moving landslide in Three Gorges Area.

2013 IEEE International Geoscience and Remote Sensing Symposium - IGARSS

Experimental study of atmospheric correction to interferogram with high-resolution radar images and DEM over shuping landslide

Methane and nitrous oxide emissions from direct-seeded and seedling-transplanted rice paddies in southeast China

This paper use CFD software for geometric modeling and structural mesh for the Cone Hindered Settling Hydro-sizer and then apply the Fluent software for three-dimensional CFD simulation. Using RNG K-ε two-equation turbulence model and Swirl Dominated Flow model respectively, and the top speed of different feeding liquid two-phase flow of water under medium CFD numerical simulation results grader internal flow field characteristics.

The Numerical Simulation Study of the Cone Hindered Settling Hydro-Sizer Based on CFD

Technology of direct hot melt, concentration and crystallization to manufacture hydrazine hydrate solid waste into Na<sub>2</sub>CO<sub>3</sub>·H<sub>2</sub>O and Na<sub>2</sub>CO<sub>3</sub> was researched, and principle of process was discussed. Effects of available chlorine dosage, pH value on hydrazine removal rate and crystallization temperature, water evaporation, crystallization time on purity and yield of Na<sub>2</sub>CO<sub>3</sub> were investigated, finding out the optimal technological conditions. This technical process did not cause secondary pollution, products reached standard of GB/T22404-2008 and GB210.2-2004 respectively.

2013 Third International Conference on Intelligent System Design and Engineering Applications

Technical Studies on Hazardfree Treatment and Resource Recovery of Hydrazine Hydrate Solid Waste

In both geographic information system and terrain analysis, drainage systems are important components. Owing to local topography and subsurface geology, a drainage system achieves a particular drainage pattern based on the form and texture of its network of stream channels and tributaries. Although research has been done on the description of drainage patterns in geography and hydrology, automatic drainage pattern recognition in river networks is not well developed. This article introduces a new method for automatic classification of drainage systems in different patterns. The method applies to river networks, and the terrain model is not required in the process. A series of geometric indicators describing each pattern are introduced. Network classification is based on fuzzy set theory. For each pattern, the level of membership of the network is given by the different indicator values. The method was implemented, and the experimental results are presented and discussed.

The Management and Relationship Between Different Frequency Noise and Subjective Annoyance

SUMMARY Rule engine technologies have been widely used in the development of enterprise information systems. However, these rule-based systems may su ﬀ er the problem of low performance, when there is a large amount of facts data to be matched with the rules. The way of cluster or grid to construct rule engines can ﬂexibly expand system processing capability by increasing cluster scale, and acquire shorter response time. In order to speed up pattern matching in rule engine, a double hash ﬁlter approach for alpha network, combined with beta node indexing, is proposed to improve Rete algorithm in this paper. By using fact type node in Rete network, a hash map about ‘fact type - fact type node’ is built in root node, and hash maps about ‘attribute constraint - alpha node’ are constructed in fact type nodes. This kind of double hash mechanism can speed up the ﬁltration of facts in alpha network. Meanwhile, hash tables with the indexes cal- culated through fact objects, are built in memories of beta nodes, to avoid unnecessary iteration in the join operations of beta nodes. In addition, rule engine based on this improved Rete algorithm is applied in the enterprise information systems. The experimental results show that this method can e ﬀ ectively speed up the pattern matching, and signiﬁcantly decrease the response time of the application systems.

An Improved Rete Algorithm Based on Double Hash Filter and Node Indexing for Distributed Rule Engine

Due to a variety of strong noises on high-frequency surface wave radar, the real-time and accuracy of ship targets detection at sea are seriously affected. As the surface wave radar is mostly affected by the ionospheric clutter and sea clutter, a model of radar target detection system with multiplicative noise is established to characterize the effect of the two kinds of clutters on the ship target. Moreover, a real-time estimation method is proposed for ship targets detection based on the fault detection theory. Furthermore, the system model and the detection method are flexible to solve many practical problems. Simulation results show the validity of the model and the detection method.

Ship target detection with surface wave radar based on fault detection method

Callus induction and plant regeneration from anthers of Dendrocalamus latiflorus Munro

Abstract Objective: Heat shock protein 70 (Hsp70), a highly conserved cellular stress protein, is produced in every organism from bacteria to man. The purpose of this study was to determine the difference in Hsp70 concentrations between term and preterm deliveries. Methods: In total, 30 healthy term delivery and 99 preterm delivery (PD) women were recruited, including 46 women with preterm labor and intact membranes (PTL) with or without an intra-amniotic infection (IAI) and 53 women with a preterm premature rupture of membranes (PPROMs) with or without IAI. The Hsp70 levels in the maternal and the umbilical cord sera were tested by an enzyme-linked immunosorbent assay (ELISA); the expression levels of Hsp70 in the placentas were determined by immunoblotting and real-time PCR. Results: In contrast to the expression levels in normal term controls, Hsp70 expression levels were upregulated in PD; similar changes in Hsp70 expression levels were detected in PD maternal and umbilical sera. Patients with IAI were associated with a higher Hsp70 concentration than those without IAI. Conclusion: These results suggest a probable contributing role of altered Hsp70 expression levels in the pathophysiology of PD.

Alteration of heat shock protein 70 expression levels in term and preterm delivery

The importance of information sharing in supply chain management is a matter of consensus between practitioners and researchers. Information sharing can increase supply chain efficiency by reducing inventories and smoothing production. Studies from different and recognised authors are reviewed, compiled and analyzed in three aspects. First, the types of shared information in supply chain are summarized. After, the value of different shared information and the factors which affect its value are presented. Moreover, the methodologies used in literature are detailed. The paper concludes with some future directions for theory construction and empirical research.

The paper presents one teaching pattern driven by the practice in order to overcome the problems found in the existing teaching pattern. The new teaching pattern stimulates the students to work in the class as they are in the real software companies. So the students can apply the theory to the practice. The practice lays the foundation of the subsequent work after graduation.

2013 IEEE International Conference on Information and Automation (ICIA)

The innovation of the teaching pattern driven by the software company

We present in this work the monitoring of terrain displacement along large scale manmade linear features in Shanghai city by integrating medium and high resolution PSInSAR data. Focused on the stability of linear features themselves and infrastructures over the path of linear features, land subsidence along Shanghai Magnetic Levitation (Maglev) and No. 10 subway tunnels have been investigated. In the first case we reported the impact of regional subsidence to Maglev line by analyzing PSInSAR measurements from ENVISAT ASAR data and Cosmo 3m resolution data. Subsidence velocity map derived through Cosmo data indicates that the Maglev line has slightly displacement although regional subsidence rate reaches 2-3 cm per year described by ENVISAT data. The second case dedicated on the assessment of subway tunnels to buildings over the path of No. 10 subway. By time series analysis of the Cosmo SAR data acquired during Nov 2008 to June 2010, terrain subsidence in the construction period and operational period of No. 10 line has been studied. The PSInSAR data demonstrated that subsidence caused by subway tunnels reaches l-2cm and it is accelerated after the running of subways since the dynamic loading effect of vehicles.

Integrating medium and high resolution PSInSAR data to monitor terrain motion along large scale manmade linear features- a case study in Shanghai

A New Method for Determination of Forming Limit Diagram Based on Digital Image Correlation

Two supersymmetric hierarchies related to the super-HS spectral problem

This paper proposes a new shadow removal approach for input single natural image by using subregion matching illumination transfer We first propose an effective and automatic shadow detection algorithm incorporating global successive thresholding scheme and local boundary refinement. Then we present a novel shadow removal algorithm by performing illumination transfer on the matched subregion pairs between the shadow regions and non‐shadow regions, and this method can process complex images with different kinds of shadowed texture regions and illumination conditions. In addition, we develop an efficient shadow boundary processing method by using alpha matte interpolation, which produces seamless transition between the shadow and non‐shadow regions. Experimental results demonstrate the capabilities of our algorithm in both the shadow removal quality and performance.

Efficient Shadow Removal Using Subregion Matching Illumination Transfer

Heavy alcohol use is a major stroke risk factor while moderate alcohol use may offer protective benefits. We have shown that moderate ethanol (EtOH) exposure reduces while excessive EtOH exposure increases cortical infarct volume after experimental stroke in male and female mice. The effect of either moderate or excessive EtOH exposure levels in cortex is lost in ovariectomized mice, indicating female sex steroids may be involved in the female response to EtOH exposure and experimental stroke. However, it is unknown if male sex steroids (androgens) might alter the effect of varying EtOH exposure levels on male stroke outcomes. We determined the role of androgens in the male response to EtOH exposure and experimental stroke. Male mice were castrated (CAST) 7-8 days before EtOH exposure and middle cerebral artery occlusion (MCAO) to reduce endogenous androgens. Intact and CAST males were given 0.25 g/kg (moderate dose, n=11) or 2.5 g/kg (excessive dose, n=11) EtOH IP 1 h before 45 min of MCAO. These doses mimic moderate (1-2 drinks daily) or excessive (>4 drinks daily) alcohol use in men based on blood EtOH concentrations. Control male (n=11) and CAST mice (n=10) were given saline (0.015 mL/g) IP 1 h before MCAO. Infarct volume (% contralateral structure) was determined at 72 h reperfusion by analysis of coronal brain slices stained with 2,3,5-triphenyltetrazolium chloride. In contrast to saline treated mice (EtOH vs. saline), acute moderate EtOH exposure reduced (p<0.05) cortical infarct volume in intact (41+3% vs. 54+1%) and CAST (23+5% vs. 34+5%) males. Following acute excessive EtOH exposure, cortical infarct volume was increased (p<0.05) in male (62+2% vs. 54+1%) and CAST (47+4% vs. 34+5%) mice compared to saline treated mice. Clinically, our findings suggest that moderate alcohol use may positively while excessive alcohol use may negatively alter stroke outcomes in men regardless of androgen status. Future studies will need to address the role of androgens in aging male brain as gradual androgen loss during aging (andropause) may not have similar effects on the male brain’s response to EtOH exposure and experimental stroke as an abrupt loss of androgens in CAST mice.

Abstract TP263: The Effect Of Moderate And Excessive Alcohol Exposure On Male Experimental Stroke Outcomes In Mice Is Androgen-Independent

Background: Interleukin-27 signaling is mediated by the JAK-STAT pathway via activation of STAT1 and STAT3, which have tumor suppressive and oncogenic activities, respectively. Epithelial–mesenchymal transition (EMT) and angiogenesis are key processes in carcinogenesis. Although IL-27 has been shown to have potent anti-tumor activity in various cancer models, the role of IL-27 in EMT and angiogenesis is poorly understood. In this study, we investigated the role of IL-27 in regulating EMT and angiogenesis through modulation of the STAT pathways in human non-small cell lung carcinoma (NSCLC) cells. Methods: STAT activation following IL-27 exposure was measured in human NSCLC cell lines. Expression of epithelial (E-cadherin, γ-catenin) and mesenchymal (N-cadherin, vimentin) markers were assessed by Western blot analysis. Production of pro-angiogenic factors (VEGF, IL-8/CXCL8, CXCL5) were examined by ELISA. Cell motility was examined by an in vitro scratch and transwell migration assays. Selective inhibitors of STAT1 (STAT1 siRNAs) and STAT3 (Stattic) were used to determine whether both STAT1 and STAT3 are required for IL-27 mediated inhibition of EMT and secretion of angiogenic factors. Results: Our results demonstrate that IL-27 stimulation in NSCLC resulted in 1) STAT1 and STAT3 activation in a JAK-dependent manner, 2) development of epithelial phenotypes, including a decrease in the expression of a transcriptional repressor for E-cadherin (SNAIL), and mesenchymal marker (vimentin) with a reciprocal increase in the expression of epithelial markers, 3) inhibition of cell migration, and 4) reduced production of pro-angiogenic factors. STAT1 inhibition in IL-27–treated cells reversed the IL-27 effect with resultant increased expression of Snail, vimentin and the pro-angiogenic factors. The inhibition of STAT3 activation had no effect on the development of the epithelial phenotype. Conclusion: IL-27 induces mesenchymal to epithelial transition and inhibits the production of pro-angiogenic factors in a STAT1–dominant pathway. These findings highlight the importance of STAT1 in repressing lung carcinogenesis and describe a new anti-tumor mechanism of IL-27.

Title : IL-27 inhibits epithelial-mesenchymal transition and angiogenic factor production in a STAT 1-dominant pathway in human non-small cell lung cancer

In this paper, we investigate the dynamic case of optical grooming in flexible bandwidth optical networks, and propose a novel dynamic optical grooming algorithm called Consecutive Spectrum based Optical Grooming (CSOG). Simulation results show that the blocking probability can be reduced and resource utilization can be improved.

A Novel Dynamic Optical Grooming Algorithm in Flexible Bandwidth Optical Networks

OBJECTIVE
To analyze and evaluate the quality and academic level of the Chinese Journal of gastrointestinal surgery.

METHODS
Based on the data from WanFang data, a statistical research was carried out with the methods of bibliometrics and citation analysis to investigate the Details of the papers from Chinese Journal of gastrointestinal surgery cited by other journal articles.The important analysis indexes included number of published papers, number of cited papers, citation frequency, citation time distribution and difference, authors and citation journal distribution, etc.

RESULTS
Of all the 1442 papers published by the Chinese Journal of gastrointestinal surgery. From 2007 to 2011, 392 papers are cited, which account for about 27.18% of all cited numbers with total cited 998 times .. Immediacy index from 2009-2011 were respectively 0.08, 0.04 and 0.08. Cited half-life was 0.08 in 2011.

A relatively large proportion of papers published in the journal have ever been cited, indicating that the whole quality of the journal is considerably high. But due to its relatively short history of publication the journal still lacks papers with deep impact and great significance.

Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery

[Citation analysis of papers from Chinese Journal of Gastrointestinal Surgery].

Hydraulic classifier is widely used in the mill plant，But the design of traditional hydraulic classifier is simple，less controllable factors, cause the inaccuracy of Classifying product particle size，low classification efficiency. In order to solve these problems, the paper puts forward a new hydraulic classifier, we can improve the efficiency of classification by improving the appearance structure of hydraulic classifier and taking two pieces of top water. In the lab，the classification test was conducted with the coarse slime (0.9~0.3 mm, 0.3~0.074 mm) from Yanma coal preparation plant under the two phase of water supplying. The results of test show that by using two phase of water supplying, the new hydraulic classifier Can improve the classification effect of coarse coal slime.

Classifying imbalanced Internet traffic based PCDD: a per concept drift detection method

MicroRNA expression signature for Satb2-induced osteogenic differentiation in bone marrow stromal cells

Objective 
To investigate the effect of adaptive statistical iterative reconstruction (ASIR) on the image quality and radiation dose reduction for abdominal computed tomography (CT) at different noise index (NI) values and ASIR values. 
 
Methods 
The phantom Catphan 500 matched with abdominal ring was scanned by the abdominal CT protocol when NIand ASIR values were 10 and 0 (group A),12 and 30% (group B),13 and 40% (group C),14 and 50% (group D),15 and 60% (group E),16 and 70% (group F) respectively on the Discovery CT750 HD.The phantom was scanned 3 times repeatedly and 6 set of images were obtained each time,so each group contained 18 set of images.Image spatial resolution and radiation dose were compared directly,and image density resolution,image noise,accuracy of CT values were compared with ANOVA. 
 
Results 
For image spatial resolution,the line pair per centimeter that can be distinguished from group A to group F were 6,6,6,6,6 and 5 lp/cm for images reconstructed with“standard”kernel,which were 7,7,7,7,7 and 6 lp/cm for images reconstructed with“edge”kernel.The difference of objective noise and their deviations[ (15.23±0.18),(14.58±0.19),(14.55±0.20),(14.39±0.20),(14.11±0.24),(13.60±0.25) HU]and the subjective quality scores (SQS) [ (3.12±0.64),(2.89±0.60),(2.78±0.44), (3.22±0.44),(2.56±0.53),(2.44±0.73) ] for image density resolution from group A to group F were statistically significant (Fnoise=118.330,FSQS=2.548,P<0.05).The CTDIvol from group A to group F were 20.99,14.54,12.37,10.67,9.30 and 8.16 mGy. 
 
When NI≤15 and ASIR≤60%,the image quality can be maintained with 55.7% of radiation dose reduction at most,but the image spatial resolution becomes lower as the values of NI and ASIR become greater.The image quality at NI equal to 15 and the ASIR equal to 60% is better than any other groups. 
 
Key words: 
Imaging processing,computer-assisted; Radiation dosage; Tomography,X-ray computed

Evaluation of dose reduction and image quality in abdominal CT using adaptive statistical iterative reconstruction in a phantom study

With the increase of interruption frequency of high-current vacuum arc (HCVA), the relaxation time of arc plasma is close to characteristic time of arc current and transient characteristics of vacuum arc plasma become more obvious. In this paper, based on a 2-D transient magneto-hydrodynamic model, HCVA under different interruption processes is simulated and analyzed. The simulation results of power-frequency (50 Hz) current show that transient simulation results are the same as those of the steady-state model, as characteristic time of current is much longer than relaxation time of plasma. For fast current drop stage in dc interruption process, simulation results show that higher frequency makes current drops faster and ion number density larger; besides, residual plasma density between electrodes at current-zero moment is higher, and interruption becomes more difficult. Finally, transient characteristics of high-frequency HCVA is also simulated and analyzed. Simulation results show that change curve of ion number density lagged behind current curve; higher ion number density in the second 1/4 cycle can lead to reignition more easily.

Transient MHD Modeling and Simulation of High-Current Vacuum Arc Under Three Kinds of Interruption Processes

Internet Background Radiation (IBR) traffic is a kind of abnormal traffic, which is ubiquitous on the Internet. Detecting or filtering out IBR traffic from all traffic is benefit to ensure network security. This paper proposes a novel IBR traffic filtering method based on relative uncertainty theory. It directly filters out IBR traffic from collected Net Flow data without specific configurations or building extra collection system. The key assumption of our approach is that the traffic source of normal users is relatively certain rather than random. The IBR traffic filtered by our approach also includes the part that sent to normal user hosts besides the traffic to unsigned IP, which is more valuable and practical to network security.

2013 Fourth International Conference on Emerging Intelligent Data and Web Technologies

A Novel Method of Filtering Internet Background Radiation Traffic

Aimed at high-confinement (H-mode) plasmas in the Experimental Advanced Superconducting Tokamak (EAST), the effect of local gas puffing from electron and ion sides of a lower hybrid wave (LHW) antenna on LHW–plasma coupling and high-density experiments with lower hybrid current drive (LHCD) are investigated in EAST. Experimental results show that gas puffing from the electron side is more favourable to improve coupling compared with gas puffing from the ion side. Investigations indicate that LHW–plasma coupling without gas puffing is affected by the density near the LHW grill (grill density), hence leading to multi-transition of low–high–low (L–H–L) confinement, with a correspondingly periodic characteristic behaviour in the plasma radiation. High-density experiments with LHCD suggest that strong lithiation gives a significant improvement on current drive efficiency in the higher density region than 2 × 1019 m−3. Studies indicate that the sharp decrease in current drive efficiency is mainly correlated with parametric decay instability. Using lithium coating and gas puffing from the electron side of the LHW antenna, an H-mode plasma is obtained by LHCD in a wide range of parameters, whether LHW is deposited inside the half-minor radius or not, implying that a central and large driven current is not a necessary condition for the H-mode plasma. H-mode is investigated with CRONOS.

Experimental investigations of LHW–plasma coupling and current drive related to achieving H-mode plasmas in EAST

In this paper, we introduced the basic knowledge of set pair analysis at the first place. Then we defined the general form of basic operations and the properties of connection number, in the end we give the corresponding application examples. The concepts and methods of the operations are the basis points of this paper. The ccomposition operation that put forward in this article makes the results that we need more realistic and it more detailed and more reasonable when describe a problem.The operations also broaden the application scope of connection number and enrich the connection number theory of set pair analysis. The mathematical meaning is clear and the method is simple of this operation, it is easy to learn and use .This research also provides the computational basis for the next studies, it has a certain theoretical and practical significance.

THE FUNDAMENTAL OPERATION ON CONNECTION NUMBER AND ITS APPLICATIONS

The drainage pattern of a river network is the arrangement in which a stream erodes the channels of its network of tributaries. It can reflect the geographical characteristics of a river network to a certain extent, because it depends on the topography and geology of the land. Whether in cartography or GIS, hydrography is one of the most important feature classes to generalise in order to produce representations at various levels of detail. Cartographic generalisation is an intricate process whereby information is selected and represented on a map at a certain scale, not necessarily preserving all geographical or other cartographic details. There are many methods for river network generalisation, but the generalized results are always inspected by expert cartographers visually. This paper proposes a method that evaluates the quality of a river network generalisation by assessing if drainage patterns are preserved. This method provides a quantitative value that estimates the membership of a river network in different drainage patterns. A set of geometric indicators describing each pattern are presented and the membership of a network is defined based on fuzzy logic. For each pattern, the fuzzy set membership is given by a defined IF-THEN rule composed of several indicators and logical operators. Assessing the quality of a generalisation is done by comparing and analysing the value before and after the network generalisation. This assessment method is tested with several river network generalisation methods on different sets of networks and results are analysed and discussed.

QUALITY ASSESSMENT IN RIVER NETWORK GENERALISATION BY PRESERVING THE DRAINAGE PATTERN

Virtual scan chains reordering using a RAM-based module for high test compression

We describe our SemEval2012 shared Task 5 system in this paper. The system includes three cascaded components: the tagging semantic role phrase, the identification of semantic role phrase, phrase and frame semantic dependency parsing. In this paper, semantic role phrase is tagged automatically based on rules, and takes Conditional Random Fields (CRFs) as the statistical identification model of semantic role phrase. A projective graph-based parser is used as our semantic dependency parser. Finally, we gain Labeled Attachment Score (LAS) of 61.84%, which ranked the first position. At present, we gain the LAS of 62.08%, which is 0.24% higher than that ranked the first position in the task 5.

Zhou qiaoli: A divide-and-conquer strategy for semantic dependency parsing

A polymer drug delivery system was developed using crosslinked self-assembled micelles, which form stable coreshell particles. The block copolymer, composed of poly [poly (ethylene glycol) methyl ether methacrylat-block-[poly (methyl methacrylate-p-nitrophenyl acrylate)] [P(PEGMEMA)-b-P(MMA-NPA)], was synthesized via reversible addition fragmentation chain transfer (RAFT) polymerization. The self-assembled micelles were stabilized by core crosslinking through the reaction of p-nitrophenyl acrylate with 1,8-octandiamine forming stable coreshell particles.

Development of Core-Crosslinked Micelles for Drug Delivery System

Huang and Liu [Generalized scrambling indices of primitive a digraph, Linear Algebra Appl. 433 (2010), pp. 1798–1808] gave the definitions of the generalized μ-scrambling indices and the generalized scrambling indices of a primitive digraph and also provided some exact lower and upper bounds for the generalized scrambling indices of various classes of primitive digraphs. In this paper, we give some exact lower and upper bounds for the generalized μ-scrambling indices of various classes of primitive digraphs.

Bounds on the generalized μ-scrambling indices of primitive digraphs

Extreme weather events over Pakistan have been increasing. This is contributing to the ever enhancing human suffering of the region. The present study investigates the extreme rainfall in Pakistan by using General Pareto Distribution (GPD) method. This in turn is used to analyze extraordinary rainfalls of summer 2010. The results indicate that during the summer 2010 northwestern parts of Pakistan received abnormally high rainfalls. Of which a few places got rainfalls with return periods of more than fifty years. Mainly northern and north eastern parts of the country have the highest return year values during the monsoon season. Similarly south eastern parts of the country also show high return year values in summer. While most western parts of the country have small return year values in the monsoon or summer season. Climatologically these areas have comparatively less precipitation during summer monsoon. The weather pattern which developed in 2010 was not the usual convective weather system which is the hall mark of the monsoon season; instead it was a mesoscale convective system with stratiform precipitation.

2012 IEEE Fifth International Conference on Advanced Computational Intelligence (ICACI)

Determination of precipitation return values in connection to severe rainfall event of 2010 in Pakistan

In this paper, we study the reliability problem of electrical system and power device of certain-type armored vehicle by Copula function. Considering the correlation relationship among variables, confirm the marginal distribution through Weibull distribution, get the Archimedes Copula function and verify it. Establish reliability binary model and get reliability function and failure rate which solves the determination of correlation degree and calculation model. It provides important reference for the computation of the reliability of the complex system.

2012 IEEE International Conference on Computer Science and Automation Engineering (CSAE)

Application of Copula function in the reliability analysis of the electrical system and the power device of certain-type armored vehicle

Computer and internet technology brought about innovative changes of students life especially their leisure time after class. In light of this, the purpose of this study is to explore learners' participation of blog-based language learning in their independent learning in order to suggest a motivated and collaborative environment to communicate and learn.

2012 2nd International Conference on Consumer Electronics, Communications and Networks (CECNet)

An analysis on Chinese learners' participation of blog-based language learning after class

Symbolic computation of normal form for Hopf bifurcation in a retarded functional differential equation with unknown parameters

bSchool of Textile and Clothing, Nantong University, Nantong, China E-mail: zhanglz1005@126.com Abstract The main objective of this paper was to simulate the three-dimensional structure of warp knitted spacer fabric using computer technology. For this purpose, the geometric structure of warp knitted spacer fabric was investigated. Specifically, a 3D spacial stitch model of warp knitted spacer fabric is developed using non-uniform rational B-spline(NURBS) curves and surfaces. Since the stitches in real fabric are usually inclined, the offset rule of special stitches is employed in order to simulate the stitches more realistically. Then the offset calculation formulas for each given point in the 3D stitch model are obtained. Finally 3D computer simulation of warp knitted spacer fabric is achieved and some simulation images of this kind of fabric are generated on the computer. The mechanism developed in this paper can model the 3D structures of common warp knitted spacer fabric interactively and accurately.

Three-dimensional Computer Simulation of Warp Knitted Spacer Fabric

A yawning detection method which can be used in drivers’ fatigue monitoring is proposed. To adapt to the variance in different mouth shapes and sizes, it based on mouth inner contour corner detection and curve fitting. First, the Harris corner detection algorithm was used to detect inner mouth feature points. Second, we established the open mouths’ mathematical model by curve fitting those points, calculated the degree of mouth openness using the mouth model, and generated the real-time M-curve. Third, the duration of big openness in successive images is divided into levels for further judgment. The validation results show that the method can obtain more precise mouth parameters and distinguish yawn from complex mouth activities. So the method achieves a higher level of accuracy.

In order to investigate the effects of the concentration of NaCl, the medium components and the recombinant type on the expression of the ectoine synthase genes ectABC in Escherichia coli BL21, ectABC and their promotor sequence from Cobetia marina CICC10367 were cloned. The cloned sequence was restructured with expression vector pET43.1 and then the recombinant vector was transformed into E. coli BL21. Two types of recombinant were obtained including recombinant ect03, the restructured ectABC and recombinant pect21, the restructured ectABC with promotor. The expression products of these two recombinants were identified by 1H-NMR and the effect of induction method and condition on the expression of ectoine was investigated. The result indicated that low concentration of NaCl was conducive to the expression of ectoine in recombinant ect03. The highest concentration of ectoine from recombinant ect03 was 216.1 g/L in MMG medium under 0.5% NaCl. The use of monosodium glutamate improved the expression of ectoine significantly. Higher concentration of NaCl (3%) was conducive to the expression of ectoine in recombinant pect21.

Expression of the Genes Encoding Ectoine Synthases from Cobetia marina CICC10367 in E. coli BL21

OBJECTIVE
To investigate the material properties of normal and degenerated intervertebral discs (IVDs) and examine the effect of degenerative changes on IVD pathology.

METHODS
A computer-based online search was undertaken to identify English articles about material properties of IVDs published from January 1950 to 2011 in PubMed database. The retrieved keywords included material properties, intervertebral disc and degeneration. Based on the principles of reliability, advancement and efficiency, the obtained data were primarily examined, and the original source was retrieved to read the full-text. Repetitive articles were excluded. The data of material properties of normal and degenerated IVDs were summarized and analyzed by meta-analysis.

RESULTS
The data of Young's modulus, Poisson's ratio, shear modulus, hydraulic permeability and intradiscal pressure of normal and degenerated IVDs were obtained. Compared with normal IVDs, the Young's modulus and shear modulus of annulus fibrosus and nucleus pulposus were higher in degenerated IVDs, the Poisson's ratio was lower while the hydraulic permeability and intradiscal pressure were higher. Besides, the degeneration-related alterations in IVDs had an influence both on itself and other spinal structures, leading to diseases such as bulging disc, discogenic pain and spinal stenosis. Meanwhile, the heavy mechanical loading and injury indicated important pathways to IVD degeneration.

To a certain extent, the degenerative changes of IVD influence its material properties. And the degeneration-related alterations of composition can cause structural failure of IVDs, leading to injuries and diseases.

Influence of degenerative changes of intervertebral disc on its material properties and pathology.

Research on county public expenditure performance evaluation system, not only create conditions for more effective, results-oriented performance budgeting reform, but also provide direction of enhancing the capacity of public services for the grass-roots government. This paper attempts to construct the county public expenditure performance evaluation index system, in order to objectively evaluate the county public-sector expenditure performance, on this basis, and provides countermeasures and proposals of improving the performance for county public expenditure.

2012 Fifth International Conference on Business Intelligence and Financial Engineering

The Construction of County Public Expenditure Performance Evaluation System in China

In GIS and in terrain analysis, drainage systems are important components. Due to local topography and subsurface geology, a drainage system achieves a particular drainage pattern based on the form and texture of its network of stream channels and tributaries. Drainage pattern recognition helps to provide a qualitative description of the terrain for analysis and classification and is useful for terrain modelling and visualization and applications in environment. Much research has been done on the description of drainage patterns in geography and hydrology. However automatic drainage pattern recognition in river networks is not well developed. This paper introduces a method based on geometric quantitative indicators to recognize drainage patterns in a river network automatically. Experiment results are presented and discussed.

a Study of Variables Characterizing Drainage Patterns in River Networks

Mussel adhesive protein has significant potential application in the field of medical adhesion. Genetic engineering method is gaining more and more attention, by which mussel adhesive protein can be heterologously expressed. In order to improve the expression efficiency of mussel adhesive protein with heterologous recombinant, it is reported that the compatible solutes Ectoine promoted to expression of adhesive protein on Pichia pastoris GS115. In this study, the adhesive protein gene msfp-1 from Mytilus sp. JHX-2002 was transformed into P. pastoris GS115. Inducement expression of adhesive protein Msfp-1 with various methanol concentrations was investigated. The promotion of Ectoine on the expression level of recombinant protein was studied. The results showed that adhesive protein Msfp-1 was induced with methanol on the recombinant GS115/msfp-1. The optimal concentration of methanol was 1% on heterologous expression. In the inducement expression phase of Msfp-1 with methanol, Ectoine could play a promotion role on expression of heterologous proteins. When the concentration of methanol was 1.5% and the addition of Ectoine was 1.5 mM, the expression of Msfp-1 was up to 2.1 g/L. Compared to fermentation broth without Ectoine, the expression was increased by 61.5%. Ectoine has an important promotion in the efficient expression of mussel adhesive protein on P. pastoris GS115.

Efficient Expression of Mussel Adhesive Protein in Pichia pastoris GS115 Promoted by Ectoine

(World Association of Medical Editors WAME) (Publication Ethics Policies for Medical Journals) [7-8] (In te r nat i o na l Co m m i ttee o f Med i c a l Journal Editors ICMJE) (Uniform Requirements for Manuscripts Submitted to Biomedical Journals) [9] (Committee on Publication Ethics COPE) (Code of Conduct and Best Practice Guidelines for Journal Editors) (Code of Conduct for Jour nal Publishers) (Ethical Editing Newsletter) (Guidelines for Retracting Articles) (A Short Guide to Ethical Editing for New Editors) (How to Handle Authorship Disputes: a Guide for New Researchers) CONSORT EQUATOR (CONSORT) [10-11]

Joint Statement for advancing the practice of publication ethics in Chinese medical journals

The college classroom teaching is an important part of the quality of undergraduate education teaching, it plays a key role in improving the quality of undergraduate education comprehensively, therefore, it has the important significance to improve quality of college teaching and personnel training by establishing a set of practical and scientific classroom teaching evaluation system and evaluation methods which adapting to the demands of social development. Classroom teaching evaluation system and evaluation methods are researched in this paper which exploring the advanced and scientific, meeting the present college classroom teaching evaluation system and method, according with "The national long-term education reform and development plan outline", it makes the contribution to raise quality of college undergraduate classroom teaching and personnel training level.

Research on College Classroom Teaching Evaluation System and Evaluation Method

We study a multi-period mean-variance portfolio selection problem with an uncertain time horizon and serial correlations. Firstly, we embed the nonseparable multi-period optimization problem into a separable quadratic optimization problem with uncertain exit time by employing the embedding technique of Li and Ng (2000). Then we convert the later into an optimization problem with deterministic exit time. Finally, using the dynamic programming approach, we explicitly derive the optimal strategy and the efficient frontier for the dynamic mean-variance optimization problem. A numerical example with AR(1) return process is also presented, which shows that both the uncertainty of exit time and the serial correlations of returns have significant impacts on the optimal strategy and the efficient frontier.

Multi-Period Mean-Variance Portfolio Selection with Uncertain Time Horizon When Returns Are Serially Correlated

WiFi and ZigBee are regarded as key technologies of smart home, they support complementary applications in terms of data rate and serving range. Since both WiFi and ZigBee are operating over 2.4GHz Industrial, Scientific, Medical(ISM) band. And their devices are possibly close to each other for huge number of sensors or controllers in smart home scenario. The coexistence between WiFi and ZigBee system under smart home scenario is a critical issue. In this paper, an overview of WiFi-ZigBee interference analysis methodology, modeling of CSMA/CA mechanism and detailed coexistence issues under smart home scenario are introduced. Afterwards, two representative network deployment cases are simulated and discussed from their Clear Channel Assessment (CCA) mode and device distribution density. Results indicate that ZigBee system can work normally under the interference of WiFi deployed in the adjacent frequency band, if proper CCA mode is applied.

2012 3rd IEEE International Conference on Network Infrastructure and Digital Content

Coexistence study for WiFi and ZigBee under smart home scenarios

With the development of science and technology, more and more cities are confronted with the water pollution of various degrees. The article is devoted to the introduction of a secondary sewage monitoring and management system which can automatically check the content of different components in the sewage discharged by enterprises and supply data reports with the help of probes, SBCs, PCs, etc. The article includes five parts. The first part introduces the research background, main research work and innovations of this system. The second part introduces the system architecture and system process. The third presents the fundamental working principles of SBCs and the relevant algorithms of PCs. The fourth expounds the problems and deficiencies which may exist in the algorithms. And the last part consists of summary and prospect, providing the possible solution to the deficiencies and looking forward to the future direction of research.

The Development of PCB Enterprise Sewage Monitoring and Management and Controlling Systems

An adaptive method to capture weldlines during the injection mold filling

The key objective of this research is to reveal the change of the Oriental white stork's habitat due to local agriculture activities in the study area at landscape scale with the aid of Geographic Information System techniques. Furthermore, an analysis of breeding captivity is done for a better understanding of the relationship between the decrease in Oriental White Stork population and habitat loss and fragmentation in the study area. Result shows that: (1). In all, about 58% of potential breeding habitat and 90% of potential feeding habitat were respectively lost due chiefly to Agriculture reclamation over 1975-2006. (2). The degree of habitat fragmentation became higher, and habitat patches were isolated, smaller and closer to farmland patches over 1975-2006. Behavioral fragmentation due to agriculture reclamation is the major cause of potential habitat fragmentation. (3). The loss and fragmentation of potential habitat lead to the decrease in suitable habitat for the Oriental White Stork. Compared with 1975, suitable breeding habitat was lost 74% in 1989 and 89% in 2006 respectively. Accordingly the number of the Oriental White Stork which can be kept by suitable habitat declined. The decrease in Oriental White Stork population has a close relation with Habitat loss and fragmentation.

The impact on the Oriental white stork habitat due to the agriculture development in Sanjiang Plain, Northeast China

Big fruit size and nice red pigmentation combined with good flavor should be the major target for red-fleshed kiwifruit (Actinidia spp.) breeding programs. Genetic diversity and plant characteristics were evaluated on a set of kiwifruit accessions with predominantly redflesh to identify the superior individuals for further breeding or study of commercial application. The leading phenotypic characters varied widely among the accessions. Accession R reached average fruit weight '100 g, whereas it ranged from 43.15 to 84.71 g for the other accessions. Fruits of L and Q were flatter in shape than the others. The core volume accounted for fruit proportions ranging from 2.33% to 11.42%. 'Chuhong', 'Honghua', and K exhibited a round fruit apex, whereas most others showed a depressed apex. R, L, and Q had the highest a* values in the inner pericarp and also the most appealing visual coloration. Results revealed significantly higher soluble solid content (SSC), total sugar, and sugar/acid ratio in Q, R, and L. The 12 pairs of simple sequence repeat (SSR) markers were successfully used to characterize the genetic variability and confirm true-to-type identity for four accessions. However, the limited number of markers had no ability to discriminate among the other 11 accessions. Based on additional 28 SSRs, six of the indistinguishable accessions were confirmed to be genetically different, and three seemed to belong to the same clone vine. The results demonstrated that application of SSR data could improve the efficiency of identifying red-fleshed kiwifruit germplasm.

Phenotypic Characterization and Simple Sequence Repeat Identification of Red-fleshed Kiwifruit Germplasm Accessions

Automatically identifying and removing above-ground laser points from terrain surface is proved to be a challenging task for complicated and discontinuous scenarios. Eight methods have been developed and contrasted with each other for filtering LiDAR (Light Detection and Ranging) data. Only one approach is difficult to acquire high precisions for various landscapes. This paper presents a method filtering point clouds in which firstly a binary quadric trend surface is used to remove most non-terrain points by a defined height threshold and subsequently a progressive morphological filter further is employed to detect ground measurements. The experimental results demonstrate that this method yields less type I and total errors compared with other eight approaches based on ISPRS sample data sets.

Filtering LiDAR Data Using Binary Quadric Trend Surface and Morphological Approaches

The main purpose of this paper is to investigate the convergence of the Euler method to stochastic differential equations with piecewise continuous arguments (SEPCAs). The classical Khasminskii-type theorem gives a powerful tool to examine the global existence of solutions for stochastic differential equations (SDEs) without the linear growth condition by the use of the Lyapunov functions. However, there is no such result for SEPCAs. Firstly, this paper shows SEPCAs which have nonexplosion global solutions under local Lipschitz condition without the linear growth condition. Then the convergence in probability of numerical solutions to SEPCAs under the same conditions is established. Finally, an example is provided to illustrate our theory.

Numerical Solutions of Stochastic Differential Equations with Piecewise Continuous Arguments under Khasminskii-Type Conditions

Optimal path for China's strategic petroleum reserve: A dynamic programming analysis

Cellulose nanocrystals are converted into fluorescent labeling nanoparticles (Py-CNC) by a three-step procedure. The fluorescence emission of pyrene is enhanced after the modification to cellulose nanocrystals. Py-CNC is evaluated for its sensing ability towards metal ions and exhibits high selectivity towards Fe3+ among other screened metal ions with good discrimination between Fe2+ and Fe3+. The excellent selectivity for Fe3+ over a wide linear concentration range is observed through changes in the emission spectra. Spectroscopic analyses prove that the coordination interaction between Fe3+ and pyrene-modified cellulose nanocrystals leads to the recognition process. This sensing nanomaterial can be employed as a chemosensor for Fe3+ and promoted for many applications in chemical, environmental, and biological systems.

Synthesis and Photophysical Behavior of Pyrene-Bearing Cellulose Nanocrystals for Fe3+ Sensing

Inverse sampling is one of the hot topics in the continuous sampling process. It is considered to be a more appropriate sampling scheme than the usual binomial sampling scheme when the subjects arrive sequentially and the underlying response of interest is acute. In this paper, we propose five confidence interval estimators for the relative difference in 2 × 2 table under inverse sample. The performance of the proposed methods is evaluated with respect to their coverage probability and expected widths. Our empirical results show that the confidence intervals based on the score statistic produce similar coverage probabilities and smaller confidence interval widths.

Confidence interval for relative difference under inverse sampling

Carbazole-substituted hydroxyethylcelluloses (Cz-HECs) are homogeneously synthesized by reacting hydroxyethylcellulose (HEC) with N-3′-bromopropyl carbazole (Br-Cz). The structure of Cz-HECs is characterized with elemental analysis and NMR, and the DS of the carbazole is in the range 0.11–0.43, determined from nitrogen content. The fluorescent properties of Cz-HECs are measured using a spectrofluorimeter. The results show that the fluorescence lifetime increases as the DS increases, and the fluorescent intensity of Cz-HECs is stronger than that of Br-Cz. All samples exhibit concentration self-quenching properties. The addition of acrylonitrile, as an electron acceptor, quenches the emission spectra of Cz-HECs, and the fluorescence quenching is found to be a dynamic quenching by analyzing with the Stern–Volmer equation.

Synthesis and Fluorescent Properties of Carbazole‐Substituted Hydroxyethylcelluloses

The resources allocation and the dynamic environment determine enterprises performance, and dynamic environment directly affects on business performance, but also indirectly affects the relationship between resources allocation and performance. This paper got resources allocation factors and dynamic environment factor by principal component analysis. Empirical results showed that financial resources allocation and product-sales allocation have positively effect on financial performance; human resources allocation and R&D resources allocation have negatively effect on financial performance. Dynamic environment as the explanatory variable has a significant positively impact on financial performance. Dynamic environment significantly moderates the relationship between different dimensions of resources allocation and financial performance, and the regulating direction and degree is different.

The influence of dynamic environment and resource allocation on enterprises financial performance

The base set of primitive zero-symmetric sign pattern matrices with zero diagonal is . In this paper, the primitive zero-symmetric sign pattern matrices with zero diagonal attaining the maximal base are characterized.

Primitive Zero-Symmetric Sign Pattern Matrices with Zero Diagonal Attaining the Maximum Base

The purpose of this paper is to investigate the comparative geometrical dimensions of Chinese and Western cervical vertebrae. A Chinese neck model, based on MRI/CT scan images and frozen slice images from a 35-year-old male cadaver, was established and compared with literature data and a newly- developed Western neck finite element model. Results showed that the geometrical dimensions of Western cervical vertebrae are approximately 20% greater than the Chinese cervical vertebra on the average, and the geometrical dimension ratio at different cervical levels (i.e. C3-C7) of these two cervical vertebrae is different (range 0.96-1.41). Besides, at every level of all cervical vertebrae except C2 there exist evident geometrical differences between the Western and Chinese neck model. In summary, it is necessary to apply the intact anatomic parameters of the Chinese neck rather than the scaled geometry of the Western neck to establish a standard mid-size Chinese neck finite element model.

Comparative Geometrical Dimensions of Chinese and Western Cervical Vertebrae

Calculation and simulation of the interior ballistic precedes the design of gun and charge construction. Modular charge system is the major development direction of large caliber howitzer, and will be as a replacement of current bag charge. It is necessary to develop a common program used to simulate interior ballistic environment of modular charge, which is a complex composite propellant charge. The characteristics of modular charge construction and the difference compared with traditional charge style were introduced at first. A simulation program of was developed based on lumped-parameters interior ballistic model using Matlab/Simulink development environment, which is relative simple, but, very suitable first stage design of interior ballistic of modular charge system. The program includes four modules, input parameters, core simulation code, calculation of form equations and data processing. The simulation results are agreeable with the experimental values according to the parameters of a certain 155mm gun. Furthermore, the program could be used in the numerical calculation of single charge or bag charge by adjusting some items.

Interior Ballistics Simulation of Modular Charge Gun System Using Matlab

In this paper, based on a two-dimensional (2D) transient magneto-hydrodynamic (MHD) model, HCVA under different interruption conditions was simulated and analyzed. The simulation results of power-frequency current show that the simulation results of the transient model are the same as those of the steady-state model, as the varying time of current is much longer than the relaxation time of plasma. This verified the correctness of previous conclusions of simulating power-frequency vacuum arc by steady-state model. For fast current drop process in DC interruption, simulation results show that higher frequency makes current drops faster and ion number density larger, besides, the density of residual plasma between electrodes at current-zero moment is higher, and interruption becomes more difficult. Finally, transient characteristics of high-frequency HCVA also was simulated and analyzed. Simulation results showed that plasma between electrodes was too slow to spread in the high-frequency condition, and the change of ion number density lagged behind the current change; the higher ion number density in the second 1/4 cycle weakens the Hall Effect, and leading to a more uniform distribution of current density.

2012 25th International Symposium on Discharges and Electrical Insulation in Vacuum (ISDEIV)

Transient modeling and simulation of high current vacuum arc under different conditions

Realizing high breakdown voltage for a novel interface charges islands structure based on partial-SOI substrate

As semiconductor process technology scales down, interconnect planning presents ever-greater challenges to designers. In this paper, we analyze, evaluate, and compare various metrics with optimized wire configurations in the contexts of different design criteria: delay minimization, delay-power minimization, and delay2 -power minimization. We show how various design criteria influence the configuration, performance, and power consumption of repeated wires.

IEEE Transactions on Very Large Scale Integration (VLSI) Systems

On-Chip Interconnect Analysis of Performance and Energy Metrics Under Different Design Goals

Design of Gearbox Fault Diagnosis System Using Empirical Mode Decomposition Algorithm and LabVIEW Software

Hot water extracts from Armillaria mellea and Hohenbuehelia serotina fruit bodies were prepared and investigated for their antioxidant capacity in three different assays, namely, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, reducing power and chelating ability on ferrous ions. Among the two mushrooms hot water extracts, extract from A. mellea was better than that from H. serotina in scavenging ability and chelating effect on ferrous ions. With regard to reducing power, EC50 value of extracts from H. serotina was 0.447 mg/mL, while that of extracts from A. mellea was 1.914. From EC50 values obtained, it can be concluded that hot water extracts from A. mellea and H. serotina were good in antioxidant properties.

Antioxidant Properties of Hot Water Extracts from Armillaria Mellea and Hohenbuehelia Serotina

Self-assembled micelles based on hydrophobically modified quaternized cellulose for drug delivery.

Base bleed propellant is an important component of the increasing rang projectile using base bleed technology. Unsteady strongly combustion leads to extinguish, reignition or critical state which produce an effect on rang dispersion. The burning behavior is determined by the initial pressure of combustion chamber and the maximum pressure decay rate, which was investigated by simulation experimental device in this study. A BP neural network prediction model of combustion state related to rapid depressurization was constructed. This prediction model is very easy to give the burning behavior according to the two pressure changing parameters. It is convenient to predict the base bleed unit combustion state at the moment of the projectile flying out of gun muzzle using this model in engineering practice.

2011 3rd International Workshop on Intelligent Systems and Applications

Rapid Depressurization Burning Behavior Prediction of Base Bleed Propellant Based on BP Neutral Network

The petroleum ether, acetic ester, methanol and water extracts of laoying tea were prepared and their antioxidant properties were studied. At 160 µg/mL, the methanol extract showed a high reducing power of 1.206. With regard to the scavenging ability on 1,1-diphenyl-2-picrylhydrazyl radicals, extracts were effective in the order: methanol > acetic ester > water > petroleum ether extracts. EC50 values for chelating ability on ferrous ions for petroleum ether, acetic ester, methanol and water extracts were 11.76, 14.32, 6.05 and 1.02 mg/mL, respectively. Based on EC50 values, the various extracts from laoying tea were effective antioxidants.

Antioxidant Properties of Laoying Tea (Litsea Coreana L.) Extracts

In this paper, we introduce a novel optimal fuzzy competitive learning self-organizing feature map (FCL-SOFM.). Different from traditional SOFM, the neurons in FCL-SOFM are updated in the whole neuron lattice based on the fuzzy competitive membership function. So, how to choose membership function is very important in FCL-SOFM. A novel optimal membership function selection scheme is proposed in this paper, in which the fuzzy exponential factor is chosen based upon the normalized Gibbs distribution of network energy in each iterative stage. This optimal FCL-SOFM network can finally converge to the base state of system energy, and achieve global minimum. We apply this optimal FCL-SOFM neural network in Vector Quantization to construct optimal codebook. The experimental result shows that this optimal FCL_SOFM Vector Quantization has a better compressing performance than JPEG.

With the improvement of technology, more cores are placed on a single chip to form a system. The volumes of test data becomes a challenges for circuits test. The paper presents a test data compression which uses hybrid prefix code and a new test set regenerating algorithm. In essence, the technique uses two formats of prefix to encode for the new regenerated test set, and the regenerated test set is better suitable to our compression scheme. So it gain better compression ratio.  Experimental results show that the proposed compression solution could re duce test data volume effectively with a simple decoding architecture.

Chroogomphis rutillus is an ectomycorrhizal edible mushroom available in China. The ethanolic, cold water and hot water extracts were prepared and their antioxidant properties studied. At 4 mg/mL, the ethanolic extract showed a high reducing power of 1.561, whereas those of cold water and hot water extracts were 1.161 and 0.808. With regard to the scavenging ability on 1,1-diphenyl-2-picrylhydrazyl radicals, extracts were effective in the order: ethanolic > cold water > hot water extracts. EC50 values for chelating ability on ferrous ions for ethanolic, cold water and hot water extracts were 15.755, 0.059, and 0.067 mg/mL, respectively. Based on EC50 values, the various extracts from C. rutillus were effective antioxidants.

This paper reports the acoustic experiment and perception test on a pair of Cantonese long and short vowels /a/ and /ɐ/ in the diphthong context. The acoustic data show that [aːi] and [ɐi] have similar targets of vowel nucleus and coda, parallel transition glide, and comparable total duration. They are different in their durational structure: [aːi] has a long steady phrase of vowel nucleus while its coda is short. In contrast, the vowel nucleus of [ɐi] is short but its coda lasts long. The situation of [aːu] and [ɐu] is also similar. In the perception test, the unidirectional gradual cutting method is adopted to change the duration ratio of vowel nucleus and coda. Progressive cutting [aːi]/[aːu] can make them sound like [ɐi]/[ɐu], while regressive cutting [ɐi]/[ɐu] can turn them into [aːi]/[aːu], which prove that these pairs of diphthongs are different in durational structure rather than vowel quality. Furthermore, borrowing the idea of the least square method, our re-analysis of the stimuli reveals that the length of vowel nucleus plays a more important role than the quality of transition glide and coda target in perception.

Spaceborne Radar Interferometry (InSAR) is well known as an accurate, time saving and low cost technique for monitoring of surface deformation phenomena ranging from land subsidence, volcano displacement, tectonic motion and even slow landslides. The Coherent Point Target SAR Interferometry (CPT-InSAR) overcomes atmospheric delay anomalies and the temporal and geometric decorrelation by the interferometric calculating of point-wise targets which maintain high coherent. The linear and no-linear subsidence can be retrieved by CPT-InSAR, which can be done well even with less than 20 SAR images by integrating the SBAS (Small Baseline Subset) and PSI (Permanent Scatterers InSAR) techniques. The application of the proposed method to monitor seasonal land subsidence in the Dezhou city, a medium city in Shandong province in North China Plain (NCP), is described. The presented results, obtained by processing of ENVISAT ASAR data acquired between Mar, 2004 and Dec, 2008, are highly agreed with the deep groundwater level, including the spatial position and variation tendency.

Seasonal subsidence retrieval with Coherent Point Target SAR Interferometry: A case study in Dezhou city

In this paper, we discuss a ray-based tomographic approach to derive 3D Q models of the subsurface and the use of those models to perform model-driven Q compensation in complex media. The proposed approach is based on attenuated traveltime tomography applied on prestack surface seismic data and is integrated into a general ray-based post-migration grid tomography for both velocity and Q model building. Once a reliable space- and depth-variant Q model is derived, it can be used to perform Q compensation during depth migration. Alternatively, the Q model can be used to design Q compensation filters to apply outside migration. Such ray-based filters yield reliable amplitude and phase compensation even at medium or far offsets and allow us to mitigate absorption effects in the final depth-migrated images. The approach is illustrated using synthetic and real data.

Ray-based Tomography for Q Estimation and Q Compensation in Complex Media

Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology

[HBV resistance mutants before and after adefovir dipivoxil treatment and the relationship with HBV genotypes].

The feasibility of incorporating copper-laden sludge into low-cost ceramic products, such as construction ceramics, was investigated by sintering simulated copper-laden sludge with four aluminum-rich ceramic precursors. The results indicated that all of these precursors (γ-Al(2)O(3), corundum, kaolinite, mullite) could crystallochemically stabilize the hazardous copper in the more durable copper aluminate spinel (CuAl(2)O(4)) structure. To simulate the process of copper transformation into a spinel structure, CuO was mixed with the four aluminum-rich precursors, and fired at 650-1150 °C for 3 h. The products were examined using powder X-ray diffraction (XRD) and scanning electron microscopic techniques. The efficiency of copper transformation among crystalline phases was quantitatively determined through Rietveld refinement analysis of the XRD data. The sintering experiment revealed that the optimal sintering temperature for CuAl(2)O(4) formation was around 1000 °C and that the efficiency of copper incorporation into the crystalline CuAl(2)O(4) structure after 3 h of sintering ranged from 40 to 95%, depending on the type of aluminum precursor used. Prolonged leaching tests were carried out by using acetic acid with an initial pH value of 2.9 to leach CuO and CuAl(2)O(4) samples for 22 d. The sample leachability analysis revealed that the CuAl(2)O(4) spinel structure was more superior to stabilize copper, and suggested a promising and reliable technique for incorporating copper-laden sludge or its incineration ash into usable ceramic products. Such results also demonstrated the potential of a waste-to-resource strategy by using waste materials as part of the raw materials with the attainable temperature range used in the production of ceramics.

Copper stabilization via spinel formation during the sintering of simulated copper-laden sludge with aluminum-rich ceramic precursors.

The cultivation of practice ability of public health personnel was studied, in order to adapt to the new public health system requirements in practical ability training. With integrating the teaching contents, setting experiment course independently, implementing 'Process-experiment', establishing the experimental skills evaluation system of the formative assessment and summative assessment, public health personnel's practice ability has been improved. 
 
Key words: 
Public health;  Practical ability;  Personnel training;  Process-experiment; Evaluation system

Study on strengthening the cultivation of practice ability of public health personnel

Test data compression using interval broadcast scan for embedded cores

Dioscorea panthaica Prain et Burkill is a traditional Chinese herb and field cultivation as the major source of this plant becomes hard to meet the increasing demand in the market. Moreover, the propagation through rhizome is both costly and causing low yield and poor quality. Here, in order to providing commercial grade seedlings through in vitro propagation, we have studied callus formation, organ differentiation and plantlet regeneration. The in vitro establishment and propagation of mature D.panthaica plant were firstly reported in present paper. Our results suggested that leaves were the best explants for callus induction, and the optimal medium were as followed: MS with 2.0 mg/L 2,4-D and 2.0 mg/L BA for callus induction; MS with 1.0 mg/L BA, 0.5 mg/L NAA, 2% sucrose at pH 6.4 for shoot differentiation; and MS with 0.5 mg/L BA, 0.1 mg/L NAA, 3% sucrose at pH 6.8 for root formation.

2011 5th International Conference on Bioinformatics and Biomedical Engineering

Notice of RetractionCallus Induction and In Vitro Plantlet Re-Generation of Dioscorea panthaica

Aiming at the limitations of existing methods of IPv6 network topology discovery, this article proposes and implements a novel algorithm of an IPv6-based topology discovery system for the next generation Internet. With the combination of network topology information discovered by general protocols and by routing protocols, the system can discover the IPv6 network effectively not only in accuracy and integrality but also in avoiding alias problem. Besides, much subnet information can be discovered by the system. The system has been tested in the real network environment, which showed the effectiveness and feasibility of this solution.

2011 International Conference on Computer Science and Service System (CSSS)

A novel algorithm of IPv6 network topology discovery for Campus Network

In order to investigate the formation reason and influence factors of anode melting pool rotation in high-current vacuum arcs (HCVAs) subjected to axial magnetic field (AMF), the rotational symmetric magnetohydrodynamic (MHD) model of anode melting pool flow (AMPF) phenomena in HCVA is established. Based on this model, the influence of different anode current density distributions (ACDDs) on AMPF is simulated and analyzed. Simulation results show that the influence of ACDDs on rotational velocity of AMPF is significant. According to simulation results, the more nonuniform ACDDs can lead to the more rotational velocity. That is to say, the more serious current constriction in HCVA will lead to the larger rotational velocity of AMPF. The changing trend of rotational velocity in simulation results at different moments is in agreement with the experimental observation. Experimental and simulation results both show that the maximal rotational velocity appears at 9–10 ms moments.

Numerical simulation of influence of anode current density distributions on anode melting pool flow in high-current vacuum arc subjected to axial magnetic fields

Thin layer cycle voltammetry is one of the most efficient methods to investigate liquid/liquid interface. The advantages of this approach lie on its simplicity and effectiveness. The paper represents the progress that has been made in experiments and theories, analyzing the factors that affect rate constants and discussing how to get steady-state currents.

Thin-layer cyclic voltammetric studies electron transfer across liquid/liquid interface

A Study on the Integration of Netblog and English Teaching with Reform of Teaching Materials

In this paper, from a given Kuper-CH spectral problem, we propose two kinds of super integrable hierarchies. One is the Kuper-CH hierarchy, the other is the generalized Kuper-Harry-Dym hierarchy. Moreover, we construct their zero curvature representations and super-bi-Hamiltonian structures.

Neural network ensemble modeling for nosiheptide fermentation process based on partial least squares regression

Erythropoietin reduces neuronal cell death and hyperalgesia induced by peripheral inflammatory pain in neonatal rats

Gestational sac (GS) diameters are commonly measured by routine ultrasound in early pregnancy. However, manually searching for the standardized plane of GS (SPGS) and measuring the diameters are time-consuming. In this paper, we develop a three-stage automatic solution for this procedure. In order to precisely and efficiently locate the position of GS in each frame, a coarse to fine GS detection scheme based on AdaBoost algorithm is explored. Then, an efficient method based on local context information is introduced to reduce the false positives (FP) generated by the above detection process. Finally, a database (DB) guided spectral segmentation is proposed to separate GS region from the background for further diameters measurement. Experiments carried out on 31 videos show that by using the proposed methods, the number of SPGS searching error is only one, and the average measurement error is 0.059 for the length diameters and 0.083 for the depth diameters.

Automatic measurement of early gestational sac diameters from one scan session

In order to investigate the efficacy of combining radiation therapy with endostar on Lewis lung carcinoma in mice and the interaction mechanisms of combined therapy. Tumor models were established in the hind limb of female C57 BL/6N mice by subcutaneous transplantation. The tumor-bearing mice were randomly divided into 4 groups: control group, endostar group (20 mg·kg−1, once daily for 15 days), radiotherapy group (2 Gray per day to 10 Gray, d6-d10), and radiotherapy plus endostar group (combination group), (n=10 in each group). The tumors were applied to analysis of the tumor inhibitory rate and growth curve. Immunohistochemisty was adopted to check the expressions of microvessel density (MVD). The expression levels of Hypoxia-inducible factor 1α (HIF-1α) mRNA was tested by real-time fluorescence quantitative polymerase chain reaction (RT-PCR). The results demonstrated that the tumor inhibitory rate in combined treatment group was higher than that in other groups. Meanwhile, MVD and the level of HIF-1α mRNA were lower than that in other groups. We concluded that endostar significantly sensitized the function of radiation on Lewis lung carcinoma in mice, and this effect is working by decreasing HIF-1α, thereby increasing the killing effect of radiation on tumor cells.

2011 4th International Conference on Biomedical Engineering and Informatics (BMEI)

Endostar enhances the radioresponse on lewis lung carcinoma by regulating HIF-1α

To solve the problem of nonlinear characteristics of spherical vessels, an immune single neuron PID controller (ISNPID) is proposed in this paper. The ISNPID controller combines the immune principle with single neuron PID, it can improve the learning rate and reduce the adjusting time of single neuron PID controller. The interim process of the spherical vessel system could also be optimized. Good control performance of nonlinear system could be realized according to the on-line self-adjusting gain by the ISNPID controller. Simulation result shows that ISNPID controller has strong adaptability and robustness. Efficiency and applicability of the ISNPID controller could be proved in practical application.

The profilogram of FAE (fuel-air explosive) fuel explosion image is the important base to analyze the explosion process. In this article, the double peak method, the iteration method, the OTSU method, and the maximum entropy criterion method are respectively used to confirm the threshold, and extract and compare the profilograms of the FAE fuel explosion image, which could establish the base for the further experiment analysis.

The Extraction of the FAE Image Profilogram Based on the Grey Level Thresholding

To further improve the localization accuracy for nodes in wireless sensor network, this paper proposes an improved range-based localization algorithm in wireless sensor network. Firstly, some anchor nodes are optimized and chosen. Then optimized anchor nodes databases are created using those optimized anchor nodes. Secondly, the distance, which between unknown node and anchor node in network, is measured by using anchor nodes from the optimized anchor nodes database. Lastly, the unknown node is located by using Euclidean and trilateration localization algorithm. Some simulation experiments results show that the improved range-based localization algorithm can improve the localization accuracy, and with the positioning process forward, the ratio of anchor nodes is gradually increasing, then localization accuracy is also gradually improved.

An improved range-based localization algorithm in wireless sensor network

This paper proposes a new feature, optical flow context histogram (OFCH) for detecting abnormal events, especially the fighting violence events from a live camera stream. The optical flow context histogram is a log-polar histogram system which combines the histogram of orientation and magnitude of optical flow together. The human action is represented by using the histogram sequence of orientation and magnitude of optical flow. PCA is adopted to reduce the dimension of the human action representation. Several machine learning methods, including random forest, support vector machine and Bayesnet are employed for sequence classification. The experiments were carried out on the video clips downloaded from the Internet. The results show that the proposed methods work well when using a fixed surveillance camera.

2011 Second International Conference on Innovations in Bio-inspired Computing and Applications

We can judge the diesel active state by measuring the turbo supercharger speed, but in practical measurement, there are always many problems. In this paper, we build the regression model of relationship between turbo supercharger speed and pressure ratio, intake flow, turbine final pressure, turbine front pressure, turbine final temperature, gas compressor final pressure, gas compressor front pressure and gas compressor front temperature by the partial least square and cross validity test. Through the test, the explanation ability for the independent variables and the dependent variables of the model exceed 99%. Comparing with the practical values, this model has higher fitting precision and better prediction ability. This method solves the problem of install difficulty during actual vehicle measuring and the low precision which has great significance to the actual vehicle test of diesel turbo supercharger in low temperature conditions.

2011 International Conference on Information Management, Innovation Management and Industrial Engineering

Application of the Partial Least Square in Prediction of Turbo Supercharger Speed

Breast cancer is one of the leading cause of death among women. Because of harmless and low cost, ultrasound is one of the most often used methods for breast cancer detection. However, tumor detection is very difficult in ultrasound images due to their specular nature and low quality of ultrasound images and most of the existing methods need to manually select ROI. In this paper, we proposed a novel automatic method for breast ultrasound (BUS) image tumor detection. We using the fuzzy logic theory and transform an US image into fuzzy domain. An iterative method is used to find threshold. The experimental results demonstrate that the proposed approach can automatically detect the tumor in BUS image with high accuracy. It can process low quality ultrasound image very well.

2011 Eighth International Conference on Fuzzy Systems and Knowledge Discovery (FSKD)

A novel automatic tumor detection for breast cancer ultrasound Images

Study the land subsidence along JingHu highway (Beijing-Hebei) using PS-InSAR technique

Current Issues and Future Trends in Analysis of Automotive Functional Safety

The loss of microRNA-122 (miR-122) expression correlates to many characteristic properties of hepatocellular carcinoma (HCC) cells, including clonogenic survival, anchorage-independent growth, migration, invasion, epithelial-mesenchymal transition, and tumorigenesis. However, all of these findings do not sufficiently explain the oncogenic potential of miR-122. In the current study, we used two-dimensional differential in-gel electrophoresis to measure changes in the expression of thousands of proteins in response to the inhibition of miR-122 in human hepatoma cells. Several proteins that were upregulated on miR-122 inhibition were involved in the unfolded protein response (UPR) pathway. The overexpression of miR-122 resulted in the repression of UPR pathway activation. Therefore, miR-122 may act as an inhibitor of the chaperone gene expression and negatively regulate the UPR pathway in HCC. We further showed that the miR-122 inhibitor enhanced the stability of the 26S proteasome non-ATPase regulatory subunit 10 (PSMD10) through the up-regulation of its target gene cyclin-dependent kinase 4 (CDK4). This process may activate the UPR pathway to prevent chemotherapy-mediated tumor cell apoptosis. The current study suggests that miR-122 negatively regulates the UPR through the CDK4-PSMD10 pathway. The down-regulation of miR-122 activated the CDK4-PSMD10-UPR pathway to decrease tumor cell anticancer drug-mediated apoptosis. We identified a new HCC therapeutic target and proclaimed the potential risk of the therapeutic use of miR-122 silencing.

Modulation of the unfolded protein response is the core of microRNA-122-involved sensitivity to chemotherapy in hepatocellular carcinoma.

With the rapid development of electronic commerce, the logistics distribution system brings to the widespread attention. And the logistics distribution routing (LDR) optimization is playing the very important role as one of core technologies in the logistics distribution system. This paper proposed a novel hybrid stochastic searching algorithm to solve the LDR optimization design problem, the algorithm unified the ant colony optimization (ACO) and particle swarm optimization (PSO) algorithm effectively, which uses the randomness, the rapidity and the global characteristics of PSO to obtain the initial pheromone distribution firstly, then uses the ACO advantages of the concurrency, the positive feedback and the higher solving precision to find the exact solution. The results of simulation experiment show that the hybrid algorithm has superior global seeking optimization ability and the rapid convergence rate. The method is quick and effective to optimize the LDR problem, and can obtain the optimal solution or approximate optimal solution.

A Novel Hybrid Stochastic Searching Algorithm Based on ACO and PSO: A Case Study of LDR Optimal Design

In computer games, a user's attention is focused on the current task, and task-irrelevant details remain unnoticed. This behavior, known as inattentional blindness, is a main problem for the optimal placement of information or advertisements. We propose a guiding principle based on Wolfe's theory of Guided Search, which predicts the saliency of objects during a visual search task. Assuming that computer games elicit visual search tasks frequently, we applied this model in a “reverse” direction: Given a target item (e.g., advertisement) which should be noticed by the user, we choose a frequently searched game item and modify it so that it shares some perceptual features (e.g., color or orientation) with the target item. A memory experiment with 36 participants showed that in an action video game, advertisements were more noticeable to users when this method is applied.

2011 IEEE 10th IVMSP Workshop: Perception and Visual Signal Analysis

Applications for video communication support that individuals or organizations share video and voice in different places. However, most of existing applications are proprietary systems that lack generality. In this paper, we present a common framework which named VCF (Video Communication Framework) for these applications. The architecture of this framework is modular, and is based on the D-Bus inter-process communication solution. To evaluate this framework, we designed a video conference system for attending conference over IPv4/IPv6. The architecture and experiments shows the good scalability and robustness of VCF in the video application development.

2011 International Conference on Electronics, Communications and Control (ICECC)

A Corpus-Based Study with Corpus Materials on Conjunctions Used by Chinese and English Authors in English Academic Article Abstracts

The energy levels and lifetimes of 3sns 3S1 (n = 4–20) and 3snd 3D1 (n = 3–20) of neutral magnesium are calculated and predicted by means of the multichannel quantum defect theory (MQDT). In addition, the analyses of perturbation images between the channels are given.

The study of energy levels and radiative lifetimes of even-parity J=1 state of magnesium

The complex adaptive system (CAS) of the complexity theory is the theoretical basis of the implementation of knowledge management. With the development of complexity theory, it gave an enormous impetus to the application of knowledge management. Due to the further study of knowledge management and technological advances, the complexity theory needs to be enriched in order to be adjusted to new concepts, environment and technology.

2011 International Conference on Intelligence Science and Information Engineering

The Supplementation and Completion of Multi-agent Knowledge Management to CAS Theory

In this paper, Ni-Co compositional coatings were electrodeposited by brush-plating and the surface topography images were obtained with the help of scanning electron microscope. The surface topography of Ni-Co coating and the Co element in Ni-Co alloy coating were changed by changing the proportion of Co in plating solution. The fractal dimensions of the surface topography of Ni-Co coating with different Cos were counted based on gray image fractal theory. The impact on the surface topography of Ni-Co coating by the proportion of Co element in plating solution was studied by fractal dimension.

2011 Fourth International Workshop on Chaos-Fractals Theories and Applications

Study of Surface Topography of Ni-Co Coating by Brush Plating Analysis Based on the Fractal Dimension of Gray Images

Not only food safety is a direct bearing on people's physical health and safety, but also it severely affects the stability of the economic and social development. At present Chinese food market faces the grime situation with continuous food safety incidents. Therefore, it is the problem urgently to be solved for the government to deal with public food safety crisis. By describing the concepts and effects of food safety crisis, and analyzing the causes of the food safety crisis, food safety are divided into three stages, and the paper points out the present proposals for construction of food safety crisis management system in China and puts forward the response to improve the food safety crisis management.

Proceedings of International Conference on Information Systems for Crisis Response and Management (ISCRAM)

An integrated evaluation of the modern main battle tank based on Tops is method is discussed in this article. The method is a technique for order preference by similarity to ideal solution which can avoid the difficulty in traditional evaluations that regard the multi-evaluation parameters as a single efficiency evaluating value. The article provides a new system to the comprehensive evaluation of the modern main battle tank.

2011 International Conference on Computational and Information Sciences

Integrated Evaluation on Weapon System of Main Battle Tank Based on Topsis Method

Laoying Tea, leaves of Litsea coreana L., is conventionally consumed as healthy tea beverage in southern China for hundreds of years. The ethanolic, cold water and hot water extracts were prepared and their antioxidant properties studied. At 160 µg/mL, the cold water extract showed a high reducing power of 1.056. With regard to the scavenging ability on 1,1-diphenyl-2-picrylhydrazyl radicals, extracts were effective in the order: ethanolic > cold water > hot water extracts. EC50 values for chelating ability on ferrous ions for ethanolic, cold water and hot water extracts were 10.23, 0.85 and 1.12 mg/mL, respectively. Total phenols were the major naturally occurring antioxidant components found and were in the order: cold water > hot water > ethanolic extracts. Based on EC50 values, the various extracts from laoying tea were effective antioxidants.

Antioxidant Properties of Various Extracts from Laoying Tea (Litsea coreana L.)

A Novel Segmentation Method for Breast Cancer Ultrasound CAD System

A method for structural damage identification using residual force vector and mode shape expansion is presented in this paper. To deal with the incompleteness of measured modal data, a mode shape expansion method is first introduced to match with all degrees of freedom of the finite element model under consideration. And then, the residual force vector is employed to locate the damage position and quantify the damage extent. In order to eliminate the influence of extra errors that caused by mode shape expansion and improve the efficiency of the methodology, residual force vector assurance criterion (RFVAC) is developed to analyze the sensitivity between two sets of residual force vectors in the health and damaged structures after mode shape expansion. Finally, the proposed method is numerically illustrated by a simply supported truss beam with three damage cases. Results indicate that the proposed method is effective for the structural damage identification when the measured mode shapes are incomplete.

A method for structural damage identification using residual force vector and mode shape expansion

Agent is not only the core concept of complexity theory, but the most elementary component in implementing knowledge management systems. This article, based on the theory of complexity and combined the obtained research results, discusses the definition, structure, composition of different agents. It also concerns the relationship among agents in knowledge management and the action mode of multiple agents.

The Behavior Modes of Multiple Agents in Knowledge Management System Based on Complexity Theory

Risk Control Research on Chang Chun Street Networks with Intelligent Materials Based on Complex Network

Prepositional phrase (PP) consists of two parts which are a preposition as the leading part and a word or phrase as the tail part. In accordance with this fact, this paper proposes a new approach for identifying PP. In this method, PP identification is transformed into the collocation identification of preposition itself and the right boundary word. The Cascaded Conditional Random Fields (CCRFs) is used in this approach. With the Penn Chinese Treebank 5.1 as our experiment corpus, the F1 rises to 94.63%. This approach obtains breakthrough in this specific field as the current F1 is about 8.6% higher than any publicly published paper.

2011 7th International Conference on Natural Language Processing and Knowledge Engineering

A collocation based approach for prepositional phrase identification

Path Queries on Massive Graphs Based on Multi-granular Graph Partitioning

Active-control algorithms such as optimal control or impulse control methods generally achieve satisfactory control effectiveness, but it often fails to control dynamic systems with time-delay effectively. In view of this reason, a novel active controller using Genetic Algorithm (GA) is proposed in this paper, which is based on discrete motion equation of multi-freedom degree system with time delay. It can solve such subsistent problems as effective control for a seismically excited structure with an explicit time delay. Meanwhile it is also prone to achieve a desired vibration state in accordance with different control objectives. Finally in order to verify its validity, the GA controller are applied to a three-storey and a eight-storey structures excited by different seismic forces, numerical examples of which are given to prove it capable of providing satisfactory control effect with time delay.

Study on Structural Vibration Control by GA Controller Involving Time Delay

Based on a 2-D magnetohydrodynamic model, high-current vacuum arcs (HCVAs) under axial magnetic fields (AMFs) with consideration of current density distribution at the cathode are simulated and analyzed. The current density distribution at the cathode used in the simulation is obtained by processing the image of cathode spots from experiments. In order to study the influence of current density distribution at the cathode on vacuum arc characteristics, HCVA is simulated under two kinds of current density distribution at the cathode. Then, for HCVA simulation in a half-sinusoidal period, the current density distribution at the cathode and the AMF delay are both taken into account. The simulation results show that the nonuniform current density at the cathode makes the values of the arc plasma parameters in the interelectrode region larger and their radial distribution more nonuniform than the uniform current density at the cathode. The more uniform current density at the cathode and the stronger AMF at the moments in the second 1/4 cycle make the values of the arc plasma parameters in the central region smaller and their radial distribution broader than those in the first 1/4 cycle. In addition, the simulation results will also be compared with the experimental results.

Numerical Simulation of High-Current Vacuum Arcs Under Axial Magnetic Fields With Consideration of Current Density Distribution at Cathode

Test Data Compression Using Four-Coded and Sparse Storage for Testing Embedded Core

The Permanent Scatterer Interferometry (PSI) technique is usually applied for surface deformation mapping at local area from 1 up to a maximum of 100 km2. Although the ability to provide deformation map of regional area exceeding 10,000 km2, the processed area of interest is mostly limited to SAR acquisitions in a single satellite track and frame. In this work we present the study of merging multi-track PSI results for land subsidence monitoring over very extended area. Apart from the description of the PSI method used for long strip SAR data processing, datum connection of multiple adjacent tracks, including conversion of a common coordinate system and the connection of the PSI derived velocity maps are demonstrated. The application of the proposed method to monitor large coverage land subsidence in the central North China Plain (NCP) is described. The presented results obtained by merging 3 adjacent tracks of ENVISAT ASAR data acquired between Jan, 2007 and Dec, 2009, with a coverage of 200×260km2 are very significant and indicate the effectiveness and potential of this technique for land subsidence mapping over very extended area.

Merging multi-track PSI result for land subsidence mapping over very extended area

use a novel approach, i.e. neutrosophic logic which is a generalization of fuzzy logic and especially of intuitionistic fuzzy logic, to image segmentation-following one of the authors (H. D. Cheng) together with his co-author Y. Guo previous published paper on neutrosophic approach to image thresholding. The authors improved the watershed algorithms using a neutrosophic approach (i.e. they consider the objects as the T set, the background as the F set, and the edges as the I set); their method is less sensitive to noise and performs better on non-uniform images since it uses the indeterminacy (I) from neutrosophic logic and set, while this indeterminacy is not featured in fuzzy logic. Since using neutrosophic logic/set/probability/statistics is a new trend in image processing and the authors prove that the neutrosophic approach is better than other methods (such as: histogram-based, edge-based, region-based, model-based, watershed/topographic in MatLab or using Toboggan-Based) I recommend the publication of this paper. Next step for these authors would be to use the neutrosophic approach to image registration and similarly compare the result with those obtained from other methods. Interesting also is to use the neutrosophic approach to the control theory.

In order to enhance the realism and vivid nature of stories in virtual cultural heritage, an Agent model is used to represent each character in virtual environment. A simple transition structure is designed to meet the needs of narrative representation in virtual environment based on key events description. It can achieve automatic and interactive events generation and their transition. And the story generated modes is adopted to construct story scripts. Finally, this method is applied to reorganize many character’s models and their behaviors of the Tujia wedding show in Virtual Badong. The result shows that it can enhance visitors’ immersion in virtual cultural heritage, make them understand cultural heritage, and increase the breadth and depth of cultural dissemination effectively.

The Representation of Virtual Cultural Heritage Based on Key Events

Human always conceptualizes the world at different granularities and deals with it hierarchically. This is one of human’s characteristics that underlie his/her power. The quotient space model that we presented is a mathematical model of human multi-granular problem solving. In the paper, we introduce the model and discuss how to use the model to deal with the granularity relation, hierarchical problem solving. We also present the future research directions.

An Update and Summary of Multi-granular Computing and Quotient Structure

In order to evaluate the shielding effectiveness of rectangular enclosure with rectangle aperture more exactly, we take the total effects of a printed circuit board (PCB), the loss of enclosure and multimode into account. A waveguide equivalent circuit model is established, and the analytical formulation of shielding effectiveness is derived from the equivalent circuit. The result obtained by the approach proposed is basically in agreement with that obtained by commercially available numerical tool CST. The results show that the closer the aperture to the centre of the enclosure wall is, the worse the shielding effectiveness is; the smaller the ratio of the length to the width is, the higher the shielding effectiveness is; the resonant frequency of the enclosure decreases along with the increase of the thickness of the PCB.

Proceedings of the 9th International Symposium on Antennas, Propagation and EM Theory

More practical considerations in the analysis of the shielding effectiveness

Bioluminescence tomography (BLT) has become a hot topic over in recent years. In this paper, a hybrid genetic reconstruction algorithm (HGA) based on quadratic penalty function is presented for BLT inverse problem. Simulation results of the single and multiple sources are reported in a molecular optical simulation environment (MOSE) which we developed to simulate the photon transportation of optical imaging in living organisms. Comparing with genetic algorithm (GA), the illustrations indicate that HGA is feasible and effective for BLT source reconstruction.

2010 3rd International Conference on Biomedical Engineering and Informatics

A hybrid genetic algorithm based on quadratic penalty function for BLT light source reconstruction

Introduction Diffusion tensor imaging (DTI) has been widely used to characterize myocardium structure nondestructively with high spatial resolution. The conventional DTI assumes that water diffusion is a free Gaussian process and the diffusion weighted signal decays with b-value in a monoexponential manner. However, as the mobility of water molecule varies with different microscopic compartments and components, this assumption may not be applicable in tissues with complex structures such as kidney, neural and breast [1-3]. In this study, impact of b-value on DTI indices of myocardium was assessed and two models for fitting diffusion-weighted imaging (DWI) data were evaluated to test whether water molecules diffuse in a free Gaussian process in left ventricular (LV) myocardium. Method Imaging experiments were conducted on a 3T Siemens Trio MR scanner. Six excised normal porcine hearts were immersed in pure water and imaged with EPI-DTI sequence with six different b values of 0, 500, 750, 1000, 1500 and 2000 s/mm. The imaging parameters were: TE = 107 ms; TR = 5.3 s; slice thickness = 2.0 mm, slice gap = 0.4 mm; gradient direction = 20; number of slices=15; and NEX=10 with in-plane resolution of 1.23 mm. The scan time was ~95 min per sample. DTI data was then processed with the software of DtiStudio (Johns Hopkins University; USA) for computation of fractional anisotropy (FA), mean apparent diffusion coefficient (MD), axial diffusivity (λ∥) and radial diffusivity (λ⊥) pixel by pixel from DWIs with two b values (0 versus 500, 750, 1000, 1500 and 2000 s/mm, respectively). For each sample, 10 representative slices were selected, from which DTI indices were measured on LV myocardium and averaged among six samples. Monoexponential fitting model DW(b)/DW(0)=exp(-bD) (Monoexp model) [1, 3] and distribution function based model DW(b)/DW(0)=exp(-bD+σb/2) (Stat model) [3] were performed from all DWIs with six b values using a home-written Matlab program. One-way ANOVA and pos-hoc Bonferroni’s multi-comparisons were performed to exam the difference in DTI indices among different b values with p<0.05 regarded as statistically significant. Signal-to-noise ratio (SNR) was measured on averaged DWIs along 20 diffusion gradients for each heart sample. Results

Impact of b-value on DTI indices of left ventricular porcine myocardium : a preliminary study

Structure and properties of hydrogels prepared from cellulose in NaOH/urea aqueous solutions

Mechanics performance test of MR damper and its application in structural seismic response control

Corporate financial distress diagnosis model and application in credit rating for listing firms in China

With the increasingly universal use of remote sensing data, related development is required to extract and enhance image information. In this paper, a SPOT image including multispectral and panchromatic bands and a Landsat5/TM image have been used to study fusion performance based on the integration of intensity, hue and saturation (IHS) and five transform methods: linear stretching, histogram matching, double histogram matching, wavelet transforming and integration filtering. The results show that the fusion images were enhanced in quality by combining information from two images, producing increased definition, and preserving the spectral fidelity of the input dataset using an appropriate fusion method. The difference in fusion performance among integration methods was obvious. As a whole, the integration of a wavelet transform and IHS had the comparative advantage because it could get a higher quality fusion image than with information capacity, definition or spectral fidelity of the input dataset. In addition, the results showed the simple integration of linear stretching and IHS transforms could produce better fusion images, and it is practicable for use by non-professionals for remote sensing in many software applications including ENVI, Matlab and Erdas. Meanwhile it could be simpler and more practicable for most users, especially those not adept with GIS technology.

Fusion Processing and Quality Evaluation of Remote Sensing Images Based on the Integration of Different Transform Methods with IHS

Longmen Shan tectonic belt located in West Sichuan Plateau, which keeps the good forests outlook and provides a unique natural environment for the growth of medicinal plants because of its unique geological features. It is a area that is one of the most abundant biological diversity in China and the whole world range, and also is the one of the most concentrated area of the origin of Chinese herbal medicines in Sichuan Province and China. Wenchuan Earthquake induced thousands of landslides, debris flows, which made a huge impact on the medicinal plant habitat by means of severe fragmentation. In this paper, through evaluating and integrating the multi-period remote sensing image data and basic geographic information data of the Longmen Shan region after earthquake by grid technology, the image group that covers the whole Longmen Shan belt and reflects the different features of ground object is acquired. Characters of Wenchuan earthquake disaster distributing is interpreted and analyzed by geographic information system platform for spatial analysis with the image group. Combine with the life habits of medicinal plants in this area and the main ecological factors impacting the spatial distribution pattern of medicinal plants, the impact on distribution pattern of medicinal plants habits during the disaster discussed, as a result, medicinal plants habitat influenced in the shock in various environmental factors is concluded. It can provide the academic evidence for medicinal plant restoration in earthquake zone.

Impact on the distribution of medicinal plant habitat by Wenchuan earthquake

With a spatial resolution of up to 1 m, the German radar satellite TerraSAR-X has significantly improved the applicability of spaceborne SAR interferometry (InSAR) technique for fast ground motion monitoring due to its high spatial resolution and short time interval. In this work we present the first Permanent Scatterer Interferometry analysis with TerraSAR-X data for urban subsidence mapping in Tianjin city in China. Totally 17 scenes strip mode SAR images have been collected from Feb to Oct 2009 to perform the PSI analysis. The resulted average subsidence velocity demonstrates the ability of high resolution data for detailed monitoring of urban subsidence. Comparison between PSI result of TerraSAR-X and ENVISAT show the potential of TerraSAR-X data for urban motion as well as large scale manmade linear infrastructure monitoring.

Introduction: Knowledge of variability and spatial distribution of iron abundance is important for understanding the petrogenesis of lunar rocks and thus the geological history of the Moon [1]. A series of models have been developed to predict the iron abundance from Clementine UVVIS images [2-5]. Among these models, Lucey’s model is the one most acceptable following with a series of refinements [5-8]. As more mission datasets (e.g., Kaguya (Japan), Chang’e-1 (China), Chandrayaan-1 (India), and LRO (United States)) [9] will be available to planetary community, it would be beneficial to compare the results from these datasets as well as to refine the algorithm of FeO mapping. Among the 8 scientific payloads on Chang’e-1, Imaging Interferometer (IIM) is selected to detect the distribution of lunar mineral and compositions on the Moon [10]. Here we present our preliminary results to produce iron abundance map from Chang’e-1 IIM images. Instrument and data overview: Imaging Interferometer (IIM) aboard Chang’e-1 lunar orbiter is a Sagnac-based pushbroom Fourier transform imaging spectrometer. It operates from visible to near infrared (0.48-0.96 μm) spectral region with 32 channels at 325.5 cm spectral interval. When on orbit of 200 km above the Moon, Chang’e-1 IIM yields a ground resolution of 200m/pixel and 25.6Km swath width. IIM has got nearly 84% coverage of the Moon between 70oS and 70oN. The data processing pipeline include dark current subtraction and relative calibration, spectrum reconstruction,radiometric calibration, photometric normalization (normalized to the standard geometry of i = 30o, e = 0o). We applied photometric normalization using a modified Lommel-Seeliger photometric model [11]. A relatively homogeneous region near Apollo 16 landing site was chosen as calibration target, and laboratory spectra of mature soil 62231 (http://www.planetary.brown.edu/relabdocs/Apollo16_6 2231.html) was used as standard to derive the absolute IIM reflectance[12]. IIM data used in this abstract is level 2C based on the above calibrations. Algorithm to derive FeO abundance: The method for calculating the FeO abundance is similar to that of Lucey et al., 2000[5]. The first step is to acquire spectra for individual Apollo and Luna landing sampling stations from Chang’e-1 IIM data. Unfortunately, IIM missed the Apollo 15 sites, thus we could only use the rest 38 sampling sites from Table of Lucey et al., 2000[5] to derive the algorithm of calculating FeO content.

Preliminary Results of Mapping Iron Abundance from Chang'e-1 IIM Data

We report an LD side-pumped continuous-wave passive mode-locked Nd:YAG laser with a Z-type folded cavity based on a semiconductor saturable absorber mirror (SESAM). The average output power 2.95 W of mode-locked laser with electro-optical conversion efficiency of 1.3% and high beam quality (M2x = 1.25 and M2y = 1.22) is achieved. The repetition rate of mode-locked pulse of 88 MHz with pulse energy of 34 nJ is obtained.

LD Side-Pumped Passive Mode-Locked TEM00 Nd:YAG Laser Based on SESAM

A neutrosophic approach to image segmentation based on watershed method

Seasonal and interannual variations in water vapor exchange and surface water balance over a grazed steppe in central Mongolia

In this paper, we propose an efficient approach to minimize the noise on power networks via the allocation of decoupling capacitors (decap) and controlled equivalent series resistors (ESR). The controlled-ESR is introduced to reduce the on-chip power voltage fluctuation, including both voltage drop and overshoot. We formulate an optimization problem of noise minimization with the constraint of decap budget. A revised sensitivity calculation method is derived to consider both voltage drop and overshoot. The sequential quadratic programming (SQP) algorithm is adopted to solve the optimization problem where the revised sensitivity is regarded as the gradient. Experimental results show that considering voltage drop without overshoot leads to underestimating noise by 4.8%. We also demonstrate that the controlled-ESR is able to reduce the noise by 25% with the same decap budget.

2010 15th Asia and South Pacific Design Automation Conference (ASP-DAC)

On-chip power network optimization with decoupling capacitors and controlled-ESRs

Knowledge sharing, which is the basis for forming a knowledge application group, allows knowledge workers in an enterprise such as knowledge salespeople, knowledge operators, knowledge directors or knowledge managers to share the knowledge of other people or of other parts of the system to solve their problems in work. So knowledge sharing is an important part of knowledge management. In this article, the authors expound multiagent-based centralized and distributed knowledge sharing models and then propose the hybrid knowledge sharing model.

2010 International Conference on E-Product E-Service and E-Entertainment

The Knowledge Sharing Models of Knowledge Management Implemented with Multi-Agents

Research on quality evaluating of fusion images is meaningful to improve the registration technology and fusion algorithms. The objective assessment metrics based on fusion image itself can not show comprehensively the fusion image quality, which could be incongruent against human eye response. Provide a new assessment method for fusion image quality by means of building artificial neural network model. The metrics inculding mean value, standard deviation, gradient is choosed as the input neural cell. A hidden layer is designed to carry out assorting perfoemance. And the artificial neural network obtain the image quality assessing mapping functions and to classify the training samples into different types by means of the supervised learning. The experiment shows the noteworthy concordance between the simulation result and human eye response to identifying samples. Compared with single evaluation indexes, the new quality evaluation model can show effectively the subjective response of human eye to fusion image.

2010 International Conference of Information Science and Management Engineering

Objective Evaluating Method to Fusion Image Quality Based on ANN

This study examined the effectiveness of reformulation and model text in a three-stage writing task (composing—comparison—revising) in an EFL writing class in a Beijing university. The study docume...

Exploring the role of reformulations and a model text in EFL students’ writing performance

Automated breast cancer detection and classification using ultrasound images: A survey

Computing the Point-to-Point Shortest Path: Quotient Space Theory's Application in Complex Network

In this paper we describe the design consideration and implementation of portscan detection module regarding to TCP analyzing of SCUT NIDS. The aim of the portscan module is to take immediate action in response to alerts generated by SCUT NIDS to protect the system from portscan attacks. Portscan module is required to maintain TCP connection records, the design of such a connection table is not trivial for a high speed IDS with large number of active connections and high packet arrival rate,especially in a resource constrains Intel IXP2400 network processor. After comparing various design options, we adapted from hash table data structure, employing the special hardware unit assist to calculate a hash over our unique ascending order quadruple which worked in a quite simple but efficient way that is totally different from the Snort scheme, our design not only differentiates both directions of a TCP connection and thus eliminates unwanted additional search operation, but also avoids data corruption and greatly reduces the probability of hash collisions. In order to improve the allocation/deallocation procedure for TCP connection nodes in our IDS systems, we further devised a large management stack caching with a local memory buffer, which is fully exploiting the specialized network processor architectures and optimizing the use of various types of memories with different speeds and size. The theoretical analysis and experiments confirmed that the combination of a large conventional hash table-based search and an array-based stack with caching improves the performance significantly.

Design Consideration and Implementation of Portscan Detection Module on NP-Based IDS

Studies on heat capacities and thermal analysis of Li–Mg–N–H hydrogen storage system

Bioluminescence tomography (BLT) allows in vivo localization and quantification of bioluminescent sources inside a small animal to reveal various molecular and cellular activities. In this paper, the overlap domain decomposition method (ODDM) of BLT is proposed, which refers to divide and conquer techniques for solving BLT by iteratively solving sub‐problems on smaller sub‐domains. Here, two triangulations of the region are adopted. We can obtain the photon density distribution on the object surface, as well as reconstruct the position of the light source by using ODDM and genetic algorithm. The numerical simulations have shown that ODDM is computationally efficient and fairly robust. Copyright © 2009 John Wiley & Sons, Ltd.

International Journal for Numerical Methods in Biomedical Engineering

Overlap domain decomposition method for bioluminescence tomography (BLT)

High power microwave (HPW) can cause the semiconductor devices failure,thereby make the electronic system work anomaly. Bipolar transistors are the typical semiconductor devices. In this paper, the effect of HPM on the bipolar transistors is studied through the HPM injection experiment. The experiment results show that the HPM injected into the devices could cause the degradation, distortion and damage of the transistor. The failure analyses of the tested devices indicate that the bipolar transistors cannot work mainly because the HPM damage the base-emitter junction in of the transistors. The HPM injected into the devices from the base significantly influenced on the characteristics of the device in the operating situation compared with the other pins.

2010 10th IEEE International Conference on Solid-State and Integrated Circuit Technology

Experimental research on the damage effect of HPM on semiconductor bipolar transistor

Collaboration and coordination is the basis for multiagents to establish relations and to form group agent, departmental agent and organizational agent. Collaboration and coordination has many in common with knowledge sharing. They all need the sharing of knowledge or information to accomplish knowledge tasks with collaboration. This article researches into the model of Collaboration and coordination and its implementation. It first deals with the definition of collaboration and coordination, and then expounds the common algorithms of collaboration and coordination. It finally proposes the trusting assigning collaboration algorithm.

The Implementation of Collaboration and Coordination of Multi-Agents in Knowledge Management

In this work we mapped the spatial and temporal patterns of the land subsidence near the city of Hangzhou, China by PSI analysis with 49 scenes of ERS-1/2 SAR images acquired from 1992 to 2006 to detect and retrieve the subsidence due to economic development. The main reason of land subsidence in Hangzhou is groundwater exploitation, which is necessary for the rapid economic development, especially in China. Xiaoshan Economic and Technological Development Zone was approved as a state-level development zone by the State Council in May, 1993. Since then the zone has been suffering land subsidence. There have been more than 300 overseas-funded enterprises with investors from 26 countries and regions by the year 2006. The development of this area can be divided into three periods according to its pace: construction period (1993-1996), stable increase period (1996-2001) and high-speed period (2001-2006).

PSI analyses of land subsidence due to economic development near the city of Hangzhou, China

It is well known that the duration reflects the difference between checked tone's syllables and other syllables in Cantonese. In this paper, aiming at improving the naturalness of the Cantonese TTS system, we use two concepts, the voice blank and pitch contour blank, to examine the particularity of the checked tone's duration with a serial designed experiments in Cantonese speech. The impact of the four factors, including the tone types of the Cantonese checked tone's syllable (CHKTS), the types of the occlusive stop of the CHKTS, the onset types of the syllables following the CHKTS, the location in the sentence of the CHKTS, have been investigated for the duration of check tones. The results are helpful to construct the context information for the prosody prediction in Cantonese TTS system. Moreover, with two perception experiments, the paper also proves that the silence segment which indicated as voice blank and extension of the onset duration following the CHKTSs in the Cantonese utterance is a kind of prosodic compensation of the CHKTSs.

2010 7th International Symposium on Chinese Spoken Language Processing

We present in this contribution the results of the first experiment to monitor land subsidence along JingJin High Speed Railway (JingJin HSR), which connects Beijing city and Tianjin city and is the first high speed railway in China, by using the Permanent Scatterer InSAR (PSI). Since the length of the railway is usually beyond the standard scenes coverage of the ongoing radar satellite, i.e. ENVISAT and RADARSAT SAR images which has a ground coverage of 100×100 km, we have developed techniques in this work for land subsidence monitoring of very extended areas with multi-track long strip SAR images. In particular, we have studied the method for integrating multi-track PSI for large coverage subsidence mapping. We applied the ENVISAT ASAR data acquired from Jan, 2007 to Dec, 2008 in neighboring tracks (Track-218 and track-447, Frame 2799 to 2817) to perform the PSI analysis. The PSI estimated subsidence velocity map in adjacent track have been integrated to generate the large coverage subsidence velocity map; these result are relevant to an area in the North China Plain that extends for about 200×150 km. For detailed investigation of JingJin HSR, a buffer zone with a width of 3 km in each side of the railway have been generated and the subsidence values have been extracted from the merged velocity map. The results clearly indicate the distribution and magnitude of the subsidence zone along Jing-Jin high speed railway and they demonstrate the approach to analyze the subsidence of very extended areas.

USING PERMANENT SCATTERER INSAR TO MONITOR LAND SUBSIDENCE ALONG HIGH SPEED RAILWAY-THE FIRST EXPERIMENT IN CHINA

In this paper a stochastic programming model is proposed to determine a relief equipment layout system for earthquake disasters. Since it is difficult to predict the timing and magnitude of any disaster and its impact, the disposition process is treated in a random manner, and both the epicenter and magnitude and the following resource requirements are represented as random variables. We will establish a multi-stage stochastic programming model for relief equipment layout. At the same time, its determinate equivalence is solved with Lingo software package. Finally, a case study is presented to highlight the significance of the proposed model. Index Terms—Emergency management,layout,stochastic pro- gramming model, Lingo-solver

Relief Equipment Layout Model for Natural Disaster with Uncertain Demands

The paper discusses a nonautonomous discrete time Lotka-Volterra competitive system with pure delays and feedback controls. New sufficient conditions for which a part of the -species is driven to extinction are established by using the method of multiple discrete Lyapunov functionals.

Extinction in Nonautonomous Discrete Lotka-Volterra Competitive System with Pure Delays and Feedback Controls

Establishment of paper assessment system based on academic disciplinary benchmarks

Spaceborne SAR interferometry (InSAR) is a well known microwave remote sensing technique which has been applied for topography mapping and ground motion monitoring by exploiting phase difference from SAR data acquisition with relevant large spatial scale and high precision. The developed Permanent Scatterers Interferometry (PSI) is a further step of InSAR technique which offers a convenient processing framework that enables the use of all data acquisitions. It aims to bypass the problem of geometric and temporal decorrelation by considering long term coherent point. Furthermore, by using a large number of data, atmospheric signal is estimated and compensated for. We present in this work the development of an improved PSI, called Coherent Point Target InSAR, for land subsidence velocity field estimation in urban area as well as rural area in China. A series of case studies demonstrate the ability of CPT InSAR for monitoring ground subsidence felid with relevant large spatial extent as well as small area.

Monitoring urban subsidence with coherent point target SAR interferometry

To address the performance limitation brought by the scaling issues of on-chip global wires, a new configuration for global wiring using on-chip lossy transmission lines is proposed and optimized. We propose a signaling structure to compensate the distortion and attenuation of on-chip transmission lines, which uses passive compensation and inserts repeated transceivers composing sense amplifiers and inverter chains. An optimization flow for designing this scheme based on eye-diagram prediction and sequential quadratic programming (SQP) is devised. This flow is used to study the latency, power dissipation and throughput performance of the new global wiring scheme as the technology scales from 90 nm to 22 nm. Comparing to repeated RC wire, experimental results demonstrate that at 22 nm technology node, the new scheme can reduce the normalized delay by 80%–95%, the normalized energy consumption by 50%–94%. The normalized latency is 10 ps/mm, the energy per bit is 20 pJ/m, and the throughput is 15 Gbps/μm. All performance metrics are scalable with technology, which makes this approach a potential candidate to break the “interconnect wall” of digital system performance.

High performance on-chip differential signaling using passive compensation for global communication

A novel optical biosensor with gold surface bound silver nanoparticles has been constructed for detection of bio-molecules like antigen, antibody protein and DNA plasmid, which exhibited distinct optical properties of localized surface plasmon resonance (LSPR). The silver colloidal nanoparticles were prepared by using sodium borohydride reduction of silver nitrate and characterized by using UV-Vis absorption spectroscopy, transmission electron microscopy (TEM), and cyclic voltammetry (CV), indicating that the silver colloidals were pure, sphere-shaped and narrow-dispersed size distribution with a diameter of 10 ± 0.5 nm. The silver nanoparticles were well assembled on the gold surface. It caused 3.08 nm of red shift in the peak wavelength (λmax) of LSPR spectrum for the nanosensor exposed to c-Myc (3C7) mouse monoclonal IgG and 3.36 nm of red shift to the corresponding antibody by the immuno-reaction subsequently. The LSPR nanobiosensor has been successfully applied to recognition of a DNA plasmid of pCMV-Myc Mammalian Expression Vector.

2009 4th IEEE International Conference on Nano/Micro Engineered and Molecular Systems

Novel optical nanobiosensor assembled with silver nanoparticles on gold surface

The Permanent Scatterers (PSs) SAR Interferometry has become an operational tool in the context of spaceborne SAR interferometry for monitoring surface deformation with millimetric accuracy. In this contribution we presented a case study in Xi'an city for land subsidence monitoring and ground fissures detection by using PS InSAR. We applied a linear regression model to retrieval land subsidence velocity by using a series interferometric phase of the coherent target. For the displacement of ground fissures monitoring, which caused by the nonuniform displacement of land subsidence and fault motion, a time series interferometric analysis of coherent target has been carried out to retrieve the history of displacement. The results archived from ENVISAT ASAR images acquired from 2005 to 2008 has demonstrated the distribution and the magnitude of the land subsidence and ground fissures. We compared the result from PS InSAR with the field surveying data and the results shown good agreement.

Using permanent scatterer InSAR to detect land subsidence and ground fissures: A case study in Xi'an city

Desired islanding detection method not only can detect islanding within acceptable duration, but also require it has less adverse impact on power quality. This paper presents an active islanding detection method for a distributed resource (DG) unit which is coupled to a utility grid through grid-connected converter. With the proposed method which is based on adding periodical disturbing current through current controller of the interface voltage-sourced inverter, islanding can be effectively detected. But when the disturbing current remains unchanged, this method still has some shortages, so this article improved it and used a changed time-varying disturbing current ending with faster detecting time and less disturbing. The studies reported in this paper are based on time-domain simulations in the PSCAD/EMTDC environment. And the results show that the proposed islanding detection method always meets the two-second UL detection requirement.

2009 International Conference on Electrical Machines and Systems

A novel active islanding detection method based on current-disturbing

The agricultural information level is on the initial stage in Hebei province, so we should pay more attention to its construction. And on this basis we can find out the influencing factors and corresponding countermeasures. To evaluate the agricultural information degree in Hebei province scientifically and accurately, this paper establish the agricultural information degree (AID) evaluation model based on self-adapting regression SVM, through establishing agricultural information degree index system, use several SVM classifier series portfolio, solve the problems that the training samples’ category and quantity are imbalance, and the data is interfered. Experimental results show that the method improved the evaluating accuracy and efficiency of the agricultural information degree.

2009 Second International Symposium on Electronic Commerce and Security

Word Sense Disambiguation (WSD) is a task of classification to identify sense of ambiguous word. Most systems choose symmetric local context window on empirical grounds, that is, the distance from the ambiguous word to both sides of the window is same, such as [-1, +1]. Why? In this paper, we do an experiment on Senseval-3 Chinese data set. Use cross–validation method to identify the optimal local context window for word features and part of speech (POS) features separately. The results show that in the same window scope, the smaller the gap, the lower the error, and the better the WSD performance. In other words, the window that tends to symmetric will get better performance.

2009 Ninth International Conference on Hybrid Intelligent Systems

Symmetric Trends: Optimal Local Context Window in Chinese Word Sense Disambiguation

The optimal path finding problem in weighted edge networks is an old and interesting one in many fields. There were many well-known algorithms to deal with that issue. But they were confronted with the high computational complexity while the network becoming larger. We present a hierarchical quotient space model based algorithm that reduces the computational complexity. The basic idea is the following. The nodes of a given network are partitioned with respect to the weights of their adjacent edges. We construct a variety of coarser versions of the given network with new nodes corresponding to the blocks of partitions at various levels of granularity. They are called the quotient spaces (networks) of the original network. The construction of the (sub- )optimal path is then done incrementally, throughout the hierarchy of quotient networks. Since each version of the network is much simpler than the original one, especially of the coarsest spaces, the computational complexity is reduced. In this paper, we present the basic principles of the algorithm and its experimental comparison to other well-known algorithms.

A New Algorithm for Optimal Path Finding in Complex Networks Based on the Quotient Space

The nesting of 3-dimensional parts problem is important for practical applications. In the field of VLSI design, the nesting of 3-dimensional parts problem arises from both the packing of the 3-D integrated circuits and the task schedule of FPGA design. In this paper, we propose a novel floor plan representation, named 3-Dimensional Corner Layout List to encode the topology of the 3-D nesting. Based on triple string, we can represent general nesting including slicing and nonslicing. Our algorithm is very effective that the transformation from 3D layout list to the real nesting need only linear time computation effort. Based on simulated annealing algorithm, we can optimize the 3D nesting effectively. Experimental results show that our algorithm is effective and efficient.

2009 International Asia Symposium on Intelligent Interaction and Affective Computing

A novel estimation algorithm for multipath number, time delay and the Doppler shift in the underwater acoustic multipath channel is proposed. A double-chirp signal with a fixed time interval T is sent. And the fractional Fourier transform (FRFT) is applied to analyze the received signal. So at a specific order, a series of peaks will appear in the corresponding u domain. The relationships between the channel parameters with the intervals among the peaks are induced. Besides, it's not necessary to search for the order of the received signal as the result of the invariant characteristic of the chirp rate, which greatly improve the algorithm efficient. The simulation results show the effectiveness of the algorithm.

2009 International Conference on Wireless Communications & Signal Processing

Multi-parameter estimation of underwater acoustic channel based on fractional Fourier transform

For a flat fading code-division multiple-access (CDMA) system, by representing it as the appropriate system model consisting of state equation, multiplicative noise equation and the nonlinear measurement equation, an optimal filtering algorithm is used for joint recursive channel estimation and multiuser detection based on the established model. It should be stressed that the new algorithm is applicable to a major class of engineering problems with the same type of nonlinear system model with correlated noises. Simulation results show that the new algorithm performs better than the extended Kalman filter in faster convergence rate and lower bit error rate.

2009 Second International Symposium on Computational Intelligence and Design

A Joint Channel Estimation and Multiuser Detection Method for Flat Fading CDMA Systems

The simulating experiment of gas hydrates often lasts a long time, has a high pressure (usually equal or more than 38bar) and has many steps. A high-pressure console was developed to lighten labor intensity and guarantee experiment safety in the Synthetic Experimental System of Gas Hydrates Simulation (SESGHS). Gas inlet/outlet, cell pressure test and overpressure protection are all managed on the console. The overpressure protection module included a gas-control valve NV1-20-6M-ATC, a solenoid valve VP542, a relay OMRON/ G2R-1, a multi-function card PCI-1711, a pressure sensor and the corresponding software. The acquired pressure data was judged whether to surpass the alarm value, if so, alarm would be send out. And if over the unloading value, number 1 will be send to the channel connecting PCI-1711 card and the relay, then relay is switched on to make electromagnetic valve open and let low pressure gas enter so that the gas-control valve can release high pressure automatically. The whole pressure-control module was operated successfully in the experiments of gas hydrates formation, drilling fluids tests and mini-drilling simulation. It worked steadily, operated conveniently and had high sensitivity for overpressure protection, which largely enhanced the safety of the experiments.

2009 Second International Conference on Intelligent Computation Technology and Automation

High Pressure Control in Synthetic Experimental System of Gas Hydrates Simulation

Changes in susceptibility and esterase activity were measured in the citrus red mite, Panonychus citri (McGregor), which was repeatedly exposed to phoxim, an organophosphorus acaricide, for 15 repeated treatments as potential selection at the 50% lethal concentration. A reference or non‐selected strain (SS) was not exposed to any acaricides throughout the experiments. After 15 repeated phoxim selection events, the resistance ratio increased to 18.6‐fold and this strain was considered resistant to phoxim and named Ph‐R. The activity and specific activity of carboxylesterase (CarE) and acetylcholinesterase (AChE) in Ph‐R were all significantly higher than those in SS. The Michaelis–Menten constants (K m) of both CarE and AChE in Ph‐R were significantly higher than those in SS, suggesting decreased affinities of the enzymes in Ph‐R to the corresponding substrates. In addition, in vitro inhibition of phoxim against CarE of the mite showed that CarE from SS was more sensitive than that from Ph‐R, and an in vitro inhibition assay of AChE by phoxim showed that there was a strong linear relationship between inhibiting action and AChE from the two strains. Similar to the situation of CarE, AChE in Ph‐R also suggested a lower sensitivity to phoxim. The results suggested that CarE and AChE might be involved in the resistance to phoxim in citrus red mite.

Susceptibility and esterase activity in citrus red mite Panonychus citri (McGregor) (Acari: Tetranychidae) after selection with phoxim

Traffic has always been the infrastructure of national economic and social development. With the pace of urbanization unprecedented speedup and the increase of vehicle possessions, traffic congestion has become a big problem in modern cities. Regional traffic guidance system provides traffic information for road travelers in pre-trip and in on-trip, and guides travelers to change travel modes, choose travel routes, and save travel time to take full advantage of road network resources. Variable message sign (VMS) is one of the main ways to provide traffic information in metropolitan road network, but traditional VMS guidance regions are designated manually by traffic administrators to cause very bad effectiveness and efficiency, and there are even some VMS used only for advertising that have nothing to do with the traffic guidance management. We analyze the traffic guidance model based on VMS, and study the dynamic regional partition problem and the dynamic traffic guidance problem under real-time traffic conditions, and put forward the architecture and two algorithms. The architecture serves mainly for the whole cycle of developing VMS based guidance from raw data collection to traffic information publish. The algorithms dynamically partition traffic guidance regions and dynamically change the vehicle turning ratio at intersections to balance traffic flow and save travel time in guidance regions. The cellular automaton method based on SWARM platform is employed to simulate traffic environment, and verify the effectiveness and efficiency of the model and the algorithms by compare with the other traditional regional guidance algorithm.

In this work we presented the first experimental results of land subsidence mapping for large areas by using Coherent Point Target SAR interferometry with a reduced set of images in the North China Plain (NCP). Since the limitations of the classical Permanent Scatterer InSAR (PSI) for short temporal span surface deformation monitoring due to the dependency on large volumes data availability, we combine the classical PS InSAR and Small Baseline Subset (SBAS) technique in the data processing chain for large coverage InSAR data processing with a reduced set images. The starting point of our study is the generation of small baseline interferograms of the continuous frames in the same track. Following that, each stack of interferograms are processed with CPT InSAR so as to minimize the effect of phase ramp caused by inaccuracy baseline estimation. For large scale land subsidence mapping, all the mean velocity map are merged into a long strip and the subsidence rate of each coherent point are retrieved. The algorithm are tested with 15 ENVISAT ASAR images collected during the period from Jun, 2007 to Nov, 2008 with an extent of 100 × 400km2 in the NCP for land subsidence mapping. The presented results indicates the large scale land subsidence in central NCP and demonstrates the effectiveness the approach.

Large scale land subsidence monitoring with a reduced set of SAR images

For the particularity of electric power enterprises themselves, the commonly methods used to forecast their financial risk is limited and inadequate. To forecast the financial risk of the power enterprises scientifically and accurately, this paper establishes a financial risk evaluation index system with the camel rating thinking, and then describes the adaptive genetic algorithm (AGA) evaluation mechanism. In this paper, we take the financial risk index data as the network operator samples. The financial risk forecast of 4 power enterprises in National Power Company shows that the improved model is stable and reliable, and this method to forecast the financial risk of the power enterprises is feasible.

A Novel Financial Risk Evaluation Model Based on Adaptive Genetic Algorithm

We explore two schemes using transmission-line (T-line) to achieve high-performance global interconnects on VLSI chips. For both schemes, we select wire dimensions to ensure T-line effects present and employ inverter chains as drivers and receivers. In order to achieve high throughput and alleviate Inter-Symbol Interference (ISI), high termination resistance is used in the second scheme. For the two schemes, we discuss how to optimize the wire dimensions and the effects of driver impedance and termination resistance on the wire bandwidth. Secondly, design methodology is proposed to determine the optimal design variables for three objectives. We adopt the proposed methodology and compare the performance metrics with repeated RC wires. Simulation results show that, the proposed T-line schemes reduce the delay and improve the throughput as much as 82% and 63%, for min-ddp (delay2-power product) objective.

Design methodology of high performance on-chip global interconnect using terminated transmission-line

Searching the World's Herbaria: A System for Visual Identification of Plant Species

Recently, peer-to-peer (P2P) applications have generated the majority of Internet traffic. In this study, we model and analyze characteristics of P2P traffic flows by measuring real P2P application data captured from operational network. With lognormal mixture distribution and lognormal distribution, we get accurate statistical models for flow size and flow duration of Maze application traffic. We also find that moderate correlation exists between flow size and flow duration. With scatter plots, we analyze the reason for correlation formed.

2008 3rd International Conference on Innovative Computing Information and Control

The occurrence cause and negative effects of the islanding are presented in the paper, and a new method is presented based on chaos system. This paper applies certain chaos system of its sensitivity to periodical voltage signal to make its periodical solution yield a dramatic change to detect islanding, existence of the islanding can be identified by discriminating operation status of chaos system. The proposed method is showed to have fast acting and little influence on power quality. The simulations of the proposed method are carried out according to IEEE Std 1547-2003, the simulation results verify its effectiveness.

Research on islanding detection method for PV power system based on chaos theory

A method of the thyristor rapid switched capacitors is presented in this paper, which breaks through the bondage of the conventional methods. In addition, a novel algorithm of two time reactive power has been presented, with which reactive power can be calculated fast. Meanwhile, with microcomputer synchronous phase lock technology, quick switching without transition can be realized, dynamic reactive compensation for impact load can be achieved, and the total response time is shorter than 16 ms. This technology not only can compensate reactive current dynamically but also can improve the voltage waveform to a certain extent. In the end, the type test waveforms and the userspsila field test waveforms are given to show the validity and effectiveness of this technology. This method is an effective way to improve power quality.

2008 International Conference on Electrical Machines and Systems

Advanced thyristor switched capacitors and its effect on improving the power quality

The hairs on the wings of Locusta migratoria were observed and mapped using light microscopy, as well as by scanning and transmission electron microscopy. Based on their ultrastructure, we can distinguish four main types of hairs on the wings of adult L. migratoria, viz, short, medium and long hairs, and sensilla chaetica. The long hairs are located only on the ventral surface of the hindwing, whereas the other three types are present both on the dorsal and ventral surfaces of forewing and hindwing in both sexes. Medium hairs and sensilla chaetica are significantly more abundant on the dorsal surface of forewings in both females and males, than on the ventral surface, whereas the opposite was observed for short hairs (P < 0.01). No significant difference between males and females was observed in the density of any type of hairs (P > 0.1). Several dendritic branches, enveloped by a dendrite sheath, are situated in the lymph cavity of sensilla chaetica. Instead, no dendritic structure was observed in the cavity of the other three types of hairs. Immunocytochemical localization of chemosensory proteins (CSPs) was performed on ultrathin sections of hairs on wings. The antiserum against chemosensory proteins from L. migratoria (LmigCSP‐II) strongly labelled sensilla chaetica, with gold granules only found in the outer sensillum lymph. In addition, the epidermal cell membrane of the wing was stained by the antiserum against LmigCSP‐II. The other three types of hairs were never labelled. The results indicate that the wings might involve in contact chemoreception process.

Expression of chemosensory proteins in hairs on wings of Locusta migratoria (Orthoptera: Acrididae)

For the mathematical model of PWM inverter under the d-q rotary coordinate system, there exists coupling between the active current and reactive current, which makes it difficult manipulating the power injected into AC grid from distributed generation system. So as to handle the problem, a novel current decoupling strategy based on the input-output linearization is employed in the paper and the PI controllers are designed in the paper, whose application effectively eliminated the interaction between the active current component and reactive current component, equipping the system with fairly excellent linear control characteristic. Simulation results demonstrate that the method adopted possesses excellent decoupling performance.

Independent control of active and reactive power of the grid-connected inverter

BPEL can automate orchestrations for cross-organizational Web services; however, it meets a serious challenge from modeling human-intensive business activities. This paper distinguishes human-driven workflow from automated process, and uses state machine to model human-driven workflow, then transforms state machine-style workflow to BPEL process, finally integrates BPEL-style human-driven process with automated process. The goal of our work is to utilize the flexibility and efficiency of state machine to model complex and dynamic business process, and provides a novel procedure to model human-intensive business activities to complement the limitation of BPEL. This procedure has been implemented in DartFlow - a service composition platform for the sharing of the knowledge and services.

22nd International Conference on Advanced Information Networking and Applications - Workshops (aina workshops 2008)

Facilitating the Flexible Modeling of Human-Driven Workflow in BPEL

To address the performance limitation brought by the scaling issues of on-chip global wires, a new configuration for global wiring using on-chip lossy transmission lines(T-lines) is proposed and optimized in this paper. Firstly, we use passive compensation and repeated transceivers composed by sense amplifier and inverter chain to compensate the distortion and attenuation of on-chip T-lines. Secondly, an optimization flow for designing this scheme based on eye-diagram prediction and sequential quadratic programming (SQP) is proposed. This flow is employed to study the latency, power dissipation and throughput performance of the new global wiring scheme as the technology scales from 90nm to 22nm. Compared with conventional repeater insertion methods, our experimental results demonstrate that, at 22nm technology node, this new scheme reduces the normalized delay by 85.1%, the normalized energy consumption by 98.8%. Furthermore, all the performance metrics are scalable as the technology advances, which makes this new signaling scheme a potential candidate to break the “interconnect wall” of digital system performance.

One of the basic characteristics in human problem solving is the ability to conceptualize the world at different granularities and translate from one abstraction level to the others easily. But so far computers can only deal with one abstraction level in problem solving generally. It seems important to develop new techniques which will in some way enable the computers to represent the world at different granularities. So the multi-granular representation is the key to machine intelligence. In the talk, we first introduce the quotient space based problem solving theory. In the theory, a problem is represented by a triplet (X,F,T), where X - the universe with the finest grain-size, F -the attribute of X, and T- the structure of X. When we view the same problem at a coarser grain size, we have a coarse-grained universe denoted by [X]. Then we have a new representation ([X],[F],[T]) of the problem. The coarse universe [X] is defined by an equivalence relation R on X. Then, representation ([X],[F],[T]) is called a quotient space of(X,F,T), where [X] -the quotient set of X, [F] -the quotient attribute of F, and [T] -the quotient structure of T. Obviously, the set of representations of a problem at different granularities composes a complete semi-order lattice. That is, in the theory the concept, quotient space, in algebra is used as a mathematical model to represent the relationship between representations with different grain-sizes. Multi-granular representation methodology can be used both in problem solving and machine learning. In multi-granular problem solving, a problem is solved from the coarse grain-size to the fine one hierarchically. The aim of hierarchical problem solving is intended to reduce the computational complexity. Multi-granular machine learning is intended to learn the knowledge from representations with different grain-size, i.e., the so-called multi-information fusion. Generally speaking, the fine representation has more details but less robustness. Conversely, the coarse representation has more robustness but less expressiveness. They are complement so multi-granular learning can benefit from them. We also present some examples in hierarchical problem solving and machine learning to show the advantages of using multi-granular representation.

2008 3rd International Conference on Intelligent System and Knowledge Engineering

Multimedia content transformation is raising increasing interest among software developers in various industries. The unique characteristics of different multimedia files are studied in this paper. An improved software architecture specialized for multimedia content transformation based on Model-View-Controller (MVC) pattern is proposed. A new multimedia content transformation method based on the improved architecture is presented. Tests show that the new method improves the flexibility and accuracy of multimedia content transformation by fully utilizing the merits of MVC model 2x.

Study and application of a multimedia content transformation method based on model-view-controller 2x pattern

Interconnect planning has been widely regarded as one of the most critical factors in determining the system performance and total power consumption as technology scales. Because of shrinking dimension, on-chip wires are getting more resistive, and the wire delay is becoming larger comparing to gate delay. On the other hand, the self capacitance of wires does not scale with feature size, and as wiring density grows, the total coupling capacitance increases, which results in substantial increment of interconnect power consumption. Two challenges have been posed for on-chip interconnect planning: (1) to quantitatively determine the interconnect impacts upon system performance and power consumption in early design stage, (2) to find novel interconnect strategies that can bridge the gap between gates and wires as technology scales. To meet these challenges, both analysis and design methods need to be developed. Off-chip interconnect is also becoming a limiting factor for system performance since the growth of chip’s I/O bandwidth has been outpaced by the growth of communication requirement. To meet the performance challenge, the per-pin interconnect bandwidth must be further improved. How to manage the power consumption of very high bandwidth interconnects can be really challenging. In this statement, I outline the contributions of my thesis to address these challenges and discuss the possible directions of my future research.

Statement Ling Zhang 2 . 2 Novel on-chip transmission line signaling scheme

An efficient frequency-based clock analysis method: CSAV is proposed in this paper. It computes the circuit response by first solving the state equation in frequency domain, and derive the rational approximate with the help of vector fitting [9]. There are two aspects that contribute to the time efficiency of the method. One is CSAV solves the state equation only on selected frequency points, which significantly reduce the amount of time for equation solving. The other is CSAV performs vector fitting and waveform recovery only on user specified nodes, which save the unnecessary computation on the nodes which are not concerned by user. The complexity of our method is O( lceillg fmaxrceilNalpha + lceillg fmaxrceil 2NaNout), where fmax is proportional to the knee frequencyquency of input signal, N is the node number of the circuit, a is a constant around 1.3, Na is the order of approximation and Nout is the number of output nodes. Our experimental results show that compared with Hspice, CSAV achieves speed-up up to 35 times while the error is only 1%. Moreover, computational saving of CSAV grows with circuit size, which makes this method especially promising for large cases.

9th International Symposium on Quality Electronic Design (isqed 2008)

Journal of University of Science and Technology Beijing, Mineral, Metallurgy, Material

Multi-scale mathematic modeling of non-isothermal polymeric flow of fiber suspensions

In order to improve the precision of attitude operator in GPS attitude determination, based on Quantum-behaved Particle Swarm Optimization(QPSO) algorithm, a new GPS carrier phase searching technology of attitude determination is proposed. In favor of the ambiguity function methodpsilas fitness function, quantum behavior is introduced to enhance the ability of global searching to achieve the GPS fast determination. The simulations show the QPSO algorithm applied to solve benchmark functions is stable, fast of the searching speed and have a high accuracy. The actual application shows the method used in GPS attitude operator based on QPSO algorithm is able to search in the complex space, and the precision is high, the speed is rapid and the application effect is notable.

Study on GPS attitude determination technology based on QPSO algorithm

The measurement of granules is the most foundational problem in granular computing. The paper is intended to study the measurement of granules on a finite or infinite set. For a finite set we discuss the measurement of granules corresponding to an equivalence relation on a finite set and introduce a definition of conditional granularity in order to distinguish those granules with the same granularity. For an infinite set we can define different granularity in different questions, but we give the basic idea of granularity, that is, the granularity of a granule is the sum of the relative information contents of its atomic granules.

This paper proposes a land vehicle navigation algorithm based on the global positioning system (GPS) and the dead reckoning (DR).To achieve high location and velocity accuracy , the extended Kalman filter smoother (EKF-smoother) is introduced for GPS/DR integrated navigation system. And the algorithm of the EKF and the EKF-smoother is given. Further, the state models and the measurement models of GPS/DR are set up. For comparision purpose, the algorithm performance of EKF and EKF-smoother is contrasted. Numerical results demonstrate that the proposed EKF-smoother algorithm gives much higher navigation accuracy than EKF algorithm for land vehicle navigation. The algorithm has obvious advantages of high accuracy.

2008 IEEE Pacific-Asia Workshop on Computational Intelligence and Industrial Application

The Application and Design of EKF Smoother Based on GPS/DR Integration for Land Vehicle Navigation

Relationship between support vector set and kernel functions in SVM

Granular computing (GC) as a new field has grown rapidly since the term was proposed. There are two basic concepts underlying GC, i.e., fuzziness/fuzzification and granularity/granulation. Fuzzy set theory is an effective tool to deal with the fuzzification problem. There has been a large number of works on this aspect such as computing with words. The difficulty is in the concept of granulation. There was only an informal definition proposed by Zadeh for the concept. So far only a few works addressed the problem such as rough set and quotient space theories. In these works, the granulation is mainly defined by equivalence relations, i.e., a partition model. For example, in quotient space theory, a problem is represented by a triplet (X,F,T), where X -the universe with the finest grain-size, F -the attribute of X, and T- the structure of X. When we view the same problem at a coarser grain size, we have a coarse-grained universe denoted by [X]. Then we have a new representation ([X],[F],[T]) of the problem. The coarse universe [X] is defined by an equivalence relation R on X. Then, representation ([X],[F],[T]) is called a quotient space of(X,F,T), where [X] -the quotient set of X, [F] -the quotient attribute of F, and [T] -the quotient structure of T. Obviously, the set of representations of a problem at different granularities composes a complete semi-order lattice. But in many real applications, we must deal with non-partition models such as tolerance relations (or similarity relations, neighboring relations). In the talk, we will discuss the granular computing based on fuzzy and tolerance relations from the quotient space theory point of view. We focus on the connections among different grain-size worlds, especially, the two basic properties between quotient spaces, i.e., falsity and truth preserving properties. We show that these two basic properties still hold in fuzzy and tolerance worlds. Using these properties, the computational complexity can be reduced either in problem solving or machine learning. We will extend the quotient space theory based multi-granular computing from crispy world to fuzzy and tolerance worlds. The optimal path finding in complex networks is given as an example to show the application of the theoretical results.

This paper presents a new logic style, named Current-Mode Differential logic (CMDL), that achieves both high operating speed and low power consumption. Inspired by the low-voltage swing (LVS) logic, CMDL uses a shunt resistor at the differential output to obtain constant low swing signal without the need to reset low. Furthermore, conditional shunt transistors are used for the internal nodes to prevent high-voltage swing, thus entirely eliminate the power-hungry clocked reset network in LVS circuits. We show that the CMDL is suitable for high-end microprocessor integer core by providing three datapath modules implemented in CMDL. Our simulation results indicate that, operating at comparable speed with LVS logic, CMDL circuits can achieve up to 50% reduction of delay-power product compared to CMOS logic and LVS logic. In addition, CMDL reduces the power consumption of LVS by up to 40%.

Attribute reduction is one of the important topics in the research on rough set theory. In confrontation with dynamic data, common methods of attributes reduction have such disadvantages as unstable reduction results, intensive computation and the difficulty in meeting the need of real-time processing. To solve these problems, a method of dynamic attributes reduction with improved PSO algorithm is proposed based on the research of particle swarm optimization. The concrete work is the following: firstly, the traditional PSO algorithm is improved to enhance the global search ability, which increases the diversity of particle population distribution. Secondly, the information decision system data extraction is divided into some subdecision tables, which are reducted by used of improved PSO algorithm. Finally, each reduction results are intersected and get the most minimal reduction. Simulation and experimental results show the dynamic reduction algorithm can overcome the shortcomings of common attribute reduction which possesses the significant effect and rapid computation.

Study on dynamic attribute reduction based on improved PSO algorithm

Based on a two-dimensional steady magnetohydrodynamic (MHD) model, the influence of gap distance change on vacuum arc characters is simulated and analyzed. Firstly, a vacuum arc with constant current and variational gap distance is studied. It could be known that, with the increase of gap distance, the magnitude of the vacuum arc plasma parameters increases and the radial asymmetry of them aggravates. Secondly, a vacuum arc with half-wave sinusoidal current and linearly increased gap distance from a time point after arc ignition is simulated. The half-wave current is discreted at a series of discrete moments and the gap distance values are also gotten at these moments, then simulations are done at these time points respectively. By comparison among these simulation results, it could be known that the magnitude of arc plasma parameters increases firstly then decreases and their radial asymmetry follows the same trend, but the transition occurs not at current peak but after it.

2008 23rd International Symposium on Discharges and Electrical Insulation in Vacuum

Simulation of vacuum arc dynamic process with consideration of the change of gap distance

One of the most attractive self-similar traffic generating methods is ON/OFF model due to its clear physical explanation. However, the simulated traffic may show very strange characteristics, e.g. the estimated Hurst parameters for simulated traffics are larger than 1 and are almost equal despite of their different ON period parameters because of wrong sampling interval. In this paper, we point out that we should pay attention to two aspects when we use ON/OFF model to simulate network traffic. First, the first part of the simulated traffic is non-stationary and should be cut off. Second, the simulated traffic might be extremely over-sampled. The simulated traffics with appropriate sampling interval and non-stationary part cut off show satisfying result.

2008 Workshop on Power Electronics and Intelligent Transportation System

CALA: A Web analysis algorithm combined with content correlation analysis method

Based on magnetohydrodynamic (MHD) model, current constriction phenomenon in high-current vacuum arc (HCVA) is researched and analyzed in this paper. According to simulation results, it can be found that the significant current constriction only near anode regions for lower current vacuum arc; but with the increase of arc current, the constriction of arc current also appears near cathode side, and with the further increase of arc current, the current constriction of cathode side can be more significant than that of anode side. The current constriction near cathode side in very high-current vacuum arc can be caused by the MHD process of arc column (associated with the increase of plasma density and plasma pressure). Current constriction phenomena in HCVA is associated with many factors, such as arc currents, AMF strengths, AMF distribution, electrode diameter, electrode separation, plasma status at cathode side and anode side, and so on. The increase of axial magnetic field strength will inhibit the current constriction of the whole arc column. Saddle-shaped AMF can get more uniform current density distribution than bell-shaped AMF. The experimental phenomena of current constriction near cathode side will also be discussed in this paper. Plasma status of cathode side and anode side will influence current distribution of arc column.

Current constriction phenomena in high-current vacuum arc and its influence factors

Information sharing is a major strategy to counteract the bullwhip effect. Previous research suggested that applying different ISS (information sharing strategy) to the supply chain may improve the supply chain performance under a simplified two-level supply chain model. In this paper, we present a simulation study that investigates the effectiveness of information sharing under different information sharing strategy scenarios within a complex multi-level supply chain model. In our research, a computer model is developed to simulate the complex multi-level supply chain model. The simulation data and results analysis show both distributors and suppliers gain significantly from information sharing no matter under different information sharing strategy except retailers and different information sharing strategy has great influence on supply chain performance.

2008 IEEE International Conference on Service Operations and Logistics, and Informatics

The impact of information sharing strategies in multi-level supply chain

Distributed generation in microgrid is mainly composed of new energy and renewable energy resources. The maximum power point of the PV cell array is various from time to time with the change of circumstance and load. The fuzzy control can react to the environment change quickly and keep the photovoltaic system work on its maximum power point all the time. However, the limitation in the fuzzy control itself and the characteristic of self-optimization lead to serious concussion of the system around the maximum power point. Whereas the PID control method is effective in the elimination of concussion and is easy to be realized. To tackle the problem, the fuzzy parameter self-tuning PID control method is adopted in the paper to achieve the MPPT control of PV system. The method can effectively eliminate the concussion around the maximum power point and improve the stability of the whole microgrid; and achieve grid-connected operation with a high power factor in combination with the harmonic elimination PWM control of inverter. Simulation results show that the scheme has merits of simple structure, high power factor and reliable operation, etc. and is worthwhile to be popularized.

Research on the control of the single-stage photovoltaic system in Microgrid

An arrangement and method for mounting a cutter body, especially a milling cutter, in which the cutter and power driven spindle have a common axis of rotation. An arbor shank is used to interconnect the cutter with the spindle with one end of the shank mating with a shouldered bore formed in one of the spindle and cutter. Radially moveable clamp elements are provided to expand and engage the shoulder so as to urge one face of the cutter body into firm abutment with one end of the spindle. Keying means are also provided between the cutter body and the power driven spindle.

Based on numerical simulation technology, the influence of arc currents and axial magnetic fields (AMFs) strength on high current vacuum arc (HCVA) characteristics is studied and analyzed. Simulation results show that electron temperature, ion number density, axial current density, plasma potential, plasma pressure and heat flux density to anode in HCVA are all increased with the increase of arc currents. For very high current vacuum arc, current constriction near cathode side can be more significant than that of anode side. The increase of AMF strength can decrease the above parameters, and will control HCVA more efficiently. The simulation results of HCVA under different arc currents are also verified by experiments.

Influence of arc currents and axial magnetic fields strength on high current vacuum arc

Study of network survivability based on multi-path routing mechanism

The Experimental System of Gas Hydrates Integrative Simulation (ESGHIS) was built to study the thermodynamics and kinetics of gas hydrates formation and dissociation, distribution characteristics of temperature and pressure in gas hydrate well drilled for exploration and exploitation, and gas hydrate drilling technologies. A control module was developed to lighten labor intensity and guarantee experiment safety in the ESGHIS. A multi-function card PCI-1711 was selected as the core of the control module, which has high-speed data acquisition and digital/analog output. A relay OMRON/G2R-1 was used to automatically manage the startup/stop of units. A solenoid valve VP542 and a gas-control valve NV1-20-6M-ATC were used to operate overpressure protection. PLC TEMI550 was used to control programmable high-low temperature test chamber HLT705P through connecting it to a computer using a RS232/RS485 converter I-7520. A proportional valve and a stepper motor were used to control lifting and rotary speed of the drilling pipe in mini-drilling module. The corresponding software was coded by using multithreading and Visual C++6.0 language. It had good quality on interface, maintainability and expansibility. The whole module was operated successfully in the experiments of gas hydrates formation and mini-drilling simulation. It worked steadily, executed quickly and had high sensitivity for overpressure protection, which largely lightens the experimental intensity of the labor and enhances the safety of the experiments.

The Experimental System of Gas Hydrates Integrative Simulation and its control module

Recently, more and more people have awareness that we should focus on the communication, cooperation and coordination (3Cs) among the actors in virtual teams. Much researches on designing methodologies for collaborative information system in academic and industrial communities in many countries. This paper introduces a new methodology called awareness net model for considering how to design collaborative information system in the virtual team. This whole processes through constructs the net graph (awareness net) to describe the relationships among the actors within virtual teams, and analyze actor's collaborative requirement of awareness by five awareness levels (level-0 to level-4 awareness). Could the awareness net model be used in Chinese company? A case study representing a collaborative process in customer service department in Gome Corporation is used throughout this paper. Finally, the author find out the application of the methodology contribute to identifying the collaborative requirement of actors and designing what kind of databases, interactive interface, communication tools, et are needed in Gome Corporation.

A new methodology for designing collaborative information system in a virtual team: A case study

Collocation is the frequent bi-grams of semantic meanings and grammatical functions. Adjacent and long distance collocations are extracted as features for a Bayesian classifier in spam filtering. Compared to the common unigram feature, collocation-based classifier shows improvement in all the evaluation metrics. The influence of mail header information is studied for the classifier, which shows a 10% change in both precision and recall.

2008 International Workshop on Education Technology and Training & 2008 International Workshop on Geoscience and Remote Sensing

AbstractWorking mechanisms of a new foundation treatment technology formed by geocell reinforced mattress and stone column were discussed. Combining with a certain engineering project, techniques of treating soft soil foundation of expressway were studied with an example of vibrosinking stone columns and geocell reinforced mattress. This foundation treatment system has an advantage of putting both geocell and stone column into full play on load transfer and support. On the basis of that, by considering the horizontal reinforced effect by geocell reinforcement, an appropriate calculation model for stone column composite foundation with geocell reinforcement located over it was set up. Furthermore, a useful design calculation method for this two-direction reinforced composite foundation system was proposed. Finally, this method was employed to design a concrete foundation treatment by geocell mattress and stone column in a certain highway project. Both the mechanism analysis and the real project study indic...

Design Calculation Method for Soft Foundation Treatment by Geocell Mattress and Stone Column

Several types of low power passive equalizer is proposed and optimized in this work. The equalizer topologies include T-junction, parallel R-C and series R-L structures. These structures can be inserted at driver or/and receiver side at either the chip or package level and the communication bandwidth can be improved with little overhead on power consumption. Using the area of the eye as the objective function to be maximized, we optimized these equalizers for the CPU-memory interconnection of an IBM POWER6trade System with and without practical constraints on the RLCG parameter values. Our experimental results show that without employing any equalizers, the data-eye is closed for a bit-rate of 6.4 Gbps. We tried twelve different equalizer schemes and found they produce very different eye diagrams. The scheme yielding the maximum eye improves the height of the eye to more than 300 mV at a total power cost of 7.2 mW, while the scheme yielding the minimum jitter limits the jitter magnitude to 10 ps at a total power cost of 9.5 mW. We also have shown that the solution resulting from the proposed optimization approach have very small sensitivity to the tolerance of the R,L,C values and the magnitude of the coupled noise.

A low power passive equalizer using RL terminator is proposed and optimized in this work. The equalizer includes an inductor in series with the resistive terminator, which boosts high frequency components and therefore improves the interconnect bandwidth with little overhead on power consumption. An analytic estimation method for eye-opening and jitter based on tritonic step response is also introduced in this work, which enables the optimization procedure. Our experimental results show that our estimation method is accurate and a board level transmission line of 50 cm wire length can achieve 15 Gb/s data rate. With 15 GHz frequency input, the power consumption of the equalizer is less than 2.5 mW, and the total power is 5 mW.

Low power passive equalizer optimization using tritonic step response

Motion planning for robots with topological dimension reduction method

Awareness net model is created for identification of process awareness requirement of the actors in collaborative business process in terms of roles, tasks and artefacts that exist within the collaborative processes. It could divide actors' awareness of knowledge sharing into five awareness levels. Consequently, people could use the model to measure actors' contribution to knowledge sharing and improve organization culture of collaboration. Unfortunately, people would meet some problems when the model is applied in practical cases. This paper evaluates the advantage and disadvantage of awareness net model in details. After that, some practicable solutions are described to be used to solve the problems and consummate the model.

Based on a magnetohydrodynamic (MHD) model, a two-dimensional transient MHD model of a vacuum arc was developed. In this model, the unsteady terms in mass, momentum, and energy conservation equations, Maxwellpsilas equations, and generalized Ohmpsilas law were considered. In energy conservation equations, work done by the electrical field, the force of friction and the thermal force were considered also.

Two-dimensional transient magneto-hydrodynamic modeling of vacuum arc

Function S-rough sets has dynamic characteristics and law characteristics. By employing function S-rough sets and the method of law generation, this paper proposes the concepts of attribute composition distribution and rough law distance. Then by using these concepts, this paper analyzes the relations between attribution composition distribution with rough law, moreover presents a series of theorems about the relations between rough law decomposition with attribute composition distribution. At last, an example is given for explaining the rough law status estimation. The results of this paper are the theory base of law mining and system status recognition.

2008 Fifth International Conference on Fuzzy Systems and Knowledge Discovery

Attribute Composition Distribution and Rough Law Status Estimation

The establishment of the likelihood model of state observation with a strong robustness is one of the core issues in the study of moving hand tracking. This paper is dedicated to building a robust likelihood model of state observation, and do some study by using the method of gaining feature points from frame images of human hand. Firstly, based on physiological models and camera projection principle, we propose a basic idea that use gesture polygon to describe the image contour of hand gesture. Secondly, Lindeberg method is improved by designing the two types of response function to get the different types of feature points on multiscale space basen on the local area of vertex in the polygon, and a novel structural response mode is presented. Then we fuse the features in different scales by using Hausdorff distance and Hausdorff matrix, and present the likelihood model of state observation. Finally, the model is used for 3D motion tracking of human hand. Our theoretical analysis and experimental results show that the approach put forward in this paper has the advantages of a low time complexity and strong robustness, compared with the Lindeberg method.

2008 International Symposium on Computer Science and Computational Technology

The Robust Likelihood Model of State Measurement and Its Applications in Articulated Object Tracking

In this letter, we propose a new optimal filtering algorithm for systems with multiplicative noise process under correlated additive noises. Different from the traditional derivation method of constructing innovation process, we derive the new algorithm based on the well-known projection theorem, which is simple in principle, convenient for recursive estimation and flexible for application. The new recursive filter is superior to the conventional Kalman filter in flexibility and applicability.

An Optimal Filtering Algorithm for Systems With Multiplicative/Additive Noises

The constructive neural networks based on the covering algorithms is suitable for large-scale data mining because it can be local processing and has little computational complexity, however, the local processing lows classification precision. In this paper, covering algorithms is firstly extended to kernel covering algorithms and we secondly construct a kind of finite mixture probabilistic model based on kernel covering algorithms according to the probability meaning of Gaussian function and finally introduce the global optimizing computation by "maximum likelihood theory", realize the global optimization problem of the covering algorithms so as to expand the range of application of covering algorithms and improve its precision. The results of the experiment are given as an example to illustrate the validation of the method.

Third International Conference on Natural Computation (ICNC 2007)

A Modified Constructive Neural Networks and Its Application for Large-scale Data Mining

The theory and applications of artificial neural networks have developed rapidly since the mathematical model of neuron was presented, but the design of network structure for a certain problem was a roadblock over a long period of time. In 1990s, the covering algorithm for forward neural network was put forward, this algorithm is a constructive machine learning method, it designs network with sphere neighborhoods built upon sample data. The theoretical analysis indicates that the general ability of this algorithm is in the inverse ratio of the number of covering domains. Some techniques is performed while constructing the sphere neighborhood set to simplify the network, such as changing the sphere neighborhoods center to the barycentre of points covered by a domain, deleting the points covered by a sphere neighborhood. In this paper, a new constructive algorithm which combines the covering algorithm and neighborhood search is presented and applied to some databases on the web site of UCI and text categorization, the results show that the algorithm can reduce the number of sphere neighborhoods with higher degree of classifying accuracy.

Covering Algorithm Based on Neighborhood Search and its Applications

How to apply natural language and speech technology is one of the important contents that increase the intelligent degree of mobile GIS and improve its serving system. From system structure and application demand of mobile GIS, this paper basically explained the application objective and key techniques of speech and natural language in mobile GIS, discussed the multi application modes of speech and natural language that includes the centralized mode and the distributed mode, the perfect natural language mode, the human-computer conversation mode and the mixed mode among them, the speaker-dependent mode and the speaker- independent mode. Finally some primary application methods, about how to adopt these speech application modes in mobile GIS, were synoptically analyzed.

Pico-size cells with a red fluorescence signature similar to marine free-living prochlorophytes have been detected by flow cytometry throughout the fresh and brackish waters of the Changjiang Estuary in August 2005. These cells could be discriminated from Synechococcus by their lack of orange (phycoerythrin) fluorescence, from Prochlorococcus by their larger side light scatter, and from picoeukaryotes by their smaller side light scatter and much lower red (chlorophyll) fluorescence. The maximum abundances of these Prochlorococcus-like particles reached 3×104 cells ml-1 in the low salinity zone upriver and declined rapidly seaward. While Synechococcus was scarce and Prochlorococcus vanished in the brackish regions, the Prochlorococcus-like cells overnumbered the picoeukaryotes and became the predominant pico-size auto- fluorescing particles there, implying they might play an important role in this estuarine ecosystem and worthy of further investigation.

Journal of the Marine Biological Association of the United Kingdom

Prochlorococcus-like populations detected by flow cytometry in the fresh and brackish waters of the Changjiang Estuary

The secondary structure prediction of protein plays an important role to obtain its tertiary structure and function. In the past thirty years, a huge amount of algorithms have been employed to this task. The better predicators are based on machine learning techniques, especially based on neural networks. But the architecture of neural network is hard to define, and the training process is time-consuming. In this paper, a constructive machine learning approach is used to predict protein secondary structure with five different encoding schemes, the results show that the constructive algorithm can achieve high predicting accuracies and the encoding schemes have influence on predicting result.

2007 1st International Conference on Bioinformatics and Biomedical Engineering

Cohesion degree is an important feature in differentiating ambiguous Chinese phrases. At the present time, there are no module in computer-oriented linguistic theories to represent this information and it is represented by additional statistical modules. The Binary Combinatorial Grammar (BCG) is based on arithmetic computing and integrates the cohesion degree as the priorities between operators. In order to resolve the share space problem and to improve the efficiency of operator-precedence shift-reduce parsing algorithm, the notion of precedence is introduced to the CYK algorithm to determine the combinatorial direction and to prune a portion of unnecessary subtrees during the parsing process. In the experiment of Chinese BCG parsing, all of the spent time, produced edges and result trees in the precedence based CYK algorithm are much less than that of the traditional CYK algorithm and the operator precedence based shift-reduce algorithm.

Eighth ACIS International Conference on Software Engineering, Artificial Intelligence, Networking, and Parallel/Distributed Computing (SNPD 2007)

Level set/ghost method for weldlines in the filling stage of injection molding is introduced in this article. The algorithm is based on non-isothermal, incompressible, generalized Hele-Shaw flow of a viscous fluid. The physical controlling equation systems are numerically simulated by the general finite difference scheme. Level set/ghost method captures the location and shape of the weldlines accurately and efficiently, the controlling equations of which are discretized by the fifth order weighted essentially non-oscillatory (WENO) scheme in space and by the total variation differencing Runge-Kutta (TVD-RK) method in time. As a result, the fusion process of weldlines is simulated accurately and the analysis of flow field is given correctly. Examples verify the proposed methodology.

In this paper, a new short-term traffic flow prediction model and method based on online support vector regression (OSVR) is proposed, according to the data collected sequentially by the probe vehicle or the loop detectors, which can update the forecasting function in real time via online learning way. As a result, it is fitter for a real engineering application. The OSVR model was tested by using 1-880 database, the result shows that this model is superior to the back-propagation neural network (BPNN) model.

Second International Multi-Symposiums on Computer and Computational Sciences (IMSCCS 2007)

Online support vector regression model for short-term traffic forecasting

A Theoretical Framework of Natural Computing - M Good Lattice Points (GLP) Method

Path diversity is an important index of the dependability and fault tolerance capability of networks. Most path diversity metrics are designed under an implicit hypothesis that all candidate paths for a divergence node are always equally chosen. This may not be true due to the effect of routing policy with consideration of cost or other factors. A new simple metric is proposed in this paper for path diversity measurement of end-to-end networks. An end-to-end network is firstly transformed into a sequence of cascading segments. With the assumption that only one of all available branches is chosen each time, a probability based metric is calculated for each segment, and the joint entropy is calculated as path diversity measurement for the overall end-to-end network. The metric is fitful for both single-hop and multi-hop topologies. A comparison between the new metric and other ones is given at the end.

13th Pacific Rim International Symposium on Dependable Computing (PRDC 2007)

As semiconductor process technologies scale down, interconnect planning presents ever-greater challenges to designers. In this paper, we analyze, evaluate and compare various metrics with optimized wire configurations in the contexts of different design criteria: delay minimization, delay-power minimization and delay2-power minimization. We show how various design criteria influence interconnect performance: (1) the optimal inverter to wire capacitance ratio depends only on the technology and design goal, not on wire pitch, (2) at min-pitch, the width pitch ratios of wire for different objective functions are different: the ratio is 0.52 for minimizing delay, 0.31 for minimizing delay2-power product and 0.21 for minimizing delay-power product, (3) the quantitative delay-energy trade-offs for the three objective functions are: the delay-power product reduces power by 67% with a cost of 40% larger delay, while the delay2-power product reduces power by 50% with a cost of 10% larger delay, which implies that delay2-power product results a decent power saving with little cost on speed and (4) the quantitative results of the impact of wire pitch on wire performance are derived. Particularly at 70nm technology node, for bandwidth, the optimal pitch is at min-pitch, while for power, the optimal pitch is 2.35x the min-pitch, and for bandwidth over power, the optimal pitch is 1.76x min-pitch

8th International Symposium on Quality Electronic Design (ISQED'07)

Repeated On-Chip Interconnect Analysis and Evaluation of Delay, Power, and Bandwidth Metrics under Different Design Goals

In this paper, a new short-term traffic flow prediction model and method based on incremental support vector regression (ISVR) is proposed, according to the data collected sequentially by the probe vehicle or loop detectors, which can update the prediction function in real time via incremental learning way. As a result, it is fitter for the real engineering application. The ISVR model was tested by using the 1-880 database, and the result shows that this model is superior to the back-propagation neural network (BPNN) model.

Short-term Traffic Flow Prediction Based on Incremental Support Vector Regression

Modeling of microstructural evolution during dynamic recrystallization in coarse Nb microalloyed austenite

A New Algorithm for Trademark Image Retrieval Based on Sub-block of Polar Coordinates

Analysis of Human Factors Integration Aspects for Aviation Accidents and Incidents

In this paper, we propose a beamforming scheme based on a radial basis function (RBF) network for multiple input multiple output (MIMO) wireless communication systems. The RBF network is an effective forward neural network, which has the advantages of easy training and fast convergence rate. This RBF network beamforming technique performs better than the higher order statistics based beamformer.

An RBF Network Based Beamformer for Mimo Wireless Communication Systems

A Novel Fairness Property of Electronic Commerce Protocols and Its Game-based Formalization

Based on MHD model, high current vacuum arc (HCVA) is simulated and analyzed. In this model, the influence of ion kinetic energy and viscosity is considered. With the increase of arc current, plasma flow transits from supersonic to subsonic status; so, boundary conditions of cathode and anode side have to be adjusted. First, we simulate and analyze the fundamental characteristics of HCVA. Then, we simulate and analyze the influence of nonuniform distributed AMF on HCVA characteristics. According to the simulation results, the saddle-shaped AMF can more effectively inhibit plasma loss from arc column than that of bell-shaped AMF. Comparisons between simulation results and experimental results show the Tightness of model and simulation

2006 International Symposium on Discharges and Electrical Insulation in Vacuum

MUD simulation of high-current vacuum arc under different axial magnetic fields

This paper analyses the operational coordination mechanisms between the core enterprise and the partners within a supply chain having private local information. For a make to order production setting, a hybrid model of synergic production scheme based on negotiation is proposed. After analyzing the characteristic of synergic production process, this paper establishes the hierarchy of synergic production process monitoring. In the production process monitoring, four monitoring modes are defined according to the significance of the items in the whole product. A Web-based synergic production management system for supply chain has been implemented with programming in ASP and Ms SQL server. The application shows that the approach proposed in this paper is applicable to practical production in supply chain

2006 10th International Conference on Computer Supported Cooperative Work in Design

Synergic Production Process Controlling in Supply Chain Management

A novel off-line anonymous digital cash protocol utilizing smart card is presented in this paper. It employs smart card as a distributed anonymity and divisibility provider agent based on Schnorr signature scheme. It provides accountable anonymity and divisibility. Its digital cash proves to be unreusable, unexpandable, untraceable, and unforgeable. Compared with Chaum and Wang's scheme, the novel protocol distributes less computation load on customers and cost less communication, thus it is efficient and adapted to mobile payment.

2006 First International Conference on Communications and Networking in China

A Novel Off-line Anonymous and Divisible Digital Cash Protocol Utilizing Smart Card for Mobile Payment

A Modified Constructive Fuzzy Neural Networks for Classification of Large-Scale and Complicated Data

This paper aims to carry out granular analysis of time sequence based on quotient space. Granular methods have long before been adopted to analyze time sequence, but the granularity was based on time, for example, day mean, month mean, year mean and so on in finance forecast. In this paper, the granularity is based on space and some significant results are obtained: we can, in certain circumstances, get characteristics of time sequence in an original space when carrying out granular analysis of it in its coarser-grain space; granular analysis of a Markov chain is equivalent to an hidden Markov model (HMM), contrarily, any HMM is equivalent to granular analysis of a Markov chain. These results deepened our understanding of HMM from the perspective of granular analysis. We can not only use the methods of HMM to study time sequence, but also use the methods of granular analysis based on quotient space theory to solve the problems of HMM.

2006 International Conference on Computational Inteligence for Modelling Control and Automation and International Conference on Intelligent Agents Web Technologies and International Commerce (CIMCA'06)

In 2004, Chang et al. presented an approach firstly to solve the problem of secret sharing with access structures in a hierarchy. After that, based on one way hash function, another proposed scheme was suggested by Lin et al. However, there is the same drawback in both schemes. When group secret keys need to be changed, the trust authority has to update related parameters of each branch in both the above schemes. In this paper, using discrete logarithm, an improved secret sharing with access structures in a hierarchy is given. It can achieve the property that related parameters do not have to update even if group secret keys are altered. So, the presented scheme may be more suitable for applications

2006 IEEE Asia-Pacific Conference on Services Computing (APSCC'06)

A proactive approach is needed to ensure all elements of the laboratory system are in compliance.

Decorrelation caused by temporal changes influences phase unwrapping of differential interferogram in repeat-pass D-InSAR phase delay due to atmosphere disturbance degrades the accuracy of D-InSAR for small deformation monitoring. In this paper, we present a stacking D-InSAR approach using multi-baseline differential interferograms to estimate the linear deformation based on Rank Defect Free Network Adjustment Model (RDFNA) and to increase the deformation temporal sampling rate and estimate the linear deformation accurately. The Minimum Cost Flow (MCF) algorithm based on Delaunay triangulation network generated with sparse grids is adapted for phase unwrapping of individual interferogram. Scatterers with high coherence values over a given threshold in the interferogram stack are selected for the network generation. Therefore, with the multi-baseline differential interferogram stack, the linear deformation rate can be calculated with the unwrapped phase of each point accurately.

Linear Deformation Rate Derivation from Multi-baseline Differential Interferogram Stacks

Effects of lead widths and pitches on reliability of soldered joints and optimum simulation for QFP devices

We propose a novel cluster parallel file system: high-throughput & scalable parallel file system (HTSPFS). There are some new features in it such as automatic adaptive file striping policy based on file size, request arrival rate, concurrent of accessing files, storage servers' networking and disk performance; prefetching read-request and writing behind write-request to enable a higher throughput in HTSPFS. We give a detail discuss of Markov spatial predicting method for read request, experiment results show that Markov predicting technology has high prediction veracity. Overall, HTSPFS has some autonomies characteristics

17th International Workshop on Database and Expert Systems Applications (DEXA'06)

A 1.8 V tri-mode ΣΔ modulator for GSM/WCDMA/WLAN wireless receiver

With the explosion of low-cost bandwidth availability, many desirable e-business features require new functionality in enterprise networking systems, and thus force the network components to be both flexible and powerful. Programmable routers (typically NP-based systems) as a platform on which to implement the enterprise applications seem to fit the bill. Meanwhile, the demands for accommodating an increasingly diverse range of novel network services in such system are still keep growing. To meet these challenges, this paper presents a novel methodology for building control plane software using component technology in programmable network environment. The proposed approach can facilitate the developing of scalable, flexible modular NP-based systems that are required to the e-business world

Applying Software Component Technology to NP-based System for Novel Network Services

A weighted balance evidence theory for structural multiple damage localization

The quotient space theory is indented to study the relationship of transform and that of dependency among the worlds with different grain-size. Compared with other granule computing tools, it has more powerful abilities of representation and absorption. The reason is that structure is introduced in its model. The paper is to study the quotient space theory based on structure. We first introduce some methods of constructing quotient structure. Then we study in detail the quotient space family based on structure, and get some good results for further research. Finally we also briefly discuss hierarchical structure of fuzzy sets

A structural fairness of electronic commerce protocols is presented. A game-based model of electronic commerce systems is built. And in the model a formalization of fairness is given. They are exactly used to analyze fairness of electronic commerce protocols. Compared with the previous work, the main contributions are the following. Firstly, a strategic game is used to model channels in various qualities and participants' dishonest behavior enables us to analyze cooperative and adversarial behaviors. Secondly, balance payoff considers both participants' income and expense but the previous one only considers participants' income. Thirdly, abortive fairness is defined because of honest participant's quitting voluntarily or aborting the protocol in response to system failures. These two help us to avoid the confusion that a system satisfies fairness definition but is not fair to some participant factually

2006 International Conference on Computational Intelligence and Security

A Structural Fairness Based on Game and Its Application to Analysis of Electronic Commerce Protocols

In this paper, a fusion model of weighted semi-order spaces is presented as well as the quotient space approachability theorem basing on measure space is proved. Fusion theory is not only concerned with information fusion, but with space structure that topology relation among elements on the space exists. We consider inductive reasoning basing on granularity analysis is also a kind of fusion in light of the quotient space approachability theorem. While qualitative thing is uncertain to the corresponding quantitative thing basing on the theory of quotient space, the theory in the paper can be used to integrate qualitative probabilistic networks, as qualitative analogues to an original Bayesian networks, abstracting from the numerical detail.

Quotient space approachability basing on measure space and fusion model of weighted graphical structure

A bearingless switched reluctance motor (BSRM) is a multi variable, nonlinear and high coupling system. So the design of its control is very complicated. Based on basic electromagnetism theory, the paper derived a radial force model of a bearingless switched reluctance motor. Reversibility of the model is proved and inverse system approach is developed to realize the dynamic decoupling of radial force. A nonlinear controller based on inverse system is designed so that the nonlinear, strongly coupled system is decoupled into two linear subsystems. Linear control system techniques are applied to these decoupled linear subsystems to synthesize desired response. To verify the effectiveness of the control scheme, some simulations are carried out and the results are satisfactory

Decoupling Control of Radial Force in Bearingless Switched Reluctance Motors Based on Inverse System

Aiming at calculating gravity anomaly of 2-D complicated and heterogeneous geological body, we propose Irregular Gravity Modeling (IGM) approach based on Delaunay triangulation. As we know, the most fundamental cell is triangle in 2-D space. With Delaunay triangulation, we can divide a two-dimensional body, extending horizontally with arbitrary cross-section, into various triangular prisms with varying density in optimal way. After inversion the density of those nodes, we can figure out the density distribution. Using analytic equations derived, our approach is convenient and efficient in calculating. In comparison with traditional approach, the implementation of Delaunay triangulation helps us to use various triangles to approximate the geometry of geological body, and varying density is more close to the real density distribution when figuring out 2-D geological body with complicated geometry and heterogeneous density. Here, we implement out method in inversing a gravity profile measured in Qianmiqiao Oil Field, analyze the result, compare our method with the conventional, and make a discussion.

2‐D Irregular Gravity Modeling and Computation of Gravity Based on Delaunay Triangulation

Hierarchical Machine Learning - A Learning Methodology Inspired by Human Intelligence

Fair mobile payment protocols ensure that both participants can engage in the exchange without the risk of suffering a disadvantage (e.g., losing their money without receiving anything for it). In general, fair payment protocols require the continuous availability of an external trusted third party (FTP), a dedicated site which is trusted by both participants. In this paper we present solutions to the fair exchange problem in mobile environments, where customers frequently disconnect from the network and thus continuous availability of the external TTP is not given. Our approach utilizes smart card on the customer's side partly taking over the duties of the TTP. A novel digital cash protocol is also proposed. In the protocol we implement a distributed anonymity provider agent with smart card on the customer's side. Thus accountable anonymity is guaranteed. Compared with Chaum's and Wang's schemes its communication cost and customer's computation are more reduced. The proposed digital cash are proved to be unreusable, unexpandable, untraceable, and unforgeable

2006 Fifth International Conference on Grid and Cooperative Computing Workshops

An Anonymous Digital Cash and Fair Payment Protocol Utilizing Smart Card in Mobile Environments

Quotient space theory (QST), a new granule computing tool dealing with imprecise, incomplete and uncertain knowledge, uses a triplet, including the universe, its structure and attributes, to describe a problem space or simply a space. As one of important theories of granular computing (GrC), QST is very helpful to the study of cognitive informatics (CI). This article summarizes the quotient spaceâ€™s model and its main principle. Then some basic operations on quotient space are introduced, and the significant properties of the fuzzy quotient space family are elaborated. Finally the main applications of quotient space theory are discussed.

To well support the real-time requirement from applications, we enhance the real-time ability in Linux kernel through two new kernel mechanisms. Firstly, we present a new microsecond-level timer mechanism based on UTIME provided by Kurt-Linux, but different from it. The new timing implementation provides more flexible mechanism to support the different-grained timing requirement, as well as more flexible and preferential management of microsecond-level timers. Secondly, we present a new interrupt handler to reduce the kernel delay, which makes it possible scheduling interrupt handler with other processes under the system scheduler. Therefore, making interrupt routine under control is achieved. The experiments show that the improvements are distinct and significant.

2006 International Conference on Software Engineering Advances (ICSEA'06)

This paper describes a GPS antenna array that is able to reject jamming signals from two different directions. The GPS array consists of five antenna elements of equal amplitude and different phases. The 5-element GPS array can produce two nulls using the phase-only technique. Ceramic substrate of high dielectric constant is used to realize a miniaturized GPS antenna element. Due to the narrow bandwidth of microstrip patch antennas printed on ceramic substrates, mutual coupling effect must be taken into account in the design of the 5-element GPS array. Closed-form solutions of the required phases to produce two nulls are obtained and given. Simulation results of the GPS antenna elements and arrays by Ansoft's HFSS are also presented and discussed

An Anti-Jamming 5-Element GPS Antenna Array Using Phase-Only Nulling

The skin tissue fluid of human contains many useful components, which can be used to realize the noninvasive detection of human body, such as noninvasive blood glucose detection. In this paper, a percutaneous exported way of skin tissue fluid is presented, which makes use of penetration enhancing of TTDS and thermal micro-fluid driving technology. Compared with minimally invasive physical ways, the body is really unharmed by the new way, and the detection of the skin tissue fluid can be continuous and on-line. The following in vitro experiment results show its effectiveness and feasibility

2006 International Conference on Machine Learning and Cybernetics

A Percutaneous Exported Way of Skin Tissue Fluid Based on Transdermal Enhancers and Thermal Gradient

Design and Implementation of HTSPFS: High-Throughput and Scalable Parallel File System

A Quotient Space Approximation Model of Multiresolution Signal Analysis

A matchup dataset that contains the SSM/I measurements from F14 satellite and the columnar water vapor (CWV) radiosoundings taken in or near the China Sea was established to cover the period from April 1998 to June 1999. CWVs retrieved from two statistical and two semistatistical retrieval algorithms were compared to radiosonde CWVs using the matchup dataset. It is indicated that the root-mean-square (RMS) error of these retrievals relative to the radiosonde data ranges from 4.483 kg m-2 to 10.180 kg m-2. Three improved algorithms were developed and validated using the matchup dataset. It is demonstrated that these improved algorithms can be applied to the China Sea for retrieving CWV from the SSM/I with better accuracies relative to the four typical existing algorithms.

A comparison and validation of algorithms for retrieving water vapor content from SSM/I over ocean

Problems associated with techniques currently used to measure the T1 of flowing blood are evaluated and a method to improve the consistency and repeatability of measurements is presented. Similar to some currently used techniques, the pulse sequence employs a nonselective adiabatic inversion pulse followed by a series of ECG-gated gradient echo EPI (echo planar imaging) images to obtain images where the blood (fluid) signal exhibits a T1-dependent inversion recovery signal from which the spin lattice relaxation constant (T1) of the flowing fluid can be measured. The new method combines curve fitting with a measure of the curve null point to acquire more accurate and consistent T1 values. Simulation and experimental results show that this combined fitting-nulling method is more stable and consistent in measuring the T1 of flowing fluid. The feasibility of temperature measurement of a flowing fluid based on the temperature dependence of the T1 of water protons is shown in this paper. ECG gating is used to reduce the effects of cyclic intensity changes for measurement of T1 in pulsatile flowing blood.

Improved accuracy and consistency in T1 measurement of flowing blood by using inversion recovery GE-EPI.

The theory of granule computing based on the quotient space is one of the three main granule computing theories. The emphasis is on the structure of the quotient space theory in this paper. Comparing with rough set theory, the authors point out the importance of the structure in granule computing theory. A new method of constructing quotient space according to the structure is also presented in this paper. The differences between the quotient structure and structure-based method are proved. Finally, some examples show the rationality and feasibility of our methods.

A Behavior-Based Ingress Rate-Limiting Mechanism Against DoS/DDoS Attacks

Network processor based system is a kind of realtime, resource-constrained and complex embedded system. Component technology is a promising approach to develop such system. We analyzed the computational model in fast data path of the network processor based system, and defined how component fits into this model. The proposed component model captures the hardware features of network processor, and it can be used to describe the functional composition, performance composition and behavior of final system.

Sixth International Conference on Parallel and Distributed Computing Applications and Technologies (PDCAT'05)

With the rapid increase of the medical images and the wide application of PACS, more and more attention is paid to the effective lossless compression of the medical images. In this paper, a compression method compatible with JPEG-LS standard and based on neighborhood's match is presented. A context vector predictive model is used to remove the redundancy of the neighborhood pixels. The experimental results show that the new method is effective in decreasing the redundant data of the medical images, and gets a high compression ratio, while keeping the low complexity of JPEG-LS algorithm.

2005 International Conference on Machine Learning and Cybernetics

A lossless compression method of medical images based on neighborhood's match

Software Component and Prediction for Network Processor based Application

More and more complex embedded system use component based development. Non-functional properties of component model are used to predict performance of the final system. We analyzed the thread properties of component in network processor based system. The proposed method is based on the thread properties and provides quantified performance of the component, and so we can predict the performance of final system at composing time. The experiments show that the difference between theoretic and simulation result is less than 10%.

Component based performance prediction for network processor based system

In Lamb wave detection of damages in smart structures, the excitation pulse is usually designed as a narrow band burst wave for the convenience of analysis and recognition. However, the wideband excitation can excite more modes in plate/shell structure and thus provides extra information for changes of the structure. This paper presents a method that can extract information in wideband Lamb wave signals. By transforming the detected signals into various sub-frequency band, the measured signal can be converted to its equivalences of narrow band excitations, therefore, the information in different frequency bands can be acquired from a single test and in the same time the complicity of wideband signal can be simplified. Some test results are provided to verify this method.

Wideband Lamb wave analysis based on continuous wavelet transform

Semantic search requires a search engine to properly interpret the meaning of a user's query and the inherent relations among the terms that a document contains with respect to a specific domain. We present the framework of such a search engine based on domain ontologies. In this framework, a search request, which can be either a keyword list as in traditional search methods or a query in complex form containing various restrictions to the search, is first processed by a query parser which then finds qualified RDF triples in domain ontologies. Web documents relevant to the requested concepts and individuals specified in these triples are then retrieved by a document retriever. And finally, the retrieved documents are ranked according to their relevance to the user's query. An extended term-document matrix is built to reflect the relevance between documents, concepts/individuals, and terms. Such a matrix makes it possible for the search engine to work even in case that there are no available domain ontologies for user requests.

Distributed Dynamic Resource Management for the AF Traffic of the Differentiated Services Networks

The quotient space theory obtains a fusion model about semi-order structure under the condition of consistency information, harnessing topology relation among elements of the universe space and hierarchical structure. It has great significance to forming a unified theory structure about information fusion technology. This paper gets a new semi-order structure fusion model under the condition of inconsistency information and proves incompleteness of its semi-order lattice . An example is presented in the paper at last as well as a new method is indicated for Bayesian network structure learning.

Semi-order structure fusion model of quotient spaces under the condition of inconsistency information

Uncertainty of parameters in control systems was described by interval variables, and some idea of the non-probabilistic reliability method that we proposed in previous papers was used for stability analysis and synthesis of uncertain systems. A new method, called robust reliability method, was presented for quadratic stability analysis and robust stabilization of dynamic systems with interval parameters. In the method, the performance function for robust reliability calculation was established by criterion of quadratic stability, and a solving method in the form of optimization for robust reliability was presented. The proposed stabilization method can take both the required energy supply for control and the control robustness into account. This makes the reasonable strategy of compromising between the control cost and system reliability become possible. By the method, robust reliability measure of the stability degree of uncertain control systems can be provided, and the maximum allowable ranges of the basic parameters can be obtained. The presented method is based on the linear matrix inequality (LMI) approach, and is convenient to implement Three numerical examples were provided to illustrate the validity and efficiency of the presented method.

Robust reliability method for quadratic stability analysis and stabilization of dynamic interval systems

A Novel SVD-Based RLS Blind Adaptive Multiuser Detector for CDMA Systems

Handwritten mathematical notation contains ambiguities of various kinds. Here we focus on ambiguity in spatial relationships; in particular, we use fuzzy logic to treat ambiguity in subscript-or-inline and inline-or-superscript spatial relationships. We extend an existing system for recognizing handwritten mathematical notation, adding the capability of producing a ranked list of interpretations rather than a single top-choice interpretation. Fuzzy membership values are assigned to each spatial relationship; a given pair of symbols can have non-zero membership in fuzzy sets subscript and inline, or in fuzzy sets inline and superscript. These fuzzy membership values are combined to produce an overall confidence value for the entire interpretation. We have modified the user interface of our system so that a user can quickly view and select from the ranked interpretations when the highest confidence interpretation is incorrect.

Eighth International Conference on Document Analysis and Recognition (ICDAR'05)

Using fuzzy logic to analyze superscript and subscript relations in handwritten mathematical expressions

Aiming at the characteristic of text categorization, this paper proposes an improved method of computing term weights, tfidfie, based on the traditional tfidf function that is generally used in most classifiers. In comparison with the tfidf function, the tfidfie function adds an information entropy factor, H, which represents the distribution of documents in the training set in which the term occurs. The experiments show tfidfie outperforms tfidf. In addition, this paper analyses the difference of using information entropy factor H between document categorization and feature selection, also finds that both two phases are all necessary for text categorization, meanwhile it can reach the best performance of classification with up to 70% of the unique terms being removed.

Extension Control Algorithm Using Extension Set in Control System

Next generations of wireless systems will support multi-standard data communication. Not only will they support voice and multimedia data through cellular network, they will also be convergent with fixed wireless access (WiMax) and WLAN to deliver voice and multimedia data over the Internet whenever possible. Due to the widely spread frequency bands and bandwidths, most existing multi-standard wireless devices use separate chipsets or stacked radios to support different standards. In this paper, a combo GSM/WCDMA/Wi-Fi triple-standard transceiver architecture, which shares as much hardware as possible, is proposed and analyzed. The system design is targeting implementation in deep submicron CMOS such as TSMC0.18-mum.

2005 12th IEEE International Conference on Electronics, Circuits and Systems

A triple-standard transceiver architecture for GSM, WCDMA and WI-FI applications

This paper presents a novel global routing algorithm, AT-PO-GR, to minimize the routing area under both congestion, timing, and RLC crosstalk constraints. The proposed algorithm is consisted of three key parts: (1) timing and congestion optimization; (2) crosstalk budgeting and estimation; and (3) crosstalk elimination and local refinement. Compared with the recent work introduced in (Zhang et al., 2003) and (Zhang et al., 2004), the proposed algorithm can achieve smaller routing area and fewer shields under the same design constraints, yet use less running time.

Proceedings of the ASP-DAC 2005. Asia and South Pacific Design Automation Conference, 2005.

A min-area solution to performance and RLC crosstalk driven global routing problem

Summary form only given. One of the basic characteristics in human problem solving is the ability to conceptualize the world at different granularities and translate from one abstraction level to the others easily, i.e., the ability of multi-granular computing. The proposed quotient space theory is intended to provide a multi-granular computing model. In this paper, we address the following four problems. The traditional single-granular computing methodology usually confronts with high computational complexity when dealing with complex problems. The main aim of multi-granular computing is intended to reduce the computational complexity. By using the quotient space model, we show in what conditions the multi-granular computing could reduce the computational complexity. Second, based on the quotient space model, the characteristics of the top-down hierarchical problem solving are discussed. Third, the well-known multi-resolution signal analysis is managed under the framework of the quotient space model. And we show the close relationship between the quotient space based multi-resolution model and the second-generation wavelet transforms. This relationship may provide a new idea for signal analysis. Finally, a quotient space based hierarchical machine-learning model is discussed. And a new hierarchical constructive learning algorithm is presented.

Dot-matrix plots are widely used for similarity analysis of biological sequences. Many algorithms and computer software tools have been developed for this purpose. Though some of these tools have been reported to handle sequences of a few 100 kb, analysis of genome sequences with a length of >10 Mb on a microcomputer is still impractical due to long execution time and computer memory requirement.

RESULTS
Two dot-matrix comparison methods have been developed for analysis of large sequences. The methods initially locate similarity regions between two sequences using a fast word search algorithm, followed with an explicit comparison on these regions. Since the initial screening removes most of random matches, the computing time is substantially reduced. The methods produce high quality dot-matrix plots with low background noise. Space requirements are linear, so the algorithms can be used for comparison of genome size sequences. Computing speed may be affected by highly repetitive sequence structures of eukaryote genomes. A dot-matrix plot of Yeast genome (12 Mb) with both strands was generated in 80 s with a 1 GHz personal computer.

Server replication is an approach often used to improve service access efficiency and availability for a large number of clients. This paper adopts a simple service model and investigates a set of efficient algorithms for server selection in an anycast group under the condition of imprecise network delay. The algorithms use ticket-based probing approach to search the path with short delay and probe the server load at the same time and try to optimize the server and path delay at the same time. The simulation results demonstrate that our algorithms are efficient in terms of server response time for sever selection compared with several other server selection algorithms.

7th International Symposium on Parallel Architectures, Algorithms and Networks, 2004. Proceedings.

Distributed server selection with imprecise state for replicated server group

. The hadronic ﬁnal states observed with the ALEPH detector at LEP in e + e − annihilation are analysed using 730 pb − 1 of data collected between 91 and 209 GeV in the framework of QCD. In particular event-shape variables and inclusive charged particle spectra are measured. The energy evolution of quantities derived from these measurements is compared to analytic QCD predictions. The mean charged particle multiplicity, the charged particle momentum spectrum and its peak position are compared to predictions of the modiﬁed-leading-logarithmic approximation. The strong coupling constant α s is determined from a ﬁt of the QCD prediction to distributions of six event-shape variables at eight centre-of-mass energies. A study of non-perturbative power law corrections is presented.

Studies of QCD at e + e − centre-of-mass energies between 91 and 209 GeV

This work presents a global routing algorithm that minimizes total wire length and satisfies RLC crosstalk constraints specified at sinks. Our algorithm is based on critical network concept and search space traversing technology (SSTT) for global routing synthesis and tabu search for shield insertion and net ordering (SINO) to eliminate noise. The algorithm achieves about 20/spl times/ speedup compared with a recent work using iterative deletion based global routing and simulated annealing based SINO. Furthermore, our algorithm increases the wire length by 4% compared with global routing without crosstalk constraints, achieving a 2.5/spl times/ reduction compared with the aforementioned recent work.

2004 IEEE International Symposium on Circuits and Systems (IEEE Cat. No.04CH37512)

On Two Problems of w-Wide Distance and (w-1)-Fault Distance, w-Wide Diameter ad (w-1)-Fault Diameter

The European Physical Journal B - Condensed Matter and Complex Systems

The stationary properties and the state transition of the tumor cell growth mode

Building Grid Monitoring System Based on Globus Toolkit: Architecture and Implementation

Performance of certain Krylov subspace methods for solving convection-diffusion equations

The paper presents three different computational schemes for achieving space vector pulse width modulation, in the control of a multilevel flying capacitor inverter. Each scheme uses the same method of achieving cell-capacitor voltage balancing. Results of realistic simulations are used to compare and contrast these approaches. The timing control of the inverter switches and output performance of each method are presented and the most suitable one is highlighted.

Multilevel space vector PWM control schemes for a flying-capacitor inverter

ASP-DAC 2004: Asia and South Pacific Design Automation Conference 2004 (IEEE Cat. No.04EX753)

A coupling and crosstalk considered timing-driven global routing algorithm for high performance circuit design

Conventional delay metrics are becoming more inadequate to handle new semiconductor process technologies and high performance design. We present in this paper a package of tools for accurate and efficient interconnect timing estimation, namely, ETEM, which combines a wire-load model and an interconnect delay model together with table-lookup method. It is capable of modeling parasitic effects and resistive shielding effects accurately, and taking into account the signal slew during delay evaluation. A probability model is adopted to estimate the wire spacing and a priority-queue-based algorithm is devised for timing computation. In our work, its application to performance-driven global routing is shown in comparison with the conventional analytical models.

ETEM: an efficient gate and interconnect timing estimator considering cross-coupling for high performance layout

An adaptive beam model and dynamic characteristics of magnetorheological materials

Performance optimization becomes an increasingly dominant factor in global routing. This paper presents a performance optimization global routing algorithm CEE-Gr with RLC crosstalk constraints, which to our knowledge, is the first to study coupling noise, timing performance, and routability simultaneously at global routing level. The CEE-Gr has been implemented and tested on MCNC benchmarks and the experimental results are promising.

Performance optimization global routing with RLC crosstalk constraints

Fabrication, morphology and structural characterization of ordered single-crystal Ag nanowires

Closure to “Structural Damage Detection from Modal Strain Energy Change” by Z. Y. Shi, S. S. Law, and L. M. Zhang

An efficient solution method for predicting indoor environment of buildings with complex geometric configuration

Multilevel inverters, including the flying-capacitor topology require more complex control due to the additional flexibility offered by the multiple output voltage levels. One such control method is based on the conventional sinusoidal pulse width modulation (SPWM) scheme and uses multiple triangular carriers. There are a number of SPWM variants that achieve the desired inverter control. This paper presents the results of an investigation into these different schemes and their influence on the power quality and efficiency of a flying-capacitor inverter.

Influence of multilevel sinusoidal PWM schemes on the performance of a flying-capacitor inverter

A new experimental procedure is proposed based on an instrumental variable method [1] for analyzing wall surface heat transfer processes and deducing wall surface heat transfer coefficients under actual conditions. Tests were carried out under a wide range of conditions, and the heat transfer coefficient was found to vary from 8 to 26 W/m 2 ” K while wind speed ranged from 0 to 7.5 m/s, and correlations were obtained in terms of wind speed. In addition, the experiments indicated that wind direction does not have a significant effect on the heat transfer coefficient of wall surfaces.

RESEARCH ON SYSTEM IDENTIFICATION OF WALL SURFACE HEAT TRANSFER PROCESSES

In China-US Million Book Digital Library, output of the digitalization process is more than one terabyte of text in OEB and PDF format. To access these data quickly and accurately, we are developing a distributed terabyte text retrieval system. With the query cache, system can search less data while maintaining acceptable retrieval accuracy. From the OEB package, we get its metadata and structural information to implement multi-scale indexing and retrieval. We are to explore some new retrieval models and text clustering approaches in the Digital Library.

Toward a distributed terabyte text retrieval system in China-US million book digital library

An improved structural damage quantification algorithm is presented based on the elemental modal strain energy change before and after the occurrence of damage in a structure. The algorithm includes the analytical stiffness and mass matrices of the system in the damage quantification. It reduces significantly the modal truncation error and the finite-element modeling error from higher analytical modes in the computation, and it improves the convergence properties of the existing algorithm by Shi et al. (2000). “Structural damage detection from elemental modal strain energy change.” [\IJ. Eng. Mech.\N, 126(12), 1216-1223]. The effectiveness of the proposed algorithm is demonstrated via a numerical example and experimental results from a two-story steel portal frame, and it is demonstrated to be an efficient and robust method for damage quantification.

Improved Damage Quantification from Elemental Modal Strain Energy Change

A Cache-Based Distributed Terabyte Text Retrieval System in CADAL

The problem of pattern recognition is formulated as a classification in the statistic learning theory. Vapnik constructed a class of learning algorithms called support vector machine (SMV) to solve the problem. The algorithm not only has strong theoretical foundation but also provides a powerful tool for solving real-life problems. But it still has some drawbacks. Tow of them are 1) the computational complexity of finding the optimal separating hyperplane is quite high in the linearly separable case, and 2) in the linearly non-separable case, for any given sample set it's hard to choose a proper nonlinear mapping (kernel function) such that the sample set is linearly separable in the new space after the mapping. To overcome these drawbacks, we presented some new approaches. The main idea and some experimental results of the approaches are presented.

Statistical learning theory and its application to pattern recognition

Membrane association and conformational change of palmitoylated Goα

We propose a video watermarking technology to hide copyright information by a slight modification of the motion vectors in an MPEG video bitstream. By selecting the inter frames in the MPEG sequence and according to the bitstream of copyright information, the motion vectors are regularized into a modified bitstream, from which the watermark information can be easily retrieved. From the experimental results, it indicates that to embed watermark in the motion vector has the advantage of little influence on the MPEG decoding speed, little degrading of the perceptive effect, capability to embed the watermark in a short video sequence, and can be used to watermark directly on compressed and uncompressed video sequences.

2001 IEEE Fourth Workshop on Multimedia Signal Processing (Cat. No.01TH8564)

In this paper, we propose a video watermarking technique to hide copyright information in MPEG motion vector. In this method, watermark is embedded in larger value motion vectors, and specially in the less phase angle changed component. Then, the motion vector is modified into a new bitstream from which the watermark information can be easily retrieved. From the experimental results, it indicates that to embed watermark in motion vector has the advantage of little degrading the video quality, little influence on the MPEG decoding speed, capability to embed watermark in a short video sequence, and can be used to watermark on both the uncompressed and compressed video sequence.

Proceedings XIV Brazilian Symposium on Computer Graphics and Image Processing

We have examined the extent of duplication in 16 reaction databases from four commercial sources, totaling nearly a million reactions, by converting them to a common format for comparison. The overlap is surprisingly small, less than 3%.

In this paper, a geometrical approach for building neural networks is proposed. With the proposed approach, it is very easy to construct an efficient neural classifier to solve the handwritten Chinese character recognition problem, as well as other pattern recognition problems of large scale. Experiments are conducted to evaluate the performance of the proposed approach and results obtained are promising.

Proceedings 15th International Conference on Pattern Recognition. ICPR-2000

A neural network based classifier for handwritten Chinese character recognition

Diffraction-contrast TEM, focused probe electron diffraction, and high-resolution X-ray diffraction were used to characterize the dislocation arrangements in a 16μm thick coalesced GaN film grown by MOVPE LEO. As is commonly observed, the threading dislocations that are duplicated from the template above the window bend toward (0001). At the coalescence plane they bend back to lie along [0001] and thread to the surface. In addition, three other sets of dislocations were observed. The first set consists of a wall of parallel dislocations lying in the coalescence plane and nearly parallel to the substrate, with Burgers vector (b) in the (0001) plane. The second set is comprised of rectangular loops with b = 1/3 [11 20] (perpendicular to the coalescence boundary) which originate in the coalescence boundary and extend laterally into the film on the (1 100). The third set of dislocations threads laterally through the film along the [1 100] bar axis with 1/3<11 20>-type Burgers vectors These sets result in a dislocation density of ~10 cm. High resolution X-ray reciprocal space maps indicate wing tilt of ~0.5o.

In this paper, a geometrical representation of McCulloch-Pitts neural model is presented. From the representation, a clear visual picture and interpretation of the model can be seen. Two interesting applications based on the interpretation are discussed. They are 1) a new design principle of feedforward neural networks and 2) a new proof of mapping abilities of three-layer feedforward neural networks.

A geometrical representation of McCulloch-Pitts neural model and its applications

The modified radioimmunoassay of serum inhibin and its value in monitoring ovarian tumor

Freeze-dried, live attenuated hepeatitis-a-live vaccine and its stabilizers

We study one-way wave propagation in the frequencywavelet domain (frequency-beamlet domain) for different wavelet bases, and compare their performances for migration/imaging. We show that the Kirchhoff operator in space domain is a dense matrix, while the compressed beamlet-propagator matrix which is the wavelet decomposition of the Kirchhoff operator (or other one-way wave propagators), is a highly sparse matrix. For sharp and short bases, such as the Daubechies 4 (D4), both the ‘interscale and intrascale coupling are strong. However, the interscale coupling is relatively weak for smooth bases, such as higher-order Daubechies wavelets, Coiflets, and spline wavelets. The images obtained by the compressed beamlet operator are almost identical to the images from a full-aperture Kirchhoff migration. Compared with the limited aperture Kirchhoff migration, beamlet migration can obtain much wider effective apertures, hense higer resolution and image quality, with similar computational efficiency. The compression ratio of the migrator ranges from a few times to a few hundred times, depending on the frequency, step length and the wavelet basis. Combining with the data (wavefield) compression, even greater efficiency can be expected.

Migration operator compression by wavelet transform: Beamlet migrator

Immunofluorescence microscopy was used to visualize the FtsZ band that marks the site of septation in Sporosarcina ureae. Image analysis indicated that the vegetative division was symmetrically located with respect to the ends of the cells. Fusions of lacZ to the sporulation loci, spoIIA and cotE, of Bacillus subtilis were introduced into S. ureae by mobilization of plasmids containing the fusions from Escherichia coli. The fusions showed similar patterns of sporulation‐associated expression in S. ureae to those observed in B. subtilis. Formation of β‐galactosidase encoded by the spoIIA–lacZ fusion made it possible to identify early sporulating cells by immunofluorescence microscopy. Analysis of the position of FtsZ bands in cells expressing spoIIA–lacZ indicated that the location of sporulation division was symmetrical with respect to the ends of the cells, in sharp contrast to the asymmetrical location of septation in sporulating Bacilli. It is inferred that asymmetry of location of the sporulation division is not essential for the compartmentalization of gene expression that follows the division.

The division during bacterial sporulation is symmetrically located in Sporosarcina ureae

Abstract 8-Hydroxyquinoline complexes of Na(I), Ca(II), Mg(II), Zn(II), Mn(II), Cu(II), Al(III), In(III) and La(III) are synthesized. Photoluminescence and UV-vis absorption spectra of them are reported. Except complexes of Cu(II), and Mn(II), these complexes show photoluminescence. With the increase of polarization force of metal cation, their photoluminescence peaks reveal red-shift and two broad absorption bands in UV-vis absorption spectra appear split and red-shift. ∗The work was supported by Chinese Academy of Sciences.

Effect of Metal Cation on Absorption and Fluorescence Spectra of Metal Complexes of 8-Hydroxyquinoline∗

The paper presents two control strategies for a matrix converter. Novel and computationally-efficient real-time control algorithms were developed and implemented using a digital signal processor. A 2 kVA prototype IGBT-based matrix converter supplying an R-L load was constructed. The matrix converter was tested and good performances were achieved using both the real-time modulators. Experimental converter waveforms and their respective harmonic spectra are compared. Key features of each modulator are highlighted.

PESC Record. 27th Annual IEEE Power Electronics Specialists Conference

Analysis and DSP-based implementation of modulation algorithms for AC-AC matrix converters

Discusses the learning problem of neural networks with self-feedback connections and shows that when the neural network is used as associative memory, the learning problem can be transformed into some sort of programming (optimization) problem. Thus, the rather mature optimization technique in programming mathematics can be used for solving the learning problem of neural networks with self-feedback connections. Two learning algorithms based on programming technique are presented. Their complexity is just polynomial. Then, the optimization of the radius of attraction of the training samples is discussed using quadratic programming techniques and the corresponding algorithm is given. Finally, the comparison is made between the given learning algorithm and some other known algorithms.

Programming based learning algorithms of neural networks with self-feedback connections

In the past 20 years, hundreds of Chinese traditional and herbal medicines with immunomodulating functions have been screened. In this paper, the immunopharmacological studies of several potent compounds isolated from them are reviewed; their medicinal plant sources and chemical structures are also presented.

Several compounds from Chinese traditional and herbal medicine as immunomodulators

The complexity of recognition in the single-layered PLN network with feedback connections

Adaptive significance of polyploidy in brine shrimp (Artemia parthenogenetica)

A relation matrix approach to labelling temporal relations in scheduling

Indistinguishability and identifiability analysis of linear compartmental models.

Monte Carlo Simulation of Diffusion in Solids: Some Recent Developments

Abstract De-mixing of the oxide solid solution (Co, Mg)O under an oxygen potential gradient by cation vacancy diffusion has been studied by Monte Carlo computer simulation. Because oxygen ions are practically immobile and form a rigid lattice, the de-mixing process can be simplified to cation diffusion under a vacancy concentration gradient in a random alloy. When the same parameters and boundary conditions were employed as those by Schmalzried et al., Akbar et al. and Vedula the simulation results showed excellent agreement with those of experiments, phenomenological approaches and analytical statistical mechanical investigations. The agreement with experiment could be illusory. When independent experimental values of cation vacancy concentrations and exchange frequency ratios were used in the simulation, the agreement between the simulation and the experimental de-mixing results deteriorated. Allowance for errors in the independent values provides sufficient room for agreement however.

This paper explores the realization of robotic arm motion planning, especially Findpath Problem, which is a basic motion planning problem that arises in the development of robotics. Findpath means: Given the initial and desired final configurations of a robotic arm in 3- dimensional space, and given descriptions of the obstacles in the space, determine whether there is a continuous collision-free motion of the robotic arm from the one configuration to the other and find such a motion if one exists. There are several branches of approach in motion planning area, but in reality the important things are feasibility, efficiency and accuracy of the method. The topological method has shown great potentiality in practice compared with the others. Here a simulation system is designed to embody the topological Dimension Reduction Method (DRM) [1]-[2] and it is in sight that DRM can be adopted in the first overall planning of real robotic arm system in the near future.

Motion Planning of Multi-Joint Robotic Arm with Topological Dimension Reduction Method

Abstract By means of Monte Carlo computer simulation we have explored the validity of the Manning relations which connect the phenomenological coefficients to the tracer diffusion coefficients in an alloy. The model chosen for calculation was the ordered binary alloy analogue of the king magnet. The vacancy mechanism was assumed. At temperatures above and below the order-disorder temperature, the Manning relations provide a good simulation, except at compositions approaching impurity levels. The relations then break down because they have built into them a requirement that ω4 = ω0 (four-frequency impurity model notation) in contrast to the model.

A computer simulation study of manning's relations in a binary alloy with order

An algol'ithm of planning collision-free paths for a moving object among obstacles is presented. Using the concepts of state space and the rotation mapping presented in £1] and (2], the relationship between the positions and the corresponding collision-free orienta­ tions of the moving object is representeq as some set of a state space. This set is called rotation mapping graph (RMG). By investigating the global topological structure of the RMG, the problem of finding collision-free paths for a moving object is thus transformed to that of finding connected paths in a

Proceedings of the 1988 IEEE International Conference on Systems, Man, and Cybernetics

Abstract Chemical diffusion via the agency of vacancies in a simple cubic binary alloy with long- and short-range order has been simulated using the Monte Carlo method. Results for the diagonal and cross-correlation functions collected with the time-correlation method of Allnatt are in very good agreement with previous results collected with the in-field method of Murch. It is found that despite the existence of a maximum in the composition dependence of the thermodynamic factor in the ordered structure, other terms predominate, with the result that intrinsic and interdiffusion coefficients both show minima in their compositional dependence in a manner similar to that found previously for the tracer diffusion coefficient.

As shown in [1], we examine search as a statistic sampling process. Based on some statistical inference method the probability that a subtree in search tree contains the goal can be decided. Thus some weight is in tentionaly added to the evaluation function of those nodes which are unlikely in the solution path so that the search will concentrate on the most promising path. It results in a new weighted algorithm-WSA. 
 
Tn a uniform m-ary tree, we show that a goal can be found by WSA in the polynomial time, although the computational complexity of A (or A*) may be O(e) for searching the same space. Where N is the depth at which the goal is located.

In this paper, we present a new heuristic searching algorithm by introducing the statistical inference method on the basis of algorithm A (or A*). It is called algorithm SA. In a simplified search space, a uniform m-ary tree, we obtain the following result. Using algorithm SA, a goal node can be found with probability one, and its mean complexity is O(N·ln N) where N is the depth at which the goal is located.

A theory for planning collision-free paths of a moving object among obstacles is described. Using the concepts of state space and rotation mapping, the relationship between the positions and the corresponding collision-free orientations of a moving object among obstacles is represented as some set of a state space. This set is called the rotation mapping graph (RMG) of that object. The problem of finding collision-free paths for an object translating and rotating among obstacles is thus transformed to that of considering the connectivity of the RMG. Since the connectivity of the graph can be solved by topological methods, the problem of planning collision-free paths is easily solved in theory. Using this theory, a topological method for planning collision-free paths of a rod-object translating and rotating among obstacles is presented. If a nonrigid robotic arm is viewed as a composite rod with some degrees of freedom, the planning of collision-free paths of a robotic arm can be solved in a similar way to a rod.

In this paper we present a new heuristic searching algorithm by introducing statistical inference method on the basic of algorithm A*. It's called algorithm SA*. The following results have been proved. (1) Algorithm SA* in superior to algorithm A*. (2) The mean complexity of SA* is CN2, but in some case A* exhibits exponential complexity (eN). (3) In a (N,d,F)- game tree, the mean complexity of SA* is CN2, but the complexity of other known game-searching algoritham (α-β , SSS* etc.) is at least dN. (4) The maximal storage-space required by SA* is C,N. 
 
This shows that under a given significance level SA* is superior to other known algorithm (e.g. A*, B*, α-β, SSS* etc.).

Automatic registration method for remote sensing images based on improved ORB algorithm

To reliably monitor the deformation of a single landslide is often a difficulty for DInSAR with mid-resolution SAR data. The high resolution SAR systems bring opportunities for the task. Among the landslides in Three Gorges area, Shuping landslide is typical and some previous works using DInSAR have been done during the last years. In this paper, 9 TerraSAR-X spotlight images are used to map the surface displacement of Shuping landslide. Conventional and coherent pixels based DInSAR are both applied. The deformation field of the landslide is mapped and 2 deformtion cones are identified. Meanwhile, this paper gives out the average deformation velocities of the coherent pixels during the period from January to March 2012. It is confirmed that DInSAR can become a valuable tool in studying and monitoring single landslides with high resolution SAR images. In the future, the DInSAR measurements along the line of sight direction should be converted to real slide direction of the landslide and analyzed joint with multi-source data.

Monitoring the deformation of Shuping landslide with TerraSAR-x spotlight images

Remote Detection and Analysis of Mass Movements in the Catchment Area of the Xiangxi River/ China

A Study on Recognition Characterization of Passive Super Low Frequency Electromagnetic Exploring Curves of Goaf

The target scattering characteristics of transmission towers in high resolution SAR images were studied. The experiment of tower cross-arm artificial icing was processed to analyze the target scattering characteristics of icing tower. Feature points based matching methods was proposed to identify the tower deformation. A Harris algorithm was adopted to detect the feature points in pre-processed target images. The detected feature points of same target in multi temporal images are matched based on their distribution to assess the deformation of tower. The experimental results of tower icing and deformation experiments show that the scattering characteristics of transmission tower cross-arm are still strong to be detected in SAR images after icing.

Monitoring Damage of State Grid Transmission Tower in Bad Weather by High-Resolution SAR Satellites

Based on open source software platform DORIS and self-developed software modules for baseline errors correction and atmospheric delay effects mitigation,ENVISAT SAR data(2003-2007) of Langfang and Shengfang town area are processed.12 GPS stations' data are used to mitigate the atmospheric delay effects in interferograms.SRTM3 DEM is introduced to estimate the residuals of flatten earth effects.The center locations of the subsidence cones are calculated and the annual subsidence rates in these areas are precisely acquired.

Study on Urban Area Subsidence Monitoring Based on InSAR Technique

In virtue of the property of light, portable, and less affected by complex terrain, the natural source magnetotelluric method and explorer is superior in complicate terrain exploration in the field. Goaf, the waste part after mining, is a ruinous geologic hidden danger. Due to the act of gravity, the wall rocks of goaves probably sink and caving to cause ground falls and other geologic disasters. This paper introduces the theory and exploring method of using natural source super low frequency (SLF) electromagnetic wave to detect goaves. The effect of exploration was proved by comparing experiment results with well logging.

IGARSS 2008 - 2008 IEEE International Geoscience and Remote Sensing Symposium

A Study on Using Natural Source Super Low Frequency Electromagnetic wave to Explore Goaf

Super low frequency remote sensing technique introduced here is, with the use of natural electromagnetic waves, used to explore the apparent resistivity of strata on the surface of the Earth, and then to reduce the degree of enrichment of gas underground and indicate the depth of the gas-bearing stratum. The simple theory, exploration method and device are presented in the text. Contrasts are made between the results obtained from experiments and those extracted by drilling at the same location for validating this technique.

In this paper, we present the results of D-InSAR technique and conventional leveling at selected area in Tianjin city, using 8 ENVISAT SAR images between 17 October 2003 and 17 February 2005.The D-InSAR results show that the subsidence rate reached over 5 cm/year (7 cm within 16 months) in highly sinking area, and it is consistent with leveling results. D-InSAR is able to provide more details of urban subsidence, and it is supplement to leveling surveys in those areas with sparse leveling benchmarks.

Bam earthquake: Surface deformation measurement using radar interferometry

The differential INSAR technique has the potential for monitoring centimeter-scale ground motion in an accurate and costeffective manner. Probably the most important limiting factor in the application of INSAR is temporal change in the complex reflectivity of the ground surface during the period between radar acquisitions. This can be due to changes in such parameters as moisture content or vegetation. The stable artificial corner reflectors can be identified from long temporal series of interferometric SAR images even with large baselines, and therefore decrease the risk of image decorrelation. This paper will discuss the following questions: 1) how to obtain the true phase of a corner reflector in a SAR complex image; 2) how to co-register the corner reflector pixels when the coherence of its surrounding area is extremely low; 3) how to select the interpolation kernel to resample the SAR image; and, 4) how to compute the interferometric phase of two co-registered corner reflectors without flat earth term and corners’ height contribution. In order to demonstrate the results, a practical example of landslide monitoring in the Three Gorges area in China is presented.

Landslide Monitoring in the Three Gorges Area Using D-INSAR and Corner Reflectors

In the former WISMUT uranium ore mining and processing area (Thuringia, Germany) controlling of small surface movements with cm-accuracy is required. A promising tool is the D-INSAR technology, which could reduce man power spending, compared with other geodetic techniques (GPS, precise levelling). The GeoForschungsZentrum Potsdam (GFZ), the DASA Jena-Optronik company (DJO) and the WISMUT company participate in a joint project (sponsored by the German Space Agency DARA) to apply INSAR in the WISMUT area, using a stable corner reflector (CR) reference net and measuring CRs. The phase difference between the CRs are investigated with the objective to monitor CR movements. The network has been initially positioned by GPS and is also controlled by terrestrial geodetic measurements. Experiments are presently being carried out by shifting CRs out of position. The project status and first results are presented in this paper.

Monitoring of small motions in mining areas by SAR interferometry

Nannochloropsissp.からの細胞壁分解と脂質抽出のための水性酵素的抽出プロセス。【Powered by NICT】

An effective coded exposure photography framework using optimal fluttering pattern generation

PURPOSE
To summarize the experience and effect of holistic quality nursing during perioperative period of maxillary sinus lateral fenestration.

METHODS
From January 2010 to December 2016, there were a total of 26 patients with maxillary sinus lateral fenestration in the First Dental Clinic Department. Through observation and analysis of nursing cooperation combined with psychological nursing in the perioperative period, coordination and postoperative nursing, the overall experience and effect of holistic quality nursing were summarized.

RESULTS
All 26 patients received effective bone increment after operations without any complications. Nursing cooperation and psychological nursing were essential and effective during perioperative period of maxillary sinus lateral fenestration.

Modern holistic quality nursing embodied thoughtful preoperative preparation, suitable psychological nursing, accurate nursing cooperation and postoperative meticulous care follow up, which plays an important role in the success of maxillary sinus lateral fenestration.

[Nursing cooperation during maxillary sinus lateral fenestration and bone grafting].

[Preliminary results on preserving fractured tooth whose margin below the gingiva by using forced eruption].

Enhanced ethanol sensing properties based on α-Fe2O3/In2O3 hollow microspheres

α-Fe2O3 hollow microspheres were successfully prepared by a hydrothermal approach using sucrose as morphology controlled agent, urea as precipitant and followed by calcination at 500°C for 4 h. The structure of α-Fe2O3 hollow microspheres was studied by XRD, SEM. The results show that the products were pure α-Fe2O3 with a hexagonal structure. And the microspheres with a diameter of 1-3μm were assembled by α-Fe2O3 nanoparticles (40-100nm), the surface of α-Fe2O3 hollow microspheres densified with the increasing of sucrose concentration. Above all, the gas sensing properties of the sensors based on the α-Fe2O3 hollow microspheres were investigated.

Synthesis and Gas-sensing Properties of α-Fe2O3 Hollow Microspheres

α-Fe2O3 hollow microspheres and nanorods were synthesized via a hydrothermal method using glucose and ethylenediaminetetraacetic acid (EDTA) as morphology controlled agents, followed by calcination at 500 °C for 4 h in air. The crystal structures of products were characterized by X-ray diffraction (XRD) and scanning electron microscope (SEM). The results show that the hollow microspheres with diameters of 1-2 μm are consist of nanoparticles (80-100 nm), and the nanorods have a structure in the diameter of 80-100 nm and length about 1 μm. Furthermore, the α-Fe2O3 hollow microspheres show higher gas response to ethanol than that of nanorods and nanoparticles.

Hydrothermal Synthesis and Gas Sensing Properties of α-Fe2O3 Hollow Microspheres and Nanorods

Structure and Photoluminescent Properties of ZnO Encapsulated in Mesoporous Silica SBA-15 Fabricated by Two-Solvent Strategy

A facile visible‐light‐assisted solution‐phase approach has been successfully developed to synthesize trigonal Te 1D nanostructures. By varying the relative amount of H2TeO3 and water‐soluble polymers, wirelike, beltlike, tubular Te, and Te nanoparticle‐joined 1D aggregates, as well as a novel thorny 1D assembly of Te nanothreads can be synthesized on a large scale. The diameter of the Te nanowires can be modulated by controlling the nucleation and growth process through modulation of the pH value of the reaction mixture. It is believed that the light irradiation and thermal effect play a significant role in this photothermally assisted technique. We have shown that the Te nanowires can be used as a template to prepare Pt–Te nanochains, where the composition of Pt in the Pt–Te 1D products can be modulated by adjusting the ratio of the Te nanowires and Pt salts. Preliminary optical investigations reveal that blue–violet emission of Te nanowires can be enhanced by the formation of defects or dislocations in the Te region through the galvanic replacement reaction between Te nanowires and H2PtCl6. In addition, we demonstrate that Te 1D nanostructures can be utilized to prepare Te at carbon‐rich nanocables and carbonaceous nanotubes. Te–Pt at carbon‐rich nanocables can also be fabricated using Te–Pt nanochains as the template. These Pt–Te nanochains and carbonaceous nanostructures are expected to find wide applications in electrochemistry, catalysis, fuel cells, sensors, and other fields. Furthermore, the successful preparation of Te 1D nanostructures with abundant shapes, Pt–Te nanochains, and their carbonaceous composite nanomaterials will offer great opportunities to explore the dependence of novel properties of nanomaterials on their morphology and composition, regulate the photoconductivity of semiconductors, and also be essential for the manufacture of potential optoelectronic devices.

1D Tellurium Nanostructures: Photothermally Assisted Morphology‐Controlled Synthesis and Applications in Preparing Functional Nanoscale Materials

This paper benchmarks the quality of project economic analysis in South Asia against other World Bank regions, using data on project exits between 1975 and 2015. The results show that the South Asia region performs on par with the other regions, in that the share of project documents that report estimated economic rates of return have declined from 70 to 36 percent for South Asia and the other regions. This finding suggests there is less attention to project economic analysis (especially for sectors where this has been a traditional practice, such as energy, transport, water, and agriculture). The finding also indicates that the incidence of reporting rates of return in project documents and the dispersion or difference between rates of return estimated at project appraisal and completion are significantly correlated with project performance (after correcting for country- and project-level variables). For the project-level variables, the task team effect is a key variable that explains project outcomes. The paper discusses the implications of the analyses for strengthening project performance and risk mitigation.

Political Economy - Development: Comparative Regional Economies eJournal

Special Study on Benchmarking the Quality of Project Economic Analysis for the South Asia Region

Disability income insurance (DI) and its pricing in mainland China is discussed with a focus on the current situation, market prospects, and the pricing process. Our study concludes that (1) there is a bright future for commercial DI, but current consumers are mainly urban residents with above-average incomes; (2) by combining health service data and experiences of the insured, one can calculate the premium rate by sex, region, and occupation; and (3) the price of DI should be higher in rural areas than in cities; the commercial DI premium rate is overpriced for people under 45, and underpriced for people over 45.

In order to analyze the influence factors of rural land circulation, based on theory analysis and empirical study, the results indicate that the farm households' behaviors result from kinds of factors. Contract land per person, non-agricultural income per person, agricultural members per family and the high school education are four main influence factors. According to the results, the paper gave some suggestions to improve rural land circulation.

The influence factors of rural land circulation based on farm households subtitle as needed

Unlike most other donors, IDA bases its country envelopes on a formal performance assessment, the Country Policy and Institutional Assessment (CPIA). This paper takes the CPIA instrument as given. It outlines the process of estimating country ratings with special reference to the (Sub-Saharan) Africa Region, and addresses a number of questions concerning (a) how the CPIA compares with other ratings, (b) the relationship between the CPIA and country performance, and (c) the likely errors of CPIA-type ratings and their implications for disclosure and performance-based allocation of development assistance. CPIA estimates are broadly correlated with the rankings of a number of other indicators, including the Kaufmann, Kraay and Zoido-Lobaton (KKZ) governance indicators and the Heritage Foundation's Economic Freedom Indicator. The closest association is found with the similar, but independently estimated, performance index of the African Development Bank. Comparing African countries as a group with others, we found no evidence of an Africa bias, either positive or negative, relative to other indicators. CPIA ratings have been quite strongly associated with medium-run growth performance. In Africa, over 1996-2002, high-rated CPIA countries typically grew 3-4 percent per year more than lower-rated countries. Countries increasing their CPIA ratings over a sustained period tend to experience a growth boost and those seeing a large decline in ratings tend to see a growth slowdown. The results do not conclusively prove causality. However, country-level changes in CPIA ratings are not associated with recent growth, suggesting that the CPIA score is not simply a mirror of observed performance.

Implementing performance-based aid in Africa: the country policy and institutional assessment

Malawi is a relatively small country with an estimated population of 11 million and a land size (excluding inland waters) of approximately 94 thousand square km. Malawi population accounts for 1.2 percent of total Sub-Saharan Africa population. Life expectancy is extremely low at 39 years and a HIV/AIDS (15-49 years) prevalence rate of about 16 percent. With the first democratically elected government in 1994, Malawi embarked on a new development initiative that had poverty alleviation as the central national policy objective. The government, I consultation with stakeholders, prepared the PRSP, dated 04/01/02. The Malawi Poverty Reduction Strategy Paper (MPRSP) emphasizes raising national productivity through sustainable broad-based economic growth and structural transformation, as well as sociocultural development.

Results of the local level institutions (LLI) action-research study give strong evidence that high-performing local level institutions will help reduce poverty and promote equitable development. Moreover, because LLIs depend upon internalized participation rather than any cultural asset of any one country, these institutions can exist across a number of countries. Combining the qualitative and quantitative analyses, key results are as follows. § Service-asset management groups (SAMs)one of three identified local level institutionshave been significant in lowering inequality. The quantitative analysis indicates that SAMs are linked with lower levels of inequality among LLI participating households, statistically significant at the 95 percent level. § SAMs are a fusion of l ong-standing development committees and indigenous management councils that collectively manage community assets. SAMs have combined the productivity goals of growth with the societal values of equity and solidarity. § Internalized participation is essential for SAMs to function. Evidently, only this kind of locally anchored participation can power the realignments and institutional revisions needed to scale-up development action. This means that LLI/SAMs have launched their communities on an equitable growth path, and are reducing poverty with little or no outside assistance all of this despite severe resource constraints. Clearly, if external development resources can augment this internal initiative and direction, the future impact can be enormous. LLI/SAMs differ in their approach on how to reduce poverty. Current development approaches use growth as a critical initiator, and assume that surpluses will be used to benefit the poor, thereby creating greater equity. SAM/ LLIs, on the other hand, reorder things to match both their values and resource constraints that is, solidarity and equity are the starting point, development and growth are the result. Recommendations for program and policy interventions The study suggests a three-step program package and a two-step policy package. Recent institutional changes in the World BankComprehensive Development Framework (CDF), Community Driven Development (CDD), and Poverty Reduction Strategy Papers (PRSP)provide a base for these initiatives. The program package includes the following: § Use LLI institutional mapping to guide new initiatives in pro-poor investment. § Use LLI mapping to formalize and increase internalized participation to quickly attain national coverage. § Use the LLI internal framework to guarantee long-term sustainability for community driven development and rural decentralization. The policy package focuses on two initiatives: § Working from LLI results, link PRSP participatory monitoring strategies to LLI/SAMs for accountability and transparency. § Working from LLI results, create …

LOCAL LEVEL INSTITUTIONS AND POVERTY ERADICATION : RURAL DECENTRALIZATION IN BURKINA FASO

ambia, which until two decades ago was one of the most prosperous countries in Sub-Saharan Africa, now ranks as one of the Least Developed Countries. Per capita GDP has shown a downward decline over the years since independence, which had the most telling effect on poverty in the country (PRSP 2002). Because poverty is concentrated in rural areas and land is abundant, agriculture is the main priority for future growth. Higher productivity mining and manufacturing

Kenya has been a relatively stable country since its independence in 1963, although there were serious political instigated ethnic clashes in the 1990. Kenyan population accounts for 4.6 percent of total Sub-Saharan Africa population, and the current HIV/AIDS prevalence is 13.9 percent. The PRSP report (September 2001) prepared by the Government of Kenya includes sustained and rapid economic growth; improved governance and security; increasing ability of the poor to raise their incomes, improving poor people's lives, and improving equity and participation. It is within this national planning framework that the government is preparing the PRSP action plan, given the budget constraints determined by economic performance. Based on the Kenya Welfare Monitoring Survey (WMS) III, poverty was estimated at 52 percent in 1997. The Millennium Development Goals (MDGs) had called for cutting poverty in half between 1990 and 2015. However, the decade of the 1990s is a lost opportunity, with an average negative GDP per capita growth rate.

Backwardness on construction of community environment has become \!the bottleneck\" of restriction to the community life. How to create a whole set of institutional arrangement with the feature of \!human\|orientated\" tendency and significance of innovation on community level in order to meet the further requirement of residents on quality of community environment will be the key issue of community construction for the metropolis in the near future. A review of community environment from ecological aspect is one area that has to be strengthened for community work. Community ecology could be regarded as an interactive phenomenon between residents and living environment while residents are behavioral subjects. To be specific, they could be divided into three ecological layers of basearea environment, community or neighboring environment and residential environment.

An Economic Analysis on Environmental Construction of Communities——With a case of study on Wuliqiao Street in Shanghai

Using primary data from the health and education ministries, and household survey data from the Ghana Statistical Service, the authors analyze equity, and efficiency issues in public spending on health, and education in Ghana in the 1990s. Public expenditures in the education sector, declined in the second half of the 1990s. Basic education enrollment has been stagnant, or declining in public schools, but increasing in private schools, resulting in a moderate increase in total enrollment. Regional disparities are significant, with lower public resource allocations, and lower enrollment ratios in the three poorest regions. The quality of basic education in public schools remains poor, while it has steadily improved in private schools. Enrollments in higher levels are lagging behind those in basic education. Ghana ranks high among West African countries in health indicators, although its health expenditures tend to favor the non-poor. While more of the rural population have gained access to health services in recent years, many still have limited access, or none. Moreover, there is no link between the pattern of public expenditures - especially the pattern of immunization across Ghana - and health outcomes. To ensure that social services are efficiently, and equitably delivered in a fiscally constrained economy, the authors argue, public expenditures need to be linked to outcomes.

Public Health and Education Spending in Ghana in 1992-98: Issues of Equity and Efficiency

Issues in Comparing Exploring poverty trends across regions and Poverty Trends Over Time

Public Health and Education Spending in Ghana in 1992-98: Issues of Equity and Efficiency. Working Paper No. 2579.

The authors present evidence that in Burkina Faso, certain high-performing local institutions contribute to equitable economic development. They link reduced levels of poverty, and inequality to a high degree of internal village organization. The structure of these high-performing local organizations means they can exist in a number of African countries, because they depend more on internal participation, rather than on nay one country's cultural assets. The authors find that: 1) Service-asset management groups (SAMs) - one of three local institutions identified in the study - have helped to significantly reduce inequality in participating households. SAMs are a fusion of long-standing development committees, and indigenous management councils that collectively manage community assets, such as water. SAMs have combined the productivity goals of growth, with the values of equity, and solidarity. 2) Current development approaches use growth as an initiator, assuming that surpluses will be used to benefit the poor. SAMs, and other local institutions in Burkina Faso, start with equity, and solidarity, and aim for a result of growth, and development. 3) Internal participation is essential for SAMs to function. Only locally anchored participation can power the realignments, and institutional revisions needed to scale up development action. SAMs, and other local institutions have launched their communities on equitable growth paths, and are reducing poverty with little, or no outside assistance, despite severe resource constraints. Their impact could be enormous if external development resources augmented their potential. World Bank programs, and policy interventions could build on local strength, and make their activities more sustainable by mapping local institutions to guide new initiatives in pro-poor investment, and using that mapping to formalize, and increase internal local participation - expanding nationwide by using a network of local institutions. SAMs, and other local institutions, could be the vehicle for ensuring transparency, and accountability. Working with the results of local activities, national policies could favor the development of indigenously based, but externally oriented local economies.

Can Local Institutions Reduce Poverty? Rural Decentralization in Burkina Faso

Using three rounds of the Ghana Living Standard Survey, conducted between 1988 and 1992, the authors present findings that shed light on the structure of inequality among different socioeconomic groups in different geographic areas, in the context of poverty reduction. First, poverty reduction can be attributed mainly to improvements in both average levels of income and the pattern of its distribution in the informal and nonfarm sectors in other cities and rural areas outside the capital city, Accra. Second, an analysis of different measures of inequality reveals that the most important changes in the degree of inequality took place at the lower end of the distribution. But the direction of change was different in Accra compared with the localities outside Accra. In Accra, while inequality increased overall, the inequality in the lower part of the distribution increased much more. In other cities, there was a more or less uniform improvement all along the distribution. But in the rural areas, there was a significant improvement at the lower end, but a deterioration at the upper end. Third, structural adjustment - which aimed to cut back public sector employment and stimulate activities in the private sector - raised living standards in rural areas and other cities, but not in Accra. The public sector is much larger in Accra than in other cities and rural areas. Contraction of the public sector in other cities and rural areas was compensated for by income growth in the informal and nonfarm sectors. But contraction of Accra's large public sector dominated the local economy, so living standards declined in both formal and informal sectors. Accra's economy will probably grow as its private and informal sectors grow. Fourth, major shifts in the population occurred in all localities from the formal to the informal sector, but the magnitude of the shift was largest in Accra - in fact, several times more than in the other localities. The deterioration of the income at the lower part of the distribution in both the formal and the informal sectors is mainly responsible for the decline in the welfare of the low income households in Accra. These findings suggest that an integrated regional strategy, taking into account the local socioeconomic structure, is necessary for achieving economic growth and poverty reduction in all regions. Another important finding: The poor do not benefit as much from education as the nonpoor do because there is very low return (in income) to primary education, the highest level most poor Ghanaians can hope for. Education helps increase, rather than decrease, inequality, so primary education for the poor should be designed to provide them with income-earning skills. Developing economic strategies for sustainable poverty reduction will require further research on activities in the informal sector. Another issue that requires investigation is the role of different administrative regions in the determination of household welfare that seems to have changed over the period under study. Findings from such an analysis will facilitate the design of appropriate regional strategies for poverty reduction in Ghana.

The Structure and Determinants of Inequality and Poverty Reduction in Ghana, 1988-92

This paper argues that China's rural enterprise are currently undergoing a second phase in transformation. In contrast to the first-phase transformation, which involved shifts in user rights, the second phase has been characterized by the transfer of asset rights from the collectives to local corporate leaders. The process was accelerated particularly after the Chinese Communist Party's Fifteenth National Congress which opened the door for diversified forms of public ownership. The argument is supported by a case study conducted in an enterprise in Daqiuzhuang in rural Tianjin. The case clearly shows that toward the end of the first phase, the enterprise transformed itself from a collectively-owned entity into a shareholding system. Yet, the asset ownership was not tied to share. Since September 1997, however, this ownership has been tied to shared, remaining nominally public, as the majority of the shares remain under control of the local community, the enterprise, and other cooperative enterprises. In essence we see a dramatic increase of shares controlled by corporate leaders in the new ownership structure, as they sever as representatives of the community and enterprise shares and own a substantial portion of the individual shares. It is argued that the ultimate objective of this transformation is to move the control of enterprise assets into the hands of corporate leaders. We also speculate, based on available information, that this phenomenon is not idiosyncratic to Daqiuzhuang but is rather a nationwide trend currently under way in China's rural enterprises.

Chinese Rural Enterprises in Transformation: The End of the Beginning

This note explores some of the factors that need to be taken into account in designing surveys, and in comparing poverty indicators over time for effective poverty monitoring. Cote d'Ivoire presents a number of household surveys that should, in principle, allow monitoring changes in poverty over time, including household surveys conducted in 1993 and 1995. Problems of comparability are highlighted, as are issues in generating poverty data, in order to be compared reliably. Serious problems that arouse from four main sources were: estimates of input housing expenditure, the effects of seasonality on household expenditure patterns, the method used to estimate purchased food expenditure, and, the deficiencies of the consumer price index.

The effect of per capita income growth on nutrient intake in less developed countries (LDCs) has been a subject of controversy in the nutrition economics literature. Income can influence nutrient intake in two ways: first, by affecting the quantity of nutrients consumed, and second, by affecting nutrient sources. Empirical studies have produced conflicting findings with regard to the magnitude of income (or food expenditure) elasticities of nutrient demand, even when income elasticities of food expenditure are high. In this article we present econometric estimates of food and nutrient intake elasticities for a prosperous area in northern China. For this purpose we use a structural model that controls for the endogeneity of nutrient costs. Our estimates of income elasticities of food and nutrient demand reveal that the relative contribution of grains to calorie and protein intake declines at higher incomes. Although income elasticities of total protein intake are low, the food-expenditure elasticity of animal protein intake is relatively high, implying a switch to more expensive protein sources as food expenditure rises. However, even in this relatively prosperous area, grain is still the major source of calorie and protein intake for the majority of households. We also find that consumers switch to higher-priced nutrients within food categories (e.g., from wheat flour to noodles) as their incomes increase. There is evidence that the income elasticity of nutrient prices is not always positive, however. We offer an explanation for the negative elasticities observed for some food items. Soybean consumption is surprisingly low in this area, which may be due to the fact that the soybean marketing infrastructure is weak and that the area does not produce soybeans.

The Impact of Income Growth on Farm Household Nutrient Intake: A Case Study of a Prosperous Rural Area in Northern China

Income Growth And Nutrient Intake In A Prosperous Rural Area Of Northern China

This paper deals with an initial-boundary value problem of the planar
compressible Hall-magnetohydrodynamic (for short, Hall-MHD) equations.
For the fixed shear viscosity and Hall coefficients, it is shown that
the strong solutions of Hall-MHD equations and corresponding MHD
equations are global. As both the shear viscosity and the Hall
coefficients tend to zero, the convergence rate for the solutions from
Hall-MHD equations to MHD equations is given. The thickness of boundary
layer is discussed by spatially weighted estimation and the
characteristic of boundary layer is described by constructing a boundary
layer function.

On vanishing limits of the shear viscosity and Hall coefficients for the planar compressible Hall-MHD system

This paper deals with an initial‐boundary value problem of the planar compressible Hall‐magnetohydrodynamic (for short, Hall‐MHD) equations. For the fixed shear viscosity and small Hall coefficients, we obtain the existence of long‐time strong solutions of Hall‐MHD equations and corresponding MHD equations. As both the shear viscosity and the Hall coefficients tend to zero, the convergence rate for the solutions from Hall‐MHD equations to MHD equations is given. The thickness of boundary layer is discussed by spatial weighted estimate and the characteristic of boundary layer is described by constructing a boundary layer function.

On vanishing limits of the shear viscosity and Hall coefficients for the planar compressible Hall‐MHD system

On the vanishing limits of the resistivity coefficient for one-dimensional compressible MHD with vacuum

Global strong solutions of the 2D tropical climate system with temperature-dependent viscosity

The Behavior of Boundary Layer for the Compressible Planar MHD Equations at Small Shear Viscosity

Boundary-layer phenomena for the boundary layer for the heat-conductive incompressible viscous fluids in the half space

Global strong solutions of the tropical climate model with temperature-dependent diffusion on the barotropic mode

ZAMM ‐ Journal of Applied Mathematics and Mechanics / Zeitschrift für Angewandte Mathematik und Mechanik

The zero limit of thermal diffusivity for the 2D density‐dependent Boussinesq equations with vacuum

Global well-posedness for the density-dependent incompressible magnetohydrodynamic flows in bounded domains

Global regularity for the 3D MHD system with partial viscosity and magnetic diffusion terms

Global Existence of Heat-Conductive Incompressible Viscous Fluids

Global well-posedness for the incompressible MHD equations with density-dependent viscosity and resistivity coefficients

Global Well-Posedness for the Heat-conductive Incompressible Viscous Fluids

On the behavior of boundary layers of one-dimensional isentropic planar MHD equations with vanishing shear viscosity limit

This paper concerns the asymptotic behavior of the solution to an initial-boundary value problem of the cylindrically symmetric Navier–Stokes equations with large data for compressible heat-conducting ideal fluids, as the shear viscosity μ goes to zero. A suitable corrector function (the so-called boundary-layer type function) is constructed to eliminate the disparity of boundary values. As by-products, the convergence rates of the derivatives in L2 are obtained and the boundary-layer thickness (BL-thickness) of the value O(μα) with α∈(0,1/2) is shown by an alternative method, compared with the results proved in Jiang and Zhang (2009 SIAM J. Math. Anal. 41 237–68) and Qin et al (2015 Arch. Ration. Mech. Anal. 216 1049–86).

Boundary-layer phenomena for the cylindrically symmetric Navier–Stokes equations of compressible heat-conducting fluids with large data at vanishing shear viscosity

On the vanishing shear viscosity limit and the boundary layers for the full perfect MHD equations with large data

This paper is concerned with an initial and boundary value problem of the one-dimensional planar MHD equations for viscous, heat-conducting, compressible, ideal polytropic fluids with constant transport coefficients and large data. The vanishing shear viscosity limit is justified and the convergence rates are obtained. To capture the behavior of the solutions at small shear viscosity, we also discuss the boundary-layer thickness and the boundary-layer solution. As by-products, the global well-posedness of strong solutions with large data is established. The proofs are based on the global (uniform) estimates which are achieved by making a full use of the "effective viscous flux", the material derivatives and the structure of the one-dimensional equations. Moreover, the lower positive bound of the density is obtained by using some new ideas, which are rather different from those in the existing literature.

Vanishing shear viscosity limit and boundary layer for the one-dimensional full compressible MHD equations with large data

A new regularity criterion for the Navier-Stokes equations via partial components of the fractional derivative

Existence and decay of global smooth solutions to the coupled chemotaxis–fluid model

We report an amino acid salt-catalyzed direct desymmetrization of 3-substituted cyclobutanones through a direct aldol reaction under mild reaction conditions. The developed method provides an array of highly functionalized cyclobutanones bearing three contiguous stereogenic centers in high yields and stereoselectivities with varied functional-group compatibility. Furthermore, the obtained adducts can be smoothly converted into polyfunctional 1,4-butyrolactones with maintained enantioselectivity.

Asymmetric Construction of Highly Functionalized Cyclobutanones Bearing Three Contiguous Stereogenic Centers by an Amino Acid Salt-Catalyzed Desymmetrization Reaction

A "smart" receptor has been newly synthesized. NMR studies demonstrated that the receptor functions as a chiral shift reagent that is highly effective for determining the enantiomeric purity of a series of carboxylic acids, particularly those that have an α-oxygen atom.

A novel amine receptor based on the binol scaffold functions as a highly effective chiral shift reagent for carboxylic acids.

(1)H NMR, in situ, determines the enantiomeric excess of reduced chiral alcohols or amines without adding any auxiliary and workup. The percent ee data determined by this method agree well with those given by HPLC. This approach may be potentially applicable to many asymmetric reductions.

In situ measurement of the enantiomeric excess of alcohols and amines under asymmetric reduction reaction by 1H NMR.

A series of novel 6-aryl-3-(1,2,3,4-tetrahydroxybutanol-1-yl)-7H-1,2,4-triazolo[3,4-b][1,3 ,4]thiadiazines were easily synthesized in high yields by means of the reactions of 4-amino-5-(1,2,3,4-tetrahydroxybutyl)-2,4-dihydro-3H-1,2,4-triazole-3-th ione (1) with substituted omega-bromoacetophenones or omega-chloroacetophenone. Nearly all of the title compounds possess plant growth-promoting activities.

A Convenient Synthesis and Biological Activities of Novel 6-Aryl-3-( 1,2,3,4-tetrahydroxybutan-1 -yl)-7H-1,2,4-triazolo-[3,4-b][ 1,3,4]thiadiazines

A Convenient Synthesis and Biological Activities of Novel 6‐Aryl‐3‐(1,2,3,4‐tetrahydroxybutan‐1‐yl)‐7H‐1,2,4‐triazolo[3,4‐b] [1,3,4]thiadiazines.

C18H18N4OS, monoclinic, P2(1)/c (no. 14), a = 7.778(2) angstrom, b = 15.453(5) angstrom, c = 14.621(4) angstrom, beta = 91.108 degrees, V = 1757.0 angstrom(3), Z = 4, R-gt(F) = 0.066 wR(ref)(F-2) = 0.134, T = 298 K.

Crystal structure of 3-(2-ethoxyphenyl)-4-(1-phenylethylidene)amino- 1H-1,2,4-triazole-5-thione, C18H18N4OS

A series of novel 6-aryl-3-(D-glucoheptonic-hexitol-1-yl)-7H-1,2,4-triazolo[3,4-b][1,3,4] thiadiazines (2a–2j) have been synthesised in high yield by means of the reaction of 4-amino-5-mercapto-3-(D-glucoheptonic-hexitol-1-yl)-1,2,4-triazole (1) with substituted ω-brom- oacetophenones. The structures of the compounds were determined by elemental analysis, IR, 1H NMR, 13C NMR and MS. Most possessed high plant growth-regulating activities.

The Synthesis and Biological Activities of 6-aryl-3-(D-glucoheptonichexitol-1-yl)-7H-1,2,4-triazolo[3,4-b][1,3,4]Thiadiazines

Some novel 1, 2, 4‐triazolo[3,4‐b][1,3,4]thiadiazines derivatives were synthesized. The complete 1H and 13C NMR chemical shift assignments were analyzed on one‐ and two‐dimensional NMR techniques, including DEPT, NOE‐DIF, COSY, HMBC, and HSQC. Copyright © 2006 John Wiley & Sons, Ltd.

1H and 13C NMR spectral characterization of some novel 7H‐1,2,4‐triazolo[3, 4‐b] [1,3,4] thiadiazine derivatives

We have synthesized a number of novel Schiff's bases from 4-amino-3-(D-glucoheptonic-hexitol-1-yl)-1H-1,2,4-triazole-5-thione. By attaching D-glucoheptonic-hexitol-1-yl residues to 1,2,4-triazole at the 3-position, the solubility of the title compounds has been improved greatly. All the products have been characterized by elemental analysis, IR, 1H-NMR, 13C-NMR and MS. The plant-growth regulating effects of the title compounds were examined. From the biological activity results, we found that most compounds showed weak to moderate activities.

Synthesis and biological evaluation of some novel Schiff's bases from 1,2,4-triazole.

Synthesis and Biological Activities of 6‐Aryl‐3‐(D‐glucoheptonic‐hexitol‐1‐yl)‐7H‐1,2,4‐triazolo[3,4‐b] [1,3,4]thiadiazines.

L-Pipecolinic acid derived formamides have been developed as highly efficient and enantioselective Lewis basic organocatalysts for the reduction of N-aryl imines with trichlorosilane. Catalyst 4b afforded high isolated yields (up to 98%) and enantioselectivities (up to 96%) under mild conditions with an unprecedented substrate spectrum.

A highly enantioselective lewis basic organocatalyst for reduction of N-aryl imines with unprecedented substrate spectrum.

Ketimine Reduction Employing a Pipecolic Acid Derived Organocatalyst

Das Bam-Erdbeben 2003: Präzise Herdparameterbestimmung mit Hilfe der differentiellen Radar-Interferometrie

This paper describes an optimization method for the design of two-dimensional (2-D) recursive digital filters that meet simultaneously magnitude and group delay specifications. The numerator in the filter is expressed in terms of a mirror-image polynomial, the denominator is represented by a set of parameters q, (i = 1, 2, . . . , 10) so that the filter stability is always guaranteed. This makes it possible to design the denominator and numerator separately. Using design centering the objective function may be discontinuous and concave. Für die Dokumentation: Zweidimensionale digitale Filter / Entwurfszentrierung / Optimierung / Spiegelpolynom 1. Einlei tung Das 2-D-Filter hat seine Anwendung auf dem Gebiet der Bildverarbeitung gefunden. Ein Bild kann durch eine zweidimensionale Helligkeitsfunktion 61(x, >·) dargestellt werden, wobei (x, y) die Ortskoordinaten sind. Sehr oft ist die Helligkeit durch Rauschen gestört. Deshalb soll das Rauschen durch ein Filter so gut wie möglich unterdrückt werden. Mit der Impulsantwort h(x, >·) des Filters ist die Helligkeit b2(x, y) am Ausgang die Faltung von bl (x, y) und h(x, y). D.h. es ist b2(x,y)= J J U~ — CO 17= — 00

Optimierung von zweidimensionalen digitalen Filtern mit Hilfe der Entwurfszentrierung

Programm zur Berechnung der quasi-dreidimensionalen Strömung durch Diagonalventilatoren

Two new flavonoid-triterpene saponin meroterpenoids from Clinopodium chinense and their protective effects against anoxia/reoxygenation-induced apoptosis in H9c2 cells.

Abstract Two metal-organic coordination polymers constructed from tris(p-carboxylphenyl)phosphine oxide (TPOH3), namely, [Zn(TPOH)(2,2′-bipy)(H2O)·H2O·DMF]n (1) and [Zn2(TPOH)2(1,4-bix)2·5H2O]n (2) (2,2′-bipy=2,2′-bipydine, 1,4-bix=1,4-bis(imidazol-1-ylmethyl)benzene), were synthesized and identified by IR, elemental analysis and single-crystal X-ray diffraction analysis. Both of the 2,2′-bipy and 1,4-bix ligands tailor the complexes 1 and 2 into chain structures. The thermal behavior and solid state photoluminescence properties correlated with the corresponding structural features were investigated.

Two 1D zinc coordination polymers based on tris(p-carboxylphenyl)phosphine oxide: syntheses, structures and photoluminescence properties

Twenty-eight compounds were isolated and purified from Clinopodium chinense by Sephedax LH-20, ODS, MCI and preparative HPLC. Their structures were identified as apigenin (1), apigenin-7-O-β-D-glucopyranoside (2), apigenin-7-O-β-D-glucuronopyranoside (3), thellungianol (4), apigenin-7-O-β-D-rutinoside (5), luteolin (6), luteolin-4'-O-β-D-glucopyranoside (7), apigenin-7-O-β-D-pyranglycuronate butyl ester (8), luteolin-7-O-β-D-rutinoside (9), luteolin-7-O-β-D-noehesperidoside (10), acacetin (11), acacetin-7-O-β-D-glucuronopyranoside (12), buddleoside (13), naringenin (14), pruning (15), nairutin (16), isosakuranetin (17), isosakuranin (18), didymin (19), hesperidin (20), kaempferol (21), quercetin (22), kaempferol-3-O-α-L-rahmnoside (23), p-hydroxycinnamic acid (24), caffeic acid (25), cis-3-[2-[1-(3,4-dihydroxy-phenyl)-1 -hydroxymethyl]-1,3-ben-zodioxol-5-yl]-(E)-2-propenoic acid (26), mesaconic acid (27), gentisic acid 5-O-β-D-(6'-salicylyl)-glucopyranoside (28). Among them, compounds 7, 9-10, 12, 23, 26-28 were isolated from the Clinopodium for the first time. The protective effects of compounds 1-6, 8-17 and 19 against H2O2-induced H9c2 cardiomyocyte injury were tested, compounds 15 exhibited significantly protective effects. Compared with the cell viability of (62.12±6.18)% in the model, pruning exhibited viabilities of (84.25±7.36)% at 25.0 mg•L⁻¹, respectively, using quercetin as a positive control [cell viability of (84.55±8.26)%, 20 mg•L⁻¹].

Abstract Two new tetracyclic triterpenoids, together with 21 known compounds, were isolated from the barks of Melia azedarach. The structures of new compounds were elucidated by the means of HRESIMS, 1D NMR, 2D NMR, and X-ray crystallography analysis.

Two new tetracyclic triterpenoids from the barks of Melia azedarach

A facile and efficient method has been developed for the preparation of seven-membered heterocycles 1,5-benzoxazepines by MeSiCl3/DMF-catalyzed domino reaction via the addition of in situ generated enamines to aldehydes . The advantages of this method are that it operates easily and achieves good yields for a broad scope of aldehyde substrates. And the corresponding products can be readily transformed to other categories of compounds, such as the hydrogenated products , which may have potential application in drug industry.

A Facile and Efficient Approach to Seven‐membered Heterocycles by Chlorosilane‐catalyzed Domino Reaction

The title compound, C30H48O2, contains a fused four-ring triterpenoid system. In the molecule, the two cyclohexane rings adopt a chair conformation and a twist boat conformation, respectively, the central cyclohexene ring adopts a half-chair conformation whereas the five membered ring adopts an envelope conformation. In the crystal, O—H⋯O hydrogen bonds between the hydroxy and carbonyl groups of adjacent molecules link the molecules into supramolecular chains propagating along the b-axis direction.

Acta Crystallographica Section E: Crystallographic Communications

The title compound, C19H20O5, is approximately planar; the dihedral angle between the benzene rings is 3.82 (8)°, and the central propenone C(=O)—C=C plane makes dihedral angles of 1.95 (10) and 3.17 (11)° with the two benzene rings. In the crystal structure, intra- and intermolecular C—H⋯O hydrogen bonds are observed.

Investigation and Experimental Study on Gearbox Vibration Fault Diagnosis Method Based on Fusion Feature Convolutional Learning Network

The healthy and reliable operation of relay protection devices is of great significance for improving the safe and stable operation of the power grid. Defect analysis of relay protection devices relies on manual experience. Defect diagnosis takes a long time, which leads to a long time exit of protection during defect. The existing intelligent defect diagnosis methods are carried out on a case-by-case basis, which limits the wide-scale application. This paper proposes a fault diagnosis method for relay protection devices based on Bayesian theory, establishes the correlation between the typical fault phenomenon of relay protection device and the defect diagnosis result, and derives the most likely defect result based on the defect phenomenon, with satisfactory defects diagnosis accuracy rate, which plays an important role for operators to quickly diagnose relay protection defects and improves the reliable operation status of protection devices. A practical example is used to verify the effectiveness of the method in this paper.

Intelligent diagnosis method of relay protection defects based on Bayesian theory

The manual feature extraction of the traditional method for vehicle license plates has no good robustness to change in diversity. And the high feature dimension that is extracted with Principal Component Analysis Network (PCANet) leads to low classification efficiency. For solving these problems, a method of vehicle license plate recognition based on PCANet and compressive sensing is proposed. First, PCANet is used to extract the feature from the images of characters. And then, the sparse measurement matrix which is a very sparse matrix and consistent with Restricted Isometry Property (RIP) condition of the compressed sensing is used to reduce the dimensions of extracted features. Finally, the Support Vector Machine (SVM) is used to train and recognize the features whose dimension has been reduced. Experimental results demonstrate that the proposed method has better performance than Convolutional Neural Network (CNN) in the recognition and time. Compared with no compression sensing, the proposed method has lower feature dimension for the increase of efficiency.

A method of vehicle license plate recognition based on PCANet and compressive sensing

The construction of smart grid has inevitably become the direction of the development of the power grid, and the use of data mining technologies to improve the level of data analysis is an important part of the construction of smart grid. In power grid scheduling, as the basis for the dispatcher to record the operation status of the power grid, the scheduling log usually uses short text to record the current state of the power grid, accident handling and abnormal alarm. However, it is lack of further analysis of the log. Aiming at the automatic classification of power grid dispatching log faults, we firstly use the custom power word and word segmentation tool to preprocess the text. After obtaining the TF-IDF feature of the text and creating the Word2Vec feature model, we compare three kinds of text classification algorithms, the nearest neighbor algorithm, Naive Bayes and support vector machine respectively. It is found that the support vector machine method is very effective in classification with a correct rate of 93% in the log short text.

Fault Classification Method for Power Dispatching Log Based on Text Mining

Hydrogen bonded-directed pure organic frameworks based on TTF-tetrabenzoic acid and bipyridine base

Anaerobic digestion of waste activated sludge was conducted to gain insight into the mechanisms underlying change in sludge dewaterability during its anaerobic digestion. Unexpectedly, the results indicated that sludge dewatering properties measured by capillary suction time only deteriorated after 10 days of anaerobic digestion, after which dewaterability recovered and remained stable. The loosely bound extracellular polymeric substance (LB-EPS) content increased three-fold after 20 days of anaerobic digestion, and did not change significantly during the remaining 30 days. The tightly bound EPS (TB-EPS) content reduced slightly after 20 days of anaerobic digestion, and stabilized during the last 30 days. Polysaccharides (PS) and proteins (PN) content in LB-EPS increased after 10 days of anaerobic digestion. However, PS and PN contents in TB-EPS decreased slightly. The relationship analysis showed that only LB-EPS correlated with dewaterability of the sludge during anaerobic digestion.

Water science and technology : a journal of the International Association on Water Pollution Research

Extracellular polymeric substances and dewaterability of waste activated sludge during anaerobic digestion.

The effects of microwave irradiation on filterability and dewaterability of waste activated sludge measured by capillary suction time (CST) and dry solids in sludge cake were investigated. The results showed that the optimum irradiation time improved filterability, but that further increase of the time was detrimental. Dewaterability was enhanced significantly and increased with microwave time. Filterability and dewaterability were improved 25 to 28% and 1.3 times at the optimum times of 30 and 90 seconds for the sludge of 5 g total suspended solids (TSS)/L and 7 g TSS/L, respectively. The floc size decreased slightly. Loosely bound extracellular polymeric substances (LB‐EPS) decreased under optimum time, but tightly bound extracellular polymeric substances did not change significantly after short irradiation time. The results implied that LB‐EPS played a more important role in the observed changes of filterability and dewaterability and that the double‐layered extracellular polymeric substances extraction method showed marked implications to dewaterability.

Effects of Microwave Irradiation on Dewaterability and Extracellular Polymeric Substances of Waste Activated Sludge

Effect of potassium ferrate on disintegration of waste activated sludge (WAS).

This paper examines the chemical constituents of extracellular polymeric substances (EPS) and physicochemical properties of eight different sludge flocs from seven full-scale wastewater treatment plants. The physicochemical properties included floc properties (floc size, turbidity and effluent suspended solids (ESS) content of the supernatant), sludge volume index, capillary suction time and specific resistance to filtration. The relationships between the chemical constituents of EPS and the flocculation, settleability and dewaterability of sludge flocs were also assessed. The results showed that higher amounts of EPS were found in the municipal sludge flocs than in the industrial sludges. The content of tightly bound EPS (TB-EPS) was much greater than that of loosely bound EPS (LB-EPS). The amounts of total EPS, LB-EPS, TB-EPS and protein in LB-EPS were strongly related to ESS. The ratios of total protein to EPS and total carbohydrate to EPS showed positive correlation to the flocs size. It was surprising that there was no correlation between settleability or dewaterability and the chemical constituents of EPS.

Investigation of extracellular polymer substances (EPS) and physicochemical properties of activated sludge from different municipal and industrial wastewater treatment plants

Effects of potassium ferrate on extracellular polymeric substances (EPS) and physicochemical properties of excess activated sludge.

Effect of C/N ratio on extracellular polymeric substances (EPS) and physicochemical properties of activated sludge flocs.

Influences of influent carbon source on extracellular polymeric substances (EPS) and physicochemical properties of activated sludge.

This paper compared four parameters evaluating the dewaterability of sludge—capillary suction time (CST), specific resistance to filtration (SRF), bound water content, and dry solids content in the centrifuged sludge cake of the different sludge flocs from seven full‐scale wastewater treatment plants. The dry solids content correlated with the normalized CST (R2 = 0.7112, p = 0.003), SRF (R2 = 0.6043, p = 0.011), and the bound water content (R2 = 0.8106, p = 0.001). The normalized CST was correlated significantly with SRF (R2 = 0.9450, p = 0.000) and correlated with the bound water (R2 = 0.5110, p = 0.0417). However, SRF correlated very weakly with the bound water (R2 = 0.3929, p = 0.0448). It is not necessary to use both CST and SRF at the same time to estimate the sludge dewaterability. The normalized CST is feasible because of its affordability, simple equipment, and measurement procedure. However, another parameter indicating the dewatering extent, such as dry solids content in sludge cake, should be applied together to evaluate the dewatering efficiency of the activated sludge.

Comparative Investigation of Parameters for Determining the Dewaterability of Activated Sludge

Response to “Technical comments on “Oxic-settling-anoxic (OSA) process combined with 3,3′,4′,5-tetrachlorosalicylanilide (TCS) to reduce excess sludge production in the activated sludge system” by Fenxia Ye and Ying Li (doi:10.1016/j.bej.2010.01.001)”

Oxic-settling-anoxic (OSA) process combined with 3,3′,4′,5-tetrachlorosalicylanilide (TCS) to reduce excess sludge production in the activated sludge system

Deodorization of swine manure slurry using horseradish peroxidase and peroxides.

Enhancement of nitrogen removal in towery hybrid constructed wetland to treat domestic wastewater for small rural communities

The activated sludge process is a core technology in wastewater treatment plants. Excess sludge produced in the process must be treated and disposed of properly and may account for up to 60% of total plant operating cost. Therefore, it is necessary to develop new biological concepts to minimize excess sludge production. The oxic-settling-anoxic process (OSA process), a modified activated sludge process, may produce less excess sludge than the conventional activated sludge process. The effect of sludge retention time in the sludge holding tank of the OSA process on excess sludge yield has been studied. Four pilot-scale activated sludge systems were employed, one of which was a conventional activated sludge process, and was used as the control system. The other three were OSA systems operated with different sludge retention times (5.5 h, 7.6 h, and 11.5 h) in the sludge holding tank. All systems were operated with synthetic wastewater for 7 months. Results showed that the three OSA processes with 5.5 h, 7.6 h, and 11.5 h sludge retention time reduced the excess sludge by 33%, 23% and 14%, respectively. Compared to the control process, chemical oxygen demand (COD) removal efficiency and effluent NH3–N concentration were not significantly influenced, but total nitrogen (TN) removal efficiency decreased by 0–9%. Total phosphorus (TP) removal efficiency of OSA processes with 7.6 h and 11.5 h sludge retention time increased by 19%. Sludge settleability was excellent in the three OSA processes. No distinct shift in the diversity of the predominant species was found in microbial populations. We conclude that the OSA system could reduce excess sludge production. Results suggest 6–7 h sludge retention time would be optimal. Copyright © 2007 Society of Chemical Industry

Effect of sludge retention time in sludge holding tank on excess sludge production in the oxic-settling-anoxic (OSA) activated sludge process

Biosorption and biodegradation of pentachlorophenol (PCP) in an upflow anaerobic sludge blanket (UASB) reactor

Reduction of excess sludge production by 3,3′,4′, 5-tetrachlorosalicylanilide in an activated sludge process

Advanced start-up of anaerobic attached film expanded bed reactor by pre-aeration of biofilm carrier.

Uncoupled metabolism stimulated by chemical uncoupler and oxic-settling-anaerobic combined process to reduce excess sludge production

Acclimation of anaerobic sludge degrading chlorophenols and the biodegradation kinetics during acclimation period.

Anaerobic granule development for removal of pentachlorophenol in an upflow anaerobic sludge blanket (UASB) reactor

Aims: To investigate the possibility of reducing excess sludge production in activated sludge processes by the addition of chemical uncouplers to greatly dissociate anabolism from catabolism.

Reduction in excess sludge production by addition of chemical uncouplers in activated sludge batch cultures

To determine whether chemical additions can be used to reduce sludge production in biological wastewater treatment, 3,3',4',5-tetrachlorosalicylanilide (TCS), served as a metabolic uncoupler was added to activated sludge cultures. The batch tests have confirmed that TCS is an effective chemical uncoupler in reducing the sludge yield when its concentration is higher than 1.0 mg/L. It was showed that TCS was able to reduce sludge yield by approximately 50% when the TCS concentration was 6.0 mg/L. It was also revealed that substrate removal capability and effluent nitrogen concentration were not affected adversely by the presence of TCS when TCS was dosed every other day in a range of 2.0-3.6 mg/L during the 40 d operation of activated sludge batch cultures. Such a sludge growth reduction is associated with the enhancement of microbial activities in terms of the SOUR and dehydrogenase activity. Sludge settleability from the treated and control samplers was comparable and not significantly different. Meanwhile, there was a finding that the filamentous bacteria still grow in sludge floc in the control reactor after 40 d operation. These results suggested that it might be possible to apply TCS in activated sludge systems to reduce the excess sludge yield.

[The use of chemical uncoupler to reduce sludge yield in activated sludge process].

STUDY QUESTION
Is CDC26 a key factor in human oocyte aging?

SUMMARY ANSWER
The lack of CDC26 disrupts the oocytes maturation process, leading to oocyte aging, but these defects could be partially rescued by overexpression of the CDC26 protein.

WHAT IS KNOWN ALREADY
Age-related oocyte aging is the main cause of female fertility decline. In mammalian oocytes, aberrant meiosis can cause chromosomal abnormalities that might lead to infertility and developmental disorders. CDC26 participates in the meiosis process.

STUDY DESIGN, SIZE, DURATION
Differential gene expression in young and old women oocytes were screened by single-cell RNA-seq technology, and the functions of differentially genes were verified on mouse oocytes. Finally, transfection technology was used to evaluate the effect of a differentially expressed gene in rescuing human oocyte from aging.

PARTICIPANTS/MATERIALS, SETTING, METHODS
Discarded human oocytes were collected for single-cell RNA-seq, q-PCR and immunocytochemical analyses to screen for and identify differential gene expression. Female KM mice oocytes were collected for IVM of oocytes, q-PCR and immunocytochemical analyses to delineate the relationships between oocyte aging and differential gene expression. Additionally, recombinant lentiviral vectors encoding CDC26 were transfected into the germinal vesicle oocytes of older women, to investigate the effects of the CDC26 gene expression on oocyte development.

MAIN RESULTS AND THE ROLE OF CHANCE
Many genes were found to be differentially expressed in the oocytes of young versus old patients via RNA-seq technology. CDC26 mRNA and protein levels in aged oocytes were severely decreased, when compared with the levels observed in young oocytes. Moreover, aged oocytes lacking CDC26 were more prone to aneuploidy. These defects in aged oocytes could be partially rescued by overexpression of the CDC26 protein.

LARGE SCALE DATA
N/A.

LIMITATIONS, REASONS FOR CAUTION
Our study delineated key steps in the oocyte aging process by identifying the key role of CDC26 in the progression of oocyte maturation. Future studies are required to address whether other signaling pathways play a role in regulating oocyte maturation via CDC26 and which genes are the direct molecular targets of CDC26.

WIDER IMPLICATIONS OF THE FINDINGS
Our results using in vitro systems for both mouse and human oocyte maturation provide a proof of principle that CDC26 may represent a novel therapeutic approach against maternal aging-related spindle and chromosomal abnormalities.

STUDY FUNDING/COMPETING INTEREST(S)
This work was supported by grants from the National Natural Science Foundation of China (81571442 and 81170571), the outstanding Talent Project of Shanghai Municipal Commission of Health (XBR2011067) and Clinical Research and Cultivation Project in Shanghai Municipal Hospitals (SHDC12019X32). The authors declare no conflict of interest.

Histone H3 variant H3mm13 gene is required for normal skeletal muscle regeneration

Resveratrol suppresses glial activation and alleviates trigeminal neuralgia via activation of AMPK

Functional analysis of novel histone variant H3mm13 in skeletal muscle

Novel Histone H3 Variant, H3mm7, tunes Skeletal Muscle Differentiation Potential

According to spontaneous combustion abnormal condition occurred in a production downtime of No. 1305 fully- mechanized top coal caving mining face in Shandong Tangkou Mine,the liquid carbon dioxide was provided to control the spontaneous combustion hidden danger occurred in the production downtime period of the fully- mechanized top coal caving mining face. The study results showed that the liquid carbon dioxide applied to the fire prevention and control could effectively reduce the density of each index gas and temperature,the oxygen volume fraction was reduced from 16. 2% to 8. 2%,the carbon monoxide volume fraction was reduced from 39 × 10- 6to 8 × 10- 6,the temperature was reduced from 29. 5 ℃ to 16. 3 ℃,the spontaneous combustion hidden danger occurred in the production downtime period of the coal mining face could be effectively eliminated and safety during the production downtime period of the coal mining face could be ensured.

Study on Liquid Carbon Dioxide Applied to Spontaneous Combustion Control in Fully- Mechanized Top Coal Caving Mining Face

Two-meters winder chamber in west parallel track roadway has the problems of large deformation of roof and the sides,serious floor heave and repeated maintenance works in kilometer deep mine in Shandong Tangkou coal mine.Based on analyzing the failure mechanism of surrounding rock with large section chamber in deep mining,the Technology of strong double shell support was put forward,the support scheme of bolt-grouting support,lining concrete with metal rack support and strong foundation beam bolting support were designed,as well as its support technology.Engineering application showed that: After 25 days,the load of cables in the roof and floor became stable and the maximum load of cables in roof and floor were 131 kN and 117 kN,which were far less than the maximum breaking load,the stress was reasonable for the cables.With strong double shell support,the surrounding rock deformation trended to be stabilized after 40 days,destruction never happened,after 90 days,the maximum roof-to-floor convergence was only 64 mm,the deformation rate was 1.14%,and the deformation of chamber had been effectively controlled.With the technology,Tangkou coal mine can get 4,490,000 yuan as direct economic benefits,the economic benefit is remarkable.

Strong Double Shell Support for Large Section Chamber in Kilometer Deep Mine

Objective Analysis carboprost tromethamine intractable postpartum hemorrhage treatment effect.Methods Our hospital intractable postpartum hemorrhage in patients 50 cases were randomly divided into two groups,the control group received conventional therapy,the experimental group received conventional therapy joint carboprost tromethamine therapy comparative effectiveness.Results The experimental group time to stop bleeding fast,less bleeding,compared with control group(P0.05),the difference was statistically significant.Conclusion Using tromethamine of Carboprost,the treatment of refractory postpartum hemorrhage.

Clinical Effects Observed of Carboprost Tromethamine Treatment of Intractable Postpartum Hemorrhage in 25 Cases

"The Scarlet Letter"is about a rebellious female-heist novel."The Scarlet Letter"by the tragic life of the heroine Hester description, reproduction of the 17th century the United States the situation of women in Puritan society, displaying the heist with the fate of the struggle in the spirit of resistance are revealed.

Analysis of the Hester's spirit of resistance in the Scarlet Letter

The vanishing limit of the diffusivity coefficient for the two-dimensional magnetic Bénard problem

The paper concerns with the nonstationary two dimensional microflow boundary layer system. By posing some restrictions on the viscous function, the existence and the uniqueness of local solutions to the system are got. The main technique we used in the paper is Oleinik line method based on a successive approximation, which is used in the study of Prandtl system. However, the corresponding calculations in our paper are much more complicated. Key–Words: Two dimensional microflow boundary layer system, Prandtl system, Existence, Local solution.

The Existence of Solution for the Nonstationary Two Dimensional Microflow Boundary Layer System

基于SA-BP算法的本体概念语义相似度综合计算 (Comprehensive Calculation of Semantic Similarity of Ontology Concept Based on SA-BP Algorithm)

M-相点数据索引SPindex (SPindex: Spatial Index Based on M-phase Points)

Peach [Prunus persica (L.) Batsch] annual shoots grow up quickly, which limits the lighting and ventilation of an orchard. Atypical bHLH proteins IBH1(INCREASED LEAF INCLINATION1 BINDING bHLH1) play substantial roles in regulating cell elongation and plant stature. In this study, three PpIBH1s (PpIBH1-1/-2/-3) were identified in peach genome and contain a conserved AS domain and a characteristic HLH domain. The transcript levels of three PpIBH1s positively correlated with internode length, which gradually increased from apex to base along the peach shoots. This positive correlation was further confirmed in apple and poplar shoots. And the PpIBH1s gene were highly expressed in the shoot tips collected from twelve dwarf peach cultivars (gid1c mutants). In tissue-specific expression analysis, PpIBH1-1 are more highly expressed in tissues at the growth-arrested stage than cell-elongating. Transgenic Arabidopsis lines showed that different plant heights depending on the dose of PpIBH1-1 transcripts. And the dwarfing PpIBH1-1 transgenic lines were caused by the shorted cell length. PpIBH1-1 interacted with two bHLH factors (PpACE2 and PpLP1). These results suggested that PpIBH1-1 probably prevents internode elongation of peach shoots in a dose-dependent manner. Our work provided a foundation for properly controlling the growth of annual peach branches.

Plant science : an international journal of experimental plant biology

PpIBH1-1 limits internode elongation of peach shoot in a dose-dependent manner.

The plant growth regulator ethylene influences rachis browning in grape (Vitis vinifera L.). Although the ethylene signaling pathway is well defined, there is limited knowledge on its mode of action during rachis browning. Here, we show that an ethylene response factor (VvERF111) positively regulates chlorophyll degradation in rachis by binding to a DRE motif in the promoter of VvCLH1. The expression of VvERF111 and VvCLH1 in rachis was induced by ethylene and inhibited by 1-methylcyclopropene (1-MCP). VvERF111 belongs to the ERF IX subfamily of the APETALA2/ethylene responsive factor (AP2/ERF) superfamily, shows transcriptional activity in yeast, and is localized in the nucleus and membrane. The transient overexpression of VvERF111 or chlorophyllase (VvCLH1) in grape leaves accelerated chlorophyll degradation. In VvERF111-overexpressing leaves, transcript levels of VvCLH1 were also increased. Our findings offer a deeper understanding of the transcriptional regulation of chlorophyll degradation during the rachis browning of grape.

VvERF111 Regulates Chlorophyll Degradation by Activating Expression of VvCLH1, Leading to Rachis Browning in Grape

Ethylene accelerates grape ripening via increasing VvERF75-induced ethylene synthesis and chlorophyll degradation

Controlling the tree size of fruit species such as peach can reduce the amount of labor and input needed for orchard management. The phytohormone gibberellin (GA) positively regulates tree size by inducing degradation of the GA signaling repressor DELLA. The N-terminal DELLA domain in this protein is critical for its GA-dependent interaction with the GA receptor GID1 and the resulting degradation of the DELLA protein, which allows for growth-promoting GA signaling. In this study, a DELLA family member, PpeDGYLA, contains a DELLA domain but has amino acid changes in three conserved motifs (DELLA into DGYLA, LEQLE into LERLE, and TVHYNP into AVLYNP). In the absence or presence of GA3, the PpeDGYLA protein did not interact with PpeGID1c and was stable in 35S-PpeDGYLA peach transgenic callus. The overexpression of PpeDGYLA in both polar and Arabidopsis showed an extremely dwarfed phenotype, and these transgenic plants were insensitive to GA3 treatment. PpeDGYLA could interact with PpeARF6-1 and -2, supposed growth-promoting factors. It is suggested that the changes in the DELLA domain of PpeDGYLA may, to some extent, account for the severe dwarf phenotype of poplar and Arabidopsis transgenic plants. In addition, our study showed that the DELLA family contained three clades (DELLA-like, DELLA, and DGLLA). PpeDGYLA clustered into the DGLLA clade and was expressed in all of the analyzed tissues. These results lay the foundation for the further study of the repression of tree size by PpeDGYLA.

Peach DELLA Protein PpeDGYLA Is Not Degraded in the Presence of Active GA and Causes Dwarfism When Overexpressed in Poplar and Arabidopsis

Fruit ripening includes several metabolic changes that lead to sweeter and softer fruit. Pectin depolymerization is one of major factors that softens developing grape berries. Pectin lyases (PLs) play important roles in pectin degradation in the grape berry. However, little is known about the temporal and spatial expression of grapevine (Vitis spp.) pectin lyase genes (VvPLs) or their function during fruit ripening and softening. In this study, 18 individual VvPL genes were identified in the grape genome. All VvPL genes were sorted into group I and group II, except VvPL12 which demonstrated higher and similar expression trends in different tissues and organs. In grape berry, VvPL1, 5, 7, 11 and 16 were highly expressed, whereas VvPL18, 15, 2, 13, 10, 14, 17, 6 and 8 showed lower expression levels at different berry developmental stages. Expression of VvPL11 firstly increased and then decreased, and the highest expression was shown at 6 weeks after full bloom (WAFB) during berry development. Over-expression of the VvPL11 gene in tomato caused higher ethylene production and lower firmness compared to wild-type fruit. Moreover, decreased propectin and increased water-soluble pectin (WSP) levels were observed in VvPL11 transgenic tomato fruit. Consistent with this result, the expression levels of SlPG2, SlEXP, and SlPME1, all of which are genes involved in fruit softening, were up-regulated in VvPL11-OE tomato fruit, which supported the idea that VvPL11 plays an important role in fruit ripening and softening. This study provided a comprehensive analysis of the grapevine PL family and advanced our knowledge of the functions of VvPLs during fruit softening.

VvPL11 Is a Key Member of the Pectin Lyase Gene Family Involved in Grape Softening

Multiple indeterminate domain (IDD)–DELLA1 complexes participate in gibberellin feedback regulation in peach

Genome-wide analysis of the GRAS transcription factor gene family in peach (Prunus persica) and ectopic expression of PpeDELLA1 and PpeDELLA2 in Arabidopsis result in dwarf phenotypes

VvEIL2 and VvEIL4 regulate ethylene synthesis and carotenoid metabolism during senescence of grape rachis

Overexpression of peach NAC25 promotes anthocyanin biosynthesis in poplar shoots

Abstract Branch number is an important agronomic trait in peach (Prunus persica) trees because plant architecture affects fruit yield and quality. Although breeders can select varieties with different tree architecture, the biological mechanisms underlying architecture remain largely unclear. In this study, a pillar peach (‘Zhaoshouhong’) and a standard peach (‘Okubo’) were compared. ‘Zhaoshouhong’ was found to have significantly fewer secondary branches than ‘Okubo’. Treatment with the synthetic strigolactone (SL) GR24 decreased branch number. Transcriptome analysis indicated that PpTCP18 (a homologous gene of Arabidopsis thaliana BRC1) expression was negatively correlated with strigolactone synthesis gene expression, indicating that PpTCP18 may play an important role in peach branching. Yeast one-hybrid, electrophoretic mobility shift, dual-luciferase assays and PpTCP18-knockdown in peach leaf buds indicated that PpTCP18 could increase expression of PpLBO1, PpMAX1, and PpMAX4. Furthermore, transgenic Arabidopsis plants overexpressing PpTCP18 clearly exhibited reduced primary rosette-leaf branches. Moreover, lncRNA sequencing and transient expression analysis revealed that lncRNA5 targeted PpTCP18, significantly increasing PpTCP18 expression. These results provide insights into the mRNA and lncRNA network in the peach SL signaling pathway and indicate that PpTCP18, a transcription factor downstream of SL signaling, is involved in positive feedback regulation of SL biosynthesis. This role of PpTCP18 may represent a novel mechanism in peach branching regulation. Our study improves current understanding of the mechanisms underlying peach branching and provides theoretical support for genetic improvement of peach tree architecture.

PpTCP18 is upregulated by lncRNA5 and controls branch number in peach (Prunus persica) through positive feedback regulation of strigolactone biosynthesis

Rapid growth of branches in a peach tree restricts the light penetration and air ventilation within the orchard, which lowers fruit quality and promotes the occurrence of diseases and insects. Our previous works showed that PpDELLA1 and PpDELLA2 repress the rapid growth of annual shoots. Proteins that interact with DELLA are vital for its function. In this study, seven PpPIFs (PpPIF1, -2, -3, -4, -6, -7 and -8) were identified in the peach genome and contain a conserved bHLH domain. Among the seven PpPIFs, PpPIF8 interacted with PpDELLA2 through an unknown motif in the C-terminal and/or the bHLH domain. Overexpression of PpPIF8 in Arabidopsis promotes plant height and branch numbers. Hypocotyl elongation was significantly enhanced by PpPIF8 under weak light intensity. PpPIF8 overexpressed in Arabidopsis and transiently expressed in peach seedlings upregulated the transcription of YUCCA and SAUR19 and downregulated SHY1 and -2. Additionally, PpPIF4 and -8 were significantly induced by weak light. Phylogentic analysis and intron patterns of the bHLH domain strongly suggested that PIFs from six species could be divided into two groups of different evolutionary origins. These results lay a foundation for the further study of the repression of shoot growth by PpDELLA2 through protein interaction with PpPIF8 in peach.

PpPIF8, a DELLA2-interacting protein, regulates peach shoot elongation possibly through auxin signaling.

The distribution of bioactive gibberellins along peach annual shoots is closely associated with PpGA20ox and PpGA2ox expression profiles

Ethylene and polyamines form a negative feedback loop to regulate peach fruit ripening via the transcription factor PpeERF113 by regulating the expression of PpePAO1

Overexpressing VvWRKY18 from grapevine reduces the drought tolerance in Arabidopsis by increasing leaf stomatal density.

Abstract The jujube witches’ broom (JWB) phytoplasma is associated with witches’ broom, dwarfism, and smaller leaves in jujube, resulting in yield losses. In this study, eight putative JWB effector proteins were identified from potential mobile units of the JWB genome. Among them, Zaofeng6 induced witches’ broom symptoms in Arabidopsis and jujube. Zaofeng6-overexpressing Arabidopsis and unrooted jujube transformants displayed witches’ broom-like shoot proliferation. Transient expression of Zaofeng6 induced hypersensitive response like cell death and expression of hypersensitive response marker genes, like harpin-induced gene 1 (H1N1), and the pathogenesis-related genes PR1, PR2, and PR3 in transformed Nicotiana benthamiana leaves, suggesting that Zaofeng6 could be a virulence effector. Yeast two-hybrid library screening and bimolecular fluorescence complementation confirmed that Zaofeng6 interacts with ZjTCP7 through its first two α-helix domains in the cell nuclei. ZjTCP7 mRNA and protein abundance decreased in Zaofeng6 transgenic jujube seedlings. The expression of some genes in the strigolactone signaling pathway (ZjCCD7, ZjCCD8, and CYP711A1) were down-regulated in jujube shoots overexpressing Zaofeng6 and in zjtcp7 CRISPR/Cas9 mutants. Zaofeng6 induces shoot proliferation through decreased expression of ZjTCP7 at the transcriptional and translational levels.

Phytoplasma effector Zaofeng6 induces shoot proliferation by decreasing the expression of ZjTCP7 in Ziziphus jujuba

The heat shock protein 20 (HSP20) proteins comprise an ancient, diverse, and crucial family of proteins that exists in all organisms. As a family, the HSP20s play an obvious role in thermotolerance, but little is known about their molecular functions in addition to heat acclimation. In this study, 42 PpHSP20 genes were detected in the peach genome and were randomly distributed onto the eight chromosomes. The primary modes of gene duplication of the PpHSP20s were dispersed gene duplication (DSD) and tandem duplication (TD). PpHSP20s in the same class shared similar motifs. Based on phylogenetic analysis of HSP20s in peach, Arabidopsis thaliana, Glycine max, and Oryza sativa, the PpHSP20s were classified into 11 subclasses, except for two unclassified PpHSP20s. cis-elements related to stress and hormone responses were detected in the promoter regions of most PpHSP20s. Gene expression analysis of 42 PpHSP20 genes revealed that the expression pattern of PpHSP20-32 was highly consistent with shoot length changes in the cultivar ‘Zhongyoutao 14’, which is a temperature-sensitive semi-dwarf. PpHSP20-32 was selected for further functional analysis. The plant heights of three transgenic Arabidopsis lines overexpressing PpHSP20-32 were significantly higher than WT, although there was no significant difference in the number of nodes. In addition, the seeds of three over-expressing lines of PpHSP20-32 treated with high temperature showed enhanced thermotolerance. These results provide a foundation for the functional characterization of PpHSP20 genes and their potential use in the growth and development of peach.

Phylogenetic and Transcriptional Analyses of the HSP20 Gene Family in Peach Revealed That PpHSP20-32 Is Involved in Plant Height and Heat Tolerance

Jujube production is threatened by jujube witches’ broom (JWB) disease, which is caused by JWB phytoplasma. The jujube TCP transcription factor (TF) ZjTCP16 may be involved in the interaction of jujube plants with JWB phytoplasma. In this study, qRT-PCR proved that the expression pattern of ZjTCP16 was altered by JWB phytoplasma. The gene functions of ZjTCP16 were analyzed by its overexpression in Arabidopsis and jujube, as well as knock-down in. The overexpression of ZjTCP16 in Arabidopsis and jujube resulted in dwarfism and small leaves, while the zjtcp16 CRISPR mutants were higher than the WT. Microscopic observation of paraffin sections of jujube stems showed that ZjTCP16 affected the size of cells. The interactions of ZjTCP16 with ZjAS2 and ZjLOB in both the cytoplasm and nucleus were demonstrated by yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays. Yeast one-hybrid (Y1H) assays and qRT-PCR further confirmed that ZjTCP16 affected the expression of genes involved in leaf morphogenesis and cell proliferation (ZjAS1, ZjKNAT1, ZjKNAT2 and ZjKNAT6) at the mRNA level through the ZjAS2 and ZjLOB pathways. In conclusion, ZjTCP16 regulates plant growth and cell size by altering the expression pattern of morphogenesis-related genes in jujube.

The Jujube TCP Transcription Factor ZjTCP16 Regulates Plant Growth and Cell Size by Affecting the Expression of Genes Involved in Plant Morphogenesis

Polyamine oxidase (PAO)–mediated polyamine catabolism plays potential roles in peach (Prunus persica L.) fruit development and ripening

Peach (Prunus persica L. Batsch) trees grow vigorously and are subject to intense pruning during orchard cultivation. Reducing the levels of endogenous gibberellins (GAs) represents an effective method for controlling branch growth. Gibberellin 2-oxidases (GA2oxs) deactivate bioactive GAs, but little is known about the GA2ox gene family in peach. In this study, we identified seven PpGA2ox genes in the peach genome, which were clustered into three subgroups: C19-GA2ox-I, C19-GA2ox-II, and C20-GA2ox-I. Overexpressing representative genes from the three subgroups, PpGA2ox-1, PpGA2ox-5, and PpGA2ox-2, in tobacco resulted in dwarf plants with shorter stems and smaller leaves than the wild type. An analysis of the GA metabolic profiles of the transgenic plants showed that PpGA2ox-5 (a member of subgroup C19-GA2ox-II) is simultaneously active against both C19-GAs and C20-GAs,which implied that C19-GA2ox-II enzymes represent intermediates of C19-GA2oxs and C20-GA2oxs. Exogenous GA3 treatment of shoot tips activated the expression of all seven PpGA2ox genes, with different response times: the C19-GA2ox genes were transcriptionally activated more rapidly than the C20-GA2ox genes. GA metabolic profile analysis suggested that C20-GA2ox depletes GA levels more broadly than C19-GA2ox. These results suggest that the PpGA2ox gene family is responsible for fine-tuning endogenous GA levels in peach. Our findings provide a theoretical basis for appropriately controlling the vigorous growth of peach trees.

Functional Analysis of the Gibberellin 2-oxidase Gene Family in Peach

Genome-wide identification and expression of the lipoxygenase gene family in jujube (Ziziphus jujuba) in response to phytoplasma infection

Summary Peach (Prunus persica) is one of the most important fruit crops globally, but its cultivation can be hindered by large tree size. ‘Zhongyoutao 14’ (CN14) is a temperature‐sensitive semi‐dwarf (TSSD) cultivar which might be useful as breeding stock. The genome of CN14 was sequenced and assembled de novo using single‐molecule real‐time sequencing and chromosome conformation capture assembly. A high‐quality genome was assembled and annotated, with 228.82 Mb mapped to eight chromosomes. Eighty‐six re‐sequenced F1 individuals and 334 previously re‐sequenced accessions were used to identify candidate genes controlling TSSD and flower type and size. An aquaporin tonoplast intrinsic protein (PpTIP2) was a strong candidate gene for control of TSSD. Sequence variations in the upstream regulatory region of PpTIP2 correlated with different transcriptional activity at different temperatures. PpB3‐1, a candidate gene for flower type (SH) and flower size, contributed to petal development and promoted petal enlargement. The locus of another 12 agronomic traits was identified through genome‐wide association study. Most of these loci exhibited consistent and precise association signals, except for flesh texture and flesh adhesion. A 6015‐bp insertion in exon 3 and a 26‐bp insertion upstream of PpMYB25 were associated with fruit hairless. Along with a 70.5‐Kb gap at the F‐M locus in CN14, another two new alleles were identified in peach accessions. Our findings will not only promote genomic research and agronomic breeding in peach but also provide a foundation for the peach pan‐genome.

De novo chromosome‐level genome of a semi‐dwarf cultivar of Prunus persica identifies the aquaporin PpTIP2 as responsible for temperature‐sensitive semi‐dwarf trait and PpB3‐1 for flower type and size

Background Heat shock factors (HSFs) play important roles during normal plant growth and development and when plants respond to diverse stressors. Although most studies have focused on the involvement of HSFs in the response to abiotic stresses, especially in model plants, there is little research on their participation in plant growth and development or on the HSF (PpHSF) gene family in peach (Prunus persica). Methods DBD (PF00447), the HSF characteristic domain, was used to search the peach genome and identify PpHSFs. Phylogenetic, multiple alignment and motif analyses were conducted using MEGA 6.0, ClustalW and MEME, respectively. The function of PpHSF5 was confirmed by overexpression of PpHSF5 into Arabidopsis. Results Eighteen PpHSF genes were identified within the peach genome. The PpHSF genes were nonuniformly distributed on the peach chromosomes. Seventeen of the PpHSFs (94.4%) contained one or two introns, except PpHSF18, which contained three introns. The in silico-translated PpHSFs were classified into three classes (PpHSFA, PpHSFB and PpHSFC) based on multiple alignment, motif analysis and phylogenetic comparison with HSFs from Arabidopsis thaliana and Oryza sativa. Dispersed gene duplication (DSD at 67%) mainly contributed to HSF gene family expansion in peach. Promoter analysis showed that the most common cis-elements were the MYB (abiotic stress response), ABRE (ABA-responsive) and MYC (dehydration-responsive) elements. Transcript profiling of 18 PpHSFs showed that the expression trend of PpHSF5 was consistent with shoot length changes in the cultivar ‘Zhongyoutao 14’. Further analysis of the PpHSF5 was conducted in 5-year-old peach trees, Nicotiana benthamiana and Arabidopsis thaliana, respectively. Tissue-specific expression analysis showed that PpHSF5 was expressed predominantly in young vegetative organs (leaf and apex). Subcellular localization revealed that PpHSF5 was located in the nucleus in N. benthamiana cells. Two transgenic Arabidopsis lines were obtained that overexpressed PpHSF5. The root length and the number of lateral roots in the transgenic seedlings were significantly less than in WT seedlings and after cultivation for three weeks. The transgenic rosettes were smaller than those of the WT at 2–3 weeks. The two transgenic lines exhibited a dwarf phenotype three weeks after transplanting, although there was no significant difference in the number of internodes. Moreover, the PpHSF5-OE lines exhibited enhanced thermotolerance. These results indicated that PpHSF5 might be act as a suppresser of growth and development of root and aerial organs.

Genome-wide identification of HSF family in peach and functional analysis of PpHSF5 involvement in root and aerial organ development

Transcript profiling provides insights into molecular processes during shoot elongation in temperature-sensitive peach (Prunus persica)

Genome-wide identification of Ziziphus jujuba TCP transcription factors and their expression in response to infection with jujube witches’ broom phytoplasma

Summary Plant stature is one important factor that affects the productivity of peach orchards. However, little is known about the molecular mechanism(s) underlying the dwarf phenotype of peach tree. Here, we report a dwarfing mechanism in the peach cv. FenHuaShouXingTao (FHSXT). The dwarf phenotype of ‘FHSXT’ was caused by shorter cell length compared to the standard cv. QiuMiHong (QMH). ‘FHSXT’ contained higher endogenous GA levels than did ‘QMH’ and did not response to exogenous GA treatment (internode elongation). These results indicated that ‘FHSXT’ is a GA‐insensitive dwarf mutant. A dwarf phenotype‐related single nucleotide mutation in the gibberellic acid receptor GID1 was identified in ‘FHSXT’ (GID1c S191F), which was also cosegregated with dwarf phenotype in 30 tested cultivars. GID1cS191F was unable to interact with the growth‐repressor DELLA1 even in the presence of GA. ‘FHSXT’ accumulated a higher level of DELLA1, the degradation of which is normally induced by its interaction with GID1. The DELLA1 protein level was almost undetectable in ‘QMH’, but not reduced in ‘FHSXT’ after GA 3 treatment. Our results suggested that a nonsynonymous single nucleotide mutation in GID1c disrupts its interaction with DELLA1 resulting in a GA‐insensitive dwarf phenotype in peach.

A single nucleotide mutation in GID1c disrupts its interaction with DELLA1 and causes a GA‐insensitive dwarf phenotype in peach

Combination of iTRAQ proteomics and RNA-seq transcriptomics reveals jasmonate-related-metabolisms central regulation during the process of Jujube witches’ broom recovery by tetracycline treatment

Genome-wide identification and transcriptome profiling reveal that E3 ubiquitin ligase genes relevant to ethylene, auxin and abscisic acid are differentially expressed in the fruits of melting flesh and stony hard peach varieties

Transcriptome profiling analysis revealed co-regulation of multiple pathways in jujube during infection by 'Candidatus Phytoplasma ziziphi'.

Expression of grape ACS1 in tomato decreases ethylene and alters the balance between auxin and ethylene during shoot and root formation.

Resveratrol contributes to a plant’s tolerance of various abiotic and biotic stresses and is highly beneficial to human health. A search for elite alleles affecting resveratrol production was undertaken to find useful grapevine germplasm resources. Resveratrol levels in both berry skins and leaves were determined in 95 grapevine accessions (including 50 wild Chinese grapevine accessions and 45 cultivars) during two consecutive years. Resveratrol contents were higher in berry skins than in leaves and in wild Chinese grapevines than in grapevine cultivars. Using genotyping data, 79 simple sequence repeat (SSR) markers linked to 44 stilbene synthase (STS) genes were detected in the 95 accessions, identifying 40 SSR markers with higher polymorphisms. Eight SSR marker loci, encompassing 19 alleles, were significantly associated with resveratrol content on (P < 0.001), and 5 SSR loci showed repeated associations. Locus Sh5 had four associations: three positive for allele 232 (including leaves in the 2 years) and one negative for allele 236 in four environments. Loci Sh9 and Sh56 for a total of 7 alleles exhibited positive effects in berry skins in the 2 years. In berry skins, locus Sh56 with positive effects was closely linked to VvSTS27, and locus Sh77 with negative effects to VvSTS17, importantly, the two candidate genes both were located on Chromosome 16. The SSR marker loci and candidate genes identified in this study will provide a useful basis for future molecular breeding for increased production of natural resveratrol and its derivatives.

Exploration of Elite Stilbene Synthase Alleles for Resveratrol Concentration in Wild Chinese Vitis spp. and Vitis Cultivars

Ethylene is important during the berry development and in the last stages of rachis development or rachis senescence. Since grapes develop in a cluster that comprises both the fruit berry and the nonfruit rachis, we measured the release of ethylene from both tissues. Detached berries from Vitis vinifera ‘Ruby Seedless’ and ‘Thompson Seedless’ showed that ethylene release peaks at the beginning of berry development and at veraison. Ethylene production in the rachis was higher than that in the berry and had an obvious peak before harvest in ‘Thompson Seedless’. In both cultivars, ethephon treatment induced ethylene production in the rachis but not in the berry. Expression of 1aminocyclopropane-1-carboxylate (ACC) synthase (ACS) and ACC oxidase (ACO) genes showed diverse temporal and spatial patterns in ‘Thompson Seedless’ and ‘Ruby Seedless’. For most gene family members, the low ACS expression levels were observed in berry and rachis. Expression levels of most of theACS andACO genes did not correlate with ethylene released in the same organ. The transcriptional level of VvACS1 did correlate with ethylene evolution in rachis of ‘Thompson Seedless’ during berry development and storage, which suggested that VvACS1 may have important roles in rachis senescence. In berries of ‘Thompson Seedless’ and ‘Ruby Seedless’, the transcriptional levels of VvACO1, VvACS2, and VvACS6 coincided with ethylene production, indicating possible roles in berry development. Expression of VvACS2–VvACO9 and VvACO1–VvACO3 was not consistent with ethylene production during storage or in response to ethephon treatment, which suggests that the expression of ACS and ACO was affected by other stress factors after harvest. Grapes (V. vinifera L.) are widely cultivated around the world and can be consumed as fresh fruit (table grape) or processed into wine, juice, molasses, or raisins (Mencarelli et al., 2005). Grape berry has a thin skin and a soft, juicy flesh with high sugar content. The berry connects to the main rachis via a short pedicel with a small brush. Table grapes are stored and sold in bunches, and dry, browning rachis and berry drop are unfavorable for storage, transportation, and sale (Balic et al., 2012; Lichter, 2016). Ethylene plays an important role in preharvest ripening in both climacteric and nonclimacteric fruit and is involved either directly or indirectly in the regulation of grape development and organ senescence (Chervin et al., 2008; Pech et al., 2008). Previous studies reported that rachis browning were induced by exogenous abscisic acid (ABA) and ethephon (Hedberg and Goodwin, 1980; Li et al., 2015), and were restrained by ethylene inhibitors, such as 1-methylcyclopropene (1-MCP) (Li et al., 2015), or other plant hormones, such as cytokinin (Balic et al., 2012) and gibberellin (Raban et al., 2013). Although many studies have linked ethylene to grape berry ripening, there is little research on the role of ethylene in rachis development or senescence before and after harvest. Increased understanding of the synthesis and regulation of ethylene production during development and senescence of grape rachis and berry would lay a foundation for prolonging shelf and storage life. The key enzymes of ethylene biosynthesis in higher plants are ACS and ACO (Yang and Hoffman, 1984), both of which are encoded by multigene families. For example, eight ACS genes and four ACO genes have been identified in tomato (Rottmann et al., 1991; Yip et al., 1992). Expression ofACS andACO genes are differentially regulated both temporally and spatially, resulting in specific expression patterns. For instance, EjACS1 and EjACO1 are specifically expressed in loquat fruit (Jiang et al., 2011), and LeACO1 is specifically expressed in tomato fruit (Barry et al., 1996). In grapes, there are at least 10 VvACS and 3 VvACO genes (Munoz-Robredo et al., 2013; Xu andWang, 2012). The highest expression of VvACO1 gene was concomitant with an ethylene peak around veraison (Chervin et al., 2008; Munoz-Robredo et al., 2013; Pech et al., 2008). Moreover, there is little published data about the temporal and spatial expression of ACS and ACO genes in grapes. To understand how ACS and ACO genes control ethylene synthesis during development and senescence of both the rachis and the berry, the expression levels of nine ACS genes and three ACO genes and the production of ethylene were measured in berry and rachis of two seedless table grape cultivars Thompson Seedless and Ruby Seedless. Material and Methods Plant materials. Grapevines (V. vinifera) of two cultivars, namely Thompson Seedless and Ruby Seedless, were grown in the National Vitis Repository of Zhengzhou Fruit Research Institute, Chinese Academy of Agricultural Sciences. ‘Ruby Seedless’ is not susceptible to berry drop, and ‘Thompson Seedless’ berry is more susceptible to berry drop (Cooper et al., 1993). Grape berry and rachis of ‘Thompson Seedless’ were sampled from adult vines at 21, 35, 49, 57, 64, and 71 d after full bloom (DAFB), with the final sample collection at harvest [71 DAFB, 21.3% total soluble solids (TSS) and 0.61% tartaric acid]. Grape berry and rachis of V. vinifera ‘Ruby Seedless’ were sampled on 35, 49, 57, 64, 81, 91, and 102 DAFB (harvest, 16.9% TSS and 0.68% tartaric acid) (Supplemental Fig. 1; Supplemental Table 1). Samples (the third to eighth node) of leaf, petiole, and tendril, young stem (the first to third node), and shoot tip were collected from the two cultivars when the berry was harvested. All samples were frozen in liquid nitrogen and stored at –80 C until analysis. For each sample, berries and rachis were collected from three or five clusters with the same maturity. The experiment was conducted in the 2014 growing season. For ethylene analysis and physiological characterization, fresh berry and rachis were taken from ‘Thompson Seedless’ and ‘Ruby Seedless’ on the above date. Fresh samples were transported to the laboratory immediately. Ethephon treatment. To investigate the expression patterns of ACO and ACS genes in response to exogenous ethephon, grape clusters of ‘Thompson Seedless’ and ‘Ruby Seedless’ from 12 grapevines were sprayed with 400 mg·L ethephon (Sigma, China) or distilled water on the vine before harvest. Then the grape clusters were harvested and kept in a chamber at 15 C and 85% to 90% relative humidity. Three days after ethephon treatments berries and rachis were collected every 1 or 2 d during storage. Nine clusters from 12 plants were selected for each treatment, and ethylene production of berry and rachis from nine clusters was measured three times. Measurement of maturity parameters. To define the stage of berry development, we randomly selected 20 berries on each Received for publication 25 Aug. 2016. Accepted for publication 12 Jan. 2017. We thank Anita K. Snyder for critical reading of the manuscript. The work was supported by National Natural Science Foundation of China (31201605) and Major Science and Technology Project in Henan Province (151100110900). These authors contributed equally to this work. Corresponding author. E-mail: jcfeng@henau. edu.cn. HORTSCIENCE VOL. 52(3) MARCH 2017 413 sampling date, measured the level of TSS with a digital refractometer (PAL-1; ATAGO, Japan). Titratable acidity (TA), diameter, and weight parameters were recorded during berry developing stages of ‘Thompson Seedless’. To guarantee berry and rachis with the similar maturity degree in the individual cultivar, different clusters with the similar TSS were collected together in each sampling date (Munoz-Robredo et al., 2013). Three replicates were conducted for each sampling. GCanalysis of ethylene production.Ethylene analysis for each sample was performed using gas chromatography (GC; GC-2010 PLUS, Shimadzu, Japan) with a flame ionization detector as described (Li et al., 2015). At each berry development stage, 200–400 g berries and 5–20 g rachis were sampled from clusters and then sealed in either a 65-mL or a 250-mL bottle or box at 20 C. Three hours later, 1 mL of the gas from the sample vial was injected into a GC Packed Column (GDX-502, Shimadzu, Janpan) for analysis. The temperatures of the injector port, column, and detector were set at 75, 80, and 60 C, respectively. For each sample, berries and rachis were collected from three or five clusters with the similar maturity. Each experiment was repeated at least three times. Quantitative real-time RT-PCR analysis and sequencing. Rachis and berries from nine clusters were homogenized in groups of three clusters and RNA extraction was performed on 100–200 mg samples from each replicate using a modified CTAB method (Gambino et al., 2008). RNA quality was evaluated in a NanoDrop 2000c spectrophotometer (Thermo Scientific, Waltham, MA), selecting RNA samples with an A260/280 ratio between 1.8 and 2.0 and an A260/230 ratio of more than 2.0 for subsequent analysis. The integrity of RNA samples was assessed by electrophoresis on a 1.5% agarose gel. The primer sequences for ACS and ACO genes were designed in Primer Express version 3.0 (Applied Biosystems, Madrid, CA), and primer efficiency for each primer pair was calculated (Table 1). First-stand cDNA synthesis from 1 mg of total RNAwas conducted with the FastQuant RT Kit (with gDNase I; Tiangen Biotech, Beijing, China). Quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) was performed using the SYBR Select Master Mix (Applied Biosystems) in an ABI PRISM 7500 Fast Sequence Detection System (Applied Biosystems). Reactions contained 1 mL primer mix (0.5 mM forward and reverse primers), 2 mL template cDNA, 10 mL SYBR Select Master Mix, and 7 mL RNase-free water to a total volume of 20 mL. Reactions were conducted using the following thermal cycling conditions: 50 C for 2 min (1 cycle), 95 C for 2 min (1 cycle), 95 C for 3 s, and 60 C for 30 s (40 cycles). The PCR products for each primer pair were sequenced (Shanghai Shenggong Company, Shangh

Expression Patterns of ACS and ACO Gene Families and Ethylene Production in Rachis and Berry of Grapes

Combination of iTRAQ proteomics and RNA-seq transcriptomics reveals multiple levels of regulation in phytoplasma-infected Ziziphus jujuba Mill

Reference gene selection for quantitative real-time PCR normalization in different cherry genotypes, developmental stages and organs

Anatomical observations of adventitious bud regeneration from leaf explants of Ziziphus jujube Mill. ‘Huizao’

This study was conducted to develop a protocol for rapid callus induction and subsequent shoot regeneration in Zizyphus jujuba Mill. ‘Huizao’. The best callus induction (95%) was obtained from young expanding leaves between the third and fifth nodes in vitro jujube shoots in MS media supplemented with 0.5 mg/L benzylamino purine (6-BA), 2.0 mg/L 2,4-dichlorophenoxyacetic acid  (2, 4-D), and 0.5 mg/L silver nitrate (AgNO3). Incubation in darkness had non-significant effects on callus induction frequency of leaf explants, while callus formation of leaf was observed five to seven days earlier in one or two weeks of dark incubation. For shoot regeneration, the results showed that combination of zeatin (ZT) and, indole-3-acetic acid (IAA) was found to be more effective than that of 6-BA and indole-3-butyric acid (IBA). A maximum of 37.34% callus differentiation occurred in MS medium supplemented with2.0 mg/L ZT and 0.1 mg/L IAA. 
 
 Key words: Callus induction, shoot regeneration, Zizyphus jujuba.

Callus induction and adventitious shoot regeneration in Zizyphus jujuba Mill. 'Huizao'

Comparision of nitrogen removal characteristic and microbial community in freshwater and marine recirculating aquaculture systems.

Effects of dietary Astragalus membranaceus (Fisch.) Bge. root extract on growth performance, plasma biochemical parameters, fish composition, liver and intestinal morphology, and genes expression in head kidney of hybrid grouper (Epinephelus lanceolatus♂ × Epinephelus fuscoguttatus♀)

Leucine promotes protein synthesis of juvenile white shrimp Litopenaeus vannamei through TOR signaling pathway

The effects of dietary compound plant extracts on growth performance, liver and intestine health, and immune related genes expression in hybrid grouper (Epinephelus lanceolatus♂ × Epinephelus fuscoguttatus♀).

Effects of DL-methionine and a methionine hydroxy analogue (MHA-Ca) on growth, amino acid profiles and the expression of genes related to taurine and protein synthesis in common carp (Cyprinus carpio)

The regulation of fenofibrate on lipid metabolism in obscure puffer (
 Takifugu obscurus
 ) is dependent on dietary lipid content

Effects of dietary inorganic phosphorus levels on growth, liver and intestinal morphology and digestive enzymes in fingerling obscure puffer (Takifugu obscurus)

Effects of dietary dandelion extract on the growth performance, serum biochemical parameters, liver histology, and immune and apoptosis-related genes expression of hybrid grouper (Epinephelus lanceolatus♂ × Epinephelus fuscoguttatus♀) at different feeding period.

The effect and mechanism of dietary monocalcium phosphate restriction on hepatic lipid deposition and immune status in obscure puffer, Takifugu obscurus

Dietary Ginkgo biloba leaf extracts supplementation improved immunity and intestinal morphology, antioxidant ability and tight junction proteins mRNA expression of hybrid groupers (Epinephelus lanceolatus ♂ × Epinephelus fuscoguttatus ♀) fed high lipid diets.

Cloning and characterization of carnitine palmitoyltransferase Iα (CPT1α) from obscure puffer (Takifugu obscurus), and its gene expression in response to different lipid sources

Dietary Radix Bupleuri extracts improves hepatic lipid accumulation and immune response of hybrid grouper (Epinephelus lanceolatus♂ × Epinephelus fuscoguttatus♀)

Comparative biochemistry and physiology. Part D, Genomics & proteomics

Liver transcriptome analysis and de novo annotation of the orange-spotted groupers (Epinephelus coioides) under cold stress.

Effects of dietary Senecio scandens buch-ham extracts on growth performance, plasma biochemical, histology and the expression of immune-related genes in hybrid grouper (Epinephelus lanceolatus♂ × Epinephelus fuscoguttatus♀).

Physiological, immune responses and liver lipid metabolism of orange-spotted grouper (Epinephelus coioides) under cold stress

Effects of dietary monocalcium phosphate supplementation on the anti-oxidative capacity, anti-bacteria function in immune organs of obscure puffer (Takifugu obscurus) after infection with Aeromonas hydrophila.

Comparative biochemistry and physiology. Toxicology & pharmacology : CBP

Effects of replacing fish meal with soybean meal on growth performance, feed utilization and physiological status of juvenile obscure puffer, Takifugu obscurus.

Xiaochaihu Decoction reduces hepatic steatosis and improves D-GalN/LPS-induced liver injury in hybrid grouper (Epinephelus lanceolatus♂ × Epinephelus fuscoguttatus♀).

Effects of dietary dandelion extracts on growth performance, liver histology, immune‐related gene expression and CCl4 resistance of hybrid grouper (Epinephelus lanceolatus♂ × Epinephelus fuscoguttatus♀)

Effects of replacing fish meal with rendered animal protein blend on growth performance, hepatic steatosis and immune status in hybrid grouper (Epinephelus fuscoguttatus♀ × Epinephelus lanceolatus♂)

Dietary Lycium barbarum extract administration improved growth, meat quality and lipid metabolism in hybrid grouper (Epinephelus lanceolatus ♂ × E. fuscoguttatus ♀) fed high lipid diets

The effects of dietary Lycium barbarum extract on growth performance, liver health and immune related genes expression in hybrid grouper (Epinephelus lanceolatus♂ × E. fuscoguttatus♀) fed high lipid diets

Effects of dietary plant protein sources influencing hepatic lipid metabolism and hepatocyte apoptosis in hybrid grouper (Epinephelus lanceolatus♂ × Epinephelus fuscoguttatus♀)

This study determined the effect of dietary supplementation with taurine on plasma biochemical indices, blood cell apoptosis rate, survival rate and expression of catalase (CAT), glutathione reductase (GR) and heat‐shock protein 70 (HSP70) gene in juvenile hybrid snakehead under ammonia stress. Six diets were formulated to contain 0, 3.0, 6.0, 9.0, 12.0 and 15.0 g/kg taurine. Each diet was fed to triplicate groups of fish in cylindrical tanks. After 8 weeks of feeding, 20 fish per tank were exposed to ammonia stress (total ammonia nitrogen = 200 mg/L) for 48 hr. The results showed that, after ammonia stress, plasma alkaline phosphatase (ALP), triacylglycerol (TG) levels and survival rate significantly decreased (p < 0.05) while plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea nitrogen (BUN), respiratory burst, blood cell apoptosis rate, hepatic CAT, GR and HSP70 mRNA expression levels significantly increased (p < 0.05). On the other hand, dietary supplementation with taurine significantly reduced levels of BUN, respiratory burst and blood cell apoptosis rate. Supplemented groups significantly increased relative mRNA expression of hepatic CAT, GR and HSP70 as well as increased survival rate (p < 0.05). These results indicated that dietary supplementation with taurine improved ability to resist ammonia stress in hybrid snakehead.

Dietary supplementation with taurine improves ability to resist ammonia stress in hybrid snakehead (Channa maculatus♀ × Channa argus♂)

Effects of dietary Panax notoginseng extract on growth performance, fish composition, immune responses, intestinal histology and immune related genes expression of hybrid grouper (Epinephelus lanceolatus ♂ × Epinephelus fuscoguttatus ♀) fed high lipid diets

The protective effects of vitamin C on apoptosis, DNA damage and proteome of pufferfish (Takifugu obscurus) under low temperature stress.

Effects of dietary dandelion extract on intestinal morphology, antioxidant status, immune function and physical barrier function of juvenile golden pompano Trachinotus ovatus

The hepatoprotective effects of Radix Bupleuri extracts against D‐galactosamine/lipopolysaccharide induced liver injury in hybrid grouper (Epinephelus lanceolatus♂ × Epinephelus fuscoguttatus♀)

Effect of dietary astaxanthin on the growth performance, non-specific immunity, and antioxidant capacity of pufferfish (Takifugu obscurus) under high temperature stress

Effects of dietary ginkgo biloba leaf extract on growth performance, plasma biochemical parameters, fish composition, immune responses, liver histology, and immune and apoptosis‐related genes expression of hybrid grouper (Epinephelus lanceolatus♂ × Epinephelus fuscoguttatus♀) fed high lipid diets

Six practical diets were formulated to contain 2.6 (the basal diet), 48.9, 95.5, 189.83, 382.4, 779.53 mg/kg vitamin C diet. After 8 weeks of feeding, growth performance, antioxidant status, and innate immunity of juvenile pufferfish were analyzed. Results showed that specific growth rate and protein efficiency ratio in fish fed diets supplemented with vitamin C were significantly higher than in fish fed the control diet. Dietary vitamin C significantly up-regulated the expression levels of growth hormone receptors and Insulin-like growth factor. Blood cell numbers and respiratory burst activity were enhanced in fish fed vitamin C diet. Serum alkaline phosphatase, glutamic-pyruvic transaminase, and glutamic-oxaloacetic transaminase activity were significantly influenced by the dietary vitamin C levels. Fish fed diets supplemented with vitamin C showed increased hepatic superoxide dismutase, glutathione peroxidase, and catalase activity, but decreased malondialdehyde activity. In addition, we found that dietary vitamin C can significantly up-regulate the expression levels of immune-related genes (HSP70, HSP90, BAFF, TNF-α and IL-6) in liver. These results indicate that dietary vitamin C can significantly influence growth performance, antioxidant status, and innate immunity of pufferfish. The IJA appears exclusively as a peer-reviewed on-line open-access journal at http://www.siamb.org.il. To read papers free of charge, please register online at registration form. Sale of IJA papers is strictly forbidden.

Effect of Dietary Vitamin C on Growth Performance , Antioxidant Status and Innate Immunity of Juvenile Pufferfish ( Takifugu obscurus )

A 10-week feeding experiment was conducted to determine the optimum dietary protein requirement of juvenile obscure puffer (Takifugu obscurus). Six isoenergetic (20 MJ kg−1 gross energy) diets were formulated to contain graded levels of 34%, 38%, 42%, 46%, 50% or 54% crude protein (as dry matter basis). The results showed final body weight, weight gain and specific growth rate (SGR) increased significantly with increasing protein levels up to 42% and then decreased thereafer. Second-order polynomial regression analysis (y = −0.0024x2 + 0.1788x − 1.3196, R2 = 0.9032) indicated a maximum SGR at protein level of 37%. Feed conversion ratio (FCR) decreased with increasing levels of dietary protein up to 42% and increased thereafter. Second-order polynomial regression analysis (y = 0.0054x2 − 0.4351x + 10.391, R2 = 0.753) indicated a minimum FCR at protein level of 40%. Protein efficiency ratio (PER) of fish fed the 34%, 38% and 42% diets was significantly higher than that of fish fed the 46%, 50% and 54% diets, and broken-line analysis indicated PER tended to decrease when dietary protein level was higher than 40%. Generally, whole body lipid content, total cholesterol, low-density lipoprotein cholesterol and triacylglycerol decreased with increasing levels of dietary protein. Fish fed the 42% protein diet showed the highest essential amino acids (histidine, isoleucine, leucine, lysine and threonine) and non-essential amino acids (aspartic acid and glutamic acid) in muscle. Based on the second-degree polynomial regression analysis of SGR and FCR and broken-line analysis of PER, the optimal dietary protein level of obscure puffer is estimated to be between 37% and 40% (% as dry matter basis).

Dietary protein requirement of juvenile obscure puffer, Takifugu obscurus

Immune and physiological responses of pufferfish (Takifugu obscurus) under cold stress

Effects of dietary protein and lipid levels on growth, body and plasma biochemical composition and selective gene expression in liver of hybrid snakehead (Channa maculata ♀×Channa argus ♂) fingerlings

Effects of dietary dandelion extracts on growth performance, body composition, plasma biochemical parameters, immune responses and disease resistance of juvenile golden pompano Trachinotus ovatus

Effect of phosphorus supplementation on cell viability, anti-oxidative capacity and comparative proteomic profiles of puffer fish (Takifugu obscurus) under low temperature stress

Comparative proteomic identification of the hepatopancreas response to cold stress in white shrimp, Litopenaeus vannamei

Identification, characterization and expression analysis of tumor suppressor protein p53 from pufferfish (Takifugu obscurus) after the Vibrio alginolyticus challenge.

Effect of acute ammonia exposure on expression of GH/IGF axis genes GHR1, GHR2 and IGF-1 in pufferfish (Takifugu obscurus)

Identification, characterization and functional analysis of anti-apoptotic protein BCL-2-like gene from pufferfish, Takifugu obscurus, responding to bacterial challenge

Isolated and combined exposure to ammonia and nitrite in giant freshwater pawn (Macrobrachium rosenbergii): effects on the oxidative stress, antioxidant enzymatic activities and apoptosis in haemocytes

A 60-d feeding trial was conducted to investigate the effect of dietary maize starch on growth performance, feed utilization, and apparent digestibility coefficient (ADC) and key hepatic enzyme activities regulating glycolytic and gluconeogenic metabolic pathways of juvenile obscure puffer, Takifugu obscurus (Abe) (initial body weight = 7.9 ± 0.2 g). Five isonitrogenous and isolipidic diets containing graded levels of maize starch (10, 15, 20, 25, and 30%) were formulated. Results demonstrated that weight gain (WG), specific growth rate (SGR), protein efficiency ratio (PER), protein productive value (PPV), and energy productive value (EPV) increased with increasing dietary maize starch up to 25% (P < 0.05), and thereafter WG, SGR, PER, PPV, and EPV declined. Hepatosomatic index and viscerosomatic index, plasma glucose, triglycerides, and liver glycogen and liver lipid concentration of fish significantly increased with increasing dietary maize starch level (P<0.05). ADC of starch reduced significantly up to 25%, while ADC of dry matter showed a contrary tendency. However, survival, whole body and muscle compositions, and ADCs of protein and lipid showed no significant differences. Dietary maize starch supplements tended to enhance gluconokinase and pyruvate kinase activities of the liver, but no significant differences were observed in activities of hexokinase, phosphofructokinase-1, fructose-1, 6-bisphosphatase, and glucose-6-phosphatase in the liver among dietary treatments. Based on WG and FCR, the appropriate dietary maize starch supplementations of juvenile obscure puffer were estimated to be 23.5 and 22.5% of diet, respectively.

Dietary Maize Starch Influences Growth Performance, Apparent Digestibility Coefficient, and Hepatic Enzyme Activities of Carbohydrate Metabolism in Obscure Puffer, Takifugu obscurus (Abe)

Effects of ammonia exposure on apoptosis, oxidative stress and immune response in pufferfish (Takifugu obscurus).

High temperature induces apoptosis and oxidative stress in pufferfish (Takifugu obscurus) blood cells.

Effects of dietary amylose/amylopectin ratio on growth performance, feed utilization, digestive enzymes, and postprandial metabolic responses in juvenile obscure puffer Takifugu obscurus

Effect of temperature decrease on hemocyte apoptosis of the white shrimp Litopenaeus vannamei

Haemocyte Apoptosis of the Tiger Shrimp Penaeus monodon Exposed to Cadmium

A feeding trial was conducted to determine the effect of dietary dextrin level on growth,activities of digestive enzyme and blood biochemical indices of juvenile obscure puffer,Takifugu obscurus.Five iso-nitrogenous(42%)and iso-lipidic(9%)diets containing graded levels of dextrin(10%,15%,20%,25% and 30%)were prepared.The fish[average weight(10.25±0.51 g)]were stocked in triplicate tanks during a feeding period of 60 days.The results showed that best specific growth rate and feed efficiency occurred for fish fed the diet with dietary dextrin level at 25%.Viscerosomatic index and hepatosomatic index of 30% group were significantly higher than those of 10% group(P0.05),meanwhile liver lipid content of 30% group was also significantly higher than other groups(P0.05).Liver glycogen and total amino acids content in plasma of 10% group were significantly lower than those of other groups(P0.05).Compared with the 10% and 15% groups,amylase activity in hepatopancreas and intestine of other groups was significantly increased(P0.05),while trypsin activity in hepatopancreas of the 30% group decreased significantly(P0.05);total cholesterol and triglycerides content in plasma of the 25% and 30% groups increased significantly(P0.05),while blood urea nitrogen in plasma of other groups decreased significantly(P0.05).Red blood cell counts of 15% and 20% groups were significantly higher than other those of groups(P0.05),while apoptosis ratio,reactive oxygen species and calcium ions content of 30% group were significantly higher than those of other groups(P0.05).However,plasma glucose concentration,aspartate aminotransferase and alanine aminotransferase activity as well as lipase activity in hepatopancreas and intestine of obscure puffer were not affected by dietary dextrin levels.The present results showed that the optimum dextrin level in diets is at 20%-25% for juvenile obscure puffer under the present research conditions.

Effect of dietary dextrin levels on growth,activities of digestive enzyme and blood biochemical indices of juvenile obscure puffer(Takifugu obscurus)

A flow cytometric approach to study intracellular nitric oxide (no) production in shrimp haemocytes

Trascriptome analysis of the Paciﬁc white shrimp Litopenaeus vannamei exposed to nitrite by RNA-seq.

Gene expression of apoptosis-related genes, stress protein and antioxidant enzymes in hemocytes of white shrimp Litopenaeus vannamei under nitrite stress.

Measurement of intracellular nitric oxide (NO) production in shrimp haemocytes by flow cytometry.

Effects of dietary manganese levels on growth, antioxidant defense and immune responses of the juvenile white shrimp, Litopenaeus vannamei, reared in low salinity water

In vitro toxicity of nitrite on haemocytes of the tiger shrimp, Penaeus monodon, using flow cytometric analysis.

Effect of long-term administration of dietary β-1,3-glucan on growth, physiological, and immune responses in Litopenaeus vannamei (Boone, 1931)

Cytotoxicity of nitrite on haemocytes of the tiger shrimp, Penaeus monodon, using flow cytometric analysis

Phagocytic activity, respiratory burst, cytoplasmic free-Ca(2+) concentration and apoptotic cell ratio of haemocytes from the black tiger shrimp, Penaeus monodon under acute copper stress.

Morphologic, physiological and immunological changes of haemocytes from Litopenaeus vannamei treated by lipopolysaccharide

The role of self-esteem and emotion regulation in the associations between childhood trauma and mental health in adulthood: a moderated mediation model

Objective 
To study the relationship of the parental rearing behaviors between the psychological status and post-traumatic stress disorder in the injured deliberately. 
 
Methods 
161 injured people were treated in five hospitals of the Urumqi and evaluated the self-reporting questionnaire-20(SRQ20), 7-items screening scale for PTSD(PTSD7), impact of event scale(IES) and symptom checklist 90(SCL-90 ) in the third and the fourth week injured, including 113 injured people aged at 14~50 years old completed the Egna Minnen av Barndoms Uppfostran (EMBU). Two months after the injury, 113 injured people were interviewed, including 106 injured people diagnosed by Structured Clinical Interview for DSM-IV-TR Axis I Disorders/Patients(SCID-I/P) and 7 injured people were lost. 
 
Results 
Father's preferences correlated with the total score of IES (r=-0.234, P<0.05) and avoid factor(r=-0.309, P<0.01) positively, Mother's emotional warmth and understand correlated with the flashback factor of IES(r=0.194, P<0.05) negatively. The injured people were divided into three groups by diagnosis: the illness-free group, the PTSD group, and other group.Parental preferences correlated with Mental symptoms negatively.Father's punish severely, interference too much, refuse or deny and Mother's interference too much , over protection and punish severely correlated mental symptoms positively.The six subscales of father's rearing behaviors and the five subscales of mother's rearing behaviors had no significant difference. 
 
Parental preferences in childhood can internalizes inside support to protect the psychological trauma in future.Father's punish severely, interference too much, refuse or deny and mother's interference too much, over protection and punish severely can damage mental health and aggravate symptoms after traumatic event.But the influence of parental rearing behaviors is limited to decide whether the injured people suffering from PTSD or other mental disorders. 
 
Key words: 
Deliberate injury; Parental rearing behaviors; Psychological status; Post-traumatic stress disorder

The relationship of the parental rearing behaviors between the psychological status and post-traumatic stress disorder in the injured deliberately

Objective 
To compare the prediction efficiency of four kinds of scale for post-traumatic stress disorder (PTSD) after emergency of a mass injury in Urumqi. 
 
Methods 
The 161 injured subjects were evaluated with 7-Item Screening Scale for PTSD (PTSD7), Self-Reporting Questionnaire-20(SRQ20) , Impact of Event Scale(IES) and Symptom Checklist90 (SCL-90) in the third or the fourth week after the injury , and 155 subjects completed the assessment.Two months after the injury , 128 injured subjects with 27 lost were interviewed and diagnosed based on the Structured Clinical Interview of DSM-IV-TR Axis I Disorders (Patients’ Edition). 
 
Results 
The highest critical scores of the scales’ Youden index were 4 with PTSD7, 10 with SRQ20, 23 with IES and 158 with SCL-90 respectively.The sensitivity rates were 62.0%(31/19), 68.0%(34/16), 77.6%(38/11)and 69.6%(32/14), and the specificity rates were 78.7%(13/48), 78.7%(13/48), 65.6%(21/40)and 62.5%(21/35)respectively for the PTSD, which showed no significant differences (χ2=2.86, 6.38 , P>0.05). The areas under the ROC curve of the four scales were 0.782, 0.777, 0.756 and 0.775 respectively (P<0.01). 
 
All of the four scales can predict PTSD efficiently.PTSD7 is simple and easy to use, so it’s a desirable rating scale to predict PTSD.Traumatic events can cause comprehensive psychological impacts and the severity of psychological trauma may be the most important predictor of PTSD. 
 
Key words: 
Scale; Post-traumatic stress disorder; Prediction efficiency

Prediction efficiency of four kinds of scale for post-traumatic stress disorder

Objective 
To understand the relationship between the post-traumatic stress disorder(PTSD) and coping style in Community residents after the emergency of group injury. 
 
Methods 
The aged 15 years and older residents along the zhong-wan street were assessed with DSM-IV-TR axis I disorder in September 5, 2009 to November 5 and diagnosed with DSM-IV. At the same time they were evaluated by Coping style Questionnaire.The relationship of the post-traumatic stress disorder between the coping style, the demographic characteristics and the degree of exposure were analyzed. 
 
Results 
(1)In comparison of the illness-free group and PTSD group, the coping style have significant difference.The scores of the avoidance, fantasy, guilt and rationalization in PTSD group(0.60±0.21, 0.59±0.21, 0.47±0.30, 0.56±0.21) were higher than the illness-free group(0.43±0.25, 0.43±0.24, 0.24±0.25, 0.40±0.23)(t=8.033, 7.346, 8.314, 7.198, P<0.01). (2)Older age, divorce or widow , more exposure and guilt were significantly associated with PTSD. 
 
The negative coping style is the dangerous factor of PTSD.The important content of the psychological crisis intervention is to guide relevant person deal with active coping style after the stress. 
 
Key words: 
Group event; Post-traumatic stress disorder; Coping style

The relationship between the post-traumatic stress disorder and coping style in Community residents after the emergency of group injury

In this study, the relationship between pruning methods and endogenous hormone contents related to flower bud differentiation of Brigitta blueberries cultivated in Southwest China was studied. We performed the top pruning in June. The contents of endogenous hormones related to flower bud differentiation of blueberry were measured and analyzed. After top pruning, there was no significant change in the content of ethylene among the five endogenous hormones, but top pruning had a significant effect on the content of the other four hormones, which indicated that top pruning could affect flower bud differentiation by regulating the content of endogenous hormones.

Effect of pruning on endogenetic hormone content associated with differentiation of blueberry flower buds

The present study investigated organic manure of southern highbush blueberry cultivated in southwestern China. We studied the efficiency of three organic fertilizers produced from locally accessible resources, namely rapeseed residue (RS-R), cattle manure (Cat-M), and chicken manure (Chi-M). Fruit quality, and soil chemical properties were analyzed. Rapeseed residue at the highest concentrations (2 or 3 kg RS-R plant−1) improved fruit sweetness (total soluble sugar and water-soluble sugar contents) and anthocyanin content, and depressed soil pH.

Effects of organic manure application on blueberry fruit quality and soil condition

A mathematic model to describe the effect of N,P and K fertilizer on potato yields was established using three factors universal quadratic rotation combination design.It indicated that the rank of factor effects on potato yields was N K P,and the interaction among the three factors was found.Based on computer analysis,N 465.00 kg.ha-1,P2O5 398.85 kg.ha-1 and K2O 479.10 kg.ha-1 were needed to reach the peak value of potato yield,44.85 t.ha-1.By testing the result in a field trial,the application of N,P2O5 and K2O selected based on the mathematic model gave the highest yield,with fertilizer cost,profit and efficiency of fertilizer investment being 6 900 Yuan.ha-1,10 800 Yuan.ha-1 and 1.57%,respectively,and the cultivation efficiency was much higher than those of other applications.

Establishment and optimization of mathematic model for N, P and K fertilizer application to potato.

Effects of freeze–thaw actions on mechanical properties and constitutive model for diesel-contaminated soil

Structure-Performance Evolution on Thermal-Oxidative Aging of Ceo2/Sbs Co-Modified Asphalt

Exploration of the Potential Prospect of Rare Earth Compounds in the Antiaging of Asphalt

Effects of Freeze–Thaw Cycles on the Mechanical Properties of the Core-Wall Contact Clay of a Dam

Reutilization of crystalline waste plastics for modified asphalt using twin‐screw extrusion: Polyethylene and polypropylene as typical subjects

Mechanical behavior and constitutive model for loess samples under simulated acid rain conditions

The application of reclaimed asphalt pavement has been widely encouraged due to its significant economic and environmental benefits. However, it is necessary to add rejuvenators to ensure its performance. Currently, bio-oil-based regenerants have attracted attention owing to their advantages of renewability and cost savings. The purpose of this paper is to study the use of recycled vegetable oil waste (R-oil) and recycled polyethylene particles for the regeneration and modification of aged asphalt. Physical, rheological, and chemical tests were used to figure out their influence on the pavement performance of aged asphalt. According to the physical test indices (penetration, softening point, and ductility), the performance of the rejuvenated asphalt was better than that of virgin asphalt. The workability and low-temperature performance of the rejuvenated asphalt were basically the same as those of virgin asphalt, and its fatigue and high-temperature performance were better. Infrared spectroscopy showed that R-oil diluted the high-polarity sulfoxide base of aged asphalt. Gel permeation chromatography showed that its molecular weight dispersion was better than that of aged asphalt. Therefore, R-oil and polyethylene can improve the pavement performance and chemical properties of aged asphalt.

Feasibility study on recycled vegetable oil waste and recycled polyethylene for the modification of aged asphalt

Confirming the content of modifier-SBS accurately is important to control the quality of engineering,the paper studied the method to confirm the content of SBS accurately and reliable.With the method,The content of SBS in the modified asphalt including 4%,5%,6% SBS were detected.The results showed that the experimental error is less than 2%,the method had a high accuracy and precision and meet the requirement for engineering and related standards.

A blow with yellow slurry appeared in the borehole of some hydropower station foundation when curtain grouting was conducting,and grout run out largely.According to the data of the deep collecting well in the workshop foundation,it was found that a weak interlayer with thickness of more than one meter exists in the underlain layer.So the construction was stopped.To find the effect on the foundation stability caused by distribution range and properties,twelve grouting boreholes were used to do the ultrasonic testing.Rock core was used for the single axis compression strength and ultrasonic wave velocity testing,then foundation quality was estimated and weak interlayer thickness and their distribution was revealed.The grouting effect is estimated by comparing ultrasonic wave velocity in grouting order Ⅰ with that of grouting order Ⅱ,finally,it provides important basis for foundation quality check and acceptance.

Rockmass Quality and Grouting Effect Evaluation of Underlain Soft Interlayer in Some Water Power Station

In this paper,the formulae are deduced for the floatation response of heated pipelines laying in liquefied soil on the basis of virtual work principle.A beam model of elastic foundation beam is set up,and a computer program based on finite element method has been developed.This research is to study the effects of several important parameters including the axial force of pipeline,the diameter of pipeline,the length of liquefied zone,and the nonlinear soil constraint.

STUDY ON THE FLOATATION RESPONSE OF HEATED PIPELINES LAYING IN LIQUEFIED SOIL

According to the contrastive in-situ direct shear test of the slide zone in the Three-gorges Reservoir Region in different conditions,changed rule of direct shear strength parameters and the value of c and■which change along with water content about three kinds of soil of slide zone in different water contents conditions,such as clay,silty clay and the earth-rock aggregate,is researched.Experimental relationship between values of c and■and water conyenton soils of slide zone is established based on plentiful data;and functionary mechanism of different characterized soil of soils zone caused by water is analyzed;then experimental formula of value of c and■when water is sluiced or water content changes;finally softening degree of direct shear strength parameters caused by water content(water level changing)is quantified.

Research on softening rule of direct shear strength parameters of soil of slide zone in Three-Gorge Reservoir Region caused by water

In this paper a data visualization components system was designed. The administrative division component, the city grid component, the statistics analysis component and the custom component were provided in the system to demonstrate the multimedia data. Various types of data and graphics could be auto analyzed by the adaptive ferry engine which was the key function in this system, then the data graphical presentation preferred list was shown to the users. So a data collection, data analysis, decision-making platform was constructed. An intelligent combination mode about the data and the data visualization was realized in this system.

2010 2nd International Workshop on Database Technology and Applications

Integration and Design of a Data Visualization Components System

A Method of the Rules Extraction for Fault Diagnosis Based on Rough Set Theory and Decision Network

Guided by the theory of "visualization" of equipment support,this paper discusses the research content and construction goals of maintenance support resource visualization management platform based on equipment maintenance support of missile troops.The overall framework model of the system is brought forward.Its hardware,software and architecture are analyzed.Application of key techniques in the visualization management platform is explained.

Construction of Visualized Management Platform for Equipment Maintenance Support Resource

This paper analyzes the product's design process and the constitution,relationship and function of design process management model.The concept and contents of task management are elaborated in this paper.On the base of analyzing the requirement of task management model,an object-oriented task model for design process management in DL-PDM system is set up,and the dynamic control of the design process management to design process is realized.

Research on Task Model Based on Design Process Management of DL-PDM System

Liquid–liquid equilibrium for the ternary systems of water + acetyl acetone + propyl acetate at several temperatures

Di-esters of lubricating oil are synthesized by the reaction of o-phthalic acid or sebacic acid with 2-ethylhexyl alcohol or dodecanol in the solvent-free conditions under microwave irradiation. Effect of catalyst amount, microwave power and reaction time on the yield was investigated. The results show that for microwave power of 280 w ∼ 320 w, catalyst amount of 2.5% ∼ 3.0% and 4.9∼ 9 min the yields of di-esters are 96% ∼ 99%. Their chromaticity and crystallization points are measured and the structures have been characterized by 1H NMR, 13C NMR and IR spectra. Compared with conventional synthesis method, the solvent-free microwave method makes the yields of the di-esters increase by 3%∼16% and the reaction times are shorted by a factor of 13.3∼24.5. The present method offers several advantages such as simple, rapid, excellent yields and good chromaticity of production.

2011 International Conference on Remote Sensing, Environment and Transportation Engineering

Solvent-free synthesis of di-esters of o-phthalic acid and sebacic acid for lubrication oil under microwave irradiation

Liquid−liquid equilibrium (LLE) data of the solubility curves for ternary systems of water + pentane-2,4-dione + ethyl ethanoate and tie-line compositions for both of the ternary systems of water + pentane-2,4-dione + ethyl ethanoate and water + pentane-2,4-dione + cyclohexane were determined at (298.15 and 313.15) K and at a pressure of 101.3 kPa. Distribution coefficients were evaluated for the immiscible region. The reliability of the experimental tie-lines has been confirmed by using the Othmer−Tobias correlation. The experimental data were fitted using the nonrandom two-liquid (NRTL) and universal quasichemical activity coefficient (UNIQUAC) equations; parameters of these two models were regressed.

Liquid−Liquid Equilibrium of (Water + Pentane-2,4-dione + Ethyl Ethanoate) and (Water + Pentane-2,4-dione + Cyclohexane) at (298.15 and 313.15) K

Isobaric vapor−liquid equilibrium (VLE) data for (acetic acid + cyclohexane) and (cyclohexane + acetylacetone) were determined at a pressure of 101.3 kPa and those for (acetic acid + acetylacetone) at a pressure of 60.0 kPa. A minimum boiling azeotrope was found for (acetic acid + cyclohexane). The nonideality of the vapor phase of (acetic acid + acetylacetone) and (acetic acid + cyclohexane) was investigated by using the Hayden−O’Connell equation. Thermodynamic consistency was tested for all of the VLE data. The experimental data were correlated satisfactorily by the Wilson, NRTL, and UNIQUAC models. Correlation results were in good agreement with experimental data.

Isobaric Vapor−Liquid Equilibria for (Acetic Acid + Cyclohexane) and (Cyclohexane + Acetylacetone) at a Pressure of 101.3 kPa and for (Acetic Acid + Acetylacetone) at a Pressure of 60.0 kPa

Mechanical, tribological and electrical properties of TiN coatings on 304 stainless steel were investigated and the effects of microstructure and residual stress on these properties were studied. Microstructure, surface roughness, hardness and preferred orientation of the coatings were investigated by AFM, SEM, nanoindentation and XRD. Residual stress of the coatings was designed and controlled in a relatively narrow range successfully using negative bias voltage based on the film thickness effect on residual stress. Residual stress was investigated by grazing-incidence X-ray diffraction using the optimized cosα sinψ method. Friction behavior and wear characteristics were evaluated using a tribometer. The results indicate a great influence of microstructure and residual stress on the properties and service behavior of TiN coatings. Based on the experimental findings, an intermediate residual stress and proper microstructure are of vital importance to achieve better performance of coatings during service.

Residual stress and microstructure e ff ects on mechanical , tribological and electrical properties of TiN coatings on 304 stainless steel

Residual stress in thin films and coatings strongly affects their properties and behavior in service. Comprehensive understanding and precise measurements of residual stress are prerequisites for preparing high quality films and coatings. Residual stresses in TiN films with different thickness were measured by X-ray diffraction (XRD) employing the cosα sinψmethod with certain optimization. Grazing incidence parallel beam optics was combined with side-inclination geometry using in-house designed sample stage to ensure results accuracy. To validate this method, TiN films with thickness ranging from 1 to 3 μm were deposited on (100) Si single crystal substrates at 300 °C by RF magnetron sputtering. High compressive −2 GPa residual stress was present in the 0.9 μm thick film and decreased with film thickness. Tensile stress of less than 0.3 GPa was present in 2 μm TiN film. Compressive-to-tensile residual stress transition was observed with the film thickness increase. Microstructure change with growth, annihilation of grain boudaries, atomic peening and recovery mechanisms are responsible for the reported stress sign transition.

Film thickness e ff ect on texture and residual stress sign transition in sputtered TiN thin fi lms

In-situ TEM observation of cementite coarsening behavior of 5Mn steel during tempering

Micro-hole texture and micro-square-column array texture were prepared on the surface of 316L stainless steel with an anosecond-laser so as to improve its wear resistance.The friction and wear behavior of the stainless steel after laser surface texturing treatment was evaluated with a UMT-2 friction and wear tester.Results indicate that,under the same normal load and sliding velocity,a deep and wide wear scar is formed on the untreated stainless steel surface,and a shallow and narrow wear scar is formed on the laser textured stainless steel surface.Besides,the frictional resistance of the textured surface is more stable than that of the untreated surface,and it declines with increasing amount of the micro-hole texture and micro-square-column array texture.In one word,both the micro-hole texture and micro-square-column array texture can increase the wear resistance of the stainless steel,and the former has a better friction-reducing ability than that of the latter.This is because the micro-hole texture is able to well store lubricating oil thereby maintaining a continuous lubricating film and improving lubricating performance through secondary lubrication under depleted oil-lubricated condition.

Friction and Wear Behavior of 316L Stainless Steel with Laser Micro-Hole Texture and Micro-Square-Column Array Texture

Complex biological processes such as plant growth and development are often under the control of transcription factors that regulate the expression of large sets of genes and activate subordinate transcription factors in a cascade-like fashion. Here, by screening candidate photosynthesis-related transcription factors in rice, we identified a DREB (Dehydration Responsive Element Binding) family member, OsDREB1C, in which expression is induced by both light and low nitrogen status. We show that OsDREB1C drives functionally diverse transcriptional programs determining photosynthetic capacity, nitrogen utilization, and flowering time. Field trials with OsDREB1C-overexpressing rice revealed yield increases of 41.3 to 68.3% and, in addition, shortened growth duration, improved nitrogen use efficiency, and promoted efficient resource allocation, thus providing a strategy toward achieving much-needed increases in agricultural productivity. Description Genetic improvement drives rice yield Improvements in agricultural productivity could lessen the impact of agriculture on the environment and perhaps supply more food from less land. Working in rice, Wei et al. identified a transcription factor that, when overexpressed, has a variety of useful effects (see the Perspective by Kelly). The gene’s expression is induced by both light and low-nitrogen status, and it regulates photosynthetic capacity, nitrogen utilization, and flowering time. In field trials, plants overexpressing this gene delivered greater yield, shortened growth duration, and improved nitrogen use efficiency. —PJH Overexpression of a single transcription factor improves the agricultural productivity of rice. INTRODUCTION Rapid population growth, rising meat consumption, and the expanding use of crops for nonfood and nonfeed purposes increase the pressure on global food production. At the same time, the excessive use of nitrogen fertilizer to enhance agricultural production poses serious threats to both human health and the environment. To achieve the required yield increases and make agriculture more sustainable, intensified breeding and genetic engineering efforts are needed to obtain new crop varieties with higher photosynthetic capacity and improved nitrogen use efficiency (NUE). However, progress has been slow, largely due to the limited knowledge about regulator genes that potentially can coordinately optimize carbon assimilation and nitrogen utilization. RATIONALE Transcription factors control diverse biological processes by binding to the promoters (or intragenic regions) of target genes, and a number of transcription factors have been identified that control carbon fixation and nitrogen assimilation. A previous comparative analysis of maize and rice leaf transcriptomes and metabolomes revealed a set of 118 candidate transcription factors that may act as regulators of C4 photosynthesis. We screened these transcription factors for their responsiveness to light and nitrogen supply in rice, and found that the gene Dehydration-Responsive Element-Binding Protein 1C (OsDREB1C), a member of the APETALA2/ethylene-responsive element binding factor (AP2/ERF) family, exhibits properties expected of a regulator that can simultaneously modulate photosynthesis and nitrogen utilization. RESULTS OsDREB1C expression is induced in rice by both light and low-nitrogen status. We generated overexpression lines (OsDREB1C-OE) and knockout mutants (OsDREB1C-KO) in rice, and conducted field trials in northern, southeastern, and southern China from 2018 to 2021. OsDREB1C-OE plants exhibited 41.3 to 68.3% higher yield than wild-type (WT) plants due to increased grain number per panicle, elevated grain weight, and enhanced harvest index. We observed that light-induced growth promotion of OsDREB1C-OE plants was accompanied by enhanced photosynthetic capacity and concomitant increases in photosynthetic assimilates. In addition, 15N feeding experiments and field studies with different nitrogen fertilization regimes revealed that NUE was improved in OsDREB1C-OE plants due to elevated nitrogen uptake and transport activity. Moreover, OsDREB1C overexpression led to more efficient carbon and nitrogen allocation from source to sink, thus boosting grain yield, particularly under low-nitrogen conditions. Additionally, the OsDREB1C-OE plants flowered 13 to 19 days earlier and accumulated higher biomass at the heading stage than WT plants under long-day conditions. OsDREB1C is localized in the nucleus and the cytosol and functions as a transcriptional activator that directly binds to cis elements in the DNA, including dehydration-responsive element (DRE)/C repeat (CRT), GCC, and G boxes. Chromatin immunoprecipitation sequencing (ChIP-seq) and transcriptomic analyses identified a total of 9735 putative OsDREB1C-binding sites at the genome-wide level. We discovered that five genes targeted by OsDREB1C [ribulose-l,5-bisphosphate carboxylase/oxygenase small subunit 3 (OsRBCS3), nitrate reductase 2 (OsNR2), nitrate transporter 2.4 (OsNRT2.4), nitrate transporter 1.1B (OsNRT1.1B), and flowering locus T-like 1 (OsFTL1)] are closely associated with photosynthesis, nitrogen utilization, and flowering, the key traits altered by OsDREB1C overexpression. ChIP-quantitative polymerase chain reaction (ChIP-qPCR) and DNA affinity purification sequencing (DAP-seq) assays confirmed that OsDREB1C activates the transcription of these genes by binding to the promoter of OsRBCS3 and to exons of OsNR2, OsNRT2.4, OsNRT1.1B, and OsFTL1. By showing that biomass and yield increases can also be achieved by OsDREB1C overexpression in wheat and Arabidopsis, we have demonstrated that the mode of action and the biological function of the transcription factor are evolutionarily conserved. CONCLUSION Overexpression of OsDREB1C not only boosts grain yields but also confers higher NUE and early flowering. Our work demonstrates that by genetically modulating the expression of a single transcriptional regulator gene, substantial yield increases can be achieved while the growth duration of the crop is shortened. The existing natural allelic variation in OsDREB1C, the highly conserved function of the transcription factor in seed plants, and the ease with which its expression can be altered by genetic engineering suggest that this gene could be the target of future crop improvement strategies toward more efficient and more sustainable food production. OsDREB1C coordinates yield and growth duration. OsDREB1C was identified by its responsiveness to light and low nitrogen in a screen of 118 transcription factors related to C4 photosynthesis. Transcriptional activation of multiple downstream target genes by OsDREB1C confers enhanced photosynthesis, improved nitrogen utilization, and early flowering. Together, the activated genes cause substantial yield increases in rice and wheat.

A transcriptional regulator that boosts grain yields and shortens the growth duration of rice

The fluorinated graphene (FG) is modified to get the amino-FG (AFG) which is applied as nanofiller of the polyimide (PI). The repulsion between the C-F bonds endows the AFG with well dispersion in polyimide (PI) matrix, and the amino groups of the AFG react with pyromellitic dianhydride to form strong physical and chemical interactions between the AFG and the PI chains. The results exhibit that the AFG obviously enhances the thermal stability, mechanical performances and wear resistant properties of the PI. When the AFG content reaches 0.5 wt%, the PI/AFG-0.5 composite shows the 35.5% higher tensile stress and 50% higher wear resistance than the PI, which are also higher than the PI/FG-0.5. The strong physical and chemical interactions between the AFG and the PI matrix enhance the interfacial compatibility of the PI/AFG composite, which is better to transfer the stress and heat, so as to enhance the mechanical and tribological properties of the PI. The worn surface changes of the PI/AFG composites indicate that the tribological mechanisms are the synergistic reaction of the abrasive wear and the fatigue wear.

Impacts of polyimide enhanced by amino-modified fluorinated graphene: Thermal, mechanical and tribological behaviors

Heterostructured rGO/MoS2 nanocomposites toward enhancing lubrication function of industrial gear oils

High performance lubricants prepared from Naphthalene-1,4,5,8-Tetracarboxylic acid: Synthesis, physicochemical and Tribological properties

Sugars are essential to the fundamental processes required for plant growth and development. The hexose sugars glucose and fructose are central to most metabolic pathways and serve as the raw material for organic matter in plants. Fructose accounts for half of the hexose generated by sucrose cleavage, and it can be phosphorylated either by fructokinase (FRK) or hexokinase (HXK). FRKs are the main fructose phosphorylating enzymes because their substrate specificity and affinity for fructose are much higher than those of the HXK, and thereby regulate fructose concentration and the distribution and flow of organic carbon in cells. Therefore, FRKs are considered to be of critical importance for all metabolic pathways and the formation of organic matter in plants. To date, all plant FRKs have been assigned to the phosphofructokinase type B subfamily, a large group within the sugar kinase family. Unlike mammalian FRKs, which phosphorylate fructose to form fructose 1-phosphate (F1P), plant FRKs, similar to bacterial FRKs, phosphorylate fructose to form fructose 6-phosphate (F6P). Moreover, there are both cytosolic and plastidic FRKs in plants, indicating that they play roles in different cellular compartments. Phylogenetic analysis shows that most of the FRK genes that are located on similar branches encode proteins with similar subcellular localizations, suggesting that they may perform similar functions. A large number of studies have implicated plant FRKs in vascular tissue development, and in recent years, it has been found that FRK is related to seed, fruit, and pollen development. FRK can also interact with the plant FLOWERING LOCUS T protein to co-regulate flowering. Additionally, a large number of experiments have shown that FRK affects chloroplast development mainly by affecting chloroplast gene expression, thus affecting photosynthesis and the source-sink relationship. Beyond these functions, FRK, as an important carbon flux-regulated kinase in plants, also plays an important role in plant stress response and can be used as an early marker of stress response signaling. Despite the fact that numerous studies have highlighted the functions and importance of FRK, detailed studies on the physiological and metabolic functions of this enzyme and the underlying regulatory mechanisms are lacking. Most research on FRK has been focused on model plants such as Arabidopsis thaliana , and limited progress has been made studying FRK functions in crops. With the aim of systematically summarizing the characteristics of FRKs and their important roles in plant life activities, this paper reviews their roles in regulating plant growth and development, responding to stress, and regulating photosynthetic and metabolic pathways. In addition, several scientific questions about FRKs are discussed, including whether they act as sugar-sensing signals, whether they are involved in plant defense processes, how they regulate plant source-sink metabolism, whether they are involved in regulating the phase transitions from the vegetative to reproductive growth, and whether there is redundancy in function among family members. Recently developed omics and gene editing technologies are expected to be applied toward answering these questions and discovering the related regulatory networks in order to fully understand the role of FRKs in plant sugar metabolism.

Self-dispersing complex lithium-based thickener fiber for high-performance anti-corrosion/wear epoxy coating filler

Tribological Properties of SiO2@Cu and SiO2@MoS2 Core–Shell Microspheres as Lubricant Additives

Abstract Nanomaterials have been developed to solve kinds of water pollution problems. Fluorinated graphene (FG) and multi-walled carbon nanotubes (MWCNTs) are used to improve the efficiency of oil/water separation of sponge via forming MWCNTs/FG/PU sponge in this work. The tests show that the two-dimensional FG can be adsorbed on the PU sponge, and one-dimensional MWCNTs can intertwine on the FG nanosheets as threads to fix on the skeletons of the PU sponge, which will form the micro-nano hierarchical structures and low surface energy surface. The surface contact angle of the MWCNTs/FG/PU sponge comes to the point of 158°, which indicates the MWCNTs/FG/PU sponge is superhydrophobic. The superhydrophobic MWCNTs/FG/PU sponge has outstanding ability to separate various oil/water mixtures effectively, and the corresponding absorbency of oils and organic reagents is over 15 g/g. Graphical Abstract

The simple preparation of superhydrophobic sponge with fluorinated graphene and carbon nanotube

Enhancing the tribological properties of boron nitride by bioinspired polydopamine modification

Evaluating tribological properties of the stearic acid-based organic nanomaterials as additives for aqueous lubricants

This paper presents the facile synthesis of two different morphologies of WS2 nanomaterials—WS2 hexagonal nanoplates and nanoflowers—by a sulfurization reaction. The phases and morphology of the samples were investigated by X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The tribological performance of the two kinds of WS2 nanomaterials as additives in paraffin oil were measured using a UMT (Universal Mechanical Tester)-2 tribotester. The results demonstrated that the friction and wear performance of paraffin oil can be greatly improved with the addition of WS2 nanomaterials, and that the morphology and content of WS2 nanomaterials have a significant effect on the tribological properties of paraffin oil. The tribological performance of lubricating oil was best when the concentration of the WS2 nanomaterial additive was 0.5 wt %. Moreover, the paraffin oil with added WS2 nanoflowers exhibited better tribological properties than paraffin oil with added WS2 hexagonal nanoplates. The superior tribological properties of WS2 nanoflowers can be attributed to their special morphology, which contributes to the formation of a uniform tribo-film during the sliding process.

Preparation and Tribological Properties of WS2 Hexagonal Nanoplates and Nanoflowers

Comparative study on corrosion resistance and lubrication function of lithium complex grease and polyurea grease

The influences of functionalized carbon nanotubes as lubricating additives: Length and diameter

Lubricating properties of ester oil prepared from bio-based 2,5-furandicarboxylic acid

Tuning the structures of boron nitride nanosheets by template synthesis and their application as lubrication additives in water

The ecotoxicity and tribological properties of choline amino acid ionic liquid lubricants

Synthesis of Ultrathin WS2 Nanosheets and Their Tribological Properties as Lubricant Additives

Tribological properties of fluorinated graphene reinforced polyimide composite coatings under different lubricated conditions

Although the fluorinated graphene (FG) possesses numerous excellent properties, it can not be really applied in aqueous environments due to its high hydrophobicity. Therefore, how to achieve hydrophilic FG is a challenge. Here, a method of solvent-free urea melt synthesis is developed to prepare the hydrophilic urea-modified FG (UFG). Some characterizations via transmission electron microscopy (TEM), atomic force microscopy (AFM), Fourier transfer infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), and thermo gravimetric analysis (TGA) demonstrate that the urea molecules can covalently functionalize the FG and the hydrophilic UFG can be prepared. According to the tribological tests run on an optimal-SRV-I reciprocation friction tester, it can be found that the antiwear ability of water can be largely improved by adding the appropriate UFG. When the concentration of UFG aqueous dispersion is 1 mg/mL, the sample of UFG-1 has the best antiwear ability with a 64.4% decrease of wear rate compared with that of the pure water (UFG-0), demonstrating the prepared UFG can be used as a novel and effective water-based lubricant additive.

Covalent Functionalization of Fluorinated Graphene and Subsequent Application as Water-based Lubricant Additive.

Synthesis of highly luminescent fluorinated graphene quantum dots with tunable fluorine coverage and size

Fluorinated graphene reinforced polyimide films with the improved thermal and mechanical properties

A novel application of mesoporous silica nanospheres on effective retention and delivery of lubricating oil

Solvothermal Synthesis of Ni/Reduced Graphene Oxide Composites as Electrode Material for Supercapacitors

Series of polyimide (PI)/mesoporous silica nanospheres (MSNs) nanocomposite films with different contents of MSNs were successfully prepared via a simple wet impregnation method. The morphologies, microstructures, mechanical properties, transmittance, and thermal properties of the prepared PI and the PI/MSNs nanocomposite films were investigated in detail. As a result, the thermal stability and mechanical performances of PI were obviously improved by incorporating MSNs into PI. The tensile stress and Young's modulus of the nanocomposite film with 5 wt % MSNs were raised up to 97.65 MPa and 2220.06 MPa, which are greatly higher than the values of 82.51 MPa and 1440.86 MPa for the pure PI film. Experimental results confirmed that the designed polymerization tactic, which occurred in the pores of the MSNs, facilitated to enhance the mechanical and physical performances of the PI/MSNs nanocomposite films, and definitely induced better integration between organic matrix and inorganic nanofillers. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 41173.

Mechanical properties and thermostability of polyimide/mesoporous silica nanocomposite via effectively using the pores

A promising direct carbon fuel cell based on the cathode-supported tubular solid oxide fuel cell technology

The distribution automation system (DAS) is vulnerable to cyber-attacks due to the widespread use of terminal devices and standard communication protocols. On account of the cost of defense, it is impossible to ensure the security of every device in the DAS. Given this background, a novel quantitative vulnerability assessment model of cyber security for DAS is developed in this paper. In the assessment model, the potential physical consequences of cyber-attacks are analyzed from two levels: terminal device level and control center server level. Then, the attack process is modeled based on game theory and the relationships among different vulnerabilities are analyzed by introducing a vulnerability adjacency matrix. Finally, the application process of the proposed methodology is illustrated through a case study based on bus 2 of the Roy Billinton Test System (RBTS). The results demonstrate the reasonability and effectiveness of the proposed methodology.

Quantitative vulnerability assessment of cyber security for distribution automation systems

In this paper, some boundary charging cases under unidirectional and bidirectional mode are considered to set the upper and lower bounds of the cumulative power delivery to PHEVs. A new index, Vflex has been proposed to quantify the flexibility provided by PHEV fleet to the power system. Empirical driving dataset is used to set up the numerical value of the boundaries. Then, based on the above idea, power constraints and energy constraints of aggregate PHEV fleet charging behavior are incorporated into the formulation of unit commitment (UC). A 10-unit system with different penetration levels of PHEVs is studied to show the benefit of system scheduling considering flexible PHEVs charging. Our study shows that a PHEV fleet used as load shifter can provide more economic benefits than used as a replacement of spinning reserve. It is also identified that the main bottleneck of flexibly using vehicle to grid technology (V2G) in unit commitment is the capacity of the batteries instead of the charging and discharging ability.

Electric vehicles (EVs) will play an important role in the future smart grids. In order to implement the charging/discharging optimization and control for numerous electric vehicles, a large amount of data will be generated and transmitted. The communication of vast information imposes a significant challenge to the performance of the communication network in a charging station of EVs. Given this background, the characteristics of different types of data are analyzed first. Then, simulations of the communication network in a charging station of EVs are carried out by employing the optimized network engineering tool (OPNET). Simulation results demonstrate that giving a higher priority to the important data is helpful for maintaining the normal work of charging/discharging when the code rate of the video monitoring information is high. In some scenarios, establishing a dedicated network for transmitting video monitoring information is a better option.

2014 IEEE PES Asia-Pacific Power and Energy Engineering Conference (APPEEC)

OPNET-based performance analysis of the communication network in a charging station of electric vehicles

Based on the interaction mode on customer side,the generation and load integrated static security checking mode and model are developed.In this mode,both the generation and demand side interactive resources can be optimized at the same time to improve the security performance of system after N-1 contingency in the stressed cases.In response to computational difficulties brought by N-1 contingency constraints and interaction loads in large scale systems,a decomposition algorithm with identification method of active interaction integer variables is proposed,and the optimization space as well as the computation complexity of the mix-integer program problem can be effectively reduced by using this algorithm.The effectiveness of the model and algorithm proposed are demonstrated by numerical experiments on a New England 39-bus system.

Generation and Load Integrated Static Security Checking on Interaction Mode on Customer Side

The operation data of bank are dispersedly stored at different databases (maybe isomorphic, or isomerous ), which are not easy to be queried by accessing. Furthermore, a large number of historical data are stored offline, so they can not be queried online. The appearance of the grid presents a new method for solving this problem. In this paper, the method of the resource sharing under the environment of financial network was designed. Based on this method, an example of financial service was put forward. On this test bed some financial services were deployed, thus realizing the accessing of the isomerous database. The result proves that the problem of resource sharing under the environment of financial grid can be well solved by using grid, and the information island can be removed.

Design of Financial Grid Frame and Simulation Analysis of Financial Data

Differential evolution-assisted salp swarm algorithm with chaotic structure for real-world problems

Boosting whale optimization with evolution strategy and Gaussian random walks: an image segmentation method

Melanoma is a malignant tumor formed by the cancerous transformation of melanocytes, and its medical images contain much information. However, the percentage of the critical information in the image is small, and the noise is non-uniformly distributed. We propose a new multi-threshold image segmentation model based on the two-dimensional histogram approach to the above problem. We present an enhanced ant colony optimization for continuous domains (EACOR) in the proposed model based on the soft besiege and chase strategies. Further, EACOR is combined with two-dimensional Kapur’s entropy to search for the optimal thresholds. An experiment on the IEEE CEC2014 benchmark function was conducted to measure the reliable global search capability of the EACOR algorithm in the proposed model. Moreover, we have also conducted several sets of experiments to test the validity of the image segmentation model proposed in this paper. The experimental results show that the segmented images from the proposed model outperform the comparison method in several evaluation metrics. Ultimately, the model proposed in this paper can provide high-quality samples for subsequent analysis of melanoma pathology images.

Multi-threshold image segmentation for melanoma based on Kapur’s entropy using enhanced ant colony optimization

The sine cosine algorithm (SCA) was proposed for solving optimization tasks, of which the way to obtain the optimal solution is mainly through the continuous iteration of the sine and cosine update formulas. However, SCA also faces low population diversity and stagnation of locally optimal solutions. Hence, we try to eliminate these problems by proposing an enhanced version of SCA, named ESCA_PSO. ESCA_PSO is proposed based on hybrid SCA and particle swarm optimization (PSO) by incorporating multiple mutation strategies into the original SCA_PSO. To validate the effect of ESCA_PSO in handling global optimization problems, ESCA_PSO was compared with quality algorithms on various types of benchmark functions. In addition, the proposed ESCA_PSO was employed to tune the best parameters of support vector machines for dealing with medical diagnosis tasks. The results prove the efficiency of the proposed algorithms in solving optimization problems.

Boosted Sine Cosine Algorithm with Application to Medical Diagnosis

The whale optimization algorithm (WOA) is a powerful swarm intelligence method which has been widely used in various fields such as parameter identification of solar cells and PV modules. In order to better balance the exploration and exploitation of WOA, we propose a novel modified WOA (MWOA) in which both the mutation strategy based on Levy flight and a local search mechanism of pattern search are introduced. On the one hand, Levy flight can make the algorithm get rid of the local optimum and avoid stagnation; thus, it is able to prevent the algorithm from losing diversity and to increase the global search capability. On the other hand, pattern search, a direct search method, has not only high convergence rate but also good stability, which can boost the local optimization ability of the WOA. Therefore, the combination of these two mechanisms can greatly improve the capability of WOA to obtain the best solution. In addition, MWOA may be employed to estimate parameters in single diode model (SDM), double diode model (DDM), and PV modules and to identify unknown parameters of two different types of PV modules under diverse light irradiance and temperature conditions. The analytical results demonstrate the validity and the practicality of MWOA for estimating parameters of solar cells and PV modules.

Modified Whale Optimization Algorithm for Solar Cell and PV Module Parameter Identification

MFeature: Towards high performance evolutionary tools for feature selection

Evolutionary shuffled frog leaping with memory pool for parameter optimization

Boosting Slime Mould Algorithm for Parameter Identification of Photovoltaic Models

Horizontal and vertical crossover of Harris hawk optimizer with Nelder-Mead simplex for parameter estimation of photovoltaic models

A multi-strategy enhanced salp swarm algorithm for global optimization

Levy-based antlion-inspired optimizers with orthogonal learning scheme

Quantum-like mutation-induced dragonfly-inspired optimization approach

Based on particle swarm optimization (PSO) algorithm and its power system reactive power optimization method to in-depth study and research proposed a new hybrid particle swarm optimization algorithm (HPSO). Algorithm combines the differential evolution algorithm and simulated annealing algorithm and particle swarm optimization algorithm, in particle searching optimal except for tracking individual and global, and tracks produced by particle information difference of the three value. At the same time, when the particle search space of one dimension speed lower than the setting value will be re initialized the dimensional particle velocity and the particle of differential evolution mutation. For the crossover and mutation operations, new solution may be worse than the original solution to, the introduction of simulated annealing algorithm, the metropolis rule in a certain extent accept bad solutions, allows the target function in a certain degree of deterioration, practical calculation is not according to the probability to choose the poor solution, but rather the judgment target function difference is less than allows the target function deterioration range. Hybrid particle swarm optimization algorithm combines the advantages of particle swarm optimization algorithm, differential evolution algorithm and simulated annealing algorithm, to maintain the diversity of particles, has very strong practicability.

Improved Particle Swarm Optimization Algorithm for Optimization of Power Communication Network

AbstractIn this paper, we present the induced uncertain Euclidean ordered weighted averaging distance (IUEOWAD) operator. It is an extension of the OWA operator that uses the main characteristics of the induced OWA (IOWA), the Euclidean distance and uncertain information represented by interval numbers. The main advantage of this operator is that it is able to consider complex attitudinal characters of the decision-maker by using order-inducing variables in the aggregation of the Euclidean distance. Moreover, it is able to deal with uncertain environments where the information is very imprecise and can be assessed with interval numbers. We study some of its main properties and particular cases such as the uncertain maximum distance, the uncertain minimum distance, the uncertain normalized Euclidean distance (UNED), the uncertain weighted Euclidean distance (UWED) and the uncertain Euclidean ordered weighted averaging distance (UEOWAD) operator. We also apply this aggregation operator to a group decision-m...

Uncertain group decision-making with induced aggregation operators and Euclidean distance

Hygrocybe pseudoacutoconica, a new species in subg. Hygrocybe sect. Hygrocybe subsect. Macrosporae, is characterized by small and non-blackening basidiomata; orange to reddish orange pileus; free, white, and broad lamellae; regular lamellar trama; and ellipsoid to oblong basidiospores [(7–)9–11(–12) × 5–7 μm]. Phylogeny overview of the genus Hygrocybe confirmed the phylogenetic position of the new species.

Hygrocybe pseudoacutoconica (Hygrocybeae, Hygrocyboideae, Hygrophoraceae), a new species from a South China Sea island

A novel Talaromyces species was isolated from a soil sample of the Xisha Islands, Hainan, China. The culture characterization on four standardized media, microscopic observations and phylogenetic analyses based ITS, BenA and CaM regions indicate that it is new to science and named as Talaromyces xishaensis sp. nov. The new species belongs to section Talaromyces , and is related to T. cnidii , T. flavovirens and T. siamensis in the phylogeny inferred from BenA and CaM genes. It is distinguished from the latter three species by colony morphology, more metulae per verticil, subglobose to ellipsoidal conidia, and slow growth rate on CYA at 37 °C.

A new species of Talaromyces (Trichocomaceae) from the Xisha Islands, Hainan, China

Marasmius albopurpureus, a new species of section Globulares from Baili Island, China

'Qiushuo'is a new later-maturing peach cultivar which is derived from the cross 'Dajiubao'×'Xuetao'in 1992.The fruits are big in size,early and gorgeous in color.The average single fruit weight is 350 g.The dense flesh is hard and sweet,freestone.The fruits have higher storability and were stored at room temperature in 7 days.It ripens in early August in Zhengzhou and has high fertility.

Graphene nanoplatelets reinforced NiCu composite manufactured by laser melting deposition

Effects of circular oscillating laser on microstructure and mechanical property of nickel-based superalloy by laser melting deposition

Effects of circular beam oscillation on microstructure, mechanical and electrochemical corrosion properties of laser melting deposited Inconel 625

The deposition samples of Cr12MoV with different scanning speeds are prepared by laser melting deposition technology. Compared with forged Cr12MoV, the mechanism of laser melting deposition technology to improve hardness and wear resistance is studied. The tensile specimens of as‐deposited Cr12MoV are prepared by using the optimal process parameters. The fracture mechanism of as‐deposited Cr12MoV and the effect of deposition direction on its mechanical properties are studied. The phase composition and microstructure of deposited and forged samples are studied by X‐Ray diffractometry (XRD) and scanning electron microscope (SEM). The results show that the martensite in the as‐deposited Cr12MoV sample increases and has a finer grain size, which achieves the effect of fine‐grain strengthening. The hardness and wear resistance of the deposited Cr12MoV samples at three laser scanning speeds (4, 8, and 12 mm s−1) are better than those of the forged samples. The tensile fracture mode of the deposited Cr12MoV sample is an intergranular brittle fracture, and the sample perpendicular to the laser scanning speed has higher tensile strength and more excellent elongation.

Study on Microstructure and Mechanical Properties of Cr12mov Alloy Deposited by Laser Melting Deposition

Circular oscillating laser melting deposition of nickel-based superalloy reinforced by WC: Microstructure, wear resistance and electrochemical properties

Numerical simulation and experimental investigation on powder transport of a new-type annular coaxial nozzle

Research on Evaluation of Distributed Enterprise Research and Development (R & D) Design Resources Sharing Based on Improved Simulated Annealing AHP: A Case Study of Server Resources

The max-min fairness is one of the most widely used fairness concepts for resource sharing in communication networks. This paper describes some results related to it.

Background Heparan sulfate proteoglycan syndecan-4 plays an important role in inflammation. However, the role of syndecan-4 in rheumatoid arthritis (RA) has not yet been elucidated. Objectives To detect serum level of syndecan-4 in RA patients and investigate its correlation with RA clinical parameters. Methods The concentration of serum syndecan-4 was assayed by enzyme-linked immunosorbent assay (ELISA). 43 patients9 serum samples from our RA cohort study between 2014 and 2016, and 20 age- and gender-matched osteoarthritis (OA) patients9 serum samples were collected and analyzed. Compared the serum syndecan-4 levels in RA patients with DAS28≥3.2 and DAS28 Results Baseline serum syndecan-4 levels of RA patients were significantly higher than the matched OA patients (1101.56 pg/mL vs 281.41 pg/mL, p Conclusions Compared with age- and gender- matched OA patients, serum syndecan-4 concentration is significantly higher in RA patients. Serum syndecan-4 level is positively correlated with RF. Syndecan-4 may play an important role in thes pathogenesis of RA. Further investigation is required to study the mechanism of syndecan-4 in RA. References Zhao J, Guo J, Wang L, et al. The role of a proliferation-inducing ligand (APRIL) in the pathogenesis of rheumatoid arthritis. Scand J Rheumatol 2014;43(6):462–9. Patterson AM, Cartwright A, David G, et al. Differential expression of syndecans and glypicans in chronically inflamed synovium. Ann Rheum Dis 2008 May;67(5):592–601. Endo T, Ito K, Morimoto J, et al. Syndecan 4 Regulation of the Development of Autoimmune Arthritis in Mice by Modulating B Cell Migration and Germinal Center Formation. Arthritis Rheumatol 2015 Sep;67(9):2512–22. Acknowledgements We are indebted to all the patients who kindly participated in this study. This study was partly supported by Peking University Clinical Research Institute. Disclosure of Interest None declared

SAT0076 Serum level of syndecan-4 and its correlation with clinical parameters in rheumatoid arthritis patients

Case Study on Protection of Property Rights as a Key to Economic Success in China

Around 60% of in vitro fertilized (IVF) human embryos irreversibly arrest before compaction between the 3- to 8-cell stage, posing a significant clinical problem. The mechanisms behind this arrest are unclear. Here, we show that the arrested embryos enter a senescent-like state, marked by cell cycle arrest, the down-regulation of ribosomes and histones and down-regulation of MYC and p53 activity. The arrested embryos can be divided into 3 types. Type I embryos fail to complete the maternal-zygotic transition, and Type II/III embryos have low levels of glycolysis and either high (Type II) or low (Type III) levels of oxidative phosphorylation. Treatment with the SIRT agonist resveratrol or nicotinamide riboside (NR) can partially rescue the arrested phenotype, which is accompanied by changes in metabolic activity. Overall, our data suggests metabolic and epigenetic dysfunctions underlie the arrest of human embryos.

Metabolic and epigenetic dysfunctions underlie the arrest of in vitro fertilized human embryos in a senescent-like state

Around 60% of in vitro fertilized (IVF) human embryos irreversibly arrest before compaction between the 3-8-cell stage, posing a significant clinical problem. The mechanisms behind this arrest are unclear. Here, we show that the arrested embryos enter a quiescent-like state, marked by cell cycle arrest, the downregulation of ribosomes and histones and downregulation of MYC and p53 activity. Mechanistically, the arrested embryos can be divided into three types. Type I embryos fail to complete the maternal-zygotic transition, and type II/III embryos have erroneously low levels of glycolysis and variable levels of oxidative phosphorylation. Treatment with resveratrol or nicotinamide riboside (NR) can partially rescue the arrested phenotype. The mechanism of reactivation involves the upregulation of SIRT1, and activation of glycolysis and fatty acid oxidation which forces the embryos out of a quiescent state. Overall, our data reveal how human embryo arrest can be overcome by modulating metabolic pathways.

Human embryos arrest in a quiescent-like state characterized by metabolic and zygotic genome activation problems

Background: The molecular mechanism in the progression of ovarian clear cell carcinoma (OCCC) remains unclear. Objective: This study aimed to investigate the potential function of RAYLY in OCCC. Methods: To validate RAYLY expression, immunohistochemistry, quantitative real-time PCR and western blotting were performed in OCCC tissues and the cell lines of OCCC and epithelial ovarian carcinoma (EOC). Subsequently, the biological effects of RALYL were evaluated through colony formation, and cell proliferation, migration and invasion assays. Finally, RNA-sequencing and gene set enrichment analysis (GSEA) were conducted to explore potential mechanism of RALYL in OCCC. Results: In our study, RALYL was significantly down-regulated in a majority of OCCC tissues compared to adjacent non-tumorous tissues, and OCCC cells had a lower expression level of RALYL than that of EOC cells. OCCC patients with high RALYL expression had a better pathological stage and prognosis. In vitro, over-expression of RALYL inhibited cell proliferation, migration and invasion in OCCC. GSEA analysis and western blot indicated an enrichment of MAPK and CDH1 signaling pathways in OCCC cells without RALYL over-expression. Conclusions: RALYL played an important role in the progression of OCCC, and might serve as a potential prognostic biomarker and novel therapeutic target for OCCC.

Over-expression of RALYL suppresses the progression of ovarian clear cell carcinoma through inhibiting MAPK and CDH1 signaling pathways

Many studies have shown that Orthosiphon stamineus extract (OE) has antioxidant activity, and we previously reported that OE protects the intestine against injury from a high-fat diet. However, the molecular mechanism underlying this protective effect of OE was unclear. Here, OE was separated according to polarity and molecular weight, and the antioxidant activity of each component was compared. The components with the highest antioxidant activity were analyzed by HPLC, which confirmed that rosmarinic acid (RA) was the main effective constituent in OE. OE and RA were then tested in a mouse high-fat diet-induced intestinal injury model. The antioxidant indices and morphological characteristics of the mouse jejunum were measured, and activation of the nuclear factor E2-related factor 2 (Nrf2) pathway and apoptosis of jejunal epithelial cells were analyzed. Of all the constituents in OE, RA contributed the most. Both RA and OE activated the Nrf2 pathway and increased downstream antioxidant enzyme activity. RA and OE protected the mouse intestine against high-fat diet-induced oxidative stress by preventing intestinal epithelial cell apoptosis via both extracellular and intracellular pathways. Thus, RA, the main effective constituent in OE, inhibits intestinal epithelial apoptosis by regulating the Nrf2 pathway in mice.

Rosmarinic Acid, the Main Effective Constituent of Orthosiphon stamineus, Inhibits Intestinal Epithelial Apoptosis Via Regulation of the Nrf2 Pathway in Mice

O-GlcNAcylation is a dynamic and reversible post-translational modification associated with the regulation of multiple cellular functions. The addition and removal of O-Linked β-N-acetylglucosamine (O-GlcNAc) on target proteins is catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. Accumulating evidence suggests that O-GlcNAcylation is associated with the malignancy of several types of human cancer. To investigate the effect of O-GlcNAcylation on ovarian cancer phenotypes, global O-GlcNAc levels were decreased by OGT silencing through RNA interference and increased by inhibiting OGA activity with Thiamet-G. Transwell assay results demonstrated that OGT silencing inhibited the migration and invasion of SKOV3 and 59M ovarian cells in vitro, while Thiamet-G treatment promoted migration and invasion. Furthermore, a pull-down assay and western blot analysis demonstrated that Thiamet-G treatment enhanced RhoA activity and the phosphorylation of the Rho-associated protein kinase (ROCK) substrate, myosin light chain (MLC), while OGT silencing attenuated RhoA activity and MLC phosphorylation. In addition, RhoA silencing via RNA interference and inhibition of ROCK activity with Y-27632 prevented Thiamet-G-induced increases in cell migration and invasion. These data suggest that O-GlcNAcylation augments the motility of ovarian cancer cells via the RhoA/ROCK/MLC signaling pathway. Therefore, O-GlcNAcylation may be a potential target for the diagnosis and treatment of ovarian cancer.

O-GlcNAcylation promotes migration and invasion in human ovarian cancer cells via the RhoA/ROCK/MLC pathway

Hydrogen sulfide prevents postoperative adhesion in a rat uterine horn model.

O-GlcNAcylation is a dynamic and reversible post‐translational modification associated with the regulation of multiple cellular functions. The addition and removal of O-Linked β‐N‐acetylglucosamine (O‐GlcNAc) on target proteins is catalyzed by O‐GlcNAc transferase (OGT) and O‐GlcNAcase (OGA), respectively. Accumulating evidence suggests that O‐GlcNAcylation is associated with the malignancy of several types of human cancer. To investigate the effect of O‐GlcNAcylation on ovarian cancer phenotypes, global O‐GlcNAc levels were decreased by OGT silencing through RNA interference and increased by inhibiting OGA activity with Thiamet‐G. Transwell assay results demonstrated that OGT silencing inhibited the migration and invasion of SKOV3 and 59M ovarian cells in vitro, while Thiamet‐G treatment promoted migration and invasion. Furthermore, a pull‐down assay and western blot analysis demonstrated that Thiamet‐G treatment enhanced RhoA activity and the phosphorylation of the Rho‐associated protein kinase (ROCK) substrate, myosin light chain (MLC), while OGT silencing attenuated RhoA activity and MLC phosphorylation. In addition, RhoA silencing via RNA interference and inhibition of ROCK activity with Y‐27632 prevented Thiamet‐G‐induced increases in cell migration and invasion. These data suggest that O‐GlcNAcylation augments the motility of ovarian cancer cells via the RhoA/ROCK/MLC signaling pathway. Therefore, O‐GlcNAcylation may be a potential target for the diagnosis and treatment of ovarian cancer.

Abstract. O-GlcNAcylation is a dynamic and reversible post‐translational modification associated with the regulation of multiple cellular functions. The addition and removal of O-Linked β‐N‐acetylglucosamine (O‐GlcNAc) on target proteins is catalyzed by O‐GlcNAc transferase (OGT) and O‐GlcNAcase (OG

We previously identified FOXA1 as a tumor-suppressor in EC cells. In the present study, we sought to delineate the different roles of FOXA1 associated with cell senescence and further investigated the correlation between FOXA1 and p16INK4a in the progression of EC. Using reverse transcription-quantitative PCR (RT-qPCR), we found that FOXA1 expression was significantly downregulated in EC cells compared to that in normal endometrial cells. Functionally, senescence‑associated β-galactosidase staining, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), clonogenic and Transwell assays showed that in addition to acting as a pioneer factor, FOXA1 was significantly upregulated in senescent EC cells. Furthermore, restoration of FOXA1 expression triggered multiple steps of cellular senescence in EC cells and activated p16INK4a expression. All of these findings indicate that FOXA1 promotes cell senescence in EC by interaction with p16INK4a, possibly via the AKT pathway. Notably, a selective PI3K inhibitor raised the possibility that FOXA1‑induced senescence is associated with the AKT pathway in EC cells. Collectively, the present study provides a conceivable molecular mechanism by which cell senescence acts as the barrier to EC, and is regulated by FOXA1-induced p16INK4a expression. This may be a newly identified regulatory mechanism of cell senescence in EC.

Forkhead-box A1 induces cell senescence in endometrial cancer by regulating p16INK4a.

Quantitation of rare circulating tumor cells by folate receptor α ligand-targeted PCR in bladder transitional cell carcinoma and its potential diagnostic significance

Cellular fibronectin (cFN) is one of the main components of tissue extracellular matrices and is involved in multiple physiologic and pathologic processes such as embryogenesis, wound healing, inflammation and tumor progression. The function of fibronectin in regulating normal cell adhesion and migration is well documented, but its function in cancer progression is only partially unraveled. We have reported previously that fibronectin stimulates the proliferation and survival of non-small lung carcinoma cells through upregulation of pro-oncogenic signals related to cyclooxygenase-2/phosphatidylinositol-3-kinase/protein kinase B (COX-2/PI3-K/AKT)/mammalian target of rapamycin triggered by activation of the integrin α5β1. Here, we extend these studies by showing that fibronectin promotes epithelial-mesenchymal transition (EMT) in lung cancer cells. We found that cFN, but not plasma fibronectin or type 1 collagen, induces lung carcinoma cell scattering in vitro, promotes cell migration and invasion of Matrigel and stimulates the expression of the mesenchymal marker α-smooth muscle actin while decreasing the expression of the epithelial marker E-cadherin through PI3-K and Erk pathways. Interestingly, the extra domain A (EDA) within cFN was found to be crucial for this process, as confirmed by testing cells overexpressing EDA or cells exposed to EDA-containing matrices. We found that the integrin α9, but not α5, mediated cFN-induced EMT as silencing integrin α9 neutralized cFN-induced EMT. Overall, our findings show that the EDA domain within cFN induces EMT in lung carcinoma cells through integrin α9-mediated activation of PI3-K and Erk.

The EDA-containing cellular fibronectin induces epithelial-mesenchymal transition in lung cancer cells through integrin α9β1-mediated activation of PI3-K/AKT and Erk1/2.

Renal cell carcinoma (RCC) is the most common malignant tumour of adult kidney (Eble et al., 2004), and RCC’s histopathology is subdivided into various categories, which clear cell renal cell carcinoma (ccRCC) is the most common pathological category, accounting for 70-80% of all RCCs (Young et al., 2001; Matsuura et al., 2011). In the last decades, there have been immense improvements in the treatment of ccRCC, but approximately 30% of the patients would develop to metastatic after surgical therapy (Janzen et al., 2003; Cohen et al., 2005; Chen et al., 2011). Although some environmental and genetic factors have been found to

Associated with Poor Prognosis in Clear Cell Renal Cell Carcinoma

The molecular mechanisms involved in the progression of clear cell renal cell carcinomas (ccRCCs) are still unclear. The aim of this study was to analyse the relationships between expression of RALYL and clinical characteristics. In 41 paired samples of ccRCCs and adjacent normal tissues, we used real-time qPCR to evaluate the expression of RALYL mRNA. RALYL protein levels were determined in 146 samples of ccRCC and 37 adjacent normal tissues by immunohistochemistry. Statistical analysis was used to explore the relationships between expression of RALYL and the clinical characteristics (gender, age, tumor size, T stage, N stage, M stage, survival times and survival outcome) in ccRCC. In addition, these patients were follow-up period 64 months (range: 4~116 months) to investigate the influence on prognosis. We found significantly differences between ccRCC tissues and normal tissues (p<0.001, paired-sample t test) in mRNA levels of RALYL. Immunohistochemistry analyses in 146 ccRCC samples and 37 adjacent normal tissues showed significantly lower RALYL protein levels in ccRCC samples (χ2-test, p<0.001), inversely correlating with tumour size (p=0.024), T stage (0.005), N stage (p<0.001) as well as M stage (p=0.019), but not age (p=0.357) and gender (p=0.348). Kaplan-Meier survival analysis demonstrated that people with lower level of RALYL expression had a poorer survival rate than those with a higher level of RALYL expression, significantly different by the log-rank test (p=0.011). Cox regression analysis indicated that RALYL expression (p=0.039), N stage (p=0.008) and distant metastasis (p<0.001) were independent prognosis factors for the overall survival of ccRCC patients. We demonstrated that the expression of RALYL was significantly low in ccRCC and correlated with a poor prognosis in a large number of clinical samples. Our findings showed that RALYL may be a potential therapeutic target as well as a poor prognostic factor.

RALY RNA binding protein-like reduced expression is associated with poor prognosis in clear cell renal cell carcinoma.

5$/<51$%LQGLQJ3URWHLQOLNH5HGXFHG((SUHVVLRQLV Associated with Poor Prognosis in Clear Cell Renal Cell Carcinoma

Objective To Investigate the effect of insulin analogue on the proliferation of human umbilical cord stem cells. Methods Human umbilical cord mesenchymal stem cells were incubated with 1,10 and 100 nmol / L of regular human insulin, insulin aspart and insulin glargine, respectively. Cell proliferation was detected by MTT assay after 24-hour, 48-hour and 72-hour culture. Result Regular human insulin, insulin aspart and insulin glargine, at dose of 10 nmol / L and 100 nmol / L, could significantly increase cell proliferation compared with control group after 24-hour culture. Human insulin, insulin aspart and insulin glargine, at dose of 1, 10 and 100 nmol / L, could significantly increase cell proliferation compared with control group after 48-hour and 72-hour culture. Human insulin, insulin aspart and insulin glargine could promote cell proliferation in a dose- dependent manner. Insulin aspart showed no significant effect on cell proliferation compared with human insulin(P 0.05). Insulin glargine showed significant effect on cell proliferation compared with human insulin after 48- hour culture (P 0.05) and 72- hour culture (P 0.05), respectively. Conclusion Both regular human insulin and insulin analogues can enhance human umbilical cord stem cell proliferation. Insulin aspart and regular human insulin have similar effects on cell proliferation, Cell proliferation effect of insulin glargine was stronger than that of human insulin. This study may provide a new way to prepare sufficient seed cells for adipose tissue engineering.

Effect of insulin analogue on the proliferation of human umbilical cord stem cells

A theoretical model incorporating the moving train, the railway track, and the elevated viaduct is established and then solved using periodic theory in this paper. The vertical wheel/rail forces and the dynamic responses of track and viaduct girder are obtained and compared for three different types of tracks, i.e., the double-block ballastless track, the rubber-pad floating slab track, and the steel-spring floating slab track. It is observed that the rubber-pad and steel-spring floating slab tracks can reduce more than 10% of the wheel/rail force and the reaction force at girder supports, when compared to those of the double-block ballastless track. Especially, the steel-spring floating slab track develops an uplifting force larger than the installation force of the fastening clip, which may cause failure of the rail fastening system.

A Comparative Study on Vertical Dynamic Responses of Three Types of Elevated Railway Tracks Subjected to a Moving Train

With consideration of the flexible vibration of car body,a high speed railway human body-vehicle system model was established to evaluate the riding comfort of human body.In this model,the human body was regarded as single degree of freedom system connecting the car body.German Low Disturbing Track Spectra was chosen as the excitation,and the differences of dynamic responses between the human body and carbody were analyzed.The effects of vehicle running speed and flexible carbody vibration on the human body riding comfort were investigated.The investigation results show that the riding comfort classification based on carbody responses,instead of human body responses,is overestimated.The vibration of human body around 1 Hz in the frequency domain is enlarged and affects the riding comfort of human body.The human body responses are magnified by 15 m wave length,and the long wave influences the human body responses heavily,which is ignored when using the dynamic responses of vehicle.

Dynamic responses of high speed railway human body-vehicle system and comfort evaluation

Thinning is an important agronomic process in pear production, thus the detection of pear inflorescence is an important technology for intelligentization of blossom thinning. In this paper, images of buds and flowers were collected under different natural conditions for model training, and the images were augmented by data augmentation methods. Model training was performed based on the YOLOv5s network with coordinate attention mechanism added to the backbone network and compared with the native YOLOv5s, YOLOv3, SSD 300, and Faster-RCNN algorithms. The mAP, F1 score and recall of the algorithm reached 93.32%, 91.10%, and 91.99%. The model size only took up 14.1 MB, and the average detection time was 27 ms, which are suitable for application in actual intelligent blossom thinning equipment.

REASEARCH ON PEAR INFLORESCENCE RECOGNITION BASED ON FUSION ATTENTION MECHANISM WITH YOLOV5

the identification of hidden faults of relay protection equipment is of significance for detecting abnormalities of relay protection equipment as soon as possible and avoiding incorrect action of relay protection equipment. A method of applying topological analysis, correlation between primary equipment and secondary equipment to search for electrical quantities that are homologous comparable is proposed. Aiming at the problem that the homologous comparison method for the identification of hidden faults of relay protection is easy to misjudge due to the lack of time synchronization of sampling data or recording data, it is proposed to weaken the process error by filtering, so that the relay protection equipment of primary equipment with power fluctuations such as traction lines are homologous comparable, and improve the hidden fault identification level of relay protection analog sampling segment.

2023 IEEE/IAS 59th Industrial and Commercial Power Systems Technical Conference (I&CPS)

A hidden fault diagnosis method of relay protection considering the lack of sample synchronization

The transient shock caused by the failure of the UHV DC transmission system is large and covers a wide range. However, the key testing technology for UHVDC transmission control and protection based on self-controllable chips is not yet perfect. This paper studies the overall design of the UHV DC control and protection system; analyzes the influence mechanism of electromagnetic interference, ambient temperature, power supply and other factors on the DC control and protection device, and proposes a general hardware test scheme and functional test for the DC control and protection equipment on an autonomous controllable chip platform scheme; studied the visualization modeling technology of UHVDC transmission system based on PSCAD, proposed a modularized DC control and protection simulation modeling scheme, and built a modular model of autonomous controllable chip DC control and protection equipment; The waveform comparison test verifies the accuracy of the simulation platform.

2022 IEEE 6th Conference on Energy Internet and Energy System Integration (EI2)

Research on Key Test Technology of UHVDC Transmission Control and Protection Based on Autonomous Controllable Chips

In the new generation of smart substations, the integration of smart high-voltage equipment and the localization of smart electronic devices are the new development directions. The operating environment is also more severe and complicated, and testing with reference to the existing EMC standards cannot fully meet the requirements of the operating environment of the secondary protection equipment. Therefore, based on GIS electromagnetic transient reality platform, this paper carries out a large number of port disturbance tests and adaptability tests of local protection devices in complex electromagnetic environment, and puts forward electromagnetic protection measures in adaptability test, which provides a new method for electromagnetic compatibility performance verification of local protection devices.

2021 International Conference on Power System Technology (POWERCON)

Study the adaptability test and protective measures of relay protection devices in a compound electromagnetic environment

With the gradual maturity of the comprehensive construction of smart grid and the integration of remote control, the State Grid Corporation of China has put forward new requirements for remote operation of relay protection. This article summarizes the meaning, general principles, system architecture and technical requirements of the remote operation of the relay protection. Then it designs a relay protection remote operation test scheme, builds a library of relay protection device fixed value remote control, soft pressure plate remote control and communication performance test cases. Finally it develops an automatic relay protection remote operation test system based on MMS communication protocol engine technology, which is applied to the professional testing of relay protection devices of the State Grid Corporation. The system has realized the “double confirmation” of remote modification of relay protection devices, solved the problems of low testing efficiency and inconsistent test data format, and ensured the smooth implementation of remote regulation and control integration and unattended substations.

2021 3rd International Conference on Smart Power & Internet Energy Systems (SPIES)

Research on Remote Operation Automatic Test of Relay Protection Based on MMS Communication Protocol Engine Technology

As the core equipment of the power grid, the relay protection device's self-control plays a key role in the safe and stable operation of the power grid. The development of high-performance, high-reliability domestic chips and the localization of core components for relay protection have become the development strategy of the State Grid Corporation of China. This paper analyzes the overall plan and future direction of the domestic chip relay protection device; according to the characteristics of each domestic core component, it proposes a targeted test plan for the relay protection device; also, it analyzes and studies the failure mechanism of the domestic chip relay protection through inspection and grid connection operation which verifies the practicability of the aforementioned test plan.

2021 IEEE 5th Conference on Energy Internet and Energy System Integration (EI2)

Research on the Development and Testing Technology of Domestic Chip Relay Protection Devices

With the steady progress of smart grid construction and domestic equipment development, non-standard problems such as relay protection alarm information, action information and intermediate contact information from different manufacturers have become increasingly prominent, affecting power grid operation, anomaly analysis and accident handling. This paper studies the information standardization verification technology of relay protection strategic standby device, designs the relay protection information standardization test scheme, establishes the test template case library, develops a set of relay protection device information standardization automatic verification system, and applies it to the professional detection of domestic relay protection devices of State Grid Corporation of China. The standardized full closed-loop and one click information specification automatic test is realized to ensure the consistency of message semantics of domestic devices in field operation.

Research on Automatic Verification Technology of Information Specification of Relay Protection Strategic Standby Device

Due to load fluctuations, it is difficult for the power system to completely rely on wind power to meet the load demand. Based on the use of LHS-Kmeans to obtain more accurate future load scenarios, the ieee6 node model is selected for power system planning and modeling for the next forty years, and Cplex is used to solve the future power system development results. The results show that although a large amount of wind power has been put into use and has grown year by year, it occupies a very high proportion of the overall power system. As the level of system fluctuations decreases, the proportion of thermal power output can be further reduced, but it still needs to be maintained at a certain level.

Power System Evolutionary Planning Based on LHS-kmeans Method for Generating Future Load Scenarios

The State Grid Corporation of China is steadily promoting the research and trial operation of localized protection devices, and the very fast transient overvoltage (VFTO) nuisance caused by disconnecting switch operation in GIS may affect the normal operation of localized protection devices, which will threaten the safe operation of GIS substations and even the whole power system once an accident occurs. This paper introduces the characteristics of localized protection devices, summarizes the EMC test methods of localized relay protection laboratory, sorts out the categories of VFTO harassment on localized protection devices. It proposes the test methods of VFTO impact on localized protection devices by combining the functions of VFTO electromagnetic transient test platform, so as to lay the foundation for the subsequent testing and evaluation of VFTO impact on localized protection devices.

Exploring the Test Plan for the Impact of VFTO on Localized Protection Devices

In the current international situation, based on the existing domestic chips, the rapid development of relay protection backup device can be used for emergency spare parts of relay protection devices in extreme cases to avoid the occurrence of “inorganic availability”. It is urgent to verify whether the relay protection device can operate safely and stably, whether the reliability meets the requirements, and whether the life expectancy is credible. For this reason, this paper proposes a reliability research strategy of the national production chip relay protection device: firstly, according to the actual operation environment and working mechanism of the national production chip relay protection device, a set of life reliability verification test method conforming to the characteristics of national production chip relay protection device is formulated; secondly, the reliability test method of national production chip relay protection device is designed; finally, the full domestic chip relay protection is evaluated in three aspects, including hardware and software, protection configuration and current environment of relay protection such as temperature and humidity. It is of great significance for the steady realization of independent and controllable relay protection device and the guarantee of reliable operation of electric power.

Reliability Research Strategy of All-domesticized Chip Relay Protection Device

In recent years, with the power network continuously developed and constructed, various new types of services are constantly emerging. Diversified business needs and the surge data of users and terminal devices pose new challenges to the current architecture of power communication network. Thus, the network need to be upgraded by using related technologies to meet the requirements of the so-called Energy Internet's development. Network slicing technology can build multiple logical networks with differentiated performance on the same physical infrastructure according to different service requirements. The personalized customization and security isolation brought by network slicing can better meet the needs of service requirements while saving network construction costs. The Integrated Space-Air-Ground (SAG) Communication Network can achieve a ubiquitous network coverage and be applied in emergency communication scenario. Therefore, network slicing technology can be introduced to the wireless communication part of the Integrated SAG network to solve the problems faced by current power communication network. This paper first introduces the concept and advantages of network slicing technology and analyzes current state of the power communication network, then proposes an Integrated SAG Network architecture based on network slicing and finally discusses its key technologies.

Research on the Integrated Space-Air-Ground Communication Network Based on Network Slicing and its Key Technologies

In recent years, with the rapid development of my country's power infrastructure level, higher requirements have been correspondingly put forward for the support of informatization, the degree of interaction of data and information, and the real-time degree and accuracy of analysis. According to the hidden dangers and safety requirements of various aspects of the electric power construction site, this paper proposes an informationized solution for the safety of the electric power construction site. In terms of power project management, build power project management applications to support power engineering project management business, and realize the integrated management of the progress of power engineering projects and construction teams by the management unit; in terms of power engineering construction plan management, monitor the power engineering construction plan, Release construction plans in a timely manner and grasp the implementation of construction plans; in terms of safety supervision of power construction sites, use on-site control terminals, integrate mobile application technology, and standardize power engineering construction operations through standardized operation guidance, strengthen the safety awareness of construction personnel, and provide The personnel adds a line of defense; in terms of safety system and standard management, the current power engineering safety rules and regulations, standards, regulations and other documents are released to facilitate mutual inquiry and reference among various units.

Theoretical Research Based on the Application of Safety Information Management in Power Construction Site

The local configuration scheme of relay protection has become the trend of substation development in the future. Based on the modular design idea, an automatic test system suitable for on-site relay protection device is developed, so as to realize synchronous closed-loop test for several local protection devices of the same type from different manufacturers. The automatic test system can synchronously modify the setting values, control words and pressing plates of multiple devices. It can synchronously apply excitation to multiple devices to complete the function test of electrical quantity, automatically generate the test report, which greatly shorten the test time of local protection device. At the same time, through the analysis of the data model of the local protection device, the protection function of the tested device configuration is obtained, and the corresponding test cases are generated intelligently, which can highly improve the development efficiency of the test cases. Under the premise of ensuring the reliability of detection, the research results are applied to three sets of local protection devices for synchronous automatic test, which extremely improves the detection efficiency of local protection devices, and it has achieved good results in preliminary application.

2020 2nd International Conference on Smart Power & Internet Energy Systems (SPIES)

Research on Automatic Test System of On-site Relay Protection Device

Power distribution internet of things (IoT) is an integrated product of distribution monitoring system and internet of things. By analyzing the security risks faced by each section in the power distribution IoT, an integrated cyber-security protection structure based on unified key system and unified security monitoring system is constructed. Security protection methods of perception layer, network layer, platform and application layer are proposed. Attacking experiments are realize to demonstrate the effectiveness of the proposed protection structure.

Cyber Security Risk Analysis and Protection Structure Design for Power Distribution IoT

The paper derives parameter equation of raceway section curve about slewing ring with elliptic ball track, and establishes the 3D finite element analysis model of elliptic and round ball track slewing ring. The finite element contact analysis is implemented on two shapes of ball track slewing ring by ANSYS software. The analysis results are consistent with Hertz theory results. The results show that the carrying capacity of slewing ring with elliptic ball track is higher than slewing ring with round ball track by about 20% in the same load.

FEM analysis of contact problem for slewing ring with elliptic ball track

Analysis the contact problem of single-row four points contact ball type slewing is exposed to bearing radial load and axial load with Hertz theory,given slewing bearing contact stress,contact angle and deformation formula,then VB program was compiled according to the slewing bearing calculation formula.Calculation the contact stress and contact angle in the different conditions with examples of hydraulic excavators.Analysis the influencing factor of slewing bearing contact stress,given means to prevent premature bearing failure for reference.

Analysis the contact stress of hydraulic excavator slewing bearing

Defined by international telecommunications union (ITU), the spectrum in the band between 30 and 300 Hz are named as super low frequency (SLF). In this band, the electromagnetic waves are rarely shielded by strata of lower resistivity and can spread strongly. Therefore, it can be used on the earth’s surface to detect goaves underground. The equipment, which use the natural SLF electromagnetic signals to obtain information of targets, is called as passive SLF explorer. In this paper, we introduce the study that uses the passive SLF explorer to detect goaves. The explorer receives the SLF electromagnetic signals on the ground, and the signals are the synthesis of resistivity, density, magnetism, depth and other characteristics of the rocks underground. After signal processing, the apparent resistivity of different depth of rocks can be work out from that and form a spectrum curve varied with depth change. According the curve, we can find if there is gob existing underground. After a great many experiments at different goaf site in different mine, we collected about a thousand spectrum curves in total and then made analysis on the characteristics of the filling in goaf and set up the interpretation marks to obtain the information of goaf and terrane from these curves. From the investigation on goaves, we found that the goaves appears several types, after a period of time, according to its filling. Those are classed as four types, goaf of no filling, goaf of water seeping or saturation, the cap of goaf falling down and goaf filled with fallen cap and water. Compared the investigation with the SLF electromagnetic curves, we find the curve’s characteristics those correspond to goaf of different type and class the SLF curves in four type correspondingly. According to the representative differences of amplitude and shape of different curves, we set up the interpretation marks of SLF electromagnetic curves of goaves. The interpretation marks can help interpreter to identify the filling type and status of goaves, and can improve the accuracy and * Thanks to the HI-TECH RESEARCH and DEVELOPMENT PROGRAM OF CHINA (2007AA12Z163), and BEIJING NATURAL SCIENCE FOUNDATION under grant number (4082013) for funding. objectivity in the interpretation work. The interpretation marks of SLF electromagnetic curves represent the relationship between apparent resistivity and filling types, which is listed below: high resistivity is identified correspondingly to no filling, low resistivity to water seeps or saturation, uneven resistivity to the cap of goaf falling down but high resistivity to unfilled part of goaf, complicated resistivity characteristics to goaf filled with fallen cap and water. The different lithology of cap and floor of coal bed also represent different characteristics of resistivity, that is, fine sandstone shows serration amplitude on SLF electromagnetic curves, medium sandstone shows a variation with a certain direction and a higher amplitude.

A PILOT STUDY ON INTERPRETATION MARKS OF SUPER LOW FREQUENCY ELECTROMAGNETIC SPECTRUM CURVES OF GOAVES IN MINE

It is found that the abandoned mine goaves, because of the different fillers, exist in below types: goaves filled with air, filled with water, and congested by falling coal bed roof after investigation. According to the goaf types and characteristics of different fillings in goaves by super low frequency (SLF) electromagnetic exploring, the SLF electromagnetic exploring curves may be classified into three major categories: the characteristic curve of air filled goaf, the characteristic curve of water filled goaf, and the characteristic curve of coal bed roof backfilled goaf. Based on the analysis above, we established the recognition characterization of passive super low frequency electromagnetic exploring spectrum curves with respect to goaves, and accordingly obtained the information of goaves.

A study on recognition characterization of passive super low frequency electromagnetic exploring curves of goaf

The actually application of magnetotelluric method to exploration of geothermal energy sources is analyzed. The basic theory of the passive SLF electromagnetic techniqueis preseated, especially the mechanism of exploring geothermal energy sources by this kind of technique. The type BD-6 passive SLF electromagnetic explorer, which is developed by the Peking University, was used in the experiments of exploring two geothermal wells in Beijing, JR. 119 and JR. 168. The reduplicative performance, attenuation compensating gain of signals and interpretable of BD-6 explorer were improved. In the experiment, industrial frequency (50Hz) noise and its harmonious waves were filtered by use of hardware filter and adjusting the horizontal orientation of sensor. The SLF electromagnetic curves of wells were obtained and their reduplicative characteristics were excellent. The lower apparent resistivity of geothermal area is the result of water and the difference of resistivity between the geothermal area and wall rocks can be detected by using passive SLF electromagnetic explorer, and then the interface between the geothermal area and cap rock and the depth of the area of lower resistivity are derived. The geothermal reservoir and cap rock were interpreted. The absolute error of the depth of geothermal reservoir is between 23 m and 50 m, and the relative error of interface of cap rock is less than 6.3%. The experiment results showed that the distribution of geothermal reservoirs can be found by using the passive SLF electromagnetic explorer.

Applications of the passive Super Low Frequency (SLF) electromagnetic technique to exploration of geothermal energy sources

Based on analysis of the significance of the coal bed methane exploration and development and the deficiency of the conventional coal bed methane exploration methods, the paper proposes a new technology of coal bed methane exploration with natural-source (passive) ultra-low frequency electromagnetic waves. The principles of passive ultra-low frequency electromagnetic detection and the mechanism of coal bed methane exploration are first introduced. The paper then shows the coal bed methane explorationexperiments and the latest research results in the Qinshui Basin of Shanxi using BD-6-ultra-low frequency electromagnetic detector developed by Peking University. Finally, the further application of the technology in the exploration of coal bed methane is discussed.

PASSIVE ULTRA-LOW FREQUENCY ELECTROMAGNETIC DETECTION TECHNOLOGY FOR COAL BED METHANE AND ITS APPLICATION

With the rapid development of the Internet, Weibo has gradually become one of the commonly used social tools in society at present. We can express our opinions on Weibo anytime and anywhere. Weibo is widely used and people can express themselves freely on it; thus, the amount of comments on Weibo has become extremely large. In order to count up the attitudes of users towards a certain event, Weibo managers often need to evaluate the position of a certain microblog in an appropriate way. In traditional position detection tasks, researchers mainly mine text semantic features through constructing feature engineering and sentiment dictionary, but it takes a large amount of manpower in feature selection and design. However, it is an effective method to analyze the sentiment state of microblog comments. Deep learning is developing in an increasingly mature direction, and the utilization of deep learning methods for sentiment detection has become increasingly popular. The application of convolutional neural networks (CNN), bidirectional GRU (BiGRU), and multihead attention mechanism- (multihead attention-) combined method CNN-BiGRU-MAttention (CBMA) to conduct Chinese microblog sentiment detection was proposed in this paper. Firstly, CNN were applied to extract local features of text vectors. Afterward, BiGRU networks were applied to extract the global features of the text to solve the problem that the single CNN cannot obtain global semantic information and the disappearance of the traditional recurrent neural network (RNN) gradient. At last, it was concluded that the CBMA algorithm is more accurate for Chinese microblog sentiment detection through a variety of algorithm experiments.

Chinese Microblog Sentiment Detection Based on CNN-BiGRU and Multihead Attention Mechanism

Bilingual education of young children is one of the international research hotspots. As a world's most populous nation, China has done abundant research on this topic and pay more attention on the teachers. This study collected 123 valid documents in the full-text database of CNKI. Based on the overall situation analysis of the published documents in the past years, the keywords were analyzed with respect to frequency, co-occurrence, co-word clustering and multidimensional Scale. Combing with the above results, the research classifies research hotspots into four categories: (a) Research on the development of professional competence of pre-school bilingual teachers; (b) Research on teacher training for pre-school bilingual teachers; (c) Research on bilingual teachers in ethnic minority areas; (d) Research on teaching strategies of preschool bilingual teachers.Based on the above research, this study puts forward the important tasks of current research and future research trends in order to provide some ideas for follow-up research. 

Preschool Bilingual Teachers' Research Hotspot Based on Co-word Clustering and Multi-dimensional Scale Analysis --123 Chinese Documents from 2003 to 2017

Sentiment analysis is a research hotspot in natural language processing in recent years. This paper proposes a sentiment analysis method that integrates LSTM and CNN in view of the fact that most existing sentiment analysis methods mix semantics and emotions. This method divides the text into semantic space and emotional space, and uses the attention model to train in two dimensions, and fuses the feature representations of the two to construct the final representation of the text. The results show that the model has achieved good results in multiple emotional review data.

Influence of GdTaO4 doping concentration on thermophysical and mechanical properties of GdPO4/GdTaO4 composites

Ag2S quantum dot (QD) photodetectors (PDs) have attracted a lot of attention in the field of imaging system and optical communication. However, the current Ag2S PDs mainly works in the near-infrared band, and its detection ability in the visible band remains to be strengthened. In this paper, we used poly(3-hexylthiophene) (P3HT) with high carrier mobility and Ag2S QDs to construct heterojunction PD. Stronger absorption in blends with polymer P3HT compared to single Ag2S QDs. The optical absorption spectra show that the Ag2S/P3HT has strong light absorption peak at 394 and 598 nm. The results show that P3HT significantly enhances the absorption of Ag2S QDs from the visible to near-infrared band. The output characteristics, transfer characteristics and fast switching capability of the device at 405 nm, 532 nm and 808 nm were tested. The device has the responsivity of 6.05 A W−1, 83.72 A W−1 and 37.31 A W−1 under 405 nm, 532 nm and 808 nm laser irradiation. This work plays an important role in improving the detection performance of Ag2S QDs and broadening its applications in photoelectric devices for weak light and wide spectrum detection.

High responsivity of VIS-NIR photodetector based on Ag2S/P3HT heterojunction

Theoretical and experimental study of ablation of fused silica by femtosecond laser bursts

Ultraviolet picosecond ultrashort pulsed laser micro glazed EB-PVD YSZ coatings for improving the molten salt (Na2SO4 + V2O5) corrosion resistance

High temperature oxidation resistance of laser shock modified NiAlHf metallic bond layer

Water-soluble Ag2S QD modified CsPbI2Br heterojunction photodetector with ultra-low dark current and ultra-fast response speed

PtSe2 Field-Effect Phototransistor with Positive and Negative Photoconductivity

Displacement current guided control of electromagnetically induced transparency in nano-discretized terahertz metamaterials

Hot corrosion behavior of EB-PVD YSZ coatings treated by nanosecond pulsed laser

High temperature oxidation resistance of arc ion plating NiCoCrAlY coating modified via laser shock peening

Although numerous studies showcase the capability of metalenses to serve as crucial elements of miniaturized optical systems, tunable focusing remains an ongoing challenge. Here, we propose a doublet zoom lens based on a Ge2Sb2Te5 (GST) metasurface at a wavelength of 1.55 μm. Multistep zooming is realized by the joint control of incident circular polarization inversion and GST phase transition. Three tight focal spots, 0.91 λ, 1.09 λ and 0.89 λ, are achieved from the composite lens. The devised highly-integrated doublet lens, with advantages such as as being multi-foci, easily operated and responding quickly, can find applications in fields that require ultracompact zoom imaging and beam focusing.

Research on Specific Identification Method of Substances Through Terahertz Metamaterial Sensors

Study of Picosecond Laser Ablation of Fused Silica with Three-Dimensional Two-Temperature Model and Experimental Verification

Tensile property and hot corrosion behavior of CrMnFeCoNi high-entropy alloy fabricated via laser melting deposition

Precise Preparation of Quartz Pendulous Reed by Using Picosecond Laser Modification Assisted Wet Etching

Combination of annealing and laser shock peening for tailoring microstructure and mechanical properties of laser directed energy deposited CrMnFeCoNi high-entropy alloy

Hot Corrosion Behavior of Aps Ysz Coatings Treated by Laser Micro Glazing (Lmg) Under Molten Salts (V2o5+Na2so4)

Strengthening mechanisms and tensile properties of 20Cr2Mn2Mo processed by laser shock peening and vacuum carbonitriding

Tracing pictogram-level chlorothalonil pesticide based on terahertz metal-graphene hybrid metasensors

High responsivity and broadband photodetector based on SnS2/Ag2S heterojunction

Mode-division multiplexing (MDM) is a promising solution to improve data transmission capacity for future optical interconnect networks. Mode converters and mode filters play a key role in on-chip MDM systems. Here, we propose and experimentally demonstrate a device, enabling mode conversion and filtering simultaneously, which is composed of asymmetrical directional couplers with subwavelength gratings, in a small footprint of 14.7 µm × 1.42 µm. The device can realize optical mode conversion between the first-order transverse electric (TE) mode and the fundamental TE mode, and can also filter the fundamental TE mode efficiently. The conversion efficiency is over 95%, with a broad 1 dB bandwidth over 80 nm and a high mode extinction ratio of >29 dB. As a mode filter, strong mode elimination of >30 dB is achieved.

Efficient mode converters and filters using asymmetrical directional couplers with subwavelength gratings.

The effect of thermal damage on mechanical strengths of CFRP cut with different pulse-width lasers

Effects of Yb and Sc co-doping on the thermal properties and CMAS corrosion of garnet-type (Y3-xYbx)(Al5-xScx)O12 ceramics

Ultrabroad-band, white light emission from carbon dot-based materials with hybrid fluorescence/phosphorescence for single component white light-emitting diodes

High-Responsivity Vis–NIR Photodetector Based on a Ag2S/CsPbBr3 Heterojunction

Femtosecond laser polishing with high pulse frequency for improving performance of specialised aerospace material systems: MCrAlY coatings in thermal barrier coating system

In this paper, a terahertz (THz) frequency-selective surface (FSS) is fabricated through picosecond (ps) laser direct writing on the silicon-based silver film. The time-domain spectroscopy (TDS) technique is used to test its electromagnetic modulation performance. Based on the finite-difference time-domain method, CST microwave studio 2016 was used to simulate its resonance characteristic. By optimizing the process parameters, the square ring structures on the FSS with the size error below 2% are fabricated. It is found that the center frequencies of the experimental and simulated resonance peaks are nearly both at 0.293 THz, and the transmission is about 0.01%. From the simulation results, when the size error is controlled below 2  μm, the resonant frequency shift is about 2.2 GHz. Combining the simulation and experimental results, if the size error of inner square is controlled below 2%, it has little effect on the THz metasurfaces’ modulation performance. By optimizing the laser scanning strategy and processing parameters, ps laser direct writing provides a new choice for the convenient fabrication of THz metamaterials.

Fabrication of frequency-selective surface by picosecond laser direct writing

High responsivity photodetector based on mixed-dimensional CsPbBr3/CsPbI2Br heterojunction

High photoresponsivity in CH3NH3PbI3-XClx perovskite vertical field effect photo transistors

A silver nanoparticles (AgNPs)-integrated terahertz (THz) metasurface sensor was presented and applied to enhance the sensitivity of substance detection. Simulations and experiments were conducted to study the influence of AgNPs on the sensor performance. The enhancement of the local electric field excited by AgNPs can substantially strengthen the interaction between the THz waves and analytes, thereby increasing detection sensitivity. The experimental results indicate that the detection limit of the AgNPs-integrated metasurface sensor is improved by two orders of magnitude compared to that of the bare metasurface sensor without AgNPs. This study provides a convenient method to enhance the sensitivity of THz metasurface sensors.

Silver nanoparticles-integrated terahertz metasurface for enhancing sensor sensitivity.

Abstract A novel microfluidic metal grating integrated terahertz sensor has been designed, which is composed of a metal microstructure array-dielectric layer-metal layer, where the dielectric layer is the microfluidic channel carrying the analyte. By adjusting the structural parameters of the metal grating sensor, a highly confined electromagnetic field can be obtained in the microfluidic channel, thereby significantly enhancing the interaction between the analyte and the terahertz wave and improving the terahertz detection sensitivity. The metal grating described in this paper is composed of an array of square holes, which is manufactured using laser micromachining technology, so that the measurement method is simplified and improved. The results show that the addition of different concentrations of carbendazim solution resulted in a redshift of the overall spectrum, with the highest sensitivity reaching 8.773 GHz/mg L−1, which is about eight times more sensitive than the traditional terahertz transmission sensor. The relative error of using this method to determine carbendazim levels in orange juice samples was less than 5.3%. The terahertz time-domain spectroscopy technology combined with the metal grating integrated microfluidic sensor can improve the sensitivity of sample detection and realize the rapid detection and analysis of trace elements.

Detection of carbendazim in oranges with metal grating integrated microfluidic sensor in terahertz

Toroidal dipole resonance can significantly reduce radiation loss of materials, potentially improving sensor sensitivity. Generally, toroidal dipole response is suppressed by electric and magnetic dipoles in natural materials, making it difficult to observe experimentally. However, as 2D metamaterials, metasurfaces can weaken the electric and magnetic dipole, enhancing toroidal dipole response. Here, we propose a new graphene-integrated toroidal resonance metasurface as an ultra-sensitive chemical sensor, capable of qualitative detection of chlorothalonil in the terahertz region, down to a detection limit of 100 pg/mL. Our results demonstrate graphene-integrated toroidal resonance metasurfaces as a promising basis for ultra-sensitive, qualitative detection in chemical and biological sensing.

Graphene-integrated toroidal resonance metasurfaces used for picogram-level detection of chlorothalonil in the terahertz region.

Different open resonant ring structures with substrate of polyimide were designed. The transmission characteristics of the structures for terahertz wave were investigated by simulation and experiment. The results show that the transmission peak of the structures moves to high frequency with increase of thickness of the metal layer. With increase of substrate thickness, the transmission peak moved to low frequency and the transmissivity decreased. The influence of number of “C” shape open resonant rings in the unit structure on the transmission characteristics of terahertz wave was also studied. It is found that when the number of “C” shape open resonant rings increases from one to two, more transmission peaks appeared in the frequency of 0.2–2 THz. The transmissivity of the designed structures was tested by terahertz time-domain spectrometer (THz-TDS). The experimental results showed good agreement to the simulation results.

Simulation and Experimental Study of Terahertz Wave Transmission Characteristics Based on Periodic Metal Open Resonant Ring Structures

Laser peen forming (LPF) is suitable for shaping sheet metals without the requirement for die/mold and without causing high temperatures. An analytical model for estimating the bending curvatures of LPF is convenient and necessary for better understanding of the physical processes involved. In this paper, we describe a new analytical model based on internal force balance and the energy transformation in LPF. Experiments on 2024 aluminum alloy sheets of 1–3 mm thickness were performed to validate the analytical model. The results showed that for 1 mm and 3 mm thick–thin plates, the curvature obtained by the analytical model changes from −14 × 10−4 mm−1 and −1 × 10−4 mm−1 to 55 × 10−4 mm−1 and −21 × 10−4 mm−1, respectively, with the increase of laser energy, which is consistent with the experimental trend. So, when either the stress gradient mechanism (SGM) or the shock bending mechanism (SBM) overwhelmingly dominated the forming process, the analytical model could give relatively accurate predicted curvatures compared with the experimental data. Under those conditions where SGM and SBM were comparable, the accuracy of the model was low, because of the complex stress distributions within the material, and the complex energy coupling process under these conditions.

An Analytical Model for Estimating the Bending Curvatures of Metal Sheets in Laser Peen Forming

Ultra-sensitive Dirac-point-based Biosensing on Terahertz Metasurfaces Comprising Patterned Graphene and Perovskites

Experimental investigation of sheet metal forming of Aluminum 2024 using nanosecond pulsed Nd: YAG laser

Low-cost, flexible and broadband terahertz absorber based on annealed carbonized sponge

Microstructure and transient oxidation behavior of NiCoCrAlYSiHf coating modified via high-current pulsed electron beam

Graphene–polyimide-integrated metasurface for ultrasensitive modulation of higher-order terahertz fano resonances at the Dirac point

Wear resistance of 20Cr2Ni4A alloy steel treated by laser shock peening and implantation of diamond nanoparticles

Achieving excellent wear and corrosion properties in laser additive manufactured CrMnFeCoNi high-entropy alloy by laser shock peening

Effect of Heat Treatment on the Microstructure and Mechanical Properties of Nickel Superalloy GH3536 Obtained by Selective Laser Melting

Two metamaterial sensors were designed to test three pesticide residues. The influences of the metamaterial structure, the analyte composition and volume on the sensitivity have been studied. The metamaterial field-enhancement ability has an important influence on the sensitivity within the high-concentration range, while the coincidence between the metamaterial resonant frequency and the analyte fingerprint peak plays a dominant role within the low-concentration range. These findings allow us to better understand the process and find a way to improve the sensitivity.

Sensitivity influencing factors during pesticide residue detection research via a terahertz metasensor.

Experimental research on plastic deformation of metal foil through ns laser-induced mechanical effects underwater

Switchable terahertz absorber based on metamaterial structure with photosensitive semiconductor

The development of phosphorescent materials with time‐dependent phosphorescence colors (TDPCs) is of considerable interest for application in advanced dynamic information encryption. In this study, TDPC is realized in carbon dots (CDs) synthesized by the one‐pot hydrothermal treatment of levofloxacin. CD ink printed on paper (CD@paper) exhibits a change in phosphorescence color from orange to green, 1 s after irradiation with 395 nm light. However, when irradiated with wavelengths shorter or longer than 395 nm, the CD@paper exhibits only green or red phosphorescence, respectively. The red and green phosphorescence originates from the low‐energy surface oxide triplet state and high‐energy N‐related triplet state, respectively. When irradiated with a suitable light energy (around 395 nm wavelength), the two phosphorescent centers can be simultaneously activated, emitting red and green phosphorescence with different decay rates. The red and green phosphorescence merge into an orange phosphorescence initially, exhibiting the TDPC phenomenon. Based on the unusual phosphorescent properties of the CDs, a kind of multilevel, dynamic phosphorescence colored 3D code is designed for advanced dynamic information encryption.

Time‐Dependent Phosphorescence Colors from Carbon Dots for Advanced Dynamic Information Encryption

Perovskites and graphene are receiving a meteoric rise in popularity in the field of active photonics because they exhibit excellent optoelectronic properties for dynamic manipulation of light-matter interactions. However, challenges still exist, such as the instability of perovskites under ambient conditions and the low Fermi level of graphene in experiments. These shortcomings limit the scope of applications when they are used alone in advanced optical devices. However, the combination of graphene and perovskites is still a promising route for efficient control of light-matter interactions. Here, we report a dual-optoelectronic metadevice fabricated by integrating terahertz metasurfaces with a sandwich complex composed of graphene, polyimide, and perovskites for ultra-wideband and multidimensional manipulation of higher-order Fano resonances. Owing to the photogenerated carriers and electrostatic doping effect, the dual optoelectronic metadevice showed different manipulation behavior at thermal imbalance (electrostatic doping state of the system). The modulation depth of the transmission amplitude reached 200%, the total resonant frequency shift was 800 GHz, and the tunable range of the resonant frequency was 68.8%. In addition, modulation of the maximum phase reached 346°. This work will inspire a new generation of metasurface-based optical devices that combine two active materials.

Dual-Stimulus Control for Ultra-Wideband and Multidimensional Modulation in Terahertz Metasurfaces Comprising Graphene and Metal Halide Perovskites.

Development of a Novel Metal Grating and Its Applications of Terahertz Spectroscopic Detection of CuSO4 in Fruit

Bonding has been used to repair carbon fiber-reinforced polymer (CFRP) materials. However, research has shown that resin residue on the surface of CFRP can cause adhesion problems. Therefore, a reliable surface cleaning procedure is necessary to remove the resin residue before bonding. In this paper, the surface resin was removed by laser cleaning, while the surface properties of CFRP were improved. A pulsed laser cleaning experiment was designed to study the chemical activity and bonding strength of CFRP treated by laser with different laser power and scanning speed. The results showed that as the contact angle of the material surface decreased, chemical activity and adhesive properties were improved. The surface pretreated with laser power of 16 W (scanning speed of 1500 mm/s) had no resin residue and the best adhesive properties; the bonding strength was 1.6 times higher than that of the untreated surface, and the failure mode was dominated by a cohesive damage mode.

Effect of laser cleaning of carbon fiber-reinforced polymer and surface modification on chemical activity and bonding strength.

Despite the growing interests for controlling terahertz (THz) scatterings via metallic metasurfaces, the avoidance of Ohmic loss resulting from the interaction between light and phonons or free ele...

Ultra-Wideband Low-Loss Control of Terahertz Scatterings via an All-Dielectric Coding Metasurface

This paper presents an investigation into the influence of laser drilling on the tensile strength of carbon fiber reinforced plastic (CFRP) laminates of 1 and 2.5 mm thickness. The CFRP laminates were drilled using the microsecond laser, nanosecond laser, and picosecond laser, and the heat-affected zone (HAZ) was characterized and measured by optical microscopy. Through setting laser parameters, specimens with different HAZs were prepared, and then tensile strength tests were conducted. The results indicate that the tensile strength linearly depends on the width of HAZ. The tensile strengths of 1 mm specimens decrease by approximately 122 MPa/mm HAZ, and 2.5 mm specimens decrease by approximately 33.9 MPa/mm HAZ. Comparing the results of different thicknesses of CFRP, the effect of HAZ on tensile strength would be weakened with the increasing of laminate’s thickness. Actually, besides HAZ, cutting-induced geometric defects also seriously influence tensile strength, because of the stress concentration around these defects during the stretching process. Additionally, the mechanism why the HAZ influences tensile strength was revealed visually through FEM simulation: the resin matrix damage within HAZ causes the tensile loads not be transferred effectively between the fibers and then weakens the strength. It was the first time the underlined mechanism is revealed for HAZ-inducing strength reduction through FEM simulation. The laser machining method is more suitable for processing the thicker CFRP composites because the negative effect of HAZ is weakened for the thicker material.

Factors influencing the tensile strength of carbon fiber reinforced plastic laminates for laser machining method and the underlined mechanisms

Given the complex pretreatment and low sensitivity of pesticide residue detection with the conventional testing method, a Terahertz metasensor consisting of the four-division ring resonator (FSRRs) was proposed and fabricated for the identification and detection of chlorothalonil. Through simulations, the theoretical sensitivity of this metasensor was found to reach 156.3 GHz /RIU (RIU, refractive index unit) under an analyte layer 1 μm thick. Through experiments, firstly, the characteristic fingerprint spectrum of chlorothalonil in the THz band was obtained by detecting solid chlorothalonil with THz time-domain spectrum system. Then, Terahertz metasensor was used to detect the chlorothalonil solutions of different concentrations. The experimental results showed that the resonant peak of the metasensor was redshifted with the increase of chlorothalonil concentration. Compared with the detection strategy only using the characteristic fingerprint spectrum, the sensitivity of the metasensor improved 106 times, which was up to a minimum of 1 mg l−1. This study indicates that the metasensor is a promising optical device for detecting the pesticide residues with a very high sensitivity.

High-sensitivity detection of chlorothalonil via terahertz metasensor

Achieving red room temperature afterglow carbon dots in composite matrices through chromophore conjugation degree controlling

Perfect state transfer of the bus topological system enables the sharing of information or excitation between nodes. Herein we report groundbreaking research on the transfer of the graphene-bridged bus topological network structure to an electromagnetic metamaterial setting, named "bus topological network metamaterials (TNMMs)." Correspondingly, the electromagnetic response imprints onto the topological excitation. We find that the bus-TNMMs display a perfect modulation of the terahertz response. The blue-shift of resonance frequency could increase to as large as 1075 GHz. The modulation sensitivity of the bus-TNMMs reaches 1027 GHz/Fermi level unit (FLU). Meanwhile, with the enhancement of modulation, the line shape of the reflection keeps underformed. Parabola, ExpDec1, and Asymptotic models are used to estimate the modulation of the resonance frequency. Besides, the bus-TNMMs system provides a fascinating platform for dynamic cloaking. By governing the Fermi level of graphene, the bus-TNMMs can decide whether it is cloaking or not in a bandwidth of 500 GHz. Also, the bus-TNMMs exhibit the immense potential for dynamically detecting the vibrational fingerprinting of an analyte. These results give a far-reaching outlook for steering dynamically the terahertz response with the bus-TNMMs. Therefore, we believe that the discovery of bus-TNMMs will revolutionize our understanding of the modulation of the electromagnetic response.

Graphene-bridged topological network metamaterials with perfect modulation applied to dynamic cloaking and meta-sensing.

Researches on the curvature adjustment of metal sheet induced by laser shock forming through experiments and simulations

Position-guided Fano resonance is observed in hybrid graphene-silicon metamaterials. An outstanding application of such resonance is slow-light metadevices. The maximum group delay is 9.73 ps, which corresponds to a group delay in free-space propagation of 2.92 mm. We employ a coupled oscillator model to illustrate anomalous transmission, where the intensity of the Fano peak increases with the Fermi level. Furthermore, we amend the GaussAmp model to serve as a suitable control equation for the group delay. The coefficient of correlation (R2) is as high as 0.99998, while the lowest values of the root-mean-square error and sum of squared errors are respectively 0.00421 and 0.00156. These results indicate that the amended GaussAmp model accurately controls the trend of the group delay. This work not only clarifies the mechanism of Fano resonance generation but also provides a promising platform for dynamically adjustable optical switches and multidimensional information sensors.

Position-guided Fano resonance and amended GaussAmp model for the control of slow light in hybrid graphene-silicon metamaterials.

Based on the influence of surface metal materials on electric field, a terahertz metamaterial absorber with a highly symmetrical open box was designed. Aiming at the traditional square ring absorber, the absorber is made of three open square rings and a pair of symmetrical strips of silicon. Starting from the structure and material of the absorber, the absorption rate of the absorber to the three-frequency band wave is regulated by changing the size of the surface metal ring, changing the thickness of the dielectric layer, changing the dielectric constant of the dielectric layer material, and adjusting the conductivity of the silicon material after the addition of semiconductor silicon. When no semiconductor silicon is added, the absorption rate of the absorber in the low frequency band reaches 94.77% and the absorption frequency band is 0.73thz. By increasing the thickness of dielectric layer, the phenomenon of redshift is obvious, which can realize the purpose of continuous frequency band absorption. By adding the silicon strip with symmetrical structure and changing the conductivity comparison, it is found that it can close the absorption peak in the high frequency band, reducing the absorption rate to less than %, and at the same time affecting the absorption rate of the low frequency band.

Laser shock forming(LSF) is an emerging method for metal sheet forming. Besides dimension accuracy, the stress distributions on the surface and within the target material are also important for the actual engineering applications. In this paper, the stress distributions along the sheet depth direction and parallel to the target surface have been made clear through simulations. The deformation mechanisms of two typical deformation modes, convex and concave, were directly verified and further explained by the temporal and spatial residual strain/stress distribution. For the convex deformation, the stress distribution along the thickness direction is roughly divided into three regions: the near surface layer, the intermediate layer and the bottom layer. Among these, both the top and bottom surface layers are mainly subjected to compressive residual stresses. For this case, the stress wave effect does not ‘penetrate’ the sheet material, and a stress gradient is induced along the depth direction of the sheet, which is responsible for final convex deformation. For the concave deformation, the stress distribution along the thickness direction is divided into two regions: the surface tensile stress zone and the lower compressive stress zone. The stress wave effect penetrates the sheet material, directly causing the overall tensile deformation of the sheet material, and finally causes the sheet material to undergo deep plastic deformation. The stress distribution characteristics of the two deformation modes can provide useful references for the practical application.

Characteristics of stress distribution within the metal sheet bent by laser shock forming

Real-time detection for living cells in vitro is essential for cell physiology, leading to a strong requirement of low cost and label free biosensors. At present, the terahertz plasmonic metamaterials (TPMMs) are an especially attractive application for biosensing owing to their sharp resonances respond. Compared with traditional biosensors, such as flow cytomertry, the TPMMs biosensors have many unique advantages, containing real-time monitoring, free label and high sensitivity. In this paper, we proposed a TPMMs which is designed by digging out periodically arranged regular hexagonal holes on the metal plate with the thickness of 200 nm. The samples of the TPMMs is used as a platform for detecting liver cancer cell GEP2 concentration at five levels (1 × 104, 5 × 104, 1 × 105, 3 × 105 and 5 × 105cells/ml). The results show that The THz PMMs biosensor cannot distinguish cell concentrations within the orders of magnitude between 1 × 104 and 5 × 104 cells/ml, however, it can distinguish cell concentrations within the orders of magnitude between 1 × 104 and 1 × 105 cells/ml based on the x-polarized reflection spectrum TPMMs biosensor. On the other hand, the transmission spectrum TPMMs biosensor has a significant detectability of the orders of magnitude cell concentration between 104 and 105 cells/ml. The proposed TPMMs biosensor paves a fascinating platform for have been widely applied for cell detection, biotechnology.

The biosensing of liver cancer cells based on the terahertz plasmonic metamaterials

Effect of laser shock peening on wear behaviors of TC11 alloy at elevated temperature

Laser additive manufacturing of FeCrCoMnNi high-entropy alloy: Effect of heat treatment on microstructure, residual stress and mechanical property

Carbon dots (CDs) have been promising candidates for metal-free room temperature phosphorescence (RTP) materials recently, but they generally exhibit extremely dim phosphorescence, mainly due to the lack of design guidelines. Herein, we present a new RTP emission enhancing strategy that induces the deprotonation of carboxyl groups on the surfaces of CDs by adjusting the pH to increase the degree of conjugation between the carboxyl group and the carbon core and decrease the surface defect. In addition, for the matrices, the C–O−⋯H hydrogen-bonding systems in cyanurate have stronger hydrogen-bonded networks than the CO⋯H hydrogen-bonding systems in cyanuric acid, minimizing nonradiative transitions of triplet excitons. Notably, their phosphorescence quantum yield (14%) at high pH is nearly 5 times higher than that of CD-based composites under acidic conditions. Furthermore, chemical sensors and light-emitting diodes based on CD-based composites are realized by taking advantage of their efficient dual emission feature.

High pH-induced efficient room-temperature phosphorescence from carbon dots in hydrogen-bonded matrices

ABSTRACT This paper investigates the influence of laser shock peening (LSP) parameters on surface integrities and high temperature wear performances of Ti–6.5Al–3.5Mo–1.5Zr–0.3Si alloy. Surface integrities include surface roughness, residual stress and micro-hardness are measured. High temperature wear performance of TC11 alloy with and without LSP are investigated. The results indicate that multiple LSP impacts can improve surface micro-hardness and induce compressive residual stress in the surface layer. Moreover, the friction coefficient and wear rate of TC11 alloy significantly decrease after LSP with optimised parameters. The improved wear performance is ascribed to the low surface roughness, higher surface micro-hardness and compressive residual stress induced by multiple LSP impacts in the surface layer.

High temperature wear performance of Ti–6.5Al–3.5Mo–1.5Zr–0.3Si alloy subjected to laser shock peening

Hole-like surface morphologies on the stainless steel surface through laser surface texturing underwater

Evolution of microstructure and grain refinement mechanism of pure nickel induced by laser shock peening

Effect of laser shock peening on microstructure and hot corrosion of TC11 alloy

Thermal stability of surface nano-crystallization layer in AZ91D magnesium alloy induced by laser shock peening

High temperature oxidation behavior of Ni-based superalloy GH586 in air

Transparent superhydrophobic solar glass prepared by fabricating groove-shaped arrays on the surface

Microstructures and isothermal oxidation behaviors of CoCrAlYTaSi coating prepared by plasma spraying on the Ni-based superalloy GH202

Low-cycle fatigue behavior of Ni-based superalloy GH586 with laser shock processing

Microstructure and hot corrosion behavior of the Ni-based superalloy GH202 treated by laser shock processing

An anti-reflective 1D rectangle grating on GaAs solar cell using one-step femtosecond laser fabrication

Purpose 
 
The purpose of this paper is to improve the forming efficiency and quality of unequal-width parts fabricated by laser direct metal deposition technology, some experiments were designed. 
 
A new method by varying laser spot was adopted to fabricate unequal-width single track using one scanning rather than multi-track overlapping in the way of the inside-beam powder feeding, and the thin-walled parts were fabricated layer by layer. The theoretical model among layer thickness of z-axis, height of single track and the section curve order of single track was established. 
 
Findings 
 
The top surface unevenness of the thin-walled parts could be compensated automatically within the laser defocusing ranges from −2.5 to −5 mm and from 0.5 to 2.5 mm. The growth rate with the large width/height ratio was more than the small ratio, while the set height of the single track was uniform. The problem of non-uniform growth rate could be solved based on a stepped single-track method. The thin-walled parts with the smooth top surface was fabricated layer by layer which had a continuously variable width from 1 to 3 mm by splicing the laser defocusing range. 
 
Practical implications 
 
The shapes of the to-be-fabricated parts affect variable laser spot process in practical applications. For example, it will be difficult to apply variable laser spot process on the parts with the hole features. 
 
This paper provided a guidance for forming unequal-width parts by laser direct metal deposition based on the inside-beam powder feeding.

Laser direct metal deposition process of thin-walled parts using variable spot by inside-beam powder feeding

Improving the high temperature oxidation resistance of Ni-based superalloy GH202 induced by laser shock processing

High temperature oxidation behavior of Ni-based superalloy GH202

The Study of Femtosecond Laser Irradiation on GaAs Solar Cells With TiO 2 /SiO 2 Anti-Reflection Films

Mold-free fs laser shock micro forming and its plastic deformation mechanism

Keywords: Femtosecond laser; Solar cell; Damage threshold; TiO2/SiO2 film. Abstract. The results of damage on the GaAs solar cells surface irradiated by femtosecond laser show that: the anti-reflective layer irradiated by laser is damaged when the laser energy is more than 1 uJ; and when the energy is increased to 5uJ, the anti-reflective layer is completely damaged. The comparison between theoretical damage depth and the experimental results reveal that: similarity between the theoretical calculation and experimental results is high when the laser energy is less than 6 uJ. There is no obvious change of the reflectance after irradiated by 1 uJ pulse energy which is about 8%, but it is increased to 32%, 38% after the pulse energy is increased to the 2 uJ and 3 uJ. The quantum efficiency are decreased to 13.71%, 55.78%, 83.01% at 500 nm and 3.94%, 35.52%, 46.78% at 800 nm when the cells are irradiated at 1 μJ, 2 μJ, 3 μJ.

Effect of Femtosecond Irradiation Laser on the Optical Properties of GaAs Solar Cell

Laser shock processing effects on isothermal oxidation resistance of GH586 superalloy

Investigation of the crater-like microdefects induced by laser shock processing with aluminum foil as absorbent layer

Cyclic oxidation resistance of In718 superalloy treated by laser peening

Fabricating micro embossments on the metal surface through spatially modulating laser-induced shock wave

Synthesis, crystal structure and fluorescence properties of Nd3+ complex with tetrabromoterephthalic acid

The paper aims to study the influence of high temperature processing on the substructure of laser shock processed titanium alloy. The titanium alloy specimens were first treated by laser shock processing (LSP), then treated at 700°C for three hours and air cooled to the room temperature to investigate the influence of the high temperature processing. To evaluate such influence, the hardness and substructure on the surface were investigated by micro hardness tester and transmission electron microscope (TEM), respectively. Results show that after three times LSP, the hardness of TC11 alloy was improved by 30.9%. The cause of such an improvement in hardness is that the crystal grains in the surface layer under the shock wave stress were strongly deformed, causing a dynamic recrystallization. The substructure is mainly twin crystals, highly tangled and dense dislocations. After high temperature processing in vacuum, the average hardness is decreased by 12% compared to that of the specimens after LSP. And the substructures are mainly small dislocation, nanocrystalline.

Influence of High Temperature Processing on the Substructure of Laser Shock Processed Titanium Alloy

Plastic deformation mechanism of polycrystalline copper foil shocked with femtosecond laser

Laser shock microforming of Aluminum(Al) foil through fs laser has been researched in this paper. The influences of confining layer, clamping method and impact times on induced dent depths were investigated experimentally. Microstructure of fs laser shock forming Al foil was observed through Transmission electron microscopy (TEM). Under the condition of tightly clamping, the dent depths increase with impact times and finally tend to saturating. Another new confining layer, the main component of which is polypropylene, was applied and the confining effect of it is better because of its higher impedance. TEM results show that dislocation is one of the main deformation mechanisms of fs laser shock forming Al foil. Specially, most of dislocations exist in the form of short and discrete dislocation lines. Parallel straight dislocation slip line also were observed. We analyzed that these unique dislocation arrangements are due to fs laser-induced ultra high strain rate.

Experimental research on laser shock forming metal foils with femtosecond laser

Hot corrosion behavior of TC11 titanium alloy treated by laser shock processing

Luminescent properties of a new Nd3+-doped complex with two different carboxylic acids and pyridine derivative

We study nanometer copper thin films prepared by magnetron sputtering and treated with laser shock processing (LSP). We observe the formation of firstborn twin crystals and some complete twin crystals in the copper thin films. After LSP, scanning electron microscope (SEM) images show obvious plastic deformation of the copper grain on the film surface, dramatically increased grain size, and the appearance of a large number of twin crystals. Moreover, the width of the crystals is a few dozen nanometers, and the cross angle is more than or close to 90o. Many vacancy defects appear during the sliding of atomic plane, which leads to a faulty structure; however, no obvious dislocation is observed. These substructures play a significant role in improving the mechanical performance of nanometer copper thin films.

Study of the substructure in nanometer copper thin films treated by laser shock processing

This paper explores the properties of Fe40NiCrSiAl alloy treated by different methods. The hardness, elastic modulus and resistivity are tested. The results indicate that: after LSP to rolled Fe40NiCrSiAl alloy, the hardness increased 25.22%, the elastic modulus increased 7.17% and the resistivity decreased 39%. TEM photographs demonstrated that there appeared dislocations, martensite transformation and twin crystals inside the material after being treated by LSP. Twin crystals are the main reason attributing to the improvement of material electrical properties.

Mechanism of Improving Mechanical and Electrical Properties of Fe40NiCrSiAl Alloy Induced by Laser Shock Wave

Fe20Ni3Mn alloy is treated by LSP. The hardness, residual stress and microstructure in the strengthened zone are studied. The results show that the hardness of the strengthened surface is increased about 15% and the surface compressive residual stress is reached about -469MPa. There exist martensite transformation and dislocation within 1mm depth from the specimen surface. Some martensitic structures have obvious trend of growth in steps. Specially, the twin crystals in martersite induced by LSP have important application.

Research on Characteristic Microstructure and Properties of Fe20Ni3Mn Alloy Induced by Laser Shock Processing

Study on Laser Transformation Hardening of HT250 by High Speed Axis Flow CO2 Laser

NEW METHOD FOR EVALUATING THE DEPTH OF HARDENED ZONE OBTAINED THROUGH LASER QUENCH

Testing complete plastomes and nuclear ribosomal DNA sequences for species identification in a taxonomically difficult bamboo genus Fargesia.

﻿Abstract The taxonomy of the Sino-Himalayan alpine bamboos is controversial due to their complex evolutionary history and further complicated by the scarcity of inflorescence. Here, we supplement the description of the inflorescence of Fargesiaangustissima T.P. Yi and Yushaniapauciramificans T.P. Yi, which shed light on the taxonomy of Fargesia Franchet, Borinda Stapleton and Yushania Keng. F.angustissima has compressed inflorescence unilateral stretching out from reduced spathe, showing a transitional state between species with condensed inflorescence embraced by spathe-like bracts and species with open inflorescence without bracts. Considering that extensive gene flow existed between several clades of Fargesia found in recent studies, a broadly-defined Fargesia s. l. should be adopted. Meanwhile, the inflorescence of Y.pauciramificans has typical characteristics of Yushania, such as axilla with tuberculate glands, rachilla internodes ciliate and cylindrical florets, supporting the delimitation of Yushania.

﻿Inflorescences of Fargesiaangustissima T.P. Yi and Yushaniapauciramificans T.P. Yi (Poaceae, Bambusoideae) shed light on the taxonomy of the Sino-Himalayan alpine bamboos

Phylogenomics of
 Fargesia
 and
 Yushania
 reveals a history of reticulate evolution

Two new species of Yushania (Poaceae: Bambusoideae) from South China, with a taxonomic revision of related species

Figure 1 from: Ye X-Y, Zhang Y-X, Li D-Z (2020) Two new species of Fargesia (Poaceae, Bambusoideae) from southwestern China. PhytoKeys 170: 25-37. https://doi.org/10.3897/phytokeys.170.58780

Figure 5 from: Ye X-Y, Zhang Y-X, Li D-Z (2020) Two new species of Fargesia (Poaceae, Bambusoideae) from southwestern China. PhytoKeys 170: 25-37. https://doi.org/10.3897/phytokeys.170.58780

Abstract Rapid evolutionary radiations are among the most challenging phylogenetic problems, wherein different types of data (e.g., morphology and molecular) or genetic markers (e.g., nuclear and organelle) often yield inconsistent results. The tribe Arundinarieae, that is, the temperate bamboos, is a clade of tetraploid originated 22 Ma and subsequently radiated in East Asia. Previous studies of Arundinarieae have found conflicting relationships and/or low support. Here, we obtain nuclear markers from ddRAD data for 213 Arundinarieae taxa and parallel sampling of chloroplast genomes from genome skimming for 147 taxa. We first assess the feasibility of using ddRAD-seq data for phylogenetic estimates of paleopolyploid and rapidly radiated lineages, optimize clustering thresholds, and analysis workflow for orthology identification. Reference-based ddRAD data assembly approaches perform well and yield strongly supported relationships that are generally concordant with morphology-based taxonomy. We recover five major lineages, two of which are notable (the pachymorph and leptomorph lineages), in that they correspond with distinct rhizome morphologies. By contrast, the phylogeny from chloroplast genomes differed significantly. Based on multiple lines of evidence, the ddRAD tree is favored as the best species tree estimation for temperate bamboos. Using a time-calibrated ddRAD tree, we find that Arundinarieae diversified rapidly around the mid-Miocene corresponding with intensification of the East Asian monsoon and the evolution of key innovations including the leptomorph rhizomes. Our results provide a highly resolved phylogeny of Arundinarieae, shed new light on the radiation and reticulate evolutionary history of this tribe, and provide an empirical example for the study of recalcitrant plant radiations. [Arundinarieae; ddRAD; paleopolyploid; genome skimming; rapid diversification; incongruence.]

Parallel ddRAD and Genome Skimming Analyses Reveal a Radiative and Reticulate Evolutionary History of the Temperate Bamboos

Figure 3 from: Ye X-Y, Zhang Y-X, Li D-Z (2020) Two new species of Fargesia (Poaceae, Bambusoideae) from southwestern China. PhytoKeys 170: 25-37. https://doi.org/10.3897/phytokeys.170.58780

Abstract Two new species of Fargesia, one from Xizang (Tibet) and one from Yunnan, China, are described and illustrated. Fargesia viridis D.Z. Li & X.Y. Ye is characterized by its densely white powder, nearly solid internodes, yellow setose sheath scar and culm sheaths, and 4–6 leaves of large size. Fargesia purpurea D.Z. Li & X.Y. Ye has thinner culms (0.5–1.4 cm in diameter), a ring of 4–5 mm tall brown setae below nodes, fewer branches, glabrous sheath scar and culm sheaths, differentiated from the related species.

Two new species of Fargesia (Poaceae, Bambusoideae) from southwestern China

Figure 2 from: Ye X-Y, Zhang Y-X, Li D-Z (2020) Two new species of Fargesia (Poaceae, Bambusoideae) from southwestern China. PhytoKeys 170: 25-37. https://doi.org/10.3897/phytokeys.170.58780

Figure 4 from: Ye X-Y, Zhang Y-X, Li D-Z (2020) Two new species of Fargesia (Poaceae, Bambusoideae) from southwestern China. PhytoKeys 170: 25-37. https://doi.org/10.3897/phytokeys.170.58780

Genome sequences provide insights into the reticulate origin and unique traits of woody bamboos.

Abstract Yushania tongpeii D.Z.Li, Y.X.Zhang & E.D.Liu, a new species of the temperate bamboo tribe Arundinarieae (Poaceae: Bambusoideae), is described and illustrated from north-eastern Yunnan, China. Yushania tongpeii is characterised by taller branching from nodes 1–2 m above the ground, usually three branches at the node, sparse purple spots and thin white powder on the internode, densely purple-spotted culm sheaths, glabrous margins of culm sheaths and tomentose leaf ligules. Based on the morphological features, this new species is assigned to section Yushania.

Yushania tongpeii (Poaceae, Bambusoideae), a new bamboo species from north-eastern Yunnan, China

The Hengduan Mountains (HDM) of southwest China is a biodiversity hotspot and harbours one of the world's richest temperate floras. However, the origin and evolution of its biota remain largely unresolved. Here we explore the impact of mountain uplift on the diversification process of biodiversity in this hotspot using alpine bamboos.

Rapid diversification of alpine bamboos associated with the uplift of the Hengduan Mountains

Genome-wide RAD sequencing data provide unprecedented resolution of the phylogeny of temperate bamboos (Poaceae: Bambusoideae)

Abstract Ampelocalamus actinotrichus (Merrill & Chun) S. L. Chen, T. H. Wen & G. Y. Sheng and Neomicrocalamus prainii (Gamble) P. C. Keng are reported with new distribution records in southern and southeastern Yunnan, China, respectively. Ampelocalamus actinotrichus was previously recorded to be endemic to Hainan, China, and Neomicrocalamus prainii to be distributed in southern Tibet and western Yunnan in China, northeastern India, and Burma. The identities of individuals collected in southern and southeastern Yunnan of these two species are confirmed by molecular evidence. The new distribution record of Ampelocalamus actinotrichus provides a case at the species level for confirming floristic affinities of southern Yunnan and Hainan Island in south China. The disjunct distribution of Neomicrocalamus prainii in Yunnan is concordant with the ecogeographical diagonal line from northwestern Yunnan to southeastern Yunnan and this may imply a tropical origin of this species. In addition, the inflorescence of Melocalamus yunnanensis (T. H. Wen) T. P. Yi is described.

New distribution records of two bamboo species in Yunnan, China with description of the inflorescence for Melocalamus yunnanensis (Poaceae, Bambusoideae)

Two-part model (TPM) is a widely appreciated statistical method for analyzing semi-continuous data. Semi-continuous data can be viewed as arising from two distinct stochastic processes: one governs the occurrence or binary part of data and the other determines the intensity or continuous part. In the regression setting with the semi-continuous outcome as functions of covariates, the binary part is commonly modelled via logistic regression and the continuous component via a log-normal model. The conventional TPM, still imposes assumptions such as log-normal distribution of the continuous part, with no unobserved heterogeneity among the response, and no collinearity among covariates, which are quite often unrealistic in practical applications. In this article, we develop a two-part nonlinear latent variable model (TPNLVM) with mixed multiple semi-continuous and continuous variables. The semi-continuous variables are treated as indicators of the latent factor analysis along with other manifest variables. This reduces the dimensionality of the regression model and alleviates the potential multicollinearity problems. Our TPNLVM can accommodate the nonlinear relationships among latent variables extracted from the factor analysis. To downweight the influence of distribution deviations and extreme observations, we develop a Bayesian semiparametric analysis procedure. The conventional parametric assumptions on the related distributions are relaxed and the Dirichlet process (DP) prior is used to improve model fitting. By taking advantage of the discreteness of DP, our method is effective in capturing the heterogeneity underlying population. Within the Bayesian paradigm, posterior inferences including parameters estimates and model assessment are carried out through Markov Chains Monte Carlo (MCMC) sampling method. To facilitate posterior sampling, we adapt the Polya-Gamma stochastic representation for the logistic model. Using simulation studies, we examine properties and merits of our proposed methods and illustrate our approach by evaluating the effect of treatment on cocaine use and examining whether the treatment effect is moderated by psychiatric problems.

Bayesian analysis of two-part nonlinear latent variable model: Semiparametric method

Semicontinuous variable analysis is a widely appreciated statistical method in such disciplines as social science, medicines, and economics. In detecting underlying structure and representing possible interrelationships, statistical analysis using a two-part model is appropriated. In this paper, we present a general extension of two-part model to the situation where the unobserved factors are included in the two parts to interpret external variability in semicontinuous variable. Auxiliary information on these factors is manifested by continuous responses via measurement model, while the interrelationships among factors are exploited through structural equation model. Moreover, under longitudinal setting, dynamic characteristics of responses between any two occasions are represented by transition model. Procedures for model fitting, parameter estimation, model selection and prediction are developed within the Bayesian paradigm. Markov Chains Monte Carlo method is used to implement posterior analysis. Empirical results including a simulation and a real example are used to illustrate the proposed methodology.

Inference on Two-Part Latent Variable Analysis Model With Multivariate Longitudinal Data

Bayesian analysis for mixture of latent variable hidden Markov models with multivariate longitudinal data

The purpose of this chapter is to provide an introduction to Bayesian approach within a general framework and develop a Bayesian procedure for analyzing multivariate longitudinal data within the hidden Markov factor analysis framework.

Cocaine addiction is chronic and persistent, and has become a major social and health problem in many countries. Existing studies have shown that cocaine addicts often undergo episodic periods of addiction to, moderate dependence on, or swearing off cocaine. Given its reversible feature, cocaine use can be formulated as a stochastic process that transits from one state to another, while the impacts of various factors, such as treatment received and individuals’ psychological problems on cocaine use, may vary across states. This article develops a hidden Markov latent variable model to study multivariate longitudinal data concerning cocaine use from a California Civil Addict Program. The proposed model generalizes conventional latent variable models to allow bidirectional transition between cocaine‐addiction states and conventional hidden Markov models to allow latent variables and their dynamic interrelationship. We develop a maximum‐likelihood approach, along with a Monte Carlo expectation conditional maximization (MCECM) algorithm, to conduct parameter estimation. The asymptotic properties of the parameter estimates and statistics for testing the heterogeneity of model parameters are investigated. The finite sample performance of the proposed methodology is demonstrated by simulation studies. The application to cocaine use study provides insights into the prevention of cocaine use.

Hidden Markov latent variable models with multivariate longitudinal data

Factor analysis models with continuous and ordinal responses are a useful tool for assessing relations between the latent variables and mixed observed responses. These models have been successfully applied to many different fields, including behavioral, educational, and social-psychological sciences. However, within the Bayesian analysis framework, most developments are constrained within parametric families, of which the particular distributions are specified for the parameters of interest. This leads to difficulty in dealing with outliers and/or distribution deviations. In this paper, we propose a Bayesian semiparametric modeling for factor analysis model with continuous and ordinal variables. A truncated stick-breaking prior is used to model the distributions of the intercept and/or covariance structural parameters. Bayesian posterior analysis is carried out through the simulation-based method. Blocked Gibbs sampler is implemented to draw observations from the complicated posterior. For model selection, the logarithm of pseudomarginal likelihood is developed to compare the competing models. Empirical results are presented to illustrate the application of the methodology.

Assessing Heterogeneity for Factor Analysis Model with Continuous and Ordinal Outcomes

Generalized linear latent models for multivariate longitudinal measurements mixed with hidden Markov models

Bayesian semiparametric analysis for latent variable models with mixed continuous and ordinal outcomes

Logistic regression model is the most popular regression technique, available for modeling categorical data especially for dichotomous variables. Classic logistic regression model is typically used to interpret relationship between response variables and explanatory variables. However, in real applications, most data sets are collected in follow-up, which leads to the temporal correlation among the data. In order to characterize the different variables correlations, a new method about the latent variables is introduced in this study. At the same time, the latent variables about AR (1) model are used to depict time dependence. In the framework of Bayesian analysis, parameters estimates and statistical inferences are carried out via Gibbs sampler with Metropolis-Hastings (MH) algorithm. Model comparison, based on the Bayes factor, and forecasting/smoothing of the survival rate of the tree are established. A simulation study is conducted to assess the performance of the proposed method and a pika data set is analyzed to illustrate the real application. Since Bayes factor approaches vary significantly, efficiency tests have been performed in order to decide which solution provides a better tool for the analysis of real relational data sets.

Bayesian Analysis for Dynamic Generalized Linear Latent Model with Application to Tree Survival Rate

Structural equation models have wide applications. One of the most important issues in analyzing structural equation models is model comparison. This article proposes a Bayesian model comparison statistic, namely the L ν-measure for both semiparametric and parametric structural equation models. For illustration purposes, we consider a Bayesian semiparametric approach for estimation and model comparison in the context of structural equation models with fixed covariates. A finite dimensional Dirichlet process is used to model the crucial latent variables, and a blocked Gibbs sampler is implemented for estimation. Empirical performance of the L ν-measure is evaluated through a simulation study. Results obtained indicate that the L ν-measure, which additionally requires very minor computational effort, gives satisfactory performance. Moreover, the methodologies are demonstrated through an example with a real data set on kidney disease. Finally, the application of the L ν-measure to Bayesian semiparametric nonlinear structural equation models is outlined.

Model Comparison of Bayesian Semiparametric and Parametric Structural Equation Models

Recently, structural equation models (SEMs) have been applied for analyzing interrelationships among observed and latent variables in biological and medical research. Latent variables in these models are typically assumed to have a normal distribution. This article considers a Bayesian semparametric SEM with covariates, and mixed continuous and unordered categorical variables, in which the explanatory latent variables in the structural equation are modeled via an appropriate truncated Dirichlet process with a stick‐breaking procedure. Results obtained from a simulation study and an analysis of a real medical data set are presented to illustrate the methodology. Copyright © 2009 John Wiley & Sons, Ltd.

Bayesian semiparametric analysis of structural equation models with mixed continuous and unordered categorical variables

Structural equation modelling has been widely applied in behavioural, educational, medical, social, and psychological research. The classical maximum likelihood estimate is vulnerable to outliers and non-normal data. In this paper, a robust estimation method for the nonlinear structural equation model is proposed. This method gives more weight to data that are likely to occur based on the structure of the posited model, and effectively downweights the influence of outliers. An algorithm is proposed to obtain the robust estimator. Asymptotic properties of the proposed method are investigated, which include the asymptotic distribution of the estimator, and some statistics for hypothesis testing. Results from a simulation study and a real data example show that our procedure is effective.

Robust model fitting for the non linear structural equation model under normal theory.

A Robust Bayesian Approach for Structural Equation Models with Missing Data

Maximum Likelihood Methods in Treating Outliers and Symmetrically Heavy-Tailed Distributions for Nonlinear Structural Equation Models with Missing Data

For any undercut region of a plastic molded part, a side core has to be designed to form the complex geometry while avoiding the interference between the injection mold and the plastic molded part (molding). Viewing undercuts as features in the context of injection mold design, this paper presents a new method to recognize both isolated and interacting undercut features extracted from a mold cavity or core. With the introduction of the face property and the EAFEG representation scheme, an undercut feature can be precisely defined by an undercut subgraph. Unlike conventional graph-based methods, which recognize features by graph matching, the proposed algorithm recognizes undercut features by searching the cut-sets of subgraphs. After recognizing undercut features, a Boolean operation is used to generate a side core for each undercut. Rules to eliminate the side core intersection are also presented for implementation.

Automatic Undercut Feature Recognition for Side Core Design of Injection Molds

An injection mould is a key mechanical system for injection moulding. The early design stages, such as selecting a suitable moulding machine, arranging cavity layout, designing the feed system and selecting the mould base, are classified as the initial design of an injection mould. This initial design can not only be used as a guide for a quotation for a mould and its later detailed design, but can also serve as a communication bridge between the product design engineers and mould design engineers. This paper discusses the algorithms for an automatic initial design of an injection mould. To implement the automatic arrangement of cavity layout, a feature box is designed that records gate information and the geometric features of the product. The proposed algorithms have been implemented in the IMOLD system developed at the National University of Singapore. IMOLD is an intelligent injection mould design and assembly system and trademark of National University of Singapore. Homepage: http://www.eng.nus.edu.sg/imold.

Plastic packing is an important component part in our country plastic industry and pack industry. It is a new large business in light industry. Plastics processing industry makes rapid progress recently. According to the present case, the present situation of development in plastic packing was analysed while the field of having much more expensive room was poited out in this paper.

 This paper discusses the methodology in developing a 3D CAD system for injection mold. There are hundreds of parts in a set of mold, these parts can be classified and managed by an assembly method. The assembly tree structure can be looked upon as a reverse tree, each branch represents a sub-assembly tree structure, and leaves are part files. The parts are created by parametric geometrical model, parameters are used to control part size. A linkage between geometrical model and part database was built up to load the standard parts automatically. Associations are created among these parts by referring parameters with each other. A version management method is discussed to keep design status and restore to previous design as necessary. Mold design specification functions such as parting, cooling, mold base, insert creation are also provided to designers. A knowledge-based 3D CAD system is currently being used in the local mold design and manufacturing companies.

Development of a Knowledge-Based 3D CAD System for Plastic Injection Mold Design

Increasing global oceanic wind speed partly counteracted water clarity management effectiveness: A case study of Hainan Island coastal waters.

PurposeThis study aims to explore how green supply chain management (GSCM) strategies can be effectively implemented for business supply chain operations, relationship management and product design to gain green competitive advantages.Design/methodology/approachAn exploratory in-depth case study was conducted with one of the largest Chinese electronics manufacturers that is considered a leading GSCM adopter in the industry, to understand how the company adopts green supply chain practices across its multiple product lines.FindingsThe findings show that businesses can build different green focuses across GSCM elements of green operation, green relationship management and green product design to form diverse hybrid strategic solutions. They include green control, lean, leagile, agile and clean innovation while taking consideration of supply chain type and product lifespan. A taxonomy of four key GSCM strategic combinations is proposed based on the findings. The strategies align with green demand and supply chain characteristics balancing a series of business competitive objectives in terms of reducing pollution and waste, improving green cost efficiency, enhancing green demand innovation and building green service effectiveness.Research limitations/implicationsThis study lends insight into the strategic alignment relationships between product supply chain types and approaches to GSCM.Practical implicationsThe findings of this study can support industry practitioners in formulating aligned GSCM strategies based on product types to achieve optimal results.Social implicationsOptimised green supply chain design, operations and relationship management incorporating product attributes can help further minimise negative impacts of business activities on the environment.Originality/valueThis research provides a systematic understanding of how product supply chain types can influence GSCM strategy formulation. It gives a holistic picture of how hybrid choices of strategies with green supply chain operations, relationship management and product design can be formulated based on product and supply chain characteristics.

Alignment of green supply chain strategies and operations from a product perspective

As a national regional development strategy and a vital region of the Belt and Road Initiative, the sustainable development of the Pan-Pearl River Delta (Pan-PRD) region is of great importance. The national development plan emphasizes improving total factor productivity (TFP) and promoting high-quality economic development. This paper uses the DEA-Malmquist index model to measure the TFP of nine provinces in the Pan-PRD region based on inter-provincial panel data from 2003 to 2020. Furthermore, it analyzes its growth trend and heterogeneity characteristics in the inter-provincial spatial, industrial, and city dimensions. The results show that in the time dimension, TFP shows a W-shaped fluctuation trend, technical efficiency grows slowly, and technical progress is the pillar of TFP improvement. The spatial dimension shows a high distribution in the center and low distribution in the south. On the industry dimension, the TFP is in descending order as follows: tertiary industry—secondary industry—primary industry. The spatial distribution is heterogeneous, exacerbating the uneven economic development within the region, and the regional industrial structure needs urgent optimization. The spatial development of city TFP is uneven, and the number of cities with a TFP below 1 is increasing. Finally, we suggest policies to accelerate regional collaborative innovation, cultivate advantageous industrial clusters, create an advantageous industrial ecosystem, and achieve sustainable development in the Pan-PRD region.

Growth Trends and Heterogeneity of Total Factor Productivity in Nine Pan-PRD Provinces in China

Extant studies identify different strategic approaches for businesses to integrate environment management (EM) into corporate supply chain management (SCM) to create different competitive market advantages. With increasing market uncertainties, stakeholder complexities, constraints of resources, companies nowadays are required to develop more context-specific solutions for mitigating sustainability risk and improving market performance in supply chain sustainability practices. To address the challenges faced by businesses, this study aims to explore how a company adapts green supply chain strategies for a competitive transformation. Specifically, we aim to identify different green supply chain capabilities that form hybrid choices of green solutions for a company to leverage an adaptive green shift. Through an extensive literature review, this study proposes a conceptual framework for exploration which is based on a qualitative in-depth case study in the electronics industry—one of the most polluting manufacturing sectors in China. The findings show that supply chain characteristics play a significant role in the selection of different green SCM solutions by businesses. We find different hybrid choices of strategic decisions are being made by the case company operating with high-volume and high-value supply chains respectively. High-volume supply chains adopt both operational pollution and waste control strategies and incremental green product strategies to balance cost of operational change and develop a competitive eco-efficient market expansion. In contrast, high-value supply chains adopt radical green product innovation strategies and operational waste prevention strategies to balance cost of product innovation and build operational efficiency to expand in a competitive eco-differentiation market. A mix of dynamic capabilities involved in different supply chain green transformations are also identified.

Competitive Green Supply Chain Transformation with Dynamic Capabilities—An Exploratory Case Study of Chinese Electronics Industry

ABSTRACT This study aims to explore dynamic pathways of business supply chain transformation under competitive market evolution. Although extensive studies have discussed the strategic alignment of managing supply chain modes of operations, i.e. lean, agile and leagile, to different product markets, how a company leverages an adaptive transformation to meet upcoming product-market requirements has never been investigated. In-depth case studies of three well-established Chinese fashion companies operating in low, middle and high value markets were conducted. Results of the study show that context of the products primarily determines how supply chain management should evolve over time. Companies having fast-moving, high-volume products are more likely to undergo an internal-to-external, operation-led supply chain transition for a lean market expansion. Comparatively, companies that have a high product mix tend to follow an external-to-internal, strategy-led transition for a radical agile market transition. Key enablers for differentiated transformations are also identified in the findings. This research is significant to the industry sector in that it identifies patterns of supply chain transformation and the associated processes required for a new market fit. It also adds to the current knowledge of supply chain management research with a focus on market management.

Transforming supply chains for a new competitive market alignment – a case study of Chinese fashion apparel companies

Purpose
The purpose of this paper is to explore the drivers and barriers to omni-channel retailing in China, and attempts to understand how companies formulate their business strategies during their transformations to omni-channel retailing.

This study adopts an exploratory case study approach to investigate the omni-channel retailing transformations of two well-established Chinese fashion apparel retailers. The study draws on multiple sources of evidence, comprising: interviews with eight business executives from three major operational departments; on-site observations in firm’s retail stores, factories and distribution centres; and secondary data review of firm business reports, news, whitepapers and archival records. The findings are established through a consistent within-case data analysis and cross-case comparison.

Findings
The study reveals that the two retailers formulated different strategies in developing their omni-channels, and exhibited different degrees of success. The similarities and differences in the drivers, as well as the barriers, were analyzed and compared in this study. Operational variations (i.e. enablers and inhibitors) due to the unique context of the Chinese market were also explored. The findings reveal that coherent leveraging firm resources and capabilities from the three perspectives – marketing, logistics and supply chain, and organizational management – is critical to the full implementation of omni-channel retailing. They provide relevant managerial insights that can assist firms in formulating appropriate strategic action plans during the transformations.

As a theoretical contribution, this paper identifies a set of drivers and barriers for omni-channel retailing in the developed market, and classifies them into three categories: marketing; logistics and supply chain; and organizational management. The empirical-based qualitative analysis reveals the key factors impacting on omni-channel retailing within the Chinese market, and suggests a series of practical implications for local retailers planning to embark on omni-channel retailing.

The purpose of this paper is to put forward a demand chain management (DCM) framework underpinned by the alignment theory and applies it to investigate the fashion apparel (FA) industry in China under the impacts of the latest economic transition.,An exploratory multiple case study methodology involving five Chinese FA firms, each with a different business model and ownership type, was employed. Semi-structured interviews, onsite observations and review of company documents were conducted to collect information for analysis.,Using a conceptual DCM framework as a guide for analysis, the study finds that companies with a higher level of alignment with the external market situation and among the three internal DCM dimensions, namely, market management, supply chain management (SCM), and organization management, appear to perform better under the rapidly changing economic conditions in China.,This study contributes to knowledge by reviewing thoroughly the literature on SCM evolution and develops a DCM framework based on alignment theory that represents the state of the art in this area. By extending the administration-integration-production-development (A-I-P-D) logic set adopted in the alignment theory, this study has also equipped the proposed framework with an empirical tool to measure alignment.,By applying the framework to examine the Chinese apparel industry under the impacts of the latest economic transition, this study provides practitioners in the industry with a framework to help formulate strategies and a tool to measure alignment. The findings of the case study also offer insights to the industry to thrive in the rapidly changing businesses environment with dynamic uncertainties.,This study extends the application of the A-I-P-D logic set under the alignment theory to the SCM field. This endeavor successfully transforms the proposed DCM framework from a theoretical concept to a practical tool to help evaluate empirically the alignment and strategic fit of a firm and potential relationship with firm performance. As the Chinese FA market has increasingly evolved under the impact of the globalization, the findings of this study not only assist the local FA companies in coping with the dynamic uncertainties but also shed light on the future developments of the global FA industry. Besides, the alignment measurement tool embedded in the proposed DCM framework can help enhance the chances of business success during implementation.

Designing a demand chain management framework under dynamic uncertainty: An exploratory study of the Chinese fashion apparel industry

Development Path Research on Shanghai’s Cruise Supporting Industry

Build the BCC model of evaluation of Guangdong province transportation operation efficiency based on the Data Envelopment Analysis(DEA )method. Select operational mileages of all kinds of transport mode as input indicators, passenger and freight turnover as output index. DEAP2.1 software used transport industry data of Guangdong province for quantitative analysis and evaluation, the evaluation results show that before 2012, the transportation efficiency of Guangdong province in the DEA is invalid, and return to scale is in an increasing stage. Guangdong should increase the scale of transportation investment. Since 2012, Guangdong province's transport efficiency has been effective in DEA,, and various modes of transportation have maintained overall dynamic coordination.

Evaluation of Transportation Efficiency in Guangdong Province Based on Data Envelopment Analysis

Regional economic development is closely related to the development of the circulation industry. From the perspective of Heyuan development scale, circulation density, infrastructure, and the contribution of circulation industry to GDP, the evaluation index of comprehensive development of circulation industry in Heyuan is constructed in this paper, The regression model analysis was carried out by using the related data of Heyuan's circulation industry for13 years during 2004-2016. The result shows: The development trend of Heyuan's circulation industry is good, and the circulation industry has a significant impact on the regional economy of Heyuan.

Analysis of Circulation Industry and Economic Development in Heyuan City

High Capacity Transport Associated with Pre- and Post- Haulage in Intermodal Rail-Road Transport

This paper 
develops a model for analyzing the potential of longer and heavier vehicles (LHVs) 
related to pre- and post-haulage in the intermodal rail-road transport chain (IRT). 
The paper considers the combined economic and emission costs among three different 
transport networks including intermodal rail-road transport with current Swedish 
regulatory framework for trucks, intermodal rail-road transport with LHVs, and direct-road 
transport. The objective is to analyse the potential of high-capacity transport associated with pre- and post-haulage 
for enhancing the competitiveness of intermodal transport from a full-costs perspective. 
The model developed is applied to a Swedish context and case study. Research findings 
reveal that the break-even of the IRT compared 
to the direct road transport could be significantly lowered, which suggests the 
LHVs contribute to exploring the market of IRT over smaller flows.

High-capacity transport associated with pre- and post-haulage in intermodal road-rail transport

Demand supply chain management (DSCM), which integrates market segmentation with supply chain strategy supported by proper alignment in organizational configuration, is regarded by researchers as the next stage of evolution of supply chain management. Through an exploratory case study of the pharmaceutical industry, this study investigates the role of information systems / information technology (IS/IT) as an enabler of DSCM. The findings reveal that there is little alignment between IS and supply chain strategy even though technology is used widely in the company that is investigated. The lack of alignment has prevented the organisation from being DSCM capable. The study highlights the impacts of lack of alignment between IS and DSCM and helps practitioners understand the implications.

Understanding Organisational Use of IT/IS for Demand and Supply Chain Management in a MNC Pharmaceutical Company

The credit guarantee system for small and medium enterprises (SMEs, here in after) has been established for more than 10 years in China. There are so many problems resulting in low-effective operation of the credit guarantee system, such as the risks share and amplification multiple of guarantee determined by financial institutions and guarantee organization to reasonably are unreasonable. Aiming at these, this article gave an analysis framework of the effective operation of credit grantee system for SMEs, and then took Shenzhen as a case to analysis. Here we demonstrate that, the effective operation of credit grantee system for SMEs in China dependent on the improving of fund indemnity mechanism, especially the government should provide an institutional environment to encourage SMEs’ own innovation.

Study on the Effective Operation Models of Credit Guarantee System for Small and Medium Enterprises in China

Objective This meta-analysis aimed to investigate the effect of bariatric surgery on CIMT in people with obesity. Methods PubMed, Web of Science, Embase, and the Cochrane Library were searched for observational studies assessing the effect of bariatric surgery on CIMT from inception to August 2022. Mean difference (MD) and 95% confidence intervals were calculated to assess CIMT. Results A total of 23 studies, including 1,349 participants, were eligible to participate in this meta-analysis. The results revealed that CIMT was significantly decreased at 6 months, 12 months, and more than 18 months after bariatric surgery compared with baseline (6 months: MD = 0.09; P < 0.01; 12 months: MD = 0.12; P < 0.01; more than 18 months: MD = 0.14; P = 0.02). Meanwhile, laparoscopic Roux-en-Y gastric bypass (LRYGB) seemed to be more effective than laparoscopic sleeve gastrectomy (LSG) in lowering CIMT in terms of the type of surgery (LSG: MD = 0.11; P < 0.01; LRYGB: MD = 0.14; P < 0.01). Lastly, the benefits of bariatric surgery on CIMT was independent of gender (Male: MD = 0.06; P = 0.04; Female: MD = 0.08; P = 0.03). Conclusions Bariatric surgery is consistently effective in reducing CIMT in people with obesity.

Effect of bariatric surgery on carotid intima-media thickness: A meta-analysis based on observational studies

Abstract This study intends to conduct a meta-analysis based on existing research results to further investigate their relationship between artificial sweetener exposure and breast cancer risk. An electronic database literature search was performed up to July 2022, using PubMed, Web of Science, Ovid and Scopus. The relationship between artificial sweetener exposure and breast cancer (BC) incidence was evaluated by odds ratio (OR) and 95% confidence interval (CI). Among the five studies (two case-control studies and three cohort studies) that met the inclusion criteria, 314,056 participants were recruited in the cohort study, 4,043 cancer cases and 3,910 controls were recruited in the case-control study. It was found that exposure of artificial sweeteners was not related to the risk of BC (OR = 0.98, 95% CI = [0.94-1.03]). Subgroup analysis showed that compared with the non-exposure/very-low-dose group, the exposure to low, medium and high doses of artificial sweeteners were not associated with the risk of BC, which were OR = 1.01, 95% CI = [0.95-1.07], OR = 0.98, 95% CI = [0.93-1.02], OR = 0.88, 95% CI = [0.74-1.06], respectively. This study confirmed that there was no relationship between the exposure of artificial sweeteners and the incidence of BC.

Association between Consumption of Artificial Sweeteners and Breast Cancer Risk: A Systematic Review and Meta-Analysis of Observational Studies

Abstract Objective: To determine whether the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) CT60 polymorphism (rs3087243) confers susceptibility to autoimmune thyroid disease (AITDs). Methods: A meta-analysis was performed using: (1) allelic contrast, (2) recessive model and (3) dominant model. Electronic search of PubMed, Medline and Chinese National Knowledge Infrastructure (CNKI) was conducted to select studies. Results: Finally, a total of 20 separate studies were available for the current meta-analysis: Graves’ disease (GD): 18 studies including 1 Iranian, 6 Caucasian and 11 Asian populations; Hashimoto’s thyroiditis (HT): seven studies including one Iranian, three Caucasian and three Asian populations. A significant association was found between the CTLA-4 CT60 polymorphism (rs3087243) and GD, with regard to comparisons between allele and genotype frequencies (all p < 0.001). After stratification by ethnicity, significant relationships were consistently identified both in Caucasian and Asian populations. Furthermore, the association between this allelic variant and HT risk was also found in overall and Asian populations (OR: 1.26, 95% CI: 1.10–1.44; OR: 1.45, 95% CI: 1.19–1.76, respectively). Conclusion: Taken together, our study suggested that the CT60 polymorphism (rs3087243) in CTLA-4 gene might confer susceptibility to the AITDs (GD/HT).

CTLA-4 CT60 (rs3087243) polymorphism and autoimmune thyroid diseases susceptibility: a comprehensive meta-analysis

Objective: The interleukin-10 (IL-10) gene polymorphism (–1082A/G) has been shown to be associated with systemic lupus erythematosus (SLE), but ﬁndings are not consistent across studies. The aim of our meta-analysis was to assess the association between the –1082A/G polymorphism in the IL-10 gene and SLE. Methods: We searched all publications on the association between the IL-10 (−1082A/G) polymorphism and SLE in PubMed, Elsevier Science Direct, Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure (CNKI) and Wanfang (Chinese). Meta-analysis was conducted using software Stata version 10.1. Meta-odds ratios (ORs) and 95% conﬁdence intervals (CIs) based on ﬁxed-/random-effects models depended on Cochran’s Q-statistic and I2 values. Results: A total of 17 studies with 2396 cases and 3653 controls were included in this meta-analysis. Meta-analysis was performed for genotypes GG versus AA, GG + AG versus AA, GG versus AG + AA, and G allele versus A allele. Significant differences were found in genotype distribution between SLE and normal controls in whole-population GG versus AA (OR = 1.428, 95% CI = 1.006–2.208). Similar results were detected in the dominant genetics effect of the G allele (OR = 1.202, 95% CI = 1.030–1.403). No significant association was found in allele distribution in whole-population G versus A (OR = 1.125, 95% CI = 0.998–1.269). In subgroup analysis by ethnicity, significant association was found when GG + AG versus AA was performed in a European population (OR = 1.240, 95% CI = 1.022–1.503) and GG versus AG + AA was performed in an Asian population (OR = 3.596, 95% CI = 1.389–9.311). Significant association was found between genotype distribution in Asians (OR = 4.491, 95% CI = 1.552–13.000). Publication year was detected as the source of heterogeneity. In the stratified analysis by publication year, the pooled OR was 1.049 (95% CI = 0.940–1.171; Pheterogeneity = 0.431; I2 = 0.4%) in subgroup 1 (publication years 1999–2004). No significant association was found between the IL-10 (−1082 G) allele and SLE in subgroup 1 (Z = 0.85, p = 0.431). In subgroup 2 (publication years 2005–2011), the pooled OR was 1.327 (95% CI = 1.125–1.565; Pheterogeneity = 0.143; I2 = 35.8%). Significant association was found between the IL-10 (−1082 G) allele and SLE (Z = 3.36, p = 0.001). Conclusions: This meta-analysis demonstrates the association between the IL-10 (−1082A/G) polymorphism and SLE. However, further studies are needed for a definitive conclusion.

Association of the interleukin-10 gene polymorphism (–1082A/G) with systemic lupus erythematosus: a meta-analysis

Based on the questionnaires of entrepreneurial capacity of 603 self-employed vendors who operating a fixed store in Wenzhou city of China, entrepreneurial capacity evaluation index system of the self-employed which contains 12 indexes on 3 factors has been constructed by exploratory factor analysis. And the results from confirmatory factor analysis show that the evaluation index system have good reliability and validity. Finally, three aspects of pioneering capacity of the self-employed i.e. innovation ,tenacity and cooperative, are preliminary evaluated.

Research on Entrepreneurial Capacity Evaluation Index System of the Self-employed——Based on 603 Samples of Wenzhou

Mixed management has become the developing trend of international finance industry and China is also catching up, since the current segregated management system constrains its development in some degree. The paper points out the problems China's finance industry is facing when mixed management system is adopted.

With the rapid development of economy, people become increasingly rich, and cars have become a common means of transportation in daily life. However, the problem of traffic safety is becoming more and more serious. And fatigue driving is one of the main causes of traffic accidents. Therefore, it is of great importance for us to study the detection of fatigue driving to improve traffic safety. In the cause of determining whether the driver is tired, the characteristic quantity related to the steering angle of the steering wheel and the characteristic quantity of the driver’s pulse are all important indicators. The fuzzy c-means clustering is used to discretize the above indexes. Because the characteristic parameters are too miscellaneous, rough set is used to filtrate these characteristics. Finally, this paper finds out the highest correlation with fatigue driving. It is proved that these selected characteristics are of great significance to the evaluation of fatigue driving.

Processing and filtrating of driver fatigue characteristic parameters based on rough set

With the development of science and technology, transportation network has grown faster. But at the same time, the quantity of traffic accidents due to fatigue driving grows faster as well. In the meantime, fatigue driving has been one of the main causes of traffic accidents. Therefore, it is indispensable for us to study the detection of fatigue driving to help to driving safety. There are numerous approaches in discrimination method. Each type of method has its reasonable theoretical basis, but the disadvantages of traditional fatigue driving detection methods have been more and more obvious since we study the traditional physiology and psychological features of fatigue drivers. So we set up a new system based on multi-information fusion and pattern recognition theory. In the paper, the fatigue driving pre-warning system discriminates fatigue by analyzing the characteristic parameters, the parameters derived from the steering wheel angle, the driver’s power of gripping and the heart rate. And the data a...

Research on fatigue driving pre-warning system based on multi-information fusion

Investigation and Identification of Fire Caused by Setting off Fireworks

Revision of the Criminal Procedure Law proposed higher requirement for normalization of the public security's law enforcement. How to adapt to the new requirements is a new question for the public fire agent which responsible for investigating the fire liability accident case. Based on the spirit of the Criminal Procedure Law's revision, combined with experience of fire liability accident case investigation, some questions existing in the fire liability accident case investigation were studied. For example, the application of graded jurisdiction prescribed too principle, direct economic losses was determined casually, investigation subject was illegal, custody was extended and evidence was illegal collected, the criminal suspect's defense right didn't guaranteed, evidence keeping was chaos, file making wasn't standard etc. Aimed at problems, some suggestions were put forward as following: First, clear applicable conditions of grade Jurisdiction, Second, pay attention to direct economic losses statistics, Third, standardize qualification of investigation subject, Forth, strengthen law enforcement supervision and fundamental construction, Fifth, establish defense system in investigation procedure, Sixth, reinforce responsibility system of evidence preservation and file management. These Suggestions will help for the fire agent to implement spirit of the Criminal Procedure Law's revision, promoting normalization's degree of the fire liability accident case investigation.

2014 7th International Conference on Intelligent Computation Technology and Automation

Research on Normalization of Fire Liability Accident Case Investigation

An analysis of the mechanical properties of precast steel fiber reinforced concrete pavement joints

Stay cables are the main components of cable-stayed bridges. Stay cable vibrations are considered one of the major concerns in long-span cable-stayed bridges. Inadequate damping of stay cables is a primary cause of these vibrations. There are two types of cables, parallel wire cables and steel strand cables. Available studies on stay cables have focused on parallel wire cables, but there has been little testing conducted and data accumulated for the damping of steel strand cables. This paper focuses on steel strand cables and their damping features based on field testing. A total of three types of steel strand cables, M8, M13 and M18 on Tongling Bridge (under construction) were tested to investigate the cables modal damping. Vibrator-induced and human-induced vibrations on the cables upon free decay were recorded, as well as the ambient vibrations. The present experiment results of the first 3 modal damping of each cable were compared with those from references of the similar types of cables. The comparison results revealed that: i) at the same mode, the longer the cable, the lower the value of damping; ii) for the same cable, the higher the mode, the lower the value of damping; and iii) modal damping of steel strand cables is of similar features but slightly larger than that of parallel wire cables.

Damping Analysis on Steel Strand Cables of A Cable-Stayed Bridge Based on Field tests *

Ground penetrating radar (GPR) is widely used to inspect underground pipelines because it is non-destructive. When the scan line of GPR is perpendicular to the pipe, it will exhibit hyperbolic features in GPR B-scan images, which have no intuitive relationship with the geometric and physical parameters of the pipeline, making the interpretation of GPR images difficult. This paper proposes a modular detection and quantitative inversion method for the hyperbolic features in GPR B-scan images, which is divided into two steps. In the first step, the YOLOv7 object detection network is used to automatically detect the hyperbolic features in GPR images. In the second step, a two-stage curve fitting method is proposed based on the characteristics of the detection model. It uses a few key point annotations of the hyperbolic pattern and some parameters of the GPR system to quantitatively invert the depth and radius of pipes. Using the same hardware and data set, YOLOv7 achieves an 11.1% improvement in detection accuracy and an 18.2% improvement in speed compared to YOLOv5. The relative errors of the proposed method for the depth and radius of the synthetic data in homogeneous media are 0.6% and 4.4%, respectively, and 4.8% and 15% in non-homogeneous media. The relative error of the depth inversion of the measured data TU1208 is less than 10%. The results show that the method can effectively invert the depth and radius of underground pipelines and reduce the difficulty of GPR data interpretation.

A Modular Method for GPR Hyperbolic Feature Detection and Quantitative Parameter Inversion of Underground Pipelines

A new approach to retrieve total electron content based on dual-band echoes of MARSIS radar sounder

The forward calculation of Ground penetrating radar (GPR) is very important for the analysis and interpretation of its echo signal. The gprMax software is widely used for forward electromagnetic simulation. However, it is still time-consuming to obtain a large amount of simulation echo data. In this paper, the ResNet-18 convolutional neural networks (CNN) is used to fast generate the A-scan echo of given detection scene. The dielectric constant of spatial grids is normalized to obtain the coding matrix as the input data of the network, and the output is the A-Scan signal. When the scene changes, only one forward propagation of the network is needed to obtain the new A-Scan signal. Several groups of experiments for different detection scenes demonstrate that this method can efficiently and accurately generate the echo signal, with the root mean square error are less than 0.0005.

Predicting Ground Penetrating Radar A-Scan Signal Using Convolutional Neural Networks

It is important to detect the subsurface structure of Mars by low-frequency synthetic aperture radar (SAR). Most researches of the subsurface structure of Mars, especially the underground water bearing minerals, were focused on the south polar layered deposits. This paper studies the subsurface structure of Tenuis Mensa (a flat-topped prominence with cliff-like edges in Mars north pole). We analyzed the radar echo of this region detected by the Mars Advanced Radar for Subsurface and Ionosphere Sounding (MARSIS) from April 2008 to March 2018. After ionospheric compensation for these echoes, we found a subsurface structure centered at longitude 265.04 and latitude 83.18, with a diameter of about 30km. The reflected signal of underground stratification can be seen by observing the range echoes in these areas.

Subsurface Structure Detection in Martian Arctic Based on Marsis

The electromagnetic (EM) scattering characteristics of the rough sea surface is very important for target surveying and detection in a sea environment. This work proposes a scaled sea surface designing method based on a rough thin-film medium. For the prototype sea surface, the permittivity is calculated with the seawater temperature, salinity, and EM wave frequency according to the Debye model. The scale film material is mixed with carbon black and epoxy, whose volume ratio is optimized with the genetic algorithm through the existing electromagnetic parameter library. This method can overcome the previous difficulties of adjusting the same permittivity of the prototype sea water. According to the EM scaled theory, the scaled geometric sample is numerically generated with the D-V spectrum for the given wind speed, and is fabricated using 3D printing to keep the similar seawater shape. Then, the sample is sprayed with a layer of film material for EM scattering measurement. The simulated and measured radar cross-section (RCS) results show good consistency for the prototype seawater and scaled materials, which indicates the proposed scaled method is a more efficient method to get the seawater scattering characteristics.

Scaled Sea Surface Design and RCS Measurement Based on Rough Film Medium

Reverse time migration (RTM) technology has been widely used in seismic imaging measurement of complex structures because it is not affected by the changes of formation structure and lithology. This paper expanded it to the Ground penetrating radar (GPR) imaging of unknown subsurface detection scenes. The gprMax tool based on the finite difference time domain method (FDTD) is used to calculate the forward and backward extrapolation of the electromagnetic wave field, and the 2D and 3D RTM is realized based on the zero-time imaging condition of the explosion reflector principle. Multiple 2D and 3D simulation experiments show that the RTM algorithm can restore the characteristics of underground structures very accurately, even if the underground structure is complex, such as multiple buried target or nonparallel layered structure.

Revers Time Migration Method of Ground Penetrating Radar Based on gprMax

When detecting the underground structure of Mars using an orbital subsurface investigation radar, it is essential to compensate for the ionosphere distortion of the received echo. The existing algorithms, such as the contrast method (CM) and the phase-gradient-autofocus (PGA) algorithm, can mainly compensate for the defocus of the echo, but it is difficult to compensate for the group delay at the same time, resulting in the deviation between the echo position and the terrain profile. This article analyzes the interference of Martian ionosphere to the echo of subsurface investigation radar and proposes a dual-band difference (DBD) ionosphere compensation algorithm. First, the group delay model of radar echo under ionospheric interference is established. Then, the equivalent plasma frequency of the ionosphere is calculated according to the group delay difference of echoes in two bands, and the Taylor coefficients of the phase error are calculated. Finally, the echoes are accurately compensated with the Taylor series model of phase shift. This algorithm can correct the defocus and sidelobe interference and simultaneously compensate for the group delay, which is greatly significant to accurately locate the subsurface structure of Mars. The experiments on the simulation data and the echo of the Mars Advanced Radar for Subsurface and Ionosphere Sounding (MARSIS) show the feasibility of this method. Compared with the traditional way, this algorithm is suitable for both high- and low-frequency situations, and the high computational efficiency without iteration makes on-orbit real-time ionosphere compensation possible. Moreover, with the effective correction of topographic offset, the total electron content (TEC) can also be accurately retrieved.

A Dual-Band Difference Ionosphere Compensation Algorithm for Mars Orbiter Subsurface Investigation Radar

On 15 May 2021, Zhu Rong Rover successful landed on the southern area of the flat Utopia Plain. The subsurface penetrating radar is used for the exploration of Mars regolith thickness and subsurface shallow geological structures. In past eight months, the rover traveled about 950 meters, and the subsurface penetrating radar has collected a large amount of echo data. This paper presents a set of process methods to analyze the high-frequency channel data. First, the predictive deconvolution algorithm is used to eliminate multiple reflections tailing of radar wavelet. Then the wavelet transform is used to remove the random noise, and the two-state SVD decomposition and reconstruction are used to remove the direct wave of the surface and suppress the fusion noise. After these processing, the signal-to-noise ratio of echo signal and data resolution is improved. The processed B-scan images in some areas show abnormal signal within 40ns. Suppose the relative permittivity of Mars' soil is 3.5, it is corresponding to the abnormal structure within 3m depth. Combined with the optical image of the navigation and terrain cameras, we infer that these abnormal structures may be the buried stones or cavities.

Primary Analysis of Mars Geological Structure Based on High Frequency Radar Data of China's Zhurong Mars Rover

Unmanned aerial vehicle (UAV) ground-penetrating radar (GPR) is an important research topic for target detection in many fields. In this paper, we develop a UAV-mounted GPR system with a frequency band at 150 MHz–309 MHz. However, the received signal in the complex background is covered by various clutter and interference, leading to the serious obscuring of the target. To meet this challenge, a cross-correlation-based background subtraction (CCBS) method and an interference suppression technique are adopted in combination for more accurate detection. The CCBS method processes the raw echo by establishing a background-removal model and using the similarity between each A−Scan and a reference wave. In addition, a Butterworth filter is adopted to get rid of the active electromagnetic interference beyond the working frequencies of the system; then, a lateral Doppler filtering (LDF) technique is introduced to suppress the passive interference generated by the rotation of the UAV rotor itself. Moreover, a practical method for estimating the dielectric constant is introduced by the calibration process of the measured radar echo. Numerical simulations and experimental results by our UAV-GPR system demonstrate that the proposed method has presented a better performance than the traditional methods, and the system has great potential in detecting deeply buried targets.

UAV-Mounted GPR for Object Detection Based on Cross-Correlation Background Subtraction Method

The finite difference time domain (FDTD) is a general numerical method to directly obtain the electric and magnetic fields of space for EM scattering and radiation problems. The numerical dispersion and the stability conditions put forward the limitation of time and space steps for FDTD, resulting in a very long simulation time, especially for the open domain scattering problem. Nowadays, Neural networks have been used to solve partial differential equations (PDEs) because it can learn the mappings between finite-dimensional Euclidean spaces. Fourier neural operator (FNO) is proposed to learn mappings between infinite-dimensional spaces of functions. And the Fourier transform makes FNO superior to the general neural operators in time complexity. In this paper, FNO is applied to solve Maxwell’s equations of a 2D scattering problem. Through three experiments, we verify the generalization ability of the FNO for source at different locations, different source type and different object shape. Because of the generalization ability, it is several hundred times faster than FDTD to solve Maxwell’s equations of a 2D scattering problem.

Fast Solver of 2D Maxwell’s Equations Based on Fourier Neural Operator

Reducing the radar cross section (RCS) of a satellite is one of the important research directions of satellite stealth design. This paper effectively reduces the RCS of the satellite by adjusting the geometry structure and using coating absorbing material in its surface. The structural design is mainly: on the basis of the conventional original satellite, the deflection of the windsurfing structure and the shielding treatment of the frequency selective surface (FSS) cover for the parabolic antenna, and the design of the metal cone film structure on the side of the satellite; the material optimization is mainly: on the basis of the structural design, the surface of the solar panel and the surface of the satellite body are applied with wave-absorbing materials. The simulation results show that the average value of RCS reduction can reach up to about 45dB.

2021 International Conference on Microwave and Millimeter Wave Technology (ICMMT)

A Integrated Design for Structure and EM Stealth of Microsatellite

Radar echo simulator is a necessary technical means for analyzing and testing radar system. This article proposes a method for software to simulate target echo. The RCS data in frequency domain is obtained with the self-developed electromagnetic simulation tool. After multiplying these data with the spectrum of the transmitted signal, the inverse Fourier transformation is performed to obtain the final echoes. The LFM signal and Gauss AM signal are used as the transmitted signal for two different scattering scenes respectively. The comparison of the simulated echo sequence with the actual ones and their high resolution range profile (HRRP) shows the effectiveness of simulation process.

Echo simulation method for arbitrary radar system with wide-band RCS data of scattering scene

The paper proposes a new and effective extraction method to generate the common character basis function (CCBF) in EM computation of 3D rough surfaces. The extraction process is based on Kirchhoff Approximation (KA) method and then the calculated CCBFs can be applied to different samples with the same roughness regardless of illumination condition. Under the limit of KA algorithm, the new extraction method can accelerate the generating process by 2000 times and ensure mean error under 3 dB.

An Effective Extraction Method of Common Characteristic Basis Functions for 3D Rough Surfaces Scattering Computation

On July 23, 2020, China's self-developed Mars rover Tianwen 1 successfully launched into space. In order to study the impact of the Martian ionosphere on the imaging of the Orbiter Subsurface Investigation Radar carried by the Tianwen 1, this paper derives the deviation of the one-dimensional and two-dimensional chirp signals of the Tianwen 1 radar under Mars ionospheric electron densities. From the simulation results, it can be seen that due to the low working frequency of the subsurface radar on the Tianwen 1 track, after pulse compression, it will produce a positive offset and defocus along the range in the range, and the maximum offset in the case of 10TECU reach 23.96 meters, defocus seriously and the lower the operating frequency band, the more serious the offset and defocus.

2021 XXXIVth General Assembly and Scientific Symposium of the International Union of Radio Science (URSI GASS)

Analysis of the Influence of Mars Ionosphere on Tianwen 1 Subsurface Detection Radar Imaging URSI Summary Paper Template

A hybrid algorithm incorporating beam simulation method (BSM) with common characteristic basis function (CCBF) is proposed in this paper. The algorithm is used to solve for electromagnetic scattering from ID dielectric rough surface, and the time and storage complexities is greatly reduced if compared with the widely-used method of moments (MoM). Numerical examples are presented to demonstrate the algorithm and good performance has been validated.

2021 International Conference on Electromagnetics in Advanced Applications (ICEAA)

A Hybrid BSM-CCBF Algorithm on Electromagnetic Scattering from ID Dielectric Rough Surface

This paper uses the Vectorization Sparse Matrix Canonical Grid (V-SMCG) method to calculate the S-parameters and Circular Polarization Ratio (CPR)of radar echo from rough surface so asto explore how the roughness of lunar surfaces affects CPR anomalies in radar detecting tasks of planetary surface such as lunar and Mars. Fast Fourier transform (FFT) method is firstly used to generate Gaussian rough surfaces. In order to accurately consider the phase coherence between discrete elements on the rough surface, the full wave numerical MoM method is used for scattering calculation, and the V-SMCG is used to accelerate the solution of matrix equations. Then the S-parameters and CPR are calculated and their relationship with roughness and incident angle is analyzed. Lots of numerical experimental results show that CPR anomalies appear more frequently on the rougher Gaussian surfaces in a larger incidence.

Impact of Roughness on Circular-Polarization-Ratio Anomalies of Lunar Rough Surfaces

In order to build the characteristic database of typical radar target, it is necessary to solve the problem that the large amount of radar data is difficult to be stored and processed directly. It is an effective way of data compression to represent the original data with a small amount of scattering centers. Based on the idea of one-dimensional GTD model, the scattering center is extracted for data compression and storage. At the same time, considering the small segment missing phenomenon of radar detection in real scene, a prediction method of RCS (radar cross section) sequence based on neural network is proposed. Taking the global-hawk as an example, the results show that under the premise of controllable error, the method of extracting scattering center has a high compression ratio. Compared with the simulation results of FEKO software, the prediction sequence of neural network has a higher degree of fitting with the simulation results, which shows that the prediction of RCS missing segment by neural network is completely feasible.

2020 IEEE MTT-S International Conference on Numerical Electromagnetic and Multiphysics Modeling and Optimization (NEMO)

Establishment of radar target characteristic database based on scattering center extraction and neural network prediction

This paper proposed a common characteristic basis function (CCBF) method in excitation domain to accelerate traditional CBF preparation time in EM computation of large random rough surface. The CCBFs can be applied to any electrically large surface sample with same roughness despite illumination condition. The numerical results show that the proposed CCBF method can considerably reduce computational cost, and ensure mean error under 3dB.

Modeling of EM Scattering from 1D Random Rough Surface with Common Characteristic Basis Function Method

This article presents a new approach to analytically compute high-frequency (HF) electromagnetic (EM) scattering from an arbitrary undulating rough surface according to the statistical characteristics of its geometric fluctuation. The integral expression of the scattering coefficient is derived from Kirchhoff approximation (KA) and extended to arbitrary spectra. Two methods are presented to calculate the integral: 1) the discrete Fourier transforming method based on the autocorrelation function (ACF) (KAC) and 2) the convolution method based on the power spectrum density function (KAW). For some analytically expressed spectra, the scattering coefficients can be calculated directly by the KAW and KAC methods according to its power spectrum density (PSD). The analytical expressions of classical KA for Gaussian and exponential spectrum are used to validate the proposed methods. For the case of unknown undulation height spectra of rough surfaces, the ACF is statistically calculated first, and then the KAC and KAW methods are used to calculate the average scattering coefficients numerically. Moreover, the numerical results show that the KAW method takes up more memory to retain enough energy of the ACF for accurate scattering coefficients. The two new methods are effective in the range of $\theta _{i} $ from 0° to 45° and have broad application prospects for real scenarios.

An Analytical Method for High-Frequency Electromagnetic Scattering of Arbitrary Undulating Rough Surfaces

This paper explores the potential of deep neural networks to fit electromagnetic scattering problems. We use numerically calculated EM scattering data to train deep neural network so that it can be used to predict scattering of a new problem. First, we calculate the induced current of a randomly rough surface incident by tapered waves using three-dimensional method of moment (MoM) based on beam simulation method[1]. Then, we use the data to train pix2pix network[2] where the rough surface is used as input and the induced current is used as the desired output. The results show the feasibility of the basic idea of this paper. It provides a new way to solve the calculation of electromagnetic forward problems and paves the way for the corresponding calculation of electromagnetic inverse problems.

2019 International Applied Computational Electromagnetics Society Symposium - China (ACES)

Fitting EM Scattering of 3D Rough Surface using Deep Neural Networks

In this paper, the generalized recursive formulations of the finite difference time domain (FDTD) for updating the electric and magnetic fields in the multi-layer anisotropic media are derived with a uniaxial perfectly matched layer. The stability condition of the proposed method is clearly analyzed and verified. Then this method is used to calculate the three-dimensional complex scattering fields in planar multilayered anisotropic microstructures with optical axis perpendicular to the layered interface and the scattering fields of arbitrary shape scatters in the anisotropic layered structures. The electric field induced by the sine dipole source is calculated in the spatial domain and the corresponding spectral domain results are achieved through Fourier transform. The scattering field of composite materials with submillimeter thicknesses used in the industrial engineering is calculated using a terahertz wave with operation frequency of 0.3 THz. Robustness of the derived formulations for the complex uniaxial anisotropic media is verified by comparing with the COMSOL software, which is based on FEM analysis. The comparison of memory and CPU time shows the efficiency of the proposed FDTD method. Finally, the scattering fields of different scatters buried in multilayer anisotropic media are studied. So it is expected to become an effective simulation tool for dealing with complex electromagnetic environment in the future, such as abnormal detection of aircraft coating materials and detection of hidden target and so on.

Fast Calculation of Scattering in Planar Uniaxial Anisotropic Multilayers

Based on the probability distribution function of the stones, the model of the stones is established using the inverse function method of Monte Carlo method. Then the full polarization radar echo is calculated according to the Maxwell integration equations, using method of moment accelerated with vector SMCG algorithm. Then the circular polarization ratio is calculated according to Mini-RF radar observation configuration. The simulation results show that random stones distribution causes surface roughness and backscattering echo enhancement. Moreover, the multiple scattering of stones can cause anomalous CPR in radar echoes, especially for the stones with size larger than wavelength.

IGARSS 2019 - 2019 IEEE International Geoscience and Remote Sensing Symposium

Numerical Simulation and Quantitative Study of Polarization Radar Echoes from Rough Lunar Surface

Based on the probability distribution function of the stones, the model of the stones is established using the inverse function method of Monte Carlo Method. Then the full polarization radar echo is calculated according to the Maxwell integration equations, using method of moment accelerated with V-SMCG algorithm. Then the circular polarization ratio (CPR) is calculated according to Mini-RF radar observation configuration. The simulation results show that random stones distribution causes surface roughness and backscattering echo enhancement. Moreover, the multiple scattering of stones can cause anomalous CPR in radar echoes, especially for the stones with size larger than wavelength.

Quantitative study of the anomalous scattering echoes of rough lunar surface by V-SMCG algorithm

Mesh merging and fusion is great important for electromagnetic (EM) scattering simulation of target embedded in extended rough surface, such as ships on ocean, stones on planetary surface etc. This paper uses computer graphics methods to extract the intersection contour of sea level cutting ship model. Then the odd-even rule and Delaunay triangle rule are used to perform mesh fusion of two groups of meshes (target mesh and rough surface mesh). Lastly, the fused meshes are used for high frequency (HF) EM scattering calculation and radar one-dimensional range image simulation of different ship models. The computation results present different radar echo signals for different ship models, which can be further used for target identification with 1D range image signal.

Grid Fusion of Rough Sea Surface and Ship for Composite EM Scattering and Image Simulation

It is well known that Small Perturbation Method (SPM) method gives analytical expressions of electromagnetic scattering from arbitrary power spectrum rough surface. However, KA method only gives explicit analytical expressions for Gauss spectrum rough surface. This paper attempts to derive the analytical expression of KA scattering from rough surfaces with arbitrary spectrum fluctuations. It is divided into three main parts. Firstly, the paper derives the formula of traditional Kirchhoff Approximation (KA) method. Then, based on the basic spectrum, such as Gaussian Spectrum and Exponential Spectrum, the paper invents two ways Fourier Transform Method (KAF) and Convolutional Method (KAC) to solve EM scattering from complex spectrum rough surface. The numerical results show that KAC is more accurate but needs more computation and memory than KAF.

KA Analytical Solution of Dielectric Rough Surface with Arbitrary Power Spectrum

An improved unsupervised algorithm is proposed in this paper based on compact polarimetric (CP) synthesis aperture radar (SAR) data. Unlike previous algorithms that ignore the purity of the dominant scattering mechanism, this algorithm effectively integrates scattering characteristics with statistical properties. With high consistency between the result of classification and decomposition, the approach is proved to be a robust and applicable one with respect to lunar terrain classification and regolith identification.

Unsupervised classification for Mini-RF SAR using $\mathrm{m}-\delta$ decomposition and Wishart classification

Interferometric synthetic aperture radar (InSAR) uses phase difference of radar echoes, either from multiple passes along the same trajectory or from multiple displaced phase centers on a single pass, to generate interferogram. Scattering correlation in the angular dimension is a critical factor determining the quality of InSAR interferogram. It can be modeled with the angular correlation function (ACF). In this letter, the ACF of a 1-D rough surface under incidence of a tapered wave, namely, a pencil beam, is studied numerically for correlation analysis of InSAR. An analytic ACF is first derived based on the first-order small perturbation method. It is then validated statistically by the method of moment of electromagnetic scattering. Analysis of the ACF simulations indicate that the ACF of backscattering from a randomly rough surface exhibits a shape of sinc function, which depends on tapering parameter <inline-formula> <tex-math notation="LaTeX">$g$ </tex-math></inline-formula>, interferometric incidence angles <inline-formula> <tex-math notation="LaTeX">$\theta _{1}$ </tex-math></inline-formula> and <inline-formula> <tex-math notation="LaTeX">$\theta _{2}$ </tex-math></inline-formula>. Several numerical simulations of different rough surface spectrums demonstrate that the analytical ACF fits well with numerical results as long as <inline-formula> <tex-math notation="LaTeX">${g}$ </tex-math></inline-formula> is the larger several correlation lengths <inline-formula> <tex-math notation="LaTeX">${l}$ </tex-math></inline-formula>.

Interferometric Angular Decorrelation Analysis of 1-D Rough Surface With Pencil Beam Incidence

This paper developed SMCG (sparse matrix canonical grid) method with vector RWG basis function for PMCHW integral equations. According to the strength of the electromagnetic interaction between discrete elements, the dense impedance matrix is decomposed into a sparse matrix for the strong interaction and flat-surface matrices for the weak interaction. Then the SMFSIA (Sparse Matrix Flat Surface Iterative Approach) is used to solve the linear equations with CG (conjugate gradient) method. The strong interaction matrix multiplies with a column vector fast, taking advantage of the sparse matrix. If the rough surface is spilt by canonical grid, flat-surface matrices are BTTB (Block-Toeplitz Toeplitz-Blocked) matrices, so that the product can be obtained by using 2D-FFT (two dimensional fast Fourier transform). Some examples show that SMCG method and the conventional method of moment (MoM) method are in good agreement. The analysis of time complexity and memory requirement indicates that The SMCG method can greatly speed up the solution without taking too much extra memory. For scattering computation of electrically large rough surface, the SMCG method has obvious advantages over the conventional Mom method.

Sparse Matrix Canonical Grid Method for Three-Dimension Rough Surface

SAR image simulation of electrically large-scale random rough surface consumes large memory storage and CPU time. Beam simulation method (BSM) has early been suggested for fast scattering field calculation. However, incident wave decomposition is based on trial and error according to previous studies. This paper proposes more reasonable decomposing parameter choices based on statistical analysis. Error of Gaussian wave and plane wave simulation is given in this paper.

2018 12th International Symposium on Antennas, Propagation and EM Theory (ISAPE)

Beam Simulation and Band-limited Matrix Decomposition for Fast Imaging of 1-D Random Rough Surface

Scattered electromagnetic wave from objects can be analyzed to obtain area's properties as well as generate the image of irradiated area and identify targets of interest. The purpose of this paper is to study the electromagnetic scattering statistical characteristics of one-dimensional randomly rough surface. In this paper, a perfectly conducting randomly rough surface equivalent model is established, and electric field integral equation (EFIE) is solved by method of moment (MoM) and forward-backward method (FBM). Finally, the effects of rough surface's geometrical parameters on statistical characteristics of forward scattering coefficients are concluded.

Statistical Characteristics of Electromagnetic Scattering from One-Dimensional Randomly Rough Surface

Dielectric inversion of lunar permanently shadowed region (PSR) of moon poles has been studied for estimation of possible water–ice content. The Campbell model was directly applied to mini-SAR data for inversion on the Hermite-A crater region. However, this letter presents quantitative analysis that the lunar surface topography, i.e., surface roughness and slopes, and underlying dielectric media, and so on, can significantly affect this inversion. The model is actually degenerated into a half-space model without topographic account. This letter presents a two-layer model of Kirchhoff-approximation surface/small perturbation approximation subsurface to take account of all these topographic factors for PSR dielectric inversion.

Dielectric Inversion of Lunar PSR Media with Topographic Mapping and Comment on “Quantification of Water Ice in the Hermite-A Crater of the Lunar North Pole”

In this communication, we propose a frequency-independent approach, the numerical steepest descent path (NSDP) method, for computing the physical optics scattered electromagnetic field on the quadratic hyperbolic surface. Due to the highly oscillatory nature of the physical optics integral, the proposed method relies on deforming the integration path of the integral into the NSDP on the complex plane. Numerical results for the PO-based EM fields from the hyperbolic surface illustrate that the proposed NSDP method is frequency independent in computational cost and error controllable in accuracy.

A Frequency-Independent Method for Computing the Physical Optics-Based Electromagnetic Fields Scattered From a Hyperbolic Surface

The main objective of the Chinese Chang'E-3 (CE-3) lunar satellite is to achieve soft-landing and roving exploration on the lunar surface. A multibeam radar in the lunar lander is implemented to measure the echoes from the lunar rough surface during its descending and to derive the speed of the lander. In this paper, numerical simulation of multiangular radar echoes and speed inversions from Doppler frequency are presented. An area of the Lunar Sinus Iridum bay, as landing site, is specifically selected. The rough surface described with the real DTM data is first divided into triangular patches for numerical Kirchhoff approximation calculation. The radar echoes of multiangular radar beams of CE-3 during the landing are numerically simulated. The echo phase and the Doppler frequency are then derived to obtain the vertical speed.

Simulation of Multiangular Radar Echoes for Speed Measurement During CE-3 Landing on the Lunar Sinus Iridum Surface

Radar sounder technology had been applied to Mars explorations, such as MARSIS (Mars Advanced Radar for Subsurface and Ionosphere Sounding) in 2003 and SHARAD (SHAllow RADar) in 2005. China is also planning to launch the Mars program in the future. To investigate the radar echoes from Mars layered media, we have developed numerical simulation of radar range echoes at 1-50 MHz from Mars rough surface/subsurface model. Furthermore, we developed the parameter inversions of Mars layered media. As an example to validate these approaches, we collect 34 orbits MARSIS data to invert the dielectric constant of surface regolith around the region of Mars south pole. The result well shows the SPLD (south polar layered deposits) with water ice and high dielectric constant of other places.

Inversion of dielectric constant of Mars south polar region using the MARSIS data

A two‐layer model of Mars' regolith/bedrock media with a cratered rough surface/subsurface is presented for radar echo simulation of planetary exploration research. The numerical approach of geometric ray tracing for the scattering of rough surfaces, which is digitized by the triangulated network, is applied to the calculation of the scattering and imaging simulation of radar range echoes. Numerical simulations of a cratered rough surface generated by the Monte Carlo method are used to analyze the functional dependence of radar range echoes at 1–50 MHz center frequencies upon the surface/subsurface feature and the parameters of the layering media, that is, layer depth and dielectric properties. The radar range echoes from two areas of the real Mars surface, which is described by digital elevation model data with a resolution of 1 m × 1 m and a vertical error of less than 1 m, are also simulated and analyzed. Based on these simulations, this study presents a numerical imaging test of radar sounder at center frequencies 1–50 MHz for exploration of different dielectric regolith and bedrock media. The channel 50 MHz with high resolution might be an optimal frequency. Finally, inversion of the dielectric constants of the two‐layer media and the regolith layer thickness are developed.

Simulation of radar echoes from Mars' surface/subsurface and inversion of surface media parameters

Radar sounder technologies have been implemented to investigate the surface/subsurface features, i.e. Mars layering media. One aim of these missions is to retrieve the physical properties of the surface/subsurface media, such as the dielectric permittivity, layer thickness, etc. In this letter, based on our numerical simulations of the radar sounder echoes from the cratered rough surface/subsurface media , the dielectric permittivity of the planetary surface is derived from the radar sounder echoes. It is found that the received echo at nadir direction preserves the functional dependence of the surface reflectivity. It leads to the inversion of the surface dielectric permittivity derived from the ratios of the received echo powers and the medium reflectivity. Employing a numerical calculation of the cratered rough surface based on the tangent plane approximation, the dataset of Mars digital elevation mapping (DEM) is applied to validate the derivations. Also, an inversion of the surface dielectric permittivity of the Mars surface is presented.

An Inversion of Planetary Rough Surface Permittivity From Radar Sounder Observations

A novel approach of dual GPOF (general pencil of functions) combined with the DCIM (the discrete complex image method) is developed to accelerate the Sommerfeld integral evaluation, when the mixed potential integral equation (MPIE) is applied to numerically calculate scattering from a conductive object partially embedded in a dielectric half-space, where the field and source points are located in different media. Firstly, the factors related with the field point are separated from the spectrum function, and the GPOF is used to find the complex image parameters at finite discrete source points. Secondly, the GPOF is used again to fit the functional relationship of each complex image parameter with the source positions to evaluate the complex image parameters for any source position in a closed functional summation. Comparing numerical results of dual GPOF and direct numerical integration, this dual GPOF process is proved highly effective. Finally, dual GPOF/DCIM is applied to computation of electromagnetic scattering from a PEC spherical object partially embedded in a dielectric half-space medium, and numerical scattering results upon different model parameters are presented and analyzed.

Dual GPOF/DCIM for Fast Computation of Sommerfeld Integrals and EM Scattering From an Object Partially Embedded in Dielectric Half-Space

An analytical iterative algorithm for fast computation of scattering from multiple conductive cylinders is developed. It takes account of the independent 1st-order, coupling 2nd-order and higher-order scattering of multiple objects. The 1st-order scattering, as independent scattering of a single object self, is derived by using the expansion of cylindrical waves in local coordinate of the object, which are solved by the boundary conditions. Exciting by the 1st-order scattering from one object, the 2nd-order scattering of multi-objects are obtained iteratively using the addition theorem of Hankel function and the boundary conditions. The same approach is applicable to calculations of the 3rd-order and higher order scattering. It is found that the phase differences caused by the cylinder centers indicate the scattering wave interferences of multi-objects. Comparison with numerical MoM results well validates the analytical iterative algorithm, which significantly accelerates the scattering computation for wide-band frequencies f and overall azimuth angles θ over 360°. In order to depress the ringing effect caused by the abrupt change of scattering field in computed region to zero field in uncomputed region, the Hamming window is used to make gradual change of the scattering field to zero. Using FFT and 2D spline interpolation, discrete scattering data over the f -θ plane yield uniform discrete data over the X —Y plane. The image reconstruction is finally performed for multiple conductive cylinders. The image can well identify the positions and sizes of multi-objects.

Analytical iterative algorithm for fast computation of scattering from multiple conductive cylinders and the image reconstruction

A new hybrid analytical‐numerical iterative algorithm, which combines the Kirchhoff approximation (KA) and the Method of Moment (MoM), is developed for computing the electromagnetic scattering from a three‐dimensional (3‐D) perfect electric conducting (PEC) target above a 2‐D infinite randomly rough dielectric surface. The equations of difference scattering due to the target presence above the rough surface are derived. The induced difference fields on the rough surface due to the interactions between the target and the rough surface are calculated by using the KA method. The excitation term on the right‐hand‐side (RHS) of target's surface integral equation (SIE), which contains the difference scattering of the rough surface, is then updated for calculating new target currents with the Conjugate Gradient (CG) procedure. Then the target currents are used to compute the difference field induced on the rough surface with the KA method. Multiple iterations take account of the multiorder interactions between the target and the underlying rough surface. Numerical quadrature upon the rough surface is performed only once to compute the coupling scattering field from the rough surface to the target, and it takes N steps (N is the discretized mesh number of rough surface). By using this hybrid KA‐MoM algorithm, the requirements of memory and CPU time can be reduced significantly. Moreover, the validity conditions and the convergence performance of this hybrid algorithm are also discussed. With Monte‐Carlo generations of randomly rough surfaces, bistatic scattering from different‐shaped targets above a Gaussian rough surface is numerically simulated. Finally, dependence of bistatic scattering pattern on the surface dielectric property and the target geometry is discussed.

A hybrid KA‐MoM algorithm for computation of scattering from a 3‐D PEC target above a dielectric rough surface

This paper presents a hybrid iterative algorithm of analytic Kirchhoff Approximation (KA) and numerical method of moment (MoM) for scattering computation from a three-dimensional (3D) perfect conducting target above a randomly rough surface. The coupling integral equations (IEs) are derived based on the Green's function and the boundary conditions. The MoM with the Conjugate Gradient (CG) approach is used to solve the target's IE, and the KA is applied to scattering from the rough surface. The coupling iteration takes account the interactions between the target and the underlying rough surface. Convergence of the hybrid KA-MoM algorithm is numerically validated. Since is only one numerical integral of induced current on the target performed by KA computation, much memory and computation time is reduced. Bistatic scattering from a PEC cubic or spheroid target above a Gaussian rough surface are numerically simulated.

Bistatic scattering from a 3D target above randomly rough surface

A hybrid algorithm, combining analytic Kirchhoff approximation (KA) and numerical method of moments (MoMs), is developed to solve the coupling electric-field integral equations (EFIEs) of scattering from a perfect electric conducting (PEC) object above a randomly rough PEC surface under TE-polarized plane-wave incidence. The MoM with the conjugate gradient approach is used to first solve the EFIE of the object. The surface fields on the rough surface are analytically expressed using the KA method, and large memory and computations for those fields are greatly reduced. An iterative approach of the surface fields induced on both object and rough surface is then utilized to take into account interactions between the object and underlying rough surface. Convergence of this hybrid algorithm is numerically validated. Making use of Monte Carlo realization, bistatic scattering from a 2-D PEC cylindrical object above a PEC rough surface is well simulated by this hybrid KA-MoM algorithm

A Hybrid Analytic-Numerical Algorithm of Scattering From an Object Above a Rough Surface

This paper presents a hybrid iterative algorithm of analytic Kirchhoff approximation (KA) and numerical method of moment (MoM) for scattering computation from a three-dimensional (3D) perfect conducting target above a randomly rough surface. The coupling integral equations (IEs) are derived based on the Green's function and the boundary conditions. The MoM with the conjugate gradient (CG) approach is used to solve the target's IE, and the KA is applied to scattering from the rough surface. The coupling iteration takes account the interactions between the target and the underlying rough surface. Convergence of the hybrid KA-MoM algorithm is numerically validated. Since is only one numerical integral of induced current on the target performed by KA computation, much memory and computation time is reduced. Bistatic scattering from a PEC cubic or spheroid target above a Gaussian rough surface are numerically simulated.

Bistatic Scattering from a 3D Target above Randomly Rough Surface

The difference field radar cross section (d-RCS) has been defined to analyze the scattering from the target above a rough surface, which takes account of scattering from the target and multiinteractions of the target and underlying rough surface. The d-RCS removes the effect of the finite illuminated surface length under the tapered wave incidence. In this paper, the electric field integral equations (EFIEs) of the difference-induced current J/sub sd/ on the rough surface and the induced current J/sub o/ on the target are derived. A small section of rough surface toward the target in the specular direction is taken to speed up computation of the scattering contribution E/sub s0/ from the moderate rough surface to the target. Then, an iterative approach is developed to solve the EFIEs of the induced currents, directly, and yields the bistatic d-RCS. A finite rough surface length for numerical iteration is taken, corresponding to the dependence on the maximum scattering angle. Using the Monte Carlo method to generate rough surface, the bistatic d-RCS of the target, e.g., a cylinder or a square column, above a Pierson-Morkowitz rough surface is numerically simulated. The induced currents on the target and the d-RCS are discussed, and compared with the case of the target in free-space.

Fast iterative approach to difference scattering from the target above a rough surface

The difference field RCS (d-RCS) has been defined to analyze the scattering from the target above a rough surface. The electric field integral equations (EFIEs) of the difference induced current on the rough surface, the induced electric current and magnetic current on the dielectric target under a TE wave incidence are derived. A small portion of the rough surface towards the target along the specular direction is taken to compute the scattering contribution from the rough surface towards the target, which improves the computation speed. A numerical iterative approach is developed to solve the EFIEs and bistatic d-RCS. The surface length for iterations is dependent on the scattering angle and discussed for comparison with Johnson's method. Using the Monte-Carlo method to generate the P-M (Pierson-Morkowitz) ocean-like rough surface, bistatic d-RCS of the dielectric target, e.g. a cylinder or a square column, above the rough surface is numerically simulated. The induced electric and magnetic currents on the dielectric target, and the difference induced current on the rough surface are numerically discussed.

The Difference Scattering dRCS from a Dielectric Target above a Rough Surface

The difference field RCS from a target above a rough surface is derived. The electric field integral equations (EFIE) of the difference induced currents Jsd on the surface and J0 on target are developed. Because of the strongest scattering in the specular direction, a small interface taken along the converse specular direction is attributed to computation of the surface scattering upon the target. A fast mutual-coupling iterative method is developed to solve the two EFIEs. The interface length for effective computation is discussed. Using the Monte Carlo method, scattering from a target, such as a cylinder and a square column, above the P-M rough surface is numerically simulated. Scattering from a cylinder above the rough surface in the specular direction is enhanced significantly. The Bi-RCS of a square column above the rough surface shows two peaks in forward and backward directions. As a model of rough sea surface, when the surface wind speed increases, the scattering peaks become lower, and more defused scattering shows the angular scattering pattern. Introduction Scattering from the targets above a rough surface has attracted more interests in recent years. In the combined target-surface problem, the difference field cross section was introduced by Johnson [1] to remove the dependence on incident taper wave width. Scattering for the combined target-surface problem and surfaceonly problem are respectively calculated, and their difference shows scattering attributed by the target and interaction between the target and rough surface. In this paper, we derive the EFIEs of the difference induced current on rough surface and current on the target. A mutual-coupling iterative approach is developed to solve the EFIEs. The interface length for the iterative calculation is discussed. As examples, scattering from a cylinder and a square column above a rough surface are simulated. It can be seen that scattering from the cylinder above a rough surface is significantly enhanced in the specular direction due to interactions of the target and the underlying surface. Variation of the difference induced currents on the interface also demonstrates such interactions. Scattering from a square column has two peaks in the backward and forward directions due to its specific geometry. As a model of a target located above the wind-driven sea surface, numerical simulations show the angular pattern of bistatic scattering versus oceanic status. When the surface wind speed increases, scattering peaks become weaker and more angular defused scattering are dominated. Theory and Method In a model of the target above rough surface, both the total and differential cross section are previously related to the surface length illuminated by incident wave. In order to remote the dependence on illuminated surface length, the difference of the scattering field, Es1, attributed by both the target and surface and the scattering field by a rough surface only, Es0, is calculated as Esd, which is used to compute the difference field cross section σd [1], which demonstrates how much the scattering attributed by the target and interaction between the target and underlying rough surface. It does not depend upon the illuminated rough surface length. As shown in Fig.1, a two-dimensional (2D) target (perfect electric conductor, PEC) is located above a 2D PEC rough surface. As the incident tapered wave is incident on the target and rough surface, the induced current on the target is defined as J0, and the induced current on the surface is Js1. The EFIEs are written as [2] 0 = ET (r)− jkη ∫ c Jo(r ′) ·G(r, r′)dr′ − jkη ∫ S Js1(r ′) ·G(r, r′)dr′(r ∈ c) (1) 202 Progress In Electromagnetics Research Symposium 2005, Hangzhou, China, August 22-26

Iterative Approach to Scattering from the Targets above a Rough Surface

The difference field RCS (d-RCS) has been defined to analyze the scattering from the target above a rough surface, which takes account of the scattering from the target and multiple interactions of the target and underlying rough surface. The d-RCS removes the effect of the finite illuminated surface length, under the tapered wave incidence. In this paper, our newly fast iterative approach is briefly reported. The electric field integral equations (EFIE) of the difference induced current oil the rough surface and the induced current oil the target are derived. An iterative approach is developed to solving the two EFIEs and scattering from both the target and underlying surface. How to choose the illuminated length of the rough surface for numerical iterations is discussed. Using the Monte Carlo method to realize the ocean-like rough surface, bistatic scatterings from the target, e.g. a cylinder or a square column, above a P-M (Pierson-Morkowitz spectrum) rough oceanic surface are numerically simulated for TE tapered wave incidence.

2005 IEEE International Symposium on Microwave, Antenna, Propagation and EMC Technologies for Wireless Communications

Difference RCS of electromagnetic scattering from the target above a randomly rough surface

The difference field RCS (d-RCS) has been defined to analyze the scattering from the target above a rough surface. The electric field integral equations (EFIEs) of the difference induced currentJsd on the rough surface, the induced electric currentJo and magnetic currentKo on the dielectric target under a TE wave incidence are derived. A small portion of the rough surface towards the target along the specular direction is taken to compute the scattering contributionEs0 from the rough surface towards the target, which improves the computation speed. A numerical iterative approach is developed to solve the EFIEs and bistatic d-RCS. The surface length for iterations is dependent on the scattering angle and discussed for comparison with Johnson’s method. Using the Monte-Carlo method to generate the Pierson-Morkowitz (P-M) ocean-like rough surface, bistatic d-RCS of the dielectric target, e.g. a cylinder or a square column, above the rough surface is numerically simulated. The induced electric and magnetic currents on the dielectric target and the difference induced current on the rough surface are numerically discussed.

Fast iterative approach to the difference scattering from a dielectric target above a rough surface

The complex scattering amplitude functions of a small metamaterial spheroid are derived under Rayleigh approximation. | fvv | and | fhh | of dielectric spheroid are symmetric along incident direction, while metamaterial spheroid along spheroid’s axis. The Mueller matrix for polarimetric scattering of a layer of random metamaterial small spheroids is constructed. Compared with dispersive FR-4 spheroids, σhh and σvv of metamaterial vary remarkably with frequency due to constitutive dispersion of e(ω) and � (ω), and take a peak at its resonance frequency. The σhh and σvv and polarizability degree ms, are simulated for a layer of nonuniformly oriented metamaterial spheroids under the illumination of an elliptically polarized plane wave. The scattering of metamaterial particles exhibits asymmetric directivity.

Polarimetric Scattering from a Layer of Spatially-Oriented Metamaterial Small Spheroids

The tapered wave with the tapering parameter g has been applied to numerical simulation of electromagnetic scattering from randomly rough surface with illuminated finite surface length L. This communication presents how to select the parameters g and L, and shows quantitative relationship with the incident angle. The parameter g, as a function of incident angle, should be large enough to make the wave equation in the range of allowable error. The surface length L, larger than several correlation lengths, should be large enough to suppress the punctuated power at the surface edges and be limited to make efficient computation. Combining these criterions, a graphical format to locate g and L for different incident angle /spl theta//sub i/ is illustrated. An empirical formula for selecting g and L as a function of /spl theta//sub i/ is proposed.

Parameterization of the tapered incident wave for numerical simulation of electromagnetic scattering from rough surface

Formulation and properties of a newly developed powder geopolymer grouting material

A series of pseudo-static tests were conducted with 4 coupling beams whose span-depth ratio 1.2. Common reinforced concrete and PVA fiber reinforced concrete were used for different specimens. In each of the specimens, there were longitudinal reinforcement, constructional reinforcement and stirrup, one of the specimens had crossed reinforcing bars. The failure mode of the coupling beams were studied, as well as hysteretic behavior. The test result indicated that using PVA fiber reinforced concrete could improve coupling beams carrying capacity, and could also reduce the amount of stirrup needed for seismic calculation; PVA members ductility was also improved.

Experimental Study on Seismic Performance of Small Span-to-Depth Ratio Coupling Beams with PVA Fiber Reinforced Concrete

In this paper, the effect of the non-uniformity settlement of ground foundation on the upper frame structure is studied. It takes a four-story space frame structure with two spans as an example. The different pedestals are installed at the joint of column footing, which respectively form the fixed supported model and the elastic supported model. Basin shaped settlement is applied in each model. The result shows that the beams are principally suffered with the bending moment and the columns principally suffered with axial force, shear force and bending moment, and that the elastic support model has certain economy.

In order to study the influence of dynamic response of frame-support-wall structure with openings on floor, six 3D models with different radio of opening are made. According to the finite element mode analysis and dynamic time-history analysis, we know that the location of openings, the size of openings etc. are important to the performance of structure. In order to keep entire structure in good condition, we suggest that the rate of openings should be smaller than 6%~8%.

Dynamic Analysis of Frame-Support-Wall Structure with Openings on Floor

Comparative analyses of twenty-eight finite element structures with filler walls were established to study dynamic characteristics of RC frame structures under seismic waves. The results of these analyses show that filler walls have little influence on vibration modes of the structure. But as a result of soft storey in the bottom of building caused by reduction of the filler walls, vibration modes have a great influence. As the stiffness of filler wall decrease, the stiffness of soft storey decrease shapely, vibration mode curve becomes much smoother. Considering the filler wall has influence on the vibration periods of framework, the reduction factor of 0.7 should be taken. The influence of filler wall to the value of lateral drift and storey displacement angle of frame can not be ignored. The main effect factors to the dynamic characteristics of framework are included quantity, location, material of the fill wall and the selection of seismic waves.

Analysis on the Effect of Filler Wall to the Dynamic Characteristics and Storey Displacement of RC Frame Structure

Ortho-chlorophenol(OCP),2,4-dichlorophenol(DCP),3,3',4',5-tetrachlorosalicylanilide(TCS),para-dinitrophenol(PNP) and 2,4-dinitrophenol(DNP) were chosen for short-term tests of their ability to reduce sludge yield by a bottle shaking test.The most effective chemicals,DNP,PNP and TCS were tested for various uncoupler concentrations and biomass concentrations.TCS was tested in a lab-scale completely mixed activated sludge batch culture.The model was verified with experimental data in a completely mixed activated sludge batch test,but the results from the bottle shaking batch test are inconsistent.The observed growth yield(Y_(obs)) is decreased with the increase of the ratio of initial uncoupler concentration to initial biomass concentration(C_u/X_o).The real strength of chemical uncoupler imposing on biomass should be C_u/X_o,not initial uncoupler concentration(C_u) alone.

In order to resolve the problems often encountered in start-up of a municipal wastewater plant with refractory industrial effluents discharged,a bench-scale experiment was conducted for a typical A/O process activated sludge system.With the ratio of the industrial wastewater influent progressively increasing,the acclimatization of sludge was studied by measuring the change of parameters such as COD and ammonia in the effluent.

Start-up of an A/O-Process Wastewater Treatment System with Industrial Effluents in Majority

3,3′,4′,5-tetrachlorosalicylanilide(TCS),served as metabolic uncoupler,was added to activated sludge cultures.Continuous-aeration batch culture test showed that the TCS addition in solid phase is better than in liquid phase,and one-time large-dosage addition is better than split small-dosage addition.TCS was able to reduce sludge yield by 55% when the TCS dosage was 24 mg/(2 d),but sludge production was only reduced by 33% if TCS was added 12 mg every day.The substrate removal capability was decreased by 12% when dosed 12 mg TCS every other day,but effluent nitrogen concentration was not affected adversely by the presence of TCS regardless of any dosage mode.SVI of sludge were slightly increased by addition of TCS,but sludge settleability was comparable and not significantly different.

Study on Control of Excess Sludge Production in Activated Sludge Process by Chemical Uncoupler

3,3′,4′,5-tetrachlorosalicylanilide (TCS), a metabolic uncoupler was added to completely mixed activated sludge process. The continuous tests have confirmed that TCS was an effective chemical uncoupler in reducing the excess sludge production by 30% when its specific concentration was higher than 0.5?mg·g~\{-1\}. It was also revealed that COD removal efficiency and sludge settleability from the treated and control samplers were comparable and not significantly different, but effluent nitrogen concentration was affected adversely by the presence of TCS during the 60?d operation. Such a sludge growth reduction was associated with the enhancement of microbial activities in terms of the SOUR. The filamentous bacteria were more in the sludge from system with addition of TCS than those in the control reactor after 60?d operation. Fewer protozoa and metazoan grow in the sludge from the system with the addition of TCS and their activities were much lower than control sludge. These results suggested that it might be possible to apply TCS in activated sludge systems to reduce the excess sludge production but it might influence the population in sludge.

Reduction of excess sludge production by chemical uncoupler in activated sludge process

The effect of aerobic precoating treatment of carrier on the starting-up of Anaerobic Attached Microbial Film Expanded Bed(AAFEB)reactor and process performance were studied. The reactor in which the crrier had aerobically precoated for 10 days accomplished staring-up 15 days ahead of the control. Moreover, it could maintain higher efficiency when it had a hydraulic or organic loading shock. But during the steady-state, there were no signifincant difference Comparing with the control.

The Effects of Aerobic Precoating of Carrier on the Performance of Anaerobic Reactor

Communication Principles is an important course for electronic information specialties.It involves a lot of theories and extensive contents;so that students feel that it is very difficult to study,especially in implementations of the communication system.In order to help readers catch the contents,many English edition books adopt Matlab,but it is not good in the system implementations.Using system simulating software SystemView to assist teaching the course is presented in this paper,and good effects in practice are obtained.The systems designed in SystemView correspond with the actual hardware system closely,and it has excellent simulating effects.

On the basis of the parallelizability of the algorithm for convolution back projection and the advantages of workstation cluster, the parallelization of image reconstruction in convolution back projection with narrow fan-beam based on workstation cluster was proposed and discussed. It was pointed out that the parallelization could play an important role in the fast image reconstruction of the high-energy ICT with high ratio of property to price.

RESEARCH ON THE PARALLEL IMAGE RECONSTRUCTION OF INDUSTRIAL COMPUTED TOMOGRAPHY IN CONVOLUTION BACK PROJECTION WITH NARROW FAN-BEAM BASED ON WORKSTATION CLUSTER

The method of the vacuum-heap carrying consociation Pre-press is an ideal method to reinforces the saturated soft soil, pass the experiment, observe the surface of roadbed sinking and move with the level, explaining that the vacuum Pre- press can make the foundation produce bigger sedimentation velocity, and raise the stability of the roadbed at the same time, the relativity between the quantity of the velocity and side offset toward load is obvious.

The Vacuum-heap Carrying Consociation Pre-press Method to Reinforce the Saturated Soft Soil

The resource endowment of western hunan makes it impossible to follow extensive economic growth mode, and people's increasing awareness of sustainable development has also prompted western hunan changing the economic development ideas. As a new economic development model, recycling economy fits the economic and social development situation in western hunan. Based on exploring in the necessity of developing recycling economics in western hunan, and with several basic principles in developing recycling economics in western hunan, author pointed out three following priorities in developing recycling economics in western hunan: tourism, mining, agriculture.

The Study of Priority Field in Developing Recycling Economics in Western Hunan

Objective To investigate pathological lesions of liver induced by cyclophosphamide in BALB/c mice.Methods Cyclophosphamide was intraperitoneally administered to BALB/c mice in a dose 15 mg/kg once daily for 8 days.Eight days later, the mice were sacrificed and their livers were subjected to paraffin sections stained with hematoxylin and eosine to examine hepatic lesions under light microscopy.Results Some pathological lesions such as focal necrosis and interstitial inflammatory cell infiltration and so on were found in the liver tissue.Conclusion Cyclophosphamide can cause the considerable damage to the liver of BALB/c mice.

Histopathological Observation on Hepatic lesions Induce by Cyclophosphamide in BALB/c Mice

Highway passenger transportation belongs to the trade of public service.After 20 years' open and reform policy,great progress has been made in this trade in Xiangxi,which reflects its economic development.Due to historical reasons,highway passenger transportation still faces many problems in this prefecture.

Problems in Xiangxi Highway Passenger Transportation and Their Countermeasures

Two ways can solve the problem of rural surplus labor tranferring of Western Hunan effectively.One is to utilizethe advantage of region and resource,adjust the structure of rural industry,exploit agriculture,tourism and farm product,accelerate the developing step of township enterprise,and transfer large quantities of rural surplus labor to inner state.Theother is to catch the chance historical train and lead the rural surplus labor to the outside state.

The Issue about Rural Surplus Labor Transferring of Western Hunan

The first choice to develop economy under the conditions of socialism market economy is the new type of industrialization.The major ways of new-type industrialization in Xiangxi Autonomous Prefecture are considered in the light of the local economic situation.

Thinking on the New Type of Industrialization in Xiangxi Autonmous Prefecture

Shade avoidance syndrome (SAS) refers to a set of plant responses that increases light capture in dense stands. This process is crucial for plants in natural and agricultural environments as they compete for resources and avoid suboptimal conditions. Although the molecular, biochemical, and physiological mechanisms underlying the SAS response have been extensively studied, the genetic basis of developmental variation in leaves in regard to leaf area, petiole length, and leaf length (i.e., their allometric relationships) remains unresolved. In this study, with the recombinant inbred line (RIL) population, the developmental traits of leaves of Arabidopsis were investigated under two growth density conditions (high- and low-density plantings). The observed changes were then reconstructed digitally, and their allometric relationships were modelled. Taking the genome-wide association analysis, the SNP genotype and the dynamic phenotype of the leaf from both densities were combined to explore the allometry QTLs. Under different densities, leaf change phenotype was analyzed from two core ecological scenarios: (i) the allometric change of the leaf area with leaf length, and (ii) the change of the leaf length with petiole length. QTLs modulating these two scenarios were characterized as ‘leaf shape QTLs’ and ‘leaf position QTLs’. With functional mapping, results showed a total of 30 and 24 significant SNPs for shapeQTLs and positionQTLs, respectively. By annotation, immune pathway genes, photosensory receptor genes, and phytohormone genes were identified to be involved in the SAS response. Interestingly, genes modulating the immune pathway and salt tolerance, i.e., systemic acquired resistance (SAR) regulatory proteins (MININ-1-related) and salt tolerance homologs (STH), were reported to mediate the SAS response. By dissecting and comparing QTL effects from low- and high-density conditions, our results elucidate the genetic control of leaf formation in the context of the SAS response. The mechanism with leaf development × density interaction can further aid the development of density-tolerant crop varieties for agricultural practices.

Functional Mapping of Genes Modulating Plant Shade Avoidance Using Leaf Traits

Introduction The cooperative strategy of phenotypic traits during the growth of plants reflects how plants allocate photosynthesis products, which is the most favorable decision for them to optimize growth, survival, and reproduction response to changing environment. Up to now, we still know little about why plants make such decision from the perspective of biological genetic mechanisms. Methods In this study, we construct an analytical mapping framework to explore the genetic mechanism regulating the interaction of two complex traits. The framework describes the dynamic growth of two traits and their interaction as Differential Interaction Regulatory Equations (DIRE), then DIRE is embedded into QTL mapping model to identify the key quantitative trait loci (QTLs) that regulate this interaction and clarify the genetic effect, genetic contribution and genetic network structure of these key QTLs. Computer simulation experiment proves the reliability and practicability of our framework. Results In order to verify that our framework is universal and flexible, we applied it to two sets of data from Populus euphratica, namely, aboveground stem length - underground taproot length, underground root number - underground root length, which represent relationships of phenotypic traits in two spatial dimensions of plant architecture. The analytical result shows that our model is well applicable to datasets of two dimensions. Discussion Our model helps to better illustrate the cooperation-competition patterns between phenotypic traits, and understand the decisions that plants make in a specific environment that are most conducive to their growth from the genetic perspective.

The genetic architecture of trait covariation in Populus euphratica, a desert tree

Corrigendum: Single nucleotide polymorphisms interactions of the surfactant protein genes associated with respiratory distress syndrome susceptibility in preterm infants

Heterophylly is an adaptive strategy used by some plants in response to environmental changes. Due to the lack of representative plants with typical heteromorphic leaves, little is known about the genetic architecture of heterophylly in plants and the genes underlying its control. Here, we investigated the genetic characteristics underlying changes in leaf shape based on the model species, Populus euphratica, which exhibits typical heterophylly. A set of 401,571 single-nucleotide polymorphisms (SNPs) derived from whole-genome sequencing of 860 genotypes were associated with nine leaf traits, which were related to descriptive and shape data using single- and multi-leaf genome-wide association studies (GWAS). Multi-leaf GWAS allows for a more comprehensive understanding of the genetic architecture of heterophylly by considering multiple leaves simultaneously. The single-leaf GWAS detected 140 significant SNPs, whereas the multi-leaf GWAS detected 200 SNP-trait associations. Markers were found across 19 chromosomes, and 21 unique genes were implicated in traits and serve as potential targets for selection. Our results provide novel insights into the genomic architecture of heterophylly, and provide candidate genes for breeding or engineering P. euphratica. Our observations also improve understanding of the intrinsic mechanisms of plant growth, evolution, and adaptation in response to climate change.

Genetic Architecture of Heterophylly: Single and Multi-Leaf Genome-Wide Association Mapping in Populus euphratica

Populus has a wide ecogeographical range spanning the Northern
Hemisphere, and exhibits abundant distinct species and hybrids globally.
Populus tomentosa Carr. is widely distributed and cultivated in
the eastern region of Asia, where it plays multiple important roles in
forestry, agriculture, conservation, and urban horticulture. Reference
genomes are available for several Populus species, however, our
goals were to produce a very high quality de novo, chromosome-level
genome assembly in P. tomentosa genome that could serve as a
reference for evolutionary and ecological studies of hybrid speciation.
Here, combining long-read sequencing and Hi-C scaffolding, we present a
high-quality, haplotype-resolved genome assembly. The genome size was
740.2 Mb, with a contig N50 size of 5.47 Mb and a scaffold N50 size of
46.68 Mb, consisting of 38 chromosomes, as expected with the known
diploid chromosome number (2n=2x=38). A total of 59,124 protein-coding
genes were identified. Phylogenomic analyses revealed that P.
tomentosa is comprised of two distinct subgenomes, which we
deomonstrate is likely to have resulted from hybridization between
Populus adenopoda as the female parent and Populus alba
var. pyramidalis as the male parent, approximately 3.93 Mya.
Although highly colinear, significant structural variation was also
found between the two subgenomes. Our study provides a valuable resource
for ecological genetics and forest biotechnology.

High quality haplotype-resolved genome assemblies of Populus tomentosa Carr., a stabilized interspecific hybrid species that is widespread in Asia

Populus has a wide ecogeographical range spanning the Northern Hemisphere, and interspecific hybrids are common. Populus tomentosa Carr. is widely distributed and cultivated in the eastern region of Asia, where it plays multiple important roles in forestry, agriculture, conservation, and urban horticulture. Reference genomes are available for several Populus species, however, our goals were to produce a very high quality de novo chromosome‐level genome assembly in P. tomentosa genome that could serve as a reference for evolutionary and ecological studies of hybrid speciation throughout the genus. Here, combining long‐read sequencing and Hi‐C scaffolding, we present a high‐quality, haplotype‐resolved genome assembly. The genome size was 740.2 Mb, with a contig N50 size of 5.47 Mb and a scaffold N50 size of 46.68 Mb, consisting of 38 chromosomes, as expected with the known diploid chromosome number (2n = 2x = 38). A total of 59,124 protein‐coding genes were identified. Phylogenomic analyses revealed that P. tomentosa is comprised of two distinct subgenomes, which we deomonstrate is likely to have resulted from hybridization between Populus adenopoda as the female parent and Populus alba var. pyramidalis as the male parent, with an origin of approximately 3.93 Ma. Although highly colinear, significant structural variation was found between the two subgenomes. Our study provides a valuable resource for ecological genetics and forest biotechnology.

High quality haplotype‐resolved genome assemblies of Populus tomentosa Carr., a stabilized interspecific hybrid species widespread in Asia

Background: Neonatal respiratory distress syndrome (RDS), due to surfactant deficiency in preterm infants, is the most common cause of respiratory morbidity. The surfactant proteins (SFTP) genetic variants have been well-studied in association with RDS; however, the impact of SNP-SNP (single nucleotide polymorphism) interactions on RDS has not been addressed. Therefore, this study utilizes a newer statistical model to determine the association of SFTP single SNP model and SNP-SNP interactions in a two and a three SNP interaction model with RDS susceptibility. Methods: This study used available genotype and clinical data in the Floros biobank at Penn State University. The patients consisted of 848 preterm infants, born <36 weeks of gestation, with 477 infants with RDS and 458 infants without RDS. Seventeen well-studied SFTPA1, SFTPA2, SFTPB, SFTPC, and SFTPD SNPs were investigated. Wang's statistical model was employed to test and identify significant associations in a case-control study. Results: Only the rs17886395 (C allele) of the SFTPA2 was associated with protection for RDS in a single-SNP model (Odd's Ratio 0.16, 95% CI 0.06–0.43, adjusted p = 0.03). The highest number of interactions (n = 27) in the three SNP interactions were among SFTPA1 and SFTPA2. The three SNP models showed intergenic and intragenic interactions among all SFTP SNPs except SFTPC. Conclusion: The single SNP model and SNP interactions using the two and three SNP interactions models identified SFTP-SNP associations with RDS. However, the large number of significant associations containing SFTPA1 and/or SFTPA2 SNPs point to the importance of SFTPA1 and SFTPA2 in RDS susceptibility.

Single Nucleotide Polymorphisms Interactions of the Surfactant Protein Genes Associated With Respiratory Distress Syndrome Susceptibility in Preterm Infants

Developmental modularity, i.e., coherent organization and function of developmentally related traits, is an emergent property of organismic development and evolution. However, knowledge about how modular variation and evolution are driven genetically is still limited. Here, using ornamental plants as an example, we propose a computational framework to map, visualize and annotate the genetic architecture of trait modularity by integrating modularity theory into system mapping, a statistical model for multifaceted genetic mapping of complex traits. A developmental module can be viewed as an ecosystem, in which the constituting components compete for space and resources or cooperate symbiotically to organize its function and behavior. This interactive process is quantified by mathematical models and evolutionarily interpreted by game theory. The proposed framework can test whether and how genes regulate the coordination of different but interconnected traits through their competition or cooperation to downstream developmental modularity.

Mapping the genetic architecture of developmental modularity in ornamental plants

Modeling genome-wide by environment interactions through omnigenic interactome networks.

How genes interact with the environment to shape phenotypic variation and evolution is a fundamental question interesting to biologists from various fields. Existing linear models built on single genes are inadequate to reveal the complexity of gene-environment (G-E) interactions. Here, we develop a conceptual model for mechanistically dissecting G-E interplay by integrating previously disconnected theories and methods. Under this integration, evolutionary game theory, developmental modularity theory, and variable selection method allow us to reconstruct environment-induced, maximally informative, sparse, and casual multilayer genetic networks. We design and conduct a mapping experiment using a salt-resistant tree species to validate the biological application of the new model. The model identifies previously uncharacterized molecular mechanisms that mediate trees’ response to saline stress. Our model provides a tool to comprehend the genetic architecture of trait variation and evolution and trace the information flow of each gene toward phenotypes within omnigenic networks.

Modeling Genome-Wide by Environment Interactions Through Omnigenic Interactome Networks

Phenotypic plasticity is the exhibition of various phenotypic traits produced by a single genotype in response to environmental changes, enabling organisms to adapt to environmental changes by maintaining growth and reproduction. Despite its significance in evolutionary studies, we still know little about the genetic control of phenotypic plasticity. In this study, we designed and conducted a genome-wide association study (GWAS) to reveal genetic architecture of how Staphylococcus aureus strains respond to increasing concentrations of vancomycin (0, 2, 4, and 6 μg/mL) in a time course. We implemented functional mapping, a dynamic model for genetic mapping using longitudinal data, to map specific loci that mediate the growth trajectories of abundance of vancomycin-exposed S. aureus strains. 78 significant single nucleotide polymorphisms were identified following analysis of the whole growth and development process, and seven genes might play a pivotal role in governing phenotypic plasticity to the pressure of vancomycin. These seven genes, SAOUHSC_00020 (walR), SAOUHSC_00176, SAOUHSC_00544 (sdrC), SAOUHSC_02998, SAOUHSC_00025, SAOUHSC_00169, and SAOUHSC_02023, were found to help S. aureus regulate antibiotic pressure. Our dynamic gene mapping technique provides a tool for dissecting the phenotypic plasticity mechanisms of S. aureus under vancomycin pressure, emphasizing the feasibility and potential of functional mapping in the study of bacterial phenotypic plasticity.

Functional Mapping of Phenotypic Plasticity of Staphylococcus aureus Under Vancomycin Pressure

Background: Plants have evolved the dual capacity for maximizing light assimilation through stem growth (phototropism) and maximizing water and nutrient absorption through root growth (gravitropism). Previous studies have revealed the physiological and molecular mechanisms of these two processes, but the genetic basis for how gravitropism and phototropism interact and coordinate with one another to determine plant growth remains poorly understood. Methods: We designed a seed germination experiment using a full-sib F1 family of Populus euphratica to simultaneously monitor the gravitropic growth of the radicle and the phototropic growth of the plumule throughout seedling ontogeny. We implemented three functional mapping models to identify quantitative trait loci (QTLs) that regulate gravitropic and phototropic growth. Univariate functional mapping dissected each growth trait separately, bivariate functional mapping mapped two growth traits simultaneously, and composite functional mapping mapped the sum of gravitropic and phototropic growth as a main axis. Results: Bivariate model detected 8 QTLs for gravitropism and phototropism (QWRF, GLUR, F-box, PCFS4, UBQ, TAF12, BHLH95, TMN8), composite model detected 7 QTLs for growth of main axis (ATL8, NEFH, PCFS4, UBQ, SOT16, MOR1, PCMP-H), of which, PCFS4 and UBQ were pleiotropically detected with the both model. Many of these QTLs are situated within the genomic regions of candidate genes. Conclusions: The results from our models provide new insight into the mechanisms of genetic control of gravitropism and phototropism in a desert tree, and will stimulate our understanding of the relationships between gravity and light signal transduction pathways and tree adaptation to arid soil.

Functional mapping of gravitropism and phototropism for a desert tree, Populus euphratica.

Heterophylly, or leaf morphological changes along plant shoot axes, is an important indicator of plant eco-adaptation to heterogeneous microenvironments. Despite extensive studies on the genetic control of leaf shape, the genetic architecture of heterophylly remains elusive. To identify genes related to heterophylly and their associations with plant saline tolerance, we conducted a leaf shape mapping experiment using leaves from a natural population of Populus euphratica. We included 106 genotypes grown under salt stress and salt-free (control) conditions using clonal seedling replicates. We developed a shape tracking method to monitor and analyze the leaf shape using principal component (PC) analysis. PC1 explained 42.18% of the shape variation, indicating that shape variation is mainly determined by the leaf length. Using leaf length along shoot axes as a dynamic trait, we implemented a functional mapping-assisted genome-wide association study (GWAS) for heterophylly. We identified 171 and 134 significant quantitative trait loci (QTLs) in control and stressed plants, respectively, which were annotated as candidate genes for stress resistance, auxin, shape, and disease resistance. Functions of the stress resistance genes ABSCISIC ACIS-INSENSITIVE 5-like (ABI5), WRKY72, and MAPK3 were found to be related to many tolerance responses. The detection of AUXIN RESPONSE FACTOR17-LIKE (ARF17) suggests a balance between auxin-regulated leaf growth and stress resistance within the genome, which led to the development of heterophylly via evolution. Differentially expressed genes between control and stressed plants included several factors with similar functions affecting stress-mediated heterophylly, such as the stress-related genes ABC transporter C family member 2 (ABCC2) and ABC transporter F family member (ABCF), and the stomata-regulating and reactive oxygen species (ROS) signaling gene RESPIRATORY BURST OXIDASE HOMOLOG (RBOH). A comparison of the genetic architecture of control and salt-stressed plants revealed a potential link between heterophylly and saline tolerance in P. euphratica, which will provide new avenues for research on saline resistance-related genetic mechanisms.

Heterophylly Quantitative Trait Loci Respond to Salt Stress in the Desert Tree Populus euphratica

The genetic control of leaf allometry in the common bean, Phaseolus vulgaris

Genome sequencing and phylogenetic analysis of allotetraploid Salix matsudana Koidz

As an important functional organ of plants, leaves alter their shapes in response to a changing environment. The variation of leaf shape has long been an important evolutionary and developmental force in plants. Despite an increasing amount of investigations into the genetic controls of leaf morphology, few have systematically studied the genetic architecture controlling shape differences among distinct altitudes. Altitude denotes a comprehensive complex of environmental factors affecting plant growth in many aspects, e.g., UV-light radiation, temperature, and humidity. To reveal how plants alter ecological adaptation to altitude through genes, we used Populus szechuanica var. tibetica growing on the Qinghai-Tibetan plateau. FST between the low- and high- altitude population was 0.00748, QST for leaf width, length and area were 0.00924, 0.1108, 0.00964 respectively. With the Elliptic Fourier-based morphometric model, association study of leaf shape was allowed, the dissection of the pleiotropic expression of genes mediating altitude-derived leaf shape variation was performed. For high and low altitudes, 130 and 131 significant single-nucleotide polymorphisms (SNPs) were identified. QTLs that affected leaf axis length and leaf width were expressed in both-altitude population, while QTLs regulating “leaf tip” and “leaf base” were expressed in low-altitude population. Pkinase and PRR2 were common significant genes in both types of populations. Auxin-related and differentiation-related genes included PIN1, CDK-like, and CAK1AT at high altitude, whereas they included NAP5, PIN-LIKES, and SCL1 at low altitude. The presence of Stress-antifung gene, CIPK3 and CRPK1 in high-altitude population suggested an interaction between genes and harsh environment in mediating leaf shape, while the senescence repression-related genes (EIN2 and JMJ18) and JMT in jasmonic acid pathway in low-altitude population suggested their crucial roles in ecological adaptability. These data provide new information that strengthens the understanding of genetic control with respect to leaf shape and constitute an entirely novel perspective regarding leaf adaptation and development in plants.

Identification of Quantitative Trait Loci for Altitude Adaptation of Tree Leaf Shape With Populus szechuanica in the Qinghai-Tibetan Plateau

Populus tomentosa is widely distributed and cultivated in the Northern and Central China, where it is of great economic and ecological importance. However, the origin of P. tomentosa remains controversial. Here, we used a PacBio+Hi-C+Illumina strategy to sequence and assemble its 740.2 Mb (2n) genome. The assembly accounts for greater than 92.1% of the 800-megabase genome, comprises 38 chromosomes, and contains 59,124 annotated protein-coding genes. Phylogenomic analyses elucidated dynamic genome evolution events among its closely related white poplars, and revealed that tomentosa is comprised of two subgenomes, which we deomonstrate is likely to have resulted from hybridization between Populus adenopoda as the female, and Populus alba var. pyramidalis as the male, around 3.93 Mya. We also detected structural variations and allele-indels across genome. Our study presents a high quality and well assembled genome, unveils the origin of the widely distributed and planted P. tomentosa, and provides a powerful resource for comparative plant biology, breeding, and biotechnology.

Hybrid origin of Populus tomentosa Carr. identified through genome sequencing and phylogenomic analysis

In recent years, the emergence of next generation sequencing (NGS) makes it possible to obtain the data of microbial genome accurately in a short period of time, and it has become a powerful tool for microbial molecular ecology research. NGS has the advantage of non-sequence dependence and it can simultaneously detect nearly all culturable and non-culturable microorganisms which have high or low contents. With the explosion of sequencing data generated by NGS and multi-omics techniques, there is a growing need for the powerful genetic statistical models to generate meaningful hypotheses about the mechanisms underlying biological interaction. In this paper, we mainly discuss the application and prospect of NGS combined with the genetic statistical models in microbial molecular ecology. The combination of the two in promoting the study of microbial interspecific interaction is discussed. Then we analyze the application of the combination in the study of bacterial phenotypic plasticity. Finally, we describe its application in constructing gene regulatory network of microbe-plant interaction, which aims to identify key genes to enhance the disease resistance of plants.

Progress in next generation sequencing (NGS) combined with genetic statistical model in microbial molecular ecology

Bivariate genome-wide association study of the growth plasticity of Staphylococcus aureus in coculture with Escherichia coli

Abstract Plant adaptation to high altitudes has long been a substantial focus of ecological and evolutionary research. However, the genetic mechanisms underlying such adaptation remain poorly understood. Here, we address this issue by sampling, genotyping, and comparing populations of Tibetan poplar, Populus szechuanica var. tibetica, distributed from low (~2,000 m) to high altitudes (~3,000 m) of Sejila Mountain on the Qinghai–Tibet Plateau. Population structure analyses allow clear classification of two groups according to their altitudinal distributions. However, in contrast to the genetic variation within each population, differences between the two populations only explain a small portion of the total genetic variation (3.64%). We identified asymmetrical gene flow from high‐ to low‐altitude populations. Integrating population genomic and landscape genomic analyses, we detected two hotspot regions, one containing four genes associated with altitudinal variation, and the other containing ten genes associated with response to solar radiation. These genes participate in abiotic stress resistance and regulation of reproductive processes. Our results provide insight into the genetic mechanisms underlying high‐altitude adaptation in Tibetan poplar.

Genetic adaptation of Tibetan poplar (Populus szechuanica var. tibetica) to high altitudes on the Qinghai–Tibetan Plateau

Crossover (CO) interference is a universal phenomenon by which the occurrence of one CO event inhibits the simultaneous occurrence of other COs along a chromosome. Because of its critical role in the evolution of genome structure and organization, the cytological and molecular mechanisms underlying CO interference have been extensively investigated. However, the genome-wide distribution of CO interference and its interplay with sex-, stress-, and age-induced differentiation remain poorly understood. Multi-point linkage analysis has proven to be a powerful tool for landscaping CO interference, especially within species for which CO mutants are rarely available. We implemented four-point linkage analysis to landscape a detailed picture of how CO interference is distributed through the entire genome of Populus euphratica, the only forest tree that can survive and grow in saline desert. We identified an extensive occurrence of CO interference, and found that its strength depends on the length of chromosomes and the genomic locations within the chromosome. We detected high-order CO interference, possibly suggesting a highly complex mechanism crucial for P. euphratica to grow, reproduce, and evolve in its harsh environment.

The Genomic Landscape of Crossover Interference in the Desert Tree Populus euphratica

Many quantitative traits are composites of other traits that contribute differentially to genetic variation. Quantitative trait locus (QTL) mapping of these composite traits can benefit by incorporating the mechanistic process of how their formation is mediated by the underlying components. We propose a dissection model by which to map these interconnected components traits under a joint likelihood setting. The model can test how a composite trait is determined by pleiotropic QTLs for its component traits or jointly by different sets of QTLs each responsible for a different component. The model can visualize the pattern of time-varying genetic effects for individual components and their impacts on composite traits. The dissection model was used to map two composite traits, stemwood volume growth decomposed into its stem height, stem diameter and stem form components for Euramerican poplar adult trees, and total lateral root length constituted by its average lateral root length and lateral root number components for Euphrates poplar seedlings. We found the pattern of how QTLs for different components contribute to phenotypic variation in composite traits. The detailed understanding of the genetic machineries of composite traits will not only help in the design of molecular breeding in plants and animals, but also shed light on the evolutionary processes of quantitative traits under natural selection.

Vegetative phase changes in plants describes the transition between juvenile and adult phases of vegetative growth before flowering. It is one of the most fundamental mechanisms for plants to sense developmental signals, presenting a complex process involving many still-unknown determinants. Several studies in annual and perennial plants have identified the conservative roles of miR156 and its targets, SBP/SPL genes, in guiding the switch of plant growth from juvenile to adult phases. Here, we review recent progress in understanding the regulation of miR156 expression and how miR156-SPLs mediated plant age affect other processes in Arabidopsis. Powerful high-throughput sequencing techniques have provided rich data to systematically study the regulatory mechanisms of miR156 regulation network. From this data, we draw an expanded miR156-regulated network that links plant developmental transition and other fundamental biological processes, gaining novel and broad insight into the molecular mechanisms of plant-age-related processes in Arabidopsis.

A Regulatory Network for miR156-SPL Module in Arabidopsis thaliana

A Drive to Driven Model of Mapping Intraspecific Interaction Networks

As overfertilization leads to environmental concerns and the cost of N fertilizer increases, the issue of how to select crop cultivars that can produce high yields on N-deficient soils has become crucially important. However, little information is known about the genetic mechanisms by which crops respond to environmental changes induced by N signaling. Here, we dissected the genetic architecture of N-induced phenotypic plasticity in bread wheat (Triticum aestivum L.) by integrating functional mapping and semiautomatic high-throughput phenotyping data of yield-related canopy architecture. We identified a set of quantitative trait loci (QTLs) that determined the pattern and magnitude of how wheat cultivars responded to low N stress from normal N supply throughout the wheat life cycle. This analysis highlighted the phenological landscape of genetic effects exerted by individual QTLs, as well as their interactions with N-induced signals and with canopy measurement angles. This information may shed light on our mechanistic understanding of plant adaptation and provide valuable information for the breeding of N-deficiency tolerant wheat varieties.

Functional mapping of N deficiency‐induced response in wheat yield‐component traits by implementing high‐throughput phenotyping

Phenotypic plasticity enables individuals to develop different phenotypes in a changing environment and promotes adaptive evolution. Genome-wide association study (GWAS) facilitates the study of the genetic basis of bacterial phenotypes, and provides a new opportunity for bacterial phenotypic plasticity research. To investigate the relationship between growth plasticity and genotype in bacteria, 41 Staphylococcus aureus strains, including 29 vancomycin-intermediate S. aureus (VISA) strains, were inoculated in the absence or presence of vancomycin for 48 h. Growth curves and maximum growth rates revealed that strains with the same minimum inhibitory concentration (MIC) showed different levels of plasticity in response to vancomycin. A bivariate GWAS was performed to map single-nucleotide polymorphisms (SNPs) associated with growth plasticity. In total, 227 SNPs were identified from 14 time points, while 15 high-frequency SNPs were mapped to different annotated genes. The P-values and growth variations between the two cultures suggest that non-coding region (SNP 738836), ebh (SNP 1394043), drug transporter (SNP 264897), and pepV (SNP 1775112) play important roles in the growth plasticity of S. aureus. Our study provides an alternative strategy for dissecting the adaptive growth of S. aureus in vancomycin and highlights the feasibility of bivariate GWAS in bacterial phenotypic plasticity research.

Phenotypic Plasticity of Staphylococcus aureus in Liquid Medium Containing Vancomycin

Despite its critical importance to our understanding of plant growth and adaptation, the question of how environment-induced plastic response is affected genetically remains elusive. Previous studies have shown that the reaction norm of an organism across environmental index obeys the allometrical scaling law of part-whole relationships. The implementation of this phenomenon into functional mapping can characterize how quantitative trait loci (QTLs) modulate the phenotypic plasticity of complex traits to heterogeneous environments. Here, we assemble functional mapping and allometry theory through Lokta-Volterra ordinary differential equations (LVODE) into an R-based computing platform, np2 QTL, aimed to map and visualize phenotypic plasticity QTLs. Based on LVODE parameters, np2 QTL constructs a bidirectional, signed and weighted network of QTL-QTL epistasis, whose emergent properties reflect the ecological mechanisms for genotype-environment interactions over any range of environmental change. The utility of np2 QTL was validated by comprehending the genetic architecture of phenotypic plasticity via the reanalysis of published plant height data involving 3502 recombinant inbred lines of maize planted in multiple discrete environments. np2 QTL also provides a tool for constructing a predictive model of phenotypic responses in extreme environments relative to the median environment.

np2 QTL: networking phenotypic plasticity quantitative trait loci across heterogeneous environments.

De novo shoot regeneration is one of the important manifestations of cell totipotency in organogenesis, which reflects a survival strategy organism evolved when facing natural selection. Compared with tissue regeneration, and somatic embryogenesis, de novo shoot regeneration denotes a shoot regeneration process directly from detatched or injured tissues of plant. Studies on plant shoot regeneration had identified key genes mediating shoot regeneration. However, knowledge was derived from Arabidopsis; the regeneration capacity is hugely distinct among species. To achieve a comprehensive understanding of the shoot regeneration mechanism from tree species, we select four genetic lines of Populus euphratica from a natural population to be sequenced at transcriptome level. On the basis of the large difference of differentiation capacity, between the highly differentiated (HD) and low differentiated (LD) groups, the analysis of differential expression identified 4920 differentially expressed genes (DEGs), which were revealed in five groups of expression patterns by clustering analysis. Enrichment showed crucial pathways involved in regulation of regeneration difference, including “plant hormone signal transduction”, “cell differentiation”, "cellular response to auxin stimulus", and “auxin-activated signaling pathway”. The expression of nine genes reported to be associated with shoot regeneration was validated using quantitative real-time PCR (qRT-PCR). For the specificity of regeneration mechanism with P. euphratica, large amount of DEGs involved in "plant-pathogen interaction", ubiquitin-26S proteosome mediated proteolysis pathway, stress-responsive DEGs, and senescence-associated DEGs were summarized to possibly account for the differentiation difference with distinct genotypes of P. euphratica. The result in this study helps screening of key regulators in mediating the shoot differentiation. The transcriptomic characteristic in P. euphratica further enhances our understanding of key processes affecting the regeneration capacity of de novo shoots among distinct species.

Identification of Shoot Differentiation-Related Genes in Populus euphratica Oliv

A mapping framework of competition–cooperation QTLs that drive community dynamics

The genetic architecture of floral traits in the woody plant Prunus mume

Surfactant proteins (SP) are involved in surfactant function and innate immunity in the human lung. Both lung function and innate immunity are altered in CF, and altered SP levels and genetic association are observed in Cystic Fibrosis (CF). We hypothesized that single nucleotide polymorphisms (SNPs) within the SP genes associate with CF or severity subgroups, either through single SNP or via SNP-SNP interactions between two SNPs of a given gene (intragenic) and/or between two genes (intergenic). We genotyped a total of 17 SP SNPs from 72 case-trio pedigree (SFTPA1 (5), SFTPA2 (4), SFTPB (4), SFTPC (2), and SFTPD (2)), and identified SP SNP associations by applying quantitative genetic principles. The results showed (a) Two SNPs, SFTPB rs7316 (p = 0.0083) and SFTPC rs1124 (p = 0.0154), each associated with CF. (b) Three intragenic SNP-SNP interactions, SFTPB (rs2077079, rs3024798), and SFTPA1 (rs1136451, rs1059057 and rs4253527), associated with CF. (c) A total of 34 intergenic SNP-SNP interactions among the 4 SP genes to be associated with CF. (d) No SNP-SNP interaction was observed between SFTPA1 or SFTPA2 and SFTPD. (e) Equal number of SNP-SNP interactions were observed between SFTPB and SFTPA1/SFTPA2 (n = 7) and SP-B and SFTPD (n = 7). (f) SFTPC exhibited significant SNP-SNP interactions with SFTPA1/SFTPA2 (n = 11), SFTPB (n = 4) and SFTPD (n = 3). (g) A single SFTPB SNP was associated with mild CF after Bonferroni correction, and several intergenic interactions that are associated (p < 0.01) with either mild or moderate/severe CF were observed. These collectively indicate that complex SNP-SNP interactions of the SP genes may contribute to the pulmonary disease in CF patients. We speculate that SPs may serve as modifiers for the varied progression of pulmonary disease in CF and/or its severity.

Genetic Association of Pulmonary Surfactant Protein Genes, SFTPA1, SFTPA2, SFTPB, SFTPC, and SFTPD With Cystic Fibrosis

How trees allocate photosynthetic products to primary height growth and secondary radial growth reflects their capacity to best use environmental resources. Despite substantial efforts to explore tree height-diameter relationship empirically and through theoretical modeling, our understanding of the biological mechanisms that govern this phenomenon is still limited. By thinking of stem woody biomass production as an ecological system of apical and lateral growth components, we implement game theory to model and discern how these two components cooperate symbiotically with each other or compete for resources to determine the size of a tree stem. This resulting allometry game theory is further embedded within a genetic mapping and association paradigm, allowing the genetic loci mediating the carbon allocation of stemwood growth to be characterized and mapped throughout the genome. Allometry game theory was validated by analyzing a mapping data of stem height and diameter growth over perennial seasons in a poplar tree. Several key quantitative trait loci were found to interpret the process and pattern of stemwood growth through regulating the ecological interactions of stem apical and lateral growth. The application of allometry game theory enables the prediction of the situations in which the cooperation, competition or altruism is an optimal decision of a tree to fully use the environmental resources it owns.

How trees allocate carbon for optimal growth: insight from a game-theoretic model

Despite its importance in understanding the emergent property of plant communities and ecosystems, the question of how genes govern species coexistence has proven very difficult to answer. In a plant community that behaves like a network game, each coexisting plant strives to maximize its fitness by pursuing a “rational self‐interest” strategy in a way that affects the decisive reaction of other plants. We integrated this principle founding game theory into a quantitative trait locus (QTL) mapping paradigm, on which to derive a game mapping model for the genetic landscaping of how plants coexist. The new mapping model dissolves the phenotype of each plant in a community into two components, autonomous phenotype, characteristic of the plant's intrinsic ability expected to be expressed in isolation, and social phenotype, determined by game theory‐guided interactions between the plant and other members. We implemented the new model into a competition experiment by pairwise growing 116 recombinant inbred lines of Arabidopsis. Most QTLs detected from this experiment reside within biologically meaningful genes, including SCL6, CAR6, CLPB1, ALDH5F1, and EMB2217, which may mediate competitive interactions in unique ways. The new model can chart more detailed genetic architecture of plant community structure and diversity by extracting the genetic effects of QTLs on social phenotypes. Our model lays the groundwork for predicting and managing dynamic relationships between biodiversity and ecosystem functioning from co‐species genotypes.

A computational‐experimental framework for mapping plant coexistence

This project proposes an approach to identify significant single nucleotide polymorphism (SNP) effects, both additive and dominant, on the dynamic growth of poplar in diameter and height. The annual changes in yearly phenotypes based on regular observation periods are considered to represent multiple responses. In total 156,362 candidate SNPs are studied, and the phenotypes of 64 poplar trees are recorded. To address this ultrahigh dimensionality issue, this paper adopts a two-stage approach. First, the conventional genome-wide association studies (GWAS) and the distance correlation sure independence screening (DC-SIS) methods (Li et al., 2012) were combined to reduce the model dimensions at the sample size; second, a grouped penalized regression was applied to further refine the model and choose the final sparse SNPs. The multiple response issue was also carefully addressed. The SNP effects on the dynamic diameter and height growth patterns of poplar were systematically analyzed. In addition, a series of intensive simulation studies was performed to validate the proposed approach.

Two‐stage identification of SNP effects on dynamic poplar growth

Whole-organism metabolic rate co-varies allometrically with body mass, and is also affected by temperature through different biochemical mechanisms. Here we implement a computational platform to map specific quantitative trait loci (QTLs) that govern the dependence of metabolic rate on size and temperature. The model was formulated within settings of genetic mapping or genome-wide association studies through a mapping population genotyped by a set of molecular markers throughout the genome and phenotyped for metabolic parameters over a range of temperature. The model, estimated by a maximum-likelihood approach, allows a genome-wide search for the underlying metabolic QTLs and the estimation of genotype-specific parameters that specify the metabolism of an organism. Our model provides a tool to detect pleiotropy and epistasis that cause the size- and temperature-dependent change of metabolic rate.

A computing platform to map ecological metabolism by integrating functional mapping and the metabolic theory of ecology

Dynamic changes in the transcriptome of Populus hopeiensis in response to abscisic acid

How a species responds to such a biotic environment in the community, ultimately leading to its evolution, has been a topic of intense interest to ecological evolutionary biologists. Until recently, limited knowledge was available regarding the genotypic changes that underlie phenotypic changes. Our study implemented GWAS (Genome-Wide Association Studies) to illustrate the genetic architecture of ecological interactions that take place in microbial populations. By choosing 45 such interspecific pairs of Escherichia coli and Staphylococcus aureus strains that were all genotyped throughout the entire genome, we employed Q-ROADTRIPS to analyze the association between single SNPs and microbial abundance measured at each time point for bacterial populations reared in monoculture and co-culture, respectively. We identified a large number of SNPs and indels across the genomes (35.69 G clean data of E. coli and 50.41 G of S. aureus). We reported 66 and 111 SNPs that were associated with interaction in E. coli and S. aureus, respectively. 23 out of 66 polymorphic changes resulted in amino acid alterations.12 significant genes, such as murE, treA, argS, and relA, which were also identified in previous evolutionary studies. In S. aureus, 111 SNPs detected in coding sequences could be divided into 35 non-synonymous and 76 synonymous SNPs. Our study illustrated the potential of genome-wide association methods for studying rapidly evolving traits in bacteria. Genetic association study methods will facilitate the identification of genetic elements likely to cause phenotypes of interest and provide targets for further laboratory investigation.

Bacterial Genetic Architecture of Ecological Interactions in Co-culture by GWAS-Taking Escherichia coli and Staphylococcus aureus as an Example

Linkage analysis has played an important role in understanding genome structure and evolution. However, two-point linkage analysis widely used for genetic map construction can rarely chart a detailed picture of genome organization because it fails to identify the dependence of crossovers distributed along the length of a chromosome, a phenomenon known as crossover interference. Multi-point analysis, proven to be more advantageous in gene ordering and genetic distance estimation for dominant markers than two-point analysis, is equipped with a capacity to discern and quantify crossover interference. Here, we review a statistical model for four-point analysis, which, beyond three-point analysis, can characterize crossover interference that takes place not only between two adjacent chromosomal intervals, but also over multiple successive intervals. This procedure provides an analytical tool to elucidate the detailed landscape of crossover interference over the genome and further infer the evolution of genome structure and organization.

A high-dimensional linkage analysis model for characterizing crossover interference

The coordination of shoots and roots is critical for plants to adapt to changing environments by fine-tuning energy production in leaves and the availability of water and nutrients from roots. To understand the genetic architecture of how these two organs covary during developmental ontogeny, we conducted a mapping experiment using Euphrates poplar (Populus euphratica), a so-called hero tree able to grow in the desert. We geminated intraspecific F1 seeds of Euphrates Poplar individually in a tube to obtain a total of 370 seedlings, whose shoot and taproot lengths were measured repeatedly during the early stage of growth. By fitting a growth equation, we estimated asymptotic growth, relative growth rate, the timing of inflection point and duration of linear growth for both shoot and taproot growth. Treating these heterochronic parameters as phenotypes, a univariate mapping model detected 19 heterochronic quantitative trait loci (hQTLs), of which 15 mediate the forms of shoot growth and four mediate taproot growth. A bivariate mapping model identified 11 pleiotropic hQTLs that determine the covariation of shoot and taproot growth. Most QTLs detected reside within the region of candidate genes with various functions, thus confirming their roles in the biochemical processes underlying plant growth.

The genetic architecture of shoot–root covariation during seedling emergence of a desert tree, Populus euphratica

Objective
We studied the interactions in a co-culture of two bacteria.

Methods
By pairwise co-culturing of 36 Escherichia coli and 36 Staphylococcus aureus strains, we monitored the growth of each species in an interaction environment. We identified numerous Single Nucleotide Polymorphisms (SNPs) by whole-genome sequencing used as genetic markers to predict variations in phenotypic traits. Genome-wide association study (GWAS) was applied to identify loci that controlled competition between the two species.

Results
In E. coli, 162 significant SNPs affected the change of maximum growth rate by comparing initials strains with those grown in co-culture, and 36 significant SNPs affected the change of maximum growth rate comparing monoculture and co-culture strains. Five of the significant E. coli genes we identified after annotation this time were also reported in other evolutionary studies. We also identified 85 significant SNPs in S. aureus that affected the change of maximum growth rate by comparing initial strains with those grown in monoculture. About the change of bacterial numbers, we found that 706 significant SNPs were associated in E. coli and 129 in S. aureus. Thirteen of the E. coli significant genes in this study were also verified in previous evolutionary reports

We found several significant genes both in monoculture and co-culture affecting the interaction of E. coli and S. aureus. GWAS has the potential to study interspecific interactions of bacteria.

[Interactions between Escherichia coli and Staphylococcus aureus determined by genome-wide association analysis].

Summary The developmental variation in stem height with respect to stem diameter is related to a broad range of ecological and evolutionary phenomena in trees, but the underlying genetic basis of this variation remains elusive. We implement a dynamic statistical model, functional mapping, to formulate a general procedure for the computational identification of quantitative trait loci (QTLs) that control stem height–diameter allometry during development. Functional mapping integrates the biological principles underlying trait formation and development into the association analysis of DNA genotype and endpoint phenotype, thus providing an incentive for understanding the mechanistic interplay between genes and development. Built on the basic tenet of functional mapping, we explore two core ecological scenarios of how stem height and stem diameter covary in response to environmental stimuli: (i) trees pioneer sunlit space by allocating more growth to stem height than diameter and (ii) trees maintain their competitive advantage through an inverse pattern. The model is equipped to characterize ‘pioneering’ QTLs (pi QTLs) and ‘maintaining’ QTLs (mi QTLs) which modulate these two ecological scenarios, respectively. In a practical application to a mapping population of full‐sib hybrids derived from two Populus species, the model has well proven its versatility by identifying several pi QTLs that promote height growth at a cost of diameter growth and several mi QTLs that benefit radial growth at a cost of height growth. Judicious application of functional mapping may lead to improved strategies for studying the genetic control of the formation mechanisms underlying trade‐offs among quantities of assimilates allocated to different growth parts.

Computational identification of genes modulating stem height–diameter allometry

Allopolyploids are a group of polyploids with more than two sets of chromosomes derived from different species. Previous linkage analysis of allopolyploids is based on the assumption that different chromosomes pair randomly during meiosis. A more sophisticated model to relax this assumption has been developed for allotetraploids by incorporating the preferential pairing behavior of homologous over homoeologous chromosomes. Here, we show that the basic principle of this model can be extended to perform linkage analysis of higher-ploidy allohexaploids, where multiple preferential pairing factors are used to characterize chromosomal-pairing meiotic features between different constituent species. We implemented the extended model into an R package, called AlloMap6, allowing the recombination fractions and preferential pairing factors to be estimated simultaneously. Allomap6 has two major functionalities, computer simulation and real-data analysis. By analyzing a real data from a full-sib family of allohexaploid persimmon, we tested and validated the usefulness and utility of this package. AlloMap6 lays a foundation for allohexaploid genetic mapping and provides a new horizon to explore the chromosomal kinship of allohexaploids.

AlloMap6: an R package for genetic linkage analysis in allohexaploids

Evo-devo is a theory proposed to study how phenotypes evolve by comparing the developmental processes of different organisms or the same organism experiencing changing environments. It has been recognized that nonallelic interactions at different genes or quantitative trait loci, known as epistasis, may play a pivotal role in the evolution of development, but it has proven difficult to quantify and elucidate this role into a coherent picture. We implement a high-dimensional genome-wide association study model into the evo-devo paradigm and pack it into the R-based Evo-Devo-EpiR, aimed at facilitating the genome-wide landscaping of epistasis for the diversification of phenotypic development. By analyzing a high-throughput assay of DNA markers and their pairs simultaneously, Evo-Devo-EpiR is equipped with a capacity to systematically characterize various epistatic interactions that impact on the pattern and timing of development and its evolution. Enabling a global search for all possible genetic interactions for developmental processes throughout the whole genome, Evo-Devo-EpiR provides a computational tool to illustrate a precise genotype-phenotype map at interface between epistasis, development and evolution.

Evo-Devo-EpiR: a genome-wide search platform for epistatic control on the evolution of development

The aim of Briefings in Bioinformatics is to provide an indispensable resource for the experimental practitioner seeking awareness of the disparate sources of data and analytical tools of contemporary biology, biotechnology and medicine based on the molecular level. This includes all areas of genomics, proteomics, metabolomics, interactomics and network biology, imaging, systems biology, chemoinformatics, computational biology and clinical/medical informatics that have a molecular foundation to the study. Large-scale instrumentation and computerisation is reducing the time that needs to be spent in the laboratory. Instead, the rate-limiting step is the analysis and interpretation of data. The journal provides topical reviews of new methodologies as they become established.

Integrating Evolutionary Game Theory into Mechanistic Genotype-Phenotype Mapping.

Phase change plays a prominent role in determining the form of growth and development. Although considerable attention has been focused on identifying the regulatory control mechanisms of phase change, a detailed understanding of the genetic architecture of this phenomenon is still lacking. We address this issue by deriving a computational model. The model is founded on the framework of functional mapping aimed at characterizing the interplay between quantitative trait loci (QTLs) and development through biologically meaningful mathematical equations. A multiphasic growth equation was implemented into functional mapping, which, via a series of hypothesis tests, allows the quantification of how QTLs regulate the timing and pattern of vegetative phase transition between independently regulated, temporally coordinated processes. The model was applied to analyze stem radial growth data of an interspecific hybrid family derived from two Populus species during the first 24 yr of ontogeny. Several key QTLs related to phase change have been characterized, most of which were observed to be in the adjacent regions of candidate genes. The identification of phase transition QTLs, whose expression is regulated by endogenous and environmental signals, may enhance our understanding of the evolution of development in changing environments.

A computational framework for mapping the timing of vegetative phase change.

Whole-genome search of genes is an essential approach to dissecting complex traits, but a marginal one-single-nucleotide polymorphism (SNP)/one-phenotype regression analysis widely used in current genome-wide association studies fails to estimate the net and cumulative effects of SNPs and reveal the developmental pattern of interplay between genes and traits. Here we describe a computational framework, which we refer to as two-side high-dimensional genome-wide association studies (2HiGWAS), to associate an ultrahigh dimension of SNPs with a high dimension of developmental trajectories measured across time and space. The model is implemented with a dual dimension-reduction procedure for both predictors and responses to select a sparse but full set of significant loci from an extremely large pool of SNPs and estimate their net time-varying effects on trait development. The model can not only help geneticists to precisely identify an entire set of genes underlying complex traits but also allow them to elucidate a global picture of how genes control developmental and dynamic processes of trait formation. We investigated the statistical properties of the model via extensive simulation studies. With the increasing availability of GWAS in various organisms, 2HiGWAS will have important implications for genetic studies of developmental compelx traits.

2HiGWAS: a unifying high-dimensional platform to infer the global genetic architecture of trait development

Overexpression of AtAP1M3 regulates flowering time and floral development in Arabidopsis and effects key flowering-related genes in poplar

Functional Mapping: How to Map Genes for Phenotypic Plasticity of Development

Unlike annuals, all perennial plants undergo seasonal transitions during ontogeny. As an adaptive response to seasonal changes in climate, the seasonal pattern of growth is likely to be under genetic control, although its underlying genetic basis remains unknown. Here, we develop a computational model that can map specific quantitative trait loci (QTLs) responsible for seasonal transitions of growth in perennials. The model is founded on functional mapping, a statistical framework to map developmental dynamics, which is reformed to integrate a seasonally adjusted growth function. The new model is equipped with a capacity to characterize the genetic effects of QTLs on seasonal alternation at different ages and then to better elucidate the genetic architecture of development. The model is implemented with a series of testing procedures, including (i) how a QTL controls an overall ontogenetic growth curve, (ii) how the QTL determines seasonal trajectories of growth within years and (iii) how it determines the dynamic nature of age-specific season response. The model was validated through computer simulation. The extension of season adjustment to other types of biological curves is statistically straightforward, facilitating a wider variety of genetic studies into ontogenetic growth and development in perennial plants.

Dynamic changes of gene expression reflect an intrinsic mechanism of how an organism responds to developmental and environmental signals. With the increasing availability of expression data across a time-space scale by RNA-seq, the classification of genes as per their biological function using RNA-seq data has become one of the most significant challenges in contemporary biology. Here we develop a clustering mixture model to discover distinct groups of genes expressed during a period of organ development. By integrating the density function of multivariate Poisson distribution, the model accommodates the discrete property of read counts characteristic of RNA-seq data. The temporal dependence of gene expression is modeled by the first-order autoregressive process. The model is implemented with the Expectation-Maximization algorithm and model selection to determine the optimal number of gene clusters and obtain the estimates of Poisson parameters that describe the pattern of time-dependent expression of genes from each cluster. The model has been demonstrated by analyzing a real data from an experiment aimed to link the pattern of gene expression to catkin development in white poplar. The usefulness of the model has been validated through computer simulation. The model provides a valuable tool for clustering RNA-seq data, facilitating our global view of expression dynamics and understanding of gene regulation mechanisms.

A multi-Poisson dynamic mixture model to cluster developmental patterns of gene expression by RNA-seq

Study of seed hair growth in Populus tomentosa, an important character of female floral bud development

Identification of glutathione S-transferase genes responding to pathogen infestation in Populus tomentosa

Heterochrony, the phylogenic change in the time of developmental events or rate of development, has been thought to play an important role in producing phenotypic novelty during evolution. Increasing evidence suggests that specific genes are implicated in heterochrony, guiding the process of developmental divergence, but no quantitative models have been instrumented to map such heterochrony genes. Here, we present a computational framework for genetic mapping by which to characterize and locate quantitative trait loci (QTLs) that govern heterochrony described by four parameters, the timing of the inflection point, the timing of maximum acceleration of growth, the timing of maximum deceleration of growth, and the length of linear growth. The framework was developed from functional mapping, a dynamic model derived to map QTLs for the overall process and pattern of development. By integrating an optimality algorithm, the framework allows the so-called heterochrony QTLs (hQTLs) to be tested and quantified. Specific pipelines are given for testing how hQTLs control the onset and offset of developmental events, the rate of development, and duration of a particular developmental stage. Computer simulation was performed to examine the statistical properties of the model and demonstrate its utility to characterize the effect of hQTLs on population diversification due to heterochrony. By analyzing a genetic mapping data in rice, the framework identified an hQTL that controls the timing of maximum growth rate and duration of linear growth stage in plant height growth. The framework provides a tool to study how genetic variation translates into phenotypic innovation, leading a lineage to evolve, through heterochrony.

A model framework for identifying genes that guide the evolution of heterochrony.

Identification and characterization of the Populus sucrose synthase gene family.

Gold nanoparticles were stabilized by a polyaniline:poly(sodium 4-styrenesulfonate) (PANI:PSS) matrix and readily dispersed in water over a wide range of pH. In contrast to nanoparticles passivated by alkanethiolates that formed a compact capping layer on the nanoparticle surface, the PANI:PSS-Au nanocomposites exhibited apparent catalytic activity in the reduction of 4-nitrophenol in the presence of excessive NaBH4, with reasonably good recyclability, which was likely due to the large accessible surface area. In addition, the PANI:PSS-Au nanocomposites also demonstrated peroxidase-like catalytic activity as evidenced by the colorimetric detection of H2O2 and glucose with PANI:PSS-Au as the enzymatic mimic. The present method may find potential applications in the design, preparation and functionalization of noble nanoparticles as efficient, versatile, and recyclable catalysts with high dispersibility and stability in aqueous media.

Polyaniline:poly(sodium 4-styrenesulfonate)-stabilized gold nanoparticles as efficient, versatile catalysts.

Erratum to: Haploid plants from anther cultures of poplar (Populus × beijingensis)

Haploid plants from anther cultures of poplar (Populus × beijingensis)

A novel sequence that functions as a promoter element for moderate constitutive expression of transgenes, designated as the PtMCP promoter, was isolated from the woody perennial Populus tomentosa. The PtMCP promoter was fused to the GUS reporter gene to characterize its expression pattern in different species. In stable Arabidopsis transformants, transcripts of the GUS reporter gene could be detected by RT-PCR in the root, stem, leaf, flower and silique. Further histochemical and fluorometric GUS activity assays demonstrated that the promoter could direct transgene expression in all tissues and organs, including roots, stems, rosette leaves, cauline leaves and flowers of seedlings and maturing plants. Its constitutive expression pattern was similar to that of the CaMV35S promoter, but the level of GUS activity was significantly lower than in CaMV35S promoter::GUS plants. We also characterized the promoter through transient expression in transgenic tobacco and observed similar expression patterns. Histochemical GUS staining and quantitative analysis detected GUS activity in all tissues and organs of tobacco, including roots, stems, leaves, flower buds and flowers, but GUS activity in PtMCP promoter::GUS plants was significantly lower than in CaMV35S promoter::GUS plants. Our results suggested that the PtMCP promoter from poplar is a constitutive promoter with moderate activity and that its function is presumably conserved in different species. Therefore, the PtMCP promoter may provide a practical choice to direct moderate level constitutive expression of transgenes and could be a valuable new tool in plant genetic engineering.

A Novel Moderate Constitutive Promoter Derived from Poplar (Populus tomentosa Carrière)

Abscisic acid (ABA) is a major plant hormone that plays an important role in responses to abiotic stresses. The ABA-responsive element binding protein/ABRE-binding factor (AREB/ABF) gene subfamily contains crucial transcription factors in the ABA-mediated signaling pathway. In this study, a total of 14 putative AREB/ABF members were identified in the Populus trichocarpa Torr. & Gray. genome using five AREB/ABF amino acid sequences from Arabidopsis thaliana L. as probes. The 14 putative Populus subfamily members showed high protein similarities, especially in the basic leucine zipper (bZIP) domain region. A neighbor-joining analysis combined with gene structure data revealed homology among the 14 genes. The expression patterns of the Populus AREB/ABF subfamily suggested that the most abundant transcripts of 11 genes occurred in leaf tissues, while two genes were most transcribed in root tissues. Significantly, eight Populus AREB/ABF gene members were upregulated after treatment with 100 μM exogenous ABA, while the other six members were downregulated. We identified the expression profiles of the subfamily members in Populus tissues and elucidated different response patterns of Populus AREB/ABF members to ABA stress. This study provided insight into the roles of Populus AREB/ABF homologues in plant response to abiotic stresses.

Identification and characterization of the Populus AREB/ABF subfamily.

Flowering involves expression of a suite of genes associated with floral development. The genome of the Chinese white poplar (Populus trichocarpa) was sequenced because of its importance as a model tree for genetic studies as well as being an economically important woody plant. However, information on expressed genes involved in poplar floral bud development is insufficient to allow annotation of genes and use of the genomic information. To isolate and characterize genes involved in flowering of Populus tomentosa, floral bud samples were collected at different developmental stages from floral bud initiation to flower maturity, and full-length enriched cDNA libraries from both male and female floral buds were constructed. The results of titer analysis showed that the titer of the female and male primary libraries were 8.00 × 10 5 and 7.20 × 10 5 pfu/ml, respectively, and the titer of the amplified

Full-length enriched multistage cDNA library construction covering floral bud development in Populus tomentosa

Ectopic expression of a poplar APETALA3-like gene in tobacco causes early flowering and fast growth

Background: Endothelial cells in the tumor microenvironment play an important role in the development of kidney renal clear cell carcinoma (KIRC). We wanted to further identify the function of endothelial cells in KIRC patients by integrating single-cell and bulk RNA sequencing data. Methods: Online databases provide the original data of this study. An endothelial-related prognostic index (ERPI) was constructed and validated by R version 3.6.3 and relative packages. Results: The ERPI consisted of three genes (CCND1, MALL, and VWF). Patients with high ERPI scores were significantly correlated with worse prognosis than those with low ERPI scores in the TCGA training group, TCGA test group, and GSE29609 group. A positive correlation was identified between the ERPI score and poor clinical features. The results of functional analysis indicated that ERPI was significantly associated with immune-related activities. We suggested that patients with high ERPI scores were more likely to benefit from immunotherapy based on the results of immune checkpoints, tumor microenvironment, stemness index, and TCIA, while patients with low ERPI scores were sensitive to gemcitabine, docetaxel, paclitaxel, axitinib, pazopanib, sorafenib, and temsirolimus according to the results of the “pRRophetic” algorithm. Therefore, this ERPI may help doctors choose the optimal treatment for patients with KIRC. Conclusion: By integrating single-cell and bulk RNA sequencing data from KIRC patients, we successfully identified the key genes from the perspective of endothelial cells in the tumor microenvironment and constructed ERPIs that had positive implications in precision medicine.

A novel endothelial-related prognostic index by integrating single-cell and bulk RNA sequencing data for patients with kidney renal clear cell carcinoma

Background and Objectives: According to recent guidelines, myocardial contrast echocardiography (MCE) is recommended for detecting residual myocardial viability (MV). However, the long-term prognostic value of MV as assessed by MCE in identifying major adverse cardiac events (MACE) after acute myocardial infarction (AMI) remains undefined. Materials and Methods: We searched multiple databases, including PubMed, EMBASE, and Web of Science for studies on the prognostic value of MCE for clinical outcomes in AMI patients. The primary endpoints were MACEs during follow-up. Six studies that evaluated a total of 536 patients with a mean follow-up of 36.8 months were reviewed. Results: The pooled sensitivity and specificity of MCE for predicting MACEs were 0.80 and 0.78, respectively, and the summary operating receiver characteristics achieved an area under the curve of 0.84. The pooled relative risks demonstrated that the MV evaluated by MCE after AMI was correlated with a high risk for total cardiac events (pooled relative risk: 2.07; 95% confidence interval: 1.28–3.37) and cardiac death (pooled relative risk: 2.48; 95% confidence interval: 1.03–5.96). MV evaluated by MCE was a highly independent predictor of total cardiac events (pooled hazard ratio: 2.09, 95% confidence interval: 1.14–3.81) in patients after AMI. Conclusions: Residual MV evaluated by MCE may be an effective long-term prognostic tool for predicting MACE in patients after AMI that can provide moderate predictive accuracy. The assessment of MV by MCE may become an alternative technique with the potential to rapidly provide important information for improving long-term risk stratification in patients after AMI, at the bedside in clinical practice, especially for patients who cannot tolerate prolonged examinations. The PROSPERO registration number is CRD42020167565.

Long-Term Prognostic Value of Myocardial Viability by Myocardial Contrast Echocardiography in Patients after Acute Myocardial Infarction: A Systematic Review and Meta-Analysis

Current diagnostic criteria for left ventricular noncompaction (LVNC) may be poorly related to adverse prognosis. Late gadolinium enhancement (LGE) is a predictor of major adverse cardiovascular events (MACE), but risk stratification of LGE in patients with LVNC remains unclear. We retrospectively analyzed the clinical and cardiovascular magnetic resonance (CMR) data of 75 patients from three institutes and examined the correlation between different LGE types and MACE based on the extent, pattern (including a specific ring-like pattern), and locations of LGE in LVNC. A total of 51 patients (68%) presented LGE. A specific ring-like pattern was observed in 9 (12%). MACE occurred in 29 (38.7%) at 4.3 years of follow-up (interquartile range: 2.1–5.7 years). The adjusted hazard ratio (HR) for patients with ring-like LGE were 6.10 (95% CI, 1.39–26.75, p < 0.05). Free-wall or mid-wall LGE was associated with an increased risk of MACE after adjustment (HR 2.85, 95% CI, 1.31–6.21; HR 4.35, 95% CI, 1.23–15.37, respectively, p < 0.05). The risk of MACE in LVNC significantly increased when the LGE extent was greater than 7.5% and ring-like, multiple segments, and free-wall LGE were associated with MACE. These results suggest the value of LGE risk stratification in patients with LVNC.

Prognostic Value of Late Gadolinium Enhancement in Left Ventricular Noncompaction: A Multicenter Study

Myocardial microvascular function assessed by CMR first-pass perfusion in patients treated with chemotherapy for gynecologic malignancies

Objective Myocardial edema is an early manifestation of chemotherapy-related myocardial injury. In this study, we used cardiac magnetic resonance (CMR) T2 mapping to assess myocardial edema and its changes during chemotherapy for gynecologic malignancies. Methods We enrolled 73 patients receiving chemotherapy for gynecologic malignancies, whose the latest cycle was within one month before the beginning of this study, and 41 healthy volunteers. All participants underwent CMR imaging. Of the 73 patients, 35 completed CMR follow-up after a median interval of 6 (3.3 to 9.6) months. The CMR sequences included cardiac cine, T2 mapping, and late gadolinium enhancement. Results Myocardial T2 was elevated in patients who were treated with chemotherapy compared with healthy volunteers [41ms (40ms to 43ms) vs. 41ms (39ms to 41ms), P = 0.030]. During follow-up, myocardial T2 rose further [40ms (39ms to 42ms) vs. 42.70 ± 2.92ms, P < 0.001]. Multivariate analysis showed that the number of chemotherapy cycles was associated with myocardial T2 elevation (β = 0.204, P = 0.029). After adjustment for other confounders, myocardial T2 elevation was independently associated with a decrease in left ventricular mass (β = −0.186; P = 0.024). Conclusion In patients with gynecologic malignancies, myocardial edema developed with chemotherapy cycles increase, and was associated with left ventricular mass decrease. T2 mapping allows the assessment of myocardial edema and monitoring of its change during chemotherapy.

Myocardial edema during chemotherapy for gynecologic malignancies: A cardiac magnetic resonance T2 mapping study

KDF1 has been identified as a key regulator of epidermal proliferation and differentiation, but it is unknown whether KDF1 is involved in the pathogenesis of malignancy. No study has reported the expression and function of KDF1 in renal cancer. To explore the pathologic significance of KDF1 in clear cell renal cell carcinoma (ccRCC), the expression level of KDF1 protein in the tumor tissue of ccRCC patients was examined by immunohistochemistry and Western blot while the expression level of KDF1 mRNA was analyzed by using the data from TCGA database. In vitro cell experiments and allogeneic tumor transplantation tests were performed to determine the effects of altered KDF1 expression on the phenotype of ccRCC cells. Both the KDF1 mRNA and protein were found to be decreasingly expressed in the tumor tissue of ccRCC patients when compared with the adjacent non-tumor control tissue. The expression level of KDF1 in the tumor tissue was found to correlate negatively with the tumor grade. Patients with higher KDF1 in the tumor tissue were found to have longer overall survival and disease-specific survival time. KDF1 was shown to be an independent factor influencing the disease-specific survival of the ccRCC patients. Overexpression of KDF1 was found to inhibit the proliferation, migration and invasion of ccRCC cells, which could be reversed by decreasing the expression of KDF1 again. ccRCC cells with KDF1 overexpression were found to produce smaller transgrafted tumors. These results support the idea that KDF1 is involved in ccRCC and may function as a tumor suppressor.

KDF1, a Novel Tumor Suppressor in Clear Cell Renal Cell Carcinoma

MicroRNA ‐ 4712 ‐ 5 p promotes proliferation of the vulvar squamous cell carcinoma cell line A 431 by targeting PTEN through the AKT / cyclin D 1 signaling pathways

Data processing software DPS is widely used in various fields of natural sciences and social sciences. In this paper, taking Heyuan City in underdeveloped areas as an example, the influence of the development of regional logistics on the growth of regional economy in Heyuan City is analyzed by using the method of grey correlation analysis. According to the analysis results, the development of regional logistics industry and the development of regional economy show a significant positive correlation, which promotes and cooperates with each other.

2020 International Conference on Computer Engineering and Application (ICCEA)

Application of Data Processing Software in logistics economy relevance—— A Case Study of Heyuan City

Research and analysis on foreign trade development level in Heyuan City

Using the parameter method in principal component analysis,the paper studies empirically the management of risks of the supply chains.

Application of PCA Parameter Method in Supply Chain Risk Management

OBJECTIVE
To observe the effect of electroacupuncture (EA) of "Tianshu"(ST25) and "Dachangshu"(BL25) on the intestinal transit function， expression level of glial cell-derived neurotrophic factor (GDNF) and methylation level of GDNF gene promoter region in colon tissue of rats with slow transit constipation (STC)， so as to explore its mechanisms underlying improvement of STC.

METHODS
Male Sprague-Dawley (SD) rats were randomized into control， saline， model and EA groups (n=16 in each group). The STC model was replicated by gavage of compound diphenoxylate suspension (10 mL· kg-1· d-1) for 28 days. Rats of the saline group received the same dose of normal saline via gavage. EA (2 Hz/15 Hz， 0.1-1 mA) was applied to bila-teral ST25 and BL25 for 15 min， once daily for 14 days. The intestinal transmission function (the intestinal propulsion rate) was assessed by recording the first black grain stool discharge time and the number and weight of the discharged stool grains in 30 min after gavage of the activated carbon suspension (1 mL/100 g， 150 g/L). The score of fecal trait and the weight of stool within 24 h were recorded. The ultrastructural changes of Cajal interstitial cells in the colon tissue were observed by transmission electron microscope. The expression levels of GDNF protein and mRNA in the colon tissue were detected by using Western blot and real-time fluorescent quantitative PCR， separately， and changes of methylation level in the promoter region of GDNF gene detected by using Bisulfite sequencing method.

RESULTS
Compared with the control group， the time of the 1st black stool grain discharging was obviously prolonged， and the number and weight of the discharged black stool grains were significantly decreased in the mo-del group (P<0.05)， suggesting a success of STC. The weight and trait score of stool in 24 h， intestinal propulsive rate， and the expression levels of GDNF protein and mRNA were significantly lower in the model group than in the control group (P<0.01， P<0.05). After EA， the weight and trait score of stool within 24 h， intestinal propulsive rate，and the expression levels of GDNF protein and mRNA were significantly increased in the EA group in contrast to the model group (P<0.01，P<0.05). The total CpGs methylation level of GDNF gene in colon tissue was considerably higher in the model group than in the control group (P<0.05)， and markedly lower in the EA group than in the model group (P<0.05). No significant differences were found between the control and saline groups in all the above-mentioned indexes (P>0.05).

EA of back-shu and front-mu acupoints can effectively improve symptoms of constipation and intestinal transport function in STC rats， which may be related to its function in up-regulating the expression of GDNF and down-regulating the methylation level in the promoter region of GDNF gene in colon tissue.

[Effect of electroacupuncture on gastrointestinal motility in rats with slow transit constipation based on GDNF methylation modification].

Background This review aims to systematically summarize and analyze recent high-quality animal research results about the use of acupuncture in Alzheimer's disease (AD) patients. This information will be useful in providing a reference for future experimental research and an experimental basis for the clinical use of acupuncture in the treatment of AD. Methods We utilized and referenced various electronic libraries from their inception to November 2021. Relevant information was reviewed and information such as the journal names, publication records, animal model selections and preparations, intervention measures, acupoint selections, detection methods, and detection indicators was extracted. Results. A total of 75 eligible studies were selected for additional review. Male SAMP8 mice, APP/PS1 double transgenic mice, Sprague–Dawley (SD) rats, and Wistar rats were the four commonly used animal strains in the experiments. The animals were categorized as transgenic and surgical mouse models. Experimental interventions included manual acupuncture (MA), Electro-acupuncture (EA), Moxibustion, and EA combined with Moxibustion. A retention time of 20 min was the optimal timing for experimental studies, with 14 sessions chosen as the most common treatment time. EA was the most prescribed acupuncture treatment type with continuous wave, 2 Hz frequency, and 1 mA electric current selected as frequently used parameters. A total of 78 acupoint prescriptions were analyzed involving 21 acupoints. The top 3 combinations of common acupoints were GV20 ⟶ EX-HN3, GV20 ⟶ BL23, and GV20 ⟶ GV26. A total of 39 articles had positive drug control groups, sham acupuncture, and/or nonacupoint control groups. Furthermore, 10 types of behavioral tests, 29 detection methods, 178 evaluation indicators, and 18 tissue samples were included in the analysis. Conclusions By collating these high-quality research studies systematically and comprehensively, acupuncture was found to be a viable and effective treatment in AD animal models. In addition, when designing experiments, researchers could refer to the detailed data provided here to make better schemes and maybe conduct more investigations in unresearched areas.

A Review on Characteristics of Experimental Research on Acupuncture Treatment for Alzheimer's Disease: Study Design

Exploration on the acupoint selection rule in modern literature for chronic gastritis treated with acupuncture and moxibustion in recent 10 years☆

PURPOSE
This study investigateed the influence of complete denture on oral bacteria flora.

METHODS
Bateria plaque samples in oral mucosa, saliva and denture surfaces in 11 edentulous patients were collected, then the 16S rRNA gene clone libraries were constructed. Pyrosequencing was used to analyze the 16S rRNA gene V3~V4 regions, oral bacteria flora were classified and identified.

RESULTS
There were 64800 sequences in complete denture-wearing subjects, Streptococcus mitis, Gemella haemolysans, Rothia mucilaginosa, Porphyromonas sp, Neisseria zoodegmatis, Granulicatella elegans, Acinetobacter baumannii, Pseudomonas citrinum, Granulicatella adiacens and Fusobacterium canifelinum were the predominant species (37416 sequences). The species of denture tissue surface were similar to these of buccal vestibule after wearing denture, and the species of denture smooth surface were similar to these of tongue ventrum and the floor of mouth.

The effect of complete denture on oral flora is still limited, and the composition of oral flora is influenced by many other factors.

[Changes of oral bacteria flora after wearing complete denture].

Objectives To investigate the clinicopathological characteristics, human papillomavirus (HPV) infection, p53 expression, and TP53 mutations in oropharyngeal squamous cell carcinoma (OPSCC) and determine their utility as prognostic predictors in a primarily eastern Chinese population. Methods The HPV infection status was tested via p16INK4A immunohistochemistry and validated using PCR, reverse blot hybridization and in situ hybridization (ISH) in 188 OPSCC samples. p53 expression levels and TP53 gene mutations were assessed through immunohistochemistry and sequencing, respectively. Clinicopathological characteristics and follow-up information were collected. Overall survival was estimated using the Log-rank test. Results Overall, 22 of the 188 OPSCC samples were associated with HPV infection. HPV16 was identified in all 22 samples, whereas no samples were positive for HPV18. All 22 HPV-associated OPSCC samples were p53 negative and lacked TP53 mutations. HPV16 positivity, female patients, non-smokers, and patients with histological grade I and stage N0 diseases showed better overall survival (p = 0.009, 0.003, 0.048, 0.009, and 0.004, respectively). No significant differences in overall survival between smoking and non-smoking patients were observed in the HPV-associated OPSCC group. Patients without mutations in TP53 exons 5–8 had better prognoses (p = 0.031) among the 43 sequenced specimens. Multivariate analysis indicated that HPV16 infection status (p = 0.011), histological grade (p = 0.017), and N stage (p = 0.019) were independent prognostic factors for patients with OPSCC. Conclusions Distinct from the situation in Europe and America, for the patients with OPSCC in this study, HPV16 infection was relatively low, although it was still the most important independent prognostic predictor for the disease. In addition to the high smoking and drinking rate in this population, HPV16 infection and TP53 dysfunction appear to be two distinct pathogens for OPSCC patients in the eastern Chinese population.

Human Papillomavirus 16 Infection and TP53 Mutation: Two Distinct Pathogeneses for Oropharyngeal Squamous Cell Carcinoma in an Eastern Chinese Population

PURPOSE
To explore the expression and clinical significance of plasma microRNA-125b (miR-125b) in patients with oral squamous cell carcinoma (OSCC).

METHODS
By Stem-loop RT real-time PCR based on the SYBR Green, we investigated the expression of plasma miR-125b in 85 OSCC patients and 46 healthy controls, then evaluated its diagnostic performance as OSCC biomarker. Data analysis was performed with SPSS 17.0 software package for one-way ANOVA and receiver operating characteristic (ROC) curve.

RESULTS
Stem-loop RT-PCR could specifically amplify miR-125b in plasma. The expression of plasma miR-125b was significantly increased in patients with OSCC compared with healthy controls (P<0.05). ROC results showed that miR-125b could differentiate OSCC from healthy controls(AUC=0.966). As fold change 3.46 was chosen for optimal cutoff value, the diagnostic sensitivity and specificity was 89.4% and 93.5%, respectively.

Due to the satisfactory diagnostic performance, plasma miR-125b can be used as a promising biomarker in OSCC.

[Expression and clinical significance of plasma microRNA-125b level in patients with oral squamous cell carcinoma].

Oral squamous cell carcinoma (OSCC) is one of the most deadly malignant tumors with high invasive potential and frequently cervical lymph node metastasis. AP-1 plays a critical role in tumor invasion and metastasis, but there are few reports on the role of c-Fos in OSCC carcinogenesis and metastasis.

METHODS
Investigate c-Fos expression in clinical samples from 58 primary patients with OSCC by immunohistochemistry. c-Fos knockdown stable cell lines were established by lentiviral infection and transwell cell invasion assay to detect the effects of c-Fos knockdown on tumor cell invasion.

RESULTS
Nuclear and cytoplasmic c-Fos protein were both overexpression in cancerous tissues compared with adjacent non-malignant epithelia (nuclear: P < 0.001, cytoplasmic: P = 0.005). Higher level nuclear c-Fos expression was found in the tumor samples of patients with lymph node metastasis than those without lymph node metastasis (4.85 ± 1.43 vs. 3.61 ± 1.28, P = 0.002). Higher level of c-Fos expression was also found in tumor invasive front margin than tumor center and high nuclear expression of c-Fos indicated poor survival. Knockdown of c-Fos greatly suppressed tumor cell proliferation and invasion and downregulated CD44 and CyclinD1 expression in HN6 and SCC9 cells. However, CyclinD3, c-myc, and Erk1/2 were found no changes to c-Fos depletion.

c-Fos promoted cell invasion and migration via CD44 pathway in OSCC. c-Fos could be used as a potential therapeutic target gene and an additional marker for evaluation of lymph node metastasis.

Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology

Overexpression of c-fos promotes cell invasion and migration via CD44 pathway in oral squamous cell carcinoma.

Association of ERCC1 polymorphisms (rs3212986 and rs11615) with the risk of head and neck carcinomas based on case–control studies

G protein-coupled receptor family C group 5 member A (GPRC5A), a member of G protein-coupled receptor family, has been shown to function as a tumor suppressor in lung tissue. The biological functions of GPRC5A have therefore been linked to lung tissue. However, the biological significance of this gene product remains obscure. In this study, we investigated the expression of GPRC5A proteins in normal oral tissue and oral squamous cell carcinoma (OSCC), and we characterized its biological activity in OSCC cell lines.

METHODS
Western blot analysis and immunohistochemical staining were used to investigate the expression of GPRC5A in both OSCC cell lines and clinical samples. GPRC5A stable transfectants and their parental OSCC cells were characterized for their biological activities in anchorage-independent growth.

RESULTS
High levels of immunohistochemical GPRC5A expression were detected in normal oral tissue, especially differentiated area. In contrast, GPRC5A expression was dramatically repressed in OSCCs (P < 0.01). The immunohistochemical GPRC5A expression was moderately well differentiated, but greatly repressed in moderately differentiated OSCCs and completely repressed in poorly differentiated OSCCs. Overexpression of GPRC5A in OSCC CAL27 cells resulted in a suppressed anchorage-independent growth activity, a transforming phenotype.

GPRC5A is expressed in normal oral epithelium. Repression of GPRC5A is associated with poorly differential grade of OSCCs. Overexpression of GPRC5A in OSCC cell line reversed the malignant phenotype. Thus, GPRC5A is important for homeostasis in oral tissue, and deletion or repression of this gene may involve in tumorigenesis of OSCCs and may serve as a prognostic marker for malignant type of OSCCs.

Repression of G protein-coupled receptor family C group 5 member A is associated with pathologic differentiation grade of oral squamous cell carcinoma.

PURPOSE
To assess the efficacy of compound Chinese traditional medicine(CTM), which is composed of gallic acid, magnolol and polysaccharide of Bletilla, against apical periodontitis in dogs and cytotoxic assay.

METHODS
A animal model of apical periodontitis was built, CTM was then used to disinfect the root canal. The effect of the restoration of periapical bone in dogs was investigated after regular root canal filling. SAS6.12 software package was used for statistical analysis, and MTT was used to test cell toxicity of CTM.

RESULTS
CTM can cure inflammation effectively, and CTM had no cytotoxic effect on periodontal ligament cells at 5-week.

The compound Chinese traditional medicine may be an effective disinfecting drug for root canal disinfection.

[Effect of compound Chinese traditional medicine on periapical periodontitis in dogs and cytotoxic assay].

This study aimed to evaluate the inhibitory effects of herbal extracts on caries-related bacteria, glucan and biofilm in vitro. Sensitive tests of bacteria were carried out by broth dilution method on a 96-microwell plate. Glucan inhibition tests were carried out using the phenol sulphate method. A minimum biofilm inhibitory concentration (MBIC) test was performed in an artificial mouth model. The results of the MBIC of agents were 8, 16 and 32 mg mL−1 for eugenol, tannic acid and magnolol, respectively. For the results of glucan inhibition tests, over 63%, 28% and 27% inhibition occurred on insoluble glucan syntheses of Streptococcus sobrinus for eugenol, magnolol and tannic acid, respectively. Over 46%, 16% and 13% inhibition on soluble glucan syntheses for eugenol, magnolol and tannic acid, respectively, were also observed. In conclusion, the inhibition of eugenol on glucan is essential for the biofilm inhibition effect on caries-related biofilm in an artificial mouth model in vitro.

The inhibition of eugenol on glucan is essential for the biofilm eradication effect on caries-related biofilm in an artificial mouth model

OBJECTIVE
To investigate the expression of cytokeratin 17 (CK17) in oral squamous cell carcinoma (OSCC) as well as its clinical significance.

METHODS
Detection of the mRNA level and protein expression of CK17 in the in vitro cellular carcinogenesis model of OSCC, some OSCC cell lines and tissue specimens from 30 primary OSCC patients were performed using real-time polymerase chain reaction (PCR), Western blot and immunohistochemistry, respectively.

RESULTS
Increased CK17 mRNA level was observed in the HB56 and OSC cell lines compared with the HIOEC using real-time PCR technique. Western blot showed increased CK17 protein expression in all the cell lines compared with the HIOEC. Increased CK17 mRNA and immunoreaction levels were also observed in the cancerous tissue specimens from OSCC patients compared with normal adjacent tissues (P<0.01).

The significantly increased CK17 gene may be associated with the tumorigenesis and development of OSCC.

Hua xi kou qiang yi xue za zhi = Huaxi kouqiang yixue zazhi = West China journal of stomatology

The aim of the present study was to investigate β2-microglobulin (β2-M) expression in normal oral mucosa and progressive oral squamous cell carcinoma (OSCC) and to assess the clinical significance of β2-microglobulin expression. The study included 10 cases of normal oral mucosa epithelium specimens, 55 cases of primary OSCC specimens, and 25 cases of OSCC metastasis specimens. Immunohistochemistry was used to determine β2-M expression, and its correlation with clinicopathological factors in progressive OSCC was evaluated. Immunohistochemistry showed that strong β2-M expression was significantly asscociated with tumor size (T3, T4 vs. T1, T2; P=0.001), positive node status (N positive vs. N negative; P=0.000) and advanced clinical stage (III, IV vs. I, II, P=0.000) in primary OSCC lesions. Compared to primary OSCC lesions, the frequency of β2-M expression was significantly increased in metastatic OSCC lesions (P=0.02). In addition, in vitro results from Western blotting showed increased β2-M expression in the two OSCC lines studied. Therefore, we speculate that the up-regulation of β2-M expression may contribute to the oncogenesis of human oral mucosa, tumor invasion and metastasis.

Upregulation of β2-microglobulin expression in progressive human oral squamous cell carcinoma

OBJECTIVE
To investigate the expression of galectin-1 in oral squamous cell carcinoma(OSCC) and its clinical significance.

METHODS
Detection of the mRNA and protein expression of galectin-1 in the in vitro cellular carcinogenesis model of OSCC, OSCC cell lines and tissue specimens from 30 primary OSCC patients were performed using real-time polymerase chain reaction (PCR), Western blotting and immunohistochemistry, respectively.

RESULTS
The value of galectin-1 mRNA and protein level in human immortalized oral epithelia cell (HIOEC) cell was 0.071 ± 0.023, 0.118 ± 0.046, Compared with the HIOEC, galectin-1 mRNA level and protein expression were increased significantly in all the cell lines (0.141 ± 0.049, 0.504 ± 0.33) (P < 0.01). The levels of mRNA and protein expression of galectin-1 were significantly higher in the cancerous tissue (0.059 ± 0.034, 1.5 ± 0.68) than in the normal adjacent tissues (0.029 ± 0.012, 0.4 ± 0.56) (P < 0.01).

The expression of galectin-1 gene up-regulated in carcinogenesis process of OSCC significantly may be related to the tumorigenesis and development of OSCC, which illustrates its potential clinical application as tumor marker for early diagnosis.

Zhonghua kou qiang yi xue za zhi = Zhonghua kouqiang yixue zazhi = Chinese journal of stomatology

[Expression of galectin-1 in carcinogenesis of oral mucosal epithelium].

Yes-associated protein promotes cell proliferation by activating Fos Related Activator-1 in oral squamous cell carcinoma.

PURPOSE
To assess the efficacy of compound Chinese traditional medicine(CTM), which composed of gallic acid, magnolol and polysaccharide of Blettila striata, against the infected root canal bacterial biofilm.

METHODS
Actinomyces viscosus (Av), Enterococcus faecalis (Ef), Fusobacterium nucleatum (Fn) were composed to form biofilm, then confocal laser scan microscope (CLSM) was used to observe and study the bacterial activity. SAS6.12 software package was used for statistical analysis.

RESULTS
The biofilm thickness reduced after treatment by both CTM and ZnO (P>0.05),while there was a significant decrease of the percentage of vital bacterias after treatment by CTM (P<0.01).

The compound Chinese traditional medicine is effective on biofilm control, so that it would be an effective disinfecting drug for root canal sealers. Supported by Research Fund of Bureau of Traditional Chinese Medicine of Shanghai Municipality (Grant No.2008L008A).

[Effect of compound Chinese traditional medicine on infected root canal bacteria biofilm].

AimThe purpose of this study was to develop a mathematical model to quantitatively describe the passive transport of macromolecules within dental biofilms.MethodologyFluorescently labeled dextrans with different molecular mass (3 kD, 10 kD, 40 kD, 70 kD, 2 000 kD) were used as a series of diffusion probes. Streptococcus mutans, Streptococcus sanguinis, Actinomyces naeslundii and Fusobacterium nucleatum were used as inocula for biofilm formation. The diffusion processes of different probes through the in vitro biofilm were recorded with a confocal laser microscope.ResultsMathematical function of biofilm penetration was constructed on the basis of the inverse problem method. Based on this function, not only the relationship between average concentration of steady‐state and molecule weights can be analyzed, but also that between penetrative time and molecule weights.ConclusionThis can be used to predict the effective concentration and the penetrative time of anti‐biofilm medicines that can diffuse through oral biofilm. Furthermore, an improved model for large molecule is proposed by considering the exchange time at the upper boundary of the dental biofilm.

Modeling of Diffusion Transport through Oral Biofilms with the Inverse Problem Method

Downregulation of tapasin expression in primary human oral squamous cell carcinoma: association with clinical outcome

Overexpression of Galectin-1 is negatively correlated with pathologic differentiation grade in oral squamous cell carcinoma

We previously established an in vitro cellular carcinogenesis model of oral squamous cell carcinoma (OSCC) with a line of human immortalized oral epithelia cells (HIOECs), a line of cancerous HB96 cells, and other cells (HB56 cells) at the early stage of carcinogenesis. In this study, comparative proteomic analysis identified a panel of differentially expressed proteins among these cells, and S100A6 was shown as one of the significantly down-regulated proteins accompanying cellular transformation. S100A6 was further validated for its expression in the three cell lines and in the clinical samples of cancerous and paracancerous tissues from 30 primary OSCC patients. Western blot analysis and real-time PCR revealed the decreased S100A6 protein and mRNA levels in the cancerous HB56 and HB96 cells over HIOECs. Immunohistochemistry and real-time PCR also showed decreased S100A6 protein and mRNA levels in the cancerous tissues compared to the paracancerous tissues from OSCC patients. The results presented here suggest that the expression of S100A6 decreases along with the cancerization in OSCC both in vitro and in vivo.

In vitro cellular model is an important tool to be used to investigate the cellular events related to pathophysiological conditions in humans. We have developed an in vitro cellular carcinogenesis model of oral squamous cell carcinoma (OSCC). In this study, we performed comparative proteomic analysis using 2‐DE and LC‐tandem mass chromatography to separate and identify differentially expressed proteins. Forty‐five proteins were identified, including 24 proteins with decreased expression and 19 proteins with increased expression during carcinogenesis from immortalized oral epithelial cells to squamous cancerous cells. The identified known proteins were classified into three ontologies of cellular component, molecular function, and biological process. Further validation of five identified proteins (ANXA1, ANXA2, CTSB, KRT17, and S100A6) in the cellular carcinogenesis model and cancerous tissues from OSCC patients confirmed the comparative proteomic results. Moreover, Annexin A1 and A2 expression levels correlated with the pathological differentiation grade of cancerous tissues. Thus, this work provides a dynamic protein file of differentially expressed proteins in oral squamous carcinoma cells, which could provide clues to study the mechanisms of OSCC carcinogenesis and possibly be developed as potential biomarkers for clinical diagnosis or prognostic monitoring.

Comparative proteomic analysis of differentially expressed proteins in an in vitro cellular carcinogenesis model of oral squamous cell carcinoma

Characteristics of a cancerous cell line, HIOEC-B(a)P-96, induced by benzo(a)pyrene from human immortalized oral epithelial cell line.

OBJECTIVE
To establish a monoclone cell line of squamous cell carcinoma (SCC) in rat buccal mucosa and to study its biological characteristics.

METHODS
SCC in rat oral mucosa was induced by adding 4-nitroquinoline-1-oxide (4NQO) into the SD rats' drinking water, and the cancer cells were then cultured to obtain mixed cells in vitro. The mixed tumor cells were purified by mono cell cloning method. The biological characteristics of the cells were studied by microscope and electronic microscope observation, chromosome analysis, Methyl thiazolyl tetrazolium (MTT) test, flow cytometry assay and immunohistochemistry staining. Hypodermic inoculations of the cells in nude mice and injection of the cells by nude mice tail veins were performed to observe the tumor formation and long distance metastasis.

RESULTS
The morphology proved that the cell line was squamous cell carcinoma cells, which were cultured from one cell. The population doubling time for passage 65 cells was 25.44 hours. The cells in S-phase accounted for 20.13% of the cell cycle. The chromosome modal number was 84. All the cells expressed the proteins of cytokeratin and vimentin. The xenograft rate and the tumor metastatic rate to the lung were 100% in nu/nu BALB/C mice, but the homograft rate was zero in SD Rats.

Rca-B was a typical oral squamous cell carcinoma cell line derived from Sprague-Dawley rat buccal mucosa carcinoma, and the cell line has high metastatic potential and its biological characteristics were well ascertained.

[Establishment and identification of biological characteristics of rat monoclone cell line Rca-B].

OBJECTIVE
To select the effective siRNA which could inhibit the expression of DNA methyltransferase 1 (DNMT-1) in adenoid cystic carcinoma (ACC) and discuss the time-, and dose-dependent effect of RNA interference (RNAi).

METHODS
Four pairs of siRNA were designed, synthesized and transfected through oligofectamine reagent into ACC cell lines ACC-2, ACC-3 and ACC-M. 24, 48 and 72 h after transfection, total RNA and protein were harvested respectively. mRNA and protein expression level of DNMT-1 were detected by real time PCR, RT-PCR and Western blot, and then the effective siRNA was subsequently selected. ACC-3 as also transfected by different concentration of siRNA and the dose-dependent effect of RNAi was discussed. Cy(3) labelled GAPDH siRNA was used as a positive control.

RESULTS
Two of 4 pairs of siRNA inhibited the mRNA expression of DNMT-1 in three ACC cell lines and the expression of DNMT-1 was downregulated by 67%, 86%, 92% and 76%, 76%, 86% respectively. The gene inhibition was detected at 24 h or 48 h after transfection, maintained only 1 - 2 days and showed direct relationship to the concentration of siRNA. The change of protein expression level of DNMT-1 was consistent to the changes of mRNA.

The effective siRNA which could inhibited the expression of DNMT-1 of ACC were achieved. The inhibition effect of RNAi was time-dependent and dose-dependent.

[Synthesized small interfering RNA inhibits the expression of DNA methyltransferase 1 in salivary adenoid cystic carcinoma].

OBJECTIVE
To explore the influence of chemosensitivity of Tca8113 cells by modified MTT assay after the animal model of Tca8113 were treated by the ultrasound hyperthermia.

METHODS
The MTT assay of the BALB/C nu/nu mice model of Tca8113 cells treated by the ultrasound hyperthermia in vivo was performed.

RESULTS
The chemosensitivity to the 9 kinds of drugs demonstrated no significant differences between the Tca8113 cells in the control group, the 39 degrees C-treated group and the groups treated from 41 degrees C to 44 degrees C. But significant differences between the 40 degrees C-treated group and the 41 degrees C or 42 degrees C-treated group existed. In the heating-time grades test, there were no significant differences in the chemosensitivity to the 9 kinds of drugs between these three pairs of group (the control group and the 15 min-treated group, the 30 min-treated and the 45 min-treated group, the 60 min-treated and the 75 min-treated group). But there were significant differences between the 30 min-treated or the 45 min-treated group and the 60 min-treated or the 75 min-treated group.

Ultrasound hyperthermia performed in 42 degrees C for 30-45 min can improve the chemosensitivity of Tca8113 cells to some drugs significantly, which confirms the rationality of synchronous combination of hyperthermia and chemotherapy in the chemosensitivity point of view for the first time.

[Experimental study on ultrasound heating affecting the sensitivity of oral carcinoma to chemotherapy drugs].

OBJECTIVE
To interfere in the Tca8113-CDDP cell line with siRNA of cyclin D1 and to investigate time and dose dependent gene silencing effect of siRNA of cyclin D1.

METHODS
siRNA of cyclin D1 was transfected into Tca8113-CDDP cells Fluorescent CY3 dye labeled siRNA GAPDH was used as the control. The transient transfecting efficiency was examined at 4, 24, 48 and 72 h. The relative quantity of the target RNA of cyclin D1 was analyzed with SYBR Green fluorescent dye kit by the Real-time PCR assay. The protein level of cyclin D1 was examined with Western blot. The changes of cisplatin sensitivity after treatment with siRNA cyclin D1 were examined with methyl thiazolyl tetrazolium (MTT) assay.

RESULTS
The optimized transfecting efficiency with CY3 labeled siRNA GAPDH in Tca8113-CDDP cells was over 90%. The silencing rate of cyclin D1 siRNA was 81.6% at 24 h, 80.7% at 48 h and 94.3% at 72 h. Dose-dependent manner of gene silencing effect was observed when the siRNA concentration was lower than 100 nmol/L, however, gene silencing effect reached its platform when the concentration was higher than 100 nmol/L. The protein levels of cyclin D1 at 24, 48 and 72 h after transfection decreased significantly, and so did the growth of cells. Inhibition rates of cell growth induced by cisplatin after administration with or without cyclin D1 siRNA were 58.4% and 34.8%, respectively.

Chemical synthesized cyclin D1 siRNA effectively silenced the expression of cyclin D1 gene in Tca8113-CDDP cells in vitro, with a time- and dose-dependent manner and target gene silence in cells increased its sensitivity to cisplatin.

[In vitro gene silencing by siRNA of cyclin D1 on tongue squamous cell carcinoma cell line resistant to cisplatin].

PURPOSE
To investigate the mechanism of apoptosis in Tca8113 cells induced by ultrasound hyperthermia by detecting changes in related index.

METHODS
Tca8113 cells were treated in vitro by ultrasound hyperthermia in different heating temperatures (38 degrees C to 44 degrees C,10 minutes) and heating times (42 degrees C,10 to 60 minutes), and then the dynamic changes of early apoptosis and secondary necrosis treated by 42 degrees C for 10 minutes were assayed to detect deltapsim and Caspase-3 levels of different groups by flow cytometry (FCM). The means of each group were compared by ANOVA with SAS6.12 software package.

RESULTS
After heated by ultrasound in 42 degrees C for 10 minutes, the early apoptosis of Tca8113 was detected. The apoptosis index reached its highest level at the 6th to 8th hour, then decreased rapidly and maintained in a lower level after 12 hours. The level of secondary necrosis increased with the level of early apoptosis, but kept in a higher level until the 10th hour, the level of secondary necrosis correlated with that of the early apoptosis (r = 0.7909, P = 0.0064). The fraction of cells with low mitochondria membrane potential and increased activity of Caspase-3 were detected either in the heating-temperature grads group or in the heating-time grads group, which showed significant relationship between thetwo apoptosis related index (r = 0.89189, P = 0.0029 in the heating-temperature grads group; r = 0.9679, P = 0.0003 in the heating-time grads group).

Tca8113 cells developed apoptosis after heated by ultrasound hyperthermia along with deltapsim level decreasing and Caspase-3 activity increasing. Ultrasound hyperthermia induces apoptosis of Tca8113 cells by the mitochondrum-Caspase pathway.

[A study on the mechanism of inducing apoptosis of Tca8113 cells by means of ultrasound hyperthermia].

OBJECTIVE
Prospective research demonstrated that Chinese regimen granules of Shenyang could prolong survival time and improve survival rate of patients with oral squamous cell carcinoma (SCC). But the mechanism was not clear. The purpose of this study was to investigate Shenyang's effect on peripheral blood lymphocyte subsets of SD rats with SCC of tongue and explore immunological mechanism.

METHODS
Among 80 SD rats fed by 0.002% 4-nitroquinoline-1-oxide (4NQO) drinking water for 36 weeks, 61 rats with SCC of tongue had been found and were randomly divided into 4 groups, namely Shenyang A, Shenyang B, positive and blank control groups. Before and after high and normal dosage of Shenyang, acanthopanax senticoside and water had been given for 15 days respectively, peripheral blood lymphocyte subsets were detected with flow cytometry. The data were statistically analyzed with paired t Test.

RESULTS
Percentage of CD3+ CD4+ T cell and CD3-CD161a+ NK cell, ratio of CD4+/CD8+ were increased. Percentage of CD3+CD8+ T cell was decreased, and the effect was better than that of acanthopanax senticoside in improving the percentage of CD3-CD161a+ NK cell.

Among anti-tumor mechanisms of Shenyang it is that corrects disorder of lymphocyte subsets and increases percentage of CD3-CD161a+ NK cell.

[Modulation of Chinese regimen granules of Shenyang on peripheral blood lymphocyte subsets of SD rats with SCC of tongue].

PURPOSE
Prospective research demonstrated that Chinese prescription Shenyang could prolong the survival time and improve the survival rate of patients with oral squamous cell carcinoma (SCC). But the mechanism was not clear. The purpose of this study was to investigate effect of Shenyang on the level of Th1/Th2 cytokines in serum of SD rats with SCC of tongue and clarify its mechanism.

METHODS
Among 80 SD rats fed by 0.002% 4-nitroquinoline-1-oxide (4NQO) drinking water for 36 weeks, 61 with SCC of tongue had been found and randomly divided into 4 groups, namely Shenyang A, Shenyang B, positive and negative control group. Before and after high and low dosage of Shenyang, acanthopanax senticoside and water had been given for 15 days respectively, peripheral blood serum was collected. Secretion of Th1-type cytokines, such as IFN-gamma, IL-2, TNF-alpha and Th2-type cytokines, such as IL-4, IL-10 were detected by enzyme-linked immunosorbent assay (ELISA). Statistical analysis was made with paired t test.

RESULTS
Shenyang significantly enhanced ,the serum levels of Th1-type cytokine, TNF-alpha and IL-2 (P<0.05), and decreased the expression of Th2-type cytokine, IL-4 and IL-10(P<0.05). Serum IFN-gamma had been increased to some extent.

Reversing Th2 to Th1 cytokines and then enhancing the immunity may be one of the mechanisms in anti-tumor effect of Shenyang. Supported by Science and Technology Development Fund (No.014319359) of Shanghai Municipality.

[Modulation of Chinese prescription Shenyang on Th1/Th2 cytokines in serum of SD rats with squamous cell carcinoma of the tongue].

P.30 Ultrasound heat-induced apoptosis in a head and neck cell line of human squamous cell carcinoma (Tca8113) via the mitochondria-caspase pathway

PURPOSE
To investigate the immunological function for patients with oral cancer undergoing operation.

METHODS
Peripheral blood was taken from patients with oral cancer before and after operation. Proportions of CD3(+) total T, CD4(+) Th, CD8(+) Tc/Ts, CD19(+) total B, CD16(+)/CD56(+)NK were detected by flow cytometry (FCM). Detections of serum tumor necrosis factor alpha (TNF-alpha) and soluble interleukin-2 receptor (sIL-2R) were performed with enzyme-linked immunosorbent assay(ELISA). Paired t test was used for statistical analysis.

RESULTS
The proportions of CD8(+)Tc/Ts, CD19(+) total B and CD4(+)/CD8(+) increased significantly after surgery. Post operative proportion of CD16(+)/CD56(+)NK decreased more significantly. The concentration of TNF-alpha was less than that before operation(P<0.05).

Surgery could change immunological function and alleviate immunosuppression of oral cancer patients. Detections for immune conditions of oral cancer patients might have important clinical values in prognosis evaluation and guiding treatment, especially immunotherapy, after operation.

[Immunodetections and analysis of peripheral blood for patients with oral cancer undergoing operation].

OBJECTIVE
To compare the clinical efficacy and toxicity of teniposide (VM26) of higher dose with those of lower dose, both combined with cisplatin (CDDP) and pingyangmycin (PYM), in the treatment of patients with squamous cell carcinoma of oral and maxillofacial region (SCCOMR).

METHODS
Sixty-five patients with SCCOMR entered into this study prospectively. Thirty-three patients were treated with higher dose of VM26 (total dose was 320 mg) combined with CDDP and PYM (PTP1), the other thirty-two patients were treated with lower dose (total dose was 158 mg) of VM26 combined with CDDP and PYM (PTP2).

RESULTS
Thirty-three patients received a total of 38 cycles of PTP1. The overall response rate was 81.82% (27/33). Thirty-two patients received a total of 36 cycles of PTP2 and showed overall response rate by 81.25% (26/32). There was no significant difference between PTP1 and PTP2 groups in response rate (P > 0.05). But the blood toxicity was more severe in PTP1 group than in PTP2 group (P < 0.01). Bone marrow depression rate (1-4 stage) was 48.48% in PTP1 group versus 25.00% in the other group.

A high response rate of 81.25% and relatively slighter adverse events could be obtained for lower dose of VM26 combined with CDDP and PYM (PTP2). So, the chemotherapy schedule, PTP2, a novel teniposide based regimen in SCCOMR could be employed and spread in clinical practice.

[Chemotherapy with higher or lower dose of teniposide combined with cisplatin and pingyangmycin for oral squamous cell carcinoma].

Short-term Origin-Destination(OD) matrix prediction in metro systems aims to predict the number of passenger demands from one station to another during a short time period. That is crucial for dynamic traffic operations, e.g., route recommendation, metro scheduling. However, existing methods need further improvement due to that they fail to take full use of the real-time traffic information and model the complex spatiotemporal correlation of traffic flows. In this paper, a Multi-View Passenger Flow (MVPF) evolution trend based OD matrix prediction method is proposed. It consists of two components focusing on individual station and cross-station learning. Specifically, the individual station level part uses Gate Recurrent Unit and Extended Graph Attention Networks combined model to learn the high-level spatiotemporal-dependent representation of each station as the roles of origin and destination respectively, by considering multiple views of real-time traffic information (i.e., Inflow, destination allocation of Inflow, Outflow, origin allocations of Outflow). The cross-station part aims to learn passenger mobility pattern from each origin to destination through defining a transition matrix under spatiotemporal context. Compared with state-of-the-art solutions, MVPF increases the OD prediction performance metric of WMAPE by 2.5% on average. The experimental results demonstrate the superiority of MVPF against other competitors. The source code is available at https://github.com/zfrInSIAT/MVPF-code.

Metro OD Matrix Prediction Based on Multi-View Passenger Flow Evolution Trend Modeling

In this paper, we investigate an efficient way for identifying passengers in a metro system across two heterogeneous but complementary trajectory data sources: AFC data recording two points per trip about when and where a passenger enters or leaves the metro system, and WiFi data recording a few points passed by a passenger in the way of some of his/her trips. The identification result can help us to complete individuals’ mobility, and benefits to lots of services, e.g., individual route choice analysis, epidemic case detecting and so on. The problem is similar to calculate the similarity between two trajectories from two data sources, where a trajectory refers to a sequence of points where a passenger appeared in a metro system on observed days. However, due to the small location space in a metro network, large number of passengers with similar travel pattern, and so on, there are lots of trip overlaps or point co-occurrences between different passengers. That results in a large number of passengers mismatched by existing trajectory similarity measurement. To address the problem, this paper proposes a novel global-local correlation based trajectory similarity measurement GLTC. Specifically, GLTC first extracts all overlapping trip pairs of two trajectories by considering the spatiotemporal inclusions from global level. Then it gets the similarity by aggregating each overlapping trip pair’s local similarity, which is calculated by considering some data-driven insights helpful to uniquely identify a passenger (e.g., uneven passenger flow distribution in different cross-sections of a metro network, the number of trips in same travel pattern of a trajectory, and so on). We evaluate GLTC based on real-world data, and the experimental result shows that GLTC outperforms other baselines.

GLTC: A Metro Passenger Identification Method Across AFC Data and Sparse WiFi Data

Accurate prediction of short-term OD Matrix (i.e. the distribution of passenger flows from various origins to destinations) is a crucial task in metro systems. It is highly challenging due to the constantly changing nature of spatiotemporal factors and the recent data collection problem. Recently, some deep learning-based models have been proposed for OD Matrix forecasting in ride-hailing or high way traffic scenarios. However, these models can not sufficiently capture the complex spatiotemporal correlations among stations in metro networks due to different prior knowledge and contextual settings. In this paper, we propose a model, namely Multi-Scale STATCN, to address OD metro matrix prediction. Specifically, it first proposes a data-driven method to solve the recent data collection problem. Then, it captures the dynamic spatial dependency in OD flows among different stations by a global self-attention mechanism. Three temporal convolutional networks are leveraged to capture three temporal trends in OD flow, i.e. recent trend, daily trend, weekly trend. Extensive experiments on three large-scale metro datasets demonstrate the superiority of our model over other competitors.

Multi-Scale STATCN: Self-Attention based Spatiotemporal Model for Short-Term Metro Origin-Destination Matrix Prediction

Understanding and predicting each individual’s real-time travel destination given the origin information in urban public transportation systems is crucial for personalized traveler recommendation, targeted demand management, dynamic traffic operations and so on. Existing methods are often based on modeling the regular travel patterns through analyzing the long-term personal travel information. They are suitable for destination prediction of individual regular trips with regular travel patterns, but may not work well for occasional trips with strong randomness and uncertainty, especially for the individuals with a few historical travel data. In this paper, we focus on more challenging issue about destination prediction of occasional trips. We design a general Multi-View Deep Learning Framework (MDLF) based on the data-driven insight that a location where a user will destine to is not only related to the user’s own travel preference to the location, but also influenced by crowd’s travel preference and the region’s characteristics of the location under certain spatiotemporal contexts. The destination of an individual’s occasional trip can be predicted by combining all these complementary influencing factors. The novelty of MDLF is mainly reflected in two aspects. The first is the effective feature extraction from multiple and complementary views. The second is that a CNN (Recurrent Neural Network) based deep learning component for predicting each occasional trip’s destination by calculating a moving trend score for each possible destination. We evaluate the MDLF based on two real-world smart card datasets collected by AFC (Automatic Fare Collection) Systems. The experimental results demonstrate the superiority of MDLF against other competitors.

MDLF: A Multi-View-Based Deep Learning Framework for Individual Trip Destination Prediction in Public Transportation Systems

Accurate traffic state prediction is the foundation of transportation control and guidance. It is very challenging due to the complex spatiotemporal dependencies in traffic data. Existing works cannot perform well for multi-step traffic prediction that involves long future time period. The spatiotemporal information dilution becomes serve when the time gap between input step and predicted step is large, especially when traffic data is not sufficient or noisy. To address this issue, we propose a multi-spatial graph convolution based Seq2Seq model. Our main novelties are three aspects: (1) We enrich the spatiotemporal information of model inputs by fusing multi-view features (time, location and traffic states) (2) We build multiple kinds of spatial correlations based on both prior knowledge and data-driven knowledge to improve model performance especially in insufficient or noisy data cases. (3) A spatiotemporal attention mechanism based on reachability knowledge is novelly designed to produce high-level features fed into decoder of Seq2Seq directly to ease information dilution. Our model is evaluated on two real world traffic datasets and achieves better performance than other competitors.

Incorporating Reachability Knowledge into a Multi-Spatial Graph Convolution Based Seq2Seq Model for Traffic Forecasting

Completion and augmentation-based spatiotemporal deep learning approach for short-term metro origin-destination matrix prediction under limited observable data

Accurate prediction of short-term OD Matrix (i.e. the distribution of passenger flows from various origins to destinations) is a crucial task in metro systems. It is highly challenging due to the constantly changing nature of many impacting factors and the real-time delayed data collection problem. Recently, some deep learning-based models have been proposed for OD Matrix forecasting in ridehailing and high way traffic scenarios. However, these models can not sufficiently capture the complex spatiotemporal correlation between stations in metro networks due to their different prior knowledge and contextual settings. In this paper we propose a hybrid framework Multi-view TRGRU to address OD metro matrix prediction. In particular, it uses three modules to model three flow change patterns: recent trend, daily trend, weekly trend. In each module, a multi-view representation based on embedding for each station is constructed and fed into a transformer based gated recurrent structure so as to capture the dynamic spatial dependency in OD flows of different stations by a global self-attention mechanism. Extensive experiments on three large-scale, real-world metro datasets demonstrate the superiority of our Multi-view TRGRU over other competitors.

Multi-View TRGRU: Transformer based Spatiotemporal Model for Short-Term Metro Origin-Destination Matrix Prediction

Graph Convolutional Network (GCN) is adopted to tackle the problem of convolution operation in non-Euclidean space. Previous works on GCN have made some progress, however, one of their limitations is that the design of Adjacency Matrix (AM) as GCN input requires domain knowledge and such process is cumbersome, tedious and error-prone. In addition, entries of a fixed Adjacency Matrix are generally designed as binary values (i.e., ones and zeros) which can not reflect the real relationship between nodes. Meanwhile, many applications require a weighted and dynamic Adjacency Matrix instead of an unweighted and fixed AM, and there are few works focusing on designing a more flexible Adjacency Matrix. To that end, we propose an end-to-end algorithm to improve the GCN performance by focusing on the Adjacency Matrix. We first provide a calculation method called node information entropy to update the matrix. Then, we perform the search strategy in a continuous space and introduce the Deep Deterministic Policy Gradient (DDPG) method to overcome the drawback of the discrete space search. Finally, we integrate the GCN and reinforcement learning into an end-to-end framework. Our method can automatically define the Adjacency Matrix without prior knowledge. At the same time, the proposed approach can deal with any size of the matrix and provide a better AM for network. Four popular datasets are selected to evaluate the capability of our algorithm. The method in this paper achieves the state-of-the-art performance on Cora and Pubmed datasets, with the accuracy of 84.6% and 81.6% respectively.

2020 25th International Conference on Pattern Recognition (ICPR)

AOAM: Automatic Optimization of Adjacency Matrix for Graph Convolutional Network

Stock price movement prediction is commonly accepted as a very challenging task due to the volatile nature of financial markets. Previous works typically predict the stock price mainly based on its own information, neglecting the cross effect among involved stocks. However, it is well known that an individual stock price is correlated with prices of other stocks in complex ways. To take the cross effect into consideration, we propose a deep learning framework, called Multi-GCGRU, which comprises graph convolutional network (GCN) and gated recurrent unit (GRU) to predict stock movement. Specifically, we first encode multiple relationships among stocks into graphs based on financial domain knowledge and utilize GCN to extract the cross effect based on these pre-defined graphs. To further get rid of prior knowledge, we explore an adaptive relationship learned by data automatically. The cross-correlation features produced by GCN are concatenated with historical records and then fed into GRU to model the temporal dependency of stock prices. Experiments on two stock indexes in China market show that our model outperforms other baselines. Note that our model is rather feasible to incorporate more effective stock relationships containing expert knowledge, as well as learn data-driven relationship.

Multi-Graph Convolutional Network for Relationship-Driven Stock Movement Prediction

Real-time individuals’ destination prediction is of great significance for real-time user tracking, service recommendation and other related applications. Traditional technology mainly used statistical methods based on the travel patterns mined from personal historytraveldata.However,itisnotclearhowtopredictthedestinationsofindividuals with only limited personal historical data. In this paper, taking the public transportation metro systems as example, we design a practical method called practical model with strong interpretability and predictability to predict each passenger’s destination. Our main novelties are two aspects: (1) We propose to predict individuals’ destination by combining personal and crowd behavior under certain context. (2) An explanatory model combining discrete choice model and neural network model is proposed to predict individuals’ stochastic trip’s destination, which can be applied to other transportation analysis scenarios about individuals’ choice behavior such as travel mode choice or route choice. We validate our method based on extensive experiments, using smart card data collected by automatic fare collection system and weather data in Shenzhen,China.Theexperimentalresultsdemonstratethatourapproachcanachieve better performance than other baselines in terms of prediction accuracy.

Practical model with strong interpretability and predictability: An explanatory model for individuals' destination prediction considering personal and crowd travel behavior

In recent years, various deep learning architectures have been proposed to solve complex challenges (e.g. spatial dependency, temporal dependency) in traffic domain, which have achieved satisfactory performance. These architectures are composed of multiple deep learning techniques in order to tackle various challenges in traffic tasks. Traditionally, convolution neural networks (CNNs) are utilized to model spatial dependency by decomposing the traffic network as grids. However, many traffic networks are graph-structured in nature. In order to utilize such spatial information fully, it’s more appropriate to formulate traffic networks as graphs mathematically. Recently, various novel deep learning techniques have been developed to process graph data, called graph neural networks (GNNs). More and more works combine GNNs with other deep learning techniques to construct an architecture dealing with various challenges in a complex traffic task, where GNNs are responsible for extracting spatial correlations in traffic network. These graph-based architectures have achieved state-of-the-art performance. To provide a comprehensive and clear picture of such emerging trend, this survey carefully examines various graph-based deep learning architectures in many traffic applications. We first give guidelines to formulate a traffic problem based on graph and construct graphs from various kinds of traffic datasets. Then we decompose these graph-based architectures to discuss their shared deep learning techniques, clarifying the utilization of each technique in traffic tasks. What’s more, we summarize some common traffic challenges and the corresponding graph-based deep learning solutions to each challenge. Finally, we provide benchmark datasets, open source codes and future research directions in this rapidly growing field.

How to Build a Graph-Based Deep Learning Architecture in Traffic Domain: A Survey

Subway passenger flow forecasting, an essential component of intelligent transportation system, is critical for traffic management, public safety, urban planning. However, it is very challenging due to the high nonlinearities and complex dynamic spatio-temporal dependencies of passenger flows. In this paper, we model the subway system as a directed weighted graph and propose a novel spatio-temporal deep learning framework, Multi-STGCnet, for forecasting short-term subway passenger flow at a station level. Specifically, Multi-STGCnet is mainly composed of two components, temporal component and spatial component. (1) The temporal component employs three long short-term memory network (LSTM)-based modules to capture three temporal properties of the target station, which are the interval closeness, daily periodicity, weekly trend. (2) The spatial component designs three spatial matrixes to extract spatial correlation of a target station with all other stations classified as near neighbors, middle neighbors and distant neighbors. Respectively, it adopts three graph convolution network (GCN) and LSTM combined modules to capture the spatio-temporal influences from different neighbors. Finally, the outputs of the two components are fused with different weights to generate prediction. We evaluate Multi-STGCnet on a real world dataset from the metro system in Shenzhen, China. Experiment results demonstrate that our model outperforms multiple baselines.

Multi-STGCnet: A Graph Convolution Based Spatial-Temporal Framework for Subway Passenger Flow Forecasting

A Data-Driven Method for Dynamic OD Passenger Flow Matrix Estimation in Urban Metro Systems

This exploratory study aims to address the problem that cash loan fraud customers are difficult to detect manually. Cash loan is a new consumption model in the concept of Internet consumer finance(ICF). Manual detection of fraudulent customers requires a lot of manpower and time, and often causes great losses to financial institutions, so our group did the research mentioned above. In this paper, we proposed a Semi-supervised Pre-loan Fraud Detection (SPFD) system via investigating various supervised and unsupervised learning algorithms on basis of 285,771 applicants’ desensitized data from MUCFC (a Chinese ICF company). In SPFD, feature selection methods consist of KL Divergence, Wasserstein Distance and Manual Selection, while the clustering algorithms we adopted was K-constrained seed clustering. Final result demonstrates good performance with the Adjusted Rand Index(ARI) reaching 81.7%. Such method would help financial institution to reduce financial losses.

2019 IEEE International Conference on Industrial Cyber Physical Systems (ICPS)

Semi-Supervised Anti-Fraud Models for Cash Pre-Loan in Internet Consumer Finance

Abstract To improve the accuracy of fish disease expert system diagnosis, this paper develops a fish disease model which combines case‐based reasoning and content retrieval from images of sick fish. In the visual inspection phase and microscope inspection phase of fish disease diagnosis the system extracts the visual features of a fish disease image which is uploaded by the user. It then uses content‐based image retrieval technology to find similar images in the fish disease image database. This can be returned to the user as a diagnosis reference and, at the same time it can be used as an index for case retrieval. During case retrieval, depending on the similar image's semantic annotation index case database, the searching scope can be reduced to improve the efficiency of case retrieval and the accuracy of reasoning.

Study on a fish disease case reasoning system based on image retrieval

Achyranthes bidentata polysaccharides alleviate endoplasmic reticulum stress in osteoarthritis via lncRNA NEAT1/miR-377-3p pathway.

 Background: Osteoarthritis (OA) and rheumatoid arthritis (RA) is the most common joint disease. The aim of my current academic work is to identify important genes associated with OA and RA, clarify their underlying mechanisms, and define differences between OA and RA.Methods: Gene expression profiles of GSE55235 were available from Gene Expression Omnibus database. Differentially expressed genes between 1) OA tissues and normal tissues, 2) RA tissues and normal tissues, were picked out by GEO2R tool, Venn diagram software, and Volcanic map. Next, we made use of the Database for Annotation, Visualization and Integrated Discovery to analyze Kyoto Encyclopedia of Gene and Genome pathway and gene ontology. The protein-protein interaction of these DEGs was visualized by Cytoscape with Search Tool for the Retrieval of Interacting Genes. Of entire PPI network analyzed by Molecular Complex Detection plug-in and obtain central nodes. Then the central nodes were re-analysis via DAVID. We next obtained the intersection of the analysis results of GSE55457 and GSE55235 to verify the results. Finally, potential biomarkers were evaluated by receiver operating characteristic.Results: Twelve genes were found to be significantly enriched in the TNF signaling pathway in OA, and eleven genes were found to be significantly enriched in the Chemokine signaling pathway in RA. Receiver operating characteristic curve suggested that the detection of JUN in OA and CCL5, CXCL9, CXCL10, CXCL11, CXCL13 in RA exhibited a high diagnostic performance.Conclusions: We have identified six significantly DEGs on the basis of integrated bioinformatical methods, which could be potential targets for differential diagnosis for OA and RA.

Differential Diagnosis of Osteoarthritis and Rheumatoid Arthritis by Bioinformatics Analysis

Ultrastructural change of the subchondral bone increases the severity of cartilage damage in osteoporotic osteoarthritis of the knee in rabbits.

Osteoarthritis (OA) is a chronic arthropathy that occurs in the middle-aged and elderly population. The present study aimed to identify gene signature differences between synovial cells from OA synovial membrane with and without inflammation, and to explain the potential mechanisms involved. The differentially expressed genes (DEGs) between 12 synovial membrane with inflammation and 12 synovial membrane without inflammation from the dataset GSE46750 were identified using the Gene Expression Omnibus 2R. The DEGs were subjected to enrichment analysis, protein-protein interaction (PPI) analysis and module analysis. The analysis results were compared with text-mining results. A total of 174 DEGs were identified. Gene Ontology enrichment results demonstrated that functional molecules encoded by the DEGs primarily had extracellular location, molecular functions predominantly involving ‘chemokine activity’ and ‘cytokine activity’, and were associated with biological processes, including ‘inflammatory response’ and ‘immune response’. The Kyoto Encyclopedia of Genes and Genomes results demonstrated that DEGS may function through pathways associated with ‘rheumatoid arthritis’, ‘chemokine signaling pathway’, ‘complement and coagulation cascades’, ‘TNF signaling pathway’, ‘intestinal immune networks for IgA production’, ‘cytokine-cytokine receptor interaction’, ‘allograft rejection’, ‘Toll-like receptor signaling pathway’ and ‘antigen processing and presentation’. The top 10 hub genes [interleukin (IL)6, IL8, matrix metallopeptidase (MMP)9, colony stimulating factor 1 receptor, FOS proto-oncogene, AP1 transcription factor subunit, insulin-like growth factor 1, TYRO protein tyrosine kinase binding protein, MMP3, cluster of differentiation (CD)14 and CD163] and four gene modules were identified from the PPI network using Cytoscape. In addition, text-mining was used to identify the commonly used drugs and their targets for the treatment of OA. It was initially verified whether the results of the present study were useful for the study of OA treatment targets and pathways. The present study provided insight for the molecular mechanisms of OA synovitis. The hub genes and associated pathways derived from analysis may be targets for OA treatment. IL8 and MMP9, which were validated by text-mining, may be used as molecular targets for the OA treatment, while other hub genes require further validation.

Bioinformatics analysis to identify key genes and pathways influencing synovial inflammation in osteoarthritis

Computer Simulation on Analgesic Functional Chemome Characteristics of Radix Saposhnikoviae

Cibotium barometz polysaccharides (CBPS) are one of the most important bioactive components extracted from the Cibotium barometz plant, which belongs to the Dicksoniaceae family. It has been widely used for the treatment of orthopedic diseases in traditional Chinese medicine. However, the molecular mechanisms behind the therapeutic effects of CBPS remain to be clarified. In the present study, the concentration of CBPS was detected by phenol-vitriol colorimetry. Furthermore, the effects stimulated by CBPS on the viability and G1/S cell cycle transition in primary chondrocytes from Sprague-Dawley rats were investigated. A cell viability assay demonstrated that chondrocyte proliferation may be enhanced by CBPS in a dose- and time-dependent manner. The mechanism underlying the promotion of chondrocyte cell cycle was suggested to involve the stimulation of G1 to S phase transition. To further confirm the results, reverse transcription-quantitative polymerase chain reaction and western blot analyses were used to detect the expression of mRNA and protein levels of cyclin D1, cyclin-dependent kinase 4 and retinoblastoma protein. The results suggested that CBPS may stimulate chondrocyte proliferation via promoting G1/S cell cycle transition. Since osteoarthritis is characterized by deficient proliferation in chondrocytes, the present study indicates that CBPS may potentially serve as a novel method for the treatment of osteoarthritis.

Cibotium barometz polysaccharides stimulate chondrocyte proliferation in vitro by promoting G1/S cell cycle transition

Study on Pharmacodynamic Material Basis and Molecular Mechanism of Wutou Tang in Pain Relief Based on Computer Simulation

The molecular mechanisms of TNF-α-induced apoptosis of chondrocyte and the role of Ca2+ mediating the effects of MW on TNF-α-induced apoptosis of chondrocytes remained unclear. In this study, we investigated the molecular mechanism underlying inhibiting TNF-α-induced chondrocytes apoptosis of MW. MTT assay, DAPI, and flow cytometry demonstrated that MW significantly increased cell activity and inhibited chromatin condensation accompanying the loss of plasma membrane asymmetry and the collapse of mitochondrial membrane potential. Our results also indicated that MW reduced the elevation of [Ca2+]i in chondrocytes by LSCM. Moreover, MW suppressed the protein levels of calpain, Bax, cytochrome c, and caspase-3, while the expressions of Bcl-2, collagen II, and aggrecan were increased. Our evidences indicated that MW treatment inhibited the apoptosis of chondrocytes through depression of [Ca2+]i. It also inhibited calpain activation, which mediated Bax cleavage and cytochrome c release and initiated the apoptotic execution phase. In addition, MW treatment increased the expression of collagen II and aggrecan of chondrocytes.

Millimeter Wave Treatment Inhibits Apoptosis of Chondrocytes via Regulation Dynamic Equilibrium of Intracellular Free Ca2+

Tumor necrosis factor-α (TNF-α) plays an important role in the abnormal metabolism of osteoblasts (OBs), which leads to subchondral bone (SB) alterations in osteoarthritis. In the present study, Tougu Xiaotong capsule (TXC), a traditional Chinese medicine, was used to treat TNF-α-injured OB-like cells. The cellular viability, mortality and ultramicroscopic morphology were evaluated. Thereafter, the activity of alkaline phosphatase (ALP), secretion of osteocalcin (OCN) and mineralization of nodules were analyzed. The results showed that TXC treatment significantly promoted cell proliferation, reduced cellular mortality and improved cellular ultrastructure, particularly that of the endoplasmic reticulum and nucleus. These data indicate that TXC is able to promote cell growth, as well as prevent inflammation in OB-like cells. Furthermore, the activity of ALP, secretion of OCN and mineralization of nodules were accelerated, and the calcium content of the TNF-α-injured OB-like cells was promoted by TXC treatment. These results indicate that TXC protected the OB-like cells from TNF-α-induced injuries. This may be a potential mechanism through which TXC regulates SB remodeling in the clinical treatment of osteoarthritis.

Protective effects of Tougu Xiaotong capsule on tumor necrosis factor-α-injured UMR-106 cells.

Tulipa edulis Bak (TEB) is an active ingredient in various traditional Chinese medicine compounds and is commonly used to treat swelling and redness, remove toxicity and eliminate stagnation, as well as to prevent and treat certain cancer types. However, the underlying molecular mechanism of the anticancer activity of TEB remains unclear. The aim of the current study was to investigate the effect and underlying mechanism of the ethanolic extract of TEB (EETEB) on SGC-7901 human gastric carcinoma cells. An MTT assay was performed to analyze cell viability. In addition, transmission electron microscopy, an Annexin V/fluorescein isothiocyanate assay, a JC-1 assay and laser scanning confocal microscopy with DAPI staining were used to determine the rate of apoptosis. Furthermore, reverse transcription-polymerase chain reaction and western blot analysis were used to detect the expression levels of the apoptosis gene and protein. EETEB was identified to inhibit the growth of SGC-7901 cells in a dose-dependent manner and induce changes in cell morphology. At the molecular level, EETEB induced SGC-7901 cell DNA fragmentation, loss of plasma membrane and asymmetrical collapse of the mitochondrial membrane potential, while it increased the expression of pro-apoptotic B-cell lymphoma-2 (Bcl-2)-associated X protein and reduced expression of anti-apoptotic Bcl-2. Thus, the results of the current study revealed that the application of EETEB may inhibit the growth of the SGC-7901 cells due to mitochondria-mediated apoptosis.

Ethanolic extract of Tulipa edulis Bak induces apoptosis in SGC-7901 human gastric carcinoma cells via the mitochondrial signaling pathway.

Diesun Miaofang (DSMF) is a traditional herbal formula, which has been reported to activate blood, remove stasis, promote qi circulation and relieve pain. DSMF holds a great promise for the treatment of traumatic injury in an integrative and holistic manner. However, its underlying mechanisms remain to be elucidated. In the present study, a systems pharmacology model, which integrated cluster ligands, human intestinal absorption and aqueous solution prediction, chemical space mapping, molecular docking and network pharmacology techniques were used. The compounds from DSMF were diverse in the clusters and chemical space. The majority of the compounds exhibited drug-like properties. A total of 59 compounds were identified to interact with 16 potential targets. In the herb-compound-target network, the majority of compounds acted on only one target; however, a small number of compounds acted on a large number of targets, up to a maximum of 12. The comparison of key topological properties in compound-target networks associated with the above efficacy intuitively demonstrated that potential active compounds possessed diverse functions. These results successfully explained the polypharmcological mechanism underlying the efficiency of DSMF for the treatment of traumatic injury as well as provided insight into potential novel therapeutic strategies for traumatic injury from herbal medicine.

Deciphering the underlying mechanisms of Diesun Miaofang in traumatic injury from a systems pharmacology perspective

Duhuo Jisheng Decoction (DHJSD) is a traditional Chinese herbal medicine that has multiple uses, including as a treatment for osteoarthritis (OA). However, the molecular mechanisms underlying the therapeutic effects of DHJSD on OA remain unknown. In the present study, a serum pharmacological method was applied to investigate the effects of DHJSD on the proliferation of chondrocytes treated with interleukin‑1β (IL‑1β) in vitro. This is a cell model commonly used to reproduce the mechanisms involved in degenerative arthropathies, including OA. The most effective intervention conditions of DHJSD serum were examined by MTT assay. The degenerative chondrocyte model was established by IL‑1β‑culture for 24 h, and was verified by optical microscopy and immunohistochemical analyses. Following the successful establishment of the degenerative chondrocyte model, the chondrocytes were subsequently randomly divided into two groups: The blank serum group and the DHJSD treatment group. Subsequent to treatment with the corresponding serum, cell proliferation was detected by MTT assay and DNA staining followed by FACS analysis, and the mRNA and protein expression levels of cyclin D1, cyclin‑dependent kinase 4 (CDK4), retinoblastoma tumor suppressor protein (Rb) and p16 were measured by reverse transcription polymerase chain reaction and western blotting, respectively. The results indicated that the most effective condition for the promotion of chondrocyte proliferation was 10% concentration of DHJSD 2‑h serum, and the degenerative chondrocyte model was successfully reproduced by IL‑1β‑treatment for 24 h. The mRNA and protein expression levels of cyclin D1, CDK4 and Rb in the DHJSD serum‑treated cells were significantly increased compared with those in the blank serum group, whereas p16 expression was significantly downregulated. These results indicate that treatment of cells with DHJSD‑containing serum is able to promote IL‑1β‑induced chondrocyte proliferation by promoting G1/S phase transition via modulating the expressions of cyclin D1, CDK4, Rb and p16, which contribute to the clinical efficacy of DHJSD in OA.

Duhuo Jisheng Decoction‑containing serum promotes proliferation of interleukin‑1β‑induced chondrocytes through the p16‑cyclin D1/CDK4‑Rb pathway.

Huoxue Huayu (HXHY) has been widely used in traditional Chinese medicine (TCM) as a key therapeutic principle for osteoarthritis (OA), and related herbs have been widely prescribed to treat OA in the clinic. The aims of the present study were to explore a multi-target therapy for OA using 10 common HXHY herbs and to investigate their potential applications for treatment of other diseases. A novel computational simulation approach that integrates chemical structure, ligand clusters, chemical space and drug‑likeness evaluations, as well as docking and network analysis, was used to investigate the properties and effects of the herbs. The compounds contained in the studied HXHY herbs were divided into 10 clusters. Comparison of the chemical properties of these compounds to those of other compounds described in the DrugBank database indicated that the properties of the former are more diverse than those of the latter and that most of the HXHY-derived compounds do not violate the 'Lipinski's rule of five'. Docking analysis allowed for the identification of 39 potential bioactive compounds from HXHY herbs and 11 potential targets for these compounds. The identified targets were closely associated with 49 diseases, including neoplasms, musculoskeletal, nervous system and cardiovascular diseases. Ligand‑target (L‑T) and ligand‑target‑disease (L‑T‑D) networks were constructed in order to further elucidate the pharmacological effects of the herbs. Our findings suggest that a number of compounds from HXHY herbs are promising candidates for mult‑target therapeutic application in OA and may exert diverse pharmacological effects, affecting additional diseases besides OA.

In silico search for multi-target therapies for osteoarthritis based on 10 common Huoxue Huayu herbs and potential applications to other diseases.

Duhuo Jisheng Decoction (DHJSD), a well known traditional Chinese folk medicine, is used for eliminating stagnation, removing blood stasis, promoting blood circulation and alleviating pain; it is commonly used for the treatment of various diseases, including osteoarthritis (OA). However, the molecular mechanisms behind the therapeutic effects of OA remain unclear. In the present study, the effects of DHJSD on the morphology of articular cartilage and the G1/S cell cycle progression in chondrocytes, as well as the underlying mechanisms, were investigated. A total of 27 two‑month‑old male Sprague Dawley rats were randomly divided into 3 groups: the control group (no papain-induced OA; received an equivalent amount of saline only), the model group (papain-induced OA; received an equivalent amount of saline only) and the DHJSD group [papain-induced OA; received a clinical oral dose of DHJSD (9.3 g/kg/day)]. After 8 consecutive weeks of treatment, the morphological changes in articular cartilage were observed under an optical microscope and by transmission electron microscopy (TEM) and the mRNA and protein expression levels of cyclin D1, CDK4, CDK6, retinoblastoma protein (Rb) and p16 were measured by RT‑PCR and immunohistochemistry, respectively. Treatment with DHJSD significantly improved the arrangement of collagen fibers in the articular cartilage, as well as its structure and reduced cell degeneration compared with the model group. The mRNA and protein expression levels of cyclin D1, CDK4, CDK6 and Rb in the DHJSD‑treated group were significantly increased compared with those in the model group, whereas p16 expression was significantly downregulated. Taken together, these results indicate that DHJSD treatment promotes chondrocyte proliferation by promoting the G1/S checkpoint transition in the cell cycle and by upregulating the expression of cyclin D1, CDK4, CDK6 and Rb and downregulating the expression of p16 and this may, in part, explain its clinical efficacy in the treatment of osteoarthritis.

Duhuo Jisheng Decoction promotes chondrocyte proliferation through accelerated G1/S transition in osteoarthritis.

The aim of the present study was to investigate the effects of electroacupuncture (EA) on the proliferation of chondrocytes and the molecular mechanism(s) involved. Passage 2 chondrocytes were randomly divided into four groups and treated with EA or nocodazole. After treatment, cell proliferation was determined using an MTT assay and DNA staining followed by FACS. The mRNA expression levels of cyclin D1, cyclin-dependent kinase (CDK)4, CDK6, phosphorylated retinoblastoma (pRb) and P16 were detected by RT-PCR, and the protein levels of cyclin D1, CDK4, CDK6, pRb and P16 were detected by western blotting. EA treatment significantly increased cell viability in a time-dependent manner and decreased the number of G0/G1 and G2/M phase chondrocytes and increased the number of S phase cells. The mRNA and protein levels of cyclin D1, CDK4, CDK6, (p)Rb and P16 consistently demonstrated a reverse trend with the levels in the chondrocytes treated with nocodazole. The expression levels of cyclin D1, CDK4, CDK6 and Rb were higher in chondrocytes receiving EA treatment when compared to levels in the untreated cells while expression of P16 was lower. In conclusion, EA treatment promotes chondrocyte proliferation via promotion of G1/S checkpoint transition in the cell cycle dependent on the activity of the P16-cyclin D1-CDK4/6-pRb pathway and this may, in part, explain its clinical effect in the treatment of osteoarthritis.

Electroacupuncture promotes chondrocyte proliferation via accelerated G1/S transition in the cell cycle.

Xiao Jin Wan (XJW) is a well-known traditional Chinese folk-medicine, which is commonly used for the treatment of various types of diseases including cancers. However, the mechanism of the anticancer activity of XJW against U-2OS human osteosarcoma cells, have not yet been reported. In the present study, we investigated the cellular effects of the XJW on the U-2OS human osteosarcoma cell line. Our results showed that XJW induced cell morphological changes, reduced cell viability in a dose- and time-dependent manner and arrested in the G2/M phase of the cell cycle suggesting that XJW inhibited the proliferation of U-2OS cells. Hoechst 33258 staining and Annexin V/propidium iodide double staining exhibited the typical nuclear features of apoptosis and increased the proportion of apoptotic Annexin V-positive cells in a dose-dependent manner, respectively. In addition, XJW treatment caused loss of plasma membrane asymmetry, collapse of mitochondrial membrane potential, activation of caspase-9 and caspase-3, and increase of the ratio of pro-apoptotic Bax to anti-apoptotic Bcl-2. Taken together, the results indicate that the U-2OS cell growth inhibitory activity of XJW was due to cell cycle arrested and mitochondrial-mediated apoptosis, which may partly explain the anticancer activity of Xiao Jin Wan.

Xiao Jin Wan, a traditional Chinese herbal formula, inhibits proliferation via arresting cell cycle progression at the G2/M phase and promoting apoptosis via activating the mitochondrial‑dependent pathway in U-2OS human osteosarcoma cells.

Millimeter wave (MW) is an electromagnetic wave with a wavelength between             1 and 10 mm and a frequency of 30-300 GHz that causes multiple biological effects             and has been used as a major component in physiotherapies for the clinical treatment             of various types of diseases including cancers. However, the precise molecular             mechanism of the anticancer activity of millimeter wave remains to be elucidated.             In the present study, we investigated the cellular effects of the MW in the U-2OS             human osteosarcoma cell line. Our results showed that MW induced cell morphological             changes and reduced cell viability in a dose- and time-dependent manner suggesting             that MW inhibited the growth of U-2OS cells as demonstrated. Hoechst 33258 staining             and Annexin V/propidium iodide double staining exhibited the typical nuclear features             of apoptosis and increased the proportion of apoptotic Annexin V-positive cells             in a dose-dependent manner, respectively. In addition, MW treatment caused loss             of plasma membrane asymmetry, release of cytochrome c, collapse of mitochondrial             membrane potential, activation of caspase-9 and -3, and increase of the ratio             of pro-apoptotic Bax to anti-apoptotic Bcl-2. Taken together, the results indicate             that the U-2OS cell growth inhibitory activity of MW was due to mitochondrial-mediated             apoptosis, which may partly explain the anticancer activity of millimeter wave             treatment.

Millimeter wave treatment induces apoptosis via activation of the mitochondrial-dependent pathway in human osteosarcoma cells.

The efficacy and safety of millimeter wave radiation has been proven for             various types of malignant tumors. However, the mechanisms underlying effects             of millimeter wave radiation on apoptosis are still unclear. The present study             was undertaken to examine the effects of millimeter wave radiation on cell apoptosis             and mitochondrial membrane potential, and to determine the molecular mechanism             of millimeter wave radiation-induced apoptosis by investigating the expression             of Bcl-2 family proteins (Bcl-2, Bax), caspase-9 and caspase-3 in SW1353 cells.             We found that millimeter wave radiation suppressed the viability of SW1353 cells,             demonstrating that millimeter wave radiation induced cell apoptosis and reduced             cell viability in a time-dependent manner. Furthermore, we observed that treatment             of cells with millimeter wave radiation significantly induced loss of mitochondrial             membrane potential, upregulated proapoptotic Bax, caspase-9 and caspase-3, but             did not significantly change levels of antiapoptotic Bcl-2. These data suggested             that millimeter wave radiation may induce apoptosis via affecting the ratio of             Bax/Bcl-2 in SW1353 cells.

Millimeter wave radiation induces apoptosis via affecting the ratio of Bax/Bcl-2 in SW1353 human chondrosarcoma cells.

Monitoring of immune responses to a herbal immuno-modulator in patients with advanced colorectal cancer.

Preclinical studies have established that the polysaccharide fractions of Ganoderma lucidum have potential antitumor activity. Recent clinical studies have demonstrated that G. lucidum polysaccharides enhance host immune functions [e.g., enhanced natural killer (NK) cell activity] in patients with advanced solid tumors, although an objective response was not observed. This open-label study aimed to evaluate the effects of water-soluble G. lucidum polysaccharides (Ganopoly, Encore International Corp., Auckland, New Zealand) on immune functions in patients with advanced lung cancer. Thirty-six patients were enrolled and treated with 5.4 g/day Ganopoly for 12 weeks. In the 30 cancer patients who completed the trial, treatment with Ganopoly did not significantly alter the mean mitogenic reactivity to phytohemagglutinin, mean counts of CD3, CD4, CD8, and CD56, mean plasma concentrations of interleukin (IL)-2, IL-6, and interferon (IFN)-gamma, or NK activity in the patients, but the results were significantly variable. However, some cancer patients demonstrated markedly modulated immune functions. The changes in IL-1 were correlated with those for IL-6, IFN-gamma, CD3, CD8, and NK activity (P < .05), and IL-2 changes were correlated with those for IL-6, CD8, and NK activity. The results suggest that subgroups of cancer patients might be responsive to Ganopoly in combination with chemotherapy/radiotherapy. Further studies are needed to explore the efficacy and safety of Ganopoly used alone or in combination with chemotherapy/radiotherapy in lung cancer patients.

Effects of water-soluble Ganoderma lucidum polysaccharides on the immune functions of patients with advanced lung cancer.

Ganoderma lucidum has been widely used to treat various diseases, including cancer, diabetes, and neurasthenia in many Asian countries. This randomized, double-blind, placebo-controlled parallel study aimed to investigate the efficacy and safety of a polysaccharide extract of G. lucidum (Ganopoly) in Chinese patients with neurasthenia. One hundred thirty-two patients with neurasthenia according to the diagnosis criteria of the 10th International Classification of Diseases were included in this study. Written consents were obtained from the patients, and the study was conducted in accordance with Good Clinical Practice guidelines. Patients were randomized to receive Ganopoly or placebo orally at 1,800 mg three times a day for 8 weeks. Efficacy assessments comprised the Clinical Global Impression (CGI) improvement of severity scale and the Visual Analogues Scales for the sense of fatigue and well-being. In 123 assessable patients in two treatment groups at the end of the study, Ganopoly treatment for 8 weeks resulted in significantly lower scores after 8 weeks in the CGI severity score and sense of fatigue, with a respective reduction of 15.5% and 28.3% from baseline, whereas the reductions in the placebo group were 4.9% and 20.1%, respectively. The score at day 56 in the sense of well-being increased from baseline to 38.7% in the Ganopoly group compared with 29.7% in the placebo group. The distribution of the five possible outcomes from very much improved to minimally worse was significantly different (X (2) = 10.55; df = 4; P = .0322) after treatment with Ganopoly or placebo. There was a percentage of 51.6% (32 of 62) in the Ganopoly group rated as more than minimally improved compared with 24.6% (15 of 61) in the placebo group (X (2) = 9.51; df = 1; P = .002). Ganopoly was well tolerated in the study patients. These findings indicated that Ganopoly was significantly superior to placebo with respect to the clinical improvement of symptoms in neurasthenia.

A randomized, double-blind and placebo-controlled study of a Ganoderma lucidum polysaccharide extract in neurasthenia.

Adoption of information and digital technologies for sustainable smart manufacturing systems for industry 4.0 in small, medium, and micro enterprises (SMMEs)

Algorithm for detecting anomalous hosts based on group activity evolution

A Novel Model for Antigen Delivery Carrier: Construction and Identification of Cytolysin A(-EGFP) Fusion Protein-integrated Recombinant Outer Membrane Vesicles

Dynamic changes in volatile components in sweet flour paste during the insulation fermentation

Generating twisted Gaussian Schell-model beam with coherent-mode superposition

B cells biology in systemic lupus erythematosus—from bench to bedside

Decreased expression of PTEN regulated by miR-7 contributes to B cell hyperresponsiveness and disturbed B cell homeostasis in SLE. “miR”roring Lupus Control Decreased expression of the B cell signaling inhibitor PTEN may contribute to lupus pathology. Wu et al. found that microRNA (miR)–mediated regulation of PTEN is altered in patients with the autoimmune disease systemic lupus erythematosus (SLE). Patients with SLE have hyperactivated B cells, which results in the production of autoantibodies. The authors found that decreased expression of PTEN in B cells from SLE patients contributes to this B cell hyperactivation. What’s more, they found that PTEN expression in these cells was regulated by miRs, and that blocking miR-7 could restore PTEN expression and function to that of healthy controls. These data support exploring miR-7 and PTEN as therapeutic targets for SLE. PTEN regulates normal signaling through the B cell receptor (BCR). In systemic lupus erythematosus (SLE), enhanced BCR signaling contributes to increased B cell activity, but the role of PTEN in human SLE has remained unclear. We performed fluorescence-activated cell sorting analysis in B cells from SLE patients and found that all SLE B cell subsets, except for memory B cells, showed decreased expression of PTEN compared with B cells from healthy controls. Moreover, the level of PTEN expression was inversely correlated with disease activity. We then explored the mechanisms governing PTEN regulation in SLE B cells. Notably, in normal but not SLE B cells, interleukin-21 (IL-21) induced PTEN expression and suppressed Akt phosphorylation induced by anti–immunoglobulin M and CD40L stimulation. However, this deficit was not primarily at the signaling or the transcriptional level, because IL-21–induced STAT3 (signal transducer and activator of transcription 3) phosphorylation was intact and IL-21 up-regulated PTEN mRNA in SLE B cells. Therefore, we examined the expression of candidate microRNAs (miRs) that could regulate PTEN: SLE B cells were found to express increased levels of miR-7, miR-21, and miR-22. These miRs down-regulated the expression of PTEN, and IL-21 stimulation increased the expression of miR-7 and miR-22 in both normal and SLE B cells. Indeed, a miR-7 antagomir corrected PTEN-related abnormalities in SLE B cells in a manner dependent on PTEN. Therefore, defective miR-7 regulation of PTEN contributes to B cell hyperresponsiveness in SLE and could be a new target of therapeutic intervention.

Defective PTEN regulation contributes to B cell hyperresponsiveness in systemic lupus erythematosus

Exploring the mechanism of Guizhi decoction’s “Jun-Chen-Zuo-Shi” in treating plant nervous disorders based on weighted network pharmacology and molecular docking techniques

Species within the genus Populus are among the fastest growing trees in regions with a temperate climate. Not only are they an integral component of ecosystems, but they are also grown commercially for fuel, fiber, and forest products in rural areas of the world. In the late 1970s, they were designated as a bioenergy crop by the U.S. Department of Energy, as a result of research following the oil embargo. Populus species also serve as model trees for plant molecular biology research. In this article, we will review recent progress in the genetic improvement of Populus, considering both classical breeding and genetic engineering for bioenergy, as well as in using transgenics to elucidate gene functionality. A perspective for future improvement of Populus via functional genomics will also be presented.

Transgenic Populus Trees for Forest Products, Bioenergy, and Functional Genomics

The function of the evergreen broad-leaved forest floor is studied. The results are as followes: The forest floor obstructed the litterfall arrived to ground. The litter of weed of floor and the forest litterfall established a very complex layer, which reduced near-ground light intensity and made it below seedling light compesation point, the complex layer obstructed soil evaporation, made near-graund over shady and wet, reduced keep ratio of the seeds of the tree dominant species and survial ratio of the forest regeneration seedling. The natural regeneration seedling of the forest come from herb gip mainly.

The study on function of evergreen broad-leaved forest floor--Tiantong, Zhejiang Province as an example

Remimazolam is a new ultra‐short‐acting benzodiazepine used to induce and maintain anesthesia and procedural sedation. Its compound structure is similar to midazolam's. Midazolam metabolism might be affected by vitamin D receptor (VDR), cytochrome P450 3A, and cytochrome P450 oxidoreductase genetic polymorphisms. This study investigated the effects of VDR, cytochrome P450 3A, and cytochrome P450 oxidoreductase genetic polymorphisms on the pharmacokinetics of remimazolam in healthy Chinese volunteers after a single intravenous injection of remimazolam besylate. Blood samples were collected from subjects (n = 62) at scheduled time intervals before and after injection. High‐performance liquid chromatography–tandem mass spectrometry was used to quantify plasma remimazolam and RF7054 (its inactive carboxylic acid metabolite) concentrations. The relationship between plasma remimazolam concentration, pharmacokinetic parameters, and polymorphic alleles was assessed for each subject. The rs4516035 allele affected the elimination half‐life of RF7054 (P = .043), while the rs1544410 allele affected the dose‐normalized maximum observed plasma concentration (Cmax/D) of remimazolam (P = .025) in 46 volunteers. Results showed that VDR genetic polymorphisms might affect the pharmacokinetics of remimazolam in the Chinese population.

Effects of Vitamin D Receptor, Cytochrome P450 3A, and Cytochrome P450 Oxidoreductase Genetic Polymorphisms on the Pharmacokinetics of Remimazolam in Healthy Chinese Volunteers

Background Gilteritinib, a novel, potent FLT3/AXL inhibitor, was recently approved in Japan and USA for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation. Purpose and Methods In this study, we aimed to develop and validate a sensitive and simple ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the quantification of gilteritinib in plasma and to investigate whether CYP3A4 inhibitors (fluconazole and itraconazole) could influence the pharmacokinetics of gilteritinib from a drug–drug interaction study in rats. Sample preparation was done by a simple protein crash with acetonitrile containing the internal standard (IS) pirfenidone, followed by UPLC-MS/MS quantification. Results The assay was successfully validated in a 1–500 ng/mL calibration range for gilteritinib, where the lower limit of quantification (LLOQ) was set at 1 ng/mL. The intra-day and inter-day precisions for gilteritinib were less than 10.6%, and the accuracies were in the range of −14.5% to 11.1%. Recovery and matrix effect of the analyte and IS were acceptable, and the analyte was stable during the assay and storage in plasma samples. The validated UPLC-MS/MS method was successfully applied to a drug–drug interaction study between gilteritinib and CYP3A4 inhibitors (fluconazole and itraconazole) in rats. Itraconazole significantly increased the exposure of gilteritinib, and affected the pharmacokinetics of gilteritinib in rats, not fluconazole. Conclusion A further clinical study should be conducted to investigate the effect of itraconazole on the metabolism of gilteritinib in subjects.

An LC-MS/MS Bioanalytical Assay for the Determination of Gilteritinib in Rat Plasma and Application to a Drug–Drug Interaction Study

Simultaneous Determination of Rivaroxaban and Enalapril in Rat Plasma by UPLC–MS/MS and Its Application to A Pharmacokinetic Interaction Study

Safety, pharmacokinetic and pharmacodynamic properties of single ascending dose and continuous infusion of remimazolam besylate in healthy Chinese volunteers

Apocynin, a potent inhibitor of NADPH-oxidase, was widely studied for activities in diseases such as inflammation-mediated disorders, asthma and cardiovascular diseases. In our recent study, a novel nitrone derivative of apocynin, AN-1, demonstrated potent inhibition to oxidative injury and to high expression of gp91phox subunit of NADPH-oxidase induced by tert-butyl hydroperoxide (t-BHP) in RAW 264.7 macrophage cells, and displayed promising preclinical protective effect against lipopolysaccharide (LPS)-induced acute lung injury in rats. In this work, the pharmacokinetic behaviors of AN-1 in Sprague-Dawley rats with single intravenous and intragastric doses were investigated for further development. Furthermore, apocynin’s pharmacokinetics remain lacking, even though its pharmacological action has been extensively evaluated. The pharmacokinetics of parent apocynin were also comparatively characterized. A simple HPLC method was developed and validated to determine both AN-1 and apocynin in rat plasma. The chromatographic separation was achieved on an Agilent HC-C18 column (250 mm×4.6 mm, 5 µm) at an isocratic flow rate of 1.0 mL/min, with the mobile phase of methanol and water (53∶47, v/v) and the UV detection set at 279 nm. Good linearity was established over the concentration range of 0.1–500 µg/mL for AN-1 and 0.2–100 µg/mL for apocynin. The absolute recovery, precision and accuracy were satisfactory. Compared with the parent compound apocynin, AN-1 yielded a much longer T1/2 (AN-1 179.8 min, apocynin 6.1 min) and higher AUC0–t (AN-1 61.89 mmol/L·min, apocynin 2.49 mmol/L·min) after equimolar intravenous dosing (0.302 mmol/kg). The absolute bioavailability of oral AN-1 was 78%, but that of apocynin was only 2.8%. The significant improvement of pharmacokinetic behavior might be accounted for the effective pharmacodynamic results we documented for the novel nitrone derivative AN-1.

Improvement of Pharmacokinetics Behavior of Apocynin by Nitrone Derivatization: Comparative Pharmacokinetics of Nitrone-Apocynin and its Parent Apocynin in Rats

Premature senescence in cotton has been occurring at increasing frequencies and causes serious reduction in yield and quality. In this study, the relationship between potassium (K) deficiency and Alternaria alternata infection, causing leaf senescence in cotton, was investigated. All experiments were performed under controlled laboratory conditions, in which cotton seedlings were treated with various concentration of K for 10 days, followed by inoculating the third and fourth true leaves with A. alternata. Subsequently, both physiological indices reflecting leaf senescence and disease index were measured. The results showed that cotton leaves treated with K deficiency were more susceptible to A. alternata in two aspects. First, the appearance of disease lesions were emerged 1-4 days earlier in cotton leaves treated with various K deficiencies compared to control. Secondly, the disease lesions developed continuously and expanded in treated leaves showing more disease lesions, the size of which increased with decreasing concentrations of K in a dose-dependent manner. In addition, the symptoms of cotton leaf senescence were pronounced in these infected leaves. Acceleration of leaf senescence also reflected in various physiological indices such as increase in electrolyte leakage and MDA content, significant decrease in chlorophyll content and reduction of Fv/Fm ratio. These results provide evidence that the combination of K deficiency and A. alternata infection accelerates cotton leaf senescence. Understanding the key factors causing and promoting cotton leaf senescence should greatly help the management of cotton crops by preventing premature leaf senescence.

Intensified Alternaria spot disease under potassium deficiency conditions results in acceleration of cotton (Gossypium hirsutum L.) leaf senescence

For stability analysis we only need estimate the bound of |∂w<sup>k</sup><sub>0</sub>/∂z<sub>k</sub> x<sub>q</sub>| such as [19], however, for stabilization, the new problem is to design the controller and determine the bound of |∂w<sup>k</sup><sub>0</sub>/∂z<sub>k</sub> u<sub>v</sub>| besides |∂w<sup>k</sup><sub>0</sub>/∂z<sub>k</sub> x<sub>q</sub>|. To solve this problem, we design the bounded non-parallel distributed compensation law, then, some linear matrices inequalities are obtained to ensure that the trajectories starting from a local region will be driven to the origin as time goes by. In the end, an example shows the effectiveness of our conclusions.

Local stabilization for continuous-time Takagi-sugeno fuzzy model: A bounded control method

Liang Shuming’s thoughts are affected by the life philosophy of Henri Bergson.Henri Bergson’s life philosophies pay attention to the experience of subject intuition and regard that intuition is superior to rationality.He makes mystery of human life phenomenon.He developed Henri Bergson’s intuitionism.He thought intuition is the only path to connect the relationship between the outer world and themselves.Especially,he explains the Confucius’ benevolence by intuition.It laid a solid foundation for modern Neo-Confucianism.

In order to clarify the influence of plant growth regulators GA3,IAA and 6-BA on seed germination of snake melon(Cucumis melo L.var.flexuosus Naud),seeds of snake melon were treated with GA3(40,120,200,280mg/L),IAA(0.5,5,50,100mg/L) and 6-BA(0.1,0.5,2.5,12.5mg/L),and the germination potential,germination rate,root length and fresh weight per plant were investigated.The results showed that among the concentrations,120mg/L of GA3 increased the seed germination rate of snake melon,while 200mg/L of GA3 improved both the seed germination potential and germination rate while increasing the seedling root length;0.5mg/L of IAA could improve the seed germination potential of snake melon,and 5mg/L and 50mg/L of IAA increased seed germination potential while improving the germination rate;0.1~12.5mg/L of 6-BA improved seed germination potential of snake melon.However,GA3,IAA and 6-BA did not have an obvious influence on the fresh weight per plant of snake melon.To sum up,200mg/L of GA3 was the best one within the whole study and improved both the seed germination potential and germination rate of snake melon,and increased the seeding root length.Also 5~50mg/L of IAA and 2.5mg/L and below the concentration of 6-BA could increase the seed germination rate of snake melon.

Effects of Different Concentrations of GA3,IAA and 6-BA on Seed Germination of Snake Melon

The key of the problems of China lies in the CPC.The future is in the hand of whom grasp the youth.Guiding the college students to set up the Party conception is related to the future and destiny of the Party,the country and the nation.At present,some college students don't speak highly of the Party,lack overall and deep understanding of the Party' progressiveness,the enthusiasm to join the Party decreases and the Party has not enough influence and appeal to them.To this,we should seriously find the reasons and take effective measures to increase the impact and appeal to the college students,strengthen the conceptual education,encourage the college students to set up healthy and progressive morality, and arm the mind with scientific development view so as to construct the scientific and strong spiritual pillar and consolidate the Party's leadership.

The Causes and Countermeasures of the College Students' Fading Conception for the Party

The researching-typed management has been increasingly showing its great significance to the cultivation of talents in private-capital sponsored universities.However,it also puts forward great challenges for the student-supervisors in their work.Student-supervisors in colleges and universities are supposed to be equipped with advanced educational concepts,researching and exploring abilities,capacities of creating context,abilities of guiding and discovering,practical researching abilities and abilities of making scientific evaluations.It is on such bases that the researching-typed student-supervisors can be qualified and are able to cultivate university students who are equipped innovative spirit and ability.

Qualities that a Researching-typed Student-Supervisor is Supposed to be Equipped with in Private-capital Sponsored Schools of Higher Education

Based on μC/OS-II operating system,by the use of ARM program, the block diagram of the system and the module are designed.The hardware circuit is designed by Proteus and the software system is designed under the ADS environment.The design mainly includes writing driver software for the LCD module,writing function modules such as the game initialization,the racket migration,and the ball path.Then several tasks are performed at the same time with the operating system.The system carries on the simulation debugging in the Proteus software platform,and the game machine design is completed.

Embedded Handheld Game Machine Design Based on μC/OS-II Operating System

Incoherent radiation of amplifying random media is investigated using Monte Carlo simulation and the characteristics of random laser are observed.The entire emission spectra of random media become narrow abruptly when pumping energies exceed certain threshold values,and when the pumping energies further increase,distinct sharp peaks emerge on spectrum background.The intensity of a certain spatial point within the scattering media is contributed from emissions of many frequencies.And the intensity of single frequency of the entire spectrum is contributed from emissions with wide spatial and angle ranges.It has been pointed out that the incoherent radiation of amplifying random media is essentially different from amplified spontaneous emission without any feedback as well as conventional resonant-feedback laser.The explanation on distinct sharp peaks is that rare photons have experienced rather more scattering events and longer paths in amplifying random media,and these photons accumulate more gain.

Objective To explore the approaches of the early discovery of suicide of university students.Methods Through the review investigation of our college's education of psychological health and crisis intervention,some operable approaches have been summed up.Results The authors suggest that the establishment of student backbone group of psychological health should be strengthened and the popularization of the knowledge of psychological health be for all the students on campus,including the revealing their physiological,psychological and social causes of formation,and the investigation of the attitude toward suicide,to discover the students with suicide intention as early as possible.Conclusion The approaches to the early discovery of suicide of university students exist in several dimensions,i.e.the establishment of student backbone group of psychological health,the popularization of the knowledge of psychological health,and the investigation of students' attitude toward suicide,etc.

Approaches to the Early Discovery of Suicide of University Students

The mode-area scaling properties of helical-core optical fibres are numerically studied and the limit of core size for achievable single-mode operation is explored. By appropriate design, helical-core fibres can operate in a single mode with possible scaling up to 300 μm in core diameter with numerical aperture 0.1.

Tris-thenoyltrifluroacetonate of Nd 3+ has been prepared and dissolved in DMF solation with very high concentration, and the contained hydrogen has not been substituted by deuterium. The absorption spectrum, emission spectrum, and fluorescence lifetime of the solution were measured. Very obvious characteristic fluorescence peaks were observed at 898 and 1058 nm. Based on Judd-Ofelt theory, three intensity parameters were obtained: Ω 2 =4.9×10 -20 cm 2 , Ω 4 =5.1×10 -20 cm 2 and Ω 6 =2.5×10 -20 cm 2 . Line strengths S cal , oscillator strengths f cal , radiative transition probabilities A ed , radiative lifetimes τ r and branch ratios β were calculated too. The measured lifetime τ of 1058 nm peak is 460 μs, and that of 898 nm 505 μs. Comparison between theoretically computed radiative lifetime τ r (682 μs) and the measured lifetime indicates that the non-radiative transition probability of the solution is very low and the fluorescence quantum efficiency very high. High values of three intensity parameters prove the high asymmetric surroundings of Nd 3+ , which is important for Nd 3+ to absorb the excitation energy. Spectropic quality factor Ω 4 / Ω 6 >1 makes radiation at 898 nm stronger than at 1058 nm.

Spectral properties of hydrogen-containing organic solution of neodymium chelate

In this paper, a refractive index profile design enabling us to obtain a flat modal field around the fibre centre is investigated. The theoretical approach for designing such multilayer large flattened mode (LFM) optical fibres is presented. A comparison is made between the properties of a three-layer LFM structure and a standard step-index profile with the same core size. The obtained results indicate that the effective area of the LFM fibre is about twice as large as that of the standard step-index fibre, but the LFM fibre has less effective ability to filter out the higher order modes than the standard step-index fibre with the same bending radius.

Design and analysis of a kind of large flattened mode optical fibre

Using the Huygens-Fresnel diffraction integral and the Fourier transform,the propagation representations of pulses with Hermite-Gaussian transverse modes passing through a hard-edged aperture are derived.Influences of the bandwidth on the transverse intensity distributions are analyzed in detail from numerical calculations.It is found that lots of intensity spikes emerge and the near field intensities are non-uniformity when the pulses pass through the aperture.However,when the bandwidth increases,the number and the amplitude of the spikes are reduced and thus the beam uniformity is improved,the intensity spike does not appear in the far field,and also the beam width decreases in the far field.Therefore,the smoothing and narrowing effects can be brought forth by increasing the bandwidth.In addition,it is found from the numerical results that the effects are similar in the pulses with Hermite-Gaussian transverse modes of mode indices 1 and 2.

Influence of the Bandwidth on Intensity Uniformity in Pulses with Hermite-Gaussian Transverse Modes

The geography information system of traffic (GIS-T) is the foundation of urban intelligent transportation management. The system structure adopts the method of combined C/S and B/S. The system mainly provides the traffic geography data source and data management, basic geography database, traffic theme database and property database, layers showing and information query, road information management, traffic information issue, analysis of traffic geography space data and query data-out and so on. In accordance with accidents analysis model(black spot, segment distinguish), the urban road traffic accidents information system of GIS-T the GIS system integrated technology is adopted. It has such functions as the traffic accidents information query, statistic and analysis based on map, etc.

Geography information system of urban traffic management design and application

In this paper, it has been studied that the hardened zones of ductile iron QT800-2 are processed through laser shock again, after laser quenched. The results indicate that properties of the zone treated through compound method is improved, compared to that through only laser quenched. The hardness increases by 18% and the wearability enhances about 100%. Especially, the residual stress of the interior of the material was changed into compressive stress.

Study on the Experiment of Laser Quenched+Shocked Processing Ductile Iron QT800-2

The surface of the workpiece is processed by laser honing to f orm lineary extending lubricant channels and grooves with predetermined width,de pth,angle,shape and gap. The said channels and grooves can be well-matched with the needs of lubrication.The advantages of laser honing are validated through s ome performance experiment that shows this technigue not only remarkably improve s t he property of wear-resistance of the cylinder and its life span, but also larg ely dece ases HC ejection of the internal combustion engine, its consumption of fuel oil and lubricant, the pollution of catalytic apparatus and the cost of piston. And then the major processing parameters of laser honing are studied and the mechani sm of the laser honing are investigated and analyzed qualitatively.

The Application of Laser Honing in the Treatment of Cylinder Surface

This article integrates intelligent 3D simulation technology with an online customized clothing system to increase the impact of customized clothing design. The user uses a 3D scanner to scan his own body and acquire 3D body data, which include information of the head, chest, upper limbs, lower limbs, hands, and feet. Furthermore, this work enhances intelligent tracking and recognition technology, enhances the impact of human body parameter collection, and combines the enhanced algorithm to create a personalised clothing design system based on intelligent 3D simulation technology. Through experimental research, it can be seen that the customized clothing design system based on intelligent 3D simulation technology proposed in this paper has good effects and can effectively improve the service quality of online customized clothing.

Fuzzy Applications in Custom Clothing Design Technology Based on Intelligent 3D Simulation Technology

Immunological laboratory as an important applied subject in the field of medicine, in the process of the change from exam-oriented education to quality-oriented education in China, the course also follows the pace of The Times, constantly optimize the teaching content and teaching form. How to explore and apply quality education scientifically and effectively in immunology laboratory teaching has become one of the most important contents in current education field. This paper analyzes the current situation of quality education in immunology laboratory teaching, and makes a strategic study and analysis on carrying out characteristic teaching of immunology laboratory and comprehensively improving academic quality. 1. Overview of immunological laboratory teaching Settings Quality-oriented education, as a kind of sustainable development thought focusing on the whole, is gradually of great value and significance in China's medical education. As shown in figure 1, in terms of compiling the textbook and changing the mode of the course, relevant scholars have made it the main goal of talent training at the present stage to integrate immunological examination teaching and quality-oriented teaching with more scientific teaching methods and contents. In the process of immunology laboratory teaching, professional courses and professional knowledge are adopted to change the traditional focus on the improvement of students' professional skills to the cultivation of students' innovative qualities, so as to promote the development of students into compound talents with natural science literacy and humanistic literacy. Then, in future practical work, I can flexibly use my knowledge to solve difficult diseases that may be encountered in clinical medicine. It can be seen that immunology teaching has the ability to promote communication and collaboration with others in quality-oriented teaching, and continuously tests future medical workers through innovative spirit [1]. Table 1. Application of quality education in immunology curriculum Experimental level Experimental target Representative course define Basic biological experiment Train students' most basic biological experimental skills Botanical experiments, zoological experiments, microbial experiments, biochemical experiments, etc. These experiments are compulsory for students in biology, and they will The experimental skill is also the professional quality that the students of the biology specialty must possess Exploring the Comprehensive Synthesis experiment Cultivate students' thinking and ability of Scientific Inquiry, Analysis and The ability to solve problems, the ability to design experiments in a preliminary way. Experiments,biochemical techniques,epidemic free experiments,genetic engineering,enzyme engineering, etc. The emergence of this part of the content is due to the fact that the development of other science disciplines has more and more influence on the development of basic research and technology of life science in recent years. The completion of these contents needs to be based on the first two levels. 2019 Asia-Pacific Conference on Advance in Education, Learning and Teaching (ACAELT 2019) Copyright © (2019) Francis Academic Press, UK DOI: 10.25236/acaelt.2019.070 343 2. Improve the teaching effect through multimedia teaching Multimedia in classroom teaching, has a clear, prominent and concise focus and other characteristics, can help the classroom atmosphere more vivid and harmonious. Multimedia teaching can better help students understand and internalize knowledge points, and while ensuring the integrity and systematicness of the teaching content, it will naturally play the role of finishing the finishing line through English. Then in the process of language balance, gradually improve the teaching effect. For example, in the process of explaining the activation of T lymphocytes, bilingual expressions can be used to help students grasp and strengthen the English expressions of professional terms such as major histocompatibility, cell receptor(TCR), interleukin(IL), molecules (MHC) through multimedia slide presentation [2]. At the same time, in the process of learning T lymphocytes, as shown in figure 2 and figure 3, the PPT courseware should help and guide students to carry out the conversion between English and Chinese through concise words, and strengthen their understanding of the activation process between T lymphocytes and B lymphocytes. Moreover, the simplest cell relationship can be listed in the PPT through multimedia slide show, as shown in figure 4, which can help students understand the antigen presentation ability between lymphocytes more intuitively, and lay a foundation for the subsequent learning of cell immunity consent through the extended related knowledge points. Thus, multimedia teaching can help students to strengthen their understanding and summary in the process of learning knowledge points[3]. Fig. 1 T Lymphocyte Learning Courseware Fig. 2 display of Lymphocyte Transformation Courseware

Research on the Strategy of carrying out quality Education in Immunology Test Teaching

An internet cored society has formed quietly into the development of information technology. Since the gradually increased scale of institutions of higher education, problems of student affairs management like too many students and inefficient number of counselors have stood out. Under such a new circumstance, it is undoubted a pioneering attempt to change the previous mode of management, and build a Blog based Project of Student Affairs Management Platform for Counselors in Colleges and Universities. Through introducing internet technology into student affairs management, combining counselor’s management with ideas such as sharing, creativeness, personality and communication is shown by the current populating Blog. On one hand, this platform can effectively manage to add information. On the other hand, it can help realizing the instant communication between counselors and students thus making the work of students’ mental health and ideological and political education more diverse. Besides, both the theory and designing principles have been got after the questionnaire survey and feasibility study of this attempt.

Blog-Based Project of Student Affairs Management Platform for Counselors in Colleges and Universities

With the rapid development of Internet and information technology, the speed of knowledge update makes lifelong education inevitable. Demands for education no longer stay at a fixed time and location, which provides a prerequisite for the germination of mobile education. People's thirst for latest knowledge lead to the emergence of an education model that enables people to learn anywhere and anytime, namely, mobile education emerges. From the basic concept of mobile education and the characteristics of mobile education, this paper expounds the basic structure of mobile education system including Internet, teaching server, mobile server and mobile terminal, elaborating on the function of mobile education and the application mode of mobile education in China amid the current research situation of mobile education at home and abroad and the theoretical basis of mobile education. With the continuous promotion of big data, cloud computing and mobile Internet and the popularization of mobile terminals, mobile education has developed rapidly, bringing infinite vitality to the growth of education and serving as a strong driver for modern education.

A Study on Educational Reform in the Context of Modern Educational Technology — — Mobile Education

Health statistics is one of the key public courses in the medical universities and colleges, and the teaching is always important and difficult in the teaching process for the undergraduate and graduate students. With the emergence and development of internet, teachers can get abundant teaching resources from the internet so as to enrich the teaching contents and methods. In this article, we took a look of the statistics teaching resources in the internet in order to provide references for statistics teachers and to promote the improvement of the teaching quality of statistics. 
 
Key words: 
Health statistics teaching; Teaching quality; Internet

Improving teaching quality of health statistics courses by internet resources

In recent years, much research has been devoted to the analysis of 128 bit architectures; on the other hand, few have evaluated the construction of wide-area networks. In fact, few cyberneticists would disagree with the understanding of IPv6. This is an important point to understand. we describe an autonomous tool for developing compilers, which we call ADZ.

Decoupling Information Retrieval Systems from Internet QoS in SMPs

Much research has been done on tagged architectures but most of it took place over 10 years ago and did not provide quantitative evidence. In this paper, we propose a tagged MIPS architecture and employ SimpleScalar simulator to make a quantitative analysis on the performance impact of tagged architecture. With SPEC 95 benchmarks we evaluate the performance loss in terms of CPU execution time and L2 cache misses. Since the tagged machine uses more registers than nontagged ones, we also measure the performance after reserving about half of registers for tags. The experiment result shows that 1) a major bottleneck to implement a high performance tagged machine is tagged penalty; 2) there is only little performance loss in terms of L2 cache misses; 3) reserving 12 out of 32 registers does not result a great performance decrease. We believe the insights from our analysis are helpful for guiding the future high performance tagged architecture design.

In the present study, mechanical and physical properties were studied about the composite which was hot pressed by different kinds of modified phenol resin, then, one modified way was decided. Orthogonal experiment and single factor experiment, as well as the effect of mixture ratio on the composite properties, were designed to study systematically hot-pressing parameters. This paper also discusses the mechanism of interfacial bonding between aluminum and PF by analyzing the surface free energy, FTIR, SEM and XPS. The findings provide theoretical and technical support for the aluminum/wood decorative board hot-pressing with modified PF.

Research on Preparation Technology of Recycled Building Decoration Materials

At the height of the 2007-2009 subprime crisis, the Federal Deposit Insurance Corporation (FDIC) has shown, once again, latitude and laxity in resolving and closing insolvent institutions. Rather than automatically close insolvent systemically important financial institutions (SIFI), the FDIC revived them by infusing funds into them. Ronn and Verma (1986) call the tolerance level below which a bank closure is triggered the regulatory policy parameter. We derive a model in which we make this policy parameter stochastic and bank-specific to infer the stock market view of the regulatory capital forbearance value. Our two-factor structural model, in which the regulatory policy parameter is modeled as an exponential of a negative Cox-Ingersoll-Ross (CIR) process, yields a closed-form solution for banks’ equity. For over 700 U.S. listed banks from 1990 to 2012, we link the model-derived forbearance fraction in equity capital to bank specific risk variables and business cycles. This forbearance fraction in capital represents 17%, on average, of the market valuation of bank equity and can go as high as 100%. We find that the market, naturally, expects banks to receive more capital forbearance in recessions. The market expectations of bank regulatory forbearance are also congruent with banks’ intrinsic owner-contributed capital, idiosyncratic risk, systemic risk, and charter value.

How Does the Market View Bank Regulatory Capital Forbearance Policies?∗

Investigation on wild economic plant resources in Duqiaoyougu scenic spot.

[Objective] To study the 36 characters of 9 species in the genus Paris L. from Guangxi Province by using numerical taxonomy. [Method] The principal components analysis (PCA) and UPGMA clustering analysis were performed to analyze the Euclidean distance. [Result] 9 species in Paris L. from Guangxi Province were divided clearly into four character groups. Paris polyphylla Smith and its variants were suggested to be treated as a new group, except for Paris polyphylla var. chinensis (Franch.) Hara, regarded as a variant in classical taxonomy. [Conclusion] It is significant to apply numerical taxonomy to solve the classification problems in the genus Paris L. or classification problems among species in Paris L. By combining numerical taxonomy, plant morphology and palynology, this study could draw a conclusion similar to classical taxonomy.

Study on the numerical taxonomy of the genus Paris L. from Guangxi Province.

THE AFFECT OF PENEHYCLIDINE ON THE POSTOPERATIVE COGNITION FUNCTION OF SENILE PATIENTS

Chirita luzhaiensis Yan Liu Y.S.Huang W.B.Xu,a new species of Gesneriaceae from limestone areas in Guangxi,China,is described and illustrated.The new species is similar to Chirita gueilinensis W.T.Wang,but it differs in its leaf-surface villous and pubescent adaxilly,athers glabrous,filaments geniculate near base,staminodes 3,glabrous,flowering period from December to January of the following year.It was only found in two karst caves from Zhongdu Town of Luzhai County,Guangxi,China.

Chirita luzhaiensis,A New Species of Gesneriaceae from Limestone Areas in Guangxi,China

Experiments were conducted on effect of different concentrations of NAA and different soaking time of Lonicera japonica cuttings on their survival rate and rooting. The results showed that any concentration of NAA had great effect on survival rate and rooting of cuttings, but soaking time had no influence on them. Comprehensive analysis demonstrated that 40mg/L NAA had the best effect with 1 hour for soaking.

Objective:To investigate the nursing effect and experiences on severe cholangitis.Method: 50 cases with severe cholangitis in our hospital from January in 2007 to January in 2009 were analyzed respectively.Result: All the patients received the operation treatment.40 cases were cured,and the recovery rate was 80%.7 cases were better,3 cases were death,and the death rate was 6%.There were 1 case died of infectious shock,1 case died of hepatic failure,1 case died of MOF.There were 15 cases(30%)with complication,and there were 5 cases with postoperative infection,2 cases with disruption of wound,2 cases with peritoneal cavity infection,2 cases with pulmonary infection,2 cases with biliary tract hemorrhage,1 case with MOF and 1 case with deep veins of lower limb venous embolism.Conclusion: The systemic nursing plays an important role in the recovery from illness on older with severe cholangitis,so it should be think highly.

A qualitative analysis is made on the energy saving for VFD on EG pump in a series/chiller upstream ITS system,points out that its actual effect is not as good as VFD on a chilled water pump in a conventional chilled water system with more complicated control.EG pump without VFD will run well if the pressure drops of all equipments in the EG systems are considered in the design stage.

Qualitative Analysis for VFD on EG Pump in a Series/chiller Upstream ITS System

From the methanol extract of the whole plant of Notoseris triflora Shih, seventeen compounds were isolated by column chromatography. Their structures were identified as dihydrosantamarine (1), sonchuside A (2), annuolides D (3), ixerisoside D (4), 11 β ,13 dihydro hyporadiolide 8 0 (2 methylacrylate)(5), hyporadiolide 8 0 (2 methylacrylate)(6), hypochoerolide G (7), hypochoerolide E (8), 11 β ,13 dihydrolactucin (9), cichorioside B (10), jacquilenin(11), austricin(12), crepidiaside A (13), crepidiaside B (14), 3,5 dimethoxyl 4 hydroxy benzaldehyde (15), β sitosterol (16) and daucosterol (17), respectively. All the compounds above were isolated from this plant for the first time. Fig 1,Tab 1,Ref 14

Monitoring human activities in Jiaozi Mountain nature reserve based on remote sensing during 1992-2018.

Monochamus alternatus Hope is the main intermediary insect of Bursaphelenchus xylophilus.According to the main ecological factors of average temperature and above 10.8 ℃ accumulated temperature,the spatial distribution of M.alternatus was modeled in order to prevent the occurrence of B.xylophilus.A method was proposed to simulate annual average temperature and above 10.8 ℃ accumulated temperature by using statistical data from conventional weather stations in Yunnan province and environment variable factors based on GIS spatial analysis and modeling.The result was presented in 90 m × 90 m spatial resolution to realize the computation,spatial pattern simulation and visualization of the adaptability of M.alternatus.The results shows that there are wide region suitable for M.alternatus besides the snow mountain in north Yunnan with no suitability,and high mountains in northwest and northeast Yunnan with low suitability.Moreover,the results are definitely related to ecological location.Since the results are presented in a quantitative,refine and visual way,so it is easy to obtain the adaptability of M.alternatus in grid cell,which can provide data for warning,risking assessment,and decision-making in disease prevention.

Spatial Simulation of the Adaptability of Monochamus alternatus Hope in Yunnan Province

Taking Larix gmelini as an example,the consociation equation set model method was used in creating duality standing tree volume model,the variance of constructing model and estimation precondition could be effectively solved to duality standing tree volume model.The usual nonlinear estimation and two steps estimations method were used to estimate the consociation equation set model method of duality standing tree volume model.As a result,the model could be estimated by two methods;two steps estimation method could reduce system error,and attain error limit than universal model,two steps estimation method was better than usual nonlinear estimation.

Study on consociation equation set model method to establish duality standing tree volume model.

Seasonal differences in the spatial patterns of wildfire drivers and susceptibility in the southwest mountains of China.

Automated geometric precise correction of medium remote sensing images based on ASTER global digital elevation model

Seasonal Differences in the Spatial Patterns of Wildfire Susceptibility and Drivers in Southwest Mountains, China

Identification of forest burn severity is essential for fire assessments and a necessary procedure in modern forest management. Due to the low efficiency and labor intensity of the current post-fire field survey in China’s Forestry Standards, the limitation of temporal resolution of satellite imagery, and poor objectivity of manual interpretations, a new method for automatic extraction of forest burn severity based on small visible unmanned aerial vehicle (UAV) images is proposed. Taking the forest fires which occurred in Anning city of Yunnan Province in 2019 as the study objects, post-fire imagery was obtained by a small, multi-rotor near-ground UAV. Some image recognition indices reflecting the variations in chlorophyll loss effects in different damaged forests were developed with spectral characteristics customized in A and C, and the texture features such as the mean, standard deviation, homogeneity, and shape index of the length–width ratio. An object-oriented method is used to determine the optimal segmentation scale for forest burn severity and a multilevel rule classification and extraction model is established to achieve the automatic identification and mapping. The results show that the method mentioned above can recognize different types of forest burn severity: unburned, damaged, dead, and burnt. The overall accuracy is 87.76%, and the Kappa coefficient is 0.8402, which implies that the small visible UAV can be used as a substitution for the current forest burn severity survey standards. This research is of great practical significance for improving the efficiency and precision of forest fire investigation, expanding applications of small UAVs in forestry, and developing an alternative for forest fire loss assessments in the forestry industry.

Automated Extraction of Forest Burn Severity Based on Light and Small UAV Visible Remote Sensing Images

A township-level assessment of forest fragmentation using morphological spatial pattern analysis in Qujing, Yunnan Province, China

Modeling the spatial patterns of human wildfire ignition in Yunnan province, China

To determine floristic units and centres of plant species endemism using quantitative methods and different taxonomic groups.

Quantitative approaches to identify floristic units and centres of species endemism in the Qinghai‐Tibetan Plateau, south‐western China

Spatial-temporal vegetation succession in Yao’an County, Yunnan Province, Southwest China during 1976–2014: A case survey based on RS technology for mountains eco-engineering

Occurrence of antibiotics and heavy metals, together with concentrations of conventional pollution indicators were assessed in digested piggery wastewater (DPW) generated in ten large-scale pig farms in Jiaxing City, China. Results showed that water quality of DPW varied in different farms as well as in different seasons. Digested piggery wastewater pollution tended to be less serious in Summer than in Spring, Autumn and Winter. Conventional pollution indicators of chemical oxygen demand (COD), total nitrogen (TN), ammonium nitrogen (NH4-N) and total phosphorus (TP) in Spring ranged 1008 18479 mg/L, 205 2228 mg/L, 119 1936 mg/L and 32.6 306 mg/L, respectively, being four times higher than those in Summer. Pollution of antibiotics and heavy metals in DPW was very severe for all farms. Six heavy metals (copper, Cu; zinc, Zn; lead, Pb; cadmium, Cd; nickel, Ni; and chromium, Cr) and ten antibiotics (three tetracyclines, two sulfonamides, three macrolides and two quinolones) were detectable in all the ten farms. Copper and Zn accounted for 97 ± 3% of the total heavy metals concentrations, and their concentrations reached the discharge limits of 0.5 mg/L (Cu) and 1.5 mg/L (Zn) in most cases. The total concentrations of the ten antibiotics were in the range of 0.155 – 1,090 μg/L. Heavy metals and antibiotics should be given intensive attention during resource utilization and treatment of DPW.

ON THE POLLUTION WITH ANTIBIOTICS, HEAVY METALS AND CONVENTIONAL INDICATORS IN DIGESTED WASTEWATER FROM LARGE-SCALE PIG FARMS IN JIAXING CITY, CHINA

In order to determine eleven commonly used veterinary antibiotics (including four tetracyclines, two sulfonamides, three quinolones and two macrolides) in piggery wastewater and activated sludge in the Yangtze River Delta region, the conditions of solid phase extraction and high performance liquid chromatography-tandem mass spectrometry were optimized. The recovery rate and relative standard deviations of the method were confirmed as 73% - 105.2%, 3.1% - 10.2% for piggery wastewater (n = 3) and 57.4% - 104.6%, 1.9% - 10.9% (n = 3) respectively for the activated sludge. Removal of antibiotics was then studied in a membrane bioreactor. The results showed that antibiotics of both tetracycline and sulfonamide species took a large portion in the wastewater, while tetracycline species were the dominant in the sludge. Tetracycline species in the wastewater were removed by 85.2%, mainly through biodegradation (51.9%) and secondly by sludge adsorption (33.2%). By comparison, sulfonamide species was removed by 95.8%, almost all through biodegradation while little by sludge adsorption. Flask tests suggested that the accumulated antibiotics in the sludge give no significant influence on the microbial removal of organics and ammonium.

[Method for Simultaneous Determination of 11 Veterinary Antibiotics in Piggery Wastewater and Sludge and Its Application in Biological Treatment].

The removal performance of 11 veterinary antibiotics in piggery wastewater and their accumulation in the activated sludge were studied in an intermittent aeration membrane bioreactor (IAMBR) at different COD/TN ratios and organic loads. The results showed that both antibiotics and chemical oxygen demand (COD) were efficiently removed at hydraulic retention time (HRT) of no less than five days and COD/TN ratio of 2.1, the removal rate was (79.1 ± 0.7)% for total antibiotics and was (88.4 ± 1.4)% for COD. As HRT was shortened to three days, the removal rate of COD was little changed but the removal rate of total antibiotics was significantly decreased. As COD/TN decreased from 2.1 to 0.7, the removal rate of total antibiotics was little changed, but the COD removal rate was significantly decreased. Antibiotics of tetracycline and quinolone species kept accumulating in the sludge at long SRT, and the accumulation amount was decreased with shorter SRT. The concentration and composition of antibiotic in the sludge were influenced by the raw wastewater.

[Performance of an Intermittent Aeration Membrane Bioreactor for Removal of Veterinary Antibiotics from Piggery Wastewater].

Liquid chromatography and tandem mass (LC-MS/MS) followed with solid-phase extraction (SPE) was developed for simultaneously determining four classes (tetracyclines, quinolones, macrolides and sulfonamides) of ten commonly used veterinary antibiotics in groundwater of Jiaxing city, an important pig breeding base in the Yangtze River Delta region. Samples were taken from 10 typical rural river sections and 21 main urban river sections. Results revealed severe pollution existed in the rural river environment. The total concentration of ten antibiotics was as high as 65.6-467.0 ng x L(-1), among which tetracyclines and sulfonamides respectively ranged in 40.8-253.0 ng x L(-1) and undetected (nd)- 165.0 ng x L(-1), macrolides and quinolones respectively ranged in 3.1-14.68 ng x L(-1) and nd-14.54 ng x L(-1). By comparison, the pollution level in urban rivers was much lower. The total concentration of ten antibiotics ranged in 20.1 ng x L(-1) to 61.2 ng x L(-1), among with tetracyclines varied from undetected to 44.0 ng x L(-1), while sulfonamides, macrolides and quinolones were respectively below 2.7 ng x L(-1), 6.3 ng x L(-1) and 21.6 ng x L(-1).

[A study on the veterinary antibiotics contamination in groundwater of Jiaxing].

The main volatile compounds belong to TVOC or odor which may generate from industrial park,special sensors were adopted to build electronic nose for detecting those compounds. TVOC pollution index (TPI) and odor pollution index (OPI) were designed as well as detecting method based on electronic nose in the field. On this basis, considering the pollution situation of chemical industrial of Zhapu port in Jiaxing, six detecting points were selected to be tested by electronic nose on site. Each sensor responses processed by principal components analysis (PCA), two principal components were extracted, that is, eight sensors can be divided into two groups including the types of TVOC (S1) and odor (S2-S8). Meanwhile, the on site collected samples were qualitatively analyzed with GC/ MS. At each testing point, integral area percentage of the compounds being a part of TVOC accumulated mostly over 90% and to odor, mostly was below 10%. Results show: (1) Choosing appropriate sensors combining PCA can preliminarily reflect the pollution condition of TVOC and odor in industrial park; (2) Combining pollution indexes measured with electronic nose and results of qualitative analysis with GC/MS can generally concluded the overall pollution situation of TVOC and odor in industrial park and distribution of each pollutant; (3) Application of electronic noses and GIS to detect TVOC and odor in industrial park can preliminary assess space pollution situation in industrial park.

[Detection of TVOC and odor in industrial park using electronic nose].

CENTRAL TUMOR NECROSIS FACTOR‐ALPHA BLOCKADE INCREASED NNOS EXPRESSION IN THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS AND IMPROVED SEXUAL BEHAVIOR DISORDER IN MALE DIABETIC RATS: MP81‐01

PD36-03 BLUNTED NNOS EXPRESSION IN THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS CONTRIBUTE TO DIABETES-ASSOCIATED MALE SEXUAL BEHAVIOR DISORDER: CENTRAL ROLE OF TNF-α

Influence of electroacupuncture on tumor necrosis factor-α and vascular endothelial growth factor in rats with experimental arthritis

A Method for Finding Groups of Related Herbs in Traditional Chinese Medicine

Abstract Suspenders are key components of suspension bridges and are prone to corrosion, fatigue and deck fires, resulting in damage or fracture. It is necessary to study the emergency replacement technology for suspenders. In this study, a long suspender replacement device was designed for the Runyang Suspension Bridge after studying the configuration of a fire-damaged suspender anchorage structure. The proposed suspender replacement technology removed the damaged suspender with the pin shaft under zero stress instead of the traditional method with the suspender under zero stress. A finite element (FE) model was established to simulate the behavior of the suspension bridge during the suspender replacement process. The change rules for typical and key parameters, such as the temporary suspender force, replaced suspender force, and vertical displacement of the main cables and stiffening girders, are presented. Furthermore, the force monitoring data on the temporary and replaced suspender were recorded during the entire construction process without interrupting traffic. The results show that the changing trend between the FE analysis results and the measured results is consistent, and the method is safe and of little influence to the bridge.

Replacement of the Fire-Damaged Long Suspenders of the Runyang Suspension Bridge

A novel method was proposed for the moving load identification of bridges based on the influence line theory and distributed optical fiber sensing technique. The method of load and vehicle speed identification was firstly theoretically studied, and then numerical simulation was also performed to study its accuracy and robustness. The numerical results showed that this method was characterized by high accuracy and excellent resistance to noise. Finally, the load identification of an actual continuous pre-stressed concrete beam bridge was carried out with the proposed method. The bridge consists of four pre-stressed box beams. At the same time, a weigh-in-motion system was also installed about 200 m in front of the bridge to measure the speed and moving loads with a purpose of comparing the load identification of the proposed method. Long gauge fiber Bragg grating (FBG) sensors with a gauge length of 1.0 m were adhered to the bottom of the beams. The individual loaded vehicles and the corresponding structure response were mainly monitored as standard samples, and the speed and weight of the sample vehicles were monitored and identified with the proposed method. The results revealed that the distributed long gauge FBG sensors were capable of sensing the structure response precisely and identifying the traffic load. On the basis of the design information and ambient vibration testing results, a refined model was established and the response under unit moving load was acquired for load identification. It was also shown that the sensors in different positions can achieve accurate vehicle speed and weight, the relative error of which are within 10% and 15%, respectively.

Moving Load Identification of Small and Medium-Sized Bridges Based on Distributed Optical Fiber Sensing

A new type of intelligent composite structure is proposed, consisting of reinforced concrete and prestressed hybrid fiber-reinforced polymer sheets. The hybrid fiber-reinforced polymer consists of basalt and carbon fibers. The carbon fibers function as both sensitive and structural materials to improve stiffness of the hybrid fiber-reinforced polymer sheets and provide a self-monitoring function, whereas basalt fibers function only as structural materials to improve their ductility and decrease the cost. A series of experiments were performed to study the mechanical and monitoring performances of the hybrid fiber-reinforced polymer–concrete composite structures. The results show that their mechanical and self-monitoring performances are markedly upgraded through prestressing the hybrid fiber-reinforced polymer sheets. The prestress improves both the strengthening and monitoring performances. Compared with the control beams, the cracking, steel yielding, and peak loads are improved by 44%, 26%, and 36%, respectively. Results reveal that the prestress also upgrades the monitoring sensitivity and stability of the hybrid fiber-reinforced polymer sheets. Since the electrical behavior is closely related to the mechanical behavior of the hybrid fiber-reinforced polymer–concrete composite beams, the strain, cracking, steel yielding, and the debonding and rupture of the hybrid fiber-reinforced polymer sheets can be well identified through the resistance measurement. A built-in health monitoring function is, thus, demonstrated for the intelligent hybrid fiber-reinforced polymer–concrete composite structures.

Self-monitoring of composite structures strengthened with prestressed hybrid fiber-reinforced polymer sheets

The deformation is an important parameter in structural health monitoring, and a conjugate beam method based on long-gauge fiber Bragg grating distributed strain sensing techniques is proposed to obtain the deformation of a structure. Some experiments are carried out to study the accuracy of this method using a four point bending RC beam under a step loading manner. The deformation obtained with the proposed method agrees well with those obtained with the conventional dial gauge in low loading steps. In addition, some measure is put forward to calibrate the proposed method and improve its accuracy at high loading steps, especially after the initiation of concrete cracks.

Study on the Structural Deformation Monitoring Based on Distributed FBG Sensing Techniques

Direct peritoneal resuscitation with pyruvate (Pyr-PDS) has emerged as an interesting candidate to alleviate injury in diverse organs, while the potential mechanism has yet to be fully elucidated. To explore the effect of autophagy in the spinal cord ischemia-reperfusion (SCIR) injury and the underlying mechanism, we established a model of SCIR in vivo and in vitro. In vivo, male SD rats underwent aortic occlusion for 60 min and then followed by intraperitoneally infused with 20 mL of pyruvate or normal saline for 30 min, and the spinal cords were removed for analysis after 48 h of reperfusion. The functional and morphological results showed that Pyr-PDS alleviated SCIR injury; meanwhile, the expression of autophagy-related genes and transmission electron microscopy displayed autophagy was activated by SCIR injury, and Pyr-PDS treatment could further upregulate the degree of autophagy which plays a protective part in the SCIR injury, while there is no significant difference after treatment with saline. In addition, SCIR injury inhibited expression of PHD2, which results to activate its downstream HIF-1α/BNIP3 pathway to promote autophagy. In the Pyr-PDS, the results revealed PHD2 was further inhibited compared to the SCIR group, which could further activate the HIF-1α/BNIP3 signaling pathway. Additionally, oxygen-glucose deprivation and reoxygenation were applied to SH-SY5Y cells to mimic anoxic conditions in vitro, and the expression of autophagy-related genes, PHD2, and its downstream HIF-1α/BNIP3 pathway showed the same trend as the results in vivo. Besides, IOX2, a specific inhibitor of PHD2 was also treated to SH-SY5Y cells during reoxygenation, in which the result is as same as the pyruvate group. Then, we observed the expression of autophagy-related genes and the HIF-1α signal pathway in the process of reoxygenation; the results showed that as the reoxygenation goes, the expression of the HIF-1α signal pathway and degree of autophagy came to decrease gradually, while treated with pyruvate could maintain autophagy high and stable through keeping PHD2 at a lower level during reoxygenation, and the latter was observed downregulated during reoxygenation process from 0 to 24 hours in a time-effect way. The above results indicated that direct peritoneal resuscitation with pyruvate showed effective protection to ischemia-reperfusion of the spinal cord through activating autophagy via acting on PHD2 and its downstream HIF-1α/BNIP3 pathway.

Direct Peritoneal Resuscitation with Pyruvate Protects the Spinal Cord and Induces Autophagy via Regulating PHD2 in a Rat Model of Spinal Cord Ischemia-Reperfusion Injury

Hydrogen exerts neuroprotective effects on OGD/R damaged neurons in rat hippocampal by protecting mitochondrial function via regulating mitophagy mediated by PINK1/Parkin signaling pathway

Objective 
To investigate the effect of hydrogen on mitochondrial membrane potential during focal cerebral ischemia-reperfusion (I/R) in rats. 
 
Methods 
Eighty-four healthy adult male SPF Sprague-Dawley rats, weighing 220-240 g, were divided into 3 groups (n=28 each) using a random number table: sham operation group (Sham group), I/R group and hydrogen group (H2 group). Focal cerebral I/R was produced by mid-cerebral artery occlusion in I/R and H2 groups.Hydrogen 10 ml/kg was intraperitoneally injected immediately after onset of reperfusion and at 12 h of reperfusion in group H2.Neurological deficit was scored at 24 h of reperfusion.The rats were then sacrificed and brain tissues in cortex were removed for microscopic examination of the pathological changes and for determination of cerebral infarct size (by TTC staining), nerve cell apoptosis (by TUNEL), mitochondrial membrane potential(by JC-1 staining) and expression of Bcl-2 and Bax (by Western blot). Apoptotic index (AI) was calculated. 
 
Results 
Compared with Sham group, the neurological deficit score, percentage of cerebral infarct size and AI were significantly increased, the mitochondrial membrane potential was decreased, Bax expression in brain tissues was up-regulated, and Bcl-2 expression in brain tissues was down-regulated in I/R and H2 groups (P<0.05). Compared with I/R group, the neurological deficit score, percentage of cerebral infarct size and AI were significantly decreased, the mitochondrial membrane potential was increased, Bax expression in brain tissues was down-regulated, and Bcl-2 expression in brain tissues was up-regulated (P<0.05), and the pathological changes of brain tissues were significantly attenuated in H2 group. 
 
The mechanism by which hydrogen reduces focal cerebral I/R injury is related to decreasing dissipation of mitochondrial membrane potential and inhibiting nerve cell apoptosis in rats. 
 
Key words: 
Hydrogen; Reperfusion injury; Brain; Membrane potential, mitochondrial

Effect of hydrogen on mitochondrial membrane potential during focal cerebral ischemia-reperfusion in rats

Objective 
To investigate the role of phosphatidylinositol 3-kinase/protein kinase B/glycogen synthase kinase-3β (PI3K/Akt/GSK-3β) signaling pathway in hydrogen-induced inhibition of neuronal apoptosis induced by focal cerebral ischemia-reperfusion (I/R)in rats. 
 
Methods 
One hundred and twenty healthy adult male Sprague-Dawley rats, weighing 200-220 g, were divided into 5 groups (n=24 each) using a random number table: sham operation group (group S); cerebral I/R group (group I/R); hydrogen group (group H2); LY294002 (specific PI3K inhibitor) group (group LY); LY294002+ hydrogen group (group LY+ H2). Focal cerebral I/R was induced by occlusion of the middle cerebral artery for 1 h followed by 24 h reperfusion.In H2 and H2+ LY groups, the animals inhaled 67% H2+ 33% O2 for 2 h starting from onset of reperfusion, and then inhaled H2 for 2 h every 6 h. In LY and LY+ H2 groups, LY294002 (10 mmol/L) 10 μl was injected into the lateral cerebral ventricle at 10 min before reperfusion.Neurologic deficit was evaluated and scored (NDS) at 24 h of reperfusion.The rats were then sacrificed, and the brains were removed for measurement of the cerebral infarct size (by TTC staining) and apoptosis in cortical neurons (by TUNEL) and for determination of the expression of Akt in the ischemic cerebral cortex, phosphorylated Akt (p-Akt), GSK-3β and phosphorylated GSK-3β (p-GSK-3β) and Bcl-2 and Bax positive cell count in the ischemic cerebral cortex (by immuno-histochemistry). The apoptosis index (AI), p-Akt/Akt ratio and p-GSK-3β/GSK3-β ratio were calculated. 
 
Results 
Compared with group S, the NDS, cerebral infarct size, AI, p-Akt/Akt ratio, p-GSK-3β/GSK-3β ratio and Bax positive cell count were significantly increased, and the Bcl-2 positive cell count was significantly decreased in group I/R (P 0.05). Compared with group H2, the NDS, cerebral infarct size, AI and Bax positive cell count were significantly increased, and the p-Akt/Akt ratio, p-GSK-3β/GSK-3β ratio and Bcl-2 positive cell count were significantly decreased in group LY+ H2(P<0.05). 
 
The mechanism by which hydrogen inhibits focal cerebral I/R-induced neuronal apoptosis is associated with the activation of PI3K/Akt/GSK-3β signaling pathway in rats. 
 
Key words: 
Hydrogen; 1-Phosphatidylinositol 3-kinase; Protein-serine-threonine kinases; Glycogen synthase kinase 3; Apoptosis; Reperfusion injury; Brain

Role of PI3K/Akt/GSK-3β signaling pathway in hydrogen-induced inhibition of neuronal apoptosis induced by focal cerebral ischemia-reperfusion in rats

Objective 
To explore the protective effect of in-taking high concentration hydrogen gas on neurons and dendritic spines in hippocampus CA1 region of rats after globe cerebral ischemia/reperfusion (I/R) injury and its mechanism. 
 
Methods 
Four-vessel occlusion (4VO) was used to establish the models of global cerebral I/R injury in rats. One hundred and twenty healthy male Sprague-Dawley rats were randomly divided into 3 groups using a random number table: sham-operated group (inhaled 67% N2 and 67% O2, n=40), model group (inhaled 67% N2 and 67% O2 during reperfusion, n=40), and treatment group (inhaled 67% H2 and 67% O2 during reperfusion, n=40). After 72 h, 5 and 9 d reperfusion, neuron-specific nuclear (NeuN) protein expression in the pyramidal neurons of the hippocampal CA1 region was detected with immumohistochemical staining and the positive cells were counted. And the contents of superoxide dismutase (SOD) and malondialdehyde (MDA) in serum were tested with colorimetry. Water maze test was used to measure the spatial orientation and memory function and Golgi staining to detect the number of dendritic spines in neurons 9 d after reperfusion. 
 
Results 
(1) Immunohistochemical staining of NeuN results showed that as compared with those in the model group, the neurons of hippocampus CA1 region were significantly closer to normal with relatively intact structure, and the number of positive neurons was significantly increased in the treatment group 72 h, 5 d, and 9 d after reperfusion (P 0.05). (2) The serum SOD activity in the treatment group was significantly higher than that in the model group and sham- operated group (P 0.05). But the MDA content at different time points of reperfusion between model group and treatment group was significantly different (P<0.05); with the reperfusion time being prolonged, the MDA content was gradually decreased in both groups. (3) Nine d after reperfusion, water maze test found that the incubation period of treatment group was significantly shorter than that of model group (P<0.05); the IV quadrant swimming time of space exploration in the treatment group was significantly longer than that in the model group (P<0.05). (4) Golgi staining showed that the complexity of the neuronal dendrites branch and the number of dendritic spines of neurons in the hippocampal CA1 region of treatment group were increased than those in the model group; high-power oil microscopy indicated that the density of dendritic spines in the treatment group was significantly higher than that in the model group (P<0.05). 
 
In-taking of high concentrations hydrogen gas during reperfusion can definitely protect neurons in hippocampal CA1 region after globe cerebral I/R injury, and improve learning and memory function, whose mechanism may be related to hydrogen protecting the structure and function of neurons and dendritic spines, and inhibiting oxidative stress to reduce oxidative damage. 
 
Key words: 
Hydrogen; Ischemia-reperfusion injury; Neuron; Dendritic spine; Oxidative stress

Protective effect of hydrogen gas on neurons and dendritic spines of hippocampus CA1 region in rats after global cerebral ischemia/reperfusion injury

Total bakkenolides is the major component of the rhizome of Petasites trichinous Franch.. In this study, we investigated its neuroprotective effects in a rat transient focal cerebral ischemia-reperfusion model, and in an in vitro cerebral ischemia model, oxygen-glucose deprivation of cultured nerve cells. Oral administration of total bakkenolides immediately after reperfusion at doses of 5, 10 and 20 mg/kg markedly reduced brain infarct volume and neurological deficits. Total bakkenolides significantly attenuated cell death and apoptosis in primarily cultured neurons subject to 1-h hypoxia followed by 24-h reoxygenation. Morphologic observations directly confirmed its protective effect on neurons. We also demonstrated that total bakkenolides could inhibit nuclear factor-κB (NF-κB) activation by blocking the classic activation pathway through suppression of phosphorylation of IκB-kinase complex, NF-κB/p65 and inhibitor protein IκB, inducing nuclear translocation of NF-κB/p65 and degradation of IκB. Further, total bakkenolides inhibited the activation of Akt and the extracellular signal-regulated kinase 1/2, two important upstream activators of NF-κB. In conclusion, our results provide a strong pharmacological basis for further understanding the potential therapeutic role of total bakkenolides in cerebral ischemic disease and shed new light on its neuroprotective mechanism.

Total bakkenolides protects neurons against cerebral ischemic injury through inhibition of nuclear factor-κB activation.

Hepatoprotective effects of oridonin against bisphenol A induced liver injury in rats via inhibiting the activity of xanthione oxidase.

The inflammatory immune response plays an important role in the pathophysiological process of cerebral ischemic injury, especially during the enlargement of damage and the secondary damage after cerebral ischemia. There are high cytokine expression and proinflammatory infiltration in damage area after ischemic cerebral injury, which aggravates brain injury especially in reperfusion period [1,2]. Interleukin-1b (IL-1b) is an inflammatory factor regulating the complex pathologic changes in acute ischemic brain injury. Increase in IL-1b mRNA and protein level was observed after cerebral ischemia–reperfusion. IL-1b plays an important role in inflammation of focal cerebral ischemia. IL-1b contributes to brain tissue injury following cerebral ischemia–reperfusion [3,4]. Anakinra, a recombinant, nonglycosylated form of human interleukin-1 receptor antagonist (rhIL-1ra), is identical to a native IL-1 receptor antagonist except for a methionine residue that has been added to the beginning of the amino acid sequence [5]. Intracerebroventricular injection of IL-1ra (10 mg) significantly reduced the lesion volume after middle cerebral artery occlusion (MCAO) in rats [6]. There are no articles about animal studies of anakinra being administered i.v. and therapeutic time window in cerebral ischemia. This study was designed to document the therapeutic effect and therapeutic time window of anakinra after transient focal MCA occlusion and its mechanism at molecular level. Male Wistar rats (250–350 g) were divided into 18 groups, normal groups, sham groups, control groups, and anakinra groups (5, 10, or 20 mg/kg, i.v.) at 3, 6, or 12 h after ischemia, respectively. Twenty-four hours after cerebral ischemia, rats were euthanized and decapitated. The brains were removed, and then, RNA was extracted. The mRNA primer of intercellular adhesion molecule 1 (ICAM-1), inducible nitric oxide synthase (iNOS), IL-1b, and tumor necrosis factor-a (TNF-a) were synthesized. Anakinra decreased infarct percentage and improved neurological deficits induced by MCAO in male Wistar rats dose dependently and time dependently in Figure 1A–C. Significant difference was found between anakinra 5 mg/kg i.v. at 3 or 6 h after ischemia and the control group. Similar findings were observed in anakinra 10 or 20 mg/kg i.v. at 3, 6, or 12 h. The effect of anakinra on ICAM-1 mRNA, iNOS mRNA, IL-1b mRNA, and TNF-a mRNA was assessed by semiquantitative reverse transcription PCR [7]. The integral gray value of normal group was set as 1, and the values of other groups were expressed as a ratio versus normal group. As shown in Figure 2A–D, ischemia–reperfusion upregulated ICAM-1, iNOS, IL-1b, and TNF-a mRNA level. Anakinra 5~20 mg/kg i.v. at 3, 6, or 12 h after ischemia could significantly downregulate their mRNA levels (P < 0.01 or P < 0.05, vs. control group). Results have demonstrated that anakinra has an inhibitory effect on these overexpression cytokine. Anakinra is a kind of biomacromolecule, which is composed of 153 amino acids, and it cannot cross blood–brain barrier by i.v. administration in normal animals. It has been reported that natural IL-1ra could improve brain injury resulting from focal cerebral ischemia through cerebral ventricle injection [8]. In this study,

The Effects of Anakinra on Focal Cerebral Ischemic Injury in Rats

SUMMARY  Aims: To investigate the anticerebral ischemic properties of YGY‐E (apigenin‐7‐O‐β‐d‐glucopyranosy l‐4′‐O‐α‐L‐rhamnopy‐ranosid, a flavonoid glycoside extracted from plant phoenix‐tail fern), focusing on its effects on neuronal apoptosis. Methods:In vitro YGY‐E treatment was examined in primary cultured rat hippocampal neurons subjected to hypoxia‐reoxygenation (H‐R) injury. In addition, in vivo effects of YGY‐E on neuronal apoptosis were measured by Hoechst staining and in situ DNA end labeling (TUNEL). Finally, B cell lymphoma/lewkmia‐2 (Bcl‐2) level in ischemic rat brain tissue was evaluated with immunohistochemistry and western blot analyses. Results:In vitro YGY‐E (50–100 μg/mL) treatment increased the survival rate compared to that of the vehicle‐treated group (P < 0.05 and P < 0.01, respectively). In in vivo experiments, YGY‐E (2.5–10 mg/kg) decreased the percentage of apoptotic neurons (P < 0.01), increased Bcl‐2 (P < 0.01) in ischemic rat brain tissue. These effects were dose dependent. Conclusions: Our findings indicate that YGY‐E's neuroprotective effects may be because of its inhibition of neuronal apoptosis by increasing Bcl‐2 expression.

A Neuroprotective Mechanism of YGY‐E in Cerebral Ischemic Injury in Rats

The difference of glutathione antioxidant system in newly weaned and young mice liver and its involvement in isoline-induced hepatotoxicity

The gender-dependent difference of liver GSH antioxidant system in mice and its influence on isoline-induced liver injury.

A series of calcium (3R,5S,6E)‐7‐[4,6,7,8‐substituted‐quinoline‐3‐yl]‐3,5‐dihydroxy‐hept‐6‐enoates was synthesized from the lactones, and the anti‐hypercholesterolemic evaluation in quails was presented in this report. It was found that most of the compounds significantly decreased levels of total cholesterol and low‐density lipoprotein. 2e showed better hypolipidemic effect than atorvastatin, and 2d and 2j exhibited comparable efficacy to atorvastatin. These three compounds were selected as the hypocholesterolemic candidates for further evaluation.

Synthesis and Anti‐Hypercholesterolemic Evaluations of Calcium Salts of 4‐Substituted Quinoline‐Based Mevalonic Acid

In vitro cell models, which can partially mimic in vivo responses, offer potentially sensitive tools for toxicological assessment. The objective of this study was to explore the possible mechanisms of acetaminophen (AP)-induced toxicity in human normal liver L-02 cells. The expression of the CYP2E1 enzyme, which is reported to transform AP to its toxic metabolites, was higher in L-02 than in Hep3B cells. Further cell viability and reduced glutathione (GSH) depletion after AP treatment were examined. After exposure to AP for 24 h, cell viability decreased in a concentration-dependent manner. Concentration-dependent GSH depletion was also observed after AP treatment for 48 h, indicating oxidative stress had occurred in L-02 cells. The effects of D, L-buthionine-(S, R)-sulfoximine (BSO), an inhibitor of GSH biosynthesis, and N-acetylcysteine (NAC), a precursor of GSH synthesis, on the cytotoxicity induced by AP were also investigated. BSO aggravated the cytotoxicity induced by AP while NAC ameliorated such cell death. Further results showed that 10 mM AP caused cell apoptosis after 48 h treatment based on the DNA fragmentation assay and western blot of caspase-3 activation, respectively. In addition, the protective effects of various well-known antioxidants against AP-induced hepatotoxicity were observed. Taken together, these results indicate that oxidative stress and cellular apoptosis are involved in AP-induced toxicity in human normal liver L-02 cells, and this cell line is a suitable in vitro cell model for AP hepatotoxicity study.

Acetaminophen-induced cytotoxicity on human normal liver L-02 cells and the protection of antioxidants

Stimulator of interferon gene (STING), an intracellular receptor in the endoplasmic reticulum, could induce the production of cytokines such as type I interferon (IFN) by activating the cGAS-STING signal pathway. In recent years, activation of STING has shown great potential to enhance anti-tumor immunity and reshape the tumor microenvironment, which is expected to be used in tumor immunotherapy. A number of STING agonists have demonstrated promising biological activity and showed excellent synergistic anti-tumor effects in combination with other cancer therapies in preclinical studies and some clinical trials. The combination of STING agonists and ICI also showed a potent effect in improving anti-tumor immunity. In this review, we introduce the cGAS-STING signaling pathway and its effect in tumor immunity and discuss the recent strategies of activation of the STING signaling pathway and its research progress in tumor immunotherapy.

Activation of Stimulation of Interferon Genes (STING) Signal and Cancer Immunotherapy

Novel Thermally Activated Delayed Fluorescence Nano-Micelle for Tumor Imaging.

Krüppel-like factor 4 (KLF4) is a transcription factor and plays a vital role in cancer initiation and development. However, the role of Krüppel-like factor 4 in the metastasis of non-small cell lung cancer (NSCLC) is not clear. Here, we demonstrated that the expression of Krüppel-like factor 4 was significantly decreased in human non-small cell lung cancer tissues compared with that in normal tissues using Western blot. We performed immunohistochemical staining and observed the decreased expression of Krüppel-like factor 4 in human lung cancer tissues, and metastatic tumor tissues located in the trachea and main bronchus. We also found that the E-cadherin expression was decreased, while vimentin expression was increased in human NSCLC tissues and metastatic tumor tissues located in the trachea and main bronchus. Additionally, enforced expression of Krüppel-like factor 4 in mouse lungs significantly inhibited the metastasis of circulating Lewis lung carcinoma cells to the lungs by attenuating mesenchymal-epithelial transition (MET). Furthermore, cell scratch assays and Matrigel invasion assays revealed that overexpression of Krüppel-like factor 4 inhibited the migration and invasion of non-small cell lung cancer cell lines A549, H1299, H226, and H1650 cells. Moreover, overexpression of Krüppel-like factor 4 attenuated TGF-β1-induced epithelial-mesenchymal transition (EMT) in A549, and inhibited the phosphorylation of c-Jun-NH2-terminal kinase (JNK), an important pathway in metastasis in non-small cell lung cancer. Our in vivo and in vitro findings illustrate that Krüppel-like factor 4 inhibited metastasis and migration of non-small cell lung cancer, and indicate that Krüppel-like factor 4 could be a potential therapeutic target for the treatment of non-small cell lung cancer.

Overexpression of Krüppel-Like Factor 4 Suppresses Migration and Invasion of Non-Small Cell Lung Cancer Through c-Jun-NH2-Terminal Kinase/Epithelial-Mesenchymal Transition Signaling Pathway

Sa1111 – Regulation of the Bmp Signaling Inhibitor Smad6 in Gastritis and Gastric Cancer

AIM
To explore the effects and mechanisms of mechanical stress and transforming growth factor-beta2 (TGF-β2) on epithelial-mesenchymal transition (EMT) in cultured human retinal pigment epithelial (RPE) cells.

METHODS
Human RPE cells were inoculated on BioFex 6-well plates and RPE cells received 0, 1, 2, 3, or 4 mild stretch injuries delivered 3h apart after 24h of culture. The device of mechanical stress parameters were set to sine wave, frequency 1 Hz, stretch strength 20%. For treatment with TGF-β2, when the inoculated RPE cells in 6-well plates were around 60% conﬂuent, serum was reduced to 0 for 12h and recombinant human TGF-β2 (0, 1, 5, 10 ng/mL) was added for 48h. α-SMA, Vimentin and N-Cadherin, fibronectin proteins expressions were detected by Western blotting, confocal cell immunofluorescence and quantitative real-time polymerase chain reaction (qRT-PCR). Then we detected the change of miRNA-29b and ascertained the changes of phosphatidylinositol 3-kinase-serine threonine protein kinase (PI3K/Akt) pathway after RPE cells were stretched by the device of mechanical stress and induced by TGF-β2 by Western blotting, confocal cell immunofluorescence and qRT-PCR.

RESULTS
Mechanical stress induce EMT and activate the PI3K/Akt pathway in ways that lead to the EMT process. TGF-β2 induce RPE cells EMT and in a certain range and TGF-β2 decrease the miRNA-29b expression in RPE cells, and the inhibitory effect is more obvious with the increase of TGF-β2 concentration.

Our findings are crucial steps in determining the critical roles of the PI3K/Akt signaling pathway and miRNA-29b in pathogenesis of proliferative vitreoretinopathy (PVR) which may be a potential target for preventing or treating PVR.

The role of mechanical stretch and TGF-β2 in epithelial-mesenchymal transition of retinal pigment epithelial cells.

Early brain injury (EBI)-induced neuronal apoptosis is primarily responsible for the subsequent complications of aneurysmal subarachnoid hemorrhage (aSAH), which may increase the risk of mortality in patients with aSAH. c-Jun N-terminal kinase (JNK) has been demonstrated to be a promoter of EBI-induced cell apoptosis, although the mechanism has yet to be fully elucidated. The present study aimed to explore whether the role of JNK1 is associated with tumor protein p53 (p53), which is one of the most important factor that triggers cell apoptosis. JNK1 expression was downregulated via in vivo small interfering RNA transfection in an aSAH rat model in order to assess differences in the behavior, survival times, morphology and genetics of the experimental animals. The results revealed that JNK1 inhibition improved the neurological scores and survival times of SAH rats by interrupting cascaded neuronal apoptosis. The interruption of EBI-induced neuronal apoptosis may originate from a decrease in the level of p53 phosphorylation and deactivation of the downstream mitochondrial apoptotic pathway. Taken together, these results suggest that JNK1 may be a promising target for improving the prognosis of patients with aSAH.

c-Jun N-terminal kinase inhibition attenuates early brain injury induced neuronal apoptosis via decreasing p53 phosphorylation and mitochondrial apoptotic pathway activation in subarachnoid hemorrhage rats

Regulation of Gastric Lgr5+ve Cell Homeostasis by Bone Morphogenetic Protein (BMP) Signaling and Inflammatory Stimuli

Regulation of CD44 Expression by Bone Morphogenetic Protein (BMP) Signaling and Inflammatory Stimuli

TGF-β-induced epithelial-mesenchymal transition (EMT) plays an important role in tumor progression. We assessed whether the TGF-β-induced EMT contributed to vasculogenic mimicry (VM) formation in glioma, we established an SHG44 cell line stably transfected with TGF-β cDNA loaded lentivirus. SB203580 was employed to inhibit the TGF-β-induced EMT. The results showed that the VM forming ability of cells could be improved by TGF-β over-expression. The migration and invasion capabilities of cells were also enhanced due to EMT. SB203580 was able to weaken cell migration, invasion and VM forming abilities via blocking p38/MAPK signaling pathways, but it had tiny influence on MMP/LAMC2 chain. Consequently, we concluded that EMT inhibition via p38/MAPK signaling pathways would partly impair TGF-β-induced VM formation in glioma.

Epithelial-mesenchymal transition regulated by p38/MAPK signaling pathways participates in vasculogenic mimicry formation in SHG44 cells transfected with TGF-β cDNA loaded lentivirus in vitro and in vivo.

MSX1 inhibits cell migration and invasion through regulating the Wnt/β-catenin pathway in glioblastoma

192 Regulation of Gastric LGR5+VE Cell Homeostasis by Bone Morphogenetic Protein (BMP) Signaling and Inflammatory Stimuli

OBJECTIVE
To investigate the effects and the potential mechanisms of RKIP on cell migration, invasion and proliferation in human glioma cell lines in vitro.

METHODS
The RKIP over-expressing and RKIP knockdown human U87 glioma cells were used to reveal the effects of RKIP on human glioma cells migration, invasion and proliferation. After the recombinant plasmid pcDNA3.0-RKIP or RKIP-shRNA was transfected into the cell lines U87 by the means of liposome assay, the cells migration, invasion and proliferation were detected by wound healing, Transwell and MTT assay. Then, the levels of RKIP, MMP-3, MMP-9 and HMGA2 mRNA transcription were measured by means of RT-qPCR and levels of proteins expressions were determined using Western blot.

RESULTS
The results of MTT assay suggested that the PKIP have little inhibitive effects on glioma cells proliferation (P>0.05). The present paper showed that the migration distances in the group of RKIP-shRNA were markedly increased compared to the pcDNA3.0-RKIP and control. Similarly, the results showed that the numbers of invasion cells in RKIP-shRNA were remarkably increased than the pcDNA3.0-RKIP group and control group. Western blot and RT-qPCR suggested that over-expressions of RKIP lessened the MMP-2, MMP-9 and HMGA2 expression, however, turning down the RKIP expression showed the inverse effects.

RKIP inhibits the cells migrations and invasions. Meanwhile, RKIP might inhibit the glioma cells through inhibiting MMPs and HMAG2 expression. Therefore, we demonstrated that RKIP is an underlying target for the treatment of glioma.

Raf kinase inhibitor protein (RKIP) inhibits the cell migration and invasion in human glioma cell lines in vitro.

LRG1 modulates invasion and migration of glioma cell lines through TGF-β signaling pathway.

Stable knockdown of LRG1 by RNA interference inhibits growth and promotes apoptosis of glioblastoma cells in vitro and in vivo

The poor therapeutic effect of traditional antiangiogenic therapy on glioblastoma multiforme (GBM) may be attributed to vasculogenic mimicry (VM), which was previously reported to be promoted by cancer stem-like cells (SLCs). All-trans retinoic acid (ATRA), a potent reagent which drives differentiation, was reported to be able to eradicate cancer SLCs in certain malignancies. The aim of the present study was to investigate the effects of ATRA on the VM formation ability of U87 glioblastoma SLCs. The expression of cancer SLC markers CD133 and nestin was detected using immunocytochemistry in order to identify U87 SLCs. In addition, the differentiation of these SLCs was observed through detecting the expression of glial fibrillary acidic protein (GFAP), β-tubulin III and galactosylceramidase (Galc) using immunofluorescent staining. The results showed that the expression levels of GFAP, β-tubulin III and Galc were upregulated following treatment with ATRA in a dose-dependent manner. Furthermore, ATRA significantly reduced the proliferation, invasiveness, tube formation and vascular endothelial growth factor (VEGF) secretion of U87 SLCs. In conclusion, the VM formation ability of SLCs was found to be negatively correlated with differentiation. These results therefore suggested that ATRA may serve as a promising novel agent for the treatment of GBM due to its role in reducing VM formation.

All-trans retinoic acid impairs the vasculogenic mimicry formation ability of U87 stem-like cells through promoting differentiation

Background: In recent years, miRNAs have been suggested to play key roles in the formation and development of human glioma. The aim of this study is to investigate the effect and mechanism of miR-184 expression on the malignant behavior of human glioma cells. Methods: The relative quantity of miR-184 was determined in human glioma cell lines, and the expression of hypoxia-inducible factor-1 alpha (HIF-1α) was explored using western blotting. The effects of miR-184 inhibition on cell viability and apoptosis were explored, and the miR-184 target gene was determined using a luciferase assay and western blotting. Flow cytometry and Hoechst staining were used to evaluate cell growth and apoptosis. Matrigel invasion and scratch assays were performed to measure the ability of cell invasion and migration. Results: miR-184 and HIF-1α protein levels were significantly upregulated in human glioma cells. Downregulation of miR-184 inhibited cell viability and increased the HEB cell apoptotic rate. Luciferase and western blot assays verified that FIH-1 was the target gene of miR-184 and negatively controlled the protein level of HIF-1α. Inhibition of HIF-1α by siRNA facilitated the apoptosis of HEB cells and suppressed A172 cell invasion and migration. Conclusion: miR-184 upregulation enhanced the malignant phenotype of human glioma cancer cells by reducing FIH-1 protein expression.

Upregulation of miR-184 Enhances the Malignant Biological Behavior of Human Glioma Cell Line A172 by Targeting FIH-1

HP-β-CD-PLGA nanoparticles improve the penetration and bioavailability of puerarin and enhance the therapeutic effects on brain ischemia–reperfusion injury in rats

In the present study, ultrasound-mediated microbubble destruction (UMMD) alone and combined with liposome technology was used as a novel nonviral technique to transfect a Nogo receptor (Nogo-R) shRNA plasmid (pNogo-R shRNA) into neural stem cells (NSCs). Using green fluorescent protein as a reporter gene, transfection efficiency of NSCs was significantly higher in the group transfected with UMMD combined with liposomes compared with that of the group transfected with UMMD or liposomes alone, and did not affect cell vitality. In addition, Nogo-R mRNA and protein expression was dramatically decreased in the UMMD combined with liposome-mediated group compared with that of other groups after 24 hours of transfection. The UMMD technique combined with liposomes is a noninvasive gene transfer method, which showed minimal effects on cell viability and effectively increased transfer of Nogo-R shRNA into NSCs.

Ultrasound microbubbles combined with liposome-mediated pNogo-R shRNA delivery into neural stem cells★

Objective: To study the effect of down-regulation of eukaryotic translation initiation factor 4E (EIF4E) induced by the siRNA expression plasmid on the proliferation and cell cycle of human breast cancer cell line MDA-MB-231. Methods: The siRNA expression plasmid pGPU6/GFP/Neo-EIF4E was constructed and then transfected into breast cancer MDA-MB-231 cells by LipofectAMINE2000. The expressions of EIF4E and cyclin D1 mRNAs and proteins were examined by RT-PCR, Western blotting and the immunocytochemistry method, respectively. The MTT method, plate colony formation assay and  flow cytometry were performed to detect the proliferation ability, cell colony formation rate and cell cycle distribution of MDA-MB-231 cells transfected with siRNA expression plasmid. Results: The siRNA expression plasmid pGPU6/GFP/Neo-EIF4E was constructed successfully. The expressions of EIF4E and cyclin D1 mRNAs and proteins were all decreased markedly after transfection with pGPU6/GFP/Neo-EIF4E (P＜0.05). The growth of MDA-MB-231 cells in the pGPU6/GFP/Neo-EIF4E-tranfected group was inhibited and the cell colony formation rate was statistically decreased (P＜0.05) as compared with those in the blank control and the pGPU6/GFP-transfected groups. The result of flow cytometry showed that the percentage of cells in G1 phase in the pGPU6/GFP/Neo-EIF4E-tranfected group was higher than that in the blank control group (71.30%±0.47% vs 53.10%±0.43%); however, the percentage of cells in S phase was signifcantly lower (12.53%±0.13% vs 26.47%±0.38%, P＜0.05). Conclusion: EIF4E siRNA can down-regulate EIF4E gene expression in human breast cancer MDA-MB-231 cells, suppress cell proliferation to some extent, and increase the number of cells in G1 phase with a decreased number of cells in S phase.EIF4E gene may become one of the important molecular targets to breast cancer. DOI:10.3781/j.issn.1000-7431.2011.03.003

The effects of EIF4E gene down-regulation induced by siRNA on the proliferation and cell cycle of human breast cancer cell line MDA-MB-231

We reported that transgenic expression of the bone morphogenetic protein (BMP) signaling inhibitor noggin in the mouse stomach, leads to parietal‐cell (PC) loss, expansion of transitional cells expressing markers of both mucus neck and zymogenic lineages, and to activation of proliferative mechanisms. Because these cellular changes were associated with increased levels of the hormone gastrin, we investigated if gastrin mediates the expression of the phenotypic changes of the noggin transgenic mice (NogTG mice). Three‐month‐old NogTG mice were crossed to gastrin‐deficient (GasKO mice) to generate NogTG;GasKO mice. Morphology of the corpus of wild type, NogTG, GasKO, and NogTG;GasKO mice was analyzed by H&E staining. Distribution of PCs and zymogenic cells (ZCs) was analyzed by immunostaining for the H+/K+‐ATPase and intrinsic factor (IF). Expression of the H+/K+‐ATPase and IF genes and proteins were measured by QRT‐PCR and western blots. Cell proliferation was assessed by immunostaining for proliferating cell nuclear antigen. The corpus of the NogTG;GasKO mice displayed a marked reduction in the number of PCs and ZCs in comparison to NogTG mice. Further, cellular proliferation was significantly lower in NogTG;GasKO mice, than in the NogTG mice. Thus, gastrin mediates the increase in gastric epithelial cell proliferation induced by inhibition of BMP signaling in vivo. Moreover, gastrin and BMP signaling exert cooperative effects on the maturation and differentiation of both the zymogenic and PC lineages. These findings contribute to a better understanding of the factors involved in the control of gastric epithelial cell homeostasis.

Regulation of gastric epithelial cell homeostasis by gastrin and bone morphogenetic protein signaling

OBJECTIVE
To explore the expression of connective tissue growth factor (CTGF) in pancreatic cancer and its influence on the proliferation and migration of cancer cells.

METHODS
The expression of CTGF in pancreatic cell line PANC-1 cells was analyzed by real-time PCR and in pancreatic carcinoma (50 cases) tissues by immunohistochemistry. The ability of proliferation and migration in vitro of PANC-1 cells was tested by MTT assay, scratch test and Boyden chamber test after the CTGF gene was overexpressed by Ad5-CTGF or silenced with Ad5-siCTGF transfection.

RESULTS
CTGF was overexpressed in both pancreatic cancer cells and tissues. Overxpression of CTGF leads to increased proliferation and migration of PANC-1 cells. The CTGF-transfected PANC-1 cells showed apparent stronger proliferation ability and scratch-repair ability than that of empty vector controls. The results of Boyden chamber test showed that there were 34 cells/field (200× magnificantion) of the CTGF-transfected overexpressing cells, much more than the 11 cells/field of the empty vector control cells; and 6 cells/microscopic field of the Ad5-siCTGF-transfected silenced cells, much less than the 15 cells/field of the control cells.

CTGF is overexpressed in both pancreatic cancer cells in vitro and in vivo, indicating that it may play an important role in the cell proliferation and migration in pancreatic cancer.

[Role of connective tissue growth factor (CTGF) in proliferation and migration of pancreatic cancer cells].

Aims and background MicroRNAs are small, noncoding, single-stranded RNAs that regulate gene expression post-transcriptionally. miR-206 is known to play an important role in breast cancer metastasis. When we sought to predict the target of miR-206 by Targetscan, Pictar and miRanda, we found Cdc42 was a potential one. In this study, we transfected miR-206 into MDA-MB-231 cells and examined Cdc42 protein expression as well as MMP-2 and MMP-9, which are also associated with metastasis of breast cancer. Since Cdc42 is involved in filopodia and invadopodia formation, we examined the morphological changes of MDA-MB-231 cells. Methods and study design miR-206 mimics were transfected into MDA-MB-231 cells using Lipofectamine™ 2000. Protein expression was detected by Western blot. Cells were stained with FITC-phalloidin to visualize F-actin. Invasive ability and migratory ability were examined by invasion assay and migration assay in vitro. Results Cdc42, MMP-2 and MMP-9 were downregulated on the protein level. The formation of filopodia, which requires Cdc42, was inhibited in miR-206 transfected cells, even under the stimulation of EGF. The invasion and migration of MDA-MB-231 cells in vitro was inhibited by miR-206 too. Conclusions The results suggest that miR-206 may suppress invasion and migration of MDA-MB-231 cells in vitro partly via regulating actin cytoskeleton remodelling such as filopodia formation. Free full text available at www.tumorionline.it

Effect of microRNA-206 on Cytoskeleton Remodelling by Downregulating Cdc42 in MDA-MB-231 Cells

AIMS AND BACKGROUND
MicroRNAs are small, noncoding, single-stranded RNAs that regulate gene expression post-transcriptionally. miR-206 is known to play an important role in breast cancer metastasis. When we sought to predict the target of miR-206 by Targetscan, Pictar and miRanda, we found Cdc42 was a potential one. In this study, we transfected miR-206 into MDA-MB-231 cells and examined Cdc42 protein expression as well as MMP-2 and MMP-9, which are also associated with metastasis of breast cancer. Since Cdc42 is involved in filopodia and invadopodia formation, we examined the morphological changes of MDA-MB-231 cells.

METHODS AND STUDY DESIGN
miR-206 mimics were transfected into MDA-MB-231 cells using LipofectamineTM 2000. Protein expression was detected by Western blot. Cells were stained with FITC-phalloidin to visualize F-actin. Invasive ability and migratory ability were examined by invasion assay and migration assay in vitro.

RESULTS
Cdc42, MMP-2 and MMP-9 were downregulated on the protein level. The formation of filopodia, which requires Cdc42, was inhibited in miR-206 transfected cells, even under the stimulation of EGF. The invasion and migration of MDA-MB-231 cells in vitro was inhibited by miR-206 too.

The results suggest that miR-206 may suppress invasion and migration of MDA-MB-231 cells in vitro partly via regulating actin cytoskeleton remodelling such as filopodia formation.

Effect of microRNA-206 on cytoskeleton remodelling by downregulating Cdc42 in MDA-MB-231 cells.

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology

Syringomyelia secondary to thoracic spinal dural arteriovenous fistula presenting as paraparesis.

We were very interested to read the analysis by Sanchez et al of the largest cohort study of anterior cranial fossa dural arteriovenous fistulas (ACF DAVFs). In this study, 60 cases of ACF DAVFs from 12 centers between 1990 and 2017 in the CONDOR database are included. Fiftythree of the 60 cases (88.8%) received treatment. The majority of the patients underwent microsurgery (66%, 35/53) or endovascular surgery (32%, 17/53). All those who received microsurgery as their first line of treatment had their ACF DAVFs completely removed. Only 53% (9/17) of patients who received an endovascular approach as firstline treatment achieved angiographic cure. Complications were lower in patients treated with microsurgery (6%, 2/35) compared with endovascular treatment (12%, 2/17). At an average of 75 days after endovascular treatment, 18% (2/11) of ACF DAVFs had angiographic recurrence. This article also goes into great detail about the clinical presentation and angioarchitecture of ACF DAVFs, which is a significant contribution to the literature. However, surgery is far more traumatic, necessitates a longer hospital stay and may expose patients to unnecessary risks. CONDOR contains 27 years of data, with data collection beginning in 1990. As a result, endovascular approaches include a wide range of techniques and devices. Recent advances in endovascular catheters, liquid embolic agents and endovascular techniques may result in a higher rate of successful embolizations, changing the conclusion that “Most ACFdAVFs should be managed with microsurgery”. In our unpublished study, 40 patients received transarterial embolization (TAE) as a firstline treatment. The complete occlusion rate for exclusive TAE was 86.8% (33/38). The ophthalmic artery, the middle meningeal artery and the sphenopalatine arteries were the most commonly used arterial access routes for complete embolization. Complications occurred in one patient (2.5%, 1/40) (retinal ischemia). There has been no recurrence of the fistulas based on imaging followup. The findings show higher obliteration rates as well as lower complication and recurrence rates than in previous studies with TAE exclusively. 3 We concluded that endovascular treatment is also a good option for ACF DAVFs. Microsurgery should be used as an adjunct or as a remedial measure. We thank the authors for introducing the largest cohort of ACF DAVFs to the readers.

Correspondence on “Natural history, angiographic presentation and outcome of anterior cranial fossa dural arteriovenous fistulas” by Sanchez et al

Background Craniocervical junction (CCJ) arteriovenous fistulas (AVFs) are rare. The current treatment strategies for AVFs with different angioarchitecture need to be clarified. The present study aimed to analyse the correlation between angioarchitecture and clinical characteristics, share our experience in treating this disease and identify risk factors associated with subarachnoid haemorrhage (SAH) and poor outcomes. Methods A total of 198 consecutive patients with CCJ AVFs from our neurosurgical centre were retrospectively reviewed. The patients were grouped according to their clinical manifestations, and their baseline clinical characteristics, angioarchitecture, treatment strategies and outcomes were summarised. Results The patients’ median age was 56 years (IQR 47–62 years). The majority of patients were men with 166 (83.8%) patients. The most common clinical manifestation was SAH (52.0%), followed by venous hypertensive myelopathy (VHM) (45.5%). The most common CCJ AVFs type was dural AVF, with 132 (63.5%) fistulas. The most frequent fistula location was C-1 (68.7%) and dural branch of vertebral artery (70.2%) was the most involved arterial feeders for fistulas. The most common direction of venous drainage was descending intradural drainage (40.9%), followed by ascending intradural drainage (36.5%). Microsurgery was the most common treatment strategy applied for 151 (76.3%) patients, 15 (7.6%) patients were treated with interventional embolisation only, and 27 (13.6%) received both interventional embolisation and microsurgical treatment. The learning curve for microsurgery only was analysed by cumulative summation method, and the turning point was the 70th case, and blood loss in post-group was lower than that in pre-group (p=0.034). At the last follow-up, there were 155 (78.3%) patients with favourable outcomes (modified Rankin Scale(mRS)<3). Age≥56 (OR 2.038, 95% CI 1.039 to 3.998, p=0.038), VHM as the clinical manifestation (OR 4.102, 95% CI 2.108 to 7.982, p<0.001) and pretreatment mRS≥3 (OR 3.127, 95% CI 1.617 to 6.047, p<0.001) were significantly associated with poor outcomes. Conclusion The arterial feeders and direction of the venous drainage were important factors in the clinical presentations. The location of fistula and drainage vein was essential for choosing different treatment strategies. Older age, VHM onset and poor pretreatment functional status predicted poor outcomes.

Clinical features, treatment strategies and outcomes of craniocervical junction arteriovenous fistulas: a cohort study of 193 patients

OBJECTIVE
Current knowledge about venous hypertensive myelopathy (VHM) is incomplete. This study was performed with the aim of clarifying the clinical features and outcomes of craniocervical VHM.

METHODS
This retrospective, single-center cohort study included 65 patients with craniocervical junction arteriovenous fistulas resulting in VHM treated in Xuanwu Hospital from January 1, 2002, to December 30, 2020. All patients underwent microsurgery or endovascular treatment. The primary outcome was neurological function assessment using the Japanese Orthopaedic Association (JOA) scale, modified Aminoff-Logue Scale (mALS), and Venous Hypertensive Myelopathy Scale (VHMS). The secondary outcomes were recurrences and postoperative adverse events. Pearson linear regression and receiver operating characteristic curves were used to evaluate the relationships among the three scales. Kaplan-Meier and multivariate logistic regression analyses were performed to predict outcomes.

RESULTS
The mean patient age was 57.4 ± 11.4 years, and 88% of patients were male. The 1-year follow-up rate was 83.1%, and the 5-year follow-up rate was 50.8%. The VHMS was correlated with the JOA (R2 = 0.6722) and mALS (R2 = 0.7399) and increased the assessment accuracy by approximately 20% when compared with the other two scales. Overall, 25.9% of patients experienced delayed neurological decline beyond the 1-year follow-up. Further logistic regression suggested that age > 65 years was an independent predictor (OR 7.831, 95% CI 1.090-56.266; p = 0.041). Embolic recanalization and new bilateral symmetry feeders were the major reasons for recurrence. Recurrence increased the risk of adverse events after the second surgery (OR 20.455, 95% CI 1.170-357.320; p = 0.039).

CCJ AVFs resulting in VHM are a rare but deadly complication, and providers should be cautious of age-related delayed neurological decline and strive for a one-time anatomical cure.

Clinical and prognostic features of venous hypertensive myelopathy from craniocervical arteriovenous fistulas: a retrospective cohort study.

Letter to the Editor. Endovascular treatment: a first-line approach for anterior cranial fossa DAVFs?

High diagnostic performance of time-resolved MR angiography in spinal arteriovenous shunts.

Concomitant thoracic spinal dural arteriovenous fistula and spinal cavernous malformation.

Objective Arteriovenous fistulas (AVFs) in the craniocervical junction (CCJ) region are a rare occurrence with special clinical manifestations. This study retrospectively reviewed patients with CCJ AVFs treated at our neurosurgical center, aiming to enhance the understanding of CCJ AVFs. Methods A total of 113 patients with CCJ AVFs treated at our neurosurgical center between January 2013 and December 2020 were enrolled. They were grouped as patients with CCJ AVFs with spinal arterial feeders (n = 20) and patients with CCJ AVF without spinal arterial feeders (n = 93). Clinical presentation, angiographic characteristics, intraoperative findings, and treatment outcomes were analyzed. Results The patients’ median age was 55 years (IQR 47.5–62 years). The proportion of males in the group without spinal arterial feeders was significantly higher (p = 0.001). Subarachnoid hemorrhage (SAH) was the most common clinical presentation, especially in the group with spinal arterial feeders (p < 0.001). There were significant differences in AVF type, fistula location, and direction of the venous drainage between the two groups (p < 0.001). Intervention embolization combined with microsurgery was more common in treating AVFs with spinal arterial feeders (p = 0.006). Spinal arterial feeders did not affect the outcome (p = 0.275). Conclusions SAH was the most common presentation of CCJ AVFs in this study. Microsurgery and interventional embolization were optional treatment strategies. The angioarchitecture of CCJ AVFs was essential for selecting treatment strategies.

Arteriovenous fistulas in the craniocervical junction region: With vs. without spinal arterial feeders

Multiple telescoping flow diverter technique in endovascular treatment of a giant petrous and cavernous carotid aneurysm.

Background Although the angioarchitecture of perimedullary arteriovenous fistulas (PMAVFs) is straightforward, their size and blood flow are highly heterogeneous. This study aimed to evaluate the differences in clinical features and outcomes of PMAVFs based on lesion size and blood flow. Methods 114 consecutive patients with PMAVFs from two institutes were retrospectively reviewed. The lesions were classified as either micro-PMAVFs (shunt point diameter <1 cm) or macro-PMAVFs (shunt point diameter ≥1 cm). Results The patients with micro-PMAVFs were older at the first presentation (33.50 vs 13.50 years, p<0.001). Macro-PMAVFs were more commonly associated with spinal metameric arteriovenous shunts (6.9% vs 28.6%, p=0.003). Compared with the macro-PMAVFs, the micro-PMAVFs showed a significantly higher risk of gradual clinical deterioration after initial onset (73.6%/year vs 10.0%/year; HR 3.888, 95% CI 1.802 to 8.390, p=0.001). A total of 58.6% of the micro-PMAVFs were treated surgically, whereas 85.7% of the macro-PMAVFs were treated via endovascular approaches. Complete obliteration was 73.7% for the whole cohort, and was more common for the micro-PMAVFs than for the macro-PMAVFs (87.9% vs 58.9%, p=0.001). At the last follow-up, spinal function was significantly improved compared with the pretreatment status, and the rate of severe disability of patients with macro-PMAVFs was slightly but not significantly higher than that of patients with micro-PMAVFs (16.1% vs 8.6%, p=0.315) Conclusions The clinical risks, treatment strategies and obliteration rates of PMAVFs differ based on their size and blood flow.

Clinical features and outcomes of perimedullary arteriovenous fistulas: comparison between micro- and macro-type lesions

BACKGROUND: The natural history of spinal cord cavernous malformations (SCCMs) remains relatively unclear. OBJECTIVE: To investigate the natural history for hemorrhagic risks and neurological outcomes, as well as relevant predicting factors, of SCCMs. METHODS: All patients between 2002 and 2019 with diagnosis of SCCMs were identified retrospectively. An observational study of patients with conservative management was performed to reveal the natural history of SCCMs. RESULTS: We identified 305 patients in the full cohort, including 126 patients who were conservatively treated for at least 6 months (median observational period, 24.0 months). Forty-five hemorrhage events occurred during 527 person-years of follow-up, yielding an annual hemorrhage rate of 8.5% per person-year. The 1-, 2-, and 5-year cumulative risks of hemorrhage were 13.9%, 26.1%, and 35.1%, respectively. Prior hemorrhage (hazard ratio [HR] = 12.948, P = .012) and pediatric patients (HR = 2.841, P = .031) were independent predictors of hemorrhage in the long-term follow-up. Familial form (adjusted odds ratio [OR] = 30.695, P = .010) and subsequent hemorrhage events (adjusted OR = 16.333, P = .000) were independent risk factors for worsening of neurological function, and baseline neurological status (adjusted OR = 78.984, P = .000) and presence of subsequent hemorrhage (adjusted OR = 9.611, P = .001) were significantly associated with neurological outcomes. CONCLUSION: The natural history of SCCMs varies. Baseline characteristics, such as pediatric patients, familial form, and baseline neurological status, as well as prior and subsequent hemorrhagic events, significantly affect the natural history of the SCCMs, which prompts a differentiated treatment strategy.

Natural History of Spinal Cord Cavernous Malformations: A Multicenter Cohort Study

Objective To define the pattern of long-term clinical outcomes and prognostic factors in patients with spinal dural arteriovenous fistulas (SDAVFs). Desgin Prospective cohort study based on constantly recruiting patients with SDAVFs in two medical centres in China. Setting Patients with SDAVFs were recruited consecutively between March 2013 and December 2014 in two referral centres. Participants A prospective cohort of 94 patients with SDAVFs was included in this study, and 86 patients (mean age 53.0 years, 71 men) completed the study. Patients who had previously undergone endovascular or neurosurgical treatment or had neurological dysfunction caused by other diseases or refused treatment were excluded. Interventions All patients underwent neurosurgery or endovascular embolisation. These patients were evaluated with the modified Aminoff and Logue’s Scale (mALS) 1 day before and 3, 6, 12 and 72 months after treatments. Results The duration of symptoms ranged from 0.5 to 66 months (average 12.8 months). The location of SDAVFs was as follows: 33.7% above T7, 50.0% between/include T7 and T12% and 16.3% below T12. 75 patients (87.2%) underwent neurosurgical treatment, and 9 patients (10.5%) underwent endovascular treatment. 58 patients (67.4%) exhibited an improvement in mALS of one point or greater at 72 months. Patients with less disability were more likely to improve at 72 months (p<0.05). 48 patients (55.8%) showed deterioration at 72 months compared with 12 months. 61% of the patients suffered numbness, and 22% had pain before treatment. However, 81% of patients had numbness, and 28% had pain after treatment. This deterioration was related to 1-year mALS and age. Conclusion Nearly two-thirds of the patients experienced clinical improvement at 72 months, and preoperative (1 day before treatment) mALS was the strongest predictor of clinical improvement. However, 55.8% of patients showed deterioration after temporary recovery. All patients with SDAVFs should accept treatment as soon as possible.

Long-term outcomes and prognostic factors in patients with treated spinal dural arteriovenous fistulas: a prospective cohort study

Background Dural arteriovenous fistulas (DAVFs) in the Galen region are the most deeply located and most complex type of dural arteriovenous fistulas. However, cases of DAVFs in this region have not been well described. Thus, we aimed to summarize the characteristics of Galenic DAVFs involving clinical symptoms, anatomical architecture, and drainage patterns, providing experientially therapeutic strategies for these lesions based on our 20 years of clinical experience. Methods We retrospectively examined 31 patients with Galenic DAVFs between January 2000 and June 2021. A comprehensive analysis was carried out based on the symptoms, imaging features, feeding arteries, draining veins, number and location of the fistulas, choice of treatment methods, and prognosis assessment. Results Twenty-nine patients received endovascular embolization, and no perioperative deaths occurred. A transarterial approach was performed in 27 patients, and a combined transarterial and transvenous approach in one. And in one case, access was established by surgical drilling and embolization was done via the venous route. Twenty-four cases were completely obliterated after first embolization, and another five cases received a second period treatment. Only one patient developed cognitive dysfunction after embolization, and the outcomes of the remaining patients were improved at long-term follow-up. Conclusion The understanding of symptoms of non-hemorrhagic neurological deficits in DAVF needs to be further clarified. Lesions with pial feeders may be considered first when determining surgical orders. Multi-approach and multi-stage embolization would be safe and effective. Excessive embolization and deep-vein system obstruction should be avoided. Approach creation by surgery would be an innovative interventional therapy.

Adult dural arteriovenous fistulas in Galen region: More to be rediscovered

Purpose Endovascular coil occlusion is a successful and rapidly evolving strategy used to treat patients who present with intracranial aneurysms. This study aimed to compare the safety and efficacy of the Avenir® and AxiumTM passive mechanically detachable coil systems. Methods A prospective, multicenter, randomized controlled study was carried out at ten medical centers from March 2018 to December 2019. A series of consecutive patients diagnosed with intracranial aneurysms were randomly assigned to undergo endovascular treatment with either the Avenir® or the AxiumTM mechanically detachable coil systems. The short-term outcomes from the two groups were compared with a focus on treatment efficacy and safety. Results A total of 162 and 161 patients were enrolled in the Avenir and Axium groups, respectively. The rate of successful coil detachment was 100% for the Avenir group and 99.38% for the Axium group. At the six-month follow-up visit, the overall aneurysm occlusion rate was 94.66% for the Avenir group and 96.95% for the Axium group (p > 0.05). We observed no statistically significant differences in clinical condition (as per the modified Rankin Scale) or the degree of aneurysm occlusion (as determined by digital subtraction angiography [DSA] and Raymond-Roy Occlusion Classification). Surgical complications were reported in 27 subjects in the Avenir group and 22 in the Axium group (p > 0.05). DSA performed at 6 months revealed complete aneurysm occlusion in 84 and 86% of patients in the Avenir and Axium groups, respectively. Conclusion We observed no significant short-term differences with respect to efficacy or safety when using either Avenir® or AxiumTM coils for the treatment of intracranial aneurysms.

Avenir® vs. AxiumTM Coils for the Treatment of Intracranial Aneurysms: Results of a Multicenter Randomized Controlled Trial With Short-Term Follow-Up

Abstract Background: In the literature, filum terminale arteriovenous shunts (FTAVSs) always feature a single shunt point. Nidus-type FTAVSs have rarely been reported, and the best treatment strategy is unclear. This is a report of one exceptional case of a nidus-type FTAVS and surgical treatment of the lesion. Case description: The patient suffered from cauda equina syndrome for 9 months. Magnetic resonance imaging and spinal angiography revealed a nidus-type FTAVF at the L2 level. Surgical resection was performed in the hybrid operating room, and the nidus was completely resected with the assistance of intraoperative methylene blue angiography and neurophysiological monitoring. The postoperative neurological function was stable. Conclusions: A nidus-type arteriovenous shunt could originate from the FT, and in such cases, complete surgical resection with intraoperative neurophysiological monitoring in a hybrid operating room should be suggested.

Filum terminale arteriovenous shunt with nidus structure: a report of rare condition and treatment consideration

Contemporary treatments for spinal cord arteriovenous shunts are only based on clinicians' treatment experiences and expertise due to its rarity. We reviewed the clinical course of the largest multi-cantered cohort to evaluate the efficacy and deficiency of contemporary interventional treatments for spinal cord arteriovenous shunts. The clinical features, treatment results and clinical outcomes of 463 spinal cord arteriovenous shunts patients were retrospectively assessed. The main outcome was the neurological deterioration that was evaluated based on the modified Aminoff and Logue scale. According to post-treatment DSA, complete obliteration was defined as disappearance of the intradural lesion, whereas partial obliteration was defined as any residual intradural lesion remaining visible and was further categorized as shunt-reduction obliteration (the nidus or shunt points was reduced) or palliative obliteration (only obliterated aneurysms or feeders). Cure rate was 40.6% for whole cohort, 58.5% after microsurgery, and 26.4% after embolization. The curative resection was associated with non-metameric lesions, lesions with a maximum diameter < 3 cm and lesions without anterior sulcal artery supply. The curative embolization was associated with fistula-type lesions, non-metameric lesions, and main drainage diameter < 1.5 mm. Permanent treatment-related neurological deficits rate was 11.2% for the whole cohort, 16.1% after microsurgery, and 5.6% after embolization. The pre-treatment clinical deterioration rate was 32.5%/year, which decreased to 9.3%/year after clinical interventions. After partial treatment, the long-term acute and gradual deterioration rate were 5.3%/year and 3.6%/year, respectively. The acute deteriorations were associated with metameric lesions, craniocervical lesions, lesions with a maximum diameter ≥2 cm and residual aneurysm. Residual aneurysm was the only predictor of acute deterioration for non-metameric spinal cord arteriovenous shunts. The gradual deteriorations were associated with palliative obliteration, absence of pre-treatment acute deterioration and intact main drainage. Although clinical risks of spinal cord arteriovenous shunts were reduced after clinical interventions, contemporary treatments for spinal cord arteriovenous shunt remains associated with considerable risks and incomplete efficacy. Individualized treatment plans should be adopted according to the angioarchitectural features and major clinical risks of specific lesions. There is a higher opportunity for complete obliteration for lesions with simple angioarchitecture. However, regarding most of spinal cord arteriovenous shunts with complex vascular anatomy, partial treatment is the only choice. For these patients, palliative obliteration targeting the aneurysms is recommended for reducing hemorrhagic risk, whereas shunt-reduction obliteration is necessary for non-haemorrhagic myelopathy. Contemporary treatment is ineffective in reducing hemorrhagic risk of incurable metameric spinal cord arteriovenous shunts.

The efficacy and deficiency of contemporary treatment for spinal cord arteriovenous shunts.

Seizure outcome in patients with seizure-associated dural arteriovenous fistulas.

Supplemental Digital Content is available in the text. Background and Purpose: Paravertebral arteriovenous shunts (PVAVSs) are rare. Whether the intradural venous system is involved in drainage may lead to differences in clinical characteristics through specific pathophysiological mechanisms. This study aims to comprehensively evaluate the natural history and clinical outcomes of PVAVSs with or without intradural drainage. Methods: Sixty-four consecutive patients with PVAVSs from 2 institutes were retrospectively reviewed. Lesions were classified as type A (n=28) if the intradural veins were involved in drainage; otherwise, they were classified as type B (n=36). The clinical course from initial presentation to the last follow-up was analyzed. Results: The patients with type A shunts were older at presentation (52.5 versus 35.5 years, P<0.0001) and more likely to have lower spinal segments affected than patients with type B PVAVSs (67.8% versus 13.9%, P=0.00006). After presentation, the deterioration rates related to gait and sphincter dysfunction were significantly higher in patients with type A than type B shunts (gait dysfunction: 71.8%/y versus 17.0%/y, P=0.0006; sphincter dysfunction: 63.7%/y versus 11.3%/y, P=0.0002). According to the angiogram at the end of the latest treatment, 79% of type A and 75% of type B PVAVSs were completely obliterated. If the lesions were partially obliterated, a significantly higher clinical deterioration rate was observed in patients with type A shunts than those with type B shunts (69.9%/y versus 3.2%/y, P=0.0253). Conclusions: Type A PVAVSs feature rapid progressive neurological deficits; therefore, early clinical intervention is necessary. For complex lesions that cannot be completely obliterated, surgical disconnection of all refluxed radicular veins is suggested.

Natural History and Clinical Outcomes of Paravertebral Arteriovenous Shunts

Background: Contemporary treatments for spinal cord arteriovenous shunt (SCAVS) are only based on clinicians’ treatment experiences and expertise due to its rarity. We reviewed the clinical course of the largest multi-cantered SCAVS cohort for efficacy and deficiency of contemporary interventional treatments for SCAVSs. 
 
Methods: The clinical features, treatment results and clinical outcomes of 459 SCAVSs patients were retrospectively assessed. Partial obliteration of SCAVS was defined as shunt-reduction obliteration (the nidus or shunt points was reduced) or palliative obliteration (only obliterated aneurysms or feeders). Neurological deterioration occurred 2 weeks after treatment was defined as long-term deterioration and further classified as acute and gradual. 
 
Findings: Cure rate was 40·3% for whole cohort, 58·5% after microsurgery, and 25·6% after embolization. Non-metameric lesions, lesions with a maximum diameter < 3 cm and lesions without anterior sulcal artery supply were independent predictors for complete resection. Fistula-type lesions and main drainage diameter < 1·5 mm were independent predictors for complete embolization. Permanent treatment-related neurological deficits rate was 11·3% for the whole cohort, 16·1% after microsurgery, and 5·6% after embolization. The pre-treatment clinical deterioration rate was 32·4%/year, which decreased to 9·2%/year after clinical interventions. After partial treatment, the long-term acute and gradual deterioration rate were 5·3%/year and 3·6%/year, respectively. The acute deteriorations were associated with metameric lesions, craniocervical lesions, lesions with a maximum diameter ≥2 cm and residual aneurysms. The gradual deteriorations were associated with palliative obliteration, absence of pre-treatment acute deterioration and intact main drainage. 
 
Interpretation: Although clinical risks of SCAVSs were reduced after clinical interventions, contemporary treatments of SCAVS remains associated with considerable risks and incomplete efficacy. Individualized treatment plans should be adopted according to the angioarchitectural features and major clinical risks of specific lesions. Contemporary treatment is ineffective in reducing hemorrhagic risk of incurable spinal metameric arteriovenous shunts. 
 
Funding Statement: None. 
 
Declaration of Interests: None. 
 
Ethics Approval Statement: The study was reviewed and approved by the local ethics committee with waiver of informed consent from patients given its retrospective nature.

Treatment for Spinal Cord Arteriovenous Shunts: The Efficacy and Deficiency of Contemporary Clinical Interventions

Cavernous malformations (CMs) affecting the central nervous system occur in approximately 0.16% to 0.4% of the general population. The majority (85%) of the CMs are in a sporadic form, but the genetic background of sporadic CMs remains enigmatic. Of the 81 patients, 73 (90.1%) patients were detected carrying somatic missense variants in 2 genes: MAP3K3 and PIK3CA by whole-exome sequencing (WES). The mutation spectrum correlated with lesion size (P = 0.001), anatomical distribution (P < 0.001), MRI appearance (P = 0.004) and haemorrhage events (P = 0.006). PIK3CA mutation was a significant predictor of overt haemorrhage events (P = 0.003, OR = 11.252, 95% CI = 2.275-55.648). Enrichment of endothelial cell (EC) population was associated with a higher fractional abundance of the somatic mutations. Overexpression of the MAP3K3 mutation perturbed angiogenesis of EC models in vitro and zebrafish embryos in vivo. Distinct transcriptional signatures between different genetic subgroups of sporadic CMs were identified by single-cell RNA-sequencing (scRNA-seq) and verified by pathological staining. Significant apoptosis in MAP3K3 mutation carriers and overexpression of GDF15 and SERPINA5 in PIK3CA mutation carriers contributed to their phenotype. We identified activating MAP3K3 and PIK3CA somatic mutations in the majority (90.1%) of sporadic CMs and PIK3CA mutations could confer a higher risk for overt haemorrhage. Our data provide insights into genomic landscapes, propose a mechanistic explanation and underscore the possibility of a molecular classification for sporadic CMs.

Somatic MAP3K3 and PIK3CA mutations in sporadic cerebral and spinal cord cavernous malformations.

Pharmacologic provocative testing in combination with intraoperative neurophysiologic monitoring during arteriovenous malformation embolization.

The purpose of this study was to evaluate the technical efficacy and safety of transvenous Onyx embolization for dural arteriovenous fistulas (DAVFs) with concomitant transvenous balloon protection of the venous sinus when transarterial route failed or was not feasible.

METHODS
Between September 2010 and December 2016, thirty-six patients presenting with intracranial DAVFs underwent transvenous balloon-assisted Onyx embolization. The technical efficacy, treatment-related complications, and angiographic and clinical outcomes were reviewed from our prospectively maintained DAVF database.

RESULTS
According to the Cognard classification, 11 patients presented with clinically symptomatic Cognard type I; 11 cases with Cognard type IIa; 10 cases with Cognard type IIb and 4 cases with Cognard type IIa+b. Complete angiographic occlusion of the DAVFs at the latest follow-up (mean 18 months after transvenous embolization) was achieved in 28 patients (77.8%), near-complete angiographic occlusion with minimal residual fistula in 5 patients (13.9%) and significant flow reduction of the DAVF in 2 patients (5.6%) and residual fistula for further treatment in 1 (2.8%) patient. Total clinical cure or remission of the pre-treatment symptoms was achieved in 31 patients (31/36, 86.1%; 26 and 5 cases respectively). Affected venous sinus was preserved in 28 patients, intentionally occluded in 7 patients and gradually occluded in 1 patient. There were no immediate or long term persistent complications after treatment.

Transvenous Onyx embolization of dural arteriovenous fistulas with combined transvenous balloon protection of the venous sinus is safe and effective in achieving high occlusion rate, low embolization-related complications and satisfactory clinical outcomes.

Transvenous onyx embolization for dural arteriovenous fistula with concomitant transvenous balloon protection of the venous sinus.

Preservation of coexisting normal superior petrosal vein in the microsurgical treatment of superior petrosal sinus dural arteriovenous fistulas assisted by indocyanine green video angiography.

Craniocervical junction dural arteriovenous fistula with rare fistulous site.

Corrigendum to Morphological Characteristics of Pericallosal Artery Aneurysms and Their High Propensity for Rupture [World Neurosurgery 133 (2020) e320-e326].

The natural history of intradural spinal cord arteriovenous shunts is unknown. We performed an observational study in a consecutive patient cohort with symptomatic intradural spinal cord arteriovenous shunts who were admitted to three institutes to investigate the clinical course of this complex disease, which would provide valuable evidence to inform clinical decision-making. The clinical course of patients with symptomatic intradural spinal cord arteriovenous shunts from initial presentation to occurrence of clinical deterioration, initiation of treatment, or last follow-up was analysed. Patients with at least 1 month of observation were included in this study. Clinical onset and deterioration patterns were divided into acute and gradual. Annual and cumulative rates of clinical deterioration as well as their risk factors were analysed using Kaplan-Meier life table analysis and Cox proportional hazards model. To assess risks and benefits of treatment, post-treatment clinical courses were further assessed. Four hundred and sixty-six patients with a mean observational period of 36.9 ± 58.8 months were included; 56.7% of patients presented with acute onset, of whom 77.3% experienced spontaneous recovery. Age of onset older than 28 years, initial modified Aminoff and Logue scale of >3, mid-thoracic lesions and non-ventral lesions were independent predictors of failure for spontaneous recovery. The annual risk of general, acute and gradual clinical deterioration after onset was 30.7%, 9.9% and 17.7%, respectively. Risk of deterioration was highest in the early period after initial onset. Acute onset was the only independent risk factor [hazard ratio 1.957 (95% confidence interval, CI 1.324-2.894); P = 0.0008] of acute deterioration and gradual onset was the strongest predictor [hazard ratio 2.350 (95% CI 1.711-3.229); P < 0.0001] of the gradual deterioration among all the stratifying factors. After invasive treatment, complete obliteration was achieved in 37.9% of patients (138 of 364) and improved or stable clinical status was noted in 80.8% of patients. Forty-two patients (11.5%) experienced permanent complications. Overall post-treatment deterioration rate was 8.4%/year, and 5.3%/year if permanent complications were excluded. The natural history of symptomatic spinal cord arteriovenous shunts is poor, especially in the early period after onset, and early intervention is thus recommended. Initial onset pattern significantly affects the natural history of the lesion, which prompts a differentiated treatment strategy.

Natural history of spinal cord arteriovenous shunts: an observational study.

AIM
Pericallosal artery aneurysms (PAAs) are highly susceptible to rupture and challenging to treat. We aimed to summarize their clinical outcomes and follow-up results and discuss the optimal therapeutic strategy.

From January 2013 to May 2017, the charts of 49 patients with PAAs, representing 2.43% of 2,018 consecutive patients with intracranial aneurysms (IAs) were reviewed. The clinical and radiological data of these patients were retrospectively analyzed.

RESULTS
There were no technical failures in the clipping group, but one patient in the coiling group presented rebleeding during the operation, resulting in a poor prognosis. Although the difference was not significant, the coiling group had a better complete recovery rate than the clipping group [overall: coiling, n=20 (87.0%) vs clipping, n=11 (68.8%), p=0.33; unruptured PAAs: coiling, n=12 (92.3%) vs clipping, n=5 (83.3%); ruptured PAAs: coiling, n=8 (80%) vs clipping, n=6 (60%), p=0.63]. One patient in the coiling group exhibited recurrence. No patients experienced rebleeding during the follow-up period in either group.

In our study, both endovascular coiling and microsurgery were technically feasible and achieved favorable clinical outcomes in patients with PAAs. Longer radiological follow-up is necessary. Patients should be evaluated by a multidisciplinary team prior to determining the optimal treatment modality.

Microsurgical and Endovascular Treatment Outcomes in Pericallosal Artery Aneurysms: A Single Center Retrospective Analysis.

The morphological characteristics of pericallosal artery aneurysms and their high propensity for rupture.

Recurrent Secondary Trigeminal Neuralgia Caused by Obliterated Tentorial Dural Arteriovenous Fistula Cured with Surgical Resection: Case Report and Literature Review.

Background The short-term outcomes and prognostic factors of patients with spinal dural arteriovenous fistulas (SDAVFs) have not been defined in large cohorts. Objective To define the short-term clinical outcomes and prognostic factors in patients with SDAVFs. Methods A prospective cohort of 112 patients with SDAVFs were included consecutively in this study. The patients were serially evaluated with the modified Aminoff and Logue’s Scale (mALS) one day before surgery and at 3 months, 6 months and 12 months after treatment. Univariate and multivariate analyses were performed to identify demographic, clinical and procedural factors related to favourable outcome. Results A total of 94 patients (mean age 53.5 years, 78 were men) met the criteria and are included in the final analyses. Duration of symptom ranged from 0.5 to 66 months (average time period of 12.7 months). The location of SDAVFs was as follows: 31.6% above T7 level, 48.4% between T7 and T12 level (including T7 and T12) and 20.0% below T12 level. A total of 81 patients (86.2%) underwent neurosurgical treatment, 10 patients (10.6%) underwent endovascular treatment, and 3 patients (3.2%) underwent neurosurgical treatment after unsuccessful embolisation. A total of 78 patients demonstrated an improvement in mALS score of one point or greater at 12 months. Preoperative mALS score was associated with clinical improvement after adjusting for age, gender, duration of symptoms, location of fistula and treatment modality using unconditional logistic regression analysis (p<0.05). Conclusion Approximately four fifths of the patients experienced clinical improvement at 12 months and preoperative mALS was the strongest predictor of clinical improvement in the cohort.

Clinical outcomes and prognostic factors in patients with spinal dural arteriovenous fistulas : a prospective cohort study in two Chinese centres

Abstract Internal carotid artery (ICA) supraclinoid segment aneurysms extending into the sellar region and leading to pituitary dysfunction are a rare occurrence. To date, long-term follow up of pituitary function 2 years post-treatment has never been reported. Herein, we present a case of pituitary dysfunction due to an unruptured ophthalmic segment internal carotid artery aneurysm and report improved 2-year follow-up results. A 76-year-old male presented with disturbed consciousness due to hyponatremia, which was caused by hypoadrenocorticism resulting from pituitary dysfunction complicated by hypogonadism and hypothyroidism. Computed tomography angiography revealed an intracranial aneurysm of the ophthalmic segment of the right ICA with an intrasellar extension. Thus, digital subtraction angiography and coil embolization were performed, followed by hormone replacement therapy. A 2-year follow-up revealed a partial improvement in the pituitary function, including complete restoration of thyroid-stimulating hormone level and other thyroid hormones levels, and partial restoration of testosterone levels, followed by discontinuation of thyroid hormone replacement therapy. However, the mechanisms of such pituitary dysfunction and the effects of various treatments, including clipping and coiling, on different hormones of pituitary function recovery remain unclear. A long-term follow-up of >2 years may elucidate the pituitary function recovery post-treatment and provide a medication adjustment for hormone replacement therapy.

Pituitary Dysfunction from an Unruptured Ophthalmic Internal Carotid Artery Aneurysm with Improved 2-year Follow-up Results: A Case Report

Objective 
To explore the application of intraprocedural C-arm CT assisted trans-perforator embolization of deep arteriovenous malformations (AVM). 
 
Methods 
From July 2015 to June 2017 at Neurosurgery Department, Xuanwu Hospital Capital Medical University, a total of 21 cases of hemorrhagic deep AVM were retrospectively reviewed. There were 11 men and 10 women with the average age of 24.3 years old. Among them, 20 lesions were located at the basal ganglia and 1 lesion at the fourth ventricle. Three lesions were classified as Spetzler-Martin grade 4 and 18 lesions were grade 3. All patients were treated with transarterial embolization under general anesthesia. The tip of microcatheter was localized with intraoperative C-arm CT technique when trans-perforator embolization was intended. 
 
Results 
Among 21 patients, a total of 49 times of embolization were performed. Twenty-five times of intraoperative C-arm CT scans were used in 37 times of trans-perforator embolization. The tip of microcatheter was positioned 22 times at the safe region and 3 times at the dangerous area. The immediate post-operative angiography revealed complete occlusion or subtotal occlusion in 8 cases, obliteration of hemorrhage-related structures in 11 and partial embolization in 2. Intraoperative ventricular hemorrhage occurred in 2 cases and 1 of them presented with numbness of contralateral extremities post embolization. Twelve cases were followed up by DSA at 4-17 months post embolization. Five lesions which were obliterated completely or subtotally developed no further changes in follow-up angiogram when compared with immediate post-operative results. In 7 lesions which were treated with obliteration of hemorrhage-related structures, the nidus of 1 lesion disappeared completely and that in 6 other lesions had residues without hemorrhage-related structures. The remaining 9 cases were clinically followed up at 6 months post embolization. Recurrent hemorrhage and new-onset neurologic deficits were not found during follow-up period. 
 
The tip of microcatheter could be localized with the assistance of intraoperative C-arm CT technique, which might facilitate more precise trans-perforator embolization for deep AVM. 
 
Key words: 
Intracranial arteriovenous malformations; Embolization, therapeutic; Tomography, X-ray computed; Perforator artery

Intraprocedural C-arm CT assisted trans-perforator embolization of deep arteriovenous malformations

Transarterial Balloon-Assisted Glue Embolization of Pial Arteriovenous Fistulas.

Transvenous balloon-assisted Onyx embolization of dural arteriovenous fistulas of hypoglossal canal

Objective 
To share the experience of surgical repair for cor triatriatum in chidren. 
 
Methods 
Between July 2008 and June 2013, 24 children with cor triatriatum underwent surgical correction in Cardiac Center of Children's Hospital of Fudan University. The minimum age at the time of operation was 1 month, median age was 5 month; the minimum body weight at the time of operation was 3.5 kg, median body weight was 7.4 kg. Retrospectively analyzed their cardiac anatomy, clinical data, surgical procedures and follow-up data. 
 
Results 
Of all 24 patients, there were 4 patients diagnosed semplice cor triatriatum, and 20 patients diagnosed cor triatriatum associated with other malformation includes cardiac and non-cardiac issues. Procedures were performed on 22 patients to correct all cardiac defects in one stage. 1 patient underwent surgical repair for cor triatriatum and Glenn procedure as well. 1 patient, diagnosed as cor triatriatum and functional single ventricle S/P Glenn, underwent surgical repair for cor tiratriatum only. 2 patients recovered from pulmonary artery hypertension crisis after operation. 1 patient dead 17 days post procedure caused by respiratory failure. 23 patients discharged from hospital. The longest follow-up was 73 months, at least 12 months after discharge. All alive patients were in New York Heart Association's function class I-II. Echo assessment revealed normal size of left atriums of almost all alive patients one year after discharge. Till April 2015, no postoperation intervention, no blood flow obstruction at level of pulmonary veins, left atrium or mitral valve. 
 
Pediatric patients diagnosed cor tiratriatum sinister need intervention, no matter hemodynamic change occurs or not. Right time of surgery is important for successful treatment. 
 
Key words: 
Heart defects, congenital; Cor triatriatum; Cardiac surgical procedures

Experience of surgical repair for cor triatriatum sinister in chirdren

Objective 
To investigate the safety and efficacy of Lvis stent-assisted embolization of intracranial wide-necked aneurysms. 
 
Methods 
Twenty-four patients with intracranial wide-neck aneurysm treated with Lvis stent-assisted embolization at the Department of Neurosurgery, Beijing Xuanwu Hospital, Capital Medical University from January to July 2014 were selected. The clinical data, endovascular treatment methods and efficacy of the 24 patients were analyzed retrospectively. The degree of aneurysm embolization was evaluated according to Raymond classification, and its clinical efficacy was evaluated according to the modified Ranking scale (mRS) scores. 
 
Results 
The stents of 24 patients with intracranial wide-necked aneurysms were released completely (100%). Raymond grade Ⅰ embolization was 18 cases (75%), Raymond grade Ⅱ embolization was 4 cases (17%), and Raymond grade Ⅲ embolization was 2 cases (8%). One patient had in-stent thrombosis in the process of embolization, and after being treated with tirofiban hydrochloride sodium chloride injection, the thrombosis disappeared. The effective rate of embolization was 92%. After six months of follow-up, 21 patients had good curative effect (the mRS score 0-2), 3 had poor effect (the mRS score 3-6), and the good rate was 88%. 
 
Lvis stent-assisted embolization of intracranial wide-neck aneurysms is safe and feasible, the short-term efficacy is reliable. Because of the short follow-up time, further research is needed to determine the long-term stability of coils and adaptability of stents after embolization. 
 
Key words: 
Intracranial aneurysm; Stents; Endovascular treatment; Treatment outcome

Application of Lvis stents in endovascular treatment of intracranial wide-necked aneurysms

Objective 
To discuss the individualizing schedule of endovascular treatment for intracranial venous sinus thrombosis based on the clinical feature and the stage of the disease. 
 
Methods 
Forty-three patients diagnosed with intracranial venous sinus thrombosis in Xuanwu Hospital，Capital University of Medical Sciences and in Zhongshan Hospital Xiamen University during period of August 2010 to August 2011 were treated with endovascular therapy designed individually based on the clinical stage of the disease development.Of all 43 cases，22 cases with acute onset ( 1 month) were given mechanical thrombus maceration combined with balloon dilation vascular surgery or stentassisted venous sinus surgery，with taking anticoagulant for 12 months.The patients were followed up for 3 to 6 months (mean 4.5 months). 
 
Results 
Their symptoms and signs were all significantly improved，with headache relief in 29 cases (67.4%)，vision improvement in 28 cases (28/31，90.3%)，cerebrospinal fluidpressure decrease to normal level in 32 cases (32/43，74.4%); no improvement in 1 case，and a complication of subdural hematoma in 1 case.Three months follow-up of 39 patients，symptoms disappeared，the pressure cerebrospinal fluid in 36 cases returned to normal (94.3%)，the papilledema in 37 cases subsided (94.9%).After 6 months，16 patients were followed up with an angiography; 8 of them were found venous sinus clear，5 were found partial recanalization of venous sinus trunk，cortical veins and deep venous was partially compensation，and 3 cases with stent-assisted venous sinus surgery were found the stent not shifted or collapsed，and venous sinuses maintained patency. 
 
Endovascular treatment for patients with intracranial venous sinus thrombosis should be treated with individually designed therapy based on their clinical features and the stage of the disease.The individualized treatment was effective and safe. 
 
Key words: 
Sinus thrombosis，intracranial; Clinical protocols; Treatment outcome

Individualized endovascular treatment of intracranial vein sinous thrombosis based on the stage of disease

OBJECTIVE
To evaluate the feasibility and efficiency of embolization of spinal dural arteriovenous fistula (SDAVF).

METHODS
From December 2010 to May 2012, there were 104 cases of SDAVF were treated, and 26 cases were selected to be treated with embolization. The inclusion criteria was as follows: (1) No anterior or posterior spinal artery originated from the fistula segment; (2) The segmental artery can be catheterized with guiding or micro catheter; (3) High flow in fistula; (4) Patient's situation was not suitable for surgery or general anesthesia. Among 26 cases, there were 22 male and 4 female patients, the average age was 55.9 years (ranged from 34 to 81 years). The locations of SDAVF were 10 cases in thoracic, 9 in lumbar and 7 in sacral segment. The main symptoms were progressive numbness and weakness in both lower extremities, most cases accompanied with difficulties in urination and defecation. The average history was 17.1 months (from 1 to 156 months). ONYX-18 liquid embolic agent or Glubran-2 surgical glue were used as embolic material. The patients not cured with embolization were treated with surgery in the following 1 - 2 weeks. Follow-up evaluation was done with MRI after 3 months and DSA after 6 months, besides physical examination.

RESULTS
Fifteen from 26 cases achieved immediate angiographic cure results: 14 in 20 cases which embolized with ONYX-18; only 1 in 6 cases with Glubran-2. Three in 10 cases of thoracic SDAVF and 12 in 16 cases of lumbar/sacral SDAVF were cured with embolization. Partially embolized cases were treated with surgical obliteration of drainage veins within 2 weeks. Cured patients experienced immediate improvement after embolization and kept getting better in the follow-up. All the patients had MRI follow-up after 3 months and DSA follow-up after 6 months. In 6 month's follow-up, MRI showed the edema and flow void signal in the spinal cord disappeared. DSA showed no fistula recurrence or remnant. There was no deterioration case in all of the embolized cases.

Particular SDAVF is suitable for embolization with ONYX-18. Most lesions located in lumbar and sacral segment are good indications for embolization.

[Feasibility and efficiency of embolization of spinal dural arteriovenous fistula].

Anterior retropharyngeal approach for ventral perimedullary arteriovenous fistula (PMAVF) in upper cervical spine: Preliminary report

OBJECTIVE
To study the safety, efficacy and perioperative complications of endovascular therapy in the treatment of subtotal conclusion of internal carotid artery(ICA) in patients. To compare the cerebral embolic load of proximal balloon protection device versus distal filter protection device during the operation.

METHODS
Review all the operations of stenting for subtotal conclusion of ICA in Xuanwu hospital. New cerebral infarction after stenting was assessed by diffusion-weighted magnetic resonance imaging. Count the number of new ischemic lesions of every patient.

RESULTS
35 patients with subtotal conclusion of ICA received endovascular stenting. Proximal protective device was used for 21 patients. Distal protective device was used for 14 patients. All procedures succeeded. 32 patients received the cerebral MRI 1 week before and within 48 hours after the operation. Compared with filter protection(n = 14), proximal balloon device(n = 18) resulted in a significant reduction in the incidence of new cerebral infarction (6/18 vs 10/14, P = 0.03). The number of new cerebral ischemic lesions were significant reduced by proximal balloon device (1/18 vs 4/14, P = 0.0006) . There were no serious cardiovascular events in 35 patients during the operation and the following up 3 months. 3 patients had restenosis which was demonstrated by ultrasound of ICA at 3 months after stenting.

Endovascular stenting may be a safe and valid method for the treatment of subtotal occlusion of ICA. For the stenting of subtotal occlusion of ICA, proximal balloon protection device as compared with filter protection may reduce the embolic load to the brain more effectively. The stenting of subtotal occlusion of ICA still needs the randomized trails to confirm the safety and validity.

[Stenting of subtotal conclusion of internal carotid artery and comparing the cerebral embolic load of proximal balloon protection device with distal filter protection device].

Objective To investigate the value of hysterosalpingography in the diagnosis of infertility.Methods Hysterosalpingographic and clinical materials of 1 320 cases with infertility were collected and analyzed retrospectively. Results Among 1 320 cases, the percentage of abnormal uterus was 9.55 ％. Bilateral patency of fallopian tubes cases were accounted for 46.67％, and bilateral obstruction and unilateral obstruction were accounted for 27. 05％ and 26.29％ respectively. The obstruction position of the interstitial portion, the isthmus, the ampulla, the complete fimbrial and the part fimbrial were 23.94％, 16.21％ ,6.13％ ,23.09％ ,30. 63％ respectively. The accidence of tubal obstruction in the secondary infertility group was significantly higher than that in the primary group (P ＜0.01 ) ,and in the secondary infertility group,the bilatral tubal obstruction frequencies for “abortion times ≥3”were significantly higher than those for “abortion times ＜ 3” ( P ＜ 0.01 ). The pregnancy rate was 27.65％ in three months after hysterosalpingography. Conclusion Hysterosalpingography was a cost-effective and indispensable method for diagnosing female infertility. 
 
Key words: 
Infertility Female;  Hysterosalpingography;  Diagnosis

Retrospective analysis of hysterosalpingography in 1 320 infertile cases

Perimedullary arteriovenous fistulas in pediatric patients: clinical, angiographical, and therapeutic experiences in a series of 19 cases

Objective To report our surgical technique and results in the treatment of idiopathic atlantoaxial dislocation (IAAD) by using direct posterior reduction and fixation, without odontoidectomy and cervical traction. Methods Twenty patients of IAAD were operated on during May 2004 to December 2007. Before and after the operation, CT and MRI were used to measure and evaluate the degree of dislocation and neural compression. Two different screw fixation techniques were used depending on whether there was C1 assimilation; C1 lateral mass - C2 pedicle screws fixation was used for patients without C1 assimilation, otherwise, C2 pedicle -Occiput scews fixation was used. Intraoperative reduction was achieved by compressing the C2 spinous process anteriorly, or by distraction between C2 pedicle and occiput screws. Results All 20 patients were followed up from 6 to 48 months, among them, there was one death due to basilar artery thrombosis one week after the operation; in all the other 19 patients, symptoms were relieved markedly. All the postoperative radiological measurements were improved significantly (paired t test, in all groups, P < 0. 01 ). MRI showed good decompression of spinal cord and oblongata medulla in all 19 cases (CMA, P < 0.01 ); in 5 patients associated with Chiari's malformation and syringomyelia, syrinx was significantly shrinked in all patients. Conclusion Using posterior approach and intraoperative reduction and fixation technique, rather than anterior decompression through transoral odontoidectomy, for the treatment of IAAD is an effective, simple and relatively safe method. 
 
Key words: 
Atlantoaxial dislocation;  Basilar invagination;  Reduction;  Fixation

Direct posterior reduction and fixation for the treatment of idiopathic atlantoaxial dislocation

OBJECTIVE
To investigate the types, clinical features and therapeutic approaches of congenital anomalies of the vagina.

METHODS
The clinical data of 81 patients with congenital anomalies of the vagina were analyzed retrospectively.

RESULTS
There were 5 types in these 81 patients, and 16 (19.7%) patients showed absence of the vagina, 15(18.5%) had vaginal obstruction, 10 (12.3%) had transverse vaginal septum,14(17.2%) had longitudinal vaginal septae,18(22.2%) had septum obliquus, and 8 (9.8%) had imperforate hymen. Forty-eight (59.2%) patients presented with primary amenorrhea, and 22(27.1%) complained of irregular pelvic pain. Fifteen of the patients with absent vagina underwent amnion artificial vaginoplasty, and the others were treated with incising and removing the septum, all having good clinical outcomes.

Amnion artificial vaginoplasty is a good option for treatment of absent vagina.

Nan fang yi ke da xue xue bao = Journal of Southern Medical University

Objective To report the results of anatomical study and clinical application of C2 pedicle screws combined with C1 lateral mass or occipital screws used for posterior eraniovertebral junction internal fixation. Methods Four cadaver specimens of head and neck fixed by formalin were used for study of C2 pedicle and C1 lateral mass screw insertion,afterwards,CT scan was performed for evaluation of the position of the screws. From May 2004 to January 2007,C2 pedical-C1 lateral mass/occipital screws internal fixation was applied in 9 patients,including 4 male and 5 female,their age ranged from 12 to 68 years old.Fixation was performed for C1-C2 sublaxion due to various reasons in 6 patients, after transoral odontoidectomy due to basilar invagination in 1 patient,before transoral removal of clival chordoma in 2 patients. Among them,C2 pedieal-C1 lateral mass screws fixation technique was used in 4 patients,C2 pedical-occipital screws fixation technique in 5. Results It was necessary to directly expose the superointerior edge of the C2 pedieal,in order to localize the entry point of the screw in the posterior part of the isthmus and to justify the screw direction; direct exposure of the posterior midline of the C1 lateral mass helps localize the screw entry point and avoid injury of the vertebral artery. Among 9 patients,postoperative CT demonstrated 2 screws breakthrough of the cortical bone in 2 patients,without neural or vascular compression or injury; in the other patients,all the screws were appropriately positioned. Follow-up ranged from 4 to 32 months,clinical improvement was found in 8 patients ; only in one patient,the symptoms did not change postoperatively. Conclusion C2 pedical-C1 lateral mass/occipital screws can be used for posterior craniovertebral junction internal fixation safely and effectively. 
 
Key words: 
Atlas;  Axis;  Occipital bone;  Screws;  Internal fixation

Objective To discuss the surgical strategy of parasagittal and falcial meningiomas in the middle 1/3 cortex area and raise resective rates of tumors and surgical effects.Methods The clinical,imaging and operative data of 74 cases of parasagittal and falcial meningiomas in the middle cortex area which underwent operation were reviewed and followed up.Results Of 74 tunors,67 were resected with Simpson Ⅱ grade,7 with Simpson Ⅲ,none of them with Simpson Ⅰ.Superior sagittal sinus and the vein of central suleus and feeders of cortex were reserved well.Severe brain injury was not occurred in 66 cases with tumors debulking(Simpson Ⅱ 61 cases,Simpson Ⅲ 5 cases),the neuro-functions of patients were normal or transient slight weakness of contralateral lower extremities postoperatively.Tumors of 8 cases were "turned over" and resected by piecemeal (Simpson Ⅱ 6 cases,Simpson Ⅲ 2 cases),weakness and paralysis of contralateral lower extremities occurred in 7 cases and 1 cases respectively after surgery.Followed-up ranged from 6 months to 4 years and 2 months,4 cases were lost to follow-up.Neuro-function of all cases with weakness of contralateral lower extremities recovered after one month.Muscle strength of the cases with paralysis of contralateral extremity recovered to grade Ⅳ 6 months later,no recurrence and death.Conclusion The measures,including piecemeal tumor reseeted mierosugically,good protection of the vein of central sulcus,excellent management of superior sagittal sinus,and avoiding damage to functional cerebral cortex during operations,are best ways for raising the tumor resection rate and nearo-function reserved. 
 
Key words: 
Meningioma; Superior sagittal sinus; Mierosurgical operation

Microsurgical treatment for superior parasagittal and falcial meningiomas in the middle 1/3 cortex area

Abstract The purpose of this study was to introduce infinite models in scoliosis and to analyze personal experience. Based on a three-dimensional patient-specific finite element model of the spine, rib cage, pelvis and abdomen, a parametric individual model of a thoracolumbosacral orthosis was built. Three standard strap tensions (20, 40, 60 N) were loaded on the back of the brace to simulate the strap tension. The I-Scan distribution pressure measurement system was used to measure the pressure of the different regions and the equivalent forces in these regions were calculated. The spinal curve changes and the forces acted on the brace generated by the strap tension were evaluated and compared with the measurement results. The reduction of the coronal curvature was approximately 60% for a strap tension of 60 N. The sacral slope and the lordosis were partially reduced in this case. The brace modified the axial rotation at the deformed vertebrae. The forces generated in finite element analysis were in good agreement with the measurement. The findings supported the feasibility of such an approach to analyze individual bracing biomechanics, which may be useful in the design of more effective individual braces.

Infinite models in scoliosis: a review of the literature and analysis of personal experience

OBJECTIVE
To find out the causes of severe surgical complications of sphenoidal ridge meningioma of and the methods to avoid them.

METHODS
The clinical data of 56 cases of sphenoidal ridge meningioma, 37 being medial (clinoidal) type, 5 being middle (alar) type, and 14 being lateral (pterional) type, with the diameters of 3.5 - 7 cm, 3.8 - 5.2 cm, and 3.8 - 7.5 cm respectively, who underwent operation.

RESULTS
The tumors of 19 cases of lateral and middle types were resected completely without surgical complication. Facial nerve injury occurred in 2 cases of medial type because of failure to know well the course of facial nerve and over-stretching of skin flap. Oculomotor nerve injury occurred in 7 cases, 5 of which were transient, and trochlear nerve injury occurred in 1 case, all caused by inappropriate manipulations. Too early resection of tumor-related vessel caused middle cerebral artery injury in one case. Resection of the tumor infiltrating the carotid artery inadequately caused injury of the carotid artery. Lenticulostriate artery injury was caused in 2 cases by over-separation of the lateral fissure.

Severe surgical complications can be avoided if the surgeons, with great skills, are able to predict different topographic changes and difficulties encountered during operation in the light of the specific conditions in operation.

[Analysis of the causes of surgical complications of medial sphenoidal ridge meningioma].

OBJECTIVE
To evaluate the treatment effect of the two surgical methods for upper eyelid retraction with thyroid associated-ophthalmopathy.

METHODS
Twenty-two patients (32 eyes) with inactive thyroid associated-ophthalmopathy were divided into 2 groups (11 for each group) randomly. 11 patients (18 eyes) in the group A were treated by central tenotomy of levator aponeurosis. Another 11 patients (14 eyes) in the group B were treated by lengthening of Mullers' muscle combined with levator muscle. The treatment effect was investigated in 6-month follow-up study.

RESULTS
All of the patients were improved with the two surgical methods, which there was very significant difference before and after the treatments (P < 0.01), but not between the two surgical methods (P > 0.05) by statistical analysis. There was recurrent retracting in 4 patients (6 eyes) of group A and in 1 patient (1 eye) of group B, which there was significant difference between the two groups (P < 0.05) by Chi-square test. None of the patients was overcorrected.

The two methods are both effective and safe in correcting upper eyelid retraction. The rate of recurrent retracting is lower in lengthening of Mullers' muscle combined with levator muscle than that in central tenotomy of levator aponeurosis.

Zhonghua zheng xing wai ke za zhi = Zhonghua zhengxing waike zazhi = Chinese journal of plastic surgery

[Two surgical methods to modify upper eyelid retraction with thyroid associated-ophthalmopathy].

PURPOSE
To determine whether intraductal perfusion with chilled saline reduces thermal injury to bile ducts during radiofrequency (RF) ablation.

In swine, anesthesia was induced and the common bile duct was surgically cannulated with a pediatric feeding tube. RF thermal lesions were created adjacent to bile ducts by using an expandable-hook 2-cm RF electrode and 90-W generator. In three pigs, chilled saline was perfused through the ducts at 1.5 L/h (26 mL/min), and in another pig, room-temperature saline was perfused at the same rate. In three pigs (control group), RF lesions were created without perfusion. After 48 hours, animals were sacrificed. Periductal sections from all animals were reviewed by a liver pathologist. The degree of injury to biliary epithelium and subepithelial glands was assessed on a scale of 0%-100%. Significance of differences between degrees of injury was assessed with the Mann-Whitney test.

RESULTS
In the control group, there was a mean of 100% injury to biliary ductal epithelium and 99.3% to subepithelial ductal glands. In the room-temperature saline group, there was a mean of 100% biliary epithelial injury and 84.4% glandular injury. In the chilled saline group, there was a mean of 52.9% ductal epithelial injury and 12.1% subepithelial glandular injury. In comparison with the control group, there was significantly less (P <.05) thermal injury to biliary epithelium in the chilled saline group and to subepithelial glands in both the room-temperature and chilled saline perfusion groups.

RF-induced bile duct injury may be decreased significantly with an intraductal infusion of chilled saline.

Minimizing central bile duct injury during radiofrequency ablation: use of intraductal chilled saline perfusion--initial observations from a study in pigs.

Nasopharyngeal carcinoma is not a disease to be treated primarily by surgery. Radiation is the first choice of treatment. But, once it recurs, a second course of radiation controls only a small portion of the patients, with a high risk of accumulated radiation injury. We discuss the outcome of salvage surgery in nine cases of nasopharyngeal recurrence and 69 cases of neck metastasis that was uncontrolled or had recurred after irradiation was evaluated. A five-year survival rate of 44% for the primary lesions and 49% for the neck node metastases justifies the rationale of surgery on selected cases of radiation failure.

The TNM staging of maxillary sinus cancer was stipulated by the UICC in 1987 using Ohngren line of demarcation. This report is to discuss the applicability of this staging based on 232 cases of maxillary sinus cancer treated in this hospital. Of 232 cases, the 3-year survival rate for those who received surgery alone was 4/6, for those after radical irradiation, 15.6% (20/128) and for those by combined irradiation and surgery, 43.9% (43/98). The 3-year survival rate for the whole series was 28.9%. To analyze the survival rates of different types of lesion separately, we found that those with involvement of the posterior wall, hence invading the pterygopalatine fossa had poor prognosis with a three year survival rate of 19.5%. And invasion of soft and/or hard palate also gave poor survival. Contrary to the common consensus, invasion of ethmoidal sinuses did not pose a serious prognosis. The feasibility of the Ohngren line in TNM staging was thus questioned. On the basis of our data, a modification of the TNM staging of JJC for maxillary sinus cancer is suggested.

Cross-Layer Congestion Control Based on Packet Rate and Queue Length for Satellite Network

Aircraft communication and satellite link handoff issues in spatial information network are very important and are focused in this paper. The simulation modules of satellite network nodes and links in network simulator version 2(NS-2) are analyzed in details in this paper. A method of extending NS-2 kernel module is proposed based on analysis of satellite network simulation principle and approach. As an example, the aircraft communication simulation module is designed and implemented. Simulation results show that flight of aircraft has effect on the link handoff characteristic, and show that the proposed extension method is feasible.

Research on Aircraft Communication and Satellite Link Handoff Simulation for Spatial Information Network

The Research of Routing Forwarding Strategies in DTNs Based on Convergence Point

AR-HS: Ant Routing Optimized Algorithm on HAPs-Satellite Integrated Networks

Robust and load-balanced routing protocol for traffic engineering is very important to stabiLity of Internet. A novel adaptive load-balanced routing algorithm(ALB) based on minimum interference and cross-layer design principle is proposed. The least interference path algorithm principle is introduced briefly, and the implementation of adaptive load-balanced routing algorithm is elaborated in detail. Simulation results show that the proposed adaptive routing algorithm can effectively avoid the occurrence of Link overload and that it can significantly reduce packet loss rate and improve network throughput.

2011 Second International Conference on Digital Manufacturing & Automation

Quality of service (QoS) in multimedia networks mainly depends on the algorithms of packet scheduling and the packets in session queues are assigned as the priority values and order transmitted in specific sequence according to the service disciplines. This paper focuses on the improvement of the strategy for heap searching and the optimization of the queue operation for a kind of algorithms of packet scheduling based on the priority queue. Then a novel algorithm for constructing heap in multi-steps is proposed. In general case, the improved algorithm has the same efficiency of searching as the common algorithm of heap searching. But in the worst case (session burst), it uses the new strategy to construct the heap, i.e. the process of constructing heap is extended and carried out in many steps. Therefore, a high efficiency of packet searching and utilization ratio of output link is obtained, thanks to the dynamic and flexible way of constructing heap.

Improvement of Packet Scheduling Based on Priority Queue in Multimedia Networks

OBJECTIVE
To explore the improvement of quality of life of patients with pelvic inflammatory disease by comprehensive nursing intervention.

METHODS
Altogether 118 patients with pelvic inflammatory disease admitted to our hospital from February 2018 to December 2019 were obtained and grouped into the control group (CG) and the experimental group (EG). The CG was given routine nursing and the EG was given comprehensive nursing intervention. The clinical efficacy, changes of serum inflammatory factors, negative emotion scores, treatment compliance and quality of life of the two groups were compared. The satisfaction of nursing care of patients in two groups was counted.

RESULTS
The total effective rate of treatment in the EG was evidently higher than that in the CG. Before nursing, there was no significant difference in serum inflammatory factors, SDS and SAS scores and quality of life scores between the two groups (P<0.05). After nursing intervention, the levels of serum inflammatory factors, SDS and SAS scores and quality of life scores in the EG were evidently better than those in the CG, and their satisfaction with nursing was evidently higher than that in the CG (all P< 0.05).

Comprehensive nursing intervention can effectively improve the quality of life of patients with pelvic inflammatory disease, and as such it is worth popularizing.

Effect of comprehensive nursing intervention on serum inflammatory factors and quality of life in patients with pelvic inflammatory disease.

Objective 
To discuss the effect of mirtazapine in depressive functional dyspepsia patients with weight loss (FD-WL). 
 
Methods 
As a randomized and controlled trial, seventy-two FD patients with weight loss and depression were randomly divided into mirtazapine group(n=24), paroxetine group(n=23) and conventional group(n=25), and all patients were treated for 8 weeks. The Nepean Dyspepsia Index (NDI)- symptom checklist, the Hamilton Rating Scale of Depression (HAMD), body weight were assessed before the treatment and after 2, 4, 6, 8 week. 
 
Results 
(1) After 2-week treatment, the scores of NDI-symptom checklist and HAMD in mirtazapine group were significantly lower than that in paroxetine group and conventional group. After 4-week, 6-week and 8-week treatment, the score of HAMD in mirtazapine group((13.34±1.52), (11.65±1.56), (10.15±1.36)) and paroxetine group((13.65±1.81), (11.34±1.21), (9.58±1.41))was significantly lower than that in conventional group((18.15±1.61), (17.20±2.14), (15.30±1.56)) (all P 0.05). (2) After 6-week and 8-week treatment, the body weight in mirtazapine group((53.17±6.46)kg, (53.55±6.52)kg)was significantly higher compared with that in paroxetine group((49.47±5.72)kg, (49.57±5.81)kg)and conventional group((48.69±5.60)kg, (48.68±5.65)kg)(all P<0.05). After 8-week treatment, patients in mirtazapine group experienced a weight gain of(3.34±1.82)kg. 
 
Mirtazapine not only can significantly improve dyspepsia symptoms and depressive scoring, but also can increase body weight. 
 
Key words: 
Functional dyspepsia; Weight loss; Mirtazapine; Depression

Effect of mirtazapine in depressive functional dyspepsia patients with weight loss

Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver

Clinical-psychological characteristics of refractory globus patients in China.

Objective To investigate clinical characteristics, quality of life, and psychological fac- tors in functional dyspepsia （FD） patients with weight loss. Methods A multi-center and prospective investigation was conducted （Clinical trial registration number： ChiCTR-TRC-12001968 ） which recruited 1341 consecutive FD outpatients from three Guangdong hospitals according to Rome In criteria between June and September in 2012. Of these, 1057 patients with complete information were divided into group A as having weight loss more than 5% （n =207） and group B as having weight loss less than 5% （n =850）. Nepean Dyspepsia Index-symptom checklist, appetite, Hamilton Rating Scale of Anxiety/Depression （HAMA/ HAMD）, Pittsburgh Sleep Quality Index （PSQI）, Nepean Dyspepsia Index-quality of life, direct medical costs were used to compare the differences between the two groups. Results There were no significant differences in total scores of NDI-symptom checklist, the severity or bothersome items between two groups （t = - 1. 301, -0. 918,0. 138,P =0. 193,0. 359,0. 890）, but significant differences were observed in the frequence item and the rating of appetite as poor or very poor between two groups （ t = - 2. 122 ,P = 0. 035 ;X2 =35. 448,P =0. 000;X2 =35. 274,P =0. 000）. Significant differences were observed in the incidence of anxiety and depression and total scores of PSQI between the two groups （X2 = 73. 939, P = 0. 000 ;X2 = 47. 046, P = O. 000 ; t = - 4. 904, P = 0. 000）. Subscales scores of NDI-quality of life in group B were all sig- nificantly higher than those in group A （t = 5. 348,2. 569,5. 809,4. 704, P = 0. 000,0. 010,0. 000,0. 000 ）. There were significant differences in the frequency of care-seeking and direct medical costs between the two groups （t = -4. 860, -3.011, P = 0. 000,0. 003 ）. The frequency of gastroseopic examinations in group A was slightly higher than that in group B （ t = - 1. 505,P = 0. 133 ）. Conclusion FD patients with weight loss is not rare, and most of them have psychological disorders, loss of appetite and sleep disturbance. More- over, care-seeking are more frequent, direct medical costs are more expensive, and impairment as assessed by NDI-QOL is more severe. Therefore, we should pay more attention to FD with weight loss in clinical setting. 
 
Key words: 
Dyspepsia;  Quality of life ;  Anxiety;  Depression

Clinical features, quality of life and psychological factors in functional dyspepsia patients with weight loss

Objective: The aim of this study was to investigate the influence of psychosocial variables on patients with multiple sclerosis (MS) and the relationship between these variables and the onset of MS. Background: The current evidence indicates that many types of psychosocial factors are involved in the development and relapse of MS, and it has been suggested that they could serve as predictors as well. So far, little has been reported on the effect of psychosocial factors on MS and the relationship between psychosocial factors and the onset of MS. Methods: Forty-one patients, 15 males and 26 females, average age 37.44 ± 12.24 years (mean ± SD), were evaluated by the Life Event Scale, Eysenck Personality Questionnaire, Social Support Revaluate Scale and Symptom Check List 90 and compared with 41 equivalent healthy control subjects, 15 males and 26 females, average age 36.38 ± 12.84 years (mean ± SD). Disease, demographic, psychosocial and lifestyle factors were measured at baseline. Patients with MS were first diagnosed by 3 neurologists according to the Poser (1983) MS diagnostic criteria. Results: Significant differences were found between the MS and the control group in their negative emotions and symptoms such as depression, anxiety, obsession, phobia, tense interpersonal relationship and somatization disorder. Significant differences were found between the two groups in the total number of negative life events, their family problems and the utilization of social support. The scores for various negative emotions in the MS group correlated positively with those for neuroticisms in personality type, and negatively with those for introverted and extroverted personality. Many kinds of negative emotions in the MS group correlated positively with the total number of life events, negative life events and family problems. Many kinds of negative emotions in the MS group correlated negatively with the utilization of social support. Conclusion: The psychosocial factors are closely associated with MS onset and may play important roles in the development of the disease.

Relationship between Psychosocial Factors and Onset of Multiple Sclerosis

Objective To investigate the influences of psyehosocial variables on the patients with muhiple Sclerosis(MS)and relations between the variables and the onset,development of MS.Methods 30 patients were measured by Life Events Scale(LES).Eysenck Personality Questionnaire(EPQ),Social Support Evaluate Scale (SSRS)and Symptom Check List 90(SCL-90).30 heahhy subjects were control group.Results 1.Significant differences on negative emotions and symptoms such as depression(2.09±0.80),anxiety(1.96±0.76),obsession(1.73 ±0.84).phobia(1.98±0.70),tense interpersonal relationship(1.94±0.66)and somatization disorder(1.93 ±0.49)were found between MS and control group.2.Significant differences on total negative life events (38.17±41.16),problems on family(33.67 ±35.27)and availability of social supports(6.97 ±1.83)were found between the two groups.3.The scores of negative emotions in MS group were correlated positively to that of neuroticisms in personality type.while negatively to that of introverted and extroverted personality(P＜0.05).4.Many kinds of negative emotions in MS group were correlated positively to total life events of patients,negative life events and problems related to family(P＜0.05).5.Many kinds of negative emotions in MS group were correlated negatively to availability of social supports(P＜0.05).Conclusions The psychosocial factors are associated with the onset of MS.As one of main factors,it plays an important role on onset of MS. 
 
Key words: 
Psychosocial factors;  Multiple Sclerosis;  Onset

We report the fatigue fracture in a mounting bracket, which is attached to a front bumper. We conducted the macro- and micro-scale fracture morphology analyses and base materials characterization. We used a bracket made of QSTE 420 TM high-strength steel and did not find any metallurgical defects. Three cracks were formed on the bracket, and the cracks were initiated from the outer edges of the screws. From the scanning electron microscopy (SEM) images, we observed ratchet marks among the three cracks at their initiation positions with a similar distance between each other. We also observed fatigue striation in the propagation zones. We deduce from the macro- and micro-scale analyses that the three cracks were initiated and then expanded spontaneously with a similar growth rate. The stress concentration, assembly operation and joining effects cause the bidirectional bending fatigue fracture in the three locations. Optimized tightening forces and new gaskets are recommended to extend the fatigue life of the mounting bracket.

The fatigue fracture of mounting bracket: A microstructure characterization

Aiming at the base metal (BM) zone, heat affected zone (HAZ) and fusion zone (FZ) of the weld, the tip plastic zone and initiation behavior of microscopic short cracks (MSCs) in the toe of cross-welded joints are studied. Based on the theory of crack tip plastic zone and the fatigue index parameter (FIP), the shape and boundary size of the plastic zone at the tip of MSCs as well as the initiation life were calculated. The results show that the plastic zone was bone-like under plane stress and butterfly-like under plane stress; when the crack length increased from 2 μm to 30 μm, the boundary size of the plastic zone at the MSC tip increased by 15 μm and 2 μm under the action of plane stress and plane strain in the X-axis direction, respectively. As the grain gradient decreased from 0.5 to 0.1, the boundary size of the plastic zone at the tip of the MSC increased about 50%. MSC initiation occurs first in the BM zone, and life of initiation was about several hundred thousand cycles, which was consistent with the experimental result. The MSC expansion rate in BM zone was the fastest, with the average expansion rate about 2.5 × 10−3 μm/cycle; the MSC expansion rate in the FZ and HAZ was about 3.1 × 10−4 μm/cycle.

Initiation Behavior of Microscopic Short Cracks in Weld Toe of Structural Steel Q345B

ABSTRACT With increasing clamping pressure, the bond density increases, the effective thickness decreases, and the plastic deformation at the Cu side near the welding interface regions below the sonotrode tip peak and valley increases; the maximum lap shear tensile load is obtained at the clamping pressure of 0.5 MPa. In the case of the Cu/Ni joint prepared at the clamping pressure of 0.5 MPa, evident mutual diffusion and nanoscale wave-like pattern appear in the Cu/Ni interfacial area, bonding between Cu and Ni sheets is formed by the interdiffusion of the parent elements. Plastic strain distribution and temperature on weld cross-section were simulated employing finite element analysis.

Characteristics of ultrasonic spot welding of Cu/Ni dissimilar metals

The relationship between cross-linking structure and silk fibroin scaffold performance for soft tissue engineering.

Ni60-WC reinforced NiCrAl coatings were prepared on the TC4 alloy by laser cladding technique with different mixed powders: 95%NiCrAl-5%Ni60-WC, 85%NiCrAl-15%Ni60-WC, 75%NiCrAl-25%Ni60-WC (wt.%). The microstructure, phases compositions, microhardness, wear properties were studied. The results showed that the mainly consists of dendrites and bulk like compounds crystal and some of flower-like microstructure formed. The XRD results indicated TiC, VC metalloceramics, Cr0.2Ti0.8C, NiTi2, Ni2W4C and AlFe3C intermetallic compounds generated. The microhardness of the coatings are 881HV0.3, 778HV0.3 and 788HV0.3, respectively. Compared with the substrate hardness about 200HV0.3, the hardness of coatings have been improved significant. The friction coefficient of coatings are 0.35, 0.42, and 0.42, respectively, and the wear rates of the coatings are 3.86×10-7mm3N-1m-1, 4.51×10-7mm3N-1m-1 and 4.34×10-7mm3N-1m-1, respectively.

Silk biomaterials with tunable mechanical properties and biological properties are of special importance for tissue engineering. Here, we fabricated silk fibroin (SF, from Bombyx mori silk) scaffolds from cryogelation under controlled temperature and catalytic cross-linking conditions. Structurally, the cryogelled scaffolds demonstrated a greater β-sheet content but significantly smaller β-sheet domains compared to that without chemical cross-linking and catalyst. Mechanically, the cryogelled scaffolds were softer and highly elastic under tension and compression. The 120% tensile elongation and >85% recoverable compressive strain were among the best properties reported for SF scaffolds. Cyclic compression tests proved the robustness of such scaffolds to resist fatigue. The mechanical properties, as well as the degradation rate of the scaffolds, can be fine-tuned by varying the concentrations of the catalyst and the cross-linker. For biological responses, in vitro rat bone mesenchymal stem cell (rBMSC) culture studies demonstrated that cryogelled SF scaffolds supported better cell attachment and proliferation than the routine freeze-thawed scaffolds. The in vivo subcutaneous implantation results showed excellent histocompatibility and tissue ingrowth for the cryogelled SF scaffolds. This straightforward approach of enhanced elasticity of SF scaffolds and fine-tunability in mechanical performances, suggests a promising strategy to develop novel SF biomaterials for soft tissue engineering and regenerative medicine.

Controlled Cryogelation and Catalytic Cross-Linking Yields Highly Elastic and Robust Silk Fibroin Scaffolds.

Laser-cladding CeO2-doped Ni-based composite coatings were prepared on the surface of a titanium alloy, and the effects of CeO2 addition on the microstructure, microhardness, and corrosion resistance of the prepared coatings were studied. The results showed that TiC, NiTi, Ni3Ti, and Ti2Ni phases were formed on the prepared coatings. Moreover, the addition of CeO2 in laser-cladding coatings effectively refined the microstructure and reduced the number of cracks generated in the laser-cladding process. When the amount of CeO2 was 2%, the number of cracks in the laser-cladding coating was significantly reduced compared with that of 0%. When the content of CeO2 was 2% or 3%, the microhardness of laser-cladding coatings reached the maximum value. At the same time, it was found that the appropriate addition of CeO2 was helpful to improve the corrosion resistance of the laser-cladding coating. However, excessive CeO2 addition could reduce the corrosion resistance of the laser-cladding coating.

Microstructure and Corrosion Behavior of Laser-Cladding CeO2-Doped Ni-Based Composite Coatings on TC4

Influencing mechanisms of heat treatments on microstructure and comprehensive properties of Al–Zn–Mg–Cu alloy formed by spray forming

Abstract In this paper, (Fe,Cr)7C3/Fe surface gradient composite was produced by solid reaction combining in situ reaction, using pure chromium plate and HT300. The chromium carbide particles were synthesized in the HT300 by in situ reaction between the chromium atoms of the chromium plate and the carbon atoms of the HT300. The phase constituent, microstructure, microhardness and modulus of the composite were characterized by X-ray diffraction, scanning electron microscopy and nano-indentation instrument. The anisotropy of (Fe,Cr)7C3 is emphatically studied. The results show that the (Fe,Cr)7C3, which is directed toward the direction of the matrix has certain preferred orientation characteristics during the in-situ reaction, and the (Fe,Cr)7C3 in preferred growth direction has a higher microhardness and elastic modulus than that of the non preferred growth direction.

Study on the microstructure and anisotropy of (Fe,Cr)7C3/Fe surface gradient composite produced by solid reaction process

Synthesis, Microstructure Evolution and Wear Properties of VCp Dense Ceramic Prepared by In Situ Synthesis

High temperature behavior of a diffusion barrier coating evolved from ZrO2 precursor layer

Abstract In this study, the phase evolution and formation kinetics of (Fe,Cr)7C3/Fe surface composite were investigated. The formation process of (Fe,Cr)7C3/Fe surface composite involves through the formation of a dense ceramic layer, short rod-like (Fe,Cr)7C3 particulates, and disappearance of the dense ceramic layer. The mathematical model was applied to study the formation kinetics of (Fe,Cr)7C3/Fe surface composite by considering the impact of heat treatment temperature and time. The results revealed a parabolic relationship between the thickness of composite layer and heat treatment time, indicating that the formation kinetics of the composite layer was governed by diffusion. The proposed formation kinetics model shows a good agreement with the experimental data. The growth rate constant of composite layer and the reaction temperature satisfy Arrhenius relationship. The activation energy for the growth of composite layer was found to be 208.68 kJ/mol.

The Influence of Carbon on Tribological Properties of Micro-Arc Oxidation Ceramic Coating

The effect of high pressure (135 MPa) and the following heat treatment on the microstructure and micro-hardness of the squeezing cast AlSi9CuMg alloy is investigated, using optical microscopy (OM), Vickers tester, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The results indicate that the application of high pressure can increase under-cooling and the cooling rate during solidification and cause the refinement of the microstructure. The enhanced melt flow resulting from high pressure can also break the dendrite to form the spherical and elliptical primary α (Al) grains during the early stage of solidification. The winter-sweet flower-shaped primary α (Al) phases can also be formed through plastic deformation caused by the flow of the partially solidified melt. The ageing treatment results showed that a maximum (peak) micro-hardness value was obtained for each of the three ageing temperatures at different ageing times, and the highest peak value was achieved at 175 °C for 480 min. The micro-hardness change of the sample under different ageing processes was attributed to the variation of type, density, and size of the precipitates.

Effects of Solidification Pressure and Heat Treatment on the Microstructure and Micro-Hardness of AlSi9CuMg Alloy

Based on linear elastic fracture mechanics (LEFM), the fatigue crack evolution process and behavior of corrugated web girders were studied. The global finite element analysis (FEA) model of corrugated web girders was first developed and the equivalent structural stress method was used to reveal the dangerous locations along the weld under the bending load. The weld toe between the tension flange and the web weld, which is near the intersection of the inclined fold and the parallel fold, was determined as the fatigue crack easy-initiating location. Then a small region containing the crack-prone site was extracted as the sub-model for a crack propagating simulation. A semi-circle initial crack with 0.1 mm radius was inserted at the crack easy-initiating location. The stress intensity factors (SIFs; KI, KII, and KIII) of some discrete points along the crack front were calculated by the M-integral method. Based on Nasgro law, the geometry of the new crack front with a given extension length was obtained. Finally, the complete evolution process of the crack propagation was simulated. Results showed that the dominant crack propagating mode is open type (Mode I) and KI is the most important propagating driving force. According to the crack front shape evolution, the whole propagating process was divided into 6 stages. An obvious kink of the crack was found in stage 1, which covered only a very short time. The stages 3, 4 and 5 accounted for the majority of life, among which the stage 3 accounted for as high as 81% of the total life. Therefore, the cycles of the weld toe crack propagating from 0.1 mm to the thickness of the flange can be defined as the prediction life of this kind of structures.

Analysis of the Fatigue Crack Evolution of Corrugated Web Girders

Abstract In this study, the (Fe,Cr)7C3/Fe dense ceramic layer was produced by in situ synthesis method with subsequent heat treatment. According to the results of thermal analysis, the as-cast specimen was subjected to heat treatment at 1186, 1208, 1230 °C for 1–5 h in argon atmosphere respectively. The microstructures of the compound region were characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM), and the kinetics of the (Fe,Cr)7C3 dense ceramic layer were analyzed. The results show that a-Fe and (Fe,Cr)7C3 are the predominant crystalline phases in the composite obtained. Depending on the layer process time and temperature, the thickness of the reaction layer formed on the substrate ranged from 12.3 to 32.6 mm. The kinetics of dense ceramic layer by the in situ synthesis method was also studied and the activation energy for the diffusion process was estimated to be 292 kJ/mol. Moreover, an attempt was made to investigate the possibility of predicting the iso-thickness of chromium carbide layer variation and to establish some empirical relationships between process parameters and dense ceramic layer thickness.

Kinetics of (Fe,Cr)7C3/Fe dense ceramic layer prepared by in situ synthesis

Serrated flow behavior of GH536 superalloy under different loading rates at room temperature

The effects of the thermal cyclic aging treatment on the microstructure and mechanical properties of 2060 Al–Li alloy laser beam welded joints were investigated. Aging treatments were conducted at different temperatures and for different cycles. Test results showed that the tensile strength of the weld joints increased and the elongation slightly decreased after the thermal cycling treatment. It was also found that the heat affected zone (HAZ) of the welds exhibited a significant increase in microhardness, whilst the microhardness variation of the nondendrite equiaxed zone (EQZ) can be neglected. The strengthening effect of the thermal cycling became more obvious as the temperature and cycles increased. The highest strength of around 513 MPa (96% of the base metal) was obtained at the temperature of 180 °C. Reprecipitation of strengthening phases such as T1 in the HAZ at 180 °C was observed by TEM, which can be considered as the main reason for the strengthening effect of the aging treatment.

Effect of thermal cycles on the laser beam welded joint of AA2060 alloys

The effect of cryogenic treatment (CT) on the microstructure, residual stress, and dimensional stability of 7075 aluminum alloy under temperatures of 0 °C, −60 °C, −120 °C, and −196 °C were studied, using optical microscopy (OM), scanning electron microscopy (SEM), transmission electron microscopy (TEM), an X-ray diffractometer, and an X-ray stress tester. The results indicated that CT can facilitate the dissolution of the coarse secondary phase into the α(Al) matrix, promote uniform distribution of Mg, Cu, Zn elements, and increase the density of fine secondary phases in the 7075 Al alloy. The CT can also induce the rotation of the α(Al) grain towards (200), through the processes of recovery and recrystallization. It was found that the residual stress was released, and a higher dimensional stability of the 7075 aluminum alloy was achieved, after CT. Experimental results demonstrated that the optimum CT temperature for the 7075 aluminum alloy is −120 °C.

Effects of Cryogenic Treatment on the Microstructure and Residual Stress of 7075 Aluminum Alloy

Effect of alloying elements on microstructure, mechanical and damping properties of Cr-Mn-Fe-V-Cu high-entropy alloys

Evolution of microstructure and microhardness of the weld simulated heat-affected zone of Ti-22Al-25Nb (at.%) alloy with continuous cooling rate

Effect of Carbide Ceramic Zone on Wear Resistance of the (Fe,Cr)7C3/Fe Surface Gradient Composite

In this study, the (Fe,Cr)7C3 particles strengthened gradient composite was produced by in situ synthesis process with subsequent heat treatment from gray cast iron (HT300) and high purity chrome plate. The microstructure, phase composition and wear resistance of the composite were studied by scanning electron microscopy (SEM), X-ray diffraction (XRD) and scratch tester. The results showed that the thickness of the gradient layer was about 758 μm after heat treatment at 900 °Cfor 4 h. And it can be divided into three areas depending on microstructure. The outermost layer which was ~60 μm of thickness, was the dense ceramic layer with high volume fraction of (Fe,Cr)7C3 ~90%. No obvious grain boundaries were observed. The subsurface layer was the particles dispersed layer, which was ~525 μm of thickness, with the volume fraction of (Fe,Cr)7C3 decreased to 70%. The lowermost layer was ferrite, with about 173 μm thickness. A good metallurgical bond generated between the composite layer and matrix. The depth and the width of surface scratch increased with the raising loads from 0 to 100 N, and the cracks mainly included micro-crack, tiny dens crack, mixture crack and through-wall crack. The (Fe,Cr)7C3 particles were broken and scraped when the load exceeded 80 N.

Research on Microstructure and Wear Resistance of (Fe,Cr)7C3/Fe Surface Gradient Composite

Tantalum carbide gradient composite was fabricated via in-situ reaction of pure tantalum plate with gray cast at high temperature. The morphology, phase constituent, microhardness, and relative abrasion resistance of the composite were characterized by scanning electron microscopy, X-ray diffraction, microhardness tester and abrasive wear testing machine. The results show that the thickness of the gradient composite is about 475 μm. The cast 170 μm thick surface layer is a dense ceramic layer consisted of ~95% submicron TaC particles, and the highest micro-hardness value of which is 2328HV0.1; In the sub-layer, there exists a gradient distribution of TaC particles from 90% to 0% in volume fraction, correspondingly the microhardness value decreased from 915HV0.1to 410HV0.1, and the size of the TaC particles increased to 0.5-1.5 μm; the interface between the composite and matrix exhibits a perfect metallurgical bonding. The TaC reinforced iron matrix surface gradient composite shows far superior wear resistance than the gray cast iron. The wear mechanism is mainly related with the local plastic deformation,micro cracking caused by misrouted broken carbide particles.

Abrasive Wear Characteristics of Surface Gradient Composites of TaC Reinforced Iron Matrix Prepared by In-Situ Technology

(Fe,Cr)7C3/Fe surface gradient composite: Microstructure, microhardness, and wear resistance

Microstructure and abrasive wear characteristics of in situ vanadium carbide particulate-reinforced iron matrix composites

In-situ production of (Fe,Cr)7C3 particulate bundles-reinforced iron matrix composites were prepared by infiltration casting between Cr wires and white cast iron at 1200°C plus subsequent heat treatment. The composites prepared under different heat treatment time were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), macrohardness test and pin-on-disc wear resistance test. The results show that the composite is mainly consist of (Fe,Cr)7C3 carbides and γ-Fe. The area of the particulate bundles gradually increases with the increase of heat treatment time, the microstructure evolved from eutectic to hypoeutectic, and the morphologies of the reinforcements present chrysanthemum-shaped, granular and intercrystalline eutectics, respectively. The (Fe,Cr)7C3 particulate bundles reinforced composite has high macrohardness and excellent wear resistance under dry sliding wear testing conditons.

Microstructure and Wear Properties of In Situ Production of (Fe,Cr)7C3 Particulate Bundles Reinforced Iron Matrix Composites

Volume Fraction Effect of V8C7 Particulates on Impact Toughness and Wear Performance of V8C7/Fe Monolithic Composites

Fabrication and microstructure of in situ vanadium carbide ceramic particulates-reinforced iron matrix composites

Microstructure, microhardness and wear resistance of VCp/Fe surface composites fabricated in situ

In-situ production of (Fe,Cr)7C3 particulate bundles -reinforced iron matrix composite was prepared by infiltration casting between Cr wires and white cast iron at 1200°C plus subsequent heat treatment. The composites under different heat treatment times were comparatively characterized by scanning electron microscopy (SEM) and pin-on-disc wear resistance tests. The results show that the area of the particle bundles gradually increases with the heat treatment time increasing, and the chemical compositions change from eutectic to hypoeutectic, the morphologies of the reinforcements present chrysanthemum-shaped, granular and intercrystalline eutectics. Under 5 N loads, the composites appear excellent wear resistance, which is 36 times for the reference sample.

In Situ Production of (Fe,Cr)7C3 Particulate Bundles Reinforced Iron Matrix Composites

Reinforced tantalum carbide particles were synthesized between tantalum wires and graphite in gray cast iron by heat treatment; the effects of different heat treatment times on the phase evolution, microstructure, and micro-hardness of the composites were investigated. The particles obtained were small and square-shaped, 1–2 µm in size, and evenly distributed through the cast iron. The maximum micro-hardness of the composite region was 1832 HV0.1. After 20 min heat treatment, the micro-hardness decreased to approximately 1077 HV0.1, between about four and five times that of the matrix. The resulting composites also presented higher wear resistance compared with unreinforced gray cast iron.

Infiltration casting and in situ fabrication of tantalum carbide particulate-reinforced iron matrix composites

In Situ NbC Particulate-Reinforced Iron Matrix Composite: Microstructure and Abrasive Wear Characteristics

The method of infiltration casting plus heat treatment process employing chromium wires and cast iron applied to in-situ synthesized (Fe,Cr)7C3 particulates bundle reinforced iron matrix composites. The phase analysis, microstructure, microhardness and wear-resistance of composite were observed and measured. The results show that it is possible to fabricate (Fe,Cr)7C3 particulates bundle reinforced iron matrix composite produced by this technology, and a special structure which called particulates bundle was fabricated. (Fe,Cr)7C3 particulates bundle were distributed in the forms of granular, lath-shaped and hexagon-shaped in the particulates bundle. The macrohardness of particulates bundle was 52 HRC, and the relative wear resistance of the composites is 2.3—23 times higher than that of the cast iron.

Infiltration Casting and In Situ Fabrication of (Fe,Cr)7C3 Particulates Bundle – Reinforced Iron Matrix Composites

Study on NbC particulate-reinforced iron matrix composite produced in situ

An in-situ synthesis process combining an infiltration casting with a subsequent heat treatment was applied to fabricate special tungsten carbide (WC) bundles-reinforced iron matrix composites in this work. The microstructure and wear-resistance of the tungsten carbide bundles reinforced iron matrix composites were studied by using scanning electron microscopy, X-ray diffraction and wear tester. Results showed that the tungsten carbide bundles distributed in the matrix with the center-to-center spacing 2.2 mm, and the diameter of each tungsten carbide bundle is about 1 mm. Most of the tungsten carbides agglomerated, but still there were tungsten carbide particles and the size of tungsten carbide particle was about 10—15 μm. The weight loss of the tungsten carbides bundle reinforced iron matrix composites increased with the increase of the loads and the weight loss of the composites is much less than those of the gray cast iron under the same condition. The wear mechanism of tungsten carbide bundles-reinforced iron matrix composites appears as: micro-cutting, micro-ploughing, broken tungsten carbide and broken particles re-embedded in the matrix.

Microstructure and Abrasive Wear Characteristics of In Situ WC Bundles – Reinforced Iron Matrix Composites

Niobium carbide (NbC) particulates -reinforced iron matrix composites were prepared by in- situ fabrication method combining an infiltration casting with a subsequent heat treatment. The microstructure and wear-resistance of NbC particulate-reinforced iron matrix composites were studied using scanning electron microscopy, X-ray diffraction, and wear testing. The results indicate that at 1172 °C for 3 hours NbC particulate-reinforced iron matrix composites were fabricated, and the size of NbC reinforcement was 0.3–3.5 μm. The relative wear resistance of the composites was 5.4 times higher than that of gray cast iron under a 20 N load. This was achieved at 22 % NbC volume fraction. Wear of the composites manifests as grooves, broken carbide particulates and some micro-cracks.

Infiltration Casting and In Situ Fabrication of NbC Particulates – Reinforced Iron Matrix Composites

Effect of whisker surface treatment on the mechanical properties of 20vol%SiCw/BAS glass-ceramic composites

The micromechanisms of fracture and fatigue crack growth are elucidated for a new class of damage-tolerant niobium aluminide Nb 3 Al-xTi intermetallics. Fatigue crack growth in alloys containing 10 and 25 at% Ti is shown to occur primarily by cleavage, while alloys containing ∼40 at% Ti are shown to exhibit similar fracture and fatigue crack growth behavior to ductile metals and their alloys. Slower elevated-temperature (750°C) crack growth rates in the Nb 3 Al-40Ti alloy are attributed largely to the effects of oxide-induced crack closure. The transition from cleavage fracture (in the Nb 3 Al-10Ti and Nb 3 Al-25Ti alloys) to ductile fracture in the Nb 3 Al-40Ti is correlated with the onset of significant levels of crack-tip plasticity, which is predicted using atomistic simulations.

The Fracture and Fatigue Crack Growth Behavior of Forged Damage-Tolerant Niobium Aluminide Intermetallics

An investigation of fracture and fatigue crack growth behavior of cast niobium aluminide intermetallics

An investigation of the fatigue and fracture behavior of a Nb-12Al-44Ti-1.5Mo intermetallic alloy

This paper presents the results of a study of the toughening and resistance-curve behavior in a hybrid molybdenum disilicide (MoSi2) composite that has been reinforced with 2 mol% yttria partially stabilized zirconia particles (TZ-2Y) and niobium layers. Toughening and resistance-curve behavior occur as a result of the combined effects of crack bridging and transformation toughening. Crack-tip shielding that is due to large-scale crack bridging and transformation toughening also is modeled using micromechanics concepts. The models show that the overall crack-tip shielding from transformation toughening is very limited. However, large-scale bridging by the ductile niobium layers promotes significant levels of toughening and resistance-curve behavior.

Investigation of Toughening and Resistance-Curve Behavior in Hybrid Molybdenum Disilicide

An investigation of the fatigue and fracture behavior of multicomponent Nb-11Al-41Ti-1.5Mo-1.5Crintermetallic

An investigation of the fracture and fatigue crack growth behavior of forged damage-tolerant niobium aluminide intermetallics

An investigation of toughening in NiAl composites reinforced with yttria-partially stabilized zirconia particles

Intrinsic and extrinsic modification of niobium aluminides and molybdenum disilicide composites

The fatigue and fracture behavior of a gamma-titanium aluminide intermetallic: Influence of ductile phase reinforcement

Abstract : Research during the past three years has focused on the study of individual transformation toughening and crack bridging mechanisms in molybdenum disilicide composites reinforced with partially stabilized zirconia and thermodynamically compatible Nb, Mo and W phases. The primary objective in the initial studies was to study the fatigue and fracture mechanisms in model composite systems prior to a focused research effort aimed at developing synergistically toughened hybrid composites reinforced with zirconia particles and ductile/brittle bridging reinforcements. The hybrid composites were described as synergistically toughened composites due to anticipated interactions between crack bridging and stress-induced phase transformations. Such interactions may promote higher toughening levels than those expected from the sum of the individual toughening components. Room temperature fatigue and fracture behavior was studied in the transformation toughened and ductile phase toughened composites during the first and second year of the project. Crack-tip scanning and transmission electron microscopy studies were performed to determine the failure mechanisms at elevated temperature. The studies showed clearly that elevated temperature crack growth in MoSi2 and MoSi2 composite occurs by a combination of mechanical fatigue and creep crack growth (viscous flow of amorphous glass phase and microvoid nucleation) mechanisms. A model was also proposed for creep-fatigue crack growth at elevated temperature. Relatively fast elevated temperature cyclic crack growth rates were thus explained by considering the combined effects of creep and fatigue crack growth components. Finally, the possible synergistic interactions between crack bridging and transformation toughening were studied during the fourth year of the program.

 The results of a recent study of the crack/microstructure interactions in layered MoSi2/Nb composites are presented. Toughening by crack bridging and blunting mechanisms will be modeled in using micromechanics concepts. Finite element models for the prediction of interfacial debonding and mixed mode crack growth are also presented. The paper will highlight use of combined mechanics and materials approaches in the engineering of damage tolerant intermetallic matrix composites.

An Investigation of Crack/Microstructure Interaction in a Layered Intermetallic Composite

Effects of reinforcement morphology on the fatigue and fracture behavior of MoSi2/Nb composites

Fatigue and fracture behavior of Nb fiber-reinforced MoSi2 composites

Fatigue crack propagation of extruded-19Vf%-SiCw/6061Al composites under mixed mode (I + II) loading

A rat model for lung injury induced by chest impact trauma: A rat model for lung injury induced by chest impact trauma

The purpose of this study was to develop a docetaxel microemulsion containing an anti-tumor synergistic ingredient (Brucea javanica oil) and to investigate the characteristics of the microemulsion. Brucea javanica oil contains oleic acid and linoleic acids that have been shown by animal and human studies to inhibit tumor formation. The microemulsion containing Brucea javanica oil, medium-chain triglyceride, soybean lecithin, Solutol®HS 15, PEG 400, and water was developed for docetaxel intravenous administration. A formulation with higher drug content, lower viscosity, and smaller particle size was developed. The droplet size distribution of the dispersed phase of the optimized microemulsion was 13.5 nm, determined using a dynamic light scattering technique. The small droplet size enabled the microemulsion droplets to escape from uptake and phagocytosis by the reticuloendothelial system and increased the circulation time of the drug. The zeta potential was −41.3 mV. The optimized microemulsion was pale yellow, transparent, and non-opalescent in appearance. The value of the combination index was 0.58, showing that there was a synergistic effect when docetaxel was combined with Brucea javanica oil. After a single intravenous infusion dose (10 mg/kg) in male Sprague Dawley rats, the area under the curve of the microemulsion was higher and the half-time was longer compared with that of docetaxel solution alone, and showed superior pharmacokinetic characteristics. These results indicate that this preparation of docetaxel in emulsion is likely to provide an excellent prospect for clinical tumor treatment.

Intravenous microemulsion of docetaxel containing an anti-tumor synergistic ingredient (Brucea javanica oil): formulation and pharmacokinetics

：Tutor system forundergraduate is an efective way to improve the comprehensive quality of students. Thepaper discussed several questions in the clinical anesthesiology' s practice includingteaching goal, mentality and method and so on,raising the high quality medicalundergraduates.

The exploration andpractice of tutorial system for undergraduate students in clinical anesthesiology

Early diagnosis of malignant hyperthermia and its treatment regimen without dantrolene: Early diagnosis of malignant hyperthermia and its treatment regimen without dantrolene

In order to study the spallation phenomenon of titanium alloy under the shock of nanosecond laser, the Neodymium-Yttrium-Aluminum Garnet laser was used to carry out laser shock experiments on the surface of titanium alloy. By observing and measuring the surface morphology of the target material, the forming factors and the changes of the surface morphology under different parameter settings, the forming criteria of the titanium alloy were obtained. The results show that under the single variable method, the change of laser energy can affect the target shape variable, and there is a positive correlation between them. When the thickness was greater than or equal to 0.08 mm, no obvious cracks were found in the targets. Moreover, the number of impact times was the key factor for the target deformation; with the growth of impact times, the target deformation gradually became larger until the crack appeared. The larger the diameter of the spot, the more likely the target was to undergo plastic deformation. The surface of titanium alloy with a thickness of 0.08 mm appeared to rebound under specific laser shock condition. The changes in the back of the target material were observed in real time through a high-speed camera, and the plasma induced by the laser was observed in the process. This study is based on the results of previous studies to obtain the titanium alloy forming criteria, which provides a basis for the setting of laser parameters and the thickness of the target when the nanosecond laser impacts the Ti-6AL-4V target.

Surface Forming Criteria of Ti-6AL-4V Titanium Alloy under Laser Loading

In order to study the interaction between a femtosecond laser and a titanium film, the method of combining the two-temperature model and molecular dynamics was used to simulate the ablation and spallation of the titanium film by the femtosecond laser with a wavelength of 800 nm. The spallation of the titanium film was explained from the perspective of the temperature and the stress wave. It is found that the femtosecond laser with a pulse width of 300 fs loads the titanium film, and the ablation threshold is around 0.05 J/cm2. The effects of different pulse widths in the range of 100–500 fs and different energy densities in the range of 0.10–0.20 J/cm2 on the spallation results of titanium films were also studied. We found that the femtosecond laser with a pulse width of 100 fs promotes the spallation phenomenon to occur more quickly. The surface spallation products of the titanium film were large clusters of atoms when the energy density is 0.10 J/cm2, but most of the surface spallation products of the titanium film were single atoms when the energy density is 0.20 J/cm2. These indicated that the energy density is an important factor affecting the spallation products of the titanium film. The evolution of maximum electron temperature, electron-lattice equilibrium temperature, and coupling time with pulse width and energy density are also given and analyzed. These results have important reference significance for studying the fracture and damage of titanium, and they help us to understand the mechanism of femtosecond laser processing materials.

Simulation of femtosecond laser ablation and spallation of titanium film based on two-temperature model and molecular dynamics

In order to study the phenomenon of spallation in titanium alloy under nanosecond laser shock, and on the basis of analyzing the advantages of laser shock forming technology and the relevant domestic and foreign research status, this paper conducts numerical simulation and experimental research on laser shock forming of titanium alloy sheet, systematically studies the effect of different laser energy and impact times on laser shock forming effect, and the deformation law of TC4 titanium alloy material in the process of laser shock forming are analyzed. The simulation model analyzes the deformation of the target material based on the target displacement cloud map at different times. In addition, the laser shock experiment verifies the correctness of the simulation results with experimental data. The results show that under the single-variable method, as the energy gradually grows, the target shape variable also increases. As the number of impacts increases, the target deformation gradually increases until cracks appear. These results provide a basis for setting laser parameters and selecting targets when nanosecond laser strikes the TC4 target.

Surface deformation of Ti-6Al-4V titanium alloy under laser loading

Erratum: “Simulation of femtosecond laser ablation and spallation of titanium film based on two-temperature model and molecular dynamics” [J. Laser Appl. 33, 012047 (2021)]

Wear behavior of Mg-3Al-1Zn alloy subjected to laser shock peening

The microstructure and electrical properties of ZnO-Bi2O3-based varistor ceramics prepared by direct high-energy ball milling of the dopants were studied. The varistor ceramics samples were characterized by XRD and SEM analysis, as well as by dc electrical measurements, such as the nonlinearity coefficients, leakage current and threshold voltage. The best electrical characteristics were found in sample P2, which exhibited the threshold voltage was 347 V/mm, nonlinear coefficient was 39.2 and leakage current was 0.18 μA.

Proceedings of 2011 International Conference on Electronic & Mechanical Engineering and Information Technology

ZnO-Bi2O3-based varistor ceramics prepared by direct high-energy ball milling of the dopants

For high power and repetitive Nd:Glass laser, there would appear serious thermal effect due to the significantly-enhanced pumping optical power density in laser rod, which would induce thermal double refraction, phase distortion, thermal focusing, thermal depolarization, etc. Thus, the laser output power and beam quality would be influenced severely. Influence of thermal lens effect and depolarization effect caused by thermal stress double refraction on laser beam were studied in this paper for high power and repetitive laser. In the experiment of thermal lens effect, change of the laser spot by thermal lens effect was recorded after a TEM00 He-Ne laser beam passing through the Nd:Glass rod pumped by Xe lamp, and the corresponding optical compensator was applied to eliminate the thermal lens effect to improve the beam quality. Configuration of polarizer was designed in our experiment to research the depolarization effect caused by thermal stress double refraction. First, emergent light distribution and loss factor caused by double refraction was calculated according to the theoretical model. Then the exiting cone-shaped polarized light intensity distribution was obtained through the experiment. It could be obtained from the experiments that thermal lens effect and depolarization effect caused by thermal double refraction would reduce the output laser beam quality to varied extents. As the number of laser pulses increased, thermal effects began to emerge and the output laser energy apparently decreased; when the thermal effects steadied, the output energy would be tending towards stability.

Experiment Study of Influence on Laser Beam Quality Induced by Thermal Lens Effect and Depolarization Effect

When a short pulse of a Q-switched high-power laser hit surface of materials, laser energy would be absorbed rapidly, thus producing explosive vaporization, and almost at the same time a high-pressure shock wave was induced, called laser shock wave. This ultra-high pressure induced by high power laser had been applied in the fields of basic research and engineering application such as inertial confined fusion, laser shock processing, etc. Influence of variable laser power density on laser shock wave was studied in this paper. Influences of variation of laser wavelength and pulse duration on laser shock waves were also discussed in laser shock processing. Piezoelectric Polyvinylidene Fluoride (PVDF) transducer and TDS3052B Digital Oscilloscope were applied in our experiments to measure the piezoelectric wave of PVDF and the corresponding stress wave induced by laser in real time. Differences and relations between laser-induced shockwave and laser pulse in laser shock processing were researched according to the obtained waves, and the detailed analyses of their causes were given based on the formation of laser-induced shock wave. The research results could have important implications for a better understanding of characteristics of laser shock wave and further studies into the interaction between high-power laser and materials.

Relation research on laser-induced shockwave and laser pulse in laser shock processing

The focusing system is very important for laser processing, especially for laser micro-processing, whose characteristics influence directly the quality of laser processing. A new optical system from the potive axicon and spherical lens combination is proposed in this paper to generate the diffraction-free beam. Only one axicon is needed in this system to produce the variable diffraction-free beam spot of micro order by changing the ordinary cheap spherical lenses. If such an optical system is used as the focusing system for laser micro-processing, the sensitivity to the workpieces' position would be zero and the adaptability to the flatness of the workpieces' surface could be enhanced. Moreover, such a system could adapt well to the different processing criterion by changing the ordinary spherical lenses and would also have potential application in the measurement field.

New design of optical focusing system from an axicon combination for laser micro-processing machine

An orthogonal projection sampling method is proposed in this paper and is applied in the reconstruction of incomplete data field by using the prior knowledge algorithm based on the modified ART, by which the satisfying reconstruction results can be obtained even with less sampling directions and limited sampling angular range. The Mean Square Error (MSE) and peak value between the origin field, the reconstructed field using orthogonal projection sampling method and traditional projection sampling method are analyzed with the numerical simulation of computer. The results indicate that the orthogonal projection sampling can reduce the MSE greatly in the reconstruction of incomplete data. Thus our researches provide a new means for the reconstruction of incomplete data field.

Research on sampling method for three-dimensional flow field reconstruction of incomplete data

In practical engineering applications, the real-time monitoring of structural physical field is very important, which requires overall performance improvements on the Brillouin optical fiber sensing, including fast measurement, quick data demodulation and small amount of data storage. A novel Brillouin optical time-domain analysis (BOTDA) scheme has been proposed based on compressed sensing and pattern recognition algorithms, which paves the way for the realtime Brillouin optical fiber sensing. In order to test the sensing performance, the Brillouin gain spectrum is measured by the traditional fast BOTDA, where the frequency step and span are 4 MHz and 500 MHz, respectively. By employing the proposed algorithms, the strain information is directly obtained with only 35% of the full data, verifying the feasibility of real-time measurements.

Proposal of real-time Brillouin optical fiber sensing based on compressed sensing and pattern recognition algorithms

Two types of fast Brillouin optical time-domain reflectometry (BOTDR) for dynamic strain measurements have been proposed and experimentally demonstrated based on the frequency-agile technology. Using the frequency-agile modulated reference wave, the spontaneous Brillouin gain spectrum (BGS) is fast scanned in the frequency domain. Then, the spontaneous BGS can be reconstructed in the time domain by employing the band-pass filter and envelope detection. The frequency-agile technology enables two fast frequency-modulation methods, optical frequency sweeping and optical chirp chain modulation. Based on these two methods, the proposed fast BOTDR allows for a distributed, one-end-access and dynamic strain measurements. Besides, the sensing performance is investigated with different experiment parameters. The dynamic strain with dozens of Hertz vibrating frequency is successfully measured for both fast BOTDR schemes, which shows the proposed fast BOTDR a bright prospect.

Fast Brillouin optical time-domain reflectometry based on frequency-agile technology for dynamic strain measurements

Real-time Photonic Measurements, Data Management, and Processing VI

Proposal of real-time Brillouin fiber sensing based on compressing sensing and pattern recognition algorithms

The performance test of precision space inertial sensors on the ground is inevitably affected by seismic noise. A traditional vibration isolation platform, generally with a resonance frequency of several Hz, cannot satisfy the requirements for testing an inertial sensor at low frequencies. In this paper, we present a pendulum bench for inertial sensor testing based on translation-tilt compensation. A theoretical analysis indicates that the seismic noise effect on inertial sensors located on this bench can be attenuated by more than 40 dB below 0.1 Hz, which is very significant for investigating the performance of high-precision inertial sensors. We demonstrate this attenuation with a dedicated experiment.

A low-frequency vibration insensitive pendulum bench based on translation-tilt compensation in measuring the performances of inertial sensors

A low-frequency digital phase measuring system is designed.Phase measuring adopts the technique of same accuracy,which can measure the phase difference between two signals which have the same frequency.The design is based on the modulized method,including two parts: CPLD and SCM.The CPLD part realized most logic circuits,for example: division of frequency,phase detection,gate control,synchronization,counting,data latch and MUX.The SCM part mainly reads the I/O port,performs data processing,data conversion,control of the display part and displays the result on the digital LED module.

Activation of mesenchymal stem cells promotes new bone formation within dentigerous cyst

Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a severe adverse reaction, which results in progressive bone destruction in the maxillofacial region of patients. To date, the pathological mechanisms remain largely unclear. Recently, we found that BRONJ patient had significantly deep periodontal pockets and severe periodontal bone defects before the exposed necrotic bone. Human periodontal ligament stem cells (hPDLSCs) play key roles in physiological maintenance and regeneration of periodontal tissues. However, the activities of hPDLSCs derived from BRONJ lesions and the role of hPDLSCs in BRONJ periodontal defect repair remain poorly understood. The aim of the present study was to elucidate the role of hPDLSCs in BRONJ. In this study, we found that the capacities of cell proliferation, adhesion and migration of hPDLSCs derived from BRONJ lesions (BRONJ-hPDLSCs) were significantly decreased compared with control-hPDLSCs. BRONJ-hPDLSCs underwent early apoptosis compared with control- hPDLSCs. Importantly, we first demonstrated that BRONJ-hPDLSCs exhibited impaired osteogenic differentiation abilities in ectopic osteogenesis of nude mice. The above results suggested that the impaired BRONJ-hPDLSCs may be an important factor in deficient periodontal repair of BRONJ lesions and provide new insight into the underlying mechanism of BRONJ.

Decreased osteogenic ability of periodontal ligament stem cells leading to impaired periodontal tissue repair in BRONJ patients.

 Studies of mandibular movement trajectories have provided a good understanding of the motion of the condyle but little information on the geometric relationships of the disc because they have not related the movements to anatomic structures.
 
 This study investigated the morphology and kinematic characteristics of the Temporomandibular Joint (TMJ) using Cine-MRI and ARCUSdigma systems.
 
 For this study population, preliminary clinical diagnoses were asymptomatic in 15 cases, unilateral anterior disc displacement with reduction (ADDWR) in 17 cases, and unilateral Anterior Disc Displacement Without Reduction (ADDWoR) in 14 cases. Patients were investigated with Cine-MRI and ARCUSdigma systems during physiological opening and closing of the mouth.
 
 In these groups, there were 13 healthy subjects, 19 patients with unilateral ADDWR and 14 patients with unilateral ADDWoR classified by Cine-MRI. (1) To assess morphology by MRI, disc deformities were evaluated as follows: biplanar, rounded, thickening in the posterior band, lengthened and folded. (2) The opening trajectory for healthy subjects was close to the closing trajectory. Conversely, the incisal and condylar trajectories during opening and closing were obviously bounced, deviated or shortened in the ADDWR and ADDWoR groups. The pathway of the kinematic axis was not parallel, and the condylar trajectory had an inflexion. (3) The mean values of the incisal and condylar paths of the ADDWoR group were significantly different from those in the healthy group (P<0.05), whereas there were no significant differences between the ADDWR and the healthy group (P>0.05).
 
 This study combined analysis of the condylar pathways and disc-condylar relationship to provide good visualization of morphology and kinematics during jaw movement. This process helps improve our understanding of the complexity of disk-condylar movements in subjects with TMJ internal derangement and may also contribute to our knowledge of the etiology of TMJ internal derangement.

Analysis of the Correlation between Morphology and Kinematics of Anteriorly Displaced TMJ Discs Using Cine-MRI and ARCUSdigma Systems

ABSTRACT Epithelial-to-mesenchymal transition (EMT) confers cancer cells the ability of invasion and metastasis. However, how does EMT contribute to evasion of immune surveillance is unclear, especially in salivary adenoid cystic carcinoma (SACC). In this study, we investigated the molecular link between EGF-induced EMT and the immune checkpoint ligand programmed death-ligand 1 (PD-L1) by immunoprecipitation (IP) and Westernblot analysis. Cell migration and invasion activity was assayed by transwell assay. Immunohistochemical (IHC) staining analysis was performed for measurement of EMT markers and PD-L1 expression levels in tumor tissues. We found that EGF-induced EGFR activation stabilized Snail expression and induced EMT in SACC. Interestingly, EGFR activation induced simultaneously both EMT and PD-L1 in SACC. Importantly, knockdown of Snail greatly suppressed EGF-induced EMT, but not EGF-induced PD-L1 expression; whereas knockdown of c-Myc strongly repressed PD-L1 expression, but not snail expression and EMT. The molecular link is strongly supported by robust correlations between the EMT markers and PD-L1 expression in human cancer samples.These results suggest that EGFR activated EMT and PD-L1 via two distinct mechanisms. EGFR activation induced EMT and PD-L1 expression in SACC. Snail is required for EGF-induced EMT, but not PD-L1 expression; whereas c-Myc is required for EGFR-mediated PD-L1 upregulation but not EMT. Thus, targeting activated EGFR may inhibit both EMT and PD-L1, which may potentiate the therapeutic effect of PD-L1-based immunotherapy, especially in the malignant subgroups of SACC patients with activated EGFR.

EGFR activation induced Snail-dependent EMT and myc-dependent PD-L1 in human salivary adenoid cystic carcinoma cells

Background/Aims: Slug protein, a transcription factor for the induction of epithelial-mesenchymal transition (EMT) and cancer cell invasion and metastasis, is frequently upregulated in human epithelial cancers. However, mutation of this gene in cancer is rare, and the mechanism of its dysregulation remains unknown, especially in head and neck squamous cell carcinoma (HNSCC). Methods: We examined the role of TNF-α in the stabilization of Slug by immunoprecipitation-westernblot analysis. Migration of HNSCC cells with or without knockdown of Slug gene expression was assayed by a wound healing assay. Immunohistochemical staining analysis was used to measurement Slug levels in both normal and HNSCC tumor tissues. Results: The inflammatory cytokine TNF-α stabilized Slug protein by inhibiting its ubiquitination through the NF-κB pathway. Inhibition of NF-κB or knockdown of p65 abrogated the TNF-α-induced stabilization of Slug. Knockdown of Slug expression inhibited cancer cell migration and EMT characteristics induced by TNF-α. Moreover, increased levels of Slug were found to correlate with lymph node metastasis and predict poor prognosis in patients with HNSCC. Conclusions: NF-κB-mediated stabilization of Slug underlies the inflammation-induced EMT and metastasis in HNSCC, which may serve as a therapeutic target for metastatic HNSCC.

Stabilization of Slug by NF-κB is Essential for TNF-α -Induced Migration and Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma Cells

Identification and characterization of a highly metastatic epithelial cancer cell line from rat tongue cancer.

ABSTRACT Defects in apoptotic pathway contribute to development and progression of oral cancer. Survivin, a member of the inhibitors of apoptosis protein (IAP) family, is increased in many types of cancers. However, it is unclear whether increased survivin is associated with oral squamous cell carcinomas (OSCC), and what mechanisms may involve in. In this study, we examined survivin expression in OSCC compared with normal oral tissues via immunohistochemical staining. The results showed that, not only total survivin is increased in OSCCs, but also the subcellular location of survivin is changed in OSCCs compared with normal oral tissues. In most of normal oral tissues, survivin staining was either negative, or cytoplasmic positive/nuclear negative; whereas in most of OSCC tissues, survivin staining was nuclear positive. Statistic analysis indicates that nuclear survivin, rather than total or cytoplasmic one, correlates with tumor TNM stage and differentiation grade. Consistently, in vitro analysis showed that survivin is in cytoplasm in normal human oral kinotinocyte (HOK) cells; whereas it is in nucleus in OSCC HN6 cells. Importantly, treatment of HOK cells with HDAC inhibitor Trichostatin A (TSA) induces survivin acetylation and promotes its nuclear localization. Moreover, nuclear survivin in OSCC cells was acetylated at K129 in its C-terminal, suggesting that the acetylation is important for nuclear location of survivin. Our study demonstrates that it is nuclear survivin, rather than total or cytoplasmic one, associates with TNM stage and tumor grade of OSCC. Thus, we propose nuclear survivin as a prognostic marker for the progression of OSCC.

Nuclear survivin promoted by acetylation is associated with the aggressive phenotype of oral squamous cell carcinoma

Mesenchymal-epithelial transition factor (c-Met) is the only high affinity receptor for hepatocyte growth factor (HGF), and is frequently activated in many human cancers. However, little is known about the role of the HGF/c-Met signaling pathway in the progression of human oral squamous cell carcinoma (OSCC). This study evaluated the role of the HGF/c-Met signaling pathway in the progression of human OSCC. We found that the expression of c-Met was significantly increased in human OSCC tissues than in normal mucosa adjacent to the tumor (P<0.05), but was not correlated with clinicopathological parameters. Additionally, the selective c-Met inhibitor JNJ was found to inhibit cell viability and migration and promote apoptosis in OSCC cell lines, and also blocked the activation AKT, ERK1/2, and NF-κB p65; thus, suggesting that HGF/c-Met signaling may play an important role in the tumorigenic properties of OSCC cells via the AKT, ERK1/2, and NF-κB pathways. Collectively, these results indicated that HGF/c-Met signaling may serve essential roles in the progression of human OSCC, and may thus be a basis for the development of novel therapeutic approaches in the treatment of OSCC.

Role of c-Met in the progression of human oral squamous cell carcinoma and its potential as a therapeutic target.

Repression of GPRC5A is associated with activated STAT3, which contributes to tumor progression of head and neck squamous cell carcinoma

Growth differentiation factor 15 promotes blood vessel growth by stimulating cell cycle progression in repair of critical-sized calvarial defect

Enhancer of zeste homolog 2 (EZH2) has been characterized as a critical oncogene and a promising drug target in human malignant tumors. The current EZH2 inhibitors strongly suppress the enhanced enzymatic function of mutant EZH2 in some lymphomas. However, the recent identification of a PRC2‐ and methyltransferase‐independent role of EZH2 indicates that a complete suppression of all oncogenic functions of EZH2 is needed. Here, we report a unique EZH2‐targeting strategy by identifying a gambogenic acid (GNA) derivative as a novel agent that specifically and covalently bound to Cys668 within the EZH2‐SET domain, triggering EZH2 degradation through COOH terminus of Hsp70‐interacting protein (CHIP)‐mediated ubiquitination. This class of inhibitors significantly suppressed H3K27Me3 and effectively reactivated polycomb repressor complex 2 (PRC2)‐silenced tumor suppressor genes. Moreover, the novel inhibitors significantly suppressed tumor growth in an EZH2‐dependent manner, and tumors bearing a non‐GNA‐interacting C668S‐EZH2 mutation exhibited resistance to the inhibitors. Together, our results identify the inhibition of the signaling pathway that governs GNA‐mediated destruction of EZH2 as a promising anti‐cancer strategy.

A covalently bound inhibitor triggers EZH2 degradation through CHIP‐mediated ubiquitination

Salivary adenoid cystic carcinoma (SACC) is characterized by invasive local growth and a high incidence of lung metastasis. Patients with lung metastasis have a poor prognosis. Treatment of metastatic SACC has been unsuccessful, largely due to a lack of specific targets for the metastatic cells. In this study, we showed that epidermal growth factor receptors (EGFR) were constitutively activated in metastatic lung subtypes of SACC cells, and that this activation was induced by autocrine expression of epiregulin (EREG), a ligand of EGFR. Autocrine EREG expression was increased in metastatic SACC-LM cells compared to that in non-metastatic parental SACC cells. Importantly, EREG-neutralizing antibody, but not normal IgG, blocked the autocrine EREG-induced EGFR phosphorylation and the migration of SACC cells, suggesting that EREG-induced EGFR activation is essential for induction of cell migration and invasion by SACC cells. Moreover, EREG-activated EGFR stabilized Snail and Slug, which promoted EMT and metastatic features in SACC cells. Of note, targeting EGFR with inhibitors significantly suppressed both the motility of SACC cells in vitro and lung metastasis in vivo. Finally, elevated EREG expression showed a strong correlation with poor prognosis in head and neck cancer. Thus, targeting the EREG-EGFR-Snail/Slug axis represents a novel strategy for the treatment of metastatic SACC even no genetic EGFR mutation.

Autocrine epiregulin activates EGFR pathway for lung metastasis via EMT in salivary adenoid cystic carcinoma

High Vimentin Expression Associated with Lymph Node Metastasis and Predicated a Poor Prognosis in Oral Squamous Cell Carcinoma

The mouse double minute 2 (MDM2) gene is an important regulator of the p53 suppressor gene. To date, evidence concerning the association of the MDM2 single nucleotide polymorphism (SNP) 309T>G (rs2279744) with the risk of developing oral squamous cell carcinoma (OSCC) remains controversial. Therefore, a meta-analysis of all the eligible studies was performed, in order to derive a more precise estimation of this association. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the degree of association in 5 previous studies, including a total of 1,369 OSCC cases and 2,167 controls. The overall analysis revealed a significant association between MDM2 SNP309 and OSCC risk in the heterozygote (TG vs. TT: OR=0.81; 95% CI: 0.68-0.96; P=0.02) and dominant models (TG+GG vs. TT: OR=0.82; 95% CI: 0.69-0.97; P=0.02). The subgroup analysis based on the source of the controls revealed a significant association between population-based controls and the heterozygote model (TG vs. TT: OR=0.75; 95% CI: 0.62-0.91; P=0.004), dominant model (TG+GG vs. TT: OR=0.76; 95% CI: 0.63-0.91; P=0.003) and allele comparison (G vs. T: OR=0.89; 95% CI: 0.79-0.99; P=0.04). Importantly, no evidence of publication bias or obvious heterogeneity were observed in the meta-analysis. The results of the present study demonstrated a decreased risk of developing OSCC for the MDM2 SNP309 group, suggesting MDM2 SNP309 may be a protection-associated genetic variation for OSCC. Additional well-designed studies, with larger sample sizes, are required to further elucidate this association.

Association of MDM2 promoter T309G polymorphism with oral cancer risk: A meta-analysis of 3,536 subjects.

Ubiquitin-specific protease 14 regulates cell proliferation and apoptosis in oral squamous cell carcinoma.

The repair of segmental mandibular defects remains challenging in the clinic. Previous studies have shown that cryopreserved bone-derived osteoblasts (CBOs) have good proliferation and osteogenicity. However, whether these cells can be used in the repair of segmental mandibular defects is largely unknown.

PURPOSE
In this study, we applied CBOs combined with beta-tricalcium phosphate (β-TCP) to repair a segmental mandibular defect in canines and thus established the feasibility of using this type of tissue-bank cell for the repair of large bone defects in the future.

Sixteen segmental mandibular defects in 16 animals were made on the right side. Sequential radiographs, computer tomography, polychrome fluorescent labeling, immunohistochemical staining, and histological analysis were used to evaluate the effects of tissue-engineered bone for segmental mandibular defects.

RESULTS
Our results demonstrated that CBOs combined with β-TCP promoted bone mineralization and deposition at the early stage, and bony union was achieved in the CBO and fresh bone-derived osteoblast (FBO) groups. However, nonunion and minimal callus were present in the β-TCP group. Furthermore, there was a large amount of newly formed bone in the CBO and FBO groups and in the autogenous bone group. Additionally, osteocalcin immunohistochemistry showed intensive osteocalcin immunoreactivity in the bone matrix of the CBO and FBO groups.

These data indicate that CBOs implanted in a scaffold can promote new bone formation, and this tissue-engineered bone can repair critically sized segmental mandibular defects in canines. The use of CBOs combined with β-TCP may be an effective approach for the reconstruction of segmental mandibular defects in the clinic.

Comprehensive Evaluation of Cryopreserved Bone-Derived Osteoblasts for the Repair of Segmental Mandibular Defects in Canines.

Head and neck squamous cell carcinoma (HNSCC) is a particularly aggressive cancer with poor prognosis, largely due to lymph node metastasis and local recurrence. Emerging evidence suggests that epithelial-to-mesenchymal transition (EMT) is important for cancer metastasis, and correlated with increased cancer stem cells (CSCs) characteristics. However, the mechanisms underlying metastasis to lymph nodes in HNSCC is poorly defined. In this study, we show that E-cadherin repression correlates with cancer metastasis and poor prognosis in HNSCC. We found that G9a, a histone methyltransferase, interacts with Snail and mediates Snail-induced transcriptional repression of E-cadherin and EMT, through methylation of histone H3 lysine-9 (H3K9). Moreover, G9a is required for both lymph node-related metastasis and TGF-β-induced EMT in HNSCC cells since knockdown of G9a reversed EMT, inhibited cell migration and tumorsphere formation, and suppressed the expression of CSC markers. Our study demonstrates that the G9a protein is essential for the induction of EMT and CSC-like properties in HNSCC. Thus, targeting the G9a-Snail axis may represent a novel strategy for treatment of metastatic HNSCC.

G9a is essential for EMT-mediated metastasis and maintenance of cancer stem cell-like characters in head and neck squamous cell carcinoma

G 9 a Is Essential for EMT-Mediated Metastasis and Maintenance of Cancer Stem Cell-Like Characters in Head and Neck Squamous Cell Carcinoma

The XPA gene participates in modulating DNA damage recognition during the DNA nucleotide excision repair process. Current data regarding the association of the XPA A23G polymorphism with the risk of head and neck squamous cell carcinoma (HNSCC) remain controversial, and meta-analyses focusing on the HNSCC risk and this polymorphism are limited. Therefore, the aim of the present study was to derive a more precise estimation of this association by a meta-analysis of all the eligible studies. Odds ratios (ORs) with 95% confidence intervals (CI) were assessed for the strength of the associations in eight studies, including 5,491 subjects (2,409 HNSCC cases and 3,082 controls). The overall analysis revealed that the XPA A23G polymorphism was not significantly associated with the overall HNSCC risk. Consistently, there was no evidence for the association between the XPA A23G polymorphism and HNSCC risk in subgroup analyses based on ethnicity and the source of controls. However, the significant associations in oral carcinoma with the increased risk among the XPA heterozygote (AG vs. AA: OR, 1.58; 95% CI, 1.06-2.37; Pheterogeneity=0.23, I2=30%) and dominant (AG +GG vs. AA: OR, 1.53; 95% CI, 1.04-2.23; Pheterogeneity=0.21, I2=36%) models were observed in the subgroup analysis by tumor site. In conclusion, the meta-analysis suggested that the XPA A23G polymorphism was not associated with overall HNSCC susceptibility, but it was associated with oral carcinoma susceptibility and it may be a risk factor for oral carcinoma. Further well-designed and large studies are required to confirm these associations.

Association of the XPA A23G polymorphism with the risk of head and neck carcinomas: Evidence from 5,491 subjects.

Stem cell-based tissue engineering shows promise for bone regeneration and requires artificial microenvironments to enhance the survival, proliferation and differentiation of the seeded cells. Silk fibroin, as a natural protein polymer, has unique properties for tissue regeneration. The present study aimed to evaluate the influence of porous silk scaffolds on rat bone marrow stem cells (BMSCs) by lenti-GFP tracking both in vitro and in vivo in cranial bone defects. The number of cells seeded within silk scaffolds in rat cranial bone defects increased from 2 days to 2 weeks after implantation, followed by a decrease at eight weeks. Importantly, the implanted cells survived for 8 weeks in vivo and some of the cells might differentiate into endothelial cells and osteoblasts induced by the presence of VEGF and BMP-2 in the scaffolds to promote angiogenesis and osteogenesis. The results demonstrate that porous silk scaffolds provide a suitable niche to maintain long survival and function of the implanted cells for bone regeneration.

Porous Silk Scaffolds for Delivery of Growth Factors and Stem Cells to Enhance Bone Regeneration

Surgical implants are widely used in the medical field but their long-term performance is limited due to failure of integration with tissues. This manuscript describes very well-known problems associated with implants and discusses novel solutions used in tissue engineering and regenerative medicine that can be implemented in this uncommonly discussed medical area.

SOURCES OF DATA
General and medical literature describing modifications of medical and surgical implants, biofunctionalization, tissue engineering and regenerative medicine.

AREAS OF AGREEMENT
Procedures for surgical implantation have grown substantially in the last few decades and provided improved quality of life for patients, regardless of area of implantation and device type and purpose.

AREAS OF CONTROVERSY
In general, implants fail because of lack of long-term integration with the surrounding tissues. Implant manufacturers have not addressed implant failure from the point of view of biointegration. In addition, some medical practitioners are inclined to treat implant failure by using anti-infection methods to prevent bacterial adhesion. However, both approaches are conceptually limited, as discussed in this manuscript.

GROWING POINTS
Implantation in the future will not be limited to medically needed procedures but also to a growing number of cosmetic body transformation procedures, which may include perceived 'improved implant functions' over natural tissues or organs. An additional trend is that implant procedures are being progressively performed in younger individuals.

AREAS TIMELY FOR DEVELOPING RESEARCH
Current implants generally do not allow the physician to have controlled long-term access to internal tissues in contact with the implants, for example to release specific compounds when medically needed to the problem area.

Implementing tissue engineering and regenerative medicine solutions in medical implants.

For artificial nerve conduits, great improvements have been achieved in mimicking the structures and components of autologous nerves. However, there are still some problems in conduit construction, especially in terms of mechanical properties, biomimetic surface tomography, electrical conductivity and sustained release of neurotrophic factors or cells. In this study, we designed and fabricated a novel electrospun nerve conduit enhanced by multi-walled carbon nanotubes (MWNTs) on the basis of a collagen/poly(ε-caprolactone) (collagen/PCL) fibrous scaffold. Our aim was to provide further knowledge about the mechanical effects and efficacy of MWNTs on nerve conduits as well as the biocompatibility and toxicology of MWNTs when applied in vivo. The results showed that as one component, carboxyl MWNTs could greatly alter the composite scaffold’s hydrophilicity, mechanical properties and degradability. The electrospun fibers enhanced by MWNTs could support Schwann cell adhesion and elongation as a substrate in vitro. In vivo animal studies demonstrated that the MWNT-enhanced collagen/PCL conduit could effectively promote nerve regeneration of sciatic nerve defect in rats and prevent muscle atrophy without invoking body rejection or serious chronic inflammation. All of these results showed that this MWNT-enhanced scaffold possesses good biocompatibility and MWNTs might be excellent candidates as engineered nanocarriers for further neurotrophic factor delivery research.

A novel electrospun nerve conduit enhanced by carbon nanotubes for peripheral nerve regeneration

Vacuum extraction enhances rhPDGF-BB immobilization on nanotubes to improve implant osseointegration in ovariectomized rats.

Protocol for serial cultivation of epithelial cells without enzymes or chemical compounds.

Vascular endothelial growth factor (VEGF) and bone morphogenetic protein-2 (BMP-2) have been widely used in the fields of tissue engineering and regenerative medicine to stimulate angiogenesis and bone formation. The goal of this study was to determine whether VEGF and BMP-2 are involved in the homing of bone marrow stem cells (BMSCs) for bone regeneration and to provide insights into their mechanism of action. The chemoattraction of BMSCs to VEGF and BMP-2 was analysed in vitro using a checkerboard assay. VEGF and BMP-2 stimulated the chemotaxis of BMSCs but not chemokinesis. In vivo, both VEGF and BMP-2 also have been confirmed to induce the homing of tail vein injected BMSCs to the site of silk scaffold subcutaneous implantation in nude mice. When the scaffolds were implanted in the rabbit skull defects, more SSEA+ mesenchymal stem cells were mobilised and homed to silk scaffolds containing VEGF and/or BMP-2. More importantly, autogenic BMSCs were reinjected via the ear vein after labelling with lenti-GFP, and the cells were detected to home to the defects and differentiate into endothelial cells and osteogenic cells induced by VEGF and BMP-2. Finally, perfusion with Microfil showed that initial angiogenesis was enhanced in tissue-engineered complexes containing VEGF. Observations based on µCT assay and histological study revealed that bone formation was accelerated on BMP-2-containing scaffolds. These findings support our hypothesis that the localised release of VEGF and BMP-2 promote bone regeneration, in part by facilitating the mobilisation of endogenous stem cells and directing the differentiation of these cells into endothelial and osteogenic lineages.

VEGF and BMP-2 promote bone regeneration by facilitating bone marrow stem cell homing and differentiation.

Calcium phosphate (Ca-P) scaffolds have been widely employed as a supportive matrix and delivery system for bone tissue engineering. Previous studies using osteoinductive growth factors loaded Ca-P scaffolds via passive adsorption often experience issues associated with easy inactivation and uncontrolled release. In present study, a new delivery system was fabricated using bone morphogenetic protein-2 (BMP-2) loaded calcium-deficient hydroxyapatite (CDHA) scaffold by lyophilization with addition of trehalose. The in vitro osteogenesis effects of this formulation were compared with lyophilized BMP-2/CDHA construct without trehalose and absorbed BMP-2/CDHA constructs with or without trehalose. The release characteristics and alkaline phosphatase (ALP) activity analyses showed that addition of trehalose could sufficiently protect BMP-2 bioactivity during lyophilization and achieve sustained BMP-2 release from lyophilized CDHA construct in vitro and in vivo. However, absorbed BMP-2/CDHA constructs with or without trehalose showed similar BMP-2 bioactivity and presented a burst release. Quantitative real-time PCR (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) demonstrated that lyophilized BMP-2/CDHA construct with trehalose (lyo-tre-BMP-2) promoted osteogenic differentiation of bone marrow stromal cells (bMSCs) significantly and this formulation could preserve over 70% protein bioactivity after 5 weeks storage at 25°C. Micro-computed tomography, histological and fluorescent labeling analyses further demonstrated that lyo-tre-BMP-2 formulation combined with bMSCs led to the most percentage of new bone volume (38.79% ±5.32%) and area (40.71% ±7.14%) as well as the most percentage of fluorochrome stained bone area (alizarin red S: 2.64% ±0.44%, calcein: 6.08% ±1.37%) and mineral apposition rate (4.13±0.62 µm/day) in critical-sized rat cranial defects healing. Biomechanical tests also indicated the maximum stiffness (118.17±15.02 Mpa) and load of fracture (144.67±16.13 N). These results lay a potential framework for future study by using trehalose to preserve growth factor bioactivity and optimize release profile of Ca-P based delivery system for enhanced bone regeneration.

Trehalose Maintains Bioactivity and Promotes Sustained Release of BMP-2 from Lyophilized CDHA Scaffolds for Enhanced Osteogenesis In Vitro and In Vivo

Engineering of bone using rhBMP-2-loaded mesoporous silica bioglass and bone marrow stromal cells for oromaxillofacial bone regeneration

Aim:To evaluate the inhibitory effect of a recombinant human papillomavirus (HPV) fusion protein vaccine on oral squamous cell carcinoma (OSCC). Materials and Methods:An animal model of OSCC was established using human peripheral blood lymphocyte reconstituted nonobese diabetic/severe combined immunodeficiency mice. HPV vaccine was subcutaneously injected into mice after tumor establishment. Tumors and spleens were measured, weighed and stained with hematoxylin and eosin. Lymphocyte subpopulations and cytotoxicity were analyzed with flow cytometric and cytotoxic T lymphocyte assay. Results:The average weight and volume of tumors were significantly lower in the vaccine group than in the control group from day 27. Mice in both groups had high percentages of human CD3+ and CD3+CD8+ T lymphocytes. An elevated percentage of human CD3−CD16+56+ natural killer cells was found in the vaccine group. Moreover, vaccine increased the infiltration of human CD3+ and UCHL-1+ cells in tumor tissues and enhanced cytotoxicity. Conclusions:The HPV fusion protein vaccine induces tumor cell death, lymphocyte infiltration and therefore suppresses tumor growth and protects against OSCC.

Inhibitory Effect of the HPV-16mE6Delta/mE7/TBhsp70Delta Vaccine on Oral Squamous Cell Carcinoma

Small ubiquitin-like modifier (SUMO) modification is an important post-translational protein modification that can be reversed by SUMO-specific proteases (SENPs); however, the physiological function of SENPs remains largely unexplored, and little is known about the regulation of SENPs themselves. As one of the crucial members of the SUMO system, SENP3 is essential for rRNA processing and cell proliferation. In the present study, we analysed the expression of SENP3 in human oral squamous cell carcinoma (OSCC) and investigated the correlation between its expression and clinicopathological parameters in OSCC patients. The expression of SENP3 was higher in OSCC tissues than that in the normal mucosa adjacent to the tumor, and a modest increase in reactive oxygen species (ROS) regulated SENP3 stability and localization. ROS induced SENP3 redistribution from the nucleoli to the nucleoplasm. Taken together, these results indicated that the expression level of SENP3 may be associated with the differentiation of OSCC and that SENP3 may play an important role in the development of OSCC under oxidative stress.

Overexpression of SENP3 in oral squamous cell carcinoma and its association with differentiation

Gambogic acid (GA) is known for its anti‐cancer activity in a phase II clinical trial. However, the detailed molecular mechanisms of its anti‐multidrug resistance remain unclear. The present study was designed to study the relationship between GA and multidrug‐resistant protein ATP‐binding cassette transporter B1 (ABCB1). GA dose dependently inhibited ABCB1 activity levels in the in vitro Pgp‐Glo assay system and increased the cellular accumulation of ABCB1 substrate adriamycin. Although GA had no significant influence on ABCB1 mRNA in the real‐time PCR assay, Western blot detection indicated the compound reduced ABCB1 protein levels. Further study showed the proteasome inhibitor MG‐132 reversed the GA‐decreased ABCB1 level and prolonged half‐life of ABCB1. It was also found that GA coordinated with other anti‐cancer drugs (such as adriamycin, docetaxel, verapamil and protopanaxadiol) to enhance cellular cytotoxicity on human epithelial cancer cell lines with higher ABCB1 expression levels. These data suggest that GA functions as a non‐competitive inhibitor of ABCB1 by directly inhibiting and reducing its expression levels by promoting protein degradation through post‐translational proteasome pathway. The results of this study will aid in the understanding of the synergistic effects of combining GA with other drugs as a new anti‐multidrug‐resistant agent.

Gambogic Acid as a Non‐Competitive Inhibitor of ATP‐Binding Cassette Transporter B1 Reverses the Multidrug Resistance of Human Epithelial Cancers by Promoting ATP‐Binding Cassette Transporter B1 Protein Degradation

Patients with advanced head and neck squamous cell carcinoma (HNSCC) have a poor prognosis with the currently available therapy, and tumor recurrence is frequently observed. The discovery of specific membrane-associated cancer stem cell (CSC) markers is crucial for the development of novel therapeutic strategies to target these CSCs. To address this issue, we established sphere cultures to enrich CSCs and used them for plasma membrane proteomics to identify specific membrane signatures of the HNSCC spheres. Of a dataset that included a total of 376 identified proteins, 200 were bona fide membrane proteins. Among them, 123 proteins were at least 1.5-fold up- or down-regulated in the spheres relative to the adherent cultures. These proteins included cell adhesion molecules, receptors, and transporter proteins. Some of them play key roles in wnt, integrin, and TGFβ signaling pathways. When we compared our dataset with two published hESC membrane protein signatures, we found 18 proteins common to all three of the databases. CD166 and CD44 were two such proteins. Interestingly, the expression of CD166, rather than that of the well-established HNSCC CSC marker CD44, was significantly related to the malignant behavior of HNSCC. Relative to CD166low HNSCC cells, CD166high HNSCC cells had a greater sphere-formation ability in vitro and tumor formation ability in vivo. Patients whose tumors expressed high levels of CD166 had a significantly poorer clinical outcome than those whose tumors expressed low levels of CD166 (cohort 1: 96 cases, p = 0.040), whereas the level of CD44 expression had only a marginal influence on the clinical outcome of patients with HNSCC (p = 0.078). The level of CD166 expression in HNSCC tumors was also associated with the tumor recurrence rate (cohort 2: 104 cases, p = 0.016). This study demonstrates that CD166 is a valuable cell surface marker for the enrichment of HNSCC stem cells and that plasma membrane proteomics is a promising biological tool for investigating the membrane proteins of CSCs.

Plasma Membrane Proteomics of Tumor Spheres Identify CD166 as a Novel Marker for Cancer Stem-like Cells in Head and Neck Squamous Cell Carcinoma*

Role of toll-like receptor 4 on the immune escape of human oral squamous cell carcinoma and resistance of cisplatin-induced apoptosis

Calcium phosphate cements (CPCs), which are widely used in bone regeneration, possess good biocompatibility and osteoconductivity and have been demonstrated to be candidate carriers for bone growth factors. However, limited release of growth factors from CPCs and slow degradation of the materials are not desirable for certain clinical applications. Previous studies have shown that calcium-deficient hydroxyapatite (CDHA) from CPCs presents more rapid degradation rate than CPCs. In this study, a hybrid growth factor delivery system was prepared by using bone morphogenetic protein 2 (BMP-2) loaded CDHA porous scaffold with sulfated chitosan (SCS) coating for improved release profile. We tested the BMP-2 release characteristic of CDHA/BMP-2/SCS composite in vitro and its ability to repair rat calvarial bone defects. A higher percentage of BMP-2 was released when sulfated chitosan coating was present compared with CDHA/BMP-2 group. Eight weeks postoperation, the repaired crania were evaluated by microcomputed tomography, sequential fluorescent labeling, histological analysis, and immunohistochemistry. CDHA/BMP-2/SCS group promoted the most extensive new bone formation than CDHA/BMP-2 and CDHA groups. Our observations suggest that sulfated chitosan coating could enhance the release profile of CDHA/BMP-2 composite in vitro and promote new bone formation in vivo. The hybrid CDHA/BMP-2/SCS system is a promising growth factor delivery strategy for bone regeneration.

Enhanced healing of rat calvarial defects with sulfated chitosan-coated calcium-deficient hydroxyapatite/bone morphogenetic protein 2 scaffolds.

The contactin 1 (CNTN1) gene exerts oncogene-like activities and its expression has been linked to several human malignancies. In this study, a possible association between CNTN1 expression and clinicopathological parameters and clinical outcomes in patients with oral squamous cell carcinoma (OSCC) was examined. CNTN1 protein expression was evaluated by immunohistochemistry in OSCC tissues of 45 patients. For the immunohistochemical assessment of CNTN1 expression, the cytoplasmic staining labeling index was analyzed using a semiquantitative score. The association between CNTN1 protein levels and clinicopathological factors was analyzed using the Mann-Whitney U test for categorical variables and the Kruskal-Wallis test for continuous variables. The effects of CNTN1 expression on overall and disease-free survival were assessed by using univariate survival analysis. The transcript levels of CNTN1 were detected in OSCC cell lines. In addition, specific siRNA against CNTN1 was applied to investigate the effect exerted by CNTN1 ablation on OSCC cell lines by proliferation and invasion assays in vitro. During follow-up, 16 patients (35.56%) had succumbed to OSCC; the median follow-up of patients was 5.0 years (range, 0.2–8.3). A high expression of CNTN1 was markedly associated with the regional lymph node metastasis of patients with OSCC (P=0.006). CNTN1 expression was significantly associated with overall survival of patients with OSCC (P=0.032; log-rank test) and disease-free survival of patients with OSCC (P=0.038; log-rank test). In addition, CNTN1 ablation notably suppressed the invasion potential of OSCC cell lines, but there was no significant change in the proliferation of OSCC cell lines by CNTN1 knockdown in vitro. The study supports CNTN1 as a novel predictor of regional lymph node metastasis in patients with OSCC and a prognostic marker for OSCC in patients.

Contactin 1 (CNTN1) expression associates with regional lymph node metastasis and is a novel predictor of prognosis in patients with oral squamous cell carcinoma

Background: The topography of an implant surface can serve as a powerful signaling cue for attached cells and can enhance the quality of osseointegration. A series of improved implant surfaces functionalized with nanoscale structures have been fabricated using various methods. Methods: In this study, using an H2O2 process, we fabricated two size-controllable sawtooth-like nanostructures with different dimensions on a titanium surface. The effects of the two nano-sawtooth structures on rat bone marrow mesenchymal stem cells (BMMSCs) were evaluated without the addition of osteoinductive chemical factors. Results: These new surface modifications did not adversely affect cell viability, and rat BMMSCs demonstrated a greater increase in proliferation ability on the surfaces of the nano-sawtooth structures than on a control plate. Furthermore, upregulated expression of osteogenic-related genes and proteins indicated that the nano-sawtooth structures promote osteoblastic differentiation of rat BMMSCs. Importantly, the large nano-sawtooth structure resulted in the greatest cell responses, including increased adhesion, proliferation, and differentiation. Conclusion: The enhanced adhesion, proliferation, and osteogenic differentiation abilities of rat BMMSCs on the nano-sawtooth structures suggest the potential to induce improvements in bone-titanium integration in vivo. Our study reveals the key role played by the nano-sawtooth structures on a titanium surface for the fate of rat BMMSCs and provides insights into the study of stem cell-nanostructure relationships and the related design of improved biomedical implant surfaces.

Biofunctionalization of a titanium surface with a nano-sawtooth structure regulates the behavior of rat bone marrow mesenchymal stem cells

Blood vessel formation in the tissue-engineered bone with the constitutively active form of HIF-1α mediated BMSCs.

Sciatic nerve regeneration in rats by a promising electrospun collagen/poly(ε-caprolactone) nerve conduit with tailored degradation rate

Establishment and characterization of an HPV16 E6/E7-expressing oral squamous cell carcinoma cell line with enhanced tumorigenicity

The aim of this study was to evaluate the effects of maxillary sinus floor elevation by a tissue-engineered bone complex with recombinant human bone morphogenetic protein-2 (rhBMP-2)-loaded porous calcium phosphate cement (CPC) scaffold and bone marrow stromal cells (bMSCs) in rabbits. bMSCs were cultured and osteogenically induced. The osteoblastic differentiation of expanded bMSCs was detected by alkaline phosphatase activity, and calcium deposits in vitro. Thirty-six rabbits were randomly allocated into week 2, 4 and 8 observation groups. At each time point, 24 maxillary sinus floor elevation surgeries in 12 rabbits were performed bilaterally and randomly implanted by (1) CPC materials alone (group A, n = 6), (2) rhBMP-2/CPC composite materials alone (group B, n = 6), (3) CPC/bMSCs complex (group C, n = 6) and (4) rhBMP-2/CPC/bMSCs complex (group D, n = 6). As for maxillary sinus floor elevation, rhBMP-2-loaded CPC could promote new bone formation as compared to CPC, while addition of bMSCs could further enhance its new bone formation and maturity significantly, as detected by histological findings, and fluorochrome labeling. Our data suggested that rhBMP-2/CPC possessed excellent osteoinductive ability, while combining with bMSCs could further promote new bone formation and maturation in maxillary sinus elevation.

Maxillary Sinus Floor Elevation Using a Tissue-Engineered Bone with rhBMP-2-Loaded Porous Calcium Phosphate Cement Scaffold and Bone Marrow Stromal Cells in Rabbits

Objectives:  Hypoxia‐inducible factor 1α (HIF‐1α) is a pivotal regulator of hypoxic and ischaemic vascular responses that drives transcriptional activation of hundreds of genes involved in vascular reactivity, angiogenesis and arteriogenesis. Previous reports based on gene knockout technology have demonstrated that HIF‐1α can promote osteogenesis. However, this protein is easily degraded in a normoxic state, which makes in vitro studies of HIF‐1α‐induced mesenchymal stem cell (MSC) osteogenesis difficult. For better understanding of HIF‐1α promoting osteogenesis, the role of HIF‐1α‐induced MSC osteogenesis in the normoxic state has been investigated here.

In vitro study of enhanced osteogenesis induced by HIF‐1α‐transduced bone marrow stem cells

Long-term outcome of cryopreserved bone-derived osteoblasts for bone regeneration in vivo.

Maintenance of phenotype and function of cryopreserved bone-derived cells.

Stem Cells and Tissue Engineering S.F. Badylak, Pittsburgh, Pa. E-Mail: badylaks@msx.upmc.edu U. Just, Kiel E-Mail: ujust@biochem.uni-kiel.de L.E. Niklason, New Haven, Conn. E-Mail: laura.niklason@yale.edu A. Ratcliffe, San Diego, Calif. E-Mail: anthonyratcliffe@synthasome.com A.M. Wobus, Gatersleben E-Mail: wobusam@ipk-gatersleben.de Tumor Cell Plasticity E. Thompson, Melbourne E-Mail: rik@medstv.unimelb.edu.au

The processes of angiogenesis and bone formation are coupled both temporally and spatially during bone repair. Bone marrow‐derived mesenchymal stem cells (BMSCs) have been effectively used to heal critical‐size bone defects. Enhancing their ability to undergo angiogenic and osteogenic differentiation will enhance their potential use in bone regeneration. Hypoxia‐inducible factor‐1α (HIF‐1α) has recently been identified as a major regulator of angiogenic‐osteogenic coupling. In this study, we tested the hypothesis that HIF‐1α gene therapy could be used to promote the repair of critical‐sized bone defects. Using lentivirus‐mediated delivery of wild‐type (HIF) or constitutively active HIF‐1α (cHIF), we found that in cultured BMSCs in vitro, HIF and cHIF significantly enhanced osteogenic and angiogenic mRNA and protein expression when compared with the LacZ group. We found that HIF‐1α‐overexpressing BMSCs dramatically improved the repair of critical‐sized calvarial defects, including increased bone volume, bone mineral density, blood vessel number, and blood vessel area in vivo. These data confirm the essential role of HIF‐1α modified BMSCs in angiogenesis and osteogenesis in vitro and in vivo. STEM CELLS 2011;29:1380–1390

Repair of Critical‐Sized Rat Calvarial Defects Using Genetically Engineered Bone Marrow‐Derived Mesenchymal Stem Cells Overexpressing Hypoxia‐Inducible Factor‐1α

RKTG inhibits angiogenesis by suppressing MAPK-mediated autocrine VEGF signaling and is downregulated in clear-cell renal cell carcinoma

Systematic evaluation of a tissue-engineered bone for maxillary sinus augmentation in large animal canine model.

The NF-kappa B inhibitor, celastrol, could enhance the anti-cancer effect of gambogic acid on oral squamous cell carcinoma

Sonic hedgehog alleviates the inhibitory effects of high glucose on the osteoblastic differentiation of bone marrow stromal cells.

Vertical alveolar ridge augmentation with beta-tricalcium phosphate and autologous osteoblasts in canine mandible.

Despite advances in the development of human papillomavirus (HPV) prophylactic vaccines, little progress has been made in the field of therapeutic vaccines in recent years. In the present study, we found a significant accumulation of immature myeloid cells (ImC) in large TC‐1 tumors and demonstrated that a HPV therapeutic vaccine restored antitumor immune responses with the correction of aberrant myeloid cell differentiation by all‐trans retinoic acid (ATRA). Our study demonstrated that combining ATRA with vaccination not only decreased the number of Gr‐1+ CD11b+ ImC, but for the first time also suppressed the function of Gr‐1+ CD11b+ ImC with decreased expression of CD80. Furthermore, large numbers of CD11c+ CD80+, CD11c+ CD86+, and CD11c+ MHCII+ mature dendritic cells were recruited. The combination therapy generated significantly increased numbers of functional E7‐specific T cells with elevated interferon‐γ secretion and enhanced cytotoxic T‐cell activity. These findings suggest potential clinical benefits for the combined use of ATRA and HPV therapeutic vaccines. (Cancer Sci 2009; 100: 334–340)

Combination of all‐trans retinoic acid and a human papillomavirus therapeutic vaccine suppresses the number and function of immature myeloid cells and enhances antitumor immunity

OBJECTIVE
Human periodontal ligament (PDL) cells occur changes in morphology and express relative protein by stretching force. However, whether stretching force, especially excessive stretching force, induces PDL cell apoptosis is not yet clearly understood. In the present study we investigated the relationship between early apoptosis and stretching force in human PDL cells in vitro.

The human PDL cells were obtained from healthy premolars. After three to five passages, the cells were stretched by strain 1%, 10% and 20% for 30 min, 1 h, 6 h and 12 h, then early apoptosis were detected through annexin fluorescein isothiocyanate (V-FITC) binding by flow cytometry and confocal laser scanning microscopy.

RESULTS
The experiments indicated that human PDL apoptotic cells in the early stage increased in a time- and force-dependent manner in response to stretching strain within 6 h, and then apoptosis decreased at 12 h. Human PDL cells which stretched inclined parallel to each other and aligned their long axis perpendicular to the stretching force vector, but in the centre of the disc, cells showed minimal deformation and unidirectional alignment of PDL cells.

The overall results suggested that stretching force not only influenced morphology but also induced early apoptosis in human PDL cells.

Cyclic stretching force-induced early apoptosis in human periodontal ligament cells.

A novel therapeutic fusion protein vaccine by two different families of heat shock proteins linked with HPV16 E7 generates potent antitumor immunity and antiangiogenesis.

Bone marrow stromal cells differentiating to chondrocytes for repairing TMJ cartilage defects

Response of lymphocyte subsets and cytokines to Shenyang prescription in Sprague-Dawley rats with tongue squamous cell carcinomas induced by 4NQO

A controlled chemical reaction on a specific bond in a single molecule is an inevitable step toward atomic engineering and fabrication. Here, we explored the debromination of a single 9,10-dibromoanthracene (DBA) molecule on a surface as stimulated by the voltage pulse through the tip of a scanning tunneling microscope (STM). A voltage threshold of about 2.2 V is obtained, and the nature of single-electron process is revealed. The spatially resolved debromination yield is obtained as a function of the pulse magnitude, which presents strong asymmetry for the two C-Br bonds. The optimal stimulation parameters including the pulse magnitude and the tip locations are suggested. The distinct dynamics in dissociation of the two bonds are illustrated by their energy diagrams and recoil paths, as derived by the first-principles density functional theory (DFT) calculation. The influence of the local electric field due to the STM tip on the dissociation of the C-Br bond has also been discussed. The study presents detailed practice for the controlled debromination in a single DBA molecule, which may lead to automated atomic engineering and fabrication of artificial nanostructures in the future.

Spatially Resolved Stimulation for the Controlled Debromination in Single Molecules on a Surface.

The Effect of Interfacial Microstructures on Joining Strength of Polymer-Metal Hybrid Interface

Monte Carlo simulations have been performed to study the phase diagram of liquid crystals formed by V-shaped molecules with an electric dipole moment. Simulation results show that as the electric dipole moment in- creases, the Landau point where phase transits directly from the isotropic to the biaxial nematic occurs not only when the bend angle is at the tetrahedral angle ( ) but also at other bend angles. In other words, the Landau point becom es a Landau line. Besides, the range of the biaxial nematic phase has been immensely expanded, indicating a more stable biaxial nematic phase. 109.47 θ  

Monte Carlo Simulations of Liquid Crystals Formed by V-Shaped Molecules

Theoretical results are given for electrolyte solutions in contact with uncharged metallic surfaces. The metal is represented by a jellium slab and the electron density distribution across the interface is obtained using density functional theory. The solution ‘‘structure’’ is found by solving the reference hypernetted‐chain approximation. The two interfacial phases interact electrostatically and fully self‐consistent electron density distributions and wall‐particle molecular correlation functions are calculated. The electron densities, wall‐induced solution structure and the electrostatic potential drop across the interface are discussed in detail and compared with the inert wall case. It is found that a highly ordered region exists near the metal surface. The dipoles are strongly ordered by the metal field and this solvent structure effectively dictates the ion distributions. The direct ion‐metal interactions are found to be less important.

Structure of the metal‐electrolyte solution interface: Theoretical results for simple models

Theoretical results are given for simple dipolar liquids in contact with a metallic slab. The metal is treated by employing a jellium model together with density functional (DF) theory. The liquid structure at the interface is given by the reference hypernetted‐chain (RHNC) approximation. The liquid and metal interact electrostatically and the coupled DF/RHNC equations are solved iteratively to obtain electron density distributions and metal–liquid correlation functions which are completely self‐consistent. The electron density, liquid structure, and potential drop across the interface are discussed in detail. It is found that dipoles in contact with the metal prefer to orient perpendicular to the surface with their positive ends out. This is in accord with earlier calculations for dipolar monolayers on metal surfaces. Further from the surface, the dipolar orientations oscillate and the liquid structure rapidly decays to the bulk fluid limit.

This study was aimed at assessing steroidogenesis stimulated by low-dose exposure to DBP in prepubertal female rats. Animals were gavaged with DBP from postnatal day 21 to 33 at 0, 1, 10 and 500 mg kg-1 day-1. 500 mg kg-1 day-1 was selected since it was used in numerous studies and the inhibitory effect could be observed at this dosage. After treatment, hormone levels in serum were detected by enzyme-linked immunosorbent assay. mRNA and protein expressions of vimentin, nuclear factor-κB (NF-κB) p65 and phosphorylation of NF-κB p65 (p-p65) were assayed by quantitative real-time polymerase chain reaction (qRT-PCR) assay, western blotting, and immunohistochemistry, respectively. Uterus weights, progesterone levels in serum, and protein expression of vimentin and p-p65 in ovaries increased significantly after the animals were exposed to DBP at 1 mg kg-1 day-1. Additionally, steroidogenesis and vimentin expression stimulated by DBP were blocked when the activity of NF-κB p65 was inhibited by the NF-κB inhibitor, pyrrolidine dithiocarbamic acid (PDTC). These results strongly suggested that DBP may activate uterus development by up-regulated steroidogenesis through the NF-κB-vimentin signaling pathway.

NF-κB-vimentin is involved in steroidogenesis stimulated by di-n-butyl phthalate in prepubertal female rats.

Toxicology in vitro : an international journal published in association with BIBRA

NF-κB-vimentin is involved in steroidogenesis stimulated by mono-butyl phthalate in primary cultured ovarian granulosa cells.

Novel agents need to be developed to overcome the limitations of the current melanoma therapeutics. Atractylenolide I (AT-I) is a sesquiterpene compound isolated from atractylodis macrocephalae rhizoma. Previous findings demonstrated that AT-I exhibited cytotoxic action in melanoma cells. However, the molecular mechanisms of AT‑1's anti-melanoma properties remain to be elucidated. In the present study, the cell cycle-arrest and apoptosis-promoting effects as well as the ERK/GSK3β signaling-related mechanism of action of AT-I were examined. B16 melanoma cells were treated with various concentrations of AT-1 (50, 75 and 100 µM) for 48 or 72 h. Cell cycle and apoptosis were analyzed by flow cytometry. Protein expression levels were detected by western blot analysis. AT-I treatment induced G1 phase arrest, which was accompanied by increased p21 and decreased CDK2 protein expression levels. Apoptosis was observed after AT-I treatment for 72 h, which was accompanied by activated caspase‑3 and ‑8. AT-I treatment significantly decreased phospho-ERK, phospho-GSK3β, c-Jun and increased p53 protein expression levels. Lithium chloride (LiCl, 5 mM), a GSK3β inhibitor, treatment alone did not increase the apoptosis of B16 cells, while pretreatment with LiCl markedly reversed AT-I-induced apoptosis. Additionally, AT-I-induced G1 phase arrest was partially reversed by LiCl pretreatment. In conclusion, ERK/GSK3β signaling was involved in the apoptotic and G1 phase arrest effects of AT-I in melanoma cells.

ERK/GSK3β signaling is involved in atractylenolide I-induced apoptosis and cell cycle arrest in melanoma cells.

Oridonin exhibits a curative effect on liver carcinoma in patients and experimental animals. In the present study, we performed proteomic and functional analyses to explore the mechanism involved in the anticancer activity of oridonin. Oridonin treatment for 24 h resulted in a dose-dependent decrease in cell viability with an IC50 value of 37.90 µM. Treatment with 40 µM oridonin for 24 h induced apoptosis as typical apoptotic nuclear alterations were observed following DAPI staining. Using a 2-DE-based proteomic approach, 3 upregulated oxidative stress markers, Hsp70-1, Hop and Prdx2, were identified in the HepG2 cells treated with 40 µM oridonin for 24 h. A pattern of alteration in Hsp70-1 was verified by western blotting. The mRNA expression patterns of Hsp70-1 and Hop as determined by qPCR were comparable to their protein expression patterns. Further investigations showed that oridonin treatment for 24 h resulted in reactive oxygen species (ROS) generation, and ROS scavenger N-acetylcysteine (NAC) completely inhibited ROS production and restored cell viability, suggesting that oxidative stress contributed to oridonin-induced HepG2 cell death. Western blot analysis of oxidative stress pathway-related proteins demonstrated that oridonin treatment increased p-JNK, p-p38 and p-p53, and decreased Bcl-2 protein expression levels, promoted cytochrome c release, decreased mitochondrial membrane potential, and activated caspase-9 and caspase-3. Furthermore, knockdown of Hsp70-1 expression with specific shRNA significantly decreased the viability of the cells treated with oridonin, suggesting a protective role of Hsp70-1 in oridonin-mediated oxidative stress. The results of the present study provide evidence for a link between oxidative stress and oridonin-induced apoptosis in HepG2 cells.

Proteomic and functional analyses demonstrate the involvement of oxidative stress in the anticancer activities of oridonin in HepG2 cells.

Inhibition of the p38 and PKA signaling pathways is associated with the anti-melanogenic activity of Qian-wang-hong-bai-san, a Chinese herbal formula, in B16 cells.

Construction of An Electrochemical Cytosensor Based on Polyaniline Nanofiber/Gold Nanoparticle Interface and Application to Detection of Cancer Cells

冬凌草甲素对HepG2细胞内质网应激蛋白IRE-1、PERK和CHOP的作用研究 = Role of endoplasmic reticulum stress proteins IRE-1,PERK and CHOP in oridonin-treated HepG2 cells

Six 1 homeoprotein suppresses human colorectal cancer cells growth by inhibiting Wnt/b-catenin signalling

Atractylenolide II induces G1 cell-cycle arrest and apoptosis in B16 melanoma cells.

It is well established that cholinergic over-stimulation can interfere with memory processes. The aim of this study was to evaluate the effect of tacrine, an acetylcholinesterase inhibitor, on recognition memory as well as the associated hepatotoxicity in juvenile (20-day-old) and adult (100-day-old) ICR male mice. Recognition memory was assessed by open-field test and step-through task without footshocks for three sessions between 08:00 and 13:00, with a 24-hr retention interval. Tacrine (10 or 40 μmol/kg) or vehicle was administered (s.c.) 20 min. prior to the first session. During the acquisition session, tacrine suppressed the open-field behaviours, including locomotor activity, rearing, grooming and defecation (by 77-100%) in mice of both ages. During the recall (observable in both ages) and re-recall (observable in juvenile mice) session, the locomotor activity and rearing number were significantly increased, indicative of impairment in recognition memory, in mice treated with tacrine 40 μmol/kg. During the training trial, tacrine decreased the step-through number in mice of both ages. In contrast, during the retention and re-retention trials, the step-through number was increased (by 92% and 93%, respectively), indicative of impairment in step-through memory, in juvenile but not adult mice treated with tacrine 40 μmol/kg. Tacrine 40 μmol/kg elevated the serum alanine aminotransferase (ALT) activity (by 135%) in juvenile mice, but reduced the ALT activity (by 42%) in adult mice. The results indicated that 20-day-old mice seemed to be more sensitive than 100-day-old mice to tacrine-induced impairment in recognition memory and the associated liver damage.

Tacrine treatment at high dose suppresses the recognition memory in juvenile and adult mice with attention to hepatotoxicity.

Proteomic identification of proteins involved in the anticancer activities of oridonin in HepG2 cells.

Anti-inflammatory activities and mechanisms of action of the petroleum ether fraction of Rosa multiflora Thunb. hips.

Hsp70.1在冬凌草甲素处理的肝癌细胞中的作用研究 = Study of the role of Hsp70.1 in oridonin-treated hepatocarcinoma cells

AIM
To investigate the effects of schisandrin B (Sch B) on free fatty acid (FFA)-induced steatosis in L-02 cells.

METHODS
Cellular steatosis was induced by incubating L-02 cells with a FFA mixture (oleate and palmitate at the ratio of 2:1) for 24 h. Cytotoxicity and apoptosis were evaluated by 3-(4, 5-dmethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide assay and Annexin V/propidium iodide staining, respectively. Cellular total lipid was determined using a photocolorimetric method after Nile red staining, and triglyceride content was measured using an enzymatic kit. To study the effects of Sch B on steatosis, L-02 cells were treated with Sch B (1-100 μmol/L) in the absence or presence of 1 mmol/L FFA for 24 h, and cellular total lipid and triglyceride levels were measured. To explore the mechanisms of action of Sch B in the steatotic L-02 cells, mRNA levels of several regulators of hepatic lipid metabolism including adipose differentiation related protein (ADRP), sterol regulatory element binding protein 1 (SREBP-1), peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ were measured by quantitative real-time polymerase chain reaction (PCR), and protein levels of ADRP and SREBP-1 were measured by immunoblotting.

RESULTS
Treatment with 1 mmol/L FFA for 24 h induced intracellular lipid accumulation in L-02 cells comparable to that in human steatotic livers without causing apparent apoptosis and cytotoxicity. Sch B mitigated cellular total lipid and triglyceride accumulations in the steatotic L-02 cells in a dose-dependent manner. Quantitative real-time PCR and Western blot analyses revealed that treatment of L-02 cells with 100 μmol/L Sch B reverted the FFA-stimulated up-regulation of ADRP and SREBP-1.

Sch B inhibits FFA-induced steatosis in L-02 cells by, at least in part, reversing the up-regulation of ADRP and SREBP-1.

Inhibitory effect of schisandrin B on free fatty acid-induced steatosis in L-02 cells.

Abstract:  We investigated the involvement of MAPK pathways in the melanogenic effect of apigenin in B16 cells. Apigenin treatment for 48 h dose (5–20 μm)‐dependently up‐regulated protein expression levels of microphthalmia‐associated transcription factor (MITF) and melanogenic enzymes including tyrosinase, tyrosinase‐related protein‐1 (TRP‐1) and TRP‐2 and enhanced the phosphorylation of p38 MAPK, without affecting the phosphorylation of JNK or ERK MAPK. Treatment with 10 μm apigenin time (6‐48 h)‐dependently elevated the protein expressions of p‐p38, MITF and melanogenic enzymes. Moreover, PD169316, a selective inhibitor of p38 kinase, suppressed the stimulatory effects of apigenin on tyrosinase activity and melanin synthesis, which were accompanied by decreased MITF protein expression. In conclusion, apigenin increased melanogenesis in B16 cells, at least in part, by activating the p38 MAPK pathway. The novel findings of this study shed light on the molecular mechanisms underlying the melanogenic activity of apigenin and suggest that apigenin/its derivatives may be potentially used for treating hypopigmentation disorders.

Activation of p38 MAPK pathway contributes to the melanogenic property of apigenin in B16 cells

Oridonin, the main active constituent of Isodon rubescen, has antihepatocarcinoma activity in experimental and clinical settings. The aims of the study were to explore the anticancer effect of oridonin in HepG2 cells and to investigate the underlying mechanisms. Results showed that oridonin treatment for 24 or 48 h resulted in a marked decrease in cell viability time- and dose-dependently. IC50 values were determined as 38.86 microM and 24.90 microM for 24-h and 48-h treatments, respectively. Flow cytometric analysis showed that a 24-h treatment of 40 microM oridonin induced G2/M cell cycle arrest and apoptosis. Typical apoptotic nucleus alterations were observed with fluorescence microscope after DAPI staining. Immunoblot analysis demonstrated that oridonin treatment increased expression levels of p-JNK, p-p38, p-p53 and p21, elevated the level of cyclin B1/p-Cdc2 (Tyr15) complex, and inhibited the expression of p-ERK. Moreover, oridonin treatment activated caspase-9 and caspase-3. In conclusion, oridonin induced G2/M cell cycle arrest and apoptosis in HepG2 cells through MAPK and p53 pathways, which advances our understanding on the molecular mechanisms of oridonin in hepatocarcinoma management.

Oridonin induces G2/M cell cycle arrest and apoptosis through MAPK and p53 signaling pathways in HepG2 cells.

Flavonoids, apigenin and icariin exert potent melanogenic activities in murine B16 melanoma cells.

Screening of Chinese herbal medicines for antityrosinase activity in a cell free system and B16 cells.

Pathogenesis of nonalcoholic fatty liver disease (NAFLD) is not clear. In this study we aimed to identify proteins involved in NAFLD development in free fatty acids (FFA)‐induced hepatosteatotic cells and in human liver biopsies. Steatosis was induced by incubating a normal human hepatocyte‐derived cell line L‐02 with FFA. Differentially expressed proteins in the steatotic cells were analyzed by two‐dimensional gel electrophoresis‐based proteomics. Involvement of one of the up‐regulated proteins in steatosis was characterized using the RNA interference approach with the steatotic cells. Protein expression levels in liver biopsies of patients with NAFLD were assessed by immunohistochemistry. Proteomic analysis of L‐02 steatotic cells revealed the up‐regulation of ERp57, a condition not previously implicated in NAFLD. Knockdown of ERp57 expression with siRNA significantly reduced fat accumulation in the steatotic cells. ERp57 expression was detected in 16 out of 17 patient biopsies and correlated with inflammation grades or fibrosis stages, while in 5 normal biopsies ERp57 expression was not detectable in hepatocytes. In conclusion, ERp57 was up‐regulated in FFA‐induced steatotic hepatic cells and in NAFLD patient livers and demonstrated steatotic properties in cultured cells. Further investigations are warranted to verify the involvement of ERp57 in NAFLD development. J. Cell. Biochem. 110: 1447–1456, 2010. © 2010 Wiley‐Liss, Inc.

ERp57 is up‐regulated in free fatty acids‐induced steatotic L‐02 cells and human nonalcoholic fatty livers

Involvement of p38 MAPK signaling pathway in the anti-melanogenic effect of San-bai-tang, a Chinese herbal formula, in B16 cells.

Inhibition of p38 and PKA signaling contributes to the anti-melanogenic activity of qian-wang-hong-bai-san, a Chinese herbal formula, in B16 cells

A quick and sensitive high-performance liquid chromatography (HPLC) method has been developed and validated for the determination of lomofungin in Streptomyces lomondensis. Extraction of lomofungin was carried out by liquid–liquid extraction. Chromatographic separation was achieved on a C18 column (5 µm, 4.6 mm × 250 mm, Agilent Inc). The mobile phase was formic acid [0.1% (v/v)]/acetonitrile of a segmented gradient, which was 8:2 in the first 4 min, then 6:4 for 16 min, and 8:2 for 10 min. The flow rate was 1 mL min−1, and the detection wavelength was 270 nm. Under these chromatographic conditions, lomofungin was eluted at 17.6 min. The calibration curve was linear over a concentration range from 10 to 400 µg mL−1, and the accuracy was within a range of 96.6 to 104.0%. The HPLC method was applied successfully to monitor dynamic lomofungin production of Streptomyces lomondensis during a 120 hr growth cycle.

HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY ANALYSIS OF LOMOFUNGIN IN STREPTOMYCES LOMONDENSIS

High-performance liquid chromatographic and pharmacokinetic analyses of an intravenous submicron emulsion of perillyl alcohol in rats.

Column switching in high-performance liquid chromatography with tandem mass spectrometric detection for high-throughput preclinical pharmacokinetic studies.

With the development of modern liver surgical techniques and the progress of perioperative management,the survival rate after resection of hepatocellular carcinoma has been greatly improved,but the high recurrence and metastasis rate still limits the long-term survival after surgery. Preoperative neoadjuvant therapy has been confirmed to significantly reduce the postoperative recurrence rate and prolong survival in other types of cancer,but there has been a lack of effective systemic therapy for hepatocellular carcinoma for a long time,so the efficacy and regimen of neoadjuvant therapy for hepatocellular carcinoma are still controversial. PD-1/PD-L1 monoclonal antibody combined with anti-angiogenic targeted drugs has become a first-line regimen in systemic therapy for advanced hepatocellular carcinoma. This regimen has definite efficacy and high safety,bringing hope for neoadjuvant therapy of hepatocellular carcinoma. Recently,three clinical trials of neoadjuvant immunotherapy for hepatocellular carcinoma have been published internationally,which preliminarily suggest the efficacy and safety of neoadjuvant immunotherapy for hepatocellular carcinoma and lay a solid foundation for carrying out larger sample clinical studies in the future.

[Status and challenges of neoadjuvant immunotherapy for hepatocellular carcinoma].

Objective: To study the surgical safety and efficacy of preoperative neoadjuvant therapy with immune checkpoint inhibitors combined with anti-angiogenic drugs in patients with China liver cancer staging(CNLC)-Ⅱb and Ⅲa resectable hepatocellular carcinoma. Methods: The data of 129 patients with Ⅱb and Ⅲa hepatocellular carcinoma who underwent surgery at the First Affiliated Hospital of Nanjing Medical University from January 2018 to December 2020 were analyzed. All patients were divided into two groups: the neoadjuvant therapy group(n=14,13 males and 1 female,aged (55.4±12.6)years(range:34 to 75 years)) received immune combined targeted therapy before surgery,immune checkpoint inhibitor camrelizumab was administered intravenously at a dose of 200 mg each time,every 2 weeks for 3 cycles,anti-angiogenesis drug apatinib was taken orally and continuously with a dose of 250 mg for 3 weeks and the conventional surgery group(n=115,103 males and 12 females,aged (55.8±12.0)years(range:21 to 83 years)) did not receive antitumor systemic therapy before surgery. There were 3 patients with CNLC-Ⅱb,11 with CNLC-Ⅲa in the neoadjuvant group;28 patients with CNLC-Ⅱb,87 with CNLC-Ⅲa in the conventional group. Student's t test or rank-sum test was used to compare the differences between two groups for quantitative data, Fisher's exact probability method was used to compare the differences of proportions between two groups, and Log-rank test was used to compare survival differences between two groups. Results: The 1-year recurrence rate in the neoadjuvant group was 42.9%,and the 1-year recurrence rate in the conventional group was 64.0%,with a statistically significant difference between the two groups(χ²=3.850,P=0.050);The 1-year survival rate in the neoadjuvant group was 100% and that in the conventional group was 74.2%,with a statistically significant difference between the two groups(χ²=5.170,P=0.023). According to the stratified analysis of the number of tumors,for single tumor,the 1-year recurrence rate in the neoadjuvant group was 25.0%,and that in the conventional surgery group was 71.0%,and the difference between the two groups was statistically significant(χ²=5.280, P=0.022). For multiple tumors, the 1-year recurrence rate in the neoadjuvant group was 66.7%,and the 1-year recurrence rate in the conventional surgery group was 58.9%,with no significant difference between the two groups(χ²=0.110,P=0.736). The operative time,intraoperative blood loss,and postoperative hospital stay in the neoadjuvant group were similar to those in the conventional group,and their differences were not statistically significant. Conclusions: Immune checkpoint inhibitors combined with anti-angiogenic targeted drugs as a neoadjuvant therapy for resectable hepatocellular carcinoma can reduce the 1-year recurrence rate and improve the 1-year survival rate,especially for those with solitary tumor. Limited by the sample size of the neoadjuvant group,the safety of immune combined targeted therapy before surgery cannot be observed more comprehensively,and further studies will be explored.

[Efficacy and safety of neoadjuvant immunotherapy for hepatocellular carcinoma].

Objective: To compare the performance of multiple machine learning algorithms in predicting recurrence after resection of early-stage hepatocellular carcinoma(HCC). Methods: Clinical data of 882 early-stage HCC patients who were admitted to the First Affiliated Hospital of Nanjing Medical University from May 2009 to December 2019 and treated with curative surgical resection were retrospectively collected. There were 701 males and 181 females,with an age of (57.3±10.5)years(range:21 to 86 years). All patients were randomly assigned in a 2∶1 ratio, the training dataset consisted of 588 patients and the test dataset consisted of 294 patients. The construction of machine learning-based prediction models included random survival forest(RSF),gradient boosting machine,elastic net regression and Cox regression model. The prediction accuracy of the model was measured by the concordance index(C-index). The prediction error of the model was measured by the integrated Brier score. Model fit was assessed by the calibration plot. The performance of machine learning models with that of rival model and HCC staging systems was compared. All models were validated in the independent test dataset. Results: Median recurrence-free survival was 61.7 months in the training dataset while median recurrence-free survival was 61.9 months in the validation dataset, there was no significant difference between two datasets in terms of recurrence-free survival(χ²=0.029,P=0.865). The RSF model consisted of 5 commonly used clinicopathological characteristics, including albumin-bilirubin grade,serum alpha fetoprotein,tumor number,type of hepatectomy and microvascular invasion. In both training and test datasets,the RSF model provided the best prediction accuracy,with respective C-index of 0.758(95%CI:0.725 to 0.791) and 0.749(95%CI:0.700 to 0.797),and the lowest prediction error,with respective integrated Brier score of 0.171 and 0.151. The prediction accuracy of RSF model for recurrence after resection of early-stage HCC was superior to that of other machine learning models,rival model(ERASL model) as well as HCC staging systems(BCLC,CNLC and TNM staging),with statistically significant difference(P<0.01). Calibration curves demonstrated good agreement between RSF model-predicted probabilities and observed outcomes.All patients could be stratified into low-risk,intermediate-risk or high-risk group based on RSF model;statistically significant differences among three risk groups were observed in both training and test datasets(P<0.01). The risk stratification of RSF model was superior to that of TNM staging. Conclusion: The proposed RSF model assembled with 5 commonly used clinicopathological characteristics in this study can predict the recurrence risk with favorable accuracy that may facilitate clinical decision-support for patients with early-stage HCC.

[Application value of machine learning algorithms for predicting recurrence after resection of early-stage hepatocellular carcinoma].

OBJECTIVE
To explore the mechanisms of Ziyin recipe for treatment of ovulatory infertility based on network pharmacology analysis and evaluate the clinical efficacy of this recipe.

OBJECTIVE
TCMSP, PubChem, Genecards, String, Swiss Target Prediction, and Uniprot databases were searched to identify all the action targets of Ziyin recipe and ovulatory infertility to construct the PPI network. Gene ontology (GO) and KEGG pathway enrichment analyses were performed and the "TCM-active ingredient-target-pathway" network was constructed using Cytoscape 3.6.0. We also designed a controlled clinical trial to verify the clinical effectiveness of Ziyin recipe. The patients were randomized into 2 groups to receive treatment with Western medicine including CC and HMG (control group) and additional treatment with Ziyin recipe, and the dosage of GN, follicular development days, E2 level of a single dominant follicle on trigger day, ovulation rate, the rate of LUFS, and clinical pregnancy rate were compared between the two groups.

OBJECTIVE
We identified 22 active ingredients and 354 targets of action in Ziyin recipe, 791 targets of ovulatory infertility, and 96 common targets of action shared by Ziyin recipe and ovulatory infertility. According to Degree, the key targets included SRC, MAPK1, HSP90aa1, MAPK3, PTPN11, ESR1, Akt1, EGFR, NR3C1 and KNG1. Enrichment analysis of GO biological process showed that Ziyin recipe mainly focused on steroid hormonemediated signaling pathway, oxidation, reduction, and apoptosis. The most significantly enriched signaling pathways included PI3K-Akt signaling pathway, RAP1 signaling pathway, HIF-1 signaling pathway, estrogen signaling pathway, ovarian steroid production, and steroid hormone biosynthesis. The results of the clinical trial showed that Ziyin recipe significantly reduced the dose of GN, accelerated follicle development, increased E2 level of single dominant follicle on the trigger day, and increased the cycle ovulation rate and pregnancy rate.

OBJECTIVE
The therapeutic effects of Ziyin recipe are probably mediated through different pathways to promote follicle development, thus improving ovulation rate and clinical pregnancy rate of infertile patients with ovulatory disorders.

[Mechanism of Ziyin recipe for treatment of ovulatory infertility: a network pharmacology-based study and clinical observations].

Objective: To summarize the experience of surgical treatment of primary liver cancer. Methods: The clinical data of 10 966 surgically managed cases with primary liver cancer, from January 1986 to December 2019 at Hepatobiliary Center, the First Affiliated Hospital of Nanjing Medical University, were retrospectively analyzed. The life table method was used to calculate the survival rate and postoperative recurrence rate. Log-rank test was used to compare the survival process of different groups, and the Cox regression model was used for multivariate analysis. In addition, 2 884 cases of hepatocellular carcinoma(HCC) with more detailed follow-up data from 2009 to 2019 were selected for survival analysis. Among 2 549 patients treated with hepatectomy, there were 2 107 males and 442 females, with an age of (56.6±11.1) years (range: 20 to 86 years). Among 335 patients treated with liver transplantation, there were 292 males and 43 females, with an age of (51.0±9.7) years (range: 21 to 73 years). The outcomes of hepatectomy versus liver transplantation, anatomic versus non-anatomic hepatectomy were compared, respectively. Results: Of the 10 966 patients with primary liver cancer, 10 331 patients underwent hepatectomy and 635 patients underwent liver transplantation. Patients with liver resection were categorized into three groups: 1986－1995(712 cases), 1996－2008(3 988 cases), 2009‒2019(5 631 cases). The 5-year overall survival rate was 32.9% in the first group(1986－1995). The 5-year overall survival rate of resected primary liver cancer was 51.7% in the third group(2009-2019), among which the 5-year overal survival rates of hepatocellular carcinoma, intrahepatic cholangiocarcinoma and mixed liver cancer were 57.4%, 26.6% and 50.6%, respectively. Further analysis was performed on 2 549 HCC patients with primary hepatectomy. The 1-, 3-, 5-, and 10-year overall survival rates were 88.1%, 71.9%, 60.0%, and 41.0%, respectively, and the perioperative mortality rate was 1.0%. Two hundred and forty-seven HCC patients underwent primary liver transplantation, with 1-, 3-, 5-, and 10-year overall survival rates of 84.0%, 64.8%, 61.9%, and 57.6%, respectively. Eighty-eight HCC patients underwent salvage liver transplantation, with the 1-, 3-, 5-, and 10-year overall survival rates of 86.8%, 65.2%, 52.5%, and 52.5%, respectively. There was no significant difference in survival rates between the two groups with liver transplantation (P>0.05). Comparing the overall survival rates and recurrence rates of primary hepatectomy (2 549 cases) with primary liver transplantation (247 cases), the 1-, 3-, 5-, and 10-year overall survival rates in patients within Milan criteria treated with hepatectomy and transplantation were 96.3%, 87.1%, 76.9%, 54.7%, and 95.4%, 79.4%, 77.4%, 71.7%, respectively (P=0.754). The 1-, 3-, 5-year recurrence rates were 16.3%, 35.9%, 47.6% and 8.1%, 11.7%, 13.9%, respectively(P<0.01). The 1-, 3-, 5-, 10-year overall survival rates in patients with no large vessels invasion beyond the Milan criteria treated with liver resection and transplantation were 87.2%, 65.9%, 53.0%, 33.0% and 87.6%, 71.8%, 71.8%, 69.3%, respectively(P=0.003); the 1-, 3-, 5-year recurrence rate were 39.2%, 57.8%, 69.7% and 29.7%, 36.7%, 36.7%, respectively (P<0.01). The 1-, 3-, 5-, and 10-year overall survival rates in patients with large vessels invasion treated with liver resection and transplantation were 62.1%, 36.1%, 22.2%, 15.0% and 62.9%, 31.8%,19.9%, 0, respectively (P=0.387); the 1-, 3-, 5-year recurrence rates were 61.5%, 74.7%, 80.8% and 59.7%, 82.9%, 87.2%, respectively(P=0.909). Independent prognostic factors for both overall survival and recurrence-free survival rates of HCC patients treated with liver resection included gender, neoadjuvant therapy, symptoms, AST, intraoperative or postoperative blood transfusion, tumor number, tumor size, cirrhosis, macrovascular invasion, microvascular invasion, and pathological differentiation. Propensity score matching analysis of 443 pairs further showed that there was no significant difference in overall survival rate between anatomical liver resection and non-anatomical liver resection(P=0.895), but the recurrence rate of non-anatomical liver resection was higher than that of anatomical liver resection(P=0.035). Conclusions: In the past decade, the overall survival rate of HCC undergoing surgical treatment is significantly higher than before. For HCC patients with good liver function reservation, surgical resection can be performed first, and salvage liver transplantation can be performed after recurrence. The effect of salvage liver transplantation is comparable to that of primary liver transplantation. As for the choice of liver resection approaches, non-anatomical resection can reserve more liver tissue and can be selected as long as the negative margin is guaranteed.

[Surgical treatment of primary liver cancer:a report of 10 966 cases].

Radiomics, as an emerging technique of omics, shows the pathophysiological information of images via extracting innumerable quantitative features from digital medical images. In recent years, it has been an exponential increase in the number of radiomics studies. The applications of radiomics in hepatobiliary diseases at present include: assessment of liver fibrosis, discrimination of malignant from benign tumors, prediction of biological behavior, assessment of therapeutic response, and prognosis. Integrating radiomics analysis with machine learning algorithms has emerged as a non-invasive method for predicting liver fibrosis stages, microvascular invasion and post-resection recurrence in liver cancers, lymph node metastasis in biliary tract cancers as well as treatment response in colorectal liver metastasis, with high performance. Although the challenges remain in the clinical transformation of this technique, radiomics will have a broad application prospect in promoting the precision diagnosis and treatment of hepatobiliary diseases, backed by multi-center study with large sample size or multi-omics study.

[Application and challenge of radiomics technique in the era of precision medicine for hepatobiliary disease].

Objective To observe the clinical effect and safety of Chinese traditional medicine(Prescription: chinese angelica,mongolian milkvetch root and bistortae each 12 g,tribulus terrestris,angelica dahurica,pearl plant,peach kernel,safflower,dodder and fructus ligustri lucidi each 10 g,prepared fleeceflower root,psoralea corylifolia and black sesame each 15 g,licorice 6g) combined with NB-UVB in the treatment of vitiligo. Methods One hundred and twenty patients of vitiligo were divided into two groups,the treatment group was treated with Chinese traditional medicine combined with NB-UVB,the control group was treated with NB-UVB. All patients received 3 months of treatment. Results The effect rate was 83. 33% and 55. 00% in treatment group and control group respectively. There was significant difference between two groups( P 0. 05). No serious adverse events were recorded in both groups. Conclusion Chinese traditional medicine combined with NBUVB is effective and safe in the treatment of vitilgo.

Clinical observation of Chinese Traditional Medicine Combined with NB-UVB in the Treatment of 60 Cases of Vitiligo

OBJECTIVE
To explore the topographic distribution and long-term outcome of catheter ablation for focal atrial tachycardia (AT).

METHOD
The data of 207 patients who underwent electrophysiologic study for AT were retrospectively analyzed.

RESULTS
A total of 200 AT were identified in 185 patients. The most common site for AT was ostium of the coronary sinus (23.8%), followed by crista terminalis (20.5%), perinodal area (20.0%), cava vena (17.8%), annulus (13.0%), and appendage (10.3%). Eighty percent AT originated from the right atrium, 17.8% originated from the left atrium. AT originated from the left atrium was more common in male than in female (25.0% vs. 13.3%, P = 0.042), while AT originated from the right atrium was more common in female than in male (69.4% vs. 86.7%, P = 0.004). Among the 185 patients, acute success ablation rate was 93.5% (n = 173). The acute success rate in the conventional mapping group was lower than that in the three-dimensional mapping group (79.3% vs. 96.5%, P < 0.01). During a median of 36 months follow up, the AT recurred in 20 patients (success ablation rate 88.4%). Success ablation rate was similar between the conventional mapping group and the three-dimensional mapping group (P > 0.05).

Focal AT commonly originates from ostium of coronary sinus, crystal terminalis, perinodal area, and cava veins. There is a gender related difference in the distribution of focal AT. The radiofrequency catheter ablation yields a satisfying success rate and very low complication rate and could be the first line choice for treating ATs in experienced electrophysiological center.

[Catheter ablation of focal atrial tachycardia:the topographic distribution and long-term outcome].

Let Uq(f(K; J)) be an extended quantum enveloping algebra associated to sl2. In this paper, we display an equitable presentation for Uq(f(K; J)), in which all generators appear on a more equal footing. We also show that the equitable generators Y and Z are not invertible. Moreover, we give a presentation for the positive even subalgebra of Uq(f(K; J)) by generators and relations.

The Equitable Presentation for the Extended Quantum Algebra Uq(f(K; J))

The extension of a quantized Borcherds superalgebra by a Hopf algebra

Basing on the quantum group ( ) 2 q U sl , we define a quantum deformed algebra ( ) ( ) q n U f K K , in this paper. Moreover, we construct its equitable presentation.

We define a weak quantum Borcherds superalgebra nqd(G), which is a weak Hopf superalgebra. We also discuss the basis and the highest weight modules of nqd(G). Then we study the weak A-form and the classical limit of nqd(G).

Symmetry in spectrum space of isotonic oscillators is studied, and a distinct fi gure is given by appropriate parametric substitution. An analytic expression of normalized eigenfunction is obtained. It is proven that linear oscillator is a degeneration of isotonic oscillator. It is revealed that an isotonic oscillator is a two_photon parametric model. Coherent state of that model is given, and that coherent state includes odd_coherent state and even_coherent state constru cted by Glauber coherent states in a natural way.

Symmetry in spectrum space of isotonic oscillator and two-photon parametric model

Background: Urinary Ammonium (NH4+) excretion is decreased in CKD but very little is known about fecal NH4+excretion. Sodium Zirconium Cyclosilicate (SZC) is a cation-exchanger that selectively captures K+ in the gastrointestinal tract. We investigated if SZC can sequester NH4+ in vivo and evaluated the effect of SZC on fecal NH4+ in a mouse model of CKD. Methods: Mice with CKD induced by 5/6 kidney ablation were fed either a regular diet or a diet containing SZC (4g/Kg) and followed for 7 days. Feces NH4+ was measured before and after addition of 50 mEq KCl/L to release NH4+ from SZC. NH4+ sequestered in SZC in the gastrointestinal tract was estimated from the delta fecal NH4+observed when KCl was added to liberate the sequestered NH4+. Results: In mice with CKD fecal NH4+ excretion was higher than in normal mice and also higher than urine NH4+ excretion measured concurrently. Using data pooled from the SZC diet, the delta NH4+ was 6.5 ± 0.6 as compared to 0.6 ± 0.6 µmol/g on the normal diet p<0.0001. Conclusions:Fecal NH4+ excretion in CKD is increased and about 6-fold higher than urine NH4+ excretion revealing an important route of elimination of NH4+ present in the GI tract. SZC administration sequesters a substantial portion of NH4+ in the GI tract suggesting that the binding of NH4+ offers therapeutic potential beyond its known primary action as a specific K+ binder.

Fecal Ammonium in mice with CKD: gastrointestinal sequestration by SZC.

A soluble ACE2 protein bioengineered to have extended duration of action and enhanced affinity for SARS-CoV-2 provides markedly improved survival and organ protection when administered intranasally. Reducing brain SARS-CoV-2 titers is an important determinant of therapeutic efficacy.

Intranasal soluble ACE2 improves survival and prevents brain SARS-CoV-2 infection

WCN23-0463 SEQUESTRATION OF NH4+ IN THE GASTROINTESTINAL TRACT BY SZC IN MICE WITH CKD

Urinary Angiotensinogen in Patients With Type 1 Diabetes With Microalbuminuria: Gender Differences and Effect of Intensive Insulin Therapy

Significance Statement A novel soluble angiotensin converting enzyme 2 (ACE2) protein with increased binding to the spike protein of the coronavirus that causes coronavirus disease 2019 (COVID-19) is protective in an animal model of severe COVID-19 , providing a proof of concept of efficacy. Administration of soluble ACE2 protein resulted in conversion of a lethal disease into a mild one that is reversible, with improved lung and kidney injury. Visual Abstract Background Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) uses full-length angiotensin converting enzyme 2 (ACE2) as a main receptor to enter target cells. The goal of this study was to demonstrate the preclinical efficacy of a novel soluble ACE2 protein with increased duration of action and binding capacity in a lethal mouse model of COVID-19. Methods A human soluble ACE2 variant fused with an albumin binding domain (ABD) was linked via a dimerization motif hinge-like 4-cysteine dodecapeptide (DDC) to improve binding capacity to SARS-CoV-2. This novel soluble ACE2 protein (ACE2–1-618-DDC-ABD) was then administered intranasally and intraperitoneally to mice before intranasal inoculation of SARS-CoV-2 and then for two additional days post viral inoculation. Results Untreated animals became severely ill, and all had to be humanely euthanized by day 6 or 7 and had pulmonary alveolar hemorrhage with mononuclear infiltrates. In contrast, all but one mouse infected with a lethal dose of SARS-CoV-2 that received ACE2–1-618-DDC-ABD survived. In the animals inoculated with SARS-CoV-2 that were untreated, viral titers were high in the lungs and brain, but viral titers were absent in the kidneys. Some untreated animals, however, had variable degrees of kidney proximal tubular injury as shown by attenuation of the proximal tubular brush border and increased NGAL and TUNEL staining. Viral titers in the lung and brain were reduced or nondetectable in mice that received ACE2–1-618-DDC-ABD, and the animals developed only moderate disease as assessed by a near-normal clinical score, minimal weight loss, and improved lung and kidney injury. Conclusions This study demonstrates the preclinical efficacy of a novel soluble ACE2 protein, termed ACE2–1-618-DDC-ABD, in a lethal mouse model of SARS-CoV-2 infection that develops severe lung injury and variable degrees of moderate kidney proximal tubular injury.

A Novel Soluble ACE2 Protein Provides Lung and Kidney Protection in Mice Susceptible to Lethal SARS-CoV-2 Infection

The present study was designed to investigate the effects of a soluble ACE2 protein termed ACE2 618-DDC-ABD, bioengineered to have long duration of action and high binding affinity to SARS-CoV-2, when administered either intranasally (IN) or intraperitoneally (IP) and before or after SARS-CoV-2 inoculation. K18hACE2 mice permissive for SARS-CoV-2 infection were inoculated with 2×104 PFU wildtype SARS-CoV-2. In one protocol, ACE2 618-DDC-ABD was given either IN or IP, pre- and post-viral inoculation. In a second protocol, ACE2 618-DDC-ABD was given either IN, IP or IN+IP but only post-viral inoculation. In addition, A549 and Vero E6 cells were used to test neutralization of SARS-CoV-2 variants by ACE2 618-DDC-ABD at different concentrations. Survival by day 5 was 0% in infected untreated mice, and 40% in mice from the ACE2 618-DDC-ABD IP-pre treated group. By contrast, in the IN-pre group survival was 90%, histopathology of brain and kidney was essentially normal and markedly improved in the lungs. When ACE2 618-DDC-ABD was administered only post viral inoculation, survival was 30% in the IN+IP group, 20% in the IN and 0% in the IP group. Brain SARS-CoV-2 titers were high in all groups except for the IN-pre group where titers were undetectable in all mice. In cells permissive for SARS-CoV-2 infection, ACE2 618-DDC-ABD neutralized wildtype SARS-CoV-2 at high concentrations, whereas much lower concentrations neutralized omicron BA. 1. We conclude that ACE2 618-DDC-ABD provides much better survival and organ protection when administered intranasally than when given systemically or after viral inoculation and that lowering brain titers is a critical determinant of survival and organ protection.

Superiority of intranasal over systemic administration of bioengineered soluble ACE2 for survival and brain protection against SARS-CoV-2 infection

There is an urgent need for approaches to prevent and treat SARS-CoV-2 infection. Administration of soluble ACE2 protein acting as a decoy to bind to SARS-CoV-2 should limit viral uptake mediated by binding to membrane-bound full-length ACE2, and further therapeutic benefit should result from ensuring enzymatic ACE2 activity to affected organs in patients with COVID-19.

METHODS
A short variant of human soluble ACE2 protein consisting of 618 amino acids (hACE2 1-618) was generated and fused with an albumin binding domain (ABD) using an artificial gene encoding ABDCon, with improved albumin binding affinity. Human kidney organoids were used for infectivity studies of SARS-CoV-2 in a BSL-3 facility to examine the neutralizing effect of these novel ACE2 variants.

RESULTS
Whereas plasma ACE2 activity of the naked ACE2 1-618 and ACE2 1-740 lasted about 8 hours, the ACE2 1-618-ABD resulted in substantial activity at 96 hours, and it was still biologically active 3 days after injection. Human kidney organoids express ACE2 and TMPRSS2, and when infected with SARS-CoV-2, our modified long-acting ACE2 variant neutralized infection.

This novel ACE2 1-618-ABD can neutralize SARS-CoV-2 infectivity in human kidney organoids, and its prolonged duration of action should ensure improved efficacy to prevent viral escape and dosing convenience.

A Novel Soluble ACE2 Variant with Prolonged Duration of Action Neutralizes SARS-CoV-2 Infection in Human Kidney Organoids.

Enhanced reactive-oxygen-species generation and photocatalytic efficiency with internal imide structures of different ratio in metal-free perylene-g-C3N4 semiconductors

Background There have been concerns that ACE inhibitors and Ang II receptor blockers may cause an increase in ACE2, the main receptor for SARs-CoV-2. Methods Kidneys from two genetic models of kidney ACE ablation and mice treated with captopril or telmisartan were used to examine ACE2 in isolated kidney and lung membranes. Results In a global ACE KO mice, ACE2 protein abundance in kidney membranes was reduced to 42 % of wild type, p < 0.05. In ACE 8/8 mice that over-expresses cardiac ACE protein but also has no kidney ACE expression, ACE2 protein in kidney membranes was also decreased (38 % of the WT, p<0.01). In kidney membranes from mice that received captopril or telmisartan for 2 weeks there was a reduction in ACE2 protein (37% in captopril treated p<0.01) and 76% in telmisartan treated p <0.05). In lung membranes the expression of ACE2 was very low and not detected by western blotting but no significant differences in terms of ACE2 activity could be detected in mice treated with captopril (118% of control) or telmisartan (93% of control). Conclusions Genetic kidney ACE protein deficiency, suppressed enzymatic activity by Captopril or blockade of the AT1 receptor with telmisartan are all associated with a decrease in ACE2 in kidney membranes. ACE2 protein in kidney or lungs is decreased or unaffected by RAS blockers indicating that these medications can not pose a risk for SARS-CoV-2 infection related to amplification of ACE2 at these two target sites for viral entry.

Kidney and Lung ACE2 expression after an ACE inhibitor or an Ang II receptor blocker: implications for COVID-19

Knockout of aminopeptidase A in mice causes functional alterations and morphological glomerular basement membrane changes in the kidneys.

Isolation and genomic characterization of a pathogenic Providencia rettgeri strain G0519 in turtle Trachemys scripta

 The AngII(1-8)-Ang(1-7) axis of the Renin Angiotensin System (RAS) encompasses three enzymes that form Ang(1-7) directly from AngII: Angiotensin Converting Enzyme 2 (ACE2), Prolyl Carboxypeptidase (PRCP) and Prolyl Endopeptidase (PEP). We studied their relative contribution to Ang(1-7) formation in-vivo and also ex-vivo in serum, lungs and kidneys using models of genetic ablation coupled with pharmacological inhibitors. In WT mice infusion of AngII resulted in a rapid increase of plasma Ang(1-7). In a model of ACE2 and PRCP double genetic ablation AngII infusion resulted in a similar increase in Ang(1-7) as in WT (505 ± 46 vs 482 ± 63 pg/ml, respectively), showing that the bulk of Ang(1-7) formation in circulation is essentially independent of ACE2 and PRCP. By contrast, a PEP inhibitor, ZPP, obliterated the rise in plasma Ang(1-7) after infusing AngII(1-8) to control WT mice. In a genetic mouse model of PEP deficiency (PEP
 -/-
 ) the increase in Ang(1-7) was also blunted as compared to WT mice (277±41 and 423±25 pg/ml, respectively p=0.01). The rate of recovery from acute AngII(1-8)-induced hypertension, in PEP
 -/-
 mice moreover, was delayed as compared to WT mice (Figure). In ex vivo studies PEP inhibition with ZZP reduced Ang(1-7) formation from Ang(1-8) in serum and in lung lysates. By contrast, in kidney lysates the absence of ACE2, but not PEP, obliterated Ang1-7 formation from added AngII. We conclude that PEP is the main enzyme responsible for AngII conversion to Ang(1-7) in the circulation and in the lungs. PEP, not ACE2, is responsible for protecting against AngII-induced hypertension.
 
Abstract P2014: Prolyl Endopeptidase (PEP) is the Main Angiotensin (1-7) Forming Enzyme From Angiotensin II (1-8) in the Circulation: Implications for Hypertension

The Ang II (Angiotensin II)-Angiotensin-(1-7) axis of the Renin Angiotensin System encompasses 3 enzymes that form Angiotensin-(1-7) [Ang-(1-7)] directly from Ang II: ACE2 (angiotensin-converting enzyme 2), PRCP (prolylcarboxypeptidase), and POP (prolyloligopeptidase). We investigated their relative contribution to Ang-(1-7) formation in vivo and also ex vivo in serum, lungs, and kidneys using models of genetic ablation coupled with pharmacological inhibitors. In wild-type (WT) mice, infusion of Ang II resulted in a rapid increase of plasma Ang-(1-7). In ACE2-/-/PRCP-/- mice, Ang II infusion resulted in a similar increase in Ang-(1-7) as in WT (563±48 versus 537±70 fmol/mL, respectively), showing that the bulk of Ang-(1-7) formation in circulation is essentially independent of ACE2 and PRCP. By contrast, a POP inhibitor, Z-Pro-Prolinal reduced the rise in plasma Ang-(1-7) after infusing Ang II to control WT mice. In POP-/- mice, the increase in Ang-(1-7) was also blunted as compared with WT mice (309±46 and 472±28 fmol/mL, respectively P=0.01), and moreover, the rate of recovery from acute Ang II-induced hypertension was delayed (P=0.016). In ex vivo studies, POP inhibition with ZZP reduced Ang-(1-7) formation from Ang II markedly in serum and in lung lysates. By contrast, in kidney lysates, the absence of ACE2, but not POP, obliterated Ang-(1-7) formation from added Ang II. We conclude that POP is the main enzyme responsible for Ang II conversion to Ang-(1-7) in the circulation and in the lungs, whereas Ang-(1-7) formation in the kidney is mainly ACE2-dependent.

Ang II (Angiotensin II) Conversion to Angiotensin-(1-7) in the Circulation Is POP (Prolyloligopeptidase)-Dependent and ACE2 (Angiotensin-Converting Enzyme 2)-Independent.

In patients with diabetic kidney disease (DKD), plasma renin activity is usually decreased, but there is limited information on urinary renin and its origin. Urinary renin was evaluated in samples from patients with longstanding type I diabetes mellitus and mice with streptozotocin-induced diabetes mellitus. Renin-reporter mouse model (Ren1d-Cre;mT/mG) was made diabetic with streptozotocin to examine whether the distribution of cells of the renin lineage was altered in a chronic diabetic environment. Active renin was increased in urine samples from patients with DKD (n=36), compared with those without DKD (n=38; 3.2 versus 1.3 pg/mg creatinine; P<0.001). In mice with streptozotocin-induced diabetes mellitus, urine renin was also increased compared with nondiabetic controls. By immunohistochemistry, in mice with streptozotocin-induced diabetes mellitus, juxtaglomerular apparatus and proximal tubular renin staining were reduced, whereas collecting tubule staining, by contrast, was increased. To examine the role of filtration and tubular reabsorption on urinary renin, mice were either infused with either mouse or human recombinant renin and lysine (a blocker of proximal tubular protein reabsorption). Infusion of either form of renin together with lysine markedly increased urinary renin such that it was no longer different between nondiabetic and diabetic mice. Megalin mRNA was reduced in the kidney cortex of streptozotocin-treated mice (0.70±0.09 versus 1.01±0.04 in controls, P=0.01) consistent with impaired tubular reabsorption. In Ren1d-Cre;mT/mG with streptozotocin-induced diabetes mellitus, the distribution of renin lineage cells within the kidney was similar to nondiabetic renin-reporter mice. No evidence for migration of cells of renin linage to the collecting duct in diabetic mice could be found. Renin mRNA in microdissected collecting ducts from streptozotocin-treated mice, moreover, was not significantly different than in controls, whereas in kidney cortex, largely reflecting juxtaglomerular apparatus renin, it was significantly reduced. In conclusion, in urine from patients with type 1 diabetes mellitus and DKD and from mice with streptozotocin-induced diabetes mellitus, renin is elevated. This cannot be attributed to production from cells of the renin lineage migrating to the collecting duct in a chronic hyperglycemic environment. Rather, the elevated levels of urinary renin found in DKD are best attributed to altered glomerular filteration and impaired proximal tubular reabsorption.

Urinary Renin in Patients and Mice With Diabetic Kidney Disease.

We examined if urinary angiotensinogen (uAOG), a marker of intrarenal renin‐angiotensin system activity, antedates stage 3 chronic kidney disease (CKD) using samples from participants in the Diabetes Control and Complications Trial (DCCT) and later in the Epidemiology of Diabetes Intervention and Complications (EDIC) trial. In a nested case–control design, cases were matched at the outcome visit (eGFR less than 60, 21‐59 mL/min per 1.73 m2) on age, gender, and diabetes duration, with controls: eGFR (95, 75‐119, mL/min per 1.73 m2.) Additionally, in an exploratory analysis progressive renal decline (PRD), defined as eGFR loss >3.5 mL/min per 1.73m2/year, was evaluated using only data from EDIC because no progressions were observed during DCCT. At the EDIC visit, which antedated the GFR outcome visit by 2 years (range 1–7years) the median uAOG/creatinine was markedly higher in cases than in controls (13.9 vs. 3.8 ng/mg P = 0.003) whereas at the DCCT visit, which antedated the GFR outcome by 17 to 20 years it was not (2.75 vs. 3.16 ng/mg, respectively). The Odds Ratio for uAOG and CKD stage 3 development was significant after adjusting for eGFR, HbA1c, and systolic blood pressure 1.82 (1.00–3.29) but no longer significant when Albumin Excretion Ratio (AER) was included 1.21 (0.65–2.24).In the PRD analysis, uAOG/creatinine was sixfold higher in participants who experienced PRD than in those who did not (26 vs. 4.0 ng/mg, P = 0.003). The Odds Ratio for uAOG and PRD was significant after adjusting for eGFR, HbA1c, and systolic blood pressure 2.48 (1.46–4.22) but no longer significant when AER was included 1.32 (0.76–2.30). In people with type1 diabetes, a robust increase in uAOG antedates the development of stage 3 CKD but is not superior to AER in predicting this renal outcome. Increased uAOG moreover is associated with PRD, an index of progression to End Stage Kidney Disease (ESKD).

Urinary angiotensinogen antedates the development of stage 3 CKD in patients with type 1 diabetes mellitus

Urinary angiotensinogen (uAOG) can be increased in patients with type 2 diabetes and in hypertension. We wanted to examine uAOG in patients with type 1 diabetes as a possible biomarker of enhanced ...

Abstract P115: Urinary Angiotensinogen is Increased in Type 1 Diabetes With Mild Albuminuria: Gender Differences

The bioactive peptides of the apelinergic system and its receptor APJ have been shown to play a protective role in experimental cardiovascular and diabetic kidney disease (DKD). Mechanisms of this renoprotective effect remain to be elucidated. In this study, we examined the localization of APJ within the normal kidney and its kidney expression in the db/db model of DKD. The effect of hyperglycemia and angiotensin II on APJ was examined in cultured podocytes. In the glomerulus, APJ colocalized with podocyte but not endothelial cell markers. In podocytes stimulated with Pyr1Apelin‐13, a change in the phosphorylation status of the signaling proteins, AKT, ERK, and p70S6K, was observed with an increase 15 min after stimulation. Apelin‐13 decreased activity of Caspase‐3 in podocytes after high glucose treatment reflecting an antiapoptotic effect of APJ stimulation. In podocytes, APJ mRNA was downregulated in high glucose, when compared to normal glucose conditions and exposure to angiotensin II led to a further significant decrease in APJ mRNA. APJ and preproapelin mRNA levels in kidneys from db/db mice were markedly decreased along with decreased tubular APJ protein by western blotting and immunostaining when compared to db/m controls. In conclusion, the apelinergic system is decreased in kidneys from db/db mice. Within the glomerulus, APJ is mainly localized in podocytes and in this cell type its activation by Apelin‐13 abolishes the proapoptotic effect of high glucose, suggesting a potential therapeutic role of apelin and emerging agonists with extended half‐life for therapy of DKD.

Apelinergic system in the kidney: implications for diabetic kidney disease

Novel ACE2-Fc chimeric fusion provides long-lasting hypertension control and organ protection in mouse models of systemic renin angiotensin system activation.

The mammalian kidney develops through reciprocal inductive signals between the metanephric mesenchyme and ureteric bud. Transcription factor 21 (Tcf21) is highly expressed in the metanephric mesenchyme, including Six2-expressing cap mesenchyme and Foxd1-expressing stromal mesenchyme. Tcf21 knockout mice die in the perinatal period from severe renal hypodysplasia. In humans, Tcf21 mRNA levels are reduced in renal tissue from human fetuses with renal dysplasia. The molecular mechanisms underlying these renal defects are not yet known.

METHODS
Using a variety of techniques to assess kidney development and gene expression, we compared the phenotypes of wild-type mice, mice with germline deletion of the Tcf21 gene, mice with stromal mesenchyme-specific Tcf21 deletion, and mice with cap mesenchyme-specific Tcf21 deletion.

RESULTS
Germline deletion of Tcf21 leads to impaired ureteric bud branching and is accompanied by downregulated expression of Gdnf-Ret-Wnt11, a key pathway required for branching morphogenesis. Selective removal of Tcf21 from the renal stroma is also associated with attenuation of the Gdnf signaling axis and leads to a defect in ureteric bud branching, a paucity of collecting ducts, and a defect in urine concentration capacity. In contrast, deletion of Tcf21 from the cap mesenchyme leads to abnormal glomerulogenesis and massive proteinuria, but no downregulation of Gdnf-Ret-Wnt11 or obvious defect in branching.

Our findings indicate that Tcf21 has distinct roles in the cap mesenchyme and stromal mesenchyme compartments during kidney development and suggest that Tcf21 regulates key molecular pathways required for branching morphogenesis.

Transcription Factor 21 Is Required for Branching Morphogenesis and Regulates the Gdnf-Axis in Kidney Development.

Angiotensin (Ang) II and apelins (AP) are intertwined by the actions of ACE2 that selectively cleaves the bond between proline and phenylalanine (Pro-Phe) at the carboxyl-termini of Ang II and AP l...

Abstract P238: A New Fluorometric Method to Evaluate Efficiencies of Carboxy-terminal Phenylalanine Cleavage From Angiotensin II, Angiotensin III and Apelin Peptides

A Fluorometric Method of Measuring Carboxypeptidase Activities for Angiotensin II and Apelin-13

Increased expression of renin in the kidney collecting tubule of rodents made diabetic by streptozotocin (STZ) has been well demonstrated but whether this site is the main source of urinary renin is unknown. We wanted to examine the origin and significance of urinary renin in diabetic kidney disease (DKD).
 
 Total and active renin was evaluated in urines from people with longstanding type 1 diabetes of more than 25 years, with (n=36) or without DKD (n=38) (eGFR 101 vs. 39 mL/min/1.73m
 2
 ; p<0.001). Mice given STZ (n=15) or vehicle (n=8) 20 weeks prior to study were also studied. In people with DKD, total renin was markedly increased compared to people without DKD (82 vs. 49 pg/mg Cr; p=0.023). Active renin was also significantly increased in people with DKD compared to people without DKD (3.2 vs. 1.3 pg/mg Cr; p<0.001). In mice with STZ-induced DKD a significant increase in renin was found compared to controls (1093±319 vs. 64±18 pg/mg Cr; p=0.0001). To examine the role of filtration and tubular reabsorption on urinary renin, human active renin was measured in urines from non-diabetic mice infused with human recombinant renin (hrRenin) (n=8), a combination of lysine and hrRenin (n=5) and non-infused controls (n=15). Urines of mice infused with a combination of lysine (a blocker of proximal tubular protein reabsorption) and hrRenin had markedly higher urinary human active renin than those of controls (179±129 vs. 1.6±0.4 pg/mg Cr; p=0.001). The values were also markedly higher than those of mice infused with hrRenin only (4.4±1.1 pg/mg Cr; p=0.003). The effect of lysine was also evaluated in regard to endogenous mouse renin. Urinary mouse renin in mice infused with lysine (n=5) was markedly increased compared to non-infused controls (n=18) (22360±8673 vs. 346±82 pg/mg Cr; p=0.001).
 
 In conclusion, in humans with DKD, urine concentrations of both total and active renin are increased. In mice with STZ-induced DKD, urine total renin is also markedly increased. The data further demonstrate that 1) renin is both filterable and reabsorbable in normal mice and 2) the increase of urinary renin in DKD can be attributed largely to impaired reabsorption mainly in the proximal tubule.

Abstract 082: On the Significance of Urinary Renin in Diabetic Kidney Disease: A Critical Role of Impaired Proximal Tubular Reabsorption

MP490FORMATION OF ANG(1−7) FROM ANGII(1−8) IS LARGELY INDEPENDENT OF ACE2 AND PRCP

Prolylcarboxypeptidase deficiency is associated with increased blood pressure, glomerular lesions, and cardiac dysfunction independent of altered circulating and cardiac angiotensin II

Angiotensin-converting enzyme 2 amplification limited to the circulation does not protect mice from development of diabetic nephropathy.

ACE2 is a monocarboxypeptidase that by converting AngII to Ang1-7 should down-regulate the renin-angiotensin system and therefore provide a means to therapeutically target diabetic kidney disease, a condition where the kidney RAS is overactive. Previous work indicated that soluble human recombinant (r)ACE2 administration for 4 weeks attenuated kidney injury in diabetic Akita mice. Whether such effect of rACE2 can be confirmed and attributed to augmented ACE2 activity is uncertain because chronic use of human rACE2 in mice induces immunogenicity and the development of antibodies that neutralize serum ACE2 activity. To examine the effect of chronic amplification of circulating ACE2 on kidney injury caused by STZ-induced diabetes and to circumvent the immunogenicity arising from xenogeneic ACE2, ACE2 of mouse origin was administered to mice using either daily i.p. injections (1 mg/kg) of mrACE2 for 4 weeks or after 20 weeks of ACE2 mini-circle (MC) (10-30ug/mouse) administration. MC provides a form of gene delivery that is resistant to gene silencing and, in addition, greatly optimizes long-term in vivo overexpression of proteins of interest. ACE2MC resulted in a profound and sustained increase in serum ACE2 activity (2.4±0.3 vs. 497±135 RFU/ul/hr, p In conclusion, profound and long-term augmentation of ACE2 activity confined to the circulation is not sufficient to attenuate glomerular pathology and albuminuria in STZ-induced diabetic kidney disease probably because of lack of kidney delivery of ACE2. Strategies to achieve over-expression of ACE2 at the kidney level are needed to demonstrate a beneficial effect of this enzyme on diabetic kidney disease.

Abstract 016: Profound and Sustained Amplification of Circulating ACE2 Activity Does Not Protect Diabetic Mice from Kidney Disease

Minicircle Gene Delivery for ACE2 Amplification in Diabetic Mice

The renin-angiotensin system is a complex regulatory hormonal network with a main biological peptide and therapeutic target, angiotensin (Ang) II (1-8). There are other potentially important Ang peptides that have not been well evaluated.

METHODS
Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for concurrent evaluation of multiple Angs downstream of Ang I (1-10) and Ang II (1-8) in kidney and plasma from wild-type (WT) mice. Angiotensin converting enzyme 2 knockout (ACE2KO) was also used as a way to examine the Angs profile in the absence of ACE2, an enzyme that cleaves both Ang I (1-10) and Ang II (1-8).

RESULTS
In plasma from both WT and ACE2KO, levels of Ang I (1-10), Ang III (2-8), and Ang (2-10) were the highest of all the renin-angiotensin system (RAS) peptides. The latter two peptides are products of aminopeptidase A cleavage of Ang II (1-8) and Ang I (1-10), respectively. In contrast, plasma levels of Ang II (1-8), and Ang (1-7), the product of Ang II (1-8) cleavage by ACE2, were low. In kidney from both WT and ACE2KO, Ang II (1-8) levels were high as compared to plasma levels. In the ACE2KO mice, a significant increase in either Ang II (1-8) or a decrease in Ang (1-7) was not observed in plasma or in the kidney.

RAS-focused peptidomic approach revealed major differences in Ang peptides between mouse plasma and kidney. These Ang peptide profiles show the dominance of the aminopeptidase A/Ang (2-10) and aminopeptidase A/Ang III (2-8) pathways in the metabolism of Ang I (1-10) and Ang II (1-8) over the ACE2/Ang (1-7) axis. Ang III (2-8) and other peptides formed from aminopeptidase A cleavage may be important therapeutic RAS targets.

Plasma and Kidney Angiotensin Peptides: Importance of the Aminopeptidase A/Angiotensin III Axis.

Pigment Epithelium Derived Factor (PEDF) encoded by SERPINF1 gene has potent anti-angiogenic and cytoprotective activities. It has been reported that PEDF protein levels are reduced in the kidneys of rodents with experimentally induced diabetes. However the effect of PEDF on blood pressure has not been elucidated. Here, we used SERPINF1 KO mice to examine the impact of PEDF deficiency on kidney pathology and blood pressure in the STZ-induced mouse model of diabetes.

Twelve weeks after diabetes induction by STZ, SERPINF1 KO mice showed exacerbated glomerular damage with ~ 2-fold increase in mesangial matrix (2.8±0.14 vs. 1.2±0.14 arbitrary units, p<0.01) and ~ 20% decrease in podocyte counts (8.2±0.0.4 vs. 9.7±0.2 podocytes/glomerulus, p<0.01) compared to the wild type controls. Of note, STZ-treated SERPINF1-/- mice displayed elevated systolic blood pressure (SBP) (127±4 vs. 109±4 mmHg, p<0.01, n=11).

Our data indicate that global PEDF deficiency intensifies glomerular injury in STZ-induced mouse model of diabetes. An important drawback of most murine models of diabetic kidney disease is the lack of hypertension, a known key factor that accelerates progression to CKD in humans. In contrast, we found that STZ-treated SERPINF1-/- mice become hypertensive. Together, our findings point to SERPINF1-/- mice as an attractive model to study diabetic kidney disease and hypertension in mice and suggest an important causative role of PEDF downregulation in glomerular pathology in diabetes.

Abstract P637: Pigment Epithelium Derived Factor (PEDF) Deficiency Increases Blood Pressure And Accentuates Glomerular Pathology In Diabetic Mice

Circulating ACE2, an enzyme that degrades Ang II, has been reported to be increased in rodent models of diabetes. Upregulation of ACE2 by increasing hydrolysis of Ang II could help downregulate RAS overactivity in a compensatory way and/or reflect increased Ang II metabolism. ACE2 activity in plasma, however, is relatively low even in diabetic conditions. Therefore, further increases in ACE2 effected by exogenous ACE2 administration could have a therapeutic action as a result of enhanced Ang II degradation and formation of Ang 1-7.
 We examined the effect of a massive increase in circulating ACE2 activity on plasma levels of Ang II and other Ang peptides in mice rendered diabetic by STZ. Circulating ACE2 was amplified using ACE2 mini-circle (ACE2MC) gene delivery. Multiple Ang peptides were evaluated in plasma from STZ-mice that received ACE2MC and sham STZ-mice (n=6/group).
 Plasma Ang II in STZ-ACE2MC mice were markedly lower than in STZ sham mice (3±1 vs. 22±13, pg/mL, respectively), but the difference was not significant owing to high variability. Since the seemingly lower Ang II levels could be influenced by either lower levels of the precursor peptide Ang I, increased degradation of Ang II, or both, a ratio between Ang II and Ang I was calculated. Ang II/Ang I ratio was significantly lower in STZ-ACE2MC as compared to STZ sham mice (0.15±0.05 vs. 0.35±0.06, p<0.05) indicating that per given amount of Ang I, there is significantly less Ang II in STZ-ACE2MC mice. This is consistent with enhanced Ang II degradation. Plasma levels of Ang 1-7 and Ang 1-9, the direct products of ACE2 cleavage of Ang I and Ang II, respectively, were very low and mostly below the level of detection. In plasma, Ang 1-7 is quickly converted to Ang 1-5, by ACE. Therefore, as an index of Ang II conversion to Ang 1-7, and as a surrogate for this conversion, we used Ang 1-5/Ang II ratio. This ratio was markedly higher in STZ-ACE2MC than in sham STZ-mice (3.15±1.5 vs. 0.38±0.07, p<0.05, respectively) suggesting an increased conversion of Ang II to Ang 1-7, and later to Ang 1-5 as a result of plasma ACE2 overexpression.
 We conclude that a massive increase in circulating ACE2 is associated with an accelerated metabolism of Ang II. The increase in Ang II degradation seems best reflected by an increase in Ang 1-5/Ang II ratio.

Abstract P629: Effect of Circulating ACE2 Activity on plasma Angiotensin Peptides

PURPOSE
We sought to determine the effects of atrasentan, a selective endothelin-A receptor antagonist, on the retinal vascular and structural integrity in a db/db mouse, an animal model of type 2 diabetes and diabetic retinopathy.

METHODS
Diabetic mice, 23 weeks old, were given either atrasentan or vehicle treatment in drinking water for 8 weeks. At the end of the treatment period, eyes underwent trypsin digest to assess the retinal vascular pathology focusing on capillary degeneration, endothelial cell, and pericyte loss. Paraffin-embedded retinal cross sections were used to evaluate retinal sublayer thickness both near the optic nerve and in the retinal periphery. Immunohistochemistry and TUNEL assay were done to evaluate retinal cellular and vascular apoptosis.

RESULTS
Compared with untreated db/db mice, atrasentan treatment was able to ameliorate the retinal vascular pathology by reducing pericyte loss (29.2% ± 0.4% vs. 44.4% ± 2.0%, respectively, P < 0.05) and capillary degeneration as determined by the percentage of acellular capillaries (8.6% ± 0.3% vs. 3.3% ± 0.41%, respectively, P < 0.05). A reduction in inner retinal thinning both at the optic nerve and at the periphery in treated diabetic mice was also observed in db/db mice treated with atrasentan as compared with untreated db/db mice (P < 0.05). TUNEL assay suggested that atrasentan may decrease enhanced apoptosis in neuroretinal layers and vascular pericytes in the db/db mice.

Endothelin-A receptor blockade using atrasentan significantly reduces the vascular and neuroretinal complications in diabetic mice. Endothelin-A receptor blockade is a promising therapeutic target in diabetic retinopathy.

Endothelin receptor-A antagonist attenuates retinal vascular and neuroretinal pathology in diabetic mice.

ACE2 is considered an important enzyme in the degradation of Angiotensin (Ang) I (1-10) and especially of Ang II (1-8), as demonstrated by the rapid dissipation of this peptide when recombinant ACE2 is infused but the steady state level of ACE2 in plasma is low. We examined levels of multiple Ang peptides in plasma under steady state conditions in WT and ACE2KO mice on C57BL genetic background (n=4 and 5, respectively). Liquid chromatography mass-spectrometry-based approach which enables concurrent evaluation of ten different angiotensins at physiologic levels (pg/mL) was used for multiple peptide quantification.
 The levels of angiotensin peptides in WT mice were highest for Ang I (1-10) (1295±313 pg/mL), Ang (2-10) (657±173 pg/mL) and Ang III (2-8) (1047±178 pg/mL). In contrast, plasma levels of Ang II (1-8), the main effector peptide of the RAS, and Ang (1-7), the product of cleavage of Ang II by ACE2, were very low (7.8±2 and 3.5±0 pg/mL, respectively). In ACE2 KO mice, Ang II and Ang (1-7) levels were not significantly different from WT. Activity of Aminopeptidase A, an enzyme that converts Ang (1-10) to Ang (2-10) and cleaves Ang II (1-8) to Ang III (2-8), was significantly increased in ACE2KO (n=11) as compared to WT (n=17) (149±11 vs. 94±9 RFU/ul/hr, respectively, p<0.001). This finding along with increased ratio of Ang (2-10)/Ang(1-8) (175±31 vs. 84±4, p<0.01, respectively) suggests increased formation of Ang (2-10) from Ang (1-10) in ACE2KO mice by APA over the formation of Ang II (1-8) from Ang (1-10).
 These results show that plasma Ang II and Ang (1-7) levels in WT and ACE2KO mice are low relative to the high levels of Ang (2-10) and Ang III (2-8). ACE2 deficiency does not result in plasma Ang II accumulation or reduced Ang (1-7) levels and is associated with an increase in serum APA activity. We conclude that in mice plasma the APA/Ang(2-10) and APA/AngIII pathways, and not ACE2/Ang(1-7), are dominant in the metabolism of Ang I and Ang II under steady state conditions.

Abstract 407: Aminopeptidase A (APA)/Ang(2-10) and APA/AngIII are the Dominant Axes in the Metabolism of Angiotensin Peptides in Mice Plasma

Angiotensin (Ang)-converting enzyme 2 (ACE2) is a key enzyme in the metabolism of Ang II. XNT (1-[(2-dimethylamino)ethylamino]-4-(hydroxymethyl)-7-[(4-methylphenyl) sulfonyl oxy]-9H-xanthene-9-one) and diminazene have been reported to exert various organ-protective effects, which are attributed to the activation of ACE2. To test the effect of these compounds, we studied Ang II degradation in vivo and in vitro as well as their effect on ACE2 activity in vivo and in vitro. In a model of Ang II–induced acute hypertension, blood pressure (BP) recovery was markedly enhanced by XNT (slope with XNT, −3.26±0.2 versus −1.6±0.2 mm Hg/min without XNT; P<0.01). After Ang II infusion, neither plasma nor kidney ACE2 activity was affected by XNT. Plasma Ang II and Ang (1–7) levels also were not significantly affected by XNT. The BP-lowering effect of XNT seen in wild-type animals was also observed in ACE2 knockout mice (slope with XNT, −3.09±0.30 versus −1.28±0.22 mm Hg/min without XNT; P<0.001). These findings show that the BP-lowering effect of XNT in Ang II–induced hypertension cannot be because of the activation of ACE2. In vitro and ex vivo experiments in both mice and rat kidney confirmed a lack of enhancement of ACE2 enzymatic activity by XNT and diminazene. Moreover, Ang II degradation in vitro and ex vivo was unaffected by XNT and diminazene. We conclude that the biological effects of these compounds are ACE2-independent and should not be attributed to the activation of this enzyme.

Angiotensin-Converting Enzyme 2–Independent Action of Presumed Angiotensin-Converting Enzyme 2 Activators: Studies In Vivo, Ex Vivo, and In Vitro

Angiotensin‐converting enzyme 2 (ACE2) is highly expressed in the kidney and hydrolyzes angiotensin II (Ang II) to Ang(1–7). Since Ang II is a strong activator of oxidative stress, we reasoned that ACE2 could be involved in the regulation of renal oxidative stress by governing the levels of Ang II. We, therefore, assessed levels of oxidative stress in kidney cortex of ACE2 knockout and wild‐type littermate mice under baseline conditions. We found multiple markers of increased oxidative stress in ACE2KO mice. NADPH oxidase activity was increased in kidney cortex from ACE2KO mice as compared to WT (227 ± 24% vs.100 ± 19%, P < 0.001). However, kidney catalase and superoxide dismutase activities were not different between groups. Exogenous Ang II was degraded less efficiently by kidneys from ACE2KO mice than WT mice, and administration of an AT1R blocker (losartan 30 mg/kg/day) resulted in normalization of NADPH oxidase activity in the ACE2KO. These findings suggest that an AT1R‐dependent mechanism contributes to increased ROS observed in the ACE2KO. This study demonstrates that genetic deficiency of ACE2 activity in mice fosters oxidative stress in the kidney in the absence of overt hypertension and is associated with reduced kidney capacity to hydrolyze Ang II. ACE2KO mice serve as a novel in vivo model to examine the role of overactivity of NADPH oxidase in kidney function.

ACE2 deficiency increases NADPH‐mediated oxidative stress in the kidney

Many of the pathophysiological effects of angiotensin II (Ang II) are attributed to its stimulation of NADPH oxidases and the consequent production of reactive oxygen species. Female sex has generally lower cardiovascular morbidity and is also less susceptible to kidney injury than males. The basis of these phenomena is not well understood but it is possible that sex-differential regulation of oxidative stress through activation of the RAS and its key effector, Ang II, plays an important contributor role. Here we hypothesized that Ang II levels are higher in male mice and that this is associated with sex-differences in kidney levels of ACE2, an Ang II-degrading enzyme abundantly expressed in the kidney.

Parameters of oxidative stress such as, NADPH oxidase activity and malondialdehyde levels (MDA) were measured in kidneys from female and age-matched male C57BL6 mice. At 40 weeks of age, NADPH oxidase activity (p<0.01) and MDA levels (p<0.05) were significantly lower in female than in male mice. Female mice had lower kidney levels of the pro-oxidant peptide, Ang II (0.94±0.19 vs. 1.66±0.17 fmol/mg total protein, p<0.05, respectively). The difference in kidney Ang II levels between females and males was also observed in the face of complete ACE2 genetic deficiency (1.08±0.16 vs 1.97±0.25 fmol/mg total protein, p<0.05, respectively). Consistent with kidney Ang II levels, urinary Ang II levels measured in urines from female WT mice were also significantly lower than in male WT mice (23.6±2.2 vs. 47.9±8.8 pg/mg creatinine, p<0.05) despite significantly higher levels of urinary ACE2 activity in male mice as compared to female mice (7.0±0.5 vs. 3.6±0.3, p<0.01, respectively).

Female mice have lower basal levels of kidney oxidative stress than males and exhibit lower levels of kidney and urinary Ang II. The mechanism involved in sex differences in the levels of kidney and urine Ang II does not appear to depend on ACE2.

Abstract 612: ACE2-Independent Sex Differences In Oxidative Stress

Chronic and sustained amplification of ACE2 activity in vivo has required the development of transgenic mice or the use of viral vectors. Minicircle is a new gene delivery technology which is resistant to gene silencing, and therefore represents an attractive platform for gene replacement strategies in vivo . Here we cloned cDNA of soluble mouse ACE2 into a circular expression cassette and the resulting ACE2 minicircle (MC) was injected to female FVB mice using iv. hydrodynamic approach (10ug or 30ug/mouse). At 3-7d after MC administration, serum ACE2 activity in mice that received 10ug ACE2MC (n=9) was over 100-fold higher than in controls (n=9) (138±48 vs 0.7±0.2 RFU/uL/hr) and in ACE2MC mice (30ug) (n=8) was almost 1000-fold higher than in controls (n=14) (480 ±153 vs 0.5±0.1 RFU/uL/hr, respectively). Mice that received 10 ug ACE2MC were followed for consecutive serum ACE2 activity monitoring, BP measurements and plasma Ang levels. The increase in serum ACE2 activity was sustained until the end of the study (up to 82 days) (Figure). Despite such a marked increase in serum ACE2 activity in ACE2MC mice, conscious SBP was not different from controls (137±8 vs 138±7 mmHg, respectively). At the end of the study, when Ang II was infused acutely (0.2 ug/kg BW i.p.), the increase in plasma Ang II in ACE2MC mice was significantly reduced compared to control mice (915±154 vs 1420±131 fmoL/mL, p Mini-circle delivery of ACE2 results in a dose-dependent and sustained long-term increase in serum ACE2 that efficiently degrades plasma Ang II. Extremely high increases in serum ACE2 activity do not reduce BP probably due to activation of non-ACE2 dependent compensatory Ang-hydrolyzing pathways.

Abstract 603: Effective And Sustained ACE2 Delivery Using Minicircles Technology

Changes in the enzymes involved in Ang II degradation may influence disease conditions such as hypertension and kidney disease. The enzyme prolylcarboxypeptidase (PRCP) catalyzes the conversion of Ang II to Ang(1-7) and its deficiency results in a phenotype characterized by a prothrombotic state, hypertension, and impaired wound healing. Here, we investigated kidney function and blood pressure in young mice, 10-16 weeks of age, with a subtotal PRCP deficiency (PRCP genetrap, PRCPgt).
 Enzyme activity based on a synthetic fluorogenic peptide was used to measure PRCP activity. The activity of recombinant PRCP was strongly pH-dependent with an optimum in the acidic range (pH 5). In keeping with this, recombinant PRCP degraded Ang II at pH 5, but not at pH 7.4 in-vitro. PRCP activity was detected in serum and in kidney of WT mice whereas PRCPgt/gt mice displayed highly diminished serum PRCP activity (about 5% of the WT).
 Kidney function was assessed by urinary protein/creatinine ratio and GFR. At 10 weeks of age, neither female nor male PRCPgt/gt animals showed elevations in urinary protein/creatinine-ratio (female PRCPgt/gt 19.9±1.4 vs. WT 23.5±1.9 and male PRCPgt/gt 32.4±3.5 vs. WT 34.8±1.8). At 16 weeks of age, the GFR (measured by clearance of FITC-Inulin) was not different (female PRCPgt/gt 4.10±0.32 vs. WT 4.33±0.29 and male PRCPgt/gt 4.41±0.50 vs. WT 4.28±0.31 ul/min/g). Systolic blood pressure was significantly elevated in PRCPgt/gt animals as compared to the respective WT controls (female PRCPgt/gt 147.8±3.4 vs. WT 117.3±7.1 mmHg, male 138.1±8.4 vs. 120.5±3.6 mmHg, p<0.05).
 PRCP deficient mice have normal GFR but elevated basal blood pressure. Whether PRCP deficiency causes hypertension as a result of impaired Ang II degradation or other mechanisms needs to be determined.

Abstract 630: Blood Pressure and Kidney Function in PRCP deficient Mice

Angiotensin-converting enzyme-2 (ACE2) enhances the degradation of ANG II and its expression is altered in diabetic kidneys, but the regulation of this enzyme in the urine is unknown. Urinary ACE2 was studied in the db/db model of type 2 diabetes and stretozotocin (STZ)-induced type 1 diabetes during several physiological and pharmacological interventions. ACE2 activity in db/db mice was increased in the serum and to a much greater extent in the urine compared with db/m controls. Neither a specific ANG II blocker, telmisartan, nor an ACE inhibitor, captopril, altered the levels of urinary ACE2 in db/db or db/m control mice. High-salt diet (8%) increased whereas low-salt diet (0.1%) decreased urinary ACE2 activity in the urine of db/db mice. In STZ mice, urinary ACE2 was also increased, and insulin decreased it partly but significantly after several weeks of administration. The increase in urinary ACE2 activity in db/db mice reflected an increase in enzymatically active protein with two bands identified of molecular size at 110 and 75 kDa and was associated with an increase in kidney cortex ACE2 protein at 110 kDa but not at 75 kDa. ACE2 activity was increased in isolated tubular preparations but not in glomeruli from db/db mice. Administration of soluble recombinant ACE2 to db/m and db/db mice resulted in a marked increase in serum ACE2 activity, but no gain in ACE2 activity was detectable in the urine, further demonstrating that urinary ACE2 is of kidney origin. Increased urinary ACE2 was associated with more efficient degradation of exogenous ANG II (10(-9) M) in urine from db/db compared with that from db/m mice. Urinary ACE2 could be a potential biomarker of increased metabolism of ANG II in diabetic kidney disease.

Jan Wysocki, Laura Garcia-Halpin, Minghao Ye, Christoph Maier, Kurt Sowers, Kevin D. Burns, and Daniel Batlle Division of Nephrology and Hypertension, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois; and Division of Nephrology, Department of Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada

Previous studies using XNT have suggested that the molecule has a unique role as a hypotensive and antifibrotic agent within the RAS acting primarily as an activator of the ACE2. In this study, we assessed the hypothesis that XNT attenuates hypertension by an ACE2-independent mechanism. Studies were performed in C57BL6 WT and ACE2KO mice. BP was monitored continuously for a period of 25 min following a bolus of Ang II infusion after either XNT or recombinant (r)ACE2 was administered. Ang peptides were examined in plasma ex-vivo using MAS spectrometry analysis (RAS-fingerprint). ACE2 activity in serum was measured after XNT and/or Ang II infusion, in order to investigate a potential effect of XNT on serum ACE2. With regard to blood pressure, both XNT (n=11) and rACE2 (n=11) were able to markedly attenuate Ang II -induced hypertension in WT mice. However, a similar decline in BP caused by XNT was also seen in ACE2KO mice (n=14), indicating that the BP-lowering effect of XNT was ACE2-independent. This was additionally evidenced by serum ACE2 activity measurements in WT mice performed 5 minutes after Ang II infusion, showing no significant variation between XNT (0.351±0.06 RFU/ul/hr) and control group (0.393±0.04 RFU/ul/hr). Moreover, results from MAS spectrometry analysis showed that the presence of XNT did not alter plasma Ang II, Ang (1-7) or Ang (1-5) levels, whereas rACE2, without XNT addition, significantly increased Ang (1-7) and Ang(1-5) levels as a result of enhanced Ang II degradation. XNT has a potent BP-lowering effect in AngII-dependent hypertension but this action is ACE2-independent and unrelated to Ang II or Ang (1-7).

Abstract 556: ACE2-Independent Effect of XNT in Ang II-Induced Hypertension

There are species differences between the currently used ACE2 inhibitors (MLN-4760 and DX600) that could be critically relevant to the proper interpretation of studies with these compounds. The effect of these inhibitors on ACE2-driven angiotensin peptides formation and degradation has not yet been studied. Accordingly, we examined the ability of MLN-4760 and two conformational variants of DX600 [a linear (L) and a cyclic (C) form] to inhibit human (h) and mouse (m) recombinant (r) ACE2 using a novel ex vivo LC-MS/MS based approach to concomitantly measure several peptides within the RAS system in plasma. Both mrACE2 and hrACE2 (5ug/mL) when added to blood plasma caused a complete disappearance of Ang II and lead to the formation of Ang-(1-7). As a result of the increase in Ang-(1-7) formation, both mrACE2 and hrACE2 lead also to the formation of Ang-(1-5). This reaction was likely driven by ACE which, like other peptidases, is present in plasma ex vivo assay. The effects of hrACE2 and mrACE2 on the above mentioned Ang peptides were inhibited by MLN-4760 at 10-5M and also at lower concentrations (10-6M and 10-7M). Both, L-DX600 and C-DX600 inhibited the effect of hrACE2 on Ang-(1-7) and Ang-(1-5) formation and this effect was also dose-dependent. By contrast, neither L-DX600 nor C-DX600, even at a high concentration (10-5M), prevented the changes on Ang peptides effected by mrACE2. hrACE2 decreased Ang I levels by 60% whereas mrACE2 did it only marginally. Of note, hrACE2 resulted in the formation of Ang-(1-9) from Ang I whereas mrACE2 did not. In conclusion, there are major differences between the known specific inhibitors of ACE2 between hrACE2 and mrACE2. MLN-4760 inhibits both hrACE2 and mrACE2 whereas DX600 inhibits hrACE2 preferentially. DX600 does not prevent mrACE2-driven formation of Ang-(1-7) from Ang II. mrACE2 effectively degrades Ang II forming Ang-(1-7) whereas it has no effect on the formation of Ang-(1-9) from Ang I. RAS “fingerprinting” is a powerful novel approach to simultaneously evaluate quantitatively several angiotensin peptides in plasma and can be used to demonstrate profound differences on the effect of available ACE2 inhibitors on the formation of various angiotensin peptides driven by human and mouse ACE2.

Abstract 382: Studies on the Effect of ACE2 Inhibitors on ACE2-driven Angiotensin Peptides Metabolism in Plasma Using RAS Fingerprinting

Background: The Apelin receptor (APJ)-Apelin system has been implicated in cardiovascular function but little is known regarding diabetic kidney disease. Apelin’s effects appear related, in part, to an interaction with angiotensin II. Apelin, like angiotensin II, is a substrate for ACE2, which we previously showed to localize in tubular and glomerular epithelial cells (podocytes). Here we wanted to investigate the localization of this peptide within the glomerulus and the overall expression of apelin and its receptor APJ within normal and diabetic mouse kidney. METHODS: We employed RT real time PCR, western blot, immunostaining, tissue and cell confocal microscopy to study apelin and APJ in kidneys from female C57BLKS mice (8 wks of age) and in cultured immortalized podocytes. Mouse podocytes were stimulated with Pyr 1 Apelin-13 (100nM) for 0, 1, 5, 15 and 60min and tested for phospho-status of AKT, p70S6K and ERK. Kidneys from 8 weeks old db/db mice were also studied. Results: Both Apelin and APJ were abundantly present in the kidney being expressed in most glomerular tufts, proximal tubules, and arterioles. In glomeruli, apelin colocalized with nephrin, PECAM-1, and a-SMA indicating its presence in podocytes, endothelial cells, and mesangial cells. APJ, by contrast, did not colocalize with PECAM-1 but also colocalized with several podocyte markers. In the proximal tubule, the APJ receptor colocalized with ACE2. Apelin and APJ mRNA were also expressed in cultured mouse podocytes where apelin-13 induced AKT, p70S6K and ERK rapid signaling (at 15min). By RT real time PCR, kidney cortex from db/db mice (n=6) had reduced APJ (0.19±0.02 vs 0.62±0.08, p db/m controls (n=6). Conclusions: Apelin and its receptor are widely expressed in the kidney, including podocytes where apelin-13 is involved in AKT, p70S6K and ERK signaling. Reduced apelinergic activity in the diabetic kidney could be possibly compensatory to the known overactivity of the RAS.

Abstract 612: Apelinergic System within the Kidney is Altered in Diabetic Mice

A newly produced murine recombinant angiotensin (Ang)-converting enzyme 2 (ACE2) was characterized in vivo and in vitro. The effects of available ACE2 inhibitors (MLN-4760 and 2 conformational variants of DX600, linear and cyclic) were also examined. When murine ACE2 was given to mice for 4 weeks, a marked increase in serum ACE2 activity was sustainable. In acute studies, mouse ACE2 (1 mg/kg) obliterated hypertension induced by Ang II infusion by rapidly decreasing plasma Ang II. These effects were blocked by MLN-4760 but not by either form of DX600. In vitro, conversion from Ang II to Ang-(1-7) by mouse ACE2 was blocked by MLN-4760 (10−6 M) but not by either form of DX600 (10−5 M). Quantitative analysis of multiple Ang peptides in plasma ex vivo revealed formation of Ang-(1-9) from Ang I by human but not by mouse ACE2. Both human and mouse ACE2 led to the dissipation of Ang II with formation of Ang (1-7). By contrast, mouse ACE2-driven Ang-(1-7) formation from Ang II was blocked by MLN-4760 but not by either linear or cyclic DX600. In conclusion, sustained elevations in serum ACE2 activity can be accomplished with murine ACE2 administration, thereby providing a strategy for ACE2 amplification in chronic studies using rodent models of hypertension and cardiovascular disease. Human but not mouse ACE2 degrades Ang I to form Ang-(1-9). There are also species differences regarding rodent and human ACE2 inhibition by known inhibitors such that MLN-4760 inhibits both human and mouse ACE2, whereas DX600 only blocks human ACE2 activity.

Murine Recombinant Angiotensin-Converting Enzyme 2: Effect on Angiotensin II–Dependent Hypertension and Distinctive Angiotensin-Converting Enzyme 2 Inhibitor Characteristics on Rodent and Human Angiotensin-Converting Enzyme 2

Objective To investigate changes in the width of the iridocorneal angle in the four quadrants (nasal, temporal, superior, inferior), central anterior chamber depth, lens thickness and intraocular pressure (IOP) in patients with chronic renal failure after hemodialysis. Methods Retrospective case series study. Thirty-five patients (70 eyes) with chronic renal failure were measured with tonometry (IOP), A/B scan (lens thickness) and ultrasound biomicroscopy (central anterior chamber depth, the trabecular iris angle and four directions of the angle opening distance) before and after hemodialysis. The patients were divided into 2 groups based on gonioscopy results: a narrow angle group (14 eyes) and an open angle group (56 eyes). IOP was measured in the 2 groups before and after hemodialysis. The patients' blood urea nitrogen (bun), creatinine (scr), albumin (alb),plasma osmotic pressure and dehydration were also checked before and after hemodialysis. All changes in the parameters were analyzed with a paired t test. Results IOP increased significantly in 35 patients (70 eyes) after hemodialysis (t=-3.389, P＜0.05). Central anterior chamber depth (t=8.043,P＜0.01), iridocorneal angle width (t=4.637, 8.893, 3.575, 3.436, P＜0.01 for all), and angle opening distance (t=3.122, 5.372, 3.838, 2.915, P＜0.01 for all) in 35 patients decreased, with the lens becoming significantly thicker (t=-9.132, P＜0.01) after hemodialysis. The IOP in narrow angle eyes (14 eyes) increased significantly (t=-0.045, P＜0.01) after hemodialysis while the IOP in open angle eyes (56 eyes) showed no significant change (t=-9.515, P＞0.05). Bun, scr and plasma osmotic pressure decreased in 35 patients (t=16.075, 13.676, 113.063, P＜0.01 for all) and alb increased (t=-7.756, P＜0.01) after hemodialysis. Conclusion Due to the movement of liquid in eyes cause by the osmotic pressure gradient after hemodialysis, the eyes of patients with chronic renal failure are characterized by a shallower central anterior chamber depth, a narrower iridocorneal angle width and a thicker lens. In addition, the IOP of narrow angle eyes increase significantly. As a result, it is recommended that the anterior chamber structure of patients with chronic renal failure should be checked and patients should receive appropriate treatment before hemodialysis. 
 
Key words: 
Renal dialysis;  Anterior chamber;  Lens,eyes;  Intraocular pressure

Investigation of changes in the biometric structure of the anterior chamber and intraocular pressure in patients with chronic renal failure after hemodialysis

Angiotensin (Ang)-converting enzyme 2 (ACE2) cleaves Ang II to form Ang-(1-7). Here we examined whether soluble human recombinant ACE2 (rACE2) can efficiently lower Ang II and increase Ang-(1-7) and whether rACE2 can prevent hypertension caused by Ang II infusion as a result of systemic versus local mechanisms of ACE2 activity amplification. rACE2 was infused via osmotic minipumps for 3 days in conscious mice or acutely in anesthetized mice. rACE2 caused a dose-dependent increase in serum ACE2 activity but had no effect on kidney or cardiac ACE2 activity. After Ang II infusion (40 pmol/min), rACE2 (1 mg/kg per day) resulted in normalization of systolic blood pressure and plasma Ang II. In acute studies, rACE2 (1 mg/kg) prevented the rapid hypertensive effect of Ang II (0.2 mg/kg), and this was associated with both a decrease in Ang II and an increase in Ang-(1-7) in plasma. Moreover, during infusion of Ang II, the effect of rACE2 on blood pressure was unaffected by a specific Ang-(1-7) receptor blocker, A779 (0.2 mg/kg), and infusing supraphysiologic levels of Ang-(1-7) (0.2 mg/kg) had no effect on blood pressure. We conclude that, during Ang II infusion, rACE2 effectively degrades Ang II and, in the process, normalizes blood pressure. The mechanism of rACE2 action results from an increase in systemic, not tissue, ACE2 activity and the lowering of plasma Ang II rather than the attendant increase in Ang-(1-7). Increasing ACE2 activity may provide a new therapeutic target in states of Ang II overactivity by enhancing its degradation, an approach that differs from the current focus on blocking Ang II formation and action.

Targeting the Degradation of Angiotensin II With Recombinant Angiotensin-Converting Enzyme 2: Prevention of Angiotensin II–Dependent Hypertension

The mechanisms involved in the development of diabetes and its complications are complex, with a long list of potential derangements on different pathways (1,2). In this commentary, we discuss angiotensin converting enzyme 2 (ACE2) as a potential participant in the development of both islet β-cell insufficiency early on and in the development of nephropathy later.

ACE has long been recognized as the key enzyme within the renin-angiotensin system (RAS) mainly by cleaving angiotensin (Ang) I to form Ang II, which is the main active peptide within the system. ACE2, a homologue of ACE, is a monocarboxypeptidase that preferentially removes carboxy-terminal amino acids from various substrates, including Ang II, Ang I, and apelin (3–6). ACE2 cleaves Ang II to form Ang-(1-7) with a high catalytic efficiency, suggesting an important role in preventing Ang II accumulation, while enhancing Ang-(1-7) formation (7) (Fig. 1). Other mammalian homologues of ACE, such as collectrin and, more recently, ACE3, have also been described (8). ACE2, however, is the only known homologue of ACE with enzymatic activity (3–5).

FIG. 1. 
Potential therapeutic role of ACE2 amplification in diabetes, both at the level of the pancreatic islets and at that of the kidney. ACE2 amplification leads to reduced Ang II overactivity and increased Ang-(1–7) activity. Please note that the actions of ACE2 on angiotensin peptides are just the opposite of those of ACE, which promotes Ang II formation while increasing Ang-(1–7) degradation. In general, the effects of Ang-(1–7) (blue) are less well documented (as reflected by the question marks) than those of Ang II (red). It is possible that the benefits of ACE2 amplification result largely from reduced ACE2 overactivity and not so much from increased Ang-(1–7) activity, but that needs to be further studied. There are also potential effects of Ang-(1–7) on …

Objective:Renal hypoxia has been proposed to be a pathophysiologic feature of diabetic kidney disease but it has been difficult to demonstrate in vivo, particularly in mouse models of diabetes. The objective of this work was to examine the sensitivity of blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) to assess renal oxygenation in vivo in a mouse model of diabetic kidney disease, the db/db mice. Research Design and Methods:Kidney BOLD MRI studies were performed on a 3.0 T scanner using multiple gradient echo sequence with a custom-designed surface coil to acquire T2*-weighted images. Studies were performed in 10-week-old db/db mice (n = 7) and db/m controls (n = 6). Results:R2* is a measure of the tissue deoxyhemoglobin concentration and higher values of R2* are associated with hypoxia. The db/db mice had higher medullary (43.1 ± 5.1 s−1 vs. 32.3 ± 3.7 s−1, P = 0.001) and cortical R2* (31.7 ± 3.1 s−1 vs. 27.1 ± 4.1 s−1, P = 0.04) values. Using pimonidazole staining as a marker of kidney hypoxia, in kidney sections from 10-week-old db/db mice neither cortex nor medulla had significant differences as compared with 10-week-old db/m mice (cortex: db/db 2.14 ± 0.05 vs. db/m 2.02 ± 0.28, medulla: db/db 2.81 ± 0.08 vs. db/m 2.6 ± 0.08). The db/db mice demonstrated further increased cortical and medullary hypoxia when scanned again at 15 weeks of age. Conclusions:The report shows that renal BOLD MRI is a sensitive method for the in vivo evaluation of renal hypoxia in a mouse model of diabetic kidney disease where progressive renal hypoxia can be documented over time. BOLD MRI may be useful to monitor therapeutic interventions that may improve tissue hypoxia in the diabetic kidney.

Angiotensin-converting enzyme (ACE)2 is a carboxypeptidase that degrades angiotensin II and other peptides. In the kidney, ACE2 localization within the glomerulus and tubules is cell specific. This study was aimed to investigate the localization of ACE2 within the renal vasculature. We also studied the effect of the administration of a specific angiotensin II type 1 receptor blocker, telmisartan, on ACE2 expression in the renal vasculature. ACE2 and ACE were localized in renal arterioles using confocal microscopy and specific cell markers. Quantitative measurements of ACE2 and ACE mRNA were estimated in kidney arterioles isolated by laser capture microdissection using real-time PCR. In kidney arterioles, ACE was localized in the endothelial layer, whereas ACE2 was localized in the tunica media. In mice treated with telmisartan (2 mg.kg(-1).day(-1)) for 2 wk, ACE2 expression was increased by immunostaining, whereas ACE expression was decreased. This was reflected in a decrease in the ACE/ACE2 ratio compared with vehicle-treated controls (0.53 +/- 0.14 vs. 7.59 +/- 2.72, P = 0.027, respectively). In kidney arterioles isolated by laser capture microdissection, the ACE/ACE2 mRNA ratio was also decreased compared with control mice (1.21 +/- 0.31 vs. 4.63 +/- 0.86, P = 0.044, respectively). In conclusion, in kidney arterioles ACE2 is preferentially localized in the tunica media, and its expression is increased after administration of the angiotensin II type 1 receptor blocker, telmisartan. Amplification of ACE2 in the renal vasculature may contribute to the therapeutic action of telmisartan by increasing angiotensin II degradation.

Localization of ACE2 in the renal vasculature: amplification by angiotensin II type 1 receptor blockade using telmisartan.

Angiotensin-converting enzyme 2 (ACE2) expression has been shown to be altered in renal tubules from diabetic mice. This study examined the localization of ACE and ACE2 within the glomerulus of kidneys from control (db/m) and diabetic (db/db) mice and the effect of chronic pharmacologic ACE2 inhibition. ACE2 co-localized with glomerular epithelial cell (podocyte) markers, and its localization within the podocyte was confirmed by immunogold labeling. ACE, by contrast, was seen only in glomerular endothelial cells. By immunohistochemistry, in glomeruli from db/db mice, strong ACE staining was found more frequently than in control mice (db/db 64.6 +/- 6.3 versus db/m 17.8 +/- 3.4%; P < 0.005). By contrast, strong ACE2 staining in glomeruli from diabetic mice was less frequently seen than in controls (db/db 4.3 +/- 2.4 versus db/m 30.6 +/- 13.6%; P < 0.05). For investigation of the significance of reduced glomerular ACE2 expression, db/db mice were treated for 16 wk with a specific ACE2 inhibitor (MLN-4760) alone or combined with telmisartan, a specific angiotensin II type 1 receptor blocker. At the end of the study, glomerular staining for fibronectin, an extracellular matrix protein, was increased in both db/db and db/m mice that were treated with MLN-4760. Urinary albumin excretion (UAE) increased significantly in MLN-4760-treated as compared with vehicle-treated db/db mice (743 +/- 200 versus 247 +/- 53.9 microg albumin/mg creatinine, respectively; P < 0.05), and the concomitant administration of telmisartan completely prevented the increase in UAE associated with the ACE2 inhibitor (161 +/- 56; P < 0.05). It is concluded that ACE2 is localized in the podocyte and that in db/db mice glomerular expression of ACE2 is reduced whereas glomerular ACE expression is increased. The finding that chronic ACE2 inhibition increases UAE suggests that ACE2, likely by modulating the levels of glomerular angiotensin II via its degradation, may be a target for therapeutic interventions that aim to reduce albuminuria and glomerular injury.

Glomerular localization and expression of Angiotensin-converting enzyme 2 and Angiotensin-converting enzyme: implications for albuminuria in diabetes.

ACE-related carboxypeptidase (ACE2) may counterbalance the angiotensin (ANG) II–promoting effects of ACE in tissues where both enzymes are found. Alterations in renal ACE and ACE2 expression have been described in experimental models of diabetes, but ACE2 activity was not assessed in previous studies. We developed a microplate-based fluorometric method for the concurrent determination of ACE and ACE2 activity in tissue samples. Enzymatic activity (relative fluorescence unit [RFU] · μg protein−1 · h−1) was examined in ACE and ACE2 knockout mice and in two rodent models of diabetes, the db/db and streptozotocin (STZ)-induced diabetic mice. In kidney cortex, preparations consisting mainly of proximal tubules and cortical collecting tubules, ACE2 activity had a strong positive correlation with ACE2 protein expression (90-kDa band) in both knockout models and their respective wild-type littermates (r = 0.94, P < 0.01). ACE activity, likewise, had a strong positive correlation with renal cortex ACE protein expression (170-kDa band) (r = 0.838, P < 0.005). In renal cortex, ACE2 activity was increased in both models of diabetes (46.7 ± 4.4 vs. 22.0 ± 4.7 in db/db and db/m, respectively, P < 0.01, and 22.1 ± 2.8 vs. 13.1 ± 1.5 in STZ-induced diabetic versus untreated mice, respectively, P < 0.05). ACE2 mRNA levels in renal cortex from db/db and STZ-induced diabetic mice, by contrast, were not significantly different from their respective controls. In cardiac tissue, ACE2 activity was lower than in renal cortex, and there were no significant differences between diabetic and control mice (db/db 2.03 ± 0.23 vs. db/m 1.85 ± 0.10; STZ-induced diabetic 0.42 ± 0.04 vs. untreated 0.52 ± 0.07 mice). ACE2 activity in renal cortex correlated positively with ACE2 protein in db/db and db/m mice (r = 0.666, P < 0.005) as well as in STZ-induced diabetic and control mice (r = 0.621, P < 0.05) but not with ACE2 mRNA (r = −0.468 and r = −0.522, respectively). We conclude that in renal cortex from diabetic mice, ACE2 expression is increased at the posttranscriptional level. The availability of an assay for concurrent measurement of ACE and ACE2 activity should be helpful in the evaluation of kidney-specific alterations in the balance of these two carboxypeptidases, which are involved in the control of local ANG II formation and degradation.

Metabolic alkalosis is a common feature of hypokalemic hypertensive syndromes associated with angiotensin II excess. The alkalosis-generating effect of angiotensin II is usually ascribed to its stimulatory effect on aldosterone secretion, a hormone that upregulates collecting duct hydrogen ion secretion. We studied the effect of angiotensin II infusions on the expression of B1 and a4 protein, subunits of the renal H+-ATPase in adrenalectomized rats. Adrenalectomized rats were given either angiotensin II or vehicle for 7 days via osmotic mini-pumps. H+-ATPase B1 protein expression was evaluated by Western blot analysis in isolated medulla and cortex plasma membrane preparations from one kidney, whereas the contralateral kidney was used for immunostaining. By Western blotting, the relative abundance of B1 protein was 2-fold higher in renal medulla membranes from rats with intact adrenal glands (sham surgery) than from adrenalectomized rats (219±47%, n=12; P<0.05). In contrast to renal medulla, adrenalectomy did not significantly alter the relative abundance of B1 protein in renal cortex. Angiotensin II also did not significantly alter the relative levels of B1 protein in the cortex, but it increased it significantly in renal medullary membranes (231±56%, n=8; P<0.005). Moreover, enhanced H+-ATPase B1 subunit protein immunoreactivity was found in medullary collecting duct segments of rats infused with angiotensin II. In contrast to B1, expression of a4, another subunit of the H+-ATPase was not altered by adrenalectomy or angiotensin II. We conclude that adrenalectomy decreases whereas angiotensin II increases H+-ATPase B1 subunit expression in medullary, but not in cortical collecting ducts. By increasing the relative abundance of the B1 subunit of H+-ATPase in the collecting duct, angiotensin II excess may lead to increased hydrogen ion secretion and thus metabolic alkalosis—a common feature of hypertensive syndromes associated with angiotensin II overactivity.

Angiotensin II Increases H+-ATPase B1 Subunit Expression in Medullary Collecting Ducts

Abstract—Unlike the ubiquitous angiotensin-converting enzyme (ACE), the ACE-related carboxypeptidase 2 (ACE 2) is predominantly expressed in the heart, kidney, and testis. ACE 2 degrades angiotensin (Ang) II to Ang (1–7) and Ang I to Ang (1–9). We investigated the expression of ACE and ACE 2 in a rodent model of type 2 diabetes. ACE and ACE 2 were measured in kidney and heart from 8-week-old no diabetic control (db/m) mice and diabetic (db/db) mice, which at this young age have obesity and hyperglycemia without nephropathy. In renal cortical tissue, ACE mRNA was reduced (db/db 0.31±0.06 versus db/m 0.99±0.05; P <0.005), whereas ACE 2 mRNA was not (db/db 0.94±0.05 versus db/m 1.03±0.11, NS). ACE protein was markedly reduced in kidney cortex of db/db mice (db/db 0.24±0.13 versus db/m 1.02±0.12; P <0.005), and this was associated with a corresponding decrease in renal ACE activity (db/db 12.7±3.7 versus db/m 61.6±4.4 mIU/mg protein; P <0.001). ACE 2 protein, by contrast, was increased in kidneys from diabetic mice (db/db 1.39±0.14 versus db/m 0.53±0.04; P <0.005). An increase in ACE 2 protein and a decrease in ACE protein, respectively, were also seen by immunostaining of renal cortical tubules from the db/db mice. In heart tissue, there were no significant differences between db/db and db/m mice in either ACE mRNA and protein or ACE 2 mRNA and protein. We conclude that in young db/db mice, ACE 2 protein in renal cortical tubules is increased, whereas ACE protein is decreased. We propose that the pattern of low ACE protein coupled with increased ACE 2 protein expression may be renoprotective in early stages of diabetes.

Increased ACE 2 and Decreased ACE Protein in Renal Tubules From Diabetic Mice: A Renoprotective Combination?

Intracellular pH and Na+/H+ Antiporter Activity in Cultured Vascular Smooth Muscle Cells from the Spontaneously Hypertensive Rat.

FGF21 promotes functional recovery after hypoxic-ischemic brain injury in neonatal rats by activating the PI3K/Akt signaling pathway via FGFR1/β-klotho

Wound healing, especially for diabetic wounds, is a lengthy and complicated process involving interactions and responses at the protein, cell, and tissue levels. Loading of growth factors into a hydrogel to construct a sustained‐release system is considered a promising approach to improve wound healing. The present study investigates the effect of thermosensitive heparin‐poloxamer (HP) hydrogel–encapsulated recombinant human fibroblast growth factor 21 (rhFGF21) on wound healing in mice with streptozotocin‐induced diabetes mellitus. First, we studied the in vitro release of rhFGF21 from the rhFGF21‐HP coacervate. The results showed that HP might control the release of rhFGF21. Next, we examined the effect of rhFGF21‐HP on skin wound healing in diabetic mice. Our data showed that rhFGF21‐HP significantly improved wound closure; promoted granulation, collagen deposition, and re‐epithelialization; and enhanced the expression of CD31. Moreover, rhFGF21‐HP had obvious advantages in diabetic wound healing. Therefore, the results suggest that the rhFGF21‐HP hydrogel polymer plays an important role in skin wound healing. This work provides a suitable sustained‐release delivery system that can continuously release rhFGF21 and presents a promising therapeutic strategy for wound healing in patients with diabetes.—Liu, H., Zhao, Y., Zou, Y., Huang, W., Zhu, L., Liu, F., Wang, D., Guo, K., Hu, J., Chen, J., Ye, L., Li, X., Lin, L. Heparin‐poloxamer hydrogel–encapsulated rhFGF21 enhances wound healing in diabetic mice. FASEB J. 33, 9858–9870 (2019). www.fasebj.org

Heparin‐poloxamer hydrogel‐encapsulated rhFGF21 enhances wound healing in diabetic mice

Hypoxic-ischemic encephalopathy (HIE) is detrimental to newborns and is associated with high mortality and poor prognosis. Thus, the primary aim of the present study was to determine whether glycine could (1) attenuate HIE injury in rats and hypoxic stress in PC12 cells and (2) downregulate mitochondria-mediated autophagy dependent on the adenosine monophosphate- (AMP-) activated protein kinase (AMPK) pathway. Experiments conducted using an in vivo HIE animal model and in vitro hypoxic stress to PC12 cells revealed that intense autophagy associated with mitochondrial function occurred during in vivo HIE injury and in vitro hypoxic stress. However, glycine treatment effectively attenuated mitochondria-mediated autophagy. Additionally, after identifying alterations in proteins within the AMPK pathway in rats and PC12 cells following glycine treatment, cyclosporin A (CsA) and 5-aminoimidazole-4-carboxamide-1-b-4-ribofuranoside (AICAR) were administered in these models and indicated that glycine protected against HIE and CoCl2 injury by downregulating mitochondria-mediated autophagy that was dependent on the AMPK pathway. Overall, glycine attenuated hypoxic-ischemic injury in neurons via reductions in mitochondria-mediated autophagy through the AMPK pathway both in vitro and in vivo.

Glycine Protects against Hypoxic-Ischemic Brain Injury by Regulating Mitochondria-Mediated Autophagy via the AMPK Pathway

Neonatal hypoxic-ischemic (HI) brain injury is a devastating disease that often leads to death and detrimental neurological deficits. The present study was designed to evaluate the ability of metformin to provide neuroprotection in a model of neonatal hypoxic-ischemic brain injury and to study the associated molecular mechanisms behind these protective effects. Here, we found that metformin treatment remarkably attenuated brain infarct volumes and brain edema at 24 h after HI injury, and the neuroprotection of metformin was associated with inhibition of neuronal apoptosis, suppression of the neuroinflammation and amelioration of the blood brain barrier breakdown. Additionally, metformin treatment conferred long-term protective against brain damage at 7 d after HI injury. Our study indicates that metformin treatment protects against neonatal hypoxic-ischemic brain injury and thus has potential as a therapy for this disease.

Metformin treatment after the hypoxia-ischemia attenuates brain injury in newborn rats

Bifurcation analysis of period-1 attractors in a soft impacting oscillator

A noninvasive scoring model for the differential diagnosis of ACTH-dependent Cushing’s syndrome: a retrospective analysis of 311 patients based on easy-to-use parameters

The safety of neoadjuvant chemoimmunotherapy before surgery in patients with non–small cell lung cancer (NSCLC) remains unclear in the perioperative stage. We describe a case of a 63‐year‐old man with IIIC stage NSCLC who received neoadjuvant chemoimmunotherapy and radical lobectomy. After the second cycle of pembrolizumab and chemotherapy (paclitaxel + carboplatin), the patient was diagnosed with immunologic enterocolitis and relieved by glucocorticoid therapy. Radical lobectomy of the right upper lobe was then performed. On postoperative day 4 (POD 4), the patient suddenly suffered suffocated wheezing during sleep. Interstitial lung disease was, therefore, identified by chest computed tomography scan. Glucocorticoids and mechanical ventilation were applied and the symptoms were relieved. On POD 10, the patient developed a bronchial fistula and underwent emergent repair surgery. This is the first case of multi‐organs, multi‐time point immune‐related adverse events (irAE) in perioperative NSCLC patients who received neoadjuvant chemoimmunotherapy. Clinicians should be on high alert for signs of irAEs in neoadjuvant chemoimmunotherapy patients, promptly requiring multidisciplinary management.

Multi‐organs perioperative immune‐related adverse events and postoperative bronchial anastomotic fistula in a patient receiving neoadjuvant immunotherapy with NSCLC

Multiformity and Evolution Characteristics of Periodic Motions in Mechanical Vibration Systems with Clearances

OBJECTIVE
To investigate the relationship between average interval time of chemotherapy and prognosis in patients with acute leukemia (AL) during intensive treatment.

METHODS
Data of 92 newly treated adult AL patients who received chemotherapy in The First Hospital of Lanzhou University from January 2010 to June 2019 were analyzed retrospectively. The patients were divided into groups according to the average interval time of chemotherapy during intensive treatment, and its influence on prognosis was analyzed.

RESULTS
The median interval of chemotherapy during intensive therapy was 38 (20-64) days. According to the average interval of chemotherapy, patients were divided into 4 groups, including < 30 days group, 30-39 days group, 40-49 days group and ≥ 50 days group. The 3-year overall survival (OS) rate of the four groups was (84.9±8.0)%, (73.5±8.7)%, (56.5±11.1)% and (41.8±13.6)%, respectively (P=0.008). The 3-year progression-free survival (PFS) rate of the four groups was (63.6±11.1)%, (52.8±10.2)%, (38.2±10.8)% and (14.0±9.0)%, respectively (P=0.001). After comparison between the 4 groups, it was found that OS and PFS in ≥ 50 days group were significantly shorter than those in < 30 days group (P<0.008). Multivariate analysis showed that risk stratification and average chemotherapy interval ≥ 50 days were the common adverse factors affecting OS and PFS.

The average chemotherapy interval ≥ 50 days during intensive therapy is an independent risk factor affecting the prognosis and survival of patients with AL. When the bone marrow is completely relieved and the peripheral hemogram recovers to an acceptable level, the consolidation therapy should be started as soon as possible. The interval < 30 days can significantly improve the prognosis compared with the interval ≥ 50 days.

[Analysis of Correlation between Interval Time of Chemotherapy and Prognosis in Patients with Acute Leukemia].

Two-parameter non-smooth bifurcations of period-one motions in a plastic impacting oscillator

Dynamic characteristics of a mechanical impact oscillator with a clearance

Two-parameter bifurcations of an impact system under different damping conditions

Objective 
To explore the application effect of a specialized team consisting of specialist nurses and some emergency care′s or intensive care′s head nurses of critically ill patients in the hospital. 
 
Methods 
From 2016 to 2018, the Critical Care Professional Group of implemented a provincial and above specialist nurses and the backbone of the specialist care departments of the acute and critical departments. A total of 23 members were composed of core members. A total of 56 liaison officers from each ward were selected to participate. The training and assessment activities presided over by the core staff of the professional group; at the same time, the professional group liaison officer is also the leader of the critical care quality control team in this ward, and implements the quality control of critical care patients; the core members are responsible for the guidance of the nursing care of critical patients in the hospital. The liaison staff carries out the training and assessment of the intensive care knowledge, skills and related nursing standards, norms, as well as the sharing of new technologies and new projects or research topics for acute and critical care, and the training of intensive care posts in the hospital. Before and after the operation of the specialized nursing team, the quality control scores of critically ill patients in 2015-2018, the satisfaction survey of nursing, the number of patents published by nurses in 2-25 years, the mortality rate of patients, and the results of unplanned extubation in 2016-2018 Compare. 
 
Results 
The quality control scores of critical care patients in 2015-2018 were 93.91±1.23, 94.07±1.38,94.33±1.24, 95.42±1.56. The difference was statistically significant (F=49.597, P < 0.01). Satisfaction survey scores were 94.92±2.28, 97.08±1.37, 97.82±1.52, 97.94±1.68, the difference was statistically significant (F=30.882, P < 0.01); work 2-20 years The number of nurses was 678, 809, 853, and 925 respectively. The number of patents published was 76, 119, 147, and 237, respectively. The difference was statistically significant (χ2=36.77, P < 0.01). 2016-2018 unplanned extubation rate was 4.98‰(127/25 517), 4.01‰(115/28 713), 3.25‰(112/34 493), the difference was statistically significant (χ2=10.958, P <0.01). 
 
The professional nursing team operation mode can improve the core ability and comprehensive quality of nursing staff's intensive care, improve the quality of care management of critically ill patients, ensure patient safety, and achieve continuous improvement of nursing quality. 
 
Key words: 
Specialist nurse; Intensive care; Professional team; Nursing quality

Evaluation of the effectiveness of specialized nursing team in the management of critical patients

Objective 
To study the effect of diversified training mode in the training of rookie nurses in ICU. 
 
Methods 
A total of 24 ICU rookie nurses in 2014 and 2015 were trained with a variety of training methods such as bedside operation teaching, scenario simulation, case study analysis,workshop activities and clinical objective nursing management practices,compared with a total of 22 rookie nurses in 2012 and 2013 who were trained with routine methods such as ICU specialist theory and custody skills, the operation of the instrument using. 
 
Results 
Through diversity training nurses in common assessment performance of the project such as central venous pressure monitoring, suctioning of artificial airway,oral intubation of tracheal intubation, operation of ventilator, operation of enteral nutrition, examination of specialist theory and routine department respectively were 95.29 ± 1.10, 94.75 ± 0.99, 94.96 ± 1.23, 94.25 ± 1.19, 95.38 ± 1.35, 87.96 ± 4.01, 88.33 ± 3.63, 96.67 ± 1.44, 96.3 ± 0.35. The scores of the new nurses who received the traditional training were 92.14 ± 2.88, 92.64 ± 2.34, 92.97 ± 2.00, 92.30 ± 2.55, 93.75 ± 2.99, 84.76 ± 5.44, 82.29 ± 5.73, 93.58 ± 1.89, 90.22 ± 3.91. The difference was statistically significant (t = -5.365-0.619, P <0.01 or 0.05). Comparison of the incidence of adverse events and satisfaction of physicians,nursing interns,patients and their families between the two groups of new nurses in the difference was statistically significant (χ2=5.112-124.819, P <0.05 or 0.01). 
 
The diversified training model enables ICU rookie nurses to quickly get familiar with the workflow of nursing, grasp the specialist theory of ICU and custodial skills,rapidly improve comprehensive capabilities such as accessing and addressing critical patients and ambulance cooperation and such comprehensive capabilities, competent ICU nursing work faster and better to avoid the occurrence of some nursing adverse events, to ensure the quality of care and patient safety, and to improve satisfaction. 
 
Key words: 
Diversified training; ICU; Rookie nurse; Specialist training

The application effect of diversity training model in ICU rookie nurse training

Objective 
To investigate the effect of pathology risk factors on prognosis of stage I rectal cancer patients. 
 
Methods 
Data of patients with stage I rectal cance from January 2011 to January 2013 in the 2nd Affiliated Hospital of Harbin Medical University were retrospectively collected. 178 cases were included and were divided into two groups according to the presence of high risk pathological factors. 119 cases were defined as high-risk group including 60 males and 59 females, and 59 cases were in non high-risk group, the male cases were 33 and females were 26 respectively. Median follow-up time was 33 months. 
 
Results 
There were no difference in the sex, age, macroscopic type, differentiation, numbers of lymph node, depth of invasion and location (χ2=0.480, t=2.023, χ2=2.244, χ2=5.614, t=2.387, χ2=1.590, χ2=3.099, all P values >0.05) . No recurrence and metastasis were observed in non-high-risk group while local recurrence and metastasis were observed in high-risk group. There was difference in survival time between two groups (HR=0.86, 95%CI 0.56~0.97). Lymph vascular infiltration, nervous invasion and low differentiation were the main factors that affected survival. 
 
Closely follow up should be performed on the high-risk stage I rectal cancer patients. 
 
Key words: 
Rectal neoplasms; Prognosis; Pathological risk factors; TNM Stage I

Pathological risk factors affect the prognosis of patients with stage I rectal cancer

Objective 
To investigate the effect of the nursing care of critically ill patients in intensive care unit(ICU) with non-invasive ventilation assisted by sedation simultaneously. 
 
Methods 
During the intervention phase from June 2012 to June 2013 of 28 patients in ICU treated by non-invasive ventilation, sedatives were adjusted according to Ramsay Scale, and the parameters of the life signs (heart rate, blood pressure, oxygen saturation,etc) were measured by nurses. 
 
Results 
89.3% (25/28) patients obtained the improvement of the disease despite of the complications such as over-sedation and instable hemodynamics. 
 
The key points can increase tolerance of non-invasive ventilation and improve clinical outcomes, develop comprehensive nursing strategies on safety and effectiveness of sedation and non-invasive ventilation. 
 
Key words: 
Ventilators, mechanical; Nursing care; Sedation

Nursing care on the sedation of patients with non-invasive ventilation

Objective 
To investigate the effect of chronotherapy (chemotherapy plus timely medication) on neutrophils in breast cancer patients with neoadjuvant chemotherapy. 
 
Methods 
Fifty breast cancer patients with neoadjuvant chemotherapy were selected from 2011 to 2014 and divided into chronotherapy group and conventional treatment group (conventional group) by random number table method with 25 cases each. Conventional group received conventional neoadjuvant chemotherapy and conventional drug treatment. Chronotherapy group received neoadjuvant chemotherapy combined with chronochemotherapy and timely medication treatment, and applied clinical nursing care pathway. Both groups were conducted three cycles of chemotherapy, three weeks after the first and the second chemotherapy,the results of routine blood and liver function were compared in patients between two groups. The number of readmission and fever because of agranulocytosis were calculated. 
 
Results 
The two groups of patients were successfully completed three cycles of chemotherapy, after the first cycle of chemotherapy, the neutrophil was (4.40±2.20)×109/L in chronotherapy group, and (3.18±1.35) × 109/L in conventional group; after the second cycle of chemotherapy, the neutrophil was (3.95±1.58) × 109/L, and (2.83±1.49) × 109/L in conventional group , the two groups were statistically significant,t=2.375, 2.563,P <0.05. Two cases needed readmission in chronotherapy group during chemotherapy,accounting for 8%(2/25), much lower than conventional group of 8 cases accounting for 32%(8/25). 
 
The use of chronotherapy in breast cancer chemotherapy has less neutropenia, mild side effects of bone marrow suppression. It is an effective and safe viable option. 
 
Key words: 
Breast neoplasms; Chronotherapy; Drug therapy; Neutropenia; Critical pathways

Effects of chronotherapy on neutrophils in breast cancer patients

A new method of combining macroporous RP (mRP) protein fractionation with RPLC peptide separation MS/MS is reported for profiling the phosphoproteome of a complex sample. In this method, an mRP‐C18 column was used to fractionate the proteins from a whole cell lysate of a breast cancer cell line, MDA‐MB‐231, into 38 fractions. Each fraction was subjected to tryptic digestion, sequential phosphopeptide enrichment by immobilized metal ion affinity chromatography and titanium dioxide (TiO2), followed by capillary RPLC‐MS/MS analysis. For comparison, the conventional method of using strong cation exchange RPLC separation of peptides combined with MS/MS was also used for analyzing the phosphoproteome. Replicate experiments by the mRP‐RPLC method identified 1585 distinct phosphoproteins with 4519 phosphopeptides, compared to 1585 phosphoproteins with 4297 phosphopeptides by strong cation exchange RPLC, with a total of 1947 phosphoproteins and 6278 phosphopeptides identified from the combined results. While the two methods have similar ability in the identification of the phosphoproteome, they produce complementary information. The phosphoproteins identified in this study, including 67 novel phosphorylation sites from 56 breast cancer related proteins, can serve as the entry point for future validation with biological implications in breast cancer. The MS proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD000948 and DOI 10.6019/PXD000948.

Macroporous reversed‐phase separation of proteins combined with reversed‐phase separation of phosphopeptides and tandem mass spectrometry for profiling the phosphoproteome of MDA‐MB‐231 cells

For the first time, a gas chromatography tandem mass spectrometry method in the multiple reaction monitoring mode was developed and validated for the separation and detection of 21 phthalate leachables in meter dose inhalers (MDI). The optimized method was reliable with high sensitivity and selectivity. Calibration curves were linear with correlation coefficients (R2) > 0.990, and limit of detection (LOD) values in the range of 0.1–4.2 ng mL−1 except for di(2-methoxyethyl) phthalate, di(2-ethoxyethyl) phthalate and di(2-n-butoxyethyl) phthalate, for which the LODs were around 10 ng mL−1. Recoveries ranged between 86.6 and 108.3%, and the relative standard devision values of precision were within 7.72%. For the five MDI batches analyzed, 5 out of 21 phthalates were detected in each sample, including dimethyl phthalate, diethyl phthalate, diisobutyl phthalate, dibutyl phthalate and di(2-ehtylhexyl) phthalate, with total phthalate amounts of less than 260 ng per canister.

Analysis of 21 phthalate leachables in metered dose inhalers by gas chromatography tandem mass spectrometry

Protein solubilization is a key step in mass spectrometry-based shotgun proteome analysis. We describe a microwave-assisted protein solubilization (MAPS) method to dissolve proteins in reagents, such as NH(4)HCO(3) and urea, with high efficiency and with an added benefit that the solubilized proteins are denatured to become more susceptible to trypsin digestion, compared to other conventional protein solubilization techniques. In this method, a sample vial containing proteins suspended in a solubilization reagent is placed inside a domestic microwave oven and subjected to microwave irradiation for 30 s, followed by cooling the sample on ice to room temperature (~40 s) and then intermittent homogenization by vortex for 2 min. This cycle of microwave irradiation, cooling, and homogenization is repeated six times. In this way, sample overheating can be avoided, and a maximum amount of protein can be dissolved. It was shown that in the case of trypsin digestion of bovine serum albumen (BSA) more peptides and higher sequence coverage could be obtained from the protein dissolved by the MAPS method than the conventional heating, sonication, or vortex method. Compared to the most commonly used vortex-assisted protein solubilization method, MAPS reduces the solubilization time significantly, increases the amount of protein dissolvable in a reagent, and increases the number of proteins and peptides identified from a proteome sample. For example, in the proteome analysis of an Escherichia coli K-12 integral membrane protein extract, the MAPS method in combination with sequential protein solubilization and shotgun two-dimensional liquid chromatography tandem mass spectrometry analysis identified a total of 1291 distinct proteins and 10363 peptides, compared to 1057 proteins and 6261 peptides identified using the vortex method. Because MAPS can be done using an inexpensive microwave oven, this method can be readily adopted.

Microwave-assisted protein solubilization for mass spectrometry-based shotgun proteome analysis.

Direct chiral separation of azelnidipine by HPLC with Pirkle-type column

Mass Spectrometric Method Development and Applications for Comprehensive Proteome Analysis

AIM
To establish HPLC chiral separation method for ketoprofen enantiomers by using Chirobiotic V chiral seperation phase (CSP) (A) and vancomycin as chiral mobile phase additives (B).

METHODS
The separation was first performed on Chirobiotic V CSP with the mobile phase of terahydrofran (THF)-0.5% triethylanine acetate(TEAA) buffer (15:85) at the flow rate of 0.7 mL.min-1. When using vancomycin as chiral mobile phase additive, the separation was carried out on C8 column (150 mm x 4.6 mm), the mobile phase was methanol-0.25% TEAA buffer (50:50), the flow rate was 0.7 mL.min-1. The effects of the concentration of vancomycin, organic modifier and the pH of the buffer on the resolution of ketoprofen enantiomers were investigated. Also, the feasibility of these two methods to be used as quantitative method was studied.

RESULTS
Ketoprofen enantiomers were separated at a baseline level under the chromatographic condition of both methods A and B, the resolution was 2.28 and 2.22, respectively. In method A the linearity of enantiomer was obtained from 0.5 mg.L-1 to 100 mg.L-1, the detectionlimit was 1 microgram.L-1. When using vancomycin as mobile phase additive the system was shown to have a high efficiency. In this system, the assay of enantiomer is linear from 2.5 mg.L-1 to 250 mg.L-1. The detection limit was 14.5 micrograms.L-1.

Both methods can be used to detect optical purity of S-(+)-ketoprofen.

[Enantiomeric separation of ketoprofen by HPLC using chirobiotic V CSP and vancomycin as chiral mobile phase additives].

Since the structure is completely mobile, lack of central coordination, multi hop communications and limited resources provided by MANETs, QoS techniques need to be optimize the scare resource. A lot of research has been focused on providing QoS assurance in MANETs. The most important QoS metrics are packet delivery ratio, delay, through put and energy. It is a challenging issue to incorporate QoS to ad-hoc multicasting. In this paper the QoS metrics of multicast routing protocols ODMRP, AM Route and PUMA have been simulated using NS2 and analyzed.

Quality of Service Optimization of Multicast Routing Protocols in Mobile Ad-Hoc Networks: AM Route, PUMA and ODMRP

This paper intends to improve the performance of MANETS – Mobile Ad-hoc networks handling high volume traffic by introducing an enhanced tree based multicast routing protocol with efficient management of topology and groups with an improvised label mechanism capable of building alternate paths and secure better transmission stability. A comparative analysis of the simulation results have shown that the proposed protocol is better performing than the existing multicast routing protocols with slightly higher control overhead.

High Performance Multicast Routing Protocol in Mobile Ad-Hoc Network

With some new features introduced by IPv6 network, such as a wider address space, a different scope based on addressing scheme, a modified protocol field and so on, IPv6 topology discovery faces some challenging problems. And many of topology discovery algorithms developed to collect IPv4 network topology information can not be readily applied to IPv6 network. In this paper, a few problems generated by IPv6 network, some methods and algorithms for IPv6 network topology discovery are discussed in detail. Their advantages and disadvantages are fully summarized. Finally, the new problems and some suggestions for the research work are put forward.

This paper introduces baseband processing procedure of CDMA2000 downlink wireless transmission technology The digital baseband processing block is given,then presents all kinds of key technologies of CDMA and hardware and software structure in design process

Objective To discuss the influence on compliance of rehabilitation exercise in the patients with fracture about motivation theory.Methods The patients with fracture was guided with rehabilitation exercise by hierarchy of needs theory,strengthen theory,expectancy theory and target incentive theory.The nurses were required in mastering the use principles of the theories.The patients were Strengthened for psychological nursing.The compliance of rehabilitation exercise of patients was dynamily assessed.The rehabilitation training was emphasized for nurses.Results The nurse-patient relationship was closed up.The active exercise consciousness and the compliance of rehabilitation exercise in patients were improved.Conclusion In the instruction of recovery exercise process,the application of the incentive theory is of importance and necessity.

The compliance of rehabilitation exercise in the patients with fracture from the incentive theory

Objective To study the distribution of allergens and its clinical characteristics among children with allergic rhinitis complicated by bronchial asthma in Haikou Area.Methods 224 children with allergic rhinitis complicated by bronchial asthma were tested with 14 kinds of international standardized allergens by skin prick test.These allergens were provided by Allergopharma Company in Germany.Results 169 of the 224 children had positive skin test results(90 males and 79 females,mean age = 8.67±1.81 years ).112 children were 3-6 years old and 57 were 7-12 years old.11 children began presenting symptoms in spring,19 in summer, 80 in autumn and 59 in winter.Most of the children with positive results were sensitive to mites and shrimps.They were particularly sensitive to moulds at the same time.The positive rate was higher in preschool children than in school-age children,depending on the season.Conclusions 75.50%of the children with allergic rhinitis complicated by bronchial asthma in Haikou Area have positive results in allergen skin tests.The positive rate is associated with the season and age.The main allergens are shrimps,mites and moulds.Most of the children with positive results are sensitive to two kinds of allergens at the same time.

Distribution of allergens and its clinical significance for children with allergic rhinitis complicated by bronchial asthma in Haikou Area

Objective: Studied the effect of different antibiotic unites in different ways to children's breath hydrogen test (BHT).Methods:The HD-1 type hydrogen test instrument was used to test fasting breath hydrogen valuses of 75 children,which were given different antibiotic unites in different ways.Results:The FBH among several infect disease had not signifieient difference (P0.05),And so did the effect of the different antibiotic unites and ways given to children's FBH values(P0.05).Conclusion:Antibiotic inhibited intestines to produce hydrogon.But those effect had no close relation with types and ways given to children.

THE EFFECT OF DIFFERENT ANTIBIOTIC UNITES USED IN THREE WAYS TO CHILDREN BREATH HYDROGEN TEST(BHT)

Set wUdq(G) as the d-type weak quantum algebra and wUdi the subalgebra of rank 1.The aim is to construct the center of wUdi as well as the isomorphism theorem for wUdq(G).

Let ■ be a finite dimensional semisimple Lie algebra and the paramter q not a root of 1.This paper defines a weak quantum algebra wU_q(■),which has a weak Hopf algebra structure. The paper also constructs the set of all grouplike elements of wU_q(■).The condition of isomorphism among weak quantum algebras is investigated.

In the paper,an inequality on Bernstein polynomial in L p norm is obtained by using Hlder inequality.

Currently, FM is a sole subjective index which depends on self-assessment of pregnant women, and it can objectively reflect the well being of intrauterine fetus. It has been the focus of obstetricians' research and attention how to quantify fetal movement (FM) and change it into a relatively objective evaluation index. We sought to predict and evaluate the well being of intrauterine fetal with umbilical cord around the neck (UCAN) by performance of daily fetal movement counting chart (DFMC).
Methods

To retrospectively select 100-case pregnant women who met the enrolled requirements, and whether the fetal was intrauterine safety or not was predicted by analysis of the DFMC before delivery. According to the different perinatal outcomes after delivery, 100-cases pregnant women were divided into intrauterine safety (IUS) group (44 cases) and intrauterine unsafe (IUNS) group (56 cases). And the independent risk factors of fetal intrauterine safety, including maternal age, gestational week, umbilical artery systolic blood flow to diastolic blood flow ratio (S/D), amniotic fluid index (AFI), modified Fischer score of non stress test (NST), DFMC and mode of delivery were analyzed by multi-factors Binary Logistic Regression.
Results

Only FM and mode of delivery were independent risk factors affecting fetal safety intrauterine (all p value < 0.05). There was no remarkable difference between DFMC prediction and clinical retrospective evaluation of fetal safety in natural delivery and forceps delivery (all P value > 0.05), except in cesarean section (p < 0.05). The sensitivity, specificity and Yuden index of DFMC for predicting the intrauterine safety in natural vaginal delivery were 86.5%, 90.0% and 0.77 respectively, and in cesarean section were 66.7%, 94.6% and 0.61, respectively. Abnormal DFMC may account for the highest proportion of emergency cesarean section (87.5%, 35/40).

DFMC can effectively predict and evaluate the well being of intrauterine fetus with UCAN. At the same time, it can also provide limited clinical proofs for pregnant women with UCAN to choose model of delivery.

The prediction and assessment of the intrauterine fetal with umbilical cord around neck well-being by daily fetal movement counting chart (DFMC)

Objective Dynamic assay of serum β-human chorionic gonadotropin(β-HCG),progesterone and estradiol value,in its analysis to identify early normal intrauterine pregnancy,abortion intrauterine pregnancy and ectopic pregnancy in value.Methods One hundred and six subject of pregnant 30～35 d of the patients were divided into three groups:early normal pregnancy group of 38 cases,early intrauterine pregnancy abortion group of 33 cases,ectopic pregnancy group of 35 cases.Determination to adopt blood β-HCG,progesterone,estradiol levels,48 h with the law after the test of the three indicators.Results β-HCG,progesterone,estradiol of normal pregnancy group were significantly higher than the pregnancy abortion group and ectopic pregnancy group.β-HCG,progesterone,estradiol of pregnancy abortion group and ectopic pregnancy group in 30～35 d was no significant difference.Retest of β-HCG,progesterone,estradiol,pregnancy abortion group progesterone decreased from(14.8±9.6)μg/L to(8.7±5.8)μg/L significantly and β-HCG,estradiol was no significant difference.To β-HCG test every 48 h increased>60%positive and progesterone=20μg/L as the threshold between the two and a joint analysis of three methods to identify normal pregnancy and abnormal pregnancy(ectopic pregnancy and pregnancy abortion),there is a better sensitivity and specificity of diagnosis.In order to test β-HCG decline>50% positive and progesterone=10μg/L as the threshold between the two and a joint analysis of three methods to identify progesterone,estradiol pregnancy abortion and ectopic pregnancy,the better sensitivity and specificity of diagnosis,analysis of both the united confirmed a higher rate.Conclusion Dynamicmonitoring of serum β-HCG, progesterone, estradiol have a certain value in early identification of the normal pregnancy, ectopic pregnancy and intrauterine pregnancy abortions. 
 
Key words: 
Chorionic gonadotropin, beta subunit, human;  Progesterone;  Estradiol;  Pregnancy; Pregnancy, ectopic;  Abortion, spontaneous

Diagnostic value of serum β-human chorionic gonadotropin,progesterone and estradiol in early normal pregnancy, pregnancy abortion and ectopic pregnancy

Although silver nanowires as plasmonic components have been investigated extensively in both theoretical and experimental studies, a systematic study is still lacking. In this work, a review is given to explain some basic features of experimentally prepared nanowires and their optical properties in different situations, such as waveguides, resonators, and antennas. The review also lists several possible applications of nanowires for enhanced light‐emitting, photonic device fabrication, sensors, lasers, and nonlinear optics. Combined with the merits of both nanowires and surface plasmon polaritons, silver nanowires are certain to show their potential in photonics in the near future.

Electrolysis synthetic silver nanoparticles enhanced light emission from CdSe quantum dots

Alliance Coordination: Explaining the Logic of Biden's Taiwan Policy†

To Engage or Not to Engage? Explaining the Logic of the US’s China Strategy in the Post-Cold War Era

How do changes in US Taiwan policy play out? What is the logic behind these changes? To address these questions, existing studies have formulated four schools of explanation, providing valuable theoretical insights. However, these studies have obvious problems with unidirectional dichotomy and thus fail to identify a causal mechanism explaining the long-term trajectory of US Taiwan policy. This article conducts a re-typology of US Taiwan policy to break the traditional strategic ambiguity–clarity dichotomy by establishing three key indicators and argues that the orientation of US China policy and Taiwan’s US policy are the two major factors triggering changes. By conceptualizing and operationalizing the two independent variables as engagement-oriented, coopetition-oriented, containment-oriented, and hedging/bandwagoning/binding, this article develops a systemic theoretical framework to demonstrate how the US Taiwan policy transits between strategic clarity, maximum pressure, partial strategic clarity, between partial strategic clarity and strategic ambiguity, strategic ambiguity, and controlling the pro-independent forces. This article conducts empirical studies by reviewing the transition of US Taiwan policy under different presidencies in post–Cold War era to demonstrate how the theoretical framework works in realpolitik.

From Strategic Ambiguity to Maximum Pressure? Explaining the Logic of the US Taiwan Policy in the Post–Cold War Era

Weizhi xianshi zhuyi: yizhong waijiao zhengce lilun [Positional realism: a theory of foreign policy]

Abstract:How China responds to the United States' Indo-Pacific strategy has become a crucial question for both policymakers and academics. The existing literature primarily focuses on how and why the United States, Japan, Australia, and India have promoted the Indo-Pacific concept and how this concept has imposed strategic pressure on China's national security. However, China's changing and complex attitudes and strategic responses to the Indo-Pacific concept have largely been overlooked. This article analyzes China's response from the perspective of a hedging strategy. It argues that while confronting the expanding range of containment, which is the crux of the Indo-Pacific strategy, China has applied a hedging strategy from two interrelated perspectives. In responding to the United States, the Chinese government adheres to the nonalliance principle and upgrades its China-Russia strategic partnership to resist the security pressure produced by the Indo-Pacific strategy. In responding to peripheral countries, China has adopted a reassurance approach to create a cooperative incentive for peripheral countries, particularly those that have security relations with the United States.

Explaining China's Hedging to the United States' Indo-Pacific Strategy

Recently, China’s core national interest proposal has drawn significant attention from scholars, triggering a wide range of discussions on this interesting phenomenon. However, the existing literature remains largely limited to single-case studies and has neglected several crucial questions: What is the major difference between China’s national interest and core national interest? What factors may cause a transition from a national interest to a core interest? How can we understand this long-term transition? Based on these questions, this article constructs a neoclassical-based analytical framework to trace that transition, arguing that the major difference between these two concepts is the scope of their application. Meanwhile, the transition in China’s national interest can be categorised as “defensive national interest,” “constructive national interest,” and “adversary core interest” from the beginning of the 1980s to 2017 – with the scope expanded accordingly from the domestic and regional levels to the inter-regional one.

Rediscovering the Transition in China’s National Interest: A Neoclassical Realist Approach

Taiwan's China Dilemma: Contested Identity and Multiple Interests in Taiwan's Cross-Strait Economy Policy by Syaru Shirley Lin (review)

Since 1970, China has become the biggest cocoon producer in the world, and made the highest historical record of cocoon output for 759,800 tons in 1995. However, in 1996 cocoon production reduced sharply to 470,900 tons. After a ten-year adjustment and reform, sericultural areas have shifted from developed regions to developing regions and from the east to the west. From 2000, the cocoon output has started to increase restoringly. By 2004 it recovered to 547,091 tons. With the development of market economy, sericulture management has been changed, including mulberry fields concentrated to the specializated households and cooperatives, cocoons produced in larger scale instead of individuals, Silkworm egg producing enterprises gradually changed into non-governmental joint-stock ones. The mechanism of market cocoon price has been gradually established. The management model of combination of trade, industry and agriculture is pushing and improving. It is the fruit of modern science and technology, especially sericultural basic research, that provides China's sericulture with the opportunity and vital force. China's sericulture, therefore, will continue to develop steadily in future.

The arid regions of China including Mongolian-Xinjiang warm-temperature arid region and Qinghai-Tibet frigid arid region are located in the West of China, administerially in whole Xinjiang, nearly whole Inner Mongolia, greater parts of Tibet, Qinghai, Gansu and Ningxia, and lesser parts of Shaanxi, Shanxi, Hebei, Henan, Liaoning and Jilin, ranging from 73°40^ to 123°40^E, 28° to 50°N. There are 120 species of rodents including Lagomorpha and Rodentia. All of the species collection since 1950^s were inspected and examined, then the distribution information including collection localities, habitat, distribution height, collection time and so on were put into database. Distributional data in literatures were also collected. Based on the revised distributional information supported by a GIS technique, MapInfo Professional Version 4.0, species ranges were predicted by a wildlife-habitat model. Based on these GIS model of species range maps the distribution patterns of rodent species were studied. 766 equal-area quadrangle grids that each had an area of 6470 square kilometers were used as geographic units to collect distributional data of the species supported by MapInfo Professional Version 4.0. All the grids with the distributional data of binary attribute were divided into groups by hierarchical cluster analysis according to Euclidean distance. In order to show species richness of rodents in the groups of distributional units, we retrieved more detailed distributional information in 766 grids from GIS database. Index of Shannon-Wiener in the grid groups was calculated as the index of species diversity according to the occurrence frequency of species in grid groups. Species density of distribution types, which were classified according to the species^ preference to thermic and moisture, in the grid groups was also calculated. Results were showed as follows. The 766 distributional units could be divided into 30, 9, 5 and 3 groups, where Euclidean distance was 11.379, 17.068, 22.758 and 28.447, respectively. All the groups had their corresponding geographic areas in maps. Specially the species richness, species diversity, fauna and ecological distributional types in 9 groups were analyzed. From these 9 groups of distributional units, three obvious distributional regions could be recognized. They were ① I Aa: forest-steppe and arid steppe in piedmont of Da Hinggan Mountain, east of Inner Mongolia Plateau and the area around, I Ab: arid steppes in Ningxia Plateau, Helan Mountain, center of Inner Mongolia Plateau, Ordus Plateau and the area around, I Ba: Qinghai-Tibet Plateau not including Qilin Mountain, and Pamir Plateau, I Bb: wide temperature desert from Alxa Desert to Tarim and Jungar Basin; ② II A: east of Qilin Mountains, II B: north slope of Qilin Mountain and its piedmont plains; ③ III A: Altay Mountain and the plains of south piedmont, III Ba: Emin Valley, boundary mountains of Jungar and its piedmont plains, III Bb: Tianshan Mountain in Ili and Ili Valley. Rodent species in these regions took on the distributional patterns as follows. ① In the lower altitude of arid regions of China, with the change of landscape prairie, semi-desert to desert, so were the relative distribution patterns of groups of distributional units, where hygrophilous species declined and xerophilous species increased. ② Rodent components in frigid desert regions of Qinghai-Tibet Plateau and Parmir Plateau were closely related to those of warm-temperature and warmer-temperature desert regions with lower species diversity. ③ Rodent components in Altay Mountains and the plains in their south slope were special, having more hypothermohygrophilous species. ④ There were complex rodent fauna in Tianshan mountains and the valley in Ili, boundary mountains and its eastern plains of Jungar, north slope and east of Qilian Mountain with the characteristic of intergradations. ⑤ Rodent species richness and diversity were higher in the ecotones, taking on edge effects.

The Saker Falcon (Falco cherrug) is on Appendix II of the Chinese Red Data list. Its breeding range spreads from Heilongjiang, in Inner Mongolia, Luya Mountains of Shanxi, the great part of Gansu and Qinghai, Jinshan of Ningxia and Northern part of Xizang, Tibet (Figure l). The wintering range is located in south part of Xizhang, central part of Shanxi, north part of Shanxi, south Hebei and northwest part Sichuan (Figure 2). There are 5 major migration routes (Figure 2). There are 3 major breeding habitat types preferred by the Sakers in China: I. Alpine meadows and steppes of temperate zone, (2300-3800m.). IITaiga of the temperate zone. (1800-3800 m); III. Forest steppes of the temperate zone, (1200-2800m) (Table 1). Sakers breed from March to August: mating and nest-refurbishment in March; egg laying from March to April (recorded clutch size 3 to 5; incubation period 28 to 30 days, chick development 40 to 45). The numbers of Sakers in China according to the preliminary estimates is 64,000-102,000 individuals. Xingjiang and Qinghai are the important breeding areas. The major problems in conservation of the Sakers in China are: 1. Smuggling: (450 Saker Falcons were smuggled from Beijing port 1993 to 1997 and 239 from Xingjiang port only in the period from September to November of 1998 (Table 4)); 2. Illegal hunting and persecution; 3. Habitat degradation; 4. Lack of knowledge of Saker falcon biology. The following measures for conservation of Saker Falcon have been suggested by this paper: 1. to curb illegal trapping and smuggling; 2. to conserve habitat; 3. to raise public awareness of conservation of Saker Falcon; 4. to study basic biology of the Saker and co-operate with relevant international projects, 5. to establish a captive breeding center; 6. to establish Strict Nature reserves with the Saker Falcon as a key protected species. 1. Distribution and Migration Routes Saker Falcon (Falco cherrug) is listed in the Appendix II in People’s Republic of China (P.R. China throughout the paper). Its global distribution range spreads from the Volga in the east to the great part of west and northeast of China. Wintering areas spread from Caucasus and north part of Africa and southwest of India (Brown and Amadon, 1989). It both breeds and winters in China. It nests in most parts of Heilongjiang; Hohhot, Hulun Buir, Xinan, Xilin Gol, Bayan Gol of Inner Mongolia; central Shanxi; north and south of Gansu; Jinshan of Ningxia; Xining, Qinghai Lake, Menyuan, Yushu and Golong of Qinghai; Altay mountains, Tianshan, Kunlunshan, Pamir Plateau, Altun shan, Zunger basin of

Human bocavirus (HBoV), a recently identified pathogen with a worldwide distribution is closely related to paediatric acute respiratory infection and gastroenteritis. The present study was performed to evaluate the immunogenicity of HBoV1 and HBoV2 virus‐like particles (VLPs) as vaccine candidates in mice. Both HBoV1 and HBoV2 VLPs were expressed in the bacmid virus–SF9 cell system. Mice were inoculated three times at 3‐week intervals with HBoV VLPs at one dose intramuscular (i.m.) or intradermal (i.d.) with or without the addition of the alum adjuvant. ELISA was used to detected antibody, and ELISPOT was used to test cellular immune responses. HBoV‐specific IgG antibodies were induced and alum adjuvant improved the antibody titres and avidity, while the inoculation pathway had no influence. T helper type 1/ type 2 immune responses were balanced induced by HBoV1 VLPs but not HBoV2 VLPs. Serum IgG antibody cross‐reactivity rates of the two subtypes were similar, but cross‐reactions of HBoV1 immunization groups were higher. The single i.m. group had more interferon‐γ‐secreting splenocytes. These data indicate that HBoV VP2 VLPs have good immunogenicity with induction of strong humoral and cellular immune responses, and they may be potential candidate vaccines for HBoV infection.

Immunogenicity of recombinant human bocavirus‐1,2 VP2 gene virus‐like particles in mice

Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology

Identification of human bocaviruses in the cerebrospinal fluid of children hospitalized with encephalitis in China.

OBJECTIVE
To obtain sufficient recombinant VP2 protein of human Bocavirus and establish it's seroepidemiology assying metbord. METHORD: Tbe capsid protein VP2 DNA genes of HBoV1 and 2 were optimized in accordance with tbe usage of the favorite codons in K coil so as to enhance its protein expression in prokaryotic expressing system. The protein was purified by Ni-NTA column, and its antigenicity was determined by Western Blot. Then establish ELISA to detect the specific anti-VP2 IgG antibodies against HBoV1 and 2 in healthy children aged 3-6 years in Nanjing, China.

RESULTS
The recombinant protein 6 x His-VP2 was produced in a larger quantity at 25 degrees C induced by IPTG (1 mmol/L) over night and purified by Ni-NTA column. Seropositive rates of HBoV1 and 2 were 62.2% and 55.5% and their mixed seropositivity was 37%.

The optimizing expression of the capsid protein VP2 from human Bocavirus constructed successfully and get a high yield under certain conditions. The established ELISA could be used to further analyze seroepidemiology of HBoV in China.

Zhonghua shi yan he lin chuang bing du xue za zhi = Zhonghua shiyan he linchuang bingduxue zazhi = Chinese journal of experimental and clinical virology

[Optimizing expression of the capsid protein VP2 from human Bocavirus and establish it's seroepidemiology assying methord].

OBJECTIVE
To study the epidemiologic characteristics of viral diarrhea in children under 5 years old in Lanzhou, understand the four major virus in children of distribution.

METHODS
In the first hospital of Lanzhou university from Jul 2009 to Jun 2010,we collected 290 stool specimens from children with diarrhea and 114 asymptomatic controls. Rotavirus was detected by ELISA,further strain characterization was carried out by nested PCR. The human calicivirus, astrovirus, adenovirus were detected by RT-multiplex PCR and PCR.

RESULTS
At least one of the four viral agents was found in 60% of the specimens. Rotavirus, human calicivirus, adenovirus, and astrovirus were identified in 39.31%, 11.38%, 10.69%, and 4.83% in 290 specimens respectively. Rotavirus G3 was the most prevailing serotype, P [8] was the most common genotype. In the 114 control samples, 7 sample was positived for calicivirus, 5 samples were positived for human adenovirus and 1 sample was positived for astrovirus.

The results indicated clearly the impact of viral agents causing diarrhea and the importance of long-term systematic surveillance.

[Molecular and epidemiological study on viral diarrhea among infants in Lanzhou].

Cognition is flexible. Behaviors can change on a moment-by-moment basis. Such flexibility is thought to rely on the brain’s ability to route information through different networks of brain regions in order to support different cognitive computations. However, the mechanisms that determine which network of brain regions is engaged are unknown. To address this, we combined cortex-wide calcium imaging with high-density electrophysiological recordings in eight cortical and subcortical regions of mice. Different dimensions within the population activity of each brain region were functionally connected with different cortex-wide ‘subspace networks’ of regions. These subspace networks were multiplexed, allowing a brain region to simultaneously interact with multiple independent, yet overlapping, networks. Alignment of neural activity within a region to a specific subspace network dimension predicted how neural activity propagated between regions. Thus, changing the geometry of the neural representation within a brain region could be a mechanism to selectively engage different brain-wide networks to support cognitive flexibility.

Multiplexed Subspaces Route Neural Activity Across Brain-wide Networks

A Goldilocks theory of cognitive control: Balancing precision and efficiency with low-dimensional control states

When performing a task in a changing world, sometimes we switch between rules already learned; at other times we must learn rules anew. Often we must do both, switching between known rules while also constantly re-estimating them. Here, we show these two processes, rule switching and rule learning, rely on distinct but intertwined computations, namely fast inference and slower incremental learning. To this end, we studied how monkeys switched between three rules. Each rule was compositional, requiring the animal to discriminate one of two features of a stimulus and then respond with an associated eye movement along one of two different response axes. By modeling behavior we found the animals learned the axis of response using fast inference (rule switching) while continuously re-estimating the stimulus-response associations within an axis (rule learning). Our results shed light on the computational interactions between rule switching and rule learning, and make testable neural predictions for these interactions.

Interplay between rule learning and rule switching in a perceptual categorization task

To adapt to a changing world, we must be able to switch between rules already learned and, at other times, learn rules anew. Often we must do both at the same time, switching between known rules while also constantly re-estimating them. Here, we show these two processes, rule switching and rule learning, rely on distinct but intertwined computations, namely fast inference and slower incremental learning. To this end, we studied how monkeys switched between three rules. Each rule was compositional, requiring the animal to discriminate one of two features of a stimulus and then respond with an associated eye movement along one of two different response axes. By modeling behavior we found the animals learned the axis of response using fast inference (rule switching) while continuously re-estimating the stimulus-response associations within an axis (rule learning). Our results shed light on the computational interactions between rule switching and rule learning, and make testable neural predictions for these interactions.

Fast rule switching and slow rule updating in a perceptual categorization task

Review for "Closed-loop automated reaching apparatus (CLARA) for interrogating complex motor behaviors"

Objective. Stimulation of neural activity is an important scientific and clinical tool, causally testing hypotheses and treating neurodegenerative and neuropsychiatric diseases. However, current stimulation approaches cannot flexibly control the pattern of activity in populations of neurons. To address this, we developed a model-free, adaptive, closed-loop stimulation (ACLS) system that learns to use multi-site electrical stimulation to control the pattern of activity of a population of neurons. Approach. The ACLS system combined multi-electrode electrophysiological recordings with multi-site electrical stimulation to simultaneously record the activity of a population of 5–15 multiunit neurons and deliver spatially-patterned electrical stimulation across 4–16 sites. Using a closed-loop learning system, ACLS iteratively updated the pattern of stimulation to reduce the difference between the observed neural response and a specific target pattern of firing rates in the recorded multiunits. Main results. In silico and in vivo experiments showed ACLS learns to produce specific patterns of neural activity (in ∼15 min) and was robust to noise and drift in neural responses. In visual cortex of awake mice, ACLS learned electrical stimulation patterns that produced responses similar to the natural response evoked by visual stimuli. Similar to how repetition of a visual stimulus causes an adaptation in the neural response, the response to electrical stimulation was adapted when it was preceded by the associated visual stimulus. Significance. Our results show an ACLS system that can learn, in real-time, to generate specific patterns of neural activity. This work provides a framework for using model-free closed-loop learning to control neural activity.

Learning to control the brain through adaptive closed-loop patterned stimulation

There are still considerable breaches between purely qualitative and quantitative approaches in many working models for group dynamics in psychology and social sciences. We argue that an interdisciplinary approach may help bridge these gaps towards more integrative models. We ran a discussion group based on the Operative Group Model (OGM), using a complex systems approach to reinterpret its dynamics, and applied network theory as well as thematic discourse analysis (DA). Finally, we consider the potential advantages of performing an acoustic analysis on the audio recordings from the group sessions. To our knowledge, this integrative approach has never been applied in the context of an OGM. In this study we provide two main levels of analysis: the participant’s personal and group experience, and the experimentation and analysis methods’ aspect. For the former, we gather data from group theory in psychology, psychoanalysis, the OGM, and the participants’ feedback. We then use DA and a bipartite graph identifying weighted “thematic nodes” as a research framework. Finally we explore possible ways to incorporate an acoustic analysis, notably implementing a Hidden Markov Model (HMM). The goal is to identify appropriate interdisciplinary models to analyze human group dynamics with both quantitative and qualitative methods. We present some preliminary results from overlapping data that might pinpoint movements towards group cohesion. We then discuss further considerations on the analysis framework and future applications. Finally we consider the advantages of implementing the OGM to foster meaningful interdisciplinary dialogue in research groups, notably to overcome communication difficulties between researchers and enhance collaboration.

Rodents are emerging as increasingly popular models of visual functions. Yet, evidence that rodent visual cortex is capable of advanced visual processing, such as object recognition, is limited. Here we investigate how neurons located along the progression of extrastriate areas that, in the rat brain, run laterally to primary visual cortex, encode object information. We found a progressive functional specialization of neural responses along these areas, with: (1) a sharp reduction of the amount of low-level, energy-related visual information encoded by neuronal firing; and (2) a substantial increase in the ability of both single neurons and neuronal populations to support discrimination of visual objects under identity-preserving transformations (e.g., position and size changes). These findings strongly argue for the existence of a rat object-processing pathway, and point to the rodents as promising models to dissect the neuronal circuitry underlying transformation-tolerant recognition of visual objects. DOI: http://dx.doi.org/10.7554/eLife.22794.001

Emergence of transformation-tolerant representations of visual objects in rat lateral extrastriate cortex

Behavioral and Neuronal Substrates of Invariant Object Recognition in Rats

OBJECTIVE: 
To compare the cumulative effect of seizure control and Medial Temporal Lobe (MTL) resection on face recognition between patients with right-sided temporal lobe epilepsy (TLE) and patients with left-sided TLE.
 BACKGROUND: 
Verbal and non-verbal episodic memories are hypothesized to be mediated through left and right medial temporal lobe structures, respectively. However, controversy exists about the role of the right medial temporal lobe in visual memory and particularly in face recognition. Recognition could be in form of recollection (remembering details) or familiarity (knowing that a face is old without remembering its details).
 DESIGN/METHODS: 
Seven patients with TLE (4 with left-sided TLE and 3 with right-sided TLE) who underwent MTL resection were tested both before and after surgery to track the changes in face recognition caused by MTL resection. We introduced a novel three-step objective remember-know test enabling us to objectively assess recollection. Overall preoperative to postoperative changes were analyzed using Mann-Whitney U-test. Preoperative to postoperative changes were compared between the groups (left-sided TLE versus right-sided TLE) using wilcoxon signed-rank test.
 RESULTS: 
After surgery, seizure was controlled in all patients. False remember response rate was decreased (P-value = 0.04). Familiarity was insignificantly increased in both groups. Recollection was decreased in the right group and was increased in the left group resulting in a significant difference between two groups (wilcoxon signed-rank test P-value = 0.03)
 CONCLUSIONS: 
Decrement of false remember responses could be because of elimination of interictal discharges that have a noise effect in the recognition system. The opposite direction of change of recollection between the two groups suggests the essential role of the right medial temporal lobe in face remembering like what is suggested in material specific model.
 Study Supported by: Disclosure: Dr. Majed has nothing to disclose. Dr. Ahmadi has nothing to disclose. Dr. Ghodsi has nothing to disclose. Dr. Tafazoli has nothing to disclose. Dr. Abbassian has nothing to disclose.

Changes of Face Recognition after Medial Temporal Lobe Resection (P6.243)

Successful use of rodents as models for studying object vision crucially depends on the ability of their visual system to construct representations of visual objects that tolerate (i.e., remain relatively unchanged with respect to) the tremendous changes in object appearance produced, for instance, by size and viewpoint variation. Whether this is the case is still controversial, despite some recent demonstration of transformation-tolerant object recognition in rats. In fact, it remains unknown to what extent such a tolerant recognition has a spontaneous, perceptual basis, or, alternatively, mainly reflects learning of arbitrary associative relations among trained object appearances. In this study, we addressed this question by training rats to categorize a continuum of morph objects resulting from blending two object prototypes. The resulting psychometric curve (reporting the proportion of responses to one prototype along the morph line) served as a reference when, in a second phase of the experiment, either prototype was briefly presented as a prime, immediately before a test morph object. The resulting shift of the psychometric curve showed that recognition became biased toward the identity of the prime. Critically, this bias was observed also when the primes were transformed along a variety of dimensions (i.e., size, position, viewpoint, and their combination) that the animals had never experienced before. These results indicate that rats spontaneously perceive different views/appearances of an object as similar (i.e., as instances of the same object) and argue for the existence of neuronal substrates underlying formation of transformation-tolerant object representations in rats.

Transformation-Tolerant Object Recognition in Rats Revealed by Visual Priming

Dynamical systems theory has helped brain scientists to cope better with brain complexity. In this paper, we proposed a novel approach to include uncertainty in dynamical system describing brain function such as one neuron or coupled neurons. Fuzzy dynamical systems represented by a set of fuzzy differential inclusions (FDI) are very convenient tools for modeling and simulation of various uncertain systems. We used fuzzy differential inclusion in modeling neural responses in several types of neurons. We showed that our results are very similar to real experimental data showing variability in neural responses. Further, we have shown that FDI has advantage in comparison with modeling uncertainty in neural systems with Stochastic Differential Equations (SDEs).

2009 IEEE Symposium on Computational Intelligence in Control and Automation

Neural system that controls movement and posture is a highly nonlinear complex system. Its adaptability and easy accommodation to changes in environment and task specifications make it an ideal system. In this paper, the muscle control system from spinal cord to muscle displacement has been studied. At first, a detailed nonlinear model is simulated in Simulink based on an already developed work. Then, three system identification techniques are examined to estimate the behavior of this complex system. The first one is based on popular linear ARX model. Then, the system is modeled by NARX neural network (Nonlinear Autoregressive Network with Exogenous Inputs) which has a powerful structural network in modeling dynamical systems. Finally, a new method of modeling using combined NARX and ARX structure is proposed in which ARX gets the linear part of the system and the NARX picks up the nonlinearities. The simulation results demonstrate the superiority of the latter method with respect to other examined approaches.

Use of combined ARX - NARX model in identification of neuromuscular system

The UiO-6x family of metal-organic frameworks has been extensively studied for applications in chemical warfare agent (CWA) capture and destruction. An understanding of intrinsic transport phenomena, such as diffusion, is key to understanding experimental results and designing effective materials for CWA capture. However, the relatively large size of CWAs and their simulants makes diffusion in the small-pored pristine UiO-66 very slow and hence impractical to study directly with direct molecular simulations because of the time scales required. We used isopropanol (IPA) as a surrogate for CWAs to investigate the fundamental diffusion mechanisms of a polar molecule within pristine UiO-66. IPA can form hydrogen bonds with the μ3-OH groups bound to the metal oxide clusters in UiO-66, similar to some CWAs, and can be studied by direct molecular dynamics simulations. We report self, corrected, and transport diffusivities of IPA in pristine UiO-66 as a function of loading. Our calculations highlight the importance of the accurate modeling of the hydrogen bonding interactions on diffusivities, with about an order of magnitude decrease in diffusion coefficients when the hydrogen bonding between IPA and the μ3-OH groups is included. We found that a fraction of the IPA molecules have very low mobility during the course of a simulation, while a small fraction are highly mobile, exhibiting mean square displacements far greater than the ensemble average.

Calculation of Self, Corrected, and Transport Diffusivities of Isopropyl Alcohol in UiO-66

The present paper investigate the forging of Aluminium metal matrix composite with Silicon Carbide particles (SiCp) as reinforcements. The generic shaped preform specimens were forged under cold conditions (room temperature) using open-die sets. The Aluminium metal matrix composite material under consideration was fabricated via liquid stir casting manufacturing route, where the pre-heated Silicon Carbide particles were mixed with the molten Aluminium casting alloy. The preforms with standard dimensions were machined obtained from the cast. To analysis the deformation characteristics, two different generic shapes of the preform were considered, i.e. disc and rectangular shape preforms. The present paper presents both theoretical (based on ‘Upper Bound’ approach) and experimental investigations, where theoretical analysis considers a modified interfacial frictional law and preform free barreling. It is expected that the present work will be useful to assess various deformation characteristics during forging of metal matrix composites.

Cold forging of silicon carbide particulate (SiCp) reinforced aluminium metal matrix composite preforms

Combined effects of composite thermal energy storage and magnetic field to enhance productivity in solar desalination

Article history Received: 1 February 2020 Accepted: 23 March 2020 Published Online: 31 March 2020 Present study focuses on the carbon fiber sizing and their effect on overall mechanical properties of composites. Fiber sizing are one of the most important component in the manufacturing of composites. As the sizing are so much of importance in the manufacturing and development of composites which governs mechanical properties such as strength and stiffness. In this review some of the important articles are referred from the widely dispersed literature. This review covers the sizing effect, adhesion between fiber and matrix and characterization of composites.

Effect of fiber sizing on Mechanical properties of carbon reinforced composites: A Review

Molecular modeling of mixture adsorption in nanoporous materials can provide insight into the molecular-level details that underlie adsorptive separations. Modeling of adsorption often employs a rigid framework approximation for computational convenience. All real materials, however, have intrinsic flexibility due to thermal vibrations of their atoms. In this article, we examine quantitative predictions of the adsorption selectivity for a dilute concentration of a chemical warfare agent, sarin, from bulk mixtures with aqueous and non-aqueous (methanol, isopropyl alcohol) solvents using metal-organic frameworks (MOFs). These predictions were made in MOFs approximated as rigid and also in MOFs allowed to have intrinsic flexibility. Including framework flexibility appears to have important consequences for quantitative predictions of adsorption selectivity, particularly for sarin/water mixtures. Our observations suggest the intrinsic flexibility of MOFs can have a nontrivial impact on adsorption modeling of molecular mixtures, especially for mixtures containing polar species and molecules of different sizes.

Impact of intrinsic framework flexibility for selective adsorption of sarin in non-aqueous solvents using metal-organic frameworks.

Analysis of a Heighted Multistory Building Frame Considering Sub Base Soil Interaction Considering Lateral Forces

Systematic collection of replicate experimental data via literature meta-analysis is a powerful approach for assessing the reproducibility of physical properties data. In this paper, we use meta-an...

Experimentally Verified Alcohol Adsorption Isotherms in Nanoporous Materials from Literature Meta-Analysis

Framework flexibility is one of the most important characteristics of metal–organic frameworks (MOFs), making them highly suitable for adsorption applications. There have been a limited number of computational efforts to study flexible MOFs in the literature, and they are mostly focused on MIL-53. We studied a flexible MOF known as LMOF-201, which was found to exhibit guest-induced flexible properties; however, the mechanism of the appearance of flexibility is still unclear. First, we validated our simulation results by reproducing the experimental isotherm and powder X-ray diffraction measurements of experimental structures using grand canonical Monte Carlo (GCMC) and reactive force field (ReaxFF) molecular dynamics (MD) simulations. Then, we demonstrated the importance of the presence of a carbonyl oxygen atom in LMOF-201 to induce flexibility. The mechanism determined in this study will enable LMOF-201 to be considered for adsorption applications in the future.

Molecular simulation study on the flexibility in the interpenetrated metal–organic framework LMOF-201 using reactive force field

Significance Researchers have synthesized many different types of colloidal particles that can convert an external stimulus into propulsion capable of propelling the particles, thereby making them “active.” The availability of active particles motivates building colloidal machines with controllable behavior. In biology, proteins are colloidal-scale machines that possess controlled morphing behavior as encoded in the sequence of their amino acids; this is an example of morphological control. Inspired by this idea, we show how to build finite colloidal machines that can morph and reconfigure their structure using active particles. The information that dictates the morphing behavior is encoded in the system by chaining sequences of active particles into loops, creating a type of colloidal robot. Micron-scale robots require systems that can morph into arbitrary target configurations controlled by external agents such as heat, light, electricity, and chemical environment. Achieving this behavior using conventional approaches is challenging because the available materials at these scales are not programmable like their macroscopic counterparts. To overcome this challenge, we propose a design strategy to make a robotic machine that is both programmable and compatible with colloidal-scale physics. Our strategy uses motors in the form of active colloidal particles that constantly propel forward. We sequence these motors end-to-end in a closed chain forming a two-dimensional loop that folds under its mechanical constraints. We encode the target loop shape and its motion by regulating six design parameters, each scale-invariant and achievable at the colloidal scale. We demonstrate the plausibility of our design strategy using centimeter-scale robots called kilobots. We use Brownian dynamics simulation to explore the large design space beyond that possible with kilobots, and present an analytical theory to aid the design process. Multiple loops can also be fused together to achieve several complex shapes and robotic behaviors, demonstrated by folding a letter shape “M,” a dynamic gripper, and a dynamic pacman. The material-agnostic, scale-free, and programmable nature of our design enables building a variety of reconfigurable and autonomous robots at both colloidal scales and macroscales.

Scale-free, programmable design of morphable chain loops of kilobots and colloidal motors

Metal organic frameworks (MOFs) are promising porous materials for the adsorption of CO2. Here, we report the study of a luminescent MOF (LMOF), called LMOF-202. We have employed Grand Canonical Monte Carlo (GCMC) simulations to understand and explain the adsorption phenomena inside LMOF-202, and based on the phenomena happening at the molecular level, we have varied the metal ions in LMOF-202 to increase the CO2 affinity and selectivity of the material. We show that the CO2 adsorption capacity and selectivity can be increased by approximately 1.5 times at 1 bar and 298 K by changing the metal ion from Zn to Ba. We also report the feasibility of using this material to capture CO2 from flue gas under realistic conditions (1 bar and 298 K). This work shows that LMOF-202 merits further consideration as a carbon capture adsorbent.

Augmenting the Carbon Dioxide Uptake and Selectivity of Metal–Organic Frameworks by Metal Substitution: Molecular Simulations of LMOF-202

Materials that respond to external stimuli by expanding or contracting provide a transduction route that integrates sensing and actuation powered directly by the stimuli. This motivates us to build colloidal scale robots using these materials that can morph into arbitrary configurations. For intelligent use of global stimuli in robotic systems, computation ability needs to be incorporated within them. The challenge is to design an architecture that is compact, material agnostic, stable under stochastic forces and can employ stimuli-responsive materials. We present an architecture that computes combinatorial logic using mechanical gates that use muscle-like response - expansion and contraction - as circuit signal with additional benefits of logic circuitry being physically flexible and able to be retrofit to arbitrary robot bodies. We mathematically analyze gate geometry and discuss tuning it for the given requirements of signal dimension and magnitude. We validate the function and stability of the design at the colloidal scale using Brownian dynamics simulations. We also demonstrate the gate design using a 3D printed model. Finally, we simulate a complete robot that folds into Tetris shapes.

Muscle-inspired flexible mechanical logic architecture for colloidal robotics

Metal-organic frameworks (MOFs) have shown potential for selective capture of chemical warfare agents (CWAs). To determine characteristic adsorption times, the kinetics of CWAs uptake in MOFs must be known. Here, we calculate diffusion coefficients of the CWA sarin and simulants in prototypical MOFs using molecular simulations. Sarin can diffuse throughout a one micron crystal in less than a second in MIL-47 and Cu-BTC but this process takes more than 3 hours in ZIF-8 and UiO-66. A simple estimate based on Knudsen diffusion is able to describe diffusion of sarin in MIL-47 but fails to do so in other MOFs. This work has implications in designing devices to detect and capture CWAs.

Determining Diffusion Coefficients of Chemical Warfare Agents in Metal-Organic Frameworks.

Significance A key goal of much chemistry and materials research is the creation of new chemicals or materials. Understanding how readily the synthesis of a material can be repeated gives important insight into how a material can be adopted by a technical community or used in practical applications. Surprisingly, little is known about how often the synthesis of new materials gets repeated. In this paper, an extensive analysis of published literature for a specific class of materials, metal-organic frameworks, is used to quantitatively address this issue. Finding examples where experimental measurements have been repeated is a powerful strategy for assessing reproducibility of scientific data. Here, we collect quantitative data to assess how often synthesis of a newly reported material is repeated in the scientific literature. We present a simple power-law model for the frequency of repeat syntheses and assess the validity of this model using a specific class of materials, metal-organic frameworks (MOFs). Our data suggest that a power law describes the frequency of repeat synthesis of many MOFs but that a small number of “supermaterials” exist that have been replicated many times more than a power law would predict. Our results also hint that there are many repeat syntheses that have been performed but not reported in the literature, which suggests simple steps that could be taken to greatly increase the number of reports of replicate experiments in materials chemistry.

Analysis and experiments on the spreading dynamics of a viscoelastic drop

Molecular simulation of adsorption in nanoporous materials has become a valuable complement to experimental studies of these materials. In almost all cases, these simulations treat that adsorbing material as rigid. We use molecular simulations to examine the validity of this approximation for the adsorption in metal-organic frameworks (MOFs) that have framework flexibility without change in their unit cells due to thermal vibrations. All nanoporous materials are subject to this kind of framework flexibility. We examine the adsorption of 9 molecules (CO2, CH4, ethane, ethene, propane, propene, butane, Xe and Kr) and four molecular mixtures (CO2/CH4, ethane/ethene, propane/propene/butane, and Xe/Kr) in 100 MOFs at dilute and non-dilute adsorption conditions. Our results show that single component adsorption uptakes at non-dilute conditions are only weakly affected by framework flexibility, but adsorption selectivities at both dilute and non-dilute conditions can be significantly affected by flexibility. The most dramatic impacts of framework flexibility occur for adsorption uptake in the limit of dilute adsorption. These results suggest that the importance of including framework flexibility when attempting to make quantitative predictions of adsorption selectivity in MOFs and similar materials may have been underestimated in the past.

Effect of intrinsic flexibility on adsorption properties of metal-organic frameworks at dilute and non-dilute loadings.

Nanoporous materials such as metal–organic frameworks (MOFs) have attractive properties for selective capture of chemical warfare agents (CWAs). For obvious reasons, most research on adsorption of CWAs is performed with simulant molecules rather than real agents. This paper examines how effectively common CWA simulants mimic the adsorption properties of sarin and soman. To this end, we perform molecular simulations in the dilute adsorption limit for four simulants [dimethyl methylphosphonate (DMMP), diethyl chlorophosphate (DCP), diisopropyl fluorophosphate, and dimethyl p-nitrophenyl phosphate (DMNP)] and sarin and soman in a set of 2969 MOFs with experimentally known crystal structures. To establish the robustness of the conclusions with respect to the force field used in these simulations, each system was examined with two independent force fields, a “generic” force field and a density functional theory (DFT)-derived force field we established based on extensive dispersion-corrected DFT calculations of...

How Useful Are Common Simulants of Chemical Warfare Agents at Predicting Adsorption Behavior?

The MIL-53 class of metal-organic frameworks (MOFs) has recently generated interest as potential adsorbents for xylene mixture separations. Cost-effective separation of xylene isomers is challenging owing to the similarity in their molecular structures, kinetic diameters and boiling points. Here we report a systematic experimental and computational study of xylene isomer adsorption in MIL-53 adsorbents, focusing particularly on the effects of different metal centers, determination of separation properties with industrially relevant quaternary liquid-phase C8 aromatic feeds, and a predictive molecular simulation methodology that accounts for all relevant modes of MIL-53 framework flexibility. Significant scale-up of MIL-53 synthesis was carried out to produce high-quality materials in sufficient quantities (300-500 g each) for detailed measurements. Single-component adsorption simulations incorporating the MIL-53 ‘breathing’ and linker flexibility effects showed good agreement with experimental isotherms. ...

Liquid Phase Multicomponent Adsorption and Separation of Xylene Mixtures by Flexible MIL-53 Adsorbents

We investigate emergent behavior in binary mixtures comprised of passive particles and contact-triggered active particles (CAPs), where a propulsion force is applied on CAPs towards passive particles when the two are in contact. We show that such mixtures phase separate into distinct dense and dilute phases with as few as 10% CAPs. Furthermore, the structure of the dense phase can be tuned by varying the fraction of CAPs and the strength of their propulsion force. The dense phase is classified into seven structure types, which includes both 6-fold and 4-fold ordered crystals, and kinetically arrested gels and clusters. Mixtures with fewer than 35% CAPs exhibit traveling density waves such that one end of the dense phase recedes while the other propagates. This phenomenon results from the spontaneous symmetry breaking of particle flux at the dense-dilute interface. We show that contact-triggered activity can be employed to develop materials with a wide range of structures and dynamics.

Tunable emergent structures and traveling waves in mixtures of passive and contact-triggered-active particles.

In this paper, we present a surface potential based compact modeling of terminal charge, terminal capacitance, and drain current for III–V channel double gate field-effect transistor (DGFET) including the effect of conduction band nonparabolicity. The proposed model is developed accounting for the two-dimensional density of states and includes the effect of quantum capacitance associated with the low density of states channel material. In addition, model incorporates contribution of the first two sub-bands and efficiently captures the step like behavior appearing in the gate capacitance and transconductance with population of the higher sub-bands. The behavior of bias-dependent terminal capacitances and drain current is verified with the numerical simulation data of InGaAs channel DGFET and shows a close agreement with the simulation data.

Compact Modeling of Charge, Capacitance, and Drain Current in III–V Channel Double Gate FETs

ABSTRACT In contrast to the different approaches currently adopted for generating basic and side-split subcolumn distillation sequence for separating zeotropic multicomponent feed mixture, we present a unified graphical method applicable towards both basic and side-split subcolumn distillation sequence. For a given number of components in the feed mixture, we enforce constraints on a base graph to eliminate violations of conservation principles and to preclude distillation sequences that demand higher heat duty in all appraised practical scenarios. A compact set of algebraic constraints is transfixed using the graph counterpart for generating basic-only distillation configurations. These algebraic constraints utilize binary variables to quantify existence of submixture streams and this considerably reduces the number of variables in generating distillation sequences. We also suggest extension of the formulation to enable the exploration of thermally coupled configurations.

A unified graphical formulation for synthesis of basic and subcolumn distillation sequences

Abstract A technoeconomic evaluation has been conducted by the US Department of Energy, for four conceptual photoelectrochemical (PEC) H2 production systems namely, single-bed particle system, dual-bed particle system, PEC planar array system and PEC tracking solar concentrator system. The present work extends the analysis to capture solar energy in the vicinity of Indian oil refineries and generate H2 at estimated costs of 42, 84, 281 and 85 in ₹/kg H2 for the four systems, respectively. This includes the capital and operating costs involved if the PEC H2 production plant is set up around these refineries. Employing PEC H2 production systems obviate the CO2 generated by conventional processes like steam reforming, and thereby earning carbon credits. Inclusion of such credits is found to increase the annual earnings of the four conceptual systems by 0.7–8% depending on the selling price of H2. The sensitivity analysis of various economic factors like payback time, H2 price, carbon credit, efficiency of the system, etc., is performed which is useful in judging economics of the venture depending on the market variations in prices or rise in efficiency of the system or variable economic constraints of the investor.

Technoeconomic Analysis of Solar H2 Production in the Vicinity of Indian Refineries

This paper focuses on the designing and development of anaerobic digester for generation of methane gas from kitchen waste. It assesses, in particular, both technical and environmental implications of a waste pre-sorting that may affect the treatment process. The scope of the study encompassed material segregation, digestion of kitchen waste, final disposal of waste. The study showed that material recycling leads to an improvement of the working conditions with respect to digestion. The study also demonstrated that digestion approach is a useful tool for the study of technical and environmental aspects of an energy system.

Topology optimization of structures sometimes gives designs that cannot be economically manufactured without postprocessing. Because post-processing of topology solutions might lead to suboptimal designs, it is useful to include manufacturing constraints at the outset. In this work, we present a method for the topology optimization of micromachined devices by including surface micromachining constraints. Instead of explicitly including manufacturing constraints, we propose a novel design parameterization that implicitly restricts the design space so that it consists of only the manufacturable designs for a chosen surface-micromachining foundry process. In surface-micromachining, the photolithographic masks determine the geometry of surface-micromachined structures. Therefore, we use the masks themselves as the design variables in topology optimization. By using the continuous mask opacities as the design variables, we developed a virtual material movement model (VMMM) in which the material from a layer deposited on top of a putatively porous layer will move down. Consequently, the virtual density of material in the design domain changes depending on the opacity values of the masks in different cells. This virtual density is similar to the fictitious density assumed in Simple Isotropic Material with Penalty (SIMP) and other material interpolation techniques. The difference is that the opacity values of the masks are design variables here whereas the densities of the cells themselves are design variables in SIMP. In this manner, surface-micromachining constraints are implicitly satisfied in this design parameterization. An optimality criteria method aided by sensitivity analysis is implemented in Comsol MultiPhysics platform. Micromachined foundry processes such as MUMPs and SUMMiT are considered in the examples presented to demonstrate the efficacy of the method. An added benefit of the new method is that lithography mask layouts are readily generated in addition to manufacturable optimal topologies. Several examples are solved and discussed to show how the optimal manufacturable solutions compare with non-manufacturable ones.

On Including Manufacturing Constraints in the Topology Optimization of Surface-Micromachined Structures

ETC~4 Abstract—As imaging and photonics technology is advancing to smaller and complex devices there is increasing interest in applications that make use of small micro-level optical elements such as micro-lenses. Micro-lens fabrication is useful in developing diffractive optical elements (DOE’s) that are used in optical communication, optical storage, optical interconnection, optical information processing and micro-optical sensors. Another area where micro-lens fabrication can be used is in characterization and optimization of illuminating sources of lithographic projection systems. The objective of this project was to fabricate eight level micro-lenses on a 5”XS” quartz substrate designed for the 193nm exposing wavelength. A micro-lens is fabricated as a Fresnel Zone Target (FZT) pattern which can be used to characterize and optimize the illuminating source of a lithographic projection system. Developing a fabrication procedure for eight level micro-lenses will be helpful for further research work in manufacturing micro-optical elements at Rochester Institute of Technology’s Semiconductor and Microsystems Fabrication Laboratory.

This aim of this study was to detect the seropositivity rate (SPR) for HIV infection in hospitalized children in Mumbai India and to assess the usefulness of screening in the detection of HIV cases. The data were prospectively collected from 1992-94 and from 1997-98 and from information obtained in a review of records from 1995-96. Subjects included children hospitalized in pediatric wards and who had a history of high-risk exposure and/or whose clinical features picture symptomatic HIV infections. A total of 821 children were screened using the enzyme-linked immunosorbent assays (ELISA) test and were later subjected to second ELISA or a rapid test. 124 were found to be sero-positive with SPR among hospitalized cases increasing from 0.21% in 1992 to 1.49% in 1998. Overall the study showed that there is a rising SPR among hospitalized children probably as a result of significant increase in seroprevalence among antenatal mothers. However this rise may also be due to more liberal screening ordered by clinicians in the wake of increased awareness and the availability of diagnostic facilities.

Seropositivity rate for HIV infection in hospitalized children on selective screening.

Health status of school girls from affluent population of Mumbai.

Congenital mesangioproliferative nephrotic syndrome associated with cytomegalovirus infection.

A retrospective analysis of 254 newborns having blood cultures positive for coagulase negative staphylococci (CONS), and admitted in the neonatal unit of a Rural Medical College Hospital over a period of five years, was done for various clinical and perinatal characteristics as well as antimicrobial sensitivity profile of isolates. Of them, 118 (46.5%) neonates had clinical evidence of sepsis with CONS as the only growth in blood culture, and were designated as having CONS septicemia. Majority of them were delivered in this hospital itself and by normal vaginal delivery. Preterms and LBW babies constituted 23.7 and 59.4% of total cases, respectively. Other high risk perinatal factors for infection were present in 66.1% cases. Approximately two third of these cases developed sepsis within first three days of life. Early onset sepsis was more frequently seen in neonates with history of assisted delivery or perinatal asphyxia. Overall mortality in these cases was 15.6%, being significantly higher in offspring of outside deliveries and normal vaginal deliveries, in preterm and LBW babies and slightly higher in presence of birth asphyxia. Only 15.3% CONS isolates were resistant to all routinely used antibiotics and sensitivity was maximum with gentamicin followed by ampicillin. A difference in sensitivity pattern of CONS causing EOS and LOS was also recorded.

Thirty eight cases of childhood hysteria admitted to a rural medical college hospital, were studied for epidemiological characteristics, clinical presentation, precipitating factors and psychosocial environment and behaviour. Hysteria was commonly seen during adolescence (73.2%) and in males (63.2%). It was more common in the lower socio-economic status (60.5%) and in children for nuclear (94.7%) and large size families (81.6%). Eldest or youngest siblings of the families were found to be more prone to develop hysteria. Motor symptoms were most frequently observed (71.1%) and 55.3% cases had more than one symptom at the time of presentation. In a majority of cases hysteria was acute in onset. Precipitating psychological event was identified in 81.6% cases; scolding (26.3%) being the commonest followed by school avoidance (13.2%), examination fear (10.5%) and quarrel with peers (10.5%). Past history of 52.6% of patients of hysteria and 18.4% of their parents revealed subtle behavioural abnormalities. All patients improved with psychotherapy and modification of the psychosocial environment.

All blood culture reports obtained from newborns admitted in a neonatal care unit during 1983-87 were reviewed to determine the current bacteriological profile of neonatal septicemia. A total of 1160 neonates of high risk category or having clinical features suggestive of septicemia were subjected to blood culture study during this period. The culture positivity rate was 73%. Of these, 24.9% cultures were polymicrobial. Among the 1059, growths obtained, 60.1% were Gram negative, with Klebsiella, E. coli and Pseudomonas as the commonest pathogens. In Gram positive group, coagulase negative Staphylococci were most frequent, constituting 24% of the total isolates. An increasing incidence of coagulase positive Staphylococci and Pseudomonas infections was observed in recent years. Another significant finding was a comparatively high prevalence of Group D beta hemolytic isolates among streptococcal growths, with S. fecalis as the single commonest streptococci isolate.

Analysis of blood-culture isolates from neonates of a rural hospital.

Implantation of autologous splenic tissue after splenectomy for trauma

A serious uro-obstetric emergency is the concurrent rupture of the uterine and urine bladder following a protracted difficult delivery. In the absence of circumstances that would make the bladder more likely to cling to the lower uterine segment, the involvement of the urinary bladder in a primigravida is unique and relatively infrequent. We discuss a case of a 21-year-old patient who had an obstructed labor complicated with bladder and vaginal injury. At laparotomy, we found a pubic bone diastasis, a vaginal injury, and a bladder injury at the urethrovesical junction. As a result, bladder neck repair with urethrovesical anastomosis and vaginal repair with an external fixator were carried out for pubic bone diastasis.

Concomitant Vaginal Laceration and Urinary Bladder Injury With Pubic Diastasis: A Case Report on a Rare Complication During Obstructed Labor

Ileal neobladder adenocarcinoma occurring 25 years post ileocystoplasty: a case report

External Validation of Briganti and Memorial Sloan-Kettering Cancer Centre Nomograms for Predicting Lymph Node Invasion in the Indian Cohort of Patients with Prostate Cancer

Introduction ureteral stents are used in managing various urological conditions. When these stents are left indwelling for a prolonged time, it results in complications like stent migration, fragmentation, and encrustation. The aim of this retrospective observational study is to analyse the incidence, risk factors, and morbidity associated with retained ureteral stents. Methods the retained/forgotten ureteral stents were defined as the stents with an indwelling period of more than six months. The records of all such patients from January 2010 to January 2020 were retrospectively reviewed. The primary reason for the placement of a stent, total indwelling time, the reason for prolonged indwelling time, and part(s) of the stent encrusted were retrospectively reviewed. Single/multistage endourological procedures were used to make the patients remove the retained stents and stone free. The type, number of procedures, and total number of sessions needed were noted. Results data of 114 patients was reviewed retrospectively. Most patients presented with abdominal pain (62 patients, 54.4%), and dysuria (41 patients, 35.1%). An average of 1.7 sessions (range 1-4) were needed to make the patients’ stent and stone free. During these sessions, single/multiple procedures (endoscopic/open/combined) were performed. Nine patients (7.9%) had permanent loss of renal unit function and who needed a nephrectomy. Poor compliance (45.6%), unawareness (35.1%), and misconception that the stent would last a lifetime (12.3%), were the most common reasons for retained ureteral stents. The incidence rate of retained stents fell from 1.1% to 0.5% after the “three steps” prevention check method was in-cooperated to ensure timely follow-up of the patients. Conclusion retained ureteral stents are a significant source of morbidity, which is avoidable by ensuring timely removal. Sincere efforts should be made to make patients aware of an indwelling foreign body. Prevention is the best strategy.

Retained ureteral stents, an avoidable source of morbidity: 10 years´ experience from a single tertiary care centre

Outcome of spongioplasty alone as second layer of tubularised incised plate urethroplasty in patients with hypospadias

OBJECTIVE
In this study, we aimed to assess the results of tunica vaginalis flap (TVF), dorsal preputial dartos flap (DPF), and spongioplasty alone as additional cover after neourethra formation in a Snodgrass repair for various types of hypospadias as per the selection criteria decided.

This was a non-randomized experimental study of 97 patients with primary hypospadias treated via Snodgrass repair using various second layers (tunica vaginalis flap, dorsal preputial dartos flap, and spongiosum alone) as per the selection criteria in a single center by a single surgeon. The outcome of the procedure was assessed in terms of cosmesis, chordee correction, urinary stream, and uroflowmetry.

RESULTS
Of the 97 patients, we used dorsal preputial dartos flap in 42 (43.3%), tunica vaginalis in 38 (39.2%), and spongioplasty only in 17 (17.5%) for primary hypospadias. Urethrocutaneous fistula developed in four patients (three in DPF and one in the TVF groups). One patient each had skin necrosis, hematoma, and wound dehiscence in the DPF group. In the spongioplasty only group, one patient had meatal stenosis which was treated by meatoplasty after failing repeated periodic calibration.

DPF should be preferably used for distal penile and TVF for mid and proximal penile hypospadias to ensure excellent result with minimum complications. Spongioplasty only as a second layer is sufficient to avoid the complications wherever it is thick and robust.

Choosing an ideal second layer cover in snodgrass repair for various types of hypospadias.

Background: Persistent mullerian duct syndrome (PMDS) is a very rare form of internal male pseudohermaphroditism in individuals who are phenotypically males with 46 XY karyotypes harboring internal female reproductive organs which are Mullerian derivatives. It occurs as a defect in the genes coding for the Mullerian inhibiting substance (MIS) or the anti Mullerian hormone (AMH) receptor, ultimately leading to failure of regression of Mullerian ducts. Case Presentation: A 29-year-old male with PMDS presented with complaints of primary infertility. Diagnosis was made with the help of high index of suspicion, radiological imaging, and karyotyping. Our patient underwent exploratory laparotomy with hysterectomy and bilateral orchidopexy. Conclusion: The purpose of this study was increasing awareness regarding rare entities and surgeons should have high clinical suspicion of PMDS when patient with bilateral undescended testis comes for the evaluation of primary infertility.

Persistent Mullerian Duct Syndrome: A Rare Case of an Adult Infertile Male with Bilateral Cryptorchidism

Traumatic dislocation of testis (TDT) is an uncommon event. During trauma, the cremasteric reflex can forcefully retract the testis out of the scrotal sac saving the testis from the injury. However, associated injuries in the form of skin degloving, penile avulsion, and amputation can be present. Early surgical intervention to locate and deposit the displaced testis to the scrotal sac is essential. We present a case of a 33-year-old man with bilateral congenital cryptorchidism who suffered blunt trauma to his genitalia following a road traffic injury. On presentation, based on a well-developed scrotum, it looked like a case of TDT. However, good history along with detailed physical and radiological evaluation helped us reach the correct diagnosis. TDT must be suspected in a case of blunt trauma to the genitalia when the scrotal sac (well-developed) is empty. This case report highlights the importance of detailed clinical and radiological evaluation in such cases.

Congenital Cryptorchidism Masquerading as Traumatic Dislocation of Testis

Supra-pubic catheterization of bladder is used as a short or long term alternative to per-urethtral catheterization.
Some catheter materials are more resistant to encrustation than others. If kept indwelling for longer duration, sooner or later all catheters cause complications like urinary tract infection (UTI), trauma, peri-catheter leakage, non-deflation of balloon, encrustations and stone formations resulting into retained catheter.
Stone formation over neglected indwelling catheter is not an unusual clinical scenario and its management depends on etiology of catheter retention and complication.
This article discusses etiopathogenesis, clinical presentations, diagnosis and varied management options used for the neglected retained supra-pubic catheter in three cases

Neglected Retained Suprapubic Catheter with Varied Management Options: A Case Series

Two cases of penile strangulation: varied presentations and vastly different outcomes

Vesical stone formation is very rare in posttransplant recipients. We describe a patient who developed hanging vesical stone more than 10 years after receiving a transplant near the ureteroneocystostomy site on polypropylene suture, treated by cystolithotripsy using the removal of suture material with cystoscopic scissors. The use of nonabsorbable suture leads to very late formation of stones over it. Hence, it should be avoided.

Hanging vesical stone in post-transplant recipient – delayed and unusual complication

Background: During pandemic of coronavirus disease 2019 (COVID-19), there is a need for prioritization of the patients. Suspension of elective procedures avoids the load on already burdened medical facilities. Our aim was to highlight the pattern of urological procedures during the pandemic, preventive protocol used, and challenges faced in their management.Methods: This was a retrospective observational study of 152 patients who underwent urological procedures between March 22 and June 30, 2020, at a tertiary care centre. Outpatient department (OPD) consultation and elective urological procedures were suspended. Only emergency, semi-emergency, and OPD room procedures were performed. Procedures were classified into four categories i.e. emergency, semi-emergency, OPD room, and elective procedures. Patient demographics and operative details were assessed. Descriptive statistics were applied.Results: A total of 152 patients were included in the study. Majority of the patients were our follow up (70.4%) and rest were new patients (29.6%). Out of the total procedures done, 67.1% were emergency or semi-emergency and 32.9% were OPD room procedures. Local anaesthesia was the most used anaesthesia (69.1%). COVID-19 swab testing was done only for the inpatients (41) of which eight patients were tested positive. In the end, none of the health care workers had symptoms of COVID-19.Conclusions: The pattern of surgeries shows that most of the urological procedures performed during COVID-19 pandemic were for either emergency or semi-emergency urological conditions. Obstructive uropathy is one of the commonest indications for the urological procedures performed during this pandemic.

The pattern, management, and preventive protocols used for urological procedures during the pandemic of COVID-19: an experience of a tertiary care centre

A neonate with ‘amphibian heart’: A rare combination of complex congenital heart diseases

A 72-year-old male with diabetes presented to the emergency department with complaints of abdominal pain and an inability to pass urine. The patient had been managed with a condom catheter for the past 2 weeks, which had been applied by staff at another hospital, for his urinary problems (severe storage symptoms with urinary incontinence). On examination, the condom catheter was secured at the base of the penis with the aid of elastic adhesive tape. On removing the condom, a ring-shaped circumferential skin erosion at the base of the penis with gangrene of the distal penile shaft was found. A clear line of demarcation was visible between the normal and gangrenous areas. (Figure 1). The scrotum and bilateral testes were normal. On suprapubic examination, the bladder was palpable.

Penile gangrene: A rare but disastrous complication of the improper application of condom catheters

Foreign bodies in the lower urinary tract are rare with self-infliction for sexual gratification as the commonest reason. Presenting complaints are lower urinary tract symptoms, abdominal pain, and haematuria. We report two cases of self-inflicted foreign bodies in the lower urinary tract of adult male patients; one by an electrical wire and another by Bengal grams. Bengal gram as the foreign body has never been reported previously. X-ray, ultrasound, and computed tomography of the KUB region help to confirm the diagnosis. The primary goals of treatment are safe removal of foreign bodies, avoiding iatrogenic injuries to the lower urinary tract, and preservation of the sexual function. Endoscopic management is the commonest procedure performed and described in such cases. We were able to manage both cases endoscopically. Psychiatric consultation and appropriate counselling should be given to prevent further repetitions of such acts in the future.

Self-inflicted urethral and vesical foreign bodies – Case report

To the Editor, We read with great interest the CLI-OPCI substudy by Romagnoli et al. on the relationship between acute stent malapposition (ASM) by optical coherence tomography (OCT) and clinical outcomes [1]. The authors found that the severity of ASM, either measured as distance between strut and vessel wall or length of strut malapposition, was not related to long-term adverse events [major adverse cardiac events (MACE)] which included the combination of death, target vessel-MI (either periprocedural or long-term), and target lesion revascularization. These data add to other studies which have not shown a relationship between ASM and long-term outcomes. We have recently presented an OCT-based classification system of ASM (Table 1) based on adequacy of stent implantation and vessel anatomy [2]. We found, as in the study by Romagnoli et al, that ASM is frequent, occurring in 74.5% of all angiographically optimized stents, very similar to the current study wherein 72.3% of stents showed ASM. Of the five classes of ASM in our study, the most frequent cause of ASM was localized vessel enlargement, i.e. the stent deployment was adequate but the vessel had some degree of positive remodeling. With this ASM cause there was relatively small strut-to-wall malapposition distance and ASM vessel length. On the other hand, stent undersizing, defined as the nominal stent diameter being smaller than the proximal reference diameter and the proximal stent segment being malapposed, showed the greatest strut distance from the wall and length of strut malapposition. We have hypothesized that differences in outcome studies evaluating the relationship of ASM on long-term outcomes may be explained by different causes of ASM as reflected in our classification system. Our question to the authors is that if they limited their analysis of ASM to stent undersizing only, would there be a relationship between ASM and MACE? We understand that this analysis was not part of their original study but do believe that such an analysis would be edifying and might help to explain the heterogeneity in long-term outcomes previously reported. We thank the authors for an important contribution in understanding the significance of ASM to long-term outcomes and appreciate their consideration of our request.

Association of acute stent strut malapposition on long‐term outcomes

Patients who present with both severe mitral and tricuspid regurgitation who are symptomatic despite optimal medical therapy and at prohibitive risk for surgery pose a significant therapeutic challenge. The MitraClip device (Abbott Vascular) is approved for percutaneous mitral valve repair in high-risk and non-operative patients, and has also been used for tricuspid valve repair. Imaging support for percutaneous edge-to-edge tricuspid valve repair has not been reported and is a vital part of the procedure. Here, we present a periprocedural imaging strategy for percutaneous tricuspid valve repair with the MitraClip device using a bicuspidization technique.

Percutaneous Tricuspid Valve Regurgitation Repair With the MitraClip Device Using an Edge-to-Edge Bicuspidization Technique.

To elucidate causes and extent of strut malapposition in angiographically optimized stenting.

Classification of mechanisms of strut malapposition after angiographically optimized stent implantation: An optical coherence tomography study

Given its high resolution, optical coherence tomography (OCT) may be a useful clinical tool to optimize stent deployment.

METHODS
We reviewed 100 patients with post-PCI OCT who had angiographically optimized coronary stent implantation to determine the frequency of further intervention based on OCT pathology. OCT pathology was classified as "significant" if an OCT finding prompted further intervention.

RESULTS
OCT pathology was found in 90% of patients and considered significant in 52%. Stent strut malapposition by OCT was the most common reason for prompting further treatment, with approximately one-half due to relative stent undersizing. Based on OCT findings, 42% underwent balloon dilation, 9% underwent another stent implantation, and 3% underwent treatment with a glycoprotein IIb/IIIa inhibitor. Minor plaque protrusion was present in 11%, which prompted no further intervention.

Post-PCI OCT in angiographically optimized vessels was helpful in improving stent deployment in more than one-half of the cases. Our findings suggest that post-PCI OCT may be a clinically useful tool in angiographically optimized stenting. Prospective studies will provide further clarity on the place of OCT in this setting.

Utility of Frequency Domain Optical Coherence Tomographic Evaluation of Angiographically Optimized Stented Lesions.

We read with great interest the article by Nordanstig et al.1 This randomized trial compared percutaneous and surgical revascularization with structured unsupervised exercise for claudication pain and peripheral artery disease. We commend the authors on their work. However, we believe the following issues should be clarified:

1. Comparison of percutaneous and surgical revascularization with unsupervised structured exercise program is of concern. The 2013 American Heart Association/American College of Cardiology guideline update states that the usefulness of unsupervised exercise programs is not well established as an effective initial treatment modality for intermittent claudication (class IIb), whereas supervised exercise training has a class I recommendation.2 …

Letter by Nairooz et al Regarding Article, "Improved Quality of Life After 1 Year With an Invasive Versus a Noninvasive Treatment Strategy in Claudicants: One-Year Results of the Invasive Revascularization or Not in Intermittent Claudication (IRONIC) Trial".

1Post Graduate Student,Department of Public Health Dentistry, Rajasthan Dental College & Hospital, Jaipur, Rajasthan, India 2Post Graduate Student,Department of Public Health Dentistry, Teerthanker Mahaveer Dental College and Research Centre, Moradabad, Uttar Pradesh, India 3Senior Lecturer,Department of Public Health Dentistry, Rajasthan Dental College & Hospital, Jaipur, Rajasthan, India 4Professor and Head, Department of Public Health Dentistry, Rajasthan Dental College & Hospital, Jaipur, Rajasthan, India 5Lecturer,Department of Conservative Dentistry and Endodontics, Rajasthan Dental College & Hospital, Jaipur, Rajasthan, India

Role of tamsulosin, tadalafil, and silodosin as the medical expulsive therapy in lower ureteric stone: a randomized trial (a pilot study).

Measure Twice, Close Once: Effect of Volume Loading on Left Atrial Appendage Closure.

Occupational Exposures to Blood among Dentists in Jaipur District

Oral Health Related Knowledge, Attitude and Practice Among Bus Conductors and Drivers in Jaipur District

Despite the fact that numerous researches have been carried out to prevent head and neck cancer (HNC) and treat those patients, there is no reduction in morbidity rate because the underlying molecular pathogenesis is still poorly understood. Endocrine microenvironment is another vital factor besides other traditional risk factors like tobacco smoking, infections, and alcohol. It has been proven that sex hormone receptors are also expressed in larynx and lungs, in addition to sex organs. Sex hormones play a vital role in gene expression involved in the plethora of biological and neoplastic processes. The role of sex hormones in HNC is still divisive and very few researches have been conducted to describe their role. So, this article is an effort to attract the attention of researchers, endocrinologists, pathologists, and clinicians toward the impending role of sex hormones, with special emphasis on progesterone, estrogen, and prolactin in HNC onset and progression, along with their therapeutic role.

Journal of International Society of Preventive & Community Dentistry

Sex hormones in gender-specific risk for head and neck cancer: A review

We appreciate the authors’ interest in our study and their agreement that the phenomenon we have described has importance in clinical management. A primary issue raised by the authors is whether the change in the fractional flow reserve (FFR) of the donor artery before and after successful percutaneous coronary intervention (PCI) of a chronic total occlusion (CTO) may be related to inherent variability of the FFR measurement at two different time points. Previous studies suggest that during a single procedure, there is high reproducibility of the FFR at different time points [1]. We suggest that changes in FFR are explained by other factors. FFR change after successful CTO PCI depends in part on the amount of viable myocardium in the area supplied by the CTO, the degree of preexisting microvascular dysfunction both in the CTO and donor artery territory, the resistance of the collateral vessels, and the donor lesion characteristics [2]. Based on differences in these factors, there might be expected differences in FFR after CTO PCI as illustrated in Fig. 1. The authors comment on the absence of any relation and claim the impact of a singular patient, but looking at the nicely plotted figure by the authors, there is again a singular patient that affects the correlation (patient with pre-procedural FFR of 0.76 and even a drop in post-procedure to 0.70 FFR. In an observational study based on small numbers, these individual outliers are an issue. Our report was not about a straight correlation, as this is not determined by FFR alone, but about the clinical caution required in assessing FFR without taking into account the role of collateral donor function. A second suggestion by the authors is that measuring donor vessel FFR after CTO PCI is a “luxury.” We cannot agree. Use of FFR for evaluation of an intermediate lesion is a class I indication in the European PCI guidelines and a class IIa recommendation in the American Fig. 1. A: CTO collateralized through a diffusely diseased donor artery with 50% angiographic stenosis. FFR is ischemic range in the donor artery. B: After successful recanalization of the CTO, there is only a slight increase in FFR because of diffuse disease in the artery with a superimposed focal narrowing. C: An identical angiographic situation exists in Panel C with an identical ischemic FFR value. D: After successful recanalization there is change in FFR to non-ischemic range because of less severe disease burden in the donor artery. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Rebuttal: Change in donor artery fractional flow reserve after recanalization of a chronic total occlusion—not as impressive as some might have us believe

WHAT ARE THE MECHANISMS OF STENT MALAPPOSITION? COMPREHENSIVE FREQUENCY DOMAIN OPTICAL COHERENCE TOMOGRAPHIC EVALUATION

Well‐developed collaterals to a myocardial segment supplied by a chronic total occlusion (CTO) and/or left ventricular dysfunction in the CTO regions in patients with chronic stable angina suggest that severe ischemia is unlikely to be present. We evaluated the presence and severity of ischemia using fractional flow reserve (FFR) of the myocardium supplied by a CTO in patients and compared the results with a non‐CTO control group.

The myocardium supplied by a chronic total occlusion is a persistently ischemic zone

Mucocele is a benign lesion characterized by an extravasation or retention of mucous in submucosal tissue from minor salivary glands. Mucoceles are known to occur most commonly on the lower lip, followed by the floor of mouth and buccal mucosa being the next most frequent sites. Trauma and lip biting habits are the main cause for these types of lesions. Mucocele is a common oral mucosal lesion but it is rarely observed in the infant. This paper highlights the successful management of a rare case of mucocele in an 11-month-old child. Diagnosis and management of mucocele are challenging. For this reason we felt it would be interesting to review the clinical characteristics, histological features, differential diagnosis, and their treatment and evolution in order to aid decision-making in daily clinical practice.

An Unusual Presentation of Oral Mucocele in Infant and Its Review

Today, herbal medicine is becoming more and more popular as a safe and effective means of treatment for many different medical conditions. Herbs are often preferred because they are natural and do not put harmful chemicals into the body. Herbs are available fresh, as capsules, powders, extracts, roots, etc.

Objective: To report a case of an adolescent with autism with clinically significant hypersexual behaviors in whom a trial of low-dose propranolol led to major clinical improvement. Case Summary: This case report describes a 13-year-old boy with a history of autism who presented to the outpatient psychiatric clinic for hypersexual behaviors that started at the onset of puberty. The behaviors affected his functioning both at school and home. A trial of low-dose propranolol, 0.3 mg/kg/d (10 mg twice a day), targeting hypersexual behavior led to remarkable clinical improvement. The behaviors remained stable on this dose of propranolol for 1 year. Discussion: Hypersexual behavior exhibited by adolescent patients with autism can be a big challenge to manage. The literature on pharmacological options to manage these behaviors in children and adolescents with autism is limited. Clinical data of propranolol use are novel. Conclusion: To our knowledge, this is the first case report of low-dose propranolol leading to clinically significant improvement in hypersexual behaviors in an adolescent with autism. Propranolol use may expand the choice of treatment option in this patient population.

Use of Propranolol for Hypersexual Behavior in an Adolescent With Autism

Today, herbal medicine is becoming more and more popular as a safe and effective means of treatment for many different medical conditions. Herbs are often preferred because they are natural and do not put harmful chemicals into the body. Herbs are available fresh, as capsules, powders, extracts, roots, etc. Some people prefer to grow their own. Always seek advice from an expert before taking herbs as a supplement or as a health remedy. Traditional healers have long used botanicals to prevent or cure infectious diseases (Dhinahar S 2011). Cloves are the aromatic dried flower buds of a tree in the family Myrtaceae, Syzygium aromaticum. Cloves are native to the Maluku islands in Indonesia and used as a spice in cuisines all over the world. Cloves are harvested primarily in Indonesia, India, Madagascar,

Introduction: Prevalence of refractive errors among students pursuing higher studies is very high. Very little data about the prevalence of refractive errors among dental students in India is available. The present study intends to throw light on the above perspective. Objectives: Cross-sectional study to determine the prevalence of refractive errors among dental students in a College and Hospital. Materials and Methods: All the students in the college were selected for the study to evaluation the refractive errors among the students. The study was carried on over a period of 30 days. All students were assessed for refractive errors using auto-refractometer (TOPCON RM-8000B, TOPCON Corporation, Tokyo, Japan). Refractive errors were further categorized according to the Diopteric power. Results: Refractive errors were found in 280 (64.81%) dental students out of which 76(27.14%) were male students and 204 (72.85%) were female students. Myopia, 197 (70.4%) was the commonest type of refractive error. According to the categorization of refractive errors in terms of diopter (D) 1-2.99D was more common. Conclusion: From the present study the significance of prevalence of refractive errors among dental medical students is very much highlighted.

s Journal of Clinical Urology 2014: 7(2) 135–142 at SAGE Publications on June 21, 2016 uro.sagepub.com Downloaded from 136 Free Paper Presentations 7(2) Journal of Clinical Urology 2014: 7(2) 135–142 uro.sagepub.com 3. The “live surgical broadcast” from the delegates’ perspective. Is there a better way? WJG Finch, J Masood, N Buchholz, B Turney, RD Smith,

BAUS Section of Endourology Annual Meeting 20-21 March 2014, Queen's College, Cambridge, UK

Introduction: Professional college students should be more aware of their health. The simple concept of oral hygiene should be understood and put into practice by them. Objectives: To assess the dentition status and treatment needs of engineering students in Lucknow city. Materials and Methods: A total of 500 subjects were included in the study. The subjects were selected from four Engineering colleges randomly selected from all parts of the city. Data were collected by using oral health assessment form by WHO (1997). The proforma included questions on oral hygiene practices, dentition status and treatment needs. Statistical analysis was performed using Statistical Package for Social Sciences version 15.0. Results: Among the total subjects, 56% of the subjects were males and 44% were females in the study. Decayed teeth were found among 52.8% of the subjects in the present study. However, frequency of filled teeth (4%), missing (4.8%), bridge abutment (0.4%) and trauma (5.2%) was small. One surface filling was required among 26.4% of the subjects, 2 or more surface filling was required among 8%, crown for 5.2%, pulp care was 6.4% and extraction was required in 4.4% of the subjects. The decayed, missing, and filled teeth score among male subjects was 1.02 ± 1.20 and females 0.82 ± 0.94. Conclusion: The dental caries among the engineering students was found to be high and were more in males when compared to the females.

Dentition status and treatment needs of engineering students in Lucknow city

The most common cause of fluorosis in India is fluoride laden water derived from bore wells dug deep into earth. High fluoride concentration in groundwater is a major public health problem in India. To present the data on the prevalence and severity of dental fluorosis in adult population of Jaipur district, Rajasthan, India, and also its relationship with source of drinking water. A total of 477 subjects from Jaipur district, aged 18 to 40 years of age were examined using type III examination. The modified WHO 1997 assessment form was used to examine each subject in a dental college setting. Dental fluorosis was present in 89.0% (425 subjects). Questionable and very mild level of fluorosis was found among 34(7.1%) and 54(11.3%) patients respectively. Maximum number of patients 146 (30.6%) presented with mild level of fluorosis and 136 (28.5%) had moderate level of fluorosis. In the study sample 55 (11.5%) patients had severe fluorosis. There is a high prevalence of mild-to-moderate fluorosis in Jaipur district. The prevalence of dental fluorosis can be attributed to the level of fluoride in the drinking water.

Prevalence and severity of dental fluorosis among patients visiting a dental college in Jaipur, Rajasthan

Pain is a comorbid and aggravating symptom that in many conditions can be perceived differently and should therefore be managed accordingly. Numerous factors, both social and cultural, are thought to influence the analgesic prescription. However, elucidation of such areas is limited. We therefore conducted a systematic literature review to test the hypothesis that variations in provider characteristics predict the prescription of pain medication.

Identification of Provider Characteristics Influencing Prescription of Analgesics: A Systematic Literature Review

We appreciate the interest in our article by Dr Fan and colleagues regarding the first descriptive series of the effect of fractional flow reserve (FFR) change in a donor artery supplying collaterals to a chronic total occlusion (CTO) after it has been successfully revascularized [1]. In a cohort of 50 CTO patients undergoing successful PCI, this phenomenon was seen in 6 out of 14 patients (42%) with intermediate donor artery stenosis. Our data add support to previous case reports that the phenomenon of FFR reversal from [2–4] ischemic to non-ischemic may occur. We agree that the sample size in our study is relatively small but is the first series to describe the phenomenon and demonstrates that it is not unusual. From the physician and patient perspective, the major question is in patients with ischemic range FFR in donor artery with an intermediate stenosis and a CTO. Do these patients need to have revascularization in the intermediate stenosis as well as the CTO, only the intermediate donor stenosis, or only the CTO? In the DEFER trial [5], the intermediate stenosis with nonischemic FFR had a very low event rate (3%) at 5 years of follow-up. Based on this landmark trial, it seems preferable not to stent a stenosis with non-ischemic FFR. Our study demonstrates that this phenomenon may occur not infrequently if CTO recanalization is performed initially. Further, there are two studies looking at the longterm effects of CTO revascularization are under way (ClinicalTrials.gov: NCT01078051; NCT01760083), but results will not be available before 2015. Fan et al. [6] raises the question as to whether FFR in intermediate stenosis of the donor artery can worsen after CTO revascularization. Although we did not observe this result, we might speculate that if the donor artery was damaged either through the FFR wire itself or via its passage in a retrograde approach, with consequent worsening of donor artery obstruction, FFR would subsequently worsen. We recommend recanalization of a CTO when feasible in order to avoid unnecessary stenting in some cases of a donor artery.

Rebuttal: Response to letter by fan and colleagues regarding “impact on fractional flow reserve of donor artery by chronic total obstruction revascularization”

The right ventricle is a difficult chamber to assess both structurally and functionally because of its complex 3-dimensional anatomy and limited echocardiographic windows. Thus, relative to the left ventricle, there is less literature on how right ventricle dysfunction affects cardiac and non-cardiac outcomes. The American Society of Echocardiography published guidelines recently on right ventricular assessment to affirm its increasing recognition and importance in cardiovascular practice. The association of right ventricular dysfunction with aortic valve disease and its effects on outcomes of surgical aortic valve replacement (SAVR) are well described in the literature. Transcatheter aortic valve implantation (TAVI) is a new technique that holds promise in changing the management of aortic valve disease by providing a relatively safe alternative to SAVR in inoperable or high-risk patients. The work published in the Journal of Invasive Cardiology by Poliacikova et al describing mortality outcomes of TAVI with pre-existing right ventricular dysfunction addresses an important, clinically relevant, and thus far undescribed topic. In this study, right ventricular systolic function was defined using tricuspid annular plane systolic excursion (TAPSE) and annular systolic velocity. Both these techniques, according to recently published American Society of Echocardiography guidelines, are simple, relatively easy to obtain, and have good reproducibility, and thus provide consistency in data. While both these techniques have been validated against radionuclide angiography with good correlation, these do carry the inherent limitation of estimating global function from single-segment analysis especially in a population with coronary artery disease (twothirds in the present study). Another limitation of TAPSE is that a cut-off value <17 mm has high specificity but low sensitivity to differentiate abnormal from normal subjects. In addition, TAPSE as a measure of right ventricular function has limited data and standardization in the elderly. In the PARTNER trial cohort, the incidence of pulmonary hypertension (PH) was 42%, which is close to 50% as seen in the patient population described in this study, but the study falls short of providing invasive/non-invasive assessment of pulmonary vascular resistance (PVR). PH is a well-known precipitant of right ventricular dysfunction. It should be emphasized here that PH as identified by systolic pulmonary artery pressure >35 mm Hg is a measure of flow x resistance. PVR distinguishes elevated pulmonary pressure due to high flow from that due to pulmonary vascular disease (resistance) and PVR is well established to play an important role in cardiac outcomes including various valvular diseases and heart transplant. Poliacikova et al’s article, which showed no significant effect of right ventricular dysfunction on mortality outcomes with TAVI, is noteworthy. This is especially important since right ventricular dysfunction in patients undergoing SAVR leads to adverse outcomes. This finding of neutral effect of right ventricular dysfunction on TAVI outcomes is in contrast to the effect of right ventricular dysfunction on balloon mitral valvotomy outcomes for mitral stenosis. Pathophysiologically, while mitral and aortic obstruction both represent left heart disease, the differential effect of right ventricular dysfunction on outcomes may reflect a largely reversible component in mitral stenosis where patients are relatively young and free of any primary pulmonary pathology, in contrast to aortic stenosis patients, where chronic obstructive pulmonary disease and other lung diseases are relatively common. However, we cannot make the assumption that poorer outcomes in patients with right ventricular dysfunction undergoing SAVR automatically translates that these patients would be better served with TAVI; future studies to develop risk models for TAVI outcomes need not use a prespecified right ventricular dysfunction variable in their predictive risk models, and may thus limit prospective sample size and maintain power for other important risk variables. While the authors have done a commendable work in reassuring us about the likely neutral effect of right ventricular dysfunction on mortality outcomes with TAVI, it is still to be seen how right ventricular dysfunction affects morbidity outcomes such as duration of hospital stay and inotrope requirement. Furthermore, as studies of balloon mitral valvotomy in mitral stenosis demonstrate improvement in right ventricular function post valvotomy, it will be important to assess the effect of TAVI on right ventricle function because regardless of etiology, right ventricle dysfunction is an independent prognostic marker for adverse cardiac outcomes.

Right ventricle: the increasing importance of half brother of the left ventricle.

Introduction: Administration of fl uoride in the form of tablet is an alternative to water fl uoridation in caries prevention. The present study was done to determine the amount of fl uoride obtained in saliva and urine after ingestion of sodium fl uoride tablet. Material and Methods: The present study was done over 20 hostel inmates. Paraffi n stimulated saliva samples were collected after the dinner as a baseline data and they were asked to swallow 1mg of sodium fl uoride tablet. Similarly urine samples were collected. Each participant were asked to abstain from drinking black tea and fl uoridated water and given same type of food and water. Follow up samples were collected at 6 hours and 12 hours interval. Sample thus collected sent for fl uoride estimation. Result: The mean fl uoride at baseline was 0.7692 + 0.15 PPM, 1.879 and after ingestion of tablet was 0.7941 + 0.17, 1.899 & 0.7741 + 0.15, 1.877PPM 6 hours and 12 hours respectively. It was observed that fl uoride present in saliva and urine after 6 hours was higher than baseline and almost similar at 12 hour. Conclusion: Ingestion of Fluoride tablets signifi cantly elevated fl uoride level both in saliva and urine which contributes to the understanding of the clinically established anti-caries properties of fl uoride by continuously bathing of tooth give topical protection to enamel against dental caries.

Fluoride Ions Concentration in Saliva and Urine after Ingestion of Sodium Fluoride Tablet in Hostel Inmates of Dental College

Case reports have shown that an intermediate stenosis in the donor artery collateralizing the myocardium of a chronic total occlusion (CTO) can produce an ischemic fractional flow reserve (FFR) value which may revert to non‐ischemic with CTO revascularization.

Reversal of ischemia of donor artery myocardium after recanalization of a chronic total occlusion

Use of Technetium99m–ciprofloxacin scan in Pott’s spine to assess the disease activity

Thoracoscopic decompression in Pott’s spine and its long-term follow-up

Muscle abscess presenting as nerve palsy is rare and has not been previously reported in the common peroneal nerve (CPN). The objective of this case report is to describe the diagnosis and treatment of an uncommon presentation of peroneal abscess in the leg of an otherwise healthy man. We present a case of CPN palsy in a 50-year-old immunocompetent man with no other comorbid medical condition secondary to peroneus longus abscess. The diagnosis was suggested by magnetic resonance imaging examination and confirmed by intraoperative findings. After surgical drainage of the abscess, the patient made a complete recovery. A review of the literature confirms that peroneus longus abscess giving rise to CPN palsy has not been described. Early diagnosis and surgical drainage of the compressing abscess can produce a favorable outcome.

Common peroneal nerve palsy secondary to peroneus longus abscess: case report.

Transcatheter aortic valve implantation in patients with single coronary artery.

Helminth infections have plagued humans since before the era of our earliest recorded history. They are the most common infectious agents of humans in developing countries and produce a global burden of disease that exceeds better known conditions. Pherithema posthuma a helminthes is commonly known as earth worm is used in the present study. In this connection the anthelminthic property of Manilkara zapota seed embryo extracts were evaluated against Pherithema posthuma as an experimental helminthes model. Piperazine citrate was used as the standard reference. Among the various concentrations of chloroform extract tested, 12.5mg/ml showed efficient anthelminthic activity and among all the concentrations of ethanolic extract tested, 12.5mg/ml showed significant results. This investigation revealed that ethanolic extract of M. zapota proved to possess significant anthelminthic activity against Pheretima posthuma when compared the chloroform extract and the standard drug. This investigation reports a new potent anthelminthic agent that can be used as a potential drug for the treatment of helminthes infection.

MANILKARA ZAPOTA SEED EMBRYO EXTRACT: A POTENT ANTHELMINTHIC AGENT

TCT-218 Evaluating Ischemia In The Myocardium Of A Chronic Total Occlusion To Determine The Value Of Percutaneous Recanalization

TCT-450 Improvement in LV systolic function with ischemia guided (fractional flow reserve) chronic total occlusion (CTO) intervention

TCT-219 Evaluating Ischemia Of An Intermediate Stenosis In A Donor Artery During Recanalization Of A Chronic Total Occlusion

Procedural MI is a frequent complication of percutaneous coronary intervention (PCI). Angiotensin converting enzyme inhibitors (ACE-I) have been shown to reduce ischemic events in the setting of acute myocardial infarction (MI) and heart failure.

OBJECTIVE
We sought to evaluate whether chronic ACE-I treatment prior to PCI reduces the incidence of procedural MI.

METHODS
The study cohort included consecutive patients from January 2003 to August 2004 undergoing PCI with normal baseline serum creatinine kinase (CK) and cardiac CK isoform (CK-MB) (n = 265). Procedural MI was defined as CK-MB elevation ≥ 3 times the upper limit of normal.

RESULTS
Patients on chronic ACE-I had a higher baseline prevalence of adverse prognostic features including diabetes (p = 0.02) and a trend towards a lower incidence of drug-eluting stent use (p = 0.07). Using multiple logistic regression, patients on chronic ACE-I therapy (n = 138) had a 64% reduction in procedural MI compared with those not on ACE-I (n = 127; odds ratio = 0.36; 95% confidence intervals 0.13-0.99; p = 0.05). Long-term outcomes, including death and major adverse cardiac events (MACE) (combined total of death, MI and target lesion revascularization were similar in the two groups. Procedural MI was, however, associated with increased MACE during follow up (60% vs. 35.4%; p = 0.035).

Chronic ACE-I therapy before PCI may reduce the incidence of procedural MI.

Effect of chronic angiotensin converting enzyme inhibitor therapy on myocardial injury in patients undergoing percutaneous coronary interventions.

Evaluation of adequacy of short-course chemotherapy for extraspinal osteoarticular tuberculosis using 99mTc ciprofloxacin scan

Use of external fixator in the postoperative management of sciatic nerve injuries

Foot and ankle surgery : official journal of the European Society of Foot and Ankle Surgeons

Modified minimally invasive approach for dynamic hip screw fixation

Introduction and Objective: Placement of a percutaneous nephrostomy tube for drainage has been an integral part of the standard percutaneous nephrolithotomy (PCNL) procedure. However, in recent years, the procedure has been modified to what has been called ‘tubeless’ PCNL, in which nephrostomy tube is replaced with internal drainage provided by a double-J stent or a ureteral catheter. The objective of this article is to review the evidence-based literature on ‘nephrostomy-free’ or ‘tubeless’ PCNL to compare the safety, effectiveness, feasibility, and advantages of tubeless PCNL over standard PCNL. Materials and Methods: We performed a MEDLINE database search to retrieve all published articles relating to ‘tubeless’ PCNL. Cross-references from retrieved articles as well as articles from urology journals not indexed in MEDLINE, were also retrieved. Results: The majority of the studies have shown ‘tubeless’ PCNL to be a safe and economical procedure, with reduced postoperative pain and morbidity and shorter hospital stay. tubeless PCNL has been found to be safe and effective even in patients with multiple stones, complex staghorn stones, concurrent ureteropelvic junction obstruction, and various degrees of hydronephrosis. The technique has been successful in obese patients, children, and in patients with recurrent stones after open surgery. Conclusion: Tubeless PCNL can be used with a favorable outcome in selected patients (stone burden <3 cm, single tract access, no significant residual stones, no significant perforation, minimal bleeding, and no requirement for a secondary procedure), with the potential advantages of decreased postoperative pain, analgesia requirement, and hospital stay. However, for extended indications, like supine PCNL, multiple, complex and staghorn stones, and concurrent PUJ obstruction, the evidence is insufficient and should come from prospective randomized trials.

Indian Journal of Urology : IJU : Journal of the Urological Society of India

Syphilis outbreaks in the United States have been reported since 2000 with highest rates in the South and many cases among HIV-infected individuals. We evaluated incident syphilis cases and concurrent gonorrhea and chlamydia screening at a southern HIV clinic. A retrospective cohort study included HIV-infected patients with at least one reactive plasma reagin (test for serum reagin antibodies to cardiolipin-cholesterol-lecithin antigen) and primary care visit from July 2004 to June 2007. Primary, secondary, and early latent syphilis cases were identified as incident syphilis and evaluation for gonorrhea and chlamydia within 1 month were described. Logistic regression was performed to determine factors associated with incident syphilis. Among 1544 patients, 40 incident syphilis cases were identified (5 primary, 29 secondary, and 6 early latent). The majority of patients were not virologically suppressed and only 25% had gonorrhea and chlamydia testing. In adjusted analyses, younger age (0.57 per 10 years, 95% confidence interval [CI] 0.41-0.80) and minority race (2.26, 95% CI 1.12-4.59) were associated with incident syphilis. Among 40 incident syphilis cases, only 1 in 4 were further tested for gonorrhea and chlamydia. These low rates are concerning as concurrent sexually transmitted infections (STIs) increase risk for HIV transmission. HIV care provider education with emphasis on STI testing in the setting of incident syphilis is key in prevention.

New syphilis cases and concurrent STI screening in a southeastern U.S. HIV clinic: a call to action.

Management of infected non-union in long bones: our experience with bone cement

Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography

Pseudoaneurysm of the mitral-aortic intervalvular fibrosa (MAIVF): A comprehensive review.

Background Low-density lipoprotein cholesterol (LDL-C) has been clearly associated with the risk of developing coronary heart disease. The best and most convenient method for determining LDL-C has come under increased scrutiny in recent years. We present comparisons of the Friedewald calculated LDL-C (C-LDL-C) and direct LDL-C (D-LDL-C) using 3 different homogenous assays. This highlights differences between the 2 methods of LDL-C measurement and how this affects the classification of samples into different LDL-C treatment goals as determined by the National Cholesterol Education Program Adult Treatment Panel III guidelines thus potentially affecting treatment strategies. Methods Lipid profiles of a total of 2208 clinic patients were retrieved from the Central Arkansas VA Healthcare System clinical laboratory database. Samples studied were of 1-week period during the 3 periods studied: 2000 (period 1), 2002 (period 2), and 2005 (period 3). Different homogenous assays for D-LDL-C measurement were used for each of the 3 periods. Results There is a fundamental disagreement between D-LDL-C and C-LDL-C, although Pearson correlation coefficients are 0.93, 0.97, and 0.98 for periods 1, 2, and 3, respectively. Using the model for period 1, when C-LDL-C is 70 mg/dL, the predicted D-LDL-C is 95 mg/dL (36% higher). The differences between C-LDL-C and predicted D-LDL-C progressively decrease at higher LDL-C cut points. In the assay used in period 3, there are 290 samples with D-LDL-C values between 100 and 130 mg/dL. Of these, only 182 samples show agreement with C-LDL-C values, whereas 90 samples with a D-LDL-C in the 100- to 130-mg/dL range are in the 70- to 100-mg/dL range using the C-LDL-C assay. Although the κ statistics suggests the LDL-C measures have relatively high levels of agreement, the significant generalized McNemar tests (P < 0.01) provide additional evidence of disagreement between C-LDL-C and D-LDL-C during all the 3 periods. Conclusions Our results highlight D-LDL-C measurements using 3 different assays during 3 different periods. In all assays, there is a substantial lack of agreement between D-LDL-C and C-LDL-C, which, in most cases, resulted in higher D-LDL-C values than C-LDL-C. This leads to clinically significant misclassification of patient's LDL-C to a different LDL-C treatment goal, which would potentially result in more drug usage, thus exposing patients to more potential adverse effects and at a much greater cost with little evidence of benefit.

Method of LDL Cholesterol Measurement Influences Classification of LDL Cholesterol Treatment Goals

PURPOSE
Placement of multiple nephrostomy tubes is the standard practice after completion of multitract percutaneous nephrolithotomy (PCNL) for complex/staghorn calculi. We conducted a study to see whether use of a single nephrostomy tube in comparison with multiple tubes reduces postoperative discomfort without compromising safety of the procedure.

One hundred and ninety-two patients with complex/staghorn renal calculi who were treated with PCNL requiring multiple tracts were included in the study. The inclusion criteria included normal renal function, complete clearance of calculi, and no significant intraoperative complication. Patients were randomized into two groups on operation table at completion of procedure-group A, single nephrostomy tube placement after multitract PCNL; group B, one nephrostomy tube for each tract.

RESULTS
Postoperative analgesia requirement in group A was significantly less than that in group B (111.9 +/- 27.4 mg meperidine in group A; 165.8 +/- 34.4 mg in group B) (p < 0.001). The difference in average blood loss for two groups was not statistically significant (drop in hemoglobin: group A, 0.48 gm%; group B, 0.51 gm%) (p = 0.55). Three patients in group A and four in group B required blood transfusion (p = 0.65). The average hospital stay in group A (42.4 +/- 8.6 hours) was significantly shorter than that in group B (68.1 +/- 6 hours) (p < 0.001). No long-term squealae were noticed in the median follow-up of 18 months in any patient.

The present study demonstrates that use of a single nephrostomy tube in multitract PCNL is safe and as effective as the conventional practice of placing multiple tubes. In addition, a single tube minimizes postoperative morbidity related to the drainage tubes.

Are multiple nephrostomy tubes necessary after multitract percutaneous nephrolithotomy? A randomized comparison of single versus multiple nephrostomy tubes.

Dupatta (scarf): a unique cause of cervical spine injury in females.

PURPOSE
We present a randomized study of tubeless or nephrostomy-free percutaneous nephrolithotomy (PCNL), a modification of the standard technique, compared with standard PCNL to evaluate the role of tubeless PCNL in minimizing postoperative discomfort and reducing duration of hospital stay.

Two hundred and two patients undergoing PCNL were randomized to two groups: Group A (standard PCNL) with nephrostomy tube placement postoperatively, and group B (tubeless PCNL) with antegrade placement of a Double-J stent without nephrostomy. Inclusion criteria were: normal renal functions, single tract procedure with complete clearance, and minimal bleeding at completion. The two groups were comparable in age and sex and in metabolic and anatomic features. Factors evaluated included postoperative pain, analgesia requirement, blood loss, postoperative morbidity, hospital stay, and time to recovery.

RESULTS
All patients had an uneventful postoperative recovery. The average visual analogue scale pain score on postoperative day 1 for group A patients was 59 +/- 5.1 compared with 31 +/- 4.8 in group B (P < 0.01). The mean analgesia requirement for group A (meperidine 126.5 +/- 33.3 mg) was significantly more compared with group B (meperidine 81.7 +/- 24.5 mg) (P < 0.01). The difference in average blood loss and urinary infection for the two groups was not statistically significant. The incidence of urinary leakage from the nephrostomy site was significantly less for the tubeless group (0/101), compared with the standard PNL group (7/101). The average hospital stay in the tubeless group (21.8 +/- 3.9 hours) was significantly shorter than that of the standard PCNL group (54.2 +/- 5 hours) (P < 0.01). Tubeless group patients took 5 to 7 days for complete convalescence whereas standard PCNL patients recovered in 8 to 10 days. No long-term sequelae were noticed in the median follow-up period of 18 months in any patient.

Nephrostomy-free or tubeless PCNL reduces postoperative urinary leakage and local pain related to the drainage tube. It also minimizes hospital stay; the majority of patients were discharged from the hospital in fewer than 24 hours.

A randomized comparison of tubeless and standard percutaneous nephrolithotomy.

The purpose of this research was to study incidence; clinical, histological, and radiological features; and outcome of primary malignant giant cell tumor (PMGCT). The authors retrospectively reviewed all cases of giant cell tumor (GCT) in which a diagnosis of GCT was related to sarcoma treated in their department between 1997 and 2004. Three cases of PMGCT were found according to the criterion of Hutter and Dahlin. Histological and radiological records of all the three cases were reviewed. In these three cases of PMGCT, the initial clinical and radiological findings were the same as those for benign giant cell tumor. Wide excision of the tumor was performed in all three cases. In two cases, knee arthrodesis was performed, and in one case a custom-made total knee replacement was performed. PMGCT was diagnosed on initial biopsy in one patient, in the second patient it was diagnosed in the excised specimen, and in third case it was only diagnosed after local recurrence 6 months after initial treatment. All the patients died within 5 months of detection of recurrence and metastasis. PMGCT has a very poor prognosis. Histological examination is highly significant in such cases. Awareness about this entity, adequate biopsy, and sampling of specimen can aid in early diagnosis, which may improve the overall prognosis.

Primary malignant giant cell tumor of bone: a series of three rare cases.

Spontaneous, simultaneous, bilateral quadriceps tendon rupture in a 16-year-old girl with severe osteomalacia

Heavy Metal Contamination in Vegetables Grown in Wastewater Irrigated Areas of Varanasi, India

INTRODUCTION: This paper describes selected findings from an interdisciplinary research project funded by the UK Department for International Development (January 2000 to April 2003) which was carried out in Delhi and Varanasi by Imperial College, London in partnership with Srishti; Delhi University; Banaras Hindu University, Varanasi; Development Tracks, New Delhi and the Indian Agricultural Research Institute.

Heavy metal contamination of vegetables in Delhi. Executive summary of technical report - March 2003.

Heavy metal contamination of vegetables in Delhi. Executive summary of technical report.

Heavy metal contamination of vegetables in Varanasi. Interim Report. Banaras Hindu University, Varanasi, India. 20 pp.

Heavy metal contamination in vegetables. Radio interview. "Parjavasaram Diwas Special (Environmental Day Special)" Akaswani Radio Station, Delhi. 5 June 2001 (20:30) 6 minutes. [National]

Heavy metal contamination of vegetables in Varanasi. November 2001. Banaras Hindu University, Varanasi, India. 74 pp.

The development of a general software for haptic integration of 6 degrees of freedom articulated robot through C language is discussed in the paper. The paper mainly focusses on development of the basic software architecture along with its algorithm. The software along with its graphical user interface has been developed and tested.

Software Architecture for Haptic Integration 6 DOF Articulated Manipulator

Delayed gratification is an important focus of research, given its potential relationship to forms of behavior, such as savings, susceptibility to addiction, and pro-social behaviors. The COVID-19 pandemic may be one of the most consequential recent examples of this phenomenon, with people's willingness to delay gratification affecting their willingness to socially distance themselves. COVID-19 also provides a naturalistic context by which to evaluate the ecological validity of delayed gratification. This article outlines four large-scale online experiments (total N = 12, 906) where we ask participants to perform Money Earlier or Later (MEL) decisions (e.g., $5 today vs. $10 tomorrow) and to also report stress measures and pandemic mitigation behaviors. We found that stress increases impulsivity and that less stressed and more patient individuals socially distanced more throughout the pandemic. These results help resolve longstanding theoretical debates in the MEL literature as well as provide policymakers with scientific evidence that can help inform response strategies in the future. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Stress, intertemporal choice, and mitigation behavior during the COVID-19 pandemic.

Discovering better theories Theories of human decision-making have proliferated in recent years. However, these theories are often difficult to distinguish from each other and offer limited improvement in accounting for patterns in decision-making over earlier theories. Peterson et al. leverage machine learning to evaluate classical decision theories, increase their predictive power, and generate new theories of decision-making (see the Perspective by Bhatia and He). This method has implications for theory generation in other domains. Science, abe2629, this issue p. 1209; see also abi7668, p. 1150 A machine learning approach suggests that people make decisions in a way that violates the assumptions of classic decision-making theories. Predicting and understanding how people make decisions has been a long-standing goal in many fields, with quantitative models of human decision-making informing research in both the social sciences and engineering. We show how progress toward this goal can be accelerated by using large datasets to power machine-learning algorithms that are constrained to produce interpretable psychological theories. Conducting the largest experiment on risky choice to date and analyzing the results using gradient-based optimization of differentiable decision theories implemented through artificial neural networks, we were able to recapitulate historical discoveries, establish that there is room to improve on existing theories, and discover a new, more accurate model of human decision-making in a form that preserves the insights from centuries of research.

Using large-scale experiments and machine learning to discover theories of human decision-making

The current study aims to analyse VR measures in correspondence with 360° virtual affective experiences to understand the underlying spatio-temporal attention processes. We selected extreme pleasant and extreme unpleasant emotional videos from the Stanford affective database and displayed to participants on HMD VR. The participants’ task was to explore the video and report their affective experience using the Self-Assessment Manikin (SAM) scale. The exploration behaviour was analysed using head-tracking parameters, such as standard deviation of all the three head-rotation axes (yaw, pitch and roll), angular speed and region-wise analysis. We observed a positive correlation between standard deviation of yaw and valence, and angular speed and valence. The result suggests that affective experience not only increases the scope of attention spatially (wide scanning), it also motivates to seek more information that leads to more head-movement during exploration. In region-wise analysis, we observed front field-of-view was primarily explored, and rear field-of-view was least explored, showing natural responses similar to real environments. In addition, we used Beck Depression Inventory-II (BDI) to assess participants’ emotional state, specifically depression symptoms. The relation between virtual affective experience and 360° exploration behaviour is discussed in light of the BDI categories. The study findings broaden the scope for VR affective research by enabling psychomotor assessment in more ecologically valid settings.

2021 IEEE 7th International Conference on Virtual Reality (ICVR)

Intertemporal choice under stress: an ongoing study during the COVID-19 pandemic

Significance Behavioral scientists need a principled methodology for working with large datasets. We offer an exploratory approach that combines ideas from machine learning and psychology, and we conduct a case study in the domain of moral reasoning. We demonstrate that our approach allows us to both build a powerful and interpretable computational model, and identify subtle principles humans employ in moral dilemmas. The method we offer can be applied in any field with large datasets. Do large datasets provide value to psychologists? Without a systematic methodology for working with such datasets, there is a valid concern that analyses will produce noise artifacts rather than true effects. In this paper, we offer a way to enable researchers to systematically build models and identify novel phenomena in large datasets. One traditional approach is to analyze the residuals of models—the biggest errors they make in predicting the data—to discover what might be missing from those models. However, once a dataset is sufficiently large, machine learning algorithms approximate the true underlying function better than the data, suggesting, instead, that the predictions of these data-driven models should be used to guide model building. We call this approach “Scientific Regret Minimization” (SRM), as it focuses on minimizing errors for cases that we know should have been predictable. We apply this exploratory method on a subset of the Moral Machine dataset, a public collection of roughly 40 million moral decisions. Using SRM, we find that incorporating a set of deontological principles that capture dimensions along which groups of agents can vary (e.g., sex and age) improves a computational model of human moral judgment. Furthermore, we are able to identify and independently validate three interesting moral phenomena: criminal dehumanization, age of responsibility, and asymmetric notions of responsibility.

Cognitive fatigue and boredom are two phenomenological states widely associated with limitations in cognitive control. In this paper, we present a rational analysis of the temporal structure of controlled behavior, which provides a new framework for providing a formal account of these phenomena. We suggest that in controlling behavior, the brain faces competing behavioral and computational imperatives, and must balance them by tracking their opportunity costs over time. We use this analysis to flesh out previous suggestions that feelings associated with subjective effort, like cognitive fatigue and boredom, are the phenomenological counterparts of these opportunity cost measures, rather then reflecting the depletion of resources as has often been assumed. Specifically, we propose that both fatigue and boredom reflect the competing value of particular options that require foregoing immediate reward but can improve future performance: Fatigue reflects the value of offline computation (internal to the organism) to improve future decisions, while boredom signals the value of exploratory actions (external in the world) to gather information. We demonstrate that these accounts provide a mechanistically explicit and parsimonious account for a wide array of findings related to cognitive control, integrating and reimagining them under a single, formally rigorous framework.

The Temporal Dynamics of Opportunity Costs: A Normative Account of Cognitive Fatigue and Boredom

Do large datasets provide value to psychologists? Without a systematic methodology for working with such datasets, there is a valid concern that exploratory analyses will produce noise artifacts rather than true effects. In this paper, we offer a way to enable researchers to systematically build models and identify novel phenomena in large datasets. One traditional approach is to analyze the residuals of models—the biggest errors they make in predicting the data—to discover what might be missing from those models. However, once a dataset is sufficiently large, machine learning algorithms approximate the true underlying function better than the data, suggesting instead that the predictions of these data-driven models should be used to guide model-building. We call this approach “Scientific Regret Minimization” (SRM) as it focuses on minimizing errors for cases that we know should have been predictable. We demonstrate this methodology on a subset of the Moral Machine dataset, a public collection of roughly forty million moral decisions. Using SRM, we found that incorporating a set of deontological principles that capture dimensions along which groups of agents can vary (e.g. sex and age) improves a computational model of human moral judgment. Furthermore, we were able to identify and independently validate three interesting moral phenomena: criminal dehumanization, age of responsibility, and asymmetric notions of responsibility.

Scaling up Psychology via Scientific Regret Minimization: A Case Study in Moral Decisions

It has recently been proposed that hippocampal replay can be explained in a reinforcement learning setting as the instantiation of the Dyna framework. This formulation lends itself to a dual-process model: an agent can choose to either act or replay at every time step. Here, we extend the proposed model by adding a controller that arbitrates between replaying and acting in order to maximize reward rate. That is, rather than give a fixed budget of replays to perform in both the starting and final state, we allow the agent to dynamically decide how much to replay in all states. The first result is that, in a Gridworld task, this algorithm is able to converge to the optimal policy faster. Second, by tracking the amount of replay selected per trial, we observe that there is only a narrow range of trials in which replay is beneficial. We propose this model as both a more efficient use of the Dyna framework as well as a normative model of how rational animal and human agents should replay.

Large-scale behavioral datasets enable researchers to use complex machine learning algorithms to better predict human behavior, yet this increased predictive power does not always lead to a better understanding of the behavior in question. In this paper, we outline a data-driven, iterative procedure that allows cognitive scientists to use machine learning to generate models that are both interpretable and accurate. We demonstrate this method in the domain of moral decision-making, where standard experimental approaches often identify relevant principles that influence human judgments, but fail to generalize these findings to "real world" situations that place these principles in conflict. The recently released Moral Machine dataset allows us to build a powerful model that can predict the outcomes of these conflicts while remaining simple enough to explain the basis behind human decisions.

Using Machine Learning to Guide Cognitive Modeling: A Case Study in Moral Reasoning

Do large datasets provide value to psychologists? Without a systematic methodology for working with such datasets, there is a valid concern that analyses will produce noise artifacts rather than true effects. In this paper, we offer a way to enable researchers to systematically build models and identify novel phenomena in large datasets. One traditional approach is to analyze the residuals of models---the biggest errors they make in predicting the data---to discover what might be missing from those models. However, once a dataset is sufficiently large, machine learning algorithms approximate the true underlying function better than the data, suggesting instead that the predictions of these data-driven models should be used to guide model-building. We call this approach "Scientific Regret Minimization" (SRM) as it focuses on minimizing errors for cases that we know should have been predictable. We demonstrate this methodology on a subset of the Moral Machine dataset, a public collection of roughly forty million moral decisions. Using SRM, we found that incorporating a set of deontological principles that capture dimensions along which groups of agents can vary (e.g. sex and age) improves a computational model of human moral judgment. Furthermore, we were able to identify and independently validate three interesting moral phenomena: criminal dehumanization, age of responsibility, and asymmetric notions of responsibility.

Scaling up Psychology via Scientific Regret Minimization: A Case Study in Moral Decision-Making

Motor symptoms in Parkinson's disease (PD) correlate with an excess in synchrony in the beta frequency band (13-30Hz) of local field potentials recorded from basal ganglia circuits. Recent results have suggested that this abnormal activity arises as a result of changes in specific dynamical features of the underlying neural signatures. In particular, patterns of activity in the beta band have been shown to be structured in bursts of longer durations and higher amplitudes in untreated patients with PD. Closed-loop deep brain stimulation (DBS) paradigms that specifically target these pathological bursts of activity hold promises to help trim, and thus normalize, their abnormal behavior in real-time. Here, we developed classification algorithms that predict pathological beta bursts based on ongoing changes in LFP frequency dynamics. We then compared simulations of prediction-based DBS profiles with existing 'adaptive DBS' alternatives. We show that model-driven stimulation profiles are more precise in restricting the delivery of stimulation to bursts that are considered pathological, while preserving physiological ones. The overall stimulation time required is also diminished, thus supporting longer battery life. These results represent a conceptual and algorithmic framework for the development of more precise DBS strategies that are selectively tailored to the electrophysiological profile of each patient.

Abstract—Motor symptoms in Parkinson's disease (PD) correlate with an excess in synchrony in the beta frequency band (13-30Hz) of local field potentials recorded from basal ganglia

The Practical Applicability Of Black Scholes Model AndMerton’s Model On Option Pricing In INDIA

Motor symptoms in Parkinson’s disease (PD) correlate with an excess in synchrony in the beta frequency band (13-30Hz) of local field potentials recorded from basal ganglia circuits. Recent results have suggested that this abnormal activity arises as a result of changes in specific dynamical features of the underlying neural signatures. In particular, patterns of activity in the beta band have been shown to be structured in bursts of longer durations and higher amplitudes in untreated patients with PD. Closed-loop deep brain stimulation (DBS) paradigms that specifically target these pathological bursts of activity hold promises to help trim, and thus normalize, their abnormal behavior in real-time. Here, we developed classification algorithms that predict pathological beta bursts based on ongoing changes in LFP frequency dynamics. We then compared simulations of prediction-based DBS profiles with existing ‘adaptive DBS’ alternatives. We show that model-driven stimulation profiles are more precise in restricting the delivery of stimulation to bursts that are considered pathological, while preserving physiological ones. The overall stimulation time required is also diminished, thus supporting longer battery life. These results represent a conceptual and algorithmic framework for the development of more precise DBS strategies that are selectively tailored to the electrophysiological profile of each patient.

Predicting beta bursts from local field potentials to improve closed-loop DBS paradigms in Parkinson’s patients

The aim of this paper is to introduce a novel non-Gaussian statistical model-based approach for medical image fusion based on the Meridian distribution. The paper also includes a new approach to estimate the parameters of generalized Cauchy distribution. The input images are first decomposed using the Dual-Tree Complex Wavelet Transform (DT-CWT) with the subband coefficients modelled as Meridian random variables. Then, the convolution of Meridian distributions is applied as a probabilistic prior to model the fused coefficients, and the weights used to combine the source images are optimised via Maximum Likelihood (ML) estimation. The superior performance of the proposed method is demonstrated using medical images.

Medical image fusion using the convolution of Meridian distributions

How Confident Was Your Reviewer? Estimating Reviewer Confidence from Peer Review Texts

PEERAssist: Leveraging on Paper-Review Interactions to Predict Peer Review Decisions

Inode is one of the subsystems of WAFL(Write
Anywhere File Layout) file system. Inode cache is a dynamic
subsystem that is percentage factor of available memory. Based on
different workflows and the datasets inode cache grows and
shrinks. Based on the study of customer related issues it is found
that deploying such a workload and datasets at the scale, that
customers typically deploy and exercise inode cache for the whole
duration of test is very challenging, considering quality assurance
test typically focuses on multiple subsystems. Inode cache
behavior differs with steady state versus performance disruptive
workflows such as volume offline, volume online, volume
migration and backup/vault use cases. Based on the behavior
observed on the internal test systems it is found inode cache
disruptive workflows are exercised only during certain stages but
not repeatedly for the duration of test and also it is hard to find out
which volume is experiencing performance issues due to inode
cache invalidation/shrink/rewarning. In this paper, trying to
exercise the performance behavior of inode subsystem like the
way customer does and try to monitor and model the subsystem
using automation. Here considering the different key attributes
and typical operations that effect the inode cache behavior and
some of the interested counters statistics that need to be monitored
for analyzing the performance behavior of inode cache.
Exercising inode cache operations requires constant focus on
how the inode cache is performing. Repeat and Rerun some of the
targeted workflows for inode cache population invalidation/
shrink operations at constant intervals to model the behavior of
the inode subsytem.

Video sharing services that allow ordinary Web users to upload video clips of their choice and watch video clips uploaded by others have recently become very popular. This article identifies invariants in video sharing workloads, through comparison of the workload characteristics of four popular video sharing services. Our traces contain metadata on approximately 1.8 million videos which together have been viewed approximately 6 billion times. Using these traces, we study the similarities and differences in use of several Web 2.0 features such as ratings, comments, favorites, and propensity of uploading content. In general, we find that active contribution, such as video uploading and rating of videos, is much less prevalent than passive use. While uploaders in general are skewed with respect to the number of videos they upload, the fraction of multi-time uploaders is found to differ by a factor of two between two of the sites. The distributions of lifetime measures of video popularity are found to have heavy-tailed forms that are similar across the four sites. Finally, we consider implications for system design of the identified invariants. To gain further insight into caching in video sharing systems, and the relevance to caching of lifetime popularity measures, we gathered an additional dataset tracking views to a set of approximately 1.3 million videos from one of the services, over a twelve-week period. We find that lifetime popularity measures have some relevance for large cache (hot set) sizes (i.e., a hot set defined according to one of these measures is indeed relatively “hot”), but that this relevance substantially decreases as cache size decreases, owing to churn in video popularity.

Collision detection and prevention for the visually impaired using computer vision and machine learning

Honking in traffic is an auditory warning to indicate: driver's actions, alert pedestrians and to convey an emergency situation requiring right of way. Though studies have shown the importance of honking in maintaining traffic flow, there have been cases where irrational use leads to an increase in stress/irritation with effects on driver decision making. Most drivers are unaware of the adverse health effects of high decibel honking. In this report, we looked at the effects of honking on driving behavior in a lab-developed VR driving simulator and anxiety/stress as indicated by changes in skin conductance/pulse rate measured using sensors.

Proceedings of the 11th International Conference on Automotive User Interfaces and Interactive Vehicular Applications: Adjunct Proceedings

Analyzing high decibel honking effect on driving behavior using VR and bio-sensors

A Heterogeneous Traffic Virtual-Reality Simulator to Study Irritation/Anger and Driving Behavior under Adverse Conditions

Abstract. Mangrove, the intertidal halophytic vegetation, are one of the most significant and diverse ecosystem in the world. They protect the coast from sea erosion and other natural disasters like tsunami and cyclone. In view of their increased destruction and degradation in the current scenario, mapping of this vegetation is at priority. Globally researchers mapped mangrove vegetation using visual interpretation method or digital classification approaches or a combination of both (hybrid) approaches using varied spatial and spectral data sets. In the recent past techniques have been developed to extract these coastal vegetation automatically using varied algorithms. In the current study we tried to delineate mangrove vegetation using LISS III and Landsat 8 data sets for selected locations of Andaman and Nicobar islands. Towards this we made an attempt to use segmentation method, that characterize the mangrove vegetation based on their tone and the texture and the pixel based classification method, where the mangroves are identified based on their pixel values. The results obtained from the both approaches are validated using maps available for the region selected and obtained better accuracy with respect to their delineation. The main focus of this paper is simplicity of the methods and the availability of the data on which these methods are applied as these data (Landsat) are readily available for many regions. Our methods are very flexible and can be applied on any region.

AUTOMATIC EXTRACTION OF MANGROVE VEGETATION FROM OPTICAL SATELLITE DATA

This paper proposes a wirelessly operated wall climbing robot, which is able to climb on vertical surfaces, rough or smooth, using air suction motor and sand paper for attachment and friction. We have used four tyres which rolls over surface of wall and can steer in any orientation using DTMF technology. Due to its unique design, a high degree of modification and applications are possible. It is semi-autonomous and some sensors are connected, to communicate it wirelessly. Various aspects of another relevant prototypes has been designed so far each having some limitations which this robot overcomes. We have used hair blower as a suction mechanism which makes it cost effective and unique. It can reliably climb on a vertical wall and can crawl on ceiling too. This robot can be used for inspection and surveillance applications and hazardous conditions like fire.

Intelligent Climber: A Wireless Wall-Climbing Robot Utilizing Vacuum Suction and Sand Paper

Heart updated failure is a very serious medical issue nowadays. It causes a lot of deaths all over the world. The bad lifestyle, bad eating habits, unusual food timings are some of the factors responsible for this disease. Artificial intelligence and machine learning is a technology which is used by many researchers for prediction of diseases. Machine Learning (ML) algorithms provide some models which are first trained on a training data and then can be used to test the input data. These models are very helpful in prediction of heart disease. In this work XGBoost, Logistic Regression and Support Vector Machine ML models are used to predict heart disease. Cross validation method is used in this work which improved the prediction accuracy of all the three models. Outcoming results ensure that the XGBoost classifier is the best ML model for heart disease prediction as compared to Logistic Regression and Support vector Machine.

2023 International Conference on Advancement in Computation & Computer Technologies (InCACCT)

Heart Failure Prediction Using XGB Classifier, Logistic Regression and Support Vector Classifier

Breast cancer is very common type of cancer now a day. It is observed in many of the women and responsible for many deaths in recent days. In this work the power of machine learning classifiers is applied in prediction of breast cancer. Three machine learning classifiers LR, KNN and Decision Tree are applied on a standard data set and their prediction accuracy is calculated. From the experiment it is concluded that the LR algorithms is best for breast cancer prediction.

2022 8th International Conference on Advanced Computing and Communication Systems (ICACCS)

Breast Cancer Prediction Using Advance Machine Learning Algorithms

Nowadays, breast cancer is a relatively common type of cancer. It's been seen in a lot of women lately, and it's been the cause of a lot of deaths. There is a need to predict the probability of cancer at early stages so that necessary actions can be taken timely to avoid this deadly disease. Machine Learning a a new Artificial Intelligence technique and its power is yet to be discovered for cancer prediction. The power of machine learning classifiers is used to predict breast cancer in this study. The prediction accuracy of four machine learning classifiers, Support Vector Classifier, Random Forest Classifier, Gradient Boosting Classifier and Ada Boost Classifier is calculated on a standard data set. According to the results of the experiment, Support Vector Classifier trumps the other three in terms of prediction accuracy.

2022 6th International Conference on Trends in Electronics and Informatics (ICOEI)

Prediction of Breast Cancer based on Various Medical Symptoms Using Machine Learning Algorithms

Breast cancer is currently a rather frequent kind of cancer. Recently, it has been observed in many women, and it has been responsible for several fatalities. In order to prevent this terrible disease, it is important to forecast the likelihood of cancer in its earliest stages. Machine learning is a novel AI approach whose potential for cancer prediction has not yet been fully understood. In this work, the ability of machine learning classifiers is employed to forecast breast cancer. Machine learning algorithms applied in this work to predict the breast cancer are Support Vector Classifier, Random Forest Classifier, KNN Classifier, and Logistic Regression Classifier. The experiment's findings show that Logistic Regression outperforms the other three prediction methods.

2022 International Conference on Automation, Computing and Renewable Systems (ICACRS)

A Novel Heuristic for Estimating Two-Colorability for Conflict-Free Coloring in Simple Graphs

Plagiarism is really a matter of concern. Plagiarism detection is a major issue while detecting at various levels. Finding plagiarism in source codes that can either be written in same language or different language, increases the complexity of plagiarism detection. People dealing with software designing and academic works are majorly affected by the plagiarism. In this paper we present a novel approach for measurement of code similarity to detect similarity between codes. With the help of the proposed approach, by using methods and functions we can compare the two source codes. This will lead to fair evaluation of assignments, as with the help of this tool we can easily detect Programming Assignment and copying of codes or function.

2020 8th International Conference on Reliability, Infocom Technologies and Optimization (Trends and Future Directions) (ICRITO)

Internet of Things (IoT) is a rapidly growing technology nowadays. It has many applications in daily life equipment and used in various ways to improve the daily life of a human being. The applications of IoT is not limited to any area. The research is going to discover more areas in which IoT is applicable. The IoT applications have many areas in which there is a need to optimize things more. Intrusion Detection System is a system that monitors an internet based application for malicious activities. Genetic Algorithm is a heuristic technique to solve optimization problems. In this paper, a new approach for IDS using a genetic algorithm is proposed. The proposed algorithm is applied on a KDD99 cup data set to check its performance.

2020 4th International Conference on Trends in Electronics and Informatics (ICOEI)(48184)

Applying Genetic Algorithm in Intrusion Detection System of IoT Applications

Travelling Salesman Problem is a very popular problem in graph theory and it is applicable to solve many problems of science and engineering. It has its applications in electronics, transportation, navigation, computer networks etc. As the number of cities increases the complexity of the algorithm to find the optimal solution increases. TSP is a maximization optimization problem. In this paper genetic algorithm is used to solve TSP problem. Genetic Algorithm is a nature inspired algorithm which is very suitable to solve optimization problems. An improved genetic algorithm is proposed and applied on standards TSP instances. The achieved results are found better as compared to other recent research works in this area.

2020 Second International Conference on Inventive Research in Computing Applications (ICIRCA)

Applying Improved Genetic Algorithm to Solve Travelling Salesman Problem

Wireless Adhoc networks (or MANETs Mobile Adhoc Networks) are in use in different areas now a day. Most of the nodes of the MANETS are battery operated. As the battery power goes down then the node of the MANET will stop working. If a node having very less remaining battery power is used in data transfer in routing, then that node lost its battery power and goes down. In this paper a power efficient routing protocol based on remaining battery power is proposed. The algorithm helps in energy consumption of the nodes of the MANET. The algorithm improves the battery lifetime of nodes which have very less remaining battery power as compared to other nodes. The algorithm is simulated on a sample MANET and results are evaluated. The algorithm is found efficient in increasing battery lifetime of nodes and lifetime of MANET.

2020 International Conference on Power Electronics & IoT Applications in Renewable Energy and its Control (PARC)

New Approach for Improving Battery Power Consumption of Wireless Mobile Adhoc Networks Nodes Using Genetic Algorithm

Credit cards are very commonly used in making online payments. In recent years’ frauds are reported which are accomplished using credit cards. It is very difficult to detect and prevent the fraud which is accomplished using credit card. Machine Learning(ML) is an Artificial Intelligence (AI) technique which is used to solve many problems in science and engineering. In this paper, machine learning algorithms are applied on a data set of credit cards frauds and the power of three machine learning algorithms is compared to detect the frauds accomplished using credit cards. The accuracy of Random Forest machine learning algorithm is best as compared to Decision Tree and XGBOOST algorithms.

Performance Analysis of Machine Learning Algorithms in Credit Cards Fraud Detection

This paper presents the result of a study undertaken with the overarching objective of investigating the impact of productivity improvement approaches in automobile industries. Optimization of robotic arm/manipulators path in focused areas helps in eliminating non value added activities and results increase in productivity. Substantial reduction in material handling and operator manual work, reduction in manpower by using MOST (Maynard operation sequence technique) is obtained in detail. The tool Kaizen (continuous improvement) is applied as a way to progress towards lean manufacturing and as a formula to lead the activities of improvement. This work is mainly concentrated to find bottle neck areas in weld, paint and assembly shop of automobile industry under consideration. The main objective is to analyze delay time and line stoppages, also to minimize down time and develop several strategies to eliminate waste on shop floor. In this paper the TSP (Travelling salesman problem) and other lean manufacturing tools such as automation, Kaizen, MOST (Maynard operational sequence technique) has been used to increase the productivity and capacity of a shop to achieve desired market demand. Results obtained are quite satisfactory in terms of improvement in market share, productivity and reducing the waiting time of vehicles in market.

Productivity Improvement and Capacity Enhancement of an Automobile Industry: A Case Study

Plagiarism is not only found in the academic work but also in the industries dealing with software designing. Plagiarism is becoming a serious problem for academician community. Academics can detect similarity of source code files with the help of plagiarism detection tools. In this paper we present JSIM (Java Similarity) tool to find out the Similarity between Source codes. Two source codes will be matched at function's level or method's level with the help of JSIM. With the help of JSIM tool teachers can find the similarity between source code and according to the similarity, teacher can easily give marks to the students in an assignment of programming subject.

2016 IEEE Uttar Pradesh Section International Conference on Electrical, Computer and Electronics Engineering (UPCON)

Plagiarism is becoming a serious problem for intellectual community. The detection of plagiarism at various levels is a major issue. The complexity of the problem increases when we are finding the plagiarism in the source codes that may be in the same language or they have been transformed into other languages. This type of plagiarism is found not only in the academic works but also in the industries dealing with software designing. The major issue with the source code plagiarism is that different programming languages may have different syntax. In this paper the authors will explain various techniques and algorithms to discover the plagiarism in source code. So organization or academic institution can simply discover plagiarism in source code using these techniques. The authors will differentiate among these given techniques of plagiarism to discover how one technique is conflicting with the other.

2016 2nd International Conference on Next Generation Computing Technologies (NGCT)

In this work, association rules are optimized by using improved particle swarm optimization algorithm (PSO Algorithm). Here improved PSO algorithm means classical PSO algorithm with additional operator in the forms of mutation of genetic algorithm. The basic shortcoming of PSO algorithm is to get trapped into local optima. So for improving this, mutation operator is used additionally in classical PSO algorithm. This operator is used after the initialization phase of PSO algorithm. Firstly, different association rules for generating frequent item sets are generated by standard Apriori algorithm, then improved PSO algorithm is applied on these generated association rules for optimizing them. Experiments are performed on different datasets taken from UCI machine learning repository and results are compared with other previously proposed algorithms, called KNN algorithm and ABC algorithm. These results show that the proposed algorithms efficiency is better than previously proposed algorithms.

This paper presents a technique for enhancing resolution of images by interpolating high frequency sub-bands generated using lifting wavelet transform (LWT) and spatial information of input low resolution (LR) image. Stationary wavelet transform (SWT) is used at intermediate stage for edge enhancement. The input image is decomposed using LWT in order to generate high frequency (HF) sub-bands. The generated HF sub-bands are interpolated further. Different high frequency sub-bands obtained through SWT are added to correct the estimated HF sub-bands. The input LR image is interpolated in parallel. All these sub-bands and estimated LR image are reconstructed by inverse lifting wavelet transformation (ILWT) to produce high resolution image. The qualitative, quantitative and visual images of the described technique show the superiority of the proposed method over conventional and state-of-the-art methods.

2014 International Conference on Electronic Systems, Signal Processing and Computing Technologies

Image Resolution Enhancement Using Lifting Wavelet and Stationary Wavelet Transform

This thesis addresses the problem of image super-resolution from a low resolution image. Spatial resoltuion of images are restricted by the size of CMOS sensors. Spatial resolution can be increased by increasing no of COMS sensors resuling in decrease in size of CMOS sensors which cause shot noise. In this thesis attempts have been made to enhance the spatial resolution of different images. Two schemes are proposed for this purpose. The basic idea behind both the techniques is to utilize the high frequency subband images derived using lifting wavelet transform. In the first scheme the high frequency subband images are interpolated using surface fitting. In another scheme lifting wavelet transform and stationary wavelet transform are used along with surface fitting interpolation to increase the spatial resolution in the frequency domain. Each technique is studied separately, and experiments are conducted to evaluate their performances. The visual, blind image quality index, visual image fidelity index as well as the peak signal to noise ratio (PSNR in dB) of high resolution images are compared with competent recent schemes. Experimental results demonstrate that the proposed approaches are very effective in increasing resolution and compare favorably to state-of-the-art super-resolution algorithms.

This paper presents an image super-resolution technique based on surface fitting the high frequency components of an image obtained by Discrete Wavelet Transform (DWT) of the image and enhanced by Stationary Wavelet Transform (SWT) of the image at intermediate stage. The high frequency sub-bands of the image were generated using DWT and interpolated using surface fitting. These sub-bands modified by high frequency Sub-bands obtained through SWT. The output image was generated through Inverse discrete Wavelet Transform (IDWT) with interpolated input image by surface fitting and high frequency sub-bands. The qualitative and quantitative results show the superiority of this method over other standard image super-resolution techniques.

2013 INTERNATIONAL CONFERENCE ON SIGNAL PROCESSING AND COMMUNICATION (ICSC)

Image super-resolution by interpolating high frequency sub-bands of image using surface fitting

Background: One of the few remaining important issues in urological and gynaecological surgery relates to fistulas between the urinary tract and the vagina. Vesicovaginal fistula (VVF) and ureterovaginal fistulas (UVF) are defined as abnormal connections between the urinary tract, on the one side, and the female genital system, on the other. Case Presentation: This study is about an unreported and undescribed case of 24 year old female who presented with the complaints of continuous urinary incontinence for 18 months following total abdominal hysterectomy. Preoperative cystoscopy and vaginal/speculum findings revealed a papillary frond like mass protruding intravesically from VVF site which was free from the edges of fistulous opening all around. Also, left ureteric orifice was not visualized. On exploration, there was evidence of intravesical herniation of right tubal fimbria through the common opening of VVF and left UVF near left vaginal vault apex mimicking a bladder mass presenting with continuous incontinence for 18 months. Modified O’ Conners VVF repair with left ureteric reimplantation was done. The postoperative period was uneventful with patient having no incontinence. Conclusion: It seems that surgical resection of ovarian cyst with VVF and UVF repair is the definitive treatment and histopathological examination is essential to exclude malignant transformation.

Intravesical Herniation of Tubal Fimbria Through Vesicovaginal Fistula Associated with Ureterovaginal Fistula Mimicking Bladder Mass: A Case Report of Unreported and Undescribed Hernia

Occupational hazards can be defined as a risk to a person usually arising out of employment. The practice of dentistry exposes dental professionals to a variety of work-related hazards. The source of these hazards is the work environment which can include physical, chemical, biological, mechanical, and social aspects. These hazards can pose significant risks to dental practitioners. The occupational hazards found among dentist and other clinical dental workers are similar worldwide and include a wide range of risks and sometimes even legal hazards

Drug abuse is a major problem in most countries of the world today. Many studies, surveys, and case reports have described the adverse social and medical effects of drug abuse; yet surprisingly little is known about the specific effects of many of these drugs in the oral cavity. . The dentist must be aware of this drug use in their individual patients in order to: 1) avoid possible contraindications during dental treatment; 2) be aware of the many oral and craniofacial manifestations of such drug use; 3) be able to provide necessary dental treatment to combat the dental oral ravages of drug use and 4) be able to refer such patients, if so desired by the patient, to the proper professionals for counselling. This review describes systemic and oral effects of Recreational Illicit Drug

 This case introduces students to data visualization by requiring them to analyze labor cost data for a fictional pharmacy. The case enhances students’ understanding of cost behavior by illustrating that an organization’s cost structure can evolve, which highlights the importance of using relevant data. This case is written for students without exposure to data analytics, but it includes suggestions for advanced data analysis. The case can be used in any course that discusses the cost equation. The case can be covered in one class and is adaptable to both online and in-person instruction. Instructors can customize their teaching of the case to further coverage of data analysis techniques or changes to a business’s cost structure. The case includes instructions for generating a new dataset each semester.

Labor Cost Visualization at Carescript: An Introductory Data Analytics Case for Management Accounting

Hopes, Dreams, and Challenges of Digital Nirvana: The State of the Art and the Art of the Possible in Digital Twin and Digital Thread

2018 Aerodynamic Measurement Technology and Ground Testing Conference

Reinventing the Arnold Engineering Development Complex: Reflections on a Decade of Progress Towards Restoring Technical Excellence at the World’s Largest and Most Advanced Complex of Flight Simulation

 Single audits provide critical accountability for federal grant awards. Our study comprehensively examines differences in single audit findings (related to both financial statements and major program compliance) by auditee type (state/local government and nonprofit) and across varying levels of auditor expertise. In a sample of 24,144 audit engagements over the period 2004 through 2010, nonprofit auditees report fewer internal control deficiencies than government auditees, but more instances of questioned costs related to major programs. Audits conducted by firms with lower single audit expertise are associated with fewer financial statement and major program compliance findings. The results by auditee type and auditor expertise are important to discussions of single audit quality.

A Comprehensive Analysis of Findings from Single Audits: The Implications of Auditee Type and Auditor Expertise

Is Digital Thread/Digital Twin Affordable? A Systemic Assessment of the Cost of DoDs Latest Manhattan Project

ABSTRACT: Lenzini Steel is an inter-disciplinary case that uses four inter-company transactions (ICTs) to demonstrate how the cost/managerial concept of transfer pricing can impact financial and/or tax disclosures on an international stage. The goal is to strengthen students' managerial/cost accounting, tax, and/or financial accounting skills by asking them to examine a transfer pricing case from the different technical perspectives. The case tells the story of an Italian parent company with significant cash flow inflexibility. It needs an infusion of cash from its U.S.-based subsidiary to remain viable, while limiting tax exposure. Students may face any or all of these issues: (1) How can the parent company best obtain the cash it so urgently needs? (2) What are the tax consequences of management's decisions to obtain this cash? (3) What are the financial accounting implications of these decisions? (4) How will they communicate potentially bad news? When using the case, instructors can use an integrated ...

Lenzini Steel: The Impact of Transfer Pricing and Taxes on International Operations

Untangling the Digital Thread: The Challenge and Promise of Model‐Based Engineering in Defense Acquisition

This paper examines Project “Tropic Thunder,” a US Air Force effort to integrate a 0.50 caliber machine gun onto the C‐145 Skytruck. The paper compares the project with relevant literature to determine where the project does and does not alignment with other rapid development models, revealing shortfalls in stakeholder identification and requirements definition that significantly delayed the project. Ultimately, the system works as desired, the design proved to be flightworthy, and the User was happy with the results. However, more up‐front rigor in the systems engineering process could potentially have resulted in a similar level of technical performance, only faster and cheaper. The case depicts the importance of the initial steps in the systems engineering process to the overall success of a rapid development effort.

7.4.1 Rapid Development Case Study: Lessons Learned From Arming the C‐145 Skytruck

This case highlights a unique program for students pursuing a graduate degree in accounting. The program’s mission is to prepare students to be effective leaders and communicators in their careers. To accomplish this mission, the program has developed a Leadership and Professional Development Center (LPDC) that uses physical, virtual, and external space to support programmatic goals through cross-disciplinary collaboration. The LPDC houses trained consultants who provide services such as feedback on written documents, mock interviews, presentation assessment, and self-awareness development. The LPDC also hosts workshops on a variety of leadership and professional development topics. Furthermore, consultants partner with faculty and professionals to provide instruction and experiential learning inside and outside the classroom. The goal of this chapter is to highlight how cross-disciplinary partnerships promote learning in physical, virtual, and external spaces. Recommendations for navigating and utilizing cross-disciplinary collaborations are provided as well as suggestions for implementation in various learning spaces. Jennifer Butler Ellis Northern Illinois University, USA Timothy D. West Northern Illinois University, USA Angela Grimaldi Northern Illinois University, USA Gerald Root Northern Illinois University, USA DOI: 10.4018/978-1-4666-5780-9.ch058

Ernst & Young Leadership and Professional Development Center: Accounting Designed for Leaders

The Lenzini Steel case extends the classic cost/managerial accounting treatment of transfer pricing to include a wider range of inter-company transactions (ICTs): (1) product sales (traditional setting), (2) royalty payments for intellectual property, (3) machine acquisition and management fees, and (4) working capital loans. As described by Ernst & Young (2010), transfer pricing is one of the most important issues facing multinational companies today, and its relevance is increasing. Yet transfer pricing often remains essentially under-taught in junior, senior and masters-level accounting classrooms. Faculty need new teaching materials that reflect the increasing complexity associated with transfer pricing. We wrote the case to begin filling the void.In this case, students must integrate concepts from three accounting disciplines: cost/managerial accounting, financial reporting (through an auditor’s view), and tax accounting. More importantly, however, students are asked to exercise their critical thinking skills by evaluating the four ITCs and establishing a defensible transfer pricing range for each. The Institute of Management Accountants (IMA 2013) and the American Institute of Certified Public Accountants (2005) have emphasized critical (or strategic) thinking skills as a key competency for accounting professionals. Based upon their analyses, students must use their critical thinking skills to assess the defense-ability of each ITC in terms of FIN 48 (codified as ASC 740-10), and recommend a reserve for uncertain tax positions that should be recorded in Lenzini’s financial statements. The case requires students to travel from the more familiar (establishing a transfer price for different inter-company transactions) to the less familiar (predicting who benefits and who suffers from the student’s transfer pricing decision), while considering an environment where division managers act in their own self-interest. As the final case requirement, students must develop the talking points they will use to convince company management to record the reserve and reduce net income, analyze which of the CFOs (1 corporate-level and 3 division-level) will push back, and anticipate the counter-arguments the CFOs might use.

Lenzini Steel: The Impact of Transfer Pricing and Taxes on Global Operations

This study examines relationships between perceived ethical climate types, as determined using Victor and Cullen’s (1988) ethical climate questionnaire, and actual cheating behavior by students completing a take-home exam problem. Data regarding students’ behavior were gathered from sixty-four students in two sections of an accounting course at a well-known university. Our major finding is that students who perceive the classroom as a benevolent climate focused on local groups (i.e. team identification is preeminent) engage in more cheating behavior than do students who perceive a benevolent climate focused on broader organization or societal groups. We conclude by discussing the ethical and pedagogical implications of this association between team-interest climate and higher levels of cheating behavior.

ABSTRACT: In recognition of the evolving body of knowledge in the accounting profession, the American Institute of Certified Public Accountants (AICPA 2010) highlights the importance of viewing learning as a lifelong process that requires self-awareness and extends beyond the academic setting. Metacognition, the assessment and regulation of one's own learning, is a crucial element in lifelong learning. We draw upon judgment of learning research and introduce mindset theory to explore the relationship among (1) exam performance, (2) calibration error, measured as expected minus actual exam scores, and (3) mindset, a person's basic beliefs about learning and ability (Dweck 2000, 2006) in the accounting classroom. We find strong evidence that exam performance is inversely related to calibration error (Kruger and Dunning 1999). We also find modest evidence that a growth mindset is associated with improved performance and decreased calibration error. While the mindset results were not entirely consistent with ...

Accounting Students' Metacognition: The Association of Performance, Calibration Error, and Mindset

Abstract : The computing environment of 2035 is projected to be vastly different from that of today. Assuming that processing power continues to double every 18 months in accordance with Moore's Law, computers will be 41,285 times more powerful. Further, the environment will likely be saturated with microchips: in our walls, our furniture, our clothes, and even in our bodies. As a result, many analysts share a common belief that it will be impossible for a clandestine group or individual to hide in such a society -- that tomorrow's Osama bin Laden does not have a prayer of staying below the radar for 10 minutes, let alone 10 years. This minority report challenges that belief by first showing that the amount of data available to be analyzed is currently growing faster than processing power, and then discussing the challenges and complexities this creates for employing global strike against a violent nonstate actor (VNSA) in the 2035 timeframe. It examines each of the six steps of the kill chain (e.g., Find, Fix, Track, Target, Engage, and Assess) and considers the actions a VNSA might employ to block that step. The paper shows that an enemy who can break even one link in the kill chain can effectively thwart global strike, at least temporarily. Further, the earlier the VNSA breaks the chain, the more likely his survival, with the ideal being to break the chain before the enemy can even find the VNSA. The author concludes that the key to a successful global strike against a VNSA in 2035 is the intelligence that enables the strike, and not the strike weapon itself. Thus, he recommends that the Air Force continue to invest in a full spectrum of intelligence, surveillance, and reconnaissance technologies.

Minority Report: Potential Challenges in Employing Global Strike Against Violent Non-State Actors in 2035

Managers at the Caterpillar plant in Aurora, Illinois were facing a request from senior executives at the home office in Peoria, Illinois for a “Footprint Study” – Identify the best global source (location) for production of the company’s new hybrid/electric exoloader. Using Caterpillar’s capital expenditure model (CapX model), students must decide whether to recommend expanding and refocusing an existing production facility in Aurora IL (Scenario A), or building a new facility in China (Scenario B). On the surface, the standard capital budgeting template looks like a clear manifestation of the rational decision making model. Decision makers, however, are subject to a predictable set of psychological biases (decision heuristics) that may surreptitiously influence the underlying assumptions used to produce a “rational decision” (Bazerman, 2009; Kahneman et al. 2011). The case introduces students to a variety of these decision biases in the context of the capital budgeting decision. Students are required to examine how the assumptions underlying Caterpillar’s capital budgeting template could be influenced by individuals’ decision biases. Furthermore, the case provides an opportunity for students identify the risk factors identified in Caterpillar’s 10-K and consider how the overall risk environment influences the company’s financial statements. Given their assessments of the overall risk environment, student must incorporate their assessments into a determination of the investment hurdle rates appropriate for the alternative capital expenditure scenarios. Ultimately, students must identify the assumptions underlying the CapX model and evaluate these assumptions on two dimensions: (1) importance of the assumption, and (2) uncertainty of the assumption. Students can use the resulting 2 × 2 matrix of assumptions to think about how they would prioritize their time in terms validating the model assumptions and assess how decision biases might influence assumptions uncertainty. In the terms of class implementation, the case is structured to essentially create a debate between those who support Scenario A (U.S. production) and those who support Scenario B (China production). For every argument in support of Scenario A, students also must develop a counter-argument against Scenario A and in favor Scenario B. The objective is to increase students’ ability to think using a 360° perspective. By pursuing a 360° perspective students open themselves up to a wider decision making perspective that might include innovative and potentially superior decision alternatives.

Caterpillar, Inc: The Impact of Decision Biases and Risk on Capital Budgeting

This chapter demonstrates (1) divergence between spending based upon a budget ratcheting model and a benchmark spending model, (2) that this divergence affects organizational performance, and (3) that internal benchmarking enables unit-to-unit performance comparisons, despite claims of organizational or unit uniqueness. We contrast two spending models to examine whether the divergence, or cost estimation gap, affects operating performance across inpatient (n=4,536) and outpatient departments (n=8,438) in 23 U.S. Army hospitals. Using a fixed-effects panel data methodology for fiscal years 2004–2006, we find that unit managers’ spending in this setting is more closely approximated by budget ratcheting. Using multiple performance metrics measured via a DuPont-like decomposition, we find that, within a specified range, operating performance generally improves as resources become constrained. Outside that range, however, we find nonlinear performance effects that approximate a quadratic loss function. Our benchmark model enables clinical department comparisons while controlling for facility, clinical specialty, and case mix severity. The resulting departmental comparability facilitates identification and communication of best practices across the entire Army hospital system. These results should be of interest to corporate executives, government officials, and agency managers who have responsibility for establishing funding mechanisms that include performance-based components.

Internal financing decisions regarding corporate real estate are not market determined. Managers calculate occupancy costs by utilizing capital allocations, financial charges, and IRRs. This process can be rather arbitrary. Although newer costing systems produce more accurate numbers, they may not create better working relations. This article demonstrates that desired organizational behavior in some instances may be motivated more effectively with three imprecise financial techniques than with truly accurate costing.

We explore how the practice of reverting unused funds (budget lapsing) affects intra‐ and inter‐year spending patterns. Data from 31 army hospitals over a period of five years provide strong support for a saving‐dissaving model. Hospital administrators appear to stockpile pharmaceuticals and other supplies toward the end of a fiscal year, leading to a significant spike in spending that potentially exhausts their budget. Interestingly, data show a decline at the start of the next fiscal year that is larger than the preceding spike, indicating that mangers build a reserve for later use. The magnitude of the reserve accumulated at the start of a year is reliably persistent across years and accelerates the upward trend in spending through the year. That is, managers increasingly expend the reserve as environmental uncertainty decreases.We conclude that risk‐aversion plays a significant role in determining intra‐year trends.

Spending Patterns with Lapsing Budgets: Evidence from U.S. Army Hospitals

The economic benefit of goal congruence and implications for management control systems

Recent work on moral reasoning has focused on the psychological relationship between the actor, the action and the outcome. The argument is that a tighter connection between these categories leads to more moral behavior. Using data from students who cheated on an exam, we extend this literature by delineating how people can rationalize non-moral behavior by loosening the above relationships. In particular, we found that students tried to distance themselves from the wrongfulness of cheating using four types of rationalization: separating themselves from the action, blaming a third-party for influencing the decision, re-defining the action as something good, and defining alternate outcomes from the behavior. Supporting these rationales are nine basic arguments based on confusion, character, professor clarity, attractive nuisance, culture, intent, acceptance, comparisons and outcome. We conclude by discussing the implications of these findings for our understanding of moral reasoning and provide some practical approaches for minimizing this behavior.

Ethical Distancing: Rationalizing Violations of Organizational Norms

In this paper, we examine whether indigent care provided by hospitals contributes to output congestion. An increase in output congestion could make the cost of delivering indigent care more costly than managers believe. We distinguish between charity (indigent) care and bad debt expense in an effort to understand the full cost of charity care. We use data from 128 Oklahoma hospitals to measure hospital productivity based upon analytical models developed in the paper using DEA methodology. Our results indicate that hospitals in this study experience roughly the same level of bad debt expense; however, hospitals differ in terms of technical efficiency due to the indigent care being delivered.

Cheating and Moral Judgment in the College Classroom: A Natural Experiment

To examine whether cost management strategies are used in a revenue-constrained environment without compromising clinical effectiveness.

Cross-sectional analysis of monthly cost and acuity-adjusted hospitalization data.

METHODS
This research included longitudinal regression analyses involving 10 years of data, 1990 through 1999, from each of 6 dialysis centers. Two sets of regression models were used: one set examined cost interactions and cost trends (P < or = .001); the second set examined clinical outcomes (P < or = .001). Four cost management strategies were examined: (1) selective reductions in targeted cost categories, (2) cost reductions through improved efficiencies, (3) cost avoidance by shifting responsibilities to external parties, and (4) uniform reductions across all cost categories.

RESULTS
Managers appeared to have limited opportunity to selectively or uniformly reduce costs because of cost "stickiness" and minimal resource substitutability. Improvements in operational efficiencies and cost shifting to external parties occurred. Over time, however, realized efficiencies increased at a decreasing rate, whereas cost shifting actually declined. Contrary to prior hospital studies, these results indicate significant economies of scale. No statistical correlation was found to indicate that the physician/clinic management teams' use of cost reduction strategies affected acuity-adjusted hospitalizations of dialysis patients.

Strategic models that include both financial and outcomes data can enable healthcare managers to predict both positive and negative results of cost management proposals. These models can help identify aspects of an organization's cost structure that affect sustainable cost savings: cost stickiness, cost substitutability, institutional experience, realized operational improvements, and economies of scale.

Identifying cost management strategies in dialysis clinics: sustainable savings with positive outcomes.

In addition to providing comparable and verifiable evidence regarding outcomes, clinical trials could also serve as sources of accurate and replicable financial information. Trial reports that identify expenses associated with effective diagnostic and therapeutic interventions enable cost controls. Standardized cost calculations could help clinicians and administrators identify more efficient health care technologies. Unfortunately, relatively few published trials include economic analyses and when they do, data are incomplete. Based on analyses of 97 clinical trial reports, this article proposes a standard costing format. Health care financial managers have the costing expertise necessary to implement and interpret standardized cost calculations for clinical trials. With the active involvement of financial managers, a standard costing format for clinical trials can be achieved.

Financial managers' costing expertise is needed in clinical trials.

OBJECTIVE
In the present era of cost containment, physicians need reliable data about specific interventions. The objectives of this study were to assist practitioners in interpretation of economic analyses and estimation of their own costs of implementing recommended interventions.

MEDLINE search from 1966 through 1995 using the text words cost or expense and medical subject heading (MeSH) terms costs and cost analysis, cost control, cost of illness, cost savings, or cost-benefit analysis.

The 4 eligibility criteria were clinical trial with random assignment; health care quality improvement intervention tested; effects measured on the process or outcome of care; and cost calculation mentioned in the report.

After independent abstraction and after consensus development, financial data were entered into a costing protocol to determine which costs related to the intervention were provided.

Of 181 articles, 97 (53.6%) included actual numbers on the costs of the intervention. Of 97 articles analyzed, the most frequently reported cost figures were in the category of operating expenses (direct cost, 61.9%; labor, 42.3%; and supplies, 32.0%). General overhead was not presented in 91 (93.8%) of the 97 studies. Only 14 (14.4%) of the 97 studies mentioned start-up costs. The text word $ in the abstract and the most useful MeSH index term of cost-benefit analysis appeared with nearly equal frequency in the articles that included actual cost data (37.1 % vs 35.1%). Two thirds of articles indexed with the MeSH term cost control did not include cost figures.

Statements regarding cost without substantiating data are made habitually in reports of clinical trials. In clinical trial reports presenting data on expenditures, start-up costs and general overhead are frequently disregarded. Practitioners can detect missing information by placing cost data in a standardized protocol. The costing protocol of this study can help bridge care delivery and economic analyses.

During the race for costing accuracy in health care, managers should acknowledge the equal importance of interdepartmental relations. Although newer costing systems can produce more accurate numbers, greater costing accuracy may not always strengthen the organization. This article demonstrates that subsidizing some capital and administrative (indirect) costs for select hospital departments may help to achieve strategic management objectives.

Managing capital and administrative (indirect) costs to achieve strategic objectives: the dialysis clinic versus the outpatient clinic.

In the name of costing accuracy, nurses are asked to track inventory use on per treatment basis when more significant costs, such as general overhead and nursing salaries, are usually allocated to patients or treatments on an average cost basis. Accurate treatment costing and financial viability require analysis of all resources actually consumed in treatment delivery, including nursing services and inventory. More precise costing information enables more profitable decisions as is demonstrated by comparing the ratio-of-cost-to-treatment method (aggregate costing) with alternative activity-based costing methods (ABC). Nurses must participate in this costing process to assure that capitation bids are based upon accurate costs rather than simple averages.

To obtain cost data needed to improve managed care decisions and negotiate profitable capitation contracts, most healthcare provider organizations use one of three costing methods: the ratio-of-costs-to-charges method, the relative value unit method, or the activity-based costing method. Although the ratio-of-costs to charges is used by a majority of provider organizations, a case study that applied these three methods in a renal dialysis clinic found that the activity-based costing method provided the most accurate cost data. By using this costing method, healthcare financial managers can obtain the data needed to make optimal decisions regarding resource allocation and cost containment, thus assuring the longterm financial viability of their organizations.

Contrasting RCC, RVU, and ABC for managed care decisions. A case study compares three widely used costing methods and finds one superior.

External auditors' risk assessment decisions : the impact of implementing activity-based costing

To describe the first Australian cases of severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV2) disease (COVID‐19) pneumonia treated with the interleukin‐6 receptor antagonist tocilizumab.

Tocilizumab for severe COVID‐19 pneumonia: Case series of 5 Australian patients

Comparison of three commercially available ELISA assays for anti-infliximab antibodies.

Understanding the sources of tremor variability in patients with essential tremor, Parkinson’s, and dystonia – a non-invasive study of movement and brain signals

Comparison of three commercially-available elisa assays for anti-infliximab antibodies

A signal-to-cutoff ratio in the roche elecsys HIV Ag/Ab assay to predict confirmed HIV-1 infection in a low-prevalence setting

Purpose of review Atrial fibrillation is increasingly common in the ageing population. Patients with atrial fibrillation and HIV have a higher stroke risk, with guidelines recommending anticoagulation in the majority. Whilst anticoagulation options have diversified in the last decade for the general population, there is limited evidence for the safety and efficacy of these medications when used concurrently with antiretroviral therapy. We review the potential for patients with HIV on antiretroviral therapy to have direct-acting oral anticoagulations (DOACs). Recent findings Several case reports have been published in the past 5 years, as well as theoretical analyses of anticipated drug interactions, which provide a starting point to guide use of DOACs with antiretroviral medications. Summary Caution is needed when prescribing DOACs in patients with atrial fibrillation and HIV due to potential drug interactions. Studies are lacking and current advice is based on case reports, expert opinion and knowledge of theoretical interactions.

Use of direct oral anticoagulants for treatment of atrial fibrillation in patients with HIV: a review

THE MEIOSIS SPECIFIC AAA+ ATPASE PCH2 INTERACTS WITH THE SYNAPTONEMAL COMPLEX PROTEIN HOP1 THROUGH THE HOP1 HORMA DOMAIN

The cortical mechanisms underlying the act of taking a step-including planning, execution, and modification-are not well understood. We hypothesized that oscillatory communication in a parieto-frontal and corticomuscular network is involved in the neural control of visually guided steps. We addressed this hypothesis using source reconstruction and lagged coherence analysis of electroencephalographic and electromyographic recordings during visually guided stepping and 2 control tasks that aimed to investigate processes involved in (i) preparing and taking a step and (ii) adjusting a step based on visual information. Steps were divided into planning, initiation, and execution phases. Taking a step was characterized by an upregulation of beta/gamma coherence within the parieto-frontal network during planning followed by a downregulation of alpha and beta/gamma coherence during initiation and execution. Step modification was characterized by bidirectional modulations of alpha and beta/gamma coherence in the parieto-frontal network during the phases leading up to step execution. Corticomuscular coherence did not exhibit task-related effects. We suggest that these task-related modulations indicate that the brain makes use of communication through coherence in the context of large-scale, whole-body movements, reflecting a process of flexibly fine-tuning inter-regional communication to achieve precision control during human stepping.

Dynamics of cortical and corticomuscular connectivity during planning and execution of visually guided steps in humans.

Objective: A transcranial magnetic stimulation system with programmable stimulus pulses and patterns is presented. The stimulus pulses of the implemented system expand beyond conventional damped cosine or near-rectangular pulses and approach an arbitrary waveform. Methods: The desired stimulus waveform shape is defined as a reference signal. This signal controls the semiconductor switches of an H-bridge inverter to generate a high-power imitation of the reference. The design uses a new paradigm for TMS, applying pulse-width modulation with a non-resonant, high-frequency switching architecture to synthesize waveforms that leverages the low-pass filtering properties of neuronal cells. The modulation technique enables control of the waveform, frequency, pattern, and intensity of the stimulus. Results: A system prototype was developed to demonstrate the technique. The experimental measurements demonstrate that the system is capable of generating stimuli up to 4 kHz with peak voltage and current values of ±1000 V and ±3600 A, respectively. The maximum transferred energy measured in the experimental validation was 100.4 Joules. To characterize repetitive TMS modalities, the efficiency of generating consecutive pulse triplets and quadruplets with interstimulus intervals of 1 ms was tested and verified. Conclusion: The implemented TMS device can generate consecutive rectangular pulses with a predetermined time interval, widths and polarities, enables the synthesis of a wide range of magnetic stimuli. Significance: New waveforms promise functional advantages over the waveforms generated by current-generation TMS systems for clinical neuroscience research.

Programmable Transcranial Magnetic Stimulation: A Modulation Approach for the Generation of Controllable Magnetic Stimuli

This thesis concerns the properties and emergence of pathologically synchronized brain networks in Parkinson’s disease (PD), a neurodegenerative disorder of the motor system. Excessive oscillatory power in the beta frequencies (14-30 Hz), measured from recordings of activity in the subthalamic nucleus (STN) in the basal ganglia, has been repeatedly linked to the motor impairment associated with PD. However, it is not yet known: (i) how this aberrant rhythmicity is generated; and (ii) how this activity may impair propagation of normal activity across the network. This work makes novel analyses of electrophysiological recordings from both patients with PD, as well as rodent models of the neuropathology. In patients, we use both local field potential (LFP) and magnetoencephalography recordings that were made following surgery for deep brain stimulation. In animal models, we investigate multisite LFP recordings from across the networks formed by the cortex and basal ganglia of animals with a pharmacological lesion designed to mimic the generation of dopamine neurons associated with the disease. The nature of altered local and long-distance synchronization is investigated using a combination of tools from signal analysis, dynamical systems theory, and computational modelling. I specifically address: 1) how altered synaptic connectivity arising due to dopamine depletion may lead to the emergence of pathologicallly rhythmic activity in the beta frequencies; 2) the determination of the time resolved dynamics of beta oscillations and their relationship to cortical input; 3) the plausibility of a hypothesis of a dynamical shift in PD of brain networks towards more stable states. I find evidence that the beta rhythm is pathologically synchronized across the STN and neighbouring structures of the basal ganglia, and that the propagation of normal rhythmic activity is impaired by dopamine depletion.

The Dysregulation of Synchronized Brain Oscillations in Parkinson's Disease

Brain oscillations involve rhythmic fluctuations of neuronal excitability and may play a crucial role in neural communication. The human corticomuscular system is characterized by beta activity and is readily probed by transcranial magnetic stimulation (TMS). TMS inputs arriving at the excitable phase of beta oscillations in the motor cortex are known to lead to muscle responses of greater amplitude. Here we explore two other possible manifestations of rhythmic excitability in the beta band; windows of reduced response variability and shortened latency. We delivered single-pulse TMS to the motor cortex of healthy human volunteers (10 females and 7 males) during electroencephalography recordings made at rest. TMS delivered at a particular phase of the beta oscillation benefited from not only stronger, but also less variable and more rapid transmission, as evidenced by the greater amplitude, lower coefficient of variation, and shorter latency of motor evoked potentials. Thus, inputs aligned to the optimal phase of the beta EEG in the motor cortex enjoy transmission amplitude gain, but may also benefit from less variability and shortened latencies at subsequent synapses. Neuronal phase may therefore impact corticospinal communication. SIGNIFICANCE STATEMENT Brain oscillations involve rhythmic fluctuations of neuronal excitability. Therefore, motor responses to transcranial magnetic stimulation are larger when a cortical input arrives at a particular phase of the beta activity in the motor cortex. Here, we demonstrate that inputs to corticospinal neurons which coincide with windows of higher excitability also benefit from more rapid and less variable corticospinal transmission. This shortening of latency and increased reproducibility may confer additional advantage to inputs at specific phases. Moreover, these benefits are conserved despite appreciable corticospinal conduction delays.

Motor Cortex Inputs at the Optimum Phase of Beta Cortical Oscillations Undergo More Rapid and Less Variable Corticospinal Propagation

ABSTRACT The ways in which cell architecture is modelled to meet cell function is a poorly understood facet of cell biology. To address this question, we have studied the cytoarchitecture of a cell with highly specialised organisation, the cochlear inner hair cell (IHC), using multiple hierarchies of three-dimensional (3D) electron microscopy analyses. We show that synaptic terminal distribution on the IHC surface correlates with cell shape, and the distribution of a highly organised network of membranes and mitochondria encompassing the infranuclear region of the cell. This network is juxtaposed to a population of small vesicles, which represents a potential new source of neurotransmitter vesicles for replenishment of the synapses. Structural linkages between organelles that underlie this organisation were identified by high-resolution imaging. Taken together, these results describe a cell-encompassing network of membranes and mitochondria present in IHCs that support efficient coding and transmission of auditory signals. Such techniques also have the potential for clarifying functionally specialised cytoarchitecture of other cell types. Summary: 3D electron microscopy reconstructs the highly organised structure of the infranuclear region of the cochlear inner hair cell, which supports synaptic functions.

Association of intracellular and synaptic organization in cochlear inner hair cells revealed by 3D electron microscopy

A computational model of the outer hair cell (OHC) of the mammalian cochlea is presented. It addresses the way in which movement of ions controls the cell shape and regulates pH. The model takes into account the possible chloride–bicarbonate exchange function of prestin, a protein highly expressed in the plasma membrane of OHCs. A model of intracellular pH transients following the imposition of a rapid acid load upon the cell has been adapted from the squid axon literature and further extended in order to investigate the effects of ion transport upon the osmotic flux of water into the cell. The model predicts the slow length changes of OHCs reported in the literature a feature which may control the contribution of OHCs to cochlear amplification.

A model of ionic transport and osmotic volume control in cochlear outer hair cells

YFP detection of chloride transport by the outer hair cell protein prestin

Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study

Myelitis is a rare neurological disorder of the spinal cord that is caused by inflammation and can have devastating neurologic effects with up to two-thirds of patients having a moderate to severe degree of residual disability. Symptoms typically develop over hours or days and then worsen over a matter of days to weeks. Patients can present with sensory alteration, weakness, and autonomic dysfunction including bowel and bladder problems, temperature dysregulation, or even bouts of hypertension. Evaluation for compressive etiologies must be a priority as compressive myelopathy and transverse myelitis are often clinically indistinguishable and emergent surgical intervention is indicated in such cases. However, if neuroimaging and CSF studies indicate inflammation within the central nervous system, then a work-up for myelitis must include autoimmune, inflammatory, and infectious etiologies. Acute management of these patients is dictated by which etiology is suspected and rapid initiation of that treatment portends a more favorable patient outcome. This review will discuss a practical clinical approach to the diagnosis and acute management of patients with myelitis including clinical symptoms, the role of neuroimaging, and the utility of both CSF and serological studies in the management of these patients.

Transverse myelitis--a review of the presentation, diagnosis, and initial management.

Natalizumab is an a-4 integrin antagonist that decreases lymphocyte trafficking into the central nervous system. Randomized controlled clinical trials have found that natalizumab treatment reduces relapse rate, progression of disability and accumulation of brain magnetic resonance image (MRI) lesions [1] and is approved throughout the world to treat relapsing multiple sclerosis (MS). In 2005, natalizumab was recognized to be associated with progressive multifocal leukoencephalopathy (PML), which is an opportunistic viral infection of the brain that often leads to death or severe disability. Prior exposure to immunosuppressant medication, seropositivity for JC virus antibodies and longer exposure to natalizumab are now known to confer increased risk of developing this infection [2]. As of August 2011, there have been 150 cases of PML worldwide in patients treated with natalizumab, including 29 deaths [2]. The current estimated overall risk of developing PML is 1.6 per 1000 patients. However, the estimated risk increased up to 7.80 per 1000 (95% CI 5.20–11.30) in anti-JC virus-positive patients with previous immunosuppressant use and natalizumab exposure over 25 months [3]. The only intervention with demonstrated efficacy against PML is immune reconstitution. Treatment interruptions have been hypothesized as a means of allowing immune reconstitution, thus decreasing the cumulative risk of developing PML [4]. However, case series have found treatment interruption may risk an aggressive return of MS disease activity [5,6]. In contrast, a post hoc analysis of pivotal natalizumab trial subjects following the 2005 natalizumab treatment suspension reported that the annualized relapse rate did not increase above the baseline, pre-trial relapse rate [7]. This study found no evidence of a rebound phenomenon amongst the group average disease activity, although it does not exclude rebound disease activity above pre-natalizumab levels amongst individual patients. With the concern for return of disease activity, some have suggested that when natalizumab dosage is interrupted for more than 2 months, another diseasemodifying therapy be started [8]. The optimal alternative MS therapy is not currently known and is complicated by many natalizumab-treated patients having either poorly tolerated or sub-optimally responded to first-line MS therapies such as interferon (IFN) and glatiramer acetate (GA). Another alternative for helping to mitigate the return of disease activity following natalizumab cessation could be pulsed intravenous (IV) corticosteroids. In this issue, Borriello [9] report an open-label observational study of pulsed IV methylprednisolone in 23 patients with MS over a 90to 150-day elective interruption of natalizumab treatment. One gram of monthly IV methylprednisolone was given throughout the interruption period. They found that despite methylprednisolone treatment, 30% (n = 7) of patients still showed active inflammation on brain MRI and 17% (n = 4) experienced a clinical relapse during a mean time of 105 days off medication (range 60– 143 days). In line with prior reports of a possible rebound effect, they also reported that approximately 9% (n = 2) of patients had a dramatic return of disease activity as evidenced by 7–11 contrast-enhancing lesions on MRI. Importantly, this type of study is unable to address whether this natalizumab interruption is effective in reducing the risk of PML. Another small study evaluated a shorter, 3-month treatment with pulse IV methylprednisolone followed by GA therapy. That regimen also did not appear to prevent return of disease activity [10]: 55.5% (n = 10) of patients showed contrast-enhancing lesions on brain MRI at 6 months, with 16.6% (n = 3) of patients experiencing a clinical relapse. Together, these natalizumab interruption studies suggest that there is a high risk of recurrent MS disease activity during a natalizumab holiday . Given the unknown efficacy in reducing the risk of PML and the high risk of recurrent inflammatory activity, natalizumab interruptions simply to reduce the risk of PML appear unwise. If PML is a significant concern for a particular patient, then alternative treatments should be considered. Despite relatively clear indications to start natalizumab therapy, the Borriello study highlights that a reliable means of safely discontinuing natalizumab continues to be elusive. With 30–50% of patients suffering a return of disease activity within 6 months of discontinuation, it seems intuitive to start another treatment as soon as possible, but which medication? Patients who previously failed IFN and/or GA would be unlikely to benefit from them after natalizumab treatment. Corticosteroids do not appear to mitigate a return of disease activity [9]. Fingolimod is another potential treatment option, but little is known about its safety following natalizumab therapy. Because fingoli-

Abstract Acute transverse myelitis is a rare neurologic condition that has an estimated incidence of up to 3 per 100,000 patient years (0.003%). Although rare, acute transverse myelitis can have devastating neurologic effects with up to two-thirds of patients having a moderate to severe degree of residual disability. The term acute transverse myelitis was previously reserved for idiopathic cases, but currently is used to encompass the general clinical syndrome, whether or not the cause is known. Once adequate neuroimaging has ruled out a compressive etiology, and a lumbar puncture has demonstrated signs of inflammation within the cerebrospinal fluid, a workup of causes for an acute transverse myelitis must be undertaken. Determining the etiology of transverse myelitis can be challenging because there are autoimmune, inflammatory, and infectious diseases associated with acute transverse myelitis. The authors discuss an approach to acute transverse myelitis including clinical symptoms, neuroimaging, and biomarkers that may aid the clinician in diagnosis.

Acute Transverse Myelitis: Demyelinating, Inflammatory, and Infectious Myelopathies

ISSN 1758-2024 10.2217/NMT.10.4 © 2011 Future Medicine Ltd Neurodegen. Dis. Manage. (2011) 1(1), 11–14 Natalizumab is a humanized anti-a4 integrin monoclonal antibody that decreases lymphocyte trafficking into the CNS. It is US FDA approved for treatment of relapsing–remitting multiple sclerosis (MS) and is proven to reduce relapse rate, progression of disability and accumulation of brain MRI lesions [1,2]. Shortly after FDA approval in 2004, two patients in the SENTINEL trial developed progressive multifocal leuko encephalopathy (PML), resulting in natalizumab’s voluntary withdrawal from the market by Biogen Idec. Following a comprehensive safety reevaluation and development of a risk evaluation mitigation strategy natalizumab was reintroduced to the market in 2006 with a black box warning regarding PML risk. As of November 2010, approximately 75,500 patients have been treated with natalizumab worldwide. There are 75 confirmed cases of natalizumab-associated PML, with 15 fatalities. The duration of exposure to natalizumab is associated with increased PML risk [3,4]. The incidence of PML in the first year of treatment is estimated to be less than 1 in 70,000. In the second year of treatment the incidence rises to 1 in 2700 and in the third year of treatment the risk increases further to 1 in 670 [Biogen Idec Medical Affairs, Pers. Comm.]. Fewer data are available for patients receiving continuous natalizumab treatment beyond 3 years; however, the risk seems to decrease in the fourth year of treatment to 1 in 1000. Scheduled dosage interruptions have been proposed to decrease the cumulative risk of developing PML [5]. The rationale for this intervention is to allow reconstitution of lymphocyte trafficking into the CNS. In theory, PML infections might be cleared by trafficking lymphocytes prior to the onset of clinical manifestations. In practice, dosage interruptions typically occur for a period of 3–6 months following at least 12 months of continuous natalizumab treatment. A 3-month dosage interruption was proposed based on the Phase II natalizumab trial in which patients received monthly natalizumab or placebo infusions for 6 months and were then observed for an additional 6 months following discontinuation of the study drugs [6,7]. During the active treatment period natalizumab treatment was associated with a 90% reduction in the cumulative number of

Is there a role for planned natalizumab dosage suspension in mitigating progressive multifocal leukoencephalopathy risk

The risk of developing progressive multifocal leukoencephalopathy increases with the duration of treatment with natalizumab. Planned dosage interruptions have been proposed as a means of decreasing cumulative risk. The clinical consequences of dosage interruption were evaluated in a single center cohort of natalizumab‐treated patients. Medical records were reviewed for 84 patients identified with multiple sclerosis who received 12 or more infusions of natalizumab at an academic multiple sclerosis center. Eighty‐one percent (68/84) underwent a dosage interruption, and 19% (16/84) had no interruption in natalizumab treatment. Of those with a treatment interruption, 27.9% (19/68) experienced a clinical relapse within 6 months of the suspension, whereas none of the patients with ongoing treatment experienced a flare during months 12 to 18 of treatment (p = 0.017, Fisher exact test). Survival analysis showed that Kaplan‐Meier curves comparing dosage interruption to ongoing treatment diverged (p = 0.025). Median time from treatment interruption to relapse onset was 3 months. No clinical predictors associated with an increased risk of developing flares during dosage interruption were identified. Among the 19 patients who had a flare, 7 had severe flares, with a mean number of 16 Gad+ lesions on brain magnetic resonance imaging (range, 6–40). Their median Expanded Disability Status Scale at natalizumab interruption was 3.0 and increased to 6.0 during the flare (p = 0.0008). Natalizumab dosage interruption is associated with clinical flares and return of radiographic inflammatory disease activity. Some of these flares can be clinically severe, with a high number of contrast‐enhanced lesions, suggesting a possible rebound of disease activity. Ann Neurol 2010;68:395–399

Background: Relapsing-remitting multiple sclerosis (RRMS) begins with an initial demyelinating event (IDE) that can be monosymptomatic, polysymptomatic, or polyregional. Failure to recover from the IDE is a known predictor of later development of disability. Factors that predict IDE recovery (outside optic neuritis) and time to second event are relatively unknown. The authors speculate that IDE recovery and time to second event are under separate biologic or genetic control, and as such, their clinical predictors are different. Methods: Data on all UCSF MS clinic patients are entered prospectively into an ACCESS database. The authors identified all patients seen at the UCSF clinic within 1 year of their IDE. Expanded Disability Status Scale scores, functional system scores, and visual acuity were used to define IDE severity and recovery. Results: The cohort included 186 patients (127 women, 59 men) with an average onset age of 34 ± 10 years with 150 whites (non-Hispanic), 15 African Americans, 11 Hispanics, eight Asians, and two unknown/unreported. Worse onset severity predicted worse IDE recovery (23.1% of the patients with severe onset vs 32.9% with moderate severity vs 56.4% with mild onset recovered completely, p < 0.001). Polyregional onset predicted poor recovery compared to monoregional onset (46.2% vs 14.4%, p < 0.001). Nonwhite patients were 2.48 times more likely than whites to experience a second episode within 1 year from onset (95% CI: 1.45 to 4.23, p < 0.001). Similarly, age younger than 30 years predicted higher risk of a second exacerbation (hazard ratio 1.92, 95% CI: 1.17 to 3.15, p = 0.010). Conclusion: Initial demyelinating event recovery and time to second event may have distinct predictors. These findings suggest that recovery and time to second event might be under separate biologic control.

Are initial demyelinating event recovery and time to second event under differential control?

Visual spatial memory is enhanced in female rats (but inhibited in males) by dietary soy phytoestrogens

Intramuscular aurothioglucose (Solganal) leading to panniculitis.

Abstract : This thesis investigates the implementation and evaluation of commercial off-the-shelf (COTS) voice recognition as an input interface within a windows-type environment. The three software packages implemented and evaluated are DragonDictate For Windows version 1.3, VoicePilot 2.0 (both manufactured by Dragon Systems, Inc.), and IN3 Voice Command for SPARCstation version 2.2.2 by Command Corp. VoicePilot and DragonDictate are both installed on PCs running MS Windows 3.1, and IN is installed on a SPARCstation running OpenWindows 3 and SunOS 4.1.3. Several applications are manipulated using voice recognition with these three software packages. The results of this study show that DragonDictate has the most flexibility and ease of use as an input device for a windows-type environment. It is also shown that as usage increases, DragonDictates recognition accuracy is able to be improved to above 98%. Other areas of future research are also suggested.

Implementation and Evaluation of Commercial Off-The-Shelf (COTS) Voice Recognition Software as an Input Device in a Windows-Type Environment.

The presence of endogenous d-stereoisomers of amino acids in mammals dispels a long-standing dogma about their existence. d-Serine and d-aspartate function as novel neurotransmitters in mammals. However, the stereoisomer with the fastest, spontaneous in vitro racemization rate, d-cysteine, has not been reported. We utilized a novel, stereospecific, bioluminescent assay to identify endogenous d-cysteine in substantial amounts in the eye, brain, and pancreas of mice. d-Cysteine is enriched in mice embryonic brains at day E9.5 (4.5 mM) and decreases progressively with development (μM levels). d-Cysteine is also present in significantly higher amounts in the human brain white matter compared with gray matter. In the luciferase assay, d-cysteine conjugates with cyano hydroxy benzothiazole in the presence of a base and reducing agent to form d-luciferin. d-Luciferin, subsequently, in the presence of firefly luciferase and ATP, emits bioluminescence proportional to the concentration of d-cysteine. The assay is stereospecific and allows the quantitative estimation of endogenous d-cysteine in tissues in addition to its specificity for d-cysteine. Future efforts aimed at bioluminescent in vivo imaging of d-cysteine may allow a more noninvasive means of its detection, thereby elucidating its function.

A Novel Stereospecific Bioluminescent Assay for Detection of Endogenous d-Cysteine.

Endogenous D-stereoisomers are being recognized as functionally important molecules in mammals. Here we report the first identification of endogenous D-cysteine in mammalian pancreas. Serine Racemase (SR) is the biosynthetic enzyme for D- cysteine. D-cysteine is present in substantial amounts in the eyes, brain and pancreas of mice. To characterize endogenous D-cysteine, we used SR deficient mice lacking racemizing ability and show 3.5 fold reduction in pancreatic D-cysteine. SR-/- mice produce 6-10 fold higher levels of insulin in the pancreas and plasma and are stored as amyloid aggregates in secretory vesicles and exosomes respectively. Lack of SR and endogenous D-cysteine globally decreased levels of nucleotides and cAMP, followed by reduced phosphorylation of CREB (S133) including lower expression of DNA methyltransferase (DNMT) 1, 3A and 3B, and reduced DNMT enzymatic and promoter activities in the pancreas. This results in decreased DNA methylation globally and specifically of the Ins1 promoter. D-cysteine is efficiently metabolized by D-amino acid oxidase and transported by ASCT2 and Asc1 transporters in cells. Dietary supplementation with methyl donors rescues the high insulin levels and low DNMT activity in SR-/- mice. Our data show that SR racemizes cysteine in the pancreas and is a physiologic down regulator of insulin promoter methylation.

Serine Racemase is a Cysteine Racemase and Physiologic Down Regulator of Insulin Promoter Methylation

Mammalian D-Cysteine is a Physiologic Down Regulator of Insulin Promoter Methylation

Isolation of three forms of DNA-dependent RNA polymerase from Heliothis zea fat body tissue

Purification and properties of deoxyribonucleic acid-dependent ribonucleic acid polymerases from the slime mold Physarum polycephalum.

Abstract This paper summarizes a study conducted to evaluate the fidelity of structural dynamic models for the space station photovoltaic arrays and determine the effect of model fidelity on the accuracy of on-orbit loads analyses. The array blankets do not possess out-of-plane stiffness, but axial forces from negator springs restrain the movement of blankets in the lateral direction. This geometric stiffening effect allows use of quasi-linear dynamic analysis in generating the linearized component model. Physical description, finite element modeling and component model reduction of the array system are discussed. Theoretical background and physical insights of geometric stiffening are also presented through a simple beam-string model. Case study results with two critical transient loading events show that the math model and analysis process can generate accurate dynamic loads responses for the array.

Dynamic loads analysis of photovoltaic arrays for the Space Station

Experimental results are described in which a rod of magnetostrictive terfenol was used in the dual capacity of a passive structural support element and an active vibration control actu ator and artificial neural networks were used for the adaptive real-time control algorithm. Tests were performed on a three-legged table, where the terfenol actuators mentioned above are the table legs. For the table experiment, shaker vibrations generated in the ground and transmitted to the tabletop (via the legs) were attenuated by counter vibrations synthesized in the table leg actuators. The goal of this experiment was to maintain a quiescent tabletop in the presence of floor vibrations. Utilizing a proportional-integral derivative and a neural network controller, actuated forces were used to cancel applied disturbance forces. The neural network architecture identifies (learns) and adapts to the tabletop forced disturbance through a fast adaptation law known as Adaptive Back Propagation, generating the required counter vibration. The architecture and hence the control was designed to be modular so cross talk (coupling in the control signal) is minimized. This puts an extra burden on the controller to decouple the spillovers but maintains modularity, an important feature for large scale implementations. This article describes work in this area and demonstrates the ability to cancel disturbances from static to the hundred hertz frequency range.

Active Vibration Control in Structures Using Magnetostrictive Terfenol with Feedback and/or Neural Network Controllers

Supplementary material from "The origin of heredity in protocells"

Here we develop a computational model that examines one of the first major biological innovations—the origin of heredity in simple protocells. The model assumes that the earliest protocells were autotrophic, producing organic matter from CO2 and H2. Carbon fixation was facilitated by geologically sustained proton gradients across fatty acid membranes, via iron–sulfur nanocrystals lodged within the membranes. Thermodynamic models suggest that organics formed this way should include amino acids and fatty acids. We assume that fatty acids partition to the membrane. Some hydrophobic amino acids chelate FeS nanocrystals, producing three positive feedbacks: (i) an increase in catalytic surface area; (ii) partitioning of FeS nanocrystals to the membrane; and (iii) a proton-motive active site for carbon fixing that mimics the enzyme Ech. These positive feedbacks enable the fastest-growing protocells to dominate the early ecosystem through a simple form of heredity. We propose that as new organics are produced inside the protocells, the localized high-energy environment is more likely to form ribonucleotides, linking RNA replication to its ability to drive protocell growth from the beginning. Our novel conceptualization sets out conditions under which protocell heredity and competition could arise, and points to where crucial experimental work is required. This article is part of the themed issue ‘Process and pattern in innovations from cells to societies’.

Czesław Miłosz, Milan Kundera, Joseph Brodsky, and the Task of the Émigré Critic

Star-Shadow: A Poem Based on William Robinson Leigh's Sioux Family Escaping

Abstract:The polemic generated by Milan Kundera's 1968 essay 'Czech Destiny' and fuelled by Vaclav Havel's sharp reply represents an important milestone in the debate over the merits of the struggle for Czech self-determination. Kundera employs his bold thesis — that the Czechs are the protagonists in a Darwinian contest that pits rationalism and creativity against brutish hegemony — to justify a puzzlingly timid political programme. This paper seeks a tool for examining the stylistic and thematic paradoxes of Kundera's essay in Mikhail Bakhtin's genre study ' Epic and Novel' and it contends that, by invoking an imagined destiny for the Czechs, Kundera becomes complicit in its realization.

Destiny as Alibi: Milan Kundera, Václav Havel and the 'Czech Question' after 1968

On the Encounter with a Divine Presence during a Near-Death Experience

The predominant stride-frequency for routine swimming in catsharks (Scyliorhinus canicula) generates high power at high efficiency in the red musculature.

ABSTRACT Active muscle performs various mechanical functions during locomotion: work output during shortening, work absorption when resisting (but not preventing) lengthening, and impulse (force–time integral) whenever there is active force. The energetic costs of these functions are important components in the energy budget during locomotion. We investigated how the pattern of stimulation and movement affects the mechanics and energetics of muscle fibre bundles isolated from wild rabbits (Oryctolagus cuniculus). The fibres were from muscles consisting of mainly fast-twitch, type 2 fibres. Fibre length was held constant (isometric) or a sinusoidal pattern of movement was imposed at a frequency similar to the stride frequency of running wild rabbits. Duty cycle (stimulation duration×movement frequency) and phase (timing of stimulation relative to movement) were varied. Work and impulse were measured as well as energy produced as heat. The sum of net work (work output−work input) and heat was taken as a measure of energetic cost. Maximum work output was produced with a long duty cycle and stimulation starting slightly before shortening, and was produced quite efficiently. However, efficiency was even higher with other stimulation patterns that produced less work. The highest impulse (considerably higher than isometric impulse) was produced when stimulation started while the muscle fibres were being lengthened. High impulse was produced very economically because of the low cost of producing force during lengthening. Thus, locomotion demanding high work, high impulse or economical work output or impulse requires a distinct pattern of stimulation and movement. Summary: Muscle can be a motor (work output) or a brake (work absorption), or can simply exert force; these functions and their costs are relevant to locomotion. This versatility is revealed by a varying stimulation pattern.

Energy turnover in mammalian skeletal muscle in contractions mimicking locomotion: effects of stimulus pattern on work, impulse and energetic cost and efficiency

Remarkable muscles, remarkable locomotion in desert-dwelling wildebeest

Full title: A post-MI power struggle: adaptations in cardiac power occur at the sarcomere level alongside MyBP-C and RLC phosphorylation. Running head: FV and PV relations define contractile compensation post-CMI

Biomechanics of predator–prey arms race in lion, zebra, cheetah and impala

Remarkable muscles, remarkable locomotion in desert-dwelling wildebeest

Compensation postchronic myocardial infarction (CMI) in rats is characterized in trabeculae as increased force and power production during physiological shortening, which occurs alongside classical hypertrophy. Sarcomeric contractile gain is influenced by mechanisms involving reduced myosin binding protein C (MyBP-C) and raised regulatory light chain (RLC) phosphorylation.

American Journal of Physiology - Heart and Circulatory Physiology

A post-MI power struggle: adaptations in cardiac power occur at the sarcomere level alongside MyBP-C and RLC phosphorylation

Force and power in cardiac muscle have a known dependence on phosphorylation of the myosin-associated regulatory light chain (RLC). We explore the effect of RLC phosphorylation on the ability of cardiac preparations to redevelop force (ktr) in maximally activating [Ca2+]. Activation was achieved by rapidly increasing the temperature (temperature-jump of 0.5–20oC) of permeabilized trabeculae over a physiological range of sarcomere lengths (1.85–1.94 μm). The trabeculae were subjected to shortening ramps over a range of velocities and the extent of RLC phosphorylation was varied. The latter was achieved using an RLC-exchange technique, which avoids changes in the phosphorylation level of other proteins. The results show that increasing RLC phosphorylation by 50% accelerates ktr by 50%, irrespective of the sarcomere length, whereas decreasing phosphorylation by 30% slows ktr by 50%, relative to the ktr obtained for in vivo phosphorylation. Clearly, phosphorylation affects the magnitude of ktr following step shortening or ramp shortening. Using a two-state model, we explore the effect of RLC phosphorylation on the kinetics of force development, which proposes that phosphorylation affects the kinetics of both attachment and detachment of cross-bridges. In summary, RLC phosphorylation affects the rate and extent of force redevelopment. These findings were obtained in maximally activated muscle at saturating [Ca2+] and are not explained by changes in the Ca2+-sensitivity of acto-myosin C © 2016 Wellcome Trust The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society DOI: 10.1113/JP272441 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. 5238 C. N. Toepfer and others J Physiol 594.18 interactions. The length-dependence of the rate of force redevelopment, together with the modulation by the state of RLC phosphorylation, suggests that these effects play a role in the Frank–Starling law of the heart. (Received 16 March 2016; accepted after revision 1 June 2016; first published online 13 June 2016) Corresponding author C. N. Toepfer: Harvard Medical School, Department of Genetics, NRB-room 256, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Email: christopher_toepfer@HMS.harvard.edu Abbreviations CF, conversion factor; DR, duty ratio; f, rate constant of cross-bridge attachment (s−1); F, force produce by an individual cross-bridge (pN); F1.85, force of a maximally activated trabecula at a sarcomere length of 1.85 μm (kN m–2); F1.90, force of a maximally activated trabecula at a sarcomere length of 1.90 μm (kN m–2); F1.94, force of a maximally activated trabecula at a sarcomere length of 1.94 μm (kN m–2); Fiso, isometric force (kN m–2); FL s–1, trabecula shortening velocity (trabecula lengths s–1); Framp, force sustained during a shortening ramp at a steady velocity (kN m–2); Frec, force recovered in isometric conditions after the end of protocol (kN m–2); g, rate constant of cross-bridge detachment (s−1); k1.85, rate of force redevelopment (ktr), at a sarcomere length of 1.85 μm (s−1); k1.90, rate of force redevelopment (ktr), at a sarcomere length of 1.90 μm (s−1); k1.94, rate of force redevelopment (ktr), at a sarcomere length of 1.94 μm (s−1); ktr, rate of force redevelopment (s–1); N, number available cross-bridges for active cycling; RLC, regulatory light chain; SL, sarcomere length (μm).

Regulatory light chain (RLC) phosphorylation has been shown to alter the ability of muscle to produce force and power during shortening and to alter the rate of force redevelopment (ktr) at submaximal [Ca2+]. Increasing RLC phosphorylation ∼50% from the in vivo level in maximally [Ca2+]‐activated cardiac trabecula accelerates ktr. Decreasing RLC phosphorylation to ∼70% of the in vivo control level slows ktr and reduces force generation. ktr is dependent on sarcomere length in the physiological range 1.85–1.94 μm and RLC phosphorylation modulates this response. We demonstrate that Frank–Starling is evident at maximal [Ca2+] activation and therefore does not necessarily require length‐dependent change in [Ca2+]‐sensitivity of thin filament activation. The stretch response is modulated by changes in RLC phosphorylation, pinpointing RLC phosphorylation as a modulator of the Frank–Starling law in the heart. These data provide an explanation for slowed systolic function in the intact heart in response to RLC phosphorylation reduction.

Revisiting Frank–Starling: regulatory light chain phosphorylation alters the rate of force redevelopment (k tr) in a length‐dependent fashion

Aquatic and aerial animal athletes: Adaptations for muscle power and speed in tuna and hummingbirds

ABSTRACT Skinned fibres have advantages for comparing the muscle properties of different animal species because they can be prepared from a needle biopsy taken under field conditions. However, it is not clear how well the contractile properties of skinned fibres reflect the properties of the muscle fibres in vivo. Here, we compare the mechanical performance of intact fibre bundles and skinned fibres from muscle of the same animals. This is the first such direct comparison. Maximum power and isometric force were measured at 25°C using peroneus longus (PL) and extensor digiti-V (ED-V) muscles from wild rabbits (Oryctolagus cuniculus). More than 90% of the fibres in these muscles are fast-twitch, type 2 fibres. Maximum power was measured in force-clamp experiments. We show that maximum power per volume was the same in intact (121.3±16.1 W l−1, mean±s.e.m.; N=16) and skinned (122.6±4.6 W l−1; N=141) fibres. Maximum relative power (power/FIM Lo, where FIM is maximum isometric force and Lo is standard fibre length) was also similar in intact (0.645±0.037; N=16) and skinned (0.589±0.019; N=141) fibres. Relative power is independent of volume and thus not subject to errors in measurement of volume. Finally, maximum isometric force per cross-sectional area was also found to be the same for intact and skinned fibres (181.9 kPa±19.1; N=16; 207.8 kPa±4.8; N=141, respectively). These results contrast with previous measurements of performance at lower temperatures where skinned fibres produce much less power than intact fibres from both mammals and non-mammalian species. Summary: Maximum isometric power and force from skinned and intact muscle fibres (wild rabbits, 25°C) match within experimental error, strengthening confidence in use of skinned fibres when intact fibres cannot be obtained.

Skinned fibres produce the same power and force as intact fibre bundles from muscle of wild rabbits

Effects of Chronic Myocardial Infarction on Cardiac Muscle Performance and Structure In-Vivo and In-Vitro

SUMMARY Muscle samples were taken from the gluteus, semitendinosus and longissimus muscles of a captive cheetah immediately after euthanasia. Fibres were ‘skinned’ to remove all membranes, leaving the contractile filament array intact and functional. Segments of skinned fibres from these cheetah muscles and from rabbit psoas muscle were activated at 20°C by a temperature-jump protocol. Step and ramp length changes were imposed after active stress had developed. The stiffness of the non-contractile ends of the fibres (series elastic component) was measured at two different stress values in each fibre; stiffness was strongly dependent on stress. Using these stiffness values, the speed of shortening of the contractile component was evaluated, and hence the power it was producing. Fibres were analysed for myosin heavy chain content using gel electrophoresis, and identified as either slow (type I) or fast (type II). The power output of cheetah type II fibre segments was 92.5±4.3 W kg−1 (mean ± s.e., 14 fibres) during shortening at relative stress 0.15 (the stress during shortening/isometric stress). For rabbit psoas fibre segments (presumably type IIX) the corresponding value was significantly higher (P<0.001), 119.7±6.2 W kg−1 (mean ± s.e., 7 fibres). These values are our best estimates of the maximum power output under the conditions used here. Thus, the contractile filament power from cheetah was less than that of rabbit when maximally activated at 20°C, and does not account for the superior locomotor performance of the cheetah.

Power output of skinned skeletal muscle fibres from the cheetah (Acinonyx jubatus)

Background: Cardiac myosin regulatory light chain (RLC) phosphorylation alters cardiac muscle function. Results: Phosphorylation affects mechanical parameters of cardiac muscle contraction during shortening. Conclusion: Phosphorylation impacts mechanical function of cardiac muscle and is altered during cardiac disease. Significance: Understanding RLC regulation by phosphorylation in cardiac muscle contraction is crucial for understanding changes in disease. Understanding how cardiac myosin regulatory light chain (RLC) phosphorylation alters cardiac muscle mechanics is important because it is often altered in cardiac disease. The effect this protein phosphorylation has on muscle mechanics during a physiological range of shortening velocities, during which the heart generates power and performs work, has not been addressed. We have expressed and phosphorylated recombinant Rattus norvegicus left ventricular RLC. In vitro we have phosphorylated these recombinant species with cardiac myosin light chain kinase and zipper-interacting protein kinase. We compare rat permeabilized cardiac trabeculae, which have undergone exchange with differently phosphorylated RLC species. We were able to enrich trabecular RLC phosphorylation by 40% compared with controls and, in a separate series, lower RLC phosphorylation to 60% of control values. Compared with the trabeculae with a low level of RLC phosphorylation, RLC phosphorylation enrichment increased isometric force by more than 3-fold and peak power output by more than 7-fold and approximately doubled both maximum shortening speed and the shortening velocity that generated peak power. We augmented these measurements by observing increased RLC phosphorylation of human and rat HF samples from endocardial left ventricular homogenate. These results demonstrate the importance of increased RLC phosphorylation in the up-regulation of myocardial performance and suggest that reduced RLC phosphorylation is a key aspect of impaired contractile function in the diseased myocardium.

Myosin Regulatory Light Chain (RLC) Phosphorylation Change as a Modulator of Cardiac Muscle Contraction in Disease*

Background: Phosphate is released by the cardiac actomyosin ATPase during contraction. Results: Stretching active cardiac muscle decreases phosphate release within milliseconds. Conclusion: Mechanical stimuli such as stretch cause an immediate change in actomyosin ATPase kinetics. Significance: Stretch facilitates a powerful contraction by increasing cross-bridges in a pre-power stroke state, and changes cytoplasmic phosphate flux, which may influence energetic homeostasis. The contractile performance of the heart is linked to the energy that is available to it. Yet, the heart needs to respond quickly to changing demands. During diastole, the heart fills with blood and the heart chambers expand. Upon activation, contraction of cardiac muscle expels blood into the circulation. Early in systole, parts of the left ventricle are being stretched by incoming blood, before contraction causes shrinking of the ventricle. We explore here the effect of stretch of contracting permeabilized cardiac trabeculae of the rat on the rate of inorganic phosphate (Pi) release resulting from ATP hydrolysis, using a fluorescent sensor for Pi with millisecond time resolution. Stretch immediately reduces the rate of Pi release, an effect observed both at full calcium activation (32 μmol/liter of Ca2+), and at a physiological activation level of 1 μmol/liter of Ca2+. The results suggest that stretch redistributes the actomyosin cross-bridges toward their Pi-containing state. The redistribution means that a greater fraction of cross-bridges will be poised to rapidly produce a force-generating transition and movement, compared with cross-bridges that have not been subjected to stretch. At the same time stretch modifies the Pi balance in the cytoplasm, which may act as a cytoplasmic signal for energy turnover.

Stretch of Contracting Cardiac Muscle Abruptly Decreases the Rate of Phosphate Release at High and Low Calcium

Key points  •  Muscle force and shortening are generated by a structural change called the working stroke in myosin motor proteins that cross‐link the myosin and actin filaments in muscle. •  Precise values for two key parameters of the myosin motor – its mechanical stiffness and the size of the working stroke at low load – were previously only available from one type of muscle in one species, fast twitch muscles of the frog, so it was not clear how generally applicable these values were. •  We show that in dogfish fast muscle the low‐load working stroke is the same as in frog muscle, but the myosin motor stiffness is smaller. •  The results provide new insights into how the molecular properties of myosin motors in different muscle types and species may be adapted for different muscle functions.

Mechanics of myosin function in white muscle fibres of the dogfish, Scyliorhinus canicula

Purpose: Type 2 diabetes (T2D) is an important risk factor for heart failure. T2D is associated with the metabolic syndrome, encompassing cardiovascular risk factors such as obesity, insulin resistance and dyslipidemia, factors also associated with left ventricular diastolic dysfunction. Patients with T2D have elevated plasma levels of free fatty acids and these are proposed to activate inflammation. Interleukin-1b (IL-1b) is activated by the NLRP3 inflammasome and a central mediator in T2D. Palmitate, the most abundant saturated fatty acid in plasma was recently shown to activate the NLRP3 inflammasome in macrophages. The aim of this study was to investigate if this mechanism operates within myocardial cells. Methods and Results: We first replicated previous findings by incubating bone marrow-derived macrophages with palmitate, and found release of active IL-1b. We went on to study primary mouse cardiac fibroblasts (CF). CF were stimulated with LPS, causing priming of the inflammasome, and then with palmitate. This caused release of active IL-1b. Importantly, this was not found in CF from NLRP3 and ASC deficient mice, demonstrating that the effect of palmitate on IL-1b release is mediated through the NLRP3 inflammasome. Other fatty acids such as eicosapentaenoic acid (EPA), oleic acid (OA), docosahexaenoic acid did not cause inflammasome activation. The omega-3 fatty EPA is known to suppress palmitate-induced metabolic stress, and when combining palmitate and EPA, we found markedly reduced release of IL-1b. By viewing CF stained with Bodipy under fluorescence microscopy, we observed an inhibitory effect of EPA on PA-induced lipid accumulation. AMP-activated protein kinase (AMPK) is a central regulator of cellular energy homeostasis and also suppresses reactive oxygen species (ROS) production. We found that palmitate markedly reduced AMPK phosphorylation and Mitosox staining revealed increased mitochondrial ROS. Addition of the pharmacological AMPK activator AICAR completely blocked palmitate-induced IL-1b production. AMPK is also involved in regulation of autophagy, and we found that palmitate reduced levels of beclin-1, indicating that reduced autophagy could represent a mechanism for palmitate-induced inflammasome activation. Conclusion: Palmitate causes activation of the NLRP3 inflammasome in cardiac fibroblasts and this may involve increased mitochondrial ROS and defective autophagy. These findings indicate that NLRP3 inflammasome may act as a sensor of metabolic stress in the heart. EPA inhibits PA-induced NLRP3 inflammasome activation, possibly via reduced lipid accumulation. Cardiovascular Research Supplements (2014) 103, S102–S141

A Method to Exchange Recombinant Differentially Phosphorylated Rhodamine-Labeled Cardiac RLC into Permeabilized Cardiac Trabeculae

Low temperature enhances the force depression by inorganic phosphate in catshark muscle

We aim to reveal the molecular mechanism underlying the force response to stretch in the heart by examining the dependence of the rate of inorganic phosphate (Pi) release in response to stretch on the degree of calcium activation. Permeabilized trabeculae of rat heart are activated by photolytic release of ATP, at 20°C, in the presence of saturating (32µM), or half-saturating (1µM), calcium concentrations, at an initial sarcomere length of 1.9 or 2.1 µm. For trabeculae with an initial sarcomere length of 1.9 µm, the trabeculae are stretched to 2.1 µm during the isometric plateau, held at a constant length and returned to their original length. The rate of Pi release is determined by the fluorescence change associated with phosphate binding to a fluorescently-labelled phosphate binding protein diffused into the preparation. At an initial sarcomere length of 1.9µm, the isometric force at full activation was 51 kN.m−2 compared to 26kN.m−2 at half-maximal activation. During the isometric phase, Pi release is at a steady rate of 8.2 and 4.8 s−1 (assuming a myosin head concentration of 120µM) at 32 and 1µM calcium, respectively. During stretch, the rate of Pi release decreases markedly at both activation levels, to1.0 and 1.4s−1 respectively. Activation from an initial sarcomere length of 2.1µm produced an isometric force of 65.5 kN.m−2 with a steady Pi release rate of 8.1 s−1 at maximal activation, and an isometric force of 49.2 kN.m−2 with a steady Pi release rate of 4.8 s−1 at half-maximal activation. The rates of Pi release during stretch and after the end of the stretch at low activation are equal to that at high activation indicating stretch-induced activation which occurs for stretches applied prior to activation, and during activation. The results demonstrate that stretch has a dramatic effect causing an immediate reduction in the rate of Pi release. Stretch contributes to activation of the trabecula's actomyosin ATPase in a calcium-independent manner, although the effect is more marked at low activation levels. Thus a direct effect of stretch on thin filament activation contributes to the Frank-Starling law.

Abstract P088: The Rate of Inorganic Phosphate Release in Contracting Rat Trabeculae Is Independent of Calcium After Stretch

FRET characterisation for cross-bridge dynamics in single-skinned rigor muscle fibres

Effect of Inorganic Phosphate on the Rate of ADP Release During Ramp Shortening in Activated Permeabilized Fibers from Rabbit Psoas Muscle

Effect of phosphate and temperature on force exerted by white muscle fibres from dogfish

Fluorescence lifetime imaging reveals that the environment of the ATP binding site of myosin in muscle senses force.

019 The time course of inorganic phosphate release and actomyosin ATPase rate in permeabilised cardiac trabeculae

We applied fluorescence lifetime imaging microscopy to map the microenvironment of the myosin essential light chain (ELC) in permeabilized skeletal muscle fibers. Four ELC mutants containing a single cysteine residue at different positions in the C-terminal half of the protein (ELC-127, ELC-142, ELC-160, and ELC-180) were generated by site-directed mutagenesis, labeled with 7-diethylamino-3-((((2-iodoacetamido)ethyl)amino)carbonyl)coumarin, and introduced into permeabilized rabbit psoas fibers. Binding to the myosin heavy chain was associated with a large conformational change in the ELC. When the fibers were moved from relaxation to rigor, the fluorescence lifetime increased for all label positions. However, when 1% stretch was applied to the rigor fibers, the lifetime decreased for ELC-127 and ELC-180 but did not change for ELC-142 and ELC-160. The differential change of fluorescence lifetime demonstrates the shift in position of the C-terminal domain of ELC with respect to the heavy chain and reveals specific locations in the lever arm region sensitive to the mechanical strain propagating from the actin-binding site to the lever arm.

Response of Rigor Cross-bridges to Stretch Detected by Fluorescence Lifetime Imaging Microscopy of Myosin Essential Light Chain in Skeletal Muscle Fibers*

Measurement Of ATPase Activity During Ramped Stretches In Contracting Skeletal Muscle Fibers Of The Rabbit

Time course and strain dependence of ADP release during contraction of permeabilized skeletal muscle fibers.

Rate of inorganic phosphate release by permeabilised dogfish fibres

The contractile and actomyosin ATPase properties of single fibres were examined in human diaphragm muscle obtained from patients with and without chronic obstructive pulmonary disease (COPD). Costal diaphragm biopsies were taken from five patients without evidence of COPD and from 11 age‐matched individuals with varying degrees of the disease. Our aim was to establish whether changes in contractile properties of COPD diaphragm could be fully explained by the previously documented shift towards a greater proportion of type I myosin heavy chain isoform in COPD. The relative proportion of type I diaphragm fibres from non‐COPD and COPD patients was measured by gel electrophoresis, and was negatively correlated with FEV1 over the full range of values investigated. There was also significant atrophy of the type I fibre population in COPD diaphragms. Isometric tension was similar among the fibre types and between the COPD and non‐COPD patients. The intrinsic energetic properties of diaphragm fibres were examined by monitoring the time‐resolved actomyosin ATPase activity in COPD and non‐COPD fibres that produced similar isometric forces. The isometric ATPase rate in COPD fibres was reduced to 50% of the rate in non‐COPD fibres; hence, the cost of isometric contraction in type I and type IIA COPD fibres was reduced to between one‐third and one‐half of the tension cost calculated for non‐COPD fibres. The rate of force development in type I COPD fibres was reduced to 50% of the rate seen in non‐COPD type‐I fibres. No difference in the rate of ATP consumption between COPD and non‐COPD fibres was evident during isovelocity shortening. These data extend previous findings showing that aspects of breathing mechanics during progressive COPD are associated with remodelling of the diaphragm fibre‐type distribution; on top of the increase in type I fibres there are fibre‐specific reductions in force development rate (type I fibres) and ATPase rate that are consistent with the impairment of cross‐bridge cycling kinetics.

Physiological properties of human diaphragm muscle fibres and the effect of chronic obstructive pulmonary disease

We investigated the use of fluorescence lifetime imaging microscopy (FLIM) of a fluorescently labeled ATP analog (3'-O-{N-[3-(7-diethylaminocoumarin-3-carboxamido)propyl]carbamoyl}ATP) to probe in permeabilized muscle fibers the changes in the environment of the nucleotide binding pocket caused by interaction with actin. Spatial averaging of FLIM data of muscle sarcomeres reduces photon noise, permitting detailed analysis of the fluorescence decay profiles. FLIM reveals that the lifetime of the nucleotide, in its ADP form because of the low concentration of nucleotide present, changes depending on whether the nucleotide is free in solution or bound to myosin, and on whether the myosin is bound to actin in an actomyosin complex. Characterization of the fluorescence decays by a multiexponential function allowed us to resolve the lifetimes and amplitudes of each of these populations, namely, the fluorophore bound to myosin, bound to actin, in an actomyosin complex, and free in the filament lattice. This novel application of FLIM to muscle fibers shows that with spatial averaging, detailed information about the nature of nucleotide complexes can be derived.

Fluorescence lifetime imaging to detect actomyosin states in mammalian muscle sarcomeres.

SUMMARY Much of Bob Boutilier's research characterised the subcellular, organ-level and in vivo behavioural responses of frogs to environmental hypoxia. His entirely integrative approach helped to reveal the diversity of tissue-level responses to O2 lack and to advance our understanding of the ecological relevance of hypoxia tolerance in frogs. Work from Bob's lab mainly focused on the role for skeletal muscle in the hypoxic energetics of overwintering frogs. Muscle energy demand affects whole-body metabolism, not only because of its capacity for rapid increases in ATP usage, but also because hypometabolism of the large skeletal muscle mass in inactive animals impacts so greatly on in vivo energetics. The oxyconformance and typical hypoxia-tolerance characteristics (e.g. suppressed heat flux and preserved membrane ion gradients during O2 lack) of skeletal muscle in vitro suggest that muscle hypoperfusion in vivo is possibly a key mechanism for (i) downregulating muscle and whole-body metabolic rates and (ii) redistributing O2 supply to hypoxia-sensitive tissues. The gradual onset of a low-level aerobic metabolic state in the muscle of hypoxic, cold-submerged frogs is indeed important for slowing depletion of on-board fuels and extending overwintering survival time. However, it has long been known that overwintering frogs cannot survive anoxia or even severe hypoxia. Recent work shows that they remain sensitive to ambient O2 and that they emerge rapidly from quiescence in order to actively avoid environmental hypoxia. Hence, overwintering frogs experience periods of hypometabolic quiescence interspersed with episodes of costly hypoxia avoidance behaviour and exercise recovery. In keeping with this flexible physiology and behaviour, muscle mechanical properties in frogs do not deteriorate during periods of overwintering quiescence. On-going studies inspired by Bob Boutilier's integrative mindset continue to illuminate the cost–benefit(s) of intermittent locomotion in overwintering frogs, the constraints on muscle function during hypoxia, the mechanisms of tissue-level hypometabolism, and the details of possible muscle atrophy resistance in quiescent frogs.

Tribute to R. G. Boutilier: The role for skeletal muscle in the hypoxia-induced hypometabolic responses of submerged frogs

We measured the effects of ionic strength (IS), 200 (standard) and 400 mmol l−1 (high), on force and ATP hydrolysis during isometric contractions of permeabilized white fibres from dogfish myotomal muscle at their physiological temperature, 12°C. One goal was to test the validity of our kinetic scheme that accounts for energy release, work production and ATP hydrolysis. Fibres were activated by flash photolysis of the P3‐1‐(2 nitrophenyl) ethyl ester of ATP (NPE‐caged ATP), and time‐resolved phosphate (Pi) release was detected with the fluorescent protein MDCC‐PBP, N‐(2[1‐maleimidyl]ethyl)‐7‐diethylamino‐coumarin‐3‐carboxamide phosphate binding protein. High IS slowed the transition from rest to contraction, but as the fibres approached the isometric force plateau they showed little IS sensitivity. By 0.5 s of contraction, the force and the rate of Pi release at standard and high IS values were not significantly different. A five‐step reaction mechanism was used to account for the observed time courses of force and Pi release in all conditions explored here. Only the rate constants for reactions of ATP, ADP and Pi with the contractile proteins varied with IS, thus suggesting that the actin–myosin interactions are largely non‐ionic. Our reaction scheme also fits previous results for intact fibres.

Influence of ionic strength on the time course of force development and phosphate release by dogfish muscle fibres

It is well known that free fatty acids (FA) and carbohydrate (CHO) support muscle energy provision in mammals and that exercise intensity and endurance adaptation are key determinants of FA and CHO oxidation. Fat oxidation is highest during moderate contractions, whereas CHO oxidation is increasingly dominant at higher work rates. The pattern is similar in endurance-adapted muscle, although FA dependence increases overall because of higher muscle mitochondrial and lipid contents, and because of increased capacity to perform (e.g. sustain high running speed) at low relative exercise intensity (Brooks, 1998; Hoppeler & Fluck, 2002). Mechanisms that regulate muscle FA and CHO oxidation are beginning to emerge. However, the growing array of acute (contraction-induced) and chronic (training-induced) responses to exercise attests to the extreme plasticity of skeletal muscle (Hoppeler & Fluck, 2002), and suggests that the mechanisms that orchestrate fuel processing are complex. Aerobic training protocols are powerful approaches for unravelling these mechanisms because adjustments in specific pathways, signals and genes can be examined in connection with general endurance-related shifts in fuel preference. 
 
In the current issue of The Journal of Physiology, LeBlanc et al. (2004) examined the regulation of pyruvate (i.e. CHO) oxidation after aerobic cycle-ergometer training in humans. They assayed muscle oxidative capacity, pryuvate dehydrogenase (PDH) activity, and pyruvate dehydrogenase kinase (PDK) activity in male subjects before training, and after 1 and 8 weeks post-training. Time courses for changes in total PDH and total PDK and for expression of the four isoforms of PDK are not known for one system. However, work on different species suggested to them that PDH and PDK adjustments would appear after prolonged, but not short-term, aerobic training. Key clues were that long-term training (i) increased total PDH in mice (Houle-Leroy et al. 2000), (ii) attenuated post-training PDH activity during submaximal exercise in humans (LeBlanc et al. 2003), and (iii) increased PDK activity in rats (Nakai et al. 1999). Since PDK inhibits PDH (see Fig. 1), it seemed likely that some or all of the PDK isoforms were a source of heightened post-training regulation of PDH. LeBlanc et al. (2004) reasoned that if training-induced changes in PDK isoforms were linked to the attenuated PDH activity in humans, then there should be clear indication that total PDK activity and total PDK isoforms change contemporaneously with total PDH activity. 
 
Figure 1 
 
Increasing pyruvate oxidation 
 
Their results do indeed confirm that long-term training increases total PDH and total PDK. The time courses for training-induced increases in these enzymes seem to match and these changes coincide with enhanced muscle oxidative capacity. Increased expression of chiefly one isoform of PDK, identified as PDK2, seems to explain the attenuated PDH activity during post-training submaximal exercise. So, while chronic exercise increases total PDH activity, the simultaneous increase in PDK2 is expected to keep tighter control (suppression) of pyruvate oxidation during bouts of acute exercise. What consequences arise from such fine-tuning of PDH activity? 
 
One consequence should be that trained muscle becomes increasingly poised to exploit elevated muscle FA reserves for energy provision. PDK-mediated control of PDH activity is in fact likely to be of general importance for the balance of FA and CHO oxidation during exercise. However, enhancement of this mechanism in more highly aerobically adapted muscle concurs with higher mitochondrial and lipid volumes, and with the capacity for trained individuals to increase performance and dependence on FA oxidation at a given level of submaximal exertion (Brooks, 1998). 
 
LeBlanc et al. (2004) argue thoughtfully that the reason PDK2 features so prominently in post-training PDH control hinges partly on PDK2 sensitivity to (inhibition by) muscle energy imbalance. On the one hand, inhibition of PDK2 by high [ADP] and [pyruvate] during high-intensity acute exercise is favourable because this will help relieve PDH inactivation and in turn raise rates of pyruvate oxidation (Fig. 1). On the other hand, up-regulation of specifically PDK2 in response to chronic high-intensity exercise suggests that this isoform adapts to protracted perturbations in muscle energy status in order to retain control over PDH activity at higher aerobic work rates. The training responses of PDK2 label it as the ‘energy-status-sensitive’ isoform, in keeping with previous views on its role in mammalian tissues (Bowker-Kinley et al. 1998). 
 
Increased gauging of CHO fluxes at near-maximal aerobic work rates is possibly a second consequence of the training-induced changes in PDK and PDH. Up-regulation of total PDH is undoubtedly part of the suite of chronic adaptations that increase CHO oxidation capacity after training. Together with greater PDK control over PDH activity, this means that there is increased scope for PDH activation and possibly enhanced synchrony between rates of pyruvate production and PDH activity during transitions to maximal aerobic work rate. Post-training up-regulation of chiefly PDK2 activity suggests that acute energy-sensitive control of PDH activity (Fig. 1) is increasingly important for oxidizing CHO reserves, possibly by augmenting the match between PDH activity and glycogenolysis. Tighter engagement between these pathways might also arise via increased integration of PDK2 and PDH activities with other energy-sensitive pathways involved with funnelling CHO into glycolysis, like isoforms of AMP-activated protein kinase (AMPK). 
 
LeBlanc et al. (2004) reveal novel aspects of PDH regulation in skeletal muscle from an elegant combination of relevant molecular techniques with established training protocols. Clearly, the pay-off from such integrative experimental designs is that specific molecular features of training-induced muscle plasticity can continue to be placed into a broad and meaningful physiological context.

Controlling pyruvate oxidation in endurance‐trained skeletal muscle

Energy turnover was measured during isometric contractions of intact and Triton‐permeabilized white fibres from dogfish (Scyliorhinus canicula) at 12°C. Heat + work from actomyosin in intact fibres was determined from the dependence of heat + work output on filament overlap. Inorganic phosphate (Pi) release by permeabilized fibres was recorded using the fluorescent protein MDCC‐PBP, N‐(2‐[1‐maleimidyl]ethyl)‐7‐diethylamino‐coumarin‐3 carboxamide phosphate binding protein. The steady‐state ADP release rate was measured using a linked enzyme assay. The rates decreased five‐fold during contraction in both intact and permeabilized fibres. In intact fibres the rate of heat + work output by actomyosin decreased from 134 ±s.e.m. 28 μW mg−1 (n= 17) at 0.055 s to 42% of this value at 0.25 s, and to 20% at 3.5 s. The force remained constant between 0.25 and 3.5 s. Similarly in permeabilized fibres the Pi release rate decreased from 5.00 ± 0.39 mmol l−1 s−1 at 0.055 s to 39% of this value at 0.25 s and to 19% at 0.5 s. The steady‐state ADP release rate at 15 s was 21% of the Pi rate at 0.055 s. Using a single set of rate constants, the time courses of force, heat + work and Pi release were described by an actomyosin model that took account of the transition from the initial state (rest or rigor) to the contracting state, shortening and the consequent work against series elasticity, and reaction heats. The model suggests that increasing Pi concentration slows the cycle in intact fibres, and that changes in ATP and ADP slow the cycle in permeabilized fibres.

Actomyosin energy turnover declines while force remains constant during isometric muscle contraction

Rate of actomyosin ATP hydrolysis diminishes during isometric contraction.

Comparison of energy release in intact and skinned muscle fibres during development of isometric force

Frogs (Rana temporaria) were submerged at 3 degrees C in either normoxic (P(O2)=155 mmHg, P(O2)=20 kPa) or hypoxic (P(O2)=60 mmHg; P(O2)=8 kPa) water for up to 16 weeks, and denied air access, to mimic the conditions of an ice-covered pond during the winter. The activity of the skeletal muscle Na(+)/K(+) pump over the first 2 months of hibernation, measured by ouabain-inhibitable (22)Na(+) efflux, was reduced by 30 % during normoxia and by up to 50 % during hypoxia. The reduction in Na(+)/K(+) pump activity was accompanied by reductions in passive (22)Na(+) influx and (86)Rb(+) efflux (effectively K(+) efflux) across the sarcolemma. This may be due to a decreased Na(+) permeability of the sarcolemma and a 75 % reduction in K(+) leak mediated by ATP-sensitive K(+) channels ('K(ATP)' channels). The lowered rates of (22)Na(+) and (86)Rb(+) flux are coincident with lowered transmembrane ion gradients for [Na(+)] and [K(+)], which may also lower Na(+)/K(+) pump activity. The dilution of extracellular [Na(+)] and intracellular [K(+)] may be partially explained by increased water retention by the whole animal, although measurements of skeletal muscle fluid compartments using (3)H-labelled inulin suggested that the reduced ion gradients represented a new steady state for skeletal muscle. Conversely, intracellular ion homeostasis within ventricular muscle was maintained at pre-submergence levels, despite a significant increase in tissue water content, with the exception of the hypoxic frogs following 4 months of submergence. Both ventricular muscles and skeletal muscles maintained resting membrane potential at pre-submergence levels throughout the entire period of hibernation. The ability of the skeletal muscle to maintain its resting membrane potential, coincident with decreased Na(+)/K(+) pump activity and lowered membrane permeability, provided evidence of functional channel arrest as an energy-sparing strategy during hibernation in the cold-submerged frog.

Factors affecting membrane permeability and ionic homeostasis in the cold-submerged frog.

Effects of reduced oxygen availability on transmembrane ion balance in skeletal muscle of Rana temporaria.

The protective effects of hypoxia-induced hypometabolism in the Nautilus

Aerobic metabolic rates (MO2) and respiratory quotients (RQ = CO2 production/MO2) were measured contemporaneously in hibernating frogs Rana temporaria (L.), submerged for 90 days at 3 degrees C. After 3 mo of submergence in fully aerated water, MO2 levels were 61% of those seen at the same temperature before hibernation. Over the first 40 days of hibernation, RQ values (< or = 0.82) favored a lipid-based metabolism that progressively shifted to an exclusively carbohydrate metabolism (RQ = 1.01) by 90 days of hibernation. Liver glycogen concentrations fell by 68% during the first 8 wk of submergence, thereafter exhibiting a less rapid rate of utilization. Conversely, muscle glycogen concentrations remained stable over the first 2 mo of the experiment before falling by 33% over the course of the remaining 2 mo, indicating that the frog was recruiting muscle glycogen reserves to fuel metabolism. Submerged frogs exhibited an extracellular acidosis during the first week of submergence, but over the course of the next 15 wk "extracellular pH" values were not significantly different from the values obtained from the control air-breathing animals. The initial extracellular acidosis was not mirrored in the intracellular compartment, and the acid-base state was not significantly different from the control values for the first 8 wk. However, over the subsequent 8- to 16-wk period, the acid-base status shifted to a lower intracellular pH-HCO3 concentration set point, indicative of a metabolic acidosis. Even so, there was no indication that the acidosis could be attributed to anaerobic metabolism, as both plasma and muscle lactate levels remained low and stable. Muscle adenylate energy charge and lactate-to-pyruvate and creatine-to-phosphocreatine ratios also remained unchanged throughout hibernation. The capacity for profound metabolic rate suppression together with the ability to match substrate use to shifts in aerobic metabolic demands and the ability to fix new acid-base homeostatic set points are highly adaptive, both in terms of survival and reproductive success, to an animal that is often forced to overwinter under the cover of ice.

Respiratory, metabolic, and acid-base correlates of aerobic metabolic rate reduction in overwintering frogs.

Aerobic metabolic rates (M˙o 2) and respiratory quotients (RQ = CO2production/M˙o 2) were measured contemporaneously in hibernating frogs Rana temporaria (L.), submerged for 90 days at 3°C. After 3 mo of submergence in fully aerated water,M˙o 2levels were 61% of those seen at the same temperature before hibernation. Over the first 40 days of hibernation, RQ values (≤0.82) favored a lipid-based metabolism that progressively shifted to an exclusively carbohydrate metabolism (RQ = 1.01) by 90 days of hibernation. Liver glycogen concentrations fell by 68% during the first 8 wk of submergence, thereafter exhibiting a less rapid rate of utilization. Conversely, muscle glycogen concentrations remained stable over the first 2 mo of the experiment before falling by 33% over the course of the remaining 2 mo, indicating that the frog was recruiting muscle glycogen reserves to fuel metabolism. Submerged frogs exhibited an extracellular acidosis during the first week of submergence, but over the course of the next 15 wk "extracellular pH" values were not significantly different from the values obtained from the control air-breathing animals. The initial extracellular acidosis was not mirrored in the intracellular compartment, and the acid-base state was not significantly different from the control values for the first 8 wk. However, over the subsequent 8- to 16-wk period, the acid-base status shifted to a lower intracellular pH-[Formula: see text] concentration set point, indicative of a metabolic acidosis. Even so, there was no indication that the acidosis could be attributed to anaerobic metabolism, as both plasma and muscle lactate levels remained low and stable. Muscle adenylate energy charge and lactate-to-pyruvate and creatine-to-phosphocreatine ratios also remained unchanged throughout hibernation. The capacity for profound metabolic rate suppression together with the ability to match substrate use to shifts in aerobic metabolic demands and the ability to fix new acid-base homeostatic set points are highly adaptive, both in terms of survival and reproductive success, to an animal that is often forced to overwinter under the cover of ice.

Many amphibians encounter conditions each winter when their body temperature is so low that normal activities are suspended and the animals enter into a state of torpor. In ice-covered ponds or lakes, oxygen levels may also become limiting, thereby forcing animals to endure prolonged periods of severe hypoxia or anoxia. Certain frogs (e.g. Rana temporaria) can dramatically suppress their metabolism in anoxia but are not as tolerant as other facultative vertebrate anaerobes (e.g. turtle, goldfish) of prolonged periods of complete O2 lack. Many overwintering amphibians do, however, tolerate prolonged bouts of severe hypoxia, relying exclusively on cutaneous gas exchange. Rana temporaria overwintering for 2 months in hypoxic water (PO2 approximately 25 mmHg) at 3 degrees C progressively reduce their blood PCO2 to levels characteristic of water-breathing fish. The result is that blood pH rises and presumably facilitates transcutaneous O2 transfer by increasing Hb O2-affinity. Even after months of severe hypoxia, there is no substantial build-up of lactate as the animals continue to rely on cutaneous gas exchange to satisfy the requirements of a suppressed aerobic metabolism. Our recent experiments have shown that the skeletal muscle of frogs oxyconforms in vitro to the amount of O2 available. The cellular basis for the oxyconformation of skeletal muscle is unknown, but the hypothesis driving our continuing experiments theories that metabolic suppression at a cellular level is synonymous with suppressed ion leak across cellular membranes.

The rules that govern the relationships between enzymatic flux capacities (Vmax) and maximum physiological flux rates (v) at enzyme-catalyzed steps in pathways are poorly understood. We relate in vitro Vmax values with in vivo flux rates for glycogen phosphorylase, hexokinase, and phosphofructokinase, enzymes catalyzing nonequilibrium reactions, from a variety of muscle types in fishes, insects, birds, and mammals. Flux capacities are in large excess over physiological flux rates in low-flux muscles, resulting in low fractional velocities (%Vmax = v/Vmax x 100) in vivo. In high-flux muscles, close matches between flux capacities and flux rates (resulting in fractional velocities approaching 100% in vivo) are observed. These empirical observations are reconciled with current concepts concerning enzyme function and regulation. We suggest that in high-flux muscles, close matches between enzymatic flux capacities and metabolic flux rates (i.e., the lack of excess capacities) may result from space constraints in the sarcoplasm.

Relationships between enzymatic flux capacities and metabolic flux rates: nonequilibrium reactions in muscle glycolysis.

The involvement of circulatory glucose in the energy provision of skeletal muscle and heart of swimming carp was examined. Plasma glucose concentration varied from 3 to 17 mM among individual carp, and estimates of glucose turnover rate (RT) were positively correlated with plasma glucose level in resting fish (range 1.6-6.3 mumol.min-1.kg-1) and in swimming fish (range 4.2-10.7 mumol.min-1.kg-1). Carp that were exercised at 80% of their critical swimming speed displayed a twofold higher RT at any given plasma glucose concentration. Metabolic clearance rate also doubled in swimming carp (1.0 +/- 0.1 ml.min-1.kg-1) relative to resting controls (0.5 +/- 0.1 ml.min-1.kg-1). Indexes of muscle glucose utilization (GUI), determined with 2-deoxy-D-[14C]glucose, indicated that glucose utilization in red muscle was not dependent on plasma glucose concentration; however, glucose utilization in this muscle mass was threefold higher in swimming fish than in resting control fish. On the basis of whole body aerobic scope measurements in carp, it was estimated that circulatory glucose potentially comprised 25-30% of the total fuel oxidation in the active red muscle mass. GUI in heart was positively correlated with plasma glucose concentration, and it is possible that glucose availability had considerable influence on the pattern of myocardial substrate oxidation in resting and active carp. Carp are somewhat more reliant than rainbow trout on glucose for locomotor energetics, correlating with species differences in swimming capability and with the greater capacity of omnivorous carp to tolerate dietary glucose.

Muscle glucose utilization during sustained swimming in the carp (Cyprinus carpio).

The importance of circulatory glucose as a fuel for skeletal muscle and heart during sustained swimming and as a glycogenic substrate for skeletal muscle during exercise-recovery was examined. In vivo glucose utilization, using14 C-2-deoxyglucose (14 C-2-DG), in swimming trout (Oncorhynchus mykiss) and carp (Cyprinus carpio) indicated similar rates of glucose utilization in red muscle of both species (20 30 nmolmin 1g). Estimates of the energetic importance of glucose, assuming red muscle accounted for the bulk of the active oxygen consumption, suggest that glucose could be more important to the slower swimming carp potentially accounting for 25 30 % of total energy provision. Glucose uptake in red muscle of the more active trout was estimated to contribute < 10 % of total substrate demands during exercise. Cardiac energetics was estimated to be largely independent of glucose utilization in trout. In vivo utilization of glucose in trout heart at rest (about 5 nmolmin 1)was considerably lower than in vitro determinations (120 nmolmin g)and measurements of glucose utilization capacity (8300 nmolmin 1g’ ,based on hexokinase activities). Nearly complete inhibition of glucose flux in vivo is likely the result of preference for alternative substrates for oxidation. In carp, cardiac glucose utilization was dependent on plasma glucose concentration, but was also estimated to be of minor energetic importance at plasma concentrations comparable to those observed in swimming trout (2 4 mmolL t). Reduced dependence of trout on glucose for swimming energetics agrees with the generalization that species with superior aerobic exercise capacities may be dependent on fat based fuels for muscle energetics. Plasma glucose concentration varied from 6 38 mmolL 1 in trout during recovery from intense burst swimming. Hyperglycemia was not related specifically to exercise. Estimated glucose turnover rate, using 63H-glucose tracer, increased proportionally with plasma glucose availability. Similar concentration-dependent kinetics were observed in carp at rest and during sustained swimming. Regardless of

Glucose utilization in fish muscle during sustained swimming and recovery from maximal swimming

Bolus-injection of radiolabels in the study of steady state glucose metabolism

In vivo rates of glucose utilization were estimated in red muscle and heart of rainbow trout using the radiolabeled glucose analogue, [14C]-2-deoxyglucose ([14C]-2-DG). The 2-DG ‘lumped constant’ (LC), representing the uptake ratio between 2-DG and glucose for each tissue, was determined in vitro using tissue slices. For both red muscle and heart, the LC was approximately 0.40. In addition, changes in circulatory glucose utilization induced in an isolated trout heart preparation had no effect on the LC. The LC was applied to calculations of in vivo rates of circulatory glucose disposal in muscle tissue of resting and swimming trout. Utilization was estimated at 0.87+/−0.15 and 5.31+/−1.04 nmol g-1 min-1 in red muscle and heart of resting fish, respectively. In trout swimming at 80 % Ucrit, glucose utilization in heart was unchanged compared to resting controls, while red muscle utilization increased by 28-fold. Estimates of the oxidative demand of heart and locomotory muscle of swimming trout indicate that glucose utilization accounted for less than 10 % of the energy production in both tissues. In trout heart, in vitro measures of glucose flux suggest an apparent excess capacity to use circulatory glucose. Preference for other intra- and extramuscular fuels may partially explain limited glucose utilization, but it remains unclear to what degree, and under what conditions, glucose utilization may be increased in vivo.

IN VIVO UTILIZATION OF GLUCOSE BY HEART AND LOCOMOTORY MUSCLES OF EXERCISING RAINBOW TROUT (ONCORHYNCHUS MYKISS)

Lactate, glycogen, and high-energy phosphate levels were measured in serial biopsies from tuna white muscle during recovery from 15 min of enforced swimming. Exercise caused glycogen and phosphocre...

Recovery metabolism of skipjack tuna (Katsuwonus pelamis) white muscle: rapid and parallel changes in lactate and phosphocreatine after exercise

Rainbow trout, Oncorhynchus mykiss, were exercise trained for 28–52 days. Trained fish were 13% larger and swam 12% faster in an aerobic swimming test. Training induced cardiac growth that was isometric with body growth, since ventricle mass relative to body mass was constant. The proportions of compact and spongy myocardia in the ventricle were also unchanged by training. Trained fish had significantly higher levels of citrate synthase, β-hydroxyacyl CoA dehydrogenase, and hexokinase in both compact and spongy myocardium. Ligation of a 0.5- to 1.0-cm section of the coronary artery produced only a temporary interruption of coronary flow to the compact myocardium because new vessels grew around the ligation site in the majority of fish during the 28- to 52-day experiment. Nonetheless, coronary ligation resulted in a significantly smaller (17%) proportion of compact myocardium with lower levels of citrate synthase, β-hydroxyacyl CoA dehydrogenase, and hexokinase. Exercise-induced increases in the levels of ...

Effects of exercise training and coronary ablation on swimming performance, heart size, and cardiac enzymes in rainbow trout, Oncorhynchus mykiss

When temperature differences are taken into account, turtle brains use glucose at one-sixth the rate reported in rat brains. Na+-K+-ATPase activities are 2- to 2.5-fold higher in rat than in turtle brains. Maximal activities of hexokinase and lactate dehydrogenase are similar, whereas citrate synthase activities are two- to threefold higher in rat than turtle brains at the respective biological temperatures. Voltage-dependent Ca2+ channel densities, when compared between the two species, showed no consistent pattern. These data, along with the threefold differences in density of voltage-dependent Na+ channels reported by Lutz et al., are consistent with the idea that lower rates of channel and pump-mediated Na+ and K+ fluxes result in lower rates of aerobic energy metabolism in turtle brains compared with rat brains.

Turtles and rats: a biochemical comparison of anoxia-tolerant and anoxia-sensitive brains.

ZIRCON U-PB GEOCHRONOLOGY AND HF ISOTOPIC COMPOSITIONS OF AMA DRIME MIGMATITIC GNEISSES: IMPLICATIONS FOR THE ASSEMBLY OF THE PALEOPROTEROZOIC SUPERCONTINENT COLUMBIA

This study focused on the effects of upstream reservoir thermal dynamics and downstream tidal influences on temperatures in a 25‐km reach of Alouette River (coastal British Columbia, Canada) below a control dam and upstream of its confluence with Pitt River. Temperature was monitored during summer 2013 using 25 sensors. Water was released from the reservoir through a low level outlet at approximately 2.7 m3 s−1, except during late spring when a higher flow was released over the dam spillway. Temperature variations in the lowest section of Alouette River, and in the lower portion of a tributary, were distinct from those further upstream due to backwatering effects associated with a semi‐diurnal tide, which can cause flow reversals in Pitt River. An internal seiche was identified in the reservoir during mid‐summer that resulted in oscillating releases of warmer and cooler water with an amplitude of up to 6°C and a period of approximately 12 hr. Wavelet analysis and band‐pass filtering indicated that the 12‐hr signal declined in strength with downstream distance, but remained detectable about 15 km below the dam. In contrast, the 24‐hr diel signal increased in strength with distance below the dam. Travel times computed via cross‐correlation of the 12‐hr signals with that at the low level outlet were within ±10% of those estimated from measured mean velocities. Lagrangian tracking of water parcels using the derived travel times indicated that the cooling effect of periodic releases of cold water during the seiching period persisted to the lower extent of the non‐tidal reach. The tidally influenced locations experienced higher temperatures than those recorded in the non‐tidal portion of Alouette River, although the relative roles of heating in the upstream tidal reach versus upstream advection of water associated with tide‐driven flow reversals in Pitt River require further study.

Influences of upstream reservoir stratification and downstream tidal fluctuations on the summer thermal regime of a regulated coastal river

ABSTRACT Uluru, once known as Ayer’s Rock, is one of Australia’s most well-known natural phenomena. A World Heritage Site, it is listed for its cultural and natural heritage attributes. Until recently it had been visited by more than 300,000 people annually, many of whom climbed the rock, despite the expressly stated wishes of the Traditional Owners that they should not. In November 2017, the Uluru Kata Tjuta National Park authority decided to permanently close the Uluru climb and remove the climb infrastructure, which included a series of 134 posts cemented into the rock and linked by chain, with a cairn at the summit. This paper details the conservation processes and remediating materials considered, then the methods employed to remove this infrastructure safely. Technical requirements included leaving no visible evidence of the posts, avoiding or minimising any damage to the rock surface, and providing a long-lasting in-fill solution that would blend into the rock surface, on the basis that the rock would never be climbed again. The logistics of a site which is some 470 km from the nearest town, has no facilities, and where the surface temperature can reach 60–70°C in mid summer, determined the removal of the evidence of human intervention on the rock site of Uluru. The broader context of Uluru’s recent history and its hand-back to the traditional owners is also discussed.

 <p>This study focused on Alouette River, located in south coastal British Columbia. During summer, water is released from shallow reservoir at a near-constant rate from an outlet about 6-10 m below the water&#160; surface. Outlet temperatures in summer 2013 were initially cool hypolimnetic water, followed by alternating cool and warm water associated with an internal seiche, and finally dominated by warm epilimnetic water during the period of highest water temperature. An energy-balance model was used to evaluate potential strategies to ameliorate thermal habitat conditions for Pacific salmon downstream of the dam. Restoration of deforested banks that represented 4% of the reach length reduced daily maximum temperatures by only about 0.5&#160;&#176;C , while releasing more flow exacerbated temperatures during the warmest week of the year. The only effective strategy for thermal amelioration would be to release water from deeper in the reservoir.</p>

River temperature dynamics downstream of a shallow reservoir: process-based modelling to evaluate thermal mitigation strategies

The Australian sugar industry is a major part of the agricultural sector within Queensland and New South Wales. Through research it was noticed that there was no easy way for producers to evaluate the traffic pathways through the field. Therefore an investigation was devised to track the machinery during sugar cane harvesting to determine the potential increase in bulk density and therefore the decrease in plant production. A field trial was conducted in the Bundaberg region to assess the validity of such a program constructed to use GPS (global positioning system) data gathered from the load-out bins. Manual observations of the load-out bins during harvesting were also conducted to help validate the program. It was concluded that the program reported the correct answer, but was not running correctly due to limitations. The program was developed to report the number of times the growing bed was crossed and to help identify the potential loss of production in terms of sugar cane yield. From the measurements taken as part of the field trial, an average increase of 0.153tonne/m3 was witnessed within the traffic lanes. From this data, a yield decrease of 5% was inferred and subsequently a profit reduction of $0.03 per metre of growing bed crossed.

Tracking machinery to investigate the effect of compaction during sugar cane harvesting

The Littlehaven promenade and seawall scheme has transformed a stretch of South Shields' seafront in north-east England from a neglected length of coastline into a desirable visitor destination. The project involved the demolition of a failing seawall, on-site reuse of excavated material in raising levels and landscaping of backing land areas, and construction of a 500 m promenade and seawall along a new, landward and more sustainable, curved alignment. High quality concrete finishes, bespoke public art and breathtaking streetscape were used to ensure this striking scheme captured the public imagination and revitalised the seafront. This paper focuses on aspects of this multiple award-winning scheme that recognise: its technical engineering excellence and ingenuity; its sustainability merits and environmental considerations; the benefits that have been created for the local community; special features of distinction; and the approach to health and safety management during design and construction. The sche...

This paper focuses on the advanced pavement design, testing and investigation methodologies for the annual pavement renewals programme in the NZ Transport Agency East Waikato Area Highway Maintenance Contract. Developed from Dr Greg Arnold’s doctorate studies and NZ Transport Agency research conducted in the last 15 years, the design, investigation and performance material testing using Repeated Load Triaxial and Flexural Beam Tests are considered the most advanced in the world in the area of granular and stabilised pavements. The benefits of this new approach to design and testing has in some cases resulted in a lower cost pavement treatment solution, in other cases the scientific approach used was able to demonstrate to NZ Transport Agency that a more robust treatment was required.

The objective of this study was to (1) identify the dominant processes affecting stream temperature and (2) develop and apply a process-based stream temperature model to assess the potential for managing the thermal regime of a regulated river in coastal BC through bank re-forestation and changes to release regime. The study spanned June to September 2013, when temperatures are highest and multiple salmonid species begin their spawning runs. Following June 14, a steady discharge of approximately 2.7 m3/s was released from the reservoir through a low level outlet. The reservoir developed two-layer stratification and an internal seiche that caused oscillating withdrawal of epilimnetic and hypolimnetic water that was observed to propagate at least 14 km downstream using wavelet analysis. The stream temperature model was developed with field measurements of hydrological, meteorological, and geomorphic variables that govern stream heat fluxes. A Lagrangian model was employed to model a 14 km reach of Alouette River beginning at the dam. Using a 10-min time step, an accuracy of 0.54 ◦C RMSE was achieved over all predictions, and 0.50 ◦C RMSE for daily peaks. Water parcels arriving at the downstream extent near sunset gained most heat through direct and diffuse shortwave radiation, with the greatest cooling effect associated with evaporation, tributary inflows, and bed heat conduction. Parcels arriving near sunrise gained most heat through bed heat conduction, with the greatest cooling effect associated with longwave radiation and tributary inflows. Modelling a bank re-forestation scenario resulted in study reach temperature reductions of less than 0.5 ◦C for mean and daily peak temperatures. A lower reservoir outlet withdrawing from the cool hypolimnion resulted in mean daily peak reductions of 4.6 ◦C, while raising the outlet into the epilimnion resulted in mean daily peak increases of 0.5 ◦C. Increased reservoir discharge caused minor increases of mean and daily peak temperatures of less than 0.15 ◦C. When combined, increased discharge amplified the effect of modified release depth. The results of this study stress the importance of basing warming mitigation efforts on a detailed understanding of stream heat fluxes and reservoir stratification regime in regulated systems.

Modelling the thermal regime of a regulated coastal British Columbia river and assessing the potential of warming mitigation strategies

The original Sydney Harbour Bridge Arch Maintenance Units (AMU) are engineering marvels inextricably bound to a national icon. Yet following decommissioning from the Bridge in 1997, they were neglected, and by 2005, were in poor condition. This paper discusses the process of conserving the AMUs, and the various challenges, constraints and opportunities encountered. Identification of the appropriate conservation approach and methodology was guided by the requirements of the various stakeholders, who included the client, communities and large collecting institutions. In addition to these factors, the approach was affected by the need to consider statutory requirements for the treatment of significant items, the retention of materials considered hazardous, and the challenges in lifting, transport and storage for a large-scale industrial movable heritage item.

Unprecedented rates of resource development and climate change at northern latitudes coupled with a lack of baseline information limits our ability to set ecologically meaningful criteria needed to protect these inherently sensitive ecosystems. We surveyed water and sediment chemistry, community composition of benthic algae and invertebrates and fish, and condition of a sentinel fish species, slimy sculpin (Cottus cognatus), in 2 rivers adjacent to metal mines and in 20 reference rivers in the headwaters of a World Heritage Site, the South Nahanni River Basin, NWT, Canada. The normal range (i.e., mean ± 2 standard deviations) of biological conditions in regional reference sites (grouped by community type) were used to set ecologically meaningful effect sizes. These effect sizes were used in noncentral hypotheses tests to assess the ecological condition of potentially impaired sites. Significant impairments at sites influenced by current and historical mining activity were indicative of mild enrichment (e.g., increased benthic abundance and sculpin condition) and bioaccumulation of metals (e.g., increased concentrations of Cu and Fe in muscle tissue of sculpin). Comparisons between our regional reference study and a concurrent upstream–downstream study showed that the sensitivity of biological endpoints was typically related to the impairment criteria used and not to the type of study design. Concentrations of metals such as Al, Cu, and Fe in river water at reference sites were above federal and regional guidelines, suggesting that these guidelines are not appropriate for the metal‐rich headwaters of the South Nahanni River. The ephemerellid mayflies Drunella spinifera and Ephemerella maculata were present in 4 of our study sites; their occurrence had not previously been documented in the Yukon or Northwest Territories. Our results confirmed that the lack of baseline information on the physiochemical and biological composition of northern rivers is hampering our ability to evaluate changes in these understudied ecosystems. However, the use of noncentral hypotheses tests based on empirically derived effect sizes enabled us to develop ecologically meaningful protection criteria, maintain statistical rigor, and provide probabilities of impairment that can be used directly in risk assessment. Integr Environ Assess Manag 2010; 6:12–27. © 2009 SETAC

Regional reference variation provides ecologically meaningful protection criteria for northern World Heritage Site

Final Report on the 2006 Prairie Creek Monitoring Program Final Report on the 2006 Prairie Creek Monitoring Program

Characterization of effluents using low level analytical method detection limits has been applied during an eighteen-month long characterization of the Massachusetts Water Resources Authority Deer Island primary treated sewage effluent. Nine metals, 40 polynuclear aromatic hydrocarbons (PAH), C{sub 10} to C{sub 14} linear alkyl benzenes (LAB), 20 polychlorinated biphenyl (PCB) congeners, and 16 persistent chlorinated pesticides were measured. Contaminant concentrations ranged as follows: total PAH, 13 and 32 {micro}g/L; total PCBs, 17--110 ng/L; total chlordanes, 0--74 ng/L; lindane, 2--16 ng/L; total LABs, 7.5--22 {micro}g/L; dieldrin < 5 {micro}g/L. Metal concentrations (in {micro}g/L) were: Ag, 3--7.5; Cd, 0.4--1.4; Cr, 2.7--11; Cu, 48--111; Hg, 0.1--0.26; Mo, 5--25; Ni, 4.6--9; Pb, 6--26; Zn, 70--136. Seasonal trends were observed for some contaminant. Organic compounds were consistently less that the acute water quality criteria in the undiluted effluent. Values p,p{prime}-DDT, Ag, Cu, Hg, and Pb and occasionally for dieldrin, endrin and heptachlor exceeded the chronic marine criteria. Dilution of the effluent will quickly reduce contaminants concentrations below the chronic criteria. Application of these methods has resulted in substantial improvements to estimates of contaminant discharge to the coastal waters of Massachusetts Bay. Further, measurements of the efficiency of the planned secondary treatment processes has demonstrated thatmore » secondary treatment will be highly effective in removal of many organic compounds and metals from the primary effluent and that secondary treatment will significantly alter the source signature of PAHs in the discharge. Availability of such information is providing environmental planners with more effective tools for monitoring impact from this treatment facility.« less

Low level contaminant detection: Implications to loading estimates and management of coastal discharges

A full-scale Lockheed Martin F-22 Raptor engine inlet and duct icing model was tested in the NASA Icing Research Tunnel to assess ice detector configurations and quantify ice accretion characteristics. Test conditions included temperatures from -4 to 28 degrees Fahrenheit, liquid water contents from 0.31 to 2.82 grams/cubic meter, and median volumetric diameters of 14 and 30 microns. The attitude, airspeed, and inlet airflows simulated landing approach conditions. An optimum ice detection configuration was selected from six candidates. The preferred configuration was a probetype ice detector located approximately three feet forward of the aerodynamic interface plane in the lower outboard section of the duct. Ice thickness on the inlet was measured. Accretion rates were derived from the measured ice thickness and compared to analytical predictions.

Corrigendum to: The Diversity and Prevalence of Sexual Orientation Self-Labels in a New Zealand National Sample (Greaves et al., 2017)

The Diversity and Prevalence of Sexual Orientation Self-Labels in a New Zealand National Sample

Facebook is Linked to Body Dissatisfaction: Comparing Users and Non-Users

Social networking sites such as Facebook are used daily by over 70% of the American online population (Duggan & Smith, 2013), and 65% of New Zealands online population (Bascand, 2013). Such sites sell themselves by claiming to help you "connect and share with the people in your life" (Facebook, 2014). The growing popularity of Facebook and other social networking sites is at the heart of a debate surrounding meanings of modern society, and how social networking may be affecting our sense of community, connectedness, and belonging. In his book Bowling Alone: America's Declining Social Capital, Putnam (2000) argues that our collective social capital--the sum of our meaningful social ties with each other--is decreasing as evidenced by the weakening of our relationships with family, friends and community (Putnam, 2000). Such observations raise the question: is Facebook, and the growing use of online social media in general, helping, hindering or hurting the way we connect with each other? Here we seek to contribute to research examining this topical issue by focusing specifically on whether the relationship between online social media usage and social capital differ across individuals, and are contingent upon the basic personality traits that regulate social interaction across numerous contexts. Put another way: is Facebook beneficial for some, but detrimental for others? Like the use of any communication medium, social network use is not good or bad on its own, and so it is important to examine the individual differences of social network users and how these differences moderate psychosocial outcomes (McKenna & Bargh, 2000). In this research, we employ a large, nationally representative sample of adult New Zealanders to examine the possible interactions between Facebook use and the Five Factor Model of personality (Goldberg, 1990; McCrae & Costa, 1997) in predicting social capital outcomes. In particular, we examine Extraversion as it reflects the extent to which people invest in engagement in social endeavours, and reflects the traits of sociability, liveliness and exhibition (Ashton & Lee, 2007; Sibley et al., 2011). As Ashton and Lee (2007) argued, Extraversion should have different adaptive benefits and costs, depending on one's social environment. On the one hand, a high level of Extraversion should be beneficial to the extent that it helps facilitate social gains in the form of friends, mates, and alliances with others. On the other hand, a high level of Extraversion may also have costs in terms of expenditure of energy and time, and also increased risks from the social environment when interacting with unfamiliar others. Here, we examine the moderating effects of Extraversion on the relationship between Facebook usage and felt belongingness. Felt belongingness is a general measure of how included and accepted someone feels, and is widely used in the psychological literature as an indicator of social capital and connection with others (Baumeister & Leary, 1995). How might Facebook usage be differentially related to the level of social capital enjoyed by extraverts and introverts? There are currently two major theories surrounding the use of social technology: the social enhancement hypothesis and the social compensation hypothesis (Kraut et al., 2002). The social enhancement perspective argues that individuals high in Extraversion will use social networking sites in the same way as they socialize offline, and thus will receive greater social benefits from the use of these sites relative to more introverted individuals (i.e., the 'rich get richer'). According to this theory, the time and energy committed to interacting with others on social media should pay off for extraverts in much the same way as it does in other contexts. The social compensation hypothesis, in contrast, argues that social networking sites afford those low in Extraversion a chance to make up for the relationships they struggle to establish or maintain offline (i. …

The Facebook Feedback Hypothesis of personality and social belonging

The relationship of household income with multiple aspects of subjective well-being was examined in a New Zealand telephone probability sample conducted in 2008 (N = 5197). Consistent with previous research, household income had positive logarithmic associations with subjective quality of life and happiness. The logarithmic function was steeper for quality of life than for happiness, indicating that income is linked more strongly to people's evaluations of their life than to their happiness. Analyses also indicated that the income well-being association was strongest for people earning below the median (NZ$ 65,000) and tended to plateau for people in the upper quartile (NZ$ 125,000). Contrary to previous research, income was negatively correlated with self-reported daily stress, after adjusting for relevant demographics (e.g., age and household crowding). This association was also logarithmic, and income was more predictive of reductions in stress for those earning below the median. Finally, we tested a log-mediation model in which the relationship between income and multiple components of well-being were mediated by the perceived ability to meet everyday life necessities. This mediator explained 55-60% of the association of income with both happiness and life quality, and fully mediated the effect of income on reduced stress. These are some of the first results to document the relationship between household income and subjective well-being in New Zealand. They also come at a time when concerns about the ability to meet everyday needs are particularly relevant to many New Zealanders in the wake of the global financial crisis.

How much happiness does money buy? Income and subjective well-being in New Zealand

This study extends the Mini-IPIP, a short measure of the Big-Five personality dimensions, to a Big-Six model of personality structure based on the HEXACO. Exploratory and Confirmatory analyses of a representative New Zealand sample (N = 5,562) validated the original Mini-IPIP five-factor structure, and supported an extended six-factor model also indexing Honesty-Humility. The Mini-IPIP6 reliably predicted variation in hours spent performing activities relating to aspects of personality (e.g., socializing, voluntary/charitable work, housework, and computer games). The Mini-IPIP6 also differentially predicted criterion outcomes such as religious affiliation and identification, political orientation, beliefs about climate change, and willingness to make personal sacrifices for the environment. The 24-item Mini-IPIP6 (four items indexing each personality dimension) fills a niche where brief markers of the Big-Six dimensions of personality are desired. A regression equation demonstrating how to integrate parameters derived using representative New Zealand data with a given individual’s Mini-IPIP6 scores to estimate his or her predicted value for each criterion outcome is provided (e.g., predicted housework in a given week), along with a copy of the scale itself, coding instructions and norms. This study represents the most detailed validation of a reliable and comprehensive broad-bandwidth public domain personality inventory for use in New Zealand to date.

The Mini-IPIP6: Validation and extension of a short measure of the Big-Six factors of personality in New Zealand.

New Zealand (NZ) is a fairly small nation by international standards, with a total population currently approaching 4. 3 million. The NZ population is diverse and, like many nations, is called home by people from a number of different ethnic backgrounds. According to 2006 census figures, roughly 67-68% of the population are of European descent (referred to here using the Maori term, Pakeha). Maori, the indigenous peoples of NZ, form between 14-15% of the population. NZ is also home to many Pacific Nations peoples, who form around 7% of the population; and a number of Asian peoples (primarily Chinese), who form approximately 9% of the population and are the fastest growing ethnic group. (i) Intergroup relations in NZ appear relatively harmonious; at least insofar as a lack of organized large-scale ethnic or national conflict is concerned. NZ was ranked as number one in the world on the 2010 Global Peace Index, indicating it was the most peaceful country in the world in which to live in that year (Institute for Economics and Peace, 2010). Despite this impressive ranking, there remain considerable differences in the equality of outcomes experienced by different ethnic groups residing in NZ. For instance, according to data reported in The Social Report (2008), Pakeha had a median hourly income of $18.94, Asian peoples (including the category "other") had a median hourly income of $15.82, and Maori and Pacific Nations peoples had lower median hourly incomes of $15.34 and $15.00, respectively. There are also numerous other differences in the ways in which Pakeha, Maori, Pacific Nations, and Asian peoples are socially constructed and (re-)presented in everyday discourse, national news media, and NZ culture in general. These vary from well-publicised political speeches and commentaries variously expressing concern about immigration policies, primarily those relating to Asian peoples (Liu & Mills, 2006) and also somewhat to Pacific Nations immigrants, to political/satirical cartoons such as the recent primetime comedy series bro'Town (produced by a Pacific Nations group), which depicts the experiences of young Pacific Nations youths living in NZ, and plays on societal ethnic stereotypes (see Teaiwa & Mallon, 2005). With regard to Maori, research shows a strong level of support for symbolic aspects of Maori culture and symbols interwoven throughout NZ society, paired with an equally strong resistance toward material reparation for historical and continuing injustices experienced by Maori at the hands of European colonials (Liu, 2005; Sibley, 2010; Sibley & Liu, 2004, 2007). New Zealanders, then, are well exposed to the different ways in which Pakeha, Maori, Pacific Nations, and Asian New Zealanders are constructed as essentialised categories. The vast majority of New Zealanders are also well aware, we maintain, of the core characteristics (or stereotyped content) used to repeatedly describe and depict these visible ethnic groups within NZ society. What might the content of ethnic group stereotypes of Pakeha, Maori, Pacific Nations, and Asian New Zealanders look like? How might such stereotypes be produced by socio-structural relations between different ethnic groups residing in NZ? And more importantly, if systematic differences in ethnic group stereotypes are observed, then what implications might this have for understanding how existing inequalities and prejudice are perpetuated and legitimised in NZ? We present data from a national postal sample examining the core content of ethnic group stereotypes in NZ. We apply recent theoretical models of stereotype content developed overseas in an attempt to understand how systemic differences in the content of stereotypes of different ethnic groups residing in NZ might arise, and how specific stereotypes of different ethnic groups might contribute to our understanding of ethnic prejudice and discrimination in NZ's unique socio-political context. It should be noted at this point that we view Pakeha, Maori, Pacific Nations, and Asian New Zealanders as socially constructed identities rather than essentialised, biologically determined, immutable categories. …

Imaginative travel: experiential aspects of user interactions with destination marketing websites

Summary terrane, mineral deposit, and metallogenic belt maps of the Russian Far East, Alaska, and the Canadian Cordillera

Mineral deposit and metallogenic belt maps of the Russian Far East, Alaska, and the Canadian cordillera

Effect of starvation on energy reserves and metabolism in the Northern abalone, Haliotis kamtschatkana

Spectrophotometric and fluorimetric methods Atomic-, mass-, X-ray-spectrometric methods, electronparamagnetic and luminescence methods Voltammetric methods Neutron activation analysis Measurement of pH in natural waters Electroanalytical measurement of trace metals complexation Trace metal complexation by inorganic ligands in sea water Adsorption of trade elements by suspended particulate matter in aquatic systems Physicochemical speciation of trace elements in oxygenated estuarine waters Chemical mechanisms operating in sea water.

Preparation and properties of N6-monobutyryl adenosine 5'-monophosphate. A major hepatic metabolite of N6,O2'-dibutyryl cyclic adenosine 3':5'-monophosphate.

Notes on the Oliver Collection of carboniferous plants. 3. Wound reactions in a petiole of Ankyropteris westphaliensis Bertrand

Notes on the Oliver Collection of Carboniferous plants. I. On the branching of Spencerites insignis (Williamson)

Notes on the Oliver collection of carboniferous plants. 2. Increased megaspore number in Bothrodendron Mundum (Will.)

Characteristics and One Year Outcomes of Melioidosis Patients in Northeastern Thailand: A Prospective, Multicenter Cohort Study.

Abstract Introduction Inhalation injury is associated with increased risk of pneumonia. Bronchoscopy with bronchoalveolar lavage (BAL) is commonly used to diagnose and grade inhalation injury while obtaining a microbiological sample. It has been shown that a quarter of patients with inhalation injury have a single bacteria isolated from initial BAL within 12-48 hours of injury. The clinical significance of this and role of antibiotics in this setting are unknown. We investigated the incidence that bacteria isolated during a pneumonia episode were previously isolated on surveillance BAL among patients with inhalation injury. Methods Among patients with inhalation injury admitted to a large ABA-verified burn center from 2009-2022, microbiological isolates from initial BAL and subsequent culture obtained during a pneumonia episode (BAL, sputum), were extracted from medical records. Abbreviated injury severity score (AIS) was used to grade inhalation injury. Hospital-acquired pneumonia (HAP) was defined using CDC PNU1 criteria, and ventilator-associated pneumonia (VAP) was defined using PNU2 criteria with BAL cutoff >10,000 colony forming units (CFU). Results Two-hundred forty-eight patients with inhalation injury who underwent bronchoscopy for airway inspection and surveillance BAL within 48 hours of injury were included in the analysis. Of the 111 who had a bacterial isolate from initial BAL, 23 (21%) subsequently developed HAP or VAP during the hospitalization. Median (IQR) days between bronchoscopy and pneumonia diagnosis was six (2-8.5). In three of the 11 VAP cases (27%), the organisms identified at pneumonia diagnosis matched the organisms identified on initial BAL. Antibiotic use on admission was not associated with re-culture of initial BAL organism during a subsequent pneumonia episode (p=0.071). Conclusions Among patients with inhalation injury and bacteria isolated on surveillance BAL, 21% developed pneumonia during their hospital stay, usually with different bacteria than those isolated at initial bronchoscopy. There was no association between empiric antibiotic use and incidence of initial BAL organisms re-cultured during subsequent pneumonia episode. Applicability of Research to Practice Findings suggest initial BAL isolates cannot guide empiric coverage of pneumonia for patients with inhalation injury. This remains an important area of future research.

Journal of Burn Care & Research: Official Publication of the American Burn Association

758 Correlation between initial and diagnostic bronchoalveolar lavage isolates among patients with inhalation injury and pneumonia

Abstract Introduction Inhalation injury is associated with increased incidence of pneumonia. Bacteria are commonly isolated from bronchoalveolar lavage (BAL) within 12-48 hours of injury with unclear clinical significance. We aimed to determine if grade of inhalation injury is associated with different bacterial species isolated from initial BAL, and if higher inhalation injury grade is associated with increased risk of pneumonia. Methods Abbreviated injury scores (AIS) and clinical microbiology isolates from diagnostic bronchoscopy with BAL performed within 48 hours of injury among adults with inhalation injuries from 2009-2022 were extracted from medical records at an ABA-verified burn center. CDC PNU1 criteria was used to identify pneumonia >48 hours after admission. Modified Poisson regression with robust standard errors was used to assess the association of inhalation injury grade and subsequent pneumonia. Results Two hundred forty-six patients with inhalation injury who underwent diagnostic bronchoscopy for airway inspection and surveillance BAL within 48 hours of injury were included in this analysis. Fourteen (5.7%) were grade 0, 106 (43.1%) grade 1, 75 (30.5%) grade 2, 51 (20.7%) grade 3-4. The most common bacterial isolate was Streptococcus spp irrespective of AIS grade. Higher AIS grade was associated with increased incidence of pneumonia (IRR 1.3; 95% CI 1.09-1.61; p = 0.01) after adjustment for age, sex, and total body surface area of burn involvement. Conclusions Bacterial species isolated did not differ by inhalation injury grade. Higher inhalation injury grade was associated with increased risk of pneumonia. Applicability of Research to Practice Providers should be vigilant that patients with higher grade of inhalation injury are at increased risk of pneumonia. Further research is urgently needed to assess the clinical significance of organisms isolated on initial BAL and their role – if any – on the development of pneumonia.

56 The Impact of Inhalation Injury Grade on Bacterial Isolates from Diagnostic Bronchoscopy with Bronchoalveolar Lavage

Inhalation Injury Grade and Risk of Ventilator-associated Pneumonia

Association Between Bacteria Isolated From Admission Bronchoalveolar Lavage and Hospital Mortality in Inhalation Injury

Melioidosis is a tropical infectious disease caused by Burkholderia pseudomallei. Melioidosis is associated with diverse clinical manifestations and high mortality. ABSTRACT Melioidosis is a tropical infectious disease caused by Burkholderia pseudomallei. Melioidosis is associated with diverse clinical manifestations and high mortality. Early diagnosis is needed for appropriate treatment, but it takes several days to obtain bacterial culture results. We previously developed a rapid immunochromatography test (ICT) based on hemolysin coregulated protein 1 (Hcp1) and two enzyme-linked immunosorbent assays (ELISAs) based on Hcp1 (Hcp1-ELISA) and O-polysaccharide (OPS-ELISA) for serodiagnosis of melioidosis. This study prospectively validated the diagnostic accuracy of the Hcp1-ICT in suspected melioidosis cases and determined its potential use for identifying occult melioidosis cases. Patients were enrolled and grouped by culture results, including 55 melioidosis cases, 49 other infection patients, and 69 patients with no pathogen detected. The results of the Hcp1-ICT were compared with culture, a real-time PCR test based on type 3 secretion system 1 genes (TTS1-PCR), and ELISAs. Patients in the no-pathogen-detected group were followed for subsequent culture results. Using bacterial culture as a gold standard, the sensitivity and specificity of Hcp1-ICT were 74.5% and 89.8%, respectively. The sensitivity and specificity of TTS1-PCR were 78.2% and 100%, respectively. The diagnostic accuracy was markedly improved if the Hcp1-ICT results were combined with TTS1-PCR results (sensitivity and specificity were 98.2% and 89.8%, respectively). Among patients with initially negative cultures, Hcp1-ICT was positive in 16/73 (21.9%). Five of the 16 patients (31.3%) were subsequently confirmed to have melioidosis by repeat culture. The combined Hcp1-ICT and TTS1-PCR test results are useful for diagnosis, and Hcp1-ICT may help identify occult cases of melioidosis.

Prospective Analysis of Antibody Diagnostic Tests and TTS1 Real-Time PCR for Diagnosis of Melioidosis in Areas Where It Is Endemic

Asthma Characteristics and Allergic Sensitization Among Adolescents With HIV and HIV-uninfected Adolescents in Nairobi, Kenya

Melioidosis is an often-fatal neglected tropical disease caused by an environmental bacterium Burkholderia pseudomallei. However, our understanding of disease-causing bacterial lineages, dissemination, and their adaptive mechanisms remains limited. To address this, we conducted comprehensive genomic analysis of 1,265 B. pseudomallei isolates collected from nine hospitals in northeast Thailand between 2015 and 2018, presenting the most densely sampled collection to date. Our study identified four dominant lineages with unique gene sets enhancing bacterial fitness, indicating lineage-specific co-colonisation strategies. Crucially, recombination was found to drive lineage-specific gene flow. Transcriptome analysis of a representative isolate from one lineage revealed upregulation of lineage-specific genes under nutrient-depletion. Our study also demonstrated the impact of river systems, monsoons, and typhoons in shaping the geographical dispersal of B. pseudomallei. Collectively, our findings underscore the importance of bacterial persistence in the environment as a prelude to exposure and infection, thereby providing insights for melioidosis prevention and control strategies.

Genetic diversity, determinants, and dissemination of Burkholderia pseudomallei lineages implicated in melioidosis in northeast Thailand

Sepsis is a complex heterogeneous condition, and the current lack of effective risk and outcome predictors hinders the improvement of its management. Using a reductionist approach leveraging publicly available transcriptomic data, we describe a knowledge gap for the role of ACVR1B (activin A receptor type 1B) in sepsis. ACVR1B, a member of the transforming growth factor-beta (TGF-beta) superfamily, was selected based on the following: 1) induction upon in vitro exposure of neutrophils from healthy subjects with the serum of septic patients (GSE49755), and 2) absence or minimal overlap between ACVR1B, sepsis, inflammation, or neutrophil in published literature. Moreover, ACVR1B expression is upregulated in septic melioidosis, a widespread cause of fatal sepsis in the tropics. Key biological concepts extracted from a series of PubMed queries established indirect links between ACVR1B and “cancer”, “TGF-beta superfamily”, “cell proliferation”, “inhibitors of activin”, and “apoptosis”. We confirmed our observations by measuring ACVR1B transcript abundance in buffy coat samples obtained from healthy individuals (n=3) exposed to septic plasma (n = 26 melioidosis sepsis cases)ex vivo. Based on our re-investigation of publicly available transcriptomic data and newly generated ex vivo data, we provide perspective on the role of ACVR1B during sepsis. Additional experiments for addressing this knowledge gap are discussed.

Abundance of ACVR1B transcript is elevated during septic conditions: Perspectives obtained from a hands-on reductionist investigation

The bacterium Burkholderia pseudomallei is the causative agent of melioidosis, a severe tropical disease associated with high mortality and relapse and persistent infections. Treatment of melioidosis requires prolonged antibiotic therapy; however, little is known about relapse and persistent infections, particularly the phenotypic and genetic alterations of B. pseudomallei in patients. In this study, we performed pulsed-field gel electrophoresis (PFGE) to compare the bacterial genotype between the initial isolate and the subsequent isolate from each of 23 suspected recurrent and persistent melioidosis patients in Northeast Thailand. We used whole-genome sequencing (WGS) to investigate multilocus sequence types and genetic alterations of within-host strain pairs. We also investigated the bacterial phenotypes associated with relapse and persistent infections, including multinucleated giant cell (MNGC) formation efficiency and intracellular multiplication. We first identified 13 (1.2%) relapse, 7 (0.7%) persistent, and 3 (0.3%) reinfection patients from 1,046 survivors. Each of the 20 within-host strain pairs from patients with relapse and persistent infections shared the same genotype, suggesting that the subsequent isolates arise from the infecting isolate. Logistic regression analysis of clinical data revealed regimen and duration of oral antibiotic therapies as risk factors associated with relapse and persistent infections. WGS analysis demonstrated 17 within-host genetic alteration events in 6 of 20 paired isolates, including a relatively large deletion and 16 single-nucleotide polymorphism (stocktickerSNP) mutations distributed across 12 genes. In 1 of 20 paired isolates, we observed significantly increased cell-to-cell fusion and intracellular replication in the second isolate compared with the initial isolate from a patient with persistent infection. WGS analysis suggested that a non-synonymous mutation in the tssB-5 gene, which encoded an essential component of the type VI secretion system, may be associated with the increased intracellular replication and MNGC formation efficiency of the second isolate of the patient. This information provides insights into genetic and phenotypic alterations in B. pseudomallei in human melioidosis, which may represent a bacterial strategy for persistent and relapse infections.

Phenotypic and genetic alterations of Burkholderia pseudomallei in patients during relapse and persistent infections

Enhanced bedside mortality prediction combining point-of-care lactate and the quick Sequential Organ Failure Assessment (qSOFA) score in patients hospitalised with suspected infection in southeast Asia: a cohort study

Age–sex differences in the global burden of lower respiratory infections and risk factors, 1990–2019: results from the Global Burden of Disease Study 2019

Background Surveillance systems are important in detecting changes in disease patterns and can act as early warning systems for emerging disease outbreaks. We hypothesized that analysis of data from existing global influenza surveillance networks early in the COVID-19 pandemic could identify outliers in influenza-negative influenza-like illness (ILI). We used data-driven methods to detect outliers in ILI that preceded the first reported peaks of COVID-19. Methods and findings We used data from the World Health Organization’s Global Influenza Surveillance and Response System to evaluate time series outliers in influenza-negative ILI. Using automated autoregressive integrated moving average (ARIMA) time series outlier detection models and baseline influenza-negative ILI training data from 2015–2019, we analyzed 8,792 country-weeks across 28 countries to identify the first week in 2020 with a positive outlier in influenza-negative ILI. We present the difference in weeks between identified outliers and the first reported COVID-19 peaks in these 28 countries with high levels of data completeness for influenza surveillance data and the highest number of reported COVID-19 cases globally in 2020. To account for missing data, we also performed a sensitivity analysis using linear interpolation for missing observations of influenza-negative ILI. In 16 of the 28 countries (57%) included in this study, we identified positive outliers in cases of influenza-negative ILI that predated the first reported COVID-19 peak in each country; the average lag between the first positive ILI outlier and the reported COVID-19 peak was 13.3 weeks (standard deviation 6.8). In our primary analysis, the earliest outliers occurred during the week of January 13, 2020, in Peru, the Philippines, Poland, and Spain. Using linear interpolation for missing data, the earliest outliers were detected during the weeks beginning December 30, 2019, and January 20, 2020, in Poland and Peru, respectively. This contrasts with the reported COVID-19 peaks, which occurred on April 6 in Poland and June 1 in Peru. In many low- and middle-income countries in particular, the lag between detected outliers and COVID-19 peaks exceeded 12 weeks. These outliers may represent undetected spread of SARS-CoV-2, although a limitation of this study is that we could not evaluate SARS-CoV-2 positivity. Conclusions Using an automated system of influenza-negative ILI outlier monitoring may have informed countries of the spread of COVID-19 more than 13 weeks before the first reported COVID-19 peaks. This proof-of-concept paper suggests that a system of influenza-negative ILI outlier monitoring could have informed national and global responses to SARS-CoV-2 during the rapid spread of this novel pathogen in early 2020.

Global influenza surveillance systems to detect the spread of influenza-negative influenza-like illness during the COVID-19 pandemic: Time series outlier analyses from 2015–2020

Respiratory support in patients with severe COVID-19 in the International Severe Acute Respiratory and Emerging Infection (ISARIC) COVID-19 study: a prospective, multinational, observational study

Morbidity and Mortality Following Melioidosis Pneumonia: Results from a Multicenter Cohort Study

Factors Associated with Abnormal Lung Function in Adolescents With and Without HIV in Nairobi, Kenya

Introduction Rapid diagnostic tests (RDTs) that can facilitate the diagnosis of a panel of tropical infectious diseases are critically needed. The ‘DPP® Fever Panel II Asia’ is a multiplex lateral flow immunoassay comprising of antigen and IgM panels for the diagnosis of pathogens that commonly cause febrile illness in Southeast Asia. Aim To evaluate sensitivity and specificity of DPP® Fever Panel II for malaria, dengue and melioidosis. Methodology We conducted a cohort-based case-control study. Both cases and controls were derived from a prospective observational study of patients presenting with community-acquired infections and sepsis in northeast Thailand (Ubon-sepsis). We included 143 and 98 patients diagnosed with malaria or dengue based on a positive PCR assay and 177 patients with melioidosis based on a culture positive for Burkholderia pseudomallei. Controls included 200 patients who were blood culture positive for Staphylococcus aureus, Escherichia coli or Klebsiella pneumoniae, and cases of the other diseases. Serum samples collected from all patients within 24 hours of admission were stored and tested using the DPP® Fever Panel II Asia antigen and IgM multiplex assays. We selected cutoff values for each individual assay corresponding to a specificity of ≥95%. When assessing diagnostic tests in combination, results were considered positive if either individual test was positive. Results Within the DPP® Fever Panel II antigen assay, a combination of pLDH and HRPII for malaria had a sensitivity of 91% and a specificity of 97%. The combination of dengue NS1 antigen and dengue antibody tests had a sensitivity of 61% and a specificity of 91%. The B. pseudomallei CPS antigen test had a sensitivity of 27% and a specificity of 97%. An odds ratio of 2.34 (95% CI 1.16-4.72, p=0.02) was observed for the association between positivity of CPS and mortality among melioidosis patients. Conclusion The performance of the DPP® Fever Panel II Asia for diagnosis of malaria was high and that for dengue and melioidosis was relatively limited. For all three diseases, performance was comparable with other established RDTs. The potential operational advantages of a multiplex and quantitative point of care assay are substantial and warrant further investigation.

Sensitivity and specificity of DPP® Fever Panel II Asia in the diagnosis of malaria, dengue and melioidosis

Critically ill patients manifest many of the same immune features seen in coronavirus disease 2019 (COVID-19), including both “cytokine storm” and “immune suppression.” However, direct comparisons of molecular and cellular profiles between contemporaneously enrolled critically ill patients with and without severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are limited. We sought to identify immune signatures specifically enriched in critically ill patients with COVID-19 compared with patients without COVID-19. We enrolled a multisite prospective cohort of patients admitted under suspicion for COVID-19, who were then determined to be SARS-CoV-2-positive (n = 204) or -negative (n = 122). SARS-CoV-2-positive patients had higher plasma levels of CXCL10, sPD-L1, IFN-γ, CCL26, C-reactive protein (CRP), and TNF-α relative to SARS-CoV-2-negative patients adjusting for demographics and severity of illness (Bonferroni P value < 0.05). In contrast, the levels of IL-6, IL-8, IL-10, and IL-17A were not significantly different between the two groups. In SARS-CoV-2-positive patients, higher plasma levels of sPD-L1 and TNF-α were associated with fewer ventilator-free days (VFDs) and higher mortality rates (Bonferroni P value < 0.05). Lymphocyte chemoattractants such as CCL17 were associated with more severe respiratory failure in SARS-CoV-2-positive patients, but less severe respiratory failure in SARS-CoV-2-negative patients (P value for interaction < 0.01). Circulating T cells and monocytes from SARS-CoV-2-positive subjects were hyporesponsive to in vitro stimulation compared with SARS-CoV-2-negative subjects. Critically ill SARS-CoV-2-positive patients exhibit an immune signature of high interferon-induced lymphocyte chemoattractants (e.g., CXCL10 and CCL17) and immune cell hyporesponsiveness when directly compared with SARS-CoV-2-negative patients. This suggests a specific role for T-cell migration coupled with an immune-checkpoint regulatory response in COVID-19-related critical illness.

American Journal of Physiology - Lung Cellular and Molecular Physiology

Chemokines, soluble PD-L1, and immune cell hyporesponsiveness are distinct features of SARS-CoV-2 critical illness

Plasma Immune Mediators Measured After Initiation of Therapy in Critically Ill COVID-19 Patients and Risk for Poor Clinical Outcomes

ISARIC-COVID-19 dataset: A Prospective, Standardized, Global Dataset of Patients Hospitalized with COVID-19

Case definitions are used to guide clinical practice, surveillance and research protocols. However, how they identify COVID‐19‐hospitalised patients is not fully understood. We analysed the proportion of hospitalised patients with laboratory‐confirmed COVID‐19, in the ISARIC prospective cohort study database, meeting widely used case definitions.

Symptom‐based case definitions for COVID‐19: Time and geographical variations for detection at hospital admission among 260,000 patients

Intro: Early innate immune responses are hypothesized to impact inflammation and therefore severity of disease and organ injury in COVID-19. Prior work in sepsis has identified CD14 as a marker of innate immune responses to bacterial infection and emerging evidence has implicated CD14 in COVID-19. CD14 exists in membrane bound and soluble (sCD14) form. A soluble N-terminal fragment of sCD14, sCD14 subtype (sCD14-ST, “Presepsin”) has been shown to have utility in diagnosis of sepsis and prognosis of associated organ failure and death. Goal: To determine the relationship between plasma sCD14 and sCD14-ST levels, COVID-19 status, and COVID-19 related outcomes in a cohort of prospectively enrolled critically ill patients admitted under suspicion for COVID-19. Methods: Critically ill patients under investigation for COVID-19 were prospectively enrolled between April 2020 and November 2020 at three hospitals affiliated with University of Washington. We ascertained COVID-19 status by SARS-CoV-2 RT-PCR upon admission. We measured plasma sCD14 and sCD14-ST levels in samples collected within 24 hours of admission. We tested for associations between biomarker levels and COVID-19 status using logistic regression adjusting for age, sex and APACHE III. In patients with COVID-19, we tested for associations between biomarker levels and disease severity and clinical outcomes using regression analyses adjusting for age, sex and APACHE III. Results: The cohort (n=222) mean age was 55 years, it was predominantly male (66%), in hospital mortality was 26%, and 50% of patients were positive by SARS-CoV-2 RT-PCR. Patients with COVID-19 had lower APACHE III scores (p: 0.013) than non-COVID-19. SCD14-ST levels were inversely associated with risk of SARS-CoV-2 positivity in multivariate regression (OR: 0.70, 95% CI: 0.57-0.84). Among patients with COVID-19, sCD14-ST levels were associated with higher APACHE III scores (beta: 7.3, 95% CI: 4.1-11), lower ventilatorfree days (beta:-1.6, 95% CI:-3.2 to-0.05) and higher risk for AKI (OR: 1.6, 95% CI: 1.0 to 2.7). SCD14-ST levels were not associated with these clinical outcomes in non-COVID-19 controls. In contrast to sCD14-ST levels, sCD14 levels did not differ between COVID-19 and non-COVID-19 patients and were not associated with COVID-19 clinical outcomes. Conclusions: In critically ill patients, sCD14-ST levels are inversely associated with risk of COVID-19 and positively associated with severity of disease and clinical outcomes among patients with COVID-19 while sCD14 levels were not associated with COVID-19 status or related outcomes. Early measurements of sCD14-ST levels could have prognostic utility in COVID-19.

Plasma sCD14-ST, but Not sCD14, Is Inversely Associated with Risk for SARS-CoV2 Positivity and Positively Associated with COVID-19-Related Respiratory Failure in Critically Ill Patients Admitted Under Suspicion for COVID-19

Rationale: Since the onset of coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), studies have suggested a high incidence of acute kidney injury (AKI) among patients with COVID-19. However, these studies lack contemporaneously enrolled critically ill patients to understand whether high rates of AKI are unique to COVID-19. It is also unknown whether the risk of AKI is related to SARS-CoV-2 genomic load. Methods: We prospectively enrolled a cohort of patients admitted to the ICU with suspicion of COVID-19 (persons under investigation) from April to September 2020. Of these patients, 78 (46%) tested positive for SARS-CoV-2 (COVID-19) and 91 (54%) tested negative (non-COVID-19). AKI was defined as an increase ≥ 0.3 mg/dL in 48 hours or ≥ 50% increase in serum creatinine (sCr) measured during hospitalization compared to a 'baseline' sCr measured at study enrollment. New dialysis was defined as initiation of dialysis during hospitalization. SARS-CoV-2 qRT-PCR was performed across four different platforms with comparable cycle threshold (Ct) values. Ct values were a semiquantitative measure of genomic load with an inverse relationship of Ct to genomic load. We used relative risk regression to determine if there was an increased risk of AKI in COVID-19 compared to non-COVID-19 and whether SARS-CoV-2 genomic load was associated with AKI. Analyses were adjusted for age, sex, body mass index, and APACHE III scores. Results: Rates of AKI and new dialysis were similar in COVID-19 compared to non-COVID-19 (AKI: n=23 (29%) vs n=24 (26%) and Dialysis: n=8 (10%) vs n=6 (6%). Unadjusted and adjusted analyses demonstrated a non-significant difference in risk of AKI (adjusted RR = 1.04 (95% CI: 0.65-1.66) or new dialysis (adjusted RR = 1.55 (95% CI 0.58-4.12) in COVID-19 compared to non-COVID-19. We had Ct values available prior to ICU admission in 47 patients. In unadjusted and adjusted analyses, a 10-unit decrement in Ct values was not associated with AKI (adjusted RR = 0.40 (95% CI: 0.14-1.14) or new dialysis (adjusted RR = 0.96 (95% CI: 0.23-2.69) (Figure 1). Conclusions: Our study demonstrates that rates of AKI and new dialysis in ICU patients with COVID-19 are similar to rates in non-COVID-19 ICU patients. Moreover, the lack of association between Ct values and AKI in COVID-19, suggests that immune and host response to SARS-CoV-2 may contribute more to risk of AKI in ICU patients rather than the pathogen itself.

TP50. TP050 COVID: NONPULMONARY CRITICAL CARE, MECHANICAL VENTILATION, BEHAVIORAL SCIENCES, AND EPI

Rates of AKI in ICU Patients Admitted Under Suspicion for COVID-19 Do Not Differ by SARS-CoV2 Status or SARS-CoV-2 Genomic Load

ABSTRACT New studies of COVID-19 are constantly updating best practices in clinical care. However, research mainly originates in resource-rich settings in high-income countries. Often, it is impractical to apply recommendations based on these investigations to resource-constrained settings in low- and middle-income countries (LMICs). We report on a set of pragmatic recommendations for tracheostomy, discharge, and rehabilitation measures in hospitalized patients recovering from severe COVID-19 in LMICs. We recommend that tracheostomy be performed in a negative pressure room or negative pressure operating room, if possible, and otherwise in a single room with a closed door. We recommend using the technique that is most familiar to the institution and that can be conducted most safely. We recommend using fit-tested enhanced personal protection equipment, with the fewest people required, and incorporating strategies to minimize aerosolization of the virus. For recovering patients, we suggest following local, regional, or national hospital discharge guidelines. If these are lacking, we suggest deisolation and hospital discharge using symptom-based criteria, rather than with testing. We likewise suggest taking into consideration the capability of primary caregivers to provide the necessary care to meet the psychological, physical, and neurocognitive needs of the patient.

Pragmatic Recommendations for Tracheostomy, Discharge, and Rehabilitation Measures in Hospitalized Patients Recovering From Severe COVID-19 in Low- and Middle-Income Countries

The value of open-source clinical science in pandemic response: lessons from ISARIC

As genomic sequencing becomes more accurate and less costly, large cohorts and consortiums of cohorts are providing high power for rare variant association studies for many conditions. When large sample sizes are not attainable and the phenotype under study is continuous, an extreme phenotypes design can provide high statistical power with a small to moderate sample size. We extend the extreme phenotypes design to the dichotomous infectious disease outcome by sampling on extremes of the pathogenic exposure instead of sampling on extremes of phenotype. We use a likelihood ratio test (LRT) to test the significance of association between infection status and presence of susceptibility rare variants. More than 10 billion simulations are studied to assess the method. The method results in high sample enrichment for rare variants affecting susceptibility. Greater than 90% power to detect rare variant associations is attained in reasonable scenarios. The ordinary case-control design requires orders of magnitude more samples to achieve the same power. The Type I error rate of the LRT is accurate even for p-values < 10-7. We find that erroroneous exposure assessment can lead to power loss more severe than excluding the observations with errors. Nevertheless, careful sampling on exposure extremes can make a study feasible by providing adequate statistical power. Limitations of this method are not unique to this design, and the power is never less than that of the ordinary case-control design. The method applies without modification to other dichotomous outcomes that have strong association with a continuous covariate.

Extreme Sampling for Genetic Rare Variant Association Analysis of Dichotomous Traits with Focus on Infectious Disease Susceptibility

Supplemental Digital Content is available in the text. IMPORTANCE: Even with its proclivity for older age, coronavirus disease 2019 has been shown to affect all age groups. However, there remains a lack of research focused primarily on the young adult population. OBJECTIVES: To describe the epidemiology and outcomes of coronavirus disease 2019 and identify the risk factors associated with critical illness and mortality in hospitalized young adults. DESIGN, SETTINGS, AND PARTICIPANTS: A retrospective cohort study of the Society of Critical Care Medicine’s Viral Infection and Respiratory Illness Universal Study registry. Patients 18–40 years old, hospitalized from coronavirus disease 2019 from March 2020 to April 2021, were included in the analysis. MAIN OUTCOMES AND MEASURES: Critical illness was defined as a composite of mortality and 21 predefined interventions and complications. Multivariable logistic regression was used to assess associations with critical illness and mortality. RESULTS: Data from 4,005 patients (152 centers, 19 countries, 18.6% non-U.S. patients) were analyzed. The median age was 32 years (interquartile range, 27–37 yr); 51% were female, 29.4% Hispanic, and 42.9% had obesity. Most patients (63.2%) had comorbidities, the most common being hypertension (14.5%) and diabetes (13.7%). Hospital and ICU mortality were 3.2% (129/4,005) and 8.3% (109/1,313), respectively. Critical illness occurred in 25% (n = 996), and 34.3% (n = 1,376) were admitted to the ICU. Older age (p = 0.03), male sex (adjusted odds ratio, 1.83 [95% CI, 1.2–2.6]), and obesity (adjusted odds ratio, 1.6 [95% CI, 1.1–2.4]) were associated with hospital mortality. In addition to the above factors, the presence of any comorbidity was associated with critical illness from coronavirus disease 2019. Multiple sensitivity analyses, including analysis with U.S. patients only and patients admitted to high-volume sites, showed similar risk factors. CONCLUSIONS: Among hospitalized young adults, obese males with comorbidities are at higher risk of developing critical illness or dying from coronavirus disease 2019.

Risk Factors for Critical Coronavirus Disease 2019 and Mortality in Hospitalized Young Adults: An Analysis of the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS) Coronavirus Disease 2019 Registry

Seasonal Variation of the Incidence and Profile of Community-Acquired Infection in Northeast Thailand

Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is a serious infectious disease with diverse clinical manifestations. The morbidity and mortality of melioidosis is high in Southeast Asia and no licensed vaccines currently exist. This study was aimed at evaluating human cellular and humoral immune responses in Thai adults against four melioidosis vaccine candidate antigens. Blood samples from 91 melioidosis patients and 100 healthy donors from northeast Thailand were examined for immune responses against B. pseudomallei Hcp1, AhpC, TssM and LolC using a variety of cellular and humoral immune assays including IFN-γ ELISpot assays, flow cytometry and ELISA. PHA and a CPI peptide pool were also used as control stimuli in the ELISpot assays. Hcp1 and TssM stimulated strong IFN-γ secreting T cell responses in acute melioidosis patients which correlated with survival. High IFN-γ secreting CD4+ T cell responses were observed during acute melioidosis. Interestingly, while T cell responses of melioidosis patients against the CPI peptide pool were low at the time of enrollment, the levels increased to the same as in healthy donors by day 28. Although high IgG levels against Hcp1 and AhpC were detected in acute melioidosis patients, no significant differences between survivors and non-survivors were observed. Collectively, these studies help to further our understanding of immunity against disease following natural exposure of humans to B. pseudomallei as well as provide important insights for the selection of candidate antigens for use in the development of safe and effective melioidosis subunit vaccines.

Melioidosis Patient Survival Correlates With Strong IFN-γ Secreting T Cell Responses Against Hcp1 and TssM

A Simple Model Predicts Clinical Deterioration in Patients Admitted with Suspected Infection and Low Severity of Illness to a Hospital in Northeastern Thailand

Background Melioidosis, an infectious disease caused by Burkholderia pseudomallei, is endemic in many tropical developing countries and has a high mortality. Here we evaluated combinations of a lateral flow immunoassay (LFI) detecting B. pseudomallei capsular polysaccharide (CPS) and enzyme-linked immunosorbent assays (ELISA) detecting antibodies against hemolysin co-regulated protein (Hcp1) or O-polysaccharide (OPS) for diagnosing melioidosis. Methodology/Principal findings We conducted a cohort-based case-control study. Both cases and controls were derived from a prospective observational study of patients presenting with community-acquired infections and sepsis in northeast Thailand (Ubon-sepsis). Cases included 192 patients with a clinical specimen culture positive for B. pseudomallei. Controls included 502 patients who were blood culture positive for Staphylococcus aureus, Escherichia coli or Klebsiella pneumoniae or were polymerase chain reaction assay positive for malaria or dengue. Serum samples collected within 24 hours of admission were stored and tested using a CPS-LFI, Hcp1-ELISA and OPS-ELISA. When assessing diagnostic tests in combination, results were considered positive if either test was positive. We selected ELISA cut-offs corresponding to a specificity of 95%. Using a positive cut-off OD of 2.912 for Hcp1-ELISA, the combination of the CPS-LFI and Hcp1-ELISA had a sensitivity of 67.7% (130/192 case patients) and a specificity of 95.0% (477/502 control patients). The sensitivity of the combination (67.7%) was higher than that of the CPS-LFI alone (31.3%, p<0.001) and that of Hcp1-ELISA alone (53.6%, p<0.001). A similar phenomenon was also observed for the combination of CPS-LFI and OPS-ELISA. In case patients, positivity of the CPS-LFI was associated with a short duration of symptoms, high modified Sequential (sepsis-related) Organ Failure Assessment (SOFA) score, bacteraemia and mortality outcome, while positivity of Hcp1-ELISA was associated with a longer duration of symptoms, low modified SOFA score, non-bacteraemia and survival outcome. Conclusions/Significance A combination of antigen-antibody diagnostic tests increased the sensitivity of melioidosis diagnosis over individual tests while preserving high specificity. Point-of-care tests for melioidosis based on the use of combination assays should be further developed and evaluated.

Evaluation of antigen-detecting and antibody-detecting diagnostic test combinations for diagnosing melioidosis

RATIONALE: Several studies have identified host immune signatures that are associated with COVID-19. However, it is unclear whether these immune signatures are specific to COVID-19 or are merely reflective of illness severity. In vitro studies have demonstrated that human T-cell responses to SARS-CoV-2-specific antigens are mediated through interferon-gamma (IFN-γ). Methods: We prospectively enrolled a multi-site cohort of patients admitted to the ICU under suspicion for COVID-19 who were then determined to be SARS-CoV-2-positive (n = 82) or-negative (n = 97) by RT-PCR. We measured multiple molecular and cellular immune profiles from blood and endotracheal aspirates (ETAs) collected on ICU admission. Our primary analysis tested for associations between IFN-γ and interferon-inducible mediators (CXCL10 and soluble PD-L1 (sPD-L1)) in blood or ETAs and SARS-CoV-2 status. We then stratified our cohort into SARS-CoV-2-negative and-positive groups and tested for associations between interferon-inducible mediators and clinical outcomes and SARS-CoV-2-copy-number. We used cytometry time-of-flight (CyTOF) to simultaneously measure 39 cell surface and intracellular markers on peripheral blood mononuclear cells collected from a subset of patients with ARDS. We then compared immune cell signatures in subjects with vs. without SARS-CoV-2. Results: The mean APACHE III score was higher in SARS-CoV-2-negative vs.-positive subjects (80±30 vs. 69±29), but the groups were otherwise well-matched. SARS-CoV-2-positive subjects had higher plasma concentrations of IFN-γ, CXCL10, and sPD-L1 relative to SARSCoV-2-negative patients adjusting for age, sex, and severity of illness (all p ≤ 0.01). The levels of IL-6, TNF-α, IL-8, MCP-1, and IL-17A were not significantly different between the two groups. SARS-CoV-2-positive subjects also had higher CXCL10 concentrations in ETAs than SARS-CoV-2-negative subjects. Higher plasma concentrations of CXCL10 and sPD-L1 were associated with higher mortality (Table 1) and more severe respiratory disease (ventilator-free days (VFDs), ARDS) in SARS-CoV-2-positive, but not-negative, patients. In contrast, higher IL-6 was associated with a lower number of VFDs and ARDS in both groups. IFN-γ and CXCL10 (but not IL-6) were associated with SARS-CoV-2-copy-number. Using CyTOF, we found SARS-CoV-2-positive subjects had a lower proportion of CXCR3+ (CXCL10 receptor) T-cells, a higher proportion of PD-L1+ monocytes, and less T-cell and monocyte intracellular cytokine staining vs. SARS-CoV-2-negative patients. Conclusion: Our findings suggest interferon-inducible mediator responses and immune cell hypofunction are characteristic of critically ill subjects with SARS-CoV-2 compared with similar patients without SARS-CoV-2. Our identification of immune signatures that are associated with SARS-CoV-2 infection but are distinct from other forms of critical illness clarifies COVID-19 pathophysiology.

TP3. TP003 COVID-19 INFECTIONS, MECHANISMS, AND CLINICAL IMPLICATIONS

Interferon-Inducible Mediators Are Associated with SARS-CoV-2 and Related Severity Amongst Critically Ill Patients Suspected of COVID-19

Introduction Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in intensive care units (ICUs). Using short-course antibiotics to treat VAP caused by Gram-negative non-fermenting bacteria has been reported to be associated with excess pneumonia recurrences. The “REducinG Antibiotic tReatment Duration for Ventilator-Associated Pneumonia” (REGARD-VAP) trial aims to provide evidence for using a set of reproducible clinical criteria to shorten antibiotic duration for individualised treatment duration of VAP. Methods and analysis This is a randomised controlled hierarchical non-inferiority–superiority trial being conducted in ICUs across Nepal, Thailand and Singapore. The primary outcome is a composite endpoint of death and pneumonia recurrence at day 60. Secondary outcomes include ventilator-associated events, multidrug-resistant organism infection or colonisation, total duration of antibiotic exposure, mechanical ventilation and hospitalisation. Adult patients who satisfy the US Centers for Disease Control and Prevention National Healthcare Safety Network VAP diagnostic criteria are enrolled. Participants are assessed daily until fever subsides for >48 hours and have stable blood pressure, then randomised to a short duration treatment strategy or a standard-of-care duration arm. Antibiotics may be stopped as early as day 3 if respiratory cultures are negative, and day 5 if respiratory cultures are positive in the short-course arm. Participants receiving standard-of-care will receive antibiotics for at least 8 days. Study participants are followed for 60 days after enrolment. An estimated 460 patients will be required to achieve 80% power to determine non-inferiority with a margin of 12%. All outcomes are compared by absolute risk differences. The conclusion of non-inferiority, and subsequently superiority, will be based on unadjusted and adjusted analyses in both the intention-to-treat and per-protocol populations. Ethics and dissemination The study has received approvals from the Oxford Tropical Research Ethics Committee and the respective study sites. Results will be disseminated to patients, their caregivers, physicians, the funders, the critical care societies and other researchers. Trial registration number NCT03382548.

Reducing antibiotic treatment duration for ventilator-associated pneumonia (REGARD-VAP): a trial protocol for a randomised clinical trial

Rationale: Analyses of blood biomarkers involved in the host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection can reveal distinct biological pathways and inform development and testing of therapeutics for COVID-19. Objective: To evaluate host endothelial, epithelial and inflammatory biomarkers in COVID-19Methods: We prospectively enrolled 169 ICU patients with suspicion of COVID-19 infection, including 78 (46%) patients positive and 91 (54%) negative for SARS-CoV-2 infection from April to September, 2020. We compared 22 plasma biomarkers in blood collected within 24 hours and 3 days after ICU admission. Measurement and Main Results: ICU patients with and without COVID-19 had similar rates of severe acute kidney injury, shock, thromboembolism and in-hospital mortality. Rates of ARDS were higher in COVID-19 (aRR = 5.9, 95% CI: 3.2-11.0). While concentrations of interleukin 6 and 8 were not different between groups, markers of epithelial cell injury (soluble receptor for advanced glycation end products, sRAGE) and acute phase proteins (serum amyloid A, SAA) were significantly higher in COVID-19 compared to non-COVID-19, adjusting for demographics and APACHE III scores (Figure 1). In contrast, angiopoietin 2:1 (Ang-2:1 ratio) and soluble tumor necrosis factor receptor 1 (sTNFR-1), markers of endothelial dysfunction and inflammation, were significantly lower in COVID-19 (Bonferroni corrected p&lt;0.002). Ang-2:1 ratio and SAA were associated with mortality only in non-COVID-19 patients.Conclusions: These studies demonstrate that, unlike other well-studied causes of critical illness, endothelial dysfunction is not characteristic of severe COVID-19 early after ICU admission. Pathways resulting in elaboration of acute phase proteins and inducing epithelial cell injury may be promising targets for therapeutics. 2 (Table Presented).

Comparison of Host Endothelial, Epithelial and Inflammatory Response in ICU Patients With and Without COVID-19

Acute Medical Complications of Sepsis Among Hospitalized Thai Adults with Community Acquired Infection

Comparison of host endothelial, epithelial and inflammatory response in ICU patients with and without COVID-19: a prospective observational cohort study

Supplemental Digital Content is available in the text. IMPORTANCE: In bacterial sepsis, CD14 and its N-terminal fragment (soluble CD14 subtype, “Presepsin”) have been characterized as markers of innate immune responses and emerging evidence has linked both to coronavirus disease 2019 pathophysiology. OBJECTIVES: Our aim was to determine the relationship between the soluble form of CD14 and soluble CD14 subtype plasma levels, coronavirus disease 2019 status, and coronavirus disease 2019-related outcomes. DESIGN: A prospective cohort study. SETTING: ICUs in three tertiary hospitals in Seattle, WA. PARTICIPANTS: Two-hundred four critically ill patients under investigation for coronavirus disease 2019. MAIN OUTCOMES AND MEASURES: We measured plasma soluble CD14 and soluble CD14 subtype levels in samples collected upon admission. We tested for associations between biomarker levels and coronavirus disease 2019 status. We stratified by coronavirus disease 2019 status and tested for associations between biomarker levels and outcomes. RESULTS: Among 204 patients, 102 patients had coronavirus disease 2019 and 102 patients did not. In both groups, the most common ICU admission diagnosis was respiratory failure or pneumonia and proportions receiving respiratory support at admission were similar. In regression analyses adjusting for age, sex, race/ethnicity, steroid therapy, comorbidities, and severity of illness, soluble CD14 subtype was 54% lower in coronavirus disease 2019 than noncoronavirus disease 2019 patients (fold difference, 0.46; 95% CI, 0.28–0.77; p = 0.003). In contrast to soluble CD14 subtype, soluble CD14 levels did not differ between coronavirus disease 2019 and noncoronavirus disease 2019 patients. In both coronavirus disease 2019 and noncoronavirus disease 2019, in analyses adjusting for age, sex, race/ethnicity, steroid therapy, and comorbidities, higher soluble CD14 subtype levels were associated with death (coronavirus disease 2019: adjusted relative risk, 1.21; 95% CI, 1.06–1.39; p = 0.006 and noncoronavirus disease 2019: adjusted relative risk, 1.19; 95% CI, 1.03–1.38; p = 0.017), shock, and fewer ventilator-free days. In coronavirus disease 2019 only, an increase in soluble CD14 subtype was associated with severe acute kidney injury (adjusted relative risk, 1.23; 95% CI, 1.05–1.44; p = 0.013). CONCLUSIONS: Higher plasma soluble CD14 subtype is associated with worse clinical outcomes in critically ill patients irrespective of coronavirus disease 2019 status though soluble CD14 subtype levels were lower in coronavirus disease 2019 patients than noncoronavirus disease 2019 patients. Soluble CD14 subtype levels may have prognostic utility in coronavirus disease 2019.

Plasma Soluble CD14 Subtype Levels Are Associated With Clinical Outcomes in Critically Ill Subjects With Coronavirus Disease 2019

Background Community acquired bacteremia (CAB) is a common cause of sepsis in low and middle-income countries (LMICs). However, knowledge about factors associated with outcomes of CAB in LMICs is limited. Methodology/Principal findings A prospective observational study (Ubon-sepsis) of adults admitted to a referral hospital with community-acquired infection in Northeastern Thailand was conducted between March 1, 2013 and February 1, 2017. In the present analysis, patients with a blood culture collected within 24 hours of admission that was positive for one of the three most common pathogens were studied. Clinical features, management, and outcomes of patients with each cause of CAB were compared. Of 3,806 patients presenting with community-acquired sepsis, 155, 131 and 37 patients had a blood culture positive for Escherichia coli, Burkholderia pseudomallei and Staphylococcus aureus, respectively. Of these 323 CAB patients, 284 (89%) were transferred from other hospitals. 28-day mortality was highest in patients with B. pseudomallei bactaeremia (66%), followed by those with S. aureus bacteraemia (43%) and E. coli (19%) bacteraemia. In the multivariable Cox proportional hazards model adjusted for age, sex, transfer from another hospital, empirical antibiotics prior to or during the transfer, and presence of organ dysfunction on admission, B. pseudomallei (aHR 3.78; 95%CI 2.31–6.21) and S. aureus (aHR 2.72; 95%CI 1.40–5.28) bacteraemias were associated with higher mortality compared to E. coli bacteraemia. Receiving empirical antibiotics recommended for CAB caused by the etiologic organism prior to or during transfer was associated with survival (aHR 0.58; 95%CI 0.38–0.88). Conclusions/Significance Mortality of patients with CAB caused by B. pseudomallei was higher than those caused by S. aureus and E. coli, even after adjusting for presence of organ dysfunction on admission and effectiveness of empirical antibiotics received. Improving algorithms or rapid diagnostic tests to guide early empirical antibiotic may be key to improving CAB outcomes in LMICs.

Comparative clinical characteristics and outcomes of patients with community acquired bacteremia caused by Escherichia coli, Burkholderia pseudomallei and Staphylococcus aureus: A prospective observational study (Ubon-sepsis)

Melioidosis is an often fatal infection in tropical regions caused by an environmental bacterium, Burkholderia pseudomallei. Current recommended melioidosis treatment requires intravenous β-lactam antibiotics such as ceftazidime (CAZ), meropenem (MEM), or amoxicillin-clavulanic acid (AMC) and oral trimethoprim-sulfamethoxazole. ABSTRACT Melioidosis is an often fatal infection in tropical regions caused by an environmental bacterium, Burkholderia pseudomallei. Current recommended melioidosis treatment requires intravenous β-lactam antibiotics such as ceftazidime (CAZ), meropenem (MEM), or amoxicillin-clavulanic acid (AMC) and oral trimethoprim-sulfamethoxazole. Emerging antibiotic resistance could lead to therapy failure and high mortality. We performed a prospective multicenter study in northeast Thailand from 2015 to 2018 to evaluate antibiotic susceptibility and characterize β-lactam resistance in clinical B. pseudomallei isolates. A collection of 1,317 B. pseudomallei isolates from patients with primary and relapse infections were evaluated for susceptibility to CAZ, imipenem (IPM), MEM, and AMC. β-Lactam-resistant isolates were confirmed by the broth microdilution method and characterized by whole-genome sequence analysis, penA expression, and β-lactamase activity. The resistant phenotype was verified via penA mutagenesis. All primary isolates were IPM susceptible, but we observed two CAZ-resistant isolates and one CAZ-intermediate isolate, two MEM-less-susceptible isolates, and one AMC-resistant and two AMC-intermediate isolates. One of 13 relapse isolates was resistant to both CAZ and AMC. Two isolates were MEM less susceptible. Strains DR10212A (primary) and DR50054E (relapse) were multidrug resistant. Genomic and mutagenesis analyses supplemented with gene expression and β-lactamase analyses demonstrated that the CAZ-resistant phenotype was caused by PenA variants: P167S (n = 2) and penA amplification (n = 1). Despite the high mortality rate in melioidosis, our study revealed that B. pseudomallei isolates had a low frequency of β-lactam resistance caused by penA alterations. Clinical data suggest that resistant variants may emerge in patients during antibiotic therapy and may be associated with a poor response to treatment.

Antibiotic Susceptibility of Clinical Burkholderia pseudomallei Isolates in Northeast Thailand from 2015 to 2018 and the Genomic Characterization of β-Lactam-Resistant Isolates

Patient: Male, 42-year-old Final Diagnosis: Pulmonary fibrosis Symptoms: Dyspnea Medication:— Clinical Procedure: — Specialty: General and Internal Medicine • Pulmonology Objective: Unusual clinical course Background: The COVID-19 global pandemic is ongoing, and despite vaccination efforts, SARS-CoV-2 continues to circulate worldwide. The spectrum of COVID-19 illness is broad, from asymptomatic infection to respiratory failure and acute respiratory distress syndrome (ARDS), and the long-term sequelae of infection are unclear. COVID-19-related pulmonary fibrosis has been previously described in the setting of critical illness and ARDS but has not been well described in cases requiring minimal supplemental oxygen. Case Report: We present the case of a 42-year-old man hospitalized with coronavirus disease 2019 (COVID-19) who initially required minimal supplemental oxygen but weeks later developed progressive pulmonary fibrosis requiring high-flow nasal cannula and ICU admission. Using novel computed tomography (CT) imaging processing techniques, we demonstrate progression from initial ground-glass opacities to pulmonary fibrosis and traction bronchiectasis over several months. Additionally, we describe clinical responsiveness to an extended course of corticosteroids. Conclusions: Although pulmonary fibrosis is a known complication of severe COVID-19-related ARDS requiring mechanical ventilation, our report suggests that patients with milder forms of COVID-19 infection may develop post-acute pulmonary fibrosis.

Progressive Pulmonary Fibrosis After Non-Critical COVID-19: A Case Report

Objective To evaluate the effectiveness of a Sepsis Fast Track (SFT) programme initiated at a regional referral hospital in Thailand in January 2015. Design A retrospective analysis using the data of a prospective observational study (Ubon-sepsis) from March 2013 to January 2017. Setting General medical wards and medical intensive care units (ICUs) of a study hospital. Participants Patients with community-acquired sepsis observed under the Ubon-sepsis cohort. Sepsis was defined as modified Sequential Organ Failure Assessment (SOFA) Score ≥2. Main exposure The SFT programme was a protocol to identify and initiate sepsis care on hospital admission, implemented at the study hospital in 2015. Patients in the SFT programme were admitted directly to the ICUs when available. The non-exposed group comprised of patients who received standard of care. Main outcome The primary outcome was 28-day mortality. The secondary outcomes were measured sepsis management interventions. Results Of 3806 sepsis patients, 903 (24%) were detected and enrolled in the SFT programme of the study hospital (SFT group) and 2903 received standard of care (non-exposed group). Patients in the SFT group had more organ dysfunction, were more likely to receive measured sepsis management and to be admitted directly to the ICU (19% vs 4%). Patients in the SFT group were more likely to survive (adjusted HR 0.72, 95% CI 0.58 to 0.88, p=0.001) adjusted for admission year, gender, age, comorbidities, modified SOFA Score and direct admission to the ICUs. Conclusions The SFT programme is associated with improved sepsis care and lower risk of death in sepsis patients in rural Thailand, where some critical care resources are limited. The survival benefit is observed even when all patients enrolled in the programme could not be admitted directly into the ICUs. Trial registration number NCT02217592.

Effectiveness of a sepsis programme in a resource-limited setting: a retrospective analysis of data of a prospective observational study (Ubon-sepsis)

Epidemiology of Acute Febrile Respiratory Illness in Senegal: A Secondary Analysis of a Senegal Cluster Randomized Trivalent Inactivated Influenza Vaccine Trial

Introduction/Hypothesis: Despite successful use of established strategies for the identification of acute kidney injury (AKI) in high-income countries, performance in other settings is unknown. We compared populations classified with AKI using 3 standard methods in a cohort of adults with acute infection in northeast Thailand. Methods: Secondary analysis of Ubon-Sepsis, a prospective cohort study of Thai adults admitted March 2013-January 2017 to a regional hospital with community-acquired infection. We evaluated 3 AKI identification strategies: 1) any serum creatinine (SCr) ≥2.0 mg/dL in patients without CKD, or new peritoneal dialysis (PD) or hemodialysis (HD) in any patient within 3 days of admission (AKI1), 2) KDIGO criteria requiring SCr change ≥0.3 mg/dL or ≥50% SCr increase from baseline, or new PD or HD within 3 days of admission (AKI2), and 3) ICD-10 discharge diagnosis codes (AKI3). We described the characteristics and outcomes of patients meeting each definition, and calculated Fleiss’ kappa statistic for agreement between definitions. We excluded patients with dialysis prior to admission. Results: Of 4989 patients in the Ubon-Sepsis study, 4866 were included. Overall, 16% (n=773) had CKD per chart review or discharge ICD-10 code, 32% received vasopressors as of study enrollment (n=1546), and 18% were found to be bacteremic (n=892). Of the 4805 patients with ≥1 SCr value, 20% (n=980) met AKI1 criteria. Of the 3162 patients with ≥2 SCr values, 53% (n=1674) met AKI2 criteria. All 4866 patients had ≥1 discharge ICD-10 code, and 27% (n=1329) met AKI3 criteria. Median age (range, 61-62 yrs) and sex (range, 59-66% male) were relatively uniform between AKI definitions. However, incidence of new HD (range, 5-9%; p=0.002), hospital mortality (range, 914%; p<0.001), and 28-day mortality (range, 22%-30%; p<0.001) differed significantly between the groups. There was fair agreement between the three definitions (Κ=0.31, p<0.001). Conclusions: Baseline characteristics, clinical outcomes, and number of patients identified with AKI varied substantially depending on the AKI identification strategy used. These strategies may not be suited to the capabilities of low-resource settings, and further work is needed to determine the optimal strategy to identify patients with infection-associated AKI in low-resource settings.

1414: STRATEGIES FOR THE IDENTIFICATION OF INFECTION-ASSOCIATED ACUTE KIDNEY INJURY IN THAILAND

Rationale: No direct comparisons of clinical features, laboratory values, and outcomes between critically ill patients with coronavirus disease (COVID-19) and patients with influenza in the United States have been reported. Objectives: To evaluate the risk of mortality comparing critically ill patients with COVID-19 with patients with seasonal influenza. Methods: We retrospectively identified patients admitted to the intensive care units (ICUs) at two academic medical centers with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or influenza A or B infections between January 1, 2019, and April 15, 2020. The clinical data were obtained by medical record review. All patients except one had follow-up to hospital discharge or death. We used relative risk regression adjusting for age, sex, number of comorbidities, and maximum sequential organ failure scores on Day 1 in the ICU to determine the risk of hospital mortality and organ dysfunction in patients with COVID-19 compared with patients with influenza. Results: We identified 65 critically ill patients with COVID-19 and 74 patients with influenza. The mean (±standard deviation) age in each group was 60.4 ± 15.7 and 56.8 ± 17.6 years, respectively. Patients with COVID-19 were more likely to be male, have a higher body mass index, and have higher rates of chronic kidney disease and diabetes. Of the patients with COVID-19, 37% identified as Hispanic, whereas 10% of the patients with influenza identified as Hispanic. A similar proportion of patients had fevers (∼40%) and lymphopenia (∼80%) on hospital presentation. The rates of acute kidney injury and shock requiring vasopressors were similar between the groups. Although the need for invasive mechanical ventilation was also similar in both groups, patients with COVID-19 had slower improvements in oxygenation, longer durations of mechanical ventilation, and lower rates of extubation than patients with influenza. The hospital mortality was 40% in patients with COVID-19 and 19% in patients with influenza (adjusted relative risk, 2.13; 95% confidence interval, 1.24–3.63; P = 0.006). Conclusions: The need for invasive mechanical ventilation was common in patients in the ICU for COVID-19 and influenza. Compared with those with influenza, patients in the ICU with COVID-19 had worse respiratory outcomes, including longer duration of mechanical ventilation. In addition, patients with COVID-19 were at greater risk for in-hospital mortality, independent of age, sex, comorbidities, and ICU severity of illness.

Comparison of Clinical Features and Outcomes in Critically Ill Patients Hospitalized with COVID-19 versus Influenza

Chronic inflammation, innate immune activation, T-cell imbalance and endothelial activation have been linked with lung diseases. We sought to determine whether markers of these pathophysiologic pathways were associated with spirometry and chest CT abnormalities among adolescents living with HIV (ALWH).

SETTING
Coptic Hope Center for Infectious Diseases in Nairobi, Kenya METHODS:: We performed a cross-sectional study of ALWH (10-19 years old). Participants underwent chest CT, spirometry and venipuncture for serum biomarkers. We also collected demographic, anthropometric, T-cell subset, antiretroviral therapy, and exposure data. We compared characteristics and biomarkers by airflow obstruction (post-bronchodilator FEV1/FVC z-score [zFEV1/FVC] < -1.64). We used multivariable linear regression to determine associations of log10-transformed biomarkers and chest CT abnormalities with lower post-bronchodilator zFEV1/FVC (airflow limitation). We performed exploratory principal components analysis on biomarkers, and determined associations of factors with post-bronchodilator zFEV1/FVC and chest CT abnormalities.

RESULTS
Of 47 participants with acceptable quality spirometry, 21 (45%) were female, median age was 13 years and 96% had perinatally-acquired HIV. Median CD4 was 672 cells/µL. Overall, 28% had airflow obstruction and 78% had a chest CT abnormality; airflow obstruction was associated with mosaic attenuation (p=0.001). Higher endothelial activation (sVCAM-1, sICAM-1), inflammation and innate immune activation (SAA, sTREM-1, sCD163), and T-cell imbalance (lower CD4/CD8) markers were associated with airflow limitation. Factors comprising endothelial and innate immune activation were associated with airflow limitation.

Endothelial activation, innate immune activation, T-cell imbalance, and chronic inflammation are associated with airflow limitation and obstruction, providing insights into chronic lung disease pathophysiology among ALWH.

Endothelial activation, innate immune activation, and inflammation are associated with post-bronchodilator airflow limitation and obstruction among adolescents living with HIV.

Background Burkholderia pseudomallei is an environmental bacterium that causes melioidosis. A facultative intracellular pathogen, B. pseudomallei can induce multinucleated giant cells (MNGCs) leading to plaque formation in vitro. B. pseudomallei can switch colony morphotypes under stress conditions. In addition, different isolates have been reported to have varying virulence in vivo, but genomic evolution and the relationship with plaque formation is poorly understood. Methodology/Principle findings To gain insights into genetic underpinnings of virulence of B. pseudomallei, we screened plaque formation of 52 clinical isolates and 11 environmental isolates as well as 4 isogenic morphotype isolates of B. pseudomallei strains K96243 (types II and III) and 153 (types II and III) from Thailand in A549 and HeLa cells. All isolates except one environmental strain (A4) and K96243 morphotype II were able to induce plaque formation in both cell lines. Intracellular growth assay and confocal microscopy analyses demonstrated that the two plaque-forming-defective isolates were also impaired in intracellular replication, actin polymerization and MNGC formation in infected cells. Whole genome sequencing analysis and PCR revealed that both isolates had a large genomic loss on the same region in chromosome 2, which included Bim cluster, T3SS-3 and T6SS-5 genes. Conclusions/Significance Our plaque screening and genomic studies revealed evidence of impairment in plaque formation in environmental isolates of B. pseudomallei that is associated with large genomic loss of genes important for intracellular multiplication and MNGC formation. These findings suggest that the genomic and phenotypic differences of environmental isolates may be associated with clinical infection.

Genomic loss in environmental and isogenic morphotype isolates of Burkholderia pseudomallei is associated with intracellular survival and plaque-forming efficiency

Abstract Background Community transmission of coronavirus 2019 (Covid-19) was detected in the state of Washington in February 2020. Methods We identified patients from nine Seattle-area hospitals who were admitted to the intensive care unit (ICU) with confirmed infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Clinical data were obtained through review of medical records. The data reported here are those available through March 23, 2020. Each patient had at least 14 days of follow-up. Results We identified 24 patients with confirmed Covid-19. The mean (±SD) age of the patients was 64±18 years, 63% were men, and symptoms began 7±4 days before admission. The most common symptoms were cough and shortness of breath; 50% of patients had fever on admission, and 58% had diabetes mellitus. All the patients were admitted for hypoxemic respiratory failure; 75% (18 patients) needed mechanical ventilation. Most of the patients (17) also had hypotension and needed vasopressors. No patient tested positive for influenza A, influenza B, or other respiratory viruses. Half the patients (12) died between ICU day 1 and day 18, including 4 patients who had a do-not-resuscitate order on admission. Of the 12 surviving patients, 5 were discharged home, 4 were discharged from the ICU but remained in the hospital, and 3 continued to receive mechanical ventilation in the ICU. Conclusions During the first 3 weeks of the Covid-19 outbreak in the Seattle area, the most common reasons for admission to the ICU were hypoxemic respiratory failure leading to mechanical ventilation, hypotension requiring vasopressor treatment, or both. Mortality among these critically ill patients was high. (Funded by the National Institutes of Health.)

Covid-19 in Critically Ill Patients in the Seattle Region — Case Series

The burden of respiratory and critical illness is high worldwide, 
yet specialist care is underrepresented in low- and middle-income countries (LMICs) [1]. For many areas of medicine, the 
past decade has witnessed tremendous growth in global health opportunities for trainees; however, these opportunities tend to be restricted to individual institutions and geographic regions and academic global pulmonary and critical care medicine (PCCM) remains 
a relatively novel concept [2]. Consequently, PCCM fellows and junior faculty at institutions with limited global health mentorship have little guidance in building successful global health careers.

Incidence of and Risk Factors for Infection-Associated Acute Kidney Injury in Northeast Thailand

Chronic inflammation, innate immune activation, T-cell imbalance and endothelial activation have been linked with lung diseases. We sought to determine whether markers of these pathophysiologic pathways were associated with spirometry and chest computed tomography (CT) abnormalities among adolescents living with HIV (ALWH).

SETTING
Coptic Hope Center for Infectious Diseases in Nairobi, Kenya.

METHODS
We performed a cross-sectional study of ALWH (10-19 years old). Participants underwent chest CT, spirometry, and venipuncture for serum biomarkers. We also collected demographic, anthropometric, T-cell subset, antiretroviral therapy, and exposure data. We compared characteristics and biomarkers by airflow obstruction [postbronchodilator FEV1/FVC z-score (zFEV1/FVC) < -1.64]. We used multivariable linear regression to determine associations of log10-transformed biomarkers and chest CT abnormalities with lower postbronchodilator zFEV1/FVC (airflow limitation). We performed exploratory principal components analysis on biomarkers, and determined associations of factors with postbronchodilator zFEV1/FVC and chest CT abnormalities.

RESULTS
Of 47 participants with acceptable quality spirometry, 21 (45%) were female, median age was 13 years and 96% had perinatally-acquired HIV. Median CD4 was 672 cells/µL. Overall, 28% had airflow obstruction and 78% had a chest CT abnormality; airflow obstruction was associated with mosaic attenuation (P = 0.001). Higher endothelial activation (sVCAM-1, sICAM-1), inflammation and innate immune activation (serum amyloid-A, sTREM-1, sCD163), and T-cell imbalance (lower CD4/CD8) markers were associated with airflow limitation. Factors comprising endothelial and innate immune activation were associated with airflow limitation.

Endothelial Activation, Innate Immune Activation, and Inflammation Are Associated With Postbronchodilator Airflow Limitation and Obstruction Among Adolescents Living With HIV.

Pulmonary Innate-Like Lymphocyte Responses in Severe Gram-Negative Pneumonia

Academic global pulmonary/critical care medicine (PCCM) remains a relatively novel concept not fully embraced by all training programs, so PCCM early-career professionals may have little guidance in building successful careers in this field. To highlight various approaches used by current PCCM faculty to incorporate global health into their academic careers, speakers from a global health careers mini symposia held at the 2017 and 2018 American Thoracic Society International Conferences were invited to submit perspectives reflecting on academic PCCM and global health. The collection of essays was collated into a single manuscript. Eight current global PCCM faculty from diverse geographic and professional backgrounds provide experiential guidance for early-career professionals interested in global academic PCCM. Trainees and junior faculty interested in academic global PCCM will find innumerable obstacles to developing this non-traditional career pathway, but there exist diverse pathways to success.

Academic careers in global pulmonary and critical care medicine: perspectives from experts in the field

sTREM-1 predicts mortality in hospitalized patients with infection in a tropical, middle-income country

Abstract Background Melioidosis, infection caused by Burkholderia pseudomallei, is a common cause of sepsis with high associated mortality in Southeast Asia. Identification of patients at high likelihood of clinical deterioration is important for guiding decisions about resource allocation and management. We sought to develop a biomarker-based model for 28-day mortality prediction in melioidosis. Methods In a derivation set (N = 113) of prospectively enrolled, hospitalized Thai patients with melioidosis, we measured concentrations of interferon-γ, interleukin-1β, interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor-ɑ, granulocyte-colony stimulating factor, and interleukin-17A. We used least absolute shrinkage and selection operator (LASSO) regression to identify a subset of predictive biomarkers and performed logistic regression and receiver operating characteristic curve analysis to evaluate biomarker-based prediction of 28-day mortality compared with clinical variables. We repeated select analyses in an internal validation set (N = 78) and in a prospectively enrolled external validation set (N = 161) of hospitalized adults with melioidosis. Results All 8 cytokines were positively associated with 28-day mortality. Of these, interleukin-6 and interleukin-8 were selected by LASSO regression. A model consisting of interleukin-6, interleukin-8, and clinical variables significantly improved 28-day mortality prediction over a model of only clinical variables [AUC (95% confidence interval [CI]): 0.86 (.79–.92) vs 0.78 (.69–.87); P = .01]. In both the internal validation set (0.91 [0.84–0.97]) and the external validation set (0.81 [0.74–0.88]), the combined model including biomarkers significantly improved 28-day mortality prediction over a model limited to clinical variables. Conclusions A 2-biomarker model augments clinical prediction of 28-day mortality in melioidosis.

A 2-Biomarker Model Augments Clinical Prediction of Mortality in Melioidosis

Community transmission of coronavirus 2019 (Covid-19) was detected in the state of Washington in February 2020.

METHODS
We identified patients from nine Seattle-area hospitals who were admitted to the intensive care unit (ICU) with confirmed infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Clinical data were obtained through review of medical records. The data reported here are those available through March 23, 2020. Each patient had at least 14 days of follow-up.

RESULTS
We identified 24 patients with confirmed Covid-19. The mean (±SD) age of the patients was 64±18 years, 63% were men, and symptoms began 7±4 days before admission. The most common symptoms were cough and shortness of breath; 50% of patients had fever on admission, and 58% had diabetes mellitus. All the patients were admitted for hypoxemic respiratory failure; 75% (18 patients) needed mechanical ventilation. Most of the patients (17) also had hypotension and needed vasopressors. No patient tested positive for influenza A, influenza B, or other respiratory viruses. Half the patients (12) died between ICU day 1 and day 18, including 4 patients who had a do-not-resuscitate order on admission. Of the 12 surviving patients, 5 were discharged home, 4 were discharged from the ICU but remained in the hospital, and 3 continued to receive mechanical ventilation in the ICU.

During the first 3 weeks of the Covid-19 outbreak in the Seattle area, the most common reasons for admission to the ICU were hypoxemic respiratory failure leading to mechanical ventilation, hypotension requiring vasopressor treatment, or both. Mortality among these critically ill patients was high. (Funded by the National Institutes of Health.).

Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study

Melioidosis is an often-severe tropical infection caused by Burkholderia pseudomallei (Bp) with high associated morbidity and mortality. Burkholderia thailandensis (Bt) is a closely related surrogate that does not require BSL-3 conditions for study. Lactoferrin is an iron-binding glycoprotein that can modulate the innate inflammatory response. Here we investigated the impact of lactoferrin on the host immune response in melioidosis. Lactoferrin concentrations were measured in plasma from patients with melioidosis and following ex vivo stimulation of blood from healthy individuals. Bt growth was quantified in liquid media in the presence of purified and recombinant human lactoferrin. Differentiated THP-1 cells and human blood monocytes were infected with Bt in the presence of purified and recombinant human lactoferrin, and bacterial intracellular replication and cytokine responses (tumor necrosis factor-α (TNF-α), interleukin-1β and interferon-γ) were measured. In a cohort of 49 melioidosis patients, non-survivors to 28 days had significantly higher plasma lactoferrin concentrations compared to survivors (median (interquartile range (IQR)): 326 ng/ml (230–748) vs 144 ng/ml (99–277), p<0.001). In blood stimulated with heat-killed Bp, plasma lactoferrin concentration significantly increased compared to unstimulated blood (median (IQR): 424 ng/ml (349–479) vs 130 ng/ml (91–214), respectively; p<0.001). Neither purified nor recombinant human lactoferrin impaired growth of Bt in media. Lactoferrin significantly increased TNF-α production by differentiated THP-1 cells and blood monocytes after Bt infection. This phenotype was largely abrogated when Toll-like receptor 4 (TLR4) was blocked with a monoclonal antibody. In sum, lactoferrin is produced by blood cells after exposure to Bp and lactoferrin concentrations are higher in 28-day survivors in melioidosis. Lactoferrin induces proinflammatory cytokine production after Bt infection that may be TLR4 dependent.

Lactoferrin is a dynamic protein in human melioidosis and is a TLR4-dependent driver of TNF-α release in Burkholderia thailandensis infection in vitro

A macrophage-targeted platform for extending drug dosing with polymer prodrugs for pulmonary infection prophylaxis.

Distinct classes and subclasses of antibodies to hemolysin co-regulated protein 1 and O-polysaccharide and correlation with clinical characteristics of melioidosis patients

Lipopolysaccharides (LPSs) of Gram-negative bacteria comprise lipid A, core, and O-polysaccharide (OPS) components. Studies have demonstrated that LPSs isolated from the pathogenic species Burkholderia pseudomallei and Burkholderia mallei and from less-pathogenic species, such as Burkholderia thailandensis, are potent immune stimulators. ABSTRACT Lipopolysaccharides (LPSs) of Gram-negative bacteria comprise lipid A, core, and O-polysaccharide (OPS) components. Studies have demonstrated that LPSs isolated from the pathogenic species Burkholderia pseudomallei and Burkholderia mallei and from less-pathogenic species, such as Burkholderia thailandensis, are potent immune stimulators. The LPS structure of B. pseudomallei, the causative agent of melioidosis, is highly conserved in isolates from Thailand; however, the LPSs isolated from other, related species have not been characterized to enable understanding of their immune recognition and antigenicities. Here, we describe the structural and immunological characteristics of the LPSs isolated from eight Burkholderia species and compare those for B. pseudomallei to those for the other seven species. Matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS), gas chromatography (GC), SDS-PAGE, Toll-like receptor 4 (TLR4) stimulation, and immunoblot analysis were performed on these Burkholderia species. MALDI-TOF profiles demonstrated that Burkholderia lipid A contains predominantly penta-acylated species modified with 4-amino-4-deoxy-arabinose residues at both terminal phosphate groups. The lipid A could be differentiated based on mass differences at m/z 1,511, 1,642, 1,773, and 1,926 and on fatty acid composition. LPSs of all species induced TLR4-dependent NF-κB responses; however, while SDS-PAGE analysis showed similar LPS ladder patterns for B. pseudomallei, B. thailandensis, and B. mallei, these patterns differed from those of other Burkholderia species. Interestingly, immunoblot analysis demonstrated that melioidosis patient sera cross-reacted with OPSs of other Burkholderia species. These findings can be used to better understand the characteristics of LPS in Burkholderia species, and they have implications for serological diagnostics based on the detection of antibodies to OPS.

Lipopolysaccharides from Different Burkholderia Species with Different Lipid A Structures Induce Toll-Like Receptor 4 Activation and React with Melioidosis Patient Sera

Longitudinal immunoprofiling of plasma cytokines predicts outcomes in melioidosis

Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases

Longitudinal profiling of plasma cytokines in melioidosis and their association with mortality: a prospective cohort study.

Lipopolysaccharide (LPS) of Gram-negative bacteria is comprised of lipid A, core, 25 and O-polysaccharide (OPS) components. Studies have demonstrated that LPS isolated from 26 the pathogenic, Burkholderia pseudomallei and B. mallei and a less-pathogenic species, such 27 as B. thailandensis are potent immune stimulators. The LPS structure of B. pseudomallei, the 28 causative agent of melioidosis, is highly conserved in isolates from Thailand, however, the 29 LPS isolated from the other related species has not been characterized to understand its 30 immune recognition and antigenicity. Here, we describe the structural and immunological 31 characteristics of the LPS isolated from eight Burkholderia species and compare these to B. 32 pseudomallei LPS. Matrix-assisted laser desorption/ionization time-of-flight mass 33 spectrometry (MALDI-TOF MS), gas chromatography (GC), SDS-PAGE, Toll-like receptor 34 4 (TLR4) stimulation and immunoblot analysis were performed on these Burkholderia 35 species. MALDI-TOF profiles demonstrated that the Burkholderia lipid A contain 36 predominantly penta-acylated species modified with 4-amino-4-deoxy-arabinose residues at 37 both terminal phosphate groups. The lipid A could be differentiated based on mass 38 differences at m/z 1511, 1642, 1773, and 1926 and fatty acid compositions . LPS of all species 39 induced TLR4-dependent NF-κB responses; however while SDS-PAGE analysis showed a 40 similar LPS ladder pattern for B. pseudomallei, B. thailandensis and B. mallei , these patterns 41 differed from other Burkholderia species . Interestingly, immunoblotting analysis 42 demonstrated that melioidosis patient sera cross-reacted with OPS of other Burkholderia 43 species. These findings can be used to better understand the characteristics of LPS in 44 Burkholderia species and have implications for serological diagnostics based on detection of 45 antibodies to OPS. different immunological of the LPSs isolated from eight Burkholderia species including pathogenic and species, and compared these with B. pseudomallei LPS. Our results showed lipid A of eight genetically-related Burkholderia species contained penta- and tetra- acylated lipid A species modified with 4-amino-4-deoxy-arabinose (Ara4N) similar to B. pseudomallei . All had a bisphosphorylated glucosamine disaccharide backbone, which is common component of Gram-negative bacteria lipid A (32). Using MALDI-TOF MS, the lipid A of Burkholderia species can be divided into three groups based on the differences in ion masses at m/z 1511, 1642, 1773, and 1926 and the fatty acid component of lipid A (Group I: B. pseudomallei , B. multivorans and B. vietnamiensis ; Group II: B. thailandensis , B. mallei , B. cepacia and B. ubonensis ; Group III: B. oklahomensis ). Our data also demonstrated that LPS can be categorized into two distinct groupings based on SDS-PAGE profiles of the OPS: Group I: B. pseudomallei , B. mallei and B. thailandensis which showed similar repeating bands with uniform spacing (LPS type A ladder), Group II: B. cepacia , B. multivoran s, B. oklahomensis , B. vietnamiensis and B. ubonensis demonstrated different LPS ladders from Group I and from each other. Even though three lipid A groups were observed by and

Lipopolysaccharides of different Burkholderia species with different lipid A structures 1 induce activation react with patient sera

PRESENTATION, MANAGEMENT, AND OUTCOMES OF ADULT PATIENTS WITH CULTURE-POSITIVE BURKHOLDERIA PSEUDOMALLEI INFECTION AT A THAI REGIONAL REFERRAL HOSPITAL

The MEK1/2-ERK1/2 pathway has been implicated in regulating the inflammatory response to lung injury and infection, and pharmacologic MEK1/2 inhibitor compounds are reported to reduce detrimental inflammation in multiple animal models of disease, in part through modulation of leukocyte responses. However, the specific contribution of myeloid MEK1 in regulating acute lung injury (ALI) and its resolution remain unknown. Here, the role of myeloid Mek1 was investigated in a murine model of LPS-induced ALI (LPS-ALI) by genetic deletion using the Cre-floxed system (LysMCre × Mekfl), and human alveolar macrophages from healthy volunteers and patients with acute respiratory distress syndrome (ARDS) were obtained to assess activation of the MEK1/2-ERK1/2 pathway. Myeloid Mek1 deletion results in a failure to resolve LPS-ALI, and alveolar macrophages lacking MEK1 had increased activation of MEK2 and the downstream target ERK1/2 on day 4 of LPS-ALI. The clinical significance of these findings is supported by increased activation of the MEK1/2-ERK1/2 pathway in alveolar macrophages from patients with ARDS compared with alveolar macrophages from healthy volunteers. This study reveals a critical role for myeloid MEK1 in promoting resolution of LPS-ALI and controlling the duration of macrophage proinflammatory responses.

MEK1 regulates pulmonary macrophage inflammatory responses and resolution of acute lung injury.

The quick sequential organ failure assessment (qSOFA) score has had limited validation in lower resource settings and was developed using data from high-income countries. We sought to evaluate the predictive validity of the qSOFA score for sepsis within a low- and middle-income country (LMIC) population with culture-proven staphylococcal infection. This was a secondary analysis of a prospective multicenter cohort in Thailand with culture-positive infection due to Staphylococcus aureus or S. argenteus within 24 h of admission and positive (≥2/4) systemic inflammatory response syndrome (SIRS) criteria. Primary exposure was maximum qSOFA score within 48 h of culture collection and primary outcome was mortality at 28 days. Baseline risk of mortality was determined using a multivariable logistic regression model with age, gender, and co-morbidities significantly associated with the outcome. Predictive validity was assessed by discrimination of mortality using area under the receiver operating characteristic (AUROC) curve compared to a model using baseline risk factors alone. Of 253 patients (mean age 54 years (SD 16)) included in the analysis, 23 (9.1%) died by 28 days after enrollment. Of those who died, 0 (0%) had a qSOFA score of 0, 8 (35%) had a score of 1, and 15 (65%) had a score ≥2. The AUROC of qSOFA plus baseline risk was significantly greater than for the baseline risk model alone (AUROCqSOFA = 0.80 (95% CI, 0.70–0.89), AUROCbaseline = 0.62 (95% CI, 0.49–0.75); p < 0.001). Among adults admitted to four Thai hospitals with community-onset coagulase-positive staphylococcal infection and SIRS, the qSOFA score had good predictive validity for sepsis.

Predictive Validity of the qSOFA Score for Sepsis in Adults with Community-Onset Staphylococcal Infection in Thailand

RATIONALE
Clinical and research training opportunities in global health are of increasing interest to medical trainees, but little is known about such opportunities in U.S.-based pulmonary and pulmonary/critical care medicine (PCCM) fellowship programs.

Summarize currently available global health-related training opportunities and identify potential barriers to implementing global health curricula among U.S.-based PCCM fellowship programs.

METHODS
We sent a confidential, online, targeted needs assessment to PCCM fellowship program directors and associate program directors. Data collected included program demographics, currently available global health-related clinical and research training opportunities, potential barriers to the implementation of global health-related programmatic content, and perceived interest in global health-related training opportunities by current and/or prospective trainees. To evaluate for non-response bias, we performed an online search to identify global health-related training opportunities offered by non-responding programs.

RESULTS
Out of 171 surveyed programs, 63 PCCM fellowship programs (37%) provided survey responses. Most responses (n=56, 89%) were from combined PCCM training programs; 66% (n=40) of programs offered at least one component of global health-related clinical or research training. Overall, 27% (n=17) had a Ruth L. Kirschstein National Research Service Award Institutional Research Training Grant (NIH T32), 73% (n=46) had fewer than 35 faculty members, and 51% (n=32) had at least one faculty member conducting global health-focused research. Most responding programs (66%, n=40) offered at least one global health-related educational component. Among programs that would like to offer global health-related training components, the most common barriers included competing priorities for lecture content and a lack of in-division mentors with global health experience, a champion for global health-related activities, and established partnerships outside the U.S.

PCCM program leaders are interested in offering global health-related training opportunities, but important barriers include lack of mentorship, dedicated fellowship time, and established global partnerships. Future research is needed to better understand global health-related interests and training needs of incoming fellows, and to design creative solutions for providing global health-related training across academic institutions with variable global health-related training capacities.

Global Health-related Training Opportunities: A National Survey of Pulmonary and Critical Care Medicine Fellowship Programs.

SEPSIS MANAGEMENT IN ADULTS ADMITTED TO A THAI REGIONAL REFERRAL HOSPITAL

Glycan targeted polymeric antibiotic prodrugs for alveolar macrophage infections.

Early management of sepsis in medical patients in rural Thailand: a single-center prospective observational study

Background Toll-like receptors (TLRs) are sentinel receptors of the innate immune system. TLR4 detects bacterial lipopolysaccharide (LPS) and TLR5 detects bacterial flagellin. A common human nonsense polymorphism, TLR5:c.1174C>T, results in a non-functional TLR5 protein. Individuals carrying this variant have decreased mortality from melioidosis, infection caused by the flagellated Gram-negative bacterium Burkholderia pseudomallei. Although impaired flagellin-dependent signaling in carriers of TLR5:c.1174C>T is well established, this study tested the hypothesis that a functional effect of TLR5:c.1174C>T is flagellin-independent and involves LPS-TLR4 pathways. Methodology/Principal findings Whole blood from two independent cohorts of individuals genotyped at TLR5:c.1174C>T was stimulated with wild type or aflagellated B. pseudomallei or purified bacterial motifs followed by plasma cytokine measurements. Blood from individuals carrying the TLR5:c.1174C>T variant produced less IL-6 and IL-10 in response to an aflagellated B. pseudomallei mutant and less IL-8 in response to purified B. pseudomallei LPS than blood from individuals without the variant. TLR5 expression in THP1 cells was silenced using siRNA; these cells were stimulated with LPS before cytokine levels in cell supernatants were quantified by ELISA. In these cells following LPS stimulation, silencing of TLR5 with siRNA reduced both TNF-α and IL-8 levels. These effects were not explained by differences in TLR4 mRNA expression or NF-κB or IRF activation. Conclusions/Significance The effects of the common nonsense TLR5:c.1174C>T polymorphism on the host inflammatory response to B. pseudomallei may not be restricted to flagellin-driven pathways. Moreover, TLR5 may modulate TLR4-dependent cytokine production. While these results may have broader implications for the role of TLR5 in the innate immune response in melioidosis and other conditions, further studies of the mechanisms underlying these observations are required.

Flagellin-independent effects of a Toll-like receptor 5 polymorphism in the inflammatory response to Burkholderia pseudomallei

Sepsis can be caused by malaria infection, but little is known about the utility of the quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) and SOFA score in malaria. We conducted a prospective observational study from March 2013 to February 2017 to examine adults admitted with community-acquired infection in a tertiary-care hospital in Ubon Ratchathani, Northeast Thailand (Ubon-sepsis). Subjects were classified as having sepsis if they had a modified SOFA score ≥2 within 24 hours of admission. Serum was stored and later tested for malaria parasites using a nested PCR assay. Presence of severe malaria was defined using modified World Health Organization criteria. Of 4,989 patients enrolled, 153 patients (3%) were PCR positive for either Plasmodium falciparum (74 [48%]), P. vivax (69 [45%]), or both organisms (10 [7%]). Of 153 malaria patients, 80 were severe malaria patients presenting with sepsis, 70 were non-severe malaria patients presenting with sepsis, and three were non-severe malaria patients presenting without sepsis. The modified SOFA score (median 5; IQR 4–6; range 1–18) was strongly correlated with malaria severity determined by the number of World Health Organization severity criteria satisfied by the patient (Spearman’s rho = 0.61, p<0.001). Of 80 severe malaria patients, 2 (2.5%), 11 (14%), 62 (77.5%) and 5 (6%), presented with qSOFA scores of 0, 1, 2 and 3, respectively. Twenty eight-day mortality was 1.3% (2/153). In conclusion, qSOFA and SOFA can serve as markers of disease severity in adults with malarial sepsis. Patients presenting with a qSOFA score of 1 may also require careful evaluation for sepsis; including diagnosis of cause of infection, initiation of medical intervention, and consideration for referral as appropriate.

Utility of qSOFA and modified SOFA in severe malaria presenting as sepsis

ABSTRACT Melioidosis, an infectious disease caused by the bacterium Burkholderia pseudomallei, is a common cause of sepsis in Southeast Asia. We investigated whether novel TLR1 coding variants are associated with outcome in Thai patients with melioidosis. We performed exonic sequencing on a discovery set of patients with extreme phenotypes (mild vs. severe) of bacteremic melioidosis. We analysed the association of missense variants in TLR1 with severe melioidosis in a by-gene analysis. We then genotyped key variants and tested the association with death in two additional sets of melioidosis patients. Using a by-gene analysis, TLR1 was associated with severe bacteremic melioidosis (P = 0.016). One of the eight TLR1 variants identified, rs76600635, a common variant in East Asians, was associated with in-hospital mortality in a replication set of melioidosis patients (adjusted odds ratio 1.71, 95% CI 1.01–2.88, P = 0.04.) In a validation set of patients, the point estimate of effect of the association of rs76600635 with 28-day mortality was similar but not statistically significant (adjusted odds ratio 1.81, 95% CI 0.96–3.44, P = 0.07). Restricting the validation set analysis to patients recruited in a comparable fashion to the discovery and replication sets, rs76600635 was significantly associated with 28-day mortality (adjusted odds ratio 3.88, 95% CI 1.43–10.56, P = 0.01). Exonic sequencing identifies TLR1 as a gene associated with a severe phenotype of bacteremic melioidosis. The TLR1 variant rs76600635, common in East Asian populations, may be associated with poor outcomes from melioidosis. This variant has not been previously associated with outcomes in sepsis and requires further study.

Exonic sequencing identifies TLR1 genetic variation associated with mortality in Thais with melioidosis

A27. PEDIATRIC LUNG INFECTION AND CRITICAL CARE AROUND THE WORLD

HIV Infection Is Independently Associated with Impaired FEV1 Among Adolescents in Nairobi

Mortality, morbidity, and hospitalisations due to influenza lower respiratory tract infections, 2017: an analysis for the Global Burden of Disease Study 2017

Tuberculosis and other bacterial co-infection in Cambodia: a single center retrospective cross-sectional study

The soil saprophyte and Tier I select agent Burkholderia pseudomallei can cause rapidly fatal infections in humans and animals. The capability of switching to an intracellular life cycle during infection appears to be a decisive trait of B. pseudomallei for causing disease. B. pseudomallei harbors multiple type VI secretion systems (T6SSs) orthologs of which are present in the surrogate organism Burkholderia thailandensis. Upon host cell entry and vacuolar escape into the cytoplasm, B. pseudomallei and B. thailandensis manipulate host cells by utilizing the T6SS-5 (also termed T6SS1) to form multinucleated giant cells for intercellular spread. Disruption of the T6SS-5 in B. thailandensis causes a drastic attenuation of virulence in wildtype but not in mice lacking the central innate immune adapter protein MyD88. This result suggests that the T6SS-5 is deployed by the bacteria to overcome innate immune responses. However, important questions in this field remain unsolved including the mechanism underlying T6SS-5 activity and its physiological role during infection. In this review, we summarize the current knowledge on the components and regulation of the T6SS-5 as well as its role in virulence in mammalian hosts.

The Burkholderia Type VI Secretion System 5: Composition, Regulation and Role in Virulence

Immune imbalance and activation are associated with lower lung function in youth with perinatally-acquired HIV.

B105. CRITICAL CARE: COUNTERPARTS - NON-PULMONARY CRITICAL CARE AND MULTI-ORGAN FAILURE

Reduced Circulating Gamma Delta T Cell Number and Effector Phenotype Is Associated with Mortality in Gram-Negative Bacteremia

Objectives: As life expectancy of people living with HIV (PLWH) improves in low-income and middle-income countries (LMICs), the spectrum of HIV-related pulmonary complications may reflect a greater burden of chronic lung diseases as in high-income countries. We determined whether the risk of abnormal spirometry was greater among adolescent compared with adult PLWH at the Coptic Hope Center for Infectious Diseases in Nairobi, Kenya, and evaluated the role of other cofactors for abnormal spirometry. Design: We prospectively enrolled adolescent and adult PLWH for this cross-sectional study. Methods: Data collection included standardized questionnaires, clinical assessment, and prebronchodilator and postbronchodilator spirometry. Adolescents additionally underwent noncontrast chest computed tomography. Multivariable logistic regression determined associations of adolescent age with abnormal spirometry, adjusting for cofactors. Results: Of 427 PLWH, 21 (40%) adolescents and 64 (17%) adults had abnormal spirometry. Among adolescents, 80% had abnormal chest CTs, and 79% had at least one respiratory symptom. Adolescent age (adjusted odds ratio 3.22; 95% confidence interval 1.48–6.98) was independently associated with abnormal spirometry, adjusting for recent CD4+, HIV clinical stage, low BMI, indoor kerosene use, smoking pack-years, and prior pulmonary tuberculosis. Additional important cofactors for abnormal spirometry included prior pulmonary tuberculosis (3.15; 1.70–5.58), kerosene use (1.77; 1.04–3.04) and smoking pack-years (1.05; 1.00–1.10). Adolescent age, prior pulmonary tuberculosis, and smoking pack-years were significantly associated with airflow limitation. Conclusion: Adolescent age was independently associated with increased risk of abnormal spirometry, particularly airflow limitation. Studies to improve prevention, detection, and management of chronic lung disease across the lifespan among PLWH are needed in LMICs.

Adolescent age is an independent risk factor for abnormal spirometry among people living with HIV in Kenya

Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017

Neutrophil extracellular traps (NETs) are increased in the alveolar spaces of patients with ventilator-associated pneumonia

Abstract Background Culture is the gold standard for the diagnosis of melioidosis, an infection caused by Burkholderia pseudomallei. Here we evaluate a lateral flow immunoassay (LFI) to detect B. pseudomallei capsular polysaccharide (CPS) in serum samples. Methods Patients with culture from any clinical specimen positive for B. pseudomallei were selected as cases. Patients who were blood culture positive for Staphylococcus aureus, Escherichia coli or Klebsiella pneumoniae as well as those who were malaria or dengue polymerase chain reaction assay positive were selected as controls. Results The sensitivity of the LFI was 31.3% (60/192 case patients [95% confidence interval {CI} 24.8 to 38.3]) and the specificity was 98.8% (559/566 control patients [95% CI 97.4 to 99.5]) in serum samples. Conclusions Although LFI may have limited sensitivity in serum, it can rapidly diagnose melioidosis in resource-limited settings.

Transactions of the Royal Society of Tropical Medicine and Hygiene

Sensitivity and specificity of a lateral flow immunoassay (LFI) in serum samples for diagnosis of melioidosis

Additional file 5: of Neutrophil extracellular traps (NETs) are increased in the alveolar spaces of patients with ventilator-associated pneumonia

Utility of SOFA score, management and outcomes of sepsis in Southeast Asia: a multinational multicenter prospective observational study

Burkholderia pseudomallei is an environmental bacterium that causes melioidosis, a major community-acquired infection in tropical regions. Melioidosis presents with a range of clinical symptoms, is often characterized by a robust inflammatory response, may relapse after treatment, and results in high mortality rates. Lipopolysaccharide (LPS) of B. pseudomallei is a potent immunostimulatory molecule comprised of lipid A, core, and O-polysaccharide (OPS) components. Four B. pseudomallei LPS types have been described based on SDS-PAGE patterns that represent the difference of OPS–type A, type B, type B2 and rough LPS. The majority of B. pseudomallei isolates are type A. We used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) followed by electrospray ionization quadrupole time-of-flight mass spectrometry (ESI-QqTOF MS) and gas chromatography to characterize the lipid A of B. pseudomallei within LPS type A isolates. We determined that B. pseudomallei lipid A is represented by penta- and tetra-acylated species modified with 4-amino-4-deoxy-arabinose (Ara4N). The MALDI-TOF profiles from 171 clinical B. pseudomallei isolates, including 68 paired primary and relapse isolates and 35 within-host isolates were similar. We did not observe lipid A structural changes when the bacteria were cultured in different growth conditions. Dose-dependent NF-κB activation in HEK cells expressing TLR4 was observed using multiple heat-killed B. pseudomallei isolates and corresponding purified LPS. We demonstrated that TLR4-dependent NF-κB activation induced by heat-killed bacteria or LPS prepared from OPS deficient mutant was significantly greater than those induced by wild type B. pseudomallei. These findings suggest that the structure of B. pseudomallei lipid A is highly conserved in a wide variety of clinical and environmental circumstances but that the presence of OPS may modulate LPS-driven innate immune responses in melioidosis.

Comprehensive analysis of clinical Burkholderia pseudomallei isolates demonstrates conservation of unique lipid A structure and TLR4-dependent innate immune activation

Infection and sepsis are leading causes of death worldwide but the epidemiology and outcomes are not well understood in resource-limited settings. We conducted a four-year prospective observational study from March 2013 to February 2017 to examine the clinical epidemiology and outcomes of adults admitted with community-acquired infection in a resource-limited tertiary-care hospital in Ubon Ratchathani province, Northeast Thailand. Hospitalized patients with infection and accompanying systemic manifestations of infection within 24 hours of admission were enrolled. Subjects were classified as having sepsis if they had a modified sequential organ failure assessment (SOFA) score ≥2 at enrollment. This study was registered with ClinicalTrials.gov, number NCT02217592. A total of 4,989 patients were analyzed. Of the cohort, 2,659 (53%) were male and the median age was 57 years (range 18–101). Of these, 1,173 (24%) patients presented primarily to the study hospital, 3,524 (71%) were transferred from 25 district hospitals or 8 smaller hospitals in the province, and 292 (6%) were transferred from one of 30 hospitals in other provinces. Three thousand seven hundred and sixteen (74%) patients were classified as having sepsis. Patients with sepsis had an older age distribution and a greater prevalence of comorbidities compared to patients without sepsis. Twenty eight-day mortality was 21% (765/3,716) in sepsis and 4% (54/1,273) in non-sepsis patients (p<0.001). After adjusting for gender, age, and comorbidities, sepsis on admission (adjusted hazard ratio [HR] 3.30; 95% confidence interval [CI] 2.48–4.41, p<0.001), blood culture positive for pathogenic organisms (adjusted HR 2.21; 95% CI 1.89–2.58, p<0.001) and transfer from other hospitals (adjusted HR 2.18; 95% CI 1.69–2.81, p<0.001) were independently associated with mortality. In conclusion, mortality of community-acquired sepsis in Northeast Thailand is considerable and transferred patients with infection are at increased risk of death. To reduce mortality of sepsis in this and other resource-limited setting, facilitating rapid detection of sepsis in all levels of healthcare facilities, establishing guidelines for transfer of sepsis patients, and initiating sepsis care prior to and during transfer may be beneficial.

Clinical epidemiology and outcomes of community acquired infection and sepsis among hospitalized patients in a resource limited setting in Northeast Thailand: A prospective observational study (Ubon-sepsis)

Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

Macrophage‐targeted drugamers with enzyme‐cleavable linkers deliver high intracellular drug dosing and sustained drug pharmacokinetics against alveolar pulmonary infections

Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

Importance The quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) score has not been well-evaluated in low- and middle-income countries (LMICs). Objective To assess the association of qSOFA with excess hospital death among patients with suspected infection in LMICs and to compare qSOFA with the systemic inflammatory response syndrome (SIRS) criteria. Design, Settings, and Participants Retrospective secondary analysis of 8 cohort studies and 1 randomized clinical trial from 2003 to 2017. This study included 6569 hospitalized adults with suspected infection in emergency departments, inpatient wards, and intensive care units of 17 hospitals in 10 LMICs across sub-Saharan Africa, Asia, and the Americas. Exposures Low (0), moderate (1), or high (≥2) qSOFA score (range, 0 [best] to 3 [worst]) or SIRS criteria (range, 0 [best] to 4 [worst]) within 24 hours of presentation to study hospital. Main Outcomes and Measures Predictive validity (measured as incremental hospital mortality beyond that predicted by baseline risk factors, as a marker of sepsis or analogous severe infectious course) of the qSOFA score (primary) and SIRS criteria (secondary). Results The cohorts were diverse in enrollment criteria, demographics (median ages, 29-54 years; males range, 36%-76%), HIV prevalence (range, 2%-43%), cause of infection, and hospital mortality (range, 1%-39%). Among 6218 patients with nonmissing outcome status in the combined cohort, 643 (10%) died. Compared with a low or moderate score, a high qSOFA score was associated with increased risk of death overall (19% vs 6%; difference, 13% [95% CI, 11%-14%]; odds ratio, 3.6 [95% CI, 3.0-4.2]) and across cohorts (P < .05 for 8 of 9 cohorts). Compared with a low qSOFA score, a moderate qSOFA score was also associated with increased risk of death overall (8% vs 3%; difference, 5% [95% CI, 4%-6%]; odds ratio, 2.8 [95% CI, 2.0-3.9]), but not in every cohort (P < .05 in 2 of 7 cohorts). High, vs low or moderate, SIRS criteria were associated with a smaller increase in risk of death overall (13% vs 8%; difference, 5% [95% CI, 3%-6%]; odds ratio, 1.7 [95% CI, 1.4-2.0]) and across cohorts (P < .05 for 4 of 9 cohorts). qSOFA discrimination (area under the receiver operating characteristic curve [AUROC], 0.70 [95% CI, 0.68-0.72]) was superior to that of both the baseline model (AUROC, 0.56 [95% CI, 0.53-0.58; P < .001) and SIRS (AUROC, 0.59 [95% CI, 0.57-0.62]; P < .001). Conclusions and Relevance When assessed among hospitalized adults with suspected infection in 9 LMIC cohorts, the qSOFA score identified infected patients at risk of death beyond that explained by baseline factors. However, the predictive validity varied among cohorts and settings, and further research is needed to better understand potential generalizability.

Association of the Quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) Score With Excess Hospital Mortality in Adults With Suspected Infection in Low- and Middle-Income Countries

Pulmonary intracellular infections, such as tuberculosis, anthrax, and tularemia, have remained a significant challenge to conventional antibiotic therapy. Ineffective antibiotic treatment of these infections can lead not only to undesired side effects, but also to the emergence of antibiotic resistance. Aminoglycosides (e.g., streptomycin) have long been part of the therapeutic regiment for many pulmonary intracellular infections. Their bioavailability for intracellular bacterial pools, however, is limited by poor membrane permeability and rapid elimination. To address this challenge, polymer-augmented liposomes (PALs) were developed to provide improved cytosolic delivery of streptomycin to alveolar macrophages, an important host cell for intracellular pathogens. A multifunctional diblock copolymer was engineered to functionalize PALs with carbohydrate-mediated targeting, pH-responsive drug release, and endosomal release activity with a single functional polymer that replaces the pegylated lipid component to simplify the liposome formulation. The pH-sensing functionality enabled PALs to provide enhanced release of streptomycin under endosomal pH conditions (70% release in 6 hours) with limited release at physiological pH 7.4 (16%). The membrane-destabilizing activity connected to endosomal release was characterized in a hemolysis assay and PALs displayed a sharp pH profile across the endosomal pH development target range. The direct connection of this membrane-destabilizing pH profile to model drug release was demonstrated in an established pyranine/p-xylene bispyridinium dibromide (DPX) fluorescence dequenching assay. PALs displayed similar sharp pH-responsive release, whereas PEGylated control liposomes did not, and similar profiles were then shown for streptomycin release. The mannose-targeting capability of the PALs was also demonstrated with 2.5 times higher internalization compared to non-targeted PEGylated liposomes. Finally, the streptomycin-loaded PALs were shown to have a significantly improved intracellular antibacterial activity in a Francisella-macrophage co-culture model, compared with free streptomycin or streptomycin delivered by control PEGylated liposomes (13× and 16×, respectively). This study suggests the potential of PALs as a useful platform to deliver antibiotics for the treatment of intracellular macrophage infections.

Polymer-augmented liposomes enhancing antibiotic delivery against intracellular infections.

Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

Learning Objectives: A topic of debate in critical care medicine involves the relationship between serum lactate and ScvO 2 . Current consensus guidelines argue that low tissue oxygenation, as evidenced by a low ScvO 2 , should result in increased lactate production through anaerobic metabolism. However, elevated lactate could also be due to reduced lactate elimination or enhanced aerobic glycolysis through epinephrine release. Hypothesis: Serum lactate inversely correlates with ScvO 2 in critically ill patients. Methods: Single center, retrospective cohort study in an urban academic medical center from 3/2007 – 3/2017. Entry criteria included age ≥ 18 years and ScvO 2 or SvO 2 analysis made +/1 hour from a lactate measurement. Central venous and mixed venous blood gases, serum lactate, serum cortisol as a surrogate for epinephrine, and markers of renal and hepatic function were collected from patient data. ICD-9 codes determined if the patients were diagnosed with sepsis or shock. The correlation between lactate and ScvO 2 was analyzed using simple linear regression models. Results: 2,348 patients were included in the study. Lactate and ScvO2 had an r = 0.0086 (n = 737, p = 0.012). Lactate and SvO 2 had an r = 0.0019 (n = 1,611, p = 0.079). When eliminating patients with high adrenal activation (cortisol ≥ 25 ug/dL), lactate and ScvO2 showed an r = 0.0041 (n = 36, p = 0.71). In patients with tissue hypoxia (ScvO2 ≤ 65), lactate and ScvO2 had an r = 0.0500 (n = 217, p < 0.01). In patients with normal liver (AST ≤ 40) and kidney (creatinine ≤ 1.2) function, lactate and ScvO2 had an r = 0.0815 (n = 94, p < 0.01). In cardiogenic shock patients, lactate and ScvO2 had an r = 0.0055 (n = 27, p = 0.71). Conclusions: In critically ill patients, lactate showed no predictive ability for ScvO 2 , even after eliminating patients with high adrenal activation, normoxia, or normal kidney and liver function. Lactate and ScvO 2 should not be assumed to be interchangeable markers of tissue oxygenation.

3: TLR1 GENETIC VARIATION IS ASSOCIATED WITH INCREASED MORTALITY IN GRAM-NEGATIVE INFECTION

Studies in human peripheral blood monocyte-derived macrophages in vitro have shown clear evidence that multiple macrophage polarization states exist. The extent to which different alveolar macrophage (AM) polarization states exist in homeostasis or in the setting of severe injury such as acute respiratory distress syndrome (ARDS) is largely unknown. We applied single-cell cytometry TOF (CyTOF) to simultaneously measure 36 cell-surface markers on CD45+ cells present in bronchoalveolar lavage from healthy volunteers, as well as mechanically ventilated subjects with and without ARDS. Visualization of the high-dimensional data with the t-distributed stochastic neighbor embedding algorithm demonstrated wide diversity of cell-surface marker profiles among CD33+CD71+CD163+ AMs. We then used a κ-nearest neighbor density estimation algorithm to statistically identify distinct alveolar myeloid subtypes, and we discerned 3 AM subtypes defined by CD169 and PD-L1 surface expression. The percentage of AMs that were classified into one of the 3 AM subtypes was significantly different between healthy and mechanically ventilated subjects. In an independent cohort of subjects with ARDS, PD-L1 gene expression and PD-L1/PD-1 pathway-associated gene sets were significantly decreased in AMs from patients who experienced prolonged mechanical ventilation or death. Unsupervised CyTOF analysis of alveolar leukocytes from human subjects has potential to identify expected and potentially novel myeloid populations that may be linked with clinical outcomes.

Cytometry TOF identifies alveolar macrophage subtypes in acute respiratory distress syndrome.

SETTING
Melioidosis-Burkholderia pseudomallei infection-is increasingly recognized in Cambodia, a country with a high incidence of tuberculosis (TB). Melioidosis and TB can be clinically indistinguishable.

OBJECTIVE
To quantify the proportion of patients with clinically suspected TB who had melioidosis by testing sputum for B. pseudomallei.

DESIGN
This was a prospective, 6-month cross-sectional single-center study at a Cambodian provincial referral hospital among patients with suspicion of TB who provided sputum specimens for testing. TB was diagnosed using sputum Xpert® MTB/RIF molecular assay or culture; melioidosis was diagnosed using sputum culture for B. pseudomallei.

RESULTS
Of 404 patients evaluated for possible TB, 52 (12.9%, 95%CI 9.8-16.5) had TB. Four patients (1.0%, 95%CI 0.3-2.5) had melioidosis; none had concurrent TB or an existing medical risk factor for melioidosis, although two were farmers, an occupational risk factor.

One per cent of patients being evaluated for TB at a Cambodian provincial referral hospital had culture-proven respiratory melioidosis, a highly lethal infection. None had previously recognized medical conditions that would increase their risk of melioidosis. Testing for melioidosis should be considered in patients presenting with suspected TB in Cambodia.

The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease

Melioidosis in patients with suspected tuberculosis in Cambodia: a single-center cross-sectional study.

Background Dengue is a common cause of infection in adults in tropical countries. Sepsis is a syndrome of systemic manifestations induced by infection of any organisms; including bacterial, fungal and viral agents. Here, we investigated the diagnosis, management and outcomes of dengue patients presenting with sepsis in a prospective study of community-acquired sepsis in Thailand. Methods From June to December 2015, 874 adult patients (age≥18 years) with suspected or documented community-acquired infection, with ≥3 diagnostic criteria for sepsis according to the Surviving Sepsis Campaign 2012, and within 24 hours of admission were evaluated. Serum was stored and later tested for dengue PCR assays. Results A total of 126 patients had dengue PCR assays positive (2 DENV-1, 12 DENV-2, 24 DENV-3 and 88 DENV-4), and 5 of them (4%) died. We found that attending physicians suspected dengue infection on admission in 84 patients (67%), and recorded dengue infection as the final diagnosis in 96 patients (76%). Four of five fatal cases were diagnosed and treated as septic shock not due to dengue. In multivariable analysis, there was a trend showing that age≥60 years, hypoxemia and misdiagnosis of dengue by attending physicians were associated with 28-day mortality. Conclusions A number of adult patients who died of dengue are misdiagnosed as severe sepsis and septic shock. Diagnosis of dengue based on clinical features alone is difficult. Rapid diagnostic tests for dengue may need to be routinely used in adult patients presenting with sepsis and septic shock in tropical countries. This approach could improve diagnosis and management of those patients.

Management and outcomes of severe dengue patients presenting with sepsis in a tropical country

TLR4 genetic variation is associated with inflammatory responses in Gram-positive sepsis.

Sepsis Assessment And Identification In Low Resource Settings: The Sailors Study

Immunomodulatory Effects of Lactoferrin during Burkholderia thailandensis Infection

Staphylococcus aureus infection is a persistent threat in resource-restricted settings in southeast Asia but informative data about this disease remain limited. We analyzed characteristics, management, and predictors of outcome in severely septic patients with community-onset S. aureus infection in northeast Thailand. We performed a prospective, multicenter observational cohort study of community-onset S. aureus sepsis in four referral hospitals recruiting patients at least 14 years of age admitted between March 2010 and December 2013. One hundred and nineteen patients with severe staphylococcal sepsis were enrolled. Diabetes was the most common underlying condition. Methicillin-resistant infection was rare. Twenty-eight-day mortality was 20%. Ninety-two percent of patients received appropriate antibiotic therapy and 82% were administered intravenous fluids on the first hospital day, although only 14% were managed in an intensive care unit (ICU). On univariable analysis, clinical variables at enrollment significantly associated with death at 28 days were coagulopathy or respiratory failure. Plasma interleukin (IL)-8 concentration alone accurately predicted mortality (area under the receiver operating curve = 0.82, 95% confidence interval = 0.73–0.90). In multivariable analysis, addition of IL-8 concentration to a mortality prediction model containing clinical variables further improved the predictive ability of the model. We conclude that severe staphylococcal sepsis in northeast Thailand causes significant mortality. Diabetes is a common preexisting condition and most patients are managed outside the ICU even if they receive vasoactive/inotropic agents or mechanical ventilation. While clinical factors apparent on presentation including coagulopathy and respiratory failure predict death, plasma IL-8 improves this prediction.

Patient Characteristics, Management, and Predictors of Outcome from Severe Community-Onset Staphylococcal Sepsis in Northeast Thailand: A Prospective Multicenter Study

Background Melioidosis, caused by the flagellated bacterium Burkholderia pseudomallei, is a life-threatening and increasingly recognized emerging disease. Toll-like receptor (TLR) 5 is a germline-encoded pattern recognition receptor to bacterial flagellin. We evaluated the association of a nonsense TLR5 genetic variant that truncates the receptor with clinical outcomes and with immune responses in melioidosis. Methodology/Principal findings We genotyped TLR5 c.1174C>T in 194 acute melioidosis patients in Thailand. Twenty-six (13%) were genotype CT or TT. In univariable analysis, carriage of the c.1174C>T variant was associated with lower 28-day mortality (odds ratio (OR) 0.21, 95% confidence interval (CI) 0.05–0.94, P = 0.04) and with lower 90-day mortality (OR 0.25, 95% CI 0.07–086, P = 0.03). In multivariable analysis adjusting for age, sex, diabetes and renal disease, the adjusted OR for 28-day mortality in carriers of the variant was 0.24 (95% CI 0.05–1.08, P = 0.06); and the adjusted OR for 90-day mortality was 0.27 (95% CI 0.08–0.97, P = 0.04). c.1174C>T was associated with a lower rate of bacteremia (P = 0.04) and reduced plasma levels of IL-10 (P = 0.049) and TNF-α (P < 0.0001). We did not find an association between c.1174C>T and IFN-γ ELISPOT (T-cell) responses (P = 0.49), indirect haemagglutination titers or IgG antibodies to bacterial flagellin during acute melioidosis (P = 0.30 and 0.1, respectively). Conclusions/Significance This study independently confirms the association of TLR5 c.1174C>T with protection against death in melioidosis, identifies lower bacteremia, IL-10 and TNF-α production in carriers of the variant with melioidosis, but does not demonstrate an association of the variant with acute T-cell IFN-γ response, indirect haemagglutination antibody titer, or anti-flagellin IgG antibodies.

A nonsense mutation in TLR5 is associated with survival and reduced IL-10 and TNF-α levels in human melioidosis

Objectives Limited data are available on sepsis in low-resource settings, particularly outside of urban referral centers. We conducted a prospective observational single-center cohort study in May 2013 to assess the presentation, management and outcomes of adult and pediatric patients admitted with sepsis to a community hospital in rural Uganda. Methods We consecutively screened all patients admitted to medical wards who met sepsis criteria. We evaluated eligible patients within 24 hours of presentation and 24–48 hours after admission, and followed them until hospital discharge. In addition to chart review, mental status evaluation, peripheral capillary oxygen saturation, and point-of-care venous whole blood lactate and glucose testing were performed. Results Of 56 eligible patients, we analyzed data on 51 (20 adults and 31 children). Median age was 8 years (IQR 2–23 years). Sepsis accounted for a quarter of all adult and pediatric medical ward admissions during the study period. HIV prevalence among adults was 30%. On enrollment, over half of patients had elevated point-of-care whole blood lactate, few were hypoglycemic or had altered mental status, and one third were hypoxic. Over 80% of patients received at least one antibiotic, all severely hypoxic patients received supplemental oxygen, and half of patients with elevated lactate received fluid resuscitation. The most common causes of sepsis were malaria and pneumonia. In-hospital mortality was 3.9%. Conclusions This study highlights the importance of sepsis among adult and pediatric patients admitted to a rural Ugandan hospital and underscores the need for continued research on sepsis in low resource settings.

Presentation, management, and outcomes of sepsis in adults and children admitted to a rural Ugandan hospital: A prospective observational cohort study

Background: Chronic lung diseases are increasingly recognized complications of vertically-acquired HIV among adolescents in sub-Saharan Africa and may manifest with hypoxia or tachypnea. We sought to determine the prevalence of and risk factors for hypoxia and tachypnea among adolescents with vertically-acquired HIV in Nairobi, Kenya. Methods: We performed a cross-sectional analysis of 258 adolescents with vertically-acquired HIV who were initiating care at the Coptic Hope Center for Infectious Diseases. Adolescents with documented pneumonia were excluded. Hypoxia was defined as resting oxygen saturation ⩽92%, and tachypnea was based on the 99th percentile of age-appropriate respiratory rates. Logistic regression models adjusted for demographics, and HIV severity estimated odds ratios for risk of hypoxia and tachypnea associated with potential risk factors. Results: Overall, 11% of adolescents had hypoxia and 55% had tachypnea. Advanced HIV [adjusted odds ratio (aOR): 2.41] and low CD4 (aOR: 1.74) were associated with greater hypoxia risk, but confidence intervals (CIs) were wide and included the null (95% CI: 0.93–6.23 and 0.69–4.39, respectively). Low CD4 (aOR: 2.45, 95% CI: 1.39–4.32), current antiretroviral therapy use (aOR: 0.48, 95% CI: 0.27–0.86) and stunted growth (aOR: 3.46, 95% CI: 1.94–6.18) were associated with altered tachypnea risk. Conclusions: Hypoxia and tachypnea are common among adolescents with vertically-acquired HIV. There was a suggestion that advanced HIV and low CD4 were associated with greater hypoxia risk. Low CD4, lack of antiretroviral therapy use and stunted growth are risk factors for tachypnea. Our findings highlight the chronic lung disease burden in this population and may inform diagnostic algorithms.

Risk Factors for Hypoxia and Tachypnea Among Adolescents With Vertically-acquired HIV in Nairobi

ABSTRACT The human pathogen Burkholderia pseudomallei and the related species Burkholderia thailandensis are facultative intracellular bacteria characterized by the ability to escape into the cytosol of the host cell and to stimulate the formation of multinucleated giant cells (MNGCs). MNGC formation is induced via an unknown mechanism by bacterial type VI secretion system 5 (T6SS-5), which is an essential virulence factor in both species. Despite the vital role of the intracellular life cycle in the pathogenesis of the bacteria, the range of host cell types permissive for initiation and completion of the intracellular cycle is poorly defined. In the present study, we used several different types of human primary cells to evaluate bacterial entry, intracellular survival, and MNGC formation. We report the capacity of B. pseudomallei to enter, efficiently replicate in, and mediate MNGC formation of vein endothelial and bronchial epithelial cells, indicating that the T6SS-5 is important in the host-pathogen interaction in these cells. Furthermore, we show that B. pseudomallei invades fibroblasts and keratinocytes and survives inside these cells as well as in monocyte-derived macrophages and neutrophils for at least 17 h postinfection; however, MNGC formation is not induced in these cells. In contrast, infection of mixed neutrophils and RAW264.7 macrophages with B. thailandensis stimulated the formation of heterotypic MNGCs in a T6SS-5-dependent manner. In summary, the ability of the bacteria to enter and survive as well as induce MNGC formation in certain host cells may contribute to the pathogenesis observed in B. pseudomallei infection.

Entry, Intracellular Survival, and Multinucleated-Giant-Cell-Forming Activity of Burkholderia pseudomallei in Human Primary Phagocytic and Nonphagocytic Cells

Lung-based intracellular bacterial infections remain one of the most challenging infectious disease settings. For example, the current standard for treating Franciscella tularensis pneumonia (tularemia) relies on administration of oral or intravenous antibiotics that poorly achieve and sustain pulmonary drug bioavailability. Inhalable antibiotic formulations are approved and in clinical development for upper respiratory infections, but sustained drug dosing from inhaled antibiotics against alveolar intracellular infections remains a current unmet need. To provide an extended therapy against alveolar intracellular infections, we have developed a macromolecular therapeutic platform that provides sustained local delivery of ciprofloxacin with controlled dosing profiles. Synthesized using RAFT polymerization, these macromolecular prodrugs characteristically have high drug loading (16-17 wt % drug), tunable hydrolysis kinetics mediated by drug linkage chemistry (slow-releasing alkyllic vs fast-releasing phenolic esters), and, in general, represent new fully synthetic nanotherapeutics with streamlined manufacturing profiles. In aerosolized and completely lethal F.t. novicida mouse challenge models, the fast-releasing ciprofloxacin macromolecular prodrug provided high cure efficiencies (75% survival rate under therapeutic treatment), and the importance of release kinetics was demonstrated by the inactivity of the similar but slow-releasing prodrug system. Pharmacokinetics and biodistribution studies further demonstrated that the efficacious fast-releasing prodrug retained drug dosing in the lung above the MIC over a 48 h period with corresponding Cmax/MIC and AUC0-24h/MIC ratios being greater than 10 and 125, respectively; the thresholds for optimal bactericidal efficacy. These findings identify the macromolecular prodrug platform as a potential therapeutic system to better treat alveolar intracellular infections such as F. tularensis, where positive patient outcomes require tailored antibiotic pharmacokinetic and treatment profiles.

Synthetic Macromolecular Antibiotic Platform for Inhalable Therapy against Aerosolized Intracellular Alveolar Infections.

A growing number of pulmonary and critical care medicine fellowship programs in the United States offer global health training opportunities. Formal, integrated global health programs within pulmonary and critical care fellowships are relatively new but are built on principles and ideals of global health that focus on the mutually beneficial exchange of knowledge and social justice. Although core competencies consistent with these overarching themes in global health education have not been formalized for pulmonary and critical care trainees, relevant competency areas include clinical knowledge, international research training, cultural competency, and clinical and research capacity building. Existing global health education in U.S. pulmonary and critical care medicine training programs can generally be classified as one of three different models: integrated global health tracks, global health electives, and additional research years. Successful global health education programs foster partnerships and collaborations with international sites that emphasize bidirectional exchange. This bidirectional exchange includes ongoing, equitable commitments to mutual opportunities for training and professional development, including a focus on the particular knowledge and skill sets critical for addressing the unique priorities of individual countries. However, barriers related to the availability of mentorship, funding, and dedicated time exist to expanding global health education in pulmonary and critical care medicine. The implementation of global health training within pulmonary and critical care medicine programs requires continued optimization, but this training is essential to prepare the next generation of physicians to address the global aspects of respiratory disease and critical illness.

Global Health Education in Pulmonary and Critical Care Medicine Fellowships.

Comparison of community-onset Staphylococcus argenteus and Staphylococcus aureus sepsis in Thailand: a prospective multicentre observational study

Lung ultrasound is still a relatively new technology, albeit one that has rapidly grown in popularity since the initial description of ultrasonographic evaluation of the pleura in the 1960s (1) and of the lung parenchyma in the 1980s (2).

Lung ultrasound in acute respiratory distress syndrome and beyond.

Initial Management Of Severe Sepsis In Adults Admitted To A Thai Regional Referral Hospital: A Prospective Observational Study

RATIONALE, AIMS AND OBJECTIVES
In the global context of population ageing, understanding and monitoring intensive care use by the elderly is a strategic issue. National-level data are needed to overcome sampling biases that often limit epidemiologic studies of the critically ill elderly. The objective of this study was to describe intensive care use for hospitalized elderly patients using secondary data from the French national hospital discharge database.

METHOD
Structured assessment of the national database coverage and accuracy; cross-sectional analysis of hospitalizations including at least one admission in an intensive care unit (ICU) for patients aged ≥ 80 years from 1 January to 31 December 2009.

RESULTS
In 2009, people aged ≥ 80 years accounted for 5.4% of the population but 15.3% of the 215 210 adult hospitalizations involving intensive care in France. In this elderly group, the mean age was 84.0 (± 3.56) years, and 51.6% were male. In-hospital mortality was 33.9%. The median time spent in the ICU was 3 [interquartile range (IQR), 2-8] days, the median time spent in hospital was 14 (IQR, 8-24) days and 9% of hospitalizations ended by the patient's death involved intensive care. A surgical procedure was included in 43% of hospitalizations. Medical and surgical diagnosis-related group hospitalizations were characterized by significant differences in volume, mortality, ICU days and costs.

There was marked clinical heterogeneity in the population of elderly patients hospitalized in the ICU. These data provide baseline information and prompt further studies comparing intensive care utilization across age groups, between countries and over time.

Elderly patients hospitalized in the ICU in France: a population-based study using secondary data from the national hospital discharge database.

Abstract Background Identification of Burkholderia pseudomallei, the cause of melioidosis, using routine methods takes several days. Use of a monoclonal antibody-based immunofluorescent assay (IFA) on positive blood cultures may speed diagnosis. Methods We tested the diagnostic accuracy of the IFA on 545 blood cultures positive for Gram-negative organisms at Udon Thani Hospital, Thailand, between June 2015 and August 2016. Results Sensitivity of the IFA was 100% and specificity was 99.6%. The median decrease in time to pathogen identification between the IFA result and routine methods was 28 h (IQR 25–51), p<0.0001. Conclusions The IFA accurately expedites the diagnosis of melioidosis.

Validation of a monoclonal antibody-based immunofluorescent assay to detect Burkholderia pseudomallei in blood cultures

The capacity to care for the critically ill has long been viewed as a fundamental element of established and comprehensive health care systems. Extending this capacity to health care systems in low- and middle-income countries is important given the burden of disease in these regions and the significance of critical care in overall health system strengthening. However, many practicalities of improving access and delivery of critical care in resource-limited settings have yet to be elucidated. We have initiated a program to build capacity for the care of critically ill patients in one low-income Southeast Asian country, Cambodia. We are leveraging existing international academic partnerships to enhance postgraduate critical care education in Cambodia. After conducting a needs assessment and literature review, we developed a three-step initiative targeting training in mechanical ventilation. First, we assessed and revised the current resident curriculum pertaining to mechanical ventilation. We addressed gaps in training, incorporated specific goals and learning objectives, and decreased the hours of lectures in favor of additional bedside training. Second, we are incorporating e-learning, e-teaching, and e-assessment into the curriculum, with both live, interactive and independent, self-paced online instruction. Third, we are developing a train-the-trainer program defined by bidirectional international faculty exchanges to provide hands-on, case-based, and bedside training to achieve competency-based outcomes. In targeting specific educational needs and a key population-the next generation of Cambodian intensivists-this carefully designed approach should address some existing gaps in the health care system and hopefully yield a lasting impact.

Bolstering medical education to enhance critical care capacity in Cambodia.

Melioidosis, infection caused by Burkholderia pseudomallei, is increasingly reported in Cambodia. We hypothesized that implementation of an enhanced sputum testing protocol in a provincial hospital diagnostic microbiology laboratory would increase detection of B. pseudomallei. We tested 241 sputum specimens that were deemed acceptable for culture, comparing culture in selective enrichment broth followed by sub-culture on Ashdown’s medium to standard culture methods. Two specimens (0.8%) were positive for B. pseudomallei using the enhanced protocol whereas one specimen (0.4%) was positive using standard methods. Given the low numbers of positive specimens, we could not conclusively determine the utility of the enhanced sputum testing protocol. However, the ramifications of identification of B. pseudomallei are substantial, and the benefit of the enhanced testing protocol may be more apparent in patients selected based on risk factors and clinical presentation. Promoting clinician awareness of the infection and encouraging utilization of diagnostic microbiology services are also likely to be important factors in facilitating identification of melioidosis.

Detection of Burkholderia pseudomallei in Sputum using Selective Enrichment Broth and Ashdown’s Medium at Kampong Cham Provincial Hospital, Cambodia

Pulmonary ultrasound and pulse oximetry versus chest radiography and arterial blood gas analysis for the diagnosis of acute respiratory distress syndrome: a pilot study

Nlrc4 contributes substantially to Caspase-1/Caspase-11 -dependent restriction of B. pseudomallei replication in the lung.

Nucleotide-binding oligomerization domain 2 (NOD2) is a cytosolic pathogen recognition receptor that regulates susceptibility to a variety of infections and chronic diseases. Burkholderia pseudomallei, a facultative intracellular bacterium, causes the tropical infection melioidosis. We hypothesized that NOD2 may participate in host defense in melioidosis. We performed a series of in vitro assays and in vivo experiments and analyzed the association of human genetic variation with infection to delineate the contribution of NOD2 to the host response to B. pseudomallei. We found that transfection with NOD2 mediated NF-κB activation induced by B. pseudomallei stimulation of HEK293 cells. After low-dose inoculation with aerosolized B. pseudomallei, Nod2-deficient mice showed impaired clinical responses and permitted greater bacterial replication in the lung and dissemination to the spleen compared with wild-type mice. IL-6 and KC levels were higher in the lungs of Nod2-deficient mice. In a cohort of 1562 Thai subjects, a common genetic polymorphism in the NOD2 region, rs7194886, was associated with melioidosis, and this effect was most pronounced in women. rs7194886 was not associated with differences in cytokine production induced by whole-blood stimulation with the NOD2 ligand, muramyl dipeptide, or B. pseudomallei. To our knowledge, these findings are the first to characterize the role of NOD2 in host defense in mammalian melioidosis.

Melioidosis infection, caused by Burkholderia pseudomallei, is increasingly reported in Cambodia. We hypothesized that implementation of an enhanced sputum testing protocol in a provincial hospital diagnostic microbiology laboratory would increase detection of B. pseudomallei. We tested 241 sputum specimens that were deemed acceptable for culture, comparing culture in selective enrichment broth followed by sub-culture on Ashdown's medium to standard culture methods. Two specimens (0.8%) were positive for B. pseudomallei using the enhanced protocol whereas one specimen (0.4%) was positive using standard methods. These findings demonstrate that B. pseudomallei is rarely detected in sputum at this hospital. The low frequency of B. pseudomallei in sputum specimens precludes drawing any conclusions about the relative benefits of an enhanced sputum testing protocol at this site. Promoting clinician awareness of the infection and encouraging utilization of diagnostic microbiology services are likely to be important factors in facilitating identification of melioidosis.

Detection of Burkholderia pseudomallei in Sputum using Selective Enrichment Broth and Ashdown's Medium at Kampong Cham Provincial Hospital, Cambodia.

Melioidosis, infection caused by the Gram-negative bacterium Burkholderia pseudomallei, is a common cause of sepsis in northeast Thailand. In white North Americans, common functional genetic variation in TLR1 is associated with organ failure and death from sepsis. We hypothesized that TLR1 variants would be associated with outcomes in Thais with melioidosis. We collated the global frequencies of three TLR1 variants that are common in white North American populations: rs5743551 (-7202A/G), rs4833095 (742A/G), and rs5743618 (1804G/T). We noted a reversal of the minor allele from white North American subjects to Asian populations that was particularly pronounced for rs5743618. In the Utah residents of European ancestry, the frequency of the rs5743618 T allele was 17% whereas in Vietnamese subjects the frequency was >99%. We conducted a genetic association study in 427 patients with melioidosis to determine the association of TLR1 variation with organ failure or death. We genotyped rs5743551 and rs4833095. The variants were in high linkage disequilibrium but neither variant was associated with organ failure or in-hospital death. In 300 healthy Thai individuals we further tested the association of TLR1 variation with ex vivo blood responses to Pam3CSK4, a TLR1 agonist. Neither variant was robustly associated with blood cytokine responses induced by Pam3CSK4. We identified additional common variation in TLR1 by searching public databases and the published literature and screened three additional TLR1 variants for associations with Pam3CSK4-induced responses but found none. We conclude that the genetic architecture of TLR1 variation differs substantially in southeast Asians compared to other populations and common variation in TLR1 in Thais is not associated with outcome from melioidosis or with altered blood responses to Pam3CSK4. Our findings highlight the need for additional studies of TLR1 and other innate immune genetic modulators of the inflammatory host response and determinants of sepsis in southeast Asian populations.

Common TLR1 Genetic Variation Is Not Associated with Death from Melioidosis, a Common Cause of Sepsis in Rural Thailand

ABSTRACT The type VI secretion system (T6SS) has emerged as a critical virulence factor for the group of closely related Burkholderia spp. that includes Burkholderia pseudomallei, B. mallei, and B. thailandensis. While the genomes of these bacteria, referred to as the Bptm group, appear to encode several T6SSs, we and others have shown that one of these, type VI secretion system 5 (T6SS-5), is required for virulence in mammalian infection models. Despite its pivotal role in the pathogenesis of the Bptm group, the effector repertoire of T6SS-5 has remained elusive. Here we used quantitative mass spectrometry to compare the secretome of wild-type B. thailandensis to that of a mutant harboring a nonfunctional T6SS-5. This analysis identified VgrG-5 as a novel secreted protein whose export depends on T6SS-5 function. Bioinformatics analysis revealed that VgrG-5 is a specialized VgrG protein that harbors a C-terminal domain (CTD) conserved among Bptm group species. We found that a vgrG-5 ΔCTD mutant is avirulent in mice and is unable to stimulate the fusion of host cells, a hallmark of the Bptm group previously shown to require T6SS-5 function. The singularity of VgrG-5 as a detected T6SS-5 substrate, taken together with the essentiality of its CTD for virulence, suggests that the protein is critical for the effector activity of T6SS-5. Intriguingly, we show that unlike the bacterial-cell-targeting T6SSs characterized so far, T6SS-5 localizes to the bacterial cell pole. We propose a model whereby the CTD of VgrG-5—, propelled by T6SS-5—, plays a key role in inducing membrane fusion, either by the recruitment of other factors or by direct participation.

VgrG-5 Is a Burkholderia Type VI Secretion System-Exported Protein Required for Multinucleated Giant Cell Formation and Virulence

Planning for mass critical care (MCC) in resource-poor or constrained settings has been largely ignored, despite their large populations that are prone to suffer disproportionately from natural disasters. Addressing MCC in these settings has the potential to help vast numbers of people and also to inform planning for better-resourced areas.

METHODS
The Resource-Poor Settings panel developed five key question domains; defining the term resource poor and using the traditional phases of disaster (mitigation/preparedness/response/recovery), literature searches were conducted to identify evidence on which to answer the key questions in these areas. Given a lack of data upon which to develop evidence-based recommendations, expert-opinion suggestions were developed, and consensus was achieved using a modified Delphi process.

RESULTS
The five key questions were then separated as follows: definition, infrastructure and capacity building, resources, response, and reconstitution/recovery of host nation critical care capabilities and research. Addressing these questions led the panel to offer 33 suggestions. Because of the large number of suggestions, the results have been separated into two sections: part 1, Infrastructure/Capacity in this article, and part 2, Response/Recovery/Research in the accompanying article.

Lack of, or presence of, rudimentary ICU resources and limited capacity to enhance services further challenge resource-poor and constrained settings. Hence, capacity building entails preventative strategies and strengthening of primary health services. Assistance from other countries and organizations is needed to mount a surge response. Moreover, planning should include when to disengage and how the host nation can provide capacity beyond the mass casualty care event.

Resource-poor settings: infrastructure and capacity building: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement.

Burkholderia pseudomallei causes the tropical infection melioidosis. Pneumonia is a common manifestation of melioidosis and is associated with high mortality. Understanding the key elements of host defense is essential to developing new therapeutics for melioidosis. As a flagellated bacterium encoding type III secretion systems, B. pseudomallei may trigger numerous host pathogen recognition receptors. TLR5 is a flagellin sensor located on the plasma membrane. NLRC4, along with NAIP proteins, assembles a canonical caspase-1-dependent inflammasome in the cytoplasm that responds to flagellin (in mice) and type III secretion system components (in mice and humans). In a murine model of respiratory melioidosis, Tlr5 and Nlrc4 each contributed to survival. Mice deficient in both Tlr5 and Nlrc4 were not more susceptible than single knockout animals. Deficiency of Casp1/Casp11 resulted in impaired bacterial control in the lung and spleen; in the lung much of this effect was attributable to Nlrc4, despite relative preservation of pulmonary IL-1β production in Nlrc4−/− mice. Histologically, deficiency of Casp1/Casp11 imparted more severe pulmonary inflammation than deficiency of Nlrc4. The human NLRC4 region polymorphism rs6757121 was associated with survival in melioidosis patients with pulmonary involvement. Co-inheritance of rs6757121 and a functional TLR5 polymorphism had an additive effect on survival. Our results show that NLRC4 and TLR5, key components of two flagellin sensing pathways, each contribute to host defense in respiratory melioidosis.

NLRC4 and TLR5 Each Contribute to Host Defense in Respiratory Melioidosis

Clinicians caring for patients infected with Ebola virus must be familiar not only with screening and infection control measures but also with management of severe disease. By integrating experience from several Ebola epidemics with best practices for managing critical illness, this report focuses on the clinical presentation and management of severely ill infants, children, and adults with Ebola virus disease. Fever, fatigue, vomiting, diarrhea, and anorexia are the most common symptoms of the 2014 West African outbreak. Profound fluid losses from the gastrointestinal tract result in volume depletion, metabolic abnormalities (including hyponatremia, hypokalemia, and hypocalcemia), shock, and organ failure. Overt hemorrhage occurs infrequently. The case fatality rate in West Africa is at least 70%, and individuals with respiratory, neurological, or hemorrhagic symptoms have a higher risk of death. There is no proven antiviral agent to treat Ebola virus disease, although several experimental treatments may be considered. Even in the absence of antiviral therapies, intensive supportive care has the potential to markedly blunt the high case fatality rate reported to date. Optimal treatment requires conscientious correction of fluid and electrolyte losses. Additional management considerations include searching for coinfection or superinfection; treatment of shock (with intravenous fluids and vasoactive agents), acute kidney injury (with renal replacement therapy), and respiratory failure (with invasive mechanical ventilation); provision of nutrition support, pain and anxiety control, and psychosocial support; and the use of strategies to reduce complications of critical illness. Cardiopulmonary resuscitation may be appropriate in certain circumstances, but extracorporeal life support is not advised. Among other ethical issues, patients' medical needs must be carefully weighed against healthcare worker safety and infection control concerns. However, meticulous attention to the use of personal protective equipment and strict adherence to infection control protocols should permit the safe provision of intensive treatment to severely ill patients with Ebola virus disease.

Clinical presentation and management of severe Ebola virus disease.

Pulmonary veno-occlusive disease is a rare condition with limited treatment options. The pathological hallmark of the disease is occlusion of pulmonary venules and small veins in the lobular septa. The etiology of the disease remains obscure. We report and discuss an extremely unusual case presenting as massive and intractable hemoptysis, in which pulmonary venous occlusion was attributed to granulomatous venulitis in the absence of other pulmonary or systemic inflammatory abnormalities.

Massive Intractable Hemoptysis Due to Idiopathic Granulomatous Pulmonary Veno-occlusive Disease

Integrating sepsis management recommendations into clinical care guidelines for district hospitals in resource-limited settings: the necessity to augment new guidelines with future research

B. pseudomallei is a gram-negative bacterium that causes the tropical infection melioidosis. In northeast Thailand, mortality from melioidosis approaches 40%. As exemplified by the lipopolysaccharide-Toll-like receptor 4 interaction, innate immune responses to invading bacteria are precipitated by activation of host pathogen recognition receptors by pathogen associated molecular patterns. Human melioidosis is characterized by up-regulation of pathogen recognition receptors and pro-inflammatory cytokine release. In contrast to many gram-negative pathogens, however, the lipopolysaccharide of B. pseudomallei is considered only weakly inflammatory. We conducted a study in 300 healthy Thai subjects to investigate the ex vivo human blood response to various bacterial pathogen associated molecular patterns, including lipopolysaccharide from several bacteria, and to two heat-killed B. pseudomallei isolates. We measured cytokine levels after stimulation of fresh whole blood with a panel of stimuli. We found that age, sex, and white blood cell count modulate the innate immune response to B. pseudomallei. We further observed that, in comparison to other stimuli, the innate immune response to B. pseudomallei is most highly correlated with the response to lipopolysaccharide. The magnitude of cytokine responses induced by B. pseudomallei lipopolysaccharide was significantly greater than those induced by lipopolysaccharide from Escherichia coli and comparable to many responses induced by lipopolysaccharide from Salmonella minnesota despite lower amounts of lipid A in the B. pseudomallei lipopolysaccharide preparation. In human monocytes stimulated with B. pseudomallei, addition of polymyxin B or a TLR4/MD-2 neutralizing antibody inhibited the majority of TNF-α production. Challenging existing views, our data indicate that the innate immune response to B. pseudomallei in human blood is largely driven by lipopolysaccharide, and that the response to B. pseudomallei lipopolysaccharide in blood is greater than the response to other lipopolysaccharide expressing isolates. Our findings suggest that B. pseudomallei lipopolysaccharide may play a central role in stimulating the host response in melioidosis.

Survey of Innate Immune Responses to Burkholderia pseudomallei in Human Blood Identifies a Central Role for Lipopolysaccharide

Screen of whole blood responses to flagellin identifies TLR5 variation associated with outcome in melioidosis

Faculty Opinions recommendation of CD271(+) bone marrow mesenchymal stem cells may provide a niche for dormant Mycobacterium tuberculosis.

Faculty of 1000 evaluation for Bidirectional Relationship between Cognitive Function and Pneumonia.

Objective:Rigorous evaluation of clinical interventions in the setting of a public health emergency is necessary to identify best practices, to develop clinical management guidelines, and to inform resource allocation. The 2009 influenza A (H1N1) pandemic necessitated care of critically ill patients around the world. To inform the World Health Organization Public Health Research Agenda for Influenza, we conducted a systematic review to identify clinical interventions other than antiviral therapies that would benefit severely ill 2009 H1N1 influenza patients (adults and children) in both high- and low-resource settings. Data Sources:PubMed, EMBASE, Cochrane Central Register of Clinical Trials, and Cochrane Database of Systematic Reviews; hand search of abstracts from six professional society annual conferences and bibliographies of clinical review articles; and personal communication with leaders in the field. Study Selection:English language; human studies; citations added to databases from January 1, 2009 (Cochrane databases) or March 15, 2009 (PubMed and EMBASE) through January 31, 2012; randomized controlled trials, prospective cohort studies, or systematic reviews/meta-analyses of non-antiviral clinical interventions in hospitalized 2009 influenza A (H1N1) patients. Data Extraction:The search identified 2,452 articles. Thirty-six potentially relevant articles were read. Seven articles met criteria. All were observational studies. Data Synthesis:One study found benefit of convalescent plasma infusion, three studies found no benefit of corticosteroids, and three studies had mixed results on the benefit of extracorporeal lung support. No study was applicable to health care delivery in low-resource settings. Conclusions:There is a paucity of high quality clinical research to inform clinical care of severe H1N1 influenza, and we found no beneficial interventions appropriate for low-resource settings. This may be due to the logistical difficulties of conducting clinical research in response to a public health emergency. Our investigation underscores the need for the development of outbreak-ready research capacity in both high- and low-resource settings.

Clinical Research During a Public Health Emergency: A Systematic Review of Severe Pandemic Influenza Management*

Melioidosis is infection caused by the flagellated saprophyte Burkholderia pseudomallei. TLR5 is a pathogen recognition receptor activated by bacterial flagellin. We studied a genetic variant that encodes a defective TLR5 protein, TLR51174C>T, to elucidate the role of TLR5 in melioidosis. We measured NF-κB activation induced by B. pseudomallei in human embryonic kidney–293 cells transfected with TLR5 and found that B. pseudomallei induced TLR51174C- but not TLR51174T-dependent activation of NF-κB. We tested the association of TLR51174C>T with outcome in 600 Thai subjects with melioidosis. In a dominant model, TLR51174C>T was associated with protection against in-hospital death (adjusted odds ratio: 0.20; 95% confidence interval: 0.08–0.50; p = 0.001) and organ failure (adjusted odds ratio: 0.37; 95% confidence interval: 0.19–0.71; p = 0.003). We analyzed blood cytokine production induced by flagellin or heat-killed B. pseudomallei by TLR51174C>T genotype in healthy subjects. Flagellin induced lower monocyte-normalized levels of IL-6, IL-8, TNF-α, IL-10, MCP-1, IL-1ra, G-CSF, and IL-1β in carriers of TLR51174T compared with carriers of TLR51174C. B. pseudomallei induced lower monocyte-normalized levels of IL-10 in carriers of TLR51174T. We conclude that the hypofunctional genetic variant TLR51174C>T is associated with reduced organ failure and improved survival in melioidosis. This conclusion suggests a deleterious immunoregulatory effect of TLR5 that may be mediated by IL-10 and identifies this receptor as a potential therapeutic target in melioidosis.

Impaired TLR5 Functionality Is Associated with Survival in Melioidosis

Faculty of 1000 evaluation for Targeted temperature management at 33°C versus 36°C after cardiac arrest.

A Systematic Review Of Clinical Interventions For Patients With Severe Pandemic Influenza A (H1N1) Virus Infection

Background The Surviving Sepsis Campaign (SSC) guidelines describe best practice for the management of severe sepsis and septic shock in developed countries, but most deaths from sepsis occur where healthcare is not sufficiently resourced to implement them. Our objective was to define the feasibility and basis for modified guidelines in a resource-restricted setting. Methods and Findings We undertook a detailed assessment of sepsis management in a prospective cohort of patients with severe sepsis caused by a single pathogen in a 1,100-bed hospital in lower-middle income Thailand. We compared their management with the SSC guidelines to identify care bundles based on existing capabilities or additional activities that could be undertaken at zero or low cost. We identified 72 patients with severe sepsis or septic shock associated with S. aureus bacteraemia, 38 (53%) of who died within 28 days. One third of patients were treated in intensive care units (ICUs). Numerous interventions described by the SSC guidelines fell within existing capabilities, but their implementation was highly variable. Care available to patients on general wards covered the fundamental principles of sepsis management, including non-invasive patient monitoring, antimicrobial administration and intravenous fluid resuscitation. We described two additive care bundles, one for general wards and the second for ICUs, that if consistently performed would be predicted to improve outcome from severe sepsis. Conclusion It is feasible to implement modified sepsis guidelines that are scaled to resource availability, and that could save lives prior to the publication of international guidelines for developing countries.

Feasibility of Modified Surviving Sepsis Campaign Guidelines in a Resource-Restricted Setting Based on a Cohort Study of Severe S. Aureus Sepsis

Melioidosis is a tropical disease caused by ingestion, percutaneous inoculation or inhalation of the Gram‐negative soil saprophyte Burkholderia pseudomallei. We developed a reproducible experimental murine model of pneumonic melioidosis induced by inhalation of aerosolized B. pseudomallei 1026b. In a series of experiments performed to bracket the lethal dose, we found that C57BL/6 mice were modestly more resistant than BALB/c mice (median lethal dose 334 CFU/lung vs 204 CFU/lung). We further characterized infection and pulmonary inflammation in C57BL/6 mice infected with a sublethal dose. We observed pulmonary replication and dissemination of bacteria to distant organs in the first days after infection, followed by bacterial containment by day 4 and no evidence of recrudescent infection for up to 2 months. We measured a robust host inflammatory response notable for a neutrophilic bronchoalveolar lavage fluid profile, elevated cytokines and chemokines in the lung and serum and scattered foci of neutrophilic infiltrates in the alveoli and in a perivascular distribution on histological analysis. We previously noted a similar pattern of inflammation in mice infected with aerosolized B. thailandensis. This report builds on the limited literature describing experimental murine pneumonic melioidosis induced by aerosol and characterizes pulmonary infection and resultant inflammation in C57BL/6 mice infected with aerosolized B. pseudomallei. This model has utility for the study of bacterial and host factors that contribute to the virulence of melioidosis.

Murine pulmonary infection and inflammation induced by inhalation of Burkholderia pseudomallei

Correction: Feasibility of Modified Surviving Sepsis Campaign Guidelines in a Resource-Restricted Setting Based on a Cohort Study of Severe S. Aureus Sepsis

Faculty Opinions recommendation of Accuracy of rapid influenza diagnostic tests: a meta-analysis.

Faculty Opinions recommendation of Viral infection in patients with severe pneumonia requiring intensive care unit admission.

Management of patients with severe melioidosis in intensive care

Faculty Opinions recommendation of Early-onset pneumonia after cardiac arrest: characteristics, risk factors and influence on prognosis.

Fitting a square peg into a round hole: are the current Surviving Sepsis Campaign guidelines feasible for Africa?

Toll-Like Receptor Pathway Gene Variants And Susceptibility To Melioidosis

Toll-Like Receptor 4 Region Genetic Variants are Associated with Susceptibility to Melioidosis

Faculty Opinions recommendation of Bacteremic community-acquired pneumonia due to Klebsiella pneumoniae: clinical and microbiological characteristics in Taiwan, 2001-2008.

Bacteria that live in the environment have evolved pathways specialized to defend against eukaryotic organisms or other bacteria. In this manuscript, we systematically examined the role of the five type VI secretion systems (T6SSs) of Burkholderia thailandensis (B. thai) in eukaryotic and bacterial cell interactions. Consistent with phylogenetic analyses comparing the distribution of the B. thai T6SSs with well-characterized bacterial and eukaryotic cell-targeting T6SSs, we found that T6SS-5 plays a critical role in the virulence of the organism in a murine melioidosis model, while a strain lacking the other four T6SSs remained as virulent as the wild-type. The function of T6SS-5 appeared to be specialized to the host and not related to an in vivo growth defect, as ΔT6SS-5 was fully virulent in mice lacking MyD88. Next we probed the role of the five systems in interbacterial interactions. From a group of 31 diverse bacteria, we identified several organisms that competed less effectively against wild-type B. thai than a strain lacking T6SS-1 function. Inactivation of T6SS-1 renders B. thai greatly more susceptible to cell contact-induced stasis by Pseudomonas putida, Pseudomonas fluorescens and Serratia proteamaculans—leaving it 100- to 1000-fold less fit than the wild-type in competition experiments with these organisms. Flow cell biofilm assays showed that T6S-dependent interbacterial interactions are likely relevant in the environment. B. thai cells lacking T6SS-1 were rapidly displaced in mixed biofilms with P. putida, whereas wild-type cells persisted and overran the competitor. Our data show that T6SSs within a single organism can have distinct functions in eukaryotic versus bacterial cell interactions. These systems are likely to be a decisive factor in the survival of bacterial cells of one species in intimate association with those of another, such as in polymicrobial communities present both in the environment and in many infections.

Burkholderia Type VI Secretion Systems Have Distinct Roles in Eukaryotic and Bacterial Cell Interactions

Melioidosis is a frequently lethal tropical infection caused by the environmental saprophyte Burkholderia pseudomallei. Although transcutaneous inoculation and inhalation are considered the primary routes of infection, suggestive clinical evidence implicates ingestion as a possible alternative route. We show that in BALB/c and C57BL/6 mice, direct gastric inoculation of high doses of B. pseudomallei causes systemic infection that may be lethal or cause chronic disseminated infection. Mice may shed bacteria in the stool for weeks after infection, and high titers of B. pseudomallei-specific IgG are detectable. This report of enteric murine melioidosis supports further consideration of this route of infection.

Pathogenicity of high-dose enteral inoculation of Burkholderia pseudomallei to mice.

Staphylococcus aureus disease and drug resistance in resource-limited countries in south and east Asia.

Background Most information on invasive Staphylococcus aureus infections comes from temperate countries. There are considerable knowledge gaps in epidemiology, treatment, drug resistance and outcome of invasive S. aureus infection in the tropics. Methods A prospective, observational study of S. aureus bacteraemia was conducted in a 1000-bed regional hospital in northeast Thailand over 1 year. Detailed clinical data were collected and final outcomes determined at 12 weeks, and correlated with antimicrobial susceptibility profiles of infecting isolates. Principal Findings Ninety-eight patients with S. aureus bacteraemia were recruited. The range of clinical manifestations was similar to that reported from temperate countries. The prevalence of endocarditis was 14%. The disease burden was highest at both extremes of age, whilst mortality increased with age. The all-cause mortality rate was 52%, with a mortality attributable to S. aureus of 44%. Methicillin-resistant S. aureus (MRSA) was responsible for 28% of infections, all of which were healthcare-associated. Mortality rates for MRSA and methicillin-susceptible S. aureus (MSSA) were 67% (18/27) and 46% (33/71), respectively (p = 0.11). MRSA isolates were multidrug resistant. Only vancomycin or fusidic acid would be suitable as empirical treatment options for suspected MRSA infection. Conclusions S. aureus is a significant pathogen in northeast Thailand, with comparable clinical manifestations and a similar endocarditis prevalence but higher mortality than industrialised countries. S. aureus bacteraemia is frequently associated with exposure to healthcare settings with MRSA causing a considerable burden of disease. Further studies are required to define setting-specific strategies to reduce mortality from S. aureus bacteraemia, prevent MRSA transmission, and to define the burden of S. aureus disease and emergence of drug resistance throughout the developing world.

Staphylococcus aureus Bacteraemia in a Tropical Setting: Patient Outcome and Impact of Antibiotic Resistance

ABSTRACT Melioidosis is a tropical disease endemic in southeast Asia and northern Australia caused by the gram-negative soil saprophyte Burkholderia pseudomallei. Although infection is often systemic, the lung is frequently involved. B. thailandensis is a closely related organism that at high doses causes lethal pneumonia in mice. We examined the role of Toll-like receptors (TLRs), essential components of innate immunity, in vitro and in vivo during murine B. thailandensis pneumonia. TLR2, TLR4, and TLR5 mediate NF-κB activation by B. thailandensis in transfected HEK293 or CHO cells. In macrophages, TLR4 and the adaptor molecule MyD88, but not TLR2 or TLR5, are required for tumor necrosis factor alpha production induced by B. thailandensis. In low-dose airborne infection, TLR4 is needed for early, but not late, bacterial containment, and MyD88 is essential for control of infection and host survival. TLR2 and TLR5 are not necessary to contain low-dose infection. In high-dose airborne infection, TLR2 deficiency confers a slight survival advantage. Lung and systemic inflammatory responses are induced by low-dose inhaled B. thailandensis independently of individual TLRs or MyD88. These findings suggest that redundancy in TLR signaling or other MyD88-dependent pathways may be important in pneumonic B. thailandensis infection but that MyD88-independent mechanisms of inflammation are also activated. TLR signaling in B. thailandensis infection is substantially comparable to signaling induced by virulent B. pseudomallei. These studies provide additional insights into the host-pathogen interaction in pneumonic Burkholderia infection.

Toll-Like Receptor Signaling in Airborne Burkholderia thailandensis Infection

ABSTRACT Acyl-homoserine lactone (acyl-HSL) quorum-sensing signaling is common to many Proteobacteria. Acyl-HSLs are synthesized by the LuxI family of synthases, and the signal response is mediated by members of the LuxR family of transcriptional regulators. Burkholderia thailandensis is a member of a closely related cluster of three species, including the animal pathogens Burkholderia mallei and Burkholderia pseudomallei. Members of this group have similar luxI and luxR homologs, and these genes contribute to B. pseudomallei and B. mallei virulence. B. thailandensis possesses three pairs of luxI-luxR homologs. One of these pairs, BtaI2-BtaR2, has been shown to produce and respond to 3OHC10-HSL and to control the synthesis of an antibiotic. By using a markerless-exhange method, we constructed an assortment of B. thailandensis quorum-sensing mutants, and we used these mutants to show that BtaI1 is responsible for C8-HSL production and BtaI3 is responsible for 3OHC8-HSL production. We also show that a strain incapable of acyl-HSL production is capable of growth on the same assortment of carbon and nitrogen sources as the wild type. Furthermore, this mutant shows no loss of virulence compared to the wild type in mice. However, the wild type self-aggregates in minimal medium, whereas the quorum-sensing mutant does not. The wild-type aggregation phenotype is recovered by addition of the BtaI1-R1 HSL signal C8-HSL. We propose that the key function of the BtaR1-BtaI1 quorum-sensing system is to cause cells to gather into aggregates once a sufficient population has been established.

Mutational Analysis of Burkholderia thailandensis Quorum Sensing and Self-Aggregation

Inhalation of Burkholderia thailandensis results in lethal necrotizing pneumonia in mice: a surrogate model for pneumonic melioidosis.

Francisella tularensis is a Gram-negative intracellular pathogen that causes the zoonosis tularemia. Because F. tularensis LPS causes weak TLR4 activation, we hypothesized that administration of a synthetic TLR4 agonist, aminoalkyl glucosaminide phosphate (AGP), would boost the innate immune system and compensate for reduced TLR4 stimulation. Intranasal administration of AGPs induced intrapulmonary production of proinflammatory cytokines and chemokines. Mice treated with AGPs before and after inhalation of Francisella novicida exhibited augmented cytokine and inflammatory responses to infection; reduced bacterial replication in lung, liver, and spleen; and increased survival, whereas all PBS-treated control mice died within 4 days of infection, all AGP-treated mice showed prolonged time-to-death, and 30–60% of AGP-treated mice survived. The protective effect of AGP was lost in mice lacking IFN-γ. Long-term survivors developed specific Th1 splenocyte responses and specific Abs dominated by IgG2 isotypes. Survivors were fully protected from rechallenge with aerosolized F. novicida. Thus, preventive administration of AGP successfully modulated innate immune responses to aerosolized F. novicida, leading to protective immunity to pneumonic tularemia. This is the first report of the protective effect of a TLR ligand on resistance to F. novicida-induced pneumonic tularemia.

Administration of a Synthetic TLR4 Agonist Protects Mice from Pneumonic Tularemia1

Inhalation of Francisella novicida Delta mglA causes replicative infection that elicits innate and adaptive responses but is not protective against invasive pneumonic tularemia.

Sharon Peacock and colleagues discuss management of adult patients with sepsis in low- and middle-income settings, with a particular emphasis on tropical regions.

Strategies to Reduce Mortality from Bacterial Sepsis in Adults in Developing Countries

ABSTRACT Burkholderia pseudomallei is a bacterial pathogen that causes a broad spectrum of clinical symptoms collectively known as melioidosis. Since it can be acquired by inhalation and is difficult to eradicate due to its resistance to a wide group of antibiotics and capacity for latency, work with B. pseudomallei requires a biosafety level 3 (BSL-3) containment facility. The bsa (Burkholderia secretion apparatus)-encoded type III secretion system (TTSS) has been shown to be required for its full virulence in a number of animal models. TTSSs are export devices found in a variety of gram-negative bacteria that translocate bacterial effector proteins across host cell membranes into the cytoplasm of host cells. Although the Bsa TTSS has been shown to play an important role in the ability of B. pseudomallei to survive and replicate in mammalian cells, escape from the endocytic vacuole, and spread from cell to cell, little is known about its effectors mediating these functions. Using bioinformatics, we identified homologs of several known TTSS effectors from other bacteria in the B. pseudomallei genome. In addition, we show that orthologs of these putative effectors exist in the genome of B. thailandensis, a closely related bacterium that is rarely pathogenic to humans. By generating a Bsa TTSS mutant B. thailandensis strain, we also demonstrated that the Bsa TTSS has similar functions in the two species. Therefore, we propose B. thailandensis as a useful BSL-1 model system to study the role of the Bsa TTSS during Burkholderia infection of mammalian cells and animals.

Burkholderia thailandensis as a Model System for the Study of the Virulence-Associated Type III Secretion System of Burkholderia pseudomallei

Administration of a Synthetic TLR 4 Agonist Protects Mice from Pneumonic Tularemia 1

Objective. To examine the cost associated with targeted surveillance for methicillin-resistant Staphylococcus aureus (MRSA) and the effect of such surveillance on the rate of nosocomial MRSA infection in a community hospital system. Design. A before-and-after study comparing the rate of MRSA infection before (BES) and after (AES) the initiation of expanded surveillance. Cost-effectiveness was calculated as the difference between the cost savings associated with preventing nosocomial MRSA bacteremias and surgical site infections AES and the cost of MRSA cultures and contact isolation for patients colonized with MRSA. Setting and Participants. Patients in a 400-bed tertiary-care facility (Roper Hospital) and a 180-bed suburban hospital (St. Francis Hospital), both in Charleston, South Carolina. Interventions. Beginning in September 2001, patients were screened for MRSA colonization upon admission to the intensive care unit and weekly thereafter. In July 2002, surveillance was expanded to include targeted screening of patients admitted to general wards who were at risk of MRSA colonization. Colonized patients were placed in contact isolation. Results. The mean rate of nosocomial MRSA infection decreased at Roper (0.76 cases per 1,000 patient-days BES and 0.45 per 1000 patient-days AES; P = .05) and at St. Francis (0.73 cases per 1,000 patient-days BES and 0.57 cases per 1000 patient-days AES; P = .35). Surveillance was cost-effective, preventing 13 nosocomial MRSA bacteremias and 9 surgical site infections, for a savings of $1,545,762. Conclusions. Targeted surveillance for MRSA colonization was cost-effective and provided substantial benefits by reducing the rate of nosocomial MRSA infections in a community hospital system.

Effect of Targeted Surveillance for Control of Methicillin-Resistant Staphylococcus aureus in a Community Hospital System

Enzyme-linked immunosorbent assay for detection of immunoglobulin G and M antibodies to teichoic acid in intravascular staphylococcal disease

The occurrence of markers, the genotypic variety of isolates and the profile of risk factors with respect to viral hepatitis C among 629 employees of the Regional Clinical Hospital (RCH) in Novosibirsk and 1,020 employees of the Central District Hospital (CDH) in Iskitim were studied in a cross-sectional investigation. The occurrence of hepatitis C virus (HCV) markers was 5.1% in RCH and 2.2% in CDH. Among the risk factors in the population under study were: the medical history of blood transfusions (TF) with 0 TF, anti-HCV = 2.3%; 1 TF, = 5.7% > 1 TF, = 13.5% (p < 0.001); general anesthesia (GA) with < or = 2 GA, anti-HCV = 2.8%; > 2 GA, = 7.8% (p = 0.002); surgical interventions (SU) with 0 SU, = 1.9%; > 0 SU, = 4.3% (p = 0.012); the intravenous use of drugs (OR = 31.8); age (< or = 25 years, anti-HCV IgG = 8.6% > 25 years, = 4.5%); the number of partners of the opposite sex < or = 4 partners, = 2.4%; > 4 partners, = 6.9%; p < 0.001). The probable risk factors at a working place (pricks and cuts, contamination of mucous membranes with blood and other biological fluids, etc.) proved to be faintly related with the status of HBV infection. HBV isolates detected in the examined persons (35 examinees) were distributed by genotypes as follows: 60% of subtype 1b, 28.6% of subtype 2a/2c, 11.4% of subtype 3a. HBV of genotype 1a was not detected in the examined specimens, while the detection rate of genotype 2a/2c was considerably greater than in specimens obtained in the European and Asian parts of Russia (according to the data reported earlier).

[Frequency of occurrence of Hepatitis C virus markers and risk factors among hospital personnel in the Novosibirsk region].

Mycobacterium haemophilum was isolated from wrist and ankle aspirates as the organism responsible for tenosynovitis in a patient with acquired immune deficiency syndrome. Mycobacterium isolates recovered from synovial fluid were identified as hemin requiring by their failure to grow on subculture unless the medium was supplemented with hemin. M. haemophilum is of low virulence and rarely associated with infections in humans. This is the first documented case of M. haemophilum infection in a patient with acquired immune deficiency syndrome.

Mycobacterium haemophilum infection in a patient with acquired immune deficiency syndrome

Exopolysaccharides (EXPs) of Staphylococcus aureus are associated with virulence in animal models. An EXP from the S. aureus strain Smith diffuse was previously detected in 64.3% of S. aureus clinical isolates. EXP was isolated from culture supernatants of this strain after DNAase, RNAase, phosphodiesterase I and lysostaphin treatment, and was further purified by cation-exchange and molecular-sieve chromatography. Isoelectric focusing revealed a pI of 3.6 for the EXP while the pI of teichoic acid was less than 2.7. Crossed immunoelectrophoresis with homologous Smith diffuse antisera indicated that the EXP contained two immunological components. A major precipitin line persisted after the antisera had been absorbed with the non-EXP-producing variant strain, Smith compact, while the second component was removed. Tandem immunoelectrophoresis also demonstrated that the EXP was distinct from teichoic acid. The EXP contained 2-amino-2-deoxyglucuronic acid, glucose, mannose and galactose. No fatty acids or nucleic acids were present and total protein content was less than 2%. Teichoic acid could not be demonstrated in the EXP, thus further substantiating the immunological studies. S. aureus EXP isolated by the present method can be used for further serological and virulence studies.

Immunological characterization of an exopolysaccharide from the Staphylococcus aureus strain Smith diffuse.

During 1984, 35 patients undergoing continuous peritoneal dialysis experienced 77 cases of peritonitis with 55 cases (71.4%) related to staphylococci. Coagulase-negative staphylococci were isolated in 41 cases, while Staphylococcus aureus was found in 14. A coexisting tunnel infection was more often associated with S. aureus (7/14) than with coagulase-negative staphylococci (2/41) (P less than 0.01). Likewise, eradication of the infection necessitated catheter removal more frequently with S. aureus (5/14) than with coagulase-negative staphylococci (2/41) (P less than 0.01). Of the 41 coagulase-negative staphylococci, 35 were characterized as to species, adherence, and production of two exopolysaccharides. Staphylococcus epidermidis was the most frequent coagulase-negative species (29/35). Peritonitis cases caused by coagulase-negative staphylococci that lacked adherence and exopolysaccharides were more frequently associated with complications (4/6) than were those organisms with either or both properties of adherence or exopolysaccharide production (5/29). There were no appreciable differences in antibiotic susceptibilities. Staphylococcal peritonitis remains a significant cause of morbidity in continuous peritoneal dialysis patients. The incidence of complications was not directly linked to staphylococcal properties of adherence or exopolysaccharide production.

Staphylococcal peritonitis in patients on continuous peritoneal dialysis

A commercial kit (Cordia-IC) from Cordis Laboratory, Miami, Fla., was compared with the Raji cell radioimmunoassay for its ability to detect circulating immune complexes (CIC) in sera from 30 control subjects and 118 patients with infectious diseases. The 118 patients were categorized into the following groups: (i) 23 patients with bacterial endocarditis, (ii) 41 patients with bacteremia from an infected intravascular catheter or access device, and (iii) 54 patients with Staphylococcus aureus bacteremia related to a deep tissue infection. The Cordia-IC was comparable to the Raji cell radioimmunoassay in intraassay variability (4.0 versus 8.0%) and interassay reproducibility (8.7 versus 20.0%). Neither assay found CIC amounts above 12.5 micrograms equivalents (eq) of aggregated human gamma globulin (AHG) per ml in any of the 30 control individuals. In group 1, Cordia-IC detected 19 of 23 positives (mean, 73.6 micrograms eq of AHG per ml), whereas the Raji cell detected 16 of 23 positives (mean, 54.8 micrograms eq of AHG per ml). In group 2, Cordia-IC detected 19 of 41 positives (mean, 20.6 micrograms eq of AHG per ml), whereas the Raji cell detected 16 of 41 positives (mean, 15.1 micrograms eq of AHG per ml). In group 3, Cordia-IC found 38 of 54 positives (mean, 28.0 micrograms eq of AHG per ml), whereas the Raji cell found 32 of 54 positives (mean, 23.9 micrograms eq of AHG per ml). Statistically, these findings were not significantly different in any of the three patient groups (P> 0.15), and there was an overall good correlation between the results obtained by the two assays (r+0.64, P<0.001). The Cordia-IC provided a suitable assay for the detection of CIC and might find application in routine clinical laboratories.

Evaluation of a Cordia-IC enzyme-linked immunosorbent assay kit for the detection of circulating immune complexes

We used an antiserum agar method to identify clinical Staphylococcus aureus strains producing an exopolysaccharide antigenically identical to the S. aureus Smith diffuse strain. S. aureus blood isolates were obtained from 137 patients, and three additional isolates were obtained from bone debridement. The 140 patients were clinically divided into the following groups: endocarditis (7 patients); pneumonia, empyema, or both (33 patients); intravascular device (34 patients); superficial or wound infection or both (35 patients); deep tissue infections (18 patients); and 6, unknown bacteremias (13 patients). Ninety (64.3%) of the total 140 S. aureus isolates were found to produce precipitin halos on the antiserum agar. The percentage was greatest in the isolates from the endocarditis group (100%) and least in deep tissue infections (55.5%). The presence of clinical S. aureus strains producing exopolysaccharides antigenically identical to the Smith diffuse strain exopolysaccharide appears to be a common phenomenon.

Antiserum agar method for identification of Smith type exopolysaccharides in clinical isolates of Staphylococcus aureus

A 30-year-old bisexual male prisoner with a history of intravenous drug abuse manifested encephalitis. Adenovirus type 2 was isolated from brain tissue obtained by a biopsy and there was a concurrent fourfold rise in the antibody titer. In addition, an initial negative result from a slide test for infectious mononucleosis heterophil antibodies (Monospot) test converted to positive and there was an increase in the IgG antibody titer to Epstein-Barr virus (EBV) viral capsid antigen. Although he was anergic to skin test antigens, T-cell subsets and lymphocyte transformation study results were normal. This case demonstrated a rare adenovirus encephalitis with a simultaneous EBV infection in a patient at risk for acquired immunodeficiency syndrome, who had minimal evidence of T-cell deficiency.

Adenovirus type 2 encephalitis and concurrent Epstein-Barr virus infection in an adult man.

We examined an antiserum agar method to study its reliability in screening Staphylococcus aureus strains for capsule production. The encapsulated S. aureus Smith diffuse strain was compared with its nonencapsulated variant, Smith compact, in CCY medium containing 0.5% NaCl and 5.0% Smith diffuse rabbit antiserum. A halo was visible surrounding colonies of the Smith diffuse strain but not the Smith compact strain. On this same medium, the protein A-producing Cowan I strain possessed a halo that was visible on photographs. Single high-salt medium is known to inhibit protein A production, halo formation by the strains was also compared in 7.5% NaCl medium. The halo surrounding the Cowan I strain was not present when the salt content of the medium was increased. In contrast, the halo surrounding the Smith diffuse strain persisted in the 7.5% NaCl medium. By use of this medium, the antiserum agar technique may be valuable for the identification of encapsulated staphylococci without appreciable interference from protein A.

Detection of encapsulation in Staphylococcus aureus by use of antiserum agar

Detection ofEncapsulation inStaphylococcus aureus byUseof Antiserum Agar

Interferon and interferon inactivators in patients with acquired immune deficiency syndrome and Kaposi's sarcoma. A preliminary report.

An enzyme-linked immunosorbent assay (ELISA) was developed for the detection of rabbit immunoglobulin G (IgG) antibodies to purified cell wall teichoic acids from the Staphylococcus aureus Lafferty strain and three strains of coagulase-negative staphylococci. Significant immunological cross-reactivity occurred only between the teichoic acid of S. aureus and one coagulase-negative preparation. The ELISA was used to determine the serum IgG response to Staphylococcus epidermidis in a rabbit model of aortic valve endocarditis. Blood samples were drawn before inoculation and then every 5 days until death or sacrifice at 32 to 35 days postinoculation. Valve vegetations were culture positive at autopsy in 16 (59%) of the 27 catheterized rabbits. Antibody titers in this culture-positive group and the culture-negative group began to rise as early as day 6. Although both groups demonstrated an antibody response, the culture-positive group attained a significantly higher titer on days 26 and 31. Antibodies also rose in a control group of rabbits without a heart catheter but which were inoculated with bacteria. Again, the antibody titer was significantly less than that for the culture-positive group. This ELISA may be useful for the diagnosis of coagulase-negative staphylococcal infections in humans.

Detection of anti-teichoic acid immunoglobulin G antibodies in experimental Staphylococcus epidermidis endocarditis

A commercial kit from Diagnostica, Inc., Miami Fla., was studied for its ability to detect antibodies to the teichoic acids of Staphylococcus aureus. A comparative study of the Diagnostica counterimmunoelectrophoresis (CIE) system and our gel double-diffusion method was undertaken with 156 serum samples from 142 patients. Included were 25 cases of staphylococcal and non-staphylococcal endocarditis, 30 cases of S. aureus bacteremia, 19 cases of nonbacteremic S. aureus infection, 39 cases of hospitalized patients without a staphylococcal infection, and 29 normal controls. Agreement between methodologies was attained in 138 (88.5%) of the 156 samples tested and in 127 (89.4%) of the 142 patients. Of 13 patients with culture-proven S. aureus endocarditis, significant antibody titers were found in all patients (100%) by CIE and in 12 patients (92.3%) by double diffusion. No significant titers were found in normal sera by CIE, but four sera were positive by double diffusion. Of 80 sera from patients with no evidence of S. aureus infection, 4 (5.0%) were positive by CIE and 7 (8.8%) were positive by double diffusion. The Diagnostica CIE kit appears to provide a suitable means for the detection of deep-seated S. aureus infections.

Evaluation of a commercial counterimmunoelectrophoresis kit for detection of Staphylococcus aureus teichoic acid antibodies

TP93. TP093 NEW DEVELOPMENTS IN DIAGNOSTICS AND TREATMENTS OF PNEUMONIA

Evaluating CURB-65 and Predictors of Mortality Among Patients Hospitalized with Suspected Community-Acquired Pneumonia in Northeastern Thailand

Laparostomy reduces complications of intra-abdominal hypertension and allows for planned relook procedures.[1][1] Temporary abdominal closure techniques have transformed damage control surgery. Mattox described Bogota bags as an early method of temporary abdominal closure where intravenous bags are

Single hem to reduce evisceration following Bogotá bag for damage control surgery: ‘sail technique’

&NA; A 37‐year‐old woman presented with an incarcerated hernia at a previous umbilical laparoscopic port site. This was found to contain an ischaemic appendix, which was managed successfully with open appendicectomy and a mesh repair. Previous imaging from a year prior to these events demonstrated a degree of intestinal malrotation with the caecal pole lying just under the umbilicus. Finding the appendix within an incisional port site is very rare, for this to occur at the umbilicus is unique.

Appendicitis due to incarceration within a laparoscopic umbilical port‐site hernia secondary to a degree of intestinal malrotation

An intussuscepting colonic lipoma causing prolapse of the sigmoid colon in an adult.

The spectral theory of compact monothetic semigroups of linear operators examined by Kaashoek and West in [1], [2] together with two block matrix theorems where the blocks are either strictly positive or zero are used to give an exposition of Perron-Frobenius theory of positive matrices. The approach in this paper is based on ideas of Smyth and West developed in [4], [5]. We consider a linear operator T in finite dimensions which has a matrix representation [T] relative to a given basis. Where there is no ambiguity we often write the matrix as T. T ≥ 0 if [T] ij ≥ 0 (∀ i,j) while T > 0 if [T] ij > 0 (∀ i,j). The spectrum and spectral radius of T will be denoted by σ(T) and r(T) respectively. The trace of T (the sum of its eigenvalues) will be written as tr(T), and the peripheral spectrum will be denoted by π(T) = {λ ∈ σ(T); |λ| = r(T)}. The i th row and j th column of T relative to the given basis will be written row i (T) and col j (T) and the diagonal of T will be denoted diag(T). The spectral projection of T relative to π(T) will be written P π. Smyth [5] has introduced a hierarchy of subsets of matrices T ≥ 0. Definitions. (i) T is positive if T > 0; (ii) T is primitive if T k > 0 for some positive integer k; (iii) T is connected if ∀ i,j ∃ a positive integer k such that [T k ] ij > 0; (iv) T is potent if diag(T k) > 0 for some positive integer k; (v) T is zero-free if no row or column is zero; (vi) T has positive spectral radius.

Averaging theorems for linear operators in compact groups and semigroups

Let X denote a Banach space over the complex field ℂ and let B(X) be the Banach algebra of all bounded linear operators on X. If T ε B(X), we write n(T) = dim ker (T) and d(T) = codim T(X). Suppose that Y is a subspace invariant under T; then TY will denote the restriction of T to Y and Y the operator on X/Y defined by Y: x/Y →(Tx)/Y

Continuity of the generalized kernel and range of semi-Fredholm operators

A. F. Ruston, Fredholm theory in Banach spaces (Cambridge Tracts in Mathematics 86, Cambridge University Press, 1986), x + 293 pp. £30.

Report on the Dublin matrix theory conference, March 1984: Barnes and support idempotents

INTRODUCTION TO LINEAR OPERATOR THEORY (Pure & Applied Mathematics: A Series of Monographs & Textbooks, 65)

Let H be a Hilbert space and let B denote the Banach algebra of all bounded linear operators on H with K denoting the closed ideal of compact operators in B. If T ∈ B, σ(T) and r(T) will denote the spectrum and spectral radius of T, respectively, and π the canonical mapping of B onto the Calkin algebra B/K.

If A is a complex Banach algebra (not necessarily unital) and x∈A, σ(x) will denote the spectrum and spectral radius of x in A. If I is a closed two-sided ideal in A let x + I denote the coset in the quotient algebra A/I containing x. Then

It is shown that the weakly closed algebra generated by a weakly compact group of operators on a Banach space is reflexive and equals its second commutant. Also, an example is given to show that the generator of a monothetic weakly compact group of operators need not have a logarithm in the algebra of all bounded linear operators on the underlying space. Let X be a complex Banach space, B(X) the algebra of all bounded linear operators on X, and I the identity operator on X. By a group in B(X) we shall mean a multiplicative group with unit I. The weak operator topology on B(X) is denoted by the letter w. Given a nonempty subset & of B(X), &' and &' denote the first and second commutants of fe, and A(ë) is the 222-closed subalgebra of B(X) generated by ë and I. The lattice of all ©-invariant closed subspaces of X is denoted by Lat fe, and Alg Lat g = ÍT £ B(X): T(L) C L (L e Lat &)]. A subalgebra A of B(X) is reflexive if Alg Lat A = A. It is clear that reflexive algebras are 222-closed and contain I. Finally, C, R, Z and T are the complex numbers, the reals, the integers and the unit circle. We present several results concerning 2f-compact groups in B(X). Such groups come within the general framework discussed by de Leeuw in [1], where the underlying space is called a G-space. The monothetic (singly generated) case has been considered in [4], [5], where an operator in B(X) generating a i^-compact group (with unit I) is called a G-operator. It was shown in [4] that, if ^¡ is a monothetic nv-compact group, then A(§) is reflexive and (-/' = A(C¿). In fact the methods developed there and in [5] can be extended to prove Theorem 1. Let § be an abelian w-compact group in B(X) (with unit I). Then A(§) is reflexive and §" = A(§). Received by the editors February 4, 1974. AUS (UOS) subject classifications (1970). Primary 47D10, 47A15, 46L20; Secondary 43A22, 43A05. Copyright © 1975, American Mathematical Society 78 License or copyright restrictions may apply to redistribution; see https://www.ams.org/journal-terms-of-use WEAKLY COMPACT GROUPS OF OPERATORS 79 Problem A. Does Theorem 1 remain valid if the hypothesis that § be abelian is omitted? G-operators have occurred in the work of Ljubic [8], where a study is made of the spectral properties of an operator S e B(X) satisfying ||exp (i r S)\\ < M (r £ R) and a certain almost-periodic condition. (The space X is taken to be weakly sequentially complete.) It is shown that each such S has a total set of eigenvectors corresponding to real eigenvalues, from which it is easily seen (via [4, Theorem 1.2]) that exp (iS) is a G-operator. Problem ß. Can every G-operator be written as exp (iS) fot some bounded S? Solution A. Theorem 1 does indeed extend to the nonabelian case and we sketch the main ideas of the proof. Let § be a i^-compact group in B(X). Lemma 2 [2, Theorem 8.1]. X is the closed linear span of finite dimen sional \yinvariant subspaces. An easy consequence of this is the following description of Lat y (cf. Corollary 1.4 of [4]). Lemma 3. Each subspace in Lat \¡ is spanned by finite dimensional y -irreducible subspaces. Write X(n) for the direct sum of n copies of X and T(n) e B(X(n>) for the 72th direct sum of T. Putting §'"^ = [T^: T e §!, it is easy to see that §("' is a »-compact group in B(X(n)) with unit I^n\ Lemma 4. Let S e Alg Lat §. Then S(n) e Alg Lat §(n) for n = 1, 2, • • •. This is the key result and we sketch its proof. A straightforward argument reduces the proof to the case n = 2. It is then sufficient, by Lemma 3, to show that each finite dimensional §^ '-irreducible subspace M of X^ is 5^ '-invariant. Using irreducibility, this is easily done in the case when M contains (0, x) for some x 4 0. Suppose therefore that M contains no elements of this form. Then there is a finite dimensional subspace N of X and a linear operator U: N — X such that M = \(x, Ux): x e N\. The hypotheses on M imply that N and UN belong to Lat § and that (UT TU)(N) = |0! (T e §). Also, N is §-irreducible and thus either (i) U(N) = N, or (ii) U(N)nN = io!. License or copyright restrictions may apply to redistribution; see https://www.ams.org/journal-terms-of-use 80 T. A. GILLESPIE AND T. T. WEST In case (i), U commutes with the irreducible set of operators §|/V on N. Hence U is a scalar, from which it follows that M e Lat .V '. In case (ii), the subspace L (I + U)N is )-¡and hence S-invariant. Therefore, given x e N, there exists y e N such that Sx y = SUx + Uy. The lefthand side of this equation is in N and the right in U(N), since N and U(N) ate 5-invariant. Therefore both sides are zero, giving SUx USx (x e N), and hence M e Lat S^h A standard argument (cf. [9, Lemma 1]) now gives Theorem 5. A(§) is reflexive. Given A = [a..] 6 m (C), the n x n complex matrices, and x = (x ,. . . , x ) e X^"\ let Ax denote the element y = (y .. . , y ) in X(n) defined by y . = 2" ,<2. x.. Let M be a finite dimensional 6-invariant subspace of X 'r; = l27 7 " r with basis \u,,---,u \. Given T e Q, let T22. = X" ,<x..(T)a.. 1' '72 °" 2 ; =1 2jv ; Lemma 6. TAe map a: T—> a(T) = [a..(T)] is an anti-representation of §^în„(C). Define the operator P in B(X(n)) by Px= f a(T-1)T(")X22'7, where dT denotes Haar measure on ^. P is a projection, but this fact is not needed here. What is needed is the following result, which is easily verified using Lemma 6. Lemma 7. PT(n)x = Pa(T)x for T e§ and x £ X(n). Defining u in X'"* by u m. («.,..., u ), we have T^u = a(T)u for each T £ §. Therefore, from the definition of P, Pu = u. Since u 4 0, it follows that ker P is strictly smaller than X^nK Thus, if X* is the dual space of X, there exists f = (/ . .. , / ) e X*(n) with f 4 0 such that f annihilates ker P (making the obvious identification of the dual space of X<"> with X*(n)). Put 77 F= Y f. ®u.. *—i ' 1 1 2 = 1 Then F 4 0. Using the fact that T(n)x a(T)x belongs to ker P for every leSj and x £ X^"\ a routine calculation gives Lemma 8. F e §'. Lemma 9. Let M be ^-irreducible and let S e §". Then M e Lat 5. License or copyright restrictions may apply to redistribution; see https://www.ams.org/journal-terms-of-use WEAKLY COMPACT GROUPS OF OPERATORS 81 To see this observe that F and S commute. Further \0\ 4 F(X) C M, and since F £ §', F(X) is ^-invariant. By irreducibility F(X) = M; but then S(M) = SF(X) = FS(X) C M. Using reflexivity, Lemmas 9 and 3 give )-¡" C Á((j). Since the reverse inclusion always holds, we have thus proved Theorem 10. §" = A(§). Solution B. We give an example of a G-operator on a weakly sequentially complete space which is not of the form exp(iS) with S bounded. This example depends on some general facts about logarithms of point measures. Let G be a LCAG and let M(G) be the commutative Banach algebra of bounded regular complex measures on G under convolution. Given x e G, we show that the point mass 8 has a logarithm in M(G) if, and only if, x is of finite order in G. The "if" proof follows from elementary spectral theory. For the converse, let MAG) be the Banach algebra of discrete measures on G. Lemma 11. If a discrete measure ß on G has a logarithm in M(G), then fi has a logarithm in MAG). This follows from the fact that if ß = exp v for some v £ M(G), then ß = exp vd where vd is the discrete part of v. Lemma 12. Let 8 = exp v in M(G). Then x is of finite order in G. By Lemma 11 we may (and do) assume that G is discrete. Then the maximal ideal space of M(G) is the compact group G dual to G. The proof can be completed by the following simple argument due to Gavin Brown. Taking Gelfand transforms in the equation 8 = exp v, we obtain x(y) = 8x(\) = exp ¿(y) (x e G), where, without loss of generality, viX\) = 0 f°r Xi tne unlt °^ G. Since x is a character on G, it follows that iXx<A) = i%x) + ̂ "A) + 2mN{x, <A) (x> ft e G) where N: G x G—>Z is continuous. Let H be the connected component containing Xl in G. Then 2mN(-^, ifj) =-j/(y,) = 0 on H. Hence v\yn) = nv(X) (y £ H, n £ Z). The boundedness of the continuous function v on the compact group H License or copyright restrictions may apply to redistribution; see https://www.ams.org/journal-terms-of-use 82 T. A. GILLESPIE AND T. T. WEST gives ¿(y) = O (y e H). Hence x(y) =1 (-y e H) and so x is of finite order in G [6, 24.20]. We can now give the counterexample for Problem B. Let R be the translation operator on L (T) defined by (Rj)(t) = f(tco-1) if e lHT), t a.e.), where co £ T and arg co is an irrational multiple of 227. R is a G-operator on L (T) [4, Example 5.4] and L (T) is weakly sequentially complete [3, IV. 8.6]. Theorem 13. R does not have a logarithm in B(L (T)). For suppose R = exp S in B(L (T)). Since the powers of co are dense in T, it follows that S commutes with every translation R (t e T). Hence S is a multiplier on L (T) and there exists p. £ M(T) such that Sf = ¡i * f (f £ Ll(T)) [7, Theorem 0.1.1]. Therefore 8a*f~*J-b*PI* */ (/ei-HT)) and so 5 = exp p.. Lemma 12 gives the required contradiction. REFERENCES 1. K. de Leeuw, Linear spaces with a compact group of operators, Illinois J. Math. 2 (1958), 367-377. MR 21 #8192. K. de Leeuw and I. Glicksberg, Applications of almost periodic compactifications, Acta Math. 105 (1961), 63-97. MR 24 #A1632. 3. N. Dunford and J. T. Schwartz, Linear operators. I: General theory, Pure and Appl. Math., vol. 7, Interscience, New York, 1958. MR 22 #8302. 4. T. A. Gillespie and T. T. West, Operators generating weakly compact groups, Indiana Univ. Math. J. 21 (1972), 671-688. 5. -, Operators generating weakly compact groups. II, Proc. Royal Irish Acad. 73A (1973), 309-326. 6. E. Hewitt and K. A. Ross, Abstract harmonic analysis. Vol. 1: Structure of topological groups. Integration theory, group representations, Die Grundlehren der math. Wissenschaften, Band 115, Academic Press, New York; Springer-Verlag, Berlin, 1963. MR 28 #158. 7. R. Larsen, An introduction to the theory of multipliers, Die Grundlehren der math. Wissenschaften, Band 175, Springer-Verlag, Berlin, 1971. 8. Ju. I. Ljubic, A

Locally Compact Semi-algebras: with Applications to Spectral Theory of Positive Operators

Bonsall and Tomiuk have shown, in (3), the connection between the local compactness of a monothetic semi-algebra and the spectral properties of a generating element. This theme was developed, in (4), to give a complete characterisation of prime, strict locally compact monothetic semi-algebras in terms of the spectrum of a generator (Theorem A). Here we extend this result to the case of a semi-simple locally compact monothetic semi-algebra (Theorem B).

A monothetic semigroup is a topological semigroup with jointly continuous multiplication which contains a dense cyclic subsemigroup. These semi-groups arise in a natural way in the study of semi-algebras. In (4) we showed that a compact monothetic semigroup in a Banach algebra can be characterized in terms of the spectral properties of a generating element. In this paper these spectral theorems are linked with the well-known structure theory of compact semigroups.

A Riesz operator is a bounded linear operator on a Banach space which possesses a Riesz spectral theory. These operators have been studied in [5] and [6]. In §2 of this paper we characterise Riesz operators in terms of their resolvent operators. In [6] it was shown that every Riesz operator on a Hilbert space can be decomposed into the sum of compact and quasi-nilpotent parts. §3 contains an example to show that these parts cannot, in general, be chosen to commute. In §4 the eigenset of a Riesz operator is defined. It is a sequence of quadruples each of which consists of an eigenvalue, the corresponding spectral projection, index and nilpotent part. This sequence satisfies certain obvious conditions, and the question arises of the existence of a Riesz operator which has such a sequence as its eigenset. We give an example of an eigenset which has no corresponding Riesz operator.

A model of a growing steady-state systme with a changing surface-volume ratio.

Let X be an infinite dimensional normed linear space over the complex field Z. X will not be complete, in general, and its completion will be denoted by . If ℬ(X) is the algebra of all bounded linear operators in X then T ∈ ℬ(X) has a unique extension and . The resolvent set of T ∈ ℬ(X) is defined to be and the spectrum of T is the complement of ρ(T) in Z.

In [2] a condition, originally due to Olagunju, was given for the spectra of certain compact operators to be on the real axis of the complex plane. Here, by using conformal mappings, this result is extended to more general curves. The problem divides naturally into two cases depending on whether or not the curve under consideration passes through the origin. Discussion is confined to the prototype curves C0 and C1. The case of C0, the unit circle of centre the origin, is considered in § 3; this problem is a simple one as the spectrum is a finite set. In § 4 results are given for C1 the unit circle of centre the point 1, and some results on ideals of compact operators, given in § 2, are needed. No attempt has been made to state results in complete generality (see [2]); this paper is kept within the framework of Hilbert space, and particularly simple conditions may be given if the operators are normal.

J. L. Kelley, I. Namioka and others, Linear Topological Spaces (University Series in Higher Mathematics, D. van Nostrand Co. Ltd., 1963)

1. Notation and definitions. In this paper necessary and sufficient conditions are found for the spectrum of a Fredholm operator in a locally convex space (always taken to be Hausdorff) to lie on the non-negative real axis of the complex plane. Some results of Grothendieck(2) allow us to obtain the results in this general form; an interesting special case is the trace-class of operators in a general Banach space. We also deal with the case of Hilbert–Schmidt operators in a Hilbert space.

Time to Care: Analysis of Time Differences and Outcomes in the Management of Pediatric Traumatic Brain Injury for a High Income and Lower-Middle Income Country.

The lungs have three main fissures: the right oblique fissure (ROF), right horizontal fissure (RHF), and left oblique fissure (LOF). These can be complete, incomplete or absent; quantifying the degree of completeness of these fissures is novel. Standard textbooks often refer to the fissures as complete, but awareness of variation is essential in thoracic surgery.

Are textbook lungs really normal? A cadaveric study on the anatomical and clinical importance of variations in the major lung fissures, and the incomplete right horizontal fissure

Introduction Haemorrhage is the major cause of early mortality following traumatic injury. Patients suffering from non-compressible torso haemorrhage are more likely to suffer early death. Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) can be effective in initial resuscitation; however, establishing swift arterial access is challenging, particularly in a severe shock. This is made more difficult by anatomical variability of the femoral vessels. Methods The femoral vessels were characterised in 81 cadaveric lower limbs, measuring specifically the distance from the inferior border of the inguinal ligament to the distal part of the origin of the profunda femoris artery (PFA), and from the distal part of the origin of the PFA to where the femoral vein lies posterior to and is completely overlapped by the femoral artery. Results The femoral vein lay deep to the femoral artery at a mean distance of 105 mm from the inferior border of the inguinal ligament. The PFA arose from the femoral artery at a mean distance of 51.1 mm from the inguinal ligament. From the results, it is predicted that the PFA originates from the common femoral artery approximately 24 mm from the inguinal ligament, and the femoral vein is completely overlapped by the femoral artery by 67.7 mm distal from the inguinal ligament, in 95% of subjects. Conclusions Based on the results, proposed is an ‘optimal access window’ of up to 24 mm inferior to the inguinal ligament for common femoral arterial catheterisation for pre-hospital REBOA, or more simply within one finger breadth.

The REBOA window: a cadaveric study delineating the optimum site for austere cannulation of the femoral artery for resuscitative endovascular balloon occlusion of the aorta

We recently provided training in the Human Dissection Room at the University of Cambridge for reservist combat medical technicians (CMTs) with a particular emphasis on improving their resilience when exposed to battlefield trauma.

Reservist medical units include individuals who receive training as

Exercise serpent anatomy: cadaveric trauma simulation training to improve the resilience of reservist combat medical technicians

Exercise Serpent Anatomy - Cadaveric Trauma Simulation for Reservist Combat Medical Technicians

In this study, 82 forearms from 41 cadavers were dissected to establish the incidence of variant additional radial wrist extensors. Three variants have been described in the literature: extensor carpi radialis intermedius (ECRI), extensor carpi radialis accessorius (ECRA) and extensor carpi radialis tertius (ECRT).

Of the 41 cadavers studied, 5/41 (12%) had an additional radial wrist extensor. Of these 5 individuals, 2 had bilateral additional muscles and 3 were unilateral. Of the 82 forearms, 7/82 (9%) had additional radial wrist extensors.

RESULTS
We found 4 examples of ECRI and 3 examples of ECRA. We did not find any examples of ECRT. One specimen of ECRA had an atypical, previously undescribed, course.

These accessory muscles are of clinical relevance, as they may be a contributing factor in tennis elbow and nerve entrapment, or cause diagnostic confusion, especially in ultrasound scans. However, they may also be used for tendon transfer. Of the 7 muscles found in the current study, 3 would have been suitable for such procedures.

An anatomical study of additional radial wrist extensors including a unique extensor carpi radialis accessorius.

The carotid sinus (CS) is a dilatation in the carotid bifurcation usually at the origin of proximal internal carotid artery (ICA). It contains baroreceptors which influence blood pressure. Variations in the location of the CS are of importance as atheromatous plaque commonly forms in this area and procedures such as carotid endarterectomy are performed to reduce the risk of stroke. Inadvertent stimulation of the CS baroreceptors during interventions can have profound effects on the patient's haemodynamic status both intra- and postoperatively, causing serious complications. The aim of this study is to determine the inter- and intra-individual variations in the location of the CS.

Eighty-two carotid arteries were dissected bilaterally from 41 cadavers. The locations of the CS were noted and divided into four potential sites.

RESULTS
The commonest site is the origin of the ICA (74.3%), but the CS can also be found in the distal part of the common carotid artery (CCA) inferior to the bifurcation (17.1%); at the bifurcation involving the distal CCA and origins of both the external carotid artery (ECA) and ICA (7.32%); and at the origin of the ECA (1.22%). In individual cadavers, the CS was located at the origin of the ICA in 97.6% on at least one side. The sites of the CS were asymmetrical in 34.1%.

Clinicians performing carotid interventions should be aware of these anatomical variations to avoid inadvertent stimulation of the CS which can cause profound bradycardia and hypotension.

Variations in carotid sinus anatomy and their relevance to carotid interventions.

IntroduconDiaries spanning three decades (1943-1964) have been discovered that tell the story of the life of missionary nurses, doctors and surgeons working at the Lui and Leer Hospitals in South Sudan (then known as Southern Sudan). The medical facility at Leer during this period covered a 300 miles radius serving approximately 60,000 of the Nilotic Western Nuer tribe [1]. It was among these records that the following case description was found. The puff adder (Bitis arietans) is one of the commonest African snakes, causing more bites in animals and humans than all other species of snake put together in sub-Saharan regions. It commonly inhabits the banks of the Nile [2]. The venom of the puff adder causes speciﬁc cytotoxic, ﬁbrinolytic, platelet-inhibiting, pro-thrombotic, vasodilating, cardiodepressant, and neurotoxic effects [3-8]. When envenomation occurs in a human tissue necrosis, coagulopathy, hypotension, thrombocytopenia and spontaneous bleeding have all been reported [9].

Medicine in the 1950s in South Sudan: amputation for a puff adder (Bitis arietans) envenomation in a child - 1954.

Politics and Power in Early Medieval Europe: Alsace and the Frankish Realm, 600–1000 - by Hans Hummer

Inventing the Pasts in North Central Europe: The National Perception of Early Medieval History and Archaeology by Matthias Hardt, Christian Lübke and Dittmar Schorkowitz

Decision Making Under Uncertainty: A New Approach to Decision Making in a Multi-Model Environment

Application of the Discrimination Inference to Reduce Expected Cost Technique (DIRECT) to a Contaminant Transport Problem.

Measurement selection for groundwater-surface water investigations using Discrimination-Inference to Reduce Expected Cost Technique (DIRECT)

The Water Erosion Prediction Project Climate Assessment Tool (WEPPCAT) was developed to be an easy-to-use, web-based erosion model that allows users to adjust climate inputs for user-specified climate scenarios. WEPPCAT allows the user to modify monthly mean climate parameters, including maximum and minimum temperatures, number of wet days, precipitation, and precipitation intensity (change in heavy precipitation events) in order to assess changes in surface runoff and soil erosion. In addition, the model allows the user to assess the impacts of a variety of land management alternatives including riparian filter strips. An important aspect of the tool is that databases for the model are pre-constructed; therefore, it does not require specialized scientific expertise to run, and scenarios are quick and easy to set up. This paper presents the conceptual and technical basis for WEPPCAT, and an example application is given for sediment delivery on a transect running north-south from Minnesota to Louisiana under several climate change scenarios.

WEPPCAT: The Effects of Changing Precipitation Regimes on Erosion in the Black Earth Creek Watershed

Combined text and relational database support is increasingly recognized as an emerging need of industry spanning applications requiring text elds as parts of their data e g for customer support to those augmenting primary text resources by conventional relational data e g for publication control In this paper we propose extensions to SQL that provide exible and e cient access to structured text described by SGML or other encodings We also propose an architecture to support a text relational database management system as a federated database environment where component databases are accessed via agents SQL agents that translate standard or extended SQL queries into vendor speci c dialects and text agents that process text sub queries on full text search engines Also available via anonymous ftp from site cs archive uwaterloo ca directory cs archive CS le CS ps Z and via the World Wide Web from page http bluebox uwaterloo ca OED trdbms html Supercedes earlier version published in Proceedings of the ADB Conference

Text/Relational Database Management Systems: Overview and Proposed SQL Extensions

Text / Relational Database Management Systems: Harmonizing SQL and SGML

Let s = (s 1 ; s 2 ; : : : ; s n) be a sequence of characters where s i 2 Z p for 1 i n. One measure of the complexity of the sequence s is the length of the shortest feedback shift register that will generate s, which is known as the maximum order complexity of s 17, 18]. We provide a proof that the expected length of the shortest feedback register to generate a sequence of length n is less than 2 log p n + o(1), and also give several other statistics of interest for distinguishing random strings. The proof is based on relating the maximum order complexity to a data structure known as a suux tree.

We survey two indices for text, with emphasis on Pat arrays (also called suux arrays). A Pat array is an index based on a new model of text which does not use the concept of word and does not need to know the structure of the text.

This paper describes work underway to develop an integrated research support system designed to link together into a unified system a generalized DBMS, a relational database query system, statistical packages, a graphics system, text editors and a generalized screen oriented output handler.The work is being carried out on the under Hewlett Packard HP9000 32 bit micro computer system under HP-UX; HP's implementation of the UNIX operating system. The intent of the project is to provide a unified environment designed specifically for the researcher.

An Integrated Research Support System for Inter-Package Communication and Handling Large Volume Output From Statistical Database Analysis Operations

Background: Radioiodine therapy (RAI) is commonly used as a definitive treatment for hyperthyroidism. However there is no agreement on the regime or the dose of RAI used and success rate is quite variable. In addition, the literature on the factors governing the success of the initial dose is conflicting. Objective: We have adopted a standard 550 MBq dose for all patients with hyperthyroidism. The aims of our study were (1) to assess the success rate of this regime in terms of cure of hyperthyroidism and (2) to evaluate the role of pre-treatment factors including age, gender, use of antithyroid medication prior to RAI, aetiology of hyperthyroidism and free thyroxine levels at diagnosis, as predictors of response to RAI. Patients and methods: The study is a retrospective analysis of 584 patients treated at this centre over a 14 year period. All patients received a fixed 550MBq dose following withdrawal of antithyroid medication for 7 days. Repeat dose was administered if patients remained hyperthyroid at the end of one year after the initial dose. Success rate in terms of cure of hyperthyroidism was calculated. The association of pre-treatment factors and failure to respond to the first dose of RAI was studied using univariate and multivariate analyses. Results: Mean age was 56 years (range 20-90 years) with female preponderance (82%). Of the 478 patients in whom the aetiology could be ascertained by the criteria used, 344(72%) patients had Graves’ disease and 134(28%) patientshad toxic nodular disease. At the end of one year 545(93%) patients were either hypothyroid (411(70%)) or euthyroid (134(23%)) and were considered to be cured, while 39(7%) patients remained hyperthyroid and required further doses of RAI. Free thyroxine level at the time of diagnosis was the only pre-treatment factor, which independently influenced post-RAI outcome and a higher free thyroxine level predicted a lower cure rate. Conclusion: A standard 550MBq dose of RAI has a low failure rate when used for the treatment of hyperthyroidism. In our experience, only high free thyroxine levels at diagnosis was associated with a lower cure rate.

Efficacy of Fixed High Dose Radioiodine Therapy for Hyperthyroidism - a 14 year Experience: A focus on Influence of Pre-treatment Factors on Outcomes

We describe an unusual cause of severe hypoglycaemia, secondary to hypopituitarism as a result of antepartum pituitary failure, in a pregnant patient with type 1 diabetes mellitus (T1DM). Antepartum pituitary failure is a very rare condition, which has been reported only in a very small number of pregnant patients with diabetes and presents with an acute onset headache and a sub-arachnoid haemorrhage-like picture. It is a potentially fatal condition to the mother and the child if not recognised and treated. Our case report highlights the importance of thinking about hypopituitarism, as a cause of recurrent hypoglycaemia in pregnant patients with T1DM as missing the diagnosis could be fatal to the mother and child.

Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association

An unusual cause of severe hypoglycaemia in type 1 diabetes mellitus. Antepartum pituitary failure: a case report and literature review.

Hormonal and metabolic effects of chlorpropamide, glibenclamide and placebo in a cross-over study in diabetics not controlled by diet alone

Answers on 666. 

In August 1993, a 42 year old woman presented for definitive treatment of hyperthyroidism secondary to Graves’ disease. In 1970 she had undergone subtotal thyroidectomy for the first episode of hyperthyroidism but after a recurrence in 1977, she had been …

Influence of pre-treatment factors on outcomes following the use of high fixed dose radioiodine treatment for hyperthyroidism

Acute lower respiratory infections (ALRI) are the main cause of death in young children worldwide. We report here the results of a study to determine the long-term survival of children admitted to hospital with severe pneumonia. The study was conducted on 190 Gambian children admitted to hospital in 1992-94 for ALRI who survived to discharge. Of these, 83 children were hypoxaemic and were treated with oxygen, and 107 were not. On follow-up in 1996-97, 62% were traced. Of the children with hypoxaemia, 8 had died, compared with 4 of those without. The mortality rates were 4.8 and, 2.2 deaths per 100 child-years of follow-up for hypoxaemic and non-hypoxaemic children, respectively (P = 0.2). Mortality was higher for children who had been malnourished (Z-score < -2) when seen in hospital (rate ratio = 3.2; 95% confidence interval (CI) = 1.03-10.29; P = 0.045). Children with younger siblings experienced less frequent subsequent respiratory infections (rate ratio for further hospitalization with respiratory illness = 0.15; 95% CI = 0.04-0.50; P = 0.002). Children in Gambia who survive hospital admission with hypoxaemic pneumonia have a good prognosis. Survival depends more on nutritional status than on having been hypoxaemic. Investment in oxygen therapy appears justified, and efforts should be made to improve nutrition in malnourished children with pneumonia.

Long-term morbidity and mortality following hypoxaemic lower respiratory tract infection in Gambian children.

The classical cause of postpartum hypopituitarism is Sheehan's syndrome, in which an obstetric catastrophe is associated with hypotension. However, with improvements in obstetric care, the most common cause now may be lymphocytic hypophysitis. Five women with postpartum hypopituitarism, whose symptoms occurred during or immediately after pregnancy, had detailed endocrine and pituitary imaging for the duration of follow-up. Two presented with visual symptoms, and three with non-specific illnesses related to varying deficiencies of anterior pituitary hormones. Four were unable to lactate, and four were initially amenorrhoeic. Initially, four of the five women had enlarged pituitary glands on magnetic resonance imaging. Four have to some extent recovered pituitary function. One patient had associated thyroiditis: in two cases antinuclear antibodies became positive during follow-up, and in one of these dsDNA antibody was also detected. In no case were pituitary antibodies detected. None had complicated pregnancies or deliveries, and the two who had caesarean sections had no episodes of hypotension. The presentation of secondary hypothyroidism combined with ACTH deficiency in four of the five women strongly suggests lymphocytic hypophysitis. This diagnosis should be considered in postpartum women with general malaise and persistent amenorrhoea, as well as in women who develop visual impairment in the last trimester of pregnancy without antecedent pituitary disease. A conservative policy of management of the pituitary enlargement should be pursued as this resolves.

An increasing number of AIDS patients have been noted to suffer severe recurrent aphthous stomatitis (RAS), a condition often associated with high morbidity that remains unresponsive to conventional therapeutic interventions. In two cases thalidomide was administered to successfully treat AIDS patients with RAS. Both patients experienced complete abatement of pain shortly after therapy was initiated. Ulcerations that were present for months resolved after three or four weeks of thalidomide therapy without any adverse effects. Thalidomide appears to be an effective agent for the treatment of severe RAS unresponsive to traditional therapies.

Thalidomide: Treatment of Severe Recurrent Aphthous Stomatitis in Patients with Aids

A 34‐year‐old male prisoner with a history of intravenous drug abuse presented with fever, lymphadenopathy, weight loss, and recent onset of congestive heart failure. Serologic testing was positive for antibodies to human immune deficiency virus. There was intense myocardial uptake of gallium. Autopsy showed a primary immunoblastic lymphoma involving only the myocardium. While primary cardiac lymphoma is an extremely rare condition, the incidence may be higher in patients with acquired immune deficiency syndrome (AIDS) and should be suspected in cases with atypical cardiomyopathy.

Primary cardiac lymphoma in a patient with acquired immune deficiency syndrome

Three cases of anaerobic abdominal abscesses showing poor uptake on Ga-67 scintiscans are presented. The significance of this and possible mechanisms for it are discussed.

The significance of the “hot spot” medial to the gallbladder fossa on a technetium99m sulphur colloid (99TcmSc) liver scan is well documented in the literature (Lee et al., 1976). Among the many different causes of intrahepatic “hot spots” not confined to a specific location are: abscess (Chayes et al., 1974), haemangioma (Volpe and Johnston,1970), focal nodular hyperplasia, hepatic adenoma (Salvo et al., 1977), and hepatic vein thrombosis (Meindok and Langer, 1976; Staab et al., 1975). In the latter condition, which is often referred to as the Budd-Chiari syndrome, the “hot spot” represents the predominant area of preserved liver tissue. We report the appearance of the liver scan in a case of hepatic vein thrombosis, including a heretofore unreported finding, which could increase the diagnostic specificity of the liver scan in this syndrome. A 25-year-old black male was diagnosed in 1974 as having paroxysmal noctural haemoglobinuria, G6PD deficiency and Hb C trait. A 99TcmSc liver-spleen scan obtained on...

Venous blood glucose concentration measured by Dextrostix-Eyetone Reflectance Meter method were compared with conventional enzymatic measurements of plasma glucose in the same 373 blood samples over the range of 0.55-22.2 mmol/l (10-400 mg/100 ml). Agreement between the two methods was good up to 5.5 mmol/l (100 mg/100 ml) but above 11.1 mmol/l (200 mg/100 ml) the Dextrostix-Eyetone method gave higher results for glucose concentration. The Dextrostix-Eyetone method is a reliable means of confirming or refuting the clinical diagnosis of hypoglycaemia and is useful in the day-to-day management of diabetes mellitus in situations where insulin dosage requirements are varying and where access to clinical laboratory facilities are not readily available.

Evaluation in clinical practice of Dextrostix and the Eyetone Reflectance Meter.

SIR,-We read with interest the paper by Dr G M Mead and his colleagues (4 June, p 1460). We have carried out a smaller study with very similar findings. Twenty-three consecutive patients referred to an emergency medical clinic (by their general practitioners) with ulcer-type dyspepsia of at least one month's duration were studied. We excluded patients with significant weight loss or a history suggestive of gastrointestinal blood loss. Alternate patients were referred for barium meal examination and all patients were given the same advice with regard to regular meals, antacids, and stopping smoking. Of the 11 patients referred for barium meal, radiological findings were normal in eight and abnormal in two (one duodenal ulcer and one hiatus hernia); one patient failed to attend for examination. All patients were asked to attend for followup one month after their initial consultation. Symptoms had resolved in all 10 patients who had attended for barium meal examination. Only nine out of the 12 not referred for barium meal attended for follow-up and symptoms had resolved in all of these. There was no significant difference between the two groups in terms of either duration of symptoms (44± 14 (SEM) months for barium meal group v 42+10 months for no barium group) or age (51 + 2 years v 47 + 3 years). Our conclusion is that routine barium meal examination is of no value in the initial management of uncomplicated dyspepsia.

During 15 labours in diabetic women blood glucose concentrations were controlled with simultaneous infusion of insulin and glucose. The mean insulin infusion rate was between 1 and 2 U/h. No infant showed evidence of neonatal hypoglycaemia. The procedure is simple to use and may be carried out in any labour ward.

Control of blood glucose during labour in diabetic women with combined glucose and low-dose insulin infusion.

Seven normal male volunteers were given a 2 h intravenous infusion of insulin (2 mu kg‐1 min‐1). During the first hour, in which normoglycaemia was maintained by glucose infusion, no detectable increase in growth hormone (GH) secretion occurred. When controlled symptomatic hypoglycaemia was produced during the second hour of the insulin infusion a brisk rise in plasma GH concentration was observed in all the subjects studied. Since it was possible that the falls in the concentration of plasma free fatty acids (FFA) occurring during infusion of insulin also acted as a stimulus to GH release the study was repeated in four subjects but normoglycaemia was maintained throughout the entire 2 h period of insulin infusion. In these experiments there was no rise in plasma GH concentration although a similar fall in plasma FFA was produced. These results clearly indicate that hypoglycaemia per se was the important stimulus to GH secretion and not hyperinsulinaemia or a lowering of plasma FFA. Furthermore there appeared to be a threshold hypoglycaemic stimulus to GH secretion. In no subject was a rise in plasma GH seen without a fall in plasma glucose greater than 1.4 mmol/l. Prolonged mild hypoglycaemia did not stimulate GH secretion.

IS THE GROWTH‐HORMONE RESPONSE TO INSULIN DUE TO HYPOGLYCAEMIA, HYPERINSULINAEMIA OR A FALL IN PLASMA FREE FATTY ACIDS?

The effects of energy and carbohydrate restriction in patients with chronic diabetes mellitus

carbamazepine are very similar to the clinical features of water intoxication. Dizziness, headaches, nausea, and mental confusion may occur with both, although it is not known what proportion of patients who develop these side effects on carbamazepine do so because of a fall in the plasma osmolality. When untoward symptoms develop during treatment and subside after the dose is reduced the mechanism of production of the side effect is usually not investigated. Water retention may itself have an adverse effect on epilepsy,6 and, as a result of our experience, we wonder whether this may account for the apparent failure of carbamazepine to improve the control of epilepsy in some patients. Measurement of serum drug levels now has a recognised place in the management of epilepsy, and if the serum carbamazepine level is high, as in our second case, the plasma sodium should be measured. If the sodium concentration is low the dose of carbamazepine should be reduced or stopped. Special care should be exercised when carbamazepine is given to elderly patients and those with cardiovascular disease. If symptoms consistent with water intoxication occur the plasma sodium and osmolality should be checked. Hyponatraemia is, then, another indication to reduce or stop carbamazepine.

Emergency treatment with calcitonin of hypercalcaemia associated with multiple myeloma.

Horner's syndrome was accompanied by ipsilateral pain in the head, face, or neck in eight patients. In all cases angiography showed narrowing of the internal carotid artery in a pattern compatible with dissection within the arterial wall. In one patient in whom this diagnosis was substantiated by surgical exploration biopsy of the arterial wall showed changes typical of cystic medial necrosis. It is suggested that this clinical presentation constitutes a distinct syndrome.

Hormonal and Metabolic Effects of Chlorpropamide and Glibenclamide in a Cross-Over Study in Patients with Diabetes Mellitus

Progression and regression of atherosclerosis R W D Turner, FRCP .................... 710 Antenatal diagnosis of the mucopolysaccharidoses R W Logan, MRCPATH .................. 711 First aid in acute myocardial infarction D P Manning, MD; P Jerie, MD ............ 711 Support for varicose veins P H Fentem,Msc,MB ........ ............. 711 Cost of phentermine preparations J F Munro, FRCPED ........ .............. 712 Curability of breast cancer June Marchant, PHD .................... 712 Fluoridation and the Government G B Winter, FDSRCS, and J J Murray, FDSRCS ................................ 712 Normotensive phaeochromocytoma with hypercalcaemia P Skrabanek, LAH ...................... 712 Vaginal candidosis G Masterton, DPH, and others ............ 712 Geriatrics in the cottage hospital J A Davis, FRCP ........................ 713 Supervision of repeat prescribing D L Crombie, FRCGP, and others ..... ..... 713 Renal lesions in a case of septicaemia E N Wardle, MD ........................ 713 Post-alcoholic hypoglycaemia in a child J F B Norris, MB, and A Robinson, MD ...... 714 Brief and clear C L Hewer, FFARCS ....................... 714 Improving the hospital service? A L Bussey, MFCM ...................... 714 General practice in the Antipodes J L Ogle, MRCS ................... 714 Specialist training in thoracic medicine G F Edwards, FRCP ............. 714 Family planning in hospitals Elizabeth S Halifax, MB ........ .......... 715 Devolution to Scotland J B Stirling, DA ........................ 715 Private practice and the Goodman proposals R J Cross, MB .......................... 715 Campaign for Independence in Medicine J S Happel, FRCGP, and J H Marks, MRCGP. . 715

Two patients are described whose acromegaly was cured by removal of a bronchial carcinoid tumour. One had an enlarged pituitary fossa and evidence is presented that in this patient the tumour was not secreting growth hormone. The evidence available suggests that the tumour was producing a growth hormone releasing substance. It is suggested that some cases of the pluriglandular syndrome may be secondary to small bronchial carcinoid tumours that produce substances as yet unidentified, that stimulate the growth and hyperactivity of other endocrine tissue.

The Secretion of Growth Hormone in Response to Insulin Infusion under Conditions of Normo- and Hypo-glycaemia

Hypoglycaemic and growth hormone responses were studied at different steady‐state plasma insulin concentrations during a graded infusion of monocomponent human insulin. The control group consisted of ten volunteer subjects. The other groups studied included women taking oral contraceptives and patients with obesity, thyrotoxicosis, myxoedema, acromegaly, diabetes mellitus (moderate and severe) and liver disease.

METABOLIC RESPONSES TO MONOCOMPONENT HUMAN INSULIN INFUSIONS IN NORMAL SUBJECTS AND PATIENTS WITH LIVER AND ENDOCRINE DISEASE

Thirty-eight patients in diabetic coma from four different centres were treated with a continuous low-dose intravenous infusion of insulin at an average dose of 7·2 IU/hr. All patients recovered rapidly except for one profoundly shocked patient who died. The mean fall in plasma glucose was 58% four hours after the start of insulin. Blood ketone bodies and plasma free fatty acids showed a similar response. There was no significant difference in plasma glucose response according to severity of acidosis or previous treatment with insulin. Hypokalaemia was uncommon. In the treatment of diabetic coma this technique has proved simple, safe, and effective.

Treatment of Diabetic Coma with Continuous Low-dose Infusion of Insulin

Treatment ofDiabetic ComawithContinuous Low-dose Infusion ofInsulin

deteriorated again because of a vitreous hxemorrhage (Fig 2). The pregnancy was further complicated by a deep vein thrombosis of the right leg. It was felt that the danger of pulmonary emboli was of greater importance than possible further vitreous hemorrhage and she was treated with i.v. heparin. When the new vessels in her right eye became worse, heparin was discontinued for twenty-four hours before and until seventy-two hours after photocoagulation. When 33j weeks pregnant, on 9 December 1971, because of falling urinary cestrogen levels, she had a Cwsarean section. The baby weighed 4 lb 9 oz (2 kg) and was normal. Following delivery the retinopathy improved (Fig 3), but only temporarily; in spite of good diabetic control and further coagulation, the new vessels continued to extend and grow forwards (Fig 4). She developed a tuft of new vessels near her left macula where photocoagulation was not possible. Pituitary ablation was therefore advised. Yttrium90 implantation (11.4.72) resulted in only slight ablation of the pituitary gland (Joplin et al. 1965), but in spite of this her retinopathy improved and has remained good (Fig 5).

Pituitary and Parathyroid Tumours: An Example of the Pluriglandular Syndrome

The plasma clearance of calcitonin (TC) was studied by following the disappearance of radioactivity after intravenous injection of labelled TC, and the disappearance of bio-assayable activity after intravenous injection of unlabelled hormone. The turnover was shown to be rapid: two exponential components were involved with half times of 4-5 and 35-40 min. respectively. Similar values were obtained in experiments in which TC was infused to obtain raised, steady concentrations after which the disappearance of biologically active material was followed for up to 100 min. The normal concentration of TC in porcine peripheral plasma was calculated to be about 9 \g=m\u./ml.

Results are presented on the development of Trace Contaminant Control (TCC) Prototypes for use in Extravehicular Activities (EVAs), and more specifically in the Primary Life Support System (PLSS). The current TC-control technology involves the use of a packed bed of acid-impregnated granular charcoal, which is non-regenerable, and the carbon-based sorbent under development in this project can be regenerated by exposure to vacuum at room temperature. Data on sorption and desorption of ammonia and formaldehyde, which are major TCs of concern, as well as pressure-drop calculations were used to design and test 1/6-scale and full-scale trace contaminant control system (TCCS) prototypes. Carbon sorbents were fabricated in both the granular and foam-supported forms. Sorbent performance was tested for ammonia sorption and vacuum regeneration in 1/6-scale, and pressure-drop characteristics were measured at flow rates relevant to the PLSS application.

Development of Trace Contaminant Control Prototypes for the Primary Life Support System (PLSS)

Measurement and Modeling of Torrefaction Processing for Human Solid Waste Management in Space

Development of Trace Contaminant Control Prototypes for the Portable Life Support System (PLSS)

This study involved a torrefaction (mild pyrolysis) processing approach that could be used to sterilize feces and produce a stable, odor-free solid product that can be stored or recycled, and also to simultaneously recover moisture. It was demonstrated that mild heating (200-250 C) in nitrogen or air was adequate for torrefaction of a fecal simulant and an analog of human solid waste (canine feces). The net result was a nearly undetectable odor (for the canine feces), complete recovery of moisture, some additional water production, a modest reduction of the dry solid mass, and the production of small amounts of gas and liquid. The liquid product is mainly water, with a small Total Organic Carbon content. The amount of solid vs gas plus liquid products can be controlled by adjusting the torrefaction conditions (final temperature, holding time), and the current work has shown that the benefits of torrefaction could be achieved in a low temperature range (< 250 C). These temperatures are compatible with the PTFE bag materials historically used by NASA for fecal waste containment and will reduce the energy consumption of the process. The solid product was a dry material that did not support bacterial growth and was hydrophobic relative to the starting material. In the case of canine feces, the solid product was a mechanically friable material that could be easily compacted to a significantly smaller volume (approx. 50%). The proposed Torrefaction Processing Unit (TPU) would be designed to be compatible with the Universal Waste Management System (UWMS), now under development by NASA. A stand-alone TPU could be used to treat the canister from the UWMS, along with other types of wet solid wastes, with either conventional or microwave heating. Over time, a more complete integration of the TPU and the UWMS could be achieved, but will require design changes in both units.

Plant, and methods for carbon dioxide sorption for fuel and gas emissions

Customizing the eighth grade advisory program for Mary Putnam Henck Intermediate School students and their teachers

Abstract Microbial source tracking efforts have traditionally focused on the input of fecal bacteria from sources such as storm drains, sewers, and runoff. Fecal coliform levels in the Mississippi Sound have been analyzed and compared to physical factors in an attempt to characterize possible non-point sources of pollution. Results from this study show that a primary factor in elevated levels of fecal coliform is barometric pressure and the resulting changes in wind direction. The passage of warm and cold fronts through the northern Gulf of Mexico cause excursions in barometric pressure and numerous 90°-180° shifts in wind direction over a period of 6-8 days. Commonly, a rise in fecal coliform counts is observed at the selected coastal monitoring station during, or immediately after a drop in barometric pressure and an abrupt shift in wind direction and wind speed. When these trends of increased fecal coliform levels occur prior to rainfall, it is inferred that the sediment may be a source of the fecal coliform bacteria observed in the water column. The changes in wind direction and velocity may induce more energetic conditions at the shoreline (e.g. increased wave heights, and increased long shore current velocities). Fecal coliform counts collected from a Mississippi Department of Environmental Quality (MDEQ) monitoring station (Station 10) along the Harrison County, Mississippi coast during October - December, 2004 have been compared with barometric pressure readings over that time interval. The occurrence of high fecal coliform counts can be qualitatively correlated with low barometric pressure. Statistically, a correlation exists between high barometric pressure and low bacterial counts. Low bacterial counts are most likely to occur (66% greater chance) when the barometric pressure exceeds 30.1 inches Hg (1019.3 mbar), with winds from a northerly direction. Analyses of fecal coliform counts in coastal waters, feeder creek waters, sewers, and coastal sediments are currently underway to determine relationships between these potential environmental sources of fecal pollution.

Meteorological Influences on Fecal Coliform Pollution in the Mississippi Sound

The aim of this study was to study the chemo-degradation of the complexing agent citric acid in mixed nuclear wastes. A nonradioactive simulant of a mixed nuclear waste, formulated to mimic a complex concentrate waste stored at the U.S. Department of Energy`s Hanford Site, was prepared by adding 42.3 mM citrate to an inorganic matrix, which was formulated based on analyses of the actual waste. The simulant was then stored in the dark at ambient temperature for 180 days, and aliquots; were taken for organic analysis at 0, 28, 35, 63, 79, 95 and 180 days. The parent compound citrate and any degradation products, or complexor fragments, formed were analyzed as methyl esters by gas chromatography (GC) and GC/mass spectrometry (GC/MS). Citrate disappeared steadily, with only 36% remaining after 180 days. Ethanedioic acid (oxalate) was the major complexor fragment, followed by butanoic and propanedioic acids, along with traces of other mono- and dicarboxylic acids. Loss of the total organic content (TOC) was fairly constant throughout the entire time period, averaging 17.6%. The GC/MS system, Hewlett-Packard`s MS Engine, was purchased via a grant from the National Science Foundation`s Instrumentation and Laboratory Improvement Program (Grant USE-9051582), along with a contribution from Syntexmore » Corporation and university matching funds.« less

Degradation of citric acid in a simulated, mixed nuclear waste: Radiolytic versus chemical forces

Metastatic implantation of laryngeal carcinoma at a PEG exit site.

Gastrostomy and jejunostomy using a transgastric tube for early enteral nutrition after pylorus-preserving pancreaticoduodenectomy.

The major maturation glycoprotein found on rat cauda epididymal sperm surface is linked to the membrane via phosphatidylinositol.

Device and method for simulating and analyzing a system with failure modes

Online learning via Bayes’ theorem allows new data to be continuously integrated into an agent’s current beliefs. However, a naive application of Bayesian methods in non-stationary environments leads to slow adaptation and results in state estimates that may converge confidently to the wrong parameter value. A common solution when learning in changing environments is to discard/downweight past data; however, this simple mechanism of “forgetting” fails to account for the fact that many real-world environments involve revisiting similar states. We propose a new framework, Bayes with Adaptive Memory (BAM), that takes advantage of past experience by allowing the agent to choose which past observations to remember and which to forget. We demonstrate that BAM generalizes many popular Bayesian update rules for non-stationary environments. Through a variety of experiments, we demonstrate the ability of BAM to continuously adapt in an ever-changing world.

Many real-world systems studied are governed by complex, nonlinear dynamics. By modeling these dynamics, we can gain insight into how these systems work, make predictions about how they will behave, and develop strategies for controlling them. While there are many methods for modeling nonlinear dynamical systems, existing techniques face a trade off between offering interpretable descriptions and making accurate predictions. Here, we develop a class of models that aims to achieve both simultaneously, smoothly interpolating between simple descriptions and more complex, yet also more accurate models. Our probabilistic model achieves this multi-scale property through a hierarchy of locally linear dynamics that jointly approximate global nonlinear dynamics. We call it the tree-structured recurrent switching linear dynamical system. To fit this model, we present a fully-Bayesian sampling procedure using Polya-Gamma data augmentation to allow for fast and conjugate Gibbs sampling. Through a variety of synthetic and real examples, we show how these models outperform existing methods in both interpretability and predictive capability.

Tree-Structured Recurrent Switching Linear Dynamical Systems for Multi-Scale Modeling

To understand the complex nonlinear dynamics of neural circuits, we fit a structured state-space model called tree-structured recurrent switching linear dynamical system (TrSLDS) to noisy high-dimensional neural time series. TrSLDS is a multi-scale hierarchical generative model for the state-space dynamics where each node of the latent tree captures locally linear dynamics. TrSLDS can be learned efficiently and in a fully Bayesian manner using Gibbs sampling. We showcase TrSLDS’ potential of inferring low-dimensional interpretable dynamical systems on a variety of examples.

2018 52nd Asilomar Conference on Signals, Systems, and Computers

Learning Structured Neural Dynamics From Single Trial Population Recording

Disentangling the effects of SARS-CoV-2 variants and vaccination on the occurrence of post-acute sequelae of SARS-CoV-2 (PASC) is crucial to estimate and reduce the burden of PASC.

METHODS
We performed a cross-sectional analysis (May/June 2022) within a prospective multicenter healthcare worker (HCW) cohort in North-Eastern Switzerland. HCW were stratified by viral variant and vaccination status at time of their first positive SARS-CoV-2 nasopharyngeal swab. HCW without positive swab and with negative serology served as controls. The sum of eighteen self-reported PASC symptoms was modeled with univariable and multivariable negative-binomial regression to analyse the association of mean symptom number with viral variant and vaccination status.

RESULTS
Among 2'912 participants (median age 44 years, 81.3% female), PASC symptoms were significantly more frequent after wild-type infection (estimated mean symptom number 1.12, p<0.001; median time since infection 18.3 months), after Alpha/Delta infection (0.67 symptoms, p<0.001; 6.5 months), and after Omicron BA.1 infections (0.52 symptoms, p=0.005; 3.1 months) compared to uninfected controls (0.39 symptoms). After Omicron BA.1 infection, the estimated mean symptom number was 0.36 for unvaccinated individuals, compared to 0.71 with 1-2 vaccinations (p=0.028) and 0.49 with ≥3 prior vaccinations (p=0.30). Adjusting for confounders, only wild-type (adjusted rate ratio [aRR] 2.81, 95% confidence interval [CI] 2.08-3.83) and Alpha/Delta infection (aRR 1.93, 95% CI 1.10-3.46) were significantly associated with the outcome.

Previous infection with pre-Omicron variants was the strongest risk factor for PASC symptoms among our HCW. Vaccination prior to Omicron BA.1 infection was not associated with a clear protective effect against PASC symptoms in this population.

Post-acute sequelae after SARS-CoV-2 infection by viral variant and vaccination status: a multicenter cross-sectional study.

Anticorrosion performance of a Zr-based architectured substrate/coating system

Abstract The effects of different types of pre‐existing immunity on the frequency of clinical symptoms caused by the SARS‐CoV‐2 breakthrough infection were prospectively assessed in healthcare workers during the Omicron period. Among 518 participants, hybrid immunity was associated with symptom reduction for dizziness, muscle or limb pain and headache as compared to vaccination only. Moreover, the frequencies of dizziness, cough and muscle or limb pain were lower in participants who had received a booster vaccine dose. Thus, hybrid immunity appeared to be superior in preventing specific symptoms during breakthrough infection compared to vaccination alone. A booster vaccine dose conferred additional symptom reduction.

Clinical symptoms of SARS‐CoV‐2 breakthrough infection during the Omicron period in relation to baseline immune status and booster vaccination—A prospective multicentre cohort of health professionals (SURPRISE study)

Investigating Action Encodings in Recurrent Neural Networks in Reinforcement Learning

To describe the burden of COVID-19 in Swiss long-term care facilities in 2020, to identify its influencing factors, and to assess vaccination rates among residents and healthcare workers at the end of the vaccine campaign in Switzerland in May 2021.

DESIGN
Cross-sectional survey.

Long-term care facilities from two Swiss cantons (St. Gallen / Eastern Switzerland and Vaud / Western Switzerland).

METHODS
We collected numbers of COVID-19 cases and related deaths and all-cause mortality for 2020, potential risk factors at the institutional level (e.g. size, infection prevention and control measures, and resident characteristics), and vaccination rates among residents and healthcare workers. Univariate and multivariate analyses were used to identify factors associated with resident mortality in 2020.

RESULTS
We enrolled 59 long-term care facilities with a median of 46 (interquartile range [IQR]: 33-69) occupied beds. In 2020, the median COVID-19 incidence was 40.2 (IQR: 0-108.6) per 100 occupied beds, with higher rates in VD (49.9%) than in SG (32.5%; p = 0.037). Overall, 22.7% of COVID-19 cases died, of which 24.8% were COVID-19-related deaths. In the univariate analysis, higher resident mortality was associated with COVID-19 rates among residents (p < 0.001) and healthcare workers (p = 0.002) and age (p = 0.013). Lower resident mortality was associated with the proportion of single rooms (p = 0.012), isolation of residents with COVID-19 in single rooms (p = 0.003), symptom screening of healthcare workers (p = 0.031), limiting the number of visits per day (p = 0.004), and pre-scheduling visits (p = 0.037). In the multivariate analysis, higher resident mortality was only associated with age (p = 0.03) and the COVID-19 rate among residents (p = 0.013). Among 2936 residents, 2042 (69.9%) received ≥1 dose of the COVID-19 vaccine before 31 May 2021. Vaccine uptake among healthcare workers was 33.8%.

CONCLUSION AND IMPLICATIONS
COVID-19 burden was high but also highly variable in Swiss long-term care facilities. severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among healthcare workers was a modifiable factor associated with increased resident mortality. Symptom screening of healthcare workers appeared to be an effective preventive strategy and should be included in routine infection prevention and control measures. Promoting COVID-19 vaccine uptake among healthcare workers should be a priority in Swiss long-term care facilities.

COVID-19 burden and influencing factors in Swiss long-term-care facilities: a cross-sectional analysis of a multicentre observational cohort.

In >100,000 observations across Swiss acute-care hospitals, hand hygiene (HH) adherence significantly increased during the first coronavirus disease 2019 (COVID-19) wave. However, despite persisting COVID-19 activity, HH adherence returned to prepandemic levels over a 2-year observation period. These results indicate that training and support remains challenging.

Impact of the coronavirus disease 2019 (COVID-19) pandemic on the adherence to hand hygiene practice in hospitals-Data from a Swiss national surveillance system.

The challenge of preventing and containing outbreaks of multidrug-resistant organisms and Candida auris during the coronavirus disease 2019 pandemic: report of a carbapenem-resistant Acinetobacter baumannii outbreak and a systematic review of the literature

Abstract Background The burden of long-term symptoms (ie, long COVID) in patients after mild COVID-19 is debated. Within a cohort of healthcare workers (HCWs), frequency and risk factors for symptoms compatible with long COVID are assessed. Methods Participants answered baseline (August/September 2020) and weekly questionnaires on SARS-CoV-2 nasopharyngeal swab (NPS) results and acute disease symptoms. In January 2021, SARS-CoV-2 serology was performed; in March, symptoms compatible with long COVID (including psychometric scores) were asked and compared between HCWs with positive NPS, seropositive HCWs without positive NPS (presumable asymptomatic/pauci-symptomatic infections), and negative controls. The effect of time since diagnosis and quantitative anti-spike protein antibodies (anti-S) was evaluated. Poisson regression was used to identify risk factors for symptom occurrence. Results Of 3334 HCWs (median, 41 years; 80% female), 556 (17%) had a positive NPS and 228 (7%) were only seropositive. HCWs with positive NPS more frequently reported ≥1 symptom compared with controls (73% vs 52%, P < .001); seropositive HCWs without positive NPS did not score higher than controls (58% vs 52%, P = .13), although impaired taste/olfaction (16% vs 6%, P < .001) and hair loss (17% vs 10%, P = .004) were more common. Exhaustion/burnout was reported by 24% of negative controls. Many symptoms remained elevated in those diagnosed >6 months ago; anti-S titers correlated with high symptom scores. Acute viral symptoms in weekly questionnaires best predicted long-COVID symptoms. Physical activity at baseline was negatively associated with neurocognitive impairment and fatigue scores. Conclusions Seropositive HCWs without positive NPS are only mildly affected by long COVID. Exhaustion/burnout is common, even in noninfected HCWs. Physical activity might be protective against neurocognitive impairment/fatigue symptoms after COVID-19.

Symptoms Compatible With Long Coronavirus Disease (COVID) in Healthcare Workers With and Without Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection—Results of a Prospective Multicenter Cohort

Impact of respirator versus surgical masks on SARS-CoV-2 acquisition in healthcare workers: a prospective multicentre cohort

High adherence to national IPC guidelines as key to sustainable VRE control in Swiss hospitals: a cross-sectional survey

Learning auxiliary tasks, such as multiple predictions about the world, can provide many benefits to reinforcement learning systems. A variety of off-policy learning algorithms have been developed to learn such predictions, but as yet there is little work on how to adapt the behavior to gather useful data for those off-policy predictions. In this work, we investigate a reinforcement learning system designed to learn a collection of auxiliary tasks, with a behavior policy learning to take actions to improve those auxiliary predictions. We highlight the inherent non-stationarity in this continual auxiliary task learning problem, for both prediction learners and the behavior learner. We develop an algorithm based on successor features that facilitates tracking under non-stationary rewards, and prove the separation into learning successor features and rewards provides convergence rate improvements. We conduct an in-depth study into the resulting multi-prediction learning system.

Outbreak investigation including molecular characterization of community associated methicillin-resistant Staphylococcus aureus in a primary and secondary school in Eastern Switzerland

Importance: Disentangling the effects of different SARS-CoV-2 variants and of vaccination on the occurrence of post-acute sequelae of SARS-CoV-2 (PASC) is crucial to estimate and potentially reduce the future burden of PASC. Objective: To determine the association of primary SARS-CoV-2 infection on the frequency of PASC symptoms by viral variant and vaccination status. Design: Cross-sectional questionnaire and SARS-CoV-2 serology (May/June 2022) performed within a prospective healthcare worker cohort (SURPRISE study). Setting: Multicenter study in nine healthcare networks from North-Eastern Switzerland. Participants: Volunteer sample of healthcare workers (HCW) from participating institutions. Of approximately 20000 eligible participants, 3870 registered for the cohort and 2912 were included in this analysis. Exposures: SARS-CoV-2 infection documented by positive nasopharyngeal swab (>4 weeks ago), stratified by viral variant and vaccination status at time of infection, compared to absence of documented infection (no positive swab, negative serology). Main Outcome: Sum score of eighteen self-reported PASC symptoms. Results: Among 2912 participants (median age 44 years, 81.3% female), SARS-CoV-2 infection was reported by 1685 (55.9%) participants, thereof 315 (18.7%) during Wild-type, 288 (17.1%) during Alpha/Delta, and 1082 (64.2%) during Omicron circulation. Mean symptom number in previously infected participants significantly exceeded that of uninfected controls (0.39), but decreased with recency of the viral variant: 1.12 (p<0.001) for Wild-type (median time since infection 18.5 months), 0.67 (p<0.001) for Alpha/Delta (6.6 months), and 0.52 (p=0.005) for Omicron BA.1 (3.1 months) infected participants. After Omicron BA.1 infection, the mean symptom score was 0.49 (p=0.30) for those with at least 3 prior vaccinations and 0.71 (p=0.028) with 1-2 previous vaccinations compared to 0.36 for unvaccinated individuals. Adjusting for confounders, Wild-type (adjusted risk ratio [aRR] 2.81, 95% confidence interval [CI] 2.08-3.83) and Alpha/Delta infection (aRR 1.93, 95% CI 1.10-3.46) showed significant associations with the outcome, whereas Omicron BA.1 infection (aRR 1.29, 95% CI 0.69-2.43) and vaccination before infection (aRR 1.27, 95% CI 0.82-1.94) did not. Conclusions and Relevance: Previous infection with pre-Omicron variants was the strongest risk factor for reporting PASC symptoms in this HCW cohort. A definite influence of prior vaccination on the prevention of PASC after Omicron BA.1 infection was not measurable.

Association of viral variant and vaccination status with the occurrence of symptoms compatible with post-acute sequelae after primary SARS-CoV-2 infection

The coronavirus disease 2019 (COVID-19) pandemic made its way from private, public, and work spaces into healthcare systems all over the world, imposing an unexpected burden on global health care. COVID-19 outbreaks in acute-care hospitals are a frequent problem, increasing morbidity and mortality among patients and leading to staff shortages. 1,2 Prevention of nosocomial severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) trans-mission in acute-care hospitals represents a major others spared. We sought to identify ward-level risk factors associated with nosocomial COVID-19 outbreaks.

Ward-level risk factors associated with nosocomial coronavirus disease 2019 (COVID-19) outbreaks: A matched case–control study

The burden of long-term symptoms (i.e. long-COVID) in patients after mild COVID-19 is debated. Within a cohort of healthcare workers (HCW), frequency and risk factors for symptoms compatible with long-COVID are assessed.

METHODS
Participants answered baseline (August/September 2020) and weekly questionnaires on SARS-CoV-2 nasopharyngeal swab (NPS) results and acute disease symptoms. In January 2021, SARS-CoV-2 serology was performed; in March, symptoms compatible with long-COVID (including psychometric scores) were asked and compared between HCW with positive NPS, seropositive HCW without positive NPS (presumable a-/pauci-symptomatic infections), and negative controls. Also, the effect of time since diagnosis and quantitative anti-S was evaluated. Poisson regression was used to identify risk factors for symptom occurrence.

RESULTS
Of 3'334 HCW (median 41 years; 80% female), 556 (17%) had a positive NPS and 228 (7%) were only seropositive. HCW with positive NPS more frequently reported ≥1 symptom compared to controls (73%vs.52%, p<0.001); seropositive HCW without positive NPS did not score higher than controls (58%vs.52%, p=0.13), although impaired taste/olfaction (16%vs.6%, p<0.001) and hair loss (17%vs.10%, p=0.004) were more common. Exhaustion/burnout was reported by 24% of negative controls. Many symptoms remained elevated in those diagnosed >6 months ago; anti-S titers correlated with high symptom scores. Acute viral symptoms in weekly questionnaires best predicted long-COVID symptoms. Physical activity at baseline was negatively associated with neurocognitive impairment and fatigue scores.

Seropositive HCW without positive NPS are only mildly affected by long-COVID. Exhaustion/burnout is common, even in non-infected HCW. Physical activity might be protective against neurocognitive impairment/fatigue symptoms after COVID-19.

Symptoms compatible with long-COVID in healthcare workers with and without SARS-CoV-2 infection - results of a prospective multicenter cohort.

Abstract As of December 2021, the coronavirus disease 2019 (COVID-19) pandemic has claimed millions of deaths and caused disruptions in health systems around the world. The short- and long-term effects of COVID-19 on antimicrobial resistance (AMR), which was already a global threat before the pandemic, are manifold and complex. In this expert review, we summarize how COVID-19 might be affecting AMR in the short term (by influencing the key determinants antibiotic use, infection control practices and international/local mobility) and which additional factors might play a role in the long term. Whereas reduced outpatient antibiotic use in high-income countries, increased awareness for hand hygiene, and reduced mobility have likely mitigated the emergence and spread of AMR in the short term, factors such as overuse of antibiotics in COVID-19 patients, shortage of personal protective equipment, lack of qualified healthcare staff, and patient overcrowding have presumably facilitated its propagation. Unsurprisingly, international and national AMR surveillance data for 2020 show ambiguous trends. Although disruptions in antibiotic stewardship programs, AMR surveillance and research might promote the spread of AMR, other developments could prove beneficial to the cause in the long term. These factors include the increased public awareness for infectious diseases and infection control issues, the strengthening of the One Health perspective as outlined by the Centers for Disease Control and Prevention, and the unprecedented number of international research collaborations and platforms. These factors could even serve as leverage and provide opportunities to better combat AMR in the future.

It is complicated: Potential short- and long-term impact of coronavirus disease 2019 (COVID-19) on antimicrobial resistance—An expert review

Background Knowledge about protection conferred by previous Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and/or vaccination against emerging viral variants allows clinicians, epidemiologists, and health authorities to predict and reduce the future Coronavirus Disease 2019 (COVID-19) burden. We investigated the risk and symptoms of SARS-CoV-2 (re)infection and vaccine breakthrough infection during the Delta and Omicron waves, depending on baseline immune status and subsequent vaccinations. Methods and findings In this prospective, multicentre cohort performed between August 2020 and March 2022, we recruited hospital employees from ten acute/nonacute healthcare networks in Eastern/Northern Switzerland. We determined immune status in September 2021 based on serology and previous SARS-CoV-2 infections/vaccinations: Group N (no immunity); Group V (twice vaccinated, uninfected); Group I (infected, unvaccinated); Group H (hybrid: infected and ≥1 vaccination). Date and symptoms of (re)infections and subsequent (booster) vaccinations were recorded until March 2022. We compared the time to positive SARS-CoV-2 swab and number of symptoms according to immune status, viral variant (i.e., Delta-dominant before December 27, 2021; Omicron-dominant on/after this date), and subsequent vaccinations, adjusting for exposure/behavior variables. Among 2,595 participants (median follow-up 171 days), we observed 764 (29%) (re)infections, thereof 591 during the Omicron period. Compared to group N, the hazard ratio (HR) for (re)infection was 0.33 (95% confidence interval [CI] 0.22 to 0.50, p < 0.001) for V, 0.25 (95% CI 0.11 to 0.57, p = 0.001) for I, and 0.04 (95% CI 0.02 to 0.10, p < 0.001) for H in the Delta period. HRs substantially increased during the Omicron period for all groups; in multivariable analyses, only belonging to group H was associated with protection (adjusted HR [aHR] 0.52, 95% CI 0.35 to 0.77, p = 0.001); booster vaccination was associated with reduction of breakthrough infection risk in groups V (aHR 0.68, 95% CI 0.54 to 0.85, p = 0.001) and H (aHR 0.67, 95% CI 0.45 to 1.00, p = 0.048), largely observed in the early Omicron period. Group H (versus N, risk ratio (RR) 0.80, 95% CI 0.66 to 0.97, p = 0.021) and participants with booster vaccination (versus nonboosted, RR 0.79, 95% CI 0.71 to 0.88, p < 0.001) reported less symptoms during infection. Important limitations are that SARS-CoV-2 swab results were self-reported and that results on viral variants were inferred from the predominating strain circulating in the community at that time, rather than sequencing. Conclusions Our data suggest that hybrid immunity and booster vaccination are associated with a reduced risk and reduced symptom number of SARS-CoV-2 infection during Delta- and Omicron-dominant periods. For previously noninfected individuals, booster vaccination might reduce the risk of symptomatic Omicron infection, although this benefit seems to wane over time.

Risk and symptoms of COVID-19 in health professionals according to baseline immune status and booster vaccination during the Delta and Omicron waves in Switzerland—A multicentre cohort study

Background There is insufficient evidence regarding the role of respirators in the prevention of SARS-CoV-2 infection. We analysed the impact of filtering facepiece class 2 (FFP2) vs. surgical masks on the risk of SARS-CoV-2 acquisition among Swiss healthcare workers (HCW). Methods Our prospective multicentre cohort enrolled patient-facing HCWs from June to August 2020. Participants were asked about COVID-19 risk exposures/behaviours, including preferred mask type when caring for COVID-19 patients outside of aerosol-generating procedures (AGP). For those performing AGPs, we asked whether they used FFP2 irrespective of the patients COVID-19 status (i.e. universal use). The impact of FFP2 on i) self-reported SARS-CoV-2-positive nasopharyngeal PCR/rapid antigen tests captured during weekly surveys, and ii) SARS-CoV-2 seroconversion between baseline and January/February 2021 was assessed. Results We enrolled 3259 participants from nine healthcare institutions, whereof 716 (22%) preferentially used FFP2 respirators. Among these, 81/716 (11%) reported a SARS-CoV-2-positive swab, compared to 352/2543 (14%) surgical mask users (median follow-up 242 days); seroconversion was documented in 85/656 (13%) FFP2 and 426/2255 (19%) surgical mask users. Adjusted for baseline characteristics, COVID-19 exposure, and risk behaviour, FFP2 use was non-significantly associated with a decreased risk for SARS-CoV-2-positive swab (adjusted hazard ratio [aHR] 0.8, 95% CI 0.6-1.0, p=0.052) and seroconversion (adjusted odds ratio [aOR] 0.7, 95% CI 0.5-1.0, p=0.053); household exposure was the strongest risk factor (aHR for positive swab 10.1, p<0.001; aOR for seroconversion 5.0, p<0.001). In subgroup analysis, FFP2 use was clearly protective among those with frequent (>20 patients) COVID-19 exposure (aHR 0.7, p<0.001; aOR 0.6, p=0.035). Universal FFP2 use during AGPs showed no protective effect (aHR 1.1, p=0.7; aOR 0.9, p=0.53). Conclusion Respirators compared to surgical masks may convey additional protection from SARS-CoV-2 for HCW with frequent exposure to COVID-19 patients.

Use of respirator vs. surgical masks in healthcare personnel and its impact on SARS-CoV-2 acquisition: a prospective multicentre cohort study

This article reviews the available evidence on the effectiveness of gloves in preventing infection during care provided to patients under contact precautions, and analyses the risks and benefits of their systematic use. Although hand hygiene with alcohol-based handrub was shown to be effective in preventing nosocomial infections, many publications put the effectiveness and usefulness of gloves into perspective. Instead, literature and various unpublished experiences point towards reduced hand hygiene compliance and increased risk of spreading pathogens with routine glove use. Therefore, hospitals should emphasise hand hygiene in their healthcare staff and, instead of the routine use of gloves when caring for patients under contact precautions, limit their use to the indications of standard precautions, i.e., mainly for contact with body fluids. Wide and easy access to alcohol-based handrub and continual teaching are essential. If such conditions are met and adherence to hand hygiene is excellent and regularly assessed, the routine use of gloves for patients under contact precautions seems no longer indicated.

Providing care to patients in contact isolation: is the systematic use of gloves still indicated?

Structural credit assignment in neural networks is a long-standing problem, with a variety of alternatives to backpropagation proposed to allow for local training of nodes. One of the early strategies was to treat each node as an agent and use a reinforcement learning method called REINFORCE to update each node locally with only a global reward signal. In this work, we revisit this approach and investigate if we can leverage other reinforcement learning approaches to improve learning. We ﬁrst formalize training a neural network as a ﬁnite-horizon reinforcement learning problem and discuss how this facilitates using ideas from reinforcement learning like off-policy learning. We show that the standard on-policy REINFORCE approach, even with a variety of variance reduction approaches, learns suboptimal solutions. We introduce an off-policy approach, to facilitate reasoning about the greedy action for other agents and help overcome stochasticity in other agents. We conclude by showing that these networks of agents can be more robust to correlated samples when learning online.

Structural Credit Assignment in Neural Networks using Reinforcement Learning

Healthcare-associated infections and antibiotic use in long-term care residents from two geographical regions in Switzerland.

Background Intensive care units (ICU) constitute a high-risk setting for antimicrobial resistance (AMR). Aim We aimed to describe secular AMR trends including meticillin-resistant Staphylococcus aureus (MRSA), glycopeptide-resistant enterococci (GRE), extended-spectrum cephalosporin-resistant Escherichia coli (ESCR-EC) and Klebsiella pneumoniae (ESCR-KP), carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa (CRPA) from Swiss ICU. We assessed time trends of antibiotic consumption and identified factors associated with CRE and CRPA. Methods We analysed patient isolate and antibiotic consumption data of Swiss ICU sent to the Swiss Centre for Antibiotic Resistance (2009–2018). Time trends were assessed using linear logistic regression; a mixed-effects logistic regression was used to identify factors associated with CRE and CRPA. Results Among 52 ICU, MRSA decreased from 14% to 6% (p = 0.005; n = 6,465); GRE increased from 1% to 3% (p = 0.011; n = 4,776). ESCR-EC and ESCR-KP increased from 7% to 15% (p < 0.001, n = 10,648) and 5% to 11% (p = 0.002; n = 4,052), respectively. CRE, mostly Enterobacter spp., increased from 1% to 5% (p = 0.008; n = 17,987); CRPA remained stable at 27% (p = 0.759; n = 4,185). Antibiotic consumption in 58 ICU increased from 2009 to 2013 (82.5 to 97.4 defined daily doses (DDD)/100 bed-days) and declined until 2018 (78.3 DDD/100 bed-days). Total institutional antibiotic consumption was associated with detection of CRE in multivariable analysis (odds ratio per DDD: 1.01; 95% confidence interval: 1.0–1.02; p = 0.004). Discussion In Swiss ICU, antibiotic-resistant Enterobacterales have been steadily increasing over the last decade. The emergence of CRE, associated with institutional antibiotic consumption, is of particular concern and calls for reinforced surveillance and antibiotic stewardship in this setting.

Antimicrobial resistance and antibiotic consumption in intensive care units, Switzerland, 2009 to 2018

What will infection prevention look like in 2030-results of the first round of a global crystal ball exercise

Longitudinal assessment of team safety culture and leadership regarding influenza and COVID-19 preventive measures: The hospital associated influenza prevention study (HAIP)N

Background The implementation of novel techniques as a complement to traditional disease surveillance systems represents an additional opportunity for rapid analysis. Objective The objective of this work is to describe a web-based participatory surveillance strategy among health care workers (HCWs) in two Swiss hospitals during the first wave of COVID-19. Methods A prospective cohort of HCWs was recruited in March 2020 at the Cantonal Hospital of St. Gallen and the Eastern Switzerland Children’s Hospital. For data analysis, we used a combination of the following techniques: locally estimated scatterplot smoothing (LOESS) regression, Spearman correlation, anomaly detection, and random forest. Results From March 23 to August 23, 2020, a total of 127,684 SMS text messages were sent, generating 90,414 valid reports among 1004 participants, achieving a weekly average of 4.5 (SD 1.9) reports per user. The symptom showing the strongest correlation with a positive polymerase chain reaction test result was loss of taste. Symptoms like red eyes or a runny nose were negatively associated with a positive test. The area under the receiver operating characteristic curve showed favorable performance of the classification tree, with an accuracy of 88% for the training data and 89% for the test data. Nevertheless, while the prediction matrix showed good specificity (80.0%), sensitivity was low (10.6%). Conclusions Loss of taste was the symptom that was most aligned with COVID-19 activity at the population level. At the individual level—using machine learning–based random forest classification—reporting loss of taste and limb/muscle pain as well as the absence of runny nose and red eyes were the best predictors of COVID-19.

Digital SARS-CoV-2 Detection Among Hospital Employees: Participatory Surveillance Study

Impact of baseline SARS-CoV-2 antibody status on syndromic surveillance and the risk of subsequent COVID-19—a prospective multicenter cohort study

Evaluation of ward-level risk factors for nosocomial COVID-19 outbreaks: A matched case-control study

Does COVID-19 trigger changes in attitudes and behaviour of respiratory infection prevention measures? First results of health-care-associated influenza prevention project (HAIP)

Background: The burden of long-term symptoms (i.e. long-COVID) in patients after mild COVID-19 is debated. Within a cohort of healthcare workers (HCW), frequency and risk factors for symptoms compatible with long-COVID are assessed. Methods: Participants answered baseline (August/September 2020) and weekly questionnaires on SARS-CoV-2 nasopharyngeal swab (NPS) results and acute disease symptoms. In January 2021, SARS-CoV-2 serology was performed; in March, symptoms compatible with long-COVID (including psychometric scores) were asked and compared between HCW with positive NPS, seropositive HCW without positive NPS (presumable a-/pauci-symptomatic infections), and negative controls. Also, the effect of time since diagnosis and quantitative anti-S was evaluated. Poisson regression was used to identify risk factors for symptom occurrence. Results: Of 3334 HCW (median 41 years; 80% female), 556 (17%) had a positive NPS and 228 (7%) were only seropositive. HCW with positive NPS more frequently reported [≥]1 symptom compared to controls (73%vs.52%, p<0.001); seropositive HCW without positive NPS did not score higher than controls (58%vs.52%, p=0.13), although impaired taste/olfaction (16%vs.6%, p<0.001) and hair loss (17%vs.10%, p=0.004) were more common. Exhaustion/burnout was reported by 24% of negative controls. Many symptoms remained elevated in those diagnosed >6 months ago; anti-S titers correlated with high symptom scores. Acute viral symptoms in weekly questionnaires best predicted long-COVID symptoms. Physical activity at baseline was negatively associated with neurocognitive impairment and fatigue scores. Conclusions: Seropositive HCW without positive NPS are only mildly affected by long-COVID. Exhaustion/burnout is common, even in non-infected HCW. Physical activity might be protective against neurocognitive impairment/fatigue symptoms after COVID-19.

Symptoms compatible with long-COVID in healthcare workers with and without SARS-CoV-2 infection - results of a prospective multicenter cohort

Non-occupational and occupational factors associated with specific SARS-CoV-2 antibodies among hospital workers – A multicentre cross-sectional study

Molecular Epidemiology and Risk Factors for Extended-Spectrum β-Lactamase-Producing Enterobacterales in Long-Term Care Residents.

Objectives: During the COVID-19 pandemic, few scientific congresses have been held on-site. We prospectively evaluated the safety concept of the congress of the Swiss Societies of Infectious Diseases and Hospital Hygiene. Methods: The congress was held in Geneva (Switzerland) while local COVID-19 incidence (with SARS-CoV-2 wild type circulating) was 65/100,000 population (September 2020). A rigorous safety concept was implemented. Congress attendees filled out a questionnaire to assess risk perception, exposures, symptoms and diagnoses of SARS-CoV-2 before, during and after the congress. Dried blood spots were taken on-site and 4 weeks later to detect SARS-CoV-2 seroconversions. Results: Of 365 congress attendees, 196 (54%) either answered the questionnaire (N = 150) or provided baseline and follow-up blood samples (N = 168). None of the participants reported a positive PCR in the 2 weeks after the congress. Five of 168 (3%) participants were seropositive at follow-up, all of which had already been positive at baseline. Conclusion: Findings indicate that congresses with a rigorous safety concept may take place, even in areas with moderately-high COVID-19 activity. Whether this holds true in vaccinated populations and with more transmissible viral variants circulating remains unclear.

Safety Evaluation of a Medical Congress Held During the COVID-19 Pandemic—A Prospective Cohort

Optimal surveillance and prevention of healthcare-associated infections (HAI) are crucial for a well-functioning health care system. With a view to establishing a national state-of-the-art programme for surveillance and prevention of HAIs, the Swiss National Center for Infection Control, Swissnoso, developed a survey to explore the options for expanding the existing Swiss HAI surveillance system.

METHODS
An online survey was sent to all Swiss acute care hospitals. Local infection prevention and control (IPC) professionals were asked to answer on behalf of their institutions. The questions covered the structure and organisation of IPC programmes, current preventive measures, availability and capacity of electronic medical record (EMR) systems, and ability and willingness to establish and participate in the proposed new surveillance modules. An invitation was sent to the 156 acute care hospitals and hospital networks in June 2020. Responses were collected up to the end of August 2020.

RESULTS
Ninety-four hospitals and hospital networks out of 156 (60%) completed the survey. Among 84 hospitals reporting the number of acute care beds, 61 (73%) were small (<200 beds), 16 (19%) medium (200–650 beds) and 7 (8%) large hospitals (>650 beds). Twenty-nine different EMR systems were used in the participating hospitals. Twenty-two hospitals were using a different EMR system in their intensive care unit. There were 17 hospitals (18%) without an EMR system but which planned to introduce one soon, and eight small hospitals (9%) neither had an EMR system nor were preparing to introduce one. Surveillance for central-line associated bloodstream infection, catheter-associated urinary tract infection and ventilator-associated pneumonia were already established in 26 (28%), 15 (16%) and 15 (16%) hospitals, respectively. Thirty hospitals (36%) would be willing to participate in the pilot phase of a new surveillance system. Of these, 15 stated that they wanted to be part of the pilot hospital network, 6 could provide hospital-wide surveillance denominators (such as catheter-days and patient-days) to compute incidence rates, and 8 indicated interest in doing both. Large hospitals interested in participating in the pilot phase reported more full-time equivalent staff available for surveillance activities than those who did not declare an interest.

Baseline information on hospital IPC structure and process indicators are essential for the roll-out of national surveillance programmes and for improving surveillance activities. Having an EMR system in place and adequate personnel resources dedicated for surveillance activities are crucial prerequisites for developing and implementing an effective HAI surveillance system. The lack of an EMR system and the diversity and capacities of EMR solutions will be the main challenges for successful implementation of national HAI surveillance modules.

Evaluation of existing and desired measures to monitor, prevent and control healthcare-associated infections in Swiss hospitals.

Risk of SARS-CoV-2 transmission by aerosols, the rational use of masks, and protection of healthcare workers from COVID-19

Antimicrobial prophylaxis administration after umbilical cord clamping in cesarean section and the risk of surgical site infection: a cohort study with 55,901 patients

The predictive representations hypothesis is that representing the state of the world in terms of predictions about the future will result in good generalization. In this thesis, good generalization is specifically quantified by good learning performance in both accuracy and speed when predicting future experiences of interest. We test the predictive representations hypothesis in different scenarios where predictions of interest vary. We observe that the predictive representations hypothesis does hold in specific scenarios. Inspired by this finding, we propose Predictive State Update (PSU), a state update rule that incrementally computes the next state from the current state, while being aware of current predictions of interest in addition to next increment of experiences. Any existing state representation approach can instantiate the PSU if it summarizes the past incrementally, updating the next state based on the current state and next increment of experiences. We empirically demonstrate that (i) the use of PSU can boost the generalization performance of existing state representation approaches, such as those based on simple recurrent neural networks, LSTM (Long Short-Term Memory) networks, and GRU (Gated Recurrent Units) networks, and (ii) these instantiations of PSU outperform approaches which represent states exclusively using predictions.

An Exploration of Predictive Representations of State by Chen Ma

Importance sampling (IS) is a common reweighting strategy for off-policy prediction in reinforcement learning. While it is consistent and unbiased, it can result in high variance updates to the weights for the value function. In this work, we explore a resampling strategy as an alternative to reweighting. We propose Importance Resampling (IR) for off-policy prediction, which resamples experience from a replay buffer and applies standard on-policy updates. The approach avoids using importance sampling ratios in the update, instead correcting the distribution before the update. We characterize the bias and consistency of IR, particularly compared to Weighted IS (WIS). We demonstrate in several microworlds that IR has improved sample efficiency and lower variance updates, as compared to IS and several variance-reduced IS strategies, including variants of WIS and V-trace which clips IS ratios. We also provide a demonstration showing IR improves over IS for learning a value function from images in a racing car simulator.

Abstract The prevalence of antimicrobial resistance (AMR) varies significantly among different patient populations. We aimed to summarise AMR prevalence data from screening studies in different patient settings in Switzerland and to identify surveillance gaps. We performed a systematic review, searching Pubmed, MEDLINE, Embase (01/2000–05/2017) and conference proceedings for Swiss studies reporting on carbapenemase-producing Enterobacteriaceae (CPE), extended-spectrum beta-lactamases (ESBL), mobilised colistin-resistance, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) within different patient settings. We identified 2345 references and included 46 studies. For acute care patients, most screening data come from admission screenings, whereas AMR prevalence among hospitalised patients is largely unknown. Universal admission screenings showed ESBL-prevalences of 5–8% and MRSA-prevalences of 2–5%. For targeted screening, ESBL-prevalence ranged from 14–21%; MRSA-prevalence from 1–4%. For refugees, high ESBL (9–24%) and MRSA (16–24%) carriage rates were reported; returning travellers were frequently (68–80%) colonised with ESBL. Screening data for other pathogens, long-term care facility (LTCF) residents and pediatric populations were scarce. This review confirms high ESBL- and MRSA-carriage rates for risk populations in Switzerland. Emerging pathogens (CPE and VRE) and certain populations (inpatients, LTCF residents and children) are understudied. We encourage epidemiologists and public health authorities to consider these findings in the planning of future surveillance studies.

Antibiotic-resistant pathogens in different patient settings and identification of surveillance gaps in Switzerland – a systematic review

This paper investigates different vector step-size adaptation approaches for non-stationary online, continual prediction problems. Vanilla stochastic gradient descent can be considerably improved by scaling the update with a vector of appropriately chosen step-sizes. Many methods, including AdaGrad, RMSProp, and AMSGrad, keep statistics about the learning process to approximate a second order update—a vector approximation of the inverse Hessian. Another family of approaches use meta-gradient descent to adapt the stepsize parameters to minimize prediction error. These metadescent strategies are promising for non-stationary problems, but have not been as extensively explored as quasi-second order methods. We first derive a general, incremental metadescent algorithm, called AdaGain, designed to be applicable to a much broader range of algorithms, including those with semi-gradient updates or even those with accelerations, such as RMSProp. We provide an empirical comparison of methods from both families. We conclude that methods from both families can perform well, but in non-stationary prediction problems the meta-descent methods exhibit advantages. Our method is particularly robust across several prediction problems, and is competitive with the state-of-the-art method on a large-scale, time-series prediction problem on real data from a mobile robot.

Emergence of vancomycin-resistant enterococci in Switzerland: a nation-wide survey

State construction is important for learning in partially observable environments. A general purpose strategy for state construction is to learn the state update using a Recurrent Neural Network (RNN), which updates the internal state using the current internal state and the most recent observation. This internal state provides a summary of the observed sequence, to facilitate accurate predictions and decision-making. At the same time, specifying and training RNNs is notoriously tricky, particularly as the common strategy to approximate gradients back in time, called truncated Back-prop Through Time (BPTT), can be sensitive to the truncation window. Further, domain-expertise—which can usually help constrain the function class and so improve trainability—can be difficult to incorporate into complex recurrent units used within RNNs. In this work, we explore how to use multi-step predictions to constrain the RNN and incorporate prior knowledge. In particular, we revisit the idea of using predictions to construct state and ask: does constraining (parts of) the state to consist of predictions about the future improve RNN trainability? We formulate a novel RNN architecture, called a General Value Function Network (GVFN), where each internal state component corresponds to a prediction about the future represented as a value function. We first provide an objective for optimizing GVFNs, and derive several algorithms to optimize this objective. We then show that GVFNs are more robust to the truncation level, in many cases only requiring one-step gradient updates.

Directed exploration strategies for reinforcement learning are critical for learning an optimal policy in a minimal number of interactions with the environment. Many algorithms use optimism to direct exploration, either through visitation estimates or upper confidence bounds, as opposed to data-inefficient strategies like \epsilon-greedy that use random, undirected exploration. Most data-efficient exploration methods require significant computation, typically relying on a learned model to guide exploration. Least-squares methods have the potential to provide some of the data-efficiency benefits of model-based approaches -- because they summarize past interactions -- with the computation closer to that of model-free approaches. In this work, we provide a novel, computationally efficient, incremental exploration strategy, leveraging this property of least-squares temporal difference learning (LSTD). We derive upper confidence bounds on the action-values learned by LSTD, with context-dependent (or state-dependent) noise variance. Such context-dependent noise focuses exploration on a subset of variable states, and allows for reduced exploration in other states. We empirically demonstrate that our algorithm can converge more quickly than other incremental exploration strategies using confidence estimates on action-values.

Context-Dependent Upper-Confidence Bounds for Directed Exploration

The ability of an agent to {\em discover} its own learning objectives has long been considered a key ingredient for artificial general intelligence. Breakthroughs in autonomous decision making and reinforcement learning have primarily been in domains where the agent's goal is outlined and clear: such as playing a game to win, or driving safely. Several studies have demonstrated that learning extramural sub-tasks and auxiliary predictions can improve (1) single human-specified task learning, (2) transfer of learning, (3) and the agent's learned representation of the world. In all these examples, the agent was instructed what to learn about. We investigate a framework for discovery: curating a large collection of predictions, which are used to construct the agent's representation of the world. Specifically, our system maintains a large collection of predictions, continually pruning and replacing predictions. We highlight the importance of considering stability rather than convergence for such a system, and develop an adaptive, regularized algorithm towards that aim. We provide several experiments in computational micro-worlds demonstrating that this simple approach can be effective for discovering useful predictions autonomously.

Discovery of Predictive Representations With a Network of General Value Functions

Kernel representations provide a nonlinear representation, through similarities to prototypes, but require only simple linear learning algorithms given those prototypes. In a continual learning setting, with a constant stream of observations, it is critical to have an efficient mechanism for sub-selecting prototypes amongst observations. In this work, we develop an approximately submodular criterion for this setting, and an efficient online greedy submodular maximization algorithm for optimizing the criterion. We extend streaming submodular maximization algorithms to continual learning, by removing the need for multiple passes—which is infeasible—and instead introducing the idea of coverage time. We propose a general block-diagonal approximation for the greedy update with our criterion, that enables updates linear in the number of prototypes. We empirically demonstrate the effectiveness of this approximation, in terms of approximation quality, significant runtime improvements, and effective prediction performance.

Adapting Kernel Representations Online Using Submodular Maximization

The objective of continual learning is to build agents that continually learn about their world, building on prior learning. In this paper, we explore an approach to continual learning based on making and updating many predictions formalized as general value functions (GVFs). The idea behind GVFs is simple: if we can cast the task of representing predictive knowledge as a prediction of future reward, then computationally efficient policy evaluation methods from reinforcement learning can be used to learn a large collection of predictions while the agent interacts with the world. We explore this idea further by analyzing how GVF predictions can be used as predictive features, and introduce two algorithmic techniques to ensure the stability of continual prediction learning. We illustrate these ideas with a small experiment in the cycle world domain.

Stable predictive representations with general value functions for continual learning

An Event-Driven Software Architecture for Multiple Unmanned Aerial Vehicles to Cooperatively Locate Mobile Targets

Cette invention decrit des schemas d'inversion de points sur de nouvelles presentations de panneaux d'affichage pourvues d'excitateurs supplementaires. Un tel panneau d'affichage comprend essentiellement un ensemble d'un groupe de repetition de sous-pixels presentant une configuration de six colonnes et de deux rangees: R R G B B G et B B G R R G, ou au moins un ensemble de sous-pixels de colonnes adjacentes partagent des donnees d'images provenant d'un seul excitateur sur le panneau d'affichage.

Inversion de points sur de nouvelles presentations de panneaux d'affichage avec excitateur supplementaire

After the introduction of immunisation against measles, mumps, and rubella, numerous outbreaks of mumps were reported in the 1980s and ‘90s in Switzerland and southern Europe.1 2 The Rubini strain is still widely used in Europe,3 and we report here a large outbreak of mumps in a population with a high vaccination rate and examine the differential efficacy of the three vaccine strains.

An outbreak was investigated in a small village in Switzerland. All children (ages 5-13) were included in the cohort. Information on immunisation status was obtained from vaccine certificates. The person who investigated the cases of mumps was blinded with regard to the vaccination status. A case was defined if mumps virus was isolated on culture, if a doctor confirmed the diagnosis, or if the typical clinical picture was described in a sibling of a patient with confirmed disease. The absence of IgG antibodies to mumps virus served as confirmation of full susceptibility to …

Comparative efficacy of three mumps vaccines during disease outbreak in eastern Switzerland: cohort study

In this work we investigate the applicability of projection based model reduction techniques in the context of dynamic optimization. Especially, we focus on the question, whether dynamic optimization with a reduced model can give the same solution in less computation time, as compared to optimization with the original model.

LPT – 2002 – 22 Projection Based Model Reduction for Dynamic Optimization

The desire to build more energy efficient homes in the United States has led to the expansion of the residential spray polyurethane foam (SPF) insulation industry. Upon application of SPF, reacting chemicals form expanding polyurethane foam that fills cracks and gaps, reducing infiltration and thermal conductivity of the building envelope. However, more information is being sought on chemical emissions from SPF to better understand occupant exposures and any potential impacts on health. The objective of this investigation was to investigate the emission of flame retardant tris (1-chloro-2-propyl) phosphate (TCPP) from SPF using both micro-chambers and a full scale residential test facility. Two high pressure, open cell foams and one high pressure, closed cell foam were tested using micro-chambers. After 100 hours, TCPP concentrations from the open cell samples were 100 times higher than TCPP concentrations from the closed cell SPF. TCPP emissions from open cell foam were found to correlate exponentially with temperature and vary with flow rate, indicating emission factors from SPF micro-chamber experiments may not directly predict TCPP concentrations in buildings without consideration of material mass transfer properties. Due to the use of TCPP in furniture, SPF has not previously been positively identified as a primary source of indoor TCPP concentrations in actual buildings. This research measured airborne TCPP concentrations in the furniture-free National Institute of Standards and Technology (NIST) Net Zero Energy Residential Test Facility (NZERTF) that contained 15 m of exposed, two-year-old, open cell SPF. The measured NZERTF TCPP emission rates were not directly predicted by emission factors from the micro-chamber measurements, which suggests a mass transfer-based modelling approach is needed for predicting TCPP concentrations from open cell SPF. More research is needed to determine how data from micro-chamber studies can be used to predict exposures of residential occupants to emissions from SPF foam.

Flame Retardant Emissions from Spray Polyurethane Foam Insulation

Characterization of Emissions from Spray Polyurethane Foam: Letter Report to U.S. Consumer Product Safety Commission Interagency Agreement CPSC-I-13-0016 | NIST

Long Term Emissions from Spray Polyurethane Foam Insulation | NIST

This study evaluated the effectiveness of a low-VOC (volatile organic compounds) specification designed to minimize occupant exposures to indoor air pollutants in a net-zero energy research house meeting the ASHRAE Standard 62.2 ventilation requirements. The results show that the use of medium density fiberboard and particleboard with no-added formaldehyde resins for cabinetry and other finished products effectively controlled the formaldehyde emissions and kept concentrations below levels in typical new homes. Monitoring of seasonal indoor VOC concentrations suggests that building envelope components may be an overlooked source for some VOCs, especially aldehydes and alkanes.

Long Term Air Quality Monitoring in a Net-Zero Energy Residential Test Facility Designed with Specifications for Low Emitting Interior Products | NIST

Abstract Dedicated integrated experiments have been used to determine in situ the corrosion rate of carbon steels in geological repository mock-ups (90°C, anaerobic, slow synthetic water flux…). Electrochemical impedance spectroscopy (EIS) measurements were performed, allowing for the extraction of instantaneous corrosion rate. In a separate but comparable set-up, occasional sampling among a batch of fifteen equivalent cells was performed, allowing for both gravimetric measurements and corrosion products characterisation. In both cases, the corrosion rate decreases continuously but the stationary state seems not to be reached within the duration of the EIS experiment. The slow kinetics and pseudo steady state of the corrosion process are confirmed by post-exposure characterisation of the corrosion products by SEM, micro-Raman spectroscopy and micro-XRD, revealing the rapid formation of an iron phyllosilicate layer that may act as a barrier layer for diffusion of the species between the clay environment and the alloy. This analysis provides good confidence on long term (over a millennium) extrapolations made from the experimental data fits, leading to an estimation of reasonable cumulated damages in the [40;120] μm range after 1000 years exposure.

On corrosion of carbon steels in Callovo-Oxfordian clay: complementary EIS, gravimetric and structural study providing insights on long term behaviour in French geological disposal conditions

The fluid movement of an arm is controlled by multiple parameters that can be set independently. Recent studies argue that arm movements are generated by the collective dynamics of neurons in motor cortex. But how these collective dynamics simultaneously encode and control multiple parameters of movement is an open question. Using a task where monkeys made sequential, varied arm movements, we show that the direction and urgency of arm movements are simultaneously encoded in the low-dimensional trajectories of population activity: each movement’s direction by a fixed, looped neural trajectory and its urgency by how quickly that trajectory was traversed. Network models showed this latent coding is potentially advantageous as it allows the direction and urgency of arm movement to be independently controlled. Our results suggest how low-dimensional neural dynamics can define multiple parameters of goal-directed movement simultaneously.

Motor cortex latent dynamics encode arm movement direction and urgency independently

Dimensionality reduction methods are frequently used to analyze high-dimensional activity of cortical neuron populations during behavior. The resulting oscillatory trajectories that consistently emerge from this analysis have been interpreted as a signature of latent dynamical systems. Here, we show that these oscillatory trajectories necessarily result from applying dimensionality reduction methods on recordings that approximately exhibit continuous variation in time, regardless of whether or not the recorded system incorporates latent dynamics.

Decoding stimuli or behaviour from recorded neural activity is a common approach to interrogate brain function in research, and an essential part of brain-computer and brain-machine interfaces. Reliable decoding even from small neural populations is possible because high dimensional neural population activity typically occupies low dimensional manifolds that are discoverable with suitable latent variable models. Over time however, drifts in activity of individual neurons and instabilities in neural recording devices can be substantial, making stable decoding over days and weeks impractical. While this drift cannot be predicted on an individual neuron level, population level variations over consecutive recording sessions such as differing sets of neurons and varying permutations of consistent neurons in recorded data may be learnable when the underlying manifold is stable over time. Classification of consistent versus unfamiliar neurons across sessions and accounting for deviations in the order of consistent recording neurons in recording datasets over sessions of recordings may then maintain decoding performance. In this work we show that self-supervised training of a deep neural network can be used to compensate for this inter-session variability. As a result, a sequential autoencoding model can maintain state-of-the-art behaviour decoding performance for completely unseen recording sessions several days into the future. Our approach only requires a single recording session for training the model, and is a step towards reliable, recalibration-free brain computer interfaces.

Capturing cross-session neural population variability through self-supervised identification of consistent neuron ensembles

Neural population activity relating to behaviour is assumed to be inherently low-dimensional despite the observed high dimensionality of data recorded using multi-electrode arrays. Therefore, predicting behaviour from neural population recordings has been shown to be most effective when using latent variable models. Over time however, the activity of single neurons can drift, and different neurons will be recorded due to movement of implanted neural probes. This means that a decoder trained to predict behaviour on one day performs worse when tested on a different day. On the other hand, evidence suggests that the latent dynamics underlying behaviour may be stable even over months and years. Based on this idea, we intro-duce a model capable of inferring behaviourally relevant latent dynamics from previously unseen data recorded from the same animal, without any need for decoder recalibration. We show that unsupervised domain adaptation combined with a sequential variational autoencoder, trained on sev-eral sessions, can achieve good generalisation to unseen data and correctly predict behaviour where conventional methods fail. Our results further sup-port the hypothesis that behaviour-related neural dynamics are low-dimensional and stable over time, and will enable more effective and flexible use of brain computer interface technologies.

Robust alignment of cross-session recordings of neural population activity by behaviour via unsupervised domain adaptation

Recorded activity of cortical neurons during behavior is often analyzed with dimensionality reduction methods. The resulting oscillatory trajectories have been interpreted as signatures of latent oscillatory dynamical systems. Here we show that oscillatory trajectories arise as a consequence of the horseshoe effect after applying dimensionality reduction methods on signals that approximately exhibit continuous variation in time, regardless of whether latent oscillatory dynamical systems are present or not. We show that task-relevant information is instead contained in deviations between oscillatory trajectories, which we account for by introducing a new model that goes beyond the dichotomy between representational and dynamical systems models of neural activity. Our findings help interpret the results of dimensionality reduction analyses.

Interpreting dynamics of neural activity after dimensionality reduction

Latent dynamics models have emerged as powerful tools for modeling and interpreting neural population activity. Recently, there has been a focus on incorporating simultaneously measured behaviour into these models to further disentangle sources of neural variability in their latent space. These approaches, however, are limited in their ability to capture the underlying neural dynamics (e.g. linear) and in their ability to relate the learned dynamics back to the observed behaviour (e.g. no time lag). To this end, we introduce Targeted Neural Dynamical Modeling (TNDM), a nonlinear state-space model that jointly models the neural activity and external behavioural variables. TNDM decomposes neural dynamics into behaviourally relevant and behaviourally irrelevant dynamics; the relevant dynamics are used to reconstruct the behaviour through a flexible linear decoder and both sets of dynamics are used to reconstruct the neural activity through a linear decoder with no time lag. We implement TNDM as a sequential variational autoencoder and validate it on simulated recordings and recordings taken from the premotor and motor cortex of a monkey performing a center-out reaching task. We show that TNDM is able to learn low-dimensional latent dynamics that are highly predictive of behaviour without sacrificing its fit to the neural data.

Rapid adaptation of brain–computer interfaces to new neuronal ensembles or participants via generative modelling

 Recovering arm control is a top priority for people with paralysis. Unfortunately, the complexity of the neural mechanisms underlying arm control practically limited the effectiveness of neurotechnology approaches. Here, we exploited the neural function of surviving spinal circuits to restore voluntary arm and hand control in three monkeys with spinal cord injury using spinal cord stimulation. Our neural interface leverages the functional organization of the dorsal roots to convey artificial excitation via electrical stimulation to relevant spinal segments at appropriate movement phases. Stimulation bursts, triggered by intracortical signals produced sustained arm movements enabling monkeys with arm paralysis to perform an unconstrained, three-dimensional reach-and-grasp task. Stimulation specifically improved strength, task performances and movement quality. Electrophysiology suggested that artificial recruitment of the sensory afferents was synergistically integrated with spared descending inputs and spinal reflexes to produce coordinated movements. The efficacy and reliability of our approach hold realistic promises of clinical translation.

Epidural Electrical Stimulation Of The Cervical Dorsal Roots Restores Voluntary Arm Control In Paralyzed Monkeys

Decision letter: Sensory restoration by epidural stimulation of the lateral spinal cord in upper-limb amputees

Behavior relies on continuous influx of sensory information about the body and the environment. In primates, cortex integrates somatic feedback to accurately reach and manipulate objects. Yet, in many experimental regimes motor cortex seems paradoxically to operate as a feedforward, rather than feedback-driven, system. Here, we recorded simultaneously from motor and somatosensory cortex as monkeys performed a naturalistic reaching and object interaction behavior. We studied how unexpected feedback from behavioral errors influences cortical dynamics. Motor cortex generally exhibited robust feedforward dynamics, yet displayed feedback-driven dynamics surrounding correction of behavioral errors. We then decomposed motor cortical activity into orthogonal subspaces capturing communication with somatosensory cortex or behavior-generating dynamics. During error correction, the communication subspace became feedback-driven, while the behavioral subspace maintained feedforward dynamics. We therefore demonstrate that cortical activity is compartmentalized within distinct subspaces that shape the population dynamics, enabling flexible integration of salient inputs with ongoing activity for robust behavior.

Motor cortical dynamics are shaped by multiple distinct subspaces during naturalistic behavior

 Regaining arm motor control is critical for people with paralysis. Despite promising results on grasping, no technology could restore effective arm control. Here, we show that electrical stimulation of the cervical spinal cord enabled three monkeys with cervical spinal injury to execute functional arm movements. We designed an epidural interface that engaged surviving spinal circuits via the recruitment of large sensory afferents to produce movement. Simple stimulation bursts produced sustained joint movements which, triggered by movement-related intracortical signals, enabled monkeys with arm paralysis to perform an unconstrained, three-dimensional reach and grasp task. This restoration of voluntary motor control was enabled by the synergistic integration of spared descending commands and electrical stimulation within the spinal cord. The simplicity of this technology promises realistic clinical translation.

Cervical Epidural Electrical Stimulation Restores Voluntary Arm Control In Paralyzed Monkeys

Altered tuning in primary motor cortex does not account for behavioral adaptation during force field learning

Bursts of activity in networks of neurons are thought to convey salient information and drive synaptic plasticity. Here we report that network bursts also exert a profound effect on Spike-Timing-Dependent Plasticity (STDP). In acute slices of juvenile rat somatosensory cortex we paired a network burst, which alone induced long-term depression (LTD), with STDP-induced long-term potentiation (LTP) and LTD. We observed that STDP-induced LTP was either unaffected, blocked or flipped into LTD by the network burst, and that STDP-induced LTD was either saturated or flipped into LTP, depending on the relative timing of the network burst with respect to spike coincidences of the STDP event. We hypothesized that network bursts flip STDP-induced LTP to LTD by depleting resources needed for LTP and therefore developed a resource-dependent STDP learning rule. In a model neural network under the influence of the proposed resource-dependent STDP rule, we found that excitatory synaptic coupling was homeostatically regulated to produce power law distributed burst amplitudes reflecting self-organized criticality, a state that ensures optimal information coding.

Towards an Ultrasound Probe with Vision: Structured Light to Determine Surface Orientation

A “Workcation” (combining work and vacation) has become increasingly common. Traditionally, the workcation focus has been on productivity; however, data showing associations between workcations and improvements in employees’ health are lacking. Therefore, this study examines the effects of a workcation on blood pressure, arterial stiffness, heart rate, autonomic nervous system function, and physical activity. Twenty healthy employees participating in a five-day workcation project at a large private company agreed to participate in this study. Data on arterial stiffness, heart rate, autonomic nerve activity, and physical activity were collected before, during, and after the workcation. Arterial stiffness, blood pressure, and heart rate significantly decreased (p < 0.05); meanwhile, physical activity levels and parasympathetic function during sleep significantly increased during the workcation (p < 0.05). Thus, a workcation implies a new way of working that improves employees’ cardiovascular indices and parasympathetic function during sleep.

A Workcation Improves Cardiac Parasympathetic Function during Sleep to Decrease Arterial Stiffness in Workers

[Purpose] This study aimed to determine the effects of aerobic exercise training frequency on arterial stiffness in postmenopausal females. [Participants and Methods] This study included 45 postmenopausal females randomly assigned to one of the following three groups: 1) low-frequency training group (aerobic exercise training twice per week); 2) high-frequency training group (aerobic exercise training four times per week); and 3) control group (no training). Each group was subjected to an 8-week intervention period. Both traditional and newer indexes were measured immediately before and after the 8-week intervention period. [Results] In the low-frequency training group, carotid-femoral pulse wave velocity and arterial velocity pulse index decreased post 8 weeks compared with those at baseline. In the high-frequency training group, carotid-femoral, brachial-ankle, and heart-brachial pulse wave velocities and arterial velocity pulse and arterial pressure-volume indexes decreased post 8 weeks compared to those at baseline. In the control group, no change in any indices post 8 weeks compared to those at baseline was observed. [Conclusion] Carotid-femoral pulse wave velocity was lower after aerobic training than before training in both the exercise groups. Thus, aerobic exercise training might have a beneficial effect on aortic stiffness, regardless of the training frequency in this population.

Effect of aerobic exercise training frequency on arterial stiffness in middle-aged and elderly females

Increased arterial stiffness during acute hyperglycemia is a risk factor for cardiovascular disease, but the type of carbohydrate that inhibits it is unknown. The purpose of this study was to determine the efficacy of low-glycemic-index isomaltulose on arterial stiffness during hyperglycemia in middle-aged and older adults. Ten healthy middle-aged and older adult subjects orally ingested a solution containing 25 g of isomaltulose (ISI trial) and sucrose (SSI trial) in a crossover study. In the SSI trial, the brachial–ankle (ba) pulse wave velocity (PWV) increased 30, 60, and 90 min after ingestion compared with that before ingestion (p < 0.01); however, in the ISI trial, the baPWV did not change after ingestion compared with that before ingestion. Blood glucose levels 30 min after intake were lower in the ISI trial than in the SSI trial (p < 0.01). The baPWV and systolic blood pressure were positively correlated 90 min after isomaltulose and sucrose ingestion (r = 0.640, p < 0.05). These results indicate that isomaltulose intake inhibits an acute increase in arterial stiffness. The results of the present study may have significant clinical implications on the implementation of dietary programs for middle-aged and elderly patients.

Effects of Different Types of Carbohydrates on Arterial Stiffness: A Comparison of Isomaltulose and Sucrose

The frequency of aerobic exercise training in reducing the increase in arterial stiffness during acute hyperglycemia, a risk factor for cardiovascular disease, is unknown. The aim of the study was to determine the aerobic exercise training frequency on arterial stiffness in a hyperglycemic state in middle-aged and elderly females. Twenty healthy elderly people were randomly assigned to a two-times-a-week (T2, n = 10) and four-times-a-week (T4, n = 10) exercise group. All participants exercised for 35 min per session, which consisted of jogging exercises with a heart rate intensity of 65%. Brachial-ankle (ba), and heart-brachial (hb) pulse wave velocity (PWV) were measured before, 4 and 8 weeks after intervention; before the oral ingestion of 75-g of glucose; and 30, 60, and 90 min after ingestion. The baPWV before and 4 weeks after the intervention increased in both groups (p < 0.05), but only increased 8 weeks after intervention in the T2 group. hbPWV was unchanged before, 4 and 8 weeks after intervention in both groups. These findings show that frequent aerobic exercise suppresses the increase in arterial stiffness following glucose intake. The results of this study can be used to support the implementation of exercise programs for middle-aged and elderly patients.

The Effect of Aerobic Exercise Training Frequency on Arterial Stiffness in a Hyperglycemic State in Middle-Aged and Elderly Females

Is individual day-to-day variation of arterial stiffness associated with variation of maximal aerobic performance?

Presbyopia is characterized by a decline in the ability to accommodate the lens. The most commonly accepted theory for the onset of presbyopia is an age-related increase in the stiffness of the lens. However, the cause of lens sclerosis remains unclear. With age, water microcirculation in the lens could change because of an increase in intracellular pressure. In the lens, the intracellular pressure is controlled by the Transient Receptor Potential Vanilloid (TRPV) 1 and TRPV4 feedback pathways. In this study, we tried to elucidate that administration of α-glucosyl-hesperidin (G-Hsd), previously reported to prevent nuclear cataract formation, affects lens elasticity and the distribution of TRPV channels and Aquaporin (AQP) channels to meet the requirement of intracellular pressure. As a result, the mouse control lens was significantly toughened compared to both the 1% and 2% G-Hsd mouse lens treatments. The anti-oxidant levels in the lens and plasma decreased with age; however, this decrease could be nullified with either 1% or 2% G-Hsd treatment in a concentration- and exposure time-dependent manner. Moreover, G-Hsd treatment affected the TRPV4 distribution, but not TRPV1, AQP0, and AQP5, in the peripheral area and could maintain intracellular pressure. These findings suggest that G-Hsd has great potential as a compound to prevent presbyopia and/or cataract formation.

Effect of Alpha-Glucosyl-Hesperidin Consumption on Lens Sclerosis and Presbyopia

Background: We assessed acute effects of palatinose (isomaltulose) consumption on arterial stiffness. Increased arterial stiffness due to elevated postprandial blood glucose levels increases the risk of cardiovascular disease. Palatinose appears to suppress an increase in BG levels while securing energy, and might decrease acute increases in arterial stiffness during hyperglycemia. However, the acute effects of palatinose consumption on arterial stiffness are unknown. 
 
Methods: Ten older adults had two interventions in the following cross-over design: (i) ingestion of 25 g of glucose solution (GSI trial) and (ii) ingestion of 25 g of palatinose solution (PSI trial). Participants fasted for 12 h and then visited the laboratory. We assessed brachialankle (ba) and heartbrachial (hb) pulse wave velocity (PWV), the cardio-ankle vascular index (CAVI), brachial and ankle blood pressure, heart rate, and blood glucose levels at baseline (before ingestion) and 30, 60, and 90 min after ingestion. 
 
Results: Changes in baPWV, hbPWV, the CAVI, and ankle systolic blood pressure were significantly increased from baseline at 30, 60, and 90 min after ingestion in the GSI trial (p < 0.05), but not in the PSI trial. The changes in baPWV, hbPWV, and CAVI were significantly lower after ingestion in the PSI trial compared with the GSI trial. Blood glucose levels were significantly lower at 30 and 60 min after ingestion in the PSI trial compared with the GSI trial (p < 0.01). 
 
Conclusions: We conclude that arterial stiffness may increase after glucose ingestion, but it is not elevated after palatinose ingestion.

Acute Changes in Arterial Stiffness with Palatinose Versus Glucose Intake in Elderly

65. Associations of toe flexor strength and other physical fitness paramerters in elderly Masataka Suwa Dept. Food Nutr., Koriyama Women’s Univ., Koriyama, Fukushima, Japan [Purpose] Toe flexor strength relates to locomotive performance, fall, prevalence of diabetes mellitus, and cognitive function. Agerelated decrease of toe flexor strength is drastic. Toe flexor strength may be useful for screening for health and aging-related problems. The characteristics of toe flexor strength remain to be fully elucidated. The purpose of this study was to examine the association of toe flexor strength and other physical fitness in elderly men and women. [Methods] Elderly Japanese men (n=50) and women (n=121), aged 65-88 years, participated in this study. Toe flexor strength, handgrip strength, knee extensor strength, sit-and-reach and functional reach were measured. [Results] Toe flexor strength (-34%), knee extensor strength (-24%) and handgrip strength (-39%) of women were significantly lower than those of men. Sit-and-reach of women was significantly higher than that of women (+17%). Functional reach did not differ between male and female. In men, toe flexor strength was significantly associated with knee extensor strength (r = 0.53), handgrip strength (r = 0.51), sit-and-reach (r = 0.33) and functional reach (r = 0.41). In women, such associations were also observed in knee extensor strength (r = 0.57), handgrip strength (r = 0.43), and functional reach (r = 0.39) except for sit-and-reach (r = 0.13). These associations were even observed if adjusted by age and body weight. [Conclusion] The results suggest that toe flexor strength is greater in men than women in elderly. Additionally, toe flexor strength is associated with other physical fitness except for sit-andreach in women.

Associations of toe flexor strength and other physical fitness paramerters in elderly

[Purpose] In the present study, we investigated the effects of regular aerobic training with different intensities and durations on new indices of arterial stiffness measured via an upper-arm oscillometric device. [Participants and Methods] We gathered data from 41 middle-aged and older people (age 65.0 ± 11.7 years). Participants were randomly divided into five groups: (1) 15 minutes of low intensity aerobic training (n=10); (2) 30 minutes of low intensity training (n=7); (3) 15 minutes of moderate-intensity training (n=9); (4) 30 minutes of moderate-intensity training (n=8); and (5) a non-training group (n=7). Training was conducted for 8 weeks, three times per week. Arterial pulse wave index, arterial pressure-volume index, brachial-ankle and heart-brachial pulse wave velocity, cardio-ankle vascular index, brachial and ankle blood pressure, heart rate, and peak oxygen uptake were measured before and after the intervention. [Results] All indicators of arterial stiffness and brachial and ankle blood pressure in the exercise groups were significantly lower after versus before the intervention. Peak oxygen uptake did not differ before versus after the intervention. [Conclusion] The present findings indicate that regular aerobic exercise may be important in reducing arterial stiffness regardless of the intensity or duration of aerobic exercise.

Effects of different intensities and durations of aerobic exercise training on arterial stiffness

ABSTRACT Purpose Blackcurrant extract mainly contains anthocyanins. Several reports suggest that anthocyanins have beneficial effect for cardiovascular functions. The aim of this study was to examine the effect of 7-day intake of New Zealand blackcurrant (NZBC) extract on arterial functions, e.g. arterial stiffness, and serum lipids. Methods A randomized, double-blind, placebo-controlled, crossover design study with a washout period of 28 days was conducted. Fourteen older adults participated in this study (age 73.3 ± 1.7 years). Participants took either a 7-day course of placebo or two capsules of NZBC extract (each 300 mg capsule contains 35% blackcurrant extract). Participants took one of the two trials first and then took the other after a washout period. Carotid-femoral pulse-wave velocity, an index of central arterial stiffness, and central blood pressure were measured at baseline and again at the end of the 7-day study period. Results Compared to baseline, carotid-femoral pulse-wave velocity (P = .03) and central blood pressure (P = .02) decreased significantly after the 7-day study period with NZBC intake. In addition, carotid-femoral pulse-wave velocity (P = .04) and central blood pressure (P = .001) in the NZBC intake trial decreased significantly more than in the placebo intake trial. No effects were observed on serum lipids. Conclusion These results suggest that short-term NZBC intake reduces central arterial stiffness and central blood pressure in older adults. Therefore, anthocyanin-rich blackcurrants might be beneficial for maintaining or improving cardiovascular health as an alternative to pharmaceutical medications. Abbreviations Aix: augmentation index; BP: blood pressure; cfPWV: carotid–femoral pulse-wave velocity; CVD: cardiovascular diseases; DBP: diastolic blood pressure; faPWV: femoral-ankle pulse-wave velocity; FG: fasting glucose; HDL: high-density lipoprotein cholesterol; LDL: low-density lipoprotein cholesterol; MBP: mean blood pressure; NZBC: New Zealand blackcurrant; PP: pulse pressure; SBP: systolic blood pressure; TG: triglycerides.

Effects of blackcurrant extract on arterial functions in older adults: A randomized, double-blind, placebo-controlled, crossover trial

We examined the effects of increasing physical activity on arterial stiffness during hyperglycemia. Nineteen glucose-intolerant elderly participated in the study. We randomly assigned 10 participants to increase their daily activity in everyday life, regardless of the time or intensity, for 1 month (PAI group) (age, 74.6 ± 1.3 years; mean ± SE) and nine participants to maintain their level of activity (CON group) (age, 79.2 ± 2.1 years; mean ± SE). The 75-g oral glucose tolerance test was conducted in each participant in both groups before and after the start of the intervention to confirm glucose intolerance. Brachial-ankle pulse wave velocity and cardio-ankle vascular index significantly increased from baseline at 30, 60, and 90 min after the 75-g glucose ingestion after the intervention in the CON group (p<0.05), but not in the PAI group. Heart-brachial pulse wave velocity did not change compared to baseline after the 75-g glucose ingestion in either group and did not change from baseline at 30, 60, and 90 min after the 75-g glucose ingestion before and after the intervention in both groups. The present findings indicate that a short-term increase in physical activity suppresses the increase in arterial stiffness after glucose intake.

Effects of a short-term increase in physical activity on arterial stiffness during hyperglycemia.

We compared arterial stiffness after glucose intake in active and inactive elderly people with impaired glucose tolerance and clarified whether physical activity was associated with arterial stiffness after ingestion of glucose. Twenty older adults with impaired glucose tolerance were analyzed in a cross-sectional design. Based on the international physical activity questionnaire, participants were divided into the active group (daily step count: 10,175.9 ± 837.8 steps/day, n = 10) or the inactive group (daily step count: 4,125.6 ± 485.9 steps/day, n = 10). Brachial-ankle (systemic) and heart-brachial (aortic) pulse wave velocity and cardio-ankle vascular index (systemic) were increased at 30, 60, and 90 min compared to baseline after a 75-g oral glucose tolerance test in the inactive but not the active group. Heart-brachial pulse wave velocity did not change compared to baseline after a 75-g oral glucose tolerance test in either group. The area under the curve for brachial-ankle pulse wave velocity was associated with daily living activity (r = -0.577, p = 0.008), daily step activity (r = -0.546, p = 0.013), and the daily step count (r = -0.797, p = 0.0001). The present findings indicate that physical activity or inactivity is associated with arterial stiffness following glucose ingestion.

Arterial stiffness during hyperglycemia in older adults with high physical activity vs low physical activity.

Isometric handgrip training reduces blood pressure and wave reflections in East Asian, non-medicated, middle-aged and older adults: a randomized control trial

Background Post-prandial hyperglycemia is associated with higher cardiovascular risk, which causes arterial stiffening and impaired function. Although post-prandial increases in blood glucose are proportional to the level of intake, the acute effects of different glucose intakes on arterial stiffness have not been fully characterized. The present study aimed to determine the acute effects of differences in glucose intake on arterial stiffness. Methods Six healthy middle-aged and elderly individuals (mean age, 60.0 ± 12.1 years) were orally administered 15, 20, and 25 g of glucose on separate days in a randomized, controlled, cross-over fashion. Brachial-ankle pulse wave velocity, heart-brachial pulse wave velocity, cardio-ankle vascular index, brachial and ankle blood pressure, heart rate, and blood glucose and serum insulin concentrations before and 30, 60, and 90 min after glucose ingestion were measured. Results Compared to baseline, brachial-ankle pulse wave velocity was higher at 30, 60 and 90 min after ingestion of 25 g glucose, and higher at 90 min after ingestion of 20 g glucose, but at no time points after ingestion of 15 g. Cardio-ankle vascular index was higher at 60 min than at baseline after ingestion of 25 g glucose, but not after ingestion of 15 or 20 g. Conclusions These results suggest that brachial-ankle pulse wave velocity and cardio-ankle vascular index is affected by the quantity of glucose ingested. Proposed presently is that glucose intake should be reduced at each meal to avoid increases in brachial-ankle pulse wave velocity and cardio-ankle vascular index during acute hyperglycemia.

Acute effects of difference in glucose intake on arterial stiffness in healthy subjects

This study compared changes in brachial-ankle pulse wave velocity (baPWV) after concentric (CON) versus eccentric (ECC) cycling. It was hypothesized that baPWV would increase after the first ECC bout (ECC1) because of muscle damage, but not after the second ECC bout (ECC2), and would decrease after CON. Fifteen young (aged 20-30 years) men performed 2 bouts of 30-min ECC (ECC1 and ECC2) at 60% of maximal CON power output and 2 bouts of 30-min CON at the same intensity as that of ECC (CON1), and at the same oxygen consumption as that of ECC (CON2) every 2 weeks. Oxygen uptake during the cycling was recorded, and baPWV was measured before and at 0.5, 1, 24, and 48 h after each cycling bout. Maximal voluntary contraction (MVC) torque and muscle soreness of the knee extensors were assessed before and at 24 and 48 h after each cycling bout. Changes in these variables over time were compared among the 4 cycling bouts by 2-way repeated-measured ANOVA. baPWV decreased (P < 0.05) 8% from the baseline (1119 ± 116 cm/s) at 0.5 h after CON1 (1028 ± 126 cm/s), but no significant changes were evident after ECC1, ECC2, and CON2. MVC torque decreased 10% from the baseline at 24 h after ECC1, but no significant changes were evident after CON1, CON2, and ECC2. These results did not support the hypothesis, and suggest that minor muscle damage induced by eccentric cycling does not affect arterial stiffness.

Changes in arterial stiffness after eccentric versus concentric cycling.

ABSTRACT The aim of this study was to investigate the acute repeated bouts of aerobic exercise decrease leg arterial stiffness. However, the influence of repeated bouts of aerobic exercise on arterial stiffness after glucose ingestion is unknown. The present study investigates the acute effects of repeated bouts of aerobic exercise on arterial stiffness after the 75-g oral glucose tolerance test (OGTT). Ten healthy young men (age, 23.2 ± 0.9 years) performed repeated bouts of aerobic exercise trial (RE, 65% peak oxygen uptake; two 15 min bouts of cycling performed 20 min apart) and control trial (CON, seated and resting in a quiet room) at 80 min before the 75-g OGTT on separate days in a randomized, controlled crossover fashion. Carotid-femoral (aortic) and femoral-ankle (leg) pulse wave velocity, carotid augmentation index, brachial and ankle blood pressure, heart rate and blood glucose and insulin levels were measured before (baseline) and 30, 60 and 120 min after the 75-g OGTT. Leg pulse wave velocity, ankle systolic blood pressure and blood glucose levels increased from baseline after the 75-g OGTT in the CON trial, but not in the RE trial. The present findings indicate that acute repeated bouts of aerobic exercise before glucose ingestion suppress increases in leg arterial stiffness following glucose ingestion. Abbreviations: RE trial repeated bouts of aerobic exercise trial; CON trial control trial; BG blood glucose; VO2peak peak oxygen uptake; PWV Pulse wave velocity; AIx carotid augmentation index; BP blood pressure; HR heart rate; CVs coefficients of variation; RPE Ratings of perceived exertion; SE standard error

Acute effects of repeated bouts of aerobic exercise on arterial stiffness after glucose ingestion

The present study investigated the acute effect of a footbath on increases in arterial stiffness after glucose ingestion in healthy young women. Nine healthy young women (aged 18.4 ± 0.2 years; mean ± SE) completed three trials in random order. They started a footbath before 75-g oral glucose ingestion, a footbath after 75-g oral glucose ingestion and no footbath (control) trials. Aortic (carotid–femoral) and leg (femoral–ankle) pulse wave velocity, the carotid augmentation index, carotid, brachial and ankle blood pressure, heart rate, blood glucose levels, insulin levels and sublingual temperature were measured before (baseline) and at 15, 30, 60 and 90 min after the 75-g oral glucose ingestion. Aortic pulse wave velocity and brachial systolic blood pressure did not change from baseline to after the 75-g oral glucose ingestion in all trials. Leg pulse wave velocity and ankle systolic blood pressure were increased from baseline to after the 75-g oral glucose ingestion in the footbath after glucose ingestion and control trials, but not in the footbath before glucose ingestion trial. These results suggest that a footbath effectively suppresses the increase in leg arterial stiffness after glucose ingestion when implemented before glucose ingestion.

Effects of acute footbath before and after glucose ingestion on arterial stiffness

Effects of interval walking training compared to normal walking training on cognitive function and arterial function in older adults: a randomized controlled trial

Arterial velocity pulse index (AVI) and arterial pressure‐volume index (API), new indicators of arterial stiffness, are risk factors for the development of cardiovascular disease. Regular aerobic exercise decreases arterial stiffness. In fact, pulse wave velocity (PWV), index of arterial stiffness, is lower in endurance‐trained than in untrained young adults. However, the effect of regular aerobic exercise on AVI and API remains unknown. This study investigates the effect of regular aerobic exercise on AVI and API, new indicators of arterial stiffness. We gathered data from 18 recreationally active females (active group, age: 18 ± 1 years, 2 ± 2 h/week, 3 ± 2 times/week, ≥2 years of aerobic endurance training) and 18 recreationally inactive females (inactive group, age: 18 ± 1 years, ≥2 years without such training) in a cross‐sectional study. Height, body weight, body mass index, AVI, API, brachial blood pressure, heart rate, and 20‐m multistage shuttle run test were measured in a quiet room at a temperature between 24°C and 25°C. AVI and API were lower in the active group than in the inactive group (P < 0.01). Number of 20‐m shuttles was negatively correlated with AVI (P < 0.01, r = −0.8) and API (P < 0.01, r = −0.8). These results suggest that regular aerobic exercise training decreases AVI and API in young females.

New indices of arterial stiffness measured with an upper‐arm oscillometric device in active versus inactive women

Effects Of Habitual Isometric Handgrip Exercise On Central Blood Pressure In Older Adults: 2212 Board #48 June 1 11

Arterial stiffness increases after glucose ingestion. Acute low‐ and moderate‐intensity aerobic exercise decreases arterial stiffness. However, the acute effects of 30 min of cycling at low‐ and moderate‐intensity [25% (LE trial) and 65% (ME trial) peak oxygen uptake, respectively] on arterial stiffness at 30, 60 and 120 min of a postexercise glucose ingestion. Ten healthy young men (age, 22·4 ± 0·5 years) performed LE and ME trials on separate days in a randomized controlled crossover fashion. Carotid–femoral (aortic) pulse wave velocity (PWV), femoral–ankle (leg) PWV, carotid augmentation index (AIx) and carotid blood pressure (BP) (applanation tonometry), brachial and ankle BP (oscillometric device), heart rate (HR) (electrocardiography), blood glucose (UV‐hexokinase method) and blood insulin (CLEIA method) levels were measured at before (baseline) and at 30, 60 and 120 min after the 75‐g OGTT. Leg PWV, ankle pulse pressure and BG levels significantly increased from baseline after the 75‐g OGTT in the LE trial (P<0·05), but not in the ME trial. Insulin levels and HR significantly increased from baseline after the 75‐g OGTT in both trials (P<0·05). Aortic PWV, carotid AIx, brachial BP and carotid BP did not change from baseline after the 75‐g OGTT in both trials. The present findings indicate that aerobic exercise at moderate intensity before glucose ingestion suppresses increases leg arterial stiffness after glucose ingestion.

Acute effects of aerobic exercise intensity on arterial stiffness after glucose ingestion in young men

[Purpose] The present study investigates the acute effects of accumulated aerobic exercise on aortic and peripheral pulse wave velocity (PWV) in healthy young males. [Subjects and Methods] We gathered data from 9 healthy young males (age, 23.4 ± 0.6 years) performed aerobic exercise group (AE, 65% peak oxygen uptake; two 15 min bouts of cycling performed with 20 min rest) and control group (CON, seated and resting in a quiet room) on separate days in a randomized, controlled crossover fashion. Carotid-femoral (aortic) and femoral-ankle (peripheral) PWV, carotid augmentation index, carotid, brachial and ankle blood pressure and heart rate were measured before (baseline) and 20 min for both groups. [Results] Aortic and peripheral PWV decreased from baseline at 20 min for the AE group, but not in the CON group. [Conclusion] The present findings indicate that acute accumulated aerobic exercise decreases aortic and peripheral PWV in healthy young males.

Acute effects of accumulated aerobic exercise on aortic and peripheral pulse wave velocity in young males

[Aims] The athletes’ active rest is mainly focused on exercise physi-ology studies, but there are few psychological studies. [Methods] The participants were 16 female collegiate volleyball players who participated in a 5-days summer training camp. They took part in daily volleyball sessions (training for technique or strategy) and non-volleyball sessions (training for physical fitness). One day after the training camp, the aquatic exercise group (n=7, age 19.4±1.5 years) performed swimming, dynamic stretches, and static stretches in the water, while the bicycle ergometer group (n=9, age 19.7±1.6 years), both groups performed corresponding to 50% heart rate re-serve for 30 min. The questionnaire survey was conducted before the training camp, the next day of the training camp, and after active rest (Japan Society for Occupational Health, 2002). [Results] After active rest in both groups, there was a significant decrease in “dullness” (F(1, 14)=10.683, p<0.01). On the other hand, there was no significant difference between the interaction and the two groups. [Conclusions] The next day after the training camp, after active rest of moderate intensity, “dullness” was lower than before training camp and the next day of training, suggesting psychological effec-tiveness. [Background] Cheerleading is a competitive sport focusing on good spirit and the beauty of physical health. In addition to physical strength and technical skill, psychological elements are very important to exhibit flawless performance. Before competing, there are many players who unable to effectively cope with anxiety resulting from extreme stress. [Aims] We explored the relationship between anxiety and breathing patterns in cheerleaders prior to competition. [Methods] Subjects were sixteen female high school cheerleaders. The study was performed on the day before a national tournament, in both the summer and winter, and measured anxiety levels and breathing rates. Anxiety level was measured using the State-Trait Anxiety Inventory (STAI) questionnaire. [Results,Discussion] There was no significant relationship between anxiety level and breathing rate at either time point examined. However, a significant positive correlation was observed between changes in breathing rate and in state anxiety from the summer to winter (r = 0.54, p < 0.05). These changes in breathing rate were accompanied anxiety levels. This result is consistent with those of previous studies of human health, demonstrating relationships between emotional respiration and anxiety levels. The current study suggests that changes in state anxiety of cheerleaders are accompanied by respiration changes. into what is the characteristic of players were chosen by the coaches who do not know what executive functions are. We did some psychological tests and physical test in selection for the professional academy, thus, it would be known which factors are important for success soccer players.497 junior soccer players aged 10 to 12 years, which belong to different soccer teams, participated in this study. To evaluate the level of executive functions, we used Stroop-test, Design Fluency Test. To assess the physical ability of the participants, we used 20 meters sprint test.The present results indicated that the passed junior soccer players had significantly bet-ter results than no passed-soccer players in the Stroop-test, Design Fluency Test and 20-meter sprint test. Our findings suggest that a good player has high-level inhibitory control and cognitive flexibil-ity. Interestingly, even though the evaluation of coaches might be independent of a preexisting bias or model, we obtained the result that the evaluation of coaches was correlated to a player who has high- level Executive Functions. of 10 training with 1 RM 70% intensity using a leg press. V ・ O 2 max (PWC 170) and 1 RM were measured one week before this experiment.Dopamine was 11.4 ± 1.65 pg/ml 2 hours before exercise, 23.6 ± 9.09 pg/ml immediately after exercise, noradrenaline was 403.9 ± 145.7 pg/ml two hours before exercise and 589.9 ± 226.35 pg/ml immediately after exercise, (p <0.05). Significant changes (p <0.05) were seen in the subjective emotional scale with euphoria and balance.There was no significant association between health level and hormone secretion, but there was a tendency that change in euphoria was greater as physical fit-ness level was higher. Even though the relative strength was the same, it seemed that people accustomed to exercise tended to feel euphoria more easily. [Aims] The aim of this study was to examine the relationship between relative age, physical size, motor ability, and sports competence among elementary school students of various academic grades. [Methods] We collected data from 353 elementary school students (181 boys, 170 girls, and 2 non-respondents; Mage = 8.67, SD = 1.85). Measures included students’ physical size (height and weight), motor ability (50-m sprint, standing broad jump, and softball throwing), and sports competence. Pearson’s correlation analysis was used to examine the relationships between variables. [Results] In the lower and middle grades, relative age and physical size were significantly correlated (r = .29 to .38, p < .001 to .01). Furthermore, there were significant correlations between physical size and motor ability (50-m sprint: r = -.20 to -.35, p <.01to.05; and softball throwing: r = .21to.27, p < .01to.05). In the middle and higher grades, motor ability and sports competence were significantly correlated (50-m sprint: r = -.24 to -.45, p < .001to.01; standing broad jump: r = .22to.53, p <.001to.01; and softball throwing: r = .20 to .46, p < .001 to .05). [Conclusions] We concluded that relative age, physical size, motor ability, and sports competence are closely associated in the younger grade. Therefore, physical educa-tion teachers in elementary school need to pay much attention to differences in physical development according to relative age, particularly for students of first to fourth grade. [PURPOSE] This research clarify the relationship between competitive abilities and resilience capabilities according to competition levels. [METHODS] The subjects were 440 university judokas (light weights 146 numbers, middle weights 208 numbers, heavy weights 84 numbers). The assessment consisted of the following Sports athletes psychological resilience scale (SRA) (Ueno et al. 2012). This scale used the internal factors of “competitive physical strength,” “competitive self-understanding,” “competitive motivation,” and “competitive mental strength. [RESULTS and DISSCUSIONN] The results of competitive physical strength and competitive self-under-standing for light weight category were significantly higher than the results of it for heavy weight category. It is thought that light weight category athletes have to fight with the heavy weight category and the middle weight category. Also they need to reduce body weight in order to body weight control. [CONCLUSION] The resilience capabilities that affecting competitive ability is difference for each weight categories, in particularly light weight category needs various resilience ability to get good tournament results. University ) [Aims] Although improvements in social skills of children through exercise are usually expected, this relationship has not been estab-lished. Therefore, we examined the relationship between frequency of exercise outside of school and social skills among elementary school students. [Methods] Participants were 362 elementary school students in 4th to 6th grades (178 boys and 184 girls, Mage = 10.49, SD = 0.91) who responded to one question assessing the frequency of exercise outside of school: How often do you exercise in a one-week period? and a social skill scale. We performed covariance analysis with age and gender as covariates, exercise frequency as an independent variable, and social skill as a dependent variable [Re-sults] Children with high exercise frequency showed greater social skills than students with low exercise frequency did. In subscales, students with high exercise frequency showed higher scores on rela-tionship-building, basic-manner, and consideration for others, than students with low exercise frequency did. [Conclusion] Students with high exercise frequency have high social skills. Thus, exercise outside of school may contribute to acquiring social skills among upper grade students of elementary school. The score of total mood disturbance (TMD) was determined by the T-score of 6 scales (tension, depression, anger, vigor, fatigue, and confusion). [Results] Thirty-one continuators (24 women, 56.6 ± 11.5 years old, BMI 28.6 ± 4.3 kg/m2) and 8 drop-outs (6 women, 60.0 ± 8.5 years old, BMI 29.3 ± 1.8 kg/m2) were analyzed. Compared to the continuators, the TMD and the scale of confusion were significantly higher, while the scale of vigor was lower in the drop-outs. Besides, the scale of tension, depression, and anger tended to be higher in the drop-outs, but no statistical differences were found. [Conclusions] It is suggested that the participant with poor psychological mood tend to drop out. To reduce the drop-out rate and to offer more effective weight-loss support, careful attention should be paid to the psychological factor of the participants.

The effect active rest at the training camp on subjective fatigue of the athletes Anxiety Level and Breathing Patterns of High School Cheerleaders during Pre-Competition The effect of transient exercise on emotion and hormone secretion

METHODS: To evaluate this hypothesis, we examined the effect of topical EMLA application on axon reflex mediated sweating induced by intradermal electrical stimulation in 10 subjects with and without EMLA application. Local sweat rate (SR) was measured by passing dry gas through a small sweat capsule mounted on the skin. The skin was stimulated at a constant current intensity of 2.5 mA for 30 s at frequencies of 0.2, 1, 2, 4, 8, 16, 32, and 64 Hz using two small stainless steel stimulating electrodes. This procedure produced a sigmoid shape stimulus-response curve when we plotted the area under the SR-time curve versus stimulus frequency. RESULTS: In control conditions peak local SR during 64 Hz stimulation averaged 0.364 ± 0.219 mg • min -1 • cm -2 which was significantly (p<0.05) reduced by application of EMLA to 0.078 ± 0.098 mg • min -1 • cm -2 . The stimulus-response curves were significantly different from each other with a significant reduction in the plateau with EMLA (11.7 ± 1.3 versus 2.6 ± 0.6, p<0.05) but with a similar EC50 values (7.2 ± 0.11 versus 9.9 ± 0.2 Hz). CONCLUSION: These data support the hypothesis that topical application of EMLA does impact cutaneous sympathetic C fiber function. As such, topical EMLA cream should not be viewed as an appropriate method to selectively eliminate superficial sensory fiber activity from studies of human cutaneous blood flow.

Effect Of Habitual Interval Walking On Arterial Stiffness In Older Adults: 2816 Board #336 June 2 9

Abstract Acute high-intensity resistance exercise increases arterial stiffness. Changes in blood concentrations of estrogen and progesterone associated with the menstrual cycle affect the degree of arterial stiffness. Therefore, high-intensity resistance exercise may affect arterial stiffness differently depending on the phase of the menstrual cycle. The purpose of this study was to investigate the effects of different phases of the menstrual cycle on arterial stiffness after one session of resistance exercise. The participants were 9 eumenorrheic females (21.3±0.8 years). All participants performed 5 sets of 5 repetitions using 80% of the one repetition maximum (1RM) bench press and 5 sets of 10 repetitions using 70% of the 1RM biceps curl during both the follicular and luteal phases. Brachial-ankle pulse wave velocity (baPWV), blood pressure, and heart rate were measured before (baseline) and at 30 and 60 min after completing the resistance exercises. During the follicular phase, baPWV was significantly increased at 30 and 60 min after the resistance exercise compared with baseline (P<0.05), whereas during the luteal phase, no significant differences were observed after the resistance exercise. These results suggest that high-intensity resistance exercise affects arterial stiffness differently depending on the phase of the menstrual cycle.

Effect of Resistance Exercise on Arterial Stiffness during the Follicular and Luteal Phases of the Menstrual Cycle

The purpose of present study was to determine the acute effects of different aerobic exercise duration on pulse wave velocity (PWV) in healthy young men.

METHODS
One week after measuring peak oxygen uptake to determine the duration of each exercise trial, 11 healthy males (age: 23.4±0.6 years, height: 172.5±2.3 cm, weight: 64.1±2.4 kg) cycled on an ergometer for 15 (15 min-EX), 30 (30 min-EX) and 45 minutes (45 min-EX) at 65% peak oxygen uptake in random order. After supine rest for at least 15 minutes, aortic (carotid-femoral) and leg (femoral-ankle) PWV were measured before and at 30, 60 and 90 minutes after each exercise trial.

RESULTS
Compared with before exercise trials, aortic PWV decreased at 30 minutes after 15, 30 and 45 min-EX (P<0.05, P<0.01 and P<0.05, respectively) and persisted for 60 minutes after 30 and 45 min-EX (P<0.05), leg PWV decreased at 30 minutes after 15, 30 and 45 min-EX (P<0.01) and persisted for 60 minutes after 30 and 45 min-EX (P<0.01, respectively).

These results suggest that PWV might be further decreased into recovery with prolonged exercise.

Acute effects of different aerobic exercise duration on pulse wave velocity in healthy young men.

Menstrual Cycle Affects Arterial Stiffness After High-intensity Resistance Exercise: 725 Board #41 June 1, 3: 30 PM - 5: 00 PM.

Arterial stiffness is substantially higher in postmenopausal than in premenopausal women. Daily cocoa intake has been shown to reduce central arterial stiffness in health adults, regardless of age; however, the effect of cocoa-intake frequency on arterial stiffness in postmenopausal women remains unclear. Therefore, the purpose of this study was to investigate the effects of cocoa-intake frequency on arterial stiffness in postmenopausal women. A total of 26 postmenopausal women (mean age ± standard deviation 64±12 years) were randomly assigned to two groups with different cocoa-intake frequencies: one group ingested 17 g of cocoa once daily except on Sundays (every-day group, n=13), and the other ingested 17 g of cocoa twice daily every other day (every-other-day group, n=13). These intake regimens were maintained in both groups for 12 weeks. Carotid–femoral pulse-wave velocity and femoral–ankle pulse-wave velocity were measured in both groups at baseline and again at the end of the 12-week study period. Compared to baseline, both pulse-wave velocities had significantly decreased after the 12-week study period in both groups (P<0.05). However, no significant difference in degree of change was observed between the two groups. Although this study did not include a sedentary control group, these results suggest that regardless of frequency, habitual cocoa intake reduces central and peripheral arterial stiffness in postmenopausal women.

Habitual cocoa intake reduces arterial stiffness in postmenopausal women regardless of intake frequency: a randomized parallel-group study

Abstract The purpose of present study was to compare the acute effects of moderate-intensity aerobic exercise (65% peak oxygen uptake, 30 min) on arterial stiffness before and after glucose ingestion. 11 healthy young males completed 4 trials in random order. They started aerobic exercise at 90 min before (−90 min-EX), 60 min before (−60 min-EX), 30 min after (30 min-EX), and 60 min after (60 min-EX) the 75-g oral glucose tolerance test (OGTT). Aortic (carotid-femoral) and leg (femoral-ankle) pulse wave velocity (PWV), brachial and ankle blood pressure (BP), blood glucose (BG) and insulin levels were measured at 90 min (baseline) and 30 min before and at 30, 60 and 120 min after the 75-g OGTT. Aortic PWV and brachial systolic BP did not change from baseline after the 75-g OGTT in all trials. Leg PWV and ankle systolic BP increased from baseline after the 75-g OGTT in the −90, 30 and 60 min-EX, but not in the −60 min-EX. Levels of BG and insulin increased from baseline after the 75-g OGTT in all trials. These results suggest that the aerobic exercise most effectively suppresses the increase in peripheral arterial stiffness after glucose ingestion when implemented before glucose ingestion.

Effects of Acute Aerobic Exercise on Arterial Stiffness Before and After Glucose Ingestion

C-3-3 Influence of physical activity on arterial stiffness after high sugar meal(The Proceedings of the 23rd Annual Meetings of Japan Society of Exercise and Sports Physiology July 25・26, (Tokyo))

Postprandial hyperglycemia increases arterial stiffness. Arterial stiffness and insulin resistance are lower in exercise-trained humans than in untrained humans. However, the effect of exercise on arterial stiffness after glucose ingestion in young adults remains unknown. The present study investigates the effect of regular aerobic exercise on arterial stiffness after glucose ingestion in young males. Ten exercise-trained males (age, 20.8 ± 0.2 years; ETR) and 9 healthy untrained males (age, 22.2 ± 0.7 years; UTR) participated in this study. Carotid-femoral (aortic) pulse wave velocity (PWV), femoral-ankle (leg) PWV, carotid augmentation index (AIx) (applanation tonometry), brachial and ankle blood pressure (BP), heart rate (oscillometric device and electrocardiography), and blood glucose (glucose oxidase method) were measured at 30 min before (baseline) and 30, 60, and 120 min after a 75-g oral glucose tolerance test. Leg PWV at 30 min after glucose ingestion was significantly higher (P < 0.01) in the UTR group than in the ETR group. Ankle systolic BP at 30 min after glucose ingestion was also significantly higher in the UTR group than in the ETR group (P < 0.05). Blood glucose increased from baseline at 30 min (P < 0.01) and 60 min (P < 0.05) after glucose ingestion in both groups. Aortic PWV, carotid AIx, and brachial systolic BP did not change from baseline after glucose ingestion in both groups. The present findings indicate that leg PWV and ankle systolic BP after glucose ingestion were significantly lower in the ETR group than in the UTR group.

Arterial stiffness after glucose ingestion in exercise-trained versus untrained men.

Efficacy and Safety of Emicizumab Prophylaxis in Patients with Acquired Hemophilia a Who Were Deemed Ineligible for Immunosuppressive Therapy: Additional Data from the Ageha Study

A prospective, multicenter, open-label phase III study of emicizumab prophylaxis in patients with acquired hemophilia A.

 BackgroundIntra-articular injection of hyaluronic acid (HA) has favorable effects on pain relief and knee function along with the low incidence of serious adverse reactions. Although various HA products are available for the treatment of knee osteoarthritis, it is still controversial whether differences in HA products have any clinically significant difference in efficacy and safety. In light of the above, the efficacy and safety of intra-articular injection of biological fermentation–derived high-molecular-weight HA (NRD101) was investigated in a double-blind comparative manner in Chinese patients with knee osteoarthritis.MethodA multicenter, prospective, randomized, double-blind, parallel, active control, non-inferiority study was conducted in Chinese patients with knee osteoarthritis. Patients were randomized to receive five consecutive weekly injections of either NRD101 or Artz (a non-crosslinked low-molecular-weight HA derived from combs of roosters) followed by 4 weeks follow-up. The primary efficacy endpoint was the change from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) NRS pain subscale score at Week 5. Secondary efficacy endpoints included WOMAC stiffness and physical function subscale score, local pain, range of joint motion, and overall improvement.ResultsAmong 267 randomized patients, 259 patients completed the study. The change from baseline in WOMAC NRS pain subscale score at Week 5 was −2.98 ± 0.193 in the NRD101 group and −2.66 ± 0.194 in the Artz group, and the trial met the non-inferiority criteria. Efficacy in the NRD101 group tended to be consistently higher than in the Artz group for most items of WOMAC. Several subgroup analyses also showed differences between the two groups, tending to favor NRD101. Adverse events were seen in 26.0% (34/131) of patients in the NRD101 group and 38.3% (51/133) in the Artz group.ConclusionsNRD101 improved knee pain in Chinese patients with osteoarthritis after five consecutive weekly injections. NRD101 tended to be somewhat more effective than Artz. No new safety concerns were identified.Trial registration: JapicCTI, JapicCTI-173531. Registered 10 March 2017, https://www.clinicaltrials.jp/cti-user/trial/Search.jsp

Efficacy and Safety of Intra-Articular Hyaluronic Acid Injection (NRD101 / SUVENYL®) in Patients With Knee Osteoarthritis: a Multicenter, Randomized, Double-blind, Parallel, Active Control, Non-Inferiority Clinical Study

This study quantitatively analyzed the effects of 3 h of constant sitting on skeletal muscle oxygenation in the lower extremities, using near-infrared time-resolved spectroscopy (NIRTRS). The effects of compression stockings were also evaluated. Eleven healthy men (age, 30.0 ± 6.7 years) maintained their knee joints at 90° flexion during 3 h of constant sitting and wore a compression stocking on either the right or left leg. The side the stocking was worn was chosen randomly. Subsequently, leg circumference and extracellular water were measured. After 3 h of sitting, both factors increased significantly in uncompressed limbs. Furthermore, intracellular water and muscle oxygenation had significantly decreased. In contrast, extracellular water had not increased in the limbs wearing compression stockings. Furthermore, the increased circumference of compressed limbs was significantly smaller than that of uncompressed limbs. Decreases in oxygenated hemoglobin and total hemoglobin were significantly smaller in compressed limbs than in uncompressed limbs (oxy-Hb; p = 0.021, total-Hb; p = 0.013). Three hours of sitting resulted in decreased intracellular water and increased extracellular water in the lower extremities, leading to reduced blood volume and oxygenation levels in skeletal muscle. Compression stockings successfully suppressed these negative effects.

Compression Stockings Suppressed Reduced Muscle Blood Volume and Oxygenation Levels Induced by Persistent Sitting

The mechanisms of respiratory muscle deoxygenation during incremental leg exercise with expired gas analysis were investigated in 29 patients with chronic heart failure and 21 normal subjects. The deoxygenation and blood volume of the respiratory muscle and exercising leg muscle were assessed by near-infrared spectroscopy (NIRS). To evaluate the influence of the leg exercise on the blood volume of the respiratory muscle, 10 normal subjects also underwent a hyperventilation test with NIRS. The respiratory muscle deoxygenation point (RDP), at which oxygenated hemoglobin starts to decrease, was observed in both groups during exercise. The oxygen consumption (VO2) and the minute ventilation at the RDP in the patients was lower (p<0.01). At the same VO2, the respiratory rate was higher in patients (p<0.01). During exercise, the blood volume of the leg muscle increased, while that of the respiratory muscle decreased. During a hyperventilation test, the minute ventilation was higher than that of the RDP during exercise, the blood volume of the respiratory muscle did not decrease, and the RDP was not detectable. In conclusion, a limited ability to increase perfusion of respiratory muscles during exercise combined with the greater work of breathing results in early respiratory muscle deoxygenation in patients with chronic heart failure.

Early occurrence of respiratory muscle deoxygenation assessed by near-infrared spectroscopy during leg exercise in patients with chronic heart failure.

Proceedings of the 29th International Conference on Low Temperature Physics (LT29)

Magnetic Properties of MnFeGe Probed Using 57Fe Mössbauer-spectroscopy

In-Magnetic-Field Heat Treatment Effects on Phase Growth of Mn-Bi-Sn Composite

Effects of magnetic field, including both steady magnetic field and alternative field, on materials processing have been studied.1–5) In-magnetic-field annealing (IFA) realized a unique crystal growth, such a grain refinement6,7) or coarsening,8,9) alignment of ferromagnetic grains in non-magnetic matrix,8) which were due to the magnetic anisotropy, dipoledipole interactions, and the Lorentz force. Magnetic states of precipitates/reactant and matrix are also important factor for controlling phase transformation or phase equilibrium by magnetic field because of Zeeman energy EM. In-magnetic-field process for Fe-C-based alloys has also been reported.12–15) For example, 10 T-class of magnetic field effectively influenced Fe–C phase diagram.13,15) In addition, the phase fraction of γ -Fe in α + γ region was controlled by magnetic field,13) which was explained by change of Fe–C phase diagram due to EM of α-Fe phase. High Magnetic Field Effects on Cu-precipitation Behavior of Fe-1mass%Cu at 773 K

High Magnetic Field Effects on Cu-precipitation Behavior of Fe-1mass%Cu at 773 K

Nitridation kinetics of Sm2Fe17 probed using Mössbauer spectroscopy

Acceleration of B2/L21 Order-disorder Transformation in Ni2MnAl Heusler Alloys by In-magnetic-field Annealing

Magnetic-field-induced selective retardation of reaction in Mn/Ga diffusion couple

Heat treatment effect on the magnetic properties and martensitic transformations of MnCoGe

Nitrogenation of Sm2Fe17 powder was performed under a zero field and a magnetic field of 5 T at 623, 673 and 743K to clarify the magnetic field effect on nitrogenation. Applying a magnetic field of 5 T induced nitrogenation compared with zero-field nitrogenation, and almost fully nitride Sm2Fe17N2.9 was obtained at 743K. Mössbauer spectroscopy results suggested that a 5-T magnetic field promoted the phase transformation to the fully-nitride Sm2Fe17N3 phase. The magnetic field effect was discussed based on the magnetic energy gain and magnetic properties of host Sm2Fe17 and fully nitride Sm2Fe17N3. [doi:10.2320/matertrans.MT-MN2019012]

Dual Acceleration of ε-τ Transformation in Mn–Al Induced by Zn-Addition and In-Magnetic-Field Annealing

The magnetic field effect on phase formations of ferromagnetic Mn - Al （ τ - phase ） was evaluated. The transformation from ε - phase with hcp - structure to τ - phase was accelerated by annealing in magnetic field. With in - field annealing at 623 K, the magnetization of the sample annealed at 15 T was a maximum of 72.2 A ･ m 2 / kg at 1.5 T, which was over 4 times larger than that annealed in a zero field. Meanwhile, the precipitation of non - ferromagnetic β - phase was suppressed by in - field annealing. Magnetic field - induced acceleration of ε - τ transformation and suppression of τ - β transformation were due to the gain of Zeeman energy of τ - phase.

Magnetic-Field-Induced Enhancement of Phase Transformation in Ferromagnetic τ-Mn-Al

An in- ﬁ eld heat treatment furnace utilized for a magnet with a 50mm room-temperature bore was made to study magnetic ﬁ eld e ﬀ ect on gas-solid reaction. Using this furnace, nitridation of Sm 2 Fe 17 powder was performed under a 5-T magnetic ﬁ eld and a 0.1-MPa nitrogen gas pressure for the temperature range 623 to 743K. Applying a magnetic ﬁ eld of 5T promoted nitridation by approximately 0.6 nitrogen atoms per formula unit compared with zero- ﬁ eld nitridation, and almost fully nitride Sm 2 Fe 17 N 2.9 was obtained at 743K.

Reduction of the crystallite size in Cu 2 MnAl alloys by in-field annealing

In-field heat treatments of an Mn­Ga diffusion couple were performed at 773K for 12, 24 and 48 h to investigate the phase formation under magnetic fields. Formation of the MnGa3, Mn2Ga5, MnGa, Mn3Ga2 and ¢-Mn phases was confirmed for magnetic fields of 0T and 5T. For a diffusion-controlled process, there is a parabolic relationship between the thickness of the phase layers and annealing time for the MnGa and Mn2Ga5 phases. The parabolic coefficients of MnGa and Mn2Ga5 for a zero magnetic field were determined as 8.7 © 1013 μm2s11 and 4.6 © 1011 μm2s11 respectively. For a magnetic field of 5 T, the parabolic coefficients were evaluated as 11 © 1013 μm2s11 for the MnGa phase and 4.5 © 1011 μm2s11 for the Mn2Ga5 phase. [doi:10.2320/matertrans.MT-MAW2019013]

Phase Formation of a Solid-Liquid Mn–Ga Diffusion Couple under a Magnetic Field

In-magnetic-field annealing (IFA) effects on Zn-modified Mn–Al and Mn–Al–C were investigated at the annealing temperature of 573 K, which was around their <inline-formula> <tex-math notation="LaTeX">$T_{\mathrm {C}}$ </tex-math></inline-formula>. Mn<sub>53</sub>Zn<sub>2</sub>Al<sub>45</sub> showed the magnetic-field-induced acceleration of the phase transformation to <inline-formula> <tex-math notation="LaTeX">$\text{L}1_{0}$ </tex-math></inline-formula>-phase (<inline-formula> <tex-math notation="LaTeX">$\tau $ </tex-math></inline-formula>-phase) and the suppression of that to nonferromagnetic equilibrium phase. For Mn<sub>55</sub>Al<sub>45</sub>C<sub>2</sub>, IFA effects were not clearly detected. These different magnetic field effects were discussed by the difference of the mechanism in stabilization of <inline-formula> <tex-math notation="LaTeX">$\tau $ </tex-math></inline-formula>-phase. It is found by a thermal analysis that the modification of Zn stabilized <inline-formula> <tex-math notation="LaTeX">$\tau $ </tex-math></inline-formula>-phase against <inline-formula> <tex-math notation="LaTeX">$\epsilon $ </tex-math></inline-formula>-phase, realizing acceleration of transformation to <inline-formula> <tex-math notation="LaTeX">$\tau $ </tex-math></inline-formula>-phase. The addition of carbon stabilized <inline-formula> <tex-math notation="LaTeX">$\epsilon $ </tex-math></inline-formula>-phase against <inline-formula> <tex-math notation="LaTeX">$\tau $ </tex-math></inline-formula>-phase. The ineffectiveness of in-field annealing for Mn–Al–C is due to the stabilization of <inline-formula> <tex-math notation="LaTeX">$\epsilon $ </tex-math></inline-formula>-phase and the reduction of the Curie temperature. The combination of Zn modification and IFA is realized to synthesize high fraction of <inline-formula> <tex-math notation="LaTeX">$\tau $ </tex-math></inline-formula>-phase for short annealing time and low annealing temperature.

Different Magnetic Field Effects on the  $\varepsilon- \tau$  Phase Transformation Between (Mn,Zn)–Al and Mn–Al–C

An in-field annealing–quenching furnace utilized for magnets with a 52 mm experimental bore was developed. The cooling rate from 663 to 473 K was 38 K/s under a magnetic field of 19 T. The phase boundary between the ferromagnetic MnBi and the paramagnetic Mn1.08Bi was examined using this furnace. The phase boundary was confirmed around 663 K. It was found that the MnBi grain became elongated during recrystallization under 19 T.

In-Field Annealing and Quenching for Ferromagnetic MnBi Under 19 T

The magnetic and structural properties of MnCo 0.92 Fe 0.08 Ge 1 ¹ x Sn x (x = 0.02, 0.05, and 0.1) were investigated. A ﬁ rst-order magnetic transition was observed, which was accompanied by the martensitic transformation from a hexagonal Ni 2 In-type to an orthorhombic TiNiSi-type structure in the vicinity of 320K for x = 0.02 and 170K for x = 0.05 with thermal hysteresis of approximately 20K. The magnetization of MnCo 0.92 Fe 0.08 Ge 0.95 Sn 0.05 was estimated to be 102Am 2 kg ¹ 1 in 5T at 10K. High ﬁ eld magnetization curves up to 55T for MnCo 0.92 Fe 0.08 Ge 0.95 Sn 0.05 indicated the ﬁ eld-induced martensitic transformation. Mössbauer spectroscopy experiments revealed that Fe atoms occupied 79 % ­ 85 % in the Co-site and 21 % ­ 15 % in the

Magnetic and Structural Properties of MnCoGe with Minimal Fe and Sn Substitution

The magnetic properties of ferrimagnetic Mn<sub>1.9</sub>Fe<sub>0.1</sub>Sb<sub>0.9</sub>Sn<sub>0.1</sub> with a Cu <sub>2</sub>Sb-type tetragonal structure were investigated in the temperature range 10 to 360 K and in magnetic fields up to 5 T. The lattice parameters <inline-formula><tex-math notation="LaTeX">$a$</tex-math> </inline-formula> and <inline-formula><tex-math notation="LaTeX">$c$</tex-math></inline-formula> were estimated to be 0.407 and 0.655 nm, respectively, at 293 K. The saturation magnetization at 10 K was 39.1 A <inline-formula><tex-math notation="LaTeX">$\cdot$</tex-math></inline-formula>m<sup>2</sup>/kg (1.62 µ<sub>B </sub> per formula unit), which was slightly smaller than the value at 75 K, and the magnetization showed thermal hysteresis between 70 and 230 K. The compound showed a first-order magnetic transition from the ferrimagnetic to a paramagnetic-like state with a thermal hysteresis in the vicinity of 320 K. The results are discussed on the basis of the ferrimagnetic and antiferromagnetic transitions and spin reorientation.

Quasi-First Order Magnetic Transition in Mn 1.9 Fe 0.1 Sb 0.9 Sn 0.1

The magnetic and structural properties of ferrimagnetic (FRI) Mn1.9Fe0.1Sb0.9Sn0.1 with a Cu2Sb-type tetragonal structure were studied by magnetization and high eld X-ray diffraction (XRD) measurements in 10 ≤ T ≤ 773 K and in magnetic elds μ0H up to 5 T. The lattice parameters a and c at 285 K were estimated to be 0.407 nm and 0.655 nm, respectively. The saturation magnetization at 10 K was determined to be 39.1 Am2/kg. It was observed that a rst order magnetic transition (FOMT) with a thermal hysteresis occurred in the vicinity of 310 K under low magnetic elds. This FOMT disappeared easily by applying magnetic elds over 0.4 T. [doi:10.2320/matertrans.M2017291]

Development of a observation instrument for yeast precipitation in magnetic field

L10-MnAl (τ-phase) is one of the Mn-based ferromagnetic alloys with high uniaxial magnetic anisotropy. Because -phase is not the equilibrium state, appearance of the non-ferromagnetic equilibriumandphases decreases the magnetization. Ferromagnetic phase stabilizes under the magnetic fields due to the gain of Zeeman energy. In-field heat treatment for ferromagnetic alloys has been perfomend so far [1-2]. We previously reported in-field heat treatment for Mn-Al bulk sample, resulting in the improvement of magnetization. This is due to the  transformation was enhanced by magnetic fields. In this study, for further investigations for synthesis of -phase, the in-field annealing for as-melted Mn-Al alloys was performed under high magnetic fields up to15 T. Mn-Al alloys were obtained by induction melting. Rod-shaped sample was cut into disks with 2 mm thick. In-field heat-treatments for as-melted samples were performed at 623 K in 0 T and 15 T. The phases in the alloy were characterized by X-ray diffraction (XRD) measurements. The magnetic properties was evaluated by the vibrating sample magnetometer. Fig. 1 shows the XRD patterns of Mn-Al alloys for as-melted sample (a) and the sample annealed in 0 T (b) and that in 15 T (c). In 0 T, diffraction peaks of residual phase and -phase were detected. Compared to this, diffraction peaks of -phase for the sample annealed in 15 T were smaller than that of 0 T. Thus, it was found that in-field heat treatment for -Mn-Al alloys suppressed the synthesis of paramagnetic -phase.

The phase formation of ferromagnetic L10-MnAl (τ-phase) was accelerated by annealing in magnetic eld. With ineld annealing at 623 K, the magnetization of the τ-phase annealed at 15 T was a maximum of 72.2 A・m2/kg at 1.5 T, which is over 4 times larger than that annealed without an external magnetic eld for the same annealing time. On the other hand, the transformation from τ-phase to β-phase was suppressed under magnetic eld. The obtained bulk sample did not show magnetic anisotropy because of the ε-τ solid-state transformation. Obtained results suggested that magnetic eld induced acceleration of transformation was due to the gain of Zeeman energy, which increases the driving force of the ε-τ transformation. [doi:10.2320/matertrans.MAW201709]

Magnetic-Field-Induced Acceleration of Phase Formation in τ-Mn-Al

Magnetic field effects on the transformation from the hexagonal close-packed <inline-formula> <tex-math notation="LaTeX">$\varepsilon$</tex-math></inline-formula>-phase to the ferromagnetic L1<sub>0</sub> <inline-formula><tex-math notation="LaTeX">$\tau$</tex-math></inline-formula>-phase were evaluated for Mn-Al alloys annealed at 573, 623 and 673 K in magnetic fields up to 15 T. The phase transformation from the <inline-formula> <tex-math notation="LaTeX">$\varepsilon$</tex-math></inline-formula>-phase to the <inline-formula> <tex-math notation="LaTeX">$\tau$</tex-math></inline-formula>-phase was enhanced by the magnetic field for the 623 K annealing temperature. These in-field annealing effects are explained by the Zeeman energy of the ferromagnetic <inline-formula><tex-math notation="LaTeX">$\tau$</tex-math></inline-formula>-phase.

Effects of Annealing Temperature and Magnetic Field on the $\varepsilon\hbox{--}\tau$ Phase Transformation in Mn-Al Alloys

The compound Mn 2 Sb has interesting magnetic properties and crystallizes in Cu 2 Sb type tetragonal structure (space group: P4/nmm) and orders ferrimagnetically (FRI) below $T_{\mathrm{C}}$ ~ 550 K [1]. This compound has received a growing interest due to the effect of magnetic field along with the tunability of the transition temperature up to and above room temperature [1]. It has been reported that the Mn 2 -Sb-based pseudo-binary compounds showed first-order transition between the FRI and antiferromagnetic (AFM) state [1]. In this work, we found that Mn-Sb-based pseudo-binary compound, Mn 1.9 Fe 0.1 Sb 0.9 Sn 0.1 , shows first-order transition between the FRI and paramagnetic (PM) state for the first time. The magnetization and X-ray diffraction (XRD) measurements were performed in $10\leq T\leq 360$ K and in magnetic fields $B$ up to 5 T to clarify the magnetic and the structural properties of the compound.

Magnetic and Structural Properties of Mn 1.9 Fe 0.l Sb 0.9 Sn 0.l Under Magnetic Fields

The compound Mn<inf>2</inf>Sb has interesting magnetic properties and crystallizes in Cu<inf>2</inf>Sb type tetragonal structure (space group: P4/nmm) and orders ferrimagnetically (FRI) below <tex>$T_{\mathrm{C}}$</tex> ~ 550 K [1]. This compound has received a growing interest due to the effect of magnetic field along with the tunability of the transition temperature up to and above room temperature [1]. It has been reported that the Mn<inf>2</inf>-Sb-based pseudo-binary compounds showed first-order transition between the FRI and antiferromagnetic (AFM) state [1]. In this work, we found that Mn-Sb-based pseudo-binary compound, Mn<inf>1.9</inf>Fe<inf>0.1</inf>Sb<inf>0.9</inf>Sn<inf>0.1</inf>, shows first-order transition between the FRI and paramagnetic (PM) state for the first time. The magnetization and X-ray diffraction (XRD) measurements were performed in <tex>$10\leq T\leq 360$</tex> K and in magnetic fields <tex>$B$</tex> up to 5 T to clarify the magnetic and the structural properties of the compound.

2016 International Conference of Asian Union of Magnetics Societies (ICAUMS)

Magnetic and Structural Properties of Mn1.9Fe0.lSb0.9Sn0.l Under Magnetic Fields

Carbon dioxide (CO2) insufflation has been shown to reduce the procedure-related pain and discomfort during colonoscopy. However, the effects of CO2 insufflation on the improvement of participant's stress had not been objectively analyzed.

METHODS
Using a randomized, double-blinded design, 100 consecutive patients undergoing colonoscopy were assigned to have their examination performed with either CO2 or air insufflation. Patients completed a questionnaire to grade their discomfort using a visual analogue scale (VAS). The salivary alpha-amylase (SAA) level was also measured at these times as a marker of stress.

RESULTS
The total VAS score did not show any statistically significant differences between the CO2 and air insufflation groups. However, the VAS score for abdominal fullness significantly decreased in the CO2 insufflation group in comparison to the air insufflation group in the patients who had a longer examination. The titer of the maximum SAA was significantly increased by colonoscopy (P <0.01). CO2 insufflation significantly reduced the total SAA after the colonoscopy in comparison with air insufflation (P < 0.05). The examination time and SAA tended to have a positive relationship in the air insuflation group. However, no such relationship was observed in the CO2 insufflation group.

CO2 insufflation significantly reduced the post-examination discomfort, as indicated by a salivary stress marker. The use of CO, rather than air insufflation reduced the patients' stress and may contribute to better acceptance of colonoscopy. The usefulness of CO2 insufflation was more prominent when a longer examination was necessary.

Carbon dioxide insufflation reduces the discomfort due to colonoscopy as objectively analyzed by salivary stress markers.

AIM: The efficacy and safety of adjunctive mosapride citrate with polyethylene glycol (PEG)-electrolyte solution for bowel preparation before colonoscopy have been reported. However, the effects of adjunctive mosapride citrate on the improvement of the participant’s stress were not fully understood. METHODS: This was a randomized, prospective, open-label study of mosapride in addition to PEG solution. A participant received one of two regimens in bowel preparation for colonoscopy [1 500 mL PEG plus mosapride citrate (mosapride group) or 2 000 mL PEG alone (control group)]. The bowel preparation status was compared between the two groups. Patients completed a questionnaire reporting the tolerability of the bowel preparation process. Salivary alphaamylase (SAA) was measured as a stress marker at 0, 30, 60, and 120 min of the bowel preparation. RESULTS: The bowel preparation status of the mosapride group was significantly better than that of the control group (P<0.05). There were no problematic adverse events in either group. A visual analogue scale (VAS) of the discomfort assessment was significantly better in the mosapride group (P<0.05). The frequency of patients that complained of nausea was significantly lower in the mosapride group (P<0.05). Salivary alpha-amylase increased with consumption of PEG, which means bowel preparation with PEG solution is stressful for participants. However, there were no differences in the SAA levels between the mosapride and control groups.

Analyses of the Efficacy of Adjunctive Mosapride Citrate with Polyethylene Glycol Solution for Bowel Preparation for Colonoscopy Using Salivary Stress Markers

Carbon dioxide insufflation reduces the discomfort due to colonoscopy as obje ctively analyzed by

Hyperexpression of NOD2 in intestinal mast cells of Crohn's disease patients: preferential expression of inflammatory cell-recruiting molecules via NOD2 in mast cells.

Hyperexpression of FcγRI and Toll-like receptor 4 in the intestinal mast cells of Crohn's disease patients

We previously reported that human mast cells (MCs) express high affinity IgG receptor (FcgammaRI) and Toll-like receptor 4 (TLR4) in response to interferon (IFN)-gamma in vitro. The number of MCs is known to increase in Crohn's disease (CD) and ulcerative colitis (UC). We aimed to examine the expression and function of the receptors in these diseases by immunohistochemistry of the colonic mucosae and by in vitro experiments. The density of MCs expressing FcgammaRI, TLR4, or both proteins was significantly higher in CD than in UC or control samples. The density of TNF-alpha(+) MCs expressing FcgammaRI or TLR4 was significantly higher in CD than in control samples. LPS and IgG1 cross-linking synergistically induced a high level of TNF-alpha production in IFN-gamma-treated human MCs. Hyperexpression of FcgammaRI and TLR4 on MCs was related to the high frequency of TNF-alpha expression in CD, suggesting the activation of MCs via these receptors in vivo.

Hyperexpression of FcgammaRI and Toll-like receptor 4 in the intestinal mast cells of Crohn's disease patients.

cough. Chest roentgenography demonstrated infiltration and cavitation in the left upper lobe. Chest CT (Fig. 1) showed patchy airspace consolidation with cavitation in the left S. Routine laboratory studies revealed anemia (Hb 12.5 g/dl) but Internal Medicine Vol. 44, No. 2 (February 2005) 156 Massive Hemoptysis Due to Pulmonary Tuberculosis

We describe a rare double metastasis of hepatocellular carcinoma to the supramaxillary gingiva and papillary muscle of the right ventricle. The patient was a 72-year-old woman who underwent three sessions of transcatheter arterial embolization for the primary lesions. Control of bleeding from the supramaxillary gingival metastasis was difficult by conservative treatment such as compression with gauze soaked in epinephrine. Therefore, radiotherapy was performed, but it failed to control the bleeding. The patient subsequently died due to hepatic failure. Autopsy revealed metastases of hepatocellular carcinoma to the papillary muscle of the right ventricle and paraaortic lymph node in the abdomen in addition to the supramaxillary gingival metastasis. Histopathological examination showed moderately differentiated hepatocellular carcinoma of both the primary site and metastatic sites to the gingiva and the heart and poorly differentiated in the paraaortic lymph node.

Metastasis of hepatocellular carcinoma to the supramaxillary gingiva and right ventricle.

A Case of Massive Adrenal Hemorrhage Secondary to Metastasis of Lung Cancer

OBJECTIVE
The aim of this study was to investigate the efficacy of metronidazole plus ciprofloxacin for the treatment of Japanese patients with active Crohn's disease.

METHODS AND PATIENTS
Seven patients (counting one patient twice with 2 enrollments at a 5-month interval) with a flare-up of Crohn's disease were enrolled. While continuing the baseline treatment under which the patients relapsed, they received metronidazole 250 mg twice (4 patients) or three times (3 patients) daily plus ciprofloxacin 200 mg three times daily for 4 weeks. The efficacy was evaluated by the changes in the assessment score of IOIBD, the International Organization for the Study of Inflammatory Bowel Disease, and the inflammation markers: C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and white blood cell count.

RESULTS
Metronidazole plus ciprofloxacin decreased the CRP in seven patients and the IOIBD score in six patients. Significant differences were detected in these parameters at weeks 2 and 4 compared with baseline. Five of the patients achieved normalization of CRP and a reduction of the IOIBD score to zero or one. Although one patient complained of taste disturbance, no other adverse events occurred and all patients completed the 4 weeks of study medication.

The addition of metronidazole plus ciprofloxacin could be a useful intervention for the treatment of Japanese patients with active Crohn's disease.

Metronidazole plus ciprofloxacin therapy for active Crohn's disease.

Primary biliary cirrhosis complicated with sigmoid colonic varices: the usefulness of computed tomographic angiography

Background & Aims : Prokinetics have been used in combination with polyethylene glycol electrolyte lavage solution (PEG-ELS) to reduce the volume of lavage solution and to ensure the preparation. However, prokinetics sometimes accompany troublesome side effects including fatal ones. The aim of this study is to elucidate the usefulness of mosapride citrate, which has fewer side effects, for colonoscopy lavage preparation.Methods : Eighty-two patients were randomly assigned to receive 2, 000 ml of PEG-ELS with sennoside (control group) or 1, 500 ml of PEG-ELS with sennoside and mosapride citrate (mosapride group). Colonoscopists blinded to group assignment scored the adequacy of colon cleansing. Time to lavage solution ingestion, time and number of motions to the appearance of clear excretion, and side effects were recorded.Results and Conclusions : The mosapride group had a favorable trend in the overall colon cleansing and a significant superiority in the residual foam over the control group. Side effects had a tendency to be less frequent in the mosapride group. Time to lavage solution ingestion was significantly reduced in the mosapride group. Mosapride citrate coadministered with sennoside and 1500 ml of PEG-ELS is applicable to bowel preparation with favorable colon cleansing and good patient acceptability.

We investigated Young's modulus of amorphous carbon (a-C) pillars that exhibited different properties depending on which of two fabrication methods were used, electron-beam-induced chemical vapor deposition (EB-CVD) or focused ion-beam-induced CVD (FIB-CVD). The Young's modulus of the FIB-CVD pillars was almost linearly proportional to the accelerating voltage, while that of the EB-CVD pillars showed a completely opposite results. Secondary electrons seemed to play an important role in the increase of Young's modulus of the pillars grown using EB-CVD.

Comparison of Young's Modulus Dependency on Beam Accelerating Voltage between Electron-Beam- and Focused Ion-Beam-Induced Chemical Vapor Deposition Pillars

We demonstrated nanotube growth on a position-controlled catalyst using electron beam-induced chemical vapor deposition (EB-CVD) ferrocene nanopillars. While solid phase graphitization was induced at 650°C, iron nanoparticles only appeared on the surface by eroding the surrounding graphite triggered by the gas phase carbon fiber growth, at a temperature higher than 800°C using ethanol vapor. The precise position control achieved by EB-CVD directly reflected that of carbon fiber growth, which is a promising position-controlled carbon nanotube growth method for future device applications.

Position-Controlled Carbon Fiber Growth Catalyzed Using Electron Beam-Induced Chemical Vapor Deposition Ferrocene Nanopillars

Position control during carbon nanotube (CNT) growth is critical for CNT device application. We have developed a technique for precisely positioning a single iron nanoparticle on a substrate using electron beam-induced chemical vapor deposition (EB-CVD) with ferrocene source gas. A single-walled carbon nanotube (SWNT) preferably grew on the iron nanoparticle. EB-CVD makes it possible to grow 3D nanoscale structures at an exact location (Koops, et al., 1988). Such nanoscale 3D structures can be used to trigger catalytic growth of carbon nanotubes. We prepared ferrocene-based amorphous carbon nanodots containing iron by using EB-CVD. Vacuum annealing of the nanodots segregated the iron, resulting in a single iron nanoparticle inside each nanodot (Fujita et al., 2002). This was followed by oxygen ashing to remove the surrounding amorphous carbon. Carbon nanotube growth was triggered on a single iron nanoparticle by using ethanol CVD.

Position-controlled carbon nanotube growth on single iron nanoparticles prepared by electron beam-induced chemical vapor deposition

Position Controlled Growth in Carbon Nanotubes Catalyzed by an Iron Nano-dot Array

We developed a double mold imprinting technique to fabricate micro-fluidic device with ultra-thin polydimethylsiloxane (PDMS) window for in-vitro X-ray microscopy. An X-ray having a specific wavelength from 2.33 nm to 4.23 nm, the so called water window region defined between the absorption edge of oxygen and the K-edge of nitrogen, has a large absorption contrast for bio-molecules against water. Therefore, the X-ray microscope imaging in Takano et al. (1995) with this wavelength is expected to reveal detailed in-vitro structure of biomaterials. Even though large contrast is gained, a specimen should be less than a few microns thick, and the biomaterial dispersed into the water should be held within this thin region. To create a specimen holder for in-vitro X-ray microscopy, we developed a micro fluidic device equipped with a 2-/spl mu/m thick PDMS window based on double mold imprinting technique in Kong et al. (2004).

Double mold imprinting of micro fluidic device with ultra-thin PDMS window for in-vitro X-ray microscopy observation

In this paper, we report our findings that Young's modulus of amorphous carbon nanopillars grown by FIB-CVD decreases with a decreasing ion-beam accelerating voltage, while that of those grown by EB-CVD increases.

Comparison of Young's modulus dependency on beam accelerating voltage between EB- and FIB-CVD pillars

We investigated the growth manner and mechanical characteristics of amorphous carbon (a-C) nanopillars formed by electron-beam-induced chemical vapor deposition (EB-CVD). The pillars' inclinations were well explained if we assumed the vertical growth rate to be almost constant within a specified distance from the substrate. The pillars' Young's modulus evaluated by deflection measurement was approximately 29 GPa, which was almost equivalent to that of bismuth, but much smaller than that observed in focused ion-beam-induced chemical vapor deposition (FIB-CVD) pillars.

Growth Manner and Mechanical Characteristics of Amorphous Carbon Nanopillars Grown by Electron-Beam-Induced Chemical Vapor Deposition

CREST JST, Japan Science and Technology Co., 4-1-8, Hon-cho, Kawaguchi, Saitama, 332-00 12, Japan Institute ofApplied Physics, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8573, Japan 3Fundamental and Environmental Research Laboratories, NEC Corporation, 34 Miyukigaoka, Tsukuba, Ibaraki, 305-8501, Japan SI1 Nanotechnology Inc., 361 Takenoshita, Oyama-cho, Suntogun, Shizuoka, 4 101393, Japan ’Himeji Institute of Technology, Graduate School of Science, LASTI, 31-2 Koto, Kamigori, Ako, Hyogo, 6781205, Japan I

Digest of Papers. 2004 International Microprocesses and Nanotechnology Conference, 2004.

Position controlled carbon fiber growth catalyzed by EB-CVD ferrocene-nanopillay

‘CREST JST, Japan Science and Technology Co., 4-1-8, Hon-cho, Kawaguchi, Saitama, 332-0012, Japan *Institute ofApplied Physics, University of Tsukuba, 1 1-1 Tennodai, Tsukuba, 305-8573, Japan 3Fundamental and Environmental Research Laboratories, NEC Corporation, 34 Miyukigaoka, Tsukuba, Ibaraki, 305-8501, Japan SI1 Nanotechnology Inc., 36-1 Takenoshita, Oyama-cho, Suntogun, Shizuoka, 410-1 393, Japan Himeji Institute of Technology, Graduate School of Science, LASTI, 3-1-2 Koto, Kamigori, Ako, Hyogo, 678-1205, Japan 4

Growth manner and mechanical characteristics of amorphous carbon nanopillar grown by EB-CVD

In recent years, studies on the fundamental principle of thrust vectoring using jets have been conducted with the aim of application to next-generation aircraft. Consequently, the improvement of aircraft motion performance is expected. Previously, a method using secondary flow with a Coanda surface was proposed for the direction control of the primary jet, and some valuable results were reported. The effect of ejection or suction on the traveling direction of the primary jet was examined. However, as many physical quantities dominate the phenomenon in this complicated situation, parametric studies are insufficient. The present study is a fundamental study of fluidic thrust vectoring. The effect of secondary injection or suction flow near the Coanda surface on the travel direction of primary jets was investigated parametrically using the momentum ratio, nozzle width ratio, etc. without changing the nozzle geometry. A larger deflection of the primary jet was observed because of the suction rather than ejection at the same momentum ratio. Furthermore, the effect of the slot width ratio on the dead zone where the traveling direction of the second jet does not depend on the momentum of the secondary flow was studied.

Flow control using jets is widely implemented. In particular, the clarification of jet technology is indispensable in the control of the blade stall control of blades and for thermal management, such as refrigeration and air conditioning. As part of the fundamental research into the topics mentioned above, various studies of the flow characteristics of steady jets have long been conducted, and the structure of the jets investigated. However, studies on flow control by synthetic jets that essentially exhibit an unsteady flow have begun only recently. Synthetic jets have a flow wherein the jet structure forms downstream of the slot, although the net flow rate is zero, because of repeated ejection and suction. Attempts have been made to control of the jet’s direction of travel by adjusting only the jet’s frequency without any geometric changes. However, many aspects of the effect of oscillation characteristics on the jet’s structure are still unclear. Moreover, since the flow rate is low, it is not suitable for large-scale fluid control, such as that required for high-power fluid machinery. In this study, excited jets are proposed, wherein the velocity distribution change with time at the slot exit and the time-averaged flow rate are considered. An attempt was made to control the jet structure by means of the oscillation characteristics. The influences of the frequency and the phase of the slot outlet velocity distribution on the maximum jet velocity and the jet width were investigated by numerical calculations and experiments. Our research led us to conclude that the staggered vortex street is generated when the phase of the slot exit velocity distribution is π. Further, we concluded that the jet structure could be controlled by the frequency under a certain specific set of conditions.

Control of jet structure utilizing the change in the outlet velocity distribution with time

Behavior of Plane Synthetic Jets Generated by an Asymmetric Stepped Slot

In recent years, studies on the fundamental principle of thrust vectoring using jets have been conducted to realize next-generation aircraft applications. Various methods for vector control of jet flow have been proposed, such as methods that achieve control via steady, continuous jets under the Coanda effect, steady suction flows near the Coanda surface, and synthetic jets from a neighbor slot as secondary jets. However, there are no studies on the flow direction control of jets using the secondary synthetic Coanda jet. In this study, the influence of synthetic jets near a circular cylinder on the flow characteristics of a primary jet was experimentally investigated. The main results obtained in the study were that the direction of the primary jet flow can be controlled using the secondary synthetic jet, and the degree of jet deflection depends on the frequency of the velocity oscillation for the secondary synthetic jet under an identical momentum ratio. Furthermore, when using the synthetic jet as the secondary flow, a controllable region larger than that obtained when using a steady and continuous injection or suction flow is expected. This is because secondary flow is generated using the ratio of the momentum between the primary jet and the secondary flow at the slot exit in conjunction with the dimensionless frequency of the synthetic jet based on the velocity of the primary flow at the slot exit.

Observation of Behavior of Synthetic Jets in Asymmetric Flow Field

This is a fundamental study on the jet vectoring control by means of adjusting the synthetic jet Strouhal number (frequency) without slot shape change with time in actuators. This work involved introduction of asymmetric slots with various beak lengths in free synthetic jets for various frequencies, experimentally and numerically. Furthermore, the behavior of synthetic jets was compared with that of the continuous jets. In our experiment, velocity measurements for both types of jets were performed using a hot-wire anemometer with an I-type probe and a traverser, and flow visualization for observing the behavior of the jets was performed using the smoke wire method. Through the experiment, typical flow patterns and time-averaged velocity distributions of synthetic jets for various beak lengths and Strouhal number were demonstrated. The time-averaged velocity was measured at a reference point on the slot centerline to evaluate the degree of the bend of the jets and the obtained data was used in the Strouhal number-beak length map.Copyright © 2016 by ASME

Mathematical analysis to coupled oscillators system with a conservation law (Applications of Renormalization Group Methods in Mathematical Sciences) Author(s) MIYAJI, Tomoyuki; OHNISHI, Isamu; KOBAYASHI, Ryo; TAKAMATSU, Atsuko Citation 数理解析研究所講究録別冊 = RIMS Kokyuroku Bessatsu (2010), B21: 129-147 Issue Date 2010-12 URL http://hdl.handle.net/2433/177024 Right Type Departmental Bulletin Paper Textversion publisher

Mathematical analysis to coupled oscillators system with a conservation law (Applications of Group Methods

Measurements of Skin-Friction Vector-Fields on a Car Body in Crosswind

We study the initial value problem for the drift-diffusion model arising in semiconductor device simulation and plasma physics. We show that the corresponding stationary problem in the whole space ℝn admits a unique stationary solution in a general situation. Moreover, it is proved that when n  ≥ 3, a unique solution to the initial value problem exists globally in time and converges to the corresponding stationary solution as time tends to infinity, provided that the amplitude of the stationary solution and the initial perturbation are suitably small. Also, we show the sharp decay estimate for the perturbation. The stability proof is based on the time weighted L p energy method.

ASYMPTOTIC STABILITY OF STATIONARY SOLUTIONS TO THE DRIFT-DIFFUSION MODEL IN THE WHOLE SPACE

We study the stationary problem in the whole space ℝn for the drift–diffusion model arising in semiconductor device simulation and plasma physics. We prove the existence and uniqueness of stationary solutions in the weighted Lp spaces. The proof is based on a fixed point theorem of the Leray–Schauder type. Copyright © 2008 John Wiley & Sons, Ltd.

Stationary solutions to the drift–diffusion model in the whole spaces

We study the drift-diffusion system arising in the semiconductor device simulation and the plasma physics. We consider the initial value problem for this system and derive the optimal Lp decay estimate of solutions by applying the time weighted Lp energy method. Furthermore, we show that the solutions approach the corresponding heat kernels as time tends to infinity. This asymptotic result is based on the optimal Lp - Lq decay estimate for the linearized problem.

Decay Estimates and Large Time Behavior of Solutions to the Drift-Diffusion System

Observation of interaction of supported lipid bilayer with polycationic liposome as a gene carrier

EDTA-extractable protein (EEP) is a major extrinsic protein of lens fiber membrane. The EEP of calf lens separated three major bands by SDS-PAGE, and the molecular weights of these major bands were 34 kilodalton (kd.), 33 kd. and 32 kd. Combination of EEP with F-actin and some kinds of phospholipid containing liposomes depends on Ca2+. In two-dimensional gel electrophoresis, some spots of the calf-EEP partially overlapped with spots of lipocortin, which is a substrate for epidermal growth factor receptor/kinase and an inhibitor of phospholipase A2. The 34 kd. protein of the EEP cross-reacted to the antibody prepared against lipocortin of pig's aorta: These results suggest the important function of EEP in lens.

EDTA-extractable protein (EEP) is a major extrinsic protein of lens membrane. EEP is composed of two major polypeptides on SDS-PAGE with apparent molecular weights of 32 kilodaltons (kd) and 34 kd. Recently it has been reported that the 34 kd protein of the EEP cross-reacted with the antibody prepared against lipocortin, an inhibitor of phospholipase A2. We have purified and characterized the 32 kd protein of the EEP (EEP 32). Crude EEP of bovine lens was applied to a Q-Sepharose column and eluted with a linear gradient system composed of 0-0.7 M NaCl. The EEP 32 was discreted at salt concentrations of approximately 0.1-0.25 M (EEP 32-A) and 0.35-0.4 M (EEP 32-B). Both EEP 32-A and EEP 32-B interact with phospholipid and F-actin in a Ca2+-dependent manner as lipocortin. Furthermore, the EEP 32-A, a major component of the EEP 32 purified by hydroxyapatite chromatography and gel filtration, inhibited phospholipase A2 activity more than lipocortin. On Western blot analysis, the 32 kd lipocortin-like protein of human placenta showed cross-reactivity to EEP 32-B, but not EEP 32-A. These results suggest that EEP 32 contains two lipocortin-like proteins differing in antigenicity and isoelectric points.

[Biochemical and immunological properties of EEP 32 kd protein].

It has been reported that the 34kDa protein of EDTA-extractable protein (EEP34k) cross-reacted with lipocortin antisera. The lipocortins are a family of proteins that have been reported to inhibit phospholipase A2. Previously, we purified two proteins from EEP34k by anion-exchange chromatography, and referred to them as 34k (A) and 34k (B). On Western-blot analysis, two proteins showed cross-reactivity to both lipocortin I and lipocortin II. In this study, four proteins (34k (A)1, 34k (A)2, 34k (B)1, 34k (B)2) were isolated from 34k (A) and 34k (B), on a cation-exchanged chromatography. By peptide mapping, immunological analysis and SDS/PAGE, we confirmed that 34k (A)1 and 34k (B)2 were identified proteins and these were called lipocortin I, and that 34k (A)2 was lipocortin II. It is concluded that at least two lipocortins, I and II are present in EEP34k. We also observed the presence of phospholipase A2 inhibitory activity in both 34k (A) and 34k (B).

[Biochemical and immunological properties of 34kDa EDTA-extractable protein (EEP34k)].

Spatial resolution of space charge distribution measurement using PEA (Pulsed electro-acoustic) method at high temperature was improved by applying a thin piezo-electric sensor film with a glass substrate. Partial discharge generation is one of problems to be solved in motor winding when the driving voltage of motor is elevated to downsize it. In the high-voltage drive of motors, the space charge accumulation in the thin insulating layer of the winding is said to affect the partial discharge generation. Therefore, it is necessary to evaluate the space charge accumulation in thin insulating materials of the winding. Especially, since high temperature characteristics of the partial discharge is said to be important, the measurement of the space charge distribution for the thin insulating layer is required at high temperature. However, the spatial resolution of the ordinary PEA measurement system was not enough to measure the space charge distribution in such thin insulating materials for windings, especially at high temperature. Therefore, the PEA measurement system was improved using a thin sensor film, which is available at a relatively high temperature, as a sensor of the PEA measurement system with a high heat-resistant glass substrate. In this report, a typical measurement result of the space charge distribution observed in 25 µm-thick polyimide sample at 80°C is introduced.

2022 9th International Conference on Condition Monitoring and Diagnosis (CMD)

Improvement of Spatial Resolution of Space Charge Measurement at High Temperature using PEA Method

Electromagnetic radiation is always headachy issue in developing various electronic systems. Because electromagnetic radiation and interference (EMI) is very sensitive to signal routing and physical layout of power distribution network (PDN) in package and board as well as chip design. Therefore, chip-package co-design is becoming important by taking into account the total PDN impedance seen from the chip. Especially, parallel resonance peaks in the PDN due to the chip-package interaction induces the unwanted power supply fluctuation, and results in serious EMI troubles. In this paper, three test chips were designed with different on-chip PDN properties. These three chips were intended to have typical characteristics; oscillatory region and damped condition. Then, the effects of the total PDN impedance on EMI have been studied. In particular, anti-resonance peak was properly suppressed by establishing critical damping condition in chip-package-board co-design. EMI has been proved to be dramatically reduced by proper combination of on-chip capacitance, on-chip resistance and package inductance.

Power integrity design has become a critical issue in digital electronic systems, as advanced CMOS LSIs operate at higher clock frequency and at lower supply voltage. Power supply fluctuation excited by core circuits or I/O buffer circuits induces logic instability and electromagnetic radiation. Therefore, total impedance of power distribution network (PDN) must be taking into consideration in the chip-package-board co-design. Especially, anti-resonance peaks in the PDN created by the parallel combination of on-chip capacitance and package inductance induce the unwanted power supply fluctuation, and results in the degradation of signal integrity and electromagnetic interference (EMI). In this paper, effects of critical damping condition for the total PDN impedance on power supply noise has been studied by adding different RC circuit to the intrinsic on-die RC circuit of chip. Three test chips were assumed to be designed on-chip PDN properties. The measurement and analysis of power supply noises for the three test chips showed typical characteristics of oscillatory region and damped regions the critical damping condition against the anti-resonance peak has been proved to be effective to suppress the power supply noise on the chip. Furthermore QFP and BGA are used for a package and the effect of anti-resonance and power supply noise control by the total impedance of a chip package board are verified from the difference in inductance.

Power integrity is a serious issue in the modern CMOS digital systems, because power supply noise excited in core circuits induces logic instability and electromagnetic radiation. Therefore, chip-package co-design is becoming important by taking into consideration the total impedance of power distribution network (PDN) seen from the chip. Especially, parallel resonance peaks in the PDN due to the chip-package interaction induces the unwanted power supply fluctuation, and results in the degradation of signal integrity and electromagnetic interference (EMI). In this paper, effects of critical damping condition for the total PDN impedance on power supply noise has been studied by adding different RC circuit to the intrinsic on-die RC circuit of chip. Three test chips were assumed to be designed with different on-chip PDN properties. The measurement and analysis of power supply noises for the three test chips showed typical characteristics of oscillatory region and damped regions The critical damping condition against the anti-resonance peak has been proved to be effective to suppress the power supply noise on the chip.

Measurement and analysis of anti-resonance peak in total PDN impedance

Power integrity design has been becoming important in the advanced CMOS digital systems, because power supply noise induces logic instability and electromagnetic radiation. Especially, anti-resonance peaks in power distribution network (PDN) due to the chip-package interaction induce the unwanted power supply fluctuation, and result in large electromagnetic radiation. In this paper, power supply noises and total impedances of power distribution network (PDN) for the variable structure of on-die capacitances have been examined. In addition, power supply noise and total PDN impedance have been examined by changing the number of power supply terminals. As a result, it has been proved that anti-resonance peaks could be controlled by on-die capacitance and the number of power supply terminals. Simulated anti-resonance peak frequencies were well correlated with the peak frequency spectra of measured power supply noise.

2013 9th International Workshop on Electromagnetic Compatibility of Integrated Circuits (EMC Compo)

Anti-resonance peak frequency control by variable on-die capacitance

Power integrity has became a serious issue in the advanced CMOS digital systems, because power supply noise must be suppressed to guarantee normal logic operation and its stability. Therefore, chip-package-board co-design has become important by taking into consideration the total impedance seen from the chip. Especially, parallel resonance peaks in the power distribution network (PDN) due to the chip-package interaction induces the unwanted power supply fluctuation, and results in the degradation of signal integrity and electromagnetic interference (EMI). In this paper, three test chips were designed with different on-chip PDN properties. The effects of critical damping condition for the total PDN impedance on power supply noise has been examined by adding different RC circuit to the intrinsic on-die RC circuit of chip. The measurement and analysis of power supply noises for the three test chips showed typical characteristics of oscillatory region and damped regions The critical damping condition against the anti-resonance peak has been proved to be effective to suppress the power supply noise on the chip.

2013 IEEE Electrical Design of Advanced Packaging Systems Symposium (EDAPS)

Power integrity improvement by controlling on-die PDN properties

Power integrity is a serious issue in the in the modern CMOS digital systems, because power supply noise excited in core circuits induces logic instability and electromagnetic radiation. Therefore, chip-package co-design is becoming important by taking into consideration the total impedance of power distribution network (PDN) seen from the chip. Especially, parallel resonance peaks in the PDN due to the chip-package interaction induces the unwanted power supply fluctuation, and results in the degradation of signal integrity and electromagnetic interference (EMI). In this paper, peak frequency shift in the total PDN impedance in three test chips with different on-die PDN properties was observed when the package inductance was changed.

Anti-resonance peak shift due to variation of effective package inductance

Power integrity design has been becoming important in the advanced CMOS digital systems, because power supply noise induces logic instability and electromagnetic radiation. Especially, anti-resonance peaks in power distribution network (PDN) due to the chip-package interaction induce the unwanted power supply fluctuation, and result in large electromagnetic radiation. In this paper, effects of damping condition of the total PDN impedance on power supply noise have been studied by adding variable on-die RC circuit to the intrinsic on-die RC circuit in chip PDN. Two types of test chips were designed with different variable on-die PDN impedances. By varying the values of on-die RC circuit, the simulated waveforms of power supply noises for the two test chips have been changed from oscillatory region to damped regions.

Power supply noise suppression by optimizing on-die PDN impedance

Power integrity is a serious issue in the modern CMOS digital systems, because power supply noise excited in core circuits induces logic instability and electromagnetic radiation. Therefore, chip-package co-design is becoming important by taking into consideration the total impedance of power distribution network (PDN) seen from the chip. Especially, parallel resonance peaks in the PDN due to the chip-package interaction induces the unwanted power supply fluctuation, and results in the degradation of signal integrity and electromagnetic interference (EMI). In this paper, effects of critical damping condition for the total PDN impedance on power supply noise has been studied by adding different RC circuit to the intrinsic on-die RC circuit of chip. Three test chips were assumed to be designed with different on-chip PDN properties. The simulated power supply noises for the three test chips showed typical characteristics of oscillatory region and damped regions The critical damping condition against the anti-resonance peak has been proved to be effective to suppress the power supply noise on the chip.

2012 IEEE 21st Conference on Electrical Performance of Electronic Packaging and Systems

Chip-package co-design for suppressing parallel resonance and power supply noise

As CMOS LSIs operate at higher clock frequency and at lower supply voltage, power integrity is becoming a critical issue to maintain digital electronic systems more stable. Power supply fluctuation excited by core circuits or I/O circuits induces logic instability and electromagnetic radiation. Therefore, total impedance of power distribution network (PDN) must be taking into consideration in the chip-package-board co-design. Especially, anti-resonance peaks in the PDN due to the parallel combination of on-chip capacitance and package inductance induces the unwanted power supply fluctuation, and results in the degradation of signal integrity and electromagnetic interference (EMI). In this paper, effects of critical damping condition for the total PDN impedance on power supply noise has been studied by designing different on-chip PDN properties. The measured power supply noises for the four test chips successfully showed typical characteristics of 3 different regions. The critical damping condition against the anti-resonance peak has been proved to be effective to suppress the power supply noise on a chip.

2012 IEEE International Symposium on Electromagnetic Compatibility

Effects of critically damped total PDN impedance in chip-package-board co-design

Power integrity design is a critical issue for advanced CMOS LSIs which operate at higher clock frequency and at lower supply voltage. Power supply fluctuation excited by core circuits or I/O buffer circuits induces logic instability and electromagnetic radiation. Therefore, total impedance of power distribution network (PDN) must be designed as low as possible in the chip-package-board co-design. Especially, anti-resonance peaks in the PDN created by the parallel combination of on-chip capacitance and package inductance induce the unwanted power supply fluctuation. In this paper, effects of critical damping condition for the total PDN impedance on power supply noise has been studied by adjusting different on-chip PDN properties. The simulated power supply noises for the three test chips showed typical characteristics of oscillatory region and damped regions. The critical damping condition against the anti-resonance peak has been proved to be effective to suppress the power supply noise on the chip.

2012 IEEE Electrical Design of Advanced Packaging and Systems Symposium (EDAPS)

On-die PDN design and analysis for minimizing power supply noise

Cerebellar injuries can cause syntax impairments. Cortical dysfunction due to cerebello-cerebral diaschisis is assumed to play a role in this phenomenon. Functional magnetic resonance imaging studies have repeatedly shown the activation of Broca's area in response to syntactic tasks. However, there have been no reports of selective syntax impairment and hypoperfusion restricted to this area after cerebellar injury. We herein report a patient with right cerebellar hemorrhage that led to marked syntax impairment along with severe hypoperfusion confined to the Brodmann area (BA) 45 (anterior part of Broca's area) and BA46.

Syntactic Impairment Associated with Hypoperfusion in the Left Middle and Inferior Frontal Gyri after Right Cerebellar Hemorrhage: A Case Report.

Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society

Improved frontal activity on functional near-infrared spectroscopy after improvement of apathy symptoms in a patient with Alzheimer's disease.

In this issue, Sakurai et al. report on relevant findings for the clinical diagnosis of argyrophilic grain disease (AGD). Their study describes a characteristic atrophy distribution restricted to the limbic lobes, namely the ambient gyrus, in AGD versus Alzheimer's disease (AD), in pathologically confirmed patients using magnetic resonance imaging by voxel- and surface-based morphometry. Here, we discuss the possibility of employing functional or molecular brain imaging to further improvement of diagnosis of AGD. Additional research is required to elucidate the contributions of comorbid AD and transactive response DNA-binding protein 43 kDa pathologies in patients with AGD.

Towards Improved Clinical Diagnosis of Argyrophilic Grain Disease Using Brain Imaging.

1 Bleicken B, Hahner S, Ventz M, Quinkler M. Delayed diagnosis of adrenal insufficiency is common: a cross-sectional study in 216 patients. Am J Med Sci 2010; 339: 525–531. 2 Graber ML, Franklin N, Gordon R. Diagnostic error in internal medicine. Arch Intern Med 2005; 165: 1493–1499. 3 Tullio-Pelet A, Salomon R, Hadj-Rabia S et al. Mutant WD-repeat protein in triple-a syndrome. Nat Genet 2000; 26: 332–335. 4 Sannarangappa V, Jalleh R. Inhaled corticosteroids and secondary adrenal insufficiency. Open Respir Med J 2014; 8: 93–100. 5 Arlt W, Allolio B. Adrenal insufficiency. Lancet 2003; 361: 1881–1893. 6 Li X, Yang H, Duan Z et al. A case series study of hypopituitarism in older patients with and without gastrointestinal symptoms. Postgrad Med 2018; 130: 501–506. 7 Croskerry P. The importance of cognitive errors in diagnosis and strategies to minimize them. Acad Med 2003; 78: 775–780.

Improvement in apathy and depression by non‐pharmacological interventions in early‐onset Alzheimer's disease: A longitudinal single‐photon emission computed tomography study

Quantification of in vivo reactive astrogliosis, which represents neural inflammation and remodeling in the brain, is an emerging methodology for the evaluation of patients with neurodegenerative diseases. [18F]THK-5351 is a positron emission tomography (PET) tracer for monoamine oxidase B (MAO-B), a molecular marker of reactive astrogliosis. We performed in vivo [18F]THK-5351 PET in a patient who at autopsy was found to have argyrophilic grain disease (AGD) with comorbid pathology to visualize reactive astrogliosis for the first time. We aimed to validate an imaging-pathology correlation using [18F]THK-5351 PET and the autopsy brain. The patient, a 78-year-old man, was pathologically diagnosed with AGD combined with limbic-predominant age-related transactive response DNA-binding protein of 43 kDa encephalopathy and Lewy body disease without Alzheimer disease-related neuropathological changes. Reactive astrogliosis in the postmortem brain was abundant in the inferior temporal gyrus, insular gyrus, entorhinal cortex, and ambient gyrus where premortem [18F]THK-5351 signals were high. We found a proportional correlation between the amount of reactive astrogliosis in the postmortem brain and the in vivo [18F]THK-5351 standardized uptake value ratio (r = 0.8535, p = 0.0004). These results indicated that reactive astrogliosis in AGD with comorbid pathology could be identified and quantified by in vivo MAO-B imaging.

In vivo [18F]THK-5351 imaging detected reactive astrogliosis in argyrophilic grain disease with comorbid pathology: A clinicopathological study.

A fatal case of fulminant neuroleptic malignant syndrome: A case report

Style changes before and after disease onset in the works of an ikebana (Japanese traditional flower arrangement) artist with semantic variant primary progressive aphasia.

Fluctuation of dopamine transporter availability in psychiatric‐onset dementia with Lewy bodies: the dilemma of treatment with antidepressants

Serotonin syndrome induced by overdose of atomoxetine alone in a patient with attention‐deficit hyperactivity disorder: A case report

Autosomal-dominant Alzheimer ’ s disease (ADAD) is a genetic disease caused by gene mutations in APP , PSEN1 and PSEN2 . 1 An amyloid positron emission tomography (PET) study in ADAD revealed that amyloid deposition occurs in the brain more than 10 years before the onset of dementia. 2 Therefore, early detection of amyloid deposition is a target for therapeutic intervention in patients with Alzheimer ’ s disease (AD). 2,3 Amyloid deposition, viewed on PET, in ADAD is characterized by striatal predominance over the cortex, unlike in patients with typi-cal sporadic AD. 4,5 Amyloid depositions localized in the striatum are observed early in the asymptomatic phase 4,5 and gradually spread to the cortex. 2,4 – 7 At the onset of dementia, amyloid depositions in the striatum as well as in the cortex are already at high levels. 2,5 – 7 Here, we report a female patient with early-onset AD with high levels of amyloid deposition localized in the striatum and slight amyloid deposition in the cortex, despite the presence of dementia. The patient was right-handed with 10 years of education. She had a family history of AD, with her mother having onset at about 65 years of age and her brother, who was 2 years younger than the patient, having a diagnosis of frontotemporal dementia. The patient ’ s pedigree is shown in Fig. 1a. The patient visited our hospital at the age of 48 years because she kept telling the same stories repeatedly, and exhibited executive dysfunction, such as the inability to perform housecleaning tasks. The Mini-Mental State Examination (MMSE) score was 20, and she had amnesia and decreased attention but preserved visuospatial function. The full-scale intelligence quotient (IQ; Wechsler Adult Intelligence Scale, Third Edition) was 69 (verbal

Focal striatal amyloid deposition in Alzheimer's disease caused by APP p.V717I mutation: Longitudinal positron emission tomography study

Ryota KOBAYASHI , Shinobu KAWAKATSU, Daichi MORIOKA, Hiroshi HAYASHI , Aya UTSUNOMIYA, Takanobu KABASAWA and Koichi OTANI Department of Psychiatry and Pathological Diagnostics, Yamagata University School of Medicine, Yamagata, Department of Neuropsychiatry, Aizu Medical Center, Fukushima Medical University, Aizuwakamatsu and Department of Occupational Therapy, Fukushima Medical University School of Health Sciences, Fukushima, Japan Correspondence: Ryota Kobayashi, MD, PhD, Department of Psychiatry, Yamagata University School of Medicine, 2-2-2 Iidanishi, Yamagata 990-9585, Japan. Email: ryo.kobayashi@med.id.yamagata-u.ac.jp Disclosure: All authors declare no conflicts of interest for this article.

Limbic‐predominant age‐related TDP‐43 encephalopathy characterised by frontotemporal dementia‐like behavioural symptoms

Dear Editor, We read with great interest Arafuka et al.’s case report on frontotemporal lobar degeneration (FTLD) with trans-activation response DNA protein 43 (TDP43) type B published in this journal. Their patient exhibited a mildly decreased dopamine transporter (DAT) availability on DAT imaging 1.5 years before the onset of dysphagia. In contrast, severely decreased DAT availability was observed in a patient with a similar disease course, based on our previously reported case without confirmatory autopsy results. The authors associated the discrepancy in the severity of the DAT findings between their patient and ours with the differences in disease stage. Our recent report discussed the reduced striatal DAT availability in six patients with FTLD with motor neuron disease (MND). It included three cases of pathologically confirmed FTLD with TDP-43 type B. Moderate to severe reduction in DAT availability was observed among patients with FTLD-MND. On pathological examination, the degeneration of the substantia nigra was apparent. Meanwhile, the pathological findings for the caudate and putamen varied among patients. The patient in Arafuka et al.’s report had mild degeneration of the substantia nigra and caudate, but there was no apparent putamen damage. The mild DAT reduction in their case was likely due to the mild or minimal degeneration of the substantia nigra, caudate, and putamen, which influenced the DAT imaging results. Based on the findings of our cases and Arafuka et al.’s case, the striatal DAT imaging findings of FTLD with TDP-43 type B varies, depending on the degree of degeneration in the substantia nigra, caudate, and putamen. Another remarkable finding in the case report by Arafuka et al. was the DAT reduction, observed prior to the onset of MND symptoms in their patient. This was consistent with the clinical course of the previously reported patients. Therefore, the development of MND should be considered in FTLD patients with abnormal findings on DAT imaging. More studies on the application of DAT imaging in patients with FTLD are needed.

Diversity of dopamine transporter images in frontotemporal lobar degeneration‐motor neuron disease

Early-onset Semantic dementia (EOSD) and early-onset Alzheimer's disease (EOAD) are often difficult to clinically differentiate in the early stages of the diseases because of the overlaps of clinical symptoms such as language symptoms. We compared the degree of atrophy in medial temporal structures between the two types of dementia using the voxel-based specific regional analysis system for Alzheimer's disease (VSRAD).

METHODS
The participants included 29 (age: 61.7±4.5 years) and 39 (age: 60.2±4.9 years) patients with EOSD and EOAD, respectively. The degree of atrophy in medial temporal structures was quantified using the VSRAD for magnetic resonance imaging data. Receiver operating characteristic (ROC) analysis was performed to distinguish patients with EOSD and EOAD using the mean Z score (Z-score) in bilateral medial temporal structures and the absolute value (laterality score) of the laterality of Z-score (| right-left |) for indicating the degree of asymmetrical atrophy in medial temporal structures.

RESULTS
The EOSD group had significantly higher Z and laterality scores than the EOAD group (Z-scores: mean ± standard deviation: 3.74±1.05 vs. 1.56±0.81, respectively; P<0.001; laterality score: mean ± standard deviation: 2.35±1.23 vs. 0.68±0.51, respectively; P<0.001). In ROC analysis, the sensitivity and specificity to differentiate EOSD from EOAD by a Z-score of 2.29 were 97% and 85%, respectively and by the laterality score of 1.05 were 93% and 85%, respectively.

EOSD leads to more severe and asymmetrical atrophy in medial temporal structures than EOAD. The VSRAD may be useful to distinguish between these dementias that have several clinically similar symptoms.

Comparing Medial Temporal Atrophy Between Early-Onset Semantic Dementia and Early-Onset Alzheimer's Disease Using Voxel-Based Morphometry: A Multicenter MRI Study.

Semantic dementia (SD) is a unique clinicopathological entity associated with TDP‐type C pathology. We present four cases of SD that illustrate the clinicopathological diversity of TDP‐43 pathology, including early‐onset cases of TDP‐type C with corticospinal tract (CST) and motor neuron pathology and late‐onset cases of TDP‐type A with combined pathology. Case 1 was a 62‐year‐old man with semantic variant of primary progressive aphasia (svPPA) with left‐predominant temporal atrophy and TDP‐type C pathology with low Alzheimer's disease neuropathologic changes (ADNC). Case 2 was a 63‐year‐old woman with right‐predominant temporal atrophy and TDP‐type C pathology who had prosopagnosia and personality changes. Phosphorylated(p)‐TDP‐43‐positive long dystrophic neurites (DNs) were observed throughout the cerebral cortex; they were more abundant in the relatively spared cortices and less so in the severely degenerated cortices. We observed CST degeneration with TDP‐43 pathology in the upper and lower motor neurons, without apparent motor symptoms, in SD with TDP‐type C pathology. Case 3 was a 76‐year‐old man who had svPPA and personality changes, with left‐predominant temporal atrophy and TDP‐type A pathology with high ADNC and argyrophilic grain (AG) stage 3. Case 4 was an 82‐year‐old man who had prosopagnosia and later developed symptoms of dementia with Lewy bodies (DLB) with right‐predominant temporal atrophy and TDP‐type A pathology with high ADNC, DLB of diffuse neocortical type, and AG stage 3. The distribution of p‐TDP‐43‐positive NCIs and short DNs was localized in the anterior and inferior temporal cortices. An inverse relationship between the extent of TDP pathology and neuronal loss was also observed in SD with TDP‐type A pathology. In contrast, the extent of AD, DLB, and AG pathology was greater in severely degenerated regions. CST degeneration was either absent or very mild in SD with TDP‐type A. Understanding the clinicopathological diversity of SD will help improve its diagnosis and treatment.

Clinicopathological diversity of semantic dementia: Comparisons of patients with early‐onset versus late‐onset, left‐sided versus right‐sided temporal atrophy, and TDP‐type A versus type C pathology

Introduction Frontotemporal lobar degeneration (FTLD) is a clinical syndrome with pathological heterogeneity, including Pick’s disease and trans-activating response region (TAR) DNA-binding protein with a molecular mass of 43 kDa (TDP-43) proteinopathy (FTLD-TDP). A previous study reported abnormal findings on dopamine transporter (DAT) imaging in 30% of patients with frontotemporal dementia (FTD) in FTLD. However, the previous study did not consider the pathological heterogeneity of FTD regarding the pathomechanism leading to abnormal DAT findings. Recently, abnormal DAT findings were reported in two patients with FTLD with motor neuron disease (MND), of which FTLD-TDP type B was the most common pathological presentation. This study investigated the DAT findings of patients with a final diagnosis of FTLD-MND to determine the frequency of occurrence of DAT abnormalities in FTLD-MND. Methods Twenty patients with FTLD who underwent DAT single photon emission computed tomography (DAT-SPECT) were screened, and six patients with a final diagnosis of FTLD-MND were ultimately included. The patients’ DAT-SPECT findings were analyzed visually and quantitatively. Neuronal loss and astrogliosis in brain regions (substantia nigra, caudate, and putamen) that could possibly affect DAT findings were evaluated in the three pathologically confirmed cases. Result All six patients with FTLD-MND showed abnormal visual DAT-SPECT findings. In addition, in a quantitative assessment, the specific binding ratio in the striatum calculated by the Southampton method was below the lower limit of the 95% prediction interval of the healthy controls by age in all the present cases. Interestingly, three of the six patients showed abnormal findings on DAT-SPECT more than half a year before the onset of MND. Neuronal loss and astrogliosis in brain regions that may affect DAT findings were observed in three pathologically confirmed cases. Conclusion Dopamine transporter single photon emission computed tomography revealed abnormal findings in patients with FTLD-MND, which may manifest even before the onset of MND symptoms. We believe that the possibility of future development of MND should be considered if DAT-SPECT shows abnormal findings in FTLD.

Dopamine Transporter Imaging for Frontotemporal Lobar Degeneration With Motor Neuron Disease

Apathy and depression are frequently observed as behavioral and psychological symptoms of dementia, respectively, and are important for ensuring adequate care. This study aims to explore effective non-pharmacological interventions for apathy and depression with mild cognitive impairment (MCI) and dementia. Five search engines including PubMed, Scopus, CINAHL, PsycInfo, and Web of Science were used to extract relevant studies. Inclusion criteria were studies that involved participants who were diagnosed with MCI or dementia, included quantitative assessments of each symptom, and employed randomized controlled trials. Twenty studies were extracted, with interventions have been conducted in care facilities, the community, and hospitals. Participants in many studies had MCI or mild-to-moderate dementia but were not diagnosed with the subtypes of dementia. Few studies had set apathy and depression as the primary outcomes of non-pharmacological interventions. The findings suggested that emotional and stimulation-oriented approaches to apathy and depression would be useful for people with MCI or mild-to-moderate dementia. It would be helpful for therapists to assess the clinical features of the target symptoms for selecting suitable interventions. Additionally, increasing the number of randomized controlled trials focusing on apathy or depression as primary outcomes would offer a more definite conclusion for future systematic reviews.

Non-pharmacological Approaches to Apathy and Depression: A Scoping Review of Mild Cognitive Impairment and Dementia

Various misidentification symptoms, such as Capgras syndrome, reduplicative paramnesia, and phantom boarder syndrome, can develop in patients with dementia with Lewy bodies (DLB). In particular, among misidentifications, Capgras syndrome has gathered attention as a prodromal symptom of DLB. Patients with DLB are often hypersensitive to antipsychotics, and parkinsonism can occur during the prodromal stage as an adverse drug reaction. In addition, antidepressants and hypnotics other than antipsychotics may induce core clinical features of DLB, including visual hallucinations, rapid eye movement sleep behaviour disorder (RBD), and parkinsonism, during the prodromal stage of DLB. Based on these findings, patients with underlying Lewy body disease may be more likely to present with core and suggestive features of DLB when they develop adverse drug reactions during the prodromal stage. This report describes misidentification induced by clonazepam in a patient with prodromal DLB. A 79-year-old right-handed woman, with 9 years of education, had an unremarkable clinical history, including psychiatric disorders. In 200X-6, the patient first experienced episodes of feelings that her deceased husband was still alive. In 200X-3, she developed finger tremors and was diagnosed with essential tremors by a neurologist. Clonazepam 1.5 mg at bedtime was prescribed. The patient’s consent for off-label use, based on an evidence-based guideline for the treatment of essential tremor (1 in Appendix S1), was obtained. After taking clonazepam, the patient frequently experienced episodes of misidentification, for example, she felt that ‘This is not my house, despite the similar appearance of the furniture’ and ‘This is the same shape house as my house’. These episodes of misidentification were resolved the following morning. Therefore, she did not consult with her doctor. The patient lived alone and independently. In September 200X, the patient was referred to our hospital due to worsening misidentification and the development of cognitive impairment. She exhibited no cognitive fluctuation or visual hallucinations; however, mild bradykinesia and resting tremors of the upper limbs were observed. She experienced mild amnesia, attention deficits, and executive dysfunction, with a Mini-Mental State Examination (MMSE) score of 21/30 and a Frontal Assessment Battery score of 7/18. The results of the magnetic resonance imaging scan were unremarkable (Fig. 1a). However, I-meta-iodobenzylguanidine myocardial scintigraphy revealed a decreased heart-to-mediastinum ratio in the delayed phase and an increased washout ratio (Fig. 1b). Dopamine transporter (DAT) imaging showed normal DAT availability on quantitative analysis, although a mild DAT reduction was noted in the putamen on visual assessment (Fig. 1c). The patient exhibited cognitive dysfunction, parkinsonism, and abnormal levels of biomarkers for DLB. Thus, she was diagnosed with probable DLB based on the diagnostic criteria (2 in Appendix S1). The discrepancy between her parkinsonism and the DAT imaging findings was supposed to be associated with mild parkinsonism corresponding to a mild DAT reduction in the putamen or tremor-dominant parkinsonism without severe DAT reduction (3, in Appendix S1). The patient’s misidentification was considered a symptom of DLB, which developed coincidentally after the clonazepam treatment. Nonetheless, her treatment with clonazepam was withdrawn to rule out clonazepam-induced misidentification. This approach resulted in the complete resolution of the misidentification, whereas the cognitive dysfunction persisted, according to her family.

Clonazepam‐induced misidentification in prodromal dementia with Lewy bodies

Valosin-containing protein Asp395Gly mutation in a patient with frontotemporal dementia: a case report

Musical hallucinations (MHs) are a type of auditory hallucination in which music is perceived despite a lack of actual sound. Few reports have described longitudinal neuroimaging findings in different conditions before and during MHs. This report describes a depressed patient whose regional cerebral blood flow (rCBF) was assessed using single-photon emission computed tomography (SPECT) before and during MHs. A 72-year-old depressed woman was admitted to our hospital. During the treatment period, she experienced MHs. Then MHs disappeared with treatment of depression or following improvement in the mood. SPECT scans were performed to assess the levels of rCBF in several brain areas before and during MHs. During MHs, rCBF was increased in the basal ganglia, thalamus, amygdala, and parietal lobes. This report suggests that increased rCBF in multiple brain areas, especially in the basal ganglia and thalamus, might be related to the pathophysiology of MHs in depressed patients.

Changes in Regional Cerebral Blood Flow of A Depressed Patient Before and During Musical Hallucinations: A Case Report

Cotard syndrome during the withdrawal of high-dose antiparkinsonian drugs in a patient with Parkinson's disease.

Akathisia, which characterized by subjective restlessness and objective hyperactivity, is induced mostly by antipsychotics and antidepressants. Chronic akathisia is defined as persistence of symptoms for more than 3 months. The pathophysiology of chronic akathisia remains unclear. This report describes a depressed patient, a 66-year-old woman with a diagnosis of major depressive disorder, with chronic akathisia. Her regional cerebral blood flow (rCBF) was measured using single photon emission computed tomography (SPECT) before and after the treatment with electroconvulsive therapy (ECT). She had experienced akathisia-like symptoms three times prior because of risperidone, escitalopram, and clomipramine administration, accompanied by major depression. After levomepromazine was added to quetiapine to treat insomnia, she developed akathisia symptoms such as a sense of restlessness and inability to sit in one place for a few minutes. These antipsychotics were withdrawn. Propranolol was administered, leading to no apparent improvement for 8 months. After she was diagnosed as having major depressive disorder and chronic akathisia, she received 10 sessions of bilateral ECT. Her depressive symptoms improved greatly. Akathisia disappeared completely after ECT. SPECT revealed that rCBF was decreased in the middle frontal gyrus and parietal lobe, that it was increased in the thalamus, fusiform gyrus, and cerebellum before ECT, and that these abnormalities in rCBF were approaching normal levels after ECT. Findings presented in this report suggest ECT as a beneficial treatment for chronic akathisia. Altered rCBF in the middle frontal gyrus, parietal lobe, thalamus, fusiform gyrus, and cerebellum, and especially decreased rCBF in the parietal lobe, may be related to the pathophysiology of chronic akathisia.

Case Report: Changes in Regional Cerebral Blood Flow in Chronic Akathisia of a Depressed Patient Before and After Electroconvulsive Therapy Treatment

Low-dose zolpidem-induced visual hallucinations in prodromal dementia with Lewy bodies.

Patient: Male, 52-year-old Final Diagnosis: Schizoaffective disorder Symptoms: Somatic delusions Medication:— Clinical Procedure: — Specialty: Psychiatry Objective: Unusual or unexpected effect of treatment Background: Somatic delusions are false and fixed beliefs about health and organ function, which are observed in various psychiatric disorders. Psychotropic drugs such as antipsychotics and antidepressants are effective for some patients, while the efficacy of electroconvulsive therapy (ECT) for pharmacotherapy-resistant cases has been reported. Previous reports suggest that somatic delusions in delusional disorder somatic type are associated with reduced regional cerebral blood flow (rCBF), but it remains unclear whether this association is also observed in other psychiatric disorders. We report the case of a patient with schizoaffective disorder whose drug-resistant somatic delusions showed remarkable improvement accompanied by altered rCBF after successful ECT. Case Report: The patient was a Japanese man aged 52 years with a diagnosis of schizoaffective disorder. He was suffering from severe and persistent somatic delusions such as “There is a thick stick or bowl in my head” and “Something like a film stretches over my head and face”, which were resistant to several antipsychotics and antidepressants. In our hospital, he received bitemporal ECT 8 times. His somatic delusions started to improve from the third administration, and they disappeared by the eighth administration. In parallel with this clinical improvement, reduction of rCBF in the bilateral parietal and occipital lobes observed before ECT disappeared. Conclusions: The present study suggests that ECT is a useful choice for drug-resistant somatic delusions. Reduction of rCBF in the bilateral parietal and occipital lobes may be associated with manifestation of somatic delusions in schizoaffective disorder.

Improvement of Somatic Delusions with Altered Regional Cerebral Blood Flow Following Electroconvulsive Therapy in a Patient with Schizoaffective Disorder

Kazutaka SAKAMOTO , Ryota KOBAYASHI , Kayoko YOKOI, Miki OTAKA, Oyuki OKADA, Kazuki HOSOKAWA, Masayuki KIMURA, Shinobu KAWAKATSU, Koichi OTANI and Kazumi HIRAYAMA Department of Neuropsychiatry, Aizu Medical Center, Fukushima Medical University, Fukushima, Chitose Shinoda Hospital, Department of Psychiatry, Yamagata University School of Medicine, Department of Occupational Therapy, Graduate School of Health Sciences, Yamagata Prefectural University of Health Sciences and Department of Rehabilitation, Shinoda General Hospital, Yamagata and Department of Rehabilitation, Akiyama Neurosurgery Hospital, Yokohama, Japan Correspondence: Kazutaka Sakamoto OTR, PhD, Department of Neuropsychiatry, Aizu Medical Center, Fukushima Medical University, 21-2, Kawahigashimachi Tanisawa, Aizuwakamatsu City, Fukushima 969-3492, Japan., Email: deltoid_np@yahoo.co.jp Disclosure: The authors have no conflicts of interest to declare and received no financial support for this report.

Trimodal hallucination and delusion after right thalamomesencephalic infarction

Comparison of Alzheimer’s disease patients and healthy controls in the easy Z-score imaging system with differential image reconstruction methods using SPECT/CT: verification using normal database of our institution

Effect of cerebrospinal fluid area mask correction on 123I-FP-CIT SPECT images in idiopathic normal pressure hydrocephalus

Suspected non‐Alzheimer's disease pathophysiology (SNAP) shows Alzheimer's disease (AD)‐like neurodegeneration; however, amyloid β, which is a biological marker in AD, remains within normal levels. Since the effectiveness of anti‐dementia drugs for AD on SNAP is unknown, it is important to distinguish between patients with SNAP and AD. We aimed to compare decreases in regional cerebral blood flow (rCBF) of the posterior cingulate cortex (PCC), precuneus, and parietal lobe critical to AD between SNAP and AD groups using the easy Z‐score imaging system in single‐photon emission computed tomography (eZIS‐SPECT).

Comparison of the decreases in regional cerebral blood flow in the posterior cingulate cortex, precuneus, and parietal lobe between suspected non‐Alzheimer's disease pathophysiology and Alzheimer's disease

We report four cases depicting the heterogeneity of Alzheimer's disease (AD) associated with pure AD pathology. Case 1 was a 77‐year‐old man with a false positive diagnosis of dementia with Lewy bodies with reduced dopamine transporter uptake activity of the striatum but no Lewy body pathology. There were tau deposits in the large neurons in the putamen, which may be related to the development of parkinsonism. Case 2 was an AD patient in his early 30s who presented with a psychotic episode and a cognitive decline, and later developed myoclonus and seizures. He demonstrated considerable amyloid‐beta deposits in the cerebral cortex, including cotton wool plaques, basal ganglia, and cerebellum. Tau deposits were also abundant in the cerebral neocortex, hippocampus, basal ganglia, and brain stem. Case 3 was a 60‐year‐old woman who exhibited typical symptoms characteristic of the logopenic variant of primary progressive aphasia (lvPPA). Case 4 was a 68‐year‐old man who exhibited the semantic variant of primary progressive aphasia (svPPA) plus repetition impairment, a rare case associated with AD pathology. In addition to tau pathology, astrocytic pathology was prominent in the white matter and cortical layers of the left temporoparietal cortices. While the main AD lesion in case 4 was evaluated by tau accumulation and astrogliosis in the left temporal lobe, that in case 3 in was evaluated by the same points in the left parietal lobe. Within the spectrum of lvPPA, case 4 may be regarded as a temporal variant of lvPPA presenting svPPA. The pathology of PPA associated with AD may have broader clinical manifestations than that in previously described cases. Case 4 also showed pathological features characteristic of cerebral amyloid angiopathy throughout the cerebral cortex. The distribution of tau and astrocytic pathologies in the cerebral cortex, basal ganglia, brain stem, and cerebellum may explain the various symptoms of atypical pure AD patients.

Clinicopathological heterogeneity of Alzheimer's disease with pure Alzheimer's disease pathology: Cases associated with dementia with Lewy bodies, very early‐onset dementia, and primary progressive aphasia

s International Psychogeriatrics is abstracted and indexed in Abstracts in Social Gerontology; Current Literature on Aging; AgeLine; Combined Health Information Database (CHID); Cumulative Index to Nursing & Allied Health Literature (CINAHL); Current

Patient: Female, 92-year-old Final Diagnosis: Dementia with Lewy bodies Symptoms: Catatonia Medication:— Clinical Procedure: Biomarker Specialty: Neurology • Psychiatry Objective: Unusual clinical course Background: Catatonia can occur in various neuropsychiatric disorders and is usually treated with benzodiazepines. So far, although 1 case of dementia with Lewy bodies (DLB) with catatonia has been reported, there have been no reports on patients with DLB whose initial symptom was a catatonia. Here, we present a patient who developed benzodiazepine-resistant catatonia and was subsequently diagnosed with DLB based on DLB biomarkers. Case Report: The patient was a 92-year-old woman who had not been diagnosed with dementia before. At the age of 91, she experienced catatonia and was initially treated with lorazepam, which did not improve her condition. Later, she transferred to our hospital and was treated with amantadine. Amantadine improved her catatonic symptoms; however, a decline in her cognitive function was observed. We therefore explored the cause of cognitive impairment through imaging studies. We found that the patient did not have the core clinical features of DLB (ie, visual hallucinations, parkinsonism, cognitive fluctuations, and rapid eye movement sleep behavior disorder) but had 2 indicative biomarkers on 123I-metaiodobenzylguanidine myocardial scintigraphy and dopamine transporter imaging. Possible DLB was diagnosed according to the diagnostic criteria. Conclusions: Our case study suggests that catatonia can be an initial symptom of DLB. Moreover, considering the plausible pathophysiology of catatonia in DLB, amantadine treatment may be the most rational choice for the condition when benzodiazepine treatment is ineffective.

Catatonia as the Initial Manifestation of Dementia with Lewy Bodies

Arnold Pick described a focal cortical syndrome caused by focal temporal and/or frontal cortical atrophy, later reffered to as Pick's disease (PiD), a prototype of frontotemporal lobar degeneration (FTLD). In contrast to the current concept of PiD, the presence of Pick bodies (tau-positive inclusions) was not thought to be necessary for the diagnosis of PiD. Four out of the seven patients in his original paper had predominant left temporal atrophy and language related symptoms corresponding to semantic dementia. It is now known that most patients with semantic dementia have transactive response DNA-binding protein 43kDa (TDP-43) pathology rather than tau pathology. The original concept of PiD was substantially similar to the current concept of FTLD, which has heterogeneous molecular pathology including tau, TDP-43 and fused in sarcoma (FUS).

[Frontotemporal Lobar Degeneration: A Historical Overview of the Concept].

Globular glial tauopathy (GGT) is a new category within the 4‐repeat tauopathies that is characterised neuropathologically by tau‐positive globular glial inclusions (GGIs), namely, globular oligodendrocytic and astrocytic inclusions (GOIs and GAIs). Occurrence of tau‐positive neuronal cytoplasmic inclusions (NCIs) is also a feature. GGT is classified into three pathological subtypes (Types I, II and III). We studied the tau pathology in 6 cases of GGT (Type II, n = 3; Type III, n = 3), with special reference to GAIs and NCIs.

Morphological characterisation of glial and neuronal tau pathology in globular glial tauopathy (Types II and III)

Detection of reduced dopamine transporter availability by 123I‐N‐omega‐fluoropropyl‐2‐beta‐carbomethoxy‐3‐beta (4‐iodophenyl) nortropane single‐photon emission computed tomography in a patient of frontotemporal dementia with motor neuron disease

Background: Easy Z-score imaging system (eZIS)-assisted SPECT accurately detects decreases in cerebral blood flow in the posterior cingulate cortex (PCC), precuneus, and parietal lobe, the cerebral regions deeply implicated in Alzheimer’s disease (AD). Several studies suggested onset age-dependent decreases in cerebral blood flow in these regions in AD, but these studies did not screen for amyloid accumulation, suggesting inclusion of non-AD patients in their subjects. Objective: By applying eZIS-SPECT to patients with amyloid deposition, it was the aim of this study to clarify onset age-dependent decreases in cerebral blood flow in the regions critical to AD. Methods: We retrospectively analyzed eZIS-SPECT data on 34 AD patients with amyloid retention confirmed by 11C-Pittsburgh compound B-PET. The subjects were divided into an early-onset group (n = 16) and a late-onset group (n = 18). The three indicators of the eZIS that had discriminated between AD patients and normal controls in previous studies were compared between the two groups. Results: The mean values for the respective indicators were significantly higher in the early-onset group than in the late-onset group. Also, the proportion of patients with abnormalities in all indicators was significantly higher in the early-onset group (93.8%) than in the late-onset group (50.0%). Conclusions: The present study, applying eZIS-SPECT to amyloid-positive AD patients, suggests that reduced cerebral blood flow in the PCC, precuneus, and parietal lobe is more pronounced in the early-onset type than in the late-onset type of the disease.

Utility of Easy Z-Score Imaging System-Assisted SPECT in Detecting Onset Age-Dependent Decreases in Cerebral Blood Flow in the Posterior Cingulate Cortex, Precuneus, and Parietal Lobe in Alzheimer's Disease with Amyloid Accumulation

COVID-19 spreads from person to person through saliva droplets and aerosols from exhalation, talking, and a cough. A systematic review and meta-analysis on the management of severe viral respiratory infections, such as COVID-19, showed that physical distancing of at least 1 m and wearing a face mask or eye protection reduce the risk of viral infections. Among individuals who do become infected with COVID-19, those with hypertension, cardiovascular diseases, and diabetes have a greater risk of having a more severe infection. Furthermore, dementia has been shown to pose an increased risk for COVID19. Therefore, preventing infection is of vital importance for patients with dementia. However, these patients may have difficulties understanding the risk of COVID-19 and taking measures against infection either by themselves or with the help of others. The purpose of the present study was to examine recognition of the COVID-19 pandemic and the status of face mask wearing in patients with Alzheimer’s disease (AD). Patients with AD who visited the Medical Center for Dementia at Shinoda General Hospital in Yamagata, Japan, between May 2020 and July 2020 and who fulfilled the criteria for AD by McKhann et al. were enrolled in the study. Patients with severe dementia who could not understand the question of examiner or with a severe reduction in activities of daily living such as eating or moving by themselves were excluded. In total, 55 patients (20 men, 35 women; mean age: 83.4 5.4 years) and their caregivers (family members) participated in this study. The means SD of the Mini-Mental State Examination and Clinical Dementia Rating (CDR) of these patients were 15.9 5.4 and 1.5 0.6, respectively. Semi-structured interviews on face mask wearing as a preventive measure against COVID-19 were conducted by a psychiatrist or clinical psychologist. The interview consisted of three questions. Question 1 was ‘Why are you, the examiner, the caregiver, and other patients wearing a face mask?’ If a patient’s answer included words or expressions such as ‘coronavirus’, ‘new pneumonia’, and ‘to prevent transmission’, he or she was regarded as recognizing the COVID-19 pandemic. This question was considered superior to direct questions such as ‘Do you know about the COVID-19 pandemic?’, which could elicit an erroneous answer as an appearance-saving response. Question 2 was directed at the caregiver: ‘Does the patient wear a face mask properly or almost properly by himself or herself when necessary?’ If the patient did not wear a face mask properly or almost properly by himself or herself, we asked the caregiver question 3: ‘Can the patient wear a face mask properly or almost properly with your help?’ Statistical analyses were performed with Student’s t-test, Fisher’s exact test, and χ test, where appropriate, using SPSS version 25 (IBM, Armonk, NY, USA). A P-value <0.05 was considered statistically significant. The results of the semi-structured interviews are shown in Table 1. Only 21 of the 55 patients (38.2%) recognized the COVID-19 pandemic. These patients had a higher mean Mini-Mental State Examination score and lower mean CDR score than those who did not recognize the COVID-19 pandemic. Fourteen patients (25.5%) wore a face mask properly by themselves, but 41 patients (74.5%) did not. Patients who wore a face mask on their own had a lower mean CDR score (P = 0.004) and recognized the COVID-19 pandemic at a higher rate (P = 0.028) than those who did not wear a face mask on their own. Of the 41 patients who did not wear a face mask on their own, 34 (82.9%) could wear one with a caregiver’s help. There were no significant differences in mean

Recognition of the coronavirus disease 2019 pandemic and face mask wearing in patients with Alzheimer's disease: an investigation at a medical centre for dementia in Japan

To the Editor: Most cases of idiopathic rapid eye movement sleep behaviour disorder (RBD) represent a prodromal phenotype of α-synucleinopathies, and almost all of them eventually phenoconvert to Parkinson’s disease, dementia with Lewy bodies, or much less frequently to multiple system atrophy (MSA). In support of this close linkage, a high proportion of RBD cases show decreased dopamine transporter (DAT) availability in the striatum, which is commonly observed in Parkinson’s disease, dementia with Lewy bodies, and MSA. However, Parkinson’s disease and dementia with Lewy bodies, but not MSA, exhibit decreased myocardial uptake of I-metaiodobenzylguanidine (I-MIBG), suggesting myocardial sympathetic denervation in the former disorders but not in the latter. Accordingly, it has been hypothesized that the combination of abnormal DAT imaging and normal I-MIBG myocardial scintigraphy predicts phenoconversion from RBD to MSA. Recently, we confirmed this hypothesis in a patient with RBD. The patient was a right-handed 68-year-old Japanese man. In January 2016, he visited our hospital because he had had dream-enacting behaviours, including speaking loudly and moving his arms and limbs during his dreams, for the last year. The patient scored 7 on the Japanese RBD screening questionnaire, which has high sensitivity and specificity for idiopathic RBD, and was diagnosed with probable idiopathic RBD. He scored 28/30 on the Mini-Mental State Examination, reflecting the absence of dementia. No abnormalities were detected on neurological examinations. Magnetic resonance imaging did not reveal any abnormal findings (Fig. 1a). I-N-omega-fluoropropyl-2-beta-carbomethoxy-3beta-(4-iodophenyl)nortropane single-photon emission computed tomography, an accurate and sensitive form of DAT imaging, showed reduced DAT availability in the bilateral striatum, especially in the left pallidum (Fig. 1b). In contrast, there was no decrease in the heart-to-mediastinum ratios in I-MIBG myocardial scintigraphy (early: 2.53, delayed: 3.37; institutional cut-off value: 2.2) (Fig. 1c). In September 2016, orthostatic hypotension was observed. In January 2017, the patient developed gait disturbance, postural instability, and frequent urination. However, he still scored 29/30 on the Mini-Mental State Examination, reflecting the absence of dementia. Even at this stage, the heart-to-mediastinum ratios of IMIBG myocardial scintigraphy had not decreased (early: 2.69, delayed: 3.02). In August 2017, his orthostatic hypotension and postural instability worsened. His gait was wide-based and ataxic, necessitating assistance to walk. He also had urinary incontinence and mild dysphagia. Eventually, he was diagnosed with probable MSA based on the published diagnostic criteria. In January 2018, he began to require a wheelchair to move. Computed tomography of the head showed atrophy of the middle cerebellar peduncles, pons, and mesencephalic tectum (Fig. 1d). The present report suggests the usefulness of combining DAT imaging and I-MIBG myocardial scintigraphy to predict phenoconversion from RBD to MSA. The presence of reduced striatal DAT availability and the absence of myocardial sympathetic denervation— a pathophysiological characteristic of MSA, which is a specific type of α-synucleinopathy—predicts future progression to this neurodegenerative disorder. There are two limitations in the present report. Firstly, our patient did not receive polysomnography, and therefore, his diagnosis of RBD remained probable. Secondly, his diagnosis of MSA was not autopsy-proven.

Phenoconversion from rapid eye movement sleep behaviour disorder to multiple system atrophy is predicted by abnormal dopamine transporter imaging combined with normal 123I‐metaiodobenzylguanidine myocardial scintigraphy: a case report

Detection of decreased striatal dopamine transporter availability by 123I-FP-CIT SPECT in a patient of carbon monoxide poisoning with severe cognitive deficits but mild parkinsonian symptoms.

Thought visualization occurring in a patient of dementia with Lewy bodies.

Globular glial tauopathies (GGTs) are four‐repeat tauopathies characterized by the presence of two types of tau‐positive globular glial inclusions (GGIs): globular oligodendrocytic and astrocytic inclusions (GOIs and GAIs). GGTs are classified into three different neuropathological subtypes: Types I, II and III. We report two patients with GGTs – a 76‐year‐old woman and a 70‐year‐old man – in whom the disease duration was 5 and 6 years, respectively. Both patients exhibited upper and lower motor neuron signs and involuntary movements, and the latter also had dementia with frontotemporal cerebral atrophy evident on magnetic resonance imaging. Neuropathologically, in both cases, the precentral gyrus was most severely affected, and at the gray‐white matter junction there was almost complete loss of Betz cells and occurrence of GOIs and coiled bodies with numerous neuropil threads. Both patients also showed neuronal loss and GGIs (mostly GOIs) in many other central nervous system regions, including the basal ganglia. Apart from the degree of regional severity, the distribution pattern was essentially the same in both cases. However, GAIs were not conspicuous in any of the affected regions. Based on the morphology and distribution pattern of the GGIs, we diagnosed the present two patients as having GGT Type II. Electron microscopic and biochemical findings in the former were consistent with the diagnosis. Type II cases are reported to be characterized by pyramidal features reflecting predominant motor cortex and corticospinal tract degeneration. The present observations suggest that a variety of neurological features, including dementia, can occur in GGT Type II reflecting widespread degeneration beyond the motor neuron system.

Globular glial tauopathy Type II: Clinicopathological study of two autopsy cases

Introduction: Dementia with Lewy bodies (DLB) often exhibits REM sleep behavior disorder (RBD) at its prodromal stage. Meanwhile, DLB is often comorbid with Alzheimer's disease (AD)-type pathology. In typical AD, amyloid-β deposition begins considerably before the onset of dementia and has already reached a plateau at the stage of mild cognitive impairment. However, it is not known when amyloid accumulation starts in DLB with AD-type pathology. In the present study, we examined amyloid deposition in patients with RBD as a prodromal symptom of DLB using [11C]-Pittsburgh compound B positron emission tomography (PiB-PET). Methods: The subjects were 12 patients with probable RBD as diagnosed by the Japanese RBD screening questionnaire. They also showed abnormality in 123I-metaiodobenzylguanidine myocardial scintigraphy, a biomarker for DLB. For comparison, 11 patients with probable DLB were included. Applying PMOD software to the PiB-PET images, the global cortical distribution volume ratio was calculated and a ratio >1.3 was regarded as PiB-positive. Results: Two of the RBD patients (16.7%) and eight of the DLB patients (72.7%) were PiB-positive. The amyloid-positive rate was significantly lower in the RBD group than in the DLB group (P = 0.012). Conclusion: The prevalence of amyloid deposition in RBD as a prodromal symptom of DLB was significantly lower than that in DLB, suggesting that amyloid accumulation does not always begin at the early stage of DLB.

Assessment of Amyloid Deposition in Patients With Probable REM Sleep Behavior Disorder as a Prodromal Symptom of Dementia With Lewy Bodies Using PiB-PET

Semantic dementia (SD) is characterized by semantic aphasia and prosopagnosia, but it may also include behavioural disturbances such as stereotypic behaviour. We report the case of a 50‐year‐old man with SD accompanied by stereotypic behaviour who committed suicide despite not being in a depressive state. He initially had major depressive disorder accompanied by suicide attempts, but he gradually showed remarkable impairment in single‐word semantic comprehension, naming memory, and facial recognition memory. After the diagnosis of SD, his suicidal behaviour by hanging with a cord became stereotypic and lacked seriousness. He repeatedly attempted to hang himself and finally completed suicide. The present report suggests that the risk for suicide in SD is increased not only by the presence of a depressive state, but also by stereotypic behaviour related to suicide attempts before the onset of the disorder.

Suicide as a result of stereotypic behaviour in a case with semantic dementia

[18F]THK-5351 PET imaging in early-stage semantic variant primary progressive aphasia: a report of two cases and a literature review

Clinical and radiological diversity in genetically confirmed primary familial brain calcification

Neuroleptic malignant syndrome following quetiapine treatment in a patient with dementia with Lewy bodies.

The International Working Group (IWG) has classified Alzheimer's disease (AD) as two different types, the typical form and the atypical form, but clinicopathological studies of atypical AD are limited. Because atypical AD cases usually present with early‐onset dementia, we investigated 12 patients with early‐onset AD, including two patients with typical AD and 10 patients with atypical AD. Of these patients, six had the posterior variant, three had the frontal variant and one had the logopenic variant mixed with semantic dementia. We reported MRI, single‐photon emission CT and neuropathological findings in six representative cases. We also described a “left temporal variant” of AD presenting with transcortical cortical sensory aphasia, which has not been reported previously and is another subtype of the posterior variant of AD. We found a significant correlation between regional cerebral blood flow and counts of NFTs in the cerebral cortices. An atypical presentation with focal neuropsychological symptoms roughly correlated with the density of NFTs in the cerebral cortex and more directly related to spongiform changes in the superficial layers of these areas. In contrast, the distribution of amyloid depositions was diffuse and did not necessarily correlate with focal neuropsychological symptoms. Braak staging or ABC score is not necessarily appropriate to evaluate atypical AD, and instead, spongiform changes in addition to tau pathology in the association cortices better explain the diversity of atypical AD. Interestingly, another patient with a posterior variant of AD had a novel type of atypical plaque, which we referred to as “lucent plaque”. They were recognizable with HE staining in the circumference and dystrophic neurites were abundant with Gallyas‐Braak staining. These plaques demonstrated intense immunoreactivity to both tau AT‐8 and amyloid β (Aβ), suggesting a peculiar coexistence pattern of amyloid and tau in these plaques. Clinicopathological studies of atypical AD will provide a new understanding of the pathophysiology of AD.

Typical and atypical appearance of early‐onset Alzheimer's disease: A clinical, neuroimaging and neuropathological study

The most characteristic symptom of Alzheimer's disease (AD) is episodic memory impairment, which is closely associated with atrophy of the entorhinal cortex. Meanwhile, atypical symptoms are more frequent in early‐onset AD than in late‐onset AD, suggesting that the former subtype has less atrophy in the entorhinal cortex. Therefore, we investigated whether the degree of atrophy in the entorhinal cortex is different between the two subtypes of AD using the voxel‐based specific regional analysis system for AD (VSRAD) targeting this region.

Comparison of entorhinal cortex atrophy between early‐onset and late‐onset Alzheimer's disease using the VSRAD, a specific and sensitive voxel‐based morphometry

Background: Previous studies using magnetic resonance imaging (MRI) showed that dementia with Lewy bodies (DLB) had less atrophy in some medial temporal structures than Alzheimer’s disease (AD). However, very few studies have focused on the entorhinal cortex, which is closely related to episodic memory. We compared the degree of entorhinal cortex atrophy between the two types of dementia using the voxel-based specific regional analysis system for AD (VSRAD) targeting this region. Methods: The subjects consisted of 60 patients with DLB and 210 patients with AD. The degree of entorhinal cortex atrophy was quantified by application of the VSRAD to MRI data, and a Z score >2 was defined as significant atrophy. Results: The DLB group had significantly lower Z scores than the AD group (mean ± SD: 2.25 ± 1.10 vs. 2.85 ± 1.33, p < 0.01). The analysis of covariance with possible confounding factors as covariates also showed that Z scores were significantly lower in the DLB group than in the AD group (p < 0.01). The proportion of patients with atrophy was significantly lower in the DLB group than in the AD group (53 vs. 72%, p < 0.01). Conclusions: The present study using the VSRAD suggests that DLB shows less atrophy in the entorhinal cortex than AD.

Application of the VSRAD, a Specific and Sensitive Voxel-Based Morphometry, to Comparison of Entorhinal Cortex Atrophy between Dementia with Lewy Bodies and Alzheimer’s Disease

This article presents a prototype <inline-formula> <tex-math notation="LaTeX">$22.4~\mu \text{m}$ </tex-math></inline-formula> pixel pitch global shutter (GS) wide dynamic range (WDR) soft X-ray CMOS image sensor (sxCMOS). Backside-illuminated (BSI) pinned photodiodes with a 45-<inline-formula> <tex-math notation="LaTeX">$\mu \text{m}$ </tex-math></inline-formula> thick Si substrate were introduced for low noise and high radiation hardness to high energy photons. Two-stage lateral overflow integration capacitor (LOFIC) and voltage domain memory bank with high-density Si trench capacitors were introduced for WDR and for GS. The developed sxCMOS achieved maximum 21.9 Me<sup>−</sup> full well capacity with a single exposure 129 dB dynamic range by GS operation. Over 70% quantum efficiency (QE) toward soft X-ray was successfully achieved. The developed prototype sxCMOS is a step forward toward a 4 M pixel detector system to be utilized in next-generation synchrotron radiation facilities and X-ray free-electron lasers.

A Global Shutter Wide Dynamic Range Soft X-Ray CMOS Image Sensor With Backside- Illuminated Pinned Photodiode, Two-Stage Lateral Overflow Integration Capacitor, and Voltage Domain Memory Bank

A prototype 22.4μm pixel pitch global shutter wide dynamic range soft X-ray CMOS image sensor (sxCMOS) is presented. The sxCMOS employs backside-illuminated (BSI) pinned photodiode with a 45μm-thick Si substrate for low noise and high light resistance to high energy photons, two-stage LOFIC for wide dynamic range and voltage domain memory bank with high density capacitors for global shutter. The developed chip successfully demonstrated a high quantum efficiency (QE) toward soft X-ray with a single exposure 129dB dynamic range by global shutter.

A Global Shutter Wide Dynamic Range Soft X-ray CMOS Image Sensor with BSI Pinned Photodiode, Two-stage LOFIC and Voltage Domain Memory Bank

The flow visualization technique was applied to the collision of two solitary waves propagating in the same and opposite directions. Measurements of the velocity and trajectory of the solitary waves were conducted using a particle image velocimetry (PIV) system consisting of an 8-W ND:YAG laser and a high-speed CCD camera. In the solitary- wave interaction tests, we set up three kinds of velocity fields—smaller, taller, and compound waves in the rear-end collision tests, and right-running, left-running, and colliding waves in the head-on collision tests. Instantaneous and spatial surface profiles were measured using the image thresholding method in which the boundary plane between the air and water can be detected as the interface having the maximum luminance value. The measured run-up elevation of the colliding wave was compared with the theoretical elevation using a third-order perturbation solution. Based on a Eulerian-Lagrangian algorithm, the PIV result was applied to the particle tracking process that occurred in the two- dimensional plane.

High-resolution PIV measurements for rear-end and head-on collisions of two solitary waves

Lidar techniques have been developed to obtain improved measurements of atmospheric temperature. Four methods have been developed for measuring the atmospheric temperature, i.e. the two-wavelength differential absorption lidar (DIAL) technique); the molecular density method; the Rayleigh spectral width method; a pure rotational Raman method. The temperature measurements with the Rayleigh backscatter method are limited above 35 km altitude where the aerosol backscatter is much less than Rayleigh backscatter. Accuracy of better than 1 K were made by the rotational Raman method above 4 km. In the paper, a rotational Raman lidar has been developed for accurate temperature measurement in the troposphere. The developed system uses an UV laser of 355 nm wavelength and anti-Stokes lines of the rotational Raman spectrum. The temperature accuracy is analyzed by considering sensitivity and signal-to-noise ratio. The simulation has been made for accurate temperature measurement of the troposphere.

Technical Digest. CLEO/Pacific Rim '99. Pacific Rim Conference on Lasers and Electro-Optics (Cat. No.99TH8464)

UV rotational Raman lidar for temperature measurement of the troposphere

In the self-assembly process of β-Si3N4 (SN)/316L stainless-steel (SUS316L) composite materials tailored via sintering of powder mixtures, the formation of a SN agglomerate resulting from condensation–dispersion reactions during the stirring of SN/SUS316L was found to play an important role in improving the thermal conductivity. Moreover, the obtained SN secondary particle groups connected to form a network through diffusion-limited aggregation. In particular, it was shown that the sample prepared at the milling speed of 150 r/min has a similar particle group area (about 1.38 μm2) to that at 120 r/min, but a higher κ (increased from 9.5 W m−1 K−1 to 11.5 W m−1 K−1). To quantitatively evaluate the microstructural morphology of the texture of the self-assembled composite material, global parameters τ(q) and D q and local parameters α(q) and f(α) were determined via multifractal analysis. These characteristics of the anisotropy, dispersion, and cohesiveness of the particle network in the material texture could be analyzed together with the capacity dimension D0, information dimension D1 (configuration entropy), correlation dimension D2, and α(q) (related to internal energy). The results suggest that α(q) reflects the differences in the cohesion of the additive particle agglomeration that constitutes the self-assembly process under the solid-state reaction.

Self-assembly process under a solid-state reaction of β-Si3N4/austenitic stainless-steel composites: stirring conditions and material texture

Direct observations of tribological behavior in cutting with textured cutting tools

We successfully fabricated dense aluminum nitride (AlN) ceramics containing AlN whiskers by low-temperature pressureless sintering and evaluated their microstructures, thermal conductivities, and mechanical strengths. Furthermore, the anisotropy of thermal conductivities caused by the orientation of AlN whiskers was also evaluated. The thermal conductivities of the samples measured in parallel and perpendicular to the longer direction of AlN whiskers were 98 and 67 W m ¹ 1 K ¹ 1 , respectively. The bending strengths of the samples without and with AlN whiskers were 147 and 235 MPa, respectively. From the observation of the fracture surface of the samples, AlN whiskers in the samples probably withstand the fracture originating from weak grain boundaries.

Thermal conductivity and mechanical strength of low-temperature-sintered aluminum nitride ceramics containing aluminum nitride whiskers

Study on Macroscopic Yield Behavior Based on Information of Microstructures of Fine-grained Aluminum

Influence of unique layered microstructure on fatigue properties of Ti-48Al-2Cr-2Nb alloys fabricated by electron beam melting

The effect of a unique layered microstructure consisting of duplex-like region and equiaxed γ grains (γ bands) on the fatigue properties of Ti-48Al-2Cr-2Nb alloy bars fabricated by electron beam melting (EBM) at an angle (θ) of 90° between the building direction and cylinder (loading) axis was investigated focusing on the layered microstructure and test temperature. We found the room temperature (RT) fatigue strength of the alloy bars fabricated at θ = 90° is higher than that of the bars fabricated at θ = 0°. Moreover, it is comparable to that of the cast alloys with hot isostatic pressing (HIP) treatment in low-cycle fatigue life region, even without HIP treatment. The high fatigue strength of the bars at RT is attributed to the γ band, which acts as a resistance for crack propagation directed perpendicular to the γ band. On the other hand, the fatigue strength of the bars at θ = 90° is lower than that of the bars at θ = 0° in low-cycle fatigue life region at 1023 K. This is because the γ bands dose not act as a resistance for crack propagation at 1023 K. Although the bars at θ = 90° exhibits low fatigue strength in the region at 1023 K, that value is comparable to that of HIP-treated cast alloys due to the fine grain size, which is one of the features for the alloys fabricated by the EBM.

Microstructure and Fatigue Properties of TiAl with Unique Layered Microstructure Fabricated by Electron Beam Melting

Contact stress analysis and fatigue strength simulation of Asymmetric tooth gears considering distribution of inclusions

FATIGUE STRENGTH SIMULATION OF GEARS WITH ASYMMETRIC TOOTH PROFILE

Mn2VAl Heusler alloy films were epitaxially grown on MgO(1 0 0) single-crystal substrates by ultra-high-vacuum magnetron sputtering. A2- and L21-type Mn2VAl order was controlled by the deposition temperature. A2-type Mn2VAl films showed no spontaneous magnetization, while L21-type Mn2VAl films showed ferrimagnetic behaviour with a maximum saturation magnetization of 220 emu cm−3 at room temperature (RT). An antiferromagnetic reflection was observed with neutron diffraction at RT for an A2-type Mn2VAl film deposited at 400 °C. A bilayer sample of the antiferromagnetic A2-type Mn2VAl and Fe showed an exchange bias of 120 Oe at 10 K.

Mn2VAl Heusler alloy thin films: appearance of antiferromagnetism and exchange bias in a layered structure with Fe

Preparation of Mo-Re-C samples containing Mo 7 Re 13 C with the β-Mn-type structure by solid state reaction of planetary-ball-milled powder mixtures of Mo, Re and C, and their crystal structures and superconductivity

Analysis of CO2 absorption reaction of Li4SiO4 on the basis of madelung potential of Li site in crystal structure

Densification of AlN ceramics by spark plasma sintering under 1550 °C

Deformation behavior of Fe-15Al-18Co-3Ti (at.%) single crystals containing the Co2AlTi precipitates was examined. In the single crystals furnace-cooled (FC) from 1373 K to room temperature, coarse Co2AlTi phase with the L21 structure was precipitated in the bcc matrix. The L21 phase showed a cuboidal shape with a misfit strain of 0.59%. It is also noted that large amount of Fe substituted for Co in the Co2AlTi precipitates. The FC single crystals exhibited high yield stress above 600 MPa up to 823 K while further increase in temperature resulted in a decrease in yield stress. In the FC crystals, 1/2<111> dislocations in the bcc matrix bypassed the coarse L21 precipitates due to their large misfit strain, resulting in high strength. In contrast, the fine L21 precipitates about 30 nm in diameter were observed in the crystals after solutionization and annealing at 823 K. The crystals with the fine L21 precipitates demonstrated high yield stress above 1400 MPa at room temperature. Paired 1/2<111> dislocations cut the fine L21 precipitates, which led to high strength. The dependence of the yield stress on the precipitate size was also discussed.

Deformation Behavior of Fe-Al-Co-Ti Single Crystals Containing Co2AlTi Precipitates

Needle-like single crystals of aluminum nitride (AlN) were synthesized by the direct nitridation of an Al­Si binary melt. The growth behavior and shape of the needles were changed by varying the Al:Si ratio. With lower Al content, needles with high aspect ratio (>20) preferentially grew on the Al­Si melt and crucible wall. With increasing Al content, needles with lower aspect ratios having various shapes such as ribbon-like and bended shapes tended to grow. The longer directions of the needles could mainly correspond to the c-axis of a wurtzite-type AlN.

Fabrication, Microstructure, and Thermal Conductivity of AlN Whisker/AlN Composite Ceramics

Sintering behavior, microstructure, and thermal conductivity of dense AlN ceramics processed by spark plasma sintering with Y2O3–CaO–B additives

Fundamental research on gas–solid reaction between CO2 and Li2CuO2 linking application for solid CO2 absorbent

306 Influence of Diameter on Tensile Property and Fatigue Life of Industrial Pure Iron Thin Wire

Entanglement couplings of dangling chains in a weak gel are found to be applicable to the design of a self-repairing polymer. It is confirmed that a cleavage applied using a razor blade is healed at room temperature without any manual intervention. Further, the healing efficiency is improved when the molecular weight of a prepolymer, which affects the length of dangling chains, is high. Because the healing occurs by interdiffusion of dangling chains, the relation between ambient temperature and glass transition temperature determines the time required for healing. In other words, a soft rubbery material whose glass transition temperature is lower than room temperature shows immediate healing. A weak gel whose tensile modulus is 100 MPa at room temperature, i.e. a leather-like material, shows healing even at room temperature in a relatively short time (ca 2 h). Finally, when a weak gel shows crystallinity, healing occurs at a temperature above the melting point. Because the material has a permanent network structure, it will not show macroscopic flow even after exposure to high temperature. Copyright © 2011 Society of Chemical Industry

Autonomic healing and welding by interdiffusion of dangling chains in a weak gel

Aluminum nitride (AlN) ceramics were fabricated by pressureless sintering with various sintering additives such as 5 mass % Y2O3, 2 mass % Y2O3–3 mass % Al2O3, 3 mass % Y2O3–1 mass % CaO–0.08 mass % B, and 6 mass % Y2O3–2 mass % CaO–0.16 mass % B. The relative density, phases present, lattice parameter c, and thermal conductivity of the samples were evaluated. The oxygen concentration in AlN lattice was estimated from the lattice parameter c by using the relation between the oxygen concentration and the lattice parameter c of AlN. To analyze the effects on the thermal conductivity of the samples, we plotted the oxygen concentration in AlN lattice estimated from the lattice parameters c versus the thermal resistivity, which is inverse of the thermal conductivity measured in this work. The data of the samples sintered with 5 mass % Y2O3 and 3 mass % Y2O3–1 mass % CaO–0.08 mass % B located on the plot of the relation between oxygen concentration in AlN lattice and thermal resistivity of AlN presented by Slack (Slack’s line) or Harris et al. (Harris’s line), respectively. In contrast, the data of the samples sintered with 2 mass % Y2O3–3 mass % Al2O3 and 6 mass % Y2O3–2 mass % CaO–0.16 mass % B, which contain excess grain boundary phases, located above the Harris’s line. It was suggested that the thermal conductivity of the samples could be influenced by the density, the oxygen content in AlN lattice, and the presence of grain boundary phases.

Relation between oxygen concentration in AlN lattice and thermal conductivity of AlN ceramics sintered with various sintering additives

Dense AlN–SiC solid solution ceramics with 25–75 mol% AlN were fabricated by spark plasma sintering using hexagonal SiC and AlN powders without additives. The bending strength reaches 800 MPa at room temperature with a fracture toughness of about 5 MPa·m1/2. The high bending strength can be retained at high temperatures, maintaining over 400 MPa at 1700°C.

High Temperature Mechanical Properties of Dense AlN–SiC Ceramics Fabricated by Spark Plasma Sintering Without Sintering Additives

In this study, we analyzed the effect of microstructure and oxygen content on the thermal conductivity of dense AlN ceramics by Slack’s plot, which plots the oxygen content estimated from the lattice parameter c versus the thermal resistivity, which is inverse of the thermal conductivity. The analyses were carried out for the AlN ceramics sintered with oxide additives such as Y2O3, Y2O3-Al2O3, or Y2O3-CaO-B. The data of AlN ceramics sintered with Y2O3 or Y2O3-CaO-B located on the plot of the relation between oxygen content in AlN lattice and thermal resistivity of AlN presented by Slack (Slack’s line) or Harris et al (Harris’s line), respectively. In contrast, the data of the sample sintered with Y2O3-Al2O3, which contains excess grain boundary phases, located above the Harris’s line. These results suggest that the thermal conductivities of AlN ceramics are influenced by not only the oxygen contents in the AlN lattices but also the contents of grain boundary phases.

Analyses of Microstructure and Oxygen Content Effects on Thermal Conductivity of AlN Ceramics by Using Slack’s Plot

Evaluation of Al‐Si‐C‐N Ceramics Fabricated by Spark Plasma Sintering

Evaluation of Grain‐Boundary Conduction of Dense AlN–SiC Solid Solution by Scanning Nonlinear Dielectric Microscopy

Synthesis and CO2 absorption properties of single-phase Li2CuO2 oxide were studied by X-ray powder diffraction and thermogravimetry. Samples of Li2CuO2 were prepared in solid state using Li2CO3 and...

Synthesis and CO2 Absorption Properties of Single-phase Li2CuO2 as a CO2 Absorbent

Electrical Properties of Ain‐SiC Solid Solutions with Additions of A1 and C

AlN–SiC solid solutions with p-type electrical conduction were fabricated with the addition of small amounts of Al and C. Powder mixtures of AlN and SiC with small amounts of Al and C (below 10 mol%) were consolidated by spark plasma sintering (SPS) at 2000°C for 10 min under 1 atm Ar, and then heat-treated at 2200°C for 3 h in an Ar flow to afford 2H AlN–SiC solid solutions. The relative densities of the 50AlN-50SiC-Al4C3 (A50-1AC) and 50AlN-50SiC-3Al4C3 (A50-3AC) samples were about 95%, whereas that of the 75AlN-25SiC-Al4C3 (A75-1AC) sample was about 86%. X-ray diffractometry (XRD) analysis showed that the samples comprised only the 2H phase, and except in the case of the A50-3AC sample, no diffraction peaks of Al and C were observed. Although the samples without the additives (Al and C) were electrical insulators, addition of Al and C introduced p-type semiconduction. The electrical conductivities at 300°C of the A50-1AC and A50-3AC samples were about 30 and 100 S/m, respectively, whereas that of the A75-1AC sample was about 10–1 S/m. It was found that addition of Al and C brought about electrical conduction in AlN–SiC solid solutions.

Fabrication and Evaluation of AlN–SiC Solid Solutions with p-Type Electrical Conduction

Dense aluminum nitride–silicon carbide (AlN–SiC) solid solutions with a 2H structure were fabricated by the post-heat treatment of dense AlN–SiC composites fabricated by spark plasma sintering (SPS). The changes in the relative density, microstructure, and phases present were investigated for the compositions of 25 mol% AlN–75 mol% SiC (AlN 25), 50 mol% AlN–50 mol% SiC (AlN 50), and 75 mol% AlN–25 mol% SiC (AlN 75). The AlN–SiC composites fabricated by the SPS were dense ceramics with fine microstructures and composed of 2H and 6H AlN–SiC solid solutions. The AlN 50 samples heat treated at 2200°C and the AlN 75 samples heat treated at 2100°C were also dense ceramics and composed of only the 2H AlN–SiC solid solution. In contrast, the AlN 25 samples heat treated at 2200°C were porous ceramics and composed of several AlN–SiC solid solutions (2H, 4H, 6H, and 15R), and the AlN 75 samples heat treated at 2200°C were decomposed into an Al melt. Dense AlN–SiC solid solutions composed of only the 2H phase can be obtained by controlling the heat-treatment temperatures, except for the AlN 25 sample.

Use of Post‐heat Treatment to Obtain a 2H Solid Solution in Spark Plasma Sintering‐Processed AlN–SiC Mixtures

AlN–SiC ceramics composed of AlN–SiC solid solutions were fabricated by pressureless sintering without sintering additives. The microstructure and electrical properties of the AlN–SiC ceramics were investigated for compositions between 0 and 75 mol% AlN. The AlN–SiC ceramics had a porous structure, and a 2H polytype was found in all compositions. The electrical conductivities and Seebeck coefficients of the AlN–SiC ceramics increased with temperature. The electrical conductivity of 25 mol% AlN–75 mol% SiC ceramics was the highest in all compositions: 32.7 S/m at 300°C. In contrast, the electrical conductivity of 75 mol% AlN–25 mol% SiC ceramics was much lower than that of other samples: 10−2 S/m at 300°C. The Seebeck coefficient of 50 mol% AlN–50 mol% SiC ceramics was the highest of all samples: 210 μV/K at 300°C. The electrical and thermoelectrical properties of SiC can be controlled by the formation of AlN–SiC solid solutions.

Temperature Dependence of the Electrical Properties and Seebeck Coefficient of AlN–SiC Ceramics

Growth of 4H-SiC bulk crystals on 4H-SiC {03-38} seeds was done. 4H-SiC {03-38} is obtained by inclining the c-plane toward <01-10> at a 54.7 degrees angle. Growth on the 4H-SiC {03-38} seed has the potential to achieve high quality crystals without micropipes and stacking faults. Micropipe-free c-plane 4H-SiC wafers were achieved by growth on the 4H-SiC {03-38} seed. A transmission X-ray topograph image of the micropipe free c-plane wafer revealed that there are no macroscopic defects with displacements.

AlN-SiC ceramics with 0 to 75 mol% of AlN were fabricated through pressureless sintering of very fine AlN and SiC. Powder compacts with different amounts of AlN were fired at 2000°C for 1 h in Argon gas flow using an induction-heating furnace. The microstructure and phases present in the products were evaluated using SEM and XRD. The AlN-SiC ceramics had a porous structure with 30% porosity, and the grain size was increased with the addition of AlN. XRD analysis showed that 2H was a main phase in all samples, though 3C and 6H phases were found in 25 mol%AlN-75 mol%SiC ceramic. The electrical properties of the AlN-SiC ceramics were evaluated at various temperatures ranging from room temperature to 300°C. The electrical conductivity of the AlN-SiC ceramics depended on the amount of AlN and on the temperature. The 75 mol%AlN-SiC ceramic had higher electrical resistance, though the other samples were electrical conductors. The highest electrical conductivity was obtained with the 25 mol% AlN composition, which was 7 S/m at room temperature and 30 S/m at 300°C. The Seebeck coefficient for the AlN-SiC ceramics increased with rising temperatures. The AlN-SiC ceramics with 50 mol%AlN had the highest Seebeck coefficient of 220 2V/K at 300°C.

We have attempted phase identification of carbon nanosized powders prepared by pulsed wire discharge (PWD) to clarify the cooling process of PWD plasma. To prepare the carbon nanosized powders, carbon fibers were discharged in nitrogen gas at 26 – 101 kPa by PWD. Volume fractions of phases in the carbon nanosized powders were analyzed by thermogravimetric analysis and powder X-ray diffraction. The volume fraction of amorphous carbon, which must be formed by quenching of carbon plasma, was increased with increasing nitrogen gas pressure. This result suggested that the cooling rate of PWD plasma increased with increasing ambient gas pressure.

Pressure Dependence of Phases in Carbon Nanosized Powders for Investigating Cooling Rate of Pulsed Wire Discharge Plasma

In-situ measurement of sintering behavior of Porous Silicon carbide ceramics

Carbon fibers were discharged in N2 and Ar gas at pressures between 200 and 750 Torr by pulsed wire discharge to prepare fullerene. In experiments using N2 gas, carbon fibers were almost completely evaporated to form soot, while the fibers were not effectively heated in Ar gas due to the occurrence of surface creepage. In the soot prepared in N2 gas, we observed C60 and C70 molecules by mass spectroscopy and ultraviolet/visible absorption spectroscopy. Since this method is very simple and inexpensive, mass production of fullerene with high energy-conversion efficiency will be possible by pulsed wire discharge.

Highly-Efficient Low-Latency HARQ Built on NOMA for URLLC: Radio Resource Allocation and Transmission Rate Control Aspects

Hybrid automatic repeat request (HARQ) is an essential technology that efficiently reduces the transmission error rate. However, for ultra-reliable low latency communications (URLLC) in the 5th generation mobile communication systems and beyond, the increase in latency due to retransmission must be minimized in HARQ. In this paper, we propose a non-orthogonal multiple access (NOMA)-based highly-efficient low-latency HARQ method for URLLC while minimizing the performance loss for coexisting services (use cases) such as enhanced mobile broadband (eMBB). In the proposed method, delay-sensitive URLLC packets are preferentially multiplexed with best-effort eMBB packets in the same channel using superposition coding to reduce the transmission latency of the URLLC packet while alleviating the throughput loss in eMBB. This is achieved using a weighted channel-aware resource allocator (scheduler). The inter-packet interference multiplexed in the same channel is removed using a successive interference canceller (SIC) at the receiver. This corresponds to non-orthogonal HARQ at the system level. Furthermore, the transmission rates for the initial transmission and retransmission are controlled in an appropriate manner for each service in order to deal with decoding errors caused by error in transmission rate control originating from a time varying channel. We show that the proposed method significantly improves the overall performance of a system that simultaneously provides eMBB and URLLC services.

Corrigendum: “Circuit models of simultaneously biased intrinsic Josephson junction stacks for terahertz radiations in high-bias regime” [Appl. Phys. Express 15, 093002 (2022)]

Experiment-based circuit models for Josephson plasma emitters (JPEs) made of cuprate superconductor Bi2Sr2CaCu2O8+δ single crystals are proposed. Introducing an LCR resonator shunting an RCSJ parallel circuit allows us to reproduce experimental radiation intensity as a function of device voltage. Mismatch in the resonance frequencies of the total device and the LCR part is related to the wide-range tuning of the radiation frequency of JPE. It is found that coupling capacitances for simultaneously biased operations provide significant increases in radiation intensities, which have been reported as synchronized radiation from multiple mesas in the literature.

Circuit models of simultaneously biased intrinsic Josephson junction stacks for terahertz radiations in high-bias regime

We examine coupling interactions used to synchronize macroscopic Josephson oscillations induced in intrinsic Josephson junction (IJJ) mesa stacks made of Bi2212 single crystals. Synchronized emissions of terahertz electromagnetic (EM) waves are detected under common voltage and current bias operations of two connected mesas with close individual emission frequencies, while uncoupled and bimodal emissions are frequently observed in two mesas with different individual emission frequencies. Detailed observations of the polarization of the EM wave emitted when two mesas are biased in parallel or series allow us to reveal the coupling matrix components, which include ratios of synchronized IJJs in the mesas and phase retardation between the macroscopic Josephson oscillations. This finding stimulates systematic survey on polarization of EM wave emitted from synchronized multiple mesa devices in order to realize powerful emissions from superconductors.

Spontaneous frequency shift and phase retardation of coupled Josephson oscillations in cuprate superconductors

There are two types of the transformers in a contactless power transfer system: solenoid type (H‐shaped) and circular type transformers. These two types of transformers are not compatible because their magnetic field structures are different. An Hc type transformer that is compatible with both transformer types has been proposed. The Hc type receiver adds a central magnetic pole by dividing the winding coil of the H‐shaped receiver. The Hc type receiver can change the magnetic field structure by changing the connections of the divided windings and can receive power from both types of transmitters. In this study, we conducted a circuit analysis and evaluated the performance of the Hc type transformer.

The Circuit Analysis and Performance Evaluation of an Hc Type Magnetic Coupling Contactless Power Transformer that is Compatible with Both Solenoid and Circular Type Transformers

We designed a digital superconducting quantum interference device (SQUID) system that contains a double relaxation oscillation SQUID (DROS) as a magnetic flux comparator that is connected to an additional relaxation oscillation (RO) circuit with mutually coupled inductances. In the designed digital SQUID, the RO circuit works as a resonator and increases the relaxation oscillation frequency without decreasing the input current of dc/SFQ converters. Numerical simulation shows that the digital SQUID system can operate up to 7 GHz. A fabricated digital SQUID using a DROS comparator with an RO circuit provides correct digital SQUID operation. For a magnetometer using the digital SQUID system, we can realize a magnetic field noise less than 1 pT/ $\sqrt{\mathrm{Hz}}$ with a small signal bandwidth of more than 10 MHz.

Noise Properties of Digital SQUID Using Double Relaxation Oscillation SQUID Comparator With Relaxation Oscillation Resonant Circuit

A contactless power transfer system using a repeater coil (repeater Coil topology) has been proposed as a method of suppressing overcurrent without power control during misalignment or no‐load. By installing a repeater coil between the primary and secondary coils, it is possible to increase the input impedance in the case of misalignment of the secondary coil or no‐load condition. In addition, another contactless power transfer system using primary parallel and secondary series resonance capacitors (PS capacitor topology) has been proposed. In the PS capacitor topology, the input impedance can be increased during misalignment of the secondary coil or no‐load condition similar to the repeater coil topology. In this paper, we evaluated the characteristics of both these topologies. First, we conducted a circuit analysis of the repeater coil topology and proposed a design method. In addition, we theoretically clarified the characteristic difference of the two topologies and experimentally evaluated the characteristics.

Circuit Analysis and Characterization of Contactless Power Transfer System with Variable Impedance

For power transfer to the rotor circuit of excitation-type synchronous motors, we propose a contactless power transfer system with a primary series capacitor (S topology) to compensate for the leakage reactance. This system does not contain secondary resonant and smoothing capacitors and can reduce the number of components in the rotor circuit. The value of the primary resonant capacitor is determined such that the input power factor is set to one for the operating frequency. The rotating shaft of the rotor is covered with an aluminum sheet to reduce the loss due to the leakage flux. Power transfer tests were performed. A high efficiency of 91.8% was achieved when power was transferred to the rotor circuit of the synchronous motor.

2014 International Power Electronics Conference (IPEC-Hiroshima 2014 - ECCE ASIA)

Excitation system by contactless power transfer system with the primary series capacitor method

Tensegrity structures have been actively studied in recent years because they are lightweight, compliant, and flexible, which are properties not typically found in conventional robots. This structure can be modularized to create soft robots that operate in unknown environments such as cave or space with more complex and effective behavior. The basic deformation elements in modularization are stretching, bending, and torsion. Among them, torsional motion is important for proper manipulation and rotational operation. However, active, and large torsion in soft tensegrity structures has not been developed. Therefore, this study describes torsional deformation and a novel arrangement method for thin artificial muscles. The proposed method leads to the optimal placement of artificial muscles for torsion, by which we generated a large torsion of $\pm$50 deg. This is more than 2.5 times larger than that of a previous tensegrity without compromising the favorable properties of the structure. Furthermore, by modularizing the tensegrity structure, a tensegrity arm capable of removing a plastic bottle cap was developed. The applicability of torsional deformation and the usefulness of modularization of the structure are demonstrated.

Large Torsion Thin Artificial Muscles Tensegrity Structure for Twist Manipulation

The Proceedings of JSME annual Conference on Robotics and Mechatronics (Robomec)

In this study, we compared the differences in brain activation associated with the different types of objects using functional magnetic resonance imaging (fMRI). Twenty-six participants in their 20s underwent fMRI while grasping four different types of objects. After the experiment, all of the participants completed a questionnaire based on the Likert Scale, which asked them about the sensations they experienced while grasping each object (comfort, hardness, pain, ease in grasping). We investigated the relationship between brain activity and the results of the survey; characteristic brain activity for each object was correlated with the results of the questionnaire, indicating that each object produced a different sensation response in the participants. Additionally, we observed brain activity in the primary somatosensory cortex (postcentral gyrus), the primary motor cortex (precentral gyrus), and the cerebellum exterior during the gripping task. Our study shows that gripping different objects produces activity in specific and distinct brain regions and suggests an “action appraisal” mechanism, which is considered to be the act of integrating multiple different sensory information and connecting it to actual action. To the best of our knowledge, this is the first study to observe brain activity in response to tactile stimuli and motor activity simultaneously.

Relationship between Tactile Sensation, Motor Activity, and Differential Brain Activity in Young Individuals

The primary role of a robot exploring an unknown space is to investigate the state and the spatial shape of the environment. We have designed a soft robot that aims to move forward in an unknown space as it recognizes and adapts to the spatial shape of the environment. We previously reported that soft tensegrity and recurrent neural network can be used to realize tensegrity structure shape recognition. In this study, a tensegrity robot was designed to actively generate propulsive force as it presses its body against a wall in its surrounding environment. This robot design includes a novel artificial muscle arrangement called “4/3 muscle winding,” which induces large deformation in the tensegrity structure. The application of this new artificial muscle arrangement allows two types of large deformations to be induced in the tensegrity structure, which results in displacements of 20% to 40% in the axial and radial directions. We have demonstrated that the robot, which was created by connecting the tensegrity structures, is lightweight and possesses passive shape adaptability in a three-dimensional environment. This tensegrity robot could enter an unknown space, such as a cave, and recognize the spatial shape of the surrounding environment by recognizing the tensegrity structure shape.

Soft Tensegrity Robot Driven by Thin Artificial Muscles for the Exploration of Unknown Spatial Configurations

Elucidation of Brain Functional Mechanisms During Tactile Stimulation Task Without Motor Activity Using fMRI

Imaging and measurement of friction forces are required in a variety of fields. If the friction forces originating from the motions of professionals are quantitatively analyzed, the data can be applied to a motion-copying system by a robot. However, weak friction forces have not been visualized and quantified using conventional sensing materials and devices because of their low sensitivity. Here we present a highly sensitive friction-imaging device based on the cascading responses of stimuli-responsive materials, namely polydiacetylene (PDA) and dry liquid (DL). Weak friction forces disrupt the DL, which is composed of liquid droplets surrounded by solid particles. The outflowing liquid under chemical stress changes the color of PDA. The cascading responses enable colorimetric imaging and measurement of weak friction forces in the range of 0.006-0.080 N. Furthermore, the device visualizes the force distribution of handwriting in calligraphy depending on the individual characteristics of an expert, a practician, and a beginner. A high-sensitivity friction-imaging device can be used to understand various motions.

A highly sensitive friction-imaging device based on cascading stimuli responsiveness.

Carpooling, a transportation service that encourages employees to pick up and drop off co workers while driving to and from work, has the potential to decrease the number of private cars used to commute, eases commuter traffic congestion, and reduce CO2 emissions. Despite this potential situation of severe traffic congestion in Japan, little work has gone into developing carpooling specifically for commuting with co-workers scenarios. To build a carpooling system that accommodates Japanese unique culture and regulations, receptivity, safety, and profitability would be essential success factors. A carpooling problem (CPP) is proposed in this article with a focus on safety to discover a safe route for each driver that picks up and drops off co-workers and drives to and from their workspace while avoiding high accident-frequency locations. The CPP defines the subsets of employees sharing each car and the routes the drivers should take to optimize and minimize the total distance. Accident location data define the risk and driving competence determined by the classification of driver’s license and grade of automobile insurance; then, a driver’s optimal route minimizes risk while decreasing the total distance sought in deriving the CPP. The effectiveness of the proposed CPP was demonstrated by an experiment using actual accident data. This article also reports the small-scale proof-of-concept (PoC) study conducted to verify the efficacy of the proposed CPP and highlight issues with its practical application. Ten employees with five drivers and five co-workers commuted via carpooling for two weeks using a mobile application with the CPP developed independently. Through the questionnaire survey conducted after the PoC, we validated the need for carpooling. We also identified some challenges: safe map navigation, incentives for the driver, and adaptation to Japanese culture when the carpooling system is in practical use.

Safe Route Carpooling to Avoid Accident Locations and Small-Scale Proof of Concept in Japan

Simultaneous optimization of hatching orientations and lattice density distribution for residual warpage reduction in laser powder bed fusion considering layerwise residual stress stacking

In recent years, the succession of expert skills has become an issue due to the declining birthrate and aging population. In this study, we focused on calligraphy, which is a traditional skill of Asian countries such as China and Japan. Motion-copying system (MCS) can store and reproduce human motion. However, in order for MCS to function properly, the environment for preservation and reproduction must be the same. Although various studies have been conducted to solve the problem, most of these studies have dealt with only positional variation or only impedance variation. In this study, we proposed an algorithm to compensate for both position and impedance changes. In concrete terms, modify the saved motion command value appropriately by modeling a calligraphy brush and estimating an environmental impedance. The effectiveness of the proposed method is verified by experiments.

2022 IEEE 17th International Conference on Advanced Motion Control (AMC)

Motion-Copying System with Compensation of Environmental Changes for Calligraphy Robot

With the declining birthrate and aging population, it is important to inherit expert skills. A motion-copying system can accurately reproduce the position, velocity, and force of human motion at the same time. However, it is difficult to reproduce the same motion in an environment different from the saved environment. One of the solutions is to model the relationship between the position, velocity, and force of motion. It is important to improve the accuracy of the model and the versatility of modeling. In this study, we model the environment by using an element description method. Focusing on the calligraphy movement, it was shown that the accuracy of the relationship between the force, position and velocity of the brush is improved compared to the conventional model.

IECON 2022 – 48th Annual Conference of the IEEE Industrial Electronics Society

Environmental Modeling for Motion-Copying System Using Element Description Method

A generative model of calligraphy based on image and human motion

Simulated Microstructure Effects on Macroscopic Mechanical Properties Based on Multiscale Crystal Plasticity

EXPERIMENTAL STUDY ON PROPERTIES AND THE FROST RESISTANCE OF CONCRETE CONTAINING MOLTEN SLAG FROM INTEGRATED COAL GASIFICATION COMBINED CYCLE AS FINE AGGREGATE

Seifu Nankai High School was established in Takaishi City in Osaka in 1963. It used to be an all-boys school, but in 1999 it became coeducational. Our school's education is based on our three core values of trustworthiness, respect and reliability. We have been able to maintain a high level of education that enables our students to pass entrance examinations at prestigious universities.

2018 IEEE 2nd Electron Devices Technology and Manufacturing Conference (EDTM)

A study on shot-vegetation-spray using fly ash without seeding foundation

EXPERIMENT STUDY ON PROPERTIES OF MORTAR AND CONCRETE CONTAINING MOLTEN SLAG FROM INTEGRATED COAL GASIFICATION COMBINED CYCLE AS FINE AGGREGATE

Modeling and simulation on ultrafine-graining based on multiscale crystal plasticity considering dislocation patterning

Ultrafine-grained metals whose grain size is less than one micron have attracted interest as high strength materials. However, a mechanism of ultrafine-graining based on evolution of dislocation structures has not been clarified. In this study, we derive reaction-diffusion equations for dislocation patterning of dislocation cell structures and subgrains. In order to express the generation of dislocation pattern responding to deformation progress, information of slip rate and stress and effect of interactions between slip systems on formation of cell structures are introduced into the reaction rate coefficients of reaction-diffusion equations. Moreover, we propose a multiscale crystal plasticity model based on dislocation patterning. Then we carry out two-dimensional FE-FD simulation for severe compression of FCC polycrystal using the present model. Some processes of ultrafine-graining, i.e., generation of dislocation cell structures, subgrains, dense dislocation walls and lamella subdivisions with high angle boundary is numerically reproduced, and we investigate the effect of dislocation behaviors on the processes of ultrafine-graining.

A multiscale crystal plasticity simulation on ultrafine-graining based on dislocation patterning

Multiscale crystal plasticity modeling and simulation on ultrafine-graining of fcc polycrystal based on evolutioin of dislocation structures

135 A Multiscale Crystal Plasticity Simulation on Ultrafine-Graining Based on Dislocation Patterning Considering GN Dislocation Density

606 A Multiscale Crystal Plasticity Simulation on Ultrafine-Graining at Giant Strain

The dispersion of self-assembled β -Si 3 N 4 (SN) agglomerates in stainless steel (SUS316L) was decided with the multifractal analysis to investigate characters of the aggregated morphology of the average secondary particle area of SN particles. The thermal conductivity ( λ e ) of SN/SUS316L with the average particle diameter of SUS316L powder of 3 μm was higher than that expected from Kanenari model because SN agglomerations were formed. On the other hand, λ e of SN/SUS316L with the average particle diameter of SUS316L powder of 8 μm was lower than that expected from Kanenari model. On the multifractal analysis, the results showed that the capacity dimension ( D 0 ) was not changed with adding SN particles. It suggested that the SN agglomerations were formed with similarity. λ e was increased with increasing the average secondary particle area of SN particles. D 0 was not increased with increasing λ e . It indicated that the forming the network of the thermal conductive particles played an important role in improving λ e .

Fractal Characters and Thermal Conductive Properties of Self-assembled Material Texture of Silicon Nitride/Stainless Steel (SUS316L) Composites

Abstract In recent years, cooperative control of multi-agents, especially formation control, has attracted considerable interest among control engineers. Comparing to a single agent performing alone, multiple cooperative agents are expected to improve the efficiency of operation, flexibility and fault-tolerance of the system. As one of the formation control methods, we deal with the leader-following formation navigation (LFFN). The LFFN is defined such that a human operator or an autonomous leader agent forms a queue of agents to guide multiple followers. The followers pass along the leader's trajectory with the same motion as the leader. When the leader passes along a safe route to avoid obstacles, the followers also pass along similar safe trajectory. However, when using the LFFN, the followers can shape only a single column formation. In this study, we first extent the above LFFN's usage to parallel single colums using adjoining virtual leaders. Next, we consider virtual leaders adjoining the leader to design virtual trajectories along which virtual leaders pass and virtual leader's velocities on the ones' path. We design the followers' target points which track the virtual leader's path with designed virtual velocity. Using our proposed method, the followers can avoid obstacles within the leader's path and shape a formation which is not a single column type. Finally, we demonstrate the effectiveness of our newly proposed method through simulation and experimentation.

Leader-following Formation Navigation with Virtual Trajectories for Dynamic Multi-agents

Spike frequency adaptation facilitates the encoding of input gradient in insect olfactory projection neurons

The in vivo estimation of α-motoneuron (MN) properties in humans is crucial to characterize the effect that neurorehabilitation technologies may elicit over the composite neuro-musculoskeletal system. Here, we combine biophysical neuronal modelling, high-density electromyography and convolutive blind-source separation along with numerical optimization to estimate geometrical and electrophysiological properties of in vivo decoded human MNs. The proposed methodology implements multi-objective optimization to automatically tune ionic channels conductance and soma size of MN models for minimizing the error between several features of simulated and in vivo decoded MN spike trains. This approach will open new avenues for the closed-loop control of motor restorative technologies such as wearable robots and neuromodulation devices.Clinical Relevance— This work proposes a non-invasive framework for the in vivo estimation of person-specific α-motoneuron properties. This will enable predicting neuronal adaptations in response to neurorehabilitation therapies in the intact human.

Optimization framework for the model-based estimation of in vivo α-motoneuron properties in the intact human

A convolutional neural network for estimating synaptic connectivity from spike trains

Computer simulations have facilitated our understanding of the dynamic behavior of the brain and the effect of the medical treatment such as deep brain stimulation. For improving the simulation model, it is essential to develop a method for optimizing parameters of a neuron model from available experimental data. In this paper, we apply Covariance Matrix Adaptation Evolutionary Strategy (CMA-ES) to the parameter optimization problem, and compare it with widely used conventional approaches including genetic algorithm (GA) and the Nelder-Mead method. A problem we have observed with CMA-ES is that the performance highly depends on the initial condition. To overcome the problem, we extend CMA-ES by making an aggregation of evolution. We analyze a public dataset recorded from a rat neocortical neuron, which shows that the proposed approach achieves higher performance than the conventional methods.

Effective and Stable Neuron Model Optimization Based on Aggregated CMA-ES

In order to understand how olfactory stimuli are encoded and processed in the brain, it is important to build a computational model for olfactory receptor neurons (ORNs). Here, we present a simple and reliable mathematical model of a moth ORN generating spikes. The model incorporates a simplified description of the chemical kinetics leading to olfactory receptor activation and action potential generation. We show that an adaptive spike threshold regulated by prior spike history is an effective mechanism for reproducing the typical phasic–tonic time course of ORN responses. Our model reproduces the response dynamics of individual neurons to a fluctuating stimulus that approximates odorant fluctuations in nature. The parameters of the spike threshold are essential for reproducing the response heterogeneity in ORNs. The model provides a valuable tool for efficient simulations of olfactory circuits.

Adaptive integrate-and-fire model reproduces the dynamics of olfactory receptor neuron responses in a moth

It is known that the probability of decoding error has a phase transition at information rate equal to the channel capacity. The corresponding thermodynamic limit requires infinite coding dimension, hence making the actual decoding practically impossible. In this Rapid Communication we analyze finite-size effects that occur in limited neural populations. We report that the achievable rate approaches the asymptote in a remarkably nonlinear manner with the population size. Qualitatively, our findings do not seem to depend on the details of the model.

Critical size of neural population for reliable information transmission.

Suppression of hyperexcitability of trigeminal nociceptive neurons associated with inflammatory hyperalgesia following systemic administration of lutein via inhibition of cyclooxygenase-2 cascade signaling

: Investigation of synaptic connectivity between neurons is essential for understanding information processing mechanisms in the brain because this connectivity determines how spikes propagate in a neural circuit. Recent advances in experimental technology have enabled simultaneous recording of the spiking activity from hundreds of neurons. In this study, we propose a method for estimating synaptic connectivity using the spike data from multiple neurons. We ﬁrst demonstrated that this method can perfectly estimate synaptic connectivity using synthetic spike data in an ideal condition. Subsequently, this method is applied to more realistic spike data generated by a large-scale network of Hodgkin − Huxley neurons. The results suggest that our estimation method is superior to a conventional method in identifying synaptic connectivity when the spiking activity from a large number of neurons is available for the analysis.

A method for estimating of synaptic connectivity from spike data of multiple neurons

Impact of slow K+ currents on spike generation can be described by an adaptive threshold model

Estimation of excitatory and inhibitory synaptic conductance variations in motoneurons during locomotor-like rhythmic activity

Optimal decoding and information transmission in Hodgkin-Huxley neurons under metabolic cost constraints

To understand information processing in neuronal circuits, it is important to infer how a sensory stimulus impacts on the synaptic input to a neuron. An increase in neuronal firing during the stimulation results from pure excitation or from a combination of excitation and inhibition. Here, we develop a method for estimating the rates of the excitatory and inhibitory synaptic inputs from a membrane voltage trace of a neuron. The method is based on a modified Ornstein-Uhlenbeck neuronal model, which aims to describe the stimulation effects on the synaptic input. The method is tested using a single-compartment neuron model with a realistic description of synaptic inputs, and it is applied to an intracellular voltage trace recorded from an auditory neuron in vivo. We find that the excitatory and inhibitory inputs increase during stimulation, suggesting that the acoustic stimuli are encoded by a combination of excitation and inhibition.

Estimation of the synaptic input firing rates and characterization of the stimulation effects in an auditory neuron

Population coding is essential for rapid information processing in the moth antennal lobe

Estimating synaptic connections from multiple spike trains based on a coupled escape rate model

Conductance estimation of a conductance-based neuron model by the differential evolution algorithm

Impact of network topology on inference of synaptic connectivity from multi-neuronal spike data simulated by a large-scale cortical network model

Abstract : One of the primary, and still largely unresolved, goals of computational neuroscience is 12 to understand how neurons process and convey information. Since the early studies, the challenges of understanding the principles of neuronal coding have attracted increasing number of scientists from different fields. Among the main themes of the workshop is: What can information theory tell us about information processing in neurons? Influence of environmental statistics on information coding in sensory neurons. Noise and its role in neuronal coding. The main impact of the workshop lies in the distribution of ideas and approaches that, although applied to different systems, share the common language of information theory. In particular, we believe that the computational neuroscience community has not yet fully benefited from the richness and generality of information theory as originally proposed by Shannon himself. Consequentially, workshops of this kind have the potential to change the perception of certain topics and perhaps, hopefully, provide solutions to some of the long-lasting questions in neuronal information processing.

Visualization of GABA release from pancreatic β-cells for hyperglycemia

We propose a state space method for estimating not only the time-varying synaptic input but also the ionic channel states from intracellularly recorded membrane potential of a neuron. The estimation performance is evaluated by applying the method to the simulated data of Hodgkin−Huxley type models. Keywords—intracellular recordings, time series analysis, single neuron models, Empirical Bayes method, neural

Inferring the time-varying synaptic input and the ion-channel dynamics from intracellular recording of a neuron

State-of-the-art statistical methods in neuroscience have enabled us to fit mathematical models to experimental data and subsequently to infer the dynamics of hidden parameters underlying the observable phenomena. Here, we develop a Bayesian method for inferring the time-varying mean and variance of the synaptic input, along with the dynamics of each ion channel from a single voltage trace of a neuron. An estimation problem may be formulated on the basis of the state-space model with prior distributions that penalize large fluctuations in these parameters. After optimizing the hyperparameters by maximizing the marginal likelihood, the state-space model provides the time-varying parameters of the input signals and the ion channel states. The proposed method is tested not only on the simulated data from the Hodgkin-Huxley type models but also on experimental data obtained from a cortical slice in vitro.

Estimating time-varying input signals and ion channel states from a single voltage trace of a neuron

The set of firing rates of the presynaptic excitatory and inhibitory neurons constitutes the input signal to the postsynaptic neuron. Estimation of the time-varying input rates from intracellularly recorded membrane potential is investigated here. For that purpose, the membrane potential dynamics must be specified. We consider the Ornstein-Uhlenbeck stochastic process, one of the most common single-neuron models, with time-dependent mean and variance. Assuming the slow variation of these two moments, it is possible to formulate the estimation problem by using a state-space model. We develop an algorithm that estimates the paths of the mean and variance of the input current by using the empirical Bayes approach. Then the input firing rates are directly available from the moments. The proposed method is applied to three simulated data examples: constant signal, sinusoidally modulated signal, and constant signal with a jump. For the constant signal, the estimation performance of the method is comparable to that of the traditionally applied maximum likelihood method. Further, the proposed method accurately estimates both continuous and discontinuous time-variable signals. In the case of the signal with a jump, which does not satisfy the assumption of slow variability, the robustness of the method is verified. It can be concluded that the method provides reliable estimates of the total input firing rates, which are not experimentally measurable.

Estimation of Time-Dependent Input from Neuronal Membrane Potential

Estimation of functional connections in the premotor center of Bombyx mori using backpropagation

Information is transmitted in the brain through various kinds of neurons that respond differently to the same signal. Full characteristics including cognitive functions of the brain should ultimately be comprehended by building simulators capable of precisely mirroring spike responses of a variety of neurons. Neuronal modeling that had remained on a qualitative level has recently advanced to a quantitative level, but is still incapable of accurately predicting biological data and requires high computational cost. In this study, we devised a simple, fast computational model that can be tailored to any cortical neuron not only for reproducing but also for predicting a variety of spike responses to greatly fluctuating currents. The key features of this model are a multi-timescale adaptive threshold predictor and a nonresetting leaky integrator. This model is capable of reproducing a rich variety of neuronal spike responses, including regular spiking, intrinsic bursting, fast spiking, and chattering, by adjusting only three adaptive threshold parameters. This model can express a continuous variety of the firing characteristics in a three-dimensional parameter space rather than just those identified in the conventional discrete categorization. Both high flexibility and low computational cost would help to model the real brain function faithfully and examine how network properties may be influenced by the distributed characteristics of component neurons.

Made-to-Order Spiking Neuron Model Equipped with a Multi-Timescale Adaptive Threshold

A simple model for predicting spike times of a variety of neurons

A fast-computational spiking neuron model adaptable to any cortical neuron

We studied the impact of a dynamical threshold on the f–I curve—the relationship between the input and the firing rate of a neuron—in the presence of background synaptic inputs. First, we found that, while the leaky integrate-and-fire model cannot reproduce the f–I curve of a cortical neuron, the leaky integrate-and-fire model with dynamical threshold can reproduce it very well. Second, we found that the dynamical threshold modulates the onset and the asymptotic behavior of the f–I curve. These results suggest that a cortical neuron has an adaptation mechanism and that the dynamical threshold has some significance for the computational properties of a neuron.

It has been established that a biological neuron reproduces the precise spike response to identical fluctuating input currents. We wish to predict the firing times of a given neuron for any input current. For this purpose, a mathematical model is introduced for mimicking the voltage response of the neuron to an input current. In predicting the firing times of a target neuron for a novel input current, we propose here the method of estimating the probability of spike occurrence, instead of naively thresholding an instantaneous value of the model voltage. The assessment is carried out maximally utilizing the information about the state space of the voltage and its time derivative(s) of the model, in advance of a possible spike, with a time lag that is determined by maximizing the mutual information. The prediction is significantly improved by the present method in comparison to the naive thresholding method.

It has been established that a neuron reproduces highly precise spike response to identical fluctuating input currents. We wish to accurately predict the firing times of a given neuron for any input current. For this purpose we adopt a model that mimics the dynamics of the membrane potential, and then take a cue from its dynamics for predicting the spike occurrence for a novel input current. It is found that the prediction is significantly improved by observing the state space of the membrane potential and its time derivative(s) in advance of a possible spike, in comparison to simply thresholding an instantaneous value of the estimated potential.

A model neuron with delay line feedback connections can learn a time series generated by another neuron. In the case that both neurons have identical transfer functions, a model neuron (student) is capable of reproducing the instruction sequence generated by another neuron (teacher), but the parameters are not uniquely determined by learning a quasi-periodic time series. A student that has completed the learning can be either faithful or unfaithful, depending on whether it continues mimicking the teacher's time series over a long interval after the learning or whether it departs from the teacher and eventually generates a time series that bears no resemblance to the teacher's. In the case that both neurons have different transfer functions, a student is generally incapable of reproducing the instruction sequence. Each student readjusts its parameters so as to minimize the mean-squared deviation between the instruction signal and its own output, but this parameter set is not uniquely determined. In this unrealizable learning, the degeneracy among faithful students is lifted and there is no more distinction between faithful and unfaithful students.

A fast-computational spiking neuron model for a variety of cortical neuron

The efficacy of trans-spinal direct current stimulation (tsDCS) as neurorehabilitation technology remains sub-optimal, partly due to the variability introduced by subject-specific neurophysiological features and stimulation conditions (e.g. electrode placement, stimulating amplitude, polarity, etc.) Hence, current therapies apply tsDCS in an open-loop fashion, resulting in a lack of standardized protocols for controlling elicited neuronal adaptations in closed-loop. Through the combination of high-density electromyogram (HD-EMG) decomposition, biophysical neuronal modelling and metaheuristic optimization, this work presents a novel neural data-driven framework for estimating subject-specific features and quantifying acute neuronal adaptations elicited by tsDCS on incomplete spinal cord injury subjects. This approach consists of calibrating the anatomical parameters (e.g. soma diameter) of in silico $\alpha-$motoneuron (MN) models for firing similarly to in vivo MNs decoded from HD-EMG. Assuming that cathodal-tsDCS elicits excitability changes in the MN pool, while preserving their anatomical parameters, optimization of an excitability gain common to the entire pool was performed to minimize discrepancies in firing rate and recruitment time between in vivo and in silico MNs after cathodal-tsDCS. This quantification of excitability changes on MN models calibrated in a person specific way enables closing the loop with neuro-modulation devices to tailor neurorehabilitation therapies. Clinical Relevance - This framework addresses a key limitation in non-invasive neuro-modulative technologies via a novel model-assisted framework that enables quantifying acute excitability changes induced on a person-specific in silico MN pool calibrated using in vivo neural data. This will enable the development of advanced controllers for modulating targeted neuronal adaptations in closed-loop.

2022 International Conference on Rehabilitation Robotics (ICORR)

Neural data-driven model of spinal excitability changes induced by transcutaneous electrical stimulation in spinal cord injury subjects

The effect of the upper limb rehabilitation training by a robotic wear

[STUDY ON THE ELECTRICAL MUSCLE ACTIVITIES EVOKED BY PROGRESSIVE STIMULATION].

脳の情報処理におけるアルゴリズムを抽出して忠実に 実装することは,優れた「知能」を設計するための一つ の方法である.近年の実験データの蓄積と計算機の発達 により,脳全体あるいはその一部を忠実にコンピュータ 上に構築してその活動を調べる「脳シミュレーション」 の研究が活発になりつつある.本稿では,脳シミュレー ションの基本的な枠組みを説明した後,大規模脳シミュ レーションを行った米国の二つの研究プロジェクトを紹 介する. 我々の脳は莫大な数(ヒト: 100億,マウス:数千万, 昆虫 :数百万)の神経細胞(ニューロン)から構成され る.他の神経細胞からの入力電流を受けて,神経細胞は スパイク(電気パルス)を生成する.脳の情報処理は, 神経細胞がスパイクを用いて情報のやり取りを行うこと によって行われている.スパイクによる神経細胞間の情 報伝達は「シナプス」(神経細胞間を接続する電線のよ うなもの)を通じて行われる.脳シミュレーションでは「脳」 をシナプスで接続された神経細胞の集団として表現し, 神経細胞とシナプスを数理モデルを用いて表現する. 神経細胞とシナプスの数理モデルから構成されている 点においては,脳シミュレーションモデルはニューラル ネットワークと同じである.しかし,その目的は大きく 異なる.脳シミュレーションは「脳機能」の理解および 再現を目的とする.そのため,シミュレーションの構成 要素が生物学的に妥当なものか,あるいは,シミュレー ションが観測される脳の振舞いを再現できる,予言能力 をもつかどうかが重要とされる.一方,ニューラルネッ トは工学的応用を目的とするため,識別問題などの実問 題に適用した際の性能の良さが重要とされる. 脳のシミュレーションを行う理由について考えてみよ う.脳科学では一般に計測を行うことが困難であり,技 術的あるいは倫理的な理由により実現不可能な実験が多 い.一方,シミュレーションでは,構成するすべての神 経細胞モデルの活動を観測できるため,どの神経活動が 重要であるかを系統的に調べることができる.また,実 現するのが難しい実験でもシミュレーションモデルを変 更することで実行できる.例えば,神経細胞の数を減ら すにはシミュレーションモデルで用いる神経細胞数を減 らせばよいし,神経細胞間のシナプス結合を遮断するた めにはシナプス結合強度を 0にすればよい.薬品の効果 が脳活動に与える影響についても,シミュレーションに よって調べることができる.例えば,ナトリウムチャネ ルを阻害する薬品としてテトロドトキシン(TTX,フグ 毒の成分)が知られている.TTXが神経細胞の電気活動 へ与える影響をシミュレーションで調べるためには,細 胞膜を流れるナトリウム電流を 0にすればよい. 本稿の構成は以下のとおりである.2章では,脳シミュ レーションの基本的な枠組みと本稿を読むために必要と なる神経科学の基礎知識を紹介する.3章では,脳全体 のシミュレーションを試みた研究 [Izhikevich 08]を紹介 する.では,脳のシミュレーションモデルを搭載したロ ボットを開発し,迷路課題実験を行った研究 [Krichmar 05]を紹介する.

LONG-TERM CHARACTERISTICS OF HIGH VOLUME FLY ASH CONCRETE STRENGTH AND DESIGN METHOD FOR THICKNESS OF THE PAVEMENT

This paper describes flexural strength characteristics of concrete with high volume fly ash. Coal-fired power plants have produce about 9,200,000tons coal ashes per year in Japan. The number of coal-fired power plants has been increasing, and amount of coal ash will increase gradually in future. About 90 percent of coal ashes is fly ash and the other bottom ash. Concrete with high volume fly ash may decrease the workability and strength. Short-term strength becomes low due to late reaction of fly ash. Slump as the pavement concrete with high volume is less than the half of the slump of the normal concrete. This results in a suitable pavement concrete. This study aims to investigate the feasibility of pavement concrete with high volume fly ash. Pavement concrete is designed based on the flexural strength. Flexural strength is determined by the failure at the weakest location in the tensile side of the specimen, and is determined by the amount of defects in the mortar and transition zone around aggregates. This may be verified by the distance of two loads over the flexural test specimen. Resultantly, high volume fly ash concrete is affected by the defect based on fly ash. In order to investigate variation of concrete strength, several tests have herein conducted. The strength variation is also analyzed by the Monte Carlo Simulation, which is based on the weakest-link-model. The numerical analysis agrees well with experimental results.

細骨材をフライアッシュに全量置換した転圧コンクリートについて, 筆者らはこれまでに配合設計方法の提案や疲労性状などを明らかにしてきた. このコンクリートの実用化を目指すためには, 舗装路面の表面性状や現場試験施工による施工性および強度発現などの確認が必要である. 本研究では, コンクリート舗装の管理項目である表面性状の確認試験や寒冷地を想定したラベリング試験を実施し, このコンクリートが耐久性に優れる点を明らかにした. また, 実機による現場施工により物性確認を行ったのでその報告をする.

THE SURFACE PROPERTIES AND SITE CONSTRUCTION OF ROLLER COMPACTED CONCRETE WITH LARGE QUANTITY OF FLY ASH

焼成ボーキサイトの水分特性, また豊浦砂およびラテライト土壌との混合土壌の水分特性および乾燥速度を測定し, 焼成ボーキサイトの保水材としての性能を検討した.700℃で1時間焼成したボーキサイトは飽和で30wt%の水分を含む. その水分特性はpF=4.5までは緩やかに脱水し, pF=5.5で最も急激に脱水することを示し, 豊浦砂およびラテライト土壌に対して保水材として利用できることを確認した. 乾燥実験でのpF変化では, ラテライト土壌の場合はpF=5以上で焼成ボーキサイト混入による乾燥遅延効果が現れ, 豊浦砂の場合はpF=3.5以上で乾燥遅延効果が現れ, 豊浦砂のような砂質土壌に混入した方がより効果的であることが示唆された.

精英樹選抜育種事業が開始された当初jにおいて,次代の精英樹は,初代の精英樹の実生によって造成された次代 検定林,育種種苗の人工林からの選抜と,初代の精英樹が選抜された林分と同様の既存林分,または当時若齢であっ た林分からの追加選抜が考えられていた冊。しかし,採種園を構成するクローンの種子生産の寄与は着花性の優良 なクローンのみで多くのクローンがあまり寄与していないへこのため,育種種苗の人工林からの選抜では,特定 の家系の子供が多く選抜され,次世代の精英樹集団には近親交配の弊害が生ずると考えられた。以上のことから, 人工交配により家系のあきらかな選抜集団を育成する必要がでてきた。 さし木品種の優秀性は,一代限りの効果として利用できるが,次世代以降の遺伝的向上は無性繁殖である限り期 待できないへしかし実生繁殖なら親より優秀な後代を作ることもできるため,さらなる遺伝的向上が期待4でき る。 これらのことから人工交配による次世代の精英樹を選抜するための母集団,すなわち育種集団林の造成が強く求 められた。育種集団林の造成と交雑育種の技術開発をするために交雑育種事業化プロジェクトが昭和55年から平成 元年まで実施され,人工交配技術を中心に技術開発と精英樹等の育種目標である成長等の特性評価が行われた。 r ; Iき続き,育種集団林の造成技術と成長,材質,抵抗性等の複数の目的形質をそなえた品種の創出をめざして第 一期交雑育種事業化プロジェクトが平成 2年から開始された。

Progress of the Second Cross Breeding Project in Kansai breeding region.

本研究は, コンクリート副産物より製造した再生骨材を用いた転圧コンクリート舗装版 (RCCP版) と普通コンクリート舗装版 (NCP版) の曲げ疲労特性を検討したものである. RCCP版の疲労特性に関しては既報で検討しているので, 本報ではNCP版について新たに求めた疲労実験結果をもとに補足検討を試みた. その結果, 再生骨材の種類がコンクリート版の疲労強度におよぼす影響, RCCP版とNCP版の疲労強度の差異, 各種分布関数の疲労寿命への適合性, 再生骨材を使用したコンクリート舗装版の適用性などが明らかになった.

STUDY ON THE BENDING FATIGUE PROPERTIES OF CONCRETE PAVEMENT WITH RECYCLED AGGREGATES

BENDING FATIGUE STRENGTH OF PAVEMENT CONCRETES WITH NORMAL AND RECYCLED AGGREGATES

(57)【要約】
【課題】 土の自然な風合い、適度なクッション性を保 ちつつ、晴天時の砂塵発生、降雨時のぬかるみ、補修の 困難さなどを改善することができる土系舗装用材料、土 系舗装構造を提供する。
【解決手段】 真砂土等の原材料とアスファルト入りア クリル樹脂系エマルジョンとを混合してなる。

本研究は, コンクリート副産物より製造した再生骨材を用いた転圧コンクリートの曲げ疲労特性を検討したものであり, まず, 各応力振幅Sにおける破壊までの繰り返し回数Nのばらつきを対数正規分布で近似することにより S-N曲線を求め, これが既存の研究結果より求めた舗装用コンクリートおよび一般の転圧コンクリートの S-N曲線よりも低い値を示すことを確認した. 次に, Weibull 分布関数と McCall 分布関数を用いて生存確率Pに関するS-N曲線すなわち P-S-N曲線を求め, これらから得られる200万回疲労強度について対数正規分布による解析結果との比較を試みた. さらに, 以上の結果をもとに, 再生骨材を使用した転圧コンクリートの舗装への適用についても考察を加えた.

STUDY ON THE BENDING FATIGUE PROPERTIES OF ROLLER COMPACTED CONCRETE MIXED WITH RECYCLED AGGREGATES

Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology

[A case of severe alcoholic hepatitis with successfully treated by the therapy for hypercytokinemia and granulocytic hyperelastasemia].

An anomalous zymogram of lactate dehydrogenase (LDH) in the serum from a patient with liver cirrhosis was reported. Agar-gel electrophoresis of serum showed an extra LDH band close to the anodic side of LDH5 and a wide band of LDH5. Gel filtration of patient's serum in Sephadex G-200 demonstrated an abnormal LDH fraction eluted between immunoglobulin G (IgG) and macroglobulin in addition to a normal LDH component. Chromatographically abnormal LDH was demonstrated on agar gel as extra and wide LDH5 bands and resembled closely human hepatic LDH in various physico-chemical properties such as inhibition by urea or substrate, stability against heat, and Michaelis-Menten's constant. Immunological analyses demonstrated that abnormal LDH could be in the state combined with IgG. Molecular weight of the complex estimated by gel filtration was approximately 300,000. Mixtures of the heated patient's serum with normal or patient's hepatic LDH showed abnormal LDH fraction by gel filtration, whereas abnormal fraction was not demonstrated when heated normal serum was mixed with normal or the patient's hepatic LDH. These results strongly suggest that the occurrence of anomalous LDH zymogram in patient's serum is due to a formation of LDH-IgG complex, which is based on the binding of essentially normal hepatic LDH and abnormal IgG.

Macromolecular lactate dehydrogenase linked to serum IgG of a patient with liver cirrhosis.

[Taeniasis. 3. Treatment of large tapeworm infection (Taenia saginata and Diphyllobothrium latum infections)].

[Taeniasis. 2. Epidemiological and clinical studies of broad tapeworm infection].

Macro lactatedehydrogenase: Possible cause of anomalous ldh zymogram

We previously reported that the cell and colony motion of oral keratinocytes are correlated with proliferative capacity, and speculated that this may be a specific index for monitoring of cell quality. However, how cell motility and proliferation are regulated by signaling pathways remains unelucidated. Here, we found that the regulation of cell motility and proliferative capacity of oral keratinocytes can be attributed to the epidermal growth factor/epidermal growth factor receptor (EGF/EGFR) axis. The EGFR downstream cascade involving the Src/PI3K/Akt/mTOR signaling pathway showed a major effect on cell motility and proliferative capacity in oral keratinocytes. Furthermore, both EGFR and Src negatively regulated E-cadherin expression. Taken together, these findings provide a potential basis for future quality control of cells for therapeutic use.

The EGF/EGFR axis and its downstream signaling pathways regulate the motility and proliferation of cultured oral keratinocytes.

In-process monitoring of a tissue-engineered oral mucosa fabricated on a micropatterned collagen scaffold: use of optical coherence tomography for quality control

Cells/colony motion of oral keratinocytes determined by non-invasive and quantitative measurement using optical flow predicts epithelial regenerative capacity

High concentrations of ascorbic acid (AA) exert pro-oxidative actions and inhibit tumor metastasis. The toxicity of AA centers on the generation of H2O2. But it remains largely unknown which process is inhibited by AA during the metastasis. The present study was designed to identify which process is suppressed by AA during the metastasis by use of malignant tumor cells lines. For this objective, we compared reduced and oxidized forms of AA in terms of cellular survival and levels of reactive oxygen species (ROS) in vitro. AA has ability to kill malignant tumor cells not binding to extracellular matrix. Once the cells detach from primary tumors, high concentrations of AA may drive them into a cell death pathway. The present results suggest that AA itself is toxic and that an oxidized form is protective. Thus, the reported neuroprotective effects may be mediated by an oxidized form, dehydroascorbate (DHA). This may be a therapeutic agent because it can penetrate the blood-brain-barrier. DHA protected the cells against oxidative stress by an anti-oxidative pathway. We did not find any protective effects by AA itself although it decreased levels of ROS much more than the oxidized form. Rather, AA induced potent toxic effects. It had selective toxic effects on non-attached cells. These selective toxic effects were suppressed by the presence of catalase, suggesting that H2O2 generation is involved in the cell death.

Protective Effects by Dehydroascorbic Acid through an Anti-Oxidative Pathway and Toxic Effects by Ascorbic Acid through a Hydrogen Peroxide-Dependent Pathway in Tumor Cell Lines

Cell adhesion has a fundamental role in the proliferation and motility of normal cells and the metastasis of tumor cells. To identify signaling pathways activated by the adherence of tumor cells, we analyzed the tyrosine phosphorylation of proteins in mouse melanoma cells before and after attachment to substrata. We discovered that cellular adherence activated the protein-tyrosine kinase of the cell surface receptor Met, whose ligand is hepatocyte growth factor and scatter factor. The activation was exceedingly prompt, affected the great majority of Met in the cells, persisted so long as the cells remained adherent, and was rapidly reversed as soon as the cells were detached from substrata. Activation of Met required that cells be adherent but not that they spread on the substratum, and it occurred in the absence of any apparent ligand for the receptor. Ligand-independent activation of Met occurred in several varieties of tumor cells but not in normal endothelial cells that express the receptor. The activation of Met described here may represent a means by which cells respond to mechanical as opposed to biochemical stimuli.

Cellular adherence elicits ligand-independent activation of the Met cell-surface receptor.

Preimplantation genetic testing for aneuploidy: a comparison of live birth rates in patients with recurrent pregnancy loss due to embryonic aneuploidy or recurrent implantation failure.

Can preimplantation genetic testing for aneuploidy (PGT-A) improve the live birth rate and reduce the miscarriage rate in patients with recurrent pregnancy loss (RPL) caused by an abnormal embryonic karyotype and recurrent implantation failure (RIF)?

PGT-A could not improve the live births per patient nor reduce the rate of miscarriage, in both groups.

PGT-A use has steadily increased worldwide. However, only a few limited studies have shown that it improves the live birth rate in selected populations in that the prognosis has been good. Such studies have excluded patients with RPL and RIF. In addition, several studies have failed to demonstrate any benefit at all. PGT-A was reported to be without advantage in patients with unexplained RPL whose embryonic karyotype had not been analysed. The efficacy of PGT-A should be examined by focusing on patients whose previous products of conception (POC) have been aneuploid, because the frequencies of abnormal and normal embryonic karyotypes have been reported as 40-50% and 5-25% in patients with RPL, respectively.

A multi-centre, prospective pilot study was conducted from January 2017 to June 2018. A total of 171 patients were recruited for the study: an RPL group, including 41 and 38 patients treated respectively with and without PGT-A, and an RIF group, including 42 and 50 patients treated respectively with and without PGT-A. At least 10 women in each age group (35-36, 37-38, 39-40 or 41-42 years) were selected for PGT-A groups.

All patients and controls had received IVF-ET for infertility. Patients in the RPL group had had two or more miscarriages, and at least one case of aneuploidy had been ascertained through prior POC testing. No pregnancies had occurred in the RIF group, even after at least three embryo transfers. Trophectoderm biopsy and array comparative genomic hybridisation (aCGH) were used for PGT-A. The live birth rate of PGT-A and non-PGT-A patients was compared after the development of blastocysts from up to two oocyte retrievals and a single blastocyst transfer. The miscarriage rate and the frequency of euploidy, trisomy and monosomy in the blastocysts were noted.

MAIN RESULT AND THE ROLE OF CHANCE
There were no significant differences in the live birth rates per patient given or not given PGT-A: 26.8 versus 21.1% in the RPL group and 35.7 versus 26.0% in the RIF group, respectively. There were also no differences in the miscarriage rates per clinical pregnancies given or not given PGT-A: 14.3 versus 20.0% in the RPL group and 11.8 versus 0% in the RIF group, respectively. However, PGT-A improved the live birth rate per embryo transfer procedure in both the RPL (52.4 vs 21.6%, adjusted OR 3.89; 95% CI 1.16-13.1) and RIF groups (62.5 vs 31.7%, adjusted OR 3.75; 95% CI 1.28-10.95). Additionally, PGT-A was shown to reduce biochemical pregnancy loss per biochemical pregnancy: 12.5 and 45.0%, adjusted OR 0.14; 95% CI 0.02-0.85 in the RPL group and 10.5 and 40.9%, adjusted OR 0.17; 95% CI 0.03-0.92 in the RIF group. There was no difference in the distribution of genetic abnormalities between RPL and RIF patients, although double trisomy tended to be more frequent in RPL patients.

The sample size was too small to find any significant advantage for improving the live birth rate and reducing the clinical miscarriage rate per patient. Further study is necessary.

WIDER IMPLICATION OF THE FINDINGS
A large portion of pregnancy losses in the RPL group might be due to aneuploidy, since PGT-A reduced the overall incidence of pregnancy loss in these patients. Although PGT-A did not improve the live birth rate per patient, it did have the advantage of reducing the number of embryo transfers required to achieve a similar number live births compared with those not undergoing PGT-A.

This study was supported by the Japan Society of Obstetrics and Gynecology and grants from the Japanese Ministry of Education, Science, and Technology. There are no conflicts of interest to declare.

N/A.

TOWARD WELL-BALANCED COUPLING BETWEEN PHASIC AND TONIC CONTROL — a CASE STUDY WITH a SERPENTINE ROBOT

SIR, Neonatal vesiculopustular eruptions suggest a number of differential diagnoses including both infectious and noninfectious aetiologies. We describe a phenotypically normal neonate with a vesiculopustular eruption arising from birth as the result of a transient myeloproliferative disorder (TMD) associated with mosaic trisomy 21. In November 2005, a Japanese girl was born at 39 weeks’ gestation, the second child of a healthy 25-year-old woman. Shortly after birth, bizarre vesiculopustular skin lesions were observed on her face, and rapidly increased in number with a tendency to appear at sites where pressure or dressings had been applied. There was no maternal history of genital herpes simplex virus infection, and application of topical aciclovir by the attending paediatrician failed to improve the skin lesions. She was referred to the dermatology clinic on day of life (DOL) 14. Physical examination revealed 3to 6-mm, reddish, small vesicular papules with yellowish crusts scattered on her face, especially on the cheeks (Fig. 1). Bacterial culture from the eruption resulted in a marginal growth of Staphylococcus aureus, Enterococcus faecalis and methicillin-resistant S. aureus. Skin biopsy of a papule on her left cheek revealed prominent infiltration of mononuclear cells with slightly atypical nuclei within the epidermis and upper dermis. There were no viral inclusions, ballooning or reticular degeneration in the epidermis (Fig. 2a). The myeloid lineage of these mononuclear cells was confirmed using myeloperoxidase staining (Fig. 2b). The baby had experienced shortness of breath on DOL 4. At the time of this episode, the white blood cell (WBC) count was 99Æ7 · 10 L, with blast cells. Acute myelogenous leukaemia (AML) was suspected; however, bone marrow aspiration demonstrated no blast cells. Thus she was diagnosed as having TMD. As TMD is known to occur mainly in infants with Down syndrome, peripheral blood fluorescence in situ hybridization (FISH) was performed. Although she was phenotypically normal, FISH analysis revealed mosaicism for trisomy 21. The vesiculopustular eruption was resistant to topical antibiotics (gentamicin or fusidic acid) and remained unchanged until DOL 17. Later, the eruption showed a tendency to improve as the WBC count decreased smoothly, and spontaneously cleared without any additional intervention at 2 months of age. Further follow-up of her blood counts at intervals of 3 months revealed no sign of haematological malignancy, and she remains healthy at 1 year of age. (a)

Neonatal vesiculopustular eruption of the face: a sign of trisomy 21‐associated transient myeloproliferative disorder

In situ hybridization of muscle mitochondrial mRNA in mitochondrial myopathies

We developed a method that allows prenatal diagnosis of Duchenne muscular dystrophy using a single nucleated erythrocyte (NRBC) isolated from maternal blood. Maternal blood was obtained at 8 to 20 weeks of gestation. NRBCs were separated with Percoll using a discontinuous density gradient method and then collected by micromanipulator under microscopic observation. The entire genome of a single cell was amplified by primer extension preamplification (PEP). Sex was determined from a small aliquot of the PEP reaction. After an NRBC was determined to be male and confirmed to be of fetal origin, dystrophin exons 4, 8, 12, 45, 48, 50, and 51 were determined from the same PEP reaction. This diagnostic method using maternal blood is safer than amniocentesis or cordocentesis and can be applied to other X-linked diseases.

Prenatal diagnosis of Duchenne muscular dystrophy using a single fetal nucleated erythrocyte in maternal blood

Mitochondrial Myopathies: Morphological Approach to Molecular Abnormalities

日本語版Body Perception Questionnaire-Body Awareness（BPQ-BA）超短縮版の作成─因子構造，および信頼性，妥当性の検討─

There are two types of the transformers in a contactless power transfer system: solenoid type (H-shaped) and circular type transformers. These two types of transformers are not compatible because their magnetic field structures are different. An Hc type transformer that is compatible with both transformer types has been proposed. The Hc type receiver adds a central magnetic pole by dividing the winding coil of the H-shaped receiver. The Hc type receiver can change the magnetic field structure by changing the connections of the divided windings and can receive power from both types of transmitters. In this study, we conducted a circuit analysis and evaluated the performance of the Hc type transformer.

円形及びソレノイド型磁界結合方式非接触給電トランスと共用可能なHc型トランスの回路解析と性能評価;円形及びソレノイド型磁界結合方式非接触給電トランスと共用可能なHc型トランスの回路解析と性能評価;The Circuit Analysis and Performance Evaluation of an Hc type Magnetic Coupling Contactless Power Transformer that is Compatible with Both Solenoid and Circular Type Transformers

1P210 長鎖リン脂質と短鎖リン脂質で構成される脂質多成分系の相挙動と構造変化に関する研究(13A. 生体膜・人工膜:構造・物性,ポスター,第52回日本生物物理学会年会(2014年度))

3P203 長鎖リン脂質と短鎖リン脂質で構成される脂質多成分系の相挙動に関する研究(13A.生体膜・人工膜:構造・物性,ポスター,日本生物物理学会年会第51回(2013年度))

データの冗長性に着目したキャッシュの回路面積削減;データの冗長性に着目したキャッシュの回路面積削減;Reducing Cache Hardware by Focusing on Data Redundancy

3PT145 長鎖リン脂質DMPCと短鎖リン脂質DHPCで構成される複雑な相挙動のダイナミクス(日本生物物理学会第50回年会(2012年度))

Multifractal characteristics of the self-assembly material texture of β-Si3N4/SUS316L austenitic stainless steel composites

Quantitative evaluation of morphological characteristics of self-assembled aggregates using multifractal analysis

Metal nanoclusters comprising several to tens of atoms are strong candidates for advanced catalysis as they are highly size-specific, with unique chemical properties, which were revealed by gas-phase molecular beam experiments. The size-specificity of nanoclusters makes them potentially suitable for fabricating tailor-made catalysts optimized by chemical composition as well as size parameters. To exploit their full catalytic potential, complete understanding of size specificity in catalysis under realistic reaction conditions is essential, together with a suitable method for fabricating single-size nanocluster catalysts. We have demonstrated herein aqueous-phase catalysis by single-size palladium nanoclusters supported on a well-defined strontium titanate surface for the Suzuki–Miyaura coupling reaction, showing that a 13-mer exhibits highly size-specific activity, as well as a general increase in catalytic activity as the nanocluster size decreases. By comparison with the reactivity of heteroatom doped nanoclusters, the relationship between the size-specific activity and site-specific charge distribution is revealed by evaluating electronic structures using X-ray photoelectron spectroscopy.

Liquid-phase catalysis by single-size palladium nanoclusters supported on strontium titanate: size-specific catalysts for Suzuki–Miyaura coupling

We here focus on the chiroptical response of a glutathione (GS)-protected bimetallic (AuAg)18 nanocluster containing comparable amounts of Au and Ag atoms. X-ray photoelectron spectroscopy (XPS) as well as the electrophoretic pattern allow us to determine the chemical composition of the nanocluster as Au8.5Ag9.5(SG)14. Chiroptical activity of the Au8.5Ag9.5 nanocluster is enhanced as compared to that of the corresponding monometallic Au counterpart, whereas that of bimetallic (AuAg)18 nanocluster with the atomic ratio of Au/Ag = 4.0 (Au14.4Ag3.6) decreases. Since thiolate-protected Au18 nanocluster has recently been revealed to consist of a face-fused Au9 bioctahedral kernel protected by one Au4(SR)5 tetramer, one Au2(SR)3 dimer, and three Au(SR)2 monomers, we use density functional theory (DFT) calculations to predict the lowest-energy structure of a model cluster compound Au9Ag9(SH)14 on the basis of this geometry, yielding a Agcore–Austaple intact core–shell configuration. This structure is in good agr...

Enhanced Chiroptical Activity in Glutathione-Protected Bimetallic (AuAg)18 Nanoclusters with Almost Intact Core–Shell Configuration

Chiral glutathione (GSH)-protected bimetallic Au–Ag nanoclusters (AuAg(SG)) are synthesized by the reduction of mixtures of Au and Ag salts at the feed mole ratio of Au/Ag = 3/1 in the presence of GSH and isolated by gel electrophoretic separation, yielding a family of magic-numbered bimetallic Au–Ag nanoclusters. The PAGE pattern similarity between Au(SG) and AuAg(SG) as well as the analyses based on small-angle X-ray scattering and X-ray photoelectron spectroscopy (XPS) allow comparisons of their chemical compositions for each family of nanoclusters, and the fractioned nanocluster compounds (three samples) are identified as Au12.2Ag2.8(SG)13, Au14.4Ag3.6(SG)14, and Au17.6Ag7.4(SG)18. The XPS study also suggests that (i) incorporation of Ag heteroatoms into smaller-sized Au nanoclusters is less favorable and (ii) Ag heteroatoms preferentially occupy sites on the cluster’s core (including the core-surface and center) rather than the peripheral semiring shell. Optical spectroscopy shows that the electronic...

Chiral Monolayer-Protected Bimetallic Au–Ag Nanoclusters: Alloying Effect on Their Electronic Structure and Chiroptical Activity

Chiral monolayer-protected Au-Pd bimetallic nanoclusters: effect of palladium doping on their chiroptical responses.

1P210 Study on the phase behavior and the structural changes of lipid multi-component system consisting of long- and short-chain phospholipids(13A. Biological & Artificial membrane: Structure & Property,Poster,The 52nd Annual Meeting of the Biophysical Society of Japan(BSJ2014))

3P203 Study on the behavior of lipid multi-component system consisting of long- and short-chain phospholipids(13A. Biological & Artifical membrane: Structure & Property,Poster)

3PT145 Dynamics of complicated phase behavior on the mixtures consisting of long-chain phospholipids DMPC and short-chain phospholipids DHPC(The 50th Annual Meeting of the Biophysical Society of Japan)

Perturbation Calculation for the 16 Lowest-Energy States in Spin Doughnut Mo75V20

We study a spin-1/2 frustrated magnetic cluster Mo75V20, whose possible Hamiltonian is SD = J?10i=1 S2i-1 ? S2i+1 J'J?20i=1 Si ? Si+1 + J?10i=1 S2i ? S2i+4. The J- and J-bonds, respectively, form a ten-spin ring and two five-spin rings, and the five-spin rings are coupled to the ten-spin ring by the J'-bonds so as to form isosceles triangles of one J-bond and two J'-bonds. It is shown that experimental susceptibility, accompanied by low-temperature Curie law, is well reproduced by J = 388 K, J' = 163 K and J = 81 K. We develop a perturbation theory to understand why the stronger J'-bonds does not wash out the low-temperature Curie law due to the doublet behavior of five-spin rings constructed by the weaker J-bonds. Calculated results of temperature dependence of specific heat under small magnetic fields are also presented.

A possible origin of the low-temperature Curie law of the spin doughnut Mo75V20

Related to absolute asymmetric synthesis, a stereospecific reaction at the solid/solid interface arising from crystal chirality of the achiral or racemic substrates has not yet been reported. Here, we demonstrate the asymmetric Strecker-type solid/solid reaction between the chiral crystal of a racemic cyanohydrin (kryptoracemate) and the achiral crystal of an ammonium salt to afford highly enantioenriched α-aminonitrile in combination with amplification of chirality. rac-Cyanohydrin provides its chiral surface as a reactive site and the reaction proceeds with dissociation of cyanohydrin; thus, an asymmetric Strecker-type reaction takes place at the interface of the substrate crystals. Strecker synthesis coupled with cyanohydrin synthesis offers a credible abiotic synthesis mechanism of α-amino acids and α-hydroxy acids. For the first time, stereochemical relationship has been found between the two chiral intermediates, aminonitrile and cyanohydrin, which are in equilibrium in the synthesis mechanism.

Synthesis, Photochemical Properties, and Cytotoxicity of 10-Alkylphenazin-2(10H)-ones

This paper proposes the new system of the noise visualization to detect the propagation path on the board. If high-voltage noise enters an electronic equipment due to electro-static discharge (ESD), it may cause the malfunction of the semiconductor component. The ESD noise has the characteristic that the rise time is short, and the propagation path of the ESD noise leading to the malfunction is unclear. So there is a problem that it tends to fall into trial and error countermeasures. There is a method of measuring the propagation path of the ESD noise using a single probe while applying ESD to the measurement object many times. However, there is a possibility that parts are broken during the evaluation test, and the propagation path cannot be estimated accurately. Therefore, we developed the new system to visualize the ESD noise on the whole printed circuit board (PCB) by applying ESD once. From this evaluation result, it was confirmed that the prototyped noise visualization system was effective for measuring the ESD noise.

Observation of ESD Propagation Path Using Noise Visualization System

This paper proposes a new structure of the near magnetic field probe. In the case of detecting noise current on printed circuit boards (PCB) using conventional loop type probe, it is necessary to rotate directions of the probe because the probe has no sensitivity to the current perpendicular to the plane of the loop. Therefore, the new type probe with less directional dependence is required to reduce the measuring time for visualizing noise propagation path. We developed “butterfly type” probe which can detect the noise current flowing to uncertain directions. The probe consists of two triangle loops connected in one stroke drawing. Two kinds of evaluations (directional dependence, and position dependency against the microstrip line trace on a PCB) of the proposed probe were performed, and good characteristics were confirmed.

Near magnetic field probe for detection of noise current flowing to uncertain directions

The evaluation of the contactless probe for measuring noise -- The consideration of the butterfly type probe having the sensitivity for the various wiring direction

We propose a method for estimating the asymptotic phase and amplitude functions of limit-cycle oscillators using observed time series data without prior knowledge of their dynamical equations. The estimation is performed by polynomial regression and can be solved as a convex optimization problem. The validity of the proposed method is numerically illustrated by using two-dimensional limit-cycle oscillators as examples. As an application, we demonstrate data-driven fast entrainment with amplitude suppression using the optimal periodic input derived from the estimated phase and amplitude functions.

Estimating asymptotic phase and amplitude functions of limit-cycle oscillators from time series data.

An extended Hilbert transform method for reconstructing the phase from an oscillatory signal

In the 3/4-filled band system θ-(BEDT-TTF)2X with a two-dimensional triangular lattice, charge ordering (CO) often occurs due to strong inter-site Coulomb repulsion. However, the strong geometrical frustration of the triangular lattice can prohibit long-range CO, resulting in a charge-glass state in which the charge configurations are randomly distributed. Here, we investigate the charge-glass states of orthorhombic and monoclinic θ-type BEDT-TTF salts by measuring the electrical resistivity and optical conductivity spectra. We find a substantial difference between the charge-glass states of the orthorhombic and monoclinic systems. The charge-glass state in the orthorhombic system with an isotropic triangular lattice exhibits larger low-energy excitations than that in the monoclinic one with an anisotropic triangular lattice and becomes more metallic as the isotropy of the triangular lattice increases. These results can be understood by the different charge-glass formation mechanisms in the two systems: in the orthorhombic system, the charge-glass state originates from geometric frustration due to the equilateral triangular lattice, leading to metallic 3-fold COs, whereas in the monoclinic system, the charge-glass formation originates from geometric frustration of the isosceles triangular lattice, in which the charge-glass state is described by the superposition of insulating 2-fold stripe COs.

Optical Conductivity Spectra of Charge-Crystal and Charge-Glass States in a Series of θ-Type BEDT-TTF Compounds

We have investigated a newly found α′′-phase bis(ethylenedithio)tetrathiafulvalene (BEDT-TTF) molecular arrangement system, namely, α′′-(BEDT-TTF)2Rb2xCo(SCN)4 (α′′-Rb2xCo), with localized S = 3/2 ...

Charge Ordering and π–d Interaction in Electron-Doped 3/4-Filling Molecular System α′′-(BEDT-TTF)2Rb2xCo(SCN)4 (x = 0.6)

Palladium‐Catalyzed Cyclopropanation of Strained Alkenes with 3‐Pinacolatoboryl‐1‐arylallyl Carboxylates.

Optical Response of a Glassy Electronic State in θ-(BEDT-TTF)2CsZn(SCN)4

The palladium-catalyzed cyclopropanation of strained alkenes with 3-pinacolatoboryl-1-arylallyl carboxylates was explored. The reactions proceeded smoothly under mild conditions, and the cyclopropanation products were obtained in good to high yields with high diastereoselectivities if CsF, 18-crown-6, and molecular sieves were used as additives. The reaction was hypothesized to proceed through the formation of a putative palladacyclobutene intermediate that needed to be considered to explain the observed stereochemistry.

Palladium-Catalyzed Cyclopropanation of Strained Alkenes with 3-Pinacolatoboryl-1-arylallyl Carboxylates

Development of a lip vermilion epithelium reconstruction model using keratinocytes from skin and oral mucosa.

OBJECTIVE
This study aimed to determine if the change in technique of soft palate closure or timing of hard palatal repair induced occlusal changes in patients with complete unilateral cleft lip and palate (CUCLP).

DESIGN
Retrospective study.

SETTINGS
A medical and dental hospital in Japan.

SUBJECTS
A total of 96 patients with CUCLP treated with 2-stage palatoplasty were included in the study and categorized into 3 groups (G1, G2, and G3) according to the protocol used.

G1 underwent soft palate repair using Perko method at 1.5 years of age and hard palate repair using vomer flap procedure at 5.5 years of age. Furlow method was used for soft palate repair in G2 at 1.5 years of age and hard palate repair using vomer flap procedure at 5.5 years of age. The Furlow method was used to repair the soft palate in G3 at 1.5 years of age and vomer flap procedure was used to repair the hard palate at 4 years of age.

Two evaluators assessed the dental arch relationship using the modified Huddart/Bodenham (mHB) index on 2 separate occasions.

RESULTS
Intra- (intraclass correlation coefficient [ICC]: 0.962) and inter-examiner (ICC: 0.950) reliability showed very good agreement. The frequency of crossbite present in the major and minor segments gradually decreased with each change in protocol. Mean segmental scores showed no significant difference between 3 protocols (P > .05). Good inter-arch alignment occurred with all 3 surgical protocols (G1:82.6%, G2:89.8%, and G3:91.7%).

There was no significant difference in the dental arch relationship outcomes between the 3 surgical protocols. The dentition status was comparable with all surgical protocols, even after the changes.

The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association

Occlusal Evaluation Using Modified Huddart and Bodenham Scoring System Following 2-Stage Palatoplasty With Hotz Plate: A Comparison Among 3 Different Surgical Protocols.

We report a case of primary intraosseous carcinoma （PIOC） of the jaw thought to be related to the crown of an impacted mandibular third molar in a 74-year-old man that was detected during a routine checkup at his family dental clinic. He was referred to our department with paresthesia affecting the right lower lip and occlusal pain in the right mandibular molar region. The right lower second molar was elongated with grade 2 mobility and the buccal gingiva was mildly swollen. There was no purulent discharge. Panoramic radiographs showed an ill-defined radiolucent lesion measuring 35×25 mm with irregular margins that was continuous with the crown of an inverted and impacted right mandibular third molar. A biopsy specimen was obtained. The histopathological diagnosis was squamous cell carcinoma （with suspicion of PIOC）. The patient underwent submandibular dissection, segmental resection of the mandible, and reconstruction of the jaw with a metal plate. PIOC is generally associated with malignant transformation of a cystic lesion. However, there were no abnormal findings on panoramic radiographs taken at his family dental clinic 8 months earlier in this case. Therefore, it is probable that the malignancy had developed without cystic changes and had increased rapidly in size. Although asymptomatic impacted mandibular third molars and periodontitis are common, dentists should keep various lesions including PIOC in mind in elderly patients despite the low risk of developmental cysts.

A case of primary intraosseous carcinoma related impacted lower third molar

ABSTRACTAn investigation of the carbonaceous components of PM2.5 (Dp < 2.5 µm) and PM0.1 (Dp < 0.1 µm) in conjunction with online measurements of gaseous and particulate pollutants, which are dominated by motor vehicle emissions, was undertaken over 15 consecutive days in a field sampling campaign at a roadside and reference site for daytime (06:00 to 17:30) and nighttime (18:00 to 05:30) conditions. The results indicated that traffic-related air pollutants strongly influenced pollution levels in the sampling area, especially during the nighttime, although the concentrations were lower than during the daytime. Water-soluble organic carbon/organic carbon (WSOC/OC) ratios in PM0.1 were 0.60 ± 0.11 and 0.63 ± 0.16 at the roadside and reference sites, respectively, while the corresponding ratios in PM2.5 were found to be 0.60 ± 0.11 and 0.63 ± 0.14. These results demonstrated the relatively high contribution of WSOC in the study area compared to in previous reports. It was observed that elemental carbon (EC) in PM0.1 are emitted approximately by a factor of 0.1 in comparison with those observed for EC in PM2.5 when considering the slopes of the linear relationship with particle-bound PAHs and NOx, while OC displayed no such relationship. Our measurements indicate that a significant portion of the OC in PM0.1 is not directly co-emitted with EC from motor vehicles but is readily adsorbed or condensed onto the existing EC fractions through condensation. The relationship between the EC2 fraction and the particle number concentration indicates that the EC2 fraction is the primary chemical component of traffic related ultrafine particles in terms of particle number concentration.

Carbonaceous components in PM2.5 and PM0.1 with online measurements of gaseous and particulate pollutants: Implication of thermal-optical derived EC2 fraction as a component of ultrafine particles in the roadside environment

Studies on water behavior in the vicinity of a catalyst layer (CL) and its effect on the cell performance are important challenges because water management is a key factor to achieve higher performance of polymer electrolyte fuel cells (PEFCs). In this study, a microdevice that contains a catalyst coated membrane (CCM) was developed (1) and in-operando infrared (IR) microscopy was conducted to visualize water behavior on the CL. Two types of CLs contain either carbon (2) or tin oxide (3) as supporting material to investigate the effects of materials on the water behavior and cell performance.
 The microdevice, which was made of a silicon wafer, contains two microchannels (100 μm-width, 200 μm-pitch) and a current-collecting layer (30 μm-width) on a rib of the cathode plate. The CCM was sandwiched by two plates. The anode channel faced the rib of the cathode. The surface of a cathode catalyst layer was coated with thin Au by sputtering to enhance IR reflectance, which did not change the porous structure of the CL significantly. The surface of the cathode catalyst layer was observed by IR microscopy through the cathode plate.
 Figure 1 shows liquid water generated during the constant current operation of the device. The catalyst layer contains carbon as the supporting material in this case. The effects of the materials and flow conditions on the water behavior and cell performance were investigated.
 Acknowledgments
 This work was supported by NEDO ECCEED’30.
 References
 (1) T. Suzuki et al., J. Therm. Sci. Technol., 11 (2016), 16-00370.
 (2) T. Suzuki et al., Int. J. Hydrogen Energy, 41 (2016), 20326.
 (3) Y. Chino et al., J. Electrochem. Soc., 162 (2015), F736.
 
 Figure 1

Investigation of Liquid Water Behavior and Performance of PEFC Catalyst Layers Using a Microdevice and in-Operando Infrared Microscopy

Optimal control of root nodulation -- prediction of life history theory of a mutualistic system.

In the Dlk1-Dio3 imprinted domain, an intergenic differentially methylated region (IG-DMR) regulates the parental allele-specific expression of imprinted genes. The maternally inherited deletion of IG-DMR (IG-DMR(−/+)) results in perinatal lethality because of the overexpression of paternally expressed genes and repression of maternally expressed noncoding RNAs (ncRNAs), including Gtl2. To better understand the possible contribution of paternally expressed genes to the lethality, we attempted to rescue the lethality of IG-DMR(−/+) mutants by restoring the paternally expressed genes. Because the paternally inherited Gtl2 deletion (Gtl2(+/−)) induced a decrease in the expression of paternally expressed genes, we crossed female IG-DMR heterozygous mice and male Gtl2 heterozygous mutant mice. The resultant IG-DMR(−/+)/Gtl2(+/−) double mutant mice had normal expression levels of paternally expressed genes, and none of them showed perinatal lethality; however, most mice showed postnatal lethality with decreased expression of the maternally expressed ncRNAs. Thus, we inferred that paternally expressed genes are necessary for perinatal survivability and that maternally expressed ncRNAs are involved in postnatal lethality.

Restoration of Dlk1 and Rtl1 Is Necessary but Insufficient to Rescue Lethality in Intergenic Differentially Methylated Region (IG-DMR)-deficient Mice*

deficient Mice Intergenic Differentially Methylated Region but Insufficient to Rescue Lethality in Is Necessary Rtl 1 and Dlk 1 Restoration of Developmental

Penta-EF-hand protein ALG-2 functions as a Ca2+-dependent adaptor that bridges Alix and TSG101.

The cluster of imprinted genes located in the Dlk1-Dio3 domain spanning 1 Mb plays an essential role in controlling pre- and postnatal growth and differentiation in mice and humans. The failure of parent-of-origin-dependent gene expression in this domain results in grave disorders, leading to death in some cases. However, little is known about the role of maternally expressed non-coding RNAs (ncRNAs) including many miRNAs and snoRNAs in this domain. In order to further understand the role of these ncRNAs, we created Gtl2-mutant mice harboring a 10 kb deletion in exons 1-5. The mutant mice exhibited a very unique inheritance mode: when the deletion was inherited from the mother (Mat-KO), the pups were born with normal phenotypes; however, all of them died within 4 weeks after birth, probably due to severely hypoplastic pulmonary alveoli and hepatocellular necrosis. Mice carrying the paternal deletion (Pat-KO) showed severe growth retardation and perinatal lethality. Interestingly, the homozygous mutants (Homo-KO) survived and developed into fertile adults. Our results show that these phenotypes occur due to altered expression of the Dlk1-Dio3 cluster genes including miRNAs and snoRNAs via the cis and trans effects.

Deletion of Gtl2, imprinted non-coding RNA, with its differentially methylated region induces lethal parent-origin-dependent defects in mice.

Characterization of the catalytic domains of Trichoderma reesei endoglucanase I, II, and III, expressed in Escherichia coli

Human Brox is a newly identified 46 kDa protein that has a Bro1 domain‐like sequence and a C‐terminal thioester‐linkage site of isoprenoid lipid (CAAX motif) (C standing for cysteine, A for generally aliphatic amino acid, and X for any amino acid). Mammalian Alix and its yeast ortholog, Bro1, are known to associate with charged multivesicular body protein 4 (CHMP4), a component of endosomal sorting complex required for transport III, via their Bro1 domains and to play roles in sorting of ubiquitinated cargoes. We investigated whether Brox has an authentic Bro1 domain on the basis of its capacity for interacting with CHMP4s. Both Strep Tactin binding sequence (Strep)‐tagged wild‐type Brox (Strep–BroxWT) and Strep‐tagged farnesylation‐defective mutant (Cys→Ser mutation; Strep–BroxC408S) pulled down FLAG‐tagged CHMP4b that was coexpressed in HEK293 cells. Treatment of cells with a farnesyltransferase inhibitor, FTI‐277, caused an electrophoretic mobility shift of Strep–BroxWT, and the mobility coincided with that of Strep–BroxC408S. The inhibitor also caused a mobility shift of endogenous Brox detected by western blotting using polyclonal antibodies to Brox, suggesting farnesylation of Brox in vivo. Fluorescence microscopic analyses revealed that Strep–BroxWT exhibited accumulation in the perinuclear area and caused a punctate pattern of FLAG–CHMP4b that was constitutively expressed in HEK293 cells. On the other hand, Strep–BroxC408S showed a diffuse pattern throughout the cell, including the nucleus, and did not cause accumulation of FLAG–CHMP4b. Fluorescent signals of monomeric green fluorescent protein (mGFP)‐fused BroxWT merged partly with those of Golgi markers and with those of abnormal endosomes induced by overexpression of a dominant negative mutant of AAA type ATPase SKD1/Vps4B in HeLa cells, but such colocalization was less efficient for mGFP–BroxC408S. These results suggest a physiological significance of farnesylation of Brox in its subcellular distribution and efficient interaction with CHMP4s in vivo.

Brox, a novel farnesylated Bro1 domain‐containing protein that associates with charged multivesicular body protein 4 (CHMP4)

Deletion of the Maternally Expressed Imprinted Gene, Gtl2, Resulted in Parental-specific Lethality in Mice.

All CHMPs (charged multivesicular body proteins) reported to date have common features: they all contain approx. 200 amino acid residues, have coiled-coil regions and have a biased distribution of charged residues (basic N-terminal and acidic C-terminal halves). Yeast orthologues of CHMPs, including an ESCRT-III component Snf7, are required for the sorting of cargo proteins to intraluminal vesicles of multivesicular bodies. We have characterized a novel human ESCRT-III-related protein, designated CHMP7, which consists of 453 amino acid residues. CHMP7 contains an SNF7 domain and a distantly SNF7-related domain in its C-terminal half and N-terminal half respectively. Among the ten CHMP proteins classified previously in six subfamilies (CHMP1-CHMP6), the C-terminal SNF7 domain of CHMP7 is most similar to the SNF7 domain of CHMP6, which associates with CHMP4 proteins and EAP20, a component of ESCRT-II. Pull-down assays using lysates of HEK-293T (human embryonic kidney) cells that overexpressed Strep-tagged CHMP7 and GFP (green fluorescent protein)-fused CHMP4b (also named Shax1) revealed a positive interaction between the C-terminal half of CHMP7 and CHMP4b. However, interaction was not observed between CHMP7 and EAP20. Confocal fluorescence microscopic analyses revealed that FLAG-CHMP7 is distributed in HeLa cells diffusely throughout the cytoplasm, but with some accumulation, especially in the perinuclear area. The distribution of FLAG-CHMP7 was altered to a cytoplasmic punctate pattern by overexpression of either CHMP4b-GFP or GFP-Vps4B(E235Q), a dominant-negative mutant of the AAA (ATPase associated with various cellular activities) Vps4B, and partially co-localized with them. Ubiquitinated proteins and endocytosed EGF accumulated in GFP-CHMP7-expressing cells. A dominant-negative effect of overexpressed GFP-CHMP7 was also observed in the release of virus-like particles from HEK-293T cells that transiently expressed the MLV (murine leukaemia virus) Gag protein. These results suggest that CHMP7, a novel CHMP4-associated ESCRT-III-related protein, functions in the endosomal sorting pathway.

CHMP7, a novel ESCRT-III-related protein, associates with CHMP4b and functions in the endosomal sorting pathway.

In this study, we investigated the fast switching and resistance control in a lateral GeTe-based phase-change memory (PCM). The resistivity of GeTe as a function of annealing temperature showed that it changed by more than 6 orders of magnitude in a very narrow temperature range. X-ray diffraction patterns of GeTe films indicated that GeTe had only one crystal structure, that is, face-centered cubic. It was demonstrated that the lateral device with a top conducting layer had a good performance. The operation characteristics of the GeTe-based lateral PCM device showed that it could be operated even when sub-10-ns voltage pulses were applied, making it much faster than a Ge2Sb2Te5-based device. The device resistance was successfully controlled by applying a staircase-like pulse, which enables the device to be used for fast multilevel storage.

Sub 10 ns fast switching and resistance control in lateral GeTe-based phase-change memory

Recrystallization process controlled by staircase pulse in phase change memory

Here, we report multi-level storage (MLS) in multi-layer (ML) and single-layer (SL) phase change memories (PCM). For the former ML-PCM device, the active medium with two layers of chalcogenide consists of a top 30 nm TiN/180 nm SbTeN/20 nm TiN/bottom 120 nm SbTeN stacked multi-layer. Three stable and distinct resistance states are demonstrated in both static and dynamic switching characteristics of the multi-layer devices. For the latter SL-PCM device, the active medium with only one layer of chalcogenide consists of a top 50 nm TiN/150 nm SbTeN. We demonstrate that the number of distinguishable resistance levels can readily reach 16 and even higher. These levels in this study result from the initial threshold switching and the subsequent current-controlled crystallization induced by Joule heating. Therefore, the latter memory allows the creation of many distinct levels, thus enabling the low-cost ultra-high-density non-volatile memory.

Multi-Level Storage in Lateral Phase Change Memory: From 3 to 16 Resistance Levels

A novel phase change memory structure with a separate heater was proposed for a multilevel storage. Finite element analysis was conducted to investigate the possibility of multilevel storage. 100 ns SET pulses, with an increasing amplitude from 0.5 V to 3 V, were applied for heating the phase change layer, Ge2Se2T5 (GST). From the simulation result, it was exhibited that the temperature in the GST layer increased gradually when an increasing pulse is applied to the separate heater layer (N-TiSi3). This implies that crystallization is well controlled by changing the amplitude of the applied SET pulse. The gradual increase in the temperature leads to gradual resistance drop, depending strongly on the capping material. The gradual resistance drop will allow multilevel storage for the memory device.

A Novel Phase Change Memory with a Separate Heater Characterized by Constant Resistance for Multilevel Storage

We have investigated random-access multilevel storage in phase change memory by staircase-like pulse programming. Staircase-like pulse consists of first sub-pulse and second sub-pulse. Our simulation exhibited that any resistance levels are expected to be randomly accessed by controlling the crystallization with different widths of second sub-pulse t2. Based on the simulation results, we did experiment on staircase-like pulse programming. Experimental results showed that the device resistance gradually increased with reducing second sub-pulse t2 to 0 ns. In other words, random access to any resistance levels was demonstrated to be possible simply by changing t2.

Random-Access Multilevel Storage in Phase Change Memory by Staircase-Like Pulse Programming

STRUCTURE ANTISALISSURE ET COMPOSANT AUTOMOBILE UTILISANT LA STRUCTURE ANTISALISSURE

La presente invention a pour but de fournir un dispositif de purification de gaz d'echappement avec lequel une diminution de l'efficacite de l'operation de reduction (operation de denitrification) peut etre eliminee. Pour atteindre ce but, l'invention porte sur un dispositif de purification de gaz d'echappement pour un navire (1) qui est pourvu : d'un corps d'injection d'agent reducteur (61) d'un dispositif d'alimentation en agent reducteur, qui distribue un agent reducteur aux gaz d'echappement traversant l'interieur d'un tuyau d'echappement d'un moteur (21) monte dans un navire ; d'un melangeur de gaz d'echappement (62), qui melange les gaz d'echappement et l'agent reducteur sur le cote aval du corps d'injection d'agent reducteur (61) dans la direction de deplacement des gaz d'echappement ; de dispositifs de reduction catalytique selective (34) et (35), qui favorisent la reduction de NOx dans les gaz d'echappement venant du moteur (21) sur le cote aval du melangeur de gaz d'echappement (62) dans la direction de deplacement des gaz d'echappement. Il y a de multiples corps d'injection d'agent reducteur (61), et des ouvertures d'injection des corps d'injection d'agent reducteur (61) sont disposees a intervalles egaux dans la direction peripherique d'un tuyau d'echappement.

Research conducted in the recent past have proposed total conviction as a factor associated with cognitive reappraisal that may produce changes in emotion and behavior. However, the factors that influence total conviction are not yet clearly identified. In this study, we focused on daily emotion regulation strategies and examined the relationship between emotion regulation strategies and total conviction. A total of 42 undergraduate and graduate students participated in this study. They measured their tendency toward daily emotion regulation strategies and then engaged in the cold pressor task (CPT) which is a distress tolerance task. Participants were then presented with information that encouraged them to engage in the task while enduring distress, creating a context for cognitive reappraisal of the task. Thereafter, they engaged in a second CPT. Finally, the degree of total conviction to the information that prompted reappraisal was measured. The results showed that total conviction in the experimental situation predicted behavior change. We found that the tendency to use routine cognitive reappraisal was not associated with total conviction, while the tendency to use expressive suppression would have a negative effect on total conviction. Furthermore, the expressive suppression tendency was found to moderate the relationship between total conviction and behavior change. These results indicate that the occurrence of total conviction in cognitive reappraisal leads to behavior change, though the tendency toward daily cognitive reappraisal is not related to the occurrence of total conviction in the experimental setting. The results also suggest that daily expressive suppression inhibits total conviction, particularly in situations where cognitive reappraisal is required.

Relationship between emotion regulation strategies and total conviction in promoting behavior change

The Relationship Between Indecisiveness and Network Integration in Scalp Resting-State EEG

Association between long-range temporal correlations in intrinsic EEG activity and subjective sense of identity

Abstract Reading literature contributes to the development of language skills and socioemotional competencies related to empathic responding. Despite implications for improving measures of empathy used by practitioners interested in reading behavior and their applications to teaching empathic skills through literature, extensions to the ability to express empathic inference of interpersonal encounters, or empathic accuracy, remains an understudied area. Comparing which traits are associated with performance on tasks that require empathic accuracy could reveal more about underlying empathic processes and their characteristics for the benefit of practitioner tools and pedagogical choices for reading. Two studies were conducted to investigate possible relationships between self-reported constructs of interpersonal reactivity and an experimental paradigm that measures empathic accuracy. Experiment 1 investigated these relationships among participants having everyday conversations, and Experiment 2 examined the same variables in a context designed to emulate a counseling setting. In both cases, scores on the Fantasy self-report scale correlated with empathic accuracy scores. The results indicate that a tendency to consume fiction and engage in narrative transportation might play a role in the ability to accurately infer the internal state of others. Implications for reader involvement as learner engagement and consequential validity for instructional scaffolds are discussed.

Fantasy Component of Interpersonal Reactivity is Associated with Empathic Accuracy: Findings from Behavioral Experiments with Implications for Applied Settings

Decentering mediates the effect of cognitive reappraisal and distraction on mental health

The relationship between emotional exhaustion and working memory in emotional regulation of nurses.

Previous studies have suggested that cognitive reappraisal, which is an effective emotion regulation strategy, enhances decentering. On the other hand, other studies have implied the reverse in regard to this relationship: that decentering supports cognitive reappraisal. However, these possibilities have not yet been examined empirically. In the present study, we investigated the causal relationship between decentering and cognitive reappraisal by conducting two wave cross-lagged analysis. One hundred and thirty-eight Japanese university students responded to a questionnaire comprising measures of decentering and cognitive reappraisal tendency; the questionnaire was administered on two occasions, with an interval of 1 month. Cross-lagged analysis indicated the positive effect of cognitive reappraisal on decentering; however, the reverse possibility, that decentering influences cognitive reappraisal, was not significant. These results suggested that habitual use of cognitive reappraisal fosters decentering.

Cognitive Reappraisal Facilitates Decentering: A Longitudinal Cross-Lagged Analysis Study

Resting-state theta/beta ratio is associated with distraction but not with reappraisal

The development of the Japanese version of Body Perception Questionnaire (BPQ)

The relationship between the auditory hallucination-like experience and the complexity of the resting-state EEG

The interaction of working memory capacity and task difficulty affects mind-wandering

The relationships between long-range temporal correlation and interoceptive sensibility

The Relationship between Individual Difference in Interoception and Difficulty in Emotion Awareness

The relationship between the self function of autobiographical memory and temporal correlation of the resting-state EEG

The relationship between the self function of autobiographical memory and long-range temporal correlation of the resting-state EEG

Affective auditory stimulus database: An expanded version of the International Affective Digitized Sounds (IADS-E)

High working memory capacity facilitates distraction as an emotion regulation strategy

An Examination of the Effect of Mood State on Empathic Accuracy in Clinical Setting

Does emotion regulation influence emotion regulation of other person?

The effect of false physiological feedback on subjective emotional experience

The effect of false physiological feedback on subjective arousal

Working Memory Capacity Influences the Effect of Distraction as an Emotion Regulation Strategy

Factor structure, reliability and validation of the Japanese version of the Body Perception Questionnaire-Body Awareness Very Short Form (BPQ-BAVSF-J)

Abstract The Cognitive Emotion Regulation Questionnaire (CERQ) is a self-report scale measuring the use of nine types of cognitive emotion regulation strategies. The present study aimed to develop a revised version of the Japanese translated CERQ (CERQ-RJ). Specifically, we revised translations of the original Japanese version CERQ (CERQ-J), and examined its psychometric properties and measurement invariance across gender. We conducted two surveys 8 weeks apart; participants were recruited from a single Internet survey company in Japan. Results indicated that the CERQ-RJ showed better fit for the predicted nine-factor model than the CERQ-J, and acceptable reliability and validity; it also showed acceptable fit for both gender groups. Results also revealed scalar invariance of the CERQ-RJ across gender groups. Lastly, most strategies showed predicted associations with mental health outcomes in concurrent analyses. The newly translated scale may prove useful in future examinations of emotion regulation among Japanese participants.

Revision and validation of the Japanese-version cognitive emotion regulation questionnaire: psychometric properties and measurement invariance across gender

Does shift-and-persist strategy buffer career choice anxiety and affect career exploration?

Generally human-symbiotic systems present information to users through electronic display devices. However, the display devices have passive nature and the users need to watch it to get the information actively. Therefore, they are not suitable for transmitting important information to the specified person rapidly and certainly. The system is desired to recognize the user's current state and present information at an appropriate position on the surrounding environment interactively to make the user notice it certainly. In this paper, we propose an interactive projection system that always presents information within a user's view. The proposed system employs the method for the estimation of the user's head pose and field of view using RGB-D cameras. The system follows the estimated view and always projects information within it using laser pico-projectors and pan-tilt platforms controlled by a PC. Therefore, the system can transmits information to the user certainly. Furthermore, the system provides the user with a virtual touch interface to operate the projected information interactively. We carry out some experiments to show that the proposed method works well.

2016 Joint 8th International Conference on Soft Computing and Intelligent Systems (SCIS) and 17th International Symposium on Advanced Intelligent Systems (ISIS)

Interactive Projection System That Always Presents Information within User’s View

The aim of this paper is to understand the learning effect by difference of display media and text contents. Thirty six subjects read two types of short texts that are literary text and descriptive one about scientific topic by using tablet computer (iPad) and paper. We compared subjective evaluation about each type of displays, reading speed per characters, score of memory test and comprehension test after reading texts. At first, the result of subjective impressions showed that iPad’s readability has already achieved the equivalent to papers’. Subjects recognized that iPad was superior to paper in terms of display sharpness and easiness of turning pages. On the other hand, subjects felt less fatigue and higher concentration while reading texts on paper. Secondly, significant difference by ANOVA was observed between two types of media on reading speed and word memory test score only using descriptive text. Finally, it is concluded that paper is still higher usability media than tablet computer for understanding sentence. 1. はじめに

Effects on Text Understanding and Memory by Types of Display Media: Comparison between E-book Readers and Papers

PLANTOPIA -- Self-moisture Sensing and Sharing the information with the plants through server and use natural languages to present their condition to human.

Evaluation of Visualization System for Pulse Noise Propagations on Printed Circuit Boards

Noise Detection Circuits for Specifying the Propagation Path on the PCB

Coordinated control of a redundant joint arm using feedback torque

Magnetic properties of Mn-based magnetic materials prepared by in-field heat treatment

Optimal information transmission in Hodgkin-Huxley neurons under metabolic cost constraints

Noise properties of digital SQUID using DROS comparator with relaxation oscillation resonant circuit

Application of Nonlinear time series analysis to Near-infrared spectroscopy (NIRS) data

Population coding of odorant information in the moth antennal lobe

Estimating parameters in Multi-timescale Adaptive Threshold model using Particle Swarm Optimization

Neuron parameter estimation by genetic algorithm using the characteristics of membrane potential

A Biological Implementation of Bayesian Estimation Algorithm in a Neural Network Architecture Based on Discrete Choice Theory

Inferring the time-varying input signals and the hidden states from the membrane potential of a neuron

A comparison of the brain activity between experts and non-experts in a basic drumming using NIRS

The Method of Mathmatical Exercises on the web by using Assignment Module of Moodle

There are no feasible real-time and direct skin dosimeters for interventional radiology. One would be available if there were x-ray phosphors that had no brightness change caused by x-ray irradiation, but the emission of the Y2O3:Eu, (Y, Gd, Eu)BO3, and YVO4:Eu phosphors investigated in our previous study was reduced by x-ray irradiation. We found that the brightness of those phosphors recovered, and the purpose of this study is to investigate their recovery phenomena. It is expected that more kinds of phosphors could be used in x-ray dosimeters if the brightness changes caused by x-rays are elucidated and prevented. Three kinds of phosphors—Y2O3:Eu, (Y, Gd, Eu)BO3, and YVO4:Eu—were irradiated by x-rays (2 Gy) to reduce their brightness. After the irradiation, brightness changes occurring at room temperature and at 80 °C were investigated. The irradiation reduced the brightness of all the phosphors by 5%–10%, but the brightness of each recovered immediately both at room temperature and at 80 °C. The recovery at 80 °C was faster than that at room temperature, and at both temperatures the recovered brightness remained at 95%–98% of the brightness before the x-ray irradiation. The brightness recovery phenomena of Y2O3:Eu, (Y, Gd, Eu)BO3, and YVO4:Eu phosphors occurring after brightness deterioration due to x-ray irradiation were found to be more significant at 80 °C than at room temperature. More kinds of phosphors could be used in x-ray scintillation dosimeters if the reasons for the brightness changes caused by x-rays were elucidated.

Red-emission phosphor’s brightness deterioration by x-ray and brightness recovery phenomenon by heating

There are case reports of injuries caused by the radiation from interventional radiology (IVR) X‐ray systems. Therefore, the management of radiation doses in IVR is important. However, no detailed report has evaluated image quality for a large number of IVR X‐ray systems. As a result, it is unclear whether the image quality of the X‐ray equipment currently used in IVR procedures is optimal. We compared the entrance surface doses and image quality of multiple IVR X‐ray systems. This study was conducted in 2014 at 13 medical facilities using 18 IVR X‐ray systems. We evaluated image quality and simultaneously measured the radiation dose. Entrance surface doses for fluoroscopy (duration, 1 min) and cineradiography (duration, 10 s) are measured using a 20‐cm‐thick acrylic plate and skin dose monitor. The image quality (such as spatial resolution and low‐contrast detectability) of both fluoroscopy and cineradiography was evaluated using a QC phantom. For fluoroscopy, the average entrance surface dose using the 20‐cm‐thick acrylic plate was 13.9 (range 2.1–28.2) mGy/min. For cineradiography, the average entrance surface dose was 24.6 (range 5.1–49.3) mGy/10 s. We found positive correlations between radiation doses and image quality scores, in general, especially for fluoroscopy. The differences in surface dose among the 18 IVR X‐ray systems were high (max/min, 9.7‐fold for cineradiography; 13.4‐fold for fluoroscopy). The differences in image quality scores (spatial resolution, low‐contrast detectability, and dynamic range) were also very large. In general, there tended to be a correlation between radiation dose and image quality. Periodical measurements of the radiation dose and image quality of the X‐ray equipment used for cineradiography and fluoroscopy in IVR are necessary. The need to minimize patient exposure requires that the dose be reduced to the minimum level that will generate an image with an acceptable degree of noise. PACS number(s): 87.57.C, 87.57.uq, 87.59.B, 87.59.bf, 87.59.C, 87.59.cf, 87.59.Dj

A cross‐sectional study of the radiation dose and image quality of X‐ray equipment used in IVR

Japan Network for Research and Information on Medical Exposures (J-RIME) released the primary diagnostic reference levels (DRLs 2015) to optimize/manage the radiation dose for interventional radiology (IVR) on June 7, 2015 in Japan. However, this DRLs 2015 has a wide range of selection bias for only certified IVR technologists' dates. Therefore, it is important to know the radiation dose including non-certified IVR technologists' facilities. In this study, we verified the fluoroscopy radiation dose rates for many IVR systems in the present situation. This study was conducted at 13 cardiac catheterization laboratories (18 X-ray systems) around Sendai. We measured the entrance doses at the patient entrance reference point (interventional reference point) using a 20-cm-thick acrylic plate and skin-dose monitor. Although the DRLs 2015 of IVR is 20 mGy/min, the result of a fluoroscopy radiation dose in 18 X-ray systems was median (inter quartile range: IQR), 24.4 (16.3, 35.5) mGy/min. The optimization/managing the radiation dose of IVR X-ray systems is an important issue. In addition, it is necessary to intensify the activities to raise awareness for DRLs 2015.

Present Situation of Fluoroscopy Radiation Doses in Many IVR Systems.

There are case reports of injuries caused by the radiation from interventional radiology (IVR) X-ray systems. Therefore, the management of radiation doses in IVR is important. However, no detailed report has evaluated image quality for a large number of IVR X-ray systems. As a result, it is unclear whether the image quality of the X-ray equipment currently used in IVR procedures is optimal. We compared the entrance surface doses and image quality of multiple IVR X-ray systems. This study was conducted in 2014 at 13 medical facilities using 18 IVR X-ray systems. We evaluated image quality and simultaneously measured the radiation dose. Entrance surface doses for fluoroscopy (duration, 1 min) and cineradiography (duration, 10 s) are measured using a 20-cm-thick acrylic plate and skin dose monitor. The image quality (such as spatial resolution and low-contrast detectability) of both fluoroscopy and cineradiography was evaluated using a QC phantom. For fluoroscopy, the average entrance surface dose using the 20-cm-thick acrylic plate was 13.9 (range 2.1-28.2) mGy/min. For cineradiography, the average entrance surface dose was 24.6 (range 5.1-49.3) mGy/10 s. We found positive correlations between radiation doses and image quality scores, in general, especially for fluoroscopy. The differences in surface dose among the 18 IVR X-ray systems were high (max/min, 9.7-fold for cineradiography; 13.4-fold for fluoroscopy). The differences in image quality scores (spatial resolution, low-contrast detectability, and dynamic range) were also very large. In general, there tended to be a correlation between radiation dose and image quality. Periodical measurements of the radiation dose and image quality of the X-ray equipment used for cineradiography and fluoroscopy in IVR are necessary. The need to minimize patient exposure requires that the dose be reduced to the minimum level that will generate an image with an acceptable degree of noise. PACS number(s): 87.57.C, 87.57.uq, 87.59.B, 87.59.bf, 87.59.C, 87.59.cf, 87.59.Dj.

A cross-sectional study of the radiation dose and image quality of X-ray equipment used in IVR.

Physica medica : PM : an international journal devoted to the applications of physics to medicine and biology : official journal of the Italian Association of Biomedical Physics

Real-time patient radiation dosimeter for use in interventional radiology.

Objective Although many patients benefi t greatly from fluoroscopically guided intervention (IVR) procedures such as percutaneous coronary intervention (PCI), one of the major disadvantages associated with these procedures, such as cardiac IVR, is the increased patient radiation dose. This study compared the entrance surface doses of x-ray equipment for cardiac IVR at the same seven cardiac catheterization laboratories between today and the past to determine the radiation doses of current cardiac IVR x-ray systems. Methods and results This study was conducted in 2001, 2007, and 2014 at the same seven cardiac catheterization laboratories in and around Sendai City, Japan. The entrance surface doses with cineangiography and fl uoroscopy were compared in 2001 (11 x-ray systems), 2007, and 2014 (12 x-ray systems) using a 20-cm-thick acrylic plate and skin dose monitor. The x-ray conditions used in the measurements, including the image receptor fi eld magnifi cation mode and the recording speed for cineangiography and fl uoroscopy, were those normally used in the facilities performing PCI. Although presently, the entrance doses of x-ray equipment used for cardiac IVR tend to be lower than previously (fl uoroscopy dose in 2001, 19.3 ± 6.3 mGy/min; in 2014, 13.2 ± 6.5 mGy/min), some equipment has a high radiation dose. In addition, the dose diff erences of the x-ray systems in 2014 were greater than those in the past (fl uoroscopy dose in 2001, 3.4-fold; in 2014, 10.5-fold). Conclusions In IVR procedures, managing the radiation dose of cardiac IVR x-ray systems is a very important issue. Periodical measurement of the radiation dose of the x-ray equipment used for both cineangiography and fl uoroscopy for cardiac IVR is necessary.

Radiation dose of cardiac IVR x-ray systems: a comparison of present and past

Poster: "ECR 2015 / C-0857 / Development of a portable X-ray system for disaster radiography" by: "R. Kobayashi1, K. Chida1, Y. Inaba1, S. Yashima1, M. Tano2, M. Zuguchi1; 1Sendai/JP, 2Tokyo/JP"

Real-time monitoring of the radiation doses received by interventional radiology (IR) staff has become highly desirable. However, occupational doses are rarely measured in real time, due to the lack of a feasible method for use in IR. Recently, the i2 system by RaySafe™ has been introduced to measure occupational exposure in IR in real time. The i2 system consists of several personal dosimeters (PDs) and a base station with a display and computer interfacing. We evaluated the fundamental performance (dose linearity, dose-rate dependence, angular dependence, batch uniformity and reproducibility) of the i2 system. The dose linearity of the i2 was excellent (R2 = 1.00) The i2 exhibited slight dose-rate dependence (~20%) at very high dose rates (250 mGy h−1). Little angular dependence (within 20%) was observed between 0° and ±45°, in either the vertical or horizontal direction. We also found that the PD was highly sensitive (about 200%) at angles behind it, e.g. 180°. However, this backscattered radiation is not a problem, in general, due to the placement of the i2 sensor (PD) on the lead apron. We conclude that the i2 system facilitates accurate real-time monitoring and management of occupational doses during IR.

Fundamental study of a real-time occupational dosimetry system for interventional radiology staff

This study described in this paper was undertaken to investigate comfort temperatures and related behaviours in Japanese homes. In it temperatures were measured in the living rooms and a thermal comfort survey of residents and related window-opening behavioural survey was completed over a full year in the Gifu region of Japan. The residents were found to be highly satisfied with the thermal environment of their houses. Significant seasonal differences were found in their comfort temperatures. The results showed that comfort temperature changes varied with changes in both the indoor and outdoor climate. The strength of the relationship between indoor and outdoor temperatures justified the adoption of the adaptive model for both prediction and design of control strategies for the provision of indoor comfort. The window-opening behaviours were shown to be related to both the indoor or outdoor air temperatures. The deadband was narrower and constraints on the window opening in the houses investigated were both considerably lower than previously found in office building studies. The adaptive model is highly supported by this study of occupant perceptions and window-opening behaviour.

Investigation of comfort temperature, adaptive model and the window-opening behaviour in Japanese houses

Novel and Efficient Method for Diagnosing Infective Endocarditis Using 16S Ribosomal RNA Gene Amplicon Sequence.

The oncogene-dependent resistance to reprogramming unveils cancer therapeutic targets.

ASO Visual Abstract: Tumor Burden Monitoring with Circulating Tumor DNA During Treatment in Patients with Esophageal Squamous Cell Carcinoma

ASO Author Reflections: Can Circulating Tumor DNA Guide Individualized Treatment for Patients with Esophageal Squamous Cell Carcinoma?

Inhibitory effect of aspirin on inflammation-induced lung metastasis of cancer cells associated with neutrophil infiltration

Tumor Burden Monitoring with Circulating Tumor DNA During Treatment in Patients with Esophageal Squamous Cell Carcinoma

ASO Author Reflections: Does AI Guided Endoscopic Response Evaluation After Neoadjuvant Chemotherapy Encourage Individualized Treatment Strategy in Esophageal Cancer Patients?

ASO Visual Abstract: Evaluation of Endoscopic Response Using Deep Neural Network in Esophageal Cancer Patients who Received Neoadjuvant Chemotherapy

Evaluation of Endoscopic Response Using Deep Neural Network in Esophageal Cancer Patients Who Received Neoadjuvant Chemotherapy

Neutrophil-to-lymphocyte ratio change predicts histological response to and oncological outcome of neoadjuvant chemotherapy for esophageal squamous cell carcinoma

Mo,ReとC,およびそれらの結晶構造と超伝導の遊星ボールミリングした粉末混合物の固相反応によるβ‐Mn型構造をもつMo_7Re_13Cを含むMo Re C試料の調製【Powered by NICT】

Conventional direct current (DC)-poling and three different types of pulse-poling were performed on MnO-added Na0.55K0.45NbO3 (NKN) ceramics. While NKN with DC-poling at 4.0 kV mm−1 for a poling time (t p) of 100 s showed a piezoelectric charge coefficient d 33 of 141.3 pC N−1, an almost equivalent d 33 (141.3 pC N−1) was recorded by pulse-poling in only 10 s under a unipolar electric field of 4.0 kV mm−1, with either triangular, or rectangular waveform. Especially when applying a triangular waveform, d 33 was enhanced remarkably with increasing the number of pulse cycles. In contrast, NKN ceramics poled by alternating current (AC) electric field showed a d 33 of less than 135 pC N−1 under any condition. Polarization–electric (P–E) field responses, and domain structure observations via scanning electron microscopy, showed the different poling behaviors for the various poling techniques. These results suggested that the pulse-poling method under unipolar electric field is an efficient poling procedure for NKN ceramics.

We study a spin-1/2 frustrated magnetic cluster Mo75V20, whose possible Hamiltonian is ℋSD = JΣ10i=1 S2i-1 · S2i+1 J'JΣ20i=1 Si · Si+1 + J"Σ10i=1 S2i · S2i+4. The J- and J"-bonds, respectively, form a ten-spin ring and two five-spin rings, and the five-spin rings are coupled to the ten-spin ring by the J'-bonds so as to form isosceles triangles of one J-bond and two J'-bonds. It is shown that experimental susceptibility, accompanied by low-temperature Curie law, is well reproduced by J = 388 K, J' = 163 K and J" = 81 K. We develop a perturbation theory to understand why the stronger J′-bonds does not wash out the low-temperature Curie law due to the doublet behavior of five-spin rings constructed by the weaker J"-bonds. Calculated results of temperature dependence of specific heat under small magnetic fields are also presented.

Background Vaccines are promising tools to control the spread of COVID-19. An effective vaccination campaign requires government policies and community engagement, sharing experiences for social support, and voicing concerns about vaccine safety and efficiency. The increasing use of online social platforms allows us to trace large-scale communication and infer public opinion in real time. Objective This study aimed to identify the main themes in COVID-19 vaccine-related discussions on Twitter in Japan and track how the popularity of the tweeted themes evolved during the vaccination campaign. Furthermore, we aimed to understand the impact of critical social events on the popularity of the themes. Methods We collected more than 100 million vaccine-related tweets written in Japanese and posted by 8 million users (approximately 6.4% of the Japanese population) from January 1 to October 31, 2021. We used Latent Dirichlet Allocation to perform automated topic modeling of tweet text during the vaccination campaign. In addition, we performed an interrupted time series regression analysis to evaluate the impact of 4 critical social events on public opinion. Results We identified 15 topics grouped into the following 4 themes: (1) personal issue, (2) breaking news, (3) politics, and (4) conspiracy and humor. The evolution of the popularity of themes revealed a shift in public opinion, with initial sharing of attention over personal issues (individual aspect), collecting information from news (knowledge acquisition), and government criticism to focusing on personal issues. Our analysis showed that the Tokyo Olympic Games affected public opinion more than other critical events but not the course of vaccination. Public opinion about politics was significantly affected by various social events, positively shifting attention in the early stages of the vaccination campaign and negatively shifting attention later. Conclusions This study showed a striking shift in public interest in Japan, with users splitting their attention over various themes early in the vaccination campaign and then focusing only on personal issues, as trust in vaccines and policies increased. An interrupted time series regression analysis showed that the vaccination rollout to the general population (under 65 years) increased the popularity of tweets about practical advice and personal vaccination experience, and the Tokyo Olympic Games disrupted public opinion but not the course of the vaccination campaign. The methodology developed here allowed us to monitor the evolution of public opinion and evaluate the impact of social events on public opinion, using large-scale Twitter data.

Evolution of Public Opinion on COVID-19 Vaccination in Japan: Large-Scale Twitter Data Analysis

Vaccines are promising tools to control the spread of COVID-19. An effective vaccination campaign requires government policies and community engagement, sharing experiences for social support, and voicing concerns about vaccine safety and efficiency. The increasing use of online social platforms allows us to trace large-scale communication and infer public opinion in real-time.

OBJECTIVE
This study aims to identify the main themes in COVID-19 vaccine-related discussion on Twitter in Japan and track how the popularity of the tweeted themes evolved during the vaccination campaign. Furthermore, we aim to understand the impact of critical social events on the popularity of the themes.

METHODS
We collected more than 100 million vaccine-related tweets written in Japanese and posted by 8 million users (approx. 6.4% of the Japanese population) from January 1 to October 31, 2021. We used the Latent Dirichlet Allocation to perform automated topic modeling of tweet texts during the vaccination campaign. In addition, we performed an interrupted time series regression to evaluate the impact of four critical social events on public opinion.

RESULTS
We identified 15 topics grouped into 4 themes: Personal issue, Breaking news, Politics, and Conspiracy and humour. The evolution of the popularity of themes revealed a shift in public opinion, initially sharing the attention over personal issues (individual aspect), collecting information from the news (knowledge acquisition), and government criticisms towards focusing on personal issues. Our analysis showed that the Tokyo Olympic Games affected public opinion more than other critical events but not the course of the vaccination. Public opinion about politics was significantly affected by various social events, positively shifting the attention in the early stages of the vaccination campaign and negatively later.

This study showed a striking shift in public interest in Japan, with users splitting their attention to various themes early in the vaccination campaign and then focusing only on personal issues, as trust in vaccines and policies built up. An interrupted time series regression analysis showed that the vaccination rollout to the general population (under 65) increased the popularity of tweets about practical advice and personal vaccination experience and the Tokyo Olympic Games disrupted public opinions but not the course of the vaccination campaign. The methodology developed here allowed us to monitor the evolution of public opinion and evaluate the impact of social events on the public opinion from large-scale Twitter data.

Evolution of the public opinion on COVID-19 vaccination in Japan

Twitter is currently one of the most influential microblogging services on which users interact with messages. It is imperative to grasp the big picture of Twitter through analyzing its huge stream data. In this study, we develop a two-stage clustering method that automatically discovers coarse-grained topics from Twitter data. In the first stage, we use graph clustering to extract micro-clusters from the word co-occurrence graph. All the tweets in a micro-cluster share a fine-grained topic. We then obtain the time series of each micro-cluster by counting the number of tweets posted in a time window. In the second stage, we use time series clustering to identify the clusters corresponding to coarse-grained topics. We evaluate the computational efficacy of the proposed method and demonstrate its systematic improvement in scalability as the data volume increases. Next, we apply the proposed method to large-scale Twitter data (26 million tweets) about the COVID-19 Vaccination in Japan. The proposed method separately identifies the reactions to news and the reactions to tweets.

Two-stage Clustering Method for Discovering People's Perceptions: A Case Study of the COVID-19 Vaccine from Twitter

The dynamics of popularity in online media are driven by a combination of endogenous spreading mechanisms and response to exogenous shocks including news and events. However, little is known about the dependence of temporal patterns of popularity on event-related information, e.g. which types of events trigger long-lasting activity. Here we propose a simple model that describes the dynamics around peaks of popularity by incorporating key features, i.e., the anticipatory growth and the decay of collective attention together with circadian rhythms. The proposed model allows us to develop a new method for predicting the future page view activity and for clustering time series. To validate our methodology, we collect a corpus of page view data from Wikipedia associated to a range of planned events, that are events which we know in advance will have a fixed date in the future, such as elections and sport events. Our methodology is superior to existing models in both prediction and clustering tasks. Furthermore, restricting to Wikipedia pages associated to association football, we observe that the specific realization of the event, in our case which team wins a match or the type of the match, has a significant effect on the response dynamics after the event. Our work demonstrates the importance of appropriately modeling all phases of collective attention, as well as the connection between temporal patterns of attention and characteristic underlying information of the events they represent.

Fake news can have a significant negative impact on society because of the growing use of mobile devices and the worldwide increase in Internet access. It is therefore essential to develop a simple mathematical model to understand the online dissemination of fake news. In this study, we propose a point process model of the spread of fake news on Twitter. The proposed model describes the spread of a fake news item as a two-stage process: initially, fake news spreads as a piece of ordinary news; then, when most users start recognizing the falsity of the news item, that itself spreads as another news story. We validate this model using two datasets of fake news items spread on Twitter. We show that the proposed model is superior to the current state-of-the-art methods in accurately predicting the evolution of the spread of a fake news item. Moreover, a text analysis suggests that our model appropriately infers the correction time, i.e., the moment when Twitter users start realizing the falsity of the news item. The proposed model contributes to understanding the dynamics of the spread of fake news on social media. Its ability to extract a compact representation of the spreading pattern could be useful in the detection and mitigation of fake news.

Fake news becomes a palpable potential risk to society because of the growing use of mobile devices and the immense increase in Internet access across the world. It is essential to develop a simple mathematical model to understand the mechanism of the online dissemination of fake news. In this paper, we propose a point process model for predicting the spreading of the fake news on Twitter. This model describes the cascade as a two-stage process: initially, a cascade spreads as an ordinary news story; a second cascade then emerges through attempts to disclose and rectify the falsity of the news story. We validate this model through the collection of two datasets of fake news cascades from Twitter. We show that the proposed model is superior to the current state-of-the-art methods in accurately predicting the evolution of the fake news cascades. Moreover, the proposed model can appropriately infer the correction time when some users realize the falsity of the news. The proposed model contributes to understand the dynamics of fake news spread in social media and is potentially advantageous in extracting a compact representation of the temporal information of the cascades.

Analyzing temporal patterns of topic diversity using graph clustering

Estimating community feedback effect on topic choice in social media with predictive modeling

Applying classical time-series analysis techniques to online content is challenging, as web data tends to have data quality issues and is often incomplete, noisy, or poorly aligned. In this paper, we tackle the problem of predicting the evolution of a time series of user activity on the web in a manner that is both accurate and interpretable, using related time series to produce a more accurate prediction. We test our methods in the context of predicting signatures for online petitions using data from thousands of petitions posted on The Petition Site - one of the largest platforms of its kind. We observe that the success of these petitions is driven by a number of factors, including promotion through social media channels and on the front page of the petitions platform. We propose an interpretable model that incorporates seasonality, aging effects, self-excitation, and external effects. The interpretability of the model is important for understanding the elements that drives the activity of an online content. We show through an extensive empirical evaluation that our model is significantly better at predicting the outcome of a petition than state-of-the-art techniques.

Proceedings of the 26th International Conference on World Wide Web

Predicting the Success of Online Petitions Leveraging Multidimensional Time-Series

We study the dynamical properties of human communication through different channels, i.e., short messages, phone calls, and emails, adopting techniques from neuronal spike train analysis in order to characterize the temporal fluctuations of successive interevent times. We first measure the so-called local variation (LV) of incoming and outgoing event sequences of users and find that these in- and out-LV values are positively correlated for short messages and uncorrelated for phone calls and emails. Second, we analyze the response-time distribution after receiving a message to focus on the input-output relationship in each of these channels. We find that the time scales and amplitudes of response differ between the three channels. To understand the effects of the response-time distribution on the correlations between the LV values, we develop a point process model whose activity rate is modulated by incoming and outgoing events. Numerical simulations of the model indicate that a quick response to incoming events and a refractory effect after outgoing events are key factors to reproduce the positive LV correlations.

Input-output relationship in social communications characterized by spike train analysis

 Online social networking services allow their users to post content in the form of text, images or videos. The main mechanism driving content diffusion is the possibility for users to re-share the content posted by their social connections, which may then cascade across the system. A fundamental problem when studying information cascades is the possibility to develop sound mathematical models, whose parameters can be calibrated on empirical data, in order to predict the future course of a cascade after a window of observation. In this paper, we focus on Twitter and, in particular, on the temporal patterns of retweet activity for an original tweet. We model the system by Time-Dependent Hawkes process (TiDeH), which properly takes into account the circadian nature of the users and the aging of information. The input of the prediction model are observed retweet times and structural information about the underlying social network. We develop a procedure for parameter optimization and for predicting the future profiles of retweet activity at different time resolutions. We validate our methodology on a large corpus of Twitter data and demonstrate its systematic improvement over existing approaches in all the time regimes.
 
TiDeH: Time-Dependent Hawkes Process for Predicting Retweet Dynamics